Synthesis and thiolation of 1,3-difluoro-2,4,6-trihaloanilines and benzenes

Article abstract of DOI:10.1016/S0022-1139(03)00172-6

Three pentahaloanilines were prepared by stepwise halogenation of 3,5-difluoroaniline and were deaminated to form pentahalobenzenes. Alternatively, two pentahalobenzenes were obtained by lithiation followed by iodination of 1,3-difluoro-4,6-dihalobenzenes

Full text of DOI:10.1016/S0022-1139(03)00172-6

Journal of Fluorine Chemistry 124 (2003) 39–43
Synthesis and thiolation of 1,3-difluoro-2,4,6-trihaloanilines
and benzenes
Jason T. Manka1, Piotr Kaszynski*
Organic Materials Research Group, Department of Chemistry, Vanderbilt University, Box 1822 Station B, Nashville, TN 37235, USA
Received 10 June 2003; received in revised form 17 June 2003; accepted 23 June 2003
Abstract
Three pentahaloanilines were prepared by stepwise halogenation of 3,5-difluoroaniline and were deaminated to form pentahalobenzenes.
Alternatively, two pentahalobenzenes were obtained by lithiation followed by iodination of 1,3-difluoro-4,6-dihalobenzenes. Alkylthiolation
reactions of pentahaloanilines and benzenes in Me2SO were investigated.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Halogenation; Deamination; Alkylthiolation
1. Introduction
It has been reported that thiolate anions selectively
replace fluorine atoms on benzene rings when both bromine
and fluorine atoms are present [7]. Some literature reports
also show that replacement of fluorine atoms with certain
nucleophiles can be accomplished in the presence of iodine
[8–10]. Therefore, we envisioned the introduction of a
propylthio group to benzene by chemoselective replacement
of the fluorine atoms in 1 and 2. Here we focused on the
preparation of triheterohalogenated anilines 1a and 1b and
the corresponding halobenzenes 2a and 2b. The tribromo
derivative 1c was isolated and the trichloro derivative 1d, the
only reported 3,5-difluoro-2,4,6-trihaloaniline to date [11],
was observed as reaction side products. We also describe
reactions of some of the anilines 1 and benzenes 2 with the
1-propanethiolate anion.
While investigating the preparation of substituted halo-
benzenes [1], we explored alkylthiolation of 3,5-difluoro-
2,4,6-trihaloanilines 1 and the corresponding 1,3-difluoro-
2,4,6-trihalobenzenes 2, with an emphasis on achieving
chemoselectivity. Such compounds with up to three types
of halogens can undergo selective transformations, and are
envisioned as building blocks for polyfunctionalized biphe-
nyls [2] and pharmacological compounds [3]. In general,
fluorine atoms can be displaced by nucleophiles [4], while
other halogens, especially iodine and bromine, undergo
metal-mediated substitution reactions [5]. This selectivity
combined with the versatility of the amino group [6] offers a
high degree of control in the functionalization process of the
benzene ring when 1 is used.
2. Results and discussion
The preparation of anilines 1a and 1b took advantage of
the directing ability of the amino group in 3,5-difluoroani-
line. Thus, iodination of 3,5-difluoroaniline under mild
conditions [12] gave 3,5-difluoro-4-iodoaniline (3) in nearly
quantitative yield (Scheme 1). The initial dibromination
attempts of 3 to obtain pentahaloaniline 1a with excess
Br2 in acetic acid resulted in displacement of the iodine
and the formation of the 2,4,6-tribromo-3,5-difluoroaniline
(1c). Even when stoichiometric amounts of Br2 were used,
significant quantities of several halogen-exchanged products
were observed in addition to the desired 1a. However,
* Corresponding author. Tel.: þ1-615-322-3458; fax: þ1-615-334-1234.
E-mail address: piotr@ctrvax.vanderbilt.edu (P. Kaszynski).
1 Present address: Roche Palo Alto LLC, Palo Alto, CA 94304, USA.
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00172-6

40
J.T. Manka, P. Kaszynski / Journal of Fluorine Chemistry 124 (2003) 39–43
Scheme 1.
bromination of 3 with stoichiometric amounts of NBS gave
the desired 2,6-dibromo-3,5-difluoro-4-iodoaniline (1a) in
good yield. It was noticed that portionwise addition of NBS
at ambient temperature is critical for achieving high selec-
tivity of the bromination.
way. Taking advantage of regioselective lithiation of fluor-
obenzenes [3,14,15] and iodination of the resulting carba-
nions [3], 1,3-difluoro-4,6-dihalobenzenes [1] 4a and 4b
were conveniently converted to the corresponding iodides 2a
and 2b in almost quantitative yields.
An analogous reaction of 3 with NCS in CHCl3 gave only
the starting aniline after 1 day at ambient temperature. In the
presence of small amounts of CF3COOH, chlorination of
aniline 3 resulted in a mixture containing 2,6-dichloro-3,5-
difluoro-4-iodoaniline (1b) and 2,4,6-trichloro-3,5-difluor-
oaniline (1d) as the major components. In addition, two
other chlorinated materials including 2,4-dichloro-3,5-
difluoro-6-iodoaniline, an isomer of 1b, were identified
by 19F NMR and mass spectrometry. When stoichiometric
amounts of NCS were used (2.0 equivalents) the ratio of
1b:1d:others was about 5:1:1 based on 19F NMR spectrum
of the crude reaction mixture. A less complex mixture of
products was obtained using only 1.8 equivalent of NCS. In
this case, the ratio of 1b to the monochloro derivative was
about 4:1 with minimum amounts of the trichloro derivative
1d and the starting aniline 3. In either case, the separation of
the mixture was difficult and only small quantities of pure 1b
were isolated by gradient sublimation. No further optimiza-
tion of the reaction conditions was attempted.
Attempts to thiolate 2a or 2b either in Me2SO or EtOH did
not give the expected substitution product 5. Instead the de-
iodination product 1,3-difluoro-4,6-dihalobenzene (4) was
formed as the sole product. The loss of iodine in the reaction
with a thiolate anion is consistent with literature reports for
other aryl halides and presumably involved radical inter-
mediates [16,17].
In contrast, the analogous thiolation of 1,3,5-tribromo-
2,4-difluorobenzene (2c) in Me2SO gave the expected pro-
duct 5c identical to that obtained from 2,4,6-tribromo-1,3-
phenylenediamine [2]. A similar reaction of the tribromo
derivative 2c with sodium 1-propanethiolate in hot ethanol
(75 8C) gave no reaction, and after 48 h only starting mate-
rial was observed.
Propanethiolation of 1,3,5-tribromo-2,4-difluoroaniline
(1c) in Me2SO appeared to be much slower than that of
2c. This is consistent with the generally deactivating proper-
ties of the amino group especially of the ortho and para
positions [18]. After 2 days, significant amounts of the
corresponding monothiolated product remained and the
bispropylthio derivative 6c was isolated in about 19% yield.
The purification of 6c was difficult due to similar polarity of
the mixture components and no analytical sample could be
isolated. Therefore, the crude mixture of the thiolated
products was deaminated and 5c was separated chromato-
graphically in about 10% yield. This represents only about
The amino group in 1a and 1c was removed using Doyle’s
procedure [13] to give the corresponding pentahalobenzenes
2a and 2c in approximately 70% yield. Unfortunately, 1b
was not available in practical quantities for deamination, and
the purification of halobenzenes obtained from the deami-
nation was difficult and inefficient. Therefore, the two
desired iodides 2a and 2b were prepared in an alternative

J.T. Manka, P. Kaszynski / Journal of Fluorine Chemistry 124 (2003) 39–43
41
2
2
1/3 of the yield of 5c obtained by thiolation of 1,3,5-
tribromo-2,4-difluorobenzene (1c).
13C NMR d 54.23 (t, JCF ¼ 32 Hz, C4), 90.0 (dd, JCF
¼
29 Hz, 4JCF ¼ 3 Hz, C2), 144.1 (t, 3JCF ¼ 5 Hz, C1), 158.0
(dd, 1JCF ¼ 241 Hz, 3JCF ¼ 8 Hz, C3); 19F NMR d ꢀ84.5; IR
(KBr) 3421 and 3310 (N–H), 1609 (C¼C) cmꢀ1; EI-MS m/z
415, 413, 411 (M, 36:78:39), 127 (100). Analytically cal-
culated for C6H2Br2F2IN: C, 17.46; H, 0.49; N, 3.39. Found:
C, 17.63; H, 0.45; N, 3.39.
3. Conclusions
2,6-Dihalogenation of 3,5-difluoro-4-iodoaniline (3)
requires mild conditions to avoid halo de-iodination. Dibro-
mination of 3 with NBS is highly chemoselective. In con-
trast, chlorination of 3 with NCS leads to a mixture of
products and the method is impractical for preparation of 1b.
Anilines 1a and 1b are the first examples of triheterohalo-
genated anilines which, in principle, can undergo selective
substitution reactions. By varying the order of the halogena-
tion reactions, it should be possible to obtain other combi-
nations of halogens in 2,5-difluoro-2,4,6-trihaloanilines.
LDA-lithiation of 1,3-difluoro-4,6-dihalobenzenes 4 fol-
lowed by iodination gives pentahalobenzenes 2 in excellent
yields (>95%). Deamination of anilines 1 is an alternative
method for preparation of halobenzenes 2 but lower yields
complicate the separation of pure products.
4.2. 2,6-Dichloro-3,5-difluoro-4-iodoaniline (1b)
NCS (209 mg, 1.56 mmol) was added in portions over a
1.5 h period to a solution of aniline 3 (200 mg, 0.78 mmol)
in CHCl3 (4 ml) containing CF3COOH (0.3 ml). The
reaction was allowed to stir overnight at room temperature
and then passed through a silica gel plug (hexanes:CH2Cl2,
2:1). The solvent was removed to give 220 mg of a solid
residue: 19F NMR d (intensity) ꢀ70.8 (1.0), ꢀ91.1 (0.4),
ꢀ92.2 (1.0), ꢀ94.3 (12.0, 1b), ꢀ112.4 (0.5), ꢀ114.8 (2.3,
1d). The two pairs of unassigned signals were attributed to 2-
chloro-3,5-difluoro-4-iodoaniline (d, ꢀ70.8 and ꢀ92.2 ppm)
and 2,4-dichloro-3,5-difluoro-6-iodoaniline (d, ꢀ91.1 and
ꢀ112.4 ppm).
Alkylthiolation of iodides 2a and 2b results in a facile de-
iodination either in EtOH or Me2SO solutions. The thiola-
tion of the bromo derivatives 1c and 2c gave the F-sub-
stituted products 6c and 5c, respectively. The low yields for
the thiolation of the aniline 1c reflect the deactivating effect
of the amino group.
Fractional sublimation of the mixture (0.8 Torr) gave
1
white crystals of 1b as the last fraction: mp 77–78 8C; H
NMR d 4.8 (br. s, NH); 13C NMR d 54.7 (t, JCF ¼ 31 Hz,
2
2
4
C4), 101.9 (dd, JCF ¼ 24 Hz, JCF ¼ 4 Hz, C2), 142.3 (t,
3JCF ¼ 4 Hz, C1), 156.6 (dd, JCF ¼ 243 Hz, JCF ¼ 8 Hz,
C3); 19F NMR d ꢀ94.3; IR (KBr) 3427 and 3304 (N–H),
1610 (C¼C) cmꢀ1; EI-MS m/z 327, 325, 323 (M, 8:61:100).
Analytically calculated for C6H2Cl2F2IN: C, 22.25; H, 0.62;
N, 4.32. Found: C, 22.41; H, 0.60; N, 4.29.
1
3
4. Experimental
Melting points were determined in open capillaries and
1
are uncorrected. H NMR spectra were measured at either
4.3. 2,4,6-Tribromo-3,5-difluoroaniline (1c)
300 or 400 MHz, and 13C NMR were measured at 75 or
100 MHz, respectively, in CDCl3 and referenced to solvent.
19F NMR were obtained at 282 MHz in CDCl3 and refer-
enced to CFCl3. IR spectra of neat liquid or microcrystalline
samples were recorded in KBr. Mass spectrometry data was
acquired using an HP GC–MS instrument in EI mode.
Elemental analyses were obtained from Atlantic Microlabs.
All reagents were used as received except as noted. Me2SO
was distilled from CaH2 and stored over molecular sieves.
19F and 13C NMR chemical shifts were assigned based on
general trends and comparison with the results from Chem-
Draw 6.0 empirical calculations.
Treatment of aniline 3 with an excess of Br2 in AcOH
gave 1c isolated as the sole white crystalline product: mp
118–119 8C; 1H NMR d 4.87 (br. s, NH); 13C NMR d 84.9 (t,
2
4
2JCF ¼ 27 Hz, C4), 90.9 (dd, JCF ¼ 27 Hz, JCF ¼ 3 Hz,
1
3
C2), 142.9 (C1), 155.8 (dd, JCF ¼ 244 Hz, JCF ¼ 6 Hz,
C3); 19F NMR d ꢀ97.1; IR (KBr) 3422 and 3311 (N–H),
1612 (C¼C) cmꢀ1; EI-MS m/z 369, 367, 365, 363 (M,
33:98:100:34). Analytically calculated for C6H2Br3F2N:
C, 19.70; H, 0.55; N, 3.83. Found: C, 19.55; H, 0.50; N, 3.83.
4.4. 1,5-Dibromo-2,4-difluoro-3-iodobenzene (2a)
4.1. 2,6-Dibromo-3,5-difluoro-4-iodoaniline (1a)
4.4.1. Method A
A solution of amine 1a (413 mg, 1 mmol) in DMF (5 ml)
was added dropwise to a solution of t-BuONO (129 mg,
1.25 mmol) in DMF (5 ml) at 60 8C. After stirring for 0.5 h,
the reaction mixture was poured into 6M HCl (150 ml) and
products extracted with hexanes. The combined extracts
were dried (Na2SO4), the solvent removed, and the crude
product passed through a silica gel plug (hexanes). The
solvent was removed to give 296 mg (74% yield) of a light
brown solid which was sublimed under reduced pressure.
3,5-Difluoro-4-iodoaniline (3, 255 mg, 1.0 mmol) was dis-
solved in CHCl3 (4 ml) and NBS (356 mg, 2.0 mmol) was
added in portions over a 1.5 h period. The reaction was
allowed to stir for 3 h at room temperature and then passed
through a silica gel plug (hexanes:CH2Cl2, 2:1). The solvent
was removed and the residue was purified on a silica gel
column (hexanes:CH2Cl2, 3:1) to give 298 mg (72% yield) of
white crystals: mp, 128–129 8C; 1H NMR d 4.9 (br. s, NH);

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J.T. Manka, P. Kaszynski / Journal of Fluorine Chemistry 124 (2003) 39–43
4.4.2. Method B
solution of sodium meta-bisulfite in water was added until
the disappearance of color and the product was extracted
with CH2Cl2. The extract was dried (Na2SO4) and solvent
removed to give 9.1 g (96% yield) of a light brown crystals:
mp 111–112 8C (lit. [19] mp 112–114 8C); 1H NMR d 3.96
(br. s, 2H, NH), 6.22–6.27 (m, 2H, ArH); 13C NMR d 55.0
(t, 2JCF ¼ 30 Hz, C4), 98.3 (dd, 2JCF ¼ 28 Hz, 4JCF ¼ 2 Hz,
C2), 149.1 (t, 3JCF ¼ 13 Hz, C1), 163.1 (dd, 1JCF ¼ 243 Hz,
3JCF ¼ 9 Hz, C3); 19F NMR d ꢀ94.2; EI-MS m/z 255
(M, 100).
A 2.4 M solution of n-BuLi (1.8 ml, 4.4 mmol) was added
dropwise to a cooled (ꢀ5 8C) solution of diisopropylamine
(464 mg, 4.6 mmol) in dry THF (15 ml). After 30 min, the
resulting solution of LDAwas added dropwise to a solution of
1,3-dibromo-4,6-difluorobenzene [1] (4a, 1.00 g, 3.7 mmol)
in THF (15 ml) at ꢀ78 8C and stirred for 45 min. A solution
of I2 (2.05 g, 8.1 mmol) in THF (15 ml) was added at once,
and the reaction was allowed to warm to room temperature.
6 M HCl (5 ml) was added, and most of the THF was
removed under reduced pressure. The concentratewas poured
into water (100 ml) and products extracted with hexanes. The
combined extracts were dried (Na2SO4) and passed through a
short silica gel column (hexanes). The solvent was removed
to give 1.41 g (96% yield) of a light brown solid. An
analytical sample was obtained by vacuum sublimation
(ꢁ60 8C/0.8 Torr) onto a cold finger to give white crystals:
4.8. Reaction of haloarenes with 1-propanethiolate:
general procedure
4.8.1. Method A
A solution of haloarene (0.5 mmol) in Me2SO (8 ml) was
added to a solution of 1-propanethiol (1.1 mmol) and NaH
(1.15 mmol) in Me2SO (5 ml), and the reaction mixture was
stirred at 90 8C for 48 h. Most of the solvent was removed
under reduced pressure, and the residue was purified on a
silica gel column (CH2Cl2:hexanes, 1:2).
mp 75–76 8C; 1H NMR d 7.75 (t, 4JCF ¼ 7:1 Hz, ArH); 13
C
NMR d 72.3 (t, 2JCF ¼ 32 Hz, C3), 103.8 (dd, 2JCF ¼ 26 Hz,
4JCF ¼ 4 Hz, C1), 136.0 (C6), 158.0 (dd, JCF ¼ 247 Hz,
1
3JCF ¼ 4 Hz, C2); 19F NMR d ꢀ83.6; EI-MS m/z 400, 398,
396 (M, 45:100:54). Analytically calculated for C6HBr2F2I:
C, 18.12; H, 0.25. Found: C, 18.32; H, 0.28.
4.8.2. Method B
A solution of haloarene (0.5 mmol), 1-propanethiol
(1.1 mmol) and NaOH (1.15 mmol) in 95% EtOH (15 ml)
was stirred overnight at 80 8C. Most of the EtOH was
removed and 6 M HCl (5 ml) was added. The mixture
was poured into water (100 ml) and extracted with CH2Cl2.
The combined extracts were dried (Na2SO4) and purified on
a silica gel column (CH2Cl2:hexanes, 1:2).
4.5. 1,5-Dichloro-2,4-difluoro-3-iodobenzene (2b)
Aniline 1b (300 mg, 0.93 mmol) was deaminated as
described in Method A for the preparation of 2a to give
205 mg (72% yield) of a pale yellow low melting solid.
Using Method B the iodide was obtained in 97% yield from
1,3-dichloro-4,6-difluorobenzene [1] (4b). An analytical
sample was obtained by sublimation (45 8C/0.8 Torr) onto
4.9. 2,4,6-Tribromo-3,5-bis(propylthio)benzene (5c) [2]
a cold finger: 1H NMR d 7.51 (t, 4JCF ¼ 7:3 Hz, ArH); 13
C
NMR d 72.7 (t, 2JCF ¼ 30 Hz, C3), 116.54–116.81 (m, C1),
4.9.1. Method A
130.9 (C6), 156.8 (dd, 1JCF ¼ 248 Hz, 3JCF ¼ 5 Hz, C2); 19
F
1,3,5-Tribromo-2,4-difluorobezene (2c) was reacted with
sodium 1-propanethiolate in Me2SO as described above. The
product was isolated by column chromatography in 36%
yield as a pale oil.
NMR d ꢀ92.4; EI-MS, m/z 312, 310, 308 (M, 13:63:100).
Analytically calculated for C6HCl2F2I: C, 23.33; H, 0.33.
Found: C, 23.34; H, 0.37.
4.9.2. Method B
4.6. 1,3,5-Tribromo-2,4-difluorobezene (2c)
Aniline 1c was reacted with sodium 1-propanethiolate in
Me2SO as described in the general procedure. The crude
product was purified chromatographically to give 6c in 19%
yield. The aniline 6c was deaminated with t-BuONO as
described for the preparation of 2a to give the bispropylthio
derivative 5c in about 10% overall yield. Similar overall
yield of 5c was obtained when a crude mixture of the
thiolated aniline 1c was deaminated prior to chromato-
graphic separation. Physical and spectroscopic properties
are identical to those reported for 5c elsewhere [2].
Aniline 1c (206 mg, 0.6 mmol) was deaminated using
Method A described for the preparation of 2a to give 140 mg
(71% yield) of a white solid: mp 60–61 8C; 1H NMR d 7.73
(t, 4JCF ¼ 6:9 Hz, ArH); 13C NMR d 99.9 (t, 2JCF ¼ 26 Hz,
1
C3), 104.6–105.0 (m, C1), 134.6 (C6), 155.9 (dd, JCF
¼
3
249 Hz, JCF ¼ 3 Hz, C2); 19F NMR d ꢀ96.3; EI-MS m/z
354, 352, 350, 348 (M, 35:98:100:33). Analytically calculated
for C6HBr3F2: C, 20.54; H, 0.29. Found: C, 20.62; H, 0.31.
4.7. 3,5-Difluoro-4-iodoaniline (3) [19]
Ice (20 g) followed by iodine (11.3 g, 45 mmol) were
added to a stirred mixture of powdered 3,5-difluoroaniline
(4.8 g, 37 mmol), NaHCO3 (4.7 g, 56 mmol) and water
(250 ml), and the mixture was stirred overnight. A 10%
Acknowledgements
This project has been supported in part by the NSF Grants
(CHE-9703002 and CHE-0096827).

J.T. Manka, P. Kaszynski / Journal of Fluorine Chemistry 124 (2003) 39–43
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