Synthesis of 3,3,3-trifluoroprop-1-enyl compounds from some enolizable aldehydes

Article abstract of DOI:10.1016/j.tet.2004.07.030

2,2,2-Trifluoroethyldiphenylphosphine oxide [Ph₂P(O)CH ₂CF₃] (2) is known to give no Horner reaction product with enolizable aldehydes. We found, however, that some enolizable aldehydes such as N-Boc-pyrrolidine-2-aldehyde (9) gave the expected 3,3,3-trifluoroprop-1-enyl compounds by reaction with 2. The products could be further transformed to some 2,2,2-trifluoroethyl-substituted nitrogen-containing heterocycles by using radical cyclization or Heck reaction. Graphical abstract

Full text of DOI:10.1016/j.tet.2004.07.030

Tetrahedron 60 (2004) 8919–8927
Synthesis of 3,3,3-trifluoroprop-1-enyl compounds from some
enolizable aldehydes
Satomi Yamamoto,a Hiroshi Sugimoto,a Osamu Tamura,a Tatsuya Mori,b Noritada Matsuob
and Hiroyuki Ishibashia,
*
aDivision of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa,
Ishikawa 920-1192, Japan
bAgricultural Chemicals Research Laboratory, Sumitomo Chemical Co. Ltd, Takarazuka, Hyogo 665-8555, Japan
Received 30 April 2004; accepted 7 July 2004
Available online 23 August 2004
Abstract—2,2,2-Trifluoroethyldiphenylphosphine oxide [Ph2P(O)CH2CF3] (2) is known to give no Horner reaction product with enolizable
aldehydes. We found, however, that some enolizable aldehydes such as N-Boc-pyrrolidine-2-aldehyde (9) gave the expected 3,3,3-
trifluoroprop-1-enyl compounds by reaction with 2. The products could be further transformed to some 2,2,2-trifluoroethyl-substituted
nitrogen-containing heterocycles by using radical cyclization or Heck reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of our studies, reaction of 2 with aliphatic
aldehydes such as 3-phenylpropanal (4) was found to afford
no desired 3,3,3-trifluoroprop-1-enyl compound and instead
to give only ester 8 (Scheme 2). Formation of 8 may be
explained by assuming that aldehyde 4 gives enolate 5 by
action of the basic TBAF, and enolate 5 attacks vinyl-
phosphine oxide 6, which is formed from 2 by an
elimination of HF under basic conditions, to give the adduct
7. This compound is then transformed to ester 8 via steps.
Therefore, the preparation of 3,3,3-trifluoroprop-1-enyl
compounds with 2 appeared to be restricted to non-
enolizable aldehydes. We soon found, however, that some
enolizable aliphatic aldehydes such as N-Boc-pyrrolidine-2-
aldehyde (9) gave the expected 3,3,3-trifluoroprop-1-enyl
compounds by reaction with 2. This paper describes the
results of our work in this area, including the conversion of
the products to some 2,2,2-trifluoroethyl-substituted
nitrogen-containing heterocycles such as 34.
The introduction of fluorine atoms into biologically active
compounds often intensifies their activities.1 A 3,3,3-
trifluoroprop-1-enyl structure (CF3CH]CH–) has been
found in candidates for medicines2 or agricultural
chemicals.3 Various methods have been developed for
synthesizing 3,3,3-trifluoroprop-1-enyl compounds, but the
methods have several disadvantages, such as the require-
ment of a multi-step sequence of reactions and the use of
expensive and/or the low boiling point reagents.4 One of the
most direct routes to synthesize trifluoropropenyl structure
seems to be the use of Wittig-type reaction of an aldehyde
with a trifluoromethyl-containing reagent. We have recently
reported a convenient method for the synthesis of 3,3,3-
trifluoroprop-1-enyl compounds 3 by means of Horner
reaction of aromatic aldehydes 1 with 2,2,2-tifluoroethyl-
diphenylphosphine oxide (2) using tetrabutylammonium
fluoride (TBAF) as a base (Scheme 1).5
Scheme 1.
Keywords: 3,3,3-Trifluoroprop-1-enyl compounds; 2,2,2-Trifluoroethyldi-
phenylphosphine oxide; Enolizable aldehydes.
* Corresponding author. Tel.: C51-76-234-4474; fax: C51-76-234-4476;
e-mail: isibasi@p.kanazawa-u.ac.jp
Scheme 2.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.030

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S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
2. Results and discussion
We initiated our investigation by examining the reaction of
2 with N-protected pyrrolidine-2-aldehydes 9–11 under
previously reported5 conditions. Treatment of a mixture of
N-Boc-pyrrolidine-2-aldehyde (9) and 2 equiv. of 2 with
10 equiv. of TBAF in THF at room temperature gave
trifluoropropenyl compound 12 in 19% yield as a mixture of
E- and Z-olefins in a ratio of 4:1 along with several
unidentified products (Scheme 3).
Scheme 3.
Encouraged by the success in obtaining 12 from 9, we
further examined a similar reaction at K40 8C using a 1:3
mixture of 9 and 2 in the presence of 9 equiv. of TBAF
to give 12 in 81% yield as a mixture of E and Z olefins in a
ratio of 1:1. Compounds 10 and 11 with 2 also gave the
corresponding trifluoropropenyl compounds 13 and 14 in
68% (E/ZZ1:1) and 66% (E/ZZ3:2) yields, respectively.
Figure 1.
The higher yield of compound 12 (81%) compared to those
of compounds 13 (68%) and 14 (66%) may be the result of
the presence of a sterically more demanding N-Boc group in
compound 9. In the enolate forms 90, 100 and 110 derived
from compounds 9–11, the C2-position of the pyrroridine
ring is an sp2 hybridization as depicted in Figure 1, and,
hence, the N-protecting group and the enolate would lie on
the same plane. It can therefore be presumed that the
presence of a large N-Boc group prevents the formation of
the enolate 90 and gives the desired Horner reaction product
12 in high yield.
Scheme 4.
Scheme 5.
The above assumption was supported by the following
evidence. Reduction of aldehyde 9 with NaBH4 gave
alcohol 15 (Scheme 4). The specific rotation of 15 thus
obtained was K47.7 (cZ0.40, CHCl3), which is virtually
identical to that [K45.1 (cZ0.40, CHCl3] for compound 15
obtained by ozonolysis of the product 12, prepared from 9,
followed by reduction of the resulting aldehyde with
NaBH4. These results clearly indicated that the starting
compound 9 did not racemize under the basic conditions
employed.
Scheme 6.
N-Boc-indoline-2-aldehyde (16) also gave the expected
(E)-trifluoropropenyl compounds 18a and its (Z)-isomer
18b in 31 and 25% yields, respectively (Scheme 5). Similar
reaction of the N-ethoxycarbonyl congener 17 gave 19a and
its isomer 19b, though their yields were slightly lower (18
and 17%, respectively) than those of 18a,b.
The reaction of Garner’s aldehyde 20 with 2 gave the
E-olefin 21a and its Z-isomer 21b in 9 and 17% yields at
K40 8C, respectively (Scheme 6). When a similar reaction
Scheme 7.

S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
8921
was carried out at K60 8C, the yields of 21a and 21b were
improved to 29 and 23%, respectively.
The reaction of piperidine derivative 22 with 2 gave 23
as the major product (69%), along with small amounts
(!6.5%) of the desired products 24a,b (Scheme 7). These
results indicate that the compound 22 is easily enolizable,
because enolate 220 generated from 22 can be twisted in its
chair form (Fig. 2). The stereochemistry of 23 as depicted in
Scheme7 was deduced byconsideringthatthe oxygen atomof
the vinyl ether (O–CH]C–N) must be located so as to avoid
the steric repulsion and the spin–spin coupling constant (JZ
34.5 and 6.1 Hz) of the alkenic proton (Ha).
Figure 2.
The azetidine-2-aldehyde 25 and aziridine-2-aldehyde 27
were expected to retard enolization due to the nature of their
small ring, but, only 15% (E/ZZ2:3) and 19% (E/ZZ1:2)
yields of the desired trifluoropropenyl compounds 26 and 28
were obtained (Scheme 8). The reasons for low yields of 26
and 28 are not known at present. However, cyclo-
propanealdehyde 29 gave the expected trifluoropropenyl
compound 30 (E/ZZ4:1) in very high yield (86%).
Finally, transformation of trifluoropropenyl compound 12 to
several fluorine-containing heterocycles was examined.
N-Deprotection of 12 with trifluoroacetic acid followed by
acylation of the resulting amine with (methylthio)acetic acid
gave (methylthio)acetamide 31. Base-promoted cyclization
of 31 using KHMDS or TBAF gave compound 32, although
the yields were low (17 and 13%, respectively) (Scheme 9).
Scheme 8.
On the other hand, chlorination of 31 with NCS followed by
treatment of the resulting a-chlorosulfide 33 with Bu3SnH
in the presence of azobisisobutyronitrile (AIBN) gave the
5-exo radical cyclization product 34 in 33% yield along with
several unidentified products, some of which might be
stereoisomers of 34.
Radical cyclization of compound 35, prepared from 12,
afforded 37 in 32% yield (Scheme 10). The Heck reaction of
35 with Pd(OAc)2 in the presence of P(o-Tol)3 and Et3N
gave a mixture of 39 and 41 in 46% overall yield in a ratio of
Scheme 9.
Scheme 10.

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S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
1:5. When this mixture was exposed to Et3N, the ratio of 39
and 41 changed to 1:10.
3.65 (2H, m, H-5), 4.03–4.30 (3H, m, H-2, CH2CH3), 9.51
(s, CHO), 9.58 (total 1H, s, CHO).
Similarly, radical reaction of 36, prepared from 21a,b, gave
38 in 68% yield. The Heck reaction of 36 gave a mixture of
40 and 42 in 54% overall yield in a ratio of 1:2.
4.2.4. 1-tert-Butoxycarbonyl-2-indolinecarboxaldehyde
(16).9 1H NMR d 1.53–1.61 (9H, m, tBu), 3.14 (1H, dd,
JZ16.7, 5.4 Hz, one of H-3), 3.29–3.52 (1H, br, one of
H-3), 4.63–4.92 (1H, br, H-2), 6.92–7.28 (3H, m, Ar-H),
7.36–7.97 (1H, br, Ar-H), 9.65 (1H, s, CHO).
3. Conclusions
4.2.5. 1-tert-Butoxycarbonyl-2-piperidinecarboxalde-
hyde (22).10 1H NMR d 1.15–1.73 (5H, m), 1.47 (9H, s,
tBu), 2.14–2.21 (1H, m), 2.75–3.00 (1H, br), 3.80–4.09 (1H,
br), 4.44–4.66 (1H, br), 9.59 (1H, s, CHO).
In conclusion, we have revealed that some enolizable
aliphatic aldehydes such as prrolidine-2-aldehydes 9–11
give the desired 3,3,3-trifluoroprop-1-enyl compounds
12–14 by reaction with 2. We assumed that the effectiveness
of formation of 12–14 from 9–11 may be a result of the
difficulty of enolization due to the presence of a sterically
more demanding N-protecting group of compound 9–11.
4.2.6. 1-tert-Butoxycarbonyl-2-azetidinecarboxaldehyde
(25).11 1H NMR d 1.44 (9H, s, tBu), 1.97–2.51 (2H, m, H-3),
3.73–4.04 (2H, m, H-4), 4.50–4.66 (1H, m, H-2), 9.78 (1H,
s, CHO).
4. Experimental
4.1. General
4.2.7. 1-Triphenylmethyl-2-aziridinecarboxaldehyde
(27).12 1H NMR d 1.55 (1H, d, JZ6.3 Hz, one of H-3),
1.98 (1H, td, JZ6.3, 2.6 Hz, H-2), 2.31 (1H, d, JZ1.7 Hz,
one of H-3), 7.19–7.54 (15H, m, Ar-H), 9.32 (s, CHO), 9.34
(total 1H, s, CHO).
Melting points are uncorrected. Optical rotations were
measured with a HORIBA SEPA-300 polarimeter. IR
spectra were recorded with a Shimadzu FTIR-8100
spectrophotometer for solutions in CHCl3. 1H and 13C
NMR spectra were measured on JEOL JNM-EX 270 and
JEOL JNM-GSX 500 spectrometers for solutions in CDCl3
[except for 1H NMR spectrum of compounds 37 and 38 and
13C NMR spectrum of compounds 32, 5,5,5-trifluoro-2-(N-
2-iodobenzoyl)amino-3-penten-1-ol (an intermediate for the
synthesis of 36), 38]. d Values quoted are relative to TMS
(tetramethylsilane). For 13C NMR, diagnostic data are
expressed. High-resolution mass spectra (HRMS) were
obtained with a JEOL JMS-SX 102A instrument. Column
chromatography was performed on Silica gel 60 PF254 under
pressure. 1 M solution of TBAF was purchased from Tokyo
Chemical Industry. Aldehydes 9,6 10,7 11,8 16,9 22,10 2511
and 2712 were prepared from the corresponding alcohols
according to the reported procedures. Aldehydes 20 and 29
were purchased from Tokyo Chemical Industry and
Sumitomo Chemical Co., Ltd, respectively.
4.3. Horner reaction of 9–11
4.3.1. (S)-1-tert-Butoxycarbonyl-2-(3,3,3-trifluoroprop-
1-enyl)pyrrolidine (12). General procedure. Molecular
sieves 4A (MS 4A) (1.5 g) were added to a 1 M solution of
TBAF in THF (1.8 mL), and the mixture was stirred at room
temperature overnight. The mixture was cooled to K40 8C,
and to the mixture was added a solution of aldehyde 9
(39.9 mg, 0.2 mmol) and phosphine oxide 2 (170.5 mg,
0.6 mmol) in THF (5 mL) at K40 8C. After the mixture was
stirred for 15 min, water (3 mL) was added dropwise and the
mixture was allowed to warm to room temperature. After
removal of MS 4A by filtration, water was added to the
filtrate, and the whole was extracted with AcOEt. The
extract was washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica
gel (hexane–AcOEt, 4:1) to give 12 (42.9 mg, 81%, E/ZZ
1:1) as a colorless oil. Rotamers of 12 were observed by 1H
and 13C NMR. IR n 1690 cmK1; H NMR d 1.43 (9H, s,
1
4.2. Physical data for compounds 9, 10, 11, 16, 22, 25 and
27
tBu), 1.66–2.28 (4H, m, H-3, 4), 3.34–3.60 (2H, m, H-5),
4.25–4.76 (1H, br, H-2), 5.47–5.71 (1H, m, CH]CHCF3),
5.86–6.05 [1/2H, br t, JZ10.3 Hz, (Z)-CH]CHCF3], 6.17–
6.35 [1/2H, br d, JZ16.2 Hz, (E)-CH]CHCF3]; 13C NMR
(for one rotamer) d 23.3, 28.7, 32.1, 46.8, 55.4, 80.2, 118.4
(q, JZ34.2 Hz), 123.5 (q, JZ272.2 Hz), 141.1, 154.7; MS
(EI) m/z (%) 265 (MC, 9.9), 209 (63), 192 (48), 96 (39), 57
(100); HRMS (FAB) calcd for C12H19F3NO2 [(MCH)C]
266.1368, found 266.1379.
4.2.1. (S)-1-tert-Butoxycarbonyl-2-pyrrolidinecarboxal-
1
dehyde (9).6 [a]D24 K98.4 (c 0.66, CHCl3); H NMR d
1.43 (s, tBu), 1.48 (total 9H, s, tBu), 1.82–2.21 (4H, m, H-3,
4), 3.41–3.63 (2H, m, H-5), 3.98–4.27 (1H, m, H-2), 9.47 (s,
CHO), 9.56 (total 1H, s, CHO).
4.2.2. (S)-1-Benzyloxycarbonyl-2-pyrrolidinecarboxal-
1
dehyde (10).7 [a]D24 K62.2 (c 1.3, MeOH); H NMR d
4.3.2. (S)-1-Benzyloxycarbonyl-2-(3,3,3-trifluoroprop-1-
enyl)pyrrolidine (13). According to the general procedure,
aldehyde 10 (116.6 mg, 0.5 mmol) was treated with
phosphine oxide 2 (426.3 mg, 1.5 mmol) in THF (10 mL)
in the presence of a 1 M solution of TBAF in THF (4.5 mL,
4.5 mmol) and MS 4A (3.6 g) at K40 8C for 15 min.
Workup and chromatography (hexane–AcOEt, 3:1) gave 13
(102.4 mg, 68%, E/ZZ1:1) as a colorless oil. Rotamers of
13 were observed by 1H and 13C NMR. IR n 1700 cmK1; 1H
1.75–2.18 (4H, m, H-3, 4), 3.51–3.62 (2H, m, H-5), 4.18–
4.32 (1H, m, H-2), 5.13 (s, CH2Ph), 5.17 (total 2H, s,
CH2Ph), 7.26–7.42 (5H, m, Ar-H), 9.49 (s, CHO), 9.59
(total 1H, s, CHO).
4.2.3. (S)-1-Ethoxycarbonyl-2-pyrrolidinecarboxalde-
hyde (11).8 [a]2D4 K97.6 (c 0.31, EtOH); H NMR d 1.19–
1.31 (3H, m, CH2CH3), 1.85–2.21 (4H, m, H-3,4), 3.49–
1

S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
8923
NMR d 1.64–2.30 (4H, m, H-3, 4), 3.38–3.65 (2H, m, H-5),
4.35–4.57 [1/2H, br d, (E)-H-2], 4.68–4.83 [1/2H, m, (Z)-H-
2], 5.02–5.20 (2H, m, CH2Ph), 5.41–5.77 (1H, m,
CH]CHCF3), 5.82–6.03 [1/2H, m, (Z)-CH]CHCF3],
6.20–6.38 [1/2H, m, (E)-CH]CHCF3], 7.18–7.42 (5H, m,
Ar-H); 13C NMR (for one rotamer) d 24.3, 34.0, 47.5, 55.3,
67.4, 118.8 (q, JZ34.2 Hz) [117.32 (q, JZ34.2 Hz)], 121.1,
128.4, 128.5, 128.8, 128.9, 136.9, 140.7, 144.8 (the signals
for CF3 could not be identified due to the low intensity and
high multiplicity); MS (FAB) m/z (%) 300 (MC1C, 16),
192 (11), 149 (7.9), 91 (100); HRMS (FAB) calcd for
C15H17F3NO2 [(MCH)C] 300.1211, found 300.1215.
3.06 mmol) in MeOH (5 mL) was added thionyl chloride
(0.34 mL, 4.59 mmol), and the mixture was heated under
reflux for 27 h. After cooling, the mixture was concentrated
under reduced pressure to give crude methyl ester
hydrochloride as a solid, which was dissolved in a mixture
of CH2Cl2 and a saturated NaHCO3 solution (1:1, 6 mL).
Ethyl chloroformate (0.44 mL, 4.59 mmol) was added to the
mixture at 0 8C, and the mixture was stirred vigorously at
room temperature for 18.5 h. Water was added and the
whole was extracted with CHCl3, and the organic phase was
washed with brine, dried (MgSO4), and concentrated. The
residue was dissolved in THF (10 mL), and this solution was
added to a solution of LiBH4 (286.8 mg, 13.2 mmol) in THF
(5 mL) at 0 8C. After stirring at room temperature for 2 h,
the mixture was diluted with water and the whole was
extracted with AcOEt. The organic phase was washed with
brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel (hexane–AcOEt, 3:1) to give
(S)-1-ethoxycarbonyl-2-indolinemethanol (508.6 mg, 75%)
as a colorless oil: [a]D22 K56.6 (c 0.40, CHCl3); IR n 3420,
4.3.3. (S)-1-Ethoxycarbonyl-2-(3,3,3-trifluoroprop-1-
enyl)pyrrolidine (14). According to the general procedure,
aldehyde 11 (85.6 mg, 0.5 mmol) was treated with phos-
phine oxide 2 (426.3 mg, 1.5 mmol) in the presence of a 1 M
solution of TBAF in THF (4.5 mL, 4.5 mmol) and MS 4A
(3.6 g) in THF (10 mL) at K40 8C for 15 min. Workup
and chromatography (hexane–AcOEt, 3:1) gave 14
(78.3 mg, 66%, E/ZZ3:2) as a colorless oil. Rotamers of
14 were observed by 1H and 13C NMR. IR n 1680 cmK1; 1H
NMR d 1.09–1.38 (3H, m, CH2CH3), 1.62–2.29 (4H, m,
H-3,4), 3.32–3.65 (2H, m, H-5), 3.95–4.28 (2H, m,
CH2CH3), 4.30–4.60 [3/5H, br, (E)-H-2], 4.65–4.81 [2/5H,
m, (Z)-H-2], 5.44–5.79 (1H, m, CH]CHCF3), 5.79–6.02
[2/5H, m, (Z)-CH]CHCF3], 6.15–6.38 [3/5H, br d, JZ
15.3 Hz, (E)-CH]CHCF3]; 13C NMR (for one rotamer) d
14.6, 22.8, 31.6, 46.5, 57.1, 61.2, 118.2 (q, JZ34.7 Hz),
123.1 (q, JZ268.1 Hz), 140.2, 155.2; HRMS (FAB) calcd
for C10H15F3NO2 [(MCH)C] 238.1055, found 238.1066.
1
1690 cmK1; H NMR d 1.39 (3H, t, JZ7.3 Hz, CH2CH3),
2.74–3.00 (1H, br d, JZ16.3 Hz, one of H-3), 3.36 (1H, dd,
JZ16.3, 10.1 Hz, one of H-3), 3.65–3.85 (2H, m, CH2OH),
4.33 (2H, q, JZ7.3 Hz, CH2CH3), 4.54–4.71 (1H, br, H-2),
6.95–7.26 (3H, m, Ar-H), 7.39–7.75 (1H, br, Ar-H); 13C
NMR d 15.0, 31.6, 61.4, 62.6, 65.9, 116.0, 123.5, 125.3,
127.9, 130.6, 142.0, 187.6; HRMS (FABC) calcd for
C12H16NO3 (MC1) 222.1130, found 222.1123. To a
solution of o-iodoxybenzoic acid (IBX) (965.2 mg,
3.45 mmol) in DMSO (8 mL) was added a solution of
(S)-1-ethoxycarbonyl-2-indolinemethanol (508.6 mg,
2.3 mmol) in THF (5 mL) at room temperature and the
mixture was allowed to stand for 7 days. White precipitates
were removed by filtration, water was added to the filtrate,
and the whole was extracted with AcOEt. The extract was
washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane–AcOEt,
from 7:1 to 5:1) to give 17 (144.9 mg, 29%) as a pale yellow
4.4. Formation of 15 from 9 or 12
4.4.1. Reduction of 9. To a solution of aldehyde 9 (300 mg,
1.51 mmol) in MeOH (5 mL) was added NaBH4 (178.7 mg,
4.72 mmol) at 0 8C, and the mixture was stirred at room
temperature for 1.5 h. The mixture was poured into water
and extracted with AcOEt. The extract was washed with
brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel (hexane–AcOEt, from 2:1 to
1:1) to give (S)-1-tert-butoxycarbonyl-2-pyrrolidinemetha-
nol (15) (241.7 mg, 80%) as a colorless oil: [a]2D6 K47.7 (c,
0.40, CHCl3) [lit.13 [a]D24 K48.83 (c 1.2, CHCl3)]; 1H NMR
d 1.47 (9H, s, tBu), 1.72–2.09 (4H, m, H-3, 4), 3.25–3.96
(4H, m, H-5, CH2OH), 3.83–4.05 (1H, br, H-2), 4.67–4.82
(1H, br, OH).
1
oil: H NMR d 1.22–1.55 (3H, m, CH2CH3), 3.19 (1H, dd,
JZ16.8, 5.0 Hz, one of H-3), 3.37–3.48 (1H, dd, JZ16.8,
11.5 Hz, one of H-3), 4.19–4.42 (2H, m, CH2CH3), 4.75–
4.94 (1H, m, H-2), 6.97–7.26 (3H, m, Ar-H), 7.45–7.98 (1H,
br, Ar-H), 9.67 (1H, s, CHO). This compound was used
immediately in the next step.
4.5. Horner reactions of 16, 17, 20, 22, 25, 27 and 29
4.5.1. (S)-1-tert-Butoxycarbonyl-2-[(E)-3,3,3-trifluoro-
prop-1-enyl]indoline (18a) and its (Z)-isomer (18b).
According to the general procedure, aldehyde 16
(78.2 mg, 0.316 mmol) was treated with phosphine oxide
2 (269.6 mg, 0.948 mmol) in the presence of a 1 M solution
of TBAF in THF (2.8 mL, 2.8 mmol) and MS 4A (2.3 g) in
THF (15 mL) at K20 8C for 15 min. The crude material was
chromatographed on silica gel (hexane–AcOEt, 12:1). The
first fraction gave 18b (24.3 mg, 25%) as a pale yellow oil:
[a]D24 K34.2 (c 0.40, CHCl3); IR n 1795 cmK1; 1H NMR d
1.53 (9H, s, tBu), 2.83 (1H, dd, JZ16.6, 4.1 Hz, one of
H-3), 3.50–3.65 (1H, m, one of H-3), 5.29–5.44 (1H, br,
H-2), 5.58 (1H, dqd, JZ11.5, 8.9, 1.3 Hz, CH]CHCF3),
6.12 (1H, dd, JZ11.9, 8.6 Hz, CH]CHCF3), 6.93–7.25
(3H, m, Ar-H), 7.65–7.85 (1H, br, Ar-H); 13C NMR d 28.3,
35.7, 56.8, 81.7, 115.2, 116.7 (q, JZ34.7 Hz), 122.7, 124.1,
4.4.2. Ozonolysis of 12 followed by reduction of 9. Ozone
was introduced into a solution of compound 12 (400 mg,
1.51 mmol) in CH2Cl2–MeOH (10:1, 5 mL) at K78 8C for
50 min. To the mixture diluted with MeOH (5 mL) was
added NaBH4 (68.5 mg, 1.81 mmol), and the mixture was
allowed to warm to 0 8C. After 3.5 h, the mixture was
poured into water and extracted with AcOEt. The extract
was washed with brine, dried (MgSO4), and concentrated.
The residue was chromatographed on silica gel (hexane–
AcOEt, 2:1) to give 15 (39.3 mg, 40%) as a colorless oil:
[a]2D6 K45.1 (c 0.40, CHCl3) [lit.13 [a]2D4 K48.83 (c 1.2,
CHCl3)].
4.4.3. 1-Ethoxycarbonyl-2-indolinecarboxaldehyde (17).
To a solution of (S)-indoline-2-carboxylic acid (500 mg,

8924
S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
124.6, 127.8, 141.8, 144.4, 144.5, 152.2 (the signals for CF3
could not be identified due to the low intensity and high
multiplicity); HRMS (FAB) calcd for C16H19F3NO2 [(MC
H)C] 314.1368, found 314.1363. The second fraction gave
18a (31.0 mg, 31%) as a pale yellow oil: [a]2D4 K24.7 (c
(61.4 mg, 23%) as an oil: [a]2D7 C4.3 (c 0.60, CHCl3); IR
n 1695 cmK1; 1H NMR d 1.43 (9H, s, tBu), 1.43–1.63 (6H,
m, 2!Me), 3.75 (1H, dd, JZ9.1, 3.5 Hz, one of H-5), 4.16
(1H, dd, JZ9.1, 6.8 Hz, one of H-5), 4.72–4.92 (1H, br,
H-4), 5.64 (1H, br quin, JZ9.9 Hz, CH]CHCF3), 6.03
(1H, br t, JZ10.3 Hz, CH]CHCF3); 13C NMR d 23.9,
26.4, 28.3, 55.0, 68.5, 80.6, 94.7, 118.0 (q, JZ34.7 Hz),
122.9 (q, JZ270.5 Hz), 143.7, 151.7; HRMS (FAB) calcd
for C13H21F3NO3 [(MCH)C] 296.1473, found 296.1477.
The second fraction gave 21a (74.0 mg, 29%) as an oil:
1
0.40, CHCl3); IR n 1700 cmK1; H NMR d 1.53 (s, tBu),
1.56 (total 9H, s, tBu), 2.83 (1H, dd, JZ16.2, 3.0 Hz, one of
H-3), 3.48 (1H, dd, JZ16.2, 10.4 Hz, one of H-3), 4.90–
5.14 (1H, br, H-2), 5.72 (1H, dqd, JZ15.8, 6.3, 1.8 Hz,
CH]CHCF3), 6.36 (1H, ddq, JZ15.8, 6.9, 2.0 Hz,
CH]CHCF3), 6.95–7.26 (3H, m, Ar-H), 7.55–7.85 (1H,
br, Ar-H); 13C NMR d 28.2, 34.1, 59.1, 81.7, 115.3, 118.6
(q, JZ34.7 Hz), 123.0, 124.1, 124.7, 125.0, 128.0, 128.1,
139.3, 152.0 (the signals for CF3 could not be identified due
to the low intensity and high multiplicity); HRMS (FAB)
calcd for C16H19F3NO2 [(MCH)C] 314.1368, found
314.1374.
1
[a]D27 K8.2 (c 0.60, CHCl3); IR n 1695 cmK1; H NMR d
1.43 (9H, s, tBu), 1.44–1.63 (6H, m, 2!Me), 3.80 (1H, dd,
JZ8.2, 2.3 Hz, one of H-5), 4.10 (1H, dd, JZ8.2, 6.0 Hz,
one of H-5), 4.31–4.57 (1H, m, H-4), 5.64–5.86 (1H, m,
CH]CHCF3), 6.23–6.41 (1H, m, CH]CHCF3); 13C NMR
d 23.5, 26.4, 28.3, 57.5, 67.2, 80.4, 94.6, 119.8 (q, JZ
34.7 Hz), 122.8 (q, JZ268.2 Hz), 138.5, 151.5; HRMS
(FAB) calcd for C13H21F3NO3 [(MCH)C] 296.1473, found
296.1464.
4.5.2. (S)-1-Ethoxycarbonyl-2-[3,3,3-trifluoroprop-1-
(E)-enyl]indoline (19a) and its (Z)-isomer (19b). Accord-
ing to the general procedure, aldehyde 17 (144.9 mg,
4.5.4. 1-tert-Butoxycarbonyl-2-{(E)-[(Z)-1-fluoro-2-
(diphenylphosphinoyl)ethenyl]oxymethylene}piperidine
(23), 1-tert-butoxycarbonyl-2-[(E)-3,3,3-trifluoroprop-1-
enyl]piperidine (24a) and its (Z)-isomer (24b). According
to the general procedure, aldehyde 22 (219.7 mg,
0.66 mmol) was treated with phosphine oxide
2
(563.9 mg, 1.98 mmol) in the presence of a 1 M solution
of TBAF in THF (5.9 mL, 5.9 mmol) and MS 4A (4.8 g) in
THF (10 mL) at K20 8C for 15 min. The crude material was
chromatographed on silica gel (hexane–AcOEt, 20:1). The
first fraction gave 19b (32.2 mg, 17%) as a white solid: mp
68–69 8C (hexane); [a]2D5 K9.6 (c 0.40, CHCl3); IR n
1.03 mmol) was treated with phosphine oxide
2
(878.3 mg, 3.09 mmol) in the presence of a 1 M solution
of TBAF in THF (9.3 mL, 9.3 mmol) and MS 4A (7.5 g) in
THF (20 mL) at K40 8C for 15 min. The crude material was
chromatographed on silica gel (hexane–AcOEt, 7:1 then 3:1
then 2:1 then 1:1 then AcOEt). The first fraction gave 24a
1
1700 cmK1; H NMR d 1.31 (3H, t, JZ6.9 Hz, CH2CH3),
2.85 (1H, dd, JZ16.5, 4.0 Hz, one of H-3), 3.55 (1H, dd,
JZ16.5, 10.5 Hz, one of H-3), 4.26 (2H, q, JZ6.9 Hz,
CH2CH3), 5.27–5.38 (1H, m, H-2), 5.59 (1H, dqd, JZ11.9,
8.5, 1.0 Hz, CH]CHCF3), 6.06 (1H, dd, JZ11.9, 9.2 Hz,
CH]CHCF3), 6.90–7.26 (3H, m, Ar-H), 7.65–7.88 (1H, br,
Ar-H); 13C NMR d 14.8, 35.8, 57.0, 62.2, 115.7, 117.6 (q,
JZ34.2 Hz), 121.4, 123.5, 125.2, 128.4, 129.4, 141.8,
143.4, 153.5 (the signals for CF3 could not be identified due
to the low intensity and high multiplicity); HRMS (FAB)
calcd for C14H15F3NO2 (MC1) 286.1055, found 286.1057.
The second fraction gave 19a (34.2 mg, 18%) as a brown
solid: mp 79–80 8C (hexane); [a]2D4 K44.3 (c 0.40, CHCl3);
1
(12.9 mg, !4%) as an oil: H NMR d 1.07–1.76 (6H, m,
H-3,4,5), 1.46 (9H, s, tBu), 2.72–2.85 (1H, m, one of H-6),
3.95–4.05 (1H, m, one of H-5), 4.88–4.94 (1H, br, H-2),
5.62 (1H, dqd, JZ15.8, 6.3, 2.0 Hz, CH]CHCF3), 6.31
(1H, ddq, JZ15.8, 4.3, 2.3 Hz, CH]CHCF3). This material
contained small amounts of inseparable by-products. The
second fraction gave 24b (7.2 mg, 2.5%) as a colorless oil:
1
IR n 1685 cmK1; H NMR d 1.39–1.71 (6H, m, H-3,4,5),
1.44 (9H, s, tBu), 2.85–2.95 (1H, m, one of H-6), 4.02–4.07
(1H, m, one of H-6), 5.21–5.29 (1H, br, H-2), 5.51 (1H, dqd,
JZ12.0, 8.8, 2.0 Hz, CH]CHCF3), 6.26 (1H, dd, JZ12.0,
9.4 Hz, CH]CHCF3), 13C NMR d 20.0, 25.5, 28.8, 31.1,
39.6, 49.3, 80.5, 118.2 (q, JZ34.2 Hz), 140.2, 155.4 (the
signals for CF3 could not be identified due to the low
intensity and high multiplicity); HRMS (FAB) calcd for
C13H21F3NO2 [(MCH)C] 280.1525, found 280.1527. The
third fraction gave 23 (326.9 mg, 69%) as a plate: mp
IR n 1700 cmK1 1H NMR d 1.33 (3H, t, JZ6.9 Hz,
;
CH2CH3), 2.86 (1H, dd, JZ16.2, 3.0 Hz, one of H-3), 3.50
(1H, dd, JZ16.2, 10.2 Hz, one of H-3), 4.15–4.39 (2H, m,
CH2CH3), 4.92–5.11 (1H, m, H-2), 5.74 (1H, dq, JZ15.5,
6.3 Hz, CH]CHCF3), 6.36 (1H, ddq, JZ15.8, 6.9, 2.0 Hz,
CH]CHCF3), 6.97–7.26 (3H, m, Ar-H), 7.57–7.92 (1H, m,
Ar-H); 13C NMR d 14.9, 34.6, 59.3, 62.3, 115.8, 119.2 (q,
JZ34.2 Hz), 121.3, 123.7, 125.3, 128.4, 129.3, 139.2,
141.9, 153.4 (the signals for CF3 could not be identified due
to the low intensity and high multiplicity); HRMS (FAB)
calcd for C14H15F3NO2 [(MCH)C] 286.1055, found
286.1056.
1
168.5–170 8C (from AcOEt–hexane); IR n 1655 cmK1; H
NMR d 1.39 (9H, s), 1.55–1.74 (4H, m, H-4,5), 2.28 (2H, t,
JZ5.6 Hz, H-6), 3.51 (2H, t, JZ5.6 Hz, H-3), 4.71 (1H, dd,
JZ34.5, 6.1 Hz, PCH]CF), 6.51 (1H, s, OCH]C), 7.43–
7.81 (10H, m, ArH); 13C NMR d 24.6, 24.7, 25.4, 28.7, 47.0,
71.8 (dd, JZ111, 22 Hz), 81.2, 127.9, 129.0 (d, JZ12 Hz),
131.5 (d, JZ11 Hz), 132.1, 133.4, 134.4 (d, JZ93 Hz),
154.1, 164.2 (d, JZ270 Hz). Anal. calcd for
C25H29F3NO4P: C, 65.64; H, 6.39; N, 3.06. Found: C,
65.44; H, 6.38; N, 2.99.
4.5.3. (S)-3-tert-Butoxycarbonyl-4-[(E)-3,3,3-trifluoro-
prop-1-enyl]-2,2-dimethyl-1,3-oxazolidine (21a) and its
(Z)-isomer (21b). According to the general procedure,
aldehyde 20 (200 mg, 0.87 mmol) was treated with
phosphine oxide 2 (743.5 mg, 2.61 mmol) in the presence
of a 1 M solution of TBAF in THF (7.85 mL, 7.85 mmol)
and MS 4A (6.3 g) in THF (40 mL) at K60 8C for 45 min.
The crude material was chromatographed on silica gel
(hexane–AcOEt, 12:1). The first fraction gave 21b
4.5.5. (S)-1-tert-Butoxycarbonyl-2-(3,3,3-trifluoroprop-
1-enyl)azetidine (26). According to the general procedure,
aldehyde 25 (128.0 mg, 0.69 mmol) was treated with
phosphine oxide 2 (589.2 mg, 2.1 mmol) in the presence

S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
8925
of a 1 M solution of TBAF in THF (6.2 mL, 6.2 mmol) and
MS 4A (5.0 g) in THF (28 mL) at K40 8C for 15 min.
Workup and chromatography (hexane–AcOEt, from 5:1 to
3:1) gave 26 (26.8 mg, 15%, E/ZZ2:3) as a colorless oil: IR
n 1695 cmK1; 1H NMR d 1.42 (9H, s, tBu), 1.97–2.10 (1H,
m, one of H-3), 2.39–2.55 (1H, m, one of H-3), 3.80–3.97
(2H, m, H-4), 4.69–4.80 [2/5H, m, (E)-H-2], 5.06–5.19
[3/5H, m, (Z)-H-2], 5.60 [3/5H, dqd, JZ11.8, 8.8, 1.3 Hz,
(Z)-CH]CHCF3], 5.82 [2/5H, dqd, JZ15.5, 6.5, 1.5 Hz,
(E)-CH]CHCF3], 6.28 [3/5H, dd, JZ11.8, 7.9 Hz, (Z)-
CH]CHCF3], 6.47 [2/5H, ddq, JZ15.5, 5.3, 2.0 Hz, (E)-
CH]CHCF3]; 13C NMR d: 22.5, 23.2, 28.3, 58.1, 80.0,
117.7 (q, JZ34.7 Hz), 139.3, 143.6, 156.4 (the signals for
CF3 of (E)- and (Z)-isomers could not be identified due to
the low intensity and high multiplicity); HRMS (FAB) calcd
for C11H17F3NO2 [(MCH)C] 252.1211, found 252.1210.
chromatographed on silica gel (hexane–AcOEt, 1:1) to give
31 (189.5 mg, 73%, E/ZZ1:1) as an oil. Rotamers of 31
1
1
were observed by H and 13C NMR. IR n 1635 cmK1; H
NMR d 1.71–2.08 (4H, m, H-3,4), 2.21 (3H, s, SMe), 3.12–
3.21 (2H, m, CH2SMe), 3.48–3.75 (2H, m, H-5), 4.69–4.82
(1/2H, br, H-2), 4.88–5.05 (1/2H, m, H-2), 5.50–5.78 (1H,
m, CH]CHCF3), 5.92 [dd, JZ12.0, 8.4 Hz, (Z)-
CH]CHCF3], 6.05 [total 1/2H, dd, JZ12.0, 8.4 Hz, (Z)-
CH]CHCF3], 6.27–6.45 [1/2H, m, (E)-CH]CHCF3]; 13
C
NMR (for one rotamer) d 15.3, 23.7, 29.8, 36.0, 47.3, 56.4,
118.2 (q, JZ34.7 Hz), 118.3 (q, JZ34.7 Hz), 119.1 (q, JZ
34.7 Hz)], 121.9, 139.1, 167.7 (the signals for CF3 could not
be identified due to the low intensity and high multiplicity);
HRMS (FAB) calcd for C10H15F3NOS [(MCH)C]
254.0827, found 254.0819.
4.5.9. (1S,2R,7aS)-Hexahydro-1-(2,2-difluorovinyl)-2-
methylthio-3H-pyrrolizin-3-one (32). To a solution of 31
(89.7 mg, 0.354 mmol) in THF (1 mL) was added a 0.5 M
solution of KHMDS in toluene (2.12 mL, 1.062 mmol) at
K78 8C and the mixture was stirred at the same temperature
for 30 min. The reaction mixture was allowed to warm to
room temperature and the mixture was poured into water
and extracted with AcOEt, washed with brine, dried
(MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane–AcOEt, 1:1) to give 32
(14.0 mg, 17%) as a pale yellow oil: [a]2D5 C15.9 (c 0.23,
CHCl3); IR n 1695 cmK1; 1H NMR d 1.43–1.54 (1H, m, one
of H-6), 2.02–2.26 (3H, m, H-7, one of H-6), 2.18 (3H, s,
SMe), 2.67 (1H, br q, JZ9.9 Hz, H-1), 3.08–3.18 (1H, m,
H-7a), 3.51 (1H, d, JZ12.0 Hz, H-2), 3.58–3.65 (2H, m,
H-5), 4.32 (ddd, JZ24.0, 9.5, 1.5 Hz, CH]CF2); 13C NMR
(C6D6) d 13.2, 26.1, 30.5, 41.9, 43.8, 55.7, 63.2, 78.4 (t, JZ
18 Hz), 157.9 (t, JZ288 Hz), 169.2; HRMS calcd for
C10H13F2NOS 233.0686, found 233.0670.
4.5.6. (S)-2-(3,3,3-Trifluoroprop-1-enyl)-1-triphenyl-
methylaziridine (28). According to the general procedure,
aldehyde 27 (57.1 mg, 0.183 mmol) was treated with
phosphine oxide 2 (155.8 mg, 0.55 mmol) in the presence
of a 1 M solution of TBAF in THF (1.65 mL, 1.65 mmol)
and MS 4A (1.3 g) in THF (20 mL) at K40 8C for 1 h.
Workup and chromatography (hexane–AcOEt, 7:1) gave 28
(13.2 mg, 19%, E/ZZ1/2) as a pale yellow oil: IR n
1
1670 cmK1; H NMR d 1.43–2.32 (3H, m, H-2,3), 5.72
[1/3H, dq, JZ11.7, 8.9 Hz, (Z)-CH]CHCF3], 5.87 [2/3H,
dq, JZ15.9, 6.3 Hz, (E)-CH]CHCF3], 5.92 [1/3H, dd, JZ
11.7, 9.4 Hz, (Z)-CH]CHCF3], 6.37 [2/3H, ddq, JZ15.9,
7.5, 2.0 Hz, (E)-CH]CHCF3], 7.22–7.48 (15H, m, Ar-H);
13C NMR d 14.1, 22.7, 29.7, 126.9, 127.5, 127.6, 129.4,
144.0 (the signals for CF3 could not be identified due to the
low intensity and high multiplicity); HRMS (FAB) calcd for
C24N21F3N [(MCH)C] 380.1627, found 380.1642.
4.5.7. (R)-trans-3-(3,3,3-Trifluoroprop-1-enyl)-2,2-
dimethylcyclopropanecarboxylic acid tert-butylester
(30). According to the general procedure, aldehyde 29
(140.0 mg, 0.707 mmol) was treated with phosphine oxide 2
(400.0 mg, 1.41 mmol) in the presence of a 1 M solution of
TBAF in THF (7.0 mL, 7.0 mmol) and MS 4A (3.5 g) in
THF (5 mL) at room temperature for 2 h. Workup and
chromatography (hexane–AcOEt, 1:1) gave 30 (160.0 mg,
4.5.10. (1S,2R,7aS)-Hexahydro-1-(2,2,2-trifluoroethyl)-
2-methylthio-3H-pyrrolizin-3-one (34). NCS (158.2 mg,
1.19 mmol) was added to a solution of 31 (250 mg,
0.99 mmol) in CCl4 (2 mL) at 0 8C, and the mixture was
stirred at room temperature for 15 min. The precipitates
were filtered off and the filtrate was concentrated to give
crude a-chlorosulfide 33. To a boiling solution of
a-chlorosulfide 33 in benzene (50 mL) was added dropwise
a solution of Bu3SnH (0.4 mL, 1.19 mmol) and AIBN
(24.2 mg, 0.15 mmol) in benzene (50 mL) over a period of
3 h. After concentration of the mixture, Et2O (30 mL) and
an 8% aqueous KF solution (30 mL) were added to the
residue, and the mixture was vigorously stirred at room
temperature overnight. After filtration of the mixture, the
organic phase was separated, and the aqueous phase was
further extracted with Et2O. The combined organic phase
was washed with brine, dried (MgSO4), and concentrated.
The crude material was chromatographed on silica gel
(hexane–AcOEt, 7:1) to give 34 (83.9 mg, 33%) as a pale
1
86%, E/ZZ4:1): H NMR d 1.18 (3H, s, Me), 1.26 (3H, s,
Me), 1.46 (9H, s, tBu), 1.5–1.8 (1H, m, H-1), 2.02 [4/5H, m,
(E)-H-3], 2.35 [1/5H, m, (Z)-H-3], 5.5–6.2 (2H, m,
CH]CHCF3); MS (FAB) m/z 265 [(MCH)C]. An
analytical sample was not obtained, since this compound
was very volatile.
4.5.8. (S)-2-(3,3,3-Trifluoroprop-1-enyl)-1-[(methyl-
thio)acetyl]pyrrolidine (31). To a solution of compound
12 (269.7 mg, 1.017 mmol) in CH2Cl2 (1 mL) was added
trifluoroacetic acid (0.78 mL, 10.17 mmol) at room tem-
perature. After stirring for 20 min, the mixture was
concentrated to give the residue, which was dissolved in
CH2Cl2 (4 mL). To this solution were added (methylthio)-
acetic acid (0.13 mL, 1.53 mmol), EDC (292.4 mg,
1.53 mmol), Et3N (0.21 mL, 1.53 mmol) and DMAP
(15 mg, 0.12 mmol) at room temperature, and the mixture
was stirred for 2 days. Water was added to the mixture and
the whole was extracted with CHCl3, washed with brine,
dried (MgSO4), and concentrated. The crude material was
yellow oil: [a]D24 C43.0 (c 1.20, CHCl3); IR n 1690 cmK1
;
1H NMR d 1.37–1.51 (1H, m, one of H-6), 2.03–2.14 (4H,
m, H-1, 7, one of H-6), 2.16 (3H, s, SMe), 2.19–2.42 (1H, m,
one of CH2CF3), 2.73 (1H, dqd, JZ14.5, 11.9, 2.6 Hz, one
of CH2CF3), 3.13 (1H, td, JZ11.5, 3.6 Hz, one of H-5), 3.41
(1H, d, JZ11.5 Hz, H-2), 3.56 (1H, dt, JZ11.5, 8.3 Hz, one
of H-5), 3.64 (1H, td, JZ8.3, 5.9 Hz, H-7a); 13C NMR d
12.7, 26.2, 31.3, 35.9 (q, JZ29.3 Hz), 41.3, 42.2, 55.3, 64.1,

8926
S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
126.1 (q, JZ277.1 Hz), 168.6; HRMS (FAB) calcd for
C10H15F3NOS [(MCH)C] 254.0827, found 254.0828.
122.1 (q, JZ34.1 Hz), 130.1, 130.2, 130.3, 130.4, 133.3,
140.1, 141.9, 142.0 (the signals for CF3 could not be
identified due to the low intensity and high multiplicity);
HRMS (FAB) calcd for C12H12F3NO2I [(MCH)C]
385.9865, found 385.9865. A mixture of 5,5,5-trifluoro-2-
(N-2-iodobenzoyl)amino-3-penten-1-ol (154.9 mg, 0.403
mmol), 2,2-dimethoxypropane (0.496 mL, 4.03 mmol),
and (C)-10-camphorsulfonic acid (18.72 mg, 0.081 mmol)
in benzene (16 mL) was heated under reflux for 1 h. After
cooling, water was added and the organic phase was
separated. The aqueous phase was extracted with AcOEt,
and the combined organic phase was washed with brine,
dried (MgSO4), and concentrated. The crude material was
chromatographed on silica gel (hexane–AcOEt, 7:1) to give
4.5.11. (S)-1-(2-Iodobenzoyl)-2-(3,3,3-trifluoroprop-1-
enyl)pyrrolidine (35). To a solution of 12 (265.26 mg,
1.0 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid
(0.77 mL, 10.0 mmol) at room temperature. After stirring
for 45 min, the mixture was concentrated to give the residue,
which was dissolved in a mixture of CH2Cl2 and a saturated
NaHCO3 solution (1:1, 6 mL). To this mixture was added a
solution of 2-iodobenzoyl chloride (799.4 mg, 3.0 mmol) in
CH2Cl2 (2 mL) at room temperature. After the mixture was
vigorously stirred for 5 h, water was added and the organic
phase was separated. The aqueous phase was extracted with
CHCl3, and the combined organic phase was washed with
brine, dried (MgSO4), and concentrated. The crude material
was chromatographed on silica gel (hexane–AcOEt, 3:1) to
36 (115.6 mg, 68%) as a pale yellow oil: IR n 1650 cmK1
;
1H NMR d 1.78 (s, Me), 1.82 (s, Me), 1.84 (total 6H, m,
Me), 3.76–3.82 (1H, m, one of H-5), 4.09–4.17 (1H, m, one
of H-5), 4.58–4.71 (br, H-4), 4.84–5.03 (total 1H, br, H-4),
5.33 (1H, dq, JZ11.9, 8.9 Hz, CH]CHCF3), 5.93–6.26
(1H, br, CH]CHCF3), 7.01–7.14 (2H, m, Ar-H), 7.27–7.38
(1H, m, Ar-H), 7.77–7.82 (1H, m, Ar-H); 13C NMR d 23.2,
26.9, 57.1, 68.5, 70.0, 97.0, 118.4, 118.9, 128.6, 131.0,
131.1, 139.6, 141.2, 142.7, 167.7 (the signals for CF3 could
not be identified due to the low intensity and high
multiplicity); HRMS (FAB) calcd for C15H16F3INO2
[(MCH)C] 426.0178, found 426.0176.
1
give 35 (370.2 mg, 94%, E/ZZ7:5) as a brown oil. H and
13C NMR showed 35 to be a mixture of rotamers. IR n
1
1630 cmK1; H NMR d 1.77–2.40 (4H, m, H-3,4), 3.16–
3.38 (1H, m, one of H-5), 3.63–3.97 (1H, m, one of H-5),
4.18–4.25 [1/2!7/12H, m, (E)-H-2], 4.55–4.69 [1/2!5/
12H, m, (Z)-H-2], 4.82–4.97 [1/2!7/12H, m, (E)-H-2],
5.05–5.15 [1/2!5/12H, m, (Z)-H-2C1/2!7/12H, m, (E)-
CH]CHCF3], 5.24 [1/2!5/12H, dqd, JZ11.5, 8.9, 1.7 Hz,
(Z)-CH]CHCF3], 5.68 [1/2!5/12H, dqd, JZ11.8, 9.0,
1.5 Hz, (Z)-CH]CHCF3], 5.85–6.02 [1/2!5/12H, m,
(Z)-CH]CHCF3C1/2!7/12H, m, (E)-CH]CHCF3],
6.09 [1/2!7/12H, ddq, JZ15.5, 6.8, 2.0 Hz, (E)-
CH]CHCF3], 6.24 [1/2!5/12H, dd, JZ11.8, 8.5 Hz,
(Z)-CH]CHCF3], 6.46 [1/2!7/12H, ddq, JZ15.8, 6.3,
2.2 Hz, (E)-CH]CHCF3], 7.01–7.44 (3H, m, Ar-H), 7.78–
7.85 (1H, m, Ar-H); 13C NMR (for one rotamer) d 24.5,
34.6, 49.1, 57.1, 119.5 (q, JZ34.2 Hz), 127.3, 128.0, 128.3,
128.9, 129.3, 130.8, 139.7, 143.6, 169.4 (the signals for CF3
could not be identified due to the low intensity and high
multiplicity); HRMS (FAB) calcd for C14H14F3INO [(MC
H)C] 396.0072, found 396.0043.
4.6. Bu3SnH-mediated radical cyclization of 35 and 36
4.6.1. (10S,10aS)-10-(2,2,2-Trifluoroethyl)-2,3,10a-tetra-
hydro-1H-pyrrolo[1,2-b]isoquinolin-5-one (37). Using a
procedure similar to that for 34, a solution of 35 (75.2 mg,
0.19 mmol) in benzene (50 mL) was treated with a solution
of Bu3SnH (0.076 mL, 0.285 mmol) and AIBN (4.7 mg,
0.0285 mmol) in benzene (50 mL). After the workup, the
residue was chromatographed on silica gel (hexane–AcOEt,
from 5:1 to 1:1) to give 37 (16.3 mg, 32%) as a white solid:
mp 106–107 8C (hexane); [a]2D8 C126.7 (c 0.56, CHCl3); IR
n 1645 cmK1; 1H NMR (C6D6) d 0.85–1.42 (4H, m, H-3,4),
1.59 (1H, dqd, JZ16.1, 11.9, 2.3 Hz, one of CH2CF3), 2.17
(1H, dqd, JZ16.1, 11.5, 6.3 Hz, one of CH2CF3), 2.43 (1H,
ddd, JZ12.5, 6.3, 2.3 Hz, H-10), 2.67–2.78 (1H, m, H-10a),
3.32–3.42 (1H, m, one of H-2), 3.57–3.66 (1H, m, one of
H-2), 7.06–7.45 (3H, m, Ar-H), 8.41–8.51 (1H, m, Ar-H);
13C NMR d 22.5, 32.8, 34.4 (q, JZ30.0 Hz), 38.4, 45.6,
61.1, 124.3, 126.8 (q, JZ258.1 Hz), 127.5, 128.2, 130.3,
132.0, 139.0, 162.7; HRMS (FAB) calcd for C14H15F3NO
[(MCH)C] 270.1106, found 270.1109.
4.5.12. (S)-4-(3,3,3-Trifluoroprop-1-enyl)-3-(2-iodo-
benzoyl)-2,2-dimethyl-1,3-oxazolidine (36). A mixture of
compound 21a,b (379.5 mg, 1.28 mmol) and TsOH
(1.222 g, 6.42 mmol) in MeOH (25 mL) was heated under
reflux for 8 h. After cooling, the mixture was concentrated,
and the residue was dissolved in a mixture of CHCl3 and a
saturated NaHCO3 solution (1:3, 20 mL). To this mixture
was added a solution of 2-iodobenzoyl chloride (513.6 mg,
1.93 mmol) in CHCl3 (3 mL) at room temperature, and the
mixture was vigorously stirred for 2 h. Water was added and
the organic phase was separated. The aqueous phase was
extracted with CHCl3, and the combined organic phase was
washed with brine, dried (MgSO4), and concentrated. The
crude material was chromatographed on silica gel (hexane–
AcOEt, 7:1) to give 5,5,5-trifluoro-2-(N-2-iodobenzoyl)-
amino-3-penten-1-ol (435.0 mg, 89%, E/ZZ1:1) as a pale
yellow solid. IR n 3420, 1670 cmK1; 1H NMR d 3.79–3.91
(2H, m, CH2OH), 4.74–4.88 (br, NHCH), 4.99–5.13 (total
1H, br, NHCH), 5.78 [1/2H, br dq, JZ11.5, 8.2 Hz, (Z)-
CH]CHCF3], 6.00 [1/2H, dqd, JZ15.9, 5.9, 1.4 Hz,
(E)-CH]CHCF3], 6.16 [1/2H, dd, JZ11.9, 9.2 Hz, (Z)-
CH]CHCF3], 6.41–6.52 [1/2H, m, (E)-CH]CHCF3],
6.71–6.85 (1H, m, NH), 7.05-7.40 (m, Ar-H), 7.78–8.04
(total 4H, m, Ar-H); 13C NMR (CD3OD) d 54.6, 65.1, 94.2,
4.6.2. (10R,10aR)-10-(2,2,2-Trifluoroethyl)-3,3-dimethy-
10,10a-dihydro-1H-oxazolo[3,4-b]isoquinolin-5-one (38).
Using a procedure similar to that for 34, a solution of 36
(110 mg, 0.259 mmol) in benzene (20 mL) was treated with
a solution of Bu3SnH (0.105 mL, 0.389 mmol) and AIBN
(6.4 mg, 0.039 mmol) in benzene (20 mL). After the
workup, the residue was chromatographed on silica gel
(hexane–AcOEt, 7:1) to give 38 (52.8 mg, 68%) as a white
solid: mp 143–145 8C (AcOEt–hexane); [a]2D8 C97.9 (c
0.60, CHCl3); IR n 1655 cmK1; 1H NMR (C6D6) d 1.53 (1H,
dqd, JZ16.5, 11.6, 3.0 Hz, one of CH2CF3), 1.69 (3H, s,
Me), 1.80 (3H, s, Me), 2.09 (1H, dqd, JZ16.5, 11.2, 5.9 Hz,
one of CH2CF3), 2.55 (1H, ddd, JZ12.5, 5.9, 3.0 Hz, H-10),
3.13 (1H, ddd, JZ12.5, 9.6, 5.3 Hz, H-10a), 3.32 (1H, dd,

S. Yamamoto et al. / Tetrahedron 60 (2004) 8919–8927
8927
JZ9.6, 8.2 Hz, one of H-11), 3.72 (1H, dd, JZ8.2, 5.3 Hz,
one of H-11), 6.78–6.81 (1H, m, Ar-H), 7.01–7.15 (2H, m,
Ar-H), 8.37–8.41 (1H, m, Ar-H); 13C NMR (C6D6) d 5.8,
27.0, 35.1 (q, JZ29.3 Hz), 36.5, 60.1, 70.0, 96.7, 125.1,
128.2, 129.6, 129.7, 129.8, 129.9, 132.8, 160.9 (the signals
for CF3 could not be identified due to the low intensity and
high multiplicity). Anal. calcd for C15H16F3NO2: C, 60.20;
H, 5.39; N, 4.68. Found: C, 60.11; H, 5.34; N, 4.74.
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
References and notes
1. For reviews, see: (a) Schlosser, M. Tetrahedron 1978, 34, 3.
(b) Kobayashi, Y.; Kumadaki, I. Acc. Chem. Res. 1978, 11,
197. (c) Ishikawa, N. Kagaku No Ryoiki 1981, 35, 441.
(d) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of
Fluorine Chemistry; Kodansha, Elsevier Biomedical: Tokyo,
1982. (e) Welch, J. T. Tetrahedron 1987, 43, 3123.
(f) Resnati, G. Tetrahedron 1993, 49, 9385. (g) Hiyama,
T. Organofluorine Compounds—Chemistry and Applications;
Springer: Berlin, 2000.
4.7. Heck reaction of 35 and 36
4.7.1. (S)-10-(2,2,2-Trifluoroethylidene)-2,3,10,10a-
tetrahydro-1H-pyrrolo[1,2-b]isoquinolin-5-one (39) and
10-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[1,2-
b]isoquinolin-5-one (41). To a solution of Pd(OAc)2
(2.24 mg, 0.01 mmol) and tris-o-tolylphosphine (3.04 mg,
0.01 mmol) in CH3CN (0.1 mL) were added a solution of 35
(39.51 mg, 0.1 mmol) in CH3CN (0.4 mL) and Et3N
(0.031 mL, 0.22 mmol) at room temperature, and then the
mixture was stirred at 80 8C for 2 days. After concentration
of the mixture, the residue was chromatographed on silica
gel (hexane–AcOEt, 1:1) to give a mixture of 39 and 41 in a
ratio of 1:5 (18.9 mg, 71%) as a brown oil: 1H NMR d 1.83–
2.13 (1/6!4H, m, H-3, 4 for 39), 2.24 (5/6!2H, quint,
JZ7.6 Hz, H-3 for 41), 3.18 (5/6!2H, t, JZ7.6 Hz, H-4 for
41), 3.51 (5/6!2H, q, JZ10.2 Hz, CH2CF3 for 41), 3.85
(1/6!2H, dd, JZ12.0, 8.8 Hz, H-2 for 39), 4.25 (5/6!2H,
t, JZ7.3 Hz, H-2 for 41), 4.38–4.56 (1/6!1H, m, H-10a for
39), 5.76 (1/6!1H, qd, JZ8.9, 2.3 Hz, C]CHCF3 for 39),
7.05–7.35 (1/6!3H, m, Ar-H for 39), 7.41–7.72 (5/6!3H,
m, Ar-H for 41), 8.10–8.14 (1/6!1H, m, Ar-H for 39),
8.45–8.48 (5/6!1H, m, Ar-H for 41); HRMS (FAB) calcd
for C14H13F3NO [(MCH)C] 268.0949, found 268.0943.
2. (a) Wataya, Y.; Matsuda, A.; Santi, D. V.; Bergstrom,
D. E.; Ruth, J. L. J. Med. Chem. 1979, 22, 339.
(b) Bergstrom, D. E.; Ruth, J. L.; Reddy, P. A.; Clercq,
E. D. J. Med. Chem. 1984, 27, 279. Noyori, R.; Morisawa,
Y.; Maeda, T.; Yasuda, S.; Uchida, K. 1990, JP-02056462.
3. (a) Bentley, P. D.; Cheetham, R.; Huff, R. K.; Pascoe, R.;
Sayle, J. D. Pestic. Sci. 1980, 11, 156. (b) Mack, H.; Hanack,
M. Angew. Chem., Int. Ed. Engl. 1986, 25, 184. (c) Mack, H.;
¨
Hanack, M. Liebigs Ann. Chem. 1989, 833. (d) Nagele,
U. M.; Hanack, M. Liebigs Ann. Chem. 1989, 847.
Scheiblich, S.; Maier, T.; Baltruschat, H. S.; Hoellmueller,
T. 2000, US-6130188.
4. (a) Bentley, P. D.; Cheetham, R.; Huff, R. K.; Pascoe, R.;
Sayle, J. D. Pestic. Sci. 1980, 11, 156. (b) Mack, H.; Hanack,
M. Angew. Chem., Int. Ed. Engl. 1986, 25, 184. (c) Mack, H.;
¨
Hanack, M. Liebigs Ann. Chem. 1989, 833. (d) Nagele,
4.7.2. (R)-3,3-Dimethyl-10-(2,2,2-trifluoroethylidene)-
10,10a-dihydro-1H-oxazolo[3,4-b]isoquinolin-5-one (40)
and 3,3-dimethyl-10-(2,2,2-trifluoroethyl)-1H-oxa-
zolo[3,4-b]isoquinolin-5-one (42). Using a procedure
similar to that for 39, compound 36 (104.7 mg,
0.246 mmol) was treated with Pd(OAc)2 (1.38 mg,
0.006 mmol), tris-o-tolylphophine (7.49 mg, 0.025 mmol)
and Et3N (72.0 mL, 0.517 mmol) in CH3CN (8.2 mL) for
8 h. After concentration of the mixture, the residue was
chromatographed on silica gel (hexane) to give a mixture of
40 and 42 in a ratio of 1:2 (39.1 mg, 54%) as a brown oil: 1H
NMR d 1.72 (1/3!3H, s, Me for 40), 1.76 (1/3!3H, s, Me
for 40), 1.86 (2/3!6H, s, 2!Me for 42), 3.42 (2/3!2H, q,
JZ10.2 Hz, CH2CF3 for 42), 4.09 (1/3!1H, dd, JZ9.0,
8.3 Hz, one of H-11 for 40), 4.40 (1/3!1H, dd, JZ8.3,
5.6 Hz, one of H-11 for 40), 4.60–4.71 (1/3!1H, m, H-10a
for 40), 5.09 (2/3!2H, s, H-11 for 42), 5.49 (1/3!3/4H, qd,
JZ8.6, 2.3 Hz, C]CHCF3 for 40), 6.31 (1/3!1/4H, qd,
JZ9.8, 3.0 Hz, C]CHCF3 for 40), 7.45–7.78 (3H, m,
Ar-H), 8.10–8.20 (2/3!1H, m, Ar-H for 42), 8.45–8.48
(1/3!1H, m, Ar-H for 40); HRMS calcd for C15H14F3NO2
297.0976, found 297.0977.
U. M.; Hanack, M. Liebigs Ann. Chem. 1989, 847.
Scheiblich, S.; Maier, T.; Baltruschat, H. S.; Hoellmueller,
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Tetrahedron 2002, 58, 265.
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Chem. 2002, 67, 3156. (b) More recently, Hanamoto et al.
have reported Wittig reaction of a trifluoromethyl-substituted
ylide with aromatic aldehydes, see: Hanamoto, T.; Morita, N.;
Shindo, K. Eur. J. Org. Chem. 2003, 4279.
6. Miles, N. J.; Sammes, P. G. J. Chem. Soc., Perkin Trans. 1
1985, 2299.
7. St-Denis, Y.; Chan, T. J. Org. Chem. 1992, 57, 3078.
8. Sato, T.; Tsujimoto, K.; Matsubayashi, K.; Ishibashi, H.;
Ikeda, M. Chem. Pharm. Bull. 1992, 40, 2308.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific