A facile approach to 2-CF3-substituted seven-membered oxacycles via stereoselective preparation and cope rearrangement of 2-CF 3-cis-2,3-bis(alkenyl)oxiranes

Article abstract of DOI:10.1246/cl.2004.438

Stereoselective preparation and Cope rearrangement of 2-CF ₃-substituted cis-2,3-bis(alkenyl)oxiranes provides a convenient route to a diverse of 2-CF₃-4,5-dihydrooxepins. The reaction sequence followed by reduction or oxidation provides 2-CF₃-substituted oxepanes or oxepins, respectively.

Full text of DOI:10.1246/cl.2004.438

438
Chemistry Letters Vol.33, No.4 (2004)
A Facile Approach to 2-CF3-Substituted Seven-membered Oxacycles via Stereoselective
Preparation and Cope Rearrangement of 2-CF3-cis-2,3-Bis(alkenyl)oxiranes
Masaki Shimizu,ꢀ Takuya Fujimoto, Xinyu Liu, and Tamejiro Hiyama
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Katsura Campus, Nishikyo-ku, Kyoto 615-8510
(Received January 6, 2004; CL-040017)
Stereoselective preparation and Cope rearrangement of
screening experiments, use of lithium 2,2,6,6-tetramethylpiperi-
dide (LiTMP, 3 molar amounts) in addition to vinyllithium was
found highly effective to give rise to the corresponding oxiranyl-
lithiums,4 which could be trapped with a variety of electrophiles
(Eþ) to give 5. The lithium amide base could deprotonate and vi-
nyllithium could behave as a nucleophile as we expected. The
modified procedure was applied to synthesis of various kinds
of 5 as summarized in Table 1. Generally, cis-5 was produced
as a single diastereomer except for 5e (cis/trans = 92:8), 5i
(89:11), and 5q (78:22).5
2-CF3-substituted cis-2,3-bis(alkenyl)oxiranes provides a con-
venient route to a diverse of 2-CF3-4,5-dihydrooxepins. The
reaction sequence followed by reduction or oxidation provides
2-CF3-substituted oxepanes or oxepins, respectively.
Incorporation of a trifluoromethyl group in biologically ac-
tive compounds can alter chemical properties as well as biolog-
ical activities of parent compounds, so that trifluoromethylated
compounds are of great significance in pharmaceutical and agro-
chemical research.1 Meanwhile, much attention is focused on
such seven-membered oxacycles as oxepanes and oxepins owing
to their occurrence in biologically active natural products.2 From
such viewpoints, development of facile synthetic methods for
CF3-substituted seven-membered oxacycles, a novel class of
CF3-containing compounds, is of particular interest for explora-
tion of potent biologically active substances.
We have recently reported that CF3-containing dichlorohy-
drins 1 (R = aryl, alkyl, alkenyl, alkynyl) react with 3 molar
amounts of R0Li (R0 = alkyl, aryl, vinyl) at ꢁ98 ꢂC to give
cis-2,3-disubstituted 2-lithio-3-trifluoromethyloxiranes 2, which
react with various electrophiles (Eþ) to give CF3-containing tri-
and tetrasubstituted oxiranes 3 stereoselectively (Scheme 1).3
We envisioned that 2-CF3-substituted 4,5-dihydrooxepins 6
could be easily prepared if stereoselective preparation of cis-
bis(alkenyl)oxiranes 5 from alkenyl-substituted dichlorohydrins
4 with alkenyllithiums and subsequent Cope rearrangement were
feasible.
Table 1. Preparation of 2-CF3-cis-2,3-bis(alkenyl)oxirane 5a
Entry
5
R1
R2
R3
R4
E
Yield/%b
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
H
H
H
H
Me
77
72
64
77
70c
72
62
Me3Sn
Me3Si
MeO2C
(Me2CO)2B
Ph2C(OH)
TBS
d
-
H
86c
75
71
80
60
56
46
25
69c
10
11
12
5j
5k
5l
Me3Si
Me3Si
H
PhCH2
Me3Sn
TBS
H
H
H
H
13 5m
14
15
16
17
5n
5o
5p
H
Ph -(CH2)3O-
H
H
Me3Si
5q -O(CH2)3-
H
aTo a solution of an alkenyllithium (3.0 mmol) in THF (5 mL) was
added dichlorohydrin 4 (1.0 mmol) at ꢁ98 ꢂC and then LiTMP
(3.0 mmol, 0.67 M in THF) at ꢁ98 ꢂC. The resulting solution
was stirred at ꢁ98 ꢂC for 3–6 h and then treated with an electro-
phile [MeOH (entries 1, 9, 12, and 16); MeI (Entry 2); Me3SnCl
(Entries 3 and 14); Me3SiCl (Entries 4, 10, 11, and 17); CO2/
Me3SiCHN2 (Entry 5); (Me2CO)2B(OiPr) (Entry 6); Ph2C=O
(Entry 7); TBSOTf (Entries 8 and 15); BnBr (Entry 13)] at
ꢁ98 ꢂC. The solution was warmed gradually to ꢁ78 ꢂC before
quenching with saturated aqueous NH4Cl solution. bIsolated
E+
HO CF3
O
O
3 R'Li
Li
CF3
R
E
CF3
R
Cl
R
R'
R'
Cl
1
2
3
R4
E
CF3
R1
O
HO CF3
O
R3
E
CF3
R1
1) 3
"Cope"
Cl
R1
R2
R4
R3
Li
R4
Cl
2) 3 LiTMP
3) E+
R3
R2
R2
c
d
4
5
6
yields. Isolated yields of a cis/trans mixture. Product 5h rear-
ranged even at room temperature.
Scheme 1. A facile route to 2-CF3-substituted 4,5-dihydrooxe-
pins 6.
With cis-bis(alkenyl)oxiranes 5 in hand, we next studied the
Cope rearrangement.6 At first, 2-phenylethenyl- and vinyl-sub-
stituted oxiranes 5a–h were selected as a typical model and heat-
ed in CCl4 solutions. The rearrangement of 5a and 5b proceeded
in high yields at 100 ꢂC in 12 and 8 h, respectively, as shown in
Entries 1 and 2 of Table 2. cis-Bis(alkenyl)oxiranes 5c–e with
Me3Sn, Me3Si, or MeO2C reacted at lower temperatures in
shorter times (Entries 3–5). In case of 5e, trans isomer did not
At first we applied the sequence of operations to synthesis of
5 and found that the original reaction protocol totally failed to
give the expected products. Considering the fact that reaction
of 4 (R1 = H, R2 = Ph) with BuLi or of 1 (R = CꢃCPh) with
vinyllithium generated the corresponding lithio-oxirane (2), we
ascribed the failure to not only lower basicity of vinyllithium
but also lower acidity of a methine proton of 4. After many
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.4 (2004)
439
Table 2. Cope rearrangement of 5a–ha
E
CF3
R
CF3
O
O
R
X
Entry
5
Temp/ꢂC
Time/h
6
Yield/%b
Pd2(dba)3 (2.5 mol%)
P(t-Bu)3 (10 mol%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
100
100
80
80
80
60
60
60
12
8
4
2
2
3
3
2
6a
6b
6c
6d
6e
6f
93
85
88
Ph
Ph
6c: iodobenzene, CsF, dioxane, 100 °C
6f: vinyl bromide, KOH, THF, rt
6f: bromophenylacetylene, KOH, THF, rt
7 (R = Ph, 80%)
8 (R = vinyl, 75%)
9 (R = C≡CPh, 78%)
92
96[c]
99
Scheme 2. Synthetic utility of metalated products
5g
5h
6g
6h
95
55[d]
E
CF3
O
E
CF3
H2 (1 atm)
Pd/C (cat.)
O
6g, 6h
or
6m, 6o
DDQ
aA solution of oxirane 5 (0.5 mmol) in CCl4 (3 mL) was heated
in a sealed tube. The progress of the reaction was monitored by
19F NMR. bIsolated yields. cIsolated yield based on reacted cis-
diastereomer of 5. Isolated yield based on the corresponding
dichlorohydrin.
toluene
100 °C
EtOH, RT
Ph
d
12 (E = TBS, 93%)
13 (E = Ph2C(OH), 82%)
10 (E = TBS, 93%, ds = 90 : 10)
11 (E = Bn, 90%, ds = 95 : 5)
Scheme 3. Conversion of 6 to oxepanes and oxepins.
undergo the rearrangement at all under the conditions and was
recovered quantitatively. Furthermore, the reaction was marked-
ly accelerated by a large group like (pinacolato)boryl or hydrox-
ydiphenylmethyl (Entries 6 and 7). Noteworthy is that tert-butyl-
dimethylsilyl (TBS)-substituted oxirane 5h rearranged even at
room temperature to prevent the isolation. Thus, bulkiness of
substituent E appears to force two terminal sp2 carbons to locate
close each other and to accelerate the Cope rearrangement.
The scope of this approach to 6 is readily seen in Table 3.
The isolated yields of 6 were generally high. Rate-enhancement
of the rearrangement by incorporation of a silyl or stannyl group
was again observed (Entries 2, 3, 6, 7, and 9). An enol moiety
also could participate in the rearrangement (Entries 8 and 9).
Thus, bicyclic oxepins 6p7 and 6q were isolated in high yields
after purification by silica gel column chromatography.
ceeded stereoselectively to give 10 and 11, respectively, with
high cis selectivity,8 while 6g and 6h were dehydrogenated effi-
ciently to afford 12 and 13 in good yields when DDQ was em-
ployed as an oxidant in toluene.
In summary, we have developed a facile synthetic route to 2-
CF3-substituted seven-membered oxacycles, which involves cis-
selective preparation of 2,3-bis(alkenyl)oxiranes substituted by a
CF3 group and an arbitrarily incorporated substituent E followed
by the Cope rearrangement. In particular, the rearranegement is
found remarkably accelerated by such a metal substituent E as a
boryl, silyl, or stannyl group that can act as a versatile functional
group for further transformation. This methodology allows us to
obtain diverse kinds of 2-trifluoromethylated oxepanes and oxe-
pins.
Table 3. Synthesis of 2-CF3-4,5-dihydrooxepins 6a
This work was supported by Grant-in-Aid for COE Research
on Elements Science, no. 12CE2005, from Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan. 1,1-Di-
chloro-3,3,3-trifluoropropan-2-one was kindly donated by Cen-
tral Glass Co. Ltd.
Entry
5
Temp/ꢂC
Time/h
6
Yield/%b
1
2
3
4
5
6
7
8
9
5i
5j
120
85
4
2
6i
6j
89c
92
5k
5l
85
100
80
80
60
140
100
2
48
5
3
3
6k
6l
95
93
100
89
94
90
86c
5m
5n
5o
5p
5q
6m
6n
6o
6p
6q
References and Notes
1
a) T. Hiyama, ‘‘Organofluorine Compounds. Chemistry and Applica-
tions,’’ Springer-Verlag, Berlin (2000). b) M. Hudlicky and A. E.
Pavlath, ‘‘Chemistry of Organic Fluorine Compounds II. A Critical
Review,’’ American Chemical Society, Washington, DC (1995). c)
J. T. Welch, Tetrahedron, 43, 3123 (1987)
6
18
aA solution of oxirane 5 (0.5 mmol) in CCl4 (3 mL) was heated
in a sealed tube. The progress of the reaction was monitored by
2
a) D. R. Boyd, in ‘‘Comprehensive Heterocyclic Chemistry,’’ ed. by A.
R. Katritzky and C. W. Rees, Pergamon Press, Oxford (1984), Vol. 7,
p 547. b) L. I. Belen’kii, in ‘‘Comprehensive Heterocyclic Chemistry
II,’’ ed. by A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Pergamon
Press, Oxford (1996), Vol. 9, p 45. c) J. O. Hoberg, Tetrahedron, 54,
12631 (1998).
c
19F NMR. bIsolated yields. Isolated yields based on reacted
cis-diastereomer of 5.
Versatility of the present approach is demonstrated by one-
pot synthesis of 6o from 1,1-dichloro-3,3,3-trifluoropropan-2-
one as well as facile and diverse transformations of 6c and 6f.
Thus, treatment of the ketone with vinyllithium (4 equiv.),
LiTMP (3 equiv.), and then TBSOTf (3 equiv.) followed by
quenching with MeOH and heating the mixture at 60 ꢂC gave
6o in 36% yield all in one-pot. Aryl, alkenyl, or alkynyl group
was easily introduced on the oxepin ring of 6c and 6f, to give
7–9 in good yields via the Pd-catalyzed cross-coupling reaction
with the corresponding halides (Scheme 2).
3
a) M. Shimizu, T. Fujimoto, H. Minezaki, T. Hata, and T. Hiyama, J.
Am. Chem. Soc., 123, 6947 (2001). b) M. Shimizu, T. Fujimoto, X. Liu,
H. Minezaki, T. Hata, and T. Hiyama, Tetrahedron, 59, 9811 (2003)
Treatment of 4 with LiTMP followed by the addition of vinyllithium
resulted in the production of complex mixture.
Cis/trans isomers of 5e, 5i, and 5q were not separable by column chro-
matography on silica gel or gel permeation chromatography.
Review on Cope rearrangement of bis(alkenyl)oxiranes: a) T.
Hudlicky, R. Fan, J. W. Reed, and K. G. Gadamasetti, in ‘‘Org.
React.,’’ John Wiley & Sons, Inc., New York (1992), Vol. 41, p 1.
Examples: b) P. v. Zezschwitz, K. Voigt, A. Lansky, M. Noltemeyer,
and A. d. Meijere, J. Org. Chem., 64, 3806 (1999). c) W.-N. Chou,
J. B. White, and W. B. Smith, J. Am. Chem. Soc., 114, 4658 (1992).
Stereochemistry of 6p was not determined at present.
4
5
6
Finally, reduction and oxidation of 6 led to 2-CF3-substitut-
ed oxepanes and oxepins, respectively, as shown in Scheme 3.
Hydrogenation of 6m and 6o with Pd/C under H2 (1 atm) pro-
7
8
cis-Stereochemistry was assigned by NOE experiment.
Published on the web (Advance View) March 20, 2004; DOI 10.1246/cl.2004.438