Deprotection of heteroaromatic carbamates via a base-catalyzed methanolysis

Article abstract of DOI:10.1016/j.tetlet.2006.06.028

A simple and mild method for the deprotection of heteroaromatic carbamates via methanolysis using a catalytic amount of base such as sodium methoxide, DBU, or Verkade's base (proazaphosphatranes) is presented. Carbamate protecting group of an aliphatic amine is not affected under these conditions.

Full text of DOI:10.1016/j.tetlet.2006.06.028

Tetrahedron Letters 47 (2006) 5645–5648
Deprotection of heteroaromatic carbamates via
a base-catalyzed methanolysis
Wen-Chung Shieh,* Song Xue, Joe McKenna, Kapa Prasad,
ˇ
Oljan Repic and Thomas Blacklock
Process R&D, Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA
Received 5 May 2006; accepted 3 June 2006
Available online 23 June 2006
Abstract—A simple and mild method for the deprotection of heteroaromatic carbamates via methanolysis using a catalytic amount
of base such as sodium methoxide, DBU, or Verkade’s base (proazaphosphatranes) is presented. Carbamate protecting group of an
aliphatic amine is not affected under these conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
Selective cleavage of a nitrogen protecting group for
heteroaromatics containing multiple functionalities is a
useful tool for the total synthesis of complex molecules.
Recently, a mild method was reported for removing
the Boc-group from indole compounds using tetrabutyl-
ammonium fluoride in refluxing THF without affecting
the rest of acid-sensitive functionalities.1 Heterogeneous
conditions involving silica gel or silica gel-supported so-
dium hydrogen sulfate/HY-zeolite were also effective for
the same purpose according to Wensbo and Apelqvist2
and Das and co-workers,3 respectively. Lipshutz et al.
reported an elegant method for the selective cleavage
of Cbz-protected heteroaromatic amines utilizing bor-
ane and a catalytic amount of Ni(0).4 Reductive cleav-
age of tryptophan and histidine side-chain protecting
groups utilizing controlled-potential electrolysis was
demonstrated by Monteiro and co-workers.5 Although
these methods are effective, they employ either stoichio-
metric amounts of reagents or special equipment. Since
developing greener chemistry is our constant goal, we
explored a simpler method such as base-catalyzed solvo-
lysis. We envisioned that the carbamate group on hetero-
aromatic nitrogens (such as indole 1) is vulnerable to
a base-catalyzed solvolysis since the resulting indolyl
anion is stabilized by the delocalization of the negative
charge (Scheme 1), especially when R0 is an electron-
withdrawing group.
To test this hypothesis, we initially used DBU as the
catalyst and Boc–Trp(Cbz)–OMe (3)6 as the substrate
in methanol (Scheme 2). The Cbz-group on the indole
nitrogen was readily cleaved under these conditions (Ta-
ble 1, entry 1). Employing triethylamine, we observed no
reaction at all (entry 2). The use of Verkade’s bases (pro-
azaphosphatranes 6c, Fig. 1) provided an equally inter-
esting result affording the desired product Boc–Trp–
OMe (5) in near 99% yield (entry 4, 22 h). Under these
conditions, we observed by HPLC the formation of
O
O
R
-
H
N
R"O
N
O
O
N
R"OH
-
R
+
R"O
+
OR''
R'
R'
R'
1
2
Scheme 1. Nucleophilic catalysis.
*
Corresponding author. Tel.: +1 8627786878; fax: +1 9737818434; e-mail: wen.shieh@novartis.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.028

5646
W.-C. Shieh et al. / Tetrahedron Letters 47 (2006) 5645–5648
O
O
O
O
H3C
H
N
N
N
O
cat.
H3C
H3C
+
O
O
H3C
H3C
H3C
H3C
O
CH3
O
N
H
O
O
CH3
CH3
O
N
H
CH3
O
N
H
O
CH3
CH3
O
O
4
5
3
Scheme 2. Deprotection of Boc–Trp(Cbz)–OMe (3).
Table 1. Cleavage of Boc–Trp(Cbz)–OMe (3)a
Entry
Catalyst
2 h
22 h
3 Yieldb (%)
4 Yieldb (%)
5 Yieldb (%)
3 Yieldb (%)
4 Yieldb (%)
5 Yieldb (%)
1
2
3
4
DBU
Et3N
NaOMe
Verkade
7.3
100
0.7
0
72.7
0
68.1
55.9
20.0
0
31.2
44.1
0
100
0
11.0
0
3.7
1.3
89.0
0
96.3
98.7
0
a All reactions were performed using 1 N solution of 3 in methanol containing 20 mol % of catalyst at rt.
b HPLC yield.
methyl carbamate 4 as a common intermediate, imply-
ing that the methoxide ion generated in situ served as
a catalyst. Based on this, we tried sodium methoxide
as the catalyst and found that it was indeed sufficient
to accomplish these deprotections (Table 1, entry 3) thus
making this solvolysis method practical and economical.
We also explored the generality of this method using
Verkade’s base,7 and the results obtained are shown in
Table 2.
R
R
P
N
N
R
N
N
N
N
In a typical experiment, deprotection of a particular
substrate was performed in methanol at room tempera-
ture employing 20 mol % of a Verkade’s base (6b or 6c).
The respective reaction was monitored by HPLC
until none or a trace amount of starting material was
DBU
6a, R = Me
6b, R = i-Pr
6c, R = i-Bu
Figure 1.
Table 2. Cleavage of carbamate protecting groups with proazaphosphatranes 6
Entry
Substrate
Catalyst
Product
Time (h)
0.5
Yielda (%)
H3C
H3C
O
H
N
1
O
7
8
6b
99
H3C
N
N
N
Br
Br
2
3
6c
0.5
97
99
N
N
N
H
CH3
O
O
O
O
Br
Br
9
6c
0.75
N
H

W.-C. Shieh et al. / Tetrahedron Letters 47 (2006) 5645–5648
5647
Table 2 (continued)
Entry Substrate
Catalyst
Product
Time (h)
Yielda (%)
Br
Br
CH3
4
N
10
6c
19
97
N
H
CH3
O
O
CH3
H3C
H3C
O
N
H
N
O
CH3
N
O
N
5
11
6c
2
99
H3C
O
H3C
H3C
O
H3C
H3C
CH3
O
N
H
O
CH3
O
N
H
O
H3C
O
O
H
N
O
N
N
O
N
6
12
6c
16
99
O
NO2
O
CH3
N
H
O
O
N
H
O
O
O
O
O
H3C
H
N
N
7
138
6b
6c
40
48
97
96
O
H3C
H3C
O
H3C
H3C
O
O
CH3
O
N
H
CH3
O
N
H
CH3
CH3
O
O
O
O
CH3
O
O
8
N
14
6b
0.25
99
NH
O
O
a HPLC yield.
detected. N-Boc–imidazole 7, although containing a bulky
protecting group, was cleaved with high efficiency (99%)
and speed (0.5 h, entry 1). For three different alkyl car-
bamates of 5-bromoindole utilizing 6c as the catalyst,
cleavage was fast for carbomethoxy- or carbo-
benzyloxyindole (0.5–0.75 h, entries 2 and 3), but slower
for N-Boc-5-bromoindole (19 h, entry 4). Applying sim-
ilar conditions to a fully protected histidine or trypto-
phan, the protecting groups on heteroaromatic
nitrogens (Boc, Cbz, and methyl carbamate) were selec-
tively deprotected without affecting those on the ali-
phatic amines (entries 5–7). This protocol is practical
and requires no special equipment as opposed to the
electrolysis methods developed by Monteiro and co-
workers.5 It is noteworthy that a transesterification reac-
tion also took place for substrate 12, where the o-nitro-
phenol group was replaced with methanol leading
exclusively to the methyl ester as the major product.
This is a predictable reaction, since 6b-catalyzed trans-
esterification of dipeptides has been reported.9 For
substrate 13 containing methyl carbamate, the
deprotection rate was slow (>40 h), and no significant
kinetic difference was observed utilizing either 6b or 6c
(entry 7). Our protocol also worked efficiently for a
non-heteroaromatic compound, N-carbethoxyphthal-
imide (14) employing 6b (entry 8, 0.25 h).
In conclusion, we have demonstrated an efficient process
for the cleavage of carbamate groups on heteroaromatic
nitrogens via methanolysis using catalytic amounts of
bases such as NaOMe, DBU or Verkade’s base, thus
providing additional options in the armamentarium
for selective carbamate deprotection. This protocol can
also selectively cleave the carbamates on the heteroaro-
matic nitrogens of histidine or tryptophan without
affecting those on the aliphatic amines.
References and notes
´
´
1. Routier, S.; Sauge, L.; Ayerbe, N.; Coudert, G.; Merour,
J.-Y. Tetrahedron Lett. 2002, 43, 589–591.

5648
W.-C. Shieh et al. / Tetrahedron Letters 47 (2006) 5645–5648
2. Apelqvist, T.; Wensbo, D. Tetrahedron Lett. 1996, 37,
1471–1472.
53.6, 52.4, 28.3, 27.8; LC/MS 475 (M++Na), 353 (M++1–
Boc).
3. Ravindranath, N.; Ramesh, C.; Reddy, M. R.; Das, B. Adv.
Synth. Catal. 2003, 345, 1207–1208.
4. Lipshutz, B. H.; Pfeiffer, S. S.; Reed, A. B. Organic Lett.
2001, 3, 4145–4148.
5. Maia, H. L. S.; Monteiro, L. S.; Sebastia˘o, J. Eur. J. Org.
Chem. 2001, 1967–1970.
6. Boc–Trp–(Cbz)–OMe (3) was prepared from commercially
available Boc–L-Trp–OMe and dibenzyl dicarbonate
employing catalytic amount of DMAP. Compound 3: mp
114–116 °C (lit. 118–120 °C, Kiso, Y.; Inai, M.; Kitagawa,
K.; Akita, T. Chem. Lett. 1983, 739–742); 1H NMR
(500 MHz, CDCl3) d 8.18 (br, 1H), 7.53–7.26 (m, 10H),
5.46 (s, 2H), 5.12 (d, J = 7.9 Hz, 1H), 4.67 (dd, J = 13.3,
5.7 Hz, 1H), 3.69 (s, 3H), 3.28 (dd, J = 14.5, 5.4 Hz, 1H),
3.20 (dd, J = 14.5, 5.4 Hz, 1H), 1.44 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 172.3, 155.1, 150.1, 135.1, 128.8,
128.5, 124.9, 123.7, 123.0, 119.0, 116.1, 115.3, 80.0, 68.7,
7. For a review on ‘Recent Applications of Proazaphosphatr-
anes in Organic Synthesis’, see: Verkade, J. G.; Kisanga, P.
B. Aldrichimica Acta 2004, 37, 3–14.
8. Boc–Trp–(COOMe)–OMe (13) was prepared from com-
mercially available Boc–L–Trp–OMe and dimethyl dicar-
bonate employing catalytic amount of DMAP. Compound
1
13: H NMR (600 MHz, CDCl3) d 8.18 (br, 1H), 7.53 (d,
J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.28
(t, J = 7.6 Hz, 1H), 5.15 (d, J = 7.9 Hz, 1H), 4.69 (m, 1H),
4.05 (s, 3H), 3.72 (s, 3H), 3.29 (dd, J = 14.8, 5.3 Hz, 1H),
3.20 (dd, J = 14.8, 5.3 Hz, 1H), 1.46 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 172.3, 155.1, 151.3, 135.4, 130.5,
124.9, 123.6, 122.9, 119.0, 116.1, 115.2, 80.1, 60.4, 54.4,
52.4, 28.3, 27.9; LC/MS 277 (M++1–Boc), 377 (M++1),
399 (M++Na).
9. Ilankumaran, P.; Verkade, J. G. J. Org. Chem. 1999, 64,
3086–3089.