Hypervalent iodine(III) promoted direct synthesis of imidazo[1,2-a] pyrimidines

Article abstract of DOI:10.1002/ejoc.201402456

An efficient and mild synthesis of imidazo[1,2-a]pyrimidine derivatives has been developed from readily available pyrimidyl arylamines or enamines through a hypervalent iodine-promoted intramolecular C-H bond cycloamination reaction. This protocol allows for the facile construction of biologically active bicyclic imidazo[1,2-a]pyrimidine skeletons as well as other imidazo[1,2-a]-type fused heterocycles.

Full text of DOI:10.1002/ejoc.201402456

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DOI: 10.1002/ejoc.201402456
Hypervalent Iodine(III) Promoted Direct Synthesis of
Imidazo[1,2-a]pyrimidines
Guangyin Qian,[a] Bingxin Liu,[a] Qitao Tan,*[a] Siwen Zhang,[a] and Bin Xu*[a,b,c]
Keywords: Synthetic methods / Nitrogen heterocycles / C–H functionalization / Amination / Iodine
An efficient and mild synthesis of imidazo[1,2-a]pyrimidine
derivatives has been developed from readily available pyrim-
idyl arylamines or enamines through a hypervalent iodine-
promoted intramolecular C–H bond cycloamination reaction.
This protocol allows for the facile construction of biologically
active bicyclic imidazo[1,2-a]pyrimidine skeletons as well as
other imidazo[1,2-a]-type fused heterocycles.
(Figure 1).[6] Furthermore, they also served as precursors
for 2-amino-imidazoles in organic synthesis.[7] Conse-
Introduction
Transition-metal-catalyzed C–H bond functionalization quently, several synthetic methods have been developed for
and subsequent direct C–N bond formation have attracted the synthesis of this class of molecules. Conventional meth-
increasing scientific interest in recent years[1] and found nu- ods involved the intermolecular cyclization of 2-aminopyr-
merous applications in organic synthesis, chemical biology imidine derivatives with other precursors such as alkynes[8]
and materials science. Nevertheless, apart from high cost and 2-halo carbonyl compounds or their equivalents,[6h,9]
and harsh conditions, the contamination of heavy metals and condensation reaction of 2-amino-imidazole derivatives
has limited their potential application in the pharmaceuti- with enones.[6c] Multicomponent reactions of 2-aminopyr-
cal industry, despite their apparent virtue of efficiency and imidines with aldehydes and isocyanides also provide ef-
atom-economy. In this context, the development of new ficient access to this valuable scaffold.[10] Despite significant
metal-free C–N bond formation reactions from non- achievements in their synthesis, development of highly ef-
prefunctionalized precursors, inspired by the gratifying ficient approaches to diversified imidazo[1,2-a]pyrimidine
achievements obtained thus far,[2] is desirable.
derivatives from readily available starting materials contin-
Hypervalent iodine reagents, owing to their mild reaction ues to be an active and rewarding research area. Recently,
conditions and environmentally friendly behavior, have Zhu and co-workers reported an elegant synthesis of imid-
been developed as highly valuable reagents in synthetic azo[1,2-a]pyridines from readily accessible N-aryl-2-amino-
chemistry and as key replacements of toxic heavy metals in pyridines by catalysis of an in situ generated hypervalent
many cases,[3] especially for those applications with metal iodine reagent by using 1,1,1,3,3,3-hexafluoro-2-propanol
contamination problems. Recently, significant achievements (HFIP) as the indispensable solvent.[11] As a part of our
have been made in hypervalent iodine(III) promoted C–H continuing interests in the chemistry and biologically ac-
bond amination reactions in both intermolecular and intra- tivity of pyrimidine-containing compounds,[12] we herein
molecular manner,[4] the latter of which has provided ef-
ficient access to various nitrogen-containing heterocycles.[5]
Imidazo[1,2-a]pyrimidines are prevalent structural motifs
in pharmaceutically and biologically active compounds
[a] Department of Chemistry, Innovative Drug Research Center,
Shanghai University,
Shanghai 200444, P. R. China
E-mail: xubin@shu.edu.cn
http://www.chem.shu.edu.cn
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
[c] Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal
University,
Shanghai 200062, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402456.
Figure 1. Bioactive compounds with imidazo[1,2-a]pyrimidine scaf-
folds.
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G. Qian, B. Liu, Q. Tan, S. Zhang, B. Xu
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describe an efficient hypervalent iodine promoted intra- (Table 1, Entry 7). However, in contrast to PIDA, use of
molecular C–H bond cycloamination reaction to give imid- PIFA in a mixture of CH3CN and AcOH with or without
azo[1,2-a]pyrimidine derivatives in good yields from readily copper triflate led to decreased yields (Table 1, Entries 8–
available N-aryl-2-aminopyrimidines or pyrimidyl en- 9). In comparison, the hypervalent iodine(III) formed in
amines. Furthermore, this protocol could be successfully situ from catalytic iodobenzene and stoichiometric m-chlo-
applied to the corresponding pyridyl and pyrazyl counter- roperbenzoic acid (m-CPBA), a strategy applied by Anton-
parts (Scheme 1).
chick for the efficient intramolecular C(sp2)–H bond amin-
ation reaction,[14] afforded either no desired product in
CH3CN (Table 1, Entry 10) or a very low yield with HFIP
as solvent (Table 1, Entry 11).[11]
With optimized reaction conditions in hand, the scope
and generality of the reaction were explored by using a
series of N-phenylpyrimidin-2-amines. Most of the reac-
tions were completed in 20 min to afford the desired prod-
ucts in moderate to good yields. As illustrated in Table 2,
reactions of N-phenylpyrimidin-2-amines that bear various
substitutions at the aniline moiety, regardless of their elec-
tronic properties, all gave imidazo[1,2-a] pyrimidines in
good yields (2b–2k). It should be noted that a substrate
with an iodo group was also compatible with the reaction
conditions, affording 2e in 64% yield. Substrates with ortho
substitutions, which were often problematic owing to their
steric hindrance, afforded desired products 2j and 2k in
53% and 78% yields, respectively. Pyrimidyl arylamines
with substitutions on the pyrimidine moiety reacted
smoothly to afford corresponding products 2l and 2m. To
our delight, the current protocol could be further extended
to the synthesis of imidazo[1,2-a]pyridines 2n and 2o, and
imidazo[1,2-a]pyrazine 2p, which would significantly ex-
pand the scope of its synthetic utility.
Scheme 1. Hypervalent iodine induced direct synthesis of imid-
azo[1,2-a] heterocycles.
Results and Discussion
We began our study by examining the reaction of N-
phenylpyrimidine-2-amine (1a) by using phenyliodine di-
acetate (PIDA) as oxidant at ambient temperature
(Table 1). Solvents were found to be vital for this reaction.
Among the solvents screened, acetonitrile afforded desired
product 2a in 72% yield after 4 h (Table 1, Entries 1–3). Ad-
dition of acetic acid as a co-solvent (CH3CN/AcOH = 1:1,
v/v; Table 1, Entry 4) or the use of copper triflate (10 mol-
%) as an additive[13] (Table 1, Entry 5) only slightly im-
proved the yields, whereas an increased yield could be
achieved in the presence of both AcOH and copper triflate
(Table 1, Entry 6). Gratifyingly, replacement of PIDA with
phenyliodine bis(trifluoroacetate) (PIFA) significantly im-
proved the yield to 88% in a much shorter reaction time
However, when (E)-ethyl 3-(pyrimidin-2-ylamino)-
acrylate (3a) was used under the optimized conditions, only
Table 2. Cyclization of N-aryl-2-aminopyrimidines.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
Oxidant
[equiv.]
Solvent
Additive
Time
[h]
Yield
[%][b]
1
2
3
4
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
DMF
–
–
–
–
4
4
4
4
n.r.
n.r.
72
DMSO
CH3CN
CH3CN/
AcOH
76
5
6
PIDA (1.5)
PIDA (1.5)
CH3CN
CH3CN/
AcOH
Cu(OTf)2
Cu(OTf)2
4
4
74
83
7
8
PIFA (1.5)
PIFA (1.5)
CH3CN
CH3CN/
AcOH
–
–
0.3
0.5
88
80
9
PIFA (1.5)
CH3CN/
AcOH
Cu(OTf)2
4
79
10
11
PhI (0.1)/
m-CPBA (1.2)
PhI (0.1)/
CH3CN
–
–
24
24
n.r.
26
HFIP
m-CPBA (1.2)
[a] Reaction conditions: 1a–1p (0.3 mmol), PIFA (1.5 equiv.),
CH3CN (1.5 mL), 20 min, in air at room temperature. [b] Isolated
[a] Reaction conditions: 1a (0.3 mmol), oxidant (1.5 equiv.), addi-
tive (10 mol-%) in solvent (1.5 mL), under air at room temperature. yield. [c] On a one-gram scale. [d] Reacted for 25 min. [e] Reacted
Cu(OTf)2 = Copper triflate; n.r.: no reaction. [b] Isolated yield. for 1 h.
2
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Iodine(III)-Promoted Synthesis of Imidazo[1,2-a]pyrimidines
20% yield of desired product 4a was afforded. To address the aniline ring of A that leads to intermediate D,[11] with
this limitation and further explore the generality and scope release of PhI and CF3COO– simultaneously, cannot be
of this approach, an extensive screening of oxidant, additive ruled out at this stage (Scheme 2, Path B).
and solvent was then carried out. When PIDA was used
instead of PIFA, the yield could be improved to 44%. Fur-
ther screening of the solvents revealed that ethanol was the
solvent of choice for this transformation, which afforded
product 4a in 85% yield (Table 3). After establishment of
the appropriate conditions, a wide variety of pyrimidyl en-
amines 3a–3i[15] were examined in this oxidative cyclization
reaction, which leads to pharmaceutically interesting pyr-
imido[1,2-a]imidazoles 4a–4i successfully. Pyrimidine-based
β-enamino esters could give targeted pyrimido[1,2-a]imid-
azoles 4b and 4c in fair yields. Similarly, pyrimidine or pyr-
idine derived β-enamino ketones afforded disubstituted
compounds 4d–4j in good yields, which are of potential
pharmaceutical interests and otherwise not easily accessible
by reported methods.[6h] In addition, cyclic enamino ketone,
5-methyl-2-(pyridin-2-ylamino)cyclopent-2-enone (3k), re-
acted smoothly to give tricyclic product 4k in 52% yield.
Table 3. Cyclization of pyrimidinyl enamines.[a,b]
Scheme 2. Plausible mechanism for synthesis of 2a from 1a.
Conclusions
In summary, we have developed a metal-free direct syn-
thesis of imidazo[1,2-a]pyrimidine derivatives with high effi-
ciency under mild reaction conditions from readily available
starting materials. This reaction benefits from being envi-
ronmentally benign, has good functional group tolerance
and operational simplicity, which should make the current
method of broad utility in the synthesis of diversified imid-
azo[1,2-a]-type fused heterocycles. Further exploration of
this reaction and biological evaluation of the synthesized
compounds are currently under investigation in our labora-
tory.
Experimental Section
General Methods: All reagents and metal catalysts were obtained
from commercial sources without further purification, and com-
mercially available solvents were purified before use. All new com-
pounds were fully characterized. All melting points were taken on a
WRS-1A or a WRS-1B Digital Melting Point Apparatus. Infrared
spectra were obtained with an AVATAR 370 FT-IR spectrometer.
[a] Reaction conditions: 3a–3p (0.3 mmol), PIDA (1.5 equiv.),
EtOH (1.5 mL), in air at room temperature. [b] Isolated yield.
Although the reaction mechanism remains to be clari-
fied, a plausible mechanism for this reaction was proposed 1H and 13C NMR spectra were recorded with a Bruker AV-500
in Scheme 2.[11,14,16] Nucleophilic substitution of the aniline
spectrometer operating at 500 and 125 MHz, respectively, with
chemical shift values being reported relative to chloroform (δ =
nitrogen on the iodine(III) center of PIFA forms intermedi-
7.26 ppm), dimethyl sulfoxide (δ = 2.50 ppm), acetone (δ =
ate A, which is then transformed into nitrenium ion B
2.05 ppm) or trimethylsilane (δ = 0.00 ppm) for 1H NMR, and
through an oxidative process[14] and intermediate B is in
chloroform (δ = 77.16 ppm), dimethyl sulfoxide (δ = 39.52 ppm) or
resonance with carbocation form C. Subsequent nucleo-
acetone (δ = 206.26, 29.84 ppm) for 13C NMR spectroscopy. Mass
philic attack of the pyrimidine nitrogen on the carbon cat-
ion center of intermediate C leads to cyclic intermediate D,
which will generate desired product 2a after a deprotonic
rearomatization process (Scheme 2, Path A). Currently, di-
spectra and high-resolution mass spectra were recorded with an
Agilent 5975N by using an Electron impact (EI) or Electrospray
ionization (ESI) techniques. Elemental analyses were carried out
with an Elementar Vario EL elemental analyzer. Silica gel plate
rect nucleophilic attack of the pyrimidyl nitrogen atom on GF254 were used for thin layer chromatography (TLC) and silica
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G. Qian, B. Liu, Q. Tan, S. Zhang, B. Xu
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gel H or 300–400 mesh were used for flash column chromatog-
raphy, yields refer to chromatographically and spectroscopically
pure compounds, unless otherwise indicated.
1606, 1501, 1453, 1380 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
8.90–8.88 (m, 2 H), 8.67 (d, J = 1.0 Hz, 1 H), 8.27 (dd, J = 8.5,
1.5 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 1 H), 7.03 (dd, J = 6.5, 4.5 Hz,
1 H), 4.44 (q, J = 7.0 Hz, 2 H), 1.44 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 166.5, 156.9, 152.4, 147.5, 133.9,
127.7, 126.7, 124.3, 120.2, 113.4, 107.6, 61.4, 14.5 ppm. MS (EI):
m/z (%) = 241 (75) [M+], 196 (100). HRMS (EI): m/z calcd. for
C13H11N3O2 [M+] 241.0851; found 241.0855.
General Procedure for the Synthesis of Imidazo[1,2-a]-Type Hetero-
cycles 2a–2p, 4a–4k: To an oven-dried flask containing substrates
(0.3 mmol, 1.0 equiv.) and oxidant (0.45 mmol, 1.5 equiv.), solvent
(2.0 mL) was added. The reaction mixture was stirred at room tem-
perature, which was monitored by TLC. Upon completion, the
mixture was extracted with ethyl acetate (3ϫ 10 mL). The com-
bined organic phase was washed with brine and dried with Na2SO4.
After that, the solid was filtered off through a thin pad of Celite,
and the filtrate was evaporated in vacuo to give the crude product,
which was purified by column chromatography on silica gel (ethyl
acetate) to give imidazo[1,2-a]-fused heterocycles.
7-Phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (2g): Yellow solid
(47.8 mg, 65%), m.p. 237–239 °C. IR (KBr): ν = 3427, 3053, 1499,
˜
1458, 1336, 1191 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 8.82–8.78
(m, J = 2.0 Hz, 2 H), 8.06–8.04 (m, 2 H), 7.82 (dd, J = 8.5, 1.5 Hz,
1 H), 7.66 (d, J = 7.0 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.38 (t,
J = 7.5 Hz, 1 H), 6.93 (dd, J = 7.0, 4.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 155.6, 151.0, 143.8, 141.1, 136.0, 133.4,
129.1, 127.6, 127.5, 126.7, 120.9, 108.9, 106.9 ppm. MS (EI): m/z
(%) = 245 (100) [M+], 218 (25). HRMS: m/z calcd. for C16H11N3
[M+] 245.0953; found 245.0956.
Benzo[4,5]imidazo[1,2-a]pyrimidine (2a):[17] Light yellow solid
(44.7 mg, 88%), m.p. 205–207 °C. IR (KBr): ν = 3441, 3082, 1626,
˜
1
1500, 1456, 1320 cm–1. H NMR (CDCl3, 500 MHz): δ 8.82 (d, J
= 6.5 Hz, 1 H), 8.76 (s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.89 (d, J
= 8.5 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H),
6.91 (dd, J = 6.5, 4.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 155.6, 150.4, 143.9, 133.5, 126.7, 126.6, 122.2, 120.4, 110.8,
106.7 ppm. MS (EI): m/z (%) = 169 (30) [M+], 154 (100).
7-(o-Tolyl)benzo[4,5]imidazo[1,2-a]pyrimidine (2h): Yellow solid
(58.3 mg, 75%), m.p. 263–265 °C. IR (KBr): ν = 3441, 3085, 1604,
˜
1
1521, 1495 1190 cm–1. H NMR (CDCl3, 500 MHz): δ = 8.84 (dd,
J = 6.5, 2.0 Hz, 1 H), 8.78 (q, J = 2.0 Hz, 1 H), 8.02 (d, J = 8.5 Hz,
1 H), 7.85 (d, J = 1.0 Hz, 1 H), 7.54 (dd, J = 8.5, 1.5 Hz, 1 H), 7.30–
7-Methylbenzo[4,5]imidazo[1,2-a]pyrimidine (2b): Light yellow solid
7.26 (m, 4 H), 6.95 (dd, J = 7.0, 4.0 Hz, 1 H), 2.29 (s, 3 H) ppm. 13
C
(45.1 mg, 82%), m.p. 205–206 °C. IR (KBr): ν = 3421, 3045, 1606,
˜
1499, 1452, 1376 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 8.79 (dd,
J = 7.0, 2.0 Hz, 1 H), 8.75–8.74 (m, 1 H), 7.89 (d, J = 8.5 Hz, 1
H), 7.69 (s, 1 H), 7.39 (dd, J = 8.5, 1.0 Hz, 1 H), 6.92 (dd, J = 6.5,
4.0 Hz, 1 H), 2.56 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 155.1, 150.3, 142.2, 133.2, 132.5, 128.6, 126.9, 120.2, 110.4, 106.6,
22.0 ppm. MS (EI): m/z (%) = 183 (15) [M+], 95 (100). HRMS (EI):
m/z calcd. for C11H9N3 [M+] 183.0796; found 183.0791.
NMR (CDCl3, 125 MHz): δ = 155.6, 150.8, 142.9, 141.6, 136.6,
135.7, 133.6, 130.5, 130.3, 128.6, 127.6, 126.8, 125.9, 119.9, 111.1,
106.9, 20.7 ppm. MS (EI): m/z (%) = 259 (100) [M+], 258 (64).
HRMS: m/z calcd. for C17H13N3 [M+] 259.1109; found 259.1114.
8-Methylbenzo[4,5]imidazo[1,2-a]pyrimidine (2i): Light yellow solid
(42.3 mg, 77%), m.p. 199–200 °C. IR (KBr): ν = 3047, 1603, 1503,
˜
1
1421, 1319, 792 cm–1. H NMR (CDCl3, 500 MHz): δ = 8.77 (dd,
7-Chlorobenzo[4,5]imidazo[1,2-a]pyrimidine (2c): Light yellow solid
J = 6.5, 2.0 Hz, 1 H), 8.74–8.73 (q, J = 2.0 Hz, 1 H), 7.77–7.75 (t,
J = 4.0 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 1 H), 6.89 (dd, J = 6.5,
4.0 Hz, 1 H), 2.55 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 155.2, 150.5, 144.2, 137.1, 133.5, 124.9, 124.1, 119.9, 110.5, 106.7,
22.2 ppm. MS (EI): m/z (%) = 183 (100) [M+], 143 (82). HRMS
(EI): m/z calcd. for C11H9N3 [M+] 183.0796; found 183.0795.
(48.1 mg, 79%), m.p. 319–320 °C. IR (KBr): ν = 3051, 1615, 1524,
˜
1498, 1460, 1201 cm–1. 1H NMR ([D6]DMSO, 500 MHz): δ = 9.51
(dd, J = 6.5, 2.0 Hz, 1 H), 8.86 (q, J = 2.0 Hz, 1 H), 8.53 (d, J =
2.0 Hz, 1 H), 7.86 (d, J = 9.0 Hz, 1 H), 7.57 (dd, J = 8.5, 2.0 Hz,
1 H), 7.20 (dd, J = 6.5, 4.0 Hz, 1 H) ppm. 13C NMR ([D6]DMSO,
125 MHz): δ = 157.1, 150.7, 142.1, 136.1, 127.5, 126.4, 125.5, 120.6,
112.9, 107.3 ppm. MS (EI): m/z (%) = 205 (33) [M+ (37Cl)], 203
(100) [M+ (35Cl)], 154 (44). HRMS (EI): m/z calcd. for C10H6N3Cl
[M+] 203.0250; found 203.0248.
9-Methylbenzo[4,5]imidazo[1,2-a]pyrimidine (2j): Yellow solid
(29.1 mg, 53%), m.p. 195–196 °C. IR (KBr): ν = 3067, 1619, 1597,
˜
1
1500, 1377, 778 cm–1. H NMR (CDCl3, 500 MHz): δ = 8.75 (dd,
J = 4.0, 2.0 Hz, 1 H), 8.72 (dd, J = 6.5, 1.5 Hz, 1 H), 7.69 (d, J =
8.0 Hz, 1 H), 7.36 (d, J = 7.0 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H),
6.87 (dd, J = 7.0, 4.0 Hz, 1 H), 2.79 (s, 3 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 155.1, 150.1, 143.5, 133.3, 130.8, 126.6,
126.3, 122.1, 107.9, 106.5, 17.1 ppm. MS (EI): m/z (%) = 183 (23)
[M+], 154 (100). HRMS (EI): m/z calcd. for C11H9N3 [M+]
183.0796; found 183.0800.
7-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (2d): Yellow solid
(60.3 mg, 81%), m.p. 270–272 °C. IR (KBr): ν = 3095, 1625, 1523,
˜
1497, 1459, 1202 cm–1. 1H NMR ([D6]DMSO, 500 MHz): δ = 9.50
(dd, J = 6.5, 2.0 Hz, 1 H), 8.85 (q, J = 2.0 Hz, 1 H), 8.64 (d, J =
2.0 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.66 (dd, J = 9.0, 2.0 Hz,
1 H), 7.18 (dd, J = 7.0, 4.0 Hz, 1 H) ppm. 13C NMR ([D6]DMSO,
125 MHz): δ = 157.1, 150.5, 142.4, 136.1, 129.0, 128.0, 120.9, 115.8,
113.1, 107.4 ppm. MS (EI): m/z (%) = 249 (95) [M+ (81Br)], 247
(100) [M+ (79Br)]. HRMS (EI): m/z calcd. for C10H6N3Br [M+]
246.9745; found 246.9747.
9-Chlorobenzo[4,5]imidazo[1,2-a]pyrimidine (2k): Light yellow solid
(47.5 mg, 78%), m.p. 262–264 °C. IR (KBr): ν = 3075, 1624, 1500,
˜
1435, 1323, 1181 cm–1. 1H NMR ([D6]DMSO, 500 MHz): δ = 9.55
(dd, J = 6.5, 1.5 Hz, 1 H), 8.91–8.90 (m, 1 H), 8.29 (d, J = 8.0 Hz,
1 H), 7.63 (d, J = 7.5 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.23 (dd,
J = 6.5, 4.0 Hz, 1 H) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ =
157.4, 150.3, 140.6, 136.4, 128.0, 125.6, 122.8, 121.8, 111.8,
107.6 ppm. MS (EI): m/z (%) = 205 (5) [M+ (37Cl)], 203 (14) [M+
(35Cl)], 154 (100). HRMS (EI): m/z calcd. for C10H6N3Cl [M+]
203.0250; found 203.0247.
7-Iodobenzo[4,5]imidazo[1,2-a]pyrimidine
(2e):
Yellow
solid
(57.2 mg, 64%), m.p. 328–330 °C. IR (KBr): ν = 3024, 1624, 1524,
˜
1
1497, 1205, 807 cm–1. H NMR ([D6]DMSO, 500 MHz): δ = 9.50
(dd, J = 6.5, 1.5 Hz, 1 H), 8.85 (d, J = 1.5 Hz, 1 H), 8.78 (s, 1 H),
7.80 (d, J = 8.5 Hz, 1 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.17 (dd, J =
6.5, 4.5 Hz, 1 H) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ =
157.6, 149.7, 141.5, 136.4, 134.8, 128.4, 121.6, 120.7, 107.9,
84.7 ppm. MS (EI): m/z (%) = 295 (100) [M+], 296 (13). HRMS
(EI): m/z calcd. for C10H6N3I [M+] 294.9606; found 294.9604.
3-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (2l): Yellow solid
(55.8 mg, 75%), m.p. 240–242 °C. IR (KBr): ν = 3049, 1618, 1512,
˜
Ethylbenzo[4,5]imidazo[1,2-a]pyrimidine-7-carboxylate (2f): Yellow
1479, 1293, 1064 cm–1. 1H NMR ([D6]DMSO, 500 MHz): δ = 9.92
(d, J = 3.0 Hz, 1 H), 8.86 (d, J = 2.0 Hz, 1 H), 8.32 (d, J = 8.0 Hz,
solid (70.1 mg, 97%), m.p. 260–262 °C. IR (KBr): ν = 3061, 1708,
˜
4
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Iodine(III)-Promoted Synthesis of Imidazo[1,2-a]pyrimidines
1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.57–7.54 (m, 1 H), 7.44 (t, J =
7.5 Hz, 1 H) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 156.3,
148.1, 143.7, 135.9, 126.8, 126.4, 122.0, 119.4, 112.9, 101.3 ppm.
MS (EI): m/z (%) = 249 (93) [M+ (81Br)], 247 (100) [M+ (79Br)],
168 (48). HRMS (EI): m/z calcd. for C10H6N3Br [M+] 246.9745;
found 246.9747.
7.45 (d, J = 7.5 Hz, 2 H), 7.41–7.36 (m, 3 H), 7.13 (dd, J = 6.5,
4.0 Hz, 1 H), 5.41 (s, 2 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 160.1, 152.5, 151.0, 142.9, 135.6, 135.5, 128.9, 128.7, 128.4, 114.3,
110.7, 66.6 ppm. MS (EI): m/z (%) = 253 (70) [M+], 91 (100).
HRMS (EI): m/z calcd. for C14H11N3O2 [M+] 253.0851; found
253.0854.
1-(2-Methylimidazo[1,2-a]pyrimidin-3-yl)ethanone (4d):[20] Light yel-
3-Phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (2m): Yellow solid
low solid (27.3 mg, 52%), m.p. 115–117 °C. IR (KBr): ν = 3415,
˜
(65.7 mg, 90%), m.p. 230–232 °C. IR (KBr): ν = 3050, 1629, 1528,
˜
3082, 1634, 1505, 1391, 1190 cm–1. 1H NMR ([D6]DMSO,
500 MHz): δ = 9.84 (dd, J = 7.0, 2.0 Hz, 1 H), 8.75 (dd, J = 4.5,
2.0 Hz, 1 H), 7.32 (dd, J = 7.0, 4.5 Hz, 1 H), 2.75 (s, 3 H), 2.59 (s,
3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 188.4, 154.5, 153.2,
149.6, 136.7, 120.2, 110.9, 30.3, 18.3 ppm. MS (EI): m/z (%) = 175
(77) [M+], 160 (100).
1486, 1302, 1178 cm–1. 1H NMR ([D6]DMSO, 500 MHz): δ = 9.84
(d, J = 1.5 Hz, 1 H), 9.21 (d, J = 2.0 Hz, 1 H), 8.43 (d, J = 8.0 Hz,
1 H), 7.89–7.85 (m, 3 H), 7.55 (t, J = 7.5 Hz, 3 H), 7.46–7.42 (m,
2 H) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 155.7, 149.5,
144.0, 133.7, 132.5, 129.2, 128.1, 127.2, 126.7, 126.2, 121.5, 119.6,
119.3, 113.0 ppm. MS (EI): m/z (%) = 245 (100) [M+], 218 (25).
HRMS (EI): m/z calcd. for C16H11N3 [M+] 245.0953; found
245.0956.
1-(2,5,7-Trimethylimidazo[1,2-a]pyrimidin-3-yl)ethanone (4e): Light
yellow solid (28.0 mg, 46%), m.p. 116–118 °C. IR (KBr): ν = 3441,
˜
2925, 1639, 1525, 1399, 1117 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 6.69 (s, 1 H), 2.74 (s, 3 H), 2.62 (s, 3 H), 2.58 (s, 3 H), 2.51 (s,
3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 187.4, 163.2, 154.0,
151.7, 148.4, 122.7, 112.6, 30.5, 24.6, 22.5, 18.1 ppm. MS (EI): m/z
(%) = 203 (47) [M+], 188 (100).
Benzo[4,5]imidazo[1,2-a]pyridine (2n):[11] Brown solid (29.3 mg,
58%), m.p. 179–181 °C. IR (KBr): ν = 3016, 1641, 1502, 1354,
˜
1258, 1142 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.40 (d, J =
7.0 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H),
7.67 (d, J = 9.0 Hz, 1 H), 7.53–7.49 (m, 1 H), 7.41–7.38 (m, 1 H),
7.36–7.33 (m, 1 H), 6.81 (td, J = 7.0, 1.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 148.4, 144.3, 129.6, 128.7, 125.8, 125.3,
121.2, 119.9, 117.9, 110.5, 110.4 ppm. MS (EI): m/z (%) = 168 (13)
[M+], 144 (100).
(2-Methylimidazo[1,2-a]pyrimidin-3-yl)(phenyl)methanone (4f): Yel-
low solid (55.5 mg, 78%), m.p. 97–99 °C. IR (KBr): ν = 3441, 3062,
˜
1612, 1525, 1392, 1210 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
9.73–9.71 (m, 1 H), 8.73 (d, J = 2.0 Hz, 1 H), 7.67–7.65 (m, 2 H),
7.61–7.58 (m, 1 H), 7.53–7.49 (m, 2 H), 7.13–7.10 (m, 1 H), 2.24
(s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 187.3, 155.1,
153.5, 150.2, 139.7, 136.3, 132.3, 128.8, 128.5, 119.8, 110.7,
17.7 ppm. MS (EI): m/z (%) = 237 (44) [M+], 105 (100). HRMS
(EI): m/z calcd. for C14H11N3O [M+] 237.0902; found 237.0901.
Imidazo[1,2-a:4,5-bЈ]dipyridine (2o):[18] Brown solid (35.5 mg, 70%),
m.p. 193–195 °C. IR (KBr): ν = 3047, 1643, 1479, 1347, 1248,
˜
1154 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 8.76 (dd, J = 5.0,
1.5 Hz, 1 H), 8.50 (d, J = 6.5 Hz, 1 H), 8.21 (dd, J = 8.0, 1.5 Hz,
1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.50–7.47 (m, 1 H), 7.24 (dd, J =
8.0, 4.5 Hz, 1 H), 6.92 (td, J = 7.0, 1.5 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 156.1, 149.5, 148.7, 130.9, 126.0, 121.2,
119.0, 118.3, 116.0, 111.5 ppm. MS (EI): m/z (%) = 169 (100) [M+].
(2-Ethylimidazo[1,2-a]pyrimidin-3-yl)(phenyl)methanone
(4g):[21]
Light yellow solid (67.1 mg, 89%), m.p. 137–138 °C. IR (KBr): ν
˜
= 3443, 3134, 1616, 1523, 1384, 1207 cm–1. 1H NMR (CDCl3,
500 MHz): δ = 9.68 (d, J = 7.0 Hz, 1 H), 8.73 (t, J = 2.0 Hz, 1 H),
7.68 (d, J = 7.5 Hz, 2 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.51 (t, J =
7.5 Hz, 2 H), 7.10 (q, J = 4.5 Hz, 1 H), 2.51 (q, J = 7.0 Hz, 2 H),
1.21 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
187.4, 160.2, 153.4, 150.5, 139.9, 136.3, 132.4, 128.8, 128.5, 119.1,
110.7, 23.7, 13.5 ppm. MS (EI): m/z (%) = 251 (87) [M+], 250 (100).
Benzo[4,5]imidazo[1,2-a]pyrazine (2p):[19] Brown solid (30.4 mg,
60%), m.p. 197–198 °C. IR (KBr): ν = 3054, 3019, 1490, 1342,
˜
1271, 1005 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 9.31 (d, J =
1.5 Hz, 1 H), 8.36 (dd, J = 5.0, 2.0 Hz, 1 H), 8.06 (d, J = 8.5 Hz,
1 H), 7.99–7.96 (m, 2 H), 7.65–7.62 (m, 1 H), 7.52–7.49 (m, 1
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 145.7, 144.1, 142.1,
127.8, 127.5, 127.4, 123.5, 121.5, 118.0, 111.4 ppm. MS (ESI): m/z
(%) = 170 [M + H].
Phenyl(2-propylimidazo[1,2-a]pyrimidin-3-yl)methanone (4h): Light
yellow solid (63.7 mg, 80%), m.p. 136–137 °C. IR (KBr): ν = 3444,
˜
2963, 1617, 1521, 1385, 1202 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 9.68 (dd, J = 7.0, 2.0 Hz, 1 H), 8.73 (q, J = 2.0 Hz, 1 H), 7.68
(d, J = 7.5 Hz, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz,
2 H), 7.12–7.09 (m, 1 H), 2.46 (t, J = 7.5 Hz, 2 H), 1.72–1.64 (m,
2 H), 0.72 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 187.5, 159.1, 153.4, 150.4, 139.9, 136.3, 132.4, 128.8, 128.4,
119.5, 110.6, 32.2, 22.9, 14.0 ppm. MS (EI): m/z (%) = 265 (9) [M+],
236 (100). C16H15N3O (265.31): calcd. C 72.43, H 5.70, N 15.84;
found C 72.40, H 5.59, N 15.47.
Ethyl Imidazo[1,2-a]pyrimidine-3-carboxylate (4a):[6c] Yellow solid
(48.8 mg, 85%), m.p. 121–123 °C. IR (KBr): ν = 3432, 2986, 1701,
˜
1614, 1407, 1284 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 9.56 (dd,
J = 7.0, 2.0 Hz, 1 H), 8.72 (dd, J = 4.0, 2.0 Hz, 1 H), 8.44 (s, 1 H),
7.13 (dd, J = 6.5, 4.0 Hz, 1 H), 4.41 (q, J = 7.0 Hz, 2 H), 1.41 (t,
J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 160.4,
152.4, 150.8, 142.4, 135.6, 114.6, 110.6, 61.1, 14.5 ppm. MS (EI):
m/z (%) = 191 (52) [M+], 95 (100).
Methyl Imidazo[1,2-a]pyrimidine-3-carboxylate (4b): Light yellow
(4-Methoxyphenyl)(2-methylimidazo[1,2-a]pyrimidin-3-yl)meth-
anone (4i): Light yellow solid (65.0 mg, 81%), m.p. 119–121 °C. IR
solid (25.5 mg, 48%), m.p. 175–176 °C. IR (KBr): ν = 3367, 3105,
˜
1705, 1616, 1529, 1286 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
9.55 (dd, J = 7.0, 2.0 Hz, 1 H), 8.73 (dd, J = 4.0, 2.0 Hz, 1 H), 8.44
(s, 1 H), 7.13 (dd, J = 6.5, 4.0 Hz, 1 H), 3.95 (s, 3 H) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 160.7, 152.5, 150.9, 142.8, 135.6,
114.3, 110.7, 51.9 ppm. MS (EI): m/z (%) = 177 (100) [M+], 146
(83).
(KBr): ν = 3441, 3063, 1613, 1598, 1387, 1262 cm–1. 1H NMR
˜
(CDCl3, 500 MHz): δ = 9.57 (d, J = 6.5 Hz, 1 H), 8.70 (q, J =
2.0 Hz, 1 H), 7.70 (AAЈ of AAЈBBЈ, J = 9.0 Hz, 2 H), 7.08–7.06
(m, 1 H), 7.00 (BBЈ of AAЈBBЈ, J = 9.0 Hz, 2 H), 3.89 (s, 3 H),
2.33 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 186.1, 163.4,
153.8, 153.1, 150.1, 136.0, 131.9, 131.3, 119.9, 114.1, 110.4, 55.7,
17.8 ppm. MS (EI): m/z (%) = 267 [M+], 135 (100). HRMS (EI):
m/z calcd. for C15H13N3O2 [M+] 267.1008; found 267.1004.
Benzyl Imidazo[1,2-a]pyrimidine-3-carboxylate (4c): Light yellow
solid (50.9 mg, 67%), m.p. 135–137 °C. IR (KBr): ν = 3447, 3105,
˜
1702, 1611, 1521, 1285 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
9.57 (d, J = 6.0 Hz, 1 H), 8.74 (d, J = 2.0 Hz, 1 H), 8.50 (s, 1 H),
Phenyl(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone (4j):[22] Light
yellow solid (76.1 mg, 85%), m.p. 130–132 °C. IR (KBr): ν = 3423,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Qian, B. Liu, Q. Tan, S. Zhang, B. Xu
FULL PAPER
3062, 1600, 1574, 1492, 1222 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 9.53 (d, J = 6.5 Hz, 1 H), 7.81 (d, J = 9.0 Hz, 1 H), 7.54–7.49
(m, 3 H), 7.32–7.30 (m, 2 H), 7.24 (t, J = 7.5 Hz, 1 H), 7.12–7.06
(m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 187.4, 154.8,
147.3, 138.6, 133.8, 131.9, 130.3, 129.6, 129.4, 128.4, 128.3, 127.8,
120.0, 117.4, 114.8 ppm. MS (EI): m/z (%) = 298 (100) [M+], 297
(73).
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2-Methyl-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3(2H)-one (4k):
[5]
[6]
Light yellow solid (29.1 mg, 52%), m.p. 212–214 °C. IR (KBr): ν
˜
= 3453, 3075, 1694, 1511, 1444, 1106 cm–1. 1H NMR (CDCl3,
500 MHz): δ = 8.01 (d, J = 6.5 Hz, 1 H), 7.66 (d, J = 9.5 Hz, 1 H),
7.29 (t, J = 7.0 Hz, 1 H), 6.91 (t, J = 6.5 Hz, 1 H), 3.44 (q, J =
6.5 Hz, 1 H), 3.17 (t, J = 5.5 Hz, 1 H), 2.76 (d, J = 16.5 Hz, 1 H),
1.41 (d, J = 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
198.3, 151.9, 148.4, 145.9, 127.3, 124.6, 120.2, 113.6, 47.4, 27.1,
17.1 ppm. MS (EI): m/z (%) = 186 (76) [M+], 157 (100). HRMS
(EI): m/z calcd. for C11H10N2O1 [M+] 186.0793; found 186.0794.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectroscopic characterization data, cop-
1
ies of the H NMR and 13C NMR spectra for all compounds are
given in the Supporting Information.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant number 21272149), the Innovation Program
of Shanghai Municipal Education Commission (grant number
14ZZ094), and the Science and Technology Commission of Shang-
hai Municipality (grant number 13ZR1416400) for financial sup-
port. The authors thank Prof. Hongmei Deng (Laboratory for Mi-
crostructures, SHU) for NMR spectroscopic measurements.
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Received: April 20, 2014
Published Online: ᭿
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Job/Unit: O42456
/KAP1
Date: 17-06-14 18:18:30
Pages: 8
G. Qian, B. Liu, Q. Tan, S. Zhang, B. Xu
FULL PAPER
Nitrogen Heterocycles
Imidazo[1,2-a]-type fused heterocycles are
prevalent structural motifs in pharmaceut-
ically and biologically active compounds.
In this paper, an efficient and mild syn-
thesis of imidazo[1,2-a]pyrimidine skel-
etons was developed from readily available
pyrimidyl arylamines or enamines through
a hypervalent iodine-promoted intramo-
lecular C–H bond cycloamination reaction.
G. Qian, B. Liu, Q. Tan,* S. Zhang,
B. Xu* ............................................... 1–8
Hypervalent Iodine(III) Promoted Direct
Synthesis of Imidazo[1,2-a]pyrimidines
Keywords: Synthetic methods / Nitrogen
heterocycles
/
C–H functionalization
/
Amination / Iodine
8
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