4854
J . Org. Chem. 1998, 63, 4854-4856
alyst added to this literature. Here, we expand on this
previous report and disclose our investigation of numer-
ous carbanilide cyclizations under µW conditions.
Micr ow a ve-Med ia ted In tr a m olecu la r
Ca r ba n ilid e Cycliza tion to Hyd a n toin s
Em p loyin g Ba r iu m Hyd r oxid e Ca ta lysis
Young-Dae Gong, Ho-Yeong Sohn, and Mark J . Kurth*
University of California, Department of Chemistry,
Davis, California 95616
Received March 5, 1998
The hydantoin moiety imparts a broad range of bio-
logical activities with both medicinal1 (cf. anticonvulsant)
and agrochemical2 (cf, fungicidal and herbicidal) applica-
tions. Given this utility, it is not surprising that a large
number of hydantoins adorned with diverse substituents
have been synthesized in solution3 and the solid phase.4
In previous studies, we developed novel routes to spiro-
fused5 and polycyclic6 hydantoin derivatives by carbanil-
ide cyclization chemistry. This strategy delivered hy-
dantoin-containing heterocycles with excellent stereo-
selective control,7 but formation of the hydantoin moiety
carbanilide cyclization required long reaction times at
relatively high temperature with excess base. Indeed,
the forcing conditions required for carbanilide cyclization
in these studies resulted in some thermal decomposition
of product. Following the pioneering work of Giguere and
Gedye,8 microwave (µW) applications in organic chemis-
try have become more prevalent.9 The principal advan-
tages of µW mediation are reaction acceleration and
accompanying minimization of product decomposition.9,10
The current literature reveals a growing number of
examples of heterocycle formation mediated by µW
irradiation,11 and our recent report12 of µW-mediated car-
banilide cyclization13 employing a barium hydroxide cat-
The results of our carbanilide cyclization study are
presented in Table 1. Our interest in exploring a µW-
mediated route to hydantoins stemmed from our effort
in the preparation of spiro[cyclopenta[d]isoxazole-4′,5-
imidazolidine] heterocycles (3 f 4; entries 1 and 2).5
Here, carbanilide cyclization of 3 required 48 h for
complete disappearance of starting material under ther-
mal conditions (2 equiv of Et3N), and the yield of 4 was
modest (62% and 82% for 4a and 4b, respectively).
Degradation of 3 is the apparent cause of this yield loss.
Prompted by the report by Bose et al.13 of µW accelera-
tion in cyclizations to nitrogen heterocycles, we submitted
carbanilide 3 to Et3N in DME using a Microwell 10
reactor14 but were disappointed to find little conversion
to 4.15 Exploration of a number of base/solvent combina-
tions16 eventually led us to catalytic barium hydroxide
(either anhydrous or octahydrate) in DMF as a nearly
ideal medium for µW mediation. Under these conditions,
carbanilide 3 delivers spiro-fused hydantoin 4 in nearly
quantitative yield (97% and 98% for 4a and 4b, respec-
tively) in only 2 min at a µW power setting of 20 W.
We next turned to the conversion of carbanilide 5 to
pyrrolo[1,2-c]imidazole 6. Thermal conditions here de-
liver 6 as the sole product in from 15 to 24 h (Table 1,
entries 6-8) in a process that also results in Hd-
epimerization to the thermodynamically preferred trans,-
anti,trans-stereochemistry. We were surprised to find
that mediating carbanilide cyclization of 5 with µW (3
min, 20 W) led to a mixture of two products plus
recovered starting material. These two products were
obtained in a ∼1:1 ratio in 40+% combined yield and
were shown to be Hd-epimers. Thus, while the conven-
tionally heated reaction 5 f 6 proceeds with complete
Hd-epimerization, µW-mediation of 5 f 6 (which is also
accompanied by reaction heating) can be accomplished
with only partial epimerization9f,17 (Table 1, entries 3-5;
(1) (a) Ware, E. Chem. Rev. 1950, 46, 403. (b) Spinks, A.; Waring,
W. S. Prog. Med. Chem. 1963, 3, 313. (c) Karolakwojciechowska, J .;
Kwiatkowski, W.; Kieckonono, K. Pharmazie 1995, 50, 114. (d)
Brouillette, Wayne J .; J estkov, V. P.; Brown, M. L.; Akhtar, M. S.;
DeLorey, T. M.; Brown, G. B. J . Med. Chem. 1994, 37, 3289. (e)
Brouillette, W. J .; Brown, G. B.; DeLorey, T. M.; Liang, G. J . Pharm.
Sci. 1990, 79, 871.
(2) Mappes, C. J .; Pommer, E.-H.; Rentzea, C.; Zeeh, B. US Patent
4,198,423, 1980 (BASF A.-G., Fed. Rep. Ger.); Chem. Abstr. 1980, 93,
71784.
(3) Ohta, H.; J ikihara, T.; Wakabayashi, K.; Fujita, T. Pestic.
Biochem. Physiol. 1980, 14, 153.
(4) (a) DeWitt, S. H.; Kiely, J . S.; Stankovic, C. J .; Schroeder, M.
C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993,
90, 6909. (b) Kim, S. W.; Ahn, S. Y.; Koh, J . S.; Lee, J . H.; Ro, S.; Cho,
H. Y. Tetrahedron Lett. 1997, 38, 4603.
(5) Park, K.-H.; Olmstead, M. M.; Kurth, M. J . J . Org. Chem. 1998,
63, 113.
(6) Gong, Y.-D.; Najdi, S.; Olmstead, M. M.; Kurth, M. J . J . Org.
Chem. 1998, in press.
(7) Najdi S.; Park, K.-H.; Olmstead, M. M.; Kurth, M. J . Tetrahedron
Lett. 1998, in press.
(8) (a) Giguere, R. J .; Bray, T. L.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945. (b) Gedye, R.; Smith, F.; Westaway,
K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J . Tetrahedron Lett.
1986, 27, 279.
(11) Majetich, G.; Wheless, K. In Microwave-Enhanced Chemistry;
Kingston, H. M., Haswell, S. J ., Eds.; American Chemical Society:
Washington, D.C., 1997; pp 455-505.
(12) Gong, Y.-D.; Kurth, M. J . Tetrahedron Lett. 1998, in press.
(13) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei, K.;
Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30, 471.
(14) The Micro Well 10 reactor consists of a power head (0-500 W),
a time control unit (0-100 min), and a variable power supply (to 600
W).
(9) For recent reviews, see: (a) Mingos, D. M. P.; Baghurst, D. R.
Chem. Soc. Rev. 1991, 20, 1. (b) Caddick, S. Tetrahedron 1995, 51,
10403. (c) Bram, G.; Galons, H.; Labidalle, S.; Loupy, A. Miocque, M.;
Petit, A.; Pigeon, P.; Sansoulet, J . Bull. Soc. Chim. Fr. 1989, 247. (d)
Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665. (e)
Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45, 567. (f) Galema,
S. A. Chem. Soc. Rev. 1997, 26, 233. (g) Bose, A. K.; Banik, B. K.;
Lavlinskaia, N.; J ayaraman, M.; Manhas, M. S. Chemtech 1997, 27,
18.
(15) We examined various bases (Et3N, DIPEA, DBU) and solvents
(benzene, toluene, DMSO, ethanol, diglyme, dimethoxy methane).
(16) We examined various bases (organic bases, see ref 15) and metal
bases (NaOH, NaH, t-BuOK, LiOH, BaCO3), Lewis acids (MgCl2, BaCl2,
LiCl), and solvents (benzene, toluene, DMSO, ethanol, diglyime,
dimethoxyethane). We belive catalytic Ba(OH)2 in DMF provides the
best conditions for solution-phase intramolecular carbanilide cycliza-
tion under mW mediation.
(17) To obtain the maximum quantity of kinetic product 6a , this
reaction was quenched before all the starting material (5a ) was
consumed.
(10) Cablewski, T.; Faux, A. F.; Strauss, C. R. J . Org. Chem. 1994,
59, 3408.
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Published on Web 06/23/1998