Cobalt-catalyzed intermolecular stereoselective bisbenzylation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2015.02.101

CoBr₂/P(OMe)Ph₂ is found to be an effective catalyst-system for intermolecular bisbenzylation of alkynes with various benzyl bromides in the presence of manganese reductant. The transformation can be carried out under mild conditions, giving rise to stereocontrolled cis-1,2-bisbenzylated alkenes in good yields.

Full text of DOI:10.1016/j.tetlet.2015.02.101

Tetrahedron Letters 56 (2015) 1735–1737
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cobalt-catalyzed intermolecular stereoselective bisbenzylation
of alkynes
⇑
Kimihiro Komeyama , Ryota Asakura, Hiroshi Fukuoka, Ken Takaki
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, 1-4-1 Higashi-Hiroshima City, Hiroshima 739-8527, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
CoBr2/P(OMe)Ph2 is found to be an effective catalyst-system for intermolecular bisbenzylation of alkynes
with various benzyl bromides in the presence of manganese reductant. The transformation can be carried
out under mild conditions, giving rise to stereocontrolled cis-1,2-bisbenzylated alkenes in good yields.
Ó 2015 Published by Elsevier Ltd.
Received 20 January 2015
Revised 14 February 2015
Accepted 19 February 2015
Available online 26 February 2015
Keywords:
Cobalt catalyst
Bisbenzylation
Carbocobaltation
Alkynes
Benzyl bromides
Stereodefined multisubstituted alkenes are found in many
biologically active molecules, drugs, and functional materials,1 and
there are a large number of their chemical transformations to access
asymmetric alkane molecules.2 In particular, stereocontrolled 1,2-
bisbenzyl alkenes are key precursor for synthesis of 1,2-bisbenzyl
alkanes like lignans present naturally.3 For their construction, one
of the most flexible and realistic approaches would be a protocol
through benzylmetalation of alkynes to afford alkenylmetal inter-
mediates, which is followed by trapping with benzyl electrophiles
to give 1,2-bisbenzylalkene moieties (Scheme 1a). Although numer-
ous catalytic or stoichiometric benzylmetalations using benzyl–Cu,4
–Mg,5 and –Zn6 have been developed, the sequent trapping with
benzyl electrophile is limited to the case of highly nucleophilic
alkenylmetals or by harsh reaction conditions.7 Moreover, the pro-
tocol requires prior preparation of benzylmetal species, which are
frequently restricted to the substrate scope without sensitive func-
tional groups.
Cobalt complex is an active catalyst for the coupling reaction of
organo(pseudo)halides with a generation of the organocobalt
species,8 which also enable carbocobaltation of alkynes.8f,9 Despite
the two catalytic behaviors of the cobalt species having been inde-
pendently well studied, the combined reaction-system has been
scarcely developed to a functionalization of alkynes. This straight-
forward approach to 1,2-bisfunctionalized alkenes is an ideal
process without using benzylmetals as starting materials.
Recently, we disclosed the cobalt-catalyzed annulation of arylio-
dides with alkynes to provide naphthalene compounds
(Scheme 1b).10 The transformation involves a generation of the
alkenylcobalt A, which preferentially reacted with another alkyne
rather than with the aryl iodides even in the presence of excess aryl
iodides owing to the bulkiness and/or the intrinsic reactivity with
aryl iodides of the cobalt center of A. Based on these results, we
envisaged that sterically less-hindered and highly reactive alkenyl-
metal like benzylated alkenylcobalt species B (Scheme 1c) might
achieve a double benzylation of alkynes. In fact, we have succeeded
the trapping of similar alkenylcobalt with intramolecularly existing
benzylic carbon–halogen bonds to provide 1,4-dihydronaph-
thalenes.11 However, expansion into an intermolecular bisbenzyla-
tion as shown in Table 1 was difficult because the intermolecular
reaction was complicated by the homocoupling of benzyl halides.
Furthermore, the trapping of alkenylcobalt B with benzyl halides
was slow; it caused an oligomerization of alkynes. Herein we would
like to present an intermolecular bisbenzylation of alkynes with
benzyl bromides using a new combination of cobalt catalyst and
phosphine ligand system. This is very simple and efficient method
for stereoselective synthesis of 1,2-bisbenzylalkenes.
The present study began with a screening of ligands for the
reaction of benzyl bromide (1a) with 1,4-dimethoxybut-2-yne (2a)
as model substrates in the presence of CoBr2 catalyst and Mn at
25 °C in MeCN (Table 1). Addition of PPh3 (10 mol %) afforded the
bisbenzylated product 3aa as one stereoisomer in 25% yield,12 along
with homocoupling product 4a in 44% yield (entry 1). Increasing
ligand loading to 30 mol % disturbed the homocoupling, leading to
⇑
Corresponding author. Tel.: +81 82 424 7747; fax: +81 82 424 5494.
E-mail address: kkome@hiroshima-u.ac.jp (K. Komeyama).
http://dx.doi.org/10.1016/j.tetlet.2015.02.101
0040-4039/Ó 2015 Published by Elsevier Ltd.

1736
K. Komeyama et al. / Tetrahedron Letters 56 (2015) 1735–1737
Scheme 1. Routes for synthesis of 1,2-bisbenzylated alkenes.
Scheme 2. Scope and limitations of benzyl bromides. Isolated yield. b 1,4-Di(tert-
butyldimethylsilyloxy)but-2-yne (2c) was used instead of 2a.
Table 1
Screening of reaction conditions for cobalt-catalyzed bisbenzylation of 1,4-
dimethoxybut-2-yne (2a) with benzyl bromide (1a)
formamide, N,N-dimethylacetoamide, 1,3-dimethyl-2-imidazolidi-
none, and N-methylpyrrolidinone were employed.
Having established the CoBr2/P(OMe)Ph2 catalytic system, we
next investigated the scope and limitations of the bisbenzylation
of 1,4-dimethoxybut-2-yne 2a using various benzyl bromides
(Scheme 2).13 Substituted benzyl bromides having methyl and
methoxy groups 1b–f were well tolerated as well as 2,4-dimethyl
benzyl bromide 1g, giving rise to the corresponding bisbenzylated
products 3ba–3ga in 39–68% yields. The present reaction was also
achieved with 2-naphthyl bromide 1h, leading to 3ha in 29% yield.
Moreover, slightly electron-deficient substrates bearing fluoro and
chloro substituents also took part in the reaction (3ja–3la). In con-
trast, no desired reactions occurred in the reaction of significantly
electron-poor 4-cyano and 4-nitro benzyl bromides. Instead, the
homocoupling and reduction of these bromides mainly proceeded.
These results obviously suggest that the electronic nature of benzyl
bromides plays an important role in the bisbenzylation. In other
words, a choice of appropriate substituents leads to a high reactivity
of the benzyl bromides in the reaction. Actually, electronically well-
controlled benzyl bromide like 1m was selectively converted to the
desired product 3mc (95% yield), which would be a useful interme-
diate for the synthesis of naturally occurring secoisolariciresinol
derivatives.14 Additionally, the bisbenzylated product containing
C–B bond 3na could be synthesized, albeit with low yield.
Entry
Ligand
x mol %
Product and yielda
(%)
3aab
4ac
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
10
20
30
—
25
36
55
Trace
17
44
35
22
86
60
80
80
69
60
64
59
60
31
20
17
36
22
none
PnBu3
30
30
30
30
30
30
30
30
30
30
30
30
30
PCy3
0
0
3
PtBu3
PMePh2
PiPrPh2
P(OPh)3
P(OiPr)3
P(OEt)Ph2
P(OPh)Ph2
P(OiPr)Ph2
P(OMe)Ph2
PPh3
9
Trace
4
18
15
30
52
57
64
79 (77)
10
11
12
13
14
15
16d
17d
Next, we tested compatibility of alkynes in the bisbenzylation
(Scheme 3). Other protected propargyl alcohols with benzyl (Bn)
and tert-butyldimethylsilyl (TBS) group were well tolerated to give
their corresponding bisbenzylated products 3ab and 3ac in satisfac-
tory yields. An activated alkyne like 2d also took part in the reac-
tion, but a mixture of E- and Z-isomers 3ad was formed due to an
enolization of alkenylcobalt species bearing ester function at the
P(OMe)Ph2
a
b
c
Determined by GC. Parenthesis value indicates an isolated yield.
Based on 2a.
Based on 1a.
1a (3.0 equiv), Mn (4.0 equiv).
d
a-carbon. The oxygen-function attached at the propargyl position
markedly enhanced the reaction. Thus, 4-octyne 2e and homo-
propargyl ether 2f were converted to the product in moderate
yields (3ae: 28%, 3af: 42%).15 An internal alkyne 2g containing a
nitrogen atom at propargyl position afforded 3ag in 12% yield. Fur-
thermore, 1-phenyl-1-propyne and 1,2-diphenylacetylene did not
participate in the reaction. In sharp contrast, the same enhance-
ment by the propargyl oxygen was observed in the transformation
of 2h or 2i. The effect of the propargyl oxygen group remains
unclear at the moment;16 however, there are two likely effects: to
electronically stabilize the transition state in the carbocobaltation17
and to act as a directing group.18 To get further mechanistic
an improved yield (entries 2 and 3). The reaction became sluggish
without PPh3 (entry 4), and no reaction took place in the absence
of both CoBr2 and Mn. Upon subsequent screening of phosphine
and phosphite ligands (entries 5–15), we identified that P(OMe)Ph2
was effective (entry 15) as well as PPh3 (entry 3). Furthermore,
excess benzyl bromide 1a (3.0 equiv) and Mn (4.0 equiv) gave better
results (entries 16 and 17). The present bisbenzylation was sensitive
to solvent used, thus acetonitrile is crucial. Low conversion of the
starting materials was observed when other solvents such as
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethyl-

K. Komeyama et al. / Tetrahedron Letters 56 (2015) 1735–1737
1737
system. This method provides a direct approach to 1,2-bisbenzylat-
ed alkenes from readily available benzyl bromides and alkynes in a
stereoselective manner. The efficiency of the bisbenzylation is
strongly affected by the presence of propargyl oxygen function.
The substituent effect has been unclear, but the control experiment
suggests that the oxygen acts as the directing group to enhance the
benzylcobaltation of alkynes.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supplementary data
Supplementary data (experimental procedure, NMR and mass
spectroscopy of all products, and CIF file of 3ga) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2015.02.101.
Scheme 3. Scope and limitations of alkynes. Isolated yield. b Stereoisomer was
formed in 7% yield.
References and notes
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information of the bisbenzylation, we carried out a reaction with
1,4-di(triisopropylsiloxy)but-2-yne 2j in Scheme 3. Thus, the bulky
triisopropylsilyl (TIPS) group would inhibit a coordination of the
metals to propargylic oxygen, but the electronic character of the
TIPS-protected oxygen is similar to that of the TBS-protected one.
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strongly suggest that the propargyl oxygen works as the directing
group in the bisbenzylation.
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powder, oxidatively adds to benzyl bromides to give a benzyl
cobalt intermediate B.19 Mn powder quickly reduces B to trans-
form into a low valent benzyl cobalt C, which is followed by inser-
tion of C into alkynes in syn-fashion to afford alkenylcobalt D. This
species intermolecularly adds to another benzyl bromide to give E,
followed by reductive elimination of E to provide the bisbenzylat-
ed product 3 and the cobalt catalyst A is regenerated.
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In summary, we have developed a mild and efficient catalytic
intermolecular bisbenzylation of alkynes by the CoBr2/P(OMe)Ph2