ORGANIC
LETTERS
2013
Vol. 15, No. 17
4366–4369
Reaction of Arynes with Vinylogous
Amides: Nucleophilic Addition to the
ortho-Quinodimethide Intermediate
Ran Li, Xuemei Wang, Zhibin Wei, Chunrui Wu, and Feng Shi*
Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province,
Henan University, Jinming Campus, Kaifeng 475004, China
Received July 6, 2013
ABSTRACT
The reaction of arynes with vinylogous amides containing no free NꢀH bonds proceeds in a [2 þ 2] cycloaddition fashion at ambient temperature.
The electronic properties of the vinylogous amides allow for the cycloadducts undergoing a facile ring-opening process, leading to electronically
biased ortho-quinodimethide intermediates. Subsequent nucleophilic addition with alcohols affords 2-substituted benzaldehydes or ketones.
In the past decade, aryne chemistry has become an
emerging area in organic synthesis.1 Among the hot topics,
those involving nucleophilic addition and pericyclic reac-
tions have been heavily studied, many of which exhibit
considerable theoretical value and/or complement conven-
tional approaches in a synthetic point of view.
Since aryne is electrophilic, efforts to seek the nucleo-
philic partner are continuing. Recently, several marked
reports have disclosed that enamides can nucleophilically
react with arynes. Depending on the structure of the
enamides, [2 þ 2] cycloaddition,2 [3 þ 2] annulation,3
[4 þ 2] annulation,4 as well as β-arylation5 can take place.
However, closely related vinylogous amides (1, Scheme 1)
have not been studied much in aryne chemistry.6 Vinylo-
gous amides have been traditionally considered a subtype
of enamides, but their CdC double bonds are more
electronically biased. We considered that the pushꢀpull
nature of this double bond should feature an easier [2 þ 2]
cycloaddition with arynes (for vinylogous amides without
free NꢀH bonds, Scheme 1, first step). Thus, unlike typical
enamides, whose [2 þ 2] cycloaddition requires 110 °C,2a,b
vinylogous amides may react with arynes under much
milder conditions. Moreover, it has been known that
the stability of the [2 þ 2] cycloadduct 3 is also heavily
dependent upon its electronic properties: the more
electron-rich the nitrogen, the easier it will undergo a
ring-opening process to afford an ortho-quinodimethide
(oQDM) (Scheme 1, second step).7,8 Mechanistically, this
can be explained as the ring-opening for the vinylogous
amide cycloadducts, compared to that for the typical
enamide cycloadducts, deviates from a strict retro-4π
(1) For recent reviews: (a) Dubrovskiy, A. V.; Markina, N. A.;
Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (b) Bhunia, A.; Yetra,
S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (c) Yoshida, H.;
Takaki, K. Synlett 2012, 23, 1725. (d) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550. (e) Wu, C.; Shi, F. Asian J. Org. Chem. 2013,
2, 116.
(2) (a) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.;
Hsung, R. P. Org. Lett. 2009, 11, 3666. (b) Ma, Z.-X.; Feltenberger, J. B.;
Hsung, R. P. Org. Lett. 2012, 14, 2742. (c) Blackburn, T.; Ramtohul,
Y. K. Synlett 2008, 1159.
(3) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc.
2008, 130, 1558.
(4) Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem.
Commun. 2012, 8105. See also refs 2c and 3.
(5) The β-arylation was reported in ref 2c with a single example. It
was not thoroughly studied.
(6) There is a report where aryne reacts with vinylogous amides
containing free NH bonds in a β-arylation fashion. See: Ramtohul,
Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(7) Oppolzer, W. Synthesis 1978, 793.
(8) For reviews of oQDMs, see: (a) Segura, J. L.; Martin, N. Chem.
Rev. 1999, 99, 3199. (b) Collier, S. J.; Storr, R. C. Heterocyclic ortho-
Quinodimethanes. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Elsevier Science: Oxford, UK, 1998; Vol. 10, pp
25ꢀ48. (c) McCullough, J. J. Acc. Chem. Res. 1980, 13, 270. (d) Fishwick,
C. W. G.; Jones, D. W. ortho-Quinonoid Compounds. In The Quinonoid
Compounds; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, UK, 1988; Vol. 1,
pp 403ꢀ453.
r
10.1021/ol4018968
Published on Web 08/19/2013
2013 American Chemical Society