Microwave-mediated facile synthesis of steroid-like 1,5-diketones from Mannich salts

Article abstract of DOI:10.1080/00397910701845514

A facile synthesis of some diketones that fit into a steroid motif was achieved from Mannich salts and cyclic ketones under microwave irradiation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845514

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Microwave‐Mediated Facile Synthesis of
Steroid‐like 1,5‐Diketones from Mannich Salts
H. Surya Prakash Rao a , E. Poonguzhali a & S. P. Senthilkumar a
a Department of Chemistry , Pondicherry University , Puducherry, India
Published online: 22 Feb 2008.
To cite this article: H. Surya Prakash Rao , E. Poonguzhali & S. P. Senthilkumar (2008) Microwave‐Mediated
Facile Synthesis of Steroid‐like 1,5‐Diketones from Mannich Salts, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:6, 937-942, DOI:
10.1080/00397910701845514
To link to this article: http://dx.doi.org/10.1080/00397910701845514
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Synthetic Communicationsw, 38: 937–942, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845514
Microwave-Mediated Facile Synthesis
of Steroid-like 1,5-Diketones from
Mannich Salts
H. Surya Prakash Rao, E. Poonguzhali, and
S. P. Senthilkumar
Department of Chemistry, Pondicherry University, Puducherry, India
Abstract: A facile synthesis of some diketones that fit into a steroid motif was achieved
from Mannich salts and cyclic ketones under microwave irradiation.
Keywords: 1,5-diketones, Mannich salt, microwave, steroids, 1,5,9-triketones
The A-ring aromatic steroids, for example, estrone 1 (Fig. 1), are an important
group of hormones and drug molecules.[1] The steroids, in general, have a
cyclopentaphenanthrene (Diels hydrocarbon) carbon framework with ABCD
rings arranged as shown in structure 1. The 1,5-diketones of type 2 (Fig. 1)
having A and D rings fit well into the steroid motif, and therefore their
synthesis assumes importance. The 1,5-diketones 2 can be prepared from
phenyl vinyl ketones and cyclic ketones under thermal activation or by
using a base.[2]
Austin and coworkers have shown that heating Mannich bases with cyclic
ketones 4 furnishes 1,5-diketones 2 in moderate yields.[3] In this case, the
Mannich bases were behaving as precursors for in situ generated phenyl
vinyl ketones. We have previously reported that heating a mixture of
Mannich bases and cyclic ketones at 1558C under solvent-free conditions
furnished 1,5-diktones 2 and 1,5,9-triketones 5 in moderate yield.[4] The
Received September 26, 2007
Address correspondence to H. Surya Prakash Rao, Department of Chemistry, Pon-
dicherry University, Puducherry 605 014, India. E-mail: hspr.che@pondiuni.edu.in
937

938
H. S. P. Rao, E. Poonguzhali, and S. P. Senthilkumar
Figure 1. Structures of estrone and 1,5-diketones.
Mannich bases are generally prepared by neutralization of the Mannich salts,
which in turn are prepared from aryl methyl ketones, formaldehyde, and
dimethylamine hydrochloride.[5] We now report that the reaction of the
Mannich salts 3 with cyclic ketones 4 can be achieved conveniently under
microwave (MW) irradiation to furnish the diketones 2 in good yield
(Scheme 1). Under the present reaction conditions, there is no need to
employ either Mannich bases or phenyl vinyl ketones as one of the reacting
partners to get diketones 2.
The Mannich salt 3a, prepared from acetophenone, formaldehyde, and
dimethylammonium chloride, was mixed well with 1 molar equivalent of
cyclopentanone 4a in 5 equivalents of PEG-200 (polyethylene glycol-200)
and irradiated in a MW oven at 370 W for 2 min to get a mixture of 1,5-
diketone 2a and 1,5,9-triketones 5a in the ratio of 44:55 in 60% combined
yield (Scheme 1 and Table 1, entry 1). The product ratio was estimated
from integration of the relevant signals in the 13C NMR spectra of the
mixture. The 1,5,9-triketones 5a were obtained as a mixture of cis and trans
isomers formed in a 1:1 ratio. Compared to the reaction in PEG-200 reflux,
the MW-mediated reaction was cleaner and faster. As anticipated, when 2
or 3 equivalents of the Mannich salt 3a were employed, the yield of the
1,5,9-triketones 5a increased at the cost of diketone 2a (entries 3 and 4). On
the other hand, when 2 or 3 equivalents of cyclopentanone 4a were
employed in the reaction, the diketone 2a was obtained in higher yield
Scheme 1. Reagents and conditions: i) PEG-200, MW (370 W), 2 min, 63–78%.

Synthesis of 1,5-Diketones from Mannich Salts
939
Table 1. Reaction of the Mannich salt 3a with cyclopentanone 4a/cyclohexanone 4b
Reactants and
their ratio
Products and
their ratio
Entry
Solventa
Yieldb (%)
1
2
3a:4a ¼ 1:1
3a:4a ¼ 1:1
3a:4a ¼ 2:1
3a:4a ¼ 3:1
3a:4a ¼ 1:2
3a:4a ¼ 1:3
3b:4a 5 1:1
3a:4b ¼ 1:1
3a:4b ¼ 1:1
3a:4b ¼ 2:1
3a:4b ¼ 3:1
3a:4b ¼ 1:2
3a:4b ¼ 1:3
3b:4b ¼ 1:1
3a:6 ¼ 1:1
PEG 200
EG
60
36
66
68
84
87
84
90
45
80
85
90
92
80
67
72
2a:5a ¼ 45:55
2a:5a ¼ 55:45
2a:5a ¼ 28:72
2a:5a ¼ 26:74
2a:5a ¼ 72:29
2a:5a ¼ 80:20
2b:5b ¼ 95:05
2c:5c ¼ 40:60
2c:5c ¼ 55:45
2c:5c ¼ 30:70
2c:5c ¼ 25:75
2c:5c ¼ 60:40
2c:5c ¼ 60:40
2d:5d ¼ 75:25
7a
3
PEG 200
PEG 200
PEG 200
PEG 200
PEG 200
PEG 200
EG
4
5
6
7
8
9
10
11
12
13
14
15
16
PEG 200
PEG 200
PEG 200
PEG 200
PEG 200
PEG 200
PEG 200
3b:6 ¼ 1:1
7b
aPEG-200 ¼ polyethylene glycol of average molecular weight of 200, EG ¼
ethylene glycol.
bCombined yield of diketone 2 and triketone 5.
(entries 5 and 6). Generality of the reaction was established by reacting
Mannich salt 3b with cyclopentanone 4a to furnish 1,5-diketone 2b and
1,5,9-triketones 5b in the ratio of 95:5, 84% yield (entry 7). The diketone
2b has a carbon skeleton that fits into estrone framework. The MW-
mediated reaction of the Mannich salts 3a with cyclohexanone 4b furnished
1,5-diketone 2c and the 1,5,9-triketone 5c in good yield (entry 8). Employ-
ment of excess Mannich salt 3a improved the yield of the triketone 5c
(entries 10 and 11), whereas when excess cyclohexanone was used,
diketone 2c was the major product (entry 12 and 13). The condensation
reaction of the Mannich salt 3b with cyclohexanone 4b furnished diketone
2d and triketone 5d in good yield (entry 14). The diketone 2d forms
structure motif on A-ring aromatic D-homosteroids. The condensation
reactions of cyclopentanone/cyclohexanone also took place in ethylene
glycol (EG) medium, however, in lower yield (entries 2, 9).
After establishing a facile synthesis of diketones 2a–d, Mannich salt 3a was
reacted with 2-methyl-1,3-cyclopentanedione 6 under MW irradiation. The
reaction provided the triketone 7a in good yield (Scheme 2, Table 1, entry 15).
Similarly, the reaction of the Mannich salt 3b with the diketone 6 provided 7b
in good yield.[6] The triketone 7b has structural similarities with estrone 1.
It is possible that under MW irradiation the Mannich salts decompose to
aryl vinyl ketones, which react with enolates of cyclic ketones to provide the

940
H. S. P. Rao, E. Poonguzhali, and S. P. Senthilkumar
Scheme 2. Reagents and conditions: i) PEG-200, MW (370 W), 2 min, 67–72%.
diketones 2. Presence of hydrochloric acid given out by the salt in the reaction
medium could facilitate enolate generation from ketones 4. In conclusion, we
have shown that MW irradiation of the Mannich salts 3 with cyclic ketones
4/6 provide diketones of type 2 in a facile manner. Some of the compounds
generated in this study fit well into a steroid carbon framework. We are
presently working on the reductive amination–cyclization of ketones 2/7 to
generate 8-azasteroids.[7]
EXPERIMENTAL
General
Polyethylene glycol-200 (PEG-200) and ethylene glycol were used as
solvents. The IR spectra were recorded with KBr using an ABB BOMEM
1
104 FT-IR spectrometer. The H and the 13C NMR spectra were recorded in
CDCl3 or CDCl3–CCl4 (1:1) mixture on Jeol 400-MHz or Brucker 300-
MHz NMR spectrometers using TMS (0 ppm) or the center line of the chloro-
form-D triplet (77.0 ppm) as the internal standard, respectively. Melting points
were recorded using a Gallenkamp melting-point apparatus. The microwave
reactions were carried out using a BPL-Sanyo (India) microwave oven
(monomade, multipower source, 230 V, 50 Hz) with operating microwave
frequency of 2450 MHz.
General Procedure for Michael Addition Reaction
A mixture of Mannich salt 3 and cyclic ketone 4 (see Table 1) suspended in PEG
medium (2 mL) was irradiated in a domestic microwave oven at 370 W for the
time indicated. The GC analysis was used to monitor progress of the reaction.
The cooled reaction mixture was poured on crushed ice (50 g), and the product
was extracted with dichloromethane (3 Â 20 mL). The organic layer, dried over
anhydrous sodium sulfate, was evaporated under reduced pressure. The crude

Synthesis of 1,5-Diketones from Mannich Salts
941
product was subjected to column chromatography (silica gel) to separate and
purify diketones 2 and triketones 5. The products 2a–d and 5a–d isolated in
the present study are known compounds.[2,3] Similarly, the reaction of
Mannich salts 3a and b with diketone 6 furnished triketones 7a and b, whose
spectral data are given next.
Data
2-Methyl-2-(3-oxo-3-phenylpropyl)-1,3-cyclopentanedione 7a: Mp 80–828C;
1
IR (KBr) nmax: 1721, 1688, 1598, 1449, 1404 cm21; H NMR (300 MHz,
CDCl3) d 1.16 (s, 3H), 2.06 (t, J ¼ 7.2 Hz, 2H), 2.72–2.88 (m, 4H), 2.98
(t, J ¼ 7.2 Hz, 2H), 7.44 (td, J ¼ 7.5, 6.9 Hz, 2H), 7.55 (t, J ¼ 7.5 Hz, 1H),
7.88 (d, J ¼ 6.9 Hz, 2H) ppm; 13C NMR (75 MHz CDCl3) d 19.0, 28.3, 32.4,
34.6, 55.2, 127.9, 128.5, 133.2, 136.3, 199.2, 215.7 ppm. Anal. calcd for
C15H16O3: C, 73.75; H, 6.60. Found: C, 73.48; H, 6.53.
2-[3-(4-Methoxyphenyl)-3-oxopropyl]-2-methyl-1,3-cyclopentanedione 7b: Mp
1
96–988C; IR nmax: 1770, 1725, 1675, 1615, 1580 cm21; H NMR (400 MHz,
CDCl3) d 1.07 (s, 3H), 1.96 (t, J ¼ 7.2 Hz, 2H), 2.71 (t, J ¼ 4.4 Hz, 2H),
2.84 (t, J ¼ 7.2 Hz, 4H), 3.77 (s, 3H), 6.83 (d, J ¼ 8.8 Hz, 2H), 7.86
(d, J ¼ 8.8 Hz, 2H) ppm; 13C NMR (100 MHz CDCl3) d 19.1, 28.6, 32.0,
34.7, 55.2, 55.3, 113.4, 129.4, 130.2, 163.5, 197.7, 215.8 ppm. Anal. calcd.
for C16H18O4: C, 69.98; H, 6.86. Found: C, 70.05; H, 6.61.
ACKNOWLEDGMENT
H. S. P. R. thanks University Grants Commission, India, Council of Scientific
and Industrial Research (CSIR), India, and Department of Science and
Technology—Faculty Improvement in Science and Technology for financial
assistance. E. P. and S. P. S. thank CSIR for awarding fellowships. We
thank Sophisticated Analytical Instrument Facility, Indian Institute of
Technology, Chennai, for recording spectra.
REFERENCES
1. Meyers, A. I.; Elworthy, T. R. Chiral formamidines. The total asymmetric synthesis
of (-)-8-azaestrone and related (-)-8-aza-12-oxo-17-desoxoestrone. J. Org. Chem.
1992, 57, 4732–4740.
2. Gill, N. S.; James, K. B.; Lions, F.; Potts, K. T. b-Acylethylation with ketonic
Mannich bases. The synthesis of some diketones, ketonic sulfides, nitroketones
and pyridines. J. Am. Chem. Soc. 1952, 74, 4923–4928.
3. Austin, E. M.; Brown, H. L.; Buchanan, G. L. The thermal Michael reaction—III:
The scope of the reaction. Tetrahedron 1969, 25, 5509–5516.

942
H. S. P. Rao, E. Poonguzhali, and S. P. Senthilkumar
4. Rao, H. S. P.; Jeyalakshmi, K.; Senthilkumar, S. P. Novel domino products from the
reaction of phenyl vinyl ketone and its derivatives with cyclic ketones. Tetrahedron
2002, 58, 2189–2199.
5. Furnis, B. S.; Hannford, A. J.; Rogers, V.; Smith, P. W. G.; Tatchell, A. R. Eds.
Vogel’s Text Book of Practical Organic Chemistry, 4th edn.; ELBS: Oxford,
1987; p. 796.
6. Sarkar, A.; Jois, H. R. Y.; Kasturi, T. R.; Dasgupta, D. On the mechanism of chiral
aldol cyclization reaction. Proc. Ind. Acad. Sci., Chem. Sci. 1982, 91, 475–481.
7. Rao, H. S. P.; Senthilkumar, S. P. Review on the synthesis of 8-azasteroids. Current
Org. Chem. 2004, 8, 1521–1528.