Copper- and cobalt-catalyzed direct coupling of sp3 α-carbon of alcohols with alkenes and hydroperoxides

Article abstract of DOI:10.1021/ja510635k

A zerovalent copper- and cobalt-catalyzed direct coupling of the sp³ α-carbon of alcohols with alkenes and hydroperoxides was developed in which the hydroperoxides acted as radical initiator and then coupling partner. 1,3-Enynes and vinylarenes

Full text of DOI:10.1021/ja510635k

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Communication
Copper and Cobalt-Catalyzed Direct Coupling of sp3 #-
Carbon of Alcohols with Alkenes and Hydroperoxides
Teck-Peng Loh
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Dec 2014
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Copper and CobaltꢀCatalyzed Direct Coupling of sp3 αꢀ
Carbon of Alcohols with Alkenes and Hydroperoxides
Journal: Journal of the American Chemical Society
Manuscript ID: ja-2014-10635k.R2
Manuscript Type: Communication
Date Submitted by the Author: 22-Dec-2014
Complete List of Authors: Cheng, Jun-Kee; Nanyang Technological University, Division of Chemistry &
Biological Chemistry, School of Physical & Mathematical Sciences
Loh, Teck-Peng; Nanyang Technological University, Division of Chemistry &
Biological Chemistry, School of Physical & Mathematical Sciences
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Copper and Cobalt-Catalyzed Direct Coupling of sp3 α-Carbon of Al-
cohols with Alkenes and Hydroperoxides
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Jun-Kee Cheng† and Teck-Peng Loh*,†,‡
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Techno-
logical University. Singapore 637616
Supporting Information Placeholder
β-peroxy alcohols. Notably, Li and co-workers have devel-
ABSTRACT: A zerovalent copper and cobalt-catalyzed
direct coupling of sp3 α-carbon of alcohols with alkenes and
oped the relevant chemistry to synthesize peroxy com-
pounds from aldehydes and 1,3-dicarbonyl compounds.10
hydroperoxides was developed in which the hydroperoxides
acted as radical initiator cum coupling partner. 1,3-Enynes
and vinylarenes underwent alkylation-peroxidation to give
an efficient method for three-component coupling of α-
β-peroxy alcohols and β-hydroxyketones correspondingly
with excellent functional group tolerance. The resulting β-
peroxy alcohols could be further transformed into β-
hydroxyynones and propargylic 1,3-diols.
Klussmann et al. later demonstrated the preparation of γ-
peroxyketones from unactivated ketones.11 Herein, we report
carbon alcohols with alkenes and hydroperoxides catalyzed
by zerovalent copper or cobalt. Hydroperoxides played a
dual role to initiate the radical reaction and also as a cou-
pling partner.
Scheme 1. Conventional and Current Approaches to
Synthesize Alcohols
The direct sp3 α-C-H bond activation and functionalization
of alcohols and ethers will provide one of the most efficient
entries to more functionalized alcohols and ethers.1-6 Par-
ticularly, the ability to construct new C-C bond with the α-
carbon of alcohols with concomitant retention of active hy-
droxyl group in the final products render this synthetic ap-
proach more attractive than the classical methods which
utilized the corresponding carbonyl compounds (Schemes 1a
and 1b).7-9 Furthermore, alcohols are expedient coupling
partner as they are readily available, more stable, less toxic
and easier to be handled than the corresponding aldehydes.
Accordingly, there has been much interest in the generation
of α-hydroxy carbon radical and the subsequent addition to
radical acceptors.5-6 Elegant work by Tu and co-workers have
shown the possibility of coupling the α-carbon of alcohol
with a series of alkene catalyzed by Rh, Ru, Pd or Fe catalyst,
generating the hydroalkylation products.4 On the other
hand, Liu and co-workers have demonstrated the coupling of
alcohols with alkynes, cinnamic acids and isocyanides under
metal free condition or employing Cu catalysts.5 However,
the direct coupling of α-carbon of alcohols with simple al-
kenes and peroxides to yield 1,3-dioxygenated compounds
have shown to be difficult.
Initial studies were focused on investigating the cou-
pling reaction of silylated 1,3-enyne 1a, 3.0 equiv of tert-butyl
hydroperoxide (in decane solution) 2 and 2-butanol 3a using
10 mol % of zerovalent copper in neat condition which gave
23% of desired oxyalkylated enyne. Switching the solvent to
DMSO enhanced the reaction efficiency to furnish 48% of
the oxylalkylated enyne in 6 h (Supporting Information).
Other copper catalysts exhibited inferior catalytic activity
and the reaction in the absence of any metal catalyst was
sluggish to give 28% of β -peroxy alcohol. After investigating
the effect of amount of alcohol substrate and TBHP to our
Inspired by these elegant works and our interest in devel-
oping an atom-economical method for the synthesis of 1,3-
dioxygenated propargylic compounds, we are especially in-
terested in the reaction of alcohols with simple alkenes and
peroxides. To the best of our knowledge, there is no report
on the oxyalkylation of simple alkenes such as 1,3-enynes
with alcohols to assemble the synthetically versatile alkynyl
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model reaction, we found that 12 equivalents of alcohol and
these substrates being amenable for further functionaliza-
1
2
3
4
5
6
4 equivalents of TBHP gave the optimal product yields (Sup-
porting Information).
tion.
Table 2. Reaction Scope of 1,3-Enynes with 3aa,b,c,e
Table 1. Optimization of Reaction Conditiona,b
tBuOO
OH
OH
metal (10 mol %)
+
tBuOOH
+
DMSO
65 oC, 0.5-6 h
R
1
2
3a
R
4
7
8
tBuOO
OH
tBuOO
OH
9
Si
entry
1d
ROH
(equiv)
TBHP
(equiv)
catalyst
(10 mol%)
Time
(h)
Yield(%)c
R1
10
11
12
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1
4a[d] Si
4e
4f
, R =4-H, 58% (52%)
=4-Cl, 51% (47%)
:
= Ph3Si,
68% (73%)
36% (66%)
-
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
Cu
24
6
23
,
4b,
= i-Pr3Si,
4g
4h
4i,
,
,
=4-Br, 58% (44%)
=4-F, 51% (52%)
=2-F, 43% (61%)
4c
,
= Me2 BuSi, 50% (56%)
t
2
14
14
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14
14
14
12
12
12
12
12
12
12
12
12
12
Cu
48
36
37
39
18
4d
= Et3Si,
33% (51%)
3
CuCl
Cu2O
CuI
4
tBuOO
OH
4
6
5
4
R
n
6
CuO
-
24
10
5
4j, n=0, R=cyclopentyl, 35% (39%)
4k, n=0, =cyclohexyl, 38% (41%)
4l, n=1, =cyclohexyl, 42% (33%)
7
28
59
68
30
<10
38
trace
-
8
Cu
9 e
10 e
11 e
12 e
13 e
15 e
16 e
17 e
18e
Cu
2
4m, n=2, =phenyl,
63% (42%)
FeBr2
FeCl2
FeBr3
Fe
3
aUnless otherwise noted, typical reaction conditions 1: 1 (0.3 mmol),
2 (1.2 mmol, 5.5 M in decane), 3a (3.6 mmol), Cu (0.03 mmol),
DMSO (1.8 mL), 65 C, under nitrogen atmosphere. Isolated yields
of inseparable diastereomers. cd.r. was approximated as 1:1. dPer-
formed with 1a (0.15 mmol), 2 (0.6 mmol, 5.5 M in decane), 3a (1.8
mmol), Cu (0.015 mmol), DMSO (0.9 mL), 65 C, under nitrogen
atmosphere. Yields in parentheses refer to isolated yields of reac-
tions performed with Co(OAc)2 instead of Cu under typical reaction
conditions.
8
°
b
3
24
8
CoCl2
Co(acac)3
CoBr2
Co(OAc)2
°
e
8
-
8
-
0.5
73
aUnless otherwise noted, typical reaction conditions: 1a (0.15
mmol), 2 (5.5 M in decane), DMSO (0.9 mL), 65 C, air. d.r. was
approximated as 1:1. cIsolated yields of inseparable diastereomers.
d3a(0.9 mL) eUnder nitrogen atmosphere.
Cyclic (4j-k) and linear (4l-m) aliphatic enynes were also
effective substrates for this transformation to furnish the
peroxidation-alkylation products in moderate to good yields.
In particular, aryl- substituted aliphatic enyne (4m) showed
good applicability for this reaction with Cu to give the β-
peroxy alcohols in 63%. With these substrates, both Cu and
Co(OAc)2 showed comparable catalytic competence except
for 4g, 4i, 4l and 4m.
°
b
It was observed that using 4 or 5 equiv of TBHP gave similar
yields for some alcohols but this was not general across all
alcohols. Hence, an excess of 5 equiv of TBHP was used to
study the alcohol substrate scope. Reaction performed with
strict exclusion of oxygen was proved to be beneficial, giving
68% of the desired product after 2 h. With this optimized
condition, we proceeded to investigate other metal catalysts
and delighted to observe augmented reaction efficiency with
cobalt (II) acetate whilst other cobalt salts shown to be non-
active (Table 1, entry 15-18).
Table 3. Reaction Scope of Alcohols with 1aa,b,c
Using copper and cobalt catalysts under the optimal reac-
tion conditions, we then probed the reaction generality of
enyne substrates using 2-butanol as the standard coupling
partner. Pleasingly, 1,3-enynes bearing different silyl protect-
ing groups such as TES, TIPS, TBDMS and TPS group, were
well accommodated to yield the corresponding products in
33-68% isolated yields with Cu (4a-d) whereas reactions with
Co(OAc)2 afforded the respective products in better yields
(51-73%). Phenyl-substituted enyne was compatible with our
reaction protocol to give β-peroxy alcohol 4e in 58% isolated
yield with Cu catalyst. Notably, when halogen substituents
were present on the phenyl ring, the reactions also proceed-
ed smoothly; giving rise to 4f-i in 51%, 58%, 51% and 43%
yield respectively. Presence of these halides would render
aReaction conditions: 1a (0.15 mmol), 2 (0.75 mmol, 5.5 M in dec-
ane), 3 (1.8 mmol), Cu (0.015 mmol), DMSO (0.9 mL), 65 C, under
°
b
nitrogen atmosphere. Isolated yields of inseparable diastereomers.
cYields in parentheses refer to isolated yields of reactions performed
d
with Co(OAc)2 instead of Cu under typical reaction conditions. d.r.
2
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cals.14 Subsequent hydrogen abstraction by the tert-butoxy
was approximated as 1:1. ed.r. was approximated as 1:1:1:1.
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8
radical generated the α-hydroxy carbon radical which added
to the double bond. This was followed by radical coupling
with tert-butylperoxy radical. This observed selectivity of
this radical coupling was steered by the persistent radical
effect.15 For the styrene substrates, the peroxy group is
cleaved to give the carbonyl group in-situ owing to the reac-
tivity of the benzylic proton. This speculation could be sup-
ported by the peroxy intermediate 10 isolated. When further
subjected under the standard reaction condition, 10 convert-
ed facilely to 7f (Scheme 4).
The generality of this reaction protocol with respect to 1a
was then examined against aliphatic primary and secondary
alcohols. Generally, both primary and secondary alcohols
were effective substrates for this transformation. Reactions
of primary alcohols gave moderate yields of the desired
products (5a-c) with both catalysts. i-Propanol furnished the
corresponding peroxy alcohol 5d in good yield and other
secondary alcohols tested were found to be well suited to
generate the products from moderate to good yields (5e-j).
Remarkably, Co(OAc)2 acted as better catalyst with most
substrates albeit the decrease in reaction efficiency when
alcohol with increasing chain length were tested (5d,e and
5i,j). Reactions of cyclic alcohols with Cu gave peroxy alco-
hols 5k-m in moderate yields. Complementarily, these prod-
ucts could be accessed using Co(OAc)2 with significantly
bettered chemical yields (60-70%).
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Scheme 3. Proposed Mechanism
We next turned our attention to the oxyalkylation of the
aryl alkenes, the commercially available substrates. Styrenes
with diversified functionalities were well tolerated, granting
entry for further functionalization. Styrene with halogen
substituents provided the products in moderate yields of 32-
50% (7b-d). Other functional motifs such as methyl ester,
cyano and acetoxy group on styrene remained intact and the
corresponding aldol products were isolated in 39%, 40% and
31% (7e-g). Notably, substrates with strongly electron-
withdrawing CF3 group (7h) as well as alkyl substituents
were suitable for this transformation to deliver the corre-
sponding product in moderate yields (7i).
Table 4. Reaction Scope of Styrene Derivatives with
3ba,b
It is worth-noting that isolability of the peroxy intermediate
differed for different styrene derivatives and this intermedi-
ate could not be observed for some substrates.
Scheme 4. Mechanistic Study
In conclusion, we have developed a novel copper and co-
balt-catalyzed three-component oxidative coupling of olefins
with hydroperoxides and alcohols which involved the α-C-H
activation of alcohols. Various aliphatic, silylated and aryl
1,3-enynes underwent alkylation-peroxidation to assemble β-
peroxy alcohols, which further allowed access to propargylic
1,3-diols and β-hydroxy ynones. Further studies directed
toward the synthetic utilization of enynes are currently un-
derway in our laboratory.
aReaction conditions: 6 (0.50 mmol), 2 (1.5 mmol, 5.5 M in decane),
3b (4.0 mmol), DMSO (3.0 mL), 80 °C, air. bIsolated yields.
Subsequently, transformation on the β-peroxy alcohol
was studied with 4a as model substrate. The respective aldol
product 8 could be furnished in the presence of catalytic
amount of base (Kornblum-DelaMare Rearrangement).12
Additionally, 1,3-diol (9) was obtained when 4a was subject-
ed under a reduction condition.13
ASSOCIATED CONTENT
Supporting Information
Scheme 2. Transformation of 4a
Detailed experiment procedures and compound characteri-
zation data. “This material is available free of charge via the
Internet at http://pubs.acs.org.”
On the basis of our experimental observation and prece-
dent reports, we have devised the mechanistic pathway as
depicted in Scheme 3. Copper/cobalt is thought to facilitate
the generation of tert-butyloxy and tert-butylperoxy radi-
AUTHOR INFORMATION
Corresponding Author
teckpeng@ntu.edu.sg
3
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge the Nanyang Technological Uni-
versity, Singapore Ministry of Education Academic Research
Fund (MOE2014-T1-001-102, MOE2012-T1-001-107) for the
funding of this research. We would like to express our sin-
cere gratitude towards the reviewers for the valuable com-
ments and recommendations.
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