to examine the relative reactivity of arynes toward CÀH
insertion vs Alder-ene reaction5 with diverse bis-1,3-diyne
substrates containing a tethered alkene moiety, and herein
we report the general reaction profiles of the Alder-ene
reaction of arynes6 formed directly from bis-1,3-diynes.
First, we examined the Alder-ene reactions of unsymmet-
rical ynamide7-based substrates 1bÀg under different
conditions with or without added silver triflate or Grubbs
ruthenium complex (Table 1).8 Substrates 1b and 1c that
contain an ene donor prenyl or genranyl group tetheredvia
either nitrogen or oxygen showed similar behavior to yield
the expected cyclization products 3b and 3c (entries 1 and 2).
Cyclic alkenes with different substituent patterns in sub-
strates 1d and 1e did not affect the efficiency of the ene
reaction, affording 3d and 3e in 90 and 94% yield, where
the former is a mixture of diastereomers (1.3:1) but the
latter isa singlediastereomer (entries 3 and 4). Notably, the
tertiary alcohol did not interfere with the ene reaction
although potentially it can react with another aryne inter-
mediate in an intermolecular manner. The effect of the
tether sizes between the ene donor and the incipient aryne
moiety was examined with substrates 1f and 1g. Surpris-
ingly, their ene reactions to form 8- and 10-membered ring
products 3f and 3g were still the major reaction pathway,
providing 3f and 3g in 60 and 59% yields, respectively, as
mixtures of diastereomers (entries 5 and 6). To the best of
our knowledge, forming medium-sized rings via Alder-ene
reaction with arynes is unprecedented.
Table 1. Silver-Catalyzed and Thermal Ene Reaction of
Putative Aryne Intermediates
The two different modes of initial cyclization to the
respective aryne intermediates and their subsequent ene
reaction are expected to be affected by the position of
heteroatom (NTs) in the tether. The heteroatom effect in
the tether was examined with substrates 1hÀ1j (Scheme 2).
Compared to the efficient ene reaction of 1h to generate
3h in 80% yield, that of 1i and 1j provided 3i in only 49%
yield and none of 3j. This significant discrepancy can be
a Conditions: A. AgOTf (5 mol %), toluene 90 °C, 6 h; B. Toluene
90 °C, 6 h. b Isolated yield after SiO2 chromatography.
(5) For a review on transition metal-catalyzed Alder ene reactions:
(a) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int.
Ed. 2005, 44, 6630. For general reviews on ene reactions: (b) Snider, B. B.
Acc. Chem. Res. 1980, 13, 426. (c) Oppolzer, W. Angew. Chem. 1984, 96,
840. (d) Baird, M. S. Top. Curr. Chem. 1988, 144. (e) Mikami, K.;
Shimizu, M. Chem. Rev. 1992, 92, 1021. (f) Dias, L. C. Curr. Org. Chem.
2000, 4, 305.
(6) Previous reports on the Alder-ene reactions with arynes: (a) Tabushi,
I.; Okazaki, K.; Oda, R. Tetrahedron 1969, 25, 4401. (b) Ahlgren, G.;
Akermark, B. Tetrahedron Lett. 1970, 11, 3047. (c) Wasserman, H. H.;
Solodar, A. J.; Keller, L. S. Tetrahedron Lett. 1968, 9, 5597. (d) Friedman,
L.; Osiewicz, R. J.; Rabideau, P. W. Tetrahedron Lett. 1968, 9, 5735. (e)
Garsky, V.; Koster, D. F.; Arnold, R. T. J. Am. Chem. Soc. 1974, 96, 4207.
(f) Wasserman, H. H.; Keller, L. S. Tetrahedron Lett. 1974, 15, 4355. (g)
Crews, P.; Beard, J. J. Org. Chem. 1973, 38, 522. (g) Nakayama, J.;
Yoshimura, K. Tetrahedron Lett. 1994, 35, 2709. (h) Aly, A. A.; Mohamed,
N. K.; Hassan, A. A.; Mourad, A.-F. E. Tetrahedron 1999, 55, 1111. (i) Aly,
A. A.; Shaker, R. M. Tetrahedron Lett. 2005, 46, 2679. (j) Candito, D. A.;
Panteleev, J.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14200. (k) Candito,
D. A.; Dobrovolsky, D.; Lautens, M. J. Am. Chem. Soc. 2012, 134, 15572.
(l) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature
2012, 490, 208.
explained by the mode selectivity of the hexadehydro
DielsÀAlder reaction6l,9 in the first step. From 1h, only a
single aryne intermediate I-1 was assumed to be generated,
which then underwent a facile ene reaction to deliver 3h,
whereas from 1i two intermediates I-2 and I-3 were gener-
ated where the former underwent ene reaction like I-1 to
afford3h, but the latterpolymerized. Similarly, substrate 1j
led selectively to the formation of a wrong regioisomeric
aryne intermediate I-4, which then polymerized, yielding
no Alder-ene product. This conclusion is further suppor-
ted by another reaction with 1k, which also can undergo
two different modes of initial aryne formation, but the
(9) (a) Meyerson, S.; Fields, E. K. Tetrahedron Lett. 1967, 8, 571. (b)
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1997,
38, 3943. (c) Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119,
9917. (d) Kociolek, M. G.; Johnson, R. P. Tetrahedron Lett. 1999, 40,
4141. (e) Kimura, H.; Torikai, K.; Miyawaki, K.; Ueda, I. Chem. Lett.
2008, 37, 662. (f) Tsui, J. A.; Sterenberg, B. T. Organometallics 2009, 28,
4906. (g) Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust,
K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P. J. Org. Chem. 2011, 76,
9320. (h) For a review on dehydro DielsÀAlder reaction, see: Wessig, P.;
(7) A review on ynamide, see: (a) DeKorver, K. A.; Li, H.; Lohse,
A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed.
2010, 49, 2840.
(8) A comparative study of the ene reaction with and without Grubbs
catalyst indicates that the overall transformation does not require any
metal catalyst, although the reaction rate with the catalyst seems to be
slightly higher. See Supporting Information for details.
€
Muller, G. Chem. Rev. 2008, 108, 2051.
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