Conversion of O-succinimidyl carbamates to N-(O-carbamoyl)-succinmonoamides and ureas: Effects of N-substituents and reaction conditions on the reaction pathway

Article abstract of DOI:10.1016/S0040-4039(02)01451-X

Whereas N-monoalkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce only ureas, N,N-dialkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce N-(O-carbamoyl)-succinmonoamides. N-Alkyl-N-aryl-O-su

Full text of DOI:10.1016/S0040-4039(02)01451-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6649–6652
Conversion of O-succinimidyl carbamates to
N-(O-carbamoyl)-succinmonoamides and ureas: effects of
N-substituents and reaction conditions on the reaction pathway
Natalya I. Vasilevich* and David H. Coy
Peptide Research Laboratory, Tulane Health Sciences Center, 1430 Tulane Avenue, SL12, New Orleans, LA 70112, USA
Received 8 May 2002; revised 9 July 2002; accepted 10 July 2002
Abstract—Whereas N-monoalkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce only ureas,
N,N-dialkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce N-(O-carbamoyl)-succin-
monoamides. N-Alkyl-N-aryl-O-succinimidyl carbamates under the same condition led to mixture of both products. The effects
of N-substituents and reaction conditions on O-succinimidyl carbamates conversion are discussed. © 2002 Elsevier Science Ltd.
All rights reserved.
A general method for symmetrical and unsymmetrical
urea synthesis utilizes nucleophilic substitution between
N-monoalkyl-O-succinimidyl carbamates and primary
or secondary amines.1–4 Recently, we demonstrated that
N,N-dialkyl-O-succinimidyl carbamates under the same
conditions afford the succinimide ring opening adducts,
N-(O-carbamoyl)-succinmonoamides or hydroxylamine
derivatives.5 This can potentially cause unexpected syn-
thetic outcomes, particularly in combinatorial studies
where intermediates are often poorly characterized, if at
all. It was also shown that this unusual reaction path-
way does not depend on the type of nucleophile
(hydroxy, alkoxy, primary and secondary amines)
employed.5
reaction without base made it much slower and
decreased yields to only 30% even after refluxing
overnight. As before, N-(O-carbamoyl)succinmono-
amide remained the only product. Carbamate 2 in all
cases afforded only the urea and DIPEA base had little
influence on the rate and the yield of conversion. Thus,
nucleophilic substitutions in N-monoalkyl- and N,N-
dialkyl-O-succinimidyl carbamates are confirmed to be
very selective and appear independent of reaction con-
ditions.
Factors potentially influencing the unexpected reaction
pathway include steric, conformational, and electronic
considerations. The central carbonyl group in N,N-
dialkyl-O-succinimidyl carbamate is more sterically hin-
dered than that in the N-monoalkyl-O-succinimidyl
carbamate and should promote nucleophilic attack on
succinimide carbonyl. However, while this is important,
it cannot be the determining factor since N-alkyl-N-
nitroso-O-succinimidyl carbamates react with amines to
produce the corresponding ureas regardless of the
degree of steric hindrance.4,6 Additionally, there is a
free hydrogen atom in N-monoalkylcarbamates that
can form an intramolecular hydrogen bond with the
carbonyl or with the nitrogen atom in a succinimide
ring thus potentially facilitating succinimide group loss
and urea formation. There is no equivalent atom for
intramolecular hydrogen bonding in N,N-dyalkylcarba-
mates and thus no possibility to facilitate urea forma-
tion this way. Again, this factor is not essential,
otherwise solvent type and base concentration effects
would be far greater than described here. Electronic
In an effort to evaluate whether other reaction condi-
tions affect the reaction pathway, we next focused on
two model reactions: the first between N,N-dibenzyl-O-
succinimidyl carbamate 1 and 3,3-diphenylpropylamine
and the second between N-3,3-diphenylpropyl-O-suc-
cinimidyl carbamate 2 and 3,3-diphenylpropylamine
(Table 1). Carbamate 1 selectively produced N-(O-car-
bamoyl)-succinmonoamide without regard to solvent
and the presence of base. In terms of solvent effects,
reaction in methylene chloride, dimethylformamide,
benzene, THF and acetonitrile led to the same product
and, moreover, yields were very similar. Performing the
Keywords: N-(O-carbamoyl)-succinmonoamides; ureas; O-succin-
imidyl carbamate.
* Corresponding author. Fax: 504-584-3586; e-mail: nvasile@
tulane.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01451-X

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N. I. Vasile6ich, D. H. Coy / Tetrahedron Letters 43 (2002) 6649–6652
Table 1. Reaction between O-succinimidyl carbamates 1 and 2 and 3,3-diphenylpropylamine
Carbamate
Solvent
Base, DIPEA
Product
Yield, %
1
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
1 equiv.
2 equiv.
0 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
1 equiv.
0 equiv.
2 equiv.
4 equiv.
1 equiv.
1 equiv.
B
B
B
B
B
B
B
A
A
A
A
A
A
68
73
30a
69
67
74
70
83
69
85
88
90
85
DMF
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
2
CH3CN
a Refluxing overnight required.
although the N-alkyl-group contributes electron-donat-
ing effects, the N-aryl group possesses some s-electron-
withdrawing properties and should facilitate urea
synthesis. Regarding a suitable molecular model, some
years ago the synthesis of ureas from N-indoline-O-suc-
cinimidyl carbamate, a derivative of a secondary N-
aryl-N-alkyl carbamate, was published.7,8 Reported
yields were poor and the authors used chromatography
columns for purification from multiple products. We
surmised that this might be due to formation of ring
opening products (B) as well as the expected ureas (A)
in the reaction scheme in Fig. 1.
effects could be manifested via the increased electron-
donating potential of two N-alkyl over monalkyl
groups being strong enough to make nucleophilic
attack on carbamate carbonyl less preferable than
attack on succinimide carbonyl.
Although all three factors favor N-monoalkyl carba-
mates conversion to ureas and N,N-dialkyl carbamates
to the N-(O-carbamoyl)-succinmonoamides, intuitively
the most important seems to be electron properties of
the two N-alkyl substituents. We theorized that it
would be possible to find some O-succinimidyl carba-
mates structures which possess electron properties aver-
aging between N-monoalkyl and N,N-dialkyl
carbamates which would be predicted to give mixtures
of both urea and hydroxylamine derivative. N-Alkyl-N-
aryl-O-succinimidyl carbamates seemed to be possible
candidates since, on the one hand, they have two
N-substituents, so that steric and conformational fac-
tors promote ring opening and, on the other hand,
To test this prediction, a number of reactions between
N-indoline-O-succinimidyl carbamates and different
nucleophiles were carried out in accordance with reac-
tion conditions described in our previous paper.5 These
are detailed in Tables 2 and 3 and, indeed, in most
cases we observed mixtures of products A and B,
which, in contrast to the N,N-dialkyl-O-succinimidyl
Figure 1. Effect of N-substituent in O-succinimidyl carbamates on pathway of the reaction.

N. I. Vasile6ich, D. H. Coy / Tetrahedron Letters 43 (2002) 6649–6652
6651
Table 2. Reaction between N-alkyl-N-aryl-O-succinimidyl carbamates and nucleophiles
Table 3. Physical properties of compounds 3–12
Compound
mp, °C (AcOH)
(M+H)+, or (M+Na)+ (MALDI)
tR, minc
HRMS (FAB)
Found m/z
Calcd M+
Formula
3A
3B
4A
4B
5A
5B
6A
6B
7A
7B
8B
9A
Oil
105–107
Oil
136–138
Oil
137–139
Unstable oil
Unstable oil
oil
38–40
116
Oil
153–155
Oil
136–139
Oil
219a
334a
295a
432b
278a
415b
231a
369b
308a
423a
307a
178a
301b
230b
344b
237b
375b
295a
410a
24.6
20.3
41.6
34.2
36.8
29.0
34.1
23.7
24.2
19.7
20.3
25.6
11.2
24.7
18.8
19.4
16.7
35.3
25.7
219.1479
334.1782
295.1788
410.2100
277.1916
392.2188
219.1497
334.1767
295.1810
410.2080
277.1916
392.2185
C13H19N2O
C17H24N3O4
C19H23N3O4
C23H28N3O4
C16H25N2O2
C20H30N3O5
346.1758
308.1769
423.2036
307.1295
178.0879
279.0970
207.1504
322.1752
237.1586
352.1866
295.2008
410.2271
346.1767
308.1763
423.2032
307.1294
178.0868
279.0981
207.1497
322.1767
237.1603
352.1872
295.2022
410.2291
C18H24N3O4
C19H22N3O
C23H27N4O4
C15H19N2O5
C10H12NO2
C13H15N2O5
C12H19N2O
C16H24N3O4
C13H21N2O2
C17H26N3O5
C16H27N2O3
C20H32N3O6
9B
10A
10B
11A
11B
12A
12B
146–148
Oil
123–125
a Denotes (M+H)+.
b Denotes (M+Na)+.
c RP-HPLC on C-18 bonded silica gel column, 20%B to 80%B (20%B to 80%B).

6652
N. I. Vasile6ich, D. H. Coy / Tetrahedron Letters 43 (2002) 6649–6652
carbamate reactions, essentially depend on the type of
nucleophile and the reaction conditions used. N-
Methyl-N-phenyl-O-succinimidyl carbamate also leads
to a mixture of products but the reduced percentage of
urea was probably due to stronger steric hindrance.
Comparison of the reaction products from N-methyl-
N-p-methoxyphenyl carbamate and N-methyl-N-
phenyl-O-succinimidyl carbamate reveals higher yields
of the ring opening product presumably because of the
electron-donating effect of p-methoxy-substituent of
the aryl-group.
5. Vasilevich, N.; Sachinvala, N.; Maskos, K.; Coy, D. Tet-
rahedron Lett. 2002, 43, 3443.
6. Suli-Vargha, H.; Jeney, A.; Lapis, K.; Medzihradszky, K.
J. Med. Chem. 1987, 30, 583.
7. Harada, H.; Morie, T.; Hirokawa, Y.; Terauchi, H.; Fuji-
wara, I.; Yoshida, N.; Kato, Sh. Chem. Pharm. Bull. 1995,
43, 1912.
8. Bermudez, J.; Dabbs, S.; Joiner, K.; King, F. J. Med.
Chem. 1990, 33, 1929.
9. 1H NMR spectra (DMSO) for N-[O-(N%-alkyl-N%-arylcar-
bamoyl)]-succinmonoamides: 3B: l 11.79 (br s, 1H); 7.87
(br s, 1H); 7.64 (br s, 1H); 6.82–7.28 (m, 3H); 4.05 (t, 2H);
3.03–3.19 (m, 4H); 2.27–2.41 (m, 4H); 1.24–1.39 (m, 4H);
0.89 (t, 3H); 4B: l 11.77 (br s, 1H); 7.87 (t, 1H); 7.64 (br
s, 1H); 7.15–7.29 (m, 7H); 7.02 (t, 1H); 4.05 (t, 2H); 3.17
(t, 2H); 3.05–3.09 (m, 2H); 2.575 (t, 2H); 2.34–2.40 (m,
4H); 1.57–1.60 (m, 2H); 1.38–1.44 (m, 2H); 5B: l 11.68 (br
s, 1H); 7.86 (t, 1H); 7.65 (br s, 1H); 7.01–7.29 (m, 3H);
4.05 (t, 1H); 3.33–3.67 (m, 4H); 3.18 (t, 2H); 3.01–3.11 (q,
2H); 2.36–2.39 (m, 4H); 1.29–1.63 (m, 6H); 0.89 (t, 3H);
6B: l 11.80 (br s, 1H); 7.62 (br d, 1H); 6.81–7.34 (m, 8H);
4.05 (t, 2H); 3.61–3.63 (m, 4H); 3.10–3.25 (m, 6H); 2.67 (t,
2H); 2.44 (t, 2H); 7B: l 11.77 (br s, 1H); 7.65 (br s, 1H);
4.05 (t, 2H); 3.39–3.43 (m, 4H); 3.17 (t, 2H); 2.59 (t, 2H);
2.40 (t, 2H); 1.42–1.60 (m, 6H); 8B: l 11.84 (br s, 1H); 7.65
(br s, 1H); 7.01–7.29 (m, 3H); 4.05–4.09 (m, 4H); 3.17 (t,
2H); 2.43–2.58 (m, 4H); 1.20 (t, 3H); 9B: l 11.07 (br s,
1H); 7.01 (d, 1H); 6.48–6.90 (m, 3H); 5.43 (br s, 1H); 3.39
(t, 2H); 2.89 (t, 2H); 2.34–2.42 (m, 4H); 10B: l 11.56 (br s,
1H); 7.83 (t, 1H); 7.26–7.43 (m, 4H); 3.28 (s, 3H); 3.01–
3.04 (q, 2H); 2.32 (s, 4H); 1.26–1.39 (m, 4H); 0.87 (t, 3H);
11B: l 11.49 (br s, 1H); 7.82 (t, 1H); 7.29 (d, 2H); 6.95 (d,
2H); 3.77 (s, 3H); 3.22 (s, 3H); 3.00–3.07 (q, 2H); 2,31 (s,
4H); 1.23–1.39 (m, 4H); 0.87 (t, 3H); 12B: l 11.51 (br s,
1H); 7.84 (t, 1H); 7.29 (d, 2H); 6.95 (d, 2H); 3.77 (s, 3H);
3.32–3.36 (m, 4H); 3.22 (s, 3H); 3.05–3.09 (q, 2H); 2.31 (s,
4H); 1.28–1.63 (m, 6H); 0.88 (t, 3H).
In conclusion, we have shown that N-substituents in
O-succinimidyl carbamates have a profound affect on
reaction pathways due primarily to their electronic
effect. While the reactions between N-monoalkyl and
N,N-dialkyl carbamates and nucleophiles are very
selective, N-aryl-N-alkyl carbamates fall in between
and seem to usually afford a mixture of urea and
hydroxylamine derivative. Although from a synthetic
standpoint it is sometimes possible to use N-aryl-N-
alkyl carbamates for urea synthesis,7,8 caution should
be exercised regarding the unavoidable production of
significant amounts of the ring opening contaminants.
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