Earlier work demonstrated that diol catalysts derived
from BINOL can promote the conjugate addition of alkenyl,
alkynyl, and arylboronate esters to β-arylenones.5 However,
with heteroaryl-appended enones, less than a 2% yield of
product was seen under those conditions.4 To accommodate
heterocyclic substrates, the mechanism of the transforma-
tion was examined to identify the sources of the problems
(Scheme 1). Briefly, the catalyst generates Lewis acidic
boronate ester 5, which coordinates to the enone 6 to form
7. The involvement of both BINOL hydroxyls in 5 is sup-
ported by studies in which a monoalkylated BINOL reacts
sluggishly and with poor stereoselectivity.6 Intramolecular
CꢀC bond formation occurs from 7 to form boron enolate
8, which is then protonolyzed to release the catalyst 10.7
substituents have a significant impact on vinyl boronate
ester addition to chalcones.7,8 Experimental and theoreti-
cal evidence suggests that electron-withdrawing substitu-
tion is needed on the catalyst to promote the formation of
zwitterionic intermediate 7 (Scheme 1).7,8 In developing a
more efficient catalyst system to effect the conjugate addi-
tion of vinyl boronic acids to β-heteroarylenones, effort
was focused on increasing the fluorination of the ortho
substituents on BINOL toimprove catalyst efficiency.9 We
postulated that doing so would increase the Lewis acidity
of BINOL boronate ester 5 and/or allow the R substituents
in 7 to stabilize the buildup of anionic charge in that
mechanistic intermediate.
A direct comparison of known and new catalysts was
made with thiophene substrate 11 (Table 1). A small
background reaction was observed in the absence of
catalyst (entry 1). BINOL (10a) slightly increased the reac-
tion rate and showed some enantioinduction (entry 2). The
catalysts 10b and 10c showed a significant increase in per-
formance and enantiocontrol (entries 3 and 4). Our first
generation bisperfluorophenyl catalyst 10d performed
even better (entry 5). None of these BINOL derivatives
were nearly as active as the bisperfluorotoluene 10e, how-
ever, which gave an 87% yield of product and a 92% ee in
only 4 h. The seemingly minor change of an additional CF3
is reasoned to increase the electron deficiency of the
fluorinated phenyl.10
Scheme 1. Putative Reaction Mechanism
Table 1. Comparison of Catalysts
Two pressing problems with this reaction required solv-
ing: (1) difficulties arising from the use of low molecular
weight vinyl boronate esters 3,5 which are volatile, hygro-
scopic, and hydrolytically unstable, and (2) the sluggish
reactivity of heteroaryl-appended substrates. The first was
avoided by the use of boronic acids 4,4 which are relatively
air-stable crystalline solids. Additionally, many more bo-
ronic acids are commercially available than boronate esters.
Either t-BuOH or Mg(Ot-Bu)2 could be used to accelerate
the reaction.6 In most cases, the latter gave a slightly higher
product yield than the former. These additives are postu-
lated to be acting as proton transfer agents to protonolyze
enolate 8.
To address the continued lack of reactivity of the sub-
strates, new catalysts were synthesized. The BINOL 3,30
a Isolated yields. b Determined via HPLC with chiral stationary
phase.
(4) Lundy, B. J.; Jansone-Popova, S.; May, J. A. Org. Lett. 2011, 13,
4958.
(5) (a) Brown, C.; Chong, J.; Shen, L. Tetrahedron 1999, 55, 14233.
(b) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122,
1822. (c) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244. (d)
Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (e) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2006, 128, 9646. (f) Wu, T. R.; Chong, J. M.
J. Am. Chem. Soc. 2007, 129, 4908. (g) Turner, H. M.; Patel, J.; Niljianskul,
N.; Chong, J. M. Org. Lett. 2011, 13, 5796.
The rate and selectivity improvements given by cata-
lyst 10e can be seen for a variety of substrates. Compa-
rable yields and enantioselectivities were sometimes ob-
tained in less than 20% of the time relative to catalyst
10d (compare entries 1/2 and 9/10, Table 2). Both 2-
and 3-substituted furans worked well (entries 1 and 4,
Table 2). Diverse nucleophiles are available for the
(6) See Supporting Information for details.
(7) (a) Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem. Soc. 2006,
128, 3116. (b) Paton, R. S.; Goodman, J. M.; Pellegrinet, S. C. J. Org.
Chem. 2008, 73, 5078.
(8) (a) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006,
128, 12660. (b) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc.
2007, 129, 15398. (c) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130,
6922. (d) Bishop, J. A.; Lou, S.; Schaus, S. E. Angew. Chem., Int. Ed.
2009, 48, 4337. (e) Barnett, D. S.; Schaus, S. E. Org. Lett. 2011, 13, 4020.
(9) In the case of ketone and aldehyde allylations, catalyst release
appears to be rate determining: Barnett, D. S.; Moquist, P. N.; Schaus,
S. E. Angew. Chem., Int. Ed. 2009, 48, 8679.
(10) Sheppard, W. A. J. Am. Chem. Soc. 1970, 92, 5419.
B
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