Rhodium-catalyzed chemo- and regioselective cross-dimerization of two terminal alkynes

Article abstract of DOI:10.1021/ol303531m

Cross-dimerization of terminal arylacetylenes and terminal propargylic alcohols/amides has been achieved in the presence of a rhodium catalyst. This method features high chemo- and regioselectivities rendering convenient and atom economical access to functionalized enynes.

Full text of DOI:10.1021/ol303531m

ORGANIC
LETTERS
2013
Vol. 15, No. 4
840–843
Rhodium-Catalyzed Chemo- and
Regioselective Cross-Dimerization
of Two Terminal Alkynes
Hua-Dong Xu,*,†,‡ Ren-Wei Zhang,† Xiaoxun Li,§ Suyu Huang,§ Weiping Tang,§ and
Wen-Hao Hu†
Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug
Development, East China Normal University, Shanghai, 200062, China,
School of Pharmaceutical Engineering and Life Science, Changzhou University,
Changzhou, Jiangsu Province, 213164, China, and School of Pharmacy,
University of Wisconsin, Madison, Wisconsin 53705, United States
huadongxu@gmail.com
Received December 24, 2012
ABSTRACT
Cross-dimerization of terminal arylacetylenes and terminal propargylic alcohols/amides has been achieved in the presence of a rhodium catalyst.
This method features high chemo- and regioselectivities rendering convenient and atom economical access to functionalized enynes.
Conjugated 1,3-enynes are an important class of build-
ing blocks with diverse applications in organic chemistry1
and material science.2 They are generally prepared from
the transition metal catalyzed cross-coupling of a terminal
alkyne and preactivated alkenes,3 Wittig olefination of
conjugated alkynals,4 or dehydration of propargylic
alcohols.5 In contrast, a more atom economical method6
for the preparation of conjugated enynes, namely direct
hydroalkynylation across CꢀC triple bonds or dimeriza-
tion of alkynes, has found fewer applications due to the
challenging issues of chemo-, regio-, and stereoselectivities
as illustrated in Scheme 1 for two terminal alkynes.7 One
way to overcome these obstacles is to take advantage of the
† East China Normal University.
‡ Changzhou University.
§ University of Wisconsin.
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r
10.1021/ol303531m
Published on Web 01/28/2013
2013 American Chemical Society

steric and/or electronic differences between the two alkynes
to render chemo- and regioselectivity. Important progress
has been made along this direction.8 However, cross-
dimerization of two different terminal alkynes with
high chemo-, regio-, and stereoselectivity awaits further
disclosure. We herein report an efficient and selective cross-
dimerization of two different terminal alkynes in a head-to-
tail fashion for the preparation of enynes 3a/3a0 (Scheme 1).
Trost’s group has extensively studied the addition of
terminal alkynes to various electron-deficient internal
alkynes using a palladium catalyst.8m,n In the absence of
the electron-deficient internal alkyne, the terminal alkyne
underwent homodimerization in a head-to-tail fashion to
form enyne 5a/5a0. Interestingly, selective cross-dimerization
of two terminal alkynes was found to be possible when
propargylic alcohols and excess 1,3-enynes were employed.8l
The head-to-tail products 3a/3a0 were obtained in synthet-
ically useful yields. Recently, Li’s group disclosed a rhodium-
catalyzed homodimerization of propargyl tosylamides to
give the head-to-tail product (5a/5a0) in high selectivity.8b
Miura’s group reported that the head-to-head cross-
dimerization product (4a/4a0) was selectively prepared
from two sterically different terminal alkynes.8f
Table 1. Effect of Ligandsa
entry
ligand
yield (%),f ratioh
1
PPh3
PPh3
PPh3
65% (3aa:4aa:5aa = 9:1:2) 62%g
2e
54% (3aa:4aa:5aa = 11:1:2.6)
62% (3aa:4aa:5aa = 10:1:1.5) 57%g
3b
4
(p-CF3C6H4)3P
53% (3aa:4aa:5aa = 7:1:2)
5
(3,5-CF3C6H4)3P
50% (3aa:4aa:5aa = 6:1:1)
6
(CF3CH2O)3P
(hfip)3P
(C6F5)3P
Cy3P
dppf
0%
7
0%
8
0%
9
40% (3aa:4aa = 5:1)
52% (3aa:4aa = 20:1)
32% (3aa:4aa = 20:1)
trace
10
11e
12
13
14
15
16
17c
18d,e
19d
dppf
dppm
dppe
trace
Scheme 1. Possible Products from Dimerization of Two Term-
inal Alkynes
dppp
trace
dppb
trace
BINAP
ꢀ
33% (3aa:4aa = 8.5:1)
0%
ꢀ
65% (3aa:4aa:5aa = 9:1:3)
55% (3aa:4aa:5aa = 4:1:2)
ꢀ
a General conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Rh(COD)Cl]2
(5 mol %) and ligand (20 mol %), DCM (1 mL), 40 °C overnight. b 30 mol
% [Rh(COD)Cl]2 was used. c No ligand. d Wilkinson catalyst was used.
e Room temperature. f NMR yield. g Isolated yield of 3aa and 4aa.
h Determined by 1H NMR analysis. hfip = hexafluoroisopropanol.
and alkynes,9 we found homodimerization of propargylic
alcohols occurred in the absence of 3-acyloxy-1,4-enynes.
We then explored the possibility of heterodimerizing phe-
nylacetylene 1a and propargylic alcohol 2a employing a
rhodium catalyst. We first examined the ligand effect using
[Rh(COD)Cl]2 as the rhodium precursor (Table 1). The
simple Ph3P ligand afforded the enyne products in 65%
yield with good selectivity for 3a (entry 1). Replacement
of Ph3P by (p-CF3C6H4)3P or (3,5-CF3C6H4)3P resulted
in lower yields and selectivity (entry 4). For phosphites or
more electron-deficient phosphine ligands, the catalyst
showed no activity (entries 6ꢀ8). When the electron-rich
cyclohexylphosphine ligand was employed, the reaction
resulted in a lower yield and selectivity (entry 9). With the
exception of dppf (entries 10 and 11), most other bidentate
ligands appeared to be ineffective (entries 12ꢀ16). Ligand
dppf actually delivered the highest regioselectivity. Yields
of the desired product 3aa, however, are moderate under
these conditions. Without any ligand, the reaction did not
During our development of rhodium-catalyzed inter-
molecular [5 þ 2] cycloaddition of 3-acyloxy-1,4-enynes
(8) (a) Trost, B. M.; Taft, B. R.; Masters, J. T.; Lumb, J.-P. J. Am.
Chem. Soc. 2011, 133, 8502. (b) Peng, H. M.; Zhao, J.; Li, X. Adv. Synth.
Catal. 2009, 351, 1371. (c) Matsuyama, N.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2009, 74, 3576. (d) Ogata, K.; Murayama,
H.; Sugasawa, J.; Suzuki, N.; Fukuzawa, S.-I. J. Am. Chem. Soc. 2009,
131, 3176. (e) Matsuyama, N.; Tsurugi, H.; Satoh, T.; Miura, M. Adv.
Synth. Catal. 2008, 350, 2274. (f) Katagiri, T.; Tsurugi, H.; Satoh, T.;
Miura, M. Chem. Commun. 2008, 3405. (g) Ogata, K.; Oka, O.; Toyota,
A.; Suzuki, N.; Fukuzawa, S.-i. Synlett 2008, 2663. (h) Tsukada, N.;
Ninomiya, S.; Aoyama, Y.; Inoue, Y. Pure Appl. Chem. 2008, 80, 1161.
(i) Tsukada, N.; Ninomiya, S.; Aoyama, Y.; Inoue, Y. Org. Lett. 2007, 9,
2919. (j) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa, F. Chem.
Commun. 2005, 4336. (k) Trost, B. M.; Gunzner, J. L.; Yasukata, T.
Tetrahedron Lett. 2001, 42, 3775. (l) Trost, B. M.; McIntosh, M. C.
Tetrahedron Lett. 1997, 38, 3207. (m) Trost, B. M.; Sorum, M. T.; Chan,
C.; Ruehter, G. J. Am. Chem. Soc. 1997, 119, 698. (n) Trost, B. M.; Chan,
C.; Ruhter, G. J. Am. Chem. Soc. 1987, 109, 3486. (o) Trost, B. M.;
Hachiya, I.; McIntosh, M. C. Tetrahedron Lett. 1998, 39, 6445.
(9) Shu, X. Z.; Li, X.; Shu, D.; Huang, S.; Schienebeck, C. M.; Zhou,
X.; Robichaux, P. J.; Tang, W. J. Am. Chem. Soc. 2012, 134, 5211.
Org. Lett., Vol. 15, No. 4, 2013
841

proceed at all (entry 17). The Wilkinson catalyst yielded
results similar to those using the [Rh(COD)Cl]2/Ph3P
combination (entries 18 and 19).
Other reaction parameters were explored using the
combination of Ph3P and [Rh(COD)Cl]2 (Table 2). Since
the homodimerization product 5aa is much more polar than
heterodimers 3aa and 4aa, it can be easily removed by column
chromatography. Only the ratio of 3aa and 4aa was exam-
ined. A higher temperature could accelerate the reaction, and
a slightly higher yield with lower selectivity was observed
(entry 1 vs 2). Increasing the ratio of 1a/2a from 1:2 to 2:3 was
beneficial for the yield (entry 4 vs 5). When the reaction was
performed in THF, the highest regioselectivity was observed.
The yield, however, dropped to 55% (entry 7). While the
halogenated solvents behave similarly, DCM was the best in
terms of yield and selectivity (entries 8 and 9). Poor yields
were obtained with lower catalyst loadings (entries 10, 11).
The optimal metal/ligand ratio appeared to be 1:2 (entry 13).
Table 2. Optimization of Reaction Conditionsa
x mol %
[Rh(COD)Cl]2/
solvent/T
(°C)
yieldb
(3aa:4aa)c
entry
1a:2a
y mol % PPh3
1
1:2
1:2
1:2
1:2
2:3
2:3
2:3
2:3
2:3
2:3
2:3
2:3
2:3
2:3
5/20 mol %
5/20 mol %
5/30 mol %
5/30 mol %
5/30 mol %
5/30 mol %
5/30 mol %
5/30 mol %
5/30 mol %
1/6 mol %
DCM/RT
DCM/40
DCM/40
DCM/RT
DCM/RT
DCM/40
THF/40
54% (11:1)
62% (9:1)
62% (10:1)
57% (10:1)
65% (10:1)
70% (10:1)
55% (15:1)
62% (10:1)
65% (5:1)
30% (ꢀ)
2
3
4
5
6
7
8
DCE/40
CHCl3/40
DCM/40
DCM/40
DCM/40
DCM/40
DCM/40
9
10
11
12
13
14
2/12 mol %
5/10 mol %
5/20 mol %
5/60 mol %
39% (10:1)
25% (ꢀ)
73% (10:1)
61% (5:1)
a Reaction conditions are enssentially the same as those for Table 1,
and changes are made according to each entry. b Isolated yield. c Deter-
mined by 1H NMR of a partially purified mixture of 3aa and 4aa after a
short column.
With the optimized conditions in hand, the scope of
terminal alkynes was then explored (Figure 1). Various
substituents on the phenyl ring of the donor alkyne
could be accommodated. Arylacetylenes with para, meta,
and ortho substituents gave comparable results. Aldehyde,
bromide, amide, and even free amino groups could be
tolerated. The 4-nitro group impaired the ratio of regio-
isomers 3ca/4ca to 4:1 in favor of the head-to-tail dimer
3ca. Interestingly, 3-indole acetylene furnished enyne 3ja
in 42% yield without the observation of the head-to-head
dimer. The free hydroxyl group is not required, as substrate
2c also participates in the cross-dimerization. In contrast,
the steric effect on the regioselectivity is pronounced, as only
head-to-head cross-dimerization product 4ab was detected
by NMR, while secondary propargylic alcohols gave a
mixture of homo- and heterodimers with low selectivity.
Figure 1. Rhodium-catalyzed cross-dimerization of arylacety-
lenes and propargylic alcohols, ethers, or amides. Reaction
conditions: arylacetylene 1 (0.5 mmol), propargylic alcohol/
ether/amide 2 (0.75 mmol), [Rh(COD)Cl]2 (5 mol %), Ph3P
(20 mol %), DCM (1 mL), 40 °C, overnight. The ratio of two
hetereodimers was determined by 1H NMR of the purified
mixtures of isomers after column chromatography, and the
yields were the isolated yield of two isomers.
It should be noted that a complex mixture was observed
when propargylic alcohol 2a was reacted with terminal alkyl
842
Org. Lett., Vol. 15, No. 4, 2013

substituted acetylenes such as 1-heptyne. Similarly, when
phenylacetylene 1a was reacted with homopropargylic al-
cohols, no significant selectivity was observed, implying that
the chelating effect might not play an important role in this
reaction and the inductive effect may operate (see Scheme SI
2 for details). Yet, we were pleased to find that propargylic
sulfonamide 2d afforded head-to-tail heterodimers 3adꢀ3jd
with generally higher yields and higher selectivity than their
corresponding propargylic alcohols. A moderate yield of
product 3ae was obtained from propargylic carbamate 2e.
The mechanism of this chemoselective cross-dimerization
of terminal alkynes involves oxidative addition of rhodium
to the arylacetylene CꢀH bond followed by hydroalkynyla-
tion of propargylic alcohols, ethers, or amides.10 Further
study is required to elucidate the details of this reaction,
especially the chemo- and regioselectivities.
In summary we have discovered a facile method for the
cross-dimerization of arylacetylenes and propargylic alco-
hols, ethers, or amides via the atom economical direct
hydroalkynylation reaction promoted by a rhodium cata-
lyst. We found that the chemo- and regioselectivities were
dependent on the steric and electronic nature of both
terminal alkynes.
Acknowledgment. H.-D.X. thanks the Natural Science
Foundation of China (21002032 and 21272077), Shanghai
Pujiang Program (11PJ1403100), Priority Academic Pro-
gram Development of Jiangsu Higher Education Institu-
tions (PAPD), and W.T. thanks the NIH (R01 GM088285)
and University of Wisconsin for financial support.
Supporting Information Available. Experimental pro-
cedures along with characterizing data and copies of
NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) For oxidative addition of various transition metals including Rh(I)
to the acetylene CꢀH bonds and followed by hydroalkynylation, please see:
~ ꢀ ~
´
(a) Villarino, L.; Garcıa-Fandino, R.;Lopez,F.;Mascarenas, J. L.Org. Lett.
2012, 14, 2996. (b) Sawano, T.; Ashouri, A.; Nishimura, T.; Hayashi, T.
J. Am. Chem. Soc. 2012, 134, 18936 and references cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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