Synthesis of trifluoromethylated [1,4]diazepines from 1,1,1-trifluoroalk-3-yn-2-ones

Article abstract of DOI:10.1016/j.mencom.2014.09.007

Reaction of 1,1,1-trifluoroalk-3-yn-2-ones with 1,2-diamines affords trifluoromethylated [1,4]diazepines.

Full text of DOI:10.1016/j.mencom.2014.09.007

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 269–271
Synthesis of trifluoromethylated [1,4]diazepines
from 1,1,1-trifluoroalk-3-yn-2-ones
Alexey R. Romanov,a Alexander Yu. Rulev,*a Igor A. Ushakov,a,b
Vasiliy M. Muzalevskiyc and Valentine G. Nenajdenko*c,d
a A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk,
Russian Federation. Fax: + 7 3952 41 9346; e-mail: rulev@irioch.irk.ru
b National Research Irkutsk State Technical University, 664074 Irkutsk, Russian Federation
c Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
E-mail: nen@acylium.chem.msu.ru, nenajdenko@gmail.com
d A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2014.09.007
Reaction of 1,1,1-trifluoroalk-3-yn-2-ones with 1,2-diamines affords trifluoromethylated [1,4]diazepines.
Diazepine derivatives exhibit anti-inflammatory, anticonvulsant,
sedative and analgesic activities and can treat cancer, cardio-
vascular disorder and AIDS.1 Some of them are used as dyes and
ferroelectrics.2
Meanwhile, incorporation of fluorine into molecule provides
binding with target receptors, better membrane permeability, and
blocking effect to metabolic decomposition. Nearly 25 per cent
of new synthetic drugs and agrochemicals contain at least one
fluorine atom or trifluoromethyl group.3 The most promising
approach to such type of compounds is the use of CF3-bearing
reactants as starting materials.
Condensation of 1,3-diketones with 1,2-diamines is a common
access to non-fluorinated diazepines.4 However, CF3-diketones
react in a different way affording benzimidazoles, amino enones, or
macrocycles.5 Considering these facts we set out a goal to obtain
trifluoromethylated diazepines from CF3-containing a,b-ynones.
Recently we have found unusual rearrangement with 1,2-shift of
CF3 group in the reaction of CF3-bearing a-bromo enones with
diamines.6
Acetylenic ketones are used for the synthesis of diazepines in
reactions with binucleophiles.7 However, this approach to target
heterocycles from CF3-ynones is still scarce. High polarity of
acetylenic bond and different nature of electrophilic sp- and sp2-
centers in ynones can provide higher selectivity of such reactions.
Herein we report results of investigation of 1,1,1-trifluoroalk-
3-yn-2-ones 1a–d with 1,2-diamines.
ditions led to the mixture of target heterocycle 3 and acyclic
products of mono- and bis-addition 4a and 5 in moderate yield.‡
Ynone 1c in this reaction transforms exclusively into amino
enone 4b (Scheme 2). E,Z-Configuration of bis-adduct 5 was
proved by 2D NMR spectroscopy (NOESY and HMBC) data.
We did not find any influence of the solvent on the reaction
course: the similar results were obtained in both protic (ethanol)
and aprotic (benzene) media. These results indicate that the attack
† General procedure. A mixture of appropriate ynone (1a,c,d) (1.0 mmol)
and o-phenylenediamine (1.0 mmol) (in the case of 7a–c) or ethylene-
diamine (2a,b) in ethanol or benzene (2 ml) was stirred at room tempe-
rature for 24 h. The volatiles were evaporated in vacuo, the residue was
purified by column chromatography [silica gel, diethyl ether–hexane (1:3)
or CHCl3–MeOH (95:5)]. Heterocycles 2a,b, 7a–c were obtained by this
method. Products 7c and 8 were described earlier.9
7-Phenyl-5-trifluoromethyl-2,3-dihydro-1H-[1,4]diazepine 2a. Brownish
viscous oil, yield 139 mg (58%). 1H NMR (400 MHz, CDCl3) d: 3.53 (s,
2H, C2H2), 4.00 (s, 2H, C3H2), 4.96 (br.s, 1H, NH), 5.33 (s, 1H, C6H),
7.40–7.65 (m, 5H, Ph). 13C NMR (100.6 MHz, CDCl3) d: 48.7, 56.0 (C2,
C3), 87.5 (C6), 121.3 (q, CF3, J 279.8 Hz), 127.4, 129.0, 130.7, 138.0 (Ph),
156.6 (q, C5, J 31.0 Hz), 158.7 (C7). 19F NMR (376.5 MHz, CDCl3) d:
–71.3. MS (EI), m/z (%): 240 (100, M+), 212 (33), 192 (26), 172 (26),
143 (50), 115(31). HRMS (ESI), m/z: 263.0774 (calc. for C12H11F3N2Na+
[M+Na+], m/z: 263.0767).
For characteristics of 7-(4-tert-butylphenyl)-5-trifluoromethyl-2,3-di-
hydro-1H-[1,4]diazepine 2b, see Online Supplementary Materials.
‡
1-Methyl-7-phenyl-5-trifluoromethyl-2,3-dihydro-1H-[1,4]diazepine 3.
Unsubstituted ethylenediamine reacts with ynones 1a,b giving
target diazepines 2a,b in moderate yield (Scheme 1).† Their
enamine tautomeric form seems to be more preferable due to the
longer conjugation chain.
Mono-substituted analogue of ethylenediamine reacts with
CF3-ynones less selectively. Thus, the treatment of ynone 1a
with N-methylethylenediamine under the optimal reaction con-
Light yellow oil, yield 85 mg (33%). 1H NMR (400 MHz, CDCl3) d: 2.75
(s, 3H, Me), 3.20 (br.s, 2H, C3H2), 3.98 (br.s, 2H, C2H2), 5.22 (s, 1H, C6H),
7.30–7.45 (m, 5H, Ph). 13C NMR (100.6 MHz, CDCl3) d: 43.8 (NMe),
55.5, 56.2 (C2, C3), 92.1 (C6), 121.5 (q, CF3, J 279.1 Hz), 128.6, 128.9, 129.9,
138.5 (Ph), 155.6 (q, C5, J 30.3 Hz), 161.1 (C7). Found (%): C, 61.27;
H, 4.85; N, 10.44. Calc. for C13H13F3N2 (%): C, 61.41; H, 5.15; N, 11.02.
1,1,1,12,12,12-Hexafluoro-5-methyl-4,9-diphenyl-5,8-diazadodeca-
3,9-diene-2,11-dione 5. White solid, yield 34 mg (15%). IR (KBr, n/cm–1):
1175, 1188 (C–F), 1524, 1615, 1656 (C=O, C=C, Ph). 1H NMR (400 MHz,
CDCl3) d: 2.88 (s, 3H, NMe), 3.36 (br.s, 4H, C6H2, C7H2), 5.28, 5.46
(2s, 2H, C3H, C10H), 6.65–7.60 (m, 10H, 2Ph), 10.97 (br.s, 1H, NH).
19F NMR (376.5 MHz, CDCl3) d: –76.7. 15N NMR (40.6 MHz, CDCl3)
d: –267.1. MS (EI), m/z (%): 471 (M+ +1, 1), 253 (54), 242 (34), 184 (100),
146 (40). Found (%): C, 59.03; H, 4.12; N, 5.97. Calc. for C23H20F6N2O2
(%): C, 58.73; H, 4.29; N, 5.95.
EtOH (for 1a) or
CF3CH2OH (for 1b)
NH2
O
2
3
HN1
4 N
+
R
room
temperature
7
5
6
CF3
NH2
R
CF3
1a,b
2a (58%)
2b (37%)
a R = Ph
b R = 4-ButC6H4
For characteristics of compounds 4a,b, see Online Supplementary
Materials.
Scheme 1
© 2014 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2014, 24, 269–271
Benzene
or EtOH
Me
HN
EtOH, room
temperature
(for 1a,d)
O
NH2
NH2
O
+
R
NH2
room
temperature,
24 h
R
+
CF3
7
6
or benzene, ∆
(for 1c)
CF3
N1
5 N
1a R = Ph
1c R = 4-ClC6H4
2
4
3
1a R = Ph
1c R = 4-ClC6H4
1d R = hexyl
o-PDA
R
CF3
Me
HN
7a R = Ph (63%)
7b R = 4-ClC6H4 (72%)
7c R = hexyl (34%)
H
2
3
Me
N1
4 N
N
O
+
7
5
6
Ph
CF3
R
CF3
NH2
3 (33%)
4a R = Ph (28%)
4b R = 4-ClC6H4 (87%)
H
o-PDA
1d
+
7c
N
O
MeCN, room
Me
temperature
Me
H
CF3
F3C
O
N
N
O
8
+
Ph
Ph
5 (15%)
Scheme 2
CF3
Scheme 4
explained by the simultaneous formation of mono and bis-aza-
Michael adducts. We showed that ketone 8 is precursor of diazepine
7c. Thus, NMR spectrum of amino enone 8, isolated by column
chromatography on silica gel, contained the signals of forming
cyclic product 7c and their intensity was gradually increasing.9
In order to get more knowledge on the mechanism of the ring
formation, we performed NMR monitoring of the reaction of
ynone 1a with o-PDA. 1D, 2D and dynamic NMR spectra analysis
allowed us to detect the principal intermediates and to follow
their further transformations in the course of reaction.
onto the triple bond of ynones 1a,c occurs with the participa-
tion of both primary and secondary amino groups of diamine.
When attacking nucleophile center is secondary amino group,
the forming intermediate undergoes intramolecular cyclization
giving [1,4]diazepine 3 or reacts with another molecule of ynone
producing bis-adduct 5.
Amino enone 4a seems to be the precursor of the bis-adduct 5.
As we expected, reaction of ynones 1a,d with symmetrically
disubstituted N,N'-dimethylethylenediamine (DMEDA), performed
under the same experimental conditions, exclusively afforded bis-
Thus, the 19F NMR spectrum recorded immediately after
the reaction start contains the signals of the initial ketone 1a
(d –77.8 ppm) and two intermediates (d –76.5 and –83.6 ppm)
in a ratio of 1:0.1:0.1. After standing at room temperature for
5 min, the second intermediate (d –83.6 ppm) disappears and
the ratio ketone:intermediate is 1:0.4 which changes to 1:1.25
within 30 min. After consumption of the starting ketone this inter-
1
adducts 6a,b (Scheme 3). H NMR and NOESY experiments,
performed in CDCl3 solution at room temperature, demonstrated
the presence of a single E,E-isomer (see Online Supplementary
Materials). The results obtained allow us to resume that secondary
amino group is not susceptible to intramolecular cyclization and
aza-Michael adduct as intermediate undergoes next the addition of
the second molecule of ynone to yield the final reaction product 6.
Recently it was reported that this kind of compounds was used as
ligands with transition metal ions to form metallomesogens.8
o-Phenylenediamine (o-PDA) reacts in the same manner as
ethylenediamine affording benzodiazepines 7a–c in good yields
(Scheme 4).§ The moderate yield in the case of ynone 1d is
1
mediate becomes a principal component. Its H NMR spectrum
exhibits singlet of an olefinic proton (d 5.80 ppm). In the 13C NMR
spectrum, the quartets of carbonyl (d 177.5 ppm, J 33.0 Hz) and
trifluoromethyl (d 117.6 ppm, J 288.0 Hz) groups as well as
singlets of sp2-carbon atoms (d 92.3 and 169.1 ppm) are observed.
These spectral data confirm clearly the structure of a push-pull
amino enone A. Its Z-configuration was proved with H-1H 2D
1
NOESY NMR: there is an intensive cross-peak between an olefinic
proton and ortho-protons of a phenyl group. The formation of
the only one geometric isomer can be explained by the presence
of an intramolecular hydrogen bond in its structure providing
higher stability. After keeping for several hours at room tempe-
rature, the signal of intermediate A gradually disappears and at
the same time the signal of a product 7a (d –70.9 ppm) grows.
O
R
N
CF3
O
Me
DMEDA
R
benzene, room
temperature,
24 h
N
R
Me
CF3
1a R = Ph
F3C
1d R = hexyl
O
6a R = Ph (67%)
NH2
6b R = hexyl (79%)
H
o-PDA
1a
7a
N
O
Scheme 3
Ph
CF3
§
2-Phenyl-4-trifluoromethyl-3H-benzo[b][1,4]diazepine 7a. Light yellow
A
solid, yield 182 mg (63%), mp 75–76°C. IR (KBr, n/cm–1): 1170, 1183,
1194 (C–F), 1590 (Ar), 1611 (Ph), 1640 (C=N). 1H NMR (400 MHz, CDCl3)
d: 3.47 (br.s, 2H, C3H2), 7.3–8.08 (m, 9H, Ar). 13C NMR (100.6 MHz,
CDCl3) d: 32.2 (C3), 121.9 (q, CF3, J 266.0 Hz), 126.1, 127.9, 128.8, 129.0,
131.5, 136.2, 137.3 (Ar), 144.7 (q, C4, J 35.5 Hz), 153.7 (C2). 19F NMR
Scheme 5
In summary, we have suggested a procedure for the synthesis
of trifluoromethyl-containing [1,4]diazepines, which excels earlier
reported method based on 1,3-diketones. The target heterocycles
are formed under mild conditions in good yields and with high
selectivity. The ring closure occurs via formation of aza-Michael
adduct as a principal intermediate.
(
376.5 MHz, CDCl3) d: –70.9. 15N NMR (40.6 MHz, CDCl3) d: –69.2, –54.6.
MS (EI), m/z (%): 288 (100, M+), 219 (78), 89 (10). Found (%): C, 66.20;
H, 4.14; N, 9.57. Calc. for C16H11F3N2 (%): C, 66.67; H, 3.85; N 9.72.
For characteristics of compounds 7b,c, see Online Supplementary
Materials.
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Mendeleev Commun., 2014, 24, 269–271
This work was supported by the Russian Foundation for Basic
Research (grant no. 13-03-00063-a,A. R. Romanov,A.Yu. Rulev,
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Russ. Chem. Bull., Int. Ed., 2010, 59, 1791 (Izv. Akad. Nauk, Ser. Khim.,
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I.A. Ushakov) and RSCF (grant no. 14-13-00083,V. M. Muzalevskiy,
V. G. Nenajdenko).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.09.007.
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Received: 30th June 2014; Com. 14/4410
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