Beyond benzoin condensation: Trimerization of aldehydes via metal-free aerobic oxidative esterification of aldehydes with benzoin products in the presence of cyanide

Article abstract of DOI:10.1021/ol5008845

An unusual trimerization of aldehydes in the presence of cyanide via metal-free aerobic oxidative esterification under ambient conditions is described. Various aromatic aldehydes provided the corresponding oxidative esterification products in good to excellent yields. Mechanistic studies suggested that this reaction would proceed via a two-step sequence: cyanide-catalyzed benzoin condensation of aldehydes and subsequent aerobic oxidative esterification of aldehydes with the resultant benzoin products. The usefulness of this protocol was further demonstrated by converting the resulting trimeric products into other biologically important compounds.

Full text of DOI:10.1021/ol5008845

Letter
pubs.acs.org/OrgLett
Beyond Benzoin Condensation: Trimerization of Aldehydes via
Metal-Free Aerobic Oxidative Esterification of Aldehydes with
Benzoin Products in the Presence of Cyanide
Yoo-Jin Kim, Na Yeun Kim, and Cheol-Hong Cheon*
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 136713, Republic of Korea
S
* Supporting Information
ABSTRACT: An unusual trimerization of aldehydes in the
presence of cyanide via metal-free aerobic oxidative
esterification under ambient conditions is described. Various
aromatic aldehydes provided the corresponding oxidative
esterification products in good to excellent yields. Mechanistic
studies suggested that this reaction would proceed via a two-
step sequence: cyanide-catalyzed benzoin condensation of
aldehydes and subsequent aerobic oxidative esterification of aldehydes with the resultant benzoin products. The usefulness of this
protocol was further demonstrated by converting the resulting trimeric products into other biologically important compounds.
ince the cyanide-catalyzed benzoin condensation1 is an
benzofused azole compounds in the presence of NaCN.
Mechanistic studies suggested that the trimeric products would
be formed via the two-step sequence: the cyanide-catalyzed
benzoin condensation of aldehydes and subsequent aerobic
oxidative esterification of aldehydes with the resulting benzoin
condensation products. Furthermore, the usefulness of this new
transformation was demonstrated by converting the resulting
trimeric compounds into other useful products, which might be
difficult to be achieved directly from the benzoin condensation
products in some cases.
S
important C−C bond formation reaction between
aldehydes leading to the construction of synthetically useful
α-hydroxyketones (Scheme 1a), this reaction has been
Scheme 1. Dimerization of Aldehydes (Benzoin
Condensation) and Trimerization of Aldehydes (This Work)
Recently, we developed an efficient method for the synthesis
of benzoxazoles under aerobic oxidative cyclization conditions
without the assistance of any metal cocatalysts using cyanide as
a nucleophilic catalyst by converting disfavored 5-endo-trig
cyclization of imines into favored 5-exo-tet cyclization.8 In the
continued effort to develop environmentally benign protocols for
the synthesis of biologically important heteroaromatic com-
pounds,8,9 we attempted to extend this nucleophile-catalyzed
aerobic oxidation protocol to the synthesis of quinazolinones
from anthranilamide and aldehydes.10 When anthranilamide 2
and benzaldehyde 1a were applied to the reaction conditions8
previously used for the preparation of benzoxazoles, the expected
quinazolinone 3 was not observed; instead, an unexpected
compound was obtained as the major product. After careful
structural analysis, the unexpected product was assigned to be
benzoylated benzoin product 4a, a trimeric compound of 1a
presumably via aerobic oxidative esterification (Scheme 2).11
With this rather unexpected result in hand, we were surprised
to find that although several examples of oxidative esterification
of aldehydes in the presence of cyanide were reported, most of the
previous methods must be carried out in the presence of oxidants12
and there have been few reports of aerobic oxidative esterification
extensively investigated by many research groups for decades.
The mechanism of this reaction, initially proposed by Lapworth
in 1903,2 and affirmed by Schowen’s group,3 is now generally
accepted by the chemical community.4,5 In contrast, most of
the mechanistic studies have focused on the elucidation of the
role of cyanide as a nucleophilic catalyst and there have been
few reports about the exact role of other reaction parameters.5
For example, although the reaction rate for benzoin condensation
was significantly enhanced in polar aprotic solvents, such as
dimethyl sulfoxide (DMSO),5,6 the exact role of DMSO in
benzoin condensation has been poorly understood.7
Here, we report the cyanide-mediated trimerization of
aldehydes in polar aprotic solvents, such as DMSO and
DMF, in an open flask under ambient conditions via metal-free
aerobic oxidative esterification of aldehydes (Scheme 1b). This
result was based on our recent findings of the unexpected
formation of trimeric compounds of aldehydes under the oxidative
cyclization conditions8 previously used for the synthesis of
Received: March 25, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Unexpected Formation of Compound 4a
We suspected that 6d might be formed through the
hydrolysis of an intermediate for the oxidative esterification
of 1d. In order to avoid the unwanted hydrolysis, we carried out
this reaction in the presence of molecular sieves (entry 8).
Delightfully, the yield of 4d was significantly increased in the
presence of molecular sieves. Furthermore, lowering the
reaction temperature had a beneficial effect on the suppression
of the direct oxidation of aldehyde to the corresponding
carboxylic acid (entries 8−10). To our surprise, this reaction
proceeded even at rt to afford the desired product in 83% yield
(entry 10). Next, we examined the amount of cyanide and
found that it has a strong influence on this transformation
(entries 10−14). The yield of 4d increased with the amount of
cyanide when a substoichiomeric amount of cyanide was used
(entries 11 and 12), and it reached a plateau after 3 equiv of
cyanide (entries 10 and 14). Thus, we decided to use 3 equiv of
cyanide for further investigation.
in the presence of cyanide without any aid of cooxidant.13 Even
more surprisingly, although cyanide-catalyzed benzoin condensa-
tion had been extensively investigated for over a century,1−4 this
type of trimerization of aldehydes in the cyanide-catalyzed benzoin
reaction has never been reported. Thus, we decided to investigate
this unusual trimerization of an aldehyde through aerobic oxidative
esterification in the presence of cyanide.14−16
Using para-tolualdehyde 1d as a model compound, we first
attempted to investigate the reaction parameters controlling
this trimerization (Table 1). Initially, we suspected that
Table 1. Optimization of Reaction Conditions
Under these optimized conditions, the substrate scope of
aldehydes for this transformation was investigated (Table 2).
Table 2. Substrate Scope
a
entry
solvent
NaCN (x equiv) temp (°C) time (h) conversion
b
1
DMSO
DMSO
DMF
3
3
100
100
100
100
100
100
100
100
70
4
100
d
2
3
4
5
6
7
4
100 (30)
100
3
6
EtOH
3
24
24
24
24
4
N.R.
a
entry
products
Ar
time (h)
yield (%)
H2O
3
N.R.
1
2
3
4a
4b
4c
4d
4e
4f
Ph
12
72
24
24
12
5
63
N.R.
71
83
45
52
96
87
90
30
57
67
53
83
72
71
45
82
dioxane
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
N.R.
4-(Me2N)Ph
4-MeOPh
4-MePh
3
N.R.
c
d
d
d
8
c
3
100 (51)
100 (65)
100 (83)
b
4
9
3
8
b
c
5
4-ClPh
10
3
rt
24
24
24
24
24
b
c
d
6
4-BrPh
11
0.5
1
rt
− (19)
− (39)
− (62)
− (82)
b
c
d
7
4g
4h
4i
3-MeOPh
3,5-(MeO)2Ph
3-MePh
8
12
rt
b
c
d
8
8
13
2
rt
c
d
9
6
14
4
rt
a
1
10
4j
3-ClPh
5
Conversion was determined by H NMR analysis of 1d remained in
the crude mixture. With 3 equiv of 2. In the presence of 4 Å
molecular sieves. The value in parentheses was the isolated yield
b
b
c
11
4k
4l
2-MeOPh
2-MePh
8
d
12
13
14
15
16
17
6
4m
4n
4o
4p
4q
4d
2-ClPh
5
of 4d.
2-furyl
3
2-thienyl
2-naphthyl
1-naphthyl
4-MePh
3
anthranilamide 2 might play some role in this transformation.
When the reaction was carried out in the absence of 2, however,
1d was still completely consumed, which led us to conclude
that anthranilamide 2 had no effect on the formation of trimeric
compound 4d (entries 1 and 2). Then, the solvent effect on this
transformation was examined (entries 2−7). Interestingly, the
choice of solvent turned out to have a strong influence on the
reactivity of this transformation. 1d was completely consumed
in DMSO and DMF (entries 2 and 3), whereas no reaction was
observed in any other solvent (entries 4−7). Since the reaction
proceeded slightly faster in DMSO than in DMF, DMSO was
chosen as the solvent of choice for further investigation.
At that moment, however, we encountered a rather serious
problem in reproducing the yield of trimeric compound 4d.
Although aldehyde 1d was completely consumed, 4d was
obtained in moderate yield along with a significant amount of
the corresponding carboxylic acid 6d (eq 1).17
15
15
24
c
18
a
b
Isolated yield of 4. In the presence of 100 mg of 4 Å molecular
c
sieves. On 30 mmol scale.
Various aromatic aldehydes could be applied to this protocol
and afforded the desired trimeric products 4 in moderate to
high yields. Interestingly, the electronic natures of the
substituents on the aromatic ring system had a significant
influence on the efficiency of this transformation. Aromatic
aldehydes bearing a strong electron-donating amino group at
the para-position did not undergo this transformation (entry 2),
whereas moderate electron-rich aromatic aldehydes provided
the desired products in good to high yields (entries 1 and 3−4).
On the other hand, aldehydes carrying electron-withdrawing
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substituents generated the desired products in only moderate
yields and a significant amount of the corresponding carboxylic
acids were obtained via direct oxidation of aldehydes (entries 5
and 6). Substituents at the meta-positions of aldehydes displayed a
similar trend in reactivity as ones with the para-substituents
(entries 7−10). Electron-rich aldehydes afforded the desired
products in high yields (entries 7−9), while an aldehyde bearing
an electron-withdrawing substituent afforded the desired product
in a low yield and a significant amount of the corresponding
benzoic acid derivative was obtained (entry 10).14 The steric bulk
of aldehydes had a harmful effect on the formation of the desired
products 4. Aromatic aldehydes bearing a substituent at the
ortho-position provided the desired products in only moderate
yields regardless of the electronic natures of the substituents
(entries 11−13). Heteroaromatic aldehydes and fused aromatic
aldehydes, such as naphthyl aldehydes, could be applied to
this protocol (entries 14−17). Furthermore, the protocol could
be performed at a 30 mmol scale without sacrificing efficiency
(entry 18).
With these rather unexpected results in hand, we performed
several experiments to gain information about the reaction
mechanism for this trimerization of aldehydes. Since the
cyanide-catalyzed benzoin reaction is well-known,1−4 we first
suspected that a trimeric product 4 might be formed through
the corresponding benzoin condensation product 5 as the key
intermediate. When a 1:1 mixture of benzoin product 5a and
aldehyde 1a was subjected to the standard reaction conditions,
the corresponding trimer 4a was obtained in a yield comparable
to that from the aldehyde (eq 2).
condensation between benzoin product 5a and benzoic acid 6a
under standard conditions (eq 5). However, when 5a and 6a
were subjected to the optimized conditions, no formation of 4a
was observed, which led us to rule out this possibility.
Based on this result, we assumed that 4 would be generated
by the reaction of the benzoin product with an activated
benzoic acid derivative in situ generated from aldehyde in
the presence of cyanide under aerobic oxidation conditions.
Since there have been a few reports of oxidative esterification
in the presence of cyanide via benzoyl cyanide 7 as the key
intermediate,12 we assumed that this reaction might also
proceed through benzoyl cyanide 7. To test this possibility, we
performed the reaction between benzoin product 5a with
benzoyl cyanide 7 (eq 6). To our delight, the reaction of
benzoin product 5a with benzoyl cyanide 7 afforded the
trimeric compound 4a in high yield.
Based on these results, we proposed the trimerization of
aldehydes (Scheme 3). Cyanohydrin intermediate I, initially
formed by cyanide addition to aldehyde 1, undergoes normal
Scheme 3. Proposed Reaction Mechanism
Then, we moved our attention to the oxidative esterification
step. When the reaction was performed under an argon
atmosphere, benzoin condensation product 5a was obtained as
the major product along with a trace amount of 4a (eq 3).18
Furthermore, when 1a was added to the above reaction mixture
and then the reaction mixture was exposed to air, however, the
oxidative esterification again took place to afford 4a in high
yield (eq 4). These results strongly suggested that the
cyanide-catalyzed benzoin condensation to afford compound 5.
Under aerobic oxidation conditions, intermediate I could also
undergo oxidation to yield benzoyl cyanide 7. Subsequent
reaction between 5 and 7 might lead to trimeric compound 4.
The proposed reaction mechanism could explain several of
the observed experimental results. Under an argon atmosphere,
benzoin condensation product 5 was obtained as the major
product along with a trace amount of trimeric products 4 (eq 3).
Since it is impossible for aldehyde 1 to undergo aerobic
oxidation to afford benzoyl cyanide 7 under such conditions,
benzoin product 5 was obtained as the major product and no
formation of 4 was observed. Furthermore, we also observed
that the formation of benzoic acid 6 was observed under the
standard conditions using wet organic solvents. Since water
could compete with the benzoin product toward 7, a significant
amount of 6 was observed in wet DMSO. However, molecular
trimerization of an aldehyde would proceed through a benzoin
condensation product of the aldehyde, followed by aerobic
oxidative esterification of aldehyde with the resulting benzoin
condensation product.
Next, we focused on the elucidation of an activated
carboxylic acid derivative from aldehyde during aerobic
oxidative esterification step. Since carboxylic acid was observed
during the optimization of the reaction conditions, we first
examined the possibility of the ester bond formation from the
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(2) (a) Lapworth, A. J. Chem. Soc. 1903, 83, 995. (b) Lapworth, A. J.
Chem. Soc. 1904, 85, 1206.
(3) Kuebrich, J. P.; Schowen, R. L.; Wang, M.-S.; Lupes, M. E. J. Am.
sieves efficiently remove water from the reaction mixture, which
suppresses the formation of benzoic acid 6.
With these results in hand, we further demonstrated the
usefulness of this protocol by converting the resulting trimeric
products into other useful compounds. When 4a was treated
with thiourea in DMF under an elevated temperature, the
corresponding oxazole 8 was obtained in excellent yield (eq 7).19
Chem. Soc. 1971, 93, 1214.
(4) For a review of the benzoin reaction, see: Hassner, A.; Rai, K. M.
L. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, U.K., 1991; p 541.
(5) The Breslow group investigated salt effects on the rate of the
cyanide-catalyzed benzoin condensation in an aqueous system; see:
(a) Breslow, R.; Connors, R. V. J. Am. Chem. Soc. 1995, 117, 6601.
(b) Kool, E. T.; Breslow, R. J. Am. Chem. Soc. 1988, 110, 1596.
(c) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(6) Safari, J.; Arani, N. M.; Isfahani, A. R. Asian J. Chem. 2011, 23,
495.
(7) For theoretical studies on the cyanide-catalyzed benzoin reaction
in DMSO, see: He, Y.; Xue, Y. J. Phys. Chem. A 2010, 114, 9222.
(8) (a) Cho, Y.-H.; Lee, C.-Y.; Ha, D.-C.; Cheon, C.-H. Adv. Synth.
Catal. 2012, 354, 2992. (b) Cho, Y.-H.; Lee, C.-Y.; Cheon, C.-H.
Tetrahedron 2013, 69, 6565.
Furthermore, when 4h was irradiated (365 nm) under
ambient conditions, the resulting benzofuran 9 was obtained in
high yields (eq 8).20 However, when the corresponding
(9) Cho, Y.-H.; Kim, K.-H.; Cheon, C.-H. J. Org. Chem. 2014, 79,
901.
(10) For the synthesis of quinazolinones via aerobic oxidation, see:
Kim, N. Y.; Cheon, C.-H. Tetrahedron Lett. 2014, 55, 2340.
(11) For a review on oxidative esterification of aldehydes, see: Ekoue-
Kovi, K.; Wolf, C. Chem.Eur. J. 2008, 14, 6302.
(12) (a) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616. (b) Castells, J.; Pujol, F.; Llitjos, H.; Moreno-Manas,
́
̃
M. Tetrahedron 1982, 38, 337. (c) Shinkai, S.; Ide, T.; Manabe, O.
Chem. Lett. 1978, 7, 583. (d) Raj, I. B. P.; Sudalai, A. Tetrahedron Lett.
benzoin product was subjected to the same reaction conditions,
no desired benzofuran product 9 was observed.
2005, 46, 8303. (e) Castells, J.; Moreno-Manas, M.; Pujol, F.
̃
In conclusion, we have described an unusual trimerization of
aldehydes in the presence of cyanide in an open flask in the
absence of any metal catalysts and co-oxidants. Various
aromatic aldehydes provided the trimeric compounds in good
to excellent yields. Mechanistic studies suggested that the
trimers of aldehydes would be formed via the cyanide-catalyzed
benzoin reaction, followed by aerobic oxidative esterification
between the resulting benzoin products and aldehydes in the
presence of cyanide. The usefulness of this protocol was further
demonstrated in the direct transformation of the resulting
products into other biologically useful compounds.
Tetrahedron Lett. 1978, 19, 385.
(13) Atta, A. K.; Kim, S.-B.; Cho, D.-G. Bull. Korean Chem. Soc. 2011,
32, 2070.
(14) Conventionally, trimeric compounds 4 are prepared through a
condensation reaction of benzoin condensation products 5 with the
corresponding carboxylic acids and their derivatives. For recent
examples, see: (a) Sarvari, M. H.; Sharghi, H. Tetrahedron 2005, 61,
10903. (b) Liu, Y.; Wang, X.; Zhang, Y. Synth. Commun. 2004, 34,
4009. (c) Baltork, I. M.; Aliyan, H.; Khosropour, A. R. Tetrahedron
2001, 57, 5851.
(15) Similar oxidative esterification of 1a leading to 4a was reported
using an NHC carbene as a catalyst in the presence of oxidants,
although the yield of 4a was quite low; see: (a) Iwahana, S.; Iida, H.;
Yashima, E. Chem.Eur. J. 2011, 17, 8009. (b) Orsini, M.; Chiarotto,
I.; Elinson, M. N.; Sotgiu, G.; Inesi, A. Electrochem. Commun. 2009, 11,
1013.
(16) Trimeric compounds 4 were also prepared via cyanobenzoy-
lation of aldehydes 1; see: (a) Watahiki, T.; Ohba, S.; Oriyama, T. Org.
Lett. 2003, 5, 2679. (b) Iwanami, K.; Hinakubo, Y.; Oriyama, T.
Tetrahedron Lett. 2005, 46, 5881.
(17) The sodium salt of 6d was obtained in the reaction mixture,
which is soluble in aqueous solution.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cheon@korea.ac.kr.
Notes
(18) The formation of 4a under an argon atmosphere would be
presumably due to oxidative esterification of oxygen remaining in the
solvent.
(19) Loner, C. M.; Luzzio, F. A.; Demuth, D. R. Tetrahedron Lett.
2012, 53, 5641.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) McCoy, C. P.; Rooney, C.; Edwards, C. R.; Jones, D. S.;
Gorman, S. P. J. Am. Chem. Soc. 2007, 129, 9572.
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT and Future Planning
(2013R1A1A1008434). C.H.C. is also thankful for the financial
support from the NRF fund by the Ministry of Education
(NRF20100020209).
REFERENCES
■
(1) For seminal reports of the cyanide-catalyzed benzoin reaction,
see: (a) Wohler, F.; Liebig. J. Ann. Pharm. 1832, 3, 249. (b) Adams, R.;
Marvel, C. S. Org. Synth. 1921, 1, 33.
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