Practical synthesis of diaryloxymethanes

Article abstract of DOI:10.1081/SCC-120018936

Diaryloxymethanes were prepared by treating phenols with sodium hydride and dichloromethane in N-methyl-pyrrolidinone (NMP) at 40°C.

Full text of DOI:10.1081/SCC-120018936

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Practical Synthesis of Diaryloxymethanes
Wenming Liu , Joanna Szewczyk , Liladhar Waykole , Oljan Repic & Thomas J.
Blacklock
To cite this article: Wenming Liu , Joanna Szewczyk , Liladhar Waykole , Oljan Repic & Thomas
J. Blacklock (2003) Practical Synthesis of Diaryloxymethanes, Synthetic Communications, 33:10,
1751-1754, DOI: 10.1081/SCC-120018936
To link to this article: http://dx.doi.org/10.1081/SCC-120018936
Published online: 17 Aug 2006.
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 10, pp. 1751–1754, 2003
Practical Synthesis of Diaryloxymethanes
Wenming Liu, Joanna Szewczyk, Liladhar Waykole,*
Oljan Repic, and Thomas J. Blacklock
Process R & D, Chemical and Analytical Development,
Novartis Institute for Biomedical Research,
East Hanover, New Jersey, USA
ABSTRACT
Diaryloxymethaneswere prepared by treating phenolswith so dium
hydride and dichloromethane in N-methyl-pyrrolidinone (NMP)
ꢀ
at 40 C.
Key Words: Diaryloxymethane; Phenol;
Methylene chloride; N-methyl-pyrrolidinone.
Sodium
hydride;
*
Correspondence: Liladhar Waykole, Process R & D, Chemical and Analytical
Development, Novartis Institute for Biomedical Research, One Health Plaza,
East Hanover, NJ 07936, USA; Fax: 973-781-2188; E-mail: liladhar.waykole@
pharma.novartis.com.
1
751
DOI: 10.1081/SCC-120018936
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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Liu et al.
INTRODUCTION
Diaryloxymethanes have been used in various areas, most recently as
[1]
fungicides. Usually they were prepared by the methylenation of
[
appropriate phenol with diiodomethane, bromochloromethane, and
2]
[3]
[
4]
[4]
dichloromethane.
Different inorganic bases, such as K CO ,
2 3
[3]
[5]
Cs CO , NaH, and several polar solvents, such as dimethylsulfoxide
2
3
(
conversion. Often the use of a sealed tube is required due to the volatility
DMSO) and dimethylformamide (DMF) have been used to facilitate the
[
3]
[6]
of the methylenating agents. Use of dibenzo 18-crown-6 ether and
biphasic phase transfer catalysis conditions using quaternary ammonium
[7]
salts are also reported albeit requiring longer reaction times.
[8]
[9]
Recently, catalyst and polymer-supported reagent have shown to
expedite the desired methylenation. Dichloromethane is particularly of
interest because it is the cheapest among these methylenation agents.
However, the use of dichloromethane to achieve the methylenation
ꢀ
[4]
requireshigher reaction temperatures(up to 120 C). In the course
of our project, we encountered a task of preparing high purity diaryl-
oxymethane at low temperature. In thisarticle, we report a method for
the synthesis of diaryloxymethanes from various phenols and dichloro-
methane in the presence of sodium hydride in N-methylpyrrolidinone
(
NMP).
RESULTS AND DISCUSSION
We judiciously selected to use dichloromethane and sodium hydride
over other reagents because of their low cost. The choice of NMP over
[
10]
DMSO and DMF was due to the safety concern during scale-up. The
results are summarized in the following table. In general, phenol (3 mmol)
ꢀ
was dissolved in 4 mL of NMP, and then the solution was cooled to 0 C.
Solid sodium hydride (3.3 mmol) was added in portions followed by the
addition of 0.5 mL of dichloromethane. The reaction mixture was sl owly
ꢀ
warmed up to 40 C. After the complete consumption of the phenol was
confirmed by HPLC, the reaction mixture wasquenched with water and
partitioned between ethyl acetate and water. The organic layer was
washed with brine and dried over MgSO . After filtration, the solution
4
was concentrated, and the residue was passed through a silica gel column.
Evaporation of the collected eluent (5% EtOAc/heptane) gave the
product with greater than 98% purity (Sch. 1).
With the exception of o-nitrophenol, other phenolswere converted
to their corresponding diaryloxymethanes in excellent yields (92–99%).

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Practical Synthesis of Diaryloxymethanes
1753
Scheme 1.
Table 1. Synthesis of diaryloxymethanes.
a
Yield (%)
Entry
R
Time (h)
1
2
3
4
5
6
7
8
H
m-Cl
24
20
9
97
97
98
93
92
98
99
0
p-Cl
m-Me
p-Me
7
4
m-MeO
p-MeO
o-NO
4
2
18
2
a
All yields refer to isolated products, fully characterized
by spectral data.
The reaction time showed strong dependence on the substituent and its
position on the phenyl ring. An electron-donating group on the phenyl
ring enhancesthe nucleophilicity of the phenoxide and therefore sh ortens
the reaction time. The effect ismore pronounced when the group isat the
para-position (Table 1, Entries 3, 5, and 7).
In summary, we have developed a method to prepare diaryloxy-
methane through the methylenation of phenol using dichloromethane
and sodium hydride in N-methyl-pyrrolidinone.
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2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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1
Received in the USA August 16, 2002