Practical synthesis of diaryloxymethanes

Article abstract of DOI:10.1081/SCC-120021995

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-120021995

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Practical Synthesis of Diaryloxymethanes
a
Wenming Liu a , Joanna Szewczyk a , Liladhar Waykole a , Oljan Repič & Thomas J.
Blacklock a
a Process R & D , Chemical and Analytical Development , Novartis Institute for Biomedical
Research , East Hanover, New Jersey, USA
Published online: 17 Aug 2006.
To cite this article: Wenming Liu , Joanna Szewczyk , Liladhar Waykole , Oljan Repič & Thomas J. Blacklock (2003) Practical
Synthesis of Diaryloxymethanes, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:15, 2719-2723, DOI: 10.1081/SCC-120021995
To link to this article: http://dx.doi.org/10.1081/SCC-120021995
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 15, pp. 2719–2723, 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 sodium
hydride and dichloromethane in N-methyl-pyrrolidinone (NMP)
at 40ꢀC.
Key Words: Diaryloxymethanes; Phenol; Sodium hydride; N-
methyl-pyrrolidinone.
*Correspondence: Liladhar Waykole, Process R & D, Chemical and Analytical
Development, Novartis Institute for Biomedical Research, One Health
Plaza, East Hanover, New Jersey, 07936, USA; Fax: 973-781-2188; E-mail:
liladhar.waykole@pharma.novartis.com.
2719
DOI: 10.1081/SCC-120021995
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2720
Liu et al.
INTRODUCTION
Diaryloxymethanes have been used in various areas, most recently
[1]
asfungicide.s
Usually they were prepared by the methylenation of
appropriate phenol with diiodomethane,[2] bromochloromethane,[3]
and dichloromethane.[4] Different inorganic bases, such as K2CO3,[4]
Cs2CO3,[3] NaH,[5] and several polar solvents, such as dimethylsulfoxide
(DMSO) and dimethylformamide (DMF) have been used to facilitate
the conversion. Often the use of a sealed tube is required due to the
volatility of the methylenating agents.[3] Use of dibenzo 18-crown-6
ether[6] and biphasic phase transfer catalysis conditions using quater-
nary ammonium salts[7] are also reported albeit requiring longer reac-
tion times. Recently, catalyst[8] and polymer-supported reagent[9] have
shown to expedite the desired methylenation. Dichloromethane is par-
ticularly of interest because it is the cheapest among these methylena-
tion agents. However, the use of dichloromethane to achieve the
methylenation requireshigher reaction temperatures(up to 120 ꢀC).[4]
In the course of our project, we encountered a task of preparing high
purity diaryloxymethane at low temperature. In thisarticle we report a
method for the synthesis of diaryloxymethanes from various phenols
and dichloromethane in the presence of sodium hydride in N-methyl-
pyrrolidinone (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
DMSO and DMF was due to the safety concern during scale-up.[10] The
results are summarized in the following Table 1. In general, phenol
(3 mmol) was dissolved in 4 mL of NMP, and then the solution was
cooled to 0ꢀC. Solid sodium hydride (3.3 mmol) was added in portions
followed by the addition of 0.5 mL of dichloromethane. The reaction
mixture wasslowly warmed up to 40 ꢀC. After the complete consumption
of the phenol wasconfirmed by HPLC, the reaction mixture was
O
O
OH
NaH, CH2Cl2
NMP, 40°C
R
R
R
Scheme 1.

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Diaryloxymethanes
2721
Table 1. Synthesis of diaryloxymethanes.
Entry
R
Time (h)
Yielda (%) [Ref.]
1
2
3
4
5
6
7
8
H
m-Cl
24
20
9
97[11a]
97[11b]
98[2,9]
93[9,11c]
92[9,11c]
98[11d]
99[9,11c]
0[9,11c]
p-Cl
m-Me
p-Me
7
4
m-MeO
p-MeO
o-NO2
4
2
18
aAll yields refer to isolated products, fully characterized
by physical and spectral data which is found in agree-
ment with literature data.
quenched with water and partitioned between ethyl acetate and water.
The organic layer waswashed with brine and dried over MgSO 4. After
filtration, the solution 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.
With the exception of o-nitrophenol, other phenolswere converted to
their corresponding diaryloxymethanes in excellent yields (92–99%). The
reaction time showed strong dependence on the substituent and its posi-
tion on the phenyl ring. An electron-donating group on the phenyl ring
enhancesthe nucleophilicity of the phenoxide and therefore shortensthe
reaction time. The effect ismore pronounced when the group isat the
para-position (Entries 3, 5, and 7). On the other hand electron-
withdrawing o-nitro group hasa strong deactivating effect that o-nitro-
phenol did not react under our mild reaction conditionsand no product
wasobtained (Entry 8).
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.
EXPERIMENTAL
1H and 13C NMR spectra were measured on
a
Bruker
ADVANCE/DPX 300 MHz and 75 MHz spectometer respectively in
CDCl3. In-process control TLC was run using EM Science Silica Gel

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2722
Liu et al.
60 F254 pre-coated platesand were vius alized with either 5% ethanolic
phosphomolybdic acid and heat or 254 UV light.
General Procedure
To a phenol (3.0 mmol) solution in 4 mL of N-methylpyrrolidinone
at 0ꢀC with stirring under nitrogen was added sodium hydride
(3.3 mmol). Then dichloromethane (0.5 mL) wasadded and the resulting
ꢀ
mixture waswarmed up to 40 C. After reaction wasindicated complete
by TLC, ethyl acetate (20 mL) wasadded to the reaction mixture. The
solution was washed with water (10 mL) and brine (10 mL). The organic
layer wasdried (MgSO 4), filtered and concentrated. The residue
wasloaded to a islica gel column and eluted with heptane to give the
product.
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Diaryloxymethanes
2723
13C NMR (75 MHz, CDCl3) ꢀ: 157.8, 135.3, 130.8, 123.3, 117.3,
115.1, 91.3. MS (EI). m/z 268 (Mþ), 141, 111. Anal. calcd. for
C13H10Cl2O2: C, 58.02; H, 3.75; Found: C, 58.69; H, 3.82; (c)
Baker, W. J. Chem. Soc. 1931, 1765–1770; (d) Delogu, G.; Fabbri,
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Received in the UK August 12, 2002

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