Synthesis and anti-HIV-1 and anti-HCMV activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil derivatives

Article abstract of DOI:10.1248/cpb.54.325

3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of

Full text of DOI:10.1248/cpb.54.325

March 2006
Chem. Pharm. Bull. 54(3) 325—333 (2006)
325
Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted
3-(3,5-Dimethylbenzyl)uracil Derivatives
Tokumi MARUYAMA,*,a Shigetada KOZAI,b Yosuke DEMIZU,a Myriam WITVROUW,c
c
Christophe PANNECOUQUE,c Jan BALZARINI,c Robert SNOECKS,c Graciella ANDREI,c and Erik DE CLERCQ
a Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University; 1314–1 Shido, Sanuki, Kagawa
769–2193, Japan: b Faculty of Pharmaceutical Sciences (Tokushima Campus), Tokushima Bunri University; Yamashiro-
c
cho, Tokushima 770–8514, Japan: and Rega Instituut, Katholieke Universiteit Leuven; Minderbroedersstraat 10, B-3000
Leuven, Belgium. Received September 9, 2005; accepted November 14, 2005
3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted
congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative
method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated ac-
cording to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is impor-
tant for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-
Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2- and 4-picolyl derivatives was particu-
larly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs,
which suggests hydrogen bonding between amide N–H of Lys 101 and nitrogen of the cyanomethyl and picolyl
group.
Key words uracil derivative; anti-human immunodeficiency virus (HIV) activity; docking study
Human immunodeficiency virus type 1 (HIV-1) contains jobs.
an important enzyme, reverse transcriptase (RT), which cat-
Synthesis To obtain a series of 1-substituted analogues
alyzes the conversion of the viral genome RNA into the dou- of 3-(3,5-dimethylbenzyl)uracil, 3-(3,5-dimethylbenzyl)-
ble-stranding DNA. Since this process is essential for viral uracil (3b) was prepared as follows. Thus, 1-(tetrahydrofu-
replication, many drugs targeting this enzyme have been de- ran-2-yl)uracil12) was condensed with 3,5-dimethylbenzyl al-
veloped. Within the class of the anti-HIV agents which in- cohol using the Mitsunobu reaction13) to afford 3-(3,5-di-
hibit reverse transcriptase, non-nucleoside reverse transcrip- methylbenzyl) congener (3a). The product was treated with
tase inhibitors (NNRTIs) are rapidly increasing.1—5) It is in- 1 M HCl to give 3b in 69% yield. Thiation of 3b with Lawes-
teresting that some NNTRIs have an aromatic group at the 6 son’s reagent15,16) gave a 4-thio derivative (4a) as a main
position of uracil. One compound of this type is 1-[(2-hy- product accompanied with a small amount of the 2,4-
droxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)6) and dithiouracil (4b). The pyrimidines (3b, 4a, b) were examined
emivirine has entered clinical phase III trials.7) Recently, to introduce various alkyl groups at N1 as follows: Com-
Buckheit et al. reported a unique and highly potent uracil pound 3b was subjected to nucleophilic substitution with
derivative,
1-(3-cyclopenten-1-yl)methyl-6-(3,5-dimethyl- allyl, ethoxymethyl, substituted benzyl or picolyl halides
benzoyl)-5-ethyl-2,4-pyrimidinedione (SJ-3366), which in the presence of K2CO3 in DMF to give their 1-substi-
showed antiviral activity against HIV-2 as well as HIV-1.8) tuted analogues 5a, b, d—h, n—s. 4-Thiouracil derivatives
Thereafter, many pyrimidine derivatives emerged as anti-HIV 6a, b, d—h were also obtained from 4a using the same
agents.9,10) Against the background of these reports, we un- method as mentioned above. In case the halides were not
dertook a search for an anti-HIV agent by the structure–ac- commercially available, alcohols were employed as reagents.
tivity relationship (SAR) of the 1,3-disubstituted uracil11). It Thus, 2-(methylthio)ethanol, 2,2-diphenylethanol, furanyl-
is demonstrated that the introduction of a cyanomethyl group
onto N1 of uracil is effective for anti-HIV-1 activity. In study
on N3-substituents, 3-benzyl derivatives bearing a methyl
function at the meta position (1b) was proved to be a better
antiviral than ortho (1a) and para congener (1c). Moreover,
1-cyanomethyl-3-(3,5-dimethylbenzyl)uracil (2a) showed ex-
cellent anti-HIV-1 activity. Based on this result, some 1-sub-
stituted 3-(3,5-dimethylbenzyl)uracils were also evaluated
and 1-benzyl- (2b) and 3,5-difluorobenzyl derivatives (2c)
were also proved to be active against HIV-1 in CEM cells
(Fig. 1). 1-Benzyl derivative (2b) is unique since it also
showed antiviral activity against HCMV as well as anti-HIV-
1 activity.11) This background prompted us to explore the an-
tiviral activity of the 3-(3,5-dimethyl-benzyl)uracil bearing
an alkyl or arylalkyl group at N1. Also reported here is
Docking Studies of 1,3-disubstituted uracils with RT nevi-
rapine binding site using the program, Glide ligand docking
Fig. 1. Non-nucleoside Reverse Transcriptase Inhibitors
∗ To whom correspondence should be addressed. e-mail: maruyama@kph.bunri-u.ac.jp © 2006 Pharmaceutical Society of Japan

326
Vol. 54, No. 3
methanols and thiophenemethanols were condensed with ity of the 2-sulfide anion formed by treatment of 4b with a
3b and 4a using N,N,Nꢀ,Nꢀ-tetramethylazodicarboxamide strong base. Thus, 1-benzylated 2-thiouracil (8a) was pre-
(TMAD)14) to give the 1-substituted congeners 5c, i—m and pared by ring closure using a known method21) and subse-
6c, i—m. The alkylation onto N1 was proved by the similar- quent condensation of 8a with 3,5-dimethylbenzyl alcohol as
ity of their spectroscopic data to that of 1,3-dibenzylu- described in the section of 3a afforded the 2-thio derivative
racil17,18) and the HMBC spectrum of 6k as shown in Fig. 2. 8b. Next, we explored the effect of 6-substituents since intro-
When reaction of 4b with bromoacetonitrile was examined, duction of a methyl group onto the 5-position of 1-benzyl-3-
however, the product was proved to be 2-cyanomethylthio- (3,5-dimethylbenzyl)uracil decreases its anti-HIV-1 activ-
3-(3,5-dimethylbenzyl)-3,4-dihydropyrimidin-4-thione (7a) ity.11) Thus, 6-chlorouracil was treated with bromoacetoni-
from the HMBC spectrum in which correlation between trile or benzyl bromide to give the corresponding 1-alkylated
methylene of the cyanomethyl group was only observed with congeners (9a, b). However, reaction of 6-methyluracil with
C2. A similar reaction of 4b with benzyl bromide also gave bromoacetonitrile afforded 3-cyanoethyl derivative (12a).
the 2-cyanomethylthio derivative (7b). It has been reported The electric effect of the 6-substituents accounts for this dis-
that methylation of 2-thiouracil gives a 2-methylthio deriva- crepancy in position on alkylation of 6-substituted uracils.
tive.19,20) This tendency was also verified in the case of 3-sub- The electron-withdrawing chlorine atom facilitates the disso-
stituted 2,4-dithiouracil 4b. The preference of substitution on ciation of N1–H to produce an intermediary uracil-1-anion.
the sulphur atom could be explained by strong nucleophilic- However, the electron-donating 6-methyl group disturbs dis-
Chart 1
Chart 2

March 2006
327
Fig. 2. HMBC Spectra of 1,3-Disubstituted Uracils and Related Compounds
sociation of N1–H and makes N3–H rather susceptible to a bulky group such as a tert-butyl group (5g) diminishes anti-
strong base.22,23) Compounds 9a, b and 12a were converted to HIV-1 activity almost completely and 2,2-diphenylethyl ana-
10a, b and 12b as described in the section of 3a. Then, 6- logue (5i) showed no antiviral activity. This evidence indi-
chloro derivative 10a was subjected to the nucleophilic sub- cates that the benzyl group is sensitive to the substitution
stitution with cyclic amines to give 6-substituted analogues which causes high steric hindrance. Therefore, a further trial
(11a, b). The piperazinyl derivative (11b) was further reacted was undertaken to change the benzene to a heterocyclic aro-
with tosyl chloride to give the N-tosyl derivative 11c.
matic ring. Thus, 1-furanylmethyl uracil such as 5j, k showed
Structure–Activity Relationship (SAR) The antiviral good anti-HIV-1 activity identical to that of 1-benzyl deriva-
effects of the 1-substituted 3-(3,5-dimethylbenzyl)uracils tive. 1-(Thiophen-2-yl)methyl derivative 5l displayed similar
were assayed according to previously established proce- activity with the 1-(furan-2-yl)methyl derivative 5j. A trial to
dures24—26) and the results are presented in Table 1. In an ear- change 1-benzyl of 2b to 1-picolyl was explored to know the
lier report11) attempts were made to enhance the antiviral effect of nitrogen, which forms a hydrogen bond as in
activity by methyl modifications in the N3-benzyl-1- cyanomethyl of 2a. It is interesting that anti-HIV-1 activity of
cyanomethyluracils. Methyl functions in the ortho (1a) or 1-(2-picolyl)- (5n) and 1-(4-picolyl) derivative (5p) increased
para position (1c) of this N-3 benzyl group proved undesir- ten times compared with that of 2b. However, the antiviral
able. However, some anti-HIV activity (EC50 of 6.70 mM) was activity of 1-(3-picoryl) derivative (5o) resembled to that of
witnessed with the methyl function substituted in the meta 2b. 4-Thio modification of the uracil moiety usually en-
position (1b) and 3-(3,5-dimethylbenzyl)-1-cyanomethyl- hances anti-HIV-1 activity of 1-substituted 3-(3,5-dimethyl-
uracil (2a) showed powerful inhibition against HIV-1, with benzyl)uracils. One exception to this rule was the relatively
an EC50 of 0.59 mM, a CC50 of ꢁ464 mM, and thus, a selectiv- strong antiviral activity of the 4-chlorophenylmethyl deriva-
ity index (SI) of ꢁ786. Therefore, the substituent at the N-3 tive of uracil (IC50ꢂ0.211 mM) compared to that of 4-
position of uracil was fixed to the 3,5-dimethylbenzyl group. thiouracil (IC50ꢂ1.19 mM). Although 1-picoryl derivatives of
At first, the ethoxymethyl derivative (5b) was prepared re- uracil (5n—p) and 4-thiouracil (6n—p) show similar anti-
sembling emivirine7). Allyl (5a) and 2-(methylthio)ethyl (5c) HIV-1 activity, the cytotoxicity profile is different, i.e. CC50
group were also introduced to N1 of 3b as non-cyclic sub- of 5n—p exceeded 100 mM and 6n—p showed cytotoxicity
stituents. However, it appeared that the anti-HIV activity even at 30 mM. Since 1-picolyl derivative could be dissolved
of these compounds was weak compared to that of 1- in water as a salt with acid, 5n, p are promising candidates as
cyanomethyl derivative (2a). This result indicates the impor- an anti-HIV-1 agent. Next, the effect of 6-substituents was
tance of a cyano group to adopt the binding site of HIV-1 RT. evaluated as shown in Table 1. Although anti-HIV activity of
Then, under the hypothesis that an electron-withdrawing 6-chloro congeners 10a, b was similar to that of original
group at N1 is essential for anti-HIV activity of 2a, ethoxy- compounds (2a, b), it appeared that this modification in-
carbonylmethyl (5q), 2-propanonyl (5r) and 2,2,2-trifluo- creased cytotoxicity. Introduction of the bulky piperidinyl
roethyl derivatives (5s) were prepared. However, these com- (11a) or piperazinyl group (11b) to 2a diminished their an-
pounds showed only weak activity, suggesting the role of tiviral activity almost completely. Compound 12b showed
hydrogen-receiving activity of cyano-nitrogen. Next, 1- no anti-HIV-1 activity, indicating replacement of N1-
arylmethyl-3-(3,5-dimethylbenzyl)uracils were examined cyanomethyl group, and N3-(3,5-dimethylbenzyl) group of
since 2b also showed good anti-HIV-1 activity (EC50 of 2a extinguishes its anti-HIV-1 activity. Antiviral activity of
0.234 mM).11) An introduction of chloro onto the 1-benzyl compounds 5a—s, 6a—p, 7a, b, 8b, 9a, 10a, b, 11a—c, 12b
(5d—f) had little influence on anti-HIV-1 activity of 2b. A was also evaluated toward HCMV, however, these com-

328
Vol. 54, No. 3
Table 1. Antiviral Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracils and Their 4-Thio Congeners against HIV-1 and HCMV
Uracil (XꢂYꢂO)
4-thiouracil
(XꢂS, YꢂO)
EC50 (mM)
HIV-1(IIIB)
AD-169 strain
IC50 (mM)
CMV
CC50 (mM)
CEM cells
Compound
R
SI
3a
5a
5b
5c
5d
5e
Tetrahydrofuran-2-yl
CH2CHꢂCH2
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
330
ꢁ190
ꢁ170
ꢁ160
21
ꢁ140
ꢁ56
ꢁ130
110
ꢁ5
ꢁ64
34
15
23
34.5
1.48
5.2
7.39
0.211
0.28
0.211
31.9
1.89
220
155
209
6
105
40
CH2OCH2CH3
CH2CH2SCH3
CH2C6H4Cl-o
CH2C6H4Cl-m
CH2C6H4Cl-p
131
18
24.0
49.6
44.0
31.3
184
22.0
115
115
44.1
ND
145
279
135
ꢁ395
ꢁ359
ꢁ400
77.5
97.9
34.3
38.8
22.2
27.5
193
36.2
ꢁ234
23.7
27.0
27.7
25.2
37.9
13.6
31.4
12.6
21.7
25.4
12.3
7.37
34.2
36.6
170
114
177
209
ꢃ1
97
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
CH2C6H4C(CH3)3-p
CH2COC6H5
CH2CH(ph)2
ꢁ10
ꢃ2
701
500
240
ND
3625
698
2547
ꢁ18
ꢁ26
ꢁ52
228
75
CH2(furan-2-yl)
CH2(furan-3-yl)
CH2(thiophen-2-yl)
0.164
0.23
0.184
ND
0.040
0.40
0.053
22.4
13.7
7.75
0.34
1.31
CH2(thiophen-3-yl)
a)
ꢁ160
31
b)
c)
ꢁ160
ꢁ160
ꢁ570
ꢁ640
28
CH2COOEt
CH2COCH3
CH2CF3
XꢂYꢂO
XꢂYꢂO
XꢂYꢂO
5s
6a
6b
6c
6d
6e
CH2CH=CH2
CH2OCH2CH3
CH2CH2SCH3
CH2C6H4Cl-o
CH2C6H4Cl-m
CH2C6H4Cl-p
CH2C6H4C(CH3)3-p
CH2COC6H5
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
XꢂS, YꢂO
55
ꢁ160
ꢁ54
ꢁ140
ꢁ54
ꢁ120
ꢁ14
ꢁ120
13
12
10
9.5
30
ꢁ59
ꢁ15
ꢁ1.7
4.5
1.25
27
0.067
0.111
1.19
8.28
0.52
579
200
23
23
70
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
7a
7b
8b
9a
10a
10b
11a
11b
11c
12b
CH2CH(Ph)2
ꢁ47
5
CH2(furan-2-yl)
CH2(furan-3-yl)
CH2(thiophen-2-yl)
0.077
0.064
0.120
0.099
0.041
0.122
0.041
0.53
308
422
231
255
924
111
766
24
142
1171
ꢃ1
8
171
ꢃ1
ꢃ1
ꢁ1
1
CH2(thiophen-3-yl)
a)
b)
c)
XꢂS, YꢂO
e)
CH2CN
CH2–C6H5
e)
0.153
0.0217
ꢁ12.4
0.89
0.200
ꢁ36.6
ꢁ170
ꢁ167
ꢁ430
CH2–C6H5
XꢂO, YꢂS
12
d)
d)
ꢁ270
ꢁ66
96
CH2CN
CH2–C6H5
CH2CN
6-Chlorouracil
6-Chlorouracil
6-(1-Piperidyl)uracil
6-(1-Piperazinyl)uracil
99
CH2CN
ꢁ570
ꢁ99
ꢁ710
CH2CN
6-(4-Tosyl-1-piperazinyl)uracil
ꢁ168
ꢁ430
d)
d)
a)
, b)
, c)
, d) Chart 2, e) Chart 1.
Table 2. Antiviral Activity of Selected 1-Substituted 3-(3,5-Dimethylbenzyl)uracils against HIV-1 and HCMV as Reported in the Literature 11
EC50 (mM)
IC50 (mM)
CMV
CC50 (mM)
CEM cells
Compd.
N1-Substituent
N3-Substituent
HIV-1(IIIB)
SI
AD-169 strain
1a
1a
1b
2a
2b
CH2CN
CH2CN
CH2CN
CH2CN
CH2C6H5
CH2C6H4CH3-o
CH2C6H4CH3-m
CH2C6H4CH3-p
CH2C6H4-3,5-CH3
CH2C6H4-3,5-CH3
78
ꢁ196
78
ꢁ74
1.00
192
ꢁ490
302
ꢁ490
ꢁ464
194
ꢁ3
45
ꢁ5
ꢁ786
829
6.70
94.8
0.59
0.234

March 2006
329
Fig. 3. Docking Structure between HIV-RT and Substrates [Left: 3-(3,5-Dimethylbenzyl)-1-cyanomethyluracil (2a) and Right: 3-(3,5-Dimethylbenzyl)-1-
(4-picolyl)uracil (5p)
The backbone is represented by cyan ribbons and the side chains by red wire style. Substrates are represented by ball and stick style.
pounds displayed no strong activity.
essential for docking of 1-substituted 3-(3,5-dimethylben-
Docking Studies of 1,3-Disubstituted Uracils X-Ray zyl)uracils.
crystal structure of HIV reverse transcriptase (HIV-RT) with
nevirapine was taken from PDB (1VRT)27) and used for
Experimental
docking studies. After cutting the residues of HIV-RT protein
off more than 20 Å with a central focus on nevirapine, the re-
ceptor grid generation was performed to create the active site
of the receptor for ligand docking. Then, 3-benzyl-1-
cyanomethyluracils bearing a methyl group at the phenyl
moiety (1a—c) were automatically oriented and minimized
within the binding site, and docked into an active site using
the program, Glide ligand docking jobs. The result was val-
ued as G-score and E-model (these values are calculated by
Glide for the combination of the posed ligand and receptor).
The methyl function in the meta position of N-3-benzyl
group 1b was better fit than the ortho 1a or para 1c position.
The meta-dimethyl (3,5-Me) analog 2a was also better fit
than the 2,5-Me or 2,4-Me position. 3,5-Me 2a was well-
adapted to the receptor by reason that the 1-cyanomethyl
group –CH2CN formed hydrogen bonding interactions (H-
Melting points (mp) were determined using a Yanagimoto micro-melting
point apparatus (hot stage type) and are uncorrected. UV spectra were
recorded with a Shimadzu UV-190 digital spectrometer. Low-resolution
mass spectra were obtained on a Shimadzu-LKB 9000B mass spectrometer
in the direct-inlet mode. High-resolution mass spectra were obtained on a
1
JMS AX-500 spectrometer in the direct-inlet mode. H-NMR spectra were
recorded on either Varian UNITY 200 (200 MHz) or Varian UNITY 600
(600 MHz) in CDCl3 (or dimethyl sulfoxide (DMSO)-d6) with tetramethylsi-
lane as an internal standard. Merck Art 5554 plates precoated with silica gel
60 containing fluorescent indicator F254 were used for thin-layer chromatog-
raphy and silica gel 60 (Merck 7734, 60—200 mesh) was employed for col-
umn chromatography.
3-(3,5-Dimethylbenzyl)-1-(tetrahydropyran-2-yl)uracil (3a) To
a
mixture of 1-(tetrahydrofuran-2-yl)uracil (5 g, 27.4 mmol) and 3,5-dimethyl-
benzyl alcohol (8.2 ml, 54.8 mmol) in dry THF (150 ml) was added triph-
enylphosphine (14.36 g, 54.8 mmol) and DIAD (diisopropyl azodicarboxy-
late) (11 ml, 54.8 mmol). The solution was stirred at 50 °C for 2 h, then con-
centrated to a small volume. The residual solution was chromatographed
over a column of silica gel G (4.2ꢄ30 cm) using 25—75% AcOEt in hexane
(2 l). Evaporation of the fraction and crystallization from hexane gave white
crystals (5.6 g, 68%): mp 92.5—94 °C; 1H-NMR (CDCl3) d 7.29 (1H, d,
Jꢂ8.1 Hz, H6), 7.08 (2H, m, two of CH2C6H3), 6.89 (1H, br s, one of
CH2C6H3), 6.00 (1H, dd, Jꢂ2.9, 6.2 Hz, H1ꢀ), 5.78 (1H, d, Jꢂ8.1 Hz, H5),
…
bond) with the amide group of Lys101 residue (CN H–N),
and the phenyl moiety existed around the hydrophobic area
(Tyr181, Tyr188, Trp229, and Leu234 residues) of HIV-RT
(Fig. 3). The 3-dimensional shape of 3,5-Me 2a in Fig. 3 was 5.03 (2H, dd, Jꢂ13.9, 23.8 Hz, CH2), 4.14—4.25 (1H, m, H4ꢀa), 3.92—4.03
(1H, m, H4ꢀb), 2.33—2.42 (1H, m, H2ꢀa), 2.28 (6H, s, CH3ꢄ2) 1.82—2.11
a good match with nevirapine complexed with HIV-RT. Next,
we evaluated docking affinity of the 1-picolyl derivatives
5n—p as follows. 4-Picolyl derivative (5p) was well-fitted to
(3H, m, H2ꢀb, H3ꢀa, H3ꢀb); UV lmax (MeOH) nm: 265; MS m/z: 300 [Mꢅ];
Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N, 9.33. Found: C, 68.09; H,
6.81; N, 9.39.
the receptor since nitrogen of the 4-picolyl formed an H-
3-(3,5-Dimethylbenzyl)uracil (3b) To a solution of 3a (4.95 g, 16.5
mmol) in 1,4-dioxane (50 ml) was added 1 M HCl (50 ml) and refluxed for
15 h, then concentrated to a small volume. The solution was neutralized at
10% NaOH. The solution was partitioned between CHCl3 (50 mlꢄ2) and
water (50 ml). The organic layer was dried over MgSO4 and concentrated to
a small volume to give a solid. The solid was crystallized from 50% EtOH to
give white crystals (2.6 g, 69%): mp 156—158 °C; 1H-NMR (CDCl3) d 9.98
(1H, br s, N1-H), 7.10 (1H, d, Jꢂ7.8 Hz, H6), 7.01 (2H, m, two of CH2C6H3),
6.89 (1H, br s, one of CH2C6H3), 5.78 (1H, d, Jꢂ7.8 Hz, H5), 5.03 (2H, s,
CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 261; UV lmax (NaOH)
nm: 288.5; MS m/z: 230 [Mꢅ]; Anal. Calcd for C13H14N2O2: C, 67.81; H,
6.13; N, 12.17. Found: C, 67.89; H, 6.18; N, 12.13.
…
bond with the amide group of Lys101 residue (N H–N),
like the 1-cyanomethyl group of 3,5-Me 2a. However, the
phenyl moiety of 5p existed around another hydrophobic
area (Val106, Pro225, Phe227, Leu234, and Pro236 residues)
of HIV-RT. All ligands 5n—p were better adapted to the re-
ceptor than 3,5-Me 2a. It has been reported that most NNR-
TIs are known to be engaged in the H-bond with the back-
bone of the amino acids Lys101 and/or Lys103.28—34) The
docking study of 2a and 5p suggests the role of the H-bond
for affinity with RT to some extent. However, a series of 1-
benzyl and related compounds, 2b, 5d—f, j—l, which will
not form an H-bond, still retain affinity with RT. On the con-
trary, the H-bond was observed when a non-active compound
such as 1-cyanomethyl-3-(4-methylbenzyl)uracil (1c) was
Thiation of 3b to Afford 4a, b A mixture of 3b (6.0 g, 26 mmol) and
Lawesson’s reagent (20.9 g, 52 mmol) in toluene (300 ml) was refluxed for
1 d, then filtered to remove the precipitation. The filtrate was concentrated to
a small volume and chromatographed over a column of silica gel G
(5ꢄ28 cm) using 25—75% AcOEt in hexane (3 l). The first fraction was
evaporated to give 3-(3,5-dimethylbenzyl)-2,4-dithiouracil (4b) as yellowish
docked with RT. These results indicate that the H-bond is not crystals (0.79 g, 12%): mp 178—180 °C; 1H-NMR (CDCl3) d 10.39 (1H,

330
Vol. 54, No. 3
br s, N1-H), 6.90 (2H, br s, two of CH2C6H3), 6.88 (1H, br s, one of
CH2C6H3), 6.85 (1H, d, Jꢂ7.1 Hz, H6), 6.73 (1H, d, Jꢂ7.1 Hz, H5), 6.16
(2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 354, 295; UV
lmax (0.1 M NaOH) nm: 378, 291, 265; MS m/z: 262 [Mꢅ]; Anal. Calcd for
C13H14N2S2: C, 59.51; H, 5.38; N, 10.68. Found: C, 59.20; H, 5.31; N, 10.49.
From the second fraction 3-(3,5-dimethylbenzyl)-4-thiouracil (4a) was ob-
1-(3-Chlorobenzyl)-3-(3,5-dimethylbenzyl)uracil (5e) Reaction of 3b
(230 mg, 1 mmol) with m-chlorobenzyl chloride (0.25 ml, 2 mmol) in a simi-
lar manner as described in the section of 5a and crystallization from hexane
1
gave white crystals (207 mg, 58%): mp 122—122.5 °C; H-NMR (CDCl3)
7.29—7.33 (3H, m, N1-CH2C6H4), 7.15—7.19 (1H, m, N1-CH2C6H4), 7.12
(1H, d, Jꢂ7.8 Hz, H6), 7.06 (2H, br s, two of CH2C6H3), 6.90 (1H, br s, one
of CH2C6H3), 5.79 (1H, d, Jꢂ7.8 Hz, H5), 5.07 (2H, s, CH2), 4.88 (2H, s,
CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 266; MS m/z: 354, 356
[Mꢅ]; Anal. Calcd for C20H19ClN2O2: C, 67.70; H, 5.39; N, 7.90. Found: C,
67.45; H, 5.53; N, 7.84.
1
tained as yellowish crystals (5.44 g, 85%): mp 156.5—157.5 °C; H-NMR
(CDCl3) d 10.21 (1H br s, N1-H), 6.96 (2H, br s, two of CH2C6H3), 6.89 (1H,
br s, one of CH2C6H3), 6.80 (1H, dd, Jꢂ5.8, 7.1 Hz, H6), 6.62 (1H, dd,
Jꢂ1.6, 7.4 Hz, H5), 5.63 (2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax
(MeOH) nm: 328; UV lmax (0.1 M NaOH) nm: 343; MS m/z: 246 [Mꢅ];
Anal. Calcd for C13H14N2S2: C, 59.51; H, 5.38; N, 10.68. Found: C, 59.20;
H, 5.31; N, 10.49.
1-(3-Chlorobenzyl)-3-(3,5-dimethylbenzyl)-4-thiouracil (6e) Crystal-
lization from EtOH gave light yellowish crystals (217 mg, 59%): mp
138.5—139.5 °C; 1H-NMR (CDCl3) 7.02—7.33 (4H, m, N1-CH2C6H4), 7.02
(2H, br s, two of N3-CH2C6H3), 6.87-6.91 (2H, m, one of N3-CH2C6H3, H6),
6.61 (1H, d, Jꢂ7.4 Hz, H5), 5.68 (2H, s, CH2), 4.88 (2H, s, CH2), 2.27 (6H,
s, CH3ꢄ2); UV lmax (MeOH) nm: 334.5; MS m/z: 370, 372 [Mꢅ]; Anal.
Calcd for C20H19ClN2OS: C, 64.77 H, 5.16; N, 7.55. Found: C, 64.87; H,
5.33; N, 7.58.
Method 1. Reaction of 3 with Alkyl Chlorides. 1-Allyl-3-(3,5-di-
methyl)benzyluracil (5a). A General Procedure for Compounds 5b, d—
h, n—s and 6a, b, d—h, n—p A mixture of 3b (230 mg, 1 mmol), allyl
bromide (0.34 ml, 4 mmol) and potassium carbonate (414 mg, 3 mmol) in
DMF (10 ml) was stirred at room temperature for 3 h, then acetic acid
(0.5 ml) was added and concentrated to a small volume. The residue was
partitioned between CHCl3 (20 ml) and water (20 ml). The organic layer was
dried over MgSO4 and concentrated to give a solid, which was crystallized
from hexane to afford white crystals (240 mg, 89%): mp 85.5—86.5 °C; 1H-
NMR (CDCl3) 7.07—7.12 (3H, m, two of N3-CH2C6H3, H6), 6.89 (1H, br s,
one of N3-CH2C6H3), 5.76—5.97 (2H, m, H5, N1-CH2CHCH2), 5.21—5.33
(2H, m, N1-CH2CHCH2), 5.06 (2H, s, CH2), 4.26 (2H, td, Jꢂ1.5, 5.9 Hz, N1-
CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 268; MS m/z: 270 [Mꢅ];
Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.70; N, 10.36. Found: C, 71.00;
H, 6.75; N, 10.26.
1-(4-Chlorobenzyl)-3-(3,5-dimethylbenzyl)uracil (5f) Reaction of 3b
(230 mg, 1 mmol) with p-chlorobenzyl chloride (322 mg, 2 mmol) in a simi-
lar manner as described in the section of 5a and crystallization from EtOH
1
gave white crystals (220 mg, 62%): mp 119—119.5 °C; H-NMR (CDCl3)
7.20—7.37 (4H, m, N1-CH2C6H4), 7.10 (1H, d, Jꢂ7.9 Hz, H6), 7.06 (2H,
br s, two of N3-CH2C6H3), 6.90 (1H, m, one of N3-CH2C6H3), 5.77 (1H, d,
Jꢂ7.9 Hz, H5), 5.07 (2H, s, CH2), 4.88 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2);
UV lmax (MeOH) nm: 266; MS m/z: 354, 356 [Mꢅ]; Anal. Calcd for
C20H19ClN2O2: C, 67.70; H, 5.39; N, 7.90. Found: C, 67.88; H, 5.35; N,
7.89.
1-(4-Chlorobenzyl)-3-(3,5-dimethylbenzyl)-4-thiouracil (6f) Crystal-
lization from EtOH gave light yellowish crystals (193 mg, 52%): mp
1-Allyl-3-(3,5-dimethylbenzyl)-4-thiouracil (6a) Crystallization from
hexane gave light yellowish crystals (128 mg, 45%): mp 76—76.5 °C; H-
1
1
140.5—141 °C; H-NMR (CDCl3) 7.21—7.37 (4H, m, N1-CH2C6H4), 7.02
NMR (CDCl3) 7.04 (2H, br s, two of CH2C6H3), 6.87—6.90 (2H, m, one of
CH2C6H3, H6), 6.63 (1H, d, Jꢂ7.7 Hz, H5), 8.12—5.94 (1H, m, CH), 5.67
(2H, s, N3-CH2), 5.24—5.36 (2H, m, CH2ꢂCH–), 4.34—4.37 (2H, m, N1-
CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 333; MS m/z: 286 [Mꢅ];
HR-MS m/z: 286.1139 (Mꢅ, C16H18N2OS requires 286.1140); Anal. Calcd
for C16H18N2OS: C, 67.10; H, 6.33; N, 9.78. Found: C, 67.23; H, 6.47; N,
9.91.
1-Ethoxymethyl-3-(3,5-dimethylbenzyl)uracil (5b) Reaction of 3b
(230 mg, 1 mmol) with chloromethyl ethyl ether (0.19 ml, 2 mmol) in a simi-
lar manner as described in the section of 5a and crystallization from
hexane–AcOEt gave white crystals (189 mg, 66%): mp 82—82.5 °C; 1H-
NMR (CDCl3) 7.27 (1H, d, Jꢂ8.0 Hz, H6), 7.06 (2H, br s, two of N3-
CH2C6H3), 6.90 (1H, br s, one of N3-CH2C6H3), 5.83 (1H, d, Jꢂ8.0 Hz, H5),
5.16 (2H, s, CH2), 5.06 (2H, s, CH2), 3.59 (2H, q, Jꢂ7.0 Hz, OCH2CH3),
2.28 (6H, s, CH3ꢄ2), 1.21 (3H, t, Jꢂ7.0 Hz, OCH2CH3); UV lmax (MeOH)
nm: 260; MS m/z: 288 [Mꢅ]; Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.98;
N, 9.72. Found: C, 66.92; H, 7.21; N, 9.76.
1-Ethoxymethyl-3-(3,5-dimethylbenzyl)-4-thiouracil (6b) Crystalliza-
tion from hexane gave light yellowish crystals (214 mg, 70%): mp 72—
72.5 °C; 1H-NMR (CDCl3) d 7.04 (1H, d, Jꢂ7.7 Hz, H6), 7.02 (2H, br s, two
of CH2C6H3), 6.88 (1H, br s, one of CH2C6H3), 6.65 (1H, d, Jꢂ7.7 Hz, H5),
5.67 (2H, s, CH2), 5.15 (2H, s, CH2), 3.60 (2H, q, Jꢂ7.1 Hz, CH2), 2.27 (6H,
s, CH3ꢄ2), 1.22 (3H, t, Jꢂ7.1 Hz, CH3); UV lmax (MeOH) nm: 328; MS
m/z: 304 [Mꢅ]; HR-MS m/z: 304.1245 (Mꢅ, C16H20N2O2S requires
304.1246); Anal. Calcd for C16H20N2O2S: C, 63.13; H, 6.61; N, 9.20. Found:
C, 63.16; H, 6.73; N, 9.37.
(2H, br s, two of N3-CH2C6H3), 6.85—6.90 (2H, m, one of N3-CH2C6H3,
H6), 6.60 (1H, d, Jꢂ7.6 Hz, H5), 5.67 (2H, s, CH2), 4.87 (2H, s, CH2), 2.27
(6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 334; MS m/z: 370, 372 [Mꢅ]; Anal.
Calcd for C20H19ClN2OS: C, 64.77 H, 5.16; N, 7.55. Found: C, 64.82; H,
5.31; N, 7.61.
1-(4-tert-Butylbenzyl)-3-(3,5-dimethylbenzyl)uracil (5g) Reaction of
3b (230 mg, 1 mmol) with 4-(t-butyl)benzyl bromide (0.37 ml, 2 mmol) in a
similar manner as described in the section of 5a and crystallization from
hexane gave white crystals (285 mg, 76%): mp 133—133.5 °C; 1H-NMR
(CDCl3) 7.38 (2H, d, Jꢂ8.3 Hz, two of N1-CH2C6H4), 7.21 (2H, d, Jꢂ8.3 Hz,
two of N1-CH2C6H4), 7.12 (1H, d, Jꢂ7.8 Hz, H6), 7.07 (2H, br s, two of N3-
CH2C6H3), 6.90 (1H, m, one of N3-CH2C6H3), 5.74 (1H, d, Jꢂ8.1 Hz, H5),
5.07 (2H, s, CH2), 4.88 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2), 1.31 (9H, s,
CH3ꢄ3); UV lmax (MeOH) nm: 268; MS m/z: 376 [Mꢅ]; Anal. Calcd for
C24H28N2O2: C, 76.56; H, 7.49; N, 7.44. Found: C, 76.75; H, 7.71; N, 7.45.
1-(4-tert-Butylbenzyl)-3-(3,5-dimethylbenzyl)-4-thiouracil (6g) Crys-
tallization from EtOH gave light yellowish crystals (139 mg, 59%): mp
130—130.5 °C; 1H-NMR (CDCl3) 7.17—7.33 (11H, m, Phꢄ2, H6), 6.97
(2H, br s, two of N3-CH2C6H3), 6.90 (1H, br s, one of N3-CH2C6H3), 6.27—
6.34 (1H, m, H5), 5.68 (2H, s, CH2), 4.48 (1H, dd, Jꢂ7.7, 8.2 Hz, CH), 4.30
(2H, d, Jꢂ7.7 Hz, CH2), 2.30 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 336;
MS m/z: 426 [Mꢅ]; Anal. Calcd for C27H26N2OS: C, 76.02; H, 6.14; N, 6.57.
Found: C, 76.19; H, 6.24; N, 6.75.
3-(3,5-Dimethylbenzyl)-1-phenacyluracil (5h) Reaction of 3b (230
mg, 1 mmol) with 2-chloroacetophenone (309 mg, 2 mmol) in a similar man-
1
ner as described in the section of 5a gave a foam (340 mg, 97%): H-NMR
1-(2-Chlorobenzyl)-3-(3,5-dimethylbenzyl)uracil (5d) Reaction of 3b
(230 mg, 1 mmol) with o-chlorobenzyl chloride (0.25 ml, 2 mmol) in a simi-
lar manner as described in the section of 5a and crystallization from EtOH
(CDCl3) d 7.47—8.01 (5H, m, CH2C6H5), 7.03—7.07 (3H, m, H6, two of
CH2C6H3), 6.88 (1H, br s, one of CH2C6H3), 5.84 (1H, d, Jꢂ7.7 Hz, H5),
5.17 (2H, s, CH2), 5.06 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax
(MeOH) nm: 248; MS m/z: 348 [Mꢅ]; HR-MS m/z: 348.1469 (Mꢅ,
C21H20N2O3 requires 348.1674).
3-(3,5-Dimethylbenzyl)-1-phenacyl-4-thiouracil (6h) Crystallization
from hexane gave light yellowish crystals (133 mg, 36%): mp 178—
178.5 °C; 1H-NMR (CDCl3) 7.48—7.98 (5H, m, Ph), 7.02 (2H, br s, two of
N3-CH2C6H3), 6.88 (1H, m, one of N3-CH2C6H3), 6.81 (1H, d, Jꢂ7.6 Hz,
H6), 6.68 (1H, d, Jꢂ7.6 Hz, H5), 5.67 (2H, s, CH2), 5.17 (2H, s, CH2), 2.27
(6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 246, 332; MS m/z: 364 [Mꢅ]; Anal.
Calcd for C21H20N2O2S: C, 69.21; H, 5.52; N, 7.69. Found: C, 69.17; H,
5.66; N, 7.62.
1
gave white crystals (256 mg, 72%): mp 133—133.5 °C; H-NMR (CDCl3)
7.27—7.44 (4H, m, N1-CH2C6H4), 7.20 (1H, d, Jꢂ7.9 Hz, H6), 7.06 (2H,
br s, two of CH2C6H3), 6.90 (1H, br s, one of CH2C6H3), 5.76 (1H, d,
Jꢂ7.9 Hz, H5), 5.08 (2H, s, CH2), 5.04 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2);
UV lmax (MeOH) nm: 265; MS m/z: 354, 356 [Mꢅ]; Anal. Calcd for
C20H19ClN2O2: C, 67.70; H, 5.39; N, 7.90. Found: C, 67.97; H, 5.40; N,
7.85.
1-(2-Chlorobenzyl)-3-(3,5-dimethylbenzyl)-4-thiouracil (6d) Crystal-
lization from EtOH gave light yellowish crystals (139 mg, 35%): mp
139.5—140 °C; 1H-NMR (CDCl3) 7.27—744 (4H, m, N1-CH2C6H4), 7.01
(2H, br s, two of N3-CH2C6H3), 6.96 (1H, d, Jꢂ7.4 Hz, H6), 6.88 (1H, br s,
one of N3-CH2C6H3), 6.59 (1H, d, Jꢂ7.4 Hz, H5), 5.68 (2H, s, CH2), 5.04
(2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 334; MS m/z:
370, 372 [Mꢅ]; Anal. Calcd for C20H19ClN2OS: C, 64.77 H, 5.16; N, 7.55.
Found: C, 64.68; H, 5.28; N, 7.67.
3-(3,5-Dimethylbenzyl)-1-(2-picolyl)uracil (5n) Reaction of 3b (230
mg, 1 mmol) with 2-picolyl chloride hydrochloride (328 mg, 2 mmol) and
potassium carbonate (1.1 g, 8 mmol) in a similar manner as described in the
section of 5a and crystallization from EtOH gave white crystals (276 mg,

March 2006
331
1
86%): mp 131—132 °C; H-NMR (CDCl3) 8.54—8.56 (1H, m, one of N1-
CH2C5H4N), 7.66—7.71 (1H, m, one of N1-CH2C5H4N), 7.38—7.41 (1H, m,
one of N1-CH2C5H4N), 7.33 (1H, d, Jꢂ8.0 Hz, H6), 7.21—7.25 (1H, m, one
of N1-CH2C5H4N), 7.03 (2H, br s, two of N3-CH2C6H3), 6.87 (1H, br s, one
of N3-CH2C6H3), 5.78 (1H, d, Jꢂ8.0 Hz, H5), 5.04 (2H, s, CH2), 4.98 (2H, s,
CH2), 2.26 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 268; MS m/z: 321 [Mꢅ];
Anal. (C19H19N3O2) C, H, N.
crystallization from hexane gave white crystals (199 mg, 64%): mp 135.5—
136.5 °C; H-NMR (CDCl3) d 7.12 (1H, d, Jꢂ8.1 Hz, H6), 7.05 (2H, br s,
two of CH2C6H3), 6.91 (1H, br s, one of CH2C6H3), 5.85 (1H, d, Jꢂ7.8 Hz,
H5), 5.06 (2H, s, CH2), 4.37 (2H, dd, Jꢂ8.3, 16.8 Hz, CH2), 2.28 (6H, s,
CH3ꢄ2); UV lmax (MeOH) nm: 259; MS m/z: 312 [Mꢅ]; Anal. Calcd for
C15H15F3N2O2: C, 57.69; H, 4.84; N, 8.97. Found: C, 57.79; H, 4.87; N,
8.96.
1
2-Cyanomethylthio-3-(3,5-dimethylbenzyl)-3,4-dihydropyrimidin-4-
thione (7a) Reaction of 4b (262 mg, 1 mmol) with bromoacetonitrile
(0.14 ml, 2 mmol) in a similar manner as described in the section of 5a and
crystallization from EtOH gave light yellowish crystals (263 mg, 87%): mp
3-(3,5-Dimethylbenzyl)-1-(2-picolyl)-4-thiouracil (6n) Crystallization
from EtOH gave light yellowish crystals (140 mg, 42%): mp 115—115.5 °C;
1H-NMR (CDCl3) 8.56—8.58 (1H, m, one of N1-CH2C5H4N), 7.65—7.74
(1H, m, one of N1-CH2C5H4N), 7.18—7.37 (3H, m, two of N1-CH2C5H4N,
H6), 7.01 (2H, br s, two of N3-CH2C6H3), 6.87 (2H, br s, one of N3-
CH2C6H3), 6.65 (1H, d, Jꢂ7.3 Hz, H5), 5.66 (2H, s, CH2), 4.99 (2H, s, CH2),
2.26 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 334; MS m/z: 337 [Mꢅ]; Anal.
Calcd for C19H19N3OS: C, 67.63; H, 5.67; N, 12.45. Found: C, 67.79; H,
5.82; N, 12.48.
1
125.5—126 °C; H-NMR (CDCl3) d 7.61 (1H, d, Jꢂ5.8 Hz, H6), 7.34 (1H,
d, Jꢂ6.0 Hz, H5), 6.93 (1H, br s, one of CH2C6H3), 6.80 (2H, br s, two of
CH2C6H3), 5.90 (2H, s, CH2), 3.88 (2H, s, CH2), 2.29 (6H, s, CH3ꢄ2); 13C-
NMR (150 MHz, CDCl3) d 187.4 (C4), 160.1 (C2), 144.8 (C8), 138.6,
132.1, 129.9 and 124.3 (CH2C6H3), 126.6 (C5), 115.1 (CN), 53.4(N3-CH2),
21.3 (CH3ꢄ2), 18.6 (S-CH2), 21.3 (CH3ꢄ2); UV lmax (MeOH) nm: 295.5,
350; MS m/z: 301 [Mꢅ]; Anal. Calcd for C15H15N3S2: C, 59.77; H, 5.02; N,
13.94. Found: C, 59.92; H, 5.15; N, 14.09.
3-(3,5-Dimethylbenzyl)-1-(3-picolyl)uracil (5o) Reaction of 3b (230
mg, 1 mmol) with 3-picolyl chloride hydrochloride (243 mg, 1.5 mmol) and
potassium carbonate (552 mg, 4 mmol) in a similar manner as described in
1
2-Benzylthio-3-(3,5-dimethylbenzyl)-3,4-dihydropyrimidin-4-thione
(7b) Reaction of 4b (262 mg, 1 mmol) with benzylbromide (0.24 ml,
2 mmol) in a similar manner as described in the section of 5a and crystal-
lization from hexane gave light yellowish crystals (232 mg, 66%): mp
the section of 5a gave a foam (576 mg, 90%): H-NMR (CDCl3) d 8.59—
8.61 (2H, m, Py), 7.66 (1H, ddd, Jꢂ1.6, 2.2, 8.0 Hz, Py), 7.30—7.32 (1H,
m, Py), 7.15 (1H, d, Jꢂ8.0 Hz, H6), 7.05 (2H, br s, two of CH2C6H3), 6.90
(1H, br s, one of CH2C6H3), 5.79 (1H, d, Jꢂ8.0 Hz, H5), 5.06 (2H, s, N3-
CH2), 4.93 (2H, s, N1-CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm:
262—268; MS m/z: 321 [Mꢅ]; HR-MS m/z: 321.1465 (Mꢅ, C19H19N3O2 re-
quires 321.1477).
1
92.5—93 °C; H-NMR (CDCl3) d 7.59 (1H, d, Jꢂ6.0 Hz, H6), 7.25—7.33
(6H, m, CH2C6H5, H5), 6.89 (1H, br s, one of CH2C6H3), 6.77 (2H, br s, two
of CH2C6H3), 5.92 (2H, s, CH2), 4.37 (2H, s, CH2), 2.26 (6H, s, CH3ꢄ2);
UV lmax (MeOH) nm: 295.5, 357; MS m/z: 352 [Mꢅ]; Anal. Calcd for
C20H20N2S2: C, 68.14; H, 5.71; N, 7.95. Found: C, 68.33; H, 5.63; N, 8.09.
Method 2. Mitsunobu Reaction of 3b or 4a with Alcohols. 3-(3,5-Di-
methylbenzyl)-1-[(2-methylthio)ethyl]uracil (5c). A General Procedure
for Compounds 5i—m, 6c, i—m To an ice-cooled mixture of 3b (230 mg,
1 mmol) and 2-(methylthio)ethanol (0.18 ml, 2 mmol) in dry THF (20 ml)
was added triphenylphosphine (524 mg, 2 mmol) and TMAD (344 mg,
2 mmol). The solution was stirred at 50 °C overnight, then concentrated to a
small volume. The residual solution was chromatographed over a column of
silica gel G (2.0ꢄ30 cm) using 0—50% AcOEt in hexane (1 l). Evaporation
of the fraction and crystallization from hexane gave white crystals (110 mg,
36%): mp 79—79.5 °C; 1H-NMR (CDCl3) 7.17 (1H, d, Jꢂ7.7 Hz, H6), 7.05
(2H, br s, two of N3-CH2C6H3), 6.89 (1H, br s, one of N3-CH2C6H3), 5.76
(1H, d, Jꢂ8.0 Hz, H5), 5.05 (2H, s, CH2), 3.91 (2H, dd, Jꢂ6.2, 6.6 Hz,
CH3SCH2CH2), 2.79 (2H, dd, Jꢂ6.2, 6.6 Hz, CH3SCH2CH2), 2.28 (6H, s,
CH3ꢄ2), 2.1 (3H, s, CH3SCH2CH2); UV lmax (MeOH) nm: 268; MS m/z:
304 [Mꢅ]; Anal. Calcd for C16H20N2O2S: C, 63.13; H, 6.61; N, 9.20. Found:
C, 63.56; H, 6.83; N, 9.26.
3-(3,5-Dimethylbenzyl)-1-(3-picolyl)-4-thiouracil (6o) Crystallization
from EtOH gave light yellowish crystals (149 mg, 44%): mp 122.5—123 °C;
1H-NMR (CDCl3) 8.62 (2H, dd, Jꢂ1.5, 4.8 Hz, two of N1-CH2C5H4N),
7.66—7.70 (1H, m, one of N1-CH2C5H4N), 7.30—7.33 (1H, m, one of N1-
CH2C5H4N), 7.03 (2H, br s, two of N3-CH2C6H3), 6.90—6.96 (2H, m, one of
N3-CH2C6H3, H6), 6.62 (1H, d, Jꢂ8.1 Hz, H5), 5.68 (2H, s, CH2), 4.93 (2H,
s, CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 333.5; MS m/z: 337
[Mꢅ]; Anal. Calcd for C19H19N3OS: C, 67.63; H, 5.67; N, 12.45. Found: C,
67.73; H, 5.82; N, 12.41.
3-(3,5-Dimethylbenzyl)-1-(4-picolyl)uracil (5p) Reaction of 3b (230
mg, 1 mmol) with 4-picolyl chloride hydrochloride (243 mg, 1.5 mmol) and
potassium carbonate (552 mg, 4 mmol) in a similar manner as described in
the section of 5a and crystallization from EtOH gave white crystals (133 mg,
35%): mp 152.5—153 °C; 1H-NMR (CDCl3) 8.59—8.62 (2H, m, two of N1-
CH2C5H4N), 7.05—7.16 (3H, m, two of N1-CH2C5H4N, H6), 7.05 (2H, br s,
two of N3-CH2C6H3), 6.90 (1H, br s, one of N3-CH2C6H3), 5.82 (1H, d,
Jꢂ7.8 Hz, H5), 5.07 (2H, s, CH2), 4.91 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2);
UV lmax (MeOH) nm: 263; MS m/z: 321 [Mꢅ]; Anal. Calcd for C19H19N3O2:
C, 71.01; H, 5.95; N, 13.08. Found: C, 71.16; H, 6.16; N, 13.06.
3-(3,5-Dimethylbenzyl)-1-[(2-methylthio)ethyl]-4-thiouracil (6c) Crys-
tallization from hexane gave light yellowish crystals (194 mg, 61%): mp
148.5—149 °C; 1H-NMR (CDCl3) d 7.02 (2H, m, two of CH2C6H3) 6.94
(1H, d, Jꢂ7.4 Hz, H6), 6.87 (1H, m, one of CH2C6H3), 6.61 (1H, d,
Jꢂ7.4 Hz, H5), 5.67 (2H, s, N3-CH2), 3.92 (2H, dd, Jꢂ6.3 6.6 Hz, CH2),
2.80 (2H, dd, Jꢂ6.3 6.6 Hz, CH2), 2.27 (6H, s, CH3ꢄ2), 2.10 (3H, s, S-
CH3); UV lmax (MeOH) nm: 334; MS m/z: 320 [Mꢅ]; HR-MS m/z:
320.0995 (Mꢅ, C16H20N2OS2 requires 320.1018); Anal. Calcd for
C16H20N2OS2: C, 59.97; H, 6.28; N, 8.74. Found: C, 60.08; H, 6.37; N, 8.91.
3-(3,5-Dimethylbenzyl)-1-(2,2-diphenylethyl)uracil (5i) Reaction of
3b (230 mg, 1 mmol) with 2,2-diphenylethanol (397 mg, 2 mmol) in a simi-
lar manner as described in the section of 5c and crystallization from EtOH
3-(3,5-Dimethylbenzyl)-1-(4-picolyl)-4-thiouracil (6p) Crystallization
from hexane gave light yellowish crystals (99 mg, 29%): mp 140.5—141
1
°C; H-NMR (CDCl3) 8.61—8.64 (2H, m, two of N1-CH2C5H4N), 7.16—
7.19 (2H, m, two of N1-CH2C5H4N), 7.02 (2H, br s, two of N3-CH2C6H3),
6.88—6.92 (2H, m, one of N3-CH2C6H3, H6), 6.64 (1H, d, Jꢂ7.6 Hz, H5),
5.68 (2H, s, CH2), 4.92 (2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax
(MeOH) nm: 332; MS m/z: 337 [Mꢅ]; Anal. Calcd for C19H19N3OS·0.2H2O:
C, 67.63; H, 5.67; N, 12.45. Found: C, 66.84; H, 5.80; N, 12.09.
Ethyl [3-(3,5-Dimethylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimid-1-
yl]acetate (5q) Reaction of 3b (230 mg, 1 mmol) with ethyl chloroacetate
(0.22 ml, 2 mmol) in a similar manner as described in the section of 5a gave
1
1
gave white crystals (199 mg, 70%): mp 165.5—166 °C; H-NMR (CDCl3)
5r as a syrup (310 mg, 98%): H-NMR (CDCl3) d 7.04—7.08 (3H, m, H6,
7.18—7.32 (10H, m, Phꢄ2), 7.00 (2H, br s, two of CH2C6H3), 6.89 (1H,
br s, one of CH2C6H3), 6.55 (1H, d, Jꢂ7.7 Hz, H6), 5.42 (1H, d, Jꢂ8.0 Hz,
H5), 5.05 (2H, s, CH2), 4.47 (1H, t, Jꢂ8.0 Hz, CH), 4.30 (2H, d, Jꢂ8.2 Hz,
CH2), 2.30 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 268; MS m/z: 410 [Mꢅ];
Anal. Calcd for C27H26N2O2·0.2 H2O: C, 78.31; H, 6.42; N, 6.77. Found: C,
78.41; H, 6.53; N, 6.79.
3-(3,5-Dimethylbenzyl)-1-(2,2-diphenylethyl)-4-thiouracil (6i) Crys-
tallization from EtOH gave light yellowish crystals (250 mg, 59%): mp
130—130.5 °C; 1H-NMR (CDCl3) 7.17—7.33 (11H, m, Phꢄ2, H6), 6.97
(2H, br s, two of N3-CH2C6H3), 6.90 (1H, br s, one of N3-CH2C6H3), 6.27-
6.34 (1H, m, H5), 5.68 (2H, s, CH2), 4.48 (1H, dd, Jꢂ7.7, 8.2 Hz, CH), 4.30
(2H, d, Jꢂ7.7 Hz, CH2), 2.30 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 336;
MS m/z: 426 [Mꢅ]; Anal. Calcd for C27H26N2OS: C, 76.02; H, 6.14; N, 6.57.
Found: C, 76.19; H, 6.24; N, 6.75.
two of CH2C6H3), 6.89 (1H, br s, one of CH2C6H3), 5.81 (1H, d, Jꢂ8.1 Hz,
H5), 5.05 (2H, s, CH2), 4.44 (2H, s, CH2), 4.24 (2H, dd, Jꢂ7.3, 14.3 Hz,
CH2CH3), 2.27 (6H, s, CH3ꢄ2), 1.28 (3H, dd, Jꢂ7.0, 7.3 Hz, CH2CH3); UV
lmax (MeOH) nm: 263; MS m/z: 316 [Mꢅ]; HR-MS m/z: 316.1412 (Mꢅ,
C17H20N2O4 requires 316.1423).
[3-(3,5-Dimethylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimid-1-yl]-2-
propanone (5r) Reaction of 3b (230 mg, 1 mmol) with chloroacetone
(0.16 ml, 2 mmol) in a similar manner as described in the section of 5a and
crystallization from hexane gave white crystals (237 mg, 83%): mp 112.5—
1
114 °C; H-NMR (CDCl3) d 7.02 (2H, br s, two of CH2C6H3), 6.95 (1H, d,
Jꢂ8.1 Hz, H6), 6.88 (1H, br s, one of CH2C6H3), 5.80 (1H, d, Jꢂ8.1 Hz,
H5), 5.04 (2H, s, CH2), 4.52 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2), 2.25 (3H, s,
CH3); UV lmax (MeOH) nm: 265; MS m/z: 286 [Mꢅ]; Anal. Calcd for
C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.25; H, 6.34; N, 9.78.
3-(3,5-Dimethylbenzyl)-1-trifluoroethyluracill (5s) Reaction of 3b
(230 mg, 1 mmol) with 2-iodo-1,1,1-trifluoroethane (0.2 ml, 2 mmol) at
80 °C overnight in a similar manner as described in the section of 5a and
3-(3,5-Dimethylbenzyl)-1-[(furan-2-yl)methyl]uracil (5j) Reaction of
3b (230 mg, 1 mmol) with furfuryl alcohol (0.17 ml, 2 mmol) in a similar
1
manner as described in the section of 5c gave a foam (206 mg, 66%): H-

332
Vol. 54, No. 3
6-Substituteduracils. 6-Chloro-1-cyanomethyluracil (9a) A mixture
of 6-chlorouracil (440 ml, 3 mmol), bromoacetonitrile (0.28 ml, 4 mmol) and
potassium carbonate (207 mg, 1.5 mmol) in DMSO (10 ml) was stirred at
70 °C for 1 h, then acetic acid (0.5 ml) was added and concentrated to a
small volume. The residue was chromatographed over a column of silica gel
G (2.8ꢄ33 cm) using 0—10% EtOH in CHCl3 (1600 ml). Evaporation of the
fraction and crystallization from H2O–EtOH gave white crystals (273 mg,
49%): mp 225—226 °C; 1H-NMR (DMSO-d6) d 11.90 (1H, br s, N3-H),
6.11 (1H, s, H5), 5.04 (2H, s, N1-CH2); UV lmax (MeOH) nm: 261; UV lmax
(NaOH) nm: 261; MS m/z: 185, 187 [Mꢅ]; HR-MS m/z: 184.9992 (Mꢅ,
C6H4ClN3O2 requires 184.9983); Anal. Calcd for C6H4ClN3O2: C, 38.84; H,
2.17; N, 22.64. Found: C, 38.88; H, 2.31; N, 22.75.
NMR (CDCl3) d 7.39—7.40 (1H, m, one of furanyl), 7.18 (1H, d, Jꢂ7.8 Hz,
H6), 7.07 (2H, br s, two of CH2C6H3), 6.89 (1H, br s, one of CH2C6H3),
6.35—6.42 (2H, m, two of furanyl), 5.76 (1H, d, Jꢂ7.8 Hz, H5), 5.04 (2H, s,
CH2), 4.89 (2H, s, CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 265;
MS m/z: 310 [Mꢅ]; HR-MS m/z: 310.1287 (Mꢅ, C18H18N2O3 requires
310.1381).
3-(3,5-Dimethylbenzyl)-1-[(furan-2-yl)methyl]-4-thiouracil
(6j) A
foam (144 mg, 44%): 1H-NMR (CDCl3) d 7.41—742 (1H, m, one of fu-
ranyl), 7.04 (2H, br s, two of CH2C6H3), 6.90 (1H, d, Jꢂ7.4 Hz, H6), 6.88
(1H, br s, one of CH2C6H3), 6.60 (1H, d, Jꢂ7.4 Hz, H5), 6.44 (1H, dd,
Jꢂ0.8, 3.3 Hz, one of furanyl), 6.37—6.38 (1H, br s, one of furanyl), 5.66
(2H, s, CH2), 4.89 (2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH)
nm: 332; MS m/z: 326 [Mꢅ]; HR-MS m/z: 326.1097 (Mꢅ, C18H18N2O2S re-
quires 326.1089).
6-Chloro-1-cyanomethyl-3-(3,5-dimethylbenzyl)uracil (10a). A Gen-
eral Procedure for Compound 10b To a mixture of 9a (2.3 g, 12.6 mmol)
and 3,5-dimethylbenzyl alcohol (3.8 ml, 25.3 mmol) in dry THF (100 ml)
was added triphenylphosphine (6.63 g, 25.3 mmol) and TMAD (4.35 g,
25.3 mmol). The solution was stirred at 50 °C for 5 h, then concentrated to a
small volume. The residual solution was chromatographed over a column of
silica gel G (3.0ꢄ52 cm) using 0—50% AcOEt in hexane (2 l). Evaporation
of the fraction and crystallization from mEtOH gave white crystals (2.78 g,
3-(3,5-Dimethylbenzyl)-1-[(furan-3-yl)methyl]uracil (5k) Reaction of
3b (230 mg, 1 mmol) with 3-furanylmethanol (0.17 ml, 2 mmol) in a similar
manner as described in the section of 5c gave white crystals (221 mg, 71%):
1
mp 72.5—73 °C; H-NMR (CDCl3) d 7.43—7.49 (2H, m, two of furanyl),
7.13 (1H, d, Jꢂ8.1 Hz, H6), 7.08 (2H, br s, two of CH2C6H3), 6.90 (1H, br s,
one of CH2C6H3), 6.37—6.38 (1H, m, one of furanyl), 5.75 (1H, d,
Jꢂ8.1 Hz, H5), 5.07 (2H, s, CH2), 4.76 (2H, s, CH2), 2.29 (6H, s, CH3ꢄ2);
UV lmax (MeOH) nm: 266; MS m/z: 310 [Mꢅ]; Anal. Calcd for C18H18N2O3:
C, 69.66; H, 5.84; N, 9.03. Found: C, 69.77; H, 6.02; N, 8.98.
1
74%): mp 125.5—126 °C; H-NMR (600 MHz, CDCl3) d 7.04 (2H, m, two
of CH2C6H3), 6.92 (1H, br s, one of CH2C6H3), 6.07 (1H, s, H5), 5.02 (2H, s,
N3-CH2), 4.95 (2H, s, N1-CH2), 2.29 (6H, s, CH3ꢄ2); 13C-NMR (150 MHz,
CDCl3) d 159.7 (C4), 150.0 (C2), 143.1 (C6), 138.1, 135.3, 129.8 and 126.8
(CH2C6H3), 113.3 (CN), 103.9 (C5), 45.3 (N3-CH2), 33.7 (N1-CH2), 21.2
(CH3ꢄ2); UV lmax (MeOH) nm: 261.5; MS m/z: 303, 305 [Mꢅ]; HR-MS
m/z: 303.0751 (Mꢅ, C15H14ClN3O2 requires 303.0774); Anal. Calcd for
C15H14ClN3O2: C, 59.31; H, 4.65; N, 13.83. Found: C, 59.38; H, 4.76; N,
13.74.
3-(3,5-Dimethylbenzyl)-1-[(furan-3-yl)methyl]-4-thiouracil (6k) Crys-
tallization from EtOH gave light yellowish crystals (196 mg, 60%): mp
1
100.5—101 °C; H-NMR (600 MHz, CDCl3) d 7.50 (1H, q, Jꢂ0.8 Hz, one
of furanyl), 7.43 (1H, t, Jꢂ1.6 Hz, one of furanyl), 7.04 (2H, br s, two of
CH2C6H3), 6.90 (1H, d, Jꢂ7.7 Hz, H6), 6.89 (1H, br s, one of CH2C6H3),
6.59 (1H, d, Jꢂ7.7 Hz, H5), 6.37 (1H, dd, Jꢂ0.8, 1.1 Hz, one of furanyl),
5.68 (2H, s, N3-CH2), 4.76 (2H, s, N1-CH2), 2.28 (6H, s, CH3ꢄ2); 13C-NMR
(150 MHz, CDCl3) d: 190.8 (C4), 149.8 (C2), 144.3, 141.5, 119.0 and 110.0
(furanyl), 137.8, 135.5 129.3 and 125.8 (CH2C6H3), 134.6 (C6), 114.6 (C5),
50.4 (N3-CH2), 44.3 (N1-CH2), 21.3 (CH3ꢄ2); UV lmax (MeOH) nm: 326;
MS m/z: 283 [Mꢅ]; Anal. Calcd for C18H18N2O2S: C, 66.23; H, 5.56; N,
8.58. Found: C, 66.33; H, 5.56; N, 8.54.
1-Benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil (10b) A syrup (358
mg, quantitative): 1H-NMR (CDCl3) d 6.90—7.37 (8H, m, CH2C6H3,
CH2C6H5), 5.96 (1H, s, H5), 5.27 (2H, s, CH2), 5.05 (2H, s, CH2), 2.28 (6H,
s, CH3ꢄ2); UV lmax (MeOH) nm: 269.5; MS m/z: 354, 356 [Mꢅ]; HR-MS
m/z: 354.1127 (Mꢅ, C20H19ClN2O2 requires 354.1135). Anal. Calcd for
C6H4ClN3O2: C, 38.84; H, 2.17; N, 22.64. Found: C, 38.88; H, 2.31; N,
22.75.
3-(3,5-Dimethylbenzyl)-1-[(thiophen-2-yl)methyl]uracil (5l) Reaction
of 3b (230 mg, 1 mmol) with 2-thiophenemethanol (0.19 ml, 2 mmol) in a
similar manner as described in the section of 5c crystallization from hexane
1-Benzyl-3-(3,5-dimethylbenzyl)-2-thiouracil (8b) Reaction of 1-ben-
zyl-2-thiouracil (8a, 230 mg, 1 mmol) with 3,5-dimethylbenzyl alcohol
(0.3 ml, 2 mmol) in a similar manner as described in the section of 10a gave
1
gave white crystals (175 mg, 54%): mp 79.5—80 °C; H-NMR (CDCl3) d
1
a foam (127 mg, 38%); H-NMR (600 MHz, CDCl3) d 7.28—7.39 (6H, m,
7.31 (1H, dd, Jꢂ1.3, 5.1 Hz, one of C4H3S), 7.16 (1H, d, Jꢂ7.9 Hz, H6),
7.07—7.09 (3H, m, one of C4H3S, two of CH2C6H3), 6.99 (1H, dd, Jꢂ3.5,
5.1 Hz, one of C4H3S), 6.90 (1H, br s, one of CH2C6H3), 5.76 (1H, d,
Jꢂ7.9 Hz, H5), 5.07 (4H, br s, CH2ꢄ2), 2.28 (6H, s, CH3ꢄ2); UV lmax
(MeOH) nm: 268; MS m/z: 326 [Mꢅ]; Anal. Calcd for C18H18N2O2S: C,
66.23; H, 5.55; N, 8.58. Found: C, 66.46; H, 5.74; N, 8.54.
H6 and CH2C6H5), 7.02 (2H, s, two of CH2C6H3), 6.88 (1H, br s, one of
CH2C6H3), 6.01 (1H, d, Jꢂ8.0 Hz, H5), 5.71 (2H, s, N3-CH2), 5.54 (2H, s,
N1-CH2), 2.28 (6H, s, CH3ꢄ2); 13C-NMR (150 MHz, CDCl3) d 178.4 (C2),
160.0 (C4), 142.3 (C6), 137.7, 135.6, 129.1 and 125.8 (CH2C6H3), 134.7,
129.1, 128.5 and 127.9 (CH2C6H5), 105.7 (C5), 58.9 (N3-CH2), 50.5 (N1-
CH2), 21.4 (CH3ꢄ2); UV lmax (MeOH) nm: 293 (sh), 276.5; MS m/z: 336
[Mꢅ]; HR-MS m/z: 336.1286 (Mꢅ, C20H20N2OS requires 336.1296).
3-(3,5-Dimethylbenzyl)-1-[(thiophen-2-yl)methyl]-4-thiouracil
(6l)
Crystallization from hexane gave light yellowish crystals (155 mg, 45%): mp
110—110.5 °C; 1H-NMR (CDCl3) d 7.31—7.33 (1H, m, one of C4H3S),
7.09—7.11 (1H, m, one of C4H3S), 7.04 (2H, br s, two of CH2C6H3), 7.00
(1H, dd, Jꢂ3.6 4.9 Hz, one of C4H3S), 6.93 (1H, d, Jꢂ7.4 Hz, H6), 6.88
(1H, br s, one of CH2C6H3), 6.58 (1H, d, Jꢂ7.4 Hz, H5), 5.68 (2H, s, CH2),
5.06 (2H, s, CH2), 2.27 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 334; MS
m/z: 342 [Mꢅ]; Anal. Calcd for C18H18N2OS2: C, 63.13; H, 5.29; N, 8.18.
Found: C, 63.18; H, 5.27; N, 8.08.
3-(3,5-Dimethylbenzyl)-1-[(thiophen-3-yl)methyl]uracil (5m) Reac-
tion of 3b (230 mg, 1 mmol) with 3-thiophenemethanol (0.19 ml, 2 mmol) in
a similar manner as described in the section of 5c crystallization from
hexane gave white crystals (257 mg, 85%): mp 86.5—87 °C; 1H-NMR
(CDCl3) d 7.34 (1H, dd, Jꢂ3.0, 4.9 Hz, one of C4H3S), 7.23—7.25 (1H, m,
one of C4H3S), 7.11 (1H, d, Jꢂ7.7 Hz, H6), 7.06 (2H, br s, two of CH2C6H3),
7.22 (1H, dd, Jꢂ1.1, 4.9 Hz, one of C4H3S), 6.89 (1H, br s, one of
CH2C6H3), 5.74 (1H, d, Jꢂ8.0 Hz, H5), 5.07 (2H, br s, CH2), 4.90 (2H, br s,
CH2), 2.28 (6H, s, CH3ꢄ2); UV lmax (MeOH) nm: 268; MS m/z: 326 [Mꢅ];
Anal. Calcd for C18H18N2O2S: C, 66.23; H, 5.55; N, 8.58. Found: C, 66.55;
H, 5.61; N, 8.54.
1-Benzyl-3-(3,5-dimethylbenzyl)-6-(1-piperidinyl)uracil
(11a). A
General Procedure for Compound 11b A mixture of 10a (152 mg,
0.5 mmol) and piperidine (0.25 ml, 2.5 mmol) in 1,4-dioxane (5 ml) was
stirred at 60 °C for 4 h, then concentrated to a small volume. The residue
was partitioned between CHCl3 (20 ml) and water (20 ml). The organic layer
was dried over MgSO4, and concentrated to a small volume. The residue was
chromatographed over a column of silica gel G (1.8ꢄ30 cm) using 0—50%
1
AcOEt in hexane (1 l) to give a foam (161 mg, 91%): H-NMR (CDCl3) d
7.09 (2H, m, CH2C6H3), 6.90 (1H, m, CH2C6H3), 5.33 (1H, s, H5), 5.02 (2H,
s, CH2), 4.69 (2H, s, CH2), 2.92 (4H, m, four of piperidine), 2.28 (6H, s,
CH3ꢄ2), 1.73 (6H, m, six of piperidine); UV lmax (MeOH) nm: 277; MS
m/z: 352 [Mꢅ]; HR-MS m/z: 352.1904 (Mꢅ, C20H24N4O2 requires 352.1900).
1-Benzyl-3-(3,5-dimethylbenzyl)-6-(1-piperazinyl)uracil
(11b) Re-
crystallization from EtOH gave white crystals (307 mg, 87%): mp 179—
180 °C; 1H-NMR (DMSO-d6) d 6.88 (3H, br s, CH2C6H3), 5.32 (1H, s, H5),
4.86 (2H, s, CH2), 4.81 (2H, s, CH2), 2.84 (8H, s, piperazine), 2.22 (6H, s,
CH3ꢄ2); UV lmax (MeOH) nm: 275.5; MS m/z: 353 [Mꢅ]; Anal. Calcd for
C19H23N5O2: C, 64.57; H, 6.56; N, 19.82. Found: C, 64.57; H, 6.68; N,
19.81.
3-(3,5-Dimethylbenzyl)-1-[(thiophen-3-yl)methyl]-4-thiouracil
(6m)
1-Benzyl-3-(3,5-dimethylbenzyl)-6-[4-(p-toluenesulfonyl)-1-piper-
azinyl]uracil (11c) A mixture of 11c (177 mg, 0.5 mmol) and p-toluene-
sulfonyl chloride (330 mg, 1.7 mmol) in pyridine (5 ml) was stirred at room
temperature for 30 min, then water (1 ml) was added and concentrated to a
small volume. The residue was partitioned between CHCl3 (20 ml) and water
(20 ml). The organic layer was dried over MgSO4 and concentrated to a
small volume. Recrystallization of the residue from EtOH gave white crys-
Crystallization from hexane gave light yellowish crystals (220 mg, 64%): mp
80.5—81.5 °C; 1H-NMR (CDCl3) d 7.36 (1H, dd, Jꢂ3.0 4.9 Hz, one of
C4H3S), 7.27—7.28 (1H, m, one of C4H3S), 7.02—7.04 (3H, m, two of
CH2C6H3, one of C4H3S), 6.88—6.90 (2H, m, one of CH2C6H3, H6), 6.58
(1H, d, Jꢂ7.4 Hz, H5), 5.68 (2H, s, CH2), 4.91 (2H, s, CH2), 2.28 (6H, s,
CH3ꢄ2); UV lmax (MeOH) nm: 334; MS m/z: 342 [Mꢅ]; HR-MS m/z:
342.0861 (Mꢅ, C18H18N3OS2 requires 342.0862); Anal. Calcd for
C18H18N2OS2: C, 63.13; H, 5.29; N, 8.18. Found: C, 63.11; H, 5.36; N, 8.30.
1
tals (247 mg, 97%): mp 215—216 °C; H-NMR (CDCl3) d 6.90—7.69 (7H,

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333
m, CH2C6H3, SO2C6H4CH3), 5.39 (1H, s, H5), 4.99 (2H, s, CH2), 4.59 (2H, 13) A review of Mitsunobu reaction: Mitsunobu O., Synthesis, 1981, 1—
s, CH2), 3.05 (8H, br s, piperazine), 2.47 (3H, s, CH3), 2.27 (6H, s, CH3ꢄ2); 28 (1981).
UV lmax (CHCl3) nm: 266; MS m/z: 507 [Mꢅ]; Anal. Calcd for 14) Recently TMAD was developed as an alternative of DEAD: Tsunoda
C26H29N5O4S: C, 61.52; H, 5.76; N, 13.80. Found: C, 61.51; H, 5.73; N,
13.83.
T., Otsuka J., Yamamiya Y., Ito S., Chem. Lett., 1994, 539—542
(1994).
3-Cyanomethyl-6-methyl-1-(3,5-dimethylbenzyl)uracil (12b) To a so- 15) Clivio P., Fourrey J.-L., Gasche J., Favre A., J. Chem. Soc., Perkin
lution of 6-methyluracil (1.26 g, 10 mmol) in DMF (25 ml) was added potas-
sium carbonate (691 mg, 5 mmol) and bromoacetonitrile (0.35 ml, 5 mmol)
and stirred at 60 °C for 7 h, then acetic acid (0.5 ml) was added and concen-
Trans. 1, 1992, 2383—2388 (1992).
16) Clivio P., Fourrey J.-L., J. Org. Chem., 59, 7273—7283 (1994).
17) Novacek A., Coll. Czech. Chem. Comm., 36, 4066—4069 (1971).
trated to a small volume. The residual solution was chromatographed over a 18) Ogilvie K. K., Beaucage S. L., Gillen M. F., Tetrahedron Lett., 19,
column of silica gel G using 0—20% EtOH in CHCl3 (2 l) to give 12a as a
solid (434 mg). To a mixture of the solid (434 mg) and 3,5-dimethylbenzyl
alcohol (0.73 ml, 5 mmol) in dry THF (40 ml) was added triphenylphosphine
(1.31 g, 5 mmol) and TMAD (860 mg, 5 mmol). The solution was stirred at
50 °C overnight, then concentrated to a small volume. The residual solution
was chromatographed over a column of silica gel G (2.5ꢄ32 cm) using 20—
1663—1666 (1978).
19) Katritzky A. R., Baykut G., Rachwal S., Szafran M., Caster K. C.,
Eyler J., J. Chem. Soc., Perkin Trans. 2, 1989, 1499—1506 (1989).
20) Kusturin C., Liebeskind L. S., Rahman H., Sample K., Schweitzer B.,
Srogl J., Neumann W. L., Org. Lett., 5, 4349—4352 (2003).
21) Winckelmann I., Larsen E. H., Synthesis, 1986, 1041—1044 (1986).
80% AcOEt in hexane (2 l). Evaporation of the fraction and crystallization 22) Leistner S., Giro A. P., Wagner G., Pharmazie, 33, 185—189 (1978).
from EtOH gave light yellowish crystals (53 mg): mp 167—168 °C; 1H-
23) Leistner S., Hentschel K., Wagner G., Zeitschrift fuer Chemie, 23,
215—216 (1983).
24) De Clercq E., Descamps J., Verhelst G., Walker R. T., Jones A. S., Tor-
rence P. F., Shugar D., J. Infect. Dis., 141, 563—574 (1980).
NMR (600 MHz, CDCl3)
d 6.94 (1H, m, CH2C6H3), 6.76 (2H, m,
CH2C6H3), 5.70 (1H, s, H5), 5.07 (2H, s, N1-CH2), 4.88 (2H, s, N3-CH2),
2.30 (6H, s, CH3ꢄ2), 2.23 (3H, s, C6-CH3); 13C-NMR (150 MHz, CDCl3) d
160.3 (C4), 153.4 (C6), 151.5 (C2), 138.9, 135.2, 129.8 and 123.9 25) De Clercq E., Holy A., Rosenberg I., Sakuma T., Balzarini J., Maudgal
(CH2C6H3), 114.5 (CꢂN), 101.4 (C5), 48.3 (N1-CH2), 28.5 (N3-CH2), 21.3
(CH3ꢄ2), 20.2 (C6-CH3); UV lmax (MeOH) nm: 268.5; MS m/z: 283 [Mꢅ];
Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.98;
H, 6.11; N, 14.87.
P. C., Nature (London), 323, 464—467 (1986).
26) Schols D., De Clercq E., Balzarini J., Baba M., Witvrouw M., Hosoya
M., Andrei G., Snoeck R., Neyts J., Pauwels R., Nagy M., Gyorgyi-
Edelenyi J., Machovich R., Horvath I., Low M., Gorog S., Antiviral
Chem. Chemother., 1, 233—240 (1990).
References and Notes
27) Ren J., Esnouf R., Garman E., Somers D., Ross C., Kirby I., Keeling
J., Darby G., Jones Y., Stuart D., Nature Struct. Biol., 2, 293—302
(1995).
28) Ren J., Milton J., Weaver K. L., Short S. A., Stuart D. I., Stammers D.
K., Structure, 8, 1089—1094 (2000).
29) Hopkins A. L., Ren J., Esnouf R. M., Willcox B. E., Jones E. Y., Ross
C., Miyasaka T., Walker R. T., Tanaka H., Stammers D. K., Stuart D.
I., J. Med. Chem., 39, 1589—1600 (1996).
30) Hsiou Y., Das K., Ding J., Clark A. D., Jr., Kleim J. P., Rösner M.,
Winkler I., Riess G., Hughes S. H., Arnold E., J. Mol. Biol., 284,
313—323 (1998).
1) De Clercq E., Clin. Microbiol. Rev., 8, 200—239 (1995).
2) De Clercq E., Med. Res. Rev., 16, 125—157 (1996).
3) De Clercq E., Med. Viol., 6, 97—117 (1996).
4) De Clercq E., Nature Reviews Microbiology, 2, 704—720 (2004).
5) De Clercq E., J. Med. Chem., 48, 1297—1313 (2005).
6) Baba M., Tanaka H., De Clercq E., Pauwels R., Balzarini J., Schols D.,
Nakashima H., Perno C.-F., Walker R. T., Miyasaka T., Biochem. Bio-
phys. Res. Commun., 165, 1375—1381 (1989).
7) Szczech G. M., Furman P., Painter G. R., Barry D. W., Borroto-esoda
K., Grizzle T. B., Blum M. R., Sommadossi J.-P., Endoh R., Niwa T.,
Yamamoto M., Moxham C., Antimicrob. Agents Chemther., 44, 123— 31) Högberg M., Sahlberg C., Engelhardt P., Noréen R., Kangasmetsä J.,
130 (2000).
Johansson N. G., Öberg B., Vrang L., Zhang H., Sahlberg B.-L., Unge
T., Lövgren S., Fridborg K., Bäckbro K., J. Med. Chem., 43, 304
(2000).
8) Buckheit R. W., Jr., Watson K., Fliakas-Boltz V., Russell J., Loftus T.
L., Osterling M. C., Turpin J. A., Pallansch L. A., White E. L., Lee J.-
W., Lee S.-H., Oh J.-W., Kwon H.-S., Chung S.-G., Cho E.-H., Antimi- 32) Ren J., Esnouf R. M., Hopkins A. L., Warren J., Balzarini J., Stuart D.
crob. Agents Chemother., 45, 393—400 (2001). I., Stammers D. K., Biochemistry, 37, 14394—14403 (1998).
9) Nugent R. A., Schlachter S. T., Murphy M. J., Cleek G. J., Poel T. J., 33) Chan J. H., Hong J. S., Hunter R. N., 3rd, Orr G. F., Cowan J. R., Sher-
Wishka D. G., Graber D. R., Yagi Y., Keiser B. J., Olmsted R. A.,
Kopta L. A., Swaney S. M., Poppe S. M., Morris J., Tarpley W. G.,
Thomas R. C., J. Med. Chem., 41, 3793—3803 (1998).
man D. B., Sparks S. M., Reitter B. E., C. Andrews W., 3rd, Hazen R.
J., Clair M. St., Boone L. R., Ferris R. G., Creech K. L., Roberts G. B.,
Short S. A., Weaver K., Ott R. J., Ren J., Hopkins A., Stuart D. I.,
Stammers D. K., J. Med. Chem., 44, 1866—1882 (2001).
10) Mai A., Artico M., Sbardella G., Massa S., Novellino E., Greco G.,
Loi A. G., Tramontano E., Marongiu M. E., La Colla P., J. Med. 34) Das K., Clark A. D., Jr., Lewi P. J., Heeres J., De Jonge M. R., Koy-
Chem., 42, 619—627 (1999).
mans L. M. H., Vinkers M., Daeyaert F., Ludovici D. W., Kukla M. J.,
Corte B. D., Kavash R. W., Ho C. Y., Ye H., Lichtenstein M. A., An-
dries K., Pauwels R., de Béthune M.-P., Boyer P. L., Clark P., Hughes
S. H., Janssen P. A. J., Eddy A., J. Med. Chem., 47, 2550—2560
(2004).
11) Maruyama T., Kozai S., Yamasaki T., Witvrouw M., Pannecouque M.,
Balzarini J., Snoeck R., Andrei G., De Clercq E., Antiviral Chem.
Chemother., 14, 271—279 (2003).
12) Noell C. W., Cheng C.-C., J. Heterocyclic Chem., 5, 25—28 (1968).