Synthesis of Tetrahydro[1,3,4]triazepines via Redox-Neutral α-C(sp3)-H Amination of Cyclic Amines

Article abstract of DOI:10.1021/acs.joc.9b01703

A Br?nsted acid-catalyzed α-C(sp³)-H amination of cyclic amines using hydrazines as coupling partners has been reported. This methodology provides a unique protocol to the one-step assembly of tetrahydro[1,3,4]triazepines via [1,5]-hydride tran

Full text of DOI:10.1021/acs.joc.9b01703

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Article
Synthesis of Tetrahydro[1,3,4]triazepines via Redox-
Neutral #-C(sp3)-H Amination of Cyclic Amines
Xiao-De An, Kang Duan, Xian-Jiang Li, Jian-Ming Yang, Yong-Na Lu, Qing Liu, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01703 • Publication Date (Web): 21 Aug 2019
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Synthesis of Tetrahydro[1,3,4]triazepines via Redox-Neutral -
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C(sp3)−H Amination of Cyclic Amines
┴
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‡
,
†,
〣
Xiao-De An,†, , Kang Duan, Xian-Jiang Li, Jian-Ming Yang, Yong-Na Lu,* § Qing Liu,
〢
〢
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Jian Xiao*,†
† College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
‡ College of Life Sciences, Qingdao Agricultural University, Qingdao 266109, China
§ School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
┴ College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao
266590, China.
〣
Shandong Kangqiao Biotechnology Co. Ltd., Binzhou, 256500, China
Corresponding author: Yong-Na Lu; Jian Xiao
E-mail address: ias_ynlu@njtech.edu.cn; chemjianxiao@163.com
Graphic Abstract
Abstract: A Brønsted acid-catalyzed -C(sp3)-H amination of cyclic amines using hydrazines as
coupling partners has been reported. This methodology provides an unique protocol to the one-step
assembly of tetrahydro[1,3,4]triazepines via [1,5]-hydride transfer-initiated C(sp3)-H amination.
This reaction features mild conditions, good yields and high atom-economy.
INTRODUCTION
The ring-fused azepine structural motifs are cores of several natural alkaloids and
pharmaceuticals,1, 2 such as stenine1c-e, 2a, 2b (stemona alkaloid, with a pyrrolo[1,2-a]azepine ring
system), cephalotaxine2c-e (cephalotaxu, with
a
pyrrolo[1,2-a]azepine ring system),
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cochinchistemonine2f-h (stemona alkaloid, with a pyrido[1,2-a]azepine ring system) and
amtramycin2i (Streptomyces, with pyrrolo[2,1-c][1,4]diazepine ring system) (Figure 1). Among
them, pyrrolo[2,1-c][1,4]benzodiazepine scaffold can be used as sequence-selective DNA-binding
agent, owing to the presence of polynitrogen-containing azepine geometry.2i, 3 Given that the
average number of nitrogen atoms per drug is 2.3 for all the small-molecule drugs,4 the
polynitrogen-containing azepines would be ideal motifs for new drug discovery.5 In comparison to
the substantial achievements that have been made to access ring-fused azepines,6 little effort has
been devoted to the construction of polynitrogen-containing azepines.
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Figure 1. Natural products and pharmaceuticals containing ring-fused azepine moieties.
Until now, approaches toward polynitrogen-containing azepines heavily relied on 1,3-dipole
involved [4 + 3] cycloadditions (Scheme 1a).7 However, the requirement of specialized 1,3-dipolar
synthons for the cycloaddition largely limits the generality and application of these reactions.
Therefore, the exploration of new methodologies to construct polynitrogen-containing azepines
derivatives is in great demand. In recent years, [1,5]-hydride transfer (HT) initiated C(sp3)-H
functionalization has emerged as a powerful tool for the rapid construction of heterocycles with high
efficiency and high step/atom economy.8-10 As our continuing interest in [1,5]-HT initiated C(sp3)-
H functionalizations,11 we intend to develop an organocatalytic -C(sp3)−H amination of cyclic
amines to access polynitrogen-containing azepines. As shown in Scheme 1b, condensation of
aldehyde 1a with hydrazines 2 would afford iminium ion I 12, which would induce the [1,5]-HT to
give access to the cyclization product 3a.
Scheme 1. -C(sp3)−H Amination of Cyclic Amines to Access [1,3,4]Triazepines.
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Herein, we report a Brønsted acid-catalyzed direct -C(sp3)-H amination reaction of cyclic
amines using hydrazines as coupling partners. This methodology provided access to ring-fused
[1,3,4]triazepine derivatives in good yields.
RESULTS AND DISCUSSION
At the outset, ortho-pyrrolidinylbenzaldehdyde 1a and 1, 2-diphenylhydrazine 2 were selected as
model substrates to test this reaction. Initially, a range of Brønsted acids catalysts were evaluated
for this reaction at 20 mol % catalyst loadings in EtOH. To our delight, when (-)-10-
camphorsulfonic acid ((-)-CSA) was used as a catalyst, the desired product 3a was isolated in 80%
yield (Table 1, entry 1). Although the yields were not improved by 1,1'-binaphthyl-2,2'-diyl
hydrogenphosphate (PA) and trifluoroacetic acid (TFA), p-toluenesulfonic acid monohydrate
(TsOH.H2O) could afford the desired product in 91% yield (Table 1, entries 2-5). Further screening
of Lewis acids such as BF3·Et2O, Mg(OTf)2, Cu(OTf)2, Sc(OTf)3 and FeCl3 led to inferior results
(Table 1, entries 6-10). Therefore, TsOH.H2O was chosen as the best catalyst for further evaluation.
The subsequent investigation of solvents showed EtOH was the best reaction media (Table 1, entries
11-16). Finally, a diminished yield was observed when 1.5 equiv of 2 was used (Table 1, entry 17).
Consequently, the most effective condition to carry out the reaction was indicated as in entry 5.
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
(−)-CSA
PA
TFA
TfOH
TsOH.H2O
BF3·Et2O
Mg(OTf)2
solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
yield (%)b
1
2
3
4
5
6
7
80
80
70
82
91
80
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Cu(OTf)2
Sc(OTf)3
FeCl3
TsOH.H2O
TsOH.H2O
TsOH.H2O
TsOH.H2O
TsOH.H2O
TsOH.H2O
TsOH.H2O
EtOH
EtOH
EtOH
DCE
DCM
TFE
toluene
THF
H2O
< 10
86
21
65
60
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17c
80
trace
trace
trace
82
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EtOH
aReaction conditions (unless otherwise noted): a solution of 1a (0.1 mmol), 2 (0.1 mmol) and catalyst (0.02 mmol)
in the indicated solvent (1.0 mL) was stirred at 40 oC for 5h. b3a was isolated in pure form by simple filtration. c1.5
equiv of 2 (0.2 mmol) was used. (−)-CSA = (−)-10-camphorsulfonic acid. PA = 1,1'-binaphthyl-2,2'-diyl hydrogen
phosphate.
With the optimized reaction conditions in hand, the substrate scope was investigated to examine
the generality of the protocol (Table 2). Generally, a series of ortho-dialkylaminobenzaldehdydes 1
were employed in the reaction, affording the corresponding products 3 in moderate to excellent
yields. With regard to the phenyl portion of 1, to our delight, ortho-pyrrolidinylbenzaldehdyde
substrates bearing electron-donating or electron-withdrawing substituents were both compatible
with the reaction conditions, providing products 3b-3p in 55-83% yields. The electron-donating
methoxy group at different positions had negligible influence on the reactivity, giving the expected
products 3c-3e in 60-65% yields. Moreover, the electron-withdrawing group such as trifluoromethyl
and fluoro groups were well tolerated and furnished the desired products 3g and 3h in 67% and 73%
yields, respectively. Notably, the success of the fluorine-substituted products indicated the potential
application of this method in drug discovery. Besides, the desired triazepine adducts with chloro
and bromo groups at various positions of benzene were all obtained in high yields (65-83%), which
held great potential for further manipulations. Encouragingly, the transformation of the ortho-
tetrahydroisoquinoline substituted benzaldehdyde were successful as well, giving pyrido[2,1-
c]triazepine ring system 3q in 69% yield. Octahydro-isoindole could also engage in this -C(sp3)-
H amination to furnish the corresponding azepine 3r in 80% yield. The relative configuration of the
product 3r has been unambiguously confirmed by X-ray crystallographic analysis. Remarkably,
when dialkylamine substrates were used, the corresponding products azepino[2,1-c]]triazepines 3s-
3v were fully accessible via this methodology, which characterized by the challenging fused [7,7]
polynitrogen-containing ring system. To further demonstrate the practicability of this established
methodology, the gram-scale synthesis of 3a was conducted in a 3 mmol scale. The reaction
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proceeded efficiently and delivered the corresponding product in 81% yield, indicating the
promising prospect in the medical industry.
Table 2. Substrate Scope of the Ring-fused [1,3,4]Triazepines a
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aReaction conditions: a solution of 1 (0.1 mmol), 2 (0.1 mmol) and TsOH (0.02 mmol) in EtOH (1.0 mL) was stirred
at 40 oC for 5h. The yields are for the isolated products after column chromatography. bThe reaction was performed
on a 3.0 mmol scale. cThe pure solid product was obtained after filtration and washed with EtOH.
In order to further investigate the mechanism of this reaction, a deuterium labeling experiment
was carried out as shown in Scheme 2. The deuteration at the benzylic position of [D]-3a fully
corroborated the occurrence of intramolecular [1,5]-HT process (Scheme 2a). Moreover, the cross-
over deuterium labeling experiment was conducted with [D]-1a and 1o as the starting materials,
leading to 100% deuterated [D]-3a and non-deuterated 3o, correspondingly. This result indicated
the nonexistence of intermolecular 1,5-HT in this reaction (Scheme 2b). On the basis of these
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experimental results, we proposed a mechanism as shown in Scheme 2c. The condensation product
I served as the key precursor for this intramolecular [1,5]-HT. The subsequent nucleophilic attack
of nitrogen atom N2 toward the resultant iminium ion II furnished the cyclization product 3a.
Scheme 2. Mechanistic Details
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A late-stage derivatization of 3a was carried out in hydrochloric acid, as depicted in Scheme 3.
Intriguingly, the six-membered diaza-heterocycle 4 was obtained in 71% yield, accompanied by the
emergence of benzidine motif. Plausible mechanistic pathway was proposed in Scheme 3. The
triazepine adducts 3a might undergo an acid-promoted retro-Mannich fragmentation to generate
iminium ion B. Assisted by the highly acidic condition, the benzidine rearrangement13 occurred to
furnish the dearomative intermediate D, which followed by deprotonation to give the rearomatic
intermediate E. Finally, the subsequent 6-endo-trig cyclization of E gave rise to the compound 4.
The structure of 4 has been confirmed by X-ray crystallographic analysis (Scheme 3).
Scheme 3. Conversion of 3a to Diaza-heterocycle 4
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CONCLUSION
In conclusion, a Brønsted acid-catalyzed -C(sp3)-H amination of cyclic amines using hydrazines
as coupling partners has been developed. This methodology enabled the one-step assembly of ring-
fused tetrahydro[1,3,4]triazepines via [1,5]-HT initiated C(sp3)-H amination. Various
[1,3,4]triazepines could be synthesized in good yields. The mild and easy handling conditions, good
yields and high atom-economy make it an appealing method for future applications in medicinal
chemistry.
Experimental Section
All commercially available reagents, unless otherwise indicated, were used without further
purification. All solvents were purified and dried according to standard methods prior to use.
Reactions were monitored by thin layer chromatography (TLC) with 0.2 mm silica gel-coated HSGF
254 plates, visualized by UV light at 254 or 365 nm. Products were isolated and purified by column
chromatography on 200-300 mesh silica gel. 1H, 13C NMR spectra were recorded on a Bruker AMX
500 (500 MHz for 1H and 125 MHz for 13C) spectrometer at room temperature. The chemical shifts
(δ) were reported in ppm with respect to an internal standard, tetramethylsilane (0 ppm), and the
solvent (CDCl3, 1H: δ = 7.26 ppm, 13C: δ = 77.16 ppm). Coupling constants (J) are given in Hertz.
Splitting patterns of apparent multiplets associated with an averaged coupling constants were
designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets)
and br (broadened). All 13C spectra were recorded with broadband proton decoupling. HRMS were
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performed on a Waters XEVO QTOF mass spectrometer. Starting material 1 were synthesized
according to the literature.11b, 11e, 12a For new compounds 1d, 1m and 1t-v, they were synthesized
and characterized as follows.
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General procedure for the synthesis of 1
To a 100-mL round bottom flask equipped with a magnetic stir bar were charged with 2-
fluorobenzaldehydes (5.0 mmol), cyclamines (5.0 mmol), K2CO3 (10.0 mmol) and DMF (30 mL).
o
The mixture was stirred at 150 C in heating blocks for 5-6 h. After the consumption of starting
material, the mixture was poured into a separatory funnel containing 20 mL of saturated NaCl and
40 mL of EtOAc. The organic layers were dried over Na2SO4 and concentrated under reduced
pressure after filtration. Further column chromatography on silica gel (EtOAc: hexane = 1:500-
1:800) afforded 1 as oil.
2-methoxy-6-(pyrrolidin-1-yl)benzaldehyde (1d). Yellow oil; 0.84 g, 82% yield; column
chromatography eluent, petroleum ether/ethyl acetate = 500:1;1H NMR (500 MHz, CDCl3) δ 10.44
(s, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H),
3.33 – 2.91 (m, 4H), 2.13 – 1.66 (m, 4H); 13C{1H}NMR (126 MHz, CDCl3) δ 188.9, 163.9, 150.3,
134.3, 112.3, 107.3, 98.0, 55.8, 52.4, 25.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H16NO2
206.1176; found 206.1182.
3-bromo-2-(pyrrolidin-1-yl)benzaldehyde (1m). Yellow oil; 0.93 g, 73% yield; column
chromatography eluent, petroleum ether/ethyl acetate = 500:1; 1H NMR (500 MHz, CDCl3)δ 10.32
(s, 1H), 7.80 (d, J = 7.9, 1H), 7.77 (d, J = 7.6, 1H), 7.14 (t, J = 7.8 Hz, 1H), 3.77 – 2.92 (m, 4H),
2.47 – 1.73 (m, 4H);13C{1H}NMR (126 MHz, CDCl3) 13C NMR (126 MHz, CDCl3) δ 192.5, 150.5,
139.8, 138.0, 127.5, 126.8, 124.7, 52.3, 26.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H13BrNO 254.0175; found 254.0177.
2-(azepan-1-yl)-6-chlorobenzaldehyde (1t). Yellow oil; 0.89 g, 75% yield; column chromatography
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eluent, petroleum ether/ethyl acetate = 500:1; 1H NMR (500 MHz, CDCl3)δ 10.31 (s, 1H), 7.23 (t,
J = 8.1 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 3.35 – 3.23 (t, J = 5.5 Hz, 4H),
1.78 (s, 4H), 1.62 (s, 4H); 13C{1H}NMR (126 MHz, CDCl3) δ 189.3, 155.4, 137.2, 133.1, 121.6,
119.8, 116.4, 54.9, 28.3, 28.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H17ClNO 238.0993;
found 238.0999.
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2-(azepan-1-yl)-5-chlorobenzaldehyde (1u). Yellow oil; 0.92 g, 77% yield; column
chromatography eluent, petroleum ether/ethyl acetate = 500:1; 1H NMR (500 MHz, CDCl3) δ 10.13
(s, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.33 (dd, J = 8.9, 2.8 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 3.37 (t, J
= 6.7Hz, 4H), 1.90 – 1.74 (m, 4H), 1.73 – 1.60 (m, 4H); 13C{1H}NMR (126 MHz, CDCl3) δ 189.9,
154.6, 133.9, 129.6, 129.6, 127.4, 124.9, 120.1, 56.0, 28.6, 27.7; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C13H17ClNO 238.0993; found 238.0995.
2-(azepan-1-yl)-3-chlorobenzaldehyde (1v). Yellow oil; 0.93 g, 78% yield; column
chromatography eluent, petroleum ether/ethyl acetate = 600:1; 1H NMR (500 MHz, CDCl3)δ 10.54
(s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 3.28 (s, 4H),
1.80-1.68 (m, 8H); 13C{1H}NMR (126 MHz, CDCl3) δ 192.7, 153.8, 136.5, 136.3, 135.5, 126.7,
126.2, 54.6, 30.5, 28.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H17ClNO 238.0993; found
238.0998.
General Procedure for the Synthesis of 3
An oven-dried reaction tube was charged with ortho-pyrrolidinylbenzaldehdyde 1 (1.0 equiv, 0.1
mmol), 1,2-diphenylhydrazine 2 (1.0 equiv, 0.1 mmol), TsOH.H2O (20 mol %) and EtOH (1 mL).
o
The reaction mixture was stirred at 40 C in heating blocks and monitored by TLC. After the
consumption of 1, the solvent was removed under reduced pressure, and the residue was purified by
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flash column chromatography (column chromatography eluent, petroleum ether/ethyl acetate =
100:1) to afford products 3.
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General Procedure for Gram-Scale Synthesis of 3a
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An oven-dried round-bottomed flask was charged with ortho-pyrrolidinylbenzaldehdyde 1a (3
mmol, 525 mg), 1,2-diphenylhydrazine 2a (3 mmol, 552 mg), TsOH.H2O (0.6 mmol, 114 mg) and
EtOH (30 mL). The reaction mixture was stirred at 40 oC in heating blocks and monitored by TLC.
After the consumption of 1a, the solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (column chromatography eluent, petroleum ether/ethyl
acetate = 100:1) to afford product 3a as a white solid in 81% yield (0.87 g).
General Procedure for the Synthesis of diaza-heterocycle 4
An oven-dried reaction tube was charged with product 3a (0.2 mmol, 68.3 mg) and 6M HCl (2
mL). The reaction mixture was stirred at room temperature and monitored by TLC. After the
consumption of 3a, the reaction was quenched with Et3N and extracted with ethyl acetate. The
organic layers were dried with Na2SO4. The solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography (column chromatography eluent, petroleum
ether/ethyl acetate = 10:1) to afford product 4 as a white solid in 70% yield (47.8 mg).
4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3a). White
solid; 31.1 mg, 91% yield; mp 153–155 °C; column chromatography eluent, petroleum ether/ethyl
acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.26 (dd, J = 13.2, 5.9 Hz, 2H), 7.10 (s, 4H), 7.05 –
6.92 (m, 3H), 6.91 – 6.73 (m, 3H), 6.68 (t, J = 6.6 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.99 (d, J =
4.0 Hz, 1H), 4.67 (q, J = 17.9 Hz, 2H), 3.26 (s, 1H), 2.85 (d, J = 7.0 Hz, 1H), 2.24 (d, J = 5.7 Hz,
1H), 2.22 – 2.04 (m, 2H), 1.91 (d, J = 5.1 Hz, 1H);13C{1H}NMR (126 MHz, CDCl3) δ 150.6, 149.0,
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145.8, 128.9, 128.9, 128.6, 127.3, 123.7, 121.1, 119.9, 117.6, 116.6, 114.4, 79.9, 49.8, 49.2, 34.0,
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23.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H24N3 342.1965; found 342.1971.
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9-methyl-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3b).
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White solid; 19.6 mg, 55% yield; mp 88–89 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H), 7.10 (t, J = 7.9 Hz,
2H), 7.03 – 6.92 (m, 4H), 6.84 (s, 2H), 6.72 – 6.63 (m, 2H), 6.43 (s, 1H), 4.96 (d, J = 5.6 Hz, 1H),
4.63 (q, J = 17.8 Hz, 2H), 3.27 (ddd, J = 10.9, 8.1, 5.7 Hz, 1H), 2.83 (t, J = 7.4 Hz, 1H), 2.32 – 2.21
(m, 4H), 2.19-2.05 (m, 2H), 1.96 – 1.86 (m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.6, 149.0,
145.7, 137.0, 128.9, 128.8, 128.6, 121.0, 120.7, 117.5, 116.6, 115.2, 79.9, 49.5, 49.2, 34.0, 23.1,
21.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H26N3 356.2121; found 356.2121.
9-methoxy-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3c).
Light pink solid; 23.4 mg, 63% yield; mp 115–117 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.25 (dd, J = 14.8, 7.2 Hz, 2H), 7.10 (t,
J = 7.9 Hz, 2H), 6.97 (dt, J = 14.7, 6.8 Hz, 4H), 6.83 (s, 2H), 6.67 (t, J = 7.2 Hz, 1H), 6.41 (dd, J =
8.3, 2.3 Hz, 1H), 6.17 (d, J = 2.2 Hz, 1H), 4.98 (d, J = 5.5 Hz, 1H), 4.60 (q, J = 17.7 Hz, 2H), 3.74
(s, 3H), 3.30 – 3.17 (m, 1H), 2.84 (t, J = 7.4 Hz, 1H), 2.24 (dd, J = 11.6, 6.3 Hz, 1H), 2.21 – 2.06
(m, 2H), 1.94 – 1.86 (m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 159.2, 150.6, 149.0, 147.0, 129.6,
128.9, 128.60, 121.1, 117.5, 116.8, 116.2, 104.5, 101.0, 79.7, 55.2, 49.3, 49.2, 34.0, 23.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H26N3O 372.2070; found 372.2072.
7-methoxy-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3d).
White solid; 24.1 mg, 65% yield; mp 175–176 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.26 (dd, J = 9.3, 6.6 Hz, 3H), 7.10 (t, J
= 7.9 Hz, 2H), 7.05 (t, J = 8.2 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 6.77 (s,
2H), 6.67 (t, J = 7.2 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 5.02 (d, J = 18.4
Hz, 1H), 4.96 (d, J = 5.4 Hz, 1H), 4.29 (d, J = 18.4 Hz, 1H), 3.83 (s, 3H), 3.25 (ddd, J = 10.6, 8.1,
5.9 Hz, 1H), 2.81 (t, J = 7.2 Hz, 1H), 2.23 (dd, J = 11.5, 6.2 Hz, 1H), 2.19 – 2.07 (m, 2H), 1.88 (dd,
J = 11.1, 5.8 Hz, 1H), -0.00 (s, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 158.2, 150.7, 149.0, 147.1,
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128.9, 128.6, 127.5, 120.9, 117.3, 116.5, 110.8, 107.4, 102.1, 80.3, 55.5, 49.3, 43.3, 33.8, 23.1;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H25N3ONa 394.1890; found 394.1899.
8-methoxy-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3e).
White solid; 22.3 mg, 60% yield; mp 151–153 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.25 (dt, J = 17.3, 8.8 Hz, 2H), 7.10 (t, J
= 7.9 Hz, 2H), 7.03 – 6.91 (m, 3H), 6.84 (s, 2H), 6.74 – 6.63 (m, 3H), 6.57 (d, J = 8.7 Hz, 1H), 4.87
(d, J = 5.7 Hz, 1H), 4.62 (q, J = 17.9 Hz, 2H), 3.75 (s, 3H), 3.23 (ddd, J = 11.1, 7.8, 5.7 Hz, 1H),
2.77 (t, J = 7.3 Hz, 1H), 2.25 – 2.11 (m, 2H), 2.11 – 2.01 (m, 1H), 1.87 (dt, J = 11.5, 5.8 Hz, 1H);
13C{1H}NMR (126 MHz, CDCl3) δ 153.5, 150.7, 148.8, 139.8, 129.0, 128.6, 125.4, 120.9, 117.6,
116.3, 115.4, 114.4, 112.3, 80.4, 55.7, 49.9, 49.4, 34.2, 23.1; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C24H25N3ONa 394.1890; found 394.1893.
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4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine-9-carbonitrile
(3f). White solid; 29.3 mg, 80% yield; mp 171–173 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 1H), 7.31 – 7.17 (m,
3H), 7.07 (t, J = 7.9 Hz, 2H), 6.99 – 6.91 (m, 4H), 6.81 (s, 2H), 6.62 (t, J = 7.2 Hz, 1H), 5.11 (d, J
= 6.2 Hz, 1H), 4.81 (d, J = 18.4 Hz, 1H), 4.59 (d, J = 18.2 Hz, 1H), 3.30 – 3.17 (m, 1H), 2.75 (t, J
= 7.6 Hz, 1H), 2.34 – 2.15 (m, 1H), 2.03 (ddd, J = 18.6, 14.7, 6.3 Hz, 2H), 1.97 – 1.86 (m, 1H);
13C{1H}NMR (126 MHz, CDCl3) δ 150.0, 148.6, 146.4, 129.8, 129.2, 129.0, 128.8, 123.4, 121.7,
119.3, 118.3, 117.5, 116.8, 111.2, 111.0, 79.7, 49.7, 49.4, 34.0, 23.0; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C24H23N4 367.1917; found 367.1924.
4,5-diphenyl-9-(trifluoromethyl)-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]
triazepine (3g). White solid; 32.7 mg, 80% yield; mp 158–160 °C; column chromatography eluent,
petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.24 (m, 2H), 7.22 –
7.16 (m, 1H), 7.10 (dd, J = 14.8, 7.1 Hz, 3H), 7.04 – 6.92 (m, 3H), 6.81 (s, 3H), 6.71 (t, J = 7.3 Hz,
1H), 5.00 (d, J = 5.5 Hz, 1H), 4.76 – 4.61 (m, 2H), 3.35 – 3.24 (m, 1H), 2.88 (t, J = 7.4 Hz, 1H),
2.27 (dd, J = 11.5, 6.2 Hz, 1H), 2.18 (tdd, J = 11.4, 9.6, 5.4 Hz, 2H), 1.95 (dd, J = 10.8, 5.2 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3) δ 150.2, 148.7, 146.1, 129.7 (q, J = 32.0 Hz), 129.3, 129.0, 128.8,
127.5, 124.3 (q, J = 272.2 Hz), 121.5, 118.1, 116.7, 116.5 (q, J = 3.7 Hz), 111.1 (q, J = 3.6Hz), 79.9,
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49.5, 49.4, 34.1, 23.1; 19F NMR (471 MHz, CDCl3) δ -62.44 (s); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C24H23F3N3 410.1839; found 410.1839.
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7-fluoro-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3h).
White solid; 26.2 mg, 73% yield; mp 189–191 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.28 (t, J = 7.3 Hz, 2H), 7.12 (t, J = 7.3
Hz, 2H), 7.07 – 6.92 (m, 4H), 6.82 (s, 2H), 6.70 (t, J = 6.9 Hz, 1H), 6.58 (t, J = 8.6 Hz, 1H), 6.36
(d, J = 8.0 Hz, 1H), 5.00 (dd, J = 22.2, 11.2 Hz, 2H), 4.42 (d, J = 18.3 Hz, 1H), 3.32 – 3.19 (m, 1H),
2.83 (t, J = 6.7 Hz, 1H), 2.24 (d, J = 5.1 Hz, 1H), 2.23 – 2.08 (m, 2H), 1.92 (d, J = 4.6 Hz, 1H);
13C{1H}NMR (126 MHz, CDCl3) δ 161.85 (d, J = 239.4 Hz), 150.2, 148.7, 147.8 (d, J = 6.8 Hz),
128.9, 128.7, 128.1 (d, J = 10.6 Hz), 121.3, 117.8, 116.7, 110.3 (d, J = 17.0 Hz), 109.8 (d, J = 2.3
Hz), 106.4 (d, J = 22.4 Hz), 79.9, 49.5, 42.3 (d, J = 7.1 Hz), 33.9, 23.1;19F NMR (471 MHz, CDCl3)
δ -117.21 (s); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H23FN3 360.1871; found 360.1880.
10-chloro-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3i).
White solid; 25.5 mg, 68% yield; mp 135–137 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.23 (m, 2H), 7.12 (t, J = 7.6 Hz,
2H), 7.07 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 3H), 6.87 – 6.79 (m, 2H), 6.70 (t, J
= 7.1 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 4.95 (d, J = 5.3 Hz, 1H), 4.61 (q, J = 18.0 Hz, 2H), 3.23 (dt,
J = 11.5, 6.8 Hz, 1H), 2.81 (t, J = 7.3 Hz, 1H), 2.29 – 2.21 (m, 1H), 2.22-2.07 (m, 2H), 1.97 – 1.83
(m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 149.0, 148.5, 141.5, 133.7, 130.6, 129.5, 129.2, 129.0,
126.6, 124.7, 120.2, 118.1, 114.6, 81.3, 50.9, 48.3, 34.1, 22.4; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H23ClN3 376.1575; found 376.1582.
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9-chloro-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3j).
Light pink solid; 26.3 mg, 70% yield; mp 114–116 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.24 (m, 2H), 7.11 (t, J = 7.9 Hz,
2H), 6.99 (dt, J = 11.2, 7.7 Hz, 4H), 6.82 (dd, J = 8.0, 1.8 Hz, 3H), 6.70 (t, J = 7.3 Hz, 1H), 6.57 (d,
J = 1.6 Hz, 1H), 4.99 (d, J = 5.6 Hz, 1H), 4.62 (q, J = 17.9 Hz, 2H), 3.27 – 3.19 (m, 1H), 2.83 (t, J
= 7.4 Hz, 1H), 2.25 (dd, J = 11.6, 6.3 Hz, 1H), 2.22 – 2.07 (m, 2H), 1.96 – 1.88 (m, 1H).
13C{1H}NMR (126 MHz, CDCl3) δ 150.3, 148.8, 146.9, 132.9, 129.9, 128.9, 128.7, 122.1, 121.4,
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119.7, 117.9, 116.7, 114.6, 79.7, 49.3, 49.3, 34.0, 23.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H23ClN3 376.1575; found 376.1581.
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White solid; 26.3 mg, 70% yield; mp 186–188 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.27 (dd, J = 13.7, 6.1 Hz, 2H), 7.12 (t,
J = 7.6 Hz, 2H), 7.07 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.97 (t, J = 8.5 Hz, 3H), 6.83 (d, J = 4.4 Hz,
2H), 6.70 (t, J = 7.1 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 4.95 (d, J = 5.3 Hz, 1H), 4.61 (q, J = 18.0
Hz, 2H), 3.31 – 3.16 (m, 1H), 2.81 (t, J = 7.3 Hz, 1H), 2.24 (dt, J = 12.7, 6.5 Hz, 1H), 2.22 – 2.05
(m, 2H), 1.91 (dd, J = 11.2, 5.9 Hz, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.3, 148.7, 144.5,
129.0, 128.7, 128.4, 127.2, 125.4, 124.5, 121.3, 117.9, 116.6, 115.6, 79.9, 49.4, 49.4, 34.0, 23.1;
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HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H23ClN3 376.1575; found 376.1579.
7-chloro-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3l).
White solid; 24.4 mg, 65% yield; mp 193–195 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J = 7.4 Hz, 2H), 7.11 (t, J = 7.6
Hz, 2H), 6.99 (t, J = 8.5 Hz, 4H), 6.89 (d, J = 7.9 Hz, 1H), 6.71 (dd, J = 24.2, 17.0 Hz, 3H), 6.49 (d,
J = 8.1 Hz, 1H), 5.07 (d, J = 18.4 Hz, 1H), 4.98 (d, J = 4.2 Hz, 1H), 4.45 (d, J = 18.4 Hz, 1H), 3.30
– 3.18 (m, 1H), 2.79 (t, J = 6.8 Hz, 1H), 2.24 (d, J = 5.3 Hz, 1H), 2.20 – 2.05 (m, 2H), 1.98 – 1.84
(m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.3, 148.7, 147.5, 134.5, 129.0, 128.8, 128.0, 121.4,
120.8, 120.4, 117.9, 116.7, 112.8, 80.0, 49.5, 47.0, 33.9, 23.1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H23ClN3 376.1575; found 376.1577.
10-bromo-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3m).
White solid; 33.2 mg, 79% yield; mp 132–134 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.8 Hz, 1H), 7.24 (dd, J =
9.7, 6.2 Hz, 3H), 7.18 (t, J = 7.8 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.95 – 6.78 (m, 5H), 6.75 (t, J =
7.3 Hz, 1H), 5.13 (d, J = 2.3 Hz, 1H), 4.77 (d, J = 17.0 Hz, 1H), 4.61 (d, J = 17.0 Hz, 1H), 3.98 (dd,
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J = 14.1, 8.3 Hz, 1H), 2.45 (dd, J = 14.5, 8.4 Hz, 1H), 2.29-2.22 (m, 1H), 2.21-2.15 (m, 1H), 2.05 –
1.90 (m, 2H); 13C{1H}NMR (126 MHz, CDCl3) δ 149.0, 148.4, 142.90, 134.8, 132.8, 129.2, 129.1,
127.3, 125.5, 122.0, 119.9, 118.1, 114.3, 80.9, 51.3, 48.6, 34.0, 22.3; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C23H22BrN3Na 442.0889; found 442.0899.
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8-bromo-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3n).
White solid; 34.7 mg, 83% yield; mp 199–200 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J = 7.8 Hz, 2H), 7.21 (s, 1H),
7.18 – 7.07 (m, 3H), 6.97 (t, J = 7.6 Hz, 3H), 6.82 (s, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.47 (d, J = 8.6
Hz, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.61 (dd, J = 42.3, 18.0 Hz, 2H), 3.29 – 3.16 (m, 1H), 2.80 (t, J
= 7.3 Hz, 1H), 2.24 (dt, J = 13.1, 6.6 Hz, 1H), 2.21 – 2.07 (m, 2H), 1.95 – 1.87 (m, 1H);
13C{1H}NMR (126 MHz, CDCl3) δ 150.2, 148.7, 144.9, 131.2, 130.2, 129.0, 128.7, 125.9, 121.4,
117.9, 116.6, 116.1, 111.8, 79.9, 49.3, 49.3, 34.0, 23.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C23H22BrN3Na 442.0889; found 442.0896.
7-bromo-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3o).
White solid; 31.5 mg, 75% yield; mp 189–191 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.28 (t, J = 7.6 Hz, 2H), 7.10 (dd, J =
16.9, 8.0 Hz, 3H), 6.98 (dd, J = 14.4, 7.6 Hz, 3H), 6.91 (t, J = 8.0 Hz, 1H), 6.71 (dd, J = 20.5, 13.3
Hz, 3H), 6.53 (d, J = 8.2 Hz, 1H), 5.02 (d, J = 18.3 Hz, 1H), 4.98 (d, J = 4.6 Hz, 1H), 4.44 (d, J =
18.3 Hz, 1H), 3.24 (dd, J = 14.3, 9.8 Hz, 1H), 2.78 (t, J = 6.9 Hz, 1H), 2.24 (d, J = 5.4 Hz, 1H), 2.19
– 2.07 (m, 2H), 1.94 – 1.85 (m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.2, 148.7, 147.5, 129.0,
128.8, 128.3, 124.8, 124.1, 121.7, 121.4, 117.9, 116.7, 113.5, 79.9, 50.0, 49.5, 33.9, 23.0; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C23H22BrN3Na 442.0889; found 442.0907.
9-bromo-4,5-diphenyl-2,3,3a,4,5,6-hexahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]triazepine (3p).
Light orange solid; 33.6 mg, 80% yield; mp 158–160 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.25 (m, 2H), 7.11 (t, J = 7.6 Hz,
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2H), 7.03 – 6.94 (m, 5H), 6.82 (s, 2H), 6.74 – 6.67 (m, 2H), 4.98 (d, J = 5.0 Hz, 1H), 4.68 – 4.52
(m, 2H), 3.28 – 3.17 (m, 1H), 2.83 (t, J = 7.1 Hz, 1H), 2.25 (dd, J = 11.3, 6.1 Hz, 1H), 2.22 – 2.08
(m, 2H), 1.92 (dd, J = 10.9, 5.7 Hz, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.2, 148.7, 147.1,
130.2, 128.9, 128.7, 122.7, 122.6, 121.4, 121.0, 117.9, 117.5, 116.7, 79.8, 49.3, 34.0, 23.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C23H23BrN3 420.1070; found 420.1068.
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1,2-diphenyl-1,2,3,9,10,14b-hexahydrobenzo[5,6][1,2,4]triazepino[3,4-a]isoquinoline
(3q).
White solid; 27.8 mg, 69% yield; mp 180–182 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 7.3
Hz, 1H), 7.30 – 7.24 (m, 4H), 7.23 – 7.19 (m, 3H), 7.15 (d, J = 7.3 Hz, 1H), 7.10 – 7.05 (m, 3H),
6.96 (d, J = 7.9 Hz, 2H), 6.91 (t, J = 7.0 Hz, 1H), 6.82 – 6.75 (m, 2H), 5.46 (s, 1H), 4.70 (s, 2H),
4.06 – 4.00 (m, 1H), 3.68 (t, J = 12.7 Hz, 1H), 3.13 (t, J = 13.2 Hz, 1H), 2.98 (d, J = 15.1 Hz, 1H);
13C{1H}NMR (126 MHz, CDCl3) δ 152.9, 148.6, 146.1, 135.9, 134.8, 131.5, 129.3, 129.1, 128.7,
128.6, 128.3, 127.3, 127.2, 127.1, 121.2, 120.1, 119.1, 117.5, 117.3, 114.3, 77.2, 52.6, 46.9, 30.4;
HRMS (ESI-TOF) m/z: [M +H]+ calcd for C28H26N3 404.2121; found 404.2131.
6,7-diphenyl-6,7,7a,7b,8,9,10,11,11a,12-decahydro-5H-benzo[5,6][1,2,4]triazepino[3,4-
a]isoindole (3r). White solid; 31.6 mg, 80% yield; mp 217–218 °C; column chromatography eluent,
petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H), 7.10 (d,
J = 6.9 Hz, 4H), 6.97 (t, J = 8.6 Hz, 3H), 6.84 (t, J = 7.2 Hz, 3H), 6.67 (t, J = 7.1 Hz, 1H), 6.62 (d,
J = 8.0 Hz, 1H), 4.69 (d, J = 17.8 Hz, 1H), 4.62 (s, 1H), 4.58 (d, J = 17.9 Hz, 1H), 3.58 – 3.47 (m,
1H), 2.79 (d, J = 4.4 Hz, 1H), 2.58 (t, J = 7.5 Hz, 1H), 2.30 – 2.22 (m, 1H), 1.91 (d, J = 10.0 Hz,
1H), 1.75 (dd, J = 22.0, 12.4 Hz, 2H), 1.58 (d, J = 12.8 Hz, 2H), 1.41 (d, J = 11.3 Hz, 1H), 1.23 (dt,
J = 21.9, 10.9 Hz, 2H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.3, 149.5, 146.2, 128.9, 128.6, 127.3,
123.4, 121.2, 119.6, 117.5, 116.6, 114.2, 86.5, 49.8, 49.1, 44.2, 33.7, 25.1, 24.8, 24.2, 21.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C27H30N3 396.2434; found 396.2434.
6,7-diphenyl-6,7,7a,8,9,10,11,12-octahydro-5H-azepino[2,1-c]benzo[e][1,2,4]triazepine
(3s).
White solid; 30.3 mg, 82% yield; mp 83–85 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.24 (dt, J = 9.5, 4.8 Hz, 2H), 7.22 – 7.16
(m, 3H), 7.15 – 7.10 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 8.3 Hz, 4H), 6.87 (t, J = 7.3 Hz,
1H), 6.82 (t, J = 7.3 Hz, 1H), 6.71 (t, J = 7.3 Hz, 1H), 5.41 (dd, J = 8.2, 6.6 Hz, 1H), 4.55 (d, J =
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7.5 Hz, 2H), 3.68 (dt, J = 15.1, 5.3 Hz, 1H), 3.35 (ddd, J = 14.8, 9.2, 5.3 Hz, 1H), 2.12 (ddd, J =
13.7, 9.3, 4.3 Hz, 1H), 1.91 – 1.81 (m, 3H), 1.75 – 1.65 (m, 2H), 1.52 – 1.43 (m, 1H), 1.40 – 1.32
(m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 150.0, 149.3, 148.3, 129. 6, 129.3, 129.1, 128.0, 127.2,
120.5, 119.9, 117.7, 117.5, 116.2, 75.9, 52.0, 51.6, 32.1, 30.3, 25. 6, 24.0; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C25H28N3 370.2278; found 370.2281.
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4-chloro-6,7-diphenyl-6,7,7a,8,9,10,11,12-octahydro-5H-azepino[2,1-c]benzo[e][1,2,4]triazepine
(3t). White solid; 28.3 mg, 70% yield; mp 220–222 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H), 7.17 (t, J = 7.8 Hz,
2H), 7.07 – 6.83 (m, 8H), 6.71 (t, J = 7.2 Hz, 1H), 5.18 (dd, J = 10.7, 4.3 Hz, 1H), 4.97 (d, J = 17.0
Hz, 1H), 4.56 (d, J = 17.0 Hz, 1H), 3.49 (ddd, J = 15.4, 7.8, 4.1 Hz, 1H), 3.03 – 2.91 (m, 1H), 2.30
– 2.20 (m, 1H), 1.91 – 1.72 (m, 4H), 1.58 (dd, J = 12.7, 7.5 Hz, 1H), 1.54 – 1.42 (m,
2H).13C{1H}NMR (126 MHz, CDCl3) δ 152.0, 149.8, 148.7, 134.2, 129.0, 128.9, 127.9, 123.6,
121.7, 121.5, 118.2, 117.7, 116.6, 50.5, 47.1, 32.9, 30.0, 27.3, 23.8; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C25H27ClN3 404.1888; found 404.1889.
3-chloro-6,7-diphenyl-6,7,7a,8,9,10,11,12-octahydro-5H-azepino[2,1-c]benzo[e][1,2,4]
triazepine (3u). White solid; 27.4 mg, 68% yield; mp 144–146 °C; column chromatography eluent,
petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.25 (m, 2H), 7.20 (dd,
J = 9.6, 5.4 Hz, 3H), 7.08 (dd, J = 8.7, 2.3 Hz, 1H), 6.98 – 6.87 (m, 6H), 6.74 (t, J = 7.3 Hz, 1H),
5.39 (dd, J = 9.9, 5.0 Hz, 1H), 4.56 – 4.46 (m, 2H), 3.63 (dt, J = 15.1, 5.2 Hz, 1H), 3.38 – 3.29 (m,
1H), 2.10 (ddd, J = 13.5, 9.2, 4.4 Hz, 1H), 1.85 (dt, J = 11.5, 5.4 Hz, 3H), 1.75 – 1.66 (m, 2H), 1.49
(dd, J = 10.1, 4.1 Hz, 1H), 1.38 – 1.30 (m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 149.7, 148.0,
147.9, 129.4, 129.2, 129.0, 128.8, 127.7, 124.5, 120.8, 118.8, 117.7, 116.3, 75.9, 51.8, 51.6, 31.9,
30.1, 25.4, 23.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H27ClN3 404.1888; found 404.1895.
1-chloro-6,7-diphenyl-6,7,7a,8,9,10,11,12-octahydro-5H-azepino[2,1-c]benzo[e][1,2,4]
triazepine (3v). White solid; 29.5 mg, 73% yield; mp 140–142 °C; column chromatography eluent,
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petroleum ether/ethyl acetate = 100:1; 1H NMR (500 MHz, CDCl3) δ 7.25 (s, 3H), 7.04 (d, J = 7.3
Hz, 1H), 6.97 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H), 6.79 (t, J = 7.3
Hz, 1H), 6.54 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 8.1 Hz, 2H), 5.10 (dd, J = 15.0, 5.0 Hz, 2H), 4.55 (d,
J = 12.9 Hz, 1H), 3.72 (dd, J = 13.8, 11.3 Hz, 1H), 2.91 (dd, J = 14.2, 3.1 Hz, 1H), 2.33 – 2.23 (m,
1H), 2.00 (dd, J = 25.2, 10.9 Hz, 1H), 1.88 (dd, J = 19.0, 12.9 Hz, 3H), 1.74 (t, J = 11.4 Hz, 1H),
1.66 – 1.58 (m, 1H), 1.37 – 1.25 (m, 1H); 13C{1H}NMR (126 MHz, CDCl3) δ 148.6, 148.2, 146.1,
138.1, 134.5, 129.5, 129.3, 129.0, 127.9, 127.1, 117.8, 117.6, 111.4, 78.4, 54.1, 49.2, 33.5, 31.9,
30.2, 24.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H27ClN3 404.1888; found 404.1889.
4'-(1,2,3,3a-tetrahydropyrrolo[1,2-a]quinazolin-4(5H)-yl)-[1,1'-biphenyl]-4-amine (4)
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White solid; 47.8 mg, 70% yield; mp 90–92 °C; column chromatography eluent, petroleum
ether/ethyl acetate = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 7.6
Hz, 2H), 7.17 (dt, J = 14.4, 9.1 Hz, 3H), 6.96 (d, J = 6.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 2H), 6.65 (t,
J = 6.9 Hz, 1H), 6.53 (d, J = 7.7 Hz, 1H), 4.70 – 4.59 (m, 1H), 4.39 (d, J = 14.8 Hz, 1H), 4.12 (d, J
= 14.9 Hz, 1H), 3.63 (s, 2H), 3.44 (d, J = 7.0 Hz, 1H), 3.41 – 3.26 (m, 1H), 2.09 (d, J = 5.0 Hz, 1H),
1.92 (dd, J = 24.2, 14.7 Hz, 2H), 1.77 (dd, J = 18.6, 9.0 Hz, 1H); 13C{1H}NMR (126 MHz, CDCl3)
δ 148.5, 145.8, 143.5, 137.7, 131.0, 127.9, 127.8, 126.8, 126.0, 125.4, 120.9, 116.3, 115.5, 111.4,
57.4, 47.2, 32.0, 22.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H24N3 342.1965; found
342.1971.
Supporting Information
This material is available free of charge via the Internet at http://pubs.acs.org. Structural proofs
and NMR spectra of products. List of the substrates and deuterium labeling experiments. X-ray
crystallography data and CIF file of compounds 3r and 4 (CIF).
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ORCID
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Xiao-De An: 0000-0002-4774-6083
Jian Xiao: 0000-0003-4272-6865
Notes
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〢
These authors contribute equally to this work. The authors declare no competing financial
interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the NSFC (21878167). The Natural Science
Foundation of Shandong Province for Distinguished Young Scholars (JQ201604) and the Key
Research and Development Program of Shandong Province (2017GSF218073) as well as
Qingdao Special Research Foundation of Science and Technology (19-6-1-38-nsh) are also
gratefully acknowledged. We thank Dr. Fengying Dong and Central Laboratory of Qingdao
Agricultural University for NMR determination.
REFERENCES
(1) (a) B. Renfroe, C. Harrington, G. Proctor, Heterocyclic Compounds: Azepines; Wiley-
Interscience: New York, 1984. (b) J. A. Builla, J. Vaguero, J. Barluenga, Modern Heterocyclic
Chemistry, Wiley-VCH: Weinheim, 2011. (c) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. d. C.
F. The chemistry of Stemona alkaloids: An update. Nat. Prod. Rep. 2010, 27, 1908-1937. (d)
Aloise Pilli, R.; da Conceição Ferreira de Oliveira, M. Recent progress in the chemistry of
the Stemona alkaloids. Nat. Prod. Rep. 2000, 17, 117-127. (e) Alibés, R.; Figueredo, M.
Strategies for the Synthesis of Stemona Alkaloids. Eur. J. Org. Chem. 2009, 2009, 2421-2435.
(2) (a) Chen, C. Y.; Hart, D. J. Total synthesis of (dl)-stenine. J. Org. Chem. 1990, 55, 6236-6240.
(b) Kakuta, D.; Hitotsuyanagi, Y.; Matsuura, N.; Fukaya, H.; Takeya, K. Structures of new
alkaloids sessilifoliamides A–D from Stemona sessilifolia. Tetrahedron 2003, 59, 7779-7786.
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Page 20 of 27
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5
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7
8
9
(c) Ju, X.; Beaudry, C. M. Total Synthesis of (−)-Cephalotaxine and (−)-Homoharringtonine
via Furan Oxidation–Transannular Mannich Cyclization. Angew. Chem., Int. Ed. 2019, 58,
6752 –6755. (d) Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y. Strain-Release Rearrangement
of N-Vinyl-2-Arylaziridines. Total Synthesis of the Anti-Leukemia Alkaloid (−)-
Deoxyharringtonine. J. Am. Chem. Soc. 2006, 128, 10370-10371. (e) Burkholder, T. P.; Fuchs,
P. L. Synthesis via Vinyl Sulfones. 38. Total Synthesis of the Cephalotaxus Alkaloids dl-
Cephalotaxine, dl-11-Hydroxycephalotaxine, and dl-Drupacine. J. Am. Chem. Soc. 1990, 112,
9601-9613. (f) Bassler, D. P.; Alwali, A.; Spence, L.; Beale, O.; Beng, T. K. Cobalt-catalyzed
arylation and alkenylation of alpha-bromo eneformamides and enecarbamates by cross-
coupling with organic bromides: Application to the synthesis of functionalized piperidines
and azepanes. J. Organomet. Chem. 2015, 780, 6-12. (g) Kaltenegger, E.; Brem, B.; Mereiter,
K.; Kalchhauser, H.; Kählig, H.; Hofer, O.; Vajrodaya, S.; Greger, H. Insecticidal pyrido[1,2-
a]azepine alkaloids and related derivatives from Stemona species. Phytochemistry 2003, 63,
803-816. (h) Mungkornasawakul, P.; Pyne, S. G.; Jatisatienr, A.; Supyen, D.; Jatisatienr, C.;
Lie, W.; Ung, A. T.; Skelton, B. W.; White, A. H. Phytochemical and Larvicidal Studies on
Stemona curtisii:ꢀ Structure of a New Pyrido[1,2-a]azepine Stemona Alkaloid. J. Nat. Prod.
2004, 67, 675-677. (i) Laura, C.; Ana, C. A.; Cristina, A.; Davide, B. Pyrrolo[2,1-
c][1,4]benzodiazepine as a Scaffold for the Design and Synthesis of Anti-Tumour Drugs.
Anti-Cancer Med. Chem. 2009, 9, 1-31.
10
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52
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57
58
59
60
(3) (a) Thurston, D. E.; Bose, D. S. Synthesis of DNA-Interactive Pyrrolo[2,1-
c][1,4]benzodiazepines. Chem Rev 1994, 94, 433-465. (b) Remers, W. A.; Mabilia, M.;
Hopfinger, A. J. Conformations of complexes between pyrrolo[1,4]benzodiazepines and
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7
DNA segments. J. Med. Chem. 1986, 29, 2492-2503. (c) Hurley, L. H.; Petrusek, R. Proposed
structure of the anthramycin–DNA adduct. Nature 1979, 282, 529-531.
8
9
(4) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution
Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved
Pharmaceuticals. J. Med. Chem. 2014, 57, 10257-10274.
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60
(5) (a) Karasyova, T. L.; Vlasyuk, S. V.; Pavlovskii, V. I.; Onufrienko, O. V.; Shandra, A. A.
Neurotropic Properties of Novel Alkyl Derivatives of 1,3,4-Benzotriazepines.
Neurophysiology 2014, 46, 387-389. (b) Gupta, A. K.; Varshney, K.; Saxena, A. K. Toward
the Identification of a Reliable 3D QSAR Pharmacophore Model for the CCK2 Receptor
Antagonism. J. Chem. Inf. Model. 2012, 52, 1376-1390. (c) McDonald, I. M.; Black, J. W.;
Buck, I. M.; Dunstone, D. J.; Griffin, E. P.; Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.;
Lilley, E. J.; Linney, I. D.; Pether, M. J.; Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K.
I. M.; Sykes, D. A.; Walker, M. K.; Watt, G. F.; Wright, L.; Wright, P. T.; Xun, W.
Optimization of 1,3,4-Benzotriazepine-Based CCK2 Antagonists to Obtain Potent, Orally
Active Inhibitors of Gastrin-Mediated Gastric Acid Secretion. J. Med. Chem. 2007, 50, 3101-
3112.
(6) For selected examples, see: (a) Zhou, G.; Liu, F.; Zhang, J. Enantioselective Gold-Catalyzed
Functionalization of Unreactive sp3 C–H Bonds through a Redox–Neutral Domino Reaction.
Chem. Eur. J. 2011, 17, 3101-3104. (b) Zhou, G.; Zhang, J. Product-selectivity control by the
nature of the catalyst: Lewis acid-catalyzed selective formation of ring-fused
tetrahydroquinolines and tetrahydroazepines via intramolecular redox reaction. Chem.
Commun. 2010, 46, 6593-6595. (c) Haibach, M. C.; Deb, I.; De, C. K.; Seidel, D. Redox-
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Neutral Indole Annulation Cascades. J. Am. Chem. Soc. 2011, 133, 2100-2103. (d) Li, Y.; Hu,
M.; Li, J.-H. Silver-Catalyzed Intermolecular [3 + 2]/[5 + 2] Annulation of N-
Arylpropiolamides with Vinyl Acids: Facile Synthesis of Fused 2H-Benzo[b]azepin-2-ones.
ACS Catal. 2017, 7, 6757-6761. (e) Chen, J.; Huang, Y. Phosphine-Catalyzed Sequential [4 +
3] Domino Annulation/Allylic Alkylation Reaction of MBH Carbonates: Efficient
Construction of Seven-Membered Heterocycles. Org. Lett. 2017, 19, 5609-5612. (f)
Yoshimatsu, M.; Tanaka, M.; Fujimura, Y.; Ito, Y.; Goto, Y.; Kobayashi, Y.; Wasada, H.; Hatae,
N.; Tanabe, G.; Muraoka, O. Synthesis of Azepines via a [6 + 1] Annulation of Ynenitriles
with Reformatsky Reagents. J. Org. Chem. 2015, 80, 9480-9494. (g) Samala, S.; Singh, G.;
Kumar, R.; Ampapathi, R. S.; Kundu, B. Metal-Free Decarboxylative Cyclization/Ring
Expansion: Construction of Five-, Six-, and Seven-Membered Heterocycles from 2-Alkynyl
Benzaldehydes and Cyclic Amino Acids. Angew. Chem., Int. Ed. 2015, 54, 9564-9567. (h)
Guo, C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, F. Cooperative N-
Heterocyclic Carbene/Palladium-Catalyzed Enantioselective Umpolung Annulations. J. Am.
Chem. Soc. 2016, 138, 7840-7843. (i) Gini, A.; Bamberger, J.; Luis-Barrera, J.; Zurro, M.;
Mas-Ballesté, R.; Alemán, J.; Mancheño, O. G. Synthesis of 3-Benzazepines by Metal-Free
Oxidative C–H Bond Functionalization–Ring Expansion Tandem Reaction. Adv. Synth. Catal.
2016, 358, 4049-4056. (j) Jiang, F.; Yuan, F.-R.; Jin, L.-W.; Mei, G.-J.; Shi, F. Metal-
Catalyzed (4 + 3) Cyclization of Vinyl Aziridines with para-Quinone Methide Derivatives.
ACS Catal. 2018, 8, 10234-10240.
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(7) For selected examples, see: (a) Li, C.; Wang, C.-S.; Li, T.-Z.; Mei, G.-J.; Shi, F. Brønsted
Acid-Catalyzed (4 + 3) Cyclization of N, N′-Cyclic Azomethine Imines with Isatoic
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Anhydrides. Org. Lett. 2019, 21, 598-602. (b) Guo, Z.; Jia, H.; Liu, H.; Wang, Q.; Huang, J.;
Guo, H. A [4 + 3] Annulation Reaction of aza-o-Quinone Methides with
Arylcarbohydrazonoyl Chlorides for Synthesis of 2,3-Dihydro-1H-benzo[e][1,2,4]triazepines.
Org. Lett. 2018, 20, 2939-2943. (c) Wang, Y.; Zhu, L.; Wang, M.; Xiong, J.; Chen, N.; Feng,
X.; Xu, Z.; Jiang, X. Catalytic Asymmetric [4 + 3] Annulation of C,N-Cyclic Azomethine
Imines with Copper Allenylidenes. Org. Lett. 2018, 20, 6506-6510. (d) Jin, Q.; Zhang, J.;
Jiang, C.; Zhang, D.; Gao, M.; Hu, S. Self [3 + 4] Cycloadditions of Isatin N,N′-Cyclic
Azomethine Imine 1,3-Dipole with N-(o-Chloromethyl)aryl Amides. J. Org. Chem. 2018, 83,
8410-8416. (e) Xu, J.; Yuan, S.; Peng, J.; Miao, M.; Chen, Z.; Ren, H. Base-mediated
diastereoselective [4 + 3] annulation of in situ generated ortho-quinone methides with C,N-
cyclic azomethine imines. Org. Biomol. Chem. 2017, 15, 7513-7517. (f) Mei, G.-J.; Zhu, Z.-
Q.; Zhao, J.-J.; Bian, C.-Y.; Chen, J.; Chen, R.-W.; Shi, F. Brønsted Acid-Catalyzed
Stereoselective [4 + 3] Cycloadditions of ortho -Hydroxybenzyl Alcohols with N, N'-Cyclic
Azomethine Imines. Chem. Commun. 2017, 53, 2768-2771.
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(8) For selected reviews on [1,5]-hydride transfer, see: (a) Wang, L.; Xiao, J. Hydrogen-Atom
Transfer Reactions. Top. Curr. Chem. 2016, 374, 17. (b) Wang, L.; Xiao, J. Advancement in
Cascade [1,n]-Hydrogen Transfer/Cyclization: A Method for Direct Functionalization of
Inactive C(sp3)–H Bonds. Adv. Synth. Catal. 2014, 356, 1137-1171. (c) Peng, B.; Maulide, N.
The Redox-Neutral Approach to C-H Functionalization. Chem.-Eur. J. 2013, 19, 13274-
13287. (d) Haibach, M. C.; Seidel, D. C-H Bond Functionalization through Intramolecular
Hydride Transfer. Angew. Chem. Int. Ed. 2014, 53, 5010-5036. (e) Wang, L.; Xiao, J. C(sp3)–
H Bond Functionalization by Sequential Hydride Transfer/Cyclization: Electronic Effect and
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Steric Effect Controlled Regioselectivity. Org. Chem. Front. 2016, 3, 635. (f) Xiao, M.; Zhu,
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6
7
S.; Shen, Y.; Wang, L.; Xiao, J. Construction of Chiral Cyclic Compounds via Asymmetric
8
9
Cascade[1,n]-Hydride Transfer/Cyclization. Chin. J. Org. Chem. 2018, 38, 328.
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(9) For selected recent examples, see: (a) Mori, K.; Umeharaa, N.; Akiyama, T. Highly
Diastereoselective Synthesis of Tricyclic Fused-Pyrans by Sequential Hydride Shift
Mediated Double C(sp3)–H Bond Functionalization. Chem. Sci. 2018, 9, 7327-7331. (b)
Idiris, F. I. M.; Majestꢁ, C. E.; Craven, G. B.; Jones, C. R. Intramolecular Hydride Transfer
onto Arynes: Redox-Neutral and Transition Metal-Free C(sp3)−H Functionalization of
Amines. Chem. Sci. 2018, 9, 2873‒2878. (c) Gandamana, D. A.; Wang, B.; Tejo, C.; Bolte,
B.; Gagosz, F.; Chiba, S. Alkyl Ethers as Traceless Hydride Donors in Brønsted Acid
Catalyzed Intramolecular Hydrogen Atom Transfer. Angew. Chem., Int. Ed. 2018, 57, 6181-
6185. (d) Liu, S.; Zhang, W.; Qu, J.; Wang, B. Engaging 2-Methyl Indolenines in a Tandem
Condensation/1,5-Hydride Transfer/Cyclization Process: Construction of a Novel
Indolenine–Tetrahydroquinoline Assembly. Org. Chem. Front. 2018, 5, 3008-3012. (e) Liu,
S.; Qu, J.; Wang, B. Substrate-Controlled Divergent Synthesis of Polycyclic Indoloazepines
and Indolodiazepines via 1,5-Hydride Shift/7-cyclization Cascades. Chem. Commun. 2018,
54, 7928-7931. (f) Yokoo, K.; Mori, K. Divergent Synthesis of CF3-Substituted Polycyclic
Skeletons Based on Control of Activation Site of Acid Catalysts. Chem. Commun. 2018, 54,
6927‒6930. (g) Zhao, S.; Wang, X.; Wang, P.; Wang, G.; Zhao, W.; Tang, X.; Guo, M.
BF3·OEt2-Promoted Propargyl Alcohol Rearrangement/[1,5]-Hydride Transfer/Cyclization
Cascade Affording Tetrahydroquinolines. Org. Lett. 2019, 21, 3990−3993. (h) Wang, B.;
Gandamana, D. A.; Gagosz, F.; Chiba, S. Diastereoselective Intramolecular Hydride
Transfer under Brønsted Acid Catalysis. Org. Lett. 2019, 21, 2298-2301. (i) Yoshida, T.;
Mori, K. Expeditious Synthesis of Multisubstituted Indoles via Multiple Hydrogen Transfers.
Chem. Commun. 2018, 54, 12686‒12689.
(10) For examples of enantioselective 1,5-HT reactions involving asymmetric acid catalysis: (a)
Yu, J.; Li, N.; Chen, D.-F.; Luo, S.-W. Catalytic Enantioselective C(sp3)−H Functionaliza-
tion: Intramolecular Benzylic [1,5]-Hydride Shift. Tetrahedron Lett. 2014, 55, 2859-2864.
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(b) He, Y.-P.; Du, Y.-L.; Luo, S.-W.; Gong, L.-Z. Asymmetric sp3 C–H Functionalization via
a Chiral Brønsted Acid-catalyzed Redox Reaction for the Synthesis of Cyclic Aminals.
Tetrahedron Lett. 2011, 52, 7064-7066. (c) Chen, L.; Zhang, L.; Lv, J.; Cheng, J.-P.; Luo, S.
Catalytic Enantioselective tert-Aminocyclization by Asymmetric Binary Acid Catalysis
(ABC): Stereospecific 1,5-Hydrogen Transfer. Chem. Eur. J. 2012, 18, 8891-8895. (d)
Zhang, L.; Chen, L.; Lv, J.; Cheng, J.-P.; Luo, S. Theoretical Studies of the Asymmetric
Binary-Acid-Catalyzed tert-Aminocyclization Reaction: Origins of the C–H Activation and
Stereoselectivity. Chem. Asian J. 2012, 7, 2569-2576. (e) Mori, K.; Ehara, K.; Kurihara, K.;
Akiyama, T. Selective Activation of Enantiotopic C(sp3)−Hydrogen by Means of Chiral
Phosphoric Acid: Asymmetric Synthesis of Tetrahydroquinoline Derivatives. J. Am. Chem.
Soc. 2011, 133, 6166-6169. (f) Zhou, G.; Liu, F.; Zhang, J. Enantioselective Gold-Catalyzed
Functionalization of Unreactive sp3 C-H Bonds through a Redox–Neutral Domino Reaction.
Chem. Eur. J. 2011, 17, 3101-3104. (g) Suh, C. W.; Kim, D. Y. Enantioselective One-Pot
Synthesis of Ring-Fused Tetrahydroquinolines via Aerobic Oxidation and 1,5-Hydride
Transfer/Cyclization Sequences. Org. Lett. 2014, 16, 5374-5377. (h) Kang, Y. K.; Kim, S.
M.; Kim, D. Y. Enantioselective Organocatalytic C−H Bond Functionalization via Tandem
1,5-Hydride Transfer/Ring Closure: Asymmetric Synthesis of Tetrahydroquinolines. J. Am.
Chem. Soc. 2010, 132, 11847-11849. (i) Mori, K.; Isogai, R.; Kamei, Y.; Yamanaka, M.;
Akiyama, T. Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp3)–H
Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process. J. Am.
Chem. Soc. 2018, 140, 6203-6207.
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(11) For our reports on [1,5]-hydride transfer reactions, see: (a) Li, S.-S.; Zhu, S.; Chen, C.; Duan,
K.; Liu, Q.; Xiao, J. Hydride Transfer Involved Redox-Neutral Cascade Cyclizations for
Construction of Spirocyclic Bisoxindoles Featuring a [3,4]-Fused Oxindole Moiety. Org. Lett.
2019, 21, 1058-1062. (b) Li, S.-S.; Lv, X.; Ren, D.; Shao, C.-L.; Liu, Q.; Xiao, J. Redox-
Triggered Cascade Dearomative Cyclizations Enabled by Hexafluoroisopropanol. Chem. Sci.
2018, 9, 8253-8259. (c) Li, S.-S.; Zhou, L.; Wang, L.; Zhao, H.; Yu, L.; Xiao, J.
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Organocatalytic C(sp3)–H Functionalization via Carbocation-Initiated Cascade [1,5]-Hydride
Transfer/Cyclization: Synthesis of Dihydrodibenzo[b,e]azepines. Org. Lett. 2018, 20, 138-
141. (d) Wang, S.; An, X.-D.; Li, S.-S.; Liu, X.; Liu, Q.; Xiao, J. Hydride Transfer Initiated
Ring Expansion of Pyrrolidines toward Highly Functionalized Tetrahydro-1-benzazepines.
Chem. Commun. 2018, 54, 13833-13836. (e) Zhu, S.; Chen, C.; Xiao, M.; Yu, L.; Wang, L.;
Xiao, J. Construction of the Tetrahydroquinoline Spiro Skeleton via Cascade [1,5]-Hydride
Transfer-Involved C(sp3)–H Functionalization “on Water”. Green Chem. 2017, 19, 5653-
5658.
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(12) For selected examples on [1,5]-hydride transfer with iminium ions working as hydride
acceptors, see: (a) Liu, S.; Zhao, T.; Qu, J.; Wang, B. Expedient Synthesis of 1,4-
Benzodiazepines via a Tandem Condensation/[1,5]-Hydride Transfer/Cyclization Process.
Adv. Synth. Catal. 2018, 360, 4094-4098. (b) Chang, Y.-Z.; Li, M.-L.; Zhao, W.-F.; Wen, X.;
Sun, H.; Xu, Q.-L. Construction of Oxadiazepines via Lewis Acid-Catalyzed Tandem 1,5-
Hydride Shift/Cyclization. J. Org. Chem. 2015, 80, 9620-9627. (c) Dieckmann, A.; Richers,
M. T.; Platonova, A. Y.; Zhang, C.; Seidel, D.; Houk, K. N. Metal-Free α-Amination of
Secondary Amines: Computational and Experimental Evidence for Azaquinone Methide and
Azomethine Ylide Intermediates. J. Org. Chem. 2013, 78, 4132-4144. (d) Bhunia, S.;
Ghorpade, S.; Huple, D. B.; Liu, R.-S. Gold-Catalyzed Oxidative Cyclizations of cis-3-En-1-
ynes To Form Cyclopentenone Derivatives. Angew. Chem., Int. Ed. 2012, 51, 2939-2942. (e)
Mori, K.; Kawasaki, T.; Akiyama, T. Concise Route to 3-Arylisoquinoline Skeleton by Lewis
Acid Catalyzed C(sp3)–H Bond Functionalization and Its Application to Formal Synthesis of
(±)-Tetrahydropalmatine. Org. Lett. 2012, 14, 1436-1439. (f) Zhang, C.; Murarka, S.; Seidel,
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D. Facile Formation of Cyclic Aminals through a Brønsted Acid-Promoted Redox Process. J.
Org. Chem. 2009, 74, 419-422. (g) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. α-Amination of
Nitrogen Heterocycles:ꢀ Ring-Fused Aminals. J. Am. Chem. Soc. 2008, 130, 416-417. (h)
Zhang, Y.; Yang, F.; Zheng, L.; Dang, Q.; Bai, X. A Cascade of Acid-Promoted C–O Bond
Cleavage and Redox Reactions: From Oxa-Bridged Benzazepines to Benzazepinones. Org.
Lett. 2014, 16, 6041-6043. (i) Mori, K.; Umehara, N.; Akiyama, T. Synthesis of 3-Aryl-1-
trifluoromethyltetrahydroisoquinolines by Brønsted Acid-Catalyzed C(sp3)–H Bond
Functionalization. Adv. Synth. Catal. 2015, 357, 901-906.
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(13) (a) Shine, H. J.; Zmuda, H.; Park, K. H.; Kwart, H.; Horgan, A. G.; Brechbiel, M. Benzidine
rearrangements. 16. The Use of Heavy-atom Kinetic Isotope Effects in Solving the
Mechanism of the Acid-catalyzed Rearrangement of Hydrazobenzene. The Concerted
Pathway to Benzidine and the Nonconcerted Pathway to Diphenyline. J. Am. Chem. Soc. 1982,
104, 2501-2509. (b) Shine, H. J.; Zmuda, H.; Park, K. H.; Kwart, H.; Horgan, A. G.; Collins,
C.; Maxwell, B. E. Mechanism of the Benzidine Rearrangement. Kinetic Isotope Effects and
Transition States. Evidence for Concerted Rearrangement. J. Am. Chem. Soc. 1981, 103, 955-
956.
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