Synthesis of arylketones by ruthenium-catalyzed cross-coupling of aldehydes with arylboronic acids

Article abstract of DOI:10.1039/c1cc12843d

The first ruthenium-catalyzed cross-coupling of aldehydes with arylboronic acids is reported. Various aliphatic and aromatic aldehydes are transformed to the corresponding arylketones. A total of 31 examples with moderate to excellent yields are presented, together with the results of an initial mechanistic investigation.

Full text of DOI:10.1039/c1cc12843d

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Synthesis of arylketones by ruthenium-catalyzed cross-coupling of
aldehydes with arylboronic acidsw
Hong Li,a Yuan Xu,a Erbo Shi,a Wei Wei,a Xiangqiang Suoa and Xiaobing Wan*ab
Received 15th May 2011, Accepted 31st May 2011
DOI: 10.1039/c1cc12843d
The first ruthenium-catalyzed cross-coupling of aldehydes with
arylboronic acids is reported. Various aliphatic and aromatic
aldehydes are transformed to the corresponding arylketones. A
total of 31 examples with moderate to excellent yields are
presented, together with the results of an initial mechanistic
investigation.
ketones upon hydrolysis.9 One example of a ruthenium-catalyzed
arylation of aldehydes with arylboronic acids to form alcohol
was recently published by Yamamoto and Miyaura et al.10
However, to the best of our knowledge, direct cross-coupling
of arylboronic acids with aldehydes to form ketones, catalyzed
by ruthenium complexes, has not been reported to date.11 We
expect this alternative strategy may open up a new pathway
for preparation of ketones. Furthermore, not unimportantly,
ruthenium is much cheaper than rhodium.
As part of our investigations into Ru chemistry,12
we initially examined coupling of benzaldehyde (1a) with
4-methoxyphenylboronic acid (2a) to furnish aryl ketone,
using ruthenium complexes. After exploring a wide array of
conditions, we determined that 2.5 mol% [Ru(CO)3Cl2]2/10 mol%
t-Bu3PÁHBF4/2.0 equiv. pinacolone/2.0 equiv. K3PO4Á3H2O
in toluene/H2O at 100 1C furnishes an excellent yield (91%)
of the desired cross-coupling product 3a (Table 1, entry 1).
Table 1 provides information on the impact of various reaction
parameters on the efficiency of this new cross-coupling
process. As expected, in the absence of a ruthenium catalyst,
no cross-coupling occurs (Table 1, entry 2). Replacement of
[Ru(CO)3Cl2]2 with [Ru(cymene)Cl2]2 or RuCl3 leads to a drop
in yield (Table 1, entries 3 and 4). Without phosphine addition,
the conversion is low, giving only trace amounts of product 3a
(Table 1, entry 5). Notably, the use of PCy3, PCy3ÁHBF4 or
PPh3 lowered the yield (Table 1, entries 6–8), and dppe
retarded the reaction (Table 1, entry 9). In addition, the
presence of base is essential for this transformation (Table 1,
entry 10). Finally, replacement of pinacolone with acetone
resulted in decreased yield (Table 1, entry 11).
Arylketones occur widely in a myriad of compounds of
pharmaceutical, agrochemical, biological, and materials of
interest. They also represent versatile intermediates for further
transformations in synthetic chemistry.1 Conventional routes
to the synthesis of arylketones have relied heavily upon
Friedel–Crafts acylations of arenes.2 Common drawbacks of
these processes are tedious procedures involved, and more
importantly, low regioselectivity and functional group tolerance.
In view of these shortcomings, alternative synthetic strategies
for arylketones have been actively pursued. Recent research
efforts have resulted in significant achievements in this field.
Hydroacylation of olefins represents one of the most promising
methods for producing ketones,3 although it generally requires
chelation assistance to suppress undesired decarbonylation
reaction. Heck-type reaction of aryl halides with aldehydes
offers another efficient approach. However, initial results have
been limited to aryl iodide and have afforded alkyl aryl ketones
in low yields.4 Recently, Xiao and co-workers reported the
elegant palladium-catalyzed coupling of aldehydes with aryl
bromides or chlorides, resulting in alkyl aryl ketones in good
yields.5 In addition, Hartwig et al. developed acylation of aryl
halides with N-pyrazyl aldimines or N-tert-butylhydrazones,
followed by hydrolysis.6
Recently, Genet7 and others,8 in their pioneering work,
developed rhodium-catalyzed coupling of aryl boron reagents
with aldehydes. Using chelation assistance strategy, Jun et al.
described ruthenium-catalyzed coupling of aldimines with
arylboronates to form aromatic ketimines, which generate
The scope of the coupling of aldehydes with 4-methoxy-
phenylboronic acid (2a) is summarized in Table 2. Both
aliphatic and aromatic aldehydes can be successfully converted
to the corresponding ketones. The reaction tolerates a wide
range of substituents on aromatic nuclei, for example halide,
CF3, nitrile, nitro, amine, BocO, OTs, and ether. Notably,
ortho substituted aromatic aldehydes also participated in the
transformation and the desired products were obtained
in satisfactory yields (Table 2, products 3g and 3h). In the
case of heteroarene aldehydes, that is, 2-furaldehyde and
2-thiophenaldehyde, the coupling products were obtained in
96% and 45% yields, respectively (Table 2, products 3o and 3s).
The scope of boronic acids was then investigated using
4-chlorobenzaldehyde as a coupling partner. These results
a Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China.
E-mail: wanxb@suda.edu.cn; Fax: +86-0512-65880890;
Tel: +86-0512-65880334
b Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and characterization data for 3a–3w, 4a–4h,
5. See DOI: 10.1039/c1cc12843d
c
7880 Chem. Commun., 2011, 47, 7880–7882
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Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Ligand
Additive
Base
Yieldb
1
2
3
4
5
6
7
8
[Ru(CO)3Cl2]2
—
[Ru(cymene)Cl2]2
RuCl3
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
[Ru(CO)3Cl2]2
t-Bu3PÁHBF4
t-Bu3PÁHBF4
t-Bu3PÁHBF4
t-Bu3PÁHBF4
—
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
t-BuCOMe
MeCOMe
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
K3PO4Á3H2O
—
91%
N.O.c
83%
Trace
Trace
44%
37%
13%
Trace
N.O.c
82%d
PCy3
PCy3ÁHBF4
PPh3
dppe
9
10
11
t-Bu3PÁHBF4
t-Bu3PÁHBF4
K3PO4Á3H2O
a
Reaction conditions: benzaldehyde (0.5 mmol), 4-methoxyphenylboronic acid (1.25 mmol), catalyst (0.0125 mmol), ligand (0.05 mmol),
b
pinacolone (1.0 mmol), K3PO4Á3H2O (1.0 mmol) in 2.0 mL toluene and 0.2 mL water at 100 1C for 24 h unless noted otherwise. Isolated yield.
c
d
Not observed. In a sealed tube.
Table 2 Cross-coupling of aldehydes with 4-methoxyphenylboronic
acida
Table 3 Cross-coupling of 4-chlorobenzaldehyde with boronic acidsa
a
Reaction conditions: aldehyde (0.5 mmol), 4-methoxyphenylboronic
acid (1.25 mmol), catalyst (0.0125 mmol), ligand (0.05 mmol),
pinacolone (1.0 mmol), K3PO4Á3H2O (1.0 mmol) in 2.0 mL toluene
and 0.2 mL water at 100 1C for 24 h unless noted otherwise.
secondary alcohol 5 were achieved with an excellent combined
yield, which implies that secondary alcohols may serve as
reaction intermediates in the transformation (eqn (1), see
supporting informationw). Subjecting secondary alcohol 5 to
the reaction, the desired ketone 3a was generated in high yield
(eqn (2), see supporting informationw).
The kinetic isotope effect (KIE) was investigated under the
standard reaction conditions. This small isotopic effect
(KIE = 1.06) was observed in the transformation (eqn (3),
see supporting informationw). In addition, no decarbonylation
was observed in the transformation,13 which implies that
aldehyde C–H activation is not involved in the catalytic cycle.
Further experiments were carried out to elucidate the
mechanism. In competition experiments carried out using 5 and
D-5, measurement of deuterium (KIE = 3.13) suggests that
hydrogen abstraction from alcohol is probably rate-limiting
during the transformation (eqn (4), see supporting informationw).
a
Reaction conditions: aldehyde (0.5 mmol), 4-methoxyphenylboronic
acid (1.25 mmol), catalyst (0.0125 mmol), ligand (0.05 mmol),
pinacolone (1.0 mmol), K3PO4Á3H2O (1.0 mmol) in 2.0 mL toluene
b
and 0.2 mL water at 100 1C for 24 h unless noted otherwise. 48 h.
indicate that boronic acids with electron-withdrawing or electron-
donating groups proceeded well and the desired coupling
products were obtained in moderate to high yields (Table 3).
Complete conversion of benzaldehyde 1a was observed
under the optimized conditions for 0.5 h. Ketone 3a and
Based upon the above results and literatures,7
a
plausible mechanism was proposed, as outlined in Scheme 1.
c
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Notes and references
1 (a) H. G. Franck and J. W. Stadelhofer, Industrial Aromatic Chemistry,
Springer-Verlag, Berlin, 1988; (b) D. Astruc, Modern Arene Chemistry,
Wiley-VCH, Weinheim, Germany, 2002; (c) H. Surburg and J. Panten,
Common Fragrance and Flavor Materials, Wiley-VCH, Weinheim,
Germany, 5th edn, 2006.
2 (a) G. A. Olah, Friedel–Crafts Chemistry, Wiley, New York,
1973; (b) G. Sartori and R. Maggi, Advances in Friedel–Crafts
Acylation Reactions: Catalytic and Green Processes, CRC Press,
2009; (c) N. J. Lawrence, J. Chem. Soc., Perkin Trans. 1, 1998,
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3 (a) H. M. Colquhoun, D. J. Thomson and M. V. Twigg,
Carbonylation: Direct Synthesis of Carbonyl Compounds, Plenum,
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Acc. Chem. Res., 2008, 41, 222; (c) M. C. Willis, Chem. Rev., 2010,
110, 725; (d) K. Hirano, A. T. Biju, I. Piel and F. Glorius, J. Am.
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Chem., 2002, 67, 1682; (b) T. Satoh, T. Itaya, M. Miura and
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Organometallics, 2009, 28, 1480; (f) M. Padmanaban, A. T. Biju
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B. C. Ranu, Tetrahedron Lett., 2010, 51, 3811.
Scheme 1 Plausible catalytic cycle.
5 (a) J. Ruan, O. Saidi, J. A. Iggo and J. Xiao, J. Am. Chem. Soc.,
2008, 130, 10510; (b) P. Colbon, J. Ruan, M. Purdie and J. Xiao,
Org. Lett., 2010, 12, 3670.
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122, 12043; (b) A. Takemiya and J. F. Hartwig, J. Am. Chem. Soc.,
2006, 128, 14800.
7 (a) M. Pucheault, S. Darses and J.-P. Genet, J. Am. Chem. Soc.,
2004, 126, 15356; (b) G. Mora, S. Darses and J.-P. Genet, Adv.
Synth. Catal., 2007, 349, 1180.
8 (a) N. Imlinger, M. Mayr, D. Wang, K. Wurst and
M. R. Buchmeiser, Adv. Synth. Catal., 2004, 346, 1836;
(b) N. Imlinger, K. Wurst and M. R. Buchmeiser, J. Organomet.
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Commun., 2004, 1192.
This mechanism includes (1) transmetalation of boronic acid
to [Ru(CO)3Cl2]2 to form an arylruthenium complex A,14 (2)
insertion of aldehyde into the ruthenium-carbon bond to give
an alkoxo-ruthenium intermediate B, (3) b-hydride elimination
from B, a rate-determining step, to release the diaryl ketone
and hydridoruthenium complex C, (4) insertion of pina-
colone into the ruthenium-hydrogen bond to give an alkoxo-
ruthenium intermediate D, (5) transmetalation of boronic acid
to intermediate D, allowing the regeneration of arylruthenium
complex A.
Further experiments were performed to verify the presumed
catalytic pathways. Recently, Darses and Genet reported
Rh-catalyzed cross-coupling of aldehydes with boron reagents
to access ketones. In the absence of base, secondary alcohol,
instead of ketone, was observed in the transformation.7b The role
of base was the regeneration of an alkoxo-rhodium intermediate.
In sharp contrast, both secondary alcohol and ketone were
achieved even in the absence of base in our transformation
(eqn (6), see supporting informationw). This suggests that base
is not essential for generation of arylruthenium intermediate A or
regeneration of alkoxo-ruthenium intermediate B.
9 Y. J. Park, E.-A. Jo and C.-H. Jun, Chem. Commun., 2005, 1185.
10 Y. Yamamoto, K. Kurihara and N. Miyaura, Angew. Chem., Int. Ed.,
2009, 48, 4414.
11 Examples using other transition-metal-catalysts have also been
reported by several groups, see: (a) C. Qin, J. Chen, H. Wua,
J. Cheng, Q. Zhang, B. Zuo, W. Su and J. Ding, Tetrahedron Lett.,
2008, 49, 1884; (b) F. Weng, C. Wang and B. Xu, Tetrahedron
Lett., 2010, 51, 2593; (c) Y. Liao and Q.-S. Hu, J. Org. Chem.,
2010, 75, 6986.
12 H. Li, W. Wei, Y. Xu, C. Zhang and X. Wan, Chem. Commun.,
2011, 47, 1497.
13 For representative examples on this topic, see: (a) K. P. Vora,
C. F. Lochow and R. G. Miller, J. Organomet. Chem., 1980,
192, 257; (b) T. B. Marder, D. C. Roe and D. Milstein,
Organometallics, 1988, 7, 1451; (c) D. P. Fairlie and B. Bosnich,
Organometallics, 1988, 7, 936; (d) C. P. Legens, P. S. White and
M. Brookhart, J. Am. Chem. Soc., 1998, 120, 6965; (e) T. Kondo,
N. Hiraishi, Y. Morisaki, K. Wada, Y. Watanabe and T. Mitsudo,
Organometallics, 1998, 17, 2131.
Reduction product, 2-naphthalenemethanol, was achieved
in 29% yield in the absence of pinacolone, which implies that
the insertion of 2-naphthaldehyde into the ruthenium-hydrogen
bond of hydridoruthenium complex C is involved in the
transformation (eqn (7), see supporting informationw).
In summary, we have described a new protocol for synthesis
of arylketones by ruthenium-catalyzed cross-coupling of
aldehydes with arylboronic acids. The reaction is effective
for aliphatic and aromatic aldehydes. More detailed investigations
into mechanisms and further applications of this methodology
are now in progress in our laboratory.
14 For transmetalation of boron compound to ruthenium complex,
see: (a) F. Kakiuchi, S. Kan, K. Igi, N. Chatani and S. Murai,
J. Am. Chem. Soc., 2003, 125, 1698; (b) F. Kakiuchi, M. Usui,
S. Ueno, N. Chatani and S. Murai, J. Am. Chem. Soc., 2004,
126, 2706; (c) F. Kakiuchi, Y. Matsuura, S. Kan and N. Chatani,
J. Am. Chem. Soc., 2005, 127, 5936; (d) S. J. Pastine, D. V. Gribkov
and D. Sames, J. Am. Chem. Soc., 2006, 128, 14220; (e) see ref. 11
and 12.
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7882 Chem. Commun., 2011, 47, 7880–7882
This journal is The Royal Society of Chemistry 2011