Mild and Efficient Synthesis of (Z)-α-Chloroalkylidene-β- lactones via the PdCl2-Catalyzed Cyclocarbonylation of 2-Alkynols

Article abstract of DOI:10.1021/ol0357245

(Equation presented) A mild and efficient methodology involving PdCl ₂-catalyzed cyclocarbonylation of 2-alkynols with CuCI2 for the synthesis of (2)-α-chloroalkylidene-β-lactones was developed. Using the readily available optically active propargylic alcohols allows convenient synthesis of the corresponding (Z)-α-chloroalkylidene-β-lactones with high ee values. cis-Chloropalladation was observed as the major pathway, which is unique as compared to the reported data.

Full text of DOI:10.1021/ol0357245

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4429-4432
Mild and Efficient Synthesis of
(Z)-r-Chloroalkylidene-â-lactones via the
PdCl2-Catalyzed Cyclocarbonylation of
2-Alkynols
Shengming Ma,* Bin Wu, and Shimin Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
Received September 9, 2003
ABSTRACT
A mild and efficient methodology involving PdCl2-catalyzed cyclocarbonylation of 2-alkynols with CuCl2 for the synthesis of (Z)-r-chloroalkylidene-
â-lactones was developed. Using the readily available optically active propargylic alcohols allows convenient synthesis of the corresponding
(Z)-r-chloroalkylidene-â-lactones with high ee values. cis-Chloropalladation was observed as the major pathway, which is unique as compared
to the reported data.
Propargylic alcohols are readily available compounds of
synthetic importance.1,2 Of particular interest is the transition
Scheme 1
metal-mediated or -catalyzed carboxylation reaction. Rosenthal
et al. reported that the transition metal-catalyzed or -mediated
reaction of 2-propynol afforded R-hydroxy (or methoxyl)
methyl acrylates together with several other acrylate deriva-
tives.3,4 For the cyclizative carboxylation reaction of prop-
argylic alcohols, three types of reaction patterns affording
butenolides, R-alkylidene-â-lactones, or R,â-unsaturated
enals, respectively, have been demonstrated (Scheme 1).5-11
(1) (a) Schubert, T.; Hummel, W.; Mu¨ller, M. Angew. Chem., Int. Ed.
2002, 41, 634. (b) Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.;
Reider, P. J. Angew. Chem., Int. Ed. 1999, 38, 711. (c) Cassel, J. A.; Leue,
S.; Gachkova, N. I.; Kann, N. C. J. Org. Chem. 2002, 67, 9460.
(2) (a) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. J. Am. Chem. Soc. 2002,
124, 4218. (b) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2002,
124, 8188. (c) Blandino, M.; McNelis, E. Org. Lett. 2002, 4, 3387. (d)
McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979. (e) Grotjahn, D. B.;
Van, S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout, M.; Meyer, C.;
Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200.
(3) Rosenthal, R. W.; Schwartzman, L. H.; Greco, N. P.; Proper, R. J.
Org. Chem. 1963, 28, 2835.
Usually, â-lactones were formed from terminal propargylic
alcohols, with the selectivity and the yield depending largely
9-11
on the structures of the alcohols.
(4) Nogi, T.; Tsuji, J. Tetrahedron 1969, 25, 4099.
(5) Van den Hoven, B. G.; Ali, B. E.; Alper, H. J. Org. Chem. 2000,
65, 4131.
(6) Fukuta, Y.; Matsuda, I.; Itoh, K. Tetrahedron Lett. 2001, 42, 1301.
(7) Larock, R. C.; Riefling, B.; Fellows, C. A. J. Org. Chem. 1978, 43,
131.
10.1021/ol0357245 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/17/2003

R-Alkylidene-â-lactones are important skeletons in some
biologically active natural products12 and considered as useful
building blocks in organic synthesis.13 Besides the methods
described above, R-alkylidene-â-lactones have also been
prepared via [2 + 2] cycloaddition of ketenes and carbonyl
compounds,14 lactonization of â-hydroxy carboxylic acids
or derivatives,15 and deoxygenation of â-peroxylactones.16
However, these known pioneering methods may, in some
cases, suffer from lengthy procedures, harsh conditions, or
low yields. Thus, new and efficient methodologies for
R-alkylidene-â-lactones are still desirable. In this paper, we
report a general and high-yielding Pd-catalyzed carbonylation
of propargylic alcohols with various structural patterns
forming (Z)-R-chloroalkylidene-â-lactones selectively.
Our initial observation of achieving (Z)-R-chloroalky-
lidene-â-lactone 2a involved the reaction of 1a, 3 equiv of
CuCl2, and CO (1 atm) with PdCl2 as the catalyst at 20 °C
in PhH, but the yield was only 29% (entry 1, Table 1). With
and error, we found that the solvent, CO pressure, and
temperature are crucial factors, and the best reaction condi-
tions are 10 mol % PdCl2, 5 equiv of CuCl2, and CO (20
atm) in THF at 30 °C for 4 h. Under these reaction
conditions, (Z)-2a was isolated in 86% yield (entry 3, Table
1).
To explore the scope of this reaction, the effect of
substituents R1 and R2 was investigated. As can be seen from
Table 2, R1 can be an alkyl group or an aryl group, including
Table 2. PdCl2-Catalyzed Cyclocarbonylation of Secondary
Propargylic Alcohols with 5 Equiv of CuCl2
entry
R1
R2
C2H5
n-C4H9
n-C4H9
Me
n-C3H7
n-C5H11
i-Pr
product isolated yield (%)
1
2
3
4
5
6a
7
8
9
10
11a
12
13a
14
15a
16a
n-C6H13
n-C5H11
n-C3H7
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
t-Bu
(Z)-2a
(Z)-2b
(Z)-2c
(Z)-2d
(Z)-2e
(Z)-2f
(Z)-2g
(Z)-2h
(Z)-2i
(Z)-2j
(Z)-2k
(Z)-2l
(Z)-2m
(Z)-2n
(Z)-2o
(Z)-2p
86
76
74
64
72
67
71
90
82
89
91
81
78
66
52
63
Table 1. PdCl2-Catalyzed Cyclocarbonylation of
Undec-4-yn-3-ol 1a with CuCl2
i-Bu
cyclohexyl
n-C4H9
i-Pr
i-Bu
cyclohexyl
CO
CuCl2
temp
(°C)
time
(h)
yielda
(%)
entry
(atm)
(equiv)
solvent
Ph
Ph
Ph
1
2
3
4
1
15
20
20
3
3
5
5
PhH
THF
THF
THF
20
25
30
70
18
17
4
29
35
86
31
PhCH2CH2 i-Pr
PhCH2CH2 i-Bu
PhCH2CH2 cyclohexyl
4
a Isolated yield.
a Reaction time was 6 h.
the pressure of CO being 15 atm, the yield was not
dramatically improved (entries 2, Table 1). After some trial
tBu, while the R2 group should be an alkyl group. The four-
membered structures of (Z)-2 were established by a single-
crystal X-ray diffractional study of (Z)-2k17 and (Z)-2n18
(Figure 1). When R2 was an aryl group, the corresponding
carbonylation of 1-(4′-methoxyphenyl)hept-2-yn-1-ol gave
only a complex mixture. The cyclocarbonylation of tertary
alcohol 2-methyloct-3-yn-2-ol 1q also gave (Z)-R-chloro-
alkylidene â-lactone (Z)-2q in 50% yield (eq 1).
(8) Buchwald, S. L.; Fang, Q.; King, S. M. Tetrahedron Lett. 1988, 29,
3445.
(9) Consorti, C. S.; Ebeling, G.; Dupont, J. Tetrahedron Lett. 2002, 43,
753.
(10) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli, G. P.
J. Chem. Soc., Perkin Trans. 1 1997, 147.
(11) Matsuda, I.; Ogiso, A.; Sato, S. J. Am. Chem. Soc. 1990, 112, 6120.
(12) (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Phytochem-
istry 1981, 20, 1069. (b) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson,
H. Phytochemistry 1983, 22, 2860. (c) Bohlmann, F.; Paul, A. H. K.
Tetrahedron Lett. 1984, 25, 1697.
(13) (a) Adam, W.; Albert, R.; Hasemann, L.; Nava Salgado, V. O.;
Nestler, B.; Peters, E.-M.; Peters, K.; Prechtl, F.; von Schnering, H. G. J.
Org. Chem. 1991, 56, 5782. (b) Danheiser, R. L.; Choi, Y. M.; Men-
ichincheri, M.; Stoner, E. J. J. Org. Chem. 1993, 58, 322. (c) Martinez, I.;
Andrews, A. E.; Emch, J. D.; Ndakala, A. J.; Wang, J.; Howell, A. R. Org.
Lett. 2003, 5, 399. (d) For a review, see: Pommier, A.; Pons, J.-M. Synthesis
1993, 441.
(14) (a) Adam, W.; Nava Salgado, V. O.; Peters, E.-M.; Peters, K.; von
Schnering, H. G. Chem. Ber. 1993, 126, 1481. (b) Payne, G. B. J. Org.
Chem. 1966, 31, 718. (c) Baxter, G. J.; Brown, R. F. C.; Eastwood, F. W.;
Gatehouse, B. M.; Nesbit, M. C. Aust. J. Chem. 1978, 31, 1757. (d) Ben
Cheikh, A.; Pommelet, J.-C.; Chuche, J. J. Chem. Soc., Chem. Commun.
1990, 615. (e) Masters, A. P.; Sorensen, T. S. Tetrahedron Lett. 1989, 30,
5869.
A detailed study showed that some amounts of (E)-R-
chloroalkylidene-â-lactone (E)-2a and butenolide 3a were
also formed, which were difficult to purify (Figure 2).
(16) (a) Adam, W.; Albert, R.; Dachs Grau, N.; Hasemann, L.; Nestler,
B.; Peters, E.-M.; Peters, K.; Prechtl, F.; von Schnering, H. G. J. Org. Chem.
1991, 56, 5778. (b) Adam, W.; Hasemann, L.; Prechtl, F. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1536.
(15) (a) Zhang, C.; Lu, X. Synthesis 1996, 586. (b) Bartels, A.; Jones,
P. G.; Liebscher, J. Synthesis 1998, 1645.
4430
Org. Lett., Vol. 5, No. 23, 2003

Table 3. Synthesis of Optically Active
(Z)-R-Chloroalkylidene-â-lactones
(S)-1a
(S)-(Z)-2
entry
R1
R2
% ee
yieldb (%), ee (%)c
1d
2
Ph
Ph
Ph
i-Pr
i-Bu
cyclohexyl
i-Pr
i-Bu
>91
>83
96
97
95
89 (S)-(Z)-2k , 92
63 (S)-(Z)-2l, 85
83 (S)-(Z)-2m , 96
68 (S)-(Z)-2n , 97
64 (S)-(Z)-2o, 92
63 (S)-(Z)-2p , 98
3d
4
5
6
PhCH2CH2
PhCH2CH2
PhCH2CH2
cyclohexyl
98
a Absolute stereochemistry was established by comparison with the
literature data.19b Enantiomeric excess was determined by HPLC on a
chiralcel OD column. b Isolated yield. c Enantiomeric excess was determined
by HPLC on a chiralcel OD-H or AS column. d Reaction time was 6 h.
complex 6, which was followed by reductive elimination to
afford the major product (Z)-2. PdCl2 was regenerated by
Scheme 2
Figure 1.
In addition, the results for the cyclocarbonylation of the
optically active secondary propargylic alcohols19 are sum-
marized in Table 3. From Table 3, it can be seen that
racemization of the chiral center in 1 was not observed. The
yields range from 63 to 89%.
A plausible mechanism is shown in Scheme 2. The
coordination of the triple bond of 1 with PdCl2 gave complex
4, which was followed by cis-chloropalladation to give 5.
The subsequent coordination and insertion of CO gave
the oxidation reaction of the in situ-generated Pd(0) with
CuCl2. It is interesting to note that here, even with a
nonterminal C-C triple bond, cis-halometalation is the major
pathway.20
(17) Crystal data for compound 2k: C13H13O2Cl, MW ) 236.68,
monoclinic, space group P2(1)/n, Mo KR, final R indices [I > 2σ(I)], R1
) 0.0502, wR2 ) 0.0963, a ) 9.8786 (13) Å, b ) 18.626 (2) Å, c )
13.5620 (17) Å, R ) 90°, â ) 101.777 (3)°, γ ) 90°, V ) 2442.9 (5) Å3,
T ) 293 (2) K, Z ) 8, reflections collected/unique: 14691/5663 (Rint
0.0761), no observation [I > 2σ(I)] 2497, parameters 393.
)
(18) Crystal data for compound 2n: C15H17O2Cl, MW ) 264.74,
monoclinic, space group C2/c, Mo KR, final R indices [I > 2σ(I)], R1 )
0.0613, wR2 ) 0.1314, a ) 30.575 (4) Å, b ) 6.3076 (9) Å, c ) 16.685
(2) Å, R ) 90°, â ) 115.390 (3)°, γ ) 90°, V ) 2907.0 (7) Å3, T ) 293
(2) K, Z ) 8, reflections collected/unique: 7296/2712 (Rint ) 0.1504), no
observation [I > 2σ(I)] 1514, parameters 212.
(19) (a) For a recent review on the synthesis of optically active
propargylic alcohols, see: Ma, S.; He, Q. Chin. J. Org. Chem. 2002, 6,
375. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806.
Figure 2.
Org. Lett., Vol. 5, No. 23, 2003
4431

In conclusion, (1) we have developed a mild, good-
yielding, and efficient methodology for the synthesis of (Z)-
R-chloroalkylidene-â-lactones; (2) using the readily available
chiral propargylic alcohols allows synthesis of the corre-
sponding (Z)-R-chloroalkylidene-â-lactones with high ee
values; (3) and cis-chloropalladation was observed as the
major reaction pathway. Further studies in this area are being
pursued in our laboratory.
State Basic Research Development Program (Grant No.
G2000077500) is greatly appreciated. Shengming Ma is the
recipient of a 1999 Qiu Shi Award for Young Scientific
Workers issued by Hong Kong Qiu Shi Foundation of
Science and Technology (1999-2003).
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products, including
CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the National
Natural Science Foundation of China and the Major
(20) (a) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (b) Li, J.; Jiang,
H.; Feng, A.; Jia, L. J. Org. Chem. 1999, 64, 5984. (c) Huang, X.; Sun, A.
J. Org. Chem. 2000, 65, 6561.
OL0357245
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