Very efficient one-pot conversion of N-aminophthalimide derivatives into the corresponding N-amino-di-tert-butyl imidodicarbonates

Article abstract of DOI:10.1016/S0040-4039(01)02128-1

The phthaloyl group can be efficiently converted in very mild conditions into bis-tert-butyloxycarbonyl group using MeNH₂, then Boc₂O/DMAP, in a one-flask protocol.

Full text of DOI:10.1016/S0040-4039(01)02128-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 249–251
Very efficient one-pot conversion of N-aminophthalimide
derivatives into the corresponding N-amino-di-tert-butyl
imidodicarbonates
Nicolas Brosse and Brigitte Jamart-Gre´goire*
Lab. Chimie organique MAEM UMR mixte CNRS-UHP no. 7567, Faculte´ des Sciences, Universite´ H. Poincare´ Nancy I,
Bld des Aiguillettes BP 239, F-54506 Vandoeuvre-le`s-Nancy Cedex, France
Received 30 October 2001; accepted 8 November 2001
Abstract—The phthaloyl group can be efficiently converted in very mild conditions into bis-tert-butyloxycarbonyl group using
MeNH2, then Boc2O/DMAP, in a one-flask protocol. © 2002 Elsevier Science Ltd. All rights reserved.
The phthalimide group has provided the classical
means for the direct introduction of masked amino
function via the Gabriel protocol1 as well as for the
protection of amino groups.2,3 Recently, we demon-
strated that phthalimide derivatives can also be
efficiently used for the synthesis of N-alkylated hydra-
zine derivatives.4 As a result, we showed that N-acyl
and N-protected aminophthalimides can be considered
as hydrazines bearing three electron-withdrawing
groups including two incorporated into the phthaloyl
moiety. This structural arrangement enabled us to use,
for the first time, these hydrazine derivatives as acidic
partners in the Mitsunobu reaction. This protocol was
highly efficient to obtain in two steps N-alkylated
hydrazides or carbazates4a and enantiomerically pure
a-hydrazinoacid derivatives4b (Scheme 1).
and concomitantly to reduce steric hindrance. Unfortu-
nately, as other authors reported,5 we were confronted
with the difficulty of finding general and mild condi-
tions to remove the phthaloyl group. In some cases, this
drawback depreciated this new strategy of synthesis of
hydrazine derivatives. N-tert-Butyloxycarbonyl (Boc) is
among the most utilized protecting groups and plays a
critical role in amino acid and peptide chemistry since it
is easily removed and is compatible with solid-phase
synthesis.2,3,6 In order to find mild and efficient condi-
tions to remove the phthaloyl group and concomitantly
to obtain Boc protection of our hydrazine derivatives,
we were interested in developing a strategy which
would enable us to transform a phthaloyl into a Boc
group.
Herein, we describe a one-flask protocol for the conver-
We showed that the presence of the phthaloyl group
was essential for the success of this reaction by con-
tributing to the increase in acidity of the sole proton
sion of phthaloyl-hydrazides or -carbazates 2 into the
corresponding
N,N-bis-tert-butyloxycarbonyl-hydra-
zides or -carbazates 3 in high yields by treatment with
methylamine followed by the action of (Boc)2O/DMAP
(Scheme 2).
O
a)
b)
In preliminary studies, we showed that compounds 2
cannot be dephthaloylated by using the MeNH2, which
R'
H
N-N
R'NNH2
COR
PhtNN
COR
COR
O
1
2
R'
R'
O
a)
b)
BocNH-N
2
(Boc)2N-N
R
R
Scheme 1. (a) R%OH, DEAD, PPh3, THF; (b) CH3NHNH2,
O
THF.
4
3
Scheme 2. (a) MeNH2, THF, rt, 3 h; evaporation; (Boc)2O,
* Corresponding author. Tel./fax: 33(0)3-83-91-27-48; e-mail:
DMAP cat., THF, rt (b) Mg(ClO4)2 cat., CH3CN.
brigitte.jamart@maem.uhp-nancy.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02128-1

250
N. Brosse, B. Jamart-Gre´goire / Tetrahedron Letters 43 (2002) 249–251
was described to allow the dephthaloylation of some
protected amines.7 Applied to compounds 2, these con-
ditions led in fact to the formation of compounds 5
resulting from an opening of the phthaloyl ring instead
of the corresponding deprotected hydrazides or car-
bazates. We reasoned that the fixation of an electron-
withdrawing group onto the acidic nitrogen atom of the
hydrazide function could allow the dephthaloylation by
favoring the split of the COꢀN bond of the hydrazide
group of 5. This strategy has been previously reported
in the literature since amides can be activated to
hydrolysis by prior conversion to the N-Boc imide
derivatives.8 As a result, we showed that the removal of
the phthaloyl group of 2 can be achieved very efficiently
by using (Boc)2O in the presence of a catalytic amount
of DMAP. These last conditions led in fact to the direct
formation of the corresponding 1,1-di-(tert-butyloxy-
carbonyl) hydrazides or carbazates 3. Systematic assays
performed on compound 2 R=OCH2Ph, R%=CH2Ph
demonstrated that the reaction was better achieved
using 3 equiv. of (Boc)2O, the use of 1 equiv. of reagent
leading to the formation of a mixture of compounds 3
and 4 (with 25 and 55% yields, respectively). To
improve our technique we investigated performing the
conversion of phthaloyl hydrazides or carbazates 2 into
the corresponding compounds 3 in a one-flask protocol
which could potentially find use in the combinatorial
synthesis of Boc-protected hydrazides or carbazates. A
general procedure is as follows: to a solution of com-
pound 2 (3 mmol) in THF (20 mL) was added at room
temperature a solution of methylamine (4.5 mmol, 2
mol L−1 in MeOH). The mixture was stirred at room
temperature until completion (monitored by tlc). The
solvent and the excess of amine were removed in vacuo.
To the white solid those obtained dissolved in THF (20
mL) was added (Boc)2O (9 mmol) and a catalytic
amount of DMAP. The mixture was stirred at room
temperature until completion (monitored by tlc); the
solvent was removed in vacuo and the residue is sepa-
rated by column chromatography.9 The results of these
transformations are shown in Table 1.10 Regardless of
the nature of R or R%, the yields in compounds 3 are
very good. It is important to note that this procedure is
still efficient when R%=CH(CH3)COOEt and could rep-
resent a new method for the preparation of orthogonal
Na,Nb-triprotected a-hydrazinoesters. The production
of compounds 3 can be explained by the reaction
mechanism given in Scheme 3. As described above the
action of the methylamine gives the corresponding
compound 5 which can be isolated if necessary. Then,
the mechanism predicts that (Boc)2O would selectively
protect the nitrogen of the hydrazide group of com-
pounds 5, leaving unprotected those of the amide group
which should react with the carbonyl group of the
phenyl hydrazide and lead to the split of the CꢀN bond.
To test this hypothesis, pyrolidine, a secondary amine
was used instead of the methylamine which allowed us
to isolate the pyrolidino analogue of compound 6
Table 1. Di- and mono-tert-butyloxycarbonyl hydrazine
derivatives produced via Scheme 2
2
3 % yielda
4 % yieldb
R
R%
CH3
CH3
Ph
Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
90
94
75
80
82
91
76
80
90
85
81
86
80
96
84
98
96
80
tBuO
tBuO
OCH2Ph
OCH2Ph
OCH2Ph
CH2Ph
CH(CH3)COOEt
a Yields of compounds 3 calculated from 2.
b Yields of compounds 4 calculated from 3.
O
O
MeNH2
NHMe
(Boc)2O
DMAP
NHMe
R'
2
R'
N
N
NH-N
COR
Boc
COR
O
O
6
5
O
(Boc)2O
DMAP
R'
3
BocN-N
+
N CH3
6
COR
O
Scheme 3. Proposed reaction mechanism for the production
of compounds 3.
The introduction of the second Boc group would be the
result of the reaction of second equivalent of (Boc)2O.
Finally, using a described procedure,11 di-tert-butyloxy-
carbonyl groups underwent mild and selective monode-
protection by action of
a catalytic amount of
Mg(ClO4)2 in CH3CN to yield compounds 4 (Scheme 2,
Table 1). In summary, it has been shown that N-
aminophthalimide derivatives can be efficiently con-
verted into the corresponding N-amino-di-tert-
butylimidodicarbonates using a three-stage one-flask
protocol in very mild conditions. A selective removal of
one Boc group on the diprotected nitrogen leads to the
formation of N-tert-butyloxycarbonyl hydrazine
derivatives in good yields. We showed on one example
that these procedures could also be used for the prepa-
ration of orthogonal Na,Nb-diprotected a-hydrazino-
esters. Extension of this method to other a-hydra-
zinoacid and peptide derivatives is currently under
investigation.
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1
which was characterized by H and 13C NMR. Further-
more, the isolation and the identification of methylph-
thalimide as a by-product of the reaction is also in
agreement with the proposed reaction mechanism.

N. Brosse, B. Jamart-Gre´goire / Tetrahedron Letters 43 (2002) 249–251
251
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2H), 4.67 (s, 2H), 1.36, 1.29 (2s, 18H); 13C NMR: l
155.5, 150.3, 136.3, 135.4, 130.6, 130.2, 128.8, 128.7,
128.6, 128.4, 84.0, 68.7, 68.3, 54.9, 53.9, 28.1. 3 R=
OCH2Ph, R%=CH(CH3)COOEt: 1H NMR (CDCl3): l
7.38–7.26 (m, 5H), 5.29–5.17 (m, 2H), 4.58 (q, J=7 Hz,
1H), 4.20 (t, J=7 Hz, 3H), 1.51, 1.47, 1.45, 1.40 (4s,
18H), 1.36 (d, J=7 Hz, 3H), 1.26 (t, J=7 Hz, 3H). 13C
NMR: l 155.5, 150.3, 136.3, 135.4, 130.6, 130.2, 128.8,
128.7, 128.6, 128.4, 84.0, 68.7, 68.3, 54.9, 53.9, 28.1.4
R=Ph, R%=CH3: 1H NMR (CDCl3): l 7.44–7.22 (m,
5H), 3.23 (s, 3H), 1.35 (s, 9H); 13C NMR: l 134.9, 130.6,
1
128.3, 127.6, 82.0, 28.4. 4 R=Ph, R%=CH2Ph: H NMR
(CDCl3): l 7.62–7.22 (m, 10H), 6.75 (s, 1H), 6.61–4.07
(m, 2H), 1.31 (s, 9H). 13C NMR: l 154.4, 136.2, 135.3,
130.5, 129.1, 129.0, 128.3, 128.0, 127.7, 82.0, 28.6. 4
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3.05 (s, 3H), 2.01 (s, 3H), 1.12 (s, 9H).13C NMR: l 174.3,
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1
154.7, 82.0, 36.0, 28.5, 20.7. 4 R=CH3, R%=CH2Ph: H
NMR (CDCl3): l 7.34–7.12 (m, 5H), 5.36–4.27 (m, 2H),
2.02 (s, 3H), 1.37 (s, 9H). 13C NMR: l 174.0, 154.6,
136.2, 129.3, 129.1, 128.1, 81.9, 50.8, 28.4, 20.1 4 R=
1
OCH2Ph, R%=CH3: H NMR (CDCl3): l 7.39–7.24 (m,
9. Merck silica gel 60 was used for all chromatographic
separations. The separation of compounds
3
was
5H), 5.14 (s, 2H), 3.17 (s, 3H), 1.42 (s, 9H). 13C NMR: l
156.8, 136.5, 128.8, 128.5, 128.3, 81.8, 68.2, 38.3, 28.6. 4
R=OCH2Ph, R%=CH2Ph: 1H NMR (CDCl3): l 7.57–
7.06 (m, 10H), 6.68–6.17 (m, 1H), 5.23 (s, 2H), 4.75 (s,
2H), 1.44 (s, 9H); 13C NMR: l 156.7, 136.9, 136.4, 129.2,
129.0, 128.6, 128.3, 128.2, 128.1, 82.0, 68.6, 54.0, 28.5. 4
R=OCH2Ph, R%=CH(CH3)COOEt: 1H NMR (CDCl3):
l 7.39–7.26 (m, 5H), 6.69–6.52 (m, 1H), 5.22 (pd, 1H),
5.10 (pd, 1H), 5.05–4.95, 4.85–4.73 (2m, 1H), 4.23–4.03
(m, 2H), 1.47 (d, J=7 Hz, 3H), 1.39, 1.35 (2s, 9H),
1.29–1.14 (m, 3H). 13C NMR: l 172.6, 156.4, 155.5,
136.1, 128.8, 128.5, 128.1, 81.6, 68.7, 61.8, 28.4, 14.5. For
the other compounds, see Ref. 12.
achieved by using a column chromatography (¥=3 cm)
and a mixture EtOAc/hexane as eluant. As an indication:
Rf (methylphthalimide)=0.45 with hexane/EtOAc 4/1.
10. 1H and 13C NMR spectra of all new compounds: 3
R=Ph, R%=CH3: 1H NMR (CDCl3): l 7.32–7.10 (m,
5H), 3.06 (s, 3H), 1.36 and 1.25 (2s, 18H); 13C NMR: l
172.7, 149.9, 134.8, 130.7, 128.2, 126.8, 84.6, 35.5, 28.1. 3
1
R=Ph, R%=CH2Ph: H NMR (CDCl3): l 7.57–7.22 (m,
10H), 4.89 (s, 2H), 1.43 and 1.29 (2s, 18H); 13C NMR: l
172.8, 135.2, 135.1, 131.1, 130.7, 128.8, 128.6, 128.3,
128.2, 84.7, 52.6, 28.2. 3 R=CH3 R%=CH3: 1H NMR
(CDCl3): l 3.06 (s, 3H), 1.93 (s, 3H), 1.50 (s, 18H); 13C
NMR: l 172.4, 150.0, 84.9, 34.9, 28.3, 20.2. 3 R=CH3
R%=CH2Ph: 1H NMR (CDCl3): l 7.27–7.16 (m, 5H),
4.61 (s, 2H), 1.91 (s, 3H), 1.27 (s, 18H); 13C NMR: l
172.6, 150.0, 135.3, 130.7, 128.7, 128.2, 54.6, 51.4, 28.1,
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1
20.5. 3 R=OCH2Ph, R%=CH3: H NMR (CDCl3): l 13C
NMR: l 155.3, 150.2, 136.4, 128.8, 128.6, 128.3, 84.1,
68.4 and 68.1, 37.4 and 36.7, 28.2. 3 R=OCH2Ph, R%=
CH2Ph: 1H NMR (CDCl3): l 7.45–7.24 (m, 10H), 5.20 (s,