Stereospecific synthesis of (E)-α,β-difluorostyrenes

Article abstract of DOI:10.1016/S0040-4039(00)01433-7

Isomerically pure (Z)-HFC=CFZnI undergoes Pd(PPh₃)₄/CuBr co-catalyzed cross-coupling reactions with aryl iodides in DMAC to give the title compounds in good yields, under mild conditions. In the absence of CuBr, the reaction is slugg

Full text of DOI:10.1016/S0040-4039(00)01433-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8045–8048
Stereospecific synthesis of (E)-a,b-difluorostyrenes
Qibo Liu and Donald J. Burton*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 21 June 2000; accepted 23 August 2000
Abstract
Isomerically pure (Z)-HFCꢀCFZnI undergoes Pd(PPh ) /CuBr co-catalyzed cross-coupling reactions
3
4
with aryl iodides in DMAC to give the title compounds in good yields, under mild conditions. In the
absence of CuBr, the reaction is sluggish, requires more vigorous reaction conditions, and gives lower
yields. © 2000 Elsevier Science Ltd. All rights reserved.
Fluorinated styrenes are useful building blocks in organofluorine chemistry and have found
1
2
3
applications as monomers, and as precursors for antiinflammatory and antifertility com-
pounds. Previous reports from our laboratories have described the general preparation of
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a,b,b-difluorostyrenes, 1-arylperfluoropropenes, b,b-difluoro-a-(trifluoromethyl)styrenes, and
Z)-a,b-difluorostyrenes, by the corresponding Pd(PPh ) catalyzed arylation of the thermally
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(
3
4
stable
perfluorovinylzinc
reagents,
CF ꢀCFZnX,
(Z)
and
(E)-CF CFꢀCFZnX,
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3
CF (ZnX)CꢀCF , and (E)-HFCꢀCFZnI. A few reports have described the formation of (E)-a,b-
difluorostyrenes; however, a general and stereospecific preparation of these compounds has not
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2
been reported. Low temperature metallation of several isomeric b,b-difluoro-a-chlorostyrenes
with an alkyllithium reagent followed by hydrolysis has been reported to give predominantly
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(
E)-a,b-difluorostyrenes. Protodesilylation of (Z)-1,2-difluoro-3-arylvinylsilanes with KF/H O
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gave (E)-a,b-difluorostyrenes. In the chemical literature, the palladium catalyzed coupling
reaction (Stille reaction) of an organobromide or iodide with organostannane or zinc reagents
has been well documented. In general, the Stille reaction with an organostannane needs a Cu(I)
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salt as a co-catalyst. However, only one report has noted co-catalysis of a Cu(I) salt in the Stille
1
0
reaction with an organozinc reagent.
We now report a general and stereospecific method for the preparation of (E)-1,2-
difluorostyrenes. This method utilizes isomerically pure (Z)-HFCꢀCFZnI coupling with aryl
iodides in DMAC under Pd(PPh ) /CuBr co-catalysis. (Z)-HFCꢀCFZnI, 3, was prepared via a
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two-step procedure as described below.
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01433-7

8046
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Via a modification of Normant’s procedure, (Z)-HFCꢀCFI, 2, was prepared in 79% yield
via protodesilylation of 1 with KF/H O, whereas Normant employed DMSO as the solvent and
2
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obtained 2, in a lower isolated yield (66%). (Z)-HFCꢀCFI, 2, was treated with acid-washed
zinc dust in DMAC to give 3 in good NMR yield (determined with PhCF internal standard in
the F NMR spectrum). A higher yield (76%) was obtained in DMAC (N,N-dimethyl-
acetamide) solvent than in DMF (<50%) (N,N-dimethylformamide).
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(Z)-1,2-Difluoroethenylzinc iodide undergoes cross-coupling reactions with aryl iodides under
mild conditions in the presence of Pd(PPh ) and CuBr. Under similar conditions, the coupling
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4
reaction was incomplete in the absence of CuBr. It has been found that addition of CuBr greatly
accelerates the sluggish palladium catalyzed coupling reaction of the (Z)-1,2-difluoroethenylzinc
iodide. In the presence of CuBr, all the coupling reactions were completed in a short period of
time (normally 2 hours) under mild conditions. Table 1 summarizes these results. The CuBr
presumably complexes the triphenylphosphine ligands and generates a higher concentration of
the active catalyst.
Table 1
Preparation of (E)-1,2-difluorostyrenes
a
Entry
Ar
Conditions
Isolated yield (%)
1
2
3
4
5
6
7
8
9
4-F-C H4
40°C/3 h
rt/1 h
rt/1 h
rt/2 h
rt/4 h
40°C/6 h
40°C/1.5 h
40°C/2.5 h
rt/1 h
rt/20 min
rt/1 h
89
95
6
4-Cl-C H4
6
b
4-Br-C H4
94
6
c
4-I-C H4
92
6
d
C H5
74
6
4-OMe-C H4
94
84
87
93
87
73
6
3-CF C H
3
6
4
1-Naphthalene
3-NO -C H
2
6
4
1
1
0
1
4-NO -C H
2
6
4
2-Thiophene
a
b
c
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1
13
All products gave satisfactory F, H, C NMR and HRMS data.
No bis-adduct detected.
Bis-adduct; 3 equiv. of zinc reagent used.
Without CuBr, the reaction with a 94:6 isomeric mixture of (Z) and (E)-1,2-difluoroethenylzinc iodides took six
d
hours at 50°C; the product was isolated in a yield of 41%, GLPC purity=95%.

8047
Our initial preparation of (E)-a,b-difluorostyrenes utilized a sequence similar to that used for
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the synthesis of (Z)-a,b-difluorostyrenes. Thus, a 94:6 isomeric mixture of (Z) and (E)-1,2-
difluoroethenylzinc iodides was utilized in the Pd(PPh ) catalyzed cross-coupling with aryl
3
4
iodides. However, the problem with using an isomeric mixture of (Z) and (E)-1,2-
difluorooethenylzinc iodides to prepare (E)-a,b-difluorostyrenes is that the cis/trans isomer ratio
increases in the products. The reason for this unsuccessful preparation of (E)-a,b-difluorostyre-
nes from a mixture of (Z) and (E)-zinc reagents is that the (E)-1,2-difluoroethylzinc iodide
undergoes the palladium catalyzed cross-coupling reaction with aryl iodides faster than the
(
Z)-isomer. Thus, pure (Z)-1,2-difluoroiodoethene must be employed in the preparation of the
zinc reagent.
In a typical procedure for the preparation of the (Z)-HFCꢀCFZnI, a two-neck 1 L round
bottom flask equipped with a Teflon-coated stir bar, dry ice/isopropanol condenser and rubber
septum, was charged with DMF (300 mL), (E)-1,2-difluoro-3-iodo-1-triethylsilylethylene (92.1 g,
purity 95%, 288 mmol), and KF (18.2 g, 314 mmol). Water (5.2 g, 289 mmol) was then gradually
introduced into the solution via a syringe over 5 minutes. A mild exothermic reaction was
observed. The reaction mixture was stirred at room temperature for 0.5 h, then distilled by flash
distillation and the distillate trapped in a liquid nitrogen cooled flask. The resultant colorless
distillate was dried over 5 g of P O and distilled by flash distillation at rt/1 mmHg. Further
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fractional distillation of the distillate through a 10 cm Vigreux column yielded 42.7 g (79%) of
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a colorless liquid, GLPC purity=100%, bp=44–45°C. F NMR (l) −132.1 (d, J=145 Hz),
1
1
13
−
158.8 (dd, J=145, 76 Hz); H NMR (l) 7.47 (dd, J=76, 1 Hz); { H} C NMR (l) 146.31 (dd,
+
J=248, 56 Hz), 104.16 (dd, J=315, 57 Hz); GCMS (m/e) 190 (M , 100), 127 (49), 63 (76), 59
(
42); HRMS: calcd for C HF I: 189.9090, observed: 189.9106. A two-neck 500 mL round
2
2
bottom flask equipped with a Teflon-coated stir bar, a dry ice/isopropanol condenser attached
to a nitrogen source and a rubber septum, was charged with 190 mL of DMAC, 30 g (461.5
mmol) of acid-washed zinc dust and 39.8 g (209.8 mmol) of (Z)-1,2-difluoroiodoethene. After
the reaction mixture had been stirred for 0.5 h, a strong exothermic reaction was observed. After
19
the exotherm had subsided, the solution was stirred for an additional 1.5 h. The F NMR
spectrum of the reaction mixture indicated complete consumption of the (Z)-1,2-
difluoroiodoethene. The NMR yield (PhCF as the internal standard) of the (Z)-1,2-
3
1
9
difluoroethenylzinc iodide was 76%. F NMR (l) (DMAC) −172.28 (dd, J=104, 12 Hz, 1F),
−
184.46 (dd, J=104, 87 Hz, 1 F).
In a typical coupling reaction, a two-neck 50 mL round bottom flask equipped with a
Teflon-coated stir bar, a cold water condenser attached to a nitrogen source and a septum, was
charged with 4-chloroiodobenzene (1.79 g, 7.43 mmol, 99%), Pd(PPh ) (0.50 g, 0.43 mmol, 5.8
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4
mol%), CuBr (1.0 g, 6.9 mmol, 0.9 equiv.) and (Z)-1,2-difluoroethenylzinc iodide (19 mL, 11.4
mmol, 0.60 M, 1.5 equiv.) in DMAC. The reaction mixture was stirred at room temperature for
1
9
1
h. F NMR analysis of the reaction mixture showed the formation of the 4-chloro-(E)-a,b-
difluoro-b-hydrostyrene; GCMS of a pre-chromatographed reaction mixture showed the com-
plete disappearance of the 4-chloroiodobenzene. The dark reaction mixture was poured onto a
silica gel column and eluted with pentane, R =0.57. Eluents with similar UV-active TLC spots
f
were combined and a majority of the pentane was removed by simple distillation. Removal of
the remaining trace amount of solvent at −35°C/1 mmHg yielded 1.23 g (95%) of a colorless
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liquid, GLPC purity >99%. F NMR (l), −167.0 (dd, J=126, 5 Hz, 1 F), −172.69 (dd, J=126,
1
1
13
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5 Hz, 1 F); H NMR (l) 7.47–7.07 (m, 5 H); { H} C NMR (l) 151.36 (dd, J=228, 31 Hz),
1
41.34 (dd, J=252, 72 Hz), 135.64 (d, J=3 Hz), 129.10 (s), 127.73 (dd, J=25, 6 Hz), 126.73 (dd

8048
+
as t, J=8 Hz); GCMS (m/e) 174 (M , 100), 139 (27), 138 (14), 119 (40), 99 (12); FTIR: 3110
w), 1598 (m), 1494 (s), 1399 (m), 1354 (m), 1151 (versus), 1121 (m), 1107 (s), 1098 (m); HRMS
(
3
5
calcd for C H Cl F : 174.0048, observed: 174.0049.
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5
2
In conclusion, we have developed a general method for the stereospecific preparation of
(
E)-a,b-difluoro-b-hydrostyrenes from (Z)-HFCꢀCFZnI via an unusual Pd(PPh ) /CuBr co-
3
4
catalyzed cross-coupling reaction. Detailed mechanistic study and applications of these fluori-
nated styrenes is in progress.
Acknowledgements
We gratefully acknowledge the National Science Foundation for financial support of this
work.
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2
5
.