Iron-catalyzed solvent-free conversion of alcohols and phenols into diphenylmethyl (DPM) ethers

Article abstract of DOI:10.1016/S0040-4039(02)00890-0

A catalytic amount of iron salts enables the solvent-free preparation of diphenylmethyl (DPM) ethers of alcohols and phenols at moderate temperatures.

Full text of DOI:10.1016/S0040-4039(02)00890-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4593–4595
Iron-catalyzed solvent-free conversion of alcohols and phenols
into diphenylmethyl (DPM) ethers†
Vasudevan V. Namboodiri and Rajender S. Varma*
Clean Processes Branch, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443,
26 W. Martin Luther King Drive, Cincinnati, OH 45268, USA
Received 27 March 2002; revised 8 May 2002; accepted 9 May 2002
Abstract—A catalytic amount of iron salts enables the solvent-free preparation of diphenylmethyl (DPM) ethers of alcohols and
phenols at moderate temperatures. © 2002 Elsevier Science Ltd. All rights reserved.
The selective protection of alcohols is a common event
in multi-step organic syntheses. The preparation of
DPM ethers is one of the significant methods in view of
their inexpensive nature and stability towards a variety
of reagents.1 Additionally, DPM ethers and DPM
groups are found as a part of several pharmacologically
active compounds.2 There are several reagents available
for the preparation of DPM ethers of alcohols which
include the use of diphenylmethyl chloride or bromide
in the presence of a base,3 diphenylmethyl diazo-
methane or diphenylmethyl phosphate–trifluoroacetic
acid,4 diphenylmethanol in the presence of concentrated
sulphuric5 or p-toluenesulphonic acid,6 xenon
difluoride7 and ytterbium triflate–ferric chloride
(FeCl3).8 Although these methods are suitable for some
synthetic operations, they require a high catalyst to
substrate ratio, relatively long reaction times and
involve the use of volatile organic solvents or large
amounts of solid supports, which eventually result in
the generation of substantial amount of wastes. Thus,
there is a need for a solventless and catalytically
efficient alternative for the protection of hydroxyl func-
tionality as DPM ether. As a part of an ongoing
research program to develop environmentally friendlier
chemical transformations,9 herein, we report an efficient
iron-catalyzed solvent-free conversion of alcohols and
phenols into DPM ethers.
The present protocol, in its entirety, simply involves
mixing an alcohol or phenol with diphenylmethanol in
the presence of a catalytic amount of an iron salt and
warming the reaction mixture to afford the correspond-
Table 1. Catalytic effect of iron salts on the formation of DPM ethera
Entry
Benzhydrol (mmol)
Time (min)
Temperature (°C)
Yield % (isolated)
1
2
3
4
5
6
7
1
1
10
30
30
30
55
80
55
80
80
80
80
95
84b
83
50
60
48
100
100
100
120
120
120
37
41c
36d
a Fe(NO3)3·9H2O (1 mmol).
b Product is benzophenone.
c FeCl3 (1 mmol).
d FeCl2·4H2O (1 mmol).
Keywords: alcohols; phenols; diphenylmethyl ethers; iron nitrate nonahydrate; solvent-free.
* Corresponding author. Fax (513)-569-7677; e-mail: varma.rajender@epa.gov
†
Presented, in part, at the IUPAC CHEMRAWN XIV Conference on Green Chemistry: Toward Environmentally Benign Processes and
Products, Boulder, Colorado, USA, 9–13 June, 2001.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00890-0

4594
V. V. Namboodiri, R. S. Varma / Tetrahedron Letters 43 (2002) 4593–4595
The preparation of DPM ether of benzyl alcohol is
representative of the general procedure employed:
iron(III) nitrate nonahydrate (1 mmol), diphenyl
methanol (50 mmol) and benzyl alcohol (55 mmol)
were mixed in a 50 mL round bottomed flask and
stirred at 80°C. The progress of the reaction was moni-
tored by TLC and GC–MS and upon completion of the
reaction the product was purified via column chro-
matography using eluent, hexane–ethyl acetate (10:1 to
1:1) to afford pure product (89%). All the DPM ethers
are known compounds and were characterized by spec-
tral analyses (GC and NMR).
ing DPM ether. After completion of the reaction, the
product is isolated by column chromatography using
hexane–ethyl acetate mixture as eluent. Table 1 pro-
vides the details of DPM ether formation under various
reaction conditions with benzhydrol as the substrate.10
Longer reaction time and higher reaction temperature
are required at elevated concentration of the substrates
(entries 1, 3, 4 and 5). Ferrous or ferric chloride can
also be used as catalysts for the preparation of ethers
(entries 6 and 7). Ether preparation at a low substrate
to catalyst ratio is preferable at a temperature ideally
around 55°C, which prevents or reduces iron nitrate-
catalyzed oxidation of alcohol to carbonyl compounds
(entry 2).
In conclusion, the present method describes an efficient
and practical alternative to the preparation of DPM
ethers of alcohols that, in contrast to most of the
existing protocols, does not require any solvent or solid
support or the use of distilled and/or dry reagents, and
consequently minimizes the generation of toxic waste.
The major advantages of this methodology are mild
reaction conditions and faster reaction rates with high
substrate to catalyst ratio. We believe this method will
find useful application for the preparation of DPM
ethers.
A variety of hydroxylated compounds are converted to
the corresponding DPM ethers via this procedure using
Fe(NO3)3·9H2O and the results are summarized in
Table 2. The reactions are reasonably fast and the order
of reactivity for various alcohols is, primary>sec-
ondary>tertiary. In the case of reactive alcohols such as
benzylic or primary alcohols or phenols, the DPM
ethers are formed in good yields with only a trace
amount (<5%) of formation of self-condensed ether of
diphenylmethanol,10 which increases in amount for less
reactive substrates, e.g. secondary alcohols (entry 3,
Table 2) and t-butanol (entry 7, Table 2). Also, rela-
tively higher temperatures or longer reaction times are
required for solid alcohols.
Acknowledgements
V.V.N. is a postgraduate research participant at the
National Risk Management Research Laboratory
administered by the Oak Ridge Institute for Science
and Education through an interagency agreement
between the US Department of Energy and the US
Environmental Protection Agency.
The chemoselective feature of this solvent-free method
is an attractive attribute as the ease of formation of
diphenylmethyl ether of primary alcohols is more pro-
nounced when compared to secondary or tertiary
alcohols.
Table 2. Iron-catalyzed preparation of diphenylmethyl ethers from alcoholsa
Fe(NO3)3.9H2O
CHOH + ROH
O R
80 oC
Entry
Alcohol
Time (h)
Temperature (°C)
Yields % (isolated)
1
2
3
4
5
6
7
8
Methanol
1-Hexanol
3-Hexanol
Cyclohexanol
Cyclohexylmethanol
Phenol
tert-Butanol
3-Methyl-2-butene-1-ol
Benzyl alcohol
4-Fluorobenzyl alcohol
2-Chlorobenzyl alcohol
3-Chlorobenzyl alcohol
4-Chlorobenzyl alcohol
Benzyl alcohol
1
2
4
3
2
2
2
2
1
1
1
1
1
1
70
80
80
80
80
80
80
80
80
80
80
80
80
80
88
85
39
43
83
71
B5
76
89
90
87
75
90
88b
9
10
11
12
13
14
a Fe(NO3)3·9H2O (1 mmol), diphenylmethanol (50 mmol) and alcohol (55 mmol).
b Ferrous chloride (1 mmol) is used as the catalyst.

V. V. Namboodiri, R. S. Varma / Tetrahedron Letters 43 (2002) 4593–4595
4595
8. Sharma, G. V. M.; Prasad, T. R.; Mahalingam, A. K.
Tetrahedron Lett. 2001, 42, 759.
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; New York: John Wiley &
Sons, Inc, 1999; p. 59 and references cited therein.
2. (a) Averback, P.; Ghanbari, H.; Baheshti, I.; Morse, D.
PCT Int. Appl. 1998 (WO 9852898, Chem. Abstr. 1998,
130, 38192); (b) Hayashi, M. et al. Drug Data Report
1997, 704 (JP 97077745, 97077754); (c) Hu¨ls, A.; Purand,
K.; Ligneau, X.; Arrang, J.-M.; Schwartz, J.-C.; Schu-
nack, W. Bioorg. Med. Chem. Lett. 1996, 6, 2013.
3. Dobson, D.; Todd, A.; Gilmore, J. Synth. Commun. 1991,
21, 611.
4. (a) Lapatsanis, L. Tetrahedron Lett. 1978, 19, 3943; (b)
Kolovos, M.; Froussios, C. Tetrahedron Lett. 1984, 25,
3909.
5. Sugsawa, S.; Fujiwara, K. Org. Synth. Coll. 1963, 4, 72.
6. (a) Parades, R.; Perez, R. L. Tetrahedron Lett. 1998, 39,
2037; (b) Fumio, T.; Koichi, O. J. Chem. Soc., Chem.
Commun. 1991, 1212; (c) Pratt, E. F.; Draper, J. D. J.
Am. Chem. Soc. 1949, 71, 2846.
9. (a) Varma, R. S. In Green Chemistry: Challenging Per-
spectives; Tundo, P.; Anastas, P. T., Eds.; Oxford Uni-
versity Press: Oxford, 2000; pp. 221–244; (b) Varma, R.
S. In Green Chemical Syntheses and Processes; Anastas,
P. T.; Heine, L. G.; Williamson, T. C., Eds.; ACS Sym-
posium Series 767, American Chemical Society: Washing-
ton, D.C., 2000; pp. 292–312; (c) Varma, R. S. J.
Heterocyclic Chem. 1999, 35, 1565; (d) Varma, R. S.
Green Chem. 1999, 1, 43; (e) Varma, R. S. Clean Prod.
Process. 1999, 1, 132; (f) Varma, R. S. Pure Appl. Chem.
2001, 73, 193; (g) Varma, R. S.; Namboodiri, V. V. Pure
Appl. Chem. 2001, 73, 1309; (h) Jesˇelnik, M.; Varma, R.
S.; Polanc, S.; Kocevar, M. Chem. Commun. 2001, 1716;
(i) Jesˇelnik, M.; Varma, R. S.; Polanc, S.; Kocevar, M.
Green Chem. 2002, 4, 35; (j) Varma, R. S. Tetrahedron
2002, 58, 1235 and reference cited therein.
10. Dibenzhydryl ether: mp 106.5–107°C (lit. mp 107–
107.5);4a 1H NMR (250 MHz; CDCl3, TMS), lH: 5.39 (s,
PhC
128.46, 142.30.
6
H), 7.2–7.37 (m, Ph); 13C NMR lC 80.11, 127.36,
7. Stavber, S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355.