Copper-Catalyzed SN2′-Selective Allylic Substitution Reaction of gem-Diborylalkanes

Article abstract of DOI:10.1021/acs.orglett.5b03692

A Cu/(NHC)-catalyzed S_N2′-selective substitution reaction of allylic electrophiles with gem-diborylalkanes is reported. Different substituted gem-diborylalkanes and allylic electrophiles can be employed in this reaction, and various synthetic valuable functional groups can be tolerated. The asymmetric version of this reaction was initially researched with chiral N-heterocyclic carbene (NHC) ligands.

Full text of DOI:10.1021/acs.orglett.5b03692

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed SN2′-Selective Allylic Substitution Reaction of
gem-Diborylalkanes
Zhen-Qi Zhang, Ben Zhang, Xi Lu, Jing-Hui Liu, Xiao-Yu Lu, Bin Xiao,* and Yao Fu*
iChEM, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Department
of Chemistry, University of Science and Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: A Cu/(NHC)-catalyzed SN2′-selective substitution reaction of allylic electrophiles with gem-diborylalkanes is
reported. Different substituted gem-diborylalkanes and allylic electrophiles can be employed in this reaction, and various synthetic
valuable functional groups can be tolerated. The asymmetric version of this reaction was initially researched with chiral N-
heterocyclic carbene (NHC) ligands.
Scheme 1. Regioselective Allylic Substitution Reactions of
opper-catalyzed cross-coupling reactions of allylic electro-
Allylic Electrophiles with gem-Diborylalkanes
C
philes are powerful methods for constructing C−C bonds,
especially for the formation of saturated C−C bonds.1 In the
past few decades, a variety of organometallic reagents have been
used in these reactions, such as Grignard, alkyllithium,
alkylaluminum, alkylzirconium, and dialkylzinc.2 Despite their
high activity, their air and moisture sensitivity have limited their
application in synthesis. In contrast, organoboronic acid
derivatives are widely used because of their stability, availability,
and good functional group tolerance.3 To date, many studies in
the field of coupling between allylic electrophiles with
organoboron compounds have been reported,4 which often
employ aryl,5 alkenyl,6 and allyl boron reagents7 and alkyl-9-
BBN.8 Among of them, allylboron reagents and alkyl-9-BBN
applied in these methods can realize the alkylation of allylic
electrophiles.
1,1-diborylalkanes (Scheme 1b).15 Through this method, we
can obtain the branched γ-substitution products through the
Cu/(NHC)-catalyzed system successfully. Various synthetic
valuable functional groups could be tolerated with mild reaction
conditions. Different side-chain-substituted gem-diborylalkanes
and allylic electrophiles can be employed. Finally, the
asymmetric version of this reaction was initially researched
with chiral N-heterocyclic carbene (NHC) ligands.
Recently, we reported Cu-catalyzed/promoted alkylation of
gem-diborylalkanes. We found that diborylmethane could react
with cinnamyl phosphate to afford the linear α-substitution
product.13 On the basis of this finding, we attempted to achieve
the synthesis of branched products by governing the catalyst
system. Subsequently, we examined the allylic substitution of
1,1-diborylalkanes with allylic electrophiles. Diborylmethane
(1) and cinnamyl electrophiles were selected as the model
substrates (Table 1). At first, we repeated our previous
conditions with cinnamyl phosphate (1b) (entry 1 and 2)
and obtained major product 2a. Then we tried THF and
dioxane (entry 3 and 4) and found that 1a was the major
product and the selectivity of 1a and 2a was reversed. We next
examined the ligand effect with SIMes, IMes, IPr, and L1
Recently, a series of novel alkylboron compounds, namely
gem-diboryalkanes, attracted attention from chemists. In the
field of construction of C−C bonds with gem-diboryalkanes,9
Shibata et al. reported the pioneering work.10 More and more
attention focused on these interesting synthons due to their
special activity and structure. Thereafter, Morken and co-
workers developed the first Pd-catalyzed stereoselective Suzuki
cross-coupling of 1,1-diborylalkanes,11 and then Morken’s12
and our group13 independently reported the coupling of alkyl
(pseudo)halides with gem-diborylalkanes. Recently, Meek’s
group also reported the addition reaction of aldehydes and
1,1-diborylalkanes.14 Despite many reaction types, allylic
substitution reactions of allylic electrophiles with 1,1-dibor-
ylalkanes have rarely been reported (Scheme 1a).10c,12,13
Furthermore, the γ-selective reaction of gem-diborylalkanes
remains challenging. Herein, we describe copper-catalyzed
SN2′-selective alkylation reactions of allylic electrophiles with
Received: December 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope for the Reaction of Allylic
Phosphates with Diborylmethane
a
entry
X
solvent
ligand
yield (%)
1a/2a
b
1
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
Cl
DMF
−
−
−
−
88
87
8:92
4:96
83:17
87:13
85:15
80:20
82:18
97:3
96:4
90:10
−
2
3
4
5
6
7
8
DMF
THF
66
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
68
SIMesHCl
IMesHCl
IPrHCl
L1
72
67
23
89
64
b
9
L1
10
11
12
L1
79
OAc
L1
trace
22
OCOOMe
OPO(OEt)2
L1
75:25
c
13
L1
0
−
a
All reactions were carried out at 60 °C on a 0.15 mmol scale, and 10
mol % of CuCl, 3 equiv of LiOMe, 2 equiv of diborylmethane (1), and
1 mL of solvent were used. The yields and the ratios of 1a/2a were
b
determined by GC (average of two GC runs). t-BuOLi was used
c
instead of LiOMe. The reaction was carried out without CuCl.
(entries 5−8; for details, see the Supporting Information).
Significantly, ligand L1 not only improved the yield to 89% but
also gave excellent regioselectivity (entry 8, 1a/2a = 98:2). In
addition to cinnamyl phosphate, we also tried some other
cinnamyl electrophiles (Cl, OAc, OCOOMe); however, all
these attempts failed to give better regioselectivity or yield.
With control experiments, we found that this reaction could not
be processed without copper catalysts (entry 13).
With the optimized conditions in hand, we investigated the
scope of this newly developed reaction. As shown in Table 2,
diborylmethane can react with both aromatic and aliphatic
allylic phosphates. A variety of halogen-substituted cinnamyl
phosphates can successfully afford the corresponding products
in good yields and SN2′ selectivity. Different substituted
positions on the cinnamyl phosphates posed no problem with
these reaction conditions (2c−6c and 8c). Many important
functional groups were also compatible, such as NO2 (7c), CF3
(9c), CN (10c), and vinyl (13c). Both (Z)- and (E)-allylic
phosphates (12b and 11b) have similar reactivity and afforded
the same product (11c). Substrates with commonly used
hydroxyl protecting groups can also be employed and give γ-
selective product in high yields (14c, 17c, and 18c). The
heterocyclic compounds (15c and 16c) survived under our
reaction conditions with good yields. In addition to primary
allylic phosphates, the secondary ones also can be used in this
reaction (19c). Finally, we examined the allylic phosphates
which can afford quaternary carbon center (20b). The desired
product (20c) was obtained with moderate yield and
regioselectivity.
a
Reactions were carried out under the conditions shown, using allylic
b
phosphates as substrates, and all yields are isolated yields. The ratios
1
of SN2′/SN2 were determined by H NMR analysis of the reaction
c
mixture. When L1 was used as ligand, the SN2′/SN2 was low (68:32).
When L2 was used, the regioselectivity ratio was improved to 85:15.
newly optimized conditions. We examined several allylic
phosphates to afford the corresponding products (1d−4d)
with good yield, SN2′-selectivity, and moderate diastereose-
lectivity. (Scheme 2; for details, see the Supporting
Information).
Allylic epoxide could be recognized as a special allylic
electrophile; thus, we also tried to employ it in this reaction and
found it can indeed react with different gem-diborylalkanes to
generate SN2′-selective products (Scheme 3).
Meanwhile, we also investigated the substituted gem-
diborylalkanes under the reaction conditions. Unfortunately,
the yield (52%, SN2′/SN2 = 82:18) and dr value (1.2:1) were
very low when 1,1-diborylalkane (2) was used. Modifications to
lead to improvements were carried out, and we determined
The asymmetric version of this reaction was initially
researched with chiral N-heterocyclic carbene (NHC) ligands.
B
DOI: 10.1021/acs.orglett.5b03692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and further efforts to improve the enantio- and diastereose-
lectivity of this reaction are underway.
Scheme 2. Substrate Scope for the Reaction of Allylic
Phosphates with Substituted gem-Diborylalkanes
a
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03692.
Detailed experimental procedures and spectra data for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: binxiao@ustc.edu.cn.
*E-mail: fuyao@ustc.edu.cn.
Notes
a
Reactions were carried out under the conditions shown, all yields
The authors declare no competing financial interest.
were isolated yields, and the ratios of SN2′/SN2 were determined by
1H NMR analysis of the reaction mixture.
ACKNOWLEDGMENTS
■
Scheme 3. Reaction of Allylic Epoxide with Substituted gem-
Diborylalkanes
We thank the 973 Program (2012CB215306), NSFC
(21302178, 21325208, 21572212, 21361140372),
IPDFHCPST (2014FXCX006), SRFDP (20133402120034),
CAS (KFJ-EW-STS-051, YIPA-2015371), FRFCU, and
PCSIRT.
a
REFERENCES
■
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a
Reactions were carried out under the conditions shown, all yields are
isolated yields, and the ee value were determined by HPLC analysis.
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substituted gem-diborylalkanes.16 A variety of synthetically
important functional groups can be compatible under these
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smoothly by IMesCuCl catalysis. However, the reaction was mainly
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D
DOI: 10.1021/acs.orglett.5b03692
Org. Lett. XXXX, XXX, XXX−XXX