β-alkyl-α-allylation of Michael acceptors through the palladium-catalyzed three-component coupling between allylic substrates, trialkylboranes, and activated olefins

Article abstract of DOI:10.1021/jo0524876

The palladium-catalyzed three-component β-alkyl-α-allylation reaction of activated olefins has been achieved. For example, in the presence of 5 mol % of Pd(PPh₃)₄, the reaction of benzylidenemalononitrile 1a with Et₃B and allyl acetate 2a in THF proceeded smoothly at 40 °C to give the corresponding β-ethyl-α- allylated product 3a in 81% yield.

Full text of DOI:10.1021/jo0524876

â-Alkyl-r-allylation of Michael Acceptors
through the Palladium-Catalyzed
Three-Component Coupling between Allylic
Substrates, Trialkylboranes, and Activated
Olefins
with allenes, bearing an activated methine at the carbon chain
terminus, gave the cyclopentanes in good to excellent yields
8
(
path G). The palladium-catalyzed cycloaddition of activated
olefins with the allylic carbonates having a hydroxy group at
the terminus of the carbon chain gave the corresponding cyclic
9
ethers (path H). Quite recently, we have reported the palladium-
catalyzed hydrocarbonation, that is to say, â-hydro-R-allylation
of activated olefins by the use of Bu3SnH and allyl acetate.10
In all of the above cases, it was found that the reactions did not
Nitin T. Patil, Zhibao Huo, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku
1
proceed when one of the two electron-withdrawing groups (E ,
UniVersity, Sendai 980-8578, Japan
2
E ) CN, CN; CN, COOEt; CN, SOOPh) was replaced by
hydrogen, indicating the special nature of the olefin of type 1
in the palladium-catalyzed processes. Although these reactions
are limited to highly activated olefins, the utility of the -CN
group for further structural manipulation prompted us to
continue research in this area. Several other researchers11 also
reported some interesting transformations using activated olefins;
however, to the best of our knowledge the alkyl-allylation of
activated olefins has not been reported yet.
yoshi@mail.tains.tohoku.ac.jp
ReceiVed December 2, 2005
We found that the palladium-catalyzed reaction of ben-
1
2
zylidenemalononitrile 1a (R ) Ph, E ) E ) CN) with Et3B
1
and allyl acetate 2a (R ) H, X ) OAc) in THF proceeded
smoothly at 40 °C to give the corresponding alkyl-allylation
product 3a in 81% yield (eq 1). Preliminary studies have been
carried out using benzylidenemalononitrile 1a, Et3B (1.2 equiv)
and allyl acetate 2a (1.2 equiv) in the presence of a series of
potential palladium catalysts (5 mol %) in THF (Table 1). The
reaction was carried out in the presence of Pd(PPh3)4 (5 mol
%) at 40 °C under an argon atmosphere (entry 1). The starting
material 1a was consumed within less than 6 h to give the
desired alkyl-allylation product 3a in 81% isolated yield. When
Pd2dba3‚CHCl3 was employed alone as a palladium source, the
reaction did not proceed (entry 2). The combination of Pd2-
dba3‚CHCl3 and phosphine ligands (20 mol % for bisphosphines
or 40 mol % for monophosphines) worked well, and the desired
compound was obtained in good to moderate yields (entries
The palladium-catalyzed three-component â-alkyl-R-allyla-
tion reaction of activated olefins has been achieved. For
example, in the presence of 5 mol % of Pd(PPh
3 4
) , the
reaction of benzylidenemalononitrile 1a with Et B and allyl
3
acetate 2a in THF proceeded smoothly at 40 °C to give the
corresponding â-ethyl-R-allylated product 3a in 81% yield.
The functionalization of Michael acceptors (activated olefins)
through palladium-catalyzed carbon-carbon bond formation is
becoming an important research area (Figure 1). These reactions
generally proceed under milder conditions and with high atom
1
economy. The three-component coupling reactions such as
3
-7). However, the use of dppe as a ligand proved unsatisfac-
2
3
alkoxy-allylation (path A), bis-allylation (path B), cyano-
tory, and the product was obtained only in 10% yield as judged
by H NMR (entry 8). Thus, Pd(PPh3)4 was chosen as the
4
5
allylation (path C), acetonation-allylation (path D), and amino-
1
6
allylation (path E) gave the corresponding â,R-functionalized
catalyst for the alkyl-allylation of activated olefins. When the
products in high yields. The palladium catalyzed [3 + 2]
reaction of 1a with either 2a or 2c was performed in the absence
cycloaddition of vinylic oxirane and aziridine with activated
12
of Pd(PPh3)4 or in the presence of a catalytic amount of PPh3,
7
olefins for the formation of five membered cyclic ether and
pyrrolidine derivatives has also been reported in our laboratories
instead of Pd(PPh3)4, no product 3a was obtained at all. These
control experiments clearly indicate that Pd(PPh3)4 is required
for the reaction to proceed.
7
(path F). The palladium-catalyzed reaction of activated olefins
(
1) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. (c) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233-1246.
(2) Nakamura, H.; Sekido, M.; Ito, M.; Yamamoto, Y. J. Am. Chem.
Soc. 1998, 120, 6838-6839. It may be argued that this reaction is a two-
component coupling, and not a three-component one. Since the addition to
the Michael acceptors takes place both at â and R-positions, we would like
to propose that this is also among the category of three component coupling.
(
3) (a) Nakamura, H.; Shim, J. G.; Yamamoto, Y. J. Am. Chem. Soc.
997, 119, 8113-8114. (b) Nakamura, H.; Aoyagi, K.; Shim, J. G.;
Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 372-377.
4) Nakamura, H.; Shibata, H.; Yamamoto, Y. Tetrahedron Lett. 2000,
1, 2911-2914.
5) Shim, J. G.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1998, 63,
470-8474.
6) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 2002, 67,
977-5980.
7) Shim, J.-G.; Yamamoto, Y. J. Org. Chem. 1998, 63, 3067-3071.
1
Once a suitable condition for the alkyl-allylation reaction was
established, we investigated the scope of the three component
(
4
8
5
(
(8) Meguro, M.; Yamamoto, Y. J. Org. Chem. 1999, 64, 694-695.
(9) Sekido, M.; Aoyagi, K.; Nakamura, H.; Kabuto, C.; Yamamoto, Y.
J. Org. Chem. 2001, 66, 7142-7147.
(10) Shim, J.-G.; Park, J. C.; Cho, C. S.; Shim, S. C.; Yamamoto, Y. J.
Chem. Soc., Chem. Commun. 2002, 852-853.
(
(
1
0.1021/jo0524876 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/18/2006
J. Org. Chem. 2006, 71, 2503-2506
2503

FIGURE 1. Palladium-catalyzed reactions of highly activated olefins.
TABLE 1. Ligand Screen for the Alkyl-allylation Reactiona
coupling using various activated olefins. The results are sum-
marized in Table 2. Treatment of the activated olefin 1b, which
has a methyl group at the para position of aromatic ring, with
2
a under the standard conditions gave the desired product 3b
in 78% yield (entry 1). The reaction of other aromatic olefins
c and 1d, which have a strong electron-donating group such
as methoxy and a strong electron-withdrawing group such as
NO2 at the para position, gave the corresponding alkyl-
allylation products 3c and 3d, respectively, in good yields
entries 2 and 3). The olefin 1e, derived from 2-furaldehyde,
1
b
-
entry
Pd catalyst (5%)
phosphine
NMR yield (%)
c
1
2
3
4
5
6
7
8
Pd(PPh3)4
87 (81)
0
d
(
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
Pd2dba3‚CHCl3
PPh3 (40 mol%)
dppb (20 mol%)
dppf (20 mol%)
dppp (20 mol%)
dppm (20 mol%)
dppe (20 mol%)
81
71
82
60
78
also gave the desired product 3e in 68% yield (entry 4). The
reaction of isopropyl- and tert-butyl-substituted olefins 1f and
1
3
g proceeded well to give the corresponding products 3f and
g in 70% and 66% yield, respectively (entries 5 and 6). Not
d
10
only activated olefins having two cyano groups but also the
activated olefin 1h bearing -CN and -COOEt groups under-
a
The reactions of 1a (0.3285 mmol) with Et3B (1.2 equiv) and allyl
acetate 2a (1.2 equiv) in the presence of palladium catalysts (5 mol%) and
b
phosphine ligands were carried out at 40 °C in THF for 6 h. Yields were
(
11) (a) Jeganmohan, M.; Shanmugasundaram, M.; Cheng, C.-H. J. Org.
1
Chem. 2004, 69, 4053-4062. (b) Marat X.; Monteiro, N.; Balme, G. Synlett
997, 845. (c) Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999,
determined by H NMR spectroscopy with dibromomethane as an internal
standard. c Isolated yield is shown in parentheses. d The starting material
was observed by TLC.
1
4
0, 1301-1304. (d) Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi,
D.; Balme, G. Tetrahedron Lett. 1997, 38, 1763-1766. (e) Bottex, M.;
Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme, G. J. Org. Chem.
2
6
1
6
001, 66, 175-179. (f) Sato, Y.; Oonishi, Y.; Mori, M. J. Org. Chem. 2003,
8, 9858-9860. (g) Xie, R. L.; Hauske, J. R. Tetrahedron Lett. 2000, 41,
0167-10170. (h) Solin, N.; Narayan, S.; Szabo, K. J. J. Org. Chem. 2001,
6, 1686-1693. (i) Jeganmohan, M.; Shanmugasundaram, M.; Cheng, C.-
went the alkyl-allylation smoothly, giving the product 3h in 81%
yield; however, the diastereoselectivity was poor in this case
(entry 7). The three-component coupling reaction also proceeded
with cinnamyl acetate to give 3i in a high yield (entry 8). It
should be noted that the allylation with cinnamyl acetate took
place exclusively at the R-position of the allylic acetate and no
C-C bond-forming product at the γ-position was obtained. We
also investigated the use of allyl chloride instead of 2a, and
virtually no difference in the rates of reaction or the overall
yields has been observed (entry 9 compare to Table 1, entry 1).
As mentioned in entry 10, tributylborane could also be used to
produce butyl-allylation product 3j in 62% yield. Similar to our
previous reports, the present reaction worked well only for the
doubly activated olefins and apparently with nitriles. The other
olefins such as diethyl 2-benzylidenemalonate does not gave
product under the standard condition.
H. Org. Lett. 2003, 5, 881-884.
(12) It was thought that the presence of catalytic amounts of PPh3,
liberated from Pd(PPh3)4, would coordinate with triethylborane to form a
more reactive tetracoordinate boron ate complex I. A delivery of one of
the ethyl groups on boron to Michael acceptor would be then facilitated.
The formation of similar complex II, from trialkylaluminum compounds
(R3Al) and phosphines, is known; see: (a) Schneider, C.; Brauner, J. Eur.
J. Org. Chem. 2001, 4445-4450. (b) Schneider, C.; Brauner, J. Tetrahedron
Lett. 2000, 41, 3043-3046.
2
504 J. Org. Chem., Vol. 71, No. 6, 2006

TABLE 2. Alkyl-allylation of Various Activated Olefinsa
a
The reactions of 1 (0.3285 mmol) with Et3B (1.2 equiv) and allylic substrates 2 (1.2 equiv) in the presence of Pd(PPh3)4 (5 mol %) were carried out at
b
c
4
0 °C in THF for 6 h. Isolated yields. A mixture of diastereomers in a ratio of 6:4 was obtained. d Bu3B was used, instead of Et3B.
FIGURE 2. Proposed mechanism for the alkyl-allylation reaction.
A plausible mechanism for the three-component alkyl-
allylation is shown in Figure 2. The oxidative addition of Pd-
π-allylpalladium complex 6 with removal of Et2BOAc. The
conversion from the intermediate 5 to 6 proceeds in a way
similar to the Tsuji-Trost allylation. The intermediate 6 could
14
(0) to allyl acetate 2a leads to the formation of π-allylpalladium
complex 4. The π-allylpalladium complex 4 thus formed would
react with the species 5, formed by the Michael addition of one
of the ethyl groups from Et3B13 to 1a, generating another
(
13) Chandrasekhar, S.; Narsihmulu, C.; Reddy, N. R.; Reddy, M. S.
Tetrahedron Lett. 2003, 44, 2583-2585.
J. Org. Chem, Vol. 71, No. 6, 2006 2505

be in equilibrium with the intermediate 8, which should more
probably be represented as the bis-π-allylpalladium complex
In conclusion, we have developed a new procedure for the
alkyl-allylation of activated olefins via the three component
coupling reaction between activated olefins, Et3B and allylic
substrates in the presence of catalytic amounts of palladium. In
combination with our previously reported methodologies on the
activated olefins, this methodology provides a novel process
for the 1,2 bis-functionalization of activated C-C bonds.
3,15
analogue 7. The intermediate 8 might give the product 9 after
reductive removal of Pd(0); however, it may again revert back
to the intermediate 8 in the presence of Pd(0).16 The π-allylpal-
ladium complex 6 is well represented as the intermediate 10.
The reductive elimination of Pd(0) from 10 gives the desired
alkyl-allylation product 3a with the regeneration of Pd(0).
Acknowledgment. N.T.P. thanks the Japan Society for the
Promotion of Science (JSPS) for a postdoctoral research
fellowship.
(
14) (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813-5837. (b) Trost, B.
M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422. (c) Tsuji, J.
Transition Metal Reagents and Catalysts; Wiley: New York, 2000; Chapter
Supporting Information Available: Experimental details,
1
13
characterization data, H and C spectra NMR of all compounds
3a-j. This material is available free of charge via the Internet at
http://pubs.acs.org.
4
.
(
15) (a) Szabo, K. J. Chem. Eur. J. 2004, 10, 5268-5275.
(16) (a) Kamijo, S.; Jin, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001 123,
9
453-9454. (b) Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
1
1940-11945.
JO0524876
2
506 J. Org. Chem., Vol. 71, No. 6, 2006