6-Substituted 2,2-Bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers

Article abstract of DOI:10.1016/S0968-0896(00)00064-X

In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00064-X

Bioorganic & Medicinal Chemistry 8 (2000) 1393±1405
6-Substituted 2,2-Bis(¯uoromethyl)-benzopyran-4-carboxamide
K+ Channel Openers
Naoki Taka,* Hiroshi Koga,* Haruhiko Sato, Takenori Ishizawa,
Tadakatsu Takahashi and Jun-ichi Imagawa
Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka, 412-8513, Japan
Received 15 December 1999; accepted 14 February 2000
AbstractÐIn the course of our study to ®nd an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-
bis(¯uoromethyl)-6-penta¯uoroethyl-2H-1-benzopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting
antihypertensive e€ect with reduced re¯ex tachycardia, together with the bene®cial e€ects of KCO such as improvement in lipid
metabolism. These pro®les identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset
of the hypotensive e€ect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The
duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03±0.3 mg/kg po range in the
antihypertensive doses in hypertensive rat models, KC-515 (13f) signi®cantly and dose-dependently reduced serum triglycerides to
less than 70% of control without a€ecting total cholesterol. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
(2) and levcromakalim (1a), an active enantiomer of
cromakalim (1), improved the serum lipid pro®le,2b
especially for patients with hyperlipidemia, possibly
more markedly than a-blockers. In addition, KCOs
were shown to ameliorate ischemia-induced cardiac
damage, possibly by mimicking the ischemic pre-
conditioning via opening of potassium channels.2d,2g
The purpose of antihypertensive therapy is not simply
to lower blood pressure, but rather to reduce the
increased risk of death and cardiovascular disease asso-
ciated with hypertension.1a Although there are many
cardiovascular risk factors, hypertension and hyper-
lipidemia are the major ones. Accordingly, ideal anti-
hypertensive drugs should have favorable e€ects on
these risk factors, especially on lipid metabolism, as well
as good antihypertensive pro®le and reduced side e€ects
for a good quality of life and good compliance. There is
currently a large number of antihypertensive agents
available.1b However, only a-blockers show bene®cial
e€ect on lipid metabolism.1c
These results, together with other bene®cial
e€ects,2d,2g,2h suggest that KCOs may be candidates as
ideal antihypertensive drugs with potential advantages
over other antihypertensive drugs. However, the clinical
utility of these prototype KCOs is hampered by the
incidence of unwanted side e€ects due to acute periph-
eral vasodilation (headache, palpitations, edema, and
¯ushing).2h They are considered to be associated with
rapid increases in plasma levels after dosing. Thus, it is
suggested that if the onset of the blood pressure low-
ering activity of KCOs is slow and if normalized blood
pressure values persist throughout the therapeutic
treatment, possible unwanted side e€ects due to re¯ex
mechanisms may be minimized.2d In this context, a
prodrug type compound Y-27152 (4), which is inactive
in vitro and is gradually converted to its active form
after oral administration, has been developed as an
antihypertensive drug with a slow onset, a long duration
of action, and less tachycardia, though the anti-
hypertensive activity appeared to be somewhat lower
than that of levcromakalim (1a).3a,3b
Potassium channel openers (KCOs) produce membrane
hyperpolarization by opening potassium channels2a fol-
lowed by increasing potassium ions permeability, and
thereby inhibit the in¯ux of calcium ion through cal-
cium channels and possibly inhibit release of calcium
ions from intracellular stores.2f Prototype KCOs such as
cromakalim (1), pinacidil (2), and Aplikalim (3) (Fig. 1)
were shown to be potent antihypertensive agents,2b,2c,2e
at least as e€ective as calcium channel blockers.2b In
contrast to most antihypertensive medications, pinacidil
*Corresponding authors. Tel.: +81-550-87-6721; fax: +81-550-87-
5219; e-mail: takanok@chugai.pharm.co.jp
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00064-X

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N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
In the course of our study to ®nd an ideal anti-
hypertensive KCO,4a m we have investigated the synthesis
of 6-substituted 2-¯uoromethylbenzopyran-4-carb-
oxamides and-4-carbothioamides, and observed N-(2-
cyanoethyl)-2,2-bis(¯uoromethyl)-6-penta¯uoroethyl-
2H-1-benzopyran-4-carboxamide (13f, KC-515) to be a
potential candidate. In this paper, we report the synth-
esis and biological activity of 6-substituted 2-¯uoro-
methylbenzopyran-4-carboxamides and 4-carbothio-
amides, and antihypertensive and lipid lowering activ-
ities of KC-515 (13f).
Schemes 1±4. The starting material was 4-oxobenzo-
pyran 6, which was prepared from acetophenone 5 and
1,3-di¯uoroacetone.5 Ketone 6 was reduced and sub-
sequently dehydrated under acidic conditions to a€ord
benzopyran 7. Benzopyran 7 was transformed to 4-bro-
mobenzopyran 8 by bromination and subsequent treat-
ment with sodium hydroxide. Except for the 6-bromo
compound, introduction of carboxyl group at the 4-
position was accomplished by palladium-catalyzed
hydroxycarbonylation in almost quantitative yield.4g
The 6-nitro-4-carboxylic acid derivative 9j was esteri®ed
and hydrogenated to a€ord the 6-amino derivative 10a
in quantitative yield. The amino group was diazotized
and replaced by iodine atom to give 10k. The 6-iodo
compound 10k was treated with potassium per¯uoro-
alkanecarboxylate in the presence of copper(I) iodide
in DMF and toluene to obtain the 6-per¯uoroalkyl
Chemistry
The compounds prepared in this study are listed in
Tables 1 and 2 and their synthetic routes are outlined in
Figure 1.
Table 1. Physical properties and vasorelaxant activities of 6-substituted 2,2-bis(¯uoromethyl)benzopyran-4-carboxamides
Rat aorta
Yield (%)a
Mp (ꢀC)
pEC50
IA (%)c
nd
b
Compd
R
12b
12c
12d
12e
12f
12g
12h
12i
12je
13a
13b
13c
13d
Br
Cl
H
CF3
C2F5
n-C3F7
n-C4F9
CN
NO2
NH2ꢁ HCl
Br
Cl
H
CF3
C2F5
n-C3F7
n-C4F9
CN
88
29
42
86
74
77
63
95
67
67
81
39
51
86
83
45
63
72
85
187±188
175±176
138±139
162±164
128±129
88±91
7.24
7.06
5.77
75.9
83.5
82.9
66.8Æ1.2
63.7Æ4.2
67.2Æ1.7
80.9Æ2.6
73.4
2
2
2
3
3
3
3
2
3
2
2
2
2
3
15
3
3
2
3
8
7.81Æ0.05
8.14Æ0.06
7.91Æ0.11
6.65Æ0.03
7.08
Oil
206±207
180±181
202±205
140±142
134±136
Oil
135±136
144±145
135±136
85±86
8.29Æ0.03
70.7Æ5.5
4.5>
7.96
66.0
75.1
74.9
66.3Æ8.0
71.0Æ2.1
74.4Æ2.7
76.8Æ1.7
78.2
7.76
7.07
13e
13f
13g
13h
8.17Æ0.15
8.43Æ0.03
8.10Æ0.06
7.17Æ0.04
7.43
13i
13je
Levcromakalim (1a)
170±172
179±180
NO2
8.65Æ0.03
72.3Æ8.7
6.97Æ0.05
72.5Æ3.6
aSatisfactory microanalysis was obtained for all crystalline compounds.
bNegative logarithm of the molar concentration required to relax rat aorta precontracted with 30 mM KCl by 50% of IA, with Æ SEM. Details are
described in Experimental.
cIntrinsic activity Æ SEM (%).
dNumber of determinations.
eSee ref 4f.

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1395
Table 2. Physical properties and vasorelaxant activities of 6-substituted 2,2-bis(¯uoromethyl)benzopyran-4-carbothioamides
Rat aorta
Mp (ꢀC)a
pEC50
IA (%)c
nd
b
Compd
R
Yield (%)
14e
14f
14g
14i
14je
15e
15f
15g
15i
15jf
CF3
C2F5
n-C3F7
CN
NO2
CF3
C2F5
n-C3F7
CN
50
96
96
50
96
52
62
44
55
80
145±147
148±149
125±126
137±138
134±135
105±106
108±109
94±95
8.72
8.06
7.35
8.22
67.6
74.0
77.6
83.5
2
2
2
2
3
2
2
2
2
7
8
9.32Æ0.11
74.5Æ8.9
8.64
8.03
66.8
72.8
7.63
8.17
58.0
82.3
191±192
156±157
NO2
9.85Æ0.24
72.5Æ3.7
Levcromakalim (1a)
6.97Æ0.05
72.5Æ3.6
aSatisfactory microanalysis was obtained for all crystalline compounds.
bNegative logarithm of the molar concentration required to relax rat aorta precontracted with 30 mM KCl by 50% of IA, with ÆSEM. Details are
described in Experimental.
cIntrinsic activity ÆSEM (%).
dNumber of determinations.
eSee ref 4f.
fSee refs 4b and 4f.
Scheme 1. (i) FCH2COCH2F, pyrrollidine, benzene (56%); (ii) (a) NaBH4, MeOH; (b) p-TsOH, toluene (88%, 2 steps); (iii) (a) Br2, CHCl3; (b) 2 N
NaOH, dioxane (quant.); (iv) COgas (balloon), Pd(OAc)2, PPh3, KOAc, KI, DMF (95%); (v) (a) H2SO4, EtOH; (b) H2, Raney-Ni (W-1), EtOH
(93%, 2 steps); (vi) (a) NaNO2, H2SO4, H2O±CH2Cl2; (b) KI, H2O±CH2Cl2 (72%, 2 steps); (vii) R1COOK (R1=CF3, C2F5, C3F7), Cul, DMF±
toluene or C4F9I, Cul, Cu, HMPA; (viii) CuCN, DMF (76%); (ix) (a) NaNO2, H2SO4, H2O±CH2Cl2; (b) CuCl; (c) H2SO4, EtOH (18% 3 steps).

1396
N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
Scheme 2. (i) CuCN, DMF (quant.); (ii) SnCl2, EtOH; (iii) (a) NaNO2, H2SO4±AcOH; (b) CuBr (42%, 3 steps); (iv) H2SO4, CaOH, H2O (76%).
Scheme 3. (i) KOH, EtOH; (ii) CDl, R2NH2, THF; (iii) Lawesson's reagent, benzene or ClCH2CH2Cl.
Scheme 4. (i) (a) SnCl2, EtOH; (b) HCl, MeOH (67%, 2 steps).
derivatives 10e±g.6 The 6-nona¯uorobutyl compound
10h was obtained by the alternative route. The iodo
compound 10k was treated with nona¯uorobutyl iodide,
copper(I) iodide, and copper in HMPA to produce 10h.
The deiodinated compound 10d was obtained as a by-
product under these conditions. The 6-cyano compound
10i was converted from the 6-iodo compound 10k by
the reaction with copper(I) cyanide. The 6-chloro com-
pound 10c was synthesized by Sandmeyer reaction from
the 6-amino compound 10a using copper(I) chloride
(Scheme 1).
The ester group of 10 was hydrolyzed under alkaline
conditions to yield the carboxylic acids 9, and then
activated with N,N0-carbonyldiimidazole (CDI), followed
by addition of methylamine or 2-cyanoethylamine to give
the carboxamide derivatives 12 and 13 (Scheme 3). The
6-amino derivative 13a was synthesized from the corre-
sponding 6-nitro derivative 13j by reduction with tin(II)
chloride in EtOH (67%) (Scheme 4). Thioamide deriva-
tives 14 and 15 were obtained by thionation of carbox-
amide derivatives 12 and 13 with Lawesson's reagent in
benzene or 1,2-dichloroethane (Scheme 3).
In the case of 6-bromo derivatives, 4-bromo-6-nitro-
benzopyran 8 was treated with copper(I) cyanide in
DMF to a€ord 4-cyanobenzopyran (11j). The nitro
group of 11j was reduced by tin(II) chloride to yield 6-
aminobenzopyran 11a, and subsequently transformed
to 6-bromo group by Sandmeyer reaction to obtain 6-
bromo-4-cyanobenzopyran (11b), whose 4-cyano group
was hydrolyzed under acidic conditions to a€ord 4-car-
boxylic acid 9b (Scheme 2).
Results and Discussion
The vasorelaxant activities of compounds were deter-
mined by the e€ects on 30 mM KCl responses in rat
isolated aorta in comparison with levcromakalim
(1a)7,8b (Tables 1 and 2). The 2-¯uoromethylbenzo-
pyran-4-carboxamides 12 and 13 exhibited vasorelaxant
activity comparable to or more potent than levcromakalim

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1397
(1a). The N-(2-cyanoethyl)carboxamide derivatives 13
had more potent vasorelaxant activity than the corre-
sponding N-methylcarboxamide derivatives 12. Increase
in the size of the 6-per¯uoroalkyl group of 12 and 13
gave a parabolic e€ect on the activity, the penta-
¯uoroethyl group (12f and 13f) being optimum. The
most active compounds 13f and 13j showed some 30-
fold more potent vasorelaxant activity than levcroma-
kalim (1a) (Table 1). The 4-carbothioamides 14 and 15
exhibited vasorelaxant activity with potency greater
than levcromakalim (1a). The SARs were somewhat
di€erent from those of the carboxamides 12. The activity
of N-methylcarbothioamide derivatives 14 was compar-
able to the N-(2-cyanoethyl)carbothioamide derivatives
15. Increase in the size of the 6-per¯uoroalkyl group of
14 and 15 reduced the activity, the tri¯uoromethyl
group (14e and 15e) being the most active. The 6-nitro
derivatives 14j and 15j were the most potent compounds
in this series (Table 2). Among these compounds, some
compounds were selected for further study from some
preclinical studies.
Antihypertensive e€ects of KC-515 (13f) and 15j (KC-
399)4b were evaluated in conscious spontaneously
hypertensive rats (SHR) in comparison with levcroma-
kalim (1a) (Figs 2 and 3). KC-515 (13f) at 0.01±0.1 mg/
kg po produced dose-dependent falls in mean blood
pressure (MBP). The onset of the hypotensive e€ect of
KC-515 (13f) was gradual and the maximum response
attained at around 6 h after dosing. The duration of
action was over 18 h for 0.1 mg/kg. But, the e€ects on
the heart rate were minimal. In contrast, the hypoten-
sive e€ect of levcromakalim (1a) (0.1 and 0.3 mg/kg po)
was rapid in onset and of short duration of action (Fig.
3). Unlike KC-515 (13f), levcromakalim (1a) dramati-
cally increased heart rate in a dose-dependent manner.
Thus, KC-515 (13f) was some 10-fold more potent than
levcromakalim (1a) in lowering blood pressure, with
slower onset, longer duration of action, and less tachy-
cardia. KC-515 (13f) (0.01±0.1 mg/kg po) also produced
dose-dependent antihypertensive e€ects with a slow
onset, a long duration of action, and less tachycardia, in
two kidney±one clip renal hypertensive rats and DOCA-
salt hypertensive rats, similar to the e€ects seen in
SHR.8a KC-399 (15j) also showed a highly potent, slow
and long-lasting antihypertensive e€ects with reduced
re¯ex tachycardia. However, KC-399 (15j) was dropped
out in toxicological test.
Figure 2. E€ects of orally administered KC-515 (13f) on (a) mean
blood pressure (% change) and (b) heart rate (% change) at various
time intervals (h) in conscious male SHR. Pretreatment values for
blood pressure (mm Hg) and heart rate (beat/min) were 155Æ5 (n=5)
and 330Æ8 (n=5) for control, 158Æ5 (n=5) and 388Æ20 (n=5) for
KC-515 (0.01 mg/kg), 158Æ7 (n=5) and 324Æ14 (n=5) for KC-515
(0.03 mg/kg), and 157Æ6 (n=5) and 350Æ9 (n=5) for KC-515 (0.1
mg/kg) groups, respectively. There was no signi®cant di€erence
between groups. Each value represents mean ÆSE (n=5). *P<0.05,
**P<0.01, signi®cant di€erence from controls. Details are described
in Experimental.
other antihypertensive drugs including the prototype
KCOs. KC-515 (13f) was shown to be an ATP-sensitive
KCO, because it strongly inhibited contraction of rat
aortic rings established with 30 mM KCl, while it pro-
duced only small inhibitory e€ects against rat aortic
rings contracted with 90 mM KCl, it accelerated 86Rb+
e‚ux from isolated rat aorta, and these e€ects were
antagonized by glibenclamide, an ATP-sensitive potas-
sium channel blocker.8b Further studies on other bene-
®cial e€ects of KC-515 (13f) are now under way.
One of the most interesting features of antihypertensive
KCOs is the bene®cial e€ect on plasma lipids.2h The
lipid lowering e€ect of KC-515 (13f) was evaluated in
obese Zucker rats, a genetic model of hyperlipidemia.
When administered to Zucker rats for 2 weeks with
0.03±0.3 mg/kg po range in the antihypertensive doses
in hypertensive rat models, KC-515 (13f) signi®cantly
and dose-dependently reduced serum triglycerides to
less than 70% of control (32, 33, and 46% decreases,
respectively, for 0.03, 0.1, and 0.3 mg/kg po dosing),
without a€ecting total cholesterol (Tables 3 and 4).8a
Conclusion
KC-515 (13f) shows a highly potent, slow and long-
lasting antihypertensive e€ect with reduced re¯ex
tachycardia, together with the bene®cial e€ects of KCO
such as improvement in lipid metabolism. These pro®les
identify KC-515 as a potential candidate for an ideal
antihypertensive drug.
Thus, as an antihypertensive agent, KC-515 (13f) pos-
sesses several properties which confer advantages over

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N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
ppm (units) down®eld from internal tetramethylsilane
as an internal standard. The following abbreviations
are used: s=singlet, d=doublet, t=triplet, q=quartet,
dd=doublet of doublets, br=broad. Mass spectra (MS)
were recorded on a Shimadzu GCMS-QP-1000 mass
spectrometer. Elemental analyses were performed at
Toray research center. Where represented by elemental
symbols, the analyses of these elements fall within
Æ0.4% of the calculated values. Column chromato-
graphies were performed with silica gel, Wakogel C-200
(0.074±0.149 mm). HPLC analyses were performed on
a Hitachi L-4000 detector with a Hitachi L-6200
pump, the column was a YMC-Pack A-312 S-5 120A
ODS.
Biological test: e€ects on KCl induced contraction
Rats (Sprague±Dawley, male 400±700 g) were killed by
decapitation. The thoracic aorta was dissected out,
immersed in cold Krebs±Henseleit (K±H) solution, and
cleaned of surrounding connective tissues. The artery
was cut into 2±3 mm long ring segments. Each ring was
mounted under a resting tension of 2 g in a 10 mL organ
bath containing a modi®ed K±H solution of the follow-
ing composition (mL): NaCl, 119; KCl, 4.8; CaCl2, 2.53;
KH2PO4, 1.2; MgSO4, 1.2;NaHCO3, 24.8; glucose, 10.
The solution was equilibrated with a gas mixture con-
taining 95% O2 and 5% CO2. One side of the ring-
preparation was ®xed to the bottom of the bath and the
other end was connected by a hook at the level of a
force±displacement
transducer
(Nihon
Koden,
TB611T). Before the initiation of the experiments, all
preparations were allowed to equilibrate for at least 1.5
h at 37 ꢀC. The artery rings were contracted by dis-
placement of normal K±H solution to the K±H solution
containing 30 mM KCl (high K+ K±H solution). After
the increased force of contraction had reached a pla-
teau, test compounds were added in a cumulative way
to construct concentration±relaxation curves. Relaxa-
tion responses were calculated as percentage of reduc-
tions of the 30 mM KCl contraction. The intrinsic
activity (IA) for each compound was calculated as a
percentage of its maximum reduction of the 30 mM KCl
contraction. Only one concentration±relaxation curve
was obtained from each preparation.
Figure 3. E€ects of orally administered levcromakalim (1a) on (a)
mean blood pressure (% change) and (b) heart rate (% change) at
various time intervals (h) in conscious male SHR. Pretreatment values
for blood pressure (mm Hg) and heart rate (beat/min) were 155Æ5
(n=5) and 330Æ8 (n=5) for control, 161Æ3 (n=5) and 394Æ15 (n=5)
for levcromakalim (0.1 mg/kg), 158Æ3 (n=5) and 340Æ16 (n=5) for
levcromakalim (0.3 mg/kg) groups, respectively. There was no sig-
ni®cant di€erence between groups. Each value represents mean ÆSE
(n=5). *P<0.05, **P<0.01, signi®cant di€erence from controls.
Details are described in Experimental.
Experimental
General
Melting points were determined on a Yanagimoto micro
melting point apparatus and are recorded. 1H NMR
spectra were recorded on a Hitachi R-24B (60 MHz) or
a JEOL FX-270 (270 MHz) instrument. Coupling con-
stants are reported in hertz (Hz) and chemical shifts in
Biological test: e€ects on mean blood pressure
Male spontaneously hypertensive rats (SHR) (16±24
weeks old, about 350 g) purchased from Charles River
Japan (Atsugi, Japan) were anesthetized with an ip
Table 3. E€ects of KC-515 (0.3 mg/kg) on plasma lipids following 2 weeks administration with single daily doses in Zucker ratsa
Vehicle (n=6)
Levcromakalim (n=5)
KC-515 (n=5)
1.0 mg/kg
10 mg/kg
0.3 mg/kg
Total cholesterol (TC) (mg/dl serum)
HDL (mg/dl serum)
HDL/TC (%)
88.00Æ4.99
67.98Æ3.21
77.59Æ1.96
189.07Æ27.45
115.62Æ5.84**
90.88Æ4.02**
78.77Æ1.46
130.46Æ6.33**
97.28Æ4.99**
74.54Æ0.69
122.86Æ5.59**
90.16Æ4.39**
73.37Æ1.11
Triglyceride (mg/dl serum)
158.44Æ15.86
124.40Æ7.34*
112.42Æ9.70*
aAll data shown as the meanÆSEM. Asterisks indicate signi®cant di€erence (*P<0.05; **P<0.01) from vehicle.

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1399
Table 4. E€ects of KC-515 (0.03, 0.1 mg/kg) on plasma lipids following 2 weeks administration with single daily doses in Zucker ratsa
Vehicle (n=5)
Beza®brate (n=5) 50 mg/kg
KC-515 (n=5)
0.03 mg/kg 0.1 mg/kg
Total cholesterol (TC) (mg/dl serum)
HDL (mg/dl serum)
HDL/TC (%)
106.00Æ10.67
70.63Æ6.23
79.92Æ2.32
55.12Æ2.60
69.03Æ3.01
277.62Æ26.02
116.52Æ18.31
84.22Æ12.99
72.47Æ0.95
127.08Æ7.99
93.40Æ4.49
66.92Æ1.82
73.93Æ2.63
Triglyceride (mg/dl serum)
351.18Æ28.87
246.60Æ22.27*
260.28Æ21.41*
aAll data shown as meanÆSEM. Asterisks indicate signi®cant di€erence (*P<0.05; **P<0.01) from vehicle.
injection of pentobarbital Na (50 mg/kg). The right
femoral artery was dissected free from the surrounding
tissue and a polyethylene tubing ®lled with heparin
(1000 U/mL) was inserted into the abdominal aorta
through the femoral artery for the measurement of
blood pressure and heart rate. The tubing was tunneled
subcutaneously and exteriorized between the scapulae.
After surgery, rats were housed individually and
allowed to recover overnight. Blood pressure was mea-
sured with a Nihon Kohden pressure transducer (DX-
312) and the heart rate with a Nihon Kohden heart rate
counter (AT-601G) in unanesthetized and unrestrained
conditions. All recordings were made on a chart with a
Graphtech linearcorder (WR-3101). Drugs were sus-
pended with 0.3% carbomethylcellulose. The drug
solution or vehicle was given in a volume of 1 mL/kg.
stirred suspension of 6 (114 g, 0.44 mol) in MeOH (800
mL) and THF (500 mL) at 10 ꢀC and the mixture was
maintained at this temperature for 40 min; 3 N HCl was
added and the product was extracted with CH2Cl2. The
organic layer was washed with 0.5 N NaOH, 3 N HCl,
dried (Na2SO4), and evaporated under reduced pressure
to a€ord a crude alcohol, which was used without
further puri®cation. A mixture of the crude alcohol and
p-toluenesulfonic acid monohydrate (12.0 g, 0.63 mol)
in toluene (1 L) was heated at re¯ux for 1.5 h. The
reaction mixture was then cooled, washed with 0.5 N
NaOH, brine, dried (Na2SO4), and evaporated under
reduced pressure. The residue was chromatographed on
silica gel with CH2Cl2 to give 7 (93.8 g, 88%) .
1
60 MHz H NMR (CDCl3, TMS) d 4.52 (4H, d, JH-F
=
47.0 Hz, C-2H), 5.77 (1H, d, J=10.0 Hz, C-3H), 6.69
(1H, d, J=10.0 Hz, C-4H), 6.92 (1H, d, J=9.0 Hz,
C-8H), 7.8±8.2 (2H, m, C-5H, C-7H); mp 125±126 ꢀC
(AcOEt:hexane); MS (EI) m/z 241 (M+); anal. (C11H9
F2NO3) C, H, N.
Biological test: e€ects on lipid metabolism
Drugs were suspended with 0.3% carbomethylcellulose.
The drug solution or vehicle was given in a volume of
1 mL/kg. The drug solution (30, 100, 300 mg/kg/day) or
vehicle were administered to Zucker rats (14 weeks) for
2 weeks. After oral administration of the experiment for
2 weeks, blood was sampled from each animal. Plasma
cholesterol and triglycerides (TG) were measured by
autoanalyzer (COBAS-FARA II).
4-Bromo-2,2-bis(¯uoromethyl)-6-nitro-2H-1-benzopyran
(8). Bromine (62 mL, 1.20 mol) was added dropwise
to a solution of 7 (93.8 g, 0.39 mol) in chloroform
(1.0 L) at 10 ꢀC, and the mixture was stirred at
10 ꢀC for 12 h. The reaction mixture was washed
with aqueous NaHCO3, 1 N NaOH, dried (Na2SO4),
and evaporated under reduced pressure to give crude
dibromide. It was taken to the next step without
puri®cation.
Synthesis of compounds
2,2-Bis(¯uoromethyl)-3,4-dihydro-6-nitro-2H-1-benzo-
pyran-4-one (6). Pyrrolidine (50 mL, 0.6 mol) was
added to a solution of 60-hydroxy-30-nitroacetophenone
(108 g, 0.6 mol) and, 2,2-bis(¯uoromethyl)acetone (70 g,
0.6 mol) in benzene (1.2 L), and the mixture was stirred
at room temperature for 1.5 h, and then heated under
re¯ux for 1 h. After cooling down to room temperature,
the mixture was then poured into water, the product
was extracted with AcOEt, and the extract was dried
(Na2SO4), and evaporated. The residual oil was chro-
matographed on silica gel (hexane:CH2Cl2, 1:1) to give
pure 6 (86.0 g, 56%).
A mixture of crude dibromide, dioxane (1.0 L), and 2 N
NaOH (300 mL) was stirred at 10 ꢀC for 2.5 h. The
reaction mixture was poured into H2O (2.5 L), and the
resulting crystal was isolated by ®ltration. The crystal
was dissolved in CH2Cl2, the organic layer was dried
(Na2SO4), and evaporated under reduced pressure. The
residue was chromatographed on silica gel with CH2Cl2
to 8 (119.2 g, quant.).
1
60 MHz H NMR (CDCl3, TMS) d 4.48 (4H, d, JH-F
=
47.0 Hz, C-2H), 6.12 (1H, s, C-3H), 6.88 (1H, d, J=9.0
Hz, C-8H), 8.04 (1H, dd, J=9.0, 2.0 Hz, C-7H), 8.24
(1H, d, J=2.0 Hz, C-5H); mp 117±118 ꢀC (AcOEt:
hexane); MS (EI) m/z 319 (M+); anal. (C11H8BrF2
NO3) C, H, N.
1
60 MHz H NMR (CDCl3, TMS) d 2.99 (2H, s, C-3H),
4.60 (4H, d, JH-F=47.0 Hz, C-2H), 7.10 (1H, d, J=9.0
Hz, C-8H), 8.28 (1H, dd, J=9.0, 3.0 Hz, C-7H), 8.65
(1H, d, J=3.0 Hz, C-5H); mp 133±134 ꢀC (EtOH); MS
(EI) m/z 257 (M+); anal. (C11H9F2NO4) C, H, N.
2,2-Bis(¯uoromethyl)-6-nitro-2H-1-benzopyran-4-carb-
oxylic acid (9j). A mixture of 8 (640 mg, 2.0 mmol),
Pd(OAc)2 (5.0 mg, 0.022 mmol), PPh3 (11.0 mg, 0.042
2,2-Bis(¯uoromethyl)-6-nitro-2H-1-benzopyran (7).
Sodium borohydride (30 g, 0.74 mol) was added to a

1400
N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
mmol), potassium acetate (800 mg, 8.15 mmol) and
potassium iodide (330 mg, 1.99 mmol) in DMF (10 mL)
was stirred under a CO balloon at 130 ꢀC for 3 h. The
reaction mixture was diluted with water, acidi®ed with
2 N HCl, and extracted with AcOEt. The organic
extracts was washed with brine, and extracted with 2 N
NaOH. The aqueous alkaline extracts were acidi®ed
with 2 N HCl, and extracted with AcOEt. The organic
extracts were washed with brine, dried (Na2SO4), and
evaporated under vacuum. The residue was chromato-
graphed on silica gel with MeOH:AcOH:CHCl3
(5:1:500) to 9j (540 mg, 95%).
washed with aqueous Na2SO3, brine, dried (Na2SO4),
and evaporated under vacuum. The residue was chro-
matographed on silica gel with hexane:AcOEt (10:1) to
10k (3.03 g, 72%).
1
60 MHz H NMR (CDCl3, TMS): d 1.38 (3H, t, J=7.0
Hz, COOCH2CH3), 4.32 (2H, q, J=7.0 Hz, COOCH2),
4.54 (4H, d, JH-F=47.0 Hz, C-2H), 6.58 (1H, s, C-3H),
6.65 (1H, d, J=9.0 Hz, C-8H), 7.50 (1H, dd, J=9.0, 2.0
Hz, C-7H), 8.30 (1H, d, J=2.0 Hz, C-5H); mp 89±90 ꢀC
(AcOEt:hexane); MS (EI) m/z 394 (M+); anal. (C14H13
F2IO3) C, H, N.
270 MHz 1H NMR (CDCl3, TMS) d 4.64 (4H, d, JH-F
=
2,2-Bis(¯uoromethyl)-6-(tri¯uoromethyl)-2H-1-benzo-
pyran-4-carboxylic acid ethyl ester (10e). A mixture of
10k (1.00 g, 2.5 mmol), potassium tri¯uoroacetate
(0.84 g, 5.5 mmol), copper(I) iodide (1.18 g, 6.0 mmol),
toluene (4 mL), and DMF (10 mL) was heated at 150 ꢀC
for 4 h under nitrogen atmosphere with Dean±Stark
trap, and heated at 160 ꢀC for 1.5 h. After cooling down
to room temperature, 2 N HCl and AcOEt were added
to the mixture, and the mixture was ®ltered through
Celite. The organic layer was separated from the ®ltrate,
and the aqueous layer was extracted with AcOEt. The
resulting organic layers were combined, washed with
brine, dried (Na2SO4), and evaporated. The residue was
chromatographed on silica gel with hexane:AcOEt
(10:1) to 10e (0.51 g, 60%).
46.5 Hz, C-2H), 6.88 (1H, s, C-3H), 7.03 (1H, d, J=8.90
Hz, C-8H), 8.14 (1H, dd, J=8.90, 2.64 Hz, C-7H), 9.09
(1H, d, J=2.64 Hz, C-5H); mp 174±175 ꢀC (AcOEt:
hexane); MS (EI) m/z 285 (M+); anal. (C12H9 F2NO5)
C, H, N.
2,2-Bis(¯uoromethyl)-6-nitro-2H-1-benzopyran-4-carb-
oxylic acid ethyl ester (10j). A mixture of 9j (41.7 g, 146
mmol), EtOH (300 mL), and concd H2SO4 (20 mL) was
re¯uxed for 7 h. The mixture was poured into ice±water,
and the resulting crystal was isolated by ®ltration. The
crystal was dissolved in AcOEt and ether, the organic
layer was washed with saturated aqueous NaHCO3,
brine, dried (Na2SO4), and evaporated under vacuum.
The residue was chromatographed on silica gel with
hexane:AcOEt (5:1) to 10j (21.4 g, 93%).
1
60 MHz H NMR (CDCl3, TMS) d 1.36 (3H, t, J=7.0
Hz, COOCH2CH3), 4.31 (2H, q, J=7.0 Hz, COOCH2),
4.53 (4H, d, JH-F=47.0 Hz, C-2H), 6.63 (1H, s, C-3H),
6.94 (1H, d, J=9.0 Hz, C-8H), 7.47 (1H, dd, J=9.0, 2.0
Hz, C-7H), 8.31 (1H, d, J=2.0 Hz, C-5H); MS (EI) m/z
336 (M+); colorless oil.
1
60 MHz H NMR (CDCl3, TMS) d 1.42 (3H, t, J=7.0
Hz, COOCH2CH3), 4.38 (2H, q, J=7.0 Hz, COOCH2),
4.58 (4H, d, JH-F=46.0 Hz, C-2H), 6.69 (1H, s, C-3H),
6.94 (1H, d, J=9.0 Hz, C-8H), 8.07 (1H, dd, J=9.0, 3.0
Hz, C-7H), 8.92 (1H, d, J=3.0 Hz, C-5H); mp 96±98 ꢀC
(AcOEt); MS (EI) m/z 313 (M+); anal. (C14H13 F2NO5)
C, H, N.
2,2-Bis(¯uoromethyl)-6-(penta¯uoroethyl)-2H-1-benzo-
pyran-4-carboxylic acid ethyl ester (10f). 60 MHz 1H
NMR (CDCl3, TMS) d 1.40 (3H, t, J=7.0 Hz,
COOCH2CH3), 4.38 (2H, q, J=7.0 Hz, COOCH2), 4.60
(4H, d, JH-F=47.0 Hz, C-2H), 6.69 (1H, s, C-3H), 7.00
(1H, d, J=9.0 Hz, C-8H), 7.45 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 8.30 (1H, d, J=2.0 Hz, C-5H); MS (EI) m/z 386
(M+); yield 64%; colorless oil.
6-Amino-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
oxylic acid ethyl ester (10a). A mixture of 10j (11.7 g,
37.3 mmol), Raney Ni (W-1) (12.0 g), and EtOH (330
mL) was stirred under a hydrogen atmosphere. After
the completion of the hydrogenation, the catalyst was
removed by ®ltration, and the solvent was removed in
vacuo to yield 10a (10.5 g, quant.).
2,2-Bis(¯uoromethyl)-6-(hepta¯uoropropyl)-2H-1-benzo-
pyran-4-carboxylic acid ethyl ester (10g). 60 MHz 1H
NMR (CDCl3, TMS) d 1.36 (3H, t, J=7.0 Hz,
COOCH2CH3), 4.32 (2H, q, J=7.0 Hz, COOCH2), 4.57
(4H, d, JH-F=48.0 Hz, C-2H), 6.69 (1H, s, C-3H), 7.02
(1H, d, J=9.0 Hz, C-8H), 7.46 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 8.29 (1H, d, J=2.0 Hz, C-5H); MS (EI) m/z 436
(M+); yield 75%.
1
60 MHz H NMR (CDCl3, TMS) d 1.38 (3H, t, J=7.0
Hz, COOCH2CH3), 4.30 (2H, q, J=7.0 Hz, COOCH2),
4.56 (4H, d, JH-F=47.0 Hz, C-2H), 6.43±7.43 (4H, m,
C-3H, C-5H, C-7H, C-8H). MS (EI) m/z 283 (M+);
colorless oil.
6-Iodo-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
oxylic acid ethyl ester (10k). A mixture of 10a (3.0 g,
10 mmol), concd H2SO4 (1.2 g, 12 mmol), CH2Cl2
(50 mL), and H2O (40 mL) was cooled to 0 ꢀC. Sodium
nitrate (0.77 g, 11 mmol) in H2O (5 mL) was added to
the mixture, and the mixture was stirred for 10 min at
0 ꢀC. A mixture of potassium iodide (2.0 g, 1.2 mmol) in
H2O (5 mL) was added to the reaction mixture, and
stirred for 50 min at room temperature. The product
was extracted with CH2Cl2. The organic extracts were
2,2-Bis(¯uoromethyl)-2H-1-benzopyran-4-carboxylic acid
ethyl ester (10d). Compound 10d was obtained as a
minor product in the reaction of 10g.
1
60 MHz H NMR (CDCl3, TMS): d 1.37 (3H, t, J=7.0
Hz, COOCH2CH3), 4.33 (2H, q, J=7.0 Hz, COOCH2),
4.58 (4H, d, JH-F=49.0 Hz, C-2H), 6.58 (1H, s, C-3H),
6.74±8.11 (4H, m, C-5H, C-6H, C-7H, C-8H); MS (EI)
m/z 268 (M+); yield 25%; colorless oil.

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1401
2,2-Bis(¯uoromethyl)-6-(nona¯uorobutyl)-2H-1-benzo-
pyran-4-carboxylic acid ethyl ester (10h). A mixture of
10k (0.30 g, 0.76 mmol), nona¯uorobutyl iodide (3.5 g,
10 mmol), copper (0.30 g, 4.8 mmol), copper(I) iodide
(0.32 g, 1.67 mmol), and hexamethylphosphoramide
(HMPA) (3 mL) was stirred for 22 h at 80 ꢀC under
nitrogen atmosphere. Nona¯uorobutyl iodide (0.8 mL,
4.76 mmol) was added and stirred at 130 ꢀC for 2 h, and
nona¯uorobutyl iodide (0.4 mL, 2.38 mmol) was added
and stirred at 155 ꢀC for 3 h. After cooling down to
room temperature, 2 N HCl and AcOEt were added to
the mixture, and the mixture was ®ltered through Celite.
The organic layer was separated from the ®ltrate, and
the aqueous layer was extracted with AcOEt. The
organic extracts were washed with aqueous Na2SO3,
brine, dried (Na2SO4), evaporated, and chromato-
graphed on silica gel with hexane:AcOEt (5:1) to give
10h (0.19 g, 51%).
NaOH. The alkaline extracts was acidi®ed with concd
HCl, and extracted with AcOEt. The AcOEt layer was
washed with brine, dried (Na2SO4), evaporated to give a
crude mixture of an ester and a carboxylic acid, which
was used without further puri®cation. A mixture of the
crude products, EtOH (50 mL) and concd H2SO4 (2
mL) was re¯uxed for 2 h. After cooling down to room
temperature, the reaction mixture was evaporated, and
H2O was added to the residue, extracted with CH2Cl2.
The organic layer was washed with brine, dried
(Na2SO4), evaporated, and chromatographed on silica
gel with hexane:AcOEt (10:1) to give 10c (0.07 g, 18%).
1
60 MHz H NMR (CDCl3, TMS) d 1.37 (3H, t, J=7.0
Hz, COOCH2CH3), 4.31 (2H, q, J=7.0 Hz, COOCH2),
4.54 (4H, d, JH-F=47.0 Hz, C-2H), 6.62 (1H, s, C-3H),
6.81 (1H, d, J=9.0 Hz, C-8H), 7.18 (1H, dd, J=9.0, 2.0
Hz, C-7H), 7.98 (1H, d, J=2.0 Hz, C-5H); mp 76±78 ꢀC
(Et2O:hexane); MS (EI) m/z 302 (M+); anal. (C14H13
ClF2O3) C, H, N.
1
60 MHz H NMR (CDCl3, TMS) d 1.38 (3H, t, J=7.0
Hz, COOCH2CH3), 4.36 (2H, q, J=7.0 Hz, COOCH2),
4.59 (4H, d, JH-F=47.0 Hz, C-2H), 6.68 (1H, s, C-3H),
7.01 (1H, d, J=9.0 Hz, C-8H), 7.48 (1H, dd, J=9.0, 3.0
Hz, C-7H), 8.30 (1H, d, J=3.0 Hz, C-5H); MS (EI) m/z
486 (M+); colorless oil.
2,2-Bis(¯uoromethyl)-6-(tri¯uoromethyl)-2H-1-benzo-
pyran-4-carboxylic acid (9e). A mixture of 10e (0.51 g,
1.52 mmol), potassium hydroxide (0.13 g, 2.0 mmol),
and EtOH (10 mL) was stirred at room temperature for
2 h. The reaction mixture was poured into ice-cooled
aqueous HCl. The resulting crystals were isolated by ®l-
tration, and washed with H2O. The crystals were dissolved
in CH2Cl2, the organic layer was washed with H2O, dried
(Na2SO4), and evaporated to give 9e (0.43 g, 92%).
6-Cyano-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
oxylic acid ethyl ester (10i). A mixture of 10k (0.40 g,
1.0 mmol), copper(I) cyanide (0.11 g, 1.1 mmol), and
DMF (3 mL) was stirred at 160 ꢀC for 2.5 h. After
cooling down to room temperature, 2 N HCl was added
to the mixture the mixture was extracted with AcOEt.
The organic extracts were washed with brine, dried
(Na2SO4), evaporated, and chromatographed on silica
gel with hexane:AcOEt (3:1) to give 10i (0.22 g, 76%).
1
270 MHz H NMR (CDCl3, TMS) d 4.63 (4H, JH-F
=
46.9 Hz, C-2H), 6.91 (1H, s, C-3H), 7.03 (1H, d, J=8.57
Hz, C-8H), 7.52 (1H, dd, J=8.57, 1.64 Hz, C-7H), 8.36
(1H, d, J=1.64 Hz, C-5H); mp 162±163 ꢀC (AcOEt:
hexane); MS (EI) m/z 308 (M+); anal. (C13H9F5O3) C,
H, N.
1
60 MHz H NMR (CDCl3, TMS) d 1.34 (3H, t, J=7.0
Hz, COOCH2CH3), 4.31 (2H, q, J=7.0 Hz, COOCH2),
4.54 (4H, d, JH-F=47.0 Hz, C-2H), 6.68 (1H, s, C-3H),
6.90 (1H, d, J=9.0 Hz, C-8H), 7.45 (1H, dd, J=9.0,
2.0 Hz, C-7H), 8.33 (1H, d, J=2.0 Hz, C-5H); mp 115±
117 ꢀC (AcOEt:hexane); MS (EI) m/z 293 (M+); anal.
(C15H13F2NO3) C, H, N.
2,2-Bis(¯uoromethyl)-2H-1-benzopyran-4-carboxylic acid
1
(9d). 270 MHz H NMR (CDCl3, TMS) d 4.60 (4H,
JH-F=46.9 Hz, C-2H), 6.77 (1H, s, C-3H), 6.93±7.28
(3H, m, C-6H, C-7H, C-8H), 7.93 (1H, d, J=7.58 Hz,
C-5H); MS (EI) m/z 240 (M+); yield 85%; colorless oil.
6-Chloro-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
oxylic acid ethyl ester (10c). A mixture of 10a (0.52 g,
1.84 mmol), concd HCl (0.5 mL), and EtOH (15 mL)
was stirred for 0.5 h at room temperature. The mixture
was concentrated in vacuo to give hydrochloric acid salt
of 10a.
2,2-Bis(¯uoromethyl)-6-(penta¯uoroethyl)-2H-1-benzo-
pyran-4-carboxylic acid (9f). 270 MHz 1H NMR
(CDCl3±acetone-d6, TMS) d 4.62 (4H, JH-F=46.5 Hz,
C-2H), 6.81 (1H, s, C-3H), 7.02 (1H, d, J=8.57 Hz, C-
8H), 7.45 (1H, dd, J=8.57, 1.98 Hz, C-7H), 8.42 (1H, d,
J=1.98 Hz, C-5H); mp 173±174 ꢀC (AcOEt:hexane);
MS (EI) m/z 358 (M+); anal. (C14H9F7O3) C, H, N;
yield quant.
A mixture of the hydrochloric acid salt of 10a (0.41 g,
1.28 mmol), H2O (10 mL) and concd H2SO4 (0.13 g,
1.28 mmol) was cooled to 0 ꢀC. An aqueous solution (10
mL) of sodium nitrite (0.10 g, 1.45 mmol) was added
dropwise with stirring. Stirring was continued for 1 h at
0 ꢀC. The reaction mixture was added dropwise to a
mixture of copper chloride (0.25 g, 2.56 mmol) and
concd HCl (10 mL) at 0 ꢀC. The mixture was stirred at
0 ꢀC for 30 min, at room temperature for 3 h, and
heated at 70 ꢀC for 3 h. After cooling down to room
temperature, the reaction mixture was extracted with
AcOEt, and the organic layer was extracted with 2 N
2,2-Bis(¯uoromethyl)-6-(hepta¯uoropropyl)-2H-1-benzo-
pyran-4-carboxylic acid (9g). 270 MHz 1H NMR
(CDCl3, TMS): d 4.63 (4H, JH-F=46.5 Hz, C-2H), 6.92
(1H, s, C-3H), 7.05 (1H, d, J=8.57 Hz, C-8H), 7.47
(1H, dd, J=8.57, 1.65 Hz, C-7H), 8.32 (1H, d, J=1.65
Hz, C-5H); mp 162±163 ꢀC (AcOEt:hexane); MS (EI) m/z
408 (M+); anal. (C15H9F9O3) C, H, N; yield 96%.
2,2-Bis(¯uoromethyl)-6-(nona¯uorobutyl)-2H-1-benzo-
pyran-4-carboxylic acid (9h). 270 MHz 1H NMR

1402
N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1
(CDCl3±acetone-d6, TMS) d 4.62 (4H, JH-F=46.5 Hz,
C-2H), 6.82 (1H, s, C-3H), 7.03 (1H, d, J=8.57 Hz, C-
8H), 7.45 (1H, dd, J=8.58, 1.65 Hz, C-7H), 8.40 (1H, d,
J=1.65 Hz, C-5H); mp 180±181 ꢀC (AcOEt:hexane);
MS (EI) m/z 458 (M+); anal. (C16H9F11O3) C, H, N;
yield 84%.
60 MHz H NMR (CDCl3, TMS) d 4.55 (4H, d, JH-F
=
47.0 Hz, C-2H), 6.41 (1H, s, C-3H), 6.75 (1H, d, J=9.0
Hz, C-8H), 7.13±7.83 (2H, m, C-5H, C-7H); mp 105±
107 ꢀC (AcOEt:hexane); MS (EI) m/z 299 (M+); anal.
(C12H8BrF2NO) C, H, N.
6-Bromo-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
oxylic acid (9b). A mixture of 11b (1.53 g, 5.10 mmol),
AcOH (30 mL), concd H2SO4 (15 mL), and H2O (15
mL) was re¯uxed for 3 h. After cooling down to room
temperature, the mixture was poured into ice±water,
extracted with Et2O. The organic extracts were washed
with brine, water, dried (Na2SO4), evaporated, and
chromatographed on silica gel with hexane:AcOEt (2:1)
to give 9b (1.23 g, 76%).
6-Cyano-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carb-
1
oxylic acid (9i). 270 MHz H NMR (CDCl3, TMS) d
4.63 (4H, JH-F=46.9 Hz, C-2H), 6.95 (1H, s, C-3H),
7.02 (1H, d, J=8.25 Hz, C-8H), 7.55 (1H, dd, J=8.28,
1.98 Hz,ꢀ C-7H), 8.46 (1H, d, J=1.98 Hz, C-5H); mp
165±167 C (AcOEt:hexane); MS (EI) m/z 265 (M+).
anal. (C13H9F2NO3) C, H, N; yield 79%.
2,2-Bis(¯uoromethyl)-6-nitro-2H-1-benzopyran-4-carbo-
nitrile (11j). A mixture of 8 (20.2 g, 63.1 mmol), cop-
per(I) cyanide (6.2 g, 69.2 mmol) and DMF (200 mL)
was re¯uxed for 6 h. The reaction mixture was poured
into ice-cooled 2 N HCl the resulting crystals were iso-
lated by ®ltration, washed with H2O, and dried. The
crystals were dissolved in CH2Cl2, the organic layer was
washed with H2O, dried (Na2SO4), evaporated, and
chromatographed on silica gel with hexane:CH2Cl2 (3:7)
to give 11j (16.8 g, quant.).
1
60 MHz H NMR (CDCl3, TMS) d 4.58 (4H, d, JH-F
=
46.0 Hz, C-2H), 6.77 (1H, d, J=9.0 Hz, C-8H), 6.83
(1H, s, C-3H), 7.29 (1H, dd, J=9.0, 2.0 Hz, C-7H), 8.14
(1H, d, J=2.0 Hz, C-5H), 9.81 (1H, br s); mp 165±
166 ꢀC (AcOEt:hexane); MS (EI) m/z 318 (M+); anal.
(C12H9BrF2O3) C, H, N.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-nitro-2H-1-benzo-
pyran-4-carboxamide (13j). A mixture of 9j (0.38 g, 1.33
mmol) and THF (5 mL) was cooled to 0 ꢀC, 1,10-carbo-
nyldiimidazole (CDI) (0.28 g, 1.73 mmol) was added
portionwise to the mixture. The mixture was stirred at
0 ꢀC for 1 h, and then 2-cyanoethylamine (0.15 g, 2.14
mmol) in THF (2 mL) was added at 0 ꢀC to the reaction
mixture, and the mixture was stirred at 0 ꢀC for 12 h.
H2O was added to the reaction mixture, and the pro-
ducts were extracted with CH2Cl2. The extracts were
washed with brine, dried (Na2SO4), evaporated, and
chromatographed on silica gel with MeOH:CH2Cl2
(5:100) to give 13j (0.38 g, 85%).
1
60 MHz H NMR (CDCl3, TMS) d 4.60 (4H, d, JH-F
=
48.0 Hz, C-2H), 6.53 (1H, s, C-3H), 7.03 (1H, d, J=9.0
Hz, C-8H), 8.10±8.40 (2H, m, C-5H, C-7H); mp 142±
143 ꢀC (EtOH); MS (EI) m/z 266 (M+); anal. (C12H8F2
N2O2) C, H, N.
6-Bromo-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-carbo-
nitrile (11b). A mixture of 11j (4.2 g, 15.8 mmol), tin(II)
chloride (9.6 g, 50.6 mmol), and EtOH (140 mL) was
stirred for 2 h at 80 ꢀC. After cooling down to room
temperature, 2 N NaOH was added to the mixture and
the mixture was extracted with CH2Cl2. The organic
extracts were extracted with 2 N HCl. The aqueous
acidic extracts were alkalinized with 2 N NaOH, and
extracted with CH2Cl2. The extracts was washed with
brine, dried (Na2SO4), and evaporated to give crude
amine 11a (2.4 g, 65%) as an oil, which was used with-
out further puri®cation.
60 MHz 1H NMR (CDCl3±DMSO-d6, TMS) d 2.69
(2H, t, J=6.0 Hz, CH2CN), 3.53 (2H, dt, J=6.0, 6.0
Hz, NHCH2), 4.55 (4H, d, JH-F=46.0 Hz, C-2H), 6.12
(1H, s, C-3H), 6.88 (1H, d, J=9.0 Hz, C-8H), 7.97 (1H,
dd, J=9.0, 2.0 Hz, C-7H), 8.43 (1H, d, J=2.0 Hz, C-
5H); mp 179±180 ꢀC (EtOH); MS (EI) m/z 337 (M+);
anal. (C15H13F2N3O4) C, H, N.
60 MHz 1H NMR (CDCl3, TMS) d 4.57 (4H, d, J=48.0
Hz, C-2H), 6.36 (1H, s, C-3H), 6.28±6.94 (3H, m, C-5H,
C-7H, C-8H); MS (EI) m/z 236 (M+).
6-Bromo-2,2-bis(¯uoromethyl)-N-methyl-2H-1-benzo-
1
pyran-4-carboxamide (12b). 60 MHz H NMR (CDCl3±
CD3OD, TMS) d 2.77 (3H, s, NHCH3), 4.56 (4H, d,
JH-F=46.0 Hz, C-2H), 5.94 (1H, s, C-3H), 6.77 (1H, d,
J=9.0 Hz, C-8H), 7.31 (1H, dd, J=9.0, 2.0 Hz, C-7H),
7.63 (1H, d, J=2.0 Hz, C-5H); mp 187±188 ꢀC (AcOEt:
hexane); MS (EI) m/z 331 (M+); anal. (C13H12BrF2
NO2) C, H, N; yield 88%.
An aqueous solution (10 mL) of sodium nitrite (760 mg,
11.0 mmol) was added to a mixture of the crude amine
11a (2.0 g, 8.47 mmol) and concd H2SO4 (20 mL)
dropwise with stirring at 0 ꢀC. Stirring was continued
for 30 min at 0 ꢀC. The reaction mixture was added
dropwise to a mixture of copper(I) bromide (2.43 g, 16.9
mmol) and 48% aqueous HBr (12 mL) at 0 ꢀC. The
mixture was stirred at 0 ꢀC for 1 h, at room temperature
for 1 h, and heated at 70 ꢀC for 1 h. After cooling down
to room temperature, the reaction mixture was extrac-
ted with CH2Cl2. The organic layer was washed with
2 N HCl, 2 N NaOH, and brine, dried (Na2SO4),
evaporated, and chromatographed on silica gel with
hexane:AcOEt (5:1) to give 11b (1.63 g, 64%).
6-Chloro-2,2-bis(¯uoromethyl)-N-methyl-2H-1-benzo-
1
pyran-4-carboxamide (12c). 60 MHz H NMR (CDCl3,
TMS) d 2.93 (3H, d, J=5.0 Hz, NHCH3), 4.56 (4H,
d, JH-F=47.0 Hz, C-2H), 5.88 (1H, br s, NH), 5.96
(1H, s, C-3H), 6.82 (1H, d, J=9.0 Hz, C-8H), 7.21
(1H, dd, J=9.0, 2.0 Hz, C-7H), 7.54 (1H, d, J=2.0 Hz,
C-5H); mp 175±176 ꢀC (AcOEt:hexane); MS (EI)
m/z 287 (M+); anal. (C13H12ClF2NO2) C, H, N; yield
29%.

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1403
2,2-Bis(¯uoromethyl)-N-methyl-2H-1-benzopyran-4-carb-
oxamide (12d). 60 MHz 1H NMR (CDCl3, TMS): d
2.85 (3H, d, J=5.0 Hz, NHCH3), 4.49 (4H, d, JH-F=
47.0 Hz, C-2H), 5.86 (1H, s, C-3H), 6.11 (1H, br s, NH),
6.70ꢀ±7.50 (4H, m, C-5H, C-6H, C-7H, C-8H); mp 138±
139 C (AcOEt:hexane); MS (EI) m/z 253 (M+); anal.
(C13H13F2NO2) C, H, N; yield 42%.
47.0 Hz, C-2H), 6.21 (1H, s, C-3H), 7.08 (1H, d, J=9.0
Hz, C-8H), 8.10 (1H, dd, J=9.0, 3.0 Hz, C-7H), 8.46
(1H, br s, NH), 8.48 (1H, d, J=3.0 Hz, C-5H); mp
180±181 ꢀC (AcOEt:hexane); MS (EI) m/z 298 (M+);
anal. (C13H12F2N2O4) C, H, N; yield 67%.
6-Bromo-N-cyanoethyl-2,2-bis(¯uoromethyl)-2H-1-benzo-
1
pyran-4-carboxamide (13b). 60 MHz H NMR (CDCl3±
CD3OD, TMS) d 2.75 (2H, t, J=6.0 Hz, CH2CN), 3.63
(2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.61 (4H, d, JH-F=
2,2-Bis(¯uoromethyl)-N-methyl-6-(tri¯uoromethyl)-2H-
1
1-benzopyran-4-carboxamide (12e). 60 MHz H NMR
(CDCl3, TMS) d 2.88(3H, d, J=5.0 Hz, NHCH3), 4.53
(4H, d, JH-F=47.0 Hz, C-2H), 5.99 (1H, s, C-3H), 6.48
(1H, br s, NH), 6.95 (1H, d, J=9.0 Hz, C-8H), 7.48
(1H, dd, J=9.0, 2.0 Hz, C-7H), 7.82 (1H, d, J=2.0 Hz,
C-5H); mp 162±164 ꢀC (AcOEt:hexane); MS (EI) m/z
321 (M+); anal. (C14H12F5NO2) C, H, N; yield 86%.
47.0 Hz, C-2H), 6.04 (1H, s, C-3H), 6.81 (1H, d, J=9.0
Hz, C-8H), 7.36 (1H, dd, J=9.0, 2.0 Hz, C-7H), 7.69
(1H, d, J=2.0 Hz, C-5H); mp 140±142 ꢀC (AcOEt:
hexane); MS (EI) m/z 370 (M+); anal. (C15H13BrF2
NO2) C, H, N; yield 81%.
6-Chloro-N-cyanoethyl-2,2-bis(¯uoromethyl)-2H-1-benzo-
1
2,2-Bis(¯uoromethyl)-N-methyl-6-(penta¯uoroethyl)-2H-
1-benzopyran-4-carboxamide (12f). 60 MHz 1H NMR
(CDCl3, TMS) d 2.87(3H, d, JH-F=5.0 Hz, NHCH3),
4.48 (4H, d, JH-F=46.0 Hz, C-2H), 5.89 (1H, s, C-3H),
6.13 (1H, br s, NH), 6.87 (1H, d, J=9.0 Hz, C-8H), 7.33
(1H, dd, J=9.0, 2.0 Hz, C-7H), 7.68 (1H, d, J=2.0 Hz,
C-5H); mp 128±129 ꢀC (AcOEt:hexane); MS (EI) m/z
371 (M+); anal. (C15H12F7NO2) C, H, N; yield 72%.
pyran-4-carboxamide (13c). 60 MHz H NMR (CDCl3,
TMS) d 2.72 (2H, t, J=6.0 Hz, CH2CN), 3.64 (2H, dt,
J=6.0, 6.0 Hz, NHCH2), 4.54 (4H, d, JH-F=47.0 Hz,
C-2H), 6.01 (1H, s, C-3H), 6.57 (1H, br s, NH), 6.82
(1H, d, J=9.0 Hz, C-8H), 7.18 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 7.51 (1H, d, J=2.0 Hz, C-5H); mp 134±136 ꢀC
(AcOEt:hexane); MS (EI) m/z 326 (M+); anal. (C15H12
ClF2N2O2) C, H, N; yield 39%.
2,2-Bis(¯uoromethyl)-6-(hepta¯uoropropyl)-N-methyl-
2H-1-benzopyran-4-carboxamide (12g). 60 MHz 1H
NMR (CDCl3, TMS) d 2.94 (3H, d, J=5.0 Hz,
NHCH3), 4.59 (4H, d, JH-F=47.0 Hz, C-2H), 6.02 (1H,
s, C-3H), 6.39 (1H, br s, NH), 7.01 (1H, d, J=9.0 Hz,
C-8H), 7.47 (1H, dd, J=9.0, 2.0 Hz, C-7H), 7.82 (1H, d,
J=2.0 Hz, C-5H); mp 88±91 ꢀC (AcOEt:hexane); MS
(EI) m/z 421 (M+); anal. (C16H12F9NO2) C, H, N; yield
77%.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-2H-1-benzopyran-4-
1
carboxamide (13d). 60 MHz H NMR (CDCl3, TMS) d
2.71 (2H, t, J=6.0 Hz, CH2CN), 3.62 (2H, dt, J=6.0,
6.0 Hz, NHCH2), 4.57 (4H, d, JH-F=47.0 Hz, C-2H),
5.99 (1H, s, C-3H), 6.20±7.60 (5H, m, C-5H, C-6H, C-
7H, C-8H, NH). MS m/z: 292 (M+). Analysis by HPLC
(solvent, CH3CN:H2O:TFA=34.95:64.95:0.1; ¯ow rate,
1.0 cm3/min; detection, 254 nm) showed the purity to be
at least 96% (retention time 14 min), and (solvent,
MeOH:H2O:TFA=44.95:54.95:0.1; ¯ow rate, 1.0 cm3/
min; detection, 254 nm) showed the purity to be at least
95% (retention time 14 min); yield 51%; colorless oil.
2,2-Bis(¯uoromethyl)-N-methyl-6-(nona¯uorobutyl)-2H-
1
1-benzopyran-4-carboxamide (12h). 60 MHz H NMR
(CDCl3, TMS) d 2.94 (3H, d, J=5.0 Hz, NHCH3), 4.56
(4H, d, JH-F=47.0 Hz, C-2H), 5.92 (1H, br s, NH), 5.98
(1H, s, C-3H), 6.99 (1H, d, J=9.0 Hz, C-8H), 7.45 (1H,
dd, J=9.0, 2.0 Hz, C-7H), 7.78 (1H, d, J=2.0 Hz, C-
5H); MS (EI) m/z 471 (M+). Analysis by HPLC
(solvent, CH3CN:H2O:TFA=64.95:34.95:0.1; ¯ow rate,
1.0 cm3/min; detection, 254 nm) showed the purity to be
at least 96% (retention time 11 min), and (solvent,
CH3OH:H2O:TFA=74.95:24.95:0.1; ¯ow rate, 1.0 cm3/
min; detection, 254 nm) showed the purity to be at least
97% (retention time 16 min); yield 63%; colorless oil.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(tri¯uoromethyl)-
2H-1-benzopyran-4-carboxamide (13e). 60 MHz 1H
NMR (CDCl3, TMS) d 2.70 (2H, t, J=6.0 Hz,
CH2CN), 3.63 (2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.57
(4H, d, JH-F=47.0 Hz, C-2H), 6.07 (1H, s, C-3H), 6.96
(1H, br s, NH). 6.98 (1H, d, J=9.0 Hz, C-8H), 7.50
(1H, dd, J=9.0, 2.0 Hz, C-7H), 7.84 (1H, d, J=2.0 Hz,
C-5H); mp 135±136 ꢀC (AcOEt:hexane); MS (EI) m/z:
360 (M+); anal. (C16H13F5N2O2) C, H, N; yield 86%.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(penta¯uoroethyl)-
2H-1-benzopyran-4-carboxamide (13f). 270 MHz 1H
NMR (CDCl3, TMS) d 2.75 (2H, t, J=6.27 Hz,
CH2CN), 3.67 (2H, dt, J=6.27, 6.27 Hz, NHCH2), 4.59
(4H, d, JH-F=47.0 Hz, C-2H), 6.08 (1H, s, C-3H), 6.80
(1H, br s, NH), 7.02 (1H, d, J=9.0 Hz, C-8H), 7.52
(1H, dd, J=9.0, 2.0 Hz, C-7H), 7.83 (1H, d, J=2.0 Hz,
C-5H); mp 144±145 ꢀC (AcOEt:hexane); MS (EI) m/z:
410 (M+); anal. (C17H13F9N2O2) C, H, N; yield 83%.
6-Cyano-2,2-bis(¯uoromethyl)-N-methyl-2H-1-benzo-
pyran-4-carboxamide (12i). 270 MHz 1H NMR
(DMSO-d6, TMS) d 2.74 (3H, d, J=4.62 Hz, NHCH3),
4.65 (4H, d, JH-F=47.8 Hz, C-2H), 6.13 (1H, s, C-3H),
7.07 (1H, d, J=8.57 Hz, C-8H), 7.68 (1H, dd, J=8.57,
1.98 Hz, C-7H), 7.87 (1H, d, J=1.98 Hz, C-5H), 8.48
(1H, d, J=4.62 Hz, NH); mp 206±207 ꢀC (AcOEt:
hexane); MS (EI) m/z 278 (M+); anal. (C14H12F2N2O4)
C, H, N; yield 95%.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(hepta¯uoropropyl)-
2H-1-benzopyran-4-carboxamide (13g). 60 MHz 1H
NMR (CDCl3, TMS): d 2.70 (2H, t, J=6.0 Hz, CH2
CN), 3.62 (2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.58 (4H,
2,2-Bis(¯uoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-
1
4-carboxamide (12j). 60 MHz H NMR (CDCl3, TMS)
d 2.80 (3H, d, J=4.5 Hz, NHCH3), 4.68 (4H, d, JH-F=

1404
N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
d, JH-F=46.0 Hz, C-2H), 6.05 (1H, s, C-3H), 6.51 (1H,
br s, NH), 7.03 (1H, d, J=8.58 Hz, C-8H), 7.43 (1H,
dd, J=8.58, 1.98 Hz, C-7H), 7.81 (1H, d, J=1.98 Hz,
C-5H); mp 135±136 ꢀC (AcOEt:hexane); MS (EI) m/z
460 (M+); anal. (C18H13F9N2O2) C, H, N; yield 45%.
Hz, C-7H), 8.32 (1H, d, J=3.0 Hz, C-5H), 8.37 (1H, br
s, NH); mp 156±157 ꢀC (AcOEt); MS (EI) m/z 353
(M+); anal. (C15H13F2N3O2S) C, H, N.
2,2-Bis(¯uoromethyl)-N-methyl-6-(tri¯uoromethyl)-2H-
1-benzopyran-4-thioamide (14e). 60 MHz 1H NMR
(CDCl3, TMS) d 3.25 (3H, d, J=5.0 Hz, NCH3), 4.54
(1H, d, JH-F=46.0 Hz, C-2H), 5.77 (1H, s, C-3H), 6.93
(1H, d, J=9.0 Hz, C-8H), 7.44 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 7.54 (1H, br s, NH), 7.66 (1H, d, J=2.0 Hz, C-
5H); mp 145±147 ꢀC (AcOEt:hexane); MS (EI) m/z 337
(M+); anal. (C14H12F5NOS) C, H, N; yield 50%.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(nona¯uorobutyl)-
2H-1-benzopyran-4-carboxamide (13h). 60 MHz 1H
NMR (CDCl3, TMS) d 2.69 (2H, t, J=6.0 Hz, CH2
CN), 3.60 (2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.55 (4H,
d, JH-F=47.0 Hz, C-2H), 6.08 (1H, s, C-3H), 6.83 (1H,
br s, NH), 6.99 (1H, d, J=9.0 Hz, C-8H), 7.47 (1H, dd,
J=9.0, 2.0 Hz, C-7H), 7.81 (1H, d, J=2.0 Hz, C-5H);
mp 85±86 ꢀC (Et2O:hexane); MS (EI) m/z 510 (M+);
anal. (C19H13F11N2O2) C, H, N; yield 63%.
2,2-Bis(¯uoromethyl)-N-methyl-6-(penta¯uoroethyl)-2H-
1-benzopyran-4-thioamide (14f). 60 MHz 1H NMR
(CDCl3, TMS) d 3.27 (3H, d, J=5.0 Hz, NCH3), 4.55
(4H, d, JH-F=46.0 Hz, C-2H), 5.80 (1H, s, C-3H), 6.97
(1H, d, J=9.0 Hz, C-8H), 7.40 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 7.55 (1H, br s, NH), 7.63 (1H, d, J=2.0 Hz, C-
5H); mp 148±149 ꢀC (AcOEt:hexane); MS (EI) m/z 387
(M+); anal. (C15H12F7NOS) C, H, N; yield 96%.
6-Cyano-N-cyanoethyl-2,2-bis(¯uoromethyl)-2H-1-benzo-
pyran-4-carboxamide (13i). 270 MHz 1H NMR
(DMSO-d6, TMS) d 2.79 (2H, t, J=6.27 Hz, CH2CN),
3.47 (2H, dt, J=6.27, 6.54 Hz, NHCH2), 4.68 (4H, d,
JH-F=47.8 Hz, C-2H), 6.15 (1H, s, C-3H), 7.09 (1H, d,
J=8.57 Hz, C-8H), 7.70 (1H, dd, J=8.57, 1.98 Hz, C-
7H), 7.78 (1H, d, J=1.98 Hz, C-5H), 8.91 (1H, br s,
NH); mp 170±172 ꢀC (AcOEt:hexane). MS (EI) m/z 317
(M+); anal. (C16H13F2N3O2) C, H, N; yield 72%.
2,2-Bis(¯uoromethyl)-N-methyl-6-(hepta¯uoropropyl)-
1
2H-1-benzopyran-4-thioamide (14g). 60 MHz H NMR
(CDCl3, TMS) d 3.24 (3H, d, J=5.0 Hz, NCH3), 4.55
(1H, d, JH-F=47.0 Hz, C-2H), 5.82 (1H, s, C-3H), 6.98
(1H, d, J=9.0 Hz, C-8H), 7.42 (1H, dd, J=9.0, 2.0 Hz,
C-7H), 7.55 (1H, br s, NH), 7.62 (1H, d, J=2.0 Hz, C-
5H); mp 125±126 ꢀC (Et2O:hexane); MS (EI) m/z 437
(M+); anal. (C16H12F9NOS) C, H, N; yield 96%.
6-Amino-N-cyanoethyl-2,2-bis(¯uoromethyl)-N-methyl-
2H-1-benzopyran-4-carboxamide hydrochloride (13a). A
mixture of 13j (0.51 g, 1.5 mmol), SnCl2 (0.99 g, 4.7
mmol), and EtOH (3 mL) was re¯uxed for 2.5 h. After
cooling down to room temperature, 2 N NaOH was
added to the mixture, and the products were extracted
with CH2Cl2. The extracts were washed with brine,
dried (Na2SO4), and evaporated under reduced pressure.
The residue was chromatographed on silica gel with
AcOEt:hexane (1:1) to give amine. A mixture of the
obtained amine, MeOH, and concd HCl was stirred for
1 h at ambient temperature. The reaction mixture was
evaporated under vacuum to give 13a (0.35 g, 67%).
6-Cyano-2,2-bis(¯uoromethyl)-N-methyl-2H-1-benzo-
pyran-4-thioamide (14i). 270 MHz 1H NMR (CDCl3,
TMS) d 3.26 (3H, d, J=4.88 Hz, NCH3), 4.58 (1H,
JH-F=46.9 Hz, C-2H), 5.80 (1H, s, C-3H), 6.95 (1H, d,
J=8.55 Hz, C-8H), 7.45 (1H, dd, J=8.55, 1.95 Hz, C-
7H), 7.77 (1H, d, J=1.95 Hz, C-5H), 8.10 (1H, br s,
NH); mp 137±138 ꢀC (Et2O:hexane); MS (EI) m/z: 294
(M+); anal. (C14H12F2N2OS) C, H, N; yield 50%.
1
270 MHz H NMR (DMSO-d6, TMS) d 2.77 (2H, t,
2,2-Bis(¯uoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-
4-thioamide (14j). 60 MHz 1H NMR (CDCl3±DMSO-d6,
TMS) d 3.14 (3H, s, NCH3), 4.51 (1H, d, JH-F=46.0 Hz,
C-2H), 5.70 (1H, s, C-3H), 6.85 (1H, d, J=9.0 Hz, C-
8H), 7.91 (1H, dd, J=9.0, 3.0 Hz, C-7H), 8.22 (1H, d,
J=3.0 Hz, C-5H); mp 135±136 ꢀC (AcOEt:hexane); MS
(EI) m/z 314 (M+); anal. (C13H12F2N2O3S) C, H, N;
yield 96%.
J=6.27 Hz, CH2CN), 3.45 (2H, dt, J=6.27, 6.27 Hz,
NHCH2), 4.64 (4H, d, JH-F=47.8 Hz, C-2H), 6.11 (1H,
s, C-3H), 7.00 (1H, d, J=8.58 Hz, C-8H), 7.16±7.23
(1H, m, C-7H), 7.51±7.55 (1H, m, C-5H), 9.3±10.2 (1H,
br s, NH); mp 202±205 ꢀC (AcOEt:EtOH); MS (EI) m/z
+
.
307 (M ); anal. (C15H16ClF2N3O2 1/4H2O) C, H, N.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-nitro-2H-1-benzo-
pyran-4-thioamide (15j). A mixture of 13j (25.9 g, 76.6
mmol), Lawesson's reagent (95%) (16.3 g, 38.3 mmol),
and 1,2-dichloroethane (520 mL) was re¯uxed for 1 h.
After cooling down to room temperature, the reaction
mixture was washed with 1 N NaOH and aqueous layer
was extracted with AcOEt. The 1,2-dichloroethane and
AcOEt layer was washed with brine, and dried
(Na2SO4), evaporated, and chromatographed on silica
gel with AcOEt:hexane (1:3) to give 15j (25.5 g, 94%).
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(tri¯uoromethyl)-
1
2H-1-benzopyran-4-thioamide (15e). 60 MHz H NMR
(CDCl3, TMS) d 2.89 (2H, t, J=6.0 Hz, CH2CN), 4.03
(2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.60 (4H, d, JH-F=
47.0 Hz, C-2H), 5.87 (1H, s, C-3H), 7.02 (1H, d, J=9.0
Hz, C-8H), 7.51 (1H, dd, J=9.0, 2.0 Hz, C-7H), 7.82
(1H, d, J=2.0 Hz, C-5H), 8.35 (1H, br s, NH); mp
105±106 ꢀC (AcOEt:hexane); MS (EI) m/z 376 (M+);
anal. (C16H13F5N2OS) C, H, N; yield 52%.
1
60 MHz H NMR (CDCl3, TMS) d 2.91 (2H, t, J=6.0
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(penta¯uoroethyl)-
1
Hz, CH2CN), 4.02 (2H, dt, J=6.0, 6.0 Hz NHCH2),
4.58 (4H, d, JH-F=46.0 Hz, C-2H), 5.86 (1H, s, C-3H),
6.95 (1H, d, J=9.0 Hz, C-8H), 8.04 (1H, dd, J=9.0, 3.0
2H-1-benzopyran-4-thioamide (15f). 60 MHz H NMR
(CDCl3, TMS) d 2.89 (2H, t, J=6.0 Hz, CH2CN), 4.04
(2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.57 (4H, d, JH-F=

N. Taka et al. / Bioorg. Med. Chem. 8 (2000) 1393±1405
1405
47.0 Hz, C-2H), 5.84 (1H, s, C-3H), 7.00 (1H, d, J=9.0
Hz, C-8H), 7.46 (1H, dd, J=9.0, 2.0 Hz, C-7H), 7.64
(1H, d, J=2.0 Hz, C-5H), 7.98±8.40 (1H, br s, NH); mp
108±109 ꢀC (AcOEt:hexane); MS (EI) m/z: 426 (M+);
anal. (C17H13F7N2OS) C, H, N; yield 62%.
Rep. Med. Chem. 1991, 26, 73. (f) Quast, U. Trends Pharma-
col. Sci. 1993, 14, 332. (g) Parratt, J. R. Trends Pharmacol. Sci.
1994, 15, 19. (i) Poyser, R. H.; Hamilton, T. C. Drugs Fut. 1994,
19, 39.
3. (a) Nakajima, T.; Shinohara, T.; Yaoka, O.; Fukunari, A.;
Shinagawa, K.; Aoki, K.; Katoh, A.; Yamanaka, T.; Seto-
guchi, M.; Tahara, T. J. Pharmacol. Exp. Ther. 1992, 261, 730.
(b) Drugs Fut. 1992, 17, 999.
N-Cyanoethyl-2,2-bis(¯uoromethyl)-6-(hepta¯uoropropyl)-
1
2H-1-benzopyran-4-thioamide (15g). 60 MHz H NMR
4. (a) Koga, H.; Ohta, M.; Sato, H.; Ishizawa, T.; Nabata, H.
Bioorg. Med. Chem. Lett. 1993, 3, 625. (b) Koga, H.; Sato, H.;
Imagawa, J.; Ishizawa, T.; Yoshida, S.; Sugo, I.; Taka, N.;
Takahashi, T.; Nabata, H. Bioorg. Med. Chem. Lett. 1993, 3,
2005. (c) Taka, N.; Koga, H.; Sato, H.; Ishizawa, T.; Takaha-
shi, T.; Imagawa, J. Bioorg. Med. Chem. Lett. 1994, 4, 2893.
(d) Takahashi, T.; Koga, H.; Sato, H.; Ishizawa, T.; Taka, N.;
Imagawa, J. Bioorg. Med. Chem. Lett. 1994, 4, 2899. (e) Ohta,
M.; Koga, H.; Sato, H.; Ishizawa, T. Bioorg. Med. Chem. Lett.
1994, 4, 2903. (f) Sato, H.; Koga, H.; Ishizawa, T.; Makino,
T.; Taka, N.; Takahashi, T.; Nabata, H. Bioorg. Med. Chem.
Lett. 1995, 5, 233. (g) Koga, H.; Sato, H.; Ishizawa, T.; Taka,
N.; Takahashi, T. Tetrahedron Lett. 1995, 36, 87. (h) Koga,
H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Nabata, H.; Ima-
gawa, J.; Yoshida, S.; Sugo, I. Bioorg. Med. Chem. Lett., 1993,
3, 1111. (i) Koga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.;
Makino, T.; Taka, N.; Takahashi, T.; Sato, T.; Nabata, H.
Bioorg. Med. Chem. Lett. 1993, 3, 1115. (j) Ishizawa, T.; Koga,
H.; Ohta, M.; Sato, H.; Makino, T.; Kuromaru, K.; Taka, N.;
Takahashi, T.; Sato, T.; Nabata, H. Bioorg. Med. Chem. Lett.
1993, 3, 1659. (k) Sato, H.; Koga, H.; Ishizawa, T.; Makino, T.;
Kuromaru, K.; Taka, N.; Takahashi, T.; Sato, T.; Nabata, H.
Bioorg. Med. Chem. Lett. 1993, 3, 2627. (l) Ishizawa, T.; Koga,
H.; Sato, H.; Makino, T.; Taka, N.; Takahashi, T.; Sato, T.;
Nabata, H. Bioorg. Med. Chem. Lett. 1994, 4, 1995. (m) Taka-
hashi, T.; Koga, H.; Sato, H.; Ishizawa, T.; Taka, N.; Imagawa,
I. Bioorg. Med. Chem., 1998, 6, 323.
(CDCl3, TMS) d 2.85 (2H, t, J=6.0 Hz, CH2CN), 3.95
(2H, dt, J=6.0, 6.0 Hz, NHCH2), 4.51 (4H, d, JH-
F=47.0 Hz, C-2H), 5.78 (1H, s, C-3H), 6.92 (1H, d,
J=9.0 Hz, C-8H), 7.37 (1H, dd, J=9.0, 2.0 Hz, C-7H),
7.56 (1H, d, J=2.0 Hz, C-5H), 8.20 (1H, br s, NH); mp
94±95 ꢀC (AcOEt:hexane); MS (EI) m/z: 476 (M+);
anal. (C18H13F9N2OS) C, H, N; yield 44%.
6-Cyano-N-cyanoethyl-2,2-bis(¯uoromethyl)-2H-1-benzo-
pyran-4-thioamide (15i). 270 MHz 1H NMR (CDCl3,
TMS) d 2.96 (2H, t, J=6.27 Hz, CH2CN), 4.05 (2H, dt,
J=6.27, 6.27 Hz, NHCH2), 4.60 (4H, d, JH-F=47.0 Hz,
C-2H), 5.87 (1H, s, C-3H), 6.98 (1H, d, J=8.54 Hz, C-
8H), 7.47 (1H, dd, J=8.54, 1.96 Hz, C-7H), 7.78 (1H, d,
J=1.96 Hz, C-5H), 8.30 (1H, br s, NH); mp 191±192 ꢀC
(AcOEt:hexane); MS m/z: 333 (M+); anal. (C16H13F2
N3OS) C, H, N; yield 55%.
References and Notes
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