Asymmetrie addition of alkenylstannanes to alkylidene meldrum's acids

Article abstract of DOI:10.1021/ol902216y

Herein, we describe enantioselective addition of alkenyltin reagents possessing a reactive and sensitive allylic functionality not readily available to other classes of alkenyl metals. This method is enabled by the use of highly electrophilic alkylidene M

Full text of DOI:10.1021/ol902216y

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5346-5349
Asymmetric Addition of
Alkenylstannanes to Alkylidene
Meldrum’s Acids
Stuart J. Mahoney, Aaron M. Dumas, and Eric Fillion*
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
Received September 24, 2009
ABSTRACT
Herein, we describe enantioselective addition of alkenyltin reagents possessing a reactive and sensitive allylic functionality not readily available
to other classes of alkenyl metals. This method is enabled by the use of highly electrophilic alkylidene Meldrum’s acids as acceptors and a
cationic Rh(I)-diene complex as catalyst.
Enantioselective conjugate additions catalyzed by chiral Rh(I)
complexes have emerged as a powerful synthetic tool over
the past decade.1 Construction of new sp3-sp2 C-C bonds
by addition of alkenylmetals to unsaturated carbonyl accep-
tors has been realized from silanes,2 trifluoroborates,3 and
especially boronic acids.4 Surprisingly, enantioselective
conjugate additions employing vinylstannanes have not been
reported, despite the potential utility of these pronucleo-
philes.5 The advantages of working with alkenyltin reagents
include their air and moisture stability, certain stoichiometry,6
and mild syntheses of both terminal (E)7 and (Z)8 isomers,
as well as internal,9 vinylstannanes from simple alkyne
precursors. Their relatively low reactivity also enables the
preparation of alkenylstannanes bearing sensitive functional
groups that may not be compatible with either the Lewis
base activation of silane reagents or the aqueous solvent
typically required for boronic acids. Further, mild reaction
(1) For the first report, see: (a) Takaya, Y.; Ogasawara, M.; Hayashi,
T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579–5580. For
a review see: (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–
2844.
(2) (a) Oi, S.; Taira, A.; Honma, Y.; Inoue, Y. Org. Lett. 2003, 5, 97–
99. (b) Otomaru, Y.; Hayashi, T. Tetrahedron: Asymmetry 2004, 15, 2647–
2651. (c) Oi, S.; Taira, A.; Honma, Y.; Sato, T.; Inoue, Y. Tetrahedron:
Asymmetry 2006, 17, 598–602. (d) Hargrave, J. D.; Herbert, J.; Bish, G.;
Frost, C. G. Org. Biomol. Chem. 2006, 4, 3235–3241. (e) Nakao, Y.; Chen,
J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 9137–9143. (f) Shintani, R.;
Ichikawa, Y.; Hayashi, T.; Chen, J.; Nakao, Y.; Hiyama, T. Org. Lett. 2007,
9, 4643–4645.
(4) For representative recent examples, see: (a) Shintani, R.; Ichikawa,
Y.; Takatsu, K.; Chen, F.; Hayashi, T. J. Org. Chem. 2009, 74, 869–873.
(b) Konno, T.; Tanaka, T.; Miyabe, T.; Morigaki, A.; Ishihara, T.
Tetrahedron Lett. 2008, 49, 2106–2110. (c) Zigterman, J. L.; Woo, J. C. S.;
Walker, S. D.; Tedrow, J. S.; Borths, C. J.; Bunel, E. E.; Faul, M. M. J.
Org. Chem. 2007, 72, 8870–8876. (d) Mauleon, P.; Carretero, J. C. Chem.
Commun. 2005, 4961–4963.
(5) There is only a single example of enantioselective conjugate addition
employing organostannanes and Rh(I) catalysis, in which PhSnMe3 was
used as nucleophile; see ref 14a.
(3) (a) Gendrineau, T.; Geneˆt, J.-P.; Darses, S. Org. Lett. 2009, 11, 3486–
3489. (b) Lalic, G.; Corey, E. J. Tetrahedron Lett. 2008, 49, 4894–4896.
(c) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923. (d) Pucheault,
M.; Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2002, 3552–3557.
(6) Dehydration of boronic acids can make determination of their exact
composition difficult: Hall, D. G. In Boronic Acids; Hall, D. G., Ed.; Wiley-
VCH, Weinheim, Germany, 2005; pp 1-99.
10.1021/ol902216y CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

conditions compatible with sensitive functional groups on
the nucleophile would also permit expansion in the scope
of available electrophiles.
Table 1. Survey of Chiral Ligands and Optimization
In this regard, we have previously reported the use of
alkylidene Meldrum’s acids 1 as acceptors for the racemic
addition of functionalized alkenylstannanes,10 as well as a
variety of other nucleophiles under nonchiral11 or enanti-
oselective catalysis.12 In this Letter, we describe the first
examples of enantioselective conjugate alkenylation employ-
ing 3-(tributylstannyl)allyl carbonates and alkylidene Mel-
drum’s acids, reactions that take place at low temperature
under mild and anhydrous conditions.
temp
(°C)
conversion
(%)
entry
ligand
time (h)
er
Cognizant that the low reactivity of the C-Sn bond
presents a barrier to transmetalation, ligand selection was a
crucial consideration (Figure 1).
1a
2a
3a
4a
5
6
7
8
9
10
11
12
13b
14
15
16c
L1
L2
L3
L4
L4
L4
L4
L4
L5
L6
L7
L8
L8
L8
L9
L8
rt
rt
rt
rt
rt
0
-10
-20
0
0
0
0
10
rt
24
24
24
24
24
37
24
24
46
45
46
45
45
45
45
45
0
0
>99
>99
>99
>99
37
20
23
0
>99
51
>99
>99
>99
>99
61:39
71:29
88:12
91:9
93:7
93:7
94:6
93:7
95:5
93:7
91:9
92:8
94:6
10
10
Figure 1. Chiral ligands for asymmetric conjugate addition.
a Entries 1-4 performed without AgSbF6. b 66% isolated yield. c 4 Å
molecular sieves added; isolated yield 84%.
Initial attempts using a [Rh(C2H4)2Cl]2 precatalyst in the
presence of phosphoramidite L1 and (R)-BINAP (L2) left
the starting materials unchanged and yielded no desired
product (Table 1, entries 1 and 2, respectively). Fortunately,
chiral diene ligands have recently emerged as a complemen-
tary alternative to privileged phosphine scaffolds as a way
of overcoming low catalytic activity while maintaining high
enantioselectivity.13,14 Employing known and easily prepared
C1-symmetric chiral diene L314b furnished the desired
product with excellent conversion and an encouraging 61:
39 er (entry 3). While introduction of an ortho-substituent
(L4, entry 4) provided an increase in selectivity, the more
interesting finding was the large gain in er observed upon
addition of AgSbF6 to sequester the chloride ion from the
Rh(I) complex (entry 5). Continuing under these cationic
conditions, it was found that while decreasing the temperature
provides increased selectivity, it does so at the eventual
expense of conversion (entries 6-8). Known ligand L5,
which has been found more effective than L3 and L4 in other
systems,14d and new, 9-anthracenyl-containing L6, both of
which have two ortho-substituents, were poorly or not at all
reactive (entries 9 and 10, respectively).
Taking these results into consideration, it was apparent
that the optimal mix of selectivity and conversion would
come from a ligand bearing an arene with a single, large
group at the ortho position. New ligands L7, L8, and L9
were prepared, and all proved to be more selective than L4
and to give higher conversion than L5 (entries 11-15).
Trifluoromethylated ligand L8 was settled upon as the ligand
of choice on the basis of its slight superiority in terms of
enantioselectivity and its higher yielding synthesis from
inexpensive starting material.15 Finally, introduction of
(7) By Pd-catalyzed hydrostannation: (a) Darwish, A.; Lang, A.; Kim,
T.; Chong, J. M. Org. Lett. 2008, 10, 861–864. (b) Zhang, H. X.; Guibe´,
F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857–1867. By radical
hydrostannation: (c) Nozaki, K.; Oshima, K.; Uchimoto, K. J. Am. Chem.
Soc. 1987, 109, 2547–2549.
(8) (a) Asao, N.; Liu, J.-X.; Sudo, T.; Yamamoto, Y. J. Org. Chem.
1996, 61, 4568–4571. (b) Corey, E. J.; Eckrick, T. M. Tetrahedron Lett.
1984, 25, 2419–2422.
(9) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett. 1999, 1, 1017–
1019.
´
(10) Fillion, E.; Carret, S.; Mercier, L. G.; Tre´panier, V. E. Org. Lett.
2008, 10, 437–440.
(14) For examples representative of the variety of available chiral diene
ligands, see refs 2f and 4a as well as: (a) Hayashi, T.; Ueyama, K.;
Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508–11509.
(b) Fisher, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628–1629. (c) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850–10851. (d) Gendrineau,
T.; Chuzel, O.; Eijberg, H.; Geneˆt, J.-P.; Darses, S. Angew. Chem., Int. Ed.
2008, 47, 7669–7672. (e) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-
Q. J. Am. Chem. Soc. 2007, 129, 5336–5337. (f) Okamoto, K.; Hayashi,
T.; Rawal, V. H. Chem. Commun. 2009, 4815–4817. (g) Hu, X.; Zhuang,
M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744–4747.
(11) (a) Mahoney, S. J.; Moon, D. T.; Hollinger, J. A.; Fillion, E.
Tetrahedron Lett. 2009, 50, 4706–4709. (b) Dumas, A. M.; Fillion, E. Org.
Lett. 2009, 11, 1919–1922. (c) Fillion, E.; Dumas, A. M.; Kuropatwa, B. A.;
Malhotra, N. R.; Silter, T. C. J. Org. Chem. 2006, 71, 409–412.
(12) (a) Fillion, E.; Zorzitto, A. K. J. Am. Chem. Soc. 2009, 131, 14608–
14609. (b) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 2066–2072. (c)
Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801–2804. (d) Fillion, E.;
Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774–2775.
(13) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M. Angew. Chem., Int.
Ed. 2008, 47, 4482–4502
.
Org. Lett., Vol. 11, No. 22, 2009
5347

powdered molecular sieves was found to be crucial to prevent
hydrolysis of the alkylidene leading to cleaner reactions and
higher isolated yields (entry 16).
It was found that the addition of 2a was general to a
number of substituted alkylidene Meldrum’s acids (Table 2),
Table 3. Enantioselective Addition of Alkenylstannanes to
Alkylidene Meldrum’s Acid 1a
Table 2. Asymmetric Addition to Alkylidene Meldrum’s Acids
using L8a
entry
R
yield (%)
er
1
2
3
4
5
(E)-CH2OCO2Et (2a)
(E)-CH2OAc (2b)
(Z)-CH2OAc (2c)
H (2d)
84 (3a)
61 (3n)
87 (3o)
NDa (3p)
NR (3q)
94:6
89:11
83:17
63:37
(E)-CO2Et (2e)
a Product 3p was inseparable from excess alkylidene 1a; see Supporting
Information for details.
entry
R
yield (%)
erb
1
2
3
4
5
6
7
8
C6H5 (1a)
84 (3a)
58 (3b)
54 (3c)
51 (3d)
57 (3e)
70 (3f)
17 (3g)
42 (3h)
39 (3i)
39 (3j)
29 (3k)
49 (3l)
73 (3m)
94:6
92:8
91:9
93:7
93:7
95:5
93:7
93:7
93:7
93:7
90:10
92:8
77:23
2-(OMe)C6H4 (1b)
3-(OMe)C6H4 (1c)
3-MeC6H4 (1d)
3-(Bpin)C6H4 (1e)
3-BrC6H4 (1f)
4-(OMe)C6H4 (1g)
4-MeC6H4 (1h)
4-(Bpin)C6H4 (1i)
4-BrC6H4 (1j)
4-ClC6H4 (1k)
2-naphthyl (1l)
Me (1m)
isomer 2c proceeded with full retention of double bond
geometry, leading to (Z)-3o. As also observed in racemic
reactions,10 addition of unfunctionalized vinylstannanes was
considerably slower, and 2d gave low conversion and
selectivity. The accelerating effects of the allylic functionality
in 2a-2c does not appear to be caused solely by electron
withdrawal by the adjacent oxygen atom, as alkenylstannane
2e gave no conversion.
9
10
11c
12c
13
In contrast to terminal alkenyltins 2a-c, geminal stannane
2f proved resistant to conjugate addition (Scheme 1a). In
a Reactions performed as in Table 1, entry 16. b Absolute configuration
assigned by analogy to a derivative of 3h; see Supporting Information. c Final
concentration of 1 was 0.4 M.
Scheme 1
.
Inter- and Intramolecular Reactions of Geminal
Alkenyl Stannanes
proceeding in comparable enantioselectivity regardless of the
nature of the substituent on the phenyl ring. Substitution was
possible at the ortho, meta, and para positions (entries 2, 3,
and 7, respectively), and the reaction tolerated aryl halides
(entries 6, 10, and 11) and even boronic esters (entries 5
and 9). The latter two examples highlight the mild nature of
these additions, while providing the potential for orthogonal
reactivity of different C-M bonds in Rh(I)-catalyzed conju-
gate additions. In some cases the highly concentrated
conditions required for good conversion led to low solubility
of the electrophile, and slight dilution provided a compromise
between reaction rate and homogeneous solution (entries 11
and 12). Nonaryl alkylidene 1m reacted with relatively good
yield but substantially lower selectivity (entry 13).
Addition of other alkenylstannanes was also successful,
although none matched carbonate 2a in enantioselectivity.
The allyl acetate containing tin reagent 2b gave the addition
product in slighly lower yield (Table 3, entry 2). Facile
introduction of either allylic carbonate or acetates provides
a useful complement in further transformations, particularly
in Pd-catalyzed allylic substitutions. Addition of the (Z)-
order to facilitate this difficult reaction, alkylidene Meldrum’s
acid 1n was prepared to allow intramolecular cyclization.
Under the conditions optimized for intermolecular reactions,
Meldrum’s acid 3r was obtained in low yield and 64:36 er,
without isomerization of the sensitive exomethylene group
(Scheme 1b).
(15) See Supporting Information for details.
5348
Org. Lett., Vol. 11, No. 22, 2009

As mentioned, Rh(I)-catalyzed additions of boronic
acids are performed under basic, protic conditions partially
in order to activate the boronic acid by formation of an
intermediate borate.16 Additionally, as demonstrated in
detailed studies by Hayashi, these reactions proceed by
formation of an oxa-π-allyl Rh(I) complex that is proto-
nated by the cosolvent (often H2O or MeOH) to turn over
the catalyst.17 On the other hand, the addition of alkenyl-
stannanes we have described is best performed under
cationic and anhydrous conditions.18 Taking into account
the significant increase in enantioselectivity observed by
introduction of AgSbF6 to remove chloride from the Rh(I)
precatalyst, we propose the mechanism outlined in Scheme
2. Here, transmetalation between Rh and the alkenylstan-
nane forms the active nucleophile while generating a
cationic Sn species, which can act as a Lewis acid.
Complexation of 1a to Sn activates the electrophile and
leads directly to the stable Sn-enolate 7 upon addition of
the alkenyl rhodium.19 Significantly, a similar cooperative
mechanism has recently been proposed in the additions
of tetraarylborates to cycloalkenones,20 and this concept
may open avenues for further improvements to our
method.
Scheme 2
.
Proposed Mechanism for Enantioselective Conjugate
Alkenylation
In conclusion, we have described the first examples of
inter- and intramolecular enantioselective conjugate alkeny-
lations employing organostannanes. The unique conditions
required for the alkenylation make this process complementary to
existing protocols employing other alkenylmetals. Further work
to fully elucidate the mechanism and apply these conditions to other
tin-based nucleophiles to expand the reaction scope is in progess.
Acknowledgment. This work was supported by the
Government of Ontario (Early Researcher Award to E.F.),
the Natural Sciences and Engineering Research Council of
Canada (NSERC), the Canadian Foundation for Innovation,
the Ontario Innovation Trust, and the University of Waterloo.
S.J.M. and A.M.D. thank the Government of Canada for
graduate scholarships (NSERC CGS-M and CGS-D, respec-
tively) and Dr. Se´bastien Carret (Universite´ Joseph Fourier,
Grenoble, France) for preliminary investigations.
(16) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000–
6004.
(17) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052–5058.
(18) Racemic conjugate additions of aryl and alkenyl trimethylstannanes
catalyzed by cationic Rh(I) in water: Oi, S.; Moro, M.; Ito, H.; Honma, Y.;
Miyano, S.; Inoue, Y. Tetrahedron 2002, 58, 91–97.
(19) Analysis of the crude reaction mixture has demonstrated that 7 is
the initial product of the reaction, which is hydrolyzed on silica gel during
purification.
Supporting Information Available: Experimental details
and characterization of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2009, 11, 13588–13589.
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