Enantioselective conjugate addition employing 2-heteroaryl titanates and zinc reagents

Article abstract of DOI:10.1021/ol9013975

A general strategy for the conjugate addition of 2-heteroaryl nucleophiles to cyclic enones, unsaturated lactones, and unsaturated lactams In high enantioselectivities and yields is reported. The use of 2-heteroaryl titanates and zinc reagents offers a pr

Full text of DOI:10.1021/ol9013975

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4200-4203
Enantioselective Conjugate Addition
Employing 2-Heteroaryl Titanates and
Zinc Reagents
Anna J. Smith, Lily K. Abbott, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received June 19, 2009
ABSTRACT
A general strategy for the conjugate addition of 2-heteroaryl nucleophiles to cyclic enones, unsaturated lactones, and unsaturated lactams in
high enantioselectivities and yields is reported. The use of 2-heteroaryl titanates and zinc reagents offers a practical alternative to
2-heteroarylboronic acids, which are prone to undergo protodeboronation.
The development of methods to induce the catalytic enan-
tioselective conjugate addition of aryl nucleophiles to
Michael acceptors is an important objective in contemporary
organic synthesis.1 It is thus not surprising that extensive
efforts over the past decade have led to the discovery of a
number of useful techniques for inducing such constructions
to form ꢀ-aryl carbonyl compounds in high yields and
enantioselectivities. Indeed, electron-poor and electron-rich
aryl groups may be transferred to R,ꢀ-unsaturated compounds
in the presence of chiral Rh,2 Pd,3 and to a lesser extent,
Cu4 catalysts. Sources of aryl nucleophiles have included
aryl boronic acids,5 aryl titanates,6 aryl trifluoroborates,7
arylzinc chlorides,2a,8 and aryl silicon9 reagents. Of these,
aryl boronic acids have been employed most frequently,
likely in part due to their commercial availability.
In the context of an ongoing synthetic project in our group,
we were interested in the enantioselective transfer of a furan-
2-yl nucleophile to cyclopentenone. Although there are
several reports of conjugate additions of furan nucleophiles
to enones,10 none of these are enantioselective. Indeed, at
the time we initiated this research program, there were no
examples of enantioselective conjugate additions involving
2-heteroaryl nucleophiles. The closest precedent was an
example reported by Hayashi of the Rh-catalyzed enanti-
oselective 1,4-addition of 3-thiopheneboronic acid to enones
and enoates,11 but these reactions suffer the disadvantage of
requiring the use of a glovebox during setup. During the last
(1) (a) Tomioka, K.; Nagoaka, Y. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
New York, 1999; Vol. 3, Chapter 31. (b) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon Press: Oxford, UK, 1992. (c)
Schmalz, H.-G. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, Chapter 1.5.
(2) Selected examples include: (a) Hayashi, T.; Yamamoto, S.; Tokuna-
ga, N. Angew. Chem., Int. Ed. 2005, 44, 4224. (b) Yamamoto, Y.; Nishikata,
T.; Miyaura, N. J. Synth. Org. Chem., Jpn. 2006, 64, 1112. (c) Kina, A.;
Ueyama, K.; Hayashi, T. Org. Lett. 2005, 7, 5889. (d) Shintani, R.;
Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240.
(e) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (f) Mariz, R.;
Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130,
2172.
(3) Selected examples include: (a) Gini, F.; Hessen, G.; Minnaard, A. J.
Org. Lett. 2005, 7, 5309. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317. (c) Nishikata, T.; Yamamoto, Y.; Miyaura,
N. Chem. Commun. 2004, 1822. (d) Nishikata, T.; Yamamoto, Y.; Miyaura,
N. Chem. Lett. 2005, 34, 720.
10.1021/ol9013975 CCC: $40.75
Published on Web 08/26/2009
 2009 American Chemical Society

year, however, and concurrent with our own investigations,
there have been two reports describing the enantioselective
conjugate additions of 2-heteroaryl nucleophiles. Ishihara and
co-workers described one example of a Rh-catalyzed enan-
tioselective addition of 2-thiopheneboronic acid to a Michael
acceptor.12 Frost and co-workers employed thiophene-2-yl-
and thiophene-3-ylzinc chloride as nucleophiles in Rh-
catalyzed enantioselective conjugate additions to cyclic
enones and 5,6-dihydro-2H-pyran-2-one.13 Although this
group also reported the addition of furan-2-ylzinc bromide
to cyclohexenone and 5,6-dihydro-2H-pyran-2-one, these
reactions proceeded in only 70 and 86% ee, respectively.
The early obstacle to using 2-heteroaryl nucleophiles in
enantioselective conjugate additions likely arose because of
the instability of 2-heteroarylboronic acids, which are known
to undergo facile protodeboronation in transition-metal-
catalyzed processes that employ water or alcohol as a
cosolvent.14 This problem has been very recently addressed
by the development of air-stable 2-heterocyclic MIDA
boronates by Burke and co-workers.15 Although these
boronates might be used in enantioselective Rh-catalyzed
conjugate additions, facile preparation of these boronates is
somewhat problematic.
the catalyst in the presence of a variety of chiral ligands;
however, the enantioselectivity in all of these reactions was
poor (Table 1, entries 1-6). On the other hand, we found
that the corresponding furan-2-yl titanate reagent furnished
the adduct 3 in both very good yield and enantioselectivity
when BINAP-derived ligands were used (Table 1, entries 7
and 8); much lower yields of product were obtained using
other chiral ligands (entries 9-11). The absolute stereo-
chemistry of 3 was not determined.
We were somewhat surprised that the addition of 5-
methylfuran-2-ylzinc chloride to 3 proceeded with such low
enantioselectivity and wondered whether a background
reaction was a contributing factor to the low ee observed in
entries 1-6 (Table 1). Accordingly, several control experi-
ments were performed. In the first of these, we discovered
that the reaction of 5-methylfuran-2-ylzinc chloride with
2-cyclopenten-1-one occurred rapidly in the absence of the
Rh(I) catalyst to provide 3 in 81% yield (Scheme 1). On the
Scheme 1. Background Reaction
Owing to the known difficulties associated with using
2-heteroarylboronic acids at the time we initiated this work,
we screened the additions of readily available furan-2-yl
organometallic reagents to 2-cyclopenten-1-one (2) in the
presence of chiral transition metal catalysts. Some of these
results using 5-methylfuran-2-ylzinc and titanate reagents 1
are summarized in Table 1. When 5-methylfuran-2-ylzinc
chloride was used as the nucleophilic component, very good
yields of the adduct 3 were obtained using [Rh(cod)Cl]2 as
other hand, in a second control experiment using a 5-
methylfuran-2-yl titanate, the yield of adduct was only 10%
in the absence of the Rh(I) catalyst. Hence, the observed
difference in ee for the Rh(I)-catalyzed additions of furylzinc
and titanates in Table 1 is consistent with a significant
background reaction for the former reagent.
Table 1. Rh-Catalyzed Conjugate Addition of Furan-2-yl
Titanate and Furan-2-ylzinc Chloride to 2-Cyclopenten-1-onea
The series of experiments summarized in Table 1 estab-
lished the viability of furan-2-yl titanates as nucleophiles in
enantioselective 1,4-additions, but the catalyst loadings were
rather high. We then discovered that using [Rh(C2H4)2Cl]2
(Table 2, entry 1) as the precatalyst with (R)-Tol-BINAP
enabled us to reduce the loading without compromising the
yield or enantioselectivity. We then began to probe the scope
of this method by examining the reactions of other heteroaryl
titanates and Michael acceptors. We quickly discovered that
the conditions that we had developed for the additions of
furan-2-yl titanates to cyclopentenone required some adjust-
ments when other heteroaryl titanates were employed. For
example, when benzofuran-2-yl titanate was added to 2-
cyclopenten-1-one (2) under conditions that had been
optimized for the addition of 4 to 2, the adduct 19 was
formed in high ee but low yield (Table 2, entry 8).
Subsequent screening of rhodium precatalysts and ligands
led to the finding that the catalyst system derived from
[Rh(cod)acac] and (R)-MeO-BIPHEP was superior (Table
2, entries 8 and 9).
a Reaction conditions: 10 mol % of [Rh(cod)Cl]2, 0.75 mmol of TMSCl,
ligand/Rh (1.1:1), 1.0 mmol of furan-2-ylzinc chloride or furan-2-yl titanate,
0.5 mmol of 2-cyclopenten-1-one. b Isolated yield of 3 after flash
chromatography. c Determined by HPLC analysis (OD-H chiral column,
98:2 hexanes/2-propanol, 0.5 mL/min). d HPLC analysis was performed
on the four diastereomeric alcohol derivatives of the product, formed by
NaBH4 reduction of 3. e Slow addition of the nucleophile (2 mmol/h). f Not
evaluated due to unsatisfactory chemical yield.
With the newly optimized conditions thus established, we
explored the reactions of a number of heteroaryl titanates
Org. Lett., Vol. 11, No. 18, 2009
4201

thiophene-2-yl, and indol-2-yl titanates added to a variety
of Michael acceptors in moderate to excellent yield and high
ee (Table 2). In view of the modest enantioselectivity
reported by Frost for the addition of thiophene-2-ylzinc
reagents to 2-cyclopenten-1-one (2),13 it is noteworthy that
the corresponding titanate added to 2 in excellent ee (Table
2, entry 7). Although the additions to both cyclic enones
and unsaturated lactones proceeded efficiently, the reactions
of enones typically furnished higher yields of adducts than
enoates.
Table 2. Enantioselective Conjugate Additions of 2-Heteroaryl
Titanates to Michael Acceptorsa
In an attempt to extend the substrate scope to R-substituted
enones, we examined the use of 2-methyl-2-cyclopenten-1-
one as a substrate, although there are few examples of such
acceptors in transition-metal-catalyzed 1,4-additions.1-9 Hence,
perhaps not surprisingly, we found in a preliminary experi-
ment that furan-2-yl titanate did not add to 2-methyl-2-
cyclopenten-1-one under our standard conditions. We did,
however, develop an expedient solution to this problem.
Namely, when TESCl was employed as the Lewis acid
instead of TMSCl, it was possible to isolate the silyl enol
ether of the conjugate addition product. The enolate generated
in situ from this intermediate could then be trapped with
MeI to give 3-(furan-2-yl)-2-methylcyclopentanone as a
single diastereomer, the relative stereochemistry of which
was not unequivocally determined.
During the course of these studies, we observed that the
yields of the additions of heteroaryl titanates to R,ꢀ-
unsaturated carbonyl compounds were sometimes lower than
desired, even though the enantioselectivities in these reactions
were consistently high. We had discovered that furan-2-ylzinc
chloride added readily to 2-cyclopenten-1-one in the absence
of a chiral catalyst, but we did not know whether such
background reactions would undermine the additions of other
heteroarylzinc reagents to Michael acceptors. Accordingly,
in those cases where the conjugate additions of titanates to
unsaturated carbonyl compounds were low yielding, the
reaction of the corresponding heteroarylzinc reagent was
examined. We screened several rhodium precatalysts and
(4) (a) Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. J. Am.
Chem. Soc. 2006, 128, 7182. (b) May, T. L.; Brown, M. K.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2008, 47, 7358. (c) Robert, T.; Velder, J.; Schmalz,
H.-G. Angew. Chem., Int. Ed. 2008, 47, 7718. (d) Hawner, C.; Li, K.; Cirriez,
V.; Alexakis, A. Angew. Chem. 2008, 47, 8211.
(5) Selected examples include: (a) Kurihara, K.; Sugishita, N.; Oshita,
K.; Piao, D.; Yamamoto, Y.; Miyaura, N. J. Organomet. Chem. 2007, 692,
428. (b) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. Org. Synth.
2002, 79, 84. (c) Takaya, Y.; Ogasawara, M.; Hayashi, T. Chirality 2000,
12, 469. (d) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921.
(e) Kuriyama, M.; Nagai, K.; Yamada, K.-I.; Miwa, Y.; Taga, T.; Tomioka,
K. J. Am. Chem. Soc. 2002, 124, 8932.
(6) (a) Tokunaga, N.; Yoshida, K.; Hayashi, T. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5445. (b) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han,
J. W. J. Am. Chem. Soc. 2002, 124, 12102. (c) Yoshida, K.; Hayashi, T.
J. Am. Chem. Soc. 2003, 125, 2872.
a Reaction conditions: 10 mol % of [Rh], Rh/L (1:1.1), [Rh] )
[Rh(cod)acac]; L ) (R)-MeO-BIPHEP, 0.45 mmol of TMSCl, 0.30 mmol
of Michael acceptor, 0.6 mmol of 2-heteroaryl titanate, THF (-78 °C f
rt). b Isolated yield after flash chromatography. c Determined by HPLC
analysis (OD-H or AD chiral column). d [Rh] ) 5 mol % of [Rh(C2H4)2Cl]2,
L ) (R)-Tol-BINAP. e HPLC analysis was performed on the four diaster-
eomeric alcohol derivatives of the product, formed by NaBH4 reduction of
the product. f TESCl was employed as the Lewis acid.
(7) (a) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313. (b)
Pucheault, M.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 3552. (c)
Pucheault, M.; Darses, S.; Genet, J.-P. Tetrahedron Lett. 2002, 43, 6155.
(8) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240.
(9) Oi, S.; Taira, A.; Honma, Y.; Inoue, Y. Org. Lett. 2003, 5, 97.
(10) (a) Ng, J. S.; Behling, J. R.; Campbell, A. L.; Nguyen, D.; Lipshutz,
B. Tetrahedron Lett. 1988, 29, 3045. (b) Kraus, G. A.; Gottschalk, T.
Tetrahedron Lett. 1983, 29, 2727. (c) Jones, P.; Reddy, C. K.; Knochel, P.
Tetrahedron 1998, 54, 1471. (d) Lin, Y.-D.; Kao, J.-Q.; Chen, C.-T. Org.
Lett. 2007, 9, 5195.
and acceptors (Table 2). In the event, we found that pyrrol-
2-yl, benzofuran-2-yl, benzothiophene-2-yl, furan-2-yl,
(11) Yoshida, K.; Hayashi, T. Heterocycles 2003, 59, 605.
4202
Org. Lett., Vol. 11, No. 18, 2009

Because this result was nearly as good as the reaction using
benzofuran-2-yl titanate (cf. Table 2, entry 9), we extended
this reaction of 23 to other cyclic enones and unsaturated
lactones and lactams, and these conjugate additions typically
also proceeded with excellent enantioselectivities (Table 3,
entries 2-4). Similarly, benzothiophene-2-ylzinc chloride
(24) added to several Michael acceptors in g98% ee (Table
3, entries 5-7).
Table 3. Enantioselective Conjugate Addition of
2-Heteroarylzinc Nucleophiles to Michael Acceptorsa
In summary, a variety of 2-heteroaryl titanate and zinc
reagents added to cyclic enones, unsaturated lactones, and
lactams in moderate to excellent yields and high enantiose-
lectivities. In some cases, the yields and enantioselectivities
in the conjugate additions of heteroaryl titanate and zinc
reagents were comparable (cf. Table 2, entries 9 and 12, and
Table 3, entries 1 and 5). However, in most cases involving
furan and in preliminary experiments using N-methylpyrrole
and N-methylindole, higher enantioselectivities were obtained
using the titanate reagents. The application of this new
methodology to the synthesis of complex natural products
is the subject of current investigations, the results of which
will be reported in due course.
Acknowledgment. We thank the National Institutes of
General Medical Sciences (GM 31077) and The Robert A.
Welch Foundation for their generous support of this work.
We are also grateful to Solvias for their generous gift of
(R)-MeO-BIPHEP ligand. A.J.S. is grateful to the National
Science Foundation for a Predoctoral Fellowship. We also
thank Dr. Chris Dockendorff (The University of Texas) and
Mr. Yuichi Yasuhara (The University of Texas) for helpful
discussions.
Supporting Information Available: Experimental pro-
a Reaction conditions: 10 mol % of [Rh], Rh:L (1:1.1), [Rh] )
[Rh(cod)acac]; L ) (R)-MeO-BIPHEP, 0.45 mmol of TMSCl, 0.30 mmol
of Michael acceptor, 0.6 mmol of 2-heteroarylzinc chloride in THF (-78
°C f rt). b Isolated yield after flash chromatography. c Determined by HPLC
analysis (OD-H chiral column).
cedures, chromatographic data, and characterization and
1
copies of H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9013975
chiral ligands (e.g., (R)-Tol-BINAP, Josiphos, Walphos, and
Carreira’s diene) and again found that the catalyst system
derived from [Rh(cod)acac] and (R)-MeO-BIPHEP was
highly effective and promoted the enantioselective addition
of benzofuran-2-ylzinc chloride (23) to 2-cyclopenten-1-one
(2) in 91% yield and 91% ee (Table 3, entry 1).
(12) Konno, T.; Tanaka, T.; Miyabe, T.; Morigaki, A.; Ishihara, T.
Tetrahedron Lett. 2008, 49, 2106.
(13) Le Notre, J.; Allen, J. C.; Frost, C. G. Chem. Commun. 2008, 3795.
(14) (a) Buchwald, S.; Billingsley, K. J. Am. Chem. Soc. 2007, 129,
3358. (b) Lautens, M.; Mancuso, J. J. Org. Chem. 2004, 69, 3478. (c) Chao,
J.; Ling, Y.; Liu, X.; Luo, X.; Brodie, A. M. H. Steroids 2006, 71, 585.
(15) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961.
Org. Lett., Vol. 11, No. 18, 2009
4203