N-carboalkoxy-2-nitrobenzenesulfonamides: A practical preparation of N- Boc-, N-Alloc-, and N-Cbz-protected primary amines

Article abstract of DOI:10.1055/s-1999-2827

N-Carboalkoxy-2-nitrobenzenesulfonamides, readily prepared by acylation of 2-nitrobenzenesulfonamide (o-NsNH₂), can be alkylated by either conventional or Mitsunobu protocols. Since the o-nosyl group can be deprotected under mild conditions, a variety of N-carboalkoxy derivatives of primary amines may be prepared in excellent yields from the corresponding alcohols and/or halides. In addition, allyloxycarbonyl (Alloc), t- butoxycarbonyl (t-Boc), and benzyloxycarbonyl (Cbz) groups can be deprotected in the presence of the o-nosyl group, allowing the resultant N-alkylated 2- nitrobenzenesulfonamides to be used for further preparation of secondary amines.

Full text of DOI:10.1055/s-1999-2827

LETTER
1301
N-Carboalkoxy-2-Nitrobenzenesulfonamides: A Practical Preparation of
N-Boc-, N-Alloc-, and N-Cbz-Protected Primary Amines
Tohru Fukuyama,a* Mui Cheung,bToshiyuki Kana
a Graduate School of Pharmaceutical Sciences, University of Tokyo, and CREST, The Japan Science and Technology Corporation (JST)
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b Department of Chemistry, Rice University, Houston, Texas 77251-1892, USA
Fax +81-3-5802-8694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 26 May 1999
SO2NH2
NO2
SO2NHBoc
NO2
Abstract: N-Carboalkoxy-2-nitrobenzenesulfonamides, readily
prepared by acylation of 2-nitrobenzenesulfonamide (o-NsNH2),
can be alkylated by either conventional or Mitsunobu protocols.
Since the o-nosyl group can be deprotected under mild conditions,
a variety of N-carboalkoxy derivatives of primary amines may be
prepared in excellent yields from the corresponding alcohols and/or
halides. In addition, allyloxycarbonyl (Alloc), t-butoxycarbonyl (t-
Boc), and benzyloxycarbonyl (Cbz) groups can be deprotected in
the presence of the o-nosyl group, allowing the resultant N-alkylat-
ed 2-nitrobenzenesulfonamides to be used for further preparation of
secondary amines.
Boc2O
Et3N, DMAP
CH2Cl2
1
2
Scheme 1
Alkylation of 2 was performed by conventional alkylation
as well as Mitsunobu conditions (Table 1). Upon treat-
ment with alkyl halides and K2CO3 in DMF, sulfonamide
2 underwent a smooth alkylation to give 3a and 3b in ex-
cellent yields. Under Mitsunobu conditions (DEAD and
Ph3P in benzene), reaction of 2 with alcohols provided 3c
and 3d. The latter case proceeded without causing an ap-
preciable racemization. Both the 2-nitrobenzenesulfonyl
group and the Boc group of alkyl sulfonamides 3a–d can
be selectively deprotected without affecting the other
functional groups. Deprotection of o-Ns group of 3a–d
was achieved by treatment with mercaptoacetic acid and
LiOH in DMF at room temperature to give N-Boc amines
4a–d. One of the advantages of this procedure is that the
by-product 2-nitrophenylthioacetic acid can be easily re-
moved by partitioning between ether and a sat. NaHCO3
solution. Alternatively, treatment of 3a–d with excess tri-
fluoroacetic acid afforded the N-monoalkylated sulfona-
mides 5a–d. N-Boc amines 4a–d can be converted to the
primary amines 6a–d, and sulfonamides 5a–d in turn
could serve as the precursors for the synthesis of second-
ary amines 7a–d (Table 1). 7
Key words: N-carboalkoxy-2-nitrobenzenesulfonamides, alkyla-
tion, Mitsunobu conditions, deprotection, primary amines
Transformation of primary alcohols and alkyl halides to
the corresponding amines has been an important subject
of organic synthesis.2 While a variety of nitrogen nucleo-
philes have been investigated to date, there appear to be
few practical methods available for direct preparation of
N-protected primary amines. Some of the well-known and
classical examples are Gabriel synthesis3 and a direct con-
version to azides. More recently, alkylations of N-Boc-p-
toluenesulfonamide4 and p-toluenesulfonamide by means
of Mitsunobu5 and modified Mitsunobu reactions6, re-
spectively, have been reported. These methods are, how-
ever, limited in scope because deprotection of p-
toluenesulfonamides requires relatively harsh conditions
(sodium naphthalenide, for example) for many sensitive
functional groups to survive. We have recently developed
a highly efficient activation-alkylation-deprotection pro-
tocol for primary amines by way of the corresponding 2-
nitro- and 2,4-dinitrobenzenesulfonamides.7 A wide vari-
ety of secondary amines can be prepared using this meth-
odology. To expand the scope of this general protocol, we
have directed our attention toward the synthesis of prima-
ry amines from primary alcohols and alkyl halides. Herein
we report the synthesis of N-carboalkoxy-2-nitrobenzene-
sulfonamides and their utility for the synthesis of protect-
ed primary amines.
To investigate this strategy’s compatibility with other N-
protecting groups (N-Alloc and N-Cbz), we prepared sul-
fonamides 8 and 9 from 1 (Scheme 2). Treatment of 8 and
9 with heptyl bromide and K2CO3 yielded 10b and 11b,
respectively, while reaction with ethyl (S)-(-)-lactate un-
der Mitsunobu conditions afforded the alanine derivatives
10d and 11d. Selective deprotection of the o-Ns groups of
10b, d and 11b, d was performed by treatment with PhSH
and K2CO3 in DMF to give N-Alloc- or N-Cbz-amines
12b, d and 13b, d, respectively, in excellent yields. These
N-protected amines 4e–h could be converted to the corre-
sponding primary amines in the usual manner. On the oth-
er hand, the N-Alloc group of 10b, d was removed by
treatment with Pd(PPh3)4, Ph3P and pyrrolidine in CH2Cl2
to afford the sulfonamides 14b, d. The Cbz group of 11b,
Commercially available 2-nitrobenzenesulfonamide (1)
was first converted to N-Boc-2-nitrobenzenesulfonamide
(2) in 95% yield by treatment with Boc2O (1.5 equiv),
Et3N (2 equiv), and DMAP (0.5 equiv) in CH2Cl2 at room
temperature (Scheme 1).
Synlett 1999, No. 8, 1301–1303 ISSN 0936-5214 © Thieme Stuttgart · New York

1302
T. Fukuyama et al.
LETTER
Table 1. Alkylation and Selective Deprotection of
N-Boc-nitrobenzenesulfonamides 2
Table 2. Alkylation and Deprotection of N-Alloc- and
N-Cbz-nitrobenzenesulfonamides 8 and 9
RS–
RS–
TFA
R1
R1NHCO2R
R1NHBoc
4a-d
R1
R1NH2
6a-d
R1
N
N
12b,d: R = allyl
13b,d: R = benzyl
R1
O2S
CO2R
NO2
R1OH
DEAD, PPh3
R1OH
DEAD, PPh3
O2S
Boc
2
N
Pd(Ph3)4,
pyrrolidine
N
NO2
O2S
H
8, 9
or
O2S
H
R1
NH
R2
or
R1X, K2CO3
DMF
NO2
TFA
ref. 7
NO2
R1X, K2CO3
DMF
or
BCl3
10b,d: R = allyl
11b,d: R = benzyl
3a-d
14b,d
15b,d
7a-d
5a-d
b Deprotection
Deprotectionc,d,e
3
3
R1X or
R1OH
aAlkylation
aAlkylation
4
R1X or
R1OH
5
4
5
amide
(% isolated yield)
(% isolated yield)
(% isolated yield)
(% isolated yield)
D
C
Boc
nC7H15
Alloc
Ph
N
3a
4a
5a
A
Ph
Br
nC7H15Br
N
12bc
(95)
5bd
(91)
8
A
10b
(97)
o-Ns
(95)
(92)
(100)
o-Ns
nC7H15
Boc
Boc
nC7H15Br
N
CO2Et
OH
A
B
4b
(94)
5b
(100)
3b
(91)
Alloc
Cbz
12dc
(93)
5dd
(92)
B
10d
8
9
EtO2C
N
o-Ns
(93)
o-Ns
Ph
Ph
N
3c
(97)
4c
(91)
5c
(100)
nC7H15Br
nC7H15
5be
(87)
A’
11b
(79)
13bc
(95)
OH
o-Ns
N
o-Ns
CO2Et
OH
CO2Et
OH
Cbz
Boc
13dc
(88)
B
9
11d
(91)
5de
(93)
4d
(94)
5d
(100)
3d
(91)
EtO2C
N
B
EtO2C
N
o-Ns
o-Ns
aA: R1X (1.5 eq), K2CO3 (5 eq), DMF, 80°C, 4h.
aA: R1X (1.5 eq), K2CO3 (5 eq), DMF, 80°C, 4h.
aB: R1OH (2 eq), DEAD (2 eq), PPh3 (2 eq), benzene, 23 °C, 1h.
bC: HSCH2CO2H (1.3 eq), K2CO3 (2 eq), DMF, 23 °C, 1 h.
bD: neat TFA (20eq), 23°C, 5 min.
A’: R1X (1.5 eq), K2CO3 (5 eq), n-Bu4I (0.2 eq), DMF, 80°C, 4h.
B: R1OH (2 eq), DEAD (2 eq), PPh3 (2 eq), benzene, 23 °C, 1h.
cC: PhSH (1.3 eq), K2CO3 (2 eq), DMF, 23 °C, 1 h.
dD: Pd(PPh3)4 (0.05 eq), PPh3 (0.2 eq), pyrrolidine (5 eq), CH2Cl2, 1h.
eE: BCl3 (2 eq), CH2Cl2, -78 °C, 1h.
SO2NH2
NO2
SO2NHCO2R
NO2
AllocCl or CbzCl
Representative experimental procedures.
Et3N, DMAP
CH2Cl2
N-Boc-o-nitrobenzenesulfonamide (2). To a solution of
2.08 g (10.3 mmol) of 2-nitrobenzenesulfonamide (1) in
20 ml of dichloromethane were added 2.15 ml (15.4
mmol) of triethylamine, 2.69 g (12.4 mmol) of di-t-butyl
dicarbonate, and catalytic amount of DMAP (126 mg,
1.03 mmol) at room temperature under argon. After 25
min the reaction mixture was poured into a solution of 1
N HCl, and the aqueous layer was extracted with ether
(4x). The combined organic extracts were washed with
brine, dried over MgSO4, and concentrated in vacuo. Pu-
1
8: R = allyl
9: R = benzyl
Scheme 2
d in turn was selectively deprotected by BCl3 to provide
the sulfonamides 15b, d, since o-Ns group cannot survive
the hydrogenolysis conditions (Table 2).
In summary, we have developed a concise and versatile rification of the residue by trituration with 40% ether in
methodology for the synthesis of protected primary hexane gave 2 (2.96 g, 95%) as a yellow powder.
amines from the the corresponding alcohols and alkyl ha-
N-Boc-N-benzyl-o-nitrobenzenesulfonamide (3a). To a
stirred solution of 304 mg (1.01 mmol) of N-Boc-2-ni-
lides using our nitrobenzenesulfonamide protocol.8, 9
trobenzenesulfonamide (2) and 694 mg (5.02 mmol) of
potassium carbonate in 3 ml of DMF was added 179 µl
(1.52 mmol) of benzyl bromide at room temperature un-
Synlett 1999, No. 8, 1301–1303 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Practical Preparation of N-Boc-, N-Alloc-, and N-Cbz-Protected Primary Amines
1303
der argon. After 20 min the reaction mixture was poured
into a solution of 3N HCl, and the aqueous layer was ex-
tracted with ether (3 x). The combined organic extracts
were washed with brine, dried over MgSO4, and concen-
trated in vacuo. Purification of the residue by chromatog-
raphy on silica gel (40% ether in hexanes) gave 3a (374
mg, 95%) as a yellow solid.
References and Notes
(1) Present Address: Medicinal Chemistry, Glaxo Wellcome, Inc.
5 Moore Drive, Research Triangle Park, NC 27709, USA.
(2) For a review of the Gabriel synthesis, see: Gibson, M. S.;
Bradshaw, R. W. Angew. Chem., Int. Ed. Engl. 1968, 7, 919.
(3) For a review of the Gabriel synthesis, see: Gibson, M. S.;
Bradshaw, R. W. Angew. Chem., Int. Ed. Engl. 1968, 7, 919.
(4) Henry, J. R, Marcin, L. R., McIntosh, M. C., Scola, P. M.,
Harris, G. D., Weinreb, S. M. Tetrahedron Lett. 1989, 30,
5709.
(5) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
React. 1992, 42, 335.
(6) Tsunoda, T.; Yamamoto, H.; Goda, K.; Ito, S. Tetrahedron
Lett. 1996, 37, 2457.
(7) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.;
Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831.
(8) For this protocol, 2,4-dinitrobenzenesulfonamide is also as
useful as 2-nitrobenzenesulfonamide (1), with the exception
of poor alkylating agents such as heptyl bromide. Upon
prolonged exposure to basic conditions, extensive
decomposition of 2,4-dinitrobenzenesulfonamide was
observed. For the deprotection of the Alloc group in the
presence of 2,4-dinitrobenzenesulfonamides, dimedone was
used as a nucleophile to avoid the pyrrolidine-induced
deprotection of the sulfoneamides.
(9) Since 2,4-dinitrobenzenesulfonamide is not commercially
available, it was prepared by bubbling ammonia into the
solution of 2,4-dinitrobenzenesulfonyl chloride in Et2O at
23 °C. After 25 min the reaction mixture was filtered through
Celite pad and washed with AcOEt. The filtrate was
evaporated and triturated with 40% ether in hexanes to give
2,4-dinitrobenzenesulfonamide as a yellow solid (97%).
(10) Satisfactory spectroscopic data were obtained on all new
compounds.
(R)-N-Boc-N-o-nitrobenzenesulfonylalanine ethyl ester
(3d). To a stirred solution of 304 mg (1.01mmol) of N-
Boc-2-nitrobenzenesulfonamide (2), 228 µl (2.01 mmol)
of L-ethyl lactate, and 528 mg (2.01 mmol) of triphe-
nylphosphine in 3 ml of benzene was slowly added 217 µl
(2.01 mmol) of diethyl azodicarboxylate at room temper-
ature under argon. After 30 min the reaction mixture was
concentrated in vacuo, and the residue was purified by
chromatography on silica gel (CH2Cl2-hexanes gradient)
to give 3d (370 mg, 91%) as a yellow solid.
N-Boc-benzylamine (4a). To a stirred solution of 101 mg
(0.259 mmol) of N-Boc-N-benzyl-2-nitrobenzenesulfona-
mide (3a) in 2 ml of DMF was added 44 mg (1.04 mmol)
of LiOH·H2O and 36.0 µl (0.518 mmol) of mercaptoacetic
acid. After 25 min the reaction mixture was poured into a
sat. NaHCO3 solution and the aqueous layer was extracted
with ether (4x). The combined organic extracts were
washed with brine, dried over MgSO4, and concentrated
in vacuo. While practically pure 4a was obtained after
work-up, further purification by chromatography on silica
gel (CH2Cl2-MeOH gradient) furnished 4a (70 mg, 92%)
as an oil.
N-Benzyl-2-nitrobenzenesulfonamide (5a). N-Boc-N-
benzyl-2-nitrobenzenesulfonamide (3a) 151 mg (0.384
mmol) was treated with TFA (1 ml), and the reaction mix-
ture was allowed to stand at room temperature for 5 min
before it was concentrated in vacuo. While practically
pure 5a was obtained after evaporation, further purifica-
tion by chromatography on silica gel (CH2Cl2-MeOH gra-
dient) provided 5a (112mg, 100%) as a yellow solid.
Article Identifier:
1437-2096,E;1999,0,08,1301,1303,ftx,en;Y11199ST.pdf
Synlett 1999, No. 8, 1301–1303 ISSN 0936-5214 © Thieme Stuttgart · New York