Imidazo[1,5-a]pyridine-1-ylalkylalcohols: Synthesis via intramolecular cyclization of N-thioacyl 1,2-aminoalcohols and their silyl ethers and molecular structures

Article abstract of DOI:10.1039/c2ob25438g

Iodine-mediated cyclization of N-thioacyl 1,2-aminoalcohols derived from aromatic aldehydes and ketones mainly produced bis(1-imidazo[1,5-a]pyridyl) arylmethanes, whereas the reaction of N-thioacyl 1,2-aminoalcohols derived from aliphatic aldehydes and N-thioacyl 1,2-aminoalcohols protected with a silyl group with iodine gave imidazo[1,5-a]pyridine-1-ylalkylalcohols as a major product.

Full text of DOI:10.1039/c2ob25438g

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PAPER
Imidazo[1,5-a]pyridine-1-ylalkylalcohols: synthesis via intramolecular
cyclization of N-thioacyl 1,2-aminoalcohols and their silyl ethers and
molecular structures†
Toshiaki Murai,* Eri Nagaya, Fumitoshi Shibahara and Toshifumi Maruyama
Received 29th February 2012, Accepted 19th April 2012
DOI: 10.1039/c2ob25438g
Iodine-mediated cyclization of N-thioacyl 1,2-aminoalcohols derived from aromatic aldehydes and
ketones mainly produced bis(1-imidazo[1,5-a]pyridyl)arylmethanes, whereas the reaction of N-thioacyl
1,2-aminoalcohols derived from aliphatic aldehydes and N-thioacyl 1,2-aminoalcohols protected with a
silyl group with iodine gave imidazo[1,5-a]pyridine-1-ylalkylalcohols as a major product.
Introduction
The design, synthesis and use of new monoanionic N,O-chelat-
ing ligands with a hydroxy group and nitrogen-containing
heterocycles are intriguing topics in chemistry. The coordination
of these ligands to a wide variety of metals has provided metal
complexes with unique properties. Pyridinemethylalcohols,1
2-hydroxymethylbenzimidazoles,2
and
hydroxyquinolines3
(Fig. 1) are major examples of the core skeletons of such ligands.
Meanwhile, imidazo[1,5-a]pyridines, which are nitrogen-
containing 10π electron heterocycles, have recently attracted
much attention because of their photophysical4 and biological
properties,5 and due to their applicability as precursors for
N-heterocyclic carbenes6 and metal ligands.7 Therefore, several
new methods8,9 have been developed for the synthesis of
imidazo[1,5-a]pyridines. In this context, we have developed
various new approaches,10 which have enabled us to produce a
wide variety of derivatives bearing unsaturated substituents at
the 1- and 3-positions of imidazo[1,5-a]pyridyl groups. For
example, the cyclization of N-2-pyridylmethyl thioamides 1 in
the presence of iodine and pyridine is complete within several
hours at room temperature and gives imidazo[1,5-a]pyridines 2
Scheme 1 Desulfurizative
thioamides.
cyclization
of
N-2-pyridylmethyl
(Scheme 1).10a Notably, application of this reaction to N-thioacyl
1,2-aminoalcohols 3 did not give similar products, and instead
compounds bearing two imidazo[1,5-a]pyridyl groups 4 were
obtained with high efficiency.10d We report here the details of the
iodine-mediated cyclization of N-thioacyl 1,2-aminoalcohols
derived from N-2-pyridylmethyl thioamides with aldehydes and
ketones via thioamide dianions.11 The distribution of the pro-
ducts 2 and 4 depended on the substituents on 3, and we deter-
mined the molecular structures of some of the products. Finally,
a synthetic procedure for the production of new types of mono-
anionic N,O-chelating ligands with a hydroxy and an imidazo-
[1,5-a]pyridyl group is described.
Fig. 1 Monoanionic N,O-chelating ligands.
Results and discussion
Initially, N-thioacyl 1,2-aminoalcohols 3 and 7 were prepared
from N-2-pyridylmethyl thioamides 1, which were readily
obtained via the Willgerodt–Kindler reaction12 of aldehydes,
elemental sulfur, and 2-picolylamine. The results are shown in
Table 1. Thioamide dianions 5 were generated from 1 and
n-BuLi in THF within 10 min, and to this were then added
aldehydes 6a–6f to give N-thioacyl 1,2-aminoalcohols 3 as a
Department of Chemistry, Faculty of Engineering, Gifu University,
Yanagido, Gifu 501-1193, Japan. E-mail: mtoshi@gifu-u.ac.jp;
http://www1.gifu-u.ac.jp/~murai_ap/; Tel: +(81)58-293-2614
†Electronic supplementary information (ESI) available: Details on X-ray
molecular structure analyses of 8a, 2e, and 9g. CCDC 868371, 868372
and 868373. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25438g
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Table 1 Addition reaction of thioamide dianions 5 with aldehydes and ketones
Entry
1
R1
6
R2
R3
T (°C)
Time (h)
3
Yielda,b (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1b
1d
1a
1e
1d
1a
1a
1a
1a
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
2-Pyridyl
Ph
6a
6b
6c
6d
6d
6e
6f
6g
6g
6g
6h
6i
CH3
H
H
H
H
H
H
H
Ph
0
0
0
0.5
0.5
0.5
3
3
3
3a
3b
3c
3d
3e
3f
3g
7a
7b
7c
7d
7e
7f
84 (60 : 40)
98 (63 : 37)
87 (60 : 40)
70 (67 : 33)
76 (60 : 40)
69 (63 : 37)
56 (54 : 46)
91
62
56
67
88
c-Hexyl
t-Butyl
2-Pyridyl
2-Pyridyl
2-Thienyl
Ph
Ph
Ph
Ph
4-ClC6H4
4-MeOC6H4
4-Me2NC6H4
Fluorenone
0–RT
0–RT
0–RT
0–RT
0
0
0
0
0
0
0
t-Butyl
3
4-MeC6H4
4-MeOC6H4
t-Butyl
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2.5
2.5
3
1.5
3
4
3
9
Ph
Ph
10
11
12
13
14
4-ClC6H4
4-MeOC6H4
4-Me2NC6H4
6k
6l
72
73
7g
a Isolated yields. b Ratio of diastereomers is in parentheses.
condensation reaction of 2a and 2a′ may proceed to give 4a. In
our preliminary results,10d N-thioacyl 1,2-aminoalcohols derived
from aromatic aldehydes selectively led to 4. Imidazo[1,5-a]-
pyridine-1-ylalkylalcohols like 2a were not formed at all. This
difference may be because aromatic aldehydes are more easily
eliminated from 2 than aliphatic aldehydes. A similar cyclization
reaction was carried out with other derivatives 3b–3g, and the
results are listed in Table 2. Compounds with cyclohexyl and
tertiary butyl groups 3b and 3c were selectively converted to the
products 2b and 2c (entries 1 and 2), whereas the reactions of
those with 2-thienyl and phenyl groups, 3f and 3g, gave the pro-
ducts 4f and 4g (entries 5 and 6). These differences can be
understood in terms of the difference between how easily
aliphatic and aromatic aldehydes are eliminated. Interestingly,
however, the cyclization of N-thioacyl 1,2-aminoalcohols 3d and
3e derived from 2-pyridinecarbaldehyde (6d) resulted in the for-
mation of products 2d and 2e, which does not involve the
elimination of 2-pyridinecarbaldehyde (entries 3 and 4).
Third, N-thioacyl 1,2-aminoalcohols obtained from ketones 7
were subjected to an iodine-mediated cyclization reaction.
As shown in Scheme 3, the cyclization of 7a, 7b, and 7g was
complete within 5 min at room temperature, but the distribution
of the products was dependent on the substituents on the thio-
carbonyl carbon atom and on the carbon atom α to the hydroxy
group. The reaction of 7a readily gave the product 8a, despite
the fact that four aromatic substituents are introduced to a qua-
ternary carbon atom of 8a, along with the formation of 2a′ and
ketone 6g, whereas 7b was converted to 9b along with the for-
mation of 8b. The reaction of 7g mainly gave 2a′ and 6l, and the
product 9g, which retained a fluorenyl group, was obtained in up
to 26% yield along with some impurities.
Scheme 2 Cyclization of N-thioacyl 1,2-aminoalcohol 3a in the pres-
ence of iodine and pyridine.
diastereomeric mixture in good to high yields (entries 1–7).
Thioamides 1 with aryl, heteroaryl, and t-butyl groups at the
carbon atom of the thiocarbonyl groups were used. The addition
of thioamide dianions 5 to aliphatic aldehydes was complete
within 30 min (entries 1–3), whereas the reactions with aromatic
aldehydes required longer reaction times (entries 4–7). Likewise,
the use of ketones 6g–6l gave the corresponding products 7
(entries 8–14). The substituents on the aromatic rings of ketone
6, such as chlorine, methoxy, and dimethylamino groups, had
almost no effect on the efficiency of the reaction. Some of the
products 7 were readily crystallized and purified.
Next, N-thioacyl 1,2-aminoalcohols 3 obtained from aldehydes
were subjected to an iodine-mediated cyclization reaction.
Treatment of 3a with iodine (3 equiv.) and pyridine (3 equiv.) in
THF gave imidazo[1,5-a]pyridine-1-ylethanol 2a and bis-
(imidazo[1,5-a]pyridyl)ethane 4a in respective yields of 42%
and 15% (Scheme 2).
The molecular structures of some of the products were
confirmed by X-ray structure analyses. A single crystal of 9g
contained one molecule of CH2Cl2. ORTEP drawings of 8a, 2e,
and 9g are shown in Fig. 2–4, respectively.
In the reaction, the elimination of aldehyde 6a from 2a may
partially occur to generate 2a′.
A
Friedel–Crafts-type
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Table 2 Cyclization of N-thioacyl 1,2-aminoalcohols derived from aldehydes 3 in the presence of iodine and pyridinea
Yielda (%)
Entry
3
R1
R2
T (°C)
Time (h)
2
4
—
1
2
3
4
5
6
3b
3c
3d
3e
3f
4-MeC6H4
4-MeC6H4
Ph
2-Pyridyl
Ph
c-Hexyl
t-Butyl
2-Pyridyl
2-Pyridyl
2-Thienyl
Ph
0
0
RT
RT
RT
RT
0.5
0.5
0.67
0.67
0.5
2b
2c
2d
2e
2f
84
93
69
82
—
—
4b
4c
4d
4e
4f
4g
—
—
—
86
60
3g
t-Butyl
0.5
2g
a Isolated yields.
Fig. 2 An ORTEP drawing of 8a. Selected bond angles (°) and
dihedral angles (°): C7–C21–C7* = 112.4(4), C7–C21–C1 = 133.39(19),
C7*–C21–C1 = 103.46(18), C7–C21–C1* = 103.46(18), C7*–C21–C1*
= 113.38(19), C1–C21–C1* = 111.0(4), C1*–C21–C7–N1 = 85.1(4),
C7*–C21–C7–N1 = −152.2(4), C1–C21–C7–N1 = −35.3(4).
carbon atom in the latter exists in an eclipsed conformation.
The pyridyl group at C13 in 2e is in nearly the same plane as
that of the imidazopyridyl group, whereas the p-tolyl group at
C20 in 9g is twisted toward the imidazopyridyl group.
Finally, to establish an efficient synthetic route to these new
types of monoanionic ligands, the protection of a hydroxy group
in N-thioacyl 1,2-aminoalcohols 7 and cyclization of the result-
ing products were examined. Among them, the silylation of 7g
with chlorotrimethylsilane in the presence of imidazole was
complete within 2 h to give 10g quantitatively (Scheme 4).
The iodine-mediated cyclization of the product 10g went to
completion within 5 min in the presence of pyridine to give
imidazopyridylmethylalcohol silyl ether 11g with high
efficiency. The deprotection of 11g led to the desired alcohol 9g.
A similar reaction was carried out with other silylated com-
pounds 10 (Table 3). Unlike in the silylation of 7g, the reactions
of 7e and 7f with chlorotrimethylsilane required longer reaction
times, and those of 7a and 7d required longer reaction times,
Scheme 3 Cyclization of N-thioacyl 1,2-aminoalcohols 7a, 7b and 7g
in the presence of iodine and pyridine.
The central quaternary carbon atom of 8a shows slightly dis-
torted tetrahedral structures. The two imidazopyridyl groups in
8a are aligned in nearly the same plane, but are oriented in oppo-
site directions. For imidazopyridylmethylalcohols 2e and 9g, the
carbon atoms with hydroxy groups have a tetrahedral geometry.
In the former case, the carbon atom is present in the bisected
conformation toward the imidazopyridyl ring, whereas the
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Table 3 Cyclization of 10 in the presence of iodine and pyridine
Entry
No.
Ar
Yielda (%)
11 : 9
1
2
10a
10d
10e
10e
10f
Ph
88
95
54
73
0
99 : 6
98 : 2
67 : 33
59 : 41
—
C6H4Cl-4
C6H4OMe-4
C6H4OMe-4
C6H4NMe2-4
3
4b
5
a Isolated yields. b Pyridine (12 equiv.) was used.
Fig. 3 An ORTEP drawing of 2e. Selected bond angles (°) and dihedral
angles (°): O1–C1–C7 = 111.0(2), C7–C1–C2 = 113.6(3), O1–C1–C2 =
obtained in high yields by the desilylation of 11a and 11d. In
contrast, the cyclization of 10e gave a mixture of 11e and 9e in
moderate yield (entry 3). Prolonging the reaction time of 10e did
not improve the yields of 11e and 9e, and instead 2a′ and the
ketone 6i were formed. The use of a large excess of pyridine
gave a mixture of 11e and 9e in higher yields (entry 4). In con-
trast to these successful results, attempts to cyclize silyl ether 10f
to produce 11f and/or 9f failed, even with excess pyridine
(entry 5). The product 2a′ and ketone 6k were mainly formed as
products.
107.0(3), C2–C1–C7–N3
= 45.3(4), O1–C1–C7–N3 = −75.4(4),
N3–C13–C14–N4 = 173.6(3).
Conclusions
In summary, the details of the iodine-mediated cyclization of
N-thioacyl 1,2-aminoalcohols and their silyl ethers in the pre-
sence of pyridine were presented. The reaction of alcohols
derived from aromatic aldehydes was complete within 30 min
and gave products with two imidazopyridyl groups, except for
the alcohols with two 2-pyridyl groups. The reactions of alcohols
derived from ketones showed three reaction pathways to the pro-
ducts, depending on the substituents on the carbon atom α to the
hydroxy group. The first pathway involves the formation of pro-
ducts with two imidazopyridyl groups on the quaternary carbon
atom. The second is accompanied by the elimination of ketones
to give imidazo[1,5-a]pyridines without substituents at their
3-positions. The third involves the formation of the desired pro-
ducts, which are available as monoanionic N,O-chelating
ligands, particularly in the reaction of N-thioacyl 1,2-amino-
alcohol silyl ethers. The formation and application of metal com-
plexes with imidazo[1,5-a]pyridine-1-ylalkylalcohols are
currently being studied.
Fig. 4 An ORTEP drawing of 9g·CH2Cl2. Selected bond angles (°)
and dihedral angles (°): O1–C1–C14 = 109.49(14), C14–C1–C2 =
112.90(14), O1–C1–C2 = 110.84(14), C2–C1–C14–N2 = 127.75(17),
O1–C1–C14–N2 = 3.7(2), N2–C20–C21–C22 = 145.59(19).
Experimental section
General remarks
Scheme 4 Cyclization of 10g in the presence of iodine and pyridine.
Characterization. The IR spectra were obtained on a JASCO
FT-IR 410 spectrophotometer. 1H NMR (399.7 MHz),
13C (100.4 MHz) NMR spectra were measured on a JNM-α400
spectrometer. 1H and 13C chemical shifts are reported in δ values
referred to tetramethylsilane or CDCl3 as an internal standard,
respectively. All spectra were acquired in the proton-decoupled
mode. The mass spectra (MS) and high resolution mass spectra
higher temperatures, and dichloroethane as a solvent. However,
in all cases, the silylated products could be isolated in good
yields. The cyclization of silyl ethers 10a and 10d proceeded
similarly to that of 10g, but silyl ethers 11 as well as small
amounts of desilylated alcohols 9 were also formed (entries
1 and 2). Nevertheless, the desired alcohols 9a and 9d were
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(HRMS) were taken on JMS-700 mass spectrometers. Melting
points were determined by using a Yanaco MP-S2 micro melting
point apparatus and are uncorrected. Elemental analyses were
carried out by Elemental Analysis Center of Kyoto University.
Hz, 3H), 2.36 (s, 3H), 4.52 (qd, J = 6.3 Hz, 2.0 Hz, 1H), 5.11
(br, 1H, OH), 5.87 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.18 (d, J = 8.3
Hz, 2H), 7.27 (ddd, J = 7.8 Hz, 4.9 Hz, 1.5 Hz, 1H), 7.65 (d,
J = 7.8 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.72 (td, J = 7.8 Hz,
1.5 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.76 (d, J = 8.5 Hz, 1H);
13C NMR (CDCl3) δ 19.4, 21.3, 62.1, 69.1, 123.4, 124.4, 126.8,
129.0, 137.3, 138.6, 141.8, 148.7, 158.4, 198.8.
Materials. Dichloromethane (CH2Cl2), and 1,2-dichloro-
ethane (ClCH2CH2Cl) were distilled over phosphorus pentoxide
(P2O5). Tetrahydrofuran (THF) dehydride, pyridine, chloroform,
p-tolualdehyde, Et2O and iodine (I2) were purchased from Kanto
Chemical Co., Ltd, and used without purification. Benzo-
phenone, hydrochloric acid (HCl), triethylamine, 2-pyridinecar-
boxaldehyde, and 2-thiophenecarboxaldehyde were purchased
from Nacalai Tesque Inc., and used without further purification.
Imidazole, 2-picolylamine, 9-fluorenone, cyclohexanecarb-
aldehyde, 4,4′-bis(dimethylamino)benzophenone, 4,4′-dichloro-
N-(2-Hydroxy-2-cyclohexyl-1-pyridin-2-ylethyl)-4-methyl-
benzenecarbothioamide (3b). A yellow solid; IR (KBr) 3313,
2924, 2846, 1596, 1570, 1529, 1504, 1438, 1369, 1226, 1205,
1185, 1077, 955, 822, 757, 719, 676, 632 cm−1 1H NMR
;
(CDCl3) δ 1.05–2.11 (m, 11H), 2.36 (s, 1.9H, major), 2.37 (s,
1.1H, minor), 3.76 (d, J = 3.9 Hz, 0.65H, major), 3.95 (d, J =
8.6 Hz, 0.35H, minor), 5.30 (br, 1H), 5.99 (dd, J = 8.1 Hz, 3.9
Hz, 0.65H, major), 6.03 (d, J = 8.6 Hz, 0.35H, minor), 7.16 (d,
J = 8.3 Hz, 1.4H, major), 7.18 (d, J = 7.8 Hz, 0.6H, minor),
7.25–7.30 (m, 1H), 7.66–7.72 (m, 3.3H), 7.74 (d, J = 7.8 Hz,
1.5 Hz, 0.7H major), 8.49–8.52 (m, 1H), 8.69 (d, J = 8.6 Hz,
0.35H minor), 8.96 (d, J = 8.1 Hz, 0.65H major); 13C NMR
(CDCl3) δ 21.2, 25.5, 25.6, 25.8, 25.9, 26.2, 28.9, 28.9, 29.4,
29.5, 40.4 (minor), 41.3 (major), 58.4 (minor), 59.0 (major),
77.7, 78.8, 123.2, 124.5, 125.7, 126.8, 128.9, 129.0, 137.1,
137.3, 138.5, 138.6, 141.6, 141.7, 148.6, 148.7, 157.4, 159.1,
197.3 (CvS, major), 197.8 (CvS, minor); MS (EI) m/z 354
(M+); HRMS calcd for C21H26N2OS: 354.1766, found:
354.1768.
benzophenone,
and
4,4′-dimethoxybenzophenone
were
purchased from Tokyo Chemical Industry Co., Ltd, and used
without further purification. Benzaldehyde, trimethylacetalde-
hyde were purchased from Aldrich Chemical Company, Inc., and
used without further purification. Acetaldehyde was purchased
from Merck Ltd, and used without further purification. n-BuLi
15 w/w% in hexane was purchased from Mitsuwa Chemicals
Co., Ltd, and used without further purification. Flash column
chromatography was run on silica gel 60N (Spherical, Neutral,
40–50 μm) from Kanto Chemical Co., Ltd. All manipulations
were carried out under an argon atmosphere.
N-(2-Hydroxy-3,3-dimethyl-1-pyridin-2-ylpropyl)-4-methyl-
benzenecarbothioamide (3c). A yellow solid; IR (KBr) 3345,
3204, 3024, 2953, 2868, 1593, 1542, 1474, 1440, 1371, 1310,
1233, 1188, 1081, 1017, 1004, 981, 897, 755 cm−1; MS (EI)
m/z 328 (M+); HRMS calcd for C19H24N2OS: 328.1609, found:
328.1583; Diastereomer major: 1H NMR (CDCl3) δ 0.77
(s, 9H), 2.35 (s, 3H), 3.84 (d, J = 2.4 Hz, 1H), 6.03 (br, 1H),
6.05 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.28
(ddd, J = 7.8 Hz, 4.9 Hz, 1.5 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H),
7.67 (d, J = 7.8 Hz, 1H), 7.74 (td, J = 7.8 Hz, 1.5 Hz, 1H), 8.50
(d, J = 4.9 Hz, 1H), 8.80 (d, J = 8.3 Hz, 1H); 13C NMR δ 21.3,
26.4, 35.3, 58.1, 82.7, 123.5, 126.0, 126.9, 129.0, 137.4, 138.7,
141.7, 148.6, 158.2, 197.0; Diastereomer minor: 1H NMR
(CDCl3) δ 1.08 (s, 9H), 2.35 (s, 3H), 3.88 (s, 1H), 5.24 (br, 1H),
6.12 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.25 (ddd,
J = 7.8 Hz, 4.9 Hz, 1.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.68
(d, J = 7.8 Hz, 1H), 7.71 (td, J = 7.8 Hz, 1.7 Hz, 1H), 8.50
(d, J = 4.9 Hz, 1H), 8.78 (d, J = 8.3 Hz, 1H); 13C NMR δ 21.3,
26.5, 34.9, 57.8, 80.1, 123.2, 123.8, 126.7, 129.0, 137.3, 138.4,
141.6, 148.9, 159.8, 196.3.
General procedure for the preparation of N-thioacyl 1,2-
aminoalcohols 3 and 7 from thioamides 1 and carbonyl
compounds 6 as an example leading to 3a
To a THF solution (12.5 mL) of N-2-pyridylmethyl-4-methyl-
benzenecarbothioamide (1a) (1.2 g, 5.0 mmol) was added
n-BuLi (1.6 M solution in hexane, 6.8 mL, 10 mmol) at 0 °C.
The mixture was stirred at 0 °C for 10 min. Then, acetaldehyde
(6a) (0.42 mL, 7.5 mmol) was added to the reaction mixture at
0 °C, and the solution was stirred at 0 °C for 30 min. The reac-
tion mixture was poured into water and extracted with Et2O. The
organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel (n-hexane–EtOAc = 3 : 1) to give N-(2-hydroxy-2-
methyl-1-pyridin-2-ylethyl)-4-methylbenzenecarbothioamide (3a)
(1.2 g, 4.2 mmol, 84% (major : minor = 60 : 40)) as a yellow
solid.
N-(2-Hydroxy-2-methyl-1-pyridin-2-ylethyl)-4-methylbenzene-
carbothioamide (3a). A yellow solid; m.p. 154–155 °C;
IR (KBr) 3282, 3057, 2932, 1599, 1571, 1536, 1506, 1442,
1369, 1319, 1230, 1127, 1064, 1007, 930, 822, 665, 564 cm−1
;
N-(2-Hydroxy-1,2-dipyridin-2-ylethyl)benzenecarbothioamide
(3d). A yellow solid; IR (KBr) 3330, 3261, 3055, 2927, 1593,
1571, 1528, 1508, 1472, 1439, 1358, 1230, 1045, 1034, 999,
MS (EI) m/z 286 (M+); HRMS calcd for C16H18N2OS:
286.1140, found: 286.1147; Diastereomer major: 1H NMR
(CDCl3) δ 1.04 (d, J = 6.8 Hz, 3H), 2.26 (s, 3H), 4.28 (qd,
J = 6.8 Hz, 2.9 Hz, 1H), 4.79 (br, 1H), 5.76 (dd, J = 7.6 Hz, 2.9
Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.19 (ddd, J = 7.8 Hz, 4.9 Hz,
1.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H),
7.65 (td, J = 7.8 Hz, 1.5 Hz, 1H), 8.45 (d, J = 4.4 Hz, 1H), 9.06
(d, J = 7.6 Hz, 1H); 13C NMR (CDCl3) δ 20.1, 21.2, 62.5, 70.6,
123.2, 125.2, 126.9, 128.9, 137.0, 138.5, 141.7, 148.8, 156.5,
198.0; Diastereomer minor: 1H NMR (CDCl3) δ 1.32 (d, J = 6.3
1
955, 775, 699 cm−1; H NMR (CDCl3) δ 5.52 (d, J = 2.9 Hz,
0.3H, minor), 5.66 (d, J = 3.4 Hz, 0.7H, major), 6.27 (dd,
J = 7.3 Hz, 3.4 Hz, 0.7H, major), 6.39 (dd, J = 8.1 Hz, 2.9 Hz,
0.3H, minor), 6.65 (d, J = 7.8 Hz, 0.7H, major), 7.16–7.12
(m, 2H), 7.37–7.55 (m, 4.3H), 7.62–7.80 (m, 2.5H), 7.89–7.91
(m, 1.5H), 8.45–8.56 (m, 2H), 9.59 (d, J = 8.1 Hz, 0.3H minor),
9.65 (d, J = 7.3 Hz, 0.7H, major); 13C NMR (CDCl3) δ 62.6
(minor), 64.1 (major), 74.1 (minor), 74.3 (major), 121.2, 121.3,
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122.75, 122.81, 122.9, 123.0, 123.6, 126.9, 127.0, 128.5, 131.2,
136.4, 136.9, 137.1, 141.5, 148.1, 148.5, 148.7, 154.8, 158.4,
198.1; MS (EI) m/z 335 (M+); HRMS calcd for C19H17N3OS:
335.1092, found: 335.1068.
1H), 6.95 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H),
7.19–7.26 (m, 4H), 7.51–7.57 (m, 1H), 8.52 (d, J = 4.9 Hz, 1H),
9.11 (d, 1H); 13C NMR δ 29.9, 44.8, 63.2, 76.2, 123.1, 124.5,
125.7, 127.4, 127.9, 136.7, 140.2, 148.4, 155.3, 213.1; Diastereo-
1
mer minor: yellow oil; H NMR (CDCl3) δ 1.19 (s, 9H), 5.35
N-(2-Hydroxy-1,2-dipyridin-2-ylethyl)2-pyridinecarbothio-
amide (3e). A yellow solid; IR (KBr) 3245, 3052, 3006, 1592,
(d, J = 3.1 Hz, 1H), 5.51 (br, 1H), 5.98 (dd, J = 7.3 Hz, 3.1 Hz,
1H), 7.15–7.25 (m, 6H), 7.43 (d, J = 7.8 Hz, 1H), 7.61 (td,
J = 7.8 Hz, 1.5 Hz, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.70 (d,
J = 7.3 Hz, 1H); 13C NMR δ 29.8, 44.7, 62.6, 74.8, 123.2,
124.6, 125.9, 127.6, 128.1, 136.9, 139.8, 148.5, 157.3, 213.5.
1502, 1436, 1328, 1150, 1071, 755 cm−1 1H NMR (CDCl3)
;
δ 5.52 (br, 0.6H, major), 5.58 (d, J = 2.7 Hz, 0.4H, minor), 5.59
(d, J = 3.4 Hz, 0.6H, major), 6.11 (br, 0.4H, minor), 6.35 (dd,
J = 8.3 Hz, 3.4 Hz, 0.6H, major), 6.39 (dd, J = 8.8 Hz, 2.7 Hz,
0.4H, minor), 6.92 (d, J = 7.8 Hz, 0.6H, major), 7.12–7.17 (m,
1.6H), 7.22 (dd, J = 7.6 Hz, 4.9 Hz, 0.4H, minor), 7.40 (dd,
J = 7.3 Hz, 4.6 Hz, 0.4H, minor), 7.43 (dd, J = 7.3 Hz, 4.6 Hz,
0.6H, major), 7.47 (dd, J = 7.8 Hz, 7.6 Hz, 0.6H, major),
7.47–7.53 (m, 1.4H), 7.62 (dd, J = 7.8 Hz, 7.6 Hz, 0.4H, minor),
7.63 (dd, J = 8.1 Hz, 7.6 Hz, 0.6H, major), 7.65 (dd, J = 8.1 Hz,
7.8 Hz, 0.4H, minor), 7.77 (dd, J = 7.8 Hz, 7.6 Hz, 0.4H,
minor), 7.81 (dd, J = 7.8 Hz, 7.6 Hz, 0.6H, major), 8.47–8.49
(m, 1H), 8.54–8.60 (m, 2.4H), 8.68 (d, J = 8.1 Hz, 0.6H major),
11.35 (d, J = 8.8 Hz, 0.4H, minor), 11.52 (d, J = 8.3 Hz, 0.6H,
major); 13C NMR (CDCl3) δ 62.3 (minor), 62.9 (major), 74.5
(minor), 74.7 (major), 120.9, 121.2, 122.2, 122.4, 122.6, 122.8,
123.2, 124.0, 124.9, 124.9, 125.9, 125.9, 136.4, 136.5, 136.6,
136.9, 136.9, 137.0, 147.2, 147.2, 148.1, 148.3, 148.4, 148.7,
151.1, 151.3, 155.7, 157.5, 158.7, 159.0, 190.5 (CvS major),
191.3 (CvS minor); MS (EI) m/z 302 (M+ − H2S); HRMS
calcd for C18H16N4OS: 336.1045, found: 336.1039.
N-(2-Hydroxy-2,2-diphenyl-1-pyridin-2-ylethyl)-4-methyl-
benzenecarbothioamide (7a). A yellow solid; m.p. 179–180 °C;
IR (KBr) 3356, 3289, 3057, 3024, 1595, 1571, 1488, 1448,
1
1351, 1258, 1187, 1174, 1061, 978, 820, 749, 702 cm−1; H
NMR (CDCl3) δ 2.29 (s, 3H), 6.87 (d, J = 8.2 Hz, 1H), 7.01
(t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 7.10 (ddd, J = 7.6
Hz, 5.0 Hz, 1.5 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.19
(t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.33 (d, J = 8.2 Hz,
2H), 7.46 (d, J = 8.5 Hz, 2H), 7.56 (td, J = 7.6 Hz, 1.5 Hz, 1H),
7.67 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.91 (br, 1H),
8.37 (d, J = 5.0 Hz, 1H), 8.75 (d, J = 8.3 Hz, 1H); 13C NMR
(CDCl3) δ 21.3, 62.3, 81.2, 123.2, 125.2, 125.3, 126.6, 126.7,
126.9, 127.2, 128.1, 128.5, 128.9, 137.1, 138.8, 141.6, 143.9,
144.9, 148.1, 157.5, 197.9; MS (EI) m/z 424 (M+); HRMS calcd
for C27H24N2OS: 424.1609, found: 424.1603.
N-(2-Hydroxy-2,2-diphenyl-1-pyridin-2-ylethyl)-4-methoxy-
benzenecarbothioamide (7b). A yellow solid; m.p. 126–127 °C;
IR (KBr) 3293, 3056, 2967, 2867, 1605, 1505, 1448, 1439,
N-(2-Hydroxy-2-thienyl-1-pyridin-2-ylethyl)benzenecarbothio-
amide (3f). A yellow solid; IR (KBr) 3324, 3056, 2933, 1597,
1571, 1484, 1448, 1435, 1355, 1223, 1072, 1030, 1009, 950,
709, 683 cm−1; MS (EI) m/z 340 (M+); HRMS calcd for
C18H16N2OS2: 340.0704, found: 340.0706; Diastereomer major:
1376, 1254, 1173, 1065, 1025, 969, 834, 755, 703 cm−1
;
1H NMR (CDCl3) δ 3.77 (s, 3H), 6.75 (d, J = 8.8 Hz, 2H), 6.86
(d, J = 8.1 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.11 (ddd, J = 7.8
Hz, 4.9 Hz, 1.5 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.19 (t,
J = 7.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.8 Hz,
4H), 7.56 (td, J = 7.8 Hz, 1.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H),
7.70 (d, J = 8.8 Hz, 2H), 7.92 (br, 1H), 8.37 (d, J = 4.9 Hz, 1H),
8.69 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3) δ 55.4, 62.3, 81.2,
113.5, 123.1, 125.20, 125.24, 126.6, 126.9, 127.2, 128.1, 128.5,
128.6, 134.0, 137.1, 143.9, 144.9, 148.1, 157.5, 162.1, 197.0;
MS (EI) m/z 406 (M+ − H2S); HRMS calcd for C27H24N2O2S:
440.1558, found: 440.1537.
1
m.p. 139–142 °C; H NMR (CDCl3) δ 5.71 (d, J = 3.4 Hz, 1H),
5.80 (br, 1H), 6.22 (dd, J = 8.3 Hz, 3.4 Hz, 1H), 6.84 (d, J = 3.4
Hz, 1H), 6.89 (dd, J = 4.9 Hz, 3.4 Hz, 1H), 7.14 (d, J = 4.9 Hz,
1H), 7.28 (ddd, J = 7.8 Hz, 4.9 Hz, 1.5 Hz, 1H), 7.29 (d, J = 7.8
Hz, 1H), 7.39 (dd, J = 8.3 Hz, 7.3 Hz, 2H), 7.47 (t, J = 7.3 Hz,
1H), 7.63 (td, J = 7.8 Hz, 1.5 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H),
8.51 (d, J = 4.9 Hz, 1H), 9.11 (d, J = 7.8 Hz, 1H); 13C NMR δ
63.0, 73.3, 123.5, 123.9, 124.7, 125.3, 126.7, 126.9, 128.5,
131.4, 137.2, 141.3, 144.5, 158.6, 155.7, 198.7; Diastereomer
1
N-(2-Hydroxy-2,2-diphenyl-1-pyridin-2-ylethyl)-2,2-dimethylthio-
propionamide (7c). A yellow solid; m.p. 127–128 °C; IR (KBr)
3389, 3192, 3084, 2953, 1595, 1571, 1501, 1475, 1450, 1377,
minor: m.p. 152–153 °C; H NMR (CDCl3) δ 5.75 (d, J = 2.4
Hz, 1H), 5.78 (br, 1H), 6.23 (dd, J = 8.1 Hz, 2.4 Hz, 1H), 6.96
(dd, J = 4.9 Hz, 3.4 Hz, 1H), 7.03 (d, J = 3.4 Hz, 1H), 7.26 (d,
J = 4.9 Hz, 1H), 7.31 (ddd, J = 7.8 Hz, 4.9 Hz, 1.7 Hz, 1H),
7.35 (dd, J = 8.3 Hz, 7.3 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H),
7.70–7.73 (m, 3H), 7.75 (td, J = 7.8 Hz, 1.7 Hz, 1H), 8.53 (d,
J = 4.9 Hz, 1H), 8.88 (d, J = 8.1 Hz, 1H); 13C NMR δ 62.5,
71.8, 123.6, 124.2, 124.8, 125.2, 126.7, 126.9, 128.4, 131.2,
137.4, 141.4, 143.2, 148.7, 157.7, 199.1.
1349, 1057, 1008, 757, 744, 704 cm−1 1H NMR (CDCl3)
;
δ 0.98 (s, 9H), 6.73 (d, J = 7.8 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H),
6.99 (ddd, J = 7.8 Hz, 4.9 Hz, 1.5 Hz, 1H), 7.02 (dd, J = 8.3 Hz,
7.3 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.21 (dd, J = 8.3 Hz, 7.3
Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.45 (td, J = 7.8 Hz, 1.5 Hz,
1H), 7.55 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.83
(br, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 7.8 Hz, 1H);
13C NMR (CDCl3) δ 29.5, 44.3, 61.6, 81.0, 122.9, 125.0, 125.1,
126.5, 126.7, 126.9, 127.9, 128.1, 137.0, 143.8, 144.8, 147.9,
157.3, 212.1; MS (EI) m/z 390 (M+); HRMS calcd for
C24H26N2OS: 390.1766, found: 390.1775.
N-(2-Hydroxy-2-benzene-1-pyridin-2-ylethyl)-2,2-dimethylthio-
propionamide (3g). IR (KBr) 3375, 3084, 2961, 1597, 1524,
1477, 1441, 1382, 1355, 1057, 1005, 768, 744, 703, 615 cm−1
;
MS (EI) m/z 280 (M+ − H2S); HRMS calcd for C18H22N2OS:
314.1453, found: 314.1444; Diastereomer major: a yellow solid;
m.p. 130–131 °C; 1H NMR (CDCl3) δ 1.39 (s, 9H), 5.16
(br, 1H), 5.48 (d, J = 3.0 Hz, 1H), 6.08 (dd, J = 7.3 Hz, 2.9 Hz,
N-(2-Hydroxy-2,2-bis(4-chlorophenyl)-1-pyridin-2-ylethyl)-
4-methylbenzenecarbothioamide (7d). A yellow solid; m.
4948 | Org. Biomol. Chem., 2012, 10, 4943–4953
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General procedure for the cyclization of N-thioacyl
1,2-aminoalcohols 3 to imidazo[1,5-a]pyridine-1-ylethanols
p. 134–135 °C; IR (KBr) 3308, 3101, 2923, 1598, 1570, 1488,
1437, 1406, 1369, 1349, 1090, 1078, 1012, 971, 817 cm−1
;
1H NMR (CDCl3) δ 2.31 (s, 3H), 6.88 (d, J = 8.3 Hz, 1H), 7.08
(d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.16 (ddd, J = 7.8
Hz, 4.9 Hz, 1.7 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.36
(d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.3
Hz, 2H), 7.62 (td, J = 7.8 Hz, 1.7 Hz, 1H), 7.69 (d, J = 7.8 Hz,
1H), 8.08 (br, 1H), 8.38 (d, J = 4.9 Hz, 1H), 8.66 (d, J = 8.3 Hz,
1H); 13C NMR (CDCl3) δ 21.3, 61.7, 80.7, 123.6, 126.6, 126.7,
126.7, 126.8, 128.4, 128.7, 129.0, 132.7, 133.3, 137.7, 138.4,
142.0, 142.1, 143.3, 148.0, 156.9, 198.0; MS (EI) m/z 458
(M+ − H2S); HRMS calcd for C27H22Cl2N2OS: 492.0830,
Found: 492.0827.
as an example leading to 2b
To a THF solution (2 mL) of N-(2-hydroxy-2-cyclohexyl-
1-pyridine-2-ylethyl)-4-methylbenzenecarbothioamide (1b) (0.17 g,
0.5 mmol) was added iodine (0.38 g, 1.5 mmol) and pyridine
(0.12 mL, 1.0 mmol) at 0 °C. The mixture was stirred at 0 °C for
30 min. To the reaction mixture was then added an aqueous
solution of sodium thiosulfate, and the aqueous layer was
extracted with dichloromethane. The organic layer was washed
with water, and dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel (n-hexane–EtOAc = 8 : 1–1 : 1) to give (3-(4-methyl-
phenyl)imidazo[1,5-a]pyridine-1-yl)cyclohexylmethanol (2b) as
a brown oil.
N-(2-Hydroxy-2,2-bis(4-methoxyphenyl)-1-pyridin-2-ylethyl)-
4-methylbenzenecarbothioamide (7e). A yellow solid; m.
p. 133–136 °C; IR (KBr) 3310, 3293, 2953, 2833, 1608, 1509,
1-(3-(4-Methylphenyl)imidazo[1,5-a]pyridine-1-yl)ethanol (2a). A
brown oil; IR (neat) 3343, 2973, 2924, 1750, 1711, 1633, 1530,
1466, 1364, 1313, 1112, 1074, 1040, 1007, 886, 825, 721,
1
1251, 1174, 1034, 822 cm−1; H NMR (CDCl3) δ 2.29 (s, 3H),
3.64 (s, 3H), 3.72 (s, 3H), 6.63 (d, J = 8.8 Hz, 2H), 6.76 (d,
J = 8.5 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.0 Hz,
2H), 7.10 (ddd, J = 7.6 Hz, 4.9 Hz, 1.2 Hz, 1H), 7.29 (d, J = 8.8
Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.55 (dt, J = 7.8 Hz, 1.7 Hz,
1H), 7.58 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.78 (br,
1H), 8.36 (d, J = 4.9 Hz, 1H), 8.76 (d, J = 8.5 Hz, 1H); 13C
NMR (CDCl3) δ 21.2, 55.0, 55.1, 62.5, 80.7, 113.3, 113.7,
123.1, 126.3, 126.7, 126.8, 128.9, 136.5, 137.0, 137.5, 138.7,
141.6, 148.1, 157.6, 157.9, 158.4, 197.7; MS (EI) m/z 484 (M+);
HRMS calcd for C29H28N2O3S: 484.1821, found: 484.1829.
1
502 cm−1; H NMR (CDCl3) δ 1.70 (d, J = 6.3 Hz, 3H), 2.40
(s, 3H), 3.29 (br, 1H), 5.29 (q, J = 6.3 Hz, 1H), 6.32–6.48
(m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 10.2 Hz, 1H),
7.61 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 7.3 Hz, 1H); 13C NMR
(CDCl3) d 21.3, 23.9, 64.8, 112.9, 118.0, 118.5, 121.3, 126.7,
127.1, 127.9, 129.6, 135.5, 136.8, 138.5; MS (EI) m/z 252 (M+);
HRMS calcd for C16H16N2O: 252.1263, found: 252.1243.
(3-(4-Methylphenyl)imidazo[1,5-a]pyridine-1-yl)cyclohexyl-
methanol (2b). A brown oil; IR (KBr) 3394, 2923, 2849, 1750,
1632, 1528, 1463, 1447, 1364, 1313, 1262, 1082, 1021, 999,
950, 823, 751, 471 cm−1 1H NMR (CDCl3) δ 0.87–2.01
;
N-(2-Hydroxy-2,2-bis(4-dimethylaminophenyl)-1-pyridin-
2-ylethyl)4-methylbenzenecarbothioamide (7f). A yellow
solid; m.p. 193–194 °C (decomp.); IR (KBr) 3351, 3196, 2882,
2792, 1614, 1521, 1490, 1360, 1224, 1063, 814 cm−1; 1H NMR
(CDCl3) δ 2.29 (s, 3H), 2.79 (s, 6H), 2.87 (s, 6H), 6.46 (d,
J = 8.8 Hz, 2H), 6.66 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.8 Hz,
2H), 7.05 (d, J = 8.3 Hz, 2H), 7.08 (dd, J = 7.3 Hz, 4.9 Hz, 1H),
7.18 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.48
(d, J = 8.8 Hz, 2H), 7.53 (dd, J = 7.8 Hz, 7.3 Hz, 1H), 7.55
(br, 1H), 7.61 (d, J = 7.8 Hz, 1H), 8.37 (d, J = 4.9 Hz, 1H), 8.82
(d, J = 8.1 Hz, 1H); 13C NMR (CDCl3) δ 21.3, 40.4, 40.5, 62.8,
80.7, 112.0, 112.5, 122.8, 125.9, 126.0, 126.8, 127.0, 128.9,
132.7, 133.6, 136.8, 138.9, 141.4, 148.0, 148.7, 149.3, 158.0,
197.4; MS (EI) m/z 510 (M+); HRMS calcd for C31H34N4OS:
510.2453, Found: 510.2423.
(m, 11H), 2.29 (s, 3H), 3.45 (br, 1H), 4.65 (d, J = 7.3 Hz, 1H),
6.36 (dd, J = 7.3 Hz, 6.3 Hz, 1H), 6.50 (dd, J = 9.3 Hz, 6.3 Hz,
1H), 7.16 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 9.3 Hz, 1H), 7.49
(d, J = 8.3 Hz, 2H), 8.00 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3)
δ 21.3, 25.9, 26.0, 26.4, 29.0, 29.3, 44.7, 73.1, 112.9, 117.9,
118.6, 121.2, 127.1, 127.7, 127.9, 129.5, 133.9, 136.9, 138.5;
MS (EI) m/z 320 (M+); HRMS calcd for C21H24N2O: 320.1889,
found: 320.1906.
(3-(4-Methylphenyl)imidazo[1,5-a]pyridine-1-yl)-2,2-dimethyl-
propanol (2c). A brown soild; m.p. 47–48 °C; IR (KBr) 3253,
2950, 2865, 1633, 1529, 1463, 1361, 1314, 1240, 1185, 1113,
1082, 1058, 1011, 964, 898, 823, 739, 716, 499 cm−1; 1H NMR
(CDCl3) δ 0.89 (s, 9H), 2.26 (s, 3H), 3.66 (br, 1H), 4.59 (s, 1H),
6.32 (dd, J = 7.3 Hz, 6.3 Hz, 1H), 6.46 (dd, J = 9.3 Hz, 6.3 Hz,
1H), 7.13 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 9.3 Hz, 1H), 7.47
(d, J = 8.3 Hz, 2H), 7.97 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3)
δ 21.5, 26.3, 37.3, 76.7, 112.9, 118.0, 119.4, 121.3, 127.4,
128.1, 128.2, 129.7, 133.3, 136.7, 138.5; MS (EI) m/z 294 (M+);
HRMS calcd for C19H22N2O: 294.1732, found: 294.1743.
N-(2-Pyridylmethyl-9H-fluoren-9-ol)-4-methylbenzene-
carbothioamide (7g). A yellow solid; m.p. 122–124 °C; IR (KBr)
3346, 3245, 3048, 3015, 2932, 1590, 1480, 1354, 1209, 1092,
1
1065, 824, 748 cm−1; H NMR (CDCl3) δ 2.36 (s, 3H), 6.37
(d, J = 8.5 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.3
Hz, 1H), 7.13–7.19 (m, 6H), 7.28–7.32 (m, 2H), 7.36 (t, J = 7.3
Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.61
(t, J = 7.3 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 4.4 Hz,
1H); 13C NMR (CDCl3) δ 21.3, 63.8, 85.4, 119.7, 120.1, 123.3,
123.8, 124.5, 124.7, 126.8, 127.9, 129.1, 129.3, 129.6, 137.1,
138.4, 139.5, 140.2, 142.0, 145.6, 145.7, 148.1, 156.8, 199.2;
MS (EI) m/z 422 (M+); HRMS calcd for C27H22N2OS:
422.1453, found: 422.1430.
(3-Phenylimidazo[1,5-a]pyridine-1-yl)-2-pyridine-1-yl-
methanol (2d). A brown oil; IR (neat) 3265, 3064, 1634, 1591,
1571, 1519, 1461, 1435, 1367, 1317, 1148, 1077, 1033, 1001,
1
961, 916, 849, 774, 740, 699 cm−1; H NMR (CDCl3) δ 5.62
(br, 1H), 6.28 (s, 1H), 6.47 (dd, J = 7.3 Hz, 6.3 Hz, 1H), 6.58
(dd, J = 9.3 Hz, 6.3 Hz, 1H), 7.17 (dd, J = 7.3 Hz, 5.1 Hz, 1H),
7.39 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.47 (t, J =
7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.62 (td, J = 7.8 Hz, 1.5
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Hz, 1H), 7.73 (d, J = 7.3 Hz, 2H), 8.13 (d, J = 7.3 Hz, 1H), 8.56
(d, J = 5.1 Hz, 1H); 13C NMR (CDCl3) δ 70.7, 113.1, 118.5,
118.8, 121.1, 121.4, 122.2, 128.0, 128.1, 128.5, 128.8, 130.0,
133.2, 136.7, 136.9, 147.6, 160.6; MS (EI) m/z 301 (M+);
HRMS calcd for C19H15N3O: 301.1215, found: 301.1204.
482 (M+); HRMS calcd for C31H22N4S: 482.1565, found:
482.1557.
Bis-(α,α-dimethylethylimidazo[1,5-a]pyridine-1-yl)phenyl-
methane (4g). A yellow oil; IR (KBr) 2967, 2928, 2870, 1759,
1632, 1600, 1490, 1462, 1363, 1305, 1219, 1071, 1003, 865,
1
799, 749, 719, 698 cm−1; H NMR (CDCl3) δ 1.51 (s, 18H),
(3-(2-Pyridin-1-yl)imidazo[1,5-a]pyridin-1-yl)-2-pyridin-1-
ylmethanol (2e). A yellow solid; m.p. 130–134 °C; IR (KBr)
6.13 (s, 1H), 6.34 (dd, J = 7.3 Hz, 6.3 Hz, 2H), 6.42 (dd, J = 9.3
Hz, 6.3 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.18 (dd, J = 7.8 Hz,
7.3 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 9.3 Hz, 2H),
7.90 (d, J = 7.3 Hz, 2H); 13C NMR (CDCl3) δ 28.2, 33.3, 44.7,
111.2, 115.4, 120.5, 122.4, 125.6, 127.8, 128.2, 128.5, 131.2,
143.1, 144.4; MS (EI) m/z 436 (M+); HRMS calcd for
C29H32N4: 436.2627, found; 436.2628.
3293, 3134, 1587, 1499, 1426, 1342, 1030, 755, 737 cm−1
;
1H NMR (CDCl3) δ 5.43 (br, 1H), 6.28 (s, 1H), 6.69 (dd,
J = 7.3 Hz, 6.6 Hz, 1H), 6.77 (dd, J = 9.0 Hz, 6.6 Hz, 1H), 7.19
(dd, J = 6.3 Hz, 4.9 Hz, 1H), 7.22 (dd, J = 6.8 Hz, 4.9 Hz, 1H),
7.42 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.64 (dd,
J = 7.8 Hz, 7.6 Hz, 1H), 7.77 (dd, J = 8.1 Hz, 7.6 Hz, 1H), 8.35
(d, J = 8.1 Hz, 1H), 8.63–8.60 (m, 2H), 9.90 (d, J = 7.3 Hz,
1H); 13C NMR (CDCl3) δ 70.8, 113.7, 118.1, 120.0, 121.5,
122.0, 122.4, 125.9, 129.6, 133.6, 134.0, 136.4, 136.8, 147.7,
148.1, 150.9, 160.5; MS (EI) m/z 302 (M+); HRMS calcd for
C18H14N4O: 302.1168, found: 302.1160.
Bis-(3-(4-methylphenyl)imidazo[1,5-a]pyridine-1-yl)-1,1-
diphenylmethane (8a). A yellow solid; m.p. 275–277 °C;
IR (KBr) 3016, 2919, 1736, 1630, 1595, 1523, 1490, 1464,
1443, 1393, 1360, 1313, 1243, 1180, 1115, 1007, 961, 877, 825,
742, 716, 696 cm−1; 1H NMR (CDCl3) δ 2.29 (s, 6H), 6.24 (dd,
J = 9.3 Hz, 6.3 Hz, 2H), 6.32 (dd, J = 7.3 Hz, 6.3 Hz, 2H), 6.36
(d, J = 9.3 Hz, 2H), 7.09–7.18 (m, 10H), 7.37 (d, J = 8.3 Hz,
4H), 7.55 (d, J = 7.8 Hz, 4H), 8.09 (d, J = 7.3 Hz, 2H); 13C
NMR (CDCl3) δ 21.3, 57.6, 112.5, 117.0, 121.2, 125.9, 127.2,
127.9, 128.1, 129.3, 129.4, 130.7, 135.6, 137.1, 137.9, 146.5;
MS (EI) m/z 580 (M+).
General procedure for the cyclization of N-thioacyl 1,2-
aminoalcohols 3 to imidazo[1,5-a]pyridinylethanols as an
example leading to 4f
To a THF solution (4 mL) of N-(2-hydroxy-2-thienyl-1-pyridin-
2-ylethyl)benzenecarbothioamide (3f) (0.17 g, 0.50 mmol) was
added I2 (0.38 g, 1.5 mmol) and pyridine (0.12 mL, 1.5 mmol)
at room temperature. The mixture was stirred at room tempera-
ture for 30 min. The reaction mixture was poured into a saturated
aqueous solution of Na2S2O3 and extracted with CH2Cl2. The
organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash column chromatography on
silica gel (n-hexane–EtOAc = 6 : 1) to give 0.10 g (0.22 mmol,
86% per 0.25 mmol) of bis-(3-phenylimidazo[1,5-a]pyridine-1-
yl)-2-thiophen-1-ylmethane (4f) as a yellow solid.
Bis-(3-(4-methoxyphenyl)limidazo[1,5-a]pyridine-1-yl)-1,1-
diphenylmethane (8b). A brown solid; m.p. 134–135 °C; IR (KBr)
3052, 3016, 2931, 1610, 1528, 1463, 1362, 1289, 1249, 1173,
1
1031, 835, 745, 701 cm−1; H NMR (CDCl3) δ 3.84 (s, 6H),
6.33 (dd, J = 7.8 Hz, 6.3 Hz, 2H), 6.41 (dd, J = 9.3 Hz, 6.3 Hz,
2H), 6.42 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 4H),
7.17–7.27 (m, 6H), 7.44 (d, J = 8.8 Hz, 4H), 7.66 (d, J = 8.8
Hz, 4H), 8.14 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3) δ 55.3,
57.5, 112.4, 114.1, 116.8, 121.1, 123.4, 125.9, 127.1, 129.0,
129.6, 130.7, 135.4, 137.0, 146.5, 159.4; MS (EI) m/z 612 (M+);
HRMS calcd for C41H32N4O2: 612.2525, found: 612.2534.
Bis-(3-(4-methylphenyl)imidazo[1,5-a]pyridine-1-yl)ethane
(4a). A brown solid; m.p. 110–111 °C; IR (KBr) 3432, 3026,
2970, 2922, 2859, 1630, 1527, 1458, 1362, 1312, 1248, 1111,
General procedure for the silylation of N-thioacyl 1,2-
aminoalcohols 7 to silyl ethers 10 as an example leading to 10a
1
1023, 954, 824, 732, 717 cm−1; H NMR (CDCl3) δ 2.01 (d,
J = 7.3 Hz, 3H), 2.42 (s, 6H), 5.02 (q, J = 7.3 Hz, 1H), 6.42 (dd,
J = 7.3 Hz, 6.3 Hz, 2H), 6.51 (dd, J = 9.3 Hz, 6.3 Hz, 2H), 7.32
(d, J = 8.0 Hz, 4H), 7.56 (d, J = 9.3 Hz, 2H), 7.68 (d, J = 8.0
Hz, 4H), 8.11 (d, J = 7.3 Hz, 2H); 13C NMR (CDCl3) 20.7,
21.4, 33.2, 122.8, 117.0, 199.4, 121.0, 127.1, 127.7, 128.0,
129.6, 136.0, 136.1, 138.3; MS (EI) m/z 442 (M+); HRMS calcd
for C30H26N4: 442.2157, found: 442.2162.
To
a ClCH2CH2Cl solution (3 mL) of N-(2,2-diphenyl-
2-hydroxy)-1-pyridin-2-ylethyl)-4-methylbenzenecarbothioamide
(7a) (0.21 g, 0.50 mmol) and imidazole (68 mg, 1.0 mmol) was
added chlorotrimethylsilane (0.13 mL, 1.0 mmol) at room temp-
erature. The mixture was stirred at reflux for 12 h. The resulting
mixture was poured into a saturated aqueous solution of NH4Cl
and extracted with Et2O. The combined organic layer was
washed with water. The organic layer was dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (n-hexane–ethyl acetate =
16 : 1) to give 0.20 g (0.40 mmol, 80%) of N-(2,2-diphenyl-1-
pyridin-2-yl-2-trimethylsilyloxyethyl)-4-methylbenzenecarbothio-
amide (10a) as a yellow solid.
Bis-(3-phenylimidazo[1,5-a]pyridine-1-yl)-2-thiophen-1-ylmethane
(4f). A yellow solid; m.p. 87–88 °C; IR (KBr) 3063, 3037,
2960, 2924, 1632, 1602, 1519, 1460, 1404, 1364, 1315, 1274,
1
1073, 1002, 961, 859, 772, 731, 698 cm−1; H NMR (CDCl3) δ
6.31 (dd, J = 7.3 Hz, 6.4 Hz, 2H), 6.44 (s, 1H), 6.45 (dd, J = 9.3
Hz, 6.4 Hz, 2H), 6.80 (dd, J = 4.9 Hz, 3.4 Hz, 1H), 6.93 (d, J =
3.4 Hz, 1H), 7.05 (d, J = 4.9 Hz, 1H), 7.24 (t, J = 7.6 Hz, 2H),
7.34 (dd, J = 7.6 Hz, 7.3 Hz, 4H), 7.53 (d, J = 9.3 Hz, 2H), 7.65
(d, J = 7.3 Hz, 4H), 8.01 (d, J = 7.3 Hz, 2H); 13C NMR (CDCl3)
δ 40.6, 112.9, 117.8, 119.5, 121.0, 124.1, 125.5, 126.2, 128.0,
128.1, 128.2, 128.7, 130.4, 133.6, 136.4, 147.1; MS (EI) m/z
N-(2,2-Diphenyl-1-pyridin-2-yl-2-trimethylsilyloxyethyl)-4-
methylbenzenecarbothioamide
(10a). A
yellow
solid;
m.p. 117–118 °C; IR (KBr) 3392, 3060, 2957, 1492, 1250,
1
1102, 1073, 880, 841, 704 cm−1; H NMR (CDCl3) δ −0.17
4950 | Org. Biomol. Chem., 2012, 10, 4943–4953
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(s, 9H), 2.25 (s, 3H), 6.77 (d, J = 9.8 Hz, 1H), 6.93 (dd, J = 7.3
Hz, 4.9 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.3 Hz,
2H), 7.14–7.21 (m, 8H), 7.29–7.31 (m, 2H), 7.35 (dd, J = 7.8
Hz, 7.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 4.9 Hz,
1H), 8.53 (d, J = 9.8 Hz, 1H); 13C NMR (CDCl3) δ 1.8, 21.3,
65.2, 84.6, 122.0, 125.2, 126.7, 127.7, 127.7, 127.9, 128.2,
128.8, 129.0, 134.5, 139.4, 141.4, 142.8, 143.0, 147.9, 156.6,
197.7; MS (EI) m/z 462 (M+ − H2S); HRMS calcd for
C30H32N2OSSi: 496.2005, found: 496.1995.
(d, J = 7.6 Hz, 1H), 6.99 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 8.3
Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.52–7.59 (m, 4H), 7.64 (t,
J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 7.3 Hz,
1H), 7.90 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 7.3 Hz, 1H), 7.99 (t,
J = 7.6 Hz, 1H), 8.64 (d, J = 9.6 Hz, 1H), 8.75 (d, J = 4.6 Hz,
1H); 13C NMR (CDCl3) δ 1.1, 21.2, 64.6, 85.6, 119.3, 119.7,
122.8, 125.6, 125.8, 126.6, 126.7, 127.0, 127.5, 128.7, 129.4,
129.6, 135.1, 139.4, 139.5, 140.6, 141.0, 144.1, 146.0, 147.9,
156.0, 198.4; MS (EI) m/z 460 (M+ − H2S); HRMS calcd for
C30H30N2OSSi: 494.1848, found: 494.1833.
N-(2,2-Bis(4-chlorophenyl)-1-pyridin-2-yl-2-trimethylsilyl-
oxyethyl)-4-methylbenzenecarbothioamide (10d). A yellow solid;
m.p. 66–69 °C; IR (KBr) 3380, 2955, 1591, 1490, 1361, 1253,
Diphenyl-3-(4-methylphenyl)imidazo[1,5-a]pyridin-1-yltri-
methylsilyloxymethane (11a). A yellow solid; m.p. 52–57 °C;
IR (KBr) 3058, 3024, 2952, 1475, 1447, 1249, 1001, 1056, 881,
840, 746, 700 cm−1; 1H NMR (CDCl3) δ −0.16 (s, 9H), 2.40 (s,
3H), 6.38–6.45 (m, 2H), 6.68–6.73 (m, 1H), 7.20 (t, J = 7.1 Hz,
2H), 7.26 (t, J = 7.3 Hz, 4H), 7.27 (d, J = 8.3 Hz, 2H), 7.59 (d,
J = 7.3 Hz, 4H), 7.64 (d, J = 8.3 Hz, 2H), 8.12–8.16 (m, 1H);
13C NMR (CDCl3) δ 1.5, 21.4, 81.8, 112.4, 117.9, 120.3, 121.3,
126.6, 127.5, 127.8, 128.1, 128.2, 129.2, 129.5, 136.2, 136.4,
138.3; MS (EI) m/z 462 (M+); HRMS calcd for C30H30N2OSi:
462.2127, found: 462.2150.
1
1092, 1013, 884, 842 cm−1; H NMR (CDCl3) δ −0.08 (s, 9H),
2.35 (s, 3H), 6.82 (d, J = 9.9 Hz, 1H), 7.05 (dd, J = 7.6 Hz, 4.9
Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.15
(d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 4H), 7.35 (d, J = 8.8
Hz, 2H), 7.48 (dd, J = 7.8 Hz, 7.6 Hz, 1H), 7.59 (d, J = 8.3 Hz,
2H), 8.21 (d, J = 4.9 Hz, 1H), 8.53 (d, J = 9.9 Hz, 1H);
13C NMR (CDCl3) δ 1.9, 21.3, 64.7, 83.9, 122.3, 125.3, 126.7,
127.9, 128.0, 129.1, 129.5, 130.3, 133.9, 134.1, 134.8, 139.2,
141.1, 141.3, 141.8, 148.1, 156.1, 198.2; MS (EI) m/z 530
(M+
− H2S); HRMS calcd for C30H30Cl2N2OSSi–CH3:
Bis(4-chlorophenyl)-3-(4-methylphenyl)imidazo[1,5-a]pyridin-
549.0990, found: 549.0993.
1-yltrimethylsilyloxymethane
(11d). A
yellow
solid;
N-(2,2-Bis(4-methoxyphenyl)-1-pyridin-2-yl-2-trimethylsilyl-
oxyethyl)-4-methylbenzenecarbothioamide (10e). A yellow
solid; m.p. 60–62 °C; IR (KBr) 3377, 2954, 2836, 1608, 1509,
1180, 1086, 1035, 840 cm−1; 1H NMR (CDCl3) δ −0.10 (s, 9H),
2.33 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 6.78 (d, J = 9.3 Hz, 2H),
6.78 (d, J = 9.8 Hz, 1H), 6.78 (d, J = 9.3 Hz, 2H), 7.02 (dd,
J = 7.3 Hz, 4.9 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.12 (d,
J = 7.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.8 Hz,
2H), 7.46 (dd, J = 7.8 Hz, 7.3 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H),
8.21 (d, J = 4.9 Hz, 1H), 8.55 (d, J = 9.8 Hz, 1H); 13C NMR
(CDCl3) δ 1.8, 21.3, 55.1, 65.5, 83.8, 112.8, 112.9, 122.0,
125.3, 126.7, 129.0, 129.5, 130.3, 134.5, 134.9, 135.1, 139.5,
141.4, 147.8, 156.8, 158.9, 159.1, 197.6; MS (EI) m/z 522
(M+ − H2S); HRMS calcd for C32H36N2O3SSi–H2S: 522.2339,
found: 522.2343.
m.p. 70–72 °C; IR (KBr) 2954, 1590, 1486, 1250, 1091, 1054,
1
1013, 886, 842, 720 cm−1; H NMR (CDCl3) δ −0.17 (s, 9H),
2.41 (s, 3H), 6.46 (d, J = 6.8 Hz, 6.3 Hz, 1H), 6.83 (dd, J = 9.3
Hz, 6.3 Hz, 1H), 6.75 (d, J = 9.3 Hz, 1H), 7.25 (d, J = 8.3 Hz,
4H), 7.30 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 4H), 7.63 (d,
J = 8.3 Hz, 2H), 8.16 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3)
δ 1.4, 21.4, 80.9, 112.6, 118.5, 120.0, 121.5, 127.4, 127.8,
128.2, 129.3, 129.6, 132.6, 134.9, 136.6, 138.6, 146.0; MS (EI)
m/z 530 (M+); HRMS calcd for C30H28Cl2N2OSi: 530.1348,
found: 530.1361.
Bis(4-methoxyphenyl)-3-(4-methylphenyl)imidazo[1,5-a]pyridin-
1-yltrimethylsilyloxymethane
(11e). A
yellow
solid;
m.p. 51–53 °C; IR (KBr) 2952, 2834, 1606, 1507, 1249, 1173,
1
1089, 1035, 888, 839 cm−1; H NMR (CDCl3) δ −0.29 (s, 9H),
2.25 (s, 3H), 3.63 (s, 6H), 6.27 (dd, J = 6.8 Hz, 6.3 Hz, 1H),
6.31 (dd, J = 8.8 Hz, 6.3 Hz, 1H), 6.66 (d, J = 8.8 Hz, 4H), 6.76
(d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.8
Hz, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 6.8 Hz, 1H);
13C NMR (CDCl3) δ 1.6, 21.4, 55.1, 81.4, 112.4, 112.7, 117.7,
120.5, 121.2, 127.8, 128.2, 128.9, 129.2, 129.4, 136.3, 136.8,
138.2, 140.2, 158.2; MS (EI) m/z 522 (M+); HRMS calcd for
C32H34N2O3Si: 522.2339, found: 522.2314.
N-(2,2-Bis(4-dimethylaminophenyl)-1-pyridin-2-yl-2-trimethyl-
silyloxyethyl)-4-methylbenzenecarbothioamide (10f). A yellow
solid; m.p. 85–89 °C (decomp.); IR (KBr) 3377, 2952, 2892,
2801, 1611, 1520, 1358, 1250, 1163, 1079, 887, 841 cm−1
;
1H NMR (CDCl3) δ −0.11 (s, 9H), 2.32 (s, 3H), 2.91 (s, 6H),
2.93 (s, 6H), 6.59 (d, J = 8.8 Hz, 4H), 6.75 (d, J = 9.3 Hz, 1H),
7.01 (dd, J = 7.3 Hz, 4.9 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.11
(dd, J = 8.1 Hz, 2H), 7.11 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.8
Hz, 2H), 7.44 (dd, J = 7.8 Hz, 7.3 Hz, 1H), 7.59 (d, J = 8.1 Hz,
2H), 8.23 (d, J = 4.9 Hz, 1H), 8.53 (d, J = 9.3 Hz, 1H);
13C NMR (CDCl3) δ 1.8, 21.2, 40.3, 65.8, 83.8, 111.0, 111.1,
121.7, 125.3, 126.8, 128.8, 129.2, 130.0, 130.3, 130.5, 134.2,
139.5, 141.1, 147.6, 149.6, 149.8, 157.3, 197.1; MS (EI) m/z 582
(M+); HRMS calcd for C34H42N4OSSi: 582.2849, found: 582.2849.
Diphenyl-3-(4-methylphenyl)imidazo[1,5-a]pyridin-1-yl-
methanol (9a). A yellow solid; m.p. 176–177 °C; IR (KBr) 3466,
3023, 1446, 1367, 1006, 823, 700 cm−1 1H NMR (CDCl3)
;
δ 2.32 (s, 3H), 5.00 (br, 1H), 6.09 (d, J = 9.0 Hz, 1H), 6.30 (dd,
J = 9.0 Hz, 6.3 Hz, 1H), 6.34 (dd, J = 7.1 Hz, 6.3 Hz, 1H),
7.17–7.25 (m, 8H), 7.30 (d, J = 7.8 Hz, 4H), 7.57 (d, J = 8.1
Hz, 2H), 8.06 (d, J = 7.1 Hz, 1H); 13C NMR (CDCl3) δ 21.4,
78.4, 112.7, 118.7, 119.0, 121.5, 127.0, 127.4, 127.5, 127.8,
128.1, 128.2, 129.6, 136.7, 137.0, 138.8, 146.2; MS (EI) m/z
390 (M+); HRMS calcd for C27H22N2O: 390.1732, found:
390.1743.
N-(2-Pyridylmethyl-9H-fluoren-9-trimethylsilyloxy)-4-methyl-
benzenecarbothioamide (10g). A yellow solid; m.p. 45–48 °C;
IR (KBr) 3222, 3059, 1714, 1610, 1498, 1186, 1091, 918,
1
738 cm−1; H NMR (CDCl3) δ 0.00 (s, 9H), 2.61 (s, 3H), 6.86
This journal is © The Royal Society of Chemistry 2012
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Diphenyl-3-(4-methoxylphenyl)imidazo[1,5-a]pyridin-1-yl-
methanol (9b). A yellow solid; m.p. 151–155 °C (decomp.);
IR (KBr) 3444, 3003, 2961, 2934, 1609, 1530, 1375, 1252,
1
1035, 1013, 702, 741 cm−1; H NMR (CDCl3) δ 3.86 (s, 3H),
5.05 (br, 1H), 6.15 (d, J = 9.3 Hz, 1H), 6.39 (d, J = 9.3 Hz, 6.3
Hz, 1H), 6.44 (dd, J = 7.3 Hz, 6.3 Hz, 1H), 7.02 (d, J = 8.8 Hz,
2H), 7.28–7.33 (m, 6H), 7.38–7.40 (m, 4H), 7.69 (d, J = 8.8 Hz,
2H), 8.11 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ 55.4, 78.4,
112.6, 114.4, 118.6, 119.0, 121.3, 122.3, 127.3, 127.8, 128.2,
129.6, 136.5, 136.9, 146.3, 160.0; MS (EI) m/z 406 (M+);
HRMS calcd for C27H22N2O2: 406.1681, found: 406.1661.
Bis(4-chlorophenyl)-3-(4-methylphenyl)imidazo[1,5-a]pyridin-
1-ylmethanol (9d). A yellow solid; m.p. 81–84 °C (decomp.);
IR (KBr) 3428, 2921, 1489, 1362, 1092, 1012, 824, 724 cm−1
;
1H NMR (CDCl3) δ 2.41 (s, 3H), 5.13 (br, 1H), 6.25–6.28
(m, 1H), 6.45–6.49 (m, 2H), 7.27 (d, J = 8.8 Hz, 4H), 7.29
(d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.8 Hz, 4H), 7.62 (d, J = 8.3
Hz, 2H), 8.16 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ 21.4,
77.7, 112.9, 118.6, 119.3, 121.6, 126.7, 127.4, 128.0, 129.5,
129.7, 133.4, 135.9, 137.0, 139.0, 144.5; MS (EI) m/z 458 (M+);
HRMS calcd for C27H20Cl2N2O: 458.0953, Found: 458.0955.
Bis(4-methoxyphenyl)-3-(4-methylphenyl)imidazo[1,5-a]pyridin-
1-ylmethanol (9e). A yellow solid; m.p. 62–66 °C (decomp.);
IR (KBr) 3491, 2925, 2833, 1607, 1507, 1304, 1245, 1016,
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and C. Nervi, Chem.–Eur. J., 2009, 15, 6415.
1
1007, 828 cm−1; H NMR (CDCl3) δ 2.42 (s, 3H), 3.80 (s, 6H),
4.95 (br, 1H), 6.23 (d, J = 8.8 Hz, 1H), 6.40–6.47 (m, 2H), 6.84
(d, J = 8.8 Hz, 4H), 7.28 (d, J = 8.8 Hz, 4H), 7.31 (d, J = 8.1
Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 8.16 (d, J = 6.8 Hz, 1H);
13C NMR (CDCl3) δ 21.3, 55.2, 77.7, 112.6, 113.0, 118.6,
119.1, 121.4, 127.0, 127.4, 128.0, 129.3, 129.5, 136.6, 137.5,
138.7, 138.8, 158.7; MS (EI) m/z 450 (M+); HRMS calcd for
C29H26N2O3: 450.1943, Found: 450.1958.
5 (a) D. Kim, L. Wang, J. J. Hale, C. L. Lynch, R. J. Budhu, M. MacCoss,
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9-(3-(4-Methylphenyl)imidazo[1,5-a]pyridin-1-yl)-9H-fluoren-
9-ol (9g). A yellow solid; m.p. 159–163 °C (decomp.); IR (KBr)
1
3488, 3088, 1515, 1449, 1371, 1028, 826, 734 cm−1; H NMR
(CDCl3) δ 2.44 (s, 3H), 5.35 (br, 1H), 6.07 (d, J = 9.3 Hz, 1H),
6.25 (dd, J = 9.3 Hz, 6.3 Hz, 1H), 6.34 (d, J = 7.3 Hz, 6.3 Hz,
1H), 7.23 (dd, J = 7.8 Hz, 7.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H),
7.37 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 7.69 (d,
J = 7.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 7.3 Hz,
1H); 13C NMR (CDCl3) δ 21.4, 79.8, 112.8, 118.1, 118.5, 120.0,
121.2, 125.0, 127.1, 127.9, 128.1, 128.9, 129.7, 133.2, 136.3,
138.8, 139.6, 149.0; MS (EI) m/z 388 (M+); HRMS calcd for
C27H20N2O: 388.1576, found: 388.1572.
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Acknowledgements
This study was supported in part by the Grant-in-Aid for Scien-
tific Research on Innovative Areas “Organic Synthesis based on
Reaction Integration. Development of New Methods and Cre-
ation of New Substances” (No. 2105).
Notes and references
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