Preparation of (Z)-1-halo-1-alkenes and (Z)-1-halo-2-alkoxy-1-alkenes using Cr(II/III) and Fe(0)

Article abstract of DOI:10.1055/s-2006-951467

Reduction of 1,1,1-trihaloalkanes by Cr(II) or Cr(III) regenerated by Fe(0) in moist tetrahydrofuran at room temperature stereoselectively generates (Z)-1-halo-1-alkenes and (Z)-1-halo-2-alkoxy-1-alkenes in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951467

2652
LETTER
Preparation of (Z)-1-Halo-1-alkenes and (Z)-1-Halo-2-alkoxy-1-alkenes Using
Cr(II/III) and Fe(0)
P
reparatio
.
nof
(
Z
)-1-H
R
.
(
Z
)
-1-Halo-
F
2-alkoxy-1-alk
a
e
nes lck,*a Anyu He,a Romain Bejot,b Charles Mioskowski*b
a
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038, USA
Fax +1(214)6486455; E-mail: j.falck@UTSouthwestern.edu
b
Laboratoire de Synthèse Bio-Organique, UMR 7175, LC1, Faculté de Pharmacie, Université Louis Pasteur, 74 Route du Rhin, BP 24,
67 401 Illkirch, France
Fax +33(3)90244306; E-mail: mioskow@aspirine.u-strasbg.fr
Received 18 May 2006
deutero-2 in a 1:0.7 ratio consistent with the internal
proton return mechanism operative with chromium
vinylidene carbenoids.5 Increasing the proportion of Fe(0)
(entries 3 and 4) had no benefit on either reaction rate or
yield, while limiting the co-reductant to one equivalent
(entry 5) reduced both reaction rate and yield. With a 1:2
ratio of CrCl2/Fe(0), the yield was restored, but the reac-
tion time remained long (entry 6). Heating to 50 °C did not
change the final outcome compared with room tempera-
ture reactions, but it did spur the Fe(0) reaction to finish in
just 3 hours (entry 7); heating had no effect on the Mn(0)
reaction (entry 13), which was already much faster than
the comparable iron reductions. The inclusion of other
additives that have been used as adjuvants in chromium-
mediated reactions, e.g., trimethylsilyl chloride,4
(Cp)2ZrCl2,6 and NiCl2(PPh3)2,7 did not help any of the
reactions. Attempts to further reduce the amount of CrCl2
to 0.5 equivalent were discouraging (entries 8 and 14).
Replacement of CrCl2 with the more easily handled and
relatively inexpensive CrCl3 proved efficacious, especial-
ly if the CrCl3/Fe(0) ratio was increased from 1:3 (entry 9)
to 1:4 (entry 10).
Abstract: Reduction of 1,1,1-trihaloalkanes by Cr(II) or Cr(III) re-
generated by Fe(0) in moist tetrahydrofuran at room temperature
stereoselectively generates (Z)-1-halo-1-alkenes and (Z)-1-halo-2-
alkoxy-1-alkenes in good to excellent yields.
Key words: alkenyl halides, carbenoids, chromium, enol ethers
Recently, our laboratories reported a convenient, stereo-
selective route1 to (Z)-1-chloro-1-alkenes and (Z)-1-chlo-
ro-2-alkoxy-1-alkenes2 via CrCl2 reduction of 1,1,1-
trichloroalkanes.3 However, the high costs of CrCl2, the
need for a large excess of reagent, and chromium’s toxic-
ity prompted us to investigate co-reductants capable of
recycling Cr(III) back to Cr(II) (Equation 1). At the same
time, we wished to extend this methodology to the prepa-
ration of synthetically more useful vinyl bromides from
1,1,1-tribromoalkanes, which failed under our previous
conditions.3
H
Cr(II)
H
R
CX3
R
co-reductant
X
Based upon the foregoing analysis, the combination of
Fe(0)–Cr(II)–H20 (3:1:1) was further evaluated for its
applicability to other substrates (Table 2). It was gratify-
ing to find acetonide 3 and diacetate 5 behaved analogous-
ly to 1 (entry 1) and afforded vinyl chlorides 4 (entry 2)
and 6 (entry 3), respectively, in good yields. In contrast 7
and 9 were sluggish and required warming to 50 °C to ob-
tain their respective products 8 (entry 4) and 10 (entry 5).
The origin of this difference in reactivity is unknown at
present, but we speculate coordination to heteroatom sub-
stituents or the presence of a proximal olefin may help
accelerate the reaction rate. Despite their well-known sen-
sitivity,2c Z enol ethers 12 (entry 6), 14 (entry 7), and 16
(entry 8) were obtained in excellent yields from 11, 13,
and 15, respectively. Use of CrBr3, instead of CrCl2, under
anhydrous conditions provided ready access to both enol-
ic bromides and vinyl bromides. This was illustrated by
the smooth transformations of 17, 19, and 21 into 188
(entry 9), 208 (entry 10), and 22 (entry 11), accordingly.
The latter reaction, however, had to be done at 4 °C to
minimize competitive side reactions and to furnish an
acceptable yield of 22, which was isolated as a Z/E mix-
ture (4:1). Control experiments showed that 22 was stable
under the reaction conditions.
R = aryl, alkyl, alkenyl, alkoxy
X = Cl, Br
Equation 1
A survey of inexpensive, eco-friendly reductants revealed
Fe(0) and Mn(0)4 were the most promising and these were
thus singled out for optimization using the conversion of
trichloride 1 to (Z)-1-chloro-1-alkene 2 as the test system
(Table 1). Utilizing one equivalents of CrCl2 and three
equivalents of either Fe(0) or Mn(0) in anhydrous tetra-
hydrofuran at ambient temperature, 2 was generated with
complete Z stereoselectivity (>99%) as judged by 1H/13C
NMR, but in moderate yields (entries 1 and 11). Notably,
the inclusion of a small amount of water, one equivalent
was sufficient, significantly accelerated the reaction rate
as well as the yields of 2 (entries 2 and 12). We speculate
that the water quenches the penultimate vinyl chromium
intermediate in situ allowing the released Cr(III) to be
recycled more efficiently (vide infra).5 Replacement of
the water with one equivalent of D2O produced 2 and 1-
SYNLETT 2006, No. 16, pp 2652–2654
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951467; Art ID: S11006ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of (Z)-1-Halo-1-alkenes and (Z)-1-Halo-2-alkoxy-1-alkenes
2653
Table 1 Optimization of Reaction Conditions
Cl
Cr/metal
Cl
Cl
Cl
THF
1
2
Entry
1
Cr salt (equiv)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (0.5)
CrCl3 (1)
CrCl3 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (1)
CrCl2 (0.5)
Co-reductant (equiv)
Fe (3)
Additive (equiv)
–
Temp (°C)/Time (h)
21/20
Yield (%)
62
2
Fe (3)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
–
21/12
92
3
Fe (5)
21/11
93
4
Fe (10)
Fe (1)
21/10
90
5
21/23
81
6
Fe (2)
21/20
92
7
Fe (3)
50/3
93
8
Fe (3)
21/24
84
9
Fe (3)
21/24
90
10
11
12
13
14
Fe (4)
21/12
93
Mn (3)
Mn (3)
Mn (3)
Mn (8)
21/24
71
H2O (1)
H2O (1)
–
21/2.5
50/2.5
50/8
81
83
57
Acknowledgment
Financial support was provided by Robert A. Welch Foundation,
NIH (GM31278, DK38226) and Ministère délégué à l’Enseigne-
ment supérieur et à la Recherche.
Synthesis of Vinyl Chlorides; General Procedure
1,1,1-Trichloroalkane (1.0 mmol) in THF (4 mL) and then H2O (1.0
mmol) were added to a stirring, r.t. suspension of anhyd CrCl2 (1.0
mmol, 1 equiv; Strem Chem., 99.9%) and Fe(0) powder (3.0 mmol,
3 equiv; Aldrich 97%, 325 mesh) in THF (15 mL) under an argon
atmosphere. The reaction mixture was stirred at the temperature and
for the time indicated in Table 2, then cooled to r.t., filtered through
a short pad of silica gel, and the filter cake was washed with Et2O.
The combined filtrates were evaporated in vacuo and the residue
was purified by SiO2 chromatography to give stereochemically pure
(>98% by 1H NMR) (Z)-1-chloro-1-alkene or (Z)-1-chloro-2-
alkoxy-1-alkene in the indicated yields (Table 2).
References and Notes
(1) For examples of alternative vinyl halide syntheses, see:
(a) Gosney, I.; Lloyd, S. In Comprehensive Organic
Functional Group Transformations, Vol. 1; Katritzky, A. R.;
Meth-Cohn, O.; Rees, C. W., Eds.; Pergamon Press: New
York, 1995, 719. (b) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965.
(c) Brown, H. C.; Blue, C. D.; Nelson, D. J.; Bhat, N. G. J.
Org. Chem. 1989, 54, 6064. (d) Takai, K.; Kataoka, Y.;
Utimoto, K. Tetrahedron Lett. 1989, 30, 4389.
Synthesis of Vinyl Bromides; General Procedure
LiAlH4 (2.4 M solution in THF, 0.5 mmol) was added to a stirring,
0 °C suspension of CrBr3 (CrBr3·6H2O, Aldrich 99%, pre-dried
overnight at 90 °C in vacuo, 1.0 mmol) and Fe(0) powder (4.0
mmol, 4 equiv; Aldrich 97%, 325 mesh) in anhyd THF (15 mL) un-
der an argon atmosphere. The reaction mixture was stirred at r.t. for
0.5 h before addition of the 1,1,1-tribromoalkane (1 equiv) in anhyd
THF (4 mL). The reaction mixture was stirred at the temperature
and for the time indicated in Table 2, then cooled to r.t., filtered
through a short pad of silica gel, and the filter cake was washed with
Et2O. The combined filtrates were evaporated in vacuo and the res-
idue was purified by SiO2 chromatography to give 1-bromo-1-alk-
ene or 1-bromo-2-alkoxy-1-alkene in the indicated yields (Table 2).
(e) Ratovelomanana, V.; Linstrumelle, G. Tetrahedron Lett.
1981, 22, 315. (f) Concellón, J. M.; Bernad, P. L.; Pérez-
Andrés, J. A. Angew. Chem. Int. Ed. 1999, 38, 2384.
(2) For examples of 1-halo-2-alkoxyvinyl ether syntheses, see:
(a) Alks, V.; Sufrin, J. R. Synth. Commun. 1989, 19, 1479.
(b) Stalick, W. M.; Khorrami, A.; Hatton, K. S. J. Org.
Chem. 1986, 51, 3577. (c) Pirrung, M. C.; Hwu, J. R.
Tetrahedron Lett. 1983, 24, 565. (d)Taskinen, E.;Sainio, E.
Tetrahedron 1976, 32, 593. (e) Corey, E. J.; Hegedus, L. S.
J. Am. Chem. Soc. 1969, 91, 1233.
(3) Baati, R.; Barma, D. K.; Krishna, U. M.; Mioskowski, C.;
Falck, J. R. Tetrahedron Lett. 2002, 43, 959.
(4) Mn(0) has been utilized previously to regenerate Cr(II):
Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(5) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. J. Am.
Chem. Soc. 2001, 123, 9196.
Synlett 2006, No. 16, 2652–2654 © Thieme Stuttgart · New York

2654
J. R. Falck et al.
LETTER
Table 2 Synthesis of (Z)-1-Halo-1-alkenes and (Z)-1-Halo-2-alkoxy-1-alkenes
Entry
1
Reactant
Product
Temp (°C)/Time (h)
21/12
Yield (%)
Cl
Cl
92
75
Cl
Cl
1
2
O
O
Cl
2
21/12
Cl
O
3
Cl
O
Cl
4
OAc
OAc
Cl
Cl
3
4
21/7
83
80
Cl
OAc
OAc
Cl
5
6
8
Cl
Cl
Cl
50/18
Cl
7
9
Cl
Cl
Cl
Cl
Cl
5
6
50/12
21/16
45
86
10
Cl
Cl
O
O
Cl
12
11
O
Cl
O
Cl
Cl
Cl
Cl
O
O
7
8
21/24
21/24
95
92
MeO
MeO
MeO
MeO
13
15
14
CO2Me
O
CO2Me
O
Cl
Cl
Cl
16
18
Br
Br
O
O
9
21/3
21/6
93
68
Br
Br
17
Br
Br
O
O
Br
Br
O
O
10
MeO
MeO
19
21
20
22
Br
Br
64
11
Br
4/16
Br
(Z/E = 4:1)
(6) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7,
5417.
136.6, 128.9, 128.5, 127.6, 83.5, 74.6. 20: 1H NMR (300
MHz, CDCl3): d = 7.89 (ddd, J = 2, 2, 9 Hz, 2 H), 6.94 (ddd,
J = 2, 2, 9 Hz, 2 H), 6.62 (d, J = 4 Hz, 1 H), 5.22 (d, J = 4 Hz,
1 H), 5.08 (s, 2 H), 3.86 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 192.6, 164.3, 147.6, 130.5, 127.2, 114.2, 83.8,
74.0, 55.7.
(7) Nakagawa, M.; Saito, A.; Soga, A.; Yamamoto, N.; Taguchi,
T. Tetrahedron Lett. 2005, 46, 5257.
(8) Spectral data for 18: 1H NMR (400 MHz, CDCl3): d = 7.31–
7.38 (m, 5 H), 6.63 (d, J = 4 Hz, 1 H), 5.13 (d, J = 4 Hz, 1
H), 4.93 (s, 2 H). 13C NMR (100 MHz, CDCl3): d = 147.2,
Synlett 2006, No. 16, 2652–2654 © Thieme Stuttgart · New York