One-pot synthesis of 3-fluoro-4-(trifluoromethyl)quinolines from pentafluoropropen-2-ol and their molecular modification

Article abstract of DOI:10.1021/jo702568z

(Chemical Equation Presented) Pentafluoropropen-2-ol (PFP) was prepared by the reaction of hexafluoroacetone (HFA) with Mg/TMSCl. The one-pot tandem sequential reactions of PFP via Mannich addition with aldimines followed by Friedel-Crafts cyclization and aromatization afforded the title quinolines. A variety of corresponding 3-substituted quinolines were derived from the title quinoline by nucleophilic substitution of 3-fluorine with nucleophiles. A defluorinative transformation of the 4-trifluoromethyl group of the title quinoline with hydrazine afforded py razoloquinoline.

Full text of DOI:10.1021/jo702568z

One-Pot Synthesis of 3-Fluoro-4-(trifluoromethyl)quinolines from
Pentafluoropropen-2-ol and Their Molecular Modification
Tsuyoshi Hosokawa, Akemi Matsumura, Toshimasa Katagiri,* and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama UniVersity, 3-1-1 Tsushimanaka,
Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp; tkata@cc.okayama-u.ac.jp
ReceiVed NoVember 29, 2007
Pentafluoropropen-2-ol (PFP) was prepared by the reaction of hexafluoroacetone (HFA) with Mg/TMSCl.
The one-pot tandem sequential reactions of PFP via Mannich addition with aldimines followed by Friedel-
Crafts cyclization and aromatization afforded the title quinolines. A variety of corresponding 3-substituted
quinolines were derived from the title quinoline by nucleophilic substitution of 3-fluorine with nucleophiles.
A defluorinative transformation of the 4-trifluoromethyl group of the title quinoline with hydrazine afforded
pyrazoloquinoline.
Introduction
transformed to highly functionalized quinolines. One of the
common structures feasible for the desired quinolines would
be fluoroalkylated haloquinolines.4 Halogen on an aromatic ring
could be replaced with other functional groups, for instance,
nucleophiles by nucleophilic substitution,5 aryl and alkenyl
groups by transition metal-catalyzed cross-coupling reactions,6
metal species by halogen-metal exchange,7 etc. In particular,
it has been recognized recently that fluorine is the most
useful halogen for nucleophilic substitution on an aromatic ring
since fluorine activates R-carbon and greatly accelerates the
initial addition step for the nucleophilic substitution.8 Based on
the background, it is interestingly to see the possibility of
Due to their unique bioactivities, quinolines often have been
regarded as leading pharmaceutical compounds.1-3 Among
them, fluoroalkylated quinolines often exhibit interesting bio-
activities, thus they have been developed as drugs, such as
Mefloquine.2,3 Because of less availability of fluorinated organic
starting materials, full survey of the quantitative structure-
activity relationship (QSAR) of fluoroalkylated quinolines has
not been addressed systematically yet. Thus, development of a
new synthetic method for fluorine-functionalized quinolines
which possess functionalities necessary for both potential
bioactivity and further functional group modification toward
target molecules has remained a subject for active research.
From this viewpoint, it is useful to design fluorine-function-
alized quinolines which can be diversely and systematically
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Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729-734. (b) Marull,
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10.1021/jo702568z CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/19/2008
1468
J. Org. Chem. 2008, 73, 1468-1474

3-Fluoro-4-(trifluoromethyl)quinoline from Pentafluoropropen-2-ol
SCHEME 1. Transformation of CF3 of HFA
SCHEME 3. Synthesis of PFP
acid-catalyzed desilylation. However, the preparation of the
triethylsilyl enol ether from hexafluoroisopropanol (HFIP)
requires rather expensive reagents: 2 equiv of n-butyllithium
and triethylsilyl chloride (TESCl).13 Thus, the development of
a conventional preparation of PFP is also one of the objectives
of the present study.
Reductive C-F bond activation of trifluoromethyl group
attached to a π-system such as carbonyl, iminyl, alkenyl, and
aromatic groups is quite easy since the π-system accepts two
electrons from metal magnesium into its low LUMO so as to
extrude a fluoride ion from the trifluoromethyl group.14 This
fact suggests that PFP 3 could be prepared by the well-known
Mg-promoted defluorination of an available hexafluoroacetone
(HFA) 1 followed by acid-catalyzed desilylation of trimethylsilyl
pentafluoropropen-2-olate 2.
SCHEME 2. C-C Bond Formation of PFP at C-2
incorporation of hexafluoroacetone (HFA) into the functional-
ized quinoline skeleton where one of the trifluoromethyl groups
of HFA is transformed into the substituted C3-carbon moiety
of quinoline via successive defluorination reactions as shown
in Scheme 1.
On this basis, one of the subjects of the research would be
C-C bond formation of pentafluoropropen-2-ol (PFP) at the
C2-carbon with aldimines which would lead subsequently to
the skeleton of 3-fluoro-4-(trifluoromethyl)quinolines. The PFP
is expected to be one of the very promising building blocks for
trifluoromethylated compounds since the difluoromethylene
carbon of PFP would be not only electrophilic but also
nucleophilic due to an enol form of pentafluoroacetone.9 And
its hydroxyl group would be acidic enough to promote acid-
catalyzed reactions since the pKa of PFP was reported to be
about 4.10b However, very few applications of PFP for the
synthesis of fluorinated molecules have been reported.11 So far,
there has been only one report on the reaction of PFP at the
C2-carbon (self-condensation of two molecules of PFP resulting
in the formation of 4-hydroxy-4-difluoromethyloctafluoro-2-
pentanone (Scheme 2)),11f presumably because PFP has been
less available since it was prepared by acid hydrolysis from
perfluoroisopropenyl phosphate or perfluoropropenyl ether
intermediates, which were derived from perfluoroisobutene
(PFIB), an extremely toxic and volatile alkene.9,12 PFP could
also be prepared from triethylsilyl pentafluoropropen-2-olate by
Here, we describe three subjects: (1) a facile preparation of
2 and PFP 3 from HFA 1, (2) one-pot synthesis of 3-fluoro-4-
(trifluoromethyl)quinolines from 3 via tandem Mannich addition/
Friedel-Crafts cyclization/aromatization sequence, and (3)
defluorinative transformation of the 3-fluoroquinoline to 3-sub-
stituted quinolines.
Results and Discussion
Preparation of PFP. The Mg-promoted defluorination reac-
tion is so moisture sensitive that a dry reaction condition is
required. Thus, dried gaseous HFA 1 was generated by the
reaction of commercially available HFA-trihydrate with concd
H2SO4, and again dried through concd H2SO4.15 Then, the dry
HFA was bubbled into dimethylformamide (DMF) on cooling
the solution at -20 °C. Defluorination of HFA 1 proceeded
smoothly in the DMF (0.25 M) solution of Mg (4 equiv) and
TMSCl (4 equiv) at -20 °C. The defluorination gave silyl enol
ether 2 in 80% yield along with hexafluoroisopropanol (HFIP)
and the trimer of HFA in 3% and 5% yields, respectively, which
were determined by 19F NMR (Scheme 3). The volatile products
were separated from DMF solution by distillation under reduced
pressure. Then, subsequent desilylation was repeated twice by
distillation of 2 over concd H2SO4 and the product was distilled
in vacuo at 0 °C and trapped into a glass tube cooled in liquid
nitrogen. Consequently, the PFP 3 was obtained in 60% yield
from HFA trihydrate, which contained trimethylsilylfluoride
(TMSF) and a trace amount of HFIP as impurities. These
impurities did not hinder subsequent Mannich reaction and
provided almost the same results as those obtained with 95%
pure PFP prepared from triethylsilyl pentafluoropropen-2-olate.16
(8) Uneyama, K. In Organofluorine Chemistry; Blackwell Publishing:
Malden, MA, 2006; pp 101-107.
(9) (a) Bekker, R. A.; Popkova, V. Y.; Knunyants, I. L. IzV. Akad. Nauk
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1974, 217, 1320-1323.
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L.; Grushina, N. M.; Logansen, A. V.; Kurkchi, G. A. Zh. Prikl. Spektrosk.
1978, 28, 106-111. (c) Kostyanovskii, R. G.; Pleshkova, A. P.; Khvostenko,
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Zh. Org. Khim. 1976, 12, 1379-1384. (d) Bekker, R. A.; Melikyan, G. G.;
Dyatkin, B. L.; Knunyants, I. L. Zh. Org. Khim. 1975, 11, 1600-1604. (e)
Bekker, R. A.; Melikyan, G. G.; Dyatkin, B. L.; Knunyants, I. L. Zh. Org.
Khim. 1975, 11, 1604-1607. (f) Bekker, R. A.; Melikyan, G. G.; Dyatkin,
B. L.; Knunyants, I. L. Zh. Org. Khim. 1975, 11, 2370-2372. (g) Bekker,
R. A.; Melikyan, G. G.; Dyatkin, B. L.; Knunyants, I. L. Dokl. Akad. Nauk
SSSR 1975, 221, 1331-1333. (h) Bekker, R. A.; Melikyan, G. G.; Lur’e,
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(16) The 95% pure PFP was prepared from triethylsilyl pentafluoropro-
pen-2-olate.13 The PFP with aldimine 4a afforded the Mannich product
quantatively (determied by 19F NMR analysis).
(12) (a) Timperley, G. M. J. Fluorine Chem. 2004, 125, 685-693. (b)
Maidment, M. P.; Patel, S. K.; Upshall, D. G.; Timperley, G. M. J. Appl.
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J. Org. Chem, Vol. 73, No. 4, 2008 1469

Hosokawa et al.
SCHEME 4. One-Pot Synthesis of
3-Fluoro-4-(trifluoromethyl)quinoline
SCHEME 5. Plausible Reaction Mechanism
Thus, the PFP 3 was used without further purification for the
following quinoline synthesis.17
Synthesis of Quinolines. The Mannich reaction of aldimines
with silyl enol ether generally needs Lewis acid or Brønsted
acid catalysts.18 Interestingly, the reaction of the enol 3 with
aldimines 4 did not need any acid catalyst. The C-C bond
formation occurred spontaneously just by mixing the enol 3 with
aldimines 4 in dichloromethane (DCM) and completed within
4 h at room temperature. However, intramolecular Friedel-
Crafts cyclization of 6 to tetrahydroquinoline 8 via 7 required
higher temperature for completion. Thus, DCM solvent was
exchanged to toluene and the toluene solution was refluxed for
7 h. Aromatization of tetrahydroquinoine 8 via dehydration and
dehydrofluorination successfully proceeded under trifluoroacetic
acid (TFA) catalysis in refluxing toluene. Use of p-toluene-
sulfonic acid (TsOH), boron trifluoride diethyl etherate (BF3‚
OEt2), trifluoroacetic acid anhydride (TFAA), or TFAA/pyridine
complex resulted in unsuccessful aromatization of tetrahydro-
quinoline 8. Consequently, one-pot synthesis via three sequential
reactions gave quinolines 5 from the PFP 3 and aromatic
aldimines 4a-d bearing an N-(4-methoxyphenyl) (PMP) group
in reasonable yields: 83% (5a), 68% (5b), 61% (5c), and 62%
(5d), respectively (Scheme 4).
SCHEME 6. Application of the Reaction to
Benzo[h]quinoline
would undergo acid-catalyzed dehydration and dehydrofluori-
nation to be converted into quinoline 5a as a final product (see
details in the Experimental Section).
Benzo[h]quinoline possesses an important skeleton for po-
tential inhibiting activity.3b Thus, the same reaction of aldimine
4f with an N-(2-naphthyl) group was examined. Benzo[h]-
quinoline 5f was obtained in 70% yield by the same one-pot
procedure (Scheme 6).
To widen the scope of the one-pot reaction, the reaction of
PFP with alkyl aldimine (R ) CH3) was examined. Because
the aldimine with R ) CH3 was difficult to isolate, the aldimine
was used after preparation in situ for the present one-pot
reaction.19 However, the reaction did not give a desired quinoline
with R ) CH3. Meanwhile, the reaction of PFP and aldimine
4e of ethyl glyoxalate gave the quinoline 5e in 64% yield.
A step-by-step 19F NMR analysis of the intermediates
suggested a mechanism of the one-pot quinoline synthesis
(Scheme 5). First, Mannich adduct 6 would be formed. The
intermediates 6 and its hydrate would be converted via
intermediate 7 into tetrahydroquinoline 8 on heating at the reflux
temperature of toluene. Subsequently, tetrahydroquinoline 8
Reaction of Quinoline. Replacements of the 3-fluorine of
quinoline 5 with nucleophiles were examined. It is well-known
that fluorine is the most reactive among halogens attached to
an aromatic ring on being subjected to nucleophilic substitution.
For instance, the enolate of ethyl cyanoacetate substitutes the
fluorine of 3-chloro-5-fluorobromobenzene exclusively to give
ethyl dihalophenylcyanoacetate.21 Therefore, the fluorine atom
on C3 of quinolines 5 must be reactive enough for nucleophilic
substitution due to the additional activation by the 4-trifluo-
romethyl group and thus would be replaced with various
nucleophiles.
Substitution of the 3-fluorine with the cyano group was
conducted by the use of 0.5 equiv of tetrabutylammonium
fluoride (TBAF) and 2 equiv of trimethylsilyl cyanide (TMSCN)
at room temperature for 48 h (Table 1, entry 1). Although the
SNAr reaction in general requires high temperature, the cyanation
of 3-fluoroquinoline 5a occurred at room temperature. It is
noteworthy that 0.5 equiv of TBAF is good enough to complete
the substitution since the fluoride ion is regenerated from the
substrate aromatic fluoride.22 Results of the nucleophilic sub-
stitution of aryl fluoride 5a by various nucleophiles are
summarized in Table 1.
(17) Further purification was conducted by precise distillation for removal
of TMSF, and desilylation in H2SO4 gave an 87% pure PFP with impurities
of TMSF and HFIP on NMR in 26% yield.
(18) (a) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2006, 4075-4080.
(b) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566-1568. (c) Akiyama, T.; Takaya, J.; Kagoshima, H. AdV.
Synth. Catal. 2002, 344, 338-347. (d) Akiyama, T.; Takaya, J.; Kagoshima,
H. Tetrahedron Lett. 2001, 42, 4025-4028.
(19) (a) Nakajima, T.; Inada, T.; Igarashi, T.; Sekioka, T.; Shimizu, I.
Bull. Chem. Soc. Jpn. 2006, 79, 1941-1949. (b) Oudeyer, S.; Dudot, B.;
Royer, J. Heterocycles 2005, 65, 823-841. Although Mannich reactions
of aldimine with R ) CH3 have been reported, they occurred on using the
aldimine prepared in situ from aldehyde and aniline.
(20) X-ray crystallographic analyses of the structures of 8a and 5a are
described in the Supporting Information.
(21) Kowalczyk, B. A. Synthesis 1997, 1411-1414.
(22) Uneyama, K. J. Fluorine Chem. 2007, 128, 1087-1090.
1470 J. Org. Chem., Vol. 73, No. 4, 2008

3-Fluoro-4-(trifluoromethyl)quinoline from Pentafluoropropen-2-ol
TABLE 1. Nucleophilc Substitutions of Aromatic Fluorine
SCHEME 7. Nucleophilic Hydrazination
2. 3-Fluoro-4-(trifluoromethyl)quinolines 5 were synthesized in
83-61% yields by the one-pot sequential Mannich addition/
Friedel-Crafts cyclization/aromatization reactions from PFP
with aldimines. Quinoline 5 experienced further nucleophilic
substitutions of 3-fluorine to give a variety of 3-substituted
quinolines (9) in good yields. A series of 3-substituted-4-
(trifluoromethyl)quinolines could be prepared from 3-fluoro-4-
(trifluoromethyl)quinolines (5) via further transformation of the
fluorine on the quinoline ring.
Similarly to the cyanation, all of the nucleophilic substitutions
examined so far were successful: alkoxylation with silyl enol
ether [CH2dC(OTMS)Ph] in DMF (entry 2), hydroxylation with
sodium hydroxide in DMF (entry 3), ethoxylation with sodium
ethoxide in EtOH (entry 4), amination23 with potassium cyanate
(KOCN) in N-methyl-2-pyrrolidone (NMP) (entry 5), and
sulfenylation with sodium thiophenoxide in DMF (entry 6).
Replacement of 3-fluorine with hydrogen by the use of NaBH4
in DMF (entry 7) also proceeded smoothly.24 The quinoline 9g
is an interesting substrate since lithium-hydrogen exchange
would occur easily at the ortho-position of the trifluoromethyl
group by treatment with butyllithium (BuLi) and incorporation
of electrophiles at the 3-carbon of quinoline 5 would provide
various 3-substituted quinolines.25
Meanwhile, nucleophilic iodination, bromination, or chlorina-
tion of the 3-fluorine has not been attained yet. The reactions
with NaX, TMSX/TBAF, or ZnX2 (X ) I, Br, Cl) resulted only
in recovery of starting quinoline 5a and with CuX2 (X ) Br,
Cl), BBr3, and AlBr3 gave no desired 3-haloquinoline.
The reaction of hydrazine with quinoline 5a accompanied
further substitution at the CF3 group to give pyrazoloquinoline
10 (Scheme 7) in 68% yield. The base-catalyzed 1,4-dehydro-
fluorination from the o-trifluoromethyl group in 2-CF3-
substituted phenols, anilines, and benzylic compounds is quite
facile, leading to the formation of o-quinone methide intermedi-
ates.26 The successive dehydrofluorinations of 9h via 11 and
12 resulted in pyrazole ring formation.
Experimental Section
General Procedure for the Preparation of Pentafluoropropen-
2-ol (PFP) (3). Dry gaseous hexafluoroacetone (HFA) was gener-
ated by dropwise addition of HFA trihydrate (13.8 mL, 100 mmol)
into concd H2SO4 (40 mL) at 90 °C over 1 h. Then, the gaseous
HFA was dried again through concd H2SO4. The dry HFA gas was
bubbled into the dimethylformamide (DMF) (400 mL) suspension
of Mg (9.72 g, 400 mmol) and triethylsilyl chloride (TMSCl) (50.8
mL, 400 mmol) at -20 °C. After the solution was stirred for an
additional 1 h, volatile products were distilled from the DMF
solution at 80 °C into a glass tube cooled in liquid nitrogen under
reduced pressure. Then, distilled PFP derivatives were combined
with H2SO4 (10.2 mL) at -30 °C under an Ar atmosphere, and the
solution was stirred for 0.5 h to decompose trimethylsilylated
compounds. After the solution was stirred at 0 °C for an additional
1.5 h, PFP derivatives were distilled from H2SO4 at 0 °C. After
mixing again with H2SO4 (10.2 mL) at -30 °C and stirring, PFP
[7.1 g (58% purity), 60%] was distilled in vacuo and used for the
next reactions.
1,1,3,3,3-Pentafluoropropen-2-ol (3). An authentic sample of
3 was prepared from triethylsilyl pentafluoropropen-2-olate by acid-
catalyzed desilylation. Spectral data of 3 were analyzed for the
authentic enol. PFP 3 from HFA was identifiable as the authentic
1
sample by 19F NMR spectra. H NMR (CDCl3) δH 3.97 (br, 1H).
19F NMR (CDCl3) δF 93.5 (dd, J ) 25, 9 Hz, 3F), 66.9 (dq, J )
58, 9, 1F), 57.3 (dq, J ) 58, 25 Hz, 1F). 13C NMR(CDCl3) δC
153.9 (ddq, J ) 295, 288, 3 Hz), 120.6 (qdd, J ) 271, 9, 7 Hz),
107.3 (qdd, J ) 39, 35, 25 Hz).
Conclusion
Pentafluoropropen-2-ol (PFP 3) was prepared in 60% yield
by reductive defluorination of HFA in the Mg/TMSCl/DMF
system followed by acid-catalyzed desilylation of silyl enol ether
General Procedure for One-Pot Synthesis of Quinoline (5).
A dichloromethane (DCM) (6 mL) solution of 58% pure PFP 3
(642 mg, 3 mmol) and aldimine was stirred at -30 °C for 0.5 h.
Then, the mixture was stirred for 2.5 h at 0 °C. After removal of
DCM under reduced pressure, the reaction mixture was dissolved
in toluene (6 mL) and the toluene solution was refluxed for 7 h.
Then, trifluoroacetic acid (TFA) (3 mL) was added into the toluene
solution and the mixture was refluxed for 8 h more. After quenched
by NaHCO3 aq, DCM solution was washed with NaCl aq and dried
with Mg2SO4. After removal of the solvent, quinoline was purified
by silica gel column chromatography (with hexane:DCM ) 5:1
eluent), and then recrystallized from hexane solution. The quinoline
(23) Shigehiro, O.; Tatsumi, K. Jpn. Kokai Tokkyo Koho 1997, JP 96-
330234; Chem. Abstr. 1997, 127, 205589.
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Angew. Chem., Int. Ed. 2005, 44, 376-393. (e) Schlosser, M. Eur. J. Org.
Chem. 2001, 3975-3984.
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J. Org. Chem, Vol. 73, No. 4, 2008 1471

Hosokawa et al.
SCHEME 8. Reaction of PFP with Iminium Salt
also could be purified by recrystallization from DCM solution and
washed by diethyl ether (DEE).
3-Fluoro-6-methoxy-2-phenyl-4-(trifluoromethyl)quinoline (5a).
White powder, 803 mg, 83% yield from 58% pure PFP (642 mg,
1
3 mmol of PFP). Mp 117.6-118.0 °C. IR (KBr) 1620. H NMR
(CDCl3) δH 8.11-8.09 (m, 1H), 8.01-7.99 (m, 2H), 7.55-7.49
(m, 3H), 7.41-7.39 (m, 2H), 3.97 (s, 3H). 19F NMR (CDCl3) δF
106.1 (d, J ) 32 Hz, 3F), 38.5 (q, J ) 32 Hz, 1F). 13C NMR
(CDCl3) δC 159.6, 153.2, 151.3, 146.8 (d, J ) 17 Hz), 141.4 (d, J
) 4 Hz), 134.9 (d, J ) 5 Hz), 132.0, 129.7, 129.2, 128.6, 124.9,
123.2 (q, J ) 276 Hz), 121.9, 117.5 (qd, J ) 32, 8 Hz), 102.1 (m),
55.6. MS (EI) m/e 321 (M+, 100), 306 (9), 278 (44). Anal. Calcd
for C17H11F4NO: C, 63.55; H, 3.45; N, 4.36. Found: C, 63.36; H,
3.42; N, 4.48.
3-Fluoro-6-methoxy-2-(4-methylphenyl)-4-(trifluoromethyl)-
quinoline (5b). Yellowish green powder, 688 mg, 68% yield from
58% pure PFP (3 mmol). Mp 112.2-113.0 °C. IR (KBr) 1630. 1H
NMR (CDCl3) δH 8.10-8.07 (m, 1H), 7.91 (dd, J ) 8, 2 Hz, 2H),
7.40-7.38 (m, 2H), 7.34 (d, J ) 8 Hz, 2H), 3.97 (s, 3H), 2.44 (s,
3H). 19F NMR (CDCl3) δF 106.2 (d, J ) 32 Hz, 3F), 38.6 (q, J )
32 Hz, 1F). 13C NMR (CDCl3) δC 159.4, 153.2, 151.4, 146.8, 146.7,
141.4 (d, J ) 4 Hz), 139.8, 132.1, 131.9, 129.2, 129.0 (d, J ) 6
Hz), 124.6, 123.3 (q, J ) 276 Hz), 121.7, 117.3 (qd, J ) 31, 8
Hz), 102.1 (m), 55.5, 21.4. MS (EI) m/e 335 (M+, 100), 320 (9),
292 (29). Anal. Calcd for C18H13F4NO: C, 64.48; H, 3.91; N, 4.18.
Found: C, 64.51; H, 3.92; N, 4.20.
7.61-7.54 (m, 3H). 19F NMR (CDCl3) δF 107.5 (dd, J ) 33, 2
Hz, 3F), 36.7 (q, J ) 33 Hz, 1F). 13C NMR (CDCl3) δC 153.2 (d,
J ) 2 Hz), 151.4 (d, J ) 2 Hz), 146.6 (d, J ) 16 Hz), 142.9 (d, J
) 5 Hz), 135.1 (d, J ) 5 Hz), 132.5, 131.0, 130.5, 129.9, 129.5 (d,
J ) 6 Hz), 128.6, 128.5, 127.6 (d, J ) 18 Hz), 124.9, 123.2 (q, J
) 276 Hz), 122.1, 120.4 (m), 119.4 (qd, J ) 32, 8 Hz). MS (EI)
m/e 341 (M+, 100). Anal. Calcd for C20H11F4N: C, 70.38; H, 3.25;
N, 4.10. Found: C, 70.45; H, 3.31; N, 4.15.
Mechanism of the Quinoline Syntheses. A step-by-step 19F
NMR analysis of the intermediates suggested a mechanism of the
one-pot quinoline synthesis (Scheme 5). First, Mannich adduct 6
would be formed although it was not isolated. The 19F NMR
chemical shifts of 6 [δ 87 ppm (d) for CF3, δ 61 (d) and 35 (ddq)
for CF2] and its hydrate [δ 81 (dd) for CF3, δ 48 (dq) and 34 (ddq)
for CF2] were similar to those of the authentic samples of the closely
related ketone 14 [δ 87 (dd) for CF3, δ 66 (d) and 42 (ddq) for
CF2] and its hydrate 15 [δ 81 (t) for CF3, δ 50 (dq) and 38 (ddq)
for CF2], which were prepared by the reaction of PFP 3 with N,N-
dimethyliminium salt 13 and were isolable (Scheme 8). On
observing the 19F NMR of the reaction solution of PFP 3 with 13,
peaks of PFP 3 [δ 94 (dd) for CF3, δ 66 (dq) and 58 (dq) for CF2]
disappeared within 2 min completely and new peaks of 15 appeared
immediately. Thus, ketone 14 would be formed, and then converted
to its hydrate 15. A trace amount of water involved in solvent and
substrates (3 and 13) may hydrate the ketone 14. In the case of the
reaction of PFP 3 with aldimine 4a, similar 19F NMR peaks ascribed
to 3, ketone 6, and its hydrate were observed, although the reaction
required more than 30 min. The intermediates 6 and its hydrate
would be converted via intermediate 7 into tetrahydroquinoline 8
on heating at the reflux temperature of toluene. The tetrahydro-
quinolines 8 were obtained as a mixture of diastereomers quanti-
tatively from aldimine 4a. One of the diastereomers, (2,4)-cis-8a,20
was crystallized from DCM solution of 8 and its stereochemistry
was confirmed by X-ray crystallographic analysis, while the other
diastereomer, (2,4)-trans-8b, remained in a powder. Subsequently,
tetrahydroquinoline 8 would undergo acid-catalyzed dehydration
and dehydrofluorination to be converted into quinoline 5a as a final
product.
Synthesis of Tetrahydroquinoline 8. In the procedure of
quinoline synthesis, the reaction was quenched without addition
of TFA. After removal of solvent, tetrahydroquinoline 8 as a mixture
of diastereomers (1.02 g, 94%) was purified by silica gel column
chromatography (hexane:DCM ) 3:1). The tetrahydroquinoline
(cis-8a) was recrystallized from DCM solution as colorless crystal.
And also, another diastereoisomer (trans-8b) was purified by silica
gel column chromathography (hexane:DEE ) 3:1).
cis-3,3-Difluoro-6-methoxy-2-phenyl-4-(trifluoromethyl)-1,2,3,4-
tetrahydroquinolin-4-ol (8a). White powder: colorless platelet
crystal. Mp 174.5-178.7 °C. IR (KBr) 3400, 3250. 1H NMR
(CDCl3) δH 7.56-7.55 (m, 2H), 7.44-7.41 (m, 3H), 7.13 (d, J )
2 Hz, 1H), 6.90 (dd, J ) 9, 3 Hz, 1H), 6.61 (d, J ) 9, 1H), 4.95
(dd, J ) 28, 3 Hz, 1H), 4.04 (br, 1H), 3.79 (s, 3H), 3.04 (d, J ) 3
Hz, 1H). 19F NMR (CDCl3) δF 87.2 (dd, J ) 16, 5 Hz, 3F), 41.9
(dd, J ) 254, 28 Hz, 1F), 38.6 (dq, J ) 254, 16 Hz, 1F). 13C NMR
[(CD3)2CO)] δC 206.2 (d, J ) 1 Hz), 152.6 (d, J ) 1 Hz), 139.2,
135.8, 130.5, 129.8, 128.9, 124.7 (q, J ) 291 Hz), 119.1, 116.4,
116.0 (dd, J ) 109, 5 Hz), 113.4, 75.7 (td, J ) 28, 21 Hz), 59.9
3-Fluoro-2-(4-fluorophenyl)-6-methoxy-4-(trifluoromethyl)-
quinoline (5c). White powder, 619 mg, 61% yield from 58% pure
1
PFP (3 mmol). Mp 152.5-154.4 °C. IR (KBr) 1630. H NMR
(CDCl3) δH 8.08 (d, J ) 9 Hz, 1H), 8.03-8.01 (m, 2H), 7.42-
7.40 (m, 2H), 7.22 (t, J ) 9 Hz, 2H), 3.98 (s, 3H). 19F NMR
(CDCl3) δF 106.1 (d, J ) 32 Hz, 3F), 50.7-50.6 (m, 1F), 38.2 (q,
J ) 32 Hz, 1F). 13C NMR (CDCl3) δC 164.5, 162.9, 159.7, 153.1,
151.2, 145.5 (d, J ) 17 Hz), 141.3 (d, J ) 5 Hz), 132.0, 131.3
(dd, J ) 9, 6 Hz), 131.1 (t, J ) 1 Hz), 124.9, 123.2 (q, J ) 276
Hz), 122.0, 117.5 (qd, 31, 7), 115.6 (d, J ) 22 Hz), 102.1 (m),
55.6. MS (EI) m/e 339 (M+, 100), 324 (9), 296 (40). Anal. Calcd
for C17H10F5NO: C, 60.18; H, 2.97; N, 4.13. Found: C, 60.14; H,
2.91; N, 4.15.
2-(3-Chlorophenyl)-3-fluoro-6-methoxy-4-(trifluoromethyl)-
quinoline (5d). White powder, 657 mg, 62% yield from 58% pure
PFP (3 mmol). Mp 88.9-89.9 °C. IR (KBr) 1620. 1H NMR (CDCl3)
δH 8.08 (d, J ) 9 Hz, 1H), 8.04-8.02 (m, 1H), 7.92-7.89 (m,
1H), 7.48-7.40 (m, 4H), 3.98 (s, 3H). 19F NMR (CDCl3) δF 106.1
(d, J ) 32 Hz, 3F), 38.2 (q, J ) 32 Hz, 1F). 13C NMR (CDCl3) δC
159.9, 153.1, 151.2, 144.9 (d, J ) 17 Hz), 141.4 (d, J ) 5 Hz),
136.6 (d, J ) 5 Hz), 134.6, 132.1, 129.7 (d, J ) 5 Hz), 129.2 (d,
J ) 6 Hz), 127.3 (d, J ) 6 Hz), 125.1, 123.2 (q, J ) 276 Hz),
122.2, 117.6 (qd, J ) 33, 7 Hz), 102.0 (m), 55.6. MS (EI) m/e 355
(M+, 100), 312 (22). Anal. Calcd for C17H10ClF4NO: C, 57.40; H,
2.83; N, 3.94. Found: C, 57.38; H, 2.77; N, 3.86.
Ethyl 3-Fluoro-6-methoxy-4-(trifluoromethyl)quinoline-2-car-
boxylate (5e). Yellowish ivory powder, 611 mg, 64% yield from
58% pure PFP (3 mmol). Mp 79.6-80.8 °C. IR (KBr) 1730, 1630.
1H NMR (CDCl3) δH 8.14 (d, J ) 10 Hz, 1H), 7.41 (dd, J ) 10,
3 Hz, 1H), 7.35-7.34 (m, 1H), 4.54 (q, J ) 7 Hz, 2H), 3.96 (s,
3H), 1.46 (t, J ) 7 Hz, 3H). 19F NMR(CDCl3) δF 106.0 (d, J ) 33
Hz, 3F), 38.8 (q, J ) 33 Hz, 1F). 13C NMR (CDCl3) δC 162.7 (d,
J ) 6 Hz), 161.2, 153.5 (d, J ) 2 Hz), 151.7 (d, J ) 2 Hz), 140.6
(d, J ) 4 Hz), 137.5 (d, J ) 17 Hz), 132.9, 127.2, 122.9, 122.7 (q,
J ) 275 Hz), 118.2 (qd, J ) 32, 7 Hz), 101.8 (m), 62.6, 55.7,
14.2. MS (EI) m/e 317 (M+, 18), 245 (100). Anal. Calcd for
C14H11F4NO3: C, 53.00; H, 3.49; N, 4.42. Found: C, 53.12; H,
3.47; N, 4.38.
3-Fluoro-2-phenyl-4-(trifluoromethyl)benzo[h]quinoline (5f).
White powder, 794 mg, 70% yield from 58% pure PFP (3 mmol).
Mp 119.6-120.5 °C. IR (KBr) No remarkable peak. 1H NMR
(CDCl3) δH 9.36 (d, J ) 8 Hz, 1H), 8.22 (d, J ) 6 Hz, 2H), 8.07-
8.04 (m, 1H), 7.95 (dd, J ) 18, 8 Hz, 2H), 7.79-7.73 (m, 2H),
1472 J. Org. Chem., Vol. 73, No. 4, 2008

3-Fluoro-4-(trifluoromethyl)quinoline from Pentafluoropropen-2-ol
(ddq, J ) 28, 22, 3 Hz), 55.9. MS (EI) m/e 359 (M+, 100), 344
(13), 290 (91). Anal. Calcd for C17H14F5NO2: C, 56.83; H, 3.93;
N, 3.90. Found: C, 56.84; H, 3.85; N, 3.85.
3 mmol) was stirred at 0 °C for 12 h. After being quenched by
NH4Cl aq, the DEE solution was washed with NaCl aq and dried
with Mg2SO4. After removal of the solvent, quinoline 9c (73 mg,
76%) was purified by silica gel column chromathography (hexane:
DEE ) 5:1). Yellow powder. Mp 120.8-122.8 °C. IR (KBr) 3580,
1620. 1H NMR (CDCl3) δH 8.00 (d, J ) 9 Hz, 1H), 7.76 (dd, J )
7, 1 Hz, 1H), 7.48 (td, J ) 7, 1 Hz, 2H), 7.43 (td, J ) 7, 1 Hz,
1H), 7.35 (br, 1H), 7.28 (dd, J ) 9, 2 Hz, 1H), 6.69 (br, 1H), 3.96
(s, 3H). 19F NMR (CDCl3) δF 107.4 (s, 3F). 13C NMR (CDCl3) δC
159.3, 149.2 (d, J ) 3 Hz), 145.9, 139.1 (d, J ) 3 Hz), 135.7,
131.6, 129.2, 128.9 (d, J ) 5 Hz), 125.4, 124.9 (q, J ) 276 Hz),
119.6, 113.5 (qd, J ) 29, 11 Hz), 102.0 (q, J ) 4 Hz), 55.5. MS
(EI) m/e 319 (M+, 100), 291 (22). Anal. Calcd for C17H12F3NO2:
C, 63.95; H, 3.79; N, 4.39. Found: C, 63.95; H, 3.82; N, 4.50.
trans-3,3-Difluoro-6-methoxy-2-phenyl-4-(trifluoromethyl)-
1,2,3,4-tetrahydroquinolin-4-ol (8b). Brown solid, 97% purity
1
(determined by 19F NMR). H NMR (CDCl3) δH 7.58-7.56 (m,
2H), 7.44-7.42 (m, 3H), 7.18 (d, J ) 2 Hz, 1H), 6.92 (dd, J ) 8,
2 Hz, 1H), 6.68 (d, J ) 8 Hz, 1H), 4.69 (d, J ) 23 Hz, 1H), 4.05
(br, 1H), 3.78 (s, 3H), 3.38 (br, 1H). 19F NMR (CDCl3) δF 91.5
(dd, J ) 16, 12 Hz, 3F), 40.3 (dq, J ) 253, 12 Hz, 1F), 34.3 (ddq,
J ) 253, 26, 16 Hz, 1F). 13C NMR (CDCl3) δC 153.1, 138.4, 133.1,
129.5, 129.4, 128.6, 124.4 (q, J ) 290 Hz), 118.9, 118.7, 117.2,
117.1, 116.1 (d, J ) 3 Hz), 115.4, 112.4, 74.0 (td, J ) 28, 21 Hz),
58.2 (dd, J ) 31, 20 Hz), 55.8. MS (EI) m/e 359 (M+, 100), 344
(13), 321 (22), 290 (91).
3-Ethoxy-6-methoxy-2-phenyl-4-(trifluoromethyl)quinoline (9d).
An ethanol (7 mL) solution of quinoline 5a (321 mg, 1.0 mmol)
and a 20% ethanol solution of sodium ethoxide (0.68 mL, 2.0 mmol)
was stirred at 78 °C for 5 h. After short silica gel column
chromathography with DEE, quinoline 9d (350 mg, 99%) was
purified by Kugerlorh distillation. White powder. Mp 74.5-76.8
4-(Dimethylamino)-1,1,1,3,3-pentafluoro-4-phenylbutan-2,2-
diol (15). A DCM (3 mL) solution of 95% pure PFP (44 mg, 0.3
mmol of PFP), which was prepared by acid-catalyzed desilylation
of triethylsilyl pentafluoropropen-2-olate, and diamine (80 mg, 0.45
mmol) was stirred for 0.5 h at -76 °C. After removal of solvent,
hydrate 15 (70 mg, 77%) was purified by silica gel column
chromathography (hexane:DCM ) 1:1, then hexane:DEE ) 1:1)
and kugerlorh distillation. White powder. IR (KBr) 3320. 1H NMR
[(CD3)2CO)] δH 7.54-7.51 (m, 2H), 7.48-7.44 (m, 3H), 4.78 (d,
J ) 31 Hz, 1H), 2.32 (s, 6H). 19F NMR [(CD3)2CO)] δF 83.6 (t, J
) 12 Hz, 3F), 52.9 (dq, J ) 263, 12 Hz, 1F), 40.3 (ddq, J ) 263,
30, 12 Hz, 1F). 13C NMR [(CD3)2CO] δC 132.1 (d, J ) 3 Hz),
129.7, 129.1, 128.7, 123.1 (q, J ) 274 Hz), 119.2(t, J ) 260 Hz),
94.4(quint d, J ) 31, 25 Hz), 68.2 (dd, J ) 30, 4 Hz), 42.1. MS
(EI) m/e 134 (M+ - 165, 100). Anal. Calcd for C12H14F5NO2: C,
48.17; H, 4.72; N, 4.68. Found: C, 48.20; H, 4.75; N, 4.64.
6-Methoxy-2-phenyl-4-(trifluoromethyl)quinoline-3-carboni-
trile (9a). A DMF (3 mL) solution of quinoline 5a (96 mg, 0.3
mmol), trimethylsilylcyanide (TMSCN) (60 mg, 0.6 mmol), and a
THF solution of tetrabutylammonium fluoride (TBAF) (0.15 mL,
0.15 mmol) were stirred at 0 °C for 1 h. After the mixture was
stirred for 47 h at room temperature, the solvent was removed in
vacuo. Then, quinoline 9a (91 mg, 92%) was purified by silica gel
column chromatography (hexane:DCM ) 1:1). Yellow powder. Mp
174.2-177.3 °C. IR (KBr) 2240, 1620. 1H NMR (CDCl3) δH 8.17
(d, J ) 10 Hz, 1H), 7.87-7.86 (m, 2H), 7.61 (dd, J ) 2, 9 Hz,
1H), 7.64-7.55 (m, 3H), 7.46 (quant, J ) 2 Hz, 1H), 4.01 (s, 3H).
19F NMR (CDCl3) δF 105.0 (s, 3F). 13C NMR (CD-Cl3) δC 159.9,
157.2, 145.8, 137.4 (q, J ) 16 Hz), 137.3, 132.2, 130.1, 129.4,
128.6, 126.6, 122.6 (q, J ) 278 Hz), 122.7, 115.1, 103.3 (q, J )
3 Hz), 102.1 (q, J ) 4 Hz), 55.8. MS (EI) m/e 328 (M+, 100), 313
(45), 285 (44), 216 (47). Anal. Calcd for C18H11F3N2O: C, 65.85;
H, 3.38; N, 8.53. Found: C, 65.92; H, 3.20; N, 8.61.
1
°C. IR (KBr) 1620. H NMR (CDCl3) δH 8.06 (d, J ) 9 Hz, 1H),
7.98-7.96 (m, 2H), 7.52-7.48 (m, 2H), 7.48-7.43 (m, 2H), 7.35
(dd, J ) 9, 3 Hz, 1H), 3.96 (s, 3H), 3.65 (q, J ) 7 Hz, 2H), 1.18
(t, J ) 7 Hz, 3H). 19F NMR (CDCl3) δF 106.5 (s, 3F). 13C NMR
(CDCl3) δC 159.0, 153.2, 149.9 (q, J ) 1.8 Hz), 141.4, 137.6, 131.8,
129.1, 129.0, 128.3, 125.2, 124.2 (q, J ) 277 Hz), 123.8 (q, J )
29 Hz), 102.4 (q, J ) 5 Hz), 71.3, 55.5, 15.1. MS (EI) m/e 347
(M+, 100), 318 (62), 303 (18), 291 (30). Anal. Calcd for C19H16F3-
NO2: C, 65.70; H, 4.64; N, 4.03. Found: C, 65.79; H, 4.68; N,
3.96.
6-Methoxy-2-phenyl-4-(trifluoromethyl)quinolin-3-amine (9e).
An N-methyl-2-pyrrolidone (NMP) (3 mL) solution of quinoline
5a (96 mg, 0.3 mmol) and sodium cyanate (117 mg, 3 mmol) was
stirred at 130 °C for 12 h. After being quenched by NH4Cl aq, the
DEE solution was washed with NaCl aq and dried with Mg2SO4.
After removal of the solvent, quinoline 9e (67 mg, 70%) was
purified by silica gel column chromathography (hexane:DEE ) 3:1).
Yellowish powder. Mp 104.2-106.1 °C. IR (KBr) 3470, 1610; 1H
NMR (CDCl3) δH 7.91 (d, J ) 9 Hz, 1H), 7.64 (dt, J ) 8, 2 Hz,
2H), 7.54 (tt, J ) 8, 1 Hz, 2H), 7.49 (tt, J ) 8, 1 Hz, 1H), 7.28 (t,
J ) 2 Hz, 1H), 7.14 (dd, J ) 9, 2 Hz, 1H), 4.83 (br, 2H), 3.94 (s,
3H). 19F NMR (CDCl3) δF 107.6 (s, 3F). 13C NMR (CDCl3) δC
159.1, 149.7, 137.3, 137.3, 136.7, 131.5, 130.1, 129.2, 128.7, 127.6,
126.3 (q, J ) 276 Hz), 125.8, 117.2, 107.6 (q, J ) 29 Hz), 101.9
(q, J ) 4 Hz), 55.3. MS (EI) m/e 318 (M+, 100), 149. Anal. Calcd
for C17H13F3N2O: C, 64.15; H, 4.12; N, 8.80. Found: C, 64.13;
H, 4.19; N, 8.73.
6-Methoxy-2-phenyl-3-(phenylsulfenyl)-4-(trifluoromethyl)-
quinoline (9f). A DMF (3 mL) solution of quinoline 5a (96 mg,
0.3 mmol), sodium borohydride (227 mg, 6 mmol), and diphenyl
disulfide (635 mg, 3 mmol) was stirred at 0 °C for 12 h. After
being quenched by NH4Cl aq, the DEE solution was washed with
NaCl aq and dried with Mg2SO4. After removal of the solvent,
quinoline 9f (312 mg, 76%) was purified by silica gel column
chromathography (hexane:DEE ) 5:1). White powder. Mp 115.3-
6-Methoxy-2-phenyl-3-[(1-phenylethenyl)oxy]-4-(trifluorom-
ethyl)quinoline (9b). A DMF (3 mL) solution of quinoline 5a (96
mg, 0.3 mmol), CsF (46 mg, 0.3 mmol), silyl enol ether (1-phenyl-
1-trimethylsiloxyethylene) (39 mg, 0.6 mmol) was stirred at 70 °C
for 12 h. After filtration and removal of the solvent, quinoline 9b
(90 mg, 71%) was purified by silica gel column chromathograpy
(hexane:DEE ) 5:1) and followed by recrystallization from hexane/
DEE eluent. White powder. Mp 126.5-128.2 °C. IR (KBr) 1630.
1H NMR (CDCl3) δH 8.14 (d, J ) 9 Hz, 1H), 7.85-7.82 (m, 2H),
7.58-7.55 (m, 2H), 7.49-7.47 (m, 1H), 7.44 (dd, J ) 9, 3 Hz,
1H), 7.36-7.31 (m, 6H), 4.65 (d, J ) 4 Hz, 1H), 3.99 (s, 3H),
3.68 (d, J ) 4 Hz, 1H). 19F NMR (CDCl3) δF 105.6 (s, 3F). 13C
NMR (CDCl3) δC 160.2, 159.2, 153.1, 144.1, 142.4, 136.9, 134.3,
131.9, 128.9, 128.1, 128.1, 125.3, 125.1, 124.6 (q, J ) 30 Hz),
123.6 (q, J ) 277 Hz), 122.0, 102.5 (dd, J ) 6, 4 Hz), 87.8, 55.6.
MS (EI) m/e 421 (M+, 17), 352 (28), 319 (32), 318 (30), 103 (100).
Anal. Calcd for C25H18F3NO2: C, 71.25; H, 4.31; N, 3.32. Found:
C, 71.28; H, 4.33; N, 3.28.
1
116.3 °C. IR (KBr) 1620. H NMR (CDCl3) δH 8.07 (d, J ) 10
Hz, 1H), 7.58 (br, 1H), 7.45 (dd, J ) 9, 2 Hz, 1H), 7.33-7.32 (m,
2H), 7.30-7.27 (m, 2H), 7.26-7.23 (m, 1H), 7.05-7.02 (m, 1H),
7.00-6.98 (m, 2H), 6.69-6.67 (m, 2H), 3.99 (s, 3H). 19F NMR
(CDCl3) δF 109.1 (s, 3F). 13C NMR (CDCl3) δC 160.5, 159.1, 144.0,
140.3, 136.5, 136.2 (q, J ) 29 Hz), 131.9, 129.7, 128.9, 128.7,
128.0, 127.7, 126.3, 124.8, 124.3 (q, J ) 279 Hz), 123.2. MS (EI)
m/e 411 (M+, 100), 334 (55). Anal. Calcd for C23H16F3NOS: C,
67.14; H, 3.92; N, 3.40. found: C, 67.19; H, 3.62; N, 3.44.
6-Methoxy-2-phenyl-4-(trifluoromethyl)quinoline (9g). A DMF
(3 mL) solution of quinoline 5a (96 mg, 0.3 mmol) and sodium
borohydride (34 mg, 0.9 mmol) was stirred at 70 °C for 12 h. After
being quenched by NH4Cl aq, the DEE solution was washed with
6-Methoxy-2-phenyl-4-(trifluoromethyl)quinolin-3-ol (9c). A
DMF (3 mL) solution of quinoline 5a (96 mg, 0.3 mmol), sodium
hydride-60% oil suspension (120 mg, 3 mmol), and water (54 mg,
J. Org. Chem, Vol. 73, No. 4, 2008 1473

Hosokawa et al.
NaCl aq and dried with Mg2SO4. After removal of the solvent,
quinoline 9g (81 mg, 89%) was purified by silica gel column
chromathograpy (hexane:DCM ) 5:1). White powder. Mp 120.8-
9 Hz, 1H) 4.02 (s, 3H). 19F NMR (CDCl3) δF 32.5 (s). 13C NMR
[(CD3)2SO] δC 158.9, 158.9, 157.3, 143.3, 137.3, 136.4, 134.2,
131.4, 130.0, 129.1, 128.6, 120.8 (d, J ) 4 Hz), 117.8, 106.6 (d, J
) 22 Hz), 102.7 (d, J ) 2 Hz), 55.8. MS (EI) m/e 293 (M+, 100),
278 (25). Anal. Calcd for C23H12FN3O: C, 69.62; H, 4.12; N, 14.33.
Found: C, 69.58; H, 4.09; N, 14.28.
1
121.6 °C. IR (KBr) 1630. H NMR (CDCl3) δH 8.17-8.11 (m,
4H), 7.54 (t, J ) 8 Hz, 2H), 7.48 (t, J ) 8 Hz, 1H), 7.45 (d, J )
9 Hz, 1H), 7.36 (s, 1H), 3.96 (s, 3H). 19F NMR (CDCl3) δF 99.5
(s, 3F). 13C NMR (CDCl3) δC 158.7, 154.0, 145.3, 138.5, 133.4 (q,
J ) 31 Hz), 132.0, 129.6, 128.9, 127.1, 123.7 (q, J ) 275 Hz),
123.1, 116.1 (q, J ) 5 Hz), 101.8 (d, J ) 2 Hz), 55.6. MS (EI) m/e
303 (M+, 100), 260 (49).
1-Fluoro-8-methoxy-4-phenyl-3H-pyrazolo[3,4-c]quinoline (10).
A DMF (3 mL) solution of quinoline 5a (96 mg, 0.3 mmol) and
hydrazine (anhydrous) (188 µL, 6 mmol) was stirred at 70 °C for
12 h. After being quenched by NH4Cl aq, the DEE solution was
washed with NaCl aq and dried with Mg2SO4. After removal of
the solvent, quinoline 10 (60 mg, 68%) was purified by silica gel
column chromathography (hexane:DEE ) 3:1). Yellowish ivory
powder. Mp 246.3-250.0 °C. IR (KBr) 3350, 1630. 1H NMR
(CDCl3) δH 9.90 (br, 1H), 8.19 (d, J ) 9 Hz, 1H), 8.00-7.98 (m,
2H), 7.63-7.60 (m, 3H), 7.56 (t, J ) 8 Hz, 1H), 7.33 (dd, J ) 3,
Acknowledgment. The authors greatly appreciate the Central
Glass Co. Ltd for providing us HFA trihydrate and also express
our gratitude to the SC-NMR Laboratory of Okayama University
for NMR analysis and the VBL Laboratory for X-ray crystal-
lographic analysis.
Supporting Information Available: Spectral data for all
previously unreported compounds 3, 5, 8, 9, 10, and 15. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO702568Z
1474 J. Org. Chem., Vol. 73, No. 4, 2008