Palladium-catalyzed three-component [3 + 2] cycloaddition of propargyl trifluoroacetates, ethylidene malononitriles, and allyltributylstannane

Article abstract of DOI:10.1021/ol9029275

A novel Pd(0)-catalyzed three-component [3 + 2] cycloaddition of propargyl trifluoroacetates 1, ethylidene malononitriles 2, and allyltributylstannane 3 afforded a variety of multiosubstituted cyclopentenes 4 in good to high yields under mild reaction con

Full text of DOI:10.1021/ol9029275

ORGANIC
LETTERS
2010
Vol. 12, No. 4
864-866
Palladium-Catalyzed Three-Component
[3 + 2] Cycloaddition of Propargyl
Trifluoroacetates, Ethylidene
Malononitriles, and Allyltributylstannane†
Shirong Lu,‡,§ Tienan Jin,*,‡ Ming Bao,§ and Yoshinori Yamamoto*,‡
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai
980-8578, Japan, WPI-AIMR (WPI-AdVanced Institute for Materials Research),
Tohoku UniVersity, Sendai 980-8577, Japan, and State Key Laboratory of Fine
Chemicals, Dalian UniVersity of Technology, Dalian 116012, China
tjin@mail.tains.tohoku.ac.jp; yoshi@mail.tains.tohoku.ac.jp
Received December 20, 2009
ABSTRACT
A novel Pd(0)-catalyzed three-component [3 + 2] cycloaddition of propargyl trifluoroacetates 1, ethylidene malononitriles 2, and
allyltributylstannane 3 afforded a variety of multisubstituted cyclopentenes 4 in good to high yields under mild reaction conditions.
Transition-metal-catalyzed [3 + 2] cycloaddition is regarded
as one of powerful strategies for the construction of the useful
five-membered carbocyles and heterocyles.1 Most recently,
the inter- and intramolecular cycloaddition of propargyl
compounds catalyzed by π-electrophilic transition metals,
such as gold and platinum, has been developed as an
attractive synthetic method.2 While propargylic derivatives
are useful substrates in the gold- and platinum-catalyzed
reactions, very few studies have been carried out on the
palladium-catalyzed cycloaddition reactions. The reaction of
hard nucleophiles such as alkyl magnesium or zinc reagents
with propargyl compounds in the presence of palladium
catalysts gives allenes.3 Tsuji explored an interesting pal-
ladium-catalyzed cycloaddition reaction of propargyl carbon-
ates with soft nucleophiles to give exo-methylenefurans
(Scheme 1).4a The reaction proceeds through the formation
of a palladium carbene complex that was isomerized to a
π-allylpalladium complex by intramolecular proton transfer.
Subsequent O-alkylation of carbonyl oxygen with π-allyl
complex gives a five-membered heterocycle. It occurred to
us that, by proper choice of nucleophiles (Nu) and electro-
philes (Ed1Nu), the three-component coupling reaction
between propargyl compounds, Nu-, and Ed1Nu should take
place in the presence of palladium catalysts (Scheme 1).
† This paper is dedicated to Professor Saverio Florio at the University
of Bari on the occasion of his 70th birthday.
‡ Tohoku University.
§ Dalian University of Technology.
(1) For recent reviews, see: (a) Schore, N. E. Chem. ReV. 1988, 88,
1081. (b) Welker, M. E. Chem. ReV. 1992, 92, 97. (c) Lautens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49. (d) Nakamura, I.; Yamamoto, Y.
Chem. ReV. 2004, 104, 2127. (e) Barluenga, J.; Santamar´ıa, J.; Toma´s, M.
Chem. ReV. 2004, 104, 2259. (f) Rubin, M.; Rubina, M.; Gevorgyan, V.
Chem. ReV. 2007, 107, 3117.
(3) (a) Jeffery-Juong, T.; Linstrumelle, G. Tetrahedron Lett. 1980, 21,
5019. (b) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer,
P. Tetrahedron Lett. 1981, 22, 1451. (c) Elsevier, C. J.; Stehouwer, P. M.;
Westmijze, H.; Vermeer, P. J. Org. Chem. 1983, 48, 1103.
(4) (a) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am. Chem.
Soc. 1985, 107, 2196. (b) Geng, L.; Lu, X. Tetrahedron Lett. 1990, 31,
111.
(2) For selected reviews, see: (a) Hashmi, A. S. K. Chem. ReV. 2007,
107, 3180. (b) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351. (c) Fu¨rstner, A.; Davis, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410. For a recent example, see: (d) Zhang, G.; Zhang, L. J. Am. Chem.
Soc. 2008, 130, 12598.
10.1021/ol9029275  2010 American Chemical Society
Published on Web 01/19/2010

showed higher reactivity compared to that of the trialky-
lphosphine ligand (PMe3) and bidentate phosphine ligand
(dppf) (entries 5-9). Propargyl mesylate (1b) was also
effective, whereas methyl propargyl carbonate (1c) and
propargyl bromide (1d) did not produce the corresponding
product 4a (entries 10-12). When allyltributylstannane 3
was added dropwise by syringe pump for 26 h, the yield of
4a increased up to 66% along with small amounts (∼5%)
of 5a (entry 13). We thought that the lower yield of 4a might
be due to the decomposition of 1a in the presence of a trace
amount of water. Thus, the reaction was carried out in the
presence of molecular sieves 4 Å, affording the correspond-
ing product 4a in 82% yield without formation of 5a (entry
14). The use of a lesser amount of PPh2(o-tol) (20 mol %)
gave 74% yield of 4a and 18% of 5a (entry 15). It is
noteworthy that the use of other nucleophiles, such as
allyltriphenylstannane, allyltrimethylsilane, and tetrabutyl-
stannane did not produce the corresponding cyclopentene
products, and 1a was always decomposed.
Scheme 1
.
Cycloaddition Reaction via Propargyl Compounds
Initiated Palladium Carbene Intermediate
Herein, we report a novel palladium(0)-catalyzed three-
component [3 + 2] cycloaddition of propargyl trifluoroac-
etates 1, ethylidene malononitriles 2, and allyltributyltin 3,
affording the highly substituted cyclopentenes 4 in good to
high yields under mild reaction conditions (Scheme 2).
Scheme 2. Pd(0)-Catalyzed Three-Component Cycloaddition of
Propargyl Trifluoroacetates, Ethylidene Malononitriles, and
Allyltributylstannane
Table 1. Screening of Reaction Conditions for the Formation of
Cyclopentenes 4aa
yield (%)b
Previously, we reported that the inter- and intramolecular
amphiphilic bisallylation of activated alkenes with bis-π-
allylpalladium, derived from allyltributylstannane-allylchlo-
ride-palladium catalyst, gave the corresponding 1,2-bisally-
lated alkanes and carbocycles efficiently.5 We further
investigated the Pd-catalyzed reaction with activated alkenes,
allyltributylstannane, and propargyl compounds instead of
allyl chlorides. The reaction of phenyl propargyl trifluoro-
acetate 1a (1 equiv), phenylethylidene malononitrile 2a (1.2
equiv), and allyltributylstannane 3 (1.2 equiv) in toluene was
carried out in the presence of Pd2(dba)3CHCl3 (10 mol %)
and PPh3 (40 mol %) under Ar atmosphere at room
temperature for 26 h. 1,2-Bisallylated alkanes 5a were
obtained in 27% yield as expected from the previous result,5,6
but the major product was 4-allyl-2,3-diphenyl-cyclopent-
3-ene-1,1-dicarbonitrile 4a (51% yield) (Table 1, entry 1).
Other palladium catalysts, such as Pd(PPh3)4, Pd(OAc)2, and
Pd(acac)2, gave lower yields of 4a (entries 2-4). Other
transition metal catalysts, such as Pt(PPh3)4 and Ni(cod)2,
were not effective. Triarylphosphine ligands, such as PPh2(o-
tol) (53%), P(o-tol)3 (46%), and P(1-naphthyl)3 (50%),
entry
Pd/L (20/40 mol %)
Pd2(dba)3CHCl3/PPh3
Pd(PPh3)4
Pd(OAc)2/PPh3
1
4a
51
5a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
27
28
27
28
27
28
32
0
46
38
38
53
46
50
0
Pd(acac)2/PPh3
Pd2(dba)3CHCl3/PPh2(o-Tol)
Pd2(dba)3CHCl3/P(o-Tol)3
Pd2(dba)3CHCl3/P(1-Naphthyl)3
Pd2(dba)3CHCl3/PMe3
Pd2(dba)3CHCl3/dppf
Pd2(dba)3CHCl3/PPh2(o-Tol)
Pd2(dba)3CHCl3/PPh2(o-Tol)
Pd2(dba)3CHCl3/PPh2(o-Tol)
Pd2(dba)3CHCl3/PPh2(o-Tol)
9
0
0
10
11
12
13c
14c,d
42
0
36
0
0
30
5
0
66
(82)
74
Pd2(dba)3CHCl3/PPh2(o-Tol)/MS 4 Å 1a
15c,d,e Pd2(dba)3CHCl3/PPh2(o-Tol)/MS 4 Å 1a
18
a To a mixture of Pd catalysts (20 mol %) and phosphine ligands (40
mol %) in toluene (0.5 mL, 0.4 M) were added propargyl acetate 1a (0.24
mmol), phenylethylidene malononitrile 2a (0.2 mmol), and allyltributyltin
3 (0.24 mmol), and the mixture was stirred at room temperature for 26 h.
b
1H NMR yield determined by using dichloroethane as an internal standard.
Isolated yield is shown in parentheses. c Allyltributyltin 3 was added by
syringe pump for 26 h. CH2Cl2 (1 mL, 0.2 M) was used as a solvent. d MS
4 Å (160 mg) was used. e 20 mol % of PPh2(o-tol) was used.
(5) (a) Nakamura, H.; Shim, J.-G.; Yamamoto, Y. J. Am. Chem. Soc.
1997, 119, 8113. (b) Nakamura, H.; Aoyagi, K.; Shim, J.-G.; Yamamoto,
Y. J. Am. Chem. Soc. 2001, 123, 372.
Various ethylidene malononitriles and propargyl trifluo-
roacetates were examined under the optimized reaction
conditions:7 10 mol % Pd2(dba)3CHCl3, 40 mol % PPh2(o-
tol), MS 4 Å, CH2Cl2 (0.2 M), and dropwise addition of 3
(6) It has been confirmed that the reaction between allyltributylstannane
and PdCl2(PPh3)2 produces bis-π-allylpalladium complex; see: Nakamura,
H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 6641. However,
5a is not formed in the present reaction conditions without propargyl
compounds.
Org. Lett., Vol. 12, No. 4, 2010
865

with syringe pump (Table 2). The reaction of phenyl
propargyl trifluoroacetate 1a and 2b-e, substituted with an
electron-donating and an electron-withdrawing aromatic
group at R2, produced the desired cyclopentenes 4b-e in
high yields (entries 1-4). The electronic characteristics of
an aromatic ring at R2 did not exert a significant influence
on the yield of 4. Not only the naphthyl-substituted alkene
2f but also a heteroaromatic ring such as 2-thiophenyl-
substituted alkene 2g afforded the corresponding cyclo-
pentenes 4f and 4g in good to high yields (entries 5 and 6).
The reaction of 1a with 2-(3-phenyl-allylidene)-malononitrile
2h gave the desired product 4h in 41% yield (entry 7). The
reaction of 1a with 2i and 2j bearing a cyclopropyl and bulky
cyclohexyl group at R2 gave the corresponding products 4i
and 4j in moderate yields (entries 8 and 9). The reaction of
2a with 1e or 1f bearing a 4-fluorophenyl or 2-thiophenyl
group at the alkynyl terminus gave the desired cyclopentenes
4k and 4l in 74% and 31% yields, respectively (entries 10
and 11). The reaction of 2a with 1g having an n-heptyl
substituent at R1 produced the corresponding cyclopentene
4m in good yield (entry 12).
sp carbon of the 1,2-propadienyl moiety to form the
palladium carbene complex B, which reacts with ethylidene
malononitrile 2a to give (σ-allyl)palladium complex C′. The
σ-allyl complex C′ is in equilibrium to (π-allyl)palladium
complex C, which undergoes intramolecular C-alkylation
with the stable carboanion to give the cyclopentene 4a.
Scheme 3. Plausible Reaction Mechanism
Table 2. Pd(0)-Catalyzed Three-Component Cycloaddition with
Various Propargyl Trifluoroacetates, Ethylidene Malononitriles,
and Allyltributylstannanea
In conclusion, we have developed a novel palladium-
catalyzed three-component [3 + 2] cycloaddition of prop-
argyl compounds, ethylidene malononitriles, and allyltribu-
tylstannane to give highly substituted cyclopenetenes under
mild reaction conditions. The reaction most probably pro-
ceeds through the intermolecular [3 + 2] cycloaddition
reaction between in situ generated palladium carbene com-
plex and activated alkene. Although various synthetic
methods for the formation of cyclopentene rings have been
reported,9 the present procedure provided an efficient and
new three-component cycloaddition method to access a
highly substituted cyclopentene ring. Further extension of
this method to the intramolecular version and application to
the synthesis of the biologically important multisubstituted
carbocycles and heterocycles are in progress.
time
(h)
yield
(%)b
entry
R1
Ph (1a)
R2
4
1
2
3
4
5
6
7
8
9
3-MeO-C6H4 (2b)
4-Cl-C6H4 (2c)
4-CN-C6H4 (2d)
4-NO2-C6H4 (2e)
2-naphthyl (2f)
2-thiophenyl (2g)
E-CHdCHPh (2h)
cyclopropyl (2i)
cyclohexyl (2j)
Ph (2a)
43
26
40
40
26
22
43
43
43
33
33
33
4b
4c
4d
4e
4f
4g
4h
4i
76
84
74
71
87
62
41
48
64
74
31
71
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-F-C6H4 (1e)
Acknowledgment. We thank the faculty members of the
Instrumental Analysis Center at Tohoku University for the
measurement of NMR and mass spectra.
4j
4k
4l
10
11
12
2-thiophenyl(1f) Ph (2a)
n-heptyl (1g) Ph (2a)
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
4m
a To a CH2Cl2 (1 mL, 0.2 M) solution of Pd2(dba)3CHCl3 (20 mol %),
PPh2(o-tol) (40 mol %), propargyl trifluoroacetates 1 (0.24 mmol), ethylidene
malononitriles 2 (0.2 mmol), and MS 4 Å (160 mg) was added allyltribu-
tylstannane 3 (0.24 mmol) by syringe pump at room temperature for the
time shown in the table. b Isolated yields.
OL9029275
(8) An alternative reaction mechanism is a [4 + 2] cycloaddition between
Pd-carbene and alkene to form a six-membered cyclic palladium species.
Subsequent reductive elimination gives the [3 + 2] cycloaddition product.
However, this pathway is less reasonable for the regioselective fromation
of the corresponding cyclopentene product.
(9) For selected examples for the formation of multisubstituted cyclo-
pentene, see: (a) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127,
4763–4776. (b) Trost, B. M.; Nanninga, T. N.; Satoh, T. J. Am. Chem.
Soc. 1985, 107, 721–723. (c) Feng, J.; Lu, X.; Kong, A.; Han, X.
Tetrahedron 2007, 63, 6035–6041. (d) Rhee, J. U.; Krische, M. J. Org.
Lett. 2005, 7, 2493–2495. (e) Barluenga, J.; Palomas, D.; Rubio, E.;
Gonza´lez, J. M. Org. Lett. 2007, 9, 2823–2826. (f) Jin, T.; Yang, F.; Liu,
C.; Yamamoto, Y. Chem Commun. 2009, 3533–3535.
A plausible reaction mechanism is shown in Scheme 3.8
Initially, the reaction of propargyl compound 1a with the
palladium catalyst forms 1,2-propadienylpalladium interme-
diate A. The nucleophile, allyltributylstannane 3, attacks the
(7) The reaction of other activated alkenes, such as 2-cyano-3-phenyl-
acrylic acid methyl ester or 3-cycanochromone, gave the corresponding
cyclopentene products in 20-30% yields under standard conditions.
866
Org. Lett., Vol. 12, No. 4, 2010