A simple synthesis of brominated analogues of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX)

Article abstract of DOI:10.1081/SCC-120024000

Three brominated analogues of the highly mutagenic drinking water micropollutant 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) have been synthesized from MX by halogen exchange reaction.

Full text of DOI:10.1081/SCC-120024000

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A Simple Synthesis of Brominated Analogues of 3-
Chloro-4-(dichloromethyl)-5-hydroxy- 2(5H)-furanone
(MX)
Keith W. Lumbard a , Neil S. Nixon a & Feodor Scheinmann a
a Ultrafine (UFC Ltd.), Synergy House, Guildhall Close, Manchester Science Park, Manchester,
UK
Version of record first published: 15 Aug 2006.
To cite this article: Keith W. Lumbard, Neil S. Nixon & Feodor Scheinmann (2003): A Simple Synthesis of Brominated
Analogues of 3-Chloro-4-(dichloromethyl)-5-hydroxy- 2(5H)-furanone (MX), Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:19, 3411-3417
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3411–3417, 2003
A Simple Synthesis of Brominated Analogues of
3-Chloro-4-(dichloromethyl)-5-hydroxy-
2(5H)-furanone (MX)
*
Keith W. Lumbard, Neil S. Nixon, and Feodor Scheinmann
Ultrafine (UFC Ltd.), Synergy House, Guildhall Close,
Manchester Science Park, Manchester, UK
ABSTRACT
Three brominated analogues of the highly mutagenic drinking
water micropollutant 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-
furanone (MX) have been synthesized from MX by halogen
exchange reaction.
Key Words: Brominated hydroxyfuranones; Disinfection by-
products; Mutagenicity.
*Correspondence: Keith W. Lumbard, Ultrafine (UFC Ltd.), Synergy House,
Guildhall Close, Manchester Science Park, Manchester M15 6SY, UK; E-mail:
k.lumbard@ultrafine.co.uk.
3411
DOI: 10.1081/SCC-120024000
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3412
Lumbard, Nixon, and Scheinmann
The chlorination of drinking water has virtually eliminated cholera,
typhoid fever, and other waterborne diseases in developed nations.
However, chlorinated compounds can be formed by the reaction of
chlorine with small amounts of organic substances dissolved in the
water and such disinfection by-products (DBPs) are now of concern
because of their widespread consumption and the uncertainty regarding
their health effects. There is some evidence from epidemiological studies
of a causal role for chlorination DBPs in human cancer, particularly
bladder cancer.[1]
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) 1 is a
DBP which has been reported to make a substantial contribution to the
mutagenic activity of chlorinated drinking water.[2,3] MX is one of
the most potent known mutagens as determined by the Ames assay.[4]
It has beenshownto produce DNA damage inmammaliancells in
vitro[5,6] and in vivo,[7,8] and to cause cancer in rats.[9] Several methods
for the synthesis of MX have been reported.[10–13]
It is known that the chlorination of drinking water samples con-
taining bromide ions often leads to the production of brominated
trihalomethanes, and Fawell and Horth[14] proposed the similar
formation of brominated analogues of MX (BMXs). Following our suc-
[15]
cessful preparationof MX,
we were requested to synthesize three
BMX compounds, 3-chloro-4-(bromochloromethyl)-5-hydroxy-2(5H)-
furanone (BMX-1) 2, 3-chloro-4-(dibromomethyl)-5-hydroxy-2(5H)-fur-
anone (BMX-2) 3, and 3-bromo-4-(dibromomethyl)-5-hydroxy-2(5H)-
furanone (BMX-3) 4, as standards for the analysis of drinking water
and for the study of their mutagenicity.
Attempts to modify the route by Padmapriya et al.[10] for the prepara-
tion of MX to produce brominated analogues were unsuccessful.[15] We
then investigated the synthesis of the BMX compounds directly from MX,
which is commercially available,[16] by halogen exchange reaction. After
trying a number of different reaction conditions we found that MX could
be converted into BMX-1, BMX-2, and BMX-3 using conditions for the
conversion of alkyl chlorides to alkyl bromides described by Willy et al.[17]
Reactionof MX with bromoethaen adn sodium bromide in1-
methyl-2-pyrrolidinone heated at reflux for 28 h gave a mixture of
BMX-1 and BMX-2 (1:1).[18] Whenthe reactionmixture was heated
to a higher temperature (100ꢀ) ina sealed tube for 24 h a mixture of
BMX-2 and BMX-3 (1:5.5) was obtained (Sch. 1). The individual
compounds were then isolated in >98% purity[19] by preparative
reverse phase HPLC and their identities were established by mass
spectrometry following derivatization of the compounds as methyl
acetals[20] (Sch. 2). The isotope patterns found in the mass spectra

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Synthesis of Brominated Analogues
3413
Scheme 1. Reagents: (i) EtBr/NaBr/1-methyl-2-pyrrolidinone/75ꢀ/28 h, (ii) EtBr/
NaBr/1-methyl-2-pyrrolidinone/100ꢀ/24 h.
Scheme 2. Formationof methyl acetal derivatives for aanlysis by mass
spectrometry.
of the BMX acetals were diagnostic of the number of chlorine and
bromine atoms present. The 1H an d13C NMR spectra of the BMX
compounds were also recorded and are in accord with published
spectral data.[21,22] The yields of BMX-1 and BMX-2, isolated from
the lower temperature reaction, were 18% and 21%, and the yields of
BMX-2 and BMX-3, isolated from the higher temperature reaction,
were 6% and 32% respectively.
Using the BMX compounds supplied by Ultrafine,[23] Horth and
co-workers tentatively identified their presence in a UK drinking
water and found the BMXs to have similar mutagenic activity to
[14,24,25]
that of MX inthe Ames test.
We repeated our synthesis of
BMX-1, BMX-2, and BMX-3 to supply material to Suzuki and
Nakanishi[26] who found the compounds to be present in some
samples of drinking water in Japan.
Alternative multi-step methods for the synthesis of the BMXs
have beenreported inrecent years by 2 research groups. The synthesis
of BMX-2 and BMX-3 has been reported by LaLonde et al.[21] and
the synthesis of BMX-1, BMX-2, and BMX-3 by Lloveras and co-
workers.[22] Both groups have reported mutagenicity studies on the
BMX compounds.[21,27]

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3414
Lumbard, Nixon, and Scheinmann
EXPERIMENTAL
Caution. MX and the BMXs are highly mutagenic and suspected
human carcinogens. Bromoethane is a carcinogen and 1-methyl-2-
pyrrolidinone is also toxic. Suitable precautions must be taken to prevent
exposure to these compounds.
NMR spectra were recorded ona Bruker AC-300E spectrometer in
CDCl3 solution(300 MHz for 1H, 75 MHz for 13C). Infrared spectra
(liquid films) were recorded ona Perki-nElmer 1310 spectrometer.
Electronimpact mass spectra were runby the Mass Spectrometry Service,
Department of Chemistry, University of Manchester, UK. Ultra Violet
spectra were recorded ona Perkin-Elmer 402 UV–VIS spectrometer in
methanol solution.
For HPLC, Gilson equipment was used with UV detection at 225 nm
and a 2 solvent system (where solvent A is methanol and solvent B is
0.1 M ammonium acetate solution containing 0.15% acetic acid).
Analytical HPLC method: Spherisorb 5ODS2 column (4.6 ꢁ 150 mm);
eluent 20% A/80% B; flow 1.0 mL/min; Rt 9.1 min(MX), 11.6 min
(BMX-1), 14.7 min(BMX-2), 17.0 min(BMX-3). Preparative HPLC
method: Rainin Dynamax Microsorb (C18, 5 m) column(10.0 ꢁ 250 mm);
eluent 1, for BMX-1 and BMX-2 mixture, 20% A/80% B; eluent 2, for
BMX-2 and BMX-3 mixture, 25% A/75% B; flow 3.0 mL/min; Rt
26.7 min (BMX-1), 36.5 min (BMX-2) using eluent 1; and Rt 33.3 min
(BMX-2), 36.3 min (BMX-3) using eluent 2.
Synthesis of BMX-1 2 and BMX-2 3
A stirred mixture of MX 1 (210 mg, 0.97 mmol), bromoethane
(8.0 mL, 107 mmol) and sodium bromide (45 mg, 0.44 mmol) in
anhydrous 1-methyl-2-pyrrolidinone (16.0 mL) was heated at reflux (oil
bath at 75ꢀ) for 28 h. The solvent was evaporated and the residue was
partitioned between ethyl acetate (12 mL) and water (8 mL). The aqueous
phase was re-extracted with ethyl acetate (12 mL) and the combined
extract was dried (MgSO4) and evaporated to afford the crude product
mixture as a dark oil. The oil was dissolved ina mixture of HPLC eluent
and methanol, and was then separated by preparative HPLC. The HPLC
product fractions were extracted with ethyl acetate (3 extractions
with volume equal to HPLC fraction) and the extracts were dried
(MgSO4) and evaporated to afford BMX-1 (45 mg, 18%) and BMX-2
(61 mg, 21%).

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Synthesis of Brominated Analogues
3415
1
BMX-1 (2 diastereomers): H NMR ꢀ 6.65, 6.62 (s, 1H, H-6), 6.48,
6.40 (s, 1H, H-5), 4.85 (br, 1H, OH). 13C NMR ꢀ 164.26 (C-2), 151.25,
150.79 (C-3), 124.56, 124.14 (C-4), 97.10, 96.57 (C-5), 44.15, 43.68 (C-6).
BMX-1 acetal: MS m/z 243, 245, 247, 249 [M-OCH3]þ. BMX-2: 1H NMR
ꢀ 6.45 (s, 1H, H-6), 6.42 (s, 1H, H-5), 4.9 (br, 1H, OH). 13C NMR ꢀ
164.52 (C-2), 151.58 (C-3), 123.73 (C-4), 97.54 (C-5), 24.86 (C-6).
BMX-2 acetal: MS m/z 287, 289, 291, 293 [M-OCH3]þ. The IR spectra
of the BMX compounds were very similar, ꢁmax 3380, 1770, 1640 cmꢂ1
,
indicating the stretching frequencies of the hydroxyl group and the
a,b-unsaturated lactone system.
Synthesis of BMX-2 3 and BMX-3 4
A stirred mixture of MX 1 (165 mg, 0.76 mmol), bromoethane
(5.0 mL, 67 mmol) and sodium bromide (135 mg, 1.31 mmol) in
anhydrous 1-methyl-2-pyrrolidinone (5.0 mL) in a sealed tube was
heated at 100ꢀ (bath temp.) for 24 h. The products were thenisolated
inthe manner described above for the mixture of BMX-1 and BMX-2.
The yields of BMX-2 and BMX-3 were 14 mg (6%) and 85 mg (32%)
respectively.
BMX-3: 1H NMR ꢀ 6.45 (s, 1H, H-6), 6.42 (s, 1H, H-5), 4.7 (br, 1H,
OH). 13C NMR ꢀ 164.77 (C-2), 155.65 (C-3), 114.27 (C-4), 98.65 (C-5),
26.54 (C-6). BMX-3 acetal: MS m/z 331, 333, 335, 337 [M-OCH3]þ.
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3416
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Synthesis of Brominated Analogues
3417
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BMX-2; 234 (" 7900) for BMX-3: ꢂmax 224 nm (" 8100) for MX.
19. Purity determined by analytical HPLC.
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inMeOH (1 mL) and the solutionwas heated at 70 ꢀ (bath temp.) for
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solvent was evaporated.
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Received inthe UK February 14, 2003

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