Short, stereoselective syntheses of α-fluoroalkenoate derivatives, α- fluoroenones and α-fluoroenals from HFC-134a

Article abstract of DOI:10.1016/S0040-4039(00)00154-4

Readily-available 1,1,1,2-tetrafluoroethane (Klea HFC-134a) can be converted, via a two-pot sequence into a range of Z-α-fluoroalkenoyl derivatives following addition reactions to aldehydes. Reaction adducts can be processed into enals and enones upon hydride reduction or Grignard reagent addition in high yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00154-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2453–2455
Short, stereoselective syntheses of α-fluoroalkenoate derivatives,
α-fluoroenones and α-fluoroenals from HFC-134a
M. Kanai † and J. M. Percy ∗
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 7 December 1999; accepted 18 January 2000
Abstract
Readily-available 1,1,1,2-tetrafluoroethane (Klea HFC-134a) can be converted, via a two-pot sequence into
a range of Z-α-fluoroalkenoyl derivatives following addition reactions to aldehydes. Reaction adducts can be
processed into enals and enones upon hydride reduction or Grignard reagent addition in high yield. © 2000 Elsevier
Science Ltd. All rights reserved.
Though they have little use directly as bioactive substances, Z-fluoroalkenoic acid derivatives have ser-
ved as precursors to a range of interesting species such as fluoroanalogues of retinals.1 Reduction affords
valuable fluoroallylic alcohols which can be transformed via rearrangement2 into fluoroapionucleosides3
and peptide isosteres.4 While a range of routes are available for the fluoroalkenoates, the one reported
by Allmendinger is perhaps best known.5 We were prompted to report our findings in this area by the
appearance of a recent paper by Lequeux and co-workers6 which described a novel synthesis of the
target compounds (esters) from a derivative of thioacetic acid. In this paper, we wish to report access to
related species from the new refridgerant and building block7 1,1,1,2-tetrafluoroethane (Klea HFC-134a)
1 which is available on a large scale. The groundwork was performed by Normant and co-workers, though
the details and scope were neither explored fully nor applied extensively. Lithiotrifluoroethene was
generated by direct deprotonation of trifluoroethylene at −135°C.8 Trapping the alkenyllithium reagent
with aldehydes and ketones, and subsequent hydrolysis afforded the reactive alkenoyl fluorides which
could be hydrolysed or trapped with ethanol or diethylamine. The Gilman reagent dimethyllithiocuprate
was also reported to intercept an acid fluoride cleanly at −80°C though this method does not appear to
have been used since.
In an extension of our recent exploration of a route to α-fluoroenones,9 we re-examined the Normant
chemistry and now wish to report that a complementary range of derivatives with useful properties can
indeed be prepared directly in two pots. Dehydrofluorination/metallation of HFC-134a occurred upon
treatment with n-butyllithium in THF10 and we prepared adducts with typical electrophiles, benzaldehyde
∗
†
Corresponding author.
Permanent address: Chemical Research Centre, Central Glass Co., Ltd, Kawagoe-Shi, Saitama-Ken 350-11, Japan.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00154-4
tetl 16434

2454
and cinnamaldehyde. Hydrolysis with aqueous sulfuric acid followed by extractive work up afforded
crude acid fluorides which were reacted further (Scheme 1), without characterisation or purification, with
nucleophiles. Given the size of the 3JH–F coupling (typically >30 Hz), the alkene configuration seemed
uncontroversial.
Scheme 1.
Adduct yields were effectively independent of the added nucleophile suggesting that the yield limiting
factor is the stability of the intermediate acid fluoride; we continue to attempt to improve this aspect of
the procedure in view of the high hydrolysis yields claimed in the original literature.8
Weinreb amides 3b and 3d are of particular value given the transformations described in Scheme 2.
Enones 4a–4c and enal 4d11 were prepared in excellent yield upon treatment of 3b with Grignard reagents
or DIBAl-H, respectively.12 Inexpensive thioesters are known to be of value, coupling with alkylzinc
halides in a mild palladium-catalysed synthesis of ketones,13 so the good yield of 3e was satisfying.
Scheme 2. Reactions of Weinreb amide 3b with nucleophiles in THF. For 4a, EtMgI (4.0 equiv.), rt, (82%); 4b, PhMgBr (3.0
equiv.), 0°C, (90%); 4c, H2C_CHCH2MgBr (3.0 equiv.), rt, (77%); 4d, DIBAl-H (2.0 equiv.), 0°C, (80%). All reactions were
run for 2 hours
Thioesters of this type can obviously be prepared from the corresponding acids, or via the route from
fluoroacetonitrile described by Pirrung14 which, while offering solutions to some special problems, is
relatively long and uses some hazardous reagents (HMPA, CS2, MeI, mercury(II) salts).
Given the generality of our recent route to α-fluoroenones,9 we believe that the hydrolysis can be
made to proceed smoothly given the correct selection of reaction conditions, allowing a wide range of
aldehydes to be deployed in the synthesis. A general retrosynthetic route to α-fluoroenones and enals
then becomes available, complementing existing routes and allowing an attractive starting material to be
used in a unifying strategy, implemented in a most concise (two- or three-pot) sequence.

2455
Acknowledgements
The authors wish to thank Central Glass Co. Ltd for a secondment to M.K. and ICI Klea for a generous
donation of HFC-134a.
References
1. Shinada, T.; Sekiya, N.; Bojkova, N.; Yoshihara, K. Tetrahedron 1999, 55, 3675.
2. Percy, J. M.; Prime, M. E. J. Fluorine Chem. 1999, 100, 147.
3. Hong, J. H.; Lee, K.; Choi, Y.; Chu, C. K. Tetrahedron Lett. 1998, 39, 3443.
4. Allmendinger, T.; Furet, P.; Hungerbühler, E. Tetrahedron Lett. 1990, 31, 7927, idem 7301.
5. Allmendinger, T. Tetrahedron 1991, 27, 4905.
6. Chevrie, D.; Lequeux, T.; Pommelet, J.-C. Org. Lett 1999, 1, 1539.
7. For a full discussion of two-carbon fluorinated building blocks, see: Percy, J. M. Top. Curr. Chem. 1997, 193, 131. For the
original report of dehydrofluorination/metallation of HFC-134a, see: Haslock, I. B.; Burdon, J.; Coe, P. L.; Powell, R. L.
Chem. Commun. 1996, 49.
8. Normant, J. F.; Foulon, J. P.; Masure, D.; Sauvêtre, R.; Villieras, J. Synthesis 1975, 122.
9. Bainbridge, J. M.; Corr, S.; Kanai, M.; Percy, J. M. Tetrahedron Lett. 2000, 41, 971.
10. n-BuLi (2.8 ml of 2.12 M solution in hexane, 6 mmol) was added dropwise to a cold (−78°C) stirred solution of HFC-
134a (134 ml, 6 mmol) in THF (10 ml). After 30 minutes, cinnamaldehyde (0.4 ml, 3 mmol) was added dropwise. After
stirring for 1 hour at −78°C, the reaction was allowed to warm to −30°C then sulfuric acid solution (concentrated sulfuric
acid:water=2 ml:0.1 ml) was added to the reaction mixture which was stirred for 20 minutes at 0°C. The reaction mixture
was then poured onto ice (30 g) and extractive work-up afforded the crude acid fluoride which was taken up in THF (10 ml).
N,O-Dimethylhydroxylamine in THF (3 ml) was cannulated into the solution at room temperature. After stirring for 2 hours,
the reaction was quenched with the addition of saturated ammonium chloride. Extractive work-up, column chromatography
and recrystallisation from Et2O/petroleum ether afforded 3d (208 mg, 31%, mp 122–124°C) as white needles. Selected data:
found: C, 66.56%; H, 6.08%; N, 5.76%; calcd for C13H14FNO2: C, 66.37%; H, 6.00%, N, 5.95%; δH (300 MHz, CDCl3)
7.43–7.40 (2H, m), 7.32–7.23 (3H, m), 7.03 (1H, dd, J 15.8, 10.7 Hz), 6.74 (1H, d, J 15.8 Hz), 6.60 (1H, dd, J 32.1, 10.7
Hz), 3.72 (3H, s), 3.21 (3H, d, J 0.7 Hz) δF (282 MHz, CDCl3) −123.00 (d, J 32.1 Hz). For details of gas handling, see:
Bainbridge, J. M.; Brown, S. J.; Ewing, P. N.; Gibson, R. R.; Percy, J. M. J. Chem. Soc., Perkin Trans. 1 1998, 2541.
11. Phenyl magnesium bromide (0.5 ml of 3 M solution, 1.5 mmol) was added to a solution of 3b (105 mg, 0.5 mmol) in THF
(5 ml) at 0°C. After stirring for 2 hours at room temperature, the reaction was quenched by the addition of saturated aqueous
ammonium chloride (20 ml). Extractive work-up, chromatography and recrystallisation from Et2O/petroleum ether afforded
4b (102 mg, 90%) reported previously (Chen, C.; Wilcoxen, K.; Zhu, Y.-F.; McCarthy, J. R. J. Org. Chem. 1999, 64, 3476)
by a considerably less convenient route.
12. Funabiki has also described an attractive enal synthesis, see: Funabiki, K.; Murata, E.; Fukushima, Y.; Matsui, M.; Shibata,
K. Tetrahedron 1999, 55, 4637.
13. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189.
14. Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683.