Double duty for cyanogen bromide in a cascade synthesis of cyanoepoxides

Article abstract of DOI:10.1002/anie.201006966

An unprecedented reaction mode of cyanogen bromide has been discovered. Under basic conditions, cyanogen bromide acts as an equivalent of both Br ⁺ and CN^- to convert enolizable ketones into the corresponding cyanoepoxides in good yields. This unique reaction mode provides new, one-pot access to densely substituted cyanoepoxides from easily available ketones (see scheme). Copyright

Full text of DOI:10.1002/anie.201006966

Communications
DOI: 10.1002/anie.201006966
Cascade Reactions
Double Duty for Cyanogen Bromide in a Cascade Synthesis of
Cyanoepoxides**
Zhou Li and Vladimir Gevorgyan*
Cyanogen bromide is a versatile reagent used in organic
gen bromide could potentially be involved in a similar
transformation as an equivalent of both Br+ and CNÀ
(Scheme 2). It was anticipated that a ketone enolate would
attack the bromine atom of cyanogen bromide to generate the
a-bromoketone 3. Then nucleophilic addition of the formed
cyanide to the ketone to give 4, would be followed by the
formation of a cyanohydrin anion, which upon intramolecular
SN2 reaction would produce the product cyanoepoxide 2.
Thus, cyanogen bromide would act as an equivalent of both
Br+ and CNÀ in one cascade transformation.
To test the above hypothesis, we examined the reaction of
isobutyrophenone (1a) and cyanogen bromide in the pres-
ence of a strong base. It was found that the deprotonation of
isobutyrophenone with NaHMDS, and subsequent addition
of cyanogen bromide resulted in the formation of cyanoep-
oxide 2a in good yield, along with trace amounts of a-
bromoketone 3, and provided support for the proposed path
for this transformation.[7]
A brief optimization of the reaction conditions (Table 1)
revealed that employment of other ethereal solvents, such as
diethyl ether or 1,4-dioxane, did not improve the yield of 2a
(Table 1, entries 2 and 5). Increasing the concentration of the
reaction mixture by adding NaHMDS solution to a neat
ketone resulted in a better yield, but this result was not
reproducible on other ketones (Table 1, entry 3). Changing
the solvent to dichloromethane suppressed the reaction
(Table 1, entry 4). Finally, employment of DMF has substan-
tially improved the yield with no traces of a-bromoketone 3
being produced (Table 1, entry 6). Switching the base to
LiHMDS slightly further improved the yield (Table 1,
entry 7). Weak bases, such as triethylamine and cesium
carbonate, gave no reaction product (Table 1, entry 8 and 9).
With the optimized conditions in hand, the generality of
this cascade transformation was examined (Table 2). a,a-
À
synthesis. Under different conditions, the Br C bond can be
cleaved in a diverse manner (Scheme 1, Modes I–IV). Thus,
BrCN was shown to serve as a donor of Br+ in reactions with
strongly nucleophilic organometallic reagents to provide the
corresponding vinyl- or arylbromides (Mode I).[1] In the
reaction with vinyltellrium bromide, cyanogen bromide
acted as an equivalent of a cyanide anion, and converts
vinyltellurium bromide into
a
vinyltellurium cyanide
(Mode II).[2] When reacted with primary or secondary
amines or alcohols, cyanogen bromide behaves as an equiv-
alent of CN+, and gives rise to cyanamides or cyanates
(Mode III).[3] In the von Braun reaction, BrCN acts as an
equivalent of both CN+ and BrÀ by fragmenting tertiary
amines into cyanamides and alkylbromides (Mode IV).[4,5]
Herein, we report an unprecedented Mode V, in which
cyanogen bromide works as an equivalent of Br+ and CNÀ
in a one-pot transformation of ketones into cyanoepoxide
derivatives (Mode V).
Our research group has recently demonstrated that
alkynyl bromides can act as equivalents of both Br+ and
alkynyl anions in a highly efficient, one-pot conversion of
ketones into alkynylepoxides.[6] We hypothesized that cyano-
Scheme 1. Diverse reactivity of cyanogen bromide.
[*] Z. Li, Prof. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 W Taylor St., Room 4500, Chicago, IL 60607 (USA)
Fax: (+1)312-355-0836
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
[**] The support of the National Science Foundation (grant no. CHE-
0710749) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006966.
Scheme 2. Proposed concept and initial trial. HMDS=1,1,1,3,3,3-hex-
amethyldisilazane.
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Angew. Chem. Int. Ed. 2011, 50, 2808 –2810

Table 1: Optimization of reaction conditions.
Disubstituted methyl aryl ketones were found to be suitable
substrates for this reaction. Thus, isopropyl, cyclopentyl, and
cyclohexyl ketones were efficient in this reaction (1a–c).
Isopropyl ketones usually provide better yield compared with
that of the corresponding cyclopentyl and cyclopentyl coun-
terparts that bear the same aryl group. A relatively lower
yield for the latter was probably caused by a competing
elimination of HBr during the reaction.[8] Certain groups at
the aromatic moiety of ketone, such as methoxy (1d) and
nitrile (1e–g), were tolerated. Cyanoepoxidation of unsym-
metrically substituted ketone 1h produced an almost 1:1
Entry
Solvent
Base
Yield [%][a]
1
2
3
4
5
6
7
8
9
THF
Et2O
NaHMDS[b]
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS[b]
TEA
77 (17% of 3)
62
88
N.R.
44
90
92
N.R.
N.R.
THF[c]
CH2Cl2
1,4-dioxane
DMF
diasteriomeric mixture of cyanoepoxide 2h in low yield.[9]
A
DMF
DMF
DMF
slightly better yield of cyanoepoxide was obtained by
cyclization of a,a-diphenylacetophenone (Table 2, entry 9).
This reaction turned out to be efficient with pyridyl-contain-
ing ketones. Thus, 3-pyridinyl ketones 1j–l (Table 2,
entries 10–12) and 2-pyridinyl ketones 1m–o (Table 2,
entries 13–15) were smoothly converted into the correspond-
ing cyanoepoxides 2j–o in good to excellent yields. Finally, it
was found that the propargyl ketone 1p is a suitable substrate
Cs2CO3
[a] Yield was determined by GC-MS analysis using diphenyl ether as an
internal standard. [b] 1m in THF. [c] A solution of NaHMDS in THF was
added to a neat ketone. DMF=N,N-dimethylformamide, N.R.=no
reaction, TEA=triethylamine, THF=tetrahydrofuran.
Table 2: Synthesis of cyanoepoxides.
Entry
1
Substrate 1
Product 2
Yield [%][a]
78, 92[b]
Entry
9
Substrate 1
Product 2
Yield [%][a]
52
1a
2a
1i
2i
2
3
1b
1c
2b
2c
75
66
10
11
1j
2j
84
70
1k
2k
4
5
6
1d
1e
1 f
2d
2e
2 f
71
70
70
12
13
14
1l
2l
80
93
90
1m
1n
2m
2n
7
8
1g
1h
2g
2h
80
40
15
16
1o
1p
2o
2p
78
85
[a] Yield of isolated product. [b] Yield determined by GC-MS analysis.
Angew. Chem. Int. Ed. 2011, 50, 2808 –2810
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Communications
Hassell, R. B. McFadyen, A. B. Miller, L. R. Miller, J. A. Payne,
L. M. Shewchuk, J. Willard, L. L. Wright, Bioorg. Med. Chem.
2005, 5, 3039; l) K. Starcevic, I. Caleta, D. Cincic, B. Kaitner, M.
Kralj, K. Ester, G. M. Karminski-Zamola, Heterocycles 2006, 68,
2285; m) L. Hwang, C. Tus, J. Wang, J. Heterocycl. Chem. 2006,
43, 889; n) U. Kꢃhn, M. Klopfleisch, H. Gꢃrls, E. Anders,
Tetrahedron: Asymmetry 2006, 17, 811; o) M. Hasegawa, N.
Nishigaki, Y. Washio, K. Kano, P. A. Harris, H. Sato, I. Mori,
R. I. West, M. Shibahara, H. Toyoda, L. Wang, R. T. Nolte, J. M.
Veal, M. Cheung, J. Med. Chem. 2007, 50, 4453; p) O. Garcꢄa
Mancheꢂo, C. Bolm, Org. Lett. 2007, 9, 2951; q) S. Nag, A.
Mishra, S. Batra, Tetrahedron 2008, 64, 10162; r) M. Saitoh, J.
Kunitomo, E. Kimura, H. Iwashita, Y. Uno, T. Onishi, N.
Uchiyama, T. Kawamoto, T. Tanaka, C. D. Mol, J. Med. Chem.
2009, 52, 6270.
for this reaction and produced the alkynyl cyanoepoxide 2p in
high yield (Table 2, entry 16).[10]
In summary, we have demonstrated that cyanogen bro-
mide can serve an equivalent of both CNÀ and Br+ in a
cascade conversion of ketones into cyanoepoxide derivatives.
This reaction proceeds through a bromination of a ketone by
cyanogen bromide, followed by a nucleophilic addition of the
produced cyanide at the ketone and a subsequent replace-
ment of the a bromide by a cyanohydrine anion. This
approach provides a convenient and efficient route[11] for
the preparation of fully substituted and diverse cyanoepoxide
derivatives[12] from easily available ketones.
[4] For selected samples of Zincke aldehyde formation involving
cyanogen bromide, see: a) T. Zincke, G. Heuser, W. Mꢃller,
Justus Liebigs Ann. Chem. 1904, 333, 296; b) A. M. Kearney,
C. D. Vanderwal, Angew. Chem. 2006, 118, 7967; Angew. Chem.
Int. Ed. 2006, 45, 7803.
[5] For von Braun reactions, see: a) W. Kꢃnig, J. Prakt. Chem. 1904,
69, 105; b) J. von Braun, K. Heider, E. Mꢅller, Ber. Dtsch. Chem.
Ges. 1918, 51, 273; c) R. C. Elderfield, H. A. Hagema, J. Org.
Chem. 1949, 14, 605; d) R. C. Elderfield, M. Green, J. Org.
Chem. 1952, 17, 431; e) S. Chambert, F. Thomasson, J. Dꢆcout, J.
Org. Chem. 2002, 67, 1898; f) R. Leung-Toung, T. F. Tam, Y.
Zhao, C. D. Simpson, W. Li, D. Desilets, K. Karimian, J. Org.
Chem. 2005, 70, 6230; g) W. S. McCall, T. A. Grillo, D. L.
Comins, J. Org. Chem. 2008, 73, 9744; h) R. L. Giles, R. A.
Nkansah, R. E. Looper, J. Org. Chem. 2010, 75, 261; i) Y.
Hayashi, T. Kumamoto, M. Kawahata, K. Yamaguchi, T.
Ishikawa, Tetrahedron 2010, 66, 3836.
Experimental Section
Ketone (0.5 mmol) was added to an oven dried conical vial, equipped
with a magnetic stirring bar and a screw cap, and the atmosphere was
replaced by argon. Then dry DMF was added and the mixture was
stirred until the ketone was completely dissolved. LiHMDS (1m in
THF, 0.75 mL) was subsequently added to the DMF solution and the
mixture was stirred for 5 min. Then a solution of BrCN (10m in THF)
was added drop wise to the mixture and the reaction mixture was
stirred for another 15 min. The mixture was quenched with water
(10 mL) and the product was extracted with ethyl acetate or diethyl
ether. The organic extract was dried over sodium sulfate and solvent
was removed in vacuo. The residue was purified by a column
chromatography on silica gel using hexanes/ethyl acetate (1:1) as an
eluent to give the final product.
Received: November 6, 2010
Revised: January 12, 2011
Published online: February 21, 2011
[6] A. Trofimov, N. Chernyak, V. Gevorgyan, J. Am. Chem. Soc.
2008, 130, 13538.
[7] In the test experiment, the commercially available a-bromoke-
tone 3, upon treatment with NaCN, was quantitatively converted
into cyanoepoxide 2a. For formation of epoxides via an addition/
substitution process of nucleophiles with a-halo ketones, see:
a) J. Hummeen, H. Wynberg, Tetrahedron Lett. 1978, 19, 1089;
b) G. A. Russell, F. Ros, J. Am. Chem. Soc. 1985, 107, 2506.
[8] A certain amount of cyclopentenyl and cyclohexenyl phenones
was observed by GC-MS analysis of the crude reaction mixtures.
[9] Cyanoepoxidation of ketone 1h produced an inseparable
mixture of diastereomers 2h. See the Supporting Information
for details.
Keywords: cascade reactions · cyanoepoxides ·
cyanogen bromide · synthetic methods
.
[1] For reaction of cyanogen bromide with aryllithium reagents, see:
a) L. A. Paquette, F. Pierre, C. E. Cottrell, J. Am. Chem. Soc.
1987, 109, 5731; b) L. A. Paquette, K. S. Learn, J. L. Romine,
H. S. Lin, J. Am. Chem. Soc. 1988, 110, 879; c) J. A. Miller, W.
Leong, G. Zweifel, J. Org. Chem. 1988, 53, 1839; d) C. Jaramillo,
J. C. Carretero, J. de Diego, M. del Prado, C. Hamdouchi, J. L.
Roldꢀn, C. Sꢀnchez-Martinez, Tetrahedron Lett. 2002, 43, 9051;
e) Y. Kobayashi, A. Fukuda, T. Kimachi, M. Ju-ichi, Y. Take-
moto, Tetrahedron Lett. 2004, 45, 677; f) A. Casoni, G. Cele-
ntano, F. Clerici, A. Contini, M. L. Gelmi, G. Mazzeo, S.
Pellegrino, C. Rosini, Tetrahedron: Asymmetry 2009, 20, 2247.
[2] T. G. Back, B. P. Dyck, M. Parvez, J. Org. Chem. 1995, 60, 4657.
[3] For preparation of cyanamide from cyanogen bromide, see:
a) W. J. Ross, R. G. Harrison, M. R. J. Jolley, M. C. Neville, A.
Todd, J. P. Verge, W. Dawson, W. J. F. Sweatman, J. Med. Chem.
1979, 22, 412; b) R. J. Sundberg, B. C. Pearce, J. Org. Chem.
1985, 50, 425; c) K. Futaki, S. Tosa, Chem. Pharm. Bull. 1986, 8,
908; d) A. Padwa, M. A. Brodney, B. Liu, K. Satake, T. Wu, J.
Org. Chem. 1999, 64, 3595; e) B. B. Snider, S. M. OꢁHare,
Tetrahedron Lett. 2001, 42, 2455; f) F. M. Rivas, A. J. Giessert,
S. T. Diver, J. Org. Chem. 2002, 67, 1708; g) M. P. Price, W.
Guida, T. Jackson, J. Nydick, P. Gladstone, J. Juarez, F. Doꢂate,
R. Ternansky, Bioorg. Med. Chem. 2003, 13, 107; h) M. Amir, K.
Shikha, Eur. J. Med. Chem. 2004, 39, 535; i) R. K. Grover, A. P.
Kesarwani, G. K. Srivastava, B. Kundu, R. Roy, Tetrahedron
2005, 61, 5011; j) Y. Cheng, Q. Zhu, Q. S. Li, O. Meth-Cohn, J.
Org. Chem. 2005, 70, 4840; k) D. G. Barrett, D. N. Deaton, A. M.
[10] Fully aliphatic ketones appeared to be unstable under these
reaction conditions.
[11] For selected examples on the preparation of cyanoepoxides, see:
a) M.-X. Wang, G. Deng, D.-X. Wang, Q.-Y. Zheng, J. Org.
Chem. 2005, 70, 2439; b) N. F. Badham, W. L. Mendelson, A.
Allen, A. M. Diederich, D. S. Eggleston, J. J. Filan, A. J. Freyer,
A. J. Killmer, C. J. Kowalski, L. Liu, V. J. Novack, F. G. Vogt,
K. S. Webb, J. Yang, J. Org. Chem. 2002, 67, 5440; c) K. A.
Bhatia, K. J. Eash, N. M. Leonard, M. C. Oswald, R. S. Mohan,
Tetrahedron Lett. 2001, 42, 8129; d) A. E. Lurain, A. Maestri,
A. R. Kelly, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2004, 126,
13608; see also: e) V. K. Aggarwal, D. M. Badine, V. A. Moor-
thie in Aziridines and Epoxides in Organic Synthesis (Ed.: A. K.
Yudin), Wiley-VCH, Weinheim, 2006, pp. 1.
[12] For selected examples on using fully substituted cyanoepoxides
in synthesis, see: a) D. M. Rathod, S. Rengaraju, M. M. Ghar-
pure, N. M. Patel, M. M. Deoahar (Alembic Limited, India),
EP1249447 (A1), 2002; b) M. Aiai, M. Baudy-Floch, A. Robert,
P. Le Grel, Synthesis 1996, 403; c) R. Deghenghi, R. Gaudry,
Can. J. Chem. 1961, 39, 1553; d) G. Stork, W. S. Worrall, J. J.
Pappas, J. Am. Chem. Soc. 1960, 82, 4315.
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