Synthesis and biological activity of strongly fluorescent tricyclic analogues of acyclovir and ganciclovir

Article abstract of DOI:10.1021/jm020827z

In search of strongly fluorescent tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2), derivatives of the 3,9-dihydro-9-oxo-5H-imidazo[1,2-α]purine system, several 6-[4- (acyloxy)-phenyl], 6-[4-(acylamino)phenyl], and 6-[4-(phenoxycarbonyloxy)phenyl]-substituted TACV and TGCV analogues were synthesized and evaluated for their activity against herpes simplex virus types 1 and 2 in cell culture. All TACV and TGCV analogues showed strong fluorescence (quantum yield of 30-65% vs 2-aminopurine 100%). The 6-[4-(phenoxycarbonyloxy)phenyl]-substituted compounds 11 and 19 displayed the best combination of the fluorescence and antiviral potency.

Full text of DOI:10.1021/jm020827z

5052
J . Med. Chem. 2002, 45, 5052-5057
Syn th esis a n d Biologica l Activity of Str on gly F lu or escen t Tr icyclic An a logu es
of Acyclovir a n d Ga n ciclovir
Tomasz Goslinski,† Bozenna Golankiewicz,*,† Erik De Clercq,‡ and J an Balzarini‡
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/ 14, 61-704 Poznan´, Poland, and
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received J anuary 23, 2002
In search of strongly fluorescent tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV,
2), derivatives of the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system, several 6-[4-(acyloxy)-
phenyl], 6-[4-(acylamino)phenyl], and 6-[4-(phenoxycarbonyloxy)phenyl]-substituted TACV and
TGCV analogues were synthesized and evaluated for their activity against herpes simplex virus
types 1 and 2 in cell culture. All TACV and TGCV analogues showed strong fluorescence
(quantum yield of 30-65% vs 2-aminopurine 100%). The 6-[4-(phenoxycarbonyloxy)phenyl]-
substituted compounds 11 and 19 displayed the best combination of the fluorescence and
antiviral potency.
We have previously reported the alkylation-conden-
sation reaction of acyclovir (ACV, 1) and ganciclovir
(GCV, 2) with phenacyl bromide, transforming 1 and 2
into their tricyclic derivatives 3,9-dihydro-3-[(2-hydroxy-
ethoxy)methyl]-9-oxo-6-phenyl-5H-imidazo[1,2-a]pur-
ine (6-Ph-TACV, 3) and 3,9-dihydro-3-[(1,3-dihydroxy-
2-propoxy)methyl]-9-oxo-6-phenyl-5H-imidazo[1,2-a]-
purine (6-Ph-TGCV, 4), respectively.1 The activity of
compound 4 against herpes simplex virus type 1 (HSV-
1) and type 2 (HSV-2), thymidine kinase deficient (TK-)
HSV-1, and varicella-zoster virus (VZV) was very simi-
lar to that of the parent ganciclovir, while compound 3
was on average approximately 15-fold less active than
the parent acyclovir.1 Both compounds are intrinsically
fluorescent (quantum yield of ∼8% of that of 2-ami-
nopurine), which makes them promising for application
in the noninvasive diagnosis of herpes virus infections.
Our recent structure-activity studies on a series of
diverse 6-aryl-substituted TACV and TGCV analogues
led to the finding of 6-(4-MeOPh)-substituted derivatives
5 and 6 showing higher antiviral potency than 3 and 4.
However, the observed increase in antiviral potency of
5 and 6 was not accompanied by an increase in
fluorescence intensity, the quantum yield remaining
below 10%.2 The aforementioned study has also dem-
onstrated that the tolerance of the 6-aryl substituent
to modifications is quite low and only variations in the
4 (para) position of the phenyl ring seem to be permitted.
We envisioned that introduction of an ester or amide
group at this position may enhance the intensity of
fluorescence. In the present paper, we describe the
synthesis and evaluation of the antiherpetic activity of
a series of strongly fluorescent tricyclic analogues
derived from 6-(4-HOPh)-TACV, 6-(4-H2NPh)-TACV,
and their ganciclovir (TGCV) counterparts.
cence may be reduced to the level of the weakly
fluorescent 6-(4-HOPh)-substituted compounds, they
could still be of interest because they might serve as
prodrugs of parent compounds. They would then con-
stitute a new type of prodrug that, in contrast to the
majority of the prodrugs of acyclovir and ganciclovir,3
would not be blocked at the side chain hydroxy group
involved in phosphorylation and would be crucial for
converting this class of compounds to their antivirally
active metabolites.
Ch em istr y
The synthesis of the 6-(4-R1Ph)-substituted tricyclic
analogues of acyclovir 9-16 and ganciclovir 17-20 is
depicted in Scheme 1. The yields of their preparation,
physical properties, and fluorescence characteristics are
given in Table 1.
The tricyclic analogues incorporating the ester or
amide functions were prepared by reacting the 1-sodium
derivative of acyclovir or ganciclovir with an appropriate
bromo ketone according to a previously described method
for an alkylation-condensation reaction using simple
bromo ketones.1,2,4 The synthesis of the bromo ketones
started from treatment of either 4-hydroxyacetophenone
or 4-aminoacetophenone in pyridine with acylating
agent (i.e., acetic anhydride, isobutyric anhydride, or
phenylchloroformate) to give 4-acyloxy (7a -c) or 4-acyl-
amino (7d -f) acetophenones, respectively, in over 85%
yield. With the exception of 7c, the following compounds
were obtained previously by diverse methods: 7a ,b,5
7d ,6 7e,7 7f. 8 For the bromination procedures to be
convenient for converting 7a -f into the desired 4-sub-
stituted phenacyl bromides 8a -f (of which only 8a 9 and
8d 6 were reported so far), literature approaches6,10,11
were explored. 4-Acyloxyphenacyl bromides could be
prepared either by reaction of 7a -c with bromine in
tetrahydrofurane solution in the presence of catalytic
amounts of aluminum chloride6 or in a heterogeneous
system consisting of copper(II) bromide in chloroform-
ethyl acetate.11 The second method was more selective;
the first one was less time-consuming and did not
We also anticipated that the ester derivatives may
be split by esterases into the parental substituted TACV
or TGCV analogues. While in this case their fluores-
* To whom correspondence should be addressed. Phone: 4861
8528503. Fax: 4861 8520532. E-mail: bogolan@ibch.poznan.pl.
† Polish Academy of Sciences.
‡ Katholieke Universiteit Leuven.
10.1021/jm020827z CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

Analogues of Acyclovir and Ganciclovir
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5053
Sch em e 1a
a
Reagents and conditions: (a) (CH3CO)2O, Py, room temp, 5 h; (b) [(CH3)2CHCO]2O, Py, room temp, 5 h; (c) ClCOOPh, Py, room temp,
5 h; (d) Br2, AlCl3, THF, 0-20 °C, 2 h; (e) CuBr2, EtOAc-CHCl3 1:1, reflux, 5 h; (f) NaH/DMF, then 8a -f, room temp, 4 h; (g) NH3-
MeOH, room temp, 3 h.
Ta ble 1. Physical Properties and Analytical and Fluorescence Data of Compounds 9-20
fluorescence (MeOH)
emission λmax, nm
recryst
formula,
(excitation at 305 nm)
compd
yield,a
%
solventb
mp, °C
anal. CHNc
(æ, %)g
9
10
11
12
13
14
15
16
17
18
19
20
53
62
34
96
33
35
18
67
59
55
29
57
A
218
224 dec
158 dec
200 dec
220 dec
250 dec
166 dec
>300 dec
176-178
190-193 efferv
157-159 efferv
197-199 dec
C18H17N5O5
384 (43.4)
383 (40.0)
388 (54.1)
369 (7.0)
375 (40.2)
372 (37.4)
364 (65.4)
363 (55.7)
384 (30.6)
383 (30.8)
388 (48.0)
371 (8.1)
MeOH
A
A or B
A
A
EtOH
A
EtOH
MeOH
EtOH
C
C
C
C
C
C
C
C
C
C
C
C
20H21N5O5
23H19N5O6‚0.5H2Od
16H15N5O4‚H2O
18H18N6O4‚0.5H2Oe
20H22N6O4‚0.75H2O
23H20N6O5‚H2O
17H17N7O4‚0.75CH3OH
19H19N5O6‚0.75H2O
21H23N5O6
f
24H21N5O7‚2.5H2O
17H17N5O5‚1.5H2O
a
b
After chromatography. (A) CH2Cl2-MeOH, 1:1; (B) EtOH-EtOAc, 4:1; (C) EtOH-H2O, 1:1. c Elemental compositions (%) were found
to be within (0.4% of the theoretical values for C, H, N unless stated otherwise. N: calcd, 14.89; found, 14.31. e N: calcd, 21.47; found
d
20.96. f Purity is 99.05% and 99.15% according to HPLC in two solvent systems. Relative to 2-aminopurine as 100% standard.
g
require heating. It was superior to the copper(II)
bromide approach in those cases in which the dibromide
side product was easily removed by crystallization. For
preparation of 4-acylaminophenacyl bromides 8d -f,
only the bromine-tetrahydrofuran approach was suit-
able.
Routine thin-layer chromatography following of the
reaction progress of 1 or 2 with bromo ketones 8a -f
indicated that, in contrast to alkylation-condensation
reactions previously described, the present reactions
went to completion without addition of aqueous am-
monia.
The most efficient way toward 6-(4-HOPh)-TACV (12)
and 6-(4-HOPh)-TGCV (20), parent compounds of esters
9-11 and 17-19, respectively, was treatment of isobu-
tyric esters 10 and 18 with saturated methanolic
ammonia. Reaction of phenyl carbamate 15 with NH3-
MeOH (satd) led smoothly to the 6-(4-ureidophenyl)
derivative 16.
Alternatively, 6-(4-acetylaminophenyl)-TACV 13 was
prepared from the recently reported2 6-(4-nitrophenyl)-
TACV (21), which was subjected to, consecutively,
O-acetylation in the acyclic moiety and reduction to the
6-aminophenyl derivative 22, acetylation of the amino
function to give 23, and O-deacetylation to 13 (Scheme
2). This approach, however, was more tedious and less
efficient than one employing the alkylation-condensa-
tion reaction of 1 with the appropriate ketone.
The fluorophoric potential of the 6-phenyl substituent
for the TACV and TGCV systems was significantly
increased with acyloxy, acylamino, phenoxycarbonyloxy,
and phenoxycarbonylamino groups in its 4-position. The
strongest effect was observed for the phenoxycarbonyl
unit; its presence resulted in an enhancement of the
fluorescence quantum yield from below 10% for 3,1 4,1
12, and 20 to around 50% (19, 48%) or more (11, 54%;
15, 65%), relative to 2-aminopurine (100%).

5054 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Goslinski et al.
Sch em e 2a
(minimum cytotoxic concentration ranging between 100
and 1000 µM).
Con clu sion
The 6-[4-(acyloxy)phenyl] and 6-[4-(phenoxycarbonyl-
oxy)phenyl] derivatives of TACV and TGCV displayed
both high antiherpetic activity and strong fluorescence.
They should be considered as antiherpetic drug candi-
dates worthy of further evaluation.
Exp er im en ta l Section
Ch em ica l P r oced u r es. Melting points were determined
on a Laboratory Devices Mel-Temp II micromelting point
apparatus in open capillaries and are uncorrected. Elemental
analyses were performed by Microanalytical Laboratories of
the Institute of Organic Chemistry, Polish Academy of Sciences
in Warsaw, Poland; the results are within 0.4% of the theoreti-
cal values unless otherwise stated. UV spectra were measured
on a Perkin-Elmer LAMBDA Ez 201 spectrophotometer in
CH3OH; λmax is reported in nm, and the extinction coefficient
is reported as ꢀ × 10-3 dm-3 mol-1 cm-1 in parentheses.
Fluorescence spectra Fl were measured on a Hitachi L-2000
fluorescence spectrophotometer in CH3OH; λexc ) 305 nm. The
quantum yield of the reference 2-aminopurine (H2O) æ is 1.0,
and λem (relative intensity in %) is reported.
a
Reagents and conditions: (a) (CH3CO)2O, Py, room temp, 5
h; (b) Pd/C, MeOH, HCOONH4, Ar, room temp, 2 h; (c) NH3-
MeOH, room temp, 24 h.
The majority of the compounds, synthesized as de-
scribed above, showed strong affinity for water, which
could not be completely removed from analytical samples
under drying conditions (Bu¨chi drying oven, P2O5, 45
°C, 5 mmHg, 2 h), established beforehand for the whole
series in terms of decomposition. The remaining water
was observed in 1H NMR spectra of these samples in
anhydrous DMSO-d6 solution prepared in a drybox. The
structural character of water was demonstrated in the
sample of the 6-(4-hydroxyphenyl) derivative 20, which,
in contrast to its ester or amide congeners, was stable
under heating at 90 °C for 2 h. An attempt at drying
20 at 90 °C for 2 h, followed by drying at 45 °C for 0.5
h resulted in a compound with identical water content
as that dried under routine conditions.
1H and 13C NMR spectra were recorded on a Varian Unity
300 FT NMR spectrometer in DMSO-d6 at 299.95 and 75.43
MHz, respectively. Chemical shifts are expressed in δ values
(parts per million) relative to tetramethylsilane as an internal
standard. NMR multiplicity data are denoted by s (singlet), d
(doublet), t (triplet), q (quartet), and m (multiplet). Capital
letters refer to the pattern resulting from directly bonded 13C-
1H couplings.
For LR-MS, the EI mass spectra were recorded on an AMD-
402 two-sector mass spectrometer (AMD Intectra, Germany).
LR- and HR-MS were recorded on an AMD-604 mass spec-
trometer (Cs gun, 10 kV, 2 A) by the liquid secondary-
ionization MS(LSIMS) method in positive mode with 3-ni-
trobenzyl alcohol (NBA) as the matrix; m/z (rel intensity in
%) is reported. Metastable ions were analyzed with B/E linked
scans.
Thin-layer chromatography (TLC) was conducted on Merck
precoated silica gel F254 type 60 plates. Column chromatogra-
phy (CC) was performed on silica gel 60H with particle size
40-60 µm (Merck). The following solvent systems (measured
by volume) were used for TLC: hexane-EtOAc, 7:3 (A), CH2-
Cl2-CH3OH, 5:1 (B), 9:1 (C), 95:5 (D). Analytical HPLC was
performed on a Waters 600E multisolvent delivery system
instrument with a 486 tunable absorbance detector using a
Nova Pak C18 column (8 mm × 100 mm Radial-Pak cartridge).
Gen er a l P r oced u r e for th e P r ep a r a tion of 4-Su bsti-
tu ted Der iva tives of 4-Hyd r oxy- a n d 4-Am in oa cetop h en -
on e 7a -f. 4-Hydroxy- or 4-aminoacetophenone (4 mmol) dried
by successive coevaporations with anhydrous pyridine (2 × 20
mL) was dissolved in anhydrous pyridine (20 mL). The solution
was concentrated to 10 mL, stirred, and treated at room
temperature under argon with an appropriate acylating agent
(6 mmol): acetic anhydride, isobutyric anhydride, or phenyl
chloroformate. After 2 h, an additional portion of the acylating
agent was added (4 mmol). The reaction was judged to be
complete by TLC (solvent A) in approximately 5 h. Then,
anhydrous ethanol was added dropwise (5 mL), the solvents
were coevaporated, and the residue was subjected to successive
coevaporations with dry ethanol (2 × 5 mL) and toluene (2 ×
50 mL). The remaining solid was extracted with EtOAc-H2O
(1:1, 50 mL). The water layer was subsequently extracted with
EtOAc (2 × 50 mL), and the organic layers were combined,
dried (Na2SO4), and concentrated under reduced pressure to
give a crude product, which could be further purified by
crystallization from EtOAc or EtOAc-hexane. The yields
ranged from 85% to 95%.
An tivir a l Activity
The antiherpetic properties of the TACV and TGCV
derivatives were determined in E6SM cell cultures
(Table 2). All tricyclic compounds showed activity
against three different HSV-1 and three different HSV-2
strains. Although the antiviral potency markedly dif-
fered from one compound to another, each compound
showed similar activity against HSV-1 and HSV-2. No
activity was noted with any of the compounds against
a TK-deficient HSV-1 strain. This points to the role of
the HSV-encoded thymidine kinase (TK) in the meta-
bolic activation of the test compounds. As a rule, the
ester derivatives of 12 (i.e., 9-11) were more active anti-
HSV agents than the corresponding amide derivatives
(i.e., 13-16). The TGCV derivatives (17-20) were
usually more inhibitory to HSV replication than the
TACV derivatives, which is in line with our present and
previous observations that GCV is also more effective
than ACV. The most effective TACV and TGCV deriva-
tives showed an antiviral activity that was the same
order of magnitude as that of ACV and GCV, respec-
tively. The ester derivatives 11 and 19 showed an
activity that was comparable to that of the free TACV
and TGCV derivatives 12 and 20, pointing to an efficient
conversion of the ester derivatives to the parental
compounds by cellular esterases. None of the compounds
was markedly cytotoxic to the E6SM cell cultures
The following reactants prepared as above, with the excep-
tion of 7c, have been obtained previously by diverse methods:

Analogues of Acyclovir and Ganciclovir
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5055
Ta ble 2. Activity against Human Herpes Simplex Virus Types 1 and 2 and Cytotoxicity of Compounds 9-20
minimum inhibitory concentrationb (µM)
minimum
cytotoxic
concentrationa
(µM)
herpes
simplex
herpes
simplex
herpes
simplex
herpes
simplex
herpes
simplex
herpes
simplex
herpes
simplex virus-1
compd
virus-1 (KOS) virus-1 (F) virus-1 (McIntyre) virus-2 (G) virus-2 (196) virus-2 (Lyons) TK- (KOS) (ACVr)
9
10
11
12
13
14
15
16
17
18
19
20
ACV
GCV
1043
972
867
703
126
975
869
209
968
906
814
1077
1776
392
0.601
0.560
0.832
0.675
6.7
2.8
1.1
15
0.049
0.116
0.008
0.041
0.341
0.030
0.200
0.311
0.166
0.225
5.0
4.7
0.834
5.0
0.062
0.035
0.031
0.041
0.341
0.045
0.200
0.187
0.166
0.225
25
4.7
0.601
0.622
0.830
0.675
8.4
0.200
0.933
0.832
0.375
25
4.7
0.200
0.933
0.832
0.225
25
4.7
626
583
694
234
25
780
174
126
23
22
19
69
249
4.4
2.5
0.834
5.0
1.4
8.3
1.4
8.3
15
97
0.116
0.417
0.960
0.242
0.060
0.186
0.1740
0.781
0.207
0.341
0.040
0.186
0.870
0.781
0.207
1.0
0.186
0.174
0.156
0.207
1.0
0.100
0.045
7.5
a
Required to cause a microscopically detectable alteration of normal cell morphology. b Required to reduce virus-induced cytopathogenicity
by 50%.
4-acetyloxyacetophenone, 7a ,5 4-isobutyryloxyacetophenone,
d6): δ 8.12, 7.59 (d, d, 2H, 2H, 4-PhOCOOPh), 7.46-7.52,
7.30-7.43 (m, m, 2H, 3H, 4-PhOCOOPh), 4.97 (s, 2H, CH2).
7b,5 4-acetylaminoacetophenone, 7d ,6 4-isobutyrylaminoac-
etophenone, 7e,7 4-[(phenoxycarbonyl)amino]acetophenone,
7f.8
4-Isobu tyr ylam in oph en acyl Br om ide (8e) fr om Meth od
A. Recrystallized from hexane-EtOAc 7:3, cream colored solid,
mp 138-140 °C. TLC with solvent A. MW ) 284.15. MS (EI)
4-[(P h en oxyca r bon yl)oxy]a cetop h en on e (7c). Recrys-
tallized from EtOAc-hexane, white solid; mp 41-44 °C. MW
1
(m/z, %): (282.9, 25.17), (284.9, 24.60). H NMR (DMSO-d6):
1
) 256.26. MS (EI) (m/z, %): (256.2, 17.56). H NMR (DMSO-
δ 10.25 (s, 1H, NH), 7.97, 7.77 (d, d, 2H, 2H, 4-(CH3)2-
CHCONHPh), 4.85 (s, 2H, CH2), 2.64 (dq, 1H, CH), 1.11 (d,
6H, 2 × CH3).
d6): δ 8.08, 7.55 (d, d, 2H, 2H, 4-PhOCOOPh), 7.16-7.52 (m,
5H, 4-PhOCOOPh), 2.61 (s, 3H, CH3).
Gen er a l P r oced u r e for th e Br om in a tion of 4-Su bsti-
tu ted Der iva tives of 4-Hyd r oxy- a n d 4-Am in oa cetop h en -
on e. Meth od A. F or Der iva tives of 4-Hyd r oxy- a n d
4-Am in oa cetop h en on e. To a solution of the appropriate
ketone (4 mmol) in THF (30 mL) containing a catalytic amount
of AlCl3 (20 mg) was added Br2 (5.2 mmol in 5 mL of THF)
dropwise for 30 min at 0 °C. Then the mixture was allowed to
warm to room temperature. After 60 min, the solvent was
removed in vacuo followed by extraction of the resulting solid
with EtOAc-H2O (1:1, 50 mL). The water layer was subse-
quently extracted with EtOAc (2 × 50 mL), and the organic
layers were combined, concentrated, and purified by crystal-
lization or silica gel column chromatography (EtOAc-hexane),
giving the appropriate bromo ketone.
Meth od B. F or Der iva tives of 4-Hyd r oxya cetop h en -
on e. All bromination reactions were performed under Ar. The
compound to be brominated (4 mmol) and ground copper(II)
bromide (6 mmol) were placed in a flask fitted with a reflux
condenser. A mixture of chloroform and ethyl acetate (1:1, 30
mL) was added, and the resulting reaction mixture was
refluxed with vigorous stirring. The completion of the reaction
was judged by the disappearance of all of the black solid and
cessation of hydrogen bromide formation (after 4-5 h). The
copper(I) bromide was removed by filtration and was washed
well with ethyl acetate. The solvents were removed from the
filtrate under reduced pressure. The product was purified by
crystallization or silica gel column chromatography (EtOAc-
hexane, 3:7).
4-[(P h en oxyca r bon yl)a m in o]p h en a cyl Br om id e (8f)
fr om Meth od A. CC, hexane-EtOAc 7:3, white fluffy crystals,
mp 168-171 °C dec. TLC with solvent A. MW ) 334.17. MS
(EI) (m/z, %): (332.9, 1.16), (334.9, 1.17). 1H NMR (DMSO-
d6): δ 10.72 (s, 1H, NH), 8.00, 7.67 (d, d, 2H, 2H, 4-PhOC-
ONHPh), 7.42-7.49, 7.24-7.32 (m, m, 2H, 3H, 4-PhOCON-
HPh), 4.86 (s, 2H, CH2).
Gen er a l P r oced u r e for th e P r ep a r a tion of 3,9-Dih y-
d r o-3-[(2-h yd r oxyeth oxy)m eth yl]-9-oxo-5H-im id a zo[1,2-
a ]p u r in es a n d 3,9-Dih yd r o-3-[1,3-d ih yd r oxyp r op oxy)-
m eth yl]-9-oxo-5H-im id a zo[1,2-a ]p u r in es Su bstitu ted in
th e 6-P osition w ith Ester or Am id op h en yl Gr ou p . All
alkylation-condensation reactions were performed under Ar.
To an anhydrous suspension of acyclovir or ganciclovir (2
mmol) in dimethylformamide was added sodium hydride in
60% suspension in oil (2.2 mmol). After being stirred with
exclusion of moisture for 1 h at room temperature, the
resulting solution was treated with bromo ketone (2 mmol).
The reaction mixture was stirred for the next 4 h. Volatile
materials were removed under reduced pressure, and the
residual oil was chromatographed in an appropriate gradient
of CH2Cl2-CH3OH. Fractions containing the main product
were evaporated to dryness and recrystallized.
Detailed data on yields, recrystallization solvents, melting
points, combustion analyses, and fluorescence spectra are
presented in Table 1, and purification methods, UV, 1H and
13C NMR, and mass spectra are given below.
6-[4-(Ace t yloxy)p h e n yl]-3,9-d ih yd r o-3-[(2-h yd r oxy-
et h oxy)m et h yl]-9-oxo-5H -im id a zo[1,2-a ]p u r in e (9). CC,
CH2Cl2-CH3OH, 97:3 f 9:1, white small crystals. TLC with
solvents B and C. UV: 254 (31.4), 310 (9.9). 1H NMR (DMSO-
d6): δ 13.14 (s, 1H, N-5-H), 8.23 (s, 1H, H-7), 8.08 (s, 1H, H-2),
7.95, 7.26 (d, d, 2H, 2H, 6-(4-CH3COOPh)), 5.53 (s, 2H,
NCH2O), 4.71 (t, 1H, OH), 3.55, 3.51 (m, m, 2H, 2H, CH2CH2),
2.31 (s, 3H, CH3). 13C NMR (DMSO-d6): δ 169.08 (Sq, CdO),
151.24 (Ss, C-9), 150.65 (Sm, C4′), 150.40 (Sm, C-3a), 146.52
(Sd, C-4a), 139.33 (Dt, C-2), 128.46 (Sdt, C-6), 126.27, 122.50
(Dd, Dd, C2′C3′), 125.56 (Sdt, C1′), 115.45 (Sd, C-9a), 103.37
(Ds, C-7), 72.38 (Ts, NCH2O), 70.56, 59.93 (Tm, Td, CH2CH2),
20.83 (Qs, CH3).
The yields of both methods ranged from 50% to 70%. Two
of the bromo ketones prepared as above (method A) have been
described previously: 4-acetyloxyphenacyl bromide 8a 9 and
4-acetylaminophenacyl bromide 8d .6
4-Isobu tyr yloxyp h en a cyl Br om id e (8b) fr om Meth od s
A a n d B. CC, hexane-EtOAc 10:1, white needles, mp 46-49
°C. TLC with solvent A. MW ) 285.14. MS (EI) (m/z, %):
1
(283.9, 6.78), (285.9, 7.09). H NMR (DMSO-d6): δ 8.07, 7.32
(d, d, 2H, 2H, 4-(CH3)2CHCOOPh), 4.95 (s, 2H, CH2), 2.84 (dq,
1H, CH), 1.25 (d, 6H, 2 × CH3).
4-[(P h en oxyca r bon yl)oxy]p h en a cyl Br om id e (8c) fr om
Meth od s A a n d B. CC, hexane-EtOAc 7:1 f 7:1.5, white
fluffy crystals, mp 84 °C. TLC with solvent A. MW ) 335.15.
MS (EI) (m/z, %): (333.8, 6.41), (335.8, 6.22). 1H NMR (DMSO-
3,9-Dih yd r o-3-[(2-h yd r oxyeth oxy)m eth yl]-6-[4-(isobu -
tyr yloxy)ph en yl]-9-oxo-5H-im ida zo[1,2-a ]pu r in e (10). CC,

5056 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Goslinski et al.
CH2Cl2-CH3OH, 7:1 f 6:1, white small crystals. TLC with
solvents B and C. UV: 254 (33.5), 310 (10.5). 1H NMR (DMSO-
d6): δ 13.14 (d, 1H, N-5-H), 8.24 (d, 1H, H-7), 8.08 (s, 1H, H-2),
7.96, 7.25 (d, d, 2H, 2H, 6-(4-(CH3)2CHCOOPh)), 5.53 (s, 2H,
NCH2O), 4.71 (s, 1H, OH), 3.55, 3.51 (m, m, 2H, 2H, CH2CH2),
2.84 (m, 1H, CH), 1.25 (d, 6H, 2 × CH3). 13C NMR (DMSO-d6):
δ 174.92 (Sdq, CdO), 151.22 (Ss, C-9), 150.75 (Sm, C-3a),
150.39 (Sdt, C4′), 146.51 (St, C-4a), 139.33 (Ds, C-2), 128.46
(Sm, C-6), 126.29, 122.42 (Dd, Dd, C2′C3′), 125.55 (St, C1′),
115.43 (Sd, C-9a), 103.38 (Dd, C-7), 72.37 (Tm, NCH2O), 70.57,
59.92 (Tm, Tt, CH2CH2), 33.31 (Ddq, CH), 18.61 (Qdq, 2 ×
CH3).
3,9-Dih yd r o-3-[(2-h yd r oxyet h oxy)m et h yl]-9-oxo-6-[4-
(p h e n oxyca r b on yloxy)p h e n yl]-5H -im id a zo[1,2-a ]p u r -
in e (11). CC, CH2Cl2-CH3OH, 97:3 f 9:1, yellowish solid. TLC
with solvents B, C, D. UV: 254 (21.0), 310 (6.2). 1H NMR
(DMSO-d6): δ 13.18 (s, 1H, N-5-H), 8.29 (s, 1H, H-7), 8.07 (s,
1H, H-2), 8.02, 7.53 (d, d, 2H, 2H, 6-(4-PhOCOOPh)), 7.48,
7.34-7.42 (d, m, 5H, 6-(4-PhOCOOPh)), 5.52 (s, 2H, NCH2O),
4.68 (t, 1H, OH), 3.53, 3.49 (m, m, 2H, 2H, CH2CH2). 13C NMR
(DMSO-d6): δ 151.41 (Ss, CdO), 151.24 (Ss, C-9), 150.69 (Sm,
C-3a), 150.64 (Sm, C1′′), 150.43 (Sm, C4′), 146.55 (Sd, C-4a),
139.36 (Dm, C-2), 129.70, 126.52, 121.18 (Dd, D, Dm,
C2′′C3′′C4′′), 128.25 (Sdt, C-6), 126.44, 121.98 (Dd, Dd, C2′C3′),
126.29 (St, C1′), 115.45 (Sd, C-9a), 103.72 (Dd, C-7), 72.38 (Ts,
NCH2O), 70.56, 59.92 (Tm, Ts, CH2CH2).
6-[4-(Acetyla m in o)p h en yl]-3,9-d ih yd r o-3-[(2-h yd r oxy-
eth oxy)m eth yl]-9-oxo-5H-im id a zo[1,2-a ]p u r in e (13). CC,
CH2Cl2-CH3OH, 9:1 f 7:1, white solid. TLC with solvents B
and C. UV: 274 (17.3), 316 (9.8). 1H NMR (DMSO-d6): δ 13.04
(d, 1H, N-5-H), 10.13 (s, 1H, NH), 8.11 (d, 1H, H-7), 8.07 (s,
1H, H-2), 7.83, 7.68 (d, d, 2H, 2H, 6-(4-CH3CONHPh)), 5.52
(s, 2H, NCH2O), 4.70 (t, 1H, OH), 3.53, 3.49 (m, m, 2H, 2H,
CH2CH2), 2.08 (s, 3H, CH3). 13C NMR (DMSO-d6): δ 168.50
(Sdq, CdO), 151.21 (Ss, C-9), 150.31 (Sm, C-3a), 146.39 (Sdt,
C-4a), 139.74 (St, C4′), 139.26 (Dt, C-2), 129.04 (Sm, C-6),
125.56, 119.07 (Dd, Dm, C2′C3′), 122.39 (St, C1′), 115.42 (Sd,
C-9a), 102.27 (Dd, C-7), 72.36 (Tm, NCH2O), 70.54, 59.91 (Tm,
Td, CH2CH2), 24.04 (Qs, CH3).
3,9-Dih yd r o-3-[(2-h yd r oxyeth oxy)m eth yl]-6-[4-(isobu -
tyr yla m in o)p h en yl]-9-oxo-5H-im id a zo[1,2-a ]p u r in e (14).
CC, CH2Cl2-CH3OH, 8:1 f 6:1, yellowish solid. TLC with
solvents B and C. UV: 274 (26.8), 316 (15.5). 1H NMR (DMSO-
d6): δ 13.04 (s, 1H, N-5-H), 10.03 (s, 1H, NH), 8.12 (s, 1H,
H-7), 8.07 (s, 1H, H-2), 7.84, 7.72 (d, d, 2H, 2H, 6-(4-(CH3)2-
CHCONHPh)), 5.53 (s, 2H, NCH2O), 4.70 (t, 1H, OH), 3.54,
3.50 (m, m, 2H, 2H, CH2CH2), 2.63 (m, 1H, CH), 1.13 (d, 6H,
2 × CH3). 13C NMR (DMSO-d6): δ 175.42 (Sm, CdO), 151.22
(Ss, C-9), 150.31 (Sdt, C-3a), 146.41 (Sd, C-4a), 139.88 (St, C4′),
139.27 (Dt, C-2), 129.07 (Sdt, C-6), 125.54, 119.23 (Dd, Dt,
C2′C3′), 122.36 (St, C1′), 115.43 (Sd, C-9a), 102.28 (Ds, C-7),
72.36 (Ts, NCH2O), 70.55, 59.92 (Ts, Td, CH2CH2), 34.98 (Ddq,
CH), 19.43 (Qdq, 2 × CH3).
1H, OH), 3.64 (m, 1H, CH), 3.44, 3.34 (m, m, 2H, 2H, 2 × CH2),
2.30 (s, 3H, CH3). 13C NMR (DMSO-d6): δ 169.09 (Sq, CdO),
151.25 (Ss, C-9), 150.66 (Sm, C4′), 150.31 (Sdt, C-3a), 146.51
(Sd, C-4a), 139.31 (Dt, C-2), 128.49 (Sdt, C-6), 126.29, 122.52
(Dd, Dd, C2′C3′), 125.61 (St, C1′), 115.41 (Sd, C-9a), 103.34
(Ds, C-7), 80.18 (Ds, CH), 71.83 (Td, NCH2O), 60.92 (Ts, 2 ×
CH2), 20.84 (Qs, CH3).
3,9-Dih yd r o-3-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]-6-[4-
(isob u t yr yloxy)p h en yl]-9-oxo-5H -im id a zo[1,2-a ]p u r in e
(18). CC, CH2Cl2-CH3OH, 6:1 f 5:1, white solid. TLC with
solvents B and C. UV: 255 (40.2), 310 (12.7). 1H NMR (DMSO-
d6): δ 13.15 (s, 1H, N-5-H), 8.23 (s, 1H, H-7), 8.06 (s, 1H, H-2),
7.96, 7.25 (d, d, 2H, 2H, 6-(4-(CH3)2CHCOOPh)), 5.62 (s, 2H,
NCH2O), 4.64 (t, 1H, OH), 3.64 (s, 1H, CH), 3.43, 3.34 (m, m,
2H, 2H, 2 × CH2), 2.84 (m, 1H, CH), 1.25 (d, 6H, 2 × CH3).
13C NMR (DMSO-d6): δ 174.88 (Sm, CdO), 151.20 (Ss, C-9),
150.67 (Sm, C4′), 150.26 (Sdt, C-3a), 146.51 (Sd, C-4a), 139.22
(Dm, C-2), 128.59 (Sm, C-6), 126.24, 122.36 (Dd, Dd, C2′C3′),
125.65 (St, C1′), 115.28 (Sd, C-9a), 103.22 (Ds, C-7), 80.09 (Dm,
CH), 71.73 (Td, NCH2O), 60.83 (Tm, 2 × CH2), 33.24 (Ddq,
CH), 18.55 (Qdq, 2 × CH3). LSIMS (positive mode): 442.6 (92,
[MH]+), 464.5 (72, [MNa]+). MS (linked scan): 442.0, 371.1,
367.1, 350.1, 338.1, 267.1. HR-MS (formula C21H24O6N5): calcd
442.172 67; found 442.174 54. For HPLC, elution was per-
formed in two systems: (1) CH3OH (A)-H2O (B), from 10% A
to 60% A in 20 min, continued with 60% A for the next 15
min, retention time of 29.36 min, purity of 99.05%; (2) 10 mM
NH4Ac (C)-10 mM NH4Ac-CH3CN 1:1 (D), from 20% D to
100% D in 20 min, continued at 100% D for the next 15 min,
retention time of 21.59 min, purity of 99.15%, flow rate of 1
mL/min. UV: detection at 257 nm.
3,9-Dih yd r o-3-[(1,3-d ih yd r oxy-2-p r op oxy)m et h yl]-9-
oxo-6-[4-(p h en oxyca r bon yloxy)p h en yl]-5H-im id a zo[1,2-
a ]p u r in e (19). CC, CH2Cl2-CH3OH, 7:1 f 5:1, white solid.
TLC with solvents B and C. UV: 255 (25.4), 310 (7.5). 1H NMR
(DMSO-d6): δ 13.19 (s, 1H, N-5-H), 8.28 (s, 1H, H-7), 8.07 (s,
1H, H-2), 8.03, 7.53 (d, d, 2H, 2H, 6-(4-PhOCOOPh)), 7.49 (d,
2H, C2′′), 7.41 (m, 2H, C3′′), 7.35 (m, 1H, C4′′), 5.62 (s, 2H,
NCH2O), 4.65 (t, 1H, OH), 3.64 (m, 1H, CH), 3.44, 3.34 (m, m,
2H, 2H, 2 × CH2). 13C NMR (DMSO-d6): δ 151.41 (CdO),
151.28 (C-9), 150.68 (C4′), 150.64 (C1′′), 150.36 (C-3a), 146.60
(C-4a), 139.33 (C-2), 129.73 (C2′′), 128.39 (C-6), 126.55 (C4′′),
126.47 (C2′), 126.44 (C1′), 122.00 (C3′), 121.21 (C3′′), 115.39
(C-9a), 103.66 (C-7), 80.18 (CH), 71.83 (NCH2O), 60.92 (2 ×
CH2). LSIMS (positive mode): 492.7 (10, [MH]+), 514.6 (5,
[MNa]+). MS (linked scan): 492.0, 416.9, 399.9, 387.9, 267.0.
HR-MS (formula C24H22O7N5): calcd 492.151 92;found 492.148 90.
3,9-Dih yd r o-3-[(2-h yd r oxyet h oxy)m et h yl]-9-oxo-6-(4-
u r eid op h en yl)-5H-im id a zo[1,2-a ]p u r in e (16). Compound
15 (47.5 mg, 0.1 mmol) was stirred with saturated methanolic
ammonia (3 mL) for 4 h under Ar and strictly anhydrous
conditions. Upon removal of NH3 under reduced pressure, a
brown precipitate of 16 separated out (26.6 mg, 0.07 mmol,
67%). Recrystalllized from solvent A, brown solid. TLC with
solvent B. UV: 273 (2.3), 314 (1.5). 1H NMR (DMSO-d6): δ
12.92 (s, 1H, N-5-H), 8.73 (s, 1H, NH), 8.05 (s, 1H, H-7), 8.04
(s, 1H, H-2), 7.76, 7.50 (d, d, 2H, 2H, 6-(4-H2NCONHPh)), 5.96
(s, 2H, NH2), 5.51 (s, 2H, NCH2O), 4.69 (t, 1H, OH), 3.53, 3.49
(m, m, 2H, 2H, CH2CH2).
3,9-Dih yd r o-3-[(2-h yd r oxyet h oxy)m et h yl]-9-oxo-6-[4-
(p h en oxyca r bon yla m in o)p h en yl]-5H-im id a zo[1,2-a ]p u r -
in e (15). CC, CH2Cl2-CH3OH, 7.5:1 f 6:1, white solid. TLC
with solvents B and C. UV: 271 (26.7), 315 (13.6). 1H NMR
(DMSO-d6): δ 13.06 (s, 1H, N-5-H), 10.47 (s, 1H, NH), 8.15 (s,
1H, H-7), 8.06 (s, 1H, H-2), 7.88, 7.62 (d, d, 2H, 2H, 6-(4-
PhOCONHPh)), 7.44, 7.25-7.31 (d, m, 5H, 6-(4-PhOCON-
HPh)), 5.52 (s, 2H, NCH2O), 4.70 (t, 1H, OH), 3.54, 3.50 (m,
m, 2H, 2H, CH2CH2). 13C NMR (DMSO-d6): δ 151.59 (Ss, Cd
O), 151.22 (Ss, C-9), 150.40 (Sm, C1′′), 150.32 (Sm, C-3a),
146.41 (Sd, C-4a), 139.28 (Dt, C-2), 139.09 (St, C4′), 129.43,
125.51, 121.90 (Dd, Dm, Dm, C2′′C3′′C4′′), 128.93 (Sdt, C-6),
125.77, 118.56 (Dm, Dm, C2′C3′), 122.46 (St, C1′), 115.43 (Sd,
C-9a), 102.41 (Ds, C-7), 72.36 (Ts, NCH2O), 70.55, 59.91 (Tm,
Td, CH2CH2).
3,9-Dih ydr o-3-[(2-h ydr oxyeth oxy)m eth yl]-6-(4-h ydr oxy-
p h en yl)-9-oxo-5H-im id a zo[1,2-a ]p u r in e (12). 12 was ob-
tained from 10 (474.7 mg, 1.15 mmol) and NH3-MeOH (10
mL), according to the procedure described above for 15 f 16.
White solid (379 mg, 1.11 mmol, 96.2%). Recrystallized from
solvent A or B. TLC with solvent B. UV: 262 (31.2), 308 (13.7).
1H NMR (DMSO-d6): δ 12.95 (d, 1H, N-5-H), 9.86 (s, 1H,
HOPh), 8.06 (s, 1H, H-2), 7.99 (d, 1H, H-7), 7.72, 6.85 (d, d,
2H, 2H, 6-(4-HOPh)), 5.51 (s, 2H, NCH2O), 4.68 (s, 1H, OH),
3.52, 3.49 (m, m, 2H, 2H, CH2CH2). 13C NMR (DMSO-d6): δ
158.11 (St, C4′), 151.26 (Ss, C-9), 150.24 (Sdt, C-3a), 146.33
(Sd, C-4a), 139.24 (Dt, C-2), 129.57 (Sdt, C-6), 126.68, 115.80
(Dd, Dm, C2′C3′), 118.72 (St, C1′), 115.43 (Sd, C-9a), 101.17
(Ds, C-7), 72.38 (Ts, NCH2O), 70.55, 59.94 (Ts, Td, CH2-CH2).
6-[4-(Acetyloxy)p h en yl]-3,9-d ih yd r o-3-[(1,3-d ih yd r oxy-
2-p r op oxy)m eth yl]-9-oxo-5H-im id a zo[1,2-a ]p u r in e (17).
CC, CH2Cl2-CH3OH, 7:1 f 5:1, white solid. TLC with solvent
B. UV: 255 (34.0), 310 (10.7). 1H NMR (DMSO-d6): δ 13.15
(s, 1H, N-5-H), 8.23 (s, 1H, H-7), 8.06 (s, 1H, H-2), 7.95, 7.26
(d, d, 2H, 2H, 6-(4-CH3COOPh)), 5.62 (s, 2H, NCH2O), 4.64 (t,

Analogues of Acyclovir and Ganciclovir
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5057
3,9-Dih yd r o-3-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]-6-(4-
h yd r oxyp h en yl)-9-oxo-5H-im id a zo[1,2-a ]p u r in e (20). 20
was obtained from 18 (208.7 mg, 0.47 mmol) and NH3-MeOH
(8 mL) according to the procedure described above for 15 f
16. Yellowish solid (100.1 mg, 0.27 mmol, 57%). Recrystallized
from solvent C. TLC with solvent B. UV: 261 (30.8), 308 (13.8).
1H NMR (DMSO-d6): δ 12.95 (d, 1H, N-5-H), 9.85 (s, 1H,
HOPh), 8.04 (s, 1H, H-2), 7.99 (d, 1H, H-7), 7.72, 6.85 (d, d,
2H, 2H, 6-(4-HOPh)), 5.60 (s, 2H, NCH2O), 4.62 (t, 1H, OH),
3.62 (m, 1H, CH), 3.32, 3.42 (m, m, 2H, 2H, 2 × CH2). 13C NMR
(DMSO-d6): δ 158.01 (C4′), 151.14 (C-9), 150.03 (C-3a), 146.21
(C-4a), 139.12 (C-2), 129.46 (C-6), 126.59, 115.70 (C2′C3′),
118.63 (C1′), 115.70 (C-9a), 101.07 (C-7), 80.08 (CH), 71.75
(NCH2O), 60.84 (2 × CH2).
plates were inoculated with 100 CCID50 of virus, 1 CCID50
being the virus dose required to infect 50% of virus-inoculated
cell cultures. After a 1 h virus adsorption period, residual virus
was removed, and the cell cultures were incubated in the
presence of 2- to 5-fold dilutions of the test compound solutions.
Viral cytopathicity was recorded as soon as it reached comple-
tion in the control virus-infected cell cultures (i.e., at day 3
postinfection).
Ack n ow led gm en t. This work was supported by the
Polish Committee for Scientific Research (KBN) Grant
No. 4PO5F00516 and the Belgian Federation against
Cancer. We thank Mrs. Anita Van Lierde and Mrs.
Frieda De Meyer for excellent technical assistance. We
are grateful to F. Hoffmann-La Roche Ltd. for the gift
of ganciclovir.
Alter n a tive Rou te to 13. F r om 3,9-Dih yd r o-3-[(2-h y-
dr oxyeth oxy)m eth yl]-6-(4-n itr oph en yl)-9-oxo-5H-im idazo-
[1,2-a ]p u r in e (21). Compound 21, described previously,2 was
converted into the corresponding 3-[(2-acetyloxyethoxy)methyl]
derivative using the acetylation procedure in pyridine de-
scribed above for 4-hydroxy- and 4-aminoacetophenone. Crude,
dried acetate (43.4 mg, 0.1 mmol) was dissolved in anhydrous
MeOH (10 mL) and subjected to reduction with a Pd/C
ammonium formate system12 (40 mg Pd/C and 64 mg, 1 mmol
HCOONH4) for 2 h. The reaction mixture was filtered through
Celite, methanol was removed from the filtrate by evaporation,
and the excessive ammonium formate was removed by subli-
mation under reduced pressure. The resulting solid was
purified by CC using a CH2Cl2-MeOH gradient of 95:5 f 9:1
to give 3-[(2-acetyloxyethoxy)methyl]-6-(4-aminophenyl)-3,9-
dihydro-9-oxo-5H-imidazo[1,2-a]purine (22) (20.3 mg, 0.053
mmol, 50.4%). CC, CH2Cl2-CH3OH, 95:5 f 9:1, tan solid. TLC
with solvents C and D. UV: 273 (21.5), 314 (14.3). 1H NMR
(DMSO-d6): δ 12.80 (s, 1H, N-5-H), 8.05 (s, 1H, H-2), 7.84 (s,
1H, H-7), 7.54, 6.62 (d, d, 2H, 2H, 6-(4-H2NPh)), 5.51 (s, 2H,
NCH2O), 5.48 (s, 2H, NH2), 4.09, 3.72 (t, t, 2H, 2H, CH2CH2),
1.95 (s, 3H, CH3).
Refer en ces
(1) Golankiewicz, B.; Ostrowski, T.; Andrei, G.; Snoeck, R.; De
Clercq, E. Tricyclic analogues of acyclovir and ganciclovir.
Influence of substituents in the heterocyclic moiety on the
antiviral activity. J . Med. Chem. 1994, 37, 3187-3190.
(2) Golankiewicz, B.; Ostrowski, T.; Goslinski, T.; J anuszczyk, P.;
Zeidler, J .; Baranowski, D.; De Clercq, E. Fluorescent tricyclic
analogues of acyclovir and ganciclovir. A structure-antiviral
activity study. J . Med. Chem. 2001, 44, 4284-4287.
(3) Gao, H.; Mitra, A. K. Synthesis of acyclovir, ganciclovir, and their
prodrugs: a review. Synthesis 2000, 329-351.
(4) Boryski, J .; Golankiewicz, B.; De Clercq, E. Synthesis and
antiviral activity of 3-substituted derivatives of 3,9-dihydro-9-
oxo-5H-imidazo[1,2-a]purines, tricyclic analogues of acyclovir
and ganciclovir. J . Med. Chem. 1991, 34, 2380-2383.
(5) Schwabe, B.; Westphal, G.; Henning, H.-G. Phasentransfer-
katalisierte O-Acylierung von 4-Acetyl-phenol (Phase-transfer
catalyzed O-acylation of 4-acetylphenol). Z. Chem. 1980, 20,
184-185.
(6) Park, Ch.-H.; Givens, R. S. New photoactivated protecting
groups. 6. p-Hydroxyphenacyl: a phototrigger for chemical and
biochemical probes. J . Am. Chem. Soc. 1997, 119, 2453-2463.
(7) Taylor, M. J .; Hoffman, T. Z.; Yli-Kauhaluoma, J . T.; Lerner, R.
A.; J anda, K. D. A light-activated antibody catalyst. J . Am.
Chem. Soc. 1998, 120, 12783-12790.
(8) Thavonekham, B. A practical synthesis of ureas from phenyl
carbamates. Synthesis 1997, 1189-1194.
(9) Hashimoto, M.; Ohta, M. Preparation of p-hydroxyphenacyl-
aniline. Nippon Kagaku Zasshi 1959, 80, 212-214; Chem. Abstr.
1961, 4406efg.
(10) (a) Buu-Hoi, Ng. Ph.; Xuong, Ng. D.; Lavit, D. Halogenated o-
and p-phenolic ketones. J . Chem. Soc. 1954, 1034-1038. (b) Buu-
Hoi, Ng. Ph.; Lavit, D. The bromination of o- and p-hydroxyaryl
ketones. J . Chem. Soc. 1955, 18-20.
(11) King, L. C.; Ostrum, G. K. Selective bromination with copper-
(II) bromide. J . Org. Chem. 1964, 29, 3459-3461.
(12) Ram, S.; Ehrenkaufer, R. E. Ammonium formate in organic
Compound 22 (16.6 mg, 0.043 mmol) was acetylated as
described above to give after CC purification (CH2Cl2-MeOH,
95:5 f 9:1) 6-[4-(acetylamino)phenyl)-3-[(2-acetyloxyethoxy)-
methyl]-3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine (23) (13.6
mg, 0.032 mmol, 74.5%). CC, CH2Cl2-CH3OH, 95:5 f 9:1,
1
white solid. TLC with solvents C and D. H NMR (DMSO-d6):
δ 13.07 (s, 1H, N-5-H), 10.17 (s, 1H, NH), 8.12 (s, 1H, H-7),
8.08 (s, 1H, H-2), 7.84, 7.68 (d, d, 2H, 2H, 6-(4-CH3CONHPh)),
5.53 (s, 2H, NCH2O), 4.09, 3.73 (t, t, 2H, 2H, CH2CH2), 2.08
(s, 3H, NHCOCH3), 1.95 (s, 3H, OCOCH3).
Compound 23 (13.6 mg, 0.032 mmol) was stirred with
saturated NH3-MeOH (1.5 mL) at room temperature for 24
h under Ar and strictly anhydrous conditions. Upon removal
of NH3 under reduced pressure, a chromatographically homo-
geneous white solid precipitated out (5.4 mg, 0.014, 44%)
identical in all respects to 13 obtained from an alkylation-
condensation reaction.
synthesis:
a versatile agent in catalytic hydrogen transfer
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