subject of numerous computational studies.12 These compu-
tational studies have confirmed our earlier observation10 that
2,5-ddp intermediates derived from the aza-Bergman cy-
clization of simple, acyclic 3-aza-3-ene-1,5-diynes undergo
an extremely facile retro-aza-Bergman ring-opening reaction
to afford â-alkynylacrylonitrile products (Figure 1). Signifi-
cantly, the only report of a product derived from trapping
the elusive 2,5-ddp intermediate has come from studies of
the aza-Bergman cyclization reaction. Chen and co-workers11
reported the detection of miniscule amounts of pyridine
product by GC/MS in the thermolysis of an acyclic aza-
enediyne under acidic conditions. One approach to produce
longer-lived diradical intermediates involves the rearrange-
ment of “skipped” 4-aza-3-ene-1,6-diynes, which we have
shown are effective, pH-dependent DNA cleavage agents.13
An alternative approach to longer-lived 2,5-ddp intermediates
has been proposed in which the carbon-nitrogen double
bond of the 3-aza-3-ene-1,5-diyne moiety is incorporated into
an amide or amidine functional group12a such that retro-
Bergman ring opening of the corresponding 2,5-ddp inter-
mediate is disfavored. We have explored a variant of this
approach in which the carbon-nitrogen double bond of the
3-aza-3-ene-1,5-diyne functionality is incorporated into a
five-membered heterocycle. This approach has the advantage
of enforcing the cis geometry of the N- and C-alkynyl groups
of the aza-enediyne required for aza-Bergman cyclization.
Here we report the synthesis of these previously unknown
heterocyclic 3-aza-3-ene-1,5-diynes. Under thermolysis con-
ditions in the presence of 1,4-cyclohexadiene, one such
heterocyclic 3-aza-3-ene-1,5-diyne affords products that arise
from reactive intermediates produced from profound mo-
lecular rearrangements that may proceed from the aza-
Bergman-retro-aza-Bergman cascade.
elimination of a N-dichloroalkene precursor in a model
system (Scheme 1). Addition of trichloroethylene to the anion
Scheme 1. Preparation of N-Ethynylbenzimidazolea
a Reaction conditions: (a) NaH, DMF, 60 °C, then Cl2CdCHCl,
rt. (b) n-BuLi, -78 °C.
derived from benzimidazole afforded chloroenamine 1, which
when treated with n-BuLi gave N-ethynylbenzimidazole 2
in modest yield.
When this same approach was undertaken with benz-
imidazoles bearing an alkyne substituent at the 2-position,
difficulties were encountered. Addition of trichloroethylene
to 2-alkynylbenzimidazoles proceeded well, although the
addition required more forcing conditions in the case of 2-(2-
triisoproplsilylethynyl)benzimidazole (Scheme 2). Elimina-
Scheme 2a
The synthesis of heterocyclic 3-aza-3-ene-1,5-diynes re-
quires the construction of a potentially unstable N-alkynyl
heterocycle. While there are reports of other N-alkynyl
aromatic heterocycles,14 no N-alkynyl benzimidazoles or
imidazoles have been reported. To generate an alkyne moiety
at the nitrogen of a benzimidazole ring, we investigated the
(9) (a) Semmelhack, M. F.; Gallagher, J. J.; Minami, T.; Date, T J. Am.
Chem. Soc. 1993, 115, 11618-11619. (b) Mastalerz, H.; Doyle, T. W.;
Kadow, J. F.; Vyas, D. M. Tetrahedron Lett. 1996, 37, 8683-8686. (c)
McPhee, M. M.; Kerwin, S. M. J. Org. Chem. 1996, 61, 9385-9393. (d)
Raeppel, S.; Toussaint, D.; Suffert, J. Synlett. 1998, 537. (e) Semmelhack,
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541-544.
(10) David, W. M.; Kerwin, S. M. J. Am. Chem. Soc. 1997, 119, 1464-
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(11) Hoffner, J. H.; Schottelius, M. J.; Feichtinger, D.; Chen, P. J. Am.
Chem. Soc. 1998, 120, 376-385.
(12) (a) Kraka, E.; Cremer, D. J. Am. Chem. Soc. 2000, 122, 8245. (b)
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Lett. 2000, 10, 2509-2512. (b) Tuntiwechapikul, W.; David, W. D.; Kumar,
D.; Salazar, M.; Kerwin, S. M. Biochemistry 2002, 41, 5283-5290.
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(b) Zaugg, H. E.; Swett, L. R.; Stone, G. R. J. Org. Chem. 1958, 23, 1389-
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274.
a Reaction conditions: (a) (Boc)2O, Et3N, DMF/MeCN. (b)
Phenylacetylene (for 9a) or (triisopropylsilyl)acetylene (for 9b),
Pd(OAc)2, PPh3, Et3N. (c) TFA, CH2Cl2. (d) NaH, DMF, 50 °C
(for 11a) or KH, DMF, 50 °C (for 11b), then Cl2CdCHCl, rt. (e)
n-BuLi, -78 °C.
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Org. Lett., Vol. 4, No. 25, 2002