Facile synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines via copper-catalyzed intramolecular C-O bond formation

Article abstract of DOI:10.1016/j.tet.2012.03.080

A novel and convenient synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines was presented. The key step involved an intramolecular C-O cross-coupling of the ortho-halopyrimidine amide via a copper (I)-mediated cyclization reaction, which provided t

Full text of DOI:10.1016/j.tet.2012.03.080

Tetrahedron 68 (2012) 4248e4251
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Facile synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines via
copper-catalyzed intramolecular CeO bond formation
,
,
b,
Dan Xu a c, Li-Ping Sun a , Qi-Dong You
*
*
a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
b School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
c Research and Development Department of New Drugs, Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd., Nanjing 210038, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and convenient synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines was presented. The key
step involved an intramolecular CeO cross-coupling of the ortho-halopyrimidine amide via a copper (I)-me-
diatedcyclizationreaction,whichprovidedtargettrisubstitutedoxazolopyrimidineinmoderatetogoodyields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 November 2011
Received in revised form 12 March 2012
Accepted 20 March 2012
Available online 28 March 2012
Keywords:
2,5,7-Trisubstituted oxazolo[5,4-d]
pyrimidines
Cu-catalyzed
CeO bond formation
Intramolecular cyclization
1. Introduction
and environmentally friendly methods for the synthesis of 2,5,7-
trisubstituted oxazolopyrimidines remains necessary. In recent
The oxazole scaffold is encountered in a number of compounds
with a broad spectrum of biological properties, either natural prod-
ucts1 or synthetic small molecules.2 In recent years, oxazolopyridine
and oxazolopyrimidine derivatives have attracted increasing interest
because of their diverse biological activities, such as antiin-
flammatory,3a analgesic,3b antimicrobial,3c and anticoagulant
agents.3d Especially the 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidine
derivatives were reported to be potent receptor tyrosine kinase
inhibitors,4a HGPRTase inhibitors,4b and adenosine receptor antago-
nists.4c,4d However, only a few synthetic procedures for the prepara-
tion of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines weredescribed.
One methodology used aminohydroxypyrimidines condensed with
acid anhydrides or acyl chlorides for forming the 2-substituted oxa-
zolo[5,4-d]pyrimidine scaffolds, and it was followed by the sub-
stitution reaction at the 7-position to provide thetarget compounds.5a
Another approach elaborated the 2-substituted 4-alkoxycarbonyl-5-
aminooxazoles to construct the pyridimine rings.5b In most cases,
these procedures suffer from one or more limitations, including harsh
reaction conditions,4a,4c unsatisfactory yields of the products,4a,5a co-
occurrence of several side reactions,5a and limitation of the diversity
of the products.5b Thus, the development of more flexible, efficient,
years, copper-mediated CeO and CeN bond formations have been
reported to be widely used in many efficient protocols for the syn-
thesis of heterocycles.6 As a continuation of our work in copper-
catalyzed cross-coupling reactions for the construction of heterocy-
clic compounds,7 we report here a novel and efficient method for the
synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines.
2. Results and discussion
The starting material 4,6-dichloro-2-methylpyrimidin-5-amine
(1) could be easily obtained from acetamidine hydrochloride and
diethyl malonate by a standard method.8 Treatment of compound 1
with diverse amines furnished the mono-amination compounds 2.
Precursors 3 were readily obtained by the acylation of 2 with aro-
matic acyl chlorides (Scheme 1). Structurally diverse intermedates
2 and 3 were obtained in good yields.
Our subsequent investigation focused on the intramolecular
CeO bond formation of intermedates
3 to afford 2,5,7-
trisubstituted oxazolopyrimidines 4. Compound 3a was selected
as the model substrate for the cyclization study (Scheme 2, Table 1).
Based on our previous work,7b we found that 1,10-
phenanthroline or N,N0-dimethylethylenediamine, and K2CO3 or
Cs2CO3 used as the ligand and base, respectively, is beneficial for
copper-catalyzed CeO bond formation reaction. Our initial attempt
* Corresponding authors. Tel./fax: þ86 25 83271351; e-mail addresses: chslp@
cpu.edu.cn (L.-P. Sun), youqd@cpu.edu.cn (Q.-D. You).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.080

D. Xu et al. / Tetrahedron 68 (2012) 4248e4251
4249
Table 2
Synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines 4a
Scheme 1. Synthesis route for compounds 3. Reagents and conditions: (i) amines,
concentrated HCl, EtOH/H2O (1:8), reflux, 6 h, then rt, 2 h, 72e99%; (ii) acyl chlorides,
pyridine, DCM, rt, 2 h, 48e90%.
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
42
48
68
83
36
88
35
52
70
65
68
2,4-Cl2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-FC6H4
4-MeOC6H4
4-NO2C6H4
2,4-Cl2C6H4
Ph
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Bn
9
Scheme 2. Copper-catalyzed synthesis of 5-methyl-N,2-diphenyloxazolo[5,4-d]py-
rimidine-7-amine 4a.
10
11
12
4j
4k
4l
CH2CH2Ph
4-NO2C6H4
Ph
4-MeOC6H4
Table 1
a
Synthetic conditions of 4aa
Reaction conditions of cyclization: CuI (10 mol %), DMEDA (20 mol %), and K2CO3
(3.0 equiv) in refluxing toluene for 6 h.
Entry
Ligandb
Base
Solvent
Yieldc (%)
b
Isolated yield.
1
2
3
4
1,10-phen
1,10-phen
DMEDA
K2CO3
K2CO3
K2CO3
CS2CO3
MeCN
43
78
90
71
3. Conclusions
Toluene
Toluene
Toluene
DMEDA
In conclusion, we have developed a novel and efficient synthetic
method for 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines. The
oxozolopyrimidine ring formation could be carried out under the
catalysis of CuI/DMEDA. Further investigation in expanding the
scope of this cyclization method for the construction of other novel
heterocyclic ring systems is underway in our laboratories.
a
Reaction conditions: compound 3a (0.5 mmol), CuI (0.05 mmol, 10 mol % rela-
tive to 3a), ligand (0.1 mmol, 20 mol % relative to 3a), and base (1.5 mmol, 3.0 equiv
relative to 3a) were dissolved in the indicated solvent (5 mL) and heated at refluxing
temperature for 6 h.
b
Ligands: 1,10-phen¼1,10-phenanthroline, DMEDA¼N,N0-dimethylethylenedia-
mine.
c
Isolated yields.
4. Experiment section
4.1. General
was made to perform the reaction in the presence of CuI (10 mol %),
1,10-phenanthroline (20 mol %), and K2CO3 (3 equiv) in MeCN at
refluxing temperature. After 6 h, the desired product 4a was
obtained in low yield (Table 1, entry 1) and most of 3a remained.
Prolonging the reaction time did not contribute to the yield, while
switching the solvent to toluene and raising the reaction tempera-
ture (110 ꢀC, refluxing temperature) could give the better result
(Table 1, entry 2). Using toluene as the solvent, when DMEDA (N,N0-
dimethylethylenediamine) was employed as the ligand, the yields
increased to 90% (Table 1, entry 3). Replacing K2CO3 with Cs2CO3 as
the base decreased the yield (Table 1, entry 4). Thus, K2CO3 was the
better choice in this cyclization reaction. Increasing the amount of
base and ligand did not lead to an improvement of product yield.
Finally, it was identified that the optimal protocol was using CuI
(10 mol %), DMEDA (20 mol %), and K2CO3 (3.0 equiv) in refluxing
toluene over 6 h under a nitrogen atmosphere.
To extend the scope of our synthesis, we next prepared a number
of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines under the opti-
mizedconditions (Table 2). Itwasfound that whenR1 isanaryl group,
such as Ph (entry 1), a higher product yield (90%) was obtained as
compared to Bn (70%) and PhCH2CH2 (65%, entries 10 and 11). Among
the aryl groups for R1, the electron-donating ones furnished the
productsinbetteryields, suchasPh(42%, entry2)versus4-totyl(52%,
entry 9) with R2 being 2,4-Cl2C6H3 and 4-NO2C6H4 (68%, entry 12)
versus 4-ClC6H4 (88%, entry 7) with R2 being 4-MeOC6H4. Both steric
and electronic effects of the substituents R2 on the product yields
were also noted. For example, with R1 being 2-ClC6H4, a lower yield
was obtained for the product with R2 being 2-ClC6H4 (48%, entry 3) as
compared with 3-ClC6H4 and 4-ClC6H4 (68% and 83%, respectively,
entries 4 and 5). In particular, lower yields were recorded for the
substrates, which possess a strongly electron-withdrawing R2
groups, such as 2-FC6H4 (36%, entry 6) and 4-NO2C6H3 (35%, entry 8).
Melting points (mp) were determined with XT-4 apparatus and
are reported without correction. Infrared spectra were obtained
with Nicolet Impact 410 spectrophotometer. 1H NMR spectra were
collected on a Brucker AMX 300 MHz spectrometer using CDCl3 or
DMSO-d6 as the solvent with TMS as the internal reference. Mass
spectra (EI) were obtained on SHIMADZU GCMS-QP2010 system.
Elemental analyses were performed with Elementar Vario EL III
elemental analysis apparatus. All reactions were monitored by
HPLC using UV light for visualization. Column chromatography was
performed on silica gel (100e200 mesh) made in Qingdao Haiyang
Chemical Co. Ltd.
4.2. General procedure for the synthesis of some
intermediates
4.2.1. 6-Chloro-N4-(3-chlorophenyl)-pyrimidine-4,5-diamine
(2a). Compound
1 (800 mg, 4.48 mmol) and benzenamine
(510 mg, 5.44 mmol) were suspended in EtOH/H2O (30 mL, 1:8).
Concentrated hydrochloric acid (0.5 mL) was added at room tem-
perature followed by warming reaction to reflux. After stirring for
10 h the reaction was cooled to room temperature and stirred for
6 h. The precipitate was collected on a sintered glass funnel and
rinsed with water (10 mL) followed by hexanes (10 mL). After
drying in vacuo, Compound 2a (850 mg) was obtained. Yield: 81%;
gray solid. MS (EI) m/z (%)¼234 (Mþ).
4.2.2. N-(4-Chloro-2-methyl-6-(phenylamino)pyrimidin-5-yl)benza-
mide (3a). Benzoyl chloride (255 mg, 1.8 mmol) was added drop-
wise to a solution of compound 2a (350 mg, 1.5 mmol) and pyridine

4250
D. Xu et al. / Tetrahedron 68 (2012) 4248e4251
(0.24 mL, 3.0 mmol) in anhydrous DCM (20 mL) at 0 ꢀC. The reaction
was allowed to be stirred at room temperature for 3 h. The solid
precipitate was filtered and washed with H2O (2ꢁ20 mL). After
drying under vacuum, the remaining residue was crystallized
(CH2Cl2/hexanes, 1:3) to afford compound 3a. Yield: 83%; white
152.7, 164.3, 165.4. MS (EI) m/z (%)¼370 (Mþ). Anal. Calcd for
C18H12Cl2N4O: C, 58.24; H, 3.26; N, 15.09. Found: C, 58.28; H, 3.42;
N, 14.88.
4.3.5. N-(2-Chlorophenyl)-2-(4-chlorophenyl)-5-ethyloxazolo[5,4-d]
pyrimidin-7-amine (4e). Chromatography (CH2Cl2/hexanes, 1:1);
yield: 83%; yellow solid; mp 204e206 ꢀC (CH2Cl2/MeOH). IR (KBr):
solid. 1H NMR (300 MHz, DMSO-d6):
d¼9.87 (s, 1H, eNHe), 9.17 (s,
1H, eNHCOe), 8.07 (d, 2H, J¼7.5 Hz, AreH), 7.95 (d, 1H, J¼8.1 Hz,
AreH), 7.50e7.66 (m, 4H, AreH), 7.34 (t, 2H, J¼7.5 Hz, AreH), 7.08
(t, 1H, J¼7.5 Hz, AreH), 2.44 (s, 3H, eCH3). MS (EI) m/z (%)¼338
(Mþ).
3454, 3387, 2921, 2850, 1627, 1515, 840, 743 cmꢂ1 1H NMR
.
(300 MHz, CDCl3):
d
¼8.23 (d, 1H, J¼8.4 Hz, AreH), 8.14 (d, 1H,
J¼8.4 Hz, AreH), 7.45e7.57 (m, 4H, AreH), 7.37 (t, 1H, J¼7.8 Hz,
AreH), 7.10 (t, 1H, J¼7.5 Hz, AreH), 2.75 (s, 3H, eCH3). 13C NMR
4.3. General procedure for the synthesis of 4ael
(75 MHz, CDCl3):
d
¼26.3, 121.5, 123.9, 124.8, 127.6, 128.7, 129.3,
129.4, 129.5, 129.7, 135.0, 138.2, 139.7, 151.5, 164.4. MS (EI) m/z (%)¼
370 (Mþ). Anal. Calcd for C18H12Cl2N4O: C, 58.24; H, 3.26; N, 15.09.
Found: C, 58.12; H, 3.61; N, 14.89.
Cuprous iodide (0.1 mmol) was added to a suspension of ap-
propriate compounds 3ael (1.0 mmol), DMEDA (0.2 mmol), and
Potassium carbonate (3.0 mmol) in toluene (8 mL) under a nitrogen
atmosphere. The reaction was refluxed at 110 ꢀC for 6 h and then
allowed to cool to room temperature. The mixture was filtered, and
the filtrate was removed reduced pressure. The product 4ael was
purified through a short silica gel column.
4.3.6. N-(4-Chlorophenyl)-2-(2-fluorophenyl)-5-ethyloxazolo[5,4-d]
pyrimidin-7-amine (4f). Chromatography (CH2Cl2/hexanes, 1:1);
yield: 36%; colorless solid; mp 97e98 ꢀC (CH2Cl2/MeOH). IR (KBr):
3454, 2922, 2851, 1639, 823, 769 cmꢂ1. 1H NMR (300 MHz, DMSO-
d6):
d
¼10.24 (s, 1H, eNHe), 8.14 (d, 1H, J¼8.4 Hz, AreH), 7.88e7.93
4.3.1. 5-Methyl-N,2-diphenyloxazolo[5,4-d]pyrimidin-7-amine
(4a). Chromatography (CH2Cl2/hexanes, 1:2); yield: 90%; colorless
solid; mp 154e156 ꢀC (CH2Cl2/MeOH). IR (KBr): 3452, 3392, 2923,
(m, 3H, AreH), 7.70 (dd, 1H, J¼8.4, 1.8 Hz, AreH), 7.36 (t, 2H,
J¼7.8 Hz, AreH), 7.10 (t, 1H, J¼7.8 Hz, AreH), 2.57 (s, 3H, eCH3). 13
C
NMR (75 MHz, DMSO-d6):
d¼26.3, 115.2, 117.6, 117.8, 122.9, 125.6,
2852, 1629, 707, 692 cmꢂ1. 1H NMR (300 MHz, DMSO-d6):
d
¼10.21
125.7, 127.2, 128.7, 130.6, 134.4, 134.5, 138.7, 152.2, 158.5, 161.9, 163.9,
165.2. MS (EI) m/z (%)¼354 (Mþ). Anal. Calcd for C18H12ClFN4O: C,
60.94; H, 3.41; N, 15.79. Found: C, 60.57; H, 3.73; N, 15.71.
(s, 1H, eNHe), 8.17 (d, 2H, J¼7.5 Hz, AreH), 7.93 (d, 2H, J¼7.8 Hz,
AreH), 7.63e7.65 (m, 3H, AreH), 7.37 (t, 2H, J¼7.5 Hz, AreH), 7.09 (t,
1H, J¼7.8 Hz, AreH), 2.57 (s, 3H, eCH3). 13C NMR (75 MHz, DMSO-
d6):
d
¼26.4, 115.4, 121.4, 123.5, 126.6, 127.4, 128.9, 129.9, 132.3,
4.3.7. N-(4-Chlorophenyl)-2-(4-methoxyphenyl)-5-methyloxazolo
[5,4-d]pyrimidin-7-amine (4g). Chromatography (CH2Cl2/hexanes,
1:2); yield: 88%; colorless solid; mp 188e191 ꢀC (CH2Cl2/MeOH). IR
(KBr): 3454, 2922, 2851, 1631, 827 cmꢂ1. 1H NMR (300 MHz, DMSO-
139.7, 152.4, 158.6, 163.6, 165.3. MS (EI) m/z (%)¼302 (Mþ). Anal.
Calcd for C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found: C, 71.25; H,
4.86; N, 18.86.
d6):
d
¼10.28 (s, 1H eNHe), 8.11 (d, 2H, J¼8.7 Hz, AreH), 7.98 (d, 2H,
4.3.2. 2-(2,4-Dichlorophenyl)-5-methyl-N-phenyloxazolo[5,4-d]pyr-
imidin-7-amine (4b). Chromatography (CH2Cl2/hexanes, 1:1);
yield: 42%; yellow solid; mp 166e167 ꢀC (CH2Cl2/MeOH). IR (KBr):
3454, 2922, 2851, 1631, 805, 744 cmꢂ1. 1H NMR (300 MHz, CDCl3):
J¼8.7 Hz, AreH), 7.41 (d, 2H, J¼8.7 Hz, AreH), 7.19 (d, 2H, J¼8.7 Hz,
AreH), 3.88 (s, 3H, eOCH3), 2.57 (s, 3H, eCH3). 13C NMR (75 MHz,
DMSO-d6):
d
¼26.3, 56.0, 114.2, 115.4, 118.9, 122.6, 126.9, 128.8,
129.3, 138.9, 151.8, 159.2, 162.6, 163.0, 165.2. MS (EI) m/z (%)¼366
(Mþ). Anal. Calcd for C19H15ClN4O2: C, 62.21; H, 4.12; N, 15.27.
Found: C, 62.51; H, 3.90; N, 15.02.
d
¼8.08 (d,1H, J¼8.4 Hz, AreH), 7.82 (d, 2H, J¼7.5 Hz, AreH), 7.70 (br
s, 1H, eNHe), 7.60 (s, 1H, AreH), 7.38e7.44 (m, 3H, AreH), 7.16 (t,
1H, J¼7.5 Hz, AreH), 2.73 (s, 3H, eCH3). 13C NMR (75 MHz, DMSO-
d6):
d¼26.3, 114.9, 121.7, 123.8, 124.7, 128.6, 128.9, 131.3, 133.4,133.5,
4.3.8. 5-Methyl-2-(4-nitrophenyl)-N-p-tolyloxazolo[5,4-d]pyr-
imidin-7-amine (4h). Chromatography (CH2Cl2); yield: 35%; yellow
solid; mp 151e152 ꢀC (CH2Cl2/MeOH). IR (KBr): 3454, 2923, 2852,
137.3, 139.5, 152.6, 155.3, 164.3, 165.3. MS (EI) m/z (%)¼370 (Mþ).
Anal. Calcd for C18H12Cl2N4O: C, 58.24; H, 3.26; N, 15.09. Found: C,
57.97; H, 3.65; N, 15.19.
1630, 1515, 814, 706 cmꢂ1. 1H NMR (300 MHz, DMSO-d6):
d¼10.13
(s, 1H, eNHe), 8.13 (d, 2H, J¼8.4 Hz, AreH), 7.78 (d, 2H, J¼8.4 Hz,
AreH), 7.69 (d, 2H, J¼8.4 Hz, AreH), 7.16 (d, 2H, J¼8.4 Hz, AreH),
2.54 (s, 3H, eCH3), 2.30 (s, 3H, AreCH3). 13C NMR (75 MHz, DMSO-
4.3.3. N,2-Bis(2-chlorophenyl)-5-methyloxazolo[5,4-d]pyrimidin-7-
amine (4c). Chromatography (CH2Cl2/hexanes, 1:2); yield: 48%;
yellow solid; mp 135e136 ꢀC (CH2Cl2/MeOH). IR (KBr): 3453, 2922,
d6):
d
¼20.9, 26.4, 115.2, 121.5, 122.5, 125.5, 128.7, 129.0, 129.3, 130.0,
2852, 1629, 1512, 773, 739 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼8.05
132.6, 136.9, 137.1, 150.1, 152.4, 157.5, 163.8, 165.2. MS (EI) m/z (%)¼
361 (Mþ). Anal. Calcd for C19H15N5O3: C, 63.15; H, 4.18; N, 19.38.
Found: C, 63.20; H, 4.39; N, 19.05.
(d, 1H, J¼7.5 Hz, AreH), 7.82 (d, 2H, J¼7.8 Hz, AreH), 7.39e7.64 (m,
5H, AreH, eNHe), 7.16 (t, 1H, J¼7.5, AreH), 2.73 (s, 3H, eCH3). 13
C
NMR (75 MHz, DMSO-d6):
d
¼26.2, 114.7, 117.6, 117.8, 125.7, 127.8,
127.9, 128.9, 130.1, 130.5, 134.4, 134.5, 135.8, 153.4, 158.5, 161.9,
164.1, 165.5. MS (EI) m/z (%)¼370 (Mþ). Anal. Calcd for
C18H12Cl2N4O: C, 58.24; H, 3.26; N, 15.09. Found: C, 58.42; H, 3.05;
N, 15.22.
4.3.9. 2-(2,4-Dichlorophenyl)-5-methyl-N-p-tolyloxazolo[5,4-d]pyr-
imidin-7-amine (4i). Chromatography (CH2Cl2/hexanes, 2:1); yield:
52%; yellow solid; mp 180e181 ꢀC (CH2Cl2/MeOH). IR (KBr): 3406,
3066, 2920, 1632, 1517, 808 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼10.15 (s, 1H, eNHe), 8.13 (d, 1H, J¼8.4 Hz, AreH), 7.92 (s, 1H,
4.3.4. N-(2-Chlorophenyl)-2-(3-chlorophenyl)-5-ethyloxazolo[5,4-d]
pyrimidin-7-amine (4d). Chromatography (CH2Cl2/hexanes, 1:2);
yield: 68%; yellow solid; mp 146e148 ꢀC (CH2Cl2/MeOH). IR (KBr):
AreH), 7.68e7.76 (m, 3H, AreH), 7.16 (d, 2H, J¼8.4 Hz, AreH), 2.55
(s, 3H, eCH3), 2.30 (s, 3H, AreCH3). 13C NMR (75 MHz, DMSO-d6):
d
¼20.9, 26.4, 114.8, 121.9, 122.1, 124.7, 128.6, 129.3, 131.3, 131.7,
3452, 3383, 2922, 2851, 1628, 1514, 747, 721 cmꢂ1
.
1H NMR
132.9,133.3,133.4,136.9,137.2,152.7,155.5,164.3,165.3. MS (EI) m/z
(%)¼384 (Mþ). Anal. Calcd for C19H14Cl2N4O: C, 59.24; H, 3.66; N,
14.54. Found: C, 58.90; H, 3.68; N, 14.43.
(300 MHz, CDCl3):
d
¼8.77 (d, 1H, J¼7.8 Hz, AreH), 8.22 (s, 1H,
AreH), 8.09 (d, 1H, J¼7.5 Hz, AreH), 8.02 (br s, 1H, eNHe),
7.45e7.54 (m, 3H, AreH), 7.37 (t, 1H, J¼7.5, AreH), 7.08 (t, 1H, J¼7.5,
AreH), 2.75 (s, 3H, eCH3). 13C NMR (75 MHz, DMSO-d6):
d
¼26.4,
4.3.10. N-Benzyl-5-methyl-2-phenyloxazolo[5,4-d]pyrimidin-7-
amine (4j). Chromatography (EtOAc/hexanes, 1:8); yield: 70%;
114.9,121.7,123.8, 124.7,128.6, 128.9, 131.2,133.4,133.5,137.3,139.5,

D. Xu et al. / Tetrahedron 68 (2012) 4248e4251
4251
colorless solid; mp 136e138 ꢀC (CH2Cl2/MeOH). IR (KBr): 3451,
Major Science and Technology Project of China (Innovation and De-
velopmentofNewDrugs;NO. 2008ZX09401-001and2009ZX09501-
003) for the financial supports.
3028, 2922, 2852, 1629, 735, 704 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼8.13 (d, 2H, J¼7.5 Hz, AreH), 7.49e7.51 (m, 3H, AreH), 7.26e7.42
(m, 5H, AreH), 5.93 (br s, 1H, eNHe), 4.92 (br s, 2H, eCH2e), 2.64
(s, 3H, eCH3). 13C NMR (75 MHz, CDCl3):
d¼26.1, 29.7, 126.7, 127.1,
Supplementary data
127.7, 127.9, 128.8, 128.9, 131.5, 138.3, 154.5, 158.8. MS (EI) m/z (%)¼
316 (Mþ). Anal. Calcd for C19H16N4O: C, 72.13; H, 5.10; N, 17.71.
Found: C, 72.45; H, 4.89; N, 17.98.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.080.
4.3.11. 5-Methyl-N-phenethyl-2-phenyloxazolo[5,4-d]pyrimidin-7-
amine (4k). Chromatography (EtOAc/hexanes, 1:8); yield: 65%;
colorless solid; mp 148e150 ꢀC (CH2Cl2/MeOH). IR (KBr): 3441,
3238, 3083, 1633, 1410, 748, 703 cmꢂ1. 1H NMR (300 MHz, CDCl3):
References and notes
1. (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995; (b) Jin, Z. Nat. Prod. Rep. 2009, 26,
382.
2. (a) Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.;
Murakami, K.; Todo, M. Bioorg. Med. Chem. 2008, 16, 981; (b) Welsch, M. E.;
Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347; (c) Rzuczek, S.
G.; Pilch, D. S.; Liu, A.; Liu, L.; LaVoie, E. J.; Rice, J. E. J. Med. Chem. 2010, 53, 3632;
(d) Kimball, F. S.; Romero, F. A.; Ezzili, C.; Garfunkle, J.; Rayl, T. J.; Hochstatter, D.
G.; Hwang, I.; Boger, D. L. J. Med. Chem. 2008, 51, 937; (e) Epple, R.; Cow, C.; Xie,
Y.; Azimioara, M.; Russo, R.; Wang, X.; Wityak, J.; Karanewsky, D. S.; Tuntland, T.;
Nguyen-Tran, V. T.; Cuc Ngo, C.; Huang, D.; Saez, E.; Spalding, T.; Gerken, A.;
Iskandar, M.; Seidel, H. M.; Tian, S. S. J. Med. Chem. 2010, 53, 77.
d
¼8.15 (d, 2H, J¼3.9 Hz, AreH), 7.50e7.52 (m, 3H, AreH), 7.27e7.37
(m, 5H, AreH), 5.73 (br s,1H, eNHe), 4.02 (br s, 2H, eCH2e), 3.02 (t,
2H, J¼7.2 Hz, eCH2e), 2.62 (s, 3H, eCH3). 13C NMR (75 MHz, CDCl3):
d
¼26.0, 36.2, 126.6, 126.7, 127.1, 128.7, 128.9, 129.0, 131.5, 138.7,
154.7, 158.7. MS (EI) m/z (%)¼330 (Mþ). Anal. Calcd for C20H17FN4O:
C, 72.71; H, 5.49; N, 16.96. Found: C, 72.81; H, 5.77; N, 16.72.
3. (a) Yildiz-Oren, I.; Yalcin, I.; Aki-Sener, E.; Ucarturk, N. Eur. J. Med. Chem. 2004,
39, 291; (b) Boger, D. L.; Miyauchi, H.; Du, W.; Hardouin, C.; Fecik, R. A.; Cheng,
H.; Hwang, I.; Hedrick, M. P.; Leung, D.; Acevedo, O.; Guimaraes, C. R.; Jorgensen,
W. L.; Cravatt, B. F. J. Med. Chem. 2005, 48, 1849; (c) Miller, D. J.; Ravikumar, K.;
Shen, H.; Suh, J. K.; Kerwin, S. M.; Robertus, J. D. J. Med. Chem. 2002, 45, 90; (d)
Deng, J. Z.; McMasters, D. R.; Rabbat, P. M.; Williams, P. D.; Coburn, C. A.; Yan, Y.;
Kuo, L. C.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Strulovici, B.; Vacca, J. P.; Lyle, T.
A.; Burgey, C. S. Bioorg. Med. Chem. Lett. 2005, 15, 4411.
4.3.12. 2-(4-Methoxyphenyl)-5-methyl-N-(4-nitrophenyl)oxazolo
[5,4-d]pyrimidin-7-amine (4l). Chromatography (EtOAc/hexanes,
1:6); yield: 68%; yellow solid; mp 212e214 ꢀC (CH2Cl2/MeOH). IR
(KBr): 3411, 2923, 2852, 1611, 1503, 1336, 847, 804, 749 cmꢂ1 1H
.
NMR (300 MHz, CDCl3):
d
¼8.11 (d, 2H, J¼8.4 Hz, AreH), 7.68 (d, 2H,
J¼8.1 Hz, AreH), 7.20 (d, 2H, J¼8.4 Hz, AreH), 7.03 (d, 2H, J¼8.7 Hz,
ꢀ
4. (a) Martin-Kohler, A.; Widmer, J.; Bold, G.; Meyer, T.; Sequin, U.; Traxler, P. Helv.
AreH), 3.89 (s, 3H, eOCH3), 2.70 (s, 3H, eCH3). 13C NMR (75 MHz,
Chim. Acta 2004, 87, 956; (b) Jadhav, A. L.; Townsend, L. B.; Nelson, J. A. Biochem.
Pharmacol. 1979, 28, 1057; (c) Bauser, M.; Delapierre, G.; Hauswald, M.; Flessner,
T.; D’Urso, D.; Hermann, A.; Beyreuther, B.; De Vry, J.; Spreyer, P.; Reissmuller, E.;
Meier, H. Bioorg. Med. Chem. Lett. 2004, 14, 1997; (d) Holschbach, M. H.; Bier, D.;
Stusgen, S.; Wutz, W.; Sihver, W.; Coenen, H. H.; Olsson, R. A. Eur. J. Med. Chem.
2006, 41, 7.
DMSO-d6):
d
¼26.3, 55.9, 115.1, 115.2, 115.4, 118.9, 121.3, 123.3, 128.9,
129.2, 139.9, 152.0, 157.2, 158.2, 158.7, 162.5, 162.9, 165.1. MS (EI) m/z
(%)¼377 (Mþ). Anal. Calcd for C25H18ClN5O2: C, 60.47; H, 4.01; N,
18.56. Found: C, 60.33; H, 3.80; N, 18.58.
5. (a) Sekiya, M.; Suzuki, J.; Kakiya, Y. Chem. Pharm. Bull. 1970, 18, 1233; (b) Turchi,
I. J.; Maryanoff, C. A. Synthesis 1983, 10, 837.
6. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (b) Kunz, K.;
Scholzb, U.; Ganzer, D. Synlett 2003, 2428.
Acknowledgements
7. (a) Xu, D.; Xu, X.; Liu, Z.; Sun, L.-P.; You, Q.-D. Synlett 2009, 1172; (b) Zhong, Q.-F.;
Sun, L.-P. Tetrahedron 2010, 66, 5107.
8. (a) Czeskis, B. A. J. Labelled Compd. Radiopharm. 2004, 47, 699; (b) Baindur, B.;
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Acknowledgements are made to National Natural Science Foun-
dation of China (NO. 20872181) and Innovation Program for the
Postgraduates in Jiangsu Province (NO. 02705116), and National