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University of Groningen

Asymmetric hydrogenation of imines, enamines and N-heterocycles using phosphoramiditeligandsMrsic, Natasa

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Chapter 5

Asymmetric hydrogenation of 2-substituted N-protected-indoles

In this chapter the asymmetric hydrogenation of indoles catalyzed by rhodium complexes of BINOL-derived phosphoramidites is described. Full conversions and enantioselectivities up to 74% were obtained in the hydrogenation of N-protected indoles.

Part of this chapter has been published:

N. Mršić, A. J. Minnaard, B. L. Feringa, J. G. de Vries, Tetrahedron:Asymmetry 2009, accepted.

176

Chapter 5

5.1 Introduction

Highly enantioselective asymmetric hydrogenation of heteroaromatics could be a valuable and straightforward method for the preparation of enantiopure heterocyclic compounds, if it could be performed successfully on a routine basis. Heterocyclic compounds represent important building blocks in the synthesis of pharmaceutical intermediates and biologically active compounds.1 As mentioned in previous chapters, asymmetric hydrogenation of heteroaromatics is still not suitable for industrial application due to the fact that the ligands employed are usually prepared through a multi-step synthesis which makes them rather expensive. Moreover, reported TOF’s are still in general low and high pressures are usually necessary due to the high stability of heteroaromatic compounds. Therefore, despite considerable progress in the field, effective hydrogenation of aromatic and heteroaromatic compounds with high enantioselectivity still remains a great challenge.2

N

O

COOH

HS

NH

COOH

Figure 5.1 (S)-indoline-2-carboxylic acid and the first ACE inhibitor Captopril

Enantiomerically enriched indoline-2-carboxylic acids are important intermediates for pharmaceutical products, in particular in the preparation of angiotensin I converting enzyme inhibitors (ACE). ACE inhibitors are useful for the treatment of hypertension. Since the discovery3 of the ACE inhibitor Captopril and its use as an effective

antihypertensive agent for primary and renal hypertension, a new field of drug discovery and development emerged.

177


N

H

H

COOH

O

NH

OO

Perindopril

NCOOH

O

OO

Pentopril

N

H

H

COOH

O

NH

OO

Indolapril

Figure 5.2 (S)-Indoline-2-carboxylic acid-derived ACE inhibitors

Enantiopure (S)-indoline-2-carboxylic acid is used as an intermediate in the preparation of Perindopril, that is an antihypertensive or cardiotonic active ingredient.4 Other useful applications of (S)-indoline-2-carboxylic acid are, for example, in the synthesis of ACE inhibitors Pentopril and Indolapril (Figure 5.2).5

COOH

ONO2

NaBH4

NH

COOH

COOH

OHNO2

H

DMF, SOCl2rt, CH2Cl2

COOH

HNO2

ClPd/CCOOH

HNH2

Cl

NH

COOH

ROH, KOHRaney nickel

H2NNH2

Scheme 5.1 Synthesis of (S)-indoline-2-carboxylic acid via reduction using (D)-Proline as a chiral auxiliary

178

Chapter 5

Preparation of enantiopure (S)-indoline-2-carboxylic acid and its methyl ester is generally achieved via classical resolution,6 chemical synthesis through an asymmetric reduction with a chiral auxiliary7 or via enzymatic methods such as resolution via hydrolysis of indole-2-carboxylic esters,8 or using phenylammonia lyase for the preparation of ortho-chlorophenylalanine followed by a copper-catalyzed ring-closure.9 The disadvantage of the classical resolution method is the fact that the resolving agent is expensive and difficult to recover. In addition, the yield never exceeds 50%. The synthesis method through asymmetric reduction, using a chiral auxiliary, involves NaBH4 reduction of prochiral 3-(ortho-nitro-phenyl)pyruvic acid applying the chiral auxiliary D-proline. The resulting alcohol derivative is then converted into enantioenriched (S)-indoline-2-carboxylic acid with an overall yield of 32%, using expensive D-(+)-proline (Scheme 5.1).7

Fe Fe

NR3

R2N

R3

1 mol% [Rh(nbd)2]SbF61.05 mol% (S,S)-(R,R)-PhTRAP

10 mol% base, 50 bar H2i-PrOH, 60 oC

(S,S)-(R,R)-PhTRAP

R1 R1R2

R1 = Me, MeO, CF3R2 = Ac, BocR3 = Bu, Ph, COOMe

up to 95% ee

Ito et al., 2000

Ph2PH

PPh2H

Scheme 5.2 Ito’s asymmetric hydrogenation of N-protected-2-substituted indoles

In 2000, Ito and co-workers reported the asymmetric hydrogenation of N-acetyl and N-Boc protected indoles with excellent conversions and enantioselectivities (up to 95% and 78% ee, respectively) using a rhodium catalyst based on the trans-chelating bis-phosphine ligand PhTRAP and

179


using cesium carbonate as a base (Scheme 5.2).10 The addition of the base was shown to play an important role in obtaining both good catalytic activity and high enantioselectivity. Authors presume that a Rh(I)H complex is an active species for the asymmetric hydrogenation. The base additive possibly deprotonates from a cationic Rh(III)H2 complex, generating a neutral Rh(I)H complex. Later on, Kuwano and co-workers reported the Rh-catalyzed asymmetric hydrogenation of N-tosyl-3-substitued indoles11 and the Rh- and Ru-catalyzed hydrogenation of N-protected-2- and 3-substituted indoles with excellent enantioselectivities and conversions using the same PhTRAP ligand.12

Fe Fe

Ph2PH

PPh2H

PPh2

PPh2

(R)-BINAP

PPh2

PPh2

(2S,3S)-Chiraphos

Fe PPh2

NMe2

PPh2

(R)-(S)-BPPFA

O

O

PPh2

PPh2

(2R,3R)-DIOP

(R,R)-Me-DUPHOS

NBoc

Ph2P

PPh2

(2S,4S)-BPPM

100% yield1% ee

100% yield1% ee

100 yield0% ee

100% yield0% ee

100% yield0% ee

100% yield0% ee

N

O

Bu

N

O

Bu

1 mol% Rh(acac)(cod)1.05 mol% Ligandi-PrOH, 50 bar H2

60 oC, 2h

(S,S)-(R,R)-PhTRAP

75% yield85% ee

PP

Scheme 5.3 Evaluation of chiral ligands for the hydrogenation of N-acetyl-2-butylindole

In Ito’s study, a broad range of chiral bidentate phosphine ligands was evaluated for the asymmetric hydrogenation of N-acetyl-2-butylindole

180

Chapter 5

using Rh(acac)(COD) (Scheme 5.3). The product was isolated in quantitative yield upon the use of various commercially available chiral phosphines. However, all ligands led to the formation of racemic product, except the trans-chelating PhTRAP ligand. The steric and electronic properties of the ligands have an enormous effect on the structure and the reactivity of metal complexes.13 The bite angle (P−M−P angle) of the bidentate ligands can have an impact on the hybridization at the metal centre and the resulting energies of valence orbitals. Thorn and Hoffmann calculated that during migration a phosphine ligand would have a tendency to widen the bite angle in the process to “pursue” the migrating group.14 It was expected that ligands enforcing an enlarged P−M−P angle (resembling the transition state), would accelerate migration reactions. Dekker et al. provided the experimental confirmation of the calculation, and discovered increasing migration rates with larger bite angles of palladium diphosphine complexes.15 Only a limited number of P ligands are known that enforce trans coordination toward a transition-metal center. Among these are the TRANSphos ligand introduced by Venanzi16 and the PhTRAP ligand developed by Ito.10 However, these ligands are rather flexible and cis complexes are accessible as well. It is noteworthy that the orientation of the lone pair at the phosphorus atoms is as important as the P−P distance. If within a certain backbone conformation the orientation of the lone pairs does not comply with the trans configuration of the metal, a slight distortion leads just as easily to a cis complex.

5.2 Goal of the research

As mentioned in earlier chapters, in our group phosphoramidite ligands have been successfully applied in rhodium, ruthenium and iridium catalyzed asymmetric hydrogenation.17 We have shown in chapters 2 and 3 that asymmetric hydrogenation of 2- and 2,6-disubstituted quinolines and quinoxalines using an iridium catalyst based on the monodentate phosphoramidite ligand (S)-PipPhos L1 proceeds with excellent conversions and ee’s. We were interested in examining the possibility to use monodentate phosphoramidites in the asymmetric hydrogenation of another class of heteroaromatic compounds; the indoles. In this chapter

181


we report the asymmetric hydrogenation of 2-substituted N-protected indoles using a rhodium catalysts with monodentate phosphoramidite ligands.

5.3 Initial screening and ligand optimization

Initial screening of reaction conditions was performed in dichloromethane at various hydrogen pressures and temperatures using methyl N-acetylindole-2-carboxylate 1 as a substrate, 5 mol% of [Rh(COD)2]BF4 precursor and 10 mol% of monodentate (S)-PipPhos ligand (Table 5.1). In reactions without additives no conversion was detected at room temperature and only low conversion and enantioselectivity were observed at 40 °C (Entries 1 and 2). As reported by Ito, the addition of a base seems to be crucial in the rhodium-catalyzed asymmetric hydrogenation of N-acetyl-2-substituted indoles.10 Indeed, when 10 mol% of cesium carbonate was added to the reaction mixture in the hydrogenation of 1, full conversion and ee’s up to 74% were obtained (Entries 3-7). Full conversion and the highest enantioselectivities were obtained at room temperature and 40 °C (73-74% ee, Entries 3 and 5). Upon increasing the temperature to 60 °C, both conversion and the ee decreased (71% conv. and 61% ee, Entry 7). At a pressure of 100 bar and room temperature the ee remained at a similar level as in the reactions at 25 bar of hydrogen pressure (61% ee, Entry 4). Doubling the amount of cesium carbonate resulted in a significant decrease of the enantioselectivity (38% ee, Entry 6). At 25 bar of hydrogen pressure and 40 °C, cesium carbonate and cesium fluoride gave similar results (74% and 72% ee respectively, Entries 5, 8). Addition of other bases like potassium acetate, sodium carbonate or lithium carbonate, led to lower conversions and enantioselectivities (Entries 9-11). Potassium hydrogenphosphate as additive also gave low conversion and ee (Entry 12). In the case of Ito’s PhTRAP-derived catalyst, addition of triethylamine resulted in the same ee as observed with the addition of cesium carbonate.10

182

Chapter 5

Table 5.1 Asymmetric hydrogenation of 1 using Rh(COD)2]BF4/(S)-PipPhosa

NCOOMe

O

NCOOMe

O

5 mol% [Rh(COD)]2BF410 mol% (S)-PipPhos

Additive, CH2Cl225 bar H2, 20h

1O

OP N

(S)-PipPhosL1

1a

Entry Additive Achiral phosphine Temp (°C) Conv.b ( %) Eec (%)

1 - - 25 0 - 2 - - 40 13 12 3 10% Cs2CO3 - 25 100 73 4 10% Cs2CO3 - 25 100 68e 5 10% Cs2CO3 - 40 100 74 6 20% Cs2CO3 - 40 95 38 7 10% Cs2CO3 - 60 71 61 8 10% CsF - 40 100 72 9 10% KOAc - 40 66 60 10 10% Na2CO3 - 40 2 24 11 10% Li2CO3 - 40 16 20 12 10% KH2PO4 - 40 15 10 13 10% Et3N - 40 100 55 14 10% Cs2CO3 5% P(o-tolyl)3 25 65 49

aReaction conditions: 0.2 mmol 1, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of CH2Cl2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was assigned by measuring the optical rotation and comparing it with literature data. eReaction performed at 100 bar.

Using phosphoramidites, the addition of triethylamine still resulted in full conversion, however the ee decreased (55% ee, Entry 13). The addition of tri-o-tolylphosphine as achiral ligand (mixed ligand approach,18 Rh/L*/L = 1/2/1) led to slightly lower conversion and ee than without the addition of the phosphine (65% conversion, 49% ee, Entry 14).

183


Table 5.2 Solvent screening in the asymmetric hydrogenation of 1 under the optimal reaction conditionsa

NCOOMe

O

NCOOMe

O

5 mol% [Rh(COD)]2BF410 mol% (S)-PipPhos

10 mol% Cs2CO3Solvent, 40 oC, 25 bar H2

1 1a

Entry Solvent Conv.b (%) Eec (%) 1 CH2Cl2 100 74 2 EtOAc 59 27 3 i-PrOH 95 8 4 MeOH 0 - 5 THF 16 4 6 Toluene 62 5

aReaction conditions: 0.2 mmol 1, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of solvent, 40 °C, 25 bar H2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was determined by measuring the optical rotation and comparing it with literature data.

We examined the influence of the solvent on the reaction outcome using cesium carbonate as an additive (Table 5.2). The best result was obtained in dichloromethane (Entry 1), while ethyl acetate, i-propanol and toluene gave moderate to high conversion, however with low ee (up to 27% ee, Entries 2, 3 and 6). The reaction in THF proceeded with low conversion and ee (Entry 5), while in methanol no conversion was observed (Entry 4). We assume that the reason for lower enantioselectivity in toluene and dichloromethane lies in lower solubility of cesium carbonate in those solvents. Although solubility of base is higher in i-propanol, methanol and THF, the ee is low possibly due to the stronger coordination of these solvents to the metal.

184

Chapter 5

O

OP R N N N N

L1a L1b L1c L1d

L1e

R =

L1f

N

Ph

PhL1g

(R, S, S) (S, S, S)

O

OP N

L2

O

OP N

L3

N

Figure 5.3 Ligands screened in the asymmetric hydrogenation of 1

Various phosphoramidite ligands were examined under the optimal conditions in the asymmetric hydrogenation of 1 (Figure 5.3). The results are presented in Table 5.3. The best result was still obtained with (S)-PipPhos L1 as a ligand (Entry 1). Excellent conversion and an ee of 59% was achieved with the ligand derived from azepane (L1d, Entry 5), while pyrrolidine-derived ligand L1c gave moderate conversion, however the product had low ee (Entry 4). With Monophos L1a 77% conversion and 33% ee was obtained, whereas use of ligand L1b surprisingly led to no conversion (Entries 2 and 3).

185


Table 5.3 Ligand screening in the asymmetric hydrogenation of 1a

NCOOMe

O

NCOOMe

O

5 mol% [Rh(COD)]2BF410 mol% L*

10 mol% Cs2CO3CH2Cl2, 40 oC, 25 bar H2

1 1a

Entry Ligand Conv.b (%) Eec (%)

1 (S)-L1 100 74 2 (S)-L1a 77 33 3 (S)-L1b 0 - 4 (S)-L1c 64 2 5 (S)-L1d 93 59 6 (S)-L1e 87 10 7 (R,S,S)-L1f 9 26e 8 (S,S,S)-L1g 0 - 9 (R)-L2 60 24e 10 (R)-L3 64 31e

aReaction conditions: 0.2 mmol 1, 0.01 mmol of Rh(COD)2BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of CH2Cl2, rt, 25 bar H2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was determined by measuring the optical rotation and comparing it with literature data). eOpposite configuration of the product obtained.

186

Chapter 5

5.4 Scope

Various indole substrates were also screened using (S)-PipPhos L1 at 25 bar of hydrogen pressure (Table 5.4).

Table 5.4 Screening of indole substrates in the Rh/PipPhos catalyzed asymmetric hydrogenationa

NR1

R2

N* R2

2-4

5 mol% [Rh(COD)2]BF410 mol% (S)-PipPhos

10 mol% Cs2CO3, 25 bar H2

2a, R1 = H, R2 = COOMe3a, R1 = Boc, R2 = COOMe4a, R1 = Acetyl, R2 = COOH

R1

Entry Indoline Solvent 10 mol% Cs2CO3 Temp (°C) Conv.b (%) Eec (%)

1 2a CH2Cl2 - 25 0 - 2 2a CH2Cl2 + 25 0 - 3 2a CH2Cl2 - 60 0 - 4 2a CH2Cl2 + 60 0 - 5 2a Toluene + 60 0 - 6 3a CH2Cl2 + 40 48 4 7 4a CH2Cl2 - 40 5 22 8 4a CH2Cl2 + 40 54 37 9 4a Toluene + 40 50 23 10 4a HOAc - 40 4 13

aReaction conditions: 0.2 mmol indole, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of solvent, rt, 25 bar H2. cConversion was determined by 1H NMR. dEnantioselectivity was determined by HPLC.

It was observed that in the hydrogenation of unprotected ester 2 to indoline 2a did not proceed in dichloromethane or toluene, at room temperature or 40 °C, with or without the addition of base (Entries 1-5). This possibly implies that the protective group on the nitrogen is required in order to achieve coordination of the substrate to the metal. Boc-protected substrate 3 was hydrogenated with 48% conversion, surprisingly only 4% ee was found (Entry 6). Hydrogenation of acid 4 was accomplished with low ee. In this case 10 mol% of Cs2CO3 was also sufficient, which suggests that it is not so much the pH that is important, but rather the

187


presence of the cation (Entries 7 and 8). The best result was obtained in dichloromethane, with the addition of cesium carbonate (54% conversion, 37% ee, Entry 8). When acetic acid was used as solvent almost no conversion was achieved (Entry 10).

5.5 Mechanistic considerations

No mechanistic proposals have been published for the base dependent rhodium-catalyzed asymmetric hydrogenation of indoles. In view of the fact that a catalytic amount of base suffices, the assumption seems justified that the base is part of the catalytic cycle. This is a well-known phenomenon in ruthenium-catalyzed hydrogenations, where the base serves to create a ruthenium monohydride species, which is the actual catalyst.19 Thus we propose the mechanism as pictured in Scheme 5.4.

[Rh(COD)2]BF4 + 2L RhL

LRh

L

L

HH

Cs2CO3

RhL

LH

NR

NR

RhL L

NR

RhH

L L

H2

N* R

A B

C

D

E

O

O

O

O

Scheme 5.4 Proposed hydrogenation mechanism

188

Chapter 5

After formation of the cationic bisligated rhodium COD-complex A, reaction with hydrogen furnishes dihydrogen complex B, which upon reaction with base will form the neutral rhodium monohydride complex C. Reaction with the substrate gives complex D. Insertion of the indole olefin into the rhodium hydride bond leads to formation of rhodium alkyl complex E, which reacts with dihydrogen to yield the product and reform hydride C. Unfortunately, so far we have not been able to observe any intermediates using ESI-MS.

5.6 Conclusion

Full conversion and up to 74% ee was obtained in the asymmetric hydrogenation of methyl N-Acetyl indole-2-carboxylate 1 using 5 mol% of rhodium catalyst with 10 mol% of monodentate phosphoramidite ligand PipPhos L1 and 10 mol% of cesium carbonate. A protective group on the nitrogen was shown to be crucial in order to obtain conversion. The presence of cesium salts has shown to be neccesary in order to obtain high ee. Boc-protected indole ester 3 was hydrogenated with 48% conversion and only 4% ee, while 1-acetyl-2,3-indoline-2-carboxylic acid 4 was hydrogenated with up to 54% conversion and 37% ee. In view of the fact that only Rh/PhTRAP catalytic system has been reported to give results in the hydrogenation of indoles, it is apparent that the field is underdeveloped. The demand for efficient catalysts and ligands which would be easily accessible is evident. Since phosphoramidites, phosphites and phosphoramidites are readily available, these classes of ligands represent good candidates. A larger library of ligands should be screened in the hydrogenation of N-acetyl-indoles. Ligands having different backbones, such as catechol or TADDOL should be considered, as well as various rhodium precursors.

5.7 Experimental section

General remarks (see Chapter 2)

The metal precursor [Rh(COD)2]BF4 was purchased from Strem. Substrates 1, 2 and 3 were prepared according to the literature

189


procedure.10 1-Acetyl-indole-2-carboxylic acid 4 was obtained as a gift from DSM Pharmaceutical Chemicals and used as such. The catalyst was prepared in situ. Reactions were performed in a stainless steal autoclave containing 7 glass vessels (8 mL volume). The vessels were closed with caps containing septa. Magnetic stir bars were placed inside of each vessel and needles were placed through the septa in order to enable entrance of hydrogen. Vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. The enantiomeric excess was determined by HPLC with chiral columns (Chiralcel OD and OD-H) or by GC with Chiralsil DEX CB, in comparison with racemic products. Ligands L1,20 L1a,20 L1b,20 L1c,21 L1d,21 L1e,21 L1f,20 L1g,20 L2,22 L322 were prepared according to the literature procedure.

General experimental procedure for Hydrogenation

A mixture of Rh(COD)2BF4 (4.06 mg, 0.01 mmol), (S)-PipPhos (7.99 mg, 0.02 mmol), substrate (0.2 mmol) and a base (0.02 mmol) were dissolved in 4 mL of solvent, in a glass vial equipped with the stirring bar. The vial was placed in a stainless steel autoclave. After the reaction, hydrogen pressure was carefully released. Solvent was removed in vacuo and conversion was determined by NMR.

Methyl N-Acetylindole-2-carboxylate (1)10

N

O

COOMe

This compound was synthesized according to a literature procedure;10 1H NMR (400 MHz, CDCl3) 2.62 (s, 3H), 3.95 (s, 3H), 7.26 − 7.33 (m, 2H), 7.46 (t, J = 8.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H) ppm.

Methyl Indole-2-carboxylate (2)23

NH

COOMe

This compound was synthesized by esterification of the indole-2-carboxylic acid with thionyl chloride in methanol.

190

Chapter 5

Yellow solid, 89% yield, Mp = 150.6 – 151.0 °C; 1H NMR (400 MHz, CDCl3) 3.90 (s, 3H), 7.08 − 7.13 (m, 1H), 7.18 − 7.21 (m, 1H), 7.25 − 7.30 (m, 1H), 7.36 − 7.39 (m, 1H), 7.63 − 7.66 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) 53.0, 109.8, 112.9, 121.8, 123.6, 126.4, 128.0, 128.4, 138.0, 163.7 ppm.

Methyl N-tert-Butoxycarbonylindole-2-carboxylate (3)10

NCOOMe

BocNH

COOMeBoc2O, DMAP

THF, rt, 1h

Methyl indole-2-carboxylate 3a (2.2 g, 12.5 mmol), Boc2O (3.2 g, 14.8 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol) were stirred in 50 mL of THF for 1h. Water was added (50 mL) and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried, solvent evaporated and the crude product was purified by column chromatography (heptane:EtOAc = 24:1). The product was isolated as a white solid in 77% yield (2.7 g).

NCOOMe

Boc

White solid, 77% yield, Mp = 66.6 − 66.9 °C; 1H NMR (400 MHz, CDCl3) 1.63 (s, 9H), 3.92 (s, 3H), 7.11 (s, 1H), 7.26 (t, J = 7.10, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.42 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) 28.6, 53.2, 85.4, 115.7, 115.8, 123.1, 124.2, 127.7, 128.4, 131.3, 138.7, 150.1, 163.2 ppm.

1-Acetyl-indole-2-carboxylic acid (4)

NCOOH

Ac

Compound was obtained from DSM- Pharmaceutical Chemicals.

191


Methyl (S)-N-Acetylindoline-2-carboxylate (1a)10

N

O

COOMe

Compound exists as mixture of two configurations due to a hindered rotation of the acetyl moiety. Both configurations are observed at rt by 1H NMR. White solid, Mp = 124.7 − 124.8 °C, 74% ee, [α]D = -43.8 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) 2.16 and 2.48 (pair of s, 3H), 3.09 and 3.26 (pair of br d, J = 16.3 Hz and J = 16.8 Hz, 1H), 3.43 − 3.65 (pair of m, 1H), 3.73 and 3.76 (pair of s, 3H), 4.91 and 5.16 (pair of d, J = 10.5 Hz and J = 10.7 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 7.13 − 7.26 (m, 2H), 8.21 (d, J = 8.0 Hz, 1H) ppm; GC Chiralsil DEX CB, (initial temp. 95 °C for 5 min, then 2 °C/min to 180 °C, then 10 °C/min to 95 °C), t1 = 81.0 min, t2 = 81.7 min.

Methyl (S)-N-tert-Butoxycarbonylindoline-2-carboxylate (3a)10

∗N

COOMe

Boc This compound exists as mixture of two configurations due to a hindered rotation of the Boc group. Both configurations are observed at rt by 1H NMR. Colorless oil; 1H NMR (400 MHz, CDCl3) 1.47 and 1.58 (pair of br, s, 9H), 3.05 (dd, J1 = 4.06 Hz, J2 = 16.57 Hz, 1H), 3.44 (dd, J1 = 11.88 Hz, J2 = 16.05 Hz, 1H), 3.70 (s, 3H), 4.82 (br, 1H), 6.90 (t, J = 7.43 Hz, 1H), 7.05 (d, J = 7.26 Hz, 1H), 7.15 (t, J = 7.57 Hz, 1H), 7.87 (d, J = 5.70 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) 28.9, 33.3, 53.0, 61.0, 81.9, 115.3, 123.2, 125.0, 125.4, 128.5, 143.2, 152.3, 173.1 ppm; HPLC (OD-H, eluent:heptane/i-PrOH = 98/2, detector: 254 nm, flow rate: 0.5 mL/min), t1 = 15.7 min, t2 = 19.3 min.

192

Chapter 5

1-Acetyl-2,3-indoline-2-carboxylic acid (4a)

∗N

COOH

Ac This compound exists as mixture of two configurations due to a hindered rotation of the acetyl moiety. Both configurations are observed at rt by 1H and 13C NMR. At 60 oC only one configuration is observed (broad signals). White solid; 1H NMR (500 MHz, (CD3)2NCOD, 60 °C) 2.38 (s, 3H), 3.46 - 3.48 (br, 1H), 3.82 − 3.84 (br, 1H), 5.37 (d, J = 8.63 Hz, 1H), 7.20 (t, J = 7.35 Hz, 1H), 7.38 − 7.44 (m, 2H), 8.36 (br, 1H), 13.3 (br, 1H) ppm; 13C NMR (125 MHz, (CD3)2NCOD, 60 °C) 23.3, 33.5, 61.5, 116.6, 123.5, 124.8, 127.5, 129.9, 143.6, 169.2, 173.4 ppm; HRMS Calcd. for C11H11NO3 (M+1) 206.07389, found 206.08064; HPLC (OD, eluent:heptane/i-PrOH/HCOOH = 80/20/1, detector: 254 nm, flow rate: 1 mL/min), t1 = 9.7 min, t2 = 11.2 min.

5.8 References

(1) Comprehensive Natural Products Chemistry, Eds. Barton, D. H. R.; Nakanishi, K.; Meth-Cohn, O. Elsevier: Oxford, 1999; Vol. 1-9. (2) a) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357; b) Bianchini, C.; Meli, A.; Vizza, F. The Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. Wiley-VCH: Weinheim, 2007; Vol. 1, Chapter 16, 455; c) Glorius, F. Org. Biomol. Chem. 2005, 3, 4171. (3) a) Cushman, D. W.; Cheung, H. S.; Sabo, E. F.; Ondetti, M. A. Biochemistry 1977, 16, 5484; b) Ondetti, M. A.; Cushman, D. W. US4046889 to Squibb & Sons Inc., 1977. (4) Remond, G.; Laubie, M.; Vincent, M. EP0049658 to Science Union et Cie Societé Française de Recherche Medical., 1982. (5) Ksander, G. M.; Zimmerman, M. B. EP0336950 to Ciba Geigy AG, 1992. (6) a) Chava, S.; Bandari, M.; Madhuresh, K. S. WO2006013581 to Matrix Lab Ltd., 2006; b) Wang, Z.-X.; Raheem, M. A.; Weeratunga, G. WO2006053440 to Apotex Pharmachem Inc. 2006; c) Fujino, T.; Ogawa, R.; Sato, H. JP2004182670 to Toray Industries, 2004; d) Souvie, J.-C.;

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Lecouve, J.-P. EP1348684 to Servier Lab., 2003; e) Hendrickx , A. J. J.; Kuilman, T. EP0937714 to DSM NV, 1999; f) Vlattas, I. US4665087 to Ciba Geigy Corp., 1987; g) Miyata, S.; Fukuda, H.; Imamura, S. EP0171616, 1986; h) Buzby, G. C. US4520205 to American Home Prod. 1985; i) Vincent, M.; Rémond, G.; Portevin, B.; Serkiz, B.; Laubie, M. Tetrahedron Lett. 1982, 23, 1677. (7) Buzby, G. C.; Winkley, M. W.; Mccaully, R. J. US4614806 to American Home Prod., 1986. (8) a) Le Goffic, F. FR2883874 to Substipharm Lab., 2006; b) Cho, N. R.; Lim, J. H.; Kim, J. K. WO2005051910 to SK Corp., 2005; c) Asada, M.; Hamaguchi, S.; Kutsuki, H.; Nakamura, Y.; Takashi, H.; Takahara, K.; Shimada, Y.; Ohashi, T.; Watanabe, K. US4898822 to Kanegafuchi Chemical Ind., 1990; d) Ghisalba, O.; Ramos, G.; Schaer, H.-P. DE3727411 to Ciba Geigy AG, 1988. (9) de Vries, A. H. M.; de Vries, J. G.; van Assema, F. B. J.; de Lange, B.; Mink, D.; Hyett, D. J.; Maas, P. J. D. WO2006069799 to DSM IP Assets bv, 2006. (10) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614. (11) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213. (12) a) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653; b) Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521. (13) a) Müller, C.; Freixa, Z.; Lutz, M.; Spek, A. L.; Vogt, D.; van Leeuwen, P. W. N. M. Organometallics 2008, 27, 834; b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895. (14) Thorn, D. L.; Hoffmann, R. J. Am. Chem. Soc. 1978, 100, 2079. (15) Dekker, G. P. C. M.; Elsevier, C. J.; Vrieze, K.; van Leeuwen, P. W. N. M. J. Organomet. Chem. 1992, 430, 357. (16) a) Bracher, G.; Grove, D. M.; Venanzi, L. M.; Bachechi, F.; Mura, P.; Zambonelli, L. Helv. Chim. Acta 1980, 63, 2519; b) DeStefano, N. J.; Johnson, D. K.; Venanzi, L. M. Angew. Chem. 1974, 86, 133. (17) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267.

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Chapter 5

(18) Reetz, M. T. Angew. Chem. Int. Ed. 2008, 47, 2556. (19) Morris, R. H. Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G. E., C. J. Wiley-VCH: Weinheim, 2007; Vol. 3, Chapter 3, 45. (20) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (21) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (22) Maciá, B.; Fernández-Ibáñez, M. Á.; Mršić, N.; Minnaard, A. J.; Feringa, B. L. Tetrahedron Lett. 2008, 49, 1877. (23) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.

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