Radical-mediated synthesis of 3,4-dihydroisocoumarins: total synthesis of hydrangenol

Article abstract of DOI:10.1016/j.tetlet.2007.03.172

A radically promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. The total synthesis of (±)-hydrangenol has been completed using this radical technology. Cp₂TiCl was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and Zn-dust in THF under argon.

Full text of DOI:10.1016/j.tetlet.2007.03.172

Tetrahedron Letters 48 (2007) 4131–4134
Radical-mediated synthesis of 3,4-dihydroisocoumarins:
total synthesis of hydrangenol
Samir Kumar Mandal and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 14 February 2007; revised 20 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—A radically promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titano-
cene(III) chloride (Cp2TiCl) as the radical initiator. The total synthesis of ( )-hydrangenol has been completed using this radical
technology. Cp2TiCl was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and Zn-dust in THF under
argon.
ꢀ 2007 Elsevier Ltd. All rights reserved.
3,4-Dihydroisocoumarins constitute a class of naturally
occurring lactones, which exhibit a wide range of biolog-
ical activities1 such as antifungal, antiallergenic, antileu-
kemic, antiulcer and antimalarial activities as well as
sweetness properties. They are also used as key interme-
diates in the synthesis of various bioactive natural prod-
ucts.2 Most of these natural products possess an aryl or
alkyl substituent at C-3 of the lactone moiety and a
hydroxyl group at C-8 of the aromatic ring of the core
structure. A number of methods have been reported
for the synthesis of 3,4-dihydroisocoumarins mainly fol-
lowing lateral- and ortho-lithiations3 along with other
strategies.4 However, many of these methods suffer from
harsh reaction conditions, multi-step procedures and
inefficiencies due to functional group intolerance. The
mildness and efficiency of radical-mediated reactions
have significantly encouraged synthetic chemists in
recent years to utilize radical technology in developing
novel methods and applications in natural product syn-
thesis. In continuation of our studies on the synthesis of
natural products through radical-induced reactions,5 we
report a radical-mediated method to construct C-3
substituted 3,4-dihydroisocoumarins 3 in a single opera-
tion with moderate to good yields from ethyl 2-bro-
O
COOEt
Br
Cp2TiCl / THF, rt
then H3O+
48-62%
O
R-CHO
+
R
3
1
2
Scheme 1.
The radical initiator, Cp2TiCl, can easily be prepared
from commercially available titanocene dichloride
(Cp2TiCl2) and zinc dust in THF.6
Thus, a series of 3,4-dihydrocoumarins 3a–j has been
prepared from various aryl and alkyl aldehydes 2a–j
via radically promoted synthesis7 and the results are
summarized in Table 1. The substrates underwent radi-
cal induced Barbier-type reaction8 followed by lacton-
ization to furnish product 3. Reaction of 1 with allyl
and propargyl substituted salicylaldehydes 2h and 2i
(Table 1, entries 8–9) furnished the expected dihydro-
isocoumarins 3h and 3i, respectively, without any intra-
molecular cyclization as reported previously by us.5i
This is probably due to the fact that formation of radi-
cals from benzyl bromides with Cp2TiCl is much faster
than with aldehydes. Ketones, such as cyclohexanone
and acetophenone, yielded only self-coupling products
in the presence of Cp2TiCl.
momethyl benzoate (1) and aldehydes
2
using
dicyclopentadienyl titanocene(III) chloride (Cp2TiCl)
as the radical initiator (Scheme 1).
After successful experiments with different aldehydes,
we applied this radical technology to the synthesis of
naturally occurring ( )-hydrangenol (7), a dihydroiso-
coumarin, isolated from Hydrangea opuloides Steud.
Keywords: Titanocene(III) chloride; Radical reaction; 3,4-Dihydroiso-
coumarins; Hydrangenol.
*
Corresponding author. Fax: +91 33 2473 2805; e-mail: ocscr@
iacs.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.172

4132
S. K. Mandal, S. C. Roy / Tetrahedron Letters 48 (2007) 4131–4134
Table 1. Radically promoted synthesis of 3,4-dihydroisocoumarins
Entry
1
Aldehyde
CHO
Producta
Yieldb (%)
O
O
62
2a
3a
O
CHO
CHO
CHO
O
O
O
2
3
4
5
6
7
8
59
51
60
56
48
53
54
O
2b
2c
3b
O
O
O
3c
O
O
Me
2d
3d
Me
OMe
Cl
O
CHO
O
O
O
MeO
2e
3e
O
CHO
Cl
2f
3f
O
CHO
MeO
OMe
OMe
OMe
2g
3g
O
CHO
O
O
O
O
2h
3h
O
CHO
O
9
56
53
O
2i
3i
O
O
O
10
H
2j
3j
a All products were obtained following a similar procedure to that described in Ref. 7 and were characterized by IR, NMR, and HRMS.
b Yields refer to pure isolated products.
var. otakusa.9 Readily available10 methyl 2-methyl-6-
methoxybenzoate (4) was used as the starting material.
Compound 4 on bromination with NBS in the presence
of a catalytic amount of AIBN yielded bromide 5 in 92%
yield. Bromide 5, on treatment with Cp2TiCl in THF
under argon at room temperature in the presence of 4-
methoxybenzaldehyde (2e), followed by quenching
afforded lactone 6 in 53% yield as a crystalline solid,

S. K. Mandal, S. C. Roy / Tetrahedron Letters 48 (2007) 4131–4134
4133
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Org. Chem. 1996, 61, 4190, and references cited therein;
(h) Uchida, K.; Watanabe, H.; Kitahara, T. Tetrahedron
1998, 54, 8975; (i) Tahara, N.; Fukuda, T.; Iwao, M.
Tetrahedron Lett. 2004, 45, 5117; (j) Clayden, J.; Stimson,
C. C.; Helliwell, M.; Keenan, M. Synlett 2006, 873.
OMe
OMe
NBS / AIBN
CCl4, 92%
CO2Me
CO2Me
CH2Br
(i) Cp2TiCl / THF
(ii)
Me
MeO
CHO
4
5
53%
OH O
OMeO
BBr3 / CH2Cl2
O
O
-78 ºC, 3 h
88%
4. (a) Napolitano, E.; Spinelli, G.; Fiaschi, R.; Marsili, A. J.
Chem. Soc., Perkin Trans. 1 1987, 2565; (b) Hamada, Y.;
Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T. Tetrahedron
1991, 47, 8635; (c) Fitzgerald, J. J.; Pagano, A. R.;
Sakoda, V. M.; Olofson, R. A. J. Org. Chem. 1994, 59,
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OH
OMe
6
7
Scheme 2.
Tetrahedron 1999, 55, 13735; (e) Gunes, M.; Speicher, A.
¨
Tetrahedron 2003, 59, 8799.
mp 152–154 ꢁC (Scheme 2). Demethylation of 6 with
boron tribromide in CH2Cl2 afforded ( )-hydrangenol
(7)11 in 88% yield12 as colorless crystals, mp 179–
181 ꢁC (lit.10 mp 181 ꢁC).
5. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem.
1998, 63, 2829; (b) Roy, S. C.; Rana, K. K.; Guin, C. J.
Org. Chem. 2002, 67, 3242; (c) Jana, S.; Guin, C.; Roy, S.
C. Tetrahedron Lett. 2004, 45, 6575; (d) Jana, S.; Guin, C.;
Roy, S. C. J. Org. Chem. 2005, 70, 8252; (e) Jana, S.; Guin,
C.; Roy, S. C. Tetrahedron Lett. 2005, 46, 1155; (f)
Mandal, S. K.; Jana, S.; Roy, S. C. Tetrahedron Lett.
2005, 46, 6115; (g) Banerjee, B.; Roy, S. C. Eur. J. Org.
Chem. 2006, 489; (h) Mandal, S. K.; Roy, S. C. Tetrahe-
dron Lett. 2006, 47, 1599; (i) Jana, S.; Roy, S. C.
Tetrahedron Lett. 2006, 47, 5949.
In conclusion, we have developed a mild radical-induced
method for the synthesis of C-3 substituted 3,4-
dihydroisocoumarins using titanium(III) chloride as
the radical initiator. This methodology has also been
applied successfully to the total synthesis of ( )-
hydrangenol.
6. RajanBabu, T. V.; Nugent, W. A. J. Am. Chem Soc. 1994,
116, 986, and references cited therein.
7. Typical procedure: A red solution of Cp2TiCl2 (747 mg,
3.0 mmol) in deoxygenated THF (40 mL) was stirred with
activated zinc dust (130 mg, 2 mmol) (activated zinc dust
was prepared by washing 20 g of commercially available
zinc dust with 60 mL of 4 N HCl followed by thorough
washing with water until the washings became neutral and
finally washing with dry acetone and then drying in vacuo)
under argon until it turned green. This green solution was
transferred to a dropping funnel via cannula and was
added dropwise over 9 h to a solution of bromide 1
(364 mg, 1.5 mmol) and aldehyde 2b (225 mg, 1.5 mmol)
in THF (20 mL). The reaction mixture was then stirred for
an additional 4 h. After completion of the reaction
(monitored by TLC), it was quenched slowly with 25%
aqueous H2SO4. Most of THF was removed under
reduced pressure and resulting residue was extracted with
diethyl ether (3 · 25 mL). The organic layer was washed
successively with water (2 · 10 mL), brine (2 · 10 mL),
and finally dried (Na2SO4). The solvent was removed
under reduced pressure and the crude material obtained
was purified by column chromatography over silica gel
(ethyl acetate in light petroleum) to furnish 3b (237 mg,
59%) as a crystalline solid, mp 138–140 ꢁC; IR (KBr):
Acknowledgments
We thank the DST, New Delhi for financial support.
S.K.M. thanks the CSIR, New Delhi for awarding a
research fellowship.
References and notes
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1705, 1448, 1255 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
3.05 (dd, J = 3.0, 16.4 Hz, 1H), 3.28 (dd, J = 12.0,
16.4 Hz, 1H), 5.42 (dd, J = 3.0, 12.0 Hz, 1H), 5.95 (s,
2H), 6.79 (d, J = 8.0 Hz, 1H), 6.89 (dd, J = 1.0, 8.0 Hz,
1H), 6.95 (d, J = 1.0 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H),
7.39 (dd, J = 7.5 Hz, 1H), 7.54 (dd, J = 7.5 Hz, 1H), 8.10
(d, J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 34.5,
78.8, 100.2, 105.7, 107.2, 118.9, 124.0, 126.3, 126.8, 129.3,
131.3, 132.8, 137.8, 146.8, 146.9, 164.2; HRMS Calcd for
C16H13O4 [M++H] 269.0808. Found: 269.0849.
8. Rosales, A.; Oller-Lopez, J. L.; Justicia, J.; Gansa¨uer, A.;
Oltra, J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628.
9. (a) Asahina, Y.; Asano, J. Chem. Ber. 1929, 62B, 171; (b)
Asahina, Y.; Asano, J. Chem. Ber. 1930, 63B,
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4134
S. K. Mandal, S. C. Roy / Tetrahedron Letters 48 (2007) 4131–4134
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12. Synthesis of ( )-hydrangenol (7): A solution of boron
tribromide (1 M, 2 mL) in CH2Cl2 (2 mL) was added
dropwise to a stirred solution of dimethyl ether 6 (142 mg,
0.5 mmol) in CH2Cl2 (5 mL) at À78 ꢁC. The reaction
mixture was then allowed to warm to room temperature
and was stirred for an additional 3 h. The reaction was
quenched with saturated aqueous NaHCO3 solution and
then extracted with CH2Cl2 (3 · 25 mL). The organic layer
was washed successively with water (2 · 10 mL), brine
(2 · 10 mL), and finally dried (Na2SO4). The solvent was
removed under reduced pressure and the crude material
obtained was purified by column chromatography over
silica gel (30% ethyl acetate in light petroleum) to furnish 7
(113 mg, 88%) as colorless crystals, mp 179–181 ꢁC (lit.10
mp 181 ꢁC); IR (KBr): 3354, 1658, 1460, 1230, 1028 cmÀ1
;
1H NMR (300 MHz, DMSO-d6): d 3.10 (dd, J = 2.5,
16.4 Hz, 1H), 3.37 (dd, J = 12.0, 16.4 Hz, 1H), 5.63 (dd,
J = 2.5, 12.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 2H), 6.83–6.89
(m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 7.9 Hz,
1H), 9.62 (s, 1H, phenolic OH), 10.92 (s, 1H, phenolic
OH); 13C NMR (75 MHz, DMSO-d6): d 34.4, 81.4, 109.3,
116.1, 116.3, 119.2, 129.2, 129.3, 137.2, 141.5, 158.7, 161.8,
170.2; HRMS Calcd for C15H12O4Na [M++Na] 279.0633.
Found: 279.0649.