Aromatic nucleophilic N-N, N-S and N-O exchange reactions: Efficient synthesis of 5,7-bis(trifluoroacetyl)-8-quinolylamines, sulfides and ethers

Article abstract of DOI:10.1055/s-2000-6243

Various 5,7-bis(trifluoroacetyl)-8-quinolylamines, sulfides and ethers were synthesized in excellent yields by aromatic nucleophilic N-N, N-S and N- O exchange reactions of N,N-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine with amines, thiols and alco

Full text of DOI:10.1055/s-2000-6243

PAPER
237
Aromatic Nucleophilic N-N, N-S and N-O Exchange Reactions: Efficient
Synthesis of 5,7-Bis(trifluoroacetyl)-8-quinolylamines, Sulfides and Ethers
Etsuji Okada,* Norikado Tsukushi, Naofumi Shimomura
Department of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe, 657-8501,
Japan
Fax +81(78)8036206; E-mail: okada@appchem.chme.kobe-u.ac.jp
Received 4 August 1999; revised 13 September 1999
In this situation, we have very recently reported that N,N-
Abstract: Various 5,7-bis(trifluoroacetyl)-8-quinolylamines, sul-
dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine (3) un-
dergoes a novel aromatic nucleophilic substitution with
fides and ethers were synthesized in excellent yields by aromatic
nucleophilic N-N, N-S and N-O exchange reactions of N,N-dimeth-
yl-5,7-bis(trifluoroacetyl)-8-quinolylamine with amines, thiols and
amines to give the corresponding 5,7-bis(trifluoroacetyl)-
alcohols. Base-catalyzed cyclization of the resulting benzyl 8- 8-quinolylamines.6 Herein, we report a full account of our
quinolyl sulfide and subsequent dehydration gave fluorine-contain-
ing thieno[3,2-h]quinolines in high yields.
systematic studies on this type of aromatic nucleophilic
substitution including the new finding of the reactions of
Key words: nucleophilic aromatic substitutions, fluorine com-
pounds, quinolylamines, quinolyl sulfides, quinolyl ethers
3 with various thiols and alcohols, which are considerably
less reactive than amines. Furthermore, we also present its
application to the synthesis of fluorine-containing 2,3-di-
hydrothieno[3,2-h]quinoline 7 and thieno[3,2-h]quinoline
8, which are greatly expected to show antibacterial,7
antitumor8 and antianaphylactic activities.9
Activated aromatic compounds bearing good leaving
groups such as halo-, alkoxy-, etc., are well known to un-
dergo aromatic nucleophilic substitution with various nu-
cleophiles.1 However, amino groups attached to aromatic
rings are seldom replaced by nucleophiles. Previously, we
have found that N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-
naphthylamine (1) reacts easily with various amines,
thiols and alcohols under mild conditions to afford the
corresponding N-N, N-S and N-O exchanged 2,4-bis(tri-
fluoroacetyl)-1-naphthylamines, sulfides and ethers 2 in
excellent yields, respectively (Scheme 1).2 Up-to-lately
we succeeded in extending the present SNAr reaction to
the less reactive N,N-dimethyl-2-trifluoroacetyl-4-halo-1-
naphthylamines.3 In recent years, considerable attention
has been paid to the development of new methodologies
for the syntheses of many kinds of fluorine-containing
heterocycles, since these compounds are now widely re-
cognized as important organic materials showing interest-
ing biological activities for their potential use in medicinal
and agricultural scientific fields.4 Besides, quinolines are
important heterocyclic systems, constituting the structure
of many naturally occurring products and having interest-
ing pharmacological properties as antimicrobial agents
and antitumor drugs.5
Starting material 3 was very easily prepared in 95% yield
through the reaction of N,N-dimethyl-8-quinolylamine
with trifluoroacetic anhydride in the presence of pyridine
at 50 ∞C for 24 hours according to our method (Scheme
2).10
NMe2
NMe2
(CF3CO)2O, pyridine
CHCl3, 50 °C, 24 h
N
N
COCF3
95%
COCF3
3
Scheme 2
First, we examined the reaction of 3 with various amines
(Scheme 3, Table 1). Reactions of 3 with ammonia and al-
iphatic primary amines such as methyl-, ethyl-, benzyl-
and i-propylamines took place very easily at room temper-
ature within 1 hour to afford the desired 8-quinolylamine
derivatives 4a-e quantitatively (entries 1-5). Bulky t-bu-
tylamine also reacted cleanly to provide 4f by merely ele-
vating the reaction temperature (50 ∞C) and extending the
reaction time (72 hours) (entry 6). The more functional-
ized N-allyl-8-quinolylamine derivative 4g was easily
synthesized in almost quantitative yield from 3 and allyl-
amine (entry 7). In the case of propargylamine, for the
sake of avoiding the formation of decomposed products,
the reaction was performed at 0 ∞C to obtain the desired
product 4h cleanly (entry 8). While secondary amines
showed lower reactivity than primary ones in the present
reaction, pyrrolidine revealed considerable enhanced re-
activity to afford 4i in 100% yield (entry 9). Aromatic
NMe2
Nu
COCF3
COCF3
NuH
(NuH=RR'NH, RSH, ROH)
COCF3
COCF3
1
2
Scheme 1
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York

238
E. Okada et al.
PAPER
amines such as p-substituted anilines underwent cleanly within 24 hours to afford the desired alkyl 8-quinolyl sul-
the desired dimethylamino-arylamino exchanges under fides 5b-d quantitatively (entries 2-4). In the case of low
slightly forced conditions to give the corresponding N- boiling n-propanethiol, the reaction was performed with
aryl-8-quinolylamine derivatives 4j-m in over 82% yields large amounts of reagent (20 equivalents), at a lower tem-
(entries 10-13).
perature (60 ∞C) and for an extended time (96 hours) to
provide cleanly 5a in 81% yield (entry 1). Aromatic thiols
such as p-substituted benzenethiols also underwent easily
the dimethylamino-arylthio exchanges under relatively
mild conditions to give the corresponding aryl 8-quinolyl
sulfides 5e-h in over 93% yields (entries 5-8).
Nu
N
COCF3
NuH
64 - 100%
3
Further, the present aromatic nucleophilic substitutions
were applied to alcohols (Table 3). In spite of the fairly
low reactivities of alcohols, compared with the corre-
sponding amines and thiols, the N-O exchange reaction of
3 with them, e.g. n-butyl, phenethyl and 2-phenoxyethyl
alcohols, proceeded cleanly without the aid of base at re-
flux temperature in toluene to provide the corresponding
5,7-bis(trifluoroacetyl)-8-quinolylethers 6b, d, e in high
yields (entries 2, 4 and 5). In the cases of n-propyl and i-
butyl alcohols, however, the desired N-O exchange reac-
tions could barely proceed in refluxing toluene.11 The at-
COCF3
4a-m: Nu=R1R2N
5a-h: Nu=R3S
6a-e: Nu=R4O
Scheme 3
Next, we attempted to carry out the N-S exchange reac-
tions of 3 with various thiols (Table 2). Reactions of 3
with aliphatic thiols such as n-butanethiol, n-hexanethiol
and benzyl mercaptan took place in refluxing acetonitrile
Table 1 Reaction of N,N-Dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine 3 with Amines
Entry
R1R2NH
Equiv
Temp. / °C
Time / h
Solvent
Product
Yield / %a
b
1
2
3
4
5
6
7
8
9
NH3
1
1
1
1
1
3
1
1
1
r.t.
r.t.
r.t.
r.t.
r.t.
50
r.t.
0
0.5
0.5
1
0.5
1
72
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
4a
4b
4c
4d
4e
4f
4g
4h
4i
100
100
100
100
100
100
98
c
MeNH2
EtNH2
PhCH2NH2
i-PrNH2
t-BuNH2
d
CH2=CHCH2NH2
CH≡CCH2NH2
100
100
r.t.
2
10
11
12
13
p-MeOC6H4NH2
C6H5NH2
p-ClC6H4NH2
p-NO2C6H4NH2
1
1
1
5
reflux
reflux
reflux
reflux
3
12
24
96
MeCN
MeCN
MeCN
PrCN
4j
4k
4l
100
100
94
4m
82
aIsolated yields.
bAq solution (28%) of ammonia was used.
cAq solution (40%) of methylamine was used.
dAq solution (70%) of ethylamine was used.
Table 2 Reaction of N,N-Dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine 3 with Thiols
Entry
R3SH
Equiv
Temp. / °C
Time / h
Solvent
Product
Yield / %a
1
2
3
4
5
6
7
8
n-PrSH
n-BuSH
20
5
5
5
3
3
3
3
60
96
24
24
8
4
4
MeCN
MeCN
MeCN
MeCN
Toluene
Toluene
Toluene
Toluene
5a
5b
5c
5d
5e
5f
81
100
100
100
96
98
93
95
reflux
reflux
reflux
reflux
reflux
reflux
reflux
n-C6H13SH
PhCH2SH
p-MeOC6H4SH
p-MeC6H4SH
PhSH
48
8
5g
5h
p-ClC6H4SH
aIsolated yields.
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 5,7-Bis(trifluoroacetyl)-8-quinolylamines, Sulfides and Ethers
239
Table 3 Reaction of N,N-Dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine 3 with Alcoholsa
Entry
R4OH
Equiv
Time / h
Solvent
Product
Yield / %b
1
2
3
4
5
n-PrOH
n-BuOH
i-BuOH
PhCH2CH2OH
PhOCH2CH2OH
54
10
43
10
20
240
168
240
96
n-PrOH
Toluene
i-BuOH
Toluene
Toluene
6a
6b
6c
6d
6e
64
81
82
71
77
168
a The reaction was carried out under reflux.
b Isolated yields.
tempted alcoholysis of 3 under reflux was successful and rine-containing thieno[3,2-h]quinoline 8 by formal dehy-
the desired ethers 6a,c were prepared in 64-82% yields dration (HO-Cl exchange and subsequent dehydro-
(entries 1 and 3). Either of the 5- or 7-trifluoroacetyl chlorination) with the use of thionyl chloride in the pres-
group of compounds (5a-c and 6b-d) was found to exist ence of pyridine.
as the hydrate form. It is of interest that the present N-O
exchange reaction proceeded faster in less polar toluene
than in butyronitrile. For instance, compound 3 was al-
lowed to react with 5 equivalents of n-butyl alcohol at
110 ∞C for 48 hours and the following result was obtained:
solvent/% conversion to 6b; toluene / 49; butyronitrile /
Thus, we succeeded in extending the novel aromatic nu-
cleophilic substitutions of 3 with amines to those with thi-
ols and alcohols and in providing an efficient synthetic
method for various 5,7-bis(trifluoro-acetyl)-8-quinolyl-
amines, sulfides and ethers, which are not easily accessi-
ble by other methods.16 Further work is currently being
30. These results were in a striking contrast to those ob-
continued in our laboratory.
tained in the cases of dimethylamino-alkylthio exchange
reactions in the present quinoline system.12
Mps were determined on an electrothermal digital melting point ap-
Moreover, we examined the differences in reactivities be-
tween the naphthalene system 1 and the quinoline one 3 in
paratus and are uncorrected. IR spectra were recorded on a Hitachi
1
EPI-G3 spectrophotometer. H NMR spectra was obtained with a
the present SNAr reaction. Interestingly, in N-O exchange
reaction naphthylamine 1 exhibited much higher reactivi-
ties than quinolylamine 3,13 in direct opposition to the cas-
es of N-N14 and N-S15 exchanges.
JEOL PMX 60SI instrument. Microanalyses were taken with a
YANACO CHN-Corder MT-5 analyzer. Chromatographic separa-
tions were carried out on a silica gel column (Fuji Silysia Chemical
BW-127ZH; 100-270 mesh). Reagents were obtained commercial-
ly and used without further purification except for N,N-dimethyl-8-
quinolylamine, which was prepared from 8-quinolylamine and tri-
methylphosphate according to literature procedure.17 Final purifica-
tion of all products for microanalyses was done by recrystallization.
Lastly, we set about the application of this type of aromat-
ic nucleophilic substitution to the syntheses of fluorine-
containing heterocycles having the quinoline skeleton.
For example, as depicted in Scheme 4, base-catalyzed cy-
clization of benzyl 8-quinolyl sulfide 5d with 1,4-diaza-
bicyclo[2.2.2]octane (Dabco) proceeded in refluxing ace-
tonitrile for 4 hours to yield 2,3-dihydrothieno[3,2-
h]quinoline 7, which was effectively converted into fluo-
N,N-Dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine (3)
To a stirred solution of N,N-dimethyl-8-quinolylamine (1.72 g, 10
mmol) and pyridine (1.98 g, 25 mmol) in CHCl3 (10 mL) was added
dropwise trifluoroacetic anhydride (5.25 g, 25 mmol) with cooling,
and stirring was continued at 50 ∞C for 24 h. The solvent was re-
moved under reduced pressure, and EtOAc (100 mL) was added to
the residue. The solution was washed with sat. Na2CO3 (200 mL),
with 1N HCl (200 mL), thoroughly with H2O (200 mL), and then
dried (Na2SO4). The solvent was evaporated in vacuo and the crude
product was chromatographed using n-hexane:EtOAc, 3:1 as eluent
to give 3; yield: 3.46 g (95%).
Ph
S
Dabco, MeCN
reflux, 4 h
N
CF3
OH
5d
N-N Exchange Reaction of 3 with Amines; General Procedures
To a solution of 3 (1.10 g, 3 mmol) in MeCN (21 mL) were added
the appropriate amines (3-15 mmol) and the mixture was stirred at
0 ∞C-reflux temperature for 0.5-96 h. The solvent was evaporated
in vacuo to give the practically pure products 4a-l. In the case of
4m, PrCN was used as a solvent, and separation and purification
were carried out by recrystallization from n-hexane/EtOAc (see Ta-
ble 1).
89%
COCF3
7
Ph
S
SOCl2 , pyridine
N
CF3
CH2Cl2, rt, 1 h
100%
N-S Exchange Reaction of 3 with Thiols; General Procedures
To a solution of 3 (1.10 g, 3 mmol) in MeCN (12 mL) were added
the appropriate thiols (9-60 mmol) and the mixture was stirred at
60 ∞C-reflux temperature for 4-96 h. The solvent was evaporated
in vacuo and the crude product was chromatographed using n-hex-
COCF3
8
Scheme 4
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York

240
E. Okada et al.
PAPER
Table 4 Physical and Spectral Data of Compounds 3−8
Com-
pound
Mp (°C)
(Solvent)
Molecular
Formulaa
IR (KBr)
1H NMR (CDCl3/TMS)
J (Hz)
u (cm–1)
3
145–146
(n-C6H14/
EtOAc)
C15H10F6N2O2
(364.2)
1687, 1663
3.49 (s, 6 H, CH3), 7.54 (dd, 1 H, J = 4, 9, H-3), 8.60 (br s,
1 H, H-6), 8.78 (dd, 1 H, J = 2, 4, H-2), 9.38 (dd, 1 H, J = 2, 9,
H-4)
4a
4b
4c
4d
4e
4f
172−173
(n-C6H14/
EtOAc)
175−176
(n-C6H14/
EtOAc)
C13H6F6N2O2
(336.2)
3410, 3295,
1651
7.74 (dd, 1 H, J = 4, 9, H-3), 8.73 (br s, 1 H, H-6), 8.86 (dd,
1 H, J = 2, 4, H-2), 9.51 (dd, 1 H, J = 2, 9, H-4), 7.55–10.20
(br, 2 H, NH2)
3.21–4.23 (br, 3 H, CH3), 7.70 (dd, 1 H, J = 4, 9, H-3), 8.68
(br s, 1 H, H-6), 8.89 (dd, 1 H, J = 2, 4, H-2), 9.51 (dd, 1 H,
J = 2, 9, H-4), 10.07–11.79 (br, 1 H, NH)b
1.45 (t, 3 H, J = 7, CH3), 3.64–5.06 (br, 2 H, CH2), 7.66 (dd,
1 H, J = 4, 9, H-3), 8.70 (br s, 1 H, H-6), 8.85 (dd, 1 H, J = 2, 4,
H-2), 9.51 (dd, 1 H, J = 2, 9, H-4), 10.19–11.67 (br, 1 H, NH)
5.06–5.82 (br, 2 H, CH2), 7.41 (s, 5 H, Ph), 7.63 (dd, 1 H,
J = 4, 9, H-3), 8.69 (br s, 1 H, H-6), 8.84 (dd, 1 H, J = 2, 4, H-
2), 9.50 (dd, 1 H, J = 2, 9, H-4), 10.63–11.66 (br, 1 H, NH)
1.45 (d, 6 H, J = 6, CH3), 5.34–6.10 (br, 1 H, CH), 7.60 (dd,
1 H, J = 4, 9, H-3), 8.65 (br s, 1 H, H-6), 8.81 (dd, 1 H, J = 2, 4,
H-2), 9.47 (dd, 1 H, J = 2, 9, H-4), 10.75–11.46 (br, 1 H, NH)
1.71 (s, 9 H, CH3), 7.61 (dd, 1 H, J = 4, 9, H-3), 8.68 (br s,
1 H, H-6), 8.87 (dd, 1 H, J = 2, 4, H-2), 9.47 (dd, 1H, J = 2, 9,
H-4), 11.27–11.83 (br, 1 H, NH)
C14H8F6N2O2
(350.2)
3125, 1675,
1633
120−121
(n-C6H14)
C15H10F6N2O2
(364.2)
3100, 1681,
1636
147−148
(n-C6H14/
EtOAc)
119−120
(n-C6H14)
C20H12F6N2O2
(426.3)
3045, 1677,
1638
C16H12F6N2O2
(378.3)
3095, 1684,
1638
140−141
(n-C6H14)
C17H14F6N2O2
(392.3)
3060, 1683,
1642
4g
4h
4i
96−97
(n-C6H14)
C16H10F6N2O2
(376.3)
3090, 1686,
1643
4.13–6.43 (m, 5 H, CH2CH=CH2), 7.57 (dd, 1 H, J = 4, 9, H-
3), 8.55 (br s, 1 H, H-6), 8.76 (dd, 1H, J = 2, 4, H-2), 9.36
(dd, 1 H, J = 2, 9, H-4), 10.07–11.77 (br, 1 H, NH)
2.40 (t, 1 H, J = 2, CH), 4.92–5.37 (m, 2 H, CH2), 7.69 (dd,
1 H, J = 4, 9, H-3), 8.73 (br s, 1 H, H-6), 8.88 (dd, 1 H, J = 2, 4,
H-2), 9.54 (dd, 1 H, J = 2, 9, H-4), 10.42–10.82 (br, 1 H, NH)
1.84–2.25 (m, 4 H, CH2), 3.70–4.09 (m, 4 H, CH2), 7.48 (dd,
1 H, J = 4, 9, H-3), 8.60–8.75 (m, 2 H, H-2, H-6), 9.30 (dd,
1 H, J = 2, 9, H-4)
111 (dec)
(n-C6H14/
EtOAc)
157−158
(n-C6H14/
EtOAc)
C16H8F6N2O2
(374.2)
3250, 3115,
1683, 1642
C17H12F6N2O2
(390.3)
1653
4j
176−177
(n-C6H14/
EtOAc)
192−193
(n-C6H14/
EtOAc)
184−185
(n-C6H14/
EtOAc)
C20H12F6N2O3
(442.3)
3250, 1683
3270, 1683
3235, 1687
3.82 (s, 3H, OCH3), 6.80–7.29 (m, 4 Harom), 7.67 (dd, 1 H,
J = 4, 9, H-3), 8.64 (br s, 1 H, H-6), 8.73 (dd, 1 H, J = 2, 4, H-
2), 9.52 (dd, 1 H, J = 2, 9, H-4), 10.47–10.79 (br, 1 H, NH)
7.03–7.51 (m, 5 H, Ph), 7.70 (dd, 1 H, J = 4, 9, H-3), 8.61
(br s, 1 H, H-6), 8.74 (dd, 1 H, J = 2, 4, H-2), 9.48 (dd, 1 H,
J = 2, 9, H-4), 10.44–10.90 (br, 1 H, NH)
6.96–7.44 (m, 4 Harom), 7.67 (dd, 1 H, J = 4, 9, H-3), 8.60–
8.75 (m, 2 H, H-2, H-6), 9.47 (dd, 1 H, J = 2, 9, H-4), 10.72–
11.22 (br , 1 H, NH)
4k
4l
C19H10F6N2O2
(412.3)
C19H9ClF6N2O2
(446.7)
4m
5a
5b
5c
5d
5e
5f
201−202
(n-C6H14/
EtOAc)
116−117
(n-C6H14/
EtOAc)
116−117
(n-C6H14/
EtOAc)
96−97
(n-C6H14/
EtOAc)
124−125
(n-C6H14/
EtOAc)
125−126
(n-C6H14)
C19H9F6N3O4
(457.3)
3170, 1685,
1502, 1340
7.27 (d, 2 H, J = 9, 2 Harom), 7.79 (dd, 1 H, J = 4, 9, H-3), 8.21
(d, 2 H, J = 9, 2 Harom), 8.65–8.89 (m, 2 H, H-2, H-6), 9.46 (dd,
1 H, J = 2, 9, H-4), 10.56–11.02 (br, 1 H, NH)b
0.78–1.83 (m, 5 H, CH2CH3), 3.11–3.52 (m, 2 H, SCH2),
4.95–6.59 (br, 2 H, OH), 7.45–8.16 (m, 2 H, H-3, H-6), 9.00–
9.43 (m, 2 H, H-2, H-4)b
0.70–1.84 [m, 7 H, (CH2)2CH3], 1.86–6.33 (br, 2 H, OH),
3.16-3.56 (m, 2 H, SCH2), 7.45-8.22 (m, 2H, H-3, H-6),
9.04–9.43 (m, 2 H, H-2, H-4)b
0.50–1.91 [m, 11 H, (CH2)4CH3], 3.13–3.55 (m, 2 H, SCH2),
5.25–6.48 (br, 2 H, OH), 7.45–8.20 (m, 2 H, H-3, H-6), 8.99–
9.38 (m, 2 H, H-2, H-4)b
C16H13F6NO3Sc
(413.3)
3350, 1736
3310, 1744
3360, 1743
1694
C17H15F6NO3Sc
(427.4)
C19H19F6NO3Sc
(455.4)
C20H11F6NO2S
(443.4)
4.58 (s, 2 H, CH2), 7.12 (s, 5 H, Ph), 7.57–7.85 (m, 1 H,
H-3), 8.09 (br s, 1 H, H-6), 9.09–9.28 (m, 2 H, H-2, H-4)
C20H11F6NO3S
(459.4)
1727, 1703
1722, 1685
3.78 (s, 3 H, OCH3), 6.83 (d, 2 H, J = 9, 2Harom), 7.30 (d, 2 H,
J = 9, 2 Harom), 7.68 (dd, 1 H, J = 4, 9, H-3), 8.15 (br s, 1 H, H-
6), 9.00 (dd, 1 H, J = 2, 4, H-2), 9.22 (dd, 1 H, J = 2, 9, H-4)
2.32 (s, 3 H, CH3), 7.02–7.36 (m, 4 Harom), 7.72 (dd, 1 H,
J = 4, 9, H-3), 8.22 (br s, 1 H, H-6), 9.05 (dd, 1 H, J = 2, 4, H-
2), 9.27 (dd, 1 H, J = 2, 9, H-4)
114−115
(n-C6H14)
C20H11F6NO2S
(443.4)
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 5,7-Bis(trifluoroacetyl)-8-quinolylamines, Sulfides and Ethers
241
Table 4 (continued)
Com-
pound
Mp (°C)
(Solvent)
Molecular
Formulaa
IR (KBr)
1H NMR (CDCl3/TMS)
J (Hz)
u (cm–1)
5g
134−135
(n-C6H14/
EtOAc)
123−124
(n-C6H14)
97−98
(n-C6H14/
EtOAc)
88−89
C19H9F6NO2S
(429.3)
1722, 1688
7.31 (s, 5 H, Ph), 7.72 (dd, 1 H, J = 4, 9, H-3), 8.25 (br s, 1 H,
H-6), 9.04 (dd, 1 H, J = 2, 4, H-2), 9.27 (dd, 1 H, J = 2, 9, H-4)
5h
6a
C19H8ClF6NO2S
(463.8)
C16H11F6NO3
(379.3)
1716, 1697
1695
7.26 (s, 4 Harom), 7.72 (dd, 1 H, J = 4, 9, H-3), 8.29 (br s, 1 H,
H-6), 9.03 (dd, 1 H, J = 2, 4, H-2), 9.23 (dd, 1 H, J = 2, 9, H-4)
1.06 (t, 3H, J = 7, CH3), 1.80–2.16 (m, 2 H, CH2), 5.07 (t,
2 H, J = 7, OCH2), 7.72 (dd, 1 H, J = 4, 9, H-3), 8.48 (br s, 1 H,
H-6), 9.06 (dd, 1 H, J = 2, 4, H-2), 9.41 (dd, 1 H, J = 2, 9, H-4)
0.89–2.29 [m, 7 H, (CH2)2CH3], 4.63–6.58 (br, 2 H, OH),
4.76–5.23 (m, 2 H, OCH2), 7.55–7.83 (m, 1 H, H-3), 8.46–
8.76 (m, 1 H, H-6), 8.97–9.16 (m, 1 H, H-2), 9.24–9.52 (m,
1 H, H-4)b
1.00–1.26 (m, 6 H, CH3), 1.95–2.73 (m, 1 H, CH), 3.83–5.47
(br, 2 H, OH), 4.61–4.90 (m, 2 H, OCH2), 7.56–7.86 (m, 1 H,
H-3), 8.46–8.68 (m, 1 H, H-6), 8.96–9.09 (m, 1 H, H-2),
9.20–9.55 (m, 1 H, H-4)b
3.05–4.94 (br, 2 H, OH), 3.16–3.51 (m, 2 H, CH2), 4.98–
5.44 (m, 2 H, OCH2), 7.29–7.82 (m, 6 H, H-3, Ph), 8.46–
8.68 (m, 1 H, H-6), 8.97–9.14 (m, 1 H, H-2), 9.22–9.48 (m,
1 H, H-4)b
4.40 (t, 2 H, J = 4, PhOCH2), 5.42 (t, 2 H, J = 4, OCH2), 6.73–
7.47 (m, 5 H, Ph), 7.67 (dd, 1 H, J = 4, 9, H-3), 8.45 (br s,
1 H, H-6), 9.00 (dd, 1 H, J = 2, 4, H-2), 9.33 (dd, 1 H, J = 2, 9,
H-4)
c
6b
6c
6d
6e
C17H15F6NO4
3340, 1698
3395, 1703
3360, 1699
1698
(n-C6H14/
EtOAc)
(411.3)
c
83−84
(n-C6H14/
EtOAc)
C17H15F6NO4
(411.3)
c
93−94
(n-C6H14/
EtOAc)
C21H15F6NO4
(459.3)
133−134
(n-C6H14/
EtOAc)
C21H13F6NO4
(457.3)
7
8
135−136
(n-C6H14/
EtOAc)
152−153
(EtOAc)
C20H11F6NO2S
(443.4)
3230, 1696
1697
3.01–3.89 (br, 1 H, OH), 5.38 (s, 1 H, H-2), 7.21–7.79 (m,
6 H, H-7, Ph), 8.28 (br s, 1 H, H-4), 8.91 (dd, 1 H, J = 2, 4,
H-8), 9.31 (dd, 1 H, J = 2, 9, H-6)
7.45–7.87 (m, 6 H, H-7, Ph), 8.77 (br s, 1 H, H-4), 9.01
(dd, 1 H, J = 2, 4, H-8), 9.27 (dd, 1 H, J = 2, 9, H-6)
C20H9F6NOS
(425.4)
aSatisfactory microanalyses were obtained: C±0.34, H±0.36, N±0.29.
bIn CD3CN/CDCl3.
cCompounds (5a–c and 6b–d) were found to exist as monohydrate form.
ane:EtOAc, 3:1 for 5a-d and n-hexane:EtOAc, 2:1 for 5e-h, as elu-
ent. In the cases of 5e-h, toluene was used as a solvent (see Table 2).
(0.71 g, 6 mmol) with cooling, and stirring was continued at room
temperature for 1 h. After evaporation of most the solvent, EtOAc
(50 mL) was added. The whole mixture was washed with sat.
Na2CO3 (100 mL) and H2O (100 mL), and the organic layer was
separated and dried (Na2SO4). The solvent was evaporated in vacuo
and the crude mixture was chromatographed using n-hex-
ane:EtOAc, 4:1 as eluent to give 8; yield: 1.28 g (100%).
N-O Exchange Reaction of 3 with Alcohols; General Procedures
To a solution of 3 (1.10 g, 3 mmol) in toluene (12 mL) was added
the appropriate alcohols (30-162 mmol) and the mixture was
stirred at reflux temperature for 96-240 h. The solvent was evapo-
rated in vacuo and the crude product was chromatographed using
n-hexane:EtOAc, 3:1 for 6d,e and n-hexane:EtOAc, 2:1 for 6a-c, as
eluent. In the cases of 6a and 6c, n-propyl and i-butyl alcohols were
used as solvents, respectively (see Table 3).
References and Notes
(1) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273.
Zoltewics, J. A. Top. Curr. Chem. 1975, 59, 33.
de Rossi, R. H.; Nunez, A. J. Org. Chem. 1982, 47, 319.
de Vargas, E. B.; de Rossi, R. H. J. Org. Chem. 1984, 49,
3978.
(2) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1987, 28,
6199.
Hojo, M.; Masuda, R.; Okada, E.; Miya, H. Synthesis 1989,
870.
(3) Okada, E.; Tsukushi, N.; Otsuki, Y.; Nishiyama, S.; Fukuda,
T. Synlett 1999, 126.
(4) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine
Chemistry; Kodansha & Elsevier Biomedical: Tokyo, 1982.
Welch, J. T. Tetrahedron 1987, 43, 3123.
(5) Bahuguna, R. P.; Joshi, Y. C.; Dobhal, M. P.; Joshi, B. C.;
Mangal, H. N. Heterocycles 1981, 16, 1955.
5-Trifluoroacetyl-3-trifluoromethyl-3-hydroxy-2-phenyl-2,3-
dihydrothieno[3,2-h]quinoline (7)
To a solution of 5d (1.33 g, 3 mmol) in MeCN (12 mL) was added
Dabco (1.01 g, 9 mmol) and the mixture was stirred at reflux tem-
perature for 4 h. Most of the solvent was evaporated and EtOAc (50
mL) was then added. The whole mixture was washed with 1N HCl
(100 mL) and H2O (100 mL), and the organic layer was separated
and dried (Na2SO4). The solvent was evaporated in vacuo and the
crude mixture was chromatographed using n-hexane:EtOAc, 9:1 as
eluent to give 7; yield: 1.18 g (89%).
Dehydration of 7 to 8
To a stirred solution of 7 (1.33 g, 3 mmol) and pyridine (0.48 g, 6
mmol) in CH2Cl2 (24 mL) was added dropwise thionyl chloride
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York

242
E. Okada et al.
PAPER
(13) For example, naphthylamine 1 and quinolylamine 3 were
Bahuguna, R. P.; Joshi, B. C. Indian J. Heterocycl. Chem.
1994, 3, 265.
Bahuguna, R. P.; Joshi, B. C. Egypt. J. Chem. 1988, 31, 89.
Denny, W. A.; Atwell, G. J.; Baguley, B. C. Anti-Cancer Drug
Des. 1987, 2, 263.
allowed to react with 5 equivalents of n-butyl alcohol in
refluxing toluene for 24 h: substrate /% conversion to n-butyl
1-[2,4-bis-(trifluoroacetyl)naphthyl] ether 2 (Nu = n-BuO)
and 6b; 1 / 93; 3 / 41.
Jones, G. Quinolines; Wiley: London, 1977.
(14) Naphthylamine 1 and quinolylamine 3 were allowed to react
with equimolar amounts of benzylamine at r.t. for 5 min in
MeCN: substrate /% conversion to N-benzyl-2,4-bis(trifluoro-
acetyl)-1-naphthylamine 2 (Nu = PhCH2NH) and 4d; 1 / 59; 3
/ 99.
(6) Okada, E.; Tsukushi, N. Synlett 1999, 210.
(7) Abdel-Rahman, A. E.; Bakhite, E. A.; Abdel-Moneam, M. I.;
Mohamed, T. A. Phosphorus, Sulfur Silicon Relat. Elem.
1992, 73, 219.
(8) Chiba, K.; Yamamoto, K.; Miyamoto, K.; Nakano, J.;
Matsumoto, J.; Nakamura, S.; Nakada, K. Jpn. Kokai Tokkyo
Koho JP 03223289, 1991; Chem. Abstr. 1992, 116, 59403a.
(9) Wagner, G.; Vieweg, H.; Leistner, S. Pharmazie 1993, 48,
576.
(15) Naphthylamine 1 and quinolylamine 3 were allowed to react
with 3 equivalents of n-butanethiol for 8 h in refluxing MeCN:
substrate /% conversion to n-butyl 1-[2,4-bis(trifluoroacetyl)-
naphthyl] sulfide 2 (Nu = n-BuS) and 5b; 1 / 38; 3 / 83.
(16) 5,7-Bis(trifluoroacetylation) of 8-quinolyl sulfides and ethers
by trifluoroacetic anhydride did not proceed at all under
forced conditions. Furthermore, compounds 5a-h and 6a-e are
not obtainable by halogen-sulfur and halogen-oxygen
exchanges of 8-halo-5,7-bis(trifluoroacetyl)quinolines with
thiols and alcohols because of difficulty in preparing the
substrates.
(10) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1986, 27,
353.
(11) For example, reaction of 3 with n-propyl alcohol (20 equiv) in
refluxing toluene for 168 h afforded the desired product 6a in
only 17% yield and substrate 3 was recovered in 83% yield.
(12) Me2N-SBu-n exchange reaction (110 °C, 4 h) of 3 with n-bu-
tanethiol (3 equiv) did not take place in toluene. However,
replacing toluene with butyronitrile as solvent allowed the
conversion of 3 to 5b (78%). As for dimethylamino-arylthio
exchange, e.g., in the reaction of 3 with 3 equivalents of
p-toluenethiol at 110 °C for 2 h, the solvent effect bore some
resemblance to that of N-O exchange (solvent /% conversion
to 5f; toluene / 92; butyronitrile / 85). There was little
difference in the reactivities attributed to changing the
solvents in N-N exchange reaction of 3 with amines.
(17) Billman, J. H.; Radike, A.; Mundy, B. W. J. Am. Chem. Soc.
1942, 64, 2977.
Article Identifier:
1437-210X,E;2000,0,02,0237,0242,ftx,en;F04799SS.pdf
Synthesis 2000, No. 2, 237–242 ISSN 0039-7881 © Thieme Stuttgart · New York