Synthesis of trifluoromethylated 1,5-benzoheteroazepines

Article abstract of DOI:10.1016/j.jfluchem.2013.06.016

Because of the great interest of benzoheteroazepines and trifluoromethylated compounds in medicinal chemistry, a simple strategy to synthesize trifluoromethylated 1,5-benzoheteroazepines have been described. Starting from β-trifluoromethylated enones and 1,2-diamines or 1,2-thioamines, various benzodiazepines and benzothiazepines bearing a CF ₃ group have been obtained in good yields.

Full text of DOI:10.1016/j.jfluchem.2013.06.016

Journal of Fluorine Chemistry 155 (2013) 118–123
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of trifluoromethylated 1,5-benzoheteroazepines
Carole Christophe a, Bernard R. Langlois a, Thierry Billard a,b,
*
a Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS 5246), Universite´ de Lyon, Universite´ Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Lyon,
France
b CERMEP – In vivo imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69003 Lyon, France
A R T I C L E I N F O
A B S T R A C T
Article history:
Because of the great interest of benzoheteroazepines and trifluoromethylated compounds in medicinal
chemistry, a simple strategy to synthesize trifluoromethylated 1,5-benzoheteroazepines have been
Received 29 March 2013
Received in revised form 24 June 2013
Accepted 25 June 2013
described. Starting from
b-trifluoromethylated enones and 1,2-diamines or 1,2-thioamines, various
benzodiazepines and benzothiazepines bearing a CF3 group have been obtained in good yields.
Available online 12 July 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Benzodiazepines
Benzothiazepines
b
-Trifluoromethylated enones
Trifluoromethyl
1. Introduction
In this context, because of the pharmacological importance of
benzodiazepines and benzothiazepines classes of compounds, it
Benzodiazepines have received much attention as an important
class of N-heterocyclic compounds exhibiting a broad spectrum of
biological and pharmacological activities, such as anti-inflamma-
tory, anticonvulsant, antianxiety, sedative, antidepressive and
hypnotic activities [1–4]. 1,5-Benzodiazepines exert a biological
activity similar to well known 1,4-derivatives and their ring system
has demonstrated considerable utility not only in central nervous
system (CNS) drug design, as illustrated by the atypical antipsy-
chotic Clozapine [5], but also as peptidomimetic scaffolds [6–19]
and key intermediates for the preparation of other fused ring
compounds [20–26].
Sulfur derivatives, namely 1,5-benzothiazepines, possess also
interesting properties as illustrated by Diltiazem, a calcium-
channel blocker used as antiarrhythmic [27].
It is now well admitted that the introduction of fluorinated
moieties onto organic molecules brings important physico-
chemical modifications which, often, allow pertinent modulations
of pharmacokinetic properties of molecules. In particular, the
increased lipophilicity of trifluoromethylated compounds could
favor the transmembrane permeation allowing a better biodispon-
ibility of trifluoromethylated drugs [28–33].
could be interesting to synthesize trifluoromethylated derivatives
of such families of molecules.
2. Results and discussion
The commonly employed methods to construct the ring
skeletons involve the cyclocondensation of 1,2-diamines with
ketones [34–43], enones [35,44–46],
b-haloketones [6–19],
alkynes [47] and require the use of various catalysts.
A few years ago, we described simple methods to obtain
b-
trifluoromethylated enones [48,49] which constitute an interest-
ing class of fluorinated building-blocks as starting materials for the
synthesis of various fluorinated molecules [49–54]. In view of the
previous methods described in literature such fluorinated enones
appeared as valuable substrates to easily synthesize various 1,5-
benzoheteroazepines.
Supposing that b-trifluoromethylated enones are more reactive
than their hydrogenated analogs, because of the CF3 group
presence, the reaction between the o-phenylenediamine (1a)
and the enone 2a has been tested without catalyst. However, in
this case no formation of the expected compound (3aa) has been
observed. In basic conditions, the 1,4-addition of 1a is favored but
the cyclization by imine formation is unfavorable. In acidic
conditions, the protonation of 1a decreases its reactivity, in
particular for the conjugated addition.
* Corresponding author at: Institute of Chemistry and Biochemistry (ICBMS –
UMR CNRS 5246), Universite´ de Lyon, Universite´ Lyon 1, CNRS, 43 Bd du 11
novembre 1918, 69622 Lyon, France. Tel.: +33 472448129.
The two steps required for the formation of the diazepine ring
are equilibriums between Michael/retro-Michael reaction and
ketone/imine formation. Consequently, if 2a is electrophilic
E-mail address: thierry.billard@univ-lyon1.fr (T. Billard).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.06.016

C. Christophe et al. / Journal of Fluorine Chemistry 155 (2013) 118–123
119
H
N
CF3
O
NH2
NH2
MS 4Å
+
F3C
Ph
CH2Cl2
r.t.
N
Ph
1a
2a
3aa
crude yield: quant.
(determined by 19F NMR titration)
Scheme 1. Condensation of o-phenylenediamine with 2a.
H
N
CF3
H
N
CF3
N
N
H
N
CF3
3ab
85% (quant.)
3aa
86% (quant.)
N
H
N
CF3
H
N
CF3
3ae
76% (quant.)a
N
N
O
O
3ac
50% (99%)
3ad
63% (quant.)
Fig. 1. Various 1,5-benzodiazepines from 1a. (Isolated yields after recrystallization. In parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal
standard. a110 8C in toluene instead of r.t. in CH2Cl2.)
enough to react with 1a, these equilibriums should be simply
displaced by favoring the formation of imine. In this logic, the o-
These conditions have been extended to other b-trifluoro-
methylated enones (Fig. 1). After filtration and evaporation, the
isolated 1,5-benzodiazepines 3 were obtained with a satisfactory
purity. However, they can be further purified by recrystallization,
because of their low solubility. All the expected 1,5-benzodiaze-
pines 3 were obtained with excellent yields. The purified yields are
phenylenediamine 1a and the
b-trifluoromethylated enone were
mixed in presence of molecular sieves in dichloromethane. With
these conditions, the expected 1,5-benzodiazepine 3aa was
quantitatively formed at room temperature in 24 h (Scheme 1).
H
N
CF3
H
N
CF3
N
N
N
N
3bb
47% (50%)
3ba
30% (90%)
H
H
N
CF3
CF3
H
N
CF3
N
N
N
N
O
3cc
42%a (69%)
de = 30%
3cb
70%a (98%)
de = 30%
3ca
89%a (99%)
de = 30%
Fig. 2. Various 1,5-benzodiazepines. (Isolated yields. In parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal standard.) apurified by flash
chromatography.

120
C. Christophe et al. / Journal of Fluorine Chemistry 155 (2013) 118–123
CF3
CF3
S
S
N
N
CF3
5ab
63% (quant.)
S
N
5aa
40% (quant.)
CF3
CF3
5ae
59% (99%)a
S
N
S
N
O
O
5ac
46% (99%)
5ad
75% (quant.)
Fig. 3. Various 1,5-benzothiazepines from 4a. (Isolated yields after recrystallization. In parentheses, crude yields determined by 19F NMR titration with PhOCF3 as internal
standard. a110 8C in toluene instead of r.t. in CH2Cl2.)
sometimes lower than crude yields because of not optimized
recrystallization conditions. In the case of the more hindered
trifluoromethylated enone arising from tetralone (2e), heating at
110 8C in toluene was required to perform the reaction.
To extend the panel of the obtained 1,5-benzodiazepines, the
diamines have been also diversified (Fig. 2).
72 h at room temperature or 110 8C. After filtration and solvent
evaporation, the crude product was purified by recrystallization in
CH2Cl2/pentane.
b
-
4.1. 4-Phenyl-2-(trifluoromethyl)-2,3-dihydro-1H-1,5-
benzodiazepine (3aa)
Because of the lower nucleophilicity of the pyridine-2,3-
diamine (1b) and the steric hindrance of the trans-cyclohexane-
1,2-diamine (1c), the reaction mixtures were heated at 110 8C in
toluene to perform the reaction. The expected 1,5-benzodiazepines
3 were then obtained with satisfactory to excellent yields. In the
case of the pyridine-2,3-diamine, a good regioselectivity was
observed. The strategy could be also applied to non aromatic
diamines, as illustrated by obtained products 3c by starting from
the trans-cyclohexane-1,2-diamine. In this case a poor diastereos-
electivity is observed.
Because of the interest of 1,5-benzothiazepines, the previous
method has been also extended to o-aminothiophenol (4a) (Fig. 3).
Similar results than with diamines were obtained with also
excellent yields. The formation of product 5ae required, as
previously, a heating to 110 8C to be formed. It should be noticed
that because of the lower nucleophilicity of o-aminothiophenol,
the reaction required 72 h, instead of 24 h for diamines, to give
similar results.
Yellow solid. Mp 83–85 8C.
1H NMR (300 MHz, CDCl3):
d 8.03 (m, 2H), 7.48–7.55 (massif,
3
4
3H), 7.32 (dd, 1H, JHH = 7.3 Hz, JHH = 1.8 Hz), 7.16 (ddd, 1H,
3JHH = 3JHH = 7.3 Hz,
4JHH = 1.7 Hz),
7.10
(ddd,
3
1H,
4
3JHH = 3JHH = 7.3 Hz, JHH = 1.8 Hz), 6.92 (dd, 1H, JHH = 7.3 Hz,
4JHH = 1.7 Hz), 4.50 (ddq, 1H, JHH = 10.6 Hz, JHH = 4.1 Hz,
3
3
3JHF = 7.0 Hz), 3.72 (bs, 1H), 3.22 (dd, 1H, JHH = 4.1 Hz,
3
2JHH = 13.5 Hz), 2.97 (dd, 1H, JHH = 10.6 Hz, JHH = 13.5 Hz).
2
2
13C NMR (75 MHz, CDCl3):
129.2, 128.3, 127.4, 127.1, 125.2 (q, JCF = 285.1 Hz, CF3), 123.8,
d 166.1, 141.4, 138.6, 135.8, 131.3,
1
2
3
122.5, 67.7 (q, JCF = 28.4 Hz), 27.4 (q, JCF = 1.6 Hz).
19F NMR (282 MHz, CDCl3):
d – 78.42 (d, JFH = 7.0 Hz).
3
Anal. calcd for C16H13F3N2: C 66.20; H 4.51; N 9.65; found: C
66.39; H 4.47; N 9.57.
4.2. 4-(2-Naphthyl)-2-(trifluoromethyl)-2,3-dihydro-1H-1,5-
benzodiazepine (3ab)
Yellow solid. Mp 90–101 8C.
3. Conclusion
1H NMR (300 MHz, CDCl3):
d 8.35 (bs, 1H), 8.32 (dd, 1H,
4
3JHH = 8.6 Hz, JHH = 1.8 Hz), 7.88–8.02 (massif, 3H), 7.52–7.63
In conclusion, trifluoromethylated 1,5-benzoheteroazepines
can be easily synthesized starting from
enones, following a simple process requiring only a filtration/
evaporation/recrystallization sequence for purification. Such
strategy should facilitate high throughput development of libraries
of such benzoheteroazepines for further screenings. These results
3
4
(massif, 2H), 7.38 (dd, 1H, JHH = 7.5 Hz, JHH = 1.7 Hz), 7.17 (ddd,
b-trifluoromethylated
3
3
4
1H, JHH = 7.5 Hz, JHH = 7.3 Hz, JHH = 1.6 Hz), 7.12 (ddd, 1H,
3JHH = 7.3 Hz, 3JHH = 7.5 Hz, 4JHH = 1.7 Hz), 6.95 (dd, 1H,
3JHH = 7.5 Hz, 4JHH = 1.6 Hz), 4.57 (ddq, 1H, 3JHH = 10.7 Hz,
3
3JHH = 4.2 Hz, JHF = 6.7 Hz), 3.75 (bs, 1H), 3.38 (dd, 1H,
3JHH = 13.5 Hz, 3JHH = 4.2 Hz), 3.07 (dd, 1H, 3JHH = 13.5 Hz,
3JHH = 10.7 Hz).
confirm also the high synthetic potential of b-trifluoromethylated
enones to access to more elaborated fluorinated molecules.
13C NMR (75 MHz, CDCl3):
d 168.9, 141.5, 136.0, 135.9, 135.0,
133.5, 129.5, 129.0, 128.5, 128.2, 128.0, 127.7, 127.1, 127.0, 125.3
(q, 1JCF = 285.2 Hz, CF3), 124.6, 123.9, 122.6, 67.8 (q, 2JCF = 28.4 Hz),
4. Experimental part
Typical procedure: To a solution of 1 mmol of
lated enone 2 in 2 mL of solvent (CH2Cl2 or toluene) was added 1 eq
b
-trifluoromethy-
27.3.
3
19F NMR (282 MHz, CDCl3):
d
– 78.22 (d, JFH = 6.8 Hz).
˚
of diamine 1 or aminothiophenol 4 following by 1 g of 4 A
molecular sieves. The reaction mixture was stirred during 24 h or
Anal. calcd for C20H15F3N2: C 70.58; H 4.44; N 8.23; found: C
70.83; H 4.18; N 7.88.

C. Christophe et al. / Journal of Fluorine Chemistry 155 (2013) 118–123
121
3
4.3. 4-(2-Furyl)-2-(trifluoromethyl)-2,3-dihydro-1H-1,5-
19F NMR (282 MHz, CDCl3):
d – 73.56 (d, JFH = 8.0 Hz).
benzodiazepine (3ac)
Anal. calcd for C15H12F3N3: C 61.85; H 4.15; N 14.43; found: C
61.76; H 4.43; N 14.27.
Yellow solid. Mp 91–96 8C.
3
1H NMR (300 MHz, CDCl3):
d
7.63 (dd, 1H, JHH = 1.7 Hz,
4.7. 4-(2-Naphthyl)-2-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-
b][1,4]diazepine (3bb)
3JHH = 0.8 Hz), 7.32 (dd, 1H, JHH = 2.0 Hz, JHH = 7.3 Hz), 7.00–
7.16 (massif, 3H), 6.89 (dd, 1H, JHH = 1.6 Hz, JHH = 7.5 Hz), 6.57
4
3
4
3
3
3
3
(dd, 1H, JHH = 1.7 Hz, JHH = 3.5 Hz), 4.48 (ddqd, 1H, JH1–
Brown solid.
3
3
3
NH = 1.7 Hz, JHH = 4.8 Hz, JHF = 6.8 Hz, JHH = 9.7 Hz), 3.72 (bs,
1H NMR (300 MHz, DMSO d6):
d 6.8–8.4 (massif, 11H), 4.90 (m
2
3
3
1H), 3.07 (dd, 1H, JHH = 13.5 Hz, JHH = 4.8 Hz), 2.89 (dd, 1H,
large, 1H), 3.86 (dd, 1H, 2JHH = 15.0 Hz), JHH = 5.5 Hz), 2.97 (dd,
2JHH = 13.5 Hz, JHH = 9.7 Hz).
1H, JHH = 15.0 Hz, 3JHH = 2.1 Hz)
3
2
13C NMR (75 MHz, CDCl3):
d
156.8, 152.9, 146.0, 140.9, 136.0,
19F NMR (282 MHz, DMSO d6):
d
– 73.42 (d, JFH = 8.0 Hz).
3
1
128.6, 127.0, 125.1 (q, JCF = 284.7 Hz, CF3), 123.9, 122.5, 113.7,
2
3
112.8, 67.6 (q, JCF = 28.5 Hz), 27.4 (q, JCF = 1.8 Hz).
4.8. Trans-4-phenyl-2-(trifluoromethyl)-2,3,5a,6,7,8,9,9a-
octahydro-1H-1,5-benzodiazepine (3ca)
19F NMR (282 MHz, CDCl3):
d – 78.58 (d, JFH = 6.8 Hz).
3
Anal. calcd for C14H11F3N2O: C 60.00; H 3.96; N 10.00; found: C
60.31; H 4.19; N 10.08.
First diastereomer (Yellow solid).
1H NMR (300 MHz, CDCl3):
d 7.72–7.80 (massif, 2H), 7.37–7.47
4.4. 4-(1-Benzofuran-2-yl)-2-(trifluoromethyl)-2,3-dihydro-1H-1,5-
benzodiazepine (3ad)
(massif, 3H), 3.69 (ddq, 1H, 3JHH = 6.7 Hz, 3JHH = 8.0 Hz,
3JHF = 8.1 Hz), 3.15–3.46 (massif, 3H), 2.76 (m, 1H), 2.23 (m, 1H),
2.06 (bs, 1H), 1.65–1.97 (massif, 4 H), 1.25–1.56 (massif, 3H).
Yellow solid. Mp 109–111 8C.
13C NMR (75 MHz, CDCl3):
d
165.6, 141.2, 130.3, 128.9, 127.3,
1H NMR (300 MHz, CDCl3):
d
7.61–7.71 (massif, 2H), 7.39–7.45
126.5 (q, JCF = 280.9 Hz, CF3), 66.1, 55.9, 50.7 (q, JCF = 28.9 Hz),
1
2
3
(massif, 2H), 7.38 (s, 1H), 7.30 (m, 1H), 7.07–7.18 (massif, 2H), 6.92
34.8, 32.9 (q, JCF = 1.5 Hz), 32.6, 25.8, 25.2.
3
3
3
3
(m, 1H), 4.54 (ddq, 1H, JHH = 4.7 Hz, JHH = 9.5 Hz, JHF = 6.9 Hz),
3.80 (bs, 1H), 3.16 (dd, 1H, 2JHH = 13.6 Hz, 3JHH = 4.7 Hz), 2.99 (dd,
19F NMR (282 MHz, CDCl3):
d
– 76.75 (d, JFH = 8.1 Hz).
Anal. calcd for C16H19F3N2: C 64.85; H 6.46; N 9.45; found: C
64.53; H 6.12; N 9.62.
3
3
1H, JHH = 13.6 Hz, JHH = 9.5 Hz).
13C NMR (75 MHz, CDCl3):
157.3, 156.4, 154.0, 140.7, 136.1,
d
Second diastereomer (Yellow solid).
1H NMR (300 MHz, CDCl3):
d 7.73–7.80 (massif, 2H), 7.36–7.47
(massif, 3H), 3.28–3.48 (massif, 3H), 2.86 (m, 1H), 2.54 (m, 1H),
2.26 (m, 1H), 2.07 (bs, 1H), 1.65–2.01 (massif, 4 H), 1.25–1.48
(massif, 3H).
1
129.0, 128.5, 127.5, 127.2, 125.1 (q, JCF = 284.7 Hz, CF3), 124.0,
2
123.9, 122.5, 122.5, 110.0, 67.8 (q, JCF = 28.6 Hz), 27.7 (q,
3JCF = 1.8 Hz).
3
19F NMR (282 MHz, CDCl3):
d
– 78.47 (d, JFH = 6.9 Hz).
Anal. calcd for C18H13F3N2O: C 65.45; H 3.97; N 8.48; found: C
65.58; H 3.78; N 8.32.
13C NMR (75 MHz, CDCl3):
d
168.3, 140.7, 130.4, 128.9, 127.1,
1
2
125.8 (q, JCF = 280.3 Hz, CF3), 66.0, 56.7 (q, JCF = 28.4 Hz), 56.5,
3
36.2, 35.1, 33.9 (q, JCF = 1.3 Hz), 24.91, 24.86.
3
4.5. 7-(Trifluoromethyl)-6.6a,7.8-tetrahydro-5H-naphtho[1,2-
b][1,5]benzodiazepine (3ae)
19F NMR (282 MHz, CDCl3):
d
– 78.23 (d, JFH = 6.9 Hz).
Anal. calcd for C16H19F3N2: C 64.85; H 6.46; N 9.45; found: C
64.95; H 6.31; N 9.83.
Yellow solid. Mp 98–102 8C.
1H NMR (300 MHz, CDCl3):
d
8.42 (dd, 1H, J = 7.7 Hz, J = 1.7 Hz),
4.9. Trans-4-(2-naphthyl)-2-(trifluoromethyl)-2,3,5a,6,7,8,9,9a-
octahydro-1H-1,5-benzodiazepine (3cb)
7.15–7.47 (massif, 5H), 7.07 (td, 1H, J = 7.5 Hz, J = 1.6 Hz), 6.93 (dd,
1H, J = 7.9 Hz, J = 1.5 Hz), 4.35 (dq, 1H, 3JHH = 11.5 Hz, 3JHF = 7.0 Hz),
3
3
3.70 (s, 1H), 3.30 (dt, 1H, JHH = 11.5 Hz, JHH = 4.6 Hz), 3.02 (ddd
Yellow solid.
2
3
3
large, 1H, JHH = 16.6 Hz, JHH = 8.4 Hz, JHH = 7.5 Hz H-5A), 2.81
1H NMR (300 MHz, CDCl3):
d
8.14 (bs, 1H), 8.01 (dd, 1H,
2
3
4
(dt, 1H, JHH = 16.6 Hz, JHH = 4.4 Hz), 2.10 (m, 2H).
3JHH = 8.7 Hz, JHH = 1.9 Hz), 7.82–7.96 (massif, 3H), 7.50–7.59
13C NMR (75 MHz, CDCl3):
d
166.1, 142.8, 140.7, 135.8, 133.2,
(massif, 2H), 3.60 (d, 1H, JHH = 14.3 Hz), 3.33–3.53 (massif, 2H),
2
131.3, 128.9, 127.4, 127.24, 127.21, 126.3, 125.4 (q, 1JCF = 288.2 Hz,
2.93 (dd, 1H, 2JHH = 14.3 Hz, 3JHH = 10.4 Hz), 2.56 (m, 1H), 2.31 (m,
2
CF3), 124.7, 123.2, 68.6 (q, JCF = 25.6 Hz), 36.2, 26.0, 24.2 (q,
1H), 1.70–2.16 (massif, 5H), 1.20–1.52 (massif, 3H).
4JCF = 2.2 Hz).
13C NMR (75 MHz, CDCl3):
d 168.0, 137.8, 134.5, 133.4, 129.3,
19F NMR (282 MHz, CDCl3):
d
– 73.24 (d, JFH = 7.0 Hz).
128.7, 128.0, 127.4, 127.0, 126.8, 125.8 (q, JCF = 280.5 Hz, CF3),
3
1
2
Anal. calcd for C18H15F3N2: C 68.35; H 4.78; N 8.86; found: C
68.08; H 4.62; N 8.65.
124.6, 66.13, 56.8 (q, JCF = 28.4 Hz), 56.54, 36.2, 35.1, 33.7 (q,
3JCF = 1.3 Hz), 24.94, 24.88.
3
19F NMR (282 MHz, CDCl3):
d
– 78.14 (d, JFH = 6.9 Hz).
4.6. 4-Phenyl-2-(trifluoromethyl)-2,3-dihydro-1H-pyrido[2,3-
b][1,4]diazepine (3ba)
Anal. calcd for C20H21F3N2: C 69.35; H 6.11; N 8.09; found: C
69.05; H 5.99; N 8.38.
Brown solid. Mp 125–130 8C.
4.10. Trans-4-(2-furyl)-2-(trifluoromethyl)-2,3,5a,6,7,8,9,9a-
octahydro-1H-1,5-benzodiazepine (3cc)
3
1H NMR (300 MHz, DMSO d6):
d
8.02 (dd, 1H, JHH = 4.6 Hz,
4JHH = 1.6 Hz), 7.95–8.00 (massif, 2H), 7.63 (dd, 1H, JHH = 7.6 Hz,
3
3JHH = 1.6 Hz), 7.43–7.53 (massif, 3H), 7.17 (d, 1H, JHH = 6.4 Hz),
Yellow solid. Mp 72–76 8C.
3
3
3
3
6.92 (dd, 1H, JHH = 7.6 Hz, JHH = 4.6 Hz), 4.83 (m large, 1H), 3.66
(dd, 1H, 2JHH = 15.0 Hz, 3JHH = 5.5 Hz), 2.86 (dd, 1H, 2JHH = 15.0 Hz,
3JHH = 1.8 Hz).
1H NMR (300 MHz, CDCl3):
d
7.55 (d large, 1H, JHH = 1.5 Hz),
6.82 (d, 1H, 3JHH = 3.5 Hz), 6.48 (dd, 1H, 3JHH = 3.5 Hz,
3JHH = 1.5 Hz), 3.20–3.44 (massif, 3H), 2.77 (dd, 1H, JH2B–
2
13C NMR (75 MHz, DMSO d6):
d
164.5, 151.2, 146.9, 139.9,
HA = 14.3 Hz, JHH = 10.6 Hz), 2.53 (m, 1H), 2.25 (m, 1H), 1.64–
3
1
139.7, 131.2, 130.4, 129.3, 127.9, 126.2 (q, JCF = 283.2 Hz, CF3),
1.98 (massif, 5H), 1.28–1.44 (massif, 3H).
2
116.4, 62.2 (q, JCF = 29.3 Hz), 29.9.

122
C. Christophe et al. / Journal of Fluorine Chemistry 155 (2013) 118–123
13C NMR (75 MHz, CDCl3):
d
158.9, 153.0, 145.7, 125.6 (q,
13C NMR (75 MHz, CDCl3):
d 159.1, 156.5, 153.2, 151.9, 136.0,
2
1
1JCF = 280.3 Hz, CF3), 113.1, 111.9, 66.0, 56.8 (q, JCF = 28.4 Hz),
131.2, 128.3, 127.7, 126.5, 126.1, 125.8 (q, JCF = 279.8 Hz, CF3),
3
2
56.7, 36.1, 35.0, 33.4 (q, JCF = 1.3 Hz), 24.9, 24.8.
124.2, 122.8, 120.8, 112.6, 111.0, 57.1 (q, JCF = 29.6 Hz), 29.4 (q,
19F NMR (282 MHz, CDCl3):
d
– 78.29 (d, JFH = 6.9 Hz).
3JCF = 2.2 Hz).
3
3
Anal. calcd for C14H17F3N2O: C 58.73; H 5.99; N 9.78; found: C
58.48; H 5.74; N 9.57.
19F NMR (282 MHz, CDCl3):
d
– 74.17 (d, JFH = 7.8 Hz).
Anal. calcd for C18H12F3NOS: C 62.24; H 3.48; N 4.03; S 9.23;
found: C 61.94; H 3.77; N 3.86; S 8.89.
4.11. 4-Phenyl-2-(trifluoromethyl)-2,3-dihydro-1,5-benzothiazepine
(5aa)
4.15. 7-(Trifluoromethyl)-5,6,6a,7-tetrahydrobenzo[b]naphtho[1,2-
e][1,4]thiazepine (5ae)
White solid. Mp 94–96 8C.
1H NMR (300 MHz, CDCl3):
d
8.08 (m, 2H), 7.66 (dd, 1H,
Green solid. Mp 95–98 8C.
4
3
3JHH = 7.6 Hz, JHH = 1.4 Hz), 7.47–7.61 (massif, 4H), 7.30 (dd, 1H,
1H NMR (300 MHz, CDCl3):
d
8.51 (dd, 1H, JHH = 7.9 Hz,
4
3
3JHH = 8.0 Hz, JHH = 1.4 Hz), 7.16 (ddd, 1H, JHH = 3JHH = 7.6 Hz,
4JHH = 1.4 Hz), 4.19 (ddq, 1H, 3JHH = 12.9 Hz, 3JHH = 5.1 Hz,
4JHF = 7.9 Hz), 3.41 (dd, 1H, 3JHH = 5.1 Hz, 2JHH = 12.9 Hz,
4JHH = 1.3 Hz), 7.68 (dd, 1H, 3J = 7.7 Hz, 4J = 1.3 Hz), 7.44–7.55
(massif, 2H), 7.35–7.43 (massif, 2H), 7.29 (m, 1H), 7.12–7.21
(massif, 1H), 4.05 (dt, 1H, 3JHH = 12.2 Hz, 3JHF = 7.9 Hz), 3.32 (dt, 1H,
3
3
2
3JHH = 5.1 Hz), 2.87 (t, 1H, JHH = 2JHH = 12.9 Hz).
3JHH = 12.2 Hz, JHH7 = 3.3 Hz), 3.08 (ddd, 1H, JHH = 17.4 Hz,
13C NMR (75 MHz, CDCl3):
d
167.7, 152.6, 137.4, 135.8, 132.0,
3JHH = 13.2 Hz, JHH = 4.2 Hz), 2.91 (ddd, 1H, JHH = 17.4 Hz,
3
2
1
3
131.1, 129.4, 127.7, 126.0, 125.9 (q, JCF = 279.8 Hz, CF3), 125.6,
3JHH = 4.0 Hz, JHH = 3.1 Hz), 2.22 (m, 1H), 2.06 (m, 1H).
2
3
120.4, 57.0 (q, JCF = 29.5 Hz), 29.1 (q, JCF = 2.0 Hz).
13C NMR (75 MHz, CDCl3):
d 167.7, 152.6, 140.4, 135.9, 132.0,
19F NMR (282 MHz, CDCl3):
d
– 74.09 (d, JFH = 7.9 Hz).
131.9, 131.2, 129.4, 127.9, 127.4, 126.1 (q, JCF = 280.8 Hz, CF3),
3
1
2
Anal. calcd for C16H12F3NS: C 62.53; H 3.94; N 4.56; S 10.43;
found: C 62.24; H 4.28; N 4.36; S 10.7.
125.6, 125.4, 120.8, 56.5 (q, JCF = 27.5 Hz), 37.9, 25.3, 25.0 (q,
4JCF = 2.2 Hz, C-17).
19F NMR (282 MHz, CDCl3):
d
– 68.30 (d, JFH = 7.9 Hz).
3
4.12. 4-(2-Naphthyl)-2-(trifluoromethyl)-2,3-dihydro-1,5-
benzothiazepine (5ab)
Anal. calcd for C18H14F3NS: C 64.85; H 4.23; N 4.2; S 9.62;
found: C 64.64; H 4.59; N 4.58; S 9.68.
Yellow solid. Mp 134–135 8C.
Acknowledgements
1H NMR (300 MHz, CDCl3):
d 8.30–8.42 (massif, 1H), 7.90–8.04
(massif, 3H), 7.50–7.72 (massif, 4H), 7.36 (dd, 1H, 3J = 7.9 Hz,
4J = 1.1 Hz), 7.18 (dd, 1H, 3J = 7.6 Hz, 4J = 1.3 Hz), 4.27 (ddq, 1H,
3JHH = 5.0 Hz, 3JHH = 13.0 Hz, 3JHF = 7.1 Hz), 3.57 (dd, 1H,
The authors thank the CNRS for their financial support and the
French Fluorine Network is also thanked for its support.
3
2
2JHH = 13.0 Hz, JHH = 5.0 Hz), 2.95 (t, 1H, JHH = 3JHH = 13.0 Hz).
References
13C NMR (75 MHz, CDCl3):
d
167.5, 152.7, 135.8, 135.3, 134.8,
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2
3
29.0 (q, JCF = 1.8 Hz).
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d
– 74.08 (d, JFH = 7.1 Hz).
3
Anal. calcd for C20H14F3NS: C 67.21; H 3.95; N 3.92; S 8.97;
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Brown solid. Mp 80–81 8C.
1H NMR (300 MHz, CDCl3):
d 7.60–7.67 (massif, 2H), 7.46 (td,
3
4
3
1H, JHH = 3JHH = 7.8 Hz, JHH = 1.3 Hz), 7.28 (dd, 1H, JHH = 7.8 Hz,
4JHH = 1.3 Hz), 7.08–7.15 (massif, 2H), 6.59 (dd, 1H, JHH = 1.9 Hz,
3
3JHH = 3.4 Hz), 4.19 (ddq, 1H, 3JHH = 13.0 Hz, 3JHF = 7.3 Hz,
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2
3
2
3
(dd, 1H, JHH = 12.9 Hz, JHH = 13.0 Hz).
13C NMR (75 MHz, CDCl3):
158.4, 152.3, 152.0, 146.4, 135.9,
d
1
131.1, 126.1, 125.9, 125.8 (q, JCF = 279.7 Hz, CF3), 120.8, 114.6,
2
3
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d – 74.23 (d, JFH = 7.3 Hz).
3
Anal. calcd for C14H10F3NOS: C 56.56; H 3.39; N 4.71; S 10.79;
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benzothiazepine (5ad)
Yellow solid. Mp 126–128 8C.
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d 7.62–7.75 (massif, 3H), 7.27–7.55
(massif, 5H), 7.16 (td, 1H, 3J = 7.5 Hz, 4J = 1.1 Hz), 4.26 (ddq, 1H,
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2
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