Regiospecific synthesis of heterosubstituted phenols from 3-alkoxycarbonyl-3,5-dienoic acids via benzannulation reaction

Full text of DOI:10.1021/jo010552f

J . Org. Chem. 2001, 66, 7883-7888
7883
Sch em e 1
Regiosp ecific Syn th esis of
Heter osu bstitu ted P h en ols fr om
3-Alk oxyca r bon yl-3,5-d ien oic Acid s via
Ben za n n u la tion Rea ction
Stefano Serra,* Claudio Fuganti, and Alberto Moro
Dipartimento di Chimica del Politecnico, Centro CNR per lo
studio delle Sostanze Organiche Naturali, Via Mancinelli,
7 I-20131 Milano, Italy
stefano.serra@dept.chem.polimi.it
Received May 31, 2001
In tr od u ction
The regiospecific preparation of polysubstituted aro-
matic compounds is one of the challenging problems in
organic synthesis. The classic approach is based on
aromatic substitution, which introduces a substituent to
a preexisting arene. A great variety of synthetic meth-
odologies based on this route have been developed, and
the most well-known are electrophilic or nucleophilic
substitutions,1 catalyzed coupling reactions,2 and meta-
lation-functionalization reactions.3 The main restriction
of this approach lies in the activating or deactivating and
orienting effects of the substituents that limit the ap-
plication of the synthetic methods.
Other approaches that build up the aromatic moiety
starting from acyclic precursors4 have received growing
interest since the preparation of highly substituted
compounds in only few steps and the avoidance of ortho-
meta-para mixtures obtained in conventional aromatic
synthesis show several advantages. These general fea-
tures are common in the most useful benzannulation
routes based on Diels-Alder [4 + 2] cycloaddition,5
transition-metal-catalyzed [2 + 2 + 2] and [4 + 2]
cycloaddition,6 [3 + 3]7 and [4 + 2]8 benzannulation, 1,6-
electrocyclic reaction,9 and Do¨tz reaction.10
enoic acids.11 The latter process is very flexible, and we
have previously shown that it can be used in the
preparation of oligoaryls,11,12 naphthalenes,13 chiral tet-
rahydronaphthalenes,14 ring-fused heterocycles,15 C-aryl-
glycosides,16 and many natural products of different
structure.17 The introduction of a heterosubstituent into
hydroxybenzoic acid derivatives by classical routes usu-
ally requires harsh conditions and often does not proceed
with high positional selectivity. Otherwise, our benzan-
nulation approach affords regiospecifically the substi-
tuted phenols and the mild conditions used allow the
introduction of different kinds of heterosubstituents. We
report herein the exploitation of this synthetic methodol-
ogy to obtain 4- and 5-heterosubstituted 3-hydroxybenzoic
acid derivatives starting from readily available 2- and
3-heterosubstituted R,â-unsaturated aldehydes.
Recently, we have developed a method of benzannu-
lation that allows the construction of 4-substituted 3-hy-
droxybenzoic acid derivatives by mild base-promoted
cyclization of substituted 3-alkoxycarbonyl-3,5-hexadi-
Resu lts a n d Discu ssion
As mentioned above, the design of our synthetic path
is based on the preparation of aldehydes 1 followed by
their homologation to the related hexadienoic acids 3 and
4 (Scheme 1), which are cyclized to phenols 5 and 6,
respectively. The 2- and 3-heterosubstituted R,â-unsatur-
ated aldehydes 1 were prepared starting from easily
available materials and using known methodologies (see
the Experimental Section). The synthesis of the 3-alkoxy-
carbonyl-3,5-hexadienoic acids 3 was performed by means
(1) (a) Olah, G. A. Acc. Chem. Res. 1971, 4, 240. (b) Hartshorn, S.
R. Chem. Soc. Rev. 1974, 3, 167. (c) Bunnett, J . F.; Zahler, R. E. Chem.
Rev. 1951, 49, 273. (d) Bunnett, J . F. Acc. Chem. Res. 1978, 11, 413.
(2) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Brown, J . M.;
Cooley, N. A. Chem. Rev. 1988, 88, 1031. (c) Mitchell, T. N. Synthesis
1992, 803. (d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(3) (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (b)
Chauder, B.; Green, L.; Snieckus, V. Pure Appl. Chem. 1999, 71, 1521.
(4) Bamfield, P.; Gordon, P. F. Chem. Soc. Rev. 1984, 13, 441.
(5) (a) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980, 9, 41.
(b) Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamont; Oxford, 1991, Vol. 5, pp 315-399.
(6) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23,
539. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
(7) (a) Katritzky, A. R.; Li, J .; Xie, L. Tetrahedron 1999, 55, 8263.
For further relevant [3 + 3] benzannulation not included in ref 7a,
see: (b) Hauser, F. M.; Rhee, R. P. J . Org. Chem. 1978, 43, 178. (c)
Cameron, D. W.; Feutrill, G. I.; Pannan, L. J . H. Aust. J . Chem. 1980,
33, 2531.
(11) Brenna, E.; Fuganti, C.; Perozzo, V.; Serra, S. Tetrahedron 1997,
53, 15029.
(12) (a) Brenna, E.; Fuganti, C.; Serra, S. J . Chem. Soc., Perkin
Trans. 1 1998, 901. (b) Brenna E.; Scaramelli, L.; Serra, S. Synlett
2000, 357.
(13) Fuganti, C.; Serra, S. J . Chem. Res., Synop. 1998, 638.
(14) Brenna, E.; Fuganti, C.; Serra, S. Synlett 1998, 365.
(15) (a) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron 1998, 54,
1585. (b) Fuganti, C.; Serra, S. Tetrahedron Lett. 1998, 39, 5609.
(16) Fuganti, C.; Serra, S. Synlett 1999, 1241.
(17) (a) Fuganti, C.; Serra, S. Synlett 1998, 1252. (b) Fuganti, C.;
Serra, S. J . Org. Chem. 1999, 64, 8728. (c) Serra, S. Synlett 2000, 890.
(8) Loebach, J . L.; Bennett, D. M.; Danheiser, R. L. J . Org. Chem.
1998, 63, 8380.
(9) (a) Bakulev, V. A. Russ. Chem. Rev. (Engl. Transl.) 1995, 64,
99. (b) Turnbull, P.; Moore, H. W. J . Org. Chem. 1995, 60, 644.
(10) (a) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b)
Do¨tz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187.
10.1021/jo010552f CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/20/2001

7884 J . Org. Chem., Vol. 66, No. 23, 2001
Ta ble 1. Syn th esis of Acid s 3, 4 a n d P h en ols 5, 6 fr om Ald eh yd es 1
Notes
a
b
After chromatography and/or crystallization. A and B are the benzannulation methods. c Combined yield of the two steps (Wittig
d
and benzannulation). Obtained as benzoic acid derivative by hydrolysis of the related ester.
of a Wittig reaction of aldehydes 1 with triphenyl(R-
carbethoxy-â-carboxyethyl)phosphonium ylide 2.18 The
reaction proceeded smoothly for all substrates (Table 1)
and the yield of isolated acid 3 range from 65 to 95%
depending either on the steric hindrance in the R position
or the presence of electron-withdrawing or electron-
releasing substituents. The steric requirements can
strongly affect the reaction trend. This was confirmed by
further experiment of Wittig reaction of ylide 2 with
different R-phenyl-â-alkoxy acroleins and R-iodo-â-alkyl
acroleins,19 which were also unaffected under forcing
(18) (a) For the preparation of this ylide, see: Hudson, R. F.;
Chopard, P. A. Helv. Chim. Acta 1963, 46, 2178. (b) Compounds 3a ,c-
f,h ,j-k were prepared starting from isomerically pure aldehydes 1,
and they were obtained as single stereoisomers. Otherwise, the
aldehydes 1g,i were available as an E/Z mixture and their homologa-
tion to dienic acids gave compounds 3g,i as a corresponding mixture
of two regioisomers (see the Experimental Section). Since the Wittig
reaction of the ylide 2 with the aldehydes affords the 3-(E)-alkylidene-
succinic acid monomethyl esters in ahighly stereoselective way, we
assigned the E stereochemistry at the new formed double bonds of the
compounds 3. For previous studies on the stereoselectivity of this
reaction, see: Ro¨der, E.; Krauss, H. Liebigs Ann. Chem. 1992, 177.
Paquette, L. A.; Schulze, M. M.; Bolin, D. J . Org. Chem. 1994, 59, 2043.
(19) The reaction of ylide 2 with 2-bromoacrolein, 2,3-dibromoac-
rolein, and 2-iodoacrolein was also tested, but quick polymerization of
the starting aldehydes occurs before the formation of dienic acids.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7885
amount (less than 10%)23 of the diethyl esters of the
starting acids. We assume that ethanol, derived from the
decomposition of mixed anhydrides, reacts in competitive
behavior with the divinylketenes to give the ethyl esters.
According to our explanation, the same procedure, per-
formed by using trifluoroacetic anhydride as activating
agent and by prolonging the reaction time (2 h), gives
the phenolic derivatives in higher yield. Furthermore, in
both procedures the conversion of starting acid was
quantitative and the resulting phenolic compounds were
formed regiospecifically.
Sch em e 2
The examination of the substitution pattern of the
acids 3a -j and 4m shows the flexibility of the present
synthetic approach: phenyl, alkyl, halo, alkoxy, and
thiophenyl groups are unaffected to give the related
phenols 5a -j and 6m , respectively, and in high yields.
The acids 3k and 4l were cyclized to phenols 5k and 6l
with partial (less than 20% for k ) and complete (l) loss
of the trimethylsilyl group. Since the amount of benzan-
nulated phenols indicate a quantitative conversion to the
aromatic compounds, these different trends can be ex-
plained in term of a low stability of the o-trimethylsilyl
phenols.24
In conclusion, these experiments demonstrate the
utility and the flexibility of this benzannulation proce-
dure in the regiospecific synthesis of heterosubstituted
phenols. The starting materials are easily available, the
experimental procedure is very simple, and the products
are obtained in high yields. Moreover, this pathway
shows many advantages over the classical routes based
on the aromatic substitution, and its claimed versatility
allows the preparation of a wide set of 2,4,5-substituted
3-hydroxybenzoic acid derivatives not easily accessible
through the available methods.
conditions. Despite this limitation, a great variety of
substituents on the starting aldehydes 1 were tolerated,
and also acroleins bearing labile substituents (such as
Br, I, and Si) reacted in a straightforward way.
Moreover, to devise a new entry to 2-substituted
3-hydroxybenzoic acids, we examined next the alkylation
in the R position20a of the acids 3. We found that the
conversion of 3 in the corresponding dianions using 2
equiv of LDA as base in the presence of 4 equiv of
DMPU20b followed by reaction with methyl iodide or allyl
bromide gave the R alkylated acids, without isomerization
of the dienic framework.21 As representative examples
we converted acids 3j and 3k to the acids 4m and 4l,
respectively, in good yields and with quite complete
regioselectivity.22 Then, the combination of Wittig reac-
tion by means of ylide 2 with R alkylation of the
so-obtained acids was a useful route to dienic acids 3 and
4 that can be easily benzannulated to phenols 5 and 6,
respectively.
This cyclization step was performed by two simple
experimental procedures that work under very mild
conditions and differ in the use of activating agent. In
both procedures, the acids 3 or 4 were treated at room
temperature and in THF solution with ethyl chlorofor-
mate (method A) or trifluoroacetic anhydride (method B)
as activating agents, followed by the addition of an excess
of triethylamine. The so-formed mixed anhydrides were
unstable in base and were converted in a divinylketene
intermediate that cyclized through a 1,6-electrocyclic
reaction (Scheme 2) to give phenols 5 or 6. Since the
activating agent and the base were used in excess, a
slight amount of carboxyethyl trifluoroacetyl derivatives
of the resulting phenols were also formed. These products
were easily converted into the suitable phenols in the
workup procedure by quick treatment with ethanolic
KOH (method A) or by reduction with NaBH4 (method
B).
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded in CDCl3
solution at room temperature, unless otherwise stated, on a
1
Bruker AC-250 spectrometer (250 MHz H). The chemical-shift
scale is based on internal tetramethylsilane. IR spectra were
recorded on a Perkin-Elmer 2000 FTIR spectrometer. Mass
spectra were measured on a Finnigan-MAT TSQ 70 spectrom-
eter. Melting points were measured on a Reichert melting point
apparatus, equipped with a Reichert microscope, and are uncor-
rected. TLC analyses were performed on Merck Kieselgel 60 F254
plates. All the chromatographic separations were carried out on
a silica gel columns.
Ald eh yd es 1a -k . The aldehydes 1a -k were prepared as
follows. (Z)-2-bromo-3-phenylpropenal25 1a , (E/Z 4:1)-2-methyl-
3-bromopropenal26 1b, (Z)-2-bromohex-2-enal27 1c, (Z)-2-meth-
oxy-3-phenylpropenal 1e, and (Z)-2-methoxyhex-2-enal28 1h have
been obtained from the corresponding unsaturated aldehydes
via a bromination-HBr elimination sequence (aldehydes 1a -
c) and a R-methoxylation procedure28 (aldehydes 1e and 1h ),
respectively. (E)-3-Iodopropenal29 1d was obtained by HI addi-
tion on propynal. 2-Methoxypropenal30 1f was obtained by
Mannich reaction on methoxyacetaldehyde. (E/Z 4:1)-3-Ethoxy-
The rates of conversion and the yields of products are
dependent on the activating agent and on the nature of
the starting acids. When ethyl chloroformate is used, the
reaction is very fast (few minutes at 0-20°) and we
obtained the phenolic derivatives together with a slight
(23) Phenol 5d was obtained together with 20% of diethyl ester of
acid 3d . This different behavior can be explained in term of major steric
hindrance around the position 6 of the hexadienoic system.
(24) Other authors noted the instability of o-triethylsilylphenols; see
ref 8c.
(25) Zincke, T.; von Hagen, D. Chem. Ber. 1884, 26, 651.
(26) Pino, P.; Ercoli, R. Gazz. Chim. Ital. 1951, 81, 757.
(27) Feutren, S.; McAlonan, H.; Montgomery, D.; Stevenson, P. J .
J . Chem. Soc., Perkin Trans. 1 2000, 1129.
(20) (a) For R-alkylation of â,γ-unsaturated acid, see: van der Veen,
R. H.; Cerfontain, H. J . Org. Chem. 1985, 50, 342. (b) We tested also
the LDA-HMPA system for this alkylation. The results were compa-
rable, so we preferred the less toxic DMPU as reagent of choice for
this reaction.
(21) Alkylation of halogen substituted dienic acids 3a -d afforded
only trace of the acids 4a -d . This behavior was probably due to the
base-induced elimination of halogen atoms.
(28) Feuerer, A.; Severin, T. J . Org. Chem. 1994, 59, 6026.
(29) Berger, D.; Bartlome, A.; Neuenschwander, M. Helv. Chim. Acta
1996, 79, 179.
(22) The products of γ alkylation were not detected in the reaction
mixture whereas R-dialkylated products were formed in slight amount
(less than 10%, GC analysis).
(30) Russell, G. A.; Ballenegger, M. Synthesis 1973, 104.

7886 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
propenal31 1g was obtained from malonaldehyde bis(diethyl
acetal). (E/Z 1:9)-3-Thiophenylpropenal 1i and (E)-3-trimethyl-
silylpropenal 1k were obtained by MnO2 oxidation of the related
allylic alcohol which was prepared by addition of thiophenol32
on propargylic alcohol and by reduction33 of 3-trimethylsilyl-2-
propyn-1-ol, respectively. (2E)-3-thiophenyl-2-methylpropenal
(1j) was synthesized by addition of sodium thiophenate on
aldehyde 1b.34
as a 4:1 mixture of (3E,5E) and (3E,5Z) isomers as confirmed
by GC analysis.
(3E,5Z)-3-(E t h oxyca r b on yl)-5-m et h oxy-3,5-n on a d ien o-
ic a cid (3h ): yield 71%; colorless oil; FT-IR (film) 1709, 1636,
1264, 1203, 1098, 1035 cm-1; EI-MS m/z 256 (M+, 4), 238 (8),
225 (15), 210 (41), 199 (57), 181 (67), 167 (54), 153 (71), 139 (73),
109 (100); 1H NMR (250 MHz, C6D6) δ 7.31 (1H, s), 4.98 (1H, t,
J ) 7.7 Hz), 4.04 (2H, q, J ) 7.2 Hz), 3.93 (2H, s), 3.18 (3H, s),
2.04-1.91 (2H, m), 1.18 (2H, sext, J ) 7.5 Hz), 0.98 (3H, t, J )
7.2 Hz), 0.77 (3H, t, J ) 7.5 Hz). Anal. Calcd for C13H20O5
(256.29): C, 60.92; H, 7.87. Found: C, 70.11; H, 7.82.
(3E,5E)-3-(Eth oxyca r bon yl)-6-th iop h en yl-3,5-h exa d ien o-
ic a cid (3i): yield 95%; colorless oil; FT-IR (film) 1711, 1618,
1558, 1280, 958, 745 cm-1; EI-MS m/z 292 (M+, 49), 248 (3), 220
(63), 191 (42), 135 (79), 123 (41), 110 (100), 91 (48); 1H NMR
(250 MHz, CDCl3) δ 7.48-7.28 (5H, m), 7.03-6.84 (2H, m), 6.38
(1H, dd, J ) 14.7, 11.7 Hz), 4.22 (2H, q, J ) 7.2 Hz), 3.4 (2H, s),
1.29 (3H, t, J ) 7.2 Hz). Anal. Calcd for C15H16O4S (292.35): C,
61.62; H, 5.52. Found: C, 61.45; H, 5.45.
Gen er a l P r oced u r e for th e Syn th esis of 3-Eth oxyca r -
bon yl-3,5-h exa d ien oic Acid s 3. The aldehyde 1 (50 mmol) in
toluene (80 mL) was treated with triphenyl(R-carbethoxy-â-
carboxyethyl)phosphonium ylide 2 (24.4 g, 60 mmol) and hydro-
quinone (50 mg, 0.45 mmol) at the temperature indicated and
stirred for the necessary period of time (see Table 1). The solvent
was removed under reduced pressure, and the residue was
purified by chromatography on a silica gel column eluting with
the suitable hexane/ethyl acetate mixture to afford pure acid 3.
(3E,5Z)-3-(Eth oxyca r bon yl)-5-br om o-6-p h en yl-3,5-h exa -
d ien oic a cid (3a ): yield 70%; colorless crystals (from hexane/
ethyl acetate); mp 82-83 °C; FT-IR (film) 1702, 1618, 1412, 1263,
(3E,5E)-3-(E t h oxyca r b on yl)-5-m et h yl-6-t h iop h en yl-3,5-
h exa d ien oic a cid (3j): yield 75%; colorless crystals (from
hexane/ethyl acetate); mp 77 °C; FT-IR (film) 3434, 1702, 1614,
1276, 1199, 1030, 816, 743 cm-1; EI-MS m/z 306 (M+, 8), 281
(7), 260 (4), 207 (10), 183 (8), 155 (9), 137 (9), 123 (100), 110
1230, 1202, 957, 689 cm-1; EI-MS m/z 339 (M+, 18), 259 (M+
-
Br, 92), 213 (32), 185 (100), 169 (6), 157 (34), 141 (55), 139 (32),
129 (36), 115 (44); 1H NMR (250 MHz, CDCl3) δ 7.72-7.63 (2H,
m), 7.52 (1H, s), 7.44-7.30 (3H, m), 7.13 (1H, s), 4.28 (2H, q, J
) 7.1 Hz), 3.71 (2H, s), 1.32 (3H, t, J ) 7.1 Hz). Anal. Calcd for
C15H15BrO4 (339.18): C, 53.12; H, 4.46. Found: C, 53.15; H, 4.45.
(3E,5E)-3-(Eth oxyca r bon yl)-5-m eth yl-6-br om o-3,5-h exa -
d ien oic a cid (3b): yield 74%; only the (3E,5E) isomer was
1
(19), 77 (11); H NMR (250 MHz, CDCl3) δ 7.44-7.22 (6H, m),
6.70 (1H, s), 4.23 (2H, q, J ) 7.2 Hz), 3.61 (2H, s), 2.04 (3H, s),
1.29 (3H, t, J ) 7.2 Hz). Anal. Calcd for C16H18O4S (306.38): C,
62.72; H, 5.92. Found: C, 62.75; H, 5.91.
(3E,5E)-3-(Eth oxyca r bon yl)-6-(tr im eth ylsilyl)-3,5-h exa -
d ien oic a cid (3k ): yield 87%; colorless crystals (from hexane);
mp 58 °C; FT-IR (film) 1713, 1629, 1416, 1286, 1207, 990, 859,
841 cm-1; EI-MS m/z 256 (M+, 4), 241 (5), 227 (6), 195 (11), 183
(100), 167 (22), 151 (21), 137 (66), 123 (32), 109 (29); 1H NMR
(250 MHz, C6D6) δ 7.46 (1H, d, J ) 10.8 Hz), 6.72 (1H, dd, J )
18, 10.8 Hz), 6.09 (1H, dd, J ) 18, 0.7 Hz), 4.00 (2H, q, J ) 7.1
Hz), 3.41 (2H, s), 0.96 (3H, t, J ) 7.1 Hz), -0.02 (9H, s). Anal.
Calcd for C12H20O4Si (256.37): C, 56.22; H, 7.86. Found: C,
56.30; H, 7.85.
obtained although
a 4:1 E/Z mixture of aldehyde 1b was
employed in the preparation; colorless oil; FT-IR (film) 3090,
1712, 1641, 1260, 1200, 1100, 1027, 767 cm-1; EI-MS m/z 197
(M+ - Br, 46), 151 (73), 123 (100), 107 (9), 95 (14), 79 (27); H
1
NMR (250 MHz, CDCl3) δ 7.23 (1H, s), 6.46 (1H, m), 4.25 (2H,
q, J ) 7.1 Hz), 3.51 (2H, s), 1.98 (3H, d, J ) 0.9 Hz), 1.31 (3H,
t, J ) 7.1 Hz). Anal. Calcd for C10H13BrO4 (277.11): C, 43.34;
H, 4.73. Found: C, 43.45; H, 4.70.
(3E,5Z)-3-(Eth oxycar bon yl)-5-br om o-3,5-n on adien oic acid
(3c): yield 68%; colorless oil; FT-IR (film) 1714, 1372, 1271,
1204, 1095, 788, 767 cm-1; EI-MS m/z 306 (M+ + 1, 1), 304 (M+
- 1, 1), 288 (5), 286 (5), 260 (M+ - OEt, 8), 225 (M+ - Br, 84),
179 (85), 161 (20), 151 (42), 123 (100), 105 (27); 1H NMR (250
MHz, CDCl3) δ 7.35 (1H, s), 6.13 (1H, dt, J ) 6.7, 1.2 Hz), 4.25
(2H, q, J ) 7.1 Hz), 3.61 (2H, s), 2.35-2.20 (2H, m), 1.49 (2H,
sext, J ) 7.5 Hz), 1.31 (3H, t, J ) 7.1 Hz), 0.96 (3H, t, J ) 7.5
Hz). Anal. Calcd for C12H17BrO4 (305.16): C, 47.23; H, 5.61.
Found: C, 47.45; H, 5.55.
(3E,5E)-3-(Eth oxyca r bon yl)-6-iod o-3,5-h exa d ien oic a cid
(3d ): yield 90%; pale yellow crystals (from hexane/ethyl acetate);
mp 106 °C; FT-IR (film) 1717, 1629, 1414, 1273, 1230, 1082, 972,
956, 768 cm-1; EI-MS m/z 310 (M+, 2), 266 (23), 237 (9), 183
(30), 137 (66), 109 (100), 82 (24), 65 (31); 1H NMR (250 MHz,
CDCl3) δ 7.37-7.20 (2H, m), 7.05 (1H, dd, J ) 12.8, 0.9 Hz),
4.24 (2H, t, J ) 7.2 Hz), 3.46 (2H, s), 1.30 (3H, t, J ) 7.2 Hz).
Anal. Calcd for C9H11IO4 (310.09): C, 34.86; H, 3.58. Found: C,
34.80; H, 3.55.
(3E,5Z)-3-(Eth oxycar bon yl)-5-m eth oxy-6-ph en yl-3,5-h exa-
d ien oic a cid (3e): yield 88%; colorless crystals (from hexane/
ethyl acetate); mp 98-100 °C; FT-IR (film) 1700, 1593, 1244,
1193, 1050, 700 cm-1; EI-MS m/z 290 (M+, 5), 259 (M+ - OMe,
6), 245 (M+ - OEt,10), 199 (100), 167 (36), 153 (14), 139 (78),
91 (29); 1H NMR (250 MHz, CDCl3) δ 7.51 (1H, s), 7.38-7.16
(5H, m), 6.10 (1H, s), 4.20 (2H, q, J ) 7.1 Hz), 3.82 (2H, s), 3.73
(3H, s), 1.24 (3H, t, J ) 7.1 Hz). Anal. Calcd for C16H18O5
(290.31): C, 66.19; H, 6.25. Found: C, 66.30; H, 6.22.
(3E)-3-(Eth oxycar bon yl)-5-m eth oxy-3,5-h exadien oic acid
(3f) a n d (3E,5E)-3-(eth oxyca r bon yl)-6-eth oxy-3,5-h exa d i-
en oic a cid (3g): colorless oil. The compounds were transformed
into the corresponding phenol immediately after the purification
step because of their instability. The compound 3g was obtained
Gen er a l P r oced u r e for t h e Syn t h esis of 2-Alk yl-3-
eth oxyca r bon yl-3,5-h exa d ien oic Acid s 4 fr om Acid s 3. A
stirred solution of diisopropylamine (8.8 mL, 63 mmol) in dry
THF (90 mL) was cooled to -78 °C and treated with a 10 M
solution of n-BuLi (6.3 mL) under
a static atmosphere of
nitrogen. After 15 min, DMPU (14.5 mL, 120 mmol) was added,
followed by the dropwise addition of a THF (20 mL) solution of
acid 3 (30 mmol). The mixture immediately turned deep red,
and the reaction was stirred for another 1 h. Then, the suitable
alkylating agent (iodometane or allyl bromide, 30 mmol) was
added rapidly and the solution became pale red within 30 min.
The temperature was raised to 0 °C, and the mixture was diluted
with ether (200 mL) and acidified with an excess of 5% aqueous
HCl (150 mL). The layers were separated, and the aqueous phase
was extracted with ether (3 × 60 mL). The combined organic
portions were washed with brine (100 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The residue
was purified by chromatography on a silica gel column eluting
with the suitable hexane/ethyl acetate mixture to afford pure
acid 4.
(3E,5E)-2-Allyl-3-(eth oxyca r bon yl)-6-(tr im eth ylsilyl)-3,5-
h exa d ien oic a cid (4l): yield 88%; colorless oil; FT-IR (film)
1713, 1642, 1622, 1570, 1416, 1208, 988, 917, 840 cm-1; EI-MS
m/z 296 (M+, 6), 255 (3), 235 (5), 223 (46), 209 (14), 177 (19) 149
(21), 133 (26), 105 (30), 75 (100); 1H NMR (250 MHz, C6D6) δ
7.52 (1H, d, J ) 10.9 Hz), 6.83 (1H, dd, J ) 18, 10.9 Hz), 6.09
(1H, d, J ) 18 Hz), 5.78-5.58 (1H, m), 5.05-4.82 (2H, m), 4.00
(2H, q, J ) 7.2 Hz), 3.85 (1H, dd, J ) 9, 5.5 Hz), 3.03-2.92 (1H,
m), 2.78-2.60 (1H, m), 0.97 (3H, t, J ) 7.2 Hz), 0.03 (9H, s).
Anal. Calcd for C15H24O4Si (296.43): C, 60.78; H, 8.16. Found:
C, 60.95; H, 8.20.
(3E,5E)-2,5-Dim eth yl-3-(eth oxyca r bon yl)-6-th iop h en yl-
3,5-h exa d ien oic a cid (4m ): yield 85%; colorless crystals (from
hexane/ethyl acetate); mp 82-83 °C; FT-IR (film) 3435, 1714,
1691, 1605, 1275, 1248, 1073, 1022, 810, 750 cm-1; EI-MS m/z
320 (M+, 2), 274 (15), 211 (64), 165 (56), 137 (100), 109 (19), 91
(31) Tamura, S.; Takeda, E. Chem. Pharm. Bull. 1979, 27, 403.
(32) (a) Behzadi, A.; Owen, L. N. J . Chem. Soc., Perkin Trans. 1
1974, 25. (b) Ruel, O.; Guittet, E.; J ulia, S. Tetrahedron Lett. 1983,
24, 61.
(33) Denmark, S. E.; J ones, T. K. J . Org. Chem. 1982, 47, 4595.
(34) For a similar addition of thiols to the aldehydes 1b see: Mapp,
A. K.; Heathcock, C. J . Org. Chem. 1999, 64, 23.
1
(15), 77 (17); H NMR (250 MHz, CDCl3) δ 7.42-7.24 (6H, m),
6.61 (1H, s), 4.20 (2H, q, J ) 7.2 Hz), 3.97 (1H, q, J ) 7.1 Hz),
2.05 (3H, s), 1.39 (3H, d, J ) 7.1 Hz), 1.27 (3H, t, J ) 7.2 Hz).

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7887
Anal. Calcd for C17H20O4S (320.4): C, 63.73; H, 6.29. Found: C,
63.54; H, 6.35.
t, J ) 7.1 Hz). Anal. Calcd for C16H16O4 (272.30): C, 70.57; H,
5.92. Found: C, 70.41; H, 5.98.
Gen er a l P r oced u r e for th e Ben za n n u la tion of Acid s 3
a n d 4 to P h en ols 5 a n d 6. Meth od A. Ethyl chloroformate
(3.8 mL, 40 mmol) was added in one portion to a solution of acid
3 or 4 (20 mmol) in dry THF (40 mL), and then Et3N (8.4 mL,
60 mmol) was added, keeping the temperature under 20 °C by
external cooling. The reaction mixture was stirred for 15 min
at room temperature, treated with an excess of 5% aqueous HCl
(100 mL), and extracted with ethyl acetate (2 × 100 mL).
Concentration of organic phase gave a residue that was treated
with ethanolic (100 mL) NaOH (2.4 g, 60 mmol) at room
temperature for 15 min.
Meth od B. TFAA (5.6 mL, 40 mmol) was added in one portion
to a solution of acid 3 or 4 (20 mmol) in dry THF (60 mL), and
then Et3N (8.4 mL, 60 mmol) was added dropwise. The mixture
was stirred at room temperature for 2 h, acidified with an excess
of 5% aqueous HCl (100 mL), and extracted with ethyl acetate
(2 × 100 mL). The organic phase was concentrated under
reduced pressure and the residue dissolved in ethanol (100 mL).
The latter mixture was cooled to 0 °C and treated with NaBH4
(1.52 g, 40 mmol), stirring for 1 h.
Both procedures continue as follows: the reaction was diluted
with ethyl acetate (100 mL) and 5% aqueous HCl (100 mL). The
layers were separated, and the aqueous phase was extracted
with ethyl acetate (3 × 60 mL). The combined organic portions
were washed with brine (100 mL), dried, and concentrated under
reduced pressure. The so-obtained crude phenol 5 or 6 was
purified by chromatography on a silica gel column eluting with
the suitable hexane/ethyl acetate mixture.
4-P h en yl-5-b r om o-3-h yd r oxyb en zoic a cid et h yl est er
(5a ): method A; yield 78%; colorless crystals (from hexane/ethyl
acetate); mp 148-149 °C; FT-IR (film) 3365, 1699, 1416, 1302,
1243, 770, 700 cm-1; EI-MS m/z 322 (M+ + 1, 42), 320 (M+ - 1,
41), 277 (M+ - EtOH, 74), 219 (10), 168 (72), 139 (100), 128 (8);
1H NMR (250 MHz, CDCl3) δ 7.90 (1H, d, J ) 1.6 Hz), 7.64 (1H,
d, J ) 1.6 Hz), 7.56-7.40 (3H, m), 7.34-7.27 (2H, m), 5.64 (1H,
s), 4.37 (2H, q, J ) 7.1 Hz), 1.39 (3H, t, J ) 7.1 Hz). Anal. Calcd
for C15H13BrO3 (321.17): C, 56.10; H, 4.08. Found: C, 56.00; H,
4.05.
4-Br om o-5-m eth yl-3-h yd r oxyben zoic a cid eth yl ester
(5b): method A; yield 89%; colorless crystals (from toluene); mp
104-105 °C; FT-IR (film) 3387, 1690, 1592, 1423, 1319, 1265,
770 cm-1; EI-MS m/z 260 (M+ + 1, 46), 258 (M+ - 1, 47), 245
(M+ - Me, 12), 243 (M+ - Me, 13), 232 (38) 230 (39), 215 (98),
213 (100), 187 (21) 185 (22), 77 (23); 1H NMR (250 MHz, CDCl3)
δ 7.53 (1H, d, J ) 1.9 Hz), 7.48 (1H, d, J ) 1.9 Hz), 5.9-6.2
(1H, bs), 4.37 (2H, q, J ) 7.1 Hz), 2.44 (3H, s), 1.39 (3H, t, J )
7.1 Hz). Anal. Calcd for C10H11BrO3 (259.10): C, 46.36; H, 4.28.
Found: C, 46.25; H, 4.30.
4-P r op yl-5-b r om o-3-h yd r oxyb en zoic a cid et h yl est er
(5c): method A; yield 72%; colorless crystals (from hexane); mp
88 °C; FT-IR (film) 3423, 1698, 1575, 1416, 1290, 1216, 1105,
854 cm-1; EI-MS m/z 288 (M+ + 1, 100), 286 (M+ - 1, 88), 259
(M+ - Et, 85), 256 (81), 243 (14), 231 (22), 229 (22), 213 (8), 77
(10); 1H NMR (250 MHz, CDCl3) δ 7.78 (1H, d, J ) 1.5 Hz), 7.58
(1H, d, J ) 1.5 Hz), 6.1-6.4 (1H, bs), 4.38 (2H, q, J ) 7.2 Hz),
2.84-2.78 (2H, m), 1.61 (2H, sext, J ) 7.2 Hz), 1.39 (3H, t, J )
7.2), 1.01 (3H, t, J ) 7.2 Hz). Anal. Calcd for C12H15BrO3
(287.15): C, 50.19; H, 5.27. Found: C, 50.05; H, 5.25.
4-Iod o-3-h yd r oxyben zoic a cid eth yl ester (5d ): method
B; yield 91%; colorless crystals (from toluene); mp 119-120 °C;
FT-IR (film) 3384, 1695, 1590, 1419, 1230, 757, 618 cm-1; EI-
MS m/z 292 (M+ + 1, 66), 277 (7), 264 (40), 247 (M+-OEt, 100),
219 (16), 119 (10), 92 (13); 1H NMR (250 MHz, CDCl3) δ 7.76
(1H, d, J ) 8.2 Hz), 7.67 (1H, d, J ) 1.9 Hz), 7.33 (1H, dd, J )
8.2, 1.9 Hz), 5.98 (1H, bs), 4.38 (2H, q, J ) 7.2 Hz), 1.39 (3H, t,
J ) 7.2 Hz). Anal. Calcd for C9H9IO3 (292.07): C, 37.01; H, 3.11.
Found: C, 37.17; H, 3.08.
5-Meth oxy-3-h yd r oxyben zoic a cid (5f): method A; yield
70%; colorless crystals (from ethanol); mp 199-200 °C; FT-IR
(film) 3288, 1694, 1617, 1255, 807, 716 cm-1; EI-MS m/z 168
(M+, 100), 151 (M+ - OH, 15), 138 (8), 121 (37), 108 (9), 95 (11),
69 (14); 1H NMR (400 MHz, CD3COCD3) δ 9.6 (2H, bs), 7.16 (1H,
s), 7.10 (1H, s) 6.66 (1H, t, J ) 2.2 Hz), 3.80 (3H, s). Anal. Calcd
for C8H8O4 (168.15): C, 57.14; H, 4.80. Found: C, 56.96; H, 4.83.
4-Eth oxy-3-h yd r oxyben zoic a cid eth yl ester (5g): method
A; yield 90%; colorless crystals (from hexane); mp 81-82 °C; FT-
IR (film) 3408, 1695, 1614, 1515, 1304, 1278, 1216, 765 cm-1
;
EI-MS m/z 210 (M+, 57), 182 (12), 165 (M+ - OH, 24), 154 (40),
1
137 (100), 109 (12), 81 (6); H NMR (250 MHz, CDCl3) δ 7.63-
7.57 (2H, m), 6.88-6.82 (1H, m), 5.71 (1H, bs), 4.33 (2H, q, J )
7.2 Hz), 4.17 (2H, q, J ) 7.2 Hz), 1.47 (3H, t, J ) 7.2 Hz), 1.37
(3H, t, J ) 7.2 Hz). Anal. Calcd for C11H14O4 (210.23): C, 62.85;
H, 6.71. Found: C, 62.70; H, 6.75.
4-P r op yl-5-m eth oxy-3-h yd r oxyben zoic a cid eth yl ester
(5h ): method B; yield 89%; colorless crystals (from hexane/ethyl
acetate); mp 91 °C; FT-IR (film) 3415, 1702, 1596, 1424, 1262,
1131, 772 cm-1; EI-MS m/z 238 (M+, 46), 209 (M+ - Et, 100),
193 (M+ - OEt, 18), 181 (14), 163 (14), 151 (13), 125 (9), 77 (7);
1H NMR (250 MHz, CDCl3) δ 7.29 (1H, d, J ) 1.4 Hz), 7.13 (1H,
d, J ) 1.4 Hz), 5.97 (1H, bs), 4.37 (2H, q, J ) 7.2 Hz), 3.85 (3H,
s), 2.70-2.60 (2H, m), 1.55 (2H, sext, J ) 7.4 Hz), 1.38 (3H, t, J
) 7.2 Hz), 0.95 (3H, t, J ) 7.4 Hz). Anal. Calcd for C13H18O4
(238.28): C, 65.53; H, 7.61. Found: C, 65.70; H, 7.55.
4-Th iop h en yl-3-h yd r oxyben zoic a cid eth yl ester (5i):
method A; yield 70%; colorless crystals (from hexane/ethyl
acetate); mp 110-111 °C; FT-IR (film) 1716, 1475, 1439, 1250,
749, 692 cm-1; EI-MS m/z 274 (M+,100), 259 (2), 246 (14), 229
((M+ - OEt, 48), 201 (6), 173 (9), 140 (7), 129 (5), 115 (4), 95 (5);
1H NMR (250 MHz, CDCl3) δ 7.71 (1H, d, J ) 1.8 Hz), 7.64-
7.50 (2H, m), 7.31-7.10 (5H, m), 6.53 (1H, bs), 4.38 (2H, q, J )
7.1 Hz), 1.39 (3H, t, J ) 7.1 Hz). Anal. Calcd for C15H14O3S
(274.34): C, 65.67; H, 5.14. Found: C, 65.49; H, 5.19.
4-Th iop h en yl-5-m eth yl-3-h yd r oxyben zoic a cid eth yl es-
ter (5j): method B; yield 86%; colorless crystals (from hexane/
ethyl acetate); mp 62 °C; FT-IR (film) 3402, 1695, 1583, 1315,
1247, 1041, 771, 732 cm-1; EI-MS m/z 288 (M+, 100), 273 (M+
-
Me, 3), 260 (7), 243 (M+ - OEt, 38), 182 (16), 171 (6), 154 (9),
1
109 (7), 77 (9); H NMR (250 MHz, CDCl3) δ 7.59 (1H, s), 7.56
(1H, s), 7.30-7.10 (3H, m), 7.04-6.97 (2H, m), 6.89 (1H, s), 4.38
(2H, q, J ) 7.2 Hz), 2.41 (3H, s), 1.40 (3H, t, J ) 7.2 Hz). Anal.
Calcd for C16H16O3S (288.36): C, 66.64; H, 5.59. Found: C, 66.47;
H, 5.56.
4-Tr im eth ylsilyl-3-h yd r oxyben zoic a cid eth yl ester (5k ):
method A; yield 50%; colorless crystals (from hexane); mp 103-
104 °C; FT-IR (film) 3351, 1690, 1408, 1300, 1220, 846, 759 cm-1
;
EI-MS m/z 238 (M+, 25), 223 (M+ - Me, 100), 222 (63), 195 (40),
177 (60), 149 (51), 135 (15), 119 (6), 105 (9), 91 (10), 75 (15); 1H
NMR (250 MHz, CDCl3) δ 7.59-7.52 (2H, m), 7.42 (1H, d, J )
7.5 Hz), 6.05 (1H, bs), 4.38 (2H, q, J ) 7.2 Hz), 1.39 (3H, t, J )
7.2 Hz), 0.32 (9H, s). Anal. Calcd for C12H18O3Si (238.36): C,
60.47; H, 7.61. Found: C, 60.55; H, 7.67.
2-Allyl-3-h yd r oxyben zoic a cid eth yl ester (6l): method B;
yield 80%; colorless crystals (from hexane/ethyl acetate); mp 56-
58 °C; FT-IR (film) 3380, 1672, 1583, 1466, 1285, 760 cm-1; EI-
MS m/z 206 (M+, 100), 191 (56), 177 (23), 161 (M+ - OEt, 86),
149 (24), 131 (76), 115 (22), 105 (47), 77 (37); 1H NMR (250 MHz,
CDCl3) δ 7.44 (1H, dd, J ) 7.7, 1.2 Hz), 7.18 (1H, t, J ) 8 Hz),
6.99 (1H, dd, J ) 8, 1.2 Hz), 6.14-5.96 (1H, m), 5.24 (1H, bs),
5.15 (1H, t, J ) 1.6 Hz), 5.12-5.06 (1H, m), 4.35 (2H, q, J ) 7.2
Hz), 3.76 (2H, dt, J ) 5.9, 1.6 Hz), 1.38 (3H, t, J ) 7.2 Hz). Anal.
Calcd for C12H14O3 (206.24): C, 69.88; H, 6.84. Found: C, 70.05;
H, 6.80.
2,5-Dim eth yl-4-th iop h en yl-3-h yd r oxyben zoic a cid eth yl
ester (6m ): method B; yield 95%; colorless oil; FT-IR (film) 3396,
1722, 1583, 1479, 1320, 1226, 1056, 738 cm-1; EI-MS m/z 302
(M+, 100), 273 (17), 257 (M+ - OEt, 36), 228 (12), 196 (7), 168
(7), 123 (5), 91 (6) 77 (5); 1H NMR (250 MHz, CDCl3) δ 7.31 (1H,
s), 7.27-7.12 (3H, m), 7.11 (1H, s), 7.04-6.96 (2H, m), 4.38 (2H,
t, J ) 7.1 Hz), 2.47 (3H, s), 2.35 (3H, s), 1.41 (3H, t, J ) 7.1 Hz).
4-P h en yl-5-m eth oxy-3-h yd r oxyben zoic a cid eth yl ester
(5e): method A; yield 88%; colorless crystals (from hexane/ethyl
acetate); mp 118-120 °C; FT-IR (film) 3411, 1699, 1589, 1464,
1320, 1250, 1097, 697 cm-1; EI-MS m/z 272 (M+, 100), 257 (M+
- Me, 6), 244 (9), 227 (M+ - OEt, 46), 200 (32), 128 (19); 1H
NMR (250 MHz, CDCl3) δ 7.55-7.32 (6H, m), 7.27-7.22 (1H,
m), 4.39 (2H, q, J ) 7.1 Hz), 3.93 (1H, s), 3.78 (3H, s), 1.40 (3H,

7888 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
1
Anal. Calcd for C17H18O3S (302.39): C, 67.52; H, 6.00. Found:
C, 67.70; H, 5.96.
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 5a -k , and 6l,m . This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The financial support of MURST
is acknowledged.
J O010552F