Selective conversion of O-succinimidyl carbamates to N-(O-carbamoyl)-succinmonoamides and ureas

Article abstract of DOI:10.1016/S0040-4039(02)00554-3

N-Monoalkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce ureas. However, N,N-dialkyl-O-succinimidyl carbamates reacted with primary and secondary amines, via succinimide ring opening, to afford N-(O-carbamoyl)-succinmonoamide derivatives. This ring-opening trend was also true with hydroxy and alkoxy nucleophiles. Herein, general methods for the synthesis and NMR characterization of N-(O-carbamoyl)-succinmonoamides are reported.

Full text of DOI:10.1016/S0040-4039(02)00554-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3443–3445
Selective conversion of O-succinimidyl carbamates to
N-(O-carbamoyl)-succinmonoamides and ureas
Natalya I. Vasilevich,a,* Navzer D. Sachinvala,b Karol Maskosc and David H. Coya
aPeptide Research Laboratory, Tulane Health Sciences Center, 1430 Tulane Avenue, SL12, New Orleans, LA 70112, USA
bSouthern Regional Research Center, USDA-ARS, 1100 Robert E. Lee Blvd., New Orleans, LA 70124, USA
cCoordinated Instrumentation Facility, Tulane University, 605 Lindy Boggs Building, New Orleans, LA 70118, USA
Received 27 November 2001; accepted 28 February 2002
Abstract—N-Monoalkyl-O-succinimidyl carbamates reacted with primary and secondary amines to produce ureas. However,
N,N-dialkyl-O-succinimidyl carbamates reacted with primary and secondary amines, via succinimide ring opening, to afford
N-(O-carbamoyl)-succinmonoamide derivatives. This ring-opening trend was also true with hydroxy and alkoxy nucleophiles.
Herein, general methods for the synthesis and NMR characterization of N-(O-carbamoyl)-succinmonoamides are reported.
© 2002 Elsevier Science Ltd. All rights reserved.
The reaction between N-monosubstituted-O-succin-
imidyl carbamates and primary or secondary amines is
a general method for producing symmetrical and
unsymmetrical ureas.1–3,5 While preparing a peptoid
combinatorial library, we wanted to obtain unsymmet-
rical ureas from N,N-disubstituted-O-succinimidyl car-
bamates (1, Fig. 1). Instead, the only products realized
from the reaction of 1 with primary or secondary
amines were the succinimide ring opening adducts,
N-(O-carbamoyl)-succinmonoamides 2, and this hap-
pened without regard to nitrogen or oxygen nucle-
ophiles (hydroxy, alkoxy, and primary or secondary
amines, see structures 2a–2k). In all cases no side
reactions were obtained. Therefore, this ring-opening
reaction could be a general method for the synthesis of
N-(O-carbamoyl)-succinmonoamide derivatives 2 (Fig.
1), which appear to be analogs of N-acyl-O-carbamoyl
hydroxylamine. To fulfill our original objective, i.e. the
synthesis of unsymmetrical urea 3, we changed the
order of events and reacted O-succinimidyl carbamates
of primary amines with secondary amines (Fig. 1).
Herein we will discuss the syntheses of eleven new
N-acyl-O-carbamoyl hydroxylamine analogs 2 and one
urea 3 to exemplify our novel discovery.
Syntheses
of
N-(O-carbamoyl)-succinmonoamide
derivatives 2a–2k were possible under both solid and
liquid phase conditions (Fig. 1). Solid-phase syntheses
of 2a–c, required the Fmoc-Rink amide resin and TFA
cleavage methods.4 The secondary amines for the syn-
thesis of 2a–c were obtained by method of Heizmann et
al.4 The deprotected Fmoc amide resin was acylated
with bromoacetic acid using DCC, and the a-bromo
substituent was then displaced with primary amines.
Reactions of the resin-bound secondary amines with
disuccinimidyl carbonate afforded resin-bound 1.5
Compounds 2a and 2b were formed by reactions of
resin-bound 1 with 4-fold molar excess of 4-phenylbutyl-
amine, and 2c was formed by reaction with propyl-
amine in DMF. TFA was then used to release com-
pounds 2a–c from the resins.4 Secondary amines for
liquid phase preparations of 2d, 2g, 2h, and 2i were
purchased commercially and those for 2e and 2f were
prepared by reductive alkylation. Their conversion to 1
was achieved by reacting the amine with excess disuc-
cinimidyl
carbonate.5
N-(O-Carbamoyl)-succin-
monoamides 2d–2i were prepared by equimolar
reaction of 1 with amines in the presence of diisopropyl-
ethylamine (DIPEA, 2-fold molar excess, 4 h). When 1
was stirred overnight in methanolic sodium hydroxide
the C-terminal acid, 2j, and the methyl ester 2k were
produced in an 8:2 ratio. However, with Na in dry
methanol only 2k was produced. Yields for all products
are shown in Fig. 1. While the conversion of the
succinimidyl carbamates 1 to hydroxylamine analogs 2
were nearly quantitative, yields reported herein (Fig. 1)
are for the overall processes, i.e. starting with amines to
Keywords: N-(O-carbamoyl)-succinmonoamides; ureas; di-N-hydroxy-
succinimidyl carbonate; O-succinimidyl carbamate; N-acyl-O-car-
bamoyl hydroxylamine derivatives.
* 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)00554-3

3444
N. I. Vasile6ich et al. / Tetrahedron Letters 43 (2002) 3443–3445
Figure 1. Syntheses of O-acyl-hydroxamic acid analogs and an urea.
solvent was evaporated and the product (2) was purified
by HPLC or crystallization (acetone, acetic acid and
water).
form the carbamates 1, and then converting them to the
N-(O-carbamoyl)-succinmonoamide derivatives 2. Urea
3 was obtained by reacting a propyl amine with disuc-
cinimidyl carbonate, followed by nucleophilic displace-
ment of N-hydroxysuccinimide with N-phenyl-
piperazine.5
Multidimensional NMR, mass spectrometry, and
reverse-phase chromatography (Dynamax® 300 A, 5 or
8 mM, 21.4×250 mm, UV detection 280 nm) were used
to characterize all new compounds. Chemical shift
assignments for compounds 2a–2k were made using 1H,
General procedure for the preparation of N-(O-car-
bamoyl)-succinmonoamides (e.g. 2d–2i): A methylene
chloride solution of the secondary amine (0.2 mol in 10
mL) and DIPEA (0.2 mol) was added to N,N%-disuccin-
imidyl carbonate in the same solvent (0.4 mol in 50
mL). After 2 h, the solution was washed serially with
10% aqueous HCl, 20% aqueous sodium bicarbonate,
and water, then dried over Na2SO4, and concentrated
in vacuo to give an oil. Excess of N,N%-disuccinimidyl
carbonate was removed by filtration through a short
silica gel column (60 angstroms, 2×2 cm) using methyl-
ene chloride. The effluent containing crude O-succin-
imidyl carbamate 1, was concentrated and a solution of
the amine (0.2 mol) and DIPEA (800 mL) in DMF (60
mL) was added, and the mixture stirred 4 h. The
1
13C, and 15N spectra. Table 1 shows the H, 13C and
15N NMR chemical shifts of the 9-atom region (includ-
ing oxygen) common to the new hydroxylamine analogs
2a–2i. Derivatives 2j and 2k contain oxygen (instead of
nitrogen) at position 1, therefore the chemical shift
entries for N1 in Table 1 are missing. Proton assign-
ments were made from the 1 and 2D, COSY,6,7
TOCSY,8,9 and ROESY10,11 spectra. Carbon and nitro-
gen assignments were made using the HSQC12–14 and
HMBC15,16 methods.
Analogs of hydroxyl amines inhibit nucleic acids syn-
thesis,17 are mutagenic,18 and may possess antimalarial

N. I. Vasile6ich et al. / Tetrahedron Letters 43 (2002) 3443–3445
3445
Table 1. 1H, 13C and 15N NMR chemical shifts in the common part of N-(O-carbamoyl)-succinmonoamidesa
Compound
N1H (C1–1H)
N1
(
13C1)
C2ꢀO
C3H
C3
C4H
C4
C5ꢀO
N6H
N6
C7ꢀO
N8
83.5
83.1
126.4
82.6
2a
7.968
116.4
171.59
2.312
31.06
2.312
28.41
28.45
28.50
28.52
170.47
170.40
170.6
170.25
170.32
11.551
11.538
11.613
11.481
11.525
175.0
174.8
175.4
174.6
174.8
155.71
155.29
155.60
155.76
155.71
155.65
155.46
155.90
155.34
155.67
155.57
154.34
155.81
155.85
154.78
2b
2c
7.848
7.835
117.0
116.8
171.48
171.52
2.389
2.315
31.01
31.10
2.389
2.319
81.6
2d
7.957
116.5
171.67
2.404
31.18
2.404
28.60
170.70
11.579
174.9
65.3
b
b
2e
2f
2g
2h
2i
7.815
7.829
7.847
7.918
117.1
117.1
116.9
116.5
113.5
171.00
171.00
171.48
171.52
170.35
173.21
2.351
2.351
2.346
2.367
2.677
2.508
31.04
31.04
31.07
31.00
28.21
28.49
2.351
2.351
2.346
2.367
2.433
2.390
28.44
28.44
28.53
28.45
28.18
26.84
170.42
170.52
170.57
170.73
170.83
169.37
11.520
11.588
11.540
11.672
11.713
11.853
174.7
175.0
174.5
175.5
175.5
176.0
80.57
b
90.1
91.7
2j
90.9
b
2k
3.605
51.34
172.27
2.587
28.11
2.428
26.65
169.05
11.722
174.9
154.72
a NMR chemical shifts on l scale; 1H shifts relative to l (DMSO)=2.500 ppm; 13C shifts relative to l (DMSO)=39.51 ppm; 15N shifts relative
to l (liquid NH3)=0.00 ppm.
b Crosspeaks not seen in the 1H–15N HMBC spectrum—concentration of the compound too low.
activity.19 In the clinic they find use as metal chela-
tors.20–24 Our new preparative methods for their
analogs are convenient and may be used in the synthe-
sis of diverse peptoid libraries that contain ureas and
N-(O-carbamoyl)-succinmonoamides. A study involv-
ing the ring-opening reactions of substituted succinic,
glutaric, and adipic imides under similar conditions is
underway. Finally, we propose the following general-
ization: When N-(O-carbamoyl)-succinmonoamides via
the succinimide ring-opening reaction are required the
synthesis should begin with N,N-dialkyl-O-succinimidyl
carbamates. When unsymmetrical ureas are required,
the synthesis should start with N-monoalkyl-O-succin-
imidyl carbamates.
Commun. 1983, 117, 479.
7. Shaka, A. J.; Freeman, R. J. Magn. Reson. 1983, 51, 169.
8. Bax, A.; Davis, D. G. J. Magn. Reson. 1985, 65, 355.
9. Davis, D. G.; Bax, A. J. Am. Chem. Soc. 1985, 107, 2820.
10. Bax, A.; Davis, D. G. J. Magn. Reson. 1985, 63, 207.
11. Hwang, T.-L.; Shaka, A. J. J. Am. Chem. Soc. 1992, 114,
3157.
12. Norwood, T. J.; Boyd, J.; Heritage, J. E.; Soffe, N.;
Campbell, I. D. J. Magn. Reson. 1990, 87, 488.
13. Palmer, A. G., III; Cavanagh, J.; Wright, P. E.; Rance,
M. J. Magn. Reson 1991, 93, 151.
14. Kay, L. E.; Keifer, P.; Saarinen, T. J. Am. Chem. Soc.
1992, 114, 10663.
15. Summers, M. F.; Marzilli, L. G.; Bax, A. J. Am. Chem.
Soc. 1986, 108, 4285.
16. Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108,
2093.
References
17. Hynes, J. B.; Gale, G. R.; Atkins, L. M.; Cline, D. M.;
Hill, K. F. J. Med. Chem. 1973, 16, 576.
1. Guichard, G.; Semetey, V.; Rodriguez, M.; Briand, J.-P.
Tetrahedron Lett. 2000, 41, 1553.
18. Skipper, P. L.; Tannenbaum, S. R.; Thilly, W. G.; Furth,
E. E.; Bishop, W. W. Cancer Res. 1980, 40, 4704.
19. Hynes, J. B.; Hack, L. G. J. Med. Chem. 1972, 15, 1194.
20. Kontodhiorghes, G. J.; Pattichi, K.; Hadjigavriel, M.;
Kolnagu, A.; Porter, J. B. Transfus. Sci. 2000, 23, 211.
21. Elihu, N.; Anandasbapathy, S.; Frishman, W. H.;
Kontodhirghes, G. J.; Pattichi, K.; Hadjigavriel, M.;
Kolnagou, A.; Porter, J. B. J. Clin. Pharmacol. 1998, 38,
101.
2. Guichard, G.; Semetey, V.; Didierjean, C.; Aubry, A.;
Briand, J.-P.; Rodriguez, M. J. Org. Chem. 1999, 64,
8702.
3. Yang, L.; Patchett, A.; Pasternak, A.; Berk, S. WO
9844921, 1998.
4. Heizmann, G.; Hildebrand, P.; Tanner, H.; Ketterer, S.;
Pansky, A.; Froidevaux, S.; Beglinger, C.; Eberle, A. N.
J. Receptor Signal Transduction Res. 1999, 19, 449.
5. Takeda, K.; Akadi, Y.; Saiki, A.; Tsukahara, T.; Ogura,
H. Tetrahedron Lett. 1983, 24, 4569.
22. Keberle, H. Ann. NY Acad. Sci. 1964, 119, 758.
23. Callender, S. T.; Weatherall, D. J. Lancet 1980, 689.
24. Peter, H. Eur. Pat. Appl. EP 271443, 1988.
6. Rance, M.; Sorensen, O. W.; Bodenhausen, G.; Wagner,
G.; Ernst, R. R; Wuthrich, K. Biochem. Biophys. Res.