Synthesis of 4-hydroxy- and 2,4-dihydroxy-homophthalates by [4+2] cycloaddition of 1,3-bis(silyloxy)-1,3-butadienes with dimethyl allene-1,3-dicarboxylate

Article abstract of DOI:10.1016/j.tet.2008.05.118

The reaction of 1,3-bis(trimethylsiloxy)-1,3-butadienes with dimethyl allene-1,3-dicarboxylate provides a convenient and regioselective approach to a variety of functionalized 4-hydroxy- and 2,4-dihydroxy-homophthalates.

Full text of DOI:10.1016/j.tet.2008.05.118

Tetrahedron 64 (2008) 8003–8009
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4-hydroxy- and 2,4-dihydroxy-homophthalates
by [4þ2] cycloaddition of 1,3-bis(silyloxy)-1,3-butadienes
with dimethyl allene-1,3-dicarboxylate
,
Ibrar Hussain a, Mirza A. Yawer a, Bettina Appel a, Muhammad Sher a b, Ahmed Mahal a,
,b,
Alexander Villinger a, Christine Fischer b, Peter Langer a
*
a
¨
Institut fu¨r Chemie, Universitat Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2008
Received in revised form 26 May 2008
Accepted 29 May 2008
Available online 3 June 2008
The reaction of 1,3-bis(trimethylsiloxy)-1,3-butadienes with dimethyl allene-1,3-dicarboxylate provides
a convenient and regioselective approach to a variety of functionalized 4-hydroxy- and 2,4-dihydroxy-
homophthalates.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
details of the methodology and a study related to the preparative
scope.
Allenes represent versatile synthetic building blocks in inter-
and intramolecular [4þ2] cycloadditions.1 The [4þ2] cycloaddition
of 2-silyloxy-1,3-dienes with allenes has been reported to give
functionalized phenols. For example, (R)-(þ)-lasiodiplodin was
prepared based on the cyclization of a cyclic allenylester with 1,1-
dimethoxy-3-trimethylsilyloxy-1,3-butadiene.2 The reaction of
allenylphenylsulfone with Danishefsky’s diene afforded 3-methyl-
4-(phenylsulfonyl)-phenol.3 Roush and Murphy were the first to
report the cycloaddition of 1-methoxy-1,3-bis(trimethylsilyloxy)-
1,3-butadiene with dimethyl allene-1,3-dicarboxylate.4 Some years
ago, we reported the synthesis of various homophthalates based on
the cycloaddition of dimethyl allene-1,3-dicarboxylate with various
1,3-bis(silyl enol ethers).5 Later on, this methodology was suc-
cessfully applied to the synthesis of an analogue of lactonamycin,6
of the N7–C25 fragment of psymberin,7 and of the 4-acetylisocou-
marins AGI-7 and sescandelin (Scheme 1).8 Herein, we report full
2. Results and discussion
The reaction of 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadi-
ene (1a), prepared from ethyl acetoacetate in two steps,9,10 with
dimethyl allene-1,3-dicarboxylate (2), available from dimethyl
acetone-1,3-dicarboxylate,11 afforded the homophthalate 3a in up
to 75% yield (Scheme 2). The best yield was obtained when a mix-
ture of the starting materials (neat) was stirred for 20 h at 20 ꢀC.
Subsequently, to the mixture was added an ethanol solution of
triethylammonium fluoride.12 The formation of 3a can be explained
Me3SiO
OSiMe3
OEt
CO2Me
Me3SiO
neat
20 °C
20 h
1a
+
CO2Me
EtO OSiMe3
H
CO2Me
MeO2C
H
HO
O
A
2
HO
HO
HNEt3F
EtOH
_
2Me3SiF
O
O
OH
O
OH
O
CO2Me
HO
O
AGI-7
sescandelin
CO2Me
_
Scheme 1. Structure of (ꢁ)-sescandelin and AGI-7.
EtOH
CO2Me
CO2Me
EtO OH
OH
3a (42%)
B
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 2. Possible mechanism for the formation of 3a.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.118

8004
I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
by [4þ2] cycloaddition to give intermediate A, cleavage of the Si–O
bonds upon addition of triethylammonium fluoride, and sub-
sequent aromatization by extrusion of ethanol, enolization and
migration of the exocyclic double bond. The yield decreased when
the reaction was carried out at elevated temperature (40 or 80 ꢀC),
or when the reaction was carried in a toluene solution (room
temperature or reflux). The yield also decreased when the reaction
time was decreased (no complete conversion) or increased (de-
composition). The stoichiometry also played an important role. The
use of an excess of the dienophile did not result in an increase of the
yield.
2,3-dienoate (containing only one ester group) and methoxyallene
(containing a -donating substituent) resulted in the formation of
complex mixtures.
The cycloaddition of 2 with 1,3-bis(trimethylsilyloxy)-1,3-bu-
tadienes 1u–ab, available from the corresponding 1,3-diketones,
afforded the 4-hydroxy-homophthalates 3u–ab (Scheme 4, Table
2). The conditions had again to be individually optimized.
Interestingly, the yields again increased when the reactions were
carried out on large scale. Danishefsky co-workers isolated 3x in
75% yield on a large scale.6
p
It should be worthwhile mentioning that the selective elimi-
nation of ethanol (formation of a 3-hydroxyphenol) rather than
water (formation of a 3-ethoxyphenol) was observed. The relatively
low yield can be explained by partial decomposition of the quite
sensitive diene, due to the long reaction time.
Me3SiO
OSiMe3
R3
R1
1) neat,
20-80 °C
2) HNEt3F
R1 R2
1u-ab
HO
R2
CO2Me
CO2Me
The cycloaddition of 2 with 1-alkoxy-1,3-bis(trimethylsilyloxy)-
1,3-butadienes 1a–t, prepared in two steps from the corresponding
+
H
CO2Me
H
R3
b-ketoesters, afforded the 2,4-dihydroxy-homophthalates 3a–t
MeO2C
3u-ab
2
(Scheme 3, Table 1). A wide range of products, including fluoro-,
chloro-, alkyl-, methoxy-, benzyloxy-, aryloxy-, arylthio-substituted
derivatives, were successfully prepared. Moderate to good yields
were obtained for all products (except for 3s). The reaction condi-
tions had to be optimized for each individual experiment (reaction
time and temperature, see Section 4). The yield increases with the
scale of the reaction. For example, Roush and Murphy reported4 the
synthesis of 3a in 70% yield on large scale. Floreancig and Rech
reported7 a 70% yield for 3f on large scale. The yield of 3s was
increased from 16% (1.4 mmol scale) to 44% (50 mmol scale). Nota-
bly, the reaction of 1a with allenes other than 2 proved to be
unsuccessful in our hands. The reaction of 1a with methyl buta-
Scheme 4. Synthesis of 4-hydroxy-homophthalates 3u–ab.
Table 2
Synthesis of 3u–ab
3
R1
R2
R3
Yield % (3)a
u
v
w
x
y
z
aa
ab
H
H
H
H
H
H
H
H
H
H
Me
Ph
55
46
44
Me
CO2Me
Cl
O[4-(EtO)C6H4]
O(4-ClC6H4)
O[4-(CN)C6H4]
Me
Me
Me
Me
Me
Me
20 (75)b
42
48
45
56
Me3SiO
OSiMe3
OR3
a
Yields of isolated products.
Ref. 8 (large scale).
b
1) neat,
20-80 °C
2) HNEt3F
R1
R1 R2
1a-t
HO
R2
CO2Me
CO2Me
+
Products 3o–rand3z–abrepresentfunctionalized diaryl ethers. It
H
CO2Me
should be worthwhile mentioning that diaryl ethers occur in various
natural products (e.g., geodinhydrate methylester, methyl chloro-
asterrate,13a,b 1-desgalloylsanguiin,13c dehydrotrigallic acid,13d epi-
phorellic acid,13e jolkianin,13f remurin A13g and micareic acid13h) and
have been shown to possess a wide range of pharmacological
activities.
The structures of all products were established by spectroscopic
methods. The structure of 3b was independently confirmed by
X-ray crystal structure analysis (Fig. 1).14
OH
3a-t
MeO2C
H
2
Scheme 3. Synthesis of 2,4-dihydroxyhomophthalates 3a–t.
Table 1
Synthesis of 2,4-dihydroxy-homophthalates 3a–t
3
R1
R2
R3
Yield % (3)a
75 (70)b
52
64
70
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
Me
Me
Et
H
Et
Cl
F
Et
Et
Et
Et
3. Conclusions
SPh
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Et
50
55 (70)c
47
In conclusion, a variety of functionalized 4-hydroxy- and 2,4-
dihydroxy-homophthalates, which are not readilyavailable by other
methods, were prepared by reaction of 1,3-bis(trimethylsiloxy)-1,3-
butadienes with dimethyl allene-1,3-dicarboxylate. Many
43
60
38
52
56
42
40
58
Allyl
n-Bu
n-Hex
n-Oct
Bn
OMe
OPh
O(2-MeC6H4)
O(3-MeC6H4)
O(4-MeC6H4)
OBn
Et
Et
Me
Me
Et
Me
Et
Et
Et
Et
Et
48
50
54
s
t
16 (44)d
41
SPh
Et
a
Yields of isolated products on a scale of approximately 1 mmol.
Ref. 4 (102 mmol scale).
Ref. 7 (77 mmol scale).
b
c
d
Figure 1. Crystal structure of 3b.
On large scale.

I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
8005
functional groups were tolerated in the cycloadditions. This includes
fluoro-, chloro-, alkyl-, methoxy- and benzyloxy-groups, and dia-
rylether- and diaryl sulfide moieties.
(m), 959 (m), 800 (m), 687 (m). GC–MS (EI, 70 eV): m/z (%)¼276
([Mþ], 37Cl,16), 274 ([Mþ], 35Cl, 48), 244 (37Cl, 20), 242 (35Cl, 42), 216
(
37Cl, 37), 214 (35Cl, 100), 201 (37Cl, 24), 199 (35Cl, 76), 185 (13), 171
(8), 155 (33). HRMS (EI): calcd for
274.02387; found: 274.02379.
C
11H11O6Cl ([Mþ], 35Cl):
4. Experimental section
4.1. General comments
4.2.4. Methyl 3-fluoro-2,4-dihydroxy-6-(2-methoxy-2-oxoethyl)-
benzoate (3d)
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spec-
trometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O) or electrospray ionization
(ESI). For preparative scale chromatography, silica gel (60–200
mesh) was used. Melting points are uncorrected.
Starting with 1d (0.920 g, 2.5 mmol), 2 (0.312 g, 2.0 mmol) and
NEt3$(HF)3 (0.483 g, 3.0 mmol), 3d was isolated as a red solid
(0.361 g, 70%), mp¼148ꢁ156 ꢀC. Reaction time: 14 h (40 ꢀC).1H NMR
(250 MHz, CD3OD):
d¼2.36 (s, 3H, COOCH3), 2.47 (s, 2H,
CH2COOCH3), 2.54 (s, 3H, CH2COOCH3), 5.04 (d, 4J¼7.6 Hz, 1H, CHAr).
13C NMR (62 MHz, CD3OD):
d
¼42.6 (CH2COOCH3), 52.4 (COOCH3),
52.5 (CH2COOCH3), 106.7 (CAr), 114.2 (d, 3J¼1.3 Hz, CHAr), 126.3 (CAr),
133.8 (d, 3J¼4.1 Hz, CAr), 140.6 (d, 1J¼234.3 Hz, CFAr), 150.8 (d,
2J¼9.6 Hz, COHAr),153.6 (d, 2J¼10.3 Hz, COHAr),171.9(COOCH3),174.0
~
4.2. General procedure for the synthesis of homophthalates
(CH2COOCH3). IR (neat, cmꢁ1):
n
¼3231 (w), 2956 (w), 1706 (s), 1657
To neat allene 2 (1.0 mmol) was added neat diene 1 (1.25 mmol)
at 0 ꢀC under argon atmosphere. The reaction mixture was stirred
at 0 ꢀC for 30 min and then the solution was stirred at 20ꢁ75 ꢀC for
several hours. To the mixture was added an ethanol solution (96%,
2 mL) of triethylammonium fluoride, which was prepared from
NEt3$(HF)3 as previously reported.12 The solution was diluted with
water and repeatedly extracted with diethyl ether or dichloro-
methane. The combined organic layers were dried (Na2SO4), fil-
tered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, heptanes/
EtOAc¼1:1 or petroleum ether/diethyl ether¼1:1) to give product 3.
(m), 1597 (m), 1437 (s), 1324 (m), 1249 (s), 1199 (s), 1105 (m), 1059
(m), 979 (s), 844 (m), 743 (s). GC–MS (EI, 70 eV): m/z (%)¼258 ([Mþ],
49), 226 (63),198 (90),183 (100),169 (13),155 (8),139 (39),110 (5), 83
(11). HRMS (EI): calcd for C11H11FO6: 258.05342; found: 258.05382.
4.2.5. Methyl 2,4-dihydroxy-6-(2-methoxy-2-oxoethyl)-
3-(phenylsulfanyl)benzoate (3e)
Starting with 1e (0.920 g, 2.5 mmol), 2 (0.312 g, 2.0 mmol) and
NEt3$(HF)3 (0.483 g, 3.0 mmol), 3e was isolated as a red viscous oil
(0.341 g, 50%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
CDCl3):
d
¼3.63 (s, 3H, COOCH3), 3.77 (s, 3H, CH2COOCH3), 3.80 (s,
2H, CH2COOCH3), 6.74 (br s, 1H, OHAr), 7.04–7.07 (m, 2H, CHPh), 7.10
4.2.1. Methyl 2,4-dihydroxy-6-(methoxycarbonylmethyl)-
benzoate (3a)
Starting with 1a (0.242 g, 0.88 mmol), 2 (0.132 g, 0.85 mmol)
and NEt3$(HF)3 (0.272 g, 1.69 mmol), 3a was isolated as a yellow
solid (0.152 g 75%). Reaction time: 20 h (20 ꢀC). 1H NMR (250 MHz,
(m, 1H, CHSPh), 7.13 (s, 1H, CHSPh), 7.15–7.18 (m, 1H, CHSPh), 7.28 (s,
1H, CHAr), 12.37 (br s, 1H, OHAr). 13C NMR (62 MHz, CDCl3):
d¼42.9
(CH2COOCH3), 52.0 (COOCH3), 52.1 (CH2COOCH3), 105.4 (CAr), 111.5
(CHSPh), 126.3 (CAr), 126.4 (CHAr), 126.8 (2CHSPh), 129.1 (2CHSPh),
129.3 (CAr), 140.7 (CSPh), 162.2, 166.0 (COHAr), 171.1 (COOCH3), 171.3
(CH2COOCH3). MS (EI, 70 eV): m/z (%)¼348 ([Mþ], 1), 238 (4), 284
(32), 150 (6), 123 (27), 110 (100), 84 (12), 66 (21), 44 (25).
CD3OD):
d
¼3.68 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.75 (s, 2H, CH2),
6.21–6.25 (m, 2H, Ar–H). The spectroscopic data were identical
with those reported.4
4.2.6. Methyl 2,4-dihydroxy-5-methyl-6-(methoxycarbonyl-
methyl)benzoate (3f)
Starting with 1f (0.399 g, 1.45 mmol), 2 (0.170 g, 1.09 mmol) and
NEt3$(HF)3 (0.351 g, 2.18 mmol), 3f was isolated as a white solid
(0.153 g, 55%). Reaction time: 18 h (20 ꢀC). 1H NMR (250 MHz,
4.2.2. Methyl 3-ethyl-2,4-dihydroxy-6-(2-methoxy-2-oxoethyl)-
benzoate (3b)
Starting with 1b (0.361 g, 1.25 mmol), 2 (0.156 g, 1.0 mmol) and
NEt3$(HF)3 (0.242 g, 1.5 mmol), 3b was isolated as a yellow viscous
oil (0.139 g, 52%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
CD3OD):
3.96 (s, 2H, CH2), 6.33 (s, 1H, Ar–H). 13C NMR (62.9 MHz, acetone-
d6):
d
¼2.08 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.73 (s, 3H, OCH3),
CD3OD):
d
¼0.98 (t, 3J¼7.4 Hz, 3H, CH2CH3), 2.53 (q, 3J¼7.4 Hz, 2H,
CH2CH3), 3.58 (s, 3H, COOCH3), 3.67 (s, 2H, CH2COOCH3), 3.71 (s, 3H,
d
¼11.3 (Ar–CH3), 36.7 (Ar–CH2CO2CH3), 52.5, 56.3 (2ꢂOCH3),
CH2COOCH3), 6.13 (s, 1H, CHAr). 13C NMR (62 MHz, CD3OD):
d
¼13.4
98.9 (Ar), 116.6 (C–CH3), 117.7 (C–CH2CO2CH3), 134.1 (C–CO2CH3),
(CH2CH3), 16.8 (CH2CH3), 43.2 (CH2COOCH3), 52.6 (COOCH3), 52.7
(CH2COOCH3), 104.6 (CAr), 113.1 (CHAr), 117.8, 136.0 (CAr), 161.1, 163.9
(COHAr), 172.6 (COOCH3), 174.2 (CH2COOCH3). IR (neat, cmꢁ1):
~
157.4, 159.1 (2ꢂC–OH), 170.7 (Ar–CO2CH3), 173.1 (CH2CO2CH3). IR
(KBr, cmꢁ1):
n
¼3410 (br), 3335 (m), 3002 (m), 2955 (m), 2851 (m),
~
2480 (w), 1710 (s, C]O), 1439 (s), 1337 (s), 1002 (m), 850 (m), 806
(m), 772 (m), 643 (w). MS (EI, 70 eV): 254 (Mþ, 64), 222 (77), 194
(100), 179 (68), 162 (19), 154 (18). Anal. Calcd for C12H14O6 (254.4):
C, 56.69; H, 5.55. Found: C, 56.58; H, 5.57.
n
¼3285 (w), 2961 (w), 1699 (s), 1646 (m), 1604 (m), 1439 (m), 1275
(s), 1193 (s), 1156 (s), 1051 (m), 984 (m), 839 (m), 746 (m). GC–MS
(EI, 70 eV): m/z (%)¼268 ([Mþ], 33), 250 (5), 236 (30), 222 (10), 208
(19), 189 (22), 176 (100), 148 (8), 91 (6), 77 (6).
4.2.7. Methyl 3-chloro-2,4-dihydroxy-6-(2-methoxy-2-oxoethyl)-
5-methylbenzoate (3g)
Starting with 1g (0.386 g, 1.25 mmol), 2 (0.156 g, 1.0 mmol) and
NEt3$(HF)3 (0.242 g, 1.5 mmol), 3g was isolated as a yellow solid
(0.135 g, 47%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
4.2.3. Methyl 3-chloro-2,4-dihydroxy-6-(2-methoxy-2-oxoethyl)-
benzoate (3c)
Starting with 1c (0.386 g, 1.25 mmol), 2 (0.156 g, 1.0 mmol) and
NEt3$(HF)3 (0.242 g, 1.5 mmol), 3c was isolated as a yellow viscous
oil (0.177 g, 64%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
CDCl3):
CH2COOCH3), 3.88 (s, 2H, CH2COOCH3), 6.21 (br, 1H, OH), 11.88 (br,
1H, OH). 13C NMR (62 MHz, CDCl3):
d¼2.13 (s, 3H, CH3), 3.64 (s, 3H, COOCH3), 3.83 (s, 3H,
CD3OD):
d
¼3.67 (s, 3H, COOCH3), 3.82 (s, 2H, CH2COOCH3), 3.85 (s,
3H, CH2COOCH3), 6.38 (s, 1H, CHAr). 13C NMR (62 MHz, CD3OD):
d
¼12.2 (CH3), 37.2
d
¼43.0 (CH2COOCH3), 52.4 (COOCH3), 52.4 (CH2COOCH3), 106.2
(CH2COOCH3), 52.0 (COOCH3), 52.4 (CH2COOCH3), 106.4, 107.1, 117.1,
(CAr), 113.5 (CHAr), 137.6 (2CAr), 159.6, 161.6 (COHAr), 172.3
134.4, 154.7, 157.4 (CAr), 171.1 (COOCH3), 171.2 (CH2COOCH3). IR
(COOCH3), 173.8 (CH2COOCH3). IR (neat, cmꢁ1):
n
¼3226 (w), 2958
(neat, cmꢁ1):
n
¼3256 (w), 2956 (w), 1716 (s), 1648 (m), 1577 (m),
~
~
(w), 1698 (m), 1654 (m), 1435 (m), 1319 (m), 1235 (s), 1189 (s), 1076
1436 (m), 1326 (s), 1216 (s), 1165 (s), 1001 (m), 962 (m), 808 (m).

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I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
GC–MS (EI, 70 eV): m/z (%)¼290 ([Mþ], 37Cl,16), 288 ([Mþ], 35Cl, 49),
258 (37Cl, 18), 256 (35Cl, 48), 230 (37Cl, 37), 228 (35Cl, 100), 215 (37Cl,
29), 213 (35Cl, 90), 196 (17), 105 (6), 77 (20). HRMS (EI): calcd for
COOCH3), 3.80 (s, 3H, CH2COOCH3), 3.87 (s, 2H, CH2COOCH3), 6.10 (s,
1H, CHAr), 6.56 (s,1H, OHAr),11.16 (br s,1H, OHAr). 13C NMR (75 MHz,
CDCl3):
d
¼14.1 ((CH2)5CH3), 22.6, 26.1, 29.5, 29.8, 31.7 ((CH2)5CH3),
C
12H13O6Cl ([Mþ], 35Cl): 288.03952; found: 288.03964.
36.8 (CH2COOCH3), 51.8 (COOCH3), 52.2 (CH2COOCH3), 102.9 (CHAr),
105.5, 128.3, 134.8 (CAr), 159.9, 162.4 (COHAr), 171.1 (COOCH3), 173.4
(CH2COOCH3). GC–MS (EI, 70 eV): m/z (%)¼324 ([Mþ], 33), 292 (24),
253 (25), 221 (100),189 (80),163 (20),134 (5),105 (5), 69 (12). HRMS
(EI): calcd for C17H24O6: 324.15674; found: 324.15600.
4.2.8. Methyl 2,4-dihydroxy-5-ethyl-6-(methoxycarbonyl-
methyl)benzoate (3h)
Starting with 1h (0.437 g, 1.44 mmol), 2 (0.174 mg, 1.11 mmol)
and NEt3$(HF)3 (0.358 mg, 2.22 mmol), 3h was isolated as a white
solid (0.125 g, 43%). Reaction time: 20 h (20 ꢀC). 1H NMR (250 MHz,
4.2.12. Methyl 3-hexyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
benzoate (3l)
acetone-d6):
d
¼1.04 (t, 3J¼7.4 Hz, 3H, CH3), 2.52 (q, 3J¼7.4 Hz, 2H,
CH2CH3), 3.63 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.97 (s, 2H,
Starting with 1l (0.465 g, 1.25 mmol), 2 (0.156 g, 1.0 mmol) and
NEt3$(HF)3 (0.242 g, 1.5 mmol), 3l was isolated as a colourless vis-
cous oil (0.197 g, 56%). Reaction time: 14 h (40 ꢀC). 1H NMR
CH2CO2CH3), 6.50 (s, 1H, Ar–H). 13C NMR (62.9 MHz, acetone-d6):
d
¼14.3 (CH2CH3), 19.7 (CH2CH3), 37.0 (CH2CO2CH3), 51.8, 52.1
(2ꢂOCH3), 102.5 (Ar), 106.1 (C–CH2CH3), 124.9 (C–CH2CO2CH3),
(250 MHz, CDCl3):
d
¼0.82 (t, 3J¼6.3 Hz, 3H, CH2(CH2)6CH3), 1.18 (m,
136.9 (C–CO2CH3), 161.5, 163.3 (2ꢂC–OH), 172.2 (Ar–CO2CH3), 172.3
12H, CH2(CH2)6CH3), 3.63 (t, 3J¼5.8 Hz, 2H, CH2(CH2)6CH3), 3.69 (s,
3H, COOCH3), 3.79 (s, 3H, CH2COOCH3), 3.86 (s, 2H, CH2COOCH3),
6.08 (s, 1H, CHAr), 6.92 (s, 1H, OHAr), 11.16 (s, 1H, OHAr). 13C NMR
(CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3351 (br), 3309 (s), 2957 (m), 1706
~
(s, C]O), 1656 (s), 1597 (s), 1487 (m), 1440 (m), 1347 (s), 1224 (s),
1080 (s), 970 (m), 849 (m), 792 (m), 639 (w). MS (EI, 70 eV): 268
(Mþ, 37), 236 (58), 208 (100), 193 (65), 176 (62), 121 (13). Anal. calcd
for C13H16O6: C, 58.21; H 6.01. Found: C, 58.38; H 5.89.
(75 MHz, CDCl3):
d
¼14.0 ((CH2)7CH3), 22.5, 26.0, 29.2, 29.4, 29.7,
29.8, 31.8 ((CH2)5CH3), 36.7 (CH2COOCH3), 51.7 (COOCH3), 52.1
(CH2COOCH3), 102.8 (CHAr), 105.2, 123.3, 134.6 (CAr), 160.1, 162.3
(COHAr), 171.0 (COOCH3), 173.5 (CH2COOCH3). IR (neat, cmꢁ1):
~
4.2.9. Methyl 5-allyl-2,4-dihydroxy-6-(methoxycarbonyl-
methyl)benzoate (3i)
Starting with 1i (0.413 mg, 1.31 mmol), 2 (0.195 mg, 1.25 mmol)
and NEt3$(HF)3 (0.402 mg, 2.50 mmol), 3i was isolated as a deep
yellow solid (0.208 g, 60%). Reaction time: 16 h (20 ꢀC). 1H NMR
n
¼3281 (w), 2923 (w), 2847 (w), 1701 (m), 1651 (m), 1592 (m), 1438
(w),1329 (m),1253 (s), 1194 (s), 1152 (s), 1096 (w), 971 (m), 841 (m),
673 (m). GC–MS (EI, 70 eV): m/z (%)¼352 ([Mþ], 43), 321 (15), 279
(5), 253 (98), 221 (100), 189 (14), 163 (13). HRMS (EI): calcd for
C19H28O6: 352.18804; found: 352.18813.
(250 MHz, acetone-d6):
d
¼3.25 (br, 1H, OH), 3.39 (m, 2H,
CH2CH]CH2), 3.62 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.92 (s, 2H,
CH2CO2CH3), 4.91 (m, 2H, CH]CH2), 5.84 (m, 1H, CH]CH2), 6.42 (s,
4.2.13. Methyl 5-benzyl-2,4-dihydroxy-6-(methoxycarbonyl-
methyl)benzoate (3m)
Starting with 1m (0.435 g, 1.19 mmol), 2 (0.107 mg, 0.69 mmol)
and NEt3$(HF)3 (0.221 g, 1.37 mmol), 3m was isolated as a yellow
solid (0.095 g, 42%). Reaction time: 10 h (20 ꢀC). 1H NMR (250 MHz,
1H, Ar–H). 13C NMR (62.9 MHz, acetone-d6):
d¼29.5 (CH2CO2CH3),
36.5 (CH2CH]CH2), 51.0, 51.4 (CO2CH3), 101.5 (Ar), 105.5 (C–
CO2CH3), 114.0 (C]CH2), 119.5, 119.5 (C–CH2CO2CH3, C–CH]CH2),
136.4 (C–CH]CH2), 137.3 (Ar–CO2CH3), 160.8, 162.8 (2ꢂC–OH),
~
acetone-d6):
d
¼3.52 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.94 (s, 2H,
169.2 (Ar–CO2CH3), 171.3 (CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3348 (s),
CH2CO2CH3), 4.18 (s, 2H, CH2Ph), 6.51 (s, 1H, Ar–H), 7.24 (m, 5H, Ph–
3290 (br), 2987 (w), 2952 (w), 1729 (s, C]O), 1706 (s), 1656 (m),
1601 (s), 1498 (w), 1431 (s), 1325 (s), 1262 (s), 1205 (s), 1153 (s), 1092
(m), 1022 (w), 850 (w), 756 (w), 614 (w). MS (CI, 70 eV): 298
([MþNH4]þ), 281 ([MþH]þ).
H), 9.52 (br s, 2H, 2ꢂOH). 13C NMR (62.9 MHz, acetone-d6):
¼31.6
d
(Ph–CH2), 37.6(CH2CO2CH3), 51.8, 52.2(2ꢂCO2CH3),102.7(C–CH2Ph),
106.6 (Ar), 121.5 (C–CH2CO2CH3), 126.5, 128.8, 129.0 (5ꢂPh–CH),
138.5 (C–CO2CH3), 141.4 (Ph–C), 161.9, 163.7 (C–OH), 171.8
~
(Ar–CO2CH3), 172.1 (CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3353 (s), 3310
4.2.10. Methyl 2,4-dihydroxy-5-(n-butyl)-6-(methoxycarbonyl-
methyl)benzoate (3j)
Starting with 1j (0.397 mg, 1.20 mmol), 2 (0.174 mg, 1.11 mmol)
and NEt3$(HF)3 (0.359 g, 2.23 mmol), 3j was isolated as a white
solid (0.108 g, 38%). Reaction time: 26 h (20 ꢀC). 1H NMR (250 MHz,
(br), 3085 (w), 3062 (w), 2956 (w), 1704 (s, C¼O), 1651 (s), 1606 (s),
1594(s),1492 (m),1439 (m),1424 (m),1386 (s),1333 (s),1253 (s),1188
(s), 1153 (m), 1008 (w), 845 (m), 735 (m), 698 (m), 522 (w). MS (EI,
70 eV): 330 (Mþ, 42), 329 (9), 298 (43), 270 (21), 238 (100), 237 (48).
acetone-d6):
d
¼0.83 (m, 3H, CH3), 1.38 (m, 4H, 2ꢂCH2), 2.60 (m, 2H,
4.2.14. Methyl 4,6-dihydroxy-3-methoxy-6-(methoxycarbonyl-
methyl)benzoate (3n)
Starting with 1n (0.342 g,1.18 mmol), 2 (0.166 g, 0.90 mmol) and
NEt3$(HF)3 (0.292 mg, 1.81 mmol), 3n was isolated as a yellow solid
(0.087 g, 40%). Reaction time: 18 h (20 ꢀC). 1H NMR (250 MHz, ac-
Ar–CH2), 3.62 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.96 (s, 2H,
CH2CO2CH3), 5.62 (s, 1H, Ar–H), 6.41 (s, 2H, OH). 13C NMR
(62.9 MHz, acetone-d6):
d¼14.2 (CH2CH3), 23.4, 26.3 (CH2CH2CH3,
CH2CH2CH3), 32.7 (Ar–CH2), 37.2 (CH2CO2CH3), 51.8, 52.1
(2ꢂCO2CH3), 102.5 (C–CH2CH2), 106.8 (Ar), 123.6 (C–CH2CO2CH3),
137.0 (C–CO2CH3), 161.7, 163.3 (2ꢂC–OH), 172.2 (Ar–CO2CH3), 172.3
~
etone-d6):
OCH3), 3.76 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 6.58 (s, 1H, Ar–H), 8.58
(s, 1H, OH). 13C NMR (62.9 MHz, acetone-d6):
d
¼3.58 (s, 3H, OCH3), 3.64 (s, 2H, CH2CO2CH3), 3.72 (s, 3H,
(CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3319 (s), 2957 (m), 2927 (m), 2852
d¼33.1 (CH2CO2CH3),
(m), 2469 (w), 1708 (s, C]O), 1651 (s), 1604 (s), 1443 (m), 1423 (m),
1347 (s), 1259 (s), 1155 (m),1083 (m), 976 (w), 948 (m), 771 (w), 637
(w). MS (EI, 70 eV): 296 (Mþ, 63), 265 (23), 264 (49), 253 (23), 236
(31), 221 (100), 204 (27), 189 (71). HRMS: calcd for C15H20O6:
296.1259; found: 296.1259ꢃ2 ppm.
51.9, 51.9 (2ꢂCO2CH3), 56.4 (COCH3), 61.0 (COCH3), 100.7 (Ar–C),
116.1 (C–CH2CO2CH3), 128.6 (C–CO2CH3), 140.8 (C–OH), 152.9
(COCH3), 155.0 (COCH3), 167.8 (Ar–CO2CH3), 171.5 (CH2CO2CH3). IR
~
(KBr, cmꢁ1):
n
¼3341 (m), 3290 (br), 3007 (w), 3958 (w), 2851 (w),
1741 (m, C]O),1655 (w),1618 (w),1440 (m),1336 (br),1079 (s), 801
(m), 573 (w), 470 (m). MS (EI, 70 eV): 284 (Mþ, 100), 270 (1), 253
(55), 237 (96), 225 (39), 209 (61),195 (12),181 (36). HRMS (EI): calcd
for C13H16O7: 284.0896; found: 284.0896ꢃ2 ppm.
4.2.11. Methyl 3-hexyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
benzoate (3k)
Starting with 1k (0.557 g, 1.5 mmol), 2 (0.187 g, 1.2 mmol) and
NEt3$(HF)3 (0.290 g, 1.8 mmol), 3k was isolated as a colourless solid
(0.170 g, 52%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
4.2.15. Methyl 4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
3-phenoxy-benzoate (3o)
Starting with 1o (0.630 g, 1.8 mmol), 2 (0.225 g, 1.4 mmol) and
NEt3$(HF)3 (0.348 g, 2.2 mmol), 3o was isolated as a yellow viscous
CDCl3):
d
¼0.80 (t, 3J¼6.8 Hz, 3H, CH2(CH2)4CH3), 1.20–1.26 (m, 8H,
CH2(CH2)4CH3), 2.43 (t, 3J¼6.8 Hz, 2H, CH2(CH2)4CH3), 3.69 (s, 3H,

I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
8007
oil (0.278 g, 58%). Reaction time: 18 h (40 ꢀC). 1H NMR (250 MHz,
CDCl3):
3H, CH2COOCH3), 6.54 (br s, 1H, CHAr), 6.78–6.82 (m, 3H, CHPh),
(COOCH3), 173.5 (CH2COOCH3). IR (neat, cmꢁ1):
n
¼3268 (w), 2434
~
d
¼3.48 (s, 3H, COOCH3), 3.78 (s, 2H, CH2COOCH3), 3.79 (s,
(w), 1702 (m), 1645 (m), 1610 (m), 1507 (m), 1440 (m), 1341 (m),
1217 (s), 1102 (m), 990 (m), 821 (s), 773 (m). GC–MS (EI, 70 eV): m/z
(%)¼346 ([Mþ],100), 314 (30), 282 (32), 271 (49), 254 (43), 239 (35),
239 (35), 191 (15), 157 (5), 129 (9), 91 (16), 69 (21). HRMS (EI): calcd
for C18H18O7: 346.10470; found: 346.10523.
6.97–7.00 (m, 1H, CHPh), 7.17–7.20 (m, 1H, CHPh), 7.24 (br s, 1H,
OHAr), 11.45 (br s, 1H, OHAr). 13C NMR (62 MHz, CDCl3):
d¼34.2
(CH2COOCH3), 51.8 (COOCH3), 51.9 (CH2COOCH3), 103.9 (CHAr),
105.4 (CAr), 114.9 (2CHPh), 123.1 (CHPh), 129.9 (2CHPh), 130.4, 133.9
(CAr), 154.8 (CPh), 157.1, 162.4 (COHAr), 170.7 (COOCH3), 171.2
~
4.2.19. Methyl 2,4-dihydroxy-5-benzyloxy-6-(methoxycarbonyl-
methyl)benzoate (3s)
(CH2COOCH3). IR (neat, cmꢁ1):
n
¼3350 (w), 2952 (w), 1734 (m),
1658 (m),1589 (m),1489 (m),1436 (m),1329 (m),1154 (s),1022 (m),
978 (m), 750 (s), 688 (s), 540 (m). MS (EI, 70 eV): m/z (%)¼332
([Mþ], 100), 300 (70), 268 (43), 240 (84), 212 (32), 191 (16), 171 (13),
109 (12), 77 (17), 69 (33). HRMS (EI): calcd for C17H16O7: 332.08905;
found: 332.08918.
Starting with 1s (0.676 g, 1.78 mmol), 2 (0.213 mg, 1.37 mmol)
and NEt3$(HF)3 (0.440 mg, 2.82 mmol), 3s was isolated as a yellow
solid (0.073 g, 16%). On a 50 mmol scale, the yield was increased to
44%. Reaction time: 21 h (20 ꢀC). 1H NMR (250 MHz, CDCl3):
d¼3.63
(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.03 (s, 2H, CH2CO2CH3), 4.84 (s,
2H, COCH2Ph), 6.08 (br s, 1H, OH), 6.44 (s, 1H, Ar–H), 7.41 (m, 5H,
4.2.16. Methyl 4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
3-(2-methylphenoxy)benzoate (3p)
Starting with 1p (0.657 g, 1.8 mmol), 2 (0.225 g, 1.4 mmol) and
NEt3$(HF)3 (0.348 g, 2.2 mmol), 3p was isolated as a yellow viscous
oil (0.249 g, 50%). Reaction time: 17 h (40 ꢀC). 1H NMR (250 MHz,
Ph–H), 11.48 (s, 1H, OH). 13C NMR (62.9 MHz, CDCl3):
d¼34.5
(CH2CO2CH3), 51.9, 52.0 (2ꢂOCH3), 77.0 (COCH2Ph),103.2 (Ar),104.6
(C–CH2CO2CH3), 128.3, 128.9, 128.9 (5ꢂPhC), 129.5 (ArC–OCH2),
136.1 (Ph–CCH2), 138.8 (C–CO2CH3), 155.2, 161.7 (2ꢂC–OH), 170.8
~
(C–CO2CH3), 172.2 (CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3267 (s, OH),
CDCl3):
d
¼2.28 (s, 3H, CH3Tol), 3.42 (s, 3H, COOCH3), 3.71 (s, 2H,
3071 (w), 2956 (m), 2875 (w), 1716 (s, C]O), 1657 (s), 1618 (w),
1592 (w), 1504 (m), 1441 (m), 1336 (s), 1258 (s), 1225 (s), 1201 (s),
1101 (s), 996 (s), 984 (s), 945 (m), 856 (w), 806 (w), 769 (m), 696
(m), 602 (w), 508 (w). MS (EI, 70 eV): 346 (Mþ, 24), 255 (34), 223
(42), 191 (47), 91 (100).
CH2COOCH3), 3.72 (s, 2H, CH2COOCH3), 6.02 (br s,1H, OHAr), 6.32 (d,
3J¼6.8 Hz, 1H, CHTol), 6.49 (s, 1H, CHAr), 6.80–6.86 (m, 1H, CHTol),
7.06–7.09 (m, 2H, CHTol), 11.38 (br s, 1H, OHAr). 13C NMR (62 MHz,
CDCl3):
d
¼16.1 (CH3Tol), 34.1 (CH2COOCH3), 51.7 (COOCH3), 51.9
(CH2COOCH3), 103.8 (CHAr), 105.3 (CAr), 112.4, 122.6 (CHTol), 126.0
(CAr), 127.1 (CTol), 130.1, 131.4 (CHTol), 134.2 (CTol), 154.8 (CAr), 155.2,
162.2 (COHAr), 170.7 (COOCH3), 171.2 (CH2COOCH3). IR (neat, cmꢁ1):
~
4.2.20. Methyl 4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
3-(phenylsulfanyl)benzoate (3t)
Starting with 1t (0.955 g, 2.5 mmol), 2 (0.312 g, 2.0 mmol) and
NEt3$(HF)3 (0.483 g, 3.0 mmol), 3t was isolated as a reddish viscous
oil (0.290 g, 41%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
n
¼3368 (w), 2952 (w), 1735 (s), 1658 (m), 1592 (m), 1489 (m), 1435
(m), 1329 (m), 1222 (s), 1187 (s), 1018 (m), 983 (m), 844 (m), 750 (s).
MS (EI, 70 eV): m/z (%)¼346 ([Mþ], 100), 314 (56), 282 (22), 271
(44), 254 (42), 226 (13), 193 (29), 105 (8), 91 (21). HRMS (EI): calcd
for C18H18O7: 346.10470; found: 346.10437.
CDCl3):
d
¼3.47 (s, 3H, COOCH3), 3.80 (s, 3H, CH2COOCH3), 4.27 (s,
2H, CH2COOCH3), 6.61 (s, 1H, CHAr), 6.91–6.95 (m, 2H, CHPh), 7.07–
7.11 (m, 1H, CHSPh), 7.11–7.16 (m, 2H, CHSPh), 7.18 (br s, 1H, OHAr),
4.2.17. Methyl 4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
3-(3-methylphenoxy)benzoate (3q)
Starting with 1q (0.951 g, 2.5 mmol), 2 (0.312 g, 2.0 mmol) and
NEt3$(HF)3 (0.242 g, 3.0 mmol), 3q was isolated as a slightly yellow
solid (0.336 g, 48%), mp¼130ꢁ133 ꢀC. Reaction time: 14 h (40 ꢀC).
11.69 (br s, 1H, OHAr). 13C NMR (62 MHz, CDCl3):
d¼39.9
(CH2COOCH3), 51.8 (COOCH3), 52.2 (CH2COOCH3), 102.8 (CHAr),
107.6,111.2 (CAr),126.2 (2CHSPh),126.3 (CHSPh),129.3 (2CHSPh),134.4
(CSPh), 143.9 (CAr), 162.2, 166.1 (COHAr), 170.6 (COOCH3), 171.1
(CH2COOCH3). GC–MS (EI, 70 eV): m/z (%)¼348 ([Mþ], 100),
316 (25), 284 (32), 256 (82), 228 (11), 207 (8), 171 (10), 128 (16),
1H NMR (250 MHz, CDCl3):
d
¼2.15 (s, 3H, CH3Tol), 3.43 (s, 3H,
COOCH3), 3.71 (s, 3H, CH3COOCH), 3.73 (s, 2H, CH2COOCH3), 6.14
(br s, 1H, OHAr), 6.47 (s, 1H, CHAr), 6.50–6.54 (m, 2H, CHTol), 6.72 (d,
3J¼7.6 Hz, 1H, CHTol), 7.01 (d, 3J¼8.4 Hz, 1H, CHTol), 11.39 (br s,
69 (16). HRMS (EI): calcd for
348.06559.
C17H16O6S: 348.0662; found:
1H, OHAr). 13C NMR (62 MHz, CDCl3):
d¼21.3 (CH3Tol), 34.1
4.2.21. Methyl 4-hydroxy-6-methyl-2-(methoxycarbonyl-
methyl)benzoate (3u)
Starting with 1u (0.323 g, 1.32 mmol), 2 (0.163 mg, 1.04 mmol)
and NEt3$(HF)3 (0.337 g, 2.09 mmol), 3u was isolated as a white
solid (0.130 g, 55%). Reaction time: 18 h (20 ꢀC). 1H NMR (250 MHz,
(CH2COOCH3), 51.7 (COOCH3), 51.8 (CH2COOCH3), 103.8 (CHAr),105.1
(CAr), 111.8, 115.4, 123.7, 129.5 (CHTol), 130.3 (CCH3Tol), 134.1, 140.1
(CAr), 154.9 (CTol), 157.1, 162.2 (COHAr), 170.7 (COOCH3), 171.4
~
(CH2COOCH3). IR (neat, cmꢁ1):
n
¼3239 (w), 2948 (w), 1700 (s), 1655
(m), 1595 (m), 1438 (m), 1328 (m), 1228 (s), 1180 (s), 1105 (m), 983
(m), 844 (m), 770 (s). GC–MS (EI, 70 eV): m/z (%)¼346 ([Mþ], 100),
314 (51), 282 (35), 271 (51), 254 (39), 226 (19), 191 (18), 157 (4), 129
(8), 91 (18). HRMS (EI): calcd for C18H18O7: 346.10470; found:
346.10525.
CDCl3):
3.92 (s, 2H, CH2CO2CH3), 5.53 (s, 1H, OH), 6.53–6.61 (m, 2H, 2ꢂAr–
H). 13C NMR (62.9 MHz, CDCl3, DEPT):
d¼2.34 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
d
¼21.0 (CH3), 39.9
(CH2CO2CH3), 51.7, 52.1 (2ꢂOCH3), 115.8, 116.7 (2ꢂAr), 125.1 (C–
CH3), 134.9 (C–CH2CO2CH3), 139.8 (C–CO2CH3), 156.8 (C–OH), 169.3
(Ar–CO2CH3), 171.9 (CH2CO2CH3). IR (KBr, cmꢁ1):
n
¼3340 (br), 3332
~
4.2.18. Methyl 4,6-dihydroxy-2-(2-methoxy-2-oxoethyl)-
3-(4-methylphenoxy)benzoate (3r)
Starting with 1r (0.951 g, 2.5 mmol), 2 (0.312 g, 2.0 mmol) and
NEt3$(HF)3 (0.483 g, 3.0 mmol), 3r was as a brown solid (0.380 g,
54%), mp¼116ꢁ124 ꢀC. Reaction time: 14 h (40 ꢀC). 1H NMR
(s), 2954 (w), 2932 (w), 1711 (s, C]O), 1616 (s), 1440 (m), 1365 (m),
1322 (s), 1291 (s), 1257 (s), 1217 (s), 1165 (s), 1103 (m), 1003 (w), 909
(w), 855 (w), 748 (w). MS (EI, 70 eV): 238 (Mþ, 60), 207 (75), 206
(100), 179 (94), 163 (90).
(250 MHz, CD3OD):
d
¼2.15 (s, 3H, CH3Tol), 3.46 (s, 3H, COOCH3), 3.73
4.2.22. Methyl 4-hydroxy-2-methoxycarbonylmethyl-6-phenyl-
benzoate (3v)
Starting with 1v (0.277 mg, 0.90 mmol), 2 (0.100 g, 0.64 mmol)
and NEt3$(HF)3 (0.207 g, 1.28 mmol), 3v was isolated as a yellow oil
(0.087 g, 46%). Reaction time: 28 h (20 ꢀC). 1H NMR (250 MHz, ac-
(s, 3H, CH2COOCH3), 3.78 (s, 2H, CH2COOCH3), 4.77 (br s, 1H, OHAr),
6.37 (s, 1H, CHAr), 6.59 (d, 3J¼8.5 Hz, 2H, CHTol), 6.93 (d, 3J¼8.4 Hz,
2H, CHTol). 13C NMR (62 MHz, CD3OD):
d
¼20.5 (CH3Tol), 34.6
(CH2COOCH3), 52.3 (COOCH3), 52.5 (CH2COOCH3), 104.4 (CHAr),
105.1 (CAr), 115.7 (2CHTol), 130.7 (2CHTol), 132.0 (CAr), 132.2
(CCH3Tol), 136.4 (CAr), 157.3 (COHAr), 157.8 (CTol), 162.8 (COHAr), 172.1
etone-d6):
d
¼3.37 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.78 (s, 2H,
CH2CO2CH3), 6.78 (d, 4J¼1.5 Hz, 1H, Ar–H), 6.82 (d, 4J¼1.5 Hz, 1H,

8008
I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
Ar–H), 7.31 (m, 5H, Ph). 13C NMR (62.9 MHz, acetone-d6):
d¼38.6
(0.359 g, 48%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
(CH2CO2CH3), 50.8, 51.2 (2ꢂOCH3), 115.5, 116.9 (2ꢂAr), 123.7, 127.3,
127.9, 128.2, 135.3 (5ꢂPh–C), 141.2 (C–CH2CO2CH3), 142.7 (C–
CO2CH3), 158.2 (C–Ph), 169.1 (Ar–CO2CH3), 171.8 (CH2CO2CH3). IR
~
CDCl3):
d
¼1.27 (t, 3J¼6.9 Hz, 3H, OCH2CH3), 2.07 (s, 3H, CH3Ar), 3.57
(s, 3H, COOCH3), 3.61 (s, 3H, CH2COOCH3), 3.71 (s, 2H, CH2COOCH3),
3.86 (q, 3J¼6.9 Hz, 2H, OCH2CH3), 6.38 (s, 1H, CHAr), 6.68 (m, 2H,
CHPh), 6.70 (m, 2H, CHPh), 6.78 (s, 1H, OHAr). 13C NMR (62 MHz,
(KBr, cmꢁ1):
n
¼3378 (s), 3310 (br), 2977 (w), 2952 (m), 1737 (s,
C]O), 1716 (s), 1605 (s), 1589 (s), 1454 (s), 1431 (s), 1327 (s), 1281
(s), 1195 (s), 1121 (s), 1081 (m), 1019 (m), 962 (m), 868 (w), 797 (m),
771 (m), 702 (m). MS (CI, 70 eV): 300 (Mþ, 7), 255 (17), 225 (12), 147
(11), 115 (9), 105 (100), 77 (52), 43 (24).
CDCl3):
d
¼14.7 (CH3Ar), 25.9 (OCH2CH3), 34.2 (CH2COOCH3), 51.5
(COOCH3), 51.9 (CH2COOCH3), 63.7 (OCH2CH3), 95.2 (CAr), 115.3
(2CHPh), 115.8 (CAr), 117.3 (2CHPh), 127.5 (CHAr), 145.1, 147.8 (CAr),
150.3, 154.5 (CPh), 165.5 (COHAr), 170.4 (COOCH3), 201.5
~
(CH2COOCH3). IR (neat, cmꢁ1):
n
¼3434 (w), 2953 (w), 1735 (s), 1502
4.2.23. Methyl 5,6-dimethyl-4-hydroxy-2-(methoxycarbonyl-
methyl)benzoate (3w)
Starting with 1w (0.249 g, 0.96 mmol), 2 (0.104 g, 0.70 mmol)
and NEt3$(HF)3 (0.292 g, 1.81 mmol), 3w was isolated as a white
solid (0.078 g, 44%). Reaction time: 22 h (20 ꢀC). 1H NMR (250 MHz,
(s), 1435 (m), 1194 (s), 1140 (m), 1044 (m), 825 (m), 774 (w). GC–MS
(EI, 70 eV): m/z (%)¼374 ([Mþ], 46), 342 (81), 313 (100), 299 (3), 271
(7), 253 (6). HRMS (EI): calcd for C20H22O7: 374.13600; found:
374.13532.
4.2.27. Methyl 3-(4-chlorophenoxy)-4-hydroxy-6-(2-methoxy-
2-oxoethyl)-2-methylbenzoate (3aa)
acetone-d6):
CH2CO2CH3), 3.62 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.71 (s, 1H, Ar–
H), 8.64 (s, 1H, OH). 13C NMR (62.9 MHz, acetone-d6, APT):
d
¼2.08 (s, 3H, CH3), 2.18 (s, 3H, CH3), 3.51 (s, 2H,
Starting with 1aa (0.560 g, 1.60 mmol) and
1.28 mmol), 3aa was isolated as a white solid (0.210 g, 45%). Re-
action time: 18 h (20 ꢀC). 1H NMR (300 MHz, CDCl3):
2 (0.200 g,
d¼10.8
(CH3), 16.6 (CH3), 38.8 (CH2CO2CH3), 50.9, 51.1 (2ꢂCO2CH3), 114.8
(Ar), 122.3 (C–CH2CO2CH3), 126.0 (C–CO2CH3), 130.6 (CCH3), 136.1
(CCH3), 155.8 (C–OH), 169.6 (Ar–CO2–CH3), 171.0 (CH2–CO2–CH3). IR
d
¼2.09 (s, 3H,
CH3), 3.68 (s, 2H, CH2), 3.70 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.92 (s,
(KBr, cmꢁ1): ¼3352 (s), 3024 (w), 2993 (w), 2950 (m), 1717 (s,
1H, OH), 6.78 (d, 2H, J¼9.0 Hz, ArH), 6.81 (s, 1H, ArH), 7.22 (d, 2H,
~
n
J¼9.0 Hz, ArH). 13C NMR (100 MHz, CDCl3):
d
¼13.9 (CH3), 29.4
C]O),1598 (s),1437 (s),1418 (s),1360 (s),1317 (s),1291 (s),1232 (s),
1178 (s), 1154 (s), 1096 (m), 1060 (m), 999 (w), 959 (w), 866 (w), 779
(w), 731 (w), 684 (w), 558 (w). MS (EI, 70 eV): 252 (Mþ, 63), 220
(99), 292 (97), 177 (100), 167 (30).
(CH2), 51.9, 52.1 (OCH3), 116.1 (2CAr), 116.8 (CAr), 126.4, 127.5 (C),
129.7 (2CAr),131.2,131.7,138.6,150.1, 155.4,168.6,171.4 (C). IR (KBr):
~
n
¼3309 (s), 2945 (m),1707 (s), 1612 (m),1487 (s), 1337 (s), 1092 (w),
1009 (m), 956 (w), 828 (s), 760 (w). GC–MS (EI, 70 eV): m/z (%): 366
(Mþ, 37Cl, 13), 364 (Mþ, 35Cl, 35), 332 (42), 305 (65), 289 (100). Anal.
Calcd for C18H17ClO6 (364.78): C, 59.27; H, 4.70. Found: C, 58.82; H,
4.61.
4.2.24. Methyl 4-hydroxy-2-methyl-3-methoxycarbonyl-
6-(methoxycarbonylmethyl)benzoate (3x)
Starting with 1x (0.327 g, 1.08 mmol), 2 (0.133 g, 0.85 mmol)
and NEt3$(HF)3 (0.274 g, 1.70 mmol), 3x was isolated as a white
solid (0.045 g, 20%). Reaction time: 18 h (20 ꢀC). 1H NMR (250 MHz,
4.2.28. Methyl 3-(4-cyanophenoxy)-4-hydroxy-6-(2-methoxy-2-
oxoethyl)-2-methylbenzoate (3ab)
CD3OD):
CH2CO2CH3), 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.76 (s, 1H, Ar–
H). 13C NMR (62.9 MHz, CDCl3):
d¼2.43 (s, 3H, CH3), 3.58 (s, 3H, OCH3), 3.64 (s, 2H,
Starting with 1ab (0.380 g, 1.07 mmol) and
0.85 mmol), 3ab was isolated as a white solid (0.180 g, 56%). Re-
action time: 18 h (20 ꢀC). 1H NMR (300 MHz, DMSO-d6):
2 (0.110 g,
d¼20.6 (CH3), 28.9, 29.7 (2ꢂAr–
d
¼2.04 (s,
CO2CH3), 39.6 (CH2CO2CH3), 112.2 (CH2CO2CH3), 118.1 (Ar), 125.3,
127.6 (2ꢂC–CO2CH3), 138.0 (C–CH3), 139.4 (C–CH2CO2CH3), 162.8
(C–OH), 169.4, 170.4 (2ꢂAr–CO2CH3), 171.4 (CH2CO2CH3). IR (KBr,
~
3H, CH3), 3.60 (s, 3H, OCH3), 3.67 (s, 2H, CH2), 3.74 (s, 3H, OCH3),
6.83 (s, 1H, ArH), 6.91 (d, 2H, J¼8.9 Hz, ArH), 7.75 (d, 2H, J¼8.9 Hz,
ArH), 10.31 (s, 1H, OH). 13C NMR (100 MHz, CDCl3):
38.7 (CH2), 51.6, 51.7 (OCH3), 105.1 (C), 116.6, 118.5 (CHAr), 119.8,
d
¼13.3 (CH3),
cmꢁ1):
n
¼3307 (s), 3043 (w), 3002 (m), 2956 (s), 2934 (w),
2855 (m), 1705 (s, C]O), 1607 (s), 1435 (s), 1365 (s), 1321 (s), 1235
(s), 1117 (s), 1051 (s), 946 (m), 866 (m), 752 (m), 649 (m). MS (EI,
70 eV): 296 (Mþ, 60), 264 (100), 239 (14), 236 (19), 232 (53),
125.7, 131.8, 132.4 (C), 135.2 (CHAr), 138.7, 151.8, 161.7, 168.8, 171.9
~
(C). IR (KBr):
n
¼3435 (m), 2949 (w), 1743 (s), 1709 (s), 1601 (m),
1426 (w), 1328 (s), 1235 (s), 1162 (s), 1057 (w), 842 (m), 759 (w),
546 (m). MS (CI): 356 ([Mþ1]þ). Anal. Calcd for C19H17NO6
(355.34): C, 64.22; H, 4.82; N, 3.94. Found: C, 64.48; H, 5.00; N,
3.98.
204 (66). HRMS (EI): calcd for
C14H16O7: 296.0896; found:
296.0896ꢃ2 ppm.
4.2.25. Methyl 3-chloro-4-hydroxy-6-(2-methoxy-2-oxoethyl)-
2-methylbenzoate (3y)
Starting with 1y (0.349 g, 1.25 mmol), 2 (0.156 g, 1.0 mmol) and
NEt3$(HF)3 (0.242 g, 1.5 mmol), 3y was isolated as a reddish viscous
oil (0.114 g, 42%). Reaction time: 14 h (40 ꢀC). 1H NMR (250 MHz,
Acknowledgements
Financial support by the state of Pakistan (HEC scholarships for
I.H. and for M.A.Y.) and by the DAAD (scholarship for A.M.) is
gratefully acknowledged.
CDCl3):
COOCH3), 3.62 (s, 1H, OHAr), 3.66 (s, 3H, CH2COOCH3), 6.32 (s, 1H,
CHAr). 13C NMR (62 MHz, CDCl3):
d¼2.31 (s, 3H, CH3), 3.59 (s, 2H, CH2COOCH3), 3.61 (s, 3H,
d
¼26.3 (CH3), 35.6 (CH2COOCH3),
51.7 (COOCH3), 51.8 (CH2COOCH3), 82.7 (CAr), 124.3 (CHAr), 144.4,
References and notes
165.2, 165.2 (CAr), 170.1 (COHAr), 198.9 (2CO). IR (neat, cmꢁ1):
~
n
¼3002 (w), 2954 (w), 1731 (s), 1649 (w), 1435 (m), 1356 (m), 1327
1. Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
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(m), 1252 (m), 1166 (s), 1012 (m), 859 (w). GC–MS (EI, 70 eV): m/z
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100), 211 (37Cl, 15), 209 (35Cl, 46),197 (5),180 (6),154 (4), 125 (5), 89
(11), 77 (6). HRMS (EI): calcd for
272.04460; found: 272.04423.
C
12H13ClO5 ([Mþ], 35Cl):
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4.2.26. Methyl 3-(4-ethoxyphenoxy)-4-hydroxy-6-(3-methoxy-
2-oxoethyl-2-methyl)benzoate (3z)
Starting with 1z (0.761 g, 2.0 mmol), 2 (0.251 g, 1.6 mmol) and
NEt3$(HF)3 (0.241 g, 1.5 mmol), 3z was isolated as a red viscous oil
12. Hu¨ nig, S.; Wehner, G. Synthesis 1975, 180.

I. Hussain et al. / Tetrahedron 64 (2008) 8003–8009
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14. CCDC-684863 (3b) contains all crystallographic details of this publication,
which are available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
or can be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: þ44 1223 336 033 or de-
posit@ccdc.cam.ac.uk.