NHC-Cu-catalyzed silyl conjugate additions to acyclic and cyclic dienones and dienoates. Efficient site-, diastereo- and enantioselective synthesis of carbonyl-containing allylsilanes

Article abstract of DOI:10.1021/om300790t

Efficient and highly diastereo- and enantioselective conjugate additions of phenyldimethylsilyl units to acyclic and cyclic dienones and dienoates are disclosed. The C-Si bond forming reactions are catalyzed by 2.0-2.5 mol % of a copper complex of a chiral monodentate N-heterocyclic carbene; the requisite reagent, PhMe₂Si-B(pin), is commercially available or can be easily prepared. Transformations generate allylsilanes in up to 98% yield and >99:1 enantiomeric ratio and proceed with complete 1,4-selectivity, unless the dienone or dienoate carries a trisubstituted alkene conjugated to the carbonyl group; in the latter cases, 1,6-addition products are obtained exclusively and in up to >98% Z selectivity.

Full text of DOI:10.1021/om300790t

Communication
pubs.acs.org/Organometallics
NHC−Cu-Catalyzed Silyl Conjugate Additions to Acyclic and Cyclic
Dienones and Dienoates. Efficient Site-, Diastereo- and
Enantioselective Synthesis of Carbonyl-Containing Allylsilanes
Kang-sang Lee, Hao Wu, Fredrik Haeffner, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Efficient and highly diastereo- and enantioselec-
tive conjugate additions of phenyldimethylsilyl units to acyclic and
cyclic dienones and dienoates are disclosed. The C−Si bond
forming reactions are catalyzed by 2.0−2.5 mol % of a copper
complex of a chiral monodentate N-heterocyclic carbene; the
requisite reagent, PhMe2Si−B(pin), is commercially available or can be easily prepared. Transformations generate allylsilanes in
up to 98% yield and >99:1 enantiomeric ratio and proceed with complete 1,4-selectivity, unless the dienone or dienoate carries a
trisubstituted alkene conjugated to the carbonyl group; in the latter cases, 1,6-addition products are obtained exclusively and in
up to >98% Z selectivity.
ilicon-containing organic molecules are of substantial utility
in chemical synthesis,1 and allylsilanes are one of the most
β,γ-unsaturated carbonyl due to kinetic protonation of dienolate
at the α position, is formed with high stereoselectivity.
S
useful among them.2 A valuable subset of chiral allylsilanes
consists of those containing a carbonyl unit β to the silyl or the
alkene unit (cf. A and B, Scheme 1);3 such entities have served
Herein, we report the results of our investigations regarding
the development of an efficient catalytic enantioselective method
for silyl conjugate additions to dienones and dienoates. The
resulting protocols allow access to an assortment of allylsilanes in
69−98% yield and 94.5:5.5 to more than 99:1 enantiomeric ratio
(er). The requisite chiral ligands are prepared in three to four
steps in ∼50% overall yield;11 the silylboron reagent ((dimethyl-
phenylsilyl)pinacolatoboron (1)) is commercially available or can
be prepared easily on a multigram scale.14 Acyclic unsaturated
ketones, esters, and thioesters as well as five-, six-, and seven-
membered-ring cyclic dienones can be used as substrates.
Depending on the substrate structure, 1,4- or 1,6-modes of addi-
tion predominate. In the case of 1,6-addition products,15 trisub-
stituted alkenes are obtained with 78% to >98% Z selectivity.
We began by probing the ability of a selection of NHC−Cu
complexes, derived from imidazolinium salts 4−6, to promote
conjugate addition of the versatile phenyldimethylsilyl moiety
to dienone 2a through reactions performed in the presence
of silylboron reagent 1. Although reasonable efficiency and
enantioselectivity is observed in every case (Table 1), with
C2-symmetric 6b serving as catalyst precursor, allylsilane 3a is
isolated in 96% yield and 99:1 er, and formation of the 1,4-
addition product is strongly favored (<2% δ C−Si bond formation).
We then determined that enantioselective synthesis of 3a can be
performed with 2.2 mol % of 6b (2.0 mol % of CuCl, 4.4 mol %
of NaO-t-Bu, −78 °C, 2.0 h) with identical efficiency and
enantioselectivity (96% yield, 99:1 er). Similar to the NHC−
Cu-catalyzed transformations involving B2(pin)2 to generate
Scheme 1. Enantioselective Synthesis of Carbonyl-
Containing Allylsilanes by NHC−Cu-Catalyzed Silyl
Conjugate Addition
in enantioselective preparation of several structurally complex
natural products.3,4 One direct approach to accessing the
carbonyl-containing allylsilanes in the enantiomerically en-
riched form5−10 involves site- and enantioselective silyl conju-
gate additions to acyclic or cyclic α,β,γ,δ-unsaturated dienones
or dienoates. We envisioned that monodentate chiral N-
heterocyclic carbenes11 (NHCs) and their derived Cu-based
complexes, developed recently in these laboratories and used
for catalytic enantioselective silyl conjugate additions,12,13
might be utilized to access allylsilanes represented by A−C
(Scheme 1). If 1,6-addition were to be predominant (i.e., B and
C are formed as major products), we would have to estab-
lish whether the alkene, likely to be generated as part of a
Special Issue: Copper Organometallic Chemistry
Received: August 15, 2012
Published: September 19, 2012
© 2012 American Chemical Society
7823
dx.doi.org/10.1021/om300790t | Organometallics 2012, 31, 7823−7826

Organometallics
Communication
contain a sterically demanding trisubstituted olefin, serve as equally
effective starting points.
Table 1. Silyl Addition to an Acyclic Dienone: NHC−Cu
a
Screening
Examining the reactions of acyclic dienones that contain a
methyl substituent at their β carbon came next (cf. 7, Table 2).
Table 2. Addition to a β-Substituted Acyclic Dienone:
a
NHC−Cu Screening
b
b
c
entry
imidazolinium salt
conversn (%)
Z:E
er
1
2
3
6a
6b
9
>98
77
91:9
95:5
b
c
d
entry
imidazolinium salt
conversn (%)
yield (%)
er
80:20
93:7
83:17
>99:1
1
2
3
4
5
6
4a
4b
4c
5
80
>98
88
77
92
87
91
94
96
86:14
93:7
91:9
96:4
95:5
99:1
81
a−c
See Table 1; er values correspond to Z product isomers.
94
The question here was whether the NHC−Cu-catalyzed addi-
tions would occur at the C4 site to generate a Si-substituted
quaternary carbon stereogenic center, or if C−Si bond forma-
tion occurs at the δ site. In both cases, there is only 1,6-addition
and the β,γ-unsaturated ketone is formed exclusively. Unlike
transformations with the less substituted dienone 2a, the Cu
complex derived from imidazolinium salt 6a promotes a more
efficient reaction and delivers the desired product (8a) with
higher enantiomeric purity (entries 1 and 2, Table 1: 95:5 vs
83:17 er). Although both processes furnish the Z trisubstituted
olefin predominantly, the reaction with 6a is more stereo-
selective (91% vs 80% Z). As mentioned above, a hallmark of
chiral monodentate NHC ligands is the ease with which their
structure can be modified.11,12 Accordingly, further screening
led us to establish that use of C2-symmetric imidazolinium salt
9 (entry 3, Table 2) leads to the formation of 8a with superior
Z selectivity and enantioselectivity (93% Z, >99:1 er).
6a
6b
>98
>98
a
b
Reactions performed under N2 atmosphere. Determined by analysis
c
of 400 MHz 1H NMR spectra of unpurified mixtures ( 2%). Yields of
d
purified products ( 5%). Determined by HPLC analysis. See the
Supporting Information for details. Mes = 2,4,6-Me3C6H2.
tertiary C−B bonds,16 silyl conjugate additions proceed readily
in the absence of MeOH, the presence of which is required
in some instances.17 Thus, the NHC−Cu−enolate appears to
be sufficiently able, likely due to the strong donor ability of
the heterocyclic ligand,16 to react with the sizable silylboron
reagent in order to regenerate the catalytically active NHC−
Cu−SiMe2Ph species.
The Cu-catalyzed additions have significant scope, as the data
presented in Scheme 2 indicate. With 2.7 mol % 6b (2.5 mol %
Scheme 2. Enantiomerically Enriched Acyclic Carbonyl-
a
Containing Allylsilanes
Enantioselective synthesis of 8a proceeds to >98% conversion
with 2.5 mol % 9 within 6 h, under the conditions shown in
Table 3; the allylsilane is generated in 93% Z selectivity and
>99:1 er (entry 1). As the findings in entries 2 and 3 of Table 3
indicate, variations in the electronic attributes of the aryl sub-
stituent do not strongly affect Z selectivity or enantioselectivity.
Formation of alkyl-substituted allylsilanes 10a,b (entries 4 and 5,
Table 3) is equally efficient and exceptionally enantioselective
(>99:1 er), but the degree of alkene stereoisomeric purity is
somewhat diminished (89% Z). Conjugate additions to the cor-
responding carboxylic and alkylthio esters, as shown in entries 6
and 7 of Table 3, generate the expected allylsilanes with complete Z
selectivity and enantioselectivity (<2% E and ≥99:1 er); the
conjugate addition with the S-containing substrate, however,
demands higher temperatures (−50 vs −78 °C) and longer
reaction times (48 vs 12 h) to proceed to completion.
a
Reactions were performed with 2.7 mol % of 6b, 2.5 mol % of CuCl
and 5.5 mol % of NaOt-Bu under a N2 atmosphere (2.0 h unless
otherwise noted). Yields are of isolated and purified products ( 5%). En-
antioselectivities were determined by HPLC analysis. See the Supporting
Information for details.
of CuCl, 5.5 mol % of NaOt-Bu, −78 °C), β-silyl-substituted
carboxylic ester 3b is formed in 85% yield and 96:4 er, although
the transformation is less facile and requires 6 h to proceed to
completion. Conjugate addition to the corresponding thioester
(cf. 3c) is still slower (>98% conversion in 12 h at −78 °C), but
the desired product is isolated in exceptionally high yield and
enantiomeric purity (98% yield, 99:1 er). Cu-catalyzed enantio-
selective syntheses of β-silylketones 3d,e illustrate that substrates
bearing an alkyl-substituted dienes (vs Ph in 3a−c), or those that
The final segment of our investigation entailed a more
extensive study of additions to cyclic dienones, two examples of
which, involving six-membered-ring substrates in entries 2 and
7 of Table 4, were reported to occur with high Z selectivity and
enantioselectivity in our initial disclosure.12a We were particularly
keen on establishing whether the reactions are sensitive to different
7824
dx.doi.org/10.1021/om300790t | Organometallics 2012, 31, 7823−7826

Organometallics
Communication
degree of Z selectivity with the cyclopentenyl system is
diminished (78% vs 96% Z). Additionally, for the trans-
formation in entry 1 of Table 4, the product mixture contains
15−20% of the derived α,β-unsaturated cyclopentenone
(inseparable from 13), formed presumably as a result of ad-
ventitious isomerization. Electronic alterations within the aryl
substituent do not cause any significant variations in the Z
selectivity or enantioselectivity of the silyl conjugate additions,
as demonstrated by reactions shown in entries 2−5 of Table 4.
Moreover, conjugate addition to the cyclic dienone in entry 6,
carrying an alkyl substituent, is equally efficient and stereoselective,
affording 15 in 92% yield, 95% Z selectivity, and 98:2 er.19
The NHC−Cu·dienone ensembles in Figure 1 provide a stereo-
chemical model regarding the outcome of the 1,6-silyl conjugate
Table 3. Additions to β-Substituted Acyclic Dienones:
Scope
a
a
Reactions performed under a N2 atmosphere; >98% conversion, <2%
α,β-unsaturated carbonyl product, and >98% 1,6-addition in all cases.
b
c
Yields of purified products ( 5%). Determined by analysis of 400 MHz
d
1H NMR spectra of unpurified mixtures ( 2%). Determined by
HPLC analysis; er values correspond to the Z alkene product. Reaction
time = 6.0 h. Performed at −50 °C for 48 h. See the Supporting
Information for details.
e
f
a
Table 4. Additions to β-Substituted Cyclic Dienones
Figure 1. Proposed stereochemical models.
additions. The NHC−Cu−SiMe2Ph complex is generated in situ
by the pathways described before.12a Such a complex can co-
ordinate with the γ,δ-alkene of the substrate, as illustrated by
I−IV, with the high Z selectivity indicating the involvement of
the s-cis conformers. Preliminary DFT calculations indicate
that although, as expected, the s-trans dienes are energeti-
cally favored (by ≥2.0 kcal/mol), reaction through the inter-
mediacy of an NHC−Cu-s-cis complex is favored.20 Elucidation
of the precise reason for such a preference requires additional
studies but might partially be attributable to the η4 nature of
the Cu−diene coordination.20 The observed enantioselectivity
can arise from the minimization of steric repulsion between
the substrate and the catalyst, forcing the more sterically de-
manding enone moiety to be oriented as depicted in I and III
(Figure 1). The relatively low Z selectivity observed for the
addition to cyclopentenone 13 (entry 1, Table 4) is difficult
to explain. However, the proposed scheme is consistent with
the lower Z selectivity delivered for the more sluggish and
relatively nonselective transformations with to dienone Z-18
(eq 1). In the latter instance, the resulting allylic strain likely
a−d
e
See Table 3. Product mixture contained 15−20% of the isomerized
α,β-unsaturated ketone. See the Supporting Information for details.
ring sizes and variations in the steric or electronic attributes of the
alkene substituent.
Five- as well as seven-membered-ring dienones serve as
effective substrates, delivering the desired allylsilanes in 85%
and 98% yields, respectively (entries 1 and 8, Table 4).18
Both products (13 and 17, Table 4) are obtained with high
enantioselectivity (95:5 and 96:4 er, respectively), but the
raises substantially the energy of the substrate’s s-cis conformer,
rendering the derived NHC−Cu−diene complex less acces-
sible. As a result, alternative complexes, such as the correspond-
ing s-trans dienone or that derived from coordination through
the other enantiotopic face of the olefin, become competitive,
causing diminution in Z selectivity and enantioselectivity.
7825
dx.doi.org/10.1021/om300790t | Organometallics 2012, 31, 7823−7826

Organometallics
Communication
Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada, M. J. Org. Chem. 1986,
51, 3772.
The protocols described here offer a convenient and direct
route to a variety of enantiomerically enriched allylsilanes. The
high Z selectivity in instances where 1,6-addition is dominant is
a noteworthy aspect of the NHC−Cu-catalyzed transforma-
tions; in the corresponding processes with C-based nucleo-
philes, only moderate stereoselectivity is observed (≤85% of
one alkene isomer favored).15 Furthermore, attempts to
perform NHC-catalyzed (Cu-free) silyl conjugate additions12b
to representative substrates mentioned above (e.g., 2a) re-
sulted in <10% yield of the desired allylsilanes and a complex
mixture of unidentifiable entities. The above attributes, together
with the high efficiency and stereoselectivity observed in the
aforementioned processes, should render the present class of
Cu-catalyzed protocols of utility in chemical synthesis. The
example shown in eq 2, involving the synthesis of β-hydroxy
(6) For synthesis of enantiomerically enriched allylsilanes by catalytic
hydrosilylation, see: (a) Hayashi, T.; Kabeta, K.; Yamamoto, T.;
Tamao, K.; Kumada, M. Tetrahedron Lett. 1983, 24, 5661. (b) Hayashi,
T.; Han, J. W.; Takeda, A.; Tang, J.; Nohmi, K.; Mukaide, K.; Tsuji,
H.; Uozumi, Y. Adv. Synth. Catal. 2001, 343, 279.
(7) For synthesis of enantiomerically enriched allylsilanes by catalytic
allylic substitution, see: (a) Hayashi, T.; Ohno, A.; Lu, S.-j.;
Matsumoto, Y.; Fukuyo, E.; Yanagi, K. J. Am. Chem. Soc. 1994, 116,
4221. (b) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2007, 46, 4554.
(8) For synthesis of enantiomerically enriched allylsilanes by catalytic
reduction of silyl-substituted allyl carbonates, see: Hayashi, T.;
Iwamura, H.; Uozumi, Y. Tetrahedron Lett. 1994, 35, 4813.
(9) For synthesis of enantiomerically enriched allylsilanes by catalytic
Si−B addition to allenes, see: Ohmura, T.; Taniguchi, H.; Suginome,
M. J. Am. Chem. Soc. 2006, 128, 13682.
(10) For synthesis of enantiomerically enriched allylsilanes by catalytic
olefin metathesis reactions, see: (a) Kiely, A. F.; Jernelius, J. A.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868. (b) Adam,
J.-M.; de Fays, L.; Laguerre, M.; Ghosez, L. Tetrahedron 2004, 60, 7325.
(11) (a) Lee, K.-s.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455.
(b) Wu, H.; Radomkit, S.; O’Brien, J. M. J. Am. Chem. Soc. 2012, 134,
8277 and references cited therein.
(12) For NHC−Cu-catalyzed enantioselective silyl conjugate
additions, see: (a) Lee, K-s.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 2898. For the corresponding metal-free processes,
catalyzed by chiral NHCs, see: (b) O’Brien, J. M.; Hoveyda, A. H. J.
Am. Chem. Soc. 2011, 133, 7712.
ketone 19, the product of an enantioselective ketone aldol
addition21 to an α,β-unsaturated ketone, is illustrative.
(13) For Pd- and Ru-catalyzed enantioselective silyl conjugate
additions, see: (a) Matsumoto, Y.; Hayashi, T. Tetrahedron 1994, 50,
335. (b) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1988,
110, 5579. (c) Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int.
Ed. 2006, 45, 5675. (d) Walter, C.; Oestreich, M. Angew. Chem., Int.
ASSOCIATED CONTENT
* Supporting Information
Text, tables, and figures giving experimental procedures,
spectral and analytical data for all products, and data for the
theoretical calculations. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
Ed. 2008, 47, 3818. (e) Walter, C.; Frohlich, R.; Oestreich, M.
̈
Tetrahedron 2009, 65, 5513.
(14) Suginome, M.; Matsuda, T.; Ito, Y. Organometallics 2000, 19, 4647.
(15) For enantioselective 1,6-conjugate additions of carbon-based
nucleophiles, see: (a) Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew.
Chem., Int. Ed. 2005, 44, 4224. (b) Fillion, E.; Wilsily, A.; Liao, E.
Tetrahedron: Asymmetry 2006, 17, 2957. (c) den Hartog, T.;
Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew.
AUTHOR INFORMATION
Corresponding Author
*E-mail: amir.hoveyda@bc.edu.
Notes
■
́
Chem., Int. Ed. 2008, 47, 398. (d) Henon, H.; Mauduit, M.; Alexakis, A.
The authors declare no competing financial interest.
Angew. Chem., Int. Ed. 2008, 47, 9122. (e) Nishimura, T.; Yasuhara, Y.;
Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7872. For a recent
case of catalytic enantioselective 1,6-addition of S-based nucleophiles, see:
(f) Tian, X.; Liu, Y.; Melciorre, P. Angew. Chem., Int. Ed. 2012, 51, 6439.
(16) Lee, K-s.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253.
ACKNOWLEDGMENTS
Financial support was provided by the NIH (GM-57212) and
the NSF (CHE-1111074).
■
́
(17) For example, see: (a) Lillo, V.; Prieto, A.; Bonet, A.; Dıaz-
REFERENCES
■
́
́ ́
Requejo, M. M.; Ramırez, J.; Perez, P. J.; Fernandez, E. Organometallics
(1) For reviews regarding the use of organosilicon species in organic
synthesis, see: (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev.
1997, 97, 2063. (b) Suginome, M.; Ito, Y. Chem. Rev. 2000, 100, 3221.
(2) For reviews on the utility of allylsilanes in organic synthesis, see:
(a) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293. (b) Barbero,
A.; Pulido, F. J. Acc. Chem. Res. 2004, 37, 817. (c) Chabaud, L.; James,
P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173.
2009, 28, 659. (b) O’Brien, J. M.; Lee, K-s.; Hoveyda, A. H. J. Am.
Chem. Soc. 2010, 132, 10630.
(18) Similar yields and enantioselectivities are obtained with the Cu
complex derived from 9. For instance, 16 is obtained in 79% yield
(>98% conversion) and 96:4 er with the latter species.
(19) The minor E isomers are likely generated enantioselectivity
(e.g., E-15 in 79% yield and 91:9 er).
(3) For a review on the utility of β-silylcarbonyls in synthesis, see: Fleming,
I, Science of Synthesis; Thieme: Stuttgart, Germany, 2002; Vol. 4, p 927.
(4) For specific examples involving the use of enantiomerically
enriched allylsilanes in natural product synthesis, see: (a) Hale, M. R.;
Hoveyda, A. H. J. Org. Chem. 1992, 57, 1643. (b) Hu, T.; Takenaka,
N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229. (c) Liu, P.; Panek, J.
S. J. Am. Chem. Soc. 2000, 122, 1235. (d) Arefolov, A.; Panek, J. S. J.
Am. Chem. Soc. 2005, 127, 5596.
(20) See the Supporting Information for details.
(21) Broadly applicable, efficient, and highly enantioselective catalytic
protocols for aldol additions to ketones remain lacking. For key reports,
see: (a) List, B.; Shabat, D.; Zhong, G.; Turner, J. M.; Li, A.; Bui, T.;
Anderson, J.; Lerner, L. A.; Barbas, C. F. J. Am. Chem. Soc. 1999, 121,
7283. (b) Denmark, S. E.; Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005,
70, 5235. For a recent review on Cu-catalyzed ketone aldol processes,
see: (c) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853. For Ag-
catalyzed aldol adition to α-keto esters, see: (d) Akullian, L. C.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 6532.
(5) For synthesis of enantiomerically enriched allylsilanes by catalytic
cross-coupling reactions, see: (a) Hayashi, T.; Konishi, M.; Ito, H.;
Kumada, M. J. Am. Chem. Soc. 1982, 104, 4962. (b) Hayashi, T.;
7826
dx.doi.org/10.1021/om300790t | Organometallics 2012, 31, 7823−7826