Reactivity switch enabled by counterion: Highly chemoselective dimerization and hydration of terminal alkynes

Article abstract of DOI:10.1021/ol403684a

A counterion-controlled reactivity tuning in Pd-catalyzed highly chemoselective and regioselective dimerization and hydration of terminal alkynes is reported. The use of acetate as counterion favors the formation of an alkenyl alkynyl palladium intermediate which forms hitherto less reported 1,3-diaryl-substituted conjugated enynes after reductive elimination. Using chloride, which is a better leaving group, leads to anion exchange on the alkenylpalladium intermediate with hydroxide which after reductive elimination and tautomerization delivered the hydration products.

Full text of DOI:10.1021/ol403684a

Letter
pubs.acs.org/OrgLett
Reactivity Switch Enabled by Counterion: Highly Chemoselective
Dimerization and Hydration of Terminal Alkynes
Caixia Xu,†,‡ Weiyuan Du,§ Yi Zeng,§ Bin Dai,*,‡ and Hao Guo*,§
†School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
‡School of Chemistry and Chemical Engineering, Shihezi University, Key Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan, Shihezi Xinjiang 832003, China
§Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
S
* Supporting Information
ABSTRACT: A counterion-controlled reactivity tuning in Pd-catalyzed highly chemoselective and regioselective dimerization
and hydration of terminal alkynes is reported. The use of acetate as counterion favors the formation of an alkenyl alkynyl
palladium intermediate which forms hitherto less reported 1,3-diaryl-substituted conjugated enynes after reductive elimination.
Using chloride, which is a better leaving group, leads to anion exchange on the alkenylpalladium intermediate with hydroxide
which after reductive elimination and tautomerization delivered the hydration products.
This study commenced with the dimerization of 4-
lkynes, one of the most important classes of organic
Acompounds, have been extensively used as important methoxyphenylacetylene 1a under conditions A (3 mol % of
building blocks and versatile synthons in organic synthesis.1
Pd(PPh3)4, 20 mol % of HOAc (aq, 0.5 M), THF, and rt),
affording 77% isolated yield of 2,4-bis(4-methoxyphenyl)but-1-
en-3-yne 2a as the single product (entry 1, Table 1) (vide infra)
(for detailed information of the optimization, see the
Supporting Information). Neither 1,4-diarylenyne isomer nor
hydration byproduct was observed from H NMR analysis of
the crude reaction mixture.
The reactions of alkynes are of considerable interest and
provide various synthetic methods for many important
products such as enynes, ketones, diynes, alkynols, metal
acetylides, and arene derivatives, etc.2 Among these important
applications, dimerization3−6 and hydration7−11 are practical
and atom-economical methods for the synthesis of conjugated
enynes and ketones, which are basic reactions in alkyne
chemistry. Much progress has been achieved in dimerization of
terminal alkynes.3 Trost disclosed the first Pd(II)-catalyzed
head-to-tail dimerization of terminal acetylenes in 1987.5a,b
Since then, many efficient applications of this neutral
dimerization method in cascade transformations have been
developed.2d,5f Very recently, Guo and Han et al. reported the
Pd(0)-catalyzed dimerization of terminal alkynes in the
presence of a catalytic amount of Brønsted acid, which
presented a powerful tool to access 1,3-disubstituted enynes.6d
On the other hand, hydration of alkynes to form carbonyl
compounds is one of the most useful and important functional
group transformations.7 Over the past several decades,
numerous catalysts have been proven to be effective for this
reaction.8−11 The mechanism has been well studied and is
generally classified into a Lewis acid or Brønsted acid catalyzed
mechanism.8,9 To our knowledge, alkyne hydration involving a
new catalytic metal hydride mechanism has not been
documented. Herein, we report our recent observation on
highly chemoselective dimerization and hydration of terminal
alkynes tuned by the counterions on the palladium catalyst,
which provides a new protocol for the synthesis of 1,3-
diarylenynes or aryl methyl ketones, respectively.
1
To obtain more insight into the mechanism of this
dimerization reaction, 4-methoxyphenylboronic acid 4 was
added under conditions A to trap some key intermediates. After
the reaction was completed, 69% of 2a together with 2% of 1,1-
bis(4-methoxyphenyl)ethene 5 were formed (Scheme S1,
Supporting Information).
On the basis of this result and consistent with previous
mechanistic proposals,5a,6d,12−14 a plausible mechanism for this
dimerization reaction is proposed (Scheme 1). Pd(PPh3)2
formed through the disassociation of two PPh3 ligands from
Pd(PPh3)4 reacted with HOAc via oxidative addition to form
palladium hydride intermediate A.6d,12 The following hydro-
palladation of alkyne yielded alkenylpalladium intermediate
B.5a,6d,13 This could be strongly supported by the formation of
the coupling product 5 which could be well rationalized as a
result of transmetalation of 4 with intermediate B and
subsequent reductive elimination.13 Intermediate B further
reacted with another molecule of alkyne to form intermediate
TS. With the association of the acetate group, deprotonation of
the terminal alkyne took place to generate intermediate C.6d,14
Received: December 19, 2013
Published: January 27, 2014
© 2014 American Chemical Society
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Table 1. Pd-Catalyzed Dimerization and Hydration of Terminal Alkynes
a,
b
c,d
conditions A
conditions B
entry
1
R
time (h)
2
yield (%)
77
time (h)
3
yield (%)
1
1a
1b
1c
1d
1e
1f
4-MeO
3-MeO
2-MeO
2,6-diMeO
2-MeO-5-Me
4-EtO
4-BunO
4-BnO
4-AcO
4-NH2
2-PhCONH
4-Me
24
24
23
26
17
25
24
23
24
8
2a
2b
2c
2d
2e
2f
24
194
168
168
168
32
3a
3b
3c
3d
3e
3f
85
2
69
89
62
77
72
87
63
63
f,g
45
e
e
e
3
15 (65)
10 (33)
29 (19)
86
4
5
6
7
1g
1h
1i
2g
2h
2i
55
3g
3h
3i
82
8
48
80
9
26
42
10
11
12
13
14
15
16
17
18
19
20
21
1j
2j
0.5
3j
70
f
h
1k
1l
6
2k
2l
60
81
76
88
72
63
71
70
57
60
3k
3l
90
12
10
11
11
12
12
11
29
10
12
120
168
168
144
192
172
178
163
144
192
56
30
29
63
61
70
35
38
1m
1n
1o
1p
1q
1r
1s
1t
3-Me
2m
2n
2o
2p
2q
2r
2s
2t
3m
3n
3o
3p
3q
3r
3s
3t
2-Me
4-Et
4-But
4-Pentyln
H
4-F
e
e
4-CN
complicated
complicated
NR (85)
NR (69)
1u
4-Ac
2u
3u
a
The reaction was carried out using 1 (0.2 mmol), 3 mol % of Pd(PPh3)4, 20 mol % of HOAc (aq, 0.5 M), and THF (3 mL) at rt under argon
b
c
atmosphere. 2:3 > 99:1 and 1,3-diarylenynes/1,4-diarylenynes >99:1, based on 1H NMR analysis of the crude reaction mixture. The reaction was
carried out using 1 (0.2−0.4 mmol), 20 mol % of Pd(PPh3)4, 120 mol % of HCl (aq, 5 M), and THF (3 mL) at 45 °C under argon atmosphere. 3/
2 > 99:1 and no arylacetaldehydes were formed, based on H NMR analysis of the crude reaction mixture. Recovery yield of 1. 10 mol % of
d
e
f
1
g
h
Pd(PPh3)4 was applied. 2j decomposed quickly. 250 mol % of HCl (aq, 5 M) was applied.
Scheme 1. Proposed Mechanism
Final reductive elimination produced 1,3-diarylenyne 2 and
regenerated the catalytically active Pd(PPh3)2. Then it was
speculated that if the counterion AcO− on B was replaced by
other anions with higher leaving ability, the resulting
intermediate B′ might be susceptible to nucleophilic attack by
water molecule to afford intermediate C′ which would undergo
reductive elimination and rapid tautomerization to produce
ketone 3 (Scheme 1).
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To test this hypothesis, HCl was used instead of HOAc, since
Cl−, as a low coordinating anion,11 is much easier to leave
under the attack of H2O. To our delight, after optimization, the
hydration of 1a under conditions B (20 mol % of Pd(PPh3)4,
120 mol % of HCl (aq, 5 M), THF, and 45 °C) afforded 85%
isolated yield of 1-(4-methoxyphenyl)ethanone 3a as the sole
product (entry 1, Table 1) (vide infra) (for detailed
information of the optimization, see the Supporting Informa-
tion). Neither aldehyde isomer nor dimerization byproduct was
observed from 1H NMR analysis of the crude reaction mixture.
To gain more information of the mechanism of this
hydration reaction, 4 was applied under conditions B to trap
possible key intermediates. After full conversion, 2% of 5 was
isolated together with 75% of 3a (Scheme S2, Supporting
Information). The formation of 5 indicated that intermediate
B′ might be involved in the reaction pathway.
To probe the possibility that the hydration reaction could be
catalyzed by the in situ formed palladium(II) intermediate
HPdCl which potentially acted as a normal Lewis acid, the
comparatively more Lewis acidic catalyst PdCl2 was tested
under the optimized reaction conditions. Either with or without
HCl, the reactions catalyzed by PdCl2 led to complicated
mixtures, with only a trace amount of the hydration product
formed (Scheme S3, Supporting Information). These results
disfavor a Lewis acid catalyzed mechanism and indicate that the
palladium hydride mechanism is more plausible.
electron-withdrawing group, such as 4-cyano and 4-acetyl
(entries 20 and 21, Table 1), did not proceed at all. Then we
checked the position effect of substituents on the phenyl ring of
alkynes. Different from dimerization reaction, the relative
position of substituents showed great influence on this
hydration reaction. The hydration of alkynes bearing a methoxy
or methyl group at the 4-, 3-, or 2-position of phenyl ring
afforded ketones in 85%, 45%, and 15% isolated yields (entries
1−3, Table 1), respectively. Similar results were also observed
in the reactions of 4-, 3-, or 2-methyl-substituted arylacetylenes
(entries 12−14, Table 1). Next, the steric effect was
investigated. The reaction of 1d (entry 4, Table 1) proceeded
slowly to generate 3d in a very low yield of 10%, which
demonstrated that steric hindrance retarded this trans-
formation. Finally, the reactivity of internal alkynes, like 1,2-
diphenylethyne and prop-1-yn-1-ylbenzene, was studied. The
desired hydration was not observed (Scheme S4, Supporting
Information).
Notably, in all these reactions, excellent chemoselectivity and
1
regioselectivity were observed from H NMR analysis of the
crude reaction mixture. Although the yields were low in some
cases, no other byproducts were formed.
The reactivity of alkyl-substituted alkynes, like hex-1-yne 6,
was also explored toward both transformations. The dimeriza-
tion of 6 gave only 31% isolated yield of 7-methyleneundec-5-
yne 7. The hydration of 6 did not take place at all (Scheme S5,
Supporting Information).
In conclusion, we have developed a counterion-controlled
reactivity shift between dimerization and hydration of terminal
alkynes. This work features the employment of Pd(0) catalyst
combined with Brønsted acid, with a neat tuning of reactivity
between dimerization and hydration, as compared to the
commonly used Pd(II) catalytic system. The employment of
chloride as counterion promotes hydration of alkynes to
ketones via an unprecedented mechanism involving a metal
hydride intermediate. The reactivity tuning enabled by the
counterion is expected to enrich the understanding of
palladium chemistry and help guide studies in other systems.
Further detailed mechanistic and synthesis studies are currently
underway in our laboratory.
With the standard conditions in hands, we next investigated
the scope of the dimerization and hydration with a variety of
terminal alkynes (Table 1).
In the study of dimerization under conditions A, we first
explored the electronic effect of substituents on the phenyl ring.
Alkynes bearing an electron-donating group, such as alkoxy,
acetoxy, benzamido, and alkyl (entries 1−9 and 11−17, Table
1), were easily converted to the desired 1,3-diarylenynes
exclusively in good yields. Reactions of phenylacetylene 1r
(entry 18, Table 1) and alkyne possessing a weak electron-
withdrawing group, like 4-fluorine atom, 1s (entry 19, Table 1),
also gave satisfactory results. The desired products 2r and 2s
were formed in 70% and 57% isolated yields, respectively.
However, reactions of alkynes with strong electron-withdrawing
groups, such as 4-cyano and 4-acetyl (entries 20 and 21, Table
1), only resulted in complicated reaction mixtures. These
results indicated that the electron effect played a key role in this
reaction. We then studied the effect of the relative position of
the substituents on the phenyl ring. Reactions of alkynes with
either a methoxy or methyl group introduced to the 4-, 3-, or 2-
position of phenyl ring (entries 1−3 and 12−14, Table 1)
proceeded smoothly to give the corresponding products in
similar yields, which suggested that the relative position of
substituents on the phenyl ring had little influence on this
reaction. Further studies with 1d (entry 4, Table 1) led to the
formation of 2d in an isolated yield of 62%, which
demonstrated that highly sterically hindered substrate was
also tolerated in this reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: db_tea@shzu.edu.cn
*E-mail: hao_guo@fudan.edu.cn.
Notes
The authors declare no competing financial interest.
Next, hydration under conditions B was examined. Similar to
conditions A, a strong electronic effect on the phenyl ring was
observed. When alkynes are substituted with electron-donating
groups, such as 4-alkoxy, 4-acetoxy, 4-amino, 2-benzamido, and
4-alkyl (entries 1, 6−12, and 15−17, Table 1), the
corresponding ketones were formed in good yields. Reactions
of alkynes with hydrogen or fluorine atom attached on the
phenyl ring (entries 18 and 19, Table 1) gave the hydration
products in low yields. Reactions of alkynes with a strong
ACKNOWLEDGMENTS
■
We greatly acknowledge financial support from the National
Basic Research Program of China (973 Program,
2012CB720300), Program for Changjiang Scholars and
Innovative Research Team in University (No IRT1161),
National Nature Science Foundation of China (21102016
and 21274023), Shanghai Pujiang Program (11PJD004), and
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Letter
(14) Li, Y.-X.; Xuan, Q.-Q.; Liu, L.; Wang, D.; Chen, Y.-J.; Li, C.-J. J.
Am. Chem. Soc. 2013, 135, 12536.
the Specialized Research Fund for the Doctoral Program of
Higher Education of China (20110071120004).
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