SNAr and palladium-catalyzed reactions of deactivated thiophene: Application to the synthesis of protein farnesyltransferase inhibitors

Article abstract of DOI:10.1002/ejoc.201100215

To investigate the influence of the 5-thioether moiety of our previously identified hit thiophene compound upon protein farnesyltransferase inhibition, we synthesized a new library of 3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylic derivatives through the application of aromatic nucleophilic substitutions benefiting from a sulfone-based leaving group and by direct palladium-catalyzed reactions on a thioalkylthiophene. This small library of ester derivatives and their corresponding acids was then evaluated for protein farnesyltransferase inhibitory activity; some library members exhibited promising submicromolar activities. Copyright

Full text of DOI:10.1002/ejoc.201100215

FULL PAPER
DOI: 10.1002/ejoc.201100215
SNAr and Palladium-Catalyzed Reactions of Deactivated Thiophene:
Application to the Synthesis of Protein Farnesyltransferase Inhibitors
Sébastien Lethu[a] and Joëlle Dubois*[a]
Keywords: Heterocycles / Enzymes / Enzyme inhibitors / Structure-activity relationships / Aromatic substitution /
Nucleophilic substitution
To investigate the influence of the 5-thioether moiety of our
previously identified hit thiophene compound upon protein
farnesyltransferase inhibition, we synthesized a new library
of 3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylic deriva-
tives through the application of aromatic nucleophilic substi-
tutions benefiting from a sulfone-based leaving group and
by direct palladium-catalyzed reactions on a thioalkylthio-
phene. This small library of ester derivatives and their corre-
sponding acids was then evaluated for protein farnesyl-
transferase inhibitory activity; some library members exhib-
ited promising submicromolar activities.
Introduction
Protein farnesyltransferase (FTase) has received con-
siderable attention since its discovery two decades ago.
FTase is a key posttranslational enzyme responsible for cat-
alyzing farnesylation of numerous proteins, thereby al-
lowing their correct binding to the intracellular mem-
brane.[1] First studied as a potential anticancer target,[2]
FTase has recently turned out to be an effective antipara-
sitic target for treating tropical pathologies such as malaria,
African sleeping sickness and Chagas disease where resis-
tance to established therapeutics has become commonplace
or where there is simply a lack of effective treatments avail-
able.[3]
Figure 1. Structure of hit thiophene 1.
Results and Discussion
Chemistry
In the course of our search for new active FTase inhibi-
tors (FTIs), we previously reported the discovery of a new
class of inhibitors in the arylthiophene series.[4] Using the
scaffold from our highly potent hit compound 1 (Figure 1),
we evaluated the importance of selected functionalities by
substituting the carboxylic acid moiety in position 2 as well
as the nature of the central aromatic ring. We also designed
an original synthesis of a new thiophene library, where the
3-aryl moiety was varied, which will be reported else-
where.[5]
This article details structure-activity relationship studies
focused on understanding the effect of position 5 of the
thiophene ring and we report herein the aromatic nucleo-
philic substitution of the thio-isopropyl group of compound
1 to afford a new library of 3-(4-chlorophenyl)-4-cyano-2-
carboxylic derivatives. The impact of alterations to 1 on
FTase inhibition by new library members is also presented.
Direct substitution of thioethers on electron-deficient
thiophene rings has only been achieved either by palladium-
catalyzed coupling with alkyl or aryl thiols[6] or by aromatic
nucleophilic substitutions with morpholine.[6–7] However,
we wished to find a common precursor allowing for facile
modification of this part of compound 1 by various groups,
especially through the application of SNAr reactions. There-
fore, we decided to activate thioether 1 by oxidation since
oxidized thioethers are better leaving groups than are thio-
ethers themselves. Additionally, successful substitutions of
thienyl sulfoxides or sulfones by amines or alcohols have
been previously described.[6,8–11] Because we thought that
the presence of a free carboxylic acid could be troublesome
during the course of our synthesis, we used ethyl 3-(4-
chlorophenyl)-4-cyano-5-(isopropylthio)thiophene-2-carb-
oxylate 2 as the starting point for the construction of new
esters which would ultimately be saponified to afford the
desired acids. In order to oxidize thiophene 2, we used 1 or
2.5 equiv. of a mild oxidant such as mCPBA which afforded
corresponding sulfoxide 3 and sulfone 4 in excellent yields,
respectively (Scheme 1).
[a] Institut de Chimie des Substances Naturelles, UPR2301 CNRS,
Centre de Recherches de Gif,
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-69077247
E-mail: joelle.dubois@icsn.cnrs-gif.fr
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
Scheme 1. Oxidation of thioether derivative 2. Reagents and condi-
tions: (a) mCPBA (1 equiv.), CH2Cl2, 18 h, 81%; (b) mCPBA
(2.5 equiv.), CH2Cl2, 4 h, 93%; (c) NaOH 2 m, THF/EtOH, 2:1,
16 h, 3a 91%, 4a quant.
Sulfone 4 was obtained in a yield superior to that of 3
and was also easier to purify than 3. Consequently, we used
4 as the precursor for our SNAr reactions.
In our initial SAR studies,[4] various commercially avail-
able 5-(thioether)thiophenes were evaluated for their ability
to inhibit FTase. However, the series in which the thioalkyl
side chain contained four carbon atoms or less were devoid
of the tert-butylthio and the n-propylthio ethers. These de-
rivatives constituted the starting point of our methodology.
Using the corresponding thiols in the presence of tBuOK
as a base, desired 5-thioalkylthiophenes 5 and 6 were ob-
tained in very good yields when 18-crown-6 ether was
added to the reaction mixture, likely due to a better ion-
pair dissociation (Scheme 2).
To further determine the influence of the 5-thioether
moiety on FTase inhibition by library members, we substi-
tuted it with analogous oxygen, carbon and nitrogen atoms.
Substitution of the isopropyl thioether with its oxygen-
ated isostere was difficult because of the lower nucleophilic-
ity of the hydroxy group relative to thiols. After several
attempts, we found that this reaction required relatively
harsh conditions (130 °C in a sealed tube) to provide de-
sired compound 7 in a moderate but sufficient yield for our
SAR studies (Scheme 2). It is notable that, under these con-
ditions, a transesterification was observed although ulti-
mately this had no effect on subsequent saponification ef-
forts.
Scheme 2. Substitution of sulfone 4. Reagents and conditions: (a)
nPrSH or tBuSH, tBuOK, 18-crown-6, THF, 16–19 h, 75–94%; (b)
K2CO3, iPrOH, 130 °C, 17 h, sealed tube, 55%; (c) NaOH 2 m,
THF/EtOH, 2:1, 16 h, 5a 95%, 6a 93%, 7a 99%, 17a 72%; (d)
ZnEt2, CH2Cl2, 7 d, 44%; (e) ZnCl2, iBuMgCl, CH2Cl2, 6 d, 19%;
(f) iPrNH2, THF, room temp., 16 h, 15 51%, 16 34%; (g) THF,
reflux, 3 d, 67%.
To avoid the formation of regioisomers, we took advantage
of a synthetic pathway devised for solid phase synthesis in
which the 3-aryl moiety is introduced after thiophene ring
closure[12] and Sandmeyer bromation.[5] Following this
pathway, desired 5-isobutyl-modified thiophene 14 was ob-
tained in a good overall yield allowing us to determine the
influence of a carbon for sulfur exchange at the 5 position.
The replacement of the 5-thioether by an analogous all
carbon moiety was first carried out under previously re-
ported conditions[6] with commercially available diethylzinc
which provided 5-ethylthiophene 8 in a reasonable yield
(Scheme 2). Based on this encouraging result, we performed
the same reaction in which di-isobutylzinc was generated
in situ by mixing zinc dichloride and isobutylmagnesium
chloride. Unfortunately, the desired compound was never
obtained. Instead, the only product observed was ketone 9;
no alteration of the sulfone was obtained.
Scheme 3. Synthesis of the carbon analogue 14. Reagents and con-
ditions: (a) K2CO3, DMF, room temp., 30 min, then CS2, 10 min,
then MeI, TBAB, 60 °C, 64 h, 66%; (b) iBuMgBr, THF, room
temp., 48 h, 41%; (c) ethyl thioglycolate, K2CO3, EtOH, reflux, 3 h,
62%; (d) CuBr2, tBuONO, CH3CN, room temp., 10 min, 56%; (e)
p-ClPhB(OH)2, Pd(PPh3)4, K2CO3, toluene/EtOH, 9:1, reflux, 4 h,
68%; (f) NaOH 2 m, THF/EtOH, 2:1, room temp., 16 h, quantita-
tive.
To get the desired isobutyl product, we found it necessary
to substitute a thiomethyl group earlier in the synthetic
To complete the series of C-5 dethio FTI candidates, we
pathway. Specifically, thiomethyl installation was achieved substituted the sulfone of 4 with isopropylamine. In this
after the formation of the ketene dithioacetal (Scheme 3). case, our SNAr strategy proved problematic due to the pres-
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S. Lethu, J. Dubois
FULL PAPER
ence of the ester which constitutes a competitive electro- Table 1. SNAr reactions with sulfone 4 and various aliphatic nitro-
genated nucleophiles.[a]
phile. Stirring sulfone 4 with isopropylamine at room tem-
perature afforded a mixture of expected 5-N-isopro-
pylamine 15 and 2-isopropylamide 16 in a 60:40 ratio
(Scheme 2). A rapid survey showed that the use of other
solvents such as 1,4-dioxane, dichloromethane, acetonitrile
or DMF increased the ratio in favour of amide byproduct
16 which was found to be preferentially formed in a strong
polar solvents such as ethanol. The same effect was ob-
served upon addition of salts like LiCl or MgCl2, leading
to 10:90 and 25:75 ratios, respectively.
These reactions were also carried out under refluxing
conditions to see if product ratios could be improved in
favour of desired amine 15. Surprisingly, the major product
of this reaction, when using THF as solvent, was com-
pound 17 where the sulfone of 4 was replaced by THF. To
understand the influence of isopropylamine in this reaction,
sulfone 4 was refluxed in THF alone for 3 d to afford the
same 2-THF adduct 17 in good yield (Scheme 2). We sus-
pected that a radical reaction, rather than the desired SNAr
reaction, might explain this unexpected substitution. We en-
visioned a spontaneous homolytic cleavage of the C-SO2
Entry Nucleophile
Solvent Time [h]
X
Yield [%][b]
1
2
3
sodium amide
cyclopentylamine
pyrrolidine
THF
THF
/
24
21
3
18
19
20
21
22
23
24
25
26
27
28
29
30
31
0
52
73
58
38
0
4
piperidine
THF
/
4
5
6
7
8
N-methylpiperazine
diethylamine
diisopropylamine
tMEDA[e]
16
20
26[c]
92[d]
5
20
48
20
7
THF
THF
THF
DMF
THF
THF
THF
THF
THF
0
30
100
80
0
43
48
0
9
sodium azide
1,2,4-triazole[f]
pyrrole[g]
10
11
12
13
14
imidazole[f]
pyrazole[g]
tetrazole[g]
8
[a] Typical reaction was performed on 0.1 to 0.3 mmol of sulfone
bond and trapping of the radical thus formed by a molecule at room temp. with 1.5–6 equiv. of solid or 50–100 equiv. of liquid
nucleophile. [b] Isolated yield after flash column chromatography.
of THF. To support this hypothesis, we showed that ad-
[c] 26 h at room temp. and 64 h at 50 °C. [d] At 40 °C. [e] tMEDA,
dition of the spin trap TEMPO to sulfone 4 in boiling THF
N,N,NЈ-trimethylethylenediamine. [f] Using 2 equiv. of nucleophile,
abolished formation of compound 17. It is notable that such
tBuOK and 18-crown-6. [g] Using 3 equiv. of nucleophile, tBuOK
adducts were not observed when using tetrahydrothiophene,
methyltetrahydrofuran or tetrahydropyrane.
and 18-crown-6.
Nevertheless, we used this methodology to substitute the
sulfone of 4 with other amine nucleophiles (Table 1). How-
ever, the latter side reaction clearly indicated that SNAr re-
actions with 4 were not compatible with refluxing condi-
tions. It turned out that substitutions were found to occur
with primary and secondary amines in moderate to good
yield (Table 1, Entries 2–5 and 8). However, the formation
of amides as non-desired products was always observed and
the reaction was not amenable to sterically hindered amines
(Table 1, Entries 6 and 7). In addition, sodium amide was
too poor a nucleophile to substitute the sulfone (Table 1,
Entry 1). Finally, substitution of the sulfone by sodium az-
ide gave us desired 5-azidothiophene 26 in quantitative yield
(Table 1, Entry 9). This was a very interesting result, open-
with either pyrrole or tetrazole. Except for tetrazole, there
was found to be a strong inverse correlation between hetero-
cycle pKa and yield; the lower the pKa of the nucleophile,
the higher the coupling yield (Figure 2).
Figure 2. Relationship of SNAr reaction yields and nucleophile
pKa.
To synthesize compounds 18, 23, 24 and 28, we took
ing the way for new 5-nitrogenated substituents from this advantage of the facile synthesis of aryl azide 26. Reduction
easily modifiable azido group. of 26 by fast catalytic hydrogenation afforded primary
As shown below by the biological results for compound amine 18 in good yield contrary to direct substitution.
20a, placement of pyrrolidine at the thiophene 5-position However, it should be noted that amine 18 could be more
induced significant FTase inhibition. Thus, we explored sul- rapidly obtained using Gewald’s procedure.[13,14] Amine 18
fone substitution by five-atom nitrogenated aromatic het- was then alkylated with iodoethane to provide 5-di-
erocycles. Reaction of starting material 4 with 1,2,4-triazole ethylamine 23 or reacted with 2,5-dimethoxytetrahydro-
was used as the model for SNAr chemistry with aryl deriva- furan to give pyrrole 28 in excellent yield (Scheme 4).[15]
tives. After several attempts, tBuOK, in the presence of 18-
Azide 26 was also converted to 1,2,3-triazole analogue
crown-6, was found to be the best system and provided de- 32 by a [2+3] Huisgen cycloaddition with (trimethylsilyl)-
sired azole derivative 27 in very good yield (80%). These acetylene.[16] Without solvent or catalyst, this reaction pro-
reaction conditions were transposed to other heterocycles ceeded in a very efficient way and gave, after removal of
of the azole family such as tetrazole, pyrazole, imidazole, the trimethylsilyl group with HF·Et3N, free 1,2,3-triazole
and pyrrole (Table 1). For all these compounds, the substi- derivative 33. [2+3] Cycloadditions of organic nitriles with
tution worked more sluggishly than had been the case with metallic azides are also frequently used to synthesize tetra-
1,2,4-triazole and the expected products were not obtained zoles. However, it is more difficult to carry out these cyclo-
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Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
Scheme 5. Liebeskind-Srogl coupling with thiophene 2. Reagents
and conditions: (a) 3-thienylboronic acid or phenylboronic acid,
Pd(PPh3)4, copper(I) thiophenecarboxylate, THF, 50 °C, 48 h, 34
61%, 35 52%; (b) NaOH 2 m, THF/EtOH, 2:1, 16 h, 34a quantita-
tive, 35a 36%.
base (LiOH, KOH, tBuOK, TMSOK) and of the solvent
(THF, EtOH, DMSO, CH3CN) used in saponification
attempts with 15 and 19 revealed that both compounds
were surprisingly resistant to hydrolysis; each was recovered
either unchanged or completely degraded when more dras-
tic conditions were applied.
Scheme 4. Derivatives synthesized from azide 26. Reagents and
conditions: (a) H2, Pd/C, EtOH, 5 min, 80%; (b) LiOH 2 m, THF/
EtOH, 2:1, 16 h, 75%; (c) EtI, K2CO3, DMF, 16 h, 68%; (d) 2,5-
dimethoxytetrahydrofuran, glacial AcOH, 90 °C, 1 h, 87%; (e)
NaOH 2 m, THF/EtOH, 2:1, 16 h, 23a 56%, 28a quantitative, 33a
93%; (f) (trimethylsilyl)acetylene, 7 h, 83%; (g) HF·Et3N, THF, 6 h,
83%.
Table 2. Saponification of esters.[a]
Entry
Ester
Acid
Yield [%][b]
1
2
3
4
5
6
7
8
15
17
19
20
21
22
23
27
28
29
30
33
15a
17a
19a
20a
21a
22a
23a
27a
28a
29a
30a
33a
0
72
0
additions with organic azides and, to the best of our knowl-
edge, very few methodologies have been described. In our
hands, the conditions reported by Sharpless and co-workers
with organic azides and p-toluenesulfonylnitrile[17] in the
presence of a catalyst such as Cu2(OTf)2·C6H6 did not af-
ford the expected tetrazole. Previous reports that aromatic
azides afforded only the 1,5-substituted tetrazole in low
yields and did not give any product when the azide is steri-
cally hindered support our results with 26.
70
91
85
56
85
100
55
66
93
9
10
11
12
In 2000, Liebeskind and Srogl described an unprece-
dented copper–palladium-catalyzed procedure to create C–
[a] Hydrolysis carried out with NaOH 2 m (5 equiv.) in THF/EtOH,
C bonds from thioesters and boronic acids.[18] Rapidly ex- 2:1 (10 mL/mmol). [b] Isolated yield.
tended to aromatic thioethers, this coupling was found to be
more powerful with π-deficient heterocycles.[19] Given the
strong electron-withdrawing nature of groups located on
our thiophene, we applied this efficient methodology to our
Biological Evaluation
starting thiophene 2. Using this approach with 2, we suc-
All acids were evaluated for their ability to inhibit recom-
cessfully obtained, in moderate but unoptimized yields, two binant FTase using a fluorescence-based assay adapted to
new products 34 and 35 bearing a 3-thienyl or a phenyl 96-well plate format.[20] Results are reported in Table 3.
moiety in the 5-position of the thiophene ring, respectively
(Scheme 5).
FTase inhibition by compounds 5a and 6a, bearing n-
propyl and tert-butyl groups, respectively (Table 3, Entries 4
To the best of our knowledge, this is only the second and 5), revealed the isopropyl group as the best substituent
example described using a thiophene. Moreover, we found to have on the C-5 sulfur atom. The bulky tBu group was
that application of this methodology to obtain other tricy- more detrimental to activity than the less hindered n-propyl
clic compounds is a very good alternative to the long se- relative to lead thiophene 1. Additionally, replacement of
quence of: oxidation of 2 – substitution of 4 by NaN3 – the sulfur atom by an oxygen or a carbon resulted in weaker
reduction of 26 – Sandmeyer reaction on 18 which ulti- FTase inhibition (Table 3, Entries 6 and 7). It is notable that
mately affords the substrate for Suzuki–Miyaura couplings. all these derivatives retained submicromolar activity. In the
Finally, esters 5–7, 17, 18 (Scheme 2), 14 (Scheme 3), 34– case of the 5-isopropylamine derivative we could only evalu-
35 (Scheme 5), 15, 19–23, 27–30 and 33 were submitted to ate the activity of ester 15 which was found to be inactive;
hydrolysis under basic conditions to afford the correspond- corresponding ester 2 inhibited FTase with an IC50
=
ing acids in fair to excellent yields except for compounds 15 3.8 μm.[4] This comparison revealed that a secondary amine
and 19 bearing secondary amines (Table 2). Variation of does not favorably replace the thioisopropyl group. Among
Eur. J. Org. Chem. 2011, 3920–3931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Lethu, J. Dubois
FULL PAPER
Table 3. Inhibitory activity of library members against recombinant
FTase.
Experimental Section
General Considerations: All reactions were carried out in oven-dried
glassware under argon. Commercial compounds were purchased
from suppliers and used without further purification. Solvents were
dried by standards methods. Analytical TLC was carried out on a
pre-coated silica gel aluminium-backed plates (SDS TLC plates,
silica gel 60F254). Column chromatography was performed with sil-
ica gel SDS 60 A CC (40–63 μm) or with prepacked Redisep col-
umns.
Entry
X
R
IC50 [μm]
1
2
3
4
5
6
7
8
1
iPrS
iPrSO
iPrSO2
nPrS
tBuS
iPrO
iBu
2-THF
0.110Ϯ0.008
21.5Ϯ1
21.4Ϯ2.8
0.17Ϯ0.03
1.2Ϯ0.4
0.41Ϯ0.008
0.26Ϯ0.03
3.0Ϯ1
3a
4a
5a
6a
7a
14a
17a
18a
20a
21a
22a
23a
27a
28a
29a
30a
33a
34a
35a
1H NMR and 13C NMR were acquired with Bruker Avance 300
(300 MHz) and Avance 500 (500 MHz) NMR spectrometers.
Chemical shifts (δ) are given relative to CDCl3 (δ = 7.26 ppm;
77.2 ppm) or CD3OD (δ = 3.34 ppm; 49.9 ppm). Splitting patterns
are designed as: s singlet, d doublet, t triplet, q quartet, qi quintu-
plet, hx hexuplet, h heptuplet, oct octuplet, n nonuplet, m mul-
tiplet, br. broad. Coupling constants J are reported in Hertz (Hz).
IR spectra were obtained with a Perkin–Elmer Spectrum BX. Mass
spectra were recorded with a Thermoquest AQA Navigator with a
TOF detector (ESI-HRMS). Elemental analyses were obtained by
the ICSN-CNRS Microanalytical Laboratory of Gif-sur-Yvette.
Melting points were measured with a Büchi b-450 apparatus. Ultra-
high pressure liquid-chromatography (UHPLC) analyses were per-
formed with a Waters Acquity UPLC system. Purities of evaluated
compounds were measured using reversed-phase UHPLC (HSS
C-18, 2.1ϫ50 mm s-1.8 μm) with two diverse solvent systems: com-
pounds were eluted with 95:5 A/B for 0.5 min then with a gradient
of 5–100% B/A for 3.5 min followed by 100% B for 1 min at a flow
rate of 0.6 mL/min, where solvent A was 0.1% formic acid in H2O
and solvent B was 0.1% formic acid in MeCN (system 1) or 0.1%
formic acid in MeOH (system 2). Purity was determined with TAC
(total absorbance current from 200 to 400 nm).
9
NH2
5.0Ϯ0.9
10
11
12
13
14
15
16
17
18
19
20
pyrrolidinyl
piperidinyl
N-methylpiperazinyl
NEt2
1,2,4-triazolyl
pyrrolyl
imidazolyl
pyrazolyl
1,2,3-triazolyl
3-thienyl
Ph
0.080Ϯ0.006
1.25Ϯ0.1
Ͼ 100
10.1Ϯ0.2
1.3Ϯ0.1
0.33Ϯ0.06
6.5Ϯ0.1
0.25Ϯ0.02
2.10Ϯ0.15
0.27Ϯ0.05
1.2Ϯ0.1
all our new derivatives, only pyrrolidine 20a exhibited ac-
tivity superior to our lead compound; 20a inhibited FTase
with an IC50 of 80 nM (Table 3, Entry 10). As previously
noticed, increasing the steric bulk of such compounds re-
sulted in partial to complete loss of activity (Table 3, En-
tries 10–13). Thus, FTase inhibitory activity decreased as
the size of the cycle or the nitrogen substitution increased.
This was apparent for diethylamine compound 23a al-
though amine substitution seemed important as shown by
the low activity of primary amine-modified thiophene 18a
(Table 3, Entry 9). In the 5-arylthiophene series, pyrrole
28a, pyrazole 30a and 5-(3-thienyl)thiophene derivative 34a
all retained submicromolar activity (Table 3, Entries 15, 17
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(isopropylsulfinyl)thiophene-2-
carboxylate (3): To a solution of ester 2 (140.7 mg, 0.385 mmol) in
CH2Cl2 (3 mL) was added mCPBA (70% pure, 94.9 mg,
0.385 mmol). After stirring at room temperature for 18 h, the reac-
tion mixture was quenched with a saturated aqueous NaHCO3
solution (3 mL) and extracted with CH2Cl2 (3ϫ4 mL). The com-
bined organic layers were dried with MgSO4, filtered and concen-
and 19) but were less active than aliphatic pyrrolidine ana- trated under reduced pressure. Chromatography on silica gel [hept-
ane/EtOAc, 10:0 to 6:4 (v/v) in 20 min] afforded sulfoxide 3
(119.0 mg, 81%) as a white solid. H NMR (500 MHz, CDCl3): δ
log 20a. Triazoles 27a and 33a, imidazole 29a and phenyl
derivative 35a exhibited 10-fold lower FTase inhibitory ac-
tivity relative to our hit compound 1 (Table 3, Entries 14,
16, 18 and 20).
1
= 7.46 (d, J = 8.5 Hz, 2 H, Har), 7.36 (d, J = 8.5 Hz, 2 H, Har),
4.26 (q, J = 7.1 Hz, 2 H, OCH2), 3.33 (h, J = 6.9 Hz, 1 H, CH),
1.46 (d, J = 6.9 Hz, 3 H, CHCH3), 1.34 (d, J = 6.9 Hz, 3 H,
CHCH3), 1.25 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 162.4, 159.8, 148.5, 136.1, 133.2, 130.9,
129.7, 128.8, 112.2, 111.7, 62.6, 57.0, 16.2, 14.1, 14.0 ppm. IR
Conclusions
(film): ν = 2984, 2237, 1728, 1314, 1251 cm–1. MS (ESI+, CH Cl /
˜
2
2
MeOH) m/z 404.0 [M + Na]+. HRMS (ESI+, CH2Cl2/MeOH)
calcd. for C17H1635ClNO3S2Na+ [M + Na]+ 404.0158; found
404.0163. C17H16ClNO3S2 (381.89): calcd. C 53.47, H 4.22, N 3.67,
O 12.57, S 16.79, Cl 9.28; found C 52.92, H 4.16, N 3.76, S 16.39.
In conclusion, we have shown that modifications to the
thioether group of our hit thiophene 1 can be easily realized
using either SNAr reactions after activation of the thioether
as the sulfone or by a direct palladium-catalyzed reaction.
These methods allowed us to create a new small library of
about 20 new esters and their corresponding acids, which
were evaluated for their ability to inhibit recombinant
FTase. This study showed that, when it comes to substitu-
tion at the 5-position of this 3-arylthiophene-2-carboxylic
acid: (i) bulky or small substituents are detrimental to ac-
tivity, (ii), five-membered heterocycles are good substitu-
ents, and (iii) the aliphatic heterocycle pyrrolidine is pre-
ferred to aromatic pyrrole or pyrazole substituents.
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(isopropylsulfonyl)thiophene-2-
carboxylate (4): To a solution of ester 2 (4.0 g, 10.9 mmol) in
CH2Cl2 (80 mL) was added mCPBA (70% pure, 6.74 g,
27.3 mmol). After stirring at room temperature for 4 h, the reaction
mixture was quenched with a saturated aqueous NaHCO3 solution
(120 mL) and extracted with CH2Cl2 (3ϫ150 mL). The combined
organic layers were dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was washed with eth-
anol and dried under vacuum to provide sulfone 4 (4.05 g, 93%)
1
as a white powder; m.p. 150 °C. H NMR (500 MHz, CDCl3): δ =
3924
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
7.48 (d, J = 8.5 Hz, 2 H, Har), 7.36 (d, J = 8.5 Hz, 2 H, Har), 4.28
(q, J = 7.1 Hz, 2 H, OCH2), 3.59 (h, J = 6.9 Hz, 1 H, CH), 1.49
(d, J = 6.9 Hz, 6 H, CHCH3), 1.26 (t, J = 7.1 Hz, 3 H,
CDCl3): δ = 7.41 (d, J = 8.5 Hz, 2 H, Har), 7.34 (d, J = 8.5 Hz, 2
H, Har), 5.03 (h, J = 6.2 Hz, 1 H, CH), 4.65 (h, J = 6.1 Hz, 1 H,
CO2CH), 1.53 (d, J = 6.1 Hz, 6 H, CHCH3), 1.17 (d, J = 6.2 Hz,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.5, 150.1, 6 H, CO2CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.2,
149.2, 136.4, 135.7, 131.0, 129.4, 128.9, 116.5, 111.6, 63.0, 57.4,
160.6, 146.0, 135.3, 131.3, 130.9, 128.4, 115.0, 113.3, 96.4, 81.6,
15.9, 14.1 ppm. IR (film): ν = 2986, 2238, 1728, 1313, 1251,
69.6, 22.1, 21.9 ppm. IR (film): ν = 2977, 2223, 1683, 1350, 1257,
˜
˜
1123 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 420.0 [M + Na]+.
1099, 1088 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 386.1 [M + Na]
+. HRMS (ESI+, CH2Cl2/MeOH) calcd. for C18H1835ClNO3SNa+
[M + Na]+ 386.0594; found 386.0604. C18H18ClNO3S (363.86):
calcd. C 59.42, H 4.99, N 3.85, O 13.19, S 8.81, Cl 9.74; found C
58.74, H 4.89, N 3.77, O 13.22, S 8.70.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C17H1635ClNO4S2Na+
[M
+
Na]+ 420.0107; found 420.0112 and calcd. for
C17H1637ClNO4S2Na+ [M + Na]+ 422.0077; found 422.0097.
C17H16ClNO4S2 (397.90): calcd. C 51.32, H 4.05, N 3.52, O 16.08,
S 16.12, Cl 8.91; found C 51.23, H 3.94, N 3.42, O 15.84, S 16.13.
2-[Bis(methylthio)methylene]malononitrile (10): To a solution of
malononitrile (2.0 g, 30.3 mmol) in DMF (70 mL) was added po-
tassium carbonate (4.6 g, 33.3 mmol). After stirring for 30 min at
room temperature, carbon disulfide (1.83 mL, 30.3 mmol) was
added dropwise and the reaction mixture was stirred at room tem-
perature for another 10 min before methyl iodide (3.96 mL,
63.6 mmol) and tetrabutylammonium bromide (1.95 g, 6.06 mmol)
were added. After being stirred for 64 h at 60 °C, the reaction mix-
ture was cooled to room temperature, diluted with water (150 mL)
and extracted with Et2O (4ϫ200 mL). The combined organic lay-
ers were dried with MgSO4, filtered and concentrated under re-
duced pressure. The crude product was purified by recrystallization
from hot Et2O, filtered and dried under vacuum to provide ketene
dithioacetal 10 (3.40 g, 66%) as a yellow solid; m.p. 78 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.74 (s, 6 H, SCH3) ppm. 13C NMR
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(propylthio)thiophene-2-carb-
oxylate (5): To a solution of sulfone 4 (80.0 mg, 0.201 mmol) in
THF (2 mL) were added n-propanethiol (27 μL, 0.302 mmol),
tBuOK (33.8 mg, 0.302 mmol) and 18-crown-6 (79.2 mg,
0.302 mmol). After stirring at room temperature for 16 h, the reac-
tion mixture was diluted with water (3 mL) and extracted with
EtOAc (3ϫ5 mL). The combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure.
Chromatography on silica gel [heptane/EtOAc, 10:0 to 7:3 (v/v) in
20 min] afforded thioether 5 (69.0 mg, 94%) as a white solid; m.p.
1
67 °C. H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 8.5 Hz, 2 H,
Har), 7.34 (d, J = 8.5 Hz, 2 H, Har), 4.21 (q, J = 7.0 Hz, 2 H,
OCH2), 3.13 (t, J = 7.2 Hz, 2 H, SCH2), 1.84 (hx, J = 7.2 Hz, 2 H,
SCH2CH2), 1.21 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.10 (t, J =
7.2 Hz, 3 H, SCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
160.2, 156.3, 148.2, 135.6, 130.9, 130.8, 128.6, 127.8, 113.6, 112.9,
(75 MHz, CDCl ): δ = 184.3, 112.9, 76.0, 19.3 ppm. IR (film): ν =
˜
3
2214, 1450, 1423, 1316, 1210, 932, 868 cm–1. MS (ESI+, CH2Cl2/
MeOH) m/z 170.0 [M + Na]+.
61.9, 38.7, 22.7, 14.2, 13.4 ppm. IR (film): ν = 2963, 2925, 2222,
˜
1721, 1694, 1486, 1264, 1182, 1083 cm–1. MS (ESI+, CH2Cl2/
MeOH) m/z 388.0 [M + Na]+. HRMS (ESI+, CH2Cl2/MeOH)
calcd. for C17H1635ClNO2S2Na+ [M + Na]+ 388.0209; found
388.0212.
2-[3-Methyl-1-(methylthio)butylidene]malononitrile (11): To a solu-
tion of compound 10 (1.5 g, 8.71 mmol) in THF (40 mL) at –40 °C
was added isobutylmagnesium bromide (2 m in Et2O, 4.44 mL,
8.80 mmol). After stirring for 30 min at –40 °C, the mixture was
warmed to room temperature and stirred for 48 h. The reaction
mixture was then quenched with a saturated aqueous NH4Cl solu-
tion (30 mL) and extracted with EtOAc (3ϫ50 mL). The combined
organic layers were dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5 (v/v) in
25 min] to afford compound 11 (644.0 mg, 41%) as a yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 2.67 (d, J = 7.0 Hz, 2 H, CH2),
2.62 (s, 3 H, SCH3), 2.00 (n, J = 6.8 Hz, 1 H, CH), 1.06 (d, J =
6.8 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 184.9,
Ethyl 5-(tert-Butylthio)-3-(4-chlorophenyl)-4-cyanothiophene-2-carb-
oxylate (6): To a solution of sulfone 4 (100.0 mg, 0.251 mmol) in
THF (2 mL) were added tert-butanethiol (42.5 μL, 0.377 mmol),
tBuOK (42.3 mg, 0.377 mmol) and 18-crown-6 (99.6 mg,
0.302 mmol). After stirring at room temperature for 19 h, the reac-
tion mixture was diluted with water (3 mL) and extracted with
EtOAc (3ϫ5 mL). The combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure.
Chromatography on silica gel [heptane/EtOAc, 10:0 to 7:3 (v/v) in
1
20 min] afforded thioether 6 (71.2 mg, 75%) as a yellow solid. H
113.0, 112.2, 78.4, 44.1, 30.0, 22.1, 15.8 ppm. IR (film): ν = 2962,
˜
NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 8.5 Hz, 2 H, Har), 7.36
(d, J = 8.5 Hz, 2 H, Har), 4.23 (q, J = 7.1 Hz, 2 H, OCH2), 1.48
(s, 9 H, tBu), 1.23 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.1, 148.8, 147.8, 135.6, 133.0, 130.9,
2872, 2220, 1510, 1466, 1427, 1134, 924, 812 cm–1. MS (ESI+,
CH2Cl2/MeOH) m/z 180.0 [M + Na]+.
Ethyl 3-Amino-4-cyano-5-isobutylthiophene-2-carboxylate (12): To a
solution of compound 11 (82.4 mg, 0.457 mmol) in ethanol (2 mL)
were successively added potassium carbonate (82.4 mg,
0.594 mmol) and ethyl thioglycolate (60 μL, 0.548 mmol). After
stirring at reflux for 3 h, the reaction mixture was quenched with
water (3 mL). The precipitated crude product was filtered and puri-
fied by chromatography on silica gel [heptane/EtOAc, 10:0 to 7:3
130.8, 128.6, 121.8, 114.0, 62.1, 51.7, 31.1, 14.2 ppm. IR (film): ν
˜
= 2964, 2230, 1724, 1702, 1485, 1367, 1256, 1183, 1156, 1083, 1014,
826, 764 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 402.0 [M + Na]+.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C18H1835ClNO2S2Na+
[M + Na]+ 402.0365; found 402.0362.
Isopropyl
3-(4-Chlorophenyl)-4-cyano-5-isopropoxythiophene-2- (v/v) in 15 min] to provide thiophene 12 (71 mg, 62%) as a white
carboxylate (7): A solution of sulfone 4 (100 mg, 0.251 mmol) and
potassium carbonate (174 mg, 1.26 mmol) in isopropanol (2 mL)
was stirred in a sealed tube at 130 °C for 5 h. After cooling to room
temperature, the reaction mixture was diluted with water (4 mL)
and extracted with EtOAc (3ϫ5 mL). The combined organic layers
were dried with MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel [heptane/EtOAc, 10:0 to 8:2 (v/v) in 15 min] to give ester 7
(50.1 g, 55%) as a white powder; m.p. 125 °C. 1H NMR (500 MHz,
solid. 1H NMR (500 MHz, CDCl3): δ = 5.77 (br. s, 2 H, NH2),
4.27 (q, J = 7.1 Hz, 2 H, OCH2), 2.74 (d, J = 7.1 Hz, 2 H, CH2),
1.99 (n, J = 7.1 Hz, 1 H, CH), 1.32 (t, J = 7.1 Hz, 3 H, OCH2CH3),
0.97 (d, J = 6.8 Hz, 6 H, CHCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 163.6, 160.5, 152.9, 113.4, 101.7, 99.4, 60.7, 39.4, 30.7,
22.3, 14.6 ppm. IR (film): ν = 3427, 3334, 3221, 2956, 2870, 2222,
˜
1672, 1626, 1549, 1300, 1214, 1129, 764 cm–1. MS (ESI+, CH2Cl2/
MeOH) m/z 253.1 [M + H]+. HRMS (ESI+, CH2Cl2/MeOH) calcd.
for C12H17N2O2S+ [M + H]+ 253.1011; found 253.1016.
Eur. J. Org. Chem. 2011, 3920–3931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3925

S. Lethu, J. Dubois
FULL PAPER
Ethyl 3-Bromo-4-cyano-5-isobutylthiophene-2-carboxylate (13): To a
solution of amine 12 (67.2 mg, 0.266 mmol) and CuBr2 (77.3 mg,
0.346 mmol) in acetonitrile (1.5 mL) was added tert-butylnitrite
(46.3 μL, 0.40 mmol). The reaction mixture was stirred at room
temperature for 10 min (until complete stop of gas release), poured
onto a 20% HCl solution (2 mL) and extracted by Et2O (3ϫ5 mL).
The combined organic layers were dried with MgSO4, filtered and
concentrated under reduced pressure. The crude product was puri-
fied by chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5
(v/v) in 15 min] to give bromo compound 13 (47.0 mg, 56%) as a
C17H17ClN2O2S (348.85): calcd. C 58.53, H 4.91, N 8.03, O 9.17,
S 9.19, Cl 10.16; found C 58.30, H 4.99, N 7.92, O 9.23, S 8.98.
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(tetrahydrofuran-2-yl)thiophene-
2-carboxylate (17): A solution of sulfone 4 (90.0 mg, 0.226 mmol)
in THF (5 mL) was refluxed for 3 d before concentration under
reduced pressure. The crude product was purified by chromatog-
raphy on silica gel [heptane/EtOAc, 10:0 to 7:3 (v/v) in 15 min] to
1
provide compound 17 (54.4 mg, 67%) as a white solid. H NMR
(500 MHz, CDCl3): δ = 7.42 (d, J = 8.5 Hz, 2 H, Har), 7.35 (d, J
= 8.5 Hz, 2 H, Har), 5.36 (t, J = 7.4 Hz, 1 H, CH THF), 4.21 (q,
J = 7.1 Hz, 2 H, OCH2), 4.16 (q, J = 7.2 Hz, 1 H, OCH2 THF),
3.97 (q, J = 7.4 Hz, 1 H, CH2), 2.61 (m, 1 H, CH2 THF), 2.09 (m,
2 H, CH2 THF), 1.99 (m, 1 H, CH2 THF), 1.22 (t, J = 7.1 Hz, 3
H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.0, 160.8,
147.9, 135.5, 130.9, 128.6, 127.5, 113.6, 108.9, 76.6, 69.7, 61.9, 34.7,
1
white solid. H NMR (500 MHz, CDCl3): δ = 4.37 (q, J = 7.1 Hz,
2 H, OCH2), 2.89 (d, J = 7.0 Hz, 2 H, CH2), 2.04 (n, J = 6.8 Hz,
1 H, CH), 1.39 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.00 (d, J = 6.8 Hz,
6 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.7, 159.7,
127.2, 117.5, 115.4, 113.3, 62.3, 39.5, 31.0, 22.3, 14.4 ppm. IR
(film): ν = 2965, 2937, 2874, 2224, 1722, 1519, 1455, 1225, 1065,
˜
26.3, 14.2 ppm. IR (film): ν = 2981, 2876, 2227, 1720, 1697, 1492,
˜
754 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 370.0 [M + Na +
1275, 1176, 1085, 1015, 826, 765 cm–1. MS (ESI+, CH2Cl2/MeOH)
m/z 384.0 [M + Na]+. HRMS (ESI+, CH2Cl2/MeOH) calcd. for
C18H1635ClNO3SNa+ [M + Na]+ 384.0437; found 384.0436 and
calcd. for C18H1637ClNO3SNa+ [M + Na]+ 386.0408; found
386.0439.
MeOH]+.
HRMS
(ESI+,
CH2Cl2/MeOH)
calcd.
for
C13H1879BrNO3SNa+ [M + Na + MeOH]+ 370.0088; found
370.0098 and calcd. for C13H1881BrNO3SNa+ [M
MeOH]+ 372.0068; found 372.0083.
+ Na +
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-isobutylthiophene-2-carboxylate Ethyl 5-Amino-3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylate
(14): A solution of compound 13 (37.0 mg, 0.117 mmol), potassium (18): To a solution of azide 26 (50.0 mg, 0.150 mmol) in ethanol
carbonate (2 m in H2O, 0.147 mL, 0.293 mmol), Pd(PPh3)4 (2 mL) was added palladium on charcoal (50 mg, 0.015 mmol). Hy-
(13.5 mg, 11.7 μmol) and p-chlorophenylboronic acid (36.6 mg, drogen in a baloon was bubbled in the stirred reaction mixture for
0.234 mmol) in a mixture toluene/EtOH, 9:1 (1 mL) was stirred at
reflux for 4 h before dilution by water (3 mL). The reaction mixture
was then extracted by EtOAc (3ϫ5 mL) and the combined organic
layers were dried with MgSO4, filtered and concentrated under re-
duced pressure. The crude product was purified by chromatography
on silica gel [heptane/EtOAc, 10:0 to 8:2 (v/v) in 15 min] to provide
1 min and the mixture was stirred another 4 min under hydrogen
atmosphere before filtration through a Celite pad. Filtrate was con-
centrated under reduced pressure and the resulting crude product
was purified by chromatography on silica gel [heptane/EtOAc, 10:0
to 5:5 (v/v) in 20 min] to give amine 18 (37.0 mg, 80%) as a grey
solid; m.p. 182 °C. H NMR (500 MHz, CDCl3): δ = 7.43 (d, J =
8.5 Hz, 2 H, Har), 7.38 (d, J = 8.5 Hz, 2 H, Har), 5.37 (br. s, 2 H,
NH2), 4.18 (q, J = 7.1 Hz, 2 H, OCH2), 1.20 (t, J = 7.1 Hz, 3 H,
1
1
product 14 (27.6 mg, 68%) as a white solid. H NMR (500 MHz,
CDCl3): δ = 7.43 (d, J = 8.5 Hz, 2 H, Har), 7.35 (d, J = 8.5 Hz, 2
H, Har), 4.21 (q, J = 7.1 Hz, 2 H, OCH2), 2.92 (d, J = 7.0 Hz, 2 CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.9, 161.2,
H, CH2), 2.08 (n, J = 7.0 Hz, 1 H, CH), 1.22 (t, J = 7.1 Hz, 3 H, 146.9, 135.3, 131.5, 130.8, 128.5, 114.5, 112.3, 92.4, 61.4, 14.3 ppm.
OCH2CH3), 1.04 (d, J = 6.8 Hz, 6 H, CHCH3) ppm. 13C NMR
IR (film): ν = 3364, 3320, 3212, 2988, 2212, 1679, 1649, 1501, 1478,
˜
(75 MHz, CDCl3): δ = 160.7, 160.4, 147.3, 135.4, 131.2, 130.9, 1318, 1269, 1173, 1088, 1070 cm–1. MS (ESI–, CH2Cl2/MeOH) m/z
128.5, 127.5, 114.2, 112.9, 61.8, 39.2, 31.0, 22.4, 14.2 ppm. IR
305.0 [M –
H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for
(film): ν = 2958, 2871, 2225, 1717, 1493, 1272, 1197, 1088, 1070,
C14H1035ClN2O2S– [M – H]– 305.0152; found 305.0155.
˜
1016, 764 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 370.1 [M + Na]+.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C18H1835ClNO2SNa+ [M
+ Na]+ 370.0644; found 370.0651.
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(cyclopentylamino)thiophene-2-
carboxylate (19): To a solution of sulfone 4 (130.0 mg, 0.327 mmol)
in THF (2 mL) was added the cyclopentylamine (1 mL). The reac-
tion mixture was stirred at room temperature for 21 h and concen-
trated under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 6:4 (v/v) in
30 min] to provide amine 19 (64.0 mg, 52%) as an off-white solid;
m.p. 182 °C. 1H NMR (500 MHz, CDCl3): δ = 7.40 (d, J = 8.5 Hz,
2 H, Har), 7.35 (d, J = 8.5 Hz, 2 H, Har), 5.39 (d, J = 5.39 Hz, 1
H, NH), 4.15 (q, J = 7.1 Hz, 2 H, OCH2), 3.80 (hx, J = 6.4 Hz, 1
H, CH), 2.15 (m, 2 H, CHCH2), 1.79 (m, 2 H, CH2CH2), 1.70 (m,
2 H, CH2CH2), 1.63 (m, 2 H, CHCH2), 1.18 (t, J = 7.1 Hz, 3 H,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4, 161.4,
147.6, 135.2, 131.7, 130.8, 128.4, 115.3, 110.6, 89.0, 61.1, 59.5, 33.1,
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(isopropylamino)thiophene-2-
carboxylate (15): To a solution of sulfone 4 (180.0 mg, 0.452 mmol)
in THF (2 mL) was added isopropylamine (2 mL) and the reaction
mixture was stirred at room temperature for 18 h before dilution by
water (3 mL). The reaction mixture was then extracted by EtOAc
(3ϫ5 mL) and the combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel [hept-
ane/EtOAc, 10:0 to 5:5 (v/v) in 20 min] to provide amine 15
(80.4 mg, 51%) as a white solid. 1H NMR (500 MHz, CDCl3): δ =
7.40 (d, J = 8.5 Hz, 2 H, Har), 7.35 (d, J = 8.5 Hz, 2 H, Har), 5.24
(d, J = 7.4 Hz, 1 H, NH), 4.15 (q, J = 7.1 Hz, 2 H, OCH2), 3.63
(oct, J = 6.7 Hz, 1 H, CH), 1.37 (d, J = 6.7 Hz, 6 H, CHCH3), 1.18
(t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 165.7, 161.2, 147.3, 135.0, 131.4, 130.6, 128.2, 115.0, 110.2, 88.8,
24.1, 14.3 ppm. IR (film): ν = 3270, 2959, 2206, 1705 cm–1. MS
˜
(ESI+, CH2Cl2/MeOH) m/z 397.1 [M + Na]+. HRMS (ESI+,
CH2Cl2/MeOH) calcd. for C19H1935ClN2O2SNa+ [M + Na]+
397.0753; found 397.0737.
60.9, 50.2, 22.3, 14.1 ppm. IR (film): ν = 3256, 2967, 2929, 2211,
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(pyrrolidin-1-yl)thiophene-2-
˜
1702 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 371.0 [M + Na]+.
carboxylate (20): A solution of sulfone 4 (96.0 mg, 0.241 mmol) in
pyrrolidine (1.5 mL) was stirred at room temperature for 3 h and
concentrated under reduced pressure. The crude product was puri-
fied by chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C17H1735ClN2O2SNa+
[M
+
Na]+ 371.0597; found 371.0594 and calcd. for
C17H1737ClN2O2SNa+ [M + Na]+ 373.0567; found 373.0588.
3926
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
(v/v) in 15 min] to provide amine 20 (63.9 mg, 73%) as a white
solid. H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 8.5 Hz, 2 H,
3.65 (q, J = 7.1 Hz, 4 H, NCH2), 1.35 (t, J = 7.1 Hz, 6 H,
NCH2CH3), 1.14 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
1
Har), 7.32 (d, J = 8.5 Hz, 2 H, Har), 4.12 (q, J = 7.1 Hz, 2 H, (75 MHz, CDCl3): δ = 165.0, 161.3, 150.0, 134.9, 132.4, 130.8,
OCH2), 3.69 (m, 4 H, NCH2), 2.10 (m, 4 H, CH2CH2), 1.15 (t, J 128.3, 117.1, 109.9, 87.2, 61.0, 48.6, 14.3, 13.1 ppm. IR (film): ν =
˜
= 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
163.4, 161.2, 149.5, 134.7, 132.1, 130.6, 128.1, 117.2, 110.0, 87.1,
2977, 2935, 2199, 1710, 1530, 1488, 1448, 1242, 1177, 1072, 1016,
820, 758 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 385.1 [M + Na]+.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C18H1935ClN2O2SNa+
60.8, 51.8, 25.9, 14.1 ppm. IR (film): ν = 2953, 2206, 1699, 1520,
˜
1257 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 383.0 [M + Na]+.
[M
+
Na]+ 385.0753; found 385.0758 and calcd. for
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C18H1735ClN2O2SNa+
C18H1937ClN2O2SNa+ [M + Na]+ 387.0724; found 387.0749.
[M
+
Na]+ 383.0597; found 383.0581 and calcd. for
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-{[2-(dimethylamino)ethyl]meth-
ylamino}thiophene-2-carboxylate (25): To a solution of sulfone 4
(80.0 mg, 0.201 mmol) in THF (1 mL) was added the N,N,NЈ-tri-
methylethylenediamine (0.5 mL). The reaction mixture was stirred
at 40 °C for 92 h, diluted with water (3 mL) and extracted with
EtOAc (3ϫ5 mL). The combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel [hept-
ane/EtOAc, 10:0 to 5:5 (v/v) in 15 min] to provide amine 25
(23.4 mg, 30%) as a white solid. 1H NMR (500 MHz, CDCl3): δ =
7.39 (d, J = 8.5 Hz, 2 H, Har), 7.30 (d, J = 8.5 Hz, 2 H, Har), 4.12
(q, J = 7.1 Hz, 2 H, OCH2), 3.85 (t, J = 7.0 Hz, 2 H, NCH2), 3.31
(s, 3 H, NCH3), 2.64 (t, J = 7.0 Hz, 2 H, NCH2), 2.30 (s, 6 H,
NCH3), 1.14 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.6, 161.1, 149.7, 135.0, 132.1, 130.8,
128.3, 117.2, 111.0, 87.9, 61.1, 56.4, 53.2, 45.5, 42.5, 14.3 ppm. MS
(ESI+, CH2Cl2/MeOH) m/z 392.1 [M + H]+. HRMS (ESI+,
CH2Cl2/MeOH) calcd. for C19H2335ClN3O2S+ [M + H]+ 392.1200;
found 392.1201.
C18H1737ClN2O2SNa+ [M + Na]+ 385.0567; found 385.0570.
C18H17ClN2O2S (360.86): calcd. C 59.91, H 4.75, N 7.76, O 8.87,
S 8.89, Cl 9.82; found C 59.90, H 4.77, N 7.85, O 9.01, S 8.75.
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(piperidin-1-yl)thiophene-2-
carboxylate (21): To a solution of sulfone 4 (81.7 mg, 0.206 mmol)
in THF (1 mL) was added the piperidine (0.25 mL). The reaction
mixture was stirred at room temperature for 4 h and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5 (v/v) in
1
15 min] to provide amine 21 (44.7 mg, 58%) as a yellow solid. H
NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 8.5 Hz, 2 H, Har), 7.31
(d, J = 8.5 Hz, 2 H, Har), 4.12 (q, J = 7.1 Hz, 2 H, OCH2), 3.65
(m, 4 H, NCH2), 1.75 (m, 4 H, CH2CH2), 1.69 (m, 2 H, CH2CH2),
1.15 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.7, 161.1, 149.5, 134.9, 132.2, 130.8, 128.3, 116.7,
111.2, 89.9, 61.0, 52.4, 25.4, 23.7, 14.2 ppm. IR (film): ν = 2936,
˜
2198, 1672, 1508, 1485, 1444, 1368, 1320, 1299, 1244, 1222, 1077,
917, 822 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 397.1 [M + Na]+.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C19H1935ClN2O2SNa+
[M + Na]+ 397.0753; found 397.0735.
Ethyl 5-Azido-3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylate
(26): To a solution of sulfone 4 (500.0 mg, 1.26 mmol) in DMF
(15 mL) was added sodium azide (246.0 mg, 3.78 mmol). The reac-
tion mixture was stirred at room temperature for 5 h, diluted with
water (3 mL) and extracted with EtOAc (3ϫ25 mL). The com-
bined organic layers were dried with MgSO4, filtered and concen-
trated under reduced pressure to provide pure azide 26 (418.0 mg,
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(4-methylpiperazin-1-yl)thio-
phene-2-carboxylate (22): A solution of sulfone 4 (260.0 mg,
0.655 mmol) in N-methylpiperazine (4 mL) was stirred at room
temperature for 16 h and diluted with water. The reaction mixture
was extracted with Et2O (3ϫ10 mL) and the combined organic
layers were dried with MgSO4, fiiltrated and concentrated under
reduced pressure. The crude product was purified by chromatog-
raphy on silica gel [CH2Cl2/MeOH, 100:0 to 95:5 (v/v) in 40 min] to
1
quantitative) as a red solid without further purification. H NMR
(500 MHz, CDCl3): δ = 7.43 (d, J = 8.5 Hz, 2 H, Har), 7.35 (d, J
= 8.5 Hz, 2 H, Har), 4.22 (q, J = 7.1 Hz, 2 H, OCH2), 1.22 (t, J =
7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
160.0, 155.4, 147.0, 135.9, 130.8, 130.2, 128.6, 121.5, 111.9, 103.0,
1
provide compound 22 (96.5 mg, 38%) as a yellow solid. H NMR
62.2, 14.1 ppm. IR (film): ν = 2119, 1724, 1494 cm–1.
(500 MHz, CDCl3): δ = 7.39 (d, J = 8.5 Hz, 2 H, Har), 7.30 (d, J
= 8.5 Hz, 2 H, Har), 4.13 (q, J = 7.1 Hz, 2 H, OCH2), 3.69 (m, 4
H, NCH2), 2.58 (m, 4 H, NCH2), 2.35 (s, 3 H, NCH3), 1.26 (t, J
= 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.7, 161.0, 149.3, 135.1, 131.9, 130.8, 128.4, 116.4, 112.3, 91.0,
˜
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(1H-1,2,4-triazol-1-yl)thio-
phene-2-carboxylate (27): A solution of sulfone 4 (100.0 mg,
0.251 mmol), 1,2,4-triazole (34.8 mg, 0.504 mmol), tBuOK
(56.5 mg, 0.504 mmol) and 18-crown-6 (133.1 mg, 0.504 mmol) in
THF (2 mL) was stirred at room temperature for 20 h and diluted
with water (5 mL). The reaction mixture was extracted with EtOAc
(3ϫ10 mL) and the combined organic layers were dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel [hept-
ane/EtOAc, 10:0 to 8:2 (v/v) in 20 min] to give compound 27
(71.8 mg, 80%) as a white powder; m.p. 135 °C. 1H NMR
(500 MHz, CDCl3): δ = 9.15 (s, 1 H, NCH5N triazole), 8.17 (s, 1
H, NCH3N triazole), 7.48 (d, J = 8.5 Hz, 2 H, Har), 7.39 (d, J =
8.5 Hz, 2 H, Har), 4.28 (q, J = 7.1 Hz, 2 H, OCH2), 1.26 (t, J =
7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
160.1, 153.4, 149.8, 146.8, 142.2, 136.2, 130.9, 129.9, 128.9, 125.0,
61.2, 54.1, 50.8, 46.1, 14.2 ppm. IR (film): ν = 2986, 2941, 2807,
˜
2210, 1704, 1493, 1222 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 390.1
[M
+
H]+. HRMS (ESI+, CH2Cl2/MeOH) calcd. for
C19H2135ClN3O2S+ [M
+
H]+ 390.1043; found 390.1039.
C19H21ClN3O2S (389.90): calcd. C 58.53, H 5.17, N 10.78, O 8.21,
S 8.22, Cl 9.09; found C 58.45, H 5.27, N 10.69, O 7.72, S 7.90.
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(diethylamino)thiophene-2-carb-
oxylate (23): A solution of amine 18 (50.0 mg, 0.163 mmol), potas-
sium carbonate (56.3 mg, 0.407 mmol) and ethyl iodide (32.6 μL,
0.407 mmol) in DMF (1 mL) was stirred at room temperature for
55 h. The reaction mixture was diluted by water (5 mL) and ex-
tracted by CH2Cl2 (3ϫ10 mL). The combined organic layers were
dried with MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by chromatography on silica
gel [Heptane + 0.5% Et3N/EtOAc + 0.5% Et3N, 10:0 to 3:7 (v/v)
in 20 min] to furnish product 23 (40.0 mg, 68%) as an orange solid.
113.3, 101.0, 62.5, 14.2 ppm. IR (film): ν = 3116, 2987, 2226, 1727,
˜
1518, 1181 cm–1. MS (ESI+, acetonitrile) m/z 359.1 [M + H]+.
HRMS (ESI+, acetonitrile): calcd. for C16H1235ClN4O2S+ [M +
H]+ 359.0370; found 359.0373.
1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 8.5 Hz, 2 H, Har), Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(1H-pyrrol-1-yl)thiophene-2-
7.31 (d, J = 8.5 Hz, 2 H, Har), 4.12 (q, J = 7.1 Hz, 2 H, OCH2), carboxylate (28): To a solution of amine 18 (48.0 mg, 0.157 mmol)
Eur. J. Org. Chem. 2011, 3920–3931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3927

S. Lethu, J. Dubois
FULL PAPER
in glacial acetic acid (2 mL) was added 2,5-dimethoxytetra-
hydrofuran (63.5 μL, 0.469 mmol) and the reaction mixture was
stirred for 1 h at 90 °C before concentration under reduced pres-
sure. The crude product was purified by chromatography on silica
gel [heptane/EtOAc, 10:0 to 7:3 (v/v) in 15 min] to give compound
28 (48.5 mg, 87%) as a pale orange solid. 1H NMR (500 MHz,
CDCl3): δ = 7.46 (d, J = 8.5 Hz, 2 H, Har), 7.38 (d, J = 8.5 Hz, 2
20 min] to give compound 32 (154.4 mg, 83%) as a purple solid.
1H NMR (500 MHz, CDCl3): δ = 8.50 (s, 1 H, H5-triazole), 7.48
(d, J = 8.5 Hz, 2 H, Har), 7.39 (d, J = 8.5 Hz, 2 H, Har), 4.27 (q,
J = 7.1 Hz, 2 H, OCH2), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.40
(s, 9 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.1, 149.7,
148.9, 146.6, 136.1, 130.9, 130.0, 128.9, 127.3, 125.2, 113.1, 101.5,
62.5, 14.2, –1.1 ppm. IR (film): ν = 2960, 2228, 1727, 1698, 1513,
˜
H, Har), 7.34 (m, 2 H, N=CH), 6.44 (m, 2 H, =CH), 4.23 (q, J = 1251, 1204, 1178, 1088, 1016, 952, 839, 759 cm–1. MS (ESI+,
7.1 Hz, 2 H, OCH2), 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13
C
CH2Cl2/MeOH) m/z 453.0 [M + Na]+. HRMS (ESI+, CH2Cl2/
MeOH) calcd. for C19H1935ClN4O2SSiNa+ [M + Na]+ 453.0584;
found 453.0603 and calcd. for C19H1937ClN4O2SSiNa+ [M + Na]+
455.0555; found 455.0574.
NMR (75 MHz, CDCl3): δ = 160.4, 154.9, 147.6, 135.8, 130.9,
130.6, 128.7, 121.3, 121.1, 114.0, 113.8, 100.5, 62.1, 14.2 ppm. IR
(film): ν = 2990, 2222, 1725, 1502, 1487, 1248, 1172, 716 cm–1. MS
˜
(ESI+, CH2Cl2/MeOH) m/z 379.0 [M + Na]+. HRMS (ESI+,
CH2Cl2/MeOH) calcd. for C18H1335ClN2O2SNa+ [M + Na]+
379.0284; found 379.0277.
Ethyl
3-(4-Chlorophenyl)-4-cyano-5-(1H-1,2,3-triazol-1-yl)thio-
phene-2-carboxylate (33): To a solution of silylated derivative 32
(50.0 mg, 0.116 mmol) in THF (1 mL) was added HF·Et3N
(95.0 μL, 0.58 mmol). The reaction mixture was stirred at room
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(1H-imidazol-1-yl)thiophene-2-
carboxylate (29): A solution of sulfone 4 (96.1 mg, 0.236 mmol), temperature for 6 h, quenched with a saturated aqueous NaHCO3
imidazole (32.2 mg, 0.473 mmol), tBuOK (53.1 mg, 0.473 mmol)
and 18-crown-6 (125.0 mg, 0.473 mmol) in THF (2 mL) was stirred
at room temperature for 20 h and diluted with water (5 mL). The
reaction mixture was extracted with EtOAc (3ϫ10 mL) and the
combined organic layers were dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5 (v/v)
solution (5 mL) and extracted with EtOAc (3ϫ5 mL). The com-
bined organic layers were dried with MgSO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5 (v/v) in
20 min] to give triazole 33 (34.7 mg, 83%) as a white solid. 1H
NMR (500 MHz, CDCl3): δ = 8.63 (br. s, 1 H, H5-triazole), 7.93
(br. s, 1 H, H4-triazole), 7.48 (d, J = 8.5 Hz, 2 H, Har), 7.40 (d, J
in 15 min] to give compound 29 (36.2 mg, 43%) as a white powder; = 8.5 Hz, 2 H, Har), 4.28 (q, J = 7.1 Hz, 2 H, OCH2), 1.26 (t, J =
1
m.p. 172 °C. H NMR (500 MHz, CDCl3): δ = 8.14 (s, 1 H, H2- 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
imidazole), 7.53 (s, 1 H, H5-imidazole), 7.47 (d, J = 8.5 Hz, 2 H,
Har), 7.39 (d, J = 8.5 Hz, 2 H, Har), 7.31 (s, 1 H, H4-imidazole),
4.28 (q, J = 7.1 Hz, 2 H, OCH2), 1.26 (t, J = 7.1 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.0, 149.9,
147.2, 136.7, 136.2, 132.2, 130.9, 130.0, 128.9, 124.2, 119.4, 112.9,
160.0, 148.6, 146.6, 136.6, 135.7, 130.9, 129.9, 128.9, 125.7, 122.7,
112.9, 102.1, 62.6, 14.2 ppm. IR (film): ν = 3148, 3126, 2986, 2229,
˜
1729, 1694, 1514, 1486, 1264, 1245, 1185, 1014 cm–1. MS (ESI+,
CH2Cl2/MeOH) m/z 381.0 [M + Na]+. HRMS (ESI+, CH2Cl2/
MeOH) calcd. for C16H1135ClN4O2SNa+ [M + Na]+ 381.0189;
found 381.0180. C16H11ClN4O2S (358.80): calcd. C 53.56, H 3.09,
N 15.61, O 8.92, S 8.94, Cl 9.88; found C 53.33, H 3.18, N 15.59,
O 8.75, S 8.52.
104.5, 62.5, 14.2 ppm. IR (film): ν = 3140, 3102, 2990, 2228, 1681,
˜
1505, 1290, 1256, 1086 cm–1. MS (ESI+, acetonitrile) m/z 358.1 [M
+ H]+. HRMS (ESI+, acetonitrile): calcd. for C17H1335ClN3O2S+
[M + H]+ 358.0417; found 358.0418.
Ethyl
4-(4-Chlorophenyl)-3-cyano-2,3Ј-bithiophene-5-carboxylate
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-(1H-pyrazol-1-yl)thiophene-2- (34): A solution of compound 2 (100.0 mg, 0.273 mmol), 3-thienyl-
carboxylate (30): A solution of sulfone 4 (100.0 mg, 0.251 mmol),
pyrazole (51.3 mg, 0.754 mmol), tBuOK (84.6 mg, 0.754 mmol)
and 18-crown-6 (199.2 mg, 0.754 mmol) in THF (2 mL) was stirred
at room temperature for one week and diluted with water (5 mL).
The reaction mixture was extracted with EtOAc (3ϫ10 mL) and
the combined organic layers were dried with MgSO4, filtered and
concentrated under reduced pressure. The crude product was puri-
fied by chromatography on silica gel [Heptane + 0.5% Et3N/EtOAc
+ 0.5% Et3N, 10:0 to 6:4 (v/v) in 15 min] to give compound 30
boronic acid (45.4 mg, 0.355 mmol), Pd(PPh3)4 (31.6 mg,
27.3 μmol) and copper(I) thiophene-2-carboxylate (78.2 mg,
0.410 mmol) in THF (1.5 mL) was stirred at 50 °C for 48 h before
quenching by 28% ammoniac solution (2 mL). The reaction mix-
ture was then extracted by EtOAc (3ϫ5 mL) and the combined
organic layers were dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 5:5 (v/v) in
15 min] and the solid obtained was washed with cold EtOH to
provide product 34 (62.0 mg, 61%) as a white solid; m.p. 120 °C.
1H NMR (500 MHz, CDCl3): δ = 8.07 (br. s, 1 H, H thiophene),
1
(41.1 mg, 46%) as a white powder. H NMR (500 MHz, CDCl3):
δ = 8.58 (d, J = 2.6 Hz, 1 H, H5-pyrazole), 7.79 (d, J = 1.7 Hz, 1
H, H3-pyrazole), 7.43 (d, J = 8.5 Hz, 2 H, Har), 7.35 (d, J = 8.5 Hz, 7.57 (br. s, 1 H, H thiophene), 7.48 (br. s, 1 H, H thiophene), 7.46
2 H, Har), 6.60 (m, 1 H, H4-pyrazole), 4.24 (q, J = 7.1 Hz, 2 H,
(d, J = 8.5 Hz, 2 H, Har), 7.39 (d, J = 8.5 Hz, 2 H, Har), 4.24 (q,
J = 7.1 Hz, 2 H, OCH2), 1.23 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm.
OCH2), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.5, 154.5, 147.0, 143.6, 135.8, 130.9, 13C NMR (75 MHz, CDCl3): δ = 160.7, 151.6, 148.8, 135.6, 131.5,
130.6, 128.8, 128.7, 122.5, 114.1, 110.7, 97.7, 62.1, 14.2 ppm. IR
131.0, 130.9, 128.7, 127.8, 127.0, 126.6, 126.2, 115.3, 108.8, 62.0,
(film): ν = 3154, 3138, 2989, 2909, 2227, 1726, 1531, 1505,
14.2 ppm. IR (film): ν = 3107, 2981, 2901, 2223, 1719, 1696, 1089,
˜
˜
1485 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 380.0 [M + Na]+.
HRMS (ESI+, CH2Cl2/MeOH) calcd. for C17H1235ClN3O2SNa+
[M + Na]+ 380.0236; found 380.0226.
784 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 396.0 [M + Na]+. HRMS
(ESI+, CH2Cl2/MeOH) calcd. for C18H12ClNO2S2Na+ [M + Na]+
395.9896; found 395.9913.
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-[4-(trimethylsilyl)-1H-1,2,3-tri-
azol-1-yl]thiophene-2-carboxylate (32): A solution of azide 26
Ethyl 3-(4-Chlorophenyl)-4-cyano-5-phenylthiophene-2-carboxylate
(35): Following the exact same procedure as for product 34 and
(144.0 mg, 0.433 mmol) in (trimethylsilyl)acetylene (1 mL, starting from compound 2 (77.0 mg, 0.191 mmol), desired ester 35
7.08 mmol) was stirred for 7 h at room temperature and concen-
trated under reduced pressure. The crude product was purified by
chromatography on silica gel [heptane/EtOAc, 10:0 to 6:4 (v/v) in
(36.5 mg, 52%) was obtained as a white solid. 1H NMR (500 MHz,
CDCl3): δ = 7.82 (m, 2 H, Har), 7.52 (m, 3 H, Har), 7.46 (d, J =
8.5 Hz, 2 H, Har), 7.40 (d, J = 8.5 Hz, 2 H, Har), 4.25 (q, J =
3928
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
7.1 Hz, 2 H, OCH2), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13
NMR (75 MHz, CDCl3): δ = 160.7, 157.5, 148.9, 135.6, 131.2,
131.1, 131.0, 130.8, 129.7, 129.4, 128.7, 128.2, 114.9, 109.9, 62.0,
C
6 (38.4 mg, 0.101 mmol), acid 6a (32.9 mg, 93%) was obtained as
a white solid. 1H NMR (500 MHz, CDCl3): δ = 7.32 (m, 4 H, Har),
1.49 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.8,
150.0, 148.4, 135.7, 131.0, 130.7, 128.7, 121.8, 113.9, 110.4, 51.9,
14.2 ppm. IR (film): ν = 2982, 2224, 1723, 1698, 1486, 1302, 1234,
˜
1172, 1090 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 390.0 [M + 31.2 ppm. IR (film): ν = 2963, 2550, 2230, 1694, 1485, 1155, 1087,
˜
Na]+.
HRMS
(ESI+,
CH2Cl2/MeOH)
calcd.
for
826 cm–1. MS (ESI+, CH2Cl2/MeOH) m/z 374.0 [M + Na]+. HRMS
(ESI+, CH2Cl2/MeOH) calcd. for C16H1435ClNO2S2Na+ [M +
N a ] + 3 7 4 . 0 0 5 2 ; f o u n d 3 7 4 . 0 0 5 2 a n d c a l c d . f o r
C16H1437ClNO2S2Na+ [M + Na]+ 376.0023; found 376.0049.
C20H14ClNO2SNa+ [M + Na]+ 390.0331; found 390.0340.
Typical Procedure for Saponification of Esters: To a solution of es-
ter (1 mmol) in a mixture THF/EtOH, 2:1 (10 mL/mmol) was
added NaOH 2 m in water (5 mL/mmol). The reaction mixture was
stirred overnight at room temperature and then acidified to pH =
4–5 with HCl 1 m in water.
3-(4-Chlorophenyl)-4-cyano-5-isopropoxythiophene-2-carboxylic
Acid (7a): According to method A for saponification of ester 7
(50.0 mg, 0.137 mmol), acid 7a (43.8 mg, 99%) was obtained as a
white powder. 1H NMR (500 MHz, CDCl3): δ = 7.41 (d, J =
8.5 Hz, 2 H, Har), 7.33 (d, J = 8.5 Hz, 2 H, Har), 4.65 (h, J =
6.1 Hz, 1 H, OCH), 1.53 (d, J = 6.1 Hz, 6 H, CHCH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 176.1, 165.8, 135.7, 131.8, 130.9,
Method A: The precipitated product was filtered, washed with
water and dried under vacuum.
Method B: If the desired acid did not precipitate, the reaction mix-
ture was extracted with EtOAc (3ϫ15 mL/mmol) and the com-
bined organic layers were washed with water (40 mL/mmol) dried
with MgSO4, filtered and concentrated under reduced pressure.
130.8, 129.1, 128.6, 113.0, 97.0, 82.0, 22.0 ppm. IR (film): ν = 2982,
˜
2535, 2225, 1676, 1643, 1087 cm–1. MS (ESI–, DMF/MeOH): m/z
= 320.0 [M – H]–. HRMS (ESI–, DMF/MeOH): calcd. for
C15H1135ClNO3S– [M – H]– 320.0148; found 320.0136.
Unless otherwise indicated, the pure desired product was obtained
without further purification.
3-(4-Chlorophenyl)-4-cyano-5-isobutylthiophene-2-carboxylic Acid
(14a): According to method B for saponification of ester 14
(25.7 mg, 0.074 mmol), acid 14a (23.5 mg, quantitative) was ob-
3-(4-Chlorophenyl)-4-cyano-5-(isopropylsulfinyl)thiophene-2-carbox-
ylic Acid (3a): According to method A for saponification of ester
3 (34.6 mg, 0.091 mmol), acid 3a (29.1 mg, 91%) was obtained as
a white solid. 1H NMR ([D6]acetone, 300 MHz): δ = 7.51 (m, 4 H,
Har), 3.38 (m, 1 H, CH), 1.31 (m, 6 H, CHCH3) ppm. 13C NMR
([D6]acetone, 75 MHz): δ = 161.0, 142.3, 133.7, 132.4, 131.8, 129.1,
1
tained as a white solid. H NMR (CDCl3, 300 MHz): δ = 7.43 (d,
J = 8.5 Hz, 2 H, Har), 7.34 (d, J = 8.5 Hz, 2 H, Har), 2.93 (d, J =
6.8 Hz, 2 H, CHCH2), 2.08 (m, 1 H, CH2CH), 1.04 (d, J = 6.8 Hz,
6 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4, 162.0,
149.1, 135.7, 130.9, 130.7, 128.8, 126.1, 114.0, 113.6, 39.3, 31.0,
129.0, 113.1, 112.7, 57.6, 15.9, 14.3 ppm. IR (film): ν = 2963, 2924,
˜
22.4 ppm. IR (film): ν = 3127, 2959, 2928, 2866, 2237, 1721, 1489,
˜
2852, 2558, 2230, 1704, 1487, 1255, 1015, 730 cm–1. MS (ESI–,
1159, 1135, 1088, 765, 668 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z
= 318.1 [M – H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for
C16H1335ClNO2S– [M – H]– 318.0356; found 318.0351. UHPLC:
3.02 min, 99% (System 1); 3.58 min, 99% (System 2).
CH2Cl2/MeOH) m/z 352.0 [M – H]–. HRMS (ESI–, CH2Cl2/
–
MeOH) calcd. for C15H1135ClNO3S2 [M – H]– 351.9869; found
–
351.9879 and calcd. for C15H1137ClNO3S2 [M – H]– 353.9839;
found 353.9883. UHPLC: 2.35 min, 89% (System 1); 2.96 min,
90% (System 2).
3-(4-Chlorophenyl)-4-cyano-5-(tetrahydrofuran-2-yl)thiophene-2-
carboxylic Acid (17a): According to method B for saponification
of ester 17 (25.7 mg, 0.074 mmol) and after chromatography on
silica gel [CH2Cl2 + 0.5% HCOOH/EtOAc + HCOOH 0.5% 10:0
to 9:1 (v/v) in 10 min], acid 17a (20.3 mg, 72%) was obtained as a
3-(4-Chlorophenyl)-4-cyano-5-(isopropylsulfonyl)thiophene-2-carb-
oxylic Acid (4a): According to method B for saponification of ester
4 (210.0 mg, 0.528 mmol), acid 4a (195.0 mg, quantitative) was ob-
tained as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ = 7.37
(d, J = 8.7 Hz, 2 H, Har), 7.31 (d, J = 8.7 Hz, 2 H, Har), 3.52 (h,
1
white solid. H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 8.5 Hz,
2 H, Har), 7.36 (d, J = 8.5 Hz, 2 H, Har), 5.38 (t, J = 6.9 Hz, 1 H,
OCH), 4.18 (m, 1 H, OCH2), 4.00 (m, 1 H, OCH2), 2.64 (m, 1 H,
CHCH2), 2.20–1.94 (m, 3 H, CHCH2 and CH2CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.6, 165.4, 149.6, 135.8, 130.9,
130.5, 128.8, 126.1, 113.4, 109.4, 76.6, 69.7, 34.7, 26.3 ppm. IR
J = 6.8 Hz, 1 H, CH), 1.41 (d, J = 6.8 Hz, 6 H, CHCH3) ppm. 13
C
NMR ([D6]acetone, 125 MHz): δ = 161.2, 149.6, 149.3, 138.3,
135.9, 132.5, 131.6, 129.1, 117.9, 112.6, 58.2, 15.9 ppm. IR (film):
ν = 2856, 2535, 2238, 1693, 1677, 1315, 1278, 1125 cm–1. MS (ESI–,
˜
CH2Cl2/MeOH) m/z 368.0 [M – H]–. HRMS (ESI–, CH2Cl2/
(film): ν = 2969, 2559, 2225, 1717, 1637, 1483, 1400 cm–1. MS
˜
MeOH) calcd. for C15H1135ClNO4S2 [M – H]– 351.9869; found
–
(ESI–, CH2Cl2/MeOH): m/z = 332.0 [M – H]–. HRMS (ESI–,
CH2Cl2/MeOH) calcd. for C16H1135ClNO3S– [M – H]– 332.0148;
found 334.0146.
351.9879. UHPLC: 2.41 min, 99% (System 1).
3-(4-Chlorophenyl)-4-cyano-5-(propylthio)thiophene-2-carboxylic
Acid (5a): According to method B for saponification of ester 5
(21.2 mg, 0.059 mmol), acid 5a (18.9 mg, 95%) was obtained as a
5-Amino-3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylic Acid
(18a): According to method A for saponification of ester 18
(10.5 mg, 0.034 mmol) and substituting NaOH with LiOH, acid
18a (7.1 mg, 75%) was obtained as a grey solid. 1H NMR ([D6]-
1
white powder; m.p. 199 °C. H NMR (CDCl3, 300 MHz): δ = 7.38
(d, J = 8.2 Hz, 2 H, Har), 7.32 (d, J = 8.2 Hz, 2 H, Har), 3.13 (t,
J = 7.2 Hz, 2 H, SCH2), 1.85 (hx, J = 7.2 Hz, 2 H, CH2CH2), 1.10
(t, J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 164.9, 158.3, 149.5, 135.8, 130.9, 130.4, 128.7, 126.1, 113.4,
acetone, 300 MHz): δ = 7.45 (m, 2 H, Har) ppm. IR (film): ν =
˜
3303, 3200, 2962, 2548, 2217, 1613, 1498, 1471, 1311, 1300, 1282,
1186, 1090 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z = 277.0 [M –
H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for C12H635ClN2O2S–
[M – H]– 276.9839; found 276.9849. UHPLC: 2.15 min, 93% (Sys-
tem 1); 2.75 min, 94% (System 2).
112.6, 38.5, 22.6, 13.6 ppm. IR (film): ν = 2961, 2922, 2851, 2551,
˜
2219, 1644, 1485, 1351, 1297 cm–1. MS (ESI–, CH2Cl2/MeOH) m/z
336.0 [M – H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for
C15H1135ClNO2S2 [M – H]– 335.9920; found 335.9927. UHPLC:
–
3-(4-Chlorophenyl)-4-cyano-5-(pyrrolidin-1-yl)thiophene-2-carbox-
ylic Acid (20a): According to method A for saponification of ester
20 (55.4 mg, 0.154 mmol), acid 20a (35.8 mg, 70%) was obtained
as a white solid; m.p. 200 °C. 1H NMR (500 MHz, CDCl3): δ =
2.97 min, 98% (System 1); 3.52 min, 98% (System 2).
5-(tert-Butylthio)-3-(4-cholorophenyl)-4-cyanothiophene-2-carbox-
ylic Acid (6a): According to method A for saponification of ester
Eur. J. Org. Chem. 2011, 3920–3931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3929

S. Lethu, J. Dubois
FULL PAPER
7.38 (m, 4 H, Har), 3.69 (m, 4 H, NCH2 ), 2.14 (m, 4 H,
CH2Cl2/MeOH): m/z = 327.0 [M – H]–. HRMS (ESI–, CH2Cl2/
CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.3, 162.2, MeOH) calcd. for C16H835ClN2O2S– [M – H]– 326.9995; found
149.9, 134.8, 134.0, 132.1, 128.7, 117.5, 110.9, 87.8, 52.7, 26.5 ppm.
326.9991. UHPLC: 2.82 min, 98% (System 1); 3.43 min, 98% (Sys-
tem 2).
IR (film): ν = 2958, 2923, 2871, 2534, 2206, 1641, 1510, 1295 cm–1.
˜
MS (ESI–, CH2Cl2/MeOH): m/z = 331.0 [M – H]–. HRMS (ESI–,
CH2Cl2/MeOH) calcd. for C16H1235ClN2O2S– [M – H]– 331.0308;
found 331.0306 and calcd. for C16H1237ClN2O2S– [M – H]–
333.0279; found 333.0311. UHPLC: 2.66 min, 99 % (System 1);
3.25 min, 99% (System 2).
3-(4-Chlorophenyl)-4-cyano-5-(1H-imidazol-1-yl)thiophene-2-carb-
oxylic Acid (29a): According to method B for saponification of
ester 29 (13.6 mg, 0.038 mmol), acid 29a (6.9 mg, 55%) was ob-
tained as a white solid; m.p. 214 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.10 (s, 1 H, H2-imidazole), 7.54 (s, 1 H, H5-imidazol), 7.43
3-(4-Chlorophenyl)-4-cyano-5-(piperidin-1-yl)thiophene-2-carboxylic
Acid (21a): According to method A for saponification of ester 21
(30.0 mg, 0.080 mmol), acid 21a (25.3 mg, 91%) was obtained as a
(m, 4 H, Har), 7.37 (s, 1 H, H4-imidazole) ppm. IR (film): ν =
˜
3147, 2922, 2422, 2226, 1704, 1501, 1091 cm–1. MS (ESI+, CH2Cl2/
MeOH): m/z = 330.0 [M + H]+. HRMS (ESI+, CH2Cl2/MeOH)
calcd. for C15H935ClN3O2S+ [M + H]+ 330.0104; found 330.0103.
UHPLC: 1.98 min, 87% (System 1); 2.68 min, 88% (System 2).
1
white solid. H NMR ([D6]acetone, 300 MHz): δ = 7.44 (m, 4 H,
Har), 3.71 (m, 2 H, NCH2), 1.82–1.68 (m, 6 H, CH2CH2) ppm. 13
C
NMR ([D6]acetone, 75 MHz): δ = 168.4, 162.1, 149.7, 134.9, 133.8,
3-(4-Chlorophenyl)-4-cyano-5-(1H-pyrazol-1-yl)thiophene-2-carbox-
ylic Acid (30a): According to method B for saponification of ester
30 (10.0 mg, 0.028 mmol), acid 30a (6.1 mg, 66%) was obtained as
132.1, 128.8, 116.9, 112.4, 90.9, 53.0, 26.0, 24.2 ppm. IR (film): ν
˜
= 2946, 2854, 2554, 2204, 1643, 1514, 1478, 1290, 1241, 1175, 1086,
1014, 915, 814 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z = 345.0 [M –
H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for C17H1435ClN2O2S–
[M – H]– 345.0465; found 345.0466.
1
a white solid; m.p. 254 °C. H NMR ([D6]acetone, 300 MHz): δ =
8.59 (d, J = 2.6 Hz, 1 H, H5-pyrazole), 7.79 (d, J = 1.7 Hz, 2 H,
H3-pyrazole), 7.55 (m, 4 H, Har), 6.74 (m, 1 H, H4-pyrazole) ppm.
IR (film): ν = 2913, 2630, 2223, 1690 cm–1. MS (ESI–, CH Cl /
3-(4-Chlorophenyl)-4-cyano-5-(4-methylpiperazin-1-yl)thiophene-2-
carboxylic Acid (22a): According to method A for saponification
of ester 22 (30.0 mg, 0.154 mmol), acid 22a (23.6 mg, 85%) was
obtained as a white solid; m.p. 211 °C. 1H NMR ([D6]acetone,
300 MHz): δ = 7.26 (m, 4 H, Har), 3.62 (m, 4 H, NCH2), 2.56 (m,
˜
2
2
MeOH): m/z = 328.0 [M – H]–. HRMS (ESI–, CH2Cl2/MeOH)
calcd. for C15H735ClN3O2S– [M – H]– 327.9948; found 327.9954.
UHPLC: 2.61 min, 100% (System 1).
3-(4-Chlorophenyl)-4-cyano-5-(1H-1,2,3-triazol-1-yl)thiophene-2-
carboxylic Acid (33a): According to method A for saponification
of ester 33 (26.6 mg, 0.074 mmol), acid 33a (22.8 mg, 93%) was
4 H, NCH ), 2.33 (s, 3 H, NCH ) ppm. IR (film): ν = 3465, 3359,
˜
2
3
2962, 2194, 1698 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z = 360.1
[ M – H ] – . H R M S ( E S I – , C H 2 C l 2 / M e O H ) c a l c d . fo r
C17H1535ClN3O2S– [M – H]– 360.0574; found 360.0578. UHPLC:
1.69 min, 100% (System 1); 2.19 min, 100% (System 2).
1
obtained as a white solid. H NMR ([D6]acetone, 300 MHz): δ =
8.67 (br. s, 1 H, H5-triazole), 7.91 (br. s, 1 H, H4-triazole), 7.47 (d,
J = 8.5 Hz, 2 H, Har), 7.43 (d, J = 8.5 Hz, 2 H, Har) ppm. 13C
NMR ([D6]acetone, 75 MHz): δ = 161.3, 136.1, 135.9, 132.3, 132.0,
3-(4-Chlorophenyl)-4-cyano-5-(diethylamino)thiophene-2-carboxylic
Acid (23a): According to method B for saponification of ester 23
(26.6 mg, 0.073 mmol), acid 23a (13.7 mg, 56%) was obtained as a
white solid; m.p. 158 °C. 1H NMR (500 MHz, CDCl3): δ = 7.37 (d,
J = 8.2 Hz, 2 H, Har), 7.29 (d, J = 8.2 Hz, 2 H, Har), 3.65 (q, J =
7.1 Hz, 4 H, NCH2), 1.34 (t, J = 7.1 Hz, 6 H, NCH2CH3), 1.14 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.1,
165.7, 152.3, 135.1, 131.9, 130.8, 128.4, 116.9, 108.9, 87.9, 48.7,
129.2, 128.9, 125.3, 113.4, ppm. IR (film): ν = 3170, 3150, 2921,
˜
2851, 2468, 2229, 1865, 1683, 1469, 1289, 1244, 1090, 1033, 1014,
822, 786, 764 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z = 329.0 [M –
H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for C14H635ClN4O2S–
[M – H]– 328.9900; found 328.9914. UHPLC: 2.32 min, 92% (Sys-
tem 1); 2.89 min, 92% (System 2).
4-(4-Chlorophenyl)-3-cyano-2,3Ј-bithiophene-5-carboxylic
Acid
13.0 ppm. IR (film): ν = 2973, 2930, 2540, 2200, 1643, 1520,
˜
1297 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z = 333.1 [M – H]–.
HRMS (ESI–, CH2Cl2/MeOH) calcd. for C17H1535ClN3O2S– [M –
H]– 333.0465; found 333.0466. UHPLC: 2.71 min, 92% (System 1);
3.27 min, 93% (System 2).
(34a): According to method B for saponification of ester 34
(15.7 mg, 0.042 mmol), acid 34a (14.7 mg, quantitative) was ob-
tained as a yellow solid; m.p. 213 °C. 1H NMR (500 MHz, CDCl3):
δ = 7.98 (br. s, 1 H, H thiophene), 7.44 (br. s, 1 H, H thiophene),
7.40 (br. s, 1 H, H thiophene), 7.31 (m, 4 H, Har) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.5, 135.7, 131.3, 131.0, 130.8, 128.8,
3-(4-Chlorophenyl)-4-cyano-5-(1H-1,2,4-triazol-1-yl)thiophene-2-
carboxylic Acid (27a): According to method B for saponification
of ester 27 (17.8 mg, 0.050 mmol), acid 27a (13.9 mg, 85%) was
obtained as a black solid; m.p. 192 °C. 1H NMR (500 MHz,
CDCl3): δ = 9.20 (s, 1 H, H5-triazole), 8.20 (s, 1 H, H3-triazole),
7.50 (d, J = 8.5 Hz, 2 H, Har), 7.42 (d, J = 8.5 Hz, 2 H, Har) ppm.
13C NMR (75 MHz, CDCl3): δ = 161.5, 153.3, 149.8, 147.0, 142.3,
128.0, 126.5, 115.1, 109.1, 100.2 ppm. IR (film): ν = 2922, 2571,
˜
2224, 1682, 1089, 781 cm–1. MS (ESI–, CH2Cl2/MeOH): m/z =
344.0 [M
–
H]–. HRMS (ESI–, CH2Cl2/MeOH) calcd. for
C16H835ClNO2S2 [M – H]– 343.9607; found 343.9610. UHPLC:
2.89 min, 96% (System 1); 3.49 min, 99% (System 2).
–
3-(4-Chlorophenyl)-4-cyano-5-phenylthiophene-2-carboxylic
Acid
136.1, 131.0, 129.9, 128.9, 128.6, 113.3, 101.4 ppm. IR (film): ν =
˜
3128, 2922, 2852, 2507, 2229, 1650, 1514, 1088, 664 cm–1. MS
(ESI–, CH2Cl2/MeOH): m/z = 329.0 [M – H]–. HRMS (ESI–,
CH2Cl2/MeOH) calcd. for C14H635ClN4O2S– [M – H]– 328.9900;
found 328.9915. UHPLC: 2.21 min, 87% (System 1); 2.86 min,
87% (System 2).
(35a): According to method A for saponification from ester 35
(19.9 mg, 0.054 mmol), acid 35a (6.7 mg, 36%) was obtained as a
white solid; m.p. 235 °C. 1H NMR ([D6]acetone, 300 MHz): δ =
7.90 (m, 2 H, Har), 7.65–7.50 (m, 7 H, Har) ppm. IR (film): ν =
˜
2923, 2228, 1737, 1487, 1142, 755 cm–1. MS (ESI–, CH2Cl2/
MeOH): m/z = 338.0 [M – H]–. HRMS (ESI–, CH2Cl2/MeOH)
calcd. for C18H935ClNO2S– [M – H]– 338.0043; found 338.0045.
UHPLC: 2.92 min, 95% (System 1); 3.50 min, 95% (System 2).
3-(4-Chlorophenyl)-4-cyano-5-(1H-pyrrol-1-yl)thiophene-2-carbox-
ylic Acid (28a): According to method B for saponification of ester
28 (5.1 mg, 0.014 mmol), acid 28a (4.7 mg, quantitative) was ob-
tained as a white solid. 1H NMR ([D6]acetone, 300 MHz): δ =
7.50–7.00 (m, 6 H, Har and N=CH), 6.37 (m, 2 H, =CH) ppm. IR
FTase Assay: Assays were performed using 96-well plates, prepared
with Biomek NKMC and Biomek 3000 from Beckman Coulter and
read using a Wallac Victor fluorimeter from Perkin–Elmer. For
(film): ν = 2922, 2852, 2223, 1503, 1369, 719 cm–1. MS (ESI–,
˜
3930
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3920–3931

Synthesis of Thiophene-Based Protein Farnesyltransferase Inhibitors
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each well 20 μL of farnesyl pyrophosphate (10 μm) was added to
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composed of 0.2 mL of partially purified recombinant yeast FTase
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Acknowledgments
We gratefully thank Dr. J. Ouazzani and P. Lopez for production
and purification of recombinant yeast FTase, O. Thoison and her
team for UHPLC analyses, M.-F. Bricot for elemental analyses as
well as the Institut de Chimie des Substances Naturelles and the
Centre National de la Recherche Scientifique for providing finan-
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Received: February 17, 2011
Published Online: May 13, 2011
Eur. J. Org. Chem. 2011, 3920–3931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3931