Copper-Catalyzed Alkoxycarbonylation of Alkanes with Alcohols

Article abstract of DOI:10.1002/cssc.201601587

Esters are important chemicals widely used in various areas, and alkoxycarbonylation represents one of the most powerful tools for their synthesis. In this communication, a new copper-catalyzed carbonylative procedure for the synthesis of aliphatic esters from cycloalkanes and alcohols was developed. Through direct activation of the C _sp3 ?H bond of alkanes and with alcohols as the nucleophiles, the desired esters were prepared in moderate-to-good yields. Paraformaldehyde could also be applied for in situ alcohol generation by radical trapping, and moderate yields of the corresponding esters could be produced. Notably, this is the first report on copper-catalyzed alkoxycarbonylation of alkanes.

Full text of DOI:10.1002/cssc.201601587

Accepted Article
Title: Copper-Catalyzed Alkoxycarbonylation of Alkanes with Alcohols
Authors: Xiao-Feng Wu, Yahui Li, Changsheng Wang, Fengxiang Zhu,
Zechao Wang, and Pierre H. Dixneuf
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201601587
Link to VoR: http://dx.doi.org/10.1002/cssc.201601587
A Journal of
www.chemsuschem.org

10.1002/cssc.201601587
ChemSusChem
COMMUNICATION
Copper-Catalyzed Alkoxycarbonylation of Alkanes with Alcohols
Yahui Li+,[a] Changsheng Wang+,[b] Fengxiang Zhu,[a] Zechao Wang,[a] Pierre H. Dixneuf,[b] and Xiao-
Feng Wu*[a]
Abstract: Esters are important chemicals widely used in various
areas and alkoxycarbonylation represents one of the most powerful
tools for their synthesis. In this communication, we developed a
novel copper-catalyzed carbonylative procedure for the synthesis of
aliphatic esters from cycloalkanes and alcohols. Through direct
activation of the C(sp3)-H bond of alkanes and with alcohols as the
nucleophiles, the desired esters were prepared in moderate to good
yields. Paraformaldehyde can also be applied for in situ alcohol
generation by radical trapping, and moderate yields of the
corresponding esters can be produced. Notably, this is the first
report on copper-catalyzed alkoxycarbonylation of alkanes.
treat influenza A and influenza B (flu), and to prevent flu after
exposure. Under all these backgrounds, we wish to report here
the first example on copper-catalyzed alkoxycarbonylation of
alkanes with alcohols via C-H activation. Moderate to good
yields of the desired esters can be obtained. Additionally,
paraformaldehyde can also be applied for in situ alcohol
generation by radical trapping, and give moderate yields of the
corresponding esters.
Transition metal-catalyzed carbonylative transformation is
already a powerful class of methodologies for the synthesis of
carbonyl-containing chemicals, it extends the carbon chain while
introduces a synthetically versatile carbonyl group.[1] However,
by go through the literature, most of the known procedures are
either requiring noble metal as the catalysts or using
(pseudo)aryl halides and analogues as the starting materials.
Due to the high price of noble metal catalysts and the tedious
substrates pre-activation and preparation steps, alternative
procedures are definitely under request. Recently, C(sp3)-H
activation and functionalization has attracted much attentions
from our synthetic communities. Carbonylative activation of
C(sp3)-H bonds with the assistant of directing groups have been
reported with palladium or ruthenium as the catalysts as well.[2,3]
Additionally, among all the transition metal catalysts, copper
salts hold many advantages including inexpensive and low
toxicity.[4] The exploring of copper catalysts in carbonylative
transformations is definitely attractive from the point of view of
both academic and industrial applications.[5]
On the other hand, esters are naturally occurring and also
important intermediates and building blocks in pharmaceutical
and natural products.[6] Selected examples of bio-active esters
are shown in Scheme 1.[7] Plavix is a thienopyridine-class
antiplatelet agent used to inhibit blood clots in coronary artery
disease, peripheral vascular disease, cerebrovascular disease,
and to prevent heart attack and stroke. Tricor is a drug for the
fibrate class. Flovent HFA is used to treat asthma, allergic
rhinitis, nasal polyps, various skin disorders and Crohn's disease
and ulcerative colitis. Tamiflu is an antiviral medication used to
Scheme 1. Selected examples of bio-active esters.
Initially, we chose cyclohexane and 1-octanol as the model
substrates to establish this carbonylation procedure. Upon the
variation of reaction conditions, different product yields could be
obtained (Table 1). Among the different tested metal catalyst
precursors (Table 1, entries 1-4), CuCl2 showed the best results
(85% NMR yield; 78% isolated yield; Table 1, entry 2). And
decreased reaction efficiency was obtained with CuBr(Me2S) or
Cu(CH3CN)4BF4 as the catalyst (Table 1, entries 3 and 4). Only
trace of the desired product can be obtained in the absence of
catalyst system (Table 1, entry 1). The amount and usage of
DTBP (di-tert-butyl peroxide) plays an important role in this
reaction. When we decreased the use of DTBP from 1.5 equiv.
to 1 equiv., only 58% of the desired product was obtained and
no ester was produced with TBHP (tert-butyl hydroperoxide
solution (70 wt. % in H2O); Table 1, entries 5 and 6). To our
delight, no obvious variation of yield was observed with
decreased loading of catalyst and ligand (Table 1, entry 7). And
the pressure of CO can also be decreased to 10 bar (Table 1,
entry 8). However, the yield drops when further decreasing the
pressure of CO (2 bar, 32% yield). Finally, two different ligands
were studied in stand of 1,10-phenanthroline and lower reaction
efficiency were obtained with 2,2'-bipyridine or PPh3 as the
ligand (Table 1, entries 9 and 10). Taking the outcome of
substrates testing into consideration, we using 10 mol% of CuCl2
and 1,10-phenanthroline together with DTBP (1.5 equiv.) under
20 bar CO for further studies.
[a]
[b]
+
Y. Li, F. Zhu, Z. Wang, Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: Xiao-Feng.Wu@catalysis.de
C. Wang, Prof. Dr. P. H. Dixneuf
Catalyse et Organométalliques, Institut Sciences Chimiques de
Rennes, UMR 6226-CNRS-Université de Rennes, Av. Général
Leclerc, 35042 Rennes (France)
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201601587
ChemSusChem
COMMUNICATION
Table 1. Screening of the reaction conditions.[a]
different regioselective products were obtained (Table 3, entries
3 and 4).
Table 2. Cu-catalyzed carbonylative synthesis of esters.[a]
Variations from the standard
Entry
Yield[b]
Trace
conditions
1
2
Without Catalyst and Ligand
-
Entry
1
Alcohol
Product
Yield [%]
78
85%
78%c
3
4
5
6
CuBr(Me2S)
Cu(CH3CN)4BF4
75 %
34%
2
3
4
5
6
7
8
54
74
65
91
81
87
63
1.0 equiv. DTBP
58%
TBHP instead of DTBP
Trace
5 mol% of CuCl2 and 1,10-
Phen
7
8
9
84%
83%
64%
10 bar instead of 20 bar
2,2'-bipyridine instead of 1,10-
Phen
PPh3 (20 mol%) instead of
1,10-Phen
10
46%
[a] 1-Octanol (0.5 mmol), catalyst (10 mol%), ligand (10 mol%), 0.75 mmol
DTBP, 20 bar CO, cyclohexane (2 mL), 24 h. [b] NMR yields using mesitylene
as the internal standard. [c] Isolated yield. DTBP: di-tert-butyl peroxide. TBHP:
tert-butyl hydroperoxide solution (70 wt. % in H2O).
With the optimized reaction conditions in hand, we examined
the scope of the reaction with a range of alcohols. As shown in
Table 2, various alcohols were texted. We tested different
aliphatic alcohols at the first stage. Moderate to good yields of
the desired products can be produced in all the cases under
standard conditions. Not only primary alcohols, but also
secondary and tertiary alcohols are all applicable here and the
reactions with tert-butanol and 4-heptanol gave good isolated
yields of the products (Table 2, entries 8 and 9; 63% and 73%
yields, respectively). To further explore the applicability of
alcohols, phenyl substituted substrates were studied
subsequently (Table 2, entries 11-17). The reactions of benzyl
9
73
10
11
12
13
14
77
81
87
86
82
alcohol,
phenethyl
alcohol,
3-phenyl-1-propanol
with
cyclohexane gave the desired products in 81%, 87% and 86%
yields respectively (Table 2, entries 11-13). To reveal the
generality of this method, other kinds of alcohols were also
tested. 2-Phenylpropan-1-ol gives a good result in 82% yield.
Interestingly, when (perfluorophenyl) methanol was used in this
reaction, excellent yield was obtained (Table 2, entry 17).
Importantly, Cholesterol, an essential structural component of all
animal cell membranes, can be reacted smoothly with
cyclohexane and gave the desired product in 61 % isolated yield
(Table 2, entry 18).
15
16
65
64
Furthermore, some alkane derivatives were tested and the
results are listed in Table 3. Cyclopentane and cycloheptane
worked well under the standard reaction conditions (Table 3,
entries 1 and 2). Good yields of the corresponding esters were
isolated (72% and 71%, respectively). Pentane and hexane
were also tested under the same conditions, a mixture of
17
92
This article is protected by copyright. All rights reserved.

10.1002/cssc.201601587
ChemSusChem
COMMUNICATION
18
61
[a] Alcohol (0.5 mmol), CuCl2 (10 mol%), 1,10-phen (10 mol%), DTBP (0.75
mmol), CO (20 bar), cyclohexane (2 mL), 120 oC, 24 h. [b] Isolated yields.
Table 3. Cu-catalyzed alkoxycarbonylation of alkanes.[a]
Entry
Alkane
Product
Yield [%]
Scheme 3. Proposed reaction mechanism.
1
72
In conclusion, a novel copper-catalyzed alkoxycarbonylation
of alkanes with alcohols has been developed. With copper salt
as the catalyst, various esters were prepared in moderate to
good yields via C(sp3)-H bond activation of alkanes.
Paraformaldehyde can also be applied for in situ alcohol
generation by radical trapping, and moderate yields of the
corresponding esters can be produced. Notably, this is the first
report on copper-catalyzed alkoxycarbonylation of alkanes.
2
3
4
71
59c
56d
[a] Benzyl alcohol (0.5 mmol), CuCl2 (10 mol%), 1,10-phen (10 mol%), 0.75
mmol DTBP, 20 bar CO, alkane (2 mL), 120 oC, 24 h. [b] Isolated yields. [c]
The ratio was determined by 1H NMR (C1:C2:C3 =1.15: 2.92: 1). [d] Mixture.
Acknowledgements
The authors thank the Chinese Scholarship Council for financial
Support. The analytic supports of Dr. W. Baumann, Dr. C. Fisher,
S. Buchholz, and S. Schareina are gratefully acknowledged. We
also appreciate the general supports from Professor Matthias
Beller in LIKAT.
To further explore the applicability of this reaction in aliphatic
esters synthesis, we used paraformaldehyde for in situ alcohol
generation by radical trapping and got the desired products in 52
% and 51 % respectively (Scheme 2).[8] In these cases, no
addition of alcohol is required.
General procedure A: A 4 mL screw-cap vial was charged with
CuCl2 (6.7 mg, 10 mol%), 1,10-phenanthroline hydrate (9 mg, 10
mol%) and an oven-dried stirring bar. The vial was closed by
Teflon septum and phenolic cap and connected with atmosphere
with a needle. After cyclohexane (2 mL), DTBP (0.75 mmol),
alcohols (0.5 mmol) were injected by syringe, the vial was fixed
in an alloy plate and put into Paar 4560 series autoclave (300
mL) under argon atmosphere. At room temperature, the
autoclave is flushed with carbon monoxide for three times and
20 bar of carbon monoxide was charged. The autoclave was
placed on a heating plate equipped with magnetic stirring and an
aluminum block. The reaction is allowed to be heated under 120
oC for 24 hours. Afterwards, the autoclave is cooled to room
temperature and the pressure was carefully released. After
removal of solvent under reduced pressure, pure product was
obtained by column chromatography on silica gel (eluent:
pentane/ethyl acetate = 100:1).
Scheme 2. Using paraformaldehyde for in situ generation of alcohols.
Based on our results, a possible reaction mechanism is
proposed (Scheme 3). The reaction started with a copper(II)-
catalyzed or thermal hemolytic cleavage of a peroxide to
generate the tert-butoxy radical, which reacts with cyclohexane
and sequential oxidation of the copper(II) species to give the
Cu(III)-cyclohexane species D. Than complex D reacts with
alcohols to produce Cu(III) intermediate E. Followed by CO
insertion forms the intermediate F or G, which then give the final
carbonylation product after reductive elimination. The meanwhile
formed Cu(I) reacted with radical and regenerate the active
Cu(II) species for the next catalytic cycle. The radical nature of
this reaction was proven by experiments with TEMPO. The
reaction was totally inhibited by the addition of 2 or 4 equivalents
of TEMPO to the standard conditions.
General procedure B: A 4 mL screw-cap vial was charged with
CuCl2 (6.7 mg, 10 mol%), 1,10-phenanthroline hydrate (9 mg, 10
mol%), paraformaldehyde (15 mg, 0.5 mmol) and an oven-dried
stirring bar. The vial was closed by Teflon septum and phenolic
cap and connected with atmosphere with a needle. After
cyclohexane (2 mL) and DTBP (0.75 mmol) were injected by
This article is protected by copyright. All rights reserved.

10.1002/cssc.201601587
ChemSusChem
COMMUNICATION
133, 8070-8073; e) G. Liao, X. Yin, K. Chen, Q. Zhang, S. Zhang, B. F.
Shi, Nat. Commun. 2016, 7, 12901-12909; f) B. Sundararaju, M. Achard,
G. V. M. Sharma, C. Bruneau, J. Am. Chem. Soc. 2011, 133, 10340-
10343.
syringe, the vial was fixed in an alloy plate and put into Paar
4560 series autoclave (300 mL) under argon atmosphere. At
room temperature, the autoclave is flushed with carbon
monoxide for three times and 20 bar of carbon monoxide was
charged. The autoclave was placed on a heating plate equipped
with magnetic stirring and an aluminum block. The reaction is
[3]
a) P. Xie, C. Xia, H. Huang, Org. Lett. 2013, 15, 3370-3373; b) P. Xie, Y.
Xie, B. Qian, H. Zhou, C. Xia, H. Huang, J. Am. Chem. Soc. 2012, 134,
9902-9905; c) H. Liu, G. Laurenczy, N. Yan, P. J. Dyson, Chem.
Commun. 2014, 50, 341-343; d) I. Ryu, A. Tani, T. Fukuyama, D.
Ravelli, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 2011, 50, 1869-
1872; e) M. Okada, T. Fukuyama, K. Yamada, I. Ryu, D. Ravelli, M.
Fagnoni, Chem. Sci. 2014, 5, 2893-2898; f) L. Lu, R. Shi, L. Liu, J. Yan,
F. Lu, A. Lei, Chem. Eur. J. 2016, 22, 14484-14488; g) Y. Fujiwara, K.
Takaki, J. Watanabe, Y. Uchida, H. Taniguchi, Chem. Lett. 1989, 1687-
1688.
o
allowed to be heated under 120 C for 24 hours. Afterwards, the
autoclave is cooled to room temperature and the pressure was
carefully released. After removal of solvent under reduced
pressure, pure product was obtained by column chromatography
on silica gel (eluent: pentane/ethyl acetate = 100:1).
[4]
[5]
S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem.
Rev. 2013, 113, 6234-6458.
Keywords: copper catalyst • alcohols • carbonylation • esters •
alkanes
a) J. M. Liu, R. Z. Zhang, S. F. Wang, W. Sun, C. G. Xia, Org. Lett.
2009, 11, 1321–1324; b) P. Tambade, Y. Patil, N. Nandurkar, B.
Bhanage, Synlett 2008, 886–888; c) Y. Li, K. Dong, F. Zhu, Z. Wang,
X.-F. Wu, Angew. Chem. Int. Ed. 2016, 55, 7227-7230; d) Y. Li, F. Zhu,
Z. Wang, X.-F. Wu, ACS Catal. 2016, 6, 5561-5564; e) S.-K. Kang, T.
Yamaguchi, T.- H. Kim, P.-S. Ho, J. Org. Chem. 1996, 61, 9082–9083.
a) Esterification: methods, reactions, and applications (Ed. J. Otera),
Wiley-VCH: Weinheim, 2010; b) K. Ekoue-Kovi, C. Wolf, Chem. Eur. J.
2008, 14, 6302-6315; c) D. Milstein, Top. Catal. 2010, 53, 915-923; d)
S. Tang, J. Yuan, C. Liu, A. Lei, Dalton Trans. 2014, 43, 13460-13470;
e) H. Miyamura, S. Kobayashi, Acc. Chem. Res. 2014, 47, 1054-1066;
f) B. Liu, F. Hu, B. F. Shi, ACS Catal. 2015, 5, 1863-1881.
N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010,
87, 1348-1349.
[1]
For selected recent reviews on carbonylation reaction, see: a) X. F. Wu,
H. Neumann, M. Beller, Chem Rev 2013, 113, 1-35; b) X. F. Wu, H.
Neumann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986-5009; c) X.-F.
Wu, H. Neumann, ChemCatChem 2012, 4, 447-458; d) Q. Liu, H.
Zhang, A. Lei, Angew Chem Int Ed 2011, 50, 10788-10799; e) ) X. F.
Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6, 229-241; f) C. H.
Schiesser, U. Wille, H. Matsubara, I. Ryu, Acc. Chem. Res. 2007, 40,
303-313; g) S. Sumino, A. Fusano, T. Fukuyama, I. Ryu, Acc. Chem.
Res. 2014, 47, 1563-1574; h) B. Gabriele, R. Mancuso, G. Salerno, Eur.
J. Org. Chem. 2012, 6825-6839; i) S. D. Friis, A. T. Lindhardt, T.
Skrydstrup, Acc. Chem. Res. 2016, 49, 594-605; j) X. F. Wu, RSC Adv.
2016, 6, 83831-83837; k) J.-B. Peng, X. Qi, X.-F. Wu, ChemSusChem
2016, 9, 2279-2283.
[6]
[7]
[8]
a) W. Li, X. F. Wu, Adv. Synth. Catal. 2015, 357, 3393-3418; b) T.
Kawamoto, T. Fukuyama, I. Ryu, J. Am. Chem. Soc. 2012, 134, 875-
877.
[2]
a) E. J. Yoo, M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 17378-
17380; b) S. Li, G. Chen, C.-G. Feng, W. Gong, J.-Q. Yu, J. Am. Chem.
Soc. 2014, 136, 5267-5270; c) A. McNally, B. Haffemayer, B. S. L.
Collins, M. J. Gaunt, Nature 2014, 510, 129-133; d) N. Hasegawa, V.
Charra, S. Inoue, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011,
This article is protected by copyright. All rights reserved.

10.1002/cssc.201601587
ChemSusChem
COMMUNICATION
COMMUNICATION
Yahui Li, Changsheng Wang, Fengxiang
Zhu, Zechao Wang, Pierre H. Dixneuf
and Xiao-Feng Wu*
Page No. – Page No.
Copper-Catalyzed
Alkoxycarbonylation of Alkanes with
Alcohols
A novel copper-catalyzed carbonylative transformation of alkanes and alcohols has
been developed. Esters were prepared in good yields by carbonylation of the C(sp3)
-
H bond of alkanes with alcohols as the nucleophiles. Notably, this is the first report
on copper-catalyzed carbonylative C-H activation between alkanes and alcohols.
This article is protected by copyright. All rights reserved.