1-Cyanoimidazole as a mild and efficient electrophilic cyanating agent

Article abstract of DOI:10.1021/ol0055263

formula presented A mild and high-yielding cyanating reaction of amine, sulfur, and carbanion nucleophiles is reported here using 1-cyanoimidazole as an electrophilic cyanating agent.

Full text of DOI:10.1021/ol0055263

ORGANIC
LETTERS
2000
Vol. 2, No. 6
795-797
1-Cyanoimidazole as a Mild and Efficient
Electrophilic Cyanating Agent
Yong-qian Wu,* David C. Limburg, Douglas E. Wilkinson, and
Gregory S. Hamilton
Department of Research, Guilford Pharmaceuticals, Inc., 6611 Tributary Street,
Baltimore, Maryland 21224
wu_y@guilfordpharm.com
Received January 10, 2000
ABSTRACT
A mild and high-yielding cyanating reaction of amine, sulfur, and carbanion nucleophiles is reported here using 1-cyanoimidazole as an
electrophilic cyanating agent.
Compounds containing cyano functional groups are found
among many pharmaceuticals and their intermediates.1,2 For
instance, the guanidine group is readily synthesized through
a cyanoamine precursor.2 There are a limited number of
reagents that can serve as a cyano cation (CN+) equivalent
when reacted with nucleophiles. Several reagents which have
been reported in the literature include cyanogen chloride/
bromide,2 2-chlorobenzyl thiocyanate,3 tosyl cyanide,4 and
most recently 1-cyanobenzotriiazole.5,6 1-Cyanoimidazole
Scheme 1
(1) Gilman, A. G.; Goodman, L. S.; Rall, T. W.; Murad, F. Goodman
and Gilman’s The Pharmacological Basis of Therapeutics, 7th Ed.;
Pergamon Press: New York, 1990; p 899.
(2) Hu, L. Y.; Guo, J.; Magar, S. S.; Fischer, J. B.; Burke-Howie, K. J.;
Durant, G. J. J. Med. Chem. 1997, 40 (26), 4281-9.
(3) Wheland, R. C.; Martin, E. L. J. Org. Chem. 1975, 40, 3101-3109.
(4) Davis, W. A.; Cava, M. P. J. Org. Chem. 1983, 48, 2774-2775.
(5) Van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett. 1970, 12, 967-
970.
(6) Hughes, T. V.; Hammond, S. D.; Cava, M. P. J. Org. Chem. 1998,
63, 401-402.
(7) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313-315.
(8) Ferris, J. P.; Huang, C. H.; Hagan, W. J., Jr. Nucleosides Nucleotides
1989, 8 (3), 407-414.
(9) Typical Experimental Procedure. Normal addition: A solution of
1-cyanoimidazole (47 mg, 0.5 mmol) in 1 mL of DMA was added to a
solution of N-methylaniline (54 mg, 0.5 mmol) in 5 mL of DMA under N2.
The mixture was allowed to stir at 100 °C, and the reaction was monitored
by TLC. After 24 h, the reaction was complete. The mixture was poured
into 10 mL of water, followed by CH2Cl2 extraction. Further workup and
silica gel purification yielded 53 mg (80%) of product: GC-MS gave
molecular ion (M+) 132; Rf ) 0.7 (50% EtAc in hexane); 1H NMR (CDCl3)
δ 7.43 (dt, 2H, J ) 6.0, 8.0 Hz), 7.14 (d, 2H, J ) 8.5 Hz), 7.12 (t, 1H, J
) 6.5 Hz), 3.34(s, 3H); 13C NMR (CDCl3) δ 140.7, 130.0, 123.4, 115.1,
114.3, 36.8. Inverse addition: 0.4 mL (2.5 M, 1 mmol) of n-BuLi was
added slowly to a solution of phenylacetylene (102 mg, 1 mmol) in 5 mL
of THF at -78 °C under N2. The solution was allowed to warm to 0 °C
and continued to stir for 30 min. After cooling to -78 °C again, the solution
was transferred via cannula to a precooled (-78 °C) solution of 1-cy-
was previously reported7 as a useful coupling agent for the
formation of polynucleotides. We now wish to report
1-cyanoimidazole as an electrophilic cyanating reagent
toward various amine, sulfur, and carbon nucleophiles.
anoimidazole (93 mg, 1 mmol) in 5 mL of THF. The reaction was complete
after 30 min of stirring. The mixture was poured into 10 mL of saturated
NH4Cl, followed by CH2Cl2 extraction. Further work up and silica gel
purification gave the pure product (118 mg, 94% yield): GC-MS gave
molecular ion (M+) 127; Rf ) 0.3 (10% EtAc in hexane); 1H NMR (CDCl3)
δ 7.58 (d, 2H, J ) 7.5 Hz), 7.47 (t, 1H, J ) 7.3 Hz), 7.35 (t, 2H, J ) 7.5
Hz); 13C NMR (CDCl3) δ 132.5, 129.7, 126.4, 116.3, 105.0, 83.1, 64.3.
10.1021/ol0055263 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000

Table 1
a Isolated yield. b The products compared with authentic samples using GC-MS. c Normal addition. d Inverse addition.
1-Cyanoimidazole was synthesized by treating cyanogen
bromide with imidazole based on a modified literature
procedure (Scheme 1).8 The reaction between 1-cyanoimi-
dazole and different nucleophiles is described by an addi-
tion-elimination process shown in Scheme 1, and the results
are summarized in Table 1.
As shown in the Table 1, the cyano group was transferred
from 1-cyanoimidazole to the nucleophile in a smooth
reaction. Both primary and secondary amines (entries 1-4)
gave cyanoamines in good to excellent yields (80-89%).
However, less nucleophilic aromatic amines (entries 1 and
2) needed longer reaction times and heated condition to
complete. In the case of the aromatic secondary amine (entry
2), the reaction failed to complete in refluxing dichlo-
romethane but was able to be completed in the polar aprotic
solvent DMA (N,N-dimethylacetamide) heated at 100 °C
over 24 h.9 Similarly, carbanions (sp, sp2, and sp3), which
were generated either by direct lithiation or lithium/halogen
exchange or from a Grignard reagent, gave excellent yields
(>86% in all cases) of the cyanated products (entries 5-7).
We chose to select the inverse addition method in the cases
where the carbanion was slowly added to the cyanating
agent.9 It was suggested that limiting nucleophiles would
limit the production of byproduct, imines presumably,
resulting in the better yields.7 In the reactions with thiols
Scheme 2
796
Org. Lett., Vol. 2, No. 6, 2000

(entries 8 and 9), lower yields were observed, as significant
amount of disulfides were generated as side products. The
inverse addition method gave somewhat better yields but
could not eliminate their formation. This is consistent with
what has been previously reported in the literature4 where
sulfonyl cyanides were used as cyanating agents. The
disulfides were generated by further addition of thiol to the
thiocyanate product as depicted in Scheme 2.
In summary, we have found and successfully demonstrated
the variability of 1-cyanoimidazole as a useful cyanating
reagent for many nucleophiles.
OL0055263
Org. Lett., Vol. 2, No. 6, 2000
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