Synthesis of the multisubstituted halogenated olefins via cross-coupling of dihaloalkenes with alkylzinc bromides

Article abstract of DOI:10.1021/jo051980e

The 1-fluoro-1-haloalkenes undergo Pd-catalyzed Negishi cross-couplings with primary alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective giving pure Z-fluoroalkenes in most cases. The highest yields were obtained with Pd₂(dba)₃ and PdCl ₂(dppb) catalysts but the best stereochemical outcome was obtained with less reactive Pd(PPh₃)₄. The tertiary alkylzincs also produced desired fluoroalkenes in high yields. Coupling of β,β- dichlorostyrene with organozinc reagent resulted in the formation of monocoupled product.

Full text of DOI:10.1021/jo051980e

Synthesis of the Multisubstituted Halogenated
Olefins via Cross-Coupling of Dihaloalkenes with
Alkylzinc Bromides
Daniela Andrei and Stanislaw F. Wnuk*
Department of Chemistry and Biochemistry, Florida
International UniVersity, Miami, Florida 33199
FIGURE 1. S-Adenosyl-L-homocysteine A and the structure of the
analogues B with sulfur atom replaced by the “vinyl unit”.
wnuk@fiu.edu
the corresponding amino acid counterparts.2 Since subsequent
addition of bromine across the C5′-C6′ double bond in
analogues of type B (X ) H) followed by dehydrobromination
(DBU) was found to be ineffective to yield vinyl 6′-bromides
B (X ) Br), we turned our attention to direct synthesis of
halovinyl analogues B via selective coupling employing diha-
lovinyl precursors of type E.
ReceiVed September 21, 2005
The Pd-catalyzed cross-coupling reactions are powerful
methods for the formation of carbon-carbon bonds under
conditions that are compatible with a broad range of functional
The 1-fluoro-1-haloalkenes undergo Pd-catalyzed Negishi
cross-couplings with primary alkylzinc bromides to give
multisubstituted fluoroalkenes. The alkylation was trans-
selective giving pure Z-fluoroalkenes in most cases. The
highest yields were obtained with Pd2(dba)3 and PdCl2(dppb)
catalysts but the best stereochemical outcome was obtained
with less reactive Pd(PPh3)4. The tertiary alkylzincs also
produced desired fluoroalkenes in high yields. Coupling of
â,â-dichlorostyrene with organozinc reagent resulted in the
formation of monocoupled product.
groups.3 However, despite the wide application of Csp-Csp and
2
2
2
3
Csp -Csp couplings, couplings involving Csp centers are less
explored4 with the exception of couplings between Csp as
2
electrophiles and Csp as nucleophiles.3c,4a Moreover, the mono-
3
cross-coupling reactions of 1,1-dihalovinyl electrophiles with
Csp or Csp nucleophiles are less common5 and monocouplings
2
3
between 1,1-dihalovinyl electrophiles and Csp nucleophiles are
scarce.3c,6 Panek et al. utilized a double coupling strategy with
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) Topics
in Current Chemistry; Miyaura, N., Ed.; Springer-Verlag: New York, 2002;
Vol. 219. (c) Negishi, E.-I.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G.
Aldrichim. Acta 2005, 38, 71-88.
In the search for more selective inhibitors of S-adenosyl-L-
homocysteine (AdoHcy, A) hydrolase,1 we attempted syntheses
of AdoHcy analogues with 5′,6′-olefin (or halovinyl) moieties
incorporated in place of the sulfur atom (B, Figure 1).2 On the
basis of the known ability of the enzyme to add water across
the 5′,6′-double bond,1c we envisioned that such compounds
should form “stable” complexes with the enzyme that would
help to identify key binding groups at the active site of the
enzyme that interact with the Hcy moiety and participate in
subsequent elimination and hydrolytic activity steps.
On the basis of retrosynthetic analysis, we had previously
attempted synthesis of analogues B (X ) H) by (a) construction
of a new C5′-C6′ double bond via either Wittig or metathesis
reactions or (b) formation of a new C6′-C7′ single bond via
Pd-catalyzed cross-couplings between readily available 6′-halo-
(or stannyl)homovinyl adenosine1a derivatives (C or D) with
2
3
(4) (a) For Csp (electrophile)-Csp coupling see: Negishi, E.-I.; Liu, F.
In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 1, pp 1-47. Dai,
C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724. (b) For
2
3
C
sp (nucleophile)-Csp see: Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003,
3
125, 3718-3719. (c) For Csp(nucleophile)-Csp see: Eckhardt, M.; Fu, G.
3
-
C. J. Am. Chem. Soc. 2003, 125, 13642-13643. (d) For review on Csp
3
Csp couplings see: Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-
387.
(5) (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509-6512 (1,1-dibromoalkenes and vinylboronic acids). (b) Xu,
C.; Negishi, E.-I. Tetrahedron Lett. 1999, 40, 431-434. Zeng, X.; Hu, Q.;
Qian, M.; Negishi, E.-I. J. Am. Chem. Soc. 2003, 125, 13636-13637. Zeng,
X.; Qian, M.; Hu, Q.; Negishi, E.-I. Angew. Chem., Int. Ed. 2004, 43, 2259-
2263 (1,1-dibromoalkenes and alkenyl zinc or zirconium). (c) Bryant-
Friedrich, A.; Neidleim, R. Synthesis 1995, 1506-1510. Uenishi, J.; Matsui,
K. Tetrahedron Lett. 2001, 42, 5353-5355. Shi, J.-C.; Zeng, X.; Negishi,
E.-I. Org. Lett. 2003, 5, 1825-1828. Negishi, E.-I.; Shi, J.-C.; Zeng, X.
Tetrahedron 2005, 61, 9886-9895 [monoalkynylation of 1,1-dibromo(or
chloro)alkenes]. (d) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-
8879 (1,1-dibromoalkenes with aryl- and vinylstannane). (e) Minato, A. J.
Org. Chem. 1991, 56, 4052-4056 (1,1-chloroalkenes with arylzinc
reagents).
(6) (a) To the best of our knowledge the only successful Pd-catalyzed
monoalkylation of vinyl dihalides was trans-selective monobutylation of
1,1-dichloro-2-phenylethene with n-C4H9ZnCl in 81% yield (dibutylation
product was obtained in 11%): Minato, A.; Suzuki, K.; Tamao, K. J. Am.
Chem. Soc. 1987, 109, 1257-1258. (b) Treatment of the (E/Z)-1-bromo-
1-fluoroalkene with BuLi/ZnCl2/Pd(PPh3)4 gave butylated Z-(fluoro)alkene
and unchanged Z-isomer: Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion,
J.-C. Org. Lett. 2004, 6, 2101-2104. (c) For iron(III)-catalyzed couplings
see: Santos, M. D.; Franck, X.; Hocquemiller, R.; Figadere, B.; Peyrat,
J.-F.; Provot, O.; Brion, J.-D.; Alami, M. Synlett 2004, 2697-2700.
(1) (a) Wnuk, S. F.; Yuan, C.-S.; Borchardt, R. T.; Balzarini, J.; De
Clercq, E.; Robins, M. J. J. Med. Chem. 1994, 37, 3579-3587. (b) Yuan,
C.-S.; Liu, S.; Wnuk, S. F.; Robins, M. J.; Borchardt, R. T. In AdVances in
AntiViral Drug Design; De Clercq, E., Ed.; JAI Press: Greenwich, 1996;
Vol. 2, pp 41-88. (c) Wnuk, S. F. Mini-ReV. Med. Chem. 2001, 1, 307-
316.
(2) (a) Wnuk, S. F.; Lalama, J.; Andrei, D.; Garmendia, C.; Robert, J.
S-Adenosylhomocysteine and S-ribosylhomocysteine analogues with sulfur
atom replaced by the vinyl unit. Abstracts of Papers, Carbohydrate DiVision;
229th National Meeting of the American Chemical Society, San Diego,
CA, March 13-17, 2005; American Chemical Society: Washington, DC,
2005; CARB-035. (b) Jennifer Lalama, M.Sc. Thesis, Florida International
University, 2004.
10.1021/jo051980e CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/07/2005
J. Org. Chem. 2006, 71, 405-408
405

SCHEME 1. Stereoselective Synthesis of
(R-iodo)vinyl silanes for the synthesis of trisubstituted alkenes
to overcome difficulties in selective alkylation of vinyl dibro-
mides.7 McCarthy8a and Burton8b and their co-workers devel-
oped coupling between 1-bromo(or chloro)-1-fluoroalkenes with
vinyl/aryl organostannanes and boranes to prepare the conju-
gated 1-substituted-1-fluoroolefins.9
1-fluoro-1-haloalkenes 4-6a
We were prompted to undertake model studies on Pd-
catalyzed cross-coupling between vinyl dihalides and alkyl
organometallics because the synthesis of analogue B (X )
halogen) via Pd-catalyzed monoalkylation between dihalo-
homovinyl nucleoside (or carbohydrate) derivatives of type E
and organozinc reagents was difficult.2,10 Moreover, there are
only a few reports on selective monoalkylation of 1,1-
dihaloalkenes.3c,6 Herein, we report a novel Negishi monoalky-
lation of 1-fluoro-1-haloalkenes, derived from the conjugated
or unconjugated aldehydes and ketones, as well as 1,1-
dichloroalkenes with alkylzinc bromides to provide access to
the multisubstituted fluoro or chloro alkenes.
a Reagents and conditions: (a) PhSO2CHFPO(OEt)2/LHMDS/THF/-
78 °C; (b) Bu3SnH/AIBN/benzene/∆; (c) NIS/CH2Cl2; (d) NBS/CH2Cl2;
(e) Cl2/CH2Cl2.
The 1-fluoro-1-haloalkenes 4-6 were chosen as precursors
to study Pd-catalyzed Negishi3c coupling with alkylzincs. We
expected formation of monoalkylated fluoroalkenes in view of
the inertia of fluorides3a toward couplings. The terminal
dihaloalkenes 4-6 were prepared in high yields by the Mc-
Carthy’s procedure11 that involves (i) condensation of aldehydes
1a-c and ketone 1d with sulfonyl-stabilized fluorophosphonates
to give (R-fluoro)vinyl sulfones 2, (ii) radical stannyldesulfo-
nylation with Bu3SnH/AIBN to yield (R-fluoro)vinyl stannanes
3, and (iii) the halodestannylation1a with NIS, NBS, or Cl2 to
give 1-fluoro-1-iodo- (4), 1-fluoro-1-bromo- (5), or 1-fluoro-
1-chloroalkenes (6), respectively (Scheme 1). It is noteworthy
that dihaloalkenes of series c with a benzyloxy substituent at
the allylic carbon are structural analogues of the dihalohomovi-
nyl nucleoside or ribofuranosyl precursors of type E, which also
has an oxygen atom at the γ carbon from the halovinyl site.
Initially, we attempted couplings of the conjugated 1-fluo-
rovinyl iodide 4a (E/Z, 95:5) with 2 equiv of primary alkylzinc
bromide [BrZn(CH2)3CO2Et] in the presence of Pd(PPh3)4 in
benzene (65 °C, 10 h), which gave fluoro alkenoate 7a as a
single Z isomer (3JF-H(trans) ) 39.8 Hz) in 70% yield (Scheme
2; Table 1, entry 1). The coupling occurred with retention of
configuration via trans-selective alkylation (vide infra) but the
E/Z descriptors changed owing to the change in Cahn-Ingold-
SCHEME 2. Couplings of 1-Fluoro-1-haloalkenes with
Alkylzincsa
a See Scheme 1 for description of R and R1.
Prelog priority at the reaction center carbon. The 1-fluorovinyl
bromide 5a and chloride 6a also underwent efficient couplings
with BrZn(CH2)3CO2Et to give 7a(Z) in 70% and 80% yield
(entries 3 and 4). The calculated yields based only on the
conversion of E isomers of 5a and 6a (from E/Z, 93:7 mixtures)
to 7a(Z) are 75% and 86%, respectively. Analogous treatment
of 4a (E/Z, 95:5) with alkylzinc bromides containing double
bond [BrZn(CH2)3CHdCH2] or acetal functionality [BrZn-
(CH2)2CH(OCH2)2] gave 8a(Z) or 9a(Z), respectively (entries
5 and 6).
To optimalize reaction conditions, we tested efficiency of
various Pd catalysts for such Negishi monoalkylation (Scheme
3). We found that tris(dibenzylideneacetone)palladium [Pd2-
(dba)3] and 1,4-bis(diphenylphosphinobutane)palladium chloride
[PdCl2(dppb)] gave smooth conversion of 4a into 9a in 2 h at
50 °C. The Pd(PPh3)4 effected only 11% conversion of 4a into
9a under analogous conditions and Pd(OAc)2 and PdCl2(dppf)
were also less effective. Coupling of 4a with BrZn(CH2)3CO2-
Et in the presence of PdCl2(dppb) gave improved yield of 7a(Z)
(93%, entry 2 vs entry 1) under milder conditions (50 °C, 2 h).
The unconjugated 1-fluorovinyl halides 4b (E/Z, 78:22)
coupled with primary alkylzinc bromides in the presence of Pd-
(PPh3)4 to give 7b, 8b, and 9b in high yields (entries 9, 13, and
14). The conversion of 4b into 7b was achieved in higher yields
under milder conditions with PdCl2(dppb) as catalyst (entry 12).
The vinyl iodide 4c (E/Z, 75:25) with benzyloxymethyl sub-
stituent at carbon â (analogue of the nucleoside precursor of
type E) reacted with BrZn(CH2)3CHdCH2 [Pd(PPh3)4] to give
the internal fluoroalkene 8c(Z) in moderate yield (56%, entry
17) in addition to unchanged 4c with enriched Z to E ratio
(56:44). The PdCl2(dppb) catalyst not only increased the yield
but also led to the formation of 8c as a mixture of E/Z isomers
(7) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 3281-
3284.
(8) (a) Chen, C.; Wilcoxen, K.; Huang, C. Q.; Strack, N.; McCarthy, J.
R. J. Fluorine Chem. 2000, 101, 285-290. (b) Xu, J.; Burton, D. J.
Tetrahedron Lett. 2002, 43, 2877-2879.
(9) (a) Approaches in ref 8 required milder conditions than couplings of
(R-fluoro)vinyl stannanes9b,c and silanes9d with alkenyl/aryl halides which
needed addition of CuI9b,c and CsF9d to overcome inductive electron-
withdrawing effects of the R-fluorine atom that lower nucleophilicity of
the stannanes and silanes.9e On the other hand, the same fluorine effect are
expected to result in a higher level of reactivity for R-fluorinated electrophilic
components.8 (b) Chen, C.; Wilcoxen, K.; Zhu, Y.-F.; Kim, K.-I.; McCarthy,
J. R. J. Org. Chem. 1999, 64, 3476-3482. (c) Liu, Q.; Burton, D. J. Org.
Lett. 2002, 4, 1483-1485. (d) Hanamoto, T.; Kobayashi, T. J. Org. Chem.
2003, 68, 6354-6359. (e) Percy, J. M.; Wilkes, R. D. Tetrahedron 1997,
53, 14749-14762. (f) For the unexpectedly facile couplings of (R-fluoro)-
vinyl tris(trimethylsilyl)germanes see: Wang, Z.; Gonzalez, A.; Wnuk, S.
F. Tetrahedron Lett. 2005, 46, 5313-5316.
(10) (a) Only dialkylated and monoalkylated products have been isolated.2
(b) Panek and co-workers reported7 that their attempts to selectively
methylate vinyl dibromides under Negishi, Stille, or Suzuki conditions were
unsuccessful despite the fact that differentiation of the two halogen groups
for the Csp -Csp and Csp -Csp cross-couplings are known.5
(11) McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Laskovics, M.; Matthews,
D. P. Tetrahedron 1996, 52, 45-58.
2
2
2
406 J. Org. Chem., Vol. 71, No. 1, 2006

TABLE 1. Pd-Catalyzed Alkylation of 1-Fluoro-1-haloalkenes
SCHEME 4. Couplings with Branched Alkyzincs
4-6a
entry substrate
E/Z
product (Z) time (h) yield,b % yield,c %
1
2
3
4
5
6
7
8
4a
4a
5a
6a
4a
4a
4a
4a
95/5
95/5
93/7
93/7
95/5
95/5
95/5
95/5
7a
10
2
70
93
70
80
65
90
92
94
74
97
75
86
69
94
96
98
7ad
7a
10
10
10
12
2
7a
8ae
9a
9af
9ad
2
9
10
11
12
13
14
15
16
4b
4b
4b
4b
4b
4b
4b
4b
78/22 7b
100/0 7b
15/85 7b
84/16 7bd
78/22 8bh
78/22 9b
100/0 9b
15/85 9b
24
12
24
8
20
20
12
24
60
88
14
82
66
74
89
14
56j
86
84
78
88g
96
98
85
94
89i
96
(E/Z, 15:85) of 1-fluoro-1-iodoalkene 4b were prepared by
separation of the corresponding (R-fluoro)vinyl stannanes 3b
followed by the stereospecific iododestannylation. Treatment
of 4b(E) with BrZn(CH2)3CO2Et or BrZn(CH2)2CH(OCH2)2
[Pd(PPh3)4/12 h/65 °C] resulted in smooth conversion (GC/MS,
19F NMR) to 7b(Z) or 9b(Z) with isolated yields of 88% and
89%, respectively (entries 10 and 15). On the other hand,
analogous Negishi treatment of 4b (E/Z, 15:85) yielded 7b(Z)
or 9b(Z) in 14% (96% conversion of E isomer; entries 11 and
16) while the corresponding 7b(E) or 9b(E) were not formed.
Prolonged reaction time and harsher conditions resulted in
decomposition of the 4b(Z) isomer (GC/MS, 19F NMR).
Generally, only in a few instances did we observe formation
(above detection limit13 of 1-2%, 19F NMR) of the correspond-
ing E isomers via cis-couplings (entries 18, 19, and 21). For
example, alkylation of 4c (iodide) and 5c (bromide) in the
presence of PdCl2(dppb) produced 8c as an E/Z (20:80) mixture.
These results are in agreement with trans-selective mono-cross-
coupling of 1,1-dihaloalkenes reported previously.3c,5,6,14 Burton
and co-workers showed that trans selectivity with 1-bromo-1-
fluoroalkenes originates in the oxidative addition step since
formation of the E-palladium complex is faster than the
formation of the Z-palladium complex, which is hampered by
steric hindrance of the vicinal cis-substituent.14a They applied
this finding for the kinetic resolution of the E and Z coupling
products.8b,14
17
18
19
4c
4c
5c
75/25 8c
48
4
6
74
67/33 8cd,k
77/23 8cd,k
20
21
22
23
4d
4d
4d
4d
49/51 7d
49/51 7dd,l
49/51 8d
49/51 9d
24
8
24
24
45
60
45
46
94
92
90
a Pd(Ph3P)4 was used as a catalyst unless otherwise specified (50-65
°C). b Isolated yield. c Isolated yield based on the conversion of the E isomer
only. d PdCl2(dppb) catalyst. e (Z,Z)-2,3-Difluoro-1,4-diphenyl-1,3-butadiene
12 was also isolated (8%; 16% consumption of 4a). f Pd2(dba)3 catalyst.
g 96% based on GC-MS. h (Z)-1-Fluoro-4-phenyl-1-butene, E isomer of 8b,
and (Z,Z)-4,5-difluoro-1,8-diphenyl-3,5-octadiene were also detected in crude
reaction mixture (19F NMR). i 98% based on GC-MS. j 56% based on 19F
NMR. k E/Z, 20:80. l E/Z, 16:84; based on 19F NMR and GC-MS.
SCHEME 3. Effect of the Pd Catalysts on the Efficiency of
Couplinga
The major byproduct isolated from the coupling reactions
resulted from the reductive homocoupling of dihalide compo-
nents. For example, the self-coupling product of 4a, e.g., (Z,Z)-
2,3-difluoro-1,4-diphenyl-1,3-butadiene 12, was isolated in 8%
yield (16% consumption of 4a) from the reaction of 4a with
BrZn(CH2)3CHdCH2 (entry 5) as well as from reactions of 4a
with branched alkylzincs.
We also examined the Pd-catalyzed coupling of 1,1-diha-
loalkenes with branched alkylzincs. Thus, PdCl2(dppb) was
found to be effective for monoalkylation of 4a (E/Z, 95:5) with
t-BuZnBr (10a) to provide 11a (80%; 3 h, 50 °C; Scheme 4).
The Pd2(dba)3 and Pd(PPh3)4 catalysts were less effective leading
to the formation of a significant amount of self-coupling
byproduct 12 [e.g, 20%, 40% consumption of 4a for Pd(PPh3)4].
Interestingly, attempted couplings of 4a with secondary 2- or
3-pentylzinc bromides (10b or 10c) gave various amounts of
desired products 11b or 11c (in the range of 5-50%) along
with the isomerization byproduct 11d (35-70%) and self-
coupled diene 12 as well as reduced (Z)-â-fluorostyrene. Since
purifications of desired products 11b and 11c from other
byproducts (especially from 11d) turned out also to be difficult
a 5% molar. b GC/MS and 19F NMR. c Only Z product was detected.
d 95% after 3.5 h. e Isolated yield 92%. f Isolated yield 94%.
(20:80, 86%; entry 18). Also bromide 5c yielded 8c as an E/Z
mixture in high yield (entry 19). The 1-fluorovinyl iodide 4d
derived from acetophenone served as a convenient starting
material for the synthesis of multisubstituted alkenes12 7d(Z),
8d(Z), and 9d(Z) (entries 20-23).
To learn more about the stereochemical outcome of the
couplings, pure E isomer and a mixture enriched in the Z isomer
(13) Robins, M. J.; Sarker, S.; Wnuk, S. F. Nucleosides Nucleotides 1998,
17, 785-790.
(14) (a) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112, 47-54.
(b) Xu, J.; Burton, D. J. J. Org. Chem. 2005, 70, 4346-4353.
(12) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.;
Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 11577-11585 (synthesis of
tetrasubstituted alkenes via sequential couplings).
J. Org. Chem, Vol. 71, No. 1, 2006 407

SCHEME 5. Couplings with 1,1-Dibromo- and
1,1-Dichloroalkenesa
(PPh3)4 (7 mg, 0.006 mmol) under N2. The resulting mixture was
heated at 65 °C for 5 h. Additional Pd(PPh3)4 (4.5 mg, 0.004 mmol)
and 4-ethoxy-4-oxobutylzinc bromide (0.20 mL, 0.10 mmol) were
then added and heating was continued for an extra 5 h. Volatiles
were evaporated and the residue was partitioned (NaHCO3/H2O//
EtOAc). The organic layer was washed (brine), dried (Na2SO4),
evaporated, and chromatographed (hexane f 15% EtOAc/hexane)
to give 7a(Z) (33 mg, 70%; 74% based on the conversion of E
isomer only): 1H NMR δ 1.26 (t, J ) 7.1 Hz, 3H), 1.95 (quint,
J ) 7.3 Hz, 2H), 2.39-2.48 (m, 4H), 4.15 (q, J ) 7.1 Hz, 2H),
5.50 (d, J ) 39.4 Hz, 1H), 7.15 (t, J ) 7.2 Hz, 1H), 7.30 (t, J )
7.4 Hz, 2H), 7.45 (d, J ) 7.4 Hz, 2H); 13C NMR δ 14.6, 22.1,
a Reagents and conditions: (a) BrZn(CH2)3CO2Et/PdCl2(dppf)/THF/65
°C (oil bath).
no further effort was undertaken to improve these reactions.
Formation of byproducts derived from isomerization of the
branched alkyl group during Negishi reaction is known.4a,15
We also investigated differentiation of the two halogens in
1,1-dibromo- or 1,1-dichloroalkenes for selective monoalkyla-
tion with alkylzincs. We found that â,â-dichlorostyrene 13
reacted [PdCl2(dppf)/THF/65 °C/14 h] with BrZn(CH2)3CO2Et
to give a desired trisubstituted chloroalkene 15 (Z, 65%) in
addition to the monocoupled/reduced byproduct 18 (22%;
Scheme 5). Analogous couplings in the presence of PdCl2(dppb)
produced 15 (53%) and 18 (15%) in addition to dialkylated
product 17 (27%). Similar couplings with more reactive â,â-
dibromostyrene 14 produced mainly dialkylated 17 (57-69%)
in addition to 18 (24-28%).
2
2
32.7 (d, JC-F ) 26.9 Hz), 33.6, 60.8, 106.9 (d, JC-F ) 8.5 Hz),
1
127.2, 128.7, 128.9, 134.0, 160.2 (d, JC-F ) 266.7 Hz), 173.5;
19F NMR δ -102.20 (dt, J ) 39.8, 19.7 Hz); MS m/z 237 (100%,
MH+). Anal. Calcd for C14H17FO2 (236.12): C, 71.16; H, 7.25.
Found: C, 70.80; H, 7.16. Analogous treatment (50 °C, 2 h total)
of 4a (0.20 mmol) with 4-ethoxy-4-oxobutylzinc bromide (0.37
mmol) and PdCl2(dppb) (6.0 mg, 0.01 mmol) gave 71(Z) (93%).
3,3-Dimethyl-2-fluoro-1-phenyl-1-butene (11a). Treatment of
4a (E/Z, 95:5, 40 mg, 0.16 mmol) with PdCl2(dppb) (5% molar)
and tert-butylzinc bromide (0.5 M; 0.6 mL, 0.32 mmol) as described
in procedure D [3 h, 50 °C] gave 11a (23 mg, 80%; 95% based on
GC-MS and 19F NMR): 1H NMR δ 1.15 (s, 9H), 5.40 (d, J )
40.7 Hz, 1H), 7.17-7.41 (m, 5H); 19F NMR δ -109.47 (d, J )
40.7 Hz); GC-MS m/z 178 [80%, M+; tR ) 10.78 min]. HRMS
Calcd for C12H15F (M + H+) 179.1237, found 179.1246.
In summary, we have developed Pd-catalyzed Negishi cross-
coupling of 1-fluoro-1-(iodo, or bromo, or chloro)alkenes with
alkylzincs, thus providing stereoselective access to the internal
fluoroalkenes. The primary alkylzincs gave the best results but
the tertiary alkylzincs also produced desired fluoroalkenes in
high yields. The â,â-dichlorostyrene gave selective coupling
to produce multisubstituted chloroalkenes. Application of 1,1-
dihaloalkenes for selective double alkylation strategy, which can
be used for the synthesis of tetrasubstituted alkenes as well as
synthesis of carbohydrate and nucleoside analogues of type B,
will be published elsewhere.
(Z)-Ethyl 5-Chloro-6-phenyl-5-hexenoate (15): Procedure E.
4-Ethoxy-4-oxobutylzinc bromide (0.5 M; 1.45 mL, 0.72 mmol)
was added via syringe to a stirring solution of 13 (50 mg, 0.29
mmol) in dried THF (3 mL) containing PdCl2(dppf) (24 mg, 0.029
mmol) under N2. The resulting mixture was heated at 65 °C
overnight. Volatiles were evaporated and the residue was partitioned
(NaHCO3/H2O//EtOAc). The organic layer was washed (brine),
dried (Na2SO4), evaporated, and chromatographed (hexane f 10%
EtOAc/hexane) to give 15 (47 mg, 65%) and 18 (14 mg, 22%).
15: 1H NMR δ 1.19 (t, J ) 7.1 Hz, 3H), 1.94 (quint, J ) 7.1 Hz,
2H), 2.30 (t, J ) 7.4 Hz, 2H), 2.47 (t, J ) 7.1 Hz, 2H), 4.08 (q,
J ) 7.1 Hz, 2H), 6.40 (s, 1H), 7.28-7.52 (m, 5H); 13C NMR δ
14.2, 22.8, 32.9, 40.28, 60.3, 125.2, 127.5, 128.2, 129.0, 133.6,
135.0, 173.2; GC-MS m/z 252 (30%, M+ [35Cl]; tR ) 20.00 min).
HRMS calcd for C14H1735ClO2 (M + H+) 253.0995, found
253.0989.
Experimental Section
Experimental procedures [A (synthesis of vinyl sulfones 2 via
Wittig reaction), B (preparation of vinylstannane 3 via stannylde-
sulfonylation 2), C (synthesis of dihaloalkenes 4-6 via halodestan-
nylation of 3), D (couplings of 1-fluoro-1-haloalkenes 4-6 with
alkylzincs), and E (couplings of 1,1-dichloro- 13 and 1,1-dibro-
moalkenes 14 with alkylzincs)] are described in the Supporting
Information.
Acknowledgment. This investigation was partially supported
by NIH/NIGMS S06GM08205. The support of US ARO
(W911NF-04-1-0022) for the purchase of the 600 MHz NMR
spectrometer is acknowledged.
Ethyl 5-Fluoro-6-phenyl-5(Z)-hexenoate (7a): Procedure D.
4-Ethoxy-4-oxobutylzinc bromide (0.5 M/THF; 0.60 mL, 0.30
mmol) was added via syringe to a stirring solution of 4a (E/Z, 95:
5; 50 mg, 0.20 mmol) in dried benzene (5 mL) containing Pd-
Supporting Information Available: Experimental procedures,
characterization data, and copies of 1 H NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163.
JO051980E
408 J. Org. Chem., Vol. 71, No. 1, 2006