A convenient synthesis of fluorine-containing dihydrobenzo[b][1,4]diazepinols and its application to a synthesis of novel N-sulfinylanilines

Article abstract of DOI:10.3987/COM-08-S(N)82

The reactions of 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)pentane-2,4-dione (1) with various benzene- 1,2-diamines gave 2,5-dihydro-3-trifluoroacetyl-2-trifluoromethyl-1H-benzo[b][1,4]diazepin es (5) in moderate to high yields under very mild conditions. Also, 2,5-dihydro-3-perhaloalkanoyl-2-perhaloalkyl-1H-benzo[b][1,4]diazepines (7) were synthesized successfully by quite similar manner. Reactions of thus obtained dihydrobenzo[b][1,4]diazepinols (5) with thionyl chloride gave unexpected novel fluorine-containing N-sulfinylanilines (9).

Full text of DOI:10.3987/COM-08-S(N)82

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1205 - 1217. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 19th May, 2008, Published online, 22nd May, 2008. COM-08-S(N)82
A
CONVENIENT
SYNTHESIS
OF
FLUORINE-CONTAINING
DIHYDROBENZO[b][1,4]DIAZEPINOLS AND ITS APPLICATION TO A
SYNTHESIS OF NOVEL N-SULFINYLANILINES
Norio Ota,a Takehisa Tomoda,a Naoya Terai,a Yasuhiro Kamitori,a*
Dai Shibata,a Maurice Médebielle,b and Etsuji Okadaa*
aDepartment of Chemical Science and Engineering, Graduate School of
Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Fax: +81(78)8036163; E-mail: kamitori@kobe-u.ac.jp
bUniversité Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie
Moléculaires et Supramoléculaires (ICBMS), UMR CNRS-UCBL 5246,
Laboratoire de Synthèse de Biomolécules, Bâtiment Chevreul, 5ème étage, 43 bd
du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Abstract – The reactions of 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)-
pentane-2,4-dione (1) with various benzene-1,2-diamines gave 2,5-dihydro-3-
trifluoroacetyl-2-trifluoromethyl-1H-benzo[b][1,4]diazepines (5) in moderate to
high yields under very mild conditions. Also, 2,5-dihydro-3-perhaloalkanoyl-2-
perhaloalkyl-1H-benzo[b][1,4]diazepines (7) were synthesized successfully by
quite similar manner.
Reactions of thus obtained dihydrobenzo[b][1,4]-
diazepinols (5) with thionyl chloride gave unexpected novel fluorine-containing
N-sulfinylanilines (9).
INTRODUCTION
Benzo[b][1,4]diazepines are attractive and important heterocycles because of being applicable to the
creation of useful biologically active substances. In medicinal scientific fields, certain
benzo[b][1,4]diazepines are useful for the antipsychotic therapy. For example, 2-amino-4-phenyl and
2-(p-fluorophenyl)-4-phenyl-8-chloro derivatives are known as tranquilizers1 and antidepressants2
respectively. It has been also reported that some 2-amino-4-methylthiobenzo[b][1,4]diazepines act as
depressants of the central nervous system and anti-convulsants, whereas 2,4-diamino derivatives showed
effects as stimulants and convulsants.3 Moreover, some benzo[b][1,4]diazepines, in particular 2-thio
derivatives, show antibacterial activity,4-6 while 2,4-dimethyl derivatives are known as anti-sarcoma.7
In agricultural scientific fields, new herbicidal agents bearing a benzo[b][1,4]diazepine unit have been

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HETEROCYCLES, Vol. 76, No. 2, 2008
developed.8
On the other hand, much attention in recent years 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 recognized as important organic materials showing interesting biological
activities useful in medicinal and agricultural fields.9-12
In the course of our investigations on the nucleophilic substitutions at olefinic carbon atoms,13-18 it was
found that 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)pentane-2,4-dione 119 readily reacted with
various amines and thiols under very mild conditions to give the corresponding O-N and O-S exchanged
products 2 in high yields.18 These findings prompted us to investigate about the application of above
nucleophilic substitutions with the use of bifunctional nucleophiles to the syntheses of a variety of novel
fluorine-containing heterocycles which have high potential leading to pharmacophores. For instance,
using the reaction of 1 with hydrazines, we succeeded in the synthesis of 3- and 5-trifluoromethyl-4-
trifluoroacetylpyrazoles (3 and 3’) which are hardly obtainable by other methods.20 As for the synthesis
of fluorine-containing benzo[b][1,4]diazepines, Reddy et al. reported the reaction of 1 with benzene-1,2-
diamines under microwave irradiation to give 1H-benzo[b][1,4]diazepines (4) (Scheme 1).21,22
COCF3
COCF3
COCF3
COCF3
NuH
i-BuO
Nu
1
2
Nu = NRR', SR
R
CF3
COCF3
N
R
N
N
N
N
CF3
CF3
R
N
H
COCF3
COCF3
3'
4
3
Scheme 1
In contrast to their results, we found the reaction of β,β-bis(perhaloalkanoyl)vinyl ethers including 1 with
benzene-1,2-diamines without microwave irradiation gave novel 2,5-dihydro-3-perhaloalkanoyl-2-
perhaloalkyl-1H-benzo[b][1,4]diazepinols (5 and 7) selectively under very mild conditions. We here
report an efficient and convenient synthetic method for these dihydrobenzo[b][1,4]diazepinols which are
expected to have remarkable anti-tumor activities.

HETEROCYCLES, Vol. 76, No. 2, 2008
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Moreover, we describe in this report a facile synthesis of novel fluorine-containing N-sulfinylanilines (9),
which were obtained unexpectedly from dihydrobenzo[b][1,4]diazepinols (5) by treatment with thionyl
chloride. These N-sulfinylanilines (9) are also expected to have noticeable anti-tumor activities.
RESULTS AND DISCUSSION
We examined the reaction of β,β-bistrifluoroacetylvinyl ether (1) with various benzene-1,2-diamines
(Scheme 2 and Table 1). The reaction of 1 with slightly excess amounts of benzene-1,2-diamine in
acetonitrile readily occurred at ambient temperature to give dihydrobenzo[b][1,4]diazepinol (5a) in 85%
yield (entry 1). Under the same conditions, the reaction of 1 with 4,5-dimethylbenzene-1,2-diamine and
4,5-dichlorobenzene-1,2-diamine afforded the corresponding diazepinols 5b and 5c in high yields (entry
2 and 3). In the 13C NMR spectra of 5b, the ring carbon (C-2’) substituted by a CF3 group appeared at
86.4 ppm as a quartet signal due to C-F geminal coupling (2JCF = 28.2 Hz) and a signal of the carbonyl
carbon was observed at 178.7 ppm as quartet (2JCF = 34.3 Hz).
R1
R2
R3
NH2
NH2
R1
OH
CF3
OH
CF3
H
N
H
N
COCF3
COCF3
R2
R3
R3
R2
i-BuO
COCF3
COCF3
+
MeCN, rt, 1h
N
H
N
H
1
R1
5a-k
5d'-k'
Scheme 2
The annulation reaction of 1 with mono-substituted benzene-1,2-diamine gave a mixture of two
regioisomers of the corresponding diazepinol. Thus a mixture of two regioisomers (5d, d’) was
obtained in 69% yield when 1 was reacted with 3-methylbenzene-1,2-diamine (entry 4). Quite similarly,
the reactions of 1 with other benzene-1,2-diamines bearing various substituents on benzene ring
proceeded successfully. The reaction of 1 with 4-chlorobenzene-1,2-diamine, 4-methylbenzene-1,2-
diamine, 4-nitrobenzene-1,2-diamine, 3,4-diaminophenyl(phenyl)methanone, 3,4-diaminobenzoic acid,
methyl 3,4-diaminobenzoate and n-butyl 3,4-diaminobenzoate gave mixtures of the corresponding 7-
substituted and 8-substituted dihydrobenzo[b][1,4]diazepinols (5e-k’) in 71-89% yields (entry 5-11).
The results of our approaches on the reactions of 1 with benzene-1,2-diamines show sharp contrast with
those reported by Reddy et al.21,22 In all cases in Table 1, dihydrobenzo[b][1,4]diazepinols (5a-k’)
were obtained selectively under very mild conditions in the absence of microwave irradiation without
any formation of the corresponding 1H-benzo[b][1,4]diazepines (4).

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Table 1. Synthesis of 2,5-dihydro-3-trifluoroacetyl-2-trifluoromethyl-1H-benzo[b][1,4]-
diazepinols 5a-k’ form 1 and benzene-1,2-diamines.a
Entry
R1
R2
R3
Product
5a
Yield (%)b
1
2
H
H
H
85
H
Me
Me
Cl
H
5b
87
3
H
Cl
5c
82
69d
71d
80d
76d
78d
74d
82d
4
Me
H
H
5d, 5d’c
5e, 5e’e
5f, 5f’e
5g, 5g’c
5h, 5h’e
5i, 5i’e
5j, 5j’e
5k, 5k’e
5
Cl
H
6
H
Me
H
7
H
NO2
COPh
CO2H
CO2Me
CO2Bu-n
H
8
H
H
9
H
H
10
11
H
H
H
H
89d
a Benzene-1,2-diamines (1.1 times molar amounts) were used.
b Isolated yield.
c Ratio of regioisomers calculated by 1H NMR spectra were 3.3/1 (5d/5d’ or 5d’/5d) and 2.5/1
(5g/5g’ or 5g’/5g) respectively.
d Combined yield of two regioisomers.
e Ratio of regioisomers could not be determined.
Our method was applicable to the synthesis of fluorine-containing dihydrobenzo[b][1,4]diazepinols from
several β,β-bisperhaloalkanoylvinyl ethers (6a-d’). As shown in Scheme 3 and Table 2, we attempted
the reactions of 6a-d’ with 4,5-dimethylbenzene-1,2-diamine employing the same reaction condition for
the synthesis of diazepinols 5a-k’ from 1. The annulation reaction of β,β-bis(chlorodifluoroacetyl)vinyl
ether (6a) with 4,5-dimethylbenzene-1,2-diamine easily proceeded at room temperature to give the
corresponding diazepinol 7a in 79% yield (entry 1). In contrast to this, the reaction of β,β-
bis(pentafluoropropanoyl)vinyl ether (6b) with 4,5-dimethylbenzene-1,2-diamine afforded enamine 8
which is thought to be a precursor of 7b together with equimolar amounts of the corresponding
diazepinol 7b (entry 2). Unfortunately, the ratio of 7b and 8 almost unchanged by prolongation of
reaction time, and 7b could not be isolated from the mixture in spite of any our effort. The formation of
diazepinol 7b was confirmed by 13C NMR measurement of a mixture of 7b and 8. The ring carbon (C-
2’) binding a CF2CF3 group of 7b appeared at 87.6 ppm as a triplet signal (2JCF = 24.3 Hz). This
chemical shift of C-2’ is compatible with that (86.4 ppm) of diazepinol 5b described above.
The structures of 7c, 7d and 7d’ were also confirmed by 13C NMR spectra. In the spectra of 7c, the ring
carbon (C-2’) binding a CF3 group appeared at 85.7 ppm as a quartet signal (2JCF = 29.8 Hz), while the

HETEROCYCLES, Vol. 76, No. 2, 2008
1209
carbonyl carbon gave a triplet signal (2JCF = 23.7 Hz) at 180.7 ppm. In the spectra of 7d, the ring
carbon (C-2’) appeared at 86.7 ppm as a quartet signal (2JCF = 29.8 Hz), while the carbonyl carbon was
observed at 182.4 ppm as a singlet signal. Although 7d’ could not be isolated, in the spectra of a
mixture of 7d and 7d’, the ring carbon (C-2’) of 7d’ appeared at 100.3 ppm as a singlet signal, and the
carbonyl carbon of 7d’ gave a quartet signal (2JCF = 32.0 Hz) at 179.0 ppm.
Me
Me
NH2
NH2
COY
COZ
COZ
COY
i-BuO
i-BuO
7a-c, d/d'
MeCN, rt, 1 h
6a-d
6c', d'
Y
Z
H
N
H
N
OH
COZ
Me
NH2
OH
COY
Me
Me
Me
COCF2CF3
COCF2CF3
Me
N
H
Me
N
H
N
H
7a-d
7c',d'
8
Scheme 3
Table 2. Synthesis of 2,5-dihydro-7,8-dimethyl-1H-benzo[b][1,4]diazepinols 7a-d’
from 6a-d’ and 4,5-dimethylbenzene-1,2-diamines.a
Entry
Substrate
6a
Y
Z
Product
Yield (%)
79b
1
2
3
4
CF2Cl
CF2CF3
CF3
CF2Cl
CF2CF3
CF2CF3
CCl3
7a
7bc
6b
46d
73b
78f
6c, 6c’e
6d, 6d’e
7c
CF3
7d, 7d’
a 4,5-Dimethylbenzene-1,2-diamines (1.1 times molar amounts) were used.
b Isolated yield.
c 7b was obtained as a mixture with enamine 8 (7b/8= 1/1).
d The yield of 7b was calculated from signal intensity in 1H NMR spectra.
e A mixture of 6c and 6c’ (6c/6c’= 1/4 or 4/1) or 6d and 6d’ (6d/6d’= 1/1) was used as a
substrate.
f Combined yield of two regioisomers.
Our attempts to dehydrate dihydrobenzo[b][1,4]diazepinol (5a) to the corresponding 1H-benzo[b][1,4]-
diazepine (4: R= H) by acid catalysis resulted in failure to give a complex mixture. So, we tried
dehydration of 5a with the use of thionyl chloride.
As shown in Scheme 4 and Table 3, the reaction of 5a with equimolar amounts of thionyl chloride in
acetonitrile completed within 5 min at ambient temperature to afford unexpected N-sulfinylaniline 9a in

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HETEROCYCLES, Vol. 76, No. 2, 2008
86% yield (entry 1), and neither expected 1H-benzo[b][1,4]diazepine (4: R= H) nor its precursor, 2-
chloro-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepine, was obtained. Similarly 7,8-
dimethyl- and 7,8-dichlorodihydrobenzo[b][1,4]diazepinols (5b, c) treated with thionyl choloride to give
the corresponding N-sulfinylanilines (9b, c) in high yields (entry 2 and 3). In the cases of the reactions
using a mixture of 7- and 8-nitrodihydrobenzo[b][1,4]diazepinol (5g, g’) and a mixture of 7- and 8-
benzoyldihydrobenzo[b][1,4]diazepinol (5h, h’), prolonged reaction time and, in the latter case, use of 2
times molar amounts of thionyl chloride were necessary to obtain the corresponding N-sulfinylanilines
(9g, g’ and 9h, h’) in high yields (entry 4 and 5).
NSO
COCF3
COCF3
NSO
COCF3
COCF3
H
H
N
N
SOCl2
5a-c, g/g', h/h'
MeCN, rt
R2
R3
R3
R2
9a-c, g, h
9g', h'
Scheme 4
Table 3. Synthesis of N-sulfinylanilines 9a-c, g/g’ and h/h’ from 5a-c, g/g’ and h/h’.
SOCl2
Time
(min)
5
Entry Substrate
R2
R3
Product Yield (%)a
(mol equiv)
1
2
3
4
5
5a
5b
H
Me
H
Me
Cl
H
1
1
1
1
2
9a
86
100
79
5
9b
5c
Cl
5
9c
5g, 5g’b
5h, 5h’b,c
NO2
COPh
30
9g, 9g’c
9h, 9h’c
98d
94d
H
30
a Isolated yield.
b A mixture of 5g and 5g’ (5g/5g’= 1/2.5 or 2.5/1) or 5h and 5h’ was used as a substrate.
c Ratio of regioisomers could not be determined.
d Combined yield of two regioisomers.
In conclusion, we present here an efficient and convenient synthetic method accessing novel fluorine-
containing dihydrobenzo[b][1,4]diazepinols which are not easily obtainable by other methods.
Moreover, we can provide a facile and convenient method to synthesize novel N-sulfinylanilines via
fluorine-containing dihydrobenzo[b][1,4]diazepinols.
In addition, we have found that dihydrobenzo[b][1,4]diazepinol (5b) and N-sulfinylaniline (9b) exert fine
anti-tumor potency on carcinomas of lung, colon and ovary.23 On the basis of our results, further

HETEROCYCLES, Vol. 76, No. 2, 2008
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biological evaluation of these novel dihydrobenzo[b][1,4]diazepinols (5 and 7) and N-sulfinylanilines (9)
is now under way to fulfill our expectations for discovery of a new pharmacophore with antineoplastic
efficacy.
EXPERIMENTAL
Mps were determined on an electrothermal digital melting point apparatus and are uncorrected. The 13C
NMR spectra were recorded on a VARIAN Unity INOVA 400 spectrometer using TMS as an internal
standard. 1H NMR spectra were obtained with a JEOL PMX 60SI spectrometer. IR spectra were taken
with a PerkinElmer Spectrum ONE FT-IR spectrometer. Microanalyses were taken with a YANACO
CHN-Corder MT-5 analyzer.
General procedure for the synthesis of 2,5-dihydro-3-trifluoroacetyl-2-trifluoromethyl-1H-
benzo[b][1,4]diazepinols (5a-k’) from 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)pentane-2,4-
dione (1).
To a solution of 119 (293 mg, 1.0 mmol) dissolved in MeCN (4 mL) was added benzene-1,2-diamines (1.1
mmol) and the mixture was stirred for 1 h at ambient temperature. After evaporation of the solvent,
purification of a residue by silica gel column chromatography using n-hexane-EtOAc (10:1) afforded 5a-
k’. In the cases of 5d, 5d’, and 5f-k’, small amount of single isomer could be isolated, while the other
isomer could not be separated from the mixture of two isomers by silica gel column chromatography.
Neither 5e nor 5e’ could be isolated from the mixture of two isomers by silica gel column
chromatography.
2,2,2-Trifluoro-1-(2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-yl)-
1
ethanone (5a): mp 86-87 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN) δ 9.60-9.05 (br, 1H, NH),
8.55 (br s, 1H, OH), 7.92 (d, J = 10.0 Hz, 1H, H-4’), 7.37-7.02 (m, 4H, Harom), 4.98 (br s, 1H, NH); IR
(KBr): 1551 (C=O) cm-1. Anal. Calcd for C12H8F6N2O2: C, 44.18; H, 2.47; N, 8.59. Found: C, 44.08;
H, 2.63; N, 8.60.
2,2,2-Trifluoro-1-(2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-
3-yl)ethanone (5b): mp 126-127 °C (n-hexane-EtOAc); 13C NMR (CD3COCD3) δ 18.8, 19.3 (CH3), 86.4
(2JCF = 28.2 Hz, C-2’), 102.9 (C-3’), 118.7 (1JCF = 290.7 Hz, COCF3), 125.8 (1JCF = 294.5 Hz, 2’-CF3),
1
122.6, 123.3, 127.0, 131.3, 132.9, 136.7 (Carom), 149.1 (C-4’), 178.7 (2JCF = 34.3 Hz, COCF3); H NMR
(CDCl3-CD3CN) δ 9.32-8.73 (br, 1H, NH), 8.55 (br s, 1H, OH), 7.82 (d, J = 10.0 Hz, 1H, H-4’), 6.78 (s,
2H, Harom), 4.65-4.37 (br, 1H, NH), 2.22 (s, 6H, CH3); IR (KBr): 1583 (C=O) cm-1. Anal. Calcd for
C14H12F6N2O2: C, 47.47; H, 3.41; N, 7.91. Found: C, 47.24; H, 3.14; N, 7.90.
1-(7,8-Dichloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-
1
trifluoroethanone (5c): mp 163-164 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN) δ 9.65-9.05 (br,

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HETEROCYCLES, Vol. 76, No. 2, 2008
1H, NH), 8.35 (br s, 1H, OH), 7.83 (d, J = 9.0 Hz, 1H, H-4’), 7.22 (s, 2H, Harom), 5.18 (br s, 1H, NH); IR
(KBr): 1544 (C=O) cm-1. Anal. Calcd for C12H6Cl2F6N2O2: C, 36.48; H, 1.53; N, 7.09. Found: C,
36.18; H, 1.79; N, 7.13.
2,2,2-Trifluoro-1-(2-hydroxy-6-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-
yl)ethanone (5d) or 2,2,2-trifluoro-1-(2-hydroxy-9-methyl-2-trifluoromethyl-2,5-dihydro-1H-
1
benzo[b][1,4]diazepin-3-yl)ethanone (5d’): mp 131-132 °C (n-hexane-EtOAc); H NMR (CDCl3-
CD3CN) δ 9.48-8.82 (br, 1H, NH), 8.57 (br s, 1H, OH), 7.85 (d, J = 10.0 Hz, 1H, H-4’), 7.28-6.80 (m, 3H,
Harom), 4.52 (br s, 1H, NH), 2.33 (s, 3H, CH3); IR (KBr): 1610 (C=O) cm-1. Anal. Calcd for
C13H10F6N2O2: C, 45.89; H, 2.96; N, 8.23. Found: C, 45.62; H, 3.00; N, 8.23.
A mixture of 1-(7-chloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-yl)-
2,2,2-trifluoroethanone (5e) and 1-(8-chloro-2-hydroxy-2-trifluormethyl-2,5-dihydro-1H-benzo-
1
[b][1,4]diazepin-3-yl)-2,2,2-trifluoroethanone (5e’): H NMR (CDCl3-CD3CN) δ 9.40-8.90 (br, 1H,
OH), 8.63-8.28 (br, 1H, NH), 7.85 (d, J = 9.0 Hz, 1H, H-4’), 7.37-6.87 (m, 3H, Harom), 4.87, 4.20 (br s,
1H, NH of two regioisomers); IR (KBr): 1555 (C=O) cm-1. Anal. Calcd for C12H7ClF6N2O2: C, 39.96;
H, 1.96; N, 7.77. Found: C, 39.93; H, 2.02; N, 7.75.
2,2,2-Trifluoro-1-(2-hydroxy-7-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-
yl)ethanone (5f) or 2,2,2-trifluoro-1-(2-hydroxy-8-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo-
1
[b][1,4]diazepin-3-yl)ethanone (5f’): mp 102-103 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN) δ
9.52-8.53 (br, 1H, NH), 8.53-7.90 (br, 1H, OH), 7.63 (br s, 1H, H-4’), 6.90-6.58 (m, 3H, Harom), 4.97 (br s,
1H, NH), 2.25 (s, 3H, CH3); IR (KBr): 1559 (C=O) cm-1. Anal. Calcd for C13H10F6N2O2: C, 45.89; H,
2.96; N, 8.23. Found: C, 45.98; H, 3.07; N, 8.03.
2,2,2-Trifluoro-1-(2-hydroxy-7-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-yl)-
ethanone (5g) or 2,2,2-trifluoro-1-(2-hydroxy-8-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo-
1
[b][1,4]diazepin-3-yl)ethanone (5g’): mp 139-140 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN) δ
8.60-7.82 (m, 5H, NH, OH, H-4’, Harom), 7.25 (d, J = 10.0 Hz, 1H, Harom), 5.98 (br s, 1H, NH); IR (KBr):
1623 (C=O) cm-1. Anal. Calcd for C12H7F6N3O4: C, 38.83; H, 1.90; N, 11.32. Found: C, 38.89; H,
2.10; N, 11.06.
1-(7-Benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-tri-
fluoroethanone (5h) or 1-(8-benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-3-yl)-2,2,2-trifluoroethanone (5h’): mp 166-167 °C (n-hexane-EtOAc); H NMR (CDCl3-
CD3CN) δ = 8.75-8.20 (br, 1H, NH), 8.00-7.50 (m, 9H, OH, H-4’, C6H5CO), 7.22 (d, J = 9.0 Hz, 1H,
Harom), 5.80 (br s, 1H, NH); IR (KBr): 1568 (C=O) cm-1. Anal. Calcd for C19H12F6N2O3: C, 53.03; H,
2.81; N, 6.51. Found: C, 52.91; H, 2.91; N, 6.53.
2-Hydroxy-3-trifluoroacetyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepine-7-carboxylic

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acid (5i) or 2-hydroxy-3-trifluoroacetyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepine-8-
carboxylic acid (5i’): mp 177-178 °C (n-hexane- EtOAc); 1H NMR (CDCl3-CD3CN) δ 11.43-10.73 (br,
1H, NH), 8.61 (s, 1H, H-4’), 8.08-7.75 (m, 3H, Harom, OH), 7.33 (d, J = 8.0 Hz, 1H, Harom), 6.45 (br s, 1H,
NH); IR (KBr): 1686 (C=O), 1611 (C=O) cm-1. Anal. Calcd for C13H8F6N2O4: C, 42.18; H, 2.18; N,
7.57. Found: C, 42.55; H, 2.26; N, 7.18.
2-Hydroxy-3-trifluoroacetyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepine-7-carboxylic
acid methyl ester (5j) or 2-hydroxy-3-trifluoroactyl-2-trifluoromethyl-2,5-dihydro-1H-
1
benzo[b][1,4]diazepine-8-carboxylic acid methyl ester (5j’): mp 160-161 °C (n-hexane-EtOAc); H
NMR (CDCl3-CD3CN) δ 9.67-9.15 (br, 1H, NH), 8.45 (s, 1H, OH), 8.09-7.79 (m, 3H, 4-H’, Harom), 7.22
(d, J = 8.8 Hz, 1H, Harom), 5.70 (br s, 1H, NH), 3.93 (s, 3H, CH3); IR (KBr): 1698 (C=O), 1627 (C=O)
cm-1. Anal. Calcd for C14H10F6N2O4: C, 43.76; H, 2.62; N, 7.29. Found: C, 44.08; H, 2.74; N, 6.85.
2-Hydroxy-3-trifluoroacetyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]diazepine-7-carboxylic
acid butyl ester (5k) or 2-hydroxy-3-trifluoroactyl-2-trifluoromethyl-2,5-dihydro-1H-
1
benzo[b][1,4]diazepine-8-carboxylic acid butyl ester (5k’): mp 158-159 °C (n-hexane-EtOAc); H
NMR (CDCl3-CD3CN) δ 9.93-9.13 (br, 1H, NH), 8.47 (s, 1H, OH), 8.13-7.81 (m, 3H, H-4’, Harom), 7.24
(d, J = 10.0 Hz, 1H, Harom), 5.70 (br s, 1H, NH), 4.37 (t, 2H, CH2(CH2)2CH3), 1.83-0.80 (m, 7H,
CH2(CH2)2CH3)); IR (KBr): 1687(C=O), 1630 (C=O) cm-1. Anal. Calcd for C17H16F6N2O4: C, 47.90; H,
3.78; N, 6.57. Found: C, 47.92; H, 3.71; N, 6.66.
General procedure for the synthesis of bisperhaloalkanoylated 2-methyl-1-(vinyloxy)propane (6).
Method A (for 6a, b).
To an ice-cooled mixture of 2-methyl-1-(vinyloxy)propane (1.00 g, 10 mmol) and pyridine (2.37 g, 30
mmol) was added dropwise a solution of perhaloalkanoic anhydride (30 mmol) in dry CHCl3 (1 mL) with
continuous stirring. After stirring for 18 h at 50 °C, the crude mixture being poured into ice-cooled n-
hexane (50 mL) resulted in the rapid precipitation of pyridinium salts. After filtration, the solution is
dried over Na2SO4 and concentrated in vacuo to give 6a (2.31 g, 71 %) or 6b (3.18 g, 80 %).
1,5-Dichloro-1,1,5,5-tetrafluoro-3-(isobutoxymethylene)pentane-2,4-dione (6a): bp 110 °C / 3 mmHg;
1H NMR (CDCl3) δ 8.10 (s, 1H, CH=C), 4.20 (d, J = 7.0 Hz, 2H, CH2), 2.47-1.78 (m, 1H, CH), 1.01 (d, J
= 7.0 Hz, 6H, CH3). Anal. Calcd for C10H10Cl2F4O3: C, 36.95; H, 3.10. Found: C, 37.19; H, 2.79.
1,1,1,2,2,6,6,7,7,7-Decafluoro-4-(isobutoxymethylene)heptane-3,5-dione (6b): bp 150 °C / 5 mmHg;
1H NMR (CDCl3) δ 8.09 (s, 1H, CH=C), 4.19 (d, J = 6.4 Hz, 2H, CH2), 2.43-1.76 (m, 1H, CH), 1.02 (d, J
= 7.6 Hz, 6H, CH3); IR (film): 1751 (C=O), 1682 (C=O) cm-1. Anal. Calcd for C12H10F10O3: C, 36.75;
H, 2.57. Found: C, 36.36; H, 2.41.
Method B (for 6c-d’)
To an ice-cooled mixture of (E)-1,1,1-trihalo-4-isobutoxybut-3-en-2-one (2 mmol) and pyridine (474 mg,

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6 mmol) was added dropwise a solution of perhaloalkanoic anhydride (6 mmol) in dry CHCl3 (0.5 mL)
with continuous stirring. After stirring for 18 h at 50 °C, the mixture was dissolved in CH2Cl2 (10 mL).
The whole mixture was washed with water (10 mL) and dried over Na2SO4. Removal of the solvent
under vacuum afforded a mixture of 6c and 6c’ (512 mg, 71 %), or that of 6d and 6d’ (458 mg, 67 %).
A mixture of (E)- and (Z)-1,1,1,5,5,6,6,6-octafluoro-3-(isobutoxymethylene)hexane-2,4-dione (6c,
c’): 1H NMR (CDCl3) δ 8.04, 8.00 (s, 1H, CH=C), 4.18 (d, J = 6.4 Hz, 2H, CH2), 2.43-1.75 (m, 1H, CH),
0.98 (d, J = 7.2 Hz, 6H, CH3); IR (film): 1750 (C=O), 1697 (C=O) cm-1. Anal. Calcd for C11H10F8O3: C,
38.61; H, 2.95. Found: C, 38.42; H, 2.91.
A mixture of (E)- and (Z)-1,1,1-trichloro-5,5,5-trifluoro-3-(isobutoxymethylene)pentane-2,4-dione
(6d, d’): 1H NMR (CDCl3) δ 8.09, 7.97 (s, 1H, CH=C), 4.25 (d, J = 6.4 Hz, 2H, CH2), 2.45-1.78 (m, 1H,
CH), 1.02 (d, J = 7.6 Hz, 6H, CH3); IR (film): 1753 (C=O), 1692 (C=O) cm-1. Anal. Calcd for
C10H10Cl3F3O3: C, 35.17; H, 2.95. Found: C, 34.99; H, 2.91.
General procedure for the synthesis of 2,5-dihydro-3-perhaloalkanoyl-2-perhaloalkyl-1H-
benzo[b][1,4]diazepines (7a-d’) from perhalo-(isobutoxymethylene)alkanediones (6).
To a solution of 6 (1.0 mmol) dissolved in MeCN (4 mL) was added 4,5-dimethylbenzene-1,2-diamine
(143 mg, 1.1 mmol) and the mixture was stirred for 1 h at ambient temperature. After evaporation of the
solvent, purification of a residue by silica gel column chromatography using n-hexane-EtOAc (10:1)
afforded 7a-d’. In the case of 7b, pure 7b could not be obtained by silica gel chromatography because
of a contamination of small amounts of 8. In the case of a mixture of 7d, and 7d’, small amount of
single isomer 7d could be isolated, while the other isomer 7d’ could not be separated from the mixture of
two isomers by silica gel column chromatography.
2-Chloro-1-[2-(chlorodifluoromethyl)-2-hydroxy-7,8-dimethyl-2,5-dihydro-1H-benzo[b][1,4]di-
1
azepin-3-yl]-2,2-difluoroethanone (7a): mp 123-124 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN)
δ 9.38-8.88 (br, 1H, NH), 8.78 (br s, 1H, OH), 7.98 (d, J = 10.0 Hz, 1H, H-4’), 6.82 (s, 2H, Harom), 4.95
(br s, 1H, NH), 2.18 (s, 6H, CH3); IR (KBr): 1563 (C=O) cm-1. Anal. Calcd for C14H12Cl2F4N2O2: C,
43.43; H, 3.12; N, 7.24. Found: C, 43.59; H, 2.76; N, 7.44.
2,2,3,3,3-Pentafluoro-1-(2-hydroxy-7,8-dimethyl-2-pentafluoroethyl-2,5-dihydro-1H-benzo-
1
[b][1,4]diazepin-3-yl)propanone (7b): H NMR (CD3CN) δ 9.45-8.98 (br, 1H, NH), 8.83 (s, 1H, OH),
7.93 (d, 1H, J = 10.0 Hz, H-4’), 6.82 (s, 2H, Harom), 5.09 (br s, 1H, NH), 2.23 (s, 6H, CH3).
2,2,3,3,3-Pentafluoro-1-(2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]-
diazepin-3-yl)propanone (7c): mp 134-135 °C (n-hexane-EtOAc); 13C NMR (CD3CN) δ 18.8, 19.4
(CH3), 86.7 (2JCF = 29.8 Hz, C-2’), 104.3 (C-3’), 110.6-130.0 (m, CF2CF3), 125.7 (1JCF = 293.7 Hz, 2’-
CF3), 122.7, 123.1, 126.8, 132.0, 132.4, 137.4 (Carom), 149.0 (C-4’), 180.7 (2JCF = 23.8 Hz, COCF2CF3);
1H NMR (CDCl3-CD3CN) δ 9.49-9.03 (br, 1H, NH), 8.46 (s, 1H, OH), 7.91 (d, J = 10.0 Hz, 1H, H-4’),

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6.89 (s, 2H, Harom), 5.00 (br s, 1H, NH), 2.20 (s, 6H, CH3); IR (KBr): 1568 (C=O) cm-1. Anal. Calcd for
C15H12F8N2O2: C, 44.57; H, 2.99; N, 6.93. Found: C, 44.55; H, 3.03; N, 6.92.
2,2,2-Trichloro-1-(2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo[b][1,4]di-
1
azepin-3-yl)ethanone (7d): mp 146-147 °C (n-hexane-EtOAc); H NMR (CDCl3-CD3CN) δ 9.60-9.10
(br, 1H, NH), 8.57 (d, J = 10.0 Hz, 1H, H-4’), 8.34 (br s, 1H, OH), 7.87 (s, 2H, Harom), 5.01 (br s, 1H,
NH), 2.20 (s, 6H, CH3); IR (KBr): 1567 (C=O) cm-1. Anal. Calcd for C14H12Cl3F3N2O2: C, 41.66; H,
3.00; N, 6.94. Found: C, 41.66; H, 3.27; N, 6.66.
4-[(2-Amino-4,5-dimethylphenylamino)methylene]-1,1,1,2,2,6,6,7,7,7-decafluoroheptane-3,5-dione
(8): mp 178-179 °C (aqueous MeCN); 1H NMR (CDCl3-CD3CN) δ 11.67-10.90 (br, 1H, NH), 8.39 (br s,
1H, CH=C), 6.99 (s, 1H, Harom), 6.74 (s, 1H, Harom), 4.92-4.49 (br, 2H, NH2), 2.20 (s, 6H, CH3); IR (KBr):
1648 (C=O) cm-1. Anal. Calcd for C16H12F10N2O2: C, 42.30; H, 2.66; N, 6.17. Found: C, 42.30; H,
2.78; N, 5.69.
General procedure for the synthesis of N-sulfinylanilines 9 from diazepinols 5.
To a solution of 5 (1 mmol) was added dropwise a solution of thionyl chloride (119 mg, 1 mmol) in
CH3CN (4 mL) with continuous stirring (in the case of a mixture of 5h and 5h’, 2 mmol of thionyl
chloride was used). After stirring for 5 – 30 min at ambient temperature, removal of the solvent under
vacuum afforded 9a-c, 9g, g’ and 9h, h’.
1,1,1,5,5,5-Hexafluoro-3-[[2-(N-sulfinylamino)phenylamino]methylene]pentane-2,4-dione (9a): mp
107-108 °C (n-hexane-CH2Cl2); 1H NMR (CD3COCD3) δ 12.77 (br s, 1H, NH), 7.75-7.42 (m, 4H, Harom
,
CH=C), 7.04-7.03 (m, 1H, H-6); IR (KBr): 1663 (C=O), 1608 (C=O) cm-1. Anal. Calcd for
C12H6F6N2O3S: C, 38.74; H, 1.62; N, 7.53. Found: C, 38.66; H, 1.58; N, 7.72.
1,1,1,5,5,5-Hexafluoro-3-[[4,5-dimethyl-2-(N-sulfinylamino)phenylamino]methylene]pentane-2,4-
dione (9b): mp 133-134 °C (n-hexane-CH2Cl2); 13C NMR (CD3COCD3) δ 19.7, 20.4 (CH3), 103.8
(C(COCF3)2), 117.2 (1JCF = 287.6 Hz, CF3), 117.6 (1JCF = 292.2 Hz, CF3), 118.2, 129.6, 130.6, 132.6,
1
138.0, 143.4 (Carom), 177.0 (2JCF = 34.3 Hz, COCF3), 180.8 (2JCF = 38.1 Hz, COCF3); H NMR
(CD3COCD3) δ 13.33-12.50 (br, 1H, NH), 8.80 (d, 1H, J = 14.0 Hz, CH=C), 8.44 (s, 1H, Harom), 7.73 (s,
1H, Harom), 2.41, 2.33 (s, 6H, CH3); IR (KBr): 1648 (C=O), 1619 (C=O) cm-1. Anal. Calcd for
C14H10F6N2O3S: C, 42.01; H, 2.52; N, 7.00. Found: C, 42.02; H, 2.67; N, 6.80.
1,1,1,5,5,5-Hexafluoro-3-[[4,5-dichloro-2-(N-sulfinylamino)phenylamino]methylene]pentane-2,4-
1
dione (9c): mp 116-118 °C (n-hexane-CH2Cl2); H NMR (CD3COCD3) δ 12.60 (br s, 1H, NH), 8.53 (d,
1H, J = 14.0 Hz, CH=C), 8.43 (s, 1H, Harom), 7.80 (s, 1H, Harom); IR (KBr): 1658 (C=O), 1611 (C=O)
cm-1. Anal. Calcd for C12H4Cl2F6N2O3S: C, 32.67; H, 0.91; N, 6.35. Found: C, 32.52; H, 1.21; N, 6.20.
A
mixture of 1,1,1,5,5,5-hexafluoro-3-[[4-nitro-2-(N-sulfinylamino)phenylamino]methylene]-
pentane-2,4-dione (9g) and 1,1,1,5,5,5-hexafluoro-3-[[5-nitro-2-(N-sulfinylamino)phenylamino]-

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1
methylene]pentane-2,4-dione (9g’): H NMR (CD3COCD3) δ 12.72-12.13 (br, 1H, NH), 8.66-7.47 (m,
4H, Harom, CH=C); IR (KBr): 1706 (C=O), 1657 (C=O), 1603 (C=O), 1585 (C=O) cm-1. Anal. Calcd for
C12H5F6N3O5S: C, 34.54; H, 1.21; N, 10.07. Found: C, 34.32; H, 1.40; N, 10.08.
A mixture of 1,1,1,5,5,5-hexafluoro-3-[[4-benzoyl-2-(N-sulfinylamino)phenylamino]methylene]-pen-
tane-2,4-dione (9h) and 1,1,1,5,5,5-hexafluoro-3-[[5-benzoyl-2-(N-sulfinylamino)phenylamino]-
1
methylene]pentane-2,4-dione (9h’): H NMR (CD3COCD3) δ 13.28-12.11 (br, 1H, NH), 8.92-8.47 (m,
1H, Harom), 8.47-8.25 (m, 1H, Harom), 7.71-7.23 (m, 7H, Harom, CH=C); IR (KBr): 1711 (C=O), 1655
(C=O), 1608 (C=O), 1589 (C=O) cm-1. Anal. Calcd for C19H10F6N2O4S: C, 47.91; H, 2.12; N, 5.88.
Found: C, 48.16; H, 2.18; N, 5.57.
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