Synthesis of symmetrical ureas by (Diacetoxyiodo)benzene-induced hofmann rearrangement

Article abstract of DOI:10.1055/s-0029-1219566

Amides undergo Hofmann rearrangement by treatment with (diacetoxyiodo) benzene (DAIB) to provide symmetrical ureas in a simple and robust transformation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219566

1104
LETTER
Synthesis of Symmetrical Ureas by (Diacetoxyiodo)benzene-Induced Hofmann
Rearrangement
S
ynthesis of Symm
i
etrical
r
U
reas k Landsberg, Markus Kalesse*
Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 22 January 2010
O
H
H
O
Abstract: Amides undergo Hofmann rearrangement by treatment
with (diacetoxyiodo)benzene (DAIB) to provide symmetrical ureas
in a simple and robust transformation.
PhI(OAc)2
N
N
C
R
R
N
R
NH2
NH2
R
R
O
2
1
5
3
Key words: Hofmann rearrangement, ureas, carbamates, diacetoxy-
iodobenzene
H2O
– CO2
H
N
OH
Because urea derivates play an important role in organic
chemistry1,2 and pharmaceutical research,3 a variety of
different synthetic approaches and molecular scaffolds
have been put forward. The significance of ureas as drugs
are exemplified by Sorafenib,4,5 a kinase inhibitor used in
cancer therapy, and the IMPDH inhibitor Merimepodib
(VX-497).6
R
O
4
Scheme 2 DAIB-induced Hofmann rearrangement
cient compounds showed increased yields (entries 4–6
and 8).
Typically, ureas are synthesized by reacting suitable
amines with isocyanates.7 However, this procedure is of-
ten circuitous and necessitates cautious handling of the
isocyanates. We report a convenient route for the synthe-
sis of symmetrical ureas 2 that requires only the appropri-
ate amides 1 and (diacetoxyiodo)benzene (DAIB).8 The
reaction proceeds without the need for an inert atmo-
sphere and does not require any unusual workup protocol
(Scheme 1). With DAIB, the amides 2 undergo a Hof-
mann rearrangement9 to generate the isocyanates 3 in situ.
On the other hand, when these reactions were performed
in the presence of methanol, the corresponding methyl
carbamate
7 was obtained in quantitative yield
(Scheme 3).11 This reaction could therefore have great po-
tential in the synthesis of carbamate subunits during the
synthesis of natural products such as myxopyronins12 or
corallopyronins (8).13
O
H
N
OMe
PhI(OAc)2
O
H
H
NH2
PhI(OAc)2, H2O
CH2Cl2
N
N
MeOH
(quant)
R
R
O
R
NH2
O
6
7
1
R = aryl, alkyl
2
O
O
OH
Scheme 1 Aryl or alkyl ureas 2 from amides 1
H
N
OH
OMe
Through reaction with water, the resulting carbamic acid
4 decomposes into amine 5, which then reacts with re-
maining isocyanate 3 to generate urea 2 (Scheme 2).
O
O
8
Scheme 3 Carbamate 7 formation and corallopyronine (8)
Purification by column chromatography affords symmet-
rical ureas 2 in good to moderate yields. Several amides 1
reacted under these conditions (Table 1).10
In conclusion, we have developed a reaction pathway to
access symmetrical alkyl and aryl ureas, and methyl car-
bamates in a straightforward and uncomplicated fashion.
Aromatic amides (entries 1–6) gave higher yields than
alkyl amides (entries 7–10). Furthermore, electron-defi-
SYNLETT 2010, No. 7, pp 1104–1106
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219566; Art ID: G01510ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Symmetrical Ureas
1105
Table 1 Synthesis of Urea Derivates 2a
O
H
H
PhI(OAc)2, H2O
CH2Cl2
N
N
R
R
R
NH2
O
1
2
Entry
1
R
Urea
Yield (%)b
H
N
H
N
Ph
1a
49
28
42
51
41
O
2a
H
H
N
N
4-MeOC6H4
1b
2
3
4
5
O
O
MeO
OMe
2b
H
N
H
N
MeO
OMe
3-MeOC6H4
1c
2c
H
H
N
N
4-ClC6H4
1d
O
Cl
Cl
2d
H
N
H
N
Cl
Cl
3-ClC6H4
1e
O
2e
H
H
N
N
4-MeO2CC6H4
1f
6
7
8
60
12
57
O
MeO2C
CO2Me
2f
H
H
N
N
t-Bu
1g
O
2g
O
O
O
H
N
H
N
MeO
OMe
MeO
O
1h
2h
O
O
O
O
H
N
H
N
9
22
47
MeO
OMe
MeO
O
O
1i
2i
O
O
H
N
H
N
10
MeO
OMe
MeO
1j
2j
a Reaction conditions: Amide (1.00 mmol), DAIB (1.3 mmol), H2O (3.00 mmol), CH2Cl2 (10 mL), r.t., 16 h, then 40 °C, 1 h.
b Yield of isolated product.
E. N. Angew. Chem. Int. Ed. 2005, 44, 466. (e) Fuerst, D.
E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964.
(f) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed.
2005, 44, 6367. (g) Taylor, M. S.; Tokunaga, N.; Jacobsen,
E. N. Angew. Chem. Int. Ed. 2005, 44, 6700. (h) Xu, X.;
References and Notes
(1) (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012. (b) Yang, D.; Chen, Y.-C.; Zhu, N.-Y. Org. Lett.
2004, 6, 1577. (c) Taylor, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 10558. (d) Yoon, T. P.; Jacobsen,
Synlett 2010, No. 7, 1104–1106 © Thieme Stuttgart · New York

1106
D. Landsberg, M. Kalesse
LETTER
Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.
Eur. J. 2006, 12, 466. (i) Lalonde, M. P.; Chen, Y.;
Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 6366.
(j) Han, C.; Porco, J. A. Jr. Org. Lett. 2007, 9, 1517.
(k) Tan, K. L.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2007,
46, 1315. (l) Procuranti, B.; Connon, S. J. Chem. Commun.
2007, 1421. (m) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007,
349, 2129. (n) Rampalakos, C.; Wulff, W. D. Adv. Synth.
Catal. 2008, 350, 1785. (o) Yalalov, D. A.; Tsogoeva, S. B.;
Shubina, T. E.; Martynova, I. M.; Clark, T. Angew. Chem.
Int. Ed. 2008, 47, 6624. (p) Fang, Y.-Q.; Jacobsen, E. N.
J. Am. Chem. Soc. 2008, 130, 5660. (q) Andrés, J. M.;
Manzano, R.; Pedrosa, R. Chem. Eur. J. 2008, 14, 5116.
(r) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2008, 130, 7198. (s) Alemán, J.; Milelli, A.;
Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem. Eur. J. 2008,
14, 10958. (t) Kotecki, B. J.; Fernando, D. P.; Haight, A. R.;
Lukin, K. A. Org. Lett. 2009, 11, 947. (u) Wang, F.; Liu,
X.; Cui, X.; Xiong, Y.; Zhou, X.; Feng, X. Chem. Eur. J.
2009, 15, 589. (v) Reis, Ö.; Eymur, S.; Reis, B.; Demir, A.
S. Chem. Commun. 2009, 1088.
Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.;
Insko, D. E.; Insko, M. A.; Lai, A. G.; Lélias, J.-M.; Mehta,
S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.;
Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. Nat.
Biotechnol. 2005, 23, 329. (b) Quesada, A. R.; Munoz-
Chápuli, R.; Medina, M. A. Med. Res. Rev. 2006, 26, 483.
(c) Liao, J. J.-L. J. Med. Chem. 2007, 50, 409.
(6) (a) Jackson, R. C.; Weber, G. Nature 1975, 256, 331.
(b) Markland, W.; McQuaid, T. J.; Jain, J.; Kwong, A. D.
Antimicrob. Agents Chemother. 2000, 44, 859. (c) Gu, H.
H.; Iwanowicz, E. J.; Guo, J.; Watterson, S. H.; Shen, Z.;
Pitts, W. J.; Dhar, T. G. M.; Fleener, C. A.; Rouleau, K.;
Sherbina, N. Z.; Witmer, M.; Tredup, J.; Hollenbaugh, D.
Bioorg. Med. Chem. Lett. 2002, 12, 1323.
(7) (a) Rudzevich, Y.; Cao, Y.; Rudzevich, V.; Böhmer, V.
Chem. Eur. J. 2008, 14, 3346. (b) Chauhan, S. M. S.; Bisht,
T.; Garg, B. Tetrahedron Lett. 2008, 49, 6646.
(c) dos Santos, C. M. G.; McCabe, T.; Watson, G. W.;
Kruger, P. E.; Gunnlaugsson, T. J. Org. Chem. 2008, 73,
9235. (d) Ye, S.; Ding, Q.; Wang, Z.; Zhou, H.; Wu, J. Org.
Biomol. Chem. 2008, 6, 4406. (e) Cui, Y.-M.; Yasutomi, E.;
Otani, Y.; Yoshinaga, T.; Ido, K.; Sawada, K.; Ohwada, T.
Bioorg. Med. Chem. Lett. 2008, 18, 5201. (f) Clayden, J.;
Lemiègre, L.; Morris, G. A.; Pickworth, M.; Snape, P. J.;
Jones, L. H. J. Am. Chem. Soc. 2008, 130, 15193.
(8) Reviews: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 2008,
108, 5299. (b) Zhdankin, V. V. ARKIVOC 2009, (i), 1.
(9) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.;
Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272.
(b) Lazbin, I. M.; Koser, G. F. J. Org. Chem. 1986, 51,
2669. (c) Vasudevan, A.; Koser, G. F. J. Org. Chem. 1988,
53, 5158.
(10) Representative Procedure (Table 1, Entry 1): A solution
of benzamide (121 mg, 1.00 mmol), PhI(OAc)2 (DAIB; 419
mg, 1.30 mmol) and H2O (54 mL, 3.00 mmol) in CH2Cl2
(10 mL) was stirred at ambient temperature for 16 h. The
resulting solution was stirred at 40 °C for 1 h, then the
solution was concentrated under vacuum and the remaining
residue was purified by column chromatography on silica
gel (hexane–EtOAc, 3:1) to yield the corresponding urea as
a colorless solid (52.4 mg, 49%).
(2) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520. (b) Connon, S. J. Chem.
Commun. 2008, 2499. (c) Zhang, Z.; Schreiner, P. R. Chem.
Soc. Rev. 2009, 38, 1187.
(3) (a) Batt, D. G.; Houghton, G. C.; Roderick, J.; Santella, J. B.
III.; Wacker, D. A.; Welch, P. K.; Orlovsky, Y. I.; Wadman,
E. A.; Trzaskos, J. M.; Davies, P.; Decicco, C. P.; Carter,
P. H. Bioorg. Med. Chem. Lett. 2004, 15, 787. (b) Vidaluc,
J.-L.; Bigg, D. USPTO 5288758, 1994. (c) Rautenberg, W.;
Harting, J.; Greiner, H.; Bartoszyk, G.; Böttcher, H.;
Van Amsterdam, C.; Matzen, L. EP 1140898, 2000.
(d) Kaplan, A. P.; Gupta, V. USPTO 20080306048, 2007.
(4) (a) Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan,
M.-K.; Sibley, R. Org. Process Res. Dev. 2002, 6, 777.
(b) Clark, J. W.; Eder, J. P.; Ryan, D.; Lathia, C.; Lenz,
H.-J. Clin. Cancer Res. 2005, 11, 5472. (c) Wilhelm, S.;
Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.
A.; Schwartz, B.; Simantov, R.; Kelley, S. Nat. Rev. Drug
Discovery 2006, 5, 835. (d) Murphy, D. A.; Makonnen, S.;
Lassoued, W.; Feldman, M. D.; Carter, C.; Lee, W. M. F.
Am. J. Pathol. 2006, 169, 1875. (e) Steinbild, S.; Mross, K.;
Frost, A.; Morant, R.; Gillessen, S.; Dittrich, C.; Strumberg,
D.; Hochhaus, A.; Hanauske, A.-R.; Edler, L.; Burkholder,
I.; Scheulen, M. Br. J. Cancer 2007, 97, 1480.
(11) See also: Moriarty, R. M.; Chany, C. J. II.; Vaid, R. K.;
Prakash, O.; Tuladhar, S. M. J. Org. Chem. 1993, 58, 2478.
(12) Irschik, H.; Gerth, K.; Höfle, G.; Kohl, W.; Reichenbach, H.
J. Antibiot. 1983, 36, 1651.
(5) (a) Fabian, M. A.; Biggs, W. H. III.; Treiber, D. K.;
Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter,
T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.;
(13) Irschik, H.; Jansen, R.; Höfle, G.; Gerth, K.; Reichenbach,
H. J. Antibiot. 1985, 38, 145.
Synlett 2010, No. 7, 1104–1106 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.