Copper-catalyzed alkyl-alkyl cross-coupling reactions using hydrocarbon additives: Efficiency of catalyst and roles of additives

Article abstract of DOI:10.1021/jo501006u

Cross-coupling of alkyl halides with alkyl Grignard reagents proceeds with extremely high TONs of up to 1230000 using a Cu/unsaturated hydrocarbon catalytic system. Alkyl fluorides, chlorides, bromides, and tosylates are all suitable electrophiles, and a TOF as high as 31200 h^-1 was attained using an alkyl iodide. Side reactions of this catalytic system, i.e., reduction, dehydrohalogenation (elimination), and the homocoupling of alkyl halides, occur in the absence of additives. It appears that the reaction involves the β-hydrogen elimination of alkylcopper intermediates, giving rise to olefins and Cu-H species, and that this process triggers both side reactions and the degradation of the Cu catalyst. The formed Cu-H promotes the reduction of alkyl halides to give alkanes and Cu-X or the generation of Cu(0), probably by disproportionation, which can oxidatively add to alkyl halides to yield olefins and, in some cases, homocoupling products. Unsaturated hydrocarbon additives such as 1,3-butadiene and phenylpropyne play important roles in achieving highly efficient cross-coupling by suppressing β-hydrogen elimination, which inhibits both the degradation of the Cu catalyst and undesirable side reactions.

Full text of DOI:10.1021/jo501006u

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Featured Article
Copper-Catalyzed Alkyl-Alkyl Cross-Coupling Reactions Using
Hydrocarbon Additives: Efficiency of Catalyst and Roles of Additives
Takanori Iwasaki, Reiko Imanishi, Ryohei Shimizu, Hitoshi Kuniyasu, Jun Terao, and Nobuaki Kambe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501006u • Publication Date (Web): 03 Jul 2014
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Copper-Catalyzed Alkyl-Alkyl Cross-Coupling Reactions Using Hydrocarbon
Additives: Efficiency of Catalyst and Roles of Additives
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†
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Takanori Iwasaki, Reiko Imanishi, Ryohei Shimizu, Hitoshi Kuniyasu, Jun Terao, and
,
†
Nobuaki Kambe*
†
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
Suita, Osaka 565-0871, Japan
‡
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
kambe@chem.eng.osaka-u.ac.jp
ABSTRACT: Cross-coupling of alkyl halides with alkyl Grignard reagents proceeds with
extremely high TONs of up to 1,230,000 using a Cu/unsaturated hydrocarbon catalytic
system. Alkyl fluorides, chlorides, bromides, and tosylates are all suitable electrophiles and
–1
a TOF as high as 31,200 h was attained using an alkyl iodide. Side-reactions of this
catalytic system, i. e., reduction, dehydrohalogenation (elimination), and the homocoupling
of alkyl halides, occur in the absence of additives. It appears that the reaction involves the
β-hydrogen elimination of alkylcopper intermediates, giving rise to olefins and Cu-H
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species and that this process triggers both side-reactions and the degradation of the Cu
catalyst. The formed Cu-H promotes the reduction of alkyl halides to give alkanes and
Cu-X or the generation of Cu(0), probably by disproportionation, which can oxidatively
add to alkyl halides to yield olefins and, in some cases, homocoupling products.
Unsaturated hydrocarbon additives such as 1,3-butadiene and phenylpropyne play
important roles in achieving highly efficient cross-coupling by suppressing β-hydrogen
elimination, which inhibits both the degradation of the Cu catalyst and undesirable
side-reactions.
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INTRODUCTION
Transition metal-catalyzed cross-coupling reactions of organohalides with
organometallic reagents are one of the most useful and reliable methods for constructing
1
carbon skeletons. A variety of catalytic systems have been developed and are widely
employed in both the laboratory and in industrial processes as indispensable synthetic
2
tools, however, large amounts of expensive catalysts (1 to 10 mol % of Pd in many cases)
and heteroatom ligands (such as phosphorous compounds) are often needed to achieve high
2
a,d
product yields. From both the environmental and economic points of view, curtailing the
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amount of noble metal catalysts and costly toxic ligands that are used, or replacing them
with lower cost metals and more readily available safer ligands has attracted considerable
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interest in modern synthetic chemistry. A great deal of effort has been paid to improve the
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,5
efficiency of the reactions
and, for example, the turnover numbers (TONs) of
2
Pd-catalyzed Suzuki-Miyaura coupling between two sp -hybridized carbons have reached
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11 4
2
the range of 10 to 10 . Concerning cross-coupling between an sp -carbon and an
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4
4h,6
sp -carbon, high TONs of 10 to 10 orders have been achieved.
However, for reactions
3
employing sp -carbon electrophiles, examples of high efficiencies are available only for the
6
reactions of benzyl halides. Since alkyl groups are the most difficult coupling patterns to
be manipulated in transition-metal-catalyzed reactions, especially in the cases of alkyl
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derivatives having a β-hydrogen(s), alkyl-alkyl cross-coupling is much less efficient and
7
a,b
the highest TON of 970 was achieved when alkyl Grignard reagents were used. This is
mainly due to the facile β-hydrogen elimination from alkylmetal intermediates that are
8
9
10
generated in situ, which triggers isomerization, elimination, and/or reduction of the alkyl
moieties. Difficulties may also arise from homolysis of alkylmetal intermediates and/or a
single electron transfer (SET) from a metal to alkyl halides to generate alkyl radical
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12
intermediates as illustrated in Scheme 1 (vide infra).
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Scheme 1. Possible pathways in metal-catalyzed alkyl-alkyl cross-coupling.
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We previously reported on alkyl-alkyl cross-coupling reactions of unactivated alkyl
halides with Grignard reagents catalyzed by Ni, Pd, Cu, or Co using unsaturated
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a-c,13,14
hydrocarbons such as 1,3-butadiene and phenylpropyne as additives.
The high
potential of these reactions as useful synthetic tools was demonstrated by their successful
application to reagents with a low reactivity, such as alkyl chlorides and fluorides as well as
7
a,b,14
alkyl tosylates
and to the synthesis of biologically active compounds and natural
1
5
products. Here we report on the use of a Cu/diene or alkyne catalytic system in the highly
efficient catalysis of cross-coupling reactions of unactivated alkyl halides with Grignard
–
6
–4
reagents using as little as molppm (defined as 10 mole ratio = 10 mol %) orders of Cu.
We also provide evidence to show that butadiene and alkyne ligands play important roles in
16
suppressing both side reactions and the degradation of the Cu catalyst.
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RESULTS AND DISCUSSION
Highly efficient alkyl-alkyl cross-coupling reaction. In initial experiments, we tested
the catalytic performance of Cu in the reaction of n-NonBr with n-BuMgCl in the presence
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4c
–4
of phenylpropyne employing small amounts of the catalyst in the molppm (10 mol %)
1
7
order. As shown in Table 1, n-NonBr coupled with n-BuMgCl to give the desired product
nearly qualitatively when only 100 molppm of catalyst was used (entry 1). When the
1
8
catalyst was reduced to 50 molppm, the yield decreased to 81% (entry 2). A similar
reaction using only 1 molppm of CuCl at 40 °C afforded the product in 40% yield
2
indicating a high TON of 400,000 (entry 3). Although n-NonCl reacted sluggishly at rt
14c
(
entry 5), it coupled with n-BuMgCl in refluxing THF using 5000 molppm (0.5 mol %)
of catalyst to give the corresponding product in 70% yield in 24 h (entry 4). The coupling
of n-NonI proceeded quantitatively in the presence of 25 molppm of Cu (entry 7). When the
reaction was stopped at an early stage after stirring for 10 min, a 52% yield of product was
–
1
found, with an unprecedentedly high turnover frequency (TOF) of 31,200 h (entry 6).
1
4a,b
Reactions of alkyl tosylates and fluorides,
which are less reactive than the
corresponding iodide but more reactive than a chloride, proceeded in nearly quantitative
yields at rt with 1000 and 3000 molppm of Cu, respectively (entries 8, 12). When the Cu
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was reduced from 3000 molppm to 1000 and 500 molppm in the reaction of n-OctF, the
yield correspondingly decreased from 92% to 44% and 22%, respectively, as shown in
entries 12, 13, and 15. Under the same conditions as entry 15 using 500 molppm of Cu, the
reaction proceeded in the absence of phenylpropyne affording a similar yield of 26% (entry
16). However, interestingly, no cross-coupling product was detected when large amounts of
Cu (1000 molppm or more) were used in the absence of phenylpropyne (entry 13 vs. 14).
The reaction mixture in the case of entry 13 using phenylpropyne was a clear brownish
yellow solution, but in the absence of phenylpropyne, a black precipitate soon (in a few
minutes) appeared after the addition of the Grignard reagent in entry 14. These results
indicate the decomposition of Cu started rapidly and was accelerated at high concentrations
in the absence of phenylpropyne, probably due to the autocatalytic decomposition observed
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earlier
and that phenylpropyne suppressed this aggregation of the copper catalyst,
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0
probably via the formation of Cu-alkyne complexes.
Table 1. Coupling Reaction of Alkyl (Pseudo)halides with n-BuMgCl Using
a
Phenylpropyne as an Additive
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b
entry RX
CuCl (molppm)
yield (%)
95
TON
9,500
16,200
400,000
140
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n-NonBr
100
50
n-NonBr
n-NonBr
n-NonCl
n-NonCl
n-NonI
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c
1
40
d
5000
25
70
nd
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e
100
25
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5,200
>29,600
>990
2,967
4,900
12,000
307
n-NonI
>99
>99
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n-OctOTs
n-OctOTs
n-OctOTs
n-OctOTs
n-OctF
1000
300
100
25
0
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2
3000
1000
1000
500
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13
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n-OctF
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440
f
n-OctF
nd
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n-OctF
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f
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n-OctF
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520
a
Reaction conditions: RX (1 mmol), n-BuMgCl (1.67-1.80 M in THF, 1.3 mmol),
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CuCl , phenylpropyne (1 mmol), decane (internal standard) in THF at 25 °C for 24 h.
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c
d
Yield was determined by GC. 10 mol % alkyne, at 40 °C for 48 h. Under reflux
e
f
conditions. 10 mol % alkyne, at 40 °C for 10 min. Without additive.
Additive effects of 1,3-butadiene in the coupling reactions of various alkyl halides with
n-BuMgCl using different amounts of CuCl were also examined and the results are
2
summarized in Table 2, which are practically quite similar to the results obtained using
phenylpropyne shown in Table 1. By using only 10 molppm (0.001 mol %) of CuCl and 1
2
equivalent of 1,3-butadiene, the reaction of n-NonBr with n-BuMgCl provided the
corresponding product in 49% yield after stirring at room temperature for 24 hours (entry
4). The yield of the product increased when the catalyst loading was increased and a nearly
quantitative yield (96%) was attained using 100 molppm of catalyst with the TON as high
as 9,600 (entry 1). A reaction of nonyl iodide was completed with only 25 molppm of
CuCl and afforded tetradecane in 86% yield with a high TON of 34,400 (entry 6), although
2
alkyl fluoride and tosylate reacted more slowly and chloride was sluggish. Satisfactory
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results for alkyl tosylate and fluoride were obtained by the use of 1000 molppm and 10000
molppm of CuCl , respectively (entries 8 and 11). In the latter case, an interesting additive
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2
effect similar to the case of phenylpropyne shown in Table 1 was observed. When catalyst
loading was less than 500 molppm, 1,3-butaidene exerted almost no effect (entry 15 vs. 16),
but a remarkable effect of 1,3-butadiene was observed in the reaction with more than 1000
molppm catalyst loading (entry 13 vs. 14), in which black precipitates were formed in the
absence of 1,3-butadiene, however a clear brownish yellow solution was kept during the
13h,14b
reaction in the presence of 1,3-butadiene. Although 1,3-butadiene
exerted additive
effects similar to that for phenylpropyne, phenylpropyne afforded slightly better yields in
coupling reactions of alkyl fluorides.
Table 2. Coupling Reaction of Alkyl (Pseudo)halides with n-BuMgCl Using
a
1,3-Butadiene as an Additive
b
entry RX
CuCl (molppm)
yield (%)
96
TON
2
1
n-NonBr
100
9,600
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n-NonBr
n-NonBr
n-NonBr
n-NonCl
n-NonI
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71
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nd
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>99
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86
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>99
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nd
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20,800
49,000
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333
n-OctOTs
n-OctOTs
n-OctOTs
n-OctOTs
n-OctF
3000
1000
500
25
970
1,720
7,200
>99
280
0
11
10000
3000
1000
1000
500
500
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n-OctF
n-OctF
310
c
n-OctF
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n-OctF
360
c
16
n-OctF
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a
Reaction conditions: A mixture of RX (1 mmol), n-BuMgCl (1.3 mmol), 1,3-butadiene
b
(
1 mmol), CuCl , and decane (internal standard) in THF was stirred at 25 °C for 24 h.
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Yield was determined by GC. Without additive.
As shown in Scheme 2, the present Cu/butadiene system provided cross-coupling
products containing alkene, alkyne, acetal, thiophene, and N-tosyl amide functionalities in
good to excellent yields with a Cu loading of only 25 molppm, with high TONs of
approximately 40,000. A reaction of N,N-diethyl-6-bromohexanamide with n-BuMgCl in
the presence of 25 molppm of CuCl gave the corresponding coupling product in 60% yield
2
with complete consumption of the amide employed. When the corresponding tert-butyl
ester was subjected to the reaction using 100 molppm of CuCl , the desired coupling
2
product was obtained in a moderate yield (45%) in 6 h with recovery of the starting
material only in 17%. Cyclohexylmethyl bromide (1b) also coupled with n-BuMgCl to
afford the corresponding coupling product somewhat less efficiently, probably due to steric
reasons. It was possible to couple an alkyl bromide bearing a hydroxyl group 1g using an in
15d
situ protection protocol
employing 2.3 equivalents of Grignard reagent. When
dihalogenated compounds 1h-j were employed as substrates, chemoselective coupling took
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place at a terminal bromomethylene carbon. In these reactions, the corresponding coupling
products bearing alkyl chloride, internal alkyl bromide, and aryl bromide moieties were
produced in 96%, 76%, and 98% yields, respectively.
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Scheme 2. Coupling of alkyl bromides catalyzed by the Cu/1,3-butadiene system
a
Reaction conditions: RX (1 mmol), n-BuMgCl (1.3 mmol), CuCl (25 molppm),
2
1,3-butadiene (1 mmol), decane (internal standard) in THF at 25 °C for 24 h. Yield was
b
c
determined by GC. 100 molppm of CuCl was used. 2.3 equivalents of n-BuMgCl were
2
used.
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Congested alkyl Grignard reagents also afforded satisfactory results, demonstrating the
applicability of the present catalyst for the construction of branched carbon skeletons
(Scheme 3). For example, β-branched Grignard reagents bearing iso-butyl or neopentyl
groups coupled with n-NonBr at 25 °C in good yields using 100 and 500 molppm of
catalyst, respectively. s-BuMgCl also underwent cross-coupling in the presence of 100
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60
molppm of CuCl giving a product in 83% yield under the same conditions. When the
2
reaction was conducted at 40 °C, a 74% yield of product was obtained using only 25
molppm of catalyst. t-BuMgCl worked perfectly to construct a quaternary carbon center
using 200 molppm of CuCl , although it has been reported that the cross-coupling of
2
tertiary alkyl Grignard reagents sometimes afford mixtures of products via
7a,b,14b,c,21
isomerization.
Liu et al. successfully developed a new Cu-catalyzed system for
cross-coupling of congested secondary alkyl halides with secondary alkyl Grignard
reagents to construct adjacent branched carbon centers by use of TMEDA and LiOMe as
21e
the additives. Hu et al. reported that Cu catalyzes cross-coupling reaction of primary
alkyl halides possessing various functional groups with secondary or tertiary alkyl Grignard
21f
reagents without any additives. In these catalytic systems, Cu catalyst in 0.5 to 10 mol %
loading was employed. It is noteworthy that Cu has potent catalytic activity to achieve the
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6
alkyl-alkyl coupling reaction with much lower levels of loadings. On the other hand,
methyl and phenyl Grignard reagents were found to be less reactive and required 500
molppm of catalyst in refluxing THF to produce good yields.
0
1
2
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8
9
0
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9
0
a
Scheme 3. Coupling reaction of various Grignard reagents
a
Reaction conditions: n-NonBr (1 mmol), RMgX (1.3 mmol), CuCl , phenylpropyne (1
2
mmol), decane (internal standard) in THF at 25 °C for 24 h. Yield was determined by GC.
The highest TON of 1,230,000 was achieved in the reaction of 1k with n-BuMgCl using
0
.5 molppm of CuCl and 1,3-butadiene as the additive, giving 2k in 62% after 48 h at 40
2
22
°
C (eq 1).
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To demonstrate the synthetic usefulness of the present coupling reaction, we carried out
a large-scale reaction. When the reaction was carried out on a 0.1 mol scale with 25
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60
molppm of CuCl and 1 mol % of 1,3-butadiene (ca. 12 mM in the reaction mixture), the
2
desired product was formed in 92% GC yield and isolated in 80% yield (15.9 g) after the
usual work-up and distillation (eq 2). It is noteworthy that the present catalyst system can
be used efficiently in large scale production without the need for phosphine or amine
ligands, which may cause difficulties in the work-up process when used in large amounts.
For example, the coupling product was obtained in an essentially pure form, 92% purity by
GC analysis, after simple aqueous work-up and removing volatiles.
Effects of unsaturated hydrocarbon additives. To shed light on the roles of
1
6,23
unsaturated hydrocarbon additives,
we examined the reaction of β-branched alkyl
bromides 1l with n-BuMgCl in the presence of 1000 molppm of CuCl in the absence of
2
any additive. After 24 hours, only 26% of the coupling product 2l was obtained along with
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% of the reduced product 3 and a significant amount (22%) of the homocoupling product
, which was likely produced via the homocoupling of 1l mediated by the reduced Cu(0)
4
0
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0
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4
5
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7
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9
0
2
4
species that was generated in situ. In the presence of phenylpropyne, the yield of 2l was
improved to 89% and side reactions were suppressed, with 4 being formed in only 4% yield
(eq 3). The more remarkable effect of phenylpropyne is shown in eq 4. The reaction of 1m
with n-BuMgCl in the absence of an additive yielded the undesired reduction product 5 as
the major product and only 5% of the coupling product 2m. In contrast to this
unsatisfactory result, the addition of phenylpropyne suppressed the reduction of 1m,
resulting in the production of 2m in 56% yield (eq 4). These results clearly indicate that the
addition of unsaturated hydrocarbon additives suppresses not only catalyst degradation but
also undesirable side reactions, such as reduction and homocoupling, thus improving both
the selectivity and yield of the reaction.
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Figure 1 shows the time course for the cross-coupling reaction of an alkyl bromide with
n-BuMgCl using 500 and 25 molppm of catalyst with and without phenylpropyne. With a
catalyst loading of 500 molppm, the addition of phenylpropyne not only improved product
yields (ꢀ vs. ꢁ) but also suppressed the reduction of halides (O vs. ꢂ) (Figure 1a). In the
absence of phenylpropyne, the cross-coupling was terminated at an early stage (in ca. 10 h).
In contrast, when the catalyst loading was reduced to 25 molppm, the formation of the
coupling product continued and the yield increased regardless of whether phenylpropyne
was present or not (Figure 1b, ꢀ and ꢁ). However, even in this case, undesirable reduction
was again dramatically suppressed when the additive was present (O vs. ꢂ). Interestingly,
the additive appeared to slow down the cross-coupling slightly (vide infra).
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4
0
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30
2
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1
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5
10
15
20
25
0
5
10
15
20
25
Figure 1. Time-course of reaction of RBr and n-BuMgCl (a) with 500 molppm CuCl (R =
2
PhCH(Me)CH : 1m) and (b) 25 molppm CuCl (R = n-Non). With alkyne R-n-Bu: ꢀ (solid
2
2
line), R-H: O (dashed line), without alkyne R-n-Bu: ꢁ (solid line), R-H: ꢂ (dashed line).
We then examined the possibility of an alkyne or diene trapping Cu-H to form the
corresponding vinyl- or allylcopper which can regenerate alkylcopper by transmetalation
with an alkyl Grignard reagent. When n-NonBr was reacted with n-BuMgCl using 10 mol
% of CuCl without an additive, 20% of nonane (200% based on the Cu used) was formed
2
along with the cross-coupling product and nonane in a roughly 1:2:1 ratio. However, as
shown in eq 5, only 2 % of reduced alkyne was obtained when the same reaction was
conducted using 1 equiv of phenylpropyne and quenched with 1N HCl aq., indicating that
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Cu-H may, in part, be trapped by phenylpropyne but this is not the main route for additives
to suppress the degradation of catalysts.
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60
To gain insights into the active species, we then examined the effects of alkynes on
reaction rates and selectivities. The coupling of n-NonBr with n-BuMgCl using 25 molppm
of CuCl was conducted in the presence of different amounts of phenylpropyne and the
2
time-course for the reactions is illustrated in Figures 2 and 3. Without the additive, the
cross-coupling reaction was fast and the yield reached 51% after 7 h (Figure 2a). In the
presence of phenylpropyne, the coupling reaction gradually and continuously became
slower as the amount of the additive was increased to 100 mol %. On the other hand, the
formation of a side product, nonane, was suppressed drastically by only small amounts of
phenylpropyne and no further change was detected for phenylpropyne at concentrations
higher than 25 mol % (Figure 2b). The relationships between the amounts of the
phenylpropyne and the yields of the products are shown in Figure 3. These observations
suggest that phenylpropyne at higher concentrations generates Cu complexes coordinated
2
5
by two acetylene molecules as a resting state of the catalytic system.
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9
0
40
2
0
0
0
5
10
15
20
25
0
5
10
15
20
25
Figure 2. Time-courses of coupling product (a) and reduced product (b) in the reaction of
n-NonBr with n-BuMgCl with 25 molppm of CuCl and 100 mol % (ꢃ), 50 mol % (ꢁ), 25
2
mol % (ꢀ), 5 mol % (ꢀ), or 0 mol % (ꢀ) of phenylpropyne.
CuCl (25 molppm)
2
Ph
Me(0-100 mol %)
n-Non–Br + n-Bu–MgCl
n-Non n-Bu + nonane
THF, 25 °C, 3 h
2
2
1
1
5
0
5
0
5
0
4
3
2
1
0
0
20
40
60
80
100
120
phenylpropyne (mol %)
Figure 3. Plots of the yields of the cross-coupling product (ꢁ, left axis) and nonane (ꢃ,
right axis) against the amount of phenylpropyne used at 3 h reaction time.
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Next, we conducted a similar experiment with lower reactive substrate, alkyl chlorides.
Since n-NonCl was much less reactive, the reaction was performed in refluxing THF and
the time-course of these reactions is shown in Figure 4. Although no reaction, neither
cross-coupling nor reduction, took place without phenylpropyne due to the quick
degradation of the Cu catalyst under the conditions employed, the yield of the coupling
product reached 76% within 1 h in the presence of 5 mol % of phenylpropyne (1 equiv to
Cu). The use of 2 equiv (10 mol %) of phenylpropyne showed similar results with a slightly
improved yield of product. Addition of larger amounts of phenylpropyne led to depression
of catalytic activity but the yield of coupling product gradually increased to ca. 80% by
prolonging the reaction time. Again, a stoichiometric amount of phenylpropyne exerted a
remarkable effect to promote the coupling reaction efficiently but the rate was gradually
retarded as the additive was increased up to 60 equiv based on Cu.
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11
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80
60
40
20
0
0
0.2
0.4
0.6
0.8
1
1.2
Figure 4. Time-courses of the cross coupling reaction of n-NonCl with n-BuMgCl with 5
mol % of CuCl and 300 mol % (ꢃ), 100 mol % (ꢁ), 50 mol % (ꢀ), 10 mol % (ꢀ), or 5
2
mol % (ꢀ) of phenylpropyne.
The time-course for the initial stage of the reaction of n-NonBr with n-BuMgCl
catalyzed by 25 molppm of CuCl using phenylpropyne, phenylbutyne, or phenylhexyne
2
≡
(PhC CR, R = Me, Et, n-Bu) is shown in Figure 5. In all cases including the reaction
without an additive, cross-coupling proceeded smoothly at rates decreasing in the order of
phenylhexyne (R = n-Bu, ꢀ), phenylbutyne (R = Et, ꢁ), phenylpropyne (R = Me, ꢃ).
Again, the addition of phenylpropyne slowed down the reaction (ꢃ) compared to the
reaction without alkynes (ꢀ). In the case of phenylbutyne (R = Et), the initial rate of the
reaction was slightly faster than the case of phenylpropyne (ꢁ vs. ꢃ). Phenylhexyne (R =
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n-Bu) did not retard the cross-coupling and the reaction proceeded at the same rate as the
reaction without an additive. This may be because the coordination of the second alkyne
molecule to Cu is unfavorable due to the bulkiness of the n-Bu group. The reduction of
n-NonBr did not occur in the presence of these additives, though the reduced product
nonane was produced in 2% yield in the absence of the additive after completion of the
reaction under these conditions.
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60
2
0
15
10
5
0
0
0.5
1
1.5
2
2.5
Figure 5. Time-courses for the coupling product in the reaction of n-NonBr with n-BuMgCl
with 25 molppm of CuCl and 100 mol % of 1-phenyl-1-propyne (R = Me, ꢃ),
2
1
-phenyl-1-butyne (R = Et, ꢁ), or 1-phenyl-1-hexyne (R = n-Bu, ꢀ). In the absence of
additive (ꢀ).
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2
6
It is known that alkylcopper species (Cu-R) undergo β-hydrogen elimination and react
2
7,28
with Grignard reagents to form more stable cuprates
which serve as the active catalytic
0
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9
0
species for cross-coupling reactions. Taking into account this body of evidence and the
results shown above, it seems likely that alkyne or diene (L) coordinates to alkylcopper to
form (L)Cu-R, which is stable to β-hydrogen elimination but still has a potent catalytic
activity as the active key species for cross-coupling reactions. Under high concentrations of
alkynes or dienes, (L)Cu-R reacts with another molecule of additive to form (L )Cu-R as a
2
resting state especially in the case of less hindered additives.
Side-reactions and catalyst degradation. Detailed pathways of side-reactions and
degradation of the catalysts has not yet been discussed in the reports concerning alkyl-alkyl
1
2
cross-coupling reactions. Therefore, we carried out several control experiments
2
8
employing various combinations of reagents and conditions (eqs 6-13). When the CuCl
and CuCl were treated separately with n-BuMgCl for 2 h in the absence of an additive
2
before the addition of n-NonBr to consciously generate decomposed Cu species, none or
only a trace amount of the coupling product, tridecane C H , was produced and, as the
1
3
28
side products, nonane C H and nonene C H were formed in nearly 1:2 and 2:1 ratio,
9
20
9
18
respectively (eqs 6 and 7). When the pretreatment time of CuCl was shortened to 5 min,
2
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similar results were obtained as shown in eq 8. These results indicate that the Cu catalyst
quickly decomposed when treated with alkyl Grignard reagents in the absence of additives
and promote the side-reactions of the alkyl bromide to yield alkane and olefins, probably
via reduction with Cu-H generated by the β-elimination of n-Bu-Cu formed from the
10
11
12
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60
1
9
reaction of CuCl with n-BuMgCl and via an oxidative addition/β-elimination sequence,
2
respectively. The same reaction as eq 7 but employing only 100 molppm of the Cu salt
afforded a 75% yield of the coupling product along with 6% of nonane and a trace amount
of nonene, even in the absence of an additive (eq 9). This difference between eqs 7 and 9
suggests that the decomposition of the catalytic active species largely depends on the
concentration of Cu and is fast at higher concentrations, as has been observed
1
7a,19
previously.
When phenylpropyne was added after an 1 h pretreatment, the catalytic
active species was not regenerated but side-reactions were efficiently suppressed in either
case of CuCl or CuCl (eqs 10 and 11). When both phenylpropyne and a second portion of
2
CuCl were added after the decomposition of the initially added catalyst by the same
2
pretreatment as eq 7, cross-coupling proceeded to give tridecane in 71 % yield (eq 12). In
addition, a similar result was obtained even when n-NonBr was added after stirring the
reaction mixture for 1 h (eq 13). These results clearly indicate that phenylpropyne protects
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1
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2
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6
the catalyst from degradation, even in the presence of Cu metal species that can accelerate
the deactivation of Cu catalysts.
0
1
2
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6
7
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9
0
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0
CuCl
3 mol %)
n-Non n-Bu nd
(
n-NonBr
+
n-BuMgCl
n-BuMgCl
n-Non H
31% (6)
66%
THF, rt, 2 h
rt, 10 min
+
nonene
CuCl2
3 mol %)
n-Non n-Bu 2%
(
n-NonBr
+
n-Non H
+
52% (7)
36%
THF, rt, 2 h
rt, 10 min
nonene
CuCl2
3 mol %)
n-Non n-Bu 3%
(
n-NonBr
+
n-BuMgCl
n-BuMgCl
n-Non H
+
66% (8)
26%
THF, rt, 5 min rt, 10 min
nonene
CuCl2
n-Non n-Bu 75%
(100 molppm) n-NonBr
+
n-Non H
6% (9)
trace
THF, rt, 2 h
rt, 24 h
+
nonene
CuCl Ph
3 mol %) (100 mol %) n-NonBr
Me
n-Non n-Bu trace
+
(
n-BuMgCl
n-BuMgCl
n-Non H 6% (10)
THF, rt, 1 h THF, rt, 1 h rt, 10 min
+
nonene
5%
CuCl2 Ph
3 mol %) (100 mol %) n-NonBr
Me
n-Non n-Bu 5%
+
(
n-Non H 6% (11)
THF, rt, 1 h THF, rt, 1 h rt, 10 min
+
nonene
8%
CuCl (3 mol %)
2
Ph
Me
CuCl2
3 mol %)
(100 mol %)
n-Non n-Bu 71%
(
n-NonBr
+
n-BuMgCl
n-BuMgCl
n-Non H
3% (12)
nd
THF, rt, 2 h
rt, 10 min
+
nonene
CuCl (3 mol %)
2
CuCl2
Ph
Me
n-Non n-Bu 76%
+
(
3 mol %) (100 mol %) n-NonBr
n-Non H 2% (13)
THF, rt, 2 h THF, rt, 1 h rt, 10 min
+
nonene
nd
In order to examine the degradation processes of Cu in the absence of additives, 1.0
mmol of n-NonBr was added to a mixture of n-OctMgCl (1.3 mmol) and 3 mol % of CuCl2
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7
8
9
in THF being stirred for 5 min at rt (eq 14). As expected from the result of eq 8, the desired
cross-coupling product was obtained only in 6% yield and nonane was formed in 64%
yield, along with octene in 57% and nonene in 30% yields. This result can be explained by
the rapid β-hydrogen elimination of n-Oct–Cu generated in situ to form octene and Cu–H
10
11
12
13
14
15
16
17
18
19
20
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23
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57
58
59
60
2
6
(9), which then reacts with n-NonBr to give nonane and CuBr.
When the same reaction as shown in eq 7 was conducted employing n-OctMgCl instead
of n-BuMgCl and the reaction was quenched with diphenyl disulfide (1.5 mmol),
n-Oct-SPh was not formed and octene and octane were formed in nearly quantitative
amounts as well as octene and nonane were formed in nearly equal amounts. This result
indicates that n-OctMgCl was completely consumed within 10 min after the addition of
n-Non-Br and may support the intermediacy of Cu-H (9) as a key species in the reduction
st
of nonyl bromide (Scheme 4, 1 run). In sharp contrast, no significant amounts of
side-products arising from either n-NonBr or n-OctMgCl were detected in the presence of
nd
an alkyne additive (Scheme 4, 2 run) and cross-coupling proceeded exclusively.
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2
3
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Effect of alkyne to side-reactions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Control experiments proved that small amounts of octane and octene (16% and 4%,
respectively) were present in the solution of the octyl Grignard reagent that was used or
b
arose during handling, so their yields were corrected by subtracting these amounts.
Average of 4 runs.
Proposed mechanisms for the present catalytic system. Based on the results shown
above, proposed catalytic pathways, including side-reactions, are illustrated in Scheme 5.
28
First, an alkylcopper 6, generated from the copper salt and the Grignard reagent, reacts
with the Grignard reagent to form dialkylcuprate 7, which undergoes nucleophilic
2
3
substitution with alkyl halides by an ionic mechanism to afford the desired coupling
products through reductive elimination of cis-oriented two alkyl groups from the complex 8
1
3h,14,23
(Cycle A).
Because the alkyl copper is less thermally stable, it undergoes
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decomposition via β-hydrogen elimination to give alkenes and Cu–H 9, which then reacts
with alkyl halides to yield the corresponding alkanes along with CuX 10 (Cycle B).
Degradation of the Cu catalyst would be triggered by the formation of Cu(0) from 9 and/or
10 via their disproportionation or related processes, and the resulting Cu(0) promotes
another side-reaction via 11 to give alkenes from alkyl halides and alkanes from Grignard
reagents (Cycle C). When β-hydrogen elimination from 11 is relatively slow, homocoupling
of the alkyl halides takes place via the disproportionation of 11 to give (RCH CH ) Cu and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
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35
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56
57
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59
60
2
2 2
24
CuX or via the homolysis of its alkyl–copper bond, as shown in eq 3. Aggregation of
2
17a,19
Cu(0) leads to the fatal deactivation of catalyst.
An alkyne or a diene coordinates to a
Cu atom to suppress β-hydrogen elimination in Cycle B by blocking this elimination
process and possibly by accelerating the competing ate complex formation leading to 7.
Scheme 5. Proposed catalytic cycles of cross-coupling (solid line) and side reactions
(dashed line).
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