Reaction pathways to 2-aminothiophenes and thiophene-3-carbonitriles

Article abstract of DOI:10.1071/CH09004

Over the past two decades 2-amino-3-benzoylthiophenes have been found to act as allosteric enhancers of the adenosine A₁ receptor (A ₁AR). As such, compounds of this type have potential applications in the therapy of a variety of dis

Full text of DOI:10.1071/CH09004

Rapid Communication
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 402–406
www.publish.csiro.au/journals/ajc
Reaction Pathways to 2-Aminothiophenes and
Thiophene-3-carbonitriles
Luigi Aurelio,A Bernard L. Flynn,A and Peter J. ScammellsA,B
AMedicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.
BCorresponding author. Email: peter.scammells@pharm.monash.edu.au
Over the past two decades 2-amino-3-benzoylthiophenes have been found to act as allosteric enhancers of the adenosine
A1 receptor (A1AR). As such, compounds of this type have potential applications in the therapy of a variety of disorders
by enhancing A1AR activation. Initial studies in this field identified various 2-amino-3-benzoylthiophenes as potential
leads and of these PD 81723 1a has become the benchmark for comparative studies due to its favourable ratio of allosteric
enhancement to antagonism. Surprisingly the synthesis and characterization of PD 81723 1a has not been previously
reported. Herein we report the synthesis and characterization of this important A1AR allosteric enhancer. As part of this
study we also found an unexpected reaction pathway to 2-phenylthiophene-3-carbonitriles.
Manuscript received: 5 January 2009.
Final version: 10 February 2009.
Our group has been actively involved in the synthesis and
pharmacological characterization of allosteric enhancers of the
human adenosine A1 receptor.[1–4] Research in the field of
allosteric enhancers of the A1AR has been well established over
the past two decades. The seminal work of Bruns et al. iden-
tified a series of 2-amino-3-benzoylthiophenes which act as
allosteric enhancers of the adenosineA1 receptor.[5,6] Of the lead
compounds found in that study, (2-amino-4,5-dimethylthiophen-
3-yl)(3-(trifluoromethyl)phenyl)methanone 1a, designated as
PD 81723 (Fig. 1), was found to have the most favourable ratio
of allosteric enhancement to antagonism and has since been the
benchmark in the discovery of new allosteric enhancers. In our
pursuit of improved allosteric enhancers we required a supply
of PD 81723 1a for our pharmacological studies. Despite this
compound being commercially available,[7] we attempted to syn-
thesize it ourselves as the simplicity of its structure suggested
that its synthesis would be straightforward with large quantities
readily obtainable. The first and only report on the synthesis
of PD 81723 1a was published in 1973 by Nakanishi et al.[8]
via the one-pot Gewald procedure.[9] In this study, a series of
2-amino-3-benzoylthiophenes were prepared as intermediates in
the synthesis of thienodiazepinones, but were not fully charac-
terized. Compound 1a was not isolated and no yield, melting
point or spectroscopic data were described. Bruns et al. reported
that the 2-amino-3-benzoylthiophenes used in their studies were
synthesized at Parke-Davis via the method of Tinney et al.[10]
Although Tinney and co-workers did synthesize a variety of
2-amino-3-benzoylthiophenes, they do not report the synthesis
of PD 81723 1a. In fact to the best of our knowledge, none of
the literature which describes PD 81723 1a (∼44 papers in the
Chemical Abstracts database) provides any synthetic or charac-
terizationdetailsforthiscompound.Thisanomalywasintriguing
because PD 81723 1a is the bench mark compound utilized in
A1AR studies and warrants characterization. We now report the
synthesis and full characterization of such an important lead
compound.
We had initially attempted the one-pot Gewald procedure
for the synthesis of 2-amino-3-benzoylthiophenes as outlined
by Nakanishi et al. (Scheme 1).[8] m-Trifluoromethylbenzoyl
acetonitrile 2a was reacted with 2-butanone and sulfur in the
presence of base (morpholine) to afford the desired product.
However, the reaction did not go to completion and chromato-
graphic purification was required to obtain the pure product in
only 12% yield. The 1H NMR spectrum of the crude product of
this one-pot synthesis showed no sign of the isomeric thiophene
5. This suggested that the Z isomer of the intermediate olefin
(Z-4a) may isomerize under basic conditions to the more stable
enolate ion before cyclization or possibly decompose under the
reaction conditions.
S
H3C
NH2
O
In search of an improved synthesis of 1a, we evaluated
the corresponding two step procedure which involved a Kno-
evenagel condensation followed by the Gewald reaction. The
rate-limiting step in the one-pot Gewald reaction is the formation
of the olefinic intermediate which proceeds via the Knoevenagel
condensation. In our experience, if a one-pot Gewald procedure
returns starting materials, it is most likely due to the Knoeve-
nagel condensation not proceeding. The standard method for the
H3C
CF3
Fig. 1. Structure of PD 81723 1a.
© CSIRO 2009
10.1071/CH09004
0004-9425/09/050402

Pathways to 2-Aminothiophenes and Thiophene-3-carbonitriles
403
S
S
CN
H3C
NH2
O
NH2
O
O
Method A
H3C
H3C
(i)
CF3
CF3
CF3
2a
1a
5
(i)
(ii)
Method B
H3C
H3C
CN
H3C
H3C
CN
O
O
ꢀ
CF3
CF3
E-4a
Z-4a
Scheme 1. Synthetic routes to PD 81723 (1a). MethodA (One-pot method): (i) 2-butanone, S8, morpholine, EtOH,
reflux; 12% yield. Method B (Two-step method): (i) 2-butanone, TiCl4, pyridine, CH2Cl2 then (ii) Et2NH, THF, S8;
23% yield (over two steps).
Cl
Cl
CN
H3C
CN
CN
H3C
H3C
(i)
H3C
ꢀ
ꢀ
O
O
O
H3C
O
H3C
R
R
Cl
R
2
3
E-4
Z-4
(ii)
a
b
c
d
e
R ꢁ 3-CF3Ph
R ꢁ 4-ClPh
R ꢁ Ph
S
S
H3C
R
NH2
O
H3C
R ꢁ 4-CH3Ph
R ꢁ OEt
ꢀ
H3C
H3C
CN
R
1
6
Scheme 2. Reagents and conditions. (i) TiCl4, pyridine, CH2Cl2, (ii) EtOH, NaSH −78 to 10◦C.
formation of the Knoevenagel product is to condense a nitrile
and ketone/aldehyde in the presence of a catalytic amount of
β-alanine and azeotropically remove water.[10] Although high
yields can be obtained on fairly large scales, we have found
that, on a smaller scale, this technique returns lower yields
due to inefficient removal of water. An alternative approach to
the Knoevenagel condensation was reported using titanium(IV)
chloride[11] providing high yields of Knoevenagel products. We
applied this technique and obtained quantitative conversion of
the nitrile and ketone to the E/Z mixture of 4a. Subjecting this
mixture to basic conditions in the presence of elemental sulfur
provided 1a in a much cleaner state than the one-pot proce-
dure and in moderate yield. Pure PD 81723 1a was obtained in
an overall yield of 23% following a chromatographic purifica-
tion and one recrystallization from petroleum spirits. The full
characterization of this compound appears for the first time in
the Experimental section of this manuscript.
It has been previously reported that improved yields of
2-aminothiophenes can be obtained by incorporating a leaving
group α to the carbonyl of unsymmetrical ketones, which can
subsequently be displaced by NaSH.[12–15] Therefore, commer-
ciallyavailable3-chloro-2-butanone3(Scheme2)wassubmitted
to Knoevenagel condensation with nitrile 2a to produce the E/Z
mixture of the olefin 4a. This mixture was then treated at −78◦C
with an excess of NaSH and upon work-up providing what ini-
tially looked like the required thiophene 1a, by virtue of two
methyl singlets at 2.30 and 2.41 ppm in the 1H NMR spectrum.
However, by comparison with results from previous procedures
where the methyl singlets for 1a are at 1.50 and 2.14 ppm, and
as only a trace amount could be detected by NMR in the crude

404
L. Aurelio, B. L. Flynn, and P. J. Scammells
Table 1. Product ratios of 2-aminothiophenes and thiophene-3-carbonitriles
Entry
Nitrile
Ketone
R
Temp. [◦C]A
Product ratioA
Isolated yieldB
1
2
3
4
5
6
7
8
9
10
2a
2a
2b
2b
2c
2c
2d
2d
2d
2e
3
3
3
3
3
3
3
3
3
3
3-CF3Ph
3-CF3Ph
4-ClPh
4-ClPh
Ph
−78
rt
1a:6a = 9:91
1a:6a = 65:35
1b:6b = 0:100
1b:6b = 33:67
1c:6c = 5:95
1c:6c = 9:91
1d:6d = 0:100
1d:6d = 38:62
1d:6d = 18:82
1e:6e = 100:0
6a 45%
nd
6b 61%
nd
6c 50%
nd
6d 40%
nd
−78
rt
−78
rt
Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
OEt
−78
rt
55
−78
nd
1e 54%
AProduct ratios of crude isolated material as determined by 1H NMR spectroscopy.
BIsolated yield of the major product after chromatography.
Cl
SH
S
S
NH
O
NH2
H3C
H3C
H3C
H3C
CN
H3C
H3C
CN
O
O
O
H3C
H3C
R
R
R
R
1
(Hꢀ workup)
H3C
H3C
CN
H3C
CN
OH
H3C
CN
CN
H3C
H3C
ꢂH2O
O
O
H3C
R
H3C
S
S
S
H
R
R
Cl R
7
6
Scheme 3. Pathways to 2-aminothiophenes versus 3-cyanothiophenes.
spectrum of the required 2-aminothiophene 1a, full characteri-
zation of this product determined that it was in fact 4,5-dimethyl-
2-(3-trifluoromethyl)phenylthiophene-3-carbonitrile (6a). The
13C NMR spectra of the product revealed the absence of a keto
group and retention of the nitrile. The IR spectra confirmed this
observation with a CN stretching frequency at 2215 cm−1 and
also afforded solely the corresponding 2-aminothiophene at this
temperature (outcome not shown in Table).
The mode of cyclization and predominance of the
2-substituted 4,5-dimethylthiophene-3-carbonitrile products
may be influenced by base mediated isomerization of the
intermediate olefin (before or after nucleophilic substitution
of the chloride by NaSH) (Scheme 3). The predominance of
the thiophene-3-carbonitrile from reactions between benzoyl-
acetonitriles and 2-chlorobutan-2-one at −78◦C suggests this
is the kinetically favoured pathway. More specifically, the
2-hydroxydihydrothiophene-3-carbonitrile 7 may be the kineti-
cally favoured species at this temperature, which then undergoes
a dehydration step during the acid quench to give 6. At room
temperature, the establishment of an equilibrium between 7
and the 2-aminothiophene would account for the formation of
a significant amount of the latter. The reduction of the pro-
portion of this 2-aminothiophene observed when the reaction
was conducted at 55◦C may have resulted from dehydra-
tion of the 2-hydroxydihydrothiophene-3-carbontrile 7, occur-
ring before the acid quench. Accordingly, a larger percentage
of more thermodynamically stable thiophene-3-carbonitrile
would be expected relative to the reaction performed at room
temperature.
the absence of a carbonyl stretching frequency at 1576 cm−1
.
The Knoevenagel products from the corresponding reac-
tions with 4-chlorobenzoylacetonitrile, benzoylacetonitrile, and
4-methylbenzoylacetonitrilewith3-chloro-2-butanone3cyclized
in a similar fashion to afford the corresponding 2-substituted
4,5-dimethylthiophene-3-carbonitriles. Only trace amounts of
the 2-aminothiophenes 1b–d (0–9%) were detected when
these reactions were conducted at −78◦C. However, at room
temperature the product ratios increased considerably, with
higher amounts of 2-aminothiophene formed. The amount of
2-aminothiophenes varied from substrate nitriles 2a–d with
up to 65% of 2-aminothiophene detected by NMR (Table 1,
entries 2, 4, 6, and 8). We note also that the percentage of
2-aminothiophene obtained using the same substrate varied
slightly from run to run. When heating the reaction at 55◦C
before addition of the sodium hydrosulfide in the case of
nitrile 2d, the product ratio actually decreased the amount of 2-
aminothiophene, relative to the reaction run at room temperature
(Table 1; entry 9).
Meth-Cohn and Narine have reported that 2-amino-
3-benzoyl-4,5-dimethylthiophene rearranges to form 4,5-
dimethyl-2-phenylthiophene-3-carbonitrile 6c under relatively
harsh basic conditions (NaOEt-EtOH, reflux, 4 h).[16] While a
mechanism in which the 2-aminothiophenes formed first can not
be ruled out in our case, this seems less likely under the reactions
conditions that were employed.
In contrast, the Knoevenagel intermediate formed from
the reaction of ethyl cyanoacetate 2e with 3-chlorobutan-2-
one 3 cyclized to give ethyl 2-amino-4,5-dimethylthiophene-
3-carboxylate 1e exclusively at −78◦C (Table 1, entry 10).
The reaction of benzoylacetonitrile 2c with phenacyl chloride

Pathways to 2-Aminothiophenes and Thiophene-3-carbonitriles
405
We note that benzoylacetonitriles were not utilized
in previously published studies on the modified Gewald
procedure,[12–15] with cyanoacetates and malononitriles used
instead. To the best of our knowledge the only pub-
lished report on the use of a benzoylacetonitrile and an α-
chloroketone (2-chlorocyclohexanone) was that by Gewald,[17]
and 2-aminothiophene was reported as the sole product isolated.
Furthermore, a literature search revealed that these thiophene-
3-carbonitriles are novel structures except for 4,5-dimethyl-
2-phenylthiophene-3-carbonitrile 6c which was reported by
Meth-Cohn and Narine.[16]
To conclude, we have synthesized the important bench-
mark A1AR allosteric enhancer, PD 81723 1a, via a two-step
procedure involving a Knoevenagel condensation and Gewald
reaction. The target compound was obtained in adequate yield
and has been fully characterized. In our pursuit to improve the
yield of 1a with 3-chloro-2-butanone 3a we have observed the
formation of an unexpected product and synthesized a small set
of novel thiophenes. We are currently investigating the effect
of different α-chloro ketones and benzoyl acetonitriles in this
modified Gewald reaction and will report these findings in due
course.
CH2Cl2 (20 mL) in a two-necked flask fitted with a rubber sep-
tum and nitrogen inlet.The mixture was cooled with an ice-water
bath and neat TiCl4 (515 µL) was added dropwise to the mix-
ture.Afterstirringfor1 hat0◦Cdrypyridine(335 µL)wasadded
dropwise and the ice-water bath was removed. After stirring at
room temperature for 1 h, a further aliquot of dry pyridine was
added (1 mL) and the mixture was allowed to stir overnight.
The mixture was partitioned between CH2Cl2 and 2 M HCl.
The organic layer was separated and the aqueous layer extracted
with CH2Cl2 (×2). The combined organics were washed with
water, dried (MgSO4), filtered, and concentrated providing the
E/Z mixture of 4a in a 54:46 ratio (determined by NMR) as an
amber/brown resin (1.24 g, 99%). δH 8.17–8.08 (m, 4H, ArH),
7.89–7.86 (m, 2H, ArH), 7.68–7.63 (m, 2H, ArH), 2.68 (q, 2H,
J = 7.6 Hz, OCH2CH3), 2.43 (q, 2H, J = 7.5 Hz, OCH2CH3),
2.36 (s, 3H, CH3), 2.13 (s, 3H, CH3), 1.28 (t, 3H, J = 7.5 Hz,
OCH2CH3), 1.16 (t, 3H, J = 7.5 Hz, OCH2CH3).
The resin is dissolved in THF (10 mL) elemental sulfur
(5.16 mmol) was added followed by Et2NH (3 mL) dropwise
and the mixture allowed to stir at room temperature for 2 h. The
mixture was concentrated to a resin and taken up in CH2Cl2
and washed with dilute HCl, water (×2) and finally with brine,
dried (MgSO4), filtered, and concentrated providing a dark
brown resin that is chromatographed on silica gel eluting with
10% EtOAc:pet ether (40–60◦C).The appropriate fractions were
collected and concentrated to give a bright yellow resin that crys-
tallizes upon standing (541 mg). Recrystallization (petroleum
ether) of this material afforded the title compound 1a (325 mg,
23%) as bright yellow powder, mp 100–104◦C. (Found: [M + H]
300.0664 C14H13F3NOS requires [M + H] 300.0664. Found: C
56.1, H 4.0, N 4.6, Calc. for C14H12F3NOS: C 56.2, H 4.0, N
4.7%). νmax/cm−1 3345, 3239 (NH2), 3123, 3040, 3010 (ArH),
3000–2800 (CH, saturated), 1576 (CO), 1428, 1387, 1337, 1322,
1260, 1164, 1117, 1097, 1069, 909, 815, 705, 690. δH 7.78–7.67
(m, 3H,ArH), 7.58–7.50 (m, 1H,ArH), 6.15 (bs, 2H, NH2), 2.13
(s, 3H, CH3), 1.49 (s, 3H, CH3). δC 190.9, 164.1, 142.5, 131.1,
130.6(q, J = 32.7 Hz), 128.8, 128.1, 126.9(q, J = 3.5 Hz), 124.9
(q, J = 3.5 Hz), 123.9(q, J = 272.5 Hz), 116.8, 115.5, 15.5, 12.6.
Experimental
Melting points were determined with an Electrothermal melting
point apparatus and are uncorrected. All 1H and 13C NMR spec-
tra were recorded on a Bruker Avance DPX 300 spectrometer
at 300.13 MHz and 75.49 MHz, respectively. Unless otherwise
stated 13C NMR spectra were recorded on a Varian Unity Inova
600 spectrometer at 150.8 MHz. Samples were dissolved in
CDCl3. Infrared spectra were recorded with a Scimitar Series
Varian 800 FT-IR Spectrometer fitted with a PIKE Technologies
MIRacleATRandsampleswererunaspuresolids. Solventswere
dried over standard drying agents[18] and freshly distilled before
use except for ethanol which was reagent grade and not dried.
Reagents were purchased from Sigma-Aldrich and used without
further purification. Benzoylacetonitriles 2a–d were synthesized
via the method of Ridge et al.[19] TLC was conducted on 0.2 mm
plates using Merck silica gel 60 F254. Column chromatography
was achieved using Merck silica gel 60 (particle size 0.063–
0.200 µm, 70–230 mesh). High resolution mass spectra were
obtained on aWaters LCT Premier XE (TOF) mass spectrometer
fitted with an ESI ion source.
General Procedure for the Synthesis of 4,5-Dimethyl-
2-phenylthiophene-3-carbonitriles 6a–d
and 2-Aminothiophenes 1c,e
The appropriate nitrile 2a–e (0.94 mmol) and 3-chlorobutan-2-
one 3 (1.03 mmol) were dissolved in dry CH2Cl2 (4 mL) in a
two-necked flask fitted with a rubber septum and nitrogen inlet.
The mixture was cooled with an ice-water bath and neat TiCl4
(206 µL) was added dropwise. After 0.5 h dry pyridine (67 µL)
was added dropwise and the ice-water bath was removed. After
stirring a further 1 h another aliquot of dry pyridine (200 µL) was
added dropwise and the reaction mixture left to stir overnight.
The reaction mixture was partitioned between 2 M HCl (50 mL)
and CH2Cl2 (20 mL).The phases were separated and the aqueous
layer was extracted with CH2Cl2 (2 × 20 mL). The combined
organic phases were washed with water and finally brine, dried
(MgSO4), filtered, and concentrated under reduced pressure to
give the E/Z mixture of olefins 4a–e as an amber resin or oil.The
crude mixtures were used directly in the next reaction without
purification.
(2-Amino-4,5-dimethylthiophen-3-yl)
(3-(trifluoromethyl)phenyl)methanone 1a
Method A. m-Trifluoromethylbenzoyl acetonitrile (2a)
(0.94 mmol) and 2-butanone (1.03 mmol) were dissolved in
EtOH (0.5 mL) and elemental sulfur (1.03 mmol) was added
to the mixture followed by morpholine (94 µL). The mixture
was refluxed for 3 h. The cooled mixture was diluted with ether
washed with dilute HCl, water (×2) and finally with brine,
dried (MgSO4), filtered, and concentrated providing a dark
brown resin that was chromatographed on silica gel eluting with
10% EtOAc:pet ether (40–60◦C).The appropriate fractions were
collected and concentrated to give a bright yellow resin that
crystallizes upon standing (80 mg). Recrystallization (petroleum
ether) of this material afforded the title compound 1a (33 mg,
12%) as a bright yellow powder.
The E/Z mixture was dissolved in EtOH (5 mL) and cooled to
−78◦C (MeOH/dry ice) and a solution of NaSH (2.0–2.2 mmol)
in EtOH (8 mL) was added dropwise over 30–60 s. The reac-
tion mixture was left to stir while the MeOH/dry ice-bath was
Method B. m-Trifluoromethylbenzoyl acetonitrile 2a
(4.69 mmol) and 2-butanone (5.16 mmol) were dissolved in dry

406
L. Aurelio, B. L. Flynn, and P. J. Scammells
kept in place but no further additions of dry ice were made.
The MeOH/dry ice-bath slowly warmed up to 10◦C (∼1 h) and
a small amount of precipitate was observed. The mixture was
diluted with CH2Cl2 and while stirring 2 M HCl (20 mL) was
added slowly with gas evolution occurring (CAUTION! H2S is
generated which is highly toxic!). The organic layer is separated
and the aqueous layer extracted with CH2Cl2. The aqueous layer
is treated with ∼4% sodium hypochlorite to oxidize residual
H2S. The combined organics were dried (MgSO4), filtered, and
concentrated under reduced pressure in a fume cupboard, to a
solid or resin. Solids were recrystallized with isopropyl alcohol,
whereas resins were chromatographed on silica gel with CH2Cl2
before recrystallization with isopropyl alcohol.
280.0792. νmax/cm−1 3354, 3242 (NH2), 3143, 3050, 3026
(ArH), 3000–2800 (CH, saturated), 1584 (CO), 1563, 1524,
1483, 1447, 1432, 1395, 1329, 1280, 909, 770, 738, 716, 699,
659, 599, 592. δH 7.34–7.32 (m, 2H, aromatic), 7.15–7.09 (m,
1H, aromatic), 7.02–6.92 (m, 7H, aromatic), 6.55 (bs, 2H, NH2),
6.19 (s, 1H, 5-H). δC (150.8 MHz) 192.9, 165.7, 141.8, 140.0,
137.3, 130.6, 128.9, 128.5, 127.6, 127.3, 126.4, 115.1, 105.5.
Ethyl 2-Amino-4,5-dimethylthiophene-3-carboxylate 1e
Off white powder (101 mg, 54%), mp 90–92◦C (lit.[9] 91–
92). Found: [M + H] 200.0747 C9H14NO2S requires [M + H]
200.0740. νmax/cm−1 3400, 3298 (NH2), 3000–2800 (CH,
saturated), 1646 (CO), 1594, 1575, 1492, 1407, 1376, 1321,
1272, 1169, 1059, 1027, 781. δH 5.31 (bs, 2H, NH2), 4.28 (q,
J = 7.1 Hz, 2H, OCH2CH3), 2.18 (s, 3H, CH3), 2.15 (s, 3H,
CH3), 1.35 (t, J = 7.1 Hz, 3H, OCH2CH3). δC (150.8 MHz)
166.1, 161.0, 130.3, 113.8, 106.9, 59.4, 14.8, 14.4, 12.28.
4,5-Dimethyl-2-(3-(trifluoromethyl)phenyl)thiophene-
3-carbonitrile 6a
Pale yellow long needles (120 mg, 45%), mp 36–37◦C.
νmax/cm−1 3049 (ArH), 3000–2800 (CH, saturated), 2215 (CN),
1495, 1329, 1251, 1200, 1116, 1073, 890, 879, 798, 695, 663.
δH 7.96–7.89 (m, 2H, ArH), 7.67–7.56 (m, 2H, ArH), 2.41 (s,
3H, CH3), 2.30 (s, 3H, CH3). δC (150.8 MHz) 147.2, 136.0,
134.6, 132.6, 131.6 (q, J = 32.6 Hz), 130.5, 129.7, 125.7 (q,
J = 3.5 Hz), 124.3 (q, J = 3.8 Hz), 123.7 (q, J = 273.3 Hz),
115.7, 109.2, 13.3, 12.9. m/z (APCI) 282 ([M + H], 34%), 212
(100), 170 (32), 145 (26). Found: C 59.7, H 3.6, N 4.9, Calc. for
C14H13NS: C 59.8, H 3.6, N 5.0%.
Acknowledgements
The authors thank the Australian Research Council (DP0877497) for
financial support.
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2-(4-Chlorophenyl)-4,5-dimethylthiophene-
3-carbonitrile 6b
Off white powder (142 mg, 61%), mp 82–83◦C. νmax/cm−1
3055, 3030, 3021 (ArH), 3000–2800 (CH, saturated), 2216
(CN), 1503, 1463, 1401, 1200, 1181, 1096, 1013, 967, 823, 692.
δH 7.64 (d, J = 8.7 Hz, 2H, ArH), 7.41 (d, J = 8.7 Hz, 2H, ArH),
2.38 (s, 3H, CH3), 2.27 (s, 3H, CH3). δC (150.8 MHz) 147.9,
135.7, 135.2, 133.8, 130.3, 129.3, 128.5, 116.0, 108.5, 13.2, 12.9.
m/z (APCI) 248 ([M + H], 34%), 212 (100), 199 (90), 171 (22).
4,5-Dimethyl-2-phenylthiophene-3-carbonitrile 6c
[7] Available from Sigma-Aldrich (catalogue number: P1123, current
price: $A710 for 50 mg).
[8] M. Nakanishi, T. Tahara, K. Araki, M. Shiroki, T. Tsumagari,
T.Takigawa, J. Med. Chem. 1973, 16, 214. doi:10.1021/JM00261A010
[9] K. Gewald, E. Schinke, H. Böttcher, Chem. Ber. 1966, 99, 94.
doi:10.1002/CBER.19660990116
[10] F. J. Tinney, J. P. Sanchez, J. A. Nogas, J. Med. Chem. 1974, 17, 624.
doi:10.1021/JM00252A011
[11] W. Lehnert, Tetrahedron 1973, 29, 635. doi:10.1016/0040-
4020(73)85007-0
Off white needles (100 mg, 50%), mp 55–56◦C (lit.[17] 38–40).
νmax/cm−1 3058, 3023 (ArH), 3000–2800 (CH, saturated), 2210
(CN), 1506, 1466, 1385, 1363, 1179, 1083, 960, 759, 686. δH
7.74–76.71 (m, 2H, ArH), 7.48–7.37 (m, 3H, ArH), 2.38 (s, 3H,
CH3), 2.28 (s, 3H, CH3). δC (150.8 MHz) 149.5, 135.5, 133.4,
131.9, 129.2, 129.1, 127.3, 116.3, 108.1, 13.2, 12.9. m/z (APCI)
214 ([M + H], 55%), 199 (92), 198 (100), 187 (10), 166 (56).
[12] A. Rosowsky, C. E. Mota, J. E. Wright, J. H. Freisheim, J. J. Heusner,
J. J. McCormack, S. F. Queener, J. Med. Chem. 1993, 36, 3103.
doi:10.1021/JM00073A009
[13] H.-P. Buchstaller, C. D. Siebert, R. H. Lyssy, I. Frank, A. Duran,
R. Gottschlich, C. R. Noe, Monatsh. Chem. 2001, 132, 279.
[14] D. Hawksley, D. A. Griffin, F. J. Leeper, J. Chem. Soc., Perkin Trans.
1 2001, 144. doi:10.1039/B006962K
[15] T. L. Fevig, W. G. Phillips, P. H. Lau, J. Org. Chem. 2001, 66, 2493.
doi:10.1021/JO001376Y
[16] O. Meth-Cohn, B. Narine, J. Chem. Res. (S) 1977, 294.
[17] K. Gewald, Chem. Ber. 1965, 98, 3571. doi:10.1002/CBER.
19650981120
4,5-Dimethyl-2-(4-(methyl)phenyl)thiophene-
3-carbonitrile 6d
Long thick needles (86 mg, 40%), mp 83–84◦C. νmax/cm−1
3053, 3020 (ArH), 3000–2800 (CH, saturated), 2211 (CN),
1515, 1464, 1442, 1381, 1363, 1320, 1191, 1177, 1129, 956,
811, 709, 671, 639. δH 7.61 (d, J = 8.1 Hz, 2H, ArH), 7.24 (d,
J = 8.1 Hz, 2H, ArH), 2.39 (s, 3H, CH3), 2.36 (s, 3H, CH3),
2.27 (s, 3H, CH3). δC (150.8 MHz) 149.8, 139.4, 135.3, 132.8,
129.8, 129.1, 127.2, 116.4, 107.7, 21.3, 13.2, 12.9. m/z (APCI)
228 ([M + H], 63%), 213 (100), 212 (75), 198 (40), 180 (40).
Found: C 73.9, H 5.7, N 6.1, Calc. for C14H13NS: C 74.0, H 5.8,
N 6.2%.
[18] W. L. F.Armarego, D. D. Perrin, Purification of Laboratory Chemicals,
3rd edn 1988 (Pergamon Press: Oxford).
[19] D. N. Ridge, J. W. Hanifin, L. A. Harten, B. D. Johnson, J. Menschik,
G. Nicolau, A. E. Sloboda, D. E. Watts, J. Med. Chem. 1979, 22, 1385.
doi:10.1021/JM00197A020
(2-Amino-4-phenylthiophen-3-yl)(phenyl)methanone 1e
Yellow powder (157 mg, 60%), mp 152–154◦C (lit.[10] 154–
156). Found: [M + H] 280.0791 C17H14NOS requires [M + H]