An improved synthesis and structural characterisation of 2-(4-acetylthiophenylethynyl)-4-nitro-5-phenylethynylaniline: The molecule showing high negative differential resistance (NDR)

Article abstract of DOI:10.1055/s-2003-41451

2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenyl-ethynylaniline (11) has been synthesised by an improved route, which has many advantages over the literature procedure. A key intermediate is 2-ethynyl-4-nitro-5-phenylethynylaniline (6) which is obtained fro

Full text of DOI:10.1055/s-2003-41451

PAPER
2089
An Improved Synthesis and Structural Characterisation of 2-(4-Acetylthio-
phenylethynyl)-4-nitro-5-phenylethynylaniline: The Molecule Showing High
Negative Differential Resistance (NDR)
Synthesis of
H
igh
h
ND
R
2-(4-A
a
cetylthiop
n
henylethyny
g
l)-4-nitro-5-p
s
henylethy
h
laniline eng Wang,a Andrei S. Batsanov,a Martin R. Bryce,*a Ian Sageb
a
Department of Chemistry, University of Durham, Durham, DH1 3LE, UK
Fax +44(191)3844737; E-mail: m.r.bryce@durham.ac.uk
b
QinetiQ, St Andrews Road, Malvern, Worcestershire WR14 3PS, UK
Received 28 May 2003; revised 24 June 2003
1) The nitration of 1 was reported to be explosive, and
therefore, the nitro derivative 2 was not isolated and puri-
fied prior to the subsequent reactions.3
Abstract: 2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenyl-ethynyl-
aniline (11) has been synthesised by an improved route, which has
many advantages over the literature procedure. A key intermediate
is 2-ethynyl-4-nitro-5-phenylethynylaniline (6) which is obtained
from 2,5-dibromoacetanilide (5 steps, 68% overall yield). Reaction
of 6 with 1-acetylthio-4-iodobenzene under Sonogashira coupling
conditions affords 11 (56%). Compound 11 is characterised by
CHN analysis, mass spectrometry and 1H and 13C NMR
spectroscopy. The crystal structures of 2-bromo-4-nitro-5-
phenylethynylaniline (4), 2-(3-hydroxy-3-methylbutynyl)-4-nitro-
5-phenylethynylaniline (5) and 2-[(4-methoxybenzylthio)phenyl-
ethynyl]-4-nitro-5-phenylethynylaniline (15), have been deter-
mined, by which the regiochemical structure of 11 is also proved.
The intramolecular contacts O(1)···C(7) of 2.692(2) Å in 4 and
2.677(2) Å in 15 are considerably shorter than the standard van der
Waals O···C contact of 3.24 Å.
2) The regioselectivity of the mono cross-coupling of 2
with phenylacetylene was not proved, but assumed. As a
result, the regiochemical structure of 11 was also not
rigorously proved. This is because phenylacetylene could
replace either of the bromine atoms in molecule 2 leading
to two different regioisomers, although the Br on C-5 is
expected to be more reactive in Sonogashira coupling
reactions.
3) The synthesis of the other key building block, i.e., 4-
acetylthiophenylacetylene proved to be problematic in
our laboratory. We were not able to reproduce the lithia-
tion of 1,4-diiodobenzene as reported4 although a modifi-
Key words: 2-(4-acetylthiophenylethynyl)-4-nitro-5-phenylethynyl-
aniline, negative differential resistance, molecular wires, Sono- cation of this procedure has been published during the
preparation of this manuscript.5 In addition, the melting
gashira coupling
point and purity of compound 11 (i.e. C,H,N analysis)
remained unreported.1,2,6
2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenylethynyl-
In this paper, we report a much improved procedure for
aniline (11) is a promising candidate for molecular elec-
the preparation of compound 11. Our improvements and
tronic devices which could perform logic and memory
modifications are as follows.
functions, due to the discovery in 1999 of its unusually
1) We optimised the reaction conditions for the nitration
high negative differential resistance (NDR) in self-assem-
of 1 (Scheme 1) and have isolated the nitro derivative 2 in
>20 g batches (86% yield after recrystallisation) without
bled monolayers.1 The synthetic details and structural
characterisation of this particularly interesting molecule
any explosion. A likely explanation for the explosions
were reported by Tour and co-workers in 2001.2 In their
encountered3 is that the reaction temperature was not pre-
cisely controlled, leading to explosive multi-nitrated side-
products. A very slow addition of nitric acid at low tem-
perature (an external temperature of –10 to –15 °C was
synthesis, 2,5-dibromoacetanilide (1) was nitrated to af-
ford 2,5-dibromo-4-nitroacetanilide (2) (Scheme 1). The
cross-coupling of 2 with phenylacetylene yielded 2-bro-
mo-4-nitro-5-phenylethynylacetanilide, which was then
needed to maintain an internal temperature of –3 to –5 °C)
deacetylated to afford the key intermediate, 2-bromo-4-
during the addition is particularly important.
nitro-5-phenylethynylaniline (4). The cross-coupling of 4
2) Instead of directly coupling 2 with phenylacetylene,
compound 2 was deacetylated to afford 3 prior to the cou-
pling reaction. We reasoned that the increased electron-
donating ability of the amino group should enhance the re-
activity difference of the bromine atoms of 3 towards So-
nogashira coupling, leading to cleaner formation of 4,
with a smaller proportion of the regioisomer arising from
displacement of the Br at C-2. We were unable to repro-
duce the reported deacetylation of 2 using 1 M HCl7 pos-
sibly because the structure claimed to be compound 2 had
been incorrectly assigned: (it was not fully characterised
with 4-acetylthiophenylacetylene afforded the final prod-
uct 11.
In seeking to prepare a sample of compound 11 with high
purity, we recognised that the following problems in the
reported procedure2 had to be overcome.
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 10 09 2003.
Art Id.1437-210X,E;2003,0,13,2089,2095,ftx,en;P04303SS.pdf.
DOI: 10.1055/s-2003-41451
© Georg Thieme Verlag Stuttgart · New York

2090
C. Wang et al.
PAPER
NHAc
and the more reactive aromatic iodide 10. Another reason
which persuaded us to avoid the reaction of 4 with 4-
acetylthiophenylacetylene was that during the attempted
synthesis of 11, by deprotection of compound 15 followed
by acetylation of the resulting thiolate (Scheme 3), the
self-coupling of the terminal acetylene 14 was the do-
minant reaction. As documented, the self-coupling of
terminal acetylenes is common when unreactive aromatic
bromides8a,b or nonaromatic halides8c are used under
Sonogashira reaction conditions. Therefore, the cross-
coupling of 14 with compound 4 to yield 15 was ineffi-
cient. This may suggest that coupling between 4 and 4-
acetylthiophenylacetylene is similarly inefficient. A side
benefit from the route we abandoned was that compound
15 was more crystalline than 11 which allowed us to ob-
tain a single crystal X-ray structure. The crystal structure
of 15 (as with 4 and 5) indirectly confirmed the regio-
chemical structure of 11.
NHAc
Br
HNO3-H2SO4
86%
Br
Br
Br
O2N
2
1
70% H2SO4
93%
NH2
Br
NH2
Br
PhCCH
Pd(II)-CuI
TEA
94%
Ph
Br
O2N
O2N
4
3
OH
92%
NH2
Ph
Another significant practical improvement in Scheme 2 is
that instead of the tricky monolithiation of 1,4-diiodoben-
zene with tert-butyllithium,4 we developed a more conve-
nient and reliable way to synthesise 1-acetylthio-4-
iodobenzene (10). 4-Iodophenol reacted with N,N-dime-
thylthiocarbamoyl chloride (DMTCC) to afford the O-es-
ter 7 in 90% yield. Using a Kugelrohr oven, the Newman–
Karnes conversion9 of 7 to the S-ester 8 proceeded in good
yield. The subsequent hydrolysis and acetylation leading
to analytically pure 10 are straightforward reactions. (The
overall yield of 10 from 4-iodophenol was 67%).
OH
O2N
5
NaH
98%
NH2
Ph
H
O2N
6
Scheme 1
DMTCC
90%
I
OH
I
O
N
S
and had mp 204–205 °C, whereas our pure sample of 2
had mp 183.9–185.3 °C). We found that the reaction of 2
in 70% sulfuric acid gave 3 in 93% yield. In contrast to the
report,7 our product was insoluble in 1 M HCl even after
sonication and heating.
H3C
CH3
7
235 o
82%
C
3) The mono cross-coupled intermediate 4 was obtained
in 94% yield and its structure was unambiguously estab-
lished by X-ray diffraction in addition to its routine anal-
ysis. Importantly, the crystal structures of 4 and 5 proved
that the phenylethynyl functionality was attached at C-5.
The eventual regiochemistry of 11, which is derived from
4, is, therefore, ascertained beyond doubt.
KOH / MeOH
92%
I
S
N
I
SH
O
H3C
9
CH3
8
AcCl
98%
4) A different route has been used to prepare 11. We
synthesised first the terminal alkyne derivative 6, then
cross-coupled it with 1-acetylthio-4-iodobenzene (10)
(Scheme 2).
This route is preferable to Tour’s procedure1,2 for several
reasons. Firstly, it enables the use of a large excess of
terminal alkyne, i.e. 2-methyl-3-butyn-2-ol, to overcome
the low reactivity of 4 (which is an aromatic bromide)
towards Sonogashira coupling. Secondly, the coupled
product 5 can be easily purified by column chromato-
graphy due to its high polarity caused by the hydroxy
group. Thirdly, in the last step of the sequence to afford
11, coupling takes place between the terminal alkyne 6
I
SAc
10
6
56%
Pd(II)/CuI/TEA
NH2
SAc
O2N
11
Scheme 2
Synthesis 2003, No. 13, 2089–2095 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Synthesis of High NDR 2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenylethylaniline
2091
CH2Cl
SH
Br
group and benzene ring ii are inclined to ring i by 2.7(13),
0.3(1) and 4.0(1)º, respectively, in 4, and by 4.7(17),
4.6(1) and 5.3(1)º in 15. The resulting intramolecular con-
tacts O(1)···C(7) of 2.692(2) Å in 4 and 2.677(2) Å in 15
are considerably shorter than the standard van der Waals
O···C contact of 3.24 Å.10 This interaction must be respon-
sible for a decrease of the C(4)–C(7)–C(8) angle to
171.6(2)º (4) and 171.7(2)º (15). The bond distances C–
NH2 [1.351(2) Å] and C–NO2 [1.446(2) Å] are identical in
4 and 15, and practically coincide with those in p-nitro-
aniline [1.355(2) and 1.433(2) Å, respectively].11 In the
latter, the benzene ring geometry is substantially quinoi-
dal, which is not pronounced in 4 and 15, probably ob-
scured by the effects of other substituents. The remaining
part of molecule 15 is not planar, with the dihedral angle
of 25.7(1)º between benzene rings i and iii, and 84.1(1)º
between rings iii and iv. In both structures, one H atom of
the amino group participates in an intermolecular hydro-
gen bond [N(2)–H···O(2) in 4; N(2)–H···S in 15]. These
bonds link molecules, related by a glide plane c (in 4) or
by an a–b translation (in 15) into an infinite chain. The
other amino H atom forms a short intramolecular contact
with the substituent at C(1), which can be interpreted as a
N–H···Br or N–H··· p(CΩC) hydrogen bond, albeit a
forced one.
S
K2CO3
89%
+
OMe
MeO
Br
12
92%
HO
S
OH
MeO
13
NaH
78%
S
H
MeO
14
4
Pd(II)/CuI/TEA
22%
H2N
Ph
S
MeO
NO2
15
Scheme 3
These new routes to both reagents 6 and 10 have allowed
us to repeat the synthesis many times and have made
available sufficient quantity of compound 11 for careful
purification, structural characterisation and physical stud-
ies. We have been unable to prepare a single crystal of 11.
Solid samples of 11 were shelf-stable at ambient condi-
tions for weeks. However, solutions in THF stored in
sealed vials decomposed within a few days on the bench
under room light, as shown by HPLC analysis and dark-
ening of the solutions.
Figure 1 Molecular structure of 4, showing 50% displacement el-
lipsoids.
In summary, this paper describes a new synthesis of the ti-
tle compound 11 which is an important molecule in con-
temporary molecular electronic device studies.1–3,6 This
route offers significant improvements over the literature
procedure2 and provides efficient access to versatile phe-
The X-ray molecular structures of 4 and 15 are shown in
Figures 1 and 2, respectively. In both molecules, the 4-ni-
tro-5-phenylethynylaniline moiety adopts a near-planar
conformation: the essentially flat amino group, the nitro
Figure 2 Molecular structure of 15.
Synthesis 2003, No. 13, 2089–2095 ISSN 1234-567-89 © Thieme Stuttgart · New York

2092
C. Wang et al.
PAPER
nylene-ethynylene derivatives, which are suitable build-
ing blocks for the construction of a range of functional
molecular wires of well-defined conjugation lengths.12
Table 1 Crystal Data for Compounds 4 and 15
Parameters
Formula
Formula weight
T, K
4
15
C14H9BrN2O2
317.14
C30H22N2O3S
490.56
2,5-Dibromoacetanilide was prepared as described3 and recrystal-
lised from EtOH as white crystals; mp 176.8–178.3 °C (Lit.3 mp
170–171 °C). THF and Et3N were dried over sodium metal and
freshly distilled before use. Petroleum ether used had bp 40–60 °C.
Flasks used to carry out Sonogashira coupling reactions were flame-
dried and coupling reactions were all protected with an argon atmo-
sphere. Dichlorobis(triphenylphosphine)palladium (II) was pre-
pared by the reported method.13 CuI was used as purchased from
Avocado (98%+ grade). The Kugelrohr apparatus used for the prep-
aration of 8 was a Büchi B-580 glass oven and the temperatures
were direct readings of the display without calibration. Most of the
1H and 13C NMR spectra were recorded on a Varian Unity-300 spec-
trometer operating at 299.91 MHz for 1H and 75.41 MHz for 13C un-
less indicated otherwise. In those cases, 400 MHz and 200 MHz
refer to Varian VXR 400s and Varian Mercury 200 spectrometers,
respectively. Chemical shifts are quoted downfield from TMS.
Electron Impact (EI) mass spectra were recorded on a Micromass
AutoSpec spectrometer operating at 70 eV. Elemental analyses
were obtained on an Exeter Analytical Inc. CE-440 elemental anal-
yser. Melting points were measured in open-end capillaries using a
Stuart Scientific SMP3 melting point apparatus. The temperatures
at the melting points were ramped at 2.5 °C/min and are uncorrect-
ed.
120
120
Symmetry
Space group
a, Å
Monoclinic
P21/c (# 14)
3.9187(3)
22.827(3)
14.152(2)
90
triclinic
P1 (# 2)
9.176(2)
10.247(2)
13.020(2)
84.81(1)
86.91(1)
79.00(1)
1196.0(4)
2
b, Å
c, Å
a, °
b, °
90.34(2)
90
g, °
V, Å3
1265.9(2)
4
Z
m, mm–1
3.25
0.17
Crystal size
Transmission
Reflections collected
Unique reflections
Rint
0.45 × 0.20 × 0.04
0.3865–0.8812
17585
0.60 × 0.27 × 0.10
0.9038–0.9844
22254
Crystallographic Studies
X-ray diffraction experiments (see Table 1) were carried out on a
SMART 3-circle diffractometer with a 6K CCD area detector, using
graphite-monochromated Mo-Ka radiation (l = 0.71073 Å) and a
Cryostream (Oxford Cryosystems) open-flow N2 cryostat. Full
sphere of reciprocal space to 2q = 60º was covered by 4 sets of 0.3º
w scans, each set with different j and/or 2q angles. The intensities
were corrected for absorption by numerical integration based on
real crystal shape. The structures were solved by direct methods and
refined by full-matrix least squares against F2 of all data, using
SHELXTL software.14 Full crystallographic data, excluding struc-
ture factors, are provided in Electronic Supplementary Information
and have been deposited at the Cambridge Crystallographic Data
Centre, CCDC nos. 209051 (4), 216572 (5) and 209052 (15).
3706
6970
0.045a
0.041
Reflections
R[F2 > 2s(F2)]
wR(F2), all data
2866
5282
0.027
0.054
0.066
0.161
a 0.114 before absorption correction.
2,5-Dibromo-4-nitroacetanilide (2)
2,5-Dibromoacetanilide (1;3 26.4 g, 90.1 mmol) was added in small
portions to H2SO4 (120 mL) at –5 °C with stirring using an overhead
stirrer, to obtain a clear viscous solution. HNO3 (36 mL, 70%,
d = 1.42 g/cm3, Fisher) was then added at a speed such that the tem-
perature was controlled between –3 to –5 °C, using a syringe pump
through a thin Teflon tubing (NOTE: An external temperature of
–10 to –15 °C achieved with an actone/dry-ice cooling bath was
needed to maintain the internal temperature under control). This
temperature and stirring were maintained for 1 h after the addition.
The clear yellow solution was then poured on to crushed ice and was
followed by a suction filtration. The off-white solid, which collect-
ed on the filter was washed with a large volume of H2O to remove
the acids. Recrystallisation of the solid from AcOH yielded 26.2 g
(86%) of compound 2 as pale-yellow needles; mp 183.9–185.3 °C.
Anal. Calcd for C8H6Br2N2O3 (337.95): C, 28.43; H, 1.79; N, 8.29.
Found: C, 28.40; H, 1.75; N, 8.22.
2,5-Dibromo-4-nitroaniline (3)
2,5-Dibromo-4-nitroacetanilide (2; 7.0 g, 20.7 mmol) was added
with stirring to 70% w/w H2SO415 (140 mL) in portions. The mix-
ture was then gradually heated until the solid was dissolved to yield
a clear yellow solution, which was stirred with heating for 1 h, then
cooled until yellow crystals appeared. H2O (200 mL) was added
slowly into the flask with stirring. The mixture was then stored at
r.t. for 1 h. Bright-yellow crystals of 3 (5.7 g, 93%) were obtained
by suction-filtration of the mixture, and recrystallisation from
MeOH; mp 182.9–183.9 °C.
1H NMR (200 MHz, DMSO-d6): d = 6.86 (s, 2 H), 7.09 (s, 1 H),
8.21 (s, 1 H).
13C NMR (200 MHz, DMSO-d6): d = 104.1, 115.5, 118.1, 131.4,
136.0, 151.5.
1H NMR (DMSO-d6): d = 2.17 (s, 3 H), 8.32 (s, 1 H), 8.41 (s, 1 H),
9.76 (s, 1 H).
13C NMR (DMSO-d6): d = 23.7, 112.8, 114.2, 129.1, 129.8, 141.0,
145.0, 169.4.
MS (EI): m/z (%) = 296 (M+, 84), 266 (100).
MS (EI): m/z (%) = 337 (M+, 12), 295 (100).
Anal. Calcd for C6H4Br2N2O2 (295.92): C, 24.35; H, 1.36; N, 9.47.
Found: C, 24.34; H, 1.34; N, 9.41.
Synthesis 2003, No. 13, 2089–2095 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Synthesis of High NDR 2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenylethylaniline
2093
2-Bromo-4-nitro-5-phenylethynylaniline (4)
O-4-Iodophenyl N,N-Dimethylthiocarbamate (7)
A mixture of 2,5-dibromo-4-nitroaniline (3; 2.96 g, 10 mmol), phe-
nylacetylene (1.1g, 10.8 mmol), Pd(PPh3)2Cl2 (150 mg) and CuI (75
mg) in freshly distilled THF (10 mL) was heated at 50 °C until the
organic solids were dissolved. Et3N (20 mL) was added and the re-
sulting clear yellow solution was stirred at r.t. for 15 min, at 50 °C
for 12 h, then at 90 °C for 1 h to yield a brown suspension. The mix-
ture was cooled to r.t. and Et2O (50 mL) was added, followed by
suction-filtration to remove the solid. The filtrate was evaporated to
dryness and the residue was chromatographed on a silica gel col-
umn eluting with CH2Cl2–petroleum ether (3:1) to afford a yellow
solid, which was recrystallised first from MeOH–H2O, then from
CHCl3–hexane to give compound 4 as yellow needles (2.99 g,
94%); mp 124.7–125.4 °C. A single crystal for X-ray analysis was
prepared by slow evaporation of a CHCl3 solution of the compound.
This is a modification of the reported general method.9 4-Iodophe-
nol (22.0 g, 0.1 mol) was dissolved in anhyd DMF (100 mL, Ald-
rich). NaH (60% dispersion, 4.0 g, 0.1 mol) was added in small
portions with stirring. The mixture was stirred at r.t. for 10 min, then
gradually heated to 80 °C and stirred for 30 min until the H2 gas evo-
lution had ceased. The heating bath was removed and the solution
was allowed to cool to r.t., followed by the addition of N,N-dimeth-
ylthiocarbamoyl chloride (15.0 g, 0.12 mol) portionwise with stir-
ring. The mixture was then stirred at r.t. for 12 h and Et2O (200 mL)
was added to the mixture. The solid, which formed during the reac-
tion was removed by suction-filtration. The filtrate was then evapo-
rated and the residue was column chromatographed on silica gel
(eluent: CH2Cl2) to afford a pale-yellow solid. Recrystallisation of
the solid from CHCl3–hexane yielded 7 as large white crystals (27.5
g, 90%); mp 111.0–112.2 °C (Lit.9 mp 109.5–110.5 °C).
1H NMR (400 MHz, CDCl3): d = 4.78 (s, 2 H), 6.94 (s, 1 H), 7.37
(m, 3 H), 7.58 (m, 2 H), 8.35 (s, 1 H).
13C NMR (400 MHz, CDCl3): d = 85.3, 96.8, 106.8, 118.3, 120.1,
122.4, 128.4, 129.2, 130.4, 132.0, 139.4, 148.5.
1H NMR (CDCl3): d = 3.33 (s, 3 H), 3.44 (s, 3 H), 6.83 (d, J = 8.7
Hz, 2 H), 7.69 (d, J = 8.7 Hz, 2 H).
13C NMR (CDCl3): d = 38.8, 43.3, 90.2, 125.0, 138.2, 153.8.
MS (EI): m/z (%) = 307 (M+, 24), 72 (100).
MS (EI): m/z = 318 (M+, 100%).
Anal. Calcd for C14H9BrN2O2 (317.14): C, 53.02; H, 2.86; N, 8.83.
Found: C, 52.78; H, 2.81; N, 8.85.
Anal. Calcd for C9H10INOS (307.15): C, 35.19; H, 3.28; N, 4.56.
Found: C, 35.58; H, 3.48; N, 4.50.
2-(3-Hydroxy-3-methylbutynyl)-4-nitro-5-phenylethynyl-
aniline (5)
S-4-Iodophenyl N,N-Dimethylthiocarbamate (8)
The flask containing 7 (8.71 g, 28.4 mmol) was placed in a Kugel-
rohr apparatus and heated to 235 °C with spinning. The melt grad-
ually darkened from colourless to light brown. TLC (silica gel,
CH2Cl2) or 1H NMR analysis was needed to determine the end point
of the reaction after ca. 1 h heating. The reaction should be stopped
at about 90% conversion based on the NMR integrals. (Note: Atten-
tion should be paid to the final stage of the reaction as excess heat-
ing can result in significant decomposition). The crude product was
purified by column chromatography (silica gel, CH2Cl2), then re-
crystallised from cyclohexane affording 8 as off-white plates (7.18
g, 82%); mp 89.5–90.6 °C (Lit.16 mp 87.5–88.8 °C).
1H NMR (CDCl3): d = 3.02 (s, 3 H), 3.06 (s, 3 H), 7.20 (d, J = 8.4
Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 36.9, 95.7, 128.7, 137.2, 138.0, 166.1.
MS (EI): m/z (%) = 307 (M+, 100).
2-Bromo-4-nitro-5-phenylethynylaniline (4; 1.755 g, 5.53 mmol)
and 2-methyl-3-butyn-2-ol (1.86 g, 22 mmol) were dissolved in
freshly distilled Et3N (40 mL). Pd(PPh3)2Cl2 (123 mg) and CuI (61
mg) were added to the solution and the mixture was stirred and heat-
ed at 90 °C for 3 h. The mixture was cooled to r.t. and then brought
to dryness by vacuum evaporation. Column chromatography of the
dark-yellow oily residue (silica gel, CH2Cl2 with 20% EtOAc)
yielded compound 5 as a yellow amorphous solid (1.63 g, 92%),
which gave yellow crystals by adding cyclohexane into its CH2Cl2
solution; mp 145.0–145.9 °C. A single crystal was obtained by slow
evaporation of its CDCl3 solution.
1H NMR (CDCl3): d = 1.64 (s, 6 H), 4.84 (s, 2 H), 6.87 (s, 1 H), 7.37
(m, 3 H), 7.58 (m, 2 H), 8.16 (s, 1 H).
13C NMR (CDCl3): d = 31.4, 65.7, 76.2, 85.9, 97.2, 102.0, 106.5,
117.8, 120.8, 122.4, 128.4, 129.2, 130.2, 132.0, 138.9, 151.3.
Anal. Calcd for C9H10INOS (307.15): C, 35.19; H, 3.28; N, 4.56.
Found: C, 35.23; H, 3.29; N, 4.51.
MS (EI): m/z (%) = 320 (M+, 40), 105 (100).
Anal. Calcd for C19H16N2O3 (320.34): C, 71.24; H, 5.03; N, 8.74.
Found: C, 69.92; H, 4.96; N, 8.58.
4-Iodothiophenol (9)
To the degassed solution of compound 8 (7.6 g, 24.7 mmol) in
MeOH (150 mL) was added KOH pellets (4.0 g). The mixture was
heated to reflux and stirred for 1 h under argon. The solution was
cooled to r.t. and HCl acid was added until the pH was ca. 1, fol-
lowed by the slow addition of H2O (ca. 100 mL) with stirring. A
pale-yellow crystalline solid was collected by suction-filtration,
then washed with a large volume of H2O to yield 4-iodothiophenol
(9) as white crystals (5.68 g, 97%); mp 84.7–85.3 °C (Lit.17 mp 86
°C). The solid was essentially analytically pure and was used for the
subsequent reactions without further purification.
1H NMR (CDCl3): d = 3.43 (s, 1 H), 7.01 (d, J = 8.4 Hz, 2 H), 7.54
(d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 90.1, 130.9, 131.1, 138.0.
MS (EI): m/z = 236 (M+, 100%).
2-Ethynyl-4-nitro-5-phenylethynylaniline (6)
Compound 5 (1.62 g, 5.06 mmol) was dissolved in anhyd benzene
(50 mL, Aldrich) by heating and stirring under argon. NaH (110 mg,
60% dispersion in mineral oil, Aldrich) was added in one portion
and the mixture was refluxed for 5–7 h (TLC monitoring). The re-
action mixture was cooled to r.t. and Celite (ca. 1 g) was added fol-
lowed by filtration through a Celite pad under vacuum. The filtrate
was evaporated in vacuo and the residue was column chromato-
graphed (silica gel, CH2Cl2) to afford a bright yellow solid, which
recystallised from CHCl3–hexane as yellow needles (1.31 g, 98%);
mp 104.2–104.8 °C.
1H NMR (CDCl3): d = 3.52 (s, 1 H), 5.04 (s, 2 H), 6.87 (s, 1 H), 7.36
(m, 3 H), 7.57–7.60 (m, 2 H), 8.21 (s, 1 H).
13C NMR (CDCl3): d = 77.7, 85.2, 85.8, 97.3, 105.5, 117.9, 121.1,
122.2, 128.3, 129.1, 130.5, 131.9, 138.5, 151.9.
Anal. Calcd for C6H6IS (236.07): C, 30.53; H, 2.13. Found; C,
30.66; H, 2.55.
MS (EI): m/z = 262 (M+, 100 %).
Anal. Calcd for C16H10N2O2 (262.26): C, 73.27; H, 3.84; N, 10.68.
Found: C, 73.00; H, 3.85; N, 10.56.
1-Acetylthio-4-iodobenzene (10)
4-Iodothiophenol (9; 2.13 g, 9.02 mmol) was dissolved in pyridine
(30 mL, dried over NaOH pellets and degassed). Acetyl chloride
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2094
C. Wang et al.
PAPER
(1.5 mL, 21 mmol) was syringed in slowly with vigorous stirring
under argon. The mixture was stirred for an additional 15 min fol-
lowed by the addition of H2O and crushed ice. The precipitated
pale-yellow solid was collected by suction-filtration then washed
with H2O. Column chromatography of the crude product on silica
gel (CH2Cl2–petroleum ether, 1:1) yielded compound 10 as a white
solid (2.47 g, 98%). The solid was recrystallised from MeOH–H2O
to form white crystals; mp 57.0–57.7 °C (Lit.18 mp 56–57 °C).
was refluxed for 2 h. Additional Pd(PPh3)2Cl2 (80 mg) and CuI (40
mg) were added and the reflux was continued for a further 10 h. The
resulting hot brown suspension was suction-filtered through a
Celite pad and the filter cake was washed with Et2O. The filtrate
was evaporated and the residue was column chromatographed (sili-
ca gel, 10% Et2O in CH2Cl2). White crystals of 13 were obtained
(1.44 g, 92%) after recrystallisation from MeOH; mp 120.4–121.4
°C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.74
(d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 30.2, 95.9, 127.7, 135.9, 138.3, 193.1.
MS (EI): m/z (%) = 278 (M+, 24), 236 (100).
1H NMR (CDCl3): d = 1.62 (s, 6 H), 2.11 (s, 1 H), 3.80 (s, 3 H), 4.10
(s, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 7.216 (d, J = 8.7 Hz, 2 H), 7.224
(d, J = 8.7 Hz, 2 H), 7.31 (d, J = 8.7 Hz, 2 H).
13C NMR (CDCl3): d = 31.4, 37.8, 55.2, 65.6, 81.7, 94.1, 113.9,
120.1, 128.71, 128.75, 129.9, 131.9, 137.3, 158.8.
Anal. Calcd for C8H7IOS (278.11): C, 34.55; H, 2.54. Found: C,
34.55; H, 2.53.
MS (EI): m/z (%) = 294 (M+ – 18, 19), 121 (100).
Anal. Calcd for C19H20O2S (312.43): C, 73.04; H, 6.45. Found: C,
72.82; H, 6.45.
2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenyethynylaniline
(11)
A flame-dried flask was charged with compound 6 (144.6 mg, 0.55
mmol), compound 10 (0.23 g, 0.83 mmol), Pd(PPh3)2Cl2 (23 mg),
CuI (14 mg), freshly distilled THF (30 mL) and Et3N (5 mL). The
mixture was stirred at r.t. for 3.5 h to obtain an orange solution. The
reaction was then continued, by heating at 50 °C for 1.5 h. The mix-
ture was evaporated in vacuo and the residue was dissolved in
CH2Cl2 and column chromatographed (silica gel, CH2Cl2). A fur-
ther purification by recrystallisation of the yellow solid from ben-
zene afforded compound 11 as bright-yellow crystals (128 mg,
56%); mp 175.8–176.6 °C.
1H NMR (CDCl3): d = 2.45 (s, 3 H), 4.90 (s, 2 H), 6.92 (s, 1 H), 7.39
(m, 3 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.59
(m, 2 H), 8.28 (s, 1 H).
13C NMR (CDCl3): d = 30.3, 84.8, 85.9, 96.4, 97.6, 106.8, 118.0,
121.0, 122.5, 123.2, 128.4, 129.1, 129.2, 130.2, 132.06, 132.11,
134.4, 139.4, 151.1, 193.3.
4-(4-Methoxybenzylthio)phenylacetylene (14)
To a solution of 13 (1.88 g, 6 mmol) in anhyd benzene (40 mL) was
added NaH (60% dispersion, 0.12 g, 3 mmol) and the mixture was
refluxed for 1 h under argon. Benzene was removed under vacuum
and the residue was column chromatographed (silica gel, CH2Cl2).
Recrystallisation of the product from MeOH yielded 14 as white
crystals (1.2 g, 78%); mp 125.8–126.3 °C.
1H NMR (CDCl3): d = 3.07 (s, 1 H), 3.78 (s, 3 H), 4.09 (s, 2 H), 6.82
(d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 4 H), 7.36 (d, J = 8.1 Hz,
2 H).
13C NMR (CDCl3): d = 37.7, 55.2, 77.5, 83.3, 113.9, 119.4, 128.5,
128.6, 129.9, 132.3, 138.2, 158.8.
MS (EI) m/z (%) = 254 (M+, 65), 121 (100).
Anal. Calcd for C16H14OS (254.35): C, 75.55; H, 5.55. Found: C,
75.48; H, 5.54.
MS (EI): m/z (%) = 412 (M+, 47), 43 (100).
2-[4-(4-Methoxybenzylthio)phenylethynyl]-4-nitro-5-phenyl-
ethynylaniline (15)
Anal. Calcd for C24H16N2O3S (412.46): C, 69.89; H, 3.91; N, 6.79.
Found: C, 69.98; H, 3.86; N, 6.83.
The solution of 4 (0.317 g, 1 mmol), 14 (0.254 g, 1 mmol),
Pd(PPh3)2Cl2 (20 mg), CuI (9.6 mg) in Et3N (15 mL) was refluxed
for 2 h. TLC analysis of the reaction mixture indicated that 14 was
completely consumed. The mixture was cooled to r.t. and then suc-
tion-filtered. The solid on the filter was washed with Et2O and then
column chromatographed twice on silica gel. The first column was
eluted with 20% petroleum ether in CH2Cl2 and the second column
was eluted with CHCl3 to afford 15 as a yellow solid (0.11 g, 22%).
A crystal for X-ray analysis was obtained by recrystallisation from
chlorobenzene; mp 200.7–201.5 °C.
4-Bromophenyl 4-Methoxybenzyl Sulfide (12)
To a degassed solution of 4-bromothiophenol (3.78 g, 20 mmol) in
anhyd DMF (30 mL) was added solid K2CO3 (2.76 g, 20 mmol).
The mixture was stirred under argon for 10 min followed by the
dropwise addition of 4-methoxybenzyl chloride (3.13 g, 20 mmol).
The mixture was then stirred at r.t. for 12 h and at 100 °C for an ad-
ditional 1 h to afford a white suspension. A white solid precipitated
gradually on slow addition of H2O (50 mL). The solid was collected
by suction-filtration, then purified by recrystallisation from MeOH
to yield compound 12 as white crystals (5.49 g, 89%); mp 100.5–
101.0 °C.
1H NMR (CDCl3): d = 3.79 (s, 3 H), 4.05 (s, 2 H), 6.82 (d, J = 8.7
Hz, 2 H), 7.15 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 7.36
(d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 38.5, 55.2, 113.9, 120.2, 128.9, 129.9,
131.4, 131.8, 135.6, 158.8.
1H NMR (CDCl3): d = 3.81 (s, 3 H), 4.15 (s, 2 H), 4.84 (s, 2 H), 6.86
(d, J = 8.4 Hz, 2 H), 6.94 (s, 1 H), 7.26 (d, J = 8.4 Hz, 2 H), 7.30 (d,
J = 8.7 Hz, 2 H), 7.40 (m, 5 H), 7.62 (m, 2 H), 8.27 (s, 1 H).
MS (EI): m/z (%) = 490 (M+, 7), 121 (100).
Anal. Calcd for C30H22N2O3S (490.57): C, 73.45; H, 4.52; N, 5.71.
Found: C, 73.24; H, 4.47; N, 5.62.
MS (EI): m/z (%) = 310 (M+, 10), 121 (100).
Acknowledgement
Anal. Calcd for C14H13BrOS (309.22): C, 54.38; H, 4.24. Found: C,
54.50; H, 4.22.
This work was supported by the Materials Domain of the UK MoD
Corporate Research Programme. We thank Professor J. A. K. Ho-
ward for the use of X-ray facilities, and EPSRC for funding the im-
provement of the X-ray instrumentation.
4-(3-Hydroxy-3-methylbutynyl)phenyl 4-Methoxylbenzyl Sul-
fide (13)
A mixture of 12 (1.55 g, 5 mmol), 2-methyl-3-butyn-2-ol (1.68 g,
20 mmol), Pd(PPh3)2Cl2 (74 mg), CuI (37 mg) and Et3N (30 mL)
Synthesis 2003, No. 13, 2089–2095 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Synthesis of High NDR 2-(4-Acetylthiophenylethynyl)-4-nitro-5-phenylethylaniline
2095
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Synthesis 2003, No. 13, 2089–2095 ISSN 1234-567-89 © Thieme Stuttgart · New York