A Novel Synthesis of 5-Perfluoroalkyl-2,3-dihydro-1,4-diazepines from 1-Perfluoroalkyl-2-iodoethylenes

Article abstract of DOI:10.1055/s-2003-41062

A novel method for the synthesis of 5-perfluoroalkyl-2,3-dihydro-1,4- diazepines using easily available starting materials is described. 1-Perfluoroalkyl-2-iodoethylenes, obtained from the reaction of perfluoroalkyl iodides and alkynes, reacted with ethylenediamine under mild conditions to give the title compounds in good yields. A possible mechanism is proposed.

Full text of DOI:10.1055/s-2003-41062

PAPER
2307
A Novel Synthesis of 5-Perfluoroalkyl-2,3-dihydro-1,4-diazepines from
1-Perfluoroalkyl-2-iodoethylenes
Synthesis
i
of 5-Pe
n
rfluoroalkyl-2,3-dihy
T
dro-1,4-diazepi
a
nes o Liu,* Fu-Lu Zhao
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
Fax +86(21)6416128; E-mail: jtliu@pub.sioc.ac.cn
Received 2 June 2003; revised 11 July 2003
fluorine-containing heterocyclic compounds, it was found
that 5-perfluoroalkyl- 2,3-dihydro-1,4-diazepines could
be conveniently obtained from the reaction of 1 and ethyl-
enediamine.
Abstract: A novel method for the synthesis of 5-perfluoroalkyl-
2,3-dihydro-1,4-diazepines using easily available starting materials
is described. 1-Perfluoroalkyl-2-iodoethylenes, obtained from the
reaction of perfluoroalkyl iodides and alkynes, reacted with ethyl-
enediamine under mild conditions to give the title compounds in
good yields. A possible mechanism is proposed.
Key words: perfluoroalkyl iodides, 1-perfluoroalkyl-2-iodoethyl-
enes, 5-perfluoroalkyl-2,3-dihydro-1,4-diazepines, ethylenedi-
amine
Scheme 1
The reaction took place readily in ethanol under reflux.
After simple work-up of the reaction mixture, 5-perfluo-
roalkyl-2,3-dihydro-1,4-diazepines 2 were obtained in
good yields (Scheme 2). The results are summarized in
Table 1. All spectral data of compounds 2 coincided with
their structure and the structure of 2g was further con-
firmed by its X-ray crystallography (Figure 1),13 which
shows that the perfluoroalkyl substituent links to the car-
bon at 5-position of the 1,4-diazepine ring. Usually excess
ethylenediamine was needed for a better conversion since
it acted as both reagent and base in the reaction. Except
ethanol, MeCN, DMF, and 1,4-dioxane could also be used
as solvent in this reaction. As shown in Table 1, the length
of perfluoroalkyl chains has little influence on the reac-
tion, but the yield was somewhat affected by the R substit-
uent in 1 and best yields were obtained when R is H,
obviously caused by steric effects.
It is well-known that the introduction of fluorine atoms or
a fluoroalkyl group into heterocyclic compounds may
have a profound influence on their biological and physical
properties.1,2 Therefore the development of synthetic
methods of fluorinated heterocyclic compounds has been
the continuous subject in the field of both organofluorine
chemistry and organic synthesis. 2,3-Dihydro-1,4-diaz-
epines are important nitrogen-containing cyclic com-
pounds and much effort has been paid to the synthesis of
their fluorinated analogues. Usually the synthetic method
for these fluorine-containing heterocyclic compounds in-
volved the formation of heterocyclic systems from fluori-
nated precursors such as fluoroalkylated 1,3-dicarbonyl
compounds,3,4 -fluoroalkyl aldehydes or ketones5 and 4-
ethoxy-1,1,1-trifluoromethyl-3-buten-2-one,6 but these
starting materials are expensive or difficult to prepare. In
2001, Ohkoshi et al. reported the synthesis of fluoroalkyl-
ated 1,4-diazepines by the photochemical reaction of
commercially available fluoroalkyl iodides with 1-phe-
nyl-1-chloroethylene and subsequent transformation of
the product, but a low yield was obtained in their case.7
Hence, we were interested to develop a facile method to
synthesize such heterocyclic system from easily available
starting materials. In this paper we report the synthesis of
5-perfluoroalkyl-2,3-dihydro-1,4-diazepines from 1-per-
fluoroalkyl-2-iodoethylenes.
1-Perfluoroalkyl-2-iodoethylenes 1 are useful intermedi-
ates obtained from the reaction of commercially available
perfluoroalkyl iodide and alkynes in almost quantitatively
yield (Scheme 1).8 As versatile fluorine-containing pre-
cursors, they have been used to synthesize fluoroalkylated
pyrazoles,9 isoxazoles,10 pyrimidines11 and indolizines.12
In continuation of our investigations on the synthesis of
Scheme 2
When 1,2-diaminopropane was allowed to react with 1d
under similar conditions, two isomeric products, 3a and
3b were obtained as expected in 69% overall yield with a
ratio of about 1.3:1 (Scheme 3). The two isomers could be
separated by column chromatography.
SYNTHESIS 2003, No. 15, pp 2307–2310
x
x.
x
x
.
2
0
0
3
Advanced online publication: 23.09.2003
DOI: 10.1055/s-2003-41062; Art ID: F05003SS.pdf
© Georg Thieme Verlag Stuttgart · New York

2308
J.-T. Liu, F.-L. Zhao
PAPER
RFF2C
H2N
R
base
-HI
RFCF2CH=CIR
+
H2NCH2CH2NH2
N
A
base -HF
RF
F
F
RF
RF
R
R
base
-HF
N
R
HN
NH
N
H2N
NH
C
B
Figure 1 The X-ray structure of compound 2g
Table 1 Reaction of 1 with Ethylenediamine
Scheme 4 Possible mechanism of the reaction
Entry
Time (h) Product
R
RF
Yield (%)a
RF
N
1
2
12
12
12
15
20
20
20
24
24
24
2a
2b
2c
2d
2e
2f
H
C3F7
83
84
82
88
66
61
64
64
62
59
H
C3F6Cl
CF2Cl
C5F11
C3F7
NH2
EtOH
N
H
N
RFCF2CH=CHI
+
3
H
NH2
Et3N
4
H
RF
N
H
5
Ph
Ph
Ph
Bu
Bu
Bu
6
C3F6Cl
CF2Cl
C3F7
a. RF=CF2CF2CF3;
b. RF=CF2CF2CF2Cl
4
7
2g
2h
2i
Scheme 5
8
9
C3F6Cl
CF2Cl
Melting points are uncorrected. IR spectra were taken on a Perkin-
Elmer Jeol 983 spectrophotometer. 1H NMR spectra were measured
on a Bruker AM 300 (300 MHz) spectrometer using TMS as inter-
nal standard. 19F NMR spectra were taken on a Bruker AM 300 (282
MHz) spectrometer using CFCl3 as external standard. MS and
HRMS were obtained on a Hewlett-Packard HP-5989A and a Finni-
gan MAT 8430 spectrometer, respectively. Column chromatogra-
phy was performed using silica gel H, particle size 10–40 m.
10
2j
a Isolated yield based on 1.
C5F11
N
C5F11
NH2
EtOH
reflux
H2N
N
HN
HN
C5F11CF2CH=CHI
+
Fluorinated 1,4-diazepines 2; General Procedure
Me
CH3
H3C
A mixture of 1 (1 mmol), 1,2-diaminoethane (0.24 g, 4 mmol) and
EtOH (2 mL) was stirred under reflux for 12–24 h (monitored by 19F
NMR spectroscopy). After completion of the reaction, the mixture
was cooled to r.t., diluted with H2O (15 mL) and then extracted with
Et2O (3 × 15 mL). The organic layers were combined, washed with
sat. NaCl solution and dried (Na2SO4). After the solvent was re-
moved by rotary evaporation, the residue was chromatographed on
silica gel eluting with CH2Cl2–MeOH to give 2 as light yellow crys-
tals (Table 1).
3a
1d
3b
Scheme 3
A possible mechanism was proposed for the reaction as
shown in Scheme 4. Namely, the nucleophilic addition of
an amino group of ethylenediamine to the electron-defi-
cient olefin followed by dehydroiodination afforded the
intermediate A.11 Dehydrofluorination of A under basic
conditions gave B which underwent intramolecular nu-
5-Heptafluoropropyl-2,3-dihydro-1H-[1,4]diazepine (2a)
Mp 116–117 °C.
IR (KBr): 3228, 3073, 2998, 1629, 1556, 1351, 1316, 1211, 1189,
cleophilic addition of amino moiety to double bond to 1118, 1092, 875, 746 cm–1.
1H NMR (CDCl3): = 6.65 (d, 1 H, JHH = 9.0 Hz), 5.22 (br, 1 H,
NH), 4.98 (d, 1 H, JHH = 9.0 Hz), 4.10 (s, 2 H), 3.43 (s, 2 H).
give C. Dehydrofluorination of C in the presence of base
resulted in the formation of the final product.
19F NMR (CDCl3): = –80.2 (t, 3 F), –115.6 (m, 2 F), –126.1 (m, 2
F).
MS (EI): m/z (%) = 265 (M+ + 1, 22.67), 264 (M+, 100.00), 236 (M+
In the presence of triethylamine, 1 could also react with
1,2-phenylenediamine. But the expected fluorine-contain-
ing 1,4-diazepine derivatives was not obtained, and 2-per-
fluoroalkylbenzoimidazole 4 was isolated in moderate
yields instead (Scheme 5).
– C2H4, 93.53).
Anal. Calcd for C8H7F7N2: C, 36.36; H, 2.65; N, 10.61; F, 50.38.
Found: C, 36.35; H, 2.62; N, 10.61; F, 50.97.
Synthesis 2003, No. 15, 2307–2310 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Perfluoroalkyl-2,3-dihydro-1,4-diazepines
2309
5-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-2,3-dihydro-1H-
[1,4]diazepine (2b)5
Mp 104–105 °C.
19F NMR (acetone-d6): = –56.9 (s).
MS (EI): m/z (%) = 256 (M+, 46.94), 255 (M+ – 1, 100.00), 221 (M+
– Cl, 20.46).
IR (KBr): 3226, 3068, 2993, 2913, 1631, 1556, 1320, 1178, 1120,
1095, 967, 794, 757 cm–1.
1H NMR (acetone-d6): = 7.19 (br, 1 H, NH), 7.01 (d, 1 H,
Anal. Calcd for C12H11ClF2N2: C, 56.25; H, 4.29; N, 10.94; F,
14.84. Found: C, 56.02; H, 4.29;, N, 10.79; F, 14.78.
JHH = 9.0 Hz), 5.01 (d, 1 H, JHH = 9.0 Hz), 4.14 (s, 2 H), 3.55 (s, 2
5-Heptafluoropropyl-7-butyl-2,3-dihydro-1H-[1,4]diazepine
H).
(2h)
Mp 73–75 °C.
19F NMR (acetone-d6): = –69.3 (t, 2 F), –113.6 (m, 2 F), –120.9
(m, 2 F).
IR (KBr): 3235, 3113, 2940, 1613, 1589, 1543, 1442, 1350, 1229,
1114, 783, 748 cm–1.
1H NMR (CDCl3): = 4.91 (s, 1 H), 4.02 (s, 2 H), 3.36 (s, 2 H), 2.19
(t, 2 H, J = 7.2 Hz), 1.53 (m, 2 H), 1.36 (m, 2 H), 0.94 (t, 3 H, J =
7.2 Hz).
19F NMR (CDCl3): = –80.6 (t, 3 F), –115.8 (m, 2 F), –126.4 (m, 2
F).
5-(Chlorodifluoromethyl)-2,3-dihydro-1H-[1,4]diazepine (2c)5
Mp 135–136 °C.
IR (KBr): 3232, 3067, 2993, 2908, 1623, 1560, 1465, 1448, 1315,
1199, 1086, 896, 757 cm–1.
1H NMR (CDCl3): = 6.69 (d, 1 H, JHH = 9.0 Hz), 5.29 (br, 1 H,
NH), 5.01 (d, 1 H, JHH = 9.0 Hz), 4.06 (s, 2 H), 3.46 (s, 2 H).
MS (EI): m/z (%) = 320 (M+, 36.32), 305 (M+ – CH3, 25.37), 291
19F NMR (CDCl3): = –57.9 (s).
(M+ – C2H5, 65.59), 278 (M+ – C3H6, 100.00).
Anal. Calcd for C12H15F7N2: C, 45.00; H, 4.69; N, 8.75; F, 41.56.
Found: C, 45.00; H, 4.81; N, 8.61; F, 41.48.
5-Undecafluoropentyl-2,3-dihydro-1H-[1,4]diazepine (2d)5
Mp 85–86 °C.
IR (KBr): 3224, 3069, 2993, 1633, 1558, 1467, 1318, 1278, 1108,
963, 807, 763, 736 cm–1.
5-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-7-butyl -2,3-dihy-
dro-1H-[1,4]diazepine (2i)
Mp 53–55 °C.
1H NMR (acetone-d6): = 7.17 (br, 1 H, NH), 7.02 (d, 1 H,
J
H).
HH = 9.0 Hz), 5.02 (d, 1 H, JHH = 9.0 Hz), 4.14 (s, 2 H), 3.54 (s, 2
IR (KBr): 3230, 3096, 2962, 2875, 1612, 1591, 1541, 1340, 1194,
1114, 778 cm–1.
19F NMR (acetone-d6): = –81.7 (t, 3 F), –113.4 (m, 2 F), –121.9
(m, 2 F), –122.5 (m, 2 F), –126.8 (m, 2 F).
1H NMR (CDCl3): = 4.93 (s, 1 H), 4.03 (s, 2 H), 3.37 (s, 2 H), 2.20
(t, 2 H, J = 7.5 Hz), 1.55 (m, 2 H), 1.38 (m, 2 H), 0.94 (t, 3 H, J =
7.5 Hz).
5-Heptafluoropropyl-7-phenyl-2,3-dihydro-1H-[1,4]diazepine
19F NMR (CDCl3): = –67.1 (t, 2 F), –114.1 (m, 2 F), –120.3 (m, 2
F).
(2e)7
Mp 75–76 °C.
MS (EI): m/z (%) = 338 (M+ + 2, 9.87), 336 (M+, 29.54), 321 (M+ –
IR (KBr): 3232, 3086, 2980, 1613, 1568, 1536, 1493, 1453, 1353,
1230, 1177, 890, 744, 697 cm–1.
1H NMR (CDCl3): = 7.52–7.41 (m, 5 H), 5.32 (s, 2 H, C=CH,
NH), 4.12 (s, 2 H), 3.51 (s, 2 H).
CH3, 27.03), 307 (M+ – C2H5, 68.29), 294 (M+ – C3H6, 100.00).
Anal. Calcd for C12H15ClF6N2: C, 42.79; H, 4.46; N, 8.32; F, 33.88.
Found: C, 42.87; H, 4.48; N, 8.12; F, 33.97.
19F NMR (CDCl3): = –80.4 (t, 3 F), –115.3 (m, 2 F), –126.1 (m, 2
F).
5-Chlorodifluoromethyl-7-butyl-2,3-dihydro-1H-[1,4]diaz-
epine (2j)
Mp 58–60 °C.
5-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-7-phenyl-2,3-dihy-
dro-1H-[1,4]diazepine (2f)
Mp 83–84 °C.
IR (KBr): 3218, 3103, 2967, 2860, 1614, 1587, 1542, 1338, 1133,
936, 851, 764 cm–1.
1H NMR (CDCl3): = 4.95 (s, 1 H), 3.99 (s, 2 H), 3.40 (s, 2 H), 2.21
(t, 2 H, J = 7.2 Hz), 1.56 (m, 2 H), 1.35 (m, 2 H), 0.94 (t, 3 H, J =
7.2 Hz).
IR (KBr): 3226, 3095, 2988, 1617, 1587, 1540, 1458, 1335, 1193,
1174, 821, 790, 757 cm–1.
1H NMR (CDCl3): = 7.54–7.40 (m, 5 H), 5.34 (s, 1 H), 5.26 (br, 1
H, NH), 4.14 (s, 2 H), 3.53 (s, 2 H).
19F NMR (CDCl3): = –66.7 (t, 2 F), –113.4 (m, 2 F), –119.9 (m, 2
F).
MS (EI): m/z (%) = 356 (M+, 17.75), 355 (M+ – 1, 100.00), 321 (M+
19F NMR (CDCl3): = –57.8 (s).
MS (EI): m/z (%) = 238 (M+ + 2, 11.84), 236 (M+, 36.11), 221 (M+
– CH3, 25.83), 207 (M+ – C2H5, 69.24), 194 (M+ – C3H6, 100.00).
Anal. Calcd for C10H15ClF2N2: C, 50.74; H, 6.34; N, 11.84; F,
16.07. Found: C, 51.20; H, 6.38; N, 11.59; F, 16.09.
– Cl, 7.80).
Anal. Calcd for C14H11ClF6N2: C, 47.12; H, 3.08; N, 7.86; Cl, 9.96;
F, 31.98. Found: C, 47.12; H, 2.87; N, 7.74; Cl, 10.27; F, 31.63.
2-Methyl-5-undecafluoropentyl-2,3-dihydro-1H-[1,4]diazepine
(3a)
Mp 85–87 °C.
5-Chlorodifluoromethyl-7-phenyl-2,3-dihydro-1H-[1,4]diaz-
epine (2g)
Mp 163–164 °C.
IR (KBr): 3223, 3070, 2993, 2900, 1627, 1551, 1242, 1198, 1141,
1058, 954, 846, 736 cm–1.
1H NMR (CDCl3): = 6.61 (d, 1 H, JHH = 8.7 Hz), 5.00 (d, 1 H,
IR (KBr): 3219, 2990, 1608, 1576, 1532, 1492, 1446, 1337, 1185,
1145, 1112, 1033, 908, 762 cm–1.
1H NMR (acetone-d6): = 7.77–7.26 (m, 5 H), 7.26 (br, 1 H, NH),
JHH = 8.7 Hz), 5.20–4.60 (br, 1 H, NH), 4.12 (m, 1 H), 3.80–3.40
(m, 2 H), 1.25 (d, 3 H, JHH = 6.9 Hz).
19F NMR (CDCl3): = –81.2 (t, 3 F), –115.2 (m, 2 F), –122.1 (m, 2
F), –122.7 (m, 2 F), –126.5 (m, 2 F).
5.38 (s, 1 H), 4.16 (s, 2 H), 3.67 (s, 2 H).
Synthesis 2003, No. 15, 2307–2310 © Thieme Stuttgart · New York

2310
J.-T. Liu, F.-L. Zhao
PAPER
MS (EI): m/z (%) = 378 (M+, 67.40), 359 (M+ – F, 10.22), 336 (M+
– C3H6, 100.00), 109 (M+ – C5F11, 19.39), 67 (M+ – C5F11 – C3H6,
90.43).
19F NMR (acetone-d6): = –68.8 (t, 2 F), –111.6 (m, 2 F), –121.9
(m, 2 F).
MS (EI): m/z (%) = 304 (M+ + 2, 20.93), 302 (M+, 61.51), 283 (M+
Anal. Calcd for C11H9F11N2: C, 34.92; H, 2.38; N, 7.41; F, 55.29.
Found: C, 35.19; H, 2.56; N, 7.18; F, 55.33.
– F, 6.67), 267 (M+ – Cl, 17.34), 167 (M+ – C2F4Cl, 100.00).
Acknowledgment
3-Methyl-5-undecafluoropentyl-2,3-dihydro-1H-[1,4]diazepine
(3b)
Mp 84–86 °C.
We thank the National Natural Science Foundation of China for fi-
nancial support (No. 20172065).
IR (KBr): 3227, 3073, 2990, 2890, 1632, 1558, 1240, 1199, 1141,
1066, 937, 842, 794, 734 cm–1.
1H NMR (CDCl3): = 6.67 (d, 1 H, JHH = 9.3 Hz), 5.82–5.20 (br, 1
H, NH), 5.00 (d, 1 H, JHH = 9.3 Hz), 4.13 (m, 1 H), 3.42–3.00 (m, 2
H), 1.33 (d, 3 H, J = 7.2 Hz).
References
(1) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993.
(2) Yoshioka, H.; Tukayama, C.; Mastuo, N. J. Synth. Org.
Chem. Jpn. 1984, 42, 809; Chem. Abstr. 1984, 101, 205911.
(3) Joshi, K. C.; Pathak, V. N.; Bhargava, S. Indian J. Chem.,
Sect. B 1976, 14, 1004.
(4) Saloutin, V. I.; Skryabina, Z. E.; Burgart, Y. V. J. Fluorine
Chem. 1992, 56, 325.
(5) Wang, Q. F.; Hu, B.; Luo, B. H.; Hu, C. M. Tetrahedron
Lett. 1998, 39, 2377.
19F NMR (CDCl3): = –81.1 (t, 3 F), –114.5 (m, 2 F), –122.0 (m, 2
F), –122.4 (m, 2 F), –126.5 (m, 2 F).
MS (EI): m/z (%) = 378 (M+, 7.58), 336 (M+ – C3H6, 24.69), 109
(M+ – C5F11, 46.30), 81 (M+ – C5F11 – CHNH, 100.00), 67 (M+ –
C5F11 – C3H6, 69.02).
Anal. Calcd for C11H9F11N2: C, 34.92; H, 2.38; N, 7.41; F, 55.29.
Found: C, 34.73; H, 2.64; N, 7.12; F, 55.12.
2-Heptafluoropropyl-1H-benzoimidazole (4a)14
Yield 49%; mp 223–225 °C.
(6) Chu, Q. L.; Wang, Y. L.; Zhu, S. Z. Synth. Commun. 2000,
30, 677.
(7) Ohkoshi, M.; Yoshida, M.; Matsuyama, H.; Iyoda, M.
Tetrahedron Lett. 2001, 42, 33.
(8) Huang, W. Y.; Lu, L.; Zhang, Y. F. Chin. J. Chem. 1990,
350; Chem. Abstr.114, 1991, 142603U.
IR (KBr): 1591, 1494, 1456, 1343, 1218, 1180, 888, 738 cm–1.
1H NMR (acetone-d6): = 12.93 (br, 1 H, NH), 7.93 (m, 2 H), 7.59
(m, 2 H).
19F NMR (acetone-d6): = –81.2 (t, 3 F), –112.7 (m, 2 F), –127.3
(m, 2 F).
MS (EI): m/z = (%) 286 (M+, 58.27), 267 (M+ – F, 12.42), 167 (M+
– C2F5, 100.00).
(9) Tang, X. Q.; Hu, C. M. J. Chem. Soc., Chem. Commun.
1994, 631.
(10) Tang, X. Q.; Hu, C. M. J. Fluorine Chem. 1995, 73, 133.
(11) Guan, H. P.; Tang, X. Q.; Luo, B. H.; Hu, C. M. Synthesis
1997, 1489.
(12) Zhang, X. C.; Huang, W. Y. Synthesis 1999, 51.
(13) X-ray data for compound 2g: C12H11ClF2N2, M = 256.68,
triclinic, a = 11.3673(12) Å, b = 11.4429(12) Å,
c = 11.4833(12) Å, V = 1191.9(2) Å3, Dc = 11.430 g/cm3,
crystal size: 0.486 × 0.272 × 0.138 mm. Data were measured
at 293 K on a Bruker SMART CCD diffractometer with
graphite monochromated Mo-K radiation.
(14) Lane, E. S. J. Chem. Soc. 1955, 534.
(15) Wang, Q. F.; Mao, Y. Y.; Zhu, S. Z.; Hu, C. M. J. Fluorine
Chem. 1999, 95, 141.
HRMS (EI): m/z calcd for C10H5F7N2: 286.03409; found:
286.03392.
2-(3-Chloro-1,1,2,2,3,3-hexafluoropropyl)-1H-benzoimidazole
(4b)15
Yield 50%; mp 201–204 °C.
IR (KBr): 1593, 1496, 1456, 1320, 1183, 1116, 819, 741 cm–1.
1H NMR (acetone-d6): = 7.84 (d, 1 H, JHH = 7.5 Hz), 7.68 (d, 1 H,
JHH = 7.5 Hz), 7.41 (m, 2 H).
Synthesis 2003, No. 15, 2307–2310 © Thieme Stuttgart · New York