J. Cheng et al. / Tetrahedron Letters 52 (2011) 3481–3484
3483
Table 3 (continued)
Entry
Substrate
Product
With 5 mol % ZnCl b
2
Without catalystc
Time (h) Yield (%)
Time (h)
Yield (%)
S
CF CH NH
2
2
2
1
0
1
6e
6a
11
80
86
45
78
1
j
N
CF H
2
1
H
3
40d
60d
1
k
CF H
2
1
1
2
3
32
2
3
32d
3d
0d
1l
6f
CH
2
FCH CH
2
2
CH OH
CH
3
CH
2
2
OH
89
86d
1m
6g
a
b
c
4
Reaction conditions: LiAlH (2–6 equiv, see Supplementary data), diethyl ether, reflux.
Yields were based on GC analysis.
See Ref. 14.
d
This work.
O
F
F
N
H
Br
N
F
- 2HF
H
N
H
N
H
N
N
H
H
F
F
F
1a
2
3
4
5
6a
4
Scheme 3. Proposed mechanism for the hydrodefluorination of difluoromethylene-containing derivatives (for example, 6a) with LiAlH .
corresponding products in high yields in shorter reaction times
than those required by our previous method in the absence of cat-
alyst. It seems that ethyl 4,4-difluoroacetoacetate 1h, a kind of 1,3-
dicarbonyl, was unfavorable for the reaction in the presence of
Shanghai Foundation of Science of Technology (09391911800),
and the Shanghai Leading Academic Discipline Project (B507).
Supplementary data
2
ZnCl , only a lower yield was obtained. When (2,2-difluoroeth-
yl)benzene 1l was used as a substrate, trace amounts of hydrodeflu-
orinated product was observed with or without catalyst even after
long reaction times. The results indicated that the heteroatom (in
2
the b position relative to CF group) exerts a significant influence
on the reactivity of difluoromethylene substrates (two examples
References and notes
of the influence of heteroatom atom on the dehydrofluorination
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purpose, 3-fluoropropan-1-ol 1m which contains only one fluorine
atom was examined. It was found that 3-fluoropropan-1-ol affor-
ded good yield of the corresponding hydrodefluorinated product
irrespective of whether catalyst is present or not.
Based on the above observations, a mechanism for the formation
of 6a–g (for example, 6a) is outlined in Scheme 3. The intermediates
2
.
(a) Jana, A.; Samuel, P. P.; Tav cˇ ar, S.; Roesky, H.; Schulzke, C. J. Am. Chem. Soc.
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3.
.
2, 3, and 5 can be detected by GC/MS, but the intermediates 4 could
4
not observed. This is because alkyne is unstable and rapidly under-
5. Fuchibe, K.; Akiyama, T. Synlett 2004, 1282–1284.
6. Reade, S. P.; Mahon, M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 1847–
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goes reduction to form alkene 5.18 The nitrogen atom in intermedi-
1
ates 3 presumably assists the cleavage of the C–F bond. The
intermediate 5 is easily to be reduced to alkane 6a in the presence
7.
(a) Jones, W. D. Dalton Trans. 2003, 3991–3995; (b) Jäger-Fiedler, U.; Klahn, M.;
Arndt, P.; Baumann, W.; Spannenberg, A.; Burlakov, V. V.; Rosenthal, U. J. Mol.
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1
8a,19
of the metal catalyst.
Unfortunately, attempts to isolate pure
8.
(a) Kuhl, S.; Schneider, R.; Fort, Y. Adv. Synth. Catal. 2003, 345, 341–344; (b)
Prikhod’ko, S. A.; Adonin, N. Y.; Parmon, V. N. Tetrahedron Lett. 2010, 51, 2265–
2268.
intermediates 2, 3, and 5 were unsuccessful.
In summary, we reported a novel system for the hydrodefluori-
nation of gem-difluoromethylene derivatives with lithium alumi-
9. (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302–1315; (b) Jerphagnon,
T.; Gabriella Pizzuti, M.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38,
20
num hydride in the presence of 5 mol % ZnCl
2
.
The catalytic
1
039–1075.
0. Sun, C.; Li, B.; Shi, Z. Chem. Rev. 2010, 111, 1293–1314.
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reaction involves a simple, inexpensive, easy available and envi-
ronment-friendly zinc chloride salt without ancillary ligands. The
method offers other advantages including high yields and short
reaction times.
1
1
Tetrahedron Lett. 2011, 52, 1498–1502; (c) Khatab, T. K.; EL-Bayouki, K. A. M.;
Basyouni, W. M. Tetrahedron Lett. 2011, 52, 1448–1451.
1
1
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Acknowledgments
8
560; (b) Gu, W.; Haneline, M. R.; Douvris, C.; Ozerov, O. V. J. Am. Chem. Soc.
We are grateful for financial supports from the National Natural
Science Foundation of China (Grant No. 21072057), the National
Basic Research Program of China (973 Program, 2010CB126101),
2009, 131, 11203–11212; (c) Fuchibe, K.; Mitomi, K.; Suzuki, R.; Akiyama, T.
Chem. Asian J. 2008, 3, 261–271; (d) Douvris, C.; Nagaraja, C. M.; Chen, C.;
Foxman, B.; Ozerov, O. V. J. Am. Chem. Soc. 2010, 132, 4946–4953.