New, general, and stereoselective synthesis of CF3-containing tri- and tetrasubstituted oxiranes and tetrasubstituted alkenes

Full text of DOI:10.1021/ja016077k

J. Am. Chem. Soc. 2001, 123, 6947-6948
6947
the expected CF3 or R1 rearrangement were detected. The same
reaction with quenching at -78 °C afforded 5a (58% yield) and
2-butyl-3-(2-phenylethyl)-3-trifluoromethyloxirane (3a, 33% yield).
When the reaction was effected and quenched at -98 °C, 3a was
solely obtained in 85% yield as a single diastereomer.
Formation of oxirane of type 3 in Scheme 1 is general
irrespective of R1 and R2 (Table 1).4 Thus, the reaction of
dichlorohydrins 1b-d (R1 ) phenyl, styryl, or phenylethynyl)
with BuLi produced the corresponding oxiranes 3b-d in good
yields with good to high stereoselectivity (runs 2-4). In addition
to BuLi, MeLi, PhLi, and vinyllithium also reacted with 1d to
give 3e-g stereoselectively (runs 5-7).5 Furthermore, we found
that treatment of 1 with BuLi and then with electrophiles gave
tetrasubstituted oxiranes 3h-n with similar high selectivity (runs
8-14).
New, General, and Stereoselective Synthesis of
CF3-Containing Tri- and Tetrasubstituted Oxiranes
and Tetrasubstituted Alkenes
Masaki Shimizu,* Takuya Fujimoto, Hiroshi Minezaki,
Takeshi Hata, and Tamejiro Hiyama
Department of Material Chemistry
Graduate School of Engineering, Kyoto UniVersity
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
ReceiVed April 24, 2001
ReVised Manuscript ReceiVed June 9, 2001
We report that treatment of 2-substituted 3,3-dichloro-1,1,1-
trifluoropropan-2-ol 11 with an organolithium reagent R2Li in THF
at -98 °C produces 2,3-disubstituted 2-lithio-3-trifluoromethyl-
oxirane 2 stereoselectively that reacts with an electrophile El-X
or an organoborane R3BR2 stereospecifically to give CF3-
containing tri- and tetrasubstituted oxirane 3 or tetrasubstituted
alkene 4, respectively, with high selectivities (Scheme 1).
In the case of alkylation, both diastereomers of tetrasubstituted
oxiranes 3 can be prepared by proper choice of R2Li and El-X as
illustrated in eq 2. Thus, 3o was obtained from 1d using BuLi
and MeI, whereas the other diastereomer 3o′ was produced by
MeLi-induced generation of 2 followed by trapping with BuI.
Scheme 1
Stereochemistry of 3 was determined by X-ray crystallographic
analysis of benzophenone adducts 3k and 3m and CF3 and El
were shown to be cis.6 These results indicate that oxiranyllithiums
2 were stereoselectively generated as intermediates with CF3 and
Li being cis in all cases.7
Stereoselective generation of 2 can be tentatively explained
by assuming a lithium-fluorine chelation model (Scheme 2).8
At first, 1 would react with 2 molar amounts of BuLi to produce
â-oxidocarbenoid 6. We assume that the conformation of 6 in
which a CF3 group and a lithium atom connecting a carbenoid
carbon are arranged synclinal is favored due to Li-F chelation.
Substitution of chlorine in 6 with BuLi from the OLi side followed
by intramolecular cyclization would generate 2 that was stable
at -98 °C and reacted with an electrophile producing 3.
Alternatively, cyclization of 6 might take place at first to give a
It is well-established that the rearrangement of â-oxido
carbenoids generated from dihalohydrins is useful for homolo-
gation of aldehydes as well as acyclic and cyclic ketones,2 while
there is no precedent regarding CF3-substituted â-oxido car-
benoids. We became interested in the carbenoids in view of novel
synthesis of CF3-containing organic molecules that are receiving
much attention in pharmaceutical and material sciences.3
(3) (a) Fluorine-containing molecules: Structure, ReactiVity, Synthesis, and
Applications; Liebman, J. F.; Greenberg, A.; W. R. Dolbier, J., Eds.; VCH:
New York, 1988. (b) Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum Press:
New York, 1994. (c) Chemistry of Organic Fluorine Compounds II A Critical
ReView; Hudlicky, M.; Pavlath, A. E., Eds.; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995. (d) Organofluorine Chemistry:
Fluorinated Alkenes and ReactiVe Intermediates, Chambers, R. D., Ed.: Top.
Curr. Chem. Vol 192; Springer: Berlin, 1997. (e) Organofluorine Chemis-
try: Techniques and Synthons, Chambers, R. D., Ed.: Top. Curr. Chem. Vol
193; Springer: Berlin, 1997. (f) Hiyama, T. Organofluorine Compounds-
Chemistry and Applications; Springer: Berlin, 2000. (g) Begue, J.-P.; Bonnet-
Delpon, D. Tetrahedron 1991, 47, 3207-3258. (h) McClinton, M. A.;
McClinton, D. A. Tetrahedron 1992, 48, 6555-6666.
We first treated 1a with 3 molar amounts of BuLi at -78 °C
and then warmed the reaction mixture to room temperature before
quenching with MeOH. Workup and purification by column
chromatography (silica gel) unexpectedly gave (E)-allylic alcohol
5a as the sole product in 58% yield. No products derived from
(4) Treatment of PhMeC(OLi)CHCl2 or Ph2C(OH)CHCl2 with excess BuLi
or PhLi was reported to produce respectively MeCOCH(Cl)Ph or Ph2CHCOPh
in ref 2f. It is not clear why no rearrangement took place in 1. The fluorine
atoms may destabilize the positively charged transition state for a migration
of either the trifluoromethyl group or R1, as one of the referees suggested.
(5) s-BuLi and t-BuLi gave complex mixtures; PhCtCLi, no reaction.
(6) For the detail, see Supporting Information.
(1) Dichlorohydrin 1 were prepared from R1MgBr and 3,3-dichloro-1,1,1-
trifluoropropan-2-one kindly provided by Central Glass Co. Ltd. For the detail,
see Supporting Information.
(2) (a) Concise review of rearrangement of â-oxido carbenoids: Wovkulich,
P. M. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 1, pp 873-877. (b) Boche, G.; Lohrenz,
J. C. W. Chem. ReV. 2001, 101, 697-756. For pioneering works, see (c)
Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem. 1972, 40, C1-
C4. (d) Ko¨brich, G.; Grosser, J. Tetrahedron Lett. 1972, 4117-4120. (e)-
Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1972, 4661-4662.
(f) Ko¨brich, G.; Grosser, J. Chem. Ber. 1973, 106, 2626-2635. (g) Villieras,
J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem. 1975, 97, 325-354. (h)
Taguchi, H.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1977, 50, 1592-
1595.
(7) Trapping of oxiranyllithium with such an electrophile as D2O, Me3-
SiCl, MeI, aldehydes, or ketones was reported to proceed with retention of
configuration at the lithiated carbon. (a) Eisch, J. J.; Galle, J. E. J. Organomet.
Chem. 1988, 341, 293-313. (b) Molander, G. A.; Mautner, K. J. Org. Chem.
1989, 54, 4042-4050. (c) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz,
A. Tetrahedron Lett. 1991, 32, 615-618.
(8) For Li-F interaction, see ref 3f, p 129. One of the referees kindly
suggested the possibility of dipole effects responsible for the cis selectivity.
10.1021/ja016077k CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/21/2001

6948 J. Am. Chem. Soc., Vol. 123, No. 28, 2001
Table 1. Synthesis of Tri- and Tetrasubstituted Oxiranesa
Communications to the Editor
Table 2. Synthesis of Tetrasubstituted Alkenes (R1 ) PhCtC)a
yield isomer
run R2
R3BR2
4
yield (%)b isomer ratioc
run
R1
R2
Bu
Bu
Elb
3
(%)c
ratiod
1
2
3
4
5
Bu EtBEt2
Bu PhB(OCMe2)2
Bu (E)-BuCHdCHB(OCMe2)2 4c
Bu PhCtCB(OCMe2)2
Ph BuB(OCMe2)2
4a
4b
45
66
56
74
84
>95:<5
97:3
>95:<5
>95:<5
4:96
1
2
3
4
5
6
7
8
9
Ph(CH2)2
Ph
(E)-PhCHdCH Bu
PhCtC
PhCtC
PhCtC
PhCtC
PhCtC
PhCtC
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
85
83
74
84
85
95
67
79
82
71
68
57
55
70
>95:<5
89:11
83:17
4d
4b
Bu
Me
Ph
C2H3
Bu
Bu
Bu
Bu
Bu
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
e
>95:<5
>95:<5
>95:<5
89:11
a To a solution of 1d (1.0 mmol) in THF (5 mL) was added R2Li (3
mmol) at -98 °C and the mixture was stirred at -98 °C for 15 min
before R3BR2 (2.0 mmol) was added. The resulting solution was
gradually warmed to room temperature and refluxed for 4 h. b Isolated
3g
3h
Me3Si
PhCH(OH) 3i
Et2C(OH)
Ph2C(OH)
Ph2C(OH)
Ph2C(OH)
C3H5
yield. c Determined by H and 19F NMR analysis.
1
10 PhCtC
11 PhCtC
12 Ph(CH2)2
13 (E)-PhCHdCH Bu
14 PhCtC Bu
3j
3k
3l
3m
3n
Scheme 3
>95:<5
a To a solution of 1 (1.0 mmol) in THF (5 mL) was added R2Li (3
mmol) at -98 °C and the mixture was stirred at -98 °C for 15 min
before adding MeOH or El-X (1.5 mmol). As for runs 8-14, the
resulting solution was gradually warmed to -78 °C and quenched with
MeOH. b The El-X employed were as follows: runs 1-7, MeOH; run
8, Me3SiCl; run 9, PhCHO; run 10, Et2CO; runs 11-13, Ph2CO; run
14, allyl bromide. c Isolated yield. d Determined by H and 19F NMR
1
analysis. e Two of four possible diastereomers were obtained in a ratio
of 60:40.
2d reacted with Et3B to give 4a in 45% yield with excellent
selectivity (Table 2).12 (Pinacolato)borane showed better reactivity,
and thus aryl, alkenyl, alkynyl, and alkyl groups were applicable
to this stereospecific alkene formation as a R3 substituent (runs
2-5). Stereochemical assignment was effected by X-ray analysis
of 4b to reveal CF3 and phenyl being cis.6 Noteworthy is that
appropriate combination of R2 and R3 allows us to selectively
prepare either stereoisomer of 4 at will as demonstrated in runs
2 and 5.
Scheme 2
Furthermore, it is remarkable that stereodivergent synthesis of
â-CF3-substituted alkenylborane 4e can be achieved, using bis-
(pinacolato)diboron or (dimethyphenysilyl)(pinacolato)borane as
the organoboron reagent (Scheme 3).13
In summary, we have developed stereoselective synthesis of a
variety of CF3-containing tetrasubsituted oxiranes and alkenes in
one pot from readily available dichlorohydrins, which would serve
as highly valuable intermediates for stereoselective construction
of CF3-containing complex organic molecules. Further study on
â-oxido carbenoids bearing a CF3 group is in progress.
chlorolithiooxirane. Subsequently, the remaining chlorine might
be substituted stereoselectively by the third BuLi to give rise to
2.9 At temperatures above -78 °C, 2 would cause ring-opening
via R-elimination followed by adjacent C-H bond insertion of
intermediate carbene 7 to give 5a.
With stereochemically defined 2 being formed at -98 °C, we
next studied the reaction of 2 with an organometallic reagent to
develop a novel method for CF3-containing tetrasubstituted
alkenes 4 (Scheme 1).10 Although 2 did not react with BuLi any
more,11 tetrasubstituted alkenes 4 were produced in low yields
when 2 was treated with Me3Al or Et2Zn. For this transformation,
organoboron compounds were found appropriate. For example,
Acknowledgment. We thank the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, for the Grand-in-Aid for COE
Research on Element Science, No. 12CE2005, and the Central Glass Co.
Ltd. for a generous gift of dichlorotrifluoroacetone.
Supporting Information Available: Typical procedures, spectral data
for new compounds, and X-ray crystallographic data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA016077K
(11) The results contrast sharply to those obtained by Mioskowski and co-
workers: Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994,
35, 7943-7946. See also, Eisch, J. J.; Galle, J. E. J. Org. Chem. 1976, 41,
2615-2621. Ukaji, Y.; Yoshida, A.; Fujisawa, T. Chem. Lett. 1990, 157-
160.
(12) The reactivity of 2d towards organoboranes contrasts to that of
oxiranyllithium generated from triphenylsilyloxirane: Taniguchi, M.; Oshima,
K.; Utimoto, K. Tetrahedron Lett. 1991, 32, 2783-2786.
(13) Hata, T.; Kitagawa, H.; Masai, H.; Kurahashi, T.; Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2001, 40, 790-792.
(9) Molines, H.; Normant, J.-M.; Wakselman, C. Tetrahedron Lett. 1974,
951-954.
(10) Reviews on oxiranyllithiums: (a) Satoh, T. Chem. ReV. 1996, 96,
3303-3325. (b) Molander, G. A.; Mautner, K. Pure Appl. Chem. 1990, 62,
707-712. Such an organometalic compound as RLi, R3Al, R2Zn, or R4CeLi
reportedly reacted with oxiranyllithiums to afford alkylated alkenes.