Facile synthesis of α-fluoro substituted amidines from imidoyl chlorides and some of its application

Article abstract of DOI:10.1016/j.jfluchem.2006.06.008

A series of α-fluoro subustituted amidines were synthesized from corresponding fluorinated imidoyl chlorides in good to excellent yields and some of its applications are outlined in our programs.

Full text of DOI:10.1016/j.jfluchem.2006.06.008

Journal of Fluorine Chemistry 127 (2006) 1168–1174
www.elsevier.com/locate/fluor
Facile synthesis of a-fluoro substituted amidines from imidoyl
chlorides and some of its application
a,b
Yong-Ming Wu a, , Min Zhang , Yi-Qun Li
*
b,**
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
b Department of Chemistry, Jinan University, Guangzhou 510632, PR China
Received 7 April 2006; received in revised form 5 June 2006; accepted 6 June 2006
Available online 15 June 2006
Abstract
A series of a-fluoro subustituted amidines were synthesized from corresponding fluorinated imidoyl chlorides in good to excellent yields
and some of its applications are outlined in our programs.
# 2006 Elsevier B.V. All rights reserved.
Keywords: a-Fluoro subustituted imidoyl chlorides; a-Fluoro subustituted amidines; Fluorinated benzoimidazole; Aryl amination; 1,4-Dihydropyridine;
Fluorinated aminals
1. Intruduction
atom [14]. In search for new CF2-containing reactive synthetic
intermediates [15], we have found that bromodifluoroacetimi-
doyl halides showed unique properties compared with their
non-fluorinated analogues because of the existence of BrCF2
group. As the continue of the research, in this report, we would
like to firstly describe a mild and novel protocol of preparing
CF2- and CF3-containing amidines by the reaction of amines
with fluoroacetimidoyl chlorides and some chemical transfor-
mation of the result fluorinated amidines.
Amidines, the nitrogen analogues of carboxylic acids, are
structural parts of numerous compounds of biological interest
including important medical and biochemical agents. They are
used as trypsin inhibitors [1], platelet fibrinogen receptor
antagonists [2], VLA-4 antagonists [3], etc. Besides their role
as a pharmacophore group in biologically active agents,
amidines are also used as valuable intermediates for the
preparation of heterocycles [4], e.g., b-lactams [5], imidazol
[6], indole [7], and pyrimidine [8].
2. Results and discussion
Numerous methods for the synthesis of amidines are
reported [9], such as the widely used Pinner synthesis [10] and
the reaction of imidoyl chloride with ammonia or primary or
secondary amines [11]. However there are few reports on the
synthesis of fluorinated arylamidines [12]. In the past few years
organofluorine chemistry has returned as an expanding and
productive area of research, as can be seen by the increasing
number of recent publications, reviews, topics, and mono-
graphs [13]. Furthermore, organofluorine chemicals have found
a wide range of applications in medicine and agriculture due, in
part, to the unique biological properties imparted by the fluorine
During the course of our research on the Sonogashira
reaction of bromodifluoroacetimidoyl halides with terminal
alkynes [15d], it was found accidentally that when diisopro-
pylamine was used as a base, a N-diisopropylamidines (A) was
obtained in moderate yield, obviously this was the result of the
nucleophilc substitution reaction of imidoyl chlorides with the
secondary amine. Then we used different kind of amines to
expand this reaction, the result was listed in Scheme 1 and
Table 1.
In all cases studied, the nucleophilic substitution reaction
proceeded smoothly to give the corresponding disubstituted
amidines in good to excellent yields. It was interesting to find
that different kind of amine had dramatically different
reactivity in this transformation. Strong electron-withdrawing
* Corresponding author. Tel.: +86 21 54925190; fax: +86 21 64166128.
** Corresponding author.
E-mail address: ymwu@mail.sioc.ac.cn (Y.-M. Wu).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.06.008

Y.-M. Wu et al. / Journal of Fluorine Chemistry 127 (2006) 1168–1174
1169
Scheme 3.
Scheme 1. The substitution reaction of imidoyl chlorides with amines.
groups in N-aryl (e.g., F) of imidoyl chlorides would promote
the reactions rates, and short reaction time was needed. On the
other side, nucleophilic reagent with strong electron-with-
drawing groups (e.g., –NO2) would prolong the reaction time
and the catalyst PdCl2(PPh3)2 was needed (entries 3, 8, 13, 18),
Usually, the reactions of aliphatic amine and ammonia (2d, 2e)
with imidoyl chlorides can proceed quickly under room
temperature and the reaction could be completed within 5–
30 min (entries 4, 5, 9, 10, 14, 15, 19, 20), while the substitution
reactions of aromatic amines needed heating to 80 8C to obtain
desired results.
Scheme 4. Six possible isomers of N,N0-disubetituted amides.
There might be six isomers in the N,N0-disubstituted
amidines (Scheme 4) [16]. Among them: a versus b and d
versus e are tautomers; a versus d, b versus c and e versus f are
E-, Z-isomer; b versus e and c versus f are rotamers. It was
interesting to note that when R was not an aromatic group, there
Generally speeking, an addition–elimination route was
involved in the active amine (i.e., Scheme 2).
But for unreactive amine, a palladium promoted coupling
mechanism is more reasonable (i.e., Scheme 3).
Scheme 2.
Table 1
Nucleophilic substitutions reaction of imidoyl chlorides with aminesa
Entry
Ar (1a–1d)
Rf
R (2a–2e)
Time/temperature
3aa–3gd/yield (%)
1
2
3,4-2F–C6H3 (1a)
3,4-2F–C6H3 (1a)
3,4-2F–C6H3 (1a)
3,4-2F–C6H3 (1a)
3,4-2F–C6H3 (1a)
3,4-2F–C6H3 (1b)
3,4-2F–C6H3 (1b)
3,4-2F–C6H3 (1b)
3,4-2F–C6H3 (1b)
3,4-2F–C6H3 (1b)
4-CH3O–C6H4 (1c)
4-CH3O–C6H4 (1c)
4-CH3O–C6H4 (1c)
4-CH3O–C6H4 (1c)
4-CH3O–C6H4 (1c)
4-CH3O–C6H4 (1d)
4-CH3O–C6H4 (1d)
4-CH3O–C6H4 (1d)
4-CH3O–C6H4 (1d)
4-CH3O–C6H4 (1d)
BrF2C
BrF2C
BrF2C
BrF2C
BrF2C
F3C
4-CH3O–C6H4 (2a)
C6H5 (2b)
4-NO2–C6H4 (2c)
n-C4H9 (2d)
NH3 (2e)
4-CH3O–C6H4 (2a)
C6H5 (2b)
4-NO2–C6H4 (2c)
n-C4H9 (2d)
NH3 (2e)
4-CH3O–C6H4 (2a)
C6H5 (2b)
4-NO2–C6H4 (2c)
n-C4H9 (2d)
NH3 (2e)
4-CH3O–C6H4 (2a)
C6H5 (2b)
4-NO2–C6H4 (2c)
n-C4H9 (2d)
NH3 (2e)
1 h/80 8C
2 h/80 8C
6 h/80 8C
5 min/room temperature
30 min/room temperature
30 min/80 8C
1 h/80 8C
4 h/80 8C
5 min/room temperature
30 min/room temperature
4 h/80 8C
5 h/80 8C
8 h/80 8C
5 min/room temperature
30 min/room temperature
5 h/80 8C
5 h/80 8C
8 h/80 8C
5 min/room temperature
3aa/92
3ab/88
3ac/60a
3ad/98
3ae/92
3ba/98
3bb/96
3bc/66a
3bd/92
3be/96
3ca/85
3cb/73
3cc/52a
3cd/96
3ce/83
3da/80
3db/71
3dc/61a
3dd/93
3de/92
3
4
5
6
7
F3C
8
F3C
9
F3C
10
11
12
13
14
15
16
17
18
19
20
F3C
F3C
F3C
F3C
F3C
F3C
BrF2C
BrF2C
BrF2C
BrF2C
BrF2C
30 min/room temperature
a
PdCl2(PPh3)2 was used as catalyst.

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Y.-M. Wu et al. / Journal of Fluorine Chemistry 127 (2006) 1168–1174
Scheme 5. Synthesis of 1,4-dihydropyridine.
3ab, 3ad, 3ae reacted wtih sodium borohydride in methanol,
the CF2Br group in amidines was converted into CF2H-
containing amidines 6, and with no reaction for CF3-containing
amidines (Scheme 6).
3. Conclusion
In conclusion, a series of bromodifluoromethylated and
trifluoromethylated amidnes were synthesized by the reaction
of N-arylbromodifluoroacetimidoyl chloride or N-aryltrifluor-
oacet-imidoyl chloride with amines under mild conditions.
These products could be used to construct different kinds of
containing bromodifluoromethyl and trifluoromethyl hetero-
cycles. Further study on this subject is in progress.
4. Experimental
Unless otherwise noted, solvents and reagents were
1
commercial available and used as received. H NMR spectra
Fig. 1. Crystal structure of 1,4-dihydropyridine.
were only two isomers were detected in 19F NMR spectra,
while if R was an aromatic group, four isomers were found.
Obviously this was due to the conjugated effects of the aromatic
group. These results also mean that because of low energy
difference between the rotamers, they could not be detected in
this amidine at room temperature.
were recorded on a Brucker AM-300 (300 MHz) spectrometer
with Me4Si as internal standard. 19F NMR spectra were taken
on Brucher AM-300 (282 MHz) spectrometer with CFCl3 as
external standard, downfield shifts being designed as positive.
Mass spectra were taken on a HP 5989a spectrometer, while
elemental analysis were performed by this institute.
With the fluorinated amidines in hand, we started to look at
the various chemical transformation that this kind of amidines
undergo. Hantzsch three components synthesis is a versatile
method for the synthesis of 1,4-dihydropyridine [17]. It was
found that if this fluorinated amidine was used as one
component to perform the same reaction, under catalysis with
ZnCl2 and refluxing in toluene for 3 h, a 1,4-dihydropyridine 5
could also be synthesized in 72% yield (Scheme 5). The
structure of pyridine was confirmed by X-ray (Fig. 1) [18].
Attempts to transfer the amidines to the corresponding
ketene Aminals by reducing with NaBH4 was not succeeded, an
unexpected products were obtained. It was found that when
4.1. General procedure for the synthesis 2-bromo-N-
(3,4-difluoro-phenyl)-2,2-difluoro-N0-(4-methoxy)-
acetamidine (3aa)
To a stirred mixture of K2CO3 (138 mg, 1 mmol) in toluene,
2-bromo-N-(3,4-difluoro-phenyl)-2,2-difluoro-acetimidoyl
chloride (1a, 305 mg, 1 mmol) and 4-methoxy-phenylamine
(2a, 135 mg, 1.1 mmol) were added successively. The mixture
was stirred at 80 8C for 1 h and then filtered, washed by ethyl
ether. After removing the solvent under reduced pressure the
crude product was purified by column chromatography on silica
gel [eluent:ethyl acetate/petroleum ether (b.p. 60–90), 1:5] to
give the product (3aa, 360 mg, 92%).
4.2. General procedure for the synthesis of 2-bromo-N-
butyl-N0-(3,4-difluoro-phenyl)-2,2-difluoro-acetamidine
(3ad)
To a stirred mixture of 2-bromo-N-(3,4-difluoro-phenyl)-
2,2-difluoro-acetimidoyl chloride (1a, 305 mg, 1 mmol) in
Scheme 6.

Y.-M. Wu et al. / Journal of Fluorine Chemistry 127 (2006) 1168–1174
1171
toluene, butylamine (2d, 183 mg, 2.5 mmol) was added. The
mixture was stirred at room temperature for 5 min and then
filtered, washed by ethyl ether, after removing the solvent under
reduced pressure, the product (3ad, 334 mg, 98%) was obtained
without any further purification.
1425, 1253, 1207, 1114, 967, 909, 829; m/z (EI) 340 (68), 261
(42), 211 (12), 139 (20), 113 (21). Calc. for C12H13BrF4N2: C,
42.25; H, 3.84; N, 8.21. Found: C, 42.28; H, 3.88; N, 8.16.
4.3.5. 2-Bromo-2,2-difluoro-N-3,4-difluorophenyl-
acetamdine (3ae)
4.3. General procedure for the synthesis of 2-bromo-N-
(3,4-difluoro-phenyl)-2,2-difluoro-acetamidine (3ae)
White solid. m.p.: 90–91 8C. 1H NMR: d 7.20 (d,
J = 9.30 Hz, 1H), 6.79 (t, J = 9.30 Hz, 1H), 6.65 (t,
J = 8.10 Hz, 1H), 4.93 (s, 2H), 3.18–3.29 (m, 2H), 1.25–1.46
(m, 4H), 0.93 (m, 3H). 19F NMR: d ꢀ57.36 (s, 2F), ꢀ135.26 to
ꢀ135.16 (m, 1F), ꢀ143.29 to 143.16 (m, 1F). IR (film, cmꢀ1):
3475, 2978, 1682, 1601, 1513, 1478, 1397, 1257, 1210, 1036,
956, 926, 871, 851, 825; m/z (EI) 284 (15), 155 (42), 139 (3),
113 (36). Calc. for C8H5BrF4N2: C, 33.71; H, 1.77; N, 9.83.
Found: C, 33.91; H, 1.79; N, 9.62.
To a stirred mixture of 2-bromo-N-(3,4-difluoro-phenyl)-
2,2-difluoro-acetimidoyl chloride (1a, 305 mg, 1 mmol) in
toluene, the gas of ammonia was aerated. The mixture was
stirred at room temperature for 30 min and then filtered, washed
by ethyl ether, after removing the solvent under reduced
pressure, the product (3ae, 263 mg, 98%) was obtained without
any further purification.
4.3.6. 2,2,2-Trifluoro-N-(4-methoxyl-phenyl)-N0-3,4-
difluorophenyl-acetamdine (3ba)
4.3.1. 2-Bromo-2,2-difluoro-N-(4-methoxyl-phenyl)-N0-3,4-
difluorophenyl-acetamdine (3aa)
1
White solid. m.p.: 114–116 8C. H NMR: d 7.46–7.52 (m,
White solid. m.p.: 80–83 8C. 1H NMR: d 6.59–6.96 (m, 8H),
3.82 (s, 3H). 19F NMR: d ꢀ51.06 (s):ꢀ51.06 (s):ꢀ51.06
(s):ꢀ56.76 (s) = 1:1:3:3, ꢀ138.51 to ꢀ138.41 (m, 1F),
ꢀ145.10 to 145.06 (m, 1F). IR (film, cmꢀ1): 3427, 3291,
2839, 1680, 1600, 1417, 1378, 1254, 1166, 862, 826; m/z (EI)
390 (36), 261 (69), 139 (12), 122 (65), 113 (19). Calc. for
C15H11BrF4N2O: C, 46.06; H, 2.83; N, 7.16. Found: C, 46.17;
H, 2.88; N, 6.92.
1H), 6.74–7.06 (m, 4H), 6.41–6.59 (m, 3H), 3.69–3.76 (d, 3H).
19F NMR: d ꢀ63.78 (s):ꢀ63.87 (s):ꢀ70.13 (s):ꢀ70.46
(s) = 2:4:1:4, ꢀ137.71 to ꢀ137.37 (m, 1F), ꢀ146.08 to
146.05 (m, 1F). IR (film, cmꢀ1): 3361, 1673, 1597, 1554,
1508, 1417, 1360, 1285, 1245, 1184, 1027, 974, 865, 821; m/z
(EI) 329 (88), 261 (15), 208 (46), 139 (5), 113 (88). Calc. for
C15H11F5N2O: C, 54.55; H, 3.36; N, 8.48. Found: C, 54.60; H,
3.43; N, 8.49.
4.3.2. 2-Bromo-2,2-difluoro-N-phenyl-N0-3,4-
4.3.7. 2,2,2-Trifluoro-N-phenyl-N0-3,4-difluorophenyl-
acetamdine (3bb)
difluorophenyl-acetamdine (3ab)
White solid. m.p.: 61–63 8C. 1H NMR: d 6.81–7.26 (m, 4H),
6.46–6.75 (m, 5H), 6.45 (s, 1H). 19F NMR: d ꢀ51.10
(s):ꢀ56.15 (s):ꢀ62.28 (s):ꢀ62.36 (s) = 1:1:3:3, ꢀ143.48 to
ꢀ143.28 (m, 1F), ꢀ149.34 to ꢀ148.99 (m, 1F). IR (film,
cmꢀ1): 3428, 1679, 1596, 1417, 1510, 1393, 1246, 1173, 1084,
872; m/z (EI) 360 (40), 231 (84), 139 (22), 113 (20), 92 (67), 77
(100). Calc. for C14H9BrF4N2: C, 46.56; H, 2.51; N, 7.76.
Found: C, 46.77; H, 2.68; N, 7.72.
Yellowish solid. m.p.: 70–72 8C. 1H NMR: d 7.54–7.64 (m,
1H), 7.20–7.36 (m, 3H), 7.05–7.10 (m, 4H), 6.47–6.56 (m, 1H).
19F NMR:
d
ꢀ63.78 (s):ꢀ63.90 (s):70.03 (s):ꢀ70.15
(s) = 5:5:1:4, ꢀ137.54 to ꢀ136.16 (m, 1F), ꢀ145.86 to
143.96 (m, 1F). IR (neat, cmꢀ1): 3238, 3061, 1679, 1598,
1552, 1510, 1425, 1342, 1259, 1151, 1028, 976, 864, 815; m/z
(EI) 300 (100), 231 (17), 208 (24), 113 (23). Calc. for
C14H9F5N2: C, 56.01; H, 3.02; N, 9.33. Found: C, 56.04; H,
3.15; N, 9.32.
4.3.3. 2-Bromo-2,2-difluoro-N-(4-nitro-phenyl)-N0-3,4-
difluorophenyl-acetamdine (3ac)
4.3.8. 2,2,2-Trifluoro-N-(4-nitro-phenyl)-N-3,4-
difluorophenyl-acetamdine (3bc)
1
Yellow solid. m.p.: 114–117 8C. H NMR: d 8.12–8.20 (d,
1
J = 10.83, 2H), 7.72–7.84 (m, 2H), 7.09–7.26 (m, 2H), 6.59–
6.98 (m, 2H). 19F NMR: d ꢀ53.20 to ꢀ51.78 (m, 2F) ꢀ137.43
to ꢀ137.41 (m, 1F), ꢀ141.66 to 140.83 (m, 1F). IR (film,
cmꢀ1): 3372, 2924, 2853, 1681, 1591, 1513, 1370, 1249, 1174,
877, 856; m/z (EI) 405 (36), 276 (100), 139 (27), 113 (32). Calc.
for C14H8BrF4N3O2: C, 41.40; H, 1.99; N, 10.35. Found: C,
41.71; H, 2.16; N, 10.16.
Yellow solid. m.p.: 140–142 8C. H NMR: d 8.17–8.22 (m,
2H), 7.82–7.86 (m, 1H), 7.65–7.73 (m, 1H), 7.20–7.34 (m, 3H),
6.57–6.96 (m, 1H). 19F NMR: d ꢀ63.79 (s):ꢀ63.90 (s):64.72
(s):ꢀ64.82 (s) = 3:3:5:5, ꢀ134.54 to ꢀ134.43 (m, 1F),
ꢀ144.47 to 144.40 (m, 1F). IR (film, cmꢀ1): 3370, 1681,
1593, 1512, 1443, 1339, 1266, 1159, 1105, 969, 855, 814; m/z
(EI) 344 (69), 276 (21), 208 (63), 113 (100). Calc. for
C14H8F5N3O2: C, 48.71; H, 2.34; N, 12.17. Found: C, 48.79; H,
2.41; N, 12.11.
4.3.4. 2-Bromo-2,2-difluoro-N-butyl-N0-3,4-difluorophenyl-
acetamdine (3ad)
Oil. 1H NMR: d 7.03 (d, J = 9.03 Hz, 1H), 6.68 (t,
J = 9.15 Hz, 1H), 6.54 (t, J = 7.80 Hz, 1H), 3.18–3.29 (m,
2H), 1.25–1.46 (m, 4H), 0.93 (m, 3H). 19F NMR: d ꢀ50.36
(s):ꢀ55.18 (s) = 2:1, ꢀ138.32 to ꢀ136.56 (m, 1F), ꢀ147.08 to
144.96 (m, 1F). IR (neat, cmꢀ1): 3462, 2962, 1667, 1600, 1510,
4.3.9. 2,2,2-Trifluoro-N-butyl-N0-3,4-difluorophenyl-
acetamdine (3bd)
Colorless oil. 1H NMR: d 7.26–7.28 (m, 1H), 6.50–6.63 (m,
2H), 5.15 (s, 1H), 3.02–3.34 (m, 2H), 1.19–1.44 (m, 4H), 0.97
(m, 3H). 19F NMR: d ꢀ64.46 (s):ꢀ70.67 (s) = 3:1, ꢀ138.09 to

1172
Y.-M. Wu et al. / Journal of Fluorine Chemistry 127 (2006) 1168–1174
ꢀ136.13 (m, 1F), ꢀ146.56 to ꢀ144.54 (m, 1F). IR (neat,
cmꢀ1): 3470, 2965, 1688, 1601, 1514, 1425, 1382, 1126, 1101,
959, 867, 817; m/z (EI) 280 (13), 223 (62), 208 (45), 113 (72).
Calc. for C12H13F5N2: C, 51.43; H, 4.68; N, 10.00. Found: C,
51.44; H, 4.86; N, 9.87.
4.3.15. 2,2,2-Trifluoro-N-4-methoxylphenyl-acetamdine
(3ce)
White solid. m.p.: 127–128 8C. 1H NMR: d 6.92 (d,
J = 9.9 Hz, 2H), 6.88 (d, J = 9.9 Hz, 2H), 4.91 (s, 2H), 3.80 (s,
3H). 19F NMR: d ꢀ73.14 (s, 3F). IR (film, cmꢀ1): 3379, 2839,
1659, 1505, 1433, 1442, 1302, 1237, 1180, 1135, 1031, 860,
803; m/z (EI) 218 (100), 202 (34), 149 (90), 122 (9). Calc. for
C9H9F3N2O: C, 49.55; H, 4.16; N, 12.84. Found: C, 49.67; H,
4.16; N, 12.77.
4.3.10. 2,2,2-Trifluoro-N-3,4-difluorophenyl-acetamdine
(3be)
White solid. m.p.: 70–72 8C. 1H NMR: d 7.11–7.26 (m, 1H),
6.74–6.81 (m, 1H), 6.62–6.68 (m, 1H), 5.01 (s, 2H). 19F NMR: d
ꢀ73.26 (s, 1H), ꢀ135.27 to ꢀ135.12 (m, 1F), ꢀ143.26 to
ꢀ143.11 (m, 1F). IR (film, cmꢀ1): 3467, 2961, 1669, 1611,
1512, 1429, 1273, 1227, 1164, 969, 909, 829; m/z (EI) 224 (62),
155 (100), 113 (55). Calc. for C8H5F5N2: C, 42.87; H, 2.25; N,
12.50. Found: C, 42.92; H, 2.23; N, 12.61.
4.3.16. 2-Bromo-2,2-difluoro-N-4-methoxylphenyl-N0-4-
methoxylphenyl-acetamdine (3da)
1
Yellow solid. m.p.: 132–134 8C. H NMR: d 7.46 (s, 1H),
6.84–6.96 (m, 4H), 6.46–6.78 (m, 4H), 3.81 (s):3.85 (s) = 1:1.
19F NMR: d ꢀ50.15 (s):ꢀ54.76 (s) = 1:3. IR (film, cmꢀ1):
3380, 2836, 1658, 1504, 1433, 1465, 1442, 1291, 1240, 1145,
1090, 1034, 957, 878, 826; m/z (EI) 385 (33), 255 (78), 133
(30), 122 (100). Calc. for C16H15BrF2N2O2: C, 49.89; H, 3.92;
N, 7.27. Found: C, 50.13; H, 4.16; N, 7.04.
4.3.11. 2,2,2-Trifluoro-N-4-methoxyphenyll-N0-4-
mehtoxylphenyl-acetamdine (3ca)
White solid. m.p.: 83–86 8C. 1H NMR: d 6.76–6.84 (m, 2H),
6.41–6.60 (m, 5H), 6.44–6.48 (d, 1H), 3.67–3.74 (d, 6H). 19F
NMR: d ꢀ63.68 (s):ꢀ68.89 (s) = 2:3. IR (film, cmꢀ1): 3354,
2839, 1668, 1504, 1466, 1415, 1247, 1180, 1034, 918, 827; m/z
(EI) 324 (100), 202 (87), 133 (7), 122 (59). Calc. for
C16H15F3N2O2: C, 59.26; H, 4.66; N, 8.64. Found: C, 59.40; H,
4.63; N, 8.53.
4.3.17. 2-Bromo-2,2-difluoro-N-phenyl-N0-4-
methoxylphenyl-acetamdine (3db)
1
Yellow solid. m.p.: 92–93 8C. H NMR: d 6.90–7.25 (m,
4H), 6.54–6.77 (m, 6H), 3.73 (m, 3H). 19F NMR: d ꢀ50.54
(s):ꢀ54.71 (s):55.69 (s):55.74 (s) = 2:2:1:1. IR (film, cmꢀ1):
3315, 2837, 1663, 1595, 1511, 1444, 1240, 1146, 1092, 1034,
957, 874; m/z (EI) 355 (100), 262 (12), 225 (58), 133 (11), 122
(73). Calc. for C15H13BrF2N2O: C, 50.72; H, 3.69; N, 7.89.
Found: C, 50.89; H, 3.82; N, 7.74.
4.3.12. 2,2,2-Trifluoro-N-phenyl-N0-4-mehtoxylphenyl-
acetamdine (3cb)
Yellowish oil. 1H NMR: d 7.55–7.65 (m, 1H), 7.31–7.36 (m,
1H), 7.06–7.11 (m, 2H), 6.94–6.99 (m, 5H), 6.62–6.72 (m, 1H),
3.76 (s, 3H). 19F NMR: d ꢀ63.71 (s):ꢀ63.77 (s):ꢀ68.87
(s):69.80 (s) = 2:1:2:1. IR (film, cmꢀ1): 3647, 1678, 1596,
1510, 1400, 1338, 1246, 1147, 1033, 829; m/z (EI) 294 (34),
225 (11), 202 (16), 122 (30). Calc. for C15H13F3N2O: C, 61.22;
H, 4.45; N, 9.52. Found: C, 61.35; H, 4.44; N, 9.37.
4.3.18. 2-Bromo-2,2-difluoro-N-4nitrophenyl-N0-4-
methoxylphenyl-acetamdine (3dc)
1
White solid. m.p.: 112–115 8C. H NMR: d 7.99–8.03 (m,
2H), 7.12–7.25 (m, 2H), 6.71–6.83 (m, 5H), 3.72 (s):3.73
(s) = 2:1. 19F NMR: d ꢀ52.91 (s):ꢀ60.33 (s) = 1:2. IR (film,
cmꢀ1): 3370, 2837, 1674, 1587, 1511, 1336, 1245, 1172, 1096,
1032, 957, 882, 830; m/z (EI) 400 (25), 270 (42), 133 (10), 122
(100). Calc. for C15H12BrF2N3O3: C, 45.02; H, 3.02; N, 10.50.
Found: C, 45.23; H, 3.36; N, 10.33.
4.3.13. 2,2,2-Trifluoro-N-4-nitrophenyl-N0-4-
mehtoxylphenyl-acetamdine (3ca)
Yellow solid. m.p.: 100–102 8C.1H NMR: d 8.04–8.07 (d,
J = 7.5 Hz, 2H), 7.21–7.26 (m, 1H), 6.91 (s, 1H), 6.77–6.85 (m,
5H), 3.74–3.76 (d, 3H). 19F NMR: d ꢀ63.67 (s):ꢀ63.77
(s):71.24 (s):75.62 (s) = 3:3:2:1. IR (film, cmꢀ1): 3373, 2839,
1680, 1590, 1510, 1417, 1342, 1249, 1107, 1032, 916, 853, 830;
m/z (EI) 339 (60), 202 (64), 122 (100). Calc. for C15H13F3N2O:
C, 53.10; H, 3.57; N, 12.39. Found: C, 53.15; H, 3.66; N, 12.39.
4.3.19. 2-Bromo-2,2-difluoro-N-butyl-N0-4-
methoxylphenyl-acetamdine (3dd)
1
Colorless oil. H NMR: d 6.72–6.92 (m, 4H), 4.88 (s):4.62
(s) = 2:3, 3.77 (s):3.78 (s) = 2:3, 3.33 (m):2.97 (m) = 2:3, 1.11–
1.38 (m, 4H), 0.75–0.92 (m, 3H). 19F NMR: d ꢀ49.88
(s):ꢀ54.34 (s) = 2:3. IR (neat, cmꢀ1): 3382, 2959, 2873, 1661,
1503, 1466, 1239, 1178, 1104, 1035, 958, 915, 851; m/z (EI)
334 (32), 255 (38), 205 (27), 133 (35). Calc. for
C13H17BrF2N2O: C, 46.58; H, 5.11; N, 8.36. Found: C,
46.81; H, 5.35; N, 8.22.
4.3.14. 2,2,2-Trifluoro-N-butyl-N0-4-mehtoxylphenyl-
acetamdine (3cd)
1
Colorless oil. H NMR: d 6.70–6.89 (m, 4H), 4.60 (s):4.58
(s) = 1:1, 3.77 (s):3:78 (s) = 1:1, 3.32 (dd, J = 6.9 Hz):3.06 (dd,
J = 6.9 Hz) = 1:1, 1.60–1.67 (m):1.18–1.26 (m) = 1:1, 1.33–
1.46 (m, 2H), 0.94–0.99 (t, J = 7.5 Hz):0.82–0.87 (t,
J = 7.5 Hz) = 1:1. 19F NMR: d ꢀ64.23 (s):ꢀ70.08 (s) = 1:1.
IR (neat, cmꢀ1): 3386, 2959, 2875, 1678, 1504, 1466, 1442,
1380, 1242, 1131, 1104, 1036, 892, 836; m/z (EI) 274 (29), 217
(27), 202 (29), 133 (30), 122 (44). Calc. for C13H17F3N2O: C,
56.93; H, 6.25; N, 10.21. Found: C, 56.87; H, 6.21; N, 10.19.
4.3.20. 2-Bromo-2,2-difluoro-N-4-methoxylphenyl-
acetamdine (3de)
White solid. m.p.: 97–99 8C. 1H NMR: d 6.88–6.91 (m, 4H),
4.89 (s, 1H), 3.78 (s):3.80 (s) = 2:3. 19F NMR: d ꢀ56.80
(s):ꢀ56.81 (s) = 3:2. IR (film, cmꢀ1): 3333, 2837, 1669, 1608,
1446, 1442, 1380, 1289, 1240, 1179, 1107, 1032, 921, 852; m/z

Y.-M. Wu et al. / Journal of Fluorine Chemistry 127 (2006) 1168–1174
1173
(EI) 278 (25), 149 (100), 133 (9). Calc. for C9H9BrF2N2O: C,
38.73; H, 3.25; N, 10.04. Found: C, 38.93; H, 3.20; N, 10.03.
4.5.3. 2-Bromo-2,2-difluoro-N-3,4-difluorophenyl-
acetamdine (6ae)
Yellowish oil. 1H NMR: d 7.08–7.19 (m, 1H), 6.72–6.80 (m,
1H), 6.62–6.66 (m, 1H), 6.06 (td, J = 3.3 Hz, 1H), 4.86 (m, 2H).
19F NMR: d ꢀ122.38 (dd, J = 3.36 Hz, 2F), ꢀ135.57 to
ꢀ135.49 (m, 1F), ꢀ143.81 to ꢀ143.72 (m, 1F). IR (neat,
cmꢀ1): 3490, 1675, 1602, 1511, 1415, 1341, 1294, 1255, 1210,
1165, 1050, 955, 870, 824; m/z (EI) 206 (28), 190 (18), 140
(85), 113 (70). Calc. for C8H6F4N2: C, 46.61; H, 2.93; N, 13.59.
Found: C, 46.73; H, 2.99; N, 13.40.
4.4. General procedure for the synthesis of 1,4-
dihydropyridine (4)
A mixture of 4-chlorobenaldehyde (1.1 mmol), amidine
(1 mmol), ethyl acetoacetate (1.2 mmol), ZnCl2 (0.1 mmol)
and toluene (2 mL) was stirred at 80 8C for 2 h. Then stopped
the reaction, filtrated, the solid part was washed with ether.
After removal of the solvent under reduced pressure, the residue
was purified by flash chromatography with 5:1 petroleum ether
and ethyl acetate as eluent affording the product 4.
Acknowledgment
The authors thank the National Natural Science Foundation
of China (NNSFC) (no. 20472104 and 20532040) for financial
support.
4.4.1. 4-(4-Chlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylic acid diethyl ester (4ce)
Yellowish solid. 1H NMR: d 7.14–7.23 (m, 4H), 5.69 (s, 1H),
4.95 (s, 1H), 4.03–4.14 (m, 4H), 2.32 (s, 6H), 1.22 (t,
J = 7.2 Hz, 6H). IR (film, cmꢀ1): 3340, 2981, 1681, 1657, 1623,
1368, 1302, 1275, 1214, 1170, 1120, 1099, 1016, 912; m/z (EI)
363 (2), 252 (100), 224 (23), 196 (34).
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5H), 6.48–6.53 (m, 1H), 6.05 (td, J = 2.4 Hz, 1H). 19F NMR: d
ꢀ121.96 (d, J = 54.62 Hz, 2F), ꢀ135.89 to ꢀ135.76 (m, 1F),
ꢀ145.72 to ꢀ145.61 (m, 1F). IR (neat, cmꢀ1): 3438, 2927,
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1
Yellowish oil. H NMR: d 6.98–7.08 (m, 1H), 6.62–6.68
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ꢀ145.86 (m, 1F). IR (neat, cmꢀ1): 3460, 2936, 2865, 1660,
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˚
˚
˚
dimensions: a = 10.1228(11) A, b = 7.5111(8) A, c = 24.575(3) A,
3
˚
a = 908, b = 97.089(3)8, g = 90(3)8; volume: 1854.2(4) A ; Z, calculated
(b) J.T. Welch, Selective Fluorination in Organic and Bioorganic Chem-
istry, ACS Symposium Series, vol. 456, American Chemical Society,
Whashington, DC, 1991;
density: 4, 1.303 mg/m3; absorption coefficient: 0.229 mmꢀ1; F(0 0 0):
708; crystal size: 0.240 mm ꢁ 0.105 mm ꢁ 0.076 mm; theta range for
data collection: 1.67–25.508; completeness to theta = 25.50, 99.5%; data/
restraints/parameters: 3428/2/242; goodness-of-fit on F2: 1.081; final R
indices [I > 2s(1)]: R1 = 0.0902, wR2 ¼ 0:2056; R indices (all data):
R1 = 0.1376, wR2 ¼ 0:2331; largest diff. peak and hole: 0.342 and
(c) R. Filler, Y. Kobayashi, L.M. Yagupolskii, Biomedical Aspects of
Fluorine Chemistry, Elsevier, Amsterdam, 1993;
(d) J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, Chichester, 1991.
ꢀ3
˚
ꢀ0.317 Einstein A
.