Expedient synthesis of functionalized conjugated enynes: Palladium-catalyzed bromoalkynylation of alkynes

Article abstract of DOI:10.1002/anie.201000003

(Chemical Equation Presented) Side by side: Direct cis addition of bro-moalkynes 1 to various alkynes 2 was found to proceed in the presence of a Pd^II catalyst to give difunctionalized enyne products 3. The method is facile for the synthesis of bromo alkenynes. Further-more, an unusual mechanism is pro-posed.

Full text of DOI:10.1002/anie.201000003

Communications
DOI: 10.1002/anie.201000003
Synthetic Methods
Expedient Synthesis of Functionalized Conjugated Enynes:
Palladium-Catalyzed Bromoalkynylation of Alkynes**
Yibiao Li, Xiaohang Liu, Huanfeng Jiang,* and Zhenning Feng
2
À
The construction of C(sp) C(sp ) bonds is an important
method for the synthesis of various conjugated structures and
biologically active compounds.[1] Among different protocols
for achieving this goal, the coupling between substituted
alkenes and terminal alkynes stands as the most widely used
method.[2] However, the synthesis of functionalized alkenynes
is problematic because of the potential of the desired
functional group to react with the catalytic system. In this
context, a more expedient and favored, although still under-
developed, route to form this structure is the direct addition
of an “activated” alkyne to other alkynes. To this end, several
groups have reported novel catalytic systems for alkynylcya-
nation, alkynylstannylation, and alkynylboranation reac-
tions,[3] which simplified the original strategies (Scheme 1a).
Therefore, the importance of the search for more direct
alkynylation modes is evident.
aforementioned direct alkynylation strategy. Herein, we
describe our preliminary results in for the bromoalkynylation
process.
Our initial attempts were aimed at studying the effect of
the solvent on the bromoalkynylation reaction (Table 1). In
the presence of the Pd(OAc)2 catalyst (5 mol%), the reaction
of phenylethynyl bromide (1a, 1.2 mmol) and 4-octyne (2a,
1 mmol) in THF at 308C afforded 3aa in a 30% yield
(entry 1). The screening of various solvents revealed that the
solvent played a very important role in this reaction
(entries 1–6). Only trace amounts of the desired product
3aa was obtained when DMSO was used (entry 2), and
unsatisfactory results were obtained using toluene (entry 4).
The best results were obtained when the reaction was carried
out with Pd(OAc)2 in CH3CN at 308C. Under these con-
ditions 3aa was formed in 91% yield, in an exclusively
cis fashion (entry 6). We next tested the bromoalkynylation
reaction in the presence of different catalysts and additives.
Pd(OAc)2 and PdBr2 were superior to any other palladium
catalysts so far tested (entries 8–12). Notably, the reaction was
sluggish when Pd/C or [Pd(PPh3)4] was employed (entrie-
s 11 and 12). Additionally, reductive additives such as nBu3P
Table 1: Optimization of the reaction conditions for the bromoalkynyla-
tion process.[a]
Scheme 1. a) Reported methods for the alkynylation and b) the method
presented herein.
Entry
Catalyst
Solvent
Additive
Yield [%][b]
During the pursuit for more catalytic possibilities in
palladium catalysis, other groups[4] as well as ours[5] have
disclosed a new mode of selective intermolecular cross-
coupling between internal alkynes (Scheme 1b). Additional
research on this subject revealed another version of the
alkyne–alkyne cross-coupling reaction: direct bromoalkyny-
lation of internal alkynes, which are important for the
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdBr2
THF
–
–
–
–
–
–
–
–
–
–
–
–
30
trace
77
32
83
91
55
89
83
81
trace
0
60
65
DMSO
CH2Cl2
toluene
MeNO2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
7[c]
8
9
PdCl2
10[d]
11
12
13
14
15
16
[Pd2(dba)3]
5% Pd/C
[Pd(PPh3)4]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[*] Y. B. Li, X. H. Liu, Prof. Dr. H. F. Jiang, Z. N. Feng
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (China)
nBu3P
CuI/Na2CO3 (1:1)
NEt3
Fax: (+86)20-8711-2906
E-mail: jianghf@scut.edu.cn
trace
85
benzoquinone
[**] We are grateful to the National Natural Foundation of China (Nos.
20625205, 20772034, and 20932002) and the Doctoral Fund of the
Ministry of Education of China (No. 20090172110014) for financial
support.
[a] Reaction conditions: 1a (1.2 mmol), 2a (1 mmol), catalyst (5 mol%)
in 2 mL of solvent at 308C for 8 h. [b] Yields of isolated product are based
on 2a. [c] Reaction was carried out at 208C for 12 h. [d] Reaction was
carried out in air for 24 h. dba=dibenzylideneacetone, DMSO=dime-
thylsulfoxide, THF=tetrahydrofuran.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000003.
3338
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 3338 –3341

Angewandte
Chemie
and NEt3, as well as an inorganic base slow down the
bromoalkynylation reaction (entries 13–15). An
organic oxidant or air does not disturb the reaction
(entries 10 and 16).
With the optimized reaction conditions in hand,
we turned our attention to the bromoalkynylation
reaction by varying bromoalkyne and alkyne com-
ponents. Gratifyingly, both symmetrical and unsym-
metrical internal alkynes exclusively gave the cis-
addition products in the presence of palladium
catalysts. As shown in Scheme 2, aromatic alkynyl
bromides with either an electron-donating or elec-
tron-withdrawing group on the benzene ring, were
able to undergo bromoalkynylation with 4-octyne to
generate the corresponding products in excellent
yields (3aa–3 fa). The reaction conditions were
compatible with alkyl, bromide, fluorine, and
methoxy groups. The bromoaryl group was tolerated
in this transformation and therefore available for
additional functionalization of the product at the
À
C Br bond (3ea). It was also mechanistically
interesting, because it is well-known that the
2
0 II
À
C(sp ) Br bond is susceptible to reaction in a Pd /
catalytic cycle. Alkynyl bromides such as 3-hydroxy-
3-methylbutynyl bromide, 5-chloropentynyl bro-
mide, and trimethylsilylethynyl bromide can also
undergo the same transformation in good yields
(3ga, 3ha, 3ia). Importantly, silylethynyl bromides
have proven to be useful starting materials for the
construction of conjugated enynes.[6] To our surprise,
the use of 1,4-bis(2-bromoethynyl)benzene resulted
in the formation of the corresponding product 3la in
79% yield in one step.
The addition of symmetrical internal alkynes
gave the single cis-isomer products in the present
palladium catalysts. Unsymmetrical disubstituted
acetylenes were also investigated as substrates.
Pleasingly, the functional groups in the unsymmet-
rical internal alkynes play a very important role in
the regioselectivity. When either 2-hexyne or
1-methyl-4-(oct-1-ynyl)benzene was treated with
1.5 equivalents of alkynyl bromide, a pair of corre-
sponding regioisomers were furnished without sig-
nificant influence from the phenyl or alkyl substitu-
ents upon the stereoselectivity of the reaction (3ab,
3af). However, introducing the electron-donating
group OH into the internal alkynes led to the
formation of single cis-isomer products in good
Scheme 2. Palladium-catalyzed bromoalkynylation of bromoalkynes with alkynes.
yields (3ac–3ae, 3bc–3ee). Interestingly, the reaction of
electron-withdrawing alkynyl ketones under similar condi-
tions afforded single cis products with opposite regioselectiv-
ity (3ah, 3ai). Unfortunately terminal alkynes, such as
phenylacetylene, only afforded a mixture of products, and
diarylacetylene gave a very low yield of the product.
Additionally, when a propargyl alcohol was employed as
the substrate, the expected product 3ac was obtained in 77%
yield when a mixed solvent system, CH2Cl2/CH3CN (1:1), was
used, whereas the bromoalkynylation in neat CH3CN gave
4aa, a dehydration product of 3ac, in 75% yield (Scheme 3).[7]
Therefore, we attempted the reaction of propargyl alcohols
with 1.5 equivalents of bromoalkyne in the mixed solvent
system, and multifunctional allylic alcohols were obtained as
single isomers in good yields (Scheme 2, 3ac–3ee).[8]
The regio- and stereochemistry of the products were
confirmed by using NMR methods. In a typical example,
NOE enhancements were observed between the methylene
and methine protons of alcohol 3ad (Figure 1), indicating a
cis relationship between these substituents. The regioselec-
tivity of 3ah and 4aa was confirmed by HMBC, HSQC,
ROESY methods.[9]
Angew. Chem. Int. Ed. 2010, 49, 3338 –3341
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3339

Communications
To gain insight into the reaction, the stoichiometric PdX2
experiments were carried out, and they showed the major
halogenated products were originated from phenylethynyl
halides (Scheme 4). These results provided evidence of a
mechanism which proceeds through an unusual oxidative
addition of PdX2 species to phenylethynyl bromide, rather
than through direct halogenopalladation of alkynes by
palladium salts. Therefore, we proposed a tentative mecha-
nism for the palladium-catalyzed bromoalkynylation in
Scheme 5.[13] Different from its alkynylcyanation, alkynyl-
stannylation, and alkynylboranation counterparts,[3] we
believed that this reaction was initialized by oxidative
addition of the PdII salt to bromoalkyne 1 to form a PdIV
species A. Then the cis-alkynyl vinylpalladium intermediate
B was formed by the addition of A to alkyne 2. A subsequent
reductive elimination of B regenerated the brominated
product 3 and the active catalyst species PdII. Notably, the
insertion of a simple palladium salt into alkynyl bromide is
very rare, however, the formation of an alkynylpalladium(IV)
complex was achieved with alkynyl iodide derivatives as
oxidative reagents.[14]
Scheme 3. Solvent-involved dehydration. Reaction conditions:
a) alkynes (1 mmol), bromoalkynes (1.5 mmol), Pd(OAc)2 (5 mol%),
CH3CN (1 mL), CH2Cl2 (1 mL), 308C, 12 h; yields of isolated products.
Reaction conditions: b) alkynes (1 mmol), bromoalkynes (1.5 mmol),
Pd(OAc)2 (5 mol%), CH3CN (2 mL), 808C, 8 h; yields of isolated
products.
In conclusion, we have discovered a novel type of
palladium-catalyzed cross-coupling reaction between bro-
Figure 1. NOE interactions were used to confirm the configuration of
the products (see the Supporting Information).
During the course of these studies, we
discovered that the Pd/Cu-catalyzed one-pot
coupling of 3aa with phenylacetylene gave
enediyne 5aga in 75% yield, which when
prepared by the current method is potentially
useful for materials science [Eq. (1)].[10]
We also extended this reaction to phenyl-
ethynyl iodide as a substrate and found that the
iodoalkynylation took place to give 3ja in
reasonable yield [Eq. (2)].[11]
Scheme 4. Stoichiometric palladium halide experiments.
moalkynes and internal alkynes. This bromoalkynylation
process provided a new idea for the regio- and stereoselective
synthesis of conjugated cis-bromo alkenynes. Preliminary
mechanistic experiments have provided evidence in support
of a rare PdII/PdIV catalytic cycle for this transformation.
The direct halogenation of the electron-deficient alkynes
by palladium(II) salts selectively afforded b-carbon halogen-
ated products.[12] To our surprise, palladium(II)-catalyzed
bromoalkynylation of alkynyl ketones afforded only the
a-carbon brominated products, indicating a different pathway
relative to the direct palladation process (Scheme 2, 3ah, 3ai).
Scheme 5. Tentative mechanism for the bromoalkynylation reaction.
3340
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 3338 –3341

Angewandte
Chemie
Takahashi, J. Org. Chem. 2002, 67, 7451 – 7456; e) A. N. Thadani,
V. H. Rawal, Org. Lett. 2002, 4, 4321 – 4323.
Current efforts are aimed at elucidating the detailed reaction
mechanism, broadening the scope of the catalytic system, and
exploring synthetic utility for advanced materials.
[4] For recent examples of transition metal catalyzed alkynes–
alkynes coupling, see: a) B. M. Trost, N. Maulide, M. T. Rudd, J.
Am. Chem. Soc. 2009, 131, 420 – 421; b) B. M. Trost, A. J.
Frontier, J. Am. Chem. Soc. 2000, 122, 11727 – 11728; c) K.
Ogata, J. Sugasawa, S. Fukuzawa, Angew. Chem. 2009, 121,
6194 – 6196; Angew. Chem. Int. Ed. 2009, 48, 6078 – 6080; d) H.
Katayama, H. Yari, M. Tanaka, F. Ozawa, Chem. Commun. 2005,
4336 – 4338; e) T. Nishimura, X. X. Guo, K. Ohnishi, T. Hayashi,
Adv. Synth. Catal. 2007, 349, 2669 – 2672; f) N. Tsukada, S.
Ninomiya, Y. Aoyama, Y. Inoue, Org. Lett. 2007, 9, 2919 – 2921.
[5] H. Jiang, X. Liu, L. Zhou, Chem. Eur. J. 2008, 14, 11305 – 11309.
[6] a) Y. Takayama, C. Delas, K. Muraoka, F. Sato, Org. Lett. 2003,
5, 365 – 368; b) M. Kivala, F. Mitzel, C. Boudon, J. P. Gissel-
brecht, P. Seiler, M. Gross, F. Diederich, Chem. Asian J. 2006, 1,
479 – 489.
[7] a) X. Zeng, M. Qian, Q. Hu, E. Negishi, Angew. Chem. 2004, 116,
2309 – 2313; Angew. Chem. Int. Ed. 2004, 43, 2259 – 2263; b) L.
Yu, B. Meng, X. Huang, J. Org. Chem. 2008, 73, 6895 – 6898;
c) S. H. Sim, H. J. Park, S. I. Lee, Y. K. Chung, Org. Lett. 2008,
10, 433 – 436; d) L. Xiong, M. Shi, Tetrahedron 2007, 63, 11938 –
11942; e) Y. Shibata, Y. Otake, M. Hirano, K. Tanaka, Org. Lett.
2009, 11, 689 – 692; f) P. Bichler, W. A. Chalifoux, S. Eisler,
A. L. K. S. Shun, E. T. Chernick, R. R. Tykwinski, Org. Lett.
2009, 11, 519 – 522.
Experimental Section
Typical procedure for the reaction of phenylethynyl bromide and
4-octyne: A mixture of Pd(OAc)2 (12 mg, 0.05 mmol), CH3CN
(2 mL), 4-octyne (110 mg, 1 mmol), phenylethynyl bromide
(216 mg, 1.2 mmol) was added successively in Schlenk tube. After
stirring for 8 h at 308C, the solution was filtered though a small
amount of silica gel. The residue was then purified by silica gel
preparative TLC (n-hexane), which furnished 3aa (264 mg, 91%) as a
1
pale-yellow oil. H NMR (CDCl3, 400 MHz): d = 7.46–7.48 (m, 2H,
=
Ph), 7.28–7.31 (m, 3H, Ph), 2.58 (t, J = 7.2 Hz, 2H, CBrCH2), 2.27 (t,
=
J = 7.2 Hz, 2H, CCH2), 1.60–1.67 (m, 4H, -CH2Me), 0.96 ppm (q,
J = 7.8 Hz, 6H, Et-CH3); 13C NMR (CDCl3, 100 Hz): d = 132.8, 131.5,
=
131.5, 128.2, 128.2, 128.1, 124.3, 123.4 (C C), 93.1, 90.3 (s, C ꢀ C), 39.0
=
=
(s, CBrCH2), 35.2 (s, CCH2), 22.0 (s, CH2), 21.9 (s, CH2), 13.7,
13.2 ppm (s, CH3); HRMS (EI) (m/z): calcd for C16H19Br 290.0670;
found 290.0664.
Received: January 1, 2010
Revised: February 17, 2010
Published online: March 25, 2010
[8] a) Y. Liu, F. Song, L. Cong, J. Org. Chem. 2005, 70, 6999 – 7002;
b) S. Guo, H. Zhang, F. Song, Y. Liu, Tetrahedron 2007, 63, 2009 –
2018.
[9] NOESY spectra of 3aa, 3ad; HMBC, HSQC, and ROESY
spectra of 3ah; HMBC spectrum of 4aa are shown in the
Supporting Information.
Keywords: alkynes · cross-coupling · palladium ·
synthetic methods
.
[1] For reviews on conjugated structures, see: a) E. Negishi, L.
Anastasia, Chem. Rev. 2003, 103, 1979 – 2017; b) E. Negishi, M.
Qian, F. Zeng, L. Anastasia, D. Babinski, Org. Lett. 2003, 5,
1597 – 1600; c) K. C. Nicolaou, H. Zhang, J. S. Chen, J. J.
Crawford, L. Pasunoori, Angew. Chem. 2007, 119, 4788 – 4791;
Angew. Chem. Int. Ed. 2007, 46, 4704 – 4707; d) Y. Liu, H. Gao,
Org. Lett. 2006, 8, 309 – 311; e) Y. Liu, C. Xi, R. Hara, K.
Nakajima, A. Yamazaki, M. Kotora, T. Takahashi, J. Org. Chem.
2000, 65, 6951 – 6957; f) X. Huang, D. Duan, W. Zheng, J. Org.
Chem. 2003, 68, 1958 – 1963; g) S. M. Lee, K. H. Bae, H. J. Sohn,
Tetrahedron Lett. 2009, 50, 416 – 418; h) X. Zeng, F. Zeng, E.
Negishi, Org. Lett. 2004, 6, 3245 – 3248; i) Z. U. Levi, T. D. Tilley,
J. Am. Chem. Soc. 2009, 131, 2796 – 2797; j) A. S. Andersson, L.
Kerndrup, A. ø. Madsen, K. Kilsꢀ, M. B. Nielsen, J. Org. Chem.
2009, 74, 375 – 382; k) X. Nie, G. Wang, J. Org. Chem. 2006, 71,
4734 – 4741.
[2] a) G. T. Hwang, H. S. Son, J. K. Ku, B. H. Kim, J. Am. Chem. Soc.
2003, 125, 11241 – 11248; b) J. A. McCubbin, M. L. Maddess, M.
Lautens, Org. Lett. 2006, 8, 2993 – 2996; c) T. Ljungdahl, T.
Bennur, A. Dallas, H. Emtenꢀs, J. Mꢀrtensson, Organometallics
2008, 27, 2490 – 2498; d) M. Feuerstein, L. Chahen, H. Doucet,
M. Santelli, Tetrahedron Lett. 2006, 62, 112 – 120; e) F. Bellina, E.
Falchi, R. Rossi, Tetrahedron 2003, 59, 9091 – 9100.
[10] a) D. Sud, T. J. Wigglesworth, N. R. Branda, Angew. Chem. 2007,
119, 8163 – 8165; Angew. Chem. Int. Ed. 2007, 46, 8017 – 8019;
b) J. Barluenga, D. de Sꢁa, A. Gꢂmez, A. Ballesteros, J.
Santamarꢃa, A. de Prado, M. Tomꢁs, A. L. Suꢁrez-Sobrino,
Angew. Chem. 2008, 120, 6321 – 6324; Angew. Chem. Int. Ed.
2008, 47, 6225 – 6228; c) L. Feng, A. Zhang, S. M. Kerwin, Org.
Lett. 2006, 8, 1983 – 1986; d) H. H. Jeon, J. B. Son, J. H. Choi,
I. H. Jeong, Tetrahedron Lett. 2007, 48, 627 – 631.
[11] The major by-product is 1,4-diphenylbuta-1,3-diyne from self-
coupling of the phenylethynyl iodine. See: S. V. Damle, D.
Seomoon, P. H. Lee, J. Org. Chem. 2003, 68, 7085 – 7087.
[12] For regioselective palladation of alkynes by palladium salts, see:
a) K. Kaneda, T. Uchiyama, Y. Fujiwara, T. Imanaka, S.
Teranishi, J. Org. Chem. 1978, 44, 55 – 63; b) S. Ma, X. Lu, J.
Chem. Soc. Chem. Commun. 1990, 733 – 734; c) S. Ma, X. Lu, Z.
Li, J. Org. Chem. 1992, 57, 709 – 713.
[13] a) G. Yin, G. Liu, Angew. Chem. 2008, 120, 5522 – 5525; Angew.
Chem. Int. Ed. 2008, 47, 5442 – 5445; b) K. M. Gericke, D. I.
Chai, N. Bieler, M. Lautens, Angew. Chem. 2009, 121, 1475 –
1479; Angew. Chem. Int. Ed. 2009, 48, 1447 – 1451; c) B. M. Trost,
C. Chan, G. Ruhter, J. Am. Chem. Soc. 1987, 109, 3486 – 3487;
d) F. Kessler, N. Szesni, K. Pꢄhako, B. Weibert, H. Fischer,
Organometallics 2009, 28, 348 – 354; e) K. Muꢅiz, Angew. Chem.
2009, 121, 9576 – 9588; Angew. Chem. Int. Ed. 2009, 48, 9412 –
9423.
[3] a) Y. Nakao, Y. Hirata, M. Tanaka, T. Hiyama, Angew. Chem.
2008, 120, 391 – 393; Angew. Chem. Int. Ed. 2008, 47, 385 – 387;
b) E. Shirakawa, H. Yoshida, T. Kurahashi, Y. Nakao, T.
Hiyama, J. Am. Chem. Soc. 1998, 120, 2975 – 2976; c) M.
Suginome, M. Shirakura, A. Yamamoto, J. Am. Chem. Soc.
2006, 128, 14438 – 14439; d) Y. Liu, Z. Zhong, K. Nakajima, T.
[14] A. J. Canty, T. Rodemann, B. W. Skelton, A. H. White, Organo-
metallics 2006, 25, 3996 – 4001.
Angew. Chem. Int. Ed. 2010, 49, 3338 –3341
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3341