Synthesis of Exocyclic Trisubstituted Alkenes via Nickel- Catalyzed Kumada-Type Cross-Coupling Reaction of gem- Difluoroalkenes with Di-Grignard Reagents

Article abstract of DOI:10.1002/adsc.201500889

A practical, nickel-catalyzed Kumada-type double cross-coupling reaction of gem-difluoroalkenes with 1,4- or 1,5-di-Grignard reagents was developed. The reaction proceeded efficiently at room temperature and a variety of cyclization products, arylmethylenecyclopentanes and arylmethylenecyclohexanes, were obtained in high to excellent yields, respectively.

Full text of DOI:10.1002/adsc.201500889

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DOI: 10.1002/adsc.201500889
Synthesis of Exocyclic Trisubstituted Alkenes via Nickel-
Catalyzed Kumada-Type Cross-Coupling Reaction of gem-
Difluoroalkenes with Di-Grignard Reagents
Wenpeng Dai,a Xuxue Zhang,a Juan Zhang,a Yingyin Lin,a and Song Caoa,*
a
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology
(ECUST), Shanghai 200237, Peopleꢀs Republic of China
Fax: (+86)-21-64252603; phone: (+86)-21-64253452; e-mail: scao@ecust.edu.cn
Received: September 25, 2015; Revised: November 3, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500889.
Abstract: A practical, nickel-catalyzed Kumada-
type double cross-coupling reaction of gem-
difluoroalkenes with 1,4- or 1,5-di-Grignard re-
agents was developed. The reaction proceeded effi-
ciently at room temperature and a variety of cycli-
zation products, arylmethylenecyclopentanes and
arylmethylenecyclohexanes, were obtained in high
to excellent yields, respectively.
for the synthesis of exocyclic trisubstituted olefins by
the reductive alkenylation of cyclic tosylhydrazones
with alkenylboronic acids (Scheme 1, c).[9] However,
the coupling reaction should be performed at high
temperatures, typically 110–1508C with the assistance
of microwaves.
The activation and functionalization of the carbon-
fluorine bond have attracted considerable attention in
recent years.[10] However, most of the research efforts
have been focused on the catalytic activation of aro-
Keywords: cyclization; fluorine; gem-difluoroal-
kenes; Grignard reaction; nickel
À
À
matic C F bonds, examples of olefinic C F activation
by transition metal complexes are few.[10a,11] Although
the reactions of gem-difluoroalkenes with strong nu-
cleophiles such as nitrogen, oxygen and sulfur nucleo-
Exocyclic alkenes are important structural motifs
found in many pharmaceuticals, agrochemicals, and
organic materials.[1] They also serve as useful building
blocks in synthetic organic chemistry.[2] Therefore,
many efforts have been devoted to the development
of new methodologies for the synthesis of exocyclic
alkenes and their derivatives.[3] However, a general
and practical method for the synthesis of exocyclic
alkenes has been rarely reported.[4]
The Wittig olefination reaction is regarded as one
of the most popular methods for exocyclic alkene syn-
thesis.[5] The main limitation of this reaction is the for-
mation of large amounts of undesired by-product, tri-
phenylphosphine oxide (Scheme 1, a).[6] Another im-
portant method for the construction of exocyclic tri-
substituted olefins is the cyclization reaction of acety-
lenic halides.[7] For example, in 2013, Cook et al.
developed a new route to exocyclic trisubstituted al-
kenes by a palladium-catalyzed alkyne insertion/re-
duction reaction of unactivated alkyl iodides
(Scheme 1, b).[8] But this method suffers from the use
of an expensive palladium catalyst and difficulties in
the preparation of the starting materials. Recently,
Scheme 1. Methods for the synthesis of exocyclic trisubsti-
ValdØs et al. reported a general and efficient method tuted alkenes.
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Wenpeng Dai et al.
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst (mol%)
Solvent
Temperature
2a (equiv.)
Yield [%][b]
1
2
3
4
5
6
7
8
none
Fe(acac)3 (5)
Pd2(dba)3 (5)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
CH2Cl2
Et2O
toluene
THF
THF
THF
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
08C
reflux
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.0
1.5
1.5
0
2
20
79
3
Pd(PPh3)4 (5)
NiCl2(dppf) (5)
NiCl2(PCy3)2 (5)
NiCl2(dppe) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (4)
NiCl2(dppp) (3)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (4)
NiCl2(dppp) (4)
NiCl2(dppp) (4)
NiCl2(dppp) (4)
7
58
97
97
63
0
9
10
11
12
13
14
15
16
17
18
9
85
96
89
67
80
86
[a]
Reaction conditions: 1a (1.0 mmol), solvent (5 mL), 1 h, under argon.
Yields refer to desired product 3aa and are determined by GC analysis based on 1a.
[b]
philes through an addition–elimination process (SNV 3 mol% would result in a lower yield (entries 9 and
reaction) have been well documented,[12] the transi- 10). Further screening of solvents revealed that both
tion metal-catalyzed cross-coupling reaction of gem- THF and toluene could afford excellent yields of 3aa
difluoroalkenes with organometallic reagents such as (entries 8 and 11–14). Considering the relatively high
Grignard reagents,[13] organozinc reagents[14] and orga- toxicity of toluene, THF was chosen as the solvent for
noboron reagents,[15] which involves activation of the the following reactions.
À
C F bond, still remains an important challenge. As
In addition, decreasing the amount of di-Grignard
a continuation of our studies on the cleavage and reagent 2a to 1.2 or 1.0 equiv. led to lower yields (en-
[16]
À
functionalization of the C F bond of fluoroalkenes,
tries 15 and 16). We also found that the concentration
in this communication, we report a mild and facile of the di-Grignard reagent (around 0.5M) had no sig-
method for the synthesis of exocyclic trisubstituted nificant impact on the reaction efficiency. Finally, the
alkenes by the nickel-catalyzed Kumada-type cross- effect of the reaction temperature on the reaction was
coupling reaction of gem-difluoroalkenes with di- examined (entries 17 and 18). The results indicated
Grignard reagents (Scheme 1, d).
Initially, the cyclization of 1-(2,2-difluorovinyl)-4- temperature to achieve a high yield of 3aa.
methoxybenzene (1a) with butane-1,4-diylbis(magne- It is noteworthy that when 1-(2,2-dichlorovinyl)-4-
that room temperature was the optimum reaction
sium bromide) (2a) was selected as the model reac- methoxybenzene or 1-(2,2-dibromovinyl)-4-methoxy-
tion to determine the optimum reaction parameters benzene were used as substrates, the reaction efficien-
(Table 1). Among several metal catalysts tested (en- cy was significantly decreased and the cyclization
tries 2–8), NiCl2(dppp) proved to be the best for this product 3aa was obtained in 70% and 65% yields
transformation, affording the expected product 3aa in (GC), respectively.
97% yield, while other metal salts gave low yields. No
With the optimized conditions in hand (Table 1,
desired product was observed when the reaction was entry 9), we next examined the scope of the novel
performed in the absence of catalyst (entry 1). It was nickel-catalyzed cyclization reactions of various gem-
observed that the amount of NiCl2(dppp) significantly difluoroalkenes with butane-1,4-diylbis(magnesium
affected the yield of the cyclization product. Using bromide) (2a) (Scheme 2). Most gem-difluoroalkenes
4 mol% of NiCl2(dppp) was effective for this transfor- could afford cyclization products in good to high
mation and decreasing the amount of NiCl2(dppp) to yields. Generally, gem-difluoroalkenes having elec-
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Synthesis of Exocyclic Trisubstituted Alkenes
Scheme 2. Reaction of gem-difluoroalkene with 1,4-di-Grignard reagent 2a. Reaction conditions: 1a–p (1.0 mmol), 2a
(1.5 mmol), 4 mol% NiCl2(dppp), THF (5 mL), room temperature, 0.5–1 h, under argon. Yields of isolated products are
given.
tron-donating substituents gave slightly higher yields tected during the reaction in most cases, it could be
than those having electron-withdrawing ones (3aa suggested that the second coupling reaction is faster
versus 3ma). The position of the substituents on the than the first coupling reaction.
benzene ring has little influence on the yield of the
Encouraged by the successful synthesis of aryl-,
reaction (1f and 1g). On replacing the aryl group by alkyl- and alkenylmethylenecyclopentanes, we next
a thienyl group in the gem-difluoroalkene the reaction investigated the reaction of gem-difluoroalkenes with
also afforded the cyclization product in high yield the 1,5-di-Grignard reagent. We were delighted to
(1n). To our delight, both aliphatic difluoroalkenes find that the nickel-catalyzed cyclization reaction of
and alkenyldifluoroalkenes could give the cyclization different gem-difluoroalkenes with pentane-1,5-diyl-
products in high yields (3oa and 3pa).
bis(magnesium bromide) (2b) also proceeded smooth-
When gem-difluoroalkene 1a was treated with ly and provided six-membered ring alkenes in good
3.0 equiv. of mono-Grignard reagents such as yields (Scheme 3). However, pentane-1,5-diylbis(mag-
CH3MgCl, PhMgBr and n-C4H9MgCl under the opti- nesium bromide) showed lower reactivity than
mized conditions, the intermolecular reaction did not butane-1,4-diylbis(magnesium bromide) and provided
proceed to completion and the double cross-coupled slightly diminished yields of the cyclization products.
products were obtained only in 53%, 81% and 49% Unfortunately, when propane-1,3-diylbis(magnesium
yields, along with 27%, 19% and 33% unreacted start- bromide) was used as coupling partner, no desired
ing material 1a (GC), respectively. The results indicat- product was observed and 75% of starting material 1a
ed that in this Kumada-type coupling reaction, the di- was recovered (GC). In the case of hexane-1,6-diyl-
Grignard reagent was more effective than a mono- bis(magnesium bromide), only a small amount of
Grignard reagent under identical conditions. Because cyclization product was detected along with some un-
the reaction was finished within 30 min to 1 h at room identified by-products. This low yield may be due to
temperature, we assumed that both the first coupling the instability of the seven-membered ring. Notably,
reaction and the second coupling reaction were fast. no mono-substituted by-product was observed in the
Considering that no mono-coupled products were de-
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Wenpeng Dai et al.
Scheme 3. Reaction of gem-difluoroalkene with 1,5-di-Grignard reagent 2b. Reaction conditions: 1a–c, 1g, 1j–l, 1n–q
(1.0 mmol), 2b (1.5 mmol), 4 mol% NiCl2(dppp), THF (5 mL), room temperature, 0.5–1 h, under argon. Yields of isolated
products are given.
reaction of gem-difluoroalkenes with 1,3- or 1,6-di- vacuum. The crude residue was then purified by column
chromatography on silica gel using n-hexane as eluent to
afford the pure target compounds.
Grignard reagents.
In summary, we have developed an efficient nickel-
catalyzed Kumada-type double cross-coupling reac-
tion of gem-difluoroalkenes with di-Grignard reagents
at room temperature. A variety of cyclization prod-
ucts such as arylmethylenecyclopentanes and arylme-
thylenecyclohexanes were obtained in high to excel-
lent yields. Because various gem-difluoroalkenes can
be easily prepared from commercially available re-
agents such as methyl 2,2-difluoro-2-(fluorosulfonyl)-
acetate (MDFA) and difluoromethyl 2-pyridyl
sulfone,[17] we believe that this method provides a new
alternative approach to exocyclic trisubstituted
alkenes.
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (Grant Nos. 21472043 and
21272070).
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