Surfactant-mediated solvent-free dealkylative cleavage of ethers and esters and trans-alkylation under neutral conditions

Article abstract of DOI:10.1016/j.tetlet.2005.11.048

A simple, surfactant-mediated, one-pot, solvent-free dealkylative cleavage of aryl ethers and esters followed by subsequent optional trans-alkylation under essentially neutral conditions has been developed.

Full text of DOI:10.1016/j.tetlet.2005.11.048

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 565–567
Surfactant-mediated solvent-free dealkylative cleavage of
ethers and esters and trans-alkylation under neutral conditions
Apurba Bhattacharya,a,* Nitin C. Patel,a Tomas Vasques,a Ritesh Tichkule,a
Gaurang Parmara and Jiejun Wub
aDepartment of Chemistry, Texas A&M University-Kingsville, Kingsville, TX 78363, USA
bJ&J Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 2 November 2005; accepted 7 November 2005
Available online 1 December 2005
Abstract—A simple, surfactant-mediated, one-pot, solvent-free dealkylative cleavage of aryl ethers and esters followed by sub-
sequent optional trans-alkylation under essentially neutral conditions has been developed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
As part of our continued interest in the preparative
utility of solvent-free ÔGreen TechnologiesÕ we wish to
report an environmentally friendly, surfactant-medi-
ated, and solvent-free cleavage of various electron-poor
aryl ethers, as well as optional trans-etherification of the
resulting phenolate anion under operationally simple,
one-pot, neutral conditions utilizing phosphate, thiocya-
nate, or nitrite ions as nucleophiles.1 This technology
was also successfully applied to the dealkylative cleav-
age/trans-esterification of various aryl esters utilizing
thioacetate as a nucleophile.2 The need for such method-
ology originated from our Industry–University collabo-
rative research program directed toward developing
efficient and environmentally friendly pharmaceutical
processes.3
anisole as a representative example with nucleophiles
such as KCl, KBr, or KI in the presence of catalytic
amount of Triton-X-405 (165 ꢁC, sealed tube) led to
unreacted starting material. It occurred to us that suc-
cess of this methodology would depend on an appropri-
ate choice of the nucleophile, whereby the by-product of
the dealkylation could not serve as a potential alkylating
agent, which proved to be the case. The solvent-free
methoxy cleavage of p-nitroanisole was successfully
achieved in >95% conversion and selectivity by treating
p-nitroanisole with KSCN (4 equiv) or KNO2 (4 equiv)
in the presence of catalytic amounts of an appropriate
surfactant such as Triton-X-405 over 4 h. Potassium
phosphate is also effective in carrying out successful
de-methylation, although longer reaction time is
required (cf. 24 h for p-nitroanisole under otherwise
identical conditions). The presence of Triton-X is
imperative; the reactions conducted without Triton-X-
405 showed only trace amounts of the desired product
under otherwise identical conditions. With Triton-X-
100, a less efficient complexing agent for K+, under
otherwise identical conditions, the extent of ether cleav-
age was only 20%.1a Also, utilizing KNO2 (amident
nucleophile), nitromethane was detected by GCMS fin-
gerprint, implying that nitrogen was the nucleophilic
center.5 Addition of allyl bromide or benzyl chloride
to the resulting p-nitrophenolate anion at this stage
directly produced the corresponding allyl or benzyl ether
in high yield, thereby adding significant value to this
strategy. The efficient, solvent-free, methoxy cleavage/
trans-etherification conditions were successfully applied
Electron-deficient aryl methyl ethers were selected as
viable substrates for the nucleophilic cleavage provided
these reactions proceed via SN2 attack on the methyl
group.4 Furthermore, selective crownether-like com-
plexation of the metal cation with the PEG units in
Triton-X should not only solubilize the nucleophilic
reagent, but also enhance the nucleophilicity of the
counter-ions. In addition, the surfactant properties of
Triton-X should improve the reaction kinetics by
increasing interfacial area, compensating for the lack
of solvation.1a Initial attempts to de-methylate p-nitro-
*
Corresponding author. Tel. +1 361 593 2664; fax: +1 361 593
3597; e-mail: kfab002@tamuk.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.048

566
A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 565–567
Table 1. Nucleophilic cleavage of electron poor aryl ethers and trans-etherification under solvent-free conditions8
KSCN (4 equiv)
RX, 70oC
Ar OCH
Ar O K
Ar OR
RX=Allyl-Br (3), Bz-Cl (4)
1!3 Yield (%), time (h)
3
Triton-X 405 (cat), 180oC
2
1
Entry
Substrate 1
1!2 Yield (%), time (h)
1!4 Yield (%), time (h)
1
2
3
4
5
6
7
8
4-Nitroanisole
3-Nitroanisole
2-Nitroanisole
3,5-Dichloroanisole
4-Cyanoanisole
2-Cyanoanisole
4-Anisaldehyde
2,4-Dinitroanisole
80 (3)
80 (7)
80 (5)
65 (6)
70 (7)
70 (8)
75 (7)
80 (4)a
85 (6)
80 (8)
75 (10)
75 (6)
70 (6)
70 (8)
75 (7)
No reaction
80 (80)
78 (15)
65 (18)
75 (75)
68 (70)
60 (68)
68 (65)
No reaction
OCH3
H3CO
OCH3
OCH3
AllO
OCH3
BzO
HO
9
CHO
CHO
CHO
CHO
80 (7)a
60 (8)
60 (12)
OCH3
OCH3
OCH3
H3CO
HO
AllO
10
No reaction
NO2
NO2
NO2
O
80 (7)a
Cl
70 (6)
Cl
O
Cl
Cl
11
12
—
—
—
—
MeO
Cl
HO
Cl
O
95 (3)
Cl
O
Cl
Cl
Cl
nPr
nPr
HO
MeO
98 (2)
a Only p-methoxy was cleaved (regioselective cleavage).
to prepare a series of electron-poor aryl/benzyl ethers
via the corresponding phenolate anions in consistently
high yields (Table 1).
(200 mg) was heated at 185 ꢁC. After 4 h, the reaction
mixture was cooled to 70 ꢁC, allyl bromide (3.55 g,
29.38 mmol) was added, and the mixture was stirred
for an additional 6 h. The mixture was cooled to room
temperature, brine (6 ml) was added, and the mixture
was extracted with tert-butyl methyl ether (MTBE,
3 · 15 ml). The combined organic layers were filtered
A typical experimental procedure is as follows: A stirred
mixture of potassium thiocyanate (2.54 g, 26.12 mmol),
p-nitroanisole (1 g, 6.53 mmol), and dry6 Triton-X-405
Table 2. Nucleophilic cleavage of aryl esters and trans-esterification under solvent-free conditions8
R X, 70 oC
1
KSCOCH (4 eq)
3
Ar-COOR
1
Ar-COO
K
Ar-COOCH
3
o
Triton X405 (cat.), 150 C
6
5
R X = Allyl-Br (7), Bz-Cl (8)
1
Entry
Ar-
5!6 (%)
5!7 (%)
5!8 (%)
1
2
3
4
5
6
7
8
Phenyl
90
92
98
91
98
87
91
85
88
90
91
92
80
92
85
87
90
64
94
91
95
93
88
80
92
96
82
94
95
81
85
87
99
88
90
77
m-Methyl phenyl
p-Methyl phenyl
2,3-Dimethyl phenyl
m-Chloro phenyl
p-Chloro phenyl
2-Methyl-4-methoxy phenyl
4-Methoxy phenyl
1-Naphthyl
9
10
11
12
2-Naphthyl
Hydrocinnamic
Benzoyl

A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 565–567
567
through a pad of silica gel and dried over MgSO4.
References and notes
Evaporation of the solvent in vacuo produced 0.88 g
of allyl-4-nitrophenol ether (75%). The intermediate phe-
nol, if desired, can be isolated as follows: After cooling
the reaction to room temperature, MTBE (45 ml) was
added and the resulting mixture was acidified to pH 3
using 1 N HCl. The organic layer was washed with brine
solution (2 · 5 ml), dried over magnesium sulfate, and
evaporation of the solvent in vacuo produced 0.68 g of
phenol (75%). Cleavage of 4-nitroanisole was faster than
3-nitroanisole (entries 1 and 2) presumably due to conju-
gation. The E(act) values for the KSCN-mediated ether
cleavage for 4-nitroanisole and 3-nitroanisole obtained
from kinetic measurements were 32.45 and 39.16 kcal/
mol, respectively. The Eact difference was exploited to
conduct a nontrivial regioselective cleavage of 1-meth-
oxy group in 1,2-dimethoxy-4-nitrobenzene (entry 10).7
1. (a) Bhattacharya, A.; Purohit, V.; Rinaldi, F. Org. Proc.
Res. Dev. 2003, 7, 254; For dealkylation of ethers see: (b)
Ranu, B. C.; Bhar, S. Org. Prep. Proced. Int. 1996, 28, 371,
and references cited therein.
2. For dealkylative cleavage of alkyl esters under neutral
conditions see: (a) Krapcho, A. P.; Weimaster, J. F.;
Eldridge, J. M.; Jahngen, E. G. E., Jr.; Lovey, A. J.;
Stephens, W. P. J. Org. Chem. 1978, 43, 138; (b) Chakra-
borti, A. K.; Nayak, M. K.; Sharma, L. J. Org. Chem. 2002,
67, 1776, and references cited therein.
3. Chemical & Engineering News; Education Concentrate,
2001; July 23 issue, p 41.
4. Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970,
16, 1327.
5. March, J. Adv. Org. Chem., 4th ed.; John Wiley, 1992,
pp 365–368 and references cited therein.
6. Triton-X-405 (70% aqueous solution) was dried by heating
to 100 ꢁC for 1 h and was more effective.
7. Dodge, J. A.; Stocksdale, M. G.; Fahey, K. J.; Jones, D. C.
J. Org. Chem. 1995, 60, 739.
The surfactant-mediated solvent-free methodology was
also extended to the dealkylative cleavage of various
aryl esters as well as optional trans-esterification of the
resulting carboxylate anion under neutral conditions uti-
lizing thioacetate as nucleophile (Table 2).2
8. NMR data for all the compounds synthesized are
consistent with their expected structures, as for instance:
6,7-Dichloro-2-(3-chloro-but-2-enyl)-5-hydroxy-2-methyl-
indan-1-one (entry 11): 1H NMR (600 MHz, DMSO-d6):
d 11.81 (s, 1H), 7.03 (s, 1H), 2.99–2.77 (d, J = 17.4 Hz,
2H), 1.43 (m, 2H), 1.20 (m, 1H), 1.12 (s, 1H), 1.09
(s, 3H), 0.99 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6): d 205.2, 159.9, 154.7, 129.9, 123.8,
120.2, 111.5, 49.5, 40.5, 38.5, 23.8, 17.5, 14.4. 6,7-
Dichloro-5-hydroxy-2-methyl-2-propyl-indan-1-one (entry
In summary, we have developed a simple, efficient, sol-
vent-free dealkylative cleavage of electron poor aryl
ethers/esters and subsequent optional trans-alkylation
under essentially neutral conditions. Excellent conver-
sions, selectivity and vessel efficiency achieved renders
the process eco-friendly, economically attractive, and
illustrates the value of the surfactant mediated solvent-
free methodology in organic synthesis.
1
12): H NMR (600 MHz, DMSO-d6): d 11.87 (s, 1H), 7.05
(s, 1H), 5.47 (t, J = 7.1, 1H), 2.90 (m, 2H), 2.40
(dd, J = 7.1 Hz, 1H), 2.31 (dd, J = 7.8 Hz, 1H), 2.05
(s, 3H), 1.49 (m, 2H), 1.14 (m, 1H), 0.94 (m, 1H), 0.79
(t, J = 7.2, 3H); 13C NMR (150 MHz, DMSO-d6): d
204.1, 160.0, 154.9, 132.1, 129.8, 124.4, 121.2, 120.3,
111.4, 52.9, 39.2, 36.0, 35.7, 25.9, 17.1, 14.4. For all
the compounds, GCMS analysis (Shimadzu QP5050A)
in the EI mode provided similarity index match of
>90% compared to the authentic samples in the NIST-
98 database.
Acknowledgments
Financial support provided by the Petroleum Research
Fund (PRF), National Institute of Health (NIH), Welch
Foundation, and Bristol Myers Squibb Corporation is
gratefully acknowledged.