Demand-based thiolate anion generation under virtually neutral conditions: Influence of steric and electronic factors on chemo- and regioselective cleavage of aryl alkyl ethers

Article abstract of DOI:10.1021/jo0256540

Thiolate anions have been generated in a "demand-based" fashion under virtually neutral conditions for chemoselective deprotection of aryl alkyl ethers. Solvents play the critical role in making the reaction effective and should have high values of ε (>30), molecular polarizabilities (>10), and DN (>27) and low values of AN (>14). However, it is the combined effect of all of these physical properties that make a particular solvent effective. The reaction rates of cleavage of various aryl alkyl ethers are dependent on the steric crowding around the O-alkyl carbon and follow the order propargyl ≈ allyl ≈ benzyl > methyl > ethyl. Electron-withdrawing substituents increase the rate of ether cleavage reaction. The influence of the steric and electronic factors have been successfully exploited for selective deprotection of aryl alkyl ethers during inter- and intramolecular competitions.

Full text of DOI:10.1021/jo0256540

Dem a n d -Ba sed Th iola te An ion Gen er a tion u n d er Vir tu a lly Neu tr a l
Con d ition s: In flu en ce of Ster ic a n d Electr on ic F a ctor s on Ch em o-
†
a n d Regioselective Clea va ge of Ar yl Alk yl Eth er s
Asit K. Chakraborti,* Lalima Sharma, and Mrinal K. Nayak
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Sector 67, S. A. S. Nagar 160 062, India
akchakraborti@ niper.ac.in
Received February 26, 2002
Thiolate anions have been generated in a “demand-based” fashion under virtually neutral conditions
for chemoselective deprotection of aryl alkyl ethers. Solvents play the critical role in making the
reaction effective and should have high values of ꢀ (>30), molecular polarizabilities (>10), and DN
(>27) and low values of AN (<14). However, it is the combined effect of all of these physical
properties that make a particular solvent effective. The reaction rates of cleavage of various aryl
alkyl ethers are dependent on the steric crowding around the O-alkyl carbon and follow the order
propargyl ≈ allyl ≈ benzyl > methyl > ethyl. Electron-withdrawing substituents increase the rate
of ether cleavage reaction. The influence of the steric and electronic factors have been successfully
exploited for selective deprotection of aryl alkyl ethers during inter- and intramolecular competitions.
In tr od u ction
widespread popularity of thiolates as effective nucleo-
philes for cleavage of aryl alkyl ethers, only a limited
number of examples are reported highlighting the scope
The cleavage of aryl alkyl ethers is a versatile trans-
formation in organic synthesis in light of its importance
for the deprotection of phenols, particularly keeping in
8
of these reagents for regioselective demethylation. In all
of these protocols, the effective thiolate reagents are
generated/required in stoichiometric amounts or more,
and in some cases the reactions are carried out in carcino-
genic hexamethylphosphoramide (HMPA). The use of
stoichiometric amounts of thiolates is often associated
1
view the ease of the generation of aryl alkyl ethers, and
its involvement in the manufacture of a number of
pharmaceuticals, drugs, and other fine chemicals. The
various approaches for the coveted transformation are
2
3
(
i) nucleophilic, (ii) reductive, and (iii) photo/electro-
9
10
with the nucleophilic displacement of nitro and halogen
groups. Furthermore, thiolate anions are strong reducing
4
chemical cleavages. However, these are not applicable
to compounds having additional functionalities sensitive
to these reactions. Thus there have been continuous
efforts to develop new reagents for chemoselective depro-
tection of aryl alkyl ethers. Since the introduction by
(6) (a) Huffman, J . W.; J oyner, H.; Lee, M. D.; J ordan,. D.; Pen-
nington, W. T. J . Org. Chem. 1991, 56, 2081. (b) Huffman, J . W.; Yu,
S.; Showalter, V.; Abood, M. E.; Wiley: J . L.; Compton, D. R.; Martin,
R.; Bramblett, R. D.; Reggio, P. H. J . Med. Chem. 1996, 39, 3875. (c)
Myers, A. G.; Tom, N. J .; Fraley, M. E.; Cohen, S. B.; Madar, D. J . J .
Am. Chem. Soc. 1997, 119, 6072. (d) Pinchart, A.; Dallaire, C.;
Bierbeek, A. V.; Gingras, M. Tetrahedron Lett. 1999, 40, 5479.
5
Feutrill and Mirrington, alkaline thiolates have been
6
the commonly employed reagents for this purpose. Hwu
7
et al. later introduced sodium trimethylsilanethiolate
(7) (a) Hwu, J . R.; Tsay, S.-C. J . Org. Chem. 1990, 55, 5987. (b) Hwu,
(
Me
3
SiSNa) for aryl alkyl ether cleavage. Despite the
J . R.; Wong, F. F.; Shiao, M.-J . J . Org. Chem. 1992, 57, 5254. (c) Shiao,
M.-J .; Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J . R. J . Org. Chem. 1993,
5
8, 4742. (d) Shiao, M.-J .; Ku, W.-S.; Hwu, J . R. Heterocycles 1993,
36, 323.
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†
Dedicated to Prof. D. V. S. J ain on the occasion of his 69th birthday.
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999. (b) Basak (n e´ e Nandi), A.;
Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1998, 39, 4883
and references therein.
110, 1548. (b) Hansson, C.; Wickberg, B. Synthesis 1979, 191. (c)
Hannan, R. L.; Barber, R. B.; Rapoport, H. J . Org. Chem. 1979, 44,
2153. (d) Loubinoux, B.; Coudert, G.; Guillaumet, G. Synthesis 1980,
638. (e) Moos, W. H.; Gless, R. D.; Rapoport, H. J . Org. Chem. 1982,
47, 1831. (f) Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.;
Montanucci, M. Tetrahedron 1982, 38, 3687. (g) Cannon, J . R.; Feutrill,
G.; Wong, L. C. H. Aust. J . Chem. 1983, 36, 2572. (h) Lal, K.; Zarate,
E. A.; Youngs, W. J .; Salomon, R. G. J . Am. Chem. Soc. 1986, 108,
1311. (i) Lal, K.; Ghosh, S.; Salomon, R. G. J . Org. Chem. 1987, 52,
1072. (j) Dodge, J . A.; Stocksdale, M. G.; Fahey, K. J .; J ones, C. D. J .
Org. Chem. 1995, 60, 739.
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(b) Beck, J . R. J . Org. Chem. 1973, 38, 4086. (c) Kornblum, N.; Cheng,
L.; Krebber, R. C.; Kestner, M. V.; Newton, B. N.; Pinnick, H. W.;
Smith, R. G.; Wade, P. A. J . Org. Chem. 1976, 41, 1560. (d) Cogolli,
P.; Maiolo, F.; Testaferri, L.; Tingoli, M.; Tiecco, M. J . Org. Chem. 1979
44, 2636. (e) Cogolli, P.; Testaferri, L.; Tingoli, M.; Tiecco, M. J . Org.
Chem. 1979, 44, 2642.
(2) (a) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249. (b) Tiecco,
M. Synthesis 1988, 749. (c) Ranu, B. C.; Bhar, S. Org. Prep. Proced.
Int. 1996, 28, 371. (d) Hwu, J . R.; Wong, F. F.; Huang, J .-J .; Tsay,
S.-C. J . Org. Chem. 1997, 62, 4097.
(3) (a) Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 972. (b)
Celina, M.; Lazana, R. L. R.; Luisa, M.; Franco, T. M. B.; Herold, B. J .
J . Am. Chem. Soc. 1989, 111, 8640. (c) Ohsawa, T.; Hatano, K.; Kayho,
K.; Kotabe, J .; Oishi, T. Tetrahedron Lett. 1992, 33, 5555. (d) Azzena,
U.; Melloni, G.; Pisano, L. J . Chem. Soc., Perkin Trans. 1 1995, 261.
(
e) Casado, F.; Pisano, L.; Farriol, M.; Gallardo, I.; Marquet, J .; Melloni,
G. J . Org. Chem. 2000, 65, 322.
4) (a) Caynon, E.; Marquet, J .; Lluch, J . M.; Martin, X. J . Am. Chem.
(
Soc. 1991, 113, 8970. (b) Marquet, J .; Cayon, E.; Martin, X.; Casado,
F.; Gallardo, I.; Moreno, M.; Lluch, J . M. J . Org. Chem. 1995, 60, 3814.
(5) Feutril, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.
1
0.1021/jo0256540 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/31/2002
6
406
J . Org. Chem. 2002, 67, 6406-6414

Demand-Based Thiolate Anion Generation
of demand-based thiolate anion generation for chemo-
and regioselective cleavage of aryl alkyl ethers.
The efficiency of the demand-based thiolate anion
generation should be dependent upon the (i) initial proton
exchange between the thiol and the base (present in
catalytic amount) (path a), (ii) nucleophilic attack by the
thiolate anion on the O-alkyl carbon (path b), and (iii)
proton exchange between the liberated aryloxide anion
and the thiol to regenerate the thiolate anion (path c).
Thus, the effectiveness of path a should depend on the
basicity of the catalyst. Path b and path c should be
influenced by the specific solvent-anion interaction; the
major factors involved in this regard are the (i) dielectric
constant (ꢀ), (ii) donor number (DN), acceptor number
F IGURE 1. Catalytic cycle for demand-based in situ thiolate
anion generation for aryl alkyl ether cleavage.
agents11 as a result of RS- to RS‚ transformation. Thus,
the chances of involvement of the radical processes are
always high when the reactions are carried out using
stoichiometric amounts of thiolate anions with substrates
having nitro7
b,c
12
and R,â-unsaturated carbonyl groups,
(
AN),18 and (iii) molecular polarizability of the solvent.
leading to the reduction of these groups. The propensity
The higher the values of ꢀ, DN, and the molecular
polarizability of a solvent the better will be its interaction
with the cation, resulting in the generation of the naked
of the thiolate anions for Michael additions to R,â-
unsaturated carbonyl groups13 add further complexicity
to the issue of chemoselectivity for substrates bearing
such functionalities. Other major disadvantages of these
protocols are the (i) need to use expensive and difficult
to handle bases (e.g., LiH, NaH, and MeLi), (ii) extra
efforts needed to make the metal hydride bases oil-free,
-
+
thiolate anion from ArS M , facilitating path b. The
thiolate anion should exhibit its nucleophilicity more
effectively in a solvent with low AN. As the dispersion
interactions (or mutual polarizabilities) are indicated by
the molecular polarizabilities of the solvents, path c
should become more effective for solvents with higher
molecular polarizabilities.
(iii) manipulations involved in using the low boiling
thiols, (iv) use of excess (1.5-8 equiv) of thiols, (v) longer
reaction time (3.4-24 h), and (vi) use of stringent reaction
conditions such as the requirement of heating in a sealed
tube.
To find out the best operative condition for aryl methyl
ether cleavage, 2-methoxynaphthalene (1a ) was subjected
to the treatment with PhSH in the presence of catalytic
2 3
amounts of K CO under various conditions (Table 1).
Resu lts a n d Discu ssion
The reaction is best carried out in dry 1-methyl-2-
pyrrolidinone (NMP) under reflux for 15-30 min. The
reaction temperature has no detrimental effects on the
products or the unreacted starting materials. Other sol-
vents such as N,N-dimethylacetamide (DMA), N,N-di-
ethylformamide (DEF), N,N-diethylacetamide (DEA),
HMPA, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi-
none (DMPU), and 1,3-dimethyl-2-imidazolidinone
We presumed that the potential problems of the use
of stoichiometric amounts of the thiolate anions would
be circumvented by devising a protocol in which the
thiolate anions would be generated in situ in “demand-
based” fashion (Figure 1). The use of catalytic amounts
-
of a base would initially generate ArS by acid-base
reaction. Nucleophilic attack by the in situ generated
-
ArS on the alkyl group of the ether should generate the
(DMEU) provided good to excellent results. The effective-
aryloxide anion, which in turn would undergo proton
exchange with the excess thiol, present in the reaction
mixture, due to the better charge dispersal of thiolate
anions compared to that of the aryloxide anions in polar
aprotic solvents. In preliminary communications we
reported that the uses of PhSH in the presence of
ness of these solvents could be explained as efficient
ionization of PhS M due to the combined effects of high
values of ꢀ (29.6-37.8), molecular polarizabilities (18.8-
-
+
9
1
.65), and DN (38.8-27.3) and low values of AN (10.6-
3.6) of these solvents. Probably the lower molecular
1
4
polarizability of DMA (9.65) compared to that of NMP
10.3) affects the proton exchange in path c and makes
2 3
catalytic amounts of K CO in NMP constitute efficient
(
-
protocols for in situ generation of PhS to deprotect aryl
it inferior (compare the result of entry 13 with those of
entries 1 and 2, Table 1). The poor results obtained with
other polar solvents with comparable/higher values of ꢀ
such as N,N-dimethylformamide DMF (36.7), dimethyl
sulfoxide (DMSO) (48.9), and formamide (109.5) may be
accounted for the low molecular polarizabilities (7.91,
7.97, and 4.219, respectively) of these solvents, making
the proton exchange step (path c) sluggish. Further, the
high AN value (39.8) of formamide measures its electro-
philic behavior, suggesting the hydrogen bonding capa-
bility of formamide with anionic species (e.g., the AN
values of protic polar solvents such as MeOH, EtOH, and
PrOH, known for their hydrogen bond formation abilities
methyl ethers,15 alkyl esters, and aryl esters. We
16
17
describe herein the scope and limitations of the methods
(
10) (a) Testaferri, L.; Tingoli, M.; Tiecco, M. Tetrahedron Lett. 1980,
2
1
1, 3099. (b) Caruso, A. J .; Colley, A. M.; Bryant, G. L. J . Org. Chem.
991, 56, 862 and references therein.
(
11) (a) Evers, M.; Christiaens, L. Tetrahedron Lett. 1983, 24, 377.
(
b) Ashby, E. C.; Park, W.-S.; Goel, A. B.; Su, W. Y. J . Org. Chem.
1
1
985, 50, 5184. (c) Surdhar, P. S.; Armstrong, D. A. J . Phys. Chem.
986, 90, 5915 and references therein.
(
12) Meissner, J . W. G.; van dar Laan, A. C.; Pandit, U. K.
Tetrahedron Lett. 1994, 35, 2757.
13) (a) Niyazymbetov, M. E.; Laikhter, A. L.; Semenov, V. V.; Evans,
(
D. H. Tetrahedron Lett. 1994, 35, 3037. (b) Tomioka, K.; Muraoka, A.;
Kanai, M. J . Org. Chem. 1995, 60, 6188. (c) Ito, A.; Konishi, K.; Aida,
T. Tetrahedron Lett. 1996, 37, 2585.
18
with anions, are 41.3, 37.1 and 33.5, respectively). The
(
(
14) Parker, A. J . Chem. Rev. 1969, 69, 1.
15) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997, 38,
zero/negative values of activity coefficients of the halide
anions in formamide are evidences of hydrogen bond
8
1
1
749.
(16) Sharma, L.; Nayak, M. K.; Chakraborti, A. K. Tetrahedron
999, 55, 9595.
(17) Chakraborti, A. K.; Nayak, M. K.; Sharma, L. J . Org. Chem.
(18) Gutmann, V. The Donor-Acceptor Approach to Molecular
Interactions; Plenum: New York, 1978.
999, 64, 8027.
J . Org. Chem, Vol. 67, No. 18, 2002 6407

Chakraborti et al.
TABLE 1. Effect of Solven t, Tem p er a tu r e, a n d Tim e on
Clea va ge of 2-Meth oxyn a p h th a len e (1a ) by P h SHa
TABLE 2. Effect of Va r iou s Ba ses on Clea va ge of 1a by
P h SH in NMP a
entry
solvent
NMP
NMP
NMP
temp (°C)b
time (h)
yield (%)c-e
entry
baseb
time (h)
yield (%)b-d
1
2
3
4
5
6
7
8
9
202
202
80
146/44 mm
106/17 mm
235
80
210
153
153
176
189
166
182
130
80
0.5
0.25
1
0.5
0.5
0.5
1
1
1
7
0.5
1
1
0.5
1
9
0.5
1
1
1
1
97
81
0
94
96
90
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
None
12
1
1
0.5
0.5
1
1
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0
14
71
97
90
0
0
10
0
Li2CO3
Na2CO3
K2CO3
Cs2CO3
MgCO3
CaCO3
BaCO3
SrCO3
ZnCO3
NaHCO3
KHCO3
LiOH‚H2O
NaOH
KOH
CsOH‚H2O
LiH
NaH
KH
CaH2
LiNH2
NaNH2
DMPU
DMEU
HMPA
HMPA
formamide
DMF
DMF
DEF
DMSO
DMA
DEA
morpholine
MeCN
sulfolane
phenyl ether
PhMe
PhMe-HMPA
PhMe-NMP
0
35f
67
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
0
g
65
90
87.5
82
90
88
82
85
70
90
87.5
93
86
62.5
49
62.5
88
0
h
i
j
0
30
0
285
259
110
110
0
0
0
k
l
110
2
2
2
3
a
The ether (2.5 mmol) was treated with 1 equiv of PhSH in
t
BuOK
the presence of 5 mol % of K2CO3 in the respective solvent under
a
heating at a bath temp of 210 °C (except for entries 3, 7, 9-11,
The ether (2.5 mmol) was treated with 1 equiv of PhSH in
1
3, 15, 16, and 19-21, for which the corresponding figures in
the presence of 5 mol % of the base in NMP under heating at a
bath temp of 210 °C. b Isolated yield of 2-naphthol. The unreacted
ether could be recovered. d The 1H NMR spectra of the products
b
c
column 3 refer to the respective reaction temperatures). Bp of
c
the respective solvents (except for entries 3 and 7). Isolated yield
of 2-naphthol. The H NMR spectra of the products were in full
d
1
25
were in full agreement with the literature.
2
5
e
agreement with the literature.
The unreacted ether could be
recovered. f A 15% yield was obtained in carrying out the reaction
g
drides, but the alkaline earth metal carbonates do not
offer any appreciable catalytic effects. The weak basicity
of the alkaline earth metal carbonates, making the
initial proton exchange with PhSH (path a) ineffective,
may be the reasons for the poor results obtained with
these salts (compare the result of entry 20 with those of
entries 6-10, Table 2). The inferior result obtained in
with a bath temp of 210 °C for 0.5 h. A 66% yield was obtained
in carrying out the reaction with a bath temp of 210 °C for 0.5 h.
A 23% yield was obtained in carrying out the reaction with a
bath temp of 210 °C for 0.5 h. Comparable yield was obtained in
carrying out the reaction with a bath temp of 210 °C for 0.5 h.
No appreciable amount of the product was obtained in carrying
out the reaction with a bath temp of 210 °C for 0.5 h. HMPA
was used in 5 mol %. NMP was used in 5 mol %.
h
i
j
k
l
t
using BuOK as the catalyst (entry 23, Table 2) could be
-
due to the reduced nucleophilicity of PhS as a result
of hydrogen bond formation between PhS and the
liberated BuOH. The presence of the catalyst is essential,
as no ether cleavage was observed in its absence (entry
formation between the solvent and the anions.14 Thiolate
anions, being more polarizable than the halide anions,
should be more prone to hydrogen bond formation with
formamide. Therefore, use of formamide as solvent
should reduce the nucleophilicity of the thiolate anion,
via hydrogen bond formation, making path b (Figure 1)
slower and thereby resulting in poor yields. Probably the
low DN (14.8) of sulfolane makes it less effective in the
-
t
1
, Table 2).
The detection/isolation (see Experimental Section) of
thioanisole in the reaction of 1a with PhSH in the
presence of K CO (5 mol %) supports the proposal of
nucleophilic attack by the in situ generated PhS on the
methoxyl carbon (path b, Figure 1). The lack of detection/
2 2
isolation of appreciable amounts of Ph S ruled out the
2
3
-
-
+
ionization of ArS M to liberate the effective nucleophile
-
(
ArS ) and is responsible for the poor results obtained
in this solvent. The low DN (14.1), high AN (19.3), and
low molecular polarizability (4.45) of MeCN make it
ineffective despite its comparable value of ꢀ (37.5). The
lack of any appreciable amount of ether cleavage in
weakly polar solvents such as morpholine, phenyl ether,
and PhMe further emphasize the role of the solvents in
controlling path b and path c (Figure 1). Although the
temperature plays an important role (compare the results
of entries 1-3 and 7, Table 1), it is not the decisive factor
as revealed by the results obtained in the use of high
boiling polar solvents such as formamide, DMSO, and
sulfolane and weekly polar solvent such as phenyl ether
possibility of demethylation involving single electron
transfer (SET) from the PhS .
The effect of the thiol was evaluated by carrying out
the reaction of 1a with various thiols in the presence of
- 11a,19
K
2
CO
3
(5 mol %) in NMP (Table 3). Although the arene
substitu-
thiolate anions bearing the Me, OMe, and NH
2
tion at C-4 are expected to be better nucleophiles, the
inferior results obtained may be due to the weak acidic
properties of these thiols compared to that of PhSH
affecting path a (compare the result of entry 1 with those
of entries 2 and 3 in Table 3 and the result of entry 2,
Table 1 with that of entry 4, Table 3). The ineffectiveness
(entries 8, 12, 17, and 18, Table 1).
of 4-NO
2 6 4
-C H SH is due to the decreased nucleophilicity
To find out the effect of the base, 1a was treated with
of the corresponding thiolate anion (entry 7, Table 3). No
PhSH in the presence of various catalysts in NMP (Table
). The ether cleavage proceeds smoothly with alkali
metal carbonates, bicarbonates, hydroxides, and hy-
2
(19) Hilhorst, E.; Chen, T. B. R. A.; Iskander, A. S.; Pandit, U. K.
Tetrahedron 1994, 50, 7837.
6
408 J . Org. Chem., Vol. 67, No. 18, 2002

Demand-Based Thiolate Anion Generation
TABLE 3. Effect of Va r iou s Th iols on Clea va ge of 1a in
a
th e P r esen ce of K2CO3 (5 m ol %) in NMP
F IGURE 2. Single electron-transfer route for aryl alkyl ether
cleavage.
(path b, Figure 2) as in such an occasion the disulfide
produced would have undergone reduction by the aryl-
oxide anion (path c, Figure 2),20 due to the lability of the
S-S bond, to regenerate the thiolate anion making the
ether cleavage feasible with catalytic amount of thiol.
To establish this protocol as a generalized method for
aryl alkyl ether cleavage various aryl alkyl ethers were
subjected to the treatment with PhSH (method A) and
2
2 6 4 2 3
-NH -C H SH (method B) in the presence of K CO (5
mol %) in NMP (Table 4). In many occasions method B
was found to be superior to method A as revealed by the
increase in product yields and/or shorter reaction times
(entries 1, 3, 10, 12, 13, 17, and 26, Table 4). The use of
2
-NH -C SH (method B) offers the additional advan-
2
6 4
H
2
1
tages that the byproducts are easily separated from the
phenolic products in the final acidification step of the
workup (see Experimental Section). Benzyl ethers are
relatively more facile to be cleaved than the correspond-
ing methyl ethers, which in turn are more reactive than
the ethyl ethers (compare entries 1-3 and 6-8, Table
4
). Substrates containing electron-withdrawing groups
a
(entries 13, 15-17, 19 and 21, Table 4) react at a faster
The ether (2.5 mmol) was treated with 1 equiv of the thiol
(
except entry 6) in the presence of 5 mol % of K2CO3 in NMP under
rate, as is reflected by the shorter reaction time or higher
b
heating at a bath temp of 210 °C. Isolated yield of 2-naphthol.
yield (compare entry 9 and the footnote of entry 17, Table
c
The unreacted ether could be recovered. d The H NMR spectra
1
8j,22
4
) in accord with the earlier observations.
Electron-
of the products were in full agreement with the literature.25 e The
donating groups retard the reaction rates (entries 10, 24,
and 25, Table 4). The excellent results obtained for
figure in parentheses (entry 5) corresponds to the yield when the
reaction was carried out at 100 °C for 1 h. f The reaction was
carried with 5 mol % of the thiol.
substrate with 2-NH
2
substituent (entry 9, Table 4) may
be explained as a result of hydrogen-bond assisted
8
i
nucleophilic attack at the ortho O-Me group. The
reactions with 2-chloroanisole, 4-chloroanisole, and 4-ni-
troanisoles (entries 11-13, Table 4) need special atten-
tion because use of stoichiometric amounts of thiolates
are associated with the replacement of the nitro group
and halogen rather than the usual ether cleavage.
Chemoselective ether cleavage is not possible by the use
displacement of the nitro group, as a result of suicidal
nucleophilic attack, could be observed. No product cor-
responding to the reduction of the nitro group, arising
out of SET from the thiolate anion, could be detected,
which further confirms that SET process is unimportant
for thiolate anion generated in demand-based fashion.
However, the presence of the nitro group would have
made electron transfer from 4-NO -C H S difficult and
2 6 4
may partly be accounted for the lack of formation of the
corresponding reduced product. The better results ob-
-
4b
3
of Me SiSNa, as it converts p-nitrophenol to p-amino
phenol, as a result of concomitant reduction of the nitro
group,7b and nitrile to thioamides. Methoxystilbene
23
(
entry 18, Table 4) and ethers containing R,â-unsaturated
2 6 4
tained with 2-NH -C H SH may be due to the increased
nucleophilicity of the corresponding thiolate anion as a
result of the field effect involving the anionic site and
carbonyl groups (entries 20-22, Table 4) are efficiently
cleaved without competitive addition to the styrenoid
double bond24 or Michael addition.
13
the lone pair electron of the 2-NH
2
group (entry 5, Table
The difference in the rates of reaction of 2f and 2g
entries 14 and 15, Table 4) led us to study the effect of
3
). The poor results obtained with the benzimidazoles,
(
benzthiazole, and thiazoline may be due to poor nucleo-
philicity of the corresponding thiolate anion as a result
of resonance stabilization (entries 8-11, Table 3). In case
of thioalkanes, lack of proton exchange, due to their weak
(20) Phenolate ions are known to give stable radicals. Altwicker, E.
R. Chem. Rev. 1967, 67, 475.
21) Apart from ArSR, arising out of the nucleophilic attack by the
thiolate anion on the aryl alkyl ether, ArSSAr is generated from the
unreacted thiol and the alkali during the workup.
(
-
acidic character, with ArO makes them ineffective
(entries 12-14, Table 3). The ineffectiveness of the use
(
(
(
22) Hansson, C.; Wickberg, B. Synthesis 1976, 191.
of catalytic quantities of thiol (entry 6, Table 3) in the
cleavage of ether further justifies that the deprotection
23) Lin, P.-Y.; Ku, W.-S.; Shiao, M.-J . Synthesis 1992, 1219.
24) (a) Katrizky, I.; Takahashi, I.; Marson, C. M. J . Org. Chem.
1986, 51, 4914. (b) Beily, M.; Zamboni, R. J . Org. Chem. 1989, 54, 2642.
1
1a,19
does not take place via SET from the thiolate anion
J . Org. Chem, Vol. 67, No. 18, 2002 6409

Chakraborti et al.
TABLE 4. Ch em oselective Dep r otection of Ar yl Alk yl
TABLE 5. Effect of Ha m m ett Su bstitu en t Con sta n t (σ)
on Meth yl Eth er Clea va ge of An isole Der iva tives by
P h SH in th e P r esen ce of K2CO3 in NMP a
-
a -d
Eth er s by Ca ta lytica lly in Situ Gen er a ted Ar S
entry
ether
σb
yield (%)c-e
1
2
3
4
5
6
7
8
9
2e: R ) 4-NO2
2i: R ) 4-CN
2h : R ) 4-COMe
2g: R ) 4-CHO
2f: R ) 3-CHO
2d : R ) 4-Cl
2p : R ) 4-NHCOPh
2b: R ) 4-Me
2q: R ) 4-NH2
0.81
0.71
0.47
0.47
0.41
68
60
85
90
70
50
12
10
<5
0.24
f
0.078
-0.14
-0.57
a
The ether (2.5 mmol) was treated with 1 equiv of PhSH in
the presence of 5 mol % of K2CO3 in NMP under heating at a bath
temp of 210 °C for 10 min. b Carey, F.; Sandberg, R. J . Advanced
Organic Chemsitry, Part A, 3rd ed.; Plenum: New York, 1990.
Gonzalez, A. G.; J orge, J . D.; Dorto, H. L. Tetrahedron Lett. 1981,
7, 2585. c Isolated yield of the corresponding phenol. The
H
d
1
3
NMR spectra of the products were in full agreement with the
literature.25 The unreacted ether could be recovered. The mp
e
f
1
13
and spectral data ( H and C NMR) of the products were in full
agreement with the literature.28
SCHEME 1
the Hammett substituent constant (σ). Thus substituted
anisoles (2) were treated with PhSH in the presence of
a
Method A: the ether (2.5 mmol) was treated with 1 equiv of
PhSH in the presence of 5 mol % of K2CO3 in NMP under heating
at a bath temp of 210 °C. Method B: the ether (2.5 mmol) was
treated with 1 equiv of 2-H2N-C6H4SH in the presence of 5 mol %
of K2CO3 in NMP under heating at a bath temp of 210 °C.
K
2
CO
3
(5 mol %) in NMP under reflux for 10 min (Table
5
). The yields of the corresponding phenolic products
clearly establish the correlation between the reaction rate
and σ. The inferior results obtained in the cases of 2e
and 2i (compared to what might have been expected with
respect to the higher σ values) may be due to the slower
rate of proton exchange in path c (Figure 1).
b
Isolated yield of the corresponding phenol. c The H NMR spectra
of the products were in full agreement with the literature.
1
2
5 d
The
e
unreacted ether could be recovered. A 20% yield was obtained
in carrying out the reaction for 10 min. f A 50% yield was obtained
g
in carrying out the reaction for 10 min. A 56% yield was obtained
in carrying out the reaction for 15 min. A 90% yield was obtained
in carrying out the reaction for 30 min. The mp and spectral data
IR and MS) of the products were in full agreement with the
h
The difference in the rates of deprotection of methyl,
ethyl, and benzyl ethers prompted us to exploit the steric
effect for selective ether cleavage. In a intermolecular
competition study, the treatment of equimolar amounts
of 1a and 1b following method A resulted in a 3:2
selectivity in favor of methyl ether cleavage (Scheme 1).
Similar treatment of 1b and 1c resulted in the selective
ed te hp yr lo te et ch t ei or .n of a benzyl ether in a ratio of ∼3:2 over an
i
(
2
6 j
literature.
The mp and spectral data (IR, UV, and MS) of the
2
7
k
products were in full agreement with the literature.
yield was obtained in carrying out the reaction for 30 min. The
mp and spectral data ( H and C NMR) of the products were in
full agreement with the literature.
in carrying out the reaction for 15 min. The mp and spectral data
H and C NMR) of the products were in full agreement with
A 53%
l
1
13
2
8 m
A 60% yield was obtained
n
1
13
(
2
9
the literature.
6
410 J . Org. Chem., Vol. 67, No. 18, 2002

Demand-Based Thiolate Anion Generation
SCHEME 2
SCHEME 4
SCHEME 3
meta to the CHO group (see Experimental Section). The
cleavage of the O-Me meta to the CHO group may be the
result of OH-directed deprotection8 of 8b.
i
The phenolic product obtained by the treatment of 2,4-
dimethoxyacetophenone (9a ) following method A, after
chromatographic separation, afforded three components
in 16.3% (eluent 5% EtOAc-PhH), 22% (eluent 10%
EtOAc-PhH), and 38% (eluent 20% EtOAc-PhH) yields
(Scheme 4). The second fraction was identified to be the
completely demethylated product 9c (see Experimental
Section). The first and third fractions absorbed at 1633
-
1
1
and 1649 cm , respectively, in the IR. The H NMR of
the first fraction showed a OH signal at δ 12.76 repre-
senting a hydrogen bonded OH. Accordingly these two
fractions were assigned the structures 9b and 9d ,
respectively. Confirmation of the structures of 9b and 9d
Being encouraged by the results of the intermolecular
competitions of ether cleavage, we subjected various
4
-alkoxyanisoles (5) to the treatment following method
were obtained through comparison of their spectral data
B (Scheme 2). Excellent regioselectivity was observed
wherein a methyl ether was selectively deprotected in
the presence of a, ethyl ether, and benzyl, allyl, and
propargyl ethers were selectively deprotected in prefer-
ence to a methyl ether.
1
(
IR and H NMR) with those of 2-hydroxy-4-methoxy-
acetophenone and 4-hydroxy-2-methoxyacetophenone,
respectively. Further support has been obtained from the
analyses of the 13C NMR spectra of the first and third
fractions wherein the COMe carbons absorbed at δ 26.19
and 31.80, respectively.30 The reaction of 9a reveals that
the O-Me para to COMe is selectively deprotected in a
ratio of 3:2 over the O-Me ortho to COMe. The slower
rate of reaction at the O-Me ortho to COMe may be due
to the electrostatic repulsion of the oxygen lone pair
electrons of the carbonyl group toward the approach of
The results in Table 5 clearly reveal the effects of
electronic factor on the rates of ether cleavage. To exploit
the influence of electronic factor for selective ether
cleavage, equimolar mixtures of 1a and 2h , 2b and 2h ,
and 2f and 2g were separately subjected to the treatment
following method A (Scheme 3). Excellent selectivities
were observed wherein 2h underwent O-demethylation
preferential to that of 1a in a ratio of ∼8:1. The electronic
effect of the Me and COMe substituents led to the
selective O-Me cleavage of 2h over that of 2b in a ratio
of ∼8:1. Interestingly, the difference in the electronic
effect of the 3-CHO and 4-CHO substituents enabled us
to achieve complete selective demethylation of 2g. To find
out whether the difference of the electronic effect of the
-
the PhS .
The results of entries 23 and 24, Table 4 showed that
the amide substituents, CONHPh and NHCOPh, have
different deactivating effects on demethylation of the
corresponding substituted anisoles. These observations
(
25) Pouchart, C. J .; J acqlynn, B. The Aldrich Library of 13C and
H FT NMR Spectra; Aldrich Chemical Co. Inc., Milwaukee, 1993; Vol.
II, ed. I.
(26) Hseih, H.-K.; Lee, T.-H.; Wang, J .-P.; Wang, J .-J .; Lin, C.-N.
Pharma. Res. 1998, 15, 39.
27) Cirovic, M. M. Properties of Organic Compounds, POC-personal
1
3
-CHO and 4-CHO substituents could be utilized for
regioselective demethylation in intramolecular compe-
tion, 3,4-dimethoxybenzaldehyde (8a ) was subjected to
the ether cleavage following method A (Scheme 4). The
monodemethylation product 8b (58%) was obtained along
with the complete demethylation product 8c (20%) ac-
counting for an overall selectivity of 78:20 for the depro-
tection of the O-Me para to the CHO group over the O-Me
(
ed., version 5.1; CRC Press Inc.: Boca Raton, FL, 1996.
(28) Suezawa, H.; Yuzuri, T.; Hiroto, M.; Ito, Y. Bull. Chem. Soc.
J pn. 1990, 63, 328.
(
29) Isikdag, I.; Ucucu, U. Chem. Abstr. 1990, 113, 184199c.
(30) The COMe carbons of 4-methoxyacetophenone and 2-methoxy-
acetophenone absorb at δ 26.92 and 32.42, respectively.
J . Org. Chem, Vol. 67, No. 18, 2002 6411

Chakraborti et al.
SCHEME 5
an overall regioselective deprotection of the methyl ether
having 4-CO substituent could be achieved.
Con clu sion s
In summary, the work embodied in this article intro-
duces the concept of demand-based thiolate anion gen-
eration for chemoselective aryl alkyl ether cleavage under
virtually neutral conditions. The solvent plays critical
roles and should have high values of ꢀ (>30), molecular
polarizabilities (>10), and DN (>27) and low values of
AN (<14) in making the reaction effective. The steric
factors around the alkoxy carbon significantly influence
the rate of the ether cleavage reactions. The reaction
rates of cleavage of various aryl alkyl ethers follow the
order propargyl ≈ allyl ≈ benzyl > methyl > ethyl. The
presence of electron-withdrawing groups accelerate the
rates of the ether cleavage reactions. A correlation
between the reaction rate and σ has been established.
The influence of the steric and electronic factors have
been successfully exploited for regioselective ether cleav-
age during inter- and intramolecular competitions.
encouraged us to exploit the deactivation effect of amide
substituents for regioselective ether cleavage during
intramolecular competitions (Scheme 5). N-(4-Methoxy-
phenyl)-4-methoxybenzamide (10a ), on treatment follow-
ing method A, resulted in complete regioselective dem-
ethylation as only one phenolic compound was isolated
Exp er im en ta l Section
(
80%). The product showed the lone OMe signal at δ 3.75
1
in the H NMR spectrum and was assigned the structure
Gen er a l Con sid er a tion s. The ethers studied were either
1
31
1,36
1
0b on comparison with the H NMR spectrum of 10a
available commercially or prepared by standard procedures.
and taking into consideration the chemical shift values
of the O-Me protons in 2o (δ 4.28) and 2p (δ 4.22).
The oxime ether 11a , when subjected to reaction
following method A, exhibited excellent selectivity (Scheme
The solvents were distilled before use. DMA, DMPU, DMEU,
DEF, DEA, HMPA, DMSO, sulfolane, formamide, PhSH, 4-
Me-C
PhCH
captothiazoline, 2-mercaptobenzimidazole, 6-methyl-2-mer-
6
H
4
SH, 4-MeO-C
6 4 2 6 4 2 6 4
H SH, 4-NH -C H SH, 2-NH -C H SH,
2
SH, EtSH, 2-furylthiol, 2-mercaptobenzthiazole, 2-mer-
5
) and afforded the monodemethylation product (75%)
captobenzimidazole, Cs
2
CO
, Li
, NaHCO
3
, CsOH‚H
2
O, LiH, KH, NaNH
, MgCO , CaCO , BaCO
, KOH, NaOH, LiOH‚H
2
,
,
1
with the O-Me protons appearing at δ 3.89 in the H
NMR. The product was assigned the structure 11b, by
comparing its H NMR data with those of 11a and
4
t
BuOK, K
SrCO , ZnCO
NaH, CaH
2
CO
3
, Na
, KHCO
2
CO
3
3
2
CO
3
3
3
3
3
2
3
3
3
2
O,
1
2
, MeCN, morpholine, toluene, phenyl ether, DMF
-methoxyacetophenoneoxime.33 Therefore, selective depro-
and NMP were available commercially. Melting points were
taken in an open capillary and were uncorrected. Unless
otherwise mentioned, chromatography was performed on silica
gel (60-120) using a glass column (i.d. 1.5 cm).
tection of the phenolic O-Me takes place in the presence
of the oxime O-Me. The result also exemplifies excellent
chemoselectivity that no competitive nucleophilic addi-
tion to the CdN takes place.
Syn th esis of Sta r tin g Ma ter ia ls a n d Rea ction P r od -
1
u cts. The H NMR and IR spectra of the following compounds
The phenolic product obtained from the reaction
were in complete agreement with those of the authentic sam-
ples: 1-naphthol, 2-naphthol, 4-nitrophenol, 4-methoxyphenol,
4-hydroxytoluene, 4-chlorophenol, 4-aminophenol, 2-aminophe-
nol, 4-hydroxyacetophenone, 2-hydroxy-4-methoxyacetophe-
none, 2,4-dihydroxyacetophenone, 4-hydroxybenzaldehyde, 3-hy-
droxybenzaldehyde, 4-cyanophenol, 4-hydroxy-3-methoxyben-
zaldehyde, 6-hydroxy-1-tetralone, 5-hydroxy-1-indanone, trans-
(method A) of 12a (Scheme 6), after chromatographic
separation, afforded two fractions eluting with 5% EtOAc-
PhH and 20% EtOAc-PhH in 63% and 20% yields,
respectively (see Experimental Section). The 1H NMR
spectrum of the first fraction showed two sets of singlets
at δ 3.67 and 3.70 and δ 9.27 and 9.53 corresponding to
the O-Me and phenolic O-H protons, respectively. The
GC-MS spectra of this fraction revealed it to be the mono
demethylation product(s). The relative intensities of the
4
-hydroxystilbene, 4-hydroxybenzylideneacetone, trans-4-hy-
droxychalcone, trans-4′-hydroxychalcone (available commer-
3
7
cially), 2-(4-methoxyphenyl)benzothiazole (3) 1-(4-methoxy-
3
8
phenyl)-2-phenylethanedione (2k ), and N-phenyl-4-methoxy-
benzamide (2o).39 Physical data of the compounds, prepared
following reported procedures, are given below.
1
two sets of singlets in the H NMR spectra suggest the
mono demethylation products to be in a ratio of 68:32
corresponding to 12b34 and 12c, respectively. The second
3-P h en yl-1-(4-m eth oxyp h en yl)-2-p r op en e-1-on e (2m ):
-
1 1
3
IR (KBr) 1655, 1602, 1572, and 1490 cm ; H NMR (CDCl )
fraction was found to be the completely demethylated
δ 3.88 (s, 3H), 6.98 (d, J ) 9 Hz, 2H), 7.37-7.72 (m, 7H), 8.06
product 12d 35 as determined by H NMR and MS. Thus
1
(
d, J ) 9 Hz, 2H); λmax 314.4 nm (log ꢀ 4.55); MS (m/z) 238
+
(M ), 135 (100), 103, 92 and 77. N-(4-Meth oxyp h en yl)-
3
6
(
31) The O-Me signals of 10a absorb at δ 3.74 and 3.80, indicating
that it is the activated O-Me that have undergone cleavage.
32) Krueger, B. W.; Kysela, E.; Stetter, J .; Beckett, B.; Homeyer,
B.; Stendel W. Chem. Abstr. 1984, 101, 23077k.
ben za m id e (2p ): mp 153 °C (lit. 154 °C); IR (KBr) 3225,
1
-1
1
640, and 1605, cm ; H NMR (CDCl
3
) δ 4.22 (s, 3H), 7.28 (d,
(
1
(
33) The H NMR chemical shift (δ) values of the phenolic and oxime
(36) Furniss, B. R.; Hannaford, A. J .; Rogers, V.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry;
Longman: London, 1996.
(37) Mourtas, S.; Gatos, D.; Barlos, K. Tetrahedron Lett. 2001, 42,
2201.
42
O-Me protons of 11a are 3.78 and 3.91, respectively. The O-Me of
4
4
-methoxyacetophenoneoxime absorbs at δ 3.80. The O-H protons of
-methoxyacetophenoneoxime and 11a appear at δ 9.43 and 6.21,
respectively.
(
(
34) Sipos, G.; Dobo, I.; Czukor, B. Chem. Abstr. 1963, 59, 5059h.
35) Geisman, T. A.; Clinton, R. O. J . Am. Chem, Soc. 1946, 68, 697.
(38) Ishibashi, H.; Matsuoka, K.; Ibeda, M. Chem. Pharm. Bull.
1991, 39, 1854.
6
412 J . Org. Chem., Vol. 67, No. 18, 2002

Demand-Based Thiolate Anion Generation
SCHEME 6
J ) 8 Hz, 2H), 7.62-7.92 (m, 5H), 8.15-8.28 (m, 3H). N-(4-
Meth oxyp h en yl)-4-m eth oxyben za m id e (10a ): mp 200 °C
Clea va ge of 2k . Treatment of 2k (480 mg, 2 mmol) with
PhSH (264 mg, 2.4 mmol) and K CO (14 mg, 0.1 mmol, 5 mol
2
3
3
9
-1
1
(
lit. mp 200 °C); IR (KBr) 3326, 1646, and 1578, cm ; H
NMR (CDCl ) δ 3.74 (s, 3H), 3.8 (s, 3H), 6.81-6.91 (q, 4H),
.45 (d, J ) 9 Hz, 2H), 7.59 (bs, 1H), 7.75 (d, J ) 9 Hz, 2H);
%) in NMP (2.5 mL) under reflux for 10 min followed by usual
workup afforded the acidic product, which on passing through
a column of silica gel (15 g) and elution with 50% EtOAc-
PhH afforded the phenolic product (385 mg, 85%): mp 128-
3
7
+
MS (m/z) 257 (M ), 135 (100). 3-(4-Meth oxyp h en yl)-1-(4-
4
0
41
m eth oxyp h en yl)-2-p r op en e-1-on e (12a ): mp 102 °C (lit.
130 °C (lit. mp 129-130 °C); IR (KBr) 3400, 1675, 1650, 1600,
mp 100-102 °C); IR (KBr) 1655, 1647, 1593, and 1572 cm -1;
and 1560 cm ; H NMR (CDCl ) δ 6.84(d, J ) 9 Hz, 2H),
-1
1
3
1
H NMR (CDCl
H), 7.52 (d, J ) 16 Hz, 1H), 7.69 (d, J ) 9 Hz, 2H), 7.87 (d,
3
) δ 3.94 (s, 3H), 3.98 (s, 3H), 7.01-7.09 (m,
7.21-8.01 (m including a doublet J ) 9 Hz, 7H); λmax 286.4
nm (log ꢀ ) 4.24).
Clea va ge of 2l. Treatment of 2l (714 mg, 3 mmol) with
4
+
J ) 16 Hz, 1H), 8.13 (d, J ) 9 Hz, 2H); MS (m/z) 268 (M,
1
Meth oxyp h en yl)eth a n on eoxim e: mp 88 °C (lit. mp 87 °C);
00), 253, 237, 225, 161, 160, 135, 120, 108, 92, 77. 1-(4-
2 3
PhSH (396 mg, 3.6 mmol) and K CO (21 mg, 0.15 mmol, 5
mol %) in NMP (2.5 mL) under reflux for 30 min followed by
3
6
-
1
1
IR (KBr) 3100-2800 and 1605 cm ; H NMR (CCl
s, 3H), 3.80 (s, 3H), 6.80 (d, J ) 9 Hz, 2H), 7.50 (d, J ) 9 Hz,
H), 9.43 (s, 1H).
Rep r esen ta tive P r oced u r e for Dep r otection of Ar yl
Alk yl Eth er . Meth od A. A mixture of 1a (395.5 mg, 2.5
mmol), PhSH (0.27 g, 2.5 mmol), and K CO (17 mg, 0.125
mmol, 5 mol %) in NMP (2.5 mL) was heated under reflux for
0 min under N . The cooled reaction mixture was made
alkaline with 5% aqueous NaOH (25 mL) and extracted with
Et
4
) δ 2.23
usual workup and recrystallization (PhH-EtOAc) afforded the
2
6
(
2
product (600 mg, 90%), identical (mp, IR, and MS) to an
authentic sample of trans-4-hydroxychalcone: 1H NMR (CDCl
)
3
δ 6.84 (d, J ) 9 Hz, 2H), 7.31-7.61 (m, 7H), 7.89-8.08 (m,
2H); λmax 334.6 nm (log ꢀ 4.34).
Clea va ge of 2m . Treatment of 2m (714 mg, 3 mmol) with
2
3
2 3
PhSH (396 mg, 3.6 mmol) and K CO (21 mg, 0.15 mmol, 5
3
2
mol %) in NMP (2.5 mL) under reflux for 10 min followed by
usual workup and recrystallization (EtOH) afforded the phe-
2
7
2
O (3 × 15 mL) to separate any neutral component (GC-
nolic product (560 mg, 83%), identical (mp, IR, UV, and MS)
1
MS of these combined ethereal extracts showed the presence
of PhSMe). The aqueous part was acidified in the cold (ice bath)
to an authentic sample of trans-4′-hydroxychalcone: H NMR
(CDCl
3
) δ 6.99 (d, J ) 9 Hz, 2H), 7.06-7.98 (m, 7H), 8.05 (d,
with 6 N HCl and extracted with Et
combined Et O extracts were washed with brine (15 mL), dried
Na SO ), and concentrated under vacuo to afford a brown
solid, which on passing through a column of silica gel (230-
2
O (3 × 15 mL). The
J ) 9 Hz, 2H).
2
Clea va ge of 2n . Treatment of 2n (528 mg, 3 mmol) with
(
2
4
PhSH (396 mg, 3.6 mmol) and K CO3 (21 mg, 0.15 mmol 5
2
mol %) in NMP (2.5 mL) under reflux for 30 min followed by
usual workup and crystallization (PhH-EtOAc) afforded the
phenolic product (350 mg, 73%), identical (mp) to an authentic
sample of 4-hydroxybenzylidineacetone: IR (KBr) 3150, 1670,
4
00, 1 g) and elution with 5% EtOAc-hexane (200 mL)
afforded the product (349 mg, 97%), which was in full agree-
ment with mp and spectral data (IR, H NMR, and GC-MS)
1
-
1
1
of an authentic sample of 2-naphthol. The reactions with the
remaining substrates were carried out following this general
procedure and in each occasion the mp and spectral data (IR,
1630, 1600, and 1515 cm ; H NMR (DMSO-d ) δ 2.31 (s,
6
3H), 6.59 (d, J ) 15 Hz, 1H), 6.79 (d, J ) 9 Hz, 2H), 7.53 (d,
J ) 15 Hz, 1H), 7.54 (d, J ) 9 Hz, 1H), 10.04 (bs, 1H); MS
1
25-29,36-40
+
H NMR, and MS) compared well with the literature.
Meth od B. The treatment of 1a (395.5 mg, 2.5 mmol) with
-NH -C SH (0.31 g, 2.5 mmol) and K CO (17 mg, 0.125
(m/z) 162 (M ), 147 (100), 119, 91; λ
max
315.4 nm (log ꢀ 4.22).
Clea va ge of 4a . Treatment of 4a (324 mg, 2 mmol) with
2
2
6
H
4
2
3
PhSH (264 mg, 2.4 mmol) and K CO (14 mg, 0.1 mmol, 5 mol
2
3
mmol, 5 mol %) in NMP (2.5 mL) under reflux for 15 min under
after usual workup afforded the product (338 mg, 94%),
%) in NMP (2.5 mL) under reflux for 30 min followed by usual
workup afforded the acidic product, which on passing through
a column of silica gel (15 g) and elution with 10% EtOAc-
PhH (200 mL) afforded the phenolic product (220 mg, 75%),
identical (mp) to an authentic sample of 5-hydroxyindanone:
N
2
which was in full agreement with mp and spectral data (IR,
1
H NMR, and GC-MS) of an authentic sample of 2-naphthol.
The reactions with the remaining substrates were carried out
following this general procedure. In most of the cases the
product could be isolated in pure form without the involvement
of chromatographic separation, and in each occasion the mp
-
1 1
IR (KBr) 3199, 1678, 1619, and 1589 cm ; H NMR (CDCl )
3
δ 2.62 (t, J ) 5.5 Hz, 2H), 2.97 (t, J ) 5.5 Hz, 2H), 7.00 (s,
1H), 7.04 (d, J ) 8.2 Hz, 1H), 7.42 (s, 1H), 7.26 (d, J ) 8.2 Hz,
1
+
and spectral data (IR, H NMR, and MS) compared well with
1H); MS (m/z) 148 (M, 100), 120, 91; λ 317.2 nm (log ꢀ 3.71).
max
2
5-29,36-40
the literature.
(
41) Gorvin, J . H. Nature 1948, 161, 208.
(
39) Fahmy, A. F. M.; Sayed, G. H.; Hamed, A. A.; Morsy, A. A.
Indian J . Chem. 1978, 16B, 869.
40) Straus, F. J ustus Liebigs Ann. Chem. 1910, 374, 121.
(42) Pouchart, C. J .; J acqlynn, B. The Aldrich Libraray of 13C and
H FT NMR Spectra; Aldrich Chemical Co. Inc.: Milwauke, 1993; Vol.
1
(
III, ed. I.
J . Org. Chem, Vol. 67, No. 18, 2002 6413

Chakraborti et al.
Clea va ge of 4b. Treatment of 4b (352 mg, 2 mmol) with
PhSH (264 mg, 2.4 mmol) and K CO (14 mg, 0.1 mmol, 5 mol
) in NMP (2.5 mL) under reflux for 30 min followed by usual
workup afforded the acidic product, which on passing through
a column of silica gel (15 g) and elution with 20% EtOAc-
PhH (200 mL) afforded the product (290 mg, 90%), identical
sample of 4-hydroxy-3-methoxybenzaldehyde. Further elution
2
3
with 50% EtOAc-PhH (100 mL) afforded 70 mg (20%) of the
1
27
%
dihydroxy compound 10c, identical (mp, IR, and H NMR )
to an authentic sample of 3,4-dihydroxybenzaldehyde.
Clea va ge of 9a . Treatment of 9a (200 mg, 1.1 mmol) in
2 3
dry NMP (5 mL) with PhSH (121 mg, 1.1 mmol) and K CO
(
mp) to an authentic sample of 6-hydroxytetralone: IR (KBr)
(7.5 mg, 0.05 mmol, 5 mol %) under reflux for 30 min followed
by usual workup afforded 180 mg of the phenolic product,
which on passing through a column of silica gel (15 g) and
elution with 5% EtOAc-PhH (200 mL) afforded 30 mg (16.3%)
3
2
1
1
350, 1665, and 1580 cm-1; 1H NMR (CDCl
3
) δ 2.06-2.19 (m,
H), 2.65 (t, J ) 6.5 Hz, 2H), 2.91 (t, J ) 5.5 Hz, 2H), 6.71 (s,
H), 6.79 (d, J ) 8.5 Hz, 1H), 7.42 (s, 1H), 7.98 (d, J ) 8.5 Hz,
H); λmax 290.6 nm (log ꢀ 3.64).
of 9b, 13C NMR (CDCl
) δ 26.12, 55.57, 100.78, 107.66, 113.88,
1
3
Regioselective Dep r otection of Ar yl Alk yl Eth er s
132.30, 165.25, 166.10, and 202.63, identical (mp, IR, H NMR,
and MS)27 to an authentic sample of 2-hydroxy-4-methoxy-
acetophenone. Further elution with 10% EtOAc-PhH (200
mL) afforded 40 mg (22%) of the dihydroxy compound 9c,
d u r in g In ter m olecu la r Com p etition s. Selectivity of 1a
vs 1b. Treatment of a mixture of 1a (395 mg, 2.5 mmol) and
1
b (430 mg, 2.5 mmol) in dry NMP (5 mL) with PhSH (275
mg, 2.5 mmol) and K CO (17 mg, 0.125 mmol, 5 mol %) under
reflux for 30 min followed by usual workup afforded the
phenolic product (360 mg, 100%), identical (mp, IR, and 1
NMR) with an authentic sample of 2-naphthol. The recovered
unreacted ether mixture was found to contain 1a (40%, t 6.50
min) and 1b (60%, t 8.05 min) by GC-MS (100 °C 2 min, 5
C/min, 200 °C 5 min) confirming a 3:2 selectivity of cleavage
1
27
2
3
identical (mp, IR, H NMR, and MS) to an authentic sample
of 2,4-dihydroxyacetophenone. Further elution with 20%
EtOAc-PhH (200 mL) afforded 70 mg (38%) of 9d : mp 138
H
°C (lit.27 139 °C); IR (KBr) 3298, 1649, and 1595 cm ; H NMR
-1
1
R
(CDCl
doublet, J ) 9 Hz, 2H), 7.77 (d, J ) 9 Hz, 1H); C NMR
(CDCl ) δ 31.80, 55.45, 98.95, 107.86, 120.36, 125.87, 132.97,
3
) δ 2.59 (s, 3H), 3.87 (s, 3H), 6.45-6.47 (m including a
13
R
°
3
+
of methyl ether over ethyl ether.
Selectivity of 1b vs 1c. Treatment of a mixture of 1b (430
mg, 2.5 mmol) and 1c (585 mg, 2.5 mmol) in dry NMP (5 mL)
161.86 and 198.74; MS (m/z) 166 (M ), 151 (100), 136, 121,
108 and 93.
Clea va ge of 10a . Treatment of 10a (642 mg, 2.5 mmol) in
with PhSH (275 mg, 2.5 mmol) and K
2
CO
3
(17 mg, 0.125 mmol,
2 3
dry NMP (5 mL) with PhSH (275 mg, 2.5 mmol) and K CO
5
mol %) under reflux for 30 min followed by usual workup
(17 mg, 0.125 mmol, 5 mol %) under reflux for 2 h followed by
usual workup afforded the phenolic product, which on passing
through a column of silica gel (20 g) and elution with 30%
EtOAc in PhH (400 mL) afforded 480 mg (80%) of 10b: mp
afforded the phenolic product (360 mg, 100%), identical (mp,
IR, and H NMR) with an authentic sample of 2-naphthol. The
recovered unreacted ether mixture was found to contain 1b
1
-
1
1
(40%, t
R
11.61 min) and 1c (60%, t
R
15.18 min) by GC-MS
220-222 °C; IR (KBr) 3389, 3230, 1644, and 1603 cm ; H
(80 °C 2 min, 5 °C/min, 200 °C 5 min) confirming a 3:2
NMR (DMSO-d
) 9 Hz, 2H), 7.75 (d, J ) 9 Hz, 2H), 8.68 (s, 1H), and 9.31 (s,
1H).
6
) δ 3.75 (s, 3H), 6.78-6.84 (m, 4H), 7.54 (d, J
selectivity of cleavage of benzyl ether over ethyl ether.
Selectivity of 1a vs 2h . Treatment of a mixture of 1a (395
mg, 2.5 mmol) and 2h (375.5 mg, 2.5 mmol) in dry NMP (5
Clea va ge of 11a . Treatment of 11a (350 mg, 1.96 mmol)
in dry NMP (5 mL) with PhSH (20 mg, 2 mmol) and K CO
2 3
mL) with PhSH (275 mg, 2.5 mmol) and K CO (17 mg, 0.125
2
3
mmol, 5 mol %) under reflux for 30 min followed by usual
workup afforded the crude product, which on passing through
a column of silica gel (20 g) and elution with PhH (200 mL)
(14 mg, 0.1 mmol, 5 mol %) under reflux for 30 min followed
by usual workup afforded the phenolic product, which on
passing through a column of silica gel (20 g) and elution with
10% EtOAc-PhH (200 mL) afforded 230 mg (75%) of 11b: mp
1
afforded 2-naphthol (40 mg, 12%), identical (mp and H NMR)
64 °C; IR (KBr) 3400-3200, 1625, and 1605 cm- ; H NMR
1
1
with an authentic sample. Further elution with 5% EtOAc-
PhH (200 mL) gave 4-hydroxyacetophenone (300 mg, 88%),
(CCl ) δ 2.11 (s, 3H), 3.89 (s, 3H), 6.21 (s, 1H), 6.51 (d, J ) 8.5
4
1
+
identical (mp and H NMR) with an authentic sample.
Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H); MS (m/z) 165 (M ), 119, 93
and 77.
Select ivit y of 2h vs 2m . Treatment of a mixture of 2h
(
375.45 mg., 2.5 mmol) and 2b (305.43 mg, 2.5 mmol) in dry
Clea va ge of 12a . Treatment of 12a (670 mg, 2.5 mmol) in
dry NMP (5 mL) with PhSH (275 mg, 2.5 mmol) and K CO
NMP (5 mL) with PhSH (275 mg, 2.5 mmol) and K CO (17
2
3
2
3
mg, 0.125 mmol, 5 mol %) under reflux for 30 min followed by
usual workup afforded the phenolic product, which on passing
(17 mg, 0.125 mmol, 5 mol %) under reflux for 30 min followed
by usual workup afforded the phenolic product, which on
passing through a column of silica gel (20 g) and elution with
5% EtOAc-PhH (200 mL) afforded 400 mg (63%) of mono
through a column of silica gel (20 g) and elution with PhH
1
(
200 mL) afforded 4-methylphenol (33 mg, 12%), identical ( H
3
4
NMR) with an authentic sample. Further elution with 10%
demethylation product: mp 185 °C; IR (KBr) 3150, 1645 and
-
1
+
EtOAc-PhH (200 mL) gave 4-hydroxyacetophenone (300 mg,
1601 cm ; MS (m/z) 254 (100, M ); λ
max
(MeCN) 350 nm (log
1
1
8
8%), identical (mp and H NMR) with an authentic sample.
ꢀ 3.66). The H NMR spectrum exhibited two singlets at δ 3.67
and 3.76 corresponding to O-Me protons and broad singlets
at δ 9.27 and 3.53 corresponding to phenolic O-H protons. The
relative intensities of these two sets of singlets revealed the
phenolic product to be a mixture of 12b and 12c in a ratio of
68:32. Further elution with 20% EtOAc-PhH (200 mL) af-
forded 120 mg (20%) of complete demethylation product 12d :
Selectivity of 2f vs 2g. Treatment of a mixture of 2f (340
mg, 2.5 mmol) and 2g (340 mg, 2.5 mmol) in dry NMP (5 mL)
with PhSH (275 mg, 2.5 mmol) and K CO (17 mg, 0.125 mmol,
mol %) under reflux for 30 min followed by usual workup
2
3
5
afforded the phenolic product, which on passing through a
column of silica gel (20 g) and elution with PhH (200 mL)
4
0
afforded 307 mg (100%) of 4-hydroxybenzaldehyde, identical
mp 201 °C (lit. mp 203.5 °C); IR (KBr) 3200, 1642, 1604 and
1
-1 1
(
mp, IR, and H NMR) to an authentic sample, indicating
1589 cm ; H NMR (CDCl ) δ 6.90-6.97 (m, 4H), 7.40 (d, J )
3
selective cleavage of 2g.
In tr a m olecu la r Com p etition s. Clea va ge of 8a . Treat-
ment of 8a (415.15 mg, 2.5 mmol) in dry NMP (5 mL) with
16 Hz, 1H), 7.54 (d, J ) 9 Hz, 2H), 7.76 (d, J ) 16 Hz, 1H),
7.97 (d, J ) 9 Hz, 2H), 9.44 (bs, 1H), 9.67 (bs, 1H); MS (m/z)
+
240 (M ), 223, 206, 147, 121 (100); λ
max
(MeCN) 336 nm (log ꢀ
PhSH (275 mg, 2.5 mmol) and K
2
CO
3
(17 mg, 0.125 mmol, 5
3.58).
mol %) under reflux for 15 min followed by usual workup
afforded 380 mg of the phenolic product, which on passing
through a column of silica gel (20 g) and elution with 5%
EtOAc-PhH (200 mL) afforded 220 mg (58%) of the phenolic
Ack n ow led gm en t. L. S. thanks CSIR, New Delhi
for award of senior research fellowship.
1
27
product 8b, identical (mp, IR, and H NMR ) to an authentic
J O0256540
6
414 J . Org. Chem., Vol. 67, No. 18, 2002