I2O5-Mediated Iodocyclization Cascade of N-(1-Arylallyl)pyridine-2-amines with Concomitant C=C Bond Cleavage: A Synthesis of 3-Iodoimidazo[1,2- a]pyridines

Article abstract of DOI:10.1021/acs.joc.9b00765

A facile method for the synthesis of 3-iodoimidazo[1,2-a]pyridines has been successfully developed involving an I₂O₅-mediated iodocyclization cascade of N-(1-arylallyl)pyridin-2-amines with concomitant C=C bond cleavage. Preliminary mechanistic studies reveal that this protocol might undergo an oxidative cyclization/decarboxylation/iodination sequence in which I₂O₅ is used as both an oxidant and an iodine source. The present protocol has advantages of wide substrate scope, simple operation, and metal-free conditions.

Full text of DOI:10.1021/acs.joc.9b00765

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Article
I2O5-Mediated Iodocyclization Cascade of N-(1-
arylallyl)pyridine-2-amines with Concomitant C=C Bond
Cleavage: A Synthesis of 3-Iodoimidazo[1,2-a]pyridines
Bingwei Zhou, Yuan Yuan, Hongwei Jin, and Yunkui Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00765 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 15, 2019
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I2O5-Mediated Iodocyclization Cascade of N-(1-arylallyl)pyridine-2-amines with
Concomitant C=C Bond Cleavage: A Synthesis of 3-Iodoimidazo[1,2-a]pyridines
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Bingwei Zhou, Yuan Yuan, Hongwei Jin,* and Yunkui Liu*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Zhejiang University of Technology, Hangzhou
310014, People’s Republic of China
E-mail: ykuiliu@zjut.edu.cn; jhwei828@zjut.edu.cn
TOC graphic
H
N
N
R1
I2O5 (2.0 equiv)
R1
R2
R2
N
MeCN/H2O = 800 : 1 (V/V)
N
I
2O5
80 C, 2 h
I

24 examples, up to 89% yield
metal-free conditions
simple operation
one-pot and straightforward procedure
broad functional group tolerance
ABSTRACT
A facile method for the synthesis of 3-iodoimidazo[1,2-a]pyridines has been successfully
developed involving an I2O5-mediated iodocyclization cascade of N-(1-arylallyl)pyridin-2-amines with
concomitant C=C bond cleavage. Preliminary mechanistic studies reveal that this protocol might
undergo an oxidative cyclization/decarboxylation/iodination sequence in which I2O5 is used as both an
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oxidant and an iodine source. The present protocol has advantages of wide substrate scope, simple
operation, and metal-free conditions.
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Introduction
Alkenes and alkynes are ubiquitous structural units in organic molecules, and they serve as
useful building blocks for the construction of molecule diversities due to their easy availability and
high reactivity.1,2 In this regard, recently, the 1,2-difunctionalizations of C=C and CC bonds have
received special attention because such reactions usually allow for the synthesis of complex
molecules in simple operation and step-economy manner (Scheme 1-a).3,4 As compared to the
extensive studies on the 1,2-difunctionalizations of C=C and CC bonds, the 1,1 (or
2,2)-difunctionalizations of C=C and CC moieties involving C–C bond cleavage (Csp2–Csp3,
Csp2–Csp2, Csp–Csp3, C=C, or CC bond, Scheme 1-b), however, have been relatively
underexplored5-8 because the cleavage of C–C bond remains a great challenge owing to the
extraordinarily large bond association energy of C–C bonds.9 Yet this type of strategy would
provide an alternative way to make fully use of alkenes and alkynes as synthetic platforms in
organic synthesis (Scheme 1-b).5-8 Regarding difunctionalization with concomitant C=C bond
cleavage, for example, we7a and Zhao’s group7b independently realized a splitting of C=C bonds in
chalcones with concomitant 2,2-oxygenation/arylation of the cleaved sp2-carbon resulting in the
formation of 9,10-phenanthraquinones and -ketoamides (esters), respectively; Meldal and
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co-workers7c reported a cleavage of C=C bonds in solid-supported peptide olefins followed by
2,2-amination/arylation of the scissored sp2-carbon to afford pyrroloisoquinolines; very recently,
Wu and Liu7d reported a palladium-catalyzed oxidative cleavage of C=C bonds with a concomitant
double amination of the resulting sp2-carbon fragments to yield quinazolinones; Xu and Liu7e,8a
described a transition-metal-free cleavage of C=C or CC bonds followed by reassembling the
cleaved fragments with S8 and amides to access aryl thioamides. Despite some progress made in
this field, it is still highly desirable to further explore novel reactions for the multifunctionalization
of C=C and CC moieties involving concomitant C–C bond cleavage.
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Scheme 1. Difunctionalization of C=C and CC bonds
(a) 1,2-difunctionalization of C=C and C C bonds

1
2
1
2
1,2-difunctionalization
FG2 FG1
FG2 FG1
extensively studied!
(b) difunctionalization of C=C and C C moities involving C-C bond cleavage

Csp2-Csp3 cleavage
or Csp2-Csp2 cleavage
or Csp-Csp3 cleavage
FG2
FG2
FG1
1
2
2
1
2
1,1-difunctionalization
FG1
FG2
R1
2
1(or 2)
FG
1
C=C cleavage
R2
R1
1,1 (or 2,2)-difunctionalization
(R2)
or CC cleavage
FG1
FG1
more challenging!
relatively underexplored!
(c) This work: cleavage of C=C bonds with concomitant 2,2-amination/iodination
H
N
N
R1
I2O5 (2.0 equiv)
R1
R2
R2
N
N
MeCN/H2O = 800 : 1 (V/V)
I
2O5
80 C, 2 h
I
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Imidazo[1,2-a]pyridines represent one class of valuable pharmacophores exhibiting unique
biological and pharmaceutical activities.10 They thus have broad applications in drug designs including
zolpidem,11 olprinone,12 zolimidine,13 necopidem,14 and saripidem,14 etc. In addition, they are widely
used in optoelectronic materials15 and abnormal NHC ligand synthesis.16 Among
imidazo[1,2-a]pyridine family, 3-halogenated imidazo[1,2-a]pyridines have received special attention
because they are versatile intermediates enabling the late-stage elaboration with the C–X (X = Cl, Br, I)
bonds.17 The traditional methods for the preparation of 3-halogenated imidazo[1,2-a]pyridines relied on
stepwise synthesis via 3-halogenation of preformed imidazo[1,2-a]pyridines with certain halogen
sources.18 Several straightforward methods have been explored including CuOx/OMS-2-catalyzed
three-component reaction of 2-aminopyridine, acetophenones and iodine,19a copper-catalyzed oxidative
coupling between 2-aminopyridine and alkenes in the presence of iodine,19b copper-mediated aerobic
oxidative coupling/cyclization of pyridines and enamides,19c and transition-metal-free chlorocyclization
cascade of 2-aminopyridines with aliphatic carboxylic acids or ketones.19d Despite their merits in
organic synthesis, these reactions have one or more limitations in terms of multiple steps, transition
metal participation, and the use of toxic halogen sources. Thus, there is high demand to develop direct
and efficient methods for the synthesis of 3-halogenated imidazo[1,2-a]pyridines using non-toxic
halogen sources under metal-free conditions. As our ongoing interests in carbon-carbon bond cleavage
reactions6,7a,20 and I2O5-mediated efficient tandem reactions,21 we herein describe a facile method for
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the construction of 3-iodoimidazo[1,2-a]pyridines through an I2O5-mediated iodocyclization cascade of
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N-(1-arylallyl)-pyridin-2-amines with concomitant C=C bond cleavage (Scheme 1-c).22
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Results and Discussion
Initially, N-(1-phenylallyl)pyridin-2-amine 1a was chosen as the model substrate for the optimization
of the reaction conditions (Table 1). When 1a was treated with 2 equivalents of I2O5 in newly
purchased acetonitrile at 80 ºC for 2 h, 3-iodoimidazo[1,2-a]pyridine 2a could be obtained in 45% yield
along with 3a in 28% yield as a side product (entry 1, Table 1). It was found that switching the iodine
source to I2 or PhI(OAc)2 failed to give the desired product, and most of 1a was recovered (entries 2, 3,
Table 1). The use of 3 equivalents of I2O5 slightly decreased the yield of 2a (43%, entry 4, Table 1).
Solvent screening experiments revealed that a solvent mixture with a ratio of MeCN/H2O = 800:1 (V/V)
gave the best yield of 2a (entries 1, 5-11, Table 1). The present reaction was quite sensitive to
temperature. Either lowering or elevating the temperature reduced the yield of 2a (60 ºC: 25%, entry 12;
100 ºC: 11%, entry 13, Table 1). Prolonging the reaction time had no obvious effect on the yield of 2a
(entry 14 vs 10), while shortening the reaction time significantly reduced the yield of 2a (36%, entry 15,
Table 1). When the dehydrated MeCN was used, the reaction could still give a small amount of 2a (<
15%, entry 16, Table 1). We think it is possibly because it is hard to completely remove water in
MeCN. The direct use of HIO3 could also give 2a in 35% yield, albeit much lower than that of I2O5
(entry 17 vs 10, Table 1).
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Table 1. Optimization of the Reaction Conditionsa
N
N
H
N
Iodine source
Ph
Ph
Ph
7
+
N
N
8
9
Solvent, Temp., Time
N
I
CHO
3a
10
11
12
13
14
15
16
17
18
19
20
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1a
2a
entry
iodine source
(mo%)
solvent
temp (ºC) time [h]
yield (%)
2a
3a
1
2
I2O5
I2
MeCNb
MeCNb
MeCNb
MeCNb
DMF
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
2
2
2
2
2
2
2
2
2
2
2
2
2
1
6
2
6
45
0
28
0
3
PhI(OAc)2
0
0
c
4
I2O5
43
40
38
22
33
53
60
42
25
11
36
59
25
20
13
5
5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
I2O5
6
DCE
7
toluene
1,4-dioxane
8
9
9
MeCN/H2O = 500:1 (V/V)
MeCN/H2O = 800:1 (V/V)
MeCN/H2O = 1000:1 (V/V)
MeCN/H2O = 800:1 (V/V)
MeCN/H2O = 800:1 (V/V)
MeCN/H2O = 800:1 (V/V)
MeCN/H2O = 800:1 (V/V)
MeCNg
34
26
18
10
4
10
11
12d
13e
14f
15
16
17
15
27
<15
35
<10
10
h
HIO3
MeCN/H2O = 800:1 (V/V)
aReaction conditions: 1a (0.2 mmol), iodine source (0.4 mmol, 2.0 equiv based on 1a), solvent (2
mL), at 60-100 °C for 1-6 h. bNew purchased MeCN was used (water content < 0.05 w/w %) was
c
d
e
used. I2O5 (0.6 mmol, 3.0 equiv). Most of 1a was recovered. The reaction resulted in a
complicated mixture which is hard to be separated.
f(2-phenylimidazo[1,2-a]pyridin-3-yl)methanol (4a) was obtained in 25% yield. Dehydrated
g
MeCN was used. h4 equivalents (0.8 mmol) were used.
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The substrate scope of N-(1-arylallyl)pyridine-2-amines 1 was then investigated under the optimized
reaction conditions (Table 2). First, the generality of 1 with various aryl groups at the 3-position of the
allyl moiety of 1 was examined (R1 = Ar). It was found that 1 containing a range of aryl groups with
various substitution patterns (para-, meta-, or ortho-) underwent the iodocyclization smoothly to afford
the desired products in modest to good yields (38%-89%, 2a-2v). The functional groups on the aryl
rings (R1) could be electron-donating groups (2b, 2c, 2h, 2m, 2n, 2q, 2s) as well as
electron-withdrawing ones (2d-2g, 2i-2k, 2o, 2p, 2r). Note that the reaction is compatible with a wide
variety of functional groups including alkanyl, ether, sulfuryl, cyano, nitro, trifluoromethyl, halo (F, Cl,
Br), ester, and even thiomethyl groups. Gratifyingly, 3-pyridyl group was fully tolerated as well (2u).
In addition, it was found that substrates with R1 as H or an alkanyl group (cyclohexanyl) were also
workable under the standard reaction conditions, albeit affording relatively lower yields of products
(2w and 2x). Finally, the substituents R2 on the pyridine ring were investigated. Pyridine bearing either
electron-donating or electron-withdrawing groups could undergo the iodocyclization smoothly and
afford the desired products in modest to good yields (2l-2x).
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Table 2. Substrate scope of N-(1-arylallyl)pyridine-2-amines 1.a
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H
N
R1
N
I2O
5 (2.0 equiv)
R1
R2
R2
N
N
MeCN/ H2O = 800 : 1 (V/V)
80 oC, 2 h
I
2
1
9
F
10
11
12
13
14
15
16
17
18
19
20
21
22
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N
N
N
N
R
N
N
I
I
R
I
2a
2b
2c
2d
2e
2h
2i
2j
: R = H, 60%;
: R = OMe, 45%;
: R = Me, 64%;
: R = SO2Me, 42%;
: R = CN, 82%;
: R = NO2, 89%;
: R = Me, 38%;
: R = Cl, 50%;
: R = NO2, 83%
2k
: 50%
2l
: R = H, 73%;
N
N
2m
: R = i-Pr, 57%;
: R = SMe, 67%;
: R = Br, 59%;
R
2n
2o
2p
2f
2g
Me
Me
: R = CF3, 68%
I
: R = CO2Me, 72%
N
N
N
N
R
N
N
Me
Me
2t
I
R
I
OMe
I
2q
2r
2s
: R = Me, 48%;
: R = Cl, 52%;
: 70%
: R = 2-napthyl, 57%;
: R = 3-pyridyl, 50%
2u
Me
N
N
N
Cy
N
H
N
N
Cl
Me
I
I
I
b
2v
: 61%
2w
: 35%
2x
: 32%
aReaction conditions: 1 (0.3 mmol), I2O5 (0.6 mmol), MeCN/ H2O = 800 : 1 (2 mL, V/V) at 80 oC for 2
h. bThe reaction time is 6 h.
To make this protocol synthetically valuable, a gram-scale (5 mmol of 1a used) synthesis of 2a was
also studied, and the desired 3-iodoimidazo[1,2-a]pyridine 2a was obtained in 46% yield (eq. 1).
H
N
N
Ph
I2O5 (2.0 equiv)
(eq. 1)
Ph
N
N
MeCN/H2O = 800 : 1 (V/V)
80 oC, 5 h
I
1a
(1.05 g, 5 mmol)
2a
(0.73 g, 46%)
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To gain insight into the possible mechanism, several mechanistic experiments were carried out
(Scheme 2). When the reaction of 1a proceeded for 30 min under the standard reaction conditions,
sample analysis indicated that both intermediate 3a and 4a were detected in 5% and 63% GC yield,
respectively (Scheme 2-a). When 3a was subjected to the standard reaction conditions or was treated
with 2 equivalents of iodine, both cases failed to give 2a, suggesting 3a is not likely the key
intermediate for the formation of 2a (Scheme 2-b). Treatment of 4a or 5a under the standard reaction
conditions failed to give 2a; while in the presence of 2 equivalents of iodine, both 4a and 5a were
converted to 2a in 59% and 50% yield, respectively (Scheme 2-c,d). These results implied that 4a and
5a might be the key intermediates for the formation of 2a and I2 might be in situ generated in the
reaction process. To probe the oxygen source in intermediate 4a, 1a was subjected to the standard
reaction conditions except using a MeCN/H2O18 = 800: 1 (V/V) system (Scheme 2-e). The
18O-incorporated product 4a-O18 ([M+H]+ m/z = 227) was detected by the MS analysis (Scheme 1-e,
also see the Supporting Information), which disclosed that the oxygen atom in 4a was originated from
H2O. In addition, radical scavenging experiments were performed by adding extra TEMPO23 into the
model reaction (Scheme 2-f). The reaction could still give 2a in 41% yield along with 3a in 37% yield
in the presence of 4 equivalents of TEMPO; while the reaction only gave 2a in 4% yield along with a
large amount of 3a in 83% yield. We presume that TEMPO may undergo redox reaction with I2O5
under the reaction conditions;21b,24 thus, the formation of 2a was suppressed.
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Scheme 2. Mechanistic Studies
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7
8
9
H
std conditions in
Table 2
except for 30 min
N
N
N
Ph
Ph
Ph
a)
+
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
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OH
CHO
: 5% (GC yield)
4a
: 63% (GC yield)
1a
3a
std conditions in
Table 2
I2 (2 equiv)
b)
c)
2a
3a
4a
2a
MeCN/H2O = 800 :1 (V/V)
80 oC, 2 h
NR
NR
conditions in
Table 2
I2 (2 equiv)
2a
2a
MeCN/H2O = 800 :1 (V/V)
80 oC, 2 h
NR
59%
std conditions in
Table 2
N
I2 (2 equiv)
Ph
N
2a
2a
1a
d)
e)
MeCN/H2O = 800 :1 (V/V)
NR
50%
CO2H
80 oC, 2 h
5a
std conditions in
Table 2
N
Ph
N
4a-18O
Determined by MS
except for 30 min
O18
18OH
3a
and using H2
std conditions in
Table 2
1a
2a
+
f)
TEMPO
TEMPO
2a
3a
Yield of
Yield of
4.0 eq.
41%
4%
37%
83%
10.0 eq.
On the basis of the preliminary mechanistic experiments and previous literature,21,25-28 a plausible
reaction mechanism is proposed in Scheme 3. First, HOI was generated from the hydrolysis of I2O5
with water followed by the decomposition of the resulting HIO3 under thermal conditions.21b,25 HOI
may release I+ and OH- species in solution. Then activation of the alkene moiety in 1a by I+ species
followed by a 5-exo-trig cyclization to give intermediate B.21 B might undergo dehydrogenative
aromatization to deliver intermediate C promoted by HIO3, and I2 might be generated in the process.26
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Oxidation of C with HIO3 delivered a vinyl-λ3-iodane intermediate D that underwent substitution by
H2O to generate alcohol 4a.21,27 According to the abovementioned mechanistic studies (Scheme 2, vide
supra), the in situ generated I2 may promote the conversion of 4a to the final product 2a where C=C
bond cleavage occurred possibly via a decarboxylation reaction of intermediate 5a.28
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Scheme 3. Proposed mechanism
O2
HO-
I+
I2O5 H O
2 HIO3
HOI
+
+
2
OH-
H
H
N
N
Ph
N
Ph
OH
-H
Ph
N
N
N
+
I
I
1a
A
B
2HIO3
dehydrogenative
aromatization
I2 + 2H2O + 2O2
HIO3
N
N
N
Ph
OH
Ph
I
-HO
N
Ph
N
N
-H2O
OH
IIII
I
OH
C
4a
(isolated)
D
H2O
I2/O2
I2 + H2O
HI
N
N
N
HOI
Ph
Ph
Ph
N
N
N
CO2
OH
H
CO2H
5a
I
CO2
I
via
2a
E
Conclusion
In summary, we have developed the synthesis of 3-iodoimidazo[1,2-a]pyridines involving an
I2O5-mediated 5-exo-trig iodocyclization of N-(1-arylallyl)pyridin-2-amines with concomitant C=C
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bond cleavage. The present protocol has competitive advantages as follows: (1) the use of inexpensive,
easily handled, and environmentally benign I2O5 as the oxidant and the iodine source, (2)
transition-metal-free reaction conditions, (3) broad functional group tolerance, and (4) simple
operation.
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Experimental Section
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without
1
purification. The H and 13C NMR spectra were recorded on a spectrometer at 25 C in CDCl3 or
DMSO-d6 at 500 MHz and 125 MHz, respectively. Proton chemical shifts (δ) are relative to
13
tetramethylsilane (TMS, δ = 0.00) as internal standard and expressed in ppm. Chemical shifts of C
NMR were reported relative to the solvent signal (CDCl3: δ = 77.16 ppm; DMSO-d6: δ = 39.51 ppm).
GC-MS experiments were performed with an Agilent 6890N GC system equipped with a 5973N
mass-selective detector with EI source; High resolution mass spectra (HRMS) were obtained on a TOF
MS instrument with EI or ESI source. Acetonitrile is dehydrated by CaH2 before preparation of the
combined MeCN/H2O solvent system. Flash column chromatography was performed on silica gel
(100-200 mesh) with the indicated solvent mixtures.
General Procedure for the Synthesis of Substrate 1.
General procedure A.14c: A mixture of 2-aminopyridine (3.0 mmol), aldehyde (3.0 mmol),
p-toluenesulfonic acid (10 mg, 0.06 mmol), and 4Å molecular sieve powders (2.0 g) in anhydrous THF
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(20 mL) was refluxed under argon for 18 h. The mixture was then cooled to -78 C before addition of
vinylmagnesium bromide (6 mL, 1.0 M in THF, 2.0 equiv). The reaction mixture was maintained at -78
oC for 30 min and then warmed up to room temperature gradually. The reaction was quenched with
saturated aqueous NH4Cl (1 mL) and then water (30 mL). The resulting mixture was extracted with
EtOAc (2 × 30 mL). The combined organic layer was washed with brine, and dried over anhydrous
Na2SO4. The concentrated crude product was purified by flash chromatography to afford the
corresponding product. Substrates 1a,14c 1l,14c, 1p,14c 1r,14c 1s,14c 1u14c and 1x14c are known compounds
and their spectra data are in line with those reported in previous literature.
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General procedure B.14c: A mixture of 3-methylpyridin-2-amine (3.0 mmol), t-BuOK (504 mg, 4.5
mmol, 1.5 equiv) in anhydrous THF (10 mL) was stirred at room temperature under argon for 1 h.
Allylbromide (3.6 mmol, 1.2 equiv, diluted in 2 mL of THF) was added dropwise to the resulting
brown and transparent solution. The reaction was stirred for another 2 h at room temperature and then
quenched with water (30 mL). The reaction mixture was extracted with EtOAc (2 × 30 mL). The
combined organic layer was washed with brine, and dried over anhydrous Na2SO4. The concentrated
crude product was purified by flash chromatography to afford the corresponding product 1w.
Characterization of unknown substrates.
N-(1-(4-methoxyphenyl)allyl)pyridin-2-amine (1b): Following the general procedure A. White
solid (0.36 g, 50%). m.p. 80-82 oC. 1H NMR (500 MHz, CDCl3): δ 8.08 (dd, J1 = 4.5 Hz, J2 = 1.0 Hz,
1H), 7.40-7.37 (m, 1H), 7.32-7.29 (m, 2H), 6.90-6.88 (m, 2H), 6.59-6.57 (m, 1H), 6.35 (d, J = 8.5 Hz,
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1H), 6.10-6.03 (m, 1H), 5.28-5.22 (m, 3H), 5.04 (d, J = 6.5 Hz, 1H), 3.80 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 158.9, 157.9, 148.2, 138.7, 137.4, 133.4, 128.3, 115.5, 114.0, 113.2, 107.0, 57.9, 55.2.
HRMS (ESI) for C15H17N2O [M+H]+: calcd 241.1335, found 241.1340.
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N-(1-(p-tolyl)allyl)pyridin-2-amine (1c): Following the general procedure A. White solid (0.51g,
71%). m.p. 47-49 oC. 1H NMR (500 MHz, CDCl3): δ 8.11-8.09 (m, 1H), 7.40-7.37 (m, 1H), 7.30-7.28
(m, 2H), 7.18-7.17 (m, 2H), 6.60-6.57 (m, 1H), 6.35 (d, J = 8.5 Hz, 1H), 6.12-6.06 (m, 1H), 5.31-5.23
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(m, 3H), 5.07 (d, J = 6.0 Hz, 1H), 2.36 (s, 3H). C{1H} NMR (125 MHz, CDCl3): δ 158.0, 148.2,
138.8, 138.5, 137.4, 137.1, 129.4, 127.0, 115.6, 113.3, 107.0, 58.3, 21.1. HRMS (ESI) for C15H17N2
[M+H]+: calcd 225.1386, found 225.1380.
N-(1-(4-(methylsulfonyl)phenyl)allyl)pyridin-2-amine (1d): Following the general procedure A.
White solid (0.42 g, 49%). m.p. 54-56 oC. 1H NMR (500 MHz, CDCl3): δ 8.04 (dd, J1 = 5.0 Hz, J2 = 1.0
Hz, 1H), 7.90-7.87 (m, 2H), 7.58(d, J = 8.5 Hz, 2H), 7.39-7.36 (m, 1H), 6.60-6.58 (m, 1H), 6.34 (d, J =
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8.0 Hz, 1H), 6.08-6.01 (m, 1H), 5.49 (t, J = 6.5 Hz, 1H), 5.28-5.21 (m, 3H), 3.04 (s, 3H). C{1H}
NMR (125 MHz, CDCl3): δ 157.3, 148.2, 148.1, 139.3, 137.5, 137.5, 128.0, 127.7, 117.2, 113.7, 107.5,
57.8, 44.4. HRMS (ESI) for C15H17N2O2S [M+H]+: calcd 289.1005, found 289.1012.
4-(1-(pyridin-2-ylamino)allyl)benzonitrile (1e): Following the general procedure A. Pale yellow
solid (0.47 g, 66%). m.p. 72-74 oC. 1H NMR (500 MHz, CDCl3): δ 8.05 (dd, J1 = 5.0 Hz, J2 = 1.0 Hz,
1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.40-7.36 (m, 1H), 6.61-6.59 (m, 1H), 6.33 (d, J
= 8.5 Hz, 1H), 6.07-6.01 (m, 1H), 5.45 (t, J = 6.0 Hz, 1H), 5.29-5.23 (m, 2H), 5.17 (d, J = 6.5 Hz, 1H).
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13C{1H} NMR (125 MHz, CDCl3): δ 157.3, 148.1, 147.3, 137.5, 137.5, 132.4, 127.8, 118.7, 117.2,
113.8, 111.1, 107.4, 58.0. HRMS (ESI) for C15H14N3 [M+H]+: calcd 236.1182, found 236.1189.
N-(1-(4-nitrophenyl)allyl)pyridin-2-amine (1f): Following the general procedure A. Yellow solid
(0.37 g, 48%). m.p. 92-94 oC. 1H NMR (500 MHz, CDCl3): δ 8.20-8.17 (m, 2H), 8.06 (dd, J1 = 5.0 Hz,
J2 = 1.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.41-7.38 (m, 1H), 6.62-6.60 (m, 1H), 6.34 (d, J = 8.5 Hz,
1H), 6.10-6.03 (m, 1H), 5.51 (t, J = 6.5 Hz, 1H), 5.31-5.25 (m, 2H), 5.15 (d, J = 6.5 Hz, 1H). 13C{1H}
NMR (125 MHz, CDCl3): δ 157.2, 149.3, 148.2, 147.2, 137.6, 137.4, 127.9, 123.9, 117.5, 113.9,
107.5, 57.8. HRMS (ESI) for C14H14N3O2 [M+H]+: calcd 256.1081, found 256.1075.
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N-(1-(4-(trifluoromethyl)phenyl)allyl)pyridin-2-amine (1g): Following the general procedure A.
White solid (0.30 g, 36%). m.p. 51-53 oC. 1H NMR (500 MHz, CDCl3): δ 8.09 (d, J = 4.5 Hz, 1H), 7.61
(d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.41-7.38 (m, 1H), 6.63-6.60 (m, 1H), 6.33 (d, J = 8.5 Hz,
1H), 6.11-6.04 (m, 1H), 5.43 (t, J = 6.5 Hz, 1H), 5.29-5.25 (m, 2H), 5.09 (d, J = 5.0 Hz, 1H). 13C{1H}
NMR (125 MHz, CDCl3): δ 157.5, 148.3, 145.7, 137.9, 137.6, 129.6 (q, J = 32.5 Hz), 127.43, 125.6 (q,
J = 3.8 Hz), 124.1 (q, J = 277.5 Hz), 116.9, 113.7, 107.2, 58.1. HRMS (ESI) for C15H14F3N2 [M+H]+:
calcd 279.1104, found 279.1111.
N-(1-(m-tolyl)allyl)pyridin-2-amine (1h): Following the general procedure A. White solid (0.35 g,
52%). m.p. 49-51 oC. 1H NMR (500 MHz, CDCl3): δ 8.10 (dd, J1 = 5.0 Hz, J2 = 1.0 Hz, 1H), 7.41-7.37
(m, 1H), 7.28-7.19 (m, 3H), 7.11 (d, J = 7.5 Hz, 1H), 6.60-6.58 (m, 1H), 6.36 (d, J = 8.5 Hz, 1H),
6.12-6.05 (m, 1H), 5.31-5.23 (m, 3H), 5.04 (d, J = 6.0 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (125 MHz,
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CDCl3): δ 158.0, 148.2, 141.4, 138.7, 138.4, 137.4, 128.6, 128.2, 127.8, 124.1, 115.6, 113.3, 107.0,
58.6, 21.4. HRMS (ESI) for C15H17N2 [M+H]+: calcd 225.1386, found 225.1380.
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N-(1-(3-chlorophenyl)allyl)pyridin-2-amine (1i): Following the general procedure A. White solid
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(0.33 g, 45%). m.p. 68-70 C. H NMR (500 MHz, CDCl3): δ 8.08-8.07 (m, 1H), 7.41-7.37 (m, 2H),
7.28-7.23 (m, 3H), 6.61-6.58 (m, 1H), 6.33 (d, J = 8.5 Hz, 1H), 6.08-6.01 (m, 1H), 5.31 (t, J = 6.5 Hz,
1H), 5.28-5.16 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 157.6, 148.2, 143.7, 137.9, 137.5, 134.5,
129.9, 127.6, 127.2, 125.3, 116.5, 113.5, 107.1, 57.9. HRMS (ESI) for C14H14ClN2 [M+H]+: calcd
245.0840, found 245.0832.
N-(1-(3-nitrophenyl)allyl)pyridin-2-amine (1j): Following the general procedure A. Yellow solid
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(0.44 g, 57%). m.p. 53-55 C. H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 8.12 (dd, J1 = 8.5 Hz, J2 =
1.5 Hz, 1H), 8.06 (dd, J1 = 5.0 Hz, J2 = 1.0 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H),
7.41-7.38 (m, 1H), 6.62-6.60 (m, 1H), 6.37 (d, J = 8.0 Hz, 1H), 6.1-6.05 (m, 1H), 5.54 (t, J = 6.0 Hz,
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1H), 5.32-5.26 (m, 2H), 5.14 (d, J = 6.5 Hz, 1H). C{1H} NMR (125 MHz, CDCl3): δ 157.2, 148.5,
148.2, 144.2, 137.6, 137.5, 133.3, 129.5, 122.4, 122.0, 117.4, 113.9, 107.6, 57.6. HRMS (ESI) for
C14H14N3O2 [M+H]+: calcd 256.1081, found 256.1089.
N-(1-(2-fluorophenyl)allyl)pyridin-2-amine (1k): Following the general procedure A. White solid
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(0.27 g, 40%). m.p. 60-62 C. H NMR (500 MHz, CDCl3): δ 8.10-8.08 (m, 1H), 7.41-7.37 (m, 2H),
7.28-7.23 (m, 1H), 7.13-7.05 (m, 2H), 6.60-6.57 (m, 1H), 6.37 (d, J = 8.5 Hz, 1H), 6.14-6.08 (m, 1H),
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5.67-5.64 (m, 1H), 5.28-5.22 (m, 3H). C{1H} NMR (125 MHz, CDCl3): δ 160.1 (d, J = 245.0 Hz),
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157.6, 148.2, 137.5 (d, J = 11.3 Hz), 129.0 (d, J = 7.5 Hz), 128.5, 128.4 (d, J = 3.8 Hz), 124.4 (d, J =
3.8 Hz), 115.9, 115.7, 115.5, 113.5, 106.8, 52.5 (d, J = 2.5 Hz).
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N-(1-(4-isopropylphenyl)allyl)-5-methylpyridin-2-amine (1m): Following the general procedure
A. Yellow solid (0.60 g, 75%). m.p. 41-43 oC. 1H NMR (500 MHz, CDCl3): δ 7.93 (d, J = 1.5 Hz, 1H),
7.33 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 3H), 6.32 (d, J = 8.5 Hz, 1H), 6.12-6.05 (m, 1H), 5.3-5.21
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(m, 3H), 4.96 (d, J = 6.5 Hz, 1H), 2.95-2.18 (m, 1H), 2.18 (s, 3H), 1.27 (d, J = 7.0 Hz, 3H). C{1H}
NMR (125 MHz, CDCl3): δ 156.2, 147.9, 147.8, 139.0, 138.9, 138.3, 127.0, 126.7, 121.9, 115.3, 106.6,
58.4, 33.7, 23.9, 17.3. HRMS (ESI) for C18H23N2 [M+H]+: calcd 267.1856, found 267.1863.
5-methyl-N-(1-(4-(methylthio)phenyl)allyl)pyridin-2-amine (1n): Following the general
procedure A. White solid (0.36 g, 44%). m.p. 55-57 oC. 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 1.5
Hz, 1H), 7.31-7.29 (m, 2H), 7.24-7.22 (m, 3H), 6.29 (d, J = 8.5 Hz, 1H), 6.08-6.02 (m, 1H), 5.28-5.20
(m, 3H), 5.06 (d, J = 6.0 Hz, 1H), 2.47 (s, 3H), 2.16 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 155.8,
147.2, 138.7, 138.5, 138.5, 137.5, 127.6, 126.9, 122.2, 115.9, 106.9, 58.4, 17.3, 15.9. HRMS (ESI) for
C16H19N2S [M+H]+: calcd 271.1263, found 271.1272.
N-(1-(4-bromophenyl)allyl)-5-methylpyridin-2-amine (1o): Following the general procedure A.
o
1
White solid (0.55 g, 60%). m.p. 96-98 C. H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 1.5 Hz, 1H),
7.47-7.44 (m, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.21 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 6.25 (d, J = 8.5 Hz,
1H), 6.07-6.00 (m, 1H), 5.26-5.22 (m, 3H), 5.03 (d, J = 6.5 Hz, 1H), 2.16 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 155.8, 147.8, 140.8, 138.4, 138.3, 131.7, 128.8, 122.3, 121.1, 116.2, 106.8, 58.1, 17.3.
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HRMS (ESI) for C15H16BrN2 [M+H]+: calcd 303.0491, found 303.0484.
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5-methyl-N-(1-(o-tolyl)allyl)pyridin-2-amine (1q): Following the general procedure A. Yield: 37%.
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White solid (0.26 g, 37%). m.p. 85-87 C. H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 1.5 Hz, 1H),
7.40-7.38 (m, 1H), 7.23-7.19 (m, 4H), 6.24 (d, J = 8.0 Hz, 1H), 6.15-6.08 (m, 1H), 5.47-5.45 (m, 1H),
5.28-5.23 (m, 2H), 4.97 (d, J = 6.5 Hz, 1H), 2.42 (s, 3H), 2.17 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 156.1, 147.8, 139.3, 138.3, 137.8, 136.1, 130.6, 127.3, 126.5, 126.2, 121.8, 115.7, 106.2,
55.1, 19.1, 17.3. HRMS (ESI) for C16H19N2 [M+H]+: calcd 239.1543, found 239.1551.
5-methyl-N-(1-(naphthalen-2-yl)allyl)pyridin-2-amine (1t): Following the general procedure A.
White solid (0.51 g, 62%). m.p. 87-89 oC. 1H NMR (500 MHz, CDCl3): δ 7.94-7.93 (m, 1H), 7.85-7.82
(m, 4H), 7.52 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.21 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz,
1H), 6.32 (d, J = 8.5 Hz, 1H), 6.20-6.14 (m, 1H), 5.43 (t, J = 6.0 Hz, 1H), 5.44-5.27 (m, 2H), 5.07 (d, J
= 6.5 Hz, 1H), 2.16 (s, 3H). C{1H} NMR (125 MHz, CDCl3): δ 156.1, 147.8, 139.0, 138.7, 138.5,
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133.4, 132.8, 128.5, 127.9, 127.6, 126.1, 125.8, 125.7, 125.4, 122.2, 116.1, 106.7, 58.9, 17.4. HRMS
(ESI) for C19H19N2 [M+H]+: calcd 275.1543, found 275.1543.
5-chloro-N-(1-phenylallyl)pyridin-2-amine (1v): Following the general procedure A. White solid
(0.35 g, 48%). m.p. 106-108 oC. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 2.0 Hz, 1H), 7.39-7.37 (m,
4H), 7.35-7.29 (m, 2H), 6.30 (d, J = 9.0 Hz, 1H), 6.11-6.05 (m, 1H), 5.29-5.23 (m, 4H). 13C{1H} NMR
(125 MHz, CDCl3): δ 156.2, 146.5, 141.0, 138.2, 137.2, 128.8, 127.6, 127.1, 120.1, 116.1, 107.8, 58.7.
HRMS (ESI) for C14H14ClN2 [M+H]+: calcd 245.0840, found 245.0840.
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Preparation
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3-iodoimidazo[1,2-a]pyridines
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from
the
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N-(1-arylallyl)pyridin-2-amines with I2O5/H2O. Typical procedure (2a as example):
(1-phenylallyl)pyridin-2-amine 1a (63.0 mg, 0.3 mmol), I2O5 (200.4 mg, 0.6 mmol) were stirred and
heated at 80 ºC in an oil bath for 2 h in mixed solvent (MeCN : H2O = 800 : 1 (V/V), 2 mL). After
completion, the reaction was quenched with saturated aqueous Na2S2O3 (10 mL) and EtOAc (10 mL)
were added to the reaction mixture. The organic phase was separated, and the aqueous phase was
further extracted with EtOAc (2×10 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed and the residue was purified by column chromatography (eluted
with petroleum ether/ethyl acetate = 6:1) to give a pure product 2a ( 57.6 mg, 60%). Other compounds
2b-x were synthesized according to this typical procedure.
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Characterization of the products.
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3-iodo-2-phenylimidazo[1,2-a]pyridine (2a)19a: White solid (57.6 mg, 60%). m.p. 145-147 C. H
NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.0 Hz, 1H), 8.09-8.08 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H),
7.52-7.49 (m, 2H), 7.44-7.40 (m, 1H), 7.30-7.26 (m, 1H), 6.96-6.93 (m, 1H). 13C{1H} NMR (125 MHz,
CDCl3): δ 148.2, 148.1, 133.6, 128.5, 128.4, 128.4, 126.5, 125.6, 117.6, 113.2, 59.5.
3-iodo-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (2b)19a: White solid (47.3 mg, 45%). m.p.
116-118 oC. 1H NMR (500 MHz, CDCl3): δ 8.23-8.21 (m, 1H), 8.04-8.01 (m, 2H), 7.63-7.61 (m, 1H),
7.27-7.24 (m, 1H), 7.04-7.02 (m, 2H), 6.94-6.91 (m, 1H), 3.88 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 159.8, 148.1, 147.9, 129.8, 126.4, 126.0, 125.5, 117.4, 113.8, 113.0, 58.8, 55.3.
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3-iodo-2-(p-tolyl)imidazo[1,2-a]pyridine (2c)19a: White solid (64.1 mg, 64%). m.p. 143-145 C. H
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NMR (500 MHz, CDCl3): δ 8.23 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.63(d, J = 9.0 Hz, 1H),
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7.31(d, J = 8.0 Hz, 2H), 7.28-26 (m, 1H), 6.95-6.92 (m, 1H), 2.43 (s, 3H). C{1H} NMR (125 MHz,
CDCl3): δ 148.2, 148.1, 138.2, 130.7, 129.1, 128.4, 126.5, 125.5, 117.5, 113.1, 59.2, 21.4.
3-iodo-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (2d)18b: White solid (50.2 mg, 42%).
m.p. 151-153 oC. 1H NMR (500 MHz, CDCl3): δ 8.33-8.31 (m, 2H), 8.25 (d, J = 7.0 Hz, 1H), 8.06-8.04
(m, 2H), 7.64 (d, J = 9.5 Hz, 1H), 7.34-7.31 (m, 1H), 7.01-6.98 (m, 1H), 3.12 (s, 3H). C{1H} NMR
13
(125 MHz, CDCl3): δ 148.3, 145.8, 139.8, 139.1, 129.1, 127.4, 126.7, 126.3, 117.9, 113.8, 60.7, 44.6.
4-(3-iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (2e):19a White solid (84.9 mg, 82%). m.p. 181-183
oC. H NMR (500 MHz, CDCl3): δ 8.24-8.22 (m, 3H), 7.76 (d, J = 7.0 Hz, 2H), 7.63 (d, J = 9.0 Hz,
1
1H), 7.33-7.28 (m, 1H), 6.99-6.96 (m, 1H). C{1H} NMR (125 MHz, CDCl3): δ 148.3, 145.8, 138.1,
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132.1, 128.8, 126.6, 126.3, 118.9, 117.9, 113.7, 111.6, 60.5.
3-iodo-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2f): Yellow solid (97.5 mg, 89%). m.p. 192-194
oC. H NMR (500 MHz, CDCl3): δ 8.36-8.31 (m, 4H), 8.28-8.26 (m, 1H), 7.66 (d, J = 9.0 Hz, 1H),
1
7.36-7.33 (m, 1H), 7.03-7.00 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 148.4, 147.5, 145.6, 140.1,
129.0, 126.7, 126.5, 123.7, 118.0, 113.9, 60.9. HRMS (ESI) for C13H9IN3O2 [M+H]+: calcd 365.9734,
found 365.9741.
3-iodo-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (2g):19a White solid (79.2 mg, 68%).
m.p. 123-125 oC. 1H NMR (500 MHz, CDCl3): δ 8.26-8.22 (m, 3H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J
= 9.0 Hz, 1H), 7.33-7.29 (m, 1H), 6.99-6.96 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): 13C{1H}
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NMR (125 MHz, CDCl3): δ 148.3, 146.5, 137.2, 130.1 (q, J = 32.5 Hz), 128.7, 126.6, 126.0, 125.3 (q, J
= 3.8 Hz), 124.2 (q, J = 271.25 Hz), 117.8, 113.6, 60.1.
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3-iodo-2-(m-tolyl)imidazo[1,2-a]pyridine (2h): White solid (38.1 mg, 38%). m.p. 107-109 C. H
NMR (500 MHz, CDCl3): δ 8.23-8.21 (m, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.64-7.61 (m, 1H), 7.40-7.37
(m, 1H), 7.27-7.22 (m, 2H), 6.93-6.90 (m, 1H), 2.46 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
148.1, 148.0, 138.0, 133.4, 129.2, 129.1, 128.1, 126.4, 125.5, 125.5, 117.5, 113.1, 59.5, 21.4. HRMS
(ESI) for C14H12IN2 [M+H]+: calcd 335.0040, found 335.0030.
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2-(3-chlorophenyl)-3-iodoimidazo[1,2-a]pyridine (2i)19a: Pale yellow solid (53.2 mg, 50%). m.p.
147-149 oC. 1H NMR (500 MHz, CDCl3): δ 8.22-8.20 (m, 1H), 8.10 (t, J = 1.5 Hz, 1H), 7.99-7.97 (m,
1H), 7.63-7.61 (m, 1H), 7.4-7.40 ( m, 1H), 7.38-7.36 (m, 1H), 7.29-7.26 (m, 1H), 6.95-6.92 (m, 1H).
13C{1H} NMR (125MHz, CDCl3): δ 148.1, 146.5, 135.4, 134.3, 129.6, 128.5, 128.3, 126.5, 126.5,
125.9, 117.7, 113.4, 59.8.
3-iodo-2-(3-nitrophenyl)imidazo[1,2-a]pyridine (2j): Yellow solid (90.7 mg, 83%). m.p. 151-153
oC. 1H NMR (500 MHz, CDCl3): δ 9.03 (s 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.27-8.25 (m, 2H), 7.67 (t, J =
8.5 Hz, 2H), 7.36-7.32 (m, 1H), 7.02-6.99 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 148.3, 147.3,
145.5, 135.4, 134.2, 129.4, 126.7, 126.3, 123.2, 123.0, 117.9, 113.8, 60.2. HRMS (ESI) for C13H9IN3O2
[M+H]+: calcd 365.9734, found 365.9742.
2-(2-fluorophenyl)-3-iodoimidazo[1,2-a]pyridine (2k): White solid (50.7 mg, 50%). 186-188 oC.
1H NMR (500 MHz, CDCl3): δ 8.19 (d, J = 7.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.63 (d, J = 9.0 Hz, 1H),
7.44-7.39 (m, 1H), 7.28-7.24 (m, 2H), 7.21 (t, J = 9.0 Hz, 2H), 6.94-6.91 (m, 1H). 13C{1H} NMR (125
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MHz, CDCl3): δ 159.8 (d, J = 248.8 Hz), 147.9, 145.3, 132.1 (d, J = 3.8 Hz), 130.4 (d, J = 7.5 Hz),
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126.4, 125.5, 124.0 (d, J = 3.8 Hz), 121.9 (d, J = 15.0 Hz), 117.7, 116.0 (d, J = 22.5 Hz), 113.3, 63.1.
HRMS (ESI) for C13H9FIN2 [M+H]+: calcd 338.9789, found 338.9785.
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3-iodo-6-methyl-2-phenylimidazo[1,2-a]pyridine (2l)29: White solid (73.1 mg, 73%). m.p. 111-113
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oC. H NMR (500 MHz, CDCl3): δ 8.08-8.06 (m, 2H), 7.99 (s, 1H), 7.54-7.47 (m, 3H), 7.41-7.38 (m,
1H), 7.10 (dd, J1 = 9.5 Hz, J2 = 1.5 Hz, 1H), 2.40 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 147.7,
147.2, 133.7, 128.7, 128.4, 128.3, 128.2, 124.3, 123.0, 116.9, 59.0, 18.3.
3-iodo-2-(4-isopropylphenyl)-6-methylimidazo[1,2-a]pyridine (2m): Pale yellow solid (64.7 mg,
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57%). m.p. 148-150 C. H NMR (500 MHz, CDCl3): δ 8.02-8.00 (m, 3H), 7.52 (d, J = 9.0 Hz, 1H),
7.35 (d, J = 8.0 Hz, 2H), 7.10 (dd, J1 = 9.5 Hz, J2 = 2.0 Hz, 1H), 3.01-2.95 (m, 1H), 2.41 (s, 3H), 1.31
13
(d, J = 7.0 Hz, 6H). C{1H} NMR (125 MHz, CDCl3): δ 149.0, 147.8, 147.1, 131.2, 128.5, 128.3,
126.4, 124.2, 122.8, 116.8, 58.6, 34.0, 23.9, 18.4. HRMS (ESI) for C17H18IN2 [M+H]+: calcd 377.0509,
found 377.0505.
3-iodo-6-methyl-2-(4-(methylthio)phenyl)imidazo[1,2-a]pyridine (2n): White solid (76.4 mg,
o
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67%). m.p. 152-154 C. H NMR (500 MHz, CDCl3): δ 8.02-7.99 (m ,3H), 7.51 (d, J = 9.5 Hz, 1H),
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7.37-7.35 (m, 2H), 7.11 (dd, J1 = 9.5 Hz, J2 = 2.0 Hz, 1H), 2.54 (s, 3H), 2.41 (s, 3H). C{1H} NMR
(125 MHz, CDCl3): δ 147.2, 147.2, 138.7, 130.4, 128.7, 128.7, 126.2, 124.2, 123.0, 116.8, 58.7, 18.4,
15.7. HRMS (ESI) for C15H14IN2S [M+H]+: calcd 380.9917, found 380.9915.
2-(4-bromophenyl)-3-iodo-6-methylimidazo[1,2-a]pyridine (2o): White solid (73.1 mg, 59%). m.p.
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150-152 oC. 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.97-7.94 (m, 2H), 7.61-7.58 (m, 2H), 7.51 (d,
J = 10.0 Hz, 1H), 7.11 (dd, J1 = 10.0 Hz, J2 = 5.0 Hz, 1H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
147.2, 146.6, 132.7, 131.5, 129.9, 128.9, 124.3, 123.2, 122.4, 116.9, 59.0, 18.4. HRMS (ESI) for
C14H11BrIN2 [M+H]+: calcd 412.9145, found 412.9139.
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methyl 4-(3-iodo-6-methylimidazo[1,2-a]pyridin-2-yl)benzoate (2p): White solid (84.7 mg, 72%).
134-136 oC. 1H NMR (500 MHz, CDCl3): δ 8.16 (dd, J1 = 16.0 Hz, J2 = 8.5 Hz, 4H), 8.01 (s, 1H), 7.53
13
(d, J = 9.5 Hz, 1H), 7.13 (dd, J1 = 9.0 Hz, J2 = 1.0 Hz, 1H), 3.95 (s, 3H), 2.41 (s, 3H). C{1H} NMR
(125 MHz, CDCl3): δ 167.0, 147.3, 146.5, 138.2, 129.6, 129.5, 129.2, 128.2, 124.3, 123.34, 117.1, 59.8,
52.1, 18.4. HRMS (ESI) for C16H14IN2O2 [M+H]+: calcd 393.0094, found 393.0090.
3-iodo-6-methyl-2-(o-tolyl)imidazo[1,2-a]pyridine (2q): White solid (50. 1 mg, 48%). m.p.
180-182 oC. 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.51 (d, J = 9.5 Hz, 1H), 7.40 (d, J = 7.5 Hz,
1H), 7.35-7.30 (m, 2H), 7.28-7.25 (m, 1H), 7.11 (dd, J1 = 9.0 Hz, J2 = 1.5 Hz, 1H), 2.41 (s, 1H), 2.33 (s,
1H). 13C{1H} NMR (125 MHz, CDCl3): δ 150.1, 146.8, 137.5, 133.5, 130.8, 130.2, 128.5, 128.3, 125.3,
124.1, 122.8, 116.9, 62.1, 20.2, 18.3. HRMS (ESI) for C15H14IN2 [M+H]+: calcd 349.0196, found
349.0191.
2-(2-chlorophenyl)-3-iodo-6-methylimidazo[1,2-a]pyridine (2r): White solid (57.5 mg, 52%). m.p.
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132-134 C. H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.55-7.49 (m, 3H), 7.39-7.34 (m, 2H), 7.13
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(dd, J1 = 9.5 Hz, J2 = 2.0 Hz, 1H), 2.42 (s, 3H). C{1H} NMR (125 MHz, CDCl3): δ 147.9, 146.8,
134.0, 133.2, 132.5, 129.9, 129.8, 128.6, 126.4, 124.1, 123.2, 117.2 , 63.0, 18.3. HRMS (ESI) for
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C14H11ClIN2 [M+H]+: calcd 368.9650, found 368.9647.
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3-iodo-2-(3-methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (2s): White solid (76.5 mg, 70%).
m.p. 141-143 oC. 1H NMR (500 MHz, CDCl3): δ 8.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 2.5
Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 7.39 (t, J = 7.0 Hz, 1H), 7.11 (dd, J1 = 9.0 Hz, J2 = 1.5 Hz, 1H),
6.96-6.94 (m, 1H), 3.90 (s, 3H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 159.5, 147.5, 147.1,
135.0, 129.3, 128.7, 124.3, 123.0, 120.9, 116.9, 114.5, 113.4, 59.2, 55.4, 18.3. HRMS (ESI) for
C15H14IN2O [M+H]+: calcd 365.0145, found 365.0141.
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3-iodo-6-methyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (2t): White solid (65.7 mg, 57%). m.p.
215-217 oC. 1H NMR (500 MHz, CDCl3): δ 8.57 (s, 1H), 8.22 (dd, , J1 = 8.5 Hz, J2 = 1.5 Hz, 1H), 8.05
(s, 1H), 7.97-7.95 (m, 2H), 7.90-7.88 (m, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.53-52 (m, 2H), 7.14 (dd, , J1
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= 9.0 Hz, J2 = 1.0 Hz, 1H), 2.43 (s, 1H). C{1H} NMR (125 MHz, CDCl3): δ 147.7, 147.3, 133.3,
133.1, 131.2, 128.8, 128.5, 127.9, 127.7, 127.7, 126.3, 126.2, 126.2, 124.3, 123.1, 117.0, 59.3, 18.4.
HRMS (ESI) for C18H14IN2 [M+H]+: calcd 385.0193, found 385.0193.
3-iodo-6-methyl-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (2u): White solid (50.2 mg, 50%). m.p.
123-125 oC. 1H NMR (500 MHz, CDCl3): δ 9.33 (d, J = 1.5 Hz, 1H), 8.63 (dd, J1 = 5.0 Hz, J2 = 1.5 Hz,
1H), 8.36-8.34 (m, 1H), 8.00 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.42-7.40 (m, 1H), 7.14 (dd, J1 = 9.0 Hz,
J2 = 1.5 Hz, 1H), 2.42 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 149.4, 149.1, 147.4, 145.0, 135.6,
129.8, 129.1, 124.3, 123.4, 123.2, 117.0, 59.4, 18.4. HRMS (ESI) for C13H11IN3 [M+H]+: calcd
335.9992, found 335.9993.
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6-chloro-3-iodo-2-phenylimidazo[1,2-a]pyridine (2v)18b: White solid (64.8 mg, 61%). m.p. 122-124
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oC. H NMR (500 MHz, CDCl3): δ 8.27-8.26 (m, 1H), 8.06-8.04 (m, 2H), 7.56 (d, J = 9.5 Hz, 1H),
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7.50-7.47 (m, 2H), 7.43-7.40 (m, 1H), 7.21 (dd, J1 = 9.5 Hz, J2 = 2.0 Hz, 1H). C{1H} NMR (125
MHz, CDCl3): δ 148.9, 146.5, 133.1, 128.6, 128.4, 128.4, 126.9, 124.5, 121.5, 117.9, 60.1.
3-iodo-8-methylimidazo[1,2-a]pyridine (2w)18b: White solid (27.1 mg, 35%). m.p. 92-194 C. H
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NMR (500 MHz, CDCl3): δ 7.98 (d, J = 6.5 Hz, 1H), 7.67 (s, 1H), 7.02-7.00 (m, 1H), 6.82 (t, J = 7.0
Hz, 1H), 2.61 (s, 1H). C{1H} NMR (125 MHz, CDCl3): δ 148.0, 139.4, 127.6, 123.8, 123.7, 113.1,
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61.1, 16.5.
2-cyclohexyl-3-iodo-6-methylimidazo[1,2-a]pyridine (2x): White solid (32.7 mg, 32%). m.p.
131-133 oC. 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.01 (dd, J1 = 8.5 Hz,
J2 = 1.5 Hz, 1H), 2.81-2.75 (m, 1H), 2.35 (s, 3H), 1.87-1.85 (m, 4H), 1.80-1.71 (m, 3H), 1.47-1.29 (m,
3H). C{1H} NMR (125 MHz, CDCl3): δ 154.9, 146.8, 127.6, 123.7, 122.3, 116.5, 59.6, 38.0, 32.3,
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26.6, 25.9, 18.2. HRMS (ESI) for C14H18IN2 [M+H]+: calcd 341.0509, found 341.0515.
Gram-scale synthesis of 2a. 1a (1.05 g, 5.0 mmol), I2O5 (3.33 g, 10.0 mmol) were stirred and
heated at 80 ºC in an oil bath for 5 h in mixed solvent (MeCN : H2O = 800 : 1 (V/V), 30 mL). After
completion, the reaction was quenched with saturated aqueous Na2S2O3 (60 mL) and EtOAc (100 mL)
were added to the reaction mixture. The organic phase was separated, and the aqueous phase was
further extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed and the residue was purified by column chromatography (eluted
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with petroleum ether/ethyl acetate = 6:1) to give a pure product 2a (0.73 g, 46%).
Mechanistic studies.
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Probe the possible reaction intermediates.
Synthesis
of
2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde
(3a).
N-(1-phenylallyl)pyridin-2-amine (63.0 mg, 0.3 mmol), I2O5 (200.4 mg, 0.6 mmol), TEMPO (468.1 mg,
3 mmol) were stirred for 2 h in mixed solvent (MeCN : H2O = 800 : 1 (V/V), 2 mL) at 80 ºC. After
completion, the reaction was quenched with saturated aqueous Na2S2O3 (10 mL) and EtOAc (10 mL)
were added to the reaction mixture. The organic phase was separated, and the aqueous phase was
further extracted with EtOAc (2×10 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed and the residue was purified by column chromatography (eluted
with petroleum ether/ethyl acetate = 5:1) to give a pure product 3a30 (50.0 mg, 75%). White solid. m.p.
1
144-145 ºC (lit.5 m.p. 141-143 ºC). H NMR (500 MHz, CDCl3): δ 10.08 (s, 1H), 9.68 (d, J = 7.0 Hz,
1H), 7.85-7.82 (m, 3H), 7.62-7.58 (m, 1H), 7.56-7.52 (m, 3H), 7.16-7.13 (m, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ 179.6, 158.3, 147.7, 132.3, 130.4, 129.8, 128.9, 128.2, 120.8, 117.4, 115.3.
Synthesis of (2-phenylimidazo[1,2-a]pyridin-3-yl)methanol (4a). N-(1-phenylallyl)pyridin-2-amine
(63 mg, 0.3 mmol), I2O5 (200.4 mg, 0.6 mmol) were stirred and heated at 80 ºC in an oil bath for 0.5 h
in mixed solvent (MeCN : H2O = 800 : 1 (V/V), 2 mL). After completion, the reaction was quenched
with saturated aqueous Na2S2O3 (10 mL) and EtOAc (10 mL) were added to the reaction mixture. The
organic phase was separated, and the aqueous phase was further extracted with EtOAc (2×10 mL). The
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combined organic layer was dried over anhydrous Na2SO4. The solvent was removed and the residue
was purified by column chromatography (eluted with petroleum ether/ethyl acetate = 1:1) to give a
pure product 4a (36.0 mg, 50%, ). m.p. 143-145 oC. 1H NMR (500 MHz, DMSO): δ 8.47 (d, J = 7.0 Hz,
1H), 7.86 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.41-7.31 (m, 2H),
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7.01-6.98 (m, 1H), 5.45 (s, 1H), 4.93 (s, 2H). C NMR (125 MHz, DMSO): δ 144.0, 142.8, 134.4,
128.5, 128.2, 127.6, 125.2, 125.0, 120.6, 116.7, 112.1, 52.2. HRMS (ESI) for C14H13N2O [M+H]+:
calcd 225.1022, found 225.1026.
Synthesis of 2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (5a).31,32 A mixture of
pyridin-2-amine (1.41 g, 15 mmol), ethyl benzoylacetate (0.96 g, 5 mmol) and CBr4 (3.3 g, 10 mmol)
o
in 20 mL of acetonitrile was stirred and heated at 80 C in an oil bath for 6 h. The reactions were
completed as monitored by TLC. Product 5a' was isolated by silica gel column chromatography using
petroleum ether/acetone (50:1 to 5:1 (V/V)) in 90% yield as a white solid. Next, to a solution of 5a'
(565.0 mg, 2.5 mmol) in EtOH (3 mL), THF (3 mL) and H2O (3 mL) was added NaOH (200.0 mg, 5
mmol). The mixture was stirred at room temperature overnight. The solvent was removed under
reduced pressure. The residue was acidified by HCl (1N) until pH = 4. The precipitate solid 5a was
collected without further purification (476.0 mg, yield 80%).
Treatment of 3a (or 4a, or 5a) under the standard reaction conditions. A mixture of substrate 3a
(or 4a, or 5a) (0.6 mmol), I2O5 (400.8 mg, 1.2 mmol, 2.0 equiv) in mixed solvent (MeCN : H2O = 800 :
o
1 (V/V), 6 mL) was stirred and heated at 80 C in an oil bath for 2 h. After completion, the reaction
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mixture was detected by TLC and GC-MS analysis. Unfortunately, no product was found in three
reactions.
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Treatment of 3a (or 4a, or 5a) in MeCN-water mixture in the presence of I2. A mixture of
substrate 3a (or 4a, or 5a) (0.6 mmol), I2 (304.8 mg, 1.2 mmol, 2.0 equiv.) in mixed solvent (CH3CN :
o
H2O = 800 : 1 (V/V), 6 mL) was stirred and heated at 80 C in an oil bath for 2 h. The reaction was
cooled down to room temperature. Saturated aqueous Na2S2O3 (10 mL), and EtOAc (10 mL) were
added to the reaction mixture successively. The organic phase was separated, and the aqueous phase
was further extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated. The residue was separated by column chromatography (eluted with
petroleum ether/ethyl acetate = 6:1) to give a pure product 2a (in case of 3a, 2a: 0%; in case of 4a, 2a:
59%; in case of 5a, 2a: 50%).
Isotope experiment. N-(1-phenylallyl)pyridin-2-amine 1a (63 mg, 0.3 mmol), I2O5 (200.4 mg, 0.6
18
mmol) were stirred and heated at 80 ºC in an oil bath for 0.5 h in mixed solvent (MeCN : H2 O = 800 :
1 (V/V), 2 mL). After completion, the reaction was quenched with saturated aqueous Na2S2O3 (10 mL)
and EtOAc (10 mL) were added to the reaction mixture. The organic phase was separated, and the
aqueous phase was further extracted with EtOAc (2×10 mL). The combined organic layer was dried
over anhydrous Na2SO4. The solvent was removed and the residue was purified by column
chromatography (eluted with petroleum ether/ethyl acetate = 1:1) to give a mixture of 4a-18O and 4a
(originated from H2O because water can not be completely excluded). The ESI/APCI-MS spectra of
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4a-18O and 4a were indicated in Figure 1S and Figure 2S, respectively.
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Radical scavenging experiment. N-(1-phenylallyl)pyridin-2-amine 1a (63.0 mg, 0.3 mmol), I2O5
(200.4 mg, 0.6 mmol, ), TEMPO were stirred and heated at 80 ºC in an oil bath for 2 h in mixed solvent
(MeCN : H2O = 800 : 1 (V/V), 2 mL). After completion, the reaction was quenched with saturated
aqueous Na2S2O3 (10 mL) and EtOAc (10 mL) were added to the reaction mixture. The organic phase
was separated, and the aqueous phase was further extracted with EtOAc (2×10 mL). The combined
organic layer was dried over anhydrous Na2SO4. The residue was purified by flash chromatography to
provide 2a and 3a, respectively.
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ASSOCIATED CONTENT
Supporting Information
1
Charts for mechanistic studies as well as copies of H and 13C NMR spectra of the products. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ykuiliu@zjut.edu.cn; jhwei828@zjut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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