Retro-claisen condensation with FeIII as catalyst under solvent-free conditions

Article abstract of DOI:10.1002/ejoc.201000140

An iron(III) salt catalyzed retro-Claisen condensation between an alcohol and a 1,3-diketone was investigated. The mechanism involves the formation of a metal-induced sixmembered cyclic transition state and cleavage of the C _sp2-C_sp3 bond. Regioselective esterification and one-pot couversion of silyl ethers into esters with good yields was observed. Simple reaction conditions, high yields, and broad scope of the reaction illustrate the good synthetic utility of this method.

Full text of DOI:10.1002/ejoc.201000140

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000140
Retro-Claisen Condensation with FeIII as Catalyst under Solvent-Free
Conditions
Chitturi Bhujanga Rao,[a] Dasireddi Chandra Rao,[a] Dokuburra Chanti Babu,[a] and
Yenamandra Venkateswarlu*[a]
Dedicated to Dr. J. S. Yadav on the occasion of his 60th birthday
Keywords: Iron / Cleavage reactions / Esters / Regioselectivity / Retro reactions
An iron(III) salt catalyzed retro-Claisen condensation be- sion of silyl ethers into esters with good yields was observed.
tween an alcohol and a 1,3-diketone was investigated. The
mechanism involves the formation of a metal-induced six-
Simple reaction conditions, high yields, and broad scope of
the reaction illustrate the good synthetic utility of this
method.
membered cyclic transition state and cleavage of the Csp2
–
Csp3 bond. Regioselective esterification and one-pot conver-
cleavage has received much attention, because new skel-
etons can be constructed directly by using such reactions.
Recently in 2007, Kuninobu, Takai et al. worked on esterifi-
cation by C–C bond cleavage by using In(OTf)3.
Iron is very useful and one of the most abundant metals
on the earth. In the recent past, iron-based catalysis has
become a powerful tool for organic synthesis. Because of
its low cost, environmentally benign characteristics, and sig-
nificant reactivity, efforts have been directed to employ iron
as an efficient catalyst for various organic transforma-
tions.[14,15] This inspired us to focus on the synthesis of es-
ters in the presence of iron.
Herein we report a solvent-free, inexpensive, and com-
mercially available ferric chloride catalyzed synthesis of es-
ters. This reaction proceeds through carbon–carbon bond
cleavage by a metal-induced six-membered cyclic transition
state with excellent yields. The solvent-free approach is sim-
ple with amazing versatility. The reaction did not proceed
in the absence of a catalyst.
Introduction
For many decades, both in the history of mankind and
in organic chemistry research, esters have been leading an
important role in daily life, as well as in academic and in-
dustrial laboratories. Because of this essentiality we need an
efficient method for the synthesis of esters.[1] Over the past
decades, so many protocols have been established for the
synthesis of esters, including condensation of alcohols and
carboxylic acids;[2–4] acid anhydrides[5] or acyl halides;[6]
transesterification;[7] ester-interchange reactions;[8] iron-,
copper-, and ruthenium-catalyzed reactions of aldehyde
and alcohols;[9] mercury- and tin-catalyzed reactions of carb-
oxylic acids with acetylenes;[10] enzyme-catalyzed meth-
ods;[11] and the preparation of amides.[12] All these methods
have disadvantages like in Fischer esterification: the use of
concentrated aqueous HCl or H2SO4 may lead to many side
products and the need for tedious procedures to isolate the
product. Exercise with acid anhydrides and acid halides is
very carcinogenic and they are toxic in nature. Transesterifi-
cation, ester-interchange reactions, mercury-catalyzed reac-
tions, and enzyme-catalyzed methods need tedious reaction
conditions and difficult work-up procedures. In most of
these methods, hazardous solvents are used and the conver-
sions are expensive and environmentally unfavorable. In
modern times, esterification[13] by carbon–carbon bond
Results and Discussion
In a preliminary reaction, 2,4-pentanedione (1) was
treated with 2,3-dihydro-1H-inden-2-ol (2a) in the presence
of FeCl3 (10 mol-%) as catalyst at 80 °C under solvent-free
conditions for 16 h to afford 2,3-dihydro-1H-inden-2-yl
acetate (3a) in 98% yield (Scheme 1). Acetone was formed
as a side product was removed by aqueous work-up. The
[a] Natural Products Laboratory, Organic Chemistry Division I
Indian Institute of Chemical Technology
Hyderabad 500007, India
1
structure of 3a was established by H NMR spectroscopy,
Fax: +91-40-27160512
E-mail: luchem@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000140.
in which the conspicuous presence of a signal due to the
acetyl group at δ = 2.00 (s, 3 H) ppm along with other
signals for 2,3-dihydro-1H-inden-2-yl acetate.
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C. B. Rao, D. C. Rao, D. C. Babu, Y. Venkateswarlu
SHORT COMMUNICATION
Table 2. Iron-catalyzed reaction of acyclic 1,3-dicarbonyl com-
pounds with aliphatic alcohols.
Scheme 1.
To investigate the scope of the reaction, several Lewis
acids were used as catalysts (Table 1) under neat conditions.
The reactivity of anhydrous FeCl3 (3a, 98% yield) differs
from that of FeCl3·6H2O (3a, 83% yield; Table 1), whereas
the use of Fe(OTf)3 afforded almost the same yields as those
obtained with FeCl3. Nevertheless, La(NO3)3 afforded 3a in
0% yield and LaCl3 provided 15% yield only (Table 1).
BiCl3 and AlCl3 offer considerable yields apart from the
remaining Lewis acids in Table 1.
Table 1. Effect of catalyst on the retro-Claisen condensation be-
tween alcohol and 1,3-diketone.[a]
Entry
Catalyst
% Yield[b]
1
2
3
4
5
6
7
FeCl3
FeCl3·6H2O
FeCl2
Fe(OTf)3
LaCl3
98
83
47
98
15
0
[a] Reaction conditions: 1,3-dicarbonyl compound (1 equiv.),
alcohol (1 equiv.), FeCl3 (10 mol-%), neat, 80 °C, 16 h. [b] Isolated
yield.
La(NO3)·6H2O
CAN
0
8
9
AlCl3
Bi(NO3)3
BiCl3
ZnCl2
ZnBr2
Zn(OTf)2
BF3 Et2O
BBr3
73
0
93
trace
trace
30
0
tained. Nevertheless, with the use of 1-phenylbutane-1,3-di-
one (3), we observed high selectivity and the corresponding
benzoates were predominantly afforded (Table 2, Entry 3).
Usually the acetylation and benzoylation of hydroxy groups
is very important in the synthesis of natural products and
carbohydrate chemistry. In general, acetylation and benzo-
ylation are carried out by using highly corrosive acetyl ha-
lides, benzoyl halides, and their acid anhydrides. In this as-
pect, our new protocol is very useful for synthetic organic
chemistry.
10
11
12
13
14
15
16
0
0
Catalyst free
[a] Reaction conditions: 2,4-pentanedione (1 equiv.), 2,3-dihydro-
1H-inden-2-ol (1 equiv.), catalyst (10 mol-%), 80 °C, 16 h. [b] Iso-
lated yield.
After optimizing the scope and limitations of the reac-
Further, we employed the reaction to cyclic 1,3-diket-
tion, we investigated the advantageous role and efficiency ones, namely, 2-acetylcyclopentanone (5), 2-acetylcyclo-
of this method by treating various 1,3-diketones with a vari- hexanone (6), and 2-benzylcyclohexanone (7), with alcohols
ety of structurally diverse alcohols. We observed outstand- 2a, 2b, 2g, 2h, 2i, and 2j to obtain the corresponding keto
ing results. All of the reactions were carried out in the pres- esters (Table 3) in high yields with good atom economy.
ence of FeCl3 as catalyst without the use of any kind of These esters might be useful in organic chemistry research,
hazardous solvent; the corresponding esters were obtained as intermediates for the total synthesis of bioactive natural
in high yields (Tables 2 and 3).
products.
The reactions of acyclic (2b, 2c) and cyclic (2a, 2d)
We observed regioselectivity for substrates 3 (Table 2),
alcohols with acyclic 1,3-dicarbonyl compounds like pen- where the esterification occurred exclusively on the car-
tane-2,4-dione (1) and 3-methylpentane-2,4-dione (2) af- bonyl group next to the benzyl group, affording predomi-
forded THE corresponding acetylated products in good nantly the corresponding benzoates in excellent yields. Nev-
yields (Table 2, Entries 1 and 2). Similarly, when alcohols ertheless, on substrates 7 (Table 3), esterification occurred
2a, 2b, and 2f were treated with 1,3-diphenylpropane-1,3- exclusively on the carbonyl group in the cyclohexanone ring
dione (4), the corresponding benzoylated products were ob- to give the corresponding ring-opened keto esters in high
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Retro-Claisen Condensation with FeIII as Catalyst
Table 3. Iron-catalyzed reaction of cyclic 1,3-dicarbonyl com-
pounds with cyclic and aliphatic alcohols.
Scheme 2. Isolated yields of the products are given.
Scheme 3. Isolated yields of the products are given.
To investigate the substrate scope and potential of the
new method, we carried out esterification on a substrate
containing sensitive protecting groups like silyl ethers (TBS
group, 10) and obtained amazing results. When the reaction
was carried out in the presence of FeCl3 under solvent-free
conditions at 80 °C for 16 h with the use of 1-phenylbutane-
1,3-dione (3) and 2-benzyl cyclohexanone (7) in one pot,
products 3b (96%) and 3r (95%) were obtained in high
yields (Scheme 4).
[a] Reaction conditions: 1,3-dicarbonyl compound (1 equiv.),
alcohol (1 equiv.), FeCl3 (10 mol-%), neat, 80 °C, 16 h. [b] Isolated
yield.
yield. It is evident that epimerization may take place in the
case of some optically active compounds.
In the synthesis of bioactive natural products and carbo-
hydrate chemistry, regioselective protections are fundamen-
tal and important. In this connection, our new method is
useful for synthetic organic chemistry. We also examined
the regioselective characteristics of this method by treating
substrates 8 and 9 with 2,4-pentanedione (1) and 1-phen-
ylbutane-1,3-dione (3); esterification occurs exclusively on
the primary hydroxy group with a unimolar stoichiometry
and predominantly afforded corresponding products 8a
(90%) and 9a (88%; Scheme 2) under same reaction condi-
tions.
By using the same protocol, 1,3-diketones reacted with
water and secondary amines instead of hydroxy com-
pounds. The reactions proceeded smoothly, affording the
Scheme 4. Isolated yields of the products are given.
The reaction proceeds through metal-induced formation
corresponding acids and amides in excellent yields of a six-membered cyclic transition state and Csp2–Csp3
(Scheme 3).
bond breakage. The reaction mechanism mimics the retro-
Eur. J. Org. Chem. 2010, 2855–2859
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C. B. Rao, D. C. Rao, D. C. Babu, Y. Venkateswarlu
SHORT COMMUNICATION
After completion of the reaction, the reaction mixture was dis-
solved in DCM (5 mL) and washed with distilled water. The or-
ganic layer was dried with Na2SO4, and the solvent was evaporated
under vacuum. Column chromatography afforded product 3a as a
pale yellowish oil in 96% yield. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.16 (m, 4 H), 5.48 (m, 1 H), 3.27 (dd, J = 6.7, 16.6 Hz,
2 H), 2.95 (dd, J = 3.0, 16.6 Hz, 2 H), 2.00 (s, 3 H) ppm. 13C NMR
(300 MHz, CDCl3, 25 °C): δ = 171.4, 140.5 (2 C), 126.8 (2 C), 124.5
Claisen condensation. Because of their strong oxophilicity,
variable valency, and strong Lewis acidity, iron(III) salts
catalyze the reaction by involving a six-membered cyclic
transition state (Scheme 5).
(2 C), 75.4, 39.8 (2 C), 21.6 ppm. IR: ν = 1734.8 cm–1. MS (ESI):
˜
m/z = 199 [M + 23].
Supporting Information (see also the footnote on the first page of
this article): General information and procedures, characterization
data of the prepared compounds.
Acknowledgments
The authors are thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial support and to the Di-
rector, IICT, for his constant encouragement.
Scheme 5. Proposed mechanism for the formation of ester.[11a]
In Scheme 6, it is evident that the benzylic carbocation
(in isomer X) is more stable and readily available for a
longer period of time than the aliphatic carbocation (in iso-
mer Y), which facilitates regioselective nucleophilic attack
predominantly on the carbonyl group next to the benzyl
group rather than the non-benzylic carbonyl group.
[1] J. Otera (Ed.), Esterification, Wiley-VCH, Weinheim, 2003.
[2] a) T. W. Greene, P. G. M. Wuts in Protective Groups in Organic
Synthesis, 3rd ed., John Wiley & Sons, New York, 1999, pp.
369–453; b) G. Benz in Comprehensive Organic Synthesis (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, vol. 6, pp.
323–380.
[3] a) I. Dhimitruka, J. SantaLucia, Org. Lett. 2006, 8, 47–50; b)
R. Moumne, S. Lavielle, P. Karoyan, J. Org. Chem. 2006, 71,
3332–3334; c) S. Velusamy, S. Borpuzari, T. Punniyamurthy,
Tetrahedron 2005, 61, 2011–2015; d) C. T. Chen, Y. S. Munot,
J. Org. Chem. 2005, 70, 8625–8627.
[4] a) K. Ishihara, S. Ohara, H. Yamamoto, Science 2000, 290,
1140–1142; b) A. G. M. Barrett, D. C. Braddock, Chem. Com-
mun. 1997, 351–352; c) K. Ishihara, M. Kubota, H. Kurihara,
H. Yamamoto, J. Org. Chem. 1996, 61, 4560–4567.
[5] a) T. S. Reddy, M. Narasimhulu, N. Suryakiran, K. C. Mahesh,
K. Ashalatha, Y. Venkateswarlu, Tetrahedron Lett. 2006, 47,
6825–6829; b) G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo,
E. Marcantoni, P. Melchiorre, L. Sambri, Synthesis 2007,
3489–3496; c) A. Orita, C. Tanahashi, A. Kakuda, J. Otera,
J. Org. Chem. 2001, 66, 8926–8934; d) V. R. Choudhary, K.
Shudiram Mantri, K. J. Suman, Catal. Commun. 2001, 2, 57–
61; e) J. H. Sun, C. A. Teleha, J. S. Yan, J. D. Rodgers, D. A.
Nugiel, J. Org. Chem. 1997, 62, 5627–5629; f) K. Ishihara, M.
Kubota, H. Kurihara, H. Yamamoto, J. Org. Chem. 1996, 61,
4560–4567.
[6] a) I. Dhimitruka, J. SantaLucia, Org. Lett. 2006, 8, 47 50; b)
Q. Guo, T. Miyaji, R. Hara, B. Shen, T. Takahashi, Tetrahedron
2002, 58, 7327–7334; c) C. Mc Nicholas, T. J. Simpson, N. J.
Willett, Tetrahedron Lett. 1996, 37, 8053–8056; d) T. Oriyama,
Y. Hori, K. Imai, R. Sasaki, Tetrahedron Lett. 1996, 37, 8543–
8546.
[7] a) N. Remme, K. Koschek, C. Schneider, Synlett 2007, 491–
493; b) R. Singh, R. M. Kissling, M. A. Letellier, S. P. Nolan,
J. Org. Chem. 2004, 69, 209–212; c) K. V. N. S. Srinivas, I.
Mahender, B. Das, Synthesis 2003, 2390–2394; d) S. P. Chavan,
R. R. Kale, K. Shivasankar, S. I. Chandake, S. B. Benjamin,
Synthesis 2003, 2695–2698.
[8] a) M. G. Stanton, C. B. Allen, R. M. Kissling, A. L. Lincoln,
M. R. Gagne, J. Am. Chem. Soc. 1998, 120, 5981–5989; b)
M. G. Stanton, M. R. Gagne, J. Am. Chem. Soc. 1997, 119,
5075–5076; c) T. Okano, Y. Hayashizaki, J. Kiji, Bull. Chem.
Soc. Jpn. 1993, 66, 1863–1865.
Scheme 6. Proposed mechanism for the possibility of substrate re-
gioselectivity.
Conclusions
In conclusion, we have developed an iron-catalyzed syn-
thesis of esters by treating 1,3-dicarbonyl compounds with
alcohols. These reactions proceed by nucleophilic attack of
the alcohol at one of the carbonyl groups of the 1,3-dike-
tone followed by carbon–carbon bond cleavage, which oc-
curs through a six-membered cyclic transition state in a
retro-Claisen condensation manner. Water, secondary
amines, and silyl ethers can also be used as nucleophiles.
We observed regioselective esterification with the use of the
same protocol.
Experimental Section
General Esterification Procedure: The 1,3-diketone (1.0 mmol) was
added to the hydroxy compound (1.0 mmol) in a 10-mL round-
bottomed flask, followed by the addition of FeCl3 (10 mol-%) un-
der solvent-free and closed-vessel conditions. The reaction mixture
was stirred for 16 h at 80 °C. The reaction was monitored by TLC.
[9] a) X.-F. Wu, C. Darcel, Eur. J. Org. Chem. 2009, 1144–1147;
b) W. J. Yoo, C. J. Li, Tetrahedron Lett. 2007, 48, 1033–1035;
2858
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Retro-Claisen Condensation with FeIII as Catalyst
c) S. Murahashi, T. Naota, K. Ito, Y. Maeda, H. Taki, J. Org.
Chem. 1987, 52, 4319–4327.
[14] a) B. Plietker (Ed.), Iron Catalysis in Organic Chemistry: Reac-
tions and Applications, Wiley-VCH, Weinheim, 2008, p. 279; b)
A. Furstner, Angew. Chem. Int. Ed. 2009, 48, 1364–1367; c)
S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48,
5586–5587; d) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem.
Rev. 2004, 104, 6217; e) S. Enthaler, K. Junge, M. Beller, An-
gew. Chem. 2008, 120, 3363–3367; f) S. Enthaler, K. Junge, M.
Beller, Angew. Chem. Int. Ed. 2008, 47, 3317–3321; g) X. F. Wu,
C. Darcel, Eur. J. Org. Chem. 2009, 1144–1147; h) K. Wang,
M. Lu, A. Yu, X. Zhu, Q. Wang, J. Org. Chem. 2009, 74, 935–
938; i) A. Correa, M. Carril, C. Bolm, Angew. Chem. Int. Ed.
2008, 47, 2880.
[10] a) Y. Kita, H. Maeda, K. Omori, T. Okuno, Y. Tamura, J.
Chem. Soc. Perkin Trans. 1 1993, 2999–3005; b) T. Mitsudo, Y.
Hori, Y. Yamakawa, Y. Watanabe, Tetrahedron Lett. 1986, 27,
2125–2126; c) P. F. Hudrlik, A. M. Hudrlik, J. Org. Chem.
1973, 38, 4254–4258; d) C. S. Cho, D. T. Kim, H. J. Choi, T. J.
Kim, S. C. Shim, Bull. Korean Chem. Soc. 2002, 23, 539–540.
[11] a) R. Morrone, M. Piattelli, G. Nicolosi, Eur. J. Org. Chem.
2001, 1441–1443; b) P. E. Sonnet, J. Org. Chem. 1987, 52, 3477–
3479; c) G. Kirchner, M. P. Scollar, A. M. Klibanov, J. Am.
Chem. Soc. 1985, 107, 7072–7076.
[12] a) R. Pflantz, J. Sluiter, M. Kricˇka, W. Saak, C. Hoenke, J.
Christoffers, Eur. J. Org. Chem. 2009, 5431–5436; b) E. Kovi,
C. Wolf, Chem. Eur. J. 2008, 14, 6302–6315; c) G. E. Veitch,
K. L. Bridgwood, S. V. Ley, Org. Lett. 2008, 10, 3623–3625; d)
A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Ko-
pecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496–6511.
[13] a) A. Kawata, K. Takata, Y. Kuninobu, K. Takai, Angew.
Chem. Int. Ed. 2007, 46, 7793–7795; b) G. Grogan, J. Graf, A.
Jones, S. Parsons, N. J. Turner, S. L. Flitsch, Angew. Chem. Int.
Ed. 2001, 40, 1111–1114; c) G. Grogan, J. Graf, A. Jones, S.
Parsons, N. J. Turner, S. L. Flitsch, Angew. Chem. 2001, 113,
1145–1148; d) G. Yatluk, Yu. S. V. Chernyak, A. L. Suvorov,
E. A. Khrustaleva, V. I. Abramova, Russ. J. Gen. Chem. 2001,
71, 965–967.
[15] a) A. Correa, O. Garcia Mancheno, C. Bolm, Chem. Soc. Rev.
2008, 37, 1108–1117; b) B. D. Sherry, A. Fürstner, Acc. Chem.
Res. 2008, 41, 1500–1511; c) W. M. Czaplik, M. Mayer, J.
Cvengros, A. Jacobi von Wangelin, ChemSusChem 2009, 2,
396–417; d) S. Gaillard, J.-L. Renaud, ChemSusChem 2008, 1,
505–509; e) S. Y. Zhang, T. Yong-Qiang, C. A. Fan, F. M.
Zhang, L. Shi, Angew. Chem. Int. Ed. 2009, 48, 1–6; f) S. K.
Xiang, L. H. Zhanga, N. Jiao, Chem. Commun. 2009, 6487–
6489; g) U. Jana, S. Biswas, S. Maiti, Eur. J. Org. Chem. 2008,
5798–5804; h) J. C. Choi, K. Kohno, D. Masuda, H. Yasuda,
T. Sakakura, Chem. Commun. 2008, 777–779.
Received: February 2, 2010
Published Online: April 6, 2010
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