Generation of 6-(Trifluoromethyl)-4,5-dihydro-2(3H)-pyridone and the Application to Synthesis of some Fused Nitrogen Heterocycles Carrying a Trifluoromethyl Group on the Bridgehead Position via Radical Cyclization of Dihydropyridones

Article abstract of DOI:10.1021/jo961030g

Staudinger/aza-Wittig reaction of 6,6,6-trifluoro-5-oxohexanoyl azide with PPha or PBua was examined. A reactive intermediate acyl imine 1 was trapped by methanol. Without nucleophile, isomerized enamide form 3 was obtained. W-Iodobenzoylation and 2V-haloalkylation of 3 and following radical cyclization via the 5-exo or 6-exo mode gave benzoindolizidinone, indolizidinone, and quinolizidinone derivatives 10-14, which have a trifluoromethyl group at the bridgehead position adjacent to nitrogen. Although LiAlH4 reduction of 10 and 11 gave a mixture of saturated benzoindolizidine 15 and amino alcohol 16, reduction with BH₃/THF selectively gave the desired 15 and indolizidine 17 from 13.

Full text of DOI:10.1021/jo961030g

8826
J . Org. Chem. 1996, 61, 8826-8830
Gen er a tion of 6-(Tr iflu or om eth yl)-4,5-d ih yd r o-2(3H)-p yr id on e a n d
th e Ap p lica tion to Syn th esis of Som e F u sed Nitr ogen Heter ocycles
Ca r r yin g a Tr iflu or om eth yl Gr ou p on th e Br id geh ea d P osition via
Ra d ica l Cycliza tion of Dih yd r op yr id on es
Takashi Okano, Tsutomu Sakaida, and Shoji Eguchi*
Department of Molecular Design and Engineering, Graduate School of Engineering,† Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-01, J apan
Received J une 3, 1996X
Staudinger/aza-Wittig reaction of 6,6,6-trifluoro-5-oxohexanoyl azide with PPh3 or PBu3 was
examined. A reactive intermediate acyl imine 1 was trapped by methanol. Without nucleophile,
isomerized enamide form 3 was obtained. N-Iodobenzoylation and N-haloalkylation of 3 and
following radical cyclization via the 5-exo or 6-exo mode gave benzoindolizidinone, indolizidinone,
and quinolizidinone derivatives 10-14, which have a trifluoromethyl group at the bridgehead
position adjacent to nitrogen. Although LiAlH4 reduction of 10 and 11 gave a mixture of saturated
benzoindolizidine 15 and amino alcohol 16, reduction with BH3/THF selectively gave the desired
15 and indolizidine 17 from 13.
Sch em e 1a
Trifluoromethylated nitrogen heterocycles are an at-
tractive class of compounds because of their potential
biological activities,1 and many 5-membered and 6-mem-
bered aromatic nitrogen heterocycles have been pre-
pared.2-4 However, saturated compounds such as quino-
lizidines, indolizidines,5 or pyrrolizidines6 have been
ignored by organofluorine chemists in spite of their wide
range of biological activities observed among the natu-
rally occurring alkaloids. Although these fused hetero-
cycles are strong bases due to their rigid tertiary amine
structures, introduction of a trifluoromethyl group near
the nitrogen atom will reduce the basicity and may
modify the biological activity. Since introduction of a
trifluoromethyl group7 into saturated heterocycles is
considerably different from that into aromatic ones, we
intended to develop a new general route to indolizidines
a
Key: (i) NaOC2H5/C2H5OH reflux; (ii) 30% H2SO4/reflux; (iii)
SOCl2; (iv) TMSN3.
and quinolizidines carrying a trifluoromethyl group on
the bridgehead carbon of those skeletons, and 6-(trifluo-
romethyl)-4,5-dihydro-2(3H)-pyridone (1) was conceived
as a reactive precursor to such fused heterocycles. In the
last decade, we have been investigating the application
of the Staudinger/aza-Wittig reaction of keto azides to
cyclic imines,8 and acyl imine should arise from the
reaction of trifluoroketoacyl azide 2 with trialkylphos-
phines.9
We report here the formation of acyl imine 1 via
Staudinger/aza-Wittig reaction and the further applica-
tion of the obtained tautomerized product 3 to the
synthesis of indolizidine and quinolizidine derivatives via
radical cyclization.
† Former address: Institute of Applied Organic Chemistry, Faculty
of Engineering.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) (a) Welch, J . T. Selective Fluorination in Organic and Bioorganic
Chemistry; ACS Symposium Series 456; Washington, D.C., 1991. (b)
Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
J ohn Wiley & Sons: New York, 1990. (c) Welch, J . T. Tetrahedron
1987, 16, 381.
(2) 5-Membered-ring-nitrogen heterocycles: (a) Abdul-Ghani, M. M.;
Tipping, A. E. J . Fluorine Chem. 1995, 73, 189. (b) Umada, A.; Okano,
T.; Eguchi, S. Synthesis 1994, 1457. (c) Meazza, G.; Zanardi, G. J .
Fluorine Chem. 1994, 67, 183. (d) Barnes, K. D.; Hu, Y.; Hunt, D. A.
Synth. Commun. 1994, 24, 1749. (e) Iwata, S.; Ishiguro, Y.; Utsugi,
M.; Mitsuhashi, K.; Tanaka, K. Bull. Chem. Soc. J pn. 1993, 66, 2432.
(f) Bouillon, J . P.; Ates, C.; J anousek, Z.; Viehe, H. G. Tetrahedron
Lett. 1993, 34, 5075. (g) Takahashi, M.; Kotashima, H.; Saitoh, T.
Heterocycles 1993, 35, 909. (h) Meazza, G.; Zanardi, G.; Piccardi, P.
J . Heterocycl. Chem. 1993, 30, 365. (i) Okano, T.; Uekawa, T.;
Morishima, N.; Eguchi, S. J . Org. Chem. 1991, 56, 5259.
(3) 6-Membered-ring-nitrogen heterocycles: (a) Eguchi, S.; Umada,
A.; Okano, T. Heterocycles 1996, 40, 333. (b) Atkinson, R. S.; Coogan,
P. M.; Cornell, C. L. J . Chem. Soc., Perkin Trans. 1 1996, 157. (c)
Bouillon, J . P.; J anousek, Z.; Viehe, H. G.; Tinant, B.; Declercq, J .-P.
Ibid. 1995, 2907. (d) Yamamoto, M.; Burton, D. J .; Swenson, D. C. J .
Fluorine Chem. 1995, 72, 49. (e) Baumann, L.; Folkerts, A.; Imming,
P.; Klindert, T.; Massa, W.; Steitz, G.; Wocadlo, S. Liebigs Ann. 1995,
661. (f) Kobayashi, M.; Uneyama, K.; Hamada, N.; Kashino, S.
Tetrahedron Lett. 1994, 35, 5235. (g) Bouillon, J . P.; Wynants, C.;
J anousek, Z.; Viehe, H. G. Heterocycles 1994, 37, 915.
Resu lts a n d Discu ssion
(1) Sta u d in ger /Aza -Wittig Rea ction of 6,6,6-Tr i-
flu or o-5-oxoh exa n oyl Azid e. As illustrated in Scheme
1, the starting keto acid, 6,6,6-trifluoro-5-oxohexanoic
(4) A few examples of synthesis of CF3-containing saturated nitrogen
heterocycles have been also reported: Begue, J . P.; Bonnet-Delpon,
D.; Lequeux, T. Tetrahedron Lett. 1993, 34, 3279.
(5) Michael, J . P. Nat. Prod. Rep. 1995, 12, 535.
(6) Robins, D. J . Nat. Prod. Rep. 1995, 12, 413.
(8) (a) Okawa, T.; Eguchi, S. Tetrahedron Lett. 1996, 37, 81. (b)
Okawa, T.; Eguchi, S.; Kakehi, A. J . Chem. Soc., Perkin Trans. 1 1996,
247. (c) Eguchi, S.; Yamashita, K.; Matsushita, Y.; Kakehi, A. J . Org.
Chem. 1995, 60, 4006.
(7) For a review on the synthesis of trifluoromethyl compounds,
see: McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(9) Sasaki, T.; Eguchi, S.; Okano, T. J . Am. Chem. Soc. 1983, 105,
5912.
S0022-3263(96)01030-4 CCC: $12.00 © 1996 American Chemical Society

Generation of 6-(Trifluoromethyl)-4,5-dihydro-2(3H)-pyridone
J . Org. Chem., Vol. 61, No. 25, 1996 8827
Sch em e 2
acid (4), was prepared by Claisen condensation of ethyl
trifluoroacetate and diethyl glutarate with sodium ethox-
ide followed by decarboxylative hydrolysis with 30%
sulfuric acid as in Tatrow’s preparation method for 5,5,5-
trifluoro-4-oxopentanoic acid.10 The total yield of the acid
4 from trifluoroacetate was 42% and somewhat lower
than that of the latter acid. Although the succinate for
the latter acid leads to a stable sodium enolate of the
addition product that is difficult to deprotonate to a
highly unstable conjugated dianion, the condensation
product, diethyl 2-trifluoroacetylglutarate, still has a
reactive site, which can be deprotonated to a nonconju-
gated dianion, and the further reaction with trifluoroac-
etate made the reaction more complicated and lowered
the yield of the condensation product even if the equi-
molar amount of base was used. Conversion of acid 4
into acyl chloride with thionyl chloride followed by
azidation with trimethylsilyl azide in THF gave a 1:1
mixture of desired acyl azide 2 and azido lactone 5 in
98% yield in total.11 Contamination of 5 to 2 and the
ratio were confirmed by the IR spectrum (1767 and 1717
cm-1 for 2 and 1782 cm-1 for 5) and the 1H NMR
spectrum, in which the complicated absorptions of 5 were
shown in addition to the simpler spectrum of 2. Since
acyl azide 2 was thermally unstable due to spontaneous
Curtius reaction, the following reaction with trialkyl-
phosphines was conducted without separation of 5
(Scheme 1).
Ta ble 1. Der iva tiza tion of En a m id e 3
At first, reaction of acyl azide 2 (1:1 mixture with
lactone 5) with triphenylphosphine was carried out in
CH3OH solution at room temperature. Accompanied by
evolution of nitrogen indicating the formation of acyl
iminophosphorane 6, methoxy lactam 7 was isolated in
9% yield as a thermally unstable compound along with
a nearly quantitative amount of triphenylphosphine oxide
from the complex reaction mixture. As described in our
earlier work,9 cyclic acyl imine is a reactive intermediate,
and the product seems to be isolated only as an adduct
of an appropriate nucleophile such as methanol.
This was supported by the fact that cyclic enamide 3,
enamine-imine tautomer of cyclic imine 1, was isolated
in 49% yield with triphenylphosphine and in 34% yield
with tributylphosphine, respectively, on the basis of the
starting acid 4, when this reaction was conducted in
benzene without any nucleophile. Several attempts to
obtain [4 + 2] adducts with some dienes including
cyclopentadiene or Danishefsky diene were unsuccessful,
and 3 was again isolated from the reaction mixture.
An alternative route employing the reaction of the
6,6,6-trifluoro-5-oxohexanoyl chloride and (trimethyl-
silylimine)triphenylphosphorane to avoid undesired for-
mation of 5 gave a comparative yields of 3 (55% from
PPh3 and 38% from PBu3) (Scheme 2).
a
NaI was added for activation of benzyl bromide.
terminally halogenated side chain as summarized in
Table 1. For activation of enamide nitrogen, sodium
hydride was used. Nucleophilicity of amide nitrogen of
3 is somewhat declined by the trifluoromethyl group and
the acylation, and alkylation reactions took long time to
complete (several days for alkylation at room tempera-
ture). For the iodobenzylation of 3 with 2-iodobenzyl
bromide, NaI was added for activation of benzyl bro-
mide.12
Radical cyclization of the o-iodobenzoyl derivative 8
and haloalkyl products 9a -d with tributyltin hydride
(SnBu3H) and a catalytic amount of azobisisobutyronitrile
(AIBN) gave the desired polycyclic products 10-14, which
were the normal 5-exo and 6-exo cyclization mode prod-
ucts, in good yields (Table 2).13 To avoid simple reduction
of halides, a benzene solution of SnBu3H and AIBN was
slowly added into the reaction mixture and the reactions
were completed in 8-10 h at 80 °C. Benzoindolizidin-
dione 10 and benzoindolizidinone 11 were obtained from
o-iodobenzoyl and o-iodobenzyl derivatives 8 and 9a ,
respectively, in good yields. (E)- and (Z)-3-bromoallyl
(2) Ra d ica l Cycliza tion of Un sa tu r a ted Alk yl a n d
Acyl Der iva tives of En a m id e 3. Although the acyl
imine intermediate 1 was not isolated because of the
spontaneous tautomerization, the enamide 3 can be still
regarded as a precursor for the fused nitrogen hetero-
cycles. Thus, 3 was derivatized with o-iodobenzoyl
chloride and various haloalkylation reagents with a
(12) Rorig, K.; J ohnston, J . D.; Hamilton, R. W.; Telinski, T. J .
Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 576.
(13) For reviews on free radicals in organic synthesis: (a) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon Press: Oxford, 1986. (b) J asperse, C. P.; Curran, D. P.
Chem. Rev. 1991, 91, 1237. (c) Curran, D. P. Synlett 1991, 63; (d)
Synthesis 1988, 417 and 489. (e) Ramaiah, M. Tetrahedron 1987, 43,
3541.
(10) Brown, P.; Burdon, J .; Tatrow, J . C. Tetrahedron 1960, 10, 164.
(11) The formation of azido lactone 5 was a result of the ring-chain
tautomerism. Such an undesired formation of azido lactone was also
observed in the preparation of o-acylbenzoyl azide: Takeuchi, H.;
Eguchi, S. J . Chem. Soc., Perkin Trans. 1 1988, 2149. For ring-chain
tautomerism, see: Valters, R. E.; Flitsch, W. In Ring-Chain Tautom-
erism; Katritzky, A. R., Ed.; Plenum Press: New York, 1985.

8828 J . Org. Chem., Vol. 61, No. 25, 1996
Okano et al.
Ta ble 2. Ra d ica l Cycliza tion of 8 a n d 9a -d w ith AIBN
Sch em e 3
a n d Bu 3Sn H
also introduced by Shibasaki and co-workers recently.15
Even without the trifluoromethyl group, cyclic acyl imine
(dihydropyridone) is unstable and tautomerizes to the
enamide form. Although the acyl imine intermediate
cannot be used as a synthetic intermediate directly, the
aza-Wittig route to dihydropyridone is still useful to
prepare indolizidine and quinolizidine compounds with
a trifluoromethyl group. Physical and biological proper-
ties of the trifluoromethylated cyclic amines are under
investigation.
Exp er im en ta l Section
derivatives 9bE,Z were separated by SiO2 chromatogra-
phy, and radical cyclization was conducted as the pure
isomer forms. However, both E- and Z-isomers gave the
same cyclization product 12 in almost the same yield (64
and 65%), indicating the fast inversion of vinyl radical
or structural change from sp2 radical to p radical (sp
carbon). This cyclization of a vinyl radical intermediate
may be important for synthesis of 1-/2-substituted in-
dolizidine analogs. Both 3-iodopropyl and 4-iodobutyl
derivatives afforded the saturated indolizidinone 13 and
quinolizidinone 14, respectively. However, the yield of
quinolizidinone 14 is relatively lower (50%) than those
of other cyclized products 10-13, and a trace amount of
the open-chain simple reduction product was also found
in the reaction mixture. This is consistent with the
previously reported less favored nature of the 6-exo
radical cyclization.14
Reduction of the cyclized products to the alkaloid-
related saturated compounds were firstly attempted with
LiAlH4. However, as the example of the reduction of 10,
a substantial amount of open-chain hydroxybutyl deriva-
tive 16 (39%) was isolated along with the desired tricyclic
15 (23%). The reduced basicity of the nitrogen caused
by the adjacent CF3 group makes the intermediate
aminal (the first step in the reduction) unreactive for
imine formation (the second intermediate to 15), and it
breaks down to the corresponding aldehyde, which is
immediately reduced to 16. Finally, more selective
reduction of these cyclic amides and imides were achieved
by BH3/THF complex at room temperature. In this
method, indolizidine 17 was also obtained in good yield
(Scheme 3).
1H and 13C-NMR spectra of CDCl3 or DMSO-d6 solutions
were recorded at 200 and 40 MHz with TMS as an internal
standard. 19F NMR spectra of CDCl3 or DMSO-d6 were
recorded at 87.67 MHz. Chemical shifts of the 19F NMR
spectra were reported in ppm (δ) relative to internal CFCl3.
6,6,6-Tr iflu or o-5-oxoh exa n oic Acid (4). Sodium (12.6 g,
663 mmol) was dissolved in anhydrous ethanol (140 mL). At
0 °C, ethyl trifluoroacetate (77.6 g, 546 mmol) was added in
one portion to the above ethanol solution. Diethyl glutarate
(25.0 g, 133 mmol) was added to the resulting solution, and
the mixture was heated at 70 °C for 3 h. Then, diethyl
glutarate (25.0 g, 133 mmol) was added to the mixture again,
and the mixture was heated overnight at 70 °C. After cooling,
20% H2SO4 (300 mL) was added to the mixture, and then the
mixture was extracted with Et2O (150 mL × 4). Removal of
the solvent under reduced pressure gave a crude product.
Without purification, to the obtained ester was added 30% H2-
SO4 (300 mL), and the mixture was heated at reflux for 7 h.
After cooling, the mixture was poured onto ice-water and
extracted with Et2O (100 mL × 4). The combined extracts
were successively washed with saturated aqueous NaCl and
water. The Et2O solution was dried over MgSO4, and the
solvent was removed under reduced pressure. Distillation
gave pure carboxylic acid 4 as a colorless solid (20.5 g, 42%):
bp 62-5 °C (4 Torr); mp 34-7 °C; 1H NMR (CDCl3) 2.02 (quint,
J ) 7.1 Hz, 2H), 2.47 (t, J ) 7.1 Hz, 2H), 2.85 (t, J ) 7.1 Hz,
2H), 10.20 (br s, 1 H); 13C NMR (CDCl3) 17.28, 32.38, 35.27,
115.80 (q, J ) 291 Hz), 179.60, 191.41 (q, J ) 35 Hz); 19F NMR
(CDCl3) -79.9 (s); IR (neat film) 1765, 1713 cm-1; CI-MS m/z
185 (M + H+, 100), 167 (13). Anal. Calcd for C6H7F3O3: C,
39.14; H, 3.83. Found: C, 39.02; H, 3.92.
6,6,6-Tr iflu or o-5-oxoh exa n oyl Azid e (2). Carboxylic acid
4 (3.70 g, 20.0 mmol) was dissolved in oxalyl chloride (8 mL),
and the solution was stirred for 2.5 h at room temperature.
The excess of oxalyl chloride was removed under reduced
pressure (IR (neat film) 1796, 1767 cm-1). The residue was
dissolved in anhydrous THF (10 mL), and trimethylsilyl azide
(5 mL) was added dropwise at 0 °C to the solution. The
mixture was stirred for 2 h at room temperature, and the
It is interesting that this cyclization strategy of ha-
loalkyl dihydropyridone to indolizidine derivatives was
(14) 6-exo-Cyclization of 6-heptenyl radical is 100 times as slow as
5-exo cyclization of 5-hexenyl radical: Fossey, J .; Lefort, D.; Sorba, J .
Free Radicals in Organic Chemistry; J ohn Wiley & Sons: Chichester,
1995; p 152.
(15) Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1993,
34, 4965.

Generation of 6-(Trifluoromethyl)-4,5-dihydro-2(3H)-pyridone
J . Org. Chem., Vol. 61, No. 25, 1996 8829
solvent was removed under reduced pressure to give a 1:1
mixture of acyl azide 2 and cyclic azide 5: 1H NMR (CDCl3)
1.88-2.15 (m, 4 H × 1/2), 2.02 (quint, J ) 7.0 Hz, 2 H × 1/2),
2.40-2.66 (m, 1 H × 1/2), 2.45 (t, J ) 7.0 Hz, 2 H × 1/2), 2.72-
2.90 (m, 1 H × 1/2), 2.84 (t, J ) 7.0 Hz, 2 H × 1/2); IR (neat
film) 2135, 1782, 1767, 1717 cm-1. This mixture was used for
further reaction without purification.
(m, 2H), 2.46-2.61 (m, 2H); 13C NMR (CDCl3) 19.19, 30.75,
51.32 (q, J ) 2.6 Hz), 97.12, 114.33 (q, J ) 5.7 Hz), 120.47 (q,
J ) 272 Hz), 125.46, 128.65, 128.99, 131.88 (q, J ) 33 Hz),
138.79, 139.90, 170.46, 170.46; 19F NMR (CDCl3) -65.2 (s);
1688 cm-1; CI-MS m/z 383 (M + 1 + H+, 14), 382 (M + H+,
100). Anal. Calcd for C13H11F3INO: C, 40.97; H, 2.91; N, 3.68.
Found: C, 40.88; H, 2.77; N, 3.76.
6-Meth oxy-6-(tr iflu or om eth yl)-2-p ip er id in on e (7). The
mixture of 2 and 5 prepared from acid 4 (184 mg, 1.00 mmol)
as above was dissolved in anhydrous methanol (6 mL). To the
solution was added PPh3 (300 mg, 1.14 mmol), and the
resulting mixture was stirred at room temperature for 2 h.
Removal of the solvent under reduced pressure and chroma-
tography on a SiO2 column (2:1 hexane-EtOAc) gave PPh3O
(274 mg, 98%) and 7 as a thermally unstable solid (17 mg,
9%): 1H NMR (CDCl3) 2.02 (m, 4H), 2.44 (m, 2 H), 3.39 (q, J
) 0.8 Hz, 3 H), 6.70 (br s, 1 H); 13C NMR (CDCl3) 16.70, 26.28,
31.19, 50.93, 85.68 (q, J ) 31 Hz), 123.85 (q, J ) 287 Hz),
173.56; IR (KBr) 1688 cm-1; CI-MS m/z 198 (M + H+; 100),
184 (33).
(E)- an d (Z)-1-(3-Br om opr op-2-en yl)-6-(tr iflu or om eth yl)-
3,4-d ih yd r o-2(1H)-p yr id on e (9bE a n d 9bZ). As similar as
above, a mixture of 3 (132 mg, 0.8 mmol), 1,3-dibromopropene
(7:3 E,Z-mixture: 0.2 mL, ca. 2 mmol), and NaH (60% oil
dispersion: 39 mg, 0.96 mmol) in THF (3 mL) was treated to
give a mixture of 9bE and 9bZ, which were separated by SiO2
preparative TLC (CH2Cl2).
1
9bE: 123 mg (54%); colorless oil; H NMR (CDCl3) 6.34 (d,
J ) 6.0 Hz, 1H), 6.19 (dt, J ) 13.8, 6.0 Hz, 1H), 6.09 (tq, J )
4.8, 0.8 Hz, 1H), 4.25 (d, J ) 6.0 Hz, 2H), 2.60-2.52 (m, 2H),
2.33-2.48 (m, 2H); 13C NMR (CDCl3) 19.05, 30.70, 44.01 (q, J
) 2.7 Hz), 110.14, 114.55 (q, J ) 5.8 Hz), 120.66 (q, J ) 272
Hz), 131.15 (q, J ) 33 Hz), 132.12, 170.19; 19F NMR (CDCl3)
-64.7 (s); IR (neat film) 1694 cm-1; MS m/z 285 (M+ + 2, 4),
283 (M+, 4), 205 (18), 204 (100). Anal. Calcd for C9H9BrF3-
NO: C, 38.05; H, 3.19; N, 4.93. Found: C, 38.09; H, 3.49; N,
4.60.
6-(Tr iflu or om et h yl)-4,5-d ih yd r o-2(1H )-p yr id on e (3).
Meth od A. Acyl azide 2 prepared from keto acid 4 (3.7 g, 20
mmol) as above was dissolved in benzene (200 mL), and then
triphenylphosphine (6.3 g, 24 mmol) was added in one portion.
After the solution was stirred for 5 h at room temperature,
the solvent was removed under reduced pressure to give a
mixture. The residue was sublimed at 80-100 °C (0.2 Torr),
and collected solid was recrystallized from Et2O to give pure
1
9bZ: 52 mg (23%); colorless oil; H NMR (CDCl3) 6.28 (dt,
J ) 7.2, 1.9 Hz, 1H), 6.01-6.12 (m, 2H), 4.45 (dd, J ) 5.2, 1.9
Hz, 2H), 2.54-2.62 (m, 2H), 2.33-2.48 (m, 2H); IR (neat film)
1694 cm-1
.
1
3: 1.52 g (49%); H NMR (CDCl3) 2.41-2.60 (m, 4 H), 5.71-
5.79 (m, 1 H), 8.52 (br s, 1 H); 13C NMR (CDCl3) 19.59, 29.39,
107.77 (q, J ) 5 Hz), 120.32 (q, J ) 271 Hz), 128.63 (q, J ) 35
Hz), 171.56; 19F NMR (CDCl3) -71.0 (s); IR (KBr) 1709, 1688
cm-1; EI-MS m/z 165 (M+, 100), 137 (42). Anal. Calcd for
C6H6F3NO: C, 43.65; H, 3.66; N 8.48. Found: C, 43.76; H,
3.49; N, 8.43.
N-(3-Iodopr opyl)-6-(tr iflu or om eth yl)-3,4-dih ydr o-2(1H)-
p yr id on e (9c). Following the procedure described above, 9c
was obtained from a mixture of 3 (248 mg, 1.50 mmol), 1,3-
diiodopropane (0.86 mL, ca. 7.5 mmol), and NaH (60% oil
dispersion: 66 mg, 1.65 mmol) in THF (3 mL) as a thermally
unstable colorless oil that turned brown on standing: 300 mg
1
(60%); H NMR (CDCl3), 6.093 (tq, J ) 4.8, 1.0 Hz, 1H), 3.73
Meth od B. Acyl chloride prepared from acid 4 (184 mg, 1
mmol) was dissolved to anhydrous THF (2 mL), and then
(trimethylsilyl)iminophosphorane (3.54 g, 2.34 mmol) was
added in one portion. The resulting mixture was stirred for 1
h at room temperature and then diluted with water (10 mL).
The mixture was extracted with Et2O, and the combined
extracts were washed with water and dried over MgSO4. The
solvent was removed under reduced pressure. The residue was
separated on a preparative SiO2 TLC plate (hexane-EtOAc
1:1) to give pure 3 (90 mg, 55%).
(t, J ) 7.2 Hz, 2H), 3.13 (t, J ) 7.2 Hz, 2H), 2.56-2.50 (m,
2H), 2.46-2.28 (m, 2H), 2.11 (quint, J ) 7.2 Hz, 2H); 13C NMR
(CDCl3) 1.06, 19.07, 30.83, 32.42, 44.03 (q, J ) 2.4 Hz), 114.56
(q, J ) 5.9 Hz), 120.71 (q, J ) 272 Hz), 131.52 (q, J ) 32 Hz),
170.62; IR (neat film) 1696 cm-1
.
N-(4-Iodobu tyl)-6-(tr iflu or om eth yl)-3,4-dih ydr opyr idin -
2-on e (9d ). Following the procedure described abve, 9d was
obtained from a mixture of 3 (165 mg, 1.00 mmol), 1,4-
diiodobutane (0.66 mL, ca. 5.5 mmol), and NaH (60% oil
dispersion: 44 mg, 1.1 mmol) in THF (3 mL) as a colorless oil:
1-(2′-Iodoben zoyl)-6-(tr iflu or om eth yl)-3,4-dih ydr o-2(1H)-
p yr id on e (8). To a solution of 3 (248 mg, 1.50 mmol) in THF
(5 mL) was added NaH (66 mg, 1.65 mmol; 60% oil dispersion)
in one portion at 0 °C. The resulting suspension was stirred
for 1 h at room temperature. To the suspension was added
o-iodobenzoyl chloride (600 mg, 2.25 mmol) and then the
mixture was stirred for 3 h at room temperature. The mixture
was poured into water and was extracted with CH2Cl2 after
neutralization of the solution with hydrochloric acid. The
combined extracts were dried over MgSO4. The solvents were
removed under reduced pressure, and the residue was chro-
matographed on a silica gel preparative TLC plate to give pure
1
264 mg (76%); H NMR (CDCl3), 6.10 (td, J ) 4.9, 1.0 Hz, 1
H), 3.69 (t, J ) 7.2 Hz, 2H), 3.19 (t, J ) 7.0 Hz, 2H), 2.57-
2.49 (m, 2H), 2.45-2.30 (m, 2H), 1.91-1.76 (m, 2H), 1.73-
1.58 (m, 2H); 13C NMR (CDCl3) 5.67, 19.06, 29.68, 30.86, 30.91,
41.79 (q, J ) 2.6 Hz), 114.70 (q, J ) 5.9 Hz), 120.76 (q, J )
272 Hz), 131.62 (q, J ) 32 Hz), 170.52; 19F NMR (CDCl3) -64.9
(s), IR (neat film) 1694 cm-1; MS m/z 347 (M+, 32), 220 (100).
Anal. Calcd for C10H13F3INO: C, 34.60; H, 3.78; N, 4.04.
Found: C, 34.98; H, 3.82; N, 4.01.
10b-(Tr iflu or om eth yl)-1,2-d ih yd r o[2,1-a ]isoin d ole-4,6-
(3H,10bH)-d ion e (10). To a refluxing solution of 8 (316 mg,
0.80 mmol) in benzene (11 mL) was added a solution of AIBN
(12 mg, 80 µmol) and Bu3SnH (0.44 mL, ca. 1.6 mmol) in
benzene (11 mL) dropwise over 5 h, and the resulting solution
was further refluxed for 5 h. The solvent was removed under
reduced pressure, and the residue was dissolved to Et2O (20
mL) and 50% aqueous KF solution (5 mL). The mixture was
stirred for 1 h at room temperature. Then the mixture was
separated, and the aqueous layer was washed with Et2O
several times. The Et2O extracts were combined and dried
over MgSO4. The solvent was removed under reduced pres-
sure, and the residue was chromatographed on a preparative
SiO2 TLC (1:1 hexane-EtOAc) to give pure 10 as a colorless
1
8 as a colorless solid: 420 mg (71%); mp 114-5 °C; H NMR
(CDCl3) 7.95 (ddd, J ) 7.9, 1.0, 0.5 Hz, 1H), 7.43-7.48 (m,
2H), 7.40 (ddd, J ) 7.9, 6.6, 1.0 Hz, 1H), 7.16 (ddd, J ) 7.9,
6.6.1.5 Hz, 1H), 6.49-6.58 (m, 1H), 2.50-2.70 (m, 4H); 13C
NMR (CDCl3) 19.61, 32.78, 120.73 (q, J ) 273 Hz), 122.64 (q,
J ) 3.9 Hz), 128.36, 129.45, 132.49, 141.01, 140.83, 132.81,
132.81 (q, J ) 36 Hz), 170.92, 170.98; IR (KBr) 1709 cm-1 19F
;
NMR (CDCl3) -61.1 (s); CI-MS m/z 396 (M + H+, 25), 231
(100). Anal. Calcd for C13H9F3INO2: C, 39.52; H, 2.30; N,
3.54. Found: C, 39.51; H, 2.24; N, 3.35.
1-(2′-Iodoben zyl)-6-(tr iflu or om eth yl)-3,4-dih ydr o-2(1H)-
p yr id on e (9a ). A mixture of 3 (198 mg, 1.20 mmol), 2-iodo-
benzyl bromide (891 mg), NaH (60% oil dispersion: 58 mg,
1.44 mmol), and NaI (450 mg, 3.00 mmol) in THF (5 mL) was
stirred at 45 °C for 60 h. The mixture was worked up as in
the above case to obtain 9a as a colorless solid: 274 mg (60%);
mp 82-83 °C; 1H NMR (CDCl3) 7.84 (dd, J ) 7.2, 1.2 Hz, 1H),
7.83 (td, J ) 7.6, 1.3 Hz, 1H), 6.95 (t-like m, 1 H), 6.85 (d-like
m, 1H), 6.16 (tq, J ) 4.8, 0.7 Hz, 1H), 4.88 (s, 2H), 2.65-2.73
1
solid: 207 mg (97%); mp 150-151 °C; H NMR (CDCl3) 8.00
(ddd, J ) 7.4, 1.3, 0.8 Hz, 1H), 7.71 (td, J ) 7.4, 1.3 Hz, 1H),
7.69-7.57 (m, 2H), 2.91-2.67 (m, 3H), 2.42-2.17 (m, 1H),
2.13-1.90 (m, 2H); 13C NMR (CDCl3) 17.59 (q, J ) 1.9 Hz),
27.47, 32.49, 67.00 (q, J ) 29 Hz), 125.11 (q, J ) 285 Hz),
122.93, 126.14, 130.05, 131.15, 135.07, 142.15, 165.74, 169.36;
19F NMR (CDCl3) -74.3 (s); IR (KBr) 1773, 1692 cm-1; MS m/z

8830 J . Org. Chem., Vol. 61, No. 25, 1996
Okano et al.
269 (M+, 96), 201 (47), 200 (100). Anal. Calcd for C13H10F3-
NO2: C, 58.00; H, 3.74; N, 5.20. Found: C, 57.87; H, 3.79; N,
5.18.
19F NMR (CDCl3) -70.5; IR (neat film) 1653 cm-1; MS m/z 222
(M+ + 1, 12), 221 (M+, 89), 152 (100). Anal. Calcd for
C10H14F3NO: C, 54.29; H, 6.38; N, 6.33. Found: C, 54.33; H,
6.63; N, 6.04.
10b-(Tr iflu or om eth yl)-1,2,6,10b-tetr a h yd r op yr id o[2,1-
a ]isoin d ol-4(3H)-on e (11). Following the procedure de-
scribed for the synthesis of 10, 11 was obtained from a solution
of 9a (229 mg, 0.60 mmol) in benzene (9 mL) and a solution of
AIBN (8 mg, 50 µmol) and Bu3SnH (0.33 mL, ca. 1.2 mmol) in
benzene (9 mL): 140 mg (92%); colorless solid; mp 100-101
°C; 1H NMR (CDCl3) 7.47-7.31 (m, 4H), 5.18 (d, J ) 15.4 Hz,
1H), 4.62 (d, J ) 15.4 Hz, 1H), 2.80-2.40 (m, 3H), 2.36-2.12
(m, 1H), 2.04-1.80 (m, 2H); 13C NMR (CDCl3) 17.14 (q, J )
1.8 Hz), 27.80, 29.78, 51.95, 69.91 (q, J ) 28 Hz), 126.43 (q, J
) 287 Hz), 123.15 (2C), 128.26, 130.05, 138.10, 138.44, 170.90;
19F NMR (CDCl3) -76.0 (s); IR (KBr) 1655 cm-1; MS m/z 256
(M+ + 1, 15), 255 (M+, 92), 186 (100). Anal. Calcd for
C13H12F3NO: C, 61.18; H, 4.74; N, 5.49. Found: C, 61.20; H,
4.64; N, 5.75.
10b-(Tr iflu or om eth yl)-1,2,3,4,6,10b-h exa h yd r op yr id o-
[2,1-a ]isoin d ole (15). To a stirred solution of 10 (54 mg, 0.20
mmol) in THF (1 mL) was added BH3/THF solution (1.0 M; 2
mL, 2.0 mmol) dropwise at -20 °C in 5 min, and then the
solution was stirred at room temperature for 2 h. To the
solution was added MeOH (2 mL), and the solvents were
removed under reduced pressure. The pure amine 15 was
obtained by preparative TLC (SiO2, 1:1 hexane-EtOAc) as a
colorless oil: 33 mg (50%); 1H NMR (CDCl3) 7.37-7.21 (m, 4H),
4.40 (d, J ) 13.4 Hz, 1H), 4.20 (d, J ) 13.4 Hz, 1H), 3.26 (br
t, J ) 14.8 Hz, 1H), 2.97 (br d, J ) 14.8 Hz, 1H), 2.30-2.20
(m, 1H), 1.78-1.40 (m, 5H); 13C NMR (CDCl3) 18.74, 19.19,
27.95, 45.75, 57.34, 69.39 (q, J ) 27 Hz), 122.84 (q, J ) 7.2
Hz), 122.92, 127.65, 128.60, 139.95, 127.75 (q, J ) 285 Hz),
141.58; MS m/z 241 (M+, 7), 172 (100). Anal. Calcd for
C13H14F3N: C, 64.72; H, 5.85; N, 5.81. Found: C, 64.98; H,
5.74; N, 5.66.
LiAlH4 Red u ction of 10. To a stirred suspension of LiAlH4
(35 mg, 0.9 mmol) in THF (2 mL) was added a solution of 10
(34 mg, 0.12 mmol) in THF (1 mL) at room temperature. The
resulting mixture was refluxed for 4 h and then diluted with
H2O (25 mL). After addition of 20% aqueous NaOH (25 µL)
and stirring for 30 min at room temperature, Et2O (4 mL) and
MgSO4 were added into the mixture. Filtration and removal
of the solvents followed by chromatography on a SiO2 TLC
plate (1:1 hexane-EtOAc) gave 15 (7 mg, 23%) and 16 (10 mg,
39%): colorless oil; 1H NMR (CDCl3) 7.39-7.23 (m, 4H), 4.45
(d, J ) 13.8 Hz, 1H), 4.32 (d, J ) 13.8 Hz, 1H), 3.62 (dt, J )
10.6, 6.4 Hz, 1H), 3.56 (dt, J ) 10.6, 6.2 Hz, 1H), 2.10 (ddd, J
) 14.0, 11.5, 5.5 Hz, 1H), 1.94 (ddd, J ) 14.0, 11.7, 5.5 Hz,
1H), 1.761 (s, 2H), 1.54 (m, 2H), 1.41-1.24 (m, 1H), 1.16-0.93
(m, 1H); 13C NMR (CDCl3) 19.28, 32.68, 33.19, 52.16, 62.48,
72.75 (q, J ) 27 Hz), 123.04, 123.83, 127.63, 127.65 (q, J )
285 Hz), 129.16, 137.71, 142.87; MS m/z 259 (M+, 5), 186 (100).
Anal. Calcd for C13H16F3NO: C, 60.22; H, 6.22; N, 5.40.
Found: C, 60.43; H, 6.09; N, 5.33.
8a -(Tr iflu or om et h yl)in d olizid in e (17). To a stirred
solution of 13 (39 mg, 0.2 mmol) in THF (1 mL) was added
BH3/THF solution (1.0 M; 2 mL, 2.0 mmol) dropwise. After
the solution was stirred for 2 h at room temperature, workup
as above gave crude 17 as a colorless oil. Picric acid EtOH
solution (ca. 5%, 1 mL) was added to the crude 17, and the
resulting precipitates were collected. Recrystallization from
MeOH gave 17‚picrate as yellow solid: 70 mg (87%); mp 176-
180 °C dec; 1H NMR (CDCl3) 8.92 (s, 2H), 4.04 (ddd, J ) 11.8,
8.8, 5.2 Hz), 3.78-3.37 (m, 3H), 2.71-2.49 (m, 2H), 2.31-1.76
(m, 8H); 13C NMR (CDCl3) 17.64, 17.81, 19.47, 25.43, 32.08,
48.43, 53.03, 68.98 (q, J ) 28 Hz), 125.19 (q, J ) 284 Hz),
129.21, 127.03, 141.89, 162.19; IR (KBr) 1634, 1562, 1366,
1273, 1175, 710 cm-1; CI-MS m/z 194 (M + H+, 100). Anal.
Calcd for C15H17F3N4O7: C, 42.66; H, 4.06; N, 13.27. Found:
C, 42.44; H, 3.98; N, 13.57.
8a-(Tr iflu or om eth yl)-3,7,8,8a-tetr ah ydr o-5(6H)-in doliz-
in on e (12). Following the procedure described for the syn-
thesis of 10, 12 was obtained from a solution of 9bE (142 mg,
0.50 mmol) in benzene (8 mL) and a solution of AIBN (8 mg,
50 µmol) and Bu3SnH (0.27 mL, ca. 1.0 mmol) in benzene (8
1
mL): 66 mg (64%); colorless oil; H NMR (CDCl3) 6.22 (dt, J
) 6.3, 1.9 Hz, 1H), 5.77 (dt, J ) 6.3, 2.2 Hz, 1H), 4.67 (ddd, J
) 16.4, 2.2, 1.9 Hz, 1H), 4.13 (ddd, J ) 16.4, 2.2, 1.9 Hz, 1H),
2.66-2.36 (m, 3 H), 2.24-1.99 (m, 1H), 1.92-1.63 (m, 2H);
13C NMR (CDCl3) 16.50, 26.71, 29.36, 54.22, 71.34 (q, J ) 29
Hz), 126.36 (q, J ) 286 Hz), 127.94, 131.63, 171.14; 19F NMR
(CDCl3) -76.7 (s); IR (neat film) 1669 cm-1; MS m/z 205 (M+,
1), 136 (100). Anal. Calcd for C9H10F3NO: C, 52.68; H, 4.91;
N, 6.83. Found: C, 52.68; H, 5.16; N, 6.58.
As similar as above, 12 was also obtained from 9bZ (23 mg,
82 µmol), Bu3SnH (45 µL, ca. 0.17 mmol), and AIBN (1.5 mg,
9 µmol): 11 mg (65%).
8a -(Tr iflu or om eth yl)-1,2,3,7,8,8a -h exa h yd r o-5(6H)-in -
d olizin on e (13). Following the procedure described for the
synthesis of 10, 13 was obtained from a solution of 9c (100
mg, 0.30 mmol) in benzene (5 mL) and a solution of AIBN (5
mg, 30 µmol) and Bu3SnH (0.16 mL, ca. 0.6 mmol) in benzene
(5 mL): 52 mg (84%); colorless oil; 1H NMR (CDCl3) 4.08-
3.94 (m, 1H), 3.47 (ddd, J ) 12.1, 9.6, 4.5 Hz, 1H), 2.59-2.29
(m, 4H), 2.16-1.41 (m, 6H); 13C NMR (CDCl3) 17.43, 20.25 (q,
J ) 1.7 Hz), 29.55, 29.72, 35.95, 46.20, 65.85 (q, J ) 27 Hz),
127.32 (q, J ) 287 Hz), 171.04; 19F NMR (CDCl3) -75.7 (s); IR
(neat film) 1659 cm-1; MS m/z 207 (M+, 15), 138 (100). Anal.
Calcd for C9H12F3NO: C, 52.17; H, 5.84; N, 6.76. Found: C,
52.13; H, 6.00; N, 6.64.
9a-(Tr iflu or om eth yl)-1,2,3,6,7,8,9,9a-octah ydr o-4H-qu in -
olizin -4-on e (14). Following the procedure described for the
synthesis of 10, 14 was obtained from a solution of 9d (104
mg, 0.30 mmol) in benzene (5 mL) and a solution of AIBN (5
mg, 30 µmol) and Bu3SnH (0.16 mL, ca. 0.6 mmol) in benzene
(5 mL): 33 mg (50%); colorless oil; 1H NMR (CDCl3) 4.72 (dqt,
J ) 13.0, 2.3, 1.3 Hz, 1H), 2.75 (br t, J ) 13.0 Hz, 1H), 2.48 (t,
J ) 6.6 Hz, 2H), 2.25-2.05 (m, 2H), 1.96-1.34 (m, 8H); 13C
NMR (CDCl3) 16.85 (q, J ) 1.9 Hz), 20.25, 24.20, 32.22, 33.16,
38.53, 60.42 (q, J ) 25 Hz), 127.72 (q, J ) 290 Hz), 171.76;
J O961030G