One-Pot Four-Component Coupling Approach to Polyheterocycles: 6 H-Furo[3,2- f]pyrrolo[1,2- d][1,4]diazepine

Article abstract of DOI:10.1021/acs.joc.0c01971

A novel polyheterocyclic chemical space, 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine, was generated by a one-pot four-component coupling reaction where multiple bonds (three C-C, one C-O, and one C-N) were formed through a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially constructed from the monocyclic pyrrole derivative under environment-friendly reaction conditions to furnish the tricyclic fused scaffold.

Full text of DOI:10.1021/acs.joc.0c01971

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One-Pot Four-Component Coupling Approach to Polyheterocycles:
6H‑Furo[3,2‑f]pyrrolo[1,2‑d][1,4]diazepine
Seok Hyun Yoon, Sung June Kim, and Ikyon Kim*
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ABSTRACT: A novel polyheterocyclic chemical space, 6H-furo[3,2-f ]pyrrolo[1,2-
d][1,4]diazepine, was generated by a one-pot four-component coupling reaction
where multiple bonds (three C−C, one C−O, and one C−N) were formed through
a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially
constructed from the monocyclic pyrrole derivative under environment-friendly
reaction conditions to furnish the tricyclic fused scaffold.
study on the construction of novel N-fused heterocyclic
chemical spaces from pyrrole derivatives such as 1,5 we hoped
to establish a highly efficient diversity-oriented synthetic route
to 4, utilizing a sequential one-pot three-component coupling
reaction as shown in Scheme 1b. We reasoned that β-
ketonitrile 3 generated in situ from the reaction of α-
haloketone with cyanide6 would react with 1 to afford 4
and/or 4′ via a Knoevenagel condensation−intramolecular
aldol cyclization cascade process.7 Contrary to our expectation,
however, 6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]diazepine 5 was
isolated as a major product. Certainly, this tricyclic ring
system has not been disclosed yet in the literature. Only a small
number of relevant ring skeletons are reported.8 Moreover,
since it contains pharmacologically interesting moieties such as
furan, diazepine, and pyrrole, we decided to investigate the
synthesis of 5−7−5 heterocyclic frameworks that rely on a
one-pot four-component coupling reaction, which is described
herein.
INTRODUCTION
■
Facile generation of new heterocyclic chemical skeletons1 by
way of multicomponent assembly2 of readily available building
blocks is highly important in many material-related sciences. In
2013, we published a domino3 Knoevenagel condensation−
intramolecular aldol condensation sequence to enable access to
a wide range of indolizines 2 with densely functionalized
pyridine units (Scheme 1a).4 In the course of our continued
Scheme 1. Synthetic Plan
RESULTS AND DISCUSSION
■
As noted in the Introduction, we initially set out to make 4a as
indolizines having an amino and a ketone at the C6 and C7
positions, respectively, have not been found in the literature.
For this purpose, β-ketonitrile 3a was first prepared by mixing
Received: August 15, 2020
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© XXXX American Chemical Society
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A

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a b
,
phenacyl bromide (1.5 equiv) and NaCN (4 equiv) in EtOH/
H2O (3.5 mL, 5:2) at rt. Without purification, 1a (0.234 mmol,
1 equiv) and piperidinium acetate (0.5 equiv) were added to
the reaction mixture, and the mixture was stirred at 100 °C for
12 h (Scheme 2). A yellow solid product (60%) was
Scheme 3. Synthesis of 5
Scheme 2. Synthesis of 5a
precipitated out during the course of the reaction. Even a
higher yield (74%) of product 5a was obtained in a scale-up
experiment.9 The characteristic medium C−N stretching of
nitrile peak is observed at 2220 cm−1 in the FT-IR spectrum of
5a. Further NMR analysis10 of the precipitate indicates it has a
tricyclic structure such as 5a, which has not been reported yet,
to the best of our knowledge. This result can be explained by
the involvement of additional CN: Michael addition of the
excess CN to the Knoevenagel adduct 611,12 would be followed
by 5-exo-dig cyclization of 7 to furnish 2-aminofuran 8. Finally,
intramolecular imine condensation would form a 7-membered
ring system, diazepine, leading to 5a.
Although polysubstituted 2-aminofurans have been synthe-
sized from the Knoevenagel adduct and cyanide through the
conjugate addition of cyanide to the Knoevenagel adduct and
5-exo-dig cyclization,13 multicomponent synthetic approaches
starting from α-bromoketone have not been reported yet.
Furthermore, the use of the resulting 2-amino group for
subsequent intramolecular reactions with the functional groups
within the molecule has not been investigated. Thus, the
reaction scope of this domino process was examined. As shown
in Scheme 3, reactions of 1a with several α-haloketones were
first conducted. Electron-rich phenacyl bromides seemed to
give better yields. Compounds 5b−5i were isolated in 55−74%
yields. Considering the chemical yield and the number of
bonds (five new bonds) formed during the reaction, each step
is deemed to proceed in ∼90% yield. When α-chloroacetone
was used, the desired product 5j was obtained in a rather low
yield. Although the yield was improved to 37% with α-
chloroacetone (3 equiv), a lower yield (32%) of 5j was isolated
with a large excess of α-chloroacetone (10 equiv).
a
α-Haloketone (1.5 equiv), NaCN (4 equiv), 1a (0.234 mmol, 1
equiv), and piperidinium acetate (0.5 equiv) in EtOH/H2O (3.5 mL,
5:2) were used. Isolated yield (%). α-Chloroacetone (3 equiv) was
used.
b
c
position of the scaffold to furnish 7 (Scheme 5b). The
application of this protocol to indole-derived 8 provided 6H-
furo[2′,3′:5,6][1,4]diazepino[1,7-a]indole skeleton 9 (Scheme
6a). When 1016 was submitted to these conditions, the
corresponding lactam 11 was obtained (Scheme 6b).
CONCLUSIONS
■
In summary, a one-pot four-component coupling of readily
available starting materials under eco-friendly conditions
allowed rapid access to a new 5−7−5 heterocyclic chemical
space through a domino process where five new bonds (three
C−C, one C−O, and one C−N) were formed with
consecutive construction of furan and diazepine. Novel
heterocyclic scaffolds described herein should be useful for
further biochemical exploration, given the importance of fused
diazepine ring systems.17 Further synthetic efforts to generate
new polyheterocyclic chemical space through multicomponent
domino reactions as well as the biological application of the
derivatives are currently in progress.
More diverse 1 and α-haloketones were employed under the
optimized conditions, which is illustrated in Scheme 4. In
general, a wide range of the corresponding polyheterocycles
5k−5aa were obtained in good yields, demonstrating a good
functional group tolerance. Products (5s, 5t, and 5aa) bearing
additional heterocyclic rings such as pyridine, thiophene, and
furan were accessed as well.
Further functionalization of the resulting compounds was
demonstrated in Scheme 5. The Mannich reaction14 of 5b with
HCHO and pyrrolidine in the presence of AcOH provided 6 in
98% yield (Scheme 5a). Vilsmeier−Haack formylation15 of 5b
allowed the introduction of the formyl group at the C8
EXPERIMENTAL SECTION
■
General Methods. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received without purification. “Concentrated” refers to the removal of
volatile solvents via distillation using a rotary evaporator. “Dried”
refers to pouring onto, or passing through, anhydrous magnesium
sulfate followed by filtration. Flash chromatography was performed
using silica gel (230−400 mesh) with hexanes, ethyl acetate, and
dichloromethane as the eluents. All reactions were monitored by thin-
layer chromatography on 0.25 mm silica plates (F-254) visualized
with UV light. Melting points were measured using a capillary melting
1
point apparatus. H and 13C NMR spectra were recorded on 400 or
B
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a b
,
Scheme 4. Synthesis of 5
Scheme 5. Derivatization
Scheme 6. Applications
described as wavenumbers (cm−1). HRMS were measured with an
electrospray ionization (ESI) and Q-TOF mass analyzer.
General Procedure for the Synthesis of 5, 9, and 11. To a stirred
solution of phenacyl bromide (70.01 mg, 1.5 equiv) in EtOH/H2O
(5:2, 3 mL) was added NaCN (45.97 mg, 4.0 equiv) at 0 °C. After the
reaction mixture was stirred at rt for 3 h, 1a (50.0 mg, 0.234 mmol)
and piperidinium acetate (17.02 mg, 0.5 equiv) were added. After the
reaction mixture was stirred at 100 °C (heating mantle was used) for
12 h, the reaction mixture was cooled to rt, filtered, and washed with
EtOH and water to give 5a (49.2 mg, 60%).
Scale-up Experiment. To a stirred solution of phenacyl bromide
(1.5 g, 1.5 equiv) in EtOH/H2O (25:10 mL) was added NaCN (0.9
g, 4.0 equiv) at 0 °C. After the reaction mixture was stirred at rt for 3
h, 1a (1 g, 4.69 mmol) and piperidinium acetate (0.3 g, 0.5 equiv)
were added. After the reaction mixture was stirred at 100 °C (heating
mantle was used) for 12 h, the reaction mixture was cooled to rt,
filtered, and washed with EtOH and water to give 5a (1.2 g, 74%).
2,5-Diphenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]diazepine-1-car-
bonitrile (5a).
Orange solid. Mp: 241.7−242.3 °C (49.2 mg, 60%). IR (ATR): ν
a
2220, 1994, 1896, 1595, 1555, 1487, 1443, 1397, 1342, 1279, 1232,
α-Haloketone (1.5 equiv), NaCN (4 equiv), 1 (0.234 mmol, 1
1
1159, 1058, 955, 923, 885, 784, 750, 710, 680 cm−1; H NMR (600
equiv), and piperidinium acetate (0.5 equiv) in EtOH/H2O (3.5 mL,
5:2) were used. Isolated yield (%).
b
MHz, CDCl3): δ 8.18−8.14 (m, 2H), 8.09−8.05 (m, 2H), 7.55−7.48
(m, 6H), 6.89 (dd, J = 3.9, 1.5 Hz, 1H), 6.82 (dd, J = 2.7, 1.5 Hz,
1H), 6.46 (dd, J = 3.6, 2.4 Hz, 1H), 5.00 (s, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 158.0, 154.6, 149.2, 136.5, 131.7, 130.8, 129.3,
129.2, 127.8, 126.0, 124.8, 120.9, 114.8, 111.8, 111.6, 107.3, 91.0,
48.0. HRMS (ESI-QTOF): m/z [M + H]+ calcd for C23H16N3O,
350.1288; found, 350.1287.
600 MHz NMR spectrometers and were described as chemical shifts,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet),
coupling constant in hertz (Hz), and number of protons. IR spectra
were recorded on FT-IR using a diamond ATR technique and were
C
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2-(4-Methoxyphenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
2-(Naphthalen-2-yl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5b).
diazepine-1-carbonitrile (5e).
Yellow solid. Mp: 256.7−257.9 °C (53.3 mg, 57%). IR (ATR): ν
3055, 2295, 2225, 1598, 1562, 1534, 1506, 1454, 1406, 1342, 1298,
1234, 1184, 1154, 1125, 1060, 1031, 996, 944, 922, 887, 856, 834,
813, 744, 714, 684 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.71−8.65
(m, 1H), 8.25 (dd, J = 9.0, 1.8 Hz, 1H), 8.11−8.08 (m, 2H), 8.00−
7.96 (m, 2H), 7.91−7.86 (m, 1H), 7.60−7.56 (m, 2H), 7.56−7.50
(m, 3H), 6.93 (dd, J = 3.9, 1.5 Hz, 1H), 6.84 (dd, J = 2.7, 1.5 Hz,
1H), 6.48 (dd, J = 3.9, 2.7 Hz, 1H), 5.03 (s, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 157.8, 154.5, 149.2, 136.3, 134.0, 133.0, 131.6,
129.0, 128.9, 127.8, 127.7, 127.6, 127.1, 126.1, 124.9, 124.6, 122.3,
120.7, 114.8, 111.6, 107.2, 91.1, 47.8. HRMS (ESI-QTOF): m/z [M
+ H]+ calcd for C27H18N3O, 400.1444; found, 400.1450.
Red-orange solid. Mp: 230.9−231.7 °C (66.1 mg, 74%). IR (ATR): ν
2909, 2837, 2324, 2217, 1902, 1608, 1536, 1509, 1447, 1425, 1396,
1340, 1300, 1258, 1178, 1120, 1060, 1028, 985, 956, 926, 885, 832,
790, 767, 717, 687 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J =
8.0 Hz, 2H), 8.06 (d, J = 4.8 Hz, 2H), 7.51 (s, 3H), 7.03 (d, J = 8.4
Hz, 2H), 6.88 (s, 1H), 6.81 (s, 1H), 6.45 (s, 1H), 4.99 (s, 2H), 3.90
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.7, 158.5, 153.8,
148.6, 136.5, 131.6, 129.1, 127.8, 127.7, 124.9, 120.8, 120.6, 115.2,
114.7, 111.7, 111.5, 107.1, 89.3, 55.7, 48.0. HRMS (ESI-QTOF): m/z
[M + H]+ calcd for C24H18N3O2, 380.1394; found, 380.1400.
2-(3-Methoxyphenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5c).
2-([1,1′-Biphenyl]-4-yl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d]-
[1,4]diazepine-1-carbonitrile (5f).
Orange solid. Mp: 229.2−230.0 °C (53.6 mg, 60%). IR (ATR): ν
3110, 3079, 2990, 2324, 2222, 2104, 1603, 1554, 1464, 1399, 1338,
1292, 1243, 1160, 1060, 1037, 993, 924, 892, 870, 840, 793, 766, 726,
685 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, J = 7.6, 2.0 Hz,
2H), 7.77 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 6.0 Hz, 3H),
7.43 (t, J = 7.6 Hz, 1H), 7.03 (dd, J = 8.0, 2.0 Hz, 1H), 6.89 (dd, J =
4.0, 1.6 Hz, 1H), 6.82 (s, 1H), 6.46 (dd, J = 3.2, 2.8 Hz, 1H), 5.00 (s,
2H), 3.91 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.0,
157.7, 154.6, 149.0, 136.3, 131.6, 130.2, 129.0, 128.7, 127.7, 124.6,
120.8, 118.3, 117.4, 114.6, 111.7, 111.4, 110.1, 107.1, 91.1, 55.5, 47.8.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C24H18N3O2,
380.1394; found, 380.1391.
Yellow solid. Mp: 247.6−248.5 °C (59.2 mg, 59%). IR (ATR): ν
2224, 1608, 1541, 1484, 1453, 1411, 1342, 1301, 1234, 1185, 1160,
1121, 1076, 1005, 956, 921, 837, 744, 708, 680 cm−1. 1H NMR (400
MHz, CDCl3): δ 8.23 (d, J = 6.8 Hz, 2H), 8.07 (s, 2H), 7.75 (d, J =
6.4 Hz, 2H), 7.65 (s, 2H), 7.50 (s, 5H), 7.40 (s, 1H), 6.90 (s, 1H),
6.82 (s, 1H), 6.46 (s, 1H), 5.00 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 157.6, 154.4, 149.1, 143.2, 139.8, 136.3, 131.6, 129.0,
129.0, 128.1, 127.6, 127.1, 126.4, 126.2, 120.7, 114.7, 111.6, 111.5,
107.1, 90.8, 47.8. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
C29H20N3O, 426.1601; found, 426.1592.
2-(4-Chlorophenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5g).
5-Phenyl-2-(p-tolyl)-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]diazepine-
1-carbonitrile (5d).
Orange solid. Mp: 230.9−231.6 °C (53.5 mg, 63%). IR (ATR): ν
Brown solid. Mp: 252.3−253.4 °C (49.5 mg, 58%). IR (ATR): ν
3064, 2220, 2147, 1911, 1541, 1484, 1446, 1407, 1337, 1282, 1232,
1185, 1158, 1094, 1059, 1012, 886, 831, 782, 749, 711, 682 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.8
Hz, 2H), 7.47−7.55 m, 5H), 6.89 (s, 1H), 6.82 (s, 1H), 6.46 (s 1H),
5.00 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 156.6, 154.8,
149.2, 136.7, 136.2, 131.7, 129.5, 129.0, 127.6, 127.0, 126.1, 124.4,
120.8, 114.4, 111.7, 111.6, 111.4, 107.2, 91.2, 47.8. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C23H15ClN3O, 384.0898; found,
384.0892.
2914, 2220, 1910, 1540, 1509, 1445, 1395, 1338, 1305, 1233, 1182,
1
1157, 1122, 1059, 1031, 885, 837, 813, 789, 752, 713, 680 cm−1. H
NMR (400 MHz, CDCl3): δ 8.05 (d, J = 6.4 Hz, 4H), 7.51 (s, 3H),
7.32 (d, J = 7.2 Hz, 2H), 6.88 (s, 1H), 6.81 (s, 1H), 6.45 (s, 1H), 4.99
(s, 2H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 158.3,
154.1, 148.7, 141.2, 136.3, 131.5, 129.8, 129.0, 127.6, 125.8, 125.8,
124.9, 124.7, 120.7, 114.8, 111.6, 111.4, 107.0, 90.1, 47.8. HRMS
(ESI-QTOF): m/z [M + H]+ calcd for C24H18N3O, 364.1444; found,
364.1443.
D
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2-(4-Bromophenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5h).
5-(4-Methoxyphenyl)-2-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5k).
Orange solid. Mp: 258.9−259.5 °C (58.7 mg, 59%). IR (ATR): ν
3064, 2290, 2218, 2144, 2013, 1593, 1446, 1403, 1340, 1281, 1232,
1184, 1158, 1114, 1074, 1008, 9554, 919, 885, 825, 784, 748, 709,
681 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 5.6 Hz, 2H),
8.02 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.52 (s, 3H), 6.89
(s, 1H), 6.82 (s, 1H), 6.46 (s, 1H), 5.00 (s, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 156.6, 154.9, 149.2, 136.2, 132.4, 131.7, 129.0,
127.6, 127.1, 126.5, 125.1, 124.4, 120.8, 114.4, 111.7, 111.4, 107.2,
91.3, 47.8. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
Yellow solid. Mp: 259.8−260.8 °C (52.0 mg, 67%). IR (ATR): ν
2996, 2833, 2574, 2289, 2228, 2062, 1998, 1605, 1535, 1513, 1489,
1424, 1341, 1319, 1259, 1180, 1155, 1113, 1062, 1038, 960, 908, 888,
1
847, 823, 801, 762, 696 cm−1. H NMR (400 MHz, CDCl3): δ 8.15
(d, J = 7.6 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.55−7.45 (m, 3H),
7.00 (d, J = 8.2 Hz, 2H), 6.85 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 4.95
(s, 2H), 3.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.6,
157.3, 154.3, 149.5, 130.5, 129.7, 129.1, 128.8, 127.7, 125.7, 124.7,
120.4, 114.7, 114.4, 111.4, 110.5, 106.7, 90.8, 55.6, 47.6. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C24H18N3O2, 380.1394; found,
380.1386.
C23H15BrN3O, 428.0393; found, 428.0386.
2-(3-Bromophenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5i).
2,5-Bis(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5l).
Orange solid. Mp: 255.3−256.3 °C (54.9 mg, 55%). IR (ATR): ν
2228, 1593, 1541, 1503, 1475, 1445, 1402, 1342, 1304, 1283, 1234,
1
1165, 1159, 1055, 993, 921, 887, 839, 774, 749, 703, 691 cm−1. H
Yellow solid. Mp: 263.7−264.0 °C (65.9 mg, 78%). IR (ATR): ν
3041, 2938, 2838, 2565, 2228, 1997, 1886, 1605, 1530, 1510, 1454,
1424, 1342, 1302, 1253, 1175, 1153, 1114, 1026, 961, 887, 845, 825,
NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H),
8.07 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.52 (s, 3H), 7.39
(d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.46 (s, 1H), 5.00 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.8, 155.1, 136.2, 133.5,
131.8, 130.7, 129.4, 129.0, 128.5, 127.7, 124.4, 124.2, 123.3, 120.9,
114.1, 111.7, 111.4, 107.3, 91.9, 47.8. HRMS (ESI-QTOF): m/z [M
+ H]+ calcd for C23H15BrN3O, 428.0393; found, 428.0397.
2-Methyl-5-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d][1,4]diazepine-1-
carbonitrile (5j).
1
771, 699 cm−1. H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 7.5 Hz,
2H), 8.04 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 7.00 (d, J =
8.7 Hz, 2H), 6.84 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 4.95 (s, 2H),
3.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.5, 161.4,
157.8, 153.5, 148.9, 129.6, 128.9, 127.6, 124.9, 120.5, 120.3, 115.1,
114.5, 114.4, 111.3, 110.4, 106.6, 89.1, 55.5, 47.6. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C25H20N3O3, 410.1499; found,
410.1494.
2-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-6H-furo[3,2-f ]-
pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (5m).
Brown solid. Mp: 161.3−162.0 °C (18.3 mg, 27%; 24.8 mg, 37%). IR
(ATR): ν 2921, 2854, 2286, 2226, 2149, 1578, 1542, 1446, 1401,
1343, 1306, 1260, 1235, 1184, 1155, 1117, 1058, 1035, 1003, 974,
919, 892, 850, 827, 779, 750, 706 cm−1. 1H NMR (400 MHz,
CDCl3): δ 8.02 (dd, J = 7.6, 2.0 Hz, 2H), 7.52−7.45 (m, 3H), 6.78 (s,
1H), 6.75 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 3.2, 2.8 Hz, 1H), 4.94 (s,
2H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.6,
153.3, 148.9, 136.3, 131.4, 128.9, 127.5, 124.9, 120.6, 113.5, 111.5,
109.5, 106.6, 93.93, 47.7, 29.7, 13.6. HRMS (ESI-QTOF): m/z [M +
H]+ calcd for C18H14N3O, 288.1131; found, 288.1125.
Yellow-orange solid. Mp: 250.8−251.6 °C (63.8 mg, 76%). IR
(ATR): ν 3120, 2836, 2222, 2107, 1903, 1601, 1535, 1516, 1469,
1448, 1336, 1305, 1264, 1236, 1180, 1160, 1083, 1063, 1036, 993,
1
960, 893, 840, 819, 787, 714 cm−1. H NMR (400 MHz, CDCl3): δ
8.05 (d, J = 7.9 Hz, 2H), 7.77 (t, J = 7.3 Hz, 1H), 7.65 (s, 1H), 7.42
(t, J = 8.0 Hz, 1H), 7.01 (t, J = 7.7 Hz, 1H), 6.85(s,, 1H), 6.79 (s,
1H), 6.44 (s, 1H), 4.96 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 162.6, 160.0, 157.2, 154.4, 149.5, 130.2,
129.7, 128.8, 124.7, 120.3, 118.3, 117.2, 114.7, 114.4, 111.5, 110.5,
E
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110.03, 106.7, 91.1, 76.7, 55.5, 47.6. HRMS (ESI-QTOF): m/z [M +
H]+ calcd for C25H20N3O3, 410.1499; found, 410.1490.
5-(4-Methoxyphenyl)-2-(p-tolyl)-6H-furo[3,2-f ]pyrrolo[1,2-d]-
[1,4]diazepine-1-carbonitrile (5n).
= 7.7 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H), 7.00
(d, J = 8.3 Hz, 2H), 6.87 (d, J = 3.4 Hz, 1H), 6.80 (s, 1H), 6.45 (s,
1H), 4.95 (s, 2H), 3.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 162.6, 157.1, 154.3, 149.5, 143.0, 139.8, 129.7, 129.0, 128.8, 128.0,
127.6, 127.1, 126.6, 126.1, 124.7, 120.4, 114.8, 114.4, 111.5, 110.6,
106.7, 90.8, 55.6, 47.6. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
C30H21N3O2, 456.1707; found, 456.1706.
2-(4-Chlorophenyl)-5-(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (5q).
Yellow solid. Mp: 257.4−258.0 °C (60.2 mg, 74%). IR (ATR): ν
3109, 3001, 2837, 2630, 2567, 2228, 2053, 1995, 1606, 1539, 1515,
1457, 1423, 1341, 1314, 1256, 1183, 1154, 1118, 1062, 1035, 960,
1
888, 845, 812, 772, 696 cm−1. H NMR (400 MHz, CDCl3): δ 8.04
(d, J = 8.7 Hz, 4H), 7.31 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H),
6.84 (dd, J = 3.8, 1.5 Hz, 1H), 6.78 (s, 1H), 6.46−6.41 (m, 1H), 4.94
(s, 2H), 3.88 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 162.5, 157.8, 153.9, 149.2, 141.0, 129.8, 129.7, 128.8,
125.7, 125.0, 124.8, 120.3, 120.2, 114.9, 114.4, 111.4, 110.4, 106.6,
90.1, 55.6, 47.5, 21.6. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
C25H20N3O2, 394.1550; found, 394.1544.
Yellow-orange solid. Mp: 258.2−258.6 °C (58.3 mg, 69%). IR
(ATR): ν 3528, 3403, 3292, 2837, 2643, 2581, 2296, 2227, 2059,
1655, 1605, 1531, 1485, 14554, 1425, 1344, 1321, 1302, 1259, 1236,
1182, 1161, 1119, 1095, 1061, 1036, 1011, 957, 886, 825, 772, 720,
702 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.5 Hz, 2H),
8.04 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 7.8 Hz,
2H), 6.84 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 4.95 (s, 2H), 3.89 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.7, 156.1, 154.6, 149.7,
136.5, 129.7, 129.4, 128.7, 126.9, 126.2, 124.5, 120.5, 114.5, 111.5,
110.5, 106.8, 91.2, 55.5, 47.6. HRMS (ESI-QTOF): m/z [M + H]+
calcd for C24H17ClN3O2 found, 414.1004; found, 414.1006.
5-(4-Methoxyphenyl)-2-(naphthalen-2-yl)-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (5o).
2-(4-Cyanophenyl)-5-(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (5r).
Yellow solid. Mp: decomposed at 266.6 °C (56.5 mg, 64%). IR
(ATR): ν 2935, 2835, 2299, 2225, 2055, 1902, 16104, 1535, 1514,
1457, 1423, 1343, 1303, 1255, 1177, 1155, 1125, 1062, 1036, 943,
1
891, 846, 808, 772, 747, 703 cm−1. H NMR (400 MHz, CDCl3): δ
8.65 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.96
(d, J = 7.6 Hz, 2H), 7.91−7.85 (m, 1H), 7.56 (dd, J = 4.4, 3.0 Hz,
2H), 7.01 (d, J = 8.7 Hz, 2H), 6.89 (dd, J = 2.3, 1.3 Hz, 1H), 6.81 (d,
J = 1.2 Hz, 1H), 6.46 (s, 1H), 4.98 (s, 2H), 3.90 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 162.6, 157.3, 154.3, 149.6, 134.0, 133.1,
129.7, 128.9, 128.8, 127.8, 127.6, 127.0, 128.9, 125.1, 124.7, 122.3,
120.4, 114.9, 114.5, 111.5, 110.7, 106.8, 91.1, 55.5, 47.6. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C28H20N3O2, 430.1550; found,
430.1548.
Red-orange solid. Mp: 262.3−262.9 °C (40.6 mg, 49%). IR (ATR): ν
3404, 2920, 2302, 2228, 2086, 1655, 1605, 1531, 1516, 1458, 1427,
1309, 1263, 1181, 1118, 1062, 1030, 956, 885, 837, 785, 709, 675
cm−1. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.8 Hz, 2H), 8.06
(d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H),
6.86 (d, J = 3.5 Hz, 1H), 6.81 (s, 1H), 6.45 (s, 1H), 4.96 (s, 2H), 3.90
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.8, 161.5, 158.2,
157.6, 150.4, 135.0, 130.6, 129.9, 129.5, 128.9, 127.6, 122.7, 121.3,
120.6, 120.3, 115.1, 114.6, 109.7, 108.4, 98.8, 89.5, 55.5, 43.5. HRMS
(ESI-QTOF): m/z [M + H]+ calcd for C25H17N4O2, 405.1346; found,
405.1341.
2-([1,1′-Biphenyl]-4-yl)-5-(4-methoxyphenyl)-6H-furo[3,2-f ]-
pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (5p).
5-(4-Methoxyphenyl)-2-(pyridin-3-yl)-6H-furo[3,2-f ]pyrrolo[1,2-
d][1,4]diazepine-1-carbonitrile (5s).
Red-orange solid. Mp: 233.6−234.6 °C (62.7 mg, 67%). IR (ATR): ν
3030, 2223, 2116, 1992, 1603, 1577, 1533, 1513, 1484, 1458, 1424,
1343, 1308, 1259, 1233, 1176, 1154, 1117, 1061, 1032, 957, 888, 848,
823, 763, 713 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.9
Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.66 (d, J
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Red-orange solid. Mp: 243.2−244.1 °C (49.0 mg, 63%). IR (ATR): ν
5-(4-Chlorophenyl)-2-(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (5v).
2228, 1605, 1573, 1539, 1517, 1460, 1342, 1303, 1269, 1235, 1178,
1
1128, 1063, 1019, 962, 848, 801, 722 cm−1. H NMR (400 MHz,
CDCl3): δ 9.35 (s, 1H), 8.69 (dd, J = 4.7, 1.5 Hz, 1H), 8.43 (ddd, J =
8.1, 2.2, 1.6 Hz, 1H), 8.06 (d, J = 8.9 Hz, 2H), 7.45 (dd, J = 7.6, 5.3
Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.86 (dd, J = 4.0, 1.6 Hz, 1H), 6.81
(d, J = 2.4, 1.4 Hz, 1H), 6.45 (dd, J = 3.8, 2.6 Hz, 1H), 4.97 (s, 2H),
3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.8, 155.2,
154.3, 150.9, 150.2, 146.8, 132.5, 129.9, 128.6, 124.3, 124.1, 123.7,
120.6, 114.5, 114.0, 111.6, 110.4, 106.9, 92.4, 55.6, 47.6. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C23H17N4O2, 381.1346; found,
Orange solid. Mp: decomposed at 258.0 °C (60.5 mg, 72%). IR
(ATR): ν 2923, 2838, 2230, 2144, 2051, 1996, 1891, 1736, 1609,
1510, 1452, 1410, 1340, 1308, 1263, 1174, 1153, 1094, 1028, 958,
886, 827, 788, 705 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J =
8.0 Hz, 2H), 7.99 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.03
(d, J = 7.9 Hz, 2H), 6.89 (s, 1H), 6.80 (s, 1H), 6.46 (s, 1H), 4.96 (s,
2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.59,
158.52, 152.0, 148.2, 137.7, 134.8, 129.3, 128.8, 127.7, 124.8, 120.7,
120.3, 114.9, 114.6, 111.7, 107.2, 89.2, 55.5, 47.7. HRMS (ESI-
QTOF): m/z [M + H]+ calcd for C24H17ClN3O2, 414.1004; found,
414.1008.
381.1343.
2-(5-Bromothiophen-2-yl)-5-(4-methoxyphenyl)-6H-furo[3,2-f ]-
pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (5t).
5-([1,1′-Biphenyl]-4-yl)-2-phenyl-6H-furo[3,2-f ]pyrrolo[1,2-d]-
[1,4]diazepine-1-carbonitrile (5w).
Brown solid. Mp: 255.9−256.6 °C (43.0 mg, 54%). IR (ATR): ν
3101, 2834, 2288, 2227, 1998, 1603, 1580, 1514, 1453, 1422, 1386,
1345, 1298, 1252, 1178, 1153, 1123, 1028, 962, 884, 848, 819, 787,
707 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.03 (d, J = 9.0 Hz, 2H),
7.63 (d, J = 3.6 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 7.00 (d, J = 9.0 Hz,
2H), 6.81 (dd, J = 3.6, 1.2 Hz, 1H), 6.80−6.78 (m, 1H), 6.45−6.42
(m, 1H), 4.94 (s, 2H), 3.89 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 162.7, 154.3, 152.2, 131.3, 129.7, 128.7, 127.6, 124.4,
120.7, 120.6, 116.5, 114.5, 113.9, 111.8, 111.5, 110.1, 106.9, 85.8,
55.6, 47.6. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
Brownsolid. Mp: decomposed at 237.1 °C (41.9 mg, 57%). IR
(ATR): ν 2285, 2227, 1676, 1597, 1561, 1535, 1489, 1446, 1413,
1341, 1282, 1238, 1194, 1159, 1062, 1005, 953, 912, 8552, 817, 756,
679 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.19−8.17 (m, 1H), 8.17−
8.15 (m, 2H), 8.15−8.14 (m, 1H), 7.75 (t, J = 1.8 Hz, 1H), 7.74 (t, J
= 1.8 Hz, 1H), 7.67−7.64 (m, 2H), 7.55−7.52 (m, 2H), 7.50−7.47
(m, 3H), 7.42−7.39 (m, 1H), 6.91 (dd, J = 3.9, 1.5 Hz, 1H), 6.85 (dd,
J = 2.4, 1.2 Hz, 1H), 6.47 (dd, J = 3.6, 3.0 Hz, 1H), 5.03 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 157.8, 153.9, 149.2, 144.2,
C22H15BrN3O2S, 464.0063; found, 464.0060.
5-(4-Methoxyphenyl)-2-methyl-6H-furo[3,2-f]pyrrolo[1,2-d][1,4]-
diazepine-1-carbonitrile (5u).
139.7, 135.0, 130.7, 129.1, 129.0, 128.2, 127.7, 127.6, 127.1, 125.8,
120.7, 114.6, 111.6, 111.4, 107.1, 91.0, 47.7. HRMS (ESI-QTOF): m/
z [M + H]+ calcd for C29H20N3O, 426.1601; found, 426.1595.
5-([1,1′-Biphenyl]-4-yl)-2-(4-methoxyphenyl)-6H-furo[3,2-f ]-
pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (5x).
Yellow solid. Mp: 169.0−169.7 °C (20.8 mg, 32%). IR (ATR): ν
3058, 2924, 2838, 2285, 2230, 2137, 1937, 1664, 1603, 1536, 1513,
1460, 1422, 1393, 1306, 1255, 1176, 1155, 1109, 1056, 1019, 1001,
1
957, 890, 845, 781, 712 cm−1. H NMR (400 MHz, CDCl3): δ 8.00
(d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 6.72 (d, J =
3.6 Hz, 1H), 6.41 (d, J = 3.6, 2.8 Hz, 1H), 4.89 (s, 2H), 3.88 (s, 3H),
2.59 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.4, 160.0,
153.2, 149.3, 129.5, 128.8, 125.0, 120.2, 114.4, 113.6, 111.3, 108.5,
106.2, 93.8, 55.5, 47.5, 13.6. HRMS (ESI-QTOF): m/z [M + H]+
calcd for C19H16N3O2, 318.1237; found, 318.1233.
Orange solid. Mp: 229.7−230.5 °C (54.2 mg, 69%). IR (ATR): ν
3009, 2937, 2836, 2223, 2045, 1893, 1607, 1530, 1508, 1450, 1411,
1337, 1299, 1261, 1177, 1157, 1115, 1063, 10126, 958, 914, 853, 828,
1
780, 755, 711 cm−1. H NMR (400 MHz, CDCl3): δ 8.13 (t, J = 6.4
Hz, 4H), 7.73 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.48 (t, J
= 7.3 Hz, 2H), 7.40 (t, J = 7.0 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.88
(s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 5.02 (s, 2H), 3.90 (s, 3H).
G
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13C{1H} NMR (100 MHz, CDCl3): δ 161.5, 158.3, 153.1, 148.6,
717, 673 cm−1. H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 9.0 Hz,
2H), 7.66 (s, 1H), 7.21 (d, J = 3.5 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H),
6.88 (d, J = 3.5 Hz, 1H), 6.75 (s, 1H), 6.62 (dd, J = 3.5, 1.7 Hz, 1H),
6.43 (s, 1H dd, J = 3.6, 2.8 Hz, 1H), 4.94 (s, 2H), 3.89 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 161.5, 158.2, 151.8, 148.4,
144.0, 139.7, 135.1, 129.0, 128.1, 128.1, 127.6, 127.5, 127.1, 124.8,
120.6, 120.4, 115.0, 114.6, 111.6, 111.3, 107.0, 89.2, 55.5, 47.7.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C30H22N3O2,
456.1707; found, 456.1708.
5-([1,1′-Biphenyl]-4-yl)-2-(4-chlorophenyl)-6H-furo[3,2-f ]-
146.6, 143.6, 127.7, 124.7, 121.0, 120.4, 115.2, 114.6, 113.4, 111.6,
111.1, 107.5, 89.2, 55.5, 47.6. HRMS (ESI-QTOF): m/z [M + H]+
calcd for C22H16N3O3, 370.1186; found, 370.1189.
pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (5y).
Synthesis of 6. To a stirred solution of 5b (30 mg, 0.079 mmol) in
THF (1 mL) were added paraformaldehyde (3.56 mg, 1.5 equiv),
pyrrolidine (8.43 mg, 1.5 equiv), and acetic acid (1 drop) at room
temperature. After being stirred at rt for 12 h, the reaction mixture
was quenched by aqueous NaHCO3 solution. The mixture was
diluted with ethyl acetate (5 mL) and washed with aqueous NaHCO3
solution (5 mL). The water layer was extracted with ethyl acetate (5
mL) one more time. The organic layer was dried over MgSO4 and
concentrated under reduced pressure to give 6 (35.9 mg, 98%).
2-(4-Methoxyphenyl)-5-phenyl-8-(pyrrolidin-1-ylmethyl)-6H-
furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine-1-carbonitrile (6).
Brown solid. Mp: decomposed at 246.9 °C (47.5 mg, 60%). IR
(ATR): ν 2909, 2376, 2226, 2087, 1595, 1561, 1535, 1503, 1483,
1449, 1410, 1330, 1300, 1280, 1238, 1190, 1158, 1095, 1062, 1005,
1
954, 851, 831, 778, 757, 696 cm−1. H NMR (400 MHz, CDCl3): δ
8.14 (d, J = 8.1 Hz, 2H), 8.09 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.8 Hz,
2H), 7.65 (d, J = 6.9 Hz, 2H), 7.52−7.44 (m, 4H), 7.41 (t, J = 6.8 Hz,
1H), 6.89 (s, 1H), 6.84 (s, 1H), 6.47 (s, 1H), 5.02 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 156.6, 154.3, 149.3, 144.4, 139.6, 136.7,
134.9, 129.5, 129.0, 128.2, 127.6, 127.1, 127.0, 126.1, 124.5, 120.8,
114.4, 111.7, 111.4, 107.2, 91.3, 47.7. HRMS (ESI-QTOF): m/z [M
+ H]+ calcd for C29H19ClN3O, 460.1211; found, 460.1214.
5-(4-Fluorophenyl)-2-(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (5z).
Yellow solid. Mp: 211.1−212.0 °C (35.9 mg, 98%). IR (ATR): ν
3019, 2968, 2787, 2225, 1741, 1663, 1609, 1505, 1448, 1429, 1378,
1347, 1308, 1256, 1175, 1150, 1117, 1084, 1024, 937, 873, 827, 781,
1
759, 727, 694 cm−1. H NMR (600 MHz, CDCl3): δ 8.34−8.27 (m,
2H), 8.11 (d, J = 9.0 Hz, 2H), 7.49−7.42 (m, 3H), 7.03 (d, J = 9.0
Hz, 2H), 6.76 (d, J = 3.6 Hz, 1H), 6.28 (d, J = 3.6 Hz, 1H), 5.27 (s,
2H), 3.89 (s, 3H), 3.73 (s, 2H), 2.49 (s, 4H), 1.68 (s, 4H). 13C{1H}
NMR (100 MHz, CDCl3): δ 161.5, 158.3, 157.7, 148.5, 137.1, 131.2,
130.6, 128.7, 128.6, 127.7, 126.0, 120.7, 115.3, 114.6, 112.2, 111.5,
105.3, 89.2, 55.6, 53.9, 52.1, 44.9, 23.6. HRMS (ESI-QTOF): m/z [M
+ H]+ calcd for C29H27N4O2, 463.2129; found, 463.2122.
Synthesis of 7. In a vial charged with DMF (1 mL) at 0 °C was
added POCl3 (5 equiv), and the reaction mixture was stirred for 15
min. To this mixture was dropwise added a solution of 5b (20 mg,
0.053 mmol) in DMF (0.5 mL) at 0 °C. After being stirred at room
temperature for 4 h, the reaction mixture was neutralized with an
aqueous NaHCO3 solution. The reaction mixture was extracted with
dichloromethane (5 mL× 2), washed with aqueous NaHCO3 solution
(5 mL × 2). The organic layers were dried over MgSO4 and
concentrated under reduced pressure to give the crude product.
Purification by flash chromatography on silica gel (hexanes/ethyl
acetate/dichloromethane = 10:1:2) afforded 7 (16.6 mg, 77%).
8-Formyl-2-(4-methoxyphenyl)-5-phenyl-6H-furo[3,2-f ]pyrrolo-
[1,2-d][1,4]diazepine-1-carbonitrile (7).
Dark orange solid. Mp: 258.8−257.4 °C (44.5 mg, 53%). IR (ATR): ν
3205, 3131, 3072, 2903, 2844, 2270, 2224, 2085, 1995, 1602, 1494,
1457, 1411, 1374, 1306, 1249, 1219, 1161, 1116, 1059, 1023, 960,
855, 833, 777, 732, 671 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.13−
8.02 (m, 4H), 7.18 (t, J = 8.3 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H),
6.92−6.83 (m, 1H), 6.79 (s, 1H), 6.50−6.40 (m, 1H), 4.96 (s, 2H),
3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 166.0 (C−F,
1
1JC−F = 252.5 Hz), 164.8 (C−F, JC−F = 252.5 Hz), 161.5, 158.3,
152.3, 148.4, 132.7, 129.8 (C−F, 3JC−F = 8.7 Hz), 129.7 (C−F, 3JC−F
2
= 8.7 Hz) 127.6, 124.8, 120.5, 120.4, 116.3 (C−F, JC−F = 21.9 Hz),
116.1 (C−F, 2JC−F = 21.9 Hz), 114.9, 114.6, 111.6, 111.3, 107.0, 89.2,
55.5, 47.8. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
C24H17FN3O2, 398.1299; found, 398.1297.
5-(Furan-2-yl)-2-(4-methoxyphenyl)-6H-furo[3,2-f ]pyrrolo[1,2-
d][1,4]diazepine-1-carbonitrile (5aa).
Yellow solid. Mp: 224.3−225.5 °C (16.6 mg, 77%). IR (ATR): ν
3072, 2836, 2749, 2222, 2114, 1996, 1925, 1741, 1655, 1606, 1539,
1500, 1401, 1396, 1357, 1308, 1255, 1205, 1174, 1142, 1091, 1046,
1020, 911, 853, 779, 753, 692 cm−1. 1H NMR (400 MHz, CDCl3): δ
9.58 (s, 1H), 8.40 (s, 2H), 8.11 (d, J = 7.5 Hz, 2H), 7.51 (s, 3H), 7.14
(s, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.92 (s, 1H), 5.77 (s, 2H), 3.90 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.9, 161.8, 158.8, 157.6,
150.7, 135.5, 134.3, 132.0, 130.3, 129.7, 129.1, 127.8, 126.6, 119.9,
114.7, 114.5, 109.0, 107.8, 89.2, 55.5, 45.0. HRMS (ESI-QTOF): m/z
Brown solid. Mp: 217.5−218.4 °C (49.5 mg, 55%). IR (ATR): ν
3139, 2288, 2216, 2005, 1782, 1608, 1584, 1541, 1510, 1475, 1341,
1309, 1260, 1185, 1122, 1092, 1029, 1010, 907, 882, 832, 789, 748,
H
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[M + H]+ calcd for C25H18N3O3, 408.1343; found, 408.1341.
Compounds 9 and 11 were synthesized by following the same
method for the syntheses of 5.
Sung June Kim − College of Pharmacy and Yonsei Institute of
Pharmaceutical Sciences, Yonsei University, Incheon 21983,
Republic of Korea
2,5-Bis(4-methoxyphenyl)-6H-furo[2′,3′:5,6][1,4]diazepino[1,7-
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01971
a]indole-1-carbonitrile (9).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Research Foundation of Korea (NRF-
2018R1A6A1A03023718 and NRF-2020R1A2C2005961) for
generous financial support.
Dark orange solid. Mp: 217.5−218.4 °C (45.9 mg, 59%). IR (ATR): ν
3048, 2838, 2219, 2104, 1891, 1603, 1542, 1505, 1455, 1423, 1396,
1364, 1306, 1255, 1175, 1150, 1116, 1024, 930, 831, 782, 738, 679
cm−1. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.3 Hz, 2H), 8.11
(d, J = 8.7 Hz, H), 7.70 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H),
7.31 (t, J = 7.1 Hz, 1H), 7.21−7.15 (m, 2H), 7.05−6.98 (m, 4H),,
5.14 (s, 2H), 3.89 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
162.8, 161.5, 158.2, 157.6, 150.4, 135.0, 130.6, 129.9, 129.5, 128.9,
127.6, 122.7, 121.3, 120.6, 120.3, 115.1, 114.6, 109.7, 108.4, 98.8,
89.5, 55.5, 43.5. HRMS (ESI-QTOF): m/z [M + H]+ calcd for
C29H22N3O3, 460.1656; found, 460.1654.
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01971.
■
sı
1H and 13C NMR spectra of synthesized compounds
(PDF)
(7) Synthetic efforts to make 4 and/or 4′ will be communicated
elsewhere.
̀
AUTHOR INFORMATION
Corresponding Author
Ikyon Kim − College of Pharmacy and Yonsei Institute of
Pharmaceutical Sciences, Yonsei University, Incheon 21983,
Republic of Korea; orcid.org/0000-0002-0849-5517;
Phone: +82-32-749-4515; Email: ikyonkim@yonsei.ac.kr;
Fax: +82-32-749-4105
(8) (a) Povazanec, F.; Decroix, B.; Morel, J. Synthesis and Reactivity
■
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Reich, M. F.; Sum, F.-W.; Delos Santos, E. G. EP 636625 A2 EP
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(9) See the Experimental Section for details.
(10) See the Supporting Information for COSY, HSQC, and HMBC
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Authors
Seok Hyun Yoon − Graduate Program of Industrial
Pharmaceutical Sciences, Yonsei University, Incheon 21983,
Republic of Korea
I
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