One-pot synthesis of ortho-hydroxycinnamate esters

Article abstract of DOI:10.1016/j.tetlet.2005.06.017

Phenols are converted to salicylaldehydes with paraformaldehyde, MgCl ₂-Et₃N in THF, and subsequent treatment with methyl (triphenylphosphoranylidene)acetate gave the corresponding methyl ortho-hydroxycinnamate derivatives. The sequence is conveniently carried out as a one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2005.06.017

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5285–5287
One-pot synthesis of ortho-hydroxycinnamate esters
Hany F. Anwar,a Lars Skattebøl,b Jan Skramstadb and Trond Vidar Hansena,*
aSchool of Pharmacy, Department of Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316, Oslo, Norway
bDepartment of Chemistry, University of Oslo, PO Box 1033 Blindern, N-0315, Oslo, Norway
Received 3 May 2005; revised 30 May 2005; accepted 8 June 2005
Available online 27 June 2005
Abstract—Phenols are converted to salicylaldehydes with paraformaldehyde, MgCl2–Et3N in THF, and subsequent treatment with
methyl (triphenylphosphoranylidene)acetate gave the corresponding methyl ortho-hydroxycinnamate derivatives. The sequence is
conveniently carried out as a one-pot procedure.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cinnamic acids and their derivatives are useful inter-
mediates for the synthesis of heterocyclic compounds.1
The Perkin reaction, the most common procedure for
the preparation of cinnamic acids, utilizes the corre-
sponding aldehydes, acetic anhydride and anhydrous
sodium or potassium acetate; esterification of the acid with
an alcohol affords the corresponding cinnamate esters.2
However, the Perkin reaction is often hampered by low
yields,3 especially for the preparation of ortho-hydroxy-
cinnamate esters from salicylaldehydes.4 Hence, efforts
Scheme 1.
Keywords: ortho-Hydroxycinnamate esters; ortho-Formylation of phenols.
*
Corresponding author. Tel.: +47 2285 7450; fax: +47 2285 5947; e-mail: t.v.hansen@farmasi.uio.no
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.017

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H. F. Anwar et al. / Tetrahedron Letters 46 (2005) 5285–5287
Scheme 2.
to develop simple and efficient procedures for their
synthesis are desirable.
References and notes
1. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Publishing: Oxford, 2000, pp 170–189; (b) Ringk,
W. F. In Kirk Othmer Encyclopedia of Chemical Technol-
ogy, 3rd ed.; John Wiley and Sons: New York, 1981; Vol. 6,
pp 143–149.
2. (a) Perkin, W. H. J. Chem. Soc. 1868, 21, 53–54; (b)
Johnson, J. R. In The Perkin Reaction and Related
Reactions in Organic Reactions; Adams, R., Ed.; John
Wiley and Sons: New York, 1942; Vol. 1, pp 218–231.
3. (a) Koepp, E.; Vo¨gtle, F. Synthesis 1987, 177–179; (b)
Aslam, M.; Stansbury, W. F.; Reiter, R. J.; Larkin, D. R.
J. Org. Chem. 1997, 62, 1550–1552.
4. (a) Adams, R.; Mathieu, J. J. Am. Chem. Soc. 1948, 70,
2120–2122; (b) Adams, R.; Bockstahler, T. E. J. Am. Chem.
Soc. 1954, 74, 5346–5348; (c) Chenault, J.; Dupin, J. F. E.
Synth. Commun. 1984, 14, 1059–1065; (d) Dupin, J. F. E.;
Chenault, J. Synth. Commun. 1985, 15, 581–586.
5. Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999,
53, 258–262.
6. Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2005, 46,
3829–3830.
7. Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2005, 46,
3357–3358.
8. (a) Cartwright, G. A.; McNab, H. J. Chem. Res. (S) 1997,
296–297; (b) Ohkatsu, Y.; Aoshima, T.; Yamaguchi, K.
Nippon Kagaku Kaishi 1998, 711–720; (c) Panetta, J. A.;
Rapoport, H. J. Org. Chem. 1982, 47, 946–950.
9. General procedure for compounds 1–8: To a stirred
solution of the phenol (2 mmol) in dry THF (20 ml),
anhydrous magnesium chloride (0.38 g, 4 mmol), triethyl-
amine (0.40 g, 4 mmol) and paraformaldehyde (0.18 g,
6 mmol) were added. The reaction mixture was heated to
reflux under an argon atmosphere, and the reaction was
monitored by TLC (EtOAc/hexane 1:1). After complete
consumption of the phenol, a solution of methyl (triphen-
ylphosphoranylidene)acetate (0.80 g, 2.4 mmol) in CH2Cl2
(10 ml) was dropwise added at ambient temperature, and
the reaction was monitored by TLC (EtOAc/hexane 1:1).
After complete consumption of the salicylaldehyde, 1 N
HCl (20 ml) was added and the reaction mixture was
extracted with Et2O (2 · 20 ml), the combined organics
dried (MgSO4) and the product purified by flash chroma-
tography (SiO2, EtOAc/hexane 1:20). For compounds 9–11,
the general procedure was employed except heating for
2–10 h was required for complete consumption of aldehydes.
Spectral data of the new compounds: methyl (E)-3-(3-
fluoro-2-hydroxyphenyl)acrylate (2): white solid; mp 116–
We have recently described a facile procedure for the
selective ortho-formylation of phenols to salicylalde-
hydes that involves heating a mixture of the phenol,
anhydrous MgCl2, triethylamine and paraformaldehyde
under reflux in acetonitrile or THF. For alkyl and halo-
gen substituted phenols excellent yields of salicylalde-
hydes were obtained.5 The salicylaldehydes can, without
isolation, be converted to salen ligands6 and the corre-
sponding catechols.7 A similar one-pot procedure
seemed feasible for the preparation of ortho-hydroxycin-
namate esters.
Accordingly, to a THF solution of the formylation reac-
tion, a solution of methyl (triphenylphosphoranylid-
ene)acetate in CH2Cl2 was added. After stirring for
4–8 h at ambient temperature, the reactions were com-
plete and the products were purified by column chroma-
tography (Scheme 1). Physical and spectral data were in
accordance with those previously reported for the
known compounds 1 and 7.8a New compounds were
characterized on the basis of spectral data.9 The (E)-
configuration of the products was established by 1H
NMR spectroscopy. The reactions were carried out with
both 2- and 4-substituted phenols as starting materials
and the yields ranged from 60% to 78% and were not
optimized. In the case of alkyl, that is R = Me, t-Bu
and phenoxy-substituted phenols, the reaction mixtures
were heated for 2–10 h at gentle reflux. The product
methyl ortho-hydroxycinnamates 9,8b 108b and 119 were
accompanied by minor amounts of the corresponding
coumarins 12,8c 13,9 and 14,9 respectively (Scheme 2).
In conclusion, using this simple one-pot procedure,
ortho-hydroxycinnamates are available from the respec-
tive phenols in considerably better overall yields than
those previously reported.
Acknowledgements
The Research Council of Norway is gratefully acknowl-
edged for a scholarship to H.F.A.

H. F. Anwar et al. / Tetrahedron Letters 46 (2005) 5285–5287
5287
118 ꢁC; 1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3H), 5.80
(br s, 1H), 6.61 (d, J = 16.2 Hz, 1H), 6.85 (m, 1H), 7.11 (m,
1H), 7.50 (m, 1H), 7.90 (d, J = 16.2 Hz, 1H); 13C NM R
(75 MHz, CDCl3): d = 168.1, 143.6, 139.3, 124.9, 124.8,
120.6, 120.2, 117.0, 116.7, 52.1; HRMS calcd for C10H9FO3
(M+): 196.0536, found: 196.0527. Methyl (E)-3-(3-chloro-2-
hydroxyphenyl)acrylate (3): white solid; mp 120–122 ꢁC; 1H
NMR (300 MHz, CDCl3): d = 3.80 (s, 3H), 6.10 (br s, 1H),
6.56 (d, J = 16.2 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 7.30–7.40
(m, 2H), 7.90 (d, J = 16.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d = 167.6, 150.3, 139.2, 130.2, 127.8, 122.8, 121.0,
120.8, 119.8, 51.7; HRMS calcd for C10H9ClO3 (M+):
212.0240, found: 212.0238; Methyl (E)-3-(3-bromo-2-
hydroxyphenyl)acrylate (4): white solid; mp 118–120 ꢁC;
1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3H), 6.00 (br s,
1H), 6.56 (d, J = 16.2, Hz, 1H), 6.80 (t, J = 7.9 Hz, 1H),
7.40 (dd, J = 7.9, 1.2 Hz, 1H), 7.45 (dd, J = 7.9, 1.4 Hz,
1H), 7.90 (d, J = 16.2, Hz, 1H); 13C NMR (75 MHz,
CDCl3): d = 167.9, 151.5, 139.8, 133.7, 129.0, 123.2, 122.0,
120.3, 111.9, 52.1; HRMS calcd for C10H9BrO3 (M+):
255.9735, found: 255.9732. Methyl (E)-3-(2-hydroxy-3-iodo-
NMR (300 MHz, CDCl3): d = 3.80 (s, 3H), 6.52 (br s, 1H),
6.55 (d, J = 16.1 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 7.50 (dd,
J = 8.5, 2.1 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.90 (d,
J = 16.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 168.8,
155.3, 140.1, 139.4, 137.8, 124.6, 119.5, 118.9, 82.9, 52.3;
HRMS calcd for C10H9IO3 (M+): 303.9596, found:
303.9599. Methyl (E)-3-(3-tert-butyl-2-hydroxyphenyl)-
acrylate (10): white solid; mp 101–103 ꢁC; 1H NM R
(300 MHz, CDCl3): d = 1.50 (s, 9H), 3.85 (s, 3H), 6.25 (br
s, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.89 (t, J = 7.7 Hz, 1H),
7.33 (m, 2H), 8.20 (d, J = 15.8 Hz, 1H); 13C NM R
(75 MHz, CDCl3): d = 168.5, 154.2, 140.8, 137.8, 129.6,
126.2, 123.0, 120.9, 118.9, 52.3, 34.9, 30.2; HRMS calcd for
C14H18O3 (M+): 234.1256, found: 234.1255. Methyl (E)-3-
(2-hydroxy-5-phenoxyphenyl)acrylate (11): white solid; mp
143–145 ꢁC; 1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3H),
6.58 (d, J = 16.2 Hz, 1H), 6.65 (br s, 1H), 6.85 (d,
J = 8.8 Hz, 1H), 6.95 (m, 3H), 7.10 (m, 1H), 7.20 (d,
J = 2.8 Hz, 1H), 7.30–7.40 (m, 2H), 8.05 (d, J = 16.2 Hz,
1H); 13C NMR (75 MHz, CDCl3): d = 169.1, 158.5, 152.0,
150.5, 140.5, 130.1, 123,5, 122.9, 119.8, 119.3, 118.9, 118.1,
117.9, 52.3; HRMS calcd for C16H14O4 (M+): 270.0892,
found: 270.0888. 8-tert-Butyl-2H-chromen-2-one (13): pale
1
phenyl)acrylate (5): white solid; mp 108–109 ꢁC; H NM R
(300 MHz, CDCl3): d = 3.85 (s, 3H), 5.90 (br s, 1H), 6.56
(d, J = 16.2 Hz, 1H), 6.71 (t, J = 7.8 Hz, 1H), 7.45 (dd,
J = 7.8, 1.2 Hz, 1H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.90 (d,
J = 16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 167.9,
153.8, 140.3, 140.2, 129.9, 122.9, 122.5, 120.1, 88.1, 52.2;
HRMS calcd for C10H9IO3 (M+): 303.9596, found:
303.9606. Methyl (E)-3-(5-fluoro-2-hydroxyphenyl)acry-
1
yellow oil; H NMR (300 MHz, CDCl3): d = 1.55 (s, 9H),
6.42 (d, J = 9.5 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.50 (dd,
J = 7.7, 1.6 Hz, 1H), 7.54 (dd, J = 7.7, 1.6 Hz, 1H), 7.72 (d,
J = 9.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 161.0,
153.1, 144.8, 138.5, 129.8, 126.7, 124.4, 119.6, 119.3, 35.4,
30.3; HRMS calcd for C13H14O2 (M+): 202.0994, found:
202.0993. 6-Phenoxy-2H-chromen-2-one (14): white solid;
1
late (6): white solid; mp 121–123 ꢁC; H NMR (300 MHz,
1
CDCl3): d = 3.80 (s, 3H), 6.50 (br s, 1H), 6.55 (d,
J = 16.2 Hz, 1H), 6.80 (m, 1H), 6.95 (m, 1H), 7.15 (dd,
J = 9.1, 3.0 Hz, 1H), 7.95 (d, J = 16.2 Hz, 1H); 13C NM R
(75 MHz, CDCl3): d = 168.8, 151.7, 139.9, 119.4, 118.6,
118.3, 117.8, 114.9, 114.6, 52.3; HRMS calcd for C10H9FO3
(M+): 196.0536, found: 196.0534. Methyl (E)-3-(2-hydroxy-
mp 119–121 ꢁC; H NMR (300 MHz, CDCl3): d = 6.41 (d,
J = 9.5 Hz, 1H), 7.00 (m, 2H), 7.07 (d, J = 2.8 Hz, 1H),
7.12–7.20 (m, 2H), 7.30–7.40 (m, 3H), 7.61 (d, J = 9.5 Hz,
1H); 13C NMR (75 MHz, CDCl3): d = 161.0, 157.3, 154.1,
150.3, 143.3, 130.4 (2 · c), 124.3, 123.4, 119.9 (2 · c), 119.3,
118.6, 117.8, 116.8; HRMS calcd for C15H10O3 (M+):
238.0630, found: 238.0628.
1
5-iodophenyl)acrylate (8): white solid; mp 163–164 ꢁC; H