Activation of chlorine and fluorine by a phenylazo group towards nucleophilic aromatic substitution. Regioselective preparation of polysubstituted anilines

Article abstract of DOI:10.1016/j.tet.2005.01.023

A phenylazo group was used for selective activation of ortho fluorine and chlorine atoms towards nucleophilic aromatic substitution with the propanethiolate anion. This enabled a regioselective synthesis of three substituted 4-alkoxyanilines. The regioselectivity of substitution was confirmed by comparison of experimental NMR chemical shifts with empirically predicted values. The observed reactivity of the substrates is discussed in the context of the substituent effect.

Full text of DOI:10.1016/j.tet.2005.01.023

Tetrahedron 61 (2005) 2327–2333
Activation of chlorine and fluorine by a phenylazo group towards
nucleophilic aromatic substitution. Regioselective preparation
of polysubstituted anilines
†
Anna Fryszkowska, Robert W. Tilford, Fengli Guo and Piotr Kaszynski
*
Organic Materials Research Group, Department of Chemistry, Vanderbilt University, Box 1822 Station B, Nashville, TN 37235, USA
Received 24 August 2004; revised 23 December 2004; accepted 10 January 2005
Available online 2 February 2005
Abstract—A phenylazo group was used for selective activation of ortho fluorine and chlorine atoms towards nucleophilic aromatic
substitution with the propanethiolate anion. This enabled a regioselective synthesis of three substituted 4-alkoxyanilines. The regioselectivity
of substitution was confirmed by comparison of experimental NMR chemical shifts with empirically predicted values. The observed
reactivity of the substrates is discussed in the context of the substituent effect.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we demonstrated1 that a phenylazo group
moderately activates ortho fluorine atoms towards nucleo-
philic aromatic substitution (NAS)2 and therefore is an
effective and attractive alternative to the nitro group in the
preparation of substituted anilines. Using this methodology,
we prepared1 a series of anilines required for the synthesis
of polyfunctionalized biphenyls.3 We also developed
synthetic access to benzo[1,2,4]thiadiazines using
2-alkylthioanilines as the staring materials.4 The
preparation of partially halogenated 7-alkoxybenzo[1,2,4]-
thiadiazines,5 requires p-alkoxyanilines 1a–c, which, in
principle, can be derived from the corresponding poly-
Scheme 1.
halogenated azo derivatives 2a–c (Scheme 1).
Here we describe the application of the phenylazo group as
an activator of ortho F and Cl atoms towards NAS with a
thiolate anion, and also as a mask for an amino group in
regioselective preparation of anilines 1. We also briefly
investigate the activating ability of the arylazo group
substituted in the para position by the strongly electron-
withdrawing sulfonyl group in 3c.
2. Results
The key step in the synthesis of anilines 1 is the
regioselective introduction of the propylthio substituent.
Following an earlier established protocol,1 the fluoro
derivatives 2a and 2b were reacted with 1.1 equiv of the
propanethiolate in boiling ethanol. Substrate 2b was
completely consumed after 4 h and the corresponding
product 4b was isolated in 75% yield (Scheme 2). In
contrast, only about half of fluoride 2a reacted after 8 h
under the same conditions to give 4a in 41% isolated yield.
In both reactions, the formation of about 15% of ethoxy
derivatives 5a and 5b was observed. Approximately the
same amounts of 5 were observed when excess PrSH
(1.6 equiv) was used with the same amount of base
Keywords: Nucleophilic aromatic substitution; Azobenzenes; Alkylthiola-
tion; Anilines.
* Corresponding author. Tel.: C1 615 322 3458; fax: C1 615 343 1234;
e-mail: piotr.kaszynski@vanderbilt.edu
† Visiting graduate student from the group of Prof. R. Ostaszewski,
Warsaw University of Technology, Poland.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.023

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A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
Scheme 2.
(1.1 equiv). This suggests that low concentration of the
nucleophile and equilibrium with the solvent (EtOH) are
responsible for the appearance of the side product 5, rather
than partial loss of the thiolate due to air oxidation. The
formation of 5b was almost completely suppressed and the
reaction time was shortened when 2.2 equiv of the thiolate
and 1 equiv of PrSH were used, and the desired product 4b
was isolated in 75% yield. Thus, higher concentrations of
the nucleophile are needed for selective substitution.
4c in a 78% isolated yield. In contrast, 3c formed a complex
mixture of products, from which 6c was obtained in about
60% yield or !10% of analytically pure sample.
The resulting substituted azo compounds 4 were reduced to
the desired amines 1 using iron powder. For comparison, the
starting azo compounds 2a and 2b were also converted to
amines 7a and 7b, respectively, and both series of amines
were generally obtained in about 90% isolated yields
(Scheme 2).
A similar thiolation reaction of the tetrachloro derivative 2c
with 1.6 equiv of PrSNa in ethanol gave about 80% yield of
an 8:1 mixture of monosubstituted product 4c and
presumably the ethoxy side product 5c. No 2,6-bispropane-
thiolated product was found despite a 60% excess of the
nucleophile. Complete conversion of the starting 2c was
observed after 36 h, which compares to 3.5 h for 2b and 24 h
for 2a under similar conditions. No reaction of 2,3,5,6-
tetrachloroanisole (lacking the azo group) with PrSNa was
detected by GC–MS after 48 h under similar conditions.
The required azo compounds 2 were prepared by a diazo
coupling reaction of the appropriate phenols 8 and
benzenediazonium chloride followed by alkylation of the
resulting crude azophenols 9 with either n-heptyl iodide (9a
and 9b) or n-hexyl bromide (9c, Scheme 4). The yields of
azophenols 9a and 9b were above 70%. In contrast, 9c was
isolated in only 44% yield, which is consistent with the
results for the tetrafluoro analog.7 Generally, the crude
phenols were pure enough for subsequent O-alkylation
under PTC conditions. This was demonstrated on 2,3,6-
trifluorophenol (8b), which gave a 90% overall yield of 2b
in two steps.
In order to increase the rate of replacement of the Cl atom in
2c by stabilization of the negative charge on the nitrogen
atoms, a strongly electron-withdrawing sulfonamido group
was introduced in substrate 3c. A small-scale reaction
demonstrated that after 18 h about half of 3c was consumed,
but NMR analysis of the crude and complex reaction
mixture showed only traces of the desired product 6c
(Scheme 3). This poor selectivity for 6c presumably resulted
from removing the electron density from the azo group in 3c
and activating it towards reduction by the thiolate anion.
The sulfonamide 3c was prepared in a similar manner in
about 20% overall yield by diazo coupling of 2,3,5,6-
tetrachlorophenol (8c) with a diazonium salt derived from
amine 10 followed by alkylation of the resulting phenol 11
(Scheme 5).
Azo compounds that are exposed to sunlight partially
isomerize to form cis/trans mixtures, as evident from the
NMR spectra. For instance, spectra of 2b and 4b show
significantly shielded aromatic hydrogen atoms in the cis
isomer up to 1 ppm relative to those in the trans isomers. At
Alternatively, the thiolation of the tetrachloro derivatives 2c
and 3c was conducted under PTC conditions, as reported for
non-activated polychlorinated substrates.6 Each substrate
was consumed within 3 h, which is comparable to the
reaction times reported for some non-activated chloroarenes
under analogous conditions.6 Compound 2c produced pure
Scheme 3.
Scheme 4.

A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
2329
Scheme 5.
a photochemical equilibrium, the ratio of the trans and cis
isomers of 2b was 3:1 in a chloroform solution. Pure trans
isomers were obtained by heating samples above 80 8C for
1 h.
Based on the observed reaction times, the reactivity of the
haloarenes follows the order 2bO2aO2c. The significantly
higher mobility of fluorine in 2b than in 2a (c.f. 3.5 h vs 24 h
reaction time) results from the activating effect of the ortho
fluorine atom in the former, which is absent in 2a.
According to a comparative study of penta- and hexafluoro-
benzenes,12 ortho substitution with fluorine, as in 2b, may
increase the NAS rate by a factor of about 30, while fluorine
in the para position, as in 2a, is expected to be modestly
deactivating. Thus, fluorine atoms in 2b and those studied
before1 are additionally activated by ortho halogens and
show significantly enhanced reactivity (shorter reaction
times).
2,3,5,6-Tetrachlorophenol (8c) was obtained in two steps in
57% overall yield by nucleophilic displacement of the nitro
group in 2,3,5,6-tetrachloronitrobenzene with the methoxy
group,8 followed by demethylation of the resulting 2,3,5,6-
tetrachloroanisole with BBr3 (Scheme 5). The original
methoxylation procedure8 was modified by using THF to
increase solubility of the starting nitro compound. p-Amino-
benzenesulfonamide 10 was prepared from 4-nitrobenzene-
sulfonyl chloride with aqueous NHMe2 followed by
catalytic reduction of the resulting nitro amide (Scheme 5).9
The lowest reactivity in the series is exhibited by the
chloroarene 2c (36 h reaction time), which reflects the
generally observed13 2–3 order-of-magnitude lower
mobility of Cl than F in NAS reactions. However, the
mobility of chlorine in 2c is increased by the presence of
three other Cl atoms exerting strong ortho, and moderate
meta and para activating effects.12,14 Therefore, it is
conceivable that a precursor lacking the additional Cl
atoms, e.g. the hypothetical chloro analog of 2a, would
exhibit low reactivity and a synthetically useful NAS
reaction would have to be performed under the PTC
conditions.6 Support for this expectation is provided by
the high selectivity for monosubstituted product 4c, which
results from lower activation of the mobile chlorine atom
(ortho to the azo group) by the SPr group in 4c than by the
Cl in the same position in 2c. According to the results for
substituted 2- and 4-chloroquinolines,14 the change of Cl to
a SMe group retards the NAS rate by a factor O20, which is
consistent with the trends in the sm values (0.37 and 0.15,
respectively).15 Interestingly, these studies found the SMe
substituent to be even less effective than H in activation of
the meta chlorine towards NAS.14
3. Discussion and conclusions
Results show that the phenylazo group effectively activates
both fluorine and chlorine towards nucleophilic substitution
and tolerates the reaction conditions. Considering the ready
accessibility of the azo precursors through diazo coupling
either to phenols or metalloarenes,1 the method is
synthetically useful for the preparation of ortho-substituted
anilines. If general, the method may be particularly valuable
for substitution of chlorine in NAS reactions, since the most
common activating group NO2 is replaced preferentially or
exclusively by nucleophiles in many polychlorinated
nitroarenes.1,10 An alternative approach to substitution of
halogen in chloroaniline derivatives requires high tempera-
tures and long reaction times.11 In contrast, NAS in
chloroazobenzenes, such as 2c, can be accomplished
selectively under mild conditions and short reaction times
(PTC).
The phenylazo group appears to be an optimum substituent
for NAS reactions due to its activating ability and synthetic
simplicity. The previously investigated 4-Me2N substituent
appears to completely compensate the moderate activating
effect of the PhN2 group,1 presumably due to the strong
donating character of the amino group. In the current study,
the 4-sulfonyl group in 3c activates other undesired reaction
pathways, which result in complex reaction mixtures.
Nucleophilic substitution in 2 occurs regioselectively,
which is expected based on the small ortho deactivating
effect of the alkoxy group16 and the moderately ortho
activating ability of the azo group. Proton NMR analysis of
the azo compounds 4 and the amines 1, combined with the
results for unsubstituted derivatives 2 and 7, shows a good
correlation between the predicted and experimental chemi-
cal shifts (Fig. 1). The plot reflects stronger solvent-solute

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A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
8H), 1.53 (sextet, JZ7.3 Hz, 2H), 1.75 (quintet, JZ6.6 Hz,
2H), 2.66 (t, JZ7.2 Hz, 2H), 3.93 (t, JZ6.6 Hz, 2H), 4.2
(brs, 2H), 6.49 (d, JZ12.6 Hz, 1H), 7.04 (d, JZ9.0 Hz, 1H);
13C NMR d 13.2, 14.0, 22.6, 22.9, 25.8, 29.0, 29.4, 31.7,
37.3, 71.0, 103.2 (d, JZ22.2 Hz), 112.5 (d, JZ3.4 Hz),
124.4 (d, JZ3.6 Hz), 139.9 (d, JZ11.8 Hz), 143.3 (d, JZ
9.9 Hz); 154.3 (d, JZ246.8 Hz); 19F NMR d K132.34 (s,
1F); IR (neat) nmax 3460 and 3360 (NH2), 1497 cmK1; MS,
m/e (relative intensity) 299 (MC, 45), 159 (100). HR-
FABMS, calcd for C16H26FNOS ([M]C): m/e 299.1719;
found: m/e 299.1704. Anal. Calcd for C16H26FNOS: C,
64.18; H, 8.75; N, 4.68. Found: C, 64.80; H, 8.84; N, 4.92.
4.1.2. 3,5-Difluoro-4-heptyloxy-2-propylothioaniline
(1b). The amine 1b was obtained in 94% yield according
to the procedure described for 1a and purified by
chromatography (CH2Cl2–hexane, 3:1) to give a transparent
quickly darkening in air oil: 1H NMR d 0.89 (t, JZ6.9 Hz,
3H), 0.98 (t, JZ7.4 Hz, 3H), 1.26–1.49 (m, 8H), 1.55
(sextet, JZ7.4 Hz, 2H), 1.72 (quintet, JZ7.2 Hz, 2H), 2.65
(t, JZ7.2 Hz, 2H), 3.96 (t, JZ6.6 Hz, 2H), 4.45 (brs, 2H),
6.27 (dd, J1Z12.3 Hz, J2Z2.0 Hz, 1H); 19F NMR d
K127.32 (d, JZ10.4 Hz, 1F), K120.18 (d, JZ10.4 Hz,
1F); IR (neat) nmax 3470 and 3371 (NH2), 1493 cmK1; MS,
m/e (relative intensity) 317 (MC, 25), 177 (100). HR-
FABMS, calcd for C16H25F2NOS ([M]C): m/e 317.1625;
found: m/e 317.1599.
Figure 1. Correlation between experimental and predicted (ChemDraw 8.0
Ultra) chemical shifts for fluorinated anilines 1 (black dots) and 7 (gray
dots), azo compounds 2 (black triangles) and 4 (gray triangles) and phenols
9 (black diamonds). Best fit lines: yZ0.92x (R2Z0.97) for 1 and 7, and yZ
0.98x (R2Z0.96) for 4 and 9. Open circles represent the calculated
chemical shift for other regioisomers of 1 and 4.
interactions for anilines 1 and 7, which are deshielded
relative to the predicted values (slope 0.92), than observed
for azo compounds 2 and 4 (slope 0.98). In contrast,
chemical shifts predicted for other regioisomers of 4 and 1
1
lie outside the correlation. The magnitude of the H–19F
coupling constants (JHF) in the NMR spectra is also
consistent with the assigned structures. For instance, in 1a
the more shielded proton adjacent to the amino group is
more strongly coupled to the 19F nucleus (JHFZ12.6 Hz)
than the downfield hydrogen atom (JHFZ9.0 Hz).
4.1.3. 3,5,6-Trichloro-4-hexyloxy-2-propylthioaniline
(1c). The amine 1c was obtained in 65% yield as a
transparent oil according to the procedure described for 1a
and purified by column chromatography (CH2Cl2–hexanes,
1:1): 1H NMR d 0.91 (t, JZ7.1 Hz, 3H), 0.99 (t, JZ7.4 Hz,
3H), 1.32–1.38 (m, 4H), 1.46–1.53 (m, 2H), 1.57 (sextet,
JZ7.3 Hz, 2H), 1.82 (quintet, JZ7.1 Hz, 2H), 2.75 (t, JZ
7.4 Hz, 2H), 3.92 (t, JZ6.6 Hz, 2H), 5.0 (brs, 2H); 13C
NMR d 13.4, 14.0, 22.6, 23.2, 25.5, 29.9, 31.6, 36.7, 73.7,
115.8, 116.1, 129.6, 134.2, 143.7, 144.2; IR (neat) nmax 3480
and 3368 (NH2), 1586, 1431 cmK1. Anal. Calcd for
C15H22Cl3NOS: C, 48.59; H, 5.98; N, 3.78. Found: C,
48.74; H, 5.98; N, 3.76.
Although the main focus of this work was the introduction
of an alkylthio substituent through the NAS process, the
isolation of the ethoxy derivatives 5 as side products
suggests a more general application of the PhN2 group as an
activating mask for the NH2 group in other NAS reactions.
4. Experimental
4.1. General
4.1.4. 2,5-Difluoro-4-(heptyloxy)azobenzene (2a). A
mixture of 2,5-difluoro-4-phenylazophenol (9a, 4.70 g,
20.1 mmol), anhydrous K2CO3 (3.60 g, 26 mmol), n-heptyl
iodide (4.70 g, 20.8 mmol), Aliquatw336 (0.2 mL) and
acetone (30 mL) was stirred and refluxed overnight. Hexane
(30 mL) was added and the mixture was filtered through a
silica gel plug and washed with CH2Cl2. The filtrate was
concentrated, the residue dissolved in hexanes and filtered
again through a silica gel plug with warm hexanes as the
eluent. The orange filtrate was evaporated to give a solid,
which was recrystallized from pentane to yield 5.25 g (79%
yield) of 2a as orange crystals: mp 80–81 8C; bp 220 8C/
1
Melting points are uncorrected. H and 13C NMR spectra
were recorded in CDCl3 at 300 and 75.5 MHz, respectively,
and referenced to the solvent, unless specified otherwise. 19F
NMR spectra were recorded at 282.4 MHz and referenced to
CF3COOH (external standard). IR spectra were recorded by
deposition of a thin film from solution on sodium chloride
plates or as KBr pellets.
4.1.1. 5-Fluoro-4-heptyloxy-2-propylothioaniline (1a).
Azo compound 4a (89 mg, 0.23 mmol) was added in one
portion to a vigorously stirred suspension of iron dust
(130 mg, 2.32 mmol) in water (3 mL) and acetic acid
(0.1 mL) at 100 8C and stirred for 1 h. The reaction mixture
was cooled down, poured into satd NaHCO3 and extracted
with diethyl ether. Combined organic layers were dried
(MgSO4) and concentrated to give an oily residue which
was short-path distilled (bp 185 8C/0.15 Torr) to give 63 mg
(90% yield) of amine 1a as a transparent oil: 1H NMR d 0.89
(t, JZ6.6 Hz, 3H), 0.99 (t, JZ7.2 Hz, 3H), 1.25–1.49 (m,
1
0.2 Torr (short path); H NMR d 0.90 (t, JZ6.6 Hz, 3H),
1.31–1.51 (m, 8H), 1.88 (quintet, JZ7.0 Hz, 2H), 4.08 (t,
JZ6.6 Hz, 2H), 6.84 (dd, J1Z11.7 Hz, J2Z7.2 Hz, 1H),
7.45–7.54 (m, 3H), 7.63 (dd, J1Z11.7 Hz, J2Z7.2 Hz, 1H),
7.88–7.94 (m, 2H); 19F NMR d K139.32 (d, JZ13.6 Hz,
1F), K126.85 (d, JZ13.6 Hz, 1F); IR (KBr) nmax 1623,
1503, 1282 cmK1; MS, m/e (relative intensity) 332 (MC,
30), 77 (100). Anal. Calcd for C19H22F2N2O: C, 68.66; H,
6.67; N, 8.43. Found: C, 68.69; H, 6.67; N, 8.44.

A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
2331
4.1.5. 2,3,5-Trifluoro-4-(heptyloxy)azobenzene (2b). The
compound 2b was synthesized in 90% overall yield based
on 8b according to the procedure described for 2a as an
orange oily mixture of trans–cis isomers in a 5:1 ratio that
solidified upon standing: bp 210 8C/0.2 Torr (short path);
mp 36–37 8C; 1H NMR (major isomer) d 0.90 (t, JZ6.6 Hz,
3H), 1.31–1.55 (m, 8H), 1.81 (quintet, JZ7.0 Hz, 2H), 4.29
(t, JZ6.6 Hz, 2H), 7.40 (ddd, J1Z11.7 Hz, J2Z3.0 Hz, JZ
0.9 Hz, 1H), 7.50–7.55 (m, 3H), 7.91–7.96 (m, 2H); (minor
isomer, selected signals) d 1.73 (quintet, JZ7.0 Hz, 2H),
4.13 (t, JZ6.6 Hz, 2H), 6.48 (ddd, J1Z10.2 Hz, J2Z
6.0 Hz, J3Z2.4 Hz, 1H), 6.88–6.92 (m, 2H), 7.29–7.34 (m,
2H); 19F NMR (major isomer) d K151.83 (d, JZ7.6 Hz,
2F), K133.46 (t, JZ7.7 Hz, 1F); (minor isomer) d K149.91
(dd, J1Z21.7 Hz, J2Z5.0 Hz, 1F), K147.86 (dd, J1Z
21.7 Hz, J2Z11.9 Hz, 1F), K132.40 (dd, J1Z11.9 Hz, J2Z
5.1 Hz, 1F); IR (KBr) nmax 1493, 1347 cmK1; MS, m/e
(relative intensity) 350 (MC, 15), 77 (100). Anal. Calcd for
C19H21F3N2O: C, 65.13; H, 6.04; N, 8.00. Found: C, 65.21;
H, 6.08; N, 8.11.
recrystallization from EtOH to give 82 mg (63% yield) of 4a
as orange needles: mp 66–67 8C; H NMR d 0.91 (t, JZ
1
6.6 Hz, 3H), 1.09 (t, JZ7.3 Hz, 3H), 1.28–1.54 (m, 8H),
1.78 (sextet, JZ7.4 Hz, 2H), 1.87 (quintet, JZ7.2 Hz, 2H),
2.97 (t, JZ7.2 Hz, 2H), 4.11 (t, JZ6.6 Hz, 2H), 6.94 (d, JZ
7.8 Hz, 1H), 7.41–7.51 (m, 3H), 7.60 (d, JZ12.0 Hz, 1H),
7.90–7.95 (m, 2H); 13C NMR d 13.7, 14.1, 22.2, 22.6, 25.9,
29.0, 29.1, 31.7, 35.1, 69.6, 104.4 (d, JCFZ20.1 Hz), 112.6
(br), 123.1 129.1, 130.8, 136.7 (d, JCFZ2.6 Hz), 143.3 (d,
JCFZ4.1 Hz), 150.0 (d, JCFZ12.2 Hz), 151.3 (d, JCF
Z
248.2 Hz), 152.7. 19F NMR d K138.1 (s, 1F); IR (KBr) nmax
1600, 1503, 1267 cmK1. Anal. Calcd for C22H29FN2OS: C,
68.01; H, 7.52; N, 7.21. Found: C, 67.87; H, 7.54; N, 7.15.
4.1.9.
3,5-Difluoro-4-heptyloxy-2-(propylthio)azo-
benzene (4b). Compound 4b was prepared in 69% yield
according to the procedure described for 4a and without
using additional PrSH. Full conversion of 2b was achieved
after 3.5 h. When double the amount of NaOH and PrSH
was used, the reaction was completed after 2 h and
compound 4b was isolated in 75% yield. The product was
purified by PTLC (hexanes) to give a red oil of 4b as a 6:1
4.1.6. 2,3,5,6-Tetrachloro-4-(hexyloxy)azobenzene (2c).
The compound 2c was synthesized in 91% yield according
to the procedure described for 2a using n-hexyl bromide and
1
mixture of trans–cis isomers: H NMR (major isomer) d
0.90 (t, JZ6.6 Hz, 3H), 0.98 (t, JZ7.3 Hz, 3H), 1.25–1.50
(m, 8H), 1.59 (sextet, JZ7.3 Hz, 2H), 1.80 (quintet, JZ
7.1 Hz, 2H), 2.94 (t, JZ7.2 Hz, 2H), 4.22 (t, JZ6.6 Hz,
2H), 7.34 (dd, J1Z11.7 Hz, J2Z2.1 Hz, 1H), 7.49–7.57 (m,
3H), 7.93–7.98 (m, 2H); (minor isomer, selected signals) d
2.88 (t, JZ7.2 Hz, 2H), 4.07 (t, JZ6.6 Hz, 2H), 5.96 (dd,
J1Z10.2 Hz, J2Z1.8 Hz, 1H), 6.86–6.90 (m, 2H); 19F NMR
(major isomer) d K127.65 (d, JZ9.4 Hz, 1F), K121.17 (d,
JZ9.5 Hz, 1F); (minor isomer) d K126.16 (d, JZ10.5 Hz,
1
acetonitrile as a solvent: mp 64–65 8C; H NMR d 0.93 (t,
JZ7.0 Hz, 3H), 1.34–1.42 (m, 4H), 1.50–1.60 (m, 2H), 1.89
(quintet, JZ7.0 Hz, 2H), 4.06 (t, JZ6.5 Hz, 2H), 7.53–7.60
(m, 3H), 7.94–7.99 (m, 2H); 13C NMR d 14.0, 22.6, 25.4,
29.9, 31.5, 74.2, 119.5, 123.2, 124.1, 128.5, 129.3, 132.9,
146.5, 152.0; IR (KBr) nmax 1371 cmK1. Anal. Calcd for
C18H18Cl4N2O: C, 51.46; H, 4.32; N, 6.67. Found: C, 51.36;
H, 4.32; N, 6.65.
1F), K121.25 (d, JZ10.6 Hz, 1F); IR (neat) nmax 1481 cmK1
;
4.1.7. N,N-Dimethyl-4-[2,3,5,6-tetrachloro-4-hexyloxy-
phenyl(azo)]benzene-sulfonamide (3c). Compound 3c
was synthesized in 65% yield as a 6:1 mixture of trans–
cis isomers according to the procedure described for 2a
using n-hexyl bromide and acetonitrile as a solvent and
FAB, m/e (relative intensity) 407 (MHC, 52) 363 (MC-
C3H7, 100). HR-FABMS, calcd for C22H29F2N2OS ([MC
H]C): m/e 407.1969; found: m/e 407.1975.
1
recrystallized from i-octane: mp 100–101 8C; H NMR d
4.1.10. 2,3,5-Trichloro-4-hexyloxy-6-(propylthio)azo-
benzene (4c). Method A. Compound 2c was reacted with
sodium propanethiolate in EtOH as described for 4a. When
TLC analysis showed full conversion of the substrate after
36 h, the reaction mixture was worked up and product 4c
contaminated with small amounts of the presumably ethoxy
derivative 5c was isolated in 78% yield.
(major isomer) 0.92 (t, JZ7.2 Hz, 3H), 1.32–1.41 (m, 4H),
1.50–1.60 (m, 2H), 1.90 (quintet, JZ6.9 Hz, 2H), 2.79 (s,
6H), 4.08 (t, JZ6.5 Hz, 2H), 7.98 (d, JZ8.4 Hz, 2H), 8.08
(d, JZ8.4 Hz, 2H); (minor isomer, selected signals) d 2.70
(s, 6H), 4.00 (t, JZ6.6 Hz, 2H), 7.13 (d, JZ8.7 Hz, 2H),
7.73 (d, JZ8.4 Hz, 2H); 13C NMR d 14.1, 22.6, 25.4, 30.0,
31.6, 37.9, 74.4, 123.6, 124.3, 128.5, 128.9, 139.1, 145.9,
152.7, 153.8; IR (KBr) nmax 1351, 1167 cmK1. HR-
FABMS, calcd for C20H24Cl4N3O3S ([MCH]C): m/e
526.0292; found: m/e 526.0278. Anal. Calcd for C20H23-
Cl4N3O3S; C, 45.56; H, 4.40; N, 7.97. Found: C, 45.93; H,
4.49; N, 7.85.
Method B. Compound 2c (1800 mg, 4.29 mmol), powdered
KOH (317 mg, 0.76 mmol), and hexadecyltributylphos-
phonium bromide (109 mg, 0.215 mmol) were stirred in
toluene (8 mL) under nitrogen. Propanethiol (343 mg,
4.51 mmol) was added via syringe, and the syringe was
washed with toluene (3 mL). The reaction was monitored by
TLC. Upon total conversion of the starting material (w3 h),
the reaction mixture was passed through a silica gel plug
using first pure hexanes and proceeding up to CH2Cl2–
hexanes in 1:1 ratio, to afford 1.54 g (78% yield) of 4c as a
dark red oil: 1H NMR d 0.87 (t, JZ7.2 Hz, 3H), 0.93 (t, JZ
7.0 Hz, 3H), 1.36–1.41 (m, 4H), 1.46 (sextet, JZ7.3 Hz,
2H), 1.51–1.59 (m, 2H), 1.89 (quintet, JZ6.9 Hz, 2H), 2.70
(t, JZ7.2 Hz, 2H), 4.05 (t, JZ6.6 Hz, 2H), 7.56–7.59 (m,
3H), 7.94–7.97 (m, 2H); 13C NMR d 13.2, 14.0, 22.6, 22.8,
25.5, 30.0, 31.6, 38.2, 73.9, 123.1, 123.2, 126.4, 129.3,
130.0, 132.4, 134.2, 151.5, 152.0, 152.3; IR (KBr) nmax
4.1.8. 5-Fluoro-4-heptyloxy-2-(propylthio)azobenzene
(4a). Compound 2a (112 mg, 0.34 mmol) was suspended
in ethanol (3 mL, 95%), then a solution of NaOH (15 mg,
0.375 mmol in 1.5 mL EtOH) was added, followed by
propanethiol (50 mL, 0.552 mmol) at rt under N2. The
mixture was stirred at 90 8C for 10 h, more propanethiol
(50 mL, 0.552 mmol) was added and the stirring was
continued overnight. When the TLC analysis showed
absence of the starting 2a (about 24 h) the reaction mixture
was evaporated to dryness. The product was purified by
flash chromatography (CH2Cl2–hexanes, 1:5) followed by

2332
A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
1363 cmK1. Anal. Calcd for C21H25Cl4N2OS: C, 54.85; H,
5.48; N, 6.09. Found: C, 55.22; H, 5.62; N, 5.77.
amine 7b was synthesized in 94% yield according to the
procedure described for 1a and purified by distillation (150–
151 8C/0.1 Torr) to give a light yellow oil: 1H NMR d 0.88
(t, JZ6.6 Hz, 3H), 1.25–1.48 (m, 8H), 1.72 (quintet, JZ
7.0 Hz, 2H), 3.7 (brs, 2H), 4.00 (t, JZ6.6 Hz, 2H), 6.30
(ddd, J1Z10.3 Hz, J2Z7.8 Hz, J3Z2.5 Hz, 1H); 19F NMR
d K163.80 (dd, J1Z19.5 Hz, J2Z10.2 Hz, 1F), K152.86
(d, JZ19.5 Hz, 1F), K135.17 (d, JZ10.2 Hz, 1F); IR (KBr)
nmax 3485 and 3390 (NH2), 1522, 1490 cmK1; MS m/e
(relative intensity) 261 (MC, 5), 163 (100). Anal. Calcd for
C13H18F3N2O: C, 59.76; H, 6.94; N, 5.36. Found: C, 60.17;
H, 7.09; N, 5.37.
4.1.11. 2-Ethoxy-5-fluoro-4-(heptyloxy)azobenzene (5a).
The ethoxy derivative 5a was isolated in about 10% yield
and w95% purity as a second fraction in chromatographic
purification of 4a (CH2Cl2–hexanes, 1:1) in the form of a
1
red oil: H NMR d 0.90 (t, JZ6.6 Hz, 3H), 1.25–1.50 (m,
8H), 1.52 (t, JZ7.1 Hz, 3H), 1.87 (quintet, JZ7.0 Hz, 2H),
4.09 (t, JZ6.6 Hz, 2H), 4.28 (q, JZ7.0 Hz, 2H), 6.67 (d,
JZ7.2 Hz, 1H), 7.41–7.54 (m, 3H), 7.62 (d, JZ12.3 Hz,
1H), 7.85–7.92 (m, 2H); 19F NMR d K143.53 (s, 1F); FAB,
m/e (relative intensity) 359 (MHC, 100). HR-FABMS,
calcd for C21H28FN2O2 ([MCH]C): m/e 359.2135; found:
m/e 359.2146.
4.1.16. 2,3,5,6-Tetrachlorophenol.17(8c) A solution
sodium metal (2.72 g, 120 mmol) in methanol (100 mL)
was added to 2,3,5,6-tetrachloronitrobenzene (26.18 g,
100 mmol) in dry THF (75 mL) at rt. The reaction mixture
was stirred for 4 h at 60 8C, filtered and solvents evaporated.
The residue was treated with water and extracted with
CH2Cl2. Combined organic layers were dried (MgSO4) and
evaporated. The residue was recrystallized from EtOH to
give 17.34 g (71% yield) of pure 2,3,5,6-tetrachloroanisole:
4.1.12. 2-Ethoxy-3,5-difluoro-4-(heptyloxy)azobenzene
(5b). The ethoxy derivative 5b was isolated in about 10%
yield and w90% purity as a second fraction in chromato-
graphic purification of 4b (CH2Cl2–hexanes, 1:1) in the
form of a red oil: 1H NMR d 0.89 (t, JZ6.6 Hz, 3H), 1.23–
1.40 (m, 8H), 1.46 (t, JZ7.0 Hz, 3H), 1.80 (quintet, JZ
7.2 Hz, 2H), 4.25 (t, JZ6.6 Hz, 2H), 4.36 (q, JZ7.0 Hz,
2H), 7.36 (dd, J1Z12.0 Hz, J2Z2.1 Hz, 1H), 7.47–7.56 (m,
3H), 7.88–7.95 (m, 2H); 19F NMR d K145.32 (d, JZ
4.5 Hz, 1F); K134.27 (d, JZ4.5 Hz, 1F); FAB, m/e
(relative intensity) 377 (MHC, 100). HR-FABMS, calcd
for C21H27F2N2O2 ([MCH]C): m/e 377.2041; found: m/e
377.2017.
1
mp 88–89 8C (lit.8 mp 89–90 8C); H NMR d 3.92 (s, 3H),
7.41 (s, 1H).
A 1.0 M solution of BBr3 in CH2Cl2 (10 mL) was added to
the anisole solution (2.46 g, 10 mmol) in CH2Cl2 (100 mL)
under inert atmosphere at 0 8C. The reaction mixture was
allowed to warm up to rt, stirred overnight, poured into
water and extracted with CH2Cl2. Combined organic layers
were dried (MgSO4) and evaporated. The crude product was
recrystallized from i-octane to give 1.86 g (80% yield or
57% overall) of phenol 8c as pale yellow crystals: mp 115–
4.1.13. N,N-Dimethyl-4-[4-hexyloxy-2,3,5-trichloro-6-
propylthiophenyl(azo)]benzenesulfonamide (6c). Follow-
ing Method B described for 4c, compound 6c was obtained
from 3c in 63% yield and about 75% purity after
chromatography (CH2Cl2). An analytical sample was
obtained by recrystallization from Et2O–heptane mixture:
mp 100–101 8C; 1H NMR d 0.88 (t, JZ7.2 Hz, 3H), 0.93 (t,
JZ6.9 Hz, 3H), 1.33–1.44 (m, 6H), 1.47 (sextet, JZ7.0 Hz,
2H), 1.90 (quintet, JZ7.0 Hz, 2H), 2.74 (t, JZ7.02 Hz, 2H),
2.80 (s, 6H), 4.07 (t, JZ6.6 Hz, 2H), AA0MM 7.98 and
1
116 8C (lit.18 mp 115 8C); H NMR d 6.10 (s, 1H), 7.23 (s,
1H). Anal. Calcd for C6H2Cl4O: C, 31.08; H, 0.87. Found:
C, 30.97; H, 0.89.
4.1.17. 2,5-Difluoro-4-phenylazophenol (9a). A solution
of benzenediazonium chloride prepared from aniline
(4.80 g, 51.6 mmol), 3 M HCl (65 mL) and a solution of
NaNO2 (4.80 g, 69.5 mmol, in 60 mL of water) and treated
with urea (0.4 g) was added dropwise to a stirred solution of
2,5-difluorophenol (8a, 5.00 g, 38.5 mmol) and NaOH
(5.40 g, 135 mmol) in water (90 mL) at 0 8C. After
30 min, the reaction mixture was allowed to warm up to rt
and was stirred for another 1 h. Diluted HCl was added and
the resulting precipitation was filtered and recrystallized
from aqueous acetic acid to give 6.70 g (74% yield) of
8.07 (d, JZ8.7 Hz, 4H); IR (KBr) nmax 1352, 1169 cmK1
.
HR-FABMS, calcd for C23H31Cl3N3O3S2 ([MCH]C): m/e
566.0872; found: m/e 566.0858.
4.1.14. 2,5-Difluoro-4-heptyloxyaniline (7a). The amine
7a was synthesized in 91% yield according to the procedure
described for 1a using 4.5 g of 2a, 5.0 g of iron 60 mL of
water and 8 mL acetic acid: bp 150 8C/0.1 Torr (short path);
mp 45–46 8C; 1H NMR d 0.89 (t, JZ6.8 Hz, 3H), 1.29–1.45
(m, 8H), 1.76 (quintet, JZ7.0 Hz, 2H), 3.5 (bs, 2H), 3.91 (t,
JZ6.6 Hz, 2H), 6.55 (dd, J1Z12.0 Hz, J2Z8.4 Hz, 1H),
6.68 (dd, J1Z11.7 Hz, J2Z7.5 Hz, 1H); 13C NMR d 14.1,
22.6, 25.8 29.0, 29.3, 31.8, 70.9, 104.6 (dd, J1Z23.9 Hz,
J1Z2.8 Hz), 105.2 (dd, J1Z23.9 Hz, J1Z4.4 Hz), 127.7
(dd, J1Z15.2 Hz, J1Z9.6 Hz), 138.8 (dd, J1Z12.6 Hz,
J1Z9.1 Hz), 147.0 (d, JZ232.1 Hz), 149.4 (d, JZ
239.6 Hz); 19F NMR d K139.69 (d, JZ13.8 Hz, 1F),
K139.26 (d, JZ13.8 Hz, 1F); IR (KBr) nmax 3411, 3307
and 3207 (NH2), 1537 cmK1; MS, m/e (relative intensity)
243 (MC, 5), 145 (100). Anal. Calcd for C13H19F2N2O: C,
64.18; H, 7.87; N, 5.76. Found: C, 64.37; H, 7.89; N, 5.79.
1
phenol 9a as brown crystals: mp 126–128 8C; H NMR d
6.91 (dd, J1Z10.2 Hz, J2Z7.5 Hz, 1H), 7.45–7.55 (m, 3H),
7.63 (dd, J1Z11.1 Hz, J2Z6.6 Hz, 1H), 7.88–7.94 (m, 2H);
19F NMR d K144.74 (d, JZ14.0 Hz, 1F), K126.89 (d, JZ
14.0 Hz, 1F); IR (KBr) nmax 3504, 1623, 1506, 1303 cmK1
.
HR-FABMS, calcd for C12H9F2N2O ([MCH]C): m/e
235.0683; found: m/e 235.0692.
4.1.18. 2,3,6-Trifluoro-4-phenylazophenol (9b). The
compound 9b was obtained as a crude brown powder
according to the procedure described for 9a and was used
without further purification: mp 117–119 8C; 1H NMR d 2.7
(br s, 1H), 7.46 (ddd, J1Z11.1 Hz, J2Z6.3 Hz, J3Z2.4 Hz,
1H), 7.50–7.57 (m, 3H), 7.89–7.96 (m, 2H); 19F NMR d
K157.86 (dd, J1Z19.5 Hz, J2Z6.0 Hz, 1F), K151.70 (dd,
4.1.15. 2,3,5-Trifluoro-4-heptyloxyaniline (7b). The

A. Fryszkowska et al. / Tetrahedron 61 (2005) 2327–2333
2333
2. Miller, J. Aromatic Nucleophilic Substitution; Elsevier: New
York, 1968.
J1Z19.5 Hz, J2Z11.1 Hz, 1F), K140.74 (dd, J1Z11.1 Hz,
J2Z6.2 Hz, 1F); IR (KBr) nmax 3535, 1518, 1333 cmK1
.
HR-FABMS, calcd for C12H8F3N2O ([MCH]C): m/e
253.0589; found: m/e 253.0596.
3. Manka, J. T.; Guo, F.; Huang, J.; Yin, H.; Farrar, J. M.;
Sienkowska, M.; Benin, V.; Kaszynski, P. J. Org. Chem. 2003,
68, 9574–9588.
4.1.19. 2,3,5,6-Tetrachloro-4-phenylazophenol (9c).
Phenol 9c was obtained according to procedure described
for 9a in 44% yield after recrystallization from aqueous
4. Zienkiewicz, J.; Kaszynski, P.; Young, V. G., Jr. J. Org. Chem.
2004, 69, 2551–2561.
5. Fryszkowska, A.; Zienkiewicz, J.; Sienkowska, M.; Guo, F.;
Kaszynski, P.; Jones, D. Submitted for publication.
6. Brunelle, D. J. J. Org. Chem. 1984, 49, 1309–1311.
1
acetic acid as orange microcrystals: mp 144–148 8C; H
NMR d 6.15 (s, 1H), 7.54–7.59 (m, 3H), 7.94–7.97 (m, 2H);
13C NMR d 119.9, 123.2, 124.6, 129.3, 132.7, 143.2, 148.3,
152.0; IR (KBr) nmax 3100 (br, OH), 1385 cmK1. Anal.
Calcd for C12H6Cl4N2O: C, 42.90; H, 1.80; N, 8.34. Found:
C, 42.65; H, 1.69; N, 8.09.
¨
7. Sander, W.; Hu¨bert, R.; Kraka, E.; Grafenstein, J.; Cremer, D.
Chem. Eur. J. 2000, 6, 4567–4578.
8. Berckmans, V. S. F.; Holleman, A. F. Recl. Trav. Chim. Pays-
Bas 1925, 44, 851–860.
9. Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro,
J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J. L.;
Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619–1633.
10. Paradisi, C. In Trost, B. M., Fleming, I., Eds.; Comprehensive
Organic Synthesis; Pergamon: New York, 1991; Vol. 4,
pp 441–444.
4.1.20. N,N-Dimethyl-4-[2,3,5,6-tetrachloro-4-hydroxy-
phenyl(azo)]benzene-sulfonamide (11). Compound 11
was obtained as orange microcrystals according to the
procedure described for 9a in 27% yield after recrystalliza-
1
tion from aqueous acetic acid: mp 235–236 8C; 0 H NMR
(acetone-d6) d 2.73 (s, 6H), 7.66 (s, 1H), AA0MM 7.94 and
8.05 (d, JZ8.4 Hz, 4H); IR (KBr) nmax 3308, 1379, 1331,
1159, 1147 cmK1. Anal. Calcd for C14H11Cl4N3O3S: C,
37.95; H, 2.50; N, 9.48. Found: C, 37.95; H, 2.52; N, 9.14.
11. Caruso, A. J.; Colley, A. M.; Bryant, G. L. J. Org. Chem. 1991,
56, 862–865.
12. Bolton, R.; Sandall, J. P. B. J. Chem. Soc. Perkin Trans. 2
1976, 1541–1545.
13. Bressan, G. B.; Giardi, I.; Illuminati, G.; Linda, P.; Sleiter, G.
J. Chem. Soc. Part B 1971, 225–230. Also Ref. 2, pp 139–174
and references therein.
Acknowledgements
14. Belli, M. L.; Illuminati, G.; Marino, G. Tetrahedron 1963, 19,
345–355.
Financial support for this work was received from the
National Science Foundation (CHE-9528029 and CHE-
0096827).
15. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91,
165–195.
16. Ref. 2 Table 21, p 109, and references therein.
17. Holleman, A. F. Recl. Trav. Chim. Pays-Bas 1920, 39,
736–750.
References and notes
18. Holleman, A. F. Recl. Trav. Chim. Pays-Bas 1921, 40,
318–319.
1. Manka, J.; McKenzie, V.; Kaszynski, P. J. Org. Chem. 2004,
69, 1967–1971.