Titanium(III) chloride mediated synthesis of furan derivatives: Synthesis of (±)-evodone

Article abstract of DOI:10.1007/s12039-010-0048-1

Titanocene(III) chloride (Cp2TiCl) mediated one-pot synthesis of furan derivatives has been accomplished. This radical method has been applied for the synthesis of a furanomonoterpene, evodone. Ti(III) species was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl ₂) and zinc dust in THF. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-010-0048-1

J. Chem. Sci., Vol. 122, No. 3, May 2010, pp. 423–426. © Indian Academy of Sciences.
Titanium(III) chloride mediated synthesis of furan derivatives:
Synthesis of ( )-evodone
S K MANDAL, M PAIRA and S C ROY*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Kolkata 700 032
e-mail: ocscr@iacs.res.in
MS received 17 September 2009; revised 6 January 2010; accepted 12 January 2010
Abstract. Titanocene(III) chloride (Cp2TiCl) mediated one-pot synthesis of furan derivatives has been
accomplished. This radical method has been applied for the synthesis of a furanomonoterpene, evodone.
Ti(III) species was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and
zinc dust in THF.
Keywords. Ti(III) chloride; radical; Furan derivatives; synthesis; Evodone.
1. Introduction
2. Experimental
The synthesis of furan derivatives has become much All melting points were taken on a Gallenkamp
significant due to their widespread occurrence in melting point apparatus and are uncorrected. The 1H
nature and versatile applications in medicinal chemis- and 13C NMR were recorded in CDCl3 using TMS as
try and pharmaceutical industry.1 Moreover, annulated an internal standard on 300 and 75 MHz spectrometer
furan derivatives such as tetrahydrobenzofurans and (Bruker) respectively and IR were recorded using a
tetrahydronaphthofurans are widely used as key Shimadzu FT IR-8300 instrument. High-resolution
intermediates for the synthesis of many indispensable mass spectra were obtained using a Qtof Micro
natural products and pioneer of other heterocyclic YA263 instrument. Diethyl ether, tetrahydrofuran
compounds.2 Evodone, containing the tetrahydro- and toluene were dried over sodium. Dimethyl sul-
benzofuran moiety, is a furanomonoterpene isolated foxide was dried over sodium hydride. Dichloro-
from Evonia hortensis Forst and exhibits strong methane was freshly distilled from phosphorus
germination inhibitory activity and stimulatory pentoxide. Pyridine was distilled over potassium hy-
effect towards Schizachyrium scoparium seeds.3 droxide prior to use. Tosyl chloride was freshly
Although several useful and elegant procedures have crystallized from benzene prior to use. Petroleum
been developed for the synthesis of active compo- ether of boiling range 60–80°C and silica gel of 60–
nents of furan derivatives,4 the use of the radical 120 mesh were used for column chromatography.
chemistry in this field is less explored. Srikrishna
and Krishnan developed5 a radical-induced synthesis
of substituted furans from α-bromo-β-keto enoleth-
ers using tributyl tinhydride (TBTH) as the radical
2.1 Representative procedure for the radical
cyclization reaction
initiator with 35–69% yield. But the use of tin com-
pounds has certain limitations due to their toxicity
and difficulties in isolation of pure products free of
tin residues. To overcome these difficulties alterna-
N-bromosuccinamide (356 mg, 2⋅0 mmol) was added
to a stirred solution of 2a (189 mg, 1⋅5 mmol) and
propargyl alcohol (112 mg, 2⋅0 mmol) in dry ben-
zene (10 mL) at 0°C during 30 min. The reaction
mixture was allowed to stir for another 2 h. After
tive methods are still desirable.
completion of the reaction (monitored by TLC) the
solvent was removed under reduced pressure and the
residue was extracted with diethyl ether (3 × 50 mL).
*For correspondence
The organic layer was washed successively with water
423

424
S K Mandal et al
(2 × 10 mL), brine (2 × 10 mL) and finally dried 41⋅3, 45⋅6, 119⋅1, 120⋅3, 126⋅7 (2C), 127⋅1, 128⋅8
(Na2SO4). After removal of the solvent under (2C), 139⋅4, 142⋅6, 166⋅6, 194⋅2; HRMS calcd for
reduced pressure, the crude residue (3a along with C15H14O2 [M]+ 227⋅1067, found 227⋅1065.
some other inidentified product) obtained was used
without further purification for the radical cycliza- 2.1c 3-Benzyl-6,6-dimethyl-6,7-dihydro-1-benzo-
tion reaction. A red solution of Cp2TiCl2 (747 mg, furan-4(5H)-one (4d): Viscous oil; IR νmax (Neat)
3⋅0 mmol) in dry deoxygenated THF (40 mL) was 2960, 1676, 1558, 1444, 1072 cm–1; 1H-NMR (CDCl3,
stirred with activated zinc dust (393 mg, 6 mmol) 300 MHz) δ (ppm) 1⋅12 (s, 6H), 2⋅34 (s, 2H), 2⋅69
under argon until it turned green. This green solu- (s, 2H), 3⋅98 (s, 2H), 6⋅88 (s, 1H), 7⋅18–7⋅27 (m,
tion was transferred to a dropping funnel by a can- 5H); 13C-NMR (CDCl3, 75 MHz) δ (ppm) 28⋅7 (2C),
nula and was added drop-wise slowly to a solution 30⋅5, 35⋅3, 37⋅7, 52⋅7, 118⋅7, 123⋅9, 126⋅3, 128⋅5
of the crude bromo compound 3a in dry deoxygen- (2C), 128⋅9 (2C), 139⋅9, 140⋅1, 167⋅0, 194⋅8; HRMS
ated THF (20 mL) under argon atmosphere. The calcd for C17H18O2Na [M + Na]+ 277⋅1205, found
reaction mixture was then stirred for an additional 277⋅1208.
2 h. After completion of the reaction (monitored by
TLC), it was decomposed slowly with 10% aqueous 2.1d 3-Methyl-3,5,6,7-tetrahydro-1-benzofuran-
H2SO4. Most of the THF was removed under 4(2H)-one (4e): Colourless oil; IR νmax (neat)
reduced pressure and resulting residue was extracted 2956, 1627, 1404, 1236, 1182 cm–1; 1H-NMR (CDCl3,
with diethyl ether (3 × 50 mL). The combined organic 300 MHz) δ (ppm) 1⋅21 (d, J = 6⋅7 Hz, 3H), 1⋅97–
layer was washed successively with water (2 × 2⋅06 (m, 2H), 2⋅30–2⋅43 (m, 4H), 3⋅24–3⋅35 (m, 1H),
10 mL), brine (2 × 10 mL) and finally dried (Na2SO4). 4⋅08 (dd, J = 5⋅8, 9⋅2 Hz, 1H), 4⋅60 (t, J = 9⋅2 Hz,
Solvent was removed under reduced pressure and 1H), 13C-NMR (CDCl3, 75 MHz) δ (ppm) 19⋅5,
the crude residue obtained was purified by column 21⋅9, 24⋅1, 34⋅0, 36⋅8, 80⋅6, 118⋅2, 178⋅3, 195⋅9;
chromatography over silica gel (5% ethyl acetate in HRMS calcd for C9H12O2Na [M + Na]+ 175⋅0735,
light petroleum) to obtain 3-methyl-6,7-dihydro-1- found 175⋅0737.
benzofuran-4(5H)-one (4a) (143 mg, 63%) as a crys-
talline solid; m.p. 61–63°C; IR νmax (KBr) 2950, 2.1e 3,6,6-Trimethyl-3,5,6,7-tetrahydro-1-benzo-
1668, 1562, 1386 cm–1; 1H-NMR (CDCl3, 300 MHz) furan-4(2H)-one (4f): Colourless oil; IR νmax (neat)
δ (ppm) 2⋅09–2⋅18 (m, 5H), 2⋅46 (t, J = 6⋅3 Hz, 2H), 2958, 1633, 1402, 1222, 1029 cm–1; 1H-NMR (CDCl3,
2⋅82 (t, J = 6⋅3 Hz, 2H), 7⋅05 (brs, 1H); 13C-NMR 300 MHz) δ (ppm) 1⋅02 (s, 6H), 1⋅14 (d, J = 6⋅7 Hz,
(CDCl3, 75 MHz) δ (ppm) 9⋅1, 22⋅8, 23⋅6, 38⋅4, 3H), 2⋅13 (s, 2H), 2⋅20 (s, 2H), 3⋅18–3⋅28 (m, 1H),
119⋅0, 120⋅4, 138⋅9, 167⋅4, 195⋅7; HRMS calcd for 4⋅03 (dd, J = 5⋅6, 9⋅2 Hz, 1H), 4⋅54 (t, J = 9⋅2 Hz,
C9H10O2 [M+ + 1] 151⋅0754, found 151⋅0750.
1H); 13C-NMR (CDCl3, 75 MHz) δ (ppm) 19⋅3,
28⋅3, 28⋅8, 33⋅8, 34⋅1, 37⋅8, 51⋅2, 80⋅5, 116⋅5, 176⋅6,
194⋅8; HRMS calcd for C11H16O2Na [M + Na]+
2.1a 3,6,6-Trimethyl-6,7-dihydro-1-benzofuran-
4(5H)-one (4b): Viscous oil; IR νmax (neat) 2960, 203⋅1048, found 203⋅1040.
1678, 1562, 1436, 1286 cm–1; 1H-NMR (CDCl3,
300 MHz) δ (ppm) 1⋅14 (s, 6H), 2⋅20 (d, J = 0⋅9 Hz, 2.1f 3-Ethyl-6,6-dimethyl-3,5,6,7-tetrahydro-1-
13
3H), 2⋅35 (s, 2H), 2⋅71 (s, 2H), 7⋅09 (brs, 1H); C- benzofuran-4(2H)-one (4g′) and 4,7,7-trimethyl-
NMR (CDCl3, 75 MHz) δ (ppm) 9⋅1, 28⋅7 (2C), 2,3,4,6,7,8-hexahydro-5H-chromen-5-one
(4g″):
35⋅3, 37⋅7, 52⋅8, 119⋅0, 119⋅4, 139⋅4, 166⋅7, 195⋅2; The compounds 4g′ and 4g″ were obtained from
HRMS calcd for C11H14O2Na [M + Na]+ 201⋅0892, crude 3g as an inseparable mixture in a 1: 1 ratio.
1
found 201⋅0880.
4g′: H-NMR (CDCl3, 300 MHz) δ (ppm) (only
distinctive signals) 0⋅83 (t, J = 6⋅8 Hz, 3H), 3⋅16–
2.1b 3-Methyl-6-phenyl-6,7-dihydro-1-benzofuran- 3⋅23 (m, 1H), 4⋅24 (dd, J = 5⋅4, 9⋅3 Hz, 1H). 4g″:
4(5H)-one (4c): Viscous oil; IR νmax (neat) 2962, 1H-NMR (CDCl3, 300 MHz) δ (ppm) (only distinc-
1668, 1560, 1398 cm–1; 1H-NMR (CDCl3, 300 MHz) tive signals) 1⋅34 (d, J = 6⋅8 Hz, 3H), 3⋅77–3⋅80
δ (ppm) 2⋅25 (s, 3H), 2⋅73–2⋅76 (m, 2H), 3⋅01 (dd, (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 10⋅7, 19⋅2,
J = 10⋅9, 17⋅0 Hz, 1H), 3⋅14 (dd, J = 5⋅2, 17⋅0 Hz, 25⋅6, 28⋅2, 28⋅3, 28⋅9, 29⋅2, 33⋅9 (2C), 37⋅8
1H), 3⋅48–3⋅59 (m, 1H), 7⋅11 (s, 1H), 7⋅26–7⋅39 (m, (2C), 40⋅4, 46⋅8, 51⋅0, 51⋅2, 57⋅0, 74⋅6, 78⋅0,
13
5H); C-NMR (CDCl3, 75 MHz) δ (ppm) 9⋅0, 31⋅4, 112⋅2, 114⋅9, 176⋅9, 178⋅7, 194⋅2, 194⋅8; HRMS

Titanium(III) chloride mediated synthesis of furan derivatives
425
Table 1. Titanocene(III) chloride mediated synthesis of furan derivatives.
Enol
ether (2)
Reactant
(alcohol used)
Furan
derivative (4)
Entry
1
Yield (%)a
63
2
3
4
5
6
7
8
68
64
54
53
51
52b
58
aYield refer to pure isolated product 4 from 2. bTwo isomers in 1 : 1 ratio
calcd for C12H18O2Na [M + Na]+ 217⋅1204, found tuted furans in considerable yields from α-bromo-β-
217⋅1205.
keto enolethers using titanocene(III) chloride
(Cp2TiCl) as the radical source (scheme 1). Cp2TiCl
was prepared in situ from commercially available ti-
tanocene dichloride (Cp2TiCl2) and zinc dust in THF.7
Initially, the α-keto enolether 2 was prepared8
from the 1,3-diketone 1 and methanol in good
yield (scheme 1). The enolether 2 underwent bromo-
propargylation/allylation on treatment with N-
bromosuccinimide and propagyl alcohol/allyl alco-
2.1g 3,6,-Dimethyl-6,7-dihydro-1-benzofuran-4(5H)-
one, Evodone (4h): Compound 4h (144 mg, 58%)
was prepared from 2d (210 mg, 1⋅5 mmol) through
3h following the procedure deacribed for 4a as a
crystalline solid; m.p. 70–72°C (lit3a 73°C); IR νmax
(KBr) 2960, 1668, 1560, 1386, 1429 cm–1; H-NMR
1
(CDCl3, 300 MHz) δ (ppm) 1⋅14 (d, J = 6⋅3 Hz, 3H),
2⋅16–2⋅24 (m, 4H), 2⋅36–2⋅52 (m, 3H), 2⋅89 (dd,
J = 4⋅1, 16⋅2 Hz, 1H), 7⋅04 (brs, 1H); 13C-NMR
(CDCl3, 75 MHz) δ (ppm) 8⋅9, 21⋅0, 30⋅8, 31⋅7, 46⋅7,
118⋅9, 120⋅0, 139⋅1, 167⋅1, 195⋅2; HRMS calcd for
C10H12O2 [M+ + 1] 165⋅0910, found 165⋅0918.
1
hol at 0°C to furnish 3 (80–90% purity, H NMR)
along with an inseparable unidentified product (10–
20%). Unfortunately, several attempts to purify
compound 3 failed due to its instability during
chromatography. The crude bromo compound 3 in
the presence of titanocene(III) chloride in THF fol-
lowed by decomposition with 10% aqueous sul-
phuric acid afforded a mass which was purified by
column chromatography to isolate the pure furan de-
rivative 4 in considerable yield. Thus, a series of
crude α-bromo carbonyl compounds were treated
with titanocene(III) chloride in THF and the results
are summarized in table 1.
3. Results and discussion
Recently, it has been established6 in our laboratory
that α-bromocarbonyl compounds can be converted
to tri-substituted tetrahydrofurans via intramolecular
radical cyclization in the presence of titanocene(III)
chloride as the radical initiator. Here, we describe a
simple and useful method for the synthesis of substi-

426
S K Mandal et al
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Scheme 1. Synthesis of substituted furans.
All the products were characterized by IR, NMR
and HRMS studies and by comparing the data with
those of reported values.4g,5 While radical cycliza-
tion of the crude bromoketones 3a–3f afforded only
a single furan derivative 4a–4f, crude 3g (entry 7,
table 1) on treatment with Cp2TiCl in THF afforded
a non-separable mixture of two isomers 4g′ and 4g″
(52%) in the ratio of 1 : 1. The pyran derivative 4g″
was formed via 6-endo-trig radical cyclization.9 The
ratio of isomers was determined from the methyl
signals in 1H NMR spectrum of the crude compound
appeared at δ 0⋅83 (t, J = 6⋅8 Hz) for 4g′ and at δ
1⋅34 (d, J = 6⋅8 Hz) for 4g″.
This radical technology was then applied for the
synthesis of a naturally occurring furanoterpene,
evodone in good yield. Thus, the crude bromoketone
(85% purity) obtained from 2d, on radical cycliza-
tion reaction in the presence of Cp2TiCl in THF at
room temperature followed by acid treatment fur-
nished ( )-evodone (4h) in 58% yield (table 1, entry
8). The spectral and analytical data are in good
agreement with the reported values.5
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4. Conclusions
In conclusion, we have developed a radical induced
method for synthesis of furan derivatives using
titanocene(III) chloride as the radical source. A
furanoterpene, ( ) evodone has been synthesized in
good yield using this radical technology.
5. Srikrishna A and Krishnan K 1988 Tetrahedron Lett.
29 4995
6. Jana S, Guin C and Roy S C 2005 Tetrahedron Lett. 46
1155
Acknowledgements
7. RajanBabu T V and Nugent W A 1994 J. Am. Chem.
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8. Banerjee B, Mandal S K and Roy S C 2006 Chem. Lett.
35 16
9. Fuse S, Hanochi M, Doi T and Takahashi T 2004 Tet-
rahedron Lett. 45 1961
The authors thank the Department of Science and
Technology (DST), New Delhi for financial assis-
tance. SKM and MP thank Council of Scientific and
Industrial Research (CSIR), New Delhi for awarding
their research fellowships.