Controllable stereoselective synthesis of trisubstituted alkenes by a catalytic three-component reaction of terminal alkynes, benzylic alcohols, and simple arenes

Article abstract of DOI:10.1039/b911954j

The acid-catalyzed three-component reaction of terminal alkynes, benzylic alcohols, and simple arenes provides convenient and atom-economic access to an array of both Z- and E-isomers of trisubstituted alkenes with excellent stereoselectivity by switching

Full text of DOI:10.1039/b911954j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Controllable stereoselective synthesis of trisubstituted alkenes by a catalytic
three-component reaction of terminal alkynes, benzylic alcohols,
and simple arenes†
Hai-Hua Li, Yin-Huan Jin, Jie-Qi Wang and Shi-Kai Tian*
Received 17th June 2009, Accepted 22nd June 2009
First published as an Advance Article on the web 30th June 2009
DOI: 10.1039/b911954j
Table 1 Optimization of reaction conditionsa
The acid-catalyzed three-component reaction of terminal
alkynes, benzylic alcohols, and simple arenes provides con-
venient and atom-economic access to an array of both
Z- and E-isomers of trisubstituted alkenes with excellent
stereoselectivity by switching reaction temperature and acidic
catalysts.
Entry Catalyst
Solvent Yield (%)b 4Aa:4Bac
Trisubstituted alkenes are not only structural motifs in many
biologically relevant molecules, but serve also as a foundation
for stereoselective synthesis. One of the most direct and versatile
approaches to access geometrically defined trisubstituted alkenes
is the regio- and stereoselective addition of a carbon electrophile
and a carbon nucleophile across a terminal carbon–carbon
triple bond in a multicomponent fashion.1,2 Previously reported
protocols for such vicinal difunctionalization of terminal alkynes
are focused on the use of organometallics as carbon nucleophiles
in conjunction with various carbon electrophiles, and in general,
transition metals are needed to catalyze these three-component
assemblies.1,3 Herein, we wish to disclose a conceptually new
method for the selective vicinal difunctionalization of terminal
alkynes using benzylic alcohols and simple arenes as carbon
electrophiles and carbon nucleophiles, respectively, in the presence
of acidic catalysts. Importantly, this three-component reaction
provides convenient and atom-economic access to an array of
both Z- and E-isomers of trisubstituted alkenes with excellent
stereoselectivity by switching reaction temperature and acidic
catalysts.4
In the course of exploring useful catalytic processes under
acidic conditions,5 we found unexpectedly that trisubstituted
alkene 4Aa was produced with high stereoselectivity by a three-
component reaction of phenylacetylene (1a) with benzhydrol
(2a) and mesitylene (3a) in the presence of acids (Table 1).
Initially, a single Brønsted or Lewis acid (20 mol%) was used
to catalyze this three-component reaction in nitromethane at an
ambient temperature of 10 ◦C (Table 1, entries 1–4). Although
the employment of trifluoromethanesulfonyl anhydride (Tf2O)
resulted in the formation of trisubstituted alkene 4Aa with an
E/Z selectivity up to 99:1, the yield was just 53%, mainly owing
to the unwanted Friedel–Crafts alkylation of mesitylene (3a)
with benzhydrol (2a) (Table 1, entry 3).6 To improve the yield,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18e
19f
20g
21h
TfOH
Tf2NH
Tf2O
FeCl3
MeNO2 29
MeNO2 52
MeNO2 53
MeNO2 32
MeNO2 70
MeNO2 66
MeNO2 60
97 : 3
96 : 4
99 : 1
98 : 2
96 : 4
96 : 4
96 : 4
96 : 4
97 : 3
95 : 5
93 : 7
96 : 4
Tf2O/FeCl3 (1:1)
Tf2O/FeCl3·6H2O (1:1)
Tf2O/FeCl3/AgOTf (1:1:1)
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 82
Tf2O/FeCl3/AgNO3 (1:1:1) EtNO2 56
Tf2O/FeCl3/AgNO3 (1:1:1) (ClCH2)2 28
Tf2O/FeCl3/AgNO3 (1:1:1) CHCl3 20
Tf2O/FeCl3/AgNO3 (1:1:1) CH2Cl2 21
Tf2O/FeCl3/AgNO3 (1:1:1) THF
Tf2O/FeCl3/AgNO3 (1:1:1) EtOAc
Tf2O/FeCl3/AgNO3 (1:1:1) MeCN
Tf2O/FeCl3/AgNO3 (1:1:1) dioxane
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 51
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 41
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 49
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 56
Tf2O/FeCl3/AgNO3 (1:1:1) MeNO2 56
0
0
0
0
96 : 4
96 : 4
97 : 3
96 : 4
97 : 3
a Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), 3a (0.40 mmol),
catalyst (20 mol%), solvent (0.20 mL), 10 ◦C, 21 h. b Isolated yield.
c Determined by 1H NMR analysis. d 10 mol% of catalyst was used.
e 1a/2a/3a = 1:1.5:1.5. f 1a/2a/3a = 1:2:2. g 0.10 mL of MeNO2 was used.
h 0.40 mL of MeNO2 was used.
combinations of two or three acids were further evaluated (Table 1,
entries 5–8), and gratifyingly, Tf2O in combination with FeCl3 and
AgNO3 could catalyze the reaction to afford trisubstituted alkene
4Aa in 82% yield and with an E/Z selectivity of 96:4 (Table 1,
entry 8).7 Further investigations revealed that the yield was
reduced significantly when using another common organic solvent
instead of nitromethane, decreasing the catalyst loading (from
20 mol%), deviating from the 1:1.5:2 ratio of substrates 1a/2a/3a,
or varying the volume of solvent (from 1 mL of nitromethane for
1 mmol of alkyne 1a) (Table 1, entries 9–21).
Upon exposure to the catalyst system of Tf2O/FeCl3/AgNO3
(1:1:1), a range of arylacetylenes coupled with benzhydrol (2a) and
mesitylene (3a) at 10 ◦C or a lower temperature to give the corre-
sponding trisubstituted alkenes in moderate to excellent yields and
with excellent stereoselectivity (Table 2, entries 1–8).8 Notably, the
opposite stereoselectivity was obtained only in the reaction with
4-methoxyphenylacetylene, the electron-rich benzene moiety of
Department of Chemistry, University of Science and Technology of China,
Hefei, Anhui 230026, China. E-mail: tiansk@ustc.edu.cn; Fax: (+86) 551-
360-1592; Tel: (+86) 551-360-0871
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H and 13C NMR spectra
for the products. See DOI: 10.1039/b911954j
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Table 2 Controllable stereoselective three-component synthesis of trisubstituted alkenesa
Entry Ar1
R1
R2
Ar2
Temp/oC
Time/h
Productb
Yield (%)c
4A:4Bd
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
10
-20
-20
-20
10
-5
10
21
24
23
24
40
27
48
24
37
4Aa
4Ab
4Ac
4Bd
4Ae
4Af
4Ag
4Ah
4Ai
82
99
99
72
62
70
56
45
60
96:4
98:2
99:1
2:98
97:3
98:2
95:5
97:3
98:2
4-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-BrC6H4
4-FC6H4
3-ClC6H4
2-FC6H4
Ph
Ph
10
10
R1, R2 =
10
11
12
13
14
15
16
17
Ph
Ph
Ph
4-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
2-MeC6H4
2-naphthyl
R1, R2 =
4-ClC6H4
(E)-PhCH CH
Me
Me
Me
Me
Me
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
10
10
10
-20
-5
10
60
22
60
24
27
22
22
22
4Aj
4Ak
4Al
4Am
4An
4Ao
4Ap
4Aq
62
89
52
65
69
82
56
63
97:3
93:7
97:3
93:7
96:4
95:5
93:7
98:2
=
10
10
18
19
20
21
22
23
24
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
Ph
4-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
2-MeC6H4
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
Me
Me
Me
Me
Ph
2,4-Me2C6H3
2,5-Me2C6H3
-20
-20
10
10
10
10
10
10
80
80
80
80
80
80
80
80
80
80
80
22
22
45
17
17
20
17
71
5
5
5
5
5
5
5
5
5
5
5
4Ar
4As
4At
4Au
4Av
4Aw
4Ax
4Ay
4Ba
4Bb
4Bc
4Bf
60e
50
48
63
68
49
46
52f
50
68
64
63
73
45
69
65
48
60
52
97:3
96:4
98:2
99:1
93:7
96:4
97:3
93:7
3:97
3:97
3:97
6:94
7:93
1:99
2:98
3:97
5:95
4:96
2:98
3-I-2,4,6-Me3C6H
3-I-2,4,6-Me3C6H
3-Br-2,4,6-Me3C6H
2,3,5,6-Me4C6H
2,3,5,6-Me4C6H
1-naphthyl
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
2,4,6-Me3C6H2
3-Br-2,4,6-Me3C6H
2,3,5,6-Me4C6H
25
26g
27
Ph
4-MeC6H4
4-tBuC6H4
4-FC6H4
Ph
4-MeC6H4
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
28
29g
30g
31
4Bj
4Bm
4Bn
4Bo
4Bp
4Bv
4Bx
32g
33g
34g
35g
36g
Ph
Ph
a Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), 3 (0.40 mmol), Tf2O/FeCl3/AgNO3 (1:1:1, 20 mol%), MeNO2 (0.20 mL). b The major stereoisomer
1
of the alkene products. c Isolated yield. d Determined by H NMR analysis. e Obtained as a 85:15 mixture of regioisomers (For the minor regioisomer,
Ar2 = 2,6-Me2C6H3). f Obtained as a 93:7 mixture of regioisomers (For the minor regioisomer, Ar2 = 2-naphthyl). g FeCl3 (50 mol%) was used as the
catalyst instead of Tf2O/FeCl3/AgNO3 (1:1:1, 20 mol%).
which did not lead to significant side reactions such as the Friedel–
Crafts alkylation (Table 2, entry 4). To our delight, a wide variety
of secondary benzylic alcohols could serve as suitable substrates
for this highly stereoselective three-component reaction (Table 2,
entries 9–17).9 Furthermore, the replacement of mesitylene (3a)
with xylene, 1,2,4,5-tetramethylbenzene, naphthalene, or an aryl
halide in this reaction resulted in the formation of structurally
diversified trisubstituted alkenes with excellent stereoselectivity
(Table 2, entries 18–25).10
Interestingly, the stereoselectivity of the three-component reac-
tion was completely reversed when the temperature was elevated
to 80 ◦C (Table 2, entries 26–36). It should be noted that in
many cases better stereoselectivity was observed when FeCl3
was used as the catalyst instead of Tf2O/FeCl3/AgNO3 (1:1:1),
and the modified reaction conditions provided a complementary
and highly stereoselective access to the trisubstituted alkenes of
opposite geometric configuration.
The Tf2O/FeCl3/AgNO3-catalyzed reaction of optically active
(R)-1-phenylethanol (97% ee) with phenylacetylene (1a) and
mesitylene (3a) at 10 ◦C gave the desired alkene product in nearly
racemic form (5% ee). This result suggests that a carbocation
intermediate is generated from an alcohol and/or its derivative(s)
during the reaction.11 Thus, a plausible reaction pathway has
been proposed for the three-component reaction of terminal
alkynes with benzylic alcohols and simple arenes (Scheme 1).
The regioselective attack of terminal alkyne 1 by carbocation 5,
generated in situ from benzylic alcohol 2 in the presence of acidic
species (LA),11,12 results in the formation of vinylic carbocation 6,
which undergoes an electrophilic aromatic substitution reaction
with simple arene 3 from the less sterically hindered side to give
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(d) Multicomponent reactions, (Eds: J. Zhu, H. Bienayme´,), Wiley-VCH,
Weinheim, Germany, 2005.
3 For recent examples of three-component carbometalation/coupling
reactions, see: (a) M. Lozanov and J. Montgomery, J. Am. Chem. Soc.,
2002, 124, 2106; (b) Y. Ni, K. K. D. Amarasinghe and J. Montgomery,
Org. Lett., 2002, 4, 1743; (c) S. J. Patel and T. F. Jamison, Angew.
Chem., Int. Ed., 2003, 42, 1364; (d) E. Shirakawa, Y. Yamamoto,
Y. Nakao, S. Oda, T. Tsuchimoto and T. Hiyama, Angew. Chem.,
Int. Ed., 2004, 43, 3448; For recent examples of one-pot, two-step
carbometalation/coupling reactions, see: (e) M. Takimoto, K. Shimizu
and M. Mori, Org. Lett., 2001, 3, 3345; (f) P. Wipf, R. L. Nunes and
S. Ribe, Helv. Chim. Acta, 2002, 85, 3478; (g) B. H. Lipshutz, T. Butler
and A. Lower, J. Am. Chem. Soc., 2006, 128, 15396; (h) B. H. Lipshutz,
T. Butler, A. Lower and J. Servesko, Org. Lett., 2007, 9, 3737; (i) Z. Lu
and S. Ma, J. Org. Chem., 2006, 71, 2655.
Scheme 1 Proposed reaction pathway.
4 In principle, water is the sole by-product for this reaction.
5 (a) C.-R. Liu, M.-B. Li, C.-F. Yang and S.-K. Tian, Chem.–Eur. J.,
2009, 15, 793; (b) C.-R. Liu, M.-B. Li, D.-J. Cheng, C.-F. Yang and
S.-K. Tian, Org. Lett., 2009, 11, 2543; (c) C.-R. Liu, M.-B. Li, C.-F.
Yang and S.-K. Tian, Chem. Commun., 2008, 1249; (d) B.-L. Yang and
S.-K. Tian, Eur. J. Org. Chem., 2007, 4646; (e) Q.-Y. Song, B.-L. Yang
and S.-K. Tian, J. Org. Chem., 2007, 72, 5407.
6 For a review of Friedel-Crafts alkylations, see: G. A. Olah, R.
Krishnamurti, G. K. Surya, in Comprehensive Organic Synthesis,
Vol. 3, (Eds: B. M. Trost, I. Fleming), Pergamon Press: Oxford, 1991,
pp. 293.
7 It should be noted that AgNO3 alone could not catalyze the three-
component reaction. Although Fe(NO3)3 and AgCl were expected to
be generated by the reaction of FeCl3 with AgNO3, the use of Tf2O in
combination with Fe(NO3)3 to catalyze the reaction just led to a much
lower yield (31%).
8 The reaction with either alkylacetylenes or internal alkynes failed to
give the desired trisubstituted alkene products. The stereochemistry of
trisubstituted alkenes was determined by 2D NOESY analysis and/or
by analogy. For details, see the ESI†.
9 No desired trisubstituted alkene was obtained from the reaction with
a primary benzylic alcohol such as benzyl alcohol or with a tertiary
alcohol such as tert-butanol. Although a few allylic alcohols, such as
2-cyclohexenol and 4-phenyl-3-buten-2-ol, could serve as substrates
for the three-component reaction, complex mixtures of products were
obtained and the yields for the desired alkene products were less than
40%.
10 The reaction of benzene with phenylacetylene (1a) and benzhydrol (2a)
gave the desired alkene product, 1,1,3,3-tetraphenylpropene, in only
15% yield under the same reaction conditions for 71 h. In addition,
no desired alkene product was obtained from the reaction with highly
activated aromatic compounds such as anisole, thiophene, and indole
mainly owing to the unwanted Friedel–Crafts alkylation.
trisubstituted alkene 4A as the major geometric isomer. It is
reasonable to conclude that vinylic carbocation 6 can also couple
with other nucleophiles such as chloride anions present in the
reaction mixture.13,14 Indeed, Ph(Cl)C CH(CHPh2) was identified
=
as a by-product in the Tf2O/FeCl3/AgNO3-catalyzed reaction of
phenylacetylene (1a) with benzhydrol (2a) and mesitylene (3a).
However, trisubstituted alkene 4A can rapidly isomerize to the
thermodynamically favored trisubstituted alkene 4B when the
acidic reaction mixture is subjected to an elevated temperature.15
Apparently, the opposite stereoselectivity occurring in the reaction
with 4-methoxyphenylacetylene at -20 ◦C could be ascribed to
the quick isomerization of the alkene product taking place at a
much lower temperature relative to the others shown in Table 2
(vide supra).
In summary, we have developed a highly stereoselective synthe-
sis of trisubstituted alkenes through a three-component reaction
of terminal alkynes with benzylic alcohols and simple arenes under
acidic conditions. Significantly, an array of both Z- and E-isomers
of trisubstituted alkenes can be accessed with excellent stereose-
lectivity by switching reaction temperature (-20 to 80 ◦C) and
acidic catalysts [Tf2O/FeCl3/AgNO3 (1:1:1) or FeCl3]. Current
efforts are directed toward further methodological refinements,
mechanistic studies, and synthetic applications.
Acknowledgements
11 At an early stage of the reaction, a significant portion of alcohol was
converted to the corresponding ether that could generate a carbocation
intermediate under acidic conditions. For our recent observation, see:
H.-H. Li, D.-J. Dong and S.-K. Tian, Eur. J. Org. Chem., 2008, 3623.
12 At present we are not aware of the exact role that each of the three acids
plays in the three-component reaction. In Scheme 1, LA represents one
or more acidic species that result from the catalyst system.
We are grateful for financial support from the National Natural
Science Foundation of China (20732006 and 20672105) and the
Chinese Academy of Sciences.
13 (a) F. Marcuzzi and G. Melloni, J. Am. Chem. Soc., 1976, 98, 3295;
(b) S. Yamazaki, K. Yamada, S. Yamabe and K. Yamamoto, J. Org.
Chem., 2002, 67, 2889; (c) Z.-Q. Liu, J. Wang, J. Han, Y. Zhao and B.
Zhou, Tetrahedron Lett., 2009, 50, 1240; (d) Z. Liu, J. Wang, Y. Zhao
and B. Zhou, Adv. Synth. Catal., 2009, 351, 371.
Notes and references
1 For reviews, see: (a) E. Negishi, Z. Huang, G. Wang, S. Mohan, C.
Wang and H. Hattori, Acc. Chem. Res., 2008, 41, 1474; (b) M. Mori,
Eur. J. Org. Chem., 2007, 4981; (c) J. Montgomery, Acc. Chem. Res.,
2000, 33, 467; (d) S. Ikeda, Acc. Chem. Res., 2000, 33, 511; (e) Prepara-
tion of Alkenes: A Practical Approach, (Ed: J. M. J. Williams,), Oxford
University Press, Oxford, UK, 1996; (f) J. F. Normant and A. Alexakis,
Synthesis, 1981, 841.
2 For recent reviews of multicomponent reactions, see: (a) B. Ganem,
Acc. Chem. Res., 2009, 42, 463; (b) A. Dondoni and A. Massi, Acc.
Chem. Res., 2006, 39, 451; (c) A. Do¨mling, Chem. Rev., 2006, 106, 17;
14 Plausibly, this side reaction can be relieved significantly by the presence
of 20 mol% of AgNO3 owing to formation of AgCl.
15 Trisubstituted alkene 4Aa (E/Z = 96:4) was smoothly converted to
its corresponding Z-isomer, 4Ba (E/Z = 1:99), by FeCl3 (50 mol%)
in nitromethane at 80 ◦C for 5 h. For the Lewis acid-catalyzed
isomerization of 1-alkyl-2,2-diarylethenes, see: (a) T. Tsuchimoto, T.
Maeda, E. Shirakawa and Y. Kawakami, Chem. Commun., 2000, 1573;
(b) R. Li, S. R. Wang and W. Lu, Org. Lett., 2007, 9, 2219.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3219–3221 | 3221
©