Highly chemoselective rhodium-catalyzed methylenation of fluorine-containing ketones.

Article abstract of DOI:10.1021/ol025730l

[reaction: see text] The rhodium(I)-catalyzed methylenation of functionalized fluorinated ketones using trimethylsilyldiazomethane proceeds to give the corresponding fluoromethylalkenes in good yields (61-90%). Remarkable chemoselectivity was observed for

Full text of DOI:10.1021/ol025730l

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1671-1674
Highly Chemoselective
Rhodium-Catalyzed Methylenation of
Fluorine-Containing Ketones
He´le`ne Lebel* and Vale´rie Paquet
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
lebelhe@chimie.umontreal.ca
Received February 16, 2002
ABSTRACT
The rhodium(I)-catalyzed methylenation of functionalized fluorinated ketones using trimethylsilyldiazomethane proceeds to give the corresponding
fluoromethylalkenes in good yields (61−90%). Remarkable chemoselectivity was observed for the synthesis of keto-substituted organofluorine
alkenes.
Organofluorine compounds have attracted considerable at-
tention in various fields, notably in medicinal chemistry, as
a result of their unique physiological and physical properties.1
As a result, numerous methodologies for the selective
introduction of fluoro substituents, such as CF3, into organic
molecules have been reported.2 The reactivity of fluorinated
molecules is also quite different from that of the related
hydrocarbons, mainly because of the strong electronic effect
of the fluorine atom.3 For instance, fluoromethylalkenes were
much more reactive than normal alkenes in a variety of
cyclization reactions.4 Functionalized gem-difluoroalkenes are
important synthetic intermediates displaying unique proper-
ties and have been used extensively in the synthesis of
fluorine-containing molecules.5 Different strategies have been
used for the preparation of fluoromethylalkenes, including
the palladium-catalyzed cross-coupling reaction of 2-bromo-
3,3,3-trifluoropropene and the Barbier-type reaction.6 The
methylenation of trifluoromethylketones has also been
reported for the preparation of trifluoromethylalkenes.7
However, to the best of our knowledge, such a strategy has
never been applied to the synthesis of mono- or difluoro-
(1) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley: New York,
1991. (b) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II: A Critical ReView. ACS Monograph Series 187; American
Chemical Society: Washington, DC, 1995. (c) Baasner, B.; Hagemann,
H.; Tatlow, J. C. Organo-Fluorine Compounds; Houben-Weyl: Thieme,
1999; Vols. 1-5. (d) Schofield, H. J. Fluorine Chem. 1999, 100, 7-11.
(e) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431-
12477.
(4) For selected examples, see: (a) Hanzawa, Y.; Suzuki, M.; Kobayashi,
Y.; Taguchi, T. J. Org. Chem. 1991, 56, 1718-1725. (b) De Clercq, P. J.;
Zhu, G. D.; Vanlancker, B.; Vanhaver, D.; Declercq, P. J. Bull. Soc. Chim.
Belg. 1994, 103, 263-271. (c) Nemoto, H.; Satoh, A.; Fukumoto, K.;
Kabuto, C. J. Org. Chem. 1995, 60, 594-600. (d) Nemoto, H.; Satoh, A.;
Fukumoto, K. Tetrahedron 1995, 51, 10159-10174. (e) Ichikawa, J.;
Fujiwara, M.; Okauchi, T.; Minami, T. Synlett 1998, 927-929. (f) Komatsu,
Y.; Sakamoto, T.; Kitazume, T. J. Org. Chem. 1999, 64, 8369-8374.
(5) (a) Begue, J. P.; Bonnetdelpon, D.; Rock, M. H. Synlett 1995, 6,
659-660. (b) Begue, J. P.; Bonnetdelpon, D.; Rock, M. H. Tetrahedron
Lett. 1995, 36, 5003-5006. (c) Begue, J. P.; Bonnetdelpon, D.; Bouvet,
D.; Rock, M. H. J. Org. Chem. 1996, 61, 9111-9114. (d) Begue, J. P.;
Bonnetdelpon, D.; Rock, M. H. J. Chem. Soc., Perkin Trans. 1996, 21,
1409-1413.
(2) (a) Synthetic Fluorine Chemistry; Olah, G. A., Prakash, G. K. S.,
Chambers, R. D., Eds.; Wiley: New York, 1992. (b) McClinton, M. A.;
McClinton, D. A. Tetrahedron 1992, 48, 6555-6666. (c) Prakash, G. K.
S.; Yudin, A. K. Chem. ReV. 1997, 97, 757-786. (d) Fei, X. S.; Tian, W.
S.; Chen, Q. Y. J. Chem. Soc., Perkin Trans. 1 1998, 1139-1142. (e) Sanin,
A. V.; Nenajdenko, V. G.; Smolko, K. I.; Denisenko, D. I.; Balenkova, E.
S. Synthesis 1998, 842-846. (f) Singh, R. P.; Shreeve, J. M. Tetrahedron
2000, 56, 7613-7632. (g) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett.
2000, 2, 2101-2103. (h) Singh, R. P.; Shreeve, J. M. J. Org. Chem. 2000,
65, 3241-3243. (i) Singh, R. P.; Leitch, J. M.; Twamley, B.; Shreeve, J.
M. J. Org. Chem. 2001, 66, 1436-1440.
(6) For selected examples, see: (a) Jiang, B. A.; Xu, Y. Y. Tetrahedron
Lett. 1992, 33, 511-514. (b) Iseki, K.; Kuroki, Y.; Nagai, T.; Kobayashi,
Y. J. Fluorine Chem. 1994, 69, 5-6. (c) Nader, B. S.; Cordova, J. A.;
Reese, K. E.; Powell, C. L. J. Org. Chem. 1994, 59, 2898-2901. (d) Peng,
S.; Qing, F. L.; Guo, Y. L. Synlett 1998, 859-860.
(3) (a) Chambers, R. D.; Vaughan, J. F. S. Top. Curr. Chem. 1997, 192,
1-38. (b) Percy, J. M. Top. Curr. Chem. 1997, 193, 131-195. (c) Lin, P.;
Jiang, J. L. Tetrahedron 2000, 56, 3635-3671.
10.1021/ol025730l CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/20/2002

methylalkenes. We have recently reported a new method for
the methylenation of aldehydes based on the in situ genera-
tion of methylenetriphenylphosphorane from the rhodium-
(I)-catalyzed decomposition of trimethylsilyldiazomethane
in the presence of triphenylphosphine and 2-propanol (eq
1).8 In this communication, we now present the methylena-
alkene derivatives were produced, albeit in low yields (entries
1 and 5). The major products observed in these cases were
the corresponding silyl enol ethers. The substitution of one
hydrogen by one fluorine atom on the ketone proved to have
a beneficial effect in improving the ketone reactivity. Indeed,
the methylenation of monofluoromethylketones under similar
reaction conditions proceeded extremely well, leading to the
formation of monofluoromethylalkenes with good yields
(entries 2 and 6).
The methylenation of difluoro- and trifluoromethylketones
was also successful, providing the corresponding alkenes with
73-81% yield (entries 3 and 4, 7 and 8). Activation by the
fluorine atom is quite remarkable, as all the reactions with
fluorine substrates presented in Table 1 were completed in
less than 2 h.
tion of fluoromethylketones, leading to a new synthesis of
fluoromethylalkenes. The chemoselectivity of this reaction
toward other keto functionalities will also be discussed.
Our interest in de novo synthesis of alkenes prompted us
to develop a new rhodium-catalyzed olefination reaction of
carbonyl derivatives using readily available reagents.8 The
reaction conditions do not require the use of a base and are
mild enough to be compatible with sensitive and enolizable
substrates, thereby allowing the synthesis of a variety of
functionalized alkenes in excellent yields. This method
constitutes a powerful means to access terminal olefins,
which are potent precursors for a variety of reactions,
including the ring-closing metathesis reaction.9 Moreover,
the chemoselectivity of the methylenation reaction is excel-
lent, and keto aldehydes react selectively to produce exclu-
sively the aldehyde methylenation product. To pursue our
work on rhodium-catalyzed methylenation reactions, we have
screened various ketones (Table 1). When aryl- or alkyl-
Table 1. Rhodium-Catalyzed Methylenation of
Fluoromethylketonesa
In a competitive experiment, we have found that the
rhodium-catalyzed methylenation of the aromatic trifluoro-
methylketone 10 was faster than with the corresponding
piperonal (9), as only the methylenation product 4 was
observed when using 0.5 equiv of trimethylsilyldiazomethane
(eq 3). However, we have observed a similar rate for the
methylenation of the corresponding aromatic monofluoro-
methylketone and piperonal, leading to a mixture both
terminal olefins.
As trifluoromethylalkenes are very useful synthetic build-
ing blocks, we surveyed the methylenation of a variety of
functionalized trifluoromethylketones. As outlined in Table
2, the yields are typically around 70-90%, which is
(7) (a) Nader, B. S.; Cordova, J. A.; Reese, K. E.; Powell, C. L. J. Org.
Chem. 1994, 59, 2898-2901. (b) Begue, J. P.; Bonnetdelpon, D.; Kornilov,
A. Org. Synth. 1998, 75, 153-160. (c) Faure, S.; Piva, O. Synlett 1998,
12, 1414-1416. (d) Yoshimatsu, M.; Sugimoto, T.; Okada, N.; Kinoshita,
S. J. Org. Chem. 1999, 64, 5162-5165. (e) Shen, Y. C.; Ni, J. H.; Li, P.;
Sun, J. J. Chem. Soc., Perkin Trans. 1 1999, 509-512.
a Conditions: TMSCHN2 (1.4 equiv), 2-propanol (1.1 equiv), triphenyl-
phosphine (1.1 equiv), and RhCl(PPh3)3 (2.5 mol %). b Isolated yield.
(8) Lebel, H.; Paquet, V.; Proulx, C. Angew. Chem., Int. Ed. 2001, 40,
2887-2890.
methylketones were reacted with trimethylsilyldiazomethane,
triphenylphosphine, and 2-propanol in THF using 2.5 mol
% of Wilkinson’s catalyst (ClRh(PPh3)3), the corresponding
(9) (a) Ackermann, L.; El Tom, D.; Furstner, A. Tetrahedron 2000, 56,
2195-2202. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29. (c) Furstner, A. Angew. Chem, Int. Ed. 2000, 39, 3013-3043.
1672
Org. Lett., Vol. 4, No. 10, 2002

trifluoromethylketone derived from enantiomerically pure
(S)-ethyl lactate. We have also synthesized trifluoromethyl-
ketone 20, starting from enantiomerically pure 3-benzyloxy-
2-methyl-propionaldehyde (18) (Scheme 1). The addition of
Table 2. Rhodium-Catalyzed Methylenation of
Trifluoromethylketones
Scheme 1. Synthesis of Trifluoromethylalkene 17
trimethylsilyltrifluoromethane catalyzed with cesium fluo-
ride10 produced the corresponding alcohol 19 as a mixture
of two diastereoisomers. Oxidation with Dess-Martin pe-
riodinane reagent provided the desired trifluoromethylketone
20 with >95% ee.11,12 This chiral ketone is prone to
racemization upon flash chromatography and was used
directly in the olefination reaction without any further
purification. However, racemic trifluoromethylalkene 17 was
isolated in 90% yield, indicating that the trifluoromethyl-
ketone 20 racemized under the reaction conditions.
Using chiral GC analysis of the olefination reaction
mixture, we have established that the racemization of
trifluoromethylketone 20 was very fast, and after only 2 min
of reaction, we observed complete racemization of the
starting material. Although usually we did not observe any
racemization when using chiral nonracemic substrates, very
sensitive substrates such as 20 cannot be converted into the
corresponding terminal olefin without racemization.
The low reactivity of methylketones in the rhodium-
catalyzed methylenation reaction suggested a possible use
of this reaction as a chemoselective method for the meth-
ylenation of fluoromethylketones in the presence of aryl or
alkyl ketones. We synthesized a number of keto fluoro-
methylketone substrates to test our hypothesis (Table 3).
Indeed the rhodium-catalyzed methylenation reaction with
trimethylsilyldiazomethane is highly chemoselective. Only
traces of the diene were observed in the methylenation of
the keto-monofluoromethylketone that produced mainly the
desired product 21 in moderate yield (entry 1). In the case
of the keto-difluoromethylketone, the methylenation favored
a Isolated yield. b Conditions: TMSCHN2 (1.4 equiv), 2-propanol (1.1
equiv), triphenylphosphine (1.1 equiv), and RhCl(PPh3)3 (2.5 mol %).
c Alkene 13 was characterized as the corresponding diol. See Supporting
Information. d Conditions: TMSCHN2 (2.8 equiv), 2-propanol (2.1 equiv),
triphenylphosphine (2.1 equiv), and RhCl(PPh3)3 (5 mol %). e Conditions:
TMSCHN2 (2.0 equiv), 2-propanol (1.5 equiv), triphenylphosphine (1.5
equiv), and RhCl(PPh3)3 (2.5 mol %).
comparable or superior to those obtained under the standard
Wittig reaction conditions (Ph3PCH3Br and NaHMDS).
Hindered substrates such as adamantyltrifluoromethyl-
ketone (Table 2, entry 1) reacted smoothly to give the
corresponding alkene (11) in an excellent yield. Numerous
protecting groups, such as methoxymethyl ether, tert-
butylcarbamate, acetonide, and benzyl and p-nitrobenzyl
ethers, are compatible with the reaction conditions. The
volatile trifluoromethylalkene 13 was converted to the
corresponding diol for isolation purpose. As the rhodium-
catalyzed methylenation reaction conditions are mild and
nonbasic, we were expecting very little racemization when
using chiral nonracemic fluoro substrates. Indeed, trifluoro-
methylalkene 14 and 15 derived from enantiomerically pure
amino acids (L-serine and L-phenylalanine) have been
recovered with 93% and 96% ee, respectively. In addition,
trifluoromethylalkene 16 was recovered in 83% yield and
95% ee starting from the corresponding enantioenriched
(10) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393-395. (b) Singh, R. P.; Cao, G.; Kirchmeier, R.; Shreeve,
J. M. J. Org. Chem. 1999, 64, 2873-2876.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(c) Linderman, R. J.; Graves, D. M. J. Org. Chem. 1989, 54, 661-668.
(12) Although there are some procedures for the direct preparation of
trifluoromethylketones from carboxylic esters, those require the use of
rigously anhydrous TBAF; see: Wiedemann, J.; Heiner, T.; Mloston, G.;
Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 1998, 37, 820-821.
We found it more practical to use the two-step procedure described above.
Org. Lett., Vol. 4, No. 10, 2002
1673

resulting from the reaction of the two carbonyls (entries 3
and 4). In comparison, only 50% yield of the keto olefin 23
was obtained when using the standard Wittig reaction
conditions (Ph3PCH3Br and NaHMDS). After 24 h, the
reaction was not complete (25% of the starting material was
recovered) and 5-10% yield of the diene was also isolated.
The chemoselectivity of the rhodium-catalyzed methylenation
reaction is quite remarkable since it is possible to discriminate
between two ketone derivatives only on the basis of their
electrophilic character. Although this concept has been
widely used for other reactions, this is one of the first
examples of such chemoselectivity in an olefination reaction.
Table 3. Chemoselective Methylenation of
Fluoromethylketonesa
In summary, we have described a versatile synthesis of
useful fluoromethylalkenes that makes use of stereoelectronic
effect of the fluorine atom. Fluoro-carbonyl substrates were
found to be very reactive toward the rhodium-catalyzed
methylenation reaction. In addition, a remarkable chemo-
selectivity was observed for the methylenation of keto-
fluoromethylketone substrates, thus eliminating the need for
protecting groups. As a result, this method provides new tools
to access organofluorine derivatives that are of primary
importance in medicinal chemistry
a Conditions: TMSCHN2 (1.4 equiv), 2-propanol (1.1 equiv), triph-
enylphosphine (1.1 equiv), and RhCl(PPh3)3 (2.5 mol %). b Isolated yield.
c Values in parentheses refer to the amount of diene derivatives. d Condi-
tions: TMSCHN2 (2.0 equiv), 2-propanol (2.0 equiv), triphenylphosphine
(1.5 equiv), and RhCl(PPh3)3 (2.5 mol %).
Acknowledgment. This research was supported by
NSERC (Canada), F.C.A.R (Que´bec), the Canadian Founda-
tion for Innovation, the Research Corporation, and the
Universite´ de Montre´al.
Supporting Information Available: Experimental pro-
also the difluoromethylketone, and the alkene 22 was isolated
in 62% yield (entry 2). In this case, the amount of diene
was slightly more important, typically between 5% and 10%.
Furthermore, products 23 and 24 were isolated in 77% and
63% yield along with 7% and 8% of the corresponding diene
1
cedures, compound characterization data, and H and 13C
spectra of all the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025730L
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Org. Lett., Vol. 4, No. 10, 2002