Reaction of (Z)-5-(Bromomethylene)thiophen-2(5 H)-one with some nucleophiles in search for new biofilm inhibitors

Article abstract of DOI:10.1080/00397911.2011.602496

(Z)-5-(Bromomethylene)thiophen-2(5H)-one reacts in a Michael-type addition across the methylene side chain with nucleophiles followed by elimination of bromide. The reaction was done at room temperature and the yields were good. The aromatic sulfur substitution products showed potent activity as biofilm inhibitors. Copyright

Full text of DOI:10.1080/00397911.2011.602496

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Reaction of (Z)-5-
(Bromomethylene)thiophen-2(5H)-one
with Some Nucleophiles in Search for
New Biofilm Inhibitors
Tore Benneche a , Elahe Jafari Chamgordani a & Anne Aamdal Scheie
b
a Department of Chemistry, University of Oslo, Oslo, Norway
b Department of Oral Biology, Faculty of Dentistry, University of
Oslo, Oslo, Norway
Accepted author version posted online: 21 Feb 2012.Published
online: 02 Nov 2012.
To cite this article: Tore Benneche , Elahe Jafari Chamgordani & Anne Aamdal Scheie (2013):
Reaction of (Z)-5-(Bromomethylene)thiophen-2(5H)-one with Some Nucleophiles in Search for New
Biofilm Inhibitors, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:3, 431-437
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Synthetic Communications1, 43: 431–437, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.602496
REACTION OF (Z)-5-(BROMOMETHYLENE)THIOPHEN-
2(5H)-ONE WITH SOME NUCLEOPHILES IN SEARCH
FOR NEW BIOFILM INHIBITORS
Tore Benneche,1 Elahe Jafari Chamgordani,1 and
Anne Aamdal Scheie2
1Department of Chemistry, University of Oslo, Oslo, Norway
2Department of Oral Biology, Faculty of Dentistry, University of Oslo,
Oslo, Norway
GRAPHICAL ABSTRACT
Abstract (Z)-5-(Bromomethylene)thiophen-2(5H)-one reacts in a Michael-type addition
across the methylene side chain with nucleophiles followed by elimination of bromide.
The reaction was done at room temperature and the yields were good. The aromatic sulfur
substitution products showed potent activity as biofilm inhibitors.
Keywords Biofilm; biofilm inhibitors; elimination; Michael addition; thiophenones
INTRODUCTION
Bacteria form biofilms on all kinds of surfaces. Such biofilms may have
substantial implications in fields ranging from various industrial processes to health
and disease.[1] In many bacteria, the mechanisms of biofilm formation include a
cell-density-regulated gene expression called quorum sensing (QS).[2] QS communi-
cation leads to regulation of a variety of physiologic functions, including biofilm for-
mation. QS thus represents an interesting novel target for control of biofilm-related
problems and has lately created great interest in the scientific community.[3]
(Z)-5-(Bromomethylene)thiophen-2(5H)-one (1) is a QS inhibitor.[4] It is also
an analog of the well-known brominated furanones 2 that have biofilm-modulating
poperties.[5] In a comparison between thiophenones and furanones, we found that
=
compound 1 was four times more active than the furanone 2 (R H) in inhibiting
Received April 28, 2011.
Address correspondence to Tore Benneche, Department of Chemistry, University of Oslo, Oslo,
Norway. E-mail: toreben@kjemi.uio.no
431

432
T. BENNECHE, E. J. CHAMGORDANI, AND A. A. SCHEIE
Scheme 1. Reaction of 3-hydroxymethyl-5-(bromomethylene)thiophen-2(5H)-one with acroyl chloride.
biofilm formation in the marine bacteria V. harveyi.[6] In a survey of structure–
activity relationship for the thiophenones, we were interested to see if replacement
of the bromo substituent with other heteroatoms would give biologically active
molecules.
In an acylation reaction between the thiophenone 3 and acroyl chloride we
noted that the product was a mixture of the 5-(bromomethylene) compound 4 and
the 5-(chloromethylene) compound 5 (Scheme 1). A mixture of these compounds
was obtained even if the acylation was carried out at 0 ꢀC and with a relatively short
reaction time (15 min).
This observation led us to believe that it might be possible to exchange the bromo
substituent in 1 with different nucleophiles. Hence we have shown that the bromo sub-
stituent in 1 can be exchanged with other halides and pseudohalides.[6] In this article,
we are concerned with other nucleophiles and their reaction with compound 1.
The mechanism for the exchange reaction between compound 1 and halides or
pseudohalides is thought to be a Michael-type addition of the nucleophile to the
methylene group followed by elimination of the bromide ion. However, the reactivity
in this reaction is dependent on the ring system. For instance, compound 1 reacted
with 1 equivalent of ammonium thiocyanate in acetone at 0 ꢀC to room temperature
to the substitution product 6k in 62% yield (Table 1, entry 13) while the corresponding
furanone needed a large excess (20 equivalents) of ammonium thiocyanate and a pro-
longed reaction time (4 d) for the exchange reaction to take place (Scheme 2).
Of course, there are possibilities for nucleophiles to react with compound 1 at
other places than the exocyclic double bond. For instance, the ring system itself,
which is a thioester, should be inclined to react at the ester function with nucleo-
philes. Indeed, when compound 1 was treated with an aqueous base, then an immedi-
ate decomposition of the ring system was observed, indicating a thioester hydrolysis.
Scheme 2. Reaction of 5-(bromomethylene)furan-2(5H)-one with ammonium thiocyanate.

SYNTHESIS OF BIOFILM INHIBITORS
433
Table 1. Exchange reactions in thiophenone 1 with different nucleophiles (Nu-X)
Entry
6
Nu-X
BuNH-H
Et2N-H
Conditions
DCM, 0 ꢀC, 2 h
CDCl3, 0 ꢀC–rt, 2.5 h
DMF, 0 ꢀC, 20 min
CDCl3, rt, 24 h
Yield (%)a
1
2
a
b
c
85
99
89b
87
60
0
3
N3-Na
PPh3
4
d
e
5
4-NO2C6H4O-H
AcO-NH4
NCO-K
CDCl3, N(Et)3, rt, 18 h
Acetone, rt, 2 d
6
—
—
f
7
MeOH, rt, 3 d
0b
8
EtS-H
CDCl3, N(Et)3, 0 ꢀC–rt, 2 h
CDCl3, N(Et)3, 0 ꢀC–rt, 2 h
DCM, N(Et)3, 0 ꢀC, 30 min
CDCl3, N(Et)3, 0 ꢀC–rt, 3 h
DMF, 0 ꢀC, 15 min
76
96
80
75
71
62c
9
g
h
i
4-ClC6H4S-H
Pyridin-2-ylthio-H
Pyrimidin-2-ylthio-H
C6H5SO2-Na
NCS-NH4
10
11
12
13
j
k
Acetone, 0 ꢀC–rt, 4 h
aZ-isomer. From the 1H NMR of the crude product, in some cases signals seem to come from minor
amounts of the E-isomer.
bRing-opening reaction occurs; see text.
cRef. 6.
In Table 1 are the results from the reaction of compound 1 with different
nucleophiles.
The nitrogen nucleophiles n-butylamine, diethylamine, and sodium azide in
nonhydroxylic solvents reacted rapidly with compound 1 in an exchange reaction
with the bromo substituent (entries 1–3, Table 1). The exchange reaction of n-
butylamine is somewhat surprising because the furan analog 4-bromo-3-butyl-
5-(bromomethylene)furan-2(5H)-one reacts with n-butylamine under the same
conditions at the ester functionality to give only the corresponding 1,5-
dihydropyrrol-2-one.[7] Pyridine and the anion of 5-chloropyrimidin-2(1H)-one in
dichloromethane (DCM) did not react with 1 at room temperature.
Triphenyl phosphine reacted with 1 at room temperature to give a vinyl phos-
phonium bromide in good yield (entry 4). Triphenyl arsine, on the other hand, did
not react even after heating in dichloroethane for 24 h.
A mixture of p-nitrophenol and triethylamine in CDCl3 reacted with 1 to give
the corresponding enol ether (entry 5). Ammonium acetate in acetone gave mainly
starting material after stirring for 2 d at room temperature (entry 6) while
ammonium acetate in dimethylformamide (DMF) led to complete decomposition
of the starting material without observation of any substitution products. Other
types of oxygen nucleophiles as KOCN in DMF and NaOMe in methanol gave com-
plex reaction mixtures, indicating degradation of the ring system. In fact, if com-
pound 1 was reacted with KOCN in methanol=water at room temperature, a
ring-opening reaction with methanol occurred and the dimer 7 and the trimer 8 were

434
T. BENNECHE, E. J. CHAMGORDANI, AND A. A. SCHEIE
Scheme 3. Reaction of 5-(bromomethylene)thiophen-2(5H)-one with a weak base in methanol.
isolated in 47% and 8% yields, respectively, together with 29% of recovered starting
material (entry 7 and Scheme 3).
The same reactivity pattern was observed with ammonium acetate in methanol.
The synthesis of compounds 7 and 8 actually represents a stereospecific synthesis of
penta-2,4-dienoates.
Thiols under basic conditions reacted readily with compound 1 to give substi-
tution products (entries 8–11). Even sodium phenylsulfinate in DMF gave a clean
exchange reaction (entry 12).
The solvent seems to play an important role in the exchange reaction, but the
softness of the nucleophile may be more important, as can be seen from entries 6 and
13. The soft thiocyanate anion reacted nicely at room temperature in acetone,
whereas the relatively hard acetate anion did not react at all under the same
conditions.
The compounds 6 were tested for biofilm inhibition activity on V. harveyi in a
Calgary biofilm model[6] (compound 6a was not tested). Only the aromatic sulfur
compounds 6g–j showed any substantial activity. Details will be published elsewhere.
In summary the bromo substituent in (Z)-5-(bromomethylene)thiophen-2(5-
H)-one (1) can be exchanged with fairly soft nucleophiles in nonhydroxylic solvents
such as DCM, CDCl3, acetone, and DMF. The reaction takes place at room tem-
perature and the yields are good. Only the aromatic sulfur compounds gave substi-
tution products (6g–j) with any essential activity against bacterial biofilm formation.
EXPERIMENTAL
Typical Procedure for the Synthesis of 6 (see also Table 1)
A mixture of 4-chlorobenzenthiol (55 mg, 0.38 mmol) and triethylamine
(43 mg, 0.38 mmol) in DCM (1 mL) was added dropwise to a solution of (Z)-
5-(bromomethylene)thiophen-2(5H)-one (71 mg, 0.38 mmol) in DCM (2 mL) at
0 ꢀC. The mixture was stirred for 1 h at room temperature before ether was added,
and the organic phase was washed with brine. The dried solution (MgSO4) was eva-
porated, and the crude product was purified by flash chromatography using hexane=
EtOAc 8:1 for elution to give (Z)-5-(((4-chlorophenyl)thio)methylene)thiophen-
2(5H)-one 6g. Yield 93 mg (96%); mp 107–108 ꢀC; d (200 MHz, CDCl3) 7.47 (1
H
H, d, J 5.8), 7.42–7.28 (4 H, m), 7.06 (1 H, s), 6.30 (1 H, d, J 5.8); d (75 MHz,
C
CDCl3) 193.75, 147.91, 136.03, 135.49, 133.28, 132.63, 131.62, 130.23, 128.72; m=z
(EI): 256 (Mþ þ 2, 50%), 254 (M þ 2, 100), 228 (17), 226 (40), 191 (19), 98 (56).
HRMS (EI) calc. for C11H7ClOS2 253.9627. Found 253.9629.

SYNTHESIS OF BIOFILM INHIBITORS
435
(Z)-5-((Butylamino)methylene)thiophen-2(5H)-one 6a
Eluent: hexane=EtOAc 1:1; d H (300 MHz, CDCl3) 7.46 (1 H, d, J 5.3), 6.95 (1
H, d, J 13.1), 5.90 (1 H, d, J 5.3), 3.32 (2 H, dd, J 13.2, 6.9), 1.69–1.52 (2 H, m), 1.39
(2 H, m), 0.95 (3 H, t, J 7.3); d (75 MHz, CDCl3) 194.14, 149.34, 142.62, 117.38,
C
108.49, 48.68, 33.27, 20.05, 14.05; m=z (EI) 183 (Mþ, 100), 141 (12), 140 (52), 127
(22), 112 (24), 99 (10); HRMS (EI) C9H13NOS 183.0718. Found 183.0718.
(Z)-5-((Diethylamino)methylene)thiophen-2(5H)-one 6b
Eluent: CHCl3=MeOH 20:1; d H (200 MHz, CDCl3) 7.39 (2 H, d, J 5.3), 6.91 (2 H, s),
5.85 (2 H, d, J 5.3), 3.42 (4 H, q, J 7.2), 1.26 (6 H, t, J 7.2); d C (75 MHz, CDCl3) 195.83,
151.21, 144.07, 114.98, 105.75, 14.78; m=z (EI) 183 (Mþ, 100%), 168 (46), 154 (6), 140 (37),
112 (15), 71 (17), 56 (40). HRMS (EI) calc. for C9H13NOS 183.0718. Found 183.0722.
(Z)-5-((Bromotriphenylphosphoranyl)methylene)thiophen-2(5H)-one 6d
Mp > 260 ꢀC; d H (200 MHz, CDCl3) 9.45 (1 H, d, J 15.7), 9.34 (1 H, dd, J 5.9,
1.4), 7.93–7.54 (15 H, m), 6.45 (1 H, dd, J 5.8, 3.5); d C (75 MHz, CDCl3) 192.25 (s),
162.45 (s), 153.33 (d, J 18.6), 136.12 (d, J 3.1), 134.64 (d, J 11.1), 131.93 (s) 131.11 (d,
J 13.2), 117.93 (d, J 91.2), 111.29 (d, J 88.1); m=z (ESI) 373 (M þ -Br, 100%). HRMS
(ESI) calc. for C23H18OPS 373.0816. Found 373.0810.
(Z)-5-((4-Nitrophenoxy)methylene)thiophen-2(5H)-one 6e
Eluent: CH2Cl2; mp 205–207 ꢀC; d H (200 MHz, CDCl3) 8.16 (2 H, d, J 9.1), 7.52
(1 H, d, J 5.8), 7.19–7.07 (3 H, m), 6.21 (1 H, d, J 5.9); d C (75 MHz, CDCl3) 160.41,
146.73, 141.40, 129.31, 126.58, 124.61, 117.51; m=z (EI) 249 (Mþ, 100%), 192 (6), 147
(17), 146 (8), 71 (11). HRMS (EI) calc. for C11H7NO4S 249.0096; found 249.0101.
(Z)-5-((Ethylthio)methylene)thiophen-2(5H)-one 6f
Eluent: hexane=EtOAc 4:1; d H (200 MHz, CDCl3) 7.43 (1 H, d, J 5.7), 7.03 (1
H, s), 6.19 (1 H, d, J 5.7), 2.92 (2 H, q, J 7.4), 1.38 (3 H, t, J 7.4); d (75 MHz,
C
CDCl3) 194.21, 147.87, 136.11, 134.24, 127.21, 29.74, 16.00; m=z (EI) 172 (Mþ,
100%), 143 (25), 116 (27), 115 (15), 112 (15), 71 (21). HRMS (EI) Calc. for
C7H8OS2 172.0017. Found 172.0019.
(Z)-5-((Pyridin-2-ylthio)methylene)thiophen-2(5H)-one 6h
Eluent: hexane=EtOAc 3:1; mp 133–135 ꢀC; d H (200 MHz, CDCl3) 8.52 (1 H, d, J
4.9), 8.20 (1 H, s), 7.73–7.55 (2 H, m), 7.31 (1 H, d, J 8.0), 7.22–7.14 (1 H, m), 6.30 (1 H,
d, J 5.7); d (75MHz, CDCl3) 193.72, 153.51, 149.66, 148.54, 138.28, 136.17, 128.76,
C
128.32, 123.71, 122.27; m=z (EI) 221 (Mþ, 26%), 193 (15), 192 (20), 161 (68), 160
(100), 135 (15), 78 (27). HRMS (EI) calc. for C10H7NOS2 220.9969. Found 220.9965.
(Z)-5-((Pyrimidin-2-ylthio)methylene)thiophen-2(5H)-one 6i
Eluent: hexane=EtOAc 1:1; mp 163–165 ꢀC; d H (200 MHz, CDCl3) 8.61 (2H, d,
J 5.4), 8.12 (1H, s), 7.62 (1 H, J 5.8), 7.14 (1 H, J 4.8), 6.33 (1 H, d 5.8); d C (75 MHz,

436
T. BENNECHE, E. J. CHAMGORDANI, AND A. A. SCHEIE
CDCl3) 193.75, 167.60, 162.71, 158.32, 148.43, 135.75, 128.98, 128.79, 118.84; m=z
(EI): 222 (Mþ, 41%), 194 (22), 162 (72), 161 (100), 136 (13), 79 (10), 53 (10), 39
(10). HRMS (EI) calc. for C9H6ON2S2: 221.9922. Found 221.9921.
(Z)-5-((Phenylsulfonyl)methylene)thiophen-2(5H)-one 6j
Eluent: hexane=EtOAc 2:1; mp 106 ꢀC; d (600 MHz, CDCl3) 7.93 (1H, d, J
H
7.5), 7.66 (1H, t, J 7.5), 7.63–7.50 (4H, m), 6.73 (1H, s), 6.53 (1 H, d, J 6.0); d
C
(151 MHz, CDCl3) 194.11, 148.76, 148.71, 139.72, 134.38, 133.64, 129.62, 127.90,
127.88; m=z (EI) 252 (Mþ, 17%), 160 (5), 125 (100), 97 (8), 83 (10), 77 (35). HRMS
(EI) calc. for C11H8O3S2 251.9915. Found 251.9920.
(2Z,4Z)-Methyl 5-bromo-4-(((Z)-(5-oxothiophen-2(5H)-ylidene)
methyl)thio)penta-2,4-dienoate 7
Eluent: hexane=EtOAc 3:1; d H (200 MHz, CDCl3) 7.45 (1 H, d, J 5.8), 6.97 (1
H, s), 6.81 (1 H, d, J 1.7), 6.38 (1 H, dd, J 11.6, 1.7), 6.28 (1 H, d, J 5.8), 6.09 (1 H, d,
J 11.6); d C (75 MHz, CDCl3) 193.57, 165.71, 147.89, 138.35, 136.86, 133.90, 129.48,
128.85, 125.46, 112.55, 52.45; m=z (EI) 334 Mþ þ 2, 1%), 332 (Mþ,1), 253 (100), 221
(20), 193 (19), 115 (9), 71 (12); HRMS (EI) calc. for C11H9BrO3S2 331.9176. Found
331.9171.
(2Z,4Z)-Methyl 5-bromo-4-(((1Z,3Z)-5-methoxy-5-oxo-2-(((Z)-(5-
oxothiophen-2(5H)-ylidene)methyl)thio)penta-1,3-dien-1-
yl)thio)penta-2,4-dienoate 8
Eluent: hexane=EtOAc 3:1; d H (200 MHz, CDCl3) 7.45 (1 H, d, J 5.6), 7.43 (1
H, d, J 1.0), 6.90 (1 H, s), 6.75 (1 H, t, J 1.8), 6.41 (1 H, dd, J 11.6, 1.6), 6.38 (1 H, dd,
J 12.0, 1.0) 6.26 (1 H, d, J 5.3), 6.05 (1 H, d, J 11.6), 5.85 (1 H, d, J 12.1), 3.72 (3 H,
s), 3.70 (3 H, s); d C (75 MHz, CDCl3) 193.86, 166.34, 165.75, 147.91, 140.15, 139.13,
138.89, 136.56, 134.54, 131.87, 128.36, 124.97, 123.32, 121.47, 111.53, 52.30, 52.13;
m=z (EI) 476 (Mþ þ 2, 0.3%), 474 (Mþ, 0.3), 395 (37), 323 (12), 284 (10), 253
(100), 221 (22),193 (26), 243 (15), 79 (21). HRMS (EI) calc. for C17H15BrO5S3
473.9265. Found 473.9255. calc. for C17H15O5S3 395.0082. Found 395.0078.
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