Preparation of fluorous DMF solvents and their use for some Pd-catalyzed cross-coupling reactions

Article abstract of DOI:10.1246/cl.2005.1548

N,N-Dimethylformamide derivatives 1a (Rf₆-DMF) and 1b (Rf ₈-DMF) with a C6 or C8 fluorous ponytail, respectively, have been synthesized and examined for some physical properties. Rf₆-DMF was tested as a solvent for Mizorok

Full text of DOI:10.1246/cl.2005.1548

1548
Chemistry Letters Vol.34, No.11 (2005)
Preparation of Fluorous DMF Solvents and Their Use
for Some Pd-catalyzed Cross-coupling Reactions
Hiroshi Matsubara,Ã Louis Maeda, and Ilhyong RyuÃ
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531
(Received August 30, 2005; CL-051113)
N,N-Dimethylformamide derivatives 1a (Rf6-DMF) and 1b
(Rf8-DMF) with a C6 or C8 fluorous ponytail, respectively, have
been synthesized and examined for some physical properties.
Rf6-DMF was tested as a solvent for Mizoroki–Heck arylation
of butyl acrylate and Sonogashira coupling reaction of iodoben-
zene with phenylacetylene. Both reactions proceeded as smooth-
ly as in DMF to give the products in high yield. Fluorous DMF
derivative 1a can be recovered easily from the reaction mixture
by a fluorous/organic biphasic workup and recycled.
MeNH2· HCl (10 eq)
TsCl
Rf
OH
Rf
OTs
K2CO3, CH3CN
reflux 24 h
pyridine
3a: 99%
3b: 92%
2a: Rf = C6F13
2b: Rf = C8F17
0 °C, 3 h
O
Rf
4a: 83%
NH
Me
H
OEt
1a: 85%
1b: 78%
reflux 20 h
4b: 84%
Scheme 1.
procedures outlined in Scheme 1. Fluorous alcohol 1H,1H,2H,
2H,3H,3H-perfluorononanol (2a) was converted to the corre-
sponding tosylate 3a in 99% yield, which was treated with ten
molar excesses of methylamine hydrochloride in the presence
of potassium carbonate in acetonitrile, giving secondary amine
4a in 83% yield. The amine 4a was treated with ethyl formate
to afford Rf6-DMF 1a in 85%. Rf8-DMF 1b was prepared by a
similar three-step procedure, which started with 1H,1H,2H,2H,
3H,3H-perfluoroundecanol (2b).
Rf6-DMF 1a is a colorless, clear, and slightly viscous liquid
with a boiling point of 110 ꢀC at 0.75 Torr, and a density of
1.544 g/cm3 (25 ꢀC), whereas Rf8-DMF 1b is a colorless semi-
solid with a melting point of 30 ꢀC. Rf6-DMF 1a does not freeze
at À35 ꢀC but transforms to a glassy state at À40 ꢀC. Since these
fluorous DMFs have a large substituent group at the nitrogen, ro-
tation barriers around the amide (C–N) bond are expected to be
higher than those of DMF. In fact, NMR spectra of 1a reveal that
signals assigned to methyl group on the nitrogen do not coalesce
even at 120 ꢀC. Fluorous DMFs are miscible with a wide range
of organic solvents, such as hexane, benzene, chloroform, ether,
acetone, ethyl acetate, and ethanol, however, they are poorly
soluble in cyclohexane and water. The approximate partition co-
efficients associated with biphasic treatment using a 1:1 mixture
of organic solvent/FC-72 (perfluorohexanes) were determined
for these newcomer solvents. We used a procedure similar to
that, which was previously reported by Curran et al.6 The results
The rapid evolution of fluorous chemistry1 requires effective
amphiphilic solvents that can dissolve both organic and fluorous
reagents, and which are easy to recycle via an organic/fluorous
biphase workup.2 We have recently reported that a fluorous ether
F-626 (1H,1H,2H,2H-perfluorooctyl-1,3-dimethylbutyl ether)3
(Chart 1) is a useful alternative to high-boiling point organic
solvents, yet can be recovered based on its fluorous nature by
an organic/fluorous biphasic workup.4 We also reported that a
Pd-carbene complex having a fluorous ponytail can be supported
in F-626, which allows for an efficient recycling system of the
reaction medium containing a catalyst.5 While F-626 is an ether
derivative, we are interested in some other fluorous amphiphilc
solvents having a polar functional group. To that end, we
chose as targets for study of DMF derivatives with a fluorous
ponytail. Herein, we report preparations and fluorous proper-
ties of fluorous DMF-type solvents, N-(1H,1H,2H,2H,3H,3H-
perfluorononanyl)-N-methyl formamide, ‘‘Rf6-DMF,’’ 1a and N-
(1H,1H,2H,2H,3H,3H-perfluoroundecyl)-N-methyl formamide,
‘‘Rf8-DMF,’’ 1b (Chart 2). We also report that the Mizoroki–
Heck and the Sonogashira reactions using ‘‘Rf6-DMF’’ 1a as a
solvent proceeded smoothly to give the coupling products in
good yields. Recycling and reuse of catalyst was achieved by
simple organic/fluorous biphasic workup of these reactions;
the second runs of the reactions gave the products in almost
the same yields as the first.
Fluorous DMFs 1a and 1b were synthesized according to the
Table 1. Partition coefficient (organic solvent/FC-72) of fluo-
rous DMF and F-626 between FC-72 with organic solventa
F
F F F F
F
O
F
Solvent
MeCN
MeOH
1a
1b
F-626 b
F
F
F
F
F F
c
1/0.078
1/0.05
1/1.13
1/0.46
1/8.30
1/0.10
1/0.20
1/0.13
—
—
1/7.3
1/3.8
1/1.6
F-626
c
C6H6
1/0.32
c
Chart 1.
c
Toluene
Cyclohexane
Acetone
AcOEt
—
1/7.35
—
F
F F F F
O
F
F
F
F
F
F
F F
O
F
F
1/1.89
1/1.1
1/0.85
1/0.85
c
c
F
—
—
—
F
N
H
N
H
c
F
F
F
F
F
F
F F
F
F
F F
F
Me
Me
c
CHCl3
"Rf -DMF": 1a
"Rf -DMF": 1b
8
6
aDetermined by gravimetric method at 20 ꢀC. Ref 4. Not
b
determined.
Chart 2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.11 (2005)
1549
are summarized in Table 1, in which those of F-626 are also
given for comparison.
DMF solution containing a fluorous catalyst was successfully
used for two more repeat experiments without reduction in the
yields of the product. Sonogashira reaction with the recycled
palladium catalyst was also able to achieve in Rf6-DMF, which
gave 81% yield of diphenylacetylene.
In summary, we have reported on preparation and some
physical properties of two types of fluorous DMFs 1a and 1b.
These have proven to have good potential as an easily recyclable
solvent alternative to original DMF for model Pd-catalyzed
cross-coupling reactions. Using Rf6-DMF 1a and an in situ pre-
pared fluorous Pd catalyst, it was demonstrated that a recyclable
solvent/catalyst system can be constructed. The development
of viable fluorous reaction media, which can replace organic
solvents, is actively pursued in this Laboratory.
Inspection of the results of Table 1 reveals some interesting
trends in partition coefficients of fluorous DMFs. Fluorous
DMFs 1a and 1b are less fluorous than F-626; however, the ma-
jority is distributed in FC-72 phase, when a nonpolar solvent
such as cyclohexane is used. This phenomenon can be explained
on that while the amide part of the fluorous DMFs should have
strong interaction with polar solvents, the fluorous alkyl chain
of the DMFs may have a significant role in the case of using
nonpolar solvents. Unexpectedly, 1b with a longer fluorous
ponytail shows less fluorous character than 1a. Poor solubility
of 1b in FC-72 might be the reason for the observed low fluorous
character. From the table, it is concluded that using biphasic
workup with cyclohexane/FC-72 as the organic/fluorous sol-
vents, fluorous DMFs will be extracted efficiently from the reac-
tion mixture into FC-72 layer.
Needless to say, DMF is a well known polar aprotic solvent
widely used for various organic and organometallic reactions.7
In order to assess whether fluorous DMFs could function as a
recyclable alternative to DMF, we decided to test the Mizoroki–
Heck arylation8 and the Sonogashira coupling reaction9 using
Rf6-DMF 1a. As shown in Scheme 2, both reactions proceeded
smoothly in Rf6-DMF as a solvent to give the desired coupling
products in good yields.
H.M. thanks Special Research Grant from Osaka Prefecture
University, 2004 and the Japan Society for the Promotion of
Science (JSPS) for financial support. I.R. appreciates the
Noguchi Foundation for partial financial support of this work.
We thank Daikin Industries, Ltd. for the generous gift of fluorous
reagents. We are gratefull to Ms Jilliarne Andropof for her useful
suggestions on the manuscript.
References
1
´
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O
Pd(OAc) (2 mol %)
2
O
I
PPh (2 mol %)
3
OBu
+
OBu
1.3 mmol
Pr N (1.5 mmol)
3
Rf -DMF (0.5 mL)
6
120 °C, 2 h
1 mmol
87%
Pd(OAc) (2 mol %)
2
´
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Pr NH (2.2 mmol)
2
Rf -DMF (0.5 mL)
6
80 °C, 2 h
1 mmol
1.5 mmol
83%
Scheme 2.
2
3
Next, we investigated a recyclable fluorous catalyst/solvent
system, which contains a fluorous palladium catalyst dissolved
in a fluorous DMF. As shown in Scheme 3, iodobenzene was
treated with butyl acrylate and tripropylamine in Rf6-DMF 1a
at 120 ꢀC for 2 h in the presence of 2 mol % of a fluorous palla-
dium carbene complex prepared in situ from palladium acetate,
triphenylphosphine, and fluorous imidazolium iodide.5,10 After
the reaction, a biphasic treatment (cyclohexane/FC-72 (perfluo-
rohexanes)) of the reaction mixture was carried out under a nitro-
gen atmosphere. From the cyclohexane phase, butyl cinnamate
was obtained in 93% yield after isolation by flash chromatogra-
phy, whereas the Rf6-DMF solution containing a fluorous cata-
lyst was recovered from the FC-72 phase by phase separation
and subsequent vacuum concentration. The recovered fluorous
4
5
6
7
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8
9
S. Brase and A. de Meijere, in ‘‘Metal-Catalyzed Cross-
¨
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I
C
F
10 21
N
N
2 mol %
O
O
I
Pd(OAc) , PPh 2 mol %
2
3
OBu
+
OBu
1.3 equiv.
Pr N 1.5 equiv.
3
Rf - DMF 0.5 mL
6
1.0 mmol
1st run 93%
2nd run 90%
3rd run 98%
120 °C, 2 h
10 J. H. Davis, Jr., K. J. Forrester, and T. L. Merrigan, Tetrahedron
Lett., 39, 8955 (1998); T. L. Merrigan, E. D. Bates, S. C.
Dorman, and J. H. Davis, Jr., Chem. Commun., 2000, 2051.
Scheme 3.
Published on the web (Advance View) October 15, 2005; DOI 10.1246/cl.2005.1548