Reactions of heteroaryl substituted propenones

Article abstract of DOI:10.1007/s00706-004-0265-8

Thienyl- and furylpropenones reacted with malonates, cyanoacetates, and malononitrile giving addition products which could be cyclized to heteroaryl substituted dihydropyranes, cyclohexanols, and piperidones. Heteroaryl substituted cyclopropyl ketones were prepared by reactions with Me ₃SO⁺ I^-, and by reaction with Lewis acids they were transformed into substituted dihydrobenzo[b]furanone or -thiophenone, or γ-hydroxy ketones. Cycloadditions with thiophene derivatives allowed the synthesis of substituted benzo[b]thiophene derivatives, but with poor yields. Structures and stereochemistry were established mainly by means of NMR spectroscopy. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-004-0265-8

Monatshefte f€ur Chemie 136, 635–653 (2005)
DOI 10.1007/s00706-004-0265-8
Reactions of Heteroaryl Substituted
ꢀ
Propenones
#
Lutz Greiner-Bechert, Thomas Sprang, and Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry, Institute of Pharmacy,
University of Greifswald, D-17487 Greifswald, Germany
Received August 19, 2004; accepted September 14, 2004
Published online January 18, 2005 # Springer-Verlag 2005
Summary. Thienyl- and furylpropenones reacted with malonates, cyanoacetates, and malononitrile
giving addition products which could be cyclized to heteroaryl substituted dihydropyranes, cyclohex-
anols, and piperidones. Heteroaryl substituted cyclopropyl ketones were prepared by reactions with
Me3SOþ Iꢁ, and by reaction with Lewis acids they were transformed into substituted dihydroben-
zo[b]furanone or -thiophenone, or ꢀ-hydroxy ketones. Cycloadditions with thiophene derivatives
allowed the synthesis of substituted benzo[b]thiophene derivatives, but with poor yields. Structures
and stereochemistry were established mainly by means of NMR spectroscopy.
Keywords. Benzo[b]thiophene; Cyclopropyl ketone; Michael addition; Thienyl propenone.
Introduction
Substituted propenones are long known typical Michael acceptors, and the adducts
allow a wide range of reactions depending on their substituents [1]. We have de-
scribed the synthesis of 1,3-diaryl and heteroaryl substituted propenones, and their
reaction with malononitrile opening an effective route to 4,6-diaryl=heteroaryl sub-
stituted pyridine-2-carbonitriles [2]. To explore further possibilities of using these
propenones in (drug) synthesis, we here report about their reactions with activated
methylene compounds, about their transformation into cyclopropyl ketones, and
about some transformations of these ketones [3].
Results and Discussion
The furylthienylpropenone 1g [4], and the thienylphenylpropenone 2d [5] re-
acted with dimethyl malonate in the presence of LDA at ꢁ78ꢂ yielding the oxo-
valerates 3a and 3b in satisfactory yields up to 83%. These adducts may be used as
ꢀ
Dedicated to Prof. F. Sauter, Vienna, with cordial thanks for many valuable advices
#
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

636
L. Greiner-Bechert et al.
Scheme 1
building blocks for the synthesis of heterocyclic substituted dihydropyrane deriv-
atives [3]. By cyclization under reductive conditions we obtained from 4e [3] or
from 3a the dihydropyrane derivative 5a, whereas 5b was obtained from the
bromothienyl propenone 6c via the addition product 7c by an analogous procedure
(Scheme 1).
Starting from 2-acetyl-3-bromothiophene (8) [6] or 2-acetyl-3-chlorothiophene
(10) [7] we prepared by basic condensation (NaOH, MeOH) with appropriate
aldehydes the parent thienylpropenones 6 and 11. These were excellent substrates
for the addition of malononitrile, which was best done by reaction in DMSO in the
presence of NaH at room temperature. Thereby, from 6a–6c and 6f the compounds
7a–7d, and from 11b compound 12 were obtained with yields of 60–90%. The
adducts 9a and 9b were accessible with yields of 60–80% by an analogous reaction
with methyl cyanoacetate.
A remarkable observation was the formation of the compounds 13a–13e. Com-
pound 13a was formed as a by-product, yield 10%, in the reaction between 2a and
methyl cyanoacetate, ratio 1:1, with Na in MeOH, reflux for 1 h, and acidic
workup. Higher yields, and the analogous products were obtained from reactions
between two equivalents of the propenone and one equivalent of malononitrile or

Heteroaryl Substituted Propenones
637
Scheme 2
methyl cyanoacetate (Scheme 2). Thus, the reaction between 11f and malononi-
trile, ratio 2:1, gave 13e with more than 70% yield when performed at room
temperature in EtOH with some drops of piperidine. Elemental analyses and spec-
troscopic data established the structure with equatorial orientation of the aromatic
groups and the acyl group. The stereochemistry of compounds 13 was deduced
1
from the H NMR data showing that the substituents in positions 2, 3, and 6 are
orientated in the equatorial positions. The following coupling constants were found
in the spectrum of 13b. The coupling between 2-H and 3-H was J ¼ 12 Hz, that
between 5-Hax and O–H J ¼ 2 Hz, that between 5-Hax and 6-H J ¼ 14 Hz, and that
between 5-Heq and 6-H J ¼ 3 Hz.
Similar reactions were described as sequences of nucleophilic additions [8], but
the formation of 13 cannot be explained as a double Michael addition as known
from reactions between malononitrile and 1,4-pentadiene-3-ones [9] or as a sequen-
tial Michael addition. Instead, structure 13 was formed by a sequence, whereby
first two Michael additions of one reactive methylene group to two molecules of

638
L. Greiner-Bechert et al.
Scheme 3
the propenone occurred followed by an intramolecular aldol addition between one
methylene group and one carbonyl group [10].
Another unusual cyclization was observed when we tried to reduce the prope-
nones 14 [11] and 7b with NaBH4 in EtOH to the corresponding alcohols. Instead
of the alcohols, we isolated the crystalline piperidone derivatives 15a and 15b with
yields of 90% and higher (Scheme 3). Their IR spectra showed an amide I band at
1630 cmꢁ1, and an N–H band around 3300 cmꢁ1. Whereas the nitrile groups in the
spectra of 14 and 7b caused a weak band at 2250–2260 cmꢁ1, the spectra of
compounds 15 exhibited a strong nitrile band at 2000 cmꢁ1. The piperidone struc-
1
ture was further established by the H NMR data. The data of 15a obtained from
spectra in CDCl3 and DMSO-d6 showed that this compound was isolated as a
mixture of two diastereoisomers with a ratio of 7:3. The coupling constants in
the spectra of the major isomer (I) suggest all substituents in equatorial positions,
whereas in the minor isomer (II) the phenyl group at C-4 was detected in the axial
position. The signals at ꢁ ¼ 4.50 and 4.55 ppm (CDCl3) or ꢁ ¼ 6.45 and 6.55 ppm
(DMSO-d6) disappeared after addition of D2O demonstrating that these signals
were caused by the acidic protons 1-H and 3-H. The formation of 15 might be
explained by a reaction sequence starting with the reduction of the carbonyl group,
followed by the addition of the newly formed hydroxyl group to one nitrile group
with formation of a (not isolated) iminodihydropyrane which was finally trans-
formed into the ꢁ-lactam by a Dimroth rearrangement [12].
Similar to the addition of cyano derivatives, the addition of nitromethane was
successful. Thus, the !-nitro ketones 16a, 16b, and 16c were prepared via reaction
of 1a, 2b, and 2d with nitromethane in the presence of Na in MeOH with yields of
60–66%. An alternative route was demonstrated by the reaction of 2-acetylthiophene

Heteroaryl Substituted Propenones
639
Scheme 4
(18) with the nitro olefin 17 and MeONa giving 16b with 68% yield. The liquid
compounds 16d, 16e, and 16f were obtained by the analogous reaction of the
3-bromothienyl substituted propenones 6a, 6b, and 6c with yields of 70–84%
(Scheme 4).
Another possibility to use the propenones for further transformations was
opened by their reaction with sulfur ylides yielding substituted cyclopropanes
[13]. We used trimethylsulfoxonium iodide (19), as all reactions conveniently
could be done at room temperature in DMSO in the presence of NaH, and we
isolated from all reactions the cyclopropyl ketones with satisfactory to good yields.
The furan derivatives 20a–20h were obtained as waxy crystals with yields of
78–95%, whereas the analogue thiophene derivatives 23a–23h were isolated as col-
orless to light yellow crystals with yields of 70–93%, and the halogeno substituted
derivatives 26b–26d and 27a–27c were isolated as crystalline compounds with
good yields, too. Only 26a was obtained as a light liquid with 83% yield. The
IR spectra of these cyclopropyl ketones were characterized by bands around 3100
(H–Ccyclopropyl), 1630 (C¼O), 1010 (C–C3-ring), and about 950 cmꢁ1. The last one
was found in the same area as the band of trans substituted, conjugated double
bonds, and therefore, could be used as an indicator for the trans substitution of the
1
3-membered ring. This was in agreement with the H NMR data showing an
ABCD system from the protons of the cyclopropyl moiety. Values from compound
20b are ꢁ ¼ 2.75 ppm (1-H, D), ꢁ ¼ 2.65 ppm (2-H, C), ꢁ ¼ 1.80 ppm (3-H, B),
and ꢁ ¼ 1.40 ppm (30-H, A) with coupling constants JAB ¼ 4 Hz, JAC ¼ 6.5 Hz,
JBC ¼ 10 Hz, JAD ¼ 8 Hz, and JBD ¼ 5 Hz. These values are in agreement with
the 1,2-trans orientation at the cyclopropane ring.
4-Aryltetralones can be prepared via intramolecular Friedel-Crafts cyclization
of substituted benzoyl aryl ketones with SnCl4 in benzene [14]. To prove if this
cyclization is possible even with our heteroaryl substituted cyclopropyl ketones we
studied some reactions with Lewis acids. When the furan derivative 20c or the
thiophene derivative 23c were reacted with SnCl4 in C6H6 at room temperature,
we isolated after acidic workup (HCl) the [b]annelated cyclohexenones 21 and 24
with yields of 94 (21) and 54% (24) after chromatographic work-up. But when the
same reaction with SnCl4 or AlCl3 was done and worked-up under basic conditions
(aq. NaOH), we isolated from the reactions of 20g, 23a, and 23c the hydroxy

640
L. Greiner-Bechert et al.
Scheme 5
compounds 22, 25a, and 25b with yields of 40–70%, probably formed by a nucleo-
philic reaction between the base and C-2 of the cyclopropane ring, activated as
complexed by the Lewis acid (Scheme 5).
The structures of the annelated ketones 21 and 24 and of the ꢀ-hydroxy ketones
22 and 25 were established by spectroscopic data, from which the shift of the
carbonyl bands in their IR spectra was significant. In the spectra of the cyclopropyl

Heteroaryl Substituted Propenones
641
ketones 20c, 23a, and 23c this band was found at 1640 (20c) and 1625 cmꢁ1 (23a,
23c), whereas the annelated cyclohexenones 21 and 24 showed the carbonyl band
shifted to 1675 and 1655 cmꢁ1. In the spectra of the ꢀ-hydroxy ketones an intensive
hydroxy band at 3400–3450 cmꢁ1 and the carbonyl band at 1655 (22), 1650 (25b),
and at 1635 cmꢁ1 (25a) were found. Furthermore, the data from 1H and 13C NMR
spectra were in full agreement with the postulated structures.
Another way to thieno annelated cyclohexenones should be the Diels-Alder
reaction between an appropriate derivative of thiophene and a dienophile. There-
fore, we prepared 2-(1-trimethylsiloxyvinyl)thiophene (28) [15] from 2-acetylthio-
phene and ClSiMe3 in THF with LDA. When we performed the synthesis as
described, we isolated 28 only in poor yields. But by strictly working at 0ꢂC,
and completing the synthesis within 20–30 minutes, we could improve the yield
to 93%. It is known that the furan analogous compounds of 28 behave as suitable
dienes for Diels-Alder reactions [16], and that vinylthiophene and derivatives
usually are less reactive. Nevertheless, we checked reactions of 28 with activated
double bonds (Scheme 6). Although we tried many different reaction conditions,
solvents, and catalysts, we obtained only from three reactions defined compounds.
From most other reactions, only 2-acetylthiophene and the dienophile were iso-
lated. Thus, the reaction between 28 and N-phenylmaleinimide in CH2Cl2 in a
sealed tube at 80ꢂC for 24 h yielded the adduct 29 with yields about 17%. Using
the acrylonitrile 30 or the nitroolefine 31 under similar conditions the yields were
Scheme 6

642
L. Greiner-Bechert et al.
significantly lower. The annelated products 32 and 33 were isolated only with
yields of 4–5%. A higher yield was obtained from the reaction between the thio-
phene derivative 34 and TCNE, whereby we obtained the benzyl substituted bicycle
1
35. The structures of compounds 29, 32, 33, and 35 were deduced from H NMR
data. The reaction of 34 forming 35 was remarkable, as it included in the first step a
thermal isomerization of 34 to the substituted vinyl derivative (not isolated), which
underwent the cycloaddition to 35.
Experimental
€
Melting points: Linstrom apparatus (uncorrected); IR spectra (KBr): Perkin-Elmer IR 841, IR 1310,
Beckmann IR 4240; NMR spectra: 1H: Varian T 60 (60 MHz), Bruker WP 80 (80 MHz), 13C: Bruker
WH 90 (22.63MHz), room temperature, internal TMS, CDCl3, values from 80MHz spectra, CDCl3, if
not otherwise noted; elemental analyses: Pharmazeutisches Institut, University of Freiburg or Pharma-
zeutisches Institut, University of Greifswald; the results agreed with the calculated values within
experimental error. Column chromatography (CC) with silica gel 60 Merck Nr. 7734. Lithium diiso-
propylamide (LDA) was freshly prepared by mixing of equimolar amounts of diisopropylamine in THF
and n-butyl lithium (BuLi, 1.6 M in n-hexane) at ꢁ78ꢂC. Abbreviations: ar ¼ aromatic. For the
syntheses of propenones 1 and 2 see Ref. [2], for 1-(2-furyl)-3-(2-thienyl)-2-propen-1-one (1g) see
Ref. [4], for 3-(3,4-dimethoxyphenyl)-1-(2-thienyl)-2-propen-1-one (2d) see Ref. [5], for 2-cyano-5-(2-
furyl)-5-oxo-3-(2-thienyl)valeronitrile (4e), 2-acetyl-3-bromothiophene (8), 1-(3-bromo-2-thienyl)-
3-(4-chlorophenyl)-2-propen-1-one (6b), 2-acetyl-3-chlorothiophene (10), 3-(4-chlorophenyl)-1-(3-
chloro-2-thienyl)-2-propen-1-one (11b), and 2-cyano-5-oxo-3-phenyl-5-(2-thienyl)valeronitrile (14)
see Ref. [2], for 2-(4-chlorophenyl)-1-nitroethene (17), and 2-cyano-3-phenylacrylonitrile (30) see
Ref. [17], and for 1-phenyl-2-(3-thienyl)propene (34) see Ref. [18]. Trimethylsulfoxonium iodide
(19) was purchased from Janssen (Nr. 14.026.58), and 1-nitro-2-phenylethene (31) from Merck
Schuchardt (Nr. 818165).
Methyl (RS)-5-(2-Furyl)-2-methoxycarbonyl-5-oxo-3-(2-thienyl)valerate (3a, C16H16O6S)
Dimethyl malonate (1.32 g, 11 mmol) was added at room temperature to a solution of 0.25g of Na
(11 mmol) in 50 cm3 of Et2O with stirring, a solution of 2.04g of 1g (10 mmol) in Et2O was added, the
mixture was refluxed for 1 h, cooled, hydrolyzed with dil. HCl, extracted 3ꢃ with Et2O, the organic
layer was dried (Na2SO4), and evaporated. Yield 2.8g (83%); colorless crystals; mp 69ꢂC (MeOH); IR:
ꢂꢀ¼ 2950 (CH), 1730, 1665 (CO), 1560 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 3.40 (d, J ¼ 7 Hz, CH2), 3.60
(s, OMe), 3.75 (s, OMe), 3.90 (d, J ¼ 8 Hz, 2-H), 4.50 (dd, J ¼ 7, 8 Hz, 3-H), 6.45 (m, 1H, 4-Hfuryl),
6.75–7.60 (m, 5 ar H) ppm.
Methyl (RS)-3-(3,4-Dimethoxyphenyl)-2-methoxycarbonyl-5-oxo-5-(2-thienyl)valerate
(3b, C20H22O7S)
From dimethyl malonate (3.2g, 20mmol) and 2.75g of 2d (10 mmol) as 3a. Yield 2.2g (55%);
1
colorless crystals; mp 88ꢂC (MeOH); IR: ꢂꢀ¼ 1735, 1650 (CO), 1130, 860 (ar) cmꢁ1; H NMR:
ꢁ ¼ 3.25–4.20 (m, 16H, OMe, aliphat. H), 6.70–7.75 (m, 6 ar H) ppm.
(RS)-2-(2-Furyl)-4-(2-thienyl)-4H-5,6-dihydropyrane (5a, C13H12O2S)
KOH (1.4g, 25 mmol) was dissolved in 20cm3 of ethyleneglycol. Compound 4e (1.35 g, 5 mmol) (a),
or 1.68 g of 3a (5mmol) (b) and 1.0 g of hydrazine hydrate (98%, 20mmol) were added with stirring.

Heteroaryl Substituted Propenones
643
Then the mixture was refluxed for 2 h. The following azeotropic distillation was finished at 180ꢂC, the
residue was poured into ice-H2O, acidified with conc. HCl, and several times extracted with Et2O. The
combined organic layers were dried (MgSO4), and evaporated in vacuo. The residue was purified
by CC (Et2O=n-pentane 1=1). Yield a) 0.87g (75%), b) 0.84g (72%); colorless liquid; IR (film):
ꢂꢀ¼ 3105, 3075, 3000 (CH), 1600 (enolether), 845 (C¼C) cmꢁ1; 1H NMR: ꢁ ¼ 1.40 (m, 3H, CH), 2.30
(m, 2H, CH), 5.75–7.35 (m, 7 ar H) ppm.
(RS)-2-(3-Bromo-2-thienyl)-4-(4-methoxyphenyl)-4H-5,6-dihydropyrane (5b, C16H15BrO2S)
From 7c (1.95 g, 5 mmol) as described for 5a. Yield 1.2 g (68%); colorless liquid; IR (film): ꢂꢀ¼ 2930
1
(CH), 1610, 860 (ar), 820 (C¼C) cmꢁ1; H NMR: ꢁ ¼ 1.15–2.85 (m, 5H, CH), 3.75 (s, OMe),
6.20–7.80 (m, 7 ar H) ppm.
General Procedure for the Synthesis of 3-Bromothienylpropenones 6
Compound 8 (10 mmol) and an equimolar amount of the aldehyde were dissolved with stirring in
20cm3 of MeOH, then some pellets of NaOH were added, and stirring was continued for 2 h. The
precipitate was separated and purified by recrystallization.
1-(3-Bromo-2-thienyl)-3-phenyl-2-propen-1-one (6a, C13H9BrOS)
From 8 (2.04 g, 10 mmol) and 1.05g of benzaldehyde (10 mmol). Yield 2.5 g (85%); colorless crystals;
1
mp 42ꢂC (MeOH); IR: ꢂꢀ¼ 1640 (CO), 1590 (ar), 975 (trans C¼C), 760, 705 (ar) cmꢁ1; H NMR
(60 MHz): ꢁ ¼ 7.30–8.15 (m, 9 ar H) ppm.
1-(3-Bromo-2-thienyl)-3-(4-methoxyphenyl)-2-propen-1-one (6c, C14H11BrO2S)
From 8 (2.04 g, 10 mmol) and 1.36 g of 4-methoxybenzaldehyde (10 mmol), 1 h reflux. Yield 2.8 g
(86%); yellow crystals; mp 73ꢂC (MeOH); IR: ꢂꢀ¼ 1635 (CO), 1580 (ar), 1260, 980 (trans C¼C), 820
1
(ar) cmꢁ1; H NMR (60 MHz): ꢁ ¼ 3.95 (s, OMe), 7.25–8.00 (m, 8 ar H) ppm.
1-(3-Bromo-2-thienyl)-3-(3,4-dimethoxyphenyl)-2-propen-1-one (6d, C15H13BrO3S)
From 8 (2.04 g, 10mmol) and 1.60g of 3,4-dimethoxybenzaldehyde (10 mmol). Yield 2.75 g (78%);
yellow crystals; mp 110ꢂC (MeOH); IR: ꢂꢀ¼ 1635 (CO), 1580 (ar), 970 (trans C¼C), 835 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 3.95 (s, 2 OMe), 7.25–7.60 (m, 5 ar H), 7.55, 7.85 (AB, J ¼ 15Hz, 7-H, 8-H) ppm;
1H NMR (benzene-d6): ꢁ ¼ 3.30 (s, OMe), 3.40 (s, OMe), 6.35–7.15 (m, 5 ar H), 7.65, 8.05
(AB, J ¼ 15Hz, 7-H, 8-H) ppm.
1-(3-Bromo-2-thienyl)-3-(4-dimethylaminophenyl)-2-propen-1-one (6e, C15H14BrNOS)
From 8 (2.04 g, 10mmol) and 1.49 g of 4-dimethylaminobenzaldehyde (10 mmol). Yield 3.0 g (85%);
red crystals; mp 92ꢂC (MeOH); IR: ꢂꢀ¼ 1625 (CO), 1610 (ar), 980 (trans C¼C), 875 (ar) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 3.10 (s, 2 Me), 6.65–7.85 (m, 8 ar H) ppm.
1-(3-Bromo-2-thienyl)-3-(4-nitrophenyl)-2-propen-1-one (6f, C13H8BrNO3S)
From 8 (2.04 g, 10mmol) and 1.51 g of 4-nitrobenzaldehyde (10 mmol). Yield 3.1 g (92%); light
yellow crystals; mp 128ꢂC (MeOH); IR: ꢂꢀ¼ 1645 (CO), 1605 (ar), 1510, 1340 (NO2), 840 (ar) cmꢁ1
.

644
L. Greiner-Bechert et al.
1-(3-Bromo-2-thienyl)-3-(2-thienyl)-2-propen-1-one (6g, C11H7BrOS2)
From 8 (2.04 g, 10 mmol) and 1.12g of thiophene-2-carbaldehyde (10 mmol, freshly distilled). Yield
2.2 g (75%); yellow crystals; mp 58ꢂC (MeOH); IR: ꢂꢀ¼ 1630 (CO), 1580 (ar), 980 (trans C¼C) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 7.30–8.45 (m, 7 ar H) ppm.
1-(3-Bromo-2-thienyl)-5-phenylpenta-2,4-dien-1-one (6i, C15H11BrOS)
From 8 (2.04 g, 10 mmol) and 1.30 g of cinnamaldehyde (10 mmol). Yield 2.75g (78%); yellow
crystals; mp 93ꢂC (MeOH); IR: ꢂꢀ¼ 1630 (CO), 1565 (ar), 990 (trans C¼C), 735, 680 (ar) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 7.05–7.95 (m, 11 ar H) ppm.
5-(3-Bromo-2-thienyl)-2-cyano-5-oxo-3-phenylvaleronitrile (7a, C16H11BrN2OS)
At room temperature and with stirring 0.12 g of NaH (5mmol) were added to a solution of 0.7 g of
malononitrile (11 mmol) in 10 cm3 of DMSO, then 2.94 g of 6a (10 mmol) dissolved in 10cm3 of
DMSO were dropwise added over 15 min. The mixture was stirred for 2 h, poured into 50cm3 of ice-
H2O, neutralized with dil. HCl, extracted with 3ꢃ30 cm3 of CHCl3, the combined organic layers were
dried (MgSO4), and evaporated in vacuo. Yield 2.9g (82%); colorless crystals; mp 105ꢂC (MeOH); IR:
ꢂꢀ¼ 2900 (CH), 2250 (CN), 1660 (CO) cmꢁ1; 1H NMR: ꢁ ¼ 3.60 (d, J ¼ 6 Hz, 2H, 4-H), 4.00 (m, 3-H),
4.65 (d, J ¼ 5 Hz, 2-H), 7.00–8.00 (m, 7 ar H) ppm; 13C NMR: ꢁ ¼ 28.89 (C-2), 40.17 (C-4), 41.41
(C-3), 111.97 (CN), 124.41 (C-3thienyl), 127.97, 129.97 (ar C), 131.71 (C-4thienyl), 133.02 (C-5thienyl),
136.33 (C-1phenyl), 144.42 (C-2thienyl), 188.24 (CO) ppm.
5-(3-Bromo-2-thienyl)-3-(4-chlorophenyl)-2-cyano-5-oxovaleronitrile (7b, C16H10BrClN2OS)
From 6b (3.28 g, 10 mmol) and 0.7g of malononitrile (11 mmol) as 7a, extraction with Et2O. Yield
3.5 g (90%); yellow crystals; mp 110ꢂC (Et2O); IR: ꢂꢀ¼ 2900 (CH), 2250 (CN), 1650 (CO), 830 (ar)
1
cmꢁ1; H NMR: ꢁ ¼ 3.30–4.20 (m, 3H, CH), 4.55 (d, J ¼ 4.5 Hz, 2-H), 6.90–7.95 (m, 6 ar H) ppm.
5-(3-Bromo-2-thienyl)-2-cyano-3-(4-methoxyphenyl)-5-oxovaleronitrile (7c, C17H13BrN2O2S)
From 6c (3.24 g, 10 mmol) and 0.7 g of malononitrile (11 mmol) as 7a, extraction with CH2Cl2.
Purification by CC (Et2O=n-hexane 2=1). Yield 2.7 g (69%); yellow-orange liquid; IR (film):
1
ꢂꢀ¼ 2900 (CH), 2210 (CN), 1650 (CO) 830 (ar) cmꢁ1; H NMR (60 MHz): ꢁ ¼ 3.30–4.20 (m, 3H,
CH), 3.80 (s, OMe), 4.55 (d, 2-H), 6.90–7.95 (m, 6 ar H) ppm.
5-(3-Bromo-2-thienyl)-2-cyano-3-(4-nitrophenyl)-5-oxovaleronitrile (7d, C16H10BrN3O3S)
From 6f (3.40 g, 10 mmol) and 0.7g of malononitrile (11 mmol) as 7a. Yield 2.5 g (63%); colorless
crystals; mp 104ꢂC (AcOH=H2O 2=1); IR: ꢂꢀ¼ 2900 (CH), 2250 (CN), 1650 (CO), 1515, 1350 (NO2),
1
850 (ar) cmꢁ1; H NMR: ꢁ ¼ 3.55 (m, 2H, 4-H), 3.75 (m, 3-H), 4.55 (d, J ¼ 5 Hz, 2-H), 6.90–7.75
(m, 6 ar H) ppm.
Methyl 5-(3-bromo-2-thienyl)-2-cyano-5-oxo-3-phenylvalerate (9a, C17H14BrNO3S)
Methyl cyanoacetate (5.0 g, 50mmol) was added at room temperature to a solution of 0.25 g of Na
(11 mmol) in 10cm3 of MeOH with stirring, a solution of 2.94 g of 6a (10mmol) in MeOH was added,
the mixture was stirred at room temperature for 3 h, hydrolyzed with dil. HCl, and concentrated invacuo.
H2O (30 cm3) was added to the residue, the mixture was extracted with 3ꢃ20cm3 of CHCl3, the organic
layer was dried (Na2SO4), and evaporated. Purification by CC (Et2O=n-hexane 2=1). Yield 2.4g (58%);

Heteroaryl Substituted Propenones
645
colorless crystals; mp 87ꢂC (MeOH); IR: ꢂꢀ¼ 3100 (CH), 2220, 2210 (CN), 1745, 1655 (CO), 1600,
875 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 3.25–4.40 (m, 7H, Me, CH2, CH, CH), 7.00–7.55 (m, 7 ar H)
ppm.
Methyl 5-(3-bromo-2-thienyl)-3-(4-chlorophenyl)-2-cyano-5-oxovalerate (9b, C17H13BrClNO3S)
From 6b (3.27 g, 10mmol) as described for 9a, 1 h stirring. Yield 6.9 g (81%); colorless crystals; mp
1
93ꢂC (MeOH); IR: ꢂꢀ¼ 2950 (CH), 2250 (CN), 1750, 1655 (CO), 875 (ar) cmꢁ1; H NMR: ꢁ ¼
3.25–4.40 (m, 7H, Me, CH2, CH, CH), 6.90–7.70 (m, 6 ar H) ppm.
General Procedure for the Synthesis of 3-Chlorothienylpropenones 11
Compound 10 (10 mmol) and an equimolar amount of the aldehyde were dissolved with stirring in
20cm3 of MeOH, then some pellets of NaOH were added, and stirring was continued for 2 h. The
precipitate was separated and purified by recrystallization.
1-(3-Chloro-2-thienyl)-3-phenyl-2-propen-1-one (11a, C13H9ClOS)
From 10 (1.61 g, 10mmol) and 1.05 g of benzaldehyde (10 mmol). Yield 2.0 g (82%); colorless
crystals; mp 58ꢂC (MeOH); IR: ꢂꢀ¼ 1635 (CO), 1585 (ar), 980 (trans C¼C), 760, 700 (ar) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 7.25–8.10 (m, 9 ar H) ppm.
1-(3-Chloro-2-thienyl)-3-(4-methoxyphenyl)-2-propen-1-one (11c, C14H11ClO2S)
From 10 (1.61 g, 10 mmol) and 1.37 g of 4-methoxybenzaldehyde (10 mmol). Yield 2.45g (88%);
yellow crystals; mp 82ꢂC (MeOH); IR: ꢂꢀ¼ 1640 (CO), 1585 (ar), 985 (trans C¼C), 825 (ar) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 3.90 (s, OMe), 7.05–8.30 (m, 8 ar H) ppm.
1-(3-Chloro-2-thienyl)-3-(3,4-dimethoxyphenyl)-2-propen-1-one (11d, C15H13ClO3S)
From 10 (1.61 g, 10 mmol) and 1.60 g of 3,4-dimethoxybenzaldehyde (10 mmol). Yield 2.50g (81%);
yellow crystals; mp 125ꢂC (MeOH); IR: ꢂꢀ¼ 1635 (CO), 1575 (ar), 970 (trans C¼C), 835 (ar) cmꢁ1
;
1H NMR (60 MHz): ꢁ ¼ 3.95 (s, 2 OMe), 7.25–8.00 (m, 7 ar H) ppm.
1-(3-Chloro-2-thienyl)-3-(4-nitrophenyl)-2-propen-1-one (11e, C13H8ClNO3S)
From 10 (1.61 g, 10 mmol) and 1.51 g of 4-nitrobenzaldehyde (10 mmol). Yield 2.5 g (85%); light
yellow crystals; mp 148ꢂC (MeOH); IR: ꢂꢀ¼ 1640 (CO), 1580 (ar), 1510, 1340 (NO2), 980 (trans
1
C¼C), 840 (ar) cmꢁ1; H NMR (60 MHz): ꢁ ¼ 7.10–8.50 (m, 8 ar H) ppm.
1-(3-Chloro-2-thienyl)-3-(2-thienyl)-2-propen-1-one (11f, C11H7ClOS)
From 10 (1.61 g, 10mmol) and 1.12 g of thiophene-2-carbaldehyde (10 mmol). Yield 1.9 g (87%);
1
yellow crystals; mp 74ꢂC (MeOH); IR: ꢂꢀ¼ 1630 (CO), 1580 (ar), 990 (trans C¼C) cmꢁ1; H NMR
(60 MHz): ꢁ ¼ 7.00–8.15 (m, 7 ar H) ppm.
3-(4-Chlorophenyl)-1-(3-chloro-2-thienyl)-2-cyano-5-oxovaleronitrile (12, C16H10Cl2N2OS)
From 11b (2.83 g, 10 mmol) and 0.7 g malononitrile (11 mmol) as described for 7a, extraction
with Et2O. Yield 2.5 g (72%); yellow crystals; mp 195ꢂC (CCl4); IR: ꢂꢀ¼ 2250 (CN), 1650 (CO),

646
L. Greiner-Bechert et al.
830 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 3.65 (d, J ¼ 6 Hz, CH2), 3.95 (m, 3-H), 4.55 (d, J ¼ 5 Hz, 2-H),
6.70–7.75 (m, 6 ar H) ppm.
Methyl 1-cyano-2,6-diphenyl-4-hydroxy-3-thienoyl-4-(2-thienyl)cyclohexane-1-
carboxylate (13a, C17H15NO3S)
As a by-product of the synthesis of methyl 2-cyano-5-oxo-3-phenyl-5-(2-thienyl)valerate [2], isolated
from the mother liquor. Yield 0.3 g (10%); colorless crystals; mp 148ꢂC (MeOH); IR: ꢂꢀ¼ 3400 (OH),
2220 (CN), 1740, 1630 (CO), 750, 700 (ar) cmꢁ1; 1H NMR (200MHz): ꢁ ¼ 2.40 (dd, J ¼ 3.5, 14 Hz,
5-H), 2.90 (dt, J ¼ 2.5, 13Hz, 3-H), 3.25 (s, OMe), 4.20 (dd, J ¼ 3, 5, 13Hz, 6-H), 4.45 (dd, J ¼ 13,
14Hz, CH2), 5.45 (d, J ¼ 2 Hz, OH), 6.60–7.50 (m, 16 ar H) ppm.
2,6-Bis(4-chlorophenyl)-3-(3-bromo-2-thienoyl)-4-(3-bromo-2-thienyl)-1-cyano-4-
hydroxycyclohexane-1-carbonitrile (13b, C29H18Br2Cl2N2O2S2)
From 6b (3.28 g, 10mmol) and 0.33g of malononitrile (5mmol) as described for 7a, 2 h stirring at
room temperature, extraction with CHCl3. Yield 2.1 g (58%); colorless crystals; mp 180ꢂC (EtOH); IR:
1
ꢂꢀ¼ 3400 (OH), 3105 (CH), 1635 (CO), 1590, 830 (ar) cmꢁ1; H NMR: ꢁ ¼ 2.20 (dd, J ¼ 2, 14 Hz,
3-H), 3.50–4.15 (m, CH2), 4.05 (d, J ¼ 12 Hz, 5-H), 4.90 (d, J ¼ 12Hz, 6-H), 5.85 (d, J ¼ 2 Hz, OH),
6.75–7.60 (m, 12 ar H) ppm.
2,6-Bis(4-methoxyphenyl)-3-(3-bromo-2-thienoyl)-4-(3-bromo-2-thienyl)-1-cyano-4-
hydroxycyclohexane-1-carbonitrile (13c, C31H24Br2N2O4S2)
As a by-product of the synthesis of 7c, isolated from the mother liquor. Yield 0.75 g (20%); colorless
crystals; mp 153ꢂC (CCl4); IR: ꢂꢀ¼ 3400 (OH), 3100 (CH), 1635 (CO), 1610, 830 (ar) cmꢁ1; 1H NMR:
ꢁ ¼ 2.85 (dd, J ¼ 2, 13 Hz, 3-H), 3.45–4.10 (m, 3H, CH), 3.60, 3.75 (2s, 2 OMe), 4.90 (d, J ¼ 12 Hz,
6-H), 5.85 (d, J ¼ 2 Hz, OH), 6.75–7.60 (m, 12 ar H) ppm.
2,6-Bis(4-chlorophenyl)-3-(3-chloro-2-thienoyl)-4-(3-chloro-2-thienyl)-4-hydroxy-1-
cyanocyclohexane-1-carbonitrile (13d, C29H18Cl4N2O2S2)
As a by-product of the synthesis of 12, isolated from the mother liquor. Yield 0.3 g (9%); colorless
crystals; mp 198ꢂC (CCl4); IR: ꢂꢀ¼ 3400 (OH), 3105 (CH), 2220 (CN), 1630 (CO), 830 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 2.20 (dd, J ¼ 3, 14Hz, 3-H), 3.30–4.10 (m, CH2), 4.05 (d, J ¼ 12Hz, 5-H), 4.95
(d, J ¼ 12 Hz, 6-H), 5.70 (d, J ¼ 2 Hz, OH), 6.70–7.60 (m, 12 ar H) ppm.
2,6-Bis(2-thienyl)-3-(3-chloro-2-thienoyl)-4-(3-chloro-2-thienyl)-1-cyano-4-
hydroxycyclohexane-1-carbonitrile (13e, C25H16Cl2N2O2S4)
Malononitrile (0.7g, 11mmol) was dissolved in 20 cm3 of EtOH, 1.42 g of 11f (5mmol) and 5 drops
piperidine were added, and the mixturewas stirred at room temperature for 2 h. After 24 h, the precipitate
was separated. Yield 2.1 g (73%); colorless crystals; mp 187ꢂC (EtOH); IR: ꢂꢀ¼ 3400 (OH), 3105 (CH),
1635 (CO) cmꢁ1; 1H NMR: ꢁ ¼ 2.35 (dd, J ¼ 3, 15Hz, 5-H, 50-H), 3.45 (m, 3-H), 4.35 (dd, J ¼ 3, 13Hz,
6-H), 4.65 (dd, J ¼ 12Hz, 2-H), 6.85 (d, J ¼ 2 Hz, OH), 6.60–7.50 (m, 10 ar H) ppm.
3-Cyano-4-phenyl-6-(2-thienyl)piperidin-2-one (15a, C16H14N2OS)
NaH (0.05 g, 1.3 mmol) was added with stirring to a solution of 0.7 g of 14 (2.5mmol) in 10cm3 of
EtOH, and after 3 h stirring at room temperature 50cm3 of H2O were added and the mixture was

Heteroaryl Substituted Propenones
647
extracted with 3ꢃ10 cm3 of CH2Cl2. The combined organic layers were washed with 50cm3 of satd.
NaCl solution, and dried (MgSO4). After a few days at room temperature, the crystals were collected.
Yield 0.65 g (92%); colorless crystals; mp 138ꢂC (CH2Cl2); IR: ꢂꢀ¼ 3300 (NH), 3010 (CH), 2200
1
(CN), 1640 (CO), 1590, 760, 700 (ar) cmꢁ1; H NMR (DMSO-d6, 200 MHz): Isomer I: ꢁ ¼ 1.81 (dt,
J ¼ 13.4, 11.3Hz, 5-Hax), 2.3–2.4 (m, 5-Heq), 3.85 (dd, J ¼ 11.4, 6.2Hz, 4-H), 5.49 (dd, J ¼ 11.3,
1.2 Hz, 6-H), 6.45, 6.55 (2s, 3-H, N–H), 6.80–7.65 (m, 8 ar H) ppm; Isomer II: ꢁ ¼ 1.96–2.17 (m,
5-Hax), 2.3–2.4 (m, 5-Heq), 3.74 (dd, J ¼ 6.0, 3.5 Hz, 4-H), 5.21 (dd, J ¼ 10.0, 1.9 Hz, 6-H), 6.45, 6.55
(2s, 3-H, N–H), 6.80–7.65 (m, 8 ar H) ppm.
6-(3-Bromo-2-thienyl)-4-(4-chlorophenyl)-3-cyanopiperidin-2-one (15b, C16H12BrClN2OS)
From 7b (3.94 g, 10 mmol), and 0.19 g of NaH (5mmol) as described for 15a. The reaction mixture
was concentrated in vacuo, 20 cm3 H2O were added to the residue, then it was extracted with Et2O.
Yield 3.5 g (90%); colorless crystals; mp 122ꢂC (EtOH); IR: ꢂꢀ¼ 3310 (NH), 2940 (CH), 2190 (CN),
1
1630 (CO), 1590, 830 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.90–2.65 (m, CH2), 3.75–4.15 (m, 3-H), 4.75 (bs,
N-H, 2-H), 5.15–5.70 (m, 5-H), 6.90–8.00 (m, 6 ar H) ppm.
1-(2-Furyl)-4-nitro-3-phenylbutan-1-one (16a, C14H13NO4)
From nitromethane (3.0g, 50 mmol) and 1.98g of 1a (10 mmol) as described for 9a. Yield 1.7 g (66%);
colorless crystals; mp 60ꢂC (MeOH); IR: ꢂꢀ¼ 1670 (CO), 1565 (ar), 1540, 1360 (NO2), 700, 760 (ar)
cmꢁ1; 1H NMR: ꢁ ¼ 3.25 (d, J ¼ 6 Hz, 2H, 2-H), 4.10 (m, 3-H), 4.70 (dd, J ¼ 3, 6 Hz, 2H, 4-H), 6.50
(m, 1H, 4-Hfuryl), 7.15–7.60 (m, 7 ar H) ppm.
3-(4-Chlorophenyl)-4-nitro-1-(2-thienyl)butan-1-one (16b, C14H12ClNO3S)
a. From nitromethane (3.0g, 50 mmol) and 2.49g of 2b (10 mmol) as described for 9a, 1 h reflux. b.
From 18 (1.3g, 10 mmol) and 1.84g of 17 (10 mmol) with MeONa (5mmol) in MeOH, 3 h reflux. The
product was purified by Kugelrohr distillation. Yield a. 1.7 g (55%), b. 2.1 g (68%); light yellow liquid;
1
bp 190ꢂC=133 Pa; IR (film): ꢂꢀ¼ 1660 (CO), 1550, 1375 (NO2), 830 (ar) cmꢁ1; H NMR: ꢁ ¼ 3.35
(d, J ¼ 7 Hz, 2H, 2-H), 4.15 (m, 3-H), 4.75 (dd, J ¼ 4, 4 Hz, 2H, 4-H), 7.00–7.75 (m, 7 ar H) ppm.
3-(3,4-Dimethoxyphenyl)-4-nitro-1-(2-thienyl)butan-1-one (16c, C16H15NO5S)
From nitromethane (3.0g, 50 mmol) and 2.49g of 2d (10 mmol) as described for 9a, 1 h reflux. Yield
2.0 g (60%); colorless crystals; mp 91ꢂC (MeOH); IR: ꢂꢀ¼ 1650 (CO), 1530, 1350 (NO2), 810 (ar)
cmꢁ1; 1H NMR: ꢁ ¼ 3.35 (d, J ¼ 7 Hz, 2H, 2-H), 3.90 (s, 2 OMe), 4.10 (m, 3-H), 4.80 (dd, J ¼ 3, 3 Hz,
2H, 4-H), 6.80–7.75 (m, 6 ar H) ppm.
1-(3-Bromo-2-thienyl)-4-nitro-3-phenylbutan-1-one (16d, C14H12BrNO3S)
From nitromethane (3.0g, 50 mmol) and 2.94g of 6a (10 mmol) as described for 9a, 1 h reflux. Yield
2.5 g (71%); brownish liquid; IR (film): ꢂꢀ¼ 3020 (CH), 1655 (CO), 1550, 1380 (NO2) cmꢁ1; 1H NMR:
ꢁ ¼ 3.40 (dd, J ¼ 7, 16Hz, 2H, 2-H), 4.15 (m, 3-H), 4.70, (dd, J ¼ 4, 7 Hz, 2H, 4-H), 6.90–7.50 (m, 7
ar H) ppm.
1-(3-Bromo-2-thienyl)-3-(4-chlorophenyl)-4-nitrobutan-1-one (16e, C14H11BrClNO3S)
From 6b (3.27 g, 10 mmol) as described 16d. Yield 3.25 g (84%); brownish liquid; IR (film): ꢂꢀ¼ 3020
1
(CH), 1655 (CO), 1550, 1380 (NO2) cmꢁ1; H NMR: ꢁ ¼ 3.45 (dd, J ¼ 7, 16 Hz, 2H, 2-H), 4.15 (m,
3-H), 4.70 (dd, J ¼ 4, 7 Hz, 2H, 4-H), 7.00–7.55 (m, 6 ar H) ppm.

648
L. Greiner-Bechert et al.
1-(3-Bromo-2-thienyl)-3-(4-methoxyphenyl)-4-nitrobutan-1-one (16f, C15H14BrNO4S)
From 6c (3.24 g, 20mmol) as described for 16d. Yield 5.8 g (76%); brownish liquid; IR (film):
1H NMR: ꢁ ¼ 3.40 (dd, J ¼ 7, 18Hz, 2H,
ꢂꢀ¼ 3010 (CH), 1655 (CO), 1550, 1385 (NO2) cmꢁ1
;
2-H), 3.70 (s, OCH3), 4.10 (m, 3-H), 4.65 (dd, J ¼ 3, 6 Hz, 2H, 4-H), 6.55–7.60 (m, 6 ar H) ppm.
General Procedure for the Synthesis of (2-Arylcyclopropyl) (2-Heteroaryl) Ketones
NaH (0.29 g, 11 mmol) was added to a suspension of 2.40g of 19 (11 mmol) in 20cm3 of DMSO. After
30min, a solution of 1 or 2 (10 mmol) in 10cm3 of DMSO was added dropwise, the mixture was stirred
for 3 h, then poured into 50 cm3 of H2O, neutralized with conc. HCl, and extracted with 3 ꢃ 20cm3 of
CHCl3. The combined organic layers were washed with 5 ꢃ 50cm3 of H2O, once with 30cm3 of satd.
NaCl solution, dried (Na2SO4), and evaporated in vacuo.
2-Furyl 2-phenylcyclopropyl ketone (20a, C14H12O2)
From 1a (1.98 g, 10 mmol). Yield 2.0 g (94%); brown waxy crystals; mp 73ꢂC (Et2O); IR: ꢂꢀ¼ 3100
(H–Ccyclopropyl), 1640 (CO), 1560, 770, 695 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 1.50, 1.80 (2m, each 1
H–Ccyclopropyl), 2.55 (m, CH2), 6.50 (m, 4-Hfuryl), 6.90–7.50 (m, 7 ar H) ppm.
2-(4-Chlorophenyl)cyclopropyl 2-furyl ketone (20b, C14H11ClO2)
From 1b (2.33 g, 10 mmol). Yield 2.35 g (95%); reddish waxy crystals; mp 77ꢂC (Et2O); IR: ꢂꢀ¼ 3100
(H–Ccyclopropyl), 1640 (CO), 1560, 810 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 1.40 (m, J ¼ 4, 6.5, 8 Hz,
3-H0cyclopropyl), 1.80 (m, J ¼ 4, 5, 10 Hz, 3-Hcyclopropyl), 2.65 (m, J ¼ 6.5, 10Hz, 2-Hcyclopropyl), 2.75
(m, J ¼ 5, 8 Hz, 1-Hcyclopropyl), 6.50 (m, 4-Hfuryl), 6.90–7.60 (m, 6 ar H) ppm.
2-Furyl 2-(4-methoxyphenyl)cyclopropyl ketone (20c, C15H14O3)
From 1c (2.33 g, 10 mmol). Yield 2.18 g (90%); reddish waxy crystals; mp 67ꢂC (Et2O); IR: ꢂꢀ¼ 3100
1
(H–Ccyclopropyl), 1640 (CO), 1560, 805 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.40, 1.80 (2m, each 1 Hcyclopropyl),
2.70 (m, CH2), 3.70 (s, OMe), 6.50 (m, 4-Hfuryl), 6.70–7.60 (m, 6 ar H) ppm; 13C NMR: ꢁ ¼ 18.68
(CH2(cyclopropyl)), 28.99 (CHcyclopropyl), 55.37 (OMe), 112.38 (C-4furyl), 114.15 (ar C), 116.69 (C-3furyl),
127.58 (ar C), 132.42 (ar C), 146.46 (C-5furyl), 153.41 (C-2furyl), 158.66 (ar C), 187.33 (CO) ppm.
2-(3,4-Dimethoxyphenyl)cyclopropyl 2-furyl ketone (20d, C16H16O4)
From 1d (2.58 g, 10 mmol). Yield 2.23g (82%); yellowish waxy crystals; mp 102ꢂC (Et2O); IR:
ꢂꢀ¼ 3110 (H–Ccyclopropyl), 1640 (CO), 1590, 790 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 1.50, 1.80 (2m, each
1Hcyclopropyl), 2.70 (m, CH2), 3.80 (s, 2 OMe), 6.50–7.60 (m, 6 ar H) ppm.
2-(4-Dimethylaminophenyl)cyclopropyl 2-furyl ketone (20e, C16H17NO2)
From 1e (2.40 g, 10mmol). Yield 2.1 g (82%); yellowish crystals; mp 122ꢂC (Et2O); IR: ꢂꢀ¼ 2910 (H–
Ccyclopropyl), 1645 (CO), 1595, 810 (ar) cmꢁ1; 1H NMR: ꢁ ¼ 2.60 (m, 2Hcyclopropyl), 2.50–3.20 (m, 8H,
Hcyclopropyl, Me), 6.45–7.90 (m, 7 ar H) ppm.
2-Furyl 2-(4-nitrophenyl)cyclopropyl ketone (20f, C14H11NO4)
From 1f (2.45 g, 10 mmol). Yield 2.0 g (78%); reddish waxy crystals; mp 139ꢂC (Et2O); IR: ꢂꢀ¼ 3100
1
(H–Ccyclopropyl), 1640 (CO), 1560 (ar), 1510, 1340 (NO2), 795 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.60, 1.95
(2m, each 1 Hcyclopropyl), 2.80 (m, CH2), 6.55 (m, 4-Hfuryl), 7.25–8.30 (m, 6 ar H) ppm.

Heteroaryl Substituted Propenones
649
2-Furyl 2-(2-thienyl)cyclopropyl ketone (20g, C12H10O2S)
From 1g (2.04 g, 10 mmol). Yield 1.9 g (90%); brown waxy crystals; mp 49ꢂC (Et2O); IR: ꢂꢀ¼ 3105
1
(H–Ccyclopropyl), 1650 (CO), 1570 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.40, 1.80 (2 m, each 1Hcyclopropyl), 2.80
(t, J ¼ 7 Hz, CH2), 6.40–7.55 (m, 6 ar H) ppm.
2-Furyl 2-styrylcyclopropyl ketone (20h, C16H14O2)
From 1i (2.24 g, 10 mmol). Yield 2.2 g (92%); yellow waxy crystals; mp 97ꢂC (Et2O); IR: ꢂꢀ¼ 3100
1
(H–Ccyclopropyl), 1640 (CO), 1560, 750, 690 cmꢁ1 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.20, 1.75 (2m, each
1Hcyclopropyl), 2.50 (m, CH2), 5.65–7.75 (m, 10 ar H) ppm.
(RS)-4-(4-Methoxyphenyl)-4,5-dihydrobenzo[b]furan-7(6H)-one (21, C15H14O3)
At room temperature, SnCl4 (3.9g, 15mmol) was added dropwise with stirring to a solution of 2.31g
of 20c (10 mmol) in 20cm3 of C6H6. After stirring for 1 h, the mixture was poured into 50cm3 of dil.
HCl, extracted with 3 ꢃ 30 cm3 of CHCl3, the combined organic layers were washed with 3 ꢃ 50cm3
of H2O, dried (MgSO4), and evaporated in vacuo. Yield 2.0g (94%); reddish waxy crystals; mp 39ꢂC
1
(C6H6); IR: ꢂꢀ¼ 3120 (CH), 1675 (CO), 1615, 770 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.95–2.65 (m, 4H, 5-H,
6-H), 3.75 (s, OMe), 4.15 (m, 4-H), 6.65–7.60 (m, 6 ar H) ppm; 13C NMR: ꢁ ¼ 32.70 (C-5), 36.52
(C-6), 40.16 (C-4), 55.31 (OMe), 106.57 (C-3), 114.34 (ar C), 122.05 (C-30), 128.87 (ar C), 131.82
(ar C), 143.36 (C-2), 159.03 (ar C), 167.62 (C-70), 194.52 (C-7) ppm.
(RS)-1-(2-Furyl)-4-hydroxy-4-(2-thienyl)butan-1-one (22, C12H12O3S)
A solution of SnCl4 (1.8cm3, 15mmol) in 5 cm3 of C6H6 was added dropwise with stirring to a
solution of 2.18g of 20g (10 mmol) in 20cm3 of C6H6. After stirring for 1 h, the solution was poured
into a solution of NaOH (10%, 50cm3), and extracted with 3 ꢃ 20cm3 of CHCl3. The combined
organic layers were washed with 3 ꢃ 50 cm3 of H2O, dried (MgSO4), and evaporated in vacuo. Yield
1.35g (57%); yellow crystals; mp 44ꢂC (C6H6); IR: ꢂꢀ¼ 3400 (OH), 3110 (CH), 1655 (CO) cmꢁ1
;
1H NMR: ꢁ ¼ 2.20 (m, CH2), 2.95 (t, J ¼ 7 Hz, CH2), 3.20 (s, OH), 4.50 (t, J ¼ 7 Hz, 4-H), 6.50 (m,
4-Hfuryl), 6.80–7.60 (m, 5 ar H) ppm.
2-Phenylcyclopropyl 2-thienyl ketone (23a, C14H12OS)
From 2a (2.14 g, 10mmol). Yield 2.10g (92%); yellow crystals; mp 72ꢂC (Et2O); IR: ꢂꢀ¼ 3075
1
(H–Ccyclopropyl), 1625 (CO), 1595 (ar), 730, 690 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.50, 1.85 (2m, each
1Hcyclopropyl), 2.70 (t, J ¼ 7 Hz, CH2), 6.90–7.75 (m, 8 ar H) ppm.
2-(4-Chlorophenyl)cyclopropyl 2-thienyl ketone (23b, C14H11ClOS)
From 2b (2.48 g, 10 mmol). Yield 2.35 g (90%); yellow crystals; mp 78ꢂC (Et2O); IR: ꢂꢀ¼ 3065
1
(H–Ccyclopropyl), 1625 (CO), 720 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.45, 1.80 (2m, each 1Hcyclopropyl), 2.65
(t, J ¼ 7 Hz, CH2), 6.90–7.80 (m, 7 ar H) ppm.
2-(4-Methoxyphenyl)cyclopropyl 2-thienyl ketone (23c, C15H14O2S)
From 2c (2.44 g, 10 mmol). Yield 2.25g (88%); light yellow crystals; mp 65ꢂC (Et2O); IR:
ꢂꢀ¼ 3070 (H–Ccyclopropyl), 1625 (CO), 1580, 800 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 1.40, 1.80 (2m, each
1Hcyclopropyl), 2.65 (t, J ¼ 7 Hz, CH2), 3.65 (s, OMe), 6.65–7.75 (m, 7 ar H) ppm; 13C NMR:

650
L. Greiner-Bechert et al.
ꢁ ¼ 18.73 (CH2(cyclopropyl)), 29.19 (CHcyclopropyl), 29.98 (CHcyclopropyl), 55.48 (OMe), 114.27 (ar C),
127.72 (ar C), 128.31 (C-4), 131.79 (C-5), 132.53 (ar C), 133.51 (C-3), 145.2 (C-2), 158.79 (ar C),
191.03 (CO) ppm.
2-(3,4-Dimethoxyphenyl)cyclopropyl 2-thienyl ketone (23d, C16H16O3S)
From 2d (2.75 g, 10mmol). Yield 2.65 g (93%); colorless crystals; mp 98ꢂC (Et2O); IR: ꢂꢀ¼ 3080
1
(H–Ccyclopropyl), 1630 (CO), 1590, 860 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.50, 1.80 (2m, each 1Hcyclopropyl),
2.55 (t, J ¼ 7 Hz, CH2), 3.65 (s, OMe), 6.90–8.10 (m, 6 ar H) ppm.
2-(4-Dimethylaminophenyl)cyclopropyl 2-thienyl ketone (23e, C16H17NOS)
From 2e (2.57 g, 10 mmol). Yield 1.90 g (70%); colorless crystals; mp 137ꢂC (Et2O); IR: ꢂꢀ¼ 3080
(H–Ccyclopropyl), 1630 (CO), 810 (ar) cmꢁ1; 1H NMR: ꢁ ¼ 1.65 (m, 2 Hcyclopropyl), 2.70 (t, J ¼ 8 Hz, CH2),
2.95 (s, 2 Me), 6.65–7.95 (m, 7 ar H) ppm.
2-(2-Thienyl)cyclopropyl 2-thienyl ketone (23f, C12H10O2S)
From 2g (2.20 g, 10 mmol). Yield 2.15 g (92%); light yellow crystals; mp 63ꢂC (Et2O); IR: ꢂꢀ¼ 3080
1
(H–Ccyclopropyl), 1620 (CO) cmꢁ1; H NMR: ꢁ ¼ 1.55, 1.90 (2m, each 1 Hcyclopropyl), 2.80 (m, CH2),
6.75–7.80 (m, 6 ar H) ppm.
2,20-(1,4-Phenylene)bis[cyclopropyl 2-thienyl ketone] (23g, C22H18O2S2)
From 19 (4.80 g, 22mmol) and 3.50 g of 2h (10 mmol). Yield 2.75g (73%); yellowish crystals; mp
150ꢂC (Et2O); IR: ꢂꢀ¼ 3090 (H–Ccyclopropyl), 1630 (CO), 840 (ar) cmꢁ1; 1H NMR: ꢁ ¼ 1.50, 1.85 (2m,
each 1 Hcyclopropyl), (t, J ¼ 7 Hz, CH2), 7.00–7.90 (m, 10 ar H) ppm.
2-(2-Bromophenyl)cyclopropyl 2-thienyl ketone (23h, C14H11BrOS)
From 2k (2.94 g, 10 mmol). Yield 2.8 g (91%); light red liquid; IR (film): ꢂꢀ¼ 3010 (H–Ccyclopropyl),
1
1645 (CO), 755, 725 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.55, 1.80 (2m, each 1 Hcyclopropyl), 2.65 (m, CH2),
6.90–7.85 (m, 7 ar H) ppm.
(RS)-4-(4-Methoxyphenyl)-4,5-dihydrobenzo[b]thiophen-7(6H)-one (24, C15H14O2S)
From 23c (2.47 g, 10mmol) and 3.9 g of SnCl4 (15 mmol) as described for 21, stirring for 4 h, CC with
Et2O=n-hexane (1=1). Yield 1.4 g (54%); brown waxy crystals; mp 48ꢂC (Et2O); IR: ꢂꢀ¼ 3100 (CH),
1655 (CO), 1610, 770 (ar) cmꢁ1; 1H NMR: ꢁ ¼ 1.85–2.80 (m, 4H, 5-H, 6-H), 3.80 (s, OMe), 4.10 (m,
4-H), 7.55–8.60 (m, 6 ar H) ppm; 13C NMR: ꢁ ¼ 33.90 (C-5), 37.11 (C-6), 42.63 (C-4), 55.23 (OMe),
114.12 (ar C), 128.82 (C-3), 129.00 (ar C), 133.69 (C-2), 134.86 (ar C), 136.81 (C-30), 155.14 (C-70),
158.64 (ar C), 191.97 (C-7) ppm.
(RS)-4-Hydroxy-4-phenyl-1-(2-thienyl)butan-1-one (25a, C14H14O2S)
From 23a (2.14 g, 10 mmol) and 1.4g of AlCl3 (11 mmol) in CH2Cl2, as described for 22, refluxing for
1 h. Yield 1.1 g (43%); brown liquid; IR (film): ꢂꢀ¼ 3450 (OH), 3100 (CH), 1635 (CO), 1610, 740, 705
(ar) cmꢁ1; 1H NMR (60 MHz): ꢁ ¼ 2.15 (m, CH2), 3.00 (t, J ¼ 7 Hz, CH2, OH), 4.85 (t, J ¼ 6 Hz, 4-H),
6.90–7.90 (m, 5 ar H) ppm.

Heteroaryl Substituted Propenones
651
(RS)-4-Hydroxy-4-(4-methoxyphenyl)-1-(2-thienyl)butan-1-one (25b, C15H16O3S)
From 23c (2.47 g, 10 mmol) and 1.8 cm3 of SnCl4 (15 mmol) in 20cm3 of C6H6, as described for 22,
1 h stirring at room temperature. Yield 1.9g (69%); light yellow liquid; IR (film): ꢂꢀ¼ 3400 (OH), 3100
(CH), 1650 (CO), 1610, 750 (ar) cmꢁ1; 1H NMR: ꢁ ¼ 2.10 (m, 2H, 5-H), 2.95 (t, J ¼ 7 Hz, 2H, 6-H),
3.70 (s, OMe), 4.75 (t, J ¼ 7 Hz, 4-H), 7.70–8.70 (m, 7 ar H) ppm.
3-Bromo-2-thienyl 2-phenylcyclopropyl ketone (26a, C14H10BrClOS)
From 19 (2.40 g, 11 mmol) and 2.93 g of 6a (10 mmol) as described for 20a. After evaporation of the
solvent a light liquid was obtained. Yield 2.55 g (83%); IR (film): ꢂꢀ¼ 3105 (H–Ccyclopropyl), 1640
1
(CO), 740, 700 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.45, 2.05, 2.70, 3.20 (4m, each 1 Hcyclopropyl), 6.65–7.95
(m, 6 ar H) ppm.
3-Bromo-2-thienyl 2-(4-chlorophenyl)cyclopropyl ketone (26b, C14H10BrClOS)
From 19 (2.40 g, 11mmol) and 3.28 g of 6b (10 mmol). Yield 2.30g (75%); yellowish crystals; mp
1
53ꢂC; IR: ꢂꢀ¼ 3100 (H–Ccyclopropyl), 1630 (CO), 800 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.50, 1.90, 2.65, 3.15
(4m, each 1 Hcyclopropyl), 6.90–7.45 (m, 7 ar H) ppm.
3-Bromo-2-thienyl 2-(4-dimethylaminophenyl)cyclopropyl ketone (26c, C16H16BrNOS)
From 19 (2.40 g, 11mmol) and 3.30 g of 6e (10 mmol). Yield 2.80 g (80%); red crystals; mp 90ꢂC
1
(Et2O=n-pentane 2=1); IR: ꢂꢀ¼ 2910 (H–Ccyclopropyl), 1630 (CO), 800 (ar) cmꢁ1; H NMR: ꢁ ¼ 1.65
(m, 2 Hcyclopropyl), 2.90 (m, 8H, Me, Hcyclopropyl), 6.60–7.60 (m, 6 ar H) ppm.
3-Bromo-2-thienyl 2-(4-nitrophenyl)cyclopropyl ketone (26d, C14H10BrNO3S)
From 19 (2.40 g, 11 mmol) and 3.40g of 6f (10 mmol). After evaporation of the solvent, some drops of
Et2O were added to the residue for crystallization. Yield 2.6 g (73%); yellowish crystals; mp 75ꢂC
(Et2O); IR: ꢂꢀ¼ 3100 (H–Ccyclopropyl), 1630 (CO), 1510, 1345 (NO2), 855 (ar) cmꢁ1
;
1H NMR:
ꢁ ¼ 1.55, 1.95, 2.75, 3.05 (4m, each 1 Hcyclopropyl), 7.00–8.20 (m, 6 ar H) ppm.
2-(4-Chlorophenyl)cyclopropyl 3-chloro-2-thienyl ketone (27a, C14H10Cl2OS)
From 19 (2.40 g, 11 mmol) and 2.83g of 11b (10 mmol). Yield 2.6 g (87%); colorless crystals;
1H NMR: ꢁ ¼ 1.50,
mp 54ꢂC (Et2O); IR: ꢂꢀ¼ 3100 (H–Ccyclopropyl), 1620 (CO), 805 (ar) cmꢁ1
;
1.95, 2.70, 3.10 (4m, each 1 Hcyclopropyl), 6.95–7.95 (m, 6 ar H) ppm.
3-Chloro-2-thienyl 2-(3,4-dimethoxyphenyl)cyclopropyl ketone (27b, C16H15ClO3S)
From 19 (2.40 g, 11 mmol) and 3.20g of 11d (10 mmol). Yield 2.8 g (87%); colorless crystals;
1H NMR: ꢁ ¼ 1.45,
mp 67ꢂC (Et2O); IR: ꢂꢀ¼ 3100 (H–Ccyclopropyl), 1625 (CO), 825 (ar) cmꢁ1
;
1.85, 2.65, 3.05 (4m, each 1 Hcyclopropyl), 3.80 (s, 2 OMe), 6.50–7.70 (m, 6 ar H) ppm.
3-Chloro-2-thienyl 2-(4-nitrophenyl)cyclopropyl ketone (27c, C14H10ClNO3S)
From 19 (2.40 g, 11 mmol) and 2.94 g of 11f (10 mmol). Yield 2.5 g (81%); colorless crystals; mp 83ꢂC
(Et2O); IR: ꢂꢀ¼ 3095 (H–Ccyclopropyl), 1620 (CO), 1510, 1340 (NO2), 865 (ar) cmꢁ1
;
1H NMR:

652
L. Greiner-Bechert et al.
ꢁ ¼ 1.60, 2.05, 2.85, 3.30 (4m, each 1 Hcyclopropyl), 7.05 (d, J ¼ 5 Hz, 4-H), 7.35 (d, J ¼ 8 Hz, 2 ar H),
7.55 (d, J ¼ 5 Hz, ar H), 8.20 (d, J ¼ 8 Hz, 2 ar H) ppm.
2-(1-Trimethylsiloxyvinyl)thiophene (28, C9H14OSSi)
With stirring, under N2, and at ꢁ78ꢂC, 18 (5.4cm3, 50 mmol) was dropwise added to a solution of
55mmol of LDA in 100 cm3 of THF within 5 min. After stirring for 15–20min 7.6 cm3 of ClSiMe3
(60 mmol) were added. After 4–5 min the mixture was diluted with 100 cm3 of ice-cooled pentane, and
poured into 150 cm3 of an ice-cooled satd. solution of NaHCO3, the organic layer was separated, twice
washed with H2O, and once with 50cm3 of a satd. solution of NaCl, dried (MgSO4), and evaporated in
1
vacuo. Yield 9.2 g (93%); colorless liquid; bp 120ꢂC=2666 Pa (Ref. [15] 73ꢂC=267 Pa); H NMR:
ꢁ ¼ 0.35, 0.40 (2s, SiMe3), 4.25, 4.75 (2d, J ¼ 2 Hz, CH2), 6.80–7.60 (m, 3 ar H) ppm.
4,5,6,7-Tetrahydro-7-oxo-N-phenylbenzo[b]thiophene-4,5-dicarboximide (29, C16H11NO3S)
Compound 28 (2.0g, 10 mmol, freshly prepared) and 1.7 g of N-phenylmaleinimide (10 mmol) dis-
solved in 10cm3 of CH2Cl2 were heated in a sealed tube to 80ꢂC for 24h. After cooling, the solvent
was evaporated in vacuo, and the residue was purified by CC (Et2O=n-hexane 1=1). Yield 0.5g (17%);
colorless crystals; mp 150ꢂC (Ref. [19] 168ꢂC); IR: ꢂꢀ¼ 1710, 1660 (CO), 1600, 740, 690 (ar) cmꢁ1
;
1H NMR: ꢁ ¼ 2.85 (dd, J ¼ 8, 18Hz, 6-Heq), 3.40 (dd, J ¼ 3, 18 Hz, 6-Hax), 3.75 (td, J ¼ 3, 8 Hz, 5-H),
4.40 (d, J ¼ 8 Hz, 4-H), 7.05–7.75 (m, 7 ar H) ppm.
4,4-Dicyano-5-phenyl-4,5-dihydrobenzo[b]thiophene-7(6H)-one (32, C16H10N2OS)
From 28 (1.0g, 5 mmol) and 0.75 g of 30 (5mmol) as described for 29. Yield 70mg (5%); brownish
crystals; mp 125ꢂC (Et2O=n-hexane 1=1); IR: ꢂꢀ¼ 2900 (CH), 2260 (CN), 1660 (CO), 730, 700
1
(ar) cmꢁ1; H NMR (60 MHz): ꢁ ¼ 2.90 (dd, J ¼ 4, 16Hz, 6-Heq), 3.45 (dd, J ¼ 12, 19Hz, 6-Hax),
4.10 (dd, J ¼ 4, 12Hz, 5-H), 7.20–7.90 (m, 7 ar H) ppm.
4-Nitro-5-phenyl-4,5-dihydrobenzo[b]thiophene-7(6H)-one (33, C14H11NO3S)
From 28 (1.0g, 5 mmol) and 0.75g of 31 (5mmol) as described for 29. Yield 50 mg (4%); yellow
1
liquid; IR (Film): ꢂꢀ¼ 3100, 2035 (CH), 1655 (CO), 1600, 730, 700 (ar) cmꢁ1; H NMR (60 MHz):
ꢁ ¼ 2.85 (dd, J ¼ 8, 18Hz, 6-Heq), 3.45 (dd, J ¼ 5, 19Hz, 6-Hax), 4.10 (dd, J ¼ 4, 12 Hz, 5-H), 7.00–
7.80 (m, 7 ar H) ppm.
4-Benzyl-4,5,6,7-tetrahydro-6,6,7,7-tetracyanobenzo[b]thiophene (35, C19H12N4S)
34 (2.0g, 10 mmol), and 1.28g of TCNE dissolved in 20 cm3 of C6H6 were refluxed for 24h. After
cooling and evaporation of the solvent, the residue was purified by CC (Et2O=n-pentane 2=1). Yield
0.65g (20%); colorless crystals; mp 116ꢂC (Et2O); IR: ꢂꢀ¼ 3080, 3060 (CH), 2260 (CN), 1710, 1660
1
(CO), 1600 (ar) cmꢁ1; H NMR: ꢁ ¼ 3.00 (d, J ¼ 3 Hz, CH2(benzyl)), 3.45 (d(s), CH2), 4.60 (m, 4-H),
6.80 (dd, J ¼ 2, 6 Hz, 2-H), 6.65 (dd, J ¼ 2, 6 Hz, 1H, 3-H), 7.05–7.50 (m, 5 ar H) ppm.
Acknowledgments
We thank E. Merck KGaG, Darmstadt, for extended generous support with chemicals, with chromatog-
raphy materials, and for biological testing, and we thank the ‘‘Fonds der Chemischen Industrie’’,
Frankfurt a. Main, for continuous financial support.

Heteroaryl Substituted Propenones
653
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¨
Verleger: Springer-Verlag GmbH, Sachsenplatz 4–6, 1201 Wien, Austria. – Herausgeber: Osterreichische Akademie der Wissen-
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schaften, Dr.-Ignaz-Seipel-Platz 2, 1010 Wien, und Gesellschaft Osterreichischer Chemiker, Eschenbachgasse 9, 1010 Wien,
Austria. – Redaktion: Getreidemarkt 9=163-OC, 1060 Wien, Austria. – Satz und Umbruch: Thomson Press Ltd., Chennai, India. –
Offsetdruck: Manz Crossmedia, 1051 Wien, Austria. – Verlagsort: Wien. – Herstellungsort: Wien. – Printed in Austria.