4-Fluoroanilines: Synthesis and decomposition

Article abstract of DOI:10.1016/S0022-1139(01)00401-8

Fourteen N- and/or 2-substituted 4-fluoroanilines were prepared (the series includes N-C2-bridged compounds). Some of them were found to be thermally unstable when dissolved in chloroform. Both ¹⁹F NMR spectra and comparison of GIAO-DFT calculated and experimental ¹³C chemical shifts were used to suggest decomposition products of 4-fluoroanilines.

Full text of DOI:10.1016/S0022-1139(01)00401-8

Journal of Fluorine Chemistry 111 ,2001) 1±10
4-Fluoroanilines: synthesis and decomposition
Anna Zakrzewskaa, Erkki Kolehmainenb, Borys Osmialowskia, Ryszard Gawineckia,*
aDepartment of Chemistry, Technical and Agricultural University, Seminaryjna 3, PL-85-326 Bydgoszcz, Poland
b
È È È È
Department of Chemistry, University of Jyvaskyla, P.O. Box 35, FIN-40351 Jyvaskyla, Finland
Received 1 November 2000; accepted 22 March 2001
Abstract
Fourteen N- and/or 2-substituted 4-¯uoroanilines were prepared ,the series includes N±C2-bridged compounds). Some of them were
found to be thermally unstable when dissolved in chloroform. Both 19F NMRspectra and comparison of GIAO-DFT calculated and
experimental 13C chemical shifts were used to suggest decomposition products of 4-¯uoroanilines. # 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Fluoroanilines; 13C NMR; 19F NMR; PFG 1H; 15N HMBC; GIAO-DFT calculations
1. Introduction
obtained are expected to follow the electron-donor strength
of the amino groups present in the molecule. This problem
will be discussed in our next paper [24]. It should be
mentioned that 1:10 dilution of the sample results in ca.
30 Hz ,<0.1 ppm) change of the signal position which is
negligible in comparison with the total chemical shift range
for these compounds. Insigni®cant effect of the concentra-
tion on the J,F, H) coupling constants has also been
observed.
No general synthetic procedure is known for N- and/or 2-
substituted 4-¯uoroanilines. Depending on type of the pro-
duct, different methods were used in the present work as
described in Section 4.
Thermal decomposition of benzenediazonium tetra¯uor-
oborates ,Schiemann reaction) [14,15] seemed a good gen-
eral method to prepare N- and/or 2-substituted 4-
¯uoroanilines. It was found, however, that the yield of that
reaction is usually very low. N-alkyl-4-¯uoroanilines were
prepared by acylation ,formylation) of 4-¯uoroaniline
,Table 4) followed by reduction ,LiAlH4) of the anilides
,Table 5). N,N-dialkyl-4-¯uoroanilines were obtained by the
same procedure from N-alkyl-4-¯uoroanilines or by reduc-
tion of N-alkyl-4-¯uoroanilides formed by reaction of 4-
¯uoroaniline with alkyl orthoformates ,Table 5).
N-,4-¯uorophenyl) substituted pyrrolidine ,9) and piper-
idine ,10) were obtained by cyclocondensation of 4-¯uor-
oaniline with a,o-dihaloalkanes ,Scheme 2).
Synthetic procedures for many ¯uoroanilines are well
known [1]. Their N-alkyl derivatives can be obtained by
alkylation of 4-¯uoroaniline [2±13], thermal decomposition
of 4-aminobenzenediazonium tetra¯uoroborates [14,15],
nucleophilic substitution of ¯uorine in 1,4-di¯uorobenzene
by different amino groups [16] and by reduction [17] or
hydrolysis [18] of 4-¯uoroanilides. Condensation of 4-¯uor-
oaniline with a,o-dihaloalkanes gives N-,4-¯uoro-phenyl)-
cyclopolymethyleneimines [19,20]. 5-Fluoroindolines are
also known [21,22] and 2-methyl-6-¯uoro-1,2,3,4-tetrahy-
droquinoline is commercially available. Although anilines
are relatively stable compounds [23], no systematic studies
on the thermal stability of the ¯uoroaniline derivatives have
been reported.
It is known that different amino groups in aromatic amines
can show varying electron-donor properties [20]. That is
why we are interested in the preparation of a series of 4-
¯uoro-anilines ,Scheme 1) needed for our studies of the
substituent effects induced by different amino groups [24].
2. Results and discussion
1H, 13C, 15N and 19F NMRparameters are collected in
Tables 1±3. The 19F NMRchemical shifts for ¯uoroanilines
Electrophilic cyclization of 2-chloro-N-,4-¯uoropheny-
l)acetamides 23 and 24 gave indolinones 25 and 26
,Scheme 3). Reduction gives 5-¯uoroindolines 11 and 12
,Table 5).
* Corresponding author. Tel.: ‡48-52-3792900; fax: ‡48-52-3731160.
E-mail address: gawiner@mail.atr.bydgoszcz.pl ,R. Gawinecki).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 , 0 1 ) 0 0 4 0 1 - 8

2
A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
Scheme 2.
Reduction of 6-¯uoroquinoline ,27) with formic acid in a
weak alkaline solution followed by formylation ,see Section
4) was found to be a good method of synthesis for 6-¯uoro-
1-formyl-1,2,3,4-tetrahydroquinoline ,28). Its hydrolysis
and reduction gives 6-¯uoro-1,2,3,4-tetrahydroquinolines
14 and 15 ,Scheme 4 and Table 5).
Cyclocondensation of 5-¯uoroindoline ,11) and 6-¯uoro-
1,2,3,4-tetrahydroquinoline ,14) with 1-bromo-3-chloropro-
pane gave 8-¯uorolilolidine ,8-¯uoro-1,2,5,6-tetra-hydro-
4H-pyrrolo-[3,2,1-ij]quinoline ,13) and 9-¯uorojulolidine
,9-¯uoro-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quino-
line ,16) ,Scheme 5).
Scheme 1.
Table 1
Experimental 1H NMRchemical shifts , d) and H, F spin±spin coupling constants ,Hz) ,in parentheses) of fluoroamines for 0.1À0.2 M solutions in CDCl3 at
303 Ka
H2
H3
H5
H6
H8
H9
H10
1b
2c,d
3f
4g
5
6.89 ,8.71)
e
6.59 ,4.42)
6.59 ,4.42)
6.59 ,4.51)
6.58 ,4.48)
6.59 ,4.48)
6.81 ,4.52)
6.76 ,4.52)
6.76 ,4.52)
6.61 ,4.51)
6.57 ,4.47)
6.59 ,4.49)
6.44 ,4.45)
6.50 ,4.17)
6.77 ,4.52)
±
6.89 ,8.71)
e
±
±
±
±
2.15
À2.82
3.14
3.01
3.43
3.41
2.16; 2.18k
3.31
3.09
3.34
3.27
3.28
3.21
±
±
6.98 ,8.80)
7.00 ,8.75)
7.12 ,8.85)
7.06 ,8.85)
6.58 ,4.48)
6.98 ,8.80)
7.00 ,8.75)
7.12 ,8.85)
7.06 ,8.85)
±
±
6.59 ,4.48)
6.81 ,4.52)
1.29
±
±
±
6h
7
6.76 ,4.52)
1.21
1.25
±
±
7.06 ,8.77)
j
6.76 ,4.52)
7.06 ,8.77)
j
±
8i
±
6.57 ,4.47)
±
9
7.05 ,8.76)
7.05 ,8.76)
2.08
1.75
2.97
2.77
2.98
2.88
±
10
6.99 ,8.73)
m
6.59 ,4.59)
6.99 ,8.73)
m
1.60
±
12l
14n
15o
16
±
±
±
±
6.72 ,8.83)
6.99 ,8.62)
6.66 ,9.06)
6.72 ,8.83)
6.99 ,8.62)
6.66 ,9.06)
1.96
2.13
2.12
a Compounds 11 and 13 are unstable.
b d,NH): 3.58 ppm.
c d,NH): 3.47 ppm.
d d,2-CH3): 3.47 ppm.
e Overlapped signals at 6.74±6.84 ppm.
f d,NH): 3.77 ppm.
g d,NH): 3.51 ppm.
h d,H80): 2.95 ppm.
i d,2-CH3): 2.88 ppm.
j Overlapped signals at 6.78±6.96 ppm.
k These methyl groups are not equivalent.
l d,H80): 2.79 ppm.
m Overlapped signals at 6.82±6.95 ppm.
n d,NH): 3.71 ppm.
o d,H80): 3.36 ppm.

A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
3
Table 2
Experimental and GIAO-DFT calculated ,bold) 13C NMRchemical shifts , d) of fluoroamines for 0.1À0.2 M solutions in CDCl3 at 303 K ,C, F spin±spin
coupling constants ,Hz) are given in parentheses)a
C1
C2
C3
C4
C5
C6
C8
±
C9
±
C10
±
1
155.97 ,234.6)
156.35
115.26 ,22.5)
117.56
115.66 ,10.4)
110.83
142.45
142.00
140.52
140.36
145.71
144.31
144.79
143.82
147.41
144.10
146.01
145.70
144.62
147.07
143.50
151.63
144.73
143.12
148.95
148.60
149.64
146.13
144.38
139.54
143.24
141.36
142.47
137.60
115.66 ,10.4)
110.83
115.26 ,22.5)
117.56
2b
3
156.03 ,235.0)
158.14
116.55 ,22.0)
117.29
123.86 ,7.2)
118.94
115.41 ,7.7)
109.92
112.80 ,22.0)
114.65
±
±
±
155.60 ,234.0)
158.59
115.33 ,22.3)
117.06
112.92 ,7.4)
111.82
112.92 ,7.4)
106.05
115.33 ,22.3)
116.84
30.94
26.19
38.66
36.60
40.75
36.83
37.64
26.75
44.73
45.87
17.07
19.53
47.87
46.06
51.45
52.70
34.49
29.52
41.82
41.27
51.09
50.94
49.91
49.56
4
155.38 ,233.8)
158.00
115.20 ,22.1)
117.04
113.20 ,7.2)
111.75
113.20 ,7.2)
106.57
115.20 ,22.1)
116.80
14.29
12.46
±
±
±
±
±
±
±
5
155.40 ,235.0)
157.04
114.88 ,21.9)
117.20
113.40 ,7.4)
110.70
113.40 ,7.4)
110.70
114.88 ,21.9)
117.20
6c
7
155.21 ,234.5)
158.00
115.12 ,21.8)
116.45
113.49 ,7.2)
109.03
113.49 ,7.2)
110.16
115.12 ,21.8)
116.58
10.82
11.49
12.21
13.76
±
154.89 ,234.2)
159.00
115.32 ,21.9)
116.23
113.45 ,7.1)
110.13
113.45 ,7.1)
110.14
115.32 ,21.9)
116.23
8d
9
156.01 ,234.0)
164.94
116.26 ,22.1)
117.69
123.59 ,7.1)
144.23
115.15 ,7.9)
126.72
116.45 ,22.1)
114.09
154.70 ,232.9)
156.93
115.22 ,21.9)
117.09
111.94 ,7.1)
111.21
111.94 ,7.1)
112.26
115.22 ,21.9)
117.24
25.29
26.09
25.79
25.97
28.53
27.68
21.80
22.48
22.30
23.21
22.01
22.80
10
157.38 ,237.9)
159.44
115.09 ,21.9)
117.04
118.04 ,7.3)
119.30
118.04 ,7.3)
115.06
115.09 ,21.9)
116.15
23.97
27.19
12e
14
156.42 ,234.2)
158.96
111.74 ,24.1)
113.32
130.98 ,8.1)
130.00
100.66 ,4.7)
100.64
112.68 ,23.0)
114.45
155.24 ,234.4)
158.10
112.73 ,22.1)
116.69
122.54 ,6.9)
120.19
114.48 ,7.4)
110.62
110.34 ,21.8)
114.82
26.84
28.85
27.72
29.63
27.54
29.64
15f
16
154.98 ,234.5)
158.57
114.89 ,21.2)
114.46
124.15 ,6.9)
108.98
115.05 ,6.9)
116.55
126.60 ,19.0)
123.00
154.22 ,234.6)
158.09
112.81 ,21.2)
114.70
122.70 ,6.8)
122.44
122.70 ,6.8)
122.44
112.81 ,21.2)
114.70
a Compounds 11 and 13 are unstable.
b d,2-CH3): 17.19 ppm, 16.07 ppm.
c d,C80): 47.35 ppm, 41.92 ppm.
d d,2-CH3): 30.88 ppm, 41.98 ppm.
e d,C80): 56.45 ppm, 51.44 ppm.
f d,C80): 39.42 ppm, 35.61 ppm.
Most of the ¯uoroamines obtained are stable. Their
structures were con®rmed by 1H, 13C and 19F NMRspectro-
scopy as well as by comparing their experimental and
calculated ,GIAO-DFT) 13C chemical shifts. Identity of
the compounds obtained was also supported by elemental
analysis and by comparison their physical data with these
previously reported. For parent 4-¯uoroaniline and its N-
substituted derivatives the coupling pattern in the 19F NMR
Scheme 3.

4
A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
Table 3
Redundant signals in the NMR spectra of solutions pre-
pared by dissolving 11 and 13 in chloroform show that these
¯uoroanilines decompose easily on standing in chloroform
solution at ambient temperature. Also some preliminary
conclusions about the structures of the decomposition pro-
ducts can be drawn especially based on the characteristic
nJ,F, H) spin±spin coupling patterns in their 19F NMR
spectra. For example, 19F NMRspectrum and the PFG
1H, 15N HMBC map of 5-¯uoroindoline contain a ``septet''
at À15.35 ppm ,a ``sextet'' was expected for this compound)
with a signal at À312.7 ppm. Thus, there is no 5-¯uoroindo-
line present in solution. Its decomposition product contains
two ortho and two meta protons with respect to the ¯uorine
atom. NMRspectra of 1-methyl-5-¯uoroindoline contain
two ``sextets'' at À12.55 and À14.59 ppm ,a single ``sextet''
was expected for 19F) and two signals at À256.9 and
À318.2 ppm in 15N. Thus, in addition to 1-methyl-5-¯uor-
oindoline ,À14.59 ppm ,19F), À318.2 ppm ,15N)) there
exists also its decomposition product in chloroform solution.
The spectra of 6-¯uoro-1,2,3,4-tetrahydroquinoline shows a
``sextet'' at À15.23 ppm ,a ``sextet'' was expected for 19F)
and two signals at À321.2 and À324.1 ppm ,15N). Thus,
there is again more than one compound present in the
solution, although 1-methyl-5-¯uoroindoline ,À15.23 ppm
,19F), À321.2 ppm ,15N)] is expected to be a relatively stable
compound. In the case of 1-methyl-6-¯uoro-1,2,3,4-tetra-
hydroquinoline a ``septet'' at À15.27 and a ``sextet'' at
À17.25 ppm as well as some minor signals in the À14.5
to À16.5 ppm range were detected ,a ``sextet'' was expected
Experimental 19F and 15N NMRchemical shifts , d) and H, F spin±spin
coupling constants of fluoroamines for 0.1À0.2 M solutions in CDCl3 at
303 K
d,19F)a
3J,19F, 1H)
4J,19F, 1H)
d,15N)b
1
2
À13.84
À13.88
À15.49
À15.32
À16.07
À16.45
À16.82
À14.01
À17.64
À12.00
À14.59
À15.23
À17.25
À16.14
8.8
9.3
8.8
8.6
8.5
8.5
8.4
9.3
8.6
8.7
8.4
8.9
8.7
9.3
4.4
5.0
4.3
4.2
4.3
4.3
4.2
4.9
4.3
4.4
4.2
5.0
4.7
±
À329.5
À331.2
À332.2
À313.2
À339.4
À327.2
À313.2
À312.8
À311.1
À315.6
À318.2
À321.2
À327.7
À318.6
3
4
5
6
7
8
9
10
12
14
15
16
a From external fluorobenzene and nitromethane, respectively.
b From external fluorobenzene and nitromethane, respectively.
spectrum is a triplet of triplets which resembles a septet
owing to an occasional overlap of resonance peaks as
described in Scheme 6. Also other observed coupling pat-
terns can be explained by a similar inspection. In case of 2-
substituted 4-¯uoroaniline the coupling pattern is formed
from three doublets amounting in total to eight peaks which
owing to partial overlaps resembles a sextet while in 2,6-
disubstituted congeners there exits only one triplet.
Table 4
Acylation ,formylation) of 4-fluoroanilines
R1
R2
R3
R4
Acylating
agent
Product
Yield ,%)
Melting point ,8C) or
Lit. melting ,8C) or boiling
point ,8C/mmHg)a
boiling point ,8C/mmHg)a
H
H
H
H
H
H
H
Et
H
H
H
HCO2Me
Ac2O
17
18
19
20
21
22g
23
24
69
97
79
75
49
95
67
76
63±65
66±68b
152±153c
45±48d
123±125/12e
92±93/14f
±
131±133h
153±157/8i
H
H
Me
H
152±153
111±115/1
96±97/1
40±42
H
Me
Et
HC,OMe)3
HC,OEt)3
Ac2O
H
H
H
Et
Me
H
Me
H
Me
H
HC,Ome)3
ClCH2COCl
ClCH2COCl
80±82/4
133±135
149±150/7
CH2Cl
CH2Cl
H
Me
a Melting or boiling point of the product.
b [25].
c [26].
d [27].
e [28].
f [29].
g Analysis calculated for C9H10FNO ,167.18): C, 64.65; H, 6.03; N, 8.38; F, 11.36. Found: C, 64.39; H, 6.13; N, 8.26 F, 11 [25].
h [30].
i [10].

A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
5
Table 5
Reduction of 4-fluoroanilines
R1
R2
R3
Product
Yield ,%)
Boiling point
,8C/mmHg)a
Lit. boiling point
,8C/mmHg)a
H
H
H
3
4
78
81
91
56
94
71
74
56
76
100±101/111
103±104/18
71±73/10
90±91/10
80±81/2
136/120b
H
Me
H
H
96/25c; 92/14d
H
Me
Me
Et
5
198±200/760e; 85±86/18f
H
Me
Me
H
6g
7
±
H
Me
92±93/14h
Me
H
8
102±103/4
79±81/4
78±80/1.7f
CH2
CH2
,CH2)2
11
12j
15k
70±72/0.3i
Me
Me
83±85/2
±
±
105±106/4
a Boiling point of the product.
b [17].
c [31].
d [32].
e [6].
f [7].
g Analysis calculated for C9H12FN ,153.98): C, 70.56; H, 7.90; N, 9.14; F, 12.40. Found: C, 70.78; H, 7.79; N, 9.01; F, 12.64.
h [29].
i [21].
j Analysis calculated for C9H10FN ,151.18): C, 71.50; H, 6.67; N, 9.27; F, 12.57. Found: C, 71.68; H, 6.79; N, 9.11; F, 12.66.
k Analysis calculated for C10H12FN ,165.21): C, 72.70; H, 7.32; N, 8.48; F, 11.50. Found: C, 72.78; H, 7.20; N, 8.27; F, 11.62.
Scheme 4.
in the 19F NMRspectrum of this compound) and two signals
at À327.7 and À330.0 ppm ,15N). Thus, there are some
decomposition products present in the sample besides 1-
methyl-6-¯uoro-1,2,3,4-tetra-hydroquinoline ,À17.25 ppm
,19F), À327.7 ppm ,15N)). The 19F NMRspectrum of a
chloroform solution of 8-¯uoro-lilolidine contains a ``sep-
tet'' at À15.27 and a sextet at À17.25 ppm as well as some
minor signals in the À14.5 to À17 ppm range ,a ``triplet''
was expected for 8-¯uorolilolidine for 19F). Two signals at
À312.6 and À318.1 ppm can be seen in the 15N NMR
spectrum of the sample. This con®rms that there is no 8-
¯uorolilolidine present in solution. Similarity of the spectra
of 8-¯uorolilolidine and 6-¯uoro-1,2,3,4-tetrahydroquino-
line proves that the latter compound and its decomposition
products are present in solution. Although, the 19F NMR
spectrum of solution of 9-¯uorojulolidine contains a triplet
at À16.14 ppm ,a triplet was expected) and there are
two signals at À318.6 and À320.2 ppm in its 15N NMR
Scheme 5.

6
A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
observed decomposition products of 5-¯uoroindoline ,11)
1
and 8-¯uorolilolidine ,13). The H, 13C, 15N and 19F NMR
chemical shifts unambiguously show that the 4-F-anilino
structural moiety is conserved during decomposition which
is expected owing to the known stability of the aromatic
system. Signi®cant differences between the calculated [33±
35] and experimental 19F NMRchemical shifts for 4-¯uor-
oanilines make them more or less impractical also in deter-
mination of the structures of these decomposition products.
3. Conclusions
A series of N- and/or 2-substituted 4-¯uoroanilines were
prepared. N-Alkyl- and N,N-dialkyl-4-¯uoroanilines were
obtained by acylation of 4-¯uoroaniline followed by reduc-
tion of the 4-¯uroanilide. N-,4-Fluorophenyl) substituted
pyrrolidine and piperidine were prepared by cyclocondensa-
tion of 4-¯uoroaniline with appropriate a,o-dihaloalkanes.
Reduction of 5-¯uoro-indolinones gives 5-¯uoroindolines.
6-Fluoro-1,2,3,4-tetrahydroquinolines and its 1-methyl
derivative were obtained by hydrolysis or reduction of
6-¯uoro-1-formyl-1,2,3,4-tetrahydro-quinoline, respectively.
Cyclocondensation of 5-¯uoroindoline and 6-¯uoro-1,2,3,4-
tetrahydro-quinoline with 1-bromo-3-chloropropane gave
8-¯uorolilolidine ,8-¯uoro-1,2,5,6-tetrahydro-4H-pyrrolo-
[3,2,1-ij]quinoline) and 9-¯uorojulolidine ,9-¯uoro-2,3,6,7-
tetrahydro-1H,5H-pyrido-[3,2,1-ij]quinoline).
Most of the ¯uoroamines obtained are stable. Their
structures were con®rmed by 1H, 13C and 19F NMRspectro-
scopy as well as by comparing their experimental and
calculated ,GIAO-DFT) 13C chemical shifts. 5-Fluoroindo-
line and 8-¯uorolilolidine decompose easily on standing in
chloroform solution at ambient temperature. The 19F NMR
spectra were found to be very useful in predicting the
existence and structures of the decomposition products ,they
show clearly separated and characteristic coupling patterns).
These compounds are probably ring opening products.
4. Experimental
Scheme 6.
The reaction yields are based on product. Melting points
are uncorrected. Amines 6, 8, and 14±16 were puri®ed by the
column chromatography ,Kieselgel 200±400 mesh, tolue-
ne:acetone ,1:1)) before the ®nal distillation.
spectrum, 9-¯uorojulolidine ,À16.14 ppm ,19F), À318.6
ppm ,15N)) is a relatively stable compound.
Comparison of experimental and predicted ,calculated)
chemical shifts can be helpful in identi®cation of the decom-
position products ,the mechanism of decomposition of 4-
¯uoro-anilines was not studied by us). Some compounds
were selected and 13C NMRchemical shifts calculated
,GIAO/B3LYP/6-311G/HF/3-21G) for them. These com-
pounds are the isomers of 11 and 13. Only the less strained
geometric isomers were considered. The values shown in
Scheme 7 suggest that 4-¯uoro-2-vinylaniline, N-ethyli-
dene-4-¯uoro-2-,1-propenyl)-aniline and N-ethylidene-4-
¯uoro-2-,2-propenyl)aniline are reasonable structures as
4-Fluoroaniline ,1) and 4-¯uoro-2-methylaniline ,2) are
commercially available. They were distilled at reduced
pressure before NMRstudies. Boiling points: 64±65 8C/
6 mmHg ,lit. 186±1878C/760 mmHg [36], 187±1888C/
762 mmHg [37]) for 1 and 90±918C/16 mmHg ,lit. 93±
948C/17.3 mmHg [38], 968C/24 mmHg [39]) for 2. 6-Fluor-
oquinoline ,27) was obtained by the Skraup method [40]. It
has bp125±1268C/27 mmHg ,lit. 125±1268C/30 mmHg
[41]. 4-Fluoro-formanilide ,17) was obtained according to
[42]. Its N-alkyl derivatives 19 and 20 were the products of

A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
7
Scheme 7.
reaction of 4-¯uoroaniline with alkyl orthoformates [43]. 4-
Fluoroacetanilide ,18) and its N-methyl derivative 21 were
prepared using a typical procedure for acetylation of aro-
matic amines [44]. 22 was obtained similarly starting from
2-methyl-4-¯uoroaniline. 2-Chloro-N-,4-¯uorophenyl)ace-
tamides 23 and 24 were prepared according to the known
procedure for similar bromo derivatives [10]. Fluoroamines
3-8, 11,12 and 15 were obtained by reduction of respective
amides ,17±24) ,lithium aluminum hydride in diethyl ether,
standard procedure). Reaction yields and properties of the
products are shown in Table 5. 4-Fluoro-N-methylaniline
,3) obtained by a reduction of 4-¯uoroformanilide was
contaminated by 4-¯uoro-aniline and its N,N-dimethyl deri-
vative. A pure sample was obtained by nitrosation to N-
methyl-N-nitroso-4-¯uoroaniline ,bp 116±1188C/10 mmHg,
lit. 1118C/7 mmHg [32]) followed by reduction ,procedure
similar to that used in puri®cation of N-methylaniline [45]).
4.1. 1-94-Fluorophenyl)pyrrolidine 99)
A
mixture of 1,4-dichlorobutane ,3.9 ml, 4.57 g,
36 mmol) and 4-¯uoroaniline ,17 ml, 20.0 g, 0.18 mol)
was heated on a water bath for 4 h. It was then acidi®ed
with hydrochloric acid and unreacted dichlorobutane
extracted with diethyl ether. The residue was carefully
treated with acetic anhydride and left for 2 h at room
temperature. Water ,1.5 l) was then added to the reaction
mixture. Extraction with ethyl ether, the water layer made
alkaline with concentrated aqueous sodium hydroxide,
extraction of the product with diethyl ether, drying of the

8
A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
extract ,K2CO3), evaporation of the solvent and distillation
gave an oil ,34%) boiling at 130±1328C/13 mmHg ,lit.
1228C/13 mmHg [36], 2468C/760 mmHg [4]).
diethyl ether, dried ,K2CO3) and distilled under reduced
pressure. It boils at 119±1218C/2 mmHg. Yield: 69%. Ana-
lysis calculated for C11H12FN ,177.22): C, 74.55; H, 6.83;
N, 7.90; F, 10.72. Found: C, 74.29; H, 6.75; N, 7.69; F,
10.84%.
4.2. 1-94-Fluorophenyl)piperidine 910)
1-,4-Fluorophenyl)piperidine ,10) ,bp: 110±1128C/
16 mmHg, lit. 110±1128C/16 mmHg [29], 708C/3 mmHg
[46]) was obtained in 45% yield by the method described
for 9, starting from 1,5-dibromopentane and 4-¯uoroaniline.
The reaction mixture was acidi®ed with hydrochloric
acid, extracted with diethyl ether to remove unreacted
dibromopentane and made alkaline with aqueous NaOH.
The product was extracted with diethyl ether, dried ,K2CO3)
and distilled.
4.6. 6-Fluoro-1-formyl-1,2,3,4-tetrahydroquinoline 928)
A
mixture of 6-¯uoroquinoline ,12.3 ml, 14.7 g,
0.40 mol), 98 % formic acid ,18.4 ml, 23.0 g, 0.5 mol)
and anhydrous sodium formate ,34.0 g, 0.5 mol) was gently
re¯uxed for 33 h with occasional stirring. It was diluted with
water and made alkaline with concentrated aqueous sodium
hydroxide. The reaction product was extracted from this
mixture with diethyl ether, dried ,K2CO3), solvent evapo-
rated and then the residue distilled. Except for some recov-
ered 6-¯uoroquinoline, 28 ,bp: 154±1568C/4 mmHg) was
obtained in 80% yield. Analysis calculated for C10H10FNO
,179.19): C, 68.02; H, 5.63; N, 7.82; F, 10.60. Found: C,
67.80; H, 5.72; N, 7.67; F, 10.79%.
4.3. 5-Fluoro,2,3-dihydroindol-2-one,
5-fluoroindolin-2-one 925)
Mixture of 2-chloro-N-,4-¯uorophenyl)acetamide ,11.3 g,
0.06 mol) previously dried at 1108C and anhydrous alumi-
nium chloride ,10.0 g, 0.07 mol) was heated at 220±2258C
on an oil bath for 30 min ,see Scheme 3). Careful addition of
ice ,650 g) to the reaction mixture results in separation of the
dark brown oil which solidi®ed overnight. The product was
®ltered off, crushed and treated with 10% hydrochloric
acid, boiled for a short time with water ,300 ml) and tarry
substances removed by ®ltration and the crystals obtained
,after cooling of the ®ltrate) were twice recrystallized from
water. Product melts at 130±1318C ,lit. 139±1408C [47],
129±1308C [48]). Yield: 54%.
4.7. 6-Fluoro-1,2,3,4-tetrahydroquinoline 914)
6-Fluoro-1-formyl-1,2,3,4-tetrahydroquinoline
,1.9 g,
0.01 mol) was treated with concentrated hydrochloric acid
,6.7 ml, 8.0 g, 0.22 mol) and then re¯uxed for 1 h. The
reaction mixture was made alkaline with concentrated
aqueous sodium hydroxide. Extraction with diethyl ether,
drying ,K2CO3), removal of the solvent and distillation
gave 38% of the liquid boiling at 108±1098C/5 mmHg.
Analysis calculated for C9H10FN ,151.18): C, 71.50; H,
6.67; N, 9.27; F, 12.57. Found: C, 71.67; H, 6.47; N, 9.41; F,
12.37%.
4.4. 5-Fluoro-2,3-dihydro-1-methylindol-2-one,
5-fluoro-1-methylindolin-2-one 926)
4.8. 9-Fluorojulolidine 916)
2-Chloro-N-,4-¯uorophenyl)-N-methylacetamide
,20.5 g, 0.1 mol) was added to a melted mixture of anhy-
drous aluminium chloride ,84.5 g, 0.64 mol) and sodium
chloride ,16.9 g, 0.29 mol) at 1408C. The temperature of the
reaction mixture was quickly raised to 2208C. After a few
minutes in that temperature evolution of hydrogen chloride
ceased and ice ,700 g) and 20% hydrochloric acid ,50 ml)
were successively added to the cold reaction mixture. The
precipitate was recrystallized from water ,charcoal). Melt-
ing points: 133±1358C ,lit. 128±1308C [10], 130.5±1328C
[49]). Yield: 58%.
Mixture of 6-¯uoro-1,2,3,4-tetrahydroquinoline ,3.7 g,
2.4 mol) and 1-bromo-3-chloropropane ,12.2 ml, 19.5 g,
0.12 mol) was heated at 150±1608C ,oil bath) for 23 h.
The cold reaction mixture was treated with 78 ml of 22%
hydrochloric acid. Unreacted bromo-chloropropane was
removed from the mixture by steam distillation. The residue
was made alkaline with concentrated aqueous sodium
hydroxide and extracted with diethyl ether. Drying of the
extract ,K2CO3), removal of solvent and distillation of the
residue gave 16 ,83%) boiling at 130±1328C/1 mmHg.
Analysis calculated for C12H14FN ,191.24): C, 75.36; H,
7.38; N, 7.32; F, 9.94. Found: C, 75.45; H, 7.56; N, 7.20; F,
9.99%.
4.5. 8-Fluorolilolidine 913)
Mixture of 5-¯uoroindolin-2-one ,5.0 g, 36 mmol) and 1-
bromo-3-chloropropane ,21.6 ml, 34.4 g, 0.22 mol) was
re¯uxed for 18 h. Unreacted bromochloro-propane was
removed from the acidi®ed ,HCl aqueous) reaction mixture
by steam distillation. The residue was made alkaline with
concentrated aqueous sodium hydroxide and again steam
distilled. The product was extracted from distillate with
4.9. NMR spectroscopy
All NMRmeasurements were run with a Bruker Avance
DRX 500 FT NMR spectrometer equipped with a 5 mm
inverse detection broad band probehead working at
1
500.133 MHz for H, 470.533 MHz for 19F, 125.773 MHz

A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
9
for 13C and 50.688 MHz for 15N NMRexperiments for
0.1±0.2 M solutions in CDCl3 at 303 K.
Regional Computing Center of S. Staszic University of
Mining and Metallurgy in Cracow for supply of computer
time and providing programs ,Grant KBN/SGI-ORIGIN-
2000/ATRBydg/072/2000).
In the 1H NMRexperiments the spectral width was
6000 Hz, the number of scans was eight, the ¯ip angle
was 308 and the number of data points in the time domain
was 65 K which was multiplied with an exponential window
function of the digital resolution ,0.1 Hz) prior to Fourier
transform ,FT). The 1H NMRchemical shifts are referenced
to the signal of residual CHCl3, 7.26 ppm from an internal
tetramethylsilane ,TMS).
In 19F NMRexperiments, the spectral width was
18,000 Hz, the number of scans was eight, the number of
data points in the time domain was 65 K which was zero
®lled and multiplied with an exponential window function of
digital resolution ,0.3 Hz) prior to Fourier transform ,FT).
The 19F NMRchemical shifts are referenced to the central
peak of external ¯uorobenzene ,in a 1 mm diameter capil-
lary inserted coaxially inside the 5 mm NMRtube) which
was set to 0.0 ppm.
References
[1] Methods of Organic Chemistry ,Houben-Weyl), 4th Edition, Vol.
E10a, E10b/1 and E10b/2, Georg Thieme Verlag, Stuttgart, 1999/
2000.
[2] N.J. Leonard, L.E. Sutton, J. Am. Chem. Soc. 70 ,1948) 1564.
[3] A.G. Giumanini, G. Chiavari, M.M. Musiani, P. Rossi, Synthesis
,1980) 743.
[4] G.H. Kerr, O. Meth-Cohn, E.B. Mullock, H. Suschitzky, J. Chem.
Soc. ,1974) 1614.
[5] R. Williams, J. Chem. Soc. ,1939) 1199.
[6] J.R.L. Smith, J.M. Linford, L.C. McKeer, P.M. Morris, J. Chem. Soc.,
Perkin Trans. 2 ,1984) 1099.
[7] R.W. Taft, E. Price, I.R. Fox, I.C. Lewis, K.K. Anderson, G.T. Davis,
J. Am. Chem. Soc. 85 ,1963) 3146.
In proton decoupled ,Waltz-16) 13C NMRexperiments,
the spectral width was 33,000 Hz, the number of scans vary
between 100 and 1000 depending on the sample, the ¯ip
angle was 308 and the number of data points in the time
domain was 65 K which was multiplied with an exponential
window function of the digital resolution ,0.5 Hz) prior to
FT. The 13C NMRchemical shifts are referenced to the
central peak of CDCl3, 77.00 ppm from internal tetramethyl-
silane ,TMS).
In PFG ,pulsed ®eld gradient) [50], 1H, 15N HMBC
,heteronuclear multiple bond correlation) [51] experiments
the two-dimensional time domain matrix was 1024/3500 Hz
,1H†  1024/22000 Hz ,15N) and the number of 1H scans for
each 15N increment was 64. The acquisition matrix was zero
®lled to 2 K along both axes and multiplied by exponential
window functions of digital resolutions along both axes prior
to FTs. The 15N NMRchemical shifts are referenced to the
signal of external nitromethane ,in a 1 mm diameter capil-
lary inserted coaxially inside the 5 mm NMRtube) which
was set to 0.0 ppm.
[8] T.L. Kruger, W.N. White, H. White, S.L. Hartzell, J.W. Kress, N.
Walter, J. Org. Chem. 40 ,1975) 77.
[9] M.J.S. Dewar, Y. Takeuchi, J. Am. Chem. Soc. 89 ,1967) 390.
[10] E.H. Wiseman, J. Chiaini, J.M. McManus, J. Med. Chem. 16 ,1973)
131.
[11] W.C. Davies, R.G. Cox, J. Chem. Soc. ,1937) 614.
[12] H.P. Crocker, B. Jones, J. Am. Chem. Soc. 83 ,1961) 3319.
[13] G.H. Parson, S.G. Cohen, J. Am. Chem. Soc. 96 ,1974) 2948.
[14] L.I. Rogovik, I.N. Chernyuk, V.Ye. Pridan, Zh. Org. Khim. 15 ,1979)
637.
[15] G. Schiemann, W. WinkelmuÈller, Ber. 66 ,1933) 727.
[16] M.F. Moreau-Hochu, P. Caubere, J. Chem. Soc. ,1959) 1808.
[17] B.L. Fox, R.J. Doll, J. Org. Chem. 38 ,1973) 1136.
È
[18] U. Schollkopf, U. Ludwig, Chem. Ber. 101 ,1968) 2224.
[19] R.T.C. Brownlee, D.G. Cameron, R.D. Topsom, A.R. Katritzky, A.F.
Pozharsky, J. Chem. Soc., Perkin Trans. 2 ,1974) 247.
[20] V.F. Bystrov, O.A. Yuzhakova, R.G. Kostyanovskii, Dokl. Akad.
Nauk SSSR147 ,1962) 843.
[21] R. Ikan, E. Hoffmann, E.D. Bergmann, A. Galun, Israel J. Chem. 2
,1964) 37.
[22] A.R. Bader, R.J. Bridgwater, P.R. Freeman, J. Am. Chem. Soc. 83
,1961) 3319.
[23] R. Gawinecki, E. Kolehmainen, R. Kauppinen, J. Chem. Soc., Perkin
Trans. 2 ,1998) 25.
[24] R. Gawinecki, A. Zakrzewska, in preparation.
[25] R.E. Carter, Acta Chem. Scand. 22 ,1968) 2643.
[26] S. Stavber, M. Zupan, J. Org. Chem. 50 ,1985) 3609.
[27] R.V. Hoffman, J.M. Salvador, J. Org. Chem. 57 ,1992) 4487.
[28] Patent Am. Cyanamid DE 2029961 ,1970) Chem. Abstr. 74 ,1971)
64101.
4.10. Quantum chemical calculations
Quantum chemical calculations were performed at the HF
and B3LYP levels of theory with the Gaussian 98W package
[52]. Geometry optimization was done at the ab initio HF
level with the 3-21G basis set. The GIAO-DFT [53] calcula-
tions for 13C chemical shifts were performed at the B3LYP
level with 6-311G basis set.
[29] M.F. Moreau-Hochu, P. Caubere, Tetrahedron 33 ,1977) 955.
[30] R. Pohloudek-Fabini, E. Schroepl, Pharmazie 23 ,1968) 561.
[31] M.L. Saccarello, R.W. Stradi, Synthesis ,1979) 727.
[32] F.L. Allen, R.E. Jewell, H. Suschitzky, J. Chem. Soc. ,1960) 5259.
[33] T. Tanuma, J. Irisawa, J. Fluorine Chem. 99 ,2000) 157.
[34] T. Tanuma, J. Irisawa, K. Ohnishi, J. Fluorine Chem. 102 ,2000) 205.
[35] P.B. Karadakov, K. Morokuma, Chem. Phys. Lett. 317 ,2000) 589.
[36] D.A. Fidler, J.S. Logan, M.M. Boudakian, J. Org. Chem. 26 ,1961)
4014.
Acknowledgements
[37] J.H. Wilkinson, I.L. Finar, J. Chem. Soc. ,1947) 759.
We are grateful to Mr. Reijo Kauppinen for his kind help
in NMRexperiments. B.O. gratefully acknowledges receipt
of a Fellowship from the Foundation for Polish Science
,FNP). We are very much indebted to the CYFRONET
Â
Â
Â
Â
[38] Z. Polõvka, J. Jõlek, J. Holubek, E. Svatek, A. Dlabac, M. Valchar, M.
Protiva, Coll. Czech. Chem. Commun. 49 ,1984) 86.
[39] T.B. Patrick, J.A. Schield, D.G. Kirchner, J. Org. Chem. 39 ,1974)
1758.

10
A. Zakrzewska et al. / Journal of Fluorine Chemistry 111 92001) 1±10
[40] A. Sveinbjornsson, H.L. Bradlow, Sh. Oae, C.A. Vanderwerf, J. Org.
Chem. 16 ,1951) 1450.
[50] R.E. Hurd, B.K. John, J. Magn. Reson. 91 ,1991) 648.
[51] A. Bax, M.F. Summers, J. Am. Chem. Soc. 108 ,1986) 2093.
[52] Gaussian'98, Revision A.7, M.J. Frisch, G.W. Trucks, H.B. Schlegel,
G.E. Scuseria, M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A.
Montgomery, R.E. Stratmann, J.C. Burant, S. Dapprich, J.M. Millam,
A.D. Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo,
S. Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui,
K. Morokuma, D.K. Malick, A.D. Rabuck, K. Raghavachari,
J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G. Baboul, B.B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts,
R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng,
A. Nanayakkara, C. Gonzalez, M. Challacombe, P.M.W. Gill,
B. Johnson, W. Chen, M.W. Wong, J.L. Andres, C. Gonzalez,
M. Head-Gordon, E.S. Replogle, J.A. Pople, Gaussian, Inc.,
Pittsburgh, PA, 1998.
[41] G.R. Pettit, M.V. Kalnins, Th.M.H. Liu, E.G. Thomas, K. Parent, J.
Org. Chem. 26 ,1961) 2563.
[42] D.H.R. Barton, Sh.I. Parekh, M. Tajbakhsh, E.A. Theodorakis, Ch.L.
Tse, Tetrahedron 50 ,1994) 639.
[43] R.M. Roberts, P.J. Vogt, J. Am. Chem. Soc. 78 ,1956) 4778.
[44] Vogel's Textbook of Practical Organic Chemistry, 4th Edition,
Longman, London, 1978, p. 684.
[45] Vogel's Textbook of Practical Organic Chemistry, 4th Edition,
Longman, London, 1978, p. 671.
[46] C. Sellers, H. Suschitzky, J. Chem. Soc. ,1965) 6186.
[47] G.J. Quallich, P.M. Morrissey, Synthesis ,1993) 51.
[48] R.D. Clark, J.M. Muchowski, L.E. Fisher, L.A. Flippin, D.B. Repke,
M. Souchet, Synthesis ,1991) 871.
[49] G.W. Rewcastle, B.D. Palmer, E.M. Dobrusin, D.W. Fry, A.J. Kraker,
W.A. Denny, J. Med. Chem. 37 ,1994) 2033.
[53] R. Ditchfield, Mol. Phys. 27 ,1974) 789.