Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins via successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazoline

Article abstract of DOI:10.1016/j.tetlet.2004.04.158

Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-BuLi, B(OMe)₃, and H₂O₂ produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44-75% overall yields. This procedure allowed the short synthesis of (±)-hydrangenol and (±)-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of pharmacological interest. A more economical synthesis of (±)-phyllodulcin via the trianion intermediate is also described.

Full text of DOI:10.1016/j.tetlet.2004.04.158

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5117–5120
Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins
via successive lateral and ortho-lithiations
of 4,4-dimethyl-2-(o-tolyl)oxazoline
Naruki Tahara, Tsutomu Fukuda and Masatomo Iwao*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 1 April 2004;revised 26 April 2004;accepted 28 April 2004
Abstract—Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-
BuLi, B(OMe)3, and H2O2 produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these
products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44–75% overall yields. This
procedure allowed the short synthesis of ( )-hydrangenol and ( )-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of
pharmacological interest. A more economical synthesis of ( )-phyllodulcin via the trianion intermediate is also described.
Ó 2004 Elsevier Ltd. All rights reserved.
Directed lithiation is the most powerful method for
regioselective functionalization of aromatic rings.1 The
reagent-controlled optional site-selective lithiation is
especially interesting in this field from mechanistic and
practical points of view.2 Recently, we have reported
that 4,4-dimethyl-2-(o-tolyl)oxazolines (1a–c) can be
lithiated at the lateral or ortho-position selectively
depending on the reaction conditions (Scheme 1).3 Thus,
the oxazolines were deprotonated at the most acidic
lateral methyl group with sec-BuLi in Et2O at )78 °C,
whereas they were lithiated at the less acidic ortho-po-
sition with sec-BuLi in the presence of TMEDA. The
latter unusual ortho-lithiation was rationalized by the
unfavorable steric interaction between TMEDA and the
methyl groups on the oxazoline ring in the transition
state for the lateral lithiation.3
The 3,4-dihydroisocoumarins constitute a class of nat-
ural products, which exhibit a wide range of pharma-
cological activities such as antifungal,4a antiulcer,4b
antileukemic,4c antiallergic,4d differentiation-inducing,4e
and antimalarial4f activities. Structurally, most of these
natural products possess an aryl or alkyl substituent at
C-3 and a hydroxy group at C-8 of the isocoumarin
core. The syntheses of this type of 3,4-di-
hydroisocoumarins have been achieved efficiently by
O
sec-BuLi, Et2O, -78 °C, 1 h
lateral lithiation
N
Li
X
X
O
N
Li
N
X
sec-BuLi, TMEDA, Et2O, -78 °C, 1 h
1a: X=H
O
1b: X=OMe
1c: X=Cl
ortho-lithiation
Scheme 1. Optional lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazolines.
* Corresponding author. Tel./fax: +81-95-819-2681;e-mail: iwao@net.nagasaki-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.158

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N. Tahara et al. / Tetrahedron Letters 45 (2004) 5117–5120
The synthesis of the desired dihydroisocoumarins has
[O]
2nd
OH
8
O
been achieved most satisfactorily as follows.6 The
oxazoline 1a was lithiated at the lateral position with
sec-BuLi (1.2 equiv) in THF at )78 °C and the generated
deep red anion was trapped with an appropriate alde-
hyde. Subsequently, the addition product was treated
with sec-BuLi (2.0 equiv) at )78 °C for 1 h and then at
)50 °C for 1 h to effect ortho-lithiation. The presumed
intermediate 2 thus generated was hydroxylated by
sequential treatment with B(OMe)3 and H2O2. After
extractive workup, the crude product was treated with
TFA in refluxing aqueous THF to give 3-substituted
8-hydroxy-3,4-dihydroisocoumarin 3. Yields of 3a–i
thus synthesized are summarized in the Table 1. A
variety of aromatic aldehydes including cinnamaldehyde
were subjected to reaction in good yields to give the
corresponding 3,4-dihydroisocoumarins (entries 1–6).
Although the yield was modest, an enolizable aliphatic
aldehyde was successfully employed in this synthesis
(entry 7). In the reactions with O-TBS-protected
p-hydroxybenzaldehyde and isovanillin, ( )-hydrange-
nol (3h) and ( )-phyllodulcin (3i), respectively, were
obtained directly in fair yields (entries 8 and 9). The silyl
protecting group may be removed during the final TFA
treatment. These natural products are the principal
O
O
3
N
O
H
(OR)
n
(OR)
n
1a
1st
Scheme 2. Synthetic design of 3-aryl-8-hydroxy-3,4-dihydro-
isocoumarins.
using lateral lithiation of 2-alkoxy-6-methylbenzoic acid
derivatives.5 For example, Watanabe and Snieckus have
synthesized the 3,4-dihydroisocoumarin natural prod-
ucts, ( )-hydrangenol and ( )-phyllodulcin, via lateral
lithiation of N,N-dimethyl-2-methoxy-6-methylbenz-
amide.5b We envisioned the construction of the 3,4-di-
hydroisocoumarins having this substitution pattern
could be accomplished in one-pot via the initial lateral
lithiation of 4,4-dimethyl-2-(o-tolyl)oxazoline (1a) fol-
lowed by addition to an aldehyde, the second ortho-
lithiation, and oxidation (Scheme 2). In this article, we
report a highly efficient synthesis of the 3-substituted
8-hydroxy-3,4-dihydroisocoumarins based upon this
strategy.
Table 1. Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins 3a–i
Li
N
O
HO
O
1. sec-BuLi (1.2 eq), THF, -78 °C, 1 h
1. B(OMe)3
2. H2O2, AcOH, rt, overnight
O
R
N
2. RCHO (1.3 eq)
O
3. sec-BuLi (2.0 eq)
-78 °C, 1 h then -50 °C, 1h
3. TFA, aq THF, reflux, 5 h
R
1a
3a-i
LiO
2
Entry
1
Aldehyde
Dihydroisocoumarin
R
3 (%)
3a
71
OHC
2
3
3b
3c
75
67
OHC
Me
Me
OHC
OMe
OMe
O
i
-Pr
OMe
OMe
OMe
OMe
Ph
O
i
-Pr
OMe
OMe
OMe
OMe
Ph
4
5
3d
3e
56
57
OHC
OHC
6
7
8
3f
60
44
59
OHC
3g
3h
n-Pr
OHC
OHC
OTBDMS
OH
OH
OMe
OTBDMS
OMe
9
3i
53
OHC

N. Tahara et al. / Tetrahedron Letters 45 (2004) 5117–5120
5119
Li
N
O
HO
O
O
1. sec-BuLi (1.2 eq), Et2O, -78 °C, 1 h
2. -anisaldehyde (1.3 eq)
1. B(OMe)3
2. H2O2, AcOH, rt, overnight
N
p
O
OH
3. sec-BuLi (4.0 eq), TMEDA (5.2 eq),
3. TFA, aq THF, reflux, 5 h
Li
-78 °C, 1 h then -50 °C, 12 h
LiO
1a
OMe
OMe
( )-phyllodulcin (3i)
4
(43%)
Scheme 3. Synthesis of ( )-phyllodulcin (3i) via the trianion intermediate 4.
S. L.;Familoni, O. B.;Snieckus, V. J. Org. Chem. 2001,
66, 3662;(h) Fukuda, T.;Mine, Y.;Iwao, M. Tetrahedron
2001, 57, 975–979.
constituents of Amacha (Hydrangeae Dulcis Folium), a
natural medicine indigenous to Japan, produced from
the leaves of Hydrangea macrophylla Seringe var. thun-
bergii Makino.7 The sweet taste of Amacha is caused by
(+)-phyllodulcin, which has been reported to be 400
times as sweet as sucrose.8
3. Tahara, N.;Fukuda, T.;Iwao, M. Tetrahedron Lett. 2002,
43, 9069–9072.
4. (a) Nozawa, K.;Yamada, M.;Tsuda, Y.;Kawai, K.;
Nakajima, S. Chem. Pharm. Bull. 1981, 29, 2689–2691;(b)
Shimojima, Y.;Shirai, T.;Baba, T.;Hayashi, H. J. Med.
Chem. 1885, 28, 3–9;(c) Fusetani, N.;Sugawar, T.;
Matsunaga, S.;Hirota, H. J. Org. Chem. 1991, 56, 4971–
4974;(d) Yoshikawa, M.;Uchida, E.;Chatani, N.;
Kobayashi, H.;Naitoh, Y.;Okuno, Y.;Matsuda, H.;
Yamahara, J.;Murakami, N. Chem. Pharm. Bull. 1992,
40, 3352–3354;(e) Uemura, K.;Matsumoto, M.;Nakam-
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Pharm. Bull. 2000, 48, 566–567;(f) Kongsaeree, P.;
Prabpai, S.;Sriubolmas, N.;Vongvein, C.;Wiyakrutta,
S. J. Nat. Prod. 2003, 66, 709–711.
5. (a) Regan, A. C.;Staunton, J. J. Chem. Soc., Chem.
Commun. 1983, 764–765;(b) Watanabe, M.;Sahara, M.;
Kubo, M.;Furukawa, S.;Billedeau, R. J.;Snieckus, V. J.
Org. Chem. 1984, 49, 742–747;(c) Fu, P. P.;Unruh, L. E.;
Miller, D. W.;Huang, L. W.;Yang, D. T. C. J. Org.
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Kohno, Y.;Hara, O.;Shioiri, T. J. Am. Chem. Soc. 1989,
111, 1524–1525;(e) Hamada, Y.;Hara, O.;Kawai, A.;
Kohno, Y.;Shioiri, T. Tetrahedron 1991, 47, 8635–8652;
Related to this lithiation-based synthesis of dihydro-
isocoumarins, we devised a more economical synthesis
of ( )-phyllodulcin, in which the use of protected iso-
vanillin is avoided (Scheme 3).9 The oxazoline 1a in
Et2O was sequentially treated with sec-BuLi (1.2 equiv)
at )78 °C for 1 h, p-anisaldehyde, sec-BuLi (4.0 equiv) in
the presence of TMEDA at )78 °C for 1 h and at )50 °C
for 12 h to generate the trianion intermediate 4. Subse-
quently, 4 was quenched with B(OMe)3 and then oxi-
dized with H2O2 in the presence of AcOH. The crude
product was treated with TFA in refluxing aqueous
THF for 5 h to give ( )-phyllodulcin (3i) in 43% yield. It
is noteworthy that the use of Et2O as a solvent and
TMEDA as an additive is critical for the efficient gen-
eration of 4.
In summary, we have developed a new general synthesis
of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins,
including ( )-hydrangenol and ( )-phyllodulcin, via
successive lateral and ortho-lithiations of 4,4-dimethyl-2-
(o-tolyl)oxazoline (1a). A specific but exceptionally effi-
cient synthesis of ( )-phyllodulcin is also devised. In
view of the easy availability of 1a from commercially
available inexpensive o-toluic acid,10 we believe the
methods developed herein are most convenient and
economical for the synthesis of this class of compounds.
(f) Broady, S. D.;Rexhausen, J. E.;Thomas, E. J.
Chem. Soc., Chem. Commun. 1991, 708–710.
J.
6. Typical procedure (synthesis of 3a). Under an argon
atmosphere, oxazoline 1a (207 mg, 1.09 mmol) was dis-
solved in dry THF (5 mL) and the solution was cooled to
)78 °C. A solution of sec-BuLi in cyclohexane–hexane
(0.960 M, 1.36 mL, 1.31 mmol) was added dropwise to this
solution. After stirring for 1 h, a solution of benzaldehyde
(144 lL, 1.42 mmol) in dry THF (4 mL) was added, and
the mixture was stirred for 1 h at )78 °C. To this solution,
sec-BuLi in cyclohexane–hexane (0.960 M, 2.27 mL,
2.18 mmol) was added dropwise. The reaction mixture
was stirred for 1 h at )78 °C and for 1 h at )50 °C. After
cooling to )78 °C, B(OMe)3 (367 lL, 3.28 mmol) was
added as a neat liquid. The mixture was stirred for 1 h at
)78 °C, allowed to warm to room temperature, and stirred
for 2 h. After addition of AcOH (375 lL, 6.55 mmol) and
30% H2O2 (670 lL, 6.55 mmol), the mixture was stirred for
16 h at room temperature. Water was added and the
mixture was extracted with Et2O. The extract was washed
successively with 10% aqueous NaHSO3 and brine, dried
over Na2SO4, and evaporated to leave an oily product. A
mixed solution of this product in THF (10 mL)–water
(1.5 mL)–TFA (0.5 mL) was refluxed for 5 h under argon
atmosphere. After cooling, the mixture was basified with
saturated aqueous NaHCO3 and extracted with Et2O. The
extract was washed successively with water and brine,
dried over Na2SO4, and evaporated. The residue was
References and notes
1. (a) Gschwend, H. W.;Rodriguez, H. R. Org. React. 1979,
26, 1–360;(b) Snieckus, V. Chem. Rev. 1990, 90, 879–933;
(c) Clark, R. D.;Jahangir, A. Org. React. 1995, 47, 1–314;
(d) Clayden, J. Organolithiums: Selectivity for Synthesis;
Pergamon: Oxford, 2002.
2. (a) Slocum, D. W.;Jennings, C. A. J. Org. Chem. 1976, 41,
3653–3664;(b) Carpenter, A. J.;Chadwick, D. J. J. Chem.
Soc., Perkin Trans. 1 1985, 173–181;(c) Katsoulos, G.;
Takagishi, S.;Schlosser, M. Synlett 1991, 731–732;(d)
Shimano, M.;Meyers, A. I. J. Am. Chem. Soc. 1994, 116,
10815–10816;(e) Maggi, R.;Schlosser, M. J. Org. Chem.
1996, 61, 5430–5434;(f) Schlosser, M.;Maccaroni, P.;
Marzi, E. Tetrahedron 1998, 54, 2763–2770;(g) MacNeil,

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N. Tahara et al. / Tetrahedron Letters 45 (2004) 5117–5120
purified by flash chromatography over silica gel (CH2Cl2–
13.3 mmol) and 30% H2O2 (1.36 mL, 13.3 mmol), the
reaction mixture was stirred for 22.5 h at room tempera-
ture. Water was added and the mixture was extracted with
Et2O. The extract was washed successively with 10%
aqueous NaHSO3 and brine, dried over Na2SO4, and
evaporated to leave an oily product. A mixed solution of
this product in THF (10 mL)–water (1.5 mL)–TFA
(0.5 mL) was refluxed for 5 h under argon atmosphere.
After cooling, the mixture was basified with saturated
aqueous NaHCO3 and extracted with Et2O. The extract
was washed successively with water and brine, dried over
Na2SO4, and evaporated. The residue was purified by flash
chromatography over silica gel (CH2Cl2–hexane ¼ 5:1 to
CH2Cl2–ethyl acetate ¼ 20:1) to give ( )-phyllodulcin (3i)
(137 mg, 43%).
hexane ¼ 1:1) to give 8-hydroxy-3-phenyl-3,4-dihydro-
isocoumarin (3a) (188 mg, 71%).
7. Yoshikawa, M.;Chatani, N.;Harada, E.;Nishino, Y.;
Yamahara, J.;Murakami, N. Yakugaku Zasshi 1994, 114,
176–181.
8. Yamato, M.;Hashigaki, K.;Mito, K.;Koyama, T. Chem.
Pharm. Bull. 1978, 26, 2321–2327.
9. Procedure. Under an argon atmosphere, oxazoline 1a
(210 mg, 1.11 mmol) was dissolved in dry Et2O (5 mL) and
the solution was cooled to )78 °C. A solution of sec-BuLi
in cyclohexane–hexane (0.870 M, 1.53 mL, 1.33 mmol) was
added dropwise to this solution. After stirring for 1 h, a
solution of p-anisaldehyde (175 lL, 1.44 mmol) in dry
Et2O (4 mL) was added dropwise and the mixture was
stirred for 1 h at )78 °C. TMEDA (869 lL, 5.76 mmol)
was added and the mixture was stirred for 10 min. A
solution of sec-BuLi in cyclohexane–hexane (0.870 M,
5.09 mL, 4.43 mmol) was added dropwise, and the mixture
was stirred for 1 h at )78 °C and for 12 h at )50 °C. After
cooling to )78 °C, B(OMe)3 (745 lL, 6.65 mmol) was
added as a neat liquid. The reaction mixture was stirred
for 1 h at )78 °C, allowed to warm to room temperature,
and stirred for 2 h. After addition of AcOH (760 lL,
10. Generally, 3-substituted 8-hydroxy-3,4-dihydroisocouma-
rins are prepared from a common starting material, ethyl
2-hydroxy-6-methylbenzoate. The synthesis of this com-
pound, however, requires a couple of tedious steps and
harmful reagents, see: Hauser, F. M.;Pogany, S. A.
Synthesis 1980, 814–815;For a recent synthesis of dihy-
droisocoumarin natural products from this starting mate-
€
rial, see: Gunes, M.;Speicher, A. Tetrahedron 2003, 59,
8799–8802.