conditions alters the course of the reaction. This strategy
provides three points of diversity; a boronic acid, a mono-
substituted alkene Heck acceptor, and an o-bromobenzalde-
hyde can be varied to provide a high degree of modularity
(Scheme 1).
ligand, as first described by Shen.17 We were pleased to
discover that not only can selectivity be reversed to give
4 (3 is no longer observed) but also the desired tandem
product 2a can be obtained simply by increasing the
reaction time (entries 3 and 4). Screening of various
parameters led us to our optimal conditions: boronic acid
(1.5 equiv), Pd2dba3 (2.5 mol %), TFP (10 mol %), and
Cs2CO3 (4 equiv) in dioxane/water 5:2 at 60 °C. We also
discovered that enhanced yields of 3 are obtained when
tBu3PHBF4 was used as the ligand (entry 6). Further
studies are in progress to explain the nature of this
selectivity.
Scheme 1. Retrosynthetic Analysis
Table 1. Screening of Reaction Parameters (Selected Entries)a
We used substrate 1a to explore conditions for the
tandem reaction (see Table 1). We began with the
conditions previously developed for tandem Suzuki/
amination and Suzuki/Heck couplings of gem-dihalo-
olefins;3a,b in both cases, conversion was poor, though a
single product was isolated and identified as 3 (entries 1 and
2). Although previous reports have indicated that intermo-
lecular coupling of a trisubstituted gem-dihaloolefin occurs
selectively at the (E)-bromide,15 it has been demonstrated
that a coordinating group such as an alkyne or heteroatom
can direct oxidative addition of Pd to the (Z)-bromide, leading
to a reversal of selectivity for certain intramolecular cou-
plings.16 Interestingly, the indenyl bromide 3 does not
undergo Suzuki coupling despite the presence of a boronic
acid.
entry
ligand
base
K3PO4
K3PO4/Et3N
Na2CO3
Na2CO3
Cs2CO3
temp (°C)
2a:3:4:5b
1
2
SPhos
110
110
60
60
60
0:15:0:0
0:24:0:0
31:0:55:nd
64:0:0:nd
77:0:0:16
0:45:0:0
Bu4NBrc
TFP
3d, e
4e
5e
6
TFP
TFP
tBu3PHBF4
Cs2CO3
110
a Reactions were run using 0.2 mmol of 1a, 1.0 equiv of 3,4-
dimethoxypheylboronic acid, 2.5 mol % of Pd2dba3, 10 mol % of ligand,
and 4.0 equiv of base in 1 mL of dioxane overnight. b Isolated yields.
In an attempt to alter the selectivity, we investigated a
mixed solvent system using trifurylphosphine (TFP) as
c 1.0 equiv of Bu4NBr was used instead of 10 mol
% of
ligand. d Reaction was run for 3 h. e 0.4 mL of water were added. Ar )
(12) For selected recent methyleneindene syntheses, see: (a) Tsuchikama,
K.; Kasagawa, M.; Endo, K.; Shibata, T. Synlett 2010, 97. (b) Furuta, T.;
Asakawa, T.; Iinuma, M.; Fujii, S.; Tanaka, K.; Kan, T. Chem. Commun.
2006, 3648. (c) Abdur Rahman, S. M.; Sonoda, M.; Ono, M.; Miki, K.;
Tobe, Y. Org. Lett. 2006, 8, 1197. (d) Basurto, S.; Garc´ıa, S.; Neo, A. G.;
Torroba, T.; Marcos, C. F.; Miguel, D.; Barbera´, J.; Blanca Ros, M.; de la
Fuente, R. Chem.sEur. J. 2005, 11, 5362. (e) Bekele, T.; Christian, C. F.;
Lipton, M. A.; Singleton, D. A. J. Am. Chem. Soc. 2005, 127, 9216. (f)
Schmittel, M.; Vavilala, C. J. Org. Chem. 2005, 70, 4865. (g) Kovalenko,
S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.; Alabugin, I. V. Org. Lett.
2004, 6, 2457. (h) Singer, R. A.; McKinley, J. D.; Barbe, G.; Farlow, R. A.
Org. Lett. 2004, 6, 2357. (i) Gilbertson, R. D.; Wu, H.-P.; Gorman-Lewis,
G.; Weakley, T. J. R.; Weiss, H. -C.; Boese, R.; Haley, M. M. Tetrahedron
2004, 60, 1215. (j) Schreiner, P. R.; Prall, M.; Lutz, V. Angew. Chem., Int.
Ed. 2003, 42, 5757.
3,4-dimethoxyphenyl.
With these optimized conditions in hand, we set out to
test the scope of our method (see Scheme 2). The reaction
tolerated a wide range of boronic acids, including electron-
rich, electron-poor, sterically crowded, and heteroaryl species
(entries 2a-h). Both electron-deficient alkenes and styryl
derivatives could be used as Heck acceptors (entries 2i-n).
The efficiency was improved as the electron density on the
aryl ring increased: a substrate bearing an electron-donating
methoxy group (entry 2p) led to higher yields than the
electron-neutral system, while electron-poor substrates gave
reduced yields (entries 2q-s). Incorporation of a sterically
demanding substituent ortho to the Heck acceptor greatly
decelerated the Heck reaction: under normal conditions, only
the Suzuki coupling occurs (entry 2t). A thiophenyl substrate
reacted sluggishly, giving the desired product in only 18%
yield (entry 2u). This could be due to coordination of the
(13) For an efficient approach to chlorinated derivatives, see: Ye, S.;
Gao, K.; Zhao, H.; Wang, X.; Wu, J. Chem. Commun. 2009, 5406.
(14) During preparation of this manuscript, an alternative route to
methyleneindenes from alkynyl gem-dibromoolefins was described: Ye, S.;
Yang, X.; Wu, J. Chem. Commun. 2010, 46, 2950.
(15) (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc. 1987,
109, 1257. (b) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron
Lett. 1990, 31, 6509. (c) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji,
J. J. Org. Chem. 1998, 63, 8965. (d) Myers, A. G.; Goldberg, S. D. Angew.
Chem., Int. Ed. 2000, 39, 2732.
(16) (a) Nuss, J. M.; Rennels, R. A.; Levine, B. H. J. Am. Chem. Soc.
1993, 115, 6991. (b) Torii, S.; Okumoto, H.; Tadokoro, T.; Nishimura, A.;
Rashid, M. A. Tetrahedron Lett. 1993, 34, 2139. We have also described
reactions of gem-dibromoolefins wherein the (Z)-bromide must react first;
see: (c) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (d)
Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M. Chem. Commun.
2009, 5236.
(17) Shen, W. Synlett 2000, 737.
Org. Lett., Vol. 12, No. 12, 2010
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