Sterically Controlled Cu-Catalyzed or Transition-Metal-Free Cross-Coupling of gem-Difluoroalkenes with Tertiary, Secondary, and Primary Alkyl Grignard Reagents

Article abstract of DOI:10.1021/acs.orglett.6b02026

A robust copper-catalyzed or transition-metal-free cross-coupling of gem-difluoroalkenes with tertiary, secondary, and primary alkyl Grignard reagents has been developed. Remarkably, the tertiary and secondary alkylation of gem-difluoroalkenes proceeded v

Full text of DOI:10.1021/acs.orglett.6b02026

Letter
pubs.acs.org/OrgLett
Sterically Controlled Cu-Catalyzed or Transition-Metal-Free Cross-
Coupling of gem-Difluoroalkenes with Tertiary, Secondary, and
Primary Alkyl Grignard Reagents
Wenpeng Dai, Hongyan Shi, Xianghu Zhao, and Song Cao*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST),
Shanghai 200237, China
S
* Supporting Information
ABSTRACT: A robust copper-catalyzed or transition-metal-free
cross-coupling of gem-difluoroalkenes with tertiary, secondary, and
primary alkyl Grignard reagents has been developed. Remarkably,
the tertiary and secondary alkylation of gem-difluoroalkenes
proceeded very smoothly in the presence of 25 mol % of CuCN
or under transition-metal-free conditions, affording the tertiary and
secondary alkyl-substituted fluoroalkenes in good to excellent
yields with excellent Z stereoselectivity.
he transition-metal-catalyzed reactions of aryl, alkenyl, and
the C−F bond is much more difficult due to the great strength of
Talkyl halides with Grignard reagents are powerful synthetic the C−F bond.11 Although alkyl, vinyl, and aryl fluorides have
been successfully coupled with different types of RMgX,12 there
has been only two reports in the literature on the coupling of
tertiary alkyl Grignard reagents with less reactive organic
fluorides. In 2013, Kambe reported the Co-catalyzed coupling
of 1-fluorooctane with t-BuMgCl in the presence of 4 mol % of LiI
and 1,3-butadiene and a moderate yield of the corresponding
product was obtained (GC yield: 62%).6 In the same year, Ogoshi
also reported the LiCl-promoted monosubstitution reaction of
tetrafluoroethene (TFE) with various Grignard reagents.
However, when t-BuMgCl was employed as the substrate, the
yield of the tertiary alkylation product dropped sharply (Scheme
1e).9e In continuation of our studies on the functionalization of
the C−F bond of fluoroalkenes,13 in this letter, we report the
sterically controlled Cu-catalyzed or transition-metal-free cou-
pling of gem-difluoroalkenes with tertiary, secondary, and primary
alkyl Grignard reagents, which afforded various mono- or
dialkylated multisubstituted alkenes depending on the Grignard
reagents, reaction conditions, and substrates involved.
methods for the construction of C−C bonds.1 Generally, primary
alkyl, alkenyl, aryl, and even secondary alkyl Grignard reagents
have been predominantly used as effective coupling partners,2
whereas tertiary alkyl Grignard reagents are considered poor
coupling partners owing to the large steric hindrance of the
tertiary alkyl group, the isomerization of metal tertiary alkyl
species, and the facile elimination of β-hydrogen.3 Therefore, the
coupling reactions of tertiary alkyl Grignard reagents with organic
halides are still undeveloped.4 Over the past decade, noteworthy
progress has been brought about regarding the cross-coupling of
tertiary alkyl Grignard reagents with organic halides such as aryl
bromides,5 alkyl halides,6 chloroazacycles,7 and alkynyl halides.8
However, utilizing alkenyl halides as electrophiles to couple with
tertiary alkyl Grignard reagents remains to be examined and only
a few examples have been reported (Scheme 1a−e).9
The activation and functionalization of the C−F bond have
attracted considerable attention in recent years.10 The cleavage of
Generally, the cross-coupling of Grignard reagents with
organic halides could be achieved by using palladium and nickel
salts as catalysts.1a,2a,14 1,1-Dichoro- and dibromo-1-alkenes are
valuable synthetic building blocks in organic synthesis and
underwent facile Pd- or Ni-catalyzed coupling with Grignard
reagents.15 Recently, we reported the Pd- and Ni-catalyzed
coupling reactions of gem-difluoroalkenes with aryl and primary
alkyl Grignard reagents.13c We found that the catalytic system
involving Pd(PPh3)4 was exceptionally effective for the coupling
reaction of gem-difluoroalkenes with Grignard reagents without
β-hydrogen atoms such as ArMgX, whereas NiCl2(dppe)
exhibited a superior reactivity in the cross-coupling of gem-
Scheme 1. Tertiary Alkylation of Alkenyl Halides
Received: July 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02026
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Organic Letters
Letter
difluoroalkenes with Grignard reagents bearing β-hydrogen
atoms such as n-C4H9MgX. However, when these two catalytic
systems were applied to tertiary or secondary alkyl Grignard
reagents, small amounts of cross-coupled products were observed
(Table 1, entries 1−2).
transition-metal-free conditions. Only a trace amount of Z-3aa
was observed when the reaction was performed in THF without
the addition of CuCN at rt (entry 14). Refluxing the reaction
mixture in THF could afford Z-3aa in good yield (entry 15).
Excitingly, when the reaction was performed in refluxing toluene,
the yield of the desired Z-3aa was remarkably improved to 99%
(entry 16). The configuration of the Z-isomer was determined by
its 3JH−F coupling constant in the 1H NMR spectra (ca. 40.0 Hz
for the Z isomer and 26.0 Hz for the E isomer).
a
Table 1. Optimization of Reaction Conditions
To gain insight into the tolerance of this reaction, we examined
the scope of this reaction with respect to a variety of gem-
difluoroalkenes and tertiary alkyl Grignard reagents under the
two optimized reaction conditions (Table 1, entries 12 and 16).
As shown in Scheme 2, this reaction exhibited good functional
b
entry
catalyst (mol %)
2a (equiv)
temp
yield (%)
1
Pd(PPh3)4 (25)
NiCl2(dppe) (25)
CuBr2 (25)
Cu(OAc)2 (25)
Cu(OAc) (25)
CuCl (25)
CuBr (25)
CuI (25)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.8
1.6
2.0
2.0
2.0
rt
10
2
2
rt
Scheme 2. Tertiary Alkylation of Various gem-
3
rt
13
31
37
38
44
45
99
97
85
99
75
1
a b
,
Difluoroalkenes
4
rt
5
rt
6
rt
7
rt
8
rt
9
CuCN (25)
CuCN (20)
CuCN (15)
CuCN (25)
CuCN (25)
none
rt
10
11
12
13
14
15
16
rt
rt
rt
rt
rt
none
reflux
76
99
none
reflux (toluene)
a
Reaction conditions: 1a (0.2 mmol), THF or toluene (3 mL), 2 h, Ar.
Yields determined by GC analysis and based on 1a.
b
a
Reaction conditions: (method A) 1a−p (1.0 mmol), 2a−d (1.8
mmol), 25 mol % CuCN, THF (5 mL), rt, 2 h, Ar; (method B) 1a−p
(1.0 mmol), 2a−c (2.0 mmol), toluene (5 mL), reflux, 2 h, Ar.
Recently, Cu-mediated or -catalyzed coupling reactions of
b
Isolated yields.
organic halides with different types of Grignard reagents have
attracted increasing attention because of the ready availability and
lower commercial costs of copper salts.16 Therefore, we initiated
our studies by investigating the reactions of 1-(2,2-difluorovinyl)-
4-methoxybenzene 1a with tBuMgCl 2a in the presence of
various copper salts (Table 1). The screening of copper salts
indicated that different copper species exhibited different
efficiency in this coupling reaction and could afford the expected
tertiary butylation product Z-3aa in low to moderate yields
(entries 3−8). To our delight, when 25 mol % CuCN was used as
a catalyst, the tertiary butylation product was formed in almost
quantitative yield within 2 h at room temperature without any
byproduct being observed. Even more surprisingly, the reaction
proceeded with complete stereoselectivity to generate Z-3aa
exclusively (entry 9). When the amount of CuCN declined to 20
mol %, the yield remained the same (entry 10). Further decrease
of the amount of CuCN to 15 mol % resulted in a significantly
reduced yield of Z-3aa (entry 11). It was found that 1.8 equiv of
tBuMgCl 2a was sufficient to carry out this reaction successfully
(entry 12); however, when the amount of 2a was reduced to 1.6
equiv, the yield of Z-3aa decreased significantly (entry 13).
The transition-metal-free coupling reaction of organic halides
with Grignard reagents is a formidable challenge in the organic
synthesis.17 In addition, a survey of the literature revealed that
there were only a few reports on the coupling reaction of organic
fluoride with Grignard reagents under transition-metal-free
conditions.12c,18 However, successful examples of these coupling
reactions are limited to substrates containing directing
groups.18c,d Encouraged by the above success, we next examined
the feasibility of tertiary butylation of gem-difluoroalkene under
group compatibility and almost all gem-difluoroalkenes could
afford tertiary alkylation products in good to excellent yields with
excellent stereoselectivity. Generally, there was no significant
difference in yield between methods A and B. Both gem-
difluoroalkenes bearing a strong electron-donating group on the
phenyl ring and gem-difluoroalkenes bearing a strong electron-
withdrawing group could provide the coupled products in
excellent yields (Z-3aa and Z-3ha). gem-Difluoroalkene having
an ortho substituent on the phenyl ring has significant influence
on the reaction, and only a moderate yield was obtained (Z-3ma
versus Z-3na). The tolerance of chloride, bromide, and iodide
substituents was particularly striking, which provides the
opportunity for further modifications. 2-(2,2-Difluorovinyl)-
thiophene (1o) and (E)-(4,4-difluorobuta-1,3-dien-1-yl)-
benzene (1p) were also good substrates for this reaction.
However, when aliphatic difluoroalkenes such as (4,4-difluor-
obut-3-en-1-yl)benzene were used as a substrate, no reaction was
observed under the two reaction conditions. The replacement of
tert-butylmagnesium chloride 2a with tert-pentylmagnesium
chloride 2b and (2-methylpentan-2-yl)magnesium chloride 2c
also afforded excellent yields (Z-3ab and Z-3ac). In the case of
adamantyl magnesium bromide 1d, the reaction did not proceed
smoothly and only 41% of 3ad was formed. Importantly, the
reaction of 1a with 2a could be scaled up from 1.0 to 10.0 mmol
(1a, 1.7 g) without any loss in effectiveness (method A) and the
Z-3aa was obtained in a nearly quantitative yield. Notably, 10 mol
% CuCN was sufficient to accomplish the desired transformation.
B
DOI: 10.1021/acs.orglett.6b02026
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Letter
To further examine the generality of this reaction, various
secondary alkyl Grignard reagents were applied to the reaction
with different gem-difluoroalkenes (Scheme 3). The Cu-catalyzed
Scheme 4. Cu-Catalyzed Primary Alkylation of gem-
Difluoroalkene
a b
,
a b
,
Scheme 3. Secondary Alkylation of gem-Difluoroalkenes
a
Reaction conditions: 1a (1.0 mmol), 2m−r (3.0 mmol), 25 mol %
b
CuCN, THF (5 mL), rt, 2 h, Ar. Isolated yields.
Scheme 5. Primary Alkylation of gem-Difluoroalkene under
a b
,
Transition-Metal-Free Conditions
a
Reaction conditions: method A: 1a, 1h, 1l, 1o (1.0 mmol), 2e−l
(1.8−3.0 mmol), 25 mol % CuCN, THF (5 mL), rt, 2 h, Ar. method
B: 1a, 1h, 1l, 1o (1.0 mmol), 2e−g, 2i (1.8−3.0 mmol), 2k (6.0
a
Reaction conditions: 1a (1.0 mmol), 2m−r (6.0 mmol), toluene (5
b
mL), reflux, 8 h, Ar. Isolated yields.
b
mmol), toluene (5 mL), reflux, 2 h, Ar. Isolated yields.
reagents under transition-metal-free reaction conditions and a
mixture of E/Z-monocoupled products was formed (Scheme 5,
4am−ap). The coupling reaction of 1a with CH3MgCl (2q) and
PhMgBr (2r) was unsuccessful under both reaction conditions.
Alkylation of ((1,2,2-trifluorovinyl)oxy)arenes (Scheme 6, 1q,
1r) with tertiary and secondary alkyl Grignard reagents under Cu-
secondary alkylation of gem-difluoroalkenes proceeded efficiently
and afforded secondary alkylation products in high yields with
good stereoselectivity. However, compared to the coupling
reaction of tertiary alkyl Grignard reagents, the coupling of
secondary alkyl Grignard reagents with gem-difluoroalkenes was
somewhat less efficient in terms of yield and stereoselectivity.
Both cyclohexyl and cyclopentyl Grignard reagents proved to be
efficient coupling partners, and cycloheptylmagnesium bromide
2l is also a suitable coupling partner. When cyclobutylmagnesium
bromide was used as a substrate, a mixture of the monocoupled
product (Z-3aj) and dicoupled product (3aj′) was obtained.
Interestingly, cyclopropylmagnesium bromide 2k only afforded
the double-cross-coupled product (3ak) in 70% yield and no
monocoupled product was detected.
Scheme 6. Cu-Catalyzed Alkylation of ((1,2,2-
a b
,
Trifluorovinyl)oxy)arenes
Subsequently, we selected representative gem-difluoroalkenes
and secondary alkyl Grignard reagents to investigate the
secondary alkylation reaction under the transition-metal-free
protocol (Scheme 3, method B). The results indicated that the
secondary alkylation of gem-difluoroalkenes under transition-
metal-free conditions also proceeded smoothly and gave
comparable yields. However, the cyano group was not tolerated
well, and only a small amount of product were detected according
to GC-MS analysis (Z-3hf, 8%, method B). In addition, the
reaction of cyclopropylmagnesium bromide 2k with 1a under
transition-metal-free reaction conditions furnished a mixture of
E/Z-fluorocyclopropylalkenes (3ak′, E/Z ≈ 1/1) in a modest
yield.
Inspired by the success in the coupling of gem-difluoroalkenes
with tertiary and secondary alkyl Grignard reagents, to further
extend the generality of this practical approach, we performed the
reaction of gem-difluoroalkene (1a as example) with primary alkyl
Grignard reagents with the two methods (Schemes 4 and 5). It
was found that when the reactions of 1a with EtMgCl (2m), n-
PrMgCl (2n), n-BuMgCl (2o), or n-pentylMgCl (2p) were
carried in the presence of 25 mol % CuCN (method A),
dicoupled products were generated in good yields (Scheme 4,
3am−ap). On the other hand, an excess amount of RMgX (6
equiv) and a longer reaction time (8 h) were required for the
alkylation of gem-difluoroalkenes with primary alkyl Grignard
a
Reaction conditions: 1q, 1r (1.0 mmol), 2a, 2g (3.0 mmol), 25 mol
b
% CuCN, THF (5 mL), rt, 2 h, Ar. Isolated yields.
catalyzed conditions produced dialkylation products (E-5qa, E-
5ra, and E-5rg). The structure of E-5qa was determined by X-ray
diffraction (see the Supporting Information, p 16). However,
when EtMgCl (2m) was used as the coupling partner, no desired
product was observed.
Based on the above observations and earlier reports,19 the
mechanism for the Cu-catalyzed tertiary and secondary alkylation
of gem-difluoroalkenes is proposed (Scheme 7). Initially, 2 equiv
of RMgX reacted with CuCN to give dialkylcuprate magnesium
halide (R2CuMgX). The addition of R2CuMgX to gem-
difluoroalkene led to the generation of the key intermediate I.
Rotation of the intermediate I by 60° would result in the
formation of two conformations, II and III. The intermediate III
was relatively unstable because there might be steric repulsion
between R2Cu and the aryl group. Finally, the elimination of
MgXF and RCu from the intermediate II and IV, respectively,
afforded tertiary and secondary alkylated fluoroalkene with
excellent Z-selectivity.
In addition, according to the literature reports,17 we suggested
that the mechanism of the reaction of gem-difluoroalkene with a
C
DOI: 10.1021/acs.orglett.6b02026
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Letter
Scheme 7. Plausible Mechanism of Cu-Catalyzed Tertiary and
Secondary Alkylation of gem-Difluoroalkenes
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02026.
Crystallographic data for E-5qa (CIF)
Experimental details, spectroscopic data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: scao@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21472043 and 21272070).
D
DOI: 10.1021/acs.orglett.6b02026
Org. Lett. XXXX, XXX, XXX−XXX