Titanium(IV) chloride promoted syntheses of new imidazo[1,2-a]pyridine derivatives under microwave conditions

Article abstract of DOI:10.1055/s-2005-918490

A new method is described for the synthesis of imidazo[1,2-a]pyridine derivatives from the reaction of 2-aminopyridines with α-haloketones. The critical reagent is titanium(IV) chloride, which appears to serve as a strong dehydrating agent to promote formation of putative Schiff base intermediates, which cyclize subsequently to form the products. The reactions were performed rapidly under microwave conditions. Multiple reaction conditions were evaluated, including reaction temperature, solvent and other Lewis acids. Various combinations of substitution patterns in both the α-haloketone and 2-aminopyridine substrates were examined to evaluate the scope of the reaction. The reaction is quite sensitive to substituents in both substrates, especially those with basicity or coordination ability. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918490

PAPER
133
Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridine
Derivatives under Microwave Conditions
T
itanium(IV
)
C
i
hloride
s
-Promote
d
h
Syntheses
o
e
f
N
ew Imid
n
azo[1,2-
a
]p
g
yridine
s
Cai,* Chad Brouwer, Kathryn Sinclair, Jessica Cuevas, Victor W. Pike
PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health,
Building 10, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Fax +1(301)4805112; E-mail: cail@intra.nimh.nih.gov
Received 6 May 2005
R2
R2
R3
Abstract: A new method is described for the synthesis of imida-
zo[1,2-a]pyridine derivatives from the reaction of 2-aminopy-
ridines with a-haloketones. The critical reagent is titanium(IV)
chloride, which appears to serve as a strong dehydrating agent to
promote formation of putative Schiff base intermediates, which cy-
clize subsequently to form the products. The reactions were per-
formed rapidly under microwave conditions. Multiple reaction
conditions were evaluated, including reaction temperature, solvent
and other Lewis acids. Various combinations of substitution pat-
terns in both the a-haloketone and 2-aminopyridine substrates were
examined to evaluate the scope of the reaction. The reaction is quite
sensitive to substituents in both substrates, especially those with ba-
sicity or coordination ability.
O
R3
N
Br
R1
+
R1
N
NH2
N
Scheme 1
isolable products in the identical conditions or other vari-
ations of its kind. Here we report our success in overcom-
ing these limitations by using titanium(IV) chloride as an
auxiliary reagent under microwave conditions. A wide
range of new substituted imidazo[1,2-a]pyridines were
rapidly accessed by this approach.
Keywords: titanium(IV) chloride, imidazo[1,2-a]pyridine, polycy-
clic, condensation, Schiff base formation, microwave
6-Amino-3,4-dihydronaphthalen-1(2H)-one Deriva-
tives
We1 and others2 have been exploring imidazo[1,2-a]pyri-
dine derivatives as ligands that potentially may bind selec-
tively to b-amyloid aggregates,3–5 benzodiazepine
receptors6 or peripheral benzodiazepine receptors (PBR),6
and which may therefore be converted into radiolabeled
probes for imaging these proteins in living brain with
positron emission tomography (PET).7,8 Usually the syn-
thesis of an imidazo[1,2-a]pyridine makes use of the con-
densation between an a-bromocarbonyl compound and a
2-aminopyridine derivative under weak basic conditions.
Three types of bromocarbonyls have been used, including
primary a-bromoketones,1 secondary a-bromoketones,6
and activated a-bromoamides (Scheme 1).9–11 A mecha-
nism for the reaction has been proposed,1 which includes
the nucleophilic substitution of the bromide by the pyri-
dine-nitrogen in the 2-aminopyridine derivative. Other
possibilities exist, such as pre-formation of a Schiff base
before ring-closure to form the final product. These reac-
tion conditions only work when bromo is on a primary
carbon or occasionally on a secondary carbon. However,
when steric hindrance on the secondary carbon is large or
when the products are fused-polycyclic compounds there
is no desired condensation. Reitmann12 condensed 2-ami-
nopyridine with 2-bromo-1-tetralone under the typical
weak basic conditions and the structure of the product was
proved later.13 However, analogous reaction of the 6-ami-
no-2-bromo-1-tetralone derivatives did not generate any
An N-methyl group was introduced at the amido group of
1 by pretreating it with sodium hydride and then reacting
with iodomethane, to generate 2 (Scheme 2).14 Oxidation
of the amide with chromium(VI) oxide gave the ketone
3b,15 with the ketone group para to the amido methyl
group. Dimethylation of the amino group of 415–18 was ac-
complished with iodomethane under basic conditions to
give 3g (Scheme 3).19–22 Formylation of the amino group
of 4 was achieved by heating the compound in formic acid
to generate 3e. Mono-methylation of 4 was possible by
controlling the amount of iodomethane used and the reac-
tion time to give 6.19,21 For the synthesis of both 5 and 7
(Scheme 4), a bromo group was introduced at the sterical-
ly demanding ortho position by using NBS as a selective
brominating agent, as confirmed by the disappearance of
the singlet 1H NMR peak in the aromatic region for both
4 and 6. N-Acylation of 5 and 7 with acetyl chloride under
basic conditions gave 3c and 3d, respectively. Formyla-
tion of the amino group in 6 was also accomplished with
formic acid, but only in the presence of DCC, reflecting
the reduction of reactivity of the amino group caused by
the attached methyl group.
O
NaH
MeI
CrO3
O
O
O
AcOH
Ac2O
N
R2
N
R2
N
H
1
2, R2 = Me (80%)
3a, R2 = H
3b, R2 = Me (50%)
SYNTHESIS 2006, No. 1, pp 0133–0145
x
x
.
x
x
.2
0
0
5
Advanced online publication: 24.11.2005
DOI: 10.1055/s-2005-918490; Art ID: M03405SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

134
L. Cai et al.
PAPER
HCOOH/DCC
or HCOOH
O
O
O
O
HCOOH/DCC
or HCOOH
MeI
R1
H
N
NaHCO3
N
R2
H2N
R2
4
3e, R2 = H (43%)
3f, R2 = Me (20%)
6, R1 = H, R2 = Me (21%)
3g, R1 = R2 = Me (43%)
Scheme 3
involves a two-step sequence.27 The first is the formation
of a,a-dibromoketone, such as 10a. The second is the se-
lective reduction of the dibromide to the mono-bromide.
The a-chloro derivative 9a was synthesized by the dis-
placement of bromide by chloride under anhydrous condi-
tions. Lithium chloride is the agent of choice for this
reaction with negligible by-product formation.
O
O
O
O
MeCOCl
TEA
NBS
N
HN
R2 Br
HN
R2
R2 Br
4, R2 = H
6, R2 = Me
5, R2 = H (82%)
7, R2 = Me (90%)
3c, R2 = H (60%)
3d, R2 = Me (46%)
Scheme 4
2-Aminopyridine Derivatives
6-Amino-2-bromo-3,4-dihydronaphthalen-1(2H)-
Except for some commercially available 2-aminopy-
ridines, others were synthesized through electrophilic
substitution or nucleophilic substitution of halide in the
pyridine ring (Scheme 6). Copper(I) cyanide was used to
introduce the cyano group in the synthesis of 11.28–30 Bro-
mination of 11 affords 12, showing the dominant para di-
recting effect of the amino group. Although the syntheses
of 1331,32 have been reported, these made use of copper as
catalyst and methanol as solvent at 150 °C under pres-
sure.11 The inconvenience of the procedure prompted us to
evaluate other solvents to replace the low boiling metha-
nol. Ethylene glycol was an excellent choice for this reac-
tion, giving high yield in a short reaction time. The
benefits of ethylene glycol as solvent in other copper or
copper(I)-catalyzed reaction have been noted.33
one Derivatives
Three types of brominating agents were adopted for the
synthesis of this type of a-bromo compounds (Scheme 5).
The first brominating agent was tetra-n-butylammonium
tribromide (Bu4NBr3),23 which was used successfully in
the syntheses of 8a,24 8c,24 and 8d. The mixed solvent of
dichloromethane and methanol is critical for the selective
formation of the mono-bromides. Either pure dichlo-
romethane or methanol promoted dibromide formation.
When tetra-n-butylammonium tribromide failed to give
the desired monobromides, a second brominating agent
was used, namely copper(II) bromide.25,26 This method
was used for the synthesis of 8b and 8e. When both meth-
ods described above failed, a third strategy was used. This
O
O
O
Cl
Br
(n-Bu)4NBr3
or CuBr2
LiCl
R1
N
R1
R1
N
N
R2 R3
R2 R3
R2 R3
3a, R1 = Ac, R2 = H, R3 = H
3b, R1 = Ac, R2 = Me, R3 = H
3c, R1 = Ac, R2 = H, R3 = Br
3d, R1 = Ac, R2 = Me, R3 = Br
3e, R1 = Formyl, R2 = H, R3 = H
9a (67%)
8a ( 34%)
8b (30%)
8c (26%)
8d (56%)
8e (24%)
O
O
O
Br
Br
Br
Br2
(EtO)2PH(O)
TEA
R1
R1
H2SO4
R1
N
N
N
R2 R3
R2 R3
R2 R3
3a, R1 = Ac, R2 = H, R3 = H
3f, R1 = Formyl, R2 = Me, R3 = H
3g, R1 = Me, R2 = Me, R3 = H
8f (79%)
8g (42%)
10a (40%)
Scheme 5
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

PAPER
Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
135
Br
170 °C, 30 s, 300 W, 300 psi; Method B: 110 °C, 30 min,
300 W, 300 psi) were used. The Lewis acids examined in-
cluded zinc chloride, tin(IV) chloride, tetra(dimethylami-
no)titanium(IV) and titanium(IV) chloride. The first two
gave no products at all. The third gave a complicated mix-
ture. Only titanium(IV) chloride gave appreciable
amounts of product. This will be the only agent to be dis-
cussed. A group of chlorinated solvents was selected and
evaluated. A high boiling solvent was desirable to en-
hance the solubility of the substrates and to allow the re-
action at elevated temperatures. Among the evaluated
chlorinated solvents (CHCl3, CCl3CH2Cl, CHCl2CH2Cl,
CHCl2CHCl2, and CHCl2CCl3), both chloroform and
1,1,2-trichloroethane gave better results, and were used in
subsequent reactions. TiCl4 in dichloromethane was used,
with no effort to remove the small amount of dichlo-
romethane.
Br2
CuCN
Br
I
N
NH2
N
NH2
N
NH2
N
N
12 (83%)
11 (53%)
S
NaSEt
Cu
N
NH2
N
NH2
Ethylene glycol
13 (76%)
Scheme 6
Reaction of a-Bromotetralone with 2-Aminopyridine
Derivatives
Taking the condensation reaction of 8c and 5-bromo-2-
aminopyridine as an example (Table 1), the effect of vary-
ing the temperature (microwave), Lewis acids, and sol-
vent on the reaction was evaluated to establish optimal
conditions for other substrates. A microwave device was
utilized as a convenient and practical source of energy for
the condensation reactions. Two conditions (Method A:
The reactions are shown in Table 1. Most of the reactions
go smoothly, giving low to moderate yields. Substitutents
in either the tetralone or the 2-aminopyridine have a sig-
nificant effect on the yield and speed of the reaction. 2-
Aminopyridine and substituted 2-aminopyridines, includ-
Table 1 Reaction of a-Bromotetralones with 2-Aminopyridine Derivatives
O
R3
Br
R
1
N
R2
R1
TiCl4
5
R1
+
N
R
CHCl3
N
4
N
R2 R3
N
NH2
3
Microwave
R
R1
R2
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
R3
H
Method
Product
Yield (%)
6-Br
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me
Ac
Ac
Ac
Ac
Ac
Ac
Ac
A or B
0
0
6-CN
H
A or B
6-CN, 5-Br
5-CN
5-NO2
5-I
H
A or B
0
H
A or B
0
H
A or B
0
H
B
A
B
B
B
A
B
B
B
B
A
B
14a
14c
15a
15c
15g
17c
18a
18c
19a
19c
20a
20c
22
9
5-I
Br
H
5-Br
17
22
46
24
30
32
45
18
0
5-Br
Br
H
5-Br
5-SEt
H
Br
H
H
Br
H
4-OEt
4-OEt
3-OBn
3-OBn
Br
H
Br
22
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

136
L. Cai et al.
PAPER
ing 5-iodo, 5-bromo, 5-ethylthio, 4-ethoxy and 3-benzyl- high yield (Scheme 9). Other six-membered a-bromo and
oxy derivatives, undergo the reactions, with the electron- a-chloroketones reacted with 2-aminopyridine derivatives
donating substituents giving better yields and faster reac- to give the desired products 22 and 23 (Scheme 10) at low
tions. Electron-withdrawing groups, such as cyano and ni- to moderate yield. Compound 23 could also be generated
tro groups inhibit the reaction and so does any substituent without TiCl4, without or with a variety of solvents (incl.
in 6-position, such as 6-bromo or 6-cyano group. The ef- EtOH, n-BuOH, MeCN, DMF, or DMSO). However,
fect of substituents in the bromotetralone derivatives dif- five-membered a-bromoketones did not give any prod-
fers according to their positions in the ring system. A ucts, although analogous compounds have been synthe-
substituent in 5-position of the dihydronaphthalene ring sized using other methods.34–40 The preference of fused
appears to have minimal effect on the reaction, except for six- and five-membered rings over two five-membered
a change in solubility of the starting materials and prod- rings in the expected products is reflected in part in the re-
ucts. However, substituents on the 6-amino group have actions involving a-bromoketones in open chains
significant impact on the reaction. We have evaluated (Scheme 11). These reactions gave overall much better
acetyl, formyl and methyl substituents. Changing from an yield, up to 90% in selected cases, such as 2441–44 and
acetyl group to a formyl group alters the reactivity dra- 25.45–47 Tertiary a-bromoketones did not give any prod-
matically. Substrates with a formyl group gave much ucts, even with a secondary bromo group at the b-position.
more complicated reactions. At least in one case, instead
of the normal product, we isolated 18f, an hydrogen chlor-
O
TiCl4
N
O
Br
ide addition product of the expected tetracyclic compound
(Scheme 7). Hydrochloride adducts of expected products
were also observed in small amount in other reactions.
When the substituents on 6-amino group were dimethyl
groups, the reaction shifted in a different direction. Except
for the expected product, 15g, we also observed the dehy-
drogenated aromatized product, 16, with the ratio of 3:1
(15g:16). The mixture of 15g and 16 was transformed
cleanly to pure 16 with DDQ (Scheme 8). It appears that
the strong electron-releasing dimethylamino group favors
the dehydrogenation of the newly formed ring. The mech-
anism is unclear at this time.
+
CHCl3
N
N
NH2
O
Microwave at 110 °C
21 (75%)
Scheme 9
TiCl4/CHCl3/
Microwave at 110 °C
O
R
N
R
Cl
+
N
or neat using microwave
NH2 at 180 °C
N
22, R = Br (2.2%)
23, R = H (50%)
Scheme 10
O
N
H
Cl
H
TiCl4
N
R
8f
+
N
CH2ClCHCl2
170 °C
O
N
N
NH2
Br
Method A or B
N
18f (33%)
+
R
N
NH2
24, R = Ph (90%)
25, R = Me (65%)
O
Cl
H
H
N
Scheme 11
N
N
18fi, Not isolated
Mechanistic Implications
Scheme 7
The proposed mechanistic model for TiCl4-promoted con-
densation is shown in Scheme 12. This model differs from
that proposed previously for the normal synthesis of imi-
dazo[1,2-a]pyridines under slightly basic conditions.1 Ti-
tanium(IV) chloride has been shown to be an efficient
promoter for Schiff base formation from ketones and ami-
no-compounds under mild conditions.48–50 The presumed
first intermediate I in Scheme 12 can proceed in two pos-
sible routes, to generate either II or the Schiff base inter-
mediate IV. Intermediate IV undergoes cyclization to
give intermediate V, which would generate the normal
‘Product 1’. Intermediate II would react similarly to give
abnormal ‘Product 2’. Both pathways are possible routes
for semi-ketal chemistry. It appears that higher tempera-
ture favors the second route, as Method A (in experimen-
tal section) normally gave various amounts of ‘Product
Br
N
Br
N
DDQ
N
N
N
N
15g
16 (47%)
Scheme 8
Reaction of Other a-Bromoketones with 2-Aminopy-
ridine Derivatives
Other a-bromo tetralones gave analogous reactions in the
presence of titanium(IV) chloride. For example, 2-bromo-
3,4-dihydro-7-methoxynaphthalen-1(2H)-one
with 2-aminopyridine to give the desired product, 21, in
reacted
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

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Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
137
HBr
N
N
N
HN
N
N+
Br-
Br
H
R
R
N
N
R
N
IV
Product 1
V
TiCl3(OH) + HCl
TiCl4
N
O
NH
HO
Br
H
Br
H
R
R
N
N
I
TiCl4
TiCl3(OH)
HBr
N
N
HN
Cl
Cl
N+
H
N
NH
Cl
H
Br
H
R
R
Br-
N
N
R
N
Product 2
III
II
Scheme 12
2’. Under basic conditions, such as treatment with aque- ethane are the best solvents, 110–170 °C the optimal
ous potassium carbonate solution, ‘Product 2’ transforms temperature range and titanium(IV) chloride the best
into ‘Product 1’.
Lewis acid of those so far tested. A variety of substrates
have been examined, giving poor to moderately high reac-
tion yields. Based on the isolated products, we have pro-
posed an overall reaction mechanism to explain the
experimental facts. The main feature of this proposal is
that the titanium(IV) chloride promotes Schiff base for-
mation preceding cyclization on to the final product. In se-
lected cases, a novel semi-ketal intermediate was trapped
before proceeding to new imidazo[1,2-a]pyridines. Sever-
al of these derivatives, especially the quite rigid and al-
most planar tetracyclic compounds, are now of further
interest for potential conversion into radioligands for PET
imaging.
An alternative mechanism, such as an elimination-addi-
tion mechanism with subsequent enamine-enamine rear-
rangement,51,52 is unlikely, since the elimination
intermediate would rearrange into a naphthol, which
would be inactive under the reaction conditions. The elim-
ination reaction would be possible as a pathway to by-
products, rationalizing the relative low yields of the
present reaction.
An alternative explanation for the observation of ‘Prod-
uct 2’ may be that ‘Product 1’ reacts with hydrogen chlo-
ride generated in the reaction media, to form the hydrogen
chloride adduct. If that is the case, we should expect to ob-
serve a different product, as shown in Scheme 13, since
the nitrogen at the N2 position should stabilize the devel-
oping charge on adjacent carbon more efficiently than that
at the N1 position. However, the 1H NMR spectrum of the
isolated product showed clearly strongly coupled protons,
as expected for 18f. Compound 18fi was not observed as
a product. This is against the argument that the product
18f arises from hydrogen chloride addition.
N1
Cl
N2
O
H
H
N
N
N
18f (observed)
O
HCl
H
N
N1
H
N2
O
In conclusion, we have developed a new method for the
synthesis of imidazo[1,2-a]pyridines, in terms of reaction
conditions and reaction scope. Good reaction conditions
were established, with respect to reaction solvent, temper-
ature and Lewis acid. Chloroform and 1,2,2-trichloro-
Cl
H
N
18fi
Scheme 13
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

138
L. Cai et al.
PAPER
N-(1,2,3,4-Tetrahydronaphthalen-7-yl)acetamide53,54
(1),
N-
EI-MS: m/z (%) = 283.0 (15), 281.0 (15), [M]+, 241.0 (40), 239.0
(40) [M + H – CH3CO]+, 213.0 (48), 211.0 (48) [M + H – CH3CO –
CO]+, 202.1 (100) [M – Br]+, 130.1 (11), 104.1 (22), 77.0 (11), 56.0
(30) [CH2CO – N]+.
HRMS (TOF+): m/z calcd for C12H12BrNO2: 283.0031; found:
283.0031.
(1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acetamide53 (3a) and 6-
amino-3,4-dihydronaphthalen-1(2H)-one53 (4) were synthesized as
reported or purchased from Pharmaron (Louisville, KY). 2-Bromo-
3,4-dihydro-7-methoxynaphthalen-1(2H)-one and 6-bromo-2-ami-
nopyridine were purchased from Aldrich (Milwaukee, WA). All
compounds synthesized have been purified by either column chro-
matography or preparative HPLC until their purity was greater than
95% as judged by analytical HPLC. lH NMR and 13C NMR spectra
were acquired on a 300, 400 or 500 MHz spectrometer (Bruker) us-
ing the chemical shifts of residual deuterated solvent as internal
standard; chemical shifts (d) for proton and carbon resonances are
reported in parts per million (ppm) relative to the internal standard.
High-resolution mass spectra (HRMS) were acquired from Mass
Spectrometry Laboratory, University of Illinois at Urbana-Cham-
paign (Urbana, IL). Low-resolution mass spectra were acquired
with either LCQDECA LC-MS (Thermo Finnigan) equipped with an
MS-HPLC column: (Luna C18; 5 mm; 2.0 × 150 mm; Phenomenex)
eluted at 150 mL/min with a MeOH–H2O mixture or with a PolarisQ
GC-MS (Thermo Finnigan) equipped with a capillary RTX-5ms
column (30 m × 0.25 mm) and helium (1 mL/min) as carrier gas.
Melting points were determined using Electrothermal Mel-Temp
Manual Melting Point Apparatus (Fisher Scientific) and are uncor-
rected. Elemental analyses were performed by Midwest Microlab
(Indianapolis, IN) or Galbraith Laboratories, Inc. (Knoxville, TN).
A CEM Discover microwave system was used (Matthews, NC).
N-(5-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-
methylacetamide (3d)
5-Bromo-3,4-dihydro-6-(methylamino)naphthalen-1(2H)-one (7;
15.4 g, 60.6 mmol) was dissolved in CH2Cl2 (200 mL). TEA (8.30
g, 82.2 mmol) was added. Acetyl chloride (5.70 g, 72.6 mmol) was
added dropwise. The progress of the reaction was monitored by
TLC. After the reaction had ended, the organic layer was washed
with H2O and dried. The solvent was removed and the residue was
separated by column chromatography on silica gel (EtOAc–hex-
anes; 1:1) to afford 3d as a white solid (8.2 g, yield: 46%); mp 114–
116 °C.
1H NMR (300 MHz, CDCl3): d = 8.12 (d, 3JHH = 8.3 Hz, 1 H, ArH),
3
7.29 (d, JHH = 6.1 Hz, 1 H, ArH), 3.20 (s, 3 H, NCH3), 3.10 (t,
3JHH = 6.1 Hz, 2 H, CH2), 2.69 (t, 3JHH = 6.6 Hz, 2 H, CH2), 2.50 (m,
2 H, CH2CH2CH2), 1.83 (s, 3 H, CH3).
EI-MS: m/z (%) = 283.0 (15), 281.0 (15) [M]+, 241.0 (40), 239.0
(40) [M + H – CH3CO]+, 255.0 (32), 253.0 (32) [M + H – CH3CO]+,
241.0 (81), 239 (81) [M + H – CH3CO – CH3 + H]+, 227.0 (32),
225.0 (32) [M + H – CH3CONCH3 + H]+, 216.0 (64) [M – Br]+,
213.0 (100), 211.0 (100) [M + H – CH3CO – CH3 – CO + H]+, 185.0
(11), 183.0 (11) [M + H – CH3CO – CH3 – CO – C2H4 + H]+, 161.1
(10), 149.0 (46), 130.1 (21), 115.1 (12), 104.1 (55), 77.0 (24), 62.0
(84).
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)-N-methylacet-
amide (3b)15
N-(1,2,3,4-Tetrahydronaphthalen-7-yl)-N-methylacetamide
(2;
15.8 g, 83.5 mmol) was dissolved in AcOH (38 mL) plus Ac2O (50
mL) to form solution A. Chromium(VI) oxide (7.90 g, 79.0 mmol)
was dissolved in H2O (8.7 mL) and AcOH (34.8 mL) to form solu-
tion B. Solution B was added dropwise to solution A at 0 °C, stirred
at that temperature for 1 h, and then stirred at r.t. overnight. The re-
action mixture was filtered and the filtrate was extracted with
CH2Cl2. The organic phase was collected. After drying and removal
of the solvent, the crude solid was purified using column chroma-
tography on silica gel (EtOAc–hexanes, 3:1) to afford 3b as a white
solid (8.4 g, 50% yield). The unreacted starting material was recov-
ered from chromatography and reused; mp 80–82 °C.
HRMS (TOF+): m/z calcd for C13H15BrNO2: 296.0286; found:
296.0296.
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)formamide (3e)
6-Amino-3,4-dihydronaphthalen-1(2H)-one (4; 30.0 g, 0.186 mol)
was added to formic acid (150 mL). The reaction mixture was re-
fluxed for 3 h. After the reaction ended, formic acid was removed
under reduced pressure. Crunched ice was added. Oily material pre-
cipitated and solidified. The crude material was extracted into
CH2Cl2 and the organic phase was dried over Na2SO4. After filtra-
tion, the solvent was removed to afford the crude product. The com-
pound was further purified by column chromatography on silica gel
(CHCl3–MeOH, 50:1) to obtain 3e as a white solid (15 g, yield:
43%), as a mixture of cis and trans isomers; mp 134–136 °C.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, 3JHH = 8.1 Hz, 1 H, ArH),
7.14 (s, 1 H, ArH), 7.10 (d, 3JHH = 5.6 Hz, 1 H, ArH), 3.28 (s, 3 H,
NCH3), 2.98 (t, 3JHH = 5.9 Hz, 2 H, CH2), 2.68 (t, 3JHH = 6.4 Hz, 2
H, CH2), 2.17 (m, 2 H, CH2CH2CH2), 1.96 (s, 3 H, COCH3).
EI-MS: m/z (%) = 217.1 (70) [M]+, 175.1 (100) [M + H – CH3CO]+,
3
1H NMR (300 MHz, CDCl3): d = 8.87 (d, JHH = 11.2 Hz, 0.5 H,
147.1 (45) [M + H – CH3CO – CO]+, 56.0 (30) [CH2CO – N]+.
ArH), 8.44 (s, 1 H, HCO), 8.04 (d, 3JHH = 8.6 Hz, 0.5 H, ArH), 8.01
(d, 3JHH = 8.5 Hz, 0.5 H, ArH), 7.72 (br s, 1 H, NH), 7.36 (br s, 0.5
H, ArH), 6.99 (d, 3JHH = 8.3 Hz, 0.5 H, ArH), 6.92 (s, 0.5 H, ArH),
2.94–2.98 (m, 2 H, CH2), 2.62–2.67 (m, 2 H, CH2), 2.09–2.18 (m, 2
H, CH2CH2CH2).
HRMS (TOF+): m/z calcd for C13H15NO2: 217.1103; found:
217.1097.
N-(5-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acet-
amide (3c)
EI-MS: m/z (%) = 189.1 (86) [M]+, 161.1 (100) [M + H – HCO]+,
147.0 (27) [M + H – HCONH + H]+, 133.1 (22), 105.1 (20), 77.0
(15), 62.0 (67).
HRMS (TOF+): m/z calcd for C11H11NO2: 189.0790; found:
189.0790.
6-Amino-5-bromo-3,4-dihydronaphthalen-1(2H)-one (5; 34.0 g,
142 mmol) was dissolved in CH2Cl2 (500 mL). The solution was
cooled to 0 °C with an ice bath. Acetyl chloride (16.7 g, 213 mmol)
and Et3N (TEA; 21.4 g, 212 mmol) were added dropwise to the
above solution. The reaction mixture was allowed to warm to r.t.
and stirred for 2 h. H2O was added to wash the organic phase. The
collected organic phase was dried and the solvent was removed. The
obtained solid was recrystallized from CH2Cl2–petroleum ether to
afford 3c as a white solid (24 g, yield: 60%); mp 174–176 °C.
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)-N-methylform-
amide (3f)
Formic acid (4.40 g, 95.6 mmol) was dissolved in CHCl3 (42 mL).
The solution was cooled to 5 °C using an ice-bath. N,N¢-Dicyclo-
hexylcarbodiimide (DCC, 7.00 g, 33.9 mmol) in CHCl3 (34 mL)
was added dropwise. After addition, the solution was stirred for an-
other 5 min and produced a white precipitate. 3,4-Dihydro-6-(meth-
ylamino)naphthalen-1(2H)-one (6; 3.00 g, 17.1 mmol) in pyridine
(15 mL) was added dropwise. The mixture was warmed to r.t. and
1H NMR (300 MHz, CDCl3): d = 8.41 (d, 3JHH = 8.7 Hz, 1 H, ArH),
3
8.06 (d, JHH = 8.8 Hz, 1 H, ArH), 7.91 (br s, 1 H, NH), 3.02 (t,
3JHH = 6.1 Hz, 2 H, CH2), 2.63 (t, 3JHH = 6.6 Hz, 2 H, CH2), 2.28 (s,
3 H, CH3), 2.17 (m, 2 H, CH2CH2CH2).
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

PAPER
Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
139
stirred for 4 h. The mixture was filtered and the solvent was re-
moved from the filtrate to give the crude product, which was further
purified by column chromatography on silica gel (EtOAc–hexanes,
1:5) to afford 3f as a white solid (1.0 g, yield: 20%); mp 71–73 °C.
2.99 (s, 3 H, NCH3), 2.65 (t, 3JHH = 6.6 Hz, 2 H, CH2), 2.14 (m, 2 H,
CH2CH2CH2).
EI-MS: m/z (%) = 255.0 (27), 253.0 (27) [M]+, 241.0 (79), 239.0
(79) [M + H – CH3 – H]+, 227 (22), 225 (22) [M – CO]+, 213.0
(100), 211.0 (100) [M + H – CO – C2H4]+, 185.0 (10), 183.0 (10) [M
+ H – CO – 2 × C2H4]+, 175.1 (15), 147.1 (12), 130.1 (17), 104.1
(51), 77.1 (20), 62.1 (63).
1H NMR (400 MHz, CDCl3): d = 8.67 (s, 1 H, HCO), 8.10 (d, 3JHH
=
8.5 Hz, 1 H, ArH), 7.14 (dd, 3JHH = 8.5 Hz, 4JHH = 2.0 Hz, 1 H, ArH),
7.05 (s, 1 H, ArH), 3.36 (s, 3 H, CH3), 3.01 (t, 3JHH = 6.0 Hz, 2 H,
CH2), 2.69 (t, 3JHH = 6.5 Hz, 2 H, CH2), 2.18 (pent, 3JHH = 6.3 Hz, 2
H, CH2CH2CH2).
HRMS (TOF+): m/z calcd for C11H12BrNO: 253.0102; found:
253.0095.
EI-MS: m/z (%) = 203.1 (100) [M]+, 175.1 (71), [M + H – HCO]+,
162.1 (12), 147.1 (26) [M + H – HCONCH3 + H]+, 134.1 (25), 118.1
(17), 91.1 (10).
N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acet-
amide (8a)24
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)acetamide (3a; 7.20
g, 35.4 mmol) was dissolved in CH2Cl2–MeOH (1:1, 200 mL). Tet-
ra-n-butylammonium tribromide (18.8 g, 39.0 mmol) was added in
one portion. The reaction mixture was stirred at r.t. for 1 h. Progress
of the reaction was monitored by TLC. As soon as by-products be-
gan to appear, the reaction was stopped. The solvent was removed
and the product was separated by column chromatography on silica
gel (EtOAc–hexanes, 4:1) to afford 8a as a pale brown solid (3.4 g,
yield: 34%); mp 166–168 °C.
1H NMR (400 MHz, CDCl3): d = 8.03 (d, 3JHH = 8.6 Hz, 1 H, ArH),
7.75 (s, 2 H, ArH, NH), 7.25 (d, 3JHH = 8.6 Hz, 1 H, ArH), 4.70 (t,
3JHH = 4.3 Hz, 1 H, CHBr), 3.27 (m, 1 H, CH2), 2.89 (m, 1 H, CH2),
2.47 (m, 2 H, CH2), 2.22 (s, 3 H, CH3).
EI-MS: m/z (%) = 283.1 (3), 281.1 (3) [M]+, 241.0 (79), 239.0 (7)
[M + H – CH3CO]+, 213.1 (5), 211.1 (5) [M + H – CH3CO – CO]+,
203.1 (13) [M – Br]+, 161.1 (15) [M + H – Br – CH3CO + H]+, 133.1
(21), [M + H – Br – CH3CO + H – CO]+, 103.1 (6), 77.1 (6), 62.0
(100).
HRMS (TOF+): m/z calcd for C12H12BrNO2: 283.0031; found:
283.0035.
HRMS: (TOF+): m/z calcd for C12H13NO2: 203.0946; found:
203.0944.
6-(Dimethylamino)-3,4-dihydronaphthalen-1(2H)-one (3g)
6-Amino-3,4-dihydronaphthalen-1(2H)-one (4; 3.80 g, 23.6 mmol),
iodomethane (8.32 g, 58.6 mmol) and NaHCO3 (4.40 g, 52.4 mmol)
were suspended in EtOH (100 mL). The reaction mixture was re-
fluxed in the dark until TLC showed complete conversion. The sol-
vents were removed under reduced pressure. The residue was
extracted using CH2Cl2 and washed wtih H2O. The organic layer
was dried (MgSO4). The solvent was removed to afford 3g as a
white solid (1.9 g, yield: 43%); mp 73–75 °C.
1H NMR (300 MHz, CDCl3): d = 7.95 (d, 3JHH = 8.9 Hz, 1 H, ArH),
6.59 (d, 3JHH = 5.6 Hz, 1 H, ArH), 6.39 (s, 1 H, ArH), 3.05 (s, 6 H,
NCH3), 2.87 (t, 3JHH = 6.0 Hz, 2 H, CH2), 2.56 (t, 3JHH = 6.3 Hz, 2
H, CH2), 2.08 (m, 2 H, CH2CH2CH2).
EI-MS: m/z (%) = 189.1 (100) [M]+, 161.1 (100) [M + H – 2 × CH3
+ H]+, 147.1 (7) [M + H – 2 × CH3 + H]+, 133.1 (11), 62.1 (21).
HRMS: (TOF+): m/z calcd for C12H15NO: 189.1154; found:
189.1158.
N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-
methylacetamide (8b)
6-Amino-5-bromo-3,4-dihydronaphthalen-1(2H)-one (5)
6-Amino-3,4-dihydronaphthalen-1(2H)-one (4; 28.0 g, 174 mmol)
was suspended in CH2Cl2 (1 L) and the mixture was cooled to 0 °C.
NBS (31.0 g, 174 mmol) was added in portions. The reaction was
allowed to warm to r.t. After 2 h, a solid precipitated out. H2O was
added into the mixture, and the organic layer was separated and
dried. Removal of the solvent generated a pale brown solid 5 (34 g,
yield: 82%); mp 186–188 °C.
1H NMR (300 MHz, CDCl3): d = 7.93 (d, 3JHH = 8.6 Hz, 1 H, ArH),
6.75 (d, 3JHH = 8.5 Hz, 1 H, ArH), 3.00 (t, 3JHH = 6.2 Hz, 2 H, CH2),
2.59 (t, 3JHH = 6.6 Hz, 2 H, CH2), 2.14 (m, 2 H, CH2CH2CH2).
EI-MS: m/z (%) = 241.0 (90), 239.0 (90) [M]+, 213.0 (100) [M –
CO]+, 185.0 (12), 183.0 (12) [M – CO – C2H4]+, 160.1 (5), 143.1 (8),
130.1 (16), 117.1 (5), 104.1 (49), 77.0 (17), 65.0 (12).
HRMS: (TOF+): m/z calcd for C10H10BrNO: 238.9946; found:
238.9949.
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)-N-methylacetamide
(3b; 1.00 g, 4.60 mmol) was dissolved in THF (10 mL). Copper(II)
bromide (2.06 g, 9.22 mmol) was added. The reaction mixture was
refluxed for 2.5 h. After cooling to r.t., the mixture was filtered and
the solid was washed with THF. After removing the solvent, the res-
idue was purified using silica gel column chromatography (EtOAc–
hexanes, 3:1) to give 8b as a pale brown solid (0.30 g, yield: 30%);
mp 72–74 °C.
1H NMR (400 MHz, CDCl3): d = 8.15 (d, 3JHH = 8.3 Hz, 1 H, ArH),
7.19 (d, 3JHH = 8.4 Hz, 1 H, ArH), 7.14 (s, 1 H, ArH), 4.74 (t, 3JHH
=
3.9 Hz, 1 H, CHBr), 3.31 (s, 3 H, NCH3), 3.10–3.15 (m, 1 H, CH2),
2.91–2.97 (m, 1 H, CH2), 2.49–2.56 (m, 2 H, CH2), 2.00 (s, 3 H,
CH3).
N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8c)24
N-(5-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acetamide
(3c; 17.4 g, 61.7 mmol) and tetra-n-butylammonium tribromide
(29.7 g, 61.6 mmol) were dissolved in CH2Cl2–MeOH (1:1, 500
mL). The reaction was refluxed for 3 h and monitored by TLC. At
the end of the reaction, the solvent was removed and the solid was
extracted (EtOAc–hexanes, 1:1). After removing the solvent, the
residue was purified using silica gel column chromatography
(EtOAc–hexanes, 1:1) to give 8c as a pale brown solid; (5.7 g, yield:
26%); mp 141–143 °C.
5-Bromo-3,4-dihydro-6-(methylamino)naphthalen-1(2H)-one
(7)
3,4-Dihydro-6-(methylamino)naphthalen-1(2H)-one (6; 12.0 g,
68.5 mmol) was dissolved in CH2Cl2 (300 mL). The solution was
heated under reflux. NBS (12.0 g, 68.2 mmol) was added in por-
tions. After addition, the reaction mixture was stirred at r.t. for 20
min. The solution was washed with H2O. The organic layer was
dried and the solvent was removed. The solid was dissolved in
CH2Cl2 and washed with H2O again. The organic layer was dried,
and the solvent was removed to afford 7 as a white solid (15.6 g,
yield: 90%); mp 187–189 °C.
1H NMR (300 MHz, CDCl3): d = 8.46 (d, 3JHH = 8.8 Hz, 1 H, ArH),
3
8.09 (d, JHH = 8.8 Hz, 1 H, ArH), 7.94 (br s, 1 H, NH), 4.68 (t,
3JHH = 4.1 Hz, 1 H, CHBr), 3.04–3.24 (m, 2 H, CH2), 2.48–2.58 (m,
1H NMR (300 MHz, CDCl3): d = 8.02 (d, 3JHH = 8.6 Hz, 1 H, ArH),
6.58 (d, 3JHH = 8.5 Hz, 1 H, ArH), 2.99 (t, 3JHH = 6.2 Hz, 2 H, CH2),
2 H CH2), 2.29 (s, 3 H, CH3).
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

140
L. Cai et al.
PAPER
EI-MS: m/z (%) = 363.0 (3), 361.0 (7), 359.0 (3) [M]+, 321.0 (8)
319.0 (17), 317.0 (8) [M + H – CH3CO]+, 282.0 (37), 280.0 (37) [M
– Br]+, 241.0 (65), 239.0 (65) [M + H – Br – CH3CO + H]+, 213.0
(100), 211.0 (100) [M + H – Br – CH3CO + H – CO]+, 202.0 (84)
[M – 2 × Br]+, 185.0 (7), 183.0 (7) [M + H – Br – CH3CO + H – CO
– C2H4]+, 174.1 (7), 159.1 (8), 130.1 (32), 104.1 (42), 77.0 (22),
62.0 (67).
ylformamide as a pale brown solid (5.0 g, yield: 94%). This com-
pound (3.90 g, 10.8 mmol) was dissolved in THF (10 mL) and the
solution was cooled to 0 °C with an ice bath. Diethyl phosphonate
(1.80 g in 10 mL THF, 13.0 mmol) and TEA (1.80 g, 17.8 mmol)
were added dropwise. The reaction mixture was stirred at r.t. for 6
h. After the reaction was complete, the solvent was removed. Ice-
water was added to wash the solid. The collected solid was purified
by column chromatography on silica gel (CHCl3) to give 8f as a pale
brown solid (2.4 g, yield: 79%); mp 104–106 °C.
HRMS: (TOF+): m/z calcd for C12H11Br2NO2: 358.9157; found:
358.9155.
1H NMR (400 MHz, CDCl3): d = 8.70 (s, 1 H, HCO), 8.16 (d, 3JHH
=
N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-
methylacetamide (8d)
8.5 Hz, 1 H, ArH), 7.19 (d, 3JHH = 8.6 Hz, 1 H, ArH), 7.07 (s, 1 H,
ArH), 4.74 (br s, 1 H, CHBr), 3.37 (s, 3 H, NCH3), 3.10–3.15 (m, 1
H, CH2), 2.92–2.97 (m, 1 H, CH2), 2.48–2.56 (m, 2 H, CH2).
N-(5-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-methyl-
acetamide (3d; 8.00 g, 27.0 mmol) was dissolved in CH2Cl2–MeOH
(1:1, 200 mL). Tetra-n-butylammonium tribromide (16.0 g, 33.2
mmol) was added in one portion. The reaction was monitored by
TLC and stirred at r.t. for 1 h. After the reaction ended, the solvent
was removed and the residue was separated by column chromatog-
raphy on silica gel (EtOAc–hexanes, 1:1) to give 8d as a pale brown
solid (5.7 g, yield: 56%); mp 128–130 °C.
1H NMR (300 MHz, CDCl3): d = 8.15 (d, 3JHH = 8.1 Hz, 1 H, ArH),
7.31 (d, 3JHH = 8.2 Hz, 1 H, ArH), 4.72 (t, 3JHH = 4.1 Hz, 1 H, CHBr),
3.20 (s, 3 H, NCH3), 3.18 (m, 2 H, CH2), 2.56 (m, 2 H, CH2), 1.84
(s, 3 H, CH3).
LC-MS: m/z (%) = 586.5 (34), 365.4 (14), 363.4 (16), 300.7 (98) [M
+ H2O]+, 298.7 (85), 284.1 (100) [M + H]+, 282.2 (92).
HRMS: (TOF+): m/z calcd for C12H13NO2Br: 282.0130; found:
282.0131.
2-Bromo-6-(dimethylamino)-3,4-dihydronaphthalen-1(2H)-one
(8g)
6-(Dimethylamino)-3,4-dihydronaphthalen-1(2H)-one (3g; 0.500
g, 2.64 mmol) was dissolved in H2SO4 (1.0 mL). The solution was
cooled down to 0 °C. Bromine (0.840 g, 5.25 mmol) was added
dropwise. The reaction mixture was stirred at r.t. for 4 h. At the end
of the reaction, the mixture was poured into ice-water, to precipitate
the dibromide intermediate as a pale brown solid (0.7 g, 2.02 mmol,
yield: 76%). The solid was then dissolved in THF (5 mL) and
cooled to 0 °C. Diethyl phosphonate (0.260 g, 1.88 mmol) and TEA
(0.200 g, 1.98 mmol) were added dropwise. The reaction mixture
was stirred at r.t. for 6 h. After removal of the solvent, ice-water was
added to afford a pale solid which was purified by column chroma-
tography on silica gel (EtOAc–hexanes, 1:2) to give 8g as a pale
brown solid (0.3 g, yield: 55% based on the dibromide, overall
yield: 42%); mp 142–144 °C.
EI-MS: m/z (%) = 335.0 (3), 333.0 (7), 331.0 (3) [M + H –
CH3CO]+, 296.1 (65), 294.1 (65) [M – Br]+, 253.0 (7), 251.0 (7) [M
– Br – CH3CO]+, 239.0 (37), 237.0 (37) [M + H – Br – CH3CO –
CH3]+, 227.0 (30), 225.0 (30) [M + H – Br – CH3CO + H – CO]+,
216.1 (100) [M + H – 2 × Br]+, 213.0 (40), 211.0 (40) [M + H – Br
– CH3CO + H – CH3 + H – CO]+, 186.1 (11), 144.1 (10), 130.1 (10),
115.1 (17), 104.1 (23), 89.1 (8), 77.1 (12), 62.1 (20).
HRMS: (TOF+): m/z calcd for C13H13Br2NO2: 371.9235; found:
371.9242.
N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)form-
amide (8e)
1H NMR (300 MHz, CDCl3): d = 7.99 (d, 3JHH = 8.9 Hz, 1 H, ArH),
6.64 (d, 3JHH = 9.0 Hz, 1 H, ArH), 6.40 (s, 1 H, ArH), 4.68 (t, 3JHH
=
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)formamide (3e; 25.0
g, 132 mmol) and copper(II) bromide (55.0 g, 246 mmol) were dis-
solved in THF (500 mL). The reaction mixture was refluxed over-
night. After cooling to r.t., the solution was filtered and the solvent
was removed from the filtrate. The solid was purified by column
chromatography on silica gel (EtOAc–hexanes, 1:1) to give 8e as a
pale brown solid (8.6 g, yield: 24%); mp 124–126 °C.
3.6 Hz, 1 H, CHBr), 3.30–3.21 (m, 1 H, CH2), 3.07 (s, 6 H, NCH3),
2.84–2.76 (m, 1 H, CH2), 2.49–2.40 (m, 2 H, CH2).
N-(2-Chloro-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acet-
amide (9a)55
2-Bromo-6-acetamidotetralone (8a, 28 mg, 0.10 mmol) and LiCL
(28 mg, 0.67 mmol) were loaded into a microwave vessel with a
stirrer-bar. DMF (1.0 mL) was added and the mixture was irradiated
(150 W) for 5 min at 150 psi and 150 °C (actual temperature rose to
186 °C). After the reaction, the solution was filtered and loaded di-
rectly onto a reverse-phase (C18) HPLC column to afford 9 as a
white solid (16 mg, yield: 67%); mp 179–181 °C.
1H NMR (400 MHz, CDCl3): d = 8.02 (d, 3JHH = 8.8 Hz, 1 H, ArH),
7.73 (s, 1 H, ArH), 7.43 (br s, 1 H, NH), 7.20 (dd, 3JHH = 8.4 Hz,
4JHH = 1.6 Hz, 1 H, ArH), 4.57–4.60 (m, 1 H, CH), 3.21–3.24 (m, 1
H, CH2), 2.93–2.95 (m, 1 H, CH2), 2.51–2.55 (m, 1 H, CH2), 2.41–
2.44 (m, 1 H, CH2), 2.20 (s, 3 H, CH3).
1H NMR (400 MHz, CDCl3): d = 8.46 (s, 1 H, HCO), 8.08 (d, 3JHH
=
8.6 Hz, 1 H, ArH), 7.79 (s, 1 H, ArH), 7.41 (br s, 1 H, NH), 7.30 (d,
3JHH = 8.4 Hz, 1 H, ArH), 4.72 (t, 3JHH = 4.1 Hz, 1 H, CHBr), 3.29–
3.35 (m, 1 H, CH2), 2.89–2.94 (m, 1 H, CH2), 2.47–2.54 (m, 2 H,
CH2).
EI–MS: m/z (%) = 269.0 (14), 267.0 (14), [M]+, 241.0 (27), 239.0
(27) [M + H – HCO]+, 213.0 (34), 211.0 (34) [M + H – HCO – CO]+,
189.1 (54) [M + H – Br]+, 161.1 (92) [M + H – Br – CO]+, 133.1
(23) [M + H – Br – 2 × CO + H]+, 104.1 (33), 77.1 (22), 62.1 (100).
HRMS: (TOF+): m/z calcd for C11H10BrNO2: 266.9895; found:
266.9888.
13C{1H} NMR (100 MHz, CDCl3): d = 189.8 (1 C, CO), 168.6 (1 C,
CO), 145.1 (1 C, ArC), 142.9 (1 C, ArC), 130.0 (1 C, ArCH), 126.3
(1 C, ArC), 118.2 (1 C, ArCH), 117.7 (1 C, ArCH), 59.6 (1 C, CCl),
32.4 (1 C, CH2), 26.5 (1 C, CH2), 24.9 (1 C, CH3).
N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-
methylformamide (8f)
N-(1,2,3,4-Tetrahydro-1-oxonaphthalen-6-yl)-N-methylformamide
(3f; 3.00 g, 14.8 mmol) was added portionwise into concd H2SO4
(30 mL) cooled by an ice bath. Bromine (2.60 g, 16.3 mmol) was
added dropwise to the above solution. After the addition, the reac-
tion mixture was stirred at r.t. for 3 h. When the reaction was com-
plete, the reaction mixture was added slowly to ice-water. A green
precipitate generated was collected by filtration and dried to afford
N-(2,2-dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-N-meth-
LC-MS: m/z (%) = 240.2 (24), 239.1 (16), 238.1 (100) [M + H]+.
N-(2,2-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)acet-
amide (10a)
6-Acetamidotetralone (3a; 20.7 mg, 0.10 mmol) was dissolved in
AcOH (1.0 mL) and bromine (12 mL, 0.24 mmol) was added. The
mixture was stirred for 1 h and then partitioned between sat.
NaHCO3 and EtOAc. The separated organic layer was washed with
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

PAPER
Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
141
H2O and dried. The solvent was removed in vacuo. The crude prod-
uct was dissolved in DMSO and loaded onto HPLC. The product
fraction was collected and the solvent was removed in vacuo. The
product was dried azeotropically with MeCN (2 ×) to yield 10 as an
off-white solid (15 mg, yield: 40%); mp > 200 °C (decomp.).
ning from H2O–MeCN (4:1) to pure MeCN over 20 min. The elu-
tion was continued for another 20 min with pure MeCN. The
fractions were checked for purity with TLC. The solvent was re-
moved from pure fractions in vacuo and the solid was azeotropical-
ly dried twice with added MeCN.
1H NMR (300 MHz, CD3OD): d = 8.02 (d, 3JHH = 8.7 Hz, 1 H, ArH),
N-(5,6-Dihydro-9-iodonaphth[1¢,2¢:4,5]imidazo[1,2-a]pyridin-
3-yl)acetamide (14a)
Method B: N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8a; 28.2 mg, 0.100 mmol), 2-amino-5-iodo-pyridine
(88.0 mg, 0.400 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M)
in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford 14a as
a white solid (9.0 mg, yield: 22%); mp > 296 °C (decomp.).
3
7.68 (d, 4JHH = 1.8 Hz, 1 H, ArH), 7.52 (dd, JHH = 8.7 Hz, 4JHH
=
2.1 Hz, 1 H, ArH), 3.04–3.10 (m, 4 H, CH2CH2), 2.16 (s, 3 H, CH3).
LC-MS: m/z (%) = 380.5 (40), 378.6 (100), 376.5 (40) [M + H2O]+,
363.9 (32), 361.9 (64), 360.0 (32) [M]+.
6-Amino-3-bromopyridine-2-carbonitrile (12)
6-Aminopyridine-2-carbonitrile (11; 4.20 g, 21.2 mmol) was dis-
solved in CH2Cl2–MeOH (1:1, 84 mL). Tetra-n-butylammonium
tribromide (11.8 g, 24.5 mmol) was added in one portion. The reac-
tion mixture was stirred at r.t. for 45 min. The solvent was removed
to afford a yellowish oil. Under constant stirring, H2O was added to
generate a white precipitate, which was collected by filtration to
give the crude product (4.0 g). The solid was further purified by
washing (EtOAc–hexanes, 1:1) to give 12 as an off-white solid (3.5
g, yield: 83%); mp 184–186 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.94 (br s, 1 H, NH), 8.66 (d,
4JHH = 1.5 Hz, 1 H, ArH), 7.68 (d, 3JHH = 8.1 Hz, 1 H, ArH), 7.54 (s,
1 H, ArH), 7.50 (dd, 3JHH = 8.1 Hz, 3JHH = 2.1 Hz, 1 H, ArH), 7.41
(d, AB system, 3JHH = 9.3 Hz, 3JHH = 0.9 Hz, 1 H, ArH), 7.37 (d, AB
system, 3JHH = 9.6 Hz, 3JHH = 1.5 Hz, 1 H, ArH), 3.09–3.11 (m, 4 H,
CH2CH2), 2.05 (s, 3 H, CH3).
13C{1H} NMR (125 MHz, DMSO-d6): d = 168.1 (1 C, CO), 143.3
(1 C, ArC), 139.8 (1 C, ArC), 138.5 (1 C, ArC), 135.8 (1 C, ArC),
130.9 (1 C, ArC), 128.9 (1 C, ArCH), 125.8 (1 C, ArC), 122.3 (1 C,
ArC), 119.5 (1 C, ArC), 118.9 (1 C, ArCH), 117.6 (1 C, ArCH),
117.3 (1 C, ArCH), 75.6 (1 C, ArI), 28.1 (1 C, CH2), 24.0 (1 C,
CH2), 18.1 (1 C, CH3).
3
1H NMR (300 MHz, DMSO-d6): d = 7.75 (d, JHH = 9.1 Hz, 1 H,
ArH), 6.68 (d, 3JHH = 9.1 Hz, 1 H, ArH).
EI-MS: m/z (%) = 199.0 (24), 197.0 (24) [M]+, 172.0 (14), 170.0
(14) [M – CN]+, 118.1 (33) [M – Br]+, 92.0 (33), 62.0 (100).
LC-MS: m/z (%) = 405.2 (10), 404.2 (100) [M + H]+.
HRMS: (TOF+): m/z calcd for C17H15ION3: 404.0260; found:
HRMS (TOF+): m/z calcd for C6H4BrN3: 196.9589; found:
196.9595.
404.0265.
5-Ethylthiopyridin-2-amine (13)31,32
N-(4-Bromo-5,6-dihydro-9-iodonaphth[1¢,2¢:4,5]imidazo[1,2-
a]pyridin-3-yl)acetamide (14c)
2-Amino-5-iodo-pyridine (2.20 g, 10 mmol), sodium ethanethiolate
(80%, 1.7 g, 16 mmol) and copper powder (190 mg, 3.00 mmol)
were loaded into a 100 mL round bottom flask under N2. Ethylene
glycol (40 mL, 0.25 mol) was added and the solution was stirred at
150 °C for 26 h. The cooled solution was filtered and partitioned be-
tween EtOAc and H2O twice. The organic layer was dried over bar-
ium oxide, filtered and the solvent was removed in vacuo to yield
13 as yellow oil (1.2 g, yield: 76%).
Method A; N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (36.1 mg, 0.10 mmol), 5-iodo-2-aminopyridine (26.4
mg, 0.12 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M) in
CH2Cl2 (75 mL), TEA (60 mL, 0.43 mmol) and 1,1,2-trichloroethane
(1.0 mL) were used. Aq K2CO3 solution (2 M, 5.0 mL) was added
to the product fraction collected from HPLC. The mixture was heat-
ed at 70 °C for 30 min. After removal of the solvent, the residue was
partitioned between EtOAc and de-ionized H2O (2 ×). After drying
and filtration, the organic solvent was removed. The solid was
washed with Et2O (3 ×) or until the Et2O layer was clear. The solid
was dried in vacuo to afford 14c as an off-white powder (6.1 mg,
yield: 13%); mp > 250 °C (decomp.).
1H NMR (300 MHz, CDCl3): d = 8.06 (d, 4JHH = 2.1 Hz, 1 H, ArH),
7.48 (dd, 3JHH = 8.7 Hz, 4JHH = 2.4 Hz, 1 H, ArH), 6.42 (dd, 3JHH
=
8.7 Hz, 5JHH = 0.6 Hz, 1 H, ArH), 2.68 (q, 3JHH = 7.3 Hz, 2 H, CH2),
1.15 (t, 3JHH = 7.2 Hz, 3 H, CH3).
Microwave Reaction; General procedure
1H NMR (300 MHz, DMSO-d6): d = 9.60 (br s, 1 H, NH), 9.46 (s,
Method A: An a-bromotetralone derivative (1 equiv) and a 2-ami-
nopyridine derivative (1.2 equiv) were put into a microwave reac-
tion tube. Anhyd 1,1,2-trichloroethane was added to give a solution
(£ 0.1 M) under N2. Titanium(IV) chloride (0.75 equiv, 1 M) in
CH2Cl2 and anhyd TEA (0.6 equiv) were added under the same con-
ditions. The reaction tube was sealed and the mixture was irradiated
(300 W) at 170 °C for 30 s with stirring. CAUTION: Pressure may
build up in the reaction tube. The mixture was cooled to r.t. and par-
titioned twice between CHCl3 and 2 M K2CO3 solution. The com-
bined organic solvent was removed in vacuo to leave a solid.
1 H, ArH), 8.68 (d, 4JHH = 0.9 Hz, 1 H, ArH), 7.78 (d, 3JHH = 8.1 Hz,
3
1 H, ArH), 7.50 (d, JHH = 8.1 Hz, 1 H, ArH), 7.44 (AB system,
2JHH = 10.3 Hz, 1 H, ArH), 7.37 (AB system, 2JHH = 10.3 Hz, 1 H,
ArH), 3.20–3.27 (m, 4 H, CH2CH2), 2.09 (s, 3 H, CH3).
13C{1H} NMR (125 MHz, DMSO-d6): d = 168.5 (1 C, CO), 143.7
(1 C, ArC), 139.0 (1 C, ArC), 135.7 (1 C, ArC), 135.0 (1 C, ArC),
131.4 (1 C, ArC), 129.2 (1 C, ArCH), 125.6 (1 C, ArC), 121.0 (1 C,
ArC), 120.0 (1 C, ArC), 117.9 (1 C, ArCH), 76.0 (1 C, ArI), 28.6 (1
C, CH2), 23.2 (1 C, CH2), 17.7 (1 C, CH3).
Method B: An a-bromotetralone derivative (1 equiv) and a 2-ami-
nopyridine derivative (4.0 equiv) were put into a microwave reac-
tion vessel. Anhyd CHCl3 was added to give a solution (£ 0.1 M)
under N2. Titanium(IV) chloride (0.75 equiv, 1 M) in CH2Cl2 and
anhyd TEA (0.6 equiv) were added under the same conditions. The
reaction vessel was sealed and the mixture was irradiated (300 W)
with stirring at 110 °C for 30 min. The workup was the same as in
Method A.
LC-MS: m/z (%) = 485.1 (14), 484.1 (100), 483.1 (22), 482.1 (100)
[M + H]+.
HRMS (TOF+): m/z calcd for C17H14N3OBrI: 481.9365; found:
481.9368.
N-(5,6-Dihydro-9-bromonaphth[1¢,2¢:4,5]imidazo[1,2-a]pyri-
din-3-yl)acetamide (15a)
Method B: N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8a; 28.2 mg, 0.100 mmol), 2-amino-5-bromo-pyri-
dine (69.2 mg, 0.400 mmol), titanium(IV) chloride (0.075 mmol,
The crude product was dissolved in a minimal amount of DMSO for
HPLC separation. On a C18 column, the mixture was eluted at 30
mL/min with a gradient (buffered with 0.25% of 50% aq NH3) run-
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142
L. Cai et al.
PAPER
1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford
15a as a white solid (6.1 mg, yield: 17%); mp > 380 °C (decomp.).
9-Bromo-3-(dimethylamino)naphth[1¢,2¢:4,5]imidazo[1,2-a]py-
ridine (16)
To a solution of 15g and 16 (6.90 mg, 0.020 mmol) in CH2Cl2 (2
mL) in a small vial was added 2,3-dichloro-5,6-dicyanoquinone
(DDQ; 96%, 5.70 mg, 0.024 mmol). The mixture was stirred for 2
h. After the reaction was complete, the mixture was partitioned be-
tween CH2Cl2 and H2O (2 ×) and the organic layer was separated
and dried over barium oxide. The slurry was filtered and the solvent
was removed in vacuo to yield 16 as a reddish-brown solid (3.2 mg,
yield: 47%); mp 112–114 °C.
1H NMR (400 MHz, CD3OD): d = 9.18 (br s, 1 H, NH), 8.45 (dd,
4JHH = 1.8 Hz, 5JHH = 0.72 Hz, 1 H, ArH), 7.81 (d, 3JHH = 8.2 Hz, 1
H, ArH), 7.66 (d, 4JHH = 1.5 Hz, 1 H, ArH), 7.54 (dd, 3JHH = 8.2 Hz,
4JHH = 2.0 Hz, 1 H, ArH), 7.49 (dd, 3JHH = 9.5 Hz, 4JHH = 0.74 Hz,
1 H, ArH), 7.27 (dd, 3JHH = 9.5 Hz, 4JHH = 1.9 Hz, 1 H, ArH), 3.19
(m, 4 H, CH2CH2), 2.10 (s, 3 H, CH3).
13C{1H} NMR (100 MHz, CD3OD): d = 168.7 (1 C, CO), 143.8 (1
C, ArC), 141.0 (1 C, ArC), 139.1 (1 C, ArC), 136.3 (1 C, ArC),
126.6 (1 C, ArC), 126.3 (1 C, ArC), 124.9 (1 C, ArC), 122.8 (1 C,
ArC), 120.6 (1 C, ArC), 119.4 (1 C, ArC), 117.8 (1 C, ArCH), 117.8
(1 C, ArCH), 106.2 (1 C, CBr), 28.6 (1 C, CH2), 24.5 (1 C, CH2),
18.7 (1 C, CH3).
1H NMR (300 MHz, CDCl3): d = 8.59 (d, 3JHH = 9.0 Hz, 1 H, ArH),
8.53 (d, 4JHH = 1.2 Hz, 1 H, ArH), 7.54 (d, 3JHH = 8.1 Hz, 1 H, ArH),
7.70 (d, 3JHH = 9.0 Hz, 1 H, ArH), 7.68 (d, 3JHH = 9.6 Hz, 1 H, ArH),
7.55 (d, 3JHH = 8.7 Hz, 1 H, ArH), 7.38 (dd, 3JHH = 9.6 Hz, 4JHH
=
1.8 Hz, 1 H, ArH), 7.26 (dd, 3JHH = 9.0 Hz, 4JHH = 2.4 Hz, 1 H, ArH),
LC-MS: m/z (%) = 359.7 (18), 358.7 (96) [M + H]+), 357.7 (20) [M
7.05 (d, 4JHH = 2.7 Hz, 1 H, ArH), 3.04 (s, 6 H, NCH3).
+ H]+, 356.7 (100) [M + H]+.
13C{1H} NMR (100 MHz, CD3OD): d = 151.4 (1 C, ArC), 146.1 (1
C, ArC), 141.1 (1 C, ArC), 135.8 (1 C, ArC), 133.0 (1 C, ArCH),
127.3 (1 C, ArCH), 124.5 (1 C, ArCH), 124.2 (1 C, ArCH), 123.9
(1 C, ArC), 118.7 (1 C, ArC), 117.7 (1 C, ArCH), 117.2 (1 C,
ArCH), 111.9 (1 C, ArCH), 109.8 (1 C, ArCH), 107.3 (1 C, ArC),
41.2 (1 C, CH3).
HRMS (TOF+): m/z calcd for C17H15BrON3: 356.0398; found:
356.0399.
N-(4-Bromo-5,6-dihydro-9-bromonaphth[1¢,2¢:4,5]imidazo[1,2-
a]pyridin-3-yl)-acetamide (15c)
Method B: N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8d; 36.1 mg, 0.100 mmol), 2-amino-5-bromopyri-
dine (21.4 mg, 0.120 mmol), titanium(IV) chloride (0.075 mmol,
1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford
15c as a white solid (9.7 mg, yield: 22%); mp > 300 °C (decomp.).
1H NMR (400 MHz, CDCl3): d = 8.30 (d, 3JHH = 8.4 Hz, 1 H, ArH),
8.00 (s, 1 H, ArH), 7.95 (d, 3JHH = 8.4 Hz, 1 H, ArH), 7.74 (br s, 1
H, NH), 7.51 (d, 3JHH = 9.5 Hz, 1 H, ArH), 7.21 (dd, 3JHH = 9.5 Hz,
4JHH = 1.8 Hz, 1 H, ArH), 3.38 (t, 3JHH = 7.9 Hz, 2 H, CH2), 3.13 (t,
3JHH = 7.9 Hz, 2 H, CH2), 2.26 (s, 3 H, CH3).
13C{1H} NMR (100 MHz, DMSO-d6): d = 168.5 (1 C, CO), 143.6
(1 C, ArCH), 139.4 (1 C, ArC), 135.7 (1 C, ArC), 135.0 (1 C, ArC),
129.7 (1 C, ArC), 126.8 (1 C, ArCH), 125.6 (1 C, ArC), 124.8 (1 C,
ArCH), 121.0 (1 C, ArCH), 120.9 (1 C, ArC), 120.6 (1 C, ArC),
117.6 (1 C, ArCH), 106.0 (1 C, ArCH), 28.6 (1 C, CH2), 23.3 (1 C,
CH2), 17.7 (1 C, CH3).
LC-MS: m/z (%) = 344.2 (16), 343.2 (16), 342.2 (100), [M + H]+,
341.2 (8), 340.4 (88, [M + H]+, 327.4 (6), 326.4 (34) [M – CH3]+,
325.4 (8), 324.5 (26) [M – CH3]+, 299.5 (4), 298.5 (10) [M –
NMe2]+, 297.5 (8), 296.5 (10) [M – NMe2]+.
HRMS (TOF+): m/z calcd for C17H15BrN3: 340.0449; found:
340.0463.
N-(4-Bromo-5,6-dihydro-9-ethylthionaphth[1¢,2¢:4,5]imida-
zo[1,2-a]pyridin-3-yl)-acetamide (17c)
Method A: N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8d; 36.1 mg, 0.100 mmol), 5-ethylthio-2-aminopyri-
dine (21.4 mg, 0.120 mmol), titanium(IV) chloride (0.075 mmol,
1.0 M) in CH2Cl2 (75 mL), and 1,1,2-trichloroethane (1.0 mL) were
used to afford 17c as a brown solid (10 mg, yield: 24%); mp 184–
186 °C.
1H NMR (400 MHz, CDCl3): d = 8.22 (d, 3JHH = 8.2 Hz, 1 H, ArH),
LC-MS: m/z (%) = 438.1 (48), 436.1 (100), 434.1 (52) [M + H]+.
HRMS (TOF+): m/z calcd for C17H14Br2ON3: 433.9504; found:
7.90 (d, 3JHH = 7.5 Hz, 1 H, ArH), 7.89 (dd, 4JHH = 1.5 Hz, 5JHH
=
0.9 Hz, 1 H, ArH), 7.66 (br s, 1 H, NH), 7.49 (d, 3JHH = 9.6 Hz, 1 H,
3
3
ArH), 7.15 (dd, JHH = 9.3 Hz, JHH = 1.8 Hz, 1 H, ArH), 3.32 (t,
3JHH = 8.0 Hz, 2 H, CH2), 3.07 (t, 3JHH = 8.0 Hz, 2 H, CH2), 2.82 (q,
3JHH = 7.3 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3), 1.23 (t, 3JHH = 7.4 Hz,
3 H, CH3).
433.9496.
9-Bromo-3-(dimethylamino)-5,6-dihydronaphth[1¢,2¢:4,5]imi-
dazo[1,2-a]pyridine (15g)
13C{1H} NMR (100 MHz, CDCl3): d = 168.1 (1 C, CO), 145.0 (1 C,
ArCH), 140.2 (1 C, ArC), 134.8 (1 C, ArCH), 134.4 (1 C, ArC),
128.7 (1 C, ArC), 128.4 (1 C, ArCH), 125.0 (1 C, ArCH), 122.1 (1
C, ArCH), 120.6 (1 C, ArC), 119.9 (1 C, ArC), 118.8 (1 C, ArC),
117.2 (1 C, ArCH), 116.0 (1 C, ArC), 29.9 (1 C, CH2), 29.1 (1 C,
CH2), 24.9 (1 C, CH2), 18.4 (1 C, CH3), 14.7 (1 C, CH3).
Method B: 2-Bromo-6-(dimethylamino)-3,4-dihydronaphthalen-
1(2H)-one (8g; 27.3 mg, 0.10 mmol), 5-bromo-2-aminopyridine
(21.4 mg, 0.12 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M)
in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford 15g and
the dehydrogenated derivative 16 in a ratio of 3:1 as a white solid
(15.7 mg, yield: 46%); mp 222–224 °C.
1H NMR (400 MHz, CD3OD): d = 8.23 (d, 4JHH = 1.5 Hz, 1 H, ArH),
7.54 (d, 3JHH = 8.1 Hz, 1 H, ArH), 7.34 (d, 3JHH = 9.3 Hz, 1 H, ArH),
7.22 (dd, 3JHH = 1.8, 9.3 Hz, 1 H, ArH), 6.58 (dd, 3JHH = 2.4, 8.1 Hz,
1 H, ArH), 6.55 (s, 1 H, ArH), 2.99–3.06 (m, 4 H, CH2CH2), 2.93
[s, 6 H, N(CH3)3].
LC-MS: m/z (%) = 420.1 (6), 419.1 (20), 418.2 (100) [M + H]+,
417.2 (25), 416.2 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C19H19OSBrN3: 416.0432; found:
416.0434.
LC-MS: m/z (%) = 345.3 (15), 344.2 (86) [M + H]+, 343.2 (18),
342.3 (100) [M + H]+, 329.4 (6), 328.4 (22) [M – CH3]+), 327.4 (6),
326.4 (26) [M – CH3]+.
HRMS (TOF+): m/z calcd for C17H17BrN3: 342.0606; found:
342.0587.
N-(5,6-Dihydronaphth[1¢,2¢:4,5]imidazo[1,2-a]pyridin-3-
yl)acetamide (18a)
Method B: N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8a; 28.2 mg, 0.100 mmol), 2-aminopyridine (11.3
mg, 0.120 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M) in
CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford 18a as a
white solid (8.2 mg, yield: 30%); mp > 300 °C (decomp.).
1H NMR (400 MHz, CD3OD): d = 8.46 (br s, 1 H, NH), 8.13 (d,
3JHH = 6.8 Hz, 1 H, ArH), 7.70 (d, 3JHH = 8.2 Hz, 1 H, ArH), 7.52 (s,
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

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Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
143
1 H, ArH), 7.47 (d, 3JHH = 9.1 Hz, 1 H, ArH), 7.34 (dd, 3JHH = 8.2
Hz, 4JHH = 2.0 Hz, 1 H, ArH), 7.21 (ddd, 3JHH = 9.1 Hz, 3JHH = 6.8
N-(5,6-Dihydro-10-ethoxynaphth[1¢,2¢:4,5]imidazo[1,2-a]pyri-
din-3-yl)acetamide (19a)
4
Hz, 4JHH = 1.2 Hz, 1 H, ArH), 6.88 (td, 3JHH = 6.8 Hz, JHH = 1.0
Method B: N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8a; 28.2 mg, 0.10 mmol), 2-amino-4-ethoxypyridine
(55.2 mg, 0.40 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M)
in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford 19a as
a white solid (5.7 mg, yield: 18%); mp > 258°C (decomp.).
Hz, 1 H, ArH), 3.05–3.16 (m, 4 H, CH2CH2), 2.09 (s, 3 H, CH3).
13C{1H} NMR (75 MHz, DMSO-d6): d = 167.7 (1 C, CO), 144.3 (1
C, ArCH), 139.0 (1 C, ArC), 137.8 (1 C, ArC), 135.1 (1 C, ArC),
125.8 (1 C, ArC), 123.7 (1 C, ArCH), 123.0 (1 C, ArC), 121.6 (1 C,
ArCH), 118.7 (1 C, ArC), 118.4 (1 C, ArCH), 116.8 (1 C, ArCH),
115.9 (1 C, ArCH), 111.3 (1 C, ArCH), 27.7 (1 C, CH2), 23.5 (1 C,
CH2), 17.6 (1 C, CH3).
LC-MS: m/z (%) = 279.4 (16), 278.3 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C17H16ON3: 278.1293; found:
1H NMR (300 MHz, CDCl3): d = 7.78 (d, 3JHH = 8.2 Hz, 1 H, ArH),
3
7.64 (d, JHH = 7.4 Hz, 1 H, ArH), 7.58 (s, 1 H, ArH), 7.17 (dd,
3JHH = 8.2 Hz, 4JHH = 1.9 Hz, 1 H, ArH), 6.84 (d, 4JHH = 2.3 Hz, 1 H,
3
ArH), 6.49 (dd, JHH = 7.4 Hz, 4JHH = 2.4 Hz, 1 H, ArH), 4.05 (q,
3JHH = 7.0 Hz, 2 H, OCH2), 3.17 (t, 3JHH = 7.0 Hz, 2 H, CH2CH2),
3.00 (t, 3JHH = 7.0 Hz, 2 H, CH2CH2), 2.17 (s, 3 H, CH3CO), 1.45 (t,
3JHH = 7.0 Hz, 3 H, OCH2CH3).
278.1293.
13C{1H} NMR (75 MHz, CDCl3): d = 168.1 (1 C, CO), 155.8 (1 C,
ArC), 146.1 (1 C, ArC), 139.0 (1 C, ArC), 137.9 (1 C, ArC), 135.2
(1 C, ArC), 126.7 (1 C, ArC), 124.9 (1 C, ArCH), 121.7 (1 C,
ArCH), 118.9 (1 C, ArCH), 118.0 (1 C, ArC), 117.3 (1 C, ArC),
106.3 (1 C, ArCH), 95.0 (1 C, ArCH), 63.5 (1 C, OCH2), 28.4 (1 C,
CH2CH2), 24.0 (1 C, CH2CH2), 18.2 (1 C, COCH3), 14.3 (1 C,
OCH2CH3).
N-(4-Bromo-5,6-dihydronaphth[1¢,2¢:4,5]imidazo[1,2-a]pyri-
din-3-yl)acetamide (18c)
Method B: N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8d; 36.1 mg, 0.100 mmol), 2-aminopyridine (11.3
mg, 0.120 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M) in
CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford 18c as a
white solid (11.4 mg, yield: 32%); mp 208–210 °C.
LC-MS: m/z (%) = 324.3 (2), 323.3 (18), 322.3 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C19H20O2N3: 322.1556; found:
1H NMR (300 MHz, CD3OD): d = 8.18 (d, 3JHH = 6.9 Hz, 1 H, ArH),
7.85 (d, 3JHH = 8.4 Hz, 1 H, ArH), 7.56 (d, 3JHH = 9.0 Hz, 1 H, ArH),
7.55 (d, 3JHH = 9.0 Hz, 1 H, ArH), 7.31 (t, 3JHH = 7.6 Hz, 1 H, ArH),
322.1556.
3
3
6.96 (t, JHH = 6.9 Hz, 1 H, ArH), 3.40 (t, JHH = 7.8 Hz, 2 H,
CH2CH2), 3.19 (t, 3JHH = 7.8 Hz, 2 H, CH2CH2), 2.20 (s, 3 H, CH3).
N-(4-Bromo-5,6-dihydro-10-ethoxynaphth[1¢,2¢:4,5]imida-
zo[1,2-a]pyridin-3-yl)acetamide (19c)
Method B: N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8d; 36.1 mg, 0.100 mmol), 4-ethoxy-2-aminopyri-
dine (55.2 mg, 0.400 mmol), titanium(IV) chloride (0.075 mmol,
1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were used to afford
19c as a brown solid (18 mg, yield: 45%); mp > 256 °C (decomp.).
13C{1H} NMR (125 MHz, CD3OD): d = 172.3 (1 C, CO), 147.4 (1
C, ArC), 139.8 (1 C, ArC), 136.9 (1 C, ArC), 136.7 (1 C, ArC),
131.6 (1 C, ArC), 126.7 (1 C, ArCH), 126.5 (1 C, ArCH), 125.3 (1
C, ArCH), 122.5 (1 C, ArCH), 122.2 (1 C, ArC), 121.7 (1 C, ArC),
117.3 (1 C, ArCH), 114.1 (1 C, ArCH), 30.3 (1 C, CH2), 23.4 (1 C,
CH2), 19.0 (1 C, CH3).
1H NMR (300 MHz, CDCl3): d = 8.24 (d, 3JHH = 6.2 Hz, 1 H, ArH),
LC-MS: m/z (%) = 359.2 (16), 358.2 (95) [M + H]+, 357.2 (21),
3
7.89 (d, JHH = 6.3 Hz, 1 H, ArH), 7.71 (br s, 1 H, NH), 7.67 (d,
356.2 (100) [M + H]+.
3JHH = 5.5 Hz, 1 H, ArH), 6.87 (d, 4JHH = 1.7 Hz, 1 H, ArH), 6.53
(dd, 3JHH = 5.5 Hz, 4JHH = 1.8 Hz, 1 H, ArH), 4.07 (q, 3JHH = 7.9 Hz,
2 H, OCH2), 3.34 (t, 3JHH = 6.0 Hz, 2 H, CH2), 3.07 (t, 3JHH = 6.0
Hz, 2 H, CH2), 2.25 (s, 3 H, COCH3), 1.46 (t, 3JHH = 5.2 Hz, 3 H,
CH3).
HRMS (TOF+): m/z calcd for C17H15BrON3: 356.0398; found:
356.0408.
N-(12a-Chloro-6a,5,6,12a-tetrahydronaphth[1¢,2¢:4,5]imida-
zo[1,2-a]pyridin-3-yl)acetamide (18f)
13C{1H} NMR (75 MHz, CDCl3): d = 168.3 (1 C, ArC), 156.8 (1 C,
ArC), 147.6 (1 C, ArC), 139.1 (1 C, ArC), 134.4 (1 C, ArC), 134.1
(1 C, ArC), 129.4 (1 C, ArC), 123.4 (1 C, ArCH), 121.8 (1 C,
ArCH), 120.8 (1 C, ArCH), 117.8 (1 C, ArC), 116.3 (1 C, ArC),
107.7 (1 C, ArCH), 95.5 (1 C, ArCH), 64.0 (1 C, OCH2), 29.3 (1 C,
CH2CH2), 25.1 (1 C, CH2CH2), 18.5 (1 C, COCH3), 14.6 (1 C,
OCH2CH3).
Method A: N-(2-Bromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-yl)-
N-methylformamide (8f; 28.2 mg, 0.100 mmol), 2-aminopyridine
(11.3 mg, 0.120 mmol), titanium(IV) chloride (0.075 mmol, 1.0 M)
in CH2Cl2 (75 mL), and 1,1,2-trichloroethane (1.0 mL) were used to
afford 18f as a white solid (10.4 mg, yield: 33%); mp > 200 °C (de-
comp.).
1H NMR (300 MHz, CD3COCD3): d = 9.27 (s, 1 H, HCO), 8.31
(ddd, 3JHH = 4.5 Hz, 4JHH = 1.8 Hz, 5JHH = 0.9 Hz, 1 H, ArH), 8.04
(d, 3JHH = 8.4 Hz, 1 H, ArH), 7.69 (td, 3JHH = 7.5 Hz, 4JHH = 2.1 Hz,
1 H, ArH), 7.40 (dd, 3JHH = 8.7 Hz, 4JHH = 2.4 Hz, 1 H, ArH), 7.35
LC-MS: m/z (%) = 404.2 (3), 403.2 (19), 402.2 (100) [M + H]+,
401.2 (20), 400.2 (96) [M + H]+.
HRMS (TOF+): m/z calcd for C19H19BrO2N3: 400.0661; found:
400.0649.
4
(d, JHH = 2.1 Hz, 1 H, ArH), 7.04–7.08 (m, 2 H, ArH), 4.82 (dd,
3JHH = 8.1 Hz, 3JHH = 3.9 Hz, 1 H, CH), 3.30 (ABdd, 2JHH = 17.4 Hz,
3JHH = 7.8 Hz, 3JHH = 4.5 Hz, 1 H, CH2), 3.15 (dd, AB system 2JHH
N-(4-Bromo-5,6-dihydro-11-benzoxynaphth[1¢,2¢:4,5]imida-
zo[1,2-a]pyridin-3-yl)acetamide (20c)
3
3
= 17.1 Hz, JHH = 6.9 Hz, JHH = 4.8 Hz, 1 H, CH2), 2.81 (s, 3 H,
CH3), 2.61–2.72 (m, 1 H, CH2), 2.38–2.52 (m, 1 H, CH2).
Method B: N-(2,5-Dibromo-1,2,3,4-tetrahydro-1-oxonaphthalen-6-
yl)acetamide (8d; 36.1 mg, 0.100 mmol), 3-(benzyloxy)pyridin-2-
amine (24 mg, 0.12 mmol), a solution of titanium(IV) chloride
(0.075 mmol, 1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were
used to afford 20c as a brown solid (10 mg, yield: 22%); mp 202–
204 °C.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, 3JHH = 6.4 Hz, 1 H, ArH),
8.12 (d, 3JHH = 6.3 Hz, 1 H, ArH), 7.72 (br s, 1 H, NH), 7.52–7.47
(m, 2 H, ArH), 7.36–7.40 (m, 2 H, ArH), 7.30–7.33 (m, 1 H, ArH),
6.63 (t, 3JHH = 5.4 Hz, 1 H, ArH), 6.43 (d, 3JHH = 5.4 Hz, 1 H, ArH),
5.41 (s, 2 H, CH2Ph), 3.36 (t, 3JHH = 6.0 Hz, 2 H, CH2CH2), 3.11 (t,
3JHH = 6.0 Hz, 2 H, CH2CH2), 2.25 (s, 3 H, COCH3).
13C{1H} NMR (125 MHz, CD3COCD3): d = 189.2 (1 C, HCO),
161.2 (1 C, ArC), 152.2 (1 C, ArCH), 149.5 (1 C, ArC), 148.6 (1 C,
ArCH), 145.7 (1 C, ArC), 138.0 (1 C, ArCH), 129.9 (1 C, ArCH),
126.3 (1 C, ArC), 119.6 (1 C, ArCH), 119.1 (1 C, ArCH), 117.8 (1
C, ArCH), 117.3 (1 C, CHCl), 60.4 (1 C, CH), 33.0 (1 C, NCH3),
32.6 (1 C, CH2), 26.9 (1 C, CH2).
LC-MS: m/z (%) = 317.1 (7), 316.1 (35) [M + H]+, 315.1 (20), 314.2
(100) [M + H]+.
HRMS (TOF+): m/z calcd for C17H17OClN3: 314.1060; found:
314.1059.
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

144
L. Cai et al.
PAPER
13C{1H} NMR (125 MHz, DMSO-d6): d = 169.1 (1 C, CO), 147.1
(1 C, ArCH), 140.3 (1 C, ArC), 138.4 (1 C, ArC), 137.2 (1 C,
ArCH), 136.0 (1 C, ArC), 135.4 (1 C, ArC), 130.9 (1 C, ArC), 129.2
(2 C, ArCH), 128.9 (2 C, ArCH), 126.3 (1 C, ArC), 121.0 (1 C,
ArCH), 121.4 (1 C, ArC), 118.2 (1 C, ArCH), 112.7 (1 C, ArCH),
103.6 (1 C, ArCH), 70.7 (1 C, OCH2), 29.4 (1 C, CH2), 24.0 (1 C,
CH2), 18.6 (1 C, CH3).
1H NMR (400 MHz, CDCl3): d = 7.80 (dt, 3JHH = 6.8 Hz, 4JHH = 1.2
Hz, 1 H, ArH), 7.52 (dt, 3JHH = 9.0 Hz, 4JHH = 2.2 Hz, 1 H, ArH),
7.10 (ddd, 3JHH = 9.0 Hz, 3JHH = 6.8 Hz, 4JHH = 1.3 Hz, 1 H, ArH),
6.76 (td, 3JHH = 6.7 Hz, 4JHH = 1.1 Hz, 1 H, ArH), 2.86 (t, 3JHH = 6.0
Hz, 2 H, CH2), 2.75 (t, 3JHH = 6.1 Hz, 2 H, CH2), 2.01–1.92 (m, 4 H,
CH2CH2).
13C{1H} NMR (125 MHz, acetone-d6): d = 144.7 (1 C, ArC), 142.8
(1 C, ArC), 123.8 (1 C, ArCH), 123.2 (1 C, ArCH), 119.4 (1 C,
ArC), 117.1 (1 C, ArCH), 111.7 (1 C, ArC), 25.6 (1 C, CH2), 24.1
(1 C, CH2), 23.2 (1 C, CH2), 20.6 (1 C, CH2).
LC-MS: m/z (%) = 466.0 (3), 465.1 (22), 464.1 (94) [M + H]+, 463.1
(32), 462.1 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C24H21BrO2N3: 462.0817; found:
462.0819.
GC-MS: m/z (%) = 172.12 (60) [M]+, 144.17 (100) [M – C2H4]+.
The compound was dissolved in Et2O and precipitated with HCl in
Et2O to give a white solid.
2-Methoxy-5,6-dihydro-naphth[1¢,2¢:4,5]imidazo[1,2-a]pyri-
dine (21)
1H NMR (400 MHz, CDCl3): d = 8.51 (br s, 1 H, NH), 7.94 (dd,
Method B: 2-Bromo-3,4-dihydro-7-methoxynaphthalen-1(2H)-one
(25.5 mg, 0.10 mmol), 2-aminopyridine (11.3 mg, 0.12 mmol), tita-
nium(IV) chloride (0.075 mmol, 1.0 M) in CH2Cl2 (75 mL), and
CH2Cl2 (1.0 mL) were used to afford 21 as a white solid (19.0 mg,
yield: 75%); mp 292–294 °C. The compound was dissolved in
MeOH and HCl (1.0 equiv) in Et2O was added. The salt was recrys-
tallized by slow diffusion of Et2O into a solution in MeOH.
3
3JHH = 6.8 Hz, 4JHH = 0.8 Hz, 1 H, ArH), 7.86 (dd, JHH = 9.1 Hz,
4JHH = 0.9 Hz, 1 H, ArH), 7.39 (td, 3JHH = 8.0 Hz, 4JHH = 1.1 Hz, 1
H, ArH), 7.02 (td, 3JHH = 6.8 Hz, 4JHH = 1.0 Hz, 1 H, ArH), 2.88 (t,
3JHH = 6.0 Hz, 2 H, CH2), 2.76 (3JHH = 6.1 Hz, 2 H, CH2), 1.93–2.02
(m, 4 H, CH2CH2).
LC-MS: m/z (%) = 174.4 (10), 173.4 (100) [M + H]+, 172.7 (3).
1H NMR (400 MHz, CD3OD): d = 8.69 (dt, 3JHH = 6.6 Hz, 4JHH
=
HRMS (TOF+): m/z calcd for C11H13N2: 173.1079; found:
173.1073.
3
1.2 Hz, 1 H, ArH), 7.95 (m, 2 H, ArH), 7.53 (ddd, JHH = 6.2 Hz,
3JHH = 6.0 Hz, 4JHH = 2.7 Hz, 1 H, ArH), 7.32 (m, 2 H, ArH), 6.95
(dd, 3JHH = 8.4 Hz, 4JHH = 2.7 Hz, 1 H, ArH), 3.87 (s, 3 H, OCH3),
3.26 (m, 4 H, CH2CH2).
2,3-Dipheny-lH-imidazo[1,2-a]pyridine (24)
Method B: 2-Bromo-1,2-diphenylethanone (28.4 mg, 0.100 mmol),
2-aminopyridine (11.3 mg, 0.120 mmol), titanium(IV) chloride
(0.075 mmol, 1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were
used to afford 24 as a white solid (24.0 mg, yield: 90%); mp 150–
152 °C.
1H NMR (400 MHz, CDCl3): d = 7.88 (d, 3JHH = 6.6 Hz, 1 H, ArH),
7.58–7.63 (m, 3 H, ArH), 7.36–7.49 (m, 5 H, ArH), 7.10–7.24 (m,
4 H, ArH), 6.66 (td, 3JHH = 6.6 Hz, 4JHH = 1.2 Hz, 1 H, ArH).
13C{1H} NMR (75 MHz, CD3OD): d = 160.8 (1 C, ArC), 141.7 (1
C, ArC), 134.2 (1 C, ArCH), 132.1 (1 C, ArC), 131.3 (1 C, ArCH),
129.0 (1 C, ArC), 127.9 (1 C, ArCH), 126.2 (1 C, ArC), 124.3 (1 C,
ArC), 118.7 (1 C, ArCH), 116.6 (1 C, ArCH), 113.1 (1 C, ArCH),
109.5 (1 C, ArCH), 56.2 (1 C, OCH3), 28.0 (1 C, CH2), 19.3 (1 C,
CH2).
LC-MS: m/z (%) = 252.4 (15) [M + H]+, 251.3 [M + H]+.
13C{1H} NMR (75 MHz, CDCl3): d = 145.0 (1 C, ArC), 142.6 (1 C,
ArC), 134.3 (1 C, ArC), 130.9 (2 C, ArCH), 130.1 (1 C, ArC), 129.7
(2 C, ArCH), 129.1 (1 C, ArCH), 128.5 (2 C, ArCH), 128.3 (2 C,
ArCH), 127.7 (1 C, ArCH), 124.9 (1 C, ArCH), 123.5 (1 C, ArCH),
121.3 (1 C, ArC), 117.7 (1 C, ArCH), 112.5 (1 C, ArCH).
HRMS (TOF+): m/z calcd for C16H15ON2: 251.1184; found:
251.1178.
Anal. Calcd for C16H15ClN2O: C, 67.02; H, 5.27; Cl, 12.36; N, 9.77.
Found: C, 66.68; H, 5.33; Cl, 12.30; N, 9.60.
LC-MS: m/z (%) = 272.5 (14) [M + H]+, 271.4 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C19H15N2: 271.1235; found:
2-Bromo-6,7,8,9-tetrahydrobenzoimidazo[1,2-a]pyridine (22)
Method B: 2-Chlorocyclohexanone (13.3 mg, 0.100 mmol), 5-bro-
mopyridin-2-amine (21.4 mg, 0.102 mmol), titanium(IV) chloride
(0.075 mmol, 1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were
used to afford 22 as a brown solid (5.5 mg, yield: 2.2%); mp > 320
°C (decomp.).
1H NMR (400 MHz, CD3OD): d = 8.31 (d, 4JHH = 1.2 Hz, 1 H, ArH),
7.39 (AB system, 2JHH = 12.8 Hz, 1 H, ArH), 7.31 (d, AB system,
2JHH = 12.4 Hz, 4JHH = 2.4 Hz, 1 H, ArH), 2.79 (t, 3JHH = 8.2 Hz, 4
H, CH2), 1.98 (m, 4 H, CH2).
13C{1H} NMR (100 MHz, CD3OD): d = 143.7 (1 C, ArC), 143.5 (1
C, ArC), 128.3 (1 C, ArCH), 124.9 (1 C, ArCH), 121.5 (1 C, ArC),
117.4 (1 C, ArCH), 107.5 (1 C, ArC), 25.5 (1 C, CH2), 24.3 (1 C,
CH2), 23.6 (1 C, CH2), 21.0 (1 C, CH2).
271.1223.
3-Methyl-2-pheny-lH-imidazo[1,2-a]pyridine (25)
Method A: 2-Bromo-1-phenylpropan-1-one (15.0 mL, 0.100 mmol),
2-aminopyridine (11.3 mg, 0.120 mmol), titanium(IV) chloride
(0.075 mmol, 1.0 M) in CH2Cl2 (75 mL), and CHCl3 (1.0 mL) were
used to afford 25 as a white solid (13.6 mg, yield: 65%); mp 238–
240 °C.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, 3JHH = 6.9 Hz, 1 H, ArH),
7.74 (dd, 3JHH = 8.4 Hz, 4JHH = 1.5 Hz, 2 H, ArH), 7.59 (dd, 3JHH
=
8.4 Hz, 4JHH = 1.2 Hz, 2 H, ArH), 7.40 (td, 3JHH = 7.2 Hz, 4JHH = 1.8
Hz, 2 H, ArH), 7.28 (td, 3JHH = 6.6 Hz, 4JHH = 1.2 Hz, 1 H, ArH),
7.12 (ddd, 3JHH = 9.0 Hz, 3JHH = 6.9 Hz, 4JHH = 1.2 Hz, 1 H, ArH),
6.79 (td, 3JHH = 6.9 Hz, 4JHH = 1.2 Hz, 1 H, ArH), 2.58 (s, 3 H, CH3).
LC-MS: m/z (%) = 253.4 (100), 251.3 (96) [M + H]+.
HRMS (TOF+): m/z calcd for C11H12BrN2: 251.0184; found:
13C{1H} NMR (125 MHz, CDCl3): d = 144.5 (1 C, ArC), 142.5 (1
C, ArC), 134.9 (1 C, ArC), 128.8 (2 C, ArCH), 128.6 (2 C, ArCH),
127.7 (1 C, ArCH), 123.9 (1 C, ArCH), 123.1 (1 C, ArCH), 117.7
(1 C, ArCH), 116.2 (1 C, ArCH), 116.2 (1 C, ArC), 112.4 (1 C,
ArCH), 29.9 (1 C, CH3).
LC-MS: m/z (%) = 210.4 (11) [M + H]+, 209.3 (100) [M + H]+.
HRMS (TOF+): m/z calcd for C14H13N2: 209.1079; found:
251.0171.
6,7,8,9-Tetrahydropyrido[1,2-a]benzimidazole (23)
2-Chlorocyclohexanone (13.3 mg, 0.10 mmol), 2-aminopyridine
(21.4 mg, 0.120 mmol), and a variety of solvents (1.0 mL), includ-
ing EtOH, n-BuOH, MeCN, DMF, and DMSO were used. The re-
action temperature ranged from 110 °C to 175 °C, with isolated
yield from 5% to 45%. Method A was also used to give 24% isolat-
ed yield of 23 as a white solid; mp > 360 °C (decomp.).
209.1083.
Synthesis 2006, No. 1, 133–145 © Thieme Stuttgart · New York

PAPER
Titanium(IV) Chloride Promoted Syntheses of New Imidazo[1,2-a]pyridines
145
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Acknowledgment
We are grateful to Dr. Shuiyu Lu (MIB, NIMH) for his help with
microwave reactions, to Dr. Umesha Shetty for some MS analysis
and NMR experiments.
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