Synthesis of substituted imidazo[1,5-a]pyridines starting from N-2-pyridyl-methylamides using Lawesson's reagent and mercury(II) acetate

Article abstract of DOI:10.1055/s-2007-983852

A new method for the synthesis of substituted imidazo[1,5-a]pyridines (2-azaindolizines) starting from carboxylic acid and 2-methylaminopyridine is described. The reaction of the obtained N-2-pyridylmethylamides with Lawesson's reagent gene-rated the targ

Full text of DOI:10.1055/s-2007-983852

PAPER
2667
Synthesis of Substituted Imidazo[1,5-a]pyridines Starting from N-2-Pyridyl-
methylamides Using Lawesson’s Reagent and Mercury(II) Acetate
S
ynthesisof Imida
l
zo[1,5-
i
a
]pyrid
n
inesfrom
N
-
2-Pyridylmethyla
M
mides oulin, Sandra Garcia, Jean Martinez, Jean-Alain Fehrentz*
Institut des Biomolécules Max Mousseron, UMR 5247 Faculté de Pharmacie, CNRS - Universités Montpellier I et II, 15 avenue Charles
Flahault, BP 1441, 34093 Montpellier Cedex 5, France
Fax +33(4)67548654; E-mail: jean-alain.fehrentz@univ-montp1.fr
Received 28 February 2007; revised 19 April 2007
rated the target compound 4 along with the corresponding
Abstract: A new method for the synthesis of substituted imida-
thioamide intermediate 3. After a simple filtration on alu-
mina to eliminate the inorganic residues from Lawesson’s
reagent, the addition of mercury(II) acetate allowed the
zo[1,5-a]pyridines (2-azaindolizines) starting from carboxylic acid
and 2-methylaminopyridine is described. The reaction of the ob-
tained N-2-pyridylmethylamides with Lawesson’s reagent gene-
rated the target imidazopyridines, along with the corresponding total conversion of the remaining N-2-pyridylmethylthio-
thioamide intermediates. After a simple filtration on alumina, addi-
tion of mercury(II) acetate allowed for total conversion of the thio-
amides into the imidazopyridines. The reaction conditions, as well
Scheme 1. The formation of the thioamide 3 is followed
as the influence of the substituent in position 3 of the imidazopyri-
dine ring were explored. We also demonstrated that this heterocy-
amide 3 into the imidazo[1,5-a]pyridine 4. A possible
mechanism for the cyclization reaction is displayed in
by a nucleophilic attack of the thiocarbonyl group by the
nitrogen of the pyridyl moiety. Then a re-aromatization
produced the final product 4. We already proposed this
type of mechanism to explain the one-pot formation of
1,2,4-triazolo[4,3-a]pyridines,18 starting from the corre-
sponding acetohydrazide. The fact that a thiophile, for ex-
ample mercury(II) acetate, is necessary to totally convert
the thioamide 3 into the imidazopyridine 4, contrary to
what was observed for the conversion of the thioacetohy-
drazides into the corresponding triazolopyridines,
suggests a lower reactivity of the N-2-methylpyridylthio-
amides compared to the thioacetohydrazides, in this type
of desulfurization-promoted cyclization.
clization was racemization free in the presence of a chiral carbon in
position a to the heterocycle.
Key words: heterocycles, imidazo[1,5-a]pyridines, 2-azaindoliz-
ines, Lawesson’s reagent, mercury(II) acetate
Imidazo[1,5-a]pyridines (2-azaindolizines) are an impor-
tant class of heterocyclic compounds. They express anti-
viral properties (e.g., HIV-protease inhibitory
activities).1–3 They can also have potential applications in
the context of organic light-emitting diodes (OLED)4–6
and organic thin-layer field effect transistors (FET).7 Fur-
thermore, they are precursors of N-heterocyclic car-
benes,8,9 whose synthesis and applications are now under
active exploration. Therefore, convenient and widely ap-
plicable methods allowing the synthesis of these com-
pounds are of interest. Despite this high interest, existing
synthetic routes which target imidazo[1,5-a]pyridines re-
lying mainly on traditional Vilsmeier-type cyclizations of
N-2-pyridylmethylamides, are only modestly efficient.10
Recent advances were described in the synthesis of these
compounds via an acetic or polyphosphoric acid mediated
condensation pathway,2,11,12 or via an oxidative path-
way.13–15
Various reaction conditions were tested for the conversion
rate of the amide 2 into the imidazopyridine 4. For this
purpose, various solvents, the influence of the reaction
temperature, the reaction time, and the number of equiva-
lents of Lawesson’s reagent were studied. These different
reaction conditions were achieved on the model amide 3-
phenyl-N-(pyridin-2-ylmethyl)propanamide (2a), bearing
a phenethyl group (R group). The conversion rates were
determined by RP-HPLC analysis at 214 nm. Results are
summarized in Table 1. Generally, one equivalent of
Lawesson’s reagent yielded to slightly better conversion
rates compared with 0.5 equivalent (see entries 2 and 4, 6
and 7, 9 and 11, 10 and 12, 13 and 15, except for entries
14 and 16). A reaction time of two hours seemed also to
be more favorable than 1 hour for the cyclization reaction
(see entries 1 and 2, 3 and 4, 7 and 8, 9 and 10, 11 and 12,
13 and 14). Neither the solvent nor the temperature
seemed to have a clear influence on the conversion rate.
The best conversion rate was obtained by performing the
reaction with one equivalent of Lawesson’s reagent for
two hours at 80 °C in DME (entry 12). In these experi-
mental conditions, 2a was totally converted to a mixture
of 3a (46%) and 4a (54%). In all the reaction conditions
tested, a mixture of thioamide 3a and imidazopyridine 4a
was obtained. After a simple filtration on alumina, the re-
action mixture (3a and 4a) was allowed to react with
In our ongoing effort to target new bioactive heterocyclic
scaffolds, we describe in this paper a new method for the
synthesis of substituted imidazo[1,5-a]pyridines. The
general synthetic route is outlined in Scheme 1. The car-
boxylic acid 1 is coupled to commercially available 2-
methylaminopyridine using BOP [benzotriazol-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate]
reagent16 to give the corresponding N-2-pyridylmethyl-
amide 2. Reaction of 2 with Lawesson’s reagent17 gene-
SYNTHESIS 2007, No. 17, pp 2667–2673
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983852; Art ID: P02607SS
© Georg Thieme Verlag Stuttgart · New York

2668
A. Moulin et al.
PAPER
R
R
HS
H
+
N
–S
N
N
HN
H
Possible mechanism
in the absence of Hg(OAc)2
H
– H2S
O
R
BOP
DIPEA
CH2Cl2
OH
1a–f
O
Lawesson's reagent
solvent, heating
S
N
R
R
R
+
HN
N
HN
2a–f
3a–f
4a–f
N
N
H2N
N
Hg(OAc)2, THF, r.t.
Possible mechanism
in the presence of Hg(OAc)2
S(HgOAc)
+
N
R
R
N
N
AcOHgS –
H
N
H
Scheme 1 General synthetic route to imidazo[1,5-a]pyridines and possible mechanisms.
Hg(OAc)2 in tetrahydrofuran as solvent to yield only imi- sponding to CH a Ala; at 6.80 ppm corresponding to NH
dazopyridine 4a after stirring overnight at room tempera- amide, H6, and H7 imidazopyridine; and at 8.10 corre-
ture.
sponding to NHBoc, H5, and H8 imidazopyridine. In each
case, compounds 5b and 5c displayed a single signal,
whereas the 50:50 (w/w) mixture showed the superposi-
tion of two distinct signals corresponding to the two dia-
stereoisomers 5b and 5c. We could conclude that the
heterocyclization reaction is racemization free for the car-
We then attempted to introduce a chiral carbon atom in
position a to the imidazopyridine ring, to examine the
possible epimerization during the cyclization reaction.
For this purpose, we synthesized diastereoisomers 5b and
5c, starting from Boc-L- and Boc-D-Alanine, according to
Scheme 2. After cyclization under the conditions de-
scribed in Table 1, entry 12, and treatment with Hg(OAc)2
1
bon in a position a to the heterocycle, in the limit of H
NMR detection.
after an alumina filtration as described previously, the To further investigate the scope of the reaction, several
amine function was deprotected in acidic medium and substituents were introduced at the R position, as summa-
Boc-L-Valine was introduced to yield the two diastereo- rized in Table 2, under the conditions described in
isomers 5b and 5c. The optical purity of these two diaste- Table 1, entry 12, and subsequently treated with 0.5
1
reoisomers was checked by H NMR spectroscopy. For equivalent of Hg(OAc)2. A wide range of substituents
this purpose, 3 samples were prepared: compounds 5b and were tolerated (such as alkyl, aryl, heteroaryl groups)
5c, and a 50:50 (w/w) mixture of compounds 5b and 5c which can in some cases lead to the formation of biaryl
1
were analyzed by H NMR in DMSO-d6. We could ob- compound 4e in good yields. All synthesized compounds
serve different chemical shifts in the spectra (Figure 1): at were fully characterized by RP-HPLC, LC/MS spectrom-
3.70 ppm, corresponding to CH a Val; at 5.60 ppm corre- etry, and 1H NMR and 13C NMR spectroscopy.
Synthesis 2007, No. 17, 2667–2673 © Thieme Stuttgart · New York

PAPER
Synthesis of Imidazo[1,5-a]pyridines Starting from N-2-Pyridylmethylamides
2669
Table 1 Influence of the Reaction Conditions on the Conversion Rate of 2a to 3a and 4a as Determined by RP-HPLC Analysis at 214 nm
Entry
Time (h)
Temp (°C)
Solvent
Lawesson’s reagent
(equiv)
Yield (%)
3a
Yield (%)
4a
1
2
1.0
2.0
1.0
2.0
1.0
1.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
60
60
60
60
80
60
60
60
80
80
80
80
60
60
60
60
toluene
toluene
toluene
toluene
toluene
DME
DME
DME
DME
DME
DME
DME
THF
0.5
0.5
1.0
1.0
0.5
0.5
1.0
1.0
0.5
0.5
1.0
1.0
0.5
0.5
1.0
1.0
55
49
36
31
4
45
51
45
55
49
47
51
53
39
46
51
54
37
48
41
40
3
4
5
6
44
28
24
34
29
4
7
8
9
10
11
12
13
14
15
16
46
44
49
42
42
THF
THF
THF
Table 2 Variation of the R Substituent
Compound
R
2
4
4
Yield (%)
Conversion (%)a
Yield (%)b
1a
1b
95
81
54
40
80
O
O
76
O
O
N
H
1c
81
90
40
56
76
83
N
H
1d
Cl
1e
1f
97
89
20
60
69
85
Cl
HN
a Conversion rate without Hg(OAc)2, determined by RP-HPLC at 214 nm.
b Isolated yield after treatment with Hg(OAc)2.
Synthesis 2007, No. 17, 2667–2673 © Thieme Stuttgart · New York

2670
A. Moulin et al.
PAPER
OH
OH
BocNH
BocNH
O
O
1b
1c
BOP
NMM
NH2
N
H
N
H
N
BocNH
N
BocNH
N
O
2c
O
2b
1. 1.0 equiv Lawesson's reagent
DME, 2 h, 80 °C
2. 0.5 equiv Hg(OAc)2
THF, r.t., overnight
N
N
BocNH
BocNH
N
N
4b
4c
1. HCl, MeOH
2. BOP, NMM
OH
BocNH
O
6
5
O
O
1
1
7
Figure 1 a) H NMR spectral data for compound 5b; b) H NMR
spectral data for compound 5c; c) 1H NMR spectral data for 50:50
(w/w) mixture of compounds 5b and 5c.
3
BocNH
BocNH
N
N
N
N
8
H
H
9
N
N
2
1
5b
5c
N-2-Pyridylmethylamides 2; General Procedure
Scheme 2 Synthesis of L,L- and L,D-imidazopyridine diastereoiso-
mers.
The carboxylic acid 1 (1 equiv) and BOP reagent (1 equiv) were dis-
solved in a minimum amount of CH2Cl2. i-Pr2NEt (2.5 equiv) was
added under stirring, followed by 2-methylaminopyridine (1.1
equiv). The mixture was stirred for 2 h, then washed with sat. aq
NaHCO3 (2 × 50 mL) and brine (2 × 50 mL). The organic layer was
dried (Na2SO4), filtered, and the solvent was removed in vacuo. The
residue was purified by flash chromatography on silica gel, eluting
with EtOAc–MeOH (100:0 to 95:5) to afford the corresponding N-
2-pyridylmethylamide.
In conclusion, we have presented a new and convenient
method for the synthesis of imidazo[1,5-a]pyridines al-
lowing the introduction of various substituents at the po-
sition 3, including substituents bearing a chiral atom at the
a position to the cycle. In this case, the optical integrity of
the carbon was conserved, as checked by 1H NMR spec-
troscopy.
2a
Yield: 95%; tR = 1.04 min.
1H NMR (DMSO-d6): d = 2.50 (t, J = 8 Hz, CH2CH2Ph, 2 H), 2.82
(t, J = 8 Hz, CH2CH2Ph, 2 H), 4.30 (d, 6 Hz, CH2-o-pyridyl, 1 H),
7.02–7.26 (m, CHar phenyl, H3 and H5 o-pyridyl, 7 H), 7.66 (t,
Jo = 8 Hz, H4 o-pyridyl, 1 H), 8.38 (br s, NH amide, 1 H), 8.44 (d,
Ja,b = 5 Hz, H6 o-pyridyl, 1 H).
13C NMR (DMSO-d6): d = 31.4 (CH2CH2Ph), 37.3 (CH2CH2Ph),
44.5 (CH2-o-pyridyl), 121.3 (C5 o-pyridyl), 122.4 (C3 o-pyridyl),
126.3 (C4 phenyl), 128.6 (C3 and C5 phenyl), 128.7 (C2 and C6 phe-
nyl), 137.1 (C4 o-pyridyl), 141.6 (C1 phenyl), 149.0 (C6 o-pyridyl),
159.0 (C2 o-pyridyl), 171.9 (C=O amide).
All reagents were of commercial quality. Solvents were dried and
purified by standard methods. Analytical HPLC chromatograms
were performed on a Beckman Gold apparatus composed with the
126 solvent module, the 168 detector and the 32 Karat software.
Runs were performed on a VWR Chromolith column (50 × 3.9 mm)
at a flow rate of 5 mL/min; from solution A: H2O with 0.1% TFA to
solution B: MeCN with 0.1% TFA in a 3 min gradient. Mass spectra
analyses were recorded on a Platform II (Micromass, Manchester,
UK) quadrupole mass spectrometer fitted with an electrospray in-
terface. 1H and 13C NMR spectra were recorded in DMSO-d6 at 300
and 75 MHz, respectively, at 300 °K on a Bruker AMX 300 appa-
ratus.
ES-MS: m/z = 241.1 (MH+).
(S)-2b and (R)-2c
Yield: 81%; tR 0.97 min.
Synthesis 2007, No. 17, 2667–2673 © Thieme Stuttgart · New York

PAPER
Synthesis of Imidazo[1,5-a]pyridines Starting from N-2-Pyridylmethylamides
2671
1H NMR (DMSO-d6): d = 1.21 (d, J = 7 Hz, CH3 Ala, 3 H), 1.35 (s,
CH3 Boc, 9 H), 4.00 (m, CH a Ala, 1 H), 4.35 (m, CH2-o-pyridyl, 2
H), 6.95 (d, J = 7 Hz, NHBoc, 1 H), 7.22 (dd, Jo = 8 Hz, Ja,b = 5 Hz,
H5 o-pyridyl, 1 H), 7.27 (d, Jo = 8 Hz, H3 o-pyridyl, 1 H), 7.70 (t,
Jo = 7 Hz, H4 o-pyridyl, 1 H), 8.33 (t, J = 6 Hz, NH amide, 1 H),
8.45 (d, Ja,b = 5 Hz, H6 o-pyridyl, 1 H).
13C NMR (DMSO-d6): d = 21.4 (CH2CH2-indole), 36.6 (CH2CH2-
indole), 44.5 (CH2-o-pyridyl), 111.7 (C7 indole), 114.1 (C3 indole),
118.5 (C4 indole), 118.8 (C5 indole), 121.2 (C6 indole), 121.3 (C5 o-
pyridyl), 122.3 (C3 o-pyridyl), 122.7 (C2 indole), 127.5 (C9 indole),
136.7 (C8 indole), 137.0 (C4 o-pyridyl), 149.1 (C6 o-pyridyl), 159.2
(C2 o-pyridyl), 172.5 (C=O amide).
13C NMR (DMSO-d6): d = 18.4 (CH3 Ala), 28.5 (CH3 Boc), 44.4
(CH2-o-pyridyl), 54.0 (CH a Ala), 78.5 (Cq Boc), 121.2 (C5 o-py-
ridyl), 122.5 (C3 o-pyridyl), 137.2 (C4 o-pyridyl), 148.9 (C6 o-py-
ridyl), 155.6 (C=O Boc), 158.8 (C2 o-pyridyl), 173.5 (C=O amide).
ES-MS: m/z = 280.1 (MH+).
Imidazo[1,5-a]pyridines 4; General Procedure
N-2-Pyridylmethylamide 2 (1 equiv) and Lawesson’s reagent (0.5
equiv) were dissolved in DME (100 mL). The mixture was stirred
for 2 h at 80 °C. The solvent was then removed in vacuo. The resi-
due was filtered on alumina (elution with CH2Cl2). After removal of
the solvent under vacuo, the residue was dissolved in THF (50 mL)
and Hg(OAc)2 (0.5 equiv) was added. After stirring overnight at r.t.,
and filtration on Celite, the residue obtained after evaporation of the
solvent was purified by flash chromatography on silica gel, eluting
with EtOAc–MeOH (100:0 to 95:5) to afford the corresponding im-
idazo[1,5-a]pyridine 4. None of the thioamide compounds 3a–g
were isolated, except compounds 3b and 3c, which were isolated by
preparative HPLC to illustrate the reaction scheme. The other thio-
amides were characterized by RP-HPLC and LC/MS; the results are
summarized in Table 3 below.
ES-MS: m/z = 280.1 (MH+).
2d
Yield: 90%; tR = 1.15 min.
1H NMR (DMSO-d6): d = 0.87 [d, J = 6 Hz, (CH3)2CH, 6 H], 1.46
[m, (CH3)2CHCH2, 3 H], 2.14 [t, J = 8 Hz, (CH3)2CHCH2CH2, 2 H],
4.99 (d, J = 6 Hz, 2 H, CH2-o-pyridyl), 7.60 (m, H3 and H5 o-py-
ridyl, 2 H), 8.13 (td, Jo = 8 Hz, Jm = 2 Hz, H4 o-pyridyl, 1 H), 8.72
(d, Ja,b = 5 Hz, H6 o-pyridyl, 1 H), 8.27 (br s, NH amide, 1 H).
13C NMR (DMSO-d6): d = 22.2 [(CH3)2CH], 27.2 [(CH3)2CH], 33.4
[(CH3)2CHCH2CH2], 34.3 [(CH3)2CHCH2], 47.5 (CH2-o-pyridyl),
123.3 (C5 o-pyridyl), 124.0 (C3 o-pyridyl), 141.6 (C4 and C6 o-py-
ridyl), 154.3 (C2 o-pyridyl), 172.2 (C=O amide).
(S)-3b and (R)-3c
tR = 1.17 min.
ES-MS: m/z = 207.1 (MH+).
1H NMR (DMSO-d6): d = 1.34 (d, J = 7 Hz, CH3 b Ala, 3 H), 1.38
(s, CH3 Boc, 9 H), 4.44 (t, J = 7 Hz, CH a Ala, 1 H), 4.99 (m, CH2-
o-pyridyl, 2 H), 7.16 (br s, NH Boc, 1 H), 7.60 (m, H3 and H5 o-py-
ridyl, 2 H), 8.13 (td, Jo = 8 Hz, Jm = 2 Hz, H4 o-pyridyl, 1 H), 8.72
(d, Ja,b = 5 Hz, H6 o-pyridyl, 1 H), 10.56 (t, J = 5 Hz, NH thioamide,
1 H).
13C NMR (DMSO-d6): d = 20.8 (CH3 b Ala), 28.1 (CH3 Boc), 47.5
(CH2-o-pyridyl), 57.0 (CH a Ala), 78.5 (Cq Boc), 123.3 (C5 o-py-
ridyl), 124.0 (C3 o-pyridyl), 141.6 (C4 and C6 o-pyridyl), 154.3 (C2
o-pyridyl), 155.1 (C=O Boc), 207.7 (C=S thioamide).
2e
Yield: 97%; tR = 1.25 min.
1H NMR (DMSO-d6): d = 4.55 (d, J = 6 Hz, CH2-o-pyridyl, 2 H),
7.21 (dd, Jo = 8 Hz, Ja,b = 5 Hz, H5 o-pyridyl, 1 H), 7.31 (d, Jo = 8
Hz, H3 o-pyridyl, 1 H), 7.73 (m, H4 m-dichlorophenyl and H4 o-py-
ridyl, 2 H), 7.94 (d, Jm = 2 Hz, H2 and H6 m-dichlorophenyl, 2 H),
8.47 (m, H6 o-pyridyl, 1 H), 9.48 (t, J = 6 Hz, NH amide, 1 H).
13C NMR (DMSO-d6): d = 53.9 (CH2-o-pyridyl), 121.4 (C5 o-py-
ridyl), 122.5 (C3 o-pyridyl), 126.6 (C2 and C6 m-dichlorophenyl),
131.0 (C4 m-dichlorophenyl), 134.6 (C3 and C5 m-dichlorophenyl),
137.0 (C4 o-pyridyl), 137.8 (C1 m-dichlorophenyl), 149.2 (C6 o-py-
ridyl), 158.6 (C2 o-pyridyl), 164.0 (C=O amide).
ES-MS: m/z = 296.2 (MH+).
4a
ES-MS: m/z = 281.2/283.0 (MH+).
Yield: 80%; tR = 1.09 min.
1H NMR (DMSO-d6): d = 3.08 (t, J = 8 Hz, CH2CH2Ph, 2 H), 3.55
(t, J = 7 Hz, CH2CH2Ph, 2 H), 6.98 (t, Jo = 7 Hz, H6 imidazopyri-
dine, 1 H), 7.08 (t, Jo = 8 Hz, H7 imidazopyridine, 1 H), 7.10–7.24
(m, CHAr phenyl, 5 H), 7.71 (d, Jo = 9 Hz, H8 imidazopyridine, 1 H),
7.96 (s, H1 imidazopyridine, 1 H), 8.41 (d, Jo = 7 Hz, H5 imidazopy-
ridine, 1 H).
13C NMR (DMSO-d6): d = 26.2 (CH2CH2Ph), 32.3 (CH2CH2Ph),
112.9 (C1 imidazopyridine), 116.7 (C6 imidazopyridine), 119.1 (C8
imidazopyridine), 123.2 (C5 and C7 imidazopyridine), 126.9 (C4
phenyl), 128.7 (C2 and C6 phenyl), 128.9 (C3 and C5 phenyl), 131.5
(C9 imidazopyridine), 137.0 (C3 imidazopyridine), 139.7 (C1 phe-
nyl).
2f
Yield = 89%; tR = 1.03 min.
1H NMR (DMSO-d6): d = 2.52 (t, J = 8 Hz, CH2CH2-indole, 2 H),
2.93 (t, J = 8 Hz, CH2CH2-indole, 2 H), 4.31 (d, J = 6 Hz, CH2-o-
pyridyl, 2 H), 6.93 (t, Jo = 7 Hz, H5 indole, 1 H), 7.04 (m, H2, H4 and
H6 indole, 3 H), 7.19 (dd, J = 6, 5 Hz, H5 o-pyridyl, 1 H), 7.30 (d,
Jo = 8 Hz, H7 indole, 1 H), 7.51 (d, Jo = 8 Hz, H3 o-pyridyl, 1 H),
7.63 (t, Jo = 8 Hz, H4 o-pyridyl, 1 H), 8.37 (t, J = 5 Hz, NH amide,
1 H), 8.45 (d, J = 5 Hz, H6 o-pyridyl, 1 H), 10.72 (s, NH indole, 1
H).
Table 3 RP-HPLC and LC/MS Characterization of Thioamides 3a,d–f
Thioamide
Molecular formula
C15H16N2S
Molecular weight
256.3659
Exact mass
256.1034
222.1191
295.9942
tR (min)
1.21
ES/MS m/z (MH+)
257.2
3a
3d
3e
C12H18N2S
222.3497
1.24
223.1
C13H10Cl2N2S
297.2029
1.44
297.0
299.0
3f
C17H17N3S
295.4020
295.1143
1.56
296.0
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2672
A. Moulin et al.
PAPER
ES-MS: m/z = 223.2 (MH+).
(S)-4b and (R)-4c
ES-MS: m/z = 189.2 (MH+).
4e
Yield: 76%; tR = 0.98 min.
Yield: 69%; tR = 1.35 min.
1H NMR (DMSO-d6): d = 1.30 (s, CH3 Boc, 9 H), 1.55 (d, J = 7 Hz,
CH3 Ala, 3 H), 5.27 (t, J = 7 Hz, CH a Ala, 1 H), 6.98 (m, H6 and
H7 imidazopyridine, 2 H), 7.63 (d, J = 5Hz, NH Boc, 1 H), 7.69 (d,
J = 8 Hz, H8 imidazopyridine, 1 H), 7.80 (s, H1 imidazopyridine, 1
H), 8.32 (d, 6 Hz, H5 imidazopyridine, 1 H).
1H NMR (DMSO-d6): d = 6.82 (t, Jo = 7 Hz, H7 imidazopyridine, 1
H), 6.94 (dd, Jo = 8, 6 Hz, H6 imidazopyridine, 1 H), 7.68 (m, H8
and H1 imidazopyridine, H4 m-dichlorophenyl, 3 H), 7.87 (s, H2 and
H6 m-dichlorophenyl, 2 H), 8.55 (d, Jo = 7 Hz, H5 imidazopyridine,
1 H).
13C NMR (DMSO-d6): d = 18.1 (CH3 Ala), 28.1 (CH3 Boc), 41.9
(CH a Ala), 78.8 (Cq Boc), 113.3 (C1 imidazopyridine), 115.3 (C6
imidazopyridine), 118.8 (C8 imidazopyridine), 121.6 (C7 imida-
zopyridine), 122.2 (C5 imidazopyridine), 129.8 (C9 imidazopyri-
dine), 138.3 (C3 imidazopyridine), 155.3 (C=O Boc).
13C NMR (75 MHz, DMSO-d6): d = 114.3 (C1 and C6 imidazopyri-
dine), 118.4 (C8 imidazopyridine), 120.3 (C5 and C7 imidazopyri-
dine), 125.7 (C2 and C6 m-dichlorophenyl), 127.6 (C4 m-
dichlorophenyl), 132.1 (C9 imidazopyridine), 134.6 (C3 imidazopy-
ridine, C3 and C5 m-dichlorophenyl).
ES-MS: m/z = 262.2 (MH+).
ES-MS: m/z = 263.0/265.0 (MH+).
5b
4f
Yield = 82%; tR = 1.23 min.
Yield: 85%: tR = 1.44 min.
1H NMR (DMSO-d6): d = 0.72 (d, J = 7 Hz, CH3 g Val, 6 H), 1.32
(s, CH3 Boc, 9 H), 1.65 (d, J = 7 Hz, CH3 b Ala, 3 H), 1.86 (m, CH
b Val, 1 H), 3.75 (m, CH a Val, 1 H), 5.58 (m, CH a Ala, 1 H), 6.64
(d, J = 8 Hz, NH amide, 1 H), 6.97 (m, H6 and H7 imidazopyridine,
2 H), 7.70 (d, Jo = 9 Hz, H8 imidazopyridine, 1 H), 7.77 (s, H1 imi-
dazopyridine, 1 H), 8.27 (d, J = 7 Hz, NH Boc, 1 H), 8.56 (d, Jo = 7
Hz, H5 imidazopyridine, 1 H).
1H NMR (DMSO-d6): d = 3.21 (t, J = 7 Hz, CH2CH2-indole, 2 H),
3.60 (t, J = 8 Hz, CH2CH2-indole, 2 H), 6.89 (t, Jo = 8 Hz, H5 indole,
1 H), 6.91–7.09 (m, H6 indole, H6 and H7 imidazopyridine, 3 H),
7.10 (s, H2 indole, 1 H), 7.28 (d, Jo = 8 Hz, H4 indole, 1 H), 7.34 (d,
Jo = 8 Hz, H7 indole, 1 H), 7.71 (d, Jo = 9 Hz, H8 imidazopyridine,
1 H), 7.99 (s, H1 imidazopyridine, 1 H), 8.35 (d, Jo = 7 Hz, H5 imi-
dazopyridine, 1 H), 10.84 (s, NH indole, 1 H).
13C NMR (DMSO-d6): d = 17.9 (Cg Val), 18.5 (Cg Val), 19.0 (Cb
Ala), 28.1 (CH3 Boc), 29.8 (Cb Val), 40.1 (CH a Ala), 60.1 (CH a
Val), 78.0 (Cq Boc), 114.4 (C1 and C6 imidazopyridine), 118.4 (C8
imidazopyridine), 121.2 (C5 and C7 imidazopyridine), 130.0 (C9 im-
idazopyridine), 137.4 (C3 imidazopyridine), 155.4 (CO Boc), 171.6
(C=O amide).
13C NMR (DMSO-d6): d = 22.3 (CH2CH2-indole), 25.7 (CH2CH2-
indole), 110.4 (C3 indole), 111.8 (C7 indole), 112.1 (C1 imidazopy-
ridine), 116.8 (C6 imidazopyridine), 118.2 (C4 indole), 118.8 (C5 in-
dole), 119.2 (C8 imidazopyridine), 121.5 (C6 indole), 123.3 (C2
indole and C7 imidazopyridine), 123.4 (C5 imidazopyridine), 127.1
(C9 indole), 129.6 (C9 imidazopyridine), 136.6 (C8 indole), 137.5
(C3 imidazopyridine).
ES-MS: m/z = 361.2 (MH+).
ES-MS: m/z = 262.1 (MH+).
5c
Yield: 78%; tR = 1.23 min.
Acknowledgment
1H NMR (DMSO-d6): d = 0.82 (d, J = 7 Hz, CH3 g Val, 6 H), 1.34
(s, CH3 Boc, 9 H), 1.64 (d, J = 7 Hz, CH3 b Ala, 3 H), 1.89 (m, CH
b Val, 1 H), 3.64 (m, CH a Val, 1 H), 5.59 (m, CH a Ala, 1 H), 6.75
(d, J = 8 Hz, NH amide, 1 H), 6.86 (t, Jo = 7 Hz, H6 imidazopyri-
dine, 1 H), 7.01 (dd, J = 9, 6 Hz, H7 imidazopyridine, 1 H), 7.70 (d,
Jo = 9 Hz, H8 imidazopyridine, 1 H), 7.76 (s, H1 imidazopyridine, 1
H), 8.22 (d, J = 7 Hz, NH Boc, 1 H), 8.59 (d, Jo = 8 Hz, H5 imida-
zopyridine, 1 H).
13C NMR (DMSO-d6): d = 17.9 (Cg Val), 18.5 (Cg Val), 19.0 (Cb
Ala), 28.1 (CH3 Boc), 29.8 (Cb Val), 40.1 (CH a Ala), 60.1 (CH a
Val), 78.0 (Cq Boc), 114.4 (C1 and C6 imidazopyridine), 118.4 (C8
imidazopyridine), 121.2 (C5 and C7 imidazopyridine), 130.0 (C9 im-
idazopyridine), 137.4 (C3 imidazopyridine), 155.4 (C=O Boc),
171.6 (C=O amide).
We are grateful to Mr. Pierre Sanchez for his indispensable help in
obtaining mass spectrometry data, and Mrs. Annie Heitz for her
help in interpreting the NMR spectral data.
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4d
Yield: 83%; tR = 1.17 min.
1H NMR (DMSO-d6): d = 0.88 [d, J = 6 Hz, (CH3)2CH, 6 H], 1.60
[m, (CH3)2CHCH2, 3 H], 3.23 [t, J = 8 Hz, (CH3)2CHCH2CH2, 2 H],
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