A facile synthesis of 1,6-diketones via a three-component Michael addition reaction

Article abstract of DOI:10.1055/s-2003-40821

A convenient one-pot synthesis of 1,6-diketones has been accomplished by a three-component Michael addition reaction of α-bromoketone, malononitrile and α,β-unsaturated keto compounds.

Full text of DOI:10.1055/s-2003-40821

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1506
LETTER
A Facile Synthesis of 1,6-Diketones via a Three-Component Michael Addition
Reaction
A
F
acile Synthesis
n
of 1,6-Dike
i
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat, 785006, India
E-mail: rc_boruah@yahoo.co.in
Received 22 April 2003
ployed for the preparation of 1,4-diketones via an aldol
Abstract: A convenient one-pot synthesis of 1,6-diketones has
been accomplished by a three-component Michael addition reaction
of a-bromoketone, malononitrile and a,b-unsaturated keto com-
pounds.
condensation reaction.15 Therefore, we were fascinated to
explore the utility of a-bromoketone to develop a new
route to 1,6-diketo compounds.2 Herein, we wish to report
an efficient one-pot preparation of 1,6-diketones using a
three-component Michael addition reaction from a-bro-
moketone, malononitrile and a,b-unsaturated keto com-
pounds.
Key words: 1,6-diketone, three-component, Michael addition, ma-
lononitrile, a,b-unsaturated ketones
We found that methanolic potassium hydroxide can effi-
ciently promote a three-component reaction of 2-bromo-
4¢-methylacetophenone 1a, malononitrile and 16-DPA
2a at 15–20 °C for 30 minutes. On completion of the
reaction (vide TLC) and work up it afforded 16-(1¢,1¢-
dicyano-3¢-p-tolyl-3¢-oxo-propano)-pregnenolone-3-ace-
tate 3a in 80% yield (Scheme 1). The product was charac-
terized on the basis of its analytical and spectral data.
Similarly, the three component reaction of malononitrile
1a,b and 2a,b afforded product 16-(1¢,1¢-dicyano-3¢-p-
tolyl-3¢-oxo-propano)-pregnenolone-3-benzoate 3b, 16-
(1¢,1¢-dicyano-3¢-phenyl-3¢-oxo-propano)-pregnenolone-
3-acetate 3c and 16-(1¢,1¢-dicyano-3¢-phenyl-3¢-oxo-pro-
pano)-pregnenolone-3-benzoate 3d in high yields
(Table 1, entry 2–4).
1,6-Diketones are highly important substance in organic
synthesis because of the fact that they are widely em-
ployed for construction of biologically potential five and
six membered carbocycles and heterocycles.1 Whereas
many ring closing reactions of 1,6-diketo compounds
have been reported in the literature,1,2 much less work
have been focussed on their synthesis. Among the conve-
nient methods reported for synthesis of 1,6-diketones are
– the oxone mediated oxidative cleavage of cyclohex-
anone,3 carbonylation of trialkyl boranes,4 decomposition
of t-butylperoxycycloalkanol,5 siloxycyclo propanes6 or
b-hydroxy hydroperoxides.7 However, most of them in-
volve multistep synthesis, high pressure reactions or easi-
ly inaccessible substrates and suffer from disadvantages
with respect to convenience, selectivity and efficiency.
The Michael addition of enolate or enamine to a,b-unsat-
urated compounds provides an efficient two-component
strategy for the preparation of 1,5-diketones.8 To the best
of our knowledge such a general methodology for the
preparation of 1,6-dicarbonyl compound is obscure.
On the other hand, multicomponent reactions (MCR) at-
tract enormous importance from the point of combinatori-
al chemistry9 and inherit advantages over two-component
reactions in several aspects such as the simplicity of a one-
pot procedure, possible structural variations, complicated
synthesis and large number of accessible compounds.10
Nevertheless, continued efforts are being made to explore
new MCRs for developing popular organic reactions.11
Recently in the context of our ongoing research work on
D-ring steroids,12 we reported a simple and efficient
Michael addition reaction for the preparation of 1,5-dike-
tones directly from conjugated enone and enamine.13 Ad-
ditionally, we employed a-bromoketone for a one-pot
preparation of indolizines by a three component reac-
tion.14 Furthermore, a-bromoketones are recently em-
Scheme 1
In order to demonstrate the efficiency and the scope of the
present reaction, we applied this three-component Micha-
el reaction to a variety of a,b-unsaturated enones.16 The
results are summarized in the Table 1. The KOH/MeOH
catalysed reactions of 1a, malononitrile and aliphatic con-
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1506,1508,ftx,en;D09403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

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LETTER
A Facile Synthesis of 1,6-Diketones
1507
jugated enones 4a–c at room temperature afforded the
1,6-diketoproducts 5a–c in 70–74% yields (Table 1, en-
tries 5–7). Similarly, acrylic esters 4d,e afforded corre-
sponding 6-ketoesters 5d,e in good yields (entries 8, 9).
The three-component Michael reaction of 1b with mal-
ononitrile and 4a–f afforded diketo- and ketoesters 5g–j in
fair to good yields (entries 10–14).
Table 1 Preparation of 1,6-Dicarbonyl Compounds 5a–j by 3-CRa
Scheme 2
In conclusion we have reported the first example for the
preparation of 1,6-diketones from a-bromoketones using
a three-component Michael reaction. The reaction is sim-
ple, facile and expected to be a general route for combina-
torial synthesis of a wide range of 1,6-diketo compounds.
Entry Productb
R
R1
R2
Reaction Yieldc
(min)
30
40
30
45
30
40
50
25
25
40
45
50
30
30
(%)
80
77
88
82
72
70
74
78
75
68
66
70
75
70
Acknowledgement
We wish to thank Dr P G Rao, Director of Regional Research labo-
ratory, Jorhat for providing laboratory facilities to carry out this
work.
1
2
3a
3b
3c
3d
5a
5b
5c
5d
5e
5f
Ac
Bz
Ac
Bz
Me
Me
Me
M
p-tolyl
p-tolyl
Ph
Ph
H
–
–
3
–
References
4
–
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a Carried out in a manner as described in experimental.
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The 3-CR is expected to proceed via initial condensation
of a-bromoketone 1 with malononitrile to afford b,b-dicy-
anoketone 6 which further undergoes in situ Michael ad-
dition reaction with a,b-unsaturated ketone 4 in presence
of base to yield product 5. In order to support the proposed
mechanism of 3-CR, the compound 6 was prepared inde-
pendently from 2-bromo-4¢-methylacetophenone 1a and
malononitrile17 and then employed in a two component re-
action with benzylideneacetophenone 4c to afford 5c in
65% yield (Scheme 2). However an attempt to carry out
condensation reaction of the Michael adduct 718 and 2-
bromo-4¢-methylacetophenone 1a failed in our hand.
(9) (a) Weber, L.; Illegen, K.; Almstetter, M. Synlett 1999, 366.
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Synlett 2003, No. 10, 1506–1508 © Thieme Stuttgart · New York

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1508
A. Saikia et al.
LETTER
(11) (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov,
A. A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D.
H. Org. Lett. 2002, 423. (b) List, B.; Castello, C. Synlett
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(g) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J.
Tetrahedron Lett. 2002, 43, 6485. (h) Bertozzi, F.;
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8251. (b) Sharma, U.; Ahmed, S.; Boruah, R. C.
H, q, J = 6.8 Hz), 3.55 (2 H, s), 2.50 (4 H, m), 2.20 (3 H, s),
1.20 ( 3H, t, J = 6.8Hz). 13C NMR (CDCl3): d = 216.7, 182.5,
127.8, 127.3, 125.6, 122.6, 119.6, 118.3, 115.3, 109.7, 59.2,
32.5, 30.2, 28.6, 20.7, 14.6, 13.6. MS (ESI): m/z = 321 (M+
+ 23). Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N,
9.39. Found: C, 68.27; H, 6.19; N, 9.31.
(17) Preparation of 1,1-Dicyano-3-(p-tolyl)-3-propanone (6):
To a 50 mL round bottom flask charged with 2-bromo-4¢-
methylacetophenone 1a (0.5 g, 2.3 mmol) and malononitrile
(0.24 g, 3.6 mmol) in MeOH (20 mL) was added powdered
KOH (0.20 g, 3.6 mmol) in small portion and stirred at r.t.
TLC monitoring showed completion of reaction after 20
min. The solvent was removed under reduced pressure in a
rotavapor and the residue was extracted with chloroform
(2 × 15 mL), washed with H2O and dried over anhyd
Na2SO4. Removal of solvent gave a crude product which
was crystallized from hexane/chloroform (10/90) to obtain 6
in 92% yield, mp 98 °C. IR (KBr): nmax = 2955, 1675, 1605,
1454, 1298 cm–1. 1H NMR (CDCl3): d = 7.68 (2 H, d, J = 8.0
Hz), 7.18 (2 H, d, J = 8.0 Hz), 4.30 (1 H, t, J = 6.5 Hz), 3.60
(2 H, d, J = 6.5 Hz), 2.40 (3 H, s). MS (ESI): m/z = 221 (M+
+ 23). Anal. Calcd for C12H10N2O: C, 72.71; H, 5.08; N,
14.13. Found: C, 72.89; H, 5.02; N, 14.24.
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(15) Nevar, N. M.; Kelin, A. V.; Kulinkovich, O. G. Synthesis
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(16) Typical Procedure for Three-Component Reaction:
Preparation of Ethyl-3,3-dicyano-4-(p-toluoyl)valerate
(5d): A 100 mL round bottom flask, equipped with a
magnetic stirrer, was charged with a mixture of 2-bromo-4¢-
methylacetophenone 1a (0.5 g, 2.34 mmol), malononitrile
(0.17 g, 2.50 mmol) and ethyl acrylate 4d (0.25 g, 2.50
mmol) in MeOH (50 mL). The reaction mixture was cooled
to 15 °C and to it was added finely powdered KOH (0.14 g,
2.50 mmol) in small portions at the maximum speed of the
magnetic stirrer. The mixture was stirred vigorously at 15–
20 °C for 25 min. On completion of reaction (TLC
monitored), it was poured into 100 mL H2O and extracted
with CH2Cl2 (2 × 30 mL), washed with H2O and dried over
Na2SO4(anhyd). Removal of solvent afforded 5d in 78%
yield, mp 70 °C (MeOH). IR (KBr): nmax = 2975, 2251,
1733, 1678, 1605, 1453, 1237 cm–1. 1H NMR (CDCl3): d =
7.60 (2 H, d, J = 8.10 Hz), 7.10 (2 H, d, J = 8.10 Hz), 4.02 (2
(18) Preparation of 3-Benzoyl-2-phenyl-1,1-dicyano-propane
(7): To a 50 mL round bottom flask charged with
benzylidene acetophenone 4c (0.5 g, 2.4 mmol) and
malononitrile (0.24 g, 3.6 mmol) in MeOH (20 mL) was
added powdered KOH (0.20 g, 3.6 mmol) in small portions
and the mixture stirred at r.t. After 20 min, the solvent was
removed under reduced pressure and the residue was
extracted with chloroform (2 × 15 mL), washed with H2O,
dried over anhyd Na2SO4 and solvent removed. The crude
product was crystallized from hexane/chloroform (10/90) to
obtain 7 in 88% yield, mp 116 °C. IR (KBr): nmax = 2902,
1682, 1596, 1449, 1235 cm–1. 1H NMR (CDCl3): d = 7.80–
6.95 (10 H, m), 4.50 (1 H, d, J = 6.0 Hz), 3.80 (1 H, m), 3.50
(2 H, d, J = 6.5 Hz). MS (ESI): m/z = 297 (M+ + 23). Anal.
Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.96; H, 5.27; N, 10.42.
Synlett 2003, No. 10, 1506–1508 © Thieme Stuttgart · New York