Sp-sp3 C-C bond formation via Fe(OTf)3/TfOH cocatalyzed coupling reaction of terminal alkynes with benzylic alcohols

Article abstract of DOI:10.1039/b911905a

An Fe(OTf)₃/TfOH cocatalyzed sp-sp³ C-C bond formation through the coupling of benzylic alcohols with terminal alkynes in the absence of base has been developed. H₂O is the sole by-product.

Full text of DOI:10.1039/b911905a

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Sp–sp3 C–C bond formation via Fe(OTf)3/TfOH cocatalyzed coupling
reaction of terminal alkynes with benzylic alcoholsw
Shi-Kai Xiang,a Li-He Zhanga and Ning Jiao*ab
Received (in Cambridge, UK) 18th June 2009, Accepted 19th August 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b911905a
An Fe(OTf)3/TfOH cocatalyzed sp–sp3 C–C bond formation
through the coupling of benzylic alcohols with terminal alkynes
in the absence of base has been developed. H2O is the sole
by-product.
product. Hence, the carbon–carbon bond formation using an
alcohol as a substrate has attracted great interest from organic
chemists.7 Recently, Kabalka and co-workers realized the
substitution of hydroxyl groups with alkynylboron dihalides.8
However, the use of alkynylboron dihalides as nucleophiles
and the requirement of
2 equiv. of n-BuLi limits its
The development of new methods for introducing an alkyne
unit into organic molecules is one of the most exciting topics in
practical organic synthesis, because alkynes are widely
distributed in a vast array of natural products, bioactive
compounds and drugs,1 as well as being ubiquitous units in
material science.2 During the past several decades, the
palladium- and/or copper-catalyzed Sonogashira cross-
coupling reactions3 of terminal alkynes with aryl or alkenyl
halides have been among the most powerful methods available
for the formation of sp–sp2 C–C bonds (eqn (1)). However,
sp–sp3 C–C bond formation via the coupling of terminal
alkynes with alkyl electrophiles has been less widely explored.4
Recently, Eckhardt and Fu achieved the Sonogashira
coupling of primary alkyl halides.5a Efficient protocols for
the alkynylation of benzyl5b or secondary alkyl halides5c were
also realized by Buchwald’s and Glorius’ groups, respectively.6
However, alkyl halides were required and halide byproducts
were produced by these methods. Alternatively, if an alcohol
could be employed as the alkyl electrophile, H2O would be the
sole by-product, making the transformation atom efficient and
environmentally benign (eqn (2)). Herein, we report an
Fe(OTf)3/TfOH cocatalyzed coupling reaction of terminal
alkynes with benzylic alcohols in the absence of base leading
to sp–sp3 C–C bond formation.
application.
Lately, iron catalysts9,10 have been extensively investigated
and it has been reported that alcohols are easily activated by
them.7a,g,h,n Moreover, the reaction of terminal alkynes can
also be facilitated by iron catalysts.11 We envisioned that the
coupling reaction between terminal alkynes and alcohols
catalyzed by an iron salt would be feasible.
Initially, we investigated the reaction of benzhydrol 1a and
phenylacetylene 2a in the presence of 5 mol% of Fe(OTf)3.
Gratifyingly, 61% of 3aa was obtained when dichloroethane
(DCE) was used as the solvent (entry 2, Table 1). Although
various Lewis acids such as In(OTf)3, AgOTf and Cu(OTf)2
can perform this transformation, their efficiencies were lower
than that of Fe(OTf)3 (see ESIw). Notably, TfOH12 can also
catalyze this reaction giving 3aa in 57% yield (entry 3,
Table 1). However, the relatively weak acid TsOH hardly led
to any of the desired product (entry 4, Table 1). In particular,
this reaction was strongly influenced by the solvents. Polar
solvents (DMF and MeNO2) were not suitable for this
transformation (entries 5–6). After a great deal of screening
on different parameters, the highest yield (77%) was reached
cocatalyzed by Fe(OTf)3 (5 mol%) and TfOH (10 mol%) in
DCE (entry 7, Table 1). The collaboration of Fe(OTf)3 and
TfOH presents positive effect on the transformation compared
to the corresponding individual employment of these catalysts
(cf. entry 7 with entries 10 and 12, Table 1). To the best of our
knowledge, this is the first Fe(OTf)3 and TfOH cooperative
catalysis.13 Markedly, even when 2 mol% of Fe(OTf)3 and
5 mol% of TfOH were employed, the coupling went well
giving 70% yield (entry 9, Table 1).
ð1Þ
ð2Þ
Compared to alkyl halides or esters, the corresponding
alcohols do not easily react with nucleophiles due to the poor
hydroxyl leaving group. Nonetheless, alcohols are plentiful
and inexpensive. In addition, the direct coupling reaction of
alcohols is environmentally benign, generating H2O as the side
The scope of this Fe(OTf)3/TfOH cocatalyzed coupling
reaction was expanded to a variety of substituted benzylic
alcohols (Table 2). Benzylic alcohols with electron-donating
groups smoothly underwent this kind of transformation,
generating 3 in moderate to excellent yields (54–86%).
Chloro-substituted benzylic alcohol 1f survived well, leading
to 3fa in 66% yield (entry 6). Notably, all para-, meta-,
and ortho-substituted benzylic alcohols could be smoothly
transformed into the desired products (entries 2–4, Table 2).
To investigate the scope of the terminal alkynes in this
transformation, benzhydrol 1a was chosen as the substrate
to react with different terminal alkynes. The results in
Table 3 show that both electron-rich and electron-deficient
a State Key Laboratory of Natural and Biomimetic Drugs,
Peking University, School of Pharmaceutical Sciences,
Peking University, Xue Yuan Rd. 38, Beijing 100191, China.
E-mail: jiaoning@bjmu.edu.cn; Fax: (+86) 010-8280-5297;
Tel: (+86) 010-8280-5297
b State Key Laboratory of Organometallic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/b911905a
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Table 1 The coupling reaction of benzhydrol 1a with phenylacetylene
2a under different conditionsa
Table 3 Fe(OTf)3 and TfOH cocatalyzed coupling reaction of
benzhydrol (1a) with different alkynes 2a
Yield of
3aa (%)b
Entry
R (2)
Yield of 3 (%)b
Entry
Catalyst (mol%)
Solvent
1
2
3
4
5
6
7
H
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
(2g)
77
56
81
75
79
80
63
(3aa)
(3ab)
(3ac)
(3ad)
(3ae)
(3af)
(3ag)
1
2
3
4
—
Fe(OTf)3 (5)
TfOH (5)
TsOH (5)
Fe(OTf)3 (5)
Fe(OTf)3 (5)
Fe(OTf)3 (5)/TfOH (10)
Fe(OTf)3 (5)/TsOH (10)
Fe(OTf)3 (2)/TfOH (5)
Fe(OTf)3 (15)
TfOH (10)
DCE
DCE
DCE
DCE
DMF
MeNO2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
61
57
Trace
Trace
Trace
77
59
70
63
64
63
18
p-Me
o-Me
m-Me
p-Br
p-F
5c
6c
7
p-Ph
8
9
10
11
12
13d
a
All the reactions were carried out in the scale of 0.5 mmol of 1a
with 0.75 mmol of 2, 0.025mmol Fe(OTf)3, 0.05 mmol TfOH
b
( 2 M in DMF), and 2 ml solvent under N2. Isolated yields.
TfOH (15)
Fe(OTf)3 (5)/TfOH (10)
a
All the reactions were carried out on the scale of 0.5 mmol of 1a with
0.75 mmol of 2a, catalyst, and 2 ml solvent under N2. The TfOH was a
b
2 M solution in DMF. Isolated yields. The reaction was carried out
c
d
at 90 1C. The reaction was carried out at 70 1C.
Table 2 Fe(OTf)3 and TfOH cocatalyzed coupling reaction of
benzylic alcohols 1 with phenylacetylene 2aa
Scheme 1 Proposed mechanism of the coupling between terminal
alkynes and benzylic alcohols cocatalyzed by Fe(OTf)3 and TfOH.
resulting in the sp–sp3 C–C bond formation in the absence of
base. Inexpensive iron and TfOH are used as catalysts.
Furthermore, H2O is the unique byproduct makes this
transformation atom efficient and environmentally benign.
This method presents a novel example of efficient cooperative
catalysis. Further studies on the scope and the synthetic
applications are ongoing in our laboratory.
Entry
R (1)
Yield of 3 (%)b
1
2
3
4
5
6
7
8
Ph
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
(1g)
(1h)
77
86
62
72
54
66
77
72
(3aa)
o-Me-C6H4–
m-Me-C6H4–
p-Me-C6H4–
p-MeO-C6H4–
p-Cl-C6H4–
p-Ph-C6H4–
p-tBu-C6H4–
(3ba)
(3ca)
(3da)
(3ea)
(3fa)
(3ga)
(3ha)
Financial support from Peking University, National Science
Foundation of China (Nos. 20702002, 20872003) and
National Basic Research Program of China (973 Program)
(Grant No. 2009CB825300) are greatly appreciated. We thank
Zhuangzhi Shi in this group for reproducing the results of 3da
in Table 2.
a
All the reactions were carried out on the scale of 0.5 mmol of 1
with 0.75 mmol of 2a, 0.025 mmol Fe(OTf)3, 0.05 mmol TfOH
b
(2 M in DMF), and 2 ml solvent under N2. Isolated yields.
Notes and references
arylacetylenes were tolerable as the coupling partners. Bromo-
substituted phenylacetylene 2e was successfully converted to
bromo-substituted product 3ae in 79% yield (entry 5, Table 3),
which could be used for further transformations. Moreover,
with a methyl substituent at the meta- or ortho-positions
(2c, 2d) a higher yield was obtained than with a methyl
substituent at the para-position (2b) (entries 2–4, Table 3).
Based on the above results, a plausible mechanism is
proposed in Scheme 1. Benzylic alcohols 1 are initially
activated by Fe(OTf)3 and TfOH, generating the cationic
intermediates A.7h Then, the intermolecular addition with
terminal alkynes 2 activated by Fe(OTf)3 would proceed to
give intermediates B,7h,14 followed by deprotonation to form
the corresponding products 3.7i
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ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6487–6489 | 6489