Grignard cross-coupling amenable to large scale production of α-fluorostyryl and α-fluorovinylthiophenes

Article abstract of DOI:10.1021/jo801647x

(Chemical Equation Presented) An efficient nickel-catalyzed Kumada-Corriu cross coupling enabled the introduction of an α-fluorovinyl functionality with excellent conversion and specificity.

Full text of DOI:10.1021/jo801647x

Grignard Cross-Coupling Amenable to Large
Scale Production of r-Fluorostyryl and
r-Fluorovinylthiophenes
Jian Qiu,† Albert Gyorokos,† Theodore M. Tarasow,‡ and
Joseph Guiles*,†
Replidyne Inc., 1450 Infinite DriVe,
LouisVille, Colorado 80027, and Tethys Bioscience,
EmeryVille, California
jguiles@replidyne.com
FIGURE 1. Example of type i and type ii coupling reactions.
ReceiVed July 24, 2008
couple with a fluorovinylhalide is referred to as a type ii process.
This strategy has been described for the Pd-catalyzed cross-
couplings with organoboranes or organostannanes.8 (Figure 1).
This approach has broadened the scope of the original vinyl to
aryl C-C bond formation to include vinyl to vinyl and vinyl to
alkyl bonds but has only been described in the case of a
ꢀ-fluorosubstituted styrene substrate. Another type ii process
via an atypical Heck Pd-catalyzed coupling has been described
for the arylation of iodobenzene9 or 5-iodotosylindole10 with
di or trifluoroethylene. In both cases moderate to high yields
were achieved but reaction conditions required high temperature
and developed very high pressure that required special apparatus
and thus pose extra challenges for industrialization.
An efficient nickel-catalyzed Kumada-Corriu cross coupling
enabled the introduction of an R-fluorovinyl functionality
with excellent conversion and specificity.
In both of the type i and type ii approaches, the metallo
species is prepared as a separate entity and thus bears the burden
of extra manufacturing time and/or costs. In general boron, tin,
zirconium or silicon containing reagents are less common and
as a consequence are higher cost than a similar alkaline earth
containing reagent (e.g., Grignard). The Grignard reagent is an
extremely important reagent in the formation of C-C bonds
and has been employed in a large variety of nucleophilic
substitution reactions.11 In 1972 Kumada,12 Corriu,13 and co-
workers described an important C-C bond forming Grignard
cross-coupling that has been used in a wide range of industrial
fields since these early disclosures of this powerful method.
Recently, Banno et al.14 have described a type ii Grignard cross-
coupling process for the industrial scale production of p-
chlorostyrene. Described herein is a type ii nickel-catalyzed
coupling between an aryl Grignard species and a R-fluoro,R-
haloethylene (Figure 2) that expands the utility of this method
substantially. The method has been studied for its generality
and specificity with regard to sensitive functional groups in
The fluorovinyl group constitutes a useful synthetic func-
tionality that has been introduced into several types of com-
pounds to elicit improved pharmaceutical qualities. Most notable
is the use of a fluorovinyl group as an amide bond isostere.1
More recently 1-ary1-1-fluorovinyl compounds bearing an
unsubstituted terminal 1-fluorovinyl group have been sited as
mechanism-based enzyme inhibitors,2 and as key functionality
in synthetase inhibitors being developed as topical antibacterial
agents.3 Two general C-C bond-forming strategies for the
assembly of R-fluorostyryls have been reported. These may be
generally classified as a type i process in which a transition
metal mediated cross coupling is carried out between a metallo-
vinyl species and an aryl halide. This strategy has been described
for the Pd-catalyzed cross-couplings of fluorovinylzinc reagents,4
fluorovinylstannanes,5 vinylzirconocenes,6 and most recently
with vinylsilanes.7 A reversal of the coupling partners that
employs a metallo-species (e.g., aryl, alkyl, alkenyl) to cross-
* To whom correspondence should be addressed. Tel.: 303-996-5549. Fax:
303-996-5599.
† Replidyne Inc.
‡ Tethys Bioscience.
(6) Fujiwara, M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett.
1999, 40, 7261.
(7) Hanamoto, T.; Kobayashi, T. J. Org. Chem. 2003, 68, 6354.
(8) Chen, C.; Wilcoxen, K.; Huang, C. Q.; Strack, N.; McCarthy, J. R. J.
Fluor. Chem 2000, 101, 285.
(9) Heitz, W.; Knelbelkamp, A. Makromol. Chem. Rapid Commun. 1991,
12, 69.
(1) Allmendinger, T.; Furet, P.; Hungerbu¨hler, E. Tetrahedron Lett. 1990,
31, 7297.
(2) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber, E. W.; Bey,
P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am. Chem. Soc. 1991, 113,
7439. (b) Mathews, D. P.; Gross, R. S.; McCarthy, J. R. Tetrahedron Lett. 1994,
35, 1027.
(3) Critchley, I. A.; Young, C. L.; Stone, K. C.; Ochsner, U. A.; Guiles,
J. W.; Tarasow, T.; Janjic, N. Antimicrob. Agents Chemother. 2005, 49 (10),
4247.
(4) Heinze, P. L.; Burton, D. J. J. Org. Chem. 1988, 53, 2714.
(5) Mathews, D. P.; Wald, P. P.; Sabol, J. S.; McCarthy, J. R. Tetrahedron
Lett. 1994, 35, 5177. (b) Chen, C.; Wilcoxen, K.; Kim, K.; McCarthy, J. R.
Tetrahedron Lett. 1997, 38, 7677. (c) Chen, C.; Wilxocen, K.; Zhu, Y.-F.; Kim,
K.; McCarthy, J. R. J. Org. Chem. 1999, 64, 3476.
(10) Gharat, L. A.; Martin, A. R. Heterocycles 1996, 43, 185.
(11) March′s AdVanced Organic Chemistry, 5th ed.; Smith, M. B., March,
J., Eds.; John Wiley & Sons: New York, 2001.
(12) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374.
(13) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc. Chem. Commun. 1972, 144.
(14) Banno, T.; Hayakawa, Y.; Umeno, M. J. Organomet. Chem. 2002, 653,
288–291.
10.1021/jo801647x CCC: $40.75
Published on Web 11/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9775–9777 9775

TABLE 1. Halogen and Catalyst Study
entry
R-fluoro, R-X-ethylene X
catalyst-M
yield (%) 3
FIGURE 2. Example of Grignard type ii coupling reaction.
1
2
3
4
5
6
7
8
9
10
F
NiCl2
NiCl2
NiCl2(dppp)
NiCl2
Ni(acac)2
Ni(COD)2
Ni on C
Pd(dba)2
Co(OAc)2
FeCl2
15-20
30-60
80-90
80-90
80-90
30-50
80-90
0
Cl
Br
Br
Br
Br
Br
Br
Br
Br
producing highly substituted phenyl or thiophene R-fluorovinyl
derivatives. In one particular substrate, a highly functionalized
thiophene, this method was employed at multikilo scale. To our
knowledge, a Grignard type method for the synthesis of
R-fluorostyrenes or R-fluorovinylthiophenes has not been dis-
closed and would serve as an important new option for the
introduction of this key functional group.
The goals of the study were several, identify process
conditions that would (a) be applicable to demanding substrates
with sensitive functionality (b) short reaction times, (c) labor
efficient, (d) high yield, (e) low energy demand, and (f) avoid
special apparatus (e.g., high temperatures and pressures). A
variety of reaction parameters including reactant types were
studied in the development of this methodology. The R-fluoro-R-
haloethylene substrate and the transition-metal catalyst had a
profound effect on reaction outcome. Other parameters such as
solvent and temperature played a lesser role but were also
studied.
<20
25-30
Mild temperature conditions of 0-5 °C were found optimal
for the efficient formation of the aryl Grignard species and the
subsequent cross-coupling reaction. In the case when R,R-
difuoroethylene was utilized, the coupling reaction was started
at -78 °C and slowly raised to ambient. Elevated temperatures
or pressures were not studied as they were not required for good
conversion and were anticipated to lead to side reactions or
reaction/degradation of the desired product. Care was taken in
the generation of aryl Grignard species to avoid moisture and
oxygen and generally required 2-3 h for complete formation.
Standard 1 or 2 M THF solutions of isopropyl or ethylmagne-
sium chloride were utilized to generate the aryl Grignard species.
The Grignard species is very stable in THF but did not promote
high yield in the subsequent cross-coupling step. Nonpolar
cosolvents, in particular toluene, gave reliable high yields. The
two-step one pot transformation was found to proceed to
completion in generally 6-8 h.
The commercial availability of R-fluoro, chloro, and bromo
R-fluoroethylenes, 1, allowed the facile study of halogen effect
on reaction outcome. In our case, the highly substituted
thiophene acetal 2 was utilized to investigate the halogen effect
on coupling outcome. Both R-fluoro and R-chloro R-fluoroet-
hylene were reactive, but gave higher amounts of proton
quenched substrate, 4, in comparison to R-bromo-R-fluoroet-
hylene. Overall the coupling reaction was found to proceed best
in the order Br > Cl > F (Table 1).
FIGURE 3. Proposed mechanism of coupling reaction.
carbon was also studied; however, the results were found
comparable to that of unsupported nickel (II) chloride.
Interestingly, the Pd catalyst studied was completely nonre-
active under the conditions employed. Other Pd(0) and Pd(II)
species were not tried. One possible explanation is that sterically
crowded aryl Grignard species, such as those studied in this
work, are less reactive and require a reasonably electrophilic
metal species such as a nickel (Figure 3.). Palladium (II)
fluorovinyl intermediates have previously been proposed as
moderately active electrophiles.8 Single examples from the
Group 9, cobalt acetate, and Group 10 iron chloride were
studied. Fe(II) chloride did provide reasonable catalytic activity
but significantly lower than nickel species. The overall reactivity
of the metal catalyst was found to be Ni > Co ) Fe > Pd. The
amount of catalyst was also studied and herein it was determined
that g0.005 equiv of NiCl2 provided maximal conversion.
A study was also conducted with R,R-difuoroethylene to
determine the feasibility of utilizing this low cost feedstock gas.
Lower reaction temperatures were utilized to avoid the genera-
tion of high pressures while working with this gas. This reaction
partner differed in reactivity with that of its higher halogen
congeners. In particular Ni(II) catalysts with phosphine ligands
were found to provide somewhat improved yield over ligand-
less Ni(II). The yield was relatively good, 60%, but the amount
of uncoupled product, approximately 30% was significant. In
the case of this particular product it was also difficult to separate
from the desired product. These results reflect that this low cost
fluorovinyl synthon is suitably reactive and should be evaluated
as a raw material on a case by case basis.
Early work in our laboratories had revealed that Ni(II) carbene
ligand catalysts gave equivalent conversion to Ni(II) catalyst
without any ligand (e.g., ligand-less) when cross coupling with
R-bromo-R-fluoroethylene. A study was conducted of repre-
sentative d8 metals of Groups 8-10 to search for an optimal
catalyst species (Table 1). In this survey it was found that a
Ni(II) species, which gets reduced in situ to the catalytically
active Ni(0) oxidation state by aryl Grignard, was superior to
using a preformed Ni(0) species, such as the capricious
Ni(COD)2. The use of a solid supported nickel (II) catalyst on
The generality of the cross-coupling reaction with representa-
tive examples of aryl iodides, aryl bromides, and bro-
mothiophenes was studied using the optimized reaction condi-
9776 J. Org. Chem. Vol. 73, No. 24, 2008

TABLE 2. Catalyst Study with r,r-Difuoroethylene
substituted heterocycles of biological interest or in the industrial
scale manufacture of fluorostyrl monomers for fine chemical
or polymer chemistry uses.
Experimental Section
4-Bromo-5-(1-fluoroethenyl)-3-methylthiophene-2-carboxalde-
hyde 3. To a 3 L, three necked, round-bottom flask equipped with
a mechanical stirrer, nitrogen inlet, thermometer and addition funnel
was added 75.0 g (227.25 mmol) of 2,3-dibromo-4-methyl-5-
dimethoxymethyl thiophene followed by 600 mL of anhydrous
toluene under a nitrogen atmosphere. The clear, colorless solution
was cooled to 5 °C with an ice-bath and 123.0 mL (258.3 mmol,
1.15 equiv, 2.1 M solution, titrated) of ethylmagnesium chloride
in tetrahydrofuran added while maintaining the reaction temperature
below 11 °C. (addition took approximately 30 min). After complete
addition, the reaction was stirred in the ice-bath for 2.5 h. After
2 h, an aliquot was drawn, quenched with methanol and analyzed
by HPLC. No starting dibromothiophene adduct was present. Nickel
chloride (0.15 g, 1.16 mmol, 0.005 equiv) was then added followed
by 115.0 mL (274.85 mmol, 1.21 equiv of a 2.39 M solution in
toluene) of 1-bromo-1-fluoroethylene.(the solution was prepared
by bubbling 1-bromo-1-fluoroethylene in a flask cooled in an ice
bath containing a known amount of toluene. The flask was weighed
before and after addition to determine quantity added and then a
molarity calculated) The mixture was stirred in the ice-bath while
monitoring by HPLC. After 3 h, HPLC analysis of an aliquot drawn
and quenched with methanol indicated less than 1% of the
monobromo thiophene adduct resulting from halogen-metal
exchange.
The reaction was quenched with the addition of 200 mL (400.0
mmol) of 2 M hydrochloric acid. The mixture was stirred at room
temperature while monitoring for completion of hydrolysis of the
acetal by HPLC. After less than 10% acetal remained, the reaction
was diluted with 200 mL of water and the organic phase separated.
The organic phase was washed with water (200 mL) and the
combined aqueous layers extracted with 250 mL of ethyl acetate.
The combined organic layers were concentrated under reduced
pressure to afford 56.5 g (99.8%) of crude FVT as a yellow-orange
solid.
entry
catalyst-M
ligand
ratio 3:4
1
2
3
4
5
NiCl2 or Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
no
A
B
C
D
0
0
64:36
14:86
15:85
tions. Representative substituents of both electron withdrawing
and electron donating nature were investigated. In general, the
reaction afforded higher yield with electron withdrawing groups
versus electron donating groups. Notable in the group is that a
highly substituted substrate was selectively converted in high
yield to the desired fluorostyryl product 6. It is worth noting
that the manner in which the aryl Grignard is generated must
be taken into account with highly functionalized substrates.
Specifically, transmetalation of aryl lithium species generated
by the reaction of alkyl lithium with a substituted aryl iodide
or bromide precursor gave much lower yields compared to
transmetalation via alkyl Grignard.
In summary, we have developed an expedient synthesis of
R-fluorostyryls and R-fluorothiophenes via a Kumada-Corriu
type Ni-catalyzed cross coupling reaction. The process ac-
complished key constraints in allowing for sensitive functionality
to be tolerated, low cost equipment and starting materials to be
used and overall high yields achieved. This process may hold
applicability as technique in the synthesis of other fluorovinyl-
Recrystallization of 4-Bromo-5-(1-fluoroethenyl)-3-methylth-
iophene-2-carboxaldehyde 3 [FVT] with 30% Charcoal. To a 500
mL round-bottom flask equipped with heating mantle, nitrogen inlet,
magnetic stirrer, condenser and thermometer was added the crude
FVT (28.0 g) followed by 275 mL of heptane and 50 mL of toluene.
The mixture was heated to 80 °C. To the clear amber color solution
was added 9.0 g of decolorizing charcoal and stirring continued at
80 °C for 30 min. The mixture was filtered through a pad of celite
503 (previously washed with heptane) and the filter cake rinsed
with 50 mL of hot heptane (80 °C). The filtrate (clear yellow color)
was allowed to stand at room temperature and then placed in an
ice-bath for 15 min. The solids were filtered, washed with 150 mL
of heptane, and dried under vacuum to afford 18.95 g (67.7%) of
product as a pale-yellow solid.
TABLE 3. Coupling Reaction with Various Iodo and Bromo
Substrates
Acknowledgment. This work is dedicated to the memory of
A. I. Meyers who touched so many people with his love of life
and chemistry. We thank Professor Lou Hegedus for helpful
discussions during the course of this work.
compd
R
yield (%) A
yield (%) B
4
5
6
7
4-CO2Me
4-OMe
2-OEt, 3-CH(OMe)2, 5-Br
2,3-diBr
70
52
67
na
na
na
na
80
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801647X
J. Org. Chem. Vol. 73, No. 24, 2008 9777