Room-temperature electrophilic 5-endo-dig chlorocyclization of alk-3-yn-1-ones with the use of pool sanitizer: Synthesis of 3-chlorofurans and 5-chlorofuropyrimidine nucleosides

Article abstract of DOI:10.1002/ejoc.200800397

The 5-endo-dig chlorocyclization of 1,4-disubstituted alk-3-yn-1-ones (propargylic ketones) with the use of trichloro-striazinetrione (trichloroisocyanuric acid, TCCA; 0.4 equiv.) in toluene, at room temperature, in the absence of base, provides 2,5-disubstituted 3-chlorofurans in high yields (79-96%). The reaction can be accomplished by using commercially available swimming pool sanitizer. Selected 3-chlorofuran was validated as a substrate for Suzuki-Miyaura coupling. In a similar manner, chlorocyclization of 5-alkynyl-2′-deoxyuridines produces 5-chlorofuropyrimidine nucleosides (76-83%), which are analogues of potent anitviral agents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800397

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800397
Room-Temperature Electrophilic 5-endo-dig Chlorocyclization of Alk-3-yn-1-
ones with the Use of Pool Sanitizer: Synthesis of 3-Chlorofurans and
5-Chlorofuropyrimidine Nucleosides
Adam Sniady,[a] Marco S. Morreale,[a] Kraig A. Wheeler,[b] and Roman Dembinski*[a]
Keywords: Alkynes / C–C coupling / Cyclizations / Halogenation / Heterocycles / Ketones / Nucleosides / Trichloro-
isocyanuric acid
The 5-endo-dig chlorocyclization of 1,4-disubstituted alk-3-
yn-1-ones (propargylic ketones) with the use of trichloro-s-
triazinetrione (trichloroisocyanuric acid, TCCA; 0.4 equiv.) in
rofuran was validated as a substrate for Suzuki–Miyaura
coupling. In a similar manner, chlorocyclization of 5-alkynyl-
2Ј-deoxyuridines produces 5-chlorofuropyrimidine nucleo-
toluene, at room temperature, in the absence of base, pro- sides (76–83%), which are analogues of potent anitviral
vides 2,5-disubstituted 3-chlorofurans in high yields (79–
96%). The reaction can be accomplished by using commer-
cially available swimming pool sanitizer. Selected 3-chlo-
agents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
philic reactions remain little explored, in part due to the
diminished electrophilic character of chlorine compared to
iodine or bromine.[5,6]
Introduction
The use of aryl chlorides has experienced recent attention
due to new developments in efficient coupling methods.
Even so, relatively few examples of arylation reactions em-
ploying heteroaryl chlorides have been reported.[1] Further-
more, because of availability and enhanced reactivity in oxi-
dative addition to transition metal complexes/catalysts,
these reports are largely limited to the use of chlorides posi-
tioned α (ortho) to a heteroatom, which is predominantly
nitrogen.[2] Heteroaryl chlorides are readily available by di-
rect chlorination of aromatic compounds. However, such
reactions are frequently restricted to activated positions, or
are less selective compared to other halogens.
Electrophilic halocyclization reactions offer an efficient
and potent methodology that leads to functionalized
heterocycles by tandem isomerization/halogenation pro-
cesses.[3] The electrophilic component serves as both a cycli-
zation catalyst and halogen donor, thus creating a very ef-
fective process from the standpoint of material economy.
Recently, several groups have extensively explored halocy-
clization reactions that yield functionalized heterocycles.[4]
Iodo, bromo, thio, and seleno derivatives can be produced
with the use of halogen or pseudohalogen reagents such as
molecular iodine, bromine, ICl, N-iodosuccinimide (NIS),
IPy2BF4, N-bromosuccinimide (NBS), ArSBr, ArSCl,
PhSeBr, PhSeCl, and BuTeBr3. However, the chloroelectro-
We previously reported NIS/NBS electrophilic cycliza-
tions leading to substituted furans and furopyrimidines.[7,8]
The 5-endo-dig electrophilic cyclization of 1,4-diarylbut-3-
yn-1-ones (propargylic ketones, 1) with NBS or NIS/ace-
tone and iodine monochloride/dichloromethane, provided
unsymmetrically 2,5-disubstituted 3-halofurans with excel-
lent regiocontrol in high yields.[9,10] Previously, this family
of compounds was difficult to prepare efficiently since di-
rect halogenation generally leads to mixtures of regioiso-
mers.[11] Given the lack of general methodology for analo-
gous chloro adducts, we were interested in extending our
work to monohalogenated β-chlorofurans, to provide a new
methodology for accessing chloroheterocycles and new sub-
strates for Suzuki–Miyaura coupling.
Results and Discussion
N-Chlorosuccinimide (NCS) gave no reaction, or negligi-
ble conversion, when mixed with butynone 1a in toluene,
dichloromethane, or acetone, at room temp. for over 20 h.
When nucleophilic activation of NCS with phenylselenyl
chloride, as described by Mellegaard and Tunge,[6] was in-
vestigated, slow formation of multiple products was ob-
served. Thus, we turned our attention to another N-chlo-
roimide, trichloro-s-triazinetrione (trichloroisocyanuric
acid, TCCA),[12] a more potent, though less selective and
seldomly used, chlorination agent.
[a] Department of Chemistry, Oakland University,
2200 N. Squirrel Road, Rochester, Michigan 48309-4477, USA
E-mail: dembinsk@oakland.edu
[b] Department of Chemistry, Eastern Illinois University,
600 Lincoln Avenue, Charleston, Illinois 61920-3099, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
The potential of trichloro-s-triazinetrione as a substitute
for chlorine in the halogenation of aromatic systems was
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A. Sniady, M. S. Morreale, K. A. Wheeler, R. Dembinski
SHORT COMMUNICATION
noted some time ago[13] but did not elicit much interest.[14]
The few synthetic reports demonstrated the high chlorina-
tion potency that led to multiple chlorination products.[15]
In addition, the combined oxidation/chlorination reactivity
hamper practical synthetic applications. There is industrial
interest in TCCA owing to the high chlorine content
(45.8% by weight). Nearly 100000 t/a of TCCA is produced
and utilized in swimming pool maintenance or food pro-
cessing, with relatively few applications in research
laboratories.
Scheme 2. Suzuki–Miyaura coupling of chlorofuran 2a.
Gratifyingly, we were able to find conditions for chloro-
cyclization of alkynones that lead to 2,5-disubstituted 3-
chlorofurans. When ketones 1a–f[10a,16] were treated with
TCCA in toluene by syringe pump addition, at room tem-
perature, in the absence of base, nearly quantitative forma-
tion of 2a–f was observed. Isolation by silica gel flash
chromatography yielded new chlorofurans 2a–f (Scheme 1,
Table 1) that were characterized spectroscopically and gave
excellent elemental analyses without further treatment.[17]
Finally, the production of 2a in 87% yield was carried out
using TCCA in the form of BioGuard, Smart Sticks which
is marketed as swimming pool sanitizer.
Scheme 1. Preparation of chlorofurans 2 with the use of TCCA.
Table 1. Preparation of chlorofurans 2 with the use of TCCA.
Figure 1. X-ray structure of furan 3a (displacement parameters at
the 50% probability level).
Ynone
R
RЈ
Furan
Yield [%][a]
1a
1b
1c
1d
1e
1f
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
p-CH3C6H4
c-C3H6
p-CH3C6H4
p-tBuC6H4
p-CH3C6H4
p-tBuC6H4
2a
2b
2c
2d
2e
2f
94[b]
79
92
96
92
Furopyrimidine nucleosides are potent and selective anti-
viral agents with high specific activity against the varicella-
zoster virus (VZV). Considering the importance of these
bicyclic nucleosides, we decided to examine the use of
TCCA for a cyclization of 5-alkynyl-2Ј-deoxyuridines 5[20]
to produce chloro-substituted analogues. The furo-nucleo-
sides containing 4-pentylphenyl and p-tolyl substituents be-
long to the group of the most effective structures with the
4-pentylphenyl compound being the most potent and selec-
tive anti-VZV agent reported.[21]
95
[a] Reactions were carried out at room temp. on a 1.0 mmol scale
with 0.4 mmol of TCCA dissolved in 8 mL of toluene (rate of ad-
dition 0.1–0.2 mL/min). [b] 87% with TCCA delivered as a pool
sanitizer (BioGuard, Smart Sticks).
The TCCA reagent makes use of all three chlorine atoms,
thus only requiring a 1:3 molar ratio. The precise stoichi-
ometry needs to be controlled, as excess reagent leads to
chlorination of both β positions producing 3,4-dichlorofu-
rans. Although the reaction of TCCA with aromatic rings
is known, chlorination of the phenyl substituents or toluene
(solvent) has not been noticed.
The chlorofuran 2a was validated as a substrate for the
Suzuki–Miyaura coupling reaction using the catalytic sys-
tem elaborated by Fu et al.[18] in DMF (Scheme 2). 2,3,5-
Triaryl-substituted furans 3a,b were obtained in high yields
(93–99%). Product 3a was characterized by X-ray crystal-
lography (Figure 1).[19] The established conditions (120 °C,
10 h) are comparable to the coupling of β-iodofurans
(90 °C, 24 h).[9a]
Scheme 3. Synthesis of 5-chlorofuropyrimidine nucleosides 5.
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3-Chlorofurans and 5-Chlorofuropyrimidine Nucleosides
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Acyl protection of the ribose hydroxy groups afforded
greater solubility of the nucleosides in toluene. TCCA com-
bined with the acetylated alkynyluridines 4a,b[22] gave 5-
chlorofuropyrimidine nucleosides 5a,b in 76–83% yield,
analogously to the reactivity observed during the synthesis
of the chlorofurans (Scheme 3).
[5]
Conclusions
[6]
[7]
[8]
[9]
We have demonstrated that TCCA is a highly efficient
reagent for the quantitative chlorocyclization of but-3-yn-1-
ones at room temperature and in the absence of a base.
Other important features of this process are ease of product
isolation and high yields. Relatively short reaction times
and an easy to handle chlorination reagent (sold as a pool
sanitizer) open new avenues to synthetically useful electro-
philic reactions. Our approach allows for straightforward
preparation of highly substituted furans. With efficient
atom economy, this method facilitates the introduction of
substituents that are not easily introduced by other meth-
ods.[23] Determination of scope of the reaction with alkyl-
only substituents is the subject of further investigation in
our laboratory. These synthetic advances were also ex-
tended to the preparation of potent antiviral furopyrimid-
ine nucleosides analogues from 5-alkynyl-2Ј-deoxyuridines.
[10]
[11]
[12]
Supporting Information (see also the footnote on the first page of
this article): 1H, 13C NMR spectra for 2, 3, and 5 (also HETCOR);
X-ray table for 3a.
[13]
[14]
Acknowledgments
We acknowledge the donors of the Petroleum Research Fund ad-
ministered by the American Chemical Society (ACS-PRF#46094),
the National Institute of Health (NIH) (CA111329), Oakland Uni-
versity and its Research Excellence Program in Biotechnology for
support of this research. A. S. is grateful for the Provost’s Graduate
Student Research Award. We are thankful to Dr. W. E. Meyer
(Chemtura) and Frontier Scientific, Inc., Logan, Utah, USA for
a generous supply of BioGuard Smart Sticks and boronic acids,
respectively.
[15]
[16]
[17]
Representative procedure: 3-Chloro-2-(4-methylphenyl)-5-phenyl-
furan (2a): A round-bottom flask, equipped with a magnetic
stir bar and a rubber septum was charged with 4-(4-methyl-
phenyl)-1-phenylbut-3-yn-1-one (1a) (0.305 g, 1.30 mmol) and
toluene (20 mL). A separate flask, equipped with a magnetic
stir bar and a rubber septum was charged with TCCA (0.121 g,
0.520 mmol) and toluene (10 mL), and the resulting mixture
was stirred until all of the TCCA had dissolved. Then the
TCCA solution was drawn into a 10 mL syringe and dispensed
into the reaction vessel with a syringe pump at a rate of 0.1–
0.2 mL/min. When the addition was complete, the reaction
mixture was stirred for an additional 1 h. The solvent was re-
moved by rotary evaporation. Silica gel column chromatog-
raphy (2.5ϫ15 cm; CHCl3) gave a colorless fraction. The sol-
vent was removed by rotary evaporation, and the residue was
dried by oil-pump vacuum to give 2a as a white solid (0.329 g,
1.22 mmol, 94%), m.p. 58–59 °C.
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CCDC-670297 (for 3a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[4] Citation of recent publications in the area exceeds the space
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A. Sniady, M. S. Morreale, K. A. Wheeler, R. Dembinski
SHORT COMMUNICATION
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Received: January 31, 2008
Published Online: May 30, 2008
Minor changes have been made to the article since its publication
in Early View.
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Eur. J. Org. Chem. 2008, 3449–3452