Palladium-catalyzed allylation of alkynes with allyl alcohol in aqueous media: Highly regio- and stereoselective synthesis of 1,4-dienes

Article abstract of DOI:10.1002/anie.200503970

(Chemical Equation Presented) The direct approach: The unprecedented result of the title reaction (see scheme) is explained by a mechanism involving competition between π-allylpalladation through cleavage of the C-O bond and the insertion of an alkene. Th

Full text of DOI:10.1002/anie.200503970

Angewandte
Chemie
Reaction Mechanisms
DOI: 10.1002/anie.200503970
Palladium-Catalyzed Allylation of Alkynes with
Allyl Alcohol in Aqueous Media: Highly Regio-
and Stereoselective Synthesis of 1,4-Dienes**
Jingmei Huang, Lei Zhou, and Huanfeng Jiang*
Carbometalation of carbon–carbon multiple bonds is an
important process in organometallic chemistry from both
theoretical and practical standpoints.[1] In particular, the
allylmetalation of alkynes to form 1,4-dienes is an area of
growing interest during recent years.[2] However, although
allyl alcohols are readily available, they have rarely been
employed directly as allylating agents. The transition-metal-
catalyzed alkyne/allyl alcohol reaction usually affords b,g- or
g,d-unsaturated carbonyl compounds,[3] or hydroalkoxylation
products.[4] Thus, it is clear that the scope and synthetic
applications of alkyne allylation would be greatly enhanced if
methods permitting the direct use of alcohols were developed.
Organic reactions in water have recently attracted much
attention, not only because of the unique reactivity observed,
but also because water is a safe and economical substitute for
conventional organic solvents.[5] Thus, the development of
atom-economical reactions in water is one of the most
important goals of synthetic chemistry. Herein we disclose
that PdCl2 catalyzes the allylation of alkynes with allyl alcohol
highly selectively aqueous media with exclusive formation of
1,4-dienes in, and we attribute this finding to a novel catalytic
cycle.[6]
In our studies on the allylation of alkynes with allyl
alcohol we found that the reaction of prop-1-ynylbenzene
with an excess of allyl alcohol (10 equiv) as the solvent in the
presence of PdCl2 (5%mol), CuCl2·2H2O (2mmol), and
HOAc (2mmol) afforded 1,4-diene products 1b and 1c in
63% yield with a low regioselectivity (63:37, Scheme 1). To
our surprise, no trace of aldehyde was detected. A compara-
tive reaction with CuCl2 instead of CuCl2·2H2O gave 1,4-
diene products in a much lower yield. Further studies on
[*] Dr. J. Huang, L. Zhou, Prof. Dr. H. Jiang
The College ofChemistry
South China University ofTechnology
Guangzhou 510640 (P.R. China)
Fax: (+86)20-8711-2906
E-mail: jianghf@scut.edu.cn
L. Zhou
Guangzhou Institute ofChemistry
Chinese Academy ofSciences
PO Box 1122, Guangzhou 510650 (P.R. China)
and
Graduate School ofthe Chinese Academy ofSciences
Beijing 100039 (P.R. China)
[**] We are grateful to the National Natural Science Foundation of China
for financial support (Grants: 20172053, 20332030, and 20572027).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 1945 –1949
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1945

Communications
optimizing the reaction conditions revealed that changing the
solvent to an aqueous mixture (HOAc:H2O, 1:1) afforded a
single regioisomer 1b, the yield of which was increased
sharply to 87%.
A range of substrates was explored in the reaction and the
results are summarized in Table 1. In most cases, the allylation
reactions proceeded smoothly and gave the desired 1,4-dienes
in good to excellent yield with extremely high selectivity. It is
noteworthy that the terminal acetylenes (entries 4, 5, 10, and
11) gave cotrimerization products from the reaction of two
Scheme 1. Comparison ofthe yield and selectivity ofthe allylation
reaction in different solvents.
Table 1: PdCl2-catalyzed allylation ofalkynes.
Entry
R1
R2
t [h]
Solvent[a]
Product[b]
Yield[c] [%]
1
2
Ph
Ph
Me
Me
12
12
allyl alcohol[d]
HOAc/H2O
1:1
1b/1c 63:37
1b/1c 99:1
63
87
HOAc/H2O
1:1
3
4
CH2Cl
H
CH2Cl
CH2Cl
6
3b
4d
91
59
HOAc/H2O
1:1
12
HOAc/H2O
1:1
5
6
7
H
CO2C2H5
COOH
12
24
12
5d
6b
7b
52
73
92
HOAc/H2O
1:1
CH3
HOAc:H2O
1:1
CO2C2H5
CO2C2H5
HOAc/H2O
1:1
8
n-C3H7
n-C3H7
12
8b
71[e]
HOAc/H2O
1:1
9
Ph
H
H
12
10
9b
74
85
HOAc/H2O
1:1
10
n-C6H13
10d
HOAc/H2O
1:1
11
12
tBu
H
14
30
11d
12b
16
53
THF/H2O[f]
5:1
Ph
Ph
[a] Standard conditions: alkyne (1 mmol), allyl alcohol (3 mmol), CuCl2·2H2O (2 mmol), HOAc (1 mL), and H2O (1 mL), with stirring at RT. [b] The
configuration was determined by 1H NMR and 13C NMR spectroscopy as well as by NOE studies. [c] Yield ofisolated product. [d] HOAc (2 mmol) and
allyl alcohol (10 equiv) as solvent. [e] A mixture of 8b/8d (71:29) was obtained. [f] HOAc (2 mmol), allyl alcohol (3 equiv), THF (1 mL), and H2O
(0.2 mL) as solvent.
1946 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1945 –1949

Angewandte
Chemie
acetylenes and one allyl alcohol. Of special interest is the
substrate but-2-ynoic acid (entry 6), which resulted in the
introduction of a carboxylic acid moiety directly into the 1,4-
diene without the need for functional group protection/
deprotection. The low yield of 11d arose from the dimeriza-
tion of the terminal alkynes to form 1,4-dihalo-1,3-dienes. In
terms of the stereoselectivity, all the products obtained in the
presence of an excess of halide ion and acetic acid in a polar
solvent resulted from trans addition.[7,8] The site of halogen
addition to asymmetric acetylenes (entries 1, 2, 4–6, 9–11) was
controlled by electronic factors.[8] The consistent preference
observed in terms of regio- and stereoselectivity suggests that
the reaction might proceed by the initial formation of a
vinylpalladium intermediate followed by trans-chloropalla-
dation of the alkynes.[7b,9,10]
Scheme 2. Mechanistic study ofthe allylation reaction between crotyl
alcohol and 1-butyn-3-ol.
The exclusive formation of 1,4-dienes in excellent yield
prompted us to study the mechanistic aspects of the trans-
formation of allyl alcohol in this reaction. To this end, allyl
alcohol was treated with PdCl2/CuCl2·2H2O in the presence of
HOAc/H2O at RT without adding
in Scheme 3. Vinylpalladium intermediate A is initially
formed by trans-chloropalladation of the alkyne in a polar
solvent system[8,13] in the presence of excess halide ions.[14]
any acetylene substrate. No allyl
chloride was detected by GC-MS
and 1H NMR spectroscopic analysis.
Hence, the possibility of an allyl
chloride
intermediate
being
involved was clearly ruled out. To
our surprise, diallyl ether was
observed in the reaction mixture.[11]
This result indicated that the reac-
tion proceeded with cleavage of the
À
C O bond of allyl alcohol to form a
vinylpalladium intermediate, fol-
lowed by the attack of another
equivalent of allyl accohol.[5a,12]
Crotyl alcohol (13a) and its
regioisomer 1-buten-3-ol (13b)
were employed as the allylic alcohol
sources in further studies. Allylation
of 13a and 13b with 1,4-dichloro-2-
butyne (3a) in the presence of
PdCl2/CuCl2 in aqueous media
(HOAc:H2O, 1:1) gave isomeric
1,4-dienes (13c and 13d, respec-
Scheme 3. Mechanistic hypothesis for the palladium-catalyzed allylation of alkynes.
tively) in moderate yields in both cases (Scheme 2). However,
the ratio 13c/13d observed from alcohol 13a and 13b is
different, thus suggesting that a reaction pathway other than
p-allylpalladation might also be involved.
This is followed by a competing reaction between the
insertion of crotyl alcohol (path a) and the formation of a
p-allylpalladium[15] species in situ by the cleavage of a C O
À
bond with the aid of acid in water (path b).[5a] The produced
intermediates D (favored) and E in path b subsequently
undergo b-halogen elimination to produce 13c and 13d and
regenerate PdCl2 in the presence of CuCl2.[16] Meanwhile, the
alcohol F produced in path a undergoes b-OH elimination to
produce 13d and regenerate the catalytic PdII species in the
presence of CuCl2. Hence, since 13cis the major product from
both path a and path b, it is rational that 13c was obtained in
90% yield when 1-buten-3-ol (13b) was employed in the
PdCl2/CuCl2 reaction system. When LiCl was used, the
reaction proceeded only minimally by path b, with b-OH
elimination to form 13d. Therefore, CuII ions are essential to
promote the reaction by path b.
The ratio 13c/13d changed sharply when CuCl2 was
replaced by LiCl in the above reaction system: a branched
chain product 13dwas obtained predominantly when 13awas
used, while the major isomer was the straight-chain product
13c when 13b was used. These results suggested that the
reaction with LiCl might proceed through a pathway involv-
ing a direct insertion of the allylic alcohol into the vinyl-
palladium intermediate. Hence, on the basis of the above
observation, we hypothesize that CuCl2 may work as a
promoter for the formation of a p-allylpalladium species.
A plausible mechanism for the allylation of alkynes in
aqueous media (HOAc/H2O, 1:1) catalyzed by PdCl2 is shown
Angew. Chem. Int. Ed. 2006, 45, 1945 –1949
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1947

Communications
1995, p. 159; e) P. Knochel in Comprehensive Organic Synthesis,
Vol. 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
p. 865; f) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207;
g) E. Negishi, D. Y. Kondakov, Chem. Rev. 1996, 96, 417; h) I.
Marek, J. F. Normant in Metal Catalyzed Cross-Coupling
Reactions (Eds.: F. Diederich, P. Stang), Wiley-VCH, New
York, 1998, p. 271.
The terminal alkynes, a group of more-reactive substrates,
were prone to undergo an additional alkyne insertion
reaction.[17] Under our reaction conditions, intermediate A’
underwent a consecutive trans addition of one more molecule
of alkyne to afford a new halopalladium intermediate G
(Scheme 4). It is noted that an additional alkyne insertion did
[2] a) D. A. Singleton, S. C. Waller, Z. Zang, D. E. Frantz, S.-W.
Leung, J. Am. Chem. Soc. 1996, 118, 9986; b) E. Negishi, J. A.
Miller, J. Am. Chem. Soc. 1983, 105, 6761; c) J. J. Eishi, M. P.
Bokslawski, J. Organomet. Chem. 1987, 334, C1; d) S. H. Yeon,
J. S. Han, E. Hong, Y. Do, I. N. Jung, J. Organomet. Chem. 1995,
494, 159; e) N. Chatani, N. Amishiro, T. Morri, T. Yamashita, S.
Murai, J. Org. Chem. 1995, 60, 1834; f) N. Fujiwara, Y.
Yamamoto, J. Org. Chem. 1997, 62, 2318; g) E. Shirakawa, H.
Yoshida, Y. Nakao, T. Hiyama, Org. Lett. 2000, 2, 2209; h) Y.
Matsukawa, A. Asao, H. Kitahara, Y. Yamamoto, Tetrahedron
1999, 55, 3779; i) E. Yoshikawa, V. Gevorgyan, N. Asao, Y.
Yamamoto, J. Am. Chem. Soc. 1997, 119, 6781; j) S. Shin, T. V.
RajanBabu, J. Am. Chem. Soc. 2001, 123, 8416; k) M. Katsukiyo,
F. Naoki, H. Akira, J. Org. Chem. 2004, 69, 2427.
[3] a) B. M. Trost, J. A. Martinez, R. J. Kulaweic, A. F. Indolese, J.
Am. Chem. Soc. 1993, 115, 10402; b) S. Deꢀrien, P. H. Dixneuf, J.
Chem. Soc. Chem. Commun. 1994, 255; c) S. Deꢀrien, D. Jan,
P. H. Dixneuf, Tetrahedron 1996, 52, 5511; d) B. M. Trost, A.
Indolese, J. Am. Chem. Soc. 1993, 115, 4361; e) B. M. Trost, R. J.
Kulawiec, J. Am. Chem. Soc. 1992, 114, 5579; f) X. Lu, G. Zhu,
Organometalics 1995, 14, 4899.
Scheme 4. Additional alkyne insertion.
not occur with the terminal alkyne 9a, where R1 is an
aromatic ring (Table 1, entry 9). This result might be a
consequence of the coordination of the aromatic ring adjacent
to the Pd moiety of the vinylpalladium intermediate A’, thus
stabilizing the vinylpalladium intermediate A’ in the catalytic
cycle. This stabilization may inhibit further insertion of
another molecule of alkyne.[17d]
In conclusion, mild conditions have been developed for
the allylation of alkynes by the direct use of allyl alcohol as
the allylating agent in aqueous media. A mechanism based on
the competition between p-allylpalladation through cleavage
[4] C. Gemel, G. Trimmel, C. Slugovc, S. Kremel, K. Mereiter, R.
Schmid, K. Kirchner, Organometalics 1996,15, 3998.
À
of the C O bond and the insertion of an alkene was employed
[5] a) K. Manabe, S. Kobayashi, Org. Lett. 2003, 52, 3241;
b) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie
Academic and Professional, London, 1998; c) C.-J. Li, T.-H.
Chan, Organic Reactions in Aqueous Media, Wiley, New York,
1997; d) U. M. Lindström, Chem. Rev. 2002, 102, 2 751; e) K.
Manabe, S. Kobayashi, Chem. Eur. J. 2002, 8, 4095.
[6] For palladium-catalyzed allylic substitution in water, see:
a) D. E. Bergbreiter, Y.-S. Liu, Tetrahedron Lett. 1997, 38,
7843; b) Y. Uozumi, H. Danjo, T. Hayashi, Tetrahedron Lett.
1997, 38, 3557; c) Y. Uozumi, H. Danjo, T. Hayashi, Tetrahedron
Lett. 1998, 39, 8303; d) H. Danjo, D. Tanaka, T. Hayashi, Y.
Uozumi, Tetrahedron 1999, 55, 14341; e) S. Kobayashi, W. W.-L.
Lam, K. Manabe, Tetrahedron Lett. 2000, 41, 6115; f) C.
Rabeyrin, C. Nguefack, D. Sinou, Tetrahedron Lett. 2000, 41,
7461; g) T. Hashizume, K. Yonehara, K. Ohe, S. Uemura, J. Org.
Chem. 2000, 65, 5197; h) A. S. Dallas, K. V. Gothelf, J. Org.
Chem. 2005, 70, 3321.
to explain the unprecedented result. The present procedure
provides a new highly stereo- and regioselective method to
construct 1,4-dienes in an economical and environmentally
benign manner. Further investigation to determine the
precise mechanism and expand the scope of this reaction is
underway.
Experimental Section
General procedure for the preparation of 4d: A test-tube (10 mL)
was charged with palladium chloride (10 mg, 0.056 mmol), CuCl2
(343 mg, 2mmol), allyl alcohol (174 mg, 3 mmol), and HOAc
(1 mL). After the resulting mixture had become homogenous through
stirring, 3-chloropropyne (74.5 mg, 1 mmol) was added, followed by
H2O (1 mL). The mixture was stirred at RT for 12h (monitored by
TLC). The reaction mixture was dissolved in diethyl ether (10 mL ” 2)
and washed with brine (5 mL). The organic layer was dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography over silica gel (petroleum ether/ethyl acetate, 15:1)
to give 4d (66 mg, 0.29 mmol, 59%) as a yellow oil.
[7] a) R. F. Heck, Palladium Reagents In Organic Synthesises,
Academic Press, London, 1985, p. 245; b) J. E. Bäckvall,
Y. I. M. Nillson, R. G. P. Gatti, Organometallics 1995, 14, 4242.
[8] K. Kaneda, T. Uchiyama, Y. Fujiwara, T. Imanaka, S. Teranishi,
J. Org. Chem. 1979, 44, 55.
[9] a) X. Lu, G. Zhu, J. Org. Chem. 1995, 60, 1087; b) Q. Zhang, X.
Lu, X. Han, J. Org. Chem. 2001, 66, 7676; c) Q. Zhang, W. Xu, X.
Lu, J. Org. Chem. 2005, 70, 1505; d) Z. Zhang, X. Lu, Z. Xu, Q.
Zhang, X. Han, Organometallics 2001, 20, 3724; e) X. Lu, G.
Zhu, S. Ma, Tetrahedron Lett. 1992, 33, 7205.
Received: November 9, 2005
Published online: February 21, 2006
Keywords: alkynes · allylation · insertion · palladium ·
.
[10] The configuration of the allylation products was further
confirmed by NOE studies on compounds 3b, 5d, and 12b.
reaction mechanisms
[1] For reviews on carbometalation, see: a) J. F. Normant, A.
Alexakis, Synthesis 1981, 841; b) W. Oppolozer, Angew. Chem.
1989, 101, 39; Angew. Chem. Int. Ed. Engl. 1989, 28, 38; c) E.
Negishi, Pure Appl. Chem. 1981, 53, 2333; d) P. Knochel in
Comprehensive Organometallic Chemistry II, Vol. 11 (Eds.:
E. W. Able, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford,
1948
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1945 –1949

Angewandte
Chemie
[11] Y. Kayaki, T. Koda, T. Ikariya, J. Org. Chem. 2004, 69, 2595.
[12] a) H. Kinoshita, H. Shinokubo, K. Oshima, Org. Lett. 2004, 6,
4085; b) Y. Tamaru, Eur. J. Org. Chem. 2005, 13, 2 647; c) N.
Tsukada, S. Sugawara, K. Nakaoka, Y. Inoue, J. Org. Chem.
2003, 68, 5961; d) O. A. Wallner, K. J. Szabo, J. Org. Chem. 2003,
68, 2934; e) M. Kimura, M. Futamata, R. Mukai, Y. Tamaru, J.
Am. Chem. Soc. 2005, 127, 4592; f) N. T. Patil, Y. Yamamoto,
Tetrahedron Lett. 2004, 45, 3101.
[13] a) T. Wakabayashi, Y. Ishii, T. Murata, Y. Mizobe, M. Hidai,
Tetrahedron Lett. 1995, 36, 5585; b) L. Zhao, X. Lu, Org. Lett.
2002, 4, 3093.
[14] The presence of excess halide ion leads to trans addition and fast
reaction; see references [8] and [9c]. In our reaction, 4 equiv of
ClÀ (from 2equiv CuCl 2) was employed. A comparative reaction
with 0.5 equiv CuCl2 (equals to 1 equiv of ClÀ) was carried out
with 7a, and the yield of 7b was decreased from 92% to 74%.
[15] a) X. Lu, X. Jiang, X. Tao, J. Organomet. Chem. 1988, 344, 109;
b) I. Satoh, M. Ikeda, M. Miura, M. Nomura, J. Org. Chem. 1997,
62, 4877; c) M. S. Viciu, R. F. Germaneau, N. F. Oscar, E. D.
Stevens, S. P. Nolan, Organomatelics, 2002, 21, 5470; d) D.
Alberti, R. Goddard, A. Rufiꢁska, K. R. Pörschke, Organo-
metallics 2003, 22, 4025; e) J. Zhang, P. Braunstein, R. Welter,
Inorg. Chem. 2004, 43, 4172; f) M. Bosch, M. Schlaf, J. Org.
Chem. 2003, 68, 5225; g) N. Solin, O. A. Wallner, K. J. Szabo,
Org. Lett. 2005, 7, 689; h) S. Chandrasekhar, V. Jagadeshwar, B.
Saritha, C. Narsihmulu, J. Org. Chem. 2005, 70, 6506; i) F.-X.
Felpin, Y. Landais, J. Org. Chem. 2005, 70, 6441.
[16] A white powder that was insoluble in water was collected after
each reaction and identified as CuCl by XRD and IR analysis. It
has been reported that CuCl2 may work as an oxidant to assist
À
the cleavage of C Pd s bonds; see: a) J. E. Bäckvall, R. E.
Nordberg, J. Am. Chem. Soc. 1980, 102, 393; b) J. Ji, C. Zhang, X.
Lu, J. Org. Chem. 1995, 60, 1160; c) G. Zhu, S. Ma, X. Lu, Q.
Huang, J. Chem. Soc. Chem. Commun. 1995, 271 and referen-
ce [17f].
[17] a) T. Satoh, S. Ogino, M. Miura, M. Nomura, Angew. Chem.
2004, 116, 5173; Angew. Chem. Int. Ed. 2004, 43, 5063; b) S.
Kawasaki, T. Satoh, M. Miura, M. Nomura, J. Org. Chem. 2003,
68, 6836; c) J.-H. Li, Y. Liang, Y.-X. Xie, J. Org. Chem. 2004, 69,
8125; d) C. Zhou, R. C. Larock, J. Org. Chem. 2005, 70, 3765;
e) X. Zeng, Q. Hu, M. Qian, E.-I. Negishi, J. Am. Chem. Soc.
2003, 125, 13636; f) J.-H. Li, H.-F. Jiang, M.-C. Chen, J. Org.
Chem. 2001, 66, 3627.
Angew. Chem. Int. Ed. 2006, 45, 1945 –1949
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 1949