Silver-catalyzed difunctionalization of terminal alkynes: Highly regio- and stereoselective synthesis of (Z)-β-Haloenol acetates

Article abstract of DOI:10.1021/ol101251n

(Figure Presented) A new silver-catalyzed highly regio- and stereoselective difunctionalization reaction of simple terminal alkynes was reported in which the (Z)-β-haloenol acetate derivatives were formed efficiently. The resulting products were versatile intermediates in organic synthesis.

Full text of DOI:10.1021/ol101251n

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3262-3265
Silver-Catalyzed Difunctionalization of
Terminal Alkynes: Highly Regio- and
Stereoselective Synthesis of
(Z)-ꢀ-Haloenol Acetates
Zhengwang Chen, Jinghao Li, Huanfeng Jiang,* Shifa Zhu, Yibiao Li, and
Chaorong Qi
School of Chemistry and Chemical Engineering, South China UniVersity of
Technology, Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received June 4, 2010
ABSTRACT
A new silver-catalyzed highly regio- and stereoselective difunctionalization reaction of simple terminal alkynes was reported in which the
(Z)-ꢀ-haloenol acetate derivatives were formed efficiently. The resulting products were versatile intermediates in organic synthesis.
Transition-metal-catalyzed reactions are versatile tools for
carbon-carbon and carbon-heteroatom bond formation and,
hence, are the focus of intense synthetic attention.1 In
particular, recent advances in the transition-metal-catalyzed
functionalization of alkynes have provided rapid and concise
access to complex chemical frameworks.2 Terminal alkynes
are readily accessible starting materials, and remarkable
progress has been made in the transition-metal-catalyzed
difunctionalization of terminal alkynes in the past decades.3
The ꢀ-haloenol acetate molecular skeletons are important
intermediates in organic synthesis, as the vinyl halide moiety
is often employed for transition-metal-catalyzed cross-
coupling reactions and halogen-metal exchange reactions,4
and enol acetates are frequently used as intermediates in
organic synthesis and pharmaceutical chemistry.5,6 However,
there are very few catalytic methods for forming the OCdCX
bond (X ) Cl, Br, I) in one step from simple terminal
alkynes.7 For example, Barluenga7b described an elegant
electrophilic addition reaction that gave anti addition (E)-
products from the terminal alkynes. On the other hand, over
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (b)
Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. ReV. 2005, 105, 2329.
(c) Bellina, F.; Rossi, R. Chem. ReV. 2010, 110, 1082. (d) Johnson, J. B.;
Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840.
(4) For recent selected examples, see: (a) Corbet, J.-P.; Mignani, G.
Chem. ReV. 2006, 106, 2651. (b) Cahiez, G.; Moyeux, A. Chem. ReV. 2010,
110, 1435. (c) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (d)
Bettinger, H. F.; Filthaus, M. J. Org. Chem. 2007, 72, 9750. (e) Uchiyama,
M.; Furuyama, T.; Kobayashi, M.; Matsumoto, Y.; Tanaka, K. J. Am. Chem.
Soc. 2006, 128, 8404. (f) Boukouvalas, J.; Loach, R. P. J. Org. Chem. 2008,
73, 8109.
(2) (a) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int. Ed. 2010,
49, 3338. (b) Minami, Y.; Kuniyasu, H.; Miyafuji, K.; Kambe, N. Chem.
Commun. 2009, 3080. (c) Beletskaya, I.; Moberg, C. Chem. ReV. 2006,
106, 2320. (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004,
104, 3079. (e) Willis, M. C. Chem. ReV. 2010, 110, 725.
(5) For selected examples, see: (a) Bruneau, C.; Dixneuf, P. H. Chem.
Commun. 1997, 507. (b) Goossen, L. J.; Paetzold, J. Angew. Chem., Int.
Ed. 2004, 43, 1095. (c) Zhang, D.; Ready, J. M. Org. Lett. 2005, 7, 5681.
(d) DeBergh, J. R.; Spivey, K. M.; Ready, J. M. J. Am. Chem. Soc. 2008,
(3) For recent selected examples of difunctionalization of terminal
alkyne, see :(a) Goossen, L. J.; Rodr´ıguez, N.; Goossen, K. Angew. Chem.,
Int. Ed. 2009, 48, 9592. (b) Mizuno, A.; Kusama, H.; Iwasawa, N. Angew.
Chem., Int. Ed. 2009, 48, 8318. (c) Sha, F.; Huang, X. Angew. Chem., Int.
Ed. 2009, 48, 3458. (d) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 3258. (e) Dutta, B.; Gilboa, N.; Marek, I. J. Am. Chem.
Soc. 2010, 132, 5588. (f) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132,
28. (g) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786.
130, 7828. (e) Tang, W.; Liu, D.; Zhang, X. Org. Lett. 2003, 5, 205
.
(6) ꢀ-Haloenol acetates are known to be effective precursors of R-keto
dianions; see: (a) Kowalski, C. J.; Haque, M. S. J. Org. Chem. 1985, 50,
5140. (b) Kowalski, C. J.; O’Dowd, M. L.; Burke, M. C.; Fields, K. W.
J. Am. Chem. Soc. 1980, 102, 5411. (c) Kowalski, C. J.; Haque, M. S.;
Fields, K. W. J. Am. Chem. Soc. 1985, 107, 1429
.
10.1021/ol101251n  2010 American Chemical Society
Published on Web 06/14/2010

the past decades, the use of silver catalysts in synthetic
organic chemistry has become well-established as a result
of the ability of silver salt to selectively activate particular
functional groups under mild reaction conditions.8 Recently,
our group has reported a series of silver-catalyzed function-
alization of different alkynes.9 As part of this continuing
project, we would like to present the first example of a silver-
catalyzed highly regio- and stereoselective difunctionalization
reaction using simple terminal alkynes, which are easily
available from commercial vendors, to afford the (Z)-ꢀ-
haloenol acetate derivatives efficiently.
alization reaction from the terminal alkynes. As shown in
Scheme 1, aromatic terminal alkynes with either electron-
donating or electron-withdrawing groups attached to the
benzene rings were able to undergo a difunctionalization
reaction smoothly and generated the corresponding ꢀ-ha-
loenol acetates in moderate to excellent yields (2a-r) except
the 4-methoxyphenylacetylene substrate, in which the mix-
ture of E- and Z- isomers were obtained (2f). The treatment
of alkyl- or aryl-substituted substrates afforded the corre-
sponding products in good yields (2b-e).
The reaction of phenylacetylene (1a) with acetic anhydride
was chosen as the model reaction. First, four different
commonly used metal salts were used as the catalyst to
conduct this reaction. To our delight, we found that AgBF4
could afford the corresponding product in 90% yield (Table
1, entry 4). The reaction did not proceed without silver salt
(Table 1, entry 5); only trace product was detected using
HBF4 as the catalyst instead (Table 1, entry 6). Then AgBF4
was used as the catalyst of choice. Except acetic anhydride,
DMF and 1,4-dioxane could afford the products as well,
albeit in lower yield (Table 1, entries 7-11). The lower
temperature disfavored the reaction, and the reaction gave
74% yield after 6 h (Table 1, entries 12-14). Furthermore,
microwave radiation can also provide satisfied reaction results
(Table 1, entry 15).
Scheme 1
.
Silver-Catalyzed Synthesis of (Z)-ꢀ-Haloenol
Acetatesa b
,
Table 1. Optimization of Reaction Conditions for the
Difunctionalization of Phenylacetylenea
entry
catalyst
solvent
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
water
HOAc
DMF
1,4-dioxane
DMSO
Ac2O
yieldb (%)
1
2
3
Pd(OAc)2
CuI
FeCl3
n.p.
n.p.
n.p.
90
n.p.
trace
trace
n.p.
73
60
trace
20
53
74
4
AgBF4
5c
6d
7
HBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
8e
9
10
11
12f
13g
14h
15i
Ac2O
Ac2O
Ac2O
67
a Reaction conditions: phenylacetylene (1.0 mmol), NBS (1.2 mmol),
acetic anhydride (5 mmol), solvent (2.0 mL), and catalyst (5 mol %) at
120 °C for 12 h. b Isolated yield. c Without catalyst. d 20 mol % of HBF4.
e The products were acetophenone and 2-bromo-1-phenylethanone. f Room
temperature. g At 60 °C. h 6 h. i Reacted at 120 °C for 0.5 h under microwave
conditions.
a Reaction conditions: terminal alkyne (1.0 mmol), NBS (1.2 mmol),
acetic anhydride (2 mL), and AgBF4 (5 mol %) at 120 °C for 12 h. b Isolated
yield. c 5:4 Z/E mixture as determined by 1H NMR spectra. d The substrate
was pent-4-yn-2-ol.
With the optimized conditions in hand (Table 1, entry 4),
we next turned our attention to the scope of the difunction-
Meanwhile, good yields were achieved when electron-
withdrawing substituted substrates were used (2g-m).
Org. Lett., Vol. 12, No. 14, 2010
3263

Interestingly, dienol diacetate formation was performed when
diyne was used (2n). NCS and NIS could afford the
corresponding ꢀ-haloenol acetates in moderate to good yields
as well (2o-r). As the challenging substrates, aliphatic
alyknes can also react with NBS and acetic anhydride giving
the (Z)-ꢀ-haloenol acetates in moderate to good yields
(2s-x). It was discovered that the alkynol afforded the 2,4-
diacetoxy product (2w). Moreover, the substrate nona-1,8-
diyne formed the mono difunctionalization product in
moderate yield (2x).
Scheme 2. Sonogashira Reaction of the (Z)-ꢀ-Haloenol Acetates
The regio- and stereochemistry of ꢀ-haloenol acetates were
determined based on X-ray diffraction and related literature.10
For example, the X-ray crystallographic analyses of 2e
clearly indicated the position of the groups (Figure 1)
could transform to 2a as well; although the yield was low,
there was no D-labeled 2a product (Scheme 3, eq 2). The
controlled experiments suggested that the difunctionalization
reaction may undergo a 4a intermediate and the vinyl
hydrogen atom of 2a resulted from the water in the solvent
or air.
Consequently, the possible mechanisms were proposed
(Scheme 4) on the basis of the previous work mechanism
and our reaction results.12,13 In the first step, the silver
phenylacetylide intermediate A is formed, which is trans-
formed to 4a. Then the silver cation attacks the triple bond
of 4a and formed a π-complex B, which is then subsequently
converted to the corresponding σ-complex C by nucleophilic
attack of the acetic anion. Perhaps the halo atom has some
stabilization action to the silver, as the silver complex C
decomposed to a ꢀ-haloenol acetate by substitution of the
silver atom with a proton in a certain direction, and the
product has high regio- and stereoselectivity.
Figure 1. X-ray structure of 2e.
The resulting product haloenol acetates appeared highly
attractive as intermediates for the preparation of more highly
functionalized enol acetates. Take 2a as an example to
increase molecular complexity via palladium- and copper-
catalyzed reactions (Schemes 2). Compound 2a underwent
a Sonogashira reaction with terminal alkynes affording the
corresponding 3a and 3b in 87 and 85% yield, respectively.
Moreover, the bromo group of 3a could be utilized for further
transformation through a transition-metal-catalyzed reaction,
and 3b was easily transformed to the functionalized terminal
alkyne.11
Scheme 3. Controlled Experiments
To elucidate the mechanism, controlled experiments were
conducted (Scheme 3). Compound 2a was obtained regio-
and stereospecifically from 4a with acetic anhydride as the
solvent in excellent yield (Scheme 3, eq 1). Compound 5a
Scheme 4. Possible Reaction Mechanisms
(7) (a) Pincock, J. A.; Yates, K. Can. J. Chem. 1970, 48, 3332. (b)
Barluenga, J.; Rodr´ıguez, M. A.; Campos, P. J. J. Org. Chem. 1990, 55,
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Chem. 2008, 10, 541. (d) Yoshida, S.; Fukui, K.; Kikuchi, S.; Yamada, T.
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Ahn, Y.; Kim, J. W. J. Am. Chem. Soc. 2010, 132, 1792. (f) Luo, Y.; Li,
Z.; Li, C.-J. Org. Lett. 2005, 7, 2675.
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10, 4283.
3264
Org. Lett., Vol. 12, No. 14, 2010

In summary, we have developed a convenient and expedi-
ent method for the synthesis of ꢀ-haloenol acetates using
silver tetrafluoroborate as the catalyst. In most cases, the (Z)-
ꢀ-haloenol acetates were obtained regio- and stereospecifi-
cally in moderate to excellent yields. The results also
indicated that the silver-catalyzed difunctionalization reaction
tolerated a variety of functional groups. The useful inter-
mediates were briefly transformed to the conjugated enyne
acetates in good yields. Further synthetic applications and
studies of the mechanism of the difunctionalization reaction
are underway.
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20625205, 20772034, and
20932002) and the Doctoral Fund of the Ministry of
Education of China (20090172110014) for financial support.
Supporting Information Available: Typical experimental
procedure and characterization for all products and X-ray
data of 2e (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) For representative preparation bromoalkynes from terminal alkynes
with silver as the catalyst, see: (a) Mu, Z.; Shu, L.; Fuchs, H.; Mayor, M.;
Chi, L. J. Am. Chem. Soc. 2008, 130, 10840. (b) Nie, X.; Wang, G. J. Org.
Chem. 2006, 71, 4734.
(13) (a) Ishino, Y.; Nishiguchi, I.; Nakao, S.; Hirashima, T. Chem. Lett.
1981, 641. (b) Lewandos, G. S.; Maki, J. W.; Ginnebaugh, J. P. Organo-
metallics 1982, 1, 1700.
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