Cycloisomerization of 1,6-enynes using acetate as a nucleophile under palladium (II) catalysis

Article abstract of DOI:10.1021/jo048414o

(Chemical Equation Presented) An efficient method for the synthesis of five-membered carbo- and heterocyclic compounds, including fused rings, was reported using acetate as a nucleophile in the cyclization of 1,6-enynes under palladium(II) catalysis. The

Full text of DOI:10.1021/jo048414o

enynes; and (3) electrophilic attack of transition metal
complexes on the alkynes. On the other hand, it is well-
known that nucleophiles may attack alkynes coordinated
to high-valent transition metal complexes; however, this
has seldom been employed to initiate the enyne cycliza-
tion in known procedures.4 More significantly, reactions
catalyzed by high-valent transition metal complexes can
be run under air, and a further advantage of introducing
nucleophiles is the generation of molecules with ad-
ditional functional groups and increased versatility. We
have developed the palladium(II)-catalyzed synthesis of
γ-butyrolactones using acetate as a nucleophile previ-
ously.5 Here, we expand the synthetic scope of the latter
method to a number of carbo- and heterocyclic compounds
starting from electron-rich alkynes, and in addition, we
provide some mechanistic insight into these reactions.
Cycloisomerization of 1,6-Enynes Using
Acetate as a Nucleophile under
Palladium(II) Catalysis
Qinghai Zhang, Wei Xu, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@pub.sioc.ac.cn
Received September 8, 2004
To illustrate the feasibility of the acetoxypalladation-
initiated enyne couplings of electron-rich alkynes, we first
examined the intermolecular reaction of dimethyl 2-(2-
butynyl)malonate with allyl acetate in the presence of
Pd(OAc)2 (5 mol %) and 2,2′-bipyridine (bpy, 6 mol %) in
acetic acid at 60 °C (Scheme 1). The reaction proceeded
smoothly, but a regiochemical issue arose with this
nonsymmetrically substituted alkyne, for which a regio-
isomeric mixture of 1 and 2 was obtained in 63%
combined yield.6 The regioselectivity was not problematic
in the coupling reactions of electron-deficient alkynes.5c
Undoubtedly, it is required to direct the regioselectivity
of the addition of acetate to the electron-rich alkynes in
order to effect the intramolecular cyclization.
An efficient method for the synthesis of five-membered
carbo- and heterocyclic compounds, including fused rings,
was reported using acetate as a nucleophile in the cyclization
of 1,6-enynes under palladium(II) catalysis. The reaction is
initiated by trans-acetoxypalladation of the alkynes and
quenched by either trans- or cis-deacetoxypalladation in the
presence of 2,2′-bipyridine as the ligand. An example of the
catalytic asymmetric cyclization is presented with moderate
enantioselectivity using chiral bisoxazoline ligand.
In fact, only the five-membered cyclic compound 4a was
obtained in 82% yield when we conducted the cyclization
of (Z)-4-(dec-2′-yn-1′-oxy)-but-2-en-1-yl acetate (3a) under
similar conditions as shown in Scheme 1 (Table 1). No
cyclization occurred in the absence of the bpy ligand, and
adding extra nucleophile (sodium acetate, 1 equiv) had
no effect on either the cyclization rate or the yield. Other
representative results are summarized in Table 1. For
the oxygen-tethered substrates, the aryl alkyne was
equally as effective as the alkyl alkyne. The enyne 5 with
an (E)-olefin could also be cyclized smoothly, in sharp
contrast to the strict geometric demand (only (Z)-olefin)
for enyne esters.4c In addition, benzoate could replace
acetate as the leaving group, and this feature should be
useful in developing an asymmetric variant, presuming
that the allylic leaving group carrying a chiral auxiliary
group may induce diastereoselectivity. Introducing a
nitrogen atom (sulfonamide) or all carbon in the tether
was as effective as the oxygen tether. The stereochem-
istry of the exocyclic double bond was deduced by NOE
Ring structures abound in naturally occurring or
biologically active molecules, and how to construct those
respective ring systems is of substantial interest to
synthetic organic chemists. Although quite a variety of
cyclization methods have been reported to date, the
development of new catalytic systems is still valuable in
order to enhance synthetic utility and efficiency.1 Cur-
rently, transition metal-catalyzed carbocyclization of R,ω-
enynes represents one of the most powerful means to
construct cyclic compounds.2 In terms of carbocyclization,
the design of a catalytic protocol centers on the formation
of a carbon-metal bond and its subsequent transfor-
mations.2c In general, the majority of the existing ap-
proaches for enyne cyclization involve the initial forma-
tion of a vinyl transition metal intermediate. Accordingly,
the main cyclization procedures can be categorized ac-
cording to the pathway by which the vinyl transition
metal intermediate is formed:3 (1) insertion of alkynes
into the metal-H(R) species; (2) cyclometalation of
(1) For recent contributions, see: (a) Cadran, N.; Cariou, K.; Herve´,
G.; Aubert, C.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J.
Am. Chem. Soc. 2004, 126, 3408. (b) Lee, S. I.; Park, J. H.; Chung, Y.
K.; Lee, S.-G. J. Am. Chem. Soc. 2004, 126, 2714. (c) Mahandru, G.
M.; Skauge, A. R. L.; Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg,
M. J.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 13481.
(2) For reviews, see: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
Rev. 2002, 102, 813. (b) Trost, B. M.; Krische, M. J. Synlett 1998, 1.
(c) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev.
1996, 96, 635.
(4) For reviews, see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B.
Chem. Rev. 2001, 101, 2067. (b) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998,
115. (c) Lu, X.; Ma, S. New Age of Divalent Palladium Catalysts. In
Transition Metal Catalyzed Reaction; Murahashi, S.-I., Davies, S. G.,
Eds.; Blackwell Science: Oxford, UK, 1999; Chapter 6, p 133.
(5) (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (b) Lu,
X.; Zhang, Q. Pure Appl. Chem. 2001, 73, 247. (c) Zhang, Q.; Lu, X.;
Han, X. J. Org. Chem. 2001, 66, 7676.
(6) Ratio of compounds 1:2 (or 2:1) is calculated according to the
signal intensity of the NMR spectra of the mixture, which is insepa-
rable on the silica gel column chromatography, and we did not assign
the spectral signal specifically to 1 and 2.
(3) Ferna´ndez-Rivas, C.; Me´ndez, M.; Echavarren, A. M. J. Am.
Chem. Soc. 2000, 122, 1221 and references therein.
10.1021/jo048414o CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/26/2005
J. Org. Chem. 2005, 70, 1505-1507
1505

SCHEME 1
SCHEME 2
TABLE 1. Palladium(II)-Catalyzed Cyclization of
1,6-Enynesa
allylic
substrate
double time
product
X
R
Y
bond
(h)
(yield,b %)
3a
3b
3c
5
O
O
O
O
O
C7H15 OAc
Z
Z
Z
E
Z
Z
Z
Z
Z
12
12
20
11
24
4
40
48
48
4a (82)
4b (94)
4c (84)
4a (70)
4a (80)
8a (97)
8b (92)
10a (87)
10b (85)
CH3
Ph
OAc
OAc
antiperiplanar arrangement.9 The respective halide ions
serve both as nucleophile and ligand, and a large excess
of halide was required to ensure a stereoselective and
fast reaction.10 Given that the present acetoxypallada-
tion-initiated cyclization is quite different in terms of the
use of only catalytic amounts of nitrogen-containing
ligands and the lack of addition of extra nucleophiles
(acetate anions), we tried to understand whether the
stereochemistry of â-heteroatom elimination in the cur-
rent reaction system could also be different from that in
the halopalladation-initiated reactions.
Two diastereomeric substrates, cis- and trans-11, were
synthesized to probe the â-elimination stereochemistry.
Presumably, we could establish the elimination stereo-
chemistry by monitoring the two reactions (Scheme 3).
The only possible cis fusion of five- and six-membered
rings directs the olefin insertion into the vinyl palladium
intermediate. As outlined in Scheme 3, the arrangement
of the palladium atom and the acetoxy group will be syn
(intermediate IV) starting from cis-11 and anti (inter-
mediate V) from trans-11. Consequently, product 12
could be afforded by cis-deacetoxypalladation from in-
termediate IV or trans-deacetoxypalladation from inter-
mediate V. However, as a matter of fact, the same
product 12 was obtained starting from either trans-11
or cis-11 in a similarly high yield (89% from cis-11 and
88% from trans-11). The structure of 12 was further
confirmed by X-ray crystallography. These results indi-
cated that the â-acetoxy elimination is nonstereospecific,
occurring readily when the palladium atom and the
acetoxy group are in both syn and anti arrangements,
which differs from the halopalladation-initiated reactions
reported previously.9 The nonstereoselectivity of the
â-elimination in the current study might be attributed
to the coordination of the acetate carbonyl oxygen with
palladium in cis-11.11
C7H15 OAc
C7H15 OBz
6
7a NTs
7b NTs
9a C(CO2Me)2 CH3
9b C(CO2Et)2
a Reaction conditions: substrate (0.5 mmol), Pd(OAc)2 (5 mol
%), bpy (6 mol %) in HOAc (2.0 mL) at 80 °C. b Isolated yield.
CH3
C7H15 OAc
OAc
C7H15 OAc
OAc
experiments on the cyclization product 4b and 8a.7 It is
noteworthy that all the cyclizations are regiospecific and
highly stereoseletive, that is, only five-membered cycles
were obtained and the acetoxypalladation of alkynes
occurred in only the trans attacking mode. The limitation
of the current method is that substrates with terminal
alkynes cannot be used since no desired cyclization
products were obtained.
Pd(bpy)(OAc)28 might be the active catalytic species in
the reaction, which was supported by the fact that
preformed complex of Pd(bpy)(OAc)2 gave the same result
as the in situ-formed catalyst. The cylization was pro-
posed to follow a sequence of trans-acetoxypalladation of
the alkyne, olefinic migratory insertion into the newly
formed vinyl-palladium intermediate II, and the final
deacetoxypalldation as outlined in Scheme 2. Our previ-
ous study has shown that the nitrogen-containing ligand
is a key factor in the palladium(II)-mediated reactions
to promote the â-heteroatom elimination and inhibit the
common â-H elimination allowing the generation of the
catalytic Pd(II) species.5c
In our previous report in which halide was applied as
the nucleophile in the cyclization of enyne esters, the
stereochemistry of â-heteroatom (halide or acetoxy group)
elimination was exclusively trans, which demonstrated
that the palladium and the leaving group existed in an
(7) Ha and Hb has a NOE correlation in the 1H NMR experiment as
shown here.
On the basis of the above results, a preliminary
attempt was made to unravel the catalytic enantioselec-
tive cyclization. We could establish a moderate enantio-
selectivity (65% ee of 8a) for the cyclization of 7a using
(9) Zhu, G.; Lu, X. Organometallics 1995, 14, 4899.
(10) Ma, S.; Lu, X. J. Org. Chem. 1991, 56, 5120.
(11) Ba¨ckvall, J. E. Tetrahedron Lett. 1977, 467.
(8) Stephenson, T. A.; Morehouse, S. M.; Powell, A. R.; Heffer, J.
P.; Wilkinson, G. J. Chem. Soc. 1965, 3632.
1506 J. Org. Chem., Vol. 70, No. 4, 2005

SCHEME 3
ether (50 mL) was added. The mixture was washed with
saturated NaHCO3 solution (2 × 20 mL), and the aqueous phase
was extracted again with ether (30 mL). Then, the organic
solutions were washed with brine (20 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was submitted
to column chromatography on silica gel (petroleum ether/ethyl
acetate 8:1), affording the product 4a in 82% yield. Oil. IR
SCHEME 4
(neat): ν 3082, 2957, 2929, 2857, 1758, 1638, 1370, 1203 cm-1
.
1H NMR (300 MHz, CDCl3): δ 5.86-5.77 (m, 1H), 5.17 (dd, J )
17.0, 1.0 Hz, 1H), 5.10 (d, J ) 10.1 Hz, 1H), 4.29 (dd, J ) 13.1,
1.0 Hz, 1H), 4.22 (d, J ) 13.1 Hz, 1H), 3.98 (dd, J ) 8.6, 6.6 Hz,
1H), 3.72 (dd, J ) 8.6, 4.0 Hz, 1H), 3.44-3.37 (m, 1H), 2.24 (t,
J ) 7.6 Hz, 2H), 2.12 (s, 3H), 1.40-1.26 (m, 10H), 0.88 (t, J )
6.8 Hz, 3H). MS (m/z): 266 (M+), 223(100), 151, 136, 123, 109,
95, 57, 43. Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found
C, 71.71; H, 9.44. Characterization data for other products in
Table 1 were shown in Supporting Information.
Cyclization of cis-11 or trans-11. Procedure similar to that
above gave product 12 as a solid. IR (neat): ν 2954, 1751, 1736,
1436, 1231, 1064 cm-1. 1H NMR (300 MHz CDCl3): δ 5.83-5.81
(m, 2H), 3.73 (d, J ) 5.8 Hz, 6H), 3.41-3.39 (m, 1H), 3.05 (d, J
) 6.8 Hz, 1H), 2.92 (dd, J ) 5.1, 12.5 Hz, 1H), 2.69 (d, J ) 7.0
Hz, 1H), 2.11 (s, 3H), 2.05-2.01 (m, 2H), 1.88 (s, 3H), 1.75-
1.11 (m, 2H). MS (m/z): 291 (M+ - MeO-), 281, 249, 202 (100),
161, 143, 135, 117, 43. HRMS: calcd for C17H22O6 322.1416,
found 322.1399.
Palladium(II)-Catalyzed Enantioselective Cyclization
of 7a. In a manner similar to that described for the palladium-
(II)-catalyzed cyclization of enynes, the reaction of 7a (0.5 mmol)
was carried out in the presence of 5 mol % Pd(OAc)2 and 10 mol
% bis-oxazoline chiral ligand 13 in HOAc (5 mL) at 60 °C to
afford the product 8a. The ee value of 8a was determined by
chiral HPLC using the chiralcel OD column eluting with hexane/
2-propanol (100:1) (λ ) 214 nm).
the bisoxazoline ligand 13 (Scheme 4).12 Further optimi-
zation of the catalytic enantioselectivity is currently being
scrutinized in our laboratory.
In summary, the acetoxypalladation-initiated cycliza-
tion of 1,6-enynes provides an efficient method to syn-
thesize functionalized five-membered carbo- and hetero-
cyclic compounds. The reaction proceeds in an acetoxy-
palladation-insertion-â-acetoxy elimination sequence to
recycle catalytic palladium(II) species. Using the two
designed diastereomers 11 as substrates for the cycliza-
tion, we could determine that the â-acetoxy elimination
was nonstereoselective in this reaction. Using chiral
bidentate nitrogen-containing ligands, this reaction also
opens up a way to its catalytic asymmetric version, as
illustrated by our preliminary result.13
Experimental Section
General Procedure for the Palladium(II)-Catalyzed
Cyclization of 1,6-Enynes. To a solution of Pd(OAc)2 (6 mg,
0.027 mmol) and 2,2′-bipyridine (5 mg, 0.032 mmol) in HOAc (2
mL) at 80 °C was added 3a (0.5 mmol) with stirring. The reaction
was monitored by TLC. After the reaction was complete, ethyl
Acknowledgment. This work was funded by
The Major State Basic Research Program (Grant
G2000077502-A). We thank the National Natural Sci-
ences Foundation of China and Chinese Academy of
Sciences for the financial support.
(12) Ee of 8a was determined by chiral HPLC using the Chiralcel
AD column eluting with 9:1 hexane/2-propanol (λ ) 214 nm). Absolute
stereochemistry of the chiral center in product 8a has not been
determined.
(13) For recent contributions to enantioselective enyne cyclizations,
see: (a) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704.
(b) Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Org. Lett. 2003, 5, 157.
(c) Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem., Int. Ed.
2002, 41, 4526. (d) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000,
39, 4104.
Supporting Information Available: Experimental pro-
1
cedure and characterization data, copies of H NMR spectra
of new compounds, and X-ray crystallography of 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048414O
J. Org. Chem, Vol. 70, No. 4, 2005 1507