Use of sonication for the coupling of sterically hindered substrates in the phenolic Mitsunobu reaction

Article abstract of DOI:10.1021/jo0345751

A vast rate increase in the Mitsunobu reaction of phenols with alcohols where either or both are sterically hindered has been achieved by the use of high concentration combined with sonication.

Full text of DOI:10.1021/jo0345751

slight preference for THF relative to the other solvents
tested. An increase in reaction temperature (to 40 and
55 °C) did enhance the rate of the coupling reaction giving
40-50% yields after 72 h. However, the warmed reac-
tions were accompanied by increased side product forma-
tion. Electron-deficient phosphines such as (m-chloro-
phenyl)3P, (p-fluorophenyl)3P, and (F5C6)3P exhibited no
improvement over triphenylphosphine. In the case of tri-
n-butylphosphine, no coupling product was obtained.
Use of Son ica tion for th e Cou p lin g of
Ster ica lly Hin d er ed Su bstr a tes in th e
P h en olic Mitsu n obu Rea ction
Salvatore D. Lepore* and Yuanjun He
Department of Chemistry, Florida Atlantic University,
Boca Raton, Florida 33431-0991
slepore@fau.edu
We also attempted to enhance the rate of the coupling
reaction by increasing the concentration. To achieve
efficient stirring, we found that the reaction concentra-
tion could not exceed 0.5 M (with respect to the phenol
substrate). More concentrated reaction mixtures were
simply too viscous for stirring with magnetic or mechan-
ical stirring equipment. Thus we initially turned our
attention to sonication5 as a means to achieve more
efficient mixing at higher reaction concentrations. At a
reaction concentration of 1.0 M combined with sonication,
the Mitsunobu reaction of methyl salicylate and neopen-
tyl alcohol gave coupling product 1 in 69% yield in 12 h.
When the concentration was further increased to 3.0 M
and submitted to sonication, coupling product 1 was
obtained in 75% yield in 15 min. Further sonication did
not lead to increased yields.
To define the scope and limitations of this new modi-
fication of the Mitsunobu reaction, a variety of phenols
and alcohols of varying degrees of steric congestion were
investigated. Thus mono- and di-o-substituted phenols
were reacted with cyclohexanol and neopentyl alcohol
(Table 1). As expected, coupling reactions involving
cyclohexanol at typical reaction concentrations (0.1 M
with respect to the phenol) were sluggish. In all cases,
high concentration combined with sonication resulted in
higher yields in 15 min than was observed with standard
Mitsunobu conditions over a 24-h period. Of particular
note is the coupling of methyl salicylate and cyclohexanol
(entry 5) yielding 85% of the coupling product under
sonication conditions. Over 5 days of reaction time was
required to achieve similar yields with standard condi-
tions (results not shown).
Received May 2, 2003
Abstr a ct: A vast rate increase in the Mitsunobu reaction
of phenols with alcohols where either or both are sterically
hindered has been achieved by the use of high concentration
combined with sonication.
The Mitsunobu reaction is extensively used in organic
synthesis for the preparation of alkyl aryl ethers under
mild conditions.1 The method has proven successful in
the coupling of a wide variety of phenol and alcohol
substrates and has been optimized for use in the solid
phase.2 However, the reaction is prohibitively slow in the
case of sterically hindered substrates.3 For example,
when we attempted the Mitsunobu reaction of methyl
salicylate with neopentyl alcohol to obtain compound 1,
a reaction time of 7 days was required to achieve
synthetically useful yields (70-75%). However, when the
reaction concentration was increased from 0.1 to 3.0 M
and submitted to sonication conditions, compound 1 was
obtained in 75% yield in only 15 min. In this report, we
demonstrate the utility of this variation of the Mitsunobu
reaction in the synthesis of a variety of hindered aryl
alkyl ethers.
The utility of the sonication approach is further
highlighted in the reaction of sterically hindered phenols
with neopentyl alcohol. Due to their high degree of steric
hindrance, neopentyl substrates generally undergo rear-
rangements and eliminations as electrophiles in SN2-type
reactions leading to significant side-product formation.6
We have observed that Mitsunobu reactions involving
neopentyl alcohols lead to minimal side product forma-
tion. However, under standard conditions, these coupling
reactions are prohibitively slow. For example, the cou-
pling reaction of neopentyl alcohol and o-tert-butyl phenol
(Entry 7) gave only a trace amount of product after 24 h
In our initial attempts to reduce reaction times in the
methyl salicylate/neopentyl alcohol coupling reaction,
several reported variations to the original Mitsunobu
reaction were examined. These included solvent (THF,
DMF, benzene, and dioxane), temperature, and various
phosphines.4 We observed that rate of the coupling
reaction was only moderately solvent dependent with a
(1) Mitsunobu, O. Synthesis 1981, 1.
(2) (a) Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994, 35, 4705.
(b) Lizarzaburu, M. E.; Shuttleworth, S. J . Tetrahedron Lett. 2002,
43, 2157.
(3) For other examples of prohibitively slow Mitsunobu coupling
reactions see: (a) Marchand, A. P.; Dave, P. R. J . Org. Chem. 1988,
53, 1212. (b) Marchand, A. P.; Dave, P. R. J . Chem. Soc., Perkin Trans.
1 1981, 124. (c) Marchand, A. P.; Dave, P. R. Tetrahedron Lett. 1989,
30, 2297.
(5) The sonication reactions described involve the partial submersion
of the reaction vessel into an ultrasonication bath at room temperature.
The model used in this study was a Mettler Electronics model 4.6 (40
kHz).
(6) Although recent modifications to the Williamson ether synthesis
reaction have led to improved results: (a) Masada, H.; Gotoh, H.;
Ohkubo, M. Chem. Lett. 1991, 10, 1739. (b) Masada, H.; Yammamoto,
T.; Yamamoto, F. Nippon Kagaku Kaishi 1995, 12, 1028.
(4) Camp, D.; J enkins, I. D. Aust. J . Chem. 1992, 45, 47.
10.1021/jo0345751 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/12/2003
J . Org. Chem. 2003, 68, 8261-8263
8261

TABLE 1. Com p a r ison of Son ica tion ver su s Sta n d a r d
Con d ition s for th e Mitsu n obu Rea ction of Ster ica lly
Hin d er ed P h en ols w ith Neop en tyl Alcoh ol a n d
Cycloh exa n ol
reasons for the dramatic increase in reaction rate that
results from high concentration and sonication are not
entirely clear. The rate acceleration effect observed with
our protocol may simply be based on the high concentra-
tion with the sonic waves providing efficient mixing of
the highly viscous reaction mixture and generating
localized hot spots.8 However, the cavitation effects of
sonication have also been attributed to the generation
of coordinatively unsaturated species or free radicals9
leading to the identification of sonochemically enhanced
radical pathways in a variety of well-known reactions.10
Since radical intermediates have been observed in the
Mitsunobu reaction,11 the observed rate increase result-
ing from sonication may be, in part, the result of an
enhancement of a radical reaction pathway. Studies to
investigate the origin of the rate enhancement in the
Mitsunobu reaction are currently underway.
In summary, the Mitsunobu coupling reaction of steri-
cally hindered phenols and alcohols is greatly accelerated
by the use of high reaction concentrations in combination
with sonication.
Exp er im en ta l Section
Rep r esen ta tive Exp er im en ta l P r oced u r e. To a round-
bottomed flask was added 2,6-dimethylphenol (500 mg, 4.10
mmol), neopentyl alcohol (378 mg, 4.30 mmol), triphenylphos-
phine (1.13 g, 4.30 mmol), and THF (1.4 mL). The reaction vessel
was then lowered into a 40-kHz sonication bath (Mettler
Electronics model 4.6) and sonicated for several minutes (to
allow for mixing) giving a clear and highly viscous solution.
While sonicating, diisopropylazodicarboxylate (0.854 mL, 4.30
mmol) was added dropwise to the reaction mixture over the
course of 2 min. Overall, the reaction mixture (amber color) was
sonicated for 15 min. The reaction mixture was triturated with
a minimal amount of cold hexanes (3 mL) to remove the majority
of the triphenylphosphine oxide byproduct. The hexane mixture
was then purified by flash chromatography (silica gel, 3% EtOAc
in hexanes) to give 2,6-dimethylphenyl neopentyl ether (Table
a
All yields shown are for products obtained pure with silica
b
gel flash chromatography. See Experimental Section for a rep-
resentative procedure. c Same stoichiometry as sonication condi-
tions except 0.1 M in solvent and slow addition of DIAD to the
reaction mixture at 0 °C with warming to room temperature.
Reported yields are after 24 h.
at typical reaction concentrations. With the use of high
concentration and sonication, o-tert-butyl phenol was
coupled to neopentyl alcohol in 39% isolated yield after
15 min of reaction. Similar rate enhancements were seen
in the coupling of neopentyl alcohol with o-methyl and
o-trifluoromethyl phenol (Entries 6 and 8), 2,6-dimeth-
ylphenol (Entry 9), and methyl salicylate (Entry 10). As
in the case of the Mitsunobu reaction of methyl salicylate
and neopentyl alcohol described above, increasing the
sonication time for the reactions reported in Table 1 did
not lead to discernible improvement in yields. The
sonication reactions seemed to have reached their ulti-
mate yields in 10 to 15 min.
1
1, Entry 9) (331 mg, 42%) as an oil. H NMR (500 MHz, CDCl3)
δ 7.01 (d, J ) 7.5 Hz, 2H), 6.92 (m, 1H), 3.42 (s, 2H), 2.29
(s, 6H), 1.11 (s, 9H). HRMS calcd for C13H20O 192.1515, found
192.1506.
The following aryl ethers from Table 1 have been reported in
the literature: Entry 1,12 Entry 4,13 Entry 5,14 Entry 6,15 and
Entry 7.16 Characterization data for new compounds are given
below.
2-(ter t-Bu tyl)p h en yl cycloh exyl eth er (Table 1, Entry 2):
1H NMR (500 MHz, CDCl3) δ 7.29 (d, J ) 7.0 Hz, 1H), 7.14 (d,
(8) Suslick, K. S.; Hammerton, D. A.; Cline, R. E. J . Am. Chem. Soc.
1986, 108, 5641.
Our modification to the Mitsunobu reaction has been
successfully applied to coupling reactions ranging from
the milligram to near-gram scales. However, due to the
explosive hazards of azodicarboxylates, we do not recom-
mend that the sonication procedure described in this
report be used for reaction scales larger than 2 g unless
precautions are taken to remove excessive heat buildup
during the reaction.
(9) Luche, J . L.; Einhorn, C.; Einhorn, J . Tetrahedron Lett. 1990,
31, 4125.
(10) A number of investigations have identified the origin of
sonochemical rate enhancement in reactions such as the following: (a)
Diels-Alder: Caulier, T. P.; Reisse, J . J . Org. Chem. 1996, 61, 2547.
(b) Barbier: Souza-Barboza, J . C.; Pe´trier, C.; Luche, J . L. J . Org.
Chem. 1988, 53, 1212. (c) Epoxide reductions: Moreno, M. J . S.; Melo,
M. L.; Neves, A. S. C. Tetrahedron Lett. 1993, 34, 353.
(11) (a) Camp, D.; Hanson, G. R.; J enkins, I. D. J . Org. Chem. 1995,
60, 2977. (b) Eberson L.; Persson, O.; Svensson, J . O. Acta Chem.
Scand. 1998, 52, 1293.
(12) Abdurasuleva, A. R.; Israilova, Sh. A. Zh. Obshch. Khim. 1962,
32, 704.
(13) Pauson, P. L.; Dalgleish, D. T.; Nonhebel, D. C. J . Chem. Soc.
Sect. C (Organic) 1971, 6, 1174.
While the mechanism for the Mitsunobu reaction has
been studied in detail by numerous investigators,7 the
(7) The following references describe studies of the Mitsunobu
reaction mechanism: (a) Ahn, C.; Correia, R.; DeShong, P. J . Org.
Chem. 2002, 67, 1751 (also see corrections: J . Org. Chem. 2003, 68,
1176). (b) Camp, D.; J enkins, I. D. J . Org. Chem. 1989, 54, 3045. (c)
Hughes, D. L.; Reamer, R. A.; Bergan, J . J .; Grabowski, E. J . J . Am.
Chem. Soc. 1988, 110, 6487.
(14) Eisner, A.; Perlstein, T.; Ault, W. C. J . Am. Oil Chem. Soc. 1963,
40 (10), 594.
(15) Seyden-Penne, J .; Habert-Somny, A.; Cohen, A. M. Bull. Soc.
Chim. France 1965, 3, 700.
(16) Masada, H.; Yammamoto, T.; Yamamoto, F. Nippon Kagaku
Kaishi 1995, 12, 1028.
8262 J . Org. Chem., Vol. 68, No. 21, 2003

J ) 7.0 Hz, 2.0 Hz, 1H), 6.84 (m, 2H), 4.38 (m, 1H), 2.02 (m,
2H), 1.82 (m, 2H), 1.63 (m, 4H), 1.47 (m, 2H), 1.40 (s, 9H). HRMS
calcd for C16H24O 232.1827, found 232.1836.
1H), 7.42 (m, 1H), 6.93 (m, 2H), 3.90 (s, 3H), 3.66 (s, 2H), 1.07
(s, 9H). HRMS calcd for C13H18O3 222.1256, found 222.1251.
Ack n ow led gm en t. The authors would like to thank
Eli Lilly and company for a generous donation of
equipment and the Daniel B. and Aurel B. Newell Fund
for a doctoral fellowship to Y.H.
2-Tr iflu or om eth ylp h en yl cycloh exyl eth er (Table 1, En-
try 3): 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J ) 8.0 Hz, 1H),
7.44 (m, 1H), 6.99 (d, J ) 9.0 Hz, 1H), 6.94 (m, 1H), 4.42 (m,
1H), 1.90 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H), 1.39 (m, 4H).
HRMS calcd for C13H15F3O 244.1075, found 244.1063.
2-Tr iflu or om eth ylp h en yl n eop en tyl eth er (Table 1, Entry
8): 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J ) 8.0 Hz, 1H), 7.46
(m, 1H), 6.97 (m, 2H), 3.66 (s, 2H), 1.07 (s, 9H). HRMS calcd for
C12H15F3O 232.1075, found 232.1071.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds given in Entries 2, 3, 8, 9, and 10 of Table 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2-(Meth oxyca r bon yl)p h en yl n eop en tyl eth er (Table 1,
Entry 10): 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J ) 7.5 Hz,
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