Tandem catalysis: Access to ketones from aldehydes and arylboronic acids via rhodium-catalyzed addition/oxidation

Article abstract of DOI:10.1002/adsc.200600530

Direct cross-coupling reactions of aromatic aldehydes with arylboronic acids afforded ketones in high yields and under mild conditions in the presence of a rhodium catalyst, acetone and a base. This new reaction, involving a formal aldehyde C-H bond activation, is believed to proceed via a tandem process involving addition of the organometallic species to the aldehyde followed by oxidation by β-hydride transfer.

Full text of DOI:10.1002/adsc.200600530

FULL PAPERS
DOI: 10.1002/adsc.200600530
Tandem Catalysis: Access to Ketones from Aldehydes and Aryl-
boronic Acids via Rhodium-Catalyzed Addition/Oxidation
Guilhem Mora,a Sylvain Darses,a,* and Jean-Pierre Geneta,*
a
Laboratoire de Synth›se SØlective Organique (UMR 7573, CNRS), Ecole Nationale SupØrieure de Chimie de Paris, 11
rue P&M Curie, 75231 Paris cedex 05, France
Fax : (+33)-1-4406-1052; e-mail: sylvain-darses@enscp.fr or jean-pierre-genet@enscp.fr
Received: October 13, 2006; Revised: February 27, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Direct cross-coupling reactions of aromatic involving addition of the organometallic species to
aldehydes with arylboronic acids afforded ketones in the aldehyde followed by oxidation by b-hydride
high yields and under mild conditions in the presence transfer.
of a rhodium catalyst, acetone and a base. This new
À
reaction, involving a formal aldehyde C H bond ac- Keywords: aldehydes; boronic acids; homogeneous
tivation, is believed to proceed via a tandem process catalysis; ketones; rhodium
Introduction
Results and Discussion
Benzophenone frameworks, a structural unit encoun- We report here the first catalytic cross-coupling reac-
tered in numerous natural products,[1] are generally tion of arylboronic acids with aryl aldehydes to afford
constructed by Friedel–Craft reaction or by addition diaryl ketones via a tandem catalytic process involv-
of arylmagnesium or lithium reagents to aryl alde- ing addition and oxidation via b-hydride transfer [Eq.
hydes followed by oxidation. In the first approach, (1)] under very mild conditions.
the generation of large amounts of salts, originating
from the Lewis acid and regioselectivity problems,
giving rise to mixture of isomers, generally results in
tedious purifications. In the second one, yields are
generally moderate and intramolecular variations
have been utilized to enhance the overall process.
Moreover, this approach requires stoichiometric
amounts of oxidant.
We recently reported[4] a direct access to ketones
A green process to access this framework via from aldehydes under rhodium catalysis in the pres-
tandem reactions[2] involving catalytic addition to the ence of potassium aryltrifluoroborates.[5] In order to
aldehyde and catalytic oxidation would be highly de- improve the scope of the reaction, we wondered if the
sirable. Examples of such processes are rare and in- readily available arylboronic acids would participate
volve oxidative addition of aryl halides to low-valent in this reaction.[6] Unfortunately, under the previous
transition metals followed by reaction with aldehydes conditions that used [Rh(CH2CH2)2Cl]2 and tri-tert-
G
or aldimines (insertion and b-hydride elimination butylphosphane, in the binary solvent system dioxane/
mechanism).[3] However, a high temperature is gener- acetone, the reaction of phenylboronic acid 2a with 4-
ally needed under basic[3b] or reductive conditions[3c] methoxybenzaldehyde 1a only afforded the carbinol
preventing the use of functionalized substrates. Fur- derivative 4a[5g,7] and not the expected ketone 3a
thermore, yields are generally moderate or limited (Table 1).
with respect to substrate tolerance.[3a]
In order to achieve exclusive formation of the ben-
zophenone adduct, several additives were evaluated.
In the presence of acids, no reaction was observed,
but the addition of bases was found to be crucial for
the formation of the expected ketone at the expense
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Ketones from Aldehydes and Arylboronic Acids
FULL PAPERS
Table 1. Optimization of the rhodium-catalyzed formation of
Table 2. Rhodium-catalyzed formation of diaryl ketones
diaryl ketones from aldehydes and arylboronic acids.[a]
from aldehydes and arylboronic acids.[a]
Entry
Ar
Ar’
Yield[b]
[%]
1
2
1a
1b
2a Ph
92
73
Entry
Base (equivs.)
Conversion
Time [h]
3a/4a
2a
1
2
3
4
5
6
7
None
40
6
0
24
24
24
24
4
8
4
4
4
0/100
57/43
KHCO3 (2)
KOH (2)
NEt3 (2)
K2CO3 (2)
K2CO3 (1)
K2CO3 (3)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
3
4
1c
1a
2b
2c
64
65
0
76
72
74
100
50
20
100
100/0
100/0
100/0
0/0[c]
70/30
10/90
0/100
8[b]
9[d]
10[e]
11[f]
24
3
5
6
1a
1d
2d
2d
74
82
[a]
Reactions conducted using 0.5 mmol of 1a, 2 equivs. of
2a, an additive, with 1.5 mol% of [Rh(CH2CH2)Cl]2 and
(t-Bu)3 at 808C in 2.5 mL 1,4-dioxane/acetone
AHCTREUNG
3 mol% P
4:1.
ACHTREUNG
7
1d
2e
85
[b]
[c]
Reaction in EtOH/acetone, 4:1.
Exclusive formation of aldolization-crotonization adduct
4-(4-methoxyphenyl)-but-3-en-2-one.
Reaction conducted at 608C.
Reaction conducted at 408C.
30 min at room temperature then 808C.
[d]
[e]
[f]
8
9
1d
1d
2f
2g
65
84
of carbinol (entries 2–7). Among the tested bases, po-
tassium carbonate was found to be the most suitable,
affording a quantitative conversion in benzophenone
3a as the sole product upon reaction of 1a with 2a
(entries 5–7). The amount of base did not appear to
be crucial, but the fastest reaction rates were achieved
using two equivalents of base compared to aldehyde
(entry 5). Among the solvent systems tested, a mix-
ture of dioxane/acetone appeared to be the most suit-
able and clean conversion to ketone was only possible
at a temperature above 808C. In may other polar or
protic solvents (see, for example, entry 8), aldehyde
1a was completely consumed but we observed only
the formation of the aldolization-crotonization prod-
uct in quantitative yield: 4-(4-methoxyphenyl)-but-3-
en-2-one. On the contrary, in dioxane, no trace of this
by-product was detected by GC/MS. The reaction
temperature has also a crucial role under these condi-
tions: lowering the temperature below 808C resulted
in a decrease of ketone formation at the expense of
carbinol (entries 9 and 10). Finally, we found that stir-
ring the reaction mixture for 30 min at room tempera-
ture before heating at 808C had a beneficial effect on
the conversion to ketone 3a (entry 11).
10
11
1e
1f
2g
2h
95
95
12
13
14
1f
1g
1h
2i
52
70
93
2d
2j
15
1i
1j
2k
2d
92
52
16
[a]
Reactions conducted using 0.5 mmol of 1, 2 equivs. of 2,
2 equivs. of K2CO3 with 1.5 mol% of [Rh(CH2CH2)Cl]2
(t-Bu)3 at 808C in 2.5 mL 1,4-dioxane/ace-
AHCTREUNG
and 3 mol% P
tone 4:1.
ACHTREUNG
Indeed, under these optimized conditions, reaction
[b]
of 1a with 2a using [Rh(CH2CH2)2Cl]2 in conjunction
A
Isolated yields of ketone.
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Guilhem Mora et al.
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with the P
(t-Bu)3 ligand[8] as catalyst afforded a 92%
A
yield of ketone 3a at 808C, using a binary mixture of
dioxane/acetone as solvent and K2CO3 as base
(Table 2, entry 1).
These conditions proved to be general and a great
variety of ketones were obtained from the reaction of
aromatic aldehydes with arylboronic acids. Good to
excellent yields were generally achieved with many
substitution patterns on the reaction partners. It ap-
peared that the electronic nature on the organoboron
reagent did not have a great influence as similar
yields and reaction rates were obtained with boronic
acids bearing either electron-withdrawing or -donating
substituents (entries 6 and 8). Yields were generally
higher with electron-rich arylaldehydes but compara-
ble yields were generally observed.
Figure 1. Reaction profile in the addition of 2a to 1a.
More specifically, acidic hydroxy substituents on
the aromatic ring were tolerated in this reaction, pre-
venting tedious protection/deprotection sequences
Indeed, it appeared that two consecutive catalytic
(entries 6–9, 14 and 15). This result is all the more sur- reactions are occurring under these conditions: addi-
prising, as, under these basic conditions, deprotona- tion of the boronic acid to aldehydes to produce the
tion of the phenol should result in an increased elec- carbinol and oxidation of the resulting alcohol to the
tron density in the aldehyde function, diminishing its ketone. The results were confirmed by the fact that in
electrophily. This result may suggest that insertion of the absence of base, only carbinol was formed in
the aldehyde into the aryl-rhodium species is not the quantitative yields, as already demonstrated by
rate-determining step of the whole process. Notewor- Miyaura et al.[7d] Similarly to potassium organotri-
thy, this reaction also allowed access to ortho-substi- fluoroborates, the presence of acetone as co-solvent
tuted benzophenones in high yields (entries 2, 4 and was found to be crucial for the process; diarylcarbi-
15). Under these conditions, reactions of aliphatic al- nols being obtained in quantitative yields in its ab-
dehydes with arylboronic acids only led to traces of sence. From these results, the overall mechanism is
the expected ketone.
believed to involve a tandem process including rhodi-
In order to get some insight into the reaction mech- um-catalyzed addition of boronic acid to aldehydes
anism, the reaction of aldehyde 1a and boronic acid (Scheme 1, cycle 1) followed by slow oxidation of the
2a was monitored by GC/MS under optimized condi- resulting carbinol via b-hydride transfer (cycle 2).
tions (Figure 1). To our surprise, and contrary to the
Indeed transmetallation of the organometallic re-
reaction profile obtained with potassium aryltrifluoro- agent to the rhodium(I) complex followed by the in-
borates, we observed fast disappearance of the alde- sertion of the aldehyde into the aryl-rhodium(I) fur-
hyde with concomitant initial formation of the carbi- nishes an alkoxo-rhodium species. It is known that
nol and not the ketone. Thereafter, the alcohol is boronic acids are prone to dehydratation, resulting in
slowly transformed to ketone.
the formation of boroxine and water.[9] Indeed, the in-
Scheme 1. Postulated mechanism.
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Ketones from Aldehydes and Arylboronic Acids
FULL PAPERS
d=6.08 (2H, s), 6.88 (1H, dd, J=1.4 Hz and 7.4 Hz), 7.16
(1H, t app, JH,H =JH,F =8.7 Hz), 7.33 (1H, s), 7.35 (1H, dd,
itial formation of the carbinol is explained by proto-
nation of this alkoxo-rhodium intermediate by the
water formed in the reaction medium (or directly by
the boronic acid), giving an active hydroxo-rhodium
species. Transmetallations of organoboron compounds
to alkoxo or hydroxo complexes of palladium,[10] rho-
dium[11] or ruthenium[12] have been described, allowing
regeneration of the aryl-metal species. We believe
that the role of the base is the regeneration of an
alkoxo-rhodium compound[13] [Eq. (2)], initiating the
J=7.4 Hz and 1.7 Hz), 7.79 (2H, dd, JH,H =8.7 Hz and JH,F
=
5.4 Hz); 13C NMR (75 MHz, CDCl3): d=101.9, 107.7, 109.8,
115.4 (d, JC,F =22 Hz), 126.6, 131.8, 132.3 (d, JC,F =9 Hz),
134.3, 148.0, 151.6, 165.1 (d, JC,F =252 Hz), 193.7; MS (IE,
70 eV): m/z=244 (M+, 73%), 149 (100%), 123 (36%), 95
(29%); HRMS: m/z=245.0607, calcd. for C14H10O3F:
245.0614.
In the case of hydroxy substituted arenes, the crude reac-
tion mixture was acidified with 10% aqueous HCl, the
aqueous phase extracted 3 times with CH2Cl2, the organic
phases dried over MgSO4 and concentrated.
Acknowledgements
The CNRS is gratefully acknowledged for financial support.
second catalytic cycle. b-Hydride elimination from the
generated alkoxo-rhodium(I) complex[14] would re-
lease the diaryl ketone and a rhodium(I) hydride spe-
cies.
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Conclusions
Thus, we have described the cross-coupling reaction
of organoboronic acids with aldehydes to access di-
À
rectly ketones under mild conditions via formal C H
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Experimental Section
Typical Procedure for Carbonylation of Arylboronic
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A
phenyl)methanone (Entry 10)
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A
nal 1e (0.5 mmol, 75 mg) in degassed dioxane (2 mL) was
added a solution of tri-tert-butylphosphane in degassed tolu-
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acetone (0.5 mL) under an argon atmosphere. After 30 min
stirring at room temperature, the flask was placed in a pre-
heated oil bath at 808C. The mixture was stirred until com-
pletion of the reaction (followed by GC analysis). After con-
centration under reduced pressure, the crude mixture was
purified by silica gel chromatography to afford the analyti-
cally pure ketone as a white solid; yield: 115.5 mg (85%).
1
CG: Rt =12.2 min; mp 1048C; H NMR (300 MHz, CDCl3):
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