chemoselective sp2 sp3 cross-couplings: iron-catalyzed alkyl transfer ... · page 1 chemoselective...

Chemoselective sp2-sp3 Cross-Couplings: Iron-Catalyzed Alkyl Transfer to Dihaloaromatics

Sushant Malhotra,* Pamela S. Seng, Stefan G. Koenig, Alan J. Deese, and Kevin A. Ford

[email protected]

SUPPORTING INFORMATION

General Information:

All reactions were performed under a nitrogen atmosphere. All solvents and Grignard reagents were used without further purification

or further analyses. All dihaloaromatics were either commercially-available or prepared using literature known methods. All

reactions were monitored using a X-Select CSH Phenyl Hexyl reverse phase column or an SL Only Monolithic C18 column using a

mobile phase containing mixtures of 0.05% aqueous TFA and acetonitrile. Silica gel chromatography was performed using RediSep®

pre-packed silica gel columns commercially-available from Teledyne Isco (Catalog 69-2203). Proton nuclear magnetic resonance (1H

NMR) spectra were acquired on either a Bruker 600 MHz or Bruker 300 MHz spectrometer. Carbon nuclear magnetic resonance (1H

NMR) spectra were acquired on a Bruker 151 MHz spectrometer. All NMR spectra are referenced internally according to residual

solvent signals. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q,

quartet; m, multiplet), integration, coupling constant (Hz). Data for 13C NMR are reported in terms of chemical shift (δ, ppm).

Melting points are uncorrected and were measured on a Büchi B-540 melting apparatus. All IR spectra were recorded on a Thermo

Electron Corporation Nicolet 6700 FT-IR instrument using a SMART Performer sampling attachment and Ge ATR crystal.

5-bromo-1,3-dimethylpyridin-2(1H)-one (2a)

N Me

OMe

BrN Me

O

Br

Br

MeMgBr

3.75 mol % Fe(acac)3

To a vial was added 3,5-dibromo-1-methylpyridin-2(1H)-one (200 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375

equiv). The vial was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5.0 mL). The

reaction mixture was treated dropwise with methylmagnesium bromide (0.62 mL of a 1.4 M solution in THF:toluene (1:3), 0.86

mmol, 1.15 equiv) at 0 ºC. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5

mL). The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 65%

EtOAc/hexanes afforded 124 mg (82%) of the desired product as a white solid. This compound has been previously reported.i m.p. =

104.0 – 105.4 ºC (lit. 106-107 ºC)i; TLC Rf = 0.33 (50% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 7.30 (d, J = 2.4 Hz, 1H),

7.25 (m, 1H), 3.52 (s, 3H), 2.13 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 162.0, 139.6, 135.4, 131.5, 97.4, 37.8, 17.2 ppm; IR

(neat): υmax 1649, 1590, 1556, 1423, 1229, 1221, 892, 761 cm-1.

Structural elucidation:

N Me

OMe

Br

2.17 (s, 3H)

3.52 (s, 3H)

N Me

OMe

Br

2.13 (s, 3H)

3.54 (s, 3H)

J. Org. Chem. 1974, 39, 2116. This work

3-chloro-1-methylisoquinoline (2b)

N ClMeN ClClMeMgBr


To a vial was added 1,3-dichloroisoquinoline (148 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5.0 mL). The reaction mixture was

treated dropwise with methylmagnesium bromide (0.62 mL of a 1.4 M solution in THF:toluene (1:3), 0.86 mmol, 1.15 equiv) at 0 ºC.

After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layers

were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 35% EtOAc/hexanes afforded 121 mg

(91%) of the desired product as a pale pink solid. m.p. = 58.3 – 59.1 ºC; TLC Rf = 0.49 (50% EtOAc/hexanes); 1H NMR (600 MHz,

CDCl3): δ 8.09 (m, 1H), 7.73 (m, 1H), 7.68 (m, 1H), 7.59 (m, 1H), 7.56 (d, J = 1.0 Hz, 1H), 2.94 (s, 3H) ppm; 13C NMR (151 MHz,

CDCl3): δ 160.0, 144.3, 137.9, 130.9, 127.2, 126.5, 126.3, 125.8, 118.1, 22.1 ppm; IR (neat): υmax 1616, 1555, 1425, 1397, 1317, 1265,

1163, 1101, 968 cm-1.


N ClMe N MeCl

2.95 (s, 3H) 2.65 (s, 3H)

H H

7.56 (d, J = 1.0 Hz, 1H) 7.25 (s, 1H)

W.O. Patent 03099274, 2003.This work

3-chloro-6-fluoro-1-methylisoquinoline (2c)

N ClMe

F

N Cl

F

ClMeMgBr


To a vial was added 1,3-dichloro-6-fluoroisoquinoline (147 mg, 0.74 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The

vial was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4.0 mL). The reaction mixture

was treated dropwise with methylmagnesium bromide (0.62 mL of a 1.4 M solution in THF:toluene (1:3), 0.86 mmol, 1.15 equiv) at

ambient temperature. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5 mL).

The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes afforded 135 mg (92%) of the desired product as a white solid. m.p. = 94.2 – 95.7 ºC; TLC Rf = 0.68 (20%

EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.04 (dd, J = 9.11, 5.33(F) Hz, 1H), 7.42 (s, 1H), 7.28 (dd, J = 7.24(F), 2.38 Hz, 1H),

7.24 (dd, J = 9.11, 7.24(F) Hz, 1H), 2.13 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 164.6-162.5, 159.8, 145.6, 139.6-139.5, 129.0-

128.9, 123.5-123.4, 117.7-117.6, 117.7-117.5, 109.9-109.7, 22.2 ppm; IR (neat): υmax 1631, 1501, 1418, 1360, 1214, 1138, 905, 873,

814, 703 cm-1.

Structural elucidation: Structure assigned based on analogy to product obtained from 1,3-dichloroisoquinoline.

3-chloro-2-methylpyridine (2d)

N

Cl

MeN

Cl

Cl MeMgBr


To a vial was added 2,3-dichloropyridine (200 mg, 1.35 mmol) and Fe(acac)3 (18 mg, 0.051 mmo, 0.0375 equiv). The vial was sealed

with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5.0 mL) and NMP (1.0 mL). The reaction

mixture was treated dropwise with methylmagnesium bromide (1.10 mL of a 1.4 M solution in THF:toluene (1:3), 1.55 mmol, 1.15

equiv) at ambient temperature. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3

x 5 mL). The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 20% – 50%

MTBE/hexanes afforded 133 mg (77%) of the desired product as a colorless oil. TLC Rf = 0.39 (50% EtOAc/hexanes); Spectral data

matches literature known valuesii: 1H NMR (600 MHz, CDCl3): δ 8.39 (d, J = 3.8 Hz, 1H), 7.62 (dd, J = 8.0, 1.2 Hz, 1H); 7.09 (dd, J

= 8.0, 4.8 Hz, 1H), 2.63 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 156.2, 147.0, 136.5, 131.5, 122.2, 22.7 ppm.


N Me

H

2.63 (s, 3H)

7.10 (dd, J = 8.0, 4.8 Hz, 1H)

7.63 (dd, J = 8.0, 1.2 Hz, 1H)

8.39 (d, J = 3.7 Hz, 1H)

H Cl

H

N Me

H

2.63 (s, 3H)

7.09 (dd, J = 8.0, 4.8 Hz, 1H)7.62 (dd, J = 8.0, 1.2 Hz, 1H)

8.39 (d, J = 3.8 Hz, 1H)

H Cl

H

This Work

N Cl

H2.39 (s, 3H)7.05 (dd, J = 7.0, 5.0 Hz, 1H)

8.1 (d, J = 5.0, 2.0 Hz, 1H)

H Me

H

Org. Lett. 2004, 6, 3517.

Synth. Commun. 2004, 34, 1097.

7-chloro-4-methylquinoline (2e)

MeMgBr


NCl

Cl

NCl

Me

To a vial was added 4,7-dichloroquinoline (150 mg, 0.76 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4.0 mL) and NMP (1.0 mL). The


mmol, 1.15 equiv) at ambient temperature. After stirring for 4 h, the reaction was quenched by adding water (5 mL) and extracted

with EtOAc (3 x 5 mL). The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of

0% – 50% EtOAc/hexanes afforded 121 mg (93%) of the desired product as a colorless oil. TLC Rf = 0.22 (20% EtOAc/hexanes); 1H

NMR (600 MHz, CDCl3): δ 8.65 (d, J = 4.39 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.35 (dd, J = 8.9, 2.2 Hz,

1H), 7.08 (d, J = 4.4, 1H), 2.55 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 151.2, 148.5, 144.4, 134.9, 128.9, 127.2, 126.7, 125.3,

122.1, 18.6 ppm; IR (neat): υmax 1605, 1591, 1497, 1092, 886, 844, 831, 766 cm-1.

Structural elucidation

N

Me

Cl

2.70 (s, 3H)

7.28 (d, J = 4.2 Hz, 1H)7.55 (d, J = 9.0, 1.8 Hz, 1H)

7.95 (d, J = 9.0, 1.8 Hz, 1H)

8.14 (d, J = 1.8 Hz, 1H)

8.75 (d, J = 4.2 Hz, 1H) 8.65 (d, J = 4.4 Hz, 1H)

2.55 (s, 3H)

7.98 (d, J = 2.2 Hz, 1H)

7.08 (d, J = 4.4, 1H)7.35 (dd, J = 8.92, 2.2 Hz, 1H)

7.75 (d, J = 8.92 Hz, 1H)

Bose, D. S.; Kumar, R. K. Heterocycles, 2006, 68, 549. This work

N

H HH

•• •HMBCHMBC

Cl

N

Me

Cl

Note: The 1H NMR data for the product isolated from the Fe-catalyzed coupling does not match literature reported

data. The assignment is based on HMBC data.

6-chloro-2-methylbenzo[d]thiazole (2f)

MeMgBr


N

SMe

Cl

N

SClCl

To a vial was added 2,6-dichlorobenzo[d]thiazole (155 mg, 0.757 mmol) and Fe(acac)3 (10 mg, 0.028 mmol, 0.0375 equiv). The vial

was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4 mL) and NMP (1 mL). The


mmol, 1.15 equiv) at ambient temperature. The reaction was monitored by HPLC, which showed partial conversion after 1h.

Additional MeMgBr (0.12 mL, 0.17 mmol, 0.22 equiv) was added dropwise. After stirring for 16 h, the reaction was quenched by

adding water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layers were combined and concentrated in vacuo. The residue

was purified by silica gel chromatography using a gradient of 0% to 30% EtOAc/hexanes, affording 0.090 g (65%) of the desired

product as a colored solid. m.p. = 82 – 83 ºC (lit 84 – 86 ºC); TLC Rf = 0.82 (50% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ

7.84 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.7, 2.1 Hz, 1H), 2.82 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ

167.7, 152.1, 137.0, 130.8, 126.9, 123.3, 121.2, 20.3 ppm; IR (neat): υmax 3049, 2921, 1589, 1548, 1520, 1444, 1433, 1402, 1373,

1305, 1271, 1167 cm-1.

Structure Elucidation:

Literature data for 6-chloro-2-methylbenzothazole: Huang, X.; Tang, J. Tetrahedron 2003, 59, 4851: 1H NMR (CDCl3, 400 MHz): δ

7.83 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.38-7.41 (dd, J2 = 8.6 Hz, J1 = 2.0 Hz, 1H), 2.82 (s, 3H) ppm; IR (neat): υmax 1548, 1523, 1446,

1305, 1271 cm-1. For regioisomeric product see Cressier, D.; Prouillac C.; Hernandez, P.; Amourette, C.; Diserbo, M.; Lion, C.;

Rima, G. Bioorg. Med. Chem. 2009, 17, 5275: m.p. = 50 – 52 ºC; 1H NMR (CDCl3, 300.1 MHz): δ 7.01-7.81 (m, 4H), 2.32 (s, 3H)

ppm; 13C NMR (CDCl3, 75.4 MHz, CDCl3): δ 172.0, 152.0, 149.0, 136.0, 128.2, 122.3, 120.8, 21.5 ppm.

Structure elucidation

N

SMe

Cl

N

SMeCl

Bioorg. Med. Chem.17, 5275, 2003.

This work &Tetrahedron 2003

59, 4851.

methyl 5-chloro-2-methylbenzoate (2g)

MeMgBr

3.75 mol % Fe(acac)3Me

CO2Me

Cl

CO2Me

Cl

Cl

To a vial was added methyl 2,5-dichlorobenzoate (155 mg, 0.76 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial

was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4 mL) and NMP (1 mL). The


mmol, 1.15 equiv) at ambient temperature. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted

with EtOAc (3 x 5 mL). The organic layers were combined and concentrated in vacuo. Preparative thin layer chromatography using

5% EtOAc/hexanes to afforded 76 mg (54%) of the desired product as a clear oil. TLC Rf = 0.66 (20% EtOAc/hexanes); 1H NMR

(600 MHz, CDCl3): δ 7.89 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.2, 2.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H), 2.56 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 167.0, 138.9, 133.2, 132.0, 131.6, 131.0, 130.6, 52.3, 21.3 ppm; IR (neat): υmax 2952, 1725, 1484,

1435, 1291, 1244, 1116, 1079 cm-1.


CO2Me

Cl

H HH

H7.18 (d, J = 8.2 Hz, 1H)

nOe

7.36 (dd, J = 8.2, 2.4 Hz, 1H) 7.89 (d, J = 2.4 Hz, 1H)H H

Preparation of isomeric methyl 2-chloro-5-methylbenzoate to determine site selectivity:

CO2MeCl

CO2HCl

MeOH

H2SO4 (cat)Me Me

To a flask containing a solution of 2-chloro-5-methylbenzoic acid (500 mg, 2.93 mmol) in methanol (15 mL) was added 1 drop of

concentrated sulfuric acid. The mixture was heated to reflux for 18h and the solvent was evaporated by distillation. The resulting oil

was dissolved in EtOAc (15 mL), the mixture was washed with saturated aq. NaHCO3 (15 mL), dried (Na2SO4), and concentrated

under reduced pressure to afford 497 mg (92%) of the desired product as a lightly colored oil. 1H NMR (300 MHz, CDCl3): δ 7.63 (d,

J = 2.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2, 2.1 Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H) ppm. This compound has been

reported previously.iii

4-chloro-2-methylpyridine (2h)

MeMgBr


N Me

Cl

N Cl

Cl

4:1 THF: NMP To a vial was added 2,4-dichloropyridine (111 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4 mL) and NMP (1 mL). The reaction

mixture was treated dropwise with methylmagnesium bromide (0.62 mL of a 1.4 M solution in THF:toluene (1:3), 0.86 mmol, 1.15

equiv) at ambient temperature. After stirring for 4 h, the reaction was quenched by adding water (5 mL) and extracted with MTBE (2

x 5 mL). The organic layers were combined, washed with water (10 mL), and concentrated in vacuo. Silica gel chromatography

using a gradient of 20%-50% MTBE/hexanes afforded 72 mg (76%) of the desired product as a colorless oil. TLC Rf = 0.38 (50%

EtOAc/hexanes); Spectral data matches literature known valuesiv: 1H NMR (600 MHz, CDCl3): δ 8.38 (d, J = 5.4 Hz, 1H), 7.18 (d, J =

1.2 Hz, 1H), 7.11 (dd, J = 5.4, 1.0 Hz, 1H), 2.54 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 160.1, 150.0, 144.2, 123.6, 121.2, 24.3

ppm.


N

Me

ClN Me

ClH H

H

H

H

H

Eur. J. Org. Chem. 2004, 2004, 3477.

8.22 (s, 1H)

Reaction with THF:NMP(major)

8.22 (s, 1H)N

Me

Cl

H

H

H

8.38 (s, 1H)

Reaction with THF:NMP(minor)

2-chloro-4-methylpyridine (2i)

MeMgBr


N Cl

Me

N Cl

Cl

THF To a vial was added 2,4-dichloropyridine (200 mg, 1.35 mmol) and Fe(acac)3 (17.9 mg, 0.051 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (9 mL). The reaction mixture was

treated dropwise with methylmagnesium bromide (1.1 mL of a 1.4 M solution in THF:toluene (1:3), 1.55 mmol, 1.15 equiv) at

ambient temperature. After stirring for 2 h, the reaction was quenched by adding satd. NH4Cl (5 mL) and extracted with EtOAc (2 x 5

mL). The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 0%-50%

EtOAc/hexanes afforded 86 mg (50%) of the desired product as a colorless oil (potential loss in yield may be due to compound

volatility). Spectral data matches literature known valuesiv: 1H NMR (600 MHz, CDCl3): δ 8.23 (d, J = 5.1 Hz, 1H), 7.15 (m, J = 1.0

Hz, 1H), 7.03 (m, J = 5.1, 1.0 Hz, 1H), 2.35 (s, 3H) ppm. Spectral data shows the presence of residual EtOAc – special care was taken

to minimize product loss due to compound volatility.

N

Me

ClN Me

ClH H

H

H

H

H

Eur. J. Org. Chem. 2004, 2004, 3477.

8.22 (s, 1H)

Reaction with just THF(minor)

8.22 (s, 1H)N

Me

Cl

H

H

H

8.38 (s, 1H)

Reaction with just THF(major)

5-bromo-3-cyclopropyl-1-methylpyridin-2(1H)-one (3a)

N Me

O

BrN Me

O

Br

Br3.75 mol % Fe(acac)3

MgBr

To a vial was added 3,5-dibromo-1-methylpyridin-2(1H)-one (200 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375

equiv). The vial was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (4.0 mL) and NMP

(1.0 mL). The reaction mixture was treated with cyclopropylmagnesium bromide (2.48 mL of a 0.5 M solution in THF, 1.12 mmol,

1.50 equiv, added over 7.5 min using a syringe pump) at ambient temperature. After stirring for 2 h, the reaction was quenched with

saturated ammonium chloride, filtered through celite, and the resulting solids were washed with EtOAc (10 mL). The mixture was

poured into a separatory funnel, the top layer was collected and the bottom aqueous layer was extracted with EtOAc (3 x 5 mL). The

organic layers were concentrated, washed with brine (2 X 25 mL), dried (Na2SO4), and concentrated in vacuo. Silica gel

chromatography using a gradient of 0% – 50% EtOAc/hexanes to afforded 76 mg (50%) of the desired product as a light yellow solid.

m.p. = 91.9 – 93.9 ºC; TLC Rf = 0.1 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 7.20, (d, J = 2.6 Hz, 1H), 6.82 (d, J = 2.6

Hz, 1H), 3.48 (s, 3H), 2.08 (m, 1H), 0.91 (m, 2H), 0.57 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3): δ 162.1,137.1, 134.7, 134.6, 97.7,

37.9, 11.0, 8.25; IR (neat): υmax 1646, 1589, 1554, 1423, 1218, 1015, 906, 888, 771, 751 cm-1. Structure assigned based on analogy to

structure obtained for compound 2a.

3-chloro-1-cyclopropylisoquinoline (3b)

N ClN ClCl


MgBr

To a vial was added 1,3-dichloroisoquinoline (150 mg, 0.757 mmol) and Fe(acac)3 (10 mg, 0.0283 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5 mL). The reaction mixture was

treated dropwise with cyclopropylmagnesium bromide (3.47 mL of a 0.5 M solution in THF, 1.741 mmol, 2.30 equiv) at ambient

temperature. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5 mL). The

organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of

0% to 10% EtOAc/hexanes, affording 0.108 g (70%) of the desired product as a lightly colored semi-solid. TLC Rf = 0.73 (20%

EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.35 (d, J = 8.52 Hz, 1H), 7.70 (d, J = 8.26 Hz, 1H), 7.65 (m, 1H), 7.57 (m, 1H),

7.45 (s, 1H), 2.70 (m, 1H), 1.31 (m, 2H), 1.14 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3): δ 163.8, 145.0, 138.2, 130.7, 127.1, 126.7,

126.5, 125.4, 117.1, 13.6, 10.6; IR (neat): υmax 3093, 3001, 2923, 1619, 1573, 1546, 1433, 1412, 1294, 1163 cm-1.


N Cl

H 7.45 (s, 1H)

This work

N

H

Cl

7.55 (s, 1H)

W. O. Patent 03099274, 2003

1.04 - 1.00 (m, 4H)2.18 - 2.11 (m, 1H)

HH2.70 (m, 1H)

1.31 (m, 2H) and1.14 (m, 2H)

3-chloro-1-cyclopropyl-6-fluoroisoquinoline (3c)

N ClN ClCl


FF

MgBr

To a vial was added 1,3-dichloro-6-fluoroisoquinoline (163 mg, 0.757 mmol) and Fe(acac)3 (10 mg, 0.0283 mmol, 0.0375 equiv). The

vial was sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5 mL). The reaction mixture

was treated dropwise with cyclopropylmagnesium bromide (3.47 mL of a 0.5 M solution in THF, 1.74 mmol, 2.30 equiv) at ambient

temperature. After stirring for 2 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5 mL). The

organic layers were combined and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of

0% to 15% EtOAc/hexanes, affording 0.118 g (70%) of the desired product as a lightly colored semi-solid. TLC Rf = 0.69 (20%

EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.38 (dd, J = 9.2, 5.41(F) Hz, 1H), 7.41 (s, 1H), 7.34 (m, 1H), 7.31 (dd, J = 9.2, 2.5

(F) Hz, 1H), 2.65 (m, 1H), 1.31 (m, 2H), 1.15 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3): δ 163.6, 163.4 (d, J = 253.4 Hz, C-6 C-F),

146.1, 139.7 (d, J = 10.68 Hz, C-4a), 128.4 (d, J = 9.85 Hz, C-8), 123.6, 117.3 (d, J = 25.29 Hz, C-7), 116.5 (d, J = 5.15 Hz, C-4),

109.8 (d, J = 21.05 Hz, C-5), 13.6, 10.6 ppm; IR (neat): υmax 3062, 3003, 2919, 1629, 1585, 1557, 1451, 1365, 1345, 1203 cm-1.

Structure assigned based on analogy to structure obtained for compound 3b.

3-chloro-2-cyclopropylpyridine (3d)

N

Cl

N

Cl

Cl


MgBr

To a vial was added 2,3-dichloropyridine (111 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial was


reaction mixture was treated with cyclopropylmagnesium bromide (1.73 mL of a 0.5 M solution in THF, 0.86 mmol, 1.15 equiv,

added over 7.5 min using a syringe pump) at ambient temperature. After stirring for 1h, the reaction mixture was treated with

additional cyclopropylmagnesium bromide (0.86 mL of a 0.5 M solution in THF, 0.43 mmol, 0.58 equiv, added over 7.5 min using a

syringe pump) at ambient temperature. After stirring for 2h, the reaction was quenched with saturated ammonium chloride, filtered

through celite, and the resulting solids were washed with EtOAc (10 mL). The mixture was poured into a separatory funnel, the top

layer was collected and the bottom aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were concentrated,

washed with brine (2 X 10 mL), dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes to afforded 81 mg (70%) of the desired product as a light yellow oil. TLC Rf = 0.72 (20% EtOAc/hexanes); 1H NMR

(600 MHz, CDCl3): δ 8.28 (dd, J = 4.6, 1.19 Hz, 1H), 7.54 (dd, J = 8.0, 1.49, 1H), 6.93 (dd, J = 8.0, 4.6 Hz, 1H), 2.48 (m, 1H), 1.07

(m, 2H), 0.99 (m, 2H) ppm; 13C NMR (X MHz, CDCl3): δ 159.6, 147.3, 136.3, 131.1, 121.0, 13.7, 10.1; IR (neat): υmax 1576, 1448,

1132, 1053, 1024, 903, 790, 755 cm-1. Structure assigned based on analogy to structure obtained for compound 2d.

7-chloro-4-cyclopropylquinoline (3e)

NClNCl

Cl3.75 mol % Fe(acac)3

MgBr



reaction mixture was treated with cyclopropylmagnesium bromide (2.26 mL of a 0.5 M solution in THF, 1.13 mmol, 1.5 equiv, added

over 7.5 min using a syringe pump) at ambient temperature. After stirring for 2h, the reaction was quenched with saturated

ammonium chloride and extracted with EtOAc (3 x 5 mL). The organic layers were combined, washed with brine, and concentrated

in vacuo. Silica gel chromatography using a gradient of 0% – 40% EtOAc/hexanes to afforded 138 mg (90%) of the desired product

as a clear oil. TLC Rf = 0.37 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.72 (d, J = 4.6 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H),

8.06 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 9.0, 2.1 Hz, 1H), 6.94 (d, J = 4.6 Hz, 1H), 2.3 (m, 1H), 1.13 (m, 2H), 0.80 (m, 2H) ppm; 13C

NMR (151 MHz, CDCl3): δ 149.3, 148.0, 146.4, 133.0, 126.8, 125.2, 125.2, 123.5, 115.3, 10.0, 6.2 ppm; IR (neat): υmax 1605, 1588,

1422, 1306, 1073, 871, 820 cm-1. Structure assigned based on analogy to structure obtained for compound 2e.

2-chloro-4-cyclopropylpyridine (3h)

N ClN Cl

Cl3.75 mol % Fe(acac)3

MgBr



reaction mixture was treated with cyclopropylmagnesium bromide (2.25 mL of a 0.5 M solution in THF, 1.13 mmol, 1.5 equiv, added

over 7.5 min using a syringe pump) at 0 ºC. After stirring for 30 min, the reaction mixture was treated with additional

cyclopropylmagnesium bromide (0.8 mL of a 0.5 M solution in THF, 0.375 mmol, 0.5 equiv, added over 7.5 min using a syringe

pump) at 0 ºC. After stirring for 2h, the reaction was quenched with saturated ammonium chloride and extracted with EtOAc (3 x 5

mL). The organic layers were combined, washed with brine, and concentrated in vacuo. Silica gel chromatography using a gradient

of 0% – 40% EtOAc/hexanes to afforded 88 mg (76%) of the desired product as a clear oil. TLC Rf = 0.5 (20% EtOAc/hexanes); 1H

NMR (600 MHz, CDCl3): δ 8.17 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 1.0 Hz, 1H), 6.84 (dd, J = 5.2, 1.5 Hz, 1H), 1.84 (m, 1H), 1.11 (m,

1H), 0.8 (m, 1H) ppm; 13C NMR (151 MHz, CDCl3): δ 159.6, 147.3, 136.3, 131.13, 121.0, 13.7, 10.1 ppm; IR (neat): υmax 1593, 1542,

1470, 1458, 1396, 10887, 913, 827cm-1.


N Cl

H

• •• HMBCHMBC

4-(2-(1,3-dioxan-2-yl)ethyl)-7-chloroquinoline (4a)


NCl

Cl

NCl

O

O

O

OBrMg



reaction mixture was treated dropwise with (1,3-dioxan-2-ylethyl)magnesium bromide (2.26 mL of a 0.5 M solution in THF, 1.5

equiv) at ambient temperature. After stirring for 4 h, the reaction was quenched by adding water (5 mL) and extracted with EtOAc (3

x 5 mL). The organic layers were combined and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes afforded 188 mg (90%) of the desired product as a colorless oil. TLC Rf = 0.12 (20% EtOAc/hexanes); 1H NMR (600

MHz, CDCl3): δ 8.71 (d, J = 4.6 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 9.0, 2.1 Hz, 1H), 7.16 (d, J=

4.6 Hz, 1H), 4.51 (t, J = 4.84 Hz, 1H), 4.06 (m, 2H), 3.69 (m, 2H), 3.08 (t, J = 16.0, 8.0 Hz, 2H), 2.04 (m, 1H), 1.94 (m, 2H), 1.29 (d,

J = 13.4 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl3): δ 151.1, 148.6, 148.2, 134.8, 128.8, 127.2, 125.9, 125.1, 120.9, 110.9, 66.8, 35.1,

26.0, 25.7 ppm; IR (neat): υmax 2961, 2852, 1591, 1241, 1145, 1131, 887 cm-1. Structure assigned based on analogy to structure

obtained for compound 2e.

7-chloro-4-propylquinoline (4b)


NCl

Cl

NCl

Me

MeBrMg



reaction mixture was treated dropwise with n-propylmagnesium bromide (0.43 mL of a 2.0 M solution in THF, 1.15 equiv) at ambient

temperature. After stirring for 75 min, the reaction was quenched by adding saturated aqueous NH4Cl (3 mL) and extracted with

MTBE (15 mL). The organic layer was concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes afforded 120 mg (78%) of the desired product as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 8.72 (d, J = 4.4 Hz,

1H), 8.04 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 9.0, 2.2 Hz, 1H), 7.12 (d, J = 4.4 Hz, 1H), 2.95 (m, 2H), 1.71 (m,

2H), 0.95 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ 151.2, 148.8, 148.7, 134.8, 129.0, 127.2, 126.1, 125.1, 121.0, 34.0,

23.2, 14.1 ppm; IR (neat): υmax 2860, 2931, 2871, 1605, 1589, 1497, 881, 833 cm-1. Structure assigned based on analogy to structure


7-chloro-4-cyclohexylquinoline (4c)


NCl

Cl

NClBrMg



reaction mixture was treated dropwise with cyclohexylmagnesium bromide (0.95 mL of a 17% solution in THF g, ~1.0 M, 1.15 equiv)

at ambient temperature. After stirring for 75 min, the reaction was quenched by adding saturated aqueous NH4Cl (3 mL) and extracted

with MTBE (15 mL). The organic layer was concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes afforded 93 mg (68%) of the desired product as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 8.81 (d, J = 4.6 Hz,

1H), 8.09 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.46 (dd, J = 9.1, 2.3 Hz, 1H), 7.24 (d, J = 4.6 Hz, 1H), 3.24 (m, 1H), 1.94-

1.32 (m, 10H) ppm; 13C NMR (151 MHz, CDCl3): δ 153.7, 151.5, 149.0, 134.8, 129.3, 127.2, 125.5, 124.7, 117.8, 39.0, 33.6, 27.0,

26.3 ppm; IR (neat): υmax 2925, 2851, 1603, 1586, 1497, 1448, 881, 860, 822 cm-1. Structure assigned based on analogy to structure


3-ethyl-1-methylisoquinoline (5)

NMeN ClCl


MeMgBr, THF; then3.75 mol % Fe(acac)3

NMP, EtMgBr

Me

To a vial was added 1,3-dichloroisoquinoline (149 mg, 0.75 mmol) and Fe(acac)3 (9.9 mg, 0.028 mmol, 0.0375 equiv). The vial was

sealed with a septum cap, evacuated, purged with nitrogen and the mixture dissolved in THF (5.0 mL). The reaction mixture was

treated dropwise with methylmagnesium bromide (0.62 mL of a 1.4 M solution in THF:toluene (1:3), 0.86 mmol, 1.15 equiv) at

ambient temperature. After stirring for 2h (reaction monitored by HPLC for complete conversion), a solution of Fe(acac)3 (9.9 mg,

0.028 mmol, 0.0375 equiv) in NMP (1 mL) and a solution of ethylmagnesium bromide (1.5 mL of a 1.0 M solution in THF, 2.0 equiv)

was added over 7.5 min at ambient temperature using a syringe pump. After stirring for 2h, the reaction was quenched by adding

saturated aqueous NH4Cl (10 mL), filtered through celite, and poured into a separatory funnel. The top organic layer was collected

and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined and washed with brine (2 x 25 mL),

dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 100% EtOAc/hexanes afforded 107

mg (84%) of the desired product as a light yellow oil. TLC Rf = 0.38 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.03 (d, J

= 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.59 (m, 1H), 7.47 (m, 1H), 7.30 (s, 3H), 2.95 (q, J = 7.7 Hz, 1H), 2.93 (s, 3H), 1.39 (t, J = 7.7

Hz, 1H) ppm; 13C NMR (151 MHz, CDCl3): δ 157.8, 155.4, 136.6, 129.6, 126.6, 125.9, 125.7, 125.3, 30.9, 22.0, 14.0 ppm; IR (neat):

υmax 2965, 2934, 1625, 1591, 1568, 1443, 1390, 1335, 878, 748 cm-1.


• HMBCHMBCN

Me

H

H

•

4-(2-(1,3-dioxan-2-yl)ethyl)-2-ethylpyridine (6)

N

Et

N

ClCl


THF:NMP (4:1); then

3.75 mol % Fe(acac)3NMP, EtMgBr

O

OMgBrO

O



reaction mixture was treated dropwise with (1,3-dioxan-2-ylethyl)magnesium bromide (4.5 mL of a 0.5 M solution in THF, 1.5 equiv,

added over 7.5 minutes by syringe pump) at ambient temperature. After stirring for 1h (reaction monitored by HPLC for complete

conversion), a solution of Fe(acac)3 (19.9 mg, 0.056 mmol, 0.0375 equiv) in NMP (1 mL) and a solution of ethylmagnesium bromide

(3.02 mL of a 1.0 M solution in THF, 2.0 equiv) was added over 10 min at ambient temperature. After stirring for 2h, the reaction was

quenched by adding saturated aqueous NH4Cl (10 mL), filtered through celite, and poured into a separatory funnel. The top organic

layer was collected and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined and washed with

brine (2 x 25 mL), dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography using a gradient of 0% – 50%

EtOAc/hexanes afforded 286 mg (86%) of the desired product as a mixture of inseparable regioisomeric products. TLC Rf = 0.1 (20%

EtOAc/hexanes); 1H NMR (600 MHz, CDCl3, major isomer): δ 8.23 (d, J = 5.1 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J = 5.1 Hz, 1H), 4.35 (t,

J = 5.10, 1H), 3.92 (m, 2H), 2.57 (m, 2H), 2.63 (q, J = 7.5 Hz, 2H), 2.53 (m, 2H), 1.90 (m, 1H), 1.73 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H),

1.06 (m, 1H) ppm; 13C NMR (151 MHz, CDCl3, major isomer): δ 163.1, 151.2, 148.7, 122.0, 121.0, 100.8, 66.6, 35.3, 31.0, 29.2, 25.6,

13.7 ppm.


N Et• •• HMBCHMBC

OO

HH

4-(2-(1,3-dioxan-2-yl)ethyl)-2-chloropyridine (7)


N

Cl

N

O

O

O

OBrMgCl Cl



reaction mixture was treated dropwise with (1,3-dioxan-2-ylethyl)magnesium bromide (2.25 mL of a 0.5 M solution in THF, 1.5

equiv) at ambient temperature. After stirring for 1h, additional (1,3-dioxan-2-ylethyl)magnesium bromide (0.75 mL of a 0.5 M

solution in THF, 0.5 equiv) at ambient temperature. After stirring for 4h, the reaction was quenched by adding water (5 mL) and

extracted with EtOAc (3 x 5 mL). The organic layers were combined and concentrated in vacuo. Analysis of the crude reaction

mixture by 1H NMR showed that the reaction had gone to roughly 80% conversion (selectivity was determined to be 4.8:1 based on 1H

NMR analysis of the crude reaction mixture. Silica gel chromatography using a gradient of 0% – 50% EtOAc/hexanes afforded 127

mg (75%) of the desired product as a colorless oil. TLC Rf = 0.17 (20% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3): δ 8.19 (d, J =

5.1 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J = 5.10 Hz, 1H), 4.45 (t, J = 5.00 Hz, 1H), 4.03 (m, 2H), 3.68 (m, 2H), 2.66 (m, 2H), 1,99 (m, 1H),

1.83 (m, 2H), 1.28 (m, 1H) ppm; 13C NMR (151 MHz, CDCl3): δ 154.2, 151.3, 149.2, 124.0, 122.5, 100.4, 66.8, 34.9, 28.8, 25.6 ppm;

IR (neat): υmax 2962, 2854, 1593, 1387, 1239, 1146, 1134, 1085, 1002, 892 cm-1. Structure assigned based on analogy to structure

obtained for compound 3j and 7.

Trace metal analysis for Fe(acac)3 used for the entire study:

Co = < 3 ppm

Cu = < 3 ppm

Mn = 8 ppm

Pd = 81 ppm

Ni = 6 ppm

Ag = 22 ppm

Zn = 3 ppm

Table 1. Crystal data and structure refinement for gscb015.

X-ray ID gscb015

Sample/notebook ID 76003-64-01

Empirical formula C10 H8 Cl N

Formula weight 177.62

Temperature 100(2) K

Wavelength 1.54178 Å

Crystal system Monoclinic

Space group P2(1)/c

Unit cell dimensions a = 6.7894(2) Å α= 90°.

b = 18.0944(5) Å β= 110.484(2)°.

c = 7.2390(2) Å γ = 90°.

Volume 833.08(4) Å3

Z 4

Density (calculated) 1.416 Mg/m3

Absorption coefficient 3.513 mm-1

F(000) 368

Crystal size 0.05 x 0.05 x 0.02 mm3

Crystal color/habit colorless needle

Theta range for data collection 4.89 to 67.69°.

Index ranges -8<=h<=8, -21<=k<=21, -8<=l<=6

Reflections collected 10339

Independent reflections 1472 [R(int) = 0.0308]

Completeness to theta = 67.00° 97.8 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.9331 and 0.8439

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 1472 / 0 / 110

Goodness-of-fit on F2 1.075

Final R indices [I>2sigma(I)] R1 = 0.0326, wR2 = 0.0847

R indices (all data) R1 = 0.0369, wR2 = 0.0879

Largest diff. peak and hole 0.326 and -0.139 e.Å-3

X-Ray Crystal Structure for Quinoline 2e

References:

i (a) Ashton, W. T.; Sisco, R. M.; Kieczykowski, G. R.; Yang, Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G.R.; Ren, R. N.; Wu, T.-J.; Shen, X.; Lyons, K. A.; Mao, A.-H.; Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Cheng, K.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2001, 11, 2597. (b) Buzuya, M.; Noguchi, A.; Mano, E.; Okuda, T. Bull. Chem. Soc. Jpn. 1985, 58, 1149. (c) Comins, D.L.; Lyle, R.E.; J. Org. Chem. 1976, 41, 2065. (d) Morrow, C. J.; Rapoport, H. J. Org. Chem. 1974, 39, 2116. ii (a) Spectral data for 3-chloro-2-methyl pyridine: Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6, 3517. (a) Spectral data for 2-chloro-3-methyl pyridine: Narendar, P.; Gangadasu, B.; Ramesh, Ch. Raju, B. C.; Rao, V. J. Synth. Commun. 2004, 34, 1097. iii Universite, L.; Attardo, G.; Tripathy, S.; Gagnon, M. Methyl Sulfanyl Pyrimidines Useful as Antiinflammatories, Analgesics, and Antiepileptics. WIPO Pat. Appl. WO2010/132999 A1, 2010. iv Connon, S. J.; Hegarty, A. F. Eur. J. Org. Chem. 2004, 2004, 3477.

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

ppm

3.00

1.130.800.970.97

0.97

PS-7

3945

-08

Ala

n D

eese

, Sep

. 15,

201

17 8

94

5

6

10

N 1

23

CH

312

Cl

11

7.6

7.7

7.8

7.9

8.0

8.1

ppm

1.13

0.80

0.97

0.97

0.978

56

7

3

12

TMS

xx

x

CD

Cl3

8

2b

160

150

140

130

120

110

100

9080

7060

5040

3020

10pp

m

-0.00

22.10

76.8377.0477.25

118.08

125.81126.29126.51127.22130.87

137.94

144.32

159.97

PS-7

3945

-08

Ala

n D

eese

, Sep

. 15,

201

1

7 89

4

5

6

10

N 1

23

CH

312

Cl

11

126.

012

6.5

127.

0pp

m

125.81

126.29

126.51

127.22

10

12

CD

Cl3

2

4

63

75

9

82b

600

MH

z Pr

oton

NM

R D

ata

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

ppm

3.00

0.960.96

0.97

3 2

4 N 1

5 6

Cl8

CH3

7

6

5

3

7

TMS

73945-17

1H N

MR

(500

MH

z, C

DC

l3)

Shi

ft pp

m 2

.54

(s,1

H)

Shi

ft pp

m 7

.11

(dd,

J=5

.40H

z, 1

.60H

z, 1

H)

Shi

ft pp

m 7

.17

(d, J

=1.6

0 H

z, 1

H)

Shi

ft pp

m 8

.39

(d, J

=5.4

0 H

z, 1

H)

2h

13C

NM

R D

ata

160

150

140

130

120

110

100

9080

7060

5040

3020

10ppm

-0.00

24.27

76.8277.0777.33

121.23123.56

144.19

150.01

160.06

73945-17

3 2

4 N 1

5 6

Cl8

CH3

7

2

6

4

3

5

CDCl3

7

TMS

2h

600

MH

z Pr

oton

NM

R D

ata

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

ppm

3.00

0.950.93

0.94

SM-7

2202

-210

2-ch

loro

-4-m

ethy

l-pyr

idin

eA

lan

Dee

se J

un 2

6, 2

013

5 6N 1

2

34CH3

8

Cl7

6

5

3

8

1H N

MR

(600

MH

z, C

DC

l3)

Shi

ft pp

m 2

.35

(d, J

=0.6

6 H

z, 1

H)

Shi

ft pp

m 7

.03

(m, J

=1.0

3 H

z,5.

10H

z 1

H)

Shi

ft pp

m 7

.15

(m, J

=0.7

2 H

z, 1

H)

Shi

ft pp

m 8

.23

(d, J

=5.1

0 H

z, 1

H)

2i

13C

NM

R D

ata

2030

4050

6070

8090

100

110

120

130

140

150

ppm

20.87

76.9977.2077.41

124.98

149.40150.56151.65

SM-7

2202

-210

2-ch

loro

-4-m

ethy

l-pyr

idin

eA

lan

Dee

se J

un 2

6, 2

013

5 6N 1

2

34CH3

8

Cl7

2

4

6

35

CD

Cl3

8

2i

1 H-1

H D

QF-

CO

SY D

ATA

ppm

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

ppm

1 2 3 4 5 6 7 8

SM-7

2202

-210

2-ch

loro

-4-m

ethy

l-pyr

idin

eA

lan

Dee

se J

un 2

6, 2

013

1 H-1

3 C M

ultip

licity

Edi

ted

HSQ

C D

ata

CH

and

CH

3 in

Red

and

CH

2 in

Blu

e

ppm

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

ppm20 40 60 80 100

120

140

SM-7

2202

-210

2-ch

loro

-4-m

ethy

l-pyr

idin

eA

lan

Dee

se J

un 2

6, 2

013

1 H-1

3 C H

MB

C D

ata

ppm

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

ppm20 30 40 50 60 70 80 90 100

110

120

130

140

150

SM-7

2202

-210

2-ch

loro

-4-m

ethy

l-pyr

idin

eA

lan

Dee

se J

un 2

6, 2

013

chemoselective sp2 sp3 cross-couplings: iron-catalyzed alkyl transfer ... · page 1 chemoselective...

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