The synthesis of spirolactones using indium-mediated allylation of cyclic anhydrides and ring-closing olefin metathesis

Article abstract of DOI:10.1055/s-2001-18084

A variety of spirolactones are prepared from cyclic anhydrides via indium-mediated allylation and ring-closing olefin metathesis (RCM) reaction as key steps.

Full text of DOI:10.1055/s-2001-18084

LETTER
1787
The Synthesis of Spirolactones Using Indium-Mediated Allylation of Cyclic
Anhydrides and Ring-Closing Olefin Metathesis1
The Synthesis of
S
o
pirolactoneswravaram Sabitha,* Ch. Srinivas Reddy, R. Satheesh Babu, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7170512; E-mail: sabitha@iict.ap.nic.in
Received 7 August 2001
text, we wish to report a novel and efficient methodology
Abstract: A variety of spirolactones are prepared from cyclic anhy-
drides via indium-mediated allylation and ring-closing olefin met-
athesis (RCM) reaction as key steps.
involving indium catalyzed allylation of cyclic anhy-
drides followed by ring closing metathesis reaction using
Grubb’s catalyst 6 for the key C–C bond formation reac-
tion for the synthesis of a variety of novel spiro- -lactones
(Scheme).
Key words: spirolactones, cyclic anhydrides, allylation, ring-clos-
ing metathesis
Spirolactones are important structural units because of
their unique molecular geometry and interesting biologi-
cal activity. This type of spiro system is present as key
framework of numerous steroids2,3 like Drospirenone 1,4
spironolactone 25 and as well as in an antihypertensive
drug Eplerenone 3.6 Construction of spirolactones can be
achieved by intramolecular free radical cyclization,7 oxi-
dative cyclization of hydroxyalkenes,8 SmI2-induced re-
ductive cross coupling of carbonyl compounds with , -
unsaturated esters,9 by oxidation of borinate esters10 and
other methods.11 Ring-Closing Metathesis (RCM) has re-
cently emerged as a powerful tool for the formation of a
variety of ring systems12 including spiroannelation.13
Scheme
Thus, the allylation reaction of cyclic acid anhydrides 4a–
e with allylbromide in DMF in the presence of indium
metal resulted in the formation of 5,5-diallyl butenolides
or 3,3-diallylphthalides 5a–e15 in good yields. The crucial
ring closing reactions of the various dienes 5a–e were per-
formed in dichloromethane using 5 mol% of the Grubb’s
ruthenium carbene catalyst 6 at room temperature. All the
reactions proceeded smoothly and were complete within 1
hour affording the corresponding spirolactones 7a–e15 in
yields ranging from 52–92% (Table). It was further noted
that, in the case of 4-fluorophthalic anhydride 4e, allyla-
tion using indium afforded an inseparable mixture of two
products. The ratio was found to be 1:1 mixture of isomers
based on 1H NMR spectral data and this mixture was fur-
ther utilized for RCM reaction to give a mixture of spiro-
lactones in 1:1 ratio as indicated by 1H NMR data.
The structures of the diallyl products and spiro com-
1
pounds were assigned based on IR, H NMR, 13C NMR
spectroscopic and mass spectrometric data.
In conclusion, we have demonstrated a synthetic protocol
utilizing indium-catalyzed allylation of cyclic anhydrides
followed by ring-closing metathesis, which affords con-
venient access to -spirolactones. In addition to the reac-
tion efficiency, reaction simplicity and generality, the
present approach may find application in natural product
synthesis and the presence of a double bond in the spiro
compounds allows for further functionalization reactions.
Figure
In 1989, Butsugan et al.14 reported a novel example of
gem-diallylation of the carbonyl group of acid anhydrides
by indium-mediated allylation, which yielding gem-dial-
lyl esters. We utilized this reaction to a variety of cyclic
acid anhydrides, which provided diallylated butenolides
and phthalides serving as substrates for RCM. In this con-
Acknowledgement
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1787,1789,ftx,en;D18101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
ChSR thank UGC and RSB thank CSIR, New Delhi for the award
of fellowships.

1788
G. Sabitha et al.
LETTER
(8) Schelecht, M. F.; Kim, H.-J. Tetrahedron Lett. 1985, 26,
Table Allylation of Cyclic Anhydrides and Ring-Closing Metathe-
sis of Lactonedienes
127.
(9) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 5763.
Entry Cyclic anhydride Lactone diene
Spirolactone
4
5
7
(10) Mandal, A. K.; Mahajan, S. W. Synthesis 1991, 311.
(11) (a) Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C.
K.; Kahane, A. L.; Lanter, J. C.; Corral, M. A. J. Org. Chem.
2001, 66, 2828. (b) Iwahama, T.; Sakaguchi, S.; Ishii, Y.
Chem. Comm. 2000, 613.
a
(12) For some recent reviews on olefin metathesis, see:
(a) Trinca, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013.
(c) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073.
(d) Fürstner, A. Synlett 1999, 371. (e) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211. (f) Grubbs, R. H.; Chang, S. J.
Chem. Soc., Perkin Trans. 1 1998, 54, 4413. (g) Amstrong,
S. K.; Chang, S. J. Chem. Soc., Perkin Trans. 1 1998, 54,
371. (h) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed.
1997, 36, 2036. (i) Grubbs, R. H.; Miller, S. J.; Fu, G. C.
Acc. Chem. Res. 1995, 28, 446. (j) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
(13) (a) Maier, M. E.; Bugl, M. Synlett 1998, 1390.
(b) Sambasivarao, K.; Manivannan, E.; Ganesh, T.;
Sreenivasachary, N.; Ashoke, D. Synlett 1999, 1618.
(14) Araki, S.; Katsumura, N.; Ito, H.; Butsugan, Y. Tetrahedron
Lett. 1989, 30, 1581.
(15) General Procedure for the Indium-mediated allylation:
A mixture of anhydride (1 mmol) and Indium (2 mmol) in
anhyd DMF (2 mL) was added allylbromide (3 mmol) in
DMF (1 mL) and the reaction mixture was stirred at r.t. for
1 h. After complete conversion as indicated by TLC, aq
NH4Cl was added and the product was extracted with Et2O
(3 10 mL). The combined organic layers were washed with
brine, dried over anhyd Na2SO4 and concentrated in vacuo to
yield crude product, which was purified by column
chromatography using silica. The products 5a–e were
characterized by their IR and 1H NMR spectral data.
General procedure for the preparation of the
83%
87%
52%
92%
90a%
71%
64%
57%
80%
83a%
b
c
d
e
spirolactones (7a–e)using RCM: To a solution of the
ruthenium carbene catalyst 6 (5 mol%) in anhyd CH2Cl2
(1 mL) was added a solution of the diallyl compound
(5a–e) (50 mg) in anhyd CH2Cl2 (1 mL). The resulting
reaction mixture was stirred at r.t. for 1 h under N2
atmosphere. After complete conversion as indicated by
TLC, the solvent was removed in vacuo and the residue
purified by silica column chromatography and eluting with
EtOAc–Hexane (4:96) to give analytically pure products
(7a–e).
a Mixture of products were formed in 1:1 ratio.
Spectroscopic data: 5a: 1H NMR (200 MHz, CDCl3) 2.03
(t, 2 H, J = 7.5 Hz, -CH2), 2.28–2.45 (m, 4 H), 2.50 (t, 2 H,
J = 7.5 Hz, -CH2), 5.10–5.28 (m, 4 H, HC=CH2), 5.65–5.90
(m, 2 H, HC=CH2). 7a: 1H NMR (200 MHz, CDCl3) 2.20
(t, 2 H, J = 4.9 Hz, -CH2), 2.45 (d, 2 H, J = 9.8 Hz), 2.50 (t,
2 H, J = 4.9 Hz, -CH2), 2.75 (d, 2 H, J = 9.8 Hz), 5.62 (s, 2
H, HC=CH). MS: m/z (%) = 138 (M+), 110, 95, 83, 77, 55,
39. 5b: 1H NMR (400 MHz, CDCl3) 2.42–2.58 (m, 4 H),
5.10–5.20 (m, 4 H, HC=CH2), 5.60–5.70 (m, 2 H, HC=CH2),
6.05 (d, 1 H, J = 8.1 Hz, -CH=CH-), 7.25 (d, 1 H, J = 8.1 Hz,
-CH=CH-). 7b: 1H NMR (200 MHz, CDCl3) 2.70 (s, 4 H,
-CH2), 5.80 (s, 2 H, HC=CH), 6.02 (d, 1 H, J = 5 Hz, -
CH=CH-), 7.40 (d, 1 H, J = 5 Hz, -CH=CH-). 5c: 1H NMR
(200 MHz, CDCl3) 1.55–1.70 (m, 4 H), 2.45–2.49 (m, 4 H,
-CH2), 2.51–2.54 (m, 4 H), 5.01–5.52 (m, 4 H, HC=CH2),
5.82–6.05 (m, 2 H, HC=CH2). 7c: 1H NMR (200 MHz,
CDCl3) 1.48–1.60 (m, 4 H), 2.20–2.30 (m, 4 H, -CH2),
2.42–2.55 (m, 4 H), 5.68 (s, 2 H, HC=CH). 5d: IR (KBr):
1760 cm–1, 1H NMR (200 MHz, CDCl3) 2.61–2.66 (dd,
References and Notes
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Synlett 2001, No. 11, 1787–1789 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2 H, J = 14.2, 6.8 Hz, -CH2), 2.70–2.76 (dd, 2 H, J = 14.2,
The Synthesis of Spirolactones
1789
1H NMR (200 MHz, CDCl3) 2.65–2.80 (dd, 2 H, J = 14.0,
7.5 Hz, -CH2), 2.82–2.90 (dd, 2 H, J = 14.0, 7.5 Hz, -CH2),
4.97–5.15 (m, 4 H, HC=CH2), 5.40–5.60 (m, 2 H, HC=CH2),
7.28 (d, 1 H, J = 7.5 Hz, ArH), 7.48 (m, 1 H, ArH), 7.65 (d,
1 H, J = 7.5 Hz, ArH). 7e: 1H NMR (500 MHz, CDCl3)
2.83 (d, 1 H, J = 16 Hz, -CH2), 3.12 (d, 2 H, J = 17 Hz,
-CH2), 5.89 (s, 2 H, HC=CH), 7.30 (m, 1 H, ArH), 7.51 (m,
1 H, ArH), 7.70 (d, 1 H, J = 7.4 Hz, ArH).
6.8 Hz, -CH2), 5.01–5.06 (m, 4 H, HC=CH2), 5.49–5.59 (m,
2 H, HC=CH2), 7.33 (d, 1 H, J = 7.8 Hz, ArH). 7d: 1H NMR
(400 MHz, CDCl3) 3.00 (s, 4 H), 5.90 (s, 2 H, HC=CH),
7.45 (d, 1 H, J = 7.5 Hz, ArH), 7.53–7.68 (m, 2 H, ArH),
7.90 (d, 1 H, J = 7.5 Hz, ArH). 13C NMR (400 MHz, CDCl3)
46, 92, 121, 125, 128, 129, 134, 153, 169. MS: m/z (%) = 185
(M–1, 100%), 172, 157, 144, 128, 114, 103, 90, 75, 40. 5e:
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