Synthesis of biarylketones and phthalides from organoboronic acids and aldehydes catalyzed by cobalt complexes

Article abstract of DOI:10.1039/c1cc13771a

A cobalt-catalyzed addition of aryl- and alkenylboronic acids to aldehydes and phthalaldehyde to give the corresponding biarylketones and 3-aryl phthalides in good to excellent yields in one pot is described.

Full text of DOI:10.1039/c1cc13771a

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COMMUNICATION
Synthesis of biarylketones and phthalides from organoboronic acids and
aldehydes catalyzed by cobalt complexesw
Jaganathan Karthikeyan, Kanniyappan Parthasarathy and Chien-Hong Cheng*
Received 24th June 2011, Accepted 1st August 2011
DOI: 10.1039/c1cc13771a
A cobalt-catalyzed addition of aryl- and alkenylboronic acids to
aldehydes and phthalaldehyde to give the corresponding
biarylketones and 3-aryl phthalides in good to excellent yields
in one pot is described.
diarylmethanols.9h During the course of our investigation,
we noticed that the reaction of organoboronic acids with
aldehydes could give biarylketones under certain special reaction
conditions. Thus, treatment of 4-methoxycarbonylbenzaldehyde
(1a) with phenylboronic acid (2a) in the presence of CoCl2,
Biarylketones are important building blocks in both natural
products and functional materials.1 Several traditional syntheses
of these compounds have been reported.2,3 Of these approaches,
transition-metal-catalyzed direct synthesis of biaryl ketones
has emerged as a powerful method in organic synthesis.4 In this
context, Ishiyama and Hartwig observed a rhodium-catalyzed
intermolecular Heck-type reaction of aryl iodides with N-hetero-
cyclic aldimines to form the corresponding ketimines, which
give ketones upon hydrolysis.5 We also developed a Ni-catalyzed
synthesis of biarylketones from the coupling of aryl iodides with
aromatic aldehydes and the synthesis of polycyclic ketones from
the cyclization of o-iodophenyl ketones with bicyclic alkenes
via a facile b-alkyl elimination in the last step.6 Genet and
co-workers also developed a rhodium-catalyzed cross coupling
reaction of potassium trifluoro(organo)borates with arylalde-
hydes that led to the formation of diaryl ketones.7 Very recently,
Chen and co-workers reported the synthesis of diaryl ketones by
Cu(OTf)2-catalyzed arylation of arylboronic acids with alde-
hydes under an oxygen atmosphere.8 The development of
cheap, environmentally benign alternative catalysts is still
desirable. Recently, the use of cobalt complexes as inexpensive,
readily available, and environmentally friendly catalysts for
organic reactions has attracted considerable attention. Our
continued interest in the cobalt-catalyzed coupling reactions,9a–f
activation of boronic acids9g,h and synthesis of arylketones6,9i
prompted us to explore the possibility of using low-cost cobalt
complexes as the catalysts for cross coupling reactions. Herein
we wish to report a direct synthesis of biarylketones and
phthalides by the cobalt-catalyzed coupling of arylboronic
acids with aldehydes and phthalaldehyde via an addition and
b-hydride elimination strategy in a one-pot manner from
commercially available simple starting materials.
tmphen
(3,4,7,8-tetramethyl-1,10-phenanthroline)
and
Cs2CO3 in CH3CN/toluene (3/1) at 80 1C under 1 atm O2
for 12 h gave biarylketone 3a in 91% isolated yield (Table 1,
entry 1). In the absence of O2, the reaction also gave ketone
Table 1 Results of cobalt-catalyzed coupling of aldehydes and
arylboronic acidsa
Yieldb
(%)
Entry
1
2
Product
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
3a: R = 4-CO2Me, R1 = H 91
3b: R = 4-NO2, R1 = H
3c: R = 3-CN, R1 = H
3d: R = 4-CN, R1 = H
3e: R = 2-Me, R1 = H
3f: R = 4-Me, R1 = H
3g: R = 4-OMe, R1 = H
3h: R = 4-Br, R1 = H
3i: R = 4-Cl, R1 = H
3j: R = H, R1 = H
84
80
94
65
67
64
73
78
66
79
71
2a
7
8
9
1g
1h
1i
10
11
12
1j
1k
1l
3k: X = O, R1 = H
3l: X = S, R1 = H
2a
2a
13
1m
3m: Y = N, Z = C, R1 = H 83
14
1n
3n: Y = C, Z = N, R1 = H 81
15
16
17
18
19
2b
2c
2d
2e
2f
3o: R1 = 4-Me
3p: R1 = 2-OMe
3q: R1 = 3-OMe
3r: R1 = 4-OMe
3s: R1 = 4-Cl
83
61
80
78
83
1d
We have earlier reported a Co-catalyzed asymmetric addition
reaction of organoboronic acids with aldehydes to give
20
2g
3t: R1 = 4-F
83
a
Unless otherwise mentioned, all reactions were carried out using aldehyde
1 (1.00 mmol), arylboronic acid 2 (1.50 mmol), CoCl2 (0.10 mmol), tmphen
(0.15 mmol), Cs2CO3 (1.50 mmol) and CH3CN/toluene (3 : 1, 4 ml) at
80 1C for 12 h under O2 (1 atm at room temperature). b Isolated yields.
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013, Taiwan. E-mail: chcheng@mx.nthu.edu.tw;
Fax: +886-3-5724698; Tel: +886-3-5721454
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13771a
c
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3a, but in only ca. 50% yield. It is noteworthy that using
a phosphine ligand such as dppe, the catalytic reaction
afforded only the corresponding diaryl methanol. Product 3a
Table 2 Results of cobalt-catalyzed coupling of phthalaldehyde and
arylboronic acidsa
1
was characterized by its H, 13C NMR and mass data.
The presence of a nitrogen ligand was crucial to the reaction.
Various nitrogen ligands were examined to understand the
effect on the product yield. Among them, tmphen gave the best
result and afforded 3a in 91% yield. Other nitrogen ligands
including 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline,
tmeda, and 2,20-bipyridine are less effective, giving 3a in 61, 58,
31, and 38%, yield, respectively. No 3a was observed in the
absence of a cobalt complex, base or nitrogen ligands (see
ESIw for the detailed studies).
Under similar reaction conditions for the reaction of 1a with
2a, various electron-withdrawing substituted benzaldehydes
reacted smoothly with 2a to give the corresponding unsym-
metrical diarylketones. Thus, 4-NO2-, 3-CN-, and 4-CN-sub-
stituted benzaldehydes (1b–d) underwent addition and b-hydride
elimination reaction with 2a to give 3b–d in 84, 80 and 94%
yield, respectively (entries 2–4). Similarly, electron-donating
groups such as 2-Me-, 4-Me- and 4-Ome-substituted benzalde-
hydes (1e–g) also reacted smoothly with 2a to give diarylketones
3e–g, albeit in lower yields (entries 5–7). The present catalytic
reaction is also compatible with bromo and chloro substituents
on the aromatic ring of benzaldehyde 1. Thus, the reaction of
4-bromo- and 4-chloro-benzaldehyde 1h–i with 2a gave sub-
stituted diarylketones 3h and 3i in 73 and 78% yield (entries 8
and 9), respectively. Benzaldehyde (1j) also underwent addition
and elimination reaction with 2a to afford 3j in 66% yield
(entry 10). The scope of the catalytic reaction was extended to
heterocyclic aldehydes 1k–n. Treatment of 2-formylfuran (1k)
with 2a gave aryl ketone 3k in 79% yield (entry 11). Similarly,
the reaction of 2-formylthiophene (1l) with 2a afforded 3l in
71% yield (entry 12). In a similar manner, both 3-formyl and
4-formylpyridines 1m–n reacted efficiently with 2a to provide
the expected aryl ketones 3m and 3n in 83 and 81% yield,
respectively (entries 13 and 14). In addition to 2a, several other
substituted boronic acids were tested for the addition and
elimination reaction. Thus, 4-methyl-, 2-methoxy-, 3-methoxy-,
4-methoxy-, 4-chloro-, and 4-fluoro-phenylboronic acids (2b–g)
all reacted well with 4-cyanobenzaldehyde (1d) to produce
substituted biarylketones in good to excellent yields (entries
15–20). Alkenyl boronic acids including trans-2-phenyl- (2h),
trans-2-(4-trifluoromethylphenyl)- (2i) and trans-2-(4-chloro-
phenyl)-vinylboronic acid (2j) also reacted with 1d smoothly,
but giving unexpected hydrogenation products 3u, 3v and 3w
in 68, 76 and 71% yield, respectively (Scheme 1). In these
cases, K2CO3 was employed as the base instead of Cs2CO3 to
improve the product yields and the reactions were carried out
under a nitrogen atmosphere.
a
Unless otherwise mentioned, all reactions were carried out using
phthalaldehyde 1 (1.00 mmol), arylboronic acid 2 (1.50 mmol), CoI2
(0.050 mmol), dppe (0.050 mmol), K2CO3 (1.50 mmol) and THF
(3 mL) under O2 (1 atm at room temperature) for 12 h.
The present cobalt-catalyzed reaction was also tested for the
addition of aryl boronic acids to phthalaldehyde 1p. The
reaction of phthalaldehyde 1p with phenylboronic acid (2a)
in the presence of CoCl2, tmphen (3,4,7,8-tetramethyl-1,
10-phenanthroline) and Cs2CO3 in CH3CN/toluene (3/1) at
80 1C under 1 atm O2 gave phthalide derivative 4a in only 62%
yield along with phthalide (5a) in 28%. In order to increase the
yield of product 4a, we optimize the reaction by examining
different metal complexes, ligands and bases (see ESIw).
Finally, we found that the combination of CoI2, dppe and
K2CO3 under nitrogen is most effective giving 4a in 89%
isolated yield (Table 2, entry 1). It is interesting to note that
five-membered lactones are present in various natural
products that show a range of unique biological activities.10
A number of metal-catalyzed syntheses of phthalides have been
reported.11,12 We reported a series of nickel and cobalt-catalyzed
efficient syntheses of five, six, and seven-membered lactones11a–c
and chiral phthalides.11b Very recently, Cheng and co-workers
have developed rhodium and palladium-catalyzed cascade
reactions of phthalaldehyde with arylboronic acids leading
to the formation of phthalides.12 Among the methods
available, an addition and b-hydride elimination strategy for
the preparation of phthalides is extremely rare.
Under the optimized reaction conditions, a variety of
boronic acids reacted well with phthalaldehyde 1 to give the
corresponding phthalide 4 in good yields (Table 2). Thus,
boronic acids with an electron-donating group (2b, 2d–e) gave
4b–d in 92, 85 and 87% yields respectively. Phenylvinylboronic
acid (2h) also reacted smoothly. In contrast to the results
shown in Scheme 1, the carbon–carbon double bond in 2h, is
not hydrogenated. Similarly, treatment of 4-bromo, 3-chloro,
Scheme 1
c
10462 Chem. Commun., 2011, 47, 10461–10463
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Scheme 2
3-fluoro, 4-phenyl, and 4-vinyl boronic acids 2k–o with 1n
gave phthalide products 4f–j in 82, 83, 87, 84 and 71% yield,
respectively. Sterically bulkier 2-naphthylboronic acid 2p also
reacted smoothly with 1p to give phthalide 4k in high yield.
To account for the present cobalt-catalyzed reaction, a
possible reaction mechanism is proposed (Scheme 2) based
on the known metal-catalyzed Heck-type reactions and
arylketones synthesis.5–7 The transmetalation of phenylboronic
acid (2a) to Co(II) in the presence of Cs2CO3 leads to the
formation of an arylcobalt(II) species 6. Coordination of
aldehyde 7 followed by insertion into arylcobalt(II) species
gives intermediate 8. Then b-hydride elimination of intermediate
8 affords the final biarylketone 3a and Co–H species. The Co–H
species reacts with O2 to regenerate the active Co(II) species for
the next cycle.
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In conclusion, we have successfully developed an effective
method for the synthesis of biarylketones and 3-aryl phthalides
via a tmphen cobalt complex catalyzed addition and b-hydride
elimination of organoboronic acids with aldehydes. This
method provides an opportunity for the synthesis of various
unsymmetrical biarylketones and 3-aryl phthalides in one pot.
Further detailed investigation on the mechanism, the substrate
scope, and the application of this methodology in natural
product synthesis are in progress.
We thank the National Science Council of Republic of
China (NSC-99-2119-M-007-010) for support of this research.
Notes and references
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c
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Chem. Commun., 2011, 47, 10461–10463 10463