Selective C-acylation of 2-aminoimidazo[1,2- a ]pyridine: Application to the synthesis of imidazopyridine-fused [1,3]diazepinones

Article abstract of DOI:10.1021/jo300364d

A series of 20 optically pure 3,4-dihydro-5H-pyrido[1′,2′:1,2] imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]diazepines were synthesized in four steps with 17-66% overall yields. The key step consists of a selecti

Full text of DOI:10.1021/jo300364d

Note
pubs.acs.org/joc
Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application
to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones
Nicolas Masurier,*,† Roberta Aruta,† Vincent Gaumet,‡ Severine Denoyelle,† Emmanuel Moreau,‡
́
Vincent Lisowski,† Jean Martinez,† and Ludovic T. Maillard†
†Institut des Biomolec
́ ́
ules Max Mousseron, UMR 5247, CNRS, Universites Montpellier I et II, UFR des Sciences Pharmaceutiques et
Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France
‡UMR 990, INSERM, Universite
́
d’Auvergne, Rue Montalembert, BP 184, 63000 Clermont-Ferrand, France
S
* Supporting Information
ABSTRACT: A series of 20 optically pure 3,4-dihydro-5H-
pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form
a new family of azaheterocycle-fused [1,3]diazepines were
synthesized in four steps with 17−66% overall yields. The key
step consists of a selective C-acylation reaction of easily
accessible 2-aminoimidazo[1,2-a]pyridine at C-3.
he concept of privileged structure, which is defined as “a
T
single molecular framework able to provide ligands for
diverse receptors”,1 has emerged as a powerful approach to
increase the chances of discovering lead compounds. The first
prototype of such structures, which led to many clinical and
commercial successes, was the diazepine scaffold.2,3 Since the
discovery of the benzodiazepine family as central nervous
system depressants, many synthetic derivatives, displaying a
wide pharmacological spectrum including antithrombotic,4
antibiotic,5 and antitumor6,7 properties, have been extensively
developed. Much attention has been paid to the replacement of
the fused benzene ring by a heterocyclic ring system such as
thiophene,8,9 pyrazole,10,11 imidazole,12 pyrrole,13−15 in-
dole,16,17 furan,13 etc. Among the different classes of diazepines,
the [1,3]diazepines have been studied to a minor extent
although their derivatives are also of interest due to their ability
to bind multiple therapeutic targets. As an example, [1,3]-
diazepines have shown inhibitory effects on HIV-1 protease,18
lymphocyte-specific kinase (Lck),19 AMP deaminase,20 adeno-
sine deaminase, and guanase,21 as well as cytotoxic effects on
Jurkat and glial cells22 (for examples of biologically active
[1,3]diazepines, see Figure 1). Consequently, the development
of efficient methodologies for the synthesis of new heterocycle-
fused [1,3]diazepine scaffolds could be of value for subsequent
biological screening programs.
Figure 1. Representative examples of [1,3]diazepines.
their promising activities for pharmaceutics, no IP-fused
[1,3]diazepine has been reported so far. In light of our interest
in accessing new skeletons containing the IP ring,33 we report
herein the synthesis of IP-fused [1,3]diazepines 1.
In order to synthesize 1, we envisioned the strategy described
in Scheme 1 that consisted of condensation of 2-amino-3-
acylimidazo[1,2-a]pyridines 7 with aldehydes. Oxidation led to
3,4-dihydro-5H-pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-
one 1. One of the most efficient reported methods to
synthesize the key intermediates 7 is the alkylation of 2-
chloropyridine with halomethyl ketones followed by nucleo-
philic chloride displacement with cyanamide and subsequent
cyclization under basic conditions.34 This method suffers from
a low number of commercially available halomethylketones and
from harsh reaction conditions, especially during alkylation of
2-chloropyridine. The direct acylation of 2-aminoimidazo[1,2-
Imidazo[1,2-a]pyridine (IP), an aza analogue of indole, is an
important pharmacophore and is widely found in many
biologically active compounds exhibiting antibacterial,23 anti-
fungal,24 antiviral,25−27 antitumorous,28,29 and anti-inflamma-
tory30 properties. Drug formulations containing imidazo[1,2-
a]pyridines currently available on the market include alpidem
(anxiolytic), zolpidem31 (hypnotic), and zolimidine (antiulcer).
Extensive studies have been performed to synthesize bioactive
polyfused heterocyclic compounds with the IP ring.28,32
However, a careful survey of the literature revealed that,
among the numerous synthesized IP derivatives, and despite
Received: February 23, 2012
Published: March 16, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
N-addition or C-addition, could occur. It is known that
aminoimidazole derivatives could give these two different
modes of addition, depending on the electrophilic reagent
used.39 However, to the best of our knowledge, Friedel−Crafts
acylation had never been studied with these ambivalent
nucleophiles. In order to study the conditions to selectively
acetylate compound 8 at C-3, N-Boc-L-Phe was selected as the
acyl donor. Activation of the N-protected amino acid was
performed at room temperature in dichloromethane using
EDC/DMAP (1 equiv; 0.1 equiv) or isobutylchloroformate (1
equiv) with DIEA (1 equiv). Reactions were monitored by
TLC on alumina oxide (DCM/EtOH, 99:1 v/v) and by HPLC.
Whatever the tested conditions, 2-aminoimidazo[1,2-a]pyridine
8 was converted into an inseparable mixture consisting of N-
and C-addition products (data not shown). No reaction
occurred when N-Boc-L-Phe was activated into acid chloride
with the Ghosez reagent. Selective C-acylation at C-3 was
finally obtained when using EDC/HOBT (1 equiv; 1 equiv) in
dichloromethane: the C-addition compound 12a was isolated
in 88% yield, while the N-addition product was only detected as
a minor compound by LC-MS. While C-3 acyclation of IP
generally required harsh conditions, compound 8 could be
acylated at room temperature, probably due to the high
reactivity of the enamine function. Moreover, the use of a soft
activation method (i.e., EDC/HOBT) led to a C-acylation
selectivity that could be seen as a powerful method to easily
functionalize the IP skeleton.
Scheme 1. Retrosynthetic Approach To Synthesize 3,4-
Dihydro-5H-pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-
ones
a]pyridine 8 is an alternate strategy. However, to the best of
our knowledge, this option has never been considered.
2-Aminoimidazo[1,2-a]pyridine 8 was prepared as depicted
in Scheme 2. 2-Aminopyridine was first reacted with
Scheme 2. Synthesis of 3,4-Dihydro-5H-pyrido[1′,2′:1,2]
imidazo[4,5-d][1,3]diazepin-5-ones
The scope of the reaction was extended to three other N-
Boc-amino acids, such as N-Boc-L-Ala, N-Boc-L-Thr(OBn), and
N-Boc-L-Pro, which respectively led to compounds 12c−e in
64, 61.5, and 88% yields. Intermediates 12 were finally
unprotected by aqueous HCl, and the resulting hydrochloride
salts were neutralized with aqueous ammonia.
To explore the formation of the IP-fused [1,3]diazepine
scaffold, diamine 7a was reacted with 1 equiv of p-nitro-
benzaldehyde under various experimental conditions. Six
different solvents were tested (i.e., toluene, THF, n-BuOH,
1,4-dioxane, chloroform, and acetonitrile) between 25 and 110
°C (Table 1). Reactions were monitored by TLC on alumina
oxide (DCM/EtOH, 99:1 v/v). Diazepinones 6a and 6a′ were
isolated by chromatography on neutral alumina oxide as pure
diastereomers. Their absolute configurations were ascertained
by X-ray crystal structures of 6a and 6a′ (see Supporting
Information). The best yields were obtained when the reaction
was performed at 50 °C in toluene or in dioxane as well as in
refluxing chloroform (Table 1, entries 2, 4, and 9). The ratio of
diastereomers appeared to be highly dependent on the
conditions used. As examples, at 50 °C in toluene, 6a and 6a′
were obtained in a 72:28 ratio, while at 110 °C, the
diastereoselectivity was inversed to a 30:70 ratio (Table 1,
entries 1 and 2). The best diastereoselectivity in the cis-
diazepinone 6a was obtained when the reaction was carried out
at 50 °C in acetonitrile (Table 1, entry 10). Adding a Lewis acid
such as SnCl2 led to a decrease of the global yield (Table 1,
entry 6).
tosylchloride in refluxing pyridine and then alkylated with
iodoacetamide to give 10 in 91% yield. Electrocyclization of 10
with trifluoroacetic anhydride in dry dichloromethane afforded
trifluoroacetamide 11 in 88% yield according to the method
reported by Hamdouchi.35 8 was finally obtained by
saponification of the trifluoroacetamide group.
1H NMR experiments have revealed a slow interconversion
of diastereomers 6a and 6a′ at room temperature with a 30:70
equilibrium ratio. In order to obtain the desired 3,4-dihydro-
5H-pyrido[1′,2′:1,2]imidazo[4,5-e][1,3]diazepin-5-one 1a, dia-
zepinones 6a and 6a′ were oxidized with a mixture of lead
tetraacetate and iodine in chloroform at room temperature.40
1a was isolated in 90% yield.
IP is known to be an electron-rich aromatic ring32,33,36,37 that
could lead to electrophilic aromatic substitutions at C-3.
However, the Friedel−Crafts acylation remains challenging and
requires an excess of acylating reagent and strong temperature
conditions.38 In the case of 2-aminoimidazo[1,2-a]pyridine 8, it
could be expected that two different modes of addition, either
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Note
Table 1. Condensation of 2-Amino-3-acylimidazo[1,2-a]pyridine 7a and p-Nitrobenzaldehyde
a
entry
solvent
toluene
T (°C)
yield (%)
6a/6a′
1
2
110
50
59
96
70
92
81
50
84
83
89
80
30/70
72/28
90/10
90/10
50/50
22/78
60/40
72/28
76/24
95/5
toluene
3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
25
4
50
5
105
50
b
6
7
50
8
n-BuOH
50
9
chloroform
acetonitrile
50
10
50
a
b
Reaction done with 50 mg of 7a and 1 equiv of p-nitrobenzaldehyde in 2 mL of solvent. Reaction done with 0.1 equiv of SnCl2.
To investigate the scope of the process, the diamine 7a and
its enantiomer 7b were reacted with various (hetero)aromatic
and aliphatic aldehydes, such as benzaldehyde, p-bromobenzal-
dehyde, o,m,p-tolualdehyde, p-anisaldehyde, and isovaleralde-
hyde. While intermediate diazepinones 6 could be detected by
LC-MS in most cases, they were not stable enough to be
isolated: purification by chromatography on alumina oxide led
to re-formation of aldehydes and diamine 7. Therefore, to
access diazepinones 1 anyway, we envisioned to perform
aldehyde condensation and oxidation in a one-pot tandem
procedure without any purification of the diazepinone
intermediates 6. Chloroform was chosen as a common solvent
for both cyclization and oxidation reactions. Diamines 7 were
stirred with 1 equiv of aldehyde at 60 °C overnight. The
mixtures were then cooled to 25 °C, and a solution of iodine
(1.1 equiv) and lead tetraacetate (1.1 equiv) was added. Stirring
was maintained until completion (monitored by TLC). The
reactions were quenched with 10% m/v sodium thiosulfate
aqueous solution, then compounds were purified by
chromatography on neutral alumina oxide. Results are
summarized in Figure 2. The best yields of the cyclization/
oxidation sequence were obtained with benzaldehyde bearing
electron-withdrawing groups such as p-nitro and p-bromoben-
zaldehyde (Figure 2, compounds 1a,b, respectively) and with 3-
pyridinecarboxaldehyde (Figure 2, compound 1i). The lack of
racemization was ascertained by determination of optical
Figure 2. Synthesis of 3,4-dihydro-5H-pyrido[1′,2′:1,2]imidazo[4,5-
d][1,3]diazepin-5-ones 1 (isolated yield after purification by
chromatography on alumina oxide). ND: not detected. NI: not
isolated. aDetermined by chiral HPLC. bUsing paraformaldehyde.
cUsing trimethylorthoformate.
order to study the influence of lateral chains, the procedure was
tested on the alanine and threonine derivatives 7c and 7d. The
nature of the substituent at the C-4 position was not a crucial
factor since yields obtained with diamines 7c and 7d were in
the same range as those obtained with 7a (Figure 2,
Compounds 1k−p). On the other hand, while proline
derivative 7e proved to be easily converted into diazepinones
6, the use of I2/Pb(OAc)4 as oxidant led in these cases to
complex mixtures and low yields (data not shown). We
therefore focused our attention on the optimization of
oxidation conditions. This led us to choose DDQ instead of
I2/Pb(OAc)4 for diamine 7e. Using this modified procedure,
the imidazopyridine-fused pyrrolodiazepinones 1q−s were
isolated with 54−73% yields (Figure 2, compounds 1q−s).
In conclusion, we have developed a practical sequence for the
synthesis of the IP-fused [1,3]diazepin-5-one heterocyclic
scaffold. The key step was a Friedel−Crafts acylation at the
C-3 position of the easily accessible 2-aminoimidazo[1,2-
rotation of both enantiomers (S)-1b ([α]20 = +1 (c 1.0,
D
CHCl3)) and (R)-1b ([α]20 = −1 (c 1.0, CHCl3)) and by
D
measuring their enantiomeric excesses by chiral HPLC (ee
>99%). With benzaldehyde, o-, m-, and p-tolualdehydes,
diazepinones were isolated with 41−54% overall yields (Figure
2, compounds 1c−f). The use of p-methoxybenzaldehyde led
to a strong decrease in yield (34% compared to 77% yield
obtained with p-nitrobenzaldehyde). This could probably be
due to the low stability of intermediate 6g. Despite lower yields,
the cascade reaction also tolerated aliphatic aldehydes like
isovaleraldehyde (Figure 2, compounds 1h). Conversely, it did
not proceed with paraformaldehyde (Figure 2, compound 1j).
Nevertheless, 1j could be quantitatively obtained by con-
densation of diamine 7a with trimethylorthoformate, but it
appeared to be highly unstable as soon as it was in solution. In
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Note
(2S)-2-Boc-amino-1-(2-aminoimidazo[1,2-a]pyridin-3-yl)-prop-
a]pyridine. Choice of conditions to activate amino acids, that is,
use of EDC/HOBT, was decisive. After removal of the amino
protecting group, the intermediate diamines were engaged in a
two-step tandem procedure to access a library of 20 compounds
in 22−85% overall yields. In light of the remarkable biological
activities of diazepine derivatives, these unusual heterocycle-
fused [1,3]diazepines are currently under investigation and
results will be reported in due course.
an-1-one 12c: White solid, m = 848 mg, 64%, mp 160−162 °C;
20
1
[α]D = −69.8 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.40
(s, 3H), 1.42 (s, 9H), 5.03 (quint, 1H, J = 7.2 Hz), 5.65 (d, 1H, J = 7.2
Hz), 5.97 (br s, 1H), 6.88 (t, 1H, J = 6.8 Hz), 7.39 (m, 2H), 9.60 (br s,
1H); 13C NMR (CDCl3, 75 MHz) δ 18.5, 28.5, 50.3, 80.4, 107.6,
113.2, 114.4, 129.4, 130.7, 147.8, 156.4, 158.6, 185.9; FT-IR γmax
(cm−1) 743, 758, 853, 1054, 1167, 1267, 1288, 1309, 1329, 1343,
1444, 1499, 1522, 1591, 1630, 1678, 2982, 3203, 3388; HPLC, Tr =
1.13 min; LC-MS (ESI+) m/z 305.2 [M + H]+; HRMS calcd for
C15H21N4O3 305.1614, found 305.1613.
EXPERIMENTAL SECTION
■
(2S,3S)-2-Boc-amino-1-(2-aminoimidazo[1,2-a]pyridin-3-yl)-3-
2-[2-{(p-Toluenesulfonyl)imino}pyridin-1-yl]acetamide 10: i-
Pr2NEt (7.7 mL, 5.7 g, 44.3 mmol, 1.1 equiv) was added to a
suspension of 4-methyl-N-pyridin-2-ylbenzenesulfonamide 941 (10 g,
40.3 mmol) in DMF (60 mL). To the resulting solution was added 2-
iodoacetamide (8.2 g, 44.3 mmol, 1.1 equiv), and the mixture was
stirred at rt for 24 h. DMF was removed in vacuo, water (250 mL) was
added and the mixture was stirred for 1 h. The solid was collected by
filtration and washed with water and dried in vacuo to give 10 as a
white solid: yield 12.25 g (91%); mp 170−172 °C; 1H NMR (DMSO-
d6, 300 MHz) δ 2.33 (s, 3H), 4.83 (s, 2H), 6.72 (t, 1H, J = 6.8 Hz),
7.27 (m, 3H), 7.37 (br s, 1H), 7.66 (d, 2H, J = 8.2 Hz), 7.71 (dd, 1H, J
= 8.5, 6.8 Hz), 7.79 (br s, 1H), 7.99 (d, 1H, J = 6.8 Hz); 13C NMR
(DMSO-d6, 75 MHz) δ 20.9, 54.3, 110.7, 116.1, 126.0, 129.1, 140.9,
141.2, 141.5, 142.3, 155.3, 167.5; FT-IR γmax (cm−1) 767.2, 982.2,
1080.7, 1131.7, 1367.7, 1502.8, 1697.4, 3173.7; HPLC, Tr = 0.97 min;
MS (ESI+) m/z 289.2 [M − NH3]+, 306.3 [M + H]+, 611.4 [2M +
H]+; HRMS calcd for C14H16N3O3S 306.0912, found 306.0915.
Trifluoro-N-imidazo[1,2-a]pyridin-2-yl-acetamide 11: In a
suspension of compound 10 (5.4 g, 17.7 mmol) in dry CH2Cl2 (55
mL) at 0 °C was added trifluoroacetic anhydride (4.9 mL, 7.4 g, 35.2
mmol, 2 equiv), and the solution was stirred a rt for 4 h. The solution
was washed with saturated sodium hydrogen carbonate solution (2 ×
50 mL). The organic layer was dried over Na2SO4, filtered, and the
solvent was evaporated in vacuo to give 3.56 g (88%) of 11 as a solid:
mp 154−158 °C (dec). The Dimroth isomer trifluoro-N-imidazo[1,2-
a]pyridine-3-ylacetamide was also detected by HPLC, Tr = 1.25 min
(22%). Analysis of 11: 1H NMR (CDCl3, 300 MHz) δ 5.56 (br s, 1H),
6.90 (dd, 1H, J = 6.9, 7.8 Hz), 7.28 (dd, 1H, J = 9.1, 7.8 Hz), 7.49 (d,
1H, J = 9.1 Hz), 8.16 (d, 1H, J = 6.8 Hz), 8.18 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 102.9, 113.3, 114.5 (q), 116.4, 126.0, 126.2,
139.3, 142.0, 154.9 (q); 19F NMR (CDCl3, 300 MHz) δ −74.8; FT-IR
γmax (cm−1) 767, 982, 1080, 1131, 1252, 1368, 1461, 1502, 1630, 1697,
3174; HPLC, Tr = 1.08 min; MS (ESI+) m/z 230.1 [M + H]+; HRMS
calcd for C9H6F3N3O 230.0541, found 230.0541.
(benzyloxy)-butan-1-one 12d: White solid, m = 1.14 g, 61.5%, mp
20
1
126−128 °C; [α]D = −4.8 (c 1.0, CHCl3); H NMR (CDCl3, 300
MHz) δ 1.25 (d, 3H, J = 6.2 Hz), 1.43 (s, 9H), 4.07 (m, 1H), 4.44 (d,
1H, J = 11.4 Hz), 4.64 (d, 1H, J = 11.4 Hz), 5.10 (dd, 1H, J = 8.4, 5.1
Hz), 5.86 (br s, 2H), 6.85 (dd, 1H, J = 7.2, 6.6 Hz), 7.24 (m, 5H), 7.31
(d, 1H, J = 8.8 Hz), 7.38 (d, 1H, J = 7.7 Hz), 9.62 (br s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 15.7, 28.5, 59.0, 74.6, 76.6, 80.1, 113.1,
114.4, 127.8, 127.9, 128.0, 128.5, 129.5, 130.7, 137.7, 147.8, 156.2,
158.9, 183.0; FT-IR γmax (cm−1) 742, 759, 1019, 1054, 1164, 1268,
1287, 1343, 1444, 1498, 1590, 1677, 2979, 3203, 3386; HPLC, Tr =
1.57 min; LC-MS (ESI+) m/z 425.2 [M + H]+; HRMS calcd for
C23H29N4O4 425.2189, found 425.2184.
(2-Aminoimidazo[1,2-a]pyridin-3-yl) [(2S)-Boc-pyrrolidin-2-yl]-
methanone 12e: White solid, m = 1.27 g, 88%, mp 184−186 °C;
20
1
[α]D = +56.2 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.43
(s, 9H), 1.90−2.11 (m, 3H), 2.30 (m, 1H), 3.45−3.70 (m, 2H), 5.13
(dd, 1H, J = 7.7, 3.0 Hz), 6.83 (t, 1H, J = 6.5 Hz), 6.90 (br s, 1H), 7.34
(m, 3H), 9.50 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 24.9, 28.5,
30.6, 47.5, 60.2, 80.1, 109.0, 112.9, 114.3, 128.9, 130.1, 147.3, 155.4,
158.8, 188.1; FT-IR γmax (cm−1) 756, 1051, 1125, 1161, 1344, 1403,
1446, 1495, 1592, 1678, 2977, 3139; HPLC, Tr = 1.39 min; LC-MS
(ESI+) m/z 331.2 [M + H]+; HRMS calcd for C17H23N4O3 331.1770,
found 331.1768.
Synthesis of 7a−e. One gram of compound 12a−e in 5 mL of 12
N aqueous hydrochloric acid was stirred a rt for 1 h. The solution was
treated with 28% aqueous ammonia solution and then extracted with
chloroform (3 × 20 mL). The organic layer was dried over Na2SO4,
filtered, and the solvent was evaporated in vacuo to lead compounds
7a−e with 88, 88, 92, 91, and 82% yields, respectively (for spectra, see
Supporting Information).
Synthesis of 6a and 6a′. To a solution of 50 mg of 7a in 2 mL of
dioxane was added 1 equiv of the appropriate p-nitrobenzaldehyde.
The solution was stirred at 50 °C for 3 h. After cooling, the solution
was concentrated under reduced pressure. The residue was dissolved
in 20 mL of dichloromethane and washed with saturated sodium
hydrogen carbonate (2 × 20 mL). The organic layer was dried over
Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue
was purified by chromatography on alumina, eluted by CH2Cl2 then by
CH2Cl2/EtOH (98:2 v/v).
(2S,4S)-4-Benzyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 6a: White solid, m = 61
mg, 82%, mp 190−193 °C; [α]D20 = −235.8 (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 3.19 (dd, 1H, J = 13.7, 7.7 Hz), 3.43 (dd, 1H, J =
13.7, 4.1 Hz), 4.20 (1H, m), 5.41 (d, 1H, J = 9.4 Hz), 6.80 (d, 1H, J =
9.4 Hz), 6.89 (dd, 1H, J = 6.8, 8.0 Hz), 7.28 (m, 7H), 7.53 (d, 2H, J =
8.7 Hz), 8.09 (d, 2H, J = 8.7 Hz), 9.80 (d, 1H, J = 6.8 Hz); 13C NMR
(CDCl3, 75 MHz) δ 38.3, 67.9, 71.8, 109.4, 113.1, 113.7, 124.1, 126.7,
127.2, 128.5, 129.5, 129.6, 130.9, 138.1, 147.7, 147.9, 148.2, 156.7,
191.4; FT-IR γmax (cm−1) 695, 755, 834, 1244, 1338, 1348, 1406, 1480,
1512, 1567, 2920, 3214,3326; HPLC, Tr = 1.71 min; LC-MS (ESI+)
m/z 414.1 [M + H]+; HRMS calcd for C23H20N5O3 414.1566, found
414.1563. Single crystals suitable for X-ray crystallographic analysis
were obtained by slow evaporation of a solution of 6a in 1:1
tetrahydrofuran/ethanol mixture.
Synthesis of 12a−e. To a suspension of 1 g of compound 11
(4.36 mmol) in 9 mL of aqueous 5 N sodium hydroxide solution was
added 1 mL of THF. The solution was stirred at rt for 2 h. The
solution was extracted with ethyl acetate (3 × 20 mL). The organic
layer was dried over Na2SO4, filtered, and the solvent was evaporated
in vacuo. The residue was dissolved in 40 mL of dichloromethane, and
BocAAOH (4.76 mmol, 1.1 equiv), HOBt (650 mg, 4.8 mmol, 1.1
equiv), and EDC (850 μL, 4.8 mmol, 1.1 equiv) were added at 0 °C.
The solution was stirred at rt for 4 h. The solution was washed with
satured sodium hydrogen carbonate solution (2 × 50 mL). The
organic layer was dried over Na2SO4, filtered, and the solvent was
evaporated in vacuo. The residue was purified by chromatography
(Al2O3, DCM/EtOH 99/1 v/v).
(2S)-2-Boc-amino-1-(2-aminoimidazo[1,2-a]pyridin-3-yl)-3-phe-
nylpropan-1-one 12a: White solid, m = 1.46 g, 88%, mp 182−184
20
1
°C; [α]D = +54.2 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz) δ
1.36 (s, 9H), 3.10 (ABX, 2H), 5.27 (m, 1H), 5.98 (d, 1H, J = 8.4 Hz),
6.11 (br s, 1H), 6.84 (dd, 1H, J = 6.3, 7.8 Hz), 7.15 (m, 5H), 7.35 (m,
2H), 9.62 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 28.4, 38.7, 55.5,
80.5, 108.3, 113.0, 114.3, 126.7, 128.4, 129.3, 129.4, 130.7, 137.0,
147.8, 156.7, 158.8, 184.9; FT-IR γmax (cm−1) 750.2, 1045.8, 1164.8,
1287.6, 1342.9, 1453.7, 1495.0, 1542.8, 1576.1, 1682.3, 2974.0, 3195.0,
3329.1; HPLC, Tr = 1.49 min; MS (ESI+) m/z 381.2 [M + H]+;
HRMS calcd for C21H25N4O3 381,1927, found 381.1930. 12b: White
(2R,4S)-4-Benzyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 6a′: White solid, m = 7
mg, 10%; mp 141−143 °C; [α]D20 = +21.5 (c 1.0, DMSO); 1H NMR
(DMSO-d6, 600 MHz) δ 2.63 (dd, 1H, J = 9.0, 13.8 Hz), 3.28 (m,
20
solid, m = 1.40 g, 85%; [α]D = +54.8 (c 1.0, CHCl3).
3682
dx.doi.org/10.1021/jo300364d | J. Org. Chem. 2012, 77, 3679−3685

The Journal of Organic Chemistry
Note
2H), 3.88 (dd, 1H, J = 9.0, 6.0 Hz), 5.66 (m, 1H), 6.99 (t, 1H, J = 6.9
Hz), 7.02 (m, 2H), 7.14 (m, 3H), 7.28 (d, 2H, J = 8.6 Hz), 7.38 (d,
1H, J = 8.8 Hz), 7.53 (dd, 1H, J = 8.8, 6.9 Hz), 7.96 (d, 2H, J = 8.8
Hz), 9.66 (d, 1H, J = 6.9 Hz); 13C NMR (DMSO-d6, 150 MHz) δ
37.1, 62.3, 66.9, 107.5, 112.1, 113.4, 123.0, 125.5, 127.7, 128.3, 128.4,
129.4, 130.5, 139.7, 146.5, 147.8, 149.0, 156.5, 190.7; FT-IR γmax
(cm−1) 697, 744, 856, 987, 1257, 1286, 1310, 1342, 1474, 1510, 1546,
1581, 3029, 3298; HPLC, Tr = 1.71 min; LC-MS (ESI+) m/z 414.1 [M
+ H]+. Single crystals were obtained by crystallization in dichloro-
methane.
Synthesis of 1a−i and 1k−p. To a solution of 0.18 mmol of 7a−
d in 2 mL chloroform was added 1 equiv of the appropriate aldehyde.
The solution was stirred at 60 °C for 6 h. After cooling, the mixture
was added to a solution of iodine (72 mg, 0.28 mmol, 1.1 equiv) in 4
mL of chloroform. Finally, a solution of lead tetraacetate (118 mg, 0.28
mmol, 1.1 equiv) in 6 mL of chloroform was added. The solution was
stirred at room temperature for 1−6 h (monitoring by TLC). The
solution was washed with 10% m/v sodium thiosulfate aqueous
solution (3 × 30 mL) and then with aqueous saturated sodium
hydrogen carbonate solution (2 × 30 mL). The organic layer was dried
over Na2SO4, filtered, and the solvent was evaporated in vacuo. The
residue was purified by chromatography on alumina, eluted by
dichoromethane.
182.5; FT-IR γmax (cm−1) 698, 765, 1252, 1336, 1423, 1465, 1524,
1623, 2922; HPLC, Tr = 1.33 min; LC-MS (ESI+) m/z 381 [M + H]+;
HRMS calcd for C24H21N4O 381.1715, found 381.1715.
(4S)-4-Benzyl-2-(3-methylphenyl)-3,4-dihydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1e: Orange powder, m =
37 mg, 54%; mp 85−87 °C; [α]D20 = +13.7 (c 0.99, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 2.16 (s, 3H), 3.04 (m, 1H), 3.34 (d, 1H, J = 11.0
Hz), 4.18 (dd, 1H, J = 11.0, 4.2 Hz), 6.92 (dd, 1H, J = 6.9, 7.7 Hz),
7.05−7.29 (m, 11H), 9.46 (d, 1H, J = 6.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 21.3, 36.4, 77.4, 113.8, 116.0, 126.3, 127.0, 128.4, 128.6,
128.8, 129.4, 129.8, 130.0, 130.3, 132.6, 135.0, 138.4, 139.7, 146.5,
146.9, 182.3; FT-IR γmax (cm−1) 764, 1253, 1336, 1424, 1465, 1557,
1625, 2921, 3027; HPLC, Tr = 1.33 min; LC-MS (ESI+) m/z 414.1 [M
+ H]+; HRMS calcd for C24H21N4O 381.1715, found 381.1712.
(4S)-4-Benzyl-2-(2-methylphenyl)-3,4-dihydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1f: Yellow powder, m =
32 mg, 47%; mp 83−85 °C; [α]D20 = −10.7 (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 2.16 (s, 3H), 3.30 (dd, 1H, J = 13.6, 9.4 Hz),
3.56 (dd, 1H, J = 13.6, 9.2 Hz), 4.11 (dd, 1H, J = 9.4, 9.2 Hz), 5.66 (d,
1H, J = 9.2 Hz), 6.84 (t, 1H, J = 6.6 Hz), 7.02−7.33 (m, 11H), 9.39 (d,
1H, J = 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 20.3, 37.0, 69.7, 113.6,
114.8, 126.1, 128.3, 129.4, 130.0, 130.1, 130.7, 131.2, 131.5, 135.8,
138.4, 140.0, 145.3, 152.7, 155.4, 181.5; FT-IR γmax (cm−1) 696, 767,
1250, 1335, 1422, 1462, 1523, 1625, 2920; HPLC, Tr = 1.33 min; LC-
MS (ESI+) m/z 381 [M + H]+; HRMS calcd for C24H21N4O 381.1715,
found 381.1710.
(4S)-4-Benzyl-2-(4-nitrophenyl)-3,4-dihydro-5H-pyrido[1′,2′:1,2]-
imidazo[4,5-d][1,3]diazepin-5-one 1a: Yellow powder, m = 57 mg,
20
77%; mp 169−171 °C (dec); [α]D = +27.4 (c 0.92, DMSO); two
1
1
(4S)-4-Benzyl-2-(4-methoxyphenyl)-3,4-dihydro-5H-pyrido-
conformers detected by H NMR in DMSO; H NMR (DMSO-d6,
300 MHz) δ 2.71 (dd, 0.6H, J = 15.1, 3.6 Hz), 3.00 (dd, 1H, J = 13.9,
4.7 Hz), 3.20 (dd, 0.6H, J = 13.5, 13.3 Hz), 3.45 (dd, 1H, J = 13.5, 13.3
Hz), 4.13 (dd, 0.6H, J = 9.3, 4.7 Hz), 4.27 (m, 1H), 7.20 (m, 5H), 7.28
(m, 3H), 7.32 (d,1H, J = 7.3 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.71 (m,
3H), 7.82 (d, 2H, J = 8.3 Hz), 7.96 (d, 1.2H, J = 7.6 Hz), 8.25 (d, 2H, J
= 8.8 Hz), 8.29 (d, 1.2H, J = 8.3 Hz), 8.82 (d, 1H, J = 6.8 Hz), 9.38 (d,
0.6H, J = 6.6 Hz), 9.50 (d, 1H, J = 6.4 Hz), 11.5 (s, 0.6H); 13C NMR
(DMSO-d6, 75 MHz) δ 35.4, 62.9, 114.1, 116.2, 123.2, 126.8, 127.7,
127.8, 128.0, 128.5, 129.4, 129.7, 130.2, 130.7, 136.6, 146.5, 149.1,
155.2, 182.2; FT-IR γmax (cm−1) 697, 760, 849, 1337, 1421, 1467,
1519, 1626, 2851, 2921; HPLC, Tr = 1.51 min; LC-MS (ESI+) m/z
412.0 [M + H]+; HRMS calcd for C23H18N5O3 412.1410, found
412.1411.
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1g: Yellow powder, m =
20
1
24 mg, 34%; mp 108−109 °C; [α]D = +22.3 (c 0.91, CHCl3); H
NMR (CDCl3, 300 MHz) δ 3.06 (dd, 1H, J = 10.2, 11.0 Hz), 3.38 (m,
1H), 3.79 (s, 3H), 4.20 (dd, 2H, J = 11.0, 4.0 Hz), 6.77 (d, 2H, J = 8.4
Hz), 7.02 (t, 1H, J = 7.0 Hz), 7.21−7.32 (m, 6H), 7.51 (m, 3H), 9.57
(d, 1H, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 36.2, 55.5, 77.4,
113.7, 113.9, 116.2, 127.0, 127.5, 128.6, 128.9, 129.8, 130.3, 130.9,
139.8, 146.6, 146.7, 147.0, 157.6, 162.8, 182.6; FT-IR γmax (cm−1) 698,
740, 1026, 1166, 1235, 1336, 1427, 1462, 1604, 1623, 2927; HPLC, Tr
= 1.18 min; LC-MS (ESI+) m/z 397.2 [M + H]+; HRMS calcd for
C24H21N4O2 397.1665, found 397.1664.
(4S)-4-Benzyl-2-isobutyl-3,4-dihydro-5H-pyrido[1′,2′:1,2]imidazo-
[4,5-d][1,3]diazepin-5-one 1h: Pale yellow powder, m = 14 mg, 22%;
20
mp 173−176 °C (dec); [α]D = −23.0 (c 1, DMSO); 1H NMR
(4S)-4-Benzyl-2-(4-bromophenyl)-3,4-dihydro-5H-pyrido
(DMSO-d6, 300 MHz) δ 0.79 (d, 6H, J = 6.6 Hz), 1.12 (dd, 1H, J =
18.4, 6.6 Hz), 1.98 (m, 1H), 2.24 (m, 2H), 2.88 (m, 1H), 3.17 (m,
1H), 3.89 (dd, 1H, J = 8.5, 4.5 Hz), 7.12−7.27 (m, 8H), 7.61 (m, 2H),
9.35 (d, 1H, J = 6.9 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 22.0, 22.1,
26.9, 29.0, 36.1, 113.5, 115.4, 116.5, 126.1, 127.6, 128.1, 128.3, 129.2,
129.3, 130.4, 130.8, 131.6, 181.0; FT-IR γmax (cm−1) 698, 760, 1324,
1337, 1414, 1479, 1567, 1625, 2285, 2918, 2953; HPLC, Tr = 1.26
min; LC-MS (ESI+) m/z 347.2 [M + H]+; HRMS calcd for
C21H23N4O 347.1872, found 347.1873.
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1b: Brown solid, m = 65
20
1
mg, 82%; mp 102−107 °C (dec); [α]D = +1.0 (c 1.0, CHCl3); H
NMR (CDCl3, 300 MHz) δ 3.06 (m, 1H), 3.40 (m, 1H), 4.27 (dd,
1H, J = 11.1, 4.1 Hz), 7.06 (m, 1H), 7.28−7.45 (m, 9H), 7.53 (m,
1H), 7.72 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 36.4, 63.2, 114.0,
116.3, 126.7, 127.0, 127.1, 127.2, 128.7, 129.0, 129.8, 130.5, 130.6,
130.7, 131.8, 134.2, 182.2; FT-IR γmax (cm−1) 699, 765, 1009, 1071,
1337, 1423, 1479, 1554, 1580, 1625, 2927; HPLC, Tr = 1.33 min; LC-
MS (ESI+) m/z 445.0 [M + H]+, 447.0 [M + 2 + H]+; HRMS calcd for
20
(4S)-4-Benzyl-2-(3-pyridinyl)-3,4-dihydro-5H-pyrido[1′,2′:1,2]-
C23H18BrN4O 445.0664, found 445.0665. (R)-1b: [α]D = −1.0 (c
imidazo[4,5-d][1,3]diazepin-5-one 1i: Pale yellow powder, m = 55
1.0, CHCl3).
20
1
mg, 85%; mp 87−89 °C; [α]D = +10.9 (c 1.0, CHCl3); H NMR
(CDCl3, 300 MHz) δ 2.85 (m,1H), 3.19−3.36 (m, 1H), 4.27 (m, 1H),
6.98 (t, 1H, J = 6.9 Hz), 7.17−7.25 (m, 7H), 7.55 (m, 2H), 8.00 (d,
1H, J = 7.5 Hz), 8.55 (d, 1H, J = 2.8 Hz), 9.51 (d, 1H, J = 6.9 Hz); 13C
NMR (CDCl3, 75 MHz) δ 36.2, 63.9, 114.0, 116.8, 123.3, 127.6, 128.6,
129.2, 129.6, 129.7, 130.5, 131.1, 131.4, 137.1, 149.6, 150.3, 152.2,
156.1, 157.9, 182.6; FT-IR γmax (cm−1) 700, 744, 919, 1025, 1078,
1202, 1254, 1337, 1412, 1427, 1472, 1558, 1584, 1622, 2923; HPLC,
Tr = 1.07 min; LC-MS (ESI+) m/z 368.0 [M + H]+; HRMS calcd for
C22H18N5O 368.1511, found 368.1515.
(4S)-4-Benzyl-2-phenyl-3,4-dihydro-5H-pyrido[1′,2′:1,2] imidazo-
[4,5-d][1,3]diazepin-5-one 1c: Yellow solid, m = 35 mg, 53%; mp
111−112 °C; [α]D20 = +16.8 (c 0.89, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 3.14 (m, 1H), 3.43 (m, 1H), 4.24 (dd, 1H, J = 10.5, 4.2 Hz),
6.96 (t, 1H, J = 7.0 Hz), 7.24−7.44 (m, 12H), 7.60 (m, 2H), 9.52 (d,
1H, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 36.5, 113.7, 115.9,
126.8, 128.5, 128.6, 128.8, 129.3, 129.9, 130.3, 131.7, 135.2, 146.2,
182.2; FT-IR γmax (cm−1) 698, 742, 1252, 1335, 1421, 1467, 1525,
1624, 2926; HPLC, Tr = 1.22 min; LC-MS (ESI+) m/z 368 [M + H]+;
HRMS calcd for C23H19N4O 367.1548, found 367.1559.
(4S)-4-Methyl-2-(4-nitrophenyl)-3,4-dihydro-5H-pyrido[1′,2′:1,2]-
(4S)-4-Benzyl-2-(4-methylphenyl)-3,4-dihydro-5H-pyrido-
imidazo[4,5-d][1,3]diazepin-5-one 1k: Pale yellow powder, m = 42
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1d: Yellow powder, m =
20
1
20
1
mg, 52%; mp 248−250 °C; [α]D = +3.5 (c 1.0, DMSO); H NMR
(DMSO-d6, 300 MHz) δ 1.33 (d, 3H, J = 7.1 Hz), 4.05 (m, 1H), 7.19
(dd, 1H, J = 6.5, 8.9 Hz), 7.67 (m, 3H), 8.27 (d, 2H, J = 8.7 Hz), 8.37
(d, 2H, J = 8.7 Hz), 8.84 (d, 1H, J = 5.2 Hz), 9.48 (d, 1H, J = 6.7 Hz);
13C NMR (DMSO-d6, 75 MHz) δ 15.5, 56.6, 111.9, 113.9, 116.1,
123.4, 127.8, 130.4, 141.7, 146.3, 149.2, 155.9, 157.3, 183.0; FT-IR γmax
28 mg, 41%; mp 108−109 °C; [α]D = +11.2 (c 0.94, CHCl3); H
NMR (CDCl3, 300 MHz) δ 2.33 (s, 3H), 3.11 (br s, 1H), 3.42 (br s,
1H), 4.24 (dd, 1H, J = 10.9, 4.0 Hz), 7.00 (t, 1H, J = 6.8 Hz), 7.10 (d,
2H, J = 8.0 Hz), 7.29−7.35 (m, 6H), 7.45 (m, 3H), 9.56 (d, 1H, J =
6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.5, 36.4, 67.5, 113.7, 116.2,
126.9, 128.6, 128.9, 129.2, 129.3, 129.8, 130.2, 132.4, 142.4, 146.6,
3683
dx.doi.org/10.1021/jo300364d | J. Org. Chem. 2012, 77, 3679−3685

The Journal of Organic Chemistry
Note
(cm−1) 698, 762, 850, 1340, 1422, 1470, 1515, 1627, 2927; HPLC, Tr
= 0.98 min; LC-MS (ESI+) m/z 336.2 [M + H]+; HRMS calcd for
C17H14N5O3 336.1097, found 336.1093.
stirred at room temperature for 6 h (monitoring by TLC). The
solution was washed with aqueous saturated sodium hydrogen
carbonate solution (2 × 30 mL). The organic layer was dried over
Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue
was purified by chromatography on alumina, eluted by dichloro-
methane.
(4S)-4-Methyl-2-(4-bromophenyl)-3,4-dihydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1l: Orange powder, m =
20
1
46 mg, 52%; mp 142−243 °C; [α]D = −6.8 (c 1.0, DMSO); H
NMR (DMSO-d6, 300 MHz) δ 1.36 (d, 3H, J = 6.6 Hz), 3.99 (q, 1H, J
= 6.6 Hz), 7.18 (dd, 1H, J = 8.3, 6.7 Hz), 7.65 (m, 2H), 7.73 (d, 2H, J
= 8.0 Hz), 7.93 (d, 2H, J = 8.0 Hz), 9.45 (d, 1H, J = 6.7 Hz); 13C
NMR (DMSO-d6, 75 MHz) δ 14.0, 69.8, 113.7, 115.8, 115.9, 125.3,
127.7, 128.7, 130.4, 131.1, 131.3, 131.5, 131.7, 145.9, 166.9, 183.2; FT-
IR γmax (cm−1) 743, 765, 1009, 1249, 1338, 1421, 1473, 1587, 1646,
2925, 3223; HPLC, Tr = 1.00 min; LC-MS (ESI+) m/z 369.0 [M +
H]+, 371.1 [M + 2 + H]+; HRMS calcd for C17H14BrN4O 369.0351,
found 369.0.349.
(11aS)-7-(4-Nitrophenyl)-9,10,11,11a-tetrahydro-12H-pyrido-
[2′,1′:2,3]imidazo[4,5-f ]pyrrolo[1,2-c][1,3]diazepin-12-one 1q: Yel-
20
low powder, m = 43 mg, 54%; mp 90−93 °C; [α]D = −285 (c 1.0,
1
CHCl3); H NMR (CDCl3, 600 MHz) δ 1.84−1.91 (m, 1H), 2.05−
2.10 (m, 1H), 2.11−2.17 (m, 1H), 3.20 (m, 1H), 3.35 (ddd, 1H, J =
2.7, 7.4, 10.0 Hz), 3.78 (td, J = 6.5, 10.0 Hz), 4.18 (dd, 1H, J = 7.9, 1.7
Hz), 7.02 (td, 1H, J = 6.7, 1.2 Hz), 7.51 (ddd, 1H, J = 8.8, 6.7, 1.2 Hz),
7.67 (d, 1H, J = 8.8 Hz), 7.86 (dd, 1H, J = 8.8 Hz), 8.30 (d, 2H, J = 8.7
Hz), 9.52 (d, 1H, J = 6.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 24.7,
25.5, 53.4, 65.0, 113.8, 114.8, 117.1, 123.8, 128.4, 130.2, 130.7, 142.6,
146.9, 149.0, 158.3, 158.5, 179.4; FT-IR γmax (cm−1) 709, 742, 853,
955, 1014, 1073, 1107, 1164, 1251, 1334, 1466, 1518, 1548, 1629,
2928; HPLC, Tr = 1.03 min; LC-MS (ESI+) m/z 362.0 [M + H]+;
HRMS calcd for C19H16N5O3 362.1253, found 362.1250.
(4S)-4-Methyl-2-phenyl-3,4-dihydro-5H-pyrido[1′,2′:1,2]imidazo-
[4,5-d][1,3]diazepin-5-one 1m: Yellow powder, m = 39 mg, 55%; mp
20
1
90−93 °C; [α]D = −32.9 (c 0.82, CDCl3); H NMR (CDCl3, 300
MHz) δ 1.65 (d, 3H, J = 6.8 Hz), 4.11 (q, 1H, J = 6.8 Hz), 6.97 (t, 1H,
J = 6.5 Hz), 7.47 (m, 5H), 8.0 (d, 2H, J = 7.0 Hz), 9.50 (d, 1H, J = 6.8
Hz), 11.11 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 16.7, 53.5,
108.9, 113.6, 114.0, 128.5, 128.8, 129.2, 130.1, 131.6, 135.3, 138.0,
147.7, 152.9, 158.4, 182.7; FT-IR γmax (cm−1) 762, 1252, 1335, 1420,
1470, 1623, 2927; HPLC, Tr = 0.85 min; LC-MS (ESI+) m/z 291.2 [M
+ H]+; HRMS calcd for C17H15N4O 291.1246, found 291.1246.
(4S)-4-[(1S)-1-(Benzyloxy)ethyl]-2-(4-bromophenyl)-3,4-dihydro-
5H-pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1n: Yellow
(11aS)-7-Phenyl-9,10,11,11a-tetrahydro-12H-pyrido [2′,1′:2,3]-
imidazo[4,5-f ]pyrrolo[1,2-c][1,3]diazepin-12-one 1r: White powder,
20
m = 51 mg, 53%; mp 209−213 °C (dec); [α]D = −204 (c 1.0,
CHCl3); 1H NMR (CDCl3, 600 MHz) δ 1.82 (m, 1H), 2.03 (m, 1H),
2.13 (m, 1H), 3.15 (m, 1H), 3.32 (m, 1H), 3.91 (m, 1H), 4.14 (d, 1H,
J = 7.1 Hz), 6.97 (t, 1H, J = 6.9 Hz), 7.38−7.48 (m, 5H), 7.67 (m,
3H), 9.50 (d, 1H, J = 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 24.7,
25.6, 53.5, 65.0, 113.5, 114.6, 116.9, 128.5, 128.6, 129.9, 130.1, 130.8,
136.3, 146.8, 158.7, 161.2, 180.0; FT-IR γmax (cm−1) 700, 721, 747,
761, 785, 828, 851, 929, 956, 1030, 1069, 11239, 1249, 1306, 1333,
1392, 1421, 1464, 1540, 1623, 2953; HPLC, Tr = 1.24 min; LC-MS
(ESI+) m/z 317.1 [M + H]+; HRMS calcd for C19H17N4O 317.1402,
found 317.1400.
20
oil, m = 35 mg, 46%; [α]D = −11.3 (c 1.1, CDCl3); 1H NMR
(CDCl3, 300 MHz) δ 1.36 (d, 3H, J = 5.8 Hz), 3.92 (d, 1H, J = 8.0
Hz), 4.09 (m, 1H), 4.33 (d, 1H, J = 10.5 Hz), 4.65 (d, 1H, J = 10.5
Hz), 7.04 (t, 1H, J = 6.9 Hz), 7.22−7.31 (m, 6H), 7.44 (d, 2H, J = 8.5
Hz), 7.53 (dd, 1H, J = 6.9, 8.5 Hz), 7.68 (d, 2H, J = 8.5 Hz), 8.7 (d,
2H, J = 8.5 Hz), 9.58 (d, 1H, J = 6.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 17.7, 71.8, 72.1, 78.6, 114.1, 116.8, 127.0, 128.2, 128.4, 128.6,
128.7, 129.7, 130.6, 130.8, 131.4, 131.9, 132.1, 134.4, 137.7, 147.0,
180.5; FT-IR γmax (cm−1) 695, 760, 837, 1009, 1070, 1253, 1339, 1425,
1455, 1555, 1582, 1623, 2927, 2975, 3207; HPLC, Tr = 1.40 min; LC-
MS (ESI+) m/z 489.0 [M + H]+, 491.0 [M + 2 + H]+; HRMS calcd for
C25H22BrN4O2 489.0926, found 489.0932.
(11aS)-7-(4-Methylphenyl)-9,10,11,11a-tetrahydro-12H-pyrido-
[2′,1′:2,3]imidazo[4,5-f ]pyrrolo[1,2-c][1,3]diazepin-12-one 1s:
20
White powder, m = 42 mg, 58%; mp 106−111 °C (dec); [α]D
=
1
−257 (c 1.0, CHCl3); H NMR (CDCl3, 600 MHz) δ 1.79 (m, 1H9,
2.01 (m, 1H), 2.12 (m, 1H), 2.37 (s, 3H), 3.14 (m, 1H), 3.32 (m, 1H),
3.95 (m, 1H), 4.15 (d, 1H, J = 7.4 Hz), 6.95 (td, 1H, J = 6.95, 1.0 Hz),
7.22 (d, 2H, J = 8.0 Hz), 7.45 (td, 1H, J = 8.5, 1.3 Hz), 7.60 (d, 2H, J =
8.0 Hz), 7.64 (d, 1H, J = 8.5 Hz), 9.50 (d, 1H, J = 6.95 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.7, 24.7, 25.7, 53.5, 65.0, 113.5, 114.6, 116.9,
128.4, 129.2, 130.1 (2C), 133.3, 141.3, 146.8, 158.8, 161.3, 180.1; FT-
IR γmax (cm−1) 698, 739, 761, 826, 959, 1071, 1141, 1251, 1334, 1440,
1467, 1536, 1624, 2924; HPLC, Tr = 1.01 min; LC-MS (ESI+) m/z
331.1 [M + H]+; HRMS calcd for C20H19N4O 331,1559, found
331.1541.
(4S)-4-[(1S)-1-(Benzyloxy)ethyl]-2-phenyl-3,4-dihydro-5H-pyrido-
[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1o: Yellow oil, m = 36
20
1
mg, 57%; [α]D = −47.0 (c 0.9, CDCl3); H NMR (CDCl3, 300
MHz) δ 1.32 (d, 3H, J = 5.9 Hz), 4.07 (m, 1H), 4.34 (d, 1H, J = 9.0
Hz), 4.62 (d, 1H, J = 9.0 Hz), 6.97 (dd, 1H, J = 7.7, 6.9 Hz), 7.25 (m,
7H), 7.32 (d, 2H, J = 7.7 Hz), 7.46 (t, 2H, J = 7.7 Hz), 8.02 (d, 2H, J =
7.7 Hz), 7.63 (d, 1H, J = 8.5 Hz), 9.55 (d, 1H, J = 6.9 Hz); 13C NMR
(CDCl3, 75 MHz) δ 17.7, 66.4, 71.8, 78.5, 113.7, 116.8, 128.0, 128.4,
128.5, 128.6, 129.3, 130.3, 130.4, 131.9, 135.7, 137.8, 147.2, 180.5; FT-
IR γmax (cm−1) 744, 926, 1027, 1071, 1253, 1338, 1423, 1449, 1558,
1590, 1622, 2861, 2928, 3063, 3248; HPLC, Tr = 1.23 min; LC-MS
(ESI+) m/z 411.1 [M + H]+; HRMS calcd for C25H23N4O2 411.1821,
found 411.1826.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data of compounds 6a and 6a′. Chiral HPLC
1
analyses of compounds (R)-1b and (S)-1b as well as H and
(4S)-4-[(1S)-1-(Benzyloxy)ethyl]-2-(4-methylphenyl)-3,4-dihydro-
13C NMR spectra of compounds 10, 11, 12a−e, 7a−e, 6a, and
1a−s. This material is available free of charge via the Internet at
http://pubs.acs.org.
5H-pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-one 1p: Yellow
20
oil, m = 38 mg, 58%; [α]D = −23.8 (c 1.1, CDCl3); 1H NMR
(CDCl3, 300 MHz) δ 1.33 (d, 3H, J = 6.1 Hz), 2.38 (s, 3H), 3.88 (d,
1H, J = 7.8 Hz), 4.10 (m, 1H), 4.38 (d, 1H, J = 10.1 Hz), 4.62 (d, 1H,
J = 10.1 Hz), 6.85 (m, 1H), 6.98 (t, 1H, J = 6.9 Hz), 7.14 (d, 2H, J =
8.0 Hz), 7.30 (m, 4H), 7.40 (d, 1H, J = 7.7 Hz), 7.48 (dd, 1H, J = 8.0,
8.2 Hz), 7.65 (d, 1H, J = 6.9 Hz), 7.94 (m, 2H), 9.56 (d, 1H, J = 7.3
Hz); 13C NMR (CDCl3, 75 MHz) δ 17.8, 21.6, 66.4, 71.8, 78.5, 113.6,
116.7, 126.6, 128.0, 128.4, 128.5, 129.2, 129.4, 130.4, 131.9, 132.8,
137.8, 142.6, 147.3, 180.6; FT-IR γmax (cm−1) 695, 763, 1337, 1425,
1455, 1555, 1621, 2857, 2923, 3257; HPLC, Tr = 1.30 min; LC-MS
(ESI+) m/z 425.1 [M + H]+; HRMS calcd for C26H25N4O2 425.1978,
found 425.1972.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nicolas.masurier@univ-montp1.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Synthesis of 1q−s. To a solution of 0.22 mmol of compound 7e
in 2 mL of chloroform was added 1 equiv of the appropriate aldehyde.
The solution was stirred at 80 °C for 6 h. After cooling, DDQ (0.44
mmol, 2 equiv) was added to the reaction mixture. The solution was
The authors thank the Institut des Biomolec
Mousseron, the Universities of Montpellier 1 and 2, and the
CNRS for financial support.
́
ules Max
3684
dx.doi.org/10.1021/jo300364d | J. Org. Chem. 2012, 77, 3679−3685

The Journal of Organic Chemistry
Note
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Andrei, G.; De Clercq, E.; Gueiffier, A. Bioorg. Med. Chem. 2008, 16,
9536−9545.
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