Regio- and chemoselective bromination of 2,3-diarylcyclopent-2-en- 1-ones

Article abstract of DOI:10.1021/jo301474j

The bromination of 2,3-diarylcyclopent-2-en-1- ones under various conditions has been studied. It was found that depending on the brominating reagent and nature of solvent the bromine atom can be introduced at the 4- or 5- position of the ethene bridge , as well as into the aryl moieties. Aryl group bromination is accomplished with such reagents as molecular bromine, N-bromosuccinimide, or tetrabutylammonium tribromide. 5-Bromocyclopentenones with very high efficiency can be obtained by the reaction with copper(II) bromide in methanol, while 4-bromoketones are prepared in n-propyl acetate. The developed methods can be highly useful for the synthesis of bromo-substituted 2-cyclopenten-1-ones and their close analogues, which are important synthons in organic synthesis and for the preparation of a variety of useful substances.

Full text of DOI:10.1021/jo301474j

Article
pubs.acs.org/joc
Regio- and Chemoselective Bromination of 2,3-Diarylcyclopent-2-en-
1-ones
Valerii Z. Shirinian,* Dmitry V. Lonshakov, Vadim V. Kachala, Igor V. Zavarzin, Alexey A. Shimkin,
Andrew G. Lvov, and Mikhail M. Krayushkin
N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky prosp., 119991 Moscow, Russian Federation
S
* Supporting Information
ABSTRACT: The bromination of 2,3-diarylcyclopent-2-en-1-
ones under various conditions has been studied. It was found
that depending on the brominating reagent and nature of
solvent the bromine atom can be introduced at the 4- or 5-
position of the ethene “bridge”, as well as into the aryl
moieties. Aryl group bromination is accomplished with such
reagents as molecular bromine, N-bromosuccinimide, or
tetrabutylammonium tribromide. 5-Bromocyclopentenones
with very high efficiency can be obtained by the reaction
with copper(II) bromide in methanol, while 4-bromoketones
are prepared in n-propyl acetate. The developed methods can
be highly useful for the synthesis of bromo-substituted 2-cyclopenten-1-ones and their close analogues, which are important
synthons in organic synthesis and for the preparation of a variety of useful substances.
precursors for preparation of a various practically useful
products.6−10 2,3-Diaryl-substituted-2-cyclopenten-1-ones are
widely investigated for the development of drugs11−15 and
pesticides;16−19 in particular, they were studied as nonsteroidal
anti-inflammatory,13,20 antitumor15,21,22 drugs and pyrethroid
insecticides.19 Besides, the cyclopentenone fragment is the basic
framework of many important biologically active natural
compounds, including jasmone, methylenomicine B, tetrahy-
drodicranenone B, acetylene dicranenone A, the aflatoxins, and
several prostaglandins. Some 2,3-substituted-2-cyclopenten-1-
ones have been used in perfumes and cosmetics as
fragrances8,23 and in medicine as antibiotics.6,24,25 In the past
decade, much interest has grown in natural and synthetic
cyclopentenone prostaglandins which represent a promising
model for the development of novel antiviral drugs that can
affect different targets during the virus life cycle.9,26
Recently, we showed that 2,3-diaryl-substituted-2-cyclo-
penten-1-ones are also a promising class of photochromic
diarylethenes for the development of the smart materials.27−29
Photochromic diarylethenes have been extensively investigated
for the development of new high technology materials,
including elements for 3D optical storage and molecular
switches.30−32 One of the key issues for the practical application
of photochromic compounds is to establish correlations
between the structure and their spectral and kinetic properties
to obtain new materials with improved characteristics.27,31,32 In
turn, this problem is solved by the development of convenient
methods for modification of photochromic compounds and the
INTRODUCTION
■
α-Bromination of carbonyl compounds is an important
transformation of organic chemistry, as the α-brominated
products are useful intermediates in organic synthesis1−3 and
they can be transformed into a number of other functionalities
under moderate reaction conditions.2,4 Traditionally, this
reaction is difficult to control due to its fast reaction rate and
exothermic character. In addition, owing to easy enolization of
the monobrominated ketones they readily react further to the
double-brominated product.
The carefully performed analysis of the scientific literature
testifies that there is no general method of ketone bromination,
although some patterns of this process are available.2,5 It should
be noted that the process of the ketone bromination depends
not only on their functionalities, but also on the nature of the
solvent and brominating agent. Even a minor change of
substituent pattern (electronic or/and steric factors) can
significantly affect both the process of bromination and the
yields of final products. So, the systematic study of the
bromination reaction even by the example of a narrow class of
ketones allows not only development of a convenient
preparative methods for their functionalization and to obtain
practically useful products, but also insights into the patterns of
the course of this process.
In this paper, we have investigated the bromination of the
cyclopentenone ring of 2,3-diarylcyclopent-2-ene-1-ones and
studied the dependence of reaction regioselectivity and final
product yields on the nature of the substituents and the
reaction conditions.
2-Cyclopenten-1-ones derivatives are key and valuable
Received: July 13, 2012
intermediates in organic synthesis, and are widely applied as
Published: August 28, 2012
© 2012 American Chemical Society
8112
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
Table 1. Diarylcyclopentenones 1a−e Bromination: Reaction Conditions, Reagents, and Products
*
Method A: NBS, MeOH, r.t.. Method B: Br2, AcOH, r.t.. Method C: NBS, CH3CN, r.t. Method D: n-BuNBr3, CH3CN, r.t.
introduction of various functional groups. The 2,3-diary-
lcyclopent-2-ene-1-ones bromination and its further function-
alization seems to be a promising way to solve this issue.
catalysts such as toluene-4-sulfonic acid, trimethylsilyltrifluor-
omethanesulfonate.45−48 Tetra-n-butylammonium tribromide,
copper(II) bromide, pyridinium tribromide, and some other
brominating reagents are less commonly used in the
bromination of alkyl carbonyl compounds.49−52 However,
despite many methods for the α-bromination of carbonyl
compounds the choice of an effective technique of bromination
of diarylcyclopentenones bearing thiophene ring is complicated
by the presence of several active centers (double bond, π-donor
aromatic systems, active methylene groups).
Recently, it has been reported that 2,3-diphenylcyclopent-1-
ene-2-ones can easily be brominated into the α-position to the
carbonyl group under the action of NBS in acetonitrile in the
presence of trimethylsilyltrifluoromethanesulfonate as a catalyst
with 60−65% yields.47 However, our studies show that in the
bromination of diarylcyclopentenones bearing thiophene cycles
as the aryl moieties NBS is not suitable. So, the bromination by
NBS occurs in the thiophene ring even when the reaction
RESULTS AND DISCUSSION
■
The various protocols of α-bromination of cyclopentenone
derivatives and its closest analoguesindanoneshave been
developed including the basic method using Br2 in acetic
acid,33−35 in ether,36−38 and in some other solvents.39−42 The
unfriendly and dangerous nature of bromine, however, urged
on the invention of milder conditions making use of
manageable reagents such as N-bromosuccinimide (NBS).
NBS is known to be a superior brominating agent in terms of
the ease of handling and to be used increasingly for α-
bromination of carbonyl compounds, including indanone and
cyclopentenone derivatives in different solvents and in the
presence of a radical initiator such as azabisisobutyronitrile
(AIBN) or dibenzoyl peroxide (BPO)43,44 or some acid
8113
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
proceeds at room temperature without a catalyst, whereas the
bromination in the cyclopentenone ring is not observed. Also,
the addition of catalytic amounts of trimethylsilyltrifluorome-
thanesulfonate does not change the reaction direction. Both
with catalyst and without it monobrominated and dibrominated
in thiophene rings products 2−5 are formed.
gradiently (for 4 h at room temperature than for 3 h at 40
°C and refluxing of the reaction mixtures until the complete
disappearance of the starting diarylcyclopentenone, entry 6 in
Table 2). At room temperature, the reaction rate is much
slower, but the side processes are not observed (entry 1 in
Table 2). Due to the formation of 5,5-dibromo derivative 7b
and 4-methoxy-substituted 9b, a significant reduction in the
yield of the target product is observed when the original
reaction mixture is refluxed (entry 2 in Table 2).
To test the technique described,47 bis-phenylcyclopentenone
1a in the presence of freshly prepared trimethylsilyltrifluor-
omethanesulfonate as a catalyst was brominated, but the
conversion of the starting compound 1a after 24 h under room
temperature was low. However, it was surprising that the
replacement of acetonitrile by methanol and the absence of the
catalyst led to the desired product 6a in good yields (74%), and
the bromination of the benzene ring is not observed. Analogous
results have been obtained for bis-naphthyl-derivative 1h (entry
1 in Table 1 and entries 1and 16 in Table 3). However, under
similar conditions (NBS in methanol) the thiophene-containing
cyclopentenones nevertheless were brominated in thiophene
cycles.
The replacement of methanol with ethyl acetate leads to the
formation of two products5- and 4-bromosubstituted
compounds 6b and 8b, respectively. The reaction at room
temperature does not occur, but the heating of the reaction
mixture under reflux results in the formation of both these
products in moderate yields. The same pattern is observed in a
number of ether solvents, “methyl acetate − ethyl acetate − i-
propyl acetate − n-propyl acetate” (entries 9, 10, 12, 13 in
Table 2). The increase of the reaction temperature leads to the
increase of the 4-isomer 8b yield, with n-butyl acetate being an
exception; in this case, there is a strong drop in the yields of
both isomers, probably due to resinification of the reaction
mixture at high temperatures (>120 °C, entry 14 in Table 2).
Unexpected results were obtained when the reaction between
dithienylcyclopentenone 1b and copper(II) bromide was
carried out in ethyl acetate in the presence of copper acetate
(entry 11 in Table 2). It was found that the addition of copper
acetate completely changes the reaction direction and only the
brominated in thiophene ring products (mono- 2a and
disubstituted 2b) under these conditions were obtained.
These results are similar to those obtained by the bromination
in acetonitrile using N-bromosuccinimide (see entry 3 in Table
1). In the case where a mix of copper bromide and copper
acetate is used, the reaction is likely also to proceed by a radical
mechanism, a possible cause for which is the formation of
copper bromoacetate (CuBrOAc) from copper acetate and
hydrogen bromide.
These results prompted us to examine in more detail the
bromination reaction of the diarylcyclopentenones of thio-
phene series to develop a convenient method for the
preparation of 5-bromo-2,3-diarylcyclopent-2-en-1-ones. The
different conditions, including molecular bromine in acetic acid,
n-BuNBr3 in acetonitrile, as well as copper(II) bromide in
various solvents, have been investigated. In the bromination of
bis-thiophene derivative 1b by molecular bromine in acetic acid,
only the dibrominated thiophene ring product 2b is formed
(entry 2 in Table 1). The replacement of one thiophene ring in
compound 1b by the phenyl moiety (compounds 1c−e) also
leads to the bromination in the thiophene cycle (entries 5, 7, 9
in Table 1), and only for compound 1c along with the product
3a (62%) was double-brominated 3b with low yield (19%) also
isolated (entry 5 in Table 1). The application of N-BuNBr3 in
acetonitrile as bromination agent also results in a complex
mixture from which only products of bromination in one and
two thiophene rings were isolated (compounds 2a and 2b,
entry 4 in Table 1).
The mechanism of the reaction of carbonyl compounds with
copper(II) bromide has been studied previously in details in
several works (Scheme 3).1,2,54−57 A key stage of this process is
the coordination of carbonyl group of ketone 1 to copper atom
resulting in complexes I and II followed by the enolization of
carbonyl compounds.
Scheme 1. Diarylcyclopentenones 1a−e Bromination with
Different Reagents under Various Conditions
In this case, the bromination at 5-position (compound 6) is
likely to proceed via intermediate III, and the formation of 4-
substituted isomer 8 is probably due to enolization of vinyl
ketone II to form an intermediate cyclopentadienol IV. The
formation of 4-brominating product 8 by a radical mechanism
seems to be unlikely, because our attempts to brominate at the
4-position of cyclopentenone ring by NBS in the presence of m-
chloroperbenzoic acid or AIBN were unsuccessful, although it
is known that the bromination of some indanone derivatives in
the β-position to the carbonyl group by NBS under these
conditions in the presence of these radical initiators was very
useful.58−60
The main side process in the monobromination of carbonyl
compounds is the formation of α,α-dibromo-derivatives, since
the enolization is facilitated for the resulting product as
compared to the parent compound. However, when dihetar-
ylcyclopentenones 6b,i were brominated by copper(II) bro-
mide in refluxing methanol along with dibromo-derivatives 7b,i
(10−15%), 4-methoxyderivatives 9b,i (8−18%) as a byproduct
were also formed (entry 2 in Table 2). The formation of 4-
methoxyderivative in this reaction can be explained by the
Some very interesting results were obtained when copper(II)
bromide was used as brominating agent. First, the use of CuBr2
excludes bromination of the thiophene ring, which significantly
reduces the number of byproduct. It was also found that in the
bromination of diatylcyclopentenones with copper(II) bromide
the reaction direction and the yields of target products strongly
depend on the nature of the solvent, reaction temperature and
also on the substituents in the aromatic cycle. Bis(2,5-
dimethylthiophen-3-yl)cyclopent-2-ene-1-one 1b was used as
a model compound in this study (Scheme 2).
The reaction was carried out in various solvents such as
methanol, ethyl acetate, acetonitrile, tetrahydrofuran, propyl
acetate, iso-propyl acetate, butyl acetate, and so forth (Table 2).
The best results for the bromination at the α-position to the
carbonyl group were obtained when the reaction was carried
out in methanol and the reaction temperature increased
8114
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
Scheme 2. Bromination of Diarylcyclopentenone 1b by Cupric Bromide under Different Conditions
Table 2. Diarylcyclopentenone 1b Bromination by CuBr2 under Different Conditions53
*
¶
#
Th = 2.5-dimethylthiophen-3-yl. 1,8-Bis(dimethylamino)naphtaline. Optimal conditions: 4 h under room temperature, then 3 h under 40 °C and
eventually under reflux to maximum conversion of initial diarylethene 1b.
protonation on the first stage of the bromine atom in the 5-
bromketones 6 (cation V) with subsequent formation of
carbocation VI, which in turn eliminates a proton by E1-
elimination mechanism giving adduct VII (Scheme 4). The
latter reacts with methanol to form 4-methoxyderivative 9
(Michael reaction). It should be noted that in the literature
there are no data on the formation of either 4- or 5-alkoxy-
substituted product in the bromination of ketones in the
alcohols. Indirect evidence in favor of the protonation of
bromine atom and the E1-elimination mechanism can be a
transformation of bromoketone 6b to methoxyderivative 9b by
refluxing in alcohol in the presence of acid catalyst (hydro-
chloric acid, hydrobromic acid, or copper bromide) (Scheme
2). Besides, it was found that the yields of 4-methoxyderivative
9b considerably increase (up to 50%) when methanesulfonic
acid as catalyst was added to the reaction of dithienylcyclo-
pentenone with copper(II) bromide in methanol (entry 5 in
Table 2). And in contrast, when proton sponge (1,8-
bis(dimethylamino)naphtaline) or calcium carbonate was
added to this reaction mixture the impurity of 4-methoxyder-
ivative 9b was not detected (entries 3 and 4 in Table 2).
Thus, the development and optimization of the cyclo-
pentenone ring monobromination conditions allowed synthe-
sizing a wide range of 4- and 5-bromo-substituted diary-
lcyclopentenones with different aryl groups (benzene, naph-
thalene, thiophene, and benzothiophene) in good yields (Table
3).
The structure of synthesized compounds was proven by
1
elemental analyses, H NMR and 13C NMR spectroscopy, and
mass spectrometry. The position of the bromine atom in
structure 6b was determined by the analysis of one- and two-
dimensional NMR spectra. The correlations in the NOESY
spectrum between methylene group protons H-4a, 4b and
proton H-4′ of thienyl group (Figure 1) is found that confirm
8115
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
Scheme 3. Reaction Mechanism of the Bromination of Ketones 1 with Copper(II) Bromide
Scheme 4. Reaction Mechanism of 4-Methoxyderivative 9 Formation
the location of bromine atom at 5-position of cyclopentenone
ring. The presence of the methoxy-group at the 4-position of
the cyclopentenone ring of diarylethene 9b has been verified by
correlation between proton H-4 of cyclopentenone cycle and
proton H-4′ of thienyl ring (Figure 1).
In addition, the structures of 5-bromoketones 6b,h were
proven by chemical transformations (Scheme 5). Thus, it was
shown that 5-bromoketones in contrast to 4-isomers, as would
be expected, react with phenylthioamide giving thiazole
derivatives 10a,b, which is indirect proof of the structures of
these bromoketones.
Also, we have found that both 4- and 5-bromo-substituted
cyclopentenones (compound 6b and 8b) react with N-, O-, and
S-nucleophiles (phenol, thiophenol, succinimide, and morpho-
line) forming the products of nucleophilic substitution
(Scheme 6). The reaction with these nucleophiles apparently
proceeds by the SN2-reaction mechanism. The only exception
is the interaction of bromketone 6b with sodium methylate in
absolute methanol, which leads to the formation of 2,3-bis(2,5-
dimethylthiophen-3-yl)-4-methoxycyclopent-2-en-1-one 9b in-
stead of the expected 5-methoxysubstituted product 16
(Scheme 7). 4-Substituted product 9b is also formed upon
the treatment of 4-bromo-substituted isomer 8b with sodium
methoxide in absolute methanol. The formation of 4-methoxy-
substituted product 9b from α-bromoketone 6b can be
explained by assuming that the reaction proceeds by the E2-
elimination reaction mechanism. The formation of the
intermediate 14 which interacts with methanol via a Michael
reaction giving the 4-substituted product is likely to take place
by the synchronous cleavage of the H−C and Br−C bonds of
the two adjacent carbon atoms under the influence of a strong
basesodium methylate. An indirect confirmation of Michael
adduct 14 formation is the reaction of morpholine with the 5-
bromketone 6b in the presence of DBU (diaza(1,3)-
bicyclo[5.4.0]undecane) that leads to 4-morpholino-substituted
product 15. The latter is also obtained from the 4-
bromocyclopentenone 8b by the treatment with morpholine.
CONCLUSION
■
The bromination of 2,3-diarylcyclopent-2-en-1-ones under
various conditions has been studied, and it was found that
the direction of the reaction depends on the nature of the
brominating reagent, solvent, as well as of the aryl moieties.
The regio- and chemoselective methods of the bromination of
2,3-diarylcyclopent-2-en-1-ones have been developed. The
reaction of 2,3-diarylcyclopent-2-en-1-ones with copper(II)
bromide in methanol proved to result in 5-bromoketones with
very high efficiency, while 4-bromoketones are prepared in n-
propyl acetate. The use of the mixture of copper(II) bromide
and copper(II) acetate as brominating reagent in ethyl acetate
leads to bromination only in aromatic (thiophene) cycles. The
reactions of 5-bromoketones synthesized with different
nucleophiles have also been studied, and it turned out that
depending on the basicity of the nucleophile it can be
introduced either at the 5-position (by SN2-mechanism) or
at the 4-position (E2-elimination followed by Michael addition
reaction) of the cyclopentenone ring. The methods developed
can be highly useful for the synthesis of different bromo-
substituted 2-cyclopenten-1-ones and their close analogues.
EXPERIMENTAL SECTION
■
Proton nuclear magnetic resonance spectra (1H NMR), carbon nuclear
magnetic resonance spectra (13C NMR), and two-dimensional
gNOESY, COSY, HSQC, and HMBC experiments (2D-NMR) were
recorded in deuterated solvents on a spectrometers working at 300
1
1
MHz for H, 75 MHz for 13C, and 400 MHz for 2D-NMR. Both H
and 13C NMR chemical shifts are referenced relative to the solvents
residual signals (CHCl3: δ 7.27 for H NMR and δ 77.16 for 13C
1
NMR) and reported in parts per million (ppm) at 25 °C, unless
otherwise stated. Data are represented as follows: chemical shift,
multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet; br, broad),
coupling constant in hertz (Hz), integration, and assignment.
8116
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
Table 3. Bromination of Diarylcyclopentenones 1a−m under Different Optimal Conditions
*
Method A: NBS, MeOH, r.t.. Method E: CuBr2, MeOH, 4 h under room temperature, then 3 h under 40 °C and eventually under reflux to maximal
#
conversion of initial diarylethenes 1. Method F: CuBr2, n-PrOAc, b.p.. Method G: CuBr2, Cu(OAc)2, EtOAc, b.p. The full conversion of initial
cyclopentenone 1m has already been attained under room temperature.
Figure 1. 2D-NOESY spectra correlations used for verifying the position of the bromine atom in diarylethene 6b and the methoxy-group in
diarylethene 9b.
Infrared spectra were measured on a FT-IR spectrometer in KBr
pellets and are reported in terms of frequency of absorption (cm−1).
Melting points (Mp) were recorded using an apparatus and not
corrected. Mass spectra were obtained on a mass spectrometer (70 eV)
with direct sample injection into the ion source. High resolution mass
spectra were obtained from a TOF mass spectrometer with an ESI
source. Microanalyses were obtained using an automatic CHNS/O
Elemental Analyzer.
All chemicals and anhydrous solvents were purchased from
commercial sources and used without further purification. Silica
8117
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
40 mL), water (40 mL), dried with magnesium sulfate, and evaporated
in vacuum; the residue was purified by column chromagraphy eluting
with petroleum ester/ethyl acetate 5:1 (for compounds 2a, 4, 5) or
11:1 (for compounds 2b, 3a).
Scheme 5. Reaction of 5-Bromo-2,3-diarylcyclopent-2-en-1-
ones 6 with Thioamides
Method D (for Ketone 1b). The mixture of ketone 1b (1.00 mmol)
and tetrabutylammonium tribromide (1.10 mmol) in acetonitrile (10
mL) was stirred at room temperature for 2 h, poured into water (130
mL), extracted with methylene chloride (3 × 40 mL). The combined
extracts were washed with diluted sodium sulphite water solution (2 ×
40 mL), water (40 mL), dried with magnesium sulfate, and evaporated
in vacuum; the residue was purified by column chromagraphy eluting
with petroleum ester/ethyl acetate 11:1.
Method E. The mixture of cyclopentenones 1 (3.00 mmol) and
cupric bromide (7.50 mmol) in methanol (15 mL) was stirred at room
temperature for 4 h, then for 3 h at 40 °C, and eventually under reflux
to maximal conversion of initial diarylethenes 1 (TLC-analysis),
poured into ice−water (200 mL), and extracted with methylene
chloride (3 × 60 mL). The combined organic phases were washed
with water (3 × 40 mL), filtered through 1 cm layer of silica gel,
evaporated, and the residue was recrystallized from appropriate
solvent. In case of need, the residue was purified by column
chromatography eluting by petroleum ester/ethyl acetate 10:1.
Method F. The mixture of cyclopentenones 1 (3.00 mmol) and
cupric bromide (7.50 mmol) in abs n-propyl acetate (15 mL) was
stirred under reflux for 1−2 h, poured into ice−water (200 mL), and
extracted with methylene chloride (3 × 60 mL). The combined
organic phases were washed with water (3 × 40 mL), filtered through
1 cm layer of silica gel, and evaporated. The residue was purified by
column chromatography eluting by petroleum ester/ethyl acetate 10:1,
and 5-bromoketones 6 and 4-bromoketones 8 were isolated.
Method G. The mixture of ketone 1 (1.00 mmol), cupric bromide
(2.50 mmol), and cupric acetate (2.50 mmol) in ethyl acetate was
refluxed for 3 h, poured into water (130 mL), extracted with
methylene chloride (3 × 40 mL). The combined extracts were washed
with diluted sodium sulfite water solution (2 × 40 mL), water (40
mL), dried with magnesium sulfate, and evaporated in vacuum; the
residue was purified by column chromagraphy eluting with petroleum
ester/ethyl acetate 5:1 (for compounds 2a, 4) or 11:1 (for compounds
2b, 3a).
Scheme 6. Nucleophilic Substitutions of Bromine Atom at
the 5-Position of Dithienylcyclopentenone 6b
Scheme 7. Reactions of 4- (8b) and 5-Bromo-substituted
(6b) Dithienylcyclopentenones with Morpholine and
Sodium Methylate
Method H (for Ketones 1b,i). The mixture of cyclopentenones 1
(3.00 mmol) and cupric bromide (7.50 mmol) in methanol (15 mL)
was stirred under reflux for 3−4 h to maximal conversion of initial
diarylethenes 1 (TLC-analysis), poured into ice−water (200 mL), and
extracted with methylene chloride (3 × 60 mL). The combined
organic phases were washed with water (3 × 40 mL), filtered through
1 cm layer of silica gel, and evaporated. The residue was purified by
column chromatography eluting by petroleum ester/ethyl acetate
10:1→6:1, and corresponding 5-bromoketones 6, dibromoketones 7,
and methoxy-derivatives 9 were isolated.
Method I (for Ketone 1b). The mixture of cyclopentenone 1b (3.00
mmol), cupric bromide (7.50 mmol), and methanesulfonic acid (1.50
mmol) in methanol (15 mL) was stirred under reflux for 3 h, poured
into ice−water (200 mL), and extracted with methylene chloride (3 ×
60 mL). The combined organic phases were washed with water
solution of NaHCO3 (40 mL), water (2 × 30 mL), filtered through 1
cm layer of silica gel, and evaporated. The residue was purified by
column chromatography eluting by petroleum ester/ethyl acetate
10:1→6:1, and corresponding 5-bromoketone 6b and methoxy-
derivative 9b were isolated.
Methods J, K (for ketone 1b). The mixture of cyclopentenone 1b
(3.00 mmol), cupric bromide (7.50 mmol), and calcium carbonate
(method J) or 1,8-bis(dimethylamino)naphtaline (method K) (3.00
mmol) in methanol (15 mL) was stirred under reflux for 5 h, poured
into ice−water (200 mL), and extracted with methylene chloride (3 ×
60 mL). The combined organic phases were washed with water (2 ×
30 mL), filtered through 1 cm layer of silica gel, and evaporated. The
residue was purified by column chromatography eluting by petroleum
ester/ethyl acetate 10:1→6:1, and corresponding 5-bromoketone 6b
and dibromoketones 7b were isolated.
column chromatography was performed using silica gel 60 (70−230
mesh); TLC analysis was conducted on silica gel 60 F254 plates.
Bromination of 2,3-Diarylcyclopent-2-en-1-ones (General
Procedures). Method A (for Bromoketones 6a and 6h). The
mixture of cyclopentenones 1 (1.00 mmol) and N-bromosuccinimide
(2.00 mmol) in absolute methanol (12 mL) was stirred at room
temperature for 12 h. The precipitate was filtered off and recrystallized
from acetonitrile.
Method B. To the solution of ketone 1 (1.00 mmol) in glacial acetic
acid (5 mL), the solution of bromine (1.05 mmol) in glacial acetic acid
(2 mL) was added dropwise at 20 °C. The mixture was stirred at room
temperature for 15 min, poured into diluted sodium sulfite water
solution (40 mL), extracted with ethyl acetate (3 × 20 mL). The
combined extracts were washed with water (2 × 15 mL), dried with
magnesium sulfate, and evaporated in vacuum, the residue was purified
by column chromagraphy eluting with petroleum ester/ethyl acetate
5:1 (for compounds 4, 5) or 11:1 (for compounds 2b, 3a, 3b).
Method C. The mixture of ketone 1 (1.00 mmol) and N-
bromosuccinimide (1.10 mmol) in abs acetonitrile (10 mL) was
stirred at room temperature for 1 h, poured into water (130 mL),
extracted with methylene chloride (3 × 40 mL). The combined
extracts were washed with diluted sodium sulfite water solution (2 ×
8118
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
2a. 3-(4-Bromo-2,5-dimethylthiophen-3-yl)-2-(2,5-dimethylthio-
phen-3-yl)cyclopent-2-en-1-one. Yield: method C 0.24 g (63%),
method D 0.17 g (45%), method G 0.17 g (45%), light brown powder.
Mp 137−139 °C (ethanol). IR (KBr), cm−1: 2950 (CH3, C−Hthioph),
2917 (CH3, C−Hthioph), 2853 (CH3, C−Hthioph), 1697 (CO), 1620,
(300 MHz, CDCl3): δ 1.97 (s, 3H, Methioph), 2.04 (s, 3H, Methioph),
2.34 (s, 3H, Methioph), 2.36 (s, 3H, Methioph), 2.64−2.73 (m, 2H, CH2),
2.99−3.10 (m, 2H, CH2), 6.49 (s, 1H, Hthioph). 13C NMR (75 MHz,
CDCl3): δ 14.5, 14.79, 15.0, 15.8, 31.2, 34.9, 110.4 (CBr), 125.1,
130.1, 131.0, 133.4, 134.2, 135.3, 136.5, 137.7, 168.0, 206.6 (CO).
MS, m/z (%): 380, 382 (3, [M]+), 301 (100, [M − Br]+), 286 (18, [M
− Br − CH3]+). HRMS−FAB: m/z [M + Na]+ calcd for
C17H17BrOS2: 404.9776; found: 404.9762.
170.0, 206.9 (CO). MS, m/z (%): 346, 348 (48, [M]+), 267 (100,
[M − Br]+). HRMS−FAB: m/z [M + Na]+ calcd for C17H15BrOS:
368.9919, 370.9899; found: 368.9915, 370.9894.
5. 2-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-(4-bromophenyl)-
cyclopent-2-en-1-one. Yield: method B 0.38 g (90%), method C
0.39 g (92%), light yellow powder. Mp 123−125 °C (ethanol). IR
(KBr), cm−1: 3070 (C−Harom), 2956 (C−Harom), 2918 (CH3, C−
1
1433, 1494, 1378, 1271, 1142, 1984, 824, 815, 553, 491. H NMR
H
arom), 2851 (CH3, C−Harom), 1699 (CO), 1617, 1582, 1481, 1358,
1287, 1186, 1171, 1007, 818 (C−Hphenyl). 1H NMR (300 MHz,
CDCl3): δ 2.05 (s, 3H, Me), 2.37 (s, 3H, Me), 2.66−2.80 (m, 2H,
CH2), 3.07−3.18 (m, 2H, CH2), 7.23 (d, J = 8.7 Hz, 2H, CHphenyl),
7.47 (d, J = 8.3 Hz, 2H, CHphenyl). 13C NMR (75 MHz, CDCl3): δ
14.4, 15.1, 29.1, 34.5, 109.9 (CBr), 125.0, 128.9, 129.7, 131.9, 132.0,
134.1, 134.3, 135.9, 168.3, 206.5 (CO). MS, m/z (%): 424, 426, 428
(43, [M]+), 345, 347 (77, [M − Br]+), 266 (39, [M − 2Br]+). Anal.
Calcd for C17H14Br2OS: C, 47.91; H, 3.31; Br, 37.50; S, 7.52. Found:
C, 47.83; H, 3.26; Br, 37.45; S, 7.50.
2b. 2,3-Bis(4-bromo-2,5-dimethylthiophen-3-yl)cyclopent-2-en-
1-one. Yield: method B 0.19 g (41%), method C 0.12 g (26%),
method D 0.04 g (9%), method G 0.23 g (50%), yellow powder. Mp
123−125 °C (ethanol). IR (KBr), cm−1: 2917 (CH3), 2851 (CH3,),
6a. 5-Bromo-2,3-diphenylcyclopent-2-en-1-one. Yield: method A
0.23 g (74%), yellow powder. Mp 121−123 °C (lit.28 122−123 °C).
1H NMR (300 MHz, CDCl3): δ = 3.38 (dd, J = 2.2, 18.7 Hz, 1H, 1/
1
1713 (CO), 1631, 1437, 1262, 1148, 1081, 788. H NMR (300
MHz, CDCl3): δ 1.92−1.99 (m, 6H, 2Me), 2.32 (br. s, 3H, Me), 2.36
(s, 3H, Me), 2.64−2.79 (m, 3H, 1.5CH2), 3.36−3.75 (m, 1H, 1/
2CH2), 3.74 (dd, J = 6.7, 18.7 Hz, 1H, 1/2CH2), 4.66 (dd, J = 2.3, 6.7
1
Hz, 1H, CH), 7.21−7.42 (m, 10H, Hphenyl).
2CH2). H NMR (300 MHz, C6D6, 298 K): δ 1.93−2.15 (m, 12H,
1
4Me), 2.31−2.48 (m, 3H, 1.5CH2), 3.03−3.61 (m, 1H, 1/2CH2). H
6b. 5-Bromo-2,3-bis(2,5-dimethylthiophen-3-yl)cyclopent-2-en-
1-one. Yield: method E 1.09 g (95%), method F 0.11 g (10%),
method H 0.51 g (45%), method I 0.48 g (42%), method J 0.57 g
(50%), method K 0.74 g (65%), green powder. Mp 125−127 °C
(ethanol). IR (KBr), cm−1: 2952 (C−Hthioph), 2916 (CH3, C−Hthioph),
2852 (CH3, C−Hthioph), 1696 (CO), 1604, 1496, 1440, 1284, 716,
504. 1H NMR (300 MHz, CDCl3): δ = 1.95 (s, 6H, 2Me), 2.38 (s, 6H,
2Me), 3.25 (dd, J = 2.2, 18.8 Hz, 1H, 1/2CH2), 3.61 (dd, J = 6.9, 18.8
Hz, 1H, 1/2CH2), 4.57 (dd, J = 2.2, 6.9 Hz, 1H, CH), 6.47 (s, 1H,
NMR (300 MHz, C6D6, 333 K): δ 1.98 (br. s, 3H, Me), 2.09 (s, 3H,
Me), 2.10 (s, 3H, Me), 2.12 (br. s, 3H, Me), 2.35−2.44 (m, 2H,
2CH2), 2.59−3.20 (m, 2H, 2CH2). 13C NMR (75 MHz, CDCl3): δ
14.8 (2 signals), 14.9, 15.0, 30.8, 35.2, 111.0 (CBr), 112.8 (CBr),
128.7, 128.9, 131.0, 131.1, 132.2, 134.5, 135.0, 168.4, 206.7 (CO).
MS, m/z (%): 458, 460, 462 (4, [M]+), 379, 381 (100, [M − Br]+),
364, 366 (78, [M − Br − CH3]+), 300 (52, [M − 2Br]+), 285 (30, [M
− 2Br − CH3]+). HRMS−FAB: m/z [M + H]+ calcd for
C17H16Br2OS2: 460.9061; found: 460.9060.
H
thioph), 6.53 (s, 1H, Hthioph). 13C NMR (75 MHz, CDCl3): δ = 14.2,
14.8, 15.1, 15.2, 42.1, 42.4, 124.8 (CHthioph), 126.4 (CHthioph), 128.2,
132.9, 133.0, 136.0, 136.2, 137.2, 138.8, 162.1, 200.5 (CO). MS (EI,
70 eV): m/z (%) = 380, 382 (12) [M]+, 301 (100) [M − Br]+, 189
(54) [M − Br − Th]+. Anal. Calcd for C17H17BrOS2: C, 53.54; H,
4.49; Br, 20.95; S, 16.82. Found: C, 53.27; H, 4.80; Br, 20.91; S, 16.75.
6c. 5-Bromo-3-(2,5-dimethylthiophen-3-yl)-2-phenylcyclopent-2-
en-1-one. Yield: method E 0.75 g (72%), method F 0.26 g (25%), pale
yellowish powder. Mp 132−133 °C (ethanol). IR (KBr), cm−1: 2954
(C−Harom), 2921 (CH3, C−Harom), 2853 (CH3, C−Harom), 1707 (C
O), 1613, 1594, 1496, 1444, 1376, 1305, 1290, 1171, 1142, 1116, 707
3a. 3-(4-Bromo-2,5-dimethylthiophen-3-yl)-2-phenylcyclopent-2-
en-1-one. Yield: method B 0.22 g (62%), method C 0.28 g (81%),
method G 0.23 g (65%), brown oil. IR (KBr), cm−1: 3055 (CH3, C−
H
H
arom), 2951 (CH3, C−Harom), 2918 (CH3, C−Harom), 2852 (CH3, C−
arom), 1706 (CO), 1629, 1496, 1443, 1435, 1365, 1293, 1166,
1149, 1116, 918, 793 (C−Hphenyl), 762 (C−Hphenyl), 744 (C−Hphenyl),
1
697 (C−Hphenyl), 564. H NMR (300 MHz, CDCl3): δ 1.89 (s, 3H,
Me), 2.39 (s, 3H, Me), 2.52−2.81 (m, 3H, 1.5CH2), 3.26−3.48 m, 1H,
1/2CH2), 7.17−7.38 (m, 5H, CHphenyl). 13C NMR (75 MHz, CDCl3):
δ 14.3, 14.9, 30.5, 35.4, 108.3 (CBr), 127.9, 128.2, 128.6, 131.5, 132.3,
132.4, 133.9, 142.8, 166.1, 207.4 (CO). MS, m/z (%): 346, 348 (42,
[M]+), 331, 333 (35, [M − CH3]+), 289, 291 (21, [M −
C(O)CH2CH2]+), 267 (100, [M − Br]+). HRMS−FAB: m/z [M +
Na]+ calcd for C17H15BrOS: 368.9919, 370.9899; found: 368.9918,
370.9898.
1
(C−Hphenyl), 696 (C−Hphenyl), 658, 595, 493. H NMR (300 MHz,
CDCl3): δ = 1.81 (s, 3H, Me), 2.40 (s, 3H, Me), 3.19−3.31 (m, 1H, 1/
2CH2), 3.53−3.67 (m, 1H, 1/2CH2), 4.55−4.69 (m, 1H, CH), 6.57 (s,
1H, Hthioph), 7.27−7.39 (s, 4H, Hphenyl). 13C NMR (75 MHz, CDCl3):
δ = 14.8, 15.1, 42.3, 42.5, 124.9, 128.1, 128.4, 129.0, 131.8, 132.4,
136.6, 137.57, 137.64, 162.5, 200.2. MS (EI, 70 eV): m/z (%) = 346,
348 (34) [M]+, 267 (100) [M − Br]+, 253 (68) [M − CH(Br)]+, 211
(74) [M − CH2CH(Br)C(O)]+. Anal. Calcd for C17H15BrOS: C,
58.80; H, 4.35; Br, 23.01; S, 9.23. Found: C, 58.71; H, 4.40; Br, 23.14;
S, 9.25.
3b. 5-Bromo-3-(4-bromo-2,5-dimethylthiophen-3-yl)-2-phenylcy-
clopent-2-en-1-one. Yield: method B 0.08 g (19%), brown oil. IR
(KBr), cm−1: 3056 (C−Harom), 2953 (CH3, C−Harom), 2919 (CH3,
C−Harom), 2852 (CH3, C−Harom), 1715 (CO), 1626, 1444, 1427,
1
1367, 1297, 1149, 1112, 797, 748, 701 (C−Hphenyl). H NMR (300
MHz, CDCl3): δ 1.80−1.94 (m, 3H, Me), 2.40 (s, 3H, Me), 3.89−3.01
(m, 1/2H, 1/4CH2), 3.18−3.37 (m, 1/2H, 1/4CH2), 3.62−3.80 (m,
1/2H, 1/4CH2), 3.91−4.06 (m, 1/2H, 1/4CH2), 4.57−4.72 (m, 1H,
CH), 7.21−7.40 (m, 5H, CHphenyl). 13C NMR (75 MHz, CDCl3): δ
14.3, 14.9, 42.1, 42.3, 128.4, 128.5, 128.6, 132.7, 133.6, 136.4, 139.1,
141.2, 144.9, 162.8, 200.4 (CO). MS, m/z (%): 424, 426, 428 (32,
[M]+), 345, 347 (26, [M − Br]+), 330, 332 (16, [M − Br − CH3]+),
266 (100, [M − 2Br]+). HRMS−FAB: m/z [M + H]+ calcd for
C17H14Br2OS: 424.9205; found: 424.9209.
4. 2-(4-Bromo-2,5-dimethylthiophen-3-yl)-3-phenylcyclopent-2-
en-1-one. Yield: method B 0.22 g (62%), method C 0.23 g (64%),
method G 0.26 g (75%), brown oil. IR (KBr), cm−1: 3057 (C−Harom),
2918 (CH3, C−Harom), 2853 (CH3, C−Harom), 1702 (CO), 1625,
1445, 1367, 1271, 1185, 1042, 808, 763 (C−Hphenyl), 691 (C−Hphenyl).
1H NMR (300 MHz, CDCl3): δ 2.04 (s, 3H, Me), 2.37 (s, 3H, Me),
6d. 5-Bromo-2-(2,5-dimethylthiophen-3-yl)-3-phenylcyclopent-2-
en-1-one. Yield: method E 0.60 g (58%), method F 0.22 g (21%),
yellow powder. Mp 72−73 °C (ethanol). IR (KBr), cm−1: 2918 (CH3,
C−Harom), 2850 (CH3, C−Harom), 1705 (CO), 1619, 1445, 1370,
1
1279, 1187, 1141, 1072, 1038, 763 (C−Hphenyl), 692 (C−Hphenyl). H
NMR (300 MHz, CDCl3): δ = 1.97 (s, 3H, Me), 2.42 (s, 3H, Me),
3.38 (dd, J = 1.5, 18.8 Hz, 1H, 1/2CH2), 3.77 (dd, J = 7.0, 18.9 Hz,
1H, 1/2CH2), 4.64 (dd, J = 1.8, 7.4 Hz, 1H, CH), 6.47 (s, 1H, Hthioph),
7.31−7.48 (m, 5H, Hphenyl). 13C NMR (75 MHz, CDCl3): δ = 14.1,
15.3, 40.7, 41.6, 126.1, 127.8, 127.8, 128.0, 128.8, 128.9, 130.9, 133.4,
134.9, 135.5, 136.9, 164.4, 200.7 (CO). MS (EI, 70 eV): m/z (%) =
346, 348 (15) [M]+, 267 (100) [M − Br]+, 233 (40) [M −
CH2CH(Br) − CH3]+, 211 (36) [M − CH2CH(Br)C(O)]+. HRMS−
FAB: m/z [M + Na]+ calcd for C17H15BrOS: 368.9919, 370.9899;
found: 368.9913, 370.9898.
2.65−2.79 (m, 2H, CH2), 3.11−3.28 (m, 2H, CH2), 7.29−7.49 (m,
5H, CHphenyl). 13C NMR (75 MHz, CDCl3): δ 14.4, 15.1, 29.3, 34.6,
110.2 (CBr), 127.4, 128.7, 130.1, 130.5, 131.6, 133.9, 135.46, 135.49,
6e. 5-Bromo-3-(4-bromophenyl)-2-(2,5-dimethylthiophen-3-yl)-
cyclopent-2-en-1-one. Yield: method E 0.96 g (75%), method F
0.40 g (31%), pale brown powder. Mp 151−152 °C (ethanol). IR
8119
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
(KBr), cm−1: 2943 (C−Harom), 2914 (CH3, C−Harom), 2853 (CH3,
C−Harom), 1703 (CO), 1614, 1368, 1072, 1008, 823 (C−Hphenyl),
494. 1H NMR (300 MHz, CDCl3): δ = 1.99 (s, 3H, Me), 2.42 (s, 3H,
Me), 3.34 (dd, J = 1.8, 18.8 Hz, 1H, 1/2CH2), 3.74 (dd, J = 7.0, 18.5
Hz, 1H, 1/2CH2), 4.62 (dd, J = 1.6, 6.8 Hz, 1H, CH), 6.43 (s, 1H,
162.1, 200.4. MS (EI, 70 eV): m/z (%) = 416, 418 (1) [M]+, 337
(100) [M − Br]+, 367 (37) [M − CH2CH(Br)C(O) − CH3]+.
HRMS−FAB: m/z [M + H]+ calcd for C20H17BrOS2: 418.9957;
found: 418.9950.
6j. 5-Bromo-3-(2,5-dimethylthiophen-3-yl)-2-(2-methyl-1-benzo-
thiophen-3-yl)cyclopent-2-en-1-one. Yield: method E 1.00 g (80%),
gray powder. Mp 83−84 °C (ethanol). IR (KBr), cm−1: 2918 (CH3,
C−Harom), 2850 (CH3, C−Harom), 1706 (CO), 1613, 1435, 1281,
1145, 757, 732. 1H NMR (300 MHz, CDCl3): δ = 1.86−1.93 (m, 3H,
Me), 2.15 (s, 1.5H, 1/2Me), 2.25 (s, 1.5H, 1/2Me), 2.31 (s, 3H, Me),
3.32−3.49 (m, 1H, 1/2CH2), 3.75−3.89 (m, 1H, 1/2CH2), 4.69 (dd, J
= 5.5, 8.4 Hz, 1H, 1/2CH), 6.48 (s, 1H, Hthioph), 7.13−7.41 (m, 3H,
H
H
thioph), 7.26 (d, J = 8.4 Hz, 2H, Hphenyl), 7.48 (d, J = 8.4 Hz, 2H,
phenyl). 13C NMR (75 MHz, CDCl3): δ = 14.1, 15.3, 40.5, 41.3, 125.5,
125.9, 127.5, 129.3, 129.4, 132.1, 132.2, 133.7, 133.8, 135.7, 137.3,
162.8, 200.5 (CO). MS (EI, 70 eV): m/z (%) = 424, 426, 428 (21)
[M]+, 345, 347 (58) [M − Br]+, 291 (19) [M − CH2CH(Br)C(O)]+,
266 (61) [M − 2Br]+, 223 (79) [M − CH2CH(Br) − CH3]+, 211
(52) [M − CH2CH(Br)C(O) − Br]+. Anal. Calcd for C17H14Br2OS:
C, 47.91; H, 3.31; Br, 37.50; S, 7.52. Found: C, 47.63; H, 3.26; Br,
37.58; S, 7.54.
H
benzthioph), 7.72 (d, J = 6.4 Hz, 1H, Hbenzthioph). 13C NMR (75 MHz,
CDCl3): δ = 14.9, 15.0, 15.1, 41.8, 42.7, 121.9, 122.0, 122.2. 122.3,
123.7, 123.9, 124.0, 124.2, 124.7, 124.8, 131.5, 131.6, 132.6, 137.20,
137.24, 138.3, 138.6, 138.8, 139.5. 139.6, 139.7, 139.8, 164.3, 200.0
(CO). MS (EI, 70 eV): m/z (%) = 416, 418 (13) [M]+, 337 (100)
[M − Br]+, 322 (32) [M − Br − CH3]+, 277 (58) [M − Br −
SC(CH3) − H]+, 225 (45) [M − Br − Th]+. HRMS−FAB: m/z [M +
H]+ calcd for C20H17BrOS2: 418.9957; found: 418.9956.
6k. 5-Bromo-2,3-bis(2-methyl-1-benzothiophen-3-yl)cyclopent-
2-en-1-one. Yield: method E 1.30 g (96%), brown powder. Mp 69−
70 °C (ethanol). IR (KBr), cm−1: 3057 (C−Harom), 2917 (CH3, C−
6f. 5-Bromo-2-(2,5-dimethylthiophen-3-yl)-3-naphthalen-1-ylcy-
clopent-2-en-1-one. Yield: method E 0.98 g (82%), brown powder.
Mp 68−69 °C (ethanol). IR (KBr), cm−1: 2955 (C−Harom), 2919
(CH3, C−Harom), 2850 (CH3, C−Harom), 1711 (CO), 1460, 1439,
1
1376, 1260, 1102, 1022, 802 (C−Hnaph), 777 (C−Hnaph). H NMR
(300 MHz, CDCl3): δ = 1.83 (s, 3H, Me), 2.22 (s, 3H, Me), 3.39−
3.51 (m, 1H, 1/2CH2), 3.80 (dd, J = 6.1, 19.2 Hz, 1H, 1/2CH2), 4.72
(d, J = 4.8 Hz, 1H, CH), 6.33 (s, 1H, Hthioph), 7.32−7.54 (m, 5H,
H
naphtyl), 7.64 (d, J = 7.7 Hz,1H, Hnaphtyl), 7.84−7.89 (m, 1H, Hnaphtyl).
H
arom), 2850 (CH3, C−Harom), 1712 (CO), 1619, 1458, 1432, 1376,
13C NMR (75 MHz, CDCl3): δ = 14.4, 15.0, 42.0, 43.8, 124.9, 125.2,
1245, 1176, 1138, 759 (C−Harom), 732 (C−Harom). H NMR (300
MHz, CDCl3): δ = 1.89−2.26 (m, 6H, 2Me), 3.28−3.51 (m, 1H, 1/
2CH2), 3.79−4.11 (m, 1H, 1/2CH2), 4.67−4.90 (m, 1H, CHBr),
7.10−7.43 (m, 4H, HBth), 7.60−7.89 (m, 4H, HBth). 13C NMR (75
MHz, CDCl3): δ = 15.1, 15.2, 42.1, 42.8, 121.7, 121.8, 121.9, 123.1,
123.7, 123.8, 123.9, 124.3, 124.8, 127.9, 135.5, 135.6, 137.7, 138.2,
138.5, 140.2, 140.3, 165.0, 200.1 (CO). MS (EI, 70 eV): m/z (%) =
452, 454 (48, [M]+), 373 (76, [M − Br]+). Anal. Calcd. for
C23H17BrOS2: C, 60.93; H, 3.78; Br, 17.62; S, 14.14. Found: C, 60.85;
H, 3.79; Br, 17.69; S, 14.17.
1
125.3, 126.1, 126.4, 126.5, 126.8, 127.1, 128.7, 129.2, 129.9, 133.7,
134.3, 135.9, 136.3, 136.5, 167.0, 200.4 (CO). MS (EI, 70 eV): m/z
(%) = 396, 398 (19) [M]+, 317 (82) [M − Br]+, 302 (11) [M − Br −
CH3]+, 274 (40) [M − CH2CH(Br) − CH3]+, 261 (23) [M −
CH2CH(Br)C(O)]+, 258 (45) [M − CH2CH(Br) − 2CH3]+.
HRMS−FAB: m/z [M + Na]+ calcd for C21H17BrOS: 419.0076,
421.0056; found: 419.0069, 421.0056.
6g. 5-Bromo-3-(2,5-dimethylthiophen-3-yl)-2-naphthalen-1-ylcy-
clopent-2-en-1-one. Yield: method E 1.05 g (88%), brown powder.
Mp 65−66 °C (ethanol). IR (KBr), cm−1: 2954 (C−Harom), 2919
(CH3, C−Harom), 2850 (CH3, C−Harom), 1703 (CO), 1605, 1439,
6l. 5-Bromo-2-(2,5-dimethylthiophen-3-yl)-3-thiophen-2-ylcyclo-
pent-2-en-1-one. Yield: method E 0.79 g (75%), brown oil. IR (KBr),
cm−1: 3088 (C−Hthioph), 2916 (CH3, C−Harom), 2854 (CH3, C−
1
1401, 1309, 1142, 1044, 802 (C−Hnaph), 779 (C−Hnaph). H NMR
(300 MHz, CDCl3): δ = 1.82 (s, 3H, Me), 2.24 (s, 3H, Me), 3.34−
3.53 (m, 1H, 1/2CH2), 3.76−3.92 (m, 1H, 1/2CH2), 4.64−4.87 (m,
1H, CH), 6.38 (s, 1H, Hthioph), 7.17−7.26 (m, 1H, Hnaphtyl), 7.35−7.57
(m, 3H, Hnaphtyl), 7.63−7.74 (m, 1H, Hnaphtyl), 7.85 (d, J = 8.1 Hz, 2H,
H
arom), 1702 (CO), 1608, 1555, 1416, 1389, 1373, 1284, 1179,
1
1139, 1076, 864, 837, 713 (C−Hthioph), 576 (C−Br). H NMR (300
MHz, CDCl3): δ = 2.15 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.43 (dd, J =
2.2, 18.3 Hz, 1H, CH2), 3.83 (dd, J = 7.0, 18.3 Hz, 1H, CH2), 4.64 (dd,
J = 2.2, 7.0 Hz, 1H, CH), 6.43 (s, 1H, Hthioph), 7.06−7.13 (m, 1H,
H
naphtyl). 13C NMR (75 MHz, CDCl3): δ = 15.0, 15.4, 41.8, 42.7,
125.2, 125.3, 125.4, 125.9, 126.0, 126.3, 128.0, 128.4, 128.5, 129.0,
131.4, 132.2, 133.8, 136.6, 136.8, 163.7, 200.5 (CO). MS (EI, 70
eV): m/z (%) = 396, 398 (18) [M]+, 317 (58) [M − Br]+, 302 (16)
[M − Br − CH3]+, 261 (26) [M − CH2CH(Br)C(O)]+, 246 (24) [M
− CH2CH(Br)C(O) − CH3]+. Anal. Calcd for C21H17BrOS: C, 63.48;
H, 4.31; Br, 20.11; S, 8.07. Found: C, 63.39; H, 4.28; Br, 20.05; S, 7.94.
6h. 5-Bromo-2,3-dinaphthalen-1-ylcyclopent-2-en-1-one. Yield:
method A 0.27 g (65%), white powder; Mp 195−197 °C
(acetonitrile). IR (KBr), cm−1: 3052 (C−Harom), 1708 (CO),
H
H
thioph), 7.41 (d, J = 3.3 Hz, 1H, Hthioph), 7.54 (d, J = 5.1 Hz, 1H,
thioph). 13C NMR (75 MHz, CDCl3): δ = 13.9, 15.4, 40.3, 41.6, 125.6,
127.4, 127.6, 130.4, 131.0, 133.0, 136.7, 137.4, 137.7, 158.1, 199.8
(CO). MS (EI, 70 eV): m/z (%) = 352, 354 (10, [M]+), 273 (100,
[M − Br]+). HRMS−FAB: m/z [M + H]+ calcd for C15H13BrOS2:
354.9663; found: 354.9637.
6m. 5-Bromo-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-
cyclopent-2-en-1-one. Yield: method E61 1.21 g (93%), orange
powder. Mp 62−63 °C (ethanol). IR (KBr), cm−1: 2997 (CH3, C−
1
1616, 1508, 1344, 808 (C−Hnaph), 772 (C−Hnaph). H NMR (300
H
arom), 2936 (CH3, C−Harom), 2838 (CH3, C−Harom), 1701 (CO),
MHz, CDCl3): δ = 3.49−3.71 (m, 1H, CH2), 3.82−4.09 (m, 1H,
CH2), 4.77−4.98 (m, 1H, CH), 7.08−7.94 (m, 14H, 14CHnaph). 13C
NMR (75 MHz, CDCl3): δ = 41.6 (CH2), 44.4 (CH), 124.7, 124.9,
124.9, 125.1, 125.1, 125.9, 126.29, 126.30, 126.6, 127.8, 128.4, 128.6,
128.6, 128.94, 128.95, 129.6, 133.47, 133.48, 133.6, 133.7, 140.7,
169.6, 200.5 (CO). MS (EI, 70 eV): m/z (%) = 412, 414 (100)
[M]+, 333 (30) [M − Br]+, 278 (58) [M − CH2CH(Br)C(O)]+. Anal.
Calcd for C25H17BrO: C, 72.65; H, 4.15. Found: C, 72.31; H, 4.08.
6i. 5-Bromo-2-(2,5-dimethylthiophen-3-yl)-3-(2-methyl-1-benzo-
thiophen-3-yl)cyclopent-2-en-1-one. Yield: method E 1.00 g (80%),
method H 0.80 g (64%), yellow powder. Mp 67−68 °C (ethanol). IR
(KBr), cm−1: 2920 (CH3, C−Harom), 2853 (CH3, C−Harom), 1710
1602 (CC), 1580 (CC), 1503, 1451, 1413, 1364 (CC), 1258
(Carom-O), 1180 (CH3), 1124 (CH3), 1024 (Carom-O), 1005, 833
(CHp‑phenyl). 1H NMR (300 MHz, CDCl3): δ = 3.33 (dd, J = 1.8, 18.7
Hz, 1H, 1/2CH2), 3.67−3.71 (m, 1H, 1/2CH2), 3.73 (s, 6H, 2Me),
3.80 (s, 3H, Me), 3.86 (s, 3H, Me), 4.63 (dd, J = 2.1, 7.5 Hz, 1H, CH),
6.48 (s, 2H, Hphenyl), 6.82 (d, J = 8.4 Hz, 2H, Hphenyl), 7.35 (d, J = 8.4
Hz, 2H, Hphenyl). 13C NMR (75 MHz, CDCl3): δ = 40.7 (CH2cyclopent),
42.1 (CHBr), 55.5, 56.2, 61.0, 106.6, 114.1, 126.6, 127.5, 130.4, 135.5,
138.2, 153.6, 161.8, 164.2, 200.4 (CO). MS (EI, 70 eV): m/z (%) =
432, 434 (100) [M]+, 418 (50) [M − CH3]+, 353 (81) [M − Br]+, 338
(45) [M − Br − CH3]+, 298 (25) [M − C(O)CH(Br) − CH3]+.
HRMS−FAB: m/z [M + Na]+ calcd for C21H21BrO5: 455.0465,
457.0445; found: 455.0459, 457.0438.
1
(CO), 1619, 1432, 1379, 1281, 1259, 1139, 1074, 759, 731. H
NMR (300 MHz, CDCl3): δ = 1.86 (s, 3H, Me), 2.15 (s, 3H, Me),
2.31(s, 3H, Me), 3.08−4.01 (m, 2H, CH2), 4.68 (t, J = 3.9 Hz, 1H,
CH), 6.41 (s, 1H, Hthioph), 7.28−7.39 (m, 2H, Hbenzthioph), 7.46−7.60
(m, 1H, Hbenzthioph), 7.77 (d, J = 7.0 Hz, 1H, Hbenzthioph). 13C NMR (75
MHz, CDCl3): δ = 14.4, 15.0, 15.1, 42.0, 42.4, 121.8, 122.3, 124.3,
124.8, 126.0, 127.3, 128.3, 136.2, 136.5, 136.6, 138.0, 138.7, 139.5,
7b. 5,5-Dibromo-2,3-bis(2,5-dimethylthiophen-3-yl)cyclopent-2-
en-1-one. Yield: method H 0.21 g (15%), method J 0.07 g (5%),
brown powder. Mp 96−99 °C (ethanol). IR (KBr), cm−1: 2952 (C−
H
thioph), 2916 (CH3, C−Hthioph), 2852 (CH3, C−Hthioph), 1696 (C
1
O), 1604, 1496, 1440, 1284, 716, 504 (C−Br). H NMR (300 MHz,
8120
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
CDCl3): δ = 1.97 (s, 3H, Me), 2.01 (s, 3H, Me), 2.39 (s, 6H, 2Me),
4.10 (s, CH2), 6.48 (s, 1H, Hthioph), 6.51 (s, 1H, Hthioph). 13C NMR (75
MHz, CDCl3): δ = 14.2, 14.9, 15.1, 15.2, 54.4, 56.1, 124.7, 126.2,
127.7, 128.7, 131.9, 136.4, 136.6, 137.5, 140.0, 157.8, 194.0 (CO).
MS (EI, 70 eV): m/z (%) = 458, 460, 462 (11, [M]+), 379, 381 (100,
[M − Br]+), 300 (50, [M − 2Br]+). HRMS−FAB: m/z [M + H]+
calcd for C17H16Br2OS2: 460.9061; found: 460.9058.
7i. 5,5-Dibromo-2-(2,5-dimethylthiophen-3-yl)-3-(2-methyl-1-
benzothiophen-3-yl)cyclopent-2-en-1-one. Yield: method H 0.15 g
(10%), brown powder. Mp 96−99 °C (ethanol). IR (KBr), cm−1: 3059
(C−Harom), 2954 (C−Harom), 2923 (CH3, C−Harom), 2854 (CH3, C−
Hz, 1H, 1/2CH2), 3.39 (dd, J = 6.4, 19.6 Hz, 1H, 1/2CH2), 5.56 (dd, J
= 1.4, 6.3 Hz, 1H, CH), 6.48 (s, 1H, Hthioph), 7.29 (d, J = 8.7 Hz, 2H,
H
CDCl3): δ = 14.2, 15.3, 44.0, 46.2, 124.9, 125.9, 126.9, 129.8, 132.0,
132.5, 136.1, 137.3, 138.0, 164.4, 202.4 (CO). MS (EI, 70 eV): m/z
(%) = 424, 426, 428 (37, [M]+), 345, 347 (100, [M − Br]+), 317, 319
(42, [M − Br − C(O)]+), 266 (39, [M − 2Br]+). Anal. Calcd for
C17H14Br2OS: C, 47.91; H, 3.31; Br, 37.50; S, 7.52. Found: C, 47.72;
H, 3.29; Br, 37.47; S, 7.49.
2,3-Diaryl-4-methoxycyclopent-2-en-1-ones (General Proce-
dure). Method L. To a solution of sodium methylate (1.20 mmol) in
abs methanol (4 mL) 5-bromocyclopentenones 6 was added (1.00
mmol), the reaction mixture was stirred for 5 h at room temperature,
the solvent was removed in vacuum, and the residue was purified by
column chromatography eluting by petroleum ester/ethyl acetate 6:1.
9b. 2,3-Bis(2,5-dimethylthiophen-3-yl)-4-methoxycyclopent-2-
en-1-one. Yield: method H 0.18 g (18%), method I 0.50 g (50%),
method L 0.07 g (22%), brown oil. 1H NMR (300 MHz, CDCl3): δ =
1.89 (s, 6H, 2Methioph), 2.38 (s, 3H, Methioph), 2.41 (s, 3H, Methioph),
2.59 (dd, J = 1.8, 16.5 Hz, 1H, 1/2CH2), 2.91 (dd, J = 6.0, 12.4 Hz,
1H, 1/2CH2), 3.39 (s, 3H, OMe), 4.88 (dd, J = 2.2, 3.7 Hz, 1H, CH),
6.47 (s, 1H, Hthioph), 6.64 (s, 1H, Hthioph). 13C NMR (75 MHz,
CDCl3): δ = 14.2, 14.6, 15.2, 15.2, 41.0, 56.7, 78.9, 125.3 (CHthioph),
126.6 (CHthioph), 128.2, 131.7, 136.0, 136.0, 136.6, 137.5, 138.3, 162.7,
203.3 (CO). MS (EI, 70 eV): m/z (%) = 332 (48, [M]+), 301 (30,
[M − OCH3]+), 245 (33, [M − CH2CH(OCH3)C(O)]+). HRMS−
FAB: m/z [M + Na]+ calcd for C18H20O2S2: 355.0797; found:
355.0800.
phenyl), 7.51 (d, J = 8.7 Hz, 2H, Hphenyl). 13C NMR (75 MHz,
H
arom), 1725 (CO), 1613, 1456, 1433, 1378, 1286, 1256, 1201,
1139, 1066, 759 (C−Hbenzthioph), 732 (C−Hbenzthioph), 651. H NMR
(300 MHz, CDCl3): δ = 1.94 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.31 (s,
3H, CH3), 3.96−4.48 (br. c, 2H, CH2), 6.41 (c, 1H, Hthioph), 7.29−
7.42 (m, 2H, Hbenzthioph), 7.47−7.55 (m, 1H, Hbenzthioph), 7.72−7.81
(m, 1H, Hbenzthioph). 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.9, 15.0,
54.5, 55.9, 121.6, 122.3, 124.4, 124.9, 125.7, 126.7, 127.2, 132.6, 136.3,
137.0, 137.7, 138.6, 140.5, 158.0, 193.6 (CO). MS (EI, 70 eV): m/z
(%) = 494, 496, 498 (15, [M]+), 415, 417 (100, [M − Br]+), 336 (71,
[M − 2Br]+). HRMS−FAB: m/z [M + Na]+ calcd for C20H16Br2OS2:
516.8901; found: 516.8910.
1
8b. 4-Bromo-2,3-bis(2,5-dimethylthiophen-3-yl)cyclopent-2-en-
1-one. Yield: method F 0.55 g (48%), gray powder. Mp 124−127
°C (ethanol). IR (KBr), cm−1: 2944 (C−Hthioph), 2912 (CH3, C−
H
thioph), 2852 (CH3, C−Hthioph), 1708 (CO), 1616, 1436, 1280,
1
1144, 832, 716, 492 (C−Br). H NMR (300 MHz, CDCl3): δ = 1.87
(s, 3H, Me), 1.90 (s, 3H, Me), 2.38 (s, 3H, Me), 2.43 (s, 3H, Me),
3.08 (dd, J = 1.5, 19.8 Hz, 1H, 1/2CH2), 3.35 (dd, J = 7.3, 20.5 Hz,
1H, 1/2CH2), 5.41 (d, J = 6.6 Hz, 1H, CH), 6.48 (s, 1H, Hthioph), 6.66
(s, 1H, Hthioph). 13C NMR (75 MHz, CDCl3): δ = 14.36, 14.39, 15.27,
15.31, 46.3, 46.5, 124.4, 126.3, 127.5, 131.5, 136.3, 136.5, 137.1, 137.9,
138.7, 163.2, 202.3 (CO). MS (EI, 70 eV): m/z (%) = 380, 382 (19,
[M]+), 301 (100, [M − Br]+), 287 (32, [M − CHBr − H]+), 246 (32,
[M − C(O)CH2CHBr]+). HRMS−FAB: m/z [M + Na]+ calcd for
C17H17BrOS2: 404.9776; found: 404.9756.
9i. 2-(2,5-Dimethylthiophen-3-yl)-4-methoxy-3-(2-methyl-1-ben-
zothiophen-3-yl)cyclopent-2-en-1-one. Yield: method H 0.09 g
(8%), brown oil. IR (KBr), cm−1: 3060 (C−Harom), 2956 (CH3, C−
H
arom), 2925 (CH3, C−Harom), 2854 (CH3, C−Harom), 1704 (CO),
1606, 1527, 1461, 1436, 1380, 1354, 1287, 1259, 1232, 1193, 1152,
1106 (OCH3), 1082, 1017, 765 (C−Hbenzthioph), 751 (C−Hbenzthioph),
730 (C−Hbenzthioph). H NMR (300 MHz, CDCl3): δ = 1.83 (s, 3H,
1
CH3), 2.04 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.60−3.14 (m, 2H, CH2),
3.22 (s, 3H, CH3), 4.93−5.31 (m, 1H, CH), 6.36 (c, 1H, Hthioph),
7.24−7.48 (m, 2H, Hbenzthioph), 7.61−7.85 (m, 2H, Hbenzthioph). 13C
NMR (75 MHz, CDCl3): δ = 14.2, 14.5, 15.1, 42.1, 57.9, 78.8, 121.3,
122.4, 124.0, 124.6, 126.2, 127.3, 136.0, 136.4, 138.6, 140.5, 140.8,
163.2, 203.2 (CO). MS (EI, 70 eV): m/z (%) = 368 (52, [M]+),
337 (25, [M − OCH3]+). HRMS−FAB: m/z [M + Na]+ calcd for
C21H20O2S2: 391.0797; found: 391.0792.
Thizoles 10 (General Procedure). The mixture of 5-bromocy-
clopentenones 6 (0.16 mmol) and thiobenzamide (0.16 mmol) in
absolute ethanol (2 mL) was refluxed for 10 h, poured into ice−water
(20 mL), and extracted with methylene chloride (2 × 10 mL). The
combined organic phases were washed with water (2 × 10 mL), dried
with magnesium sulfate and evaporated; the residue was crystallized
from ethanol.
8c. 4-Bromo-3-(2,5-dimethylthiophen-3-yl)-2-phenylcyclopent-2-
en-1-one. Yield: method F 0.30 g (29%), brown powder. Mp 127−
129 °C (ethanol). IR (KBr), cm−1: 3061 (C−Harom), 3064 (C−Harom),
2966 (C−Harom), 2943 (C−Harom), 2914 (CH3, C−Harom), 2852
(CH3, C−Harom), 1698 (CO), 1618, 1499, 1443, 1369, 1304, 1185,
1175, 1124, 772, 716 (C−Hphenyl), 695 (C−Hphenyl), 655, 579, 495
(C−Br). 1H NMR (300 MHz, CDCl3): δ = 1.77 (s, 3H, Me), 2.45 (s,
3H, Me), 3.12 (dd, J = 1.5, 19.4 Hz, 1H, 1/2CH2), 3.37 (dd, J = 6.6,
19.5 Hz, 1H, 1/2CH2), 5.38 (dd, J = 1.1, 6.2 Hz, 1H, CH), 6.66 (s,
1H, Hthioph), 7.25−7.39 (m, 5H, Hphenyl). 13C NMR (75 MHz, CDCl3):
δ = 14.3, 15.3, 46.5, 46.5, 124.5, 128.4, 128.5, 129.0, 130.8, 131.0,
137.5, 137.6, 141.1, 163.4, 202.0 (CO). MS (EI, 70 eV): m/z (%) =
346, 348 (16, [M]+), 267 (100, [M − Br]+), 211 (32, [M −
C(O)CH2CHBr − H]+). HRMS−FAB: m/z [M + Na]+ calcd for
C17H15BrOS: 368.9919, 370.9899; found: 368.9919, 370.9895.
8d. 4-Bromo-2-(2,5-dimethylthiophen-3-yl)-3-phenylcyclopent-2-
en-1-one. Yield: method F 0.26 g (25%), brown powder. Mp 60−61
°C (ethanol). IR (KBr), cm−1: 3025 (C−Harom), 2917 (CH3, C−
10a. 4,5-Bis(2,5-dimethylthiophen-3-yl)-2-phenyl-6H-cyclopenta-
[d][1,3]thiazole. Yield: 0.05 g (77%), gray powder. Mp 144−145 °C
(ethanol). IR (KBr), cm−1: 2936 (C−Harom), 2912 (CH3, C−Harom),
1
2848 (CH3, C−Harom), 1452, 1440, 1136, 768, 688. H NMR (300
arom), 2852 (CH3, C−Harom), 1704 (CO), 1444, 1368, 1184, 775,
MHz, CDCl3): δ = 1.95 (s, 3H, Me), 2.09 (s, 3H, Me), 2.43 (s, 3H,
Me), 2.45 (s, 3H, Me), 3.76 (s, 2H, CH2), 6.57 (s, 1H, Hthioph), 6.80
(s, 1H, Hthioph), 7.38−7.51 (m, 3H, Ph), 8.00 (d, J = 6.2 Hz, 2H, Ph).
13C NMR (75 MHz, CDCl3): δ = 14.3, 14.5, 15.3, 15.4, 37.7
H
692 (C−Hphenyl), 493 (C−Br). 1H NMR (300 MHz, CDCl3): δ = 1.89
(s, 3H, Me), 2.42 (s, 3H, Me), 3.14 (d, J = 19.4 Hz, 1H, 1/2CH2),
3.39 (dd, J = 6.4, 19.2 Hz, 1H, 1/2CH2), 5.61 (dd, J = 1.1, 6.2 Hz, 1H,
CH), 6.51 (s, 1H, Hthioph), 7.32−7.48 (m, 5H, Hphenyl). 13C NMR (75
MHz, CDCl3): δ = 14.2, 15.3, 44.4, 46.3, 126.2, 127.9, 128.3, 128.7,
128.8, 130.4, 133.7, 136.0, 136.9, 165.9, 202.7 (CO). MS (EI, 70
eV): m/z (%) = 346, 348 (27, [M]+), 267 (100, [M − Br]+). HRMS−
FAB: m/z [M + Na]+ calcd for C17H15BrOS: 368.9919, 370.9899;
found: 368.9916, 370.9897.
(CH2cyclopent), 126.5, 126.5, 127.1, 128.9, 129.6, 131.4, 131.8, 132.2,
133.2, 134.4, 134.8, 134.9, 135.4, 135.7, 140.1, 167.0, 170.7. MS (EI,
70 eV): m/z (%) = 419 (100) [M]+. HRMS−FAB: m/z [M + H]+
calcd for C24H21NS3: 420.0909; found: 420.0905.
10b. 4,5-Dinaphthalen-1-yl-2-phenyl-6H-cyclopenta[d][1,3]-
thiazole. Yield: 0.02 g (22%), yellow powder. Mp 205−207 °C
(ethanol). IR (KBr), cm−1: 3048 (C−Harom), 2961 (C−Harom), 2923
(CH3, C−Harom), 2853 (CH3, C−Harom), 1504, 1449, 1391, 1374,
1261, 1097, 1028, 800 (C−Harom), 777 (C−Harom), 763 (C−Harom),
692, 685. 1H NMR (300 MHz, CDCl3): δ = 4.11 (s, 2H, CH2), 7.19−
7.52 (m, 11H, Harom), 7.65−7.73 (m, 2H, Harom), 7.78 (t, J = 7.2 Hz,
2H, Harom), 7.90−8.03 (m, 3H, Harom), 8.08 (d, J = 8.1 Hz, 1H, Harom).
8e. 4-Bromo-3-(4-bromophenyl)-2-(2,5-dimethylthiophen-3-yl)-
cyclopent-2-en-1-one. Yield: method F 0.45 g (35%), brown powder.
Mp 82−83 °C (ethanol). IR (KBr), cm−1: 2919 (CH3, C−Harom),
2850 (CH3, C−Harom), 1705 (CO), 1586, 1396, 1240, 1183, 1145,
1073, 1009, 830 (C−Hphenyl), 494 (C−Br). 1H NMR (300 MHz,
CDCl3): δ = 1.92 (s, 3H, Me), 2.42 (s, 3H, Me), 3.14 (dd, J = 1.6, 19.6
8121
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
13C NMR (75 MHz, CDCl3): δ = 39.6 (CH2cyclopent), 125.25, 125.31,
Introduction of Morpholine Residue into the Ethene
“Bridge” (General Procedures). Method M. The solution of
bromoketone 6b (for compound 13) or 9b (for compound 15) (0.30
mmol) in morpholine (2 mL) was stirred at room temperature for 20
min, poured into cold water (30 mL), and extracted with ethyl acetate
(2 × 15 mL). The combined organic phases were washed with water
(2 × 10 mL), dried with magnesium sulfate, and solvent was removed
under vacuum. The residue was recrystallized from petroleum ester.
Method N. To a solution of 5-bromoketone 6b (0.50 mmol) in abs
dichloromethane (3 mL) at −70 °C, DBU (2.50 mmol) was added;
after the reaction mixture stirred for 30 min at (−60 to −70) °C,
morpholine (2.00 mmol) was added, and the mixture was allowed to
slowly (during 2 h) heat to room temperature. The solvent was
removed in vacuum and the residue was purified by flash
chromatography eluting by petroleum ester/ethyl acetate 2:1→1:1.
13. 2,3-Bis(2,5-dimethylthiophen-3-yl)-5-morpholin-4-ylcyclo-
pent-2-en-1-one. Yield: method M 0.11 g (91%), gray powder. Mp
121−123 °C (hexane). IR (KBr), cm−1: 2944 (C−Hthioph), 2916 (CH3,
C−Hthioph), 2864 (CH3, C−Hthioph), 1696 (CO), 1612, 1440, 1292,
125.4, 125.6, 125.7, 125.9, 125.9, 126.6, 126.8, 127.4, 127.7, 127.8,
128.1, 128.2, 128.3, 128.8, 128.9, 129.7, 131.9, 132.0, 132.4 133.0,
133.6, 133.8, 134.7, 135.4, 138.0, 145.7, 160.3, 167.3, 171.1. MS (EI,
70 eV): m/z (%) = 451 (100, [M]+), 347 (36, [M − PhCN − H]+).
HRMS−FAB: m/z [M + H]+ calcd for C32H21NS: 452.1467; found:
452.1461.
Nucleophilic Substitutions of Bromine Atom by Phenol and
Thiophenol (General Procedure). To a solution of phenol or
thiophenol (1.20 mmol) in abs benzene (5 mL), metallic sodium (1.25
mmol) was added, and the reaction mixture was stirred at room
temperature overnight (sodium was dissolved entirely); then, 5-
bromoketone 6b (1.00 mmol) was added, and reaction mixture was
refluxed for 2 h, poured into cold water (70 mL), and extracted with
ethyl acetate (3 × 20 mL). The combined organic phases were washed
with water (30 mL), dried with magnesium sulfate, and solvent was
removed under vacuum. The residue was purified by column
chromatography eluting by petroleum ester/ethyl acetate 10:1.
11a. 2,3-Bis(2,5-dimethylthiophen-3-yl)-5-phenoxycyclopent-2-
en-1-one. Yield: 0.24 g (60%), brown oil. IR (KBr), cm−1: 3062
(C−Harom), 3039 (C−Harom), 2946 (C−Harom), 2916 (CH3, C−
1
1144 (C−N), 1116 (C−O), 856. H NMR (300 MHz, CDCl3): δ =
1.91 (s, 3H, Me), 1.92 (s, 3H, Me), 2.36 (s, 3H, Me), 2.39 (s, 3H,
Me), 2.57−2.71 (m, 2H, CH2N), 2.82−2.96 (m, 2H, CH2N), 2.99 (d,
J = 5.1 Hz, 2H, CH2cyclopent), 3.57 (t, J = 5.0 Hz, 1H, CH), 3.76 (t, J =
4.0 Hz, 4H, 2CH2O), 6.43 (s, 1H, Hthioph), 6.56 (s, 1H, Hthioph). 13C
NMR (75 MHz, CDCl3): δ = 14.3, 14.8, 15.1, 15.2, 33.4 (CH2cyclopent),
49.9 (2CH2N), 67.15 (2CH2O), 67.20 (CHN), 125.1, 126.5, 128.8,
133.7, 135.4, 135.9, 136.9, 137.9, 162.5, 205.6 (CO). MS (EI, 70
eV): m/z (%) = 387 (2, [M]+), 302 (64, [M − morph]+), 246 (100,
[M − CH2CH(morph)C(O)]+), 190 (32, [M − morph − Th]+).
HRMS−FAB: m/z [M + Na]+ calcd for C21H25NO2S2: 410.1219;
found: 410.1216.
H
arom), 2856 (CH3, C−Harom), 1711 (CO), 1598, 1589, 1449, 1438,
1387, 1280, 1244, 1226, 1142, 1071, 828, 753 (C−Harom), 691, 495.
1H NMR (300 MHz, CDCl3): δ = 1.95 (s, 6H, 2Me), 2.39 (s, 6H,
2Me), 3.07 (dd, J = 2.4, 17.7 Hz, 1H, 1/2CH2), 3.45 (dd, J = 6.3, 17.5
Hz, 1H, 1/2CH2), 5.01 (dd, J = 2.4, 6.0 Hz, 1H, CHO), 6.53 (s, 1H,
H
thioph), 6.56 (s, 1H, Hthioph), 7.01−7.13 (m, 3H, HPh), 7.28−7.39 (m,
2H, HPh). 13C NMR (75 MHz, CDCl3): δ = 14.3, 14.8, 15.1, 15.2, 38.8
(CH2cyclopent), 75.8 (CHO), 115.4, 115.7, 121.6, 124.9, 126.4, 128.4,
129.5, 133.3, 135.7, 136.0, 138.6, 158.0, 161.6, 202.5 (CO). MS (EI,
70 eV): m/z (%) = 394 (45, [M]+), 301 (100, [M − PhO]+). HRMS−
FAB: m/z [M + Na]+ calcd for C23H22O2S2: 417.0953; found:
417.0946.
15. 2,3-Bis(2,5-dimethylthiophen-3-yl)-4-morpholin-4-ylcyclo-
pent-2-en-1-one. Yield: method M 0.07 g (59%), method N 0.08 g
(40%), brown powder. Mp 191−121 °C (hexane). IR (KBr), cm−1:
2958 (C−Hthioph), 2918 (CH3, C−Hthioph), 2853 (CH3, C−Hthioph),
2816 (C−Hthioph), 1703 (CO), 1616, 1495, 1446, 1346, 1280, 1257,
11b. 2,3-Bis(2,5-dimethylthiophen-3-yl)-5-(phenylsulfanyl)-
cyclopent-2-en-1-one. Yield: 0.27 g (67%), brown oil. IR (KBr),
cm−1: 3057 (C−Harom), 2919 (CH3, C−Harom), 2854 (CH3, C−Harom),
1698 (CO), 1626, 1438, 1381, 1280, 1142, 1074, 831, 747, 692,
490. 1H NMR (300 MHz, CDCl3): δ = 1.78 (s, 3H, Me), 1.79 (s, 3H,
Me), 2.36 (s, 3H, Me), 2.38 (s, 3H, Me), 2.96 (dd, J = 2.5, 18.6 Hz,
1H, 1/2CH2), 3.42 (dd, J = 7.8, 19.3 Hz, 1H, 1/2CH2), 3.92 (dd, J =
2.9, 7.3 Hz, 1H, CHS), 6.43 (m, 2H, Hthioph), 7.25−7.33 (m, 2H, HPh),
7.49−7.58 (m, 3H, HPh). 13C NMR (75 MHz, CDCl3): δ = 14.1, 14.6,
15.1, 15.3, 39.6 (CH2cyclopent), 48.3 (CHS), 124.8, 126.4, 127.2, 127.6,
128.1, 128.6, 129.0, 129.1, 132.6, 133.2, 133.4, 134.9, 135.4, 135.9,
136.9, 137.1, 137.7, 163.6, 203.5 (CO). MS (EI, 70 eV): m/z (%) =
410 (9, [M]+), 301 (100, [M − SPh]+). HRMS−FAB: m/z [M + Na]+
calcd for C23H22OS3: 433.0725; found: 433.0709.
1
1142 (C−N), 1115 (C−O), 1014, 857, 827, 755, 734, 492. H NMR
(300 MHz, CDCl3): δ = 1.86 (s, 3H, Me), 1.92 (s, 3H, Me), 2.38 (s,
3H, Me), 2.40 (s, 3H, Me), 2.43−2.52 (m, 4H, 2CH2N), 2.53−2.78
(m, 2H, CH2cyclopent), 3.54−3.69 (m, 4H, 2CH2O), 4.38−4.45 (m, 1H,
CH), 6.45 (s, 1H, Hthioph), 6.63 (s, 1H, Hthioph). 13C NMR (75 MHz,
CDCl3): δ = 14.3, 14.6, 15.3 (2 signals), 34.2 (CH2cyclopent), 48.6
(2CH2N), 65.2, 67.2, 125.8, 126.6, 128.4, 132.4, 135.6, 135.9, 136.0,
137.5, 138.2, 164.4, 204.7 (CO). MS (EI, 70 eV): m/z (%) = 387
(14, [M − morph]+), 257 (30, [M − CH2C(O) − H2]+). HRMS−
FAB: m/z [M + Na]+ calcd for C21H25NO2S2: 410.1219; found:
410.1215.
ASSOCIATED CONTENT
1-[3,4-Bis(2,5-dimethylthiophen-3-yl)-2-oxocyclopent-3-en-1-yl]-
pyrrolidine-2,5-dione 12. The mixture of 5-bromoketone 6b (0.26
mmol), succinimide (0.29 mmol), and potassium carbonate (0.26
mmol) in abs acetone (5 mL) was stirred at room temperature for 24
h, poured into cold water (60 mL), and extracted with ethyl acetate (3
× 20 mL). The combined organic phases were washed with water (2 ×
30 mL), dried with magnesium sulfate, and solvent was removed under
vacuum. The residue was purified by column chromatography eluting
by petroleum ester/ethyl acetate 1:1.
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra and 2D-NMR experiments of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: shir@ioc.ac.ru.
Notes
■
Yield: 0.06 g (55%), gray powder. Mp 58−59 °C (hexane). IR
(KBr), cm−1: 2950 (C−Hthioph), 2918 (CH3, C−Hthioph), 2857 (CH3,
1
C−Hthioph), 1707 (CO), 1399, 1282, 1165, 1143, 824. H NMR
The authors declare no competing financial interest.
(300 MHz, CDCl3): δ = 1.96 (s, 3H, Me), 1.97 (s, 3H, Me), 2.38 (s,
6H, 2Me), 2.71−2.98 (m, 4H, 2CH2succ), 3.14−3.29 (m, 2H,
CH2cyclopent), 4.81−4.95 (m, 1H, CHN), 6.45 (s, 1H, Hthioph), 6.54
(s, 1H, Hthioph). 13C NMR (75 MHz, CDCl3): δ = 14.2, 14.8, 15.1,
15.2, 28.4 (2CH2succ), 35.5 (2CH2cyclopent), 52.5 (CHN), 125.0, 126.4,
128.5, 133.2, 134.6, 135.9, 136.0, 136.9, 138.3, 162.1, 176.4 (2C
ACKNOWLEDGMENTS
Financial support by Russian Foundation for Basic Research
(RFBR Grant -11-03-00799) is gratefully acknowledged.
■
O
succ), 200.3 (COcyclopent). MS (EI, 70 eV): m/z (%) = 399 (100,
[M]+), 384 (56, [M − CH3]+), 300 (45, [M − succinimide]+), 285
(26, [M − succinimide − CH3]+). HRMS−FAB: m/z [M + H]+ calcd
for C21H21NO3S2: 400.1036; found: 400.1035.
REFERENCES
■
(1) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
VCH Publishers Inc.: New York, 1999; pp 715−719.
8122
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123

The Journal of Organic Chemistry
Article
(2) de Kimpe, N.; Verhe, R. The chemistry of a -haloketones, or-
haloaldehydes and a-haloimines, Patai, S., Rappoport, Z., Eds.; ; John
Wiley & Sons Ltd.: New York, 1988; pp 1−225.
(34) Mignani, S.; Bohme, G. A.; Boireau, A.; Cheve, M.; Damour, D.;
Debono, M.-W.; Genovois-Borella, A.; Imperato, A.; Jimonet, P.; Pratt,
J.; Randle, J. C. R.; Ribeill, Y.; Vuilhorgne, M.; Stutzmann, J. M. Bioorg.
Med. Chem. Lett. 2000, 10, 591.
(35) Esses-Reiter, K.; Reiter, J. J. Heterocycl. Chem. 1996, 33, 879.
(36) Tandon, V. K.; Awasthi, A. K.; Singh, K. A.; Maurya, H. K.;
Gautam, S. K. Heterocycles 2010, 80, 593.
(3) Dagani, M. J.; Barda, H. J.; Benya, T. J.; Sanders, D. C. Ullmann’s
Encyclopedia of Industrial Chemistry: Bromine Compounds; Wiley-WCH
Verlag GmbH & Co.: Weinheim, 2002.
(4) Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2008, 8, 793−
865.
(37) Boberg, F.; Deters, K.; Schulz, J.; Torges, K.-F. Phosph., Sulf.,
Silic. Relat. Elem. 1994, 91, 69.
(5) Smith, M. B.; March, J. March’s Advanced Organic Chemistry,
Reactions, Mechanisms and Structure, 6th ed.; John Wiley & Sons: New
Jersey, 2006.
(6) Mikolajczyk, M. in Antibiotics and Antiviral Compounds, Krohn,
K., Kirst, H. A., Maag, H., Eds.; VCH: Weinheim, 1993; pp 205−213.
(7) Diaz-Maroto, M. C.; Perez-Coello, M. S.; Vinas, M. A. G.;
Cabezudo., M. D. J. Agric. Food Chem. 2003, 51, 1265−1269.
(8) Kirchhoff, E. W.; Aikens, J.; Cassidy, C. Chem. Innovation 2000,
30, 52−53.
(9) Santoro, M. G. Trends Microbiol. 1997, 5, 276−281.
(10) Behrendt, J. Microbiology 2011, 157, 3435−3445.
(11) Gurjar, M. K.; Wakharkar, R. D.; Singh, A. T.; Jaggi, M.; Borate,
H. B.; Shinde, P. D.; Verma, R.; Rajendran, P.; Dutt, S.; Singh, G.;
Sanna, V. K.; Singh, M. K.; Srivastava, S. K.; Mahajan, V. A.; Jadhav, V.
H.; Dutta, K.; Krishnan, K.; Chaudhary, A.; Agarwal, S. K.; Mukherjee,
R.; Burman, A. C. J. Med. Chem. 2007, 50, 1744−1753.
(12) Mull, E.; Sattigeri, V.; Rodriguez, A.; Katzenellenbogen, J.
Bioorg. Med. Chem. 2002, 10, 1381.
(13) Zhao, D.; Xu, F.; Chen, C.; Tillyer, R.; Grabowski, E.; Reider, P.;
Black, C. W.; Ouimet, N.; Prasit, P. Tetrahedron 1999, 55, 6001.
(14) Brian, P.; Riggle, P. J.; Santos, R. A.; Champness, W. C. J.
Bacteriol. 1996, 178, 3221−3231.
(15) Nam, N.-H.; Kim, Y.; You, Y.; Hong, D.; Kim, H.; Ahn, B.
Bioorg. Med. Chem. Lett. 2002, 12, 1955.
(16) Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 12317−12319
(17) Patent WO2011073060
(18) U.S. Patent 1956 2768965
(19) Class, T. J.; Ando, T.; Casida, J. E. J. Agric. Food. Chem. 1990,
(38) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Strazzari, S; Zanardi, G.; Calestani, G. Tetrahedron 2002, 58, 3485.
(39) Prakash, O.; Aneja, D. K.; Hussain, K.; Lohan, P.; Ranjan, P.;
Arora, S.; Sharma, C.; Aneja, K., R. Eur. J. Med. Chem. 2011, 46, 5065.
(40) Rorer S. A. U. S. Patent 5,902,803; 1999.
(41) Jimonet, P.; Bohme, G. A.; Bouquerel, J.; Boireau, A.; Damour,
D.; Debono, M. W.; Genevois-Borella, A.; Hardy, J.-C.; Hubert, P.;
Manfre, F.; Nemecek, P. Bioorg. Med. Chem. Let. 2001, 11, 127.
(42) Chatterjee, A.; Banerjee, S. J. Ind. Chem. Soc. 1964, 41, 643.
(43) Fouad, F. S.; Xi, Z.; Goldberg, I. H.; Jones, G. B. Bioorg. Med.
Chem. Lett. 2004, 14, 3337.
(44) Seeger, D. E.; Lahti, P. M.; Rossi, A. R.; Berson, J. A. J. Am.
Chem. Soc. 1986, 108, 1251.
(45) Pravst, I.; Zupan, M; Stavber, S Tetrahedron Lett. 2006, 47,
4707.
(46) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron. 2008, 64, 5191.
(47) Chiba, S; Xu, Y.-J.; Wang, Y.-F. J. Am. Chem. Soc. 2009, 131,
12886.
(48) Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.; Yadav,
J. S. Tetrahedron Lett. 2006, 47, 991.
(49) Voets, M.; Antes, I.; Scherer, C.; Mueller-Vieira, U.; Biemel, K.;
Marchais-Oberwinkler, S.; Hartmann, R. W. J. Med. Chem. 2006, 49,
2222.
(50) Fitzgerald, D. H.; Muirhead, K. M.; Botting, N. P. Bioorg. Med.
Chem. 2001, 9, 983.
(51) Tillu, V. H.; Shinde, P. D.; Bedekar, A. V.; Wakharkar, R. D.
Synth. Commun. 2003, 33, 1399.
(52) Zhang, R.; Dong, J.; Xu, Y.-g.; Hua, W.-y.; You, Q.-d.; Wen, N.
Eur. J. Med. Chem. 2009, 44, 3771.
38, 529−537.
(20) Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.; Chauret,
N.; Claveau, D.; Ethier, D.; Gordon, R.; Greig, G.; Guay, J.; Hughes,
G.; Jolicoeur, P.; Leblanc, Y.; Nicoll-Griffith, D.; Ouimet, N.;
Riendeau, D.; Visco, D.; Wang, Z.; Xu, L.; Prasit, P. J. Med. Chem.
1999, 42, 1274−1281.
(53) A full version of this table includes studies in other solvents and
is available in the Supporting Information.
(54) Kosower, E. M.; Cole, W. J.; Wu, G. S.; Cardy, D. E.; Meisters,
G. J. Org. Chem. 1963, 28, 630.
(55) Kosower, E. M.; Wu, G. S. J. Org. Chem. 1963, 28, 633.
(56) Kojima, J.; Kawaguchi, Sh. Bull. Chem. Soc. Jpn. 1972, 45, 1293.
(57) Kojima, J.; Usui, K.; Kawaguchi, Sh. Bull. Chem. Soc. Jpn. 1972,
45, 3127.
(21) Nam, N.-H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.; Ahn,
B.-Z. Bioorg. Med. Chem. 2003, 11, 1021−1029.
(22) Gurjar, M. K.; Wakharkar, R. D.; Singh, A. T.; Jaggi, M.; Borate,
H. B.; Shinde, P. D.; Verma, R.; Rajendran, P.; Dutt, S.; Singh, G.;
Sanna, V. K.; Singh, M. K.; Srivastava, S. K.; Mahajan, V. A.; Jadhav, V.
H.; Dutta, K.; Krishnan, K.; Chaudhary, A.; Agarwal, S. K.; Mukherjee,
R.; Burman, A. C. J. Med. Chem. 2007, 50, 1744−1753.
(23) Rouhi, A. M. Chem. Eng. News 1999, 77 (43), 38−46.
(24) Tonari, K.; Sameshima., K. J. Jpn. Oil Chem. Soc. 2000, 49, 583.
(25) Hobbs, G.; Obanye, A. I.; Petty, J. J. Bacteriol. 1992, 174, 1487−
1494.
(26) Straus, D. S.; Glass, C. K. Med. Res. Rev 2001, 21, 185−210.
(27) Shirinian, V. Z.; Shimkin, A. A.; Lonshakov, D. V.; Lvov, A. G.;
Krayushkin, M. M. J. Photochem. Photobiol. A: Chem. 2012, 233, 1.
(28) Ayt, A.; Barachevsky, V.; Kobeleva, O.; Valova, T.; Gorelik, A.;
Krayushkin, M.; Komlenok, M.; Kononenko, V. Phys. Status Solidi C
2011, 8, 2866.
(58) Rioz-Martinez, A.; De Gonzalo, G.; Gotor, V. Synthesis 2010,
110.
(59) Minuti, L.; Taticchi, A.; Gacs-Baitz, E.; Marrocchi, A.
Tetrahedron. 1995, 51, 8953.
(60) Gupta, R. C.; Nautiyal, P.; Jhingran, A. G.; Kamboj, V. P.; Setty,
B. S.; Anand, N. Ind. J. Chem., Sect. B: Org. Chem. Med. Chem. 1981, 20,
303.
(61) The full conversion of initial compound 1m in contrast of other
cyclopentenones 1b-l has already been attained under room
temperature.
(29) Barachevsky, V. A.; Kobeleva, O. I.; Valova, T. M.; Ait, A. O.;
Dunaev, A. A.; Gorelik, A. M.; Krayushkin, M. M.; Levchenko, K. S.;
Yarovenko, V. N.; Kyiko, V. V.; Grebennikov, E. H. Proc. SPIE 2010,
7722, 772225−1.
(30) Durr, H., Bouas-Laurent, H., Eds. Photochromism: Molecules and
̈
Systems; Elsevier: Amsterdam, 2003.
(31) Irie, M. Chem. Rev. 2000, 100, 1685.
(32) Tian, H.; Yang, S. Chem. Soc. Rev. 2004, 33, 85.
(33) Choi, T.; Ma, E. Molecules 2007, 12, 74.
8123
dx.doi.org/10.1021/jo301474j | J. Org. Chem. 2012, 77, 8112−8123