CL-150881
Received: September 22, 2015 | Accepted: December 7, 2015 | Web Released: December 16, 2015
Copper-catalyzed Borylation of Primary and Secondary Alkyl Halides
with Bis(neopentyl glycolate) Diboron at Room Temperature
Xin Lou,*1,2 Zhen-Qi Zhang,2 Jing-Hui Liu,2 and Xiao-Yu Lu2
1School of Material Science and Chemical Engineering, Chuzhou University, Chuzhou 239000, P. R. China
2Anhui Province Key Laboratory of Biomass Clean Energy, Department of Chemistry,
University of Science and Technology of China, Hefei 230026, P. R. China
(E-mail: louxin@ustc.edu.cn)
Borylation reactions are heavily dependent on diboron agents,
evaluated to see if it could achieve the level of catalysis desired for
borylation. This is the first work to systematically investigate
borylation substitution of unactivated alkyl halides using B2npg2
as a source of boron in the preparation of alternative alkylboro-
nates for further Suzuki-Miyaura coupling reactions.
In this work, 2-bromopentane (1a) served as a model
substrate of unactivated secondary alkyl electrophiles and reacted
with diboron compound B2npg2 to produce 2-pentyl boronate.
A wide range of components, including solvents, ligands, copper
sources, and bases, were screened to assess their performance in
the catalysis system for boryl substitution reactions.
During the first stage of condition optimization, a variety of
catalysis systems composed of a copper(I) salt, ligand, base, and
solvent were screened for the desired boryl substitution reactions.
Copper bromide (CuBr) was found to perform better as a catalyst
than CuI or CuCl (Table 1, Entries 3, 5, and 9). This differs from
the findings of other works on copper-catalyzed borylation
reactions.1 Among the ligands, PPh3 was unexpectedly found
to take the lead on catalytic performance over other frequently
reported ligands such as xantphos, dppe, and dppf (Entries 4, 5,
and 6); among the solvents, DMF and DMSO were found to be
whose structures prescribe the reaction conditions. It necessitates
extended investigation of borylation reactions using other diboron
agents as a boron source than B2pin2. In this work, borylation
of unactivated primary and secondary alkyl halides with
bis(neopentyl glycolato)diboron (B2npg2) was investigated, and
a favorable catalysis system was constructed for B2npg2-based
borylation reaction after probing a variety of catalysis systems
composed of a copper salt, ligand, and base. The investigation
showed that this boryl substitution could proceed at room
temperature, producing alkylboronates with high yield. This work
provides an alternative method to the synthesis of alkylboronate
for further Suzuki-Miyaura cross-coupling reactions.
Alkylboronates have a broad range of applications both as
functional compounds for medical chemistry and intermediate
nucleophilic agents, unlike other alkyl nucleophilic agents, as
Grignard agents and organolithium compounds alkylboronates
boast mild character and better compatibility with a variety of
functional groups.1 Alkylboronate can be produced using a variety
of methods such as hydroboration of olefins,2 activation of C-H
bonds with the catalysis of transition metal,3 and β-borylation
of unsaturated carbonyl.4 However, all of these methods have
drawbacks. Considerable effort has recently been directed to
Miyaura-type borylation reactions, which have broader scope and
adaptivity. This borylation reaction of alkyl halide is usually
accomplished with the catalysis of a transition metal, and a variety
of transition metals such as Pd,5 Rh,6 Ir,3 Cu,7 Ni,8 Zn,9 and Fe10
have been used as catalysts to prepare versatile alkylboronates. Cu
seems to be currently taking the lead as a catalyst for borylation
substitution. It has the combined advantages of low cost and
supercatalyzing performance. In recent years, copper(I) salts
have been widely used to prepare a great number of functional
organoboronates such as 2-boryl-1,3-butadienes,11 α-chiral linear
and carbocyclic (E)-γ-alkoxyallylboronates,12 boron-substituted
enynes,13 aryl-borylstannane compounds,14 and α-alkoxyorgano-
boronate esters.15 In contrast to the versatile range of transition-
metal catalysts available, sources of boron for boryl substitution
have been almost entirely limited to bis(pinacolato)diboron
(B2pin2). This is partially because of its commercial availability
and low cost. So far, little work has been done regarding the
adoption of other diboron agents as sources of boron, which would
include bis(neopentyl glycolato)diboron (B2npg2).6b,16 For this
reason, there are almost no alkylboronates other than B2pin2-based
ones available for Suzuki-Miyaura cross-coupling reactions. In
this work, B2npg2 was assessed for use as a source of boron for
borylation of inactivated alkyl halides, and the catalysis system
corresponding to the structure of B2npg2 was systematically
Table 1. Studies of reaction conditions for copper(I)-catalyzed
boryl substitution of alkyl halide 1aa
10% CuX, x Ph3P
O
O
O
Br
2 equiv Base
B
B
+
0.5 mL solvent
under Ar, r.t., 18 h
O
O
O
B
0.25 mmol
0.37 mmol
1a
2
3a
Entry
Catalyst
Ligand
Base
Solvent
Yieldb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
CuI
CuI
dppe
dppe
xantphos
PPh3
xantphos
dppf
PPh3
dppe
xantphos
dppe
PPh3
LiOt-Bu
KOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
NaOt-Bu
LiOt-Bu
LiOt-Bu
LiOt-Bu
KOt-Bu
NaOt-Bu
LiOt-Bu
LiOMe
DMF
DMF
DMSO
DMF
DMF
DMSO
DMF
DMF
THF
DMSO
DMF
DMF
DMF
DMF
DMF
30
33
22
58
32
41
35
51
13
43
40
39
30
12
26
CuBr
CuBr
CuBr
CuCl
CuCl
CuCl
CuCl
CuSCN
CuCN
Cu(OTf)2
CuCl
CuI
xantphos
dppf
dppe
PPh3
LiOMe
aConditions: 1a (0.25 mmol), CuX (0.025 mmol), ligand (0.025 mmol),
base (0.5 mmol), base/solvent (1.0 M, 0.5 mL). bYield was determined
using GC analysis of crude mixture with an internal standard.
© 2016 The Chemical Society of Japan