Synthesis of Amino-Substituted Indoles using The Bartoli Reaction

55 Pages·2012·4.45 MB·English

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
Supplementary Information

Synthesis of Amino-Substituted Indoles using The Bartoli Reaction
Laura Wylie, Paolo Innocenti, Daniel K. Whelligan and Swen Hoelder

Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The
Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey,
SM2 5NG, UK

Contents

S2. Experimental procedures for the synthesis of substrates
S16. NMR Spectra of Nitroaniline compounds 1, 4b-l (Table 1 and Table 2)
S28. NMR Spectra of Nitroaniline compounds 6a-c (Table 3)
S31. NMR Spectra of Nitroaniline compounds 8a-k, 12 (Table 4)
S38. NMR Spectra of Indoles 3, 5a-l (Table 1 and Table 2)
S46. NMR Spectra of Indoles 7a-c (Table 3)
S49. NMR Spectra of Indoles 3a-c, 9a-k (Table 4)
S1
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
Synthesis of reaction substrates:

tert-Butyl 4-bromo-3-nitrophenylcarbamate (1) To a suspension of 4-bromo-3-
nitroaniline (2.0 g, 9.22 mmol) in MeCN (46 ml) were added Et N (2 ml, 27.6 mmol), DMAP
3
(0.11 g, 0.92 mmol) and di-tert-butyl dicarbonate (3.02 g, 13.8 mmol) sequentially. This
solution was then stirred overnight at room temperature. The solution was partitioned
between EtOAc (100 ml) and brine (50 ml), and concentrated. The crude mixture was
purified using silica column chromatography (10% EtOAc in cyclohexane) to yield the title
compound as white needles (1.963 g, 67%). m.p = 119-120°C; R = 0.32 (10% EtOAc in
f
cyclohexane); 1H NMR (500MHz, CDCl ) δ 1.53 (9H, s), 6.71 (1H, br s), 7.39 (1H, dd, J =
3
8.5, 2.5), 7.61 (1H, d, J = 8.5), 8.05 (1H, d, J = 2.5); 13C NMR (126MHz, CDCl ) δ 28.2,
3
82.0, 106.6, 115.0, 122.4, 135.1, 138.8, 150.1, 152.0; IR (film) 3337, 1731, 1585, 1394,
1369, 1240, 1155; HRMS (ESI) m/z calcd for C H BrN O [M – Boc]+ 214.9456, found [M –
6 4 2 2
Boc + H]+ 214.9460; HPLC purity >95%.

N-benzyl-4-bromo-3-nitroaniline (4b) Benzaldehyde (0.35 ml, 3.456 mmol) and 4-bromo-
3-nitroaniline (0.50 g, 2.304 mmol) were added to a solution of dibutyl tin dichloride (70
mg, 0.2304 mmol) in THF (4.6 ml) at rt in a microwave vial. Phenylsilane (0.44 ml, 4.608
mmol) was added and the vial was capped. The mixture was heated with stirring in a
microwave for 7 minutes (2 mins ramp time) at 100 °C. The resultant mixture was cooled
and concentrated in vacuo. The residue was purified by silica column chromatography (10-
35% DCM in cyclohexane) to yield the title compound as a bright orange oily solid (0.395
g, 56%). m.p = 51-53°C; R = 0.39 (20% EtOAc in cyclohexane); 1H NMR (500MHz,
f
CDCl ) δ 4.34 (2H, d, J = 5, 1’-H), 4.42 (1H, br s, 1-NH), 6.64 (1H, dd, J = 9, 3, 5-H), 7.06
3
(1H, d, J = 3, 6-H), 7.29-7.34 (3H, m, 4’-H, 5’-H), 7.35-7.39 (2H, m, 3’-H), 7.41 (1H, d, J =
9, 2-H); 13C NMR (126MHz, CDCl ) δ 48.1 (1’-C), 100.1 (4-C), 109.0 (6-C), 117.7 (5-C),
3
S2
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
127.5 (3’-C), 128.0 (5’-C), 129.1 (4’-C), 135.3 (2-C), 137.6 (2’-C), 147.9 (1-C), 150.6 (3-C);
IR (solid) 3405, 1607, 1537, 1336; HRMS (ESI) m/z calcd for C H BrN O [M+H]+
13 12 2 2
307.0077, found [M+H]+ 307.0055; HPLC purity >98%.

4-bromo-N-(4-methoxybenzyl)-3-nitroaniline (4c) 4-methoxybenzaldehyde (71 µl, 0.461
mmol) and 4-bromo-3-nitroaniline (0.11 g, 0.461 mmol) were added to a solution of dibutyl
tin dichloride (14 mg, 0.046 mmol) in THF (0.92 ml) in a microwave vial. Phenylsilane (88
µl, 0.922 mmol) was added and the vial was capped. The mixture was heated with stirring
in a microwave for 7 minutes (2 mins ramp time) at 100 °C. The resultant mixture was
cooled and concentrated in vacuo. The residue was purified by silica column
chromatography (10-35% DCM in cyclohexane) to yield the title compound as a yellow
solid (0.132 g, 85%). m.p = 82-83°C; R = 0.29 (30% DCM in cyclohexane); 1H NMR
f
(500MHz, CDCl ) δ 3.81 (3H, s), 4.26 (2H, s), 6.64 (1H, dd, J = 9, 3), 6.87-6.92 (2H, m),
3
7.05 (1H, d, J = 3), 7.25 (2H, d, J = 9), 8.78 (1H, d, J = 9, 5); 13C NMR (126MHz, CDCl ) δ
3
47.6, 55.3, 99.9, 108.8, 114.3, 117.6, 128.8, 129.4, 135.1, 147.6, 150.5, 159.3; IR (film)
3367, 1504, 1238, 1206; HRMS (ESI) m/z calcd for C H BrN O [M-H]- 335.0037, found
14 12 2 3
[M-H]- 335.0048; HPLC purity >95%.

benzyl 4-bromo-3-nitrophenylcarbamate (4d) 4-bromo-3-nitroaniline (0.50 g, 2.30
mmol) and K CO (0.35 g, 2.53 mmol) were added to a flask. CHCl (7 ml) and water (50
2 3 3
µl) were added to the flask and the suspension was cooled to 0°C. Benzyl chloroformate
(0.52 ml, 2.53 mmol) was added dropwise with vigorous stirring. Once addition was
complete ice water was added (5 ml), then saturated aq. NaHCO (5 ml). The aqueous
3
layer was separated and extracted using DCM (3 x10 ml), and the organic layer dried over
MgSO and concentrated in vacuo. The crude material was purified by silica column
4
chromatography (5-30% EtOAc in cyclohexane) to yield the title compound as a bright
S3
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
yellow waxy solid (0.801 g, 99%). m.p = 113-114°C; R = 0.56 (30% EtOAc in
f
cyclohexane); 1H NMR (500MHz, CDCl ) δ 5.22 (2H, s), 6.86 (1H, br s), 7.34-7.40 (5H, m),
3
7.43 (1H, dd, J = 9, 2), 7.62 (1H, d, J = 9), 8.03 (1H, d, J = 2); 13C NMR (126MHz, CDCl )
3
δ 67.8, 107.4, 115.2, 122.6, 128.5, 128.7, 128.8, 135.3, 138.2, 150.1, 152.7; IR (solid)
3313, 1724, 1527, 1228; HRMS (ESI) m/z calcd for C H BrN O [M+H]+ 350.9975, found
14 12 2 4
[M+H]+ 350.9970; HPLC purity >95%.

Allyl 4-bromo-3-nitrophenylcarbamate (4e) 4-bromo-3-nitroaniline (0.50 g, 2.30 mmol)
was dissolved in THF (5 ml) and cooled to 0°C. DIPEA (0.27 ml, 2.76 mmol) was added,
followed by allyl chloroformate (0.35 ml, 2.53 mmol) dropwise. The solution was stirred for
2h. The solution was partitioned between ether (30 ml) and saturated aq. NaHCO (30 ml).
3
The aqueous layer was separated and extracted using EtOAc (3 x 20 ml), dried over
MgSO and concentrated in vacuo. The crude material was purified by silica column
4
chromatography (0-30% EtOAc in cyclohexane) to yield the title compound as a bright
yellow waxy solid (0.694 g, quantitative yield). R = 0.54 (30% EtOAc in cyclohexane); 1H
f
NMR (500MHz, CDCl ) δ 4.69 (2H, d, J = 5.5), 5.29 (1H, dd, J = 10, 1), 5.37 (1H, dq, J =
3
17, 1), 5.95 (1H, ddt, J = 17, 10, 5.5), 7.13 (1H, br s), 7.46 (1H, dd, J = 8.5, 2.5), 7.62 (1H,
d, J = 8.5), 8.04 (1H, d, J = 2.5); 13C NMR (126MHz, CDCl ) δ 66.5, 107.3, 115.3, 118.9,
3
122.8, 131.8, 135.3, 138.3, 150.0, 152.8; IR (film) 3344, 3106, 1739, 1217, 923, 822;
HRMS (ESI) m/z calcd for C H BrN O [M + H]+ 300.9818, found [M + H]+ 300.9820;
10 10 2 4
HPLC purity >95%.

N-(4-bromo-3-nitrophenyl)acetamide (4f) 4-bromo-3-nitroaniline (0.50 g, 2.30 mmol)
was dissolved in DCM (3 ml). Pyridine (0.32 ml) was added and then acetyl chloride (0.22
ml, 2.53 mmol) was added slowly. After the solution was stirred for 2h it was washed with
1N HCl (5 ml) and brine (10 ml). The aqueous layer was separated and extracted using
S4
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
DCM (3 x 10 ml) and the organic layer was dried over MgSO and concentrated in vacuo.
4
The crude material was purified by silica column chromatography (15-50% EtOAc in
cyclohexane) to yield the title compound as a pale yellow crystalline solid (0.421 g, 70%).
m.p = 147-149°C; R = 0.26 (30% EtOAc in cyclohexane); 1H NMR (500MHz, CDCl ) δ
f 3
2.22 (3H, s), 7.45 (1H, br s), 7.61 (1H, dd, J = 9, 2), 7.65 (1H, d, J = 9), 8.13 (1H, d, J = 2);
13C NMR (126MHz, CDCl ) δ 24.6, 108.2, 116.3, 123.8, 135.3, 138.0, 150.0, 168.5; IR
3
(solid) 3249, 1538, 1318; HRMS (ESI) m/z calcd for C H BrN O [M + H]+ 260.9693, found
8 8 2 3
[M + H]+ 260.9694; HPLC purity >95%.

N-(4-bromo-3-nitrophenyl)benzamide (4g) 4-bromo-3-nitroaniline (0.50 g, 2.30 mmol)
was dissolved in DCM (3 ml). Pyridine (0.32 ml) was added and then benzoyl chloride
(0.43 ml, 2.53 mmol) was added slowly. After the solution was stirred for 2h it was washed
with 1N HCl (5 ml) and brine (10 ml). The aqueous layer was separated and extracted
using DCM (3 x 10 ml) and the organic layer was dried over MgSO and concentrated in
4
vacuo. The crude material was purified by silica column chromatography (5-25% EtOAc in
cyclohexane) to yield the title compound as a pale yellowy green crystalline solid (0.484 g,
65%). m.p = 165-166°C; R = 0.44 (30% EtOAc in cyclohexane); 1H NMR (500MHz,
f
CDCl ) δ 7.53 (2H, dd, J = 10, 5), 7.58-7.62 (1H, m), 7.72 (1H, d, J = 9), 7.79 (1H, dd, J =
3
9, 2.5), 7.88 (2H, dd, J = 5, 3), 7.99 (1H, br s), 8.29 (1H, d, J = 2.5); 13C NMR (126MHz,
CDCl ) δ 108.5, 116.8, 124.2, 127.1, 129.1, 132.6, 133.8, 135.4, 138.2, 151.4, 165.7; IR
3
(solid) 3407, 1682, 1510, 1308; HRMS (ESI) m/z calcd for C H BrN O [M + H]+
13 10 2 3
322.9850, found [M + H]+ 322.9849; HPLC purity >95%.

N-(4-bromo-3-nitrophenyl)-4-methylbenzenesulfonamide (4h) 4-bromo-3-nitroaniline
(0.50 g, 2.30 mmol) was dissolved in DCM (7 ml). Pyridine (1 ml) was added and then
tosyl chloride (0.53 g, 2.77 mmol) was added slowly. The solution was stirred overnight, at
S5
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
which point the solution was washed with 5% HCl (5 ml). The aqueous layer was
separated and extracted using DCM (3 x 10 ml) and the organic layer was dried over
MgSO and concentrated in vacuo. The crude material was purified by silica column
4
chromatography (0-30% EtOAc in cyclohexane) to yield the title compound as a red/peach
crystalline solid (0.826 g, 97%). m.p = 130-132°C; R = 0.45 (30% EtOAc in cyclohexane);
f
1H NMR (500MHz, CDCl ) δ 2.42 (3H, s), 7.22 (1H, dd, J = 8.5, 2.5), 7.31 (2H, d, J = 8),
3
7.59 (1H, d, J = 6), 7.60 (1H, s), 7.74 (2H, d, J = 8); 13C NMR (126MHz, CDCl ) δ 21.6,
3
109.6, 117.0, 124.6, 127.3, 130.2, 135.2, 135.8, 137.1, 145.1, 150.0; IR (film) 3253, 1599,
1531, 1474, 1328; HRMS (ESI) m/z calcd for C H BrN O S [M]+ 369.9623, found [M]+
13 11 2 4
369.9627; HPLC purity >95%.

tert-Butyl 4-bromo-3-nitrophenyl(4-methoxybenzyl)carbamate (4i) 4-bromo-N-(4-
methoxybenzyl)-3-nitroaniline (0.56 g, 1.65 mmol) was dissolved in THF (8 ml). Boc O
2
(0.72 g, 3.29 mmol), DIPEA (0.39 ml, 4.12 mmol) and DMAP (0.30 g, 2.47 mmol) were
added in sequence and the resulting solution was stirred overnight. The solution was
concentrated in vacuo and the crude material was purified by silica column
chromatography (0-10% EtOAc in cyclohexane) to yield the title compound as a pale
yellow oil (0.512 g, 71%). R = 0.29 (5% EtOAc in cyclohexane); 1H NMR (500MHz, CDCl )
f 3
δ 1.47 (9H, s), 3.79 (3H, s), 4.82 (2H, s), 6.85 (2H, d, J = 8.5), 7.12 (2H, dd, J = 6.5, 2),
7.21 (1H, dd, J = 8.5, 2.5), 7.59 (1H, d, J = 8.5), 7.75 (1H, d, J = 2.5); 13C NMR (126MHz,
CDCl ) δ 28.2, 52.7, 55.2, 82.0,110.3, 114.2, 123.2, 128.5, 129.3, 130.5, 134.8, 142.8,
3
149.5, 153.8, 159.1; IR (solid) 1700, 1536, 1366, 1244, 1152, 1033; HRMS (ESI) m/z calcd
for C H BrN O Na [M + Na]+ 461.0508, found [M + Na]+ 461.0510; HPLC purity >95%.
19 21 2 5

Benzyl 4-bromo-3-nitrophenyl(4-methoxybenzyl)carbamate (4j) 4-bromo-N-(4-
methoxybenzyl)-3-nitroaniline (0.243 g, 0.722 mmol) was dissolved in THF and cooled to
S6
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
0°C. NaH (60% w/w in mineral oil, 32 mg, 0.794 mmol) was slowly added to the solution
and the mixture was warmed to rt. After stirring for 1h, benzyl chloroformate (0.19 ml,
0.938 mmol) was added dropwise and the solution was left to stir for 72h. The solution was
concentrated in vacuo and the crude material was purified by silica column
chromatography (0-15% EtOAc in cyclohexane) to yield the title compound as a pale
yellow oil (0.322 g, 95%). R = 0.54 (30% EtOAc in cyclohexane); 1H NMR (500MHz,
f
CDCl ) δ 3.80 (3H, s), 4.86 (2H, s), 5.22 (2H, s), 6.83 (2H, d, J = 8.5), 7.10 (2H, d, J = 8.5),
3
7.20 (1H, d, J = 7.5), 7.29 (2H, dd, J = 9, 3), 7.32-7.38 (3H, m), 7.62 (1H, d, J = 8.5), 7.71
(1H, br s); 13C NMR (126MHz, CDCl ) δ 53.2, 55.3, 68.2, 111.4, 114.2, 123.7, 128.1,
3
128.4, 128.57-128.62, 129.0, 131.2, 135.1, 135.7, 142.0, 149.6, 154.8, 159.2; IR (film)
1732, 1373, 1329, 1044; HRMS (ESI) m/z calcd for C H BrN O [M-PMB] 348.9824,
14 10 2 4
found [M-PMB] 348.9830; HPLC purity >95%.

tert-butyl 4-bromo-3-nitrophenyl(ethyl)carbamate (4k) 4-bromo-3-nitroaniline (0.50 g,
2.304 mmol) and acetaldehyde (0.13 ml, 2.304 mmol) were dissolved in DCE (8 ml) and
stirred at rt. NaBH(OAc) (0.68 g, 3.226 mmol) was added portionwise, followed by glacial
3
AcOH (0.13 ml). The solution was stirred at rt for 24h, at which point it was quenched with
1N NaOH (2 ml). Water was added, and the aqueous layer was separated and extracted
using EtOAc (4 x 20 ml). The combined organic layers were dried over MgSO ,
4
concentrated in vacuo and the crude material purified by silica column chromatography (0-
20% EtOAc in cyclohexane) to yield the title compound as a bright orange solid (0.243 g,
43%). m.p = 55-57°C; R = 0.45 (20% EtOAc in cyclohexane); 1H NMR (500MHz, CDCl ) δ
f 3
1.30 (3H, t, J = 7), 3.19 (2H, qd, J = 7, 5), 3.95 (1H, br s), 6.63 (1H, dd, J = 8.5, 3), 7.02
(1H, d, J = 3), 7.43 (1H, d, J = 8.5); 13C NMR (126MHz, CDCl ) δ 14.4, 38.3, 99.3, 108.3,
3
117.4, 135.1, 148.1, 150.5; IR (solid) 3392, 1606, 1521, 1328; HRMS (ESI) m/z calcd for
C H BrN O Na [M+Na]+ 266.9740, found [M+Na]+ 266.9735; HPLC purity >95%.
8 9 2 2
S7
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
4-bromo-N-ethyl-3-nitroaniline (0.25 g, 1.02 mmol) and di-tert-butyl dicarbonate (0.45 g,
2.04 mmol) were dissolved in THF (5 ml). DMAP (0.19 g, 1.53 mmol) and Et3N (0.36 ml,
2.55 mmol) were added and the solution was left to stir overnight. Water was added, and
the aqueous layer was separated and extracted using EtOAc (3 x 5 ml). The organic layers
were combined, dried over MgSO and concentrated in vacuo. The crude material was
4
purified by silica column chromatography (0-10% EtOAc in cyclohexane) to yield the title
compound as a yellow oil (0.280 g, 80%). R = 0.43 (20% EtOAc in cyclohexane); 1H NMR
f
(500MHz, CDCl ) δ 1.19 (3H, t, J = 7), 1.47 (9H, s), 3.72 (2H, q, J = 7), 7.32 (1H, dd, J =
3
8.5, 2.5), 7.66 (1H, d, J = 8.5), 7.77 (1H, d, J = 2.5); 13C NMR (126MHz, CDCl ) δ 13.9,
3
28.3, 44.7, 81.6, 110.2, 123.2, 130.7, 134.9, 142.8, 149.6, 153.4; IR (film) 2977, 1698,
1536, 1366, 1146; HRMS (ESI) m/z calcd for C H BrN O [M+H]+ 345.0444, found
13 18 2 4
[M+H]+ 345.0434; HPLC purity >95%.

tert-butyl (4-bromo-3-nitrophenyl)(cyclopropylmethyl)carbamate (4l) 4-bromo-3-
nitroaniline (0.50 g, 2.30 mmol) and cyclopropanecarbaldehyde (0.26 ml, 3.46 mmol) were
dissolved in THF (11.6 ml). Glacial AcOH (0.26 ml, 4.61 mmol) was added, followed by
NaBH CN (0.145 g, 2.30 mmol) portionwise. The mixture was stirred at 55°C overnight, at
3
which point saturated aq. NaHCO (10 ml) was added. The aqueous layer was separated
3
and extracted using EtOAc (4 x 10 ml) and the combined organic layers dried over MgSO
4
and concentrated in vacuo. The crude material was purified by silica column
chromatography (0-20% EtOAc in cyclohexane) to yield the title compound as a bright
orange oil (0.258 g, 41%). R = 0.39 (20% EtOAc in cyclohexane); 1H NMR (500MHz,
f
CDCl ) δ 0.26 (2H, dt, J = 6, 5), 0.54-0.67 (2H, m), 1.04-1.12 (1H, m), 2.96 (2H, dd, J = 7,
3
3), 4.16 (1H, br s), 6.62 (1H, dd, J = 9, 3), 6.99 (1H, d, J = 3), 7.40 (1H, d, J = 9); 13C NMR
(126MHz, CDCl ) δ 3.6, 10.5, 48.7, 99.3, 108.3, 117.4, 135.0, 148.1, 150.4; IR (film) 3403,
3
S8
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
3198, 1517, 1299; HRMS (ESI) m/z calcd for C H BrN O [M+H]+ 273.0057, found
10 12 2 2
[M+H]+ 273.0051; HPLC purity >95%.
4-bromo-N-(cyclopropylmethyl)-3-nitroaniline (0.25 g, 0.922 mmol) and di-tert-butyl
dicarbonate (0.40 g, 1.84 mmol) were dissolved in THF (4.6 ml). DMAP (0.17 g, 1.38
mmol) and Et N (0.32 ml, 2.31 mmol) were added and the solution was left to stir
3
overnight. Water was added, and the aqueous layer was separated and extracted using
EtOAc (3 x 5 ml). The organic layers were combined, dried over MgSO and concentrated
4
in vacuo. The crude material was purified by silica column chromatography (0-10% EtOAc
in cyclohexane) to yield the title compound as a pale yellow oil (0.333 g, 97%). R = 0.41
f
(20% EtOAc in cyclohexane); 1H NMR (500MHz, CDCl ) δ 0.18 (2H, dt, J = 6, 5), 0.44-
3
0.58 (2H, m), 0.96-1.05 (1H, m), 1.47 (9H, s), 3.56 (2H, d, J = 7), 7.37 (1H, dd, J = 8.5,
2.5), 7.69 (1H, d, J = 8.5), 7.82 (1H, d, J = 2.5); 13C NMR (126MHz, CDCl ) δ 3.9, 10.4,
3
28.3, 54.2, 81.5, 110.8, 124.2, 131.8, 134.9, 143.1, 149.6, 153.8; IR (film) 2978, 1698,
1536, 1365, 1146; HRMS (ESI) m/z calcd for C H BrN O Na [M+Na]+ 393.0420, found
15 19 2 4
[M+Na]+ 393.0414; HPLC >95%.

N-(4-bromo-3-nitrophenyl)-pivalamide (6a) 4-bromo-3-nitroaniline (0.50 g, 2.304 mmol)
and Et N (0.32 ml, 2.304 mmol) were dissolved in THF (5 ml) and stirred at rt. Pivalyl
3
chloride (0.28 ml, 2.304 mmol) was dissolved in THF (1 ml) and added dropwise to the
stirred solution. The resulting suspension was stirred for 3h at which point it was
concentrated in vacuo. The crude material was purified using silica column
chromatography (0-20% EtOAc in Cyclohexane) to yield the title compound as a pale
yellow solid (0.678 g, 98%). m.p = 111-112°C; R = 0.61 (30% EtOAc in cyclohexane); 1H
f
NMR (500MHz, CDCl ) δ 1.32 (9H, s), 7.47 (1H, br s), 7.62-7.64 (2H, m), 8.17 (1H, dd, J =
3
2, 1); 13C NMR (126MHz, CDCl ) δ 27.5, 39.9, 108.0, 116.6, 124.0, 135.2, 138.3, 149.8,
3
S9
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012
176.9; IR (solid) 3321, 1658, 1587, 1513, 1477; HRMS (ESI) m/z calcd for
C H BrN O Na [M+Na]+ 323.0002, found [M+Na]+ 322.9987; HPLC purity >95%.
11 13 2 3

Isopropyl 4-bromo-3-nitrophenylcarbamate (6b) 4-bromo-3-nitroaniline (0.50g, 2.304
mmol) was dissolved in THF (5.5 ml) and cooled to 0°C. NaH (60% w/w in mineral oil, 0.13
g, 3.23 mmol) was slowly added, followed by isopropyl chloroformate (2.8 ml, 2.77 mmol).
The solution was warmed to rt and stirred overnight. Water (5 ml) was added and the
aqueous layer was separated and extracted using EtOAc (3 x 10 ml). The combined
organic layers were dried over MgSO and concentrated in vacuo. The crude material was
4
purified using silica column chromatography (0-20% EtOAc in Cyclohexane) to yield the
title compound as a peach waxy solid (0.373 g, 53%). m.p = 91-93°C; Rf = 0.61 (30%
EtOAc in cyclohexane); 1H NMR (500MHz, CDCl ) δ 1.31 (6H, d, J = 6), 5.03 (1H, dt, J =
3
12.5, 6), 6.71 (1H, br s), 7.43 (1H, dd, J = 8.5, 2), 7.62 (1H, d, J = 8.5), 8.03 (1H, d, J =
2.5); 13C NMR (126MHz, CDCl ) δ 22.1, 70.1, 107.1, 115.2, 122.6, 135.4, 138.6, 150.0,
3
152.7; IR (solid) 3278, 1694, 1524, 1236; HRMS (ESI) m/z calcd for C H BrN O [M+H]+
10 12 2 4
302.9975, found [M+H]+ 302.9987; HPLC purity >95%.

Ethyl 4-bromo-3-nitrophenylcarbamate (6c) 4-bromo-3-nitroaniline (0.50 g, 2.304 mmol)
was dissolved in THF (5.5 ml) and cooled to 0°C. NaH (60% w/w in mineral oil, 0.13 g,
3.23 mmol) was slowly added, followed by isopropyl chloroformate (2.8 ml, 2.77 mmol).
The solution was warmed to rt and stirred overnight. Water (5 ml) was added and the
aqueous layer was separated and extracted using EtOAc (3 x 10 ml). The combined
organic layers were dried over MgSO and concentrated in vacuo. The crude material was
4
purified using silica column chromatography (0-20% EtOAc in Cyclohexane) to yield the
title compound as a pale yellow solid (0.490 g, 74%). m.p = 70-71°C; Rf = 0.49 (30%
EtOAc in cyclohexane); 1H NMR (500MHz, CDCl ) δ 1.33 (3H, t, J = 7), 4.26 (2H, q, J = 7),
3
S10