Preparation and NMR analysis of 2,6-heterodifunctional halobenzenes as precursors for substituted biphenyls

Article abstract of DOI:10.1016/S0040-4020(99)01019-4

Preparation and complete characterization of 16 2,6-disubstituted halobenzenes, including nine new compounds, from two common starting materials is described. Seven of the new compounds contain one or two propylthio groups, which have been introduced in two ways. Direct reaction of arenediazonium salts with 1-propanethiolate gives yields comparable to those obtained in a three-step method through sulfonyl chlorides. The ¹H- and ¹³C NMR chemical shifts of 17 1,2,3-trisubstituted benzenes have been correlated with the predicted values and the observed trends explained using commonly available modeling packages.

Full text of DOI:10.1016/S0040-4020(99)01019-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 165–173
Preparation and NMR Analysis of 2,6-Heterodifunctional
Halobenzenes as Precursors for Substituted Biphenyls
*
Monika Sienkowska, Vladimir Benin and Piotr Kaszynski
Organic Materials Research Group, Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA
Received 5 October 1999; accepted 17 November 1999
Abstract—Preparation and complete characterization of 16 2,6-disubstituted halobenzenes, including nine new compounds, from two
common starting materials is described. Seven of the new compounds contain one or two propylthio groups, which have been introduced
in two ways. Direct reaction of arenediazonium salts with 1-propanethiolate gives yields comparable to those obtained in a three-step method
through sulfonyl chlorides. The 1H- and 13C NMR chemical shifts of 17 1,2,3-trisubstituted benzenes have been correlated with the predicted
values and the observed trends explained using commonly available modeling packages. ᭧ 1999 Elsevier Science Ltd. All rights reserved.
Introduction
obtained from 2,6-dinitroaniline19 (6) or anhydro-2-
hydroxymercuri-3-nitrobenzoic acid20 (7) whose syntheses
are well described in the literature and which are also avail-
able commercially. Other more specific methods for
2,6-Disubstituted halobenzenes (I) are relatively rare and
constitute a class of important precursors to biologically
active1,2 and naturally occurring compounds,3–5 inter-
mediates for heterocycles,1,6–11 and building blocks for
ortho-polysubstituted biphenyls.12–14 Most of the known
halobenzenes I contain carbon-, nitrogen-, and oxygen-
based substituents X and Y. There is only a handful of
compounds I with a sulfur substituent and their preparation
is poorly documented.15,16
preparation of halobenzenes
I include electrophilic
nitration, halogenation or chlorosulfonation15 of disubsti-
tuted benzenes followed by separation of isomers. ortho-
Lithiation of 1,3-disubstituted benzenes followed by
halogenation provides an alternative method for generation
of some 2,6-disubstituted halides.3,21
Here we describe the synthesis and complete characteriza-
tion of several halobenzenes 2–5 from commercially
available precursors.
Our need for 2,6-disubstituted halobenzenes, especially
those containing alkylthio substituents, stems from our
research on heterocyclic compounds containing sulfur and
nitrogen atoms.17 Their synthesis has been realized from
halobenzenes 1–5 via corresponding biphenyls in which
the functional groups X and Y are used to close heterocyclic
rings at the later stages of synthesis. The choice of the
halogen in 1–5 depends on the relative reactivity of the
halobenzenes in the Ullmann reaction18 and the efficiency
of the cross-coupling reactions.
Results and Discussion
The synthetic strategy relies on readily available 2,6-
dinitroaniline19 (6) and anhydro-2-hydroxymercuri-3-nitro-
benzoic acid20 (7). Diazotization of aniline 6 followed by
Compounds 1 and 2 have been reported in the literature,
while halobenzenes 3–5 containing an alkylthio substituent
are unknown and require development of a reliable synthetic
method. Most substituted halobenzenes I are conveniently
Keywords: aryl halide; aldehydes; sulfides; NMR; solvent effects.
* Corresponding author. Tel.: ϩ1-615-322-3458; fax: ϩ1-615-322-3458;
e-mail: piotr@ctrvax.vanderbilt.edu
Scheme 1. a, HalˆCl; b, HalˆBr; c, Halˆl.
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01019-4

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M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
The reduction–oxidation sequence of 8 gives 2 in about
75% overall yield and constitutes a convenient alternative
to another procedure for preparation of 2a from 2-chloro-3-
nitrotoluene.25
Preparation of 2-chloro-3-nitrophenyl propyl sulfide 3a.
Partial reduction of 2,6-dinitrochlorobenzene (1a) with
electrolytic grade fine iron powder in acetic acid, according
to a literature procedure,26 gave amine 9a in 62% yield
(Scheme 3).27 A similar yield was obtained for analogous
reduction of dinitroiodobenzene (1c) to the corresponding
amine 9c. Diazotization of amine 9a and conversion to sul-
fonyl chloride 10 was accomplished in 83% crude yield
according to a general literature procedure for an analogous
compound.26 The chloride was also obtained by direct
chlorosulfonation of 2-chloronitrobenzene, according to
patent literature.15 Crude sulfonyl chloride 10 was subse-
quently transformed to disulfide 11 under general conditions
using hydroiodic acid.28 The disulfide was converted to
2-chloro-3-nitropropylthiobenzene (3a) using mild reduc-
Scheme 2.
tive alkylation conditions described for
a
similar
compound.29 Thus, treatment of disulfide 11 with NaBH4
in ethanol generated the corresponding thiolate in situ,
which was subsequently alkylated with propyl iodide to
give sulfide 3a.
Alternatively, a direct conversion of aniline 9a to the sulfide
3a was successfully achieved using a modified literature
procedure.30 Aniline 9a was diazotized and the diazonium
salt was subsequently reacted with aqueous sodium propane-
thiolate. The initially formed thiodiazene31 was thermally
decomposed by heating the reaction mixture in the presence
of a nickel salt. The sulfide 3a was isolated in 60% yield
based on 9a which compares to 48% obtained in the
previous three-step procedure. The product, sulfide 3a,
was found to be unstable to long-term storage at ambient
temperature.
Scheme 3.
reactions with the appropriate cuprous halide or KI give
access to 2,6-dinitrohalobenzene (1),22 a precursor to
derivatives 3 and 5 (Scheme 1). Reaction of anhydride 7
with a halogen under basic conditions yields the correspond-
ing halobenzoic acid 8,23 which is a convenient precursor to
aldehydes 2 and 4.
Preparation of benzaldehydes 2a and 2b. 2-Halo-3-nitro-
benzaldehydes 2a24 and 2b6 were prepared according to
modified literature procedures by reduction of acid 8 and
partial oxidation of the resulting alcohol (Scheme 2). Acid 8
was conveniently reduced with BH3·THF complex instead
of a borane gas in diglyme (8b)6 or NaBH4 used in reduction
of a mixed anhydride of 8a.24 Oxidation of the intermediate
carbinol to aldehyde 2 was accomplished using PCC in
place of Swern conditions (2a)24 or activated MnO2 (2b).6
Synthesis of 2-bromo-3-propylthiobenzaldehyde 4b. Initial
attempts at conversion of the aldehyde 2b to 2-bromo-3-
propylthiobenzaldehyde (4b) using a general method32
were unsuccessful. Reduction of 2b with SnCl2 followed
by diazotization and treatment with propanethiol gave a
major product, isolated in 40% yield, which was identified
as the corresponding thiodiazene, based on 1H NMR analy-
sis. Attempts at thermal decomposition of the thiodiazene to
Scheme 4.

M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
167
Preparation of 2,6-bispropylthiohalobenzenes 5a and 5c.
2-Chloro-3-nitro-propylthiobenzene (3a) was used as
precursor for chloride 5a and the synthesis is shown in
Scheme 5. The nitro group in 3a was catalytically reduced
to the amine 17, which was converted to 5a in a one-pot
reaction involving direct substitution of the diazonium
group with a propylthio functionality via a thiodiazene
intermediate (vide supra). The overall yield for 5a is 35%
based on amine 17.
Scheme 5.
the desired sulfide 4b resulted in intractable materials only.
Since the presence of the aldehyde group was suspected to
complicate the formation of sulfide 4b, it was decided to
introduce the propylthio group before the aldehyde
functionality.
The iodide 5c, with enhanced reactivity towards Ullmann
coupling reaction, was prepared in a sequence of reactions
shown in Scheme 6. In an adaptation of an earlier pro-
cedure,35 2,6-dichloroaniline was oxidized to 2,6-dichloro-
nitrobenzene (18) with peroxyacetic acid according to a
general method.36 Subsequent reaction of 18 with an
ethanolic solution of 1-propanethiolate resulted in a double
substitution to yield 2,6-bispropylthionitrobenzene (19) in
analogy to a similar literature procedure.37 The combined
yield for 19 was 28% based on the starting amine. Reduction
of the nitro group followed by diazotization of the resulting
amine 20 and reaction with KI furnished the desired iodide
5c. The overall yield for the preparation of 5c was about 8%
based on 2,6-dichloroaniline which is comparable to the
yield of the chloro analog 5a obtained via a different route
from 1a.
Bromo acid 8b was converted into its methyl ester 12 using
a standard method with PCl5 (or SOCl2 ) followed by
1
methanolysis. The nitro group in 12 was reduced with iron
powder to form amino ester 13 (Scheme 4), while catalytic
reduction over Pt gave methyl 3-aminobenzoate as the sole
product. The subsequent transformation of amine 13 to the
corresponding sulfide was accomplished using the single-
step method (cf. preparation of 3a) under neutral non-
aqueous conditions best suited for the ester functionality.
Thus, amine 13 was converted to diazonium tetrafluoro-
borate 14 with t-butyl nitrite under anhydrous conditions,33
which was reacted with propanethiol in acetonitrile in the
presence of triethylamine. The reaction mixture was
refluxed and the initially formed diazene 15 was thermally
decomposed to yield propylthio ester 16 accompanied by
about 50% of the deamination product, methyl 2-bromo-
benzoate. The progress of the reaction could be followed
NMR Spectroscopy
1H NMR spectra of 1,2,3-trisubstituted benzenes exhibit a
characteristic first order pattern of doublets of doublets for
the H(4) and H(6) protons and a triplet or pseudo-triplet for
the H(5) hydrogen. Compounds 5a and 16 are exceptions,
showing second order spectra. The 3JHH coupling constants
1
by H NMR monitoring the position of the a methylene
group triplet, which is shifted downfield by ca. 0.5 ppm in
15 relative to that in 16. The choice of the solvent was
based on the reported higher yields for the formation of
the desired sulfides in acetonitrile as compared to other
solvents.34
4
in the benzene ring are typically about 7.9 Hz and JHH
couplings are about 1.4 Hz. The structural assignment of
the aromatic proton resonances was based on the relative
chemical shifts (CS) calculated using empirical substituent
chemical shift parameters (SCSP). The results collected in
Table 1 show that while CS for some compounds corre-
spond very closely to the predicted values (e.g. 5a, 5c and
17), for some others the discrepancies are large, reaching
Ϫ1.8 ppm (1c). These differences between the calculated
and experimental CS may be related to either steric inter-
actions or solvent effects, since SCSP were developed
largely for strain-free monosubstituted benzenes in CDCl3
The overall yield of the ester 16 is 30–38% based on the
starting amine 13.
Reduction of the ester 16 with 2 equiv. of DIBAL-H
followed by PCC oxidation furnished the desired aldehyde
4b in 82% yield. Direct preparation of the aldehyde by
partial reduction of ester 14 with 1 equiv. of DIBAL-H
was less successful and the aldehyde was obtained in a
moderate yield only.
Scheme 6.

168
M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173

M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
169
Figure 1. NMR chemical shifts: (a) correlation of the difference between calculated and experimental 1H chemical shifts (D(CS)) and the energy of the LUMO;
(b) correlation of experimental (exp) and calculated (calc) 13C chemical shifts (CS). Best fit lines: (a) yˆ0:18Ϫx×1:14; rˆ0:971; (b) yˆ7:10ϩx×0:95
ꢀrˆ0:964† or yˆx×1:01 ꢀrˆ0:962†:
as the solvent.38 A closer inspection of Table 1 shows a trend
between the magnitude of the CS differences and the
number and strength of electron withdrawing substituents
in each compound in the series. Thus, the more electron
deficient the ring, the more shielded the protons are.
the 13C NMR resonance of the para carbon atom relative to
the nitro group by about 5 ppm, while the ipso carbon is
little affected. This was observed previously in 2-nitro-m-
xylene and attributed to inhibition of resonance of the nitro
group with the benzene ring.40 The ipso carbon atom in
aniline derivative 20 shows a downfield deviation of
7.6 ppm from the predicted value, which is consistent with
similar observations in other 2,6-derivatives of aniline.41
The observed trend is best explained by non-equivalent
solvation of the analyte molecule by benzene.39 The p inter-
actions with benzene and the resulting anisotropic shielding
of aromatic protons are expected to be stronger for the more
electron deficient derivatives. The magnitude of the shield-
ing should then approximately correlate with the energy of
the LUMO localized on the aromatic ring, which is a rough
reflection of electron density in the ring. Indeed, the LUMO
energies listed in Table 1 correlate surprisingly well with the
observed differences in chemical shifts, D(CS), as shown for
the H(4) protons in Fig. 1a. The H(4) protons are least
affected by possible conformational changes imposed by
the steric congestion of the three substituents, and the corre-
lation factor r is higher (0.971) than that when all protons
are included in the correlation ꢀrˆ0:919†: When the two
most outlying values attributed to protons in the ortho posi-
tions to SPr in 20 and NO2 in 10 are removed, the r is
increased to 0.951.
Conclusions
Commercially available 2,6-dinitroaniline (6), mercurio-
benzoic acid 7, and dichloroaniline serve as convenient
precursors to a variety of previously reported and new
1,2,3-trisubstituted halobenzene derivatives. Particular
emphasis was placed on the preparation of the alkylthio
derivatives, which were virtually unknown in the literature.
Out of the two methods used in their synthesis, the direct
conversion of arylamines to the corresponding aryl alkyl
sulfides was found to be more convenient. This previously
reported method was successfully extended to the prepara-
tion of several new compounds with different functionalities
and modified to be compatible with either aqueous or
anhydrous media. The results of Ullmann coupling reactions
will be reported elsewhere.
The structural assignment of the 13C NMR signals was made
based on relative intensity of the signals and best fit to the
1
predicted values (Table 1). In contrast to H NMR, 13C
spectra show no significant solvent effect, which is consis-
tent with a smaller effect of the magnetic anisotropy on the
shielding of carbon nuclei (Ͻ2 ppm) than the protons.38 The
experimental chemical shifts correlate well with those
predicted using standard SCSP, as shown in Fig. 1b. The
largest deviation from the predicted values are observed for
the chemical shifts of C(1)-I in 5c (Ϫ10.3 ppm) and C(3)-H
in 20 (Ϫ12.4 ppm). With these two points removed, the
mean difference is ϩ1.4 ppm and STD is 2.8 ppm for the
remaining 73 pairs of chemical shifts in the series of
compounds. This is a rather surprisingly good correlation
considering the steric congestion in these 1,2,3-trisubsti-
tuted benzene derivatives.
The structural assignment of NMR chemical shifts was
based on empirical prediction using the additivity of sub-
stituent chemical shift parameters (SCSP). The relatively
large number of completely characterized 1,2,3-trisubsti-
tuted derivatives allowed for generalization of the observed
trends and anomalies. Thus, the results of NMR analysis
performed in benzene-d6 are consistent with expectations.
1H NMR spectra are significantly affected by solvent, while
the 13C chemical shifts show low sensitivity to solvent and
steric effects. The solvent effect observed in 1H NMR spec-
tra was attributed to electronic interactions with the solvent
and correlated with the LUMO energy of the analyte. The
analysis of the NMR data using ChemDraw and CAChe
programs provides an example of application of simple
and commonly available computational and modeling
packages to physical–organic problems.
The steric interactions do, however, influence the chemical
shift and this is evident from the systematic upfield shift of

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M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
Experimental
2-Bromo-3-nitrobenzaldehyde (2b).6 2b was obtained in
an analogous way to the preparation of 2a. Reduction of
2-bromo-3-nitrobenzoic acid (8b, 4.96 g, 20.00 mmol)
gave 3.60 g (77% yield) of crude 2-bromo-3-nitrobenzyl
alcohol which upon oxidation furnished 3.73 g (76% overall
yield) of the aldehyde. The crude aldehyde was purified on a
silica gel column (hexane/EtOAc in 5:1 ratio) to yield a pale
yellow solid: mp 107–108ЊC (lit.6 108–109ЊC). Anal. Calcd
for C7H4BrNO3: C, 36.55; H, 1.75; N, 6.09. Found: C,
36.67; H, 1.67; N, 5.99.
Melting points were performed on a Mel-temp apparatus
and are uncorrected. NMR spectra were obtained on a
Bruker instrument at the 300 MHz field (1H spectra) and
75 MHz field (13C spectra) in C6D6 and referenced to the
solvent peak at 7.15 ppm (1H) and 128.0 ppm (13C), unless
specified otherwise. The chemical shifts and their partial
assignments are shown in Table 1. IR spectra of samples
deposited from CH2Cl2 solutions on a NaCl disc were
recorded using ATI Mattson, Genesis Series FTIR instru-
ment. Mass spectrometry was performed using Hewlett-
Packard 5890 instrument (GCMS). Elemental analysis was
provided by Atlantic Microlab, Norcross, Georgia. Fine
electrolytic iron powder was obtained from Fischer
Scientific.
1-Chloro-2-nitro-6-propylthiobenzene (3a). Method A:
Disulfide 11 (7.49 g, 20.0 mmol) was dissolved in pyridine
(130 mL) and the solution was cooled to 5–10ЊC. A slurry
of sodium borohydride (7.30 g) in absolute ethanol
(130 mL) was added portionwise to the stirred solution
and stirring was continued for 10 min. Propyl iodide
(16.95 g, 100 mmol, 9.7 mL), dissolved in 95% ethanol,
was then added dropwise, and, after 1.5 h additional stirring,
the mixture was poured into water. The product was
extracted with ether, the organic layer was dried and the
solvent was evaporated. The residue was passed through a
short silica gel column (hexane/CH2Cl2 in 3:1 ratio) giving
6.13 g (66% yield) of a light yellow oil: IR 3075, 2965,
2931, 1530, 1355 cmϪ1; MS m/e (relative intensity) 233
((Mϩ2)ϩ, 37), 231 (Mϩ, 95), 191 (37), 189 (100). Anal.
Calcd for C9H10ClNO2S: C, 46.66; H, 4.35; N, 6.04.
Found: C, 46.48; H, 4.35; N, 6.00.
Chemical shifts were calculated using ChemDraw 5.0 Ultra
program (CambridgeSoft Co.). Simulation of second order
spectra was done using PC NMR 1.0 program from Serena
Software.
Quantum-mechanical
calculations
were
performed using the AM1 method in the CAChe 3.7 suite
of programs (CAChe Scientific, Inc.). No symmetry
constraints were used and molecular geometries were fully
optimized with the keyword GNORMˆ0.
2,6-Dinitroiodobenzene (1c).22 Sodium nitrite (0.83 g,
12.00 mmol) was added portionwise to sulfuric acid
(9 mL) and the mixture was stirred and heated to 70ЊC
until the full dissolution of the solid. The resultant solution
was cooled below 40ЊC. 2,6-Dinitroaniline (6, 2.00 g,
11.00 mmol), dissolved in AcOH (22 mL), was added drop-
wise to the sodium nitrite solution while the temperature
was maintained below 40ЊC. The stirring was continued
for an additional 0.5 h, then the reaction mixture was poured
into a stirred solution of KI (2.00 g, 12.00 mmol) in water
(20 mL) at 70ЊC. The resultant mixture was stirred for
15 min then poured into 200 mL of water. The solid material
was filtered, washed with water and dried to give 2.80 g
(87% yield) of product which was used without further
purification: MS m/e (relative intensity) 294 (Mϩ, 100), 75
(65).
Method B: A suspension of well-ground aniline 9a (2.03 g,
11.76 mmol) in conc. HCl (12.5 mL) was stirred at 70ЊC
until the aniline was converted to the hydrochloride salt
(change of color from intense yellow to a very pale yellow).
The suspension was cooled to 0–5ЊC and a solution of
sodium nitrite (1.05 g, 15.43 mmol) in water (2.5 mL) was
added dropwise. Stirring was continued for an additional
0.5 h at the same temperature at which point the mixture
was vacuum filtered. The filtrate was rapidly added to a
solution of NaOH (0.54 g, 13.23 mmol) and 1-propanethiol
(1.00 g, 13.23 mmol, 1.23 mL) in water (12 mL) containing
a few crystals of solid Ni(AcO)2. The resultant mixture was
stirred for 0.5 h at ambient temperature followed by 12 h at
70ЊC. The organic materials were extracted with methylene
chloride, the organic layer was dried (Na2SO4) and the
solvent removed under reduced pressure. The crude mixture
was separated on a silica gel column (hexane/CH2Cl2 in 3:1
ratio) to yield the product as a light yellow oil (1.62 g, 60%),
identical to that obtained in Method A.
2-Chloro-3-nitrobenzaldehyde (2a).24 Acid 8a (0.505 g,
2.51 mmol) was dissolved in dry THF (3 mL). A solution
of BH3·THF complex (1M, 4.6 mL) was added at a
moderate rate under nitrogen and the solution was stirred
for 12 h at ambient temperature. The reaction mixture was
poured into aqueous HCl (4%, 110 mL) and the organic
components were extracted with diethyl ether. The organic
layer was dried (Na2SO4) and the solvent removed under
reduced pressure to yield 0.444 g (95% yield) of crude
2-chloro-3-nitrobenzyl alcohol (pale yellow crystals): mp
67ЊC (lit.24 67–70ЊC). Without further purification, the
alcohol (0.441 g, 2.35 mmol) was dissolved in methylene
chloride (30 mL) and PCC (0.494 g, 2.29 mmol) was
added. The solution turned black almost immediately.
Stirring was continued for 2.5 h under nitrogen and the
resulting mixture was passed through a silica gel plug
using additional methylene chloride for flushing. The
solvent was removed under reduced pressure to leave
0.355 g (76% overall yield) of the product: mp 91–92ЊC
(lit.24 93–95ЊC).
2-Bromo-3-propylthiobenzaldehyde (4b). Method A:
Ester 16 (0.555 g, 1.92 mmol) was dissolved in dry toluene
(5 mL) and the solution was cooled to Ϫ78ЊC. DIBAL-H
(3.84 mmol, 2.53 mL of 25 wt% in toluene) was added
dropwise and stirring continued for 1 h at Ϫ78ЊC. 1N HCl
(1.3 mL) was added followed by ether (25 mL) and the
mixture was warmed to ambient temperature. More ether
and 1N HCl were added and the organic layer was separated
and dried (Na2SO4). The solvent was evaporated to give
0.450 g (90% yield) of 2-bromo-3-propylthiobenzyl alcohol
as white crystals: mp 72.5–74ЊC; 1H NMR d 0.77 (t,
Jˆ7.4 Hz, 3H), 1.24 (t, Jˆ6.0 Hz, 1H), 1.36–1.46 (m,
2H), 2.47 (t, Jˆ7.3 Hz, 3H), 4.72 (d, Jˆ5.9 Hz, 2H), 6.84
(dd, J1ˆ7.8 Hz, J2ˆ1.4 Hz, 1H), 6.96 (t, Jˆ7.7 Hz, 1H),

M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
171
7.20 (dd, J1ˆ7.7 Hz, J2ˆ1.2 Hz, 1H); 13C NMR d 13.5,
22.0, 34.9, 65.1, 122.7, 124.6, 126.2, 127.6, 139.7, 142.0.
Without further purification, the alcohol (0.445 g,
1.70 mmol) was dissolved in methylene chloride (30 mL)
and PCC (0.403 g, 1.87 mmol) was added. The solution
turned black almost immediately. Stirring was continued
for 2.5 h under nitrogen and the resulting mixture was
passed through a silica gel plug using additional methylene
chloride for flushing. The solvent was removed under
reduced pressure to leave 0.404 g (91% yield) of the crude
product which was short-path distilled (150ЊC/0.07 torr) to
yield 0.362 g (73% overall yield) of aldehyde 4b: IR 2963,
continued for an additional 0.5 h at the same temperature.
At this point a solution of KI (2.26 g, 13.5 mmol) in water
(20 mL) was added quickly. The resultant mixture was
stirred for an additional 20 min at 70ЊC and then poured
into 150 mL of water. The organic materials were extracted
with methylene chloride, the organic layer was dried
(MgSO4) and passed through a silica gel plug. The solvent
was removed under reduced pressure and the resultant
crude mixture was separated on a silica gel column
(hexane) to yield the product as a white crystalline solid
(0.58 g, 50% yield). Additional purification was achieved
via recrystallization from petroleum ether: mp 64–65ЊC;
IR 2965, 2929, 2869, 1555, 1423, 751 cmϪ1; MS m/e
(relative intensity) 352 (Mϩ, 100), 310 (21), 268 (63).
Anal. Calcd for C12H17IS2: C, 40.91; H, 4.86. Found: C,
41.10; H, 4.85.
2930, 2871, 1726, 1689, 1554, 1371, 1234, 1145, 779 cmϪ1
;
MS m/e (relative intensity) 260 ((Mϩ2)ϩ, 100), 258 (Mϩ,
98), 218 (82), 217 (47), 216 (83), 215 (39), 137 (55), 136
(59), 108 (37).
2,4-Dinitrophenylhydrazone: mp 180–180.5ЊC. Anal.
Calcd for C16H15BrN4O4S: C, 43.75; H, 3.44; N, 12.75.
Found: C, 43.86; H, 3.50; N, 12.54.
2-Chloro-3-nitroaniline (9a).26 This compound was
prepared according to the literature procedure.26 2,6-
Dinitrochlorobenzene (1a, 16.06 g, 80.0 mmol) was added
to glacial acetic acid (240 mL) and the mixture heated to
120ЊC. Fine iron powder (13.0 g) was added in portions and
the mixture was heated at reflux for 2.5 h. The hot reaction
mixture was poured into cold water and the precipitate was
filtered off and washed with cold water to give 8.58 g (62%
yield) of the product as a yellow solid: mp 95ЊC (lit.26
95–96ЊC).
Method B: Ester 16 (0.11 g, 0.38 mmol) was dissolved in
dry toluene (1 mL) and the solution was cooled to Ϫ78ЊC
(dry ice–acetone bath). DIBAL-H (0.38 mmol, 0.25 mL of
25 wt.% in toluene) was added dropwise and stirring con-
tinued for 1 h at Ϫ78ЊC. 1N HCl (0.25 mL) was then added
followed by ether (5 mL) and the mixture was warmed to
ambient temperature. More ether and 1N HCl were added
and the organic layer was separated and dried. The solvent
was removed under reduced pressure and the residue was
separated on a silica gel column (benzene/hexane in 3:1
ratio) to yield the product as a yellow oil (0.04 g, 42%
yield).
3-Nitro-2-iodoaniline (9c). 9c was obtained from 2,6-
dinitroiodobenzene (1c, 0.70 g, 2.40 mmol) as described
for 1a. The crude material was extracted with CH2Cl2 and
the extract was passed through a silica gel plug to give
0.40 g (63% yield) of the aniline as a yellow solid: mp
101–102ЊC; IR 3463, 3367, 1619, 1514, 1461, 793,
731 cmϪ1; MS m/e (relative intensity) 264 (Mϩ, 88), 218
(42), 91 (100). Anal. Calcd for C6H5IN2O2: C, 27.30; H,
1.91; N, 10.61. Found: C, 27.52; H, 1.84; N, 10.55.
2,6-Bis(propylthio)chlorobenzene (5a). A mixture of
amine 17 (0.58 g, 2.90 mmol) and conc. HCl (3.30 mL)
was stirred at 80ЊC for 15 min. Water was added
(3.30 mL) and the mixture was cooled to 0ЊC (ice–salt–
water bath). A solution of NaNO2 (0.19 g, 3.20 mmol) in
water (1.30 mL) was added dropwise and the mixture was
stirred for 20 min at 0ЊC. The resulting diazonium salt was
added to a stirred solution of NaOH (0.13 g, 3.20 mmol) and
1-propanethiol (0.24 g, 3.20 mmol, 0.29 mL) in water
(3.00 mL) containing a few crystals of Ni(NO3)2. The
resultant mixture was stirred for 0.5 h at ambient tempera-
ture and then for 12 h at 60ЊC. Organic materials were
extracted with methylene chloride and the residue after
removal of the solvent was passed through a silica gel
column (hexane/CH2Cl2 in 5:1 ratio) to yield 0.26 g (35%
yield) of a white solid of the chloride: mp 43–44ЊC; IR
2965, 2933, 2872, 1562, 1453, 1432, 1389, 753 cmϪ1; MS
m/e (relative intensity) 262 ((Mϩ2)ϩ, 33), 260 (Mϩ, 78),
218 (58), 178 (42), 176 (100). Anal. Calcd for C12H17ClS2:
C, 55.26; H, 6.57. Found: C, 55.15; H, 6.50.
Bis(2-chloro-3-nitrophenyl)disulfide (11). A suspension
of well ground aniline 9a (2.52 g, 15.00 mmol) in conc.
HCl (15 mL) was cooled to 5–10ЊC and a solution of
sodium nitrite (1.30 g, 19.00 mmol) in water (2.5 mL) was
added dropwise. Stirring was continued for 0.5 h, after
which the mixture was vacuum filtered and the filtrate was
added, simultaneously with aq. Na2SO3 (4.70 g,
37.30 mmol, in 8 mL of water), to a stirred solution of
Na2SO3 (4.70 g, 37.30 mmol) and CuSO4 (0.37 g,
2.28 mmol) in HCl (35 mL) and water (8 mL) at 3–5ЊC.
Stirring was continued for 0.5 h and the resulting precipitate
was filtered off, washed with water and dried to give 3.20 g
(83% yield) of pure 2-chloro-3-nitrobenzenesulfonyl
chloride (10): mp 73–74ЊC (lit.15 76–78ЊC).
A mixture of sulfonyl chloride 10 (0.75 g, 2.93 mmol) and
HI (22.90 mmol, 3.00 mL of 57 wt%) was stirred at 120ЊC
for 3 h. After cooling to ambient temperature, solid sodium
bisulfite was added until all of the iodine was reacted. The
product was then filtered off, washed abundantly with water
and dried to give 0.48 g (87% yield) of the disulfide 11. An
analytical sample was obtained by recrystallization from
toluene: mp 175–178ЊC (lit.15 179–181ЊC). Anal. Calcd
for C12H6Cl2N2O4S2: C, 38.22; H, 1.60; N, 7.43. Found:
C, 38.28; H, 1.63; N, 7.38.
2,6-Bis(propylthio)iodobenzene (5c). Sodium nitrite
(0.25 g, 3.6 mmol) was added portionwise to sulfuric acid
(3.5 mL) and the resultant mixture was stirred and heated to
70ЊC until full dissolution of the solid. The resultant color-
less solution was then cooled to 0ЊC. Aniline 20 (0.79 g,
3.27 mmol), dissolved in acetic acid (6 mL), was added
dropwise to the sodium nitrite solution and the temperature
was maintained at 0ЊC during the addition. Stirring was

172
M. Sienkowska et al. / Tetrahedron 56 (2000) 165–173
Methyl 2-bromo-3-nitrobenzoate (12).1 Acid 8b (5.30 g,
21.50 mmol) was mixed in the solid state with PCl5 (4.48 g,
21.50 mmol). The solid mixture was placed in an oil bath at
150ЊC, where it quickly turned into liquid, with evolution of
HCl gas. Stirring was continued for 5 min at 150ЊC followed
by the removal of the byproduct, POCl3, under reduced
pressure. The liquid was cooled to ambient temperature
and MeOH (50 mL) was added in one portion. A vigorous
reaction ensued and the resultant solution was stirred at
reflux for 1 h. Solvent was removed under reduced pressure
leaving the ester as a pale yellow solid (5.26 g, 94% yield).
The ester was recrystallized from ethanol to give 4.82 g
(86% yield) of white crystals: mp 74.5–76ЊC (lit.1 76.5–
77ЊC); IR 1737, 1528, 1427, 1363, 1292, 1274, 1210,
Calcd for C11H13BrO2S: C, 45.69; H, 4.53; S, 11.09.
Found: C, 45.83; H, 4.51; S, 11.19.
2-Chloro-3-propylthioaniline (17). Nitro compound 3a
(1.82 g, 7.90 mmol) was dissolved in absolute ethanol
(50 mL) in
a
hydrogenation bottle. PtO2 (0.18 g,
0.78 mmol) was added and the resultant mixture was
subjected to hydrogenation at 40–45 psi for 6 h at ambient
temperature followed by 1 h at 80ЊC. The mixture was
filtered through a Celite pad and the solvents were evapo-
rated. The residue was redissolved in methylene chloride
and passed through a silica gel plug to give the product as
a colorless oil (1.43 g, 90% yield), which was used without
further purification: MS m/e (relative intensity) 203
((Mϩ2)ϩ, 20), 201 (Mϩ, 35), 159 (100), 124 (39).
1137 cmϪ1
.
Methyl 3-amino-2-bromobenzoate (13).11 Ester 12
(3.00 g, 11.50 mmol) was dissolved in glacial acetic acid
(15 mL) and the solution was heated to 120ЊC. Reduced
iron powder (2.15 g, 38.60 mmol) was added in one portion
and the mixture was stirred at 120ЊC for 2 h. The hot
mixture was poured into water, the organic materials were
extracted with methylene chloride, and the solution was
passed through a silica gel plug to give 2.30 g (87% yield)
of the product as a light yellow oil, which was used without
additional purification: MS m/e (relative intensity) 231
((Mϩ2)ϩ, 96), 229 (Mϩ, 92), 200 (88), 198 (100), 90(72).
2,6-Bis(propylthio)nitrobenzene (19). 2,6-Dichloroaniline
(12.32 g, 76 mmol), acetic acid (300 mL), hydrogen perox-
ide (30%, 100 mL) and sulfuric acid (6 mL) were stirred at
80ЊC for 8 h. The resulting yellow solution was cooled,
water (1200 mL) added and the precipitated product filtered
and dried to give crude 2,6-dichloronitrobenzene (18, 9.5 g).
The crude product 18 (2.16 g, 11 mmol) was added to a
solution of 1-propanethiol (1.77 g, 23 mmol) and NaOH
(0.93 g, 23 mmol) in ethanol (25 mL). The mixture was
gently refluxed for 4 h, poured into water and the product
extracted with methylene chloride. Crude material was
separated by flash column chromatography (hexane/
CH2Cl2 in 2:5 ratio) to give 1.20 g (28% overall yield) of
yellow solid of pure 19: mp 44–45ЊC; IR 2960, 2926, 1569,
1533, 1439, 1362 cmϪ1; MS m/e (relative intensity) 271
(Mϩ, 11), 242 (35), 182 (100), 122 (35). Anal. Calcd for
C12H17NO2S2: C, 53.11; H, 6.31; N, 5.16. Found: C, 53.23;
H, 6.48; N, 5.15.
Methyl 2-bromo-3-propylthiobenzoate (16). Amine 15
(0.37 g, 1.60 mmol) was dissolved in dry methylene
chloride (2 mL) and cooled to Ϫ15ЊC. BF3·(C2H5)2O
(0.34 g, 2.30 mmol, 0.30 mL) was added dropwise as the
temperature was maintained at Ϫ15ЊC. A precipitate sepa-
rated and was redissolved by adding dry ether to the
mixture. t-C4H7ONO (0.19 g, 1.90 mmol, 0.22 mL), in
methylene chloride (2 mL) was added dropwise at Ϫ15ЊC
and stirring continued for 15 min at this temperature and
then for 5 min at 5ЊC (ice–water bath). Pentane (10 mL)
was added and the mixture was vacuum filtered. The
solid was washed with cold ether and dried to give 0.48 g
(91% yield) of dry diazonium salt 14: 1H NMR (acetonitrile-
d3) d 3.97 (s, 3H), 7.99 (t, Jˆ8.1 Hz, 1H), 8.59 (dd,
J1ˆ8.0 Hz, J2ˆ1.6 Hz, 1H), 8.67 (dd, J1ˆ8.5 Hz, J2ˆ
1.5 Hz, 1H).
2,6-Bis(propylthio)aniline (20). Nitro compound 19
(1.80 g, 6.60 mmol) was dissolved in glacial acetic acid
(30 mL) and the solution was heated to 120ЊC. Fine iron
powder (1.24 g, 22.10 mmol) was added in one portion
and the mixture was stirred at 120ЊC for 2 h. The hot
mixture was poured into water and the organic materials
were extracted with methylene chloride. The solvent was
removed and the residue was passed through a silica gel
column (hexane/CH2Cl2 in 3:1 ratio) to give 0.90 g (56%
yield) of the product as a light oil: IR 3459, 3352, 2961,
2929, 2870, 1588, 1550, 1430, 1235, 736 cmϪ1; MS m/e
(relative intensity) 241 (Mϩ, 100), 199 (25), 157 (90), 155
(93), 124 (54). Anal. Calcd for C12H19NS2: C, 59.70; H,
7.93; N, 5.80. Found: C, 59.45; H, 7.88; N, 5.63.
Dry diazonium salt 14 (0.30 g, 0.91 mmol) was dissolved in
acetonitrile (3 mL) and added to a solution of 1-propane-
thiol (0.08 g, 0.91 mmol, 0.10 mL) in acetonitrile (2 mL),
containing an equimolar amount of triethylamine (0.10 g,
0.91 mmol, 0.13 mL). The solution was stirred for 18 h at
80ЊC. It was then poured into water and the organic compo-
nents were extracted with methylene chloride. The organic
layer was dried (MgSO4) and passed through a silica gel
plug. The solvent was removed under reduced pressure
and the residue was separated on a silica gel column
(hexane/CH2Cl2 in 1:1 ratio) to yield the product as pale
yellow crystals (0.10 g, 0.35 mmol, 38%). In the 10 mmol
scale reaction, ester 16 was isolated from the crude mixture
by short-path distillation (170ЊC/0.6 torr) followed by
recrystallization from methanol in the overall yield of
30%: mp 60.5–61ЊC; IR 2965, 1730, 1291, 1284, 1253,
1238, 1206, 750 cmϪ1; MS m/e (relative intensity) 290
((Mϩ2)ϩ, 100), 288 (Mϩ, 96), 248 (81), 246 (77). Anal.
Acknowledgements
This project has been supported by NSF (CHE-9528029)
and Vanderbilt University (V.B.). We thank Mr Daniel E.
McBrayer and Mr Kristopher B. McNeil for their technical
assistance.
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