Table 8. Grignard reactions in MeTHF and THF
% yielda
addition
% yield
addition
product in product in
Figure 3. Nickel cross-coupling.
halide reagent
bromobenzene
chlorobenzene
1-chlorobutane
benzylbromide
electrophile
MeTHF
THF
to work like THF as a solvent in the Ni-catalyzed coupling
of alkynylzinc bromides with nitriles.16 MeTHF was found
to give better diastereoselection than THF in a series of
copper-mediated biaryl couplings.17 An illustrative example
of nickel-mediated cross-coupling with MeTHF is shown in
Figure 3.
butanal
butanal
MEK
75
71
73
76
58
75
73
76
72
20
12
78
MEK
2-chlorobenzyl chloride MEK
2-bromofuran
triethylborate
a Nonisolated yields
Biphasic Reactions in MeTHF
MeTHF is finding applications as a replacement for highly
regulated chlorinated solvents like dichloromethane in bi-
phasic reactions. MeTHF can often be used as a direct
replacement for dichloromethane and was shown to give high
reactivity when used in several biphasic reactions.18 The
advantages of MeTHF compared to dichloromethane are that
it has a moderate bp, is more resistant to reactions with
nucleophiles like amines, and provides clean organic-water
phase separations. MeTHF has been used as a solvent in two-
phase displacement reactions with allylbromide19 and to
remove BOC from an amine group with an aqueous base
mixture.20 MeTHF was used as the solvent in a reductive
amination process that first involved freeing-up an aldehyde
from its sulfite adduct using aqueous NaOH then azeotro-
pically drying the aldehyde with MeTHF before carrying out
the reductive amination in MeTHF.21
Our work has shown that MeTHF is a very effective
solvent for extracting polar compounds from water mixtures.
For example, two extractions with equal portions of MeTHF
removed about 94% of 2-propanol from water, but under
the same conditions only 68% of 2-propanol was removed
with toluene. This behavior was also seen in the efficient
extraction of a water-soluble carbamate in a process where
MeTHF was used to react an amine with dimethyl carbon-
ate.22
Figure 2. Lithium exchange in MeTHF.
than in THF. This solubility difference is reflected in the
high solubility of anhydrous magnesium bromide in MeTHF
(>40 g/100 g) compared to 7 g/100 g MgBr2 soluble in THF.
The high solubility of MgBr2 in MeTHF means that highly
concentrated homogeneous solutions of bromo Grignard
reagents can be prepared. For example, 4.5 M ethylmagne-
sium bromide and 4.0 M phenylmagnesium bromide homo-
geneous solutions can be made in MeTHF at 25 °C (both
are viscous solutions). Following this trend, about 10 g/100
g of MgI2 dissolves in MeTHF at rt but <0.1 g/100 g is
soluble in THF.
Reformatsky Reaction. MeTHF has also been used as a
solvent for the Reformatsky reaction.12 The high solubility
of ZnBr2 in MeTHF (measured in our labs at >40 g/100 g
at 25 °C) means MeTHF should be a good solvent for
formation of zinc reagents by reaction of ZnBr2 with
Grignard or lithium reagents.
Lithiation Reactions. MeTHF is a good solvent for low-
temperature lithiation reactions because of its low mp, low
viscosity at low temperatures, and similar Lewis base strength
as THF. Figure 2 shows an illustrative example of lithium
exchange of n-butyllithium with 3-bromofuran at -70 °C
in MeTHF, followed by reaction with DMF to give 3-fural-
dehyde.
MeTHF is reported to be more stable than THF to some
lithium reagents.13,14 A comparison study of the stability of
n-butyllithium in MeTHF and THF showed a 70 min half-
life in MeTHF and a 10 min half-life in THF at 35 °C.15
Hydride Reductions. LiAlH4 has good solubility in
MeTHF (at least 1.8 M), and our results showed similar
product yields as found in THF for a survey of aldehydes,
esters, and acids reduced with LiAlH4.
Conclusions
2-Methyltetrahydrofuran can be used as a solvent for most
organometallic reactions that require a strong Lewis base
like THF. When MeTHF is used to replace THF in
organometallic reaction processes, it can conveniently be
used to recover the reaction product because it is only
partially water miscible. The MeTHF/water azeotrope can
be used to dry the reaction product for subsequent process
steps and to recycle dry MeTHF. MeTHF can also be used
as an efficient replacement for dichloromethane in biphasic
(16) Miller, J.; Penney, J. U.S. Patent 20050137402.
(17) Krishnan, S.; Schreiber, S. Organic Letters 2004, 6 (22), 4021. Spring, D.;
Krishnan, S.; Schreiber, S. J. Am. Chem. Soc. 2000, 122 (23), 5656.
(18) Ripin, D.; Vetelino, M. Synlett 2003, 15, 2353.
(19) Ripin, D.; Vetelino, M.; Wei, L. U.S. Patent 20050026940.
(20) Tom, N.; Ripin, D.; Castaldi, M. U.S. Patent 20050020625.
(21) Ragan, J.; Ende, D.; Brenek, S.; Eisenbeis, S.; Singer, R.; Tickner, D.;
Teixeira, J.; Vanderplas, B.; Weston, N. Org. Process Res. DeV. 2003, 7,
155.
Coupling Reactions. THF is often used as the solvent
for many metal-catalyzed coupling reactions, and MeTHF
should also work well in these reactions. MeTHF was found
(12) Nuwa, S.; Handa, S.; Miki, S. U.S. Patent 20050043544.
(13) Hintze, M.; Wen, J. U.S. Patent 6861011.
(14) Hage, M.; Ogle, C.; Rathman, T.; Hubbard, J. Main Group Metal Chemistry
1998, 21 (12), 777.
(22) Cai, W.; Colony, J.; Frost, H.; Hudspeth, J.; Kendall, P.; Krishnan, A.;
Makoski, T.; Mazur, D.; Phillips, J.; Ripin, D.; Ruggeri, S.; Stearns, J.;
White, T. Org. Process Res. DeV. 2005, 9, 51.
(15) Bates, R. J. Org. Chem. 1972, 37 (4), 560.
158
•
Vol. 11, No. 1, 2007 / Organic Process Research & Development