Highly regioselective one-pot synthesis of 7-hydroxy-6-methylphthalide from 3-hydroxy-4-methylbenzylalcohol

Article abstract of DOI:10.1080/00397910500297214

7-Hydroxy-6-methylphthalide 2 was synthesized with high regioselectivity and moderate yield using a novel one-pot synthesis that employed 3-hydroxy-4-methylbenzylalcohol 1 and formaldehyde in the presence of tin(IV) chloride as catalyst and triethylamine

Full text of DOI:10.1080/00397910500297214

Synthetic Communicationsw, 35: 2869–2874, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500297214
Highly Regioselective One-Pot Synthesis of
7-Hydroxy-6-methylphthalide from
3-Hydroxy-4-methylbenzylalcohol
Meili Duan and Michael D. Toney
Department of Chemistry, University of California at Davis,
Davis, California, USA
Abstract: 7-Hydroxy-6-methylphthalide 2 was synthesized with high regioselectivity
and moderate yield using a novel one-pot synthesis that employed 3-hydroxy-4-
methylbenzylalcohol 1 and formaldehyde in the presence of tin(IV) chloride as
catalyst and triethylamine as base. The proposed mechanism of the formation of 2
involves ortho-formylation followed by hemiacetal formation and oxidation.
Keywords: 3-Hydroxy-4-methylbenzylalcohol, 7-hydroxy-6-methylphthalide, one-
pot synthesis, regioselective
INTRODUCTION
The 7-hydroxyphthalides are medicinal components of some natural
products.[1] Recent agricultural,[2] pharmaceutical,[3] and other potential
applications motivate for the development of facile synthetic routes. The pre-
paration of 7-hydroxy-6-methylphthalide 2 was previously reported using a
complex flash-vacuum pyrolysis of ortho-allyl salicylic methyl ester, which
was derived in three steps from 3-methylsalicylic acid.[4] A method for the
preparation of 7-hydroxyphthalides from the furanones has been reported[5]
but the procedure requires harsh reaction conditions. As shown in
Scheme 1a, during the synthesis of the natural product espicufolin, attempts
Received in the USA June 6, 2005
Address correspondence to Michael D. Toney, Department of Chemistry,
University of California at Davis, 1 Shields Avenue, Davis, CA 95616, USA.
Tel.: (530) 754-5282; Fax: (530) 752-8995; E-mail: mdtoney@ucdavis.edu
2869

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M. Duan and M. D. Toney
Scheme 1.
at introducing an acetyl group into the starting material, naphthol, by Friedel–
Crafts acylation and Fries arrangement failed.[6] No similar ortho-formylation
of sterically hindered phenols has been reported. Herein, we describe such a
reaction in the synthesis of product 2 through a highly regioselective
one-pot approach from the diol 3-methyl-4-hydroxybenzylalcohol
1
(Scheme 1b). The latter is readily obtained by borane reduction of commer-
cially available 3-hydroxy-4-methylbenzoic acid.[7] As show in Scheme 1,
the diol 1 and formaldehyde (7 eq) were refluxed in acetonitrile in the
presence of excess tin(IV) chloride (1.5 eq) as catalyst and triethylamine
(4 eq) as base. The product 2 was isolated in high purity and moderate
yield. An oxidation product of 1, 3-hydroxy-4-methylbenzaldehyde 3, also
was detected.
RESULTS AND DISCUSSION
The one-pot synthesis of 2 from 1 was discovered in the course of the synthesis
of 2-hydroxy-6-hydroxymethyl-3-methyl-benzaldehyde 4, an analogue of
pyridoxine. Our initial procedure employed magnesium chloride and triethyl
amine as base, formaldehyde as formylating/oxidizing agent, and reflux in
acetonitrile–benzene mixed solvent. Interestingly, instead of the ortho-
formylation product 4, an unexpected colorless product 2 was detected and
isolated in 18% yield. Under reaction conditions that were otherwise
identical but in which dry solvent was employed, neither 2 nor 4 was
obtained using a literature procedure for unhindered phenols.[8]
The structure of the product 2 was not easy to distinguish from the
expected ortho-formylation product 4 because of the similar molecular

7-Hydroxy-6-methylphthalide Synthesis
2871
structures. The proton NMR of the colorless solid showed a sharp peak around
7.85ppm, similar to that for the expected aldehydic proton but sharper than that
reported.[4] When the NMR sample was exchanged with D2O, the peak
intensity decreased, suggesting that it corresponds to the phenolic proton. An
IR absorption at 1736 cm21 is close to 1737 cm21 of 7-hydroxy-4,6-
dimethylphthalide[9a] and differentfrom 1654 cm21 for 3-methyl-5-decylsalicylic
aldehyde[9b] and1716 cm21 for 3-hydroxybenzene-1,2- dicarbaldehyde.[10] These
results as well as other analytical data confirm the structure of 2 as the product.
Because the one-pot reaction from 1 to 2 is base dependent, the influence
of catalyst, base, and solvent were investigated. The results are given in
Table 1. Tin(IV) chloride is the best catalyst tried here (30% yield), and
magnesium chloride was also effective. Other Lewis acid catalysts such as
Fe, Li, and B halides were also tested, but no product was detected. Benzene
as solvent gave results similar to acetonitrile. Reactions with various bases
showed strong and sterically hindered ones to be effective in this reaction.
The mechanism shown in Scheme 2, based on that reported by Casiraghi
et al.[11] and Hofslokken and Skattebol,[8] is proposed for the production of 2.
The phenolic oxygen of diol 1 initially reacts with tin (IV) chloride to give the
phenoxide salt 2(a). The intermediate 2(b) is formed by reaction of 2(a) with
formaldehyde through a coordination complex. Enolization affords 2(c),
which is then oxidized to the aldehyde intermediate 4 by a second molecule
of formaldehyde. The aldehyde undergoes facile internal hemiacetal
formation to give 5, which is oxidized by a third molecule of formaldehyde
to give the major product 2. The intermediates 4/5 have not been detected
by proton NMR analysis in our experiments. This suggests that steps from 4
Table 1. Yields for the one-pot synthesis of 2
Reaction
time (h)
Isolated yield
of 2 (%)
Entry
Catalyst
Base
Et3N
Et3N
Solvents
1
2
3
4
5
6
7
8
SnCl4
MgCl2
AlCl3
SnCl2
SnCl4
SnCl4
SnCl4
SnCl4
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
THF
17
25
20
24
22
23
17
17
33
9
Et3N
Et3N
Trace
—
12
Et3N
Et3N
Benzene
30
12
2,6-lutidine
Me3N
Acetonitrile
Acetonitrile:
benzene (1:2)
Acetonitrile
Acetonitrile:
benzene (1:2)
6
9
10
SnCl4
MgCl2
DMAP
Et3N
19
42
—
18
Reaction condition: Diol 1 (1.0 eq), formaldehyde (7.0 eq), catalyst (1.0–1.5 eq) and
base (4.0 eq), reflux.

2872
M. Duan and M. D. Toney
Scheme 2.
to product 2 should be fast. The observation of 3 as a secondary product would
result from direct oxidation of the benzylic alcohol of 1 by formaldehyde.
The formation of 7-hydroxy-6-methylphthalide 2 is the first example of
a Friedel–Crafts acylation achieved by a highly regioselective one-pot
synthesis from a sterically hindered diol such as 1. The one-pot reaction
provides a simple and mild approach to the synthesis of 7-hydroxyphthalides.
An advantage of the current procedure is the simple experimental setup
(i.e., open reaction vessel and undried solvent), which could allow the
procedure to become a convenient and practical operation for laboratory
and industrial use. To this end, the development of a higher-yield procedure
for this reaction is in progress.
EXPERIMENTAL
All commercially available reagents and solvents were employed without
further purification. NMR spectra were recorded on Varian INOVA-400
spectrometer (1H: 400 MHz and 13C: 101 MHz). Chemical shifts are
reported in D ppm from CD3Cl as internal standard. Mass spectra were
performed on a Virian Saturn GC-MS spectrometer. Elemental analysis
was performed at the Midwest Microlab, Indianapolis. Melting points are
uncorrected. Infrared spectra were obtained on a Galaxy series FT-IR 3000
spectrometer.

7-Hydroxy-6-methylphthalide Synthesis
2873
3-Hydroxy-4-methylbenzyl alcohol (1). Into a solution of 3-hydroxy-4-
methylbenzoic acid (2.28 g, 15.0 mmol) in dry THF (30 ml) at 08C under
Ar atmosphere, 1.0 M BH3-THF solution (25.5 ml, 25.5 mmol) was added
dropwise over 1 h. Hydrogen gas evolved and a white solid precipitated.
The resulting mixture was stirred at rt overnight. The mixture was treated
with aqueous 3.0 M sodium hydroxide (30 ml). The basic aqueous phase was
neutralized with 3.0 N hydrochloric acid solution (pH , 7.0) at 08C and
extracted with ether (5 ꢀ 50 ml). The extract was dried over magnesium
sulfate and concentrated in vacuo. The residue was purified on silica gel (1 : 1
ether/hexane) to afford product 1 (1.93 g) in 93% yield as a colorless solid.
Analytical data: mp 98–1008C (lit.[12] 102–1038C); 1H NMR (CDCl3):
d 2.24 (s, 3H), 4.61 (s, 2H), 6.82 (s, 1H), 6.82 (d, J ¼ 6.4 Hz, 1H), 7.08
(d, J ¼ 8.0 Hz, 1H) ppm; GC-MS (m/z): Mþ 138, Mþ-OH 121.
7-Hydroxy-6-methylphthalide (2). Triethylamine (1.045 ml, 7.5 mmol) and
tin(IV) chloride (0.351 ml, 3.0 mmol) were added dropwise under Ar atmos-
phere to a colorless solution of diol 1 (0.276 g, 2.0 mmol) in acetonitrile
(20 ml), the mixture was stirred for 20 min, and formaldehyde (0.426 g,
13.5 mmol) was added. The yellowish mixture was refluxed for 17 h. The
color changed gradually to brown. The progress of the reaction was
checked with TLC (dichloromethane). After cooling, the dark brown
mixture was filtered and extracted with ether (3 ꢀ 15 ml). The ether extracts
were dried over sodium sulfate and concentrated in vacuo. The orange-red
oily residue was purified on a silica-gel column with hexane/dichloromethane
(4 : 1) as eluent. This gave product 2 (0.11 g) as a colorless solid (lit.[4] brown
solid) in 33% yield. Pale yellow plate crystals were recrystallized from
a hexane/ether mother liquor. Analytical data: mp 135–1368C (lit.[4]
1
127–129 8C); H NMR (400 MHz, CDCl3): d 2.30 (s, 3H), 5.28 (s, 2H),
6.87 (d, J ¼ 7.6 Hz, 1H), 7.40 (d, J ¼ 8.0 Hz, 1H), 7.86 (s, 1H); 13C NMR
(101 MHz, CDCl3): d 172.9, 154.5, 143.9, 138.0, 124.7, 112.7, 110.3, 70.3,
14.4; IR(KBr, cm21): 3440 (OH), 1736 (C¼O); GC-MS m/z (%): Mþ 164
(100), 135 (78). Anal. calcd. for C9H8O3: C, 65.85; H, 4.91. Found: C,
65.81; H, 4.90.
ACKNOWLEDGMENT
The author thanks the National Institutes of Health for its financial support
(Grant No. GM54779).
REFERENCES
1. (a) Dean, F. M. Naturally Occurring Organic Ring Compounds; Butterworths:
London, 1963; 166; (b) Turner, W. B. Fungal Metabolites; Academic Press:

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M. Duan and M. D. Toney
London, 1971; Chap. 5, 74–213 ; (c) Turner, W. B.; Aldridge, D. C. Fungal
Metabolites II; Academic Press: London, 1983; p. 68.
2. Luethy, C.; Obrecht, J. P. Preparation of (pyrimidinyloxy)- and (triazinyloxy)
phthalides, benzothiophenones, and isobenzofuranthiones as herbicides or
plant-growth regulators. PCT Int. Appl., WO 9105781 1991.
3. Tsukamoto, M.; Nakashima, S.; Hirayama, M.; Ojiri, K.; Suda, H. Antibiotic
BE-39589 and its manufacture with Microtetraspora species. Jpn. Kokai Tokkyo
Koho, JP 10017527, 1998.
4. Black, M.; Cadogan, J. I. G.; McNab, H. Pyrolysis of O-allyl salicylic amides and
esters, and related compounds: Formation of isoindolones and phthalides. J. Chem.
Soc., Perkin Trans. 1 1994, 2, 155–159.
5. Asaoka, M.; Miyake, K.; Takei, H. Synthesis of 7-hydroxyphthalides starting from
unsaturated lactones via 2-trialkylsiloxyfurans. Chem. Lett. 1977, 2, 167–170.
6. Uno, H.; Sakamoto, K.; Honda, E.; Fukuhara, K.; Ono, N.; Tanaka, J.;
Sakanaka, M. Synthesis of espicufolin based on 6-endo ring closure of
o-alkynoylnaphthols. J. Chem. Soc., Perkin Trans. 1 2001, 3, 229–238.
7. Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. Selective
reductions. XIX. Rapid reaction of carboxylic acids with borane-tetrahydrofuran.
Remarkably convenient procedure for the selective conversion of carboxylic acids
to the corresponding alcohols in the presence of other functional groups. J. Org.
Chem. 1973, 38 (4), 2786–2792.
8. Hofslokken, N. U.; Skattebol, L. Convenient method for the ortho-formylation of
phenols. Acta Chem. Scand. 1999, 53 (17), 258–262.
9. (a) Duncanson, L. A.; Grove, J. F.; Zealley, J. Infrared spectroscopy and structural
chemistry. V. Hydroxyphthlides. J. Chem. Soc., Abstracts 1953, 1331; (b) Bigi, F.;
Conforti, M. L.; Maggi, R.; Sartori, G. Trialkylamine controlled phenol-
formaldehyde reaction over clay catalysts: selective and environmentally benign
synthesis of salicylic aldehydes. Tetrahedron 2000, 56 (17), 2709–2712.
10. Shimizu, N.; Kuwahara, Y. 7-Hydroxyphthalide: A new natural salicylaldehyde
analog from Oulenzia sp. (Astigmata: Winterschmitiidae). Biosci. Biotechnol.
Biochem. 2001, 65 (4), 990–992.
11. Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G. Selective reactions
between phenols and formaldehyde. A novel route to salicylaldehydes. J. Chem.
Soc., Perkin Trans. 1 1980, 9, 1862–1865.
12. Brown, J. J.; Newbold, G. T. Phthalaldehydes and related compounds. II. Synthesis
of isogladiolic acid. J. Chem. Soc., Abstracts 1953, 1285–1289.