Nickel-catalyzed three-component domino reactions of aryl grignard reagents, alkynes, and aryl halides producing tetrasubstituted alkenes

Article abstract of DOI:10.1021/ja513166w

Three-component reaction of aryl Grignard reagents, alkynes, and aryl halides in the presence of 1 mol % of NiCl₂ proceeded sequentially through carbomagnesiation of the alkyne followed by cross-coupling of the resulting alkenyl Grignard reagent with aryl halide to give tetrasubstituted alkenes in high yields.

Full text of DOI:10.1021/ja513166w

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Three-Component Domino Reactions of Aryl
Grignard Reagents, Alkynes, and Aryl Halides Producing
Tetrasubstituted Alkenes
Fei Xue,† Jin Zhao,*,† T. S. Andy Hor,*,†,‡ and Tamio Hayashi*,†,‡
†Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
‡Institute of Materials Research and Engineering, Agency for Science, Technology and Research, Singapore 117602, Singapore
S
* Supporting Information
Scheme 1. Three-Component Reactions of Organometallics,
Alkynes, and Aryl Halides Producing Tetrasubstituted
Alkenes
ABSTRACT: Three-component reaction of aryl Grignard
reagents, alkynes, and aryl halides in the presence of 1 mol
% of NiCl2 proceeded sequentially through carbomagne-
siation of the alkyne followed by cross-coupling of the
resulting alkenyl Grignard reagent with aryl halide to give
tetrasubstituted alkenes in high yields.
ransition-metal-catalyzed multicomponent domino and
Ttandem reactions have been powerful tools for constructing
complex molecules in a single flask.1 One representative reaction
is the Pd-catalyzed three-component reaction, reported by
Larock, of internal alkynes, aryl iodides, and arylboronic acids
producing tetrasubstituted alkenes.2,3 The reaction proceeds
through an alkenylpalladium species as a key intermediate, which
is formed by oxidative addition of aryl iodide to Pd(0) followed
by arylpalladation of alkyne. It reacts with arylboronic acid to give
the tetrasubstituted alkene through reductive elimination
(Scheme 1a).4,5 Another synthesis scheme to produce
tetrasubstituted alkenes from alkynes, aryl halides, and arylmetal
reagents can be via alkenyl metals generated by carbometalation
of alkynes. There have been several reports on the addition of
organomagnesium6 or -zinc7 reagents to unfunctionalized
alkynes forming the corresponding alkenyl metals, catalyzed by
transition metal salts or complexes, and these have been
subjected to further reactions to produce tetrasubstituted alkenes
by taking advantage of their high reactivity.8 Scheme 1b
illustrates some reactions where the alkenyl metal reagents
were used for the next step. Alkenyl Grignard reagents generated
by Fe- or Cr-catalyzed carbomagnesiation of alkynes are mixed
with organic halides in the presence of a Ni or Pd complex that
catalyzes the cross-coupling to give tetrasubstituted alkenes.6e,g
Alternatively, the alkenyl metal reagents are converted first into
alkenyl iodides and then they are subjected to Ni- or Pd-catalyzed
cross-coupling with organometallic reagents.7a,f,9 To our knowl-
edge, there have been no reports on the reactions where a
mixture of alkyne, organometallic reagent, and organic halide
produces a tetrasubstituted alkene by the carbometalation/cross-
coupling sequence8 (Scheme 1c). The three-component reaction
should consist of two sequential reactions: carbometalation
generating alkenyl metal species (cm1) and its cross-coupling
with organic halide (cc1). One serious problem in a three-
component reaction would be a possible side reaction where R1−
MX reacts with organic halide X−R2 (cc2) before the reaction
with alkyne. Another problem is the carbometalation of alkyne
with the alkenyl metal generating dienyl metal species (cm2). To
realize the three-component reaction, cm1 must be much faster
Received: December 26, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja513166w
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
than the unfavorable competing cross-coupling (cc2), and cc1
must be much faster than cm2.
During our studies on the NiCl2-catalyzed arylmagnesiation of
arylalkynes generating alkenylmagnesium reagents,6b we found
that the three-component domino reaction of aryl Grignard
reagents, alkynes, and aryl halides is also efficiently catalyzed by
NiCl2. Table 1 summarizes the results obtained for the reaction
that 7a is formed by cross-coupling of 8a with phenyl iodide that
is generated by the Mg/I exchange reaction.10 No 1,3-dienes,
which would be formed by the addition of 8a to 1a, were
detected.11
The toluene/THF mixed-solvent system is important for high
selectivity of 4a. Using all THF gave 4a in only 51% yield, with a
greater amount of the side products (entry 2). The yield of 4a
was 77% using diethyl ether in place of toluene as a diluting
solvent (entry 3). Interestingly, arylmagnesiation or cross-
coupling did not take place with 2a in diethyl ether, with starting
1a being recovered intact (entry 4). Addition of a small amount
of THF to the toluene/diethyl ether mixed-solvent system gave
essentially the same result as that of toluene/THF (entry 5).
NiCl2·6H2O catalyzed the three-component reaction as well as
NiCl2 to give 4a in a comparable yield (81%, entry 6). Because of
its easy handling, NiCl2·6H2O was used as one of the standard
conditions for the present study (vide infra). Other Ni salts,
Ni(acac)2 and Ni(OAc)2·4H2O, also catalyzed the reaction, but
the yield of 4a was a little lower (entries 7 and 8). NiCl2(PPh3)2,
known to catalyze both cross-coupling of Grignard reagents12
and arylmagnesiation of alkynes,6a gave 6a as a main product
together with a minor amount of three-component coupling
product 4a in both THF/toluene and Et2O/toluene (entries 9
and 10). PdCl2(PPh3)2 did not catalyze the formation of 3-
component coupling product 4a at all, whereas 6a was formed at
a high yield (70%, entry 12). Reactions in the presence of
Fe(acac)3/IPr (entry 13) and MnCl2 (entry 14), both of which
have been reported to catalyze arylmagnesiation,6c,e either did
not produce 4a at all or gave 4a in a very low yield, respectively,
although phenylmagnesiation proceeded to some extent. The
present system can be scaled up 10-fold without difficulty (entry
15, 4a in 81% yield).
Table 1. Three-Component Reaction of Diphenylacetylene
(1a), Phenylmagnesium Bromide (2a), and 4-Iodoanisole
a
(3a)
yield
recovd
yield
yield
b
yield
entry
1
catalyst
NiCl2
4a
1a
5a
6a
7a
82
51
77
0
0
0
5
12
8
11
17
13
0
5
9
7
0
3
5
3
3
9
0
3
0
2
2
6
c
2
NiCl2
d
3
NiCl2
0
e
4
f
NiCl2
98
0
<1
6
5
NiCl2
82
81
75
62
33
32
30
0
12
11
15
27
53
55
15
70
3
6
7
8
9
NiCl2·6H2O
Ni(acac)2
Ni(OAc)2·4H2O
NiCl2(PPh3)2
NiCl2(PPh3)2
NiCl2(dppe)
PdCl2(PPh3)2
0
7
0
8
0
15
18
2
25
55
10
88
40
52
0
c
10
11
12
55
9
By monitoring the reaction progress of 1a, 2a, and 3a in the
presence of 1 mol % NiCl2 (Table 1, entry 1), we gained
substantial information on the reaction mechanism (Figure 1).
The most significant feature is that phenylmagnesiation of 1a to
form 8a is very fast. Within 10 min, more than 70% of 1a is
converted into 8a, and in 20 min all 1a is consumed. Second, the
cross-coupling of 8a with 3a, giving final product 4a, is slow
g
h
13
Fe(acac)3/IPr
0
38
33
5
i
14
j
MnCl2
NiCl2
5
5
15
81
15
a
To a mixture of 1a (0.50 mmol), 3a (0.60 mmol), and catalyst (0.005
mmol, 1 mol %) in toluene (2.0 mL) was added PhMgBr (2a: 1.0 M in
THF, 0.60 mL, 0.60 mmol), and the mixture was stirred under N2 at
b
30 °C for 2 h. Values given are percent isolated yield. Based on the
c
amount of 3a used. PhMgBr (2a: 1.0 M in THF, 0.60 mL) + THF
d
(2.0 mL). PhMgBr (2a: 1.0 M in THF, 0.60 mL) + Et2O (2.0 mL).
e
f
PhMgBr (2a: 1.0 M in Et2O, 0.60 mL) + toluene (2.0 mL). PhMgBr
(2a: 1.5 M in Et2O, 0.40 mL) + toluene (2.0 mL) + THF (0.20 mL).
g
h
Fe(acac)3 (5 mol %) and IPr (20 mol %) at 60 °C for 16 h. IPr =
i
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. MnCl2 (10 mol %)
at 100 °C for 16 h. The reaction was scaled up 10-fold.
j
of diphenylacetylene (1a) with phenylmagnesium bromide (2a)
and 4-iodoanisole (3a) in the presence of transition metal salts
and complexes that have been reported to catalyze the
carbomagnesiation and/or cross-coupling reactions. The highest
selectivity in forming the tetrasubstituted alkene was obtained
with NiCl2 as a catalyst in a THF/toluene mixed solvent. Thus, to
a mixture of 1a (0.50 mmol), 3a (0.60 mmol), and NiCl2 (0.005
mmol, 1 mol %) in toluene (2.0 mL), was added PhMgBr/THF
(2a, 0.60 mL of 1.0 M THF solution, 0.60 mmol), and the
mixture was stirred at 30 °C for 2 h (entry 1). Aqueous workup
gave 82% yield of the three-component coupling product 4a.
Formation of a minor amount of triphenylethene (5a, 5%) and
tetraphenylethene (7a, 5%), together with biaryl 6a (11%), was
also observed. It is likely that 5a is formed by hydrolysis of 8a and
Figure 1. Time-dependent percentage of 1a, 4a, 5a, 6a, and 7a in the
reaction of 1a (0.50 mmol), 2a (0.60 mmol), and 3a (0.60 mmol) in the
presence of NiCl2 (1 mol %) in toluene (2.0 mL) at 30 °C (Table 1,
entry 1). Reaction was quenched by addition of H2O, and organic layer
was analyzed by GC-MS using hexadecane as an internal standard. The
amount of 5a should correspond to that of alkenylmagnesium 8a.
B
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Journal of the American Chemical Society
Communication
compared with phenylmagnesiation of 1a. We observed that 8a
was gradually converted into cross-coupling product 4a over 90
min. Third, the cross-coupling of 2a with 3a giving 6a took place
in an initial stage. The yield of 6a was 16% at 20 min and
remained thus until the end of the reaction. This is ascribed to the
fast consumption (<20 min) of all of 2a, mainly by the
phenylmagnesiation of 1a and partly by the cross-coupling with
3a. Furthermore, 7a formed between 8a and phenyl iodide (vide
supra) can be detected after 20 min, and the yield of 7a remained
5% over the course of the reaction.
Table 2. Reaction of Diarylacetylenes with Aryl Iodides and
the Grignard Reagents
a
b
entry
Ar1
Ar2
Ar3-X
yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph-I
77 (4b)
71 (4c)
78 (4d)
64 (4e)
65 (4f)
64 (4a)
64 (4c)
83 (4d)
62 (4e)
60 (4g)
70 (4h)
64 (4i)
62 (4b)
61 (4d)
3-MeC6H4-I
4-MeC6H4-I
4-FC6H4-I
1-naphthyl-I
Ph-I
A competition reaction (Scheme 2) demonstrates that 2a is
more reactive than 8a toward the Ni-catalyzed cross-coupling
4-MeOC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
2-MeC6H4
Ph
Scheme 2. Competition between Alkenylmagnesium 8a and
PhMgBr (2a) in NiCl2-Catalyzed Cross-Coupling
Ph-I
Ph-I
c
9
Ph-I
d
10
Ph-I
e
11
3-MeC6H4
3-MeC6H4-I
4-MeC6H4-I
Ph-Br
e
12
4-MeC6H4
Ph
d
d
f
,
,
e
e
13
14
15
16
17
Ph
Ph
Ph
Ph
4-MeC6H4-Br
4-MeOC6H4-I
4-MeOC6H4-I
Ph-I
g
Ph
4-MeOC6H4
4-FC6H4
2-MeC6H4
73 (4j)
h
Ph
66 (4k)
c
,
d
i
2-MeC6H4, Ph
51 (4l)
a
All reactions were carried out with diarylacetylene (0.50 mmol), Ar2
MgBr/THF (0.60 mmol), Ar3X (0.60 mmol), and NiCl2·6H2O (0.005
b
mmol) in toluene (2.0 mL) under N2 at 30 °C for 2 h. Isolated yield.
with 3a under the present conditions. Thus, to the solution of 8a
generated by the NiCl2-catalyzed phenylmagnesiation of 1a, an
equivalent amount of PhMgBr/THF 2a was added, and the
resulting mixture of 8a and 2a, containing the Ni catalyst, was
allowed to react with 3a. Aqueous workup gave 78% yield of 5a
and 63% of 6a with a minor amount (5%) of 4a and 7a.
The high selectivity in giving the three-component arylmag-
nesiation/cross-coupling product is mainly ascribed to the very
fast arylmagnesiation of 1a with 2a in the presence of NiCl2
catalyst (Scheme 1, cm1). Although the cross-coupling of the
resulting alkenylmagnesium reagent 8a with 3a to form 4a (cc1)
is slower than the cross-coupling of 2a with aryl iodide (cc2),
most of 2a is first consumed by the phenylmagnesiation of 1a; as
a result, only a small amount of the unreacted 2a participates in
the cross-coupling with 3a. Under the present conditions, the
carbomagnesiation of 1a with 8a which would generate
dienylmagnesium species (cm2) is not observed.
c
d
e
f
g
h
For 6 h. At 60 °C. For 16 h. At 40 °C. Z/E = 93:7. Z/Ε = 88:12.
i
Mixture of three isomers in a ratio of 70:25:5; 2-MeC6H4MgBr (2.0
M in Et2O, 0.30 mL) + toluene (2.0 mL) + THF (0.30 mL).
olefin geometry. In the reaction of unsymmetrically substituted
diarylacetylene (entry 17), the arylmagnesiation step is not
highly regioselective to give a mixture of isomers.
The domino reaction of alkyl(aryl)acetylenes also proceeded
successfully (Scheme 3). The regiochemistry is consistent with
Scheme 3. Reaction of Alkyl(aryl)acetylenes with Aryl Iodides
a
and the Grignard Reagents
The scope of the diarylacetylenes 1, arylmagnesium bromides
2, and aryl halides 3 in the three-component domino reaction is
summarized in Table 2. This method applies well to 2 and 3 with
an electron-donating or -withdrawing group on the phenyl ring at
different positions. The aryl iodides with a substituent in the para
position gave higher yields than those in the ortho or meta
position (entries 1−5). The electron-donating substituent on the
aryl iodides gave a higher yield of 4 than an electron-withdrawing
substituent (entries 3 and 4). Similar electronic and steric effects
were also observed for aryl Grignards. Aryl Grignard with a
methyl group in the para position gave as high as 83% yield (entry
8), but the ortho-methyl gave 4 in 60% yield at higher
temperature (entry 10). Diarylacetylenes with an electron-rich
substituent in the meta or para position position produced
tetrasubstituted olefin only after longer reaction time (16 h,
entries 11−12). The reaction also works well with aryl bromides
at an elevated temperature and after a longer reaction time
(entries 13−14). High Z selectivity was observed in entries 15
and 16, which demonstrates that the cross-coupling of
alkenylmagnesium with aryl iodides proceeds with retention of
a
Alkyl(aryl)acetylene 1 (0.50 mmol), Ar2 MgBr/THF 2 (0.60 mmol),
Ar3I 3 (0.60 mmol), and NiCl2·6H2O (0.005 mmol) in toluene (2.0
mL). Ratio of 4/4′
b
C
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
326−336. (d) Wen, Y.; Huang, L.; Jiang, H. J. Org. Chem. 2012, 77,
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our previous work on the arylmangesiation where magnesium
attaches the aryl-substituted carbon.6b An array of arylmagne-
sium bromides with electron-rich or -poor substituents reacted
with 1-phenyl-1-hexyne and iodobenzene to give tetrasubstituted
alkenes 4m,n,o with exclusive regioselectivity. The aryl iodides
with electron-rich and -deficient groups at para or meta position
gave corresponding olefins 4r,s,t with highly stereo- and
regioselectivity. The olefin products bearing a chloroalkyl (4p)
or -aryl (4u), methyl ether (4q), and an amino group (4w,
Tamoxifen)13 were prepared by the present domino reaction.
The molecular structures of 4m,r,t,v were determined by X-ray
single crystal diffraction.
We have studied a three-component domino coupling of
internal alkynes with aryl Grignard reagents and aryl iodides,
which is catalyzed by a simple Ni salt, NiCl2. Monitoring the
reaction progress revealed that the arylmagnesiation of alkyne
generating alkenylmagnesium species is extremely fast, which
realizes the selective three-component coupling with a minimal
amount of side products. This Ni-catalyzed reaction provides us
with a new operationally simple method of synthesizing
tetrasubstituted alkenes with high stereo- and regioselectivity.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectra, and crystallographic data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
■
(8) Reviews on catalytic carbometalation of alkynes: (a) Flynn, A. B.;
Ogilvie, W. W. Chem. Rev. 2007, 107, 4698−4745. (b) Itami, K.;
Yoshida, J.-I. Carbomagnesiation Reactions. In The Chemistry of
Organomagnesium Compounds; Rappoport, Z.; Marek, I., Eds.; Wiley:
Chichester, U.K., 2008; pp 631−679. (c) Lorthiois, E.; Meyer, C.
Carbozincation of Alkenes and Alkynes. Patai’s Chemistry of Functional
Groups [Online] ; Wiley: New York, 2009. (d) Murakami, K.; Yorimitsu,
H. Beilstein J. Org. Chem. 2013, 9, 278−302.
Corresponding Authors
*chmzhaoj@nus.edu.sg
*andyhor@nus.edu.sg
*chmtamh@nus.edu.sg
Notes
The authors declare no competing financial interests.
(9) Pioneering work in the three-component reaction forming
tetrasubstituted alkenes from alkynes by palladium-catalyzed bromoal-
lylation and cross-coupling: Thadani, A. N.; Rawal, V. H. Org. Lett. 2002,
4, 4317−4320.
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P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
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ACKNOWLEDGMENTS
■
We thank the Agency for Science, Technology, and Research
(A*Star) of Singapore (R-143-000-566-305) and GlaxoSmithK-
line (R-143-000-492-592) for financial support.
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DOI: 10.1021/ja513166w
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