One pot synthesis of 5-per(poly)fluoroalkyl-2,3-dihydro-1,4-diazepines

Article abstract of DOI:10.1016/S0022-1139(98)00337-6

A series of 5-per(poly)fluoroalkyl-2,3-dihydro-1,4-diazepines have been synthesized from reaction of R_fCF₂I with vinyl ethyl ether and ethylenediamine. A possible reaction pathway is suggested.

Full text of DOI:10.1016/S0022-1139(98)00337-6

Journal of Fluorine Chemistry 94 (1999) 79±81
One pot synthesis of 5-per(poly)¯uoroalkyl-2,3-dihydro-1,4-diazepines
*
Quan-Fu Wang , Yun-Yu Mao, Chang-Ming Hu
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 27 April 1998; accepted 18 November 1998
Abstract
A series of 5-per(poly)¯uoroalkyl-2,3-dihydro-1,4-diazepines have been synthesized from reaction of R CF I with vinyl ethyl ether and
f
2
ethylenediamine. A possible reaction pathway is suggested. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Per(poly)¯uoroalkyl iodide; Vinyl ethyl ether; Ethylenediamine; a-Per(poly)¯uoroalkyl aldehydes; 5-Per(poly)¯uoroalkyl-2,3-dihydro-1,4-
diazepines
1
. Introduction
The length of the per(poly)¯uoroalkyl chain and the
presence of w-chlorine or bromine had little effect on the
reaction and all the substrates afforded product 2 in nearly
the same yield.
Regioselective replacement of hydrogen by ¯uorine or
uoroalkyl on a heterocyclic system might have a profound
¯
in¯uence on the biological and physical properties of such
molecules [1,2]. As a result, considerable efforts have been
devoted in recent years to the development of methodologies
for the synthesis of ¯uorine-containing heterocyclic com-
pounds. a-Per(poly)¯uoroalkyl aldehydes, as important
The following two reactions might give some clue about
the mechanism of the above reaction. When a-¯uoroalkyl
aldehyde reacted with semicarbazide or thiosemicarbazide,
the corresponding semicarbazone or thiosemicarbazone was
obtained (Scheme 3).
Thus, though the intermediate A has not been separated
from the reaction mixture, the possible reaction pathway is
suggested in Scheme 4.
¯
uorine-containing building blocks, can be conveniently
prepared [3,4] and have been utilized in the synthesis of
various aromatic heterocycles [5]. However, little work has
been done on the synthesis of seven-membered ¯uorine-
containing non-aromatic rings.
Firstly, ethylenediamine initiated the addition of R CF I
2
f
to vinyl ethyl ether to give a a-per(poly)¯uoroalkyl alde-
hyde. This aldehyde then reacted with ethylenediamine to
give the corresponding imine derivative, followed by elim-
ination of HF and ring closure with the loss of another HF
molecule to give the desired product.
2
. Results and discussions
Our recent work has showed that ethylenediamine could
be used as a dinucleophile to react with a-per(poly)¯uoro-
alkyl aldehydes (Scheme 1). Thus, a new kind of com-
pounds, 5-per(poly)¯uoroalkyl-2,3-dihydro-1,4-diazepines
were obtained and the structure of 5-tri¯uoromethyl-2,3-
dihydro-1,4-diazepine was con®rmed by X-ray diffraction
3. Experimental
All melting points were uncorrected. UV spectra were
recorded on a Perkin-Elmer, Lambda 5, UV/Vis Spectro-
meter, using methanol as solvent. IR spectra were measured
with a Shimadzu IR-440 spectrometer using KBr pellets for
[
6].
Considering that the addition of R CF I to alkenes can be
f
2
1
initiated by organic amines [7] the present work further
showed that the above mentioned reaction could be simpli-
®ed and accomplished in one pot (Scheme 2). The results are
shown in Table 1.
solids. H NMR spectra were recorded at 90 and 300 MHz
and 13C NMR spectra at 300 MHz on JEDLFX-90Q, Bruker
AM300, respectively, using tetramethylsilane (TMS) as
internal standard and CD COCD as solvent unless other-
3
3
wise noted. 19F NMR spectra were recorded on an EM-360L
*
Corresponding author. Fax: +86-21-641-66128.
spectrometer at 56.4 MHz using TFA as the external stan-
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 3 3 7 - 6

8
0
Q.-F. Wang et al. / Journal of Fluorine Chemistry 94 (1999) 79±81
Scheme 1. Reaction of a-per(poly)fluoroalkyl aldehydes with ethylene-
diamine.
Scheme 2. A one pot reaction of R
ethylenediamine.
f 2
CF I with vinyl ethyl ether and
Scheme 4. A possible mechanism for the preparation of 5-per(poly)-
fluoroalkyl-2,3-dihydro-1,4-diazepines from R
ethylenediamine.
f 2
CF I, vinyl ethyl ether and
Table 1
Preparation of 5-per(poly)fluoroalkyl-2,3-dihydro-1,4-diazepines
a
Yield (%)
Entry
Substrate
R
f
Product
using a mixture of petroleum ether (b.p. 60±908C) and ethyl
acetate as eluant (1:1 by volume).
1
2
3
4
5
1a
1b
1c
1d
1e
CF
ClCF
BrCF
Cl(CF
CF (CF
3
2a
2b
2c
2d
2e
80
83
78
84
82
2
Procedure for the preparation of compounds 3 and 4 was
as follows:
ClC F CF CH CHO (10 mmol), semicarbazide or thio-
2
2 3
)
3
2 4
)
3
6
2
2
a
Isolated yield based on R
CF
f 2
I.
semicarbazide (40 mmol) were dissolved in 40 ml 95%
ethanol. After re¯uxing at 808C for 6 h, the mixture was
cooled, poured into 50 ml ice water and extracted with
diethyl ether (3Â40 ml). The organic extracts were com-
bined, washed with brine and dried over Na SO . The
2
4
solvent was removed by distillation.The crude product
was further puri®ed by silica gel column chromatography
using a mixture of petroleum ether (b.p. 60±908C) and ethyl
acetate as eluant (2:1 by volume).
Data for compound 2a: m.p. 176±1778C; UV (nm) 327;
IR ꢀmax (cm ) 3230, 3070, 2994, 2911, 1628, 1555, 1320,
�
1
1
1
135, 1095; H NMR (300 MHz) ꢁ 6.92 (d, Jˆ9 Hz, 1H),
.84 (d, Jˆ9 Hz, 1H), 4.03 (s, 2H), 2.93 (broad, NH
4
exchangeable singlet), 3.41 (s, 2H); C NMR (300 MHz)
13
1
ꢁ
49.42, 56.91, 85.61, 122.60 (q, JCF ˆ 3:7 ppm), 47.27,
2 19
CF
3
Scheme 3. Reaction of ClC
thiosemicarbazide.
3
F
6
CF
2
CH
2
CHO with semicarbazide or
158.80 (q, J ˆ 0:4 ppm); F NMR ꢁ � 5.50 (s, CF ); MS
‡
‡
‡
m/z (%), 164 (M , 100), 136(M ±NCH , 64), 116 (M ±
2
NCH ±HF, 49); analysis: C H F N requires: C, 43.90; H,
2
6 7 3 2
4.27; F, 34.76; N, 17.07; found: C, 43.79; H, 4.03; F, 34.84;
N, 17.53%.
dard and positive for up®eld shifts. Mass and HRMS spectra
were taken on a Finnigan GC±MS-4021 spectrometer. Ele-
mental analyses were done by the Elemental Analysis
Group of SIOC.
Compound 2b: m.p. 138±1398C; UV (nm) 330; IR ꢀ
(cm ) 3232, 3066, 2999, 1623, 1559, 1315, 1141, 1086,
max
�
1
1
1036: H NMR (90 MHz) ꢁ 6.45 (d, Jˆ9 Hz, 1H), 4.45 (d,
A general procedure for the preparation of compounds
a±2e was as follows:
Compound 1 (10 mmol), vinyl ethyl ether (12 mmol) and
Jˆ9 Hz, 1H), 3.50 (s, 2H), 2.95 (broad, NH, exchangeable
1
9
2
singlet), 2.90 (s, 2 H); F NMR ꢁ � 20.0 (s, CF Cl); MS m/z
2
‡
‡
‡
(%), 180 (M , 100), 152 (M ±NCH , 23), 145 (M ±Cl, 65);
2
ethylenediamine (40 mmol) were dissolved in 40 ml 95%
ethanol. After re¯uxing at 808C for 8 h, the mixture was
cooled, poured into 50 ml ice water and extracted with
diethyl ether (3Â40 ml). The organic extracts were com-
bined, washed with brine and dried over Na SO . The
analysis C H ClF N requires: C, 40.00; H, 3.89; F, 21.11;
2 2
6
7
N, 15.55; found: C, 40.03; H, 3.88; F, 21.29; N, 15.30%.
Compound 2c: m.p. 125±1268C; UV (nm) 334; IR ꢀ
(cm ) 3227, 3065, 2990, 1629, 1558, 1322, 1147, 1086,
max
�
1
1
1034; H NMR (90 MHz) ꢁ 6.45 (d, Jˆ9 Hz, 1H), 4.45 (d,
2
4
solvent was removed by distillation. The crude product
was further puri®ed by silica gel column chromatography
Jˆ9 Hz, 1H), 3.50 (s, 2H), 2.95 (broad, NH, exchangeable
singlet), 2.90 (s, 2H); 19F NMR ꢁ � 25.0 (s, CF Br); MS m/z
2

Q.-F. Wang et al. / Journal of Fluorine Chemistry 94 (1999) 79±81
81
‡
‡
� 1
(
C H Br F N : 223.9761. Found: 223.9757%.
%), 225 (M , 22), 145 (M ±Br, 100); HRMS. Calcd. for
7
Compound 4: IR ꢀmax (cm ) 3429, 3261, 3161, 3013,
1683, 1603, 1534, 1469, 1373, 1291, 1182, 1122, 1071; 19F
NMR ꢁ � 8.0 (s, CF Cl), 41.0 (m, CF ), 45.3 (m, CF ), 50.7
9
6
7
2 2
Compound 2d: m.p. 105±1078C; UV (nm) 330; IR ꢀ
cm ) 3226, 3068, 2993, 1631, 1556, 1320, 1178, 1121,
max
2
2
2
�
1
1
(
(m, CF); H NMR ꢁ 7.74 (d, Jˆ9 Hz, 1 H), 6.23 (dd,
J ˆ33 Hz, J ˆ9 Hz, 1H), 2.86 (s, 3 NH, exchangeable
1
1
095; H NMR (90 MHz) ꢁ 6.45 (d, Jˆ9 Hz, 1H), 4.45 (d,
1
2
‡
Jˆ9 Hz, 1H), 3.50 (s, 2H), 2.95 (broad, NH, exchangeable
singlet when D O is used.); MS (m/e): 331 (M , 75);
2
singlet), 2.90 (s, 2H); 19F NMR ꢁ � 10.7 (s, CF Cl), 36.6 (m,
analysis C H ClF N S requires: C, 25.38; H, 1.51; F,
7 3
2
7
5
‡
‡
CF ), 43.0 (m, CF ); MS m/z (%), 280 (M , 100), 252 (M ±
2
40.18; N, 12.69; found: C, 25.50; H, 1.78; F, 39.92; N,
12.22%.
2
‡
NCH , 87), 245 (M ±Cl, 51); analysis C H ClF N
6 2
2
8
7
requires: C, 34.28; H, 2.50; F, 40.71; N, 10.00; found: C,
4.18; H, 2.27; F, 40.87; N, 9.83%.
3
Compound 2e: m.p. 86±888C; UV (nm) 330; IR ꢀ
cm ) 3223, 3068, 2992, 1633, 1558, 1318, 1229, 1205,
Acknowledgements
max
�
1
(
1
1
150, 1138, 1108, 1089; H NMR (90 MHz) ꢁ 6.45 (d,
Jˆ9 Hz, 1H), 4.45 (d, Jˆ9 Hz, 1H), 3.50 (s, 2H), 2.95
broad, NH, exchangeable singlet), 2.90 (s, 2H); 19F NMR ꢁ
.0 (s, 3F), 32.0 (m, 2F), 45.5 (m, 4F), 50.0 (m, 2F); MS m/z
We thank the National Natural Science Foundation of
China for ®nancial support (no. 29772003).
(
5
‡
‡
(%), 364 (M , 69), 336 (M ±NCH , 70); analysis
C H F N requires: C, 32.98; H, 1.92; F, 57.41; N,
References
2
1
0 7 11 2
7
.69; found: C, 32.86; H, 1.65; F, 57.07; N, 7.63%.
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�
1
[
2] H. Yoshioka, C. Takayama, N. Mastuo, J. Synth. Org. Chem. Jpn. 42
(1984) 809.
Compound 3: IR ꢀmax (cm ) 3472, 3292, 3165, 1699,
592, 1532, 1435, 1362, 1325, 1190, 1124, 1071; 19F NMR
� 8.0 (s, CF Cl), 40.7 (m, CF ), 45.0 (m, CF ), 53.7 (m,
1
ꢁ
[
[
3] W.Y. Huang, L. Lu, Chinese J. Chem. 9 (1991) 167.
4] S.Z. Zhu, C.Y. Qin, B. Xu, J. Fluorine Chem. 79 (1996) 77.
2
2
2
1
CF); H NMR ꢁ 7.50 (d, Jˆ9 Hz, 1H), 6.19 (dd, J ˆ33 Hz,
1
[5] X.Q. Tang, C.M. Hu, J. Chem. Soc., Perkin 1 (1994) 2161, and
references cited therein.
J ˆ9 Hz, 1H), 2.86 (s, 3 NH, exchangeable singlet when
2
‡
[
6] Q.F. Wang, C.M. Hu, Tetrahedron Lett., Tetrahedron Lett. 39(16)
1998) 2377.
7] N.O. Brace, J. Org. Chem. 44 (1979) 212.
D O is used.); MS (m/e): 316 (M ‡1, 87); analysis
2
(
C H ClF N O requires: C, 26.67; H, 1.59; F, 42.22; N,
7
5
7 3
[
1
3.33; found: C, 26.82; H, 1.35; F, 42.21; N, 12.99%.