Synthesis of substituted N-hydroxyureas via the in situ generation of t-butoxy isocyanate

Article abstract of DOI:10.1016/j.tetlet.2010.05.002

Treatment of primary and secondary amines with tert- butylmesitylenesulfonoxycarbamate and a base afforded tert-butoxyurea, which when treated with an acid ultimately yielded substituted N-hydroxyureas. It is proposed that this proceeded via the generation of t-butoxy isocyanate in situ. This method allows for the synthesis of both mono and disubstituted N-hydroxyureas.

Full text of DOI:10.1016/j.tetlet.2010.05.002

Tetrahedron Letters 51 (2010) 3568–3570
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted N-hydroxyureas via the in situ generation of
t-butoxy isocyanate
*
Josef G. Krause, Brian D. Leskiw, Michelle L. Emery, Megan E. McGahan, Mary P. McCourt, Ronny Priefer
Department of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of primary and secondary amines with tert-butylmesitylenesulfonoxycarbamate and a base
afforded tert-butoxyurea, which when treated with an acid ultimately yielded substituted N-hydroxy
ureas. It is proposed that this proceeded via the generation of t-butoxy isocyanate in situ. This method
allows for the synthesis of both mono and disubstituted N-hydroxyureas.
Received 10 April 2010
Revised 29 April 2010
Accepted 3 May 2010
Available online 7 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In our quest to synthesize hydrazines for our antimicrobial
study,1 we explored the possible reaction of amines with tert-buty-
lmesitylenesulfonoxycarbamate (1) to form the Boc-protected
hydrazine carbamate, which when coupled with deprotection
should ultimately yield the hydrazine. Based upon the amination
work by Boger, Genêt, and Zheng on phenols,2 boranes,3 carba-
nions,4 and enolates,5 respectively, we felt encouraged that this
route would be successful. The arenesulfonyloxycarbamates are
relatively shelf stable and have also been used in intramolecular
Sharpless aminohydroxylation reactions6 as well as aziridination7
on numerous alkenes, including fullerenes,8 where a nitrene inter-
mediate was proposed. When we attempted our synthesis, what
we ultimately obtained was the N-substituted hydroxyurea, 2
(Fig. 1).
A Lossen-type rearrangement seemed to be the most likely
mechanistic pathway (Scheme 1) whereby there is a base-induced
deprotonation of the carbamate, simultaneous migration of the t-
butoxy, and mesylsulfonyloxy removal.9 This would generate the
t-butoxy isocyanate (3) which is then attacked by the amine. This
was previously observed by Bauer for the synthesis of ureas.9
Genêt,4a Hanessian,10 and Pellacani11 have also proposed a similar
mechanism with the use of other tert-butyl aryloxycarbamates, in
the synthesis of hydroxamic esters and imidazolidin-2-ones,
respectively.
(NO).17 The most common route for their synthesis is via iso-
cyanate.18 This however, will produce only mono-N-substituted
hydroxyureas. Very few methods have been developed to obtain
N,N-disubstituted hydroxyureas. One approach involves the initial
synthesis of 1-(4-nitrophenol)-N-(O-benzylhydroxy)carbamate,
reacting with various amines, followed by hydrogenation depro-
tection.19 Synthesis of N,N-disubstituted carbamoyl chloride, via
phosgene, and reaction with hydroxylamine;16,20 reacting second-
ary amines with aryl-N-hydroxycarbamates;21 as well as the use of
triphosgene22 have all shown limited but positive results. Since t-
butoxy isocyanate that is generated in situ can be reacted with
both primary as well as secondary amines, both mono and disub-
stituted hydroxyureas could be produced in this manner. We here-
in report our two-step procedure for obtaining hydroxyurea
derivatives.
Although tert-butylmesitylenesulfonoxycarbamate (1) is com-
mercially available, it is quite easily prepared from the t-butyl-N-
hydroxycarbamate and 2-mesitylenesulfonyl chloride in nearly
quantitative yields,23 and can be used as it is without further puri-
fication. Initially we reacted 1 (1 equiv) with dibenzylamine
(1 equiv) in DMF (1 M) with DBU (1 equiv) as a base. After an hour
at 0 °C, ice water was added to the mixture which precipitated the
tert-butoxyurea in 47% yield. We explored the use of different
bases, and the highest yield was obtained with sodium hydride
(Table 1, entry 3). Changes to other polar solvents (i.e., DMSO,
MeOH, t-BuOH) did not enhance the yield. We therefore focused
on NaH in DMF as our reaction condition. The cleavage of the t-bu-
tyl group to form the corresponding hydroxyurea was attempted
with various acids. TFA, HI, HF, and BF3 all gave yields that were
significantly lower than those with HCl. Thus, we used 10 min re-
flux in conc HCl as our final deprotection step for all our
compounds.
As hydroxyureas have numerous biological uses, we further ex-
plored this synthetic path. N-hydroxyurea and many of its deriva-
tives have been explored as possible antineoplastic agents,12 used
in the treatment of sickle cell anemia,13 and are under investiga-
tion for the treatment of HIV.14 In addition, they have also shown
promise as hypoglycemic agents,15 possible antimicrobial
agents,16, and have been shown to be a source of nitric oxide
Numerous primary and secondary amines were used in this
manner to synthesize substituted N-hydroxyureas (Table 2). Both
* Corresponding author. Tel.: +1 716 286 8261; fax: +1 716 286 8254.
E-mail address: rpriefer@niagara.edu (R. Priefer).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.002

J. G. Krause et al. / Tetrahedron Letters 51 (2010) 3568–3570
3569
R
H
O
O
O
H
N
N
O
S
, Base
1)
R
NH2
R
OH
R'
N
N
N
H
O
2) H3O+
1
R'
R'
O
2
not observed
only product
Figure 1. Hydroxyurea synthesis, 2, from reacting amines with tert-butylmesitylenesulfonoxycarbamate (1).
H
R
O
N
H
O
O
B-
R
t-BuO
N
R'
t-Bu
O
N
C
O
N
H
N
MsSO3
R'
1
3
Scheme 1. Proposed mechanism of hydroxyurea synthesis via a Lossen-type rearrangement.
the initial formation of the tert-butyl protected urea as well as the
deprotection were successful in moderate to good yields. Aniline
derivatives tended to give yields in the 60% range for the initial
coupling (Table 2, entries 4–7). Best results were obtained with
dibenzylamine, thus negating any steric concerns. What was inter-
esting was when either 1-naphthylamine (4) or 1,4-dihydro-naph-
thalen-1,4-imine (5)24 was used as the initial amine source, N-
hydroxy-N0-1-naphthalenyl-urea (6) was obtained25 (Table 2, en-
tries 9 and 10, Fig. 2). Based upon NMR, the initial coupling to form
the tert-butyl protected urea proceeded without incident. The aro-
matization of 1,4-dihydro-naphthalen-1,4-imine occurred during
the deprotection with HCl to afford N-hydroxy-N0-1-naphthale-
nyl-urea (6).
In summary, this two-step procedure, via t-butoxy isocyanate,
allows for the synthesis of both mono and disubstituted hydroxyu-
reas in moderate to good yields. This novel method does have some
major advantages over other techniques. The copious amounts of
primary and secondary amines, as well as aniline derivatives, al-
lows for numerous hydroxyureas to be synthesized. In addition,
the common technique for synthesizing monosubstituted deriva-
tives typically employs isocyanates, which have safety concerns.
Finally, our method does not employ phosgene, which is also noto-
riously dangerous.
Table 1
Yield of dibenzyl tert-butoxyurea with differing bases
Entry #
Base
Yield (%)
1
2
3
4
5
6
DBU
DMAP
NaH
NaOCH3
KOH
KOtBu
47
60
84
76
70
50
Table 2
Yields of substituted N-hydroxyureas for both initially coupling and deprotection
Entry Amine
Yield of
Yield of
R1R2NCONHOtBu (%) R1R2NCONHOH
(%)
1
2
3
4
5
6
7
8
9
C6H5CH2NH2
45
85
59
65
62
67
60
58
84
90
70
43
63
65
68
55
53
92
86
(C6H5CH2)NH
C6H5CH2NHCH3
C6H5CH2NHC6H5
C6H5NH2
p-Cl-C6H4NH2
C6H5NHCH3
C6H11NH2
1-Napthylamine
1,4-Dihydro-naphthalen- 81
1,4-imine
Acknowledgments
We thank the Niagara University and the Niagara University
Academic Center for Integrated Science for the financial support.
M.P.M. would like to thank the National Science Foundation, James
Cummings Foundation, and GeNYsis for the additional financial
support.
10
O
OH
NH2
N
H
HN
Entry 9
Entry 10
NH
4
6
5
Figure 2. Synthesis of N-hydroxy-N0-1-naphthalenyl-urea (6) from both 1-naphthylamine (4) or 1,4-dihydro-naphthalen-1,4-imine (5).

3570
J. G. Krause et al. / Tetrahedron Letters 51 (2010) 3568–3570
Barton, F. B.; Moore, R. D.; Terrin, M. L.; Steinberg, M. H.; Dover, G. J.; Ballas, S.
References and notes
K.; McMahon, R. P.; Castro, O.; Orringer, E. P. Medicine 1996, 75, 300.
14. Simonelli, C.; Nasti, G.; Vaccher, E.; Tirelli, U.; Zanussi, S.; De Paoli, P.; Comar,
M.; Giacca, M. JAIDS—J. Acquir. Immune Defic. Syndr. 1996, 13, 462.
15. Goldstein, S. W.; McDermott, R. E.; Gibbs, E. M.; Stevenson, R. W. J. Med. Chem.
1993, 36, 2238.
16. Thorarensen, A.; Douglas, M. R., Jr.; Rohrer, D. C.; Vosters, A. F.; Yem, A. W.;
Marshall, V. D.; Lynn, J. C.; Bohanon, M. J.; Tomich, P. K.; Zurenko, G. E.;
Sweeney, M. T.; Jensen, R. M.; Nielsen, J. W.; Seest, E. P.; Dolak, L. A. Bioorg. Med.
Chem. Lett. 2001, 11, 1355.
1. Ingalsbe, M. L.; St. Denis, J. D.; McGahan, M. E.; Steiner, W. W.; Priefer, R. Bioorg.
Med. Chem. Lett. 2009, 19, 4984.
2. Jin, W.; Trzupek, J. D.; Rayl, T. J.; Broward, M. A.; Vielhauer, G. A.; Weir, S. J.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2007, 129, 15391.
3. Genêt, J.-P.; Hajicek, J.; Bischoff, L.; Greck, C. Tetrahedron Lett. 1992, 33, 2677.
4. (a) Greck, C.; Genêt, J. P. Synlett 1997, 741; (b) Greck, C.; Bischoff, L.; Ferreira, F.;
Genêt, J. P. J. Org. Chem. 1995, 60, 7010.
5. Zheng, N.; Armstrong, J. D., III; McWilliams, J. C.; Volante, R. P. Tetrahedron Lett.
1997, 38, 2817.
6. (a) de la Pradilla, R. F.; Lwoff, N.; del Águila, M. Á.; Tortosa, M.; Viso, A. J. Org.
Chem. 2008, 73, 8929; (b) de la Pradilla, R. F.; Lwoff, N.; Viso, A. Tetrahedron Lett.
2007, 48, 8141; (c) Donohoe, T. J.; Chughai, M. J.; Klauber, D. J.; Griffin, D.;
Campbell, A. D. J. Am. Chem. Soc. 2006, 128, 2514.
7. (a) Arai, H.; Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.; Hamada, Y.
Tetrahedron Lett. 2009, 50, 3329; (b) Pesciaioli, F.; De Vincentiis, F.; Galzerano,
P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed.
2008, 47, 8703; (c) Fioravanti, S.; Massari, D.; Morreale, A.; Pellacani, L.;
Tardella, P. A. Tetrahedron 2008, 64, 3204; (d) Martina, E.; Stiefl, N.; Degel, B.;
Schulz, F.; Breuning, A.; Schiller, M.; Vicik, R.; Baumann, K.; Ziebuhr, J.;
Schirmeister, T. Bioorg. Med. Chem. Lett. 2005, 15, 5365; (e) Fioravanti, S.;
Morreale, A.; Pellacani, L.; Tardella, P. A. Synthesis 2001, 1975.
8. Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Hodgson, P. K. G.; Langridge-Smith, P.
R. R.; Millar, J. R. A.; Taylor, A. T. J. Chem. Soc., Chem. Commun. 1995, 885.
9. Pihuleac, J.; Bauer, L. Synthesis 1989, 61.
17. King, S. B. Curr. Med. Chem. 2003, 10, 437.
18. Clifton, G.; Bryant, S. R.; Skinner, C. G. J. Med. Chem. 1970, 13, 377.
19. Parrish, D. A.; Zou, Z.; Allen, C. L.; Day, C. S.; King, S. B. Tetrahedron Lett. 2005,
46, 8841.
20. (a) Criton, M.; Le Mellay-Hamon, V. Bioorg. Med. Chem. Lett. 2008, 18, 3607; (b)
Huang, J.; Zou, Z.; Kim-Shapiro, D. B.; Ballas, S. K.; King, S. B. J. Med. Chem. 2003,
46, 3748.
21. Campestre, C.; Agamennone, M.; Tortorella, P.; Preziuso, S.; Biasone, A.;
Gavuzzo, E.; Pochetti, G.; Mazza, F.; Hiller, O.; Tschesche, H.; Consalvi, V.;
Gallina, C. Bioorg. Med. Chem. Lett. 2006, 16, 20.
22. Mannino, C.; Nievo, M.; Machetti, F.; Papakyriakou, A.; Calderone, V.; Fragai,
M.; Guarna, A. Bioorg. Med. Chem. 2006, 14, 7392.
23. (a) Mendiola, J.; Rincón, J. A.; Mateos, C.; Soriano, J. F.; de Frutos, Ó.; Niemeier, J.
K.; Davis, E. M. Org. Process Res. Dev. 2009, 13, 263; (b) Krause, J. G. Synthesis
1971, 140; (c) Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 3133.
24. Davies, J. W.; Durrant, M. L.; Walker, M. P.; Belkacemi, D.; Malpass, J. R.
Tetrahedron 1992, 48, 861.
10. Hanessian, S.; Johnstone, S. J. Org. Chem. 1999, 64, 5896.
25. 1H NMR (400 MHz, DMSO-d6) d 5.74 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.50–7.56
(m, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.90–7.94 (m, 2H), 8.85
(s, 1H), 8.98 (s, 1H). 13C NMR (100 MHz, DMSO-d6) d 120.8, 122.3, 124.6, 125.9,
126.0, 126.1, 128.0, 128.4, 133.9, 134.0, 159.5. Exact mass calculated for
C11H10O2N2 202.0737, found 202.07382.
11. Fioravanti, S.; Marchetti, F.; Morreale, A.; Pellacani, L.; Tardella, P. A. Org. Lett.
2003, 5, 1019.
12. Thatcher, G. R. J. Curr. Top. Med. Chem. 2005, 5, 597.
13. (a) Charache, S.; Terrin, M. L.; Moore, R. D.; Dover, G. J.; Barton, F. B.; Eckert, S.
V.; McMahon, R. P.; Bonds, D. R. N. Eng. J. Med. 1995, 332, 1317; (b) Charache, S.;