Copper-Catalyzed Cross-Coupling Reaction of Allyl Boron Ester with 1°/2°/3°-Halogenated Alkanes

Article abstract of DOI:10.1021/acs.orglett.5b01612

The cross-coupling reaction of allyl boron ester with 1°/2°/3°-halogenated alkanes in the presence of copper has been developed for the first time, which provides a mild and efficient method for the construction of saturated C(sp³)-C(sp³) bonds. This protocol shows excellent compatibility with the nonactivated primary, secondary, and even tertiary halogenated alkanes under mild conditions.

Full text of DOI:10.1021/acs.orglett.5b01612

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cross-Coupling Reaction of Allyl Boron Ester with
1°/2°/3°-Halogenated Alkanes
Guang-Zu Wang,† Jian Jiang,† Xiao-Song Bu,† Jian-Jun Dai,† Jun Xu,‡ Yao Fu,*,‡ and Hua-Jian Xu*,†
†School of Medical Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, P. R.
China
‡Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: The cross-coupling reaction of allyl boron ester with 1°/
2°/3°-halogenated alkanes in the presence of copper has been developed
for the first time, which provides a mild and efficient method for the
construction of saturated C(sp3)−C(sp3) bonds. This protocol shows
excellent compatibility with the nonactivated primary, secondary, and
even tertiary halogenated alkanes under mild conditions.
ransition-metal-catalyzed cross-coupling reactions of
KOtBu as the base, attaining a relatively low yield of 15%. To
Torganometallic reagents (e.g., Mg and Li) with improve the yield, bases were first optimized in our system.
When replacing the KOtBu with less basic NaOtBu, LiOtBu,
halogenated alkanes provide an effective method for the
construction of C−C bonds in organic synthesis.1 For instance,
LiOMe, and K2CO3, we found that alkalinity had a significant
the Pd- and Ni-catalyzed aryl−alkyl2 and alkyl−alkyl3 cross-
coupling reactions have been widely developed. Recently, as an
efficient and environmentally friendly catalytic species, the
development of Cu-catalyzed cross-coupling reactions of
halogenated alkanes with organometallic reagents have
attracted great attention by chemists in the past decades.4 In
2011, Liu et al. successfully achieved the Cu-catalyzed cross-
coupling reactions between aryl boronate esters and primary
alkyl electrophiles.5 Lately, for the formation of C(sp3)−C(sp3)
bonds, the cross-coupling reaction of halogenated alkanes with
alkyl Grignard reagents under Cu catalysis has also been
achieved.6 However, the disadvantages of Grignard reagents are
well-known, including moisture-sensitivity, manipulation diffi-
culty, and decreased functional-group tolerance. Therefore, it
remains a great challenge to develop more general and efficient
Cu-catalyzed C(sp3)−C(sp3) cross-coupling reactions for
constructing saturated C−C bonds.
Herein, we describe a mild and convenient method for the
coupling reaction of allyl boron ester with primary, secondary,
and even tertiary halogenated alkanes, thus providing a practical
means for the construction of saturated C−C bonds. The
advantages of this approach are as follows: (1) Compared with
Grignard reagents, the organoboron reagents show better
commercial availability and higher functional-group tolerance.7
(2) This protocol shows excellent compatibility with the
nonactivated primary, secondary, and even tertiary halogenated
alkanes under mild conditions. It is worth noting that
nucleophilic substitution reactions of unactivated secondary
halogenated alkanes always suffer from E2 elimination and
remain challenging.8
effect on the yield and LiOtBu proving to be optimal giving a
yield of 83% (Table 1, entries 1−5). Next, the influence of
catalyst and solvent were investigated (Table 1, entries 6−12).
We screened a variety of copper salts, including copper(I) and
copper(II); however, they did not show better catalytic activity
compared with CuI. Utilizing coordinating solvents such as
THF, toluene, and DMA resulted in lower activity. To further
optimize the reaction conditions, the influence of the ligand was
investigated by use of three different ligands. Unfortunately,
neither the phosphine ligands nor the nitrogen ones showed
any positive effect (Table 1, entries 13−15). When we
decreased the temperature from 60 to 40 °C and room
tempreture, a drastically decreased yield was observed (Table 1,
entries 16−17). When 5 mol % of catalyst was employed in the
system, we found that only 72% yield was obtained (Table 1,
entry 18). Meanwhile, the alkyl iodide was also acceptable
coupling partners in this coupling reaction, but the alkyl
chloride was not (Table 1, entries 19 and 20). When 1a was
treated under the conditions for the nonactivated alkanes, a
lower yield of 65% was obtained (Table 1, entry 21). Finally,
the necessity for catalyst and base was confirmed by the blank
reaction, and we found that the reactions did not occur if they
were omitted (Table 1, entries 22 and 23).
Having identified the optimum reaction conditions, we next
set out to examine the scope and limitations of this reaction,
and the results are summarized in Scheme 1. First, (3-
bromopropyl)benzene (1a), (2-bromoethyl)benzene (1b), and
(4-bromobutyl)benzene (1c) were employed to investigate the
effect of chain length on the reaction. We found that all of them
could participate in the reaction to give a good yield.
Our study began by examining the cross-coupling of (3-
bromopropyl)benzene (1a) with allyl boron ester [allylB(pin)].
We initially used CuI as the catalyst, DMF as the solvent, and
Received: June 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01612
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Copper-Catalyzed Cross-Coupling Reaction of
Allyl Boron Ester with Primary Halogenated Alkanes
a
b
entry
catalyst
CuI
base
solvent
T (°C)
yield (%)
1
KOtBu
NaOtBu
LiOtBu
LiOMe
K2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
25
60
60
60
60
60
60
15
30
2
CuI
3
CuI
83
4
CuI
6
5
CuI
trace
60
6
CuCl
CuO
CuBr2
Cu(acac)2
CuI
7
15
8
39
9
28
10
11
12
3
CuI
toluene
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
trace
32
CuI
c
13
CuI
27
d
14
e
CuI
48
15
CuI
55
16
17
CuI
68
CuI
48
f
18
CuI
72
g
19
CuI
79
h
20
CuI
23
i
21
CuI
65
22
23
trace
trace
CuI
a
Reaction conditions: 1a (0.25 mmol) (X = Br), catalyst (10 mol %),
base (2 equiv), and solvent (1 mL) at 60 °C for 24 h under an Ar
b
c
atmosphere. GC yield using diphenyl as an internal standard. With
d
e
a
20 mol % of Pph3. With 20 mol % of Pcy3. With 20 mol % of
TMEDA. 5 mol % of catalyst was employed. X = I. X = Cl.
Reaction conditions: halogenated alkanes (0.25 mmol), allylB(pin)
f
g
h
(2 equiv), CuI (10 mol %), LiOtBu (0.5 mmol), and DMF(1 mL) at
i
Halogenated alkanes (0.25 mmol), allylB(pin) (2 equiv), CuI (10 mol
60 °C for 24 h under an Ar atmosphere.
%), TMEDA (20 mol %), LiOtBu (0.5 mmol), and DMF (1 mL) at 0
°C for 48 h under an Ar atmosphere. Cu(acac)2 = cupric
acetylacetonate, DMF = N,N-dimethylformamide, THF = tetrahy-
drofuran, Pcy3 = tricyclohexylphosphine, TMEDA = tetramethylethy-
lenediamin.
byproduct (such as olefin) produced via loss of hydrogen
halide is formed more easily for the nonactivated alkanes in the
reaction process.9 Unfortunately, we can obtain only trace
amounts of product under the standard conditions. However,
by adding the catalytic amount of TMEDA and decreasing the
temperature to 0 °C, we were surprised that the reaction could
proceed smoothly in good yield (3j−m). Unfortunately, for
substrate 3n, we could not obtain the desired product; instead,
a rearrangement product was obtained in good yield (see part 3
in the Supporting Information). For the chiral alkyl tosylate
(3o), the reaction system is limited. In short, this work shows
excellent compatibility with the nonactivated primary, secon-
dary, and even tertiary halogenated alkanes under mild
conditions.
Next, we attempted the reastion using the 3-substituted
allylboronates. However, none of them led to the desired
products. Moreover, we also used the allyl alkyl bromide, and
the results are shown in the Supporting Information, part 3.
We chose 5a as the representative to study the reactivity
difference between alkyl and aryl halogen atoms. When 5a was
treated with allylB(pin), only the desired alkyl−alkyl cross-
coupling product 6a was obtained in high yield (Scheme 3 (a)),
indicating a good chemoselectivity of this reaction. We allowed
1a and 5b to react under the same conditions, and as
anticipated, only 2a was formed (Scheme 3 (b)). Subsequently,
the reactivity difference between alkyl bromine and chlorine
Furthermore, various substrates with synthetically important
functional groups such as ether (1d, 1h), ketal (1e), ester (1f),
olefin (1g), amide (1i), and silyl ether (1k) were studied. Most
of them were well tolerated with yields as desired except for the
secondary amine with a lower yield of 31% (1l), which may be
due to the effect of active hydrogen on the nitrogen atom.
Finally, compounds with heteroatoms, which are typically the
skeleton structures of drug molecules, were good substrates for
this reaction system (1j,m−q).
Apart from the primary halogenated alkanes, secondary and
even tertiary halogenated alkanes were also good substrates in
our system (Scheme 2). Moreover, the alkyl bromide, alkyl
chloride, and alkyl iodide all reacted well in our system. For the
activited halogenated alkanes, such as halogen-substituted
benzyl (3a−e), ortho-halogen-substituted ester (3f), ortho-
halogen-substituted amide (3g), and halogen-substituted
adamantane (3h), we could obtain the desired result under
the optimal reaction conditions. For the dichlorodiphenyl-
methane (3i), the diallyl-substituted products were obtained
with good yield. To further illustrate the importance of the
copper−allylB(pin) system, we next investgated the compati-
bility of nonactivated alkanes. It should be noted that
B
DOI: 10.1021/acs.orglett.5b01612
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Letter
In a scale-up experiment (Scheme 4), 1j was successfully
executed on a larger scale (5 mmol) under the optimum
conditions, attaining 2j with a relatively high yield of 72%.
Scheme 2. Copper-Catalyzed Cross-Coupling Reaction of
Allyl Boron Ester with Secondary and Tertiary Halogenated
Alkanes
a
Scheme 4. Gram-Scale Experiment
Finally, to shed light on the mechanism of the new Cu-
catalyzed C(sp3)−C(sp3) cross-coupling reaction, TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl) and BHT (butylated
hydroxytoluene) were employed as the radical scavengers as
shown in Scheme 5. The results demonstrated lower yields
Scheme 5. Investigation of the Mechanism
(68% and 71% for the TEMPO and BHT, respectively)
compared with those performed under standard conditions
(76%), which ruled out the possibility of a radical mechanism.
On the basis of the literature,10,11 we proposed that the
reaction may undergo a transmetalation between CuI and the
allylB(pin) to form an allylcopper species intermediate. After
that, the organocopper species would react with the
halogenated alkanes to afford the final product. As for the
mechanism, it may be very complex. By adding TEMPO and
BHT, we ruled out the possibility of a radical mechanism of the
primary alkanes. However, for the tertiary alkanes, it probably
underwent a radical mechanism,12,8a and continuing research
will be carried out in our laboratory in the future.
a
Reaction conditions: halogenated alkanes (0.25 mmol), allylB(pin)
(2 equiv), CuI (10 mol %), LiOtBu (0.5 mmol), and DMF(1 mL) at
60 °C for 24 h under an Ar atmosphere. Reaction conditions:
halogenated alkanes (0.25 mmol), allylB(pin) (2 equiv), CuI (10 mol
%), TMEDA (20 mol %), LiOtBu (0.5 mmol), and DMF (1 mL) at 0
°C for 48 h under an Ar atmosphere.
b
Scheme 3. Selectivity of the Cross-Coupling Reaction
To summarize, an efficient and general method for the
coupling reaction of allyl boron ester with primary, secondary,
and even tertiary halogenated alkanes has been described for
the construction of diverse C(sp3)−C(sp3) bonds. The
compatibility of nonactivated secondary and even tertiary
alkyl halides expands the concept and scope of copper-catalyzed
cross-coupling reactions in a fundamental sense. Additionally,
this reaction showed good chemselectivity for the alkyl
halogens compared with aryl ones.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectra data for all
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01612.
atom was investigated by employing 6-chlorohexyl bromide
(5c) as an example, and only the bromine-substituted product
6b was obtained, demonstrating the reactivity order Br > Cl
(Scheme 3 (c)) (for detailed results, see part 4 of the
Supporting Information). When we reduced the amount of the
allylBpin to 1 equiv, a drastically decreased yield was observed
for 6a, 2a, and 6b. However, we did not observe any products
of the aryl-Br and alkyl-Cl.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fuyao@ustc.edu.cn.
*E-mail: hjxu@hfut.edu.cn.
C
DOI: 10.1021/acs.orglett.5b01612
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21272050,
21472033, 21325208, 21361140372) and the Program for
New Century Excellent Talents in University of the Chinese
Ministry of Education (NCET-11-0627).
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