Simple and selective removal of the t-butyloxycarbonyl (Boc) protecting group on indoles, pyrroles, indazoles, and carbolines

Article abstract of DOI:10.1080/00397910601033724

A highly selective and efficient deprotection of the N-t-butoxy carbonyl (N-Boc) group on indoles, pyrroles, indazoles, and carbolines has been achieved in high yields using a catalytic amount of NaOMe as a base in dry MeOH, at ambient temperature. Copyright Taylor & Francis Group, LLC.

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Simple and Selective Removal of the
t‐Butyloxycarbonyl (Boc) Protecting Group on
Indoles, Pyrroles, Indazoles, and Carbolines
K. Ravinder a , A. Vijender Reddy a , K. Chinni Mahesh a , M. Narasimhulu a
Y. Venkateswarlu a
&
a Natural Products Laboratory, Organic Chemistry Division I, Indian Institute
of Chemical Technology, Hyderabad, India
Published online: 25 Jul 2007.
To cite this article: K. Ravinder , A. Vijender Reddy , K. Chinni Mahesh , M. Narasimhulu & Y. Venkateswarlu
(2007): Simple and Selective Removal of the t‐Butyloxycarbonyl (Boc) Protecting Group on Indoles, Pyrroles,
Indazoles, and Carbolines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:2, 281-287
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Synthetic Communicationsw, 37: 281–287, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601033724
Simple and Selective Removal of the
t-Butyloxycarbonyl (Boc) Protecting Group
on Indoles, Pyrroles, Indazoles, and
Carbolines
K. Ravinder, A. Vijender Reddy, K. Chinni Mahesh,
M. Narasimhulu, and Y. Venkateswarlu
Natural Products Laboratory, Organic Chemistry Division I, Indian
Institute of Chemical Technology, Hyderabad, India
Abstract: A highly selective and efficient deprotection of the N-t-butoxy carbonyl
(N-Boc) group on indoles, pyrroles, indazoles, and carbolines has been achieved in
high yields using a catalytic amount of NaOMe as a base in dry MeOH, at ambient
temperature.
Keywords: +-butyloxycarbonyl (BOC), indoles, pyrroles, indazoles, carbolines,
sodium methoxide
The t-butoxy carbonyl group is frequently used as a protecting group for l8 and
28 amines[1] and amino acids in peptide chemistry[2] because of its stability in
mildly acidic as well as basic conditions. A number of reagents have been
known to effect clean removal of this protecting group; most of them
involve the use of strong acids such as CF3COOH, HCl, H2SO4, TSOH, and
.
MeOH or Lewis acids such as BF3 OEt2,TMSI, TMSOTf, TiCl4, SnCl4,
AlCl3, Sn(OTf)2, and ZnBr2.[3] The deprotection can also be effected with
mildly acidic conditions such as montomorillonite K-10 clay catalyst[4] and
silica gel at low pressure.[5] The N-Boc group can also be removed in the
presence of other sensitive functionalities such as t-butyl esters and trityl
Received May 25, 2006
IICT Communication No. 060512.
Address correspondence to Y. Venkateswarlu, Natural Products Laboratory,
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad
500 007, India. E-mail: luchem@iict.res.in
281

282
K. Ravinder et al.
groups with the acid catalysts such as 1M HCl in EtOAc,[6] H2SO4 in
t-BuOAc, or MeSO3H in t-BuOAc/CH2Cl2.[7] It is also deprotected in
thermolytic conditions.[8] Recently, selective deprotection of t-butyl ester
[9]
was reported using a CeCl3 7H2O-NaI system or silica gel in refluxing
.
toluene.[10]
During the synthesis of the natural product tiruchanduramine,[11] an inter-
mediate 1 was prepared, and we have envisaged the deprotection of triflate[12]
with NaOMe in methanol, while the Boc group is present on the b-carboline
group (Scheme 1). As the reaction proceeds, we observed that Boc was
deprotected and triflate was still retained. We extended this reaction on
various substrates such as substituted pyrroles, b-carbolines, indazoles, and
indoles (Table 1).
4-Bromo pyrrole-2-carboxylamide[13] was isolated from the sponge
Axinella carteri, collected from Gulf of Mannar, Tamilnadu, India, which
was protected with a Boc group using sodium hydride to give compound 2
(entry 2). Compound 2 was reacted with NaOMe in methanol to give 2a
with 92% yield.
Most assays described in Table l were carried out using a catalytic amount
of NaOMe in dry methanol, and the reaction time is limited to 3 h. In entry 8
(Table 1), the compound has two acid labile acetonide and Boc protecting
groups. Using the present conditions, Boc group can be selectively depro-
tected, and under any acidic conditions both would have deprotected.
We have performed the same reaction on substituted indazoles where
N-Boc is located on indazole and piperazine (entries 5 and 6) and found
indazole N-Boc was selectively deprotected to give corresponding amines
in excellent yields.
We also performed the reaction on substituted indole compounds (entries
9 and 10) as well as on Boc protected tryptophan (entry 3) and Boc protected
tryptamine (entry 4). In entries 3 and 4, the Boc group on indole nitrogen was
deprotected in excellent yields, retaining primary amine Boc.
EXPERIMENTAL PROCEDURE
To a solution of Boc derivative (0.5 mmol) in dry methanol, a catalytic
amount of NaOMe (20 mmol%) was added and stirred at ambient temperature
for an appropriate time (Table l). After complete conversion as indicated by
Scheme 1.

t-Butyloxycarbonyl Selective Removal
283
Table 1. Deprotection of Boc with NaOMe in dry MeOH
Yield
(%)b
Entry
1
Substrate
Time
3 h
Producta
92
2
3
30 min
92
90
3 h
4
5
3 h
94
86
10 min
6
7
30 min
90
96
1 h
8
2 h
98
9
30 min
92
96
10
1 h
1
aAll products were characterized by H NMR, IR, and mass spectra.
bIsolated and unoptimized yields.

284
K. Ravinder et al.
thin-layer chromatography (TLC), the reaction mixture was diluted with water
(10 ml) and extracted into ethyl acetate (2 ꢀ 20 ml). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure to yield the crude product, which was purified
by column chromatography on silica gel to afford the pure Boc deprotected
product with 85–98% yield.
SPECTROSCOPIC DATA
Compound (1)
1
IR (KBr) nmax: 3417, 1625, 1618, 1353, 1219 cm21; H NMR (300 MHz,
CDCl3): d 1.80 (9H, s), 1.96 (2H, m), 3.42 (1H, dd, J ¼ 7.6, 1.6 Hz), 3.50
(1H, m), 3.84 (2H, m), 4.10 (1H, m), 6.96 (1H, bs, NH), 7.38 (1H, t,
J ¼ 7.0 Hz), 7.48 (1H, t, J ¼ 7.0 Hz), 7.74 (bs, NH), 8.04 (1H, d,
J ¼ 8.0 Hz), 8.28 (1H, d, J ¼ 8.0 Hz), 8.40 (bt, NH), 8.70 (1H, s), 9.40
(1H, s); FABMS: 555 (Mþ þ l).
Compound (1a)
1
IR (KBr) nmax: 3415, 1637, 1527, 1350, 1220 cm21; H NMR (400 MHz,
DMSO-d6): d 1.86 (2H, m), 3.54 (2H, m), 3.68 (2H, m), 7.20 (1H, t,
J ¼ 7.0 Hz), 7.48 (2H, m), 7.80 (bs, NH), 8.10 (1H, d, J ¼ 8.2 Hz), 8.22
(bs, NH), 8.60 (bt, NH), 8.76 (1H, s), 8.78 (1H, s), 11.38 (1H, bs); FABMS:
455 (Mþ þ l).
Compound (2)
1
IR (KBr) nmax: 3270, 2965, 1672, 1650, 1460, 1365, 828 cm21; H NMR
(300 MHz, CDCl3): 1.42 (9H, s), 1.58 (9H, s), 6.58 (1H, d, J ¼ 1.2 Hz),
7.26 (1H, J ¼ 1.2 Hz), 8.30 (bs, NH). LCMSD: 411 (Mþ þ Na).
Compound (2a)
1
IR (KBr) nmax: 3412, 2985, 1670, 1642, 1442, 1365, 1220 cm21; H NMR
(200 MHz, CDCl3): 1.56 (9H, s), 6.84 (d, J ¼ 1.2 Hz), 7.04 (d, J ¼ 1.2 Hz),
8.06 (bs, NH); LCMSD: 311 (Mþ þ Na).
Compound (4)
IR (KBr) nmax: 3385, 2927, 2360, 1735, 1700, 1457, 1372, 1224, 1166 cm21
1H NMR (200 MHz, CDCl3): d 1.42 (9H, s), 1.65 (9H, s), 2.88 (2H, t,
;

t-Butyloxycarbonyl Selective Removal
285
J ¼ 6.4 Hz), 3.42 (2H, m), 4.68 (1H, bt), 7.22 (2H, m), 7.34 (1H, s), 7.48 (1H,
d, J ¼ 7.2 Hz), 8.09 (1H, d, J ¼ 7.2 Hz); LCMSD: 359 (Mþ 2 1).
Compound (4a)
IR (KBr) nmax: 3413, 2976, 2927, 2360, 1691, 1604, 1510, 1456, 1393, 1366, 1336,
1
1253, 1221, 1169 cm21; H NMR (200 MHz, CDCl3): 1.42 (9H, s), 2.88 (2H,
t, J ¼ 6.4 Hz), 3.40 (2H, m), 4.64 (1H, bs), 6.8 (1H, s), 7.04 (1H, t, J ¼ 7.0 Hz),
7.10 (1H, t, J ¼ 7.0 Hz), 7.24 (1H, d, J ¼ 7.4 Hz), 7.50 (1H, d, J ¼ 7.4 Hz),
8.50 (1H, bs, NH); LCMSD: 283 (Mþ þ Na), 261, 127, 205, 161, 144.
Compound (5)
1
IR (KBr) nmax: 2981, 1694, 1522, 1338, 1249, 1155, 1048 cm21; H NMR
(400 MHz, CDCl3): d 1.52 (9H, s), 1.70 (9H, s), 3.56 (4H, m), 3.64 (4H,
m), 8.24 (1H, d, J ¼ 7.8 Hz), 8.18 (1H, d, J ¼ 7.8 Hz), 8.60 (1H, bs);
LCMSD: 447 (Mþ), 391, 335, 126.
Compound (5a)
IR (KBr) nmax: 3412, 2926, 2345, 1692, 1518, 1393, 1253, 1169, 1028 cm21
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6): d 1.40 (9H, s), 3.36 (4H, m), 3.58
(4H, m), 7.26 (1H, d, J ¼ 8.2 Hz), 8.02 (1H, dd, J ¼ 8.2, 1.2 Hz), 12.19
(s, NH); LCMSD: 348 (Mþ þ l).
Compound (6)
IR (KBr) nmax: 2978, 2932, 2361, 1697, 1536, 1483, 1340, 1368, 1250, 1156,
1
1051 cm21; H NMR (200 MHz, CDCl3): d 1.48 (9H, s), 1.67 (9H, s), 3.45
(4H, m), 3.62 (4H, m), 3.82 (3H, s), 6.96 (1H, d, J ¼ 2.4 Hz), 7.08 (1H, dd,
J ¼ 8.8, 2.4 Hz), 7.94 (1H, d, J ¼ 8.8 Hz); LCMSD: 455 (Mþ þ Na), 433,
377, 321, 192.
Compound (6a)
IR (KBr) nmax: 3412, 2986, 2928, 2312, 1686, 1527, 1468, 1328, 1210 cm21
;
1H NMR (200 MHz, CDCl3): d 1.50 (9H, s), 3.34 (4H, m), 3.65 (4H, m), 3.88
(3H, s), 6.92 (1H, d, J ¼ 1.7 Hz), 6.98 (1H, dd, J ¼ 8.6, 1.7 Hz), 7.22 (1H, d,
J ¼ 8.6 Hz); LCMSD: 333 (Mþ þ 1).

286
K. Ravinder et al.
Compound (7)
IR (KBr) nmax: 2934, 2354, 1665, 1456, 1347, 1245 cm21; 1H NMR (200 MHz,
CDCl3): d 1.78 (9H, s), 4.02 (3H, s), 7.40 (1H, t, J ¼ 6.0 Hz), 7.60 (1H, t,
J ¼ 6.0 Hz), 8.06 (1H, d, J ¼ 7.8 Hz), 8.40 (1H, d, J ¼ 7.8 Hz), 8.90 (1H, s),
9.58 (1H, s); EIMS: m/z 326 (08) [Mþ], 270 (22), 226 (100), 168 (96).
Compound (7a)
IR (KBr) nmax: 3412, 2364, 1656, 1459, 1337, 1253 cm21 1H NMR
;
(200 MHz, CDCl3): d 4.02 (3H, s), 7.30 (1H, t, J ¼ 7.0 Hz), 7.58 (1H, t,
J ¼ 7.0 Hz), 7.62 (1H, d, J ¼ 7.8 Hz), 8.10 (1H, d, J ¼ 7.8 Hz), 8.84 (1H,
s), 9.18 (1H, s), 10.70 (1H, bs); EIMS: m/z 226 (100) [Mþ].
Compound (8)
IR (KBr) nmax: 3182, 1938, 1736, 1652, 1440, 1344, 1263, 1171, 1014 cm21
;
1H NMR (400 MHz, CDCl3): d 1.36 (3H, s), 1.42 (3H, s), 1.80 (9H, s), 1.96
(2H, m), 3.60 (3H, m), 4.06 (1H, dd, J ¼ 7.0, 6.0 Hz), 4.22 (1H, m), 7.42
(1H, t, J ¼ 8.0 Hz), 7.62 (1H, t, J ¼ 8.0 Hz), 8.12 (1H, d, J ¼ 8.0 Hz), 8.36
(1H, d, J ¼ 8.0 dHz), 8.40 (bt, J ¼ 6.5 Hz, NH), 8.78 (1H, s), 9.42 (1H, s);
FABMS: 440 (Mþ)
Compound (8a)
1
IR (KBr) nmax: 4315, 1637, 1527, 1350, 1220 cm21; H NMR (300 MHz,
CDCl3): d 1.38 (3H, s), 1.46 (3H, s), 1.96 (2H, m), 3.65 (3H, m), 4.12 (1H,
dd. J ¼ 7.0, 6.0 Hz), 4.28 (1H, m), 7.32–7.46 (1H, m), 7.60 (1H, m), 7.82
(bt, NH), 8.20 (1H, d, J ¼ 8.0 Hz), 8.50 (bt, NH), 8.82 (1H, s), 8.90 (1H, s),
9.54 (1H, bs); FABMS: 340 (Mþ þ l).
ACKNOWLEDGMENTS
K. R., A. V. R., and C. M. thank University Grants Commission (UGC), Council
of Scientific and Industrial Research (CSIR), New Delhi, for providing fellow-
ships, we thank Department of Ocean Development (DOD) for financial
assistance, and we thank J. S. Yadav, director Indian Institute of Chemical
Technology (IICT)-Hyderabad, India, for his constant encouragement.
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