Chemoselective arylsulfenylation of 2-aminoimidazo[1,2-α]pyridines by phenyliodine(III) bis(trifiuoroacetate) (PIFA)

Article abstract of DOI:10.1055/s-1998-2078

A series of 2-(trifluoroacetamido)imidazo[1,2-a]pyridines was prepared and treated with phenyliodine(III) bis(trifluoroacetate) (PIFA) in the presence of a variety of thiols leading chemoselectively to the corresponding 3-sulfides. Exposure of these adducts to silica gel in MeOH/CH₂Cl₂ provides a convenient method for the cleavage of the trifluoroacetamide group.

Full text of DOI:10.1055/s-1998-2078

June 1998
SYNTHESIS
867
Chemoselective Arylsulfenylation of 2-Aminoimidazo[1,2-a]pyridines by
Phenyliodine(III) Bis(trifluoroacetate) (PIFA)
Chafiq Hamdouchi,* Concha Sanchez, Jesús Ezquerra
Centro de Investigación Lilly, S. A. Paraje de la Cruz S/N, E-28130 Valdeolmos, Madrid, Spain
E-mail: Hamdouchi_Chafiq@Lilly.com
Received 6 October 1997; revised 17 November 1997
Abstract:
A series of 2-(trifluoroacetamido)imidazo[1,2-a]-
pyridines was prepared and treated with phenyliodine(III) bis(tri-
fluoroacetate) (PIFA) in the presence of a variety of thiols leading
chemoselectively to the corresponding 3-sulfides. Exposure of
these adducts to silica gel in MeOH/CH2Cl2 provides a convenient
method for the cleavage of the trifluoroacetamide group.
Key words: chemoselective sulfenylation, phenyliodine(III)
bis(trifluoroacetate), imidazopyridines, trifluoroacetamide hydrol-
ysis
Imidazopyridines and analogues,1 structurally related to
benzimidazoles, have demonstrated significant potential
in the search for new drugs.2 Their pharmacological pro-
file is critically dependent on the nature of the substitution
at the 3-position.2 Although sulfenyl, sulfinyl and sulfonyl
groups have been recognised for their distinguishing fea-
tures in structure–activity relationship studies,3 a conve-
nient approach to their incorporation in heterocyclic
systems, such as imidazopyridines and analogues, re-
mained unknown.
Scheme 1
Elegant approaches involving carbanions as intermedi-
ates, such as halogen–metal exchange,4 single electron
transfer (SET) reactions mediated by aromatic anion rad-
icals,5 Rieke metals,6 or the use of palladium-catalysed
cross-coupling reactions,7 suffer from the deficiency of
chemoselectivity.
We found an urgent need for a general, selective and con-
vergent approach that would allow the introduction of a
large variety of sulfur groups at C-3 of imidazopyridines
(Scheme 1) and be compatible with the presence of substit-
uents, such as iodo, chloro and methoxycarbonyl groups.
Benzenesulfenyl chloride has been already employed in an
electrophilic sulfenylation of imidazo[1,2-a]pyridine.2e
However, the reported yield was only 22% and the limited
number of the commercially available sulfenyl chlorides
precludes a structure–activity relationship investigation.
Scheme 2
In a recent report, Kita’s reagent, phenyliodine(III) bis(tri-
fluoroacetate) (PIFA), has been described as an efficient
mediator for the direct substitution of phenol ethers by
various thiophenols.8 Herein, we wish to report a new ap-
plication of this reagent in the sulfenylation of function-
alised imidazopyridmes.9
pyridine using the classical procedure and subsequent
treatment of the pyridin-2(1H)-imine 2 with iodoacet-
amide in the presence of Hünig’s base (i-Pr2NEt) in DMF
provided the corresponding carboxamides 3a–c in good
yield. In our hands, the use of Hünig’s base instead of the
reported NaH2e considerably enhanced the yield of the
alkylation. We were unable to detect the exo-alkylated
isomer that was reported to be the major product when the
reaction was performed in the presence of NaH.2e Conver-
sion of 3a–c to the desired 2-(trifluoroacetamido)imid-
azopyridines 4a–c was accomplished by treatment with
trifluoroacetic anhydride.11
For this investigation, we have designed and synthesised
the imidazopyridines 4a–c which differ by the type of
functionality at the 6-position in order to permit further
transformations.
The synthesis of 4a–c is outlined in Scheme 2. Reaction
of aminopyridines 110 with p-toluenesulfonyl chloride in

868
Papers
SYNTHESIS
Table 2. Hydrolysis of Trifluoroacetamides in the Presence of Silica
Gel (Scheme 4)
The sulfenylation of imidazo[1,2-a]pyridines 4a–c medi-
ated by the hypervalent iodine(III) reagent, phenylio-
dine(III) bis(trifluoroacetate) (PIFA), was investigated
using a variety of thiols. It should be noted that when the
thiol was injected into the mixture of imidazopyridine/
PIFA in 1,1,1,3,3,3-hexafluoropropan-2-ol, the reaction
failed to give the sulfenylated product. The PIFA should
be added after dissolving or suspending the substrate and
the thiol in hexafluoropropanol.
Substrate
R6
Ar
Compound
Yield (%)
7a
11a
7b
7c
11c
8c
Cl
Cl
I
CO2Me
CO2Me
CO2Me
4-ClC6H4
3-ClC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
4-FC6H4
12a
13a
12b
12c
13c
14c
70
72
81
88
65
55
Scheme 3
As noted in Table 1, a series of sulfenylated imidazopyri-
dine derivatives was prepared via reaction of the imid-
azopyridine with the appropriate and commercially
available thiol in the presence of PIFA. Substrates 4a–c
were converted to the corresponding sulfides 6a–11a, 6b–
9b, and 6c–11c in high yield. Only p-nitrobenzenethiol
failed to react and the starting material was recovered un-
changed. It should be emphasised that neither the ester
function in the substrate 4c nor the halogen in substrates 4a
and 4b were affected during the sulfenylation process.
Scheme
In conclusion, a direct and chemoselective sulfenylation
of imidazopyridine at C-3 has been developed. The high
yield observed in the examples reported, and the compat-
ibility with sensitive functions present in the molecule,
promise its application for the incorporation of sulfur
groups into a variety of heterocyclic analogues. A conve-
nient method for the hydrolysis of the appropriate trifluo-
roacetamides has also been described.
Table 1. Reaction of 4a–c with Arenethiols in the Presence of PIFA
Substrate Ar
Time
(h)
Compound Yield
(%)
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
Ph
4.5
4
5
4.5
4.5
20
4.5
4
6a
7a
8a
77
72
96
91
0
69
84
75
73
82
0
83
80
74
82
0
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
3-ClC6H4
Ph
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
Ph
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
3-ClC6H4
9a
10a
11a
6b
7b
8b
9b
10b
6c
7c
8c
All reagents were purchased from Aldrich and used without further
purification unless otherwise stated. Column chromatography was
carried out on flash silica gel (Merck 230–400 mesh). TLC analysis
was conducted on Whatman silica gel plates. 1H and 13C NMR spectra
were recorded at 200 MHz with DMSO-d6 or CDCl3 as solvent with
a Bruker AC-200 instrument. Chemicals shifts (d values) and cou-
pling constants (J values) are given in ppm and Hz respectively. C as-
signments were realised by DEPT and HMQC experiments. MS were
recorded on a VG-Autospec mass spectrometer.
5
4.5
4.5
4.5
4
5
4.5
4
9c
10c
11c
5-Chloro-N-tosylpyridin-2(1H)-imine (2a):
4
87
5-Chloropyridin-2-amine (1a) (10 g, 77.78 mmol) was dissolved in
anhyd pyridine (60 mL). TsCl (16.31 g, 85.56 mmol) was added and
the solution was heated at 80–90°C under argon overnight. Pyridine
was removed in vacuo to give a white solid. Water (1.5 L) was added
and the mixture was stirred for 90 min. The white solid was collected,
dried in vacuo and then crystallised (EtOAc, 200 mL) to give 21.2 g
(96%) of 2a as a white solid; mp 176°C (EtOAc).
All attempts to detrifluoroacetylate compounds 7a, 11a,
7b, 7c, 11c, and 8c using strongly basic conditions such as
NaOH or Hünig’s base failed to yield the respective
amines 12a, 13a, 12b, 12c, 13c, and 14c. Instead, the re-
action led to imidazo ring opening providing the aminopy-
ridine as the main product (Scheme 4). Surprisingly, the
trifluoro-acetamide group was hydrolysed when support-
ed on silica gel in a mixture of MeOH/CH2Cl2 (2:98) in
good yield (Table 2).
1H NMR (200 MHz, CDCl3): d = 2.39 (s, 3H), 7.41 (d,1H, J34 = 8.6
Hz, H3), 7.47 (AA¢BB¢ system, 4H, J = 8.4 Hz, ArH), 7.62 (dd, 1H,
J34= 8.6 Hz, J46 = 2.5 Hz, H4), 8.39 (d, 1H, J46 = 2.5 Hz, H6).
13C NMR (50 MHz, DMSO-d6): d = 21.0 (Me), 113.2, 125.0, 127.1,
129.6, 137.2, 138.3, 143.5, 146.2, 150.1.
MS (EI+): m/z (%) = 284.04 (M+ + 2, 2.0), 282.04 (M+, 5.6), 217.0
(100.0).

June 1998
SYNTHESIS
6-(Methoxycarbonyl)-2-(trifluoroacetamido)imidazo[1,2-a]pyri-
869
5-Iodo-N-tosylpyridin-2(1H)-imine (2b):
Compound 2b was prepared as described for 2a, starting from 5-io- dine (4c):
dopyridin-2-amine6 (1b). 2b was isolated as a brown solid in 85% Compound 3c (5 g, 13.76 mmol) in anhyd CH2Cl2 (75 mL) was dis-
yield; mp 205°C (EtOAc).
solved in TFAA and the solution was refluxed for 3 h. Solvents were
removed in vacuo and the solid was suspended in EtOAc (150 mL).
1H NMR (200 MHz, DMSO-d6): d = 2.34 (s, 3H), 6.92 (d, 1H, J34
=
8.7 Hz, H3), 7.56 (AA¢BB¢ system, 4H, J = 8.1 Hz, ArH), 7.98 (d, 1H, After stirring for 30 min, the solid was collected and again stirred in
J34 = 8.7 Hz, J46 = 2.2 Hz, H4), 8.34 (d, 1H, J46 = 2.2 Hz, H6), 11.23 water (50 mL) for 30 min. The solid was collected and dried in vacuo
(bs, 1H, NH). to give 1.92 g (49%) of 4c as a white solid; mp 216.2–217.9°C.
13C NMR (50 MHz, DMSO-d6): d = 21.2 (Me), 85.6 (C5), 114.3, 1H NMR (300 MHz, DMSO-d6): d = 3.88 (s, 3H), 7.57 (dd, 1H, J58
=
127.3, 129.8, 137.4, 143.6, 146.4, 150.9, 153.3.
0.7 Hz, J78 = 9.5 Hz, H8), 7.69 (dd, 1H, J57 = 1.7 Hz, J78 = 9.5 Hz, H7),
MS (FAB+): m/z = 374.9 (M + H)+, calcd 374.2.
8.41 (s, 1H, H3), 9.38 (dd, 1H, J57 = 1.7 Hz, J58 = 0.7 Hz, H5).
13C NMR (75 MHz, DMSO-d6, assigned by HMQC experiment): d =
52.3 (Me), 103.8 (C3), 115.2 (C8), 115.5 (q, JCF = 287.7 Hz, COCF3),
115.6, 124.3 (C7), 131.2 (C5), 140.6, 141.9, 154.1 (q, JCF = 39.0 Hz,
COCF3), 164.8 (CO2Me).
5-(Methoxycarbonyl)-N-tosylpyridin-2(1H)-imine (2c):
Compound 2c was prepared as described for 2a, starting from 5-
(methoxycarbonyl)pyridin-2-amine (1c). 2c was isolated as a white
solid in 93% yield; mp 214°C (EtOAc).
MS (FAB+): m/z = 288.1 (M + H)+, calcd 288.0.
1H NMR (200 MHz, DMSO-d6): d = 2.33 (s, 3H, ArMe), 3.79 (s, 3H,
CO2Me), 7.15 (d, 1H, J34 = 8.9 Hz, H3), 7.58 (AA¢BB¢ system, 4H, J
= 8.2 Hz, ArH), 8.12 (dd, 1H, J46 = 2.2 Hz, J34 = 8.9 Hz, H4), 8.57 (d,
1H, J46 = 2.2 Hz, H6), 12.06 (bs, 1H, NH).
6-Chloro-2-(trifluoracetamido)imidazo[1,2-a]pyridine (4a):
Compound 4a was prepared as described for 4c, starting from 3a.
After 5 h 4a was isolated as a white solid in 76% yield (25 mL of
EtOAc were required for 2.09 g of 3a and 50 mL of water); mp 243.9–
244.5°C (EtOAc).
13C NMR (50 MHz, DMSO-d6): d = 21.0 (ArMe), 52.1 (CO2Me),
112.0, 118.6, 127.1, 129.6, 137.5, 139.6, 143.4, 147.6, 155.1, 164.5
(CO2Me).
1H NMR (200 MHz, DMSO-d6): d = 7.33 (dd, 1H, J57 = 2.1 Hz, J78
= 9.5 Hz, H7), 7.55 (d, 1H, J78 = 9.5 Hz, H8), 8.24 (s, 1H, H3), 8.88 (d,
1H, J57 = 2.1 Hz, H5), 12.54 (bs, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 103.4 (C3), 115.7 (q, JCF = 287.3
Hz, COCF3), 116.6 (CH), 119.1, 125.0 (CH), 126.1 (CH), 139.8,
140.1, 154.1 (q, JCF = 38.5 Hz, COCF3).
1-(Carbamoylmethyl)-6-(methoxycarbonyl)-N-tosylpyridin-
2(1H)-imine (3c):
i-Pr2NEt (125.2 mL, 71.82 mmol) was added to a suspension of 2c (20
g, 65.3 mmol) in anhyd DMF (120 mL) under argon. To the resulting
solution was added 2-iodoacetamide (13.28 g, 71.82 mmol) and the
mixture was stirred at r.t. for 24 h. The solution was poured onto water
(60 mL) and stirred for 90 min. The solid was collected by filtration
and washed with water (1 L) then with Et2O (200 mL) and dried in
vacuo to give 3c as a white solid; yield: 21.76 g (92%).
1H NMR (200 MHz, DMSO-d6): d = 2.34 (s, 3H), 3.82 (s, 3H,
CO2Me), 4.89 (s, 2H), 7.39 (d, 1H, J34 = 9.5 Hz, H3), 7.39 (bs, 1H,
NH), 7.47 (AA¢BB¢ system, 4H, J = 8.1 Hz, ArH), 7.79 (bs, 1H, NH),
8.07 (dd, 1H, J34 = 9.5 Hz, J46 = 2.2 Hz, H4), 8.73 (d, 1H, J46 = 2.2 Hz,
H6).
MS (FAB+): m/z = 264.0 (M + H)+, calcd 264.0.
Anal. Calcd for C9H5ClF3N3O·0.33 H2O: C, 40.09; H, 2.12; N,
15.58. Found: C, 40.12; H, 2.13; N, 15.07.
6-Iodo-2-(trifluoroacetamido)imidazo[1,2-a]pyridine (4b):
Compound 4b was prepared as described for compound 4c, starting
from 3b. After 5 h, 4b was isolated as a white solid in 63% yield
(8 mL of EtOAc were required for 0.751 g of 3b and 50 mL of water);
mp 247°C (EtOAc).
1H NMR (200 MHz, DMSO-d6): d = 7.35 (dd, 1H, J58 = 0.9 Hz, J78
=
9.3 Hz, H8), 7.47 (dd, 1H, J57 = 1.6 Hz, J78 = 9.3 Hz, H7), 8.19 (s, 1H,
H3), 8.96 (dd,1H, J58 = 0.9 Hz, J57 = 1.6 Hz, H5), 12.50 (bs,1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 76.0 (C6), 102.6 (C3), 115.7 (q,
13C NMR (50 MHz, DMSO-d6): d = 20.9 (Me), 52.3 (Me), 54.7
(CH2), 112.6, 115.6 (CH), 125.9 (CH), 129.2 (CH), 139.6 (CH),
140.3, 141.8, 146.1 (CH), 156.1, 163.6 (CO2Me), 167.2 (CONH2).
MS (FAB+): m/z = 364.1 (M + H)+, calcd 363.4.
JCF = 287.3 Hz, COCF3), 117.1 (CH), 131.7 (CH), 132.9 (CH), 139.5
(C2 or C9), 139.9 (C9 or C2), 154.1 (q, JCF = 37.9 Hz, COCF3).
MS (FAB+): m/z = 356.0 (M + H)+, calcd 355.9.
1-(Carbamoylmethyl)-6-chloro-N-tosylpyridin-2(1H)-imine
(3a):
Anal. Calcd for C9H5F3IN3O·0.25 H2O: C, 30.06; H, 1.54; N, 11.69.
Found: C, 30.11; H, 1.65; N, 11.45.
Compound 3a was prepared as described for 3c, starting from 2a. 3a
was isolated as a white solid in 85% yield.
Sulfenylation at the 3-Position; General Procedure:
1H NMR (200 MHz, DMSO-d6): d = 2.32 (s, 3H), 4.78 (s, 2H), 7.32
(d, 1H, J34 = 9.7 Hz, H3), 7.43 (bs, 1H, NH), 7.45 (AA¢BB¢ system,
4H, J = 8.1 Hz, ArH), 7.81 (bs, 1H, NH), 7.82 (dd, 1H, J34 = 9.7 Hz,
PIFA (1.5 equiv) was added to a stirred solution (or suspension) of
imidazo[1,2-a]pyridine 4a–c (50 mg) and arenethiol (2 equiv) in
1,1,1,3,3,3-hexafluoropropan-2-ol (1 mL) at r.t. under argon. The
mixture was stirred for several hours (see Table). The solvents were
removed and the resulting solid was dissolved in CH2Cl2 (15 mL) and
washed with brine. After drying (Na2SO4) the solvent was removed.
The solid was washed with CH2Cl2 or CH2Cl2/hexane (1:1) to give
the sulfenylated material as a white solid in its pure form.
J
46 = 2.7 Hz, H4), 8.33 (d, 1H, J46 = 2.7 Hz, H6).
13C NMR (50 MHz, DMSO-d6): d = 20.9 (Me), 54.5 (CH2), 115.6,
116.9, 125.9, 140.1, 140.5, 141.5, 154.1, 167.1 (CONH2).
MS (EI+): m/z (%) = 341.1 (M+ + 2, 6.4), 339.1 (M+, 17.4), 91 (100.0).
1-(Carbamoylmethyl)-6-iodo-N-tosylpyridin-2(1H)-imine (3b):
Compound 3b was prepared as described for 3c, starting from 2b. 3b
was isolated as a brown solid in 86% yield; mp 246.7–247.5°C.
1H NMR (200 MHz, DMSO-d6): d = 2.32 (s, 3H), 4.75 (s, 2H), 7.15
(d, 1H, J34 = 9.5 Hz, H3), 7.38 (bs, 1H, NH), 7.43 (AA¢BB¢ system,
4H, J = 8.2 Hz, ArH), 7.77 (bs, 1H, NH), 7.90 (dd, 1H, J34 = 9.5 Hz,
6-Chloro-3-(phenylthio)-2-(trifluoroacetamido)imidazo[1,2-a]pyridine
(6a): isolated in 77% yield after washing with CH2Cl2/hexane (1:1).
1H NMR (200 MHz, CDCl3): d= 6.91–6.97 (m, 2H,ArH), 7.14–7.20 (m,
3H, ArH), 7.30 (dd, 1H, J57 = 2.0 Hz, J78 = 9.5 Hz, H7), 7.59 (d, 1H, J78
= 9.5 Hz, H8), 8.13 (d, 1H, J57 = 2.0 Hz, H5), 8.84 (bs, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 105.7 (C3), 115.7 (q, JCF
=
J
46 = 2.2 Hz, H4), 8.35 (d, 1H, J46 = 2.2 Hz, H6).
13C NMR (50 MHz, DMSO-d6): d = 20.9 (Me), 54.2 (CH2), 71.6
(C5), 117.6 (CH), 125.9 (CH), 129.2 (CH), 140.6, 141.5, 146.5 (CH),
148.3, 154.2, 167.3 (CONH2).
288.6 Hz, COCF3), 118.3, (CH), 121.5 (CH), 122.5 (CH), 126.8 (CH),
128.5 (CH), 133.1 (CH), 133.1, 143.0, 144.1, 155.8 (q, JCF = 37.0 Hz,
COCF3).
MS (FAB+): m/z = 432.0 (M + H)+, calcd 432.2.
MS (FAB+): m/z = 372.1 (M + H)+, calcd 371.0.

870
Papers
SYNTHESIS
13C NMR (50 MHz, DMSO-d6): d = 52.7 (CO2Me), 105.2 (C3), 115.8
(q, JCF = 286.0 Hz, COCF3), 117.3, 117.5 (CH), 126.6 (CH), 127.4
Anal. Calcd for C15H9ClF3N3OS ·0.2 H2O: C, 48.46; H, 2.44; N, 11.3.
Found: C, 48.31; H, 2.56; N, 11.03.
(CH), 128.0 (CH), 129.6 (CH), 131.4, 132.4, 145.4, 155.3 (q, JCF
37.5 Hz, COCF3), 164.2 (CO2Me).
=
6-Iodo-3-(phenylthio)-2-(trifluoroacetamido)imidazo[1,2-a]pyridine
(6b): isolated in 84% yield after washing with CH2Cl2/hexane (1:1).
1H NMR (200 MHz, CDCl3): d = 6.85–6.98 (m, 2H, ArH), 7.12–7.26
(m, 3H, ArH), 7.41 (dd, 1H, J58 = 0.7 Hz, J78 = 9.4 Hz, H8), 7.49 (dd,
1H, J57 = 1.6 Hz, J78 = 9.4 Hz, H7), 8.32 (m, 1H, H5), 9.05 (bs, 1H,
NH).
MS (FAB+): m/z = 430.0 (M + H)+, calcd 430.1.
Anal. Calcd for C17H11ClF3N3O3S ·1 H2O: C, 45.59; H, 2.93 ; N, 9.38.
Found: C, 45.54; H, 2.56; N, 9.05.
6-Chloro-3-(4-fluorophenylthio)-2-(trifluoroacetamido)imidazo[1,2-
a]pyridine (8a): isolated in 96% yield after washing with CH2Cl2/
hexane (1:1).
13C NMR (50 MHz, DMSO-d6): d = 78.9 (C6), 104.6 (C3), 115.9 (q,
JCF = 286.5 Hz, COCF3), 118.6 (CH), 126.6 (CH), 126.7 (CH), 128.9
(CH), 129.6 (CH), 133.2, 135.3 (CH), 143.2, 143.8, 155.8 (q, JCF
35.9 Hz, COCF3).
=
1H NMR (200 MHz, CDCl3): d = 6.86–7.03 (m, 4H, ArH), 7.30 (dd,
1H, J57 = 2.0 Hz, J78 = 9.5 Hz, H7), 7.58 (dd, 1H, J58 = 0.7 Hz, J78
=
MS (FAB+): m/z = 464.0 (M + H)+, calcd 463.9.
9.5 Hz, H8), 8.13 (dd, 1H, J57 = 2.0 Hz, J58 = 0.7 Hz, H5), 8.69 (bs,
1H, NH).
Anal. Calcd for C15H9F3IN3OS: C, 38.59; H, 2.03; N, 9.00. Found: C,
38.69; H, 2.16; N, 8.63.
13C NMR (50 MHz, DMSO-d6): d = 106.3 (C3), 115.8 (q, JCF = 288.2
Hz, COCF3), 116.6 (d, CH, JCF = 22.2 Hz), 118.3 (CH), 118.7, 121.6,
122.6 (CH), 128.5 (CH), 129.6 (d, CH, JCF = 8.1 Hz), 143.0, 143.9,
155.9 (q, JCF = 37.5 Hz, COCF3), 161.3 (d, JCF = 244.6 Hz).
MS (FAB+): m/z = 390.1 (M + H)+, calcd 390.1.
6-(Methoxycarbonyl)-3-(phenylthio)-2-(trifluoracetamido)imid-
azo[1,2-a]pyridine (6c): isolated in 83% yield after washing with
CH2Cl2/hexane (1:1).
1H NMR (200 MHz, CDCl3): d = 3.86 (s, 3H, CO2Me), 6.93–6.98 (m,
Anal. Calcd for C15H8ClF4N3OS: C, 45.80; H, 2.15; N, 10.68. Found:
C, 45.70; H, 2.17; N, 10.66.
2H, ArH), 7.13–7.24 (m, 3H, ArH), 7.66 (dd, 1H, J58 = 0.9 Hz, J78
=
9.4 Hz, H8), 7.88 (dd, 1H, J57 = 1.7 Hz, J78 = 9.4 Hz, H7), 8.80 (bs,
1H, NH), 8.83 (dd, 1H, J57 = 1.7 Hz, J78 = 9.4 Hz, H5).
13C NMR (50 MHz, DMSO-d6): d = 52.7 (CO2Me), 106.0 (C3), 115.8
(q, JCF = 288.6 Hz, COCF3), 117.2 (CH), 117.3, 126.4 (CH), 126.5
(CH), 126.8 (CH), 127.4 (CH), 129.7 (CH), 133.1, 145.2, 145.3,
155.7 (q, JCF = 37.5 Hz, COCF3), 164.2 (CO2Me).
3-(4-Fluorophenylthio)-6-iodo-2-(trifluoroacetamido)imidazo[1,2-
a]pyridine (8b): isolated in 73% yield after washing with CH2Cl2.
1H NMR (200 MHz, CDCl3): d = 6.87–7.02 (m, 4H), 7.41 (dd, J58
=
0.9 Hz, J78 = 9.3 Hz, 1H, H8), 7.52 (dd, J57 = 1.6 Hz, J78 = 9.3 Hz, 1H,
H7), 8.33 (dd, J57 = 1.6 Hz, J58 = 0.9 Hz, 1H, H5), 8.71 (bs, 1H).
13C NMR (50 MHz, DMSO-d6): d = 79.0 (C6), 105.1 (C3), 115.8 (q,
MS (FAB+): m/z = 396.1 (M + H)+, calcd 396.1.
Anal. Calcd for C17H12F3N3O3S: C, 51.64; H, 3.06; N, 10.63. Found:
C, 51.58; H, 3.14; N, 10.70.
JCF = 286.5 Hz, COCF3), 116.6 (d, JCF = 22.3 Hz), 118.6 (CH), 128.6
(d, JCF = 3.0 Hz), 128.9 (CH), 129.4 (d, JCF = 8.2 Hz), 134.5 (CH),
143.2, 143.3, 155.8 (q, JCF = 37.0 Hz, COCF3), 161.2 (d, JCF = 244.1
Hz).
6-Chloro-3-(4-chlorophenylthio)-2-(trifluoroacetamido)imid-
azo[1,2-a]pyridine (7a): isolated in 72% yield after washing with
CH2Cl2.
MS (FAB+): m/z = 482.1 (M + H)+, calcd 481.9.
Anal. Calcd for C15H8F4IN3OS: C, 37.00; H, 1.79; N, 8.62. Found: C,
36.94; H, 1.82; N, 8.44.
1H NMR (200 MHz, CDCl3): d = 7.03 (AA¢BB¢ system, 4H, J = 8.7
Hz, ArH), 7.32 (dd, 1H, J57 = 2.0 Hz, J78 = 9.5 Hz, H7), 7.59 (dd, 1H,
J58 = 0.8 Hz, J78 = 9.5 Hz, H8), 8.09 (dd, 1H, J57 = 2.0 Hz, J58
0.8 Hz, H5), 8.79 (bs, 1H, NH).
=
3-(4-Fluorophenylthio)-6-(methoxycarbonyl)-2-(trifluoroacetami-
do)imidazo[1,2-a]pyridine (8c): isolated in 74% yield after washing
with CH2Cl2.
13C NMR (50 MHz, DMSO-d6): d = 105.1 (C3), 115.8 (q, JCF
=
285.0 Hz, COCF3), 118.4, (CH), 121.6 (CH), 122.5 (CH), 128.4
(CH), 128.7 (CH), 129.4 (CH), 131.4, 132.4, 143.2, 144.3, 155.8 (q,
1H NMR (200 MHz, CDCl3): d = 3.87 (s, 3H, CO2Me), 6.86–7.06 (m,
4H, ArH), 7.64 (dd, 1H, J58 = 0.9 Hz, J78 = 9.4 Hz, H8), 7.89 (dd, 1H,
JCF = 38.3 Hz, COCF3).
MS (FAB+): m/z = 406.0 (M + H)+, calcd 406.0.
Anal. Calcd for C15H8Cl2F3N3OS·0.2 H2O: C, 43.96; H, 2.07; N,
10.25. Found: C, 43.97; H, 2.37; N, 9.95.
J57 = 1.7 Hz, J78 = 9.4 Hz, H7), 8.85 (dd, 1H, J57 = 1.7 Hz, J58
0.9 Hz, H5), 8.88 (bs,1H, NH).
=
13C NMR (50 MHz, DMSO-d6): d = 52.7 (CO2Me), 106.4 (C3), 115.8
(q, JCF = 288.6 Hz, COCF3), 116.8 (d, CH, JCF = 18.3 Hz), 117.3
(CH), 117.4, 126.5 (CH), 127.4 (CH), 128.5 (d, JCF = 2.2 Hz), 129.0
(d, CH, JCF = 8.2 Hz), 145.0, 145.3, 155.7 (q, JCF = 38.5 Hz, COCF3),
161.2 (d, JCF = 244.2 Hz), 164.3 (CO2Me).
3-(4-Chlorophenylthio)-6-iodo-2-(trifluoroacetamido)imidazo[1,2-
a]pyridine (7b): isolated in 75% yield after washing with CH2Cl2.
1H NMR (200 MHz, DMSO-d6): d = 7.20 (AA¢BB¢ system, 4H, J =
MS (FAB+): m/z = 414.1 (M + H)+, calcd 414.1.
8.6 Hz, ArH), 7.58 (dd, 1H, J78 = 9.4 Hz, H8), 7.73 (dd, 1H, J57
1.6 Hz, J78 = 9.4 Hz, H7), 8.47 (m, 1H, H5), 11.93 (bs, 1H, NH).
=
Anal. Calcd for C17H11F4N3O3S: C, 48.34; H, 2.86; N, 9.90. Found:
C, 48.45; H, 2.58; N, 9.89.
13C NMR (50 MHz, DMSO-d6): d = 79.6 (C6), 104.0 (C3), 115.8 (q,
JCF = 285.7 Hz, COCF3), 118.6 (CH), 128.2 (CH), 129.0 (CH), 129.5
(CH), 131.4, 132.5, 135.5 (CH),143.4, 143.7, 155.8 (q, JCF = 38.1 Hz,
COCF3).
6-Chloro-3-(4-methoxyphenylthio)-2-(trifluoroacetamido)imid-
azo[1,2-a]pyridine (9a): isolated in 91% yield after washing with
CH2Cl2/hexane (1:1).
MS (FAB+): m/z = 497.9 (M + H)+, calcd 497.9.
Anal. Calcd for C15H8ClF3IN3OS·0.25 H2O: C, 35.88; H, 1.71; N,
8.37. Found: C, 35.92; H, 1.72; N, 8.07.
1H NMR (200 MHz, DMSO-d6): d = 3.69 (s, 3H, OMe), 7.04 (AA¢BB¢
system, 4H, J = 8.8 Hz, ArH), 7.54 (dd, 1H, J57 = 1.9 Hz, J78 = 9.4 Hz,
H7), 7.76 (d, 1H, J78 = 9.4 Hz, H8), 8.50 (d, 1H, J57 = 1.9 Hz, H5),
11.92 (bs, 1H, NH).
3-(4-Chlorophenylthio)-6-(methoxycarbonyl)-2-(trifluoroacetami-
do)imidazo[1,2-a]pyridine (7c): isolated in 80% yield after washing
with CH2Cl2.
13C NMR (50 MHz, DMSO-d6): d = 55.2 (OMe), 107.9 (C3), 115.2
(CH), 115.3 (q, JCF = 286.0 Hz, COCF3), 118.3, (CH), 121.3, 122.5
1H NMR (200 MHz, CDCl3): d = 3.98 (s, 3H, CO2Me), 7.04 (AA¢BB¢
system, 4H, J = 8.6 Hz, ArH), 7.65 (dd, 1H, J58 = 1.0 Hz, J78 = 9.4 Hz,
(CH), 122.8, 128.2 (CH), 130.4, (CH), 142.6, 143.4, 155.9 (q, JCF
36.8 Hz, COCF3), 158.9.
=
H8), 7.90 (dd, 1H, J57 = 1.7 Hz, J78 = 9.4 Hz, H7), 8.81 (dd, 1H, J57
1.7 Hz, J58 = 1.0 Hz, H5), 10.15 (bs, 1H, NH).
=
MS (FAB+): m/z = 402.1 (M + H)+, calcd 402.0.

June 1998
SYNTHESIS
871
6-Iodo-3-(4-methoxyphenylthio)-2-(trifluoroacetamido)imidazo[1,2- 2-Amino-6-chloro-3-(4-chlorophenylthio)imidazo[1,2-a]pyridine
a]pyridine (9b): isolated in 82% yield after washing with CH2Cl2/ (12a): isolated in 70% yield after column chromatography.
hexane (1:1).
1H NMR (200 MHz, CDCl3): d = 4.43 (bs, 2H, NH2), 7.06 (AA¢BB¢
1H NMR (200 MHz, DMSO-d6): d = 3.69 (s, 3H, OMe), 7.00 (AA¢BB¢ system, 4H, J = 8.6 Hz, ArH), 7.07 (dd, 1H, J57 = 2.0 Hz, J78 = 9.3 Hz,
system, 4H, J = 8.8 Hz, ArH), 7.55 (d, 1H, J78 = 9.4 Hz, H7), 7.69 (dd, H7), 7.34 (dd, 1H, J58 = 0.8 Hz, J78 = 9.5 Hz, H8), 8.05 (dd, 1H, J57
1H, J57 = 1.6 Hz, J78 = 9.4 Hz, H8), 8.52 (m, 1H, H5), 11.90 (bs, 1H, 2.0 Hz, J58 = 0.8 Hz, H5).
=
NH).
13C NMR (50 MHz, CDCl3): d = 89.9, 115.2 (CH), 120.2, 121.5 (CH),
13C NMR (50 MHz, DMSO-d6): d = 55.3 (OMe), 78.8 (C6), 106.7 126.6 (CH), 127.0 (CH), 129.4, (CH), 132.1, 133.9, 144.0, 157.0.
(C3), 115.3 (CH), 115.9 (q, JCF = 286.5 Hz, COCF3), 118.6 (CH),
122.9, 128.9 (CH), 130.2 (CH), 135.0 (CH), 142.6, 142.8, 155.7 (q,
2-Amino-3-(4-chlorophenylthio)-6-iodoimidazo[1,2-a]pyridine
JCF = 37.6 Hz, COCF3), 158.8.
(12b): isolated in 81% yield after washing with hexane.
MS (FAB+): m/z = 494.0 (M + H)+, calcd 493.9.
Anal. Calcd for C16H11F3IN3O2S: C, 35.70; H, 3.00; N, 7.81. Found:
C, 35.90; H, 2.20; N, 7.84.
1H NMR (200 MHz, DMSO-d6): d = 4.37 (bs, 2H, NH2), 6.99
(AA¢BB¢ system, 4H, J = 8.5 Hz, ArH), 7.11 (dd, 1H, J58 = 0.6 Hz, J78
= 9.1 Hz, H8), 7.35 (dd, 1H, J57 = 1.7 Hz, J78 = 9.1 Hz, H7), 8.16 (dd,
1H, J57 = 1.7 Hz, J58 = 0.6 Hz, H5).
6-(Methoxycarbonyl)-3-(4-methoxyphenylthio)-2-(trifluoroacetami-
do)imidazo[1,2-a]pyridine (9c): isolated in 82% yield after washing (CH), 127.3 (CH), 129.3 (CH), 130.5, 133.2 (CH), 135.3, 144.1,
13C NMR (50 MHz, CDCl3): d = 74.5 (C6), 86.7, 115.3 (CH), 126.9
with CH2Cl2/hexane (1:1).
157.9.
1H NMR (200 MHz, DMSO-d6): d = 3.68 (s, 3H, OMe), 3.86 (s, 3H, MS (FAB+): m/z = 402.0 (M + H)+, calcd 401.9.
CO2Me), 7.01 (AA¢BB¢ system, 4H, J = 8.6 Hz, ArH), 7.79 (d, 1H, J78 HRMS (FAB) calcd for C13H10ClN2S 401.932874, found
= 9.4 Hz, H8), 7.87 (dd, 1H, J57 = 1.3 Hz, J78 = 9.4 Hz, H7), 8.79 (m, 401.931500.
1H, H5), 12.02 (bs,1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 52.7 (CO2Me), 55.2 (OMe),
2-Amino-3-(4-chlorophenylthio)-6-(methoxycarbonyl)imidazo[1,2-
108.0 (C3), 115.4 (CH), 115.9 (q, JCF = 288.6 Hz, COCF3), 117.3
(CH), 122.9, 126.2 (CH), 127.5 (CH), 129.8 (CH), 144.4, 144.9,
155.8 (q, JCF = 37.4 Hz, COCF3), 158.8, 164.3 (CO2Me).
MS (FAB+): m/z = 426.1 (M + H)+, calcd 426.1.
Anal. Calcd for C18H14F3N3O4S: C, 50.29; H, 3.40; N, 9.77. Found:
C, 50.25; H, 3.17; N, 9.58.
a]pyridine (12c): isolated in 88% yield after washing with hexane.
1H NMR (200 MHz, CDCl3): d = 3.84 (s, 3H, CO2Me), 4.47 (bs, 2H,
NH2), 7.00 (AA¢BB¢ system, 4H, J = 8.7 Hz, ArH), 7.33 (dd, 1H, J58
= 0.8 Hz, J78 = 9.2 Hz, H8), 7.75 (dd, 1H, J57 = 1.8 Hz, J78 = 9.2 Hz,
H7), 8.68 (dd, 1H, J57 = 1.8 Hz, J58 = 0.8 Hz, H5), 10.15 (bs, 1H, NH).
13C NMR (50 MHz, DMSO-d6): d = 51.7 (CO2Me), 87.2, 112.9 (CH),
114.4, 124.8 (CH), 125.2 (CH), 126.7 (CH), 129.0 (CH), 130.5,
134.7, 146.1, 158.8, 164.4 (CO2Me).
6-Chloro-3-(3-chlorophenylthio)-2-(trifluoroacetamido)imid-
azo[1,2-a]pyridine (11a): isolated in 69% yield after washing with
hexane.
MS (FAB+): m/z = 334.1 (M + H)+, calcd 334.0.
HRMS (FAB) calcd for C15H13ClN3O2S 334.041701, found
334.042000.
1H NMR (200 MHz, CDCl3): d = 6.77–6.83 (m, 1H, ArH), 6.92–6.94
(m, 1H, ArH), 7.10–7.14 (m, 2H, ArH), 7.33 (dd, 1H, J57 = 2.0 Hz, J78
= 9.5 Hz, H7), 7.61 (dd, 1H, J58 = 0.8 Hz, J78 = 9.5 Hz, H8), 8.11 (dd,
1H, J57 = 2.0 Hz, J58 = 0.8 Hz, H5), 8.96 (bs, 1H, NH).
2-Amino-6-chloro-3-(3-chlorophenylthio)imidazo[1,2-a]pyridine
(13a): isolated in 72% yield after column chromatography.
13C NMR (50 MHz, DMSO-d6): d = 104.6 (C3), 115.8 (q, JCF
=
1H NMR (200 MHz, CDCl3): d = 4.49 (bs, 2H, NH2), 6.74–6.79 (m,
1H, ArH), 6.87–6.89 (m, 1H, ArH), 7.00–7.07 (m, 2H, ArH), 7.11
(dd, 1H, J57 = 2.0 Hz, J78 = 9.3 Hz, H7), 7.25 (dd, 1H, J58 = 0.8 Hz,
288.1 Hz, COCF3), 118.4 (CH), 121.7, 122.7 (CH), 125.1 (CH),
126.0 (CH), 126.7 (CH), 128.8 (CH), 131.0 (CH), 134.1, 135.8,
143.2, 144.5, 155.8 (q, JCF = 37.9 Hz, COCF3).
J
78 = 9.3 Hz, H8), 8.07 (dd, 1H, J57 = 2.0 Hz, J58 = 0.8 Hz, H5).
MS (FAB+): m/z = 406.1 (M + H)+, calcd 406.0.
13C NMR (50 MHz, CDCl3): d = 89.2, 115.1 (CH), 120.1, 121.5 (CH),
123.2 (CH), 124.9 (CH), 126.3 (CH), 127.1 (CH), 130.3, (CH), 135.3,
137.7, 144.1, 157.3.
Anal. Calcd for C15H8Cl2F3N3OS: C, 44.07; H, 2.04; N, 10.28.
Found: C, 44.08; H, 2.09; N, 10.04.
MS (FAB+): m/z = 310.1 (M + H)+, calcd 310.0.
HRMS (FAB) calcd for C13H10NCl2N3S 309.997250, found
309.996300.
3-(3-Chlorophenylthio)-6-(methoxycarbonyl)-2-(trifluoroacetami-
do)imidazo[1,2-a]pyridine (11c): isolated in 87% yield after washing
with CH2Cl2.
1H NMR (200 MHz, CDCl3): d = 3.87 (s, 3H, CO2Me), 6.83–6.88 (m,
1H, ArH), 6.95–6.97 (m, 1H, ArH), 7.06–7.11(m, 1H, ArH), 7.62 (dd,
2-Amino-3-(3-chlorophenylthio)-6-(methoxycarbonyl)imidazo[1,2-
a]pyridine (13c): isolated in 65% yield after column chromatography.
1H NMR (200 MHz, CDCl3): d = 3.84 (s, 3H, CO2Me), 4.50 (bs, 2H,
1H, J58 = 0.8 Hz, J78 = 9.3 Hz, H8), 7.92 (dd, 1H, J57 = 1.7 Hz, J78
=
NH2), 7.00 (AA¢BB¢ system, 4H, J = 8.6 Hz, ArH), 7.33 (d, 1H, J78
=
9.3 Hz, H7), 8.81 (dd, 1H, J57 = 1.7 Hz, J58 = 0.8 Hz, H5), 10.52
(bs,1H, NH).
9.1 Hz, H8), 7.76 (dd, 1H, J57 = 1.7 Hz, J78 = 9.1 Hz, H7), 8.68 (d, 1H,
13C NMR (50 MHz, CDCl3): d = 52.8 (CO2Me), 103.5 (C3), 115.7 (q,
JCF = 287.5 Hz, COCF3), 116.8, 118.3, 124.4, 126.1, 127.2, 127.6,
127.9, 130.6, 135.3, 135.5, 145.6, 146.0, 154.9 (q, JCF = 39.0 Hz,
COCF3), 164.5 (CO2Me).
J
57 = 1.7 Hz, H5).
13C NMR (50 MHz, DMSO-d6): d = 52.7 (CO2Me), 87.2, 112.9 (CH),
114.4, 124.8 (CH), 125.2 (CH), 126.7 (CH), 129.0 (CH), 130.5,
134.7, 146.1, 158.8, 164.4 (CO2Me).
MS (FAB+): m/z = 334.1 (M + H)+, calcd 334.0.
MS (FAB+): m/z = 430.0 (M + H)+, calcd 430.0.
2-Amino-3-(4-fluorophenylthio)-6-(methoxycarbonyl)imidazo[1,2-
a]pyridine (14c): isolated in 55% yield after column chromatography.
1H NMR (200 MHz, CDCl3): d = 3.84 (s, 3H, CO2Me), 4.53 (bs, 2H,
NH2), 6.82–6.96 (m, 4H, ArH), 7.31 (dd, J58 = 0.9 Hz, J78 = 9.2 Hz,
H8), 7.74 (dd, J57 = 1.7 Hz, J78 = 9.2 Hz, H7), 8.71 (dd, J57 = 1.7 Hz,
Hydrolysis of Trifluoroacetamides; General Procedure:
The respective imidazopyridine trifluoroacetamide derivative was dis-
solved in CH2Cl2/MeOH (98:2, 15 mL). Silica gel was added to the so-
lution. The mixture was stirred vigorously for 1–2 d. The conversion to
the amine was followed by TLC (CH2Cl2/MeCN 4:1). The residue was
filtered and the silica gel was washed with MeCN (10 mL). Removal of
the solvents gave the desired compound as a pale-yellow solid.
J58 = 0.9 Hz, H5).
13C NMR (50 MHz, CDCl3): d = 52.3 (CO2Me), 90.6, 113.9 (CH),
115.9, 116.4 (d, CH, JCF = 22.3 Hz), 126.0 (CH), 126.9 (CH), 127.4

872
Papers
SYNTHESIS
(d, CH, JCF = 8.0 Hz), 130.5 (d, JCF = 3.1 Hz), 146.5, 157.6, 161.5 (d,
JCF = 245.9 Hz), 164.4 (CO2Me).
Newall, C. E.; Hallam, D. P. In Comprehensive Medicinal Chem-
istry; Hansch, C.; Sammes, P. G.; Taylor, J. B., Eds.; Pergamon:
Oxford, 1990; Vol. 2; pp 609–653.
MS (FAB+): m/z = 318.1 (M + H)+, calcd 318.0.
HRMS (FAB) calcd for C15H13FN3O2S 318.07125, found 318.07040.
(4) Griffen, E. J.; Roe, D. G.; Snieckus, V. J. Org. Chem. 1995, 60,
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Freeman, P. K.; Hutchinson, L. L. J.Org. Chem. 1983, 48, 4705
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Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
(6) Fürstner, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 164.
Rieke, R. D. Science 1989, 246, 1260.
This research was supported by a CDTI programme (Plan concer-
tado 96/0036) and the Spanish Farma III programme (Ministerio de
Industria y Ministerio de Sanidad). C. S. is grateful to the Spanish
Ministery of Education for a postdoctoral fellowship. We are also
grateful to the Lilly Infectious Disease Action Group and Lilly
Research Process and Development for stimulating discussions.
Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1988, 53, 4482.
Wu Tse, C.; Xiong, H.; Rieke, R. D. J. Org. Chem. 1990, 55,
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Minguez, L. M.; Gandásegui, T.; Vaquero, J. J.; Alvarez-Builla,
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(9) For leading references on the use of hypervalent iodine(III) see:
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(11) During the formation of 4c we were able to isolate 4.8% of
another regioisomer that probably is derived from the migration
of the CF3CO from the amino group to the 3-position.
(3) Caldwell, C.; Mitchell, S. C. In Comprehensive Medicinal Chem-
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