catalysis.7 However, in both strategies, chemists have to use
THIQs with N-aromatic or N-acyl substitutions, greatly
limiting its use in synthesizing THIQs with various R1
and R2 groups. In addition, stoichiometric exogenous oxi-
dants have to be used in the traditional CDC alkynyla-
tion reaction.8 Here we report a new C1-alkynylation of
THIQ through an A3 reaction with tunable iminium ions
(Reaction 2, Scheme 1). Four salient features of this new
reaction are as follows: various aldehydes and alkynes can
be used, leading to a broad library of THIQ derivatives; the
reaction is redox-neutral; the reaction can be carried out
under mild conditions (generally at 50 °C or even at rt); the
substituent on the N-atom of the products can be the benzyl
group, which can be easily removed and, consequently,
would allow functionalization of THIQs to be realized.9
We recently developed a mild condition allene synthesis
mediated by THIQ from aldehydes and alkynes (Reaction 3,
Scheme 2).10,11 In this reaction, an A3 reaction occurs first to
give exo-yne-THIQs, which can then give allenes via a [1,5]-
H shift process promoted by ZnI2. During our optimization
of the A3 reaction,12ꢀ14 we found that the regioselectivity
of this reaction can be, to some extent, well tuned by using
different copper catalysts (Reaction 4, Scheme 2). When
Scheme 1. Two C1-Alkynylation Strategies of THIQs
Scheme 2. Discovery of this Work and a Previous Report with a
Similar Iminium Isomerization Process
(6) Schreiber and Taylor described a direct reaction of the iminium
ion and copper acetylides to give endo-yne-THIQs: Taylor, A. M.;
Schreiber, S. L. Org. Lett. 2006, 8, 143.
ꢀ
ꢀ
(7) (a) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464. (b) Freeman, D. B.; Furst, L.;
Condie, A. G.; Stephenson, C. R. J. Org. Lett. 2012, 14, 94.
(8) An internal oxidant strategy was used by Nakamura for alkyny-
lations of propargylic amines including only one example of THIQ; see:
Sugiishi, T.; Nakamura, H. J. Am. Chem. Soc. 2012, 134, 2504.
(9) For discussions of removing protecting groups in CDC reactions
of THIQs, see: (a) Tsang, A. S.-K.; Ingram, K.; Keiser, J.; Hibbert,
D. B.; Todd, M. H. Org. Biomol. Chem. 2013, 11, 4921. (b) Schweitzer-
Chaput, B.; Klussmann, M. Eur. J. Org. Chem. 2013, 666.
(10) Jiang, G.-J.; Zheng, Q.-H.; Dou, M.; Zhuo, L.-G.; Meng, W.;
Yu, Z.-X. J. Org. Chem., in press, DOI: 10.1021/jo4018183.
(11) In the previous allene synthesis (ref 10), only two of all the exo-
yne-THIQswere isolated and characterized. In the present paper, several
exo-yne-THIQs as side products, shown in Schemes 2 and 3, were
synthesized by using the CuBr catalyst and were characterized (see the
Supporting Information), which is a demonstration that the A3 reactions
of THIQs can be tuned by using either CuI or CuBr as the catalyst.
(12) For selected reviews on the A3 reaction, see: (a) Peshkov, V. A.;
Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790.
(b) Yoo, W. J.; Zhao, L.; Li, C.-J. Aldrichimica Acta 2011, 44, 43. (c)
Kouznetsov, V. V.; Mendez, L. Y. V. Synthesis 2008, 491. (d) Zani, L.;
Bolm, C. Chem. Commun. 2006, 4263. (e) Wei, C.; Li, Z.; Li, C.-J. Synlett
2004, 15, 1472.
(13) For selected reports on A3 reaction, see: (a) Dyatkin, A. B.;
Rivero, R. A. Tetrahedron Lett. 1998, 39, 3647. (b) Kabalka, G. W.;
Wang, L.; Pagni, R. M. Synlett 2001, 676. (c) Li, C.-J.; Wei, C. M. Chem.
Commun. 2002, 268. (d) Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 9584. (e) Gomermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763.
CuBr was utilized, exo-yne-THIQ was the major product.
However, endo-yne-THIQ was the dominant product
by using CuI as the catalyst. We proposed that the CuI-
catalyzed reaction starts from generation of an exo-
iminium ion from a secondary amine and aldehyde. The
exo-iminium ion then isomerizes into an endo-iminium
ion,15,16 which reacts with copper acetylide to give endo-
yne-THIQ. A similar iminium isomerization process has
been proposed by Seidel in their Cu(II)-catalyzed alkynyla-
tion of pyrrolidines (Reaction 5, Scheme 2).16a Compared
toReaction 5, the synthesis of endo-yne-THIQ (Reaction 2,
Scheme 1) was conducted under much milder conditions.
More importantly, both exo- and endo-yne-THIQs can be
(14) For THIQ’s A3 reaction using a silver supermolecular catalyst,
see: Zhao, Y.; Zhou, X.; Okamura, T.-A.; Chen, M.; Lu, Y.; Sun, W.-Y.;
Yu, J.-Q. Dalton Trans. 2012, 41, 5889. Only two examples with
moderate yields of exo-yne-THIQs were reported.
(15) B3LYP/6-311þG(d,p) calculations indicated the endo-iminium
ion is more stable than the exo-iminium ion by 8.2 kcal/mol (in terms of
enthalpy) in the gas phase with R1dPh in Reaction 4 of Scheme 2.
(16) (a) Das, D.; Sun, A. X.; Seidel, D. Angew. Chem., Int. Ed. 2013,
52, 3765. For other iminium isomerizations, see: (b) Zheng, L.; Yang, F.;
Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889. (c) Zhang, C.; Seidel, D.
J. Am. Chem. Soc. 2010, 132, 1798. (d) Das, D.; Richers, M. T.; Ma, L.;
Seidel, D. Org. Lett. 2011, 13, 6584. (e) Ma, L.; Chen, W.; Seidel, D.
J. Am. Chem. Soc. 2012, 134, 15305. (f) Dieckmann, A.; Richers, M. T.;
Platonova, A. Y.; Zhang, C.; Seidel, D.; Houk, K. N. J. Org. Chem.
2013, 78, 4132. (g) Das, D.; Seidel, D. Org. Lett. 2013, 15, 4358.
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