Free-radical-initiated coupling reaction of alcohols and alkynes: Not co but C-C bond formation

Article abstract of DOI:10.1021/ol900145u

This work demonstrates an efficient method to prepare allylic alcohols via direct C-C bond formation using electron-rich alkynes and aliphatic alcohols initiated by tert-butyl hydroperoxide.

Full text of DOI:10.1021/ol900145u

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1437-1439
Free-Radical-Initiated Coupling Reaction
of Alcohols and Alkynes: Not C-O but
C-C Bond Formation
Zhong-Quan Liu,*,† Liang Sun,‡ Jian-Guo Wang,‡ Jie Han,‡ Yan-Kai Zhao,† and
Bo Zhou†
Institute of Organic Chemistry, Gannan Normal UniVersity, Ganzhou,
Jiangxi 341000, P. R. China, and State Key Laboratory of Applied Organic Chemistry
and Department of Chemistry, Lanzhou UniVersity, Lanzhou 730000, P. R. China
liuzhongquan@yahoo.cn
Received January 24, 2009
ABSTRACT
This work demonstrates an efficient method to prepare allylic alcohols via direct C-C bond formation using electron-rich alkynes and aliphatic
alcohols initiated by tert-butyl hydroperoxide.
Addition of alcohols to alkynes promoted by mercury(II),
generating one and/or two new carbon-oxygen bonds, has
been known for 86 years.1 Over the past decades, many
efficient systems have been developed for this transforma-
tion.2 Although it offers a powerful method to prepare enol
ethers and acetals, alcoholysis of the triple bond seems to
be the dominant interaction of alcohols and alkynes. Very
few efficient protocols for direct radical-mediated carbon-
carbon bond formation between alcohols and alkynes have
been developed.3 Uckun et al. found the unexpected product
of an allylic alcohol in the thermolysis of 1,2-diethylnyl-
benzene in isopropyl alcohol at 165 °C.3a Later Nakagawa
et al. also observed a C-C bond formation product in the
reaction of alkynes and alcohols at 350 °C.3b Recently, Ishii
et al. reported a coupling reaction of electron-deficient
alkynes and alcohols by using the NHPI/CoII/O2 system.3c
A month ago, Geraghty et al. reported a photoinduced C-C
bond coupling reaction of alcohols and alkynes.3d However,
these systems suffer from relatively high temperature,3a,b
substrate limitation (alkynes with electron-withdrawing
groups are necessary), and relatively low yields of the allylic
alcohols.3c,d Recently, Krische et al.3e reported a very
efficient ruthenium-catalyzed alcohol-alkyne C-C bond
coupling. We wish to report herein an efficient reaction of
alkynes and alcohols for direct sp2-sp3 C-C bond formation
via peroxide-initiated C-H bond activation.
Radical initiators such as tert-butyl hydroperoxide (TBHP)
and di-tert-butyl peroxide have been successfully used for
† Lanzhou University.
‡ Gannan Normal University.
(1) Reichert, J. S.; Bailey, J. H.; Niewland, J. A. J. Am. Chem. Soc.
1923, 45, 1552.
(2) For selected reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem.
ReV. 2004, 104, 3079. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew.
Chem., Int. Ed. 2004, 43, 3368.
(4) (a) Urry, W. H.; Stacey, F. W.; Huyser, E. S.; Juveland, O. O. J. Am.
Chem. Soc. 1954, 76, 450. (b) LaZerte, J. D.; Koshar, R. J. J. Am. Chem.
Soc. 1955, 77, 910. (c) Walling, C.; Huyser, E. S. Org. React. 1963, 13,
91. (d) Stacey, F. W.; Harris, J. F. Org. React. 1963, 13, 150. (e) Curran,
D. P. Synthesis 1988, 489. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004,
126, 11810. (g) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (h) Li,
Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (i) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2006, 128, 56. (j) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl.
Acad. Sci. 2006, 103, 8928. (k) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem.,
Int. Ed. 2007, 46, 6505. (l) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008,
47, 7075. (m) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497.
(3) (a) Thoen, K. K.; Thoen, J. C.; Uckun, F. M. Tetrahedron Lett. 2000,
41, 4019. (b) Nakagawa, T.; Ozaki, H.; Kamitanaka, T.; Takagi, H.;
Matsuda, T.; Kitamura, T.; Harada, T. J. Supercrit. Fluids 2003, 27, 255.
(c) Oka, R.; Nakayama, M.; Sakaguchi, S.; Ishii, Y. Chem. Lett. 2006, 35,
1104. (d) Geraghty, N. W. A.; Hernon, E. M. Tetrahedron Lett. 2009, 50,
570. (e) Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J.
J. Am. Chem. Soc. 2009, 131, 2066–2067.
10.1021/ol900145u CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society

activation and/or functionalization of the sp3 C-H bond and
generation of R-hydroxyalkyl radicals from alcohols.4 How-
ever, most of these procedures need a transition metal as
the active catalyst. We successfully accomplished a metal-
free, TBHP-initiated sp2-sp3 C-C bond formation via
coupling of aliphatic alcohols with electron-rich alkynes
(Scheme 1). To the best of our knowledge, this is the first
benzoyl peroxide (BPO) was used (entry 10). No products
were detected by using K2S2O8 as the radical initiator (entry
11). The coupling reaction did not proceed at a low
temperature such as 90 °C (entry 12).
As depicted in Table 2, various alkynes and alcohols were
tested as substrates for the coupling reaction under typical
Table 2. Direct C-C Bond Formation by Using Alcohols with
Alkynesa
Scheme 1
.
C-C Bond Formation via Coupling of Alcohols with
Alkynes
yield
entry
alkynes (R1, R2)
alcohols product (%)b
example of a C-C bond formation via coupling of electron-
rich alkynes with alcohols mediated by a radical initiator.
Initially, we chose ethanol and phenyl ethyne as standard
substrates to optimize suitable conditions for this reaction
(Table 1). The initial concentrations of phenyl ethyne
1
2
3
4
5
6
7
8
9
R1 ) Ph, R2 ) H; 1a
Ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
3a
3b
3c
3d
3e
3f
95
90
85
87
66
65
0
R1 ) 4-MeC6H4, R2 ) H; 1b
R1 ) 4-FC6H4, R2 ) H; 1c
R1 ) 4-OMeC6H4, R2 ) H; 1d
R1 ) Ph, R2 ) Me; 1e
R1 ) Ph, R2 ) Ph; 1f
R1 ) 2-Py, R2 ) H; 1g
R1 ) C(Ph)(Me)(OH), R2 ) H; 1h ethanol
3g
70c
0
1a
methanol
n-propanol
n-butanol
i-butanol
i-propanol
10 1a
11 1a
12 1a
13 1a
3h
3i
3j
3k
70
60
40
48
Table 1. Optimization of Typical Reaction Conditionsa
a Reaction conditions: alkynes (0.5 mmol), TBHP (5-6 M in decane,
1.0 mmol), alcohol (10 mL) as solvent, 120 °C, 15 h. b Isolated overall
yield of the E/Z isomer; the ratio of the E/Z isomers was approximate 1:1
as analyzed by isolation of the pure isomer. c Only the E isomer was
obtained.
entry
initiators
concn (M)b t (°C) yield (%)c
1
2
3
4
5
6
2.0 equiv TBHP
2.0 equiv TBHP
2.0 equiv TBHP
0.2 equiv TBHP
0.5 equiv TBHP
1.0 equiv TBHP
2.0 equiv TBHP
0.2 equiv TBHP
2.0 equiv tBuOOtBu
2.0 equiv BPO
0.1
120
120
120
120
120
120
120
120
120
120
120
90
73
95
76
75
60
68
63
41
14
38
0
0.05
0.01
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
conditions. Reaction of terminal phenyl alkynes 1a-1d and
ethanol 2a produced the desired product 3a-3d in good to
excellent yields (Table 2, entries 1-4). The electronic effect
was not obvious as phenyl alkynes bearing an electron-
withdrawing p-fluoro group 1c or an electron-donating
p-methoxy group 1d gave similar yields of the product.
Alkynes with internal triple bond such as 1-phenyl-1-propyne
1e and diphenyl ethyne 1f gave good isolated yields of the
corresponding product 3e and 3f (entries 5 and 6). In the
case of 1e, the major product was not 3-phenyl-3-penten-
2-ol but 4-phenyl-3-methyl-3-buten-2-ol 3e, which may be
due to the stability of the alkenyl radical intermediate.
2-Ethynyl pyridine 1g was inactive in this system (entry 7).
It is noteworthy that propargyl alcohol 1h also produced the
product 3g in 70% yield (entry 8). In addition, only the trans-
allylic diol 3g was obtained. We next studied the coupling
reaction of phenyl ethyne with various aliphatic alcohols
(entries 9-13). Methanol did not give the desired product
due to its relatively low reactivity (entry 9). n-Propanol and
n-butanol gave the corresponding allylic alcohols 3h and 3i
in good yields (entries 10 and 11), while isobutyl alcohol
gave relatively lower yields of the products 3j (entry 12).
The corresponding allylic alcohol can be also obtained in
moderate yield by using secondary alcohols such as isopropyl
alcohol (entry 13). However, when benzyl alcohols were used
as the substrates coupling with phenyl ethyne, the corre-
7d
8d
9
10
11
12
2.0 equiv K2S2O8
2.0 equiv TBHP
0
a Reaction conditions: phenylacetylene (0.5 mmol), TBHP (5-6 M in
decane), unless otherwise noted, ethanol as solvent, 15 h. b Concentration
of phenyl ethyne. c Isolated yield of the E/Z isomer; the ratio of the E/Z
isomers was approximate 1:1 as analyzed by crude 1H NMR. d TBHP (70%
aqueous solution).
demonstrated that 0.05 M (entry 2) was the ideal concentra-
tion for this reaction (entries 1-3). Reduction of the amount
of TBHP gave relatively lower isolated yields (entries 4-6).
The yields of the desired product decreased to 63% and 41%
by using 2.0 and 0.2 equiv of TBHP (70% aqueous solution),
respectively (entries 7 and 8). This indicated that the allylic
alcohol could be obtained in moderate yield even in the
presence of water, while the hydrolysis product was not
observed. The use of di-tert-butyl peroxide instead of TBHP
as an initiator gave only 14% yield of the product (entry 9).
A 38% yield of the desired product was isolated when
1438
Org. Lett., Vol. 11, No. 6, 2009

sponding allylic alcohols were obtained in very low yields,
and the appropriate solvent has not been found at present.
Although the system is limited in alcohol scope and the E/Z
ratio of the products is almost 1:1, the direct C-C bond
construction and the sp3 C-H bond activation features make
this procedure very attractive.
Scheme 3
.
Possible Mechanism for C-C Bond Formation via
Coupling of Alcohols with Alkynes
It is believed that the alkoxyl radical would be generated
in the procedure. Similar C-C coupling products were also
obtained in the reactions of phenylacetylene 1a with tet-
rahydrofuran (THF) and 1,4-dioxane (Scheme 2).
Scheme 2
.
Couplings of Phenylacetylene with THF and
1,4-Dioxane
using electron-rich alkynes and aliphatic alcohols initiated
by tert-butyl hydroperoxide. Compared with the traditional
C-O bond formation reaction between alkynes and alcohols,
the direct C-C bond construction via activation of the sp3
C-H bond in this work might be novel and attractive in
radical chemistry. Further investigation of this procedure
including extension of the substrate scope is underway in
our laboratory.
A plausible mechanism for this coupling reaction is
depicted in Scheme 3 and may involve a radical chain
process. Homolytic cleavage of the radical initiator TBHP
produces the alkoxyl radical and hydroxyl radical (eq 1).
They abstract hydrogen from the alcohol, forming the
R-hydroxyalkyl radical (eqs 2 and 3). Subsequently, an
alkenyl radical is generated by addition of the R-hydroxyalkyl
radical to the alkyne (eq 4). The hydroxyalkyl radical is
regenerated via abstraction of hydrogen from alcohol by the
alkenyl radical, and the radical chain grows (eq 5). The chain
will be terminated once the alkyne is completely consumed.
In summary, this work demonstrates an efficient method
to prepare allylic alcohols via direct C-C bond formation
Acknowledgment. We thank Gannan Normal University
for financial support. Z.-Q.L. thanks Prof. Wei Wang (State
Key Laboratory of Applied Organic Chemistry and Depart-
ment of Chemistry, Lanzhou University) for GC-MS detec-
tion and helpful discussions.
Supporting Information Available: Full experimental
details and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900145U
Org. Lett., Vol. 11, No. 6, 2009
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