Nickel-catalyzed Kumada reaction of tosylalkanes with Grignard reagents to produce alkenes and modified arylketones

Article abstract of DOI:10.1002/anie.201205969

Open a new door: The first example of alkene synthesis from alkyl electrophiles with Grignard reagents using the Kumada cross-coupling reaction strategy is reported. This method opens a new door for the Kumada cross-coupling reaction, allowing alkenes to be prepared from the reaction of tosylalkanes with Grignard reagents. Copyright

Full text of DOI:10.1002/anie.201205969

Angewandte
Chemie
DOI: 10.1002/anie.201205969
Cross-Coupling
Nickel-Catalyzed Kumada Reaction of Tosylalkanes with Grignard
Reagents to Produce Alkenes and Modified Arylketones**
Ji-Cheng Wu, Lu-Bing Gong, Yuanzhi Xia, Ren-Jie Song, Ye-Xiang Xie, and Jin-Heng Li*
The cross-coupling of an organic electrophile with a nucleo-
philic organometallic reagent is one of the most important
and common methods for the construction of carbon–carbon
bonds.[1,2] Despite considerable progress in the field, examples
of the transition-metal-catalyzed Kumada cross-coupling of
an alkyl electrophile with a Grignard reagent are much less
abundant and are more limited.[1–3] The products are generally
modified alkanes, a carbonyl group in the substrates can often
not be tolerated, and the alkyl electrophiles are focused on
alkyl halides and pseudohalides (often tosylates).
and arylketones, are valuable synthetic intermediates and
important structural units found in numerous natural prod-
ucts, pharmaceutical molecules, and functional materials.[6]
Our investigation began with the reaction of 1-methoxy-4-
(1-tosylethyl)benzene (1a) with MeMgBr (2a) and 5 mol%
Ni(cod)2 (cod = 1,5-cyclooctadiene) in THF at 708C under
argon atmosphere (Table 1, entry 1): the desired 1-methoxy-
Table 1: Condition screening.[a]
Sulfonylalkanes (often tosylalkanes) are an important
class of organic compounds that are found in various agro-
chemicals, pharmaceuticals, and polymers.[4] They also serve
as versatile synthetic building blocks in organic synthesis.[5]
However, to our knowledge, the Kumada reaction of sulfo-
nylalkanes with Grignard reagents remains an unexploited
area. Herein, we report a mild selective synthesis of alkenes
and modified arylketones through the NiI2(PPh3)2/PCy3
catalyzed Kumada coupling of tosylalkanes with Grignard
reagents (Scheme 1). This is the first example of alkene
synthesis from alkyl electrophiles with Grignard reagents
using the Kumada reaction strategy. Furthermore, the car-
bonyl groups in tosylalkyl ketones are well-tolerated under
the NiI2(PPh3)2 and PCy3 conditions.[3m] The products, alkenes
Entry [Ni] (mol%)
PCy3 [mol%] Solvent
T [8C] Yield [%][b]
(product)
1
2
3
4
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (10)
NiI2(PPh3)2 (5)
0
10
20
10
THF
THF
THF
THF
THF
THF
THF
THF
70
70
70
70
70
70
70
70
53 (3)
68 (3)
66 (3)
74 (3)
57 (3)
54 (3)
64 (3)
76 (3)
30 (3)
58 (4)
91 (4)
86 (3)
84 (3)
5
NiCl2(dppe)2 (5) 10
6
NiCl2 (5)
10
10
10
10
10
10
10
0
7[c]
8[d]
9
NiI2(PPh3)2 (5)
NiI2(PPh3)2 (5)
NiI2(PPh3)2 (5)
NiI2(PPh3)2 (5)
NiI2(PPh3)2 (5)
diethylether 30
toluene 120
cyclohexane 80
10
11
12[e] NiI2(PPh3)2 (5)
13[e] NiI2(PCy3)2 (5)
THF
THF
70
70
[a] Reaction conditions: 1a (0.3 mmol), 2a (5 equiv), [Ni] (see table),
PCy3 (see table), and anhydrous solvent (2 mL) overnight under argon
atmosphere. [b] Yield of isolated product. [c] 2a (2 equiv). [d] 2a
(10 equiv). [e] Undried THF was used. cod=1,5-cyclooctadiene,
Cy =cyclohexyl, dppe=1,2-bis(diphenylphosphino)ethane.
Scheme 1. Ni-Catalyzed Kumada reaction of tosylalkanes.
[*] J.-C. Wu, L.-B. Gong, R.-J. Song, Y.-X. Xie, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan University
Changsha 410082 (China)
4-(prop-1-en-2-yl)benzene (3) was isolated in 53% yield. The
yield was enhanced to 68% when PCy3 was used (entry 2; the
ligand effect is summarized in Table S1 of Supporting
Information). The effects of varying the amount of Ni(cod)2
were examined, and 10 mol% Ni(cod)2 produced identical
results to 5 mol% Ni(cod)2 (entry 3). Subsequently, a number
of Ni catalysts, including NiI2(PPh3)2, NiCl2(dppe)2 (dppe =
1,2-bis(diphenylphosphino)ethane) and NiCl2, were tested
(entries 4–6). Gratifyingly, NiI2(PPh3)2 was more effective
than Ni(cod)2 (entry 4 vs. entry 2) and the yield was increased
to 74% in the presence of 5 mol% NiI2(PPh3)2. However, the
other catalysts displayed less catalytic reactivity than Ni(cod)2
(entries 5 and 6). Screening revealed that the amount
MeMgBr (2a) used affected the reaction in the presence of
E-mail: jhli@hnu.edu.cn
J.-C. Wu, L.-B. Gong
Key Laboratory of Chemical Biology & Traditional Chinese Medicine
Research (Ministry of Education), Hunan Normal University
Changsha 410081 (China)
Dr. Y. Xia
College of Chemistry and Materials engineering
Wenzhou University, Wenzhou, 325035 (China)
[**] We thank the Natural Science Foundation of China (No. 21172060)
and Fundamental Research Funds for the Central Universities
(Hunan University) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205969.
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NiI2(PPh3)2. Whereas the yield was lowered to 64% when the
loading of MeMgBr (2a) was decreased to 2 equiv (entry 7),
the reaction with 10 equiv MeMgBr (2a) gave the same
results as 5 equiv MeMgBr (2a) (entry 8). It was found that
diethylether was less effective for the reaction (entry 9).
Surprisingly, the chemoselectivity was shifted completely
toward the traditional cross-coupled product 4, 1-isopropyl-4-
methoxybenzene, using either toluene or cyclohexane as the
solvent (entries 10 and 11). The reaction in cyclohexane, for
example, furnished product 4 in 91% yield (entry 11).
Interestingly, the yield of 3 is enhanced to 86% yield using
undried THF solvent (entry 12). Also, NiI2(PCy3)2 gave the
same effect as the NiI2(PPh3)2/PCy3 system (entry 13).
cross-coupled with MeMgBr (2a) during the alkene forma-
tion process (91% yield; Scheme 2, product 10). Screening
showed that both 1-(1-tosylethyl)benzene and 1-(1-tosyl-
ethyl)naphthalene were suitable for the reaction, furnishing
the corresponding products 11 and 12 in good to excellent
yields. Notably, substrates with a six-membered ring or a five-
membered ring successfully underwent the reaction with
MeMgBr (2a), NiI2(PPh3)2, and PCy3, leading to the corre-
sponding endocyclic double-bond-containing products 13 and
14 in good yields. Surprisingly, the substrate with a five-
membered ring gave 2-methylation product 14 instead of the
desired 1-methylation product. Using (tosylmethylene)diben-
zene, ethene-1,1-diyldibenzene (15) was obtained in 91%
yield under the optimized conditions. The common alkenes,
including 1-methoxy-4-vinylbenzene (16), 1-methyl-4-vinyl-
benzene (17), and styrene (18), could also be synthesized in
good yields, which makes this method more useful for organic
synthesis.
With the optimized reaction conditions in hand, the above
method was applied to the synthesis of various alkenes from
tosylalkanes 1 and Grignard reagents 2 (Scheme 2). Initially,
As shown in Equation (1), two other sulfonyl-containing
compounds were investigated in the presence of MeMgBr
(2a), NiI2(PPh3)2 and PCy3. However, they were inferior to
tosyl-containing substrates (Scheme 2, product 15).
We next planed to synthesize some other functional-
group-containing alkene products using the NiI2(PPh3)2/PCy3
catalytic system. Although our plan failed after a series of
trials, the carbonyl groups in 1-aryl-2-tosylethanones 1 were
found to be well-tolerated in the presence of Grignard
reagents 2 under the optimized conditions (Scheme 3). A
variety of modified arylketones were prepared from the
reaction of 1-aryl-2-tosylketones 1 with Grignard reagents 2,
NiI2(PPh3)2 and PCy3. For example, the treatment of
1-phenyl-2-tosylethanone with three Grignard reagents,
Scheme 2. NiI2(PPh)2/PCy3 catalyzed synthesis of alkenes. Reaction
conditions: 1 (0.3 mmol), 2 (5 equiv), NiI2(PPh3)2 (5 mol%), PCy3
(10 mol%), and THF (undried, 2 mL) at 708C overnight under argon
atmosphere. [a] THF was dried at 808C. [b] A by-product, 4-(tert-butyl)-
1,2-dimethoxybenzene (9’), was obtained in 11% yield. Ts=p-toluene-
sulfonyl.
1-methoxy-4-(1-tosylethyl)benzene (1a) was reacted with
four different Grignard reagents, EtMgBr, BnMgBr,
PhMgBr, and o-MeC6H4MgBr, in the presence of NiI2(PPh3)2
and PCy3 (Products 5–8). Unfortunately, the reaction of
substrate 1a with EtMgBr gave a mixture of products
(determined by GC-MS analysis), including (Z/E)-1-(but-2-
en-2-yl)-4-methoxybenzene and 1-sec-butyl-4-methoxyben-
zene (5), the desired product. Gratifyingly, the internal
alkene 6 was obtained in 80% yield from the reaction of
substrate 1a with BnMgBr. Moderate yields were still
obtained using two aryl Grignard reagents when they were
conducted in dried THF (Scheme 2, products 7 and 8).
Subsequently, substituents on the aryl ring of 1-tosylaryl-
alkanes, such as dimethoxy, Me, and Cl, were examined in the
presence of MeMgBr (2a), NiI2(PPh3)2, and PCy3 (Products 9
and 10). The results demonstrated that both dimethoxy and
Me substituents were well-tolerated, but the Cl group was
Scheme 3. NiI2(PPh3)2/PCy3 catalyzed Kumada cross-coupling of 1-aryl-
2-tosylethanones (1) with Grignard reagents (2). Reaction conditions:
1 (0.3 mmol), 2 (5 equiv), NiI2(PPh3)2 (5 mol%), PCy3 (10 mol%), and
THF (dried, 2 mL) at 808C overnight under argon atmosphere. [a] A Cl-
coupled product, 27, was isolated in 38% yield.
2
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MeMgBr (2a), PhMgBr, and o-MeC6H4MgBr, afforded the
corresponding new arylketones 19–21 in good yields. The
substrate 1-(naphthalen-1-yl)-2-tosylethanone was also suit-
able for reaction with either alkyl or aryl Grignard reagents
(Product 22 and 23). It was noted that substrates with Me, Ph,
or Cl substituents on the aryl ring were compatible with the
optimized conditions (Scheme 3, products 24–29). The
Cl group is perfectly tolerated in the reaction with MeMgBr
(Scheme 3, product 28). However, there was some coupling
with PhMgBr when it was used to treat a Cl-substituted
substrate (Scheme 3, products 29 and 27).
in situ FTIR analysis),[9,10] 4,4’-dimethylbiphenyl, and tolu-
ene.[1] Intermediate B is readily formed from intermediate A
with MeMgBr base, followed by oxidative addition of the
active Ni0 species to the Cvinyl S bond affords intermediate
À
C.[8] Transmetalation of intermediate C with MeMgBr (2a)
furnishes intermediate D.[8a,b] Finally, reductive elimination of
intermediate E affords the desired alkenes and the active Ni0
species.
Pathway (b), which involves intermediate IN-II, produces
intermediate E by oxidative addition of the active Ni0 species
À
to the Calkyl S bond followed by transmetalation with
The results demonstrated that NiI2(PCy3)2 gave the same
catalytic activity as the NiI2(PPh3)2/PCy3 system (Table 1,
entry 21), suggesting that the ligand exchange of PPh3 with
PCy3 takes place in the present procedure, and NiI2(PCy3)2 is
superior to NiI2(PPh3)2 alone. To our surprise, 1,2-dimethoxy-
4-(1-tosylethyl)benzene was found to yield a by-product,
4-(tert-butyl)-1,2-dimethoxybenzene (9’; a dimethyl-addition
product; Scheme 2). These results imply that Ni carbenes may
be involved in this process. However, the corresponding
carbene product was not trapped by ethyl 2-diazoacetate
during a control experiment (see the Supporting Information,
Eq. (S5) of Scheme S1).
Based on our experiments, we propose the mechanisms
shown in Scheme 4.[1–3,7–11] Initially, the ligand exchange of
NiI2(PPh3)2 with PCy3 gives more reactive NiI2(PCy3)2,
followed by conversion of NiI2(PCy3)2 into the active Ni0L2
species with the aid of Grignard reagent 2. The active Ni0
species subsequently undergoes oxidative addition of tosyl-
MeMgBr. Intermediate E undergoes b-hydrogen elimination
leading to a nickel–hydride complex intermediate F.[2,3,7] An
addition reaction takes place on intermediate F to furnish
intermediate G. Finally, b-hydrogen elimination and reduc-
tive elimination of intermediate G generates the desired
alkenes, H2, and the active Ni0 species.
Pathway (c) is also proposed to generate intermediate I
from tosylalkane 1 through a-deprotonation, oxidative addi-
tion, and b-deprotonation.[8]
As shown in Table 2 and Equation (2), some experiments
were conducted to trap the proposed intermediates. Initially,
we rechecked the GC-MS data from the reaction between
substrate 1a and MeMgBr (Table 2, entry 1 and Table 1,
entry 20). The data shows an 88% yield of 3 and a 27% yield
À
alkane 1 at two possible positions: a) to the C(aryl) S bond,
À
or b) to the C(alkyl) S bond. Pathway (a) results in inter-
mediate IN-I by oxidative addition of the active Ni0 species to
the CAr S bond.[7] Reductive elimination of intermediate IN-I
of 4,4’-dimethylbiphenyl (32), together with a 4% yield of
product 33 and a trace of products 4, 34, and others, all of
which suggests that there is a competition between pathway
(a) (supported by 32) and pathway (b) (supported by 4 and
33). This is also supported by DFT calculations.[11] If
À
with MeMgBr offers sulfene intermediate A (supported by
Table 2: Trapping experiments.
Entry PhB(OH)2
[equiv]
30
3
4
31
32
33
34
[%][b] [%][b] [%][b] [%][b] [%][b] [%][b] [%][b]
1
2
3
4
5
none
0.8
1.0
0
0
0
0
0
88
78
56
37
71
trace
10
5
9
23
0
27
11
11
6
4
12
trace
7
31
40
52
29
trace trace
trace trace
14
2.0
2.0[c]
4
trace
[a] Reaction conditions: 1a (0.3 mmol), 2a (5 equiv), [Ni] (5 mol%),
PCy3 (10 mol%), PhB(OH)2 (see table), and anhydrous THF (2 mL) at
708C overnight under argon atmosphere. [b] Yield determined by GC-MS
analysis using nitrobenzene as an internal standard. [c] 8 equiv of 2a was
used.
Scheme 4. Possible mechanisms. L=PCy3.
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Communications
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entry 2). Using 1 equiv PhB(OH)2, the total yield of the tolyl
group (62%) is nearly consistent with the yield of product 3
(56%). However, little yield of products 4 and 33 was
generated (entry 3). Screening revealed that the yield of
product 31 from substrate 1a coupled with 2 equiv PhB(OH)2
was enhanced to 52%, whereas the yield of 3 was lowered
(entry 4). The reason may be that some MeMgBr is consumed
in the coupling of intermediate IN-I with PhB(OH)2. As
expected, the yield of 3 was enhanced to 71% by increasing
MeMgBr to 8 equiv (entry 5). Notably, in none of the
experiments was PhB(OH)2-coupled product 30 observed.
The results in (Table 2) clearly support pathway (a).[11]
Intermediate IN-II in pathway (b) can also be generated
simultaneously, which results in product 4, not product 3.
Generally, a-tosyl elimination is faster than a-hydrogen
elimination when using strong bases. Indeed, only the
a-tosyl/b-hydrogen elimination product (35) was observed
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(c) [Eq. (2)].
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In summary, we have developed a new route to alkenes
and modified arylketones through the Ni-catalyzed Kumada
cross-coupling reaction. Alkenes can be prepared from the
reaction of tosylalkanes with Grignard reagents, and the
carbonyl group of the tosylalkane is well-tolerated using the
NiI2(PPh3)2/PCy3/THF system. Furthermore, the mechanism
was evaluated based on in situ FTIR analysis, DFT calcu-
lations, and experimental results. Applications of this Ni-
catalyzed Kumada cross-coupling transformation in organic
synthesis are currently underway in our laboratory.
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Experimental Section
Typical Experimental Procedure: Sulfonylalkane
1
(0.3 mmol),
Grignard reagent
2 (1.5 mmol), NiI2(PPh3)2 (5 mol%), PCy3
(10 mol%), and THF (2 mL) were added to a Schlenk tube. The
tube was then charged with argon, and stirred at 708C overnight until
the starting material was completely consumed, as indicated by TLC
and GC-MS analysis. After the reaction was finished, the reaction
mixture was washed with brine, and the aqueous phase was re-
extracted with ethyl acetate. The combined organic extracts were
dried over Na2SO4, concentrated in vacuum, and the resulting residue
was purified by silica gel column chromatography (n-hexane/ethyl
acetate 200:1) to afford the desired product.
Received: July 26, 2012
Published online: && &&, &&&&
Keywords: arylketones · cross-coupling · Kumada reaction ·
.
nickel · tosylalkanes
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[10] The in situ FTIR analysis of the results of the reaction between
substrate 1a and MeMgBr indicate that the sulfene intermediate
=
A is produced, based on the S O symmetric stretching vibration,
and that the step from intermediate IN-I to intermediate A is
rate-limiting (see the Supporting Information, Figure S1);
a) Structure Determination of Organic Compounds, Tables of
Spectral Data, 4th ed. (Eds.: E. Pretsch, P. Bꢄhlmannn, C.
Affolter), Springer, Berlin, 2009, p. 305; b) Y. Hu, J. Liu, Z. Lꢄ,
X. Luo, H. Zhang, Y. Lan, A. Lei, J. Am. Chem. Soc. 2010, 132,
3153; c) Q. Liu, Y. Lan, J. Liu, G. Li, Y.-D. Wu, A. Lei, J. Am.
Chem. Soc. 2009, 131, 10201.
[11] DFT calculations indicate that the activation barrier for the
generation of intermediate IN-I is lower than that of intermedi-
ate IN-II. See the Supporting Information for details.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Cross-Coupling
J.-C. Wu, L.-B. Gong, Y. Xia, R.-J. Song,
Y.-X. Xie, J.-H. Li*
&&&& — &&&&
Nickel-Catalyzed Kumada Reaction of
Tosylalkanes with Grignard Reagents to
Produce Alkenes and Modified
Arylketones
Open A New Door: The first example of
alkene synthesis from alkyl electrophiles
with Grignard reagents using the Kumada
cross-coupling reaction strategy is
for the Kumada cross-coupling reaction,
allowing alkenes to be prepared from the
reaction of tosylalkanes with Grignard
reagents.
reported. This method opens a new door
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!