Atom-economical synthesis of unsymmetrical ketones through photocatalyzed C-H activation of alkanes and coupling with CO and electrophilic alkenes

Article abstract of DOI:10.1002/anie.201004854

A three-component coupling between alkanes, CO, and electron-deficient alkenes in the presence of a catalytic amount of (nBu₄N) ₄W₁₀O₃₂ (TBADT) has resulted in the efficient formation of unsymmetrical ketones. This process is based on the carbonylation of alkyl radicals photocatalytically generated by C-H activation of alkanes and the subsequent addition to alkenes (see scheme; EWG=electron-withdrawing group).

Full text of DOI:10.1002/anie.201004854

DOI: 10.1002/anie.201004854
À
C H Carbonylation
Atom-Economical Synthesis of Unsymmetrical Ketones through
À
Photocatalyzed C H Activation of Alkanes and Coupling with CO and
Electrophilic Alkenes**
Ilhyong Ryu,* Akihiro Tani, Takahide Fukuyama, Davide Ravelli, Maurizio Fagnoni,* and
Angelo Albini
Multicomponent processes are highly desirable in modern
organic synthesis because they allow the rapid generation of
the targeted compounds.[1] Our research group has previously
reported that unsymmetrical ketones can be synthesized by
free-radical mediated, three-component coupling reactions of
haloalkanes, CO, and electron-deficient alkenes, which
employ Group 14 metal hydrides, such as tributyltin hydri-
de[2a] or tris(trimethylsilyl)silane (TTMSS),[2b,c] as radical
mediators.[3] We recently reported a related transformation
that can be achieved by using tetrabutylammonium cyano-
has recently attracted attention because of the high photo-
À
activity in the C H bond homolytic hydrogen abstraction in
alkanes[9] and in other substrates including aldehydes[10] and
amides.[11] We supposed that a three-component coupling
À
reaction through alkane C H cleavage under photocatalysis
by TBADT and a radical carbonylation would lead to the
desired products. In 1995, Hill and Jaynes reported the 8%
formation of cyclohexanecarboxaldehyde by a related photo-
catalytic reaction of cyclohexane with CO (1 atm).[12] We
chose the three-component coupling involving cyclohexane
(1a), CO, and dibutyl maleate (2a) as a model reaction, by
using a xenon lamp as the light source and a stainless-steel
autoclave equipped with two quartz windows as a pressure-
durable apparatus (see the Supporting Information for
details). The results are summarized in Table 1. When a
solution of 1a, 2a, and TBADT (4 mol%) in acetonitrile was
irradiated for 20 hours under a CO pressure of 80 atm, the
desired reaction proceeded to give the ester-functionalized
unsymmetrical ketone 3a in a modest yield (51%; Table 1,
entry 1) because a significant amount of dibutyl succinate 4
was likewise formed. However, the formation of 4 was
effectively suppressed by simply changing the quartz liner to a
borohydride as an alternative for toxic tin hydride.[2d]
A
breakthrough would be obtained by replacing haloalkanes
with alkanes and by avoiding the use of tin and silicon hydride
reagents.[4] Provided that a convenient catalytic activation of
the alkane would be available,[5] an atom-economical and eco-
friendly process would result.[6] Herein, we report a viable
photocatalytic alternative (Scheme 1).
Scheme 1. Atom-economical three-component coupling reactions lead-
ing to unsymmetrical ketones. EWG=electron-withdrawing group,
TBADT=tetrabutylammonium decatungstate, (nBu4N)4W10O32.
Table 1: TBADT photocatalyzed three-component coupling reaction of
cyclohexane (1a), CO, and dibutyl maleate (2a).[a]
This process is based on the use of tetrabutylammonium
decatungstate (TBADT) as the photocatalyst.[7,8] This species
[*] Prof. I. Ryu, A. Tani, Dr. T. Fukuyama
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Sakai, Osaka 599-8531 (Japan)
Fax: (+81)72-254-9695
E-mail: ryu@c.s.osakafu-u.ac.jp
Homepage: http://www.c.s.osakafu-u.ac.jp/~ryu/index.htm
D. Ravelli, Prof. M. Fagnoni, Prof. A. Albini
Department of Organic Chemistry
University of Pavia
Via Taramelli 10, 27100 Pavia (Italy)
Fax: (+39)0382-987-323
Entry 1a [equiv] CO [atm] Conversion [%][b] Liner
Yield [%][c]
3a
4
1
5
5
80
80
80
80
40
>99
80
quartz 51
10
2
2
5
2
2
3
Pyrex
Pyrex
Pyrex
Pyrex
45
59
77
60
10
20
20
89
>99
89
4
5[d]
E-mail: fagnoni@unipv.it
Homepage: http://www.unipv.it/photochem
[a] Reaction conditions: 1a (2.5–10 mmol), 2a (0.5 mmol), TBADT
(4 mol%), CO (80 or 40 atm), MeCN (5 mL), irradiation by 500 W Xenon
lamp for 20 h. [b] Determined by 1H NMR analysis of the crude reaction
mixture using 1,1,2,2-tetrachloroethane as an internal standard. [c] Yield
of product isolated after flash chromatography on SiO2. [d] Dibutyl 2-
cyclohexylsuccinate was obtained in 8% yield.
[**] I.R. acknowledges a Grant-in-Aid for Scientific Research from MEXT
(Japan). Partial support of this work by MURST (Rome) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004854.
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À
Table 2: TBADT photocatalyzed, three-component coupling reactions comprised of R H 1, CO, and
electron deficient alkenes 2.[a]
Pyrex-glass liner (Table 1, entry 2).
With the use of an excess amount
(20 equiv) of cyclohexane (1a), the
yield of 3a was increased to 77%
(Table 1, entry 4). The reaction
under lower CO pressure (40 atm)
resulted in a lower yield of 3a (60%;
Table 1, entry 5) because of the
competitive formation of the non-
carbonylated product dibutyl 2-
cyclohexylsuccinate.
Entry
1
Alkane
Alkene
Product
Yield [%][b]
77
1a
1b
2a
2a
3a
3b
2
68
Encouraged by the result
reported in Table 1, we then applied
these reaction conditions to the
3
1c
1c
1d
2a
2a’
2a
3c[c]
3c’[e]
3d
60
three-component
synthesis
of
4[d]
5
74
unsymmetrical ketones 3 using a
variety of alkanes 1 and alkenes 2
(Table 2). The carbonylation of
cyclopentane (1b) worked well,
and led to the corresponding unsym-
metrical ketone 3b in 68% yield
after isolation by chromatography
on silica gel (Table 2, entry 2). In a
similar manner, cycloheptane (1c)
and cyclooctane (1d) gave good
yields of 3c and 3d, respectively
(60% and 58%; Table 2, entries 3
and 5). The reaction of 1c with
dimethyl maleate (2a’) gave the
corresponding keto dimethyl ester
3c’ in 74% yield (Table 2, entry 4).
The carbonylation of adamantane
(1e) suffered from poor solubility in
acetonitrile. Accordingly, we used a
1:1 mixture of acetonitrile and ben-
zene dissolving 2 equivalents of ada-
mantane (1e). This gave a 1:1.3
mixture of the 1- and 2-carbonylated
products 3e and 3e’ in a 35% over-
all yield (73% based on 48% con-
version of 2a; Table 2, entry 6).
Among other electron-deficient
alkenes, a,b-unsaturated ketones
generally gave good results. For
example, methyl vinyl ketone (2b),
2-cyclopentenone (2c), 2-cyclohex-
enone (2d), 3-methylene-2-norbor-
nanone (2e), and trans-3-decen-2-
one (2 f) were all used in a three-
component coupling reaction with
cyclohexane and CO to give the
corresponding 1,4-diketones 3 f–j in
good yields (Table 2, entries 7–11).
The reaction of an acyclic alkane,
2,4-dimethylpentane (1 f), with CO
and ethyl vinyl ketone (2g) was not
selective, and gave a mixture of
58[f]
6[g]
1e
2a[h]
3e
35[i]
3e’
7
1a
1a
1a
1a
2b
2c
2d
2e
3 f
3g
3h
3i
58
62
61
8
9
61
(endo)
10
11[d]
1a
1 f
2 f
3j
60
12[d,j]
2g
3k
3k’
3l
13
10
35
13
1a
1a
1a
1a
2h
2i
14[d]
15[d]
16[d]
3m
3n
3o
67
58
55
2j
2k
[a] Reaction conditions: 1 (10 mmol), 2 (0.5 mmol), TBADT (4 mol%), CO (80 atm), MeCN (5 mL),
irradiation by 500 W Xenon lamp for 20 h. [b] Yields of product isolated after flash chromatography on
SiO2. [c] R=nBu.[d] The reaction was carried out for 30 h. [e] R=Me. [f] Dibutyl 2-cyclooctylsuccinate
was likewise obtained in 9% yield. [g] The reaction was carried out using 2 equiv of 1e in C6H6/MeCN
(1:1, 5 mL). [h] 48% conversion of 2a. [i] 3e/3e’=1:1.3. [j] 40 equiv of 1 f was used.
several
products
(Table 2,
entry 12). Among them, 1,4-dike-
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Angew. Chem. Int. Ed. 2011, 50, 1869 –1872

tone 3k, which was formed through carbonylation at primary
À
C H bonds, and the noncarbonylated product 3k’, formed
À
through a tertiary C H cleavage, were isolated as the main
products.[13]
In the reaction of butyl acrylate (2h) with 1a, the yield of
ketoester 3l was rather low and we observed the formation of
appreciable amounts of polyacrylate, (Table 2, entry 13).
When methyl crotonate (2i) and methyl methacrylate (2j)
were used, however, the expected products 3m and 3n were
obtained in 67% and 58% yield, respectively (Table 2,
entries 14 and 15). The reaction with crotonitrile (2k) gave
ketonitrile 3o in 55% yield (Table 2, entry 16). The reaction
of 1a with 1-undecene or ethyl vinyl ether did not give the
corresponding three-component coupling products. These
results may be rationalized by the well-established nucleo-
philic character of the acyl radical intermediates.[14]
coupling reaction (Scheme 2), in which the scrambling may
be rationalized by assuming a D/H exchange of H+W10O32
5À
with D2O.[9d] This confirmed again that hydrogen was
exclusively donated by the reduced photocatalyst, which
was thus regenerated, and not by the reaction medium.[15]
The formation of dibutyl succinate (4; Table 1) conceiv-
ably arises from the photodecomposition of the initially
formed product 3a through a Norrish I cleavage of the weak
bond between the acyl and the carboxyl-substituted methine
carbon atoms. Thus, the photoirradiation of isolated 3a was
examined under different reaction conditions (Table 3).
Table 3: Photodecomposition studies of 3a.[a]
Scheme 2. Proposed reaction mechanism for the photocatalyzed three-
component coupling synthesis of ketones. R’=EWG, H, alkyl group.
Entry
Liner
CO [atm]
Yield [%][b]
À
Summing up, the carbonylation of unactivated C H bonds
3a
4
is an important challenge in radical chemistry.[3a] The present
reaction protocol, which is based on the use of photocatalyst
TBADT and a Pyrex-glass filter, gave access to a variety of
functionalized unsymmetrical ketones. This process consists
of an atom-economical three-component coupling that uses a
smooth reaction occurring at room temperature and poten-
tially abundant feedstocks. We are now exploring other
multicomponent processes based on photocatalyzed radical
carbonylation reactions.
1
2
3
quartz
Pyrex
Pyrex
0
0
80
34%
59%
94%
47%
13%
6%
[a] Reaction conditions: 3a (0.1 mmol), MeCN (5 mL). [b] Determined
by NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard.
Our observations are the following: 1) the photodecom-
position of 3a indeed proceeded to give 4, 2) the use of a
Pyrex filter suppressed the photodecomposition channel
(Table 3, entry 2), and 3) CO pressures contributed to the
slowing of the undesired photodecomposition path (Table 3,
entry 3). In the absence of TBADT, the photodecomposition
of 3a resulted in a complex mixture and only a trace amount
of 4 was detected. Reasonably, the reduced form of the
photocatalyst (H+W10O325À) present under these conditions
delivers a hydrogen atom to the succinate radical A to give 4
(Table 3).
Deuterium-labeling experiments were also carried out
[Eq. (1)]. Whereas no deuterium incorporation from
[D3]acetonitrile was observed, the addition of deuterium
oxide resulted in the deuteration at the 3-position with a D/H
ratio of 47:53. On the basis of these observations, we proposed
a reaction mechanism for the present three-component
Experimental Section
Typical synthetic procedure:
A
magnetic stirring bar, MeCN
(tetrabutylammonium decatungstate,
(5.0 mL),
TBADT
(nBu4N)4W10O32, 66.4 mg, 0.02 mmol), cyclohexane (1a, 841.6 mg,
10 mmol), and dibutyl maleate (2a, 114.1 mg, 0.5 mmol) were placed
in a stainless-steel autoclave for photoreaction equipped with an
inserted Pyrex-glass liner. The autoclave was closed, purged three
times with carbon monoxide, pressurized with 80 atm of CO and then
irradiated by xenon arc lamp (500 W) under stirring for 20 h. After
the reaction, excess CO was discharged at RT. The solvent was
removed under reduced pressure. The residue was purified by flash
Angew. Chem. Int. Ed. 2011, 50, 1869 –1872
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Communications
chromatography on silica gel (hexane/AcOEt = 10:1) to give 3a
(128.7 mg, 77%).
[7] For recent reviews on photocatalysis, see: a) D. Ravelli, D.
Dondi, M. Fagnoni, A. Albini, Chem. Soc. Rev. 2009, 38, 1999;
b) M. Fagnoni, D. Dondi, D. Ravelli, A. Albini, Chem. Rev. 2007,
107, 2725.
Received: August 4, 2010
[8] For reviews on decatungstate photocatalysis, see: a) C. L. Hill,
Synlett 1995, 127; b) C. Tanielian, Coord. Chem. Rev. 1998, 178–
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Eur. J. 2006, 12, 4153; d) D. Dondi, M. Fagnoni, A. Molinari, A.
Maldotti, A. Albini, Chem. Eur. J. 2004, 10, 142; e) S. Protti, D.
Ravelli, M. Fagnoni, A. Albini, Chem. Commun. 2009, 7351;
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[10] a) M. D. Tzirakis, M. Orfanopoulos, J. Am. Chem. Soc. 2009, 131,
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Revised: October 30, 2010
Published online: January 18, 2011
À
Keywords: carbonylation · C H activation ·
multicomponent reactions · photocatalysis · radicals
.
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