Enantioselective conjugate addition of alkenylboronic acids to indole-appended enones

Article abstract of DOI:10.1021/ol2020847

An enantioselective addition of alkenylboronic acids and alkynylboronic esters to unprotected indole-appended enones is reported. This transformation proceeds with high enantioselectivity and high product yields via the use of catalytic amounts of 3,3′-bis(pentafluorophenyl)-BINOL and Mg(Ot-Bu) ₂. A range of α-branched indole derivatives are available from the transformation.

Full text of DOI:10.1021/ol2020847

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4958–4961
Enantioselective Conjugate Addition
of Alkenylboronic Acids to
Indole-Appended Enones
Brian J. Lundy, Santa Jansone-Popova, and Jeremy A. May*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003,
United States
jmay@uh.edu
Received August 1, 2011
ABSTRACT
An enantioselective addition of alkenylboronic acids and alkynylboronic esters to unprotected indole-appended enones is reported. This
transformation proceeds with high enantioselectivity and high product yields via the use of catalytic amounts of 3,30-bis(pentafluorophenyl)-
BINOL and Mg(Ot-Bu)2. A range of R-branched indole derivatives are available from the transformation.
Indoles are important and essential active structural
components in many biologically active small molecules.1
Many of these compounds have stereocenters at the carbon
adjacent to the indole. However, the difficulty in stereoselec-
tively forming such centers is illustrated by the relative lack
of compounds not derived2 from natural sources.3 Only
recently have approaches been explored to create stereocen-
ters adjacent to indoles enantioselectively,4 and of these
approaches, many are not viable with unprotected indoles.
The conjugate addition5 of a vinyl or alkynyl nucleophile to
an indole-appended enone potentially provides a direct route
to create the stereocenter in ketoindoles such as B(Scheme 1).6
However, very few examples exist of conjugate additions
performed on enones appended at the β-position with an
unprotected indole (e.g., A).7 Moreover, none of these
examples are enantioselective.8 To address the lack of such
(3) (a) Pousset, J.; Kerharo, J.; Maynart, G.; Monseur, X.; Cave, A.;
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Dmitrenko, O.; Fox, J. M. J. Am. Chem. Soc. 2011, 133, 1650–1653. (h)
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r
10.1021/ol2020847
Published on Web 08/16/2011
2011 American Chemical Society

toaccessketonessuchasB stereoselectively. Thisapproach
was inspired by work described by A. Suzuki10 and H. C.
Brown11 and later elaborated by others for asymmetric
transformations.12ꢀ14 However, existing conditions af-
forded at best ∼2% yield when an unprotected indole
was present in the enone.15 The use of low molecular
weight boronic esters was problematic for reasons of
volatility, hydrolytic instability, and loss of purity during
storage. Additionally, the unreactive indole substrate 1
(Table 1) required long reaction times that led to the
production of various side products.
Scheme 1. Formation of an R-Branched Indole
methods, we have developed a catalytic enantioselective
addition of vinyl nucleophiles to indolo enones.
As unprotected indolo enones are generally incompati-
ble with strongly basic organometallic agents,9 we chose to
investigate neutral organocatalytic 1,4-addition conditions
Table 1. Optimization of the BINOL-Catalyzed Conjugate
Addition of 2-cis-Butenylboronic Acid
(5) (a) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63,
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€
J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279–1300. (d)
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Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852. (e) Nishimura, T.;
Sawano, T.; Hayashi, T. Angew. Chem., Int. Ed. 2009, 48, 8057–8059. (f)
Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645–648. (g)
Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc.
2011, 133, 6902–6905. (h) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160–163. (i) Austin,
J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173. (j)
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Prabhakaran, E. N.; Johnston, J. N. J. Org. Chem. 2008, 73, 3040–3046.
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(n) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc.
2011, 133, 3339–3341.
yield
entry
1
R0
additive
none
solvent
CH2Cl2,
(SM)a
eeb
I
<2% (85%) n.d.c
25 °C
THF, reflux
2
3
I
I
none
none
<2% (96%) n.d.c
ClCH2CH2Cl, 21% (77%) n.d.c
70 °C
~
(6) (a) Nielsen, M.; Jacobsen, C. B.; Paixao, M. W.; Holub, N.;
~
4
5
6
7
8
C6F5
C6F5
C6F5
C6F5
C6F5
none
ClCH2CH2Cl, 32% (63%) 98%
Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581–10586. (b) Paixao,
M. W.; Holub, N.; Vila, C.; Nielsen, M.; Jørgensen, K. A. Angew. Chem.,
70 °C
Int. Ed. 2009, 48, 7338–7342.
Cs2CO3
ClCH2CH2Cl, 11% (81%) n.d.c
(7) (a) Bergman, J.; Koch, E.; Pelcman, B. J. Chem. Soc., Perkin
Trans. 1 2000, 2609–2614. (b) Kidwai, M.; Mohan, R.; Rastogi, S. Synth.
Commun. 2003, 33, 3747–3759. (c) Ma, S.; Yu, S. Org. Lett. 2005, 7,
5063–5065.
(8) Two instances of enantioselective conjugate addition in the pre-
sence of protected indoles exist: (a) Wilsily, A.; Fillion, E. J. Org. Chem.
2009, 74, 8583–8594. (b) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc.
2008, 130, 4978–4983.
(0.1 equiv)
LiCl
70 °C
ClCH2CH2Cl, 38% (54%) 99%
(0.1 equiv)
Mg(Ot-Bu)2
(0.1 equiv)
Mg(Ot-Bu)2
(0.1 equiv)
70 °C
ClCH2CH2Cl, 48% (51%) 99%
70 °C
ClCH2CH2Cl, 49% (36%) 98%
reflux
(9) (a) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009,
11, 3458–3461. (b) Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.;
a Yields determined by comparison of NMR peaks to an internal
standard.15 b Determined for the purified product via analytical HPLC.
c ee’s were not determined.
€
€
Garg, N. K. Tetrahedron 2010, 66, 4687–4695. (c) C-elebi-Olc-um, N.;
Boal, B. W.; Huters, A. D.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc.
2011, 133, 5752–5755.
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Soc. 1985, 107, 5225–5228. (b) Hara, S.; Hyuga, S.; Aoyama, M.; Sato,
M.; Suzuki, A. Tetrahedron Lett. 1990, 31, 247–250. (c) Fujishima, H.;
Takada, E.; Hara, S.; Suzuki, A. Chem. Lett. 1992, 695–698. (d) Hara, S.;
Ishimura, S.; Suzuki, A. Synlett 1996, 993–994. (e) Hara, S.; Shudoh, H.;
Ishimura, S.; Suzuki, A. Bull. Chem. Soc. Jpn. 1998, 71, 2403–2408.
(11) (a) Suzuki, A.; Arase, A.; Matsumoto, H.; Itoh, M.; Brown,
H. C.; Rogic, M. M.; Rathke, M. W. J. Am. Chem. Soc. 1967, 89, 5708–
5709. (b) Brown, H. C.; Rogic, M. M.; Rathke, M. W.; Kabalka, G. W.
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12094–12095. (b) McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.;
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12660–12661. (d) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem.
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2008, 130, 6922–6923. (g) Moquist, P. N.; Kodama, T.; Schaus, S. E.
Angew. Chem., Int. Ed. 2010, 49, 7096–7100.
To address the first of these issues, we looked to use
readily available, easily purified, and conveniently handled
boronic acids or their dehydrated congeners, boroxines.16
We reasoned that boroxines could act as reactive surro-
gates for boronicestersforthe initial formation of BINOL-
boronic esters 5 (Figure 1).17,18 Importantly, these vinyl
nucleophiles are usually more easily accessed, functiona-
lized, and stored than their zinc, copper, aluminum, or
magnesium congeners. The use of a boronic acid did not
initially fare well with enone 1 and the known catalyst 3
(entry 1, Table 1). However, when elevated temperatures
and a nonpolarsolvent were used, someproduct formation
occurred (entry 3).
(14) (a) Inokuma, T.; Takasu, K.; Sakaeda, T.; Takemoto, Y. Org.
Lett. 2009, 11, 2425–2428. (b) Sugiura, M.; Tokudomi, M.; Nakajima,
M. Chem. Commun. 2010, 46, 7799–7800.
Org. Lett., Vol. 13, No. 18, 2011
4959

hypothesis. While acidic additives inhibited the reaction
and neutral salts had little effect, Mg(Ot-Bu)2 improved
the reaction (entry 7). Whether this is due to catalyst
activation by deprotonation or due to the presence of
t-BuOH as a proton shuttle is now under investigation.
Examples of successfully treating indole-appended en-
ones with trans-2-phenylvinylboronic acid and 15 mol %
of (R)-3,30-bis(pentafluorophenyl)-BINOL (4) are shown
in Scheme 2. With these conditions, the ketone substituent
could be a methyl (8), isopropyl (9), or phenyl (10). A tert-
butyl group (11) is tolerated, though it causes the reaction
to be sluggish. An unprotected indole is not necessary for
the reaction, as both Boc- (12) and methyl-protected (13)
indoles reacted well. Cyclic ketones (14) are also compe-
tent, as long as the enone can adopt an s-cis configura-
tion.10,11 In this case, a 1.2:1 mixture of diastereomers was
observed in the product, likely due to an unselective
protonation of the enol borate 7. Both diastereomers were
found in high enantiomeric excess, which indicates that
the carbonꢀcarbon bond formation occurred with
high enantioselectivity. Neither electron-donating
Figure 1. Proposed mechanism for the conjugate addition.18,19
To compensate for the unreactive substrate, a more
reactive catalyst was needed. The literature suggested a
potential correlation between reaction conversion for
chalcone substrates and the strength of the electron-with-
drawing group at the 3 and 30 positions of a BINOL
catalyst.12,13 This effect could be due to an increase in
formation of the ate complex 6 postulated in Pellegrinet
and Goodman’s proposed mechanism for boronic ester
nucleophiles shown in Figure 1 (R = Me).18,19 Next, the
transformation would proceed via an intramolecular alke-
nyl transfer from the boron ate complex in the s-cis
conformation10,11 to form the enol borate 7. If the forma-
tion of complex 6 was the slow step in the transformation,
then a more Lewis acidic boronic ester 5 would accelerate
the reaction. However, if the alkyl transfer is slowest, then
a more Lewis acidic boronic ester 5 would stabilize ate
complex 6 and consequently slow the reaction.
Scheme 2. 1,4-Addition Products of β-Indolo Enonesa
The possibility that the formation of ate complex 6 is the
reaction’s slow step prompted the synthesis of (R)-3,
30-bis(pentafluoro-phenyl)-BINOL (4, Table 1).20 When
added to the enone 1 and 2-cis-butenylboronic acid, the
bispentafluorophenyl derivative showed a reproducible
increase in product formation with excellent enantiomeric
excess (Table 1, entries 3 and 4). Although steric or confor-
mational effects cannot be excluded, we view the increase
in product formation as a partial validation of the above
(15) See Supporting Information for detailed optimization trails,
experimental conditions, and compound data.
(16) A different approach uses the dibutyl ester for stability: Bishop,
J. A.; Lou, S.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 4337–4340.
(17) A control experiment in CDCl3 without catalyst or substrate
showed that the boroxine was substantially generated in situ from the
boronic acid. Also: (a) Storgaard, M.; Ellman, J. A. Org. Synth. 2009,
360–373. (b) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem.
Soc. 2009, 131, 17750–17752.
(18) (a) Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem. Soc. 2006,
128, 3116–3117. (b) Paton, R. S.; Goodman, J. M.; Pellegrinet, S. C. J.
Org. Chem. 2008, 73, 5078–5089.
(19) For an alternate activation mode, see: Barnett, D. S.; Moquist,
P. N.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 8679–8682.
(20) (a) Goldys, A.; McErlean, C. S. P. Tetrahedron Lett. 2009, 50,
3985–3987. (b) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8,
5097–5100. (c) Singh, R.; Czekelius, C; Schrock, R. R.; Muller, P.;
Hoveyda, A. H. Organometallics 2007, 26, 2528–2539. (d) Momiyama,
N.; Nishimoto, H.; Terada, M. Org. Lett. 2011, 13, 2126–2129.
a Isolated yields averaged over 2ꢀ3 reactions. b Recycled catalyst
used. c Reaction time 48 h. d Determined through integration of NMR
peaks for the crude mixture. e Reaction time 36 h. f 20% catalyst 3 used
with 3 equiv of 2,2-dimethylvinylboronic acid. g Yield based on recov-
ered starting material.22
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Org. Lett., Vol. 13, No. 18, 2011

nor electron-withdrawing groups on the indole ring
affected reactivity (see 15 and 16). Importantly, the
catalyst could be recovered during purification and
recycled. The yields and enantioselectivity reported
for ketoindoles 9 and 15 were obtained using recycled
catalyst. Finally, the enone could be in either the 3- or
2-position of the indole (compare 8 and 17), though
the significantly hindered substrate in the latter
case was more reactive with (R)-3,30-bisiodo-BINOL.
This catalyst bears smaller groups than that with bis-
pentafluorophenyl substitution, likely lowering steric
repulsion.
Next, enone 1 was treated with a range of boronic acids
(Table 2). Both alkylvinylboronic acids (entries 1ꢀ3) and
arylvinylboronic acids (entries 4ꢀ6) proved amenable to
the reaction conditions, giving products 18 in respectable
yields and with good to excellent enantioselectivity. 1-Sub-
stituted vinylboronic acids are almost as reactive as their
less-hindered counterparts (compare entries 1 and 2).
Electron-withdrawing groups (entry 5) and electron-do-
nating groups (entry 6) are well tolerated and produce no
drop inreactivityorselectivity. While alkynylboronicacids
were found to be too unstable for convenient handling, the
diisopropyl ester21 could be used effectively with excellent
enantioselectivity (entry 7).
In conclusion, the use of (R)-3,30-bis(pentafluoro-
phenyl)-BINOL has enabled the conjugate addition of
alkenylboronic acids and alkynylboronic esters to in-
dole-appended enones in good yields and with excellent
enantioselectivity. Both 2- and 3-functionalized indoles
are tolerated, and additional indole substitution or
altered indole electronics are compatible. In addition,
alkenyl or alkynyl nucleophiles both work well and
have a variety of substitutions. The resulting enan-
tioenriched R-branched indoles have an alkene or al-
kyne at the stereocenter to facilitate further synthetic
transformations.
Table 2. Alkenyl and Alkynyl Nucleophilesa
Acknowledgment. We thank Christabel Tanifum (UT-
Health) for the starting material for product 17 and the
Welch Foundation (Grant No. E-1744) and the University
of Houston for financial support in conducting this research.
Supporting Information Available. Additional optimiza-
tion data, experimental procedures, and characterization
data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a All yields are isolated yields averaged over 2ꢀ3 reactions. b 3 equiv
of boronic acid or ester.22 c PhMe was used as solvent at 115 °C in a
sealed tube. d Mg(Ot-Bu)2 omitted.
(21) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
29, 2631–2634.
(22) Because of decomposition, 1.2 equiv of hexynylboronic ester
gave the product 21g in 58% yield and 96% ee.
Org. Lett., Vol. 13, No. 18, 2011
4961