A novel practical synthesis of C-2-arylpurines

Article abstract of DOI:10.1002/adsc.200404159

Suzuki-Miyaura cross-coupling of halopurines with arylboronic acids would be one of the most efficient methods to synthesize C-2-arylpurines. However, as this approach implied some potential disadvantages, we needed to devise a more efficient process. Sta

Full text of DOI:10.1002/adsc.200404159

FULL PAPERS
A Novel Practical Synthesis of C-2-Arylpurines
Takahiro Itoh,* Kimihiko Sato, Toshiaki Mase
Process R & D, Laboratories for Technology Development, Banyu Pharmaceutical, Kamimutsuna 3-Chome-9-1, Okazaki,
Aichi 444-0858, Japan
Fax: (þ81)-564-51-7086, e-mail: takahiro_itoh@merck.com
Received: June 2, 2004; Accepted: August 30, 2004
Abstract: Suzuki–Miyaura cross-coupling of halopur- zuki–Miyaura protocol. Excellent yields were ob-
ines with arylboronic acids would be one of the tained with 1,1’-bis(di-tert-butylphosphino)ferrocene
most efficient methods to synthesize C-2-arylpurines. (¼D-t-BPF) under anhydrous conditions. Tolerance
However, as this approach implied some potential of various arylboronic acids was also found. Subse-
disadvantages, we needed to devise a more efficient quent reduction with H2/Pd-C of one of the coupling
process. Starting with 4-amino-2-chloro-5-nitropyri- adducts, 4-amino-5-nitro-2-phenylpyrimidine, gave
midine, readily prepared from 5-nitrouracil, seemed the diamine, which was further condensed with acti-
to potentially obviate our concerns, and the applica- vated acid derivatives to afford a wide variety of the
bility of the Suzuki–Miyaura coupling was examined 2-phenylpurine derivatives in excellent yields.
in detail. Considerable competitive hydrolysis oc-
curred simultaneously with the desired reaction under Keywords: P ligands; metallocenes; palladium; purine;
the aqueous conditions typically employed in the Su- pyrimidine; Suzuki–Miyaura cross-coupling
Introduction
pling with chloropurine is not precedented and poten-
tially requires specific conditions; (ii) less active aryl or-
In recent years, there has been interest in the synthesis of ganometallics such as phenylboronic acids with elec-
purine derivatives including nucleoside and nucleotide tron-withdrawing groups are potentially hard to react;
analogues due to the broad range of discovered biolog- (iii) it is not readily applicable to analogues at C-8; (iv)
ically active compounds.[1] Purines bearing carbon sub- in those cases where the R group is precious, the cou-
stituents at the ring carbons have attracted much atten- pling reaction preferably should be implemented prior
tion due to their potential biological activities. In partic- to introduction of R group. In this context, 4-amino-2-
ular, C-2-arylpurine derivatives are becoming especially chloro-5-nitropyrimidine (4) is thought to be the most
important for drug discovery programs such as those to- likely candidate for the introduction of an aryl group
wards anxiolytic agents[2] and interferon inducers,[3] po- due to the presence of the nitro group. In addition, it po-
tent/selective c-AMP phosphodiesterase inhibitors,[4] tentially tolerates simple organometallics such as
angiotensin II antagonists,[5], b-AST-IV inhibitors,[6] A1 Grignard reagents. The nitro group acts not only as an
adenosine receptor antagonists,[7] or ADA (adenosine activator but also as an amine equivalent. The putative
deaminase) inhibitors.[8] Despite their importance, syn- diamine generally would react with a wide variety of car-
thetic efforts have not been sufficiently directed to the boxylic acids to afford the desired products in high yield
identification of synthetic pathways to provide ready ac- (Scheme 1). In conjunction with development of our
cess to these compounds.
drug candidate, we required an efficient synthesis of 2-
There are relatively few methods available to produce
C-2-arylpurine derivatives. Classical approaches for this
involve ring construction by condensation of two com-
ponents that needs the preparation of specific inter-
mediates.[9] A simpler and more efficient approach
would be the direct arylation of purine derivatives.[10–12]
In recent research, the Pd-catalyzed cross-coupling of
halopurines has been demonstrated to be among the
most promising methods.[13,14] Of these methods, the Su-
zuki–Miyaura cross-coupling reaction[15] appears to be
practically superior.[16,17] However, this approach im-
plies some potential synthetic difficulties: (i) cross-cou- Scheme 1.
Adv. Synth. Catal. 2004, 346, 1859–1867
DOI: 10.1002/adsc.200404159
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Takahiro Itoh et al.
FULL PAPERS
aryl-8-substituted purines, and this task also seemed to with Pd(PPh3)4 or Pd(OAc)2 in DME in the presence
be quite challenging. Therefore, our efforts have been of aqueous Na2CO3.[15k] The relatively less reactive 4-flu-
focused on the development of an efficient synthesis of orophenylboronic acid (5) was used as a coupling part-
8-substituted analogues. Herein we report a novel and ner for the reaction. However, the reactions did not pro-
practical synthesis of 2-phenylpurines and 2-phenyl-8- duce the desired product but rather gave the hydrolyzed
substituted purines.
product 7 predominantly under these conditions (Ta-
ble 1, entries 1 and 2). Attempts to accelerate the de-
sired reaction under aqueous condition met with failure
(entries 3 and 4). When DPPF was used as the ligand,
43% of the desired product was obtained with 50% of
Results and Discussion
It has been reported that 4-amino-2-chloro-5-nitropyri- pyrimidinone 7 (entry 5). Eventually, a variety of other
midine (4) was readily prepared from 5-nitrouracil.[18,19] palladium catalysts and ligands were screened for
We first tried reaction of 4 with simple aryl organometal- cross-coupling; however, the Pd(OAc)2/DPPF system
lics such as aryllithium, aryl-Grignard or milder arylzinc was proven to be the optimal among those examined.
reagents. Unfortunately the reactions with these re- Solvents other than DME such as THF, DMF, DMSO,
agents were not successful, and resulted in only complex MeOH, EtOH, i-PrOH, toluene, CPME (cyclopentyl
mixtures containing small amounts of the desired prod- methyl ether) did not give any detectable amount of
uct and the side product reacted at the C-6 position even the desired product 6. The optimal result was obtained
when excess amounts of organometallic reagents were by minimizing the amount of water (3 equivs.) giving
used. Our attention was therefore focused on the transi- 82% of the desired product 6 with 12% of the hydro-
tion metal-catalyzed cross-coupling reaction, and the lyzed product 7 (entry 6). PdCl2(dppf) was also accept-
Suzuki–Miyaura coupling was doubtlessly chosen since able (entry 7). However, under anhydrous conditions
it has been proven to practically offer distinctive advan- (KF of DME is 13 ppm), the desired reaction did not
tages over other approaches to date. In addition, this ap- proceed and almost all the starting material was recov-
proach would allow us to eliminate the protection of the ered (entry 8). Since it would be difficult to eliminate
amino group due to its inert nucleophilic nature.
the hydrolysis under aqueous condition, further investi-
gation to accelerate the desired reaction vs. the hydrol-
ysis was discontinued.
Synthesis of 4-Amino-5-nitro-2-(4-
fluorophenyl)pyrimidine
Suzuki–Miyaura Coupling under Anhydrous Condi-
tions
Suzuki–Miyaura Coupling under Aqueous Conditions
The typical Suzuki–Miyaura conditions we selected as a We therefore turned our attention to the coupling reac-
baseline reaction involved heating 4 and boronic acid tion under anhydrous conditions. We attributed the fail-
Table 1. Suzuki–Miyaura coupling of 4 with 5 under aqueous conditions.
Entry
Pd Cat.
Ligand
Base
Solvent
Yield of 6
Yield of 7
1
2
3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
–
aq. Na2CO3
aq. Na2CO3
aq. Na2CO3
DME
DME
DME
ND
80%
65%
80%
PPh3
ꢀ10%
ND
4
Pd(OAc)2
aq. Na2CO3
DME
trace
73%
5
6
7
8
Pd(OAc)2
Pd(OAc)2
PdCl2(dppf)
Pd(OAc)2
DPPF
DPPF
none
aq. Na2CO3
DME
43%
82%
65%
trace
50%
12%
23%
ND
anhyd. Na2CO3
anhyd. Na2CO3
anhyd. Na2CO3
DME[a]
DME[a]
DME[b]
DPPF
[a]
With 3 equivs. of H2O.
KF¼13 ppm.
[b]
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A Novel Practical Synthesis of C-2-Arylpurines
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Table 2. Suzuki–Miyaura coupling of 4 with 5 under anhydrous conditions.
Entry
Pd Cat.
Ligand
Base[a]
Solvent[b]
Yield
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DPPF
DPPF
DPPF
BINAP
Na2CO3/TBAB
Et3N
Cs2CO3
DME
DME
DME
1,4-dioxane
trace
ND
ND
ND
Cs2CO3
5
Pd2(dba)3
Cs2CO3
1,4-dioxane
ND
6
7
Pd(OAc)2
Pd(OAc)2
K3PO4
K3PO4
1,4-dioxane
1,4-dioxane
15%
trace
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(t-Bu)3
DPPF
DPPF
DPPF
DPPE
K3PO4
Na2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
trace
12%
28%
31%
trace
trace
76%
93%
10
11
12
13
14
15
DPPP
D-i-PrPF[c]
D-t-BPF[d]
16
Pd(OAc)2
K3PO4
1,4-dioxane
40%
17
18
Pd(OAc)2
Pd(OAc)2
D-t-BPF[d]
D-t-BPF[d]
K2CO3
K2CO3
1,4-dioxane
2-MeTHF
95%
95%
[a]
Anhydrous inorganic base, dried organic base.
KF<50 ppm.
[b]
[c]
D-i-PrPF:
.
[d]
D-t-BPF:
.
ure to the insolubility of Na2CO3 in most of the organic PO4 increased the yields in that order (entries 9–11).
solvents and so phase-transfer agents and amine bases The bidentate phosphine, 1,2-bis(diphenylphosphino)-
were examined to promote the desired reaction. How- ethane (DPPE)[22] and 1,3-bis(diphenylphosphino)pro-
ever, addition of tetrabutylammonium bromide pane (DPPP)[23] were also inactive under anhydrous
(TBAB)[20] was not effective to enhance the rate of the conditions (entries 12 and 13). In analogy with DPPF,
coupling reaction (Table 2, entry 1). Triethylamine in- the ferrocenyl phosphine ligand substituted with a bulky
stead of Na2CO3 resulted in the addition of the diethyl- alkyl group, 1,1’-bis(diisopropylphosphino)ferrocene
amino group (entry 2). The Hünig base, pyridine and (D-i-PrPF)[24] improved the yield (entry 14). The more
Cs2CO3 (entry 3) did not give the desired product. The sterically hindered and electron-rich 1,1’-bis(di-tert-bu-
literature conditions[17d, e] did not give any product in tylphosphino)ferrocene (D-t-BPF)[25] was superior to
good yield (entries 4–8). Solvent screening revealed all others tested. Even when 0.5 mol % Pd(OAc)2 and
that 1,4-dioxane was best with 12% yield (entry 9), 0.5 mol % D-t-BPF were employed, the reaction was
and inorganic base[21] such as Na2CO3, K2CO3 and K3 completed in 93% yield within 16 h with no adduct of
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Table 3. Synthesis of various arylated aminopyrimidines.
Entry
1
Arylboronic acid
Product
Yield
88%
Entry
10
Arylboronic acid
Product
Yield
92%
3a
3j
2
3b
80%
11
3k
82%
3
4
5
3c
3d
3e
0%
12
13
14
3l
90%
92%
84%
90%
87%
6
3m
6
3f
76%
15
3n
75%
7
8
3 g
3 h
78%
86%
16
17
3o
3p
85%
85%
9
3i
72%
self-condensation at the amino group (entry 15). The high yields (entries 11 and 12). More importantly, even
bulky monodentate ferrocenyldialkylphosphine ligand more electron-deficient boronic acids were well tolerat-
di-tert-butylphosphino pentaphenylferrocene, CTC-Q- ed and gave fairly good yields (entries 13–17).
PHOS[26] gave a much decreased the yield (entry 16).
Finally, we examined synthesis of 2-phenylpurines
K3PO4 was switched to K2CO3 since K2CO3 was found possessing various substituents at the C-8 position. The
to be less sensitive over fluctuation of the particle size Suzuki–Miyaura coupling adduct, 4-amino-5-nitro-2-
(entry 17). Finally, the best yield was obtained with 2- phenylpyrimidines (3l), was readily reduced with Pd-
MeTHF[27] which was preferred due to the carcinoge- C/H2 to give corresponding 4,5-diamino-2-phenylpyri-
necity of 1,4-dioxane (entries 17 and 18). When the reac- midine (8)[28] in excellent yield. Diamine 8 was reacted
tion was run using D-t-BPF under aqueous conditions, with activated esters of carboxylic acids such as acid an-
20% of the hydrolyzed product 7 was obtained together hydrides, orthoformate, isothiocyanate, carbonyldiimi-
with 72% of the desired product 6.
dazole, xanthic acid to give a variety of 8-substituted 2-
We next examined the tolerability of various arylbor- phenylpurines as depicted in Table 4. Orthoformate
onic acids for our system under anhydrous conditions. was reacted with 8 in toluene and DMFat 908C to afford
The coupling of 4 with a wide variety of arylboronic the corresponding 2-phenylpurine (9a) in high yield (en-
acids is shown in Table 3. In our system, electron-rich ar- try 1). 8-Phenyl- (9b),[29] 8-methyl- (9c),[19e] 8-phenyl-
ylboronic acids and/or more sterically hindered arylbor- amino- (9d),[30] 8-hydroxy- (9e),[31] and 8-mercapto-
onic acids reasonably resulted in good yields (entries 1, (9f)[30] derivatives were easily prepared in good yields
2, 4–10). Exceptionally, the reaction with 2-methoxy- by the reported methods listed in Table 4 (entries 2–6).
phenylboronic acid did not occur (entry 3). This might
be due to the tight coordination of both the oxygen in
the aryl moiety and one of the nitrogens on the pyrimi- Conclusion
dine ring of the product to palladium, leading to termi-
nation of the catalytic cycle.[17d] Electronically neutral We have developed a novel and efficient synthesis of 2-
arylboronic acids were coupled with the substrate in phenylpurine derivatives from 4-amino-2-chloro-5-ni-
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A Novel Practical Synthesis of C-2-Arylpurines
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Table 4. Synthesis of C-8 substituted purines from 4,5-diamino-2-phenylpyrimidine (8).
Entry
R
Conditions
Product
Yield
1
2
3
4
5
6
H
Ph
Me
PhNH
OH
SH
(EtO)3CH, toluene/DMF, 908C
9a
9b
9c
9d
9e
9f
92%
88%
85%
62%
82%
87%
1) (PhCO)2, pyridine, rt, 2) t-BuOK, IPA, 508C
1) Ac2O, pyridine, rt, 2) t-BuOK, IPA, 508C
1) PhNCS, DMF, 2) MeI, DMF
(imidazolyl)2CO, THF, rt, 2 h
EtOCS2K, EtOH, reflux, 20 h
(0.04ꢀ0.63 mm particle size). NMR data was acquired on a
tropyrimidine (4) via the Suzuki–Miyaura reaction as
key step. In general, the Suzuki–Miyaura reaction typi-
cally runs under aqueous conditions to generate a better
reactivity than under anhydrous conditions. The reac-
tive substrate 4, which is readily hydrolyzed under aque-
ous conditions, was required for a break-through discov-
ery under anhydrous conditions to obtain a satisfactory
reactivity. Detailed studies allowed us to find specific
conditions using D-t-BPF as ligand, which produced
the desired product 6 in 95% yield even under anhy-
drous conditions without any protection of the amino
Bruker AV-500.
Representative Procedure for the Suzuki–Miyaura
Cross-Coupling Reaction
To a round-bottomed flask were added chloropyrimidine 4
(1.0 g), the boronic acid (1.5 equivs.), K3PO4 (2.0 equivs.), dry
1,4-dioxane (30 mL) or 2-MeTHF (30 mL). The mixture was
degassed by three vacuum/N2 cycles. Catalyst Pd(OAc)2
(5 mol %) and D-t-BPF (5 mol %) were added and the mixture
group at C-2. Under the optimal conditions, the cou- was degassed twice more. The mixture was heated to reflux (ꢀ
1008C) for 4 h and HPLC confirmed the completion of the re-
action. The mixture was cooled to ambient temperature then
the slurry was filtered to remove salts. The filter cake was wash-
ed with i-PrOAc. The filtrate was concentrated under vacuum
to ca. 30 mL. To the solution were added i-PrOAc and 1 N
aqueous NaOH to remove residual boronic acid. The organic
layer was separated, washed with fresh 1 N aqueous NaOH
and 20% aqueous NaCl successively, and evaporated to dry-
ness. The product was purified by column chromatography
on silica gel or crystallization using appropriate solvents (listed
under individual compound headings, vide infra).
plings with the electron-rich, sterically hindered, elec-
tronically neutral, and even in particular electron-defi-
cient arylboronic acids proceeded in high yields. Hydro-
genation of 4-amino-5-nitro-2-arylpyrimidines gave di-
amines, which were reacted with a variety of activated
esters to afford the corresponding 2-phenyl-8-substitut-
ed purines in high yields. This novel approach would al-
low for the rapid construction of 2-phenyl- and 2-phe-
nyl-8-substituted purines.
4-Amino-5-nitro-2-(4-methoxyphenyl)pyrimidine
(3a):
Crystallization from i-PrOAc/n-heptane, colorless crystals, Rf
(50% EtOAc in n-heptane)¼0.57. 1H NMR (500 MHz,
DMSO-d6): d¼9.17 (s, 1H, pyrimidine-H), 8.69 (s, 1H, NH2),
8.35 (d, J¼8.8 Hz, 2H, Ar-H), 8.29 (s, 1H, NH2), 7.09 (d, J¼
8.8 Hz, 2H, Ar-H), 3.86 (s, 3H, OCH3); 13C NMR (125 MHz,
DMSO-d6): d¼165.62, 162.95, 156.66, 156.17, 131.16, 128.58,
125.18, 114.45, 55.81; HRMS: calcd. for C11H11N4O3 (Mþ þ
H): 247.0831; found: 247.0836.
Experimental Section
Pd(OAc)2 and D-t-BPF were purchased from Johnson Mat-
they. Anhydrous inorganic bases, K3PO4, K2CO3, Na2CO3
were purchased from Wako (40ꢀ70 mm particle size). Other
reagents were purchased from either Tokyo Kasei, Wako, or
Strem. All reagents were used as received. 1H NMR confirmed
that each boronic acid contained the boroxine (anhydrous bor-
onic acid) to less than 30%. Organic solvents, purchased from
Tokyo Kasei, were dried over 4 Š molecular sieves and de-
gassed prior to use. CPME (cyclopentyl methyl ether) was pur-
chased from ZEON Corporation. All reactions were per-
formed under a dry nitrogen atmosphere in oven-dried glass-
ware.
HPLC was performed on a Hitachi D-7000 instrument, with
a YMC basic reverse-phase column. Thin-layer chromatogra-
phy was performed on EM Science silica gel 60 plates with F-
254 indicator (250 mm thickness). Visualization was accom-
plished by UV light or photomolybdic acid/ninhydrin solution.
Column chromatography was performed with EM silica gel 60
4-Amino-5-nitro-2-(3-methoxyphenyl)pyrimidine
(3b):
crystallization from i-PrOAc/n-heptane, colorless crystals.
1H NMR (500 MHz, DMSO-d6): d¼9.21 (s, 1H, pyrimidine-
H), 8.79 (bs, 1H, NH2), 8.35 (bs, 1H, NH2), 7.98 (d, J¼7.7 Hz,
1H, Ar-H), 7.92 (dd, J¼1.1, 1.2 Hz, 1H, Ar-H), 7.46 (dd, J¼
7.7, 8.1 Hz, 1H, Ar-H), 7.17 (d, J¼8.1 Hz, 1H, Ar-H), 3.84 (s,
3H, CH3); 13C NMR (125 MHz, DMSO-d6): d¼165.60,
159.84, 156.68, 156.18, 137.68, 130.14, 125.79, 121.57, 118.31,
113.94, 55.61; HRMS: calcd. for C11H11N4O3 (Mþ þH):
247.0831; found: 247.0841.
4-Amino-5-nitro-2-(4-methylphenyl)pyrimidine (3d): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals.
1H NMR (500 MHz, DMSO-d6): d¼9.19 (s, 1H, pyrimidine-
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Takahiro Itoh et al.
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H), 8.74 (s, 1H, NH2), 8.32 (s, 1H, NH2), 8.28 (d, J¼8.2 Hz, 2H,
Ar-H), 7.35 (d, J¼8.3 Hz, 2H, Ar-H), 2.39 (s, 3H, CH3);
13C NMR (125 MHz, DMSO-d6): d¼165.89, 156.69, 156.19,
142.61, 133.52, 129.67, 129.19, 125.52, 21.47; HRMS: calcd.
for C11H11N4O2 (Mþ þH): 231.0882; found: 231.0881.
(50% EtOAc in n-heptane)¼0.25. 1H NMR (500 MHz,
CDCl3): d¼9.41 (s, 1H, pyrimidine-H), 8.68 (d, J¼8.6 Hz,
1H, Ar-H), 8.13 (dd, J¼1.0, 7.2 Hz, 1H, Ar-H), 8.01 (d, J¼
8.2 Hz, 1H, Ar-H), 7.92 (d, J¼7.5 Hz, Ar-H), 7.91 (s, 1H,
NH2), 7.59–7.52 (m, 3H, Ar-H), 6.37 (s, 1H, NH2); 13C NMR
(125 MHz, CDCl3): d¼170.14, 156.41, 155.66, 134.09, 134.04,
132.11, 130.80, 130.24, 128.73, 127.26, 126.21, 125.67, 125.45,
125.04; HRMS: calcd. for C14H11N4O2 (Mþ þH): 267.0882;
found: 267.0876.
4-Amino-5-nitro-2-(3-thiophene)pyrimidine (3k): Crystalli-
zation from i-PrOAc/n-heptane, colorless crystals, Rf (50%
EtOAc in n-heptane)¼0.58. 1H NMR (500 MHz, DMSO-d6):
d¼9.16 (s, 1H, pyrimidine-H), 8.74 (s, 1H, NH2), 8.44 (dd,
J¼1.1, 3.0 Hz, 1H, thiophene-H), 8.31 (s, 1H, NH2), 7.76 (dd,
J¼1.0, 5.0 Hz, 1H, thiophene-H), 7.68 (dd, J¼3.0, 5.0 Hz,
1H, thiophene-H); 13C NMR (125 MHz, DMSO-d6): d¼
162.55, 156.40, 155.89, 140.04, 131.36, 127.47, 127.31, 124.73;
HRMS: calcd. for C8H7N4O2S (Mþ þH): 223.0290; found:
223.0266.
4-Amino-5-nitro-2-phenylpyrimidine (3l): Crystallization
from i-PrOAc/n-heptane, colorless crystals. 1H NMR
(500 MHz, DMSO-d6): d¼9.22 (s, 1H, pyrimidine-H), 8.79 (s,
1H, NH2), 8.39 (dd, J¼7.2, 8.7 Hz, 2H, Ar-H), 8.35 (s, 1H,
NH2), 7.62–7.54 (m, 3H, Ar-H); 13C NMR (125 MHz,
DMSO-d6): d¼165.86, 156.72, 156.22, 136.19, 132.40, 129.12,
129.04, 125.74; HRMS: calcd. for C10H9N4O2 (Mþ þH):
217.0725; found: 217.0744.
4-Amino-5-nitro-2-(4-fluorophenyl)pyrimidine (6): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals.
1H NMR (500 MHz, CDCl3): d¼9.31 (s, 1H, pyrimidine-H),
8.47 (d, J¼8.9 Hz, 1H, Ar-H), 8.46 (d, J¼8.9 Hz, 1H, Ar-H),
7.93 (bs, 1H, NH2), 7.18 (d, J¼8.7 Hz, 1H, Ar-H), 7.16 (d,
J¼8.7 Hz, 1H, Ar-H), 6.10 (bs, 1H, NH2); 13C NMR
(125 MHz, CDCl3): d¼164.85, 156.68, 156.26, 131.70, 131.63,
125.69, 116.18, 116.00; HRMS: calcd. for C10H8FN4O2 (Mþ þ
H): 235.0631; found: 235.0631.
4-Amino-5-nitro-2-(2-methylphenyl)pyrimidine (3e): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals, Rf
(50% EtOAc in n-heptane)¼0.66. 1H NMR (500 MHz,
CDCl3): d¼9.32 (s, 1H, pyrimidine-H), 7.85 (d, J¼8.0 Hz,
1H, Ar-H), 7.84 (bs, 1H, NH2), 7.39 (d, J¼7.5 Hz, 1H, Ar-H),
7.31 (d, J¼8.0 Hz, 1H, Ar-H), 7.29 (d, J¼7.5 Hz, 1H, Ar-H),
6.43 (bs, 1H, NH2), 2.57 (s, 3H, CH3); 13C NMR (125 MHz,
CDCl3): d¼170.99, 156.66, 155.83, 138.48, 136.72, 132.05,
131.15, 131.04, 126.38, 125.65, 21.81; HRMS: calcd. for
C11H11N4O2 (Mþ þH): 231.0882 found: 231.0877.
4-Amino-5-nitro-2-(4-phenoxyphenyl)pyrimidine
(3f):
Crystallization from i-PrOAc/n-heptane, colorless crystals, Rf
(50% EtOAc in n-heptane)¼0.61. 1H NMR (500 MHz,
DMSO-d6): d¼9.19 (s, 1H, pyrimidine-H), 8.76 (s, 1H, NH2),
8.39 (d, J¼6.9 Hz, 2H, Ar-H), 8.33 (s, 1H, NH2), 7.47 (d, J¼
7.5 Hz, 2H, Ar-H), 7.24 (d, J¼7.4 Hz, 1H, Ar-H), 7.15 (d, J¼
7.6 Hz, 2H, Ar-H), 7.11 (d, J¼6.9 Hz, 2H, Ar-H); 13C NMR
(125 MHz, DMSO-d6): d¼164.84, 160.46, 156.24, 155.77,
155.21, 130.92, 130.41, 130.21, 124.99, 124.45, 119.74, 117.45;
HRMS: calcd. for C16H13N4O3 (Mþ þH): 309.0988; found:
309.1009.
4-Amino-5-nitro-2-(4-dibenzofuran)pyrimidine (3g): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals, Rf
(50% EtOAc in n-heptane)¼0.73. 1H NMR (500 MHz,
DMSO-d6): d¼9.34 (s, 1H, pyrimidine-H), 8.88 (s, 1H, NH2),
8.41 (s, 1H, NH2), 8.39 (d, J¼7.5 Hz, 1H, Ar-H), 8.31 (d, J¼
7.7 Hz, 1H, Ar-H), 8.23 (d, J¼7.7 Hz, 1H, Ar-H), 7.78 (d, J¼
8.0 Hz, 1H, Ar-H), 7.59 (dd, J¼7.5, 8.0 Hz, 1H, Ar-H), 7.57
(d, J¼7.7 Hz, 1H, Ar-H), 7.46 (d, J¼7.5 Hz, 1H, Ar-H);
13C NMR (125 MHz, DMSO-d6): d¼165.31, 156.68, 156.09,
154.18, 129.49, 128.41, 125.75, 125.60, 124.83, 123.71, 123.34,
123.30, 122.32, 121.60, 112.19; HRMS: calcd. for C16H11N4O3
(Mþ þH): 307.0831; found: 307.0826.
4-Amino-5-nitro-2-(2,5-difluorophenyl)pyrimidine (3 m):
Crystallization from EtOAc/n-heptane, off-white solid, Rf
(50% EtOAc in n-heptane)¼0.66. 1H NMR (500 MHz,
CDCl3): d¼9.35 (s, 1H, pyrimidine-H), 7.94 (bs, 1H, NH2),
7.87–7.83 (m, 1H, Ar-H), 7.22–7.14 (m, 2H, Ar-H), 6.22 (bs,
1H, NH2); 13C NMR (125 MHz, CDCl3): d¼156.45, 155.78,
120.05, 119.97, 119.85, 119.78, 118.59, 118.50, 118.39, 118.30;
HRMS: calcd. for C10H7N4O2F2 (Mþ þH): 253.0537; found:
253.0520.
4-Amino-5-nitro-2-[(3,4-methylenedioxy)phenyl]pyrimi-
dine (3 h): Crystallization from i-PrOAc/n-heptane, colorless
crystals, Rf (50% EtOAc in n-heptane)¼0.68. 1H NMR
(500 MHz, DMSO-d6): d¼9.16 (s, 1H, pyrimidine-H), 8.70 (s,
1H, NH2), 8.30 (s, 1H, NH2), 8.03 (dd, J¼1.6, 8.3 Hz, 1H, Ar-
H), 7.81 (d, J¼1.6 Hz, 1H, Ar-H), 7.07 (d, J¼8.3 Hz, 1H, Ar-
H), 6.14 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6): d¼
165.20, 156.59, 156.13, 151.17, 148.18, 130.38, 125.29, 124.86,
108.74, 108.48, 102.27; HRMS: calcd. for C11H9N4O4 (Mþ þ
H): 261.0624; found, 261.0640.
4-Amino-5-nitro-2-(1-thianthrene)pyrimidine (3i): Crystal-
lization from i-PrOAc/n-heptane, yellow crystals, Rf (50%
EtOAc in n-heptane)¼0.70. 1H NMR (500 MHz, DMSO-d6):
d¼9.27 (s, 1H, pyrimidine-H), 8.96 (s, 1H, NH2), 8.46 (s, 1H,
NH2), 7.88 (dd, J¼7.6, 7.7 Hz, 1H, Ar-H), 7.75 (d, J¼7.8 Hz,
1H, Ar-H), 7.58 (dd, J¼7.7, 7.8 Hz, 1H, Ar-H), 7.46 (dd, J¼
7.6, 7.7 Hz, 2H, Ar-H), 7.34 (d, J¼7.6 Hz, 1H, Ar-H), 7.29
(dd, J¼7.6 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6):
d¼166.87, 156.19, 155.50, 138.38, 137.62, 135.98, 135.63,
134.41, 131.71, 130.03, 129.06, 128.93, 128.72, 128.49, 127.54,
125.62; HRMS: calcd. for C16H11N4O2S2 (Mþ þH): 355.0323;
found: 355.0303.
4-Amino-5-nitro-2-(4-acetylphenyl)pyrimidine (3n): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals, Rf
(50% EtOAc in n-heptane)¼0.77. 1H NMR (500 MHz,
CDCl3): d¼9.25 (s, 1H, pyrimidine-H), 8.89 (bs, 1H, NH2),
8.49 (d, J¼6.8 Hz, 1H, Ar-H), 8.48 (d, J¼6.8 Hz, 1H, Ar-H),
8.41 (bs, 1H, NH2), 8.12 (d, J¼6.8 Hz, 1H, Ar-H), 8.11 (d,
J¼6.8 Hz, 1H, Ar-H), 2.65 (s, 3H, CH3); 13C NMR
(125 MHz, CDCl3): d¼198.13, 164.90, 156.74, 156.27, 140.09,
139.39, 129.26, 128.86, 126.05, 27.34; HRMS: calcd. for C12H10
N4O3 (Mþ þH): 259.0831; found: 259.0829.
4-Amino-5-nitro-2-(4-trifluoromethylphenyl)pyrimidine
(3o): Crystallization from i-PrOAc/n-heptane, colorless crys-
tals, Rf (50% EtOAc in n-heptane)¼0.73. 1H NMR
(500 MHz, DMSO-d6): d¼9.25 (s, 1H, pyrimidine-H), 8.92 (s,
1H, NH2), 8.55 (d, J¼8.2 Hz, 2H, Ar-H), 8.43 (s, 1H, NH2),
7.93 (d, J¼8.5 Hz, 2H, Ar-H); 13C NMR (125 MHz, DMSO-
d6): d¼164.43, 156.75, 156.30, 139.98, 129.71, 126.21, 126.03,
4-Amino-5-nitro-2-(1-naphthalene)pyrimidine (3j): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals, Rf
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A Novel Practical Synthesis of C-2-Arylpurines
FULL PAPERS
126.00; HRMS: calcd. for C11H8N4O2F3 (Mþ þH): 285.0599;
found: 285.0600.
d¼13.53 (bs, 1H, NH), 9.22 (s, 1H, pyrimidine-H), 8.61 (bs,
1H, purine-8H), 8.46 (d, J¼8.4 Hz, 1H, Ar-H), 8.46 (d, J¼
8.0 Hz, 1H, Ar-H), 7.55–7.49 (m, 3H, Ar-H); 13C NMR
(125 MHz, DMSO-d6): d¼158.57, 157.99, 136.78, 136.28,
130.29, 128.96, 127.95, 122.36; HRMS: calcd. for C11H9N4
(Mþ þH): 197.0827; found: 197.0828.
4-Amino-5-nitro-2-(3-nitrophenyl)pyrimidine (3p): Crys-
tallization from i-PrOAc/n-heptane, colorless crystals.
1H NMR (500 MHz, DMSO-d6): d¼9.26 (s, 1H, pyrimidine-
H), 9.11 (s, 1H, Ar-H), 8.99 (s, 1H, NH2), 8.75 (d, J¼7.8 Hz,
1H, Ar-H), 8.46–8.42 (m, 2H, NH2, Ar-H), 7.86 (d, J¼
8.0 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6): d¼
163.70, 156.76, 156.38, 148.57, 137.83, 134.96, 130.89, 126.69,
126.30, 123.37; HRMS: calcd. for C10H8N5O4 (Mþ þH):
262.0576; found: 262.0555.
2,8-Diphenylpurine (9b)
4,5-Diamino-2-phenylpyrimidine hydrochloride (223 mg,
1 mmol) was treated with benzoic acid anhydride (250 mg,
1.1 mmol) in pyridine (2.2 mL) and THF (4.0 mL). The suspen-
sion was stirred for 15 h at ambient temperature, at which time
HPLC analysis showed complete disappearance of the starting
material. The solvent was evaporated under vacuum to dry-
ness. The resulting amide was converted to benzimidazole by
treatment with KO-t-Bu (337 mg, 3.0 mmol) in isopropyl alco-
hol (2.2 mL) at 508C for 15 h. The solvent was evaporated un-
der vacuum to dryness, the residue was diluted with ethyl ace-
tate and washed with H2O. The organic layer was separated and
evaporated under vacuum to dryness and crude product was
chromatographed on silica gel to afford the title compound
as a white solid; yield: 240 mg (88% diamine). 1H NMR
(500 MHz, DMSO-d6): d¼9.20 (s, 1H, pyrimidine-H), 8.48
(d, J¼8.5 Hz, 1H, Ar-H), 8.48 (d, J¼8.1 Hz, 1H, Ar-H), 8.30
(d, J¼7.9 Hz, 1H, Ar-H), 8.30 (d, J¼7.3 Hz, 1H, Ar-H),
7.64–7.59 (m, 3H, Ar-H), 7.56–7.46 (m, 3H, Ar-H);
13C NMR (125 MHz, DMSO-d6): d¼157.84, 138.50, 131.60,
130.24, 129.50, 128.98, 127.88, 127.53; HRMS: calcd. for
C17H13N4 (Mþ þH): 273.1140; found: 273.1118.
4,5-Diamino-2-phenylpyrimidine hydrochloride (8)
A solution of 4-amino-5-nitro-2-phenylpyrimidine 3 l (1.0 g) in
DME (15 mL) was charged into a 100-mL reactor with a me-
chanical stirrer, thermocouple, and N2/H2 inlet. The addition
funnel was charged with the 10% palladium-on-carbon catalyst
(100 mg, 50% wet). The batch was hydrogenated at 408C under
H2 atmosphere (0.1ꢀ0.15 MPa) for 5 h with vigorous stirring.
The reaction time is measured by looking for the disappear-
ance of the respective starting materials as judged by HPLC.
The catalyst was filtered off and then washed with DME
(20 mL). The filtrate and washings were combined, and con-
centrated under vacuum to ca. 20 mL. The DME solution
was treated with activated charcoal (Shirasagi P, 100 g) for
2 h at ambient temperature. The charcoal was filtered off and
the filter cake was washed with DME (10 mL). The filtrate
and washings were concentrated under vacuum to ca. 20 mL
and checked residual water. If the residual water level was>
0.2%, to the DME solution was added fresh DME (20 mL)
then concentrated under vacuum to ca. 10 mL and fresh
DME (10 mL) added. After reducing the water level (<
0.2%), the DME solution (ca. 20 mL) was diluted with
MeOH (2.0 mL). To the solution was added 4 N HCl
(2.6 mL, in EtOAc) dropwise over 0.5 h at ambient tempera-
ture, then agitated for 1 h at ambient temperature. The result-
ing slurry was filtered and the filter cake waswashedwith DME
(20 mL), then dried overnight at 408C under vacuum to give
4,5-diamino-2-phenyl)pyrimidine hydrochloride as a white sol-
2-Phenyl-8-methylpurine (9c)
4,5-Diamino-2-phenylpyrimidine hydrochloride (223 mg,
1.0 mmol) was treated with acetic anhydride (0.1 mL,
1.1 mmol) in pyridine (2.2 mL). The suspension was stirred
for 15 h at ambient temperature, at which time HPLC analysis
showed complete disappearance of the starting material. The
solvent was evaporated under vacuum to dryness. The resulting
amide was converted to benzimidazole by treatment with t-
BuOK (337 mg, 3.0 mmol) in isopropyl alcohol (2.2 mL) at
508C for 15 h. The solvent was evaporated under vacuum to
dryness, the residue was diluted with ethyl acetate and washed
with H2O. The organic layer was separated and evaporated un-
der vacuum to dryness and the crude product was chromato-
graphed on silica gel to afford the title compound as a white sol-
1
id; yield: 873 mg (85%). H NMR (500 MHz, DMSO-d6): d¼
8.81 (bs, 2H, NH2), 8.43 (bs, 2H, NH2), 8.20 (s, 1H, pyrimi-
dine-H), 8.19–8.18 (m, 2H, Ar-H), 7.62–7.56 (m, 4H, Ar-H);
13C NMR (125 MHz, DMSO-d6): d¼156.31, 147.77, 131.98,
131.25, 129.33, 127.83, 127.48, 120.45; HRMS: calcd. for
C10H11ClFN4 (Mþ þH): 241.0553; found: 241.0611.
1
id; yield: 178 mg (85% from diamine). H NMR (500 MHz,
DMSO-d6): d¼8.96 (s, 1H, pyrimidine-H), 8.42 (d, J¼
7.2 Hz, 2H, Ar-H), 7.51–7.43 (m, 3H, Ar-H), 2.57 (s, 3H,
Me); 13C NMR (125 MHz, DMSO-d6): d¼158.28, 156.62,
143.49, 138.97, 129.76, 128.81, 127.72, 16.07; HRMS: calcd.
for C12H11N4 (Mþ þH): 211.0984; found: 211.1008.
Preparation of 8-Substituted-2-phenylpurines from
4,5-Diamino-2-phenylpyrimidine
2-Phenylpurine (9a): To a suspension of 4,5-diamino-2-phenyl-
pyrimidine hydrochloride (223 mg, 1 mmol) in toluene/DMF
(2:1, 3.0 mL) was added ethyl orthoformate (0.25 mL,
1.5 mmol) at ambient temperature. The solution was stirred
for 13 h at 908C, at which time HPLC analysis showed com-
plete disappearance of the starting material. The resulting slur-
ry was concentrated under reduced pressure to remove the sol-
vent. The residue was diluted with EtOAc, and crystallized by
addition of n-heptane to afford the title compound as a white
8-Aminophenyl-2-phenylpurine (9d)
Benzyl isothiocyanate (230 mg, 1.7 mmol) was mixed with
4,5-diamino-2-phenylpyrimidine hydrochloride (223 mg,
1.0 mmol) in dimethylformamide (4.5 mL) containing triethyl-
amine (0.5 mL). The suspension was stirred for 2 h at ambient
temperature, by which time a reddish solution was obtained.
1
sold; yield: 873 mg (85%). H NMR (500 MHz, DMSO-d6):
Adv. Synth. Catal. 2004, 346, 1859–1867
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Takahiro Itoh et al.
FULL PAPERS
The solution was added to toluene, and the precipitate was al-
lowed to settle at 0ꢀ58C for 2 h then collected by filtration,
rinsed with toluene, and resuspended in H2O. The tan precipi-
tate which formed on cooling was collected by filtration and
dried under vacuum to afford 257 mg (80% yield) of the corre-
sponding thiourea. The thiourea was dissolved in dimethylfor-
mamide (5.0 mL) and treated with CH3I (0.5 mL, 8 mmol) for
1 h at ambient temperature, at which time HPLC analysis
showed complete disappearance of thiourea. The solvent was
evaporated under vacuum, the residue was triturated with
CHCl3 to yield the methylisothiuronium salt. The solution of
isothiuronium salt in dimethylformamide was converted to
the corresponding benzimidazole by heating for 3 h at 908C.
Conversion appeared nearly quantitative by HPLC, and recov-
ery was 177 mg (62% yield from diamine) as white solid after
References and Notes
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1
the column purification (EtOAc/n-heptane¼1:2). H NMR
(500 MHz, DMSO-d6): d¼13.54 (bs, 1H, NH), 8.97 (s, 1H, pyr-
imidine-H), 8.42–8.40 (m, 3H, Ar-H), 8.34–8.32 (m, 1H, Ar-
H), 7.53–7.45 (m, 6H, Ar-H); 13C NMR (125 MHz, DMSO-
d6): d¼171.60, 157.34, 152.73, 137.29, 135.04, 129.99, 129.67,
128.52, 128.47, 127.32, 127.22, 123.51, 13.39; HRMS: calcd.
for C17H14N5 (Mþ þH): 288.1249; found: 288.1271.
´
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A stirred mixture of 4,5-diamino-2-phenylpyrimidine hydro-
chloride (223 mg, 1.0 mmol) and (imidazolyl)2CO (243 mg,
1.5 mmol) in THF (2.2 mL) was agitated for 2 h at ambient
temperature. The solid was collected by filtration. The residual
solid was washed with THF and dried under vacuum to afford
the desired compound as hydrochloride salt; yield: 204 mg
(82%). 1H NMR (500 MHz, DMSO-d6): d¼11.91 (bs, 1H,
NH), 11.19 (bs, 1H, NH), 8.66 (s, 1H, pyrimidine-H), 8.29 (d,
J¼6.1 Hz, 1H, Ar-H), 7.49–7.43 (m, 4H, Ar-H); 13C NMR
(125 MHz, DMSO-d6): d¼156.28, 154.37, 151.70, 138.22,
132.98, 129.94, 128.84, 127.32, 121.99, 120.36; HRMS: calcd.
for C11H9N4O (Mþ þH): 223.0290; found: 213.0784.
8-Mercapto-2-phenylpurine (9f)
A stirred mixture of 4,5-diamino-2-phenylpyrimidine (223 mg,
1.0 mmol) and O-potassium O-ethyldithiocarbonate (260 mg,
1.8 mmol) in EtOH (4.5 mL) was refluxed for overnight and
then concentrated under reduced pressure. The yellow solid
residue was dissolved in water and filtered. The filtrate was
acidified with acetic acid and the resulting yellow solid was col-
lected, washed with H2O and dried under vacuum to afford the
title compound; yield: 198 mg (87%). 1H NMR (500 MHz,
DMSO-d6): d¼8.34–8.32 (m, 2H, Ar-H), 8.26 (s, 1H, pyrimi-
dine-H), 7.46–7.37 (m, 4H, Ar-H, NH); 13C NMR (125 MHz,
DMSO-d6): d¼155.27, 139.49, 133.08, 129.10, 128.58, 127.32,
126.67; HRMS: calcd. for C11H9N4S (Mþ þH): 229.0548; found:
229.0550.
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´
´
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Acknowledgements
We would like to thank Dr. Shinji Kato for sample of 4-amino-2-
chloro-5-nitropyrimidine and helpful discussion. We thank Mr.
Moriaki Ishikawa for HRMS analysis.
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A Novel Practical Synthesis of C-2-Arylpurines
FULL PAPERS
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