Ph2S2-CaH2 in N-methyl-2-pyrrolidone as an efficient protocol for chemoselective cleavage of aryl alkyl ethers

Article abstract of DOI:10.1016/j.tet.2006.02.013

CaH₂ was been found, for the first time, as a mild reducing agent to generate thiophenolate anion from Ph₂S₂ in N-methyl-2-pyrrolidone (NMP) for deprotection of aryl alkyl ethers. Excellent chemoselctivity was observed for substrates having chloro and nitro groups without displacement of the chlorine atom and the nitro group. Selective ether cleavage took place in the presence of α,β-unsaturated carbonyl and nitro groups without reduction and conjugate addition (to the α,β-unsaturated carbonyl group).

Full text of DOI:10.1016/j.tet.2006.02.013

Tetrahedron 62 (2006) 4201–4204
Ph2S2–CaH2 in N-methyl-2-pyrrolidone as an efficient protocol for
chemoselective cleavage of aryl alkyl ethers
*
Navnath S. Gavande, Sonia Kundu, Naresh S. Badgujar, Gurmeet Kaur and Asit K. Chakraborti
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar,
Punjab 160 062, India
Received 17 September 2005; revised 17 January 2006; accepted 2 February 2006
Available online 28 February 2006
Dedicated to Professor Srinivasan Chandrasekaran on his 60th birth anniversary.
Abstract—CaH2 was been found, for the first time, as a mild reducing agent to generate thiophenolate anion from Ph2S2 in N-methyl-2-
pyrrolidone (NMP) for deprotection of aryl alkyl ethers. Excellent chemoselctivity was observed for substrates having chloro and nitro
groups without displacement of the chlorine atom and the nitro group. Selective ether cleavage took place in the presence of a,b-unsaturated
carbonyl and nitro groups without reduction and conjugate addition (to the a,b-unsaturated carbonyl group).
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
were obtained using this method, we felt that the use of
highly moisture sensitive sodium metal still demands milder
reagent for reductive generation of the thiophenolate anion
from Ph2S2. This led us to develop a better reducing agent
for in situ generation of thiophenolate anion from Ph2S2 and
we report herein, for the first time, CaH2 as a mild reducing
agent to generate thiophenolate anion from Ph2S2 in NMP
for chemoselective cleavage of aryl alkyl ethers.8
The phenolic moiety constitutes an important pharmaco-
phore due to the wide spread biological activity of
compounds containing phenolic hydroxyl group. Thus, the
cleavage of aryl alkyl ethers is a versatile organic reaction
keeping in view the ease of the generation of aryl alkyl
ethers.1 Although various methods such as nucleophilic,2
reductive,3 and photo/electrochemical cleavage4 of aryl
alkyl ethers are available, alkaline thiolates have been the
commonly employed reagents for this purpose.5 However,
due to their obnoxious smell and radical generation ability,
handling of thiols become difficult. The requirement of
stoichiometric amount of bases such as NaH or MeLi to
generate the thiolate anions do not make these procedures
attractive. Moreover, the propensity of the thiolate anion to
undergo oxidation to form the corresponding disulfides also
necessitates special attention in using alkaline thiolates.
Recently, Me3SiSNa has been introduced for aryl alkyl ether
cleavage.6 However, the use of Me3SiSNa requires stringent
reaction conditions such as heating in sealed tube in DMEU/
DMPU and is not compatible with functional groups (e.g.,
NO2) that are susceptible to reduction. Recently, we have
demonstrated Ph2S2 and Na in NMP as an efficient protocol
for in situ generation of thiophenolate anion for selective
deprotection of aryl alkyl ethers.7 Although excellent results
In the pursuit for a suitable reducing agent, we came across
the use of potassium triisopropoxyborohydride9 and lithium
tri-tert-butoxyaluminiumhydride10 for generation of thio-
late anions from the corresponding disulfides and sub-
sequent reaction with various alkyl halides. However, these
reducing agents are not suitable for substrates bearing
reducible functionalities such as carbonyl and nitro groups.
Recently lanthanoid metals,11 transition metal complex and
salt such as benzyltriethylammonium tetrathiomolybdate12
and indium(I) chloride13 have been used for generation of
thiolate anions from the corresponding disulfides. However,
the high cost of these reagents does not make them attractive
for routine applications. Other methods involve the
treatment with Cu2O-bpy (10 mol%) and Mg (0.6 equiv)
in DMF at 110 8C for 18–72 h14 and NiBr2-bpy (10 mol%)
and zinc (200 mol%) in DMF at 110 8C for 48 h.15 In all of
these reports the thiolate anion has been used either for
conjugate addition to a,b-unsaturated carbonyl com-
pounds11,12,13b or aryl sulfide formation by reaction with
aromatic halides.13a,14,15
Keywords: Ether cleavage; Diphenyl disulfide; Calcium hydride; Chemo-
selective; Thiophenolate anion.
Corresponding author. Tel.: C91 172 2214683 86; fax: C91 172
2214692; e-mail: akchakraborti@niper.ac.in
*
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.013

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N. S. Gavande et al. / Tetrahedron 62 (2006) 4201–4204
Table 2. Chemoselective deprotection of aryl alkyl ethersa
Entry Ether
2. Results and discussion
Yield (%)b,c
To find out the best reducing agent(s), 2-methoxy-
naphthalene (1) was treated with Ph2S2 in NMP in the
presence of various metals such as Mg, Fe and In under
varied experimental conditions such as the amount of Ph2S2
and the reducing agent, reaction temperature and time. The
reactions conditions providing the optimum results in each
case are provided in Table 1. In each occasion, the progress
of the reaction was monitored by GCMS and HPLC.
Moderate result was obtained in using Fe affording
2-hydroxynaphthalene (2) in 38% yield. The use of Mg
and In were proved to be ineffective as evidenced by the
formation of 2 in 2 and 1% yields, respectively (GCMS and
HPLC). As calcium metal (Ca) has been reported to be a
milder reducing agent compared to the alkali metals,16 we
planned to use Ca as the reducing agent. However, the use of
Ca afforded 46% conversion to 2. We next choose NaH and
CaH2 as alkali metal hydrides were known to possess
reducing property17 and generated alkali selenoates from
diorganodiselenides.18 We were delighted to observe that 95
and 90% conversion (HPLC) to 2 took place in the presence
of NaH and CaH2, respectively. The best result was obtained
by the treatment of 1 (1 equiv) with Ph2S2 (0.6 equiv) and
MH (1.6 equiv) in NMP by heating under reflux for 30 min.
1
RZMe
RZEt
RZCH2–CH]CH2
RZCH2–C^CH
RZCH2-Ph
80
69
42
35
2
3
4
5
100
6
7
8
RZMe
RZCH2–CH]CH2
RZCH2-Ph
76
47
95
9
R1ZH; R2ZCl
99
88
83
98
100
100
10
11
12
13
14
R1ZH; R2ZCOMe
R1ZCOCH3; R2ZH
R1ZH; R2ZCHO
R1ZH; R2ZCN
R1ZH; R2ZNO2
Table 1. Reaction of 1 with Ph2S2 in NMP in the presence of various
reducing agentsa
15
16
RZCN
RZCOCH3
100
88
Entry
Reducing agent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
Mg
Fe
In
Ca
NaH
CaH2
CaH2
30
30
30
30
30
30
15
2
38
1
48
96
90
64
17
18
RZCN
RZCOCH3
100
100
a 1 (1 mmol) was treated with Ph2S2 (0.6 equiv) and the reducing agent
(1.6 equiv) by heating under reflux in NMP (w220 8C).
b GCMS and HPLC yields of 2.
R1ZOMe; R2ZH
R1ZH; R2ZOMe
100
100
To establish the generality, various aryl alkyl ethers were
subjected to the treatment with Ph2S2 and CaH2 in NMP
(Table 2). Although the use of NaH afforded marginally
better result than that of CaH2 (compare the results of entries
5 and 6, Table 1), we planned to carry out the remaining
reactions with CaH2 as NaH is highly moisture sensitive and
its strong basic property may induce sulfenylation as major
side reaction with substrates bearing enolisable proton.
Excellent results were obtained with methyl, ethyl and
benzyl ethers. However, allyl and propargyl ethers afforded
moderate yields (Table 2: entries 3, 4 and 7). In each
occasion, the isolated (after aqueous work up) product was
pure (GCMS, NMR) and the reaction temperature had no
detrimental effect on purity of the product. The rate of ether
cleavage was affected by the steric and electronic factors of
the alkyl group. Inferior yield was obtained during the
cleavage of ethyl ether compared to that of methyl ether
under identical reaction conditions (compare entries 1 and 2,
Table 2). The cleavage of benzyl ether was more facile
compared to that of methyl ether (compare the results of
entry 1 with that of 5 and the result of entry 6 with that of 8,
Table 2). The presence of an electron withdrawing group
made the ether cleavage facile as evidenced by the excellent
19
20
a The ether (1 mmol) was treated with Ph2S2 (0.6 equiv) and CaH2
(1.6 equiv) by heating under reflux in NMP (w220 8C) for 30 min.
b Isolated yields of the corresponding phenol.
c The products were characterized by GCMS and NMR.
(83–100%) yields of the phenolic products for substrates
bearing electron withdrawing groups such as Cl, COMe,
CHO, CN, NO2, and a,b-unsaturated carbonyl (Table 2:
entries 9–20). Excellent chemoselectivity was observed
with substrates that are susceptible to undergo competitive
aromatic nucleophilic substitution, conjugate addition and
reduction. Exclusive ether cleavage took place for 4-chloro
anisole (Table 2: entry 9) and 4-nitro anisole (Table 2: entry
14) without displacement of the chlorine atom19 and the
nitro group.20 No reduction of the nitro group (Table 2:
entry 14)6b,c and a,b-unsaturated double bond (Table 2:
entries 19 and 20)16,21 was observed although thiolate
anions have reducing properties.22 The reactions with the
1,3-diaryl-2-propenones (Table 2: entries 19 and 20) further

N. S. Gavande et al. / Tetrahedron 62 (2006) 4201–4204
4203
demonstrated chemoselectivity of ether cleavage without
any competitive conjugate addition.23,24
(MCK29); identical with an authentic sample.5g,35 The
remaining reactions were carried out following this general
procedure and the isolated product was purified either by
crystallization (MeOH) or passing through a column of
silica gel and eluting with eluting with hexane–EtOAc (9/1).
The physical data (mp, IR, NMR and MS) of 1-hydro-
xynaphthalene,35 4-chlorophenol,35 4-hydroxyaceto-
3. Conclusion
In conclusions, we have described Ph2S2–CaH2 in NMP as a
highly efficient protocol for in situ generation of thiophe-
nolate anion for chemoselective deprotection of aryl alkyl
ethers. We have demonstrated, for the first time, the use of
CaH2 as a reducing agent to generate thiolate anion from
disulfides. The mildness of CaH2 should find its application
in various other organic transformations.
phenone,35
3-hydroxyacetophenone,35
4-hydroxy-
benzaldehyde,35 4-cyanophenol,35 4-nitrophenol,35
1-phenyl-3-(4-hydroxyphenyl)-2-propenone5f and 1-(4-
hydroxyphenyl)-3-phenyl-2-propenone5f were in complete
agreement with those of authentic samples.
4. Experimental
4.1. General
References and notes
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1
The H and 13C spectra were recorded on Bruker Avance
DPX 300 (300 MHz) spectrometer in CDCl3 using TMS as
internal standard. The IR spectra were recorded on Nicolet
Impact 400 spectrometer as KBr pellets for solid and neat
for liquid samples. Mass spectra were recorded on QCP
5000 (Shimadzu) GCMS. The reactions were monitored by
TLC (Merck). Evaporation of solvents were performed
under reduced pressure using a Bu¨chi rotary evaporator.
Indium and calcium metals, 2-methoxynaphthalene,
4-methoxyacetophenone, 3-methoxyacetophenone, 4-meth-
oxybenzaldehyde were purchased from Aldrich,
India. Magnesium and iron metals, NaH, CaH2 and
N-methyl 2-pyrrolidone were from S-D Fine
Chemicals, India. 4-Methoxychlorobenzene,25 4-methoxy-
nitrobenzene,25 4-methoxybenzonitrile,25 2-ethoxy-
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naphthalene,27 2-allyloxynaphthalene,28 1-allyloxy-
naphthalene,29 2-propynyloxynaphthalene,30 4-benzyl-
oxyacetophenone,31 4-allyloxyacetophenone,32 4-allyloxy-
benzonitrile,33 1-phenyl-3-(4-methoxyphenyl)-2-prope-
none34 and 1-(4-methoxyphenyl)-3-phenyl-2-propenone34
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Methoxynaphthalene (1) (158 mg, 1 mmol) in NMP
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Ph2S2 (130 mg, 0.6 mmol) and CaH2 (70 mg, 1.6 mmol) in
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