tuning reactivity in pd-catalysed c(sp3)-h arylations via

doi.org/10.26434/chemrxiv.12235514.v1

Tuning Reactivity in Pd-Catalysed C(sp3)-H Arylations via DirectingGroup Modifications and Solvent SelectionCharlotte Coomber, Michael Porter, Abil Aliev, Peter Smith, Tom Sheppard

Submitted date: 03/05/2020 • Posted date: 06/05/2020Licence: CC BY 4.0Citation information: Coomber, Charlotte; Porter, Michael; Aliev, Abil; Smith, Peter; Sheppard, Tom (2020):Tuning Reactivity in Pd-Catalysed C(sp3)-H Arylations via Directing Group Modifications and SolventSelection. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12235514.v1

The palladium-catalysed sp3 C-H arylation of a selection of saturated amine scaffolds was investigated usingsubstituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takesplace using unsubstituted picolinamide or 3-methylpicolinamide, whereas a double C-H arylation occurs withother substituents present, becoming a significant product with 3-trifluoromethylpicolinamide. DFTcalculations were used to help rationalise the effect of directing groups on the C-H palladation steps whichwere found experimentally to be irreversible. The substituted picolinamide directing groups were alsoexamined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtainedusing methylpicolinamides. For a selection of other amine scaffolds, the yield of C-H arylation could beimproved significantly using 3-methylpicolinamide as the directing group and/or 3-methylpentan-3-ol as thesolvent

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Tuning Reactivity in Pd-catalysed C(sp3)-H Arylations via Directing Group Modifications and Solvent Selection

Charlotte E. Coombera, Michael J. Porter,a Abil E. Alieva, Peter D. Smithb and Tom D. Shepparda*

aDepartment of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, U.K [[email protected]]

bEarly Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, U.K

Abstract. The palladium-catalysed sp3 C-H arylation of a selection of saturated amine scaffolds was

investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly

selective monoarylation takes place using unsubstituted picolinamide or 3-methylpicolinamide,

whereas a double C-H arylation occurs with other substituents present, becoming a significant product

with 3-trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of

directing groups on the C-H palladation steps which were found experimentally to be irreversible. The

substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many

cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of

other amine scaffolds, the yield of C-H arylation could be improved significantly using 3-

methylpicolinamide as the directing group and/or 3-methylpentan-3-ol as the solvent.

Introduction Palladium-mediated C-H functionalisation reactions provide a powerful approach for selective transformation of individual C-H bonds on sp3-rich scaffolds.[1] Given the increasing importance of these compounds in medicinal chemistry,[2] the ability to selectively introduce novel functionality at particular locations in the molecular framework could provide a highly useful tool in drug development. Building upon pioneering work on the use of stoichiometric quantities of palladium(II) salts to mediate selective reactions of C-H bonds in sp3-rich scaffolds,[3] catalytic reactions employing a directing group to coordinate to the palladium(II) catalyst to control the site of reaction have proved to be especially effective.[4-5] In most cases, the directing group incorporates one or more heteroatoms which can act as ligands for the palladium and deliver it to an adjacent C-H bond. Nitrogen-rich scaffolds are of particular importance in a wide range of chemistry-related fields, so nitrogen-linked directing groups have been the focus of considerable attention.[5] In 2005 Daugulis introduced the 8-aminoquinoline and picolinamide directing groups,[5a] and since then a number of nitrogen-linked directing groups for C-H activation have been reported (Figure 1).[5] Typically, these directing groups deliver the palladium catalyst to a nearby C-H bond via the formation of a 5- or 6-membered palladacycle, though transannular functionalisation reactions have been observed in some cases.[5e]

Figure 1. Amide-linked directing groups employed in Pd-catalysed C-H functionalisation reactions of sp3-rich

scaffolds.[5a-5e]

Two major drawbacks of many of these reactions are the requirement for excess silver salt in the C-H activation reaction, as well as difficulty in removing the directing group from the product molecule to recover a free amine for use in further synthetic manipulation. In recent work we have shown that selective monoarylation of bicyclic amine scaffolds can be achieved efficiently under silver-free conditions using the 2-picolinamide directing group.[6] The picolinamide group can readily be removed under mild reductive conditions using Zn/HCl.[7] We envisaged (Fig. 2) that by manipulating the electronic and steric properties of the picolinamide directing group, it should be possible to enhance the efficiency and selectivity of Pd-catalysed C-H functionalisation reactions, as well as potentially enabling C-H functionalisation at different reaction sites within a molecule.

Figure 2. Proposed use of functionalised picolinamides for controlling reactivity on Pd-catalysed C-H activation.

Results & Discussion We elected to study three different scaffolds which each contain two chemically distinct C-H bonds capable of undergoing C-H activation to yield a 5-membered palladacycle (Fig. 2). A wide range of picolinic acids are available commercially and we selected seven examples bearing both electron-donating (Me, MeO) and electron-withdrawing (CF3) substituents at a variety of positions around the ring, alongside the unsubstituted picolinic acid as a benchmark. In the case of the bornylamine scaffold, despite the proximity of the methyl C-H bond to the directing group, we had not observed C-H activation taking place at that site during our original study with an unsubstituted picolinamide directing group.[6] Interestingly, in our evaluation of the substituted picolinic acid directing groups, it rapidly became apparent that the substituent on the directing group exerts a significant effect on the reactivity of the methyl group (Table 1). As reported previously, the unsubstituted picolinamide 1a gives an excellent yield of monoarylated product 2a under our

optimised reaction conditions, with no trace of methyl C-H activation. The 3-methylpicolinamide 1b also gives the monoarylated product 2b with complete selectivity and with the highest yield.

Table 1. C-H arylation of the bornylamine scaffold using different picolinamide directing groups

Directing Group Yielda Ratio of 2:3

1a

91% >98:2

1b

97% >98:2

1c

97%

88:12

1d

99% 89:11

1e

100% 51:49b

1f

73% 73:27

1g

99% 79:21

1h

100% 88:12

Conditions: 5 mol% Pd(OAc)2, 4 equiv. CsOAc, 10 mol% CuBr2, 4 equiv. 4-iodoanisole, tAmOH 1 M, 140 °C, 24

h. aCombined isolated yield. bDiarylated product 3e was isolated in 43% yield.

Interestingly, upon changing the position of the methyl substituent to the 4 or 5 positions on the pyridine ring (1c/1d), a novel diarylated compound (3c/3d) was observed as a minor product, perhaps suggesting that the conformational or electronic effects of the substituent are able to facilitate C-H activation on the methyl group, although the C-H activation still evidently occurs preferentially at the CH2 in both substrates.[8] Introduction of an electron withdrawing CF3 group at the 3-position (1e) increased the quantity of diarylated product formed, giving almost equal amounts of monoarylated product 2e and diarylated product 3e. The 5-CF3 derivative 1f gave the lowest overall conversion, with

a mixture of monoarylated 2f and diarylated 3f products being generated. The 4- and 5-methoxypicolinamides 1g and 1h gave similar overall yields of product, with small quantities of diarylated product in both cases.[9] As a general rule, high overall yields were obtained with all of the picolinamides bearing the moderately electron-donating methyl group, with the 3-methylpicolinamide giving the highest yield of monoarylated product 2b with no observable formation of the corresponding diarylated compound 3b. The 3-trifluoromethylpicolinamide 1e provided the largest quantity of diarylated product 3e as well as giving a high overall product yield. Control experiments (Scheme 1) demonstrated that the C-H insertion step for the initial methylene arylation reaction was not reversible as no deuterium exchange was observed at the methylene unit to give d1-1a upon heating 1a in the presence of Pd(OAc)2 and CsOAc in deuterated tert-butanol.[10] Furthermore, the palladated complex 1a-Pd (L=CD3CN) generated from 1a and Pd(OAc)2/CsOAc in acetonitrile[6] did not undergo deuteration upon treatment with either deuterated tert-butanol or deuterated acetic acid. In addition we observed that the monoarylated product 2e was not converted into the diarylated product 3e upon resubmission to the reaction conditions. This suggests that the selectivity in the Pd-catalysed C-H arylation is under kinetic control, and hence determined by the energy barriers of the C-H insertion steps. The diarylation product must be formed via two sequential C-H arylation processes, without dissociation of the palladium catalyst as dissociation of the palladium from the monoarylated product 2e seems to be irreversible.

Scheme 1. Control experiments.

On changing the coupling partner from an aryl iodide to an aryl bromide,[11] the formation of the diarylated product was no longer observed (Scheme 2). Electron withdrawing directing groups gave lower overall yields of the arylated products (2e and 2f) and higher yields were seen with the unsubstituted picolinamide and substrates bearing electron donating groups (2a-2c and 2h). This monoarylation reaction almost certainly provides a better reflection of the inherent reactivity of each directing group in terms of facilitating the catalytic cycle. The improved efficency of the reaction with 3-methylpicolinamide perhaps reflects conformational effects on the palladium complexation/decomplexation steps which enable better catalytic turnover. More generally, electron-donating substituents on the picolinamide are clearly preferable to electron-withdrawing substituents in terms of reaction efficiency. Again, the 3-methylpicolinamide 1b gave the highest yield of monoarylated product. Subsequent results (vide infra, Scheme 5) suggested that bromide ions could suppress C-H activation processes, so this is probably the reason why no arylation of the methyl group is observed in these reactions.

Scheme 2. Reactions of bornylamine scaffold with 4-bromoanisole. Conditions: 5 mol% Pd(OAc)2, 4 equiv.

CsOAc, 10 mol% CuBr2, 4 equiv. 4-bromoanisole, tAmOH 1 M, 140 °C, 24 h.

To gain further insight into the regioselectivity of the arylation processes, we undertook computational studies of the various possible C-H activation steps. Density functional theory (DFT) calculations were carried out with the M06 functional,[12] using the 6-31+G(d) basis set for C, H, N, O and F atoms and the LANL2DZ basis set for Pd. All optimised structures were confirmed by the presence of zero or one imaginary frequencies for minima and transition states respectively, and transition states were shown to link the correct minima through IRC calculations.[13] Calculated free energies were corrected to the reaction temperature of 413 K.[14] Initially, we modelled an adduct Ia in which a palladium atom with a bidentate acetate ligand was chelated by the two nitrogens of a deprotonated molecule of 1a (Scheme 3). Transition states for a concerted metalation-deprotonation (CMD) mechanism could then be located for both methylene and methyl groups (IIa and IIIa respectively; Scheme 3 and Table 2). As expected, these calculations indicated that insertion into the methylene group had a much lower energy barrier (G‡ = 18.1 kJ mol–1). A second insertion step was then investigated, starting from the monophenylated adduct VIIa. From this complex, the free energy of activation for insertion into a C-H bond of the methyl group (transition state VIIIa) was found to be considerably lower than that for methyl group activation in the initial complex Ia via transition state IIIa (93.1 kJ mol–1 vs. 101.7 kJ mol–1). The corresponding calculations were repeated for the remaining picolinamide substrates 1b–1h. The free energy of activation for each of the C-H insertion steps is shown in Table 2 For all compounds, the activation energy for initial CH3 insertion is considerably higher than for CH2 insertion (G‡ = 15.9 kJ mol–1 on average), explaining why monoarylation at the CH3 is not observed. In all cases except for 1g, arylation of the CH2 leads to a lowering of the transition state energy for a subsequent CH3 insertion with this effect being most pronounced for substrates 1e and 1f (G‡ = 10.3 kJ mol–1 and 11.0 kJ mol–1 respectively) which notably were the substrates which yielded the largest proportion of diarylated product. Given the fact that decomplexation of the monoarylated product 2 from the palladium appears to be irreversible (Scheme 1), the quantity of the diarylated product 3 obtained from each substrate probably reflects the relative rates of the CH3 insertion step and the decomplexation. In the case of substrate 1e, where the largest proportion of diarylated product was observed, the activation energy of the second CH3 insertion step (VIIIe) from the arylated palladium complex VIIe is comparable to that of the initial CH2 insertion (IIe) from complex Ie. In the case of substrates 1a and 1b, the decomplexation of the monoarylated product 2 from palladium is presumably much more rapid than C-H insertion into the methyl group so only monoarylated product

is formed, even though the C-H insertion into the methyl group has a lower activation energy in the arylated product.

Scheme 3. Catalytic cycle for the Pd-catalysed arylation of bornylamine picolinamides, showing the key transition

states for C-H palladation (II, III & VII). Energies shown on the scheme are for the C-H insertion transition states

(relative to the preceding PdOAc adduct) for the unsubstituted compounds (R=H).

To discover whether such calculations could be used to predict the selectivity for an untested directing group, we calculated the corresponding energy barriers for reactions of the 3-phenylpicolinamide derivative 1i (Scheme 4). Similar values (88.2, 103.0 and 94.0 kJ mol–1 respectively for the three C-H insertion transition states as shown in table 2) were obtained to the methyl derivatives 1c/1d so we expected that this substrate would provide ~10% of the diarylated product. 3-Phenylpicolinamide was synthesised according to a modified literature procedure,[15] and coupled to bornylamine to give 1i. In the event, the arylation reaction of 1i gave 13% of diarylated product 3i alongside 65% of 2i (Scheme 4). We can conclude that the calculated energy barriers for the C-H insertion steps can only provide a

qualitative guide to the likely reaction outcomes. This is a consequence of the difficulties of accurately modelling the decomplexation step which is in competition with the second C-H insertion reaction. Further work will be required to understand the complexation/decomplexation mechanisms in order to make more accurate predictions of the effect of different directing groups on the C-H insertion selectivity.

Table 2. Calculated free energies of activation.

G‡ (M06/6-31+G(d)/LANL2DZ)/kJ mol–1

Amide CH2 insertion

(GII – GI)

CH3 insertion

(GIII – GI)

CH3 insertion in monophenyl adduct

(GVIII – GVII)

1a 83.6 101.7 93.1

1b 85.2 101.8 95.6

1c

88.0 101.2 95.3

1d 85.5 103.2 94.6

1e 88.6 100.3 90.0

1f 82.9 100.9 89.9

1g 85.3 98.2 101.2

1h 86.2 104.9 96.1

Energies are given relative to the immediately preceding Pd(OAc) adduct and are corrected to 413 K.

Scheme 4. Arylation reactions of 3-methylpicolinamide derivative 1i.

We then set out to explore whether these directing group effects could be observed with other substrates. In contrast to the bornylamine framework, most acyclic scaffolds show a preference for methyl C-H activation over methylene C-H activation.[8] The unsubstituted picolinamide 4a derived from (1-methylcyclohexyl)methylamine[16] gives a ~3:1 ratio of monoarylated product 5a and diarylated product 6a with the monoarylation occurring exclusively on the methyl group (Table 3). Analysis of the 1H and 13C NMR spectra of 6a and comparison with calculated 1H and 13C NMR shifts was used to assign the stereochemistry of the major isomer of 6a as the syn compound (Figure 3). Interestingly, the 3-methylpicolinamide undergoes a more selective reaction with 57% of the monoarylated product 5b being isolated, alongside traces of diarylated compound 6b, with the balance of the material being unreacted starting material. The 4- and 5-methyl derivatives 4c and 4d give similar levels of selectivity with the former giving a high overall yield of arylated products (5c and 6c) which was comparable to the unsubstituted system 4a. On this amine scaffold, the trifluoromethyl derivatives (4e/4f) gave relatively low yields in the arylation reaction, as did the 4-methoxy derivative 4h. The 4-methoxy derivative 4g gave a good overall yield with reasonable selectivity for the monoarylated product. Unlike the bornylamine scaffold above, resubmission of 5c to the reaction conditions gave a 26% yield of the diarylated compound 6c (Scheme 5), indicating that the monoarylated compound 5c can

effectively form a reactive complex with palladium, perhaps because the picolinamide is less hindered than in 2e. In contrast to bornylamine above, arylation of the (1-methylcyclohexyl)methylamine scaffold with aryl bromides was ineffective. Furthermore, the arylation reaction with an aryl iodide could be suppressed by the addition of 30 mol% tetrabutylammonium bromide to the reaction mixture.[17] It seems that the presence of bromide in the reaction mixture retards the C-H activation step, presumably by outcompeting acetate as a ligand on the intermediate palladium complex. This may also explain why only monoarylation of the bornylamine scaffolds is seen when aryl bromides are employed (Schemes 2 & 4)

Table 3. C-H arylation of the (1-methylcyclohexyl)methylamine scaffold using different picolinamide directing groups

Amide Directing group Yield[a] Ratio of 5:6

4a

88 76:24

4b

62 83:17

4c

86

78:22

4d

54 78:22

4e

35 82:18

4f

57 77:23

4g

77 79:21

4h

38 62:38

Conditions: 5 mol% Pd(OAc)2, 4 equiv. CsOAc, 10 mol% CuBr2, 4 equiv. 4-iodoanisole, tAmOH 1 M, 140 °C, 24 h .[a] Combined isolated yield.

Figure 3. Stereochemical assignment of diarylated product 6a was confirmed via DFT calculation of NMR shifts.

The average difference between the calculated and observed chemical shift (for the major isomer) is shown in

parentheses.

Scheme 5. Further reactions on the methylcyclohexylmethylamine scaffold. Arylation of 5c to give 6c and

attempted arylation of 4f with PMPBr or PMPI in the presence of Bu4NBr.

Next we explored the effect of the eight different picolinamide directing groups on the flexible open-chain scaffold 2-methylbut-1-ylamine (Table 4).[18] As anticipated, arylation of the methyl group occurs preferentially, followed by a second arylation on the ethyl group. Reaction of the unsubstituted amide 7a gives 72% yield of monoaryl product 8a and 21% of the diaryl compound 9a. Complete control over the formation of mono or diarylation products is more challenging in this case, but once again the 3-methylpicolinamide gives the highest levels of selectivity yielding only 5% of diaryl compound 9b alongside a synthetically useful 73% yield of monoarylated compound 8b. Good selectivity was also observed with the 5-methyl (7d) and 5-methoxy (7h) derivatives which both also gave improved yields of the monoaryl derivatives 8d and 8h respectively. The 4-methylpicolinamide gave a poor overall yield as well as showing no selectivity in the arylation reaction with equal amounts of 8c and 9c being produced. In this latter reaction, it was possible to detect a third product 10c in which diarylation had taken place on the two methyl groups (Figure 5). Trifluoromethyl picolinamides 7e and 7f gave high selectivity for the monoarylated products 8e and 8f but in only moderate yield. 4-Methoxypicolinamide 7g gave a similarly low overall yield but with high selectivity for monoarylation.

Table 4. C-H arylation of the 2-methylbut-1-ylamine scaffold using different picolinamide directing groups

Entry Directing group Yielda Ratio of 8:9b

7a

93

88:22

(72%, 21%)

7b

78 (73%, 5%)

7c

52 (26%, 26%[c])

7d

98 (87%, 11%)

7e

57 >95:5

(52%, 5%)

7f

45 (41%, 4%)

7g

55 >98:2

7h

91 (82%, 9%)

Conditions: 5 mol% Pd(OAc)2, 4 equiv. CsOAc, 10 mol% CuBr2, 4 equiv.4-iodoanisole, tAmOH 1 M, 140 °C, 24 h. [a]Combined isolated yield; yields of each product calculated by 1H NMR shown in parentheses. [b]Ratio of products 8:9 determined from crude 1H NMR; it was not possible to accurately determine this ratio for all reactions. [c]A mixture of two diarylated products was obtained including 10c (Figure 5); see SI for further details.

Figure 5. A second diarylation product 10c observed during arylation of 4-methylpicolinamide 7c.

As a final example, we explored the arylation of substrates 11a/11b derived from isobutylamine, in which two equivalent methyl groups are present (Scheme 6).[19] Switching from the unsubstituted picolinamide 11a to the 3-methylpicolinamide 11b led to a slightly increased selectivity for monoarylation (12b vs 13b), albeit with the diarylated compound being the major product in both cases. The overall arylation yield with the 3-methylpicolinamide was also slightly higher.

Scheme 6. Arylation of isobutylamine picolinamides 11

The directing group effects in the above reactions are not trivial to fully disentangle, but broadly speaking one or more of the methyl-substituted picolinamides appear to be advantageous in terms of improving the selectivity of arylation reactions, and typically leading to slightly higher overall yields of the C-H arylation products than the unsubstituted picolinamide. There was no observable benefit to employing systems with the more electron-donating methoxy group, and the electron-withdrawing trifluoromethyl group generally led to lower-yielding reactions. The arylation reaction of bornylamine with aryl bromides perhaps provides the most useful insight into the inherent efficiency of each directing group for mediating catalytic arylation. This likely involves several effects including the efficiency of complexation to/decomplexation from the palladium catalyst as well as the C-H insertion and arylation steps themselves. Some combinations of directing group and scaffold led to greater promiscuity in the terms of the C-H activation site (1e, 7c), but none of these combinations led to a complete change in the initial reaction site. We envisaged that these insights may prove useful for enhancing the yield of more challenging C-H arylation reactions in which the overall conversion under our previously developed conditions is low. In particular, the 3-methylpicolinamide often provided enhanced yield and selectivity in the C-H arylation reactions, which can potentially be attributed to the steric effect of the methyl group accelerating decomplexation from the monoarylated product. The DFT calculations for the bornylamine scaffold suggest that there is little difference in the activation energies for the C-H insertion steps between 3-methylpicolinamide and the unsubstituted system. With this in mind, we then went onto examine other sp3 C-H arylation reactions to see if improved conditions could be identified. Reaction of cyclohexyl[20] picolinamide 14a and p-fluoroiodobenzene under our standard conditions led to the formation of the arylated product 15a in 70% yield (Scheme 7). By changing the solvent to 3-methylpentan-3-ol (tHxOH, bp 123 °C),[21] without changing the external temperature, the yield of 15a was increased to 80%. 3-Methylpentan-3-ol is available commercially in reasonably large quantities, but has rarely been used as a reaction solvent for C-H activation.[22] Changing the directing group to 3-methylpicolinamide 14b led to a further improvement in reaction yield (91%, 15b). These conditions could also be used to improve the arylation yield of the same substrate with p-anisyl iodide from 68% to 85% (15c/15d). We also extended the reaction to a small selection of other substrates including cyclohexylmethylamine 16[16] (to give diarylated product 17a, along with small quantities of monoarylated derivative 18a), cycloheptylamine 19 (to give 20),[23] and 4-aminotetrahydropyran 21 (to give 22).[24] In all cases, the combination of 3-methylpicolinamide as the directing group and tHxOH as solvent gave an improved yield of the arylation product. In the reaction to form 17a only, the use of CsOPiv as base was beneficial.

The selectivity in the arylation of 16a is noteworthy in that the monoarylated product 18a is formed almost exclusively as the trans isomer, whereas the diarylated product 17a is formed exclusively as the all cis isomer. This can be rationalised (Scheme 7) by assuming that the directing group can more effectively mediate the C-H activation step when it occupies an axial position, giving cis selectivity. Thus, arylation cis to the directing group gives a disubstituted cyclohexane cis-18a with one substituent is axial and one equatorial. This effectively lowers the energy of the conformation in which the directing group is axial, promoting a second C-H insertion reaction. In contrast, the formation of trans-18a presumably involves some distortion of the chair in the intermediate Pd complex trans-23. The conformation of trans-18a in which both substituents are equatorial is likely to be overwhelmingly favoured and this will make the molecule more rigid, preventing further C-H insertion steps from taking place. It is possible that trans-18a is formed via epimerisation of the intermediate palladium complex from cis-23 to trans-23 prior to the arylation reaction with the iodoarene. Similarly, monoarylation of 14 and 21 almost certainly occurs selectively due to the requirement for the directing group to be axial in order for the palladium to reach the C-3 hydrogen atom. In the products 15/22, the conformation with both substituents axial is likely to be energetically unfavourable, so no second arylation takes place.

Scheme 7. Improved yields of C-H arylation products were obtained using tHxOH as solvent and 3-

methylpicolinamide as the directing group. *CsO2CtBu was used in place of CsOAc.

Scheme 8. Potential explanation of the stereoselectivity observed in arylation of 16a to give 17a and trans-18a.

Conclusions In summary, it has been shown that the substituents on the picolinamide directing group can have a significant effect on the yield and selectivity of C-H functionalisation reactions conducted under silver-free conditions. A variety of electron rich and electron poor picolinamides were investigated on a range of amine substrates, with the latter generally leading to lower yielding reactions. Highest yields were obtained with a methylpicolinamide directing group which gave some improvements over the unsubstituted system. Most notably, the use of 3-methylpicolinamide typically led to increased yields of C-H arylation reactions in most cases, and also to reduced quantities of diarylation products. The beneficial effect of this directing group can perhaps tentatively be explained by accelerated decomplexation from the palladium leading to more efficient catalytic turnover, and deceleration of overarylation reactions due to the increased steric hindrance. Further improvements in reaction yields could often be obtained by performing reactions in 3-methyl-3-pentanol (tHxOH) as solvent. These conditions enabled us to obtain synthetically useful yields of arylation products from a range of substrates. Experimental Preparation of substrates Picolinamides were prepared via HATU coupling or B(OCH2CF3)3-catalysed amidation reactions.[25] General procedure for arylation of picolinamides. A tube was charged with a picolinamide (1 eq), CuBr2 (10 mol%), Pd(OAc)2 (5 mol%), CsOAc (4 eq), tAmOH (1 M) and an aryl iodide or bromide (4 eq). The tube was sealed with a PTFE lined cap and heated to 140 °C for 24 hours. The reaction mixture was then cooled and filtered through a pad of Celite®, washing with EtOAc. The filtrate was concentrated in vacuo and the resulting crude residue purified by flash column chromatography. Acknowledgements We thank AstraZeneca and the UCL MAPS faculty for providing an EPSRC CASE award to support a Ph.D. studentship. References [1] a) X. Chen, K. M. Engle, D. -H. Wany, J. -Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; b) O. Baudoin, Chem.

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[4] a) R. Parella, B. Gopalakrishnan, S. A. Babu, Org. Lett. 2013, 15, 3238; b) D. P. Affron, O. A. Davis, J. A. Bull, Org. Lett. 2014, 16, 4956; c) R. W. Gutekunst, P. S. Baran, J. Org. Chem. 2014, 79, 2430; d) D. Affron, J. A. Bull, Eur. J. Org. Chem. 2015, 139; e) K. S. Chan, H. Y. Fu, J. Q. Yu, J. Am. Chem. Soc. 2015, 137, 2042; f) J. Kim, M. Sim, N. Kim, S. Hong, Chem. Sci. 2015, 6, 3611; g) S. St-John-Campbell, A. J. P. White, J. A. Bull, Org. Lett. 2020, 22, 1807.

[5] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154; b) N. Rodríguez, J. A. Romero-Revilla, M. A Fernández-Ibáñez, J. C. Carretero, Chem. Sci. 2013, 4, 175; c) M. Wasa, K. S. L. Chan, X. -G. Zhang, J. He, M. Miura, J. -Q. Yu, J. Am. Chem. Soc. 2012, 134, 18570; d) J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford, Nature 2016, 531, 220; e) J. Han, Y. Zheng, C. Wang, Y. Zhu, D. -Q. Shi, R. Zeng, Z. -B. Huang, Y. Zhao. J. Org. Chem. 2015, 80, 9297; f) X. Ye, A. He, T. Ahmed, K. Weise, N. G. Akhmedov, J. L. Petersen, X. Shi, Chem. Sci. 2013, 4, 3712; g) J. Yang, X. Fu, S. Tang, K. Deng, L. Zhang, X. Yang, J. Org. Chem. 2019, 84, 10221; h) H. Wang, H.-R. Tong, G. He, G. Chen, Angew. Chem., Int. Ed. 2016, 55, 15387; i) D. Zhou, C. Wang, M. Li, Z. Long, J. Lan, Chin. Chem. Lett. 2018, 29, 191; j) M. Fan, D. Ma, Angew. Chem., Int. Ed. 2013, 52, 12152; k) K. K. Pasunooti, B. Banerjee, T. Yap, Y. Jiang, C. -F. Liu, Org. Lett. 2015, 17, 6094; l) J. Han, Y. Zheng, C. Wang, Y. Zhu, D., -Q. Shi, R. Zeng, Z. -B. Huang, Y. J. Zhao, J. Org. Chem. 2015, 80, 9297; m) J. Han, Y. Zheng, C. Wang, Y. Zhu, Z. -B. Huang, D. -Q. Shi, R. Zeng, Y. Zhao, J. Org. Chem. 2016, 81, 5681; n) W. Gong, G. Zhang, T. Liu, R. Giri, J. -Q. Yu, J. Am. Chem. Soc. 2014, 136, 16940; o) T. Toba, Y. Hu, A. T. Tran, J. -Q. Yu, Org. Lett. 2015, 17, 5966; p) Y. Liu, H. Ge, Nature Chem. 2017, 9, 26. G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192; q) M. Larrosa, S. Heiles, J. Becker, B. Spengler, R. Hrdina, Adv. Synth. Catal. 2016, 358, 2163; r) D. S. Roman, A. B. Charette, Org. Lett. 2013, 15, 4394

[6] C. E. Coomber, L. Benhamou, D. -K. Bucar, P. D. Smith, M. J. Porter, T. D. Sheppard, J. Org. Chem. 2018, 83, 2495.

[7] D. H. O’ Donovan, C. De Fusco, D. R. Spring, Tetrahedron Lett. 2016, 57, 2962.

[8] Methyl groups are typically more reactive than methylene groups in Pd-catalysed C-H activation reactions: Y. -F. Zhang, H. -W. Zhao, H. Wang, J. -B. Wei, Z. -J. Shi, Angew. Chem. Int. Ed. 2015, 54, 13686.

[9] We also examined reactions of the corresponding 3-methoxypicolinamide but both the starting material and the arylated amides proved problematic to purify by chromatography. As this directing group did not appear to offer any advantages in terms of yield or selectivity in the preliminary experiments, we did not carry out any further work with this directing group.

[10] E. Y. Aguilera, M. S. Sanford, Organometallics 2019, 38¸138.

[11] There are relatively few examples of the use of aryl bromides in sp3-CH arylation reactions: see refs [5j] and [20a]

[12] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215.

[13] K. Fukui, Acc. Chem. Res. 1981, 14, 363.

[14] a) S. Grimme, Chem. Eur. J. 2012, 18, 9955. b) I. Funes-Ardoiz, R. S. Paton, GoodVibes v1.0.2, 2017, https://zenodo.org/record/841362.

[15] D. R. St. Laurent, M. H. Serrano-Wu, M. Belema, M. Ding, H. Fang, M. Gao, J. T. Goodrich, R. G. Krause, J. A. Lemm, M. Liu, O. D. Lopez, V. N. Nguyen, P. T. Nower, D. R. O’Boyle II, B. C. Pearce, J. L. Romine, L. Valera, J. -H. Sun, Y. -K Wang, F. Yang, X. Yang, N. A. Meanwell, L. B. Snyder, J. Med. Chem. 2014, 57, 1976.

[16] J. Zhao, X, -J, Zhao, P. Cao, J. -K. Lio, B. Wu, Org. Lett. 2017, 19, 4880.

[17] For a previous observation that the regioselectivity of C-H activation reaction could be affected by changing from an aryl iodide to an alkenyl bromide as the reaction partner (with silver salts present), see ref [8].

[18] S.-Y. Zhang, G. He, Y. Zhao, K. Wright, W. A. Nack, G. Chen, J. Am. Chem. Soc. 2012, 134, 7313

[19] W. A. Nack, G. He, S.-Y. Zhang, C. Lu, G. Chen, Org. Lett. 2013, 15, 13, 3440 isobutyl

[20] a) E. T. Nadres, G. I. F. Santos, D. Shabashov, O. J. Daugulis, J. Org. Chem. 2013, 78, 9689; b) Y. Wu, Y. -Q. Chen, T. Liu, M. D. Eastgate, J. -Q. Yu, J. Am. Chem. Soc. 2016, 138, 14554; c) A. Seki, Y. Takahashi, T. Miyake, Tetrahedron. Lett. 2014, 55, 2838

[21] 3-Methyl-3-pentanol is used as a flavouring in the food industry and forms part of the core of the tranquiliser emylcamate: B. Melander, J. Med. Chem. 1958, 1, 443.

[22] The Scifinder database contains 4254 reactions in 34 references where 3-methyl-3-pentanol was used as the solvent (as of 26th Feb 2020). There is a single paper reporting its use in C-H activation of aromatic systems, see ref [16].

[23] Preliminary experiments suggested that directed arylation of cyclooctylamine and cyclododecylamine picolinamides was also possible, but the presence of multiple arylation products and rotamers made satisfactory characterisation of the products extremely difficult.

[24] S. Ye, W. Yang, T. Coon, D. Fanning, T. Neubert, D. Stamos, J. -Q. Yu, Chem. Eur. J. 2016, 22, 4748.

[25] a) C. E. Coomber, V. Laserna, L. T. Martin, P. D. Smith, H. C. Hailes, M. J. Porter, T. D. Sheppard, Org. Biomol. Chem. 2019, 17, 6465; b) M. T. Sabatini, L. T. Boulton, T. D. Sheppard, Sci. Adv. 2017, 3, e1701028.

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1

Supporting Information

Tuning Reactivity in Pd-catalysed sp3 C-H Arylations via Directing Group Modifications

Charlotte E. Coombera, Michael J. Portera, Abil A. Alieva, Peter D. Smithb, and Tom D. Shepparda*

a Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street,

London WC1H 0AJ, U.K

[[email protected]] b Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield

SK10 2NA, U.K

Table of contents

1. General methods

2. Experimental

3.1H and 13C NMR spectra

2

1. General Methods

All reagents and solvents were purchased and used as supplied unless otherwise stated. All

reactions were carried out at atmospheric pressure with stirring and under argon atmosphere

unless otherwise indicated. Pd(OAc)2 was purchased from Sigma-Aldrich and CsOAc from

Fisher Scientific. In vacuo is used to describe evaporation of solvent by Büchi rotary

evaporator between 17 ºC and 50 ºC at a pressure of ~ 10 mmHg. All reactions were

monitored by TLC or 1H NMR. TLC plates used were pre-coated with silica gel 60 F254 on

aluminium (Merck KGaA). The spotted TLCs were visualised by UV light (254 nm or 365 nm)

or chemically stained (KMnO4, or Ninhydrin). 1H NMR and 13C NMR spectra were recorded

at 400, 500, 600 or 700 MHz (for 1H) and 125, 150 or 175 MHz (for 13C) on a Bruker

AMX400, AMX500, AMX600 or NEO700 at ambient temperature, unless otherwise

indicated. Deuterated solvents for NMR detection used were CDCl3, MeOD-d4 or DMSO-d6

as stated in the spectrum. Peaks are assigned as singlet (s), doublet (d), triplet (t), quartet

(q), quintet (qn) or multiplet (m). All shifts are reported in parts per million (ppm) and

compared against residual CDCl3 (δ = 7.26 ppm, s) as the internal standard. Coupling

constants (J) are quoted in Hertz (Hz) to one decimal place. Mass spectrometry was

performed on VG70 SE (ES+, CI, ES- modes). Infra-red spectra were obtained using a

Perkin-Elmer Spectrum 100 FTIR Spectrometer operating in ATR mode, all frequencies

given in reciprocal centimetres (cm-1). Melting points were measured with a Gallenkamp

heating block and are uncorrected. Reactions performed above the solvent boiling point in

sealed tubes were carried out in Radley Quick-Thread Glass Reaction Tube 24x150mm, and

the solvent volume did not exceed 4 ml. [α]D values are given in 10-1 deg cm2 g-1,

concentration (c) in g per 100 ml. Full details of the DFT calculations can be found in the

DFT supporting information file.

3

Purification of 3-methyl-3-pentanol

Commercial 3-methyl-3-pentanol purchased from Sigma Aldrich was found to contain 3-

methylpent-1-en-3-ol as an impurity, which underwent a Heck reaction when used in C-H

functionalisation reactions. To remove this, the solvent was purified by the hydrogenation of

the alkene to 3-methyl-3-pentanol before use in reactions.

Hydrogen gas was bubbled through a mixture of 3-methyl-3-penanol and 3-methylpent-1-en-

3-ol (100 ml, ~3% alkene present) for 5 minutes. Pd/C (10%, 2 g) was added and the

reaction stirred for 1 hour in a hydrogen atmosphere. The mixture was filtered through

Celite® to give the pure 3-methyl-3-pentanol.

Methyl 3-hydroxypicolinate

A suspension of 3-hydoxypicolinic acid (2.07 g, 15 mmol) in MeOH (30 ml) and sulphuric

acid (2.4 ml, 4.4 mmol) was heated to reflux for 6 hours. The resulting solution was

concentrated in vacuo and NHCO3 (aq. sat.) added to the residue until the pH reached 8.5.

The aqueous solution was extracted with EtOAc (3 × 30 ml), the organic fractions combined,

washed with brine, dried over MgSO4 and concentrated to give the ester as a white solid

(2.12 g, 13.8 mmol, 86%).

1H NMR (700 MHz, CDCl3) δ 10.60 (s, 1H), 8.26 (s, 1H), 7.41 – 7.39 (m, 1H), 7.35 (d, J = 8.4

Hz, 1H), 4.03 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 170.0, 158.9, 141.6, 130.1, 129.7,

126.3, 53.3.

Data in accordance with literature1

Methyl 3-(((trifluoromethyl)sulfonyl)oxy)picolinate1

4

Triflic anhydride (1.2 ml, 7.18 mmol) was added dropwise to a solution of methyl 3-

hydroxypicolinate (1.0 g, 6.53 mmol) and triethylamine (1.0 ml, 7.18 mmol) at 0 °C. The

reaction was warmed to room temperature and stirred for 1 hour, before the addition of water

(20 ml) and CHCl3 (20 ml). The aqueous and organic layers were separated, and the

aqueous layer extracted with CHCl3 (2 × 30 ml). The combined organic fractions were

washed with brine, dried over MgSO4 and concentrated in vacuo. The crude residue was

purified by flash column chromatography (20 – 30% EtOAc in petrol) to give the product as a

white solid (1.40 g, 4.90 mmol, 75%).

1H NMR (700 MHz, CDCl3) δ 8.76 (dd, J = 4.5, 1.3 Hz, 1H), 7.73 (dd, J = 8.4, 1.1 Hz, 1H),

7.62 (dd, J = 8.4, 4.5 Hz, 1H), 4.05 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 163.0, 149.2,

146.4, 141.8, 131.5, 128.2, 118.7 (q J = 320.7 Hz), 53.5.

Compound prepared according to literature procedure2

Methyl 3-phenylpicolinate

A suspension of methyl 3-(((trifluoromethyl)sulfonyl)oxy)picolinate (1.40 g, 4.9 mmol),

PhB(OH)2 (627 mg, 5.1 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), K2CO3 (1.4 g, 9.8 mmol)

and PhMe (23 ml) was heated at 90 °C for 1 hour. The reaction was then cooled and filtered

through Celite®, washing with EtOAc. The filtrate was concentrated in vacuo and the residue

purified by flash column chromatography (20% EtOAc in petrol) to give the product as a

colourless oil (950 mg, 4.5 mmol, 91%).


7.48 (dd, J = 7.9, 4.7 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.36 – 7.32 (m, 2H), 3.77 (s, 3H); 13C

NMR (176 MHz, CDCl3) δ 167.2, 148.5, 148.2, 138.8, 138.3, 137.8, 128.6, 128.4, 128.3,

125.5, 52.7.


3-Phenylpicolinic acid

5

To a solution of methyl 3-phenylpicolinate (894 mg, 4.2 mmol) in MeOH (17 ml) was added

NaOH (1 M, 5.5 ml) and the reaction stirred for 30 minutes. NaOH (1 M, 8.4 ml) was added

and the reaction stirred for a further 2 hours at room temperature, and then heated to 50 °C

for 16 hours. The reaction was cooled and HCl (2 M) was added until pH 2 was reached.

The aqueous solution was extracted with DCM (3 × 30 ml) and the combined organic layers

washed with brine, dried over MgSO4 and concentrated to give the product as an off-white

solid (650 mg, 3.26 mmol, 78%).

1H NMR (700 MHz, CDCl3) δ 8.68 – 8.58 (m, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 7.48 – 7.40 (m,

3H), 7.38 – 7.33 (m, 2H); 13C NMR (176 MHz, CDCl3) δ 163.5, 146.6, 143.3, 141.5, 140.5,

137.9, 128.8, 128.4, 128.2, 127.3.


Preparation of Picolinamides

General amidation procedure A

A solution of amine (1 equiv.) in DMF was added to DIPEA (1.2 equiv.), a picolinic acid (1.2

equiv.) and HATU (1.2 equiv.) in dimethylformamide (0.2 M). The resulting solution was

stirred at room temperature for 16 hours. Saturated aqueous lithium chloride was added and

the aqueous layer was extracted with ethyl acetate (× 3). The combined organic layers were

washed with water, brine, dried over MgSO4 and concentrated. The crude residue was

purified by flash column chromatography.

General amidation procedure B

A suspension of a picolinic acid (5 mmol, 1 equiv.), amine (5 mmol, 1 equiv.) and

B(OCH2CF3)3 (108 µl, 0.5 mmol, 10 mol%) in tBuOAc (5 ml, 1 M) with a Dean-Stark

apparatus (side arm filled with tBuOAc) was heated to reflux. An air condenser was fitted

and the reaction mixture heated for 1 – 48 hours. Upon completion, the reaction was cooled

to room temperature and water (0.5 ml), dimethyl carbonate (5 ml) Amberlite IRA-743 (0.25

g) and A-26(OH) (0.5 g) resins were added and the resulting suspension was stirred for 30

min. MgSO4 (~0.5 g) was added and the mixture filtered and the resins washed with EtOAc

(2 × 5 ml). The combined filtrates were concentrated in vacuo to yield the pure amide.

6

N((1S,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1a

Prepared according to general amidation procedure A on a 2.0 mmol scale. Purified by flash

column chromatography (0 – 40% EtOAc in petrol) to give the product as a white solid

(387 mg, 1.51 mmol, 75%).

M.p 78 – 80 °C; [α]D18 +1.20 (c = 4, CHCl3); νmax (film/cm-1) 3375 (NH), 2982 (CH), 1673

(CO); 1H NMR (400 MHz, CDCl3) δ 8.57 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.23 – 8.11 (m, 2H),

7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 4.48 – 4.39 (m, 1H), 2.48 –

2.37 (m, 1H), 1.83 (dtd, J = 12.2, 8.0, 4.0 Hz, 1H), 1.71 (ddd, J = 13.7, 8.2, 3.4 Hz, 2H), 1.49

– 1.39 (m, 1H), 1.36 – 1.29 (m, 1H), 1.03 – 0.96 (m, 4H), 0.92 (s, 3H), 0.88 (s, 3H); 13C NMR

(151 MHz, CDCl3) δ 164.3, 150.3, 148.1, 137.5, 126.1, 122.3, 53.9, 50.0, 48.4, 45.2, 37.7,

28.6, 28.2, 20.0, 18.9, 13.9; LRMS (CI) 259.2 ([M+H]+).


3-Methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1b


column chromatography (0 – 40% EtOAc in petrol) to give the product as a colourless oil

(82 mg, 0.30 mmol, 75%).

[α]D24 +4.67 (c = 0.3, CHCl3); νmax (film/cm-1) 3384 (NH), 2976 (CH), 2876 (CH), 1666 (CO),

1506 (CC); 1H NMR (600 MHz, CDCl3) δ 8.42 – 8.39 (m, 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.57

(t, J = 7.7 Hz, 1H), 7.29 (dt, J = 9.0, 4.5 Hz, 1H), 4.43 – 4.35 (m, 1H), 2.74 (s, 3H), 2.46 –

2.37 (m, 1H), 1.85 – 1.78 (m, 1H), 1.73 – 1.68 (m, 2H), 1.46 – 1.40 (m, 1H), 1.34 – 1.28 (m,

1H), 1.01 (s, 3H), 0.97 (dd, J = 13.4, 4.6 Hz, 1H), 0.91 (s, 3H), 0.88 (s, 3H); 13C NMR (151

7

MHz, CDCl3) δ 166.1, 147.6, 145.5, 141.0, 135.5, 125.6, 53.6, 49.9, 48.3, 45.2, 37.7, 28.8,

28.3, 20.9, 20.0, 18.8, 13.9; LRMS (CI NH3) 273.20 ([M+H]+); HRMS found (CI NH3) [M+H]+

273.1961 C17H24N2O+H requires 273.1961.

4-Methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1c

Prepared according to general amidation procedure A, on a 0.5 mmol scale. Purified by flash


(74 mg, 0.27 mmol, 54%).

[α]D24 +4.20 (c = 1, CHCl3); νmax (film/cm-1) 3384 (NH), 2952 (CH), 2880 (CH), 1673 (CO),

1516 (CC); 1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 4.9 Hz, 1H), 8.26 – 8.10 (m, 1H), 8.04 –

8.00 (m, 1H), 7.25 – 7.19 (m, 1H), 4.43 (dddd, J = 11.5, 9.6, 4.6, 2.3 Hz, 1H), 2.46 – 2.39 (m,

4H), 1.87 – 1.78 (m, 1H), 1.74 – 1.67 (m, 2H), 1.43 (dqd, J = 14.9, 4.8, 2.5 Hz, 1H), 1.36 –

1.28 (m, 1H), 1.06 – 0.96 (m, 4H), 0.90 (s, 3H), 0.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ

164.2, 149.7, 148.4, 147.5, 126.5, 122.8, 53.5, 49.6, 47.9, 44.7, 37.2, 28.1, 27.8, 20.8, 19.6,

18.5, 13.5; HRMS found (ES) [M+H]+ 273.1966 C17H24N2O+H requires 273.1961.

5-Methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1d


column chromatography (0 – 30% EtOAc in petrol) to give the amide as a colourless oil

(118 mg, 0.43 mmol, 87%).

[α]D24 +4.00 (c = 0.7, CHCl3); 1H NMR (700 MHz, CDCl3) δ 8.36 – 8.34 (m, 1H), 8.14 (d, J =

8.5 Hz, 1H), 8.07 (d, J = 6.9 Hz, 1H), 7.63 – 7.61 (m, 1H), 4.42 (dddd, J = 11.5, 9.5, 4.6, 2.3

Hz, 1H), 2.44 – 2.37 (m, 4H), 1.85 – 1.78 (m, 1H), 1.72 – 1.67 (m, 2H), 1.42 (dddd, J = 14.2,

12.2, 4.6, 2.3 Hz, 1H), 1.34 – 1.29 (m, 1H), 1.01 (s, 3H), 0.98 (dd, J = 13.4, 4.6 Hz, 1H), 0.90

8

(s, 3H), 0.86 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.6, 148.6, 147.9, 137.8, 136.2, 121.9,

53.9, 50.0, 48.4, 45.2, 37.7, 28.6, 28.3, 20.0, 18.9, 18.7, 13.9; HRMS found (ES) [M+H]+

273.1966 C17H24N2O+H requires 273.1961.

3-(Trifluoromethyl)-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide

1e

Prepared according to general amidation procedure A, on a 0.5 mmol scale. Purified by flash

column chromatography (0 – 5% MeOH in DCM) to give the product as a white solid

(131 mg, 0.40 mmol, 80%).

M.p 95-96 °C; [α]D24 +5.20 (c = 1, CHCl3); νmax (film/cm-1) 3043 (NH), 3078 (CH), 2943 (CH),

1690 (CO), 1513 (CC); 1H NMR (500 MHz, CDCl3) δ 8.77 – 8.72 (m, 1H), 8.16 (d, J = 8.0

Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.0, 4.8 Hz, 1H), 4.45 (tdd, J = 9.6, 4.5, 2.2

Hz, 1H), 2.45 (ddt, J = 14.1, 11.1, 3.9 Hz, 1H), 1.82 (tq, J = 12.2, 4.1 Hz, 1H), 1.73 (t, J = 4.5

Hz, 1H), 1.65 (ddd, J = 13.8, 9.4, 4.4 Hz, 1H), 1.50 – 1.40 (m, 1H), 1.28 (ddd, J = 13.4, 9.3,

4.5 Hz, 1H), 1.03 – 0.99 (s, 3H), 0.97 (dd, J = 13.5, 4.6 Hz, 1H), 0.90 (m, 6H); 13C NMR (126

MHz, CDCl3) δ 162.9, 150.2, 149.5, 135.9 (q, J = 6.4 Hz), 125.6 (q, J = 34.3 Hz), 123.7,

122.6 (q, J = 273.1 Hz), 53.8, 49.6, 48.0, 44.7, 37.2, 28.1, 27.8, 19.5, 18.3, 13.4; HRMS

found (ES) [M+H]+ 327.1670 C17H21N2OF3+H requires 327.1679.


1f

Prepared according to general amidation procedure A, on a 1 mmol scale. Purified by flash

column chromatography (20% EtOAc in petrol) to give the product as a white solid (298 mg,

0.92 mmol, 92%).

9

M.p 78-80 °C; [α]D24 +9.00 (c = 0.8, CHCl3); νmax (film/cm-1) 3375 (NH), 2939 (CH), 2889

(CH), 1670 (CO), 1552 (CC); 1H NMR (700 MHz, CDCl3) δ 8.84 (s, 1H), 8.33 (d, J = 8.1 Hz,

1H), 8.14 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 4.43 (ddd, J = 11.2, 4.2, 2.2 Hz, 1H),

2.48 – 2.40 (m, 1H), 1.84 (ddd, J = 16.5, 8.4, 4.0 Hz, 1H), 1.74 (t, J = 4.4 Hz, 1H), 1.66 (dt, J

= 9.5, 6.2 Hz, 1H), 1.48 – 1.42 (m, 1H), 1.34 – 1.29 (m, 1H), 1.01 (s), 0.98 (dd, J = 13.5, 4.4

Hz, 1H), 0.93 – 0.90 (m, 3H), 0.87 (s, 3H). 13C NMR (176 MHz, CDCl3) δ 162.9, 153.2, 145.3

(q, J = 3.9 Hz), 134.9 (q, J = 3.4 Hz), 128.8 (q, J = 33.2 Hz), 123.35 (q, J = 272.7 Hz), 122.2,

54.2, 50.1, 48.4, 45.1, 37.7, 28.5, 28.2, 19.9, 18.8, 13.9; HRMS found (ES) [M+H]+ 327.1683

C17H22N2OF3+H requires 327.1684.

4-Methoxy-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1g


column chromatography (20% EtOAc in petrol) to give the amide as a colourless oil (250 mg,

0.87 mmol, 87%).

[α]D24 −7.00 (c = 0.4, CHCl3); νmax (film/cm-1) 3384 (NH), 2952 (CH), 2880 (CH), 1672 (CO),

1509 (CC); 1H NMR (700 MHz, CDCl3) δ 8.35 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H),

7.73 (s, 1H), 6.90 (dd, J = 5.2, 2.1 Hz, 1H), 4.44 – 4.39 (m, 1H), 3.91 (s, 3H), 2.45 – 2.39 (m,

1H), 1.81 (tt, J = 12.4, 4.0 Hz, 1H), 1.72 (t, J = 4.5 Hz, 1H), 1.71 – 1.67 (m, 1H), 1.43 (ddd, J

= 13.9, 4.4, 2.2 Hz, 1H), 1.34 – 1.29 (m, 1H), 1.01 (s, 3H), 0.99 (dd, J = 13.5, 4.4 Hz, 1H),

0.91 (s, 3H), 0.87 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 167.1, 164.3, 152.4, 149.3, 113.0,

107.4, 55.6, 54.0, 50.1, 48.4, 45.2, 37.6, 28.5, 28.3, 20.0, 18.9, 13.9; HRMS found (ES)

[M+H]+ 289.1912 C17H25N2O2+H requires 289.1916.

5-Methoxy-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1h

10

Prepared according to general amidation procedure A on a 1 mmol scale. Purified by flash

column chromatography (20% EtOAc in petrol) to give the product as a colourless oil (282

mg, 0.98 mmol, 98%).


1519 (CC); 1H NMR (700 MHz, CDCl3) δ 8.22 (d, J = 2.2 Hz, 1H), 8.13 (t, J = 7.8 Hz, 1H),

7.98 (d, J = 8.6 Hz, 1H), 7.29 – 7.26 (m, 1H), 4.44 – 4.38 (m, 1H), 3.89 (d, J = 7.1 Hz), 2.46

– 2.37 (m, 1H), 1.86 – 1.78 (m, 1H), 1.98 (m, 2H) 1.46 – 1.40 (m, 1H), 1.34 – 1.28 (m, 1H),

1.00 (s, 3H), 0.97 (dd, J = 13.4, 4.5 Hz, 1H), 0.90 (s, 3H), 0.86 (s, 3H); 13C NMR (176 MHz,

CDCl3) δ 164.3, 157.8, 143.1, 136.5, 123.4, 120.3, 55.9, 53.8, 50.0, 48.4, 45.2, 37.7, 28.6,

28.3, 20.0, 18.9, 13.9; HRMS found (ES) [M+H]+ 289.1911 C17H25N2O2+H requires 289.1916.

3-phenyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide



mg, 0.81 mmol, 81%).

[α]D24 +5.21 (c = 1, CHCl3); νmax (film/cm-1) 3381 (NH), 2921 (CH), 2888 (CH), 1668 (CO),

1512 (CC); 1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 4.7, 1.7 Hz, 1H), 7.78 (d, J = 9.2 Hz,

1H), 7.69 (dd, J = 7.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.8, 4.7 Hz, 1H), 7.43 – 7.30 (m, 5H), 4.36 –

4.26 (m, 1H), 2.40 – 2.29 (m, 1H), 1.85 – 1.73 (m, 1H), 1.67 (t, J = 4.5 Hz, 1H), 1.65 – 1.58

(m, 1H), 1.45 – 1.36 (m, 1H), 1.29 – 1.26 (m, 1H), 0.94 – 0.89 (m, 4H), 0.87 (s, 3H), 0.80 (s,

3H).; 13C NMR (176 MHz, CDCl3) δ 165.1, 148.5, 146.9, 140.4, 139.6, 138.3, 128.5, 128.1,

127.7, 125.1, 53.7, 49.8, 48.3, 45.1, 37.7, 28.5, 28.3, 20.0, 18.8, 13.8.

N-((1-Methylcyclohexyl)methyl)picolinamide 4a

11



(209 mg, 0.90 mmol, 90%).

νmax (film/cm-1) 3393 (NH), 2925 (CH), 2851 (CH), 1675 (CO), 1527 (CC); 1H NMR (700

MHz, CDCl3) δ 8.54 (d, J = 4.7 Hz, 1H), 8.20 (d, J = 7.81, 1H), 8.17 (b s, 1H) 7.84 (td, J =

7.7, 1.7 Hz, 1H), 7.43 – 7.39 (m, 1H), 3.33 (d, J = 6.6 Hz, 2H), 1.58 – 1.52 (m, 2H), 1.51 –

1.43 (m, 3H), 1.39 – 1.30 (m, 5H), 0.97 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.5, 150.2,

148., 137.5, 126.1, 122.4, 49.6, 35.6, 34.8, 26.4, 23.4, 22.0; HRMS found (ES) [M+H]+

233.1655 C14H20N2O+H requires 233.1654.

3-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4b



0.84 mmol, 84%).


MHz, CDCl3) δ 8.36 (d, J = 4.0 Hz, 1H), 8.22 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.27 (dd, J =

7.7, 4.6 Hz, 1H), 3.27 (d, J = 6.5 Hz, 2H), 2.73 (s, 3H), 1.57 – 1.50 (m, 2H), 1.50 – 1.40 (m,

3H), 1.38 – 1.28 (m, 5H), 0.95 (s, 3H);13C NMR (176 MHz, CDCl3) δ 166.2, 147.7, 145.5,

140.9, 135.5, 125.6, 49.4, 35.7, 34.7, 26.5, 23.4, 22.0, 20.7; HRMS found (ES) [M+H]+

247.1802 C15H22N2O+H requires 247.1810.

4-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4c

P

12


column chromatography (0 – 30 % EtOAc in petrol) to give the amide as a colourless oil (110

mg, 0.48 mmol, 48%).


MHz, CDCl3) δ 8.39 (d, J = 4.8 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.22 (d, J = 4.7 Hz, 1H),

3.31 (d, J = 6.6 Hz, 2H), 2.42 (s, 3H), 1.54 (dt, J = 11.3, 5.6 Hz, 2H), 1.51 – 1.41 (m, 3H),

1.40 – 1.28 (m, 5H), 0.97 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.8, 150.0, 148.9, 148.0,

126.9, 123.3, 49.6, 35.6, 34.8, 26.4, 23.4, 22.0, 21.2; HRMS found (ES) [M+H]+ 247.1814

C15H22N2O+H requires 247.1810.

5-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4d


column chromatography (10 – 30 % EtOAc in petrol) to give the product as a colourless oil

(201 mg, 0.82 mmol, 82%).


MHz, CDCl3) δ 8.35 (dd, J = 1.4, 0.7 Hz, 1H), 8.15 – 8.06 (m, 2H), 7.65 – 7.60 (m, 1H), 3.32

(d, J = 6.6 Hz, 2H), 2.39 (s, 3H), 1.57 – 1.51 (m, 2H), 1.50 – 1.42 (m, 3H), 1.39 – 1.30 (m,

5H), 0.96 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.7, 148.6, 147.8, 137.8, 136.2, 122.0,

49.5, 35.6, 34.8, 26.5, 23.4, 22.0, 18.6; HRMS found (ES) [M+H]+ 247.1812 C15H22N2O+H

requires 247.1812

N-((1-Methylcyclohexyl)methyl)-3-(trifluoromethyl)picolinamide 4e


column chromatography (20 – 40% EtOAc in petrol) to give the amide as an off-white solid

(279 mg, 0.93 mmol, 93%).

13

M.p 76 – 79 °C; νmax (film/cm-1) 3308 (NH), 2923 (CH), 2855 (CH), 1645 (CO), 1558 (CC); 1H

NMR (700 MHz, CDCl3) δ 8.71 (d, J = 4.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H),

7.54 (dd, J = 8.0, 4.8 Hz, 1H), 3.33 (d, J = 6.6 Hz, 2H), 1.56 – 1.51 (m, 2H), 1.50 – 1.42 (m,

3H), 1.38 – 1.29 (m, 5H), 0.96 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 163.6, 150.7, 150.1,

136.3 (q, J = 5.9), 126.1 (q, J = 34.4 Hz), 125.2, 123.0 (q, J = 273.2 Hz), 49.7, 35.6, 34.7,

26.4, 23.4, 21.9; HRMS found (ES) [M+H]+ 301.1521 C15H19N2OF3+H requires 301.1528.

N-((1-Methylcyclohexyl)methyl)-5-(trifluoromethyl)picolinamide 4f


column chromatography (0 – 30% EtOAc in petrol) to give the product as an off-white solid

(298 mg, 0.99 mmol, 99%).

M.p 75 – 77 °C; νmax (film/cm-1) 3362 (NH), 2919 (CH), 2853 (CH), 1657 (CO), 1529 (CC); 1H

NMR (700 MHz, CDCl3) δ 8.82 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.10 (m, 2H), 3.34 (d, J =

8.6 Hz, 2H), 1.58 – 1.42 (m, 5H), 1.41 – 1.29 (m, 5H), 0.97 (s, 3H); 13C NMR (176 MHz,

CDCl3) δ 163.1, 153.1, 145.26 (q, J = 3.9 Hz), 134.89 (q, J = 3.4 Hz), 128.80 (q, J = 33.3

Hz), 123.34 (q, J = 272.7 Hz), 122.3, 49.7, 35.6, 34.8, 26.4, 23.4, 21.9; HRMS found (ES)

[M+H]+ 301.1527 C15H22N2OF3+H requires 301.1528.

4-Methoxy-N-((1-methylcyclohexyl)methyl)picolinamide 4g



mg, 0.77 mmol, 77%).


MHz, CDCl3) δ 8.32 (d, 5.8 Hz, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 6.92 – 6.86 (m, 1H), 3.89 (s,

3H), 3.30 (d, J = 6.6 Hz, 2H), 1.58 – 1.49 (m, 2H), 1.49 – 1.40 (m, 3H), 1.37 – 1.28 (m, 5H),

14

0.95 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 167.1, 164.5, 152.3, 149.2, 113.1, 107.5, 55.6,

49.6, 35.6, 34.8, 26.4, 23.4, 21.9; HRMS found (ES) [M+H]+ 263.1763 C15H23N2O2+H

requires 263.1760.

5-Methoxy-N-((1-methylcyclohexyl)methyl)picolinamide 4h



(222 mg, 0.85 mmol, 85%).


MHz, CDCl3) δ 8.20 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.05 – 7.88 (br s, 1H), 7.27

(dd, J = 8.7, 2.2 Hz, 1H), 3.90 (s, 3H), 3.30 (d, J = 6.6 Hz, 2H), 1.53 (dt, J = 11.6, 5.8 Hz,

2H), 1.44 (ddd, J = 12.9, 8.0, 3.6 Hz, 3H), 1.38 – 1.29 (m, 5H), 0.96 (s, 3H); 13C NMR (176

MHz, CDCl3) δ 164.5, 157.9, 143.0, 136.5, 123.5, 120.3, 55.9, 49.5, 35.6, 34.7, 26.5, 23.4,

22.0; HRMS found (ES) [M+H]+ 263.1764 C15H23N2O2+H requires 263.1760.

N-(2-Methylbutyl)picolinamide 7a


column chromatography (0 – 30% EtOAc in petrol) to give the product as a yellow oil (174

mg, 0.91 mmol, 91%).

1H NMR (700 MHz, CDCl3) δ 8.45 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.10 – 7.97

(s, 1H), 7.74 (td, J = 7.7, 1.7 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 3.35 – 3.29 (m,

1H), 3.21 (dt, J = 13.4, 6.7 Hz, 1H), 1.64 – 1.57 (m, 1H), 1.41 – 1.35 (m, 1H), 1.16 – 1.10 (m,

1H), 0.88 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 164.4,

150.1, 148.1, 137.4, 126.1, 122.2, 45.1, 35.2, 27.1, 17.3, 11.4; HRMS found (ES) [M+H]+

193.1343 C11H16N2O+H requires 193.1341.


15

3-Methyl-N-(2-methylbutyl)picolinamide 7b



0.81 mmol, 81%).

νmax (film/cm-1) 3389 (NH), 2962 (CH), 2929 (CH), 2875 (CH), 1667 (CO), 1517 (CC); 1H

NMR (700 MHz, CDCl3) δ 8.33 (s, 1H), 8.25 – 8.12 (b s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.26 –

7.22 (m, 1H), 3.36 – 3.31 (m, 1H), 3.20 (ddd, J = 13.4, 9.7, 3.7 Hz, 1H), 2.70 (s, 3H), 1.65

(dq, J = 12.6, 6.1 Hz, 1H), 1.49 – 1.40 (m, 1H), 1.22 – 1.17 (m, 1H), 0.93 (dd, J = 6.8, 1.4

Hz, 3H), 0.90 (td, J = 7.4, 1.4 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 166.1, 147.6, 145.5,

140.9, 135.4, 125.6, 45.0, 35.2, 27.3, 20.7, 17.4, 11.4; HRMS found (ES) [M+H]+ 207.1497

C12H18N2O+H requires 207.1497.

4-Methyl-N-(2-methylbutyl)picolinamide 7c


column chromatography (20% EtOAc in petrol) to give the amide as a pale yellow oil (180

mg, 0.87 mmol, 87%).


MHz, CDCl3) δ 8.36 (d, J = 4.8 Hz, 1H), 8.19 – 8.03 (m, 1H), 8.00 (s, 1H), 7.19 (d, J = 4.7

Hz, 1H), 3.41 – 3.35 (m, 1H), 3.27 (dt, J = 13.4, 6.7 Hz, 1H), 2.39 (s, 3H), 1.71 – 1.63 (m,

1H), 1.49 – 1.42 (m, 1H), 1.20 (dt, J = 14.3, 7.1 Hz, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (t, J =

7.5 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 164.7, 150.0, 148.9, 148.0, 126.9, 123.2, 45.1,

35.2, 27.2, 21.2, 17.4, 11.4; HRMS found (ES) [M+H]+ 207.1498 C12H18N2O+H requires

207.1497.

5-Methyl-N-(2-methylbutyl)picolinamide 7d

16



(195 mg, 0.95 mmol, 95%).


MHz, CDCl3) δ 8.34 (d, J = 0.7 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.62 (ddd, J =

7.9, 1.3, 0.7 Hz, 1H), 3.42 – 3.37 (m, 1H), 3.27 (dt, J = 13.4, 6.7 Hz, 1H), 2.38 (s, 3H), 1.72 –

1.64 (m, 1H), 1.51 – 1.44 (m, 1H), 1.25 – 1.18 (m, 1H), 0.96 (dd, J = 6.7, 1.3 Hz, 3H), 0.94 –

0.91 (m, 3H); 13C NMR (176 MHz, CDCl3) δ 164.7, 148.6, 147.8, 137.8, 136.3, 122.0, 45.1,

35.3, 27.2, 18.6, 17.4, 11.5; HRMS found (ES) [M+H]+ 207.1495 C12H18N2O+H requires

207.1497.

N-(2-Methylbutyl)-3-(trifluoromethyl)picolinamide 7e


column chromatography (0 – 30% EtOAc in petrol) to give the amide as a white solid (229

mg, 0.88 mmol, 88%).

M.p 76 – 78 °C; νmax (film/cm-1) 3282 (NH), 2964 (CH), 2877 (CH), 1670 (CO), 1562 (CC);

1H NMR (700 MHz, CDCl3) δ 8.71 (m, 1H), 8.15 (t, J = 6.6 Hz, 1H), 7.77 – 7.58 (s, 1H), 7.57

– 7.51 (m, 1H), 3.44 – 3.38 (m, 1H), 3.31 – 3.25 (m, 1H), 1.75 – 1.67 (m, 1H), 1.51 – 1.43

(m, 1H), 1.27 – 1.19 (m, 1H), 0.99 – 0.95 (m, 3H), 0.93 (ddd, J = 9.4, 5.8, 1.8 Hz, 3H); 13C

NMR (176 MHz, CDCl3) δ 163.4, 150.6, 149.9, 136.3 (q, J = 5.7 Hz), 126.1 (q, J = 33.3 Hz),

125.3, 123.0 (q, J = 273.2 Hz), 45.2, 35.1, 27.2, 17.3, 11.4; HRMS found (ES) [M+H]+

261.1212 C12H15N2OF3+H requires 261.1215.

N-(2-Methylbutyl)-5-(trifluoromethyl)picolinamide 7f

17

Prepared according to the general amidation procedure, on a 1 mmol scale. Purified by flash

column chromatography (20% EtOAc in petrol) to give the amide as a pale yellow oil (253

mg, 0.97 mmol, 97%).

νmax (film/cm-1) 3400 (NH), 2963 (CH), 2930 (CH), 2877 (CH), 167 (CO), 1527 (CC); 1H NMR

(700 MHz, CDCl3) δ 8.79 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.09 (m, 2H), 3.45 – 3.39 (m, 1H),

3.30 (dt, J = 13.3, 6.6 Hz, 1H), 1.74 – 1.65 (m, 1H), 1.49 – 1.41 (m, 1H), 1.26 – 1.20 (m, 1H),

0.95 (d, J = 6.7 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 163.0, 153.1,

145.2 (q, J = 3.8 Hz), 134.9 (q, J = 3.4 Hz), 128.8 (q, J = 33.3 Hz), 123.3 (q, J = 272.7 Hz),

122.2, 45.3, 35.2, 27.2, 17.3, 11.4; HRMS found (ES) [M+H]+ 261.1212 C15H15N2OF3+H

requires 261.1215

4-Methoxy-N-(2-methylbutyl)picolinamide 7g



(176 mg, 0.79 mmol, 79%).


MHz, CDCl3) δ 8.32 (t, J = 5.3 Hz, 1H), 8.19 – 8.06 (m, 1H), 7.73 (d, J = 2.6 Hz, 1H), 6.89

(dd, J = 5.6, 2.6 Hz, 1H), 3.90 (s, 3H), 3.39 (dt, J = 12.7, 6.2 Hz, 1H), 3.28 (dt, J = 13.4, 6.7

Hz, 1H), 1.68 (dq, J = 13.3, 6.7 Hz, 1H), 1.49 – 1.44 (m, 1H), 1.24 – 1.19 (m, 1H), 0.96 (d, J

= 6.7 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 167.1, 164.4, 152.3,

149.3, 113.0, 107.4, 55.6, 45.2, 35.2, 27.2, 17.4, 11.5; HRMS found (ES) [M+H]+ 223.1450

C12H18N2O2+H requires 223.1447.

5-Methoxy-N-(2-methylbutyl)picolinamide 7h

18

Prepared according to general procedure A, on a 1 mmol scale. Purified by flash column

chromatography (0 – 30% EtOAc in petrol) to give the product as a colourless oil (169 mg,

0.76 mmol, 76%)


MHz, CDCl3) δ 8.16 (t, J = 2.5 Hz, 1H), 8.11 (dd, J = 8.6, 2.2 Hz, 1H), 7.86 (s, 1H), 7.24 (dt,

J = 8.7, 2.5 Hz, 1H), 3.86 (d, J = 2.6 Hz, 3H), 3.36 (dtd, J = 8.3, 6.2, 2.2 Hz, 1H), 3.24 (tdd, J

= 8.7, 6.9, 2.1 Hz, 1H), 1.68 – 1.61 (m, 1H), 1.47 – 1.42 (m, 1H), 1.21 – 1.16 (m, 1H), 0.93

(dd, J = 6.7, 2.3 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 164.4, 157.8,

143.0, 136.5, 123.4, 120.2, 55.8, 45.1, 35.3, 27.2, 17.4, 11.4; HRMS found (ES) [M+H]+

223.1444 C12H19N2O2+H requires 223.1447.

N-Isobutylpicolinamide 11a



mg, 1.81 mmol, 90%).


MHz, CDCl3) δ 8.54 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.20 (dt, J = 7.8, 1.0 Hz, 1H), 8.18 – 8.06

(s, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 3.33 – 3.28 (m,

2H), 1.92 (non, J = 6.7 Hz, 1H), 0.99 (d, J = 6.7 Hz, 6H); 13C NMR (176 MHz, CDCl3) δ

164.4, 150.2, 148.1, 137.5, 126.1, 122.4, 46.9, 28.9, 20.3; HRMS found (ES) [M+H]+

179.1180, C10H14N2O+H requires 179.1184.


N-Isobutyl-3-methylpicolinamide 11b

19



mg, 1.85 mmol, 92%).


MHz, CDCl3) δ 8.37 (d, J = 4.5 Hz, 1H), 8.18 (s, 1H), 7.60 – 7.53 (m, 1H), 7.30 – 7.26 (m,

1H), 3.27 – 3.23 (m, 2H), 2.74 (s, 3H), 1.91 (non, J = 6.7 Hz, 1H), 1.00 – 0.96 (m, 6H); 13C

NMR (176 MHz, CDCl3) δ 166.1, 147.6, 145.5, 140.9, 135.5, 125.6, 46.8, 28.8, 20.7, 20.4;

HRMS found (ES) [M+H]+ 193.1341, C11H16N2O+H requires 193.1341.

N-Cyclohexylpicolinamide 14a

Prepared according to general amidation procedure B, on a 5 mmol scale, heating to reflux

for 48 h to give the product as a white solid (930 mg, 4.55 mmol, 91%)

M.p 54 – 56 °C; νmax (solid/cm-1) 3379, 2935, 2857, 1666; 1H NMR (400 MHz, CDCl3) δ 8.52

(ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.18 (dt, J = 7.8, 1.1 Hz, 1H), 7.93 (s, 1H), 7.82 (td, J = 7.7,

1.7 Hz, 1H), 7.39 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 4.03 – 3.89 (m, 1H), 2.05 – 1.95 (m, 2H),

1.80 – 1.70 (m, 2H), 1.68 – 1.59 (m, 1H), 1.48 – 1.16 (m, 5H); 13C NMR (151 MHz, CDCl3) δ

163.4, 150.4, 148.1, 137.4, 126.1, 122.3, 48.3, 33.2, 25.7, 25.0.

Prepared according to literature procedure7

N-Cyclohexyl-3-methylpicolinamide 14b


column chromatography (20% EtOAc in petrol) to give the product as a white solid (336 mg,

1.54 mmol, 77%).

M.p 72 – 74 °C; νmax (film/cm-1) 3302 (NH), 2933 (CH), 2851 (CH), 1641 (CO), 1529 (CC);

1H NMR (700 MHz, CDCl3) δ 8.36 (d, J = 3.9 Hz, 1H), 8.02 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H),

20

7.27 (dd, J = 7.7, 4.5 Hz, 1H), 3.95 – 3.87 (m, 1H), 2.73 (s, 3H), 2.02 – 1.97 (m, 2H), 1.78 –

1.73 (m, 2H), 1.66 – 1.61 (m, 1H), 1.45 – 1.38 (m, 2H), 1.33 – 1.27 (m, 2H), 1.26 – 1.19 (m,

1H); 13C NMR (176 MHz, CDCl3) δ 165.2, 147.7, 145.4, 141.0, 135.5, 125.6, 48.1, 33.3,

25.8, 25.1, 20.7; HRMS found (ES) [M+H]+ 219.1495, C13H18N2O+H requires 219.1497.

N-(Cyclohexylmethyl)picolinamide 16a

Prepared according to general amidation procedure B, on a 5 mmol scale, heating to reflux

for 24 h to give the amide as a white solid (1.00 g, 4.60 mmol, 92%).

M.p 65 - 67 °C; νmax (solid/cm-1) 3354 (NH), 2916 (CH), 2847 (CH), 1657 (CO), 1525 (CC);

1H NMR (700 MHz, CDCl3) δ 8.49 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H),

7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 3.27 (t, J = 6.6 Hz, 2H),

1.75 (dd, J = 13.6, 1.9 Hz, 2H), 1.71 – 1.65 (m, 2H), 1.61 (ddd, J = 12.5, 5.0, 2.6 Hz, 1H),

1.55 (ttd, J = 10.5, 7.0, 3.4 Hz, 1H), 1.23 – 1.15 (m, 2H), 1.15 – 1.08 (m, 1H), 1.01 (qd, J =

12.1, 2.9 Hz, 2H); 13C NMR (176 MHz, CDCl3) δ 164.4, 150.2, 148.1, 137.4, 126.1, 122.3,

45.7, 38.2, 31.0, 26.5, 26.0.


N-Cycloheptylpicolinamide 19a

Prepared according to general amidation procedure B. Product further purified by flash


(875 mg, 4.01 mmol, 80%).


MHz, CDCl3) δ 8.51 – 8.45 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.80 –

7.76 (m, 1H), 7.37 – 7.33 (m, 1H), 4.14 – 4.09 (m, 1H), 2.02 – 1.94 (m, 2H), 1.68 – 1.48 (m,

10H); 13C NMR (176 MHz, CDCl3) δ 163.1, 150.4, 148.1, 137.4, 126.1, 122.3, 50.5, 35.2,

28.2, 24.3.


21

N-Cycloheptyl-3-methylpicolinamide 19b



mg, 1.81 mmol, 91%).


MHz, CDCl3) δ 8.33 (d, J = 4.0 Hz, 1H), 8.18 – 7.98 (d, J = 6.6 Hz, 1H), 7.52 (d, J = 7.7 Hz,

1H), 7.24 (dd, J = 7.7, 4.5 Hz, 1H), 4.06 (tt, J = 12.6, 6.2 Hz, 1H), 2.71 (s, 3H), 2.02 – 1.97

(m, 2H), 1.69 – 1.49 (m, 10H); 13C NMR (176 MHz, CDCl3) δ 164.9, 147.7, 145.5, 140.9,

135.4, 125.5, 50.3, 35.2, 28.2, 24.4, 20.7; HRMS found (ES) [M+H]+ 233.1648, C14H20N2O+H

requires 233.1654.

N-(tetrahydro-2H-pyran-4-yl)picolinamide 21a

Prepared according to general amidation procedure A on a 1 mmol scale. Purified using 0 -

2% methanol in DCM to give the amide as a sticky white solid (179 mg, 0.87 mmol, 87%).


MHz, CDCl3) δ 8.58 – 8.53 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H,), 7.86 (td, J = 7.7,

1.7 Hz, 1H), 7.44 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 4.20 (tdt, J = 12.6, 8.5, 4.3 Hz, 1H), 4.01

(dt, J = 12.0, 3.4 Hz, 2H), 3.56 (td, J = 11.7, 2.2 Hz, 2H), 2.00 (dd, J = 12.6, 2.2 Hz, 2H),

1.69 – 1.63 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 163.7, 150.0, 148.1, 137.5, 126.3, 122.4,

66.9, 45.8, 33.2; LRMS (CI NH3) 207.11 ([M+H]+); HRMS found (CI NH3) [M+H]+ 207.1128,


3-Methyl-N-(tetrahydro-2H-pyran-4-yl)picolinamide 21b

22


column chromatography (0 - 30% EtOAc in petrol) to give the product as colourless oil (91

mg, 0.41 mmol, 41%).

νmax (film/cm-1) 3380 (NH), 2964 (CH), 2877 (CH), 1664 (CO), 1512 (CC), 1156 (CO); 1H

NMR (700 MHz, CDCl3) δ 8.38 – 8.32 (m, 1H), 8.15 – 8.00 (s, 1H), 7.55 (dd, J = 7.7, 0.8 Hz,

1H), 7.29 – 7.24 (m, 1H), 4.15 – 4.07 (m, 1H), 3.99 – 3.94 (m, 2H), 3.51 (td, J = 11.6, 2.2 Hz,

2H), 2.70 (s, 3H), 1.98 – 1.92 (m, 2H), 1.64 – 1.56 (m, 2H); 13C NMR (176 MHz, CDCl3) δ

165.4, 147.2, 145.5, 141.0, 135.6, 125.8, 67.0, 45.6, 33.2, 20.7; HRMS found (ES) [M+H]+

221.1288, C12H16N2O2+H requires 221.1290.

General arylation procedure A

A tube was charged with a picolinamide (1 equiv.), CuBr2 (10 mol%), Pd(OAc)2 (5 mol%),

CsOAc (4 equiv.), tAmOH (1 M) and an aryl iodide or bromide (4 equiv.). The tube was

sealed with a PTFE lined cap and heated to 140 °C for 24 hours. The reaction mixture was

then cooled and filtered through a pad of Celite®, washing with EtOAc. The filtrate was

concentrated in vacuo and the resulting crude residue purified by flash column

chromatography.

General arylation procedure B

A tube was charged with a picolinamide (1 eq), CuBr2 (10 mol%), Pd(OAc)2 (5 mol%),

CsOAc (4 eq), tHxOH (1 M) and an aryl iodide (4 eq). The tube was sealed with a PTFE

lined cap and heated to 130 or 140 °C for 24 hours. The reaction mixture was then cooled

and filtered through a pad of Celite®, washing with EtOAc. The filtrate was concentrated in

vacuo and the resulting crude residue purified by flash column chromatography.

N-((1S,2S,4R,6S)-6-(4-Methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-

yl)picolinamide 2a

23

Prepared according to general arylation procedure A on a 0.1 mmol scale. Purified by flash

column chromatography (0 – 40% EtOAc in petrol) to give the product as a white solid; 91%

(aryl iodide), 93% (aryl bromide).

M.p 113-115 °C; [α]D18 +43.2 (c = 1, CHCl3); νmax (film/cm-1) 3366 (NH), 2953 (CH), 2928

(CH), 1672 (CO); 1H NMR (600 MHz, CDCl3) δ 8.21 – 8.18 (m, 1H), 7.95 (dt, J = 7.8, 1.0 Hz,

1H), 7.74 (d, J = 9.2 Hz, 1H), 7.68 (td, J = 7.7, 1.7 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.26

(ddd, J = 7.6, 4.7, 1.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 4.49 (dddd, J = 11.3, 9.3, 6.0, 1.9

Hz, 1H), 3.79 (s, 3H), 3.29 (dd, J = 11.8, 4.8 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.27 – 2.19 (m,

1H), 2.00 (dt, J = 12.2, 6.1 Hz, 1H), 1.92 (t, J = 4.6 Hz, 1H), 1.28 – 1.24 (m, 1H), 1.08 (d, J =

5.6 Hz, 6H), 1.05 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 164.5, 158.2, 149.9, 147.5, 136.9,

133.8, 129.8, 125.7, 121.8, 114.5, 55.3, 54.5, 53.8, 51.0, 46.8, 43.7, 36.9, 32.9, 20.3, 20.0,

13.8; LRMS (CI) 365.2 ([M+H]+), 729.0 ([2M+H]+).


N-((1S,2S,4R,6S)-6-(4-Methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-3-

methylpicolinamide 2b

Prepared according to general arylation procedure A on a 0.1 mmol scale. Purified by flash

column chromatography (0 – 30% EtOAc in petrol) to give the product as a white solid; 33

mg, 0.091 mmol, 91% (aryl iodide), 34 mg, 0.093 mmol, 93% (aryl bromide).

M.p 128-130 °C; [α]D24 +5.93 (c = 0.3, CHCl3); 1H NMR (700 MHz, CDCl3) δ 8.02 (ddd, J =

4.6, 1.6, 0.5 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.34 (d, J = 8.5 Hz, 2H),

7.14 (dd, J = 7.7, 4.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 4.47 (dddd, J = 11.3, 9.3, 6.0, 2.0 Hz,

1H), 3.77 (s, 3H), 3.28 (dd, J = 11.9, 4.5 Hz, 1H), 2.60 (s, 3H), 2.54 (dddd, J = 13.4, 11.4,

5.0, 3.3 Hz, 1H), 2.24 (tt, J = 12.5, 3.9 Hz, 1H), 1.99 (dd, J = 13.1, 5.8 Hz, 1H), 1.91 (t, J =

4.7 Hz, 1H), 1.24 (dd, J = 12.0, 4.7 Hz, 1H), 1.09 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H); 13C NMR

(176 MHz, CDCl3) δ 166.3, 158.1, 147.5, 144.9, 140.3, 134.7, 134.0, 129.9, 125.0, 114.4,

55.3, 54.1, 53.8, 50.9, 47.0, 43.7, 37.1, 33.0, 20.5, 20.3, 20.0, 13.8; HRMS found (ES)

[M+H]+ 379.2383 C24H30N2O2+H requires 379.2386.

24


methylpicolinamide 2c

Prepared according to general arylation procedure A, using 4-bromoanisole on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 30 % EtOAc in petrol) to give the

product as colourless oil (32 mg, 0.085 mmol, 85%).


MHz, CDCl3) δ 8.05 (d, J = 4.9 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J = 9.9 Hz, 1H), 7.35 (d, J =

8.4 Hz, 2H), 7.07 (dd, J = 4.9, 0.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 4.49 (dddd, J = 11.3,

9.2, 6.0, 1.9 Hz, 1H), 3.79 (s, 3H), 3.29 (dd, J = 11.7, 5.1 Hz, 1H), 2.59 – 2.50 (m, 1H), 2.33

(s, 3H), 2.24 (tt, J = 12.6, 3.8 Hz, 1H), 2.04 – 1.98 (m, 1H), 1.92 (t, J = 4.6 Hz, 1H), 1.26 (dd,

J = 13.0, 6.3 Hz, 1H), 1.09 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H); 13C NMR (176 MHz, CDCl3) δ

164.8, 158.2, 149.9, 148.2, 147.4, 133.9, 129.8, 126.4, 122.6, 114.5, 55.3, 54.5, 53.9, 50.9,

46.9, 43.7, 37.0, 32.9, 21.2, 20.3, 20.0, 13.8; HRMS found (ES) [M+H]+ 379.2375


N-((1S,2S,4R,6S)-6-(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-4-

methylpicolinamide 2c and N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-4-methylpicolinamide 3c

Prepared according to general arylation procedure A using 4-iodoanisole on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 30 % EtOAc in petrol) to give the title

compounds as the mono aryl product and a mixture of mono and diarylated products; ratio in

crude mono:di 88:12.

25

Isolated material overall (39 mg, 97%).

Mono (27 mg, 0.071 mmol, 71%)

Mixture (10 mg) Mono 0.016 mmol 16%; Di 0.010 mmol, 10%

3c: 1H NMR (700 MHz, CDCl3) δ 8.07 (d, J = 8.9 Hz, 1H) 8.08 – 8.04 (m, 1H)*, 7.89 – 7.87

(m, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.11 – 7.09 (m, 1H), 7.08 – 7.04 (m, 2H), 6.93 (d, J = 8.7

Hz, 2H), 6.78 – 6.75 (m, 2H), 4.79 – 4.72 (m, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 3.50 (dd, J =

12.0, 5.4 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H), 2.82 (d, J = 14.3 Hz, 1H), 2.59 – 2.51 (m, 1H),

2.36 (d, J = 6.9 Hz, 3H), 2.28 – 2.21 (m, 1H)*, 1.97 (dd, J = 13.1, 5.7 Hz, 1H) 1.71 (t, J = 4.6

Hz, 1H), 1.28 – 1.25 (m, 1H)*, 1.19 (s, 3H), 0.58 (s, 3H); 13C NMR (176 MHz, CDCl3) δ

164.8, 158.5, 158.0, 150.0, 148.2, 147.5, 133.2, 130.8, 130.3, 129.8, 126.5, 122.7, 114.6,

113.6, 55.4, 55.3, 51.0, 50.7, 49.0, 45.6, 36.8, 35.4, 33.5, 21.2, 21.0, 20.4.

*Peaks overlapping with monoarylation compound.


methylpicolinamide 2d

Prepared according to general arylation procedure A using 4-bromoanisole, on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 20% EtOAc in petrol) to give the

product as a colourless oil (26 mg, 0.0687 mmol, 69%).

[α]D24 −10.0 (c = 0.1, CHCl3); νmax (film/cm-1) 3367 (NH), 2927 (CH), 2851 (CH), 1669 (CO),


1H), 7.63 (d, J = 9.0 Hz, 1H), 7.49 – 7.46 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8

Hz, 2H), 4.48 (dddd, J = 11.3, 9.3, 6.0, 2.0 Hz, 1H), 3.80 (s, 3H), 3.29 (dd, J = 11.8, 4.6 Hz,

1H), 2.57 – 2.50 (m, 1H), 2.32 (s, 3H), 2.24 (tt, J = 12.5, 3.8 Hz, 1H), 2.01 (dd, J = 13.1, 5.8

Hz, 1H), 1.91 (t, J = 4.7 Hz, 1H), 1.28 – 1.23 (m, 1H), 1.08 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H);

13C NMR (176 MHz, CDCl3) δ 164.7, 158.2, 148.0, 147.7, 137.2, 135.5, 133.9, 129.8, 121.3,

114.5, 55.2, 54.4, 53.6, 50.9, 46.9, 43.7, 37.0, 32.9, 20.3, 20.0, 18.6, 13.8; HRMS found

(ES) [M+H]+ 379.2388 C24H30N2O2+H requires 379.2380.

26


methylpicolinamide 2d and N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-5-methylpicolinamide 3d

Prepared using general arylation procedure A using 4-iodoanisole, on a 0.1 mmol scale.

Purified by flash column chromatography (0 – 30% EtOAc in petrol) to give the title

compounds as an inseparable mixture (41 mg).

Mono 2d (0.088 mmol, 88%)

Di 3d (0.011 mmol, 11%)

1H NMR (700 MHz, CDCl3) δ 8.03 – 8.00 (m, 2H)*, 7.93 (d, J = 7.9 Hz, 1H), 7.53 – 7.50 (m,

1H), 7.48 – 7.43 (m, 2H)*, 7.07 – 7.04 (m, 2H), 6.95 – 6.92 (m, 2H), 6.77 – 6.75 (m, 2H),

4.78 – 4.72 (m, 1H), 3.86 (s, 3H), 3.73 (d, J = 2.3 Hz, 3H), 3.51 – 3.48 (m, 1H), 3.05 (d, J =

14.3 Hz, 1H), 2.82 (d, J = 14.3 Hz, 1H), 2.57 – 2.50 (m, 1H)*, 2.33 (s, 3H), 2.25 – 2.22 (m,

1H)*, 1.98 – 1.95 (m, 1H), 1.70 (t, J = 4.6 Hz, 1H), 1.27 – 1.24 (m, 1H)*, 1.15 (s, 3H), 0.58

(s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.7, 158.5, 158.0, 148.1, 147.7, 137.3, 135.7,

133.3, 131.5, 131.0, 130.8, 130.3, 121.4, 113.6, 55.8, 55.3, 51.0, 50.7, 49.0, 45.6, 41.1,

36.8, 35.4, 29.8, 24.0, 21.0, 14.8.

*Peaks overlapping with monoarylation compound


(trifluoromethyl)picolinamide 2e

Prepared according to general arylation procedure A using 4-bromoanisole on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 20% EtOAc in petrol). Further purified

27

by recrystallisation from hot petrol/DCM, to give the product as a yellow crystalline solid (15

mg, 0.034 mmol, 34%).

M.p 130-132 °C; νmax (film/cm-1) 3363 (NH), 2923 (CH), 2860 (CH), 1673 (CO), 1512 (CC);


7.39 (dd, J = 7.9, 4.7 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 9.1 Hz, 1H), 6.79 (d, J =

8.9 Hz, 2H), 4.51 – 4.46 (m, 1H), 3.70 (s, 3H), 3.28 (dd, J = 11.9, 4.5 Hz, 1H), 2.58 – 2.53

(m, 1H), 2.24 (tt, J = 12.8, 3.9 Hz, 1H), 1.99 (dd, J = 13.2, 5.8 Hz, 1H), 1.92 (t, J = 4.7 Hz,

1H), 1.25 (dd, J = 13.4, 5.9 Hz, 1H), 1.07 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H); 13C NMR (176

MHz, CDCl3) δ 163.3 (C), 158.1 (C), 150.1 (CH), 149.7 (C), 135.7 (q, J = 5.9 Hz, CH), 134.1

(C), 129.8 (CH), 125.3 (q, J = 34.2 Hz, C), 124.6 (CH), 123.0 (q, J = 273.2 Hz, C), 114.3

(CH), 55.2 (CH3), 54.7 (CH), 54.0 (C), 50.9 (C), 46.8 (CH), 43.7 (CH), 36.8 (CH2), 32.7

(CH2), 20.2 (CH3), 19.9 (CH3), 13.7 (CH3); HRMS found (ES) [M+H]+ 433.2098,

C24H27N2O2F3+H requires 433.2103.


(trifluoromethyl)picolinamide 2e and N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)picolinamide

3e

Prepared according to general arylation procedure A using 4-iodoanisole, on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 40% EtOAc in petrol) to give the title

compounds as an inseparable mixture (48 mg).

Mono 2e (0.051 mmol, 51%)

Di 3e (0.048 mmol, 48%)


7.56 – 7.50 (m, 2H), 7.45 – 7.43 (m, 2H), 7.07 – 7.04 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H6.77 –

6.75 (m, 2H), 4.75 – 4.70 (m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.48 (dd, J = 12.1, 4.5 Hz, 1H),

28

3.00 (d, J = 14.3 Hz, 1H), 2.80 (d, J = 14.3 Hz, 1H), 2.59 – 2.52 (m, 1H)*, 2.28 – 2.20 (m,

1H)*, 2.01 – 1.97 (m, 1H)*, 1.72 (t, J = 4.5 Hz, 1H), 1.26 – 1.23 (m, 1H)*, 1.19 (s, 3H), 0.58

(s, 3H); 13C NMR (176 MHz, CDCl3) δ 163.4, 158.4, 158.1, 150.6, 150.2, 136.3 (q, J = 6.0

Hz), 133.4, 131.4, 130.9, 130.1, 125.20, 124.7, 123.1 (q, J = 273.2 Hz) 114.3, 113.7, 55.8,

55.33, 55.2, 54.2, 51.0, 48.9, 37.6, 35.3, 34.0, 33.4, 20.91, 20.87.

*Peaks overlapping with monoarylated product

[not all 13C signals were seen clearly due to overlapping peaks]


(trifluoromethyl)picolinamide 2f

Prepared according to general arylation procedure A using 4-bromoanisole, on a 0.1 mmol


product as a white solid (10 mg, 0.023 mmol, 23%).

M.p 117 – 118 °C; [α]D24 +58.8 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J =

1.4, 0.8 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.99 – 7.91 (m, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.35

(d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.52 – 4.41 (m, 1H), 3.78 (s, 3H), 3.31 (dd, J =

11.9, 4.5 Hz, 1H), 2.61 – 2.49 (m, 1H), 2.26 (ddd, J = 16.1, 7.5, 3.8 Hz, 1H), 2.03 (dd, J =

13.2, 5.7 Hz, 1H), 1.94 (t, J = 4.6 Hz, 1H), 1.29 – 1.26 (m, 1H), 1.09 (s, 6H), 1.06 (s, 3H); 13C

NMR (176 MHz, CDCl3) δ 163.0, 158.3, 152.9, 144.61 (q, J = 4.0 Hz), 134.28 (q, J = 3.3 Hz),

133.8, 128.20 (q, J = 33.1 Hz), 129.8, 123.40 (q, J = 272.6 Hz), 121.5, 55.1, 54.8, 53.9, 50.9,

46.7, 43.7, 36.9, 32.7, 20.2, 20.0, 13.9; HRMS found (ES) [M+H]+ 433.2100 C24H28N2O2F3+H

requires 433.2103.

N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-7,7-

dimethylbicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)picolinamide 3f

29

Prepared according to general arylation procedure A, using 4-iodoanisole on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 10% EtOAc in petrol) to give the tittle

compound as a yellow oil (9 mg, 0.017 mmol, 17%). Also isolated the monoarylation product

(24 mg, 0.056 mmol, 56%).



1H), 8.04 (d, J = 8.9 Hz, 1H), 8.00 – 7.98 (m, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.05 – 7.03 (m,

2H), 6.96 – 6.93 (m, 2H), 6.78 – 6.75 (m, 2H), 4.77 – 4.72 (m, 1H), 3.85 (s, 3H), 3.74 (s, 3H),

3.52 (dd, J = 12.1, 4.4 Hz, 1H), 3.04 (d, J = 14.4 Hz, 1H), 2.84 (d, J = 14.4 Hz, 1H), 2.60 –

2.54 (m, 1H), 2.31 – 2.26 (m, 1H), 1.99 (dd, J = 13.2, 5.6 Hz, 1H), 1.73 (t, J = 4.6 Hz, 1H),

1.28 (t, J = 5.1 Hz, 1H), 1.20 (s, 3H), 0.59 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 163.0,

158.7, 158.1, 153.0, 144.7 (q, J = 4.2 Hz), 134.4 (q, J = 3.5 Hz), 133.1, 131.4, 130.8, 130.1,

128.4 (q, J = 33.1 Hz), 123.2 (q, J = 337.6 Hz), 121.6, 114.6, 113.7, 55.9, 55.3, 55.2, 51.1,

51.0, 45.6, 36.7, 35.4, 33.3, 20.9, 20.4; HRMS found (ES) [M+H]+ 539.2514 C31H33N2O3F3+H

requires 539.2516.

4-Methoxy-N-((1S,2S,4R,6S)-6-(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-

2-yl)picolinamide 2g

Prepared according to general arylation procedure A, on a 0.1 mmol scale, using 4-

bromoanisole. Purified by flash column chromatography (0 – 40% EtOAc in petrol) to give

the product as a white solid (29 mg, 0.074 mmol, 74%).

30

M. p 127 – 129 °C; [α]D24 +52.0 (c = 0.5, CHCl3); νmax (film/cm-1) 3359 (NH), 2983 (CH),

2951 (CH), 1671 (CO), 1509 (CC); 1H NMR (700 MHz, CDCl3) δ 7.99 (d, J = 5.6 Hz, 1H),

7.70 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.7

Hz, 2H), 6.78 – 6.74 (m, 1H), 4.50 – 4.44 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.28 (dd, J =

11.7, 5.3 Hz, 1H), 2.53 (ddd, J = 14.4, 8.2, 4.6 Hz, 1H), 2.24 (tt, J = 12.8, 3.8 Hz, 1H), 2.01

(dd, J = 13.1, 5.8 Hz, 1H), 1.91 (t, J = 4.6 Hz, 1H), 1.28 – 1.25 (m, 1H), 1.08 (s, 3H), 1.08 (s,

3H), 1.05 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 166.7, 164.5, 158.3, 152.1, 148.6, 133.8,

129.8, 114.5, 112.5, 106.8, 55.5, 55.3, 54.6, 53.8, 50.9, 46.9, 43.7, 36.9, 32.9, 20.3, 20.0,

13.8; HRMS found (ES) [M+H]+ 395.2234 C22H30N2O3+H requires 395.2235.


2-yl)picolinamide 2g and 4-Methoxy-N-((1S,2S,4R,6S)-1-(4-methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 3g



product as a mixture of mono and diarylation products (31 mg).

Mono 2g (0.066 mmol, 66%)

Di 3g (0.009 mmol, 9%)

3g: 1H NMR (700 MHz, CDCl3) δ 8.10 (d, J = 7.1 Hz, 1H, NH), 8.00 - 7.98 (m, 1H)*, 7.60 (d,

J = 2.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H),

6.80 (dd, J = 5.6, 2.6 Hz, 1H), 6.78 – 6.76 (m, 2H)*, 4.77 – 4.71 (m, 1H), 3.86 (s, 3H), 3.85

(s, 3H), 3.74 (s, 3H), 3.50 (dd, J = 11.9, 5.1 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H), 2.82 (d, J =

14.3 Hz, 1H), 2.58 – 2.50 (m, 1H)*, 2.30 – 2.20 (m, 1H)*, 1.96 (dd, J = 13.1, 5.7 Hz, 1H),

1.71 (t, J = 4.6 Hz, 1H), 1.26 (dd, J = 13.4, 6.0 Hz, 1H)*, 1.19 (s, 3H), 0.58 (s, 3H); 13C NMR

(176 MHz, CDCl3) δ 166.8, 164.5, 158.5, 158.1, 152.2, 148.7, 133.2, 131.5, 130.8, 130.3,

114.6, 114.0, 113.6, 112.7, 55.8, 55.5, 55.4, 55.3, 51.0, 50.8, 49.0, 45.6, 36.8, 35.4, 33.5,

20.4, 14.8.

*Peaks overlapping with monoarylation product

31


2-yl)picolinamide 2h

Prepared according to general arylation procedure A, using 4-bromoanisole on a 0.1 mmol

scale. Purified by flash column chromatography (0 – 20 % EtOAc in petrol) to give the

product as a yellow solid (34 mg, 0.086 mmol, 86%).

M.p 137-140 °C; [α]D24 +62.5 (c = 0.8, CHCl3); νmax (film/cm-1) 3384 (NH), 2954 (CH), 2931

(CH), 1672 (CO), 1508 (CC); 1H NMR (700 MHz, CDCl3) δ 7.91 – 7.88 (m, 1H), 7.87 (d, J =

2.9 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 8.6, 2.9 Hz, 1H),

6.90 (d, J = 8.7 Hz, 2H), 4.50 – 4.44 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.29 (dd, J = 11.7,

5.2 Hz, 1H), 2.53 (ddd, J = 14.4, 8.2, 4.7 Hz, 1H), 2.24 (tt, J = 12.7, 3.8 Hz, 1H), 2.01 (dd, J

= 13.1, 5.7 Hz, 1H), 1.91 (t, J = 4.6 Hz, 1H), 1.25 – 1.23 (m, 1H), 1.08 (2 × s, 6H), 1.05 (s,

3H); 13C NMR (176 MHz, CDCl3) δ 164.4, 158.3, 157.4, 142.9, 135.6, 133.9, 129.8, 122.8,

120.0, 114.5, 55.7, 55.2, 54.4, 53.8, 50.9, 46.9, 43.7, 37.0, 32.9, 20.3, 20.0, 13.8; HRMS

found (ES) [M+H]+ 395.2338 C24H31N2O3+H requires 395.2335.


2-yl)picolinamide 2h and 5-Methoxy-N-((1S,2S,4R,6S)-1-(4-methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 3h

32


scale. Purified by flash column chromatography (0 – 20% EtOAc in petrol) to give a mixture

of the mono and di arylated products. (32 mg, 79%).

Mono 2h (0.071 mmol, 71%)

Di 3h (0.008 mmol, 8%)

3h: 1H NMR (700 MHz, CDCl3) δ 8.00 – 7.98 (m, 1H), 7.91 – 7.89 (m, 1H)*, 7.88 – 7.85 (m,

1H)*, 7.45 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 8.6, 2.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.94

(d, J = 8.8 Hz, 2H), 6.79 – 6.74 (m, 2H), 4.76 – 4.71 (m, 1H), 3.87 (s, 6H), 3.74 (s, 3H), 3.50

(dd, J = 12.0, 4.7 Hz, 1H), 3.05 (d, J = 14.3 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 2.56 – 2.50

(m, 1H)*, 2.29 – 2.21 (m, 1H)*, 1.97 (dd, J = 13.2, 5.7 Hz, 1H), 1.70 (t, J = 4.6 Hz, 1H), 1.26

– 1.24 (m, 1H), 1.19 (s, 3H), 0.57 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 164.4, 158.7, 158.0,

157.5, 143.0, 135.7, 133.3, 131.5, 130.8, 130.3, 122.9, 120.1, 114.5, 113.6, 55.8, 55.7,

55.32, 55.26, 50.9, 50.7, 49.0, 36.9, 35.4, 33.5, 29.8, 21.0, 20.4.

*Peaks overlapping with the monoarylation product


phenylpicolinamide 2i

Prepared according to general arylation procedure A, on a 0.1 mmol scale using 4-

bromoanisole. Purified by flash column chromatography (0 – 20% EtOAc in cyclohexane) to

give the product as a colourless oil (35 mg, 0.080 mmol, 80%).


7.38 – 7.27 (m, 6H), 7.22 – 7.14 (m, 3H), 6.86 (t, J = 5.9 Hz, 2H), 4.33 (dddd, J = 11.3, 9.4,

5.9, 1.9 Hz, 1H), 3.74 (s, 3H), 3.25 (dd, J = 11.8, 4.8 Hz, 1H), 2.51 – 2.40 (m, 1H), 2.26 –

2.16 (m, 1H), 1.95 (dd, J = 13.1, 5.9 Hz, 1H), 1.86 (t, J = 4.6 Hz, 1H), 1.15 (dd, J = 13.3, 5.9

Hz, 1H), 1.04 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H); 13C NMR (176 MHz, CDCl3) δ 165.3, 158.2,

148.7, 146.6, 139.6, 139.4, 137.3, 134.1, 129.9, 128.5, 128.0, 127.5, 124.5, 114.3, 55.3,

54.3, 53.8, 50.8, 47.0, 43.72, 37.1, 32.9, 27.1, 20.3, 20.0, 13.6.

33


phenylpicolinamide 2i and N-((1S,2S,4R,6S)-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-

7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-phenylpicolinamide 3i

Prepared according to general arylation procedure A, on a 0.1 mmol scale using 4-

iodoanisole. Purified by flash column chromatography (0 – 20% EtOAc in cyclohexane) to

give a mixture of the mono and diarylated products (36 mg, 78%).

Mono 2i (0.065 mmol, 65%)

Di 3i (0.013 mmol, 13%)

3i: 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 4.7, 1.6 Hz, 1H), 7.57 (dd, J = 7.8, 1.7 Hz, 1H),

7.44 (d, J = 8.7 Hz, 2H), 7.38 – 7.26 (m, 6H), 7.21 – 7.18 (m, 1H)*, 7.15 (s, 1H), 7.02 (d, J =

8.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.76 – 6.71 (m, 2H), 4.67 – 4.59 (m, 1H), 3.80 (s, 3H),

3.75 (s, 3H), 3.47 (dd, J = 11.9, 5.2 Hz, 1H), 2.95 (d, J = 14.3 Hz, 1H), 2.76 (d, J = 14.2 Hz,

1H), 2.50 – 2.41 (m, 1H)*, 2.26 – 2.13 (m, 1H)*, 1.98 – 1.93 (m, 1H)*, 1.66 (t, J = 4.6 Hz,

1H), 1.16 (s, 3H), 1.16 – 1.12 (m, 1H)*, 0.49 (s, 3H).

*Peaks overlapping with the monoarylation product

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)picolinamide 5a




34


MHz, CDCl3) δ 8.54 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.19 (dt, J = 7.8, 1.1 Hz, 1H), 8.11 (s,

1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.13 – 7.10 (m, 2H),

6.85 – 6.82 (m, 2H), 3.79 (s, 3H), 3.35 (d, J = 6.4 Hz, 2H), 2.64 (s, 2H), 1.58 (m, 4H), 1.47

(dd, J = 11.7, 6.0 Hz, 1H), 1.43 – 1.41 (m, 2H), 1.40 – 1.36 (m, 3H); 13C NMR (176 MHz,

CDCl3) δ 164.4, 158.2, 150.2, 148.2, 137.4, 131.5, 130.2, 126.1, 122.3, 113.7, 55.3, 44.9,


requires 339.2072.

N-(1-(4-methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)picolinamide 6a

Isolated from the reaction to from 5a, d.r 85:15 (10 mg, 0.022 mmol, 22%).


MHz, CDCl3) δ 8.24 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.04 (dt, J = 7.8, 1.0 Hz, 1H), 7.73 (td, J

= 7.7, 1.7 Hz, 1H), 7.35 (m, 1H), 7.29 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 7.23 – 7.21 (m, 2H),

7.07 – 7.04 (m, 2H), 6.85 – 6.83 (m, 2H), 6.82 – 6.79 (m, 2H), 4.28 (dd, J = 13.1, 9.2 Hz,

1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.10 – 3.06 (m, 1H), 2.75 (d, J = 13.5 Hz, 1H), 2.64 (dd, J =

12.8, 3.5 Hz, 1H), 2.50 (d, J = 13.5 Hz, 1H), 2.17 (qd, J = 12.9, 3.9 Hz, 1H), 1.89 (dd, J =

17.2, 13.8 Hz, 2H), 1.76 – 1.71 (m, 1H), 1.54 – 1.51 (m, 1H), 1.46 (dt, J = 13.4, 3.3 Hz, 1H),

1.27 – 1.24 (m, 2H); 13C NMR (176 MHz, CDCl3) δ 164.1, 158.6, 158.3, 150.0, 147.7, 137.1,

134.8, 131.4, 130.5, 130.5, 125.8, 121.8, 114.0, 113.4, 55.4, 55.3, 52.7, 47.0, 41.4, 40.5,


N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-3-methylpicolinamide 5b

35





MHz, CDCl3) δ 8.36 (dd, J = 4.5, 1.0 Hz, 1H), 8.18 (s, 1H), 7.57 (dd, J = 7.7, 0.8 Hz, 1H),

7.29 (dd, J = 7.7, 4.6 Hz, 1H), 7.10 (t, J = 5.7 Hz, 2H), 6.84 – 6.81 (m, 2H), 3.78 (s, 3H), 3.31

(d, J = 6.3 Hz, 2H), 2.74 (s, 3H), 2.63 (s, 2H), 1.59 – 1.55 (m, 4H), 1.49 – 1.43 (m, 2H), 1.42

(t, J = 4.9 Hz, 1H), 1.37 (m, 3H); 13C NMR (176 MHz, CDCl3) δ 166.1, 158.2, 147.6, 145.5,

140.9, 135.4, 131.5, 130.3, 125.6, 113.7, 55.3, 44.7, 42.9, 38.1, 33.6, 29.8, 26.3, 21.8, 20.6;

HRMS found (ES) [M+H]+ 353.2230 C22H28N2O2+H requires 353.2229.

N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-3-methylpicolinamide 6b

Isolated from the reaction to form 5b, d.r 84:16 (2 mg, 0.005 mmol, 5%).


MHz, CDCl3) δ 8.06 – 8.03 (m, 1H), 7.46 (ddd, J = 7.7, 1.6, 0.7 Hz, 1H), 7.43 (d, J = 7.4 Hz,

1H), 7.23 – 7.21 (m, 2H), 7.17 (dd, J = 7.7, 4.6 Hz, 1H), 7.07 – 7.04 (m, 2H), 6.85 – 6.83 (m,

2H), 6.80 – 6.78 (m, 2H), 4.27 (dd, J = 12.9, 9.2 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.01 (dd,

J = 13.9, 2.8 Hz, 1H), 2.73 (d, J = 13.1, 1H), 2.67 (s, 3H), 2.65 – 2.62 (m, 1H), 2.49 (d, J =

36

13.4 Hz, 1H), 2.18 (qd, J = 13.0, 3.4 Hz, 1H), 1.92 (d, J = 13.5 Hz, 1H), 1.87 (d, J = 12.9 Hz,

1H), 1.72 (d, J = 14.1 Hz, 1H), 1.52 (s, 1H), 1.50 – 1.44 (m, 1H), 1.40 – 1.34 (m, 1H), 1.27

(dd, J = 8.0, 4.2 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ 165.7, 158.4, 158.2, 147.3, 145.1,

140.6, 134.9, 134.9, 131.5, 130.59, 130.55, 125.3, 113.9, 113.4, 55.34, 55.26, 52.8, 47.2,

41.5, 40.1, 34.4, 29.4, 27.0, 21.9, 20.6; HRMS found (ES) [M+H]+ 459.2659 C28H32N2O3+H

requires 459.2648.

N-((1-(4-methoxybenzyl)cyclohexyl)methyl)-4-methylpicolinamide 5c



product as a white solid (27 mg, 0.077 mmol, 77%).

νmax (film/cm-1) 3376 (NH), 2908 (CH), 2865 (CH), 2850 (CH), 1663 (CO), 1511 (CC); 1H

NMR (700 MHz, CDCl3) δ 8.38 (d, J = 4.9 Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.22 (d, J = 4.5

Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 3.78 (s, 3H), 3.33 (d, J = 6.3 Hz,

2H), 2.62 (s, 2H), 2.42 (s, 3H), 1.60 – 1.53 (m, 4H), 1.50 – 1.44 (m, 1H), 1.43 – 1.33 (m, 5H);

13C NMR (176 MHz, CDCl3) δ 164.7, 158.2, 150.0, 148.9, 148.0, 131.5, 130.2, 126.9, 123.2,

113.7, 55.3, 44.8, 42.7, 38.1, 33.5, 26.3, 21.8, 21.2; HRMS found (ES) [M+H]+ 353.2221


N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-4-methylpicolinamide

6c

37

Isolated from the reaction to form 5c, d.r 85:15 (4 mg, 0.009 mmol, 9%).


MHz, CDCl3) δ 8.09 (d, J = 4.8 Hz, 1H), 7.87 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.22 (d, J =

8.2 Hz, 2H), 7.10 (d, J = 4.4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 7.9 Hz, 2H), 6.80

(d, J = 8.0 Hz, 2H), 4.26 (dd, J = 13.8, 9.2 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.07 (d, J =

14.0 Hz, 1H), 2.74 (d, J = 13.5 Hz, 1H), 2.67 – 2.61 (m, 1H), 2.50 (d, J = 13.5 Hz, 1H), 2.36

(s, 3H), 2.21 – 2.13 (m, 1H), 1.87 (t, J = 11.3 Hz, 2H), 1.76 – 1.70 (m, 1H), 1.51 – 1.43 (m,

2H), 1.39 – 1.31 (m, 3H); 13C NMR (176 MHz, CDCl3) δ 164.3, 158.5, 158.3, 149.8, 148.4,

147.6, 134.9, 131.4, 130.6, 130.5, 126.6, 122.7, 113.9, 113.4, 55.3, 55.3, 52.7, 46.9, 41.5,


requires 459.2648.

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-5-methylpicolinamide 5d





MHz, CDCl3) δ 8.35 (dd, J = 1.4, 0.7 Hz, 1H), 8.10 – 8.04 (m, 2H), 7.65 – 7.61 (m, 1H), 7.12

– 7.08 (m, 2H), 6.86 – 6.79 (m, 2H), 3.79 (s, 3H), 3.33 (d, J = 6.4 Hz, 2H), 2.64 – 2.62 (m,

2H), 2.42 (s, 3H), 1.60 – 1.55 (m, 4H), 1.50 – 1.44 (m, 1H), 1.44 – 1.34 (m, 5H); 13C NMR

38

(176 MHz, CDCl3) δ 164.7, 158.2, 148.7, 147.8, 137.7, 136.2, 131.5, 130.2, 121.9, 113.7,

55.3, 44.8, 42.7, 38.1, 33.5, 26.3, 21.8, 18.7; HRMS found (ES) [M+H]+ 353.2234



6d

Isolated from the reaction to form 5d, dr 85:15 (5 mg, 0.011 mmol, 11%).


MHz, CDCl3) δ 8.06 – 8.05 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.52 (ddd, J = 7.9, 2.2, 0.7 Hz,

1H), 7.30 (d, J = 6.8 Hz, 1H), 7.23 – 7.21 (m, 2H), 7.07 – 7.04 (m, 2H), 6.85 – 6.83 (m, 2H),

6.82 – 6.79 (m, 2H), 4.25 (dd, J = 13.6, 9.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.07 (dd, J =

13.9, 3.0 Hz, 1H), 2.74 (d, J = 13.5 Hz, 1H), 2.66 – 2.61 (m, 1H), 2.50 (d, J = 13.5 Hz, 1H),

2.33 (s, 3H), 2.17 (qd, J = 13.0, 3.9 Hz, 1H), 1.88 (t, J = 12.5 Hz, 2H), 1.72 (d, J = 11.0 Hz,

1H), 1.54 – 1.52 (m, 1H), 1.50 – 1.44 (m, 1H), 1.36 (ddd, J = 12.2, 6.0, 3.0 Hz, 1H), 1.28 –

1.26 (m, 1H); 13C NMR (176 MHz, CDCl3) δ 164.3, 158.5, 158.3, 148.3, 147.6, 137.4, 135.8,

134.9, 131.4, 130.6, 130.5, 121.4, 113.9, 113.4, 55.33, 55.30, 55.27, 52.7, 46.9, 41.4, 40.4,

34.4, 29.4, 27.0, 21.9, 18.6. HRMS found (ES) [M+H]+ 459.2652 C29H34N2O3+H requires

459.2648.

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-3-(trifluoromethyl)picolinamide 5e

39


scale. Purified by flash column chromatography (0 – 20% EtOAc in petrol) to give the mono

and diarylated products as an inseparable mixture (15 mg, 35%).

νmax (film/cm-1) 3363 (NH), 2923 (CH), 2852 (CH), 189 (CO), 1510 (CC); 1H NMR (700 MHz,

CDCl3) δ 8.67 (dd, J = 4.7, 1.4 Hz, 1H), 8.15 (dd, J = 8.1, 1.1 Hz, 1H), 7.54 (dd, J = 7.9, 4.8

Hz, 2H), 7.11 – 7.08 (m, 2H), 6.84 – 6.81 (m, 2H), 3.78 (s, 3H), 3.37 (d, J = 6.3 Hz, 2H), 2.62

(s, 2H), 1.59 – 1.55 (m, 6H), 1.47 (dd, J = 10.9, 5.0 Hz, 1H), 1.42 (d, J = 5.7 Hz, 1H), 1.39 –

1.37 (m, 2H); 13C NMR (176 MHz, CDCl3) δ 163.3, 158.3, 150.6, 149.9, 136.3 (q, J = 6.0 Hz

Hz), 131.4, 130.2, 126.0 (q, J = 34.4 Hz), 125.2, 123.0 (q, J = 273.2 Hz) 113.8, 55.3, 45.2,

43.2, 38.2, 33.6, 26.3, 21.8; HRMS found (ES) [M+H]+ 407.1932 C22H25N2O2F3+H requires

407.1946.

N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-3-(trifluoromethyl)picolinamide 6e

Isolated in the reaction to form 5e as an inseparable mixture. d.r = 88:12 (5%)

1H NMR (700 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.4 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.45 – 7.40

(m, 1H), 7.21 – 7.19 (m, 2H), 7.06 – 7.02 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.85 – 6.83 (m,

2H), 6.79 – 6.76 (m, 2H), 4.35 (dd, J = 13.9, 10.5 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.02 –

2.99 (m, 1H), 2.73 (d, J = 13.4 Hz, 1H), 2.65 – 2.63 (m, 1H), 2.49 (d, J = 12.9 Hz, 1H), 2.21 –

40

2.13 (m, 1H), 1.92 (d, J = 13.5 Hz, 1H), 1.88 (d, J = 13.1 Hz, 1H), 1.82 – 1.77 (m, 1H), 1.73

(t, J = 16.0 Hz, 2H); 13C NMR (176 MHz, CDCl3) δ 162.6, 158.5, 158.3, 150.0, 136.0 134.7,

131.4, 130.6, 130.5, 124.9, 113.9, 113.4, 55.3, 52.9, 47.4, 46.0, 41.5, 40.6, 35.6, 34.4, 27.0,

21.9; HRMS found (ES) [M+H]+ 407.1932 C22H25N2O2F3+H requires 407.1946.

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-5-(trifluoromethyl)picolinamide 5f





MHz, CDCl3) δ 8.81 – 8.78 (m, 1H), 8.32 (t, J = 8.9 Hz, 1H), 8.09 (dd, J = 8.2, 2.1 Hz, 1H),

8.05 – 7.92 (m, 1H), 7.13 – 7.08 (m, 2H), 6.86 – 6.82 (m, 2H), 3.79 (s, 3H), 3.37 (d, J = 6.4

Hz, 2H), 2.63 (s, 2H), 1.60 – 1.54 (m, 4H), 1.48 (dd, J = 11.0, 5.2 Hz, 1H), 1.45 – 1.37 (m,

5H); 13C NMR (176 MHz, CDCl3) δ 163.0, 158.3, 153.0, 145.2 (q, J = 3.9 Hz), 134.9 (q, J =

3.4 Hz), 131.4, 130.1, 128.8 (q, J = 33.3 Hz), 123.4 (q, J = 272.7 Hz), 122.1, 113.8, 55.3,

45.2, 43.1, 38.2, 33.6, 26.3, 21.8; HRMS found (ES) [M+H]+ 407.1939 C22H25N2O2F3+H

requires 407.1946.

N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-5-


41

Isolated from the reaction to form 5f, colourless oil d.r = 83:17 (9 mg, 0.018 mmol, 18%).


MHz, CDCl3) δ 8.49 (dd, J = 1.4, 0.7 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.99 (dd, J = 8.2, 2.2

Hz, 1H), 7.23 – 7.20 (m, 2H), 7.05 – 7.03 (m, 2H), 6.85 – 6.84 (m, 3H), 6.80 (dd, J = 5.7, 3.7

Hz, 2H), 4.28 (dd, J = 13.4, 9.7 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.09 – 3.05 (m, 1H), 2.78

– 2.74 (m, 1H), 2.65 (dd, J = 12.9, 3.5 Hz, 1H), 2.53 – 2.49 (m, 1H), 2.21 – 2.13 (m, 1H),

1.89 (s, 2H), 1.74 (d, J = 12.6 Hz, 1H), 1.53 (d, J = 4.3 Hz, 1H), 1.43 (dd, J = 5.8, 2.7 Hz,

1H), 1.39 – 1.34 (m, 2H); 13C NMR (176 MHz, CDCl3) δ 162.6, 158.6, 158.4, 152.8, 144.8 (q,

J = 3.9 Hz), 134.6, 134.5 (q, J = 3.5 Hz), 131.4, 131.3, 130.5, 130.4, 121.6, 114.0, 113.5,

55.3, 55.2, 52.8, 47.2, 41.0, 40.6, 34.4, 29.3, 26.9, 21.9; HRMS found (ES) [M+H]+ 513.2310

C29H31N2O3F3+H requires 513.2360.

4-Methoxy-N-((1-(4-methoxybenzyl)cyclohexyl)methyl)picolinamide 5g





MHz, CDCl3) δ 8.35 – 8.31 (m, 1H), 8.18 (s, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.12 – 7.09 (m,

2H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.85 – 6.81 (m, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.33 (d, J

= 5.6 Hz, 2H), 2.63 (s, 2H), 1.59 – 1.55 (m, 4H), 1.47 (dt, J = 17.8, 5.8 Hz, 1H), 1.43 – 1.34

(m, 5H); 13C NMR (176 MHz, CDCl3) δ 167.1, 164.4, 158.2, 152.3, 149.3, 131.5, 130.2,

113.7, 113.1, 107.3, 55.7, 55.3, 44.9, 42.7, 38.1, 33.5, 26.3, 21.8; HRMS found (ES) [M+H]+

369.217 C22H28N2O3 requires 369.2178.

4-Methoxy-N-((1-(4-methoxybenzyl)-2-(4-

methoxyphenyl)cyclohexyl)methyl)picolinamide 6g

42

Isolated from the reaction to form 5g. d.r = 81:19 (11 mg, 0.023 mmol, 23%).


MHz, CDCl3) δ 8.04 (d, J = 5.9 Hz, 1H), 7.59 (d, J = 4.2 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.23 –

7.21 (m, 2H), 7.07 – 7.03 (m, 2H), 6.85 – 6.84 (m, 2H), 6.80 (dd, J = 7.1, 1.5 Hz, 2H), 6.79

(d, J = 3.9 Hz, 1H), 4.26 (dd, J = 13.6, 9.4 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H),

3.07 (dd, J = 13.9, 3.0 Hz, 1H), 2.74 (d, J = 13.5 Hz, 1H), 2.64 (dd, J = 12.8, 3.5 Hz, 1H),

2.50 (d, J = 13.5 Hz, 1H), 2.16 (qd, J = 13.0, 3.9 Hz, 1H), 1.90 – 1.85 (m, 2H), 1.73 – 1.68

(m, 2H), 1.53 (s, 1H), 1.51 – 1.43 (m, 2H); 13C NMR (176 MHz, CDCl3) δ 166.8, 164.0,

158.6, 158.3, 152.1, 148.9, 134.8, 131.4, 130.5, 130.4, 114.0, 113.5, 112.7, 106.9, 55.5,

55.4, 55.3, 52.6, 46.9, 41.5, 40.6, 34.4, 29.4, 26.9, 21.9; HRMS found (ES) [M+H]+ 475.2582


5-Methoxy-N-((1-(4-methoxybenzyl)cyclohexyl)methyl)picolinamide 5h

Prepared according to general arylation procedure A, purified by flash column

chromatography (0 – 40% EtOAc in petrol), to give the product as a colourless oil (14 mg,

0.038 mmol, 38%).


MHz, CDCl3) δ 8.20 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.27 (dd, J =

8.6, 2.7 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 9.6 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H),

43

3.32 (d, J = 6.3 Hz, 2H), 2.62 (s, 2H), 1.57 (dt, J = 11.4, 5.5 Hz, 4H), 1.47 (td, J = 11.2, 5.3

Hz, 1H), 1.43 – 1.33 (m, 5H); 13C NMR (176 MHz, CDCl3) δ 164.4, 158.2, 157.9, 143.0,

136.5, 131.5, 130.2, 123.4, 120.3, 113.7, 55.9, 55.3, 44.8, 42.8, 38.1, 33.5, 26.3, 24.0, 21.8;



methoxyphenyl)cyclohexyl)methyl)picolinamide 6h

Isolated from the reaction to form 5h. d.r 86:14 (9 mg, 0.019 mmol, 19%).


MHz, CDCl3) δ 7.99 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.17

(dd, J = 8.7, 2.8 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4

Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.25 (dd, J = 13.9, 9.3 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H),

3.79 (s, 3H), 3.08 – 3.02 (m, 1H), 2.74 (d, J = 13.5 Hz, 1H), 2.66 – 2.60 (m, 1H), 2.49 (d, J =

13.5 Hz, 1H), 2.17 (qd, J = 13.2, 3.6 Hz, 1H), 1.88 (t, J = 13.1 Hz, 2H), 1.72 (d, J = 12.4 Hz,

1H), 1.52 (d, J = 8.5 Hz, 1H), 1.46 (d, J = 13.2 Hz, 1H), 1.36 (dd, J = 7.9, 3.9 Hz, 1H), 1.27 –

1.26 (m, 1H); 13C NMR (176 MHz, CDCl3) δ 164.0, 158.5, 158.3, 157.6, 142.8, 136.0, 134.9,

131.4, 130.6, 130.5, 122.9, 120.0, 113.9, 113.4, 55.8, 55.34, 55.26, 52.7, 47.0, 41.5, 40.4,


N-(2-(4-Methoxybenzyl)butyl)picolinamide 8a

44





MHz, CDCl3) δ 8.54 – 8.51 (m, 1H), 8.18 (dt, J = 7.8, 1.1 Hz, 1H), 8.10 – 7.98 (m, 1H), 7.83

(ddt, J = 7.8, 5.1, 2.5 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.13 – 7.10 (m, 2H), 6.83

– 6.81 (m, 2H), 3.77 (s, 3H), 3.45 (dt, J = 13.5, 6.3 Hz, 1H), 3.39 (dt, J = 13.6, 6.1 Hz, 1H),

2.64 (dd, J = 13.9, 6.9 Hz, 1H), 2.58 (dd, J = 14.0, 7.4 Hz, 1H), 1.92 – 1.85 (m, 1H), 1.44 –

1.38 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 164.5, 158.0, 150.2,

148.1, 137.4, 132.6, 130.1, 126.1, 122.3, 113.9, 55.4, 42.2, 42.1, 37.7, 24.4, 11.3; HRMS

found (ES) [M+H]+ 299.1758 C18H22N2O2+H requires 299.1758.

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)picolinamide 9a

Isolated as a mixture with the monoarylated product 8a.

1H NMR (400 MHz, CDCl3) δ 8.49 – 8.46 (m, 1H), 8.15 – 8.11 (m, 1H), 7.84 – 7.77 (m, 1H),

7.61 (s, 1H), 7.39 – 7.36 (m, 1H), 7.20 – 7.16 (m, 2H), 7.08 – 7.04 (m, 2H), 6.87 – 6.83 (m,

2H), 6.87 – 6.83 (m 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.54 (dd, J = 13.4, 6.4 Hz, 1H), 3.14 (dt,

J = 13.7, 5.7 Hz, 1H), 2.91 (dd, J = 13.7, 6.8 Hz, 1H), 2.76 (dd, J = 14.1, 4.5 Hz, 1H), 2.45

(dt, J = 17.9, 7.5 Hz, 1H), 2.14 (s, 1H), 1.37 – 1.36 (m, 3H).

N-(2-(4-Methoxybenzyl)butyl)-3-methylpicolinamide 8b

45



product as a mixture of mono and di arylated products (25 mg)

Mono 0.073 mmol, 73%


MHz, CDCl3) δ 8.36 (ddd, J = 4.6, 1.6, 0.5 Hz, 1H), 8.12 (s, 1H), 7.57 (ddd, J = 7.7, 1.6, 0.7

Hz, 1H), 7.30 – 7.27 (m, 1H), 7.13 – 7.09 (m, 2H), 6.83 – 6.80 (m, 2H), 3.77 (s, 3H), 3.42 (dt,

J = 13.5, 6.2 Hz, 1H), 3.34 (dt, J = 13.6, 6.2 Hz, 1H), 2.74 (s, 3H), 2.65 – 2.57 (m, 2H), 1.91

– 1.84 (m, 1H), 1.43 – 1.34 (m, 2H), 0.99 – 0.96 (m, 3H); 13C NMR (176 MHz, CDCl3) δ

166.1, 158.0, 147.5, 145.5, 140.9, 135.4, 132.7, 130.1, 125.6, 113.9, 55.4, 42.1, 42.0, 37.7,

24.4, 20.7, 11.2; HRMS found (ES) [M+H]+ 313.1915 C19H24N2O2+H requires 313.1916.

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)-3-methylpicolinamide 9b

Isolated as a mixture with the monoarylated product 8a, 0.005 mmol, 5%.

1H NMR (700 MHz, CDCl3) δ 8.39 – 8.37 (m, 1H), 7.92 (s, 1H), 7.55 - 7.53 (m, 1H), 7.19 –

7.16 (m, 2H), 7.07 – 7.05 (m, 3H), 6.86 – 6.83 (m, 2H), 6.79 – 6.77 (m, 2H), 3.78 (s, 3H),

3.75 (s, 3H), 3.54 – 3.50 (m, 1H), 3.24 (ddd, J = 13.4, 7.2, 6.3 Hz, 1H), 3.14 – 3.09 (m, 1H),

2.91 (dd, J = 13.4, 6.7 Hz, 1H), 2.71 (s, 3H), 2.46 (dd, J = 14.1, 9.0 Hz, 1H), 2.41 – 2.33 (m,

1H), 1.36 - 1.35 (m, 3H); HRMS found (ES) [M+H]+ 419.2339 C26H30N2O3+H requires

419.2335.

N-(2-(4-Methoxybenzyl)butyl)-4-methylpicolinamide 8c

46


scale. Purified by flash column chromatography to give the product as a colourless oil (8 mg,

0.0256 mmol, 26%).


MHz, CDCl3) δ 8.39 – 8.35 (m, 1H), 8.03 (s, 1H), 8.02 – 8.01 (m, 1H), 7.22 (ddd, J = 4.9, 1.7,

0.7 Hz, 1H), 7.13 – 7.09 (m, 2H), 6.84 – 6.80 (m, 2H), 3.77 (s, 3H), 3.44 (dt, J = 13.5, 6.3 Hz,

1H), 3.39 (dt, J = 13.6, 6.1 Hz, 1H), 2.63 (dd, J = 13.9, 6.9 Hz, 1H), 2.57 (dd, J = 13.9, 7.4

Hz, 1H), 2.42 (s, 3H), 1.91 – 1.84 (m, 1H), 1.43 – 1.38 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H,); 13C

NMR (176 MHz, CDCl3) δ 164.7, 158.0, 149.9, 148.9, 148.0, 132.6, 130.1, 126.9, 123.2,

113.9, 55.4, 42.2, 42.0, 37.6, 24.4, 21.3, 11.2; HRMS found (ES) [M+H]+ 313.1917


N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)-4-methylpicolinamide 9c

Isolated in the reaction to form 8c. Yellow oil. 11 mg, 0.026 mmol, 26%; The 1H NMR

signals for these compounds were assigned by using TOCSY NMR experiments (vide infra).

9c: 1H NMR (700 MHz, CDCl3) δ 8.35 (dd, J = 4.9, 0.5 Hz, 1H, pyNCH), 8.01 – 7.99 (m, 1H,

pyNCCH), 7.93 (s, 1H, NH), 7.23 – 7.22 (m, 1H, pyNCHCH), 7.16 – 7.14 (m, 2H, OCCHCH),

7.08 – 7.06 (m, 2H, OCCHCH), 6.85 – 6.84 (m, 2H, OCCH), 6.80 – 6.78 (m, 2H OCCH),

47

3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.52 – 3.50 (m, 1H, NHCH2), 3.42 – 3.40 (m, 1H,

NHCH2), 2.85 – 2.82 (m, 1H, ArCH), 2.66 (s, 1H, ArCH2), 2.43 (s, 3H, ArCH3), 2.38 – 2.36

(m, 1H, ArCH2), 2.13 – 2.11 (m, 1H, ArCHCH), 1.37 – 1.35 (m, 3H, CHCH3).

1H NMR (700 MHz, CDCl3) δ 8.34 (dd, J = 4.9, 0.5 Hz, 1H, pyNCH), 7.98 – 7.97 (m, 1H,

PyNCCH), 7.88 (s, 1H, NH), 7.21 – 7.20 (m, 1H, pyNCHCH), 7.19 – 7.17 (m, 2H, OCCHCH),

7.08 – 7.06 (m, 2H, OCCHCH), 6.86 – 6.84 (m, 2H, OCCH), 6.79 – 6.78 (m, 2H, OCCH),

3.79 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.56 – 3.52 (m, 1H, NHCH2), 3.15 – 3.11 (m, 1H,

NHCH2), 2.92 – 2.88 (m, 1H, ArCH), 2.75 (dd, J = 14.1, 4.5 Hz, 1H, ArCH2), 2.47 – 2.44 (m,

1H, ArCH2), 2.41 (s, 3H, ArCH3), 2.16 – 2.13 (m, 1H, ArCHCH), 1.39 – 1.36 (m, 3H, CHCH3).

10c: 1H NMR (700 MHz, CDCl3) δ 8.37 (dd, J = 4.9, 0.8 Hz, 1H, pyNCH), 8.07 (s, 1H, NH),

8.03 – 8.02 (m, 1H, pyNCCH), 7.24 – 7.22 (m, 1H, pyNCHCH), 7.11 – 7.09 (m, 2H,

OCCHCH), 7.07 - 7.05 (m, 2H, OCCHCH), 6.82 – 6.81 (m, 2H, OCCH), 6.79 – 6.78 (m, 2H,

OCCH), 3.79 (s, 3H OCH3), 3.78 (s, 3H, OCH3), 3.51 – 3.48 (m, 1H, NHCH2), 3.46 – 3.44

(m, 1H, NHCH2), 2.69 – 2.61 (m, 4H, ArCH2), 2.43 (s, 3H, ArCH3), 2.00 – 1.96 (m, 1H,

NHCH2CH), 1.68 – 1.63 (m, 2H, CHCH2CH2).

N-(2-(4-methoxybenzyl)butyl)-5-methylpicolinamide 8d



product as a yellow oil (27 mg, 0.087 mmol, 87%).

1H NMR (700 MHz, CDCl3) δ 8.34 (dd, J = 1.4, 0.7 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.96 (s,

1H), 7.64 – 7.61 (m, 1H), 7.13 – 7.09 (m, 2H), 6.84 – 6.79 (m, 2H), 3.77 (s, 3H), 3.46 – 3.41

(m, 1H), 3.38 (dt, J = 13.6, 6.1 Hz, 1H), 2.63 (dd, J = 13.9, 6.9 Hz, 1H), 2.57 (dd, J = 13.9,

7.3 Hz, 1H), 2.39 (s, 3H), 1.91 – 1.84 (m, 1H), 1.42 – 1.37 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H);

13C NMR (176 MHz, CDCl3) δ 164.7, 158.0, 148.6, 147.7, 137.8, 136.3, 132.6, 130.1, 121.9,

113.9, 55.3, 42.2, 42.0, 37.6, 24.4, 18.6, 11.2; HRMS found (ES) [M+H]+ 313.1914


48

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)-5-methylpicolinamide 9d

Isolated as a mixture with the monoarylated product 8d (0.011 mmol, 11%)

1H NMR (400 MHz, CDCl3) δ 8.31 – 8.29 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.60

(d, J = 6.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.07 – 7.05 (m, 2H), 6.87 – 6.84 (m, 2H), 6.79 –

6.76 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.53 (dd, J = 13.4, 6.6 Hz, 1H), 3.16 – 3.09 (m, 1H),

2.93 – 2.88 (m, 1H), 2.74 (dd, J = 14.1, 4.6 Hz, 1H), 2.44 (dd, J = 14.0, 9.2 Hz, 1H), 2.39 (s,

3H), 1.37 (d, J = 7.1 Hz, 3H).

N-(2-(4-Methoxybenzyl)butyl)-3-(trifluoromethyl)picolinamide 8e



monoarylated product as a colourless oil (17 mg) and a mixture of monoarylated and

diarylated (7 mg).

Mono (17 mg, 0.046 mmol, 46%)

1H NMR (700 MHz, CDCl3) δ 8.68 (dd, J = 4.7, 1.4 Hz, 1H), 8.15 (dt, J = 8.0, 3.9 Hz, 1H),

7.54 (dd, J = 7.6, 4.7 Hz, 2H), 7.12 – 7.08 (m, 2H), 6.83 – 6.79 (m, 2H), 3.77 (s, 3H), 3.49

(dt, J = 13.6, 6.2 Hz, 1H), 3.39 – 3.34 (m, 1H), 2.65 (dd, J = 13.9, 6.9 Hz, 1H), 2.57 (dd, J =

13.9, 7.4 Hz, 1H), 1.93 – 1.86 (m, 1H), 1.43 – 1.38 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C

NMR (176 MHz, CDCl3) δ 163.3, 158.0, 150.6, 149.8, 136.3 (q, J = 5.9 Hz), 132.5, 130.1,

126.0 (q, J = 34.3 Hz), 125.2, 123.0 (q, J = 273.3 Hz), 114.0, 55.4, 42.6, 42.0, 37.8, 24.5,

11.2; HRMS found (ES) [M+H]+ 367.1633 C19H21N2O2F3+H requires 367.1633.

49

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)-3-(trifluoromethyl)picolinamide 9e

Isolated with the monoarylated compound 8e (0.002 mmol, 2%).

1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.18 – 7.14 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.87

– 6.82 (m, 2H), 6.76 (d, J = 3.3 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.53 – 3.51 (m, 1H), 3.21

– 3.11 (m, 1H), 2.91 (m, 1H), 2.73 (m, 1H), 2.50 – 2.40 (m, 1H), 2.13 – 2.06 (m, 1H), 1.38 –

1.36 (m, 3H).

N-(2-(4-Methoxybenzyl)butyl)-5-(trifluoromethyl)picolinamide 8f





MHz, CDCl3) δ 8.79 – 8.77 (m, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.10 – 8.06 (m, 1H), 7.94 (s,

1H), 7.12 – 7.09 (m, 2H), 6.83 – 6.80 (m, 2H), 3.77 (s, 3H), 3.50 – 3.46 (m, 1H), 3.40 (dt, J =

13.6, 6.2 Hz, 1H), 2.67 (dd, J = 14.0, 6.6 Hz, 1H), 2.56 – 2.53 (m, 1H), 1.90 (dt, J = 13.8, 6.4

Hz, 1H), 1.41 (dq, J = 14.2, 7.2 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (176 MHz, CDCl3)

δ 163.0, 158.1, 153.0, 145.2 (q, J = 3.9 Hz), 134.8 (q, J = 3.4 Hz), 132.4, 130.1, 128.8 (q, J =

33.3 Hz), 123.3 (q, J = 272.7), 122.1, 114.0, 55.3, 42.4, 42.1, 37.9, 24.6, 11.3; HRMS found

(ES) [M+H]+ 367.1621, C19H21N2O2F3+H requires 367.1628.

50

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)butyl)-5-(trifluoromethyl)picolinamide 9f

Isolated with the monoaryl compound 8f (0.004 mmol, 4%).

1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.18 – 7.16

(m, 2H), 6.88 – 6.83 (m, 2H), 6.79 – 6.75 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.60 – 3.52 (m,

1H), 3.22 – 3.13 (m, 1H), 2.89 – 2.79 (m, 1H), 2.47 – 2.33 (m, 1H), 2.19 – 2.12 (m, 1H), 2.01

– 1.99 (m, 1H), 1.39 (d, J = 7.1 Hz, 3H); HRMS found (ES) [M+H]+ 473.2033,

C26H27N2O3F3+H requires 473.2034

4-Methoxy-N-(2-(4-methoxybenzyl)butyl)picolinamide 8g





MHz, CDCl3) δ 8.32 – 8.30 (m, 1H), 8.06 (s, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.13 – 7.08 (m,

2H), 6.91 – 6.89 (m, 1H), 6.84 – 6.81 (m, 2H), 3.91 (s, 3H), 3.78 (s, 3H), 3.45 – 3.36 (m, 2H),

2.63 (dd, J = 13.9, 6.9 Hz, 1H), 2.57 (dd, J = 14.0, 7.4 Hz, 1H), 1.91 – 1.83 (m, 1H), 1.42 –

1.38 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ 167.1, 164.4, 158.0,

152.2, 149.2, 132.6, 130.1, 113.9, 113.1, 107.3, 55.7, 55.4, 42.2, 42.1, 37.6, 24.4, 11.3;


51

4-Methoxy-N-(2-(4-methoxybenzyl)-3-(4-methoxyphenyl)butyl)picolinamide 9g

Not isolated.

5-Methoxy-N-(2-(4-methoxybenzyl)butyl)picolinamide 8h


scale. Purified by flash column chromatography to give a mixture of the mono and di arylated

products (31 mg).

Mono 0.082 mmol, 82%


MHz, CDCl3) δ 8.18 (dd, J = 2.9, 0.5 Hz, 1H), 8.13 (dd, J = 8.6, 0.5 Hz, 1H), 7.84 (s, 1H),

7.28 – 7.26 (m, 1H), 7.12 – 7.10 (m, 2H), 6.83 – 6.81 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.45

– 3.41 (m, 1H), 3.39 – 3.35 (m, 1H), 2.62 (dd, J = 13.9, 6.9 Hz, 1H), 2.57 (dd, J = 13.9, 7.3

Hz, 1H), 1.86 (dq, J = 13.1, 6.6 Hz, 1H), 1.42 – 1.36 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H); 13C

NMR (176 MHz, CDCl3) δ 164.4, 158.0, 157.9, 142.9, 136.5, 132.6, 130.1, 123.4, 120.3,

113.9, 55.9, 55.3, 42.2, 42.1, 37.7, 24.4, 11.3; HRMS found (ES) [M+H]+ 329.1871


5-Methoxy-N-(2-(4-methoxybenzyl)-3-(4-methoxyphenyl)butyl)picolinamide 9h

52

Isolated as a mixture with 8h (0.009 mmol, 9%).

1H NMR (700 MHz, CDCl3) δ 8.20 – 8.19 (m, 1H), 8.16 – 8.15 (m, 1H), 8.08 (dd, J = 8.7, 0.5

Hz, 1H), 7.68 (m, 1H), 7.18 – 7.16 (m, 2H), 7.06 (dd, J = 5.3, 3.2 Hz, 2H), 6.86 – 6.84 (m,

2H), 6.79 – 6.77 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.56 – 3.51 (m, 1H), 3.12

(dt, J = 13.7, 5.6 Hz, 1H), 2.90 (p, J = 7.1 Hz, 1H), 2.74 (dd, J = 14.1, 4.5 Hz, 1H), 2.44 (dd,

J = 14.1, 9.3 Hz, 1H), 2.38 – 2.33 (m, 1H), 1.37 – 1.35 (m, 3H); HRMS found (ES) [M+H]+

435.2261 C26H30N2O4+H requires 435.2284.

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)propyl)picolinamide 13a



product as a yellow oil (53 mg, 0.14 mmol, 68%).

νmax (solid/cm-1) 3364 (NH), 2909 (CH), 2852 (CH), 1660 (CO), 1520 (CC); 1H NMR (400

MHz, CDCl3) δ 8.51 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17 (dt, J = 7.8, 1.1 Hz, 1H), 8.00 (s,

1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.40 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.14 – 7.06 (m, 4H),

6.85 – 6.79 (m, 4H), 3.77 (s, 6H), 3.41 (t, J = 6.2 Hz, 2H), 2.67 – 2.56 (m, 4H), 2.31 – 2.18

(m, 1H); 13C NMR (176 MHz, CDCl3) δ 164.3, 158.1, 149.9, 147.9, 137.6, 132.3, 130.1,

126.2, 122.4, 114.0, 55.4, 42.9, 42.4, 37.9; HRMS found (ES) [M+H]+ 391.2007,


N-(3-(4-methoxyphenyl)-2-methylpropyl)picolinamide 12a

53

Isolated from the reaction to form 13a, (0.024 mmol, 12%).

1H NMR (400 MHz, CDCl3) δ 8.55 – 8.51 (m, 1H), 8.22 – 8.18 (m, 1H), 8.13 (s, 1H), 7.85 –

7.79 (m, 1H), 7.41 – 7.36 (m, 1H), 7.22 – 7.16 (m, 2H), 6.77 – 6.72 (m, 2H), 3.77 (s, 3H),

3.46 – 3.43 (m, 1H), 3.37 – 3.35 (m, 1H), 2.70 – 2.68 (m, 1H), 2.45 – 2.41 (m, 1H), 2.09 –

2.05 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H).

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)propyl)-3-methylpicolinamide 13b




νmax (solid/cm-1) 3351 (NH), 2952 (CH), 2871 (CH), 1664 (CO), 1518 (CC); 1H NMR (700

MHz, CDCl3) δ 8.33 (ddd, J = 4.6, 1.6, 0.5 Hz, 1H), 8.09 (t, J = 5.6 Hz, 1H), 7.57 – 7.54 (m,

1H), 7.29 – 7.26 (m, 1H), 7.12 – 7.07 (m, 4H), 6.83 – 6.79 (m, 4H), 3.77 (s, 6H), 3.39 – 3.36

(m, 2H), 2.73 (s, 3H), 2.65 – 2.58 (m, 4H), 2.26 – 2.19 (m, 1H); 13C NMR (176 MHz, CDCl3)

δ 166.1, 158.0, 147.4, 145.4, 140.9, 135.4, 132.4, 130.2, 125.6, 114.0, 55.4, 42.9, 42.3,

37.9, 20.7; HRMS found (ES) [M+H]+ 405.2165, C25H28N2O3+H requires 405.2173.

N-(3-(4-methoxyphenyl)-2-methylpropyl)-3-methylpicolinamide 12b

54

Isolated from the reaction to form 13b, (0.046 mmol, 23%)

1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.6 Hz, 1H), 8.02 (s, 1H), 7.66 (dd, J = 4.7, 3.8 Hz,

1H), 7.42 (dd, J = 7.8, 4.6 Hz, 1H), 7.12 – 7.06 (m, 2H), 6.84 – 6.79 (m, 2H), 3.78 (s, 3H),

3.39 (dd, J = 12.9, 6.7 Hz, 1H), 3.34 – 3.29 (m, 1H), 2.73 – 2.67 (m, 1H), 2.59 (s, 3H), 2.44 –

2.42 (m, 4H), 2.07 – 2.03 (m, 1H), 0.95 (d, J = 6.7 Hz, 3H).

N-(3-(4-fluorophenyl)cyclohexyl)picolinamide 15a

Prepared according to general arylation procedure B on a 0.2 mmol scale using 4-

iodofluorobenzene at 130 °C. Purified by flash column chromatography (0 – 40 % EtOAc in

petrol) Product was further purified by recrystalisation from hot petrol/CHCl3 to give the

product as a white crystalline solid (48 mg, 0.16 mmol, 80%).

M.p 96-99 °C; νmax (film/cm-1) 3354 (NH), 2932 (CH), 2857 (CH), 1650 (CO), 1525 (CC); 1H

NMR (500 MHz, CDCl3) δ 8.53 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.20 (dt, J = 7.8, 1.1 Hz, 1H),

7.97 (d, J = 8.1 Hz, 1H), 7.90 – 7.77 (m, 1H), 7.46 – 7.36 (m, 1H), 7.23 – 7.12 (m, 2H), 7.04

– 6.90 (m, 2H), 4.12 (tdt, J = 12.3, 8.3, 4.0 Hz, 1H), 2.72 (tt, J = 12.3, 3.3 Hz, 1H), 2.32 –

2.23 (m, 1H), 2.19 – 2.11 (m, 1H), 2.00 – 1.93 (m, 1H), 1.93 – 1.87 (m, 1H), 1.59 (qt, J =

13.2, 3.5 Hz, 1H), 1.47 – 1.29 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 163.1, 161.0 (d, J =

243.5 Hz), 149.8, 147.7, 141.6 (d, J = 3.1 Hz), 137.1, 127.8 (d, J = 7.8 Hz), 125.8, 121.9,

114.8 (d, J = 21.0 Hz), 48.4, 42.1, 40.7, 33.1, 32.4, 24.8; HRMS found (ESI) [M+H]+

299.1554, C18H19N2O+H requires 299.1557.

55

N-3-(4-Fluorophenyl)cyclohexyl)-3-methylpicolinamide 15b

Prepared according to general arylation procedure A or B, on a 0.2 mmol scale using 4-

iodofluorobenzene. Purified by flash column chromatography (0 – 20% EtOAc in petrol) to

give the product as a colourless oil.

A (45 mg, 1.44 mmol, 72%)

B (57 mg, 1.84 mmol, 91%)


MHz, CDCl3) δ 8.36 (dd, J = 4.6, 1.1 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.57 (ddd, J = 7.8,

1.5, 0.7 Hz, 1H), 7.29 (dd, J = 7.7, 4.6 Hz, 1H,), 7.19 – 7.13 (m, 2H), 6.99 – 6.92 (m, 2H),

4.07 (tdt, J = 12.1, 8.2, 3.9 Hz, 1H), 2.79 – 2.65 (m, 4H), 2.29 – 2.21 (m, 1H), 2.13 (d, J =

12.4 Hz, 1H), 1.95 (ddt, J = 13.2, 6.5, 3.3 Hz, 1H), 1.91 – 1.85 (m, 1H), 1.58 (qt, J = 13.1, 3.4

Hz, 1H), 1.45 – 1.30 (m, 3H); 13C NMR (176 MHz, CDCl3) δ 165.2, 161.4 (d, J = 243.5 Hz),

147.4, 145.4, 142.1 (d, J = 3.1 Hz), 141.1, 135.6, 128.3 (d, J = 4.3 Hz), 125.7, 115.2 (d, J =

20.1 Hz), 48.7, 42.8, 41.2, 33.6, 32.9, 25.3, 20.7; HRMS (ES) m/z [M + H]+ found

313.13715, C19H20N2OF+H requires 313.1716.

N-(3-(4-Methoxyphenyl)cyclohexyl)picolinamide 15c

Prepared according to general arylation procedure A at 130 °C, using N-

cyclohexylpicolinamide (97 mg, 0.50 mmol) and 4-iodoanisole (498 mg, 2.0 mmol). Purified

by flash column chromatography (0 – 40% EtOAc in petrol) to give the product as a

colourless oil (105 mg, 0.36 mmol, 68%).

56

νmax (film/cm-1) 3380 (NH), 3057 (CH), 2998 (CH), 2928 (CH), 2854 (CH), 1666 (CO); 1H


7.97 (d, J = 8.5 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),

7.16 – 7.12 (m, 2H), 6.85 – 6.81 (m, 2H), 4.12 (tdt, J = 12.2, 8.3, 4.0 Hz, 1H), 3.78 (s, 3H),

2.69 (tt, J = 12.2, 3.3 Hz, 1H), 2.28 – 2.22 (m, 1H), 2.15 (d, J = 12.3 Hz, 1H), 1.98 – 1.92 (m,

1H), 1.92 – 1.86 (m, 1H), 1.63 – 1.54 (m, 1H), 1.45 – 1.28 (m, 3H); 13C NMR (151 MHz,

CDCl3) δ 163.4, 158.0, 150.2, 148.1, 138.6, 137.5, 127.7, 126.2, 122.4, 113.9, 55.4, 48.9,

42.4, 41.2, 33.6, 32.9, 25.3.


N-((3-(4-Methoxyphenyl)cyclohexyl)-3-methylpicolinamide 15d

Prepared according to general arylation procedure B, using 4-iodoanisole on a 0.2 mmol

scale at 130 °C. Purified by flash column chromatography (0 – 20% EtOAc in petrol) to give

the product as a colourless oil (55 mg, 0.17 mmol, 85%).


MHz, CDCl3) δ 8.36 (dd, J = 4.6, 1.0 Hz, 1H), 8.12 – 7.99 (m, 1H), 7.56 (ddd, J = 7.7, 1.6,

0.7 Hz, 1H), 7.28 (dd, J = 7.7, 4.6 Hz, 1H), 7.15 – 7.11 (m, 2H), 6.86 – 6.80 (m, 2H), 4.07

(tdt, J = 12.1, 8.2, 4.0 Hz, 1H), 3.78 (d, J = 4.1 Hz, 3H), 2.74 (s, 3H), 2.68 (tt, J = 12.2, 3.3

Hz, 1H), 2.25 (dtd, J = 9.3, 3.5, 1.8 Hz, 1H), 2.13 (dd, J = 7.2, 5.3 Hz, 1H), 1.97 – 1.91 (m,

1H), 1.91 – 1.86 (m, 1H), 1.62 – 1.52 (m, 1H), 1.46 – 1.34 (m, 2H), 1.34 – 1.27 (m, 1H); 13C

NMR (176 MHz, CDCl3) δ 165.2, 158.0, 147.6, 145.4, 141.0, 138.7, 135.6, 127.8, 125.6,

113.9, 55.4, 48.8, 42.5, 41.3, 33.7, 33.0, 25.4, 20.7; HRMS (ES) m/z [M + H]+ found

325.1916, C20H23N2O2+H requires 325.1916.

When prepared according to general arylation procedure A, the yield was 84%. Determined

using 1,3,5-trimethoxybenzene as the internal standard.

N-((2,6-Bis(4-methoxyphenyl)cyclohexyl)methyl)picolinamide 17a

57

A sealed tube was charged with N-(Cyclohexylmethyl)picolinamide (43 mg, 0.20 mmol, 1

eq), Pd(OAc)2 (2.2 mg, 0.01 mmol, 5 mol%), CuBr2 (4.4 mg, 0.02 mmol, 10 mol%), CsOAc

(154 mg, 0.8 mmol, 4 eq), 4-iodoanisole (281 mg, 1.2 mmol, 6 eq) and 3-methyl-3-pentanol

(0.2 ml). The mixture was heated at 150 °C for 24 hours, cooled and filtered through Celite®,

washing with EtOAc. The crude product was purified by flash Column chromatography (10 –

40% EtOAc in petrol) to give the title compound as a white solid (60 mg, 0.13 mmol, 65%).


MHz, CDCl3) δ 8.21 (d, J = 4.7 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.67 (td, J = 7.7, 1.7 Hz,

1H), 7.24 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H), 7.20 (d, J = 8.6 Hz, 4H), 6.78 – 6.73 (m, 4H), 6.72

(s, 1H), 3.64 (s, 6H), 3.33 (t, J = 5.8 Hz, 2H), 3.14 (dt, J = 12.7, 3.5 Hz, 2H), 2.51 – 2.47 (m,

1H), 2.17 – 2.12 (m, 1H), 1.93 – 2.88 (m, 4H, ArCHCH2), 1.63 – 1.56 (m, 1H, ArCHCH2CH2);

13C NMR (151 MHz, CDCl3) δ 163.2, 158.0, 149.8, 147.4, 136.74, 136.69, 128.1, 125.7,

121.5, 113.9, 55.1, 48.2, 46.2, 34.4, 26.7, 24.8; LRMS (CI NH3) 431.24 ([M+H]+); HRMS

found (CI NH3) [M+H]+ 431.2250, C27H30N2O3+H requires 431.2251.

N-((2-(4-Methoxyphenyl)cyclohexyl)methyl)picolinamide 18a

Colourless oil (10 mg, 0.032 mmol, 16%)


MHz, CDCl3) δ 8.49 (d, J = 4.3 Hz, 1H), 8.12 (t, J = 7.1 Hz, 1H), 7.81 (td, J = 7.7, 1.6 Hz,

2H), 7.39 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.17 – 7.14 (m, 2H), 6.86 – 6.83 (m, 2H), 3.77 (s,

3H), 3.27 – 3.22 (m, 1H), 3.15 – 3.10 (m, 1H), 2.28 (td, J = 11.6, 3.2 Hz, 1H), 2.00 (d, J =

58

13.3 Hz, 1H), 1.86 – 1.78 (m, 4H), 1.52 – 1.45 (m, 1H), 1.39 – 1.33 (m, 2H), 1.20 (m, 1H);

13C NMR (151 MHz, CDCl3) δ 164.2, 158.2, 150.2, 137.8, 137.2, 128.4, 128.3, 126.0, 122.2,

114.2, 55.3, 48.4, 43.9, 43.4, 36.0, 31.2, 26.8, 26.2; LRMS (CI NH3) 325.20 ([M+H]+); HRMS

found (CI NH3) [M+H]+ 325.1910, C20H24N2O2+H requires 325.1911.

IR and mass spec as a mixture of isomers (trace amount of syn compound present).

N-(3-(4-Methoxyphenyl)cycloheptyl)picolinamide 20a

Prepared according to general arylation procedure B at 140 °C, on a 0.5 mmol scale using

4-iodoanisole. Purified by flash column chromatography (0 – 30% EtOAc in petrol) to give

the product as a colourless oil (30 mg, 0.15 mmol, 31%). Mixture of diastereoisomers d.r =

92:8


MHz, CDCl3) δ 8.51 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 6.5 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H),

7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.13 – 7.09 (m, 2H), 6.82 – 6.79 (m, 2H),

4.28 – 4.22 (m, 1H), 3.77 (s, 3H), 2.85 – 2.80 (m, 1H), 2.19 – 2.11 (m, 2H), 1.96 (ddd, J =

13.4, 7.2, 4.0 Hz, 1H), 1.85 (dt, J = 13.2, 11.2 Hz, 1H), 1.81 – 1.63 (m, 6H); 13C NMR (176

MHz, CDCl3) δ 163.0, 157.8, 150.3, 148.1, 141.2, 137.4, 127.6, 127.6, 126.1, 122.3, 114.0,

113.9, 55.4, 50.2, 44.4, 42.8, 37.1, 35.2, 26.5, 23.9; HRMS (ES) m/z [M + H]+ found

325.1916, C20H23N2O2+H requires 325.1916.


N-(3-(4-methoxyphenyl)cycloheptyl)-3-methylpicolinamide 20b

Prepared according to general arylation procedure B at 140 °C, on a 0.5 mmol scale using

4-iodoanisole. Purified by flash column chromatography (5 – 25% EtOAc in petrol) to give

the product as a yellow oil (65 mg, 0.19 mol, 38%).

59


MHz, CDCl3) δ 8.34 (ddd, J = 4.6, 1.6, 0.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.56 – 7.53 (m,

1H), 7.26 (dd, J = 7.7, 4.6, 1H), 7.13 – 7.10 (m, 2H), 6.82 – 6.79 (m, 2H), 4.23 – 4.15 (m,

1H), 3.77 (s, 3H), 2.85 – 2.80 (m, 1H), 2.72 (s, 3H), 2.18 – 2.10 (m, 2H), 1.98 – 1.93 (m, 1H),

1.88 – 1.82 (m, 1H), 1.81 – 1.66 (m, 6H); 13C NMR (176 MHz, CDCl3) δ 164.8, 157.8, 147.6,

145.4, 141.3, 141.0, 135.5, 127.6, 125.6, 113.9, 55.4, 50.0, 44.5, 43.0, 37.1, 35.2, 26.4,


N-(2-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)picolinamide 22a


iodoanisole at 150 °C. Purified by flash column chromatography (5 – 40% EtOAc in petrol) to

give the product as a colourless oil (47 mg, 0.15 mmol, 75%).



7.99 (d, J = 8.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),

7.32 – 7.26 (m, 2H), 6.90 – 6.84 (m, 2H), 4.44 (dd, J = 11.3, 1.9 Hz, 1H), 4.36 (tdd, J = 12.4,

8.1, 4.3 Hz, 1H), 4.21 (ddd, J = 11.8, 4.7, 1.5 Hz, 1H), 3.79 (s, 3H), 3.74 (td, J = 12.2, 2.1

Hz, 1H), 2.27 (ddt, J = 12.7, 4.1, 2.0 Hz, 1H), 2.06 (ddd, J = 12.7, 4.2, 2.2 Hz, 1H), 1.76 –

1.66 (m, 1H), 1.63 – 1.59 (m, 1H); 13C NMR (176 MHz, CDCl3) δ 163.6, 159.2, 149.9, 148.1,

137.6, 134.3, 127.3, 126.4, 122.5, 113.9, 78.6, 67.3, 55.4, 46.7, 40.5, 32.9; HRMS found

(ES) [M+H]+ 313.1552, C18H20N2O3+H requires 313.1552.

N-(2-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl)-3-methylpicolinamide 22b


iodoanisole at 150 °C. Purified by flash column chromatography (5 – 40% EtOAc in petrol) to

give the product as a yellow oil (55 mg, 0.17 mmol, 85%).

60


NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 4.6, 1.1 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.59 (ddd,

J = 7.8, 1.6, 0.7 Hz, 1H), 7.33 – 7.25 (m, 3H), 6.89 – 6.84 (m, 2H), 4.43 (dd, J = 11.3, 1.9 Hz,

1H), 4.37 – 4.25 (m, 1H), 4.21 (ddd, J = 11.8, 4.7, 1.5 Hz, 1H), 3.79 (s, 3H), 3.73 (td, J =

12.1, 2.1 Hz, 1H), 2.74 (s, 3H), 2.27 (ddt, J = 12.7, 4.1, 2.0 Hz, 1H), 2.05 (ddd, J = 12.7, 4.2,

2.0 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.65 – 1.55 (m, 1H); 13C NMR (176 MHz, CDCl3) δ 165.3,

159.2, 147.1, 145.4, 141.2, 135.7, 134.4, 127.3, 125.8, 113.9, 78.7, 67.3, 55.4, 46.5, 40.7,


Deuteration experiments

A suspension of 1a (26 mg, 0.1 mmol, 1 equiv.), Pd(OAc)2 (1.1 mg, 0.005 mmol, 5 mol%),

CsOAc (77 mg, 0.4 mmol, 4 equiv.) and CuBr2 (2.2 mg, 0.01 mmol, 10 mol%) in tBuOD (0.1

ml) was heated in a sealed tube to 140 °C for 24 hours. The reaction mixture was cooled,

filtered through Celite® washing with EtOAc, and concentrated in vacuo. Crude 1H NMR

(700 MHz, CDCl3) analysis showed no deuterium exchange had taken place.

A tube was charged with picolinamide 2e (37 mg, 0.1 mmol, 1 equiv.), CuBr2 (2.2 mg, 0.01

mmol, 10 mol%), Pd(OAc)2 (1.1 mg, 0.005 mmol, 5 mol%), CsOAc (77 mg, 0.4 mmol, 4

equiv.), tAmOH (0.1 ml, 1 M) and 4-iodoanisole (94 mg, 0.4 mmol, 4 equiv.). The tube was

sealed with a PTFE lined cap and heated to 140 °C for 24 hours. The reaction mixture was

then cooled and filtered through a pad of Celite®, washing with EtOAc. The filtrate was

61

concentrated in vacuo. 1H NMR analysis of the crude reaction mixture showed that only 2e

was present, and none of the diarylated product 3e has been formed.

Palladacycle4 (41 mg, 0.1 mmol) was dissolved in acetic acid-d4 and the resulting solution

heated at reflux for 72 hours. The resulting solution was analysed by 1H NMR (CD3CO2D,

700 MHz) and it was observed that only the starting palladacycle was present.

62

3-Methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide

1b

63

4-methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide

1c

64

5-Methyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1d

66


1e

67


1f

68

4-Methoxy-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1g

69

5-Methoxy-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1h

71

3-phenyl-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 1i

72

N-((1-Methylcyclohexyl)methyl)picolinamide 4a

73

3-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4b

74

4-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4c

76

5-Methyl-N-((1-methylcyclohexyl)methyl)picolinamide 4d

77

N-((1-Methylcyclohexyl)methyl)-3-(trifluoromethyl)picolinamide 4e

78

N-((1-Methylcyclohexyl)methyl)-5-(trifluoromethyl)picolinamide 4f

80

4-Methoxy-N-((1-methylcyclohexyl)methyl)picolinamide 4g

81

5-Methoxy-N-((1-methylcyclohexyl)methyl)picolinamide 4h

82

N-(2-Methylbutyl)picolinamide 7a

83

3-Methyl-N-(2-methylbutyl)picolinamide 7b

85

4-Methyl-N-(2-methylbutyl)picolinamide 7c

86

5-Methyl-N-(2-methylbutyl)picolinamide 7d

87

N-(2-Methylbutyl)-3-(trifluoromethyl)picolinamide 7e

88

N-(2-Methylbutyl)-5-(trifluoromethyl)picolinamide 7f

90

4-Methoxy-N-(2-methylbutyl)picolinamide 7g

91

5-Methoxy-N-(2-methylbutyl)picolinamide 7h

92

N-Isobutylpicolinamide 11a

94

N-Isobutyl-3-methylpicolinamide 11b

95

N-(Cyclohexylmethyl)picolinamide 16a

96

N-Cyclohexylpicolinamide 14a

97

N-Cyclohexyl-3-methylpicolinamide 14b

99

N-(tetrahydro-2H-pyran-4-yl)picolinamide 21a

100

3-methyl-N-(tetrahydro-2H-pyran-4-yl)picolinamide 21b

101

N-Cycloheptylpicolinamide 19a

102

N-Cycloheptyl-3-methylpicolinamide 19b

104


methylpicolinamide 2b

106


methylpicolinamide 2c

107


dimethylbicyclo[2.2.1]heptan-2-yl)-4-methylpicolinamide 3c and N-((1S,2S,4R,6S)-6-(4-

Methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-4-methylpicolinamide 2c

109


methylpicolinamide 2d

110


methylpicolinamide 2d and N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-

methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-5-methylpicolinamide 3d

111


(trifluoromethyl)picolinamide 2e

112

N-((1S,2S,4R,6S)-1-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-

yl)-3-(trifluoromethyl)picolinamide 3e and N-((1S,2S,4R,6S)-6-(4-Methoxyphenyl)-1,7,7-

trimethylbicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)picolinamide 2e

114



116


dimethylbicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)picolinamide 3f

117


2-yl)picolinamide 2g

118

4-Methoxy-N-((1S,2S,4R,6S)-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-7,7-

dimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 3g and 4-Methoxy-N-((1S,2S,4R,6S)-6-

(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 2g

119


2-yl)picolinamide 2h

121

5-Methoxy-N-((1S,2S,4R,6S)-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-7,7-

dimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 3h and 5-Methoxy-N-((1S,2S,4R,6S)-6-

(4-methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)picolinamide 2h

122

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)picolinamide 5a

124

N-(1-(4-methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)picolinamide 6a

125

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-3-methylpicolinamide 5b

126

N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-3-methylpicolinamide 6b

127

N-((1-(4-methoxybenzyl)cyclohexyl)methy l)-4-methylpicolinamide 5c

129


6c

130

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-5-methylpicolinamide 5d

131


6d

132

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-3-(trifluoromethyl)picolinamide 5e

134

N-((1-(4-Methoxybenzyl)cyclohexyl)methyl)-5-(trifluoromethyl)picolinamide 5f

135

N-((1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)cyclohexyl)methyl)-5-


136

4-Methoxy-N-((1-(4-methoxybenzyl)cyclohexyl)methyl)picolinamide 5g

137


methoxyphenyl)cyclohexyl)methyl)picolinamide 6g

138

5-Methoxy-N-((1-(4-methoxybenzyl)cyclohexyl)methyl)picolinamide 5h

139


methoxyphenyl)cyclohexyl)methyl)picolinamide 6h

140

N-(2-(4-Methoxybenzyl)butyl)picolinamide 8a

142

N-(2-(4-Methoxybenzyl)butyl)-3-methylpicolinamide 8b and N-(2-(4-Methoxybenzyl)-3-

(4-methoxyphenyl)butyl)-3-methylpicolinamide 9b

143

N-(2-(4-Methoxybenzyl)butyl)-4-methylpicolinamide 8c

144

TOCSY Experiments for assignment of 10c

146

N-(2-(4-Methoxybenzyl)butyl)picolinamide 8d

147

N-(2-(4-Methoxybenzyl)butyl)picolinamide 8d and N-(2-(4-methoxybenzyl)-3-(4-

methoxyphenyl)butyl)-5-methylpicolinamide 9d

148

N-(2-(4-Methoxybenzyl)butyl)-3-(trifluoromethyl)picolinamide 8e

149

N-(2-(4-Methoxybenzyl)butyl)-5-(trifluoromethyl)picolinamide 8f

151

4-Methoxy-N-(2-(4-methoxybenzyl)butyl)picolinamide 8g

152

5-Methoxy-N-(2-(4-methoxybenzyl)butyl)picolinamide 8h and 5-Methoxy-N-(2-(4-

methoxybenzyl)-3-(4-methoxyphenyl)butyl)picolinamide 9h

153

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)propyl)picolinamide 13a

154

N-(2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)propyl)-3-methylpicolinamide 13b

155

N-(3-(4-fluorophenyl)cyclohexyl)picolinamide 15a

156

N-3-(4-Fluorophenyl)cyclohexyl)-3-methylpicolinamide 15b

158

N-(3-(4-Methoxyphenyl)cyclohexyl)picolinamide 15c

159

N-((3-(4-Methoxyphenyl)cyclohexyl)-3-methylpicolinamide 15d

160

N-((2,6-Bis(4-methoxyphenyl)cyclohexyl)methyl)picolinamide 17a

162

N-((2-(4-Methoxyphenyl)cyclohexyl)methyl)picolinamide 18a

163

N-(3-(4-Methoxyphenyl)cycloheptyl)picolinamide 20a

164

N-(3-(4-methoxyphenyl)cycloheptyl)-3-methylpicolinamide 20b

165

N-(2-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)picolinamide 22a

167

N-(2-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-yl)-3-methylpicolinamide 22b

168

References

1 Y. Wang, X. Deng, Y. Liu, M. Ni, M. Liu, H. Tan, X. Li, W. Zhu, Y. Cao, Tetrahedron 2011, 67, 2118

2 D. R. St. Laurent, M. H. Serrano-Wu, M. Belema, M. Ding, H. Fang, M. Gao, J. T. Goodrich, R. G. Krause, J. A. Lemm, M. Liu, O. D. Lopez, V. N. Nguyen, P. T. Nower, D. R. O’Boyle II, B. C. Pearce, J. L. Romine, L. Valera, J. -H. Sun, Y. -K Wang, F. Yang, X. Yang, N. A. Meanwell, L. B. Snyder, J. Med. Chem. 2014, 57, 1976

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4 C. E. Coomber, L. Benhamou, D. -K. Bucar, P. D. Smith, M. J. Porter, T. D. Sheppard, J. Org. Chem. 2018, 83, 2495

5 G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc. 2012, 134, 3

6 W. A. Nack, G. He, S.-Y. Zhang, C. Lu, G. Chen, Org. Lett. 2013, 15, 3440

7 C. E. Coomber, V. Laserna, L. T. Martin, P. D. Smith, H. C. Hailes, M. J. Porter, T. D. Sheppard, Org. Biomol. Chem. 2019, 17, 6465

8 J. Zhao, X.-J. Zhao, P. Cao, J.-K. Liu, B. Wu, Org. Lett. 2017, 19, 4880

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