Reductive cleavage of heteroaryl C-halogen bonds by iodotrimethylsilane. Facile and regioselective dechlorination of antibiotic pyrrolnitrin

Full text of DOI:10.1021/jo001644s

3610
J . Org. Chem. 2001, 66, 3610-3612
Red u ctive Clea va ge of Heter oa r yl
C-Ha logen Bon d s by Iod otr im eth ylsila n e.
F a cile a n d Regioselective Dech lor in a tion
of An tibiotic P yr r oln itr in
Magoichi Sako,* Toshiyuki Kihara, Katsuyuki Okada,
Yasujiro Ohtani, and Hiromi Kawamoto
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical
University, 5-6-1, Mitahora-higashi, Gifu 502-8585, J apan
sako@gifu-pu.ac.jp
Received November 20, 2000
Iodotrimethylsilane (Me3SiI) is a commercially avail-
able reagent and, as an inexpensive in situ alternative,
can be easily prepared by treatment of chlorotrimethyl-
silane (Me3SiCl) with sodium (or lithium) iodide in
acetonitrile (as an Me3SiI equivalent)1 or without any
solvents2 under mild conditions. This reagent has been
widely used for the cleavage of the C-O bonds in esters
(including lactones, carbamates, and phosphonates) and
ethers (including epoxides and acetals) leading to the
corresponding iodides and carboxylic acids or alcohols as
the ultimate products, as well as for the conversion of
alcohols into the corresponding iodides and for the
deoxygenation of sulfoxides.3,4 These chemical properties
of Me3SiI are due to the weak Si-I bond and an intrinsic
high affinity of the silicon atom for the oxygen atom. The
F igu r e 1.
reductive C-O bond cleavage in benzyl alcohols or benzyl
ethers5 and the reduction of azides leading to amines6
by Me3SiI have also been observed. However, to the best
of our knowledge, there are no precedents for the reduc-
tive dehalogenation of aryl halides by Me3SiI.
During the course of our investigations on the chemical
modifications of the antifungal chemotherapeutic pyr-
rolnitrin, 3-chloro-4-(3-chloro-2-nitrophenyl)pyrrole (1a ),
we observed a regioselective reductive dechlorination of
1a during the reaction with Me3SiI, providing a simple
method for the preparation of 3-(3-chloro-2-nitrophenyl)-
pyrrole (1b) having a high antifungal activity and, in
addition, the first example for the reductive cleavage of
heteroaryl C-halogen bonds by Me3SiI. When the anti-
biotic 1a was treated with two equimolar amounts of Me3-
SiI in dry chloroform at ambient temperature under an
argon atmosphere, the starting 1a was smoothly con-
sumed and converted into a more polar compound (1b),
accompanied by a color change from pale yellow to purple
and then brown. After stirring for 2 h, TLC densitometric
analysis of the reaction mixture showed 10% of remaining
1a and the formation of a trace amount of an uncharac-
terized byproduct together with 1b. UV-visible spectral
analysis of the mixture indicated the formation of almost
an equimolar amount of iodine (λmax: 510 nm) during the
reaction. After treatment of the reaction mixture with
sodium thiosulfate to reduce the generated iodine fol-
lowed by column chromatographic separation, isolation
of 1b in 82% yield as pale yellow crystals occurred. On
the basis of its spectral data, the structure of the product
1b was assigned to 3-(3-chloro-2-nitrophenyl)pyrrole, a
previously reported compound without a detailed de-
scription of its spectral data.7
(1) Morita, T.; Okamoto, Y.; Sakurai, H. J . Chem. Soc., Chem.
Commun. 1978, 874-875; Idem. Tetrahedron Lett. 1978, 2523-2526;
Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. Synthesis
1979, 61-62; Idem. J . Org. Chem. 1979, 44, 1247-1251.
(2) Lissel, M.; Drechsler, K. Synthesis 1983, 459.
(3) J ung, M. E.; Martinelli, M. J . In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; Vol. 4,
p 2854. Olah, G. A.; Prakash, G. K.; Krishnamurti, R. Adv. Silicon
Chem. 1991, 1, 1; Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38,
2225-2277.
(4) Recent reports on synthetic applications of this reagent are as
follows, (a) for the dealkylation of esters: Cha, K. H.; Kang, T. W.;
Cho, D. O.; Lee, H.-W.; Shin, J .; J in, K. Y.; Kim, K.-W.; Kim, J .-W.;
Hong, C., II. Synth. Commun. 1999, 29, 3533-3540; Russell, M. G.
N.; Baker, R.; Castro, J . L. Tetrahedron Lett. 1999, 40, 8667-8670.
Ray, A. K.; Chen, Z.-J .; Stark, R. E. Phytochemistry 1998, 49, 65-70.
Ubasawa, M.; Takashima, H.; Sekiya, K. Nucleosides Nucleotides 1998,
17, 2241-2247. Gervay, J .; Nguyen, T. N.; Hadd, M. J . Carbohydr.
Res. 1997, 300, 119-125. (b) For the dealkylation of carbamates:
Iwashina, T.; Scott. P. G.; Tredget, E. E. Appl. Radiat. Isot. 1997, 48,
1187-1191. (c) For the dealkylation of phosphonates: Vayron, P.;
Renard, P.-Y.; Valleix, A.; Mioskowski, C. Chem. Eur. J . 2000, 6, 1050-
1063; Nakhle, B. M.; Trammell, S. A.; Sigel, K. M.; Meyer, T. J .;
Erickson, B. W. Tetrahedron 1999, 55, 2835-2846. Cipolla, L.; La
Ferla, B.; Panza, L.; Nicotra, F. J . Carbohydr. Chem. 1998, 17, 1003-
1013. Cipolla, L.; La Ferla, B.; Nicotra, F.; Panza, L. Tetrahedron Lett.
1997, 38, 5567-5568. (d) For the dealkylation of ethers: Kamal, A.;
Laxman, E.; Rao, N. V. Tetrahedron Lett. 1999, 40, 371-372. Kraus,
G. A.; Louw, S. V. J . Org. Chem. 1998, 63, 7520-7521. Sato, N.;
Matsumoto, K.; Takishima, M.; Mochizuki, K. J . Chem. Soc., Perkin
Trans. 1 1997, 3167-3172. (e) For the dealkylation of alkylamines:
Begtrup, M.; Vedsoe, P. Acta Chem. Scand. 1996, 50, 549-555. (f) For
the conversion of alcohols to the corresponding iodides: Ivanova, M.
E.; Kurteva, V. B.; Lyapova, M. J .; Pojarlieff, I. G. J . Chem. Res., Synop.
1998, 658-659. Ejjiyar, S.; Saluzzo, C.; Amouroux, R.; Massoui, M.
Tetrahedron Lett. 1997, 38, 1575-1576. (g) For the conversion of
epoxides into azilidines; Chern, J .-H.; Wu, H.-J . Tetrahedron 1998, 54,
5967-5982. Wu, H.-J .; Chern, J .-H. Tetrahedron Lett. 1997, 38, 2887-
2890. (h) For the silyl enol etheration of ketones: Eriksson, M.; Iliefski,
T.; Nilsson, M.; Olsson, T. J . Org. Chem. 1997, 62, 182-187; Eriksson,
M.; J ohansson, A.; Nilsson, M.; Olsson, T. J . Am. Chem. Soc. 1996,
118, 10904-10905. (i) For the cleavage of sulfonamides: Sabitha, G.;
Reddy, B. V. S.; Abraham, S.; Yadav, J . S. Tetrahedron Lett. 1999, 40,
1569-1570.
When the reaction was carried out in deuterochloro-
form followed by 1H NMR spectral measurements, an
increase in the peak signal assignable to the methyl
groups of Me3SiCl at δH 0.44 ppm (δC 4 ppm), ac-
(5) Sabitha, G.; Yadav, J . S. Synth. Commun. 1998, 28, 3065-3071.
Perry, P. J .; Pavlidis, V. H.; Coutts, G. C. Synth. Commun. 1996, 26,
101-111. Stoner, E. J .; Cothron, D. A.; Balmer, M. K.; Roden, B. A.
Tetrahedron 1995, 51, 11043-11062. Sakai, T.; Miyata, K.; Utaka, M.;
Takeda, A. Tetrahedron Lett. 1987, 28, 3817-3818.
(6) Kamal, A.; Laxman, E.; Laxman, N.; Rao, N. V. Tetrahedron Lett.
1998, 39, 8733-8734. Kamal, A.; Rao, N. V.; Laxman, E. Tetrahedron
Lett. 1997, 38, 6945-6948.
(7) Umio, S.; Kariyone, K.; Tanaka, K.; Kishimoto, T.; Nakamura,
H.; Nishida, M. Chem. Pharm. Bull. 1970, 18, 1414-1425. Tanaka,
K.; Kariyone, K.; Umio, S. Chem. Pharm. Bull. 1969, 17, 611-615.
10.1021/jo001644s CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

Notes
Sch em e 1. A P la u sible Mech a n ism for th e
J . Org. Chem., Vol. 66, No. 10, 2001 3611
employed.11 Analogous dehalogenations were observed in
the reactions of 3′,5′-O-diacetyl-5-iodo-3-(3-iodobenzyl)-
2′-deoxyuridine (2a ), 5-bromo-1,3-bis(4-bromobenzyl)-1H-
pyrimidine-2,4-dione (3a ), and 5-bromo-1H-pyrimidine-
2,4-diones (4a ,c), which are susceptible to the single-
electron reduction,12 with Me3SiI to give the corresponding
dehalogenated products, 3′,5′-O-diacetyl-3-(3-iodobenzyl)-
2′-deoxyuridine (2b), 1,3-bis(4-bromobenzyl)-1H-pyrimi-
dine-2,4-dione (3b), and 1H-pyrimidine-2,4-diones (4b,d ),
in moderate yields. Thus, the reductive dehalogenation
with Me3SiI is also applicable to other halogenated
heterocycles.
Dech lor in a tion of 1a by Me3SiI
Exp er im en ta l Section
The melting points are uncorrected. The 1H and 13C NMR
spectra were obtained at 400 and 75 MHz, respectively, using
deuterochloroform unless otherwise noted as the solvent. Mass
spectra were determined at an ionizing voltage of 70 eV. For
the thin-layer chromatographic (TLC) analyses, Merck precoated
TLC plates (Merck No. 5715; silica gel 60-F254) were used.
Column chromatography was performed with silica gel (Merck
No. 9385-5B; silica gel 60). Unless otherwise noted, materials
obtained from commercial suppliers were used without further
purification.
companied by a decrease in the peak signal for Me3SiI
at δH 0.80 (9H, s) ppm was observed. The formation of
Me3SiCl in this reaction was also proven by GC-MS
analysis of the reaction mixture. In further stoichiometry
studies, two or more equimolar amounts of Me3SiI was
shown to be required for the complete consumption of
the starting 1a . Employment of bromotrimethylsilane in
place of Me3SiI was not effective for the formation of 1b,
resulting in the almost complete recovery of the starting
1a .
Rea ction of P yr r oln itr in (1a ) w ith Iod otr im eth ylsila n e
(Me3SiI) or Br om otr im eth ylsila n e (Me3SiBr ). To a solution
of 1a (200 mg, 0.78 mmol) in dry chloroform (80 mL; freshly
distilled after the treatment with anhydrous calcium chloride
overnight) was added Me3SiI (97% purity, Aldrich) (323 µL, 2.2
mmol), and the mixture was stirred at ambient temperature
under an argon atmosphere for 2 h. TLC densitometric analysis
of the reaction mixture showed the formation of a more polar
compound as the major product and a trace amount of a less
polar uncharacterized product, together with the 10% recovery
of the starting 1a . After treatment with saturated sodium
thiosulfate solution (80 mL), the organic solution was well
washed with brine (10 mL, two times), dried over anhydrous
magnesium sulfate, and evaporated to dryness. The resulting
residue was subjected to a silica gel column eluting with toluene
to isolate the recovered 1a (14 mg, 7%) and 3-(3-chloro-2-
nitrophenyl)pyrrole (1b ) (146 mg, 82%): mp 122 °C (lit.5 mp
121-122 °C); IR (KBr) 3415, 1530, 1378 cm-1; UV (MeCN) 271
On the basis of these facts and the chemical reactivity
of Me3SiI,3 we propose a plausible reaction sequence for
the present reductive dechlorination as shown in Scheme
1.8 The initial step of this reaction should be the N-
trimethylsilylation of 1a leading to an N-protected in-
termediate A accompanied by the generation of hydrogen
iodide.9 A single-electron transfer from Me3SiI, having a
low oxidation potential (Eox ) +0.42V vs. SCE, in dry
p
acetonitrile), to A (cf. Ered of 1a ) -1.31V vs SCE, in
1/2
dry acetonitrile) results in the formation of a radical
anion (B), which can release a chloride ion to give a
pyrrolyl radical (D), accompanying the formation of the
Me3SiI radical cation (C). The subsequent reduction of
1
(ꢀ 8 × 103), 207 nm; H NMR δ 6.35 (1H, dd, J ) 2 and 4 Hz),
the radical D by the generated hydrogen iodide (Eox of
p
iodide ) +0.7 V in acetonitrile)10 followed by protonation
affords the ultimate product 1b. The chloride ion can be
trapped by the radical cation C to give Me3SiCl with
release of an iodine atom. The coupling of the generated
iodine atoms forms molecular iodine to color the solution
purple and then brown.
6.82 (1H, dd, J ) 3 and 4 Hz), 6.94 (1H, dd, J ) 2 and 3 Hz),
7.32 (1H, dd, J ) 2 and 8 Hz), 7.37 (1H, t, J ) 8 Hz), 7.44 (1H,
dd, J ) 2 and 8 Hz), 8.42 (1H, br); 13C NMR δ 108, 117, 118,
119, 125, 127, 128, 130 (2), 148; Mass (relative intensity) m/z
224 (M+ for C10H737ClN2O2, 16%), 222 (M+ for C10H735ClN2O2,
52), 197 (32), 195 (100), 166 (22), 149 (24); Anal. Calcd for C10H7-
ClN2O2: m/z 222.0196. Found: m/z 222.0198.
The reaction of 1a (10.0 mg, 0.04 mmol) with Me3SiI (5.7 µL,
0.04 mmol) in deuterochloroform (0.4 mL) was followed by
Characteristics of the present reaction are that the
reductive cleavage of the C-Cl bond smoothly and
efficiently proceeded even under mild conditions and, in
addition, with high chemoselectivity, e.g., the 2-chloro-
nitrobenzene moiety in 1a was inert under the conditions
1
measurement of the H and 13C NMR spectra. In these spectra,
the increase in the characteristic peak signals (δH 0.44 ppm and
δC 4 ppm) for chlorotrimethylsilane (Me3SiCl), accompanied by
a decrease in the peak signals for Me3SiI at δH 0.80 ppm and δC
3 ppm was observed during the reaction. The GC-MS spectrum
of the reaction mixture obtained after stirring for 35 min showed
the presence of a molecular ion peak (m/z 108) for Me3SiCl.
After stirring the solution of 1a (25.6 mg, 0.1 mmol) in dry
chloroform (5.0 mL) containing 0.75, 1.0, 1.5, or 2.0 equiv of Me3-
(8) At this stage, we have no direct evidence strongly supporting
the proposed mechanism. The involvement of a single-electron transfer
process in this reaction, however, is plausible, taking account of (a)
the reasonable redox potentials of the compounds, 1a , Me3SiI, and
hydrogen iodide; (b) the requirement of two equimolar amounts of
Me3SiI for the complete consumption of the starting halide 1a in the
reaction with Me3SiI; (c) the formation of almost equimolar amount of
the oxidation product, molecular iodine, and the expected Me3SiCl.
(9) In further experiments carried out according to referees’ sug-
gestion, the halogenated compounds, 1a , 3a , and 4a ,c, were shown to
be highly stable in chloroform containing an equimolar amount of
hydrogen iodide (57 wt % in distilled water) even after prolonged
reaction time (after 1 day), indicating that hydrogen iodide is not the
reactive species (at least, in the initial stage) for the present dehalo-
genation. In the case of the 3′,5′-O-diacetylated nucleoside 2a , the
occurrence of acid hydrolysis leading to the corresponding deacylated
product was observed under the conditions employed.
(11) The treatment of 2-chloro-3-nitropyridine with Me3SiI under
the conditions analogous to the case of 1a resulted in the reductive
dechlorination to give 3-nitropyridine in 41% yield with the 31%
recovery of the starting chloronitropyridine. In this reaction, the
formation of 3-amino-2-chloropyridine (29%) was also observed. In
sharp contrast to these facts, 2-chloronitrobenzene was stable under
the conditions employed even after prolonged reaction time (after 1
day).
(12) These 5-bromo-1H-pyrimidine-2,4-diones 4a ,c underwent the
reductive debromination with ease via
a single-electron-transfer
process upon treatment with 1-benzyl-1,4-dihydronicotinamide under
thermal conditions, see Sako, M.; Hirota, K.; Maki, Y. Tetrahedron
1983, 39, 3919-3921.
(10) Stonbury, D. M.; Wilmarth, W. K.; Khalaf, S.; Po, H. N.; Byrd,
J . E. Inorg. Chem. 1980, 19, 2715-2722.

3612 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
SiI under analogous conditions (for 2 h), TLC densitometric
analyses of the reaction mixtures were carried out and showed
the formation of 1b in the following yields: 15% (the remaining
of 1a : 72%) in the case of Me3SiI (0.75 equiv); 43% (the
remaining of 1a : 45%) in the case of Me3SiI (1.0 equiv); 77%
(the remaining of 1a : 14%) in the case of Me3SiI (1.5 equiv);
85% (the remaining of 1a : 10%) in the case of Me3SiI (2.0 equiv).
The reaction of 1a (15 mg, 0.06 mmol) with Me3SiBr (97%
purity, Aldrich) (20 µL, 0.15 mmol) was carried out under the
conditions analogous to the case of Me3SiI. TLC analysis of the
reaction mixture showed the formation of a trace amount of 1b
and the almost complete recovery of the starting 1a in this
reaction.
mmol) dropwise, and the mixture was stirred at ambient
temperature for 0.5 h. After removal of the solvent under
reduced pressure, the residue was dissolved into ethyl acetate
(30 mL), and then the solution was washed with brine (10 mL,
two times), dried over anhydrous magnesium sulfate, and
evaporated to dryness. The resulting residue was purified by
column chromatography eluted with chloroform to isolate the
desired product 3a (516 mg, 98%): colorless powder; mp 183-
184 °C; IR (KBr) 1705, 1657 cm-1; UV (MeOH) 284 (ꢀ 1.14 ×
104), 219 (2.81 × 104) nm; 1H NMR δ 4.87 and 5.11 (each 2H,
each s), 7.16, 7.38, 7.43, and 7.52 (each 1H, each d, each J ) 8
Hz), 7.46 (1H, s); Mass (relative intensity) m/z 532 (M+ for
C
18H1381Br3N2O2, 20%), 530 (M+ for C18H1381Br279BrN2O2, 57),
79
P r ep a r a tion of 3′,5′-O-Dia cetyl-5-iod o-3-(3-iod oben zyl)-
2′-d eoxyu r id in e (2a ). A mixture of 5-iodo-2′-deoxyuridine (98%
purity, Aldrich) (361 mg, 1.0 mmol), 3-iodobenzyl bromide (95%
purity, Aldrich) (406 mg, 1.3 mmol), and anhydrous potassium
carbonate (560 mg, 4.0 mmol) in dry N,N-dimethylformamide
(5 mL) was stirred at ambient temperature overnight. After
removal of the precipitate by suction and of the solvent under
reduced pressure, the residual oil was purified by column
chromatography eluting with chloroform-methanol (30/1) to
isolate 5-iodo-3-(3-iodobenzyl)-2′-deoxyuridine (441 mg, 77%):
528 (M+ for C18H1381Br79Br2N2O2, 57), 526 (M+ for C18H13
-
Br3N2O2, 20), 361 (7), 359 (13), 357 (7), 318 (7), 316 (13), 314
(7), 171 (100), 169 (97). Anal. Calcd for C18H13Br3N2O2: C, 40.87;
H, 2.48; N, 5.30. Found: C, 40.85; H, 2.63; N, 5.29.
Rea ction of th e 5-Iod o-2′-d eoxyu r id in e Der iva tive 2a
w ith Me3SiI. The iodide 2a (65.4 mg, 0.1 mmol) was treated
with Me3SiI (42.6 µL, 0.3 mmol) in dry chloroform (3 mL) under
the conditions analogous to the case of 1a described above. TLC
densitometric analysis of the reaction mixture showed the
formation of a more polar compound as the major product,
together with the 55% recovery of the starting 2a (after 2 h).
The after-treatment of the reaction mixture in a manner similar
to the case of 1a followed by chromatographic separation eluted
with chloroform-acetone (20/1) afforded the recovered 2a (32
mg) and 3′,5′-O-diacetyl-3-(3-iodobenzyl)-2′-deoxyuridine (2b) (21
mg, 40%): 1H NMR δ 2.10 and 2.11 (each 3H, each s), 2.15 and
2.54 (each 1H, each m), 4.26 (1H, dd, J ) 3 and 6 Hz), 4.31 and
4.35 (each 1H, each dd, each J ) 3 and 12 Hz), 5.01 and 5.05
(each 1H, each d, each J ) 14 Hz), 5.21 (1H, m), 5.84 (1H, d, J
) 8 Hz), 6.28 (1H, dd, J ) 6 and 8 Hz), 7.04 (1H, t, J ) 8 Hz),
7.43 (1H, d, J ) 8 Hz), 7.45 (1H, d, J ) 8 Hz), 7.61 (1H, br d, J
) 8 Hz), 7.81 (1H, br s); Mass (relative intensity) m/z 528 (M+,
48%), 328 (60), 296 (10), 258 (3), 217 (12), 201 (21), 81 (100).
Anal. Calcd for C20H21IN2O7: m/z 528.0393. Found: m/z 528.0402.
Reaction of th e 5-Br om opyr im idin edion e 3a with Me3SiI.
The bromide 3a (53.0 mg, 0.1 mmol) was treated with Me3SiI
(42.6 µL, 0.3 mmol) in dry chloroform (3 mL) under the
conditions analogous to the case of 2a described above. TLC
densitometric analysis of the reaction mixture showed the
formation of the expected 3b (10%), together with the 74%
recovery of the starting 3a (after 2 h). The structure of the
debrominated product 3b was confirmed by spectral comparison
with the authentic compound, after chromatographic separation
of the reaction mixture eluted with chloroform-acetone (100/1).
Rea ction of 5-Br om o-1H-p yr im id in e-2,4-d ion es (4a ,c)
w ith Me3SiI. A suspension of 5-bromo-1H-pyrimidine-2,4-dione
(4a ) (19 mg, 0.1 mmol) in dry acetonitrile (10 mL) containing
Me3SiI (29 µL, 0.2 mmol) was stirred at ambient temperature
under an argon atmosphere for 2 h. TLC densitometric analysis
of the reaction mixture using chloroform-methanol (5/1) as a
developing solvent showed the formation of 1H-pyrimidine-2,4-
dione (4b) (7%) in this reaction, accompanied by the recovery of
the starting material. The low conversion of this reaction seems
to be mainly from the low solubility of the starting 4a in the
employed solvent. The structure of this product was confirmed
colorless powder; mp 198-199 °C; IR (KBr) 1695, 1654 cm-1
;
UV (MeOH) 285 (e 6.7 × 103), 215 (1.76 × 104) nm; 1H NMR
(DMSO-d6) δ 2.15 (2H, m), 3.53-3.66 (2H, m), 3.80 (1H, dd, J )
3 and 6 Hz), 4.23 (1H, m), 4.96 (2H, t, J ) 14 Hz), 5.17 (1H, t,
J ) 5 Hz), 5.24 (1H, d, J ) 4 Hz), 6.11 (1H, t, J ) 6 Hz), 7.11
(1H, t, J ) 8 Hz), 7.26 (1H, d, J ) 8 Hz), 7.62 (1H, d, J ) 8 Hz),
7.66 (1H, br s), 8.51 (1H, s); Mass (relative intensity) m/z 570
(M+, 7%), 454 (M+ - I, 100). Anal. Calcd for C16H16I2N2O5: C,
33.71; H, 2.83; N, 4.91. Found: C, 33.71; H, 3.08, N, 4.88.
A suspension of the benzylated 2′-deoxyuridine (285 mg, 0.5
mmol) in dry pyridine (2 mL) containing acetic anhydride (0.5
mL) was stirred at ambient temperature overnight. After
removal of the solvent under reduced pressure, the resulting
residual oil was chromatographed over silica gel by elution with
chloroform-acetone (50/1) to isolate the desired diacetate 2a
(225 mg, 69%): amorphous powder; mp 68-70 °C; IR (KBr) 1744,
1708, 1660 cm-1; UV (MeOH) 283 (ꢀ 8.7 × 103), 215 (2.3 × 104)
1
nm; H NMR δ 2.11 and 2.20 (each 3H, each s), 2.16 and 2.55
(each 1H, each m), 4.29 (1H, dd, J ) 3 and 6 Hz), 4.33 and 4.40
(each 1H, each dd, J ) 3 and 12 Hz), 5.08 (2H, t, J ) 11 Hz),
5.22 (1H, m), 6.30 (1H, dd, J ) 5 and 8 Hz), 7.04 (1H, t, J ) 8
Hz), 7.47 (1H, d, J ) 8 Hz), 7.62 (1H, d, J ) 8 Hz), 7.83 (1H, br
s), 7.96 (1H, s); Mass (relative intensity) m/z 654 (M+, 11%), 610
(2), 455 (13), 454 (21), 201, 140, 81 (100). Anal. Calcd for
C20H20I2N2O7: C, 36.72; H, 3.08; N, 4.28. Found: C, 36.77; H,
3.30; N, 4.30.
P r ep a r a t ion of 5-Br om o-1,3-b is(4-b r om ob en zyl)-1H -
p yr im id in e-2,4-d ion e (3a ). To a suspension of 1H-pyrimidine-
2,4-dione (>98% purity, Tokyo Kasei) (224 mg, 2.0 mmol) and
anhydrous potassium carbonate (1.12 g, 8 mmol) in dry N,N-
dimethylformamide (10 mL) was added 4-bromobenzyl bromide
(98% purity, Aldrich) (1.27 g, 5.0 mmol), and the mixture was
stirred at ambient temperature overnight. After removal of the
solvent under reduced pressure, the residue was dissolved into
a mixed solvent of ethyl acetate (30 mL) and water (10 mL),
and the organic phase was separated, washed with 0.5 N HCl
(10 mL) and then brine (10 mL), and evaporated to dryness. The
resulting residue was purified by column chromatography eluted
with chloroform-acetone (100/1) to isolate 1,3-bis(4-bromo-
benzyl)-1H-pyrimidine-2,4-dione (3b) (806 mg, 90%): mp 134-
135 °C (from diethyl ether); IR (KBr) 1711, 1663 cm-1; UV
by the spectral comparison with
a commercially available
authentic sample after isolation using column chromatographic
separation of the reaction mixture.
Analogous results were obtained in the reaction of 5-bromo-
3-methyl-1H-pyrimidine-2,4-dione (4c) (20 mg, 0.1 mmol) with
Me3SiI (29 µL, 0.2 mmol) under similar conditions to afford the
expected 3-methyl-1H-pyrimidine-2,4-dione (4d ) in 44% yield.
1
(MeOH) 265 (ꢀ 9.2 × 103), 218 (2.1 × 104) nm; H NMR δ 4.85
and 5.07 (each 2H, each s), 5.77 (1H, d, J ) 8 Hz), 7.10, 7.14,
7.35, and 7.42 (each 1H, each d, each J ) 8 Hz), 7.50 (1H, d, J
81
) 8 Hz); Mass (relative intensity) m/z 452 (M+ for C18H14
-
Su p p or tin g In for m a tion Ava ila ble: MS, IR, NMR, and
UV spectra for the compounds 1b, 2a ,b, and 3a ,b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Br2N2O2, 50%), 450 (M+ for C18H1481Br79BrN2O2, 100), 448 (M+
for C18H1479Br2N2O2, 50), 281 (21), 279 (21), 238 (25), 236 (25),
212 (8), 210 (8), 171 (49), 169 (51). Anal. Calcd for C18H14
-
Br2N2O2: C, 48.03; H, 3.13; N, 6.22. Found: C, 48.00; H, 3.27;
N, 6.16.
To a solution of the benzylated pyrimidinedione 3b (450 mg,
1.0 mmol) in acetic acid (5 mL) was added bromine (62 µL, 1.2
J O001644S