I2-promoted cross-dehydrogenative coupling of α-carbonyl aldehydes with alcohols for the synthesis of α-ketoesters

Article abstract of DOI:10.1039/c4ra06028h

A facile and efficient method for the synthesis of α-ketoesters from alcohols and α-carbonyl aldehydes has been developed at room temperature under metal-free conditions for the first time. Various alcohols and α-carbonyl aldehydes could participate in this reaction to afford the desired products in excellent yields. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra06028h

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I2-promoted cross-dehydrogenative coupling of
a-carbonyl aldehydes with alcohols for the
synthesis of a-ketoesters†
Cite this: RSC Adv., 2014, 4, 37047
Received 20th June 2014
Accepted 6th August 2014
*
A. Sagar, Shinde Vidyacharan and Duddu S. Sharada
DOI: 10.1039/c4ra06028h
www.rsc.org/advances
A facile and efficient method for the synthesis of a-ketoesters from oxygen. The previous studies mainly focused on metal cata-
alcohols and a-carbonyl aldehydes has been developed at room lysts for the synthesis of a-ketoesters as depicted in Scheme
temperature under metal-free conditions for the first time. Various 1.11 Therefore, the development of mild, efficient and envi-
alcohols and a-carbonyl aldehydes could participate in this reaction to ronmentally benign metal-free methods is still greatly
afford the desired products in excellent yields.
desirable.
Cross-dehydrogenative coupling (CDC) between two part-
ners with C–H and O–H bonds, became an attractive strategy
in organic synthesis.12 In particular, in recent years, the
iodine catalyzed CDC reactions have received special atten-
tion due to various advantages: (1) versatility of iodine in the
formation of C–C,13 C–O14 and C–N15 bonds in an environ-
mentally benign manner from unfunctionalized starting
materials via C–H bond activation16 (2) the direct dehydro-
genative transformation maximizes atom economy with
lower cost and less waste, which is one of the most efficient
and straightforward strategies to construct complex mole-
cules from simple starting materials.
As a part of our ongoing research in developing sustainable
synthetic methodologies,17 herein we wish to report a simple,
efficient and metal-free synthesis of a-ketoesters promoted by
iodine at room temperature for the rst time. So far, to the best
of our knowledge no methods for the synthesis of a-ketoesters
under I2 catalyst have been developed.
Introduction
a-Ketoesters have attracted considerable attention not only
because of their biological activity but also due to their wide
application as synthetic precursors for a variety of organic
transformations,1 especially in enantioselective synthesis,2
resulting in many synthetically and biologically useful
products. Recently, Yian Shi et al. have reported asymmetric
biomimetic transamination of a-ketoesters to chiral a-ami-
noesters,3 and Martin Hiersemann et al. have developed total
synthesis of (ꢀ)-9,10-dihydroecklonialactone B.4 Conse-
quently, numerous synthetic methodologies for the
construction of this important unit have been developed in
the past decades. For example, highly implemented classical
synthetic methods5 for accessing of a-ketoesters usually
suffer from drawbacks such as requirement of stoichiometric
amount of metal oxidants leading to the generation of a large
amount of waste in the reaction. Later, some alternative
procedures such as reaction of diethyl oxalate and phenyl-
lithium,6 aerobic oxidation of a-aryl halogen esters,7 and
tandem transformation of b-diketones8 have been developed.
Very recently, two new approaches were reported for the
synthesis of a-ketoesters via electrochemical method9 and
copper catalysis.10 However, they suffer from drawbacks such
as (1) high temperature; (2) excess of starting material; (3)
large amount of by-products; (4) requirement of additives; (5)
longer reaction time; (6) requirement of pure molecular
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance
Factory Estate, Yeddumailaram-502 205, Medak district, AP, India. E-mail:
sharada@iith.ac.in; Tel: +91-40-23017058
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra06028h
Scheme 1 Methods for synthesis of a-ketoester.
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Surveying the effect of different solvents showed that the
toluene to be the most suitable solvent for the synthesis
whereas solvents such as DMF, MeCN and 1,2-dichloroethene
(DCE) gave low yields of the product. It should be noted that no
product was formed either in the absence of the catalyst or base.
This indicating the role played by catalyst and base in the
formation of product (Table 1, entry 18 & 19).
With the optimized conditions in hand, the scope and
generality of the reaction was tested with respect to various
alcohols and a-carbonyl aldehydes, resulting in a series of
substituted a-ketoesters in excellent yields (Table 2). Under
standard conditions, the uoro, bromo and methoxy groups at
para-positions of arene group in a-carbonyl aldehydes did not
obviously affect the yield of desired products (3h–t). This novel
protocol has been successfully implemented for simple alkyl
alcohols such as methanol, ethanol and butanol which resulted
in various a-ketoesters (3b–d) with excellent yields. We are
delighted to mention that we were successful in utilizing the
secondary alcohols such as isopropanol, cyclohexanol and
L-menthol to afford a-ketoesters (3m, 3s & 3t). All the products
were conrmed by FT-IR, NMR spectroscopic techniques and
mass spectrometry.
Results and discussion
Use of iodine to replace toxic rare metals and transition-metal
catalysts in various organic transformations is well known in
literature.18 Compared to transition-metal catalysts, iodine is a
readily available mild Lewis acid,19 in addition to this operational
simplicity, low cost, and less toxicity makes it more important as
an environmentally benign catalyst for organic functional group
conversions. Thus, it's use as a green catalyst in various organic
transformations is well documented in the literature.20
For the present study, our investigation commenced with a
iodine catalyst for the reaction of a-carbonyl aldehyde (2a) with
alcohol (1a). To our delight, when 2a was treated with alcohol
(1a) in the presence of 0.25 equiv. of I2 and 2 equiv. of 1,8-dia-
zabicyclo[5.4.0]undec-7-ene (DBU) as base in MeCN as solvent at
rt for 45 min, the desired benzyl-2-oxo-2-phenylacetate (3a) was
isolated in 40% yield (Table 1, entry 1). Encouraged by this
result and to probe further for optimal reaction conditions, we
screened a range of bases in presence of iodine as catalyst
(different equivalents) in different solvents (Table 1).
Among bases tested, K2CO3 was the most effective (entry 15),
while organic bases such as DBU, piperidine, pyrrolidine, pyri-
dine and 1,4-diazabicyclo[2.2.2]octane (DABCO) gave lower
yields. With K2CO3 as choice of base we performed experiments
with various equivalents of I2 and observed that yield
signicantly increased to 94% with 1 equiv. of I2 (Table 1,
entries 12–15).
To illuminate the role of I2 for the metal-free CDC reaction
with phenylglyoxal monohydrate, we conducted couple of
control experiments (Scheme 2).
When the reaction was performed under standard condi-
tions in open ask or molecular oxygen, the desired product (3a)
Table 1 Optimization of the model reaction conditionsa
Entry
Catalyst (equiv.)
Base (equiv.)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
0.25
0.25
0.5
1
1.5
1
1
1
1
1
DBU (2)
DBU (2)
DBU (2)
DBU (2)
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
0.75
8
8
8
8
12
12
12
10
4
4
4
5
5
8
1
1
1
40
45
52
60
60
Trace
40
Trace
38
55
70
50
30
55
70
94
94
82
0
DBU (2)
DABCO (2)
Piperidine (2)
Et3N (2)
8
9
Pyrrolidine (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (1.5)
K2CO3 (2)
—
10
11
12
13
14
15
16
17
18
19
1
1
CH3CN
DCE
0.25
0.5
0.75
1
1.5
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
1
12
12
0
a
Standard reaction conditions: 1a (0.79 mmol), 2a (0.66 mmol), 1 equiv. of I2 catalyst, K2CO3 (2 equiv.), toluene (2 mL), at room temperature, 1 h.
Yield of isolated product aer silica gel column chromatography.
b
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Table 2 Substrate scope of a-carbonyl aldehydes and alcoholsab
Scheme 2 The controlled experiments to prove the mechanism.
Scheme 3 The plausible mechanism for the present reaction.
(2ab) was activated by Lewis acid I2. Then benzyl alcohol (1a)
could attack the activated aldehyde group of a-carbonyl alde-
hyde (2ab) to give the alcohol (A), which is nally oxidised by I2
and base to give the desired product (3a).
a
Standard reaction conditions: 1a (0.79 mmol), 2a (0.66 mmol), 1 equiv.
of I2 catalyst, K2CO3 (2 equiv.), toluene (2 mL), at room temperature, 1 h.
b
Yield of isolated product aer silica gel column chromatography.
was obtained in 94% yield (Scheme 2, eqn (1)). Similarly in the
presence of argon also we could get the product (3a) in 94%
yield (Scheme 2, eqn (2)). Thus indicating that aerobic condi-
tions are not prerequisite for CDC reaction of a-carbonyl alde-
hyde (2a) with alcohol (1a). However no product was formed
either in the absence of iodine or base (Scheme 2, eqn (3) & (4)).
When we performed a control experiment with anhydrous 2-
oxo-2-phenylacetaldehyde (2ab) obtained the product (3a) in
90% (Scheme 2, eqn (5)). This clearly indicates water does not
play any role in the mechanism and also phenylglyoxal mono-
hydrate (2a) and anhydrous 2-oxo-2-phenylacetaldehyde (2ab)
exist in equilibrium in the presence of iodine.
Conclusions
A metal-free and environmentally benign iodine-mediated cross
dehydrogenative coupling of a-carbonyl aldehydes and alcohols for
the synthesis of a-ketoesters was developed at room temperature
for the rst time. A series of substituted a-ketoesters could be
conveniently obtained from simple and readily available starting
materials. The advantages of this methodology are (1) mild reac-
tion conditions with excellent yields; (2) high atom economy; (3) an
inexpensive catalyst and (4) broad substrate scope.
Experimental
Representative experimental procedure for the synthesis of
On the basis of the results described above we assume that
the CDC reaction occurs through oxidative coupling in the
presence of iodine and K2CO3 and a plausible mechanism for I2
benzyl-2-oxo-2-phenylacetate (3a)
promoted cross-dehydrogenative coupling is illustrated in To a mixture of phenylglyoxal monohydrate 2a (100 mg, 0.66
Scheme 3. Initially the aldehyde group of a-carbonyl aldehyde mmol) and benzyl alcohol 1a (85 mg, 0.79 mmol) in toluene
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(2 mL), iodine (167 mg, 0.66 mmol) and K2CO3 (168 mg, 1.32
mmol) were added and the resulting mixture was stirred at rt for
1 h. Aer disappearance of the reactant (monitored by TLC),
and added 50 mL water to the mixture, then extracted with
EtOAc three times (3 ꢁ 50 mL). The extract was washed with
saturated Na2S2O3 solution and dried over anhydrous Na2SO4.
The residue was puried by column chromatography on silica
gel (60–120 mesh, petroleum ether–EtOAc ¼ 10 : 1) to yield the
desired product 3a as a colourless liquid (148 mg, 94% yield).
717; (j) R. Lerebours and C. Wolf, J. Am. Chem. Soc., 2006,
128, 13052.
6 A. Nagaki, D. Ichinari and J.-i. Yoshida, Chem. Commun.,
2013, 49, 3242.
7 Y. Su, L. Zhang and N. Jiao, Org. Lett., 2011, 13, 2168.
8 Y. Xiao, Y. Xia, C. Rong, H. Huang, L. Mao, Z. Fu, N. Yu and
D. Yin, Catal. Commun., 2013, 37, 109.
9 Z. Zhang, J. Su, Z. Zha and Z. Wang, Chem.–Eur. J., 2013, 19,
17711.
10 (a) C. Zhang, P. Feng and N. Jiao, J. Am. Chem. Soc., 2013,
135, 15257; (b) C. Zhang and N. Jiao, Front. Org. Chem.,
2014, 1, 109.
Acknowledgements
11 (a) T. Sakakura, H. Yamashita, T.-a. Kobayashi, T. Hayashi
and M. Tanaka, J. Org. Chem., 1987, 52, 5733; (b)
H. Shimizu and M. Murukani, Chem. Commun., 2007, 2855;
(c) Y. Su, L. Zhang and N. Jiao, Org. Lett., 2011, 13, 2168.
12 Selected review papers for CDC reactions: (a) C. S. Yeung and
V. M. Dong, Chem. Rev., 2011, 111, 1215; (b) S. H. Cho,
J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40,
5068; (c) X. Shang and Z.-Q. Liu, Chem. Soc. Rev., 2013, 42,
3253; (d) S. I. Kozhushkov and L. Ackermann, Chem. Sci.,
2013, 4, 886; (e) M.-L. Louillat and F. W. Patureau, Chem.
Soc. Rev., 2014, 43, 901; (f) J. Le Bras and J. Muzart, Chem.
Rev., 2011, 111, 1170; (g) G. Wu, J. Zhou, M. Zhang, P. Hu
and W. Su, Chem. Commun., 2012, 48, 8964; (h) D. P. Ojha
and K. R. Prabhu, J. Org. Chem., 2013, 78, 12136; (i)
X.-Z. Shu, Y.-F. Yang, X.-F. Xia, K.-G. Ji, X.-Y. Liu and
Y.-M. Liang, Org. Biomol. Chem., 2010, 8, 4077; (j) J. Zhou,
B. Li, Z.-C. Qian and B.-F. Shi, Adv. Synth. Catal., 2014, 356,
1038.
We thank the Council of Scientic and Industrial Research
(CSIR), New Delhi, and the Indian Institute of Technology,
Hyderabad, for nancial support. A.S thank CSIR and S.V.C
thank UGC, New Delhi, for the award of a research fellowship.
Notes and references
1 (a) Y. Nie, R. Xiao, Y. Xu and G. T. Montelione, Org. Biomol.
Chem., 2011, 9, 4070; (b) M. F. Elsebai, S. Kehraus,
¨
U. Lindequist, F. Sasse, S. Shaaban, M. Gutschow,
¨
M. Josten, H.-G. Sahl and G. M. Konig, Org. Biomol. Chem.,
2011, 9, 802; (c) I. Hemeon and A. J. Bennet, Synthesis,
2007, 1899; (d) Y. Aoki, S. Tanimoto, D. Takahashi and
K. Toshima, Chem. Commun., 2013, 49, 1169; (e)
¨
Y. Gravenfors, J. Viklund, J. Blid, T. Ginman, S. Karlstrom,
¨
¨
J. Kihlstrom, K. Kolmodin, J. Lindstrom, S. Berg,
F. Kieseritzky, C. Slivo, B.-M. Swahn, L.-L. Olsson,
¨
¨
P. Johansson, S. Eketjall, J. Falting, F. Jeppsson, 13 (a) G. Majji, S. Guin, A. Gogoi, S. K. Rout and B. K. Patel,
¨
K. Stromberg, J. Janson and F. Rahm, J. Med. Chem., 2012,
Chem. Commun., 2013, 49, 3031; (b) M. Uyanik, D. Suzuki,
T. Yasui and K. Ishihara, Angew. Chem., Int. Ed., 2011, 50,
5331; (c) E. Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang
and X. Wan, Org. Lett., 2012, 14, 3384.
55, 9297; (f) B. A. Boughton, L. Hor, J. A. Gerrard and
C. A. Hutton, Bioorg. Med. Chem., 2012, 20, 2419; (g)
S. D. Burke and G. M. Sametz, Org. Lett., 1999, 1, 71; (h)
V. Bette, A. Mortreux, D. Savoia and J.-F. Carpentier, Adv. 14 (a) Z.-Q. Lao, W.-H. Zhong, Q.-H. Lou, Z.-J. Li and X.-B. Meng,
Synth. Catal., 2005, 347, 289.
Org. Biomol. Chem., 2012, 10, 7869; (b) Y. Yan, Y. Zhang,
C. Feng, Z. Zha and Z. Wang, Angew. Chem., Int. Ed., 2012,
51, 8077; (c) Q. Xue, J. Xie, H. Li, Y. Cheng and C. Zhu,
Chem. Commun., 2013, 49, 3700.
2 (a) G. Blay, I. F. andez, M. C. Mu-noz, J. R. Pedro, A. Recuenco
and C. Vila, J. Org. Chem., 2011, 76, 6286; (b) E. Sanchez-
Larios, K. Thai, F.-o. Bilodeau and M. Gravel, Org. Lett.,
2011, 13, 4942.
3 X. Xiao, M. Liu, C. Rong, F. Xue, S. Li, Y. Xie and Y. Shi, Org.
Lett., 2012, 14, 5270.
4 J. Becker, L. Butt, V. Kiedrowski, E. Mischler, F. Quentin and
M. Hiersemann, J. Org. Chem., 2014, 79, 3040.
5 For some selected examples, see: (a) N. Lu, N. Lu and
15 (a) T. Nobuta, N. Tada, A. Fujiya, A. Kariya, T. Miura and
A. Itoh, Org. Lett., 2013, 15, 574; (b) T. Nobuta, A. Fujiya,
T. Yamaguchi, N. Tada, T. Miura and A. Itoh, RSC. Adv.,
2013, 3, 10189.
16 S. V. N. Vuppalapati and Y. Rok Lee, Tetrahedron, 2012, 68,
8286.
Y.-C. Lin, Tetrahedron Lett., 2007, 48, 8823; (b) M. Oba, 17 (a) S. Vidyacharan, A. H. Shinde, B. Satpathi and
M. Endo, K. Nishiyama, A. Ouchi and W. Ando, Chem.
Commun., 2004, 14, 1672; (c) K. Yamada, M. Kato, M. Iyoda
and Y. Hirata, J. Chem. Soc., Chem. Commun., 1973, 4, 499;
D. S. Sharada, Green Chem., 2014, 16, 1168; (b)
A. H. Shinde, S. Vidyacharan and D. S. Sharada,
Tetrahedron Lett., 2014, 55, 3064.
(d) J. P. Burkhart, N. P. Peet and P. Bey, Tetrahedron Lett., 18 P. Finkbeiner and B. J. Nachtsheim, Synthesis, 2013, 979.
1988, 29, 3433; (e) A. Wusiman, X. Tusun and C.-D. Lu, 19 P. T. Parvatkar, P. S. Parameswaran and S. G. Tilve, Chem.–
Eur. J. Org. Chem., 2012, 3088; (f) G. Urgoitia, R. SanMartin,
Eur. J., 2012, 18, 5460.
M. T. Herrero and E. Dominguez, Green Chem., 2011, 13, 20 (a) S. Pal, N. Khan, S. Karamthulla and L. H. Choudhury, RSC
2161; (g) A. Ianni and S. R. Waldvogel, Synthesis, 2006,
2103; (h) J. M. Photis, Tetrahedron Lett., 1980, 21, 3539; (i)
A. E. Metz and M. C. Kozlowski, J. Org. Chem., 2013, 78,
Adv., 2013, 3, 15705; (b) T. Dohi and Y. Kita, Chem. Commun.,
2009, 2073; (c) M. Uyanik and K. Ishihara, Chem. Commun.,
2009, 2086.
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