Alumina-promoted fast solid-phase Michael addition of enamines with conjugated enones under microwave irradiation

Article abstract of DOI:10.1016/S0040-4039(01)02049-4

A fast alumina-promoted solid-phase Michael addition of enamines to conjugated enones is described under microwave irradiation in high yields. The 1,5-diketo Michael adducts have been converted into a novel class of 1′,2′-diazepino(17,16-d′) steroids.

Full text of DOI:10.1016/S0040-4039(01)02049-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 143–145
Alumina-promoted fast solid-phase Michael addition of enamines
with conjugated enones under microwave irradiation
Utpal Sharma,† Utpal Bora, Romesh C. Boruah* and Jagir S. Sandhu
Organic Chemistry Division, Regional Research Laboratory, Jorhat 785006, India
Received 18 September 2001; revised 18 October 2001; accepted 26 October 2001
Abstract—A fast alumina-promoted solid-phase Michael addition of enamines to conjugated enones is described under microwave
irradiation in high yields. The 1,5-diketo Michael adducts have been converted into a novel class of 1%,2%-diazepino(17,16-d%)
steroids. © 2001 Elsevier Science Ltd. All rights reserved.
The Michael addition has attracted enormous attention
as one of the most important carbonꢀcarbon bond
forming reactions in organic synthesis.1 In general,
Michael additions are conjugate additions of enolates
to a,b-unsaturated carbonyl compounds affording 1,5-
dioxo compounds and are generally carried out under
strongly basic conditions.2 However, such base-cata-
lyzed methods are sometimes detrimental3 to base sensi-
tive functionalities and often lead to side reactions like
auto-oxidation or retro-Michael type decompositions.1a
In order to circumvent this problem considerable atten-
tion has been directed towards the search for more
convenient methods.4 On the other hand, enamines
constitute an important class of Michael donors that
Scheme 1.
Keywords: Michael addition; enamine; enone; microwave; alumina.
* Corresponding author. Tel.: 091 376 3370327; fax: 091 376 3370011; e-mail: rc boruah@yahoo.com
–
† Present address: Department of Chemistry, University of Hawaii, Manoa, Honolulu, HI, USA.
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02049-4

144
U. Sharma et al. / Tetrahedron Letters 43 (2002) 143–145
have been utilized in complicated syntheses.5 However,
a literature survey revealed that in comparison to eno-
lates, the use of enamines as Michael donors is signifi-
cantly less common. The major disadvantage associated
with enamines is their susceptibility to hydrolysis,6
causing restrictions to their general use in Michael
reactions. Consequently, the development of the use of
enamines in Michael reactions that are efficient and
offer operational advantages, remains a challenging
problem to organic chemists.
When freshly prepared 1-morpholino-1-cyclohexene
(2a, 1.5 mmol) was mixed thoroughly with 16-DPA (1a,
1.0 mmol) and basic alumina (1 g) and irradiated in the
solid phase at 80% power for 6 min, the 3b-acetoxy-16-
(2%-cyclohexanoyl)pregnenolone (3a) was isolated in
79% yield. The product was identified on the basis of
analytical and spectroscopic data.13 The 13C NMR
spectra (300 MHz) indicated the presence of the two
characteristic carbonyl signals at l 219.8 and 207.6 for
the diketo adduct 3a. In a similar manner, the corre-
sponding Michael adducts 3b–f were obtained from
pregnenolones 1a–c and enamines 2a–b in high yields,
under microwave irradiation (Table 1).
Microwave energy is an unconventional energy source
whose utility in synthetic organic chemistry has been
increasingly recognized in recent years.7 Microwave-
promoted solid-phase heterogeneous reactions have
attracted immense interest as environmentally benign
reaction methodologies.8 These methods are advanta-
geous over conventional homogeneous reactions in the
fact that they provide greater selectivity, enhanced reac-
tion rates, cleaner products and manipulative
simplicity.9
We have also examined the Michael addition of enam-
ines (2a–b) with alicyclic conjugated enones (1d–f) in
solid phase under microwave irradiation. The forma-
tion of the 1,5-diketo products 3g–l could be achieved
from 2a–b and 1d–f within 5–8 min, in 82–88% yields
(Scheme 2).
However, it was observed that the reactions were slug-
gish in the absence of basic alumina, which indicated
the catalytic role of alumina in this solid-phase reac-
tion. In addition, the conventional thermal reactions of
1a–f with 2a–b failed to yield the expected products
even on prolonged heating.
In continuation of our research on the chemistry of
steroids,10 we required an efficient preparation of 1,5-
diketones as precursors to D-ring annelated hetero-
steroids.11 As shown in Scheme 1, we considered readily
available 16-dehydropregnenolone acetate (16-DPA) to
be an ideal substrate as a Michael acceptor. Herein, we
report our results on the alumina catalysed, fast, solid-
phase Michael addition reaction of cyclic enamines with
conjugated enones for carbonꢀcarbon bond formation
under microwave irradiation.12
In order to investigate the scope of this reaction the
adduct 3a was reacted with hydrazine hydrochloride in
refluxing ethanol for 4 h to afford 3b-acetoxy-3%-
Table 1. Alumina-promoted Michael addition of enamines to enones under microwave irradiationa
Entry
Enone
Ar
Enamineb
Productc
Ar
Yieldd (%)
Reaction time (min)
R
R
n
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
Ac
Ac
Bz
Bz
H
–
–
–
–
–
–
Ph
Ph
p-ClPh
p-ClPh
p-Tolyl
p-Tolyl
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ac
Ac
Bz
Bz
H
–
–
–
–
–
–
Ph
Ph
p-ClPh
p-ClPh
p-Tolyl
p-Tolyl
2
1
2
1
2
1
2
1
2
1
2
1
89
86
87
85
83
81
83
80
85
82
88
86
6
5
6
7
8
8
5
6
6
6
7
8
H
H
Me
Me
Me
Me
Ph
Ph
Me
Me
Me
Me
Ph
Ph
9
10
11
12
3j
3k
3l
1f
a Reactions were carried using a Synthwave 402 Prolabo focussed microwave equipment at 80% power and temperature limitation of 250°C.
b Freshly prepared enamines.
c All products gave satisfactory spectroscopic and analytical data.
d Isolated yields after separation by column chromatography.
Scheme 2.

U. Sharma et al. / Tetrahedron Letters 43 (2002) 143–145
145
methyl-(6%,7%-cyclohexano)-1%,2%-diazepino(17,16-d%)and-
rost-5-ene (4a) in 80% yield.13 The heterosteroids 4b–f
were similarly prepared from 3b–f in 77–86% yields.
R. Tetrahedron 1998, 54, 6293; (c) Varma, R. S.;
Meshram, H. M. Tetrahedron Lett. 1997, 38, 7973.
8. (a) Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett.
2000, 41, 531; (b) Kabalka, G. W.; Wang, L.; Pagni, R.
M. Synlett 2001, 676.
9. (a) Varma, R. S. Green Chem. 1999, 43 and references
cited therein; (b) Ranu, B. C.; Guchhait, S. K.; Ghosh,
K.; Patre, A. Green Chem. 2000, 2, 5.
10. (a) Ahmed, S.; Boruah, R. C. Tetrahedron Lett. 1996, 37,
8251; (b) Boruah, R. C.; Ahmed, S.; Sharma, U.; Sandhu,
J. S. J. Org. Chem. 2000, 65, 922; (c) Ahmed, S.; Boruah,
R. C. Tetrahedron Lett. 1997, 38, 6749; (d) Ahmed, S.;
Boruah, R. C. Ind. J. Chem. 1998, 37B, 838; (e) Ahmed,
S.; Boruah, R. C. Tetrahedron Lett. 1997, 38, 1845; (f)
Boruah, R. C.; Ahmed, S.; Sharma, U.; Sandhu, J. S. Ind.
J. Chem. 1999, 38B, 274; (g) Ahmed, S.; Sharma, U.;
Longchar, M.; Boruah, R. C.; Sandhu, J. S. Synth.
Commun. 2000, 30, 771.
11. (a) Jarman, M.; Barrie, S. E.; Llera, J. M. J. Med. Chem.
1998, 41, 5375; (b) Potter, G. A.; Barrie, S. E.; Jarman,
M.; Rowlands, M. G. J. Med. Chem. 1995, 38, 2463.
12. Sharma, U.; Ahmed, S.; Boruah, R. C. Tetrahedron Lett.
2000, 41, 3493.
In conclusion, we have reported an efficient solid-phase
Michael reaction of enamines with enones promoted by
alumina. The reaction is noteworthy, as it constitutes
the first known example of the fast Michael addition of
enamines using microwave irradiation. The method is
advantageous over conventional methods because it
avoids strongly basic or acidic conditions. Moreover,
the easy work-up procedure and solvent-free conditions
provides an environmentally friendly method. Further
work on the generalization of this reaction is in
progress.
Acknowledgements
We are grateful to the Department of Science and
Technology, Government of India, New Delhi, for
financial support of this work.
13. Selected analytical data for Michael adducts and
heterosteroids.
3b-Acetoxy-16-(2%-cyclohexanoyl)pregnenolone (3a): yield
79%; mp 178°C (hexane); [h]2D5=+20.5 (c 0.3%, CHCl3);
References
IR (KBr): wmax 2950, 1740, 1710, 1460, 1440 cm−1 1H
;
NMR (CDCl3): l 5.37 (bs, 1H), 4.65 (bs, 1H), 2.17–3.00
(m, 4H), 2.15 (s, 3H), 2.06–2.14 (m, 7H), 2.02 (s, 3H),
1.02–2.01 (m, 17H), 1.01 (s, 3H), 0.63 (s, 3H); 13C NMR
(CDCl3): l 219.8, 207.6, 169.5, 138.8, 121.2, 72.8, 67.1,
54.4, 52.3, 48.9, 44.0, 37.7, 37.3, 37.0, 36.4, 36.0, 35.7,
30.8, 30.6, 30.1, 30.1, 27.9, 26.8, 20.5, 19.7, 19.3, 18.3,
13.2; MS (EI) m/z 394 (M+−CH3COOH). Anal. calcd for
C29H42O4: C, 76.61; H, 9.31. Found: C, 76.65; H, 9.39.
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3b-Acetoxy-16-(2%-cyclopentanoyl)pregnenolone
(3b):
yield 79%, mp 175°C (hexane); [h]2D5=+18.5 (c 0.3%,
CHCl3); IR (KBr): wmax 2910, 1725, 1710, 1690, 1650,
1
1460, 1440 cm−1; H NMR (CDCl3): l 5.32 (bs, 1H), 4.61
(bs, 1H), 2.00–3.05 (m, 4H), 2.16–2.10 (m, 5H), 2.15 (s,
3H), 2.03 (s, 3H), 2.01–1.02 (m, 17H), 1.01 (s, 3H), 0.63
(s, 3H); 13C NMR (CDCl3): l 220.0, 207.9, 169.8, 139.1,
121.3, 73.0, 67.0, 54.6, 52.5, 49.2, 44.0, 38.2, 37.3, 36.7,
36.3, 35.9, 31.1, 31.0, 30.0, 29.8, 28.2, 27.0, 20.7, 20.2,
19.5, 18.6, 13.4; MS (EI) m/z 380 (M+−CH3COOH).
Anal. calcd for C28H40O4: C, 76.32; H, 9.15. Found: C,
76.35; H, 9.10.
3b-Acetoxy-3%-methyl-(6%,7%-cyclohexano)-1%,2%-diazepino-
(17,16-d%)androst-5-ene (4a): yield 80%; mp 181°C (dec.);
IR (KBr): wmax 2900, 1725, 1710, 1695, 1605, 1400 cm−1
;
1H NMR (CDCl3): l 5.25 (bs, 1H), 4.51 (m, 1H), 2.20–
2.70 (m, 4H), 1.98 (s, 3H), 1.92 (s, 3H), 2.95–1.10 (m,
24H), 0.80 (s, 3H), 0.50 (s, 3H); MS (EI) m/z 390
(M+−CH3COOH). Anal. calcd for C29H42O2N2: C, 77.29;
H, 9.39, N, 6.21. Found: C, 77.22; H, 9.35, N, 6.23.
3b-Acetoxy-3%-methyl-(6%,7%-cyclopentano)-1%,2%-diazepino-
(17,16-d%)androst-5-ene (4b): yield 78%; mp 176°C (dec.);
6. (a) Stamhuis, E. J.; Maas, W. J. Org. Chem. 1965, 30,
2156; (b) Maas, W.; Janssen, M. J.; Stamhuis, E. J.;
Wynberg, H. J. Org. Chem. 1967, 32, 1111.
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ville, OH, 1997; pp. 357–365; (b) Varma, R. S.; Dahiya,
IR (KBr): wmax 2910, 1730, 1690, 1605, 1450 cm−1 1H
;
NMR (CDCl3): l 5.20 (bs, 1H), 4.30 (m, 1H), 2.10–2.75
(m, 4H), 1.93 (s, 3H), 1.88 (s, 3H), 2.95–1.10 (m, 22H),
0.89 (s, 3H), 0.50 (s, 3H); MS (EI) m/z 376 (M+−
CH3COOH). Anal. calcd for C28H40O2N2: C, 77.02; H,
9.23, N, 6.41. Found: C, 77.07; H, 9.27, N, 6.49.