Rapid and regioselective hydrogenation of α,β-unsaturated ketones and alkylidene malonic diesters using Hantzsch ester catalyzed by titanium tetrachloride

Article abstract of DOI:10.1055/s-0030-1258556

A regioselective hydrogenation of α,β-unsaturated ketones and alkylidene malonic diesters using Hantzsch ester as the reducing agent and titanium tetrachloride as a catalyst is described. The short reaction times and mild reaction conditions are the advantages of this method. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258556

LETTER
2415
Rapid and Regioselective Hydrogenation of a,b-Unsaturated Ketones and
Alkylidene Malonic Diesters Using Hantzsch Ester Catalyzed by Titanium
Tetrachloride
H
ydroge
n
u
ation of
a
,
b
-U
n
nsaturated
K
etone
C
s
and
A
lkylidene
h
Malonic Di
e
ester
s
, Yulin Lam*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Fax +6567791691; E-mail: chmlamyl@nus.edu.sg
Received 2 July 2010
interest in finding applications for HEH as a biomimetic
reducing agent and various catalysts have been developed
to accomplish these transformations.4 In our continuing
efforts to develop HEH-based synthetic methods,5 we
have recently explored the development of an alternative
acid catalyst for the conjugate reduction of a,b-unsaturat-
ed ketones 1 and herein report our findings. To our knowl-
edge, various catalysts for this reaction have already been
reported but the reactions still require both heating and
long reaction times.4b–4f,6 Herein we report that TiCl4 is an
active catalyst for a mild and expeditious transfer hydro-
genation of a variety of a,b-unsaturated ketones 1 with
HEH to give saturated ketones 2 in good yields.
Abstract: A regioselective hydrogenation of a,b-unsaturated ke-
tones and alkylidene malonic diesters using Hantzsch ester as the
reducing agent and titanium tetrachloride as a catalyst is described.
The short reaction times and mild reaction conditions are the advan-
tages of this method.
Key words: hydrogen transfer, reduction, a,b-unsaturated ketone,
alkylidene malonic diester, titanium tetrachloride
Hydrogenation is one of the most important transforma-
tions both in biological organisms and chemistry. In bio-
chemical reductions, this is commonly achieved by
enzymes and hydride reduction cofactors such as dihydro-
pyridine-based nucleotides NADH (reduced nicotinamide
adenine dinucleotide) and NADPH (reduced nicotinamide
adenine dinucleotide phosphate) whilst in chemical hy-
drogenations, the reaction has generally relied on metal
catalysts,1 metal hydrides,2 or the Hantzsch 1,4-dihydro-
pyridine (HEH) systems.3
To search for an alternative catalyst for the regioselective
reduction of a,b-unsaturated ketones with HEH, various
acids and Lewis acids were examined. With 1,3-diphenyl-
propenone (1a), the best result was observed with TiCl4
(entry 10, Table 1). To optimize the reaction, we screened
various solvents and found the reaction to be dependent
on both solvent and the amount of catalyst used (Table 2).
Amongst the solvents screened, THF was the best solvent
as the reaction gave the highest yield and was completed
within one hour (entry 2, Table 2).
The advantage of using HEH lies in the mildness of its re-
ducing ability thus enabling selective reduction of a par-
ticular functional group. Thus there has been much
Table 1 Reduction of Compound 1a
O
O
O
O
catalyst
EtO
OEt
+
N
H
1a (1 mmol)
HEH (1.5 mmol)
2a
Entry
Catalyst (equiv)
TCA (2)
Reaction conditions
Yield (%)a
30
1
2
3
4
5
toluene, reflux, 24 h
TCA (2)
MeCN, MW, 110 °C, 30 min
toluene, reflux, 24 h
trace
32
AcOH (2)
TFA (2)
toluene, reflux, 24 h
30
TFA (2)
MeCN, MW, 110 °C, 30 min
trace
6
HCl–H2O (2)
toluene, reflux, 24 h
NRb
SYNLETT 2010, No. 16, pp 2415–2420
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.09.2010
DOI: 10.1055/s-0030-1258556; Art ID: D17310ST
© Georg Thieme Verlag Stuttgart · New York

2416
J. Che, Y. Lam
LETTER
Table 1 Reduction of Compound 1a (continued)
O
O
O
O
catalyst
EtO
OEt
+
N
H
1a (1 mmol)
HEH (1.5 mmol)
2a
Entry
7
Catalyst (equiv)
proline (2)
Reaction conditions
toluene, reflux, 20 h
Yield (%)a
trace
8
9
TsOH·H2O (2)
TiCl4 (1.2)
TiCl4 (1.2)
AlCl3 (1.2)
AlCl3 (2)
toluene, r.t., 4 h
toluene, r.t., 1 h
THF, r.t., 1 h
trace
90
10
11
12
13
14
15
95
toluene, r.t., 1 h
toluene, r.t., 1 h
THF, r.t., 1 h
58
72
AlCl3 (1.2)
FeCl3 (2)
75
toluene, r.t., 4 h
toluene, r.t., 4 h
53
ZnCl2 (2)
42
a Isolated yield.
b NR means no apparent reaction.
Table 2 Optimization of the Reduction of 1a
O
O
O
O
EtO
OEt
TiCl4, r.t., 1 h
+
N
H
1a (1 mmol)
2a
HEH (1.5 mmol)
Entry
Equiv of TiCl4
Solvent
THF
Yield (%)a
1
2
3
4
5
6
7
0.2
1.2
2.2
1.2
1.2
1.2
1.2
52
95
86
60
62
70
90
THF
THF
CH2Cl2
CHCl3
MeCN
toluene
a Isolated yield.
We next explored the use of TiCl4 in the reduction of a va- strates the versatility of TiCl4 as a catalyst for the regiose-
riety of a,b-unsaturated ketones with HEH under the opti- lective reduction of a,b-unsaturated ketones. A plausible
mized conditions. The reaction proceeded selectively and mechanism for this reaction is shown in Scheme 1.
gave very good yields in all cases (Table 3). This demon-
Synlett 2010, No. 16, 2415–2420 © Thieme Stuttgart · New York

LETTER
Hydrogenation of a,b-Unsaturated Ketones and Alkylidene Malonic Diesters
2417
Table 3 Library of Compound 2
Entry
Substrate
Product
Yield (%)a
O
O
1
95 (96,b 94c)
1a
2a
O
O
O
O
2
3
4
5
90
95
95
90
1b
2b
O
O
S
S
1c
2c
O
O
1d
2d
O
O
O
O
OMe
NO2
OMe
NO2
1e
1f
2e
2f
6
7
90
85
O
O
O
O
1g
2g
8
9
82 (54d)
1h
2h
O
O
O
O
85
1i
2i
O
O
10
92
MeO
OMe
MeO
1j
OMe
2j
O
O
O
O
11
93
1k
2k
Synlett 2010, No. 16, 2415–2420 © Thieme Stuttgart · New York

2418
J. Che, Y. Lam
LETTER
Table 3 Library of Compound 2 (continued)
Entry
12
Substrate
Product
Yield (%)a
99
O
O
S
S
1l
2l
O
O
13
14
82
88
1m
1n
2m
2n
O
O
O
O
15
94
O
O
1o
2o
a Isolated yield.
b Reaction was carried out with HEH, Pd/C in refluxing EtOH for 8 h.4c
c Reaction was carried out with HEH in the presence of silica gel in benzene at 80 °C for 17 h.4d
d Reaction was carried out with HEH–AcOH in toluene at 100 °C for 15 h.4f
Encouraged by these results, we extended our study to reduced product 4a in quantitative yield. With this suc-
alkylidene malonic diesters. Earlier studies have shown cess, the scope of this protocol was extended to other
that benzylidene malonic diethyl ester 3a was unreactive alkylidene malonic diesters and the results obtained show
towards HEH even under reflux conditions.3d,7 However, that the procedure affords a very efficient approach for a
in the presence of Mg(ClO4)2 in acetonitrile or acetoni- selective reduction of these compounds (Table 4).
trile–methanol mixture and 2–6.5 hours of reflux, the car-
In summary, we have shown that the TiCl4-catalyzed
bon–carbon double bond of 3a and 4-nitrobenzylidene
HEH reduction of a,b-unsaturated ketones and alkylidene
malonic diethyl ester (3b) were shown to be selectively
malonic diesters is a rapid and experimentally simple pro-
cedure for the preparation of saturated ketones and alkyl
malonic diesters. The reaction expends the application of
HEH as a biomimetic reducing agent in synthetic organic
reduced with HEH or N-benzyl-1,4-dihydronicotinamide,
a NADH model, to provide 4a and 4b, respectively, in ca.
97% yields.7,8 For our initial study, 3a was treated with
HEH and TiCl4 in THF at room temperature for one hour.
transformations.
This gave the corresponding carbon–carbon double-bond-
TiCl4
H+ H–
O
O
Cl4Ti
O
O
O
TiCl4
EtO
EtO
OEt
OEt
R1
R2
R2
R1
R1
R2
N
H
O
O
O
O
Cl4Ti
O
O
EtO
OEt
R2
R1
R1
R2
N
H
N
Scheme 1 Proposed mechanism for the TiCl4-Hantzsch ester reduction of a,b-unsaturated ketones
Synlett 2010, No. 16, 2415–2420 © Thieme Stuttgart · New York

LETTER
Hydrogenation of a,b-Unsaturated Ketones and Alkylidene Malonic Diesters
2419
Table 4 Library of Compound 4
Entry
Substrate
Product
Yield (%)a
99 (96b)
COOEt
COOEt
1
COOEt
COOEt
3a
4a
COOEt
COOEt
2
93 (97c)
COOEt
COOEt
O2N
O2N
4b
3b
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
O
O
3
4
99
99
3c
4c
COOEt
COOEt
S
S
3d
4d
COOEt
COOEt
5
90
COOEt
COOEt
Et
Et
3e
4e
a Isolated yield.
b Reaction was carried out with N-benzyl-1,4-dihydronicotinamide, Mg(ClO4)2 in refluxing MeCN for 2 h.7
c Reaction was carried out with HEH, Mg(ClO4)2 in refluxing MeCN–MeOH for 6.5 h.8
Acknowledgment
General Procedure for the Reduction of a,b-Unsaturated Ke-
tones
The authors thank the National University of Singapore for the fun-
ding support provided (R-143-000-399-112).
To the respective a,b-unsaturated ketone (1 mmol) in THF (5.0 mL)
was added HEH (0.38g, 1.5mmol) and TiCl4 (1.2 mL of 1 M TiCl4
in CH2Cl2, 1.2 mmol). The reaction mixture was stirred at r.t. for 60
min. Thereafter, the reaction mixture was concentrated and purified
by flash column chromatography (Merck silica gel 60, F254).
References
(1) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 6797. (b) Knowles,
W. S. Angew. Chem. Int. Ed. 2002, 41, 1998.
General Procedure for the Synthesis of Alkylidene Malonic Di-
esters
(c) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett.
2003, 5, 2417. (d) Lipshutz, B. H.; Servesko, J. M.;
Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6,
1273.
Compound 3a was synthesized according to a procedure which was
reported earlier.3d Compounds 3b–e were synthesized as follows:
To a solution of the respective aldehyde (5 mmol), AcOH (0.0601
g, 1 mmol), and piperidine (0.0852 g, 1 mmol) in toluene (25 mL)
was added diethyl malonate (0.8009 g, 5 mmol). The reaction mix-
ture was refluxed for 12 h during which the H2O produced was re-
moved with a Dean–Stark trap. Thereafter, the reaction mixture was
concentrated under reduced pressure and the residue obtained was
dissolved in EtOAc (20 mL), washed with H2O, concentrated, and
purified by flash column chromatography (Merck silica gel 60,
F254) to give compounds 3b–e.
(2) (a) Yoon, N. M. Pure Appl. Chem. 1996, 68, 843.
(b) Brown, H. C. Tetrahedron 1979, 35, 567.
(3) (a) Murakami, Y.; Kikuchi, J.-I.; Hisaeda, Y.; Hayashida, O.
Chem. Rev. 1996, 96, 721. (b) Stout, D. M.; Meyers, A. I.
Chem. Rev. 1982, 82, 223. (c) Eisner, U.; Kuthan, J. Chem.
Rev. 1972, 72, 1. (d) Garden, S. J.; Guimarães, C. R. W.;
Corréa, M. B.; de Oliveira, C. A. F.; Pinto, A. C.;
Alencastro, R. B. J. Org. Chem. 2003, 68, 8815. (e) Zhu,
X.-Q.; Wang, H.-Y.; Wang, J.-S.; Liu, Y.-C. J. Org. Chem.
2001, 66, 344.
General Procedure for the Reduction of Alkylidene Malonic Di-
esters
(4) (a) You, S.-L. Chem. Asian J. 2007, 2, 820. (b) Fujii, M.;
Nakamura, K.; Yasui, S.; Oka, S.; Ohno, A. Bull. Chem. Soc.
Jpn. 1987, 60, 2423. (c) Liu, Q.; Li, J.; Shen, X.-X.; Xing,
R.-G.; Yang, J.; Liu, Z.; Zhou, B. Tetrahedron Lett. 2009,
50, 1026. (d) Nakamura, K.; Fujii, M.; Ohno, A.; Oka, S.
Tetrahedron Lett. 1984, 25, 3983. (e) Yasui, S.; Fujii, M.;
Nakamura, K.; Ohno, A. Bull. Chem. Soc. Jpn. 1987, 60,
963. (f) Inoue, Y.; Imaizumi, S.; Itoh, H.; Shinya, T.;
Hashimoto, H.; Miyano, S. Bull. Chem. Soc. Jpn. 1988, 61,
3020. (g) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C.
Acc. Chem. Res. 2007, 40, 1327. (h) Barbe, G.; Charette,
A. B. J. Am. Chem. Soc. 2008, 130, 18.
To the alkylidene malonic diester (0.5 mmol) in THF (2.0 mL) was
added Hantzsch ester (0.1898 g, 0.75 mmol) and TiCl4 (0.6 mL of 1
M TiCl4 in CH2Cl2, 0.6 mmol). The reaction mixture was stirred at
r.t. for 60 min, concentrated, and then purified by flash column
chromatography (Merck silica gel 60, F254) to give compound 4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 16, 2415–2420 © Thieme Stuttgart · New York

2420
J. Che, Y. Lam
LETTER
(5) He, R.; Toy, P. H.; La, Y. Adv. Synth. Catal. 2008, 350, 54.
(6) (a) Fujii, M.; Aida, T.; Yoshihara, M.; Ohno, A. Bull. Chem.
Soc. Jpn. 1990, 63, 1255. (b) Yasui, S.; Fujii, M.; Ohno, A.
Bull. Chem. Soc. Jpn. 1987, 60, 4019. (c) Xu, H.-J.; Liu,
Y.-C.; Fu, Y. Chin. J. Chem. 2008, 26, 599.
(7) Shinkai, S.; Kusano, Y.; Ide, T.; Sone, T.; Manabe, O. Bull.
Chem. Soc. Jpn. 1978, 51, 3544.
(8) Xu, H.-J.; Deng, G.; Yu, Q. J. Chem. Soc., Chem. Commun.
1987, 916.
Synlett 2010, No. 16, 2415–2420 © Thieme Stuttgart · New York