Regioselective, Diastereoselective, and Enantioselective One-Pot Tandem Reaction Based on an in Situ Formed Reductant: Preparation of 2,3-Disubstituted 1,5-Benzodiazepine

Preparation of 2,3-Disubstituted 1,5-Benzodiazepine

Article

Regioselective, Diastereoselective, and Enantioselective One-Pot

Tandem Reaction Based on an in Situ Formed Reductant:

Gao-feng Yang, Guang-xun Li,* Jin Huang, Ding-qiang Fu, Xiao-kang Nie, Xin Cui, Jin-zhong Zhao,

and Zhuo Tang *

Cite This: J. Org. Chem. 2021, 86, 5110 −5119

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sı Supporting Information

ABSTRACT: The 1,5-benzodiazepines are important skeletons

frequently contained in medicinal chemistry. Herein, we described

an unexpected tandem cyclization/transfer hydrogenation reaction

for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The

enolizable aryl aldehydes were chosen as substrates to react with

symmetric and unsymmetric o-phenylenediamines. The unforeseen

tandem reaction occurred among many possible latent side

reactions under chiral phosphoric acid catalysis and aﬀords the

corresponding products in moderate yields and regioselectivities,

good diastereoselectivities, and enantiomeric ratio (up to 99:1).

INTRODUCTION

Scheme 1. Selected Examples of Enantioselective Synthesis

of 1,5-BDP

■

The 1,5-benzodiazepines (1,5-BDPs) and their polycyclic

derivatives have received great attention, because of their

wide range of therapeutic and pharmacological properties. For

example, some of them were recognized as HCV NS5B

inhibitors, Caspase-1 (ICE) inhibitor, antimicrobial, diet

pills, etc.; thus, these are referred to as “privileged structures,”

a term ﬁrst used to describe the benzodiazepine. Because of

their wide range of biological and synthetic applications,

several methods have been developed. Among these reactions,

domino reactions of o-phenylenediamine (o-PDA) with

carbonyl compounds were systematically investigated, includ-

ing the use of Lewis acids as catalysts, and the employment of

microwave irradiation. A series of functionalized 1,5-BDP

derivatives were obtained as racemates. Though chiral 1,5-

BDPs were a fundamental skeleton in many bioactive

molecules, relatively few of these scaﬀolds have been

enantioselectively synthesized.

Generally, the preparation of chiral 1,5-BDP can be divided

into two categories including the enantioselective reduction of

the obtained cyclic imine and the enantioselective construction

of the seven-membered ring. Fan and co-workers developed

a useful asymmetric hydrogenation strategy, which could

obtain both enantiomers with the same enantiomer of the

ligand but in the presence of diﬀerent achiral counteranions

Received: December 31, 2020

Published: March 16, 2021

(

Scheme 1a).

Gong and Akiyama developed a similar way via the

dynamic kinetic asymmetric transfer hydrogenation of racemic

cyclic imine (Scheme 1a). The above methods elegantly

2021 American Chemical Society

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ensured the preparation of 2,4-disubstituted 1,5-BDP through

the enantioselective reduction of the cyclized imine substrates

in diﬀerent ways. On the other hand, researchers were trying to

construct the 1,5-BDP ring directly in an enantioselective way.

for product 3a. This unexpected result inspired us to

investigate the reaction deeply. We speculated that the key

imine enamine intermediate A could be formed, which could

be cyclized to aﬀord the seven-membered 1,5-BDP ring B with

two adjacent chiral centers through the similar mechanism

Feng and co-workers developed an enantioselective domino

reaction of o-PDA and chalcone derivatives, which produced

the corresponding 1,5-BDP ring in one step in up to 82% ee

report by the Shi group. Then the cyclic imine intermediate

B was reduced probably by the in situ formed imidazoline 3a′,

(

Scheme 1b). Shi and co-workers developed an interesting

yielding the 1,5-BDP 3a and imidazole 4a, respectively. If the

way for enantioselective construction of the 1,5-BDP ring

through a chiral phosphoric acid catalyzed tandem reaction

with reactive 5,5-dimethyl cyclohexane-1,3-dione, o-PDA, and

aromatic aldehyde or isatin as substrates (Scheme 1b). The

reaction proceeded through the formation of the key enamine

intermediate, which was followed by an enantioselective

intramolecular Mannich reaction. These methods ensured

the enantioselective construction of 1,5-BDP possessing only

one chiral center by ingeniously utilizing a special substrate

according to the diﬀerence of the reactivity. However, the

eﬃcient synthesis of 2,3-disubstituted 1,5-BDPs has not been

investigated. Herein, a unique tandem cyclization/transfer

hydrogenation reaction was unexpectedly found to be an

eﬃcient way to construct 2,3-disubstituted 1,5-BDP, and its

chiral derivatives could be obtained with high enantioselectiv-

ity by using phosphoric acid as catalysts.

reaction proceeds according to the speculated mechanism, the

outcome observed is completely incredible due to the fact that

there are many possible side reactions (Scheme 2b): (i) the

possible reductive amination between o-PDA and aldehydes;

(ii) the formation of imidazolines with o-PDA, and the

following reductive amination to yield N-substituted o-PDA;

(

iii) the direct formation of imidazoles; (iv) aldol reaction to

yield β-hydroxyl aldehyde or α,β-unsaturated aldehyde, which

might react with o-PDA as roads i−iii to get more complicated

products. However, the reaction aﬀorded 2,3-disubstituted 1,5-

BDP as the unanticipated main product; thus, we optimized

the reaction conditions for obtaining 1,5-BDP 3a in the

tandem one-pot reaction (Table S1; see Supporting

Information). According to the result, the reaction could be

catalyzed under catalytic diphenyl phosphate (5 mol %), and

the corresponding product 3a could be obtained in 63% yield

in high diastereoselectivity (>25:1).

RESULTS AND DISCUSSION

Then, we moved on to investigate the corresponding

enantioselective reaction with chiral phosphoric acid as catalyst

(Table 1). First, the phosphoric acid catalysts 5a−5g were

■

Imidazoline was used as an interesting hydride donor in the

literature. When we intended to prepare alkyl substituted

imidazoline 3a′, to our surprise, the obtained main product

was 1,5-BDP 3a with aromatized imidazole 4a (Scheme 2a).

Moreover, the high diastereoselectivity (>25:1) was observed

Table 1. Optimization of Reaction Conditions

Scheme 2. The Discovery and the Property of the Reaction

entry

cat

T (°C)

solvent

yield (%)

DCM

ACN

68:32

63:37

57:43

59:41

63:37

78:22

65:35

87:13

68:16

95:5

ACN/CHCl (1/1)

ACN/DCM (1/1)

ACN/PhCH (1/1)

ACN/DCM (1/1)

99:1

96:4

98:2

96:4

ACN/PhCH (1/1)

98:2

Condition: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol %),

solvent 2 mL, under a N atmosphere overnight. Calculated based on

puriﬁcation with silicon column; dr value was analyzed based on

crude H NMR (>25:1). Analyzed by chiral HPLC. ACN is the

short name of CH CN. 4 Å molecular sieves were added. HEH (1.2

equiv) was added. BTL (1.2 equiv) was added.

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screened (entries 1−7). Fortunately, both the enantioselectiv-

ity and yield were improved with 5f as a catalyst. Then the

reaction solvents were screened with 5f as a catalyst. The

reaction yield and er value were slightly improved when we

In addition, various halogen substituents (F, Cl, Br) were also

investigated, which proved that the desired products were

obtained with moderate yields and good er values (3d−3f).

Then the ortho-substituents were evaluated, which demon-

strated the o-methyl substituent was good for high yield (70%)

and bad for er value (87:13, 3g). However, the ortho-Cl

substituent was good for high er value (95:5, 3h). In addition,

the meta-F substituent was investigated, which also aﬀorded

the corresponding product with a pleasant er value (94.5:5.5,

3i). Meanwhile, ortho-disubstituted phenylacetaldehyde with

big steric hindrance was evaluated, which aﬀorded the desired

product 3j in slightly lower yield (43%) and moderate er value

used acetonitrile (CH CN) as solvent (entry 8). However, the

reaction yield and er value were decreased after decreasing the

reaction temperature to 0 °C (entry 9). To improve the

reaction yield and er value, when 4 Å molecular sieves were

used for absorbing the produced water, both the reaction yield

and er value could be improved (entry 10). Next, mixed

solvents were investigated, which demonstrated that the

mixture of CH CN:CHCl (1:1) was the optimal solvent

(

88.5:11.5).

(

entries 11−13). Then the addition of extra reduction reagents

Then we turned to investigate the reaction with substituted

such as Hantzch ester (HEH) or 2-phenyl-2,3-dihydrobenzo-

o-PDAs as substrates (Scheme 4). To our delight, symmetric

[

d]thiazole (BTL) were investigated (entries 14 and 15).

However, the reaction yield was not increased and the

aromatized Hantzch pyridine or thiazole was not found. On

the basis of this result, we realized that the in situ formed

Scheme 4. Investigation of the Reaction with Symmetric and

Unsymmetric o-PDA as Substrate

imidazoline (BBI) was an irreplaceable hydride donor due to

the fact that its reduction ability is generally higher than that of

the HEH and BTL. Therefore, the optimal reaction

conditions were obtained as follows: 1 equiv of o-PDA 1 and

.5 equiv of phenylacetaldehyde 2 reacted in the mixture of

CH CN:CHCl (1:1) with catalytic 5f (5 mol %) at 15 °C for

2 h without the addition of external H-donor. On the basis of

the optimal reaction conditions, the 2,3-disubstituted-1,5-BDP

a could be obtained in 65% yield, good dr value (>25:1), and

excellent er value (99:1).

Having the optimal conditions in hand, we began to explore

the scope of the aromatic phenylacetaldehydes. From the

results presented in Scheme 3, we could see that all chosen

substrates reacted with 1 to give desired products (3b−3j) in

excellent dr values (>25:1), moderate yields (43−70%), and

moderate to good er values (87:13−95:5). Initially, the para-

substituents of the phenylacetaldehydes were evaluated, which

demonstrated that the reaction proceeded well with an

electron-donating (3b) or electron-withdrawing (3c) group.

Scheme 3. Investigation of the Phenylacetaldehyde

Substrate

disubstituted o-PDAs (e.g., ﬂuoro, chloro, bromo) performed

well in this transformation, aﬀording the corresponding

products (3k−3m) in excellent dr values (>25:1), moderate

yields (52−66%), and good er values (93.5:6.5−96:4).

Meanwhile, the absolute conﬁguration of 3m was conﬁrmed

by X-ray single crystal analysis and other products were

assigned by analogy. The universalities of the reaction

prompted us to investigate the reaction with unsymmetric o-

PDAs as substrate (Scheme 4). The reaction would become

very complicated due to the incorporation of regioselectivity,

diastereoselectivity, and enantioselectivity. To our surprise, 4-

Cl-o-PDA and 4-Br-o-PDA reacted smoothly, aﬀording the

The reaction temperature was decreased to 5 °C for better er.

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corresponding products (3n, 3o) in pleasant regioselectivity

Scheme 6. Investigation of the Reaction Mechanism

(

6:1) and moderate yields. Moreover, high diastereoselectivity

>25:1) and good enantioselectivity were maintained. Then

the 3-CH -o-PDA was investigated, which aﬀorded 3p in better

regioselectivity (7:1), high diastereoselectivity (>25:1), and

good enantioselectivity (94.5:5.5). Meanwhile, other substi-

tuted phenylacetaldehydes were used to react with 3-CH -o-

PDA, and the corresponding products (3q, 3r) were obtained

in good regioselectivity (7:1), high diastereoselectivity

(

>25:1), moderate yield, and good enantioselectivity as well.

On the basis of this unique regioselectivity, other unsymmetric

disubstituted o-PDAs were evaluated. Interestingly, the 3,5-di-

CH -o-PDA proceeded well and aﬀorded 3s in good

regioselectivity (6:1) and moderate er value (91:9). Mean-

obtained product was cis-3a rather than trans-3a. According to

this result, we concluded that the reaction proceeded via road

while, 5-Br-3-CH -o-PDA aﬀorded the corresponding product

2. Meanwhile, the production of the reaction intermediate B

t in moderate regioselectivity (5:1) and good er value

was detected via the NMR experiment (Figure S1; see

Supporting Information). Moreover, the imine/enamine

isomerization could be proved via the deuteration experiment

(

96.5:3.5). The structures of these products were aﬃrmed

based on 2D NMR (see Supporting Information). Interest-

ingly, when N-CH -o-PDA was used as substrate, the

(

Scheme 6b). Therefore, road 1 might be the reasonable

corresponding product was not obtained.

reaction process.

Then, we moved on to investigate the reaction mechanism.

On the basis of the reaction results as well as the previous

According to the reaction mechanism and the previous

1,21

report, the chirality of the reaction might be formed through

the intramolecular Mannich reaction. Therefore, we proposed

that the bifunctional nature of the chiral phosphoric acid is

responsible for concurrent activation of both the enamine

nucleophile and the imine electrophile through hydrogen

literature,

two possible reaction roads were proposed

(Scheme 5). On the ﬁrst road, o-PDA reacts with phenyl-

Scheme 5. Plausible Reaction Mechanism

bonding (Scheme 7, TsA).

Scheme 7. Proposing the Reasonable Transition State

To demonstrate the synthetic practicality of this approach, a

large-scale synthesis of 3a was performed. The reaction

proceeded smoothly to give the corresponding product in

8% isolated yield with high dr value (>25:1) and only a slight

loss in er value (96.5:3.5) (Scheme 8).

Scheme 8. Large-Scale Synthesis of 3a

acetaldehyde to form imine intermediate A, which could easily

isomerize into intermediate B through imine/enamine isomer-

ization. Next, cyclic imine C is formed through the

intramolecular enantioselective Mannich reaction under the

chiral phosphoric catalyst. Finally, the in situ formed

imidazoline E selectively reduces the imine C and aﬀords the

ﬁnal product 3a and the corresponding aromatized imidazole

4a. On the second road, α,β-unsaturated aldehyde F might be

formed from 2a by aldol condensation. Then, α,β-unsaturated

imine G is formed, which reacts through intramolecular

Michael reaction to form the cyclic imine intermediate C.

Finally, intermediate C is reduced with E to aﬀord the product

CONCLUSIONS

■

In summary, we have developed an unexpected tandem

reaction for eﬃcient preparation of 2,3-disubstituted-1,5-

BDPs which was incompetent with previous ways. There was

no need to add any extra reductant to reduce the imine

intermediate, and the in situ formed imidazoline was the

irreplaceable reductant for the reaction. A series of 2,3-

In order to verify the reaction road 2, α,β-unsaturated

aldehyde F was prepared and used as a substrate under the

optimal reaction conditions (Scheme 6a). Interestingly, the

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disubstituted-1,5-BDP were obtained in good er (up to 99:1),

good dr (>25:1), and especially acceptable rr (up to 7:1) for

the unsymmetric o-PDAs. The reaction mechanism was

investigated which demonstrated that the reaction probably

proceeds through the enantioselective intramolecular Mannich

reaction/transfer hydrogenation tandem reaction.

Hz, 4H), 7.30 (dt, J = 13.4, 7.3 Hz, 4H), 7.16 (d, J = 7.2 Hz, 2H),

.76 (t, J = 7.0 Hz, 1H), 6.66 (dd, J = 14.1, 6.9 Hz, 2H), 6.30 (d, J =

.6 Hz, 1H), 3.85 (dd, J = 13.2, 4.2 Hz, 1H), 3.77−3.51 (m, 2H), 3.13

(

dd, J = 13.2, 6.2 Hz, 1H), 2.94−2.79 (m, 2H), 2.53 (dd, J = 14.3,

1.2 Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ 143.5, 140.4,

³⁸^.⁷^,¹³⁸^.⁶^,¹²⁸^.⁹^,¹²⁸^.⁸^,¹²⁸^.⁷^,¹²⁸^.⁰^,¹²⁶^.⁸^,¹²⁶^.⁷^,¹²¹^.³^,¹²⁰^.⁶+^,

19.6, 118.4, 62.2, 53.4, 52.6, 40.8. HRMS (ESI-TOF) m/z [M + H]

Calcd for C H N 315.1856; Found 315.1862.

EXPERIMENTAL SECTION

(2S,3R)-2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-2,3,4,5-tetra-

hydro-1H-benzo[b][1,4]diazepine (3b). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (10:1) to aﬀord a

yellow oil (23 mg, yield 62%), with er 92.5:7.5 (HPLC, Daicel

Chiralcel AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254

■

General Information. Unless otherwise stated, all reagents were

purchased from commercial suppliers and used without further

puriﬁcation. All solvents employed in the reactions were distilled from

appropriate drying agent prior to use. All kinds of phenylenediamines

are commercially available. All chiral phosphoric acid was purchased

from DAICEL CHIRAL TECHNOLOGIES (CHINA) CO., Ltd.

Organic solutions were concentrated under reduced pressure on a

nm; t = 12.4 min; t_R₂= 23.4 min; [α]_D= +43° (c 0.04, CH Cl ).

H NMR (400 MHz, CDCl ) δ 7.30 (d, J = 8.7 Hz, 2H), 7.07 (d, J =

.4 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.79

Buchi rotary evaporator. The heating reaction condition was

(dt, J = 14.7, 7.4 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.33 (d, J = 7.5

performed under an oil bath with a magnetic stirrer DF-101T. The

cooling reaction condition was performed with a ChangCheng cooler

DFY-5L. Melting points are uncorrected and recorded on a digital

melting point apparatus WRS-1B. Reactions were monitored by thin

layer chromatography using 0.25 mm Merck silica gel precoated plates

Hz, 1H), 3.83 (d, J = 5.1 Hz, 7H), 3.60−3.45 (m, 1H), 3.08 (dd, J =

3.1, 7.0 Hz, 1H), 2.90 (t, J = 9.9 Hz, 1H), 2.77 (dd, J = 14.2, 2.3 Hz,

H), 2.44 (dd, J = 14.3, 11.2 Hz, 1H). C{ H} NMR (101 MHz,

CDCl ) δ 158.5, 158.3, 139.4, 135.1, 130.5, 129.9, 128.9, 121.5, 120.0,

19.1, 114.1, 114.0, 62.6, 55.3, 52.9, 52.0, 39.8. HRMS (ESI-TOF)

(

60F-254). Visualization was accomplished by irradiation with UV

light at 254 nm. Column chromatography was performed using

m/z [M + H] Calcd for C H N O 375.2067; Found 375.2061.

(

2S,3R)-2-(4-(Triﬂuoromethyl)benzyl)-3-(4-(triﬂuoromethyl)-

Macherey-Nagel silica gel 60 M (particle size 0.040−0.063 mm).

phenyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (3c). Pre-

pared according to the general procedure and puriﬁed by column

chromatography on silica gel and eluted with petroleum ether/ethyl

acetate (10:1) to aﬀord a yellow oil (24 mg, yield 53%), with er 89:11

Chemical yields refer to pure isolated substances. H and C NMR

spectra were recorded at 25 °C on Bruker spectrometers at 400 or 101

MHz, respectively, using CDCl or DMSO-d as the solvent and TMS

as the internal reference. Structural assignments were made with

additional information from gHMBC, and gDEPT 135° experiments.

The following abbreviations were used to designate chemical shift

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p =

pentet, m = multiplet, b = broad. HRMS (ESI) determinations were

performed on a Bruker micrOTOF II spectrometer (TOF analyzer).

X-ray crystallographic structure determination was carried out on a

Bruker SMART CCD. Enantiomeric ratios (er) were determined by

chiral HPLC using Daicel CHIRALCEL OJ-H, AD-H, and AS-H

columns with hexane/2-propanol as the eluents. Optical rotations

were measured on an Autopol IV Polarimeter and reported as follows:

(

HPLC, Daicel Chiralcel OJ-H column, 95:5 hexane/2-propanol, 1

mL/min, 254 nm; t = 26.9 min; t_R₂= 35.2 min); [α]_D= +51° (c

.04, CH Cl ). H NMR (400 MHz, CDCl ) δ 7.64 (d, J = 8.2 Hz,

H), 7.59−7.54 (m, 4H), 7.29−7.23 (m, 2H), 6.81−6.73 (m, 1H),

.67 (t, J = 7.6 Hz, 2H), 6.37−6.31 (m, 1H), 3.96 (dd, J = 13.4, 4.5

Hz, 1H), 3.88 (ddd, J = 10.7, 9.2, 3.3 Hz, 3H), 3.18 (dd, J = 13.4, 5.0

Hz, 1H), 2.98 (dt, J = 9.2, 4.7 Hz, 1H), 2.86 (dd, J = 14.5, 2.7 Hz,

H), 2.72 (dd, J = 14.5, 10.8 Hz, 1H). C{ H} NMR (101 MHz,

CDCl ) δ 147.7, 142.5, 139.6, 137.5, 129.3 (C-F, J = 33.3 Hz),

C‑F

29.2, 128.3, 125.7 (C-F, J = 4.0 Hz), 124.1 (C-F, J = 273.7

C‑F C‑F

Hz), 121.4, 120.5, 119.3, 118.1, 61.8, 52.5, 51.6, 40.8. F NMR (376

[

^α^]D (c in g per 100 mL, solvent).

MHz, CDCl ) δ −62.4, −62.5. HRMS (ESI-TOF) m/z [M + H]

Calcd for C H F N 451.1603; Found 451.1591.

Synthesis of Phenylacetaldehydes. Phenylacetaldehyde 2a was

purchased. Others (2b−j) were prepared by oxidation of the

(

2S,3R)-2-(4-Fluorobenzyl)-3-(4-ﬂuorophenyl)-2,3,4,5-tetrahy-

corresponding aryl ethanol according to a reported literature. IBX (10

dro-1H-benzo[b][1,4]diazepine (3d). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a

yellow oil (20 mg, yield 56%), with er 91:9 (HPLC, Daicel Chiralcel

mmol) was added to a solution of aryl ethanol (5 mmol) in CH CN

15 mL) at room temperature. Then the reaction mixture was moved

to an oil bath, which was reﬂuxed at 80 °C under a N atmosphere for

.5 h. After cooling to room temperature, ﬁltration, and evaporation,

followed by ﬂash column chromatography on silica gel (petroleum

ether/ethyl acetate = 10/1−7/1), the desired product was obtained.

Preparation of Chiral 2,3-Disubstituted 1,5-BDPs with

Diﬀerent Phenylacetaldehydes (3a−3j). To a tube were added

a solution of o-DPA (0.2 mmol, 1.0 equiv), 4 Å MS (50 mg), acid

catalyst 5f (7.5 mg, 10 μmol, 0.05 equiv), and 1 mL of mixed solvent

(

AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t

.2 min; t_R₂= 16.8 min); [α]_D= +146° (c 0.04, CH Cl ). H NMR

2 2

(

400 MHz, CDCl ) δ 7.40 (dd, J = 8.4, 5.6 Hz, 2H), 7.15−7.04 (m,

H), 7.01 (t, J = 8.6 Hz, 2H), 6.77 (t, J = 7.4 Hz, 1H), 6.72−6.59 (m,

H), 6.32 (d, J = 7.3 Hz, 1H), 3.89 (dd, J = 13.3, 4.3 Hz, 1H), 3.75−

.19 (m, 3H), 3.11 (dd, J = 13.3, 5.7 Hz, 1H), 2.88 (dt, J = 9.6, 5.0

Hz, 1H), 2.83−2.69 (m, 1H), 2.53 (dd, J = 14.4, 11.1 Hz, 1H).

(

CH CN:CHCl₃= 1:1); the tube was sealed with a septum,

C{ H} NMR (101 MHz, CDCl ) δ 161.8 (C-F, J = 245.4 Hz),

evacuated, and backﬁlled with nitrogen three times. Next, phenyl-

acetaldehyde (0.3 mmol, 1.5 equiv) was dissolved in 1 mL of mixed

solvent (CH CN:CHCl = 1:1), which was added into the above

C‑F

(

68.7 (C-F, J = 245.4 Hz), 139.8, 139.3 (C-F, J = 3.0 Hz),

38.3, 134.1 (C-F, J = 3.0 Hz), 130.3 (C-F, J = 7.1 Hz), 129.3

C-F, J = 8.1 Hz), 121.4, 120.7, 119.5, 118.3, 115.6 (C-F, J

1.2 Hz), 115.5 (C-F, J = 20.2 Hz), 62.5, 52.3, 52.1, 40.0.

C‑F

solution by syringe under a nitrogen atmosphere, and it was stirred at

°C overnight, Next, the reaction mixture was concentrated. The

desired product was isolated by column chromatography on silica gel

eluent: petroleum ether/ethyl acetate = 15/1−8/1). The enantio-

meric ratio of the product was determined by HPLC analysis.

2S,3R)-2-Benzyl-3-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]-

diazepine (3a). Prepared according to the general procedure, but the

reaction temperature was 15 °C, and puriﬁed by column

chromatography on silica gel and eluted with petroleum ether/ethyl

acetate (13:1) to aﬀord a yellow oil (20 mg, yield 65%), with er 99:1

C‑F

NMR (376 MHz, CDCl ) δ −116.0, −116.1. HRMS (ESI-TOF) m/z

(

[M + H] Calcd for C22H F N 351.1667; Found 351.1664.

21 2 2

(2S,3R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-2,3,4,5-tetrahy-

dro-1H-benzo[b][1,4]diazepine (3e). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (12:1) to aﬀord a

yellow oil (22 mg, yield 57%), with er 91.5:8.5 (HPLC, Daicel

Chiralcel AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254

(

HPLC, Daicel Chiralcel OJ-H column, 80:20 hexane/2-propanol, 1

nm; tR1 = 8.7 min; tR2 = 10.9 min); [α]

= +28° (c 0.04, CH Cl ).

2 2

mL/min, 254 nm; t = 17.8 min; t_R₂= 20.4 min; [α]_D= +35° (c

H NMR (400 MHz, CDCl ) δ 7.44−7.32 (m, 4H), 7.29 (d, J = 4.2

Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.76 (t, J = 7.0 Hz, 1H), 6.66 (t, J =

.04, CH Cl ). H NMR (400 MHz, CDCl ) δ 7.40 (dt, J = 14.9, 7.4

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J. Org. Chem. 2021, 86, 5110−5119

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.9 Hz, 2H), 6.32 (d, J = 7.3 Hz, 1H), 3.89 (dd, J = 13.3, 4.4 Hz, 1H),

.78−3.20 (m, 3H), 3.11 (dd, J = 13.3, 5.4 Hz, 1H), 2.85 (dt, J = 9.4,

.8 Hz, 1H), 2.78 (dd, J = 14.4, 2.6 Hz, 1H), 2.54 (dd, J = 14.4, 11.1

7.1 Hz), 139.4, 138.2, 130.3 (C-F, J = 8.1 Hz), 130.2 (C-F, J

C‑F

8.1 Hz), 124.5 (C-F, J = 2.0 Hz), 123.7 (C-F, J = 3.0 Hz),

121.5, 120.9, 119.5, 118.5, 115.7 (C-F, J = 21.2 Hz), 114.7 (C-F,

C‑F

Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ 142.1, 139.8, 138.0,

J_C_‑_F= 22.2 Hz), 113.8 (C-F, J = 21.2 Hz), 113.7 (C-F, J

C‑F₁

C‑F

36.9, 132.6, 132.5, 130.2, 129.3, 128.9, 128.8, 121.4, 120.6, 119.4,

21.2 Hz), 62.0, 52.5, 52.0, 40.5. F NMR (376 MHz, CDCl ) δ

18.2, 62.1, 52.2, 52.0, 40.2. HRMS (ESI-TOF) m/z [M + H] Calcd

−112.7, −112.8. HRMS (ESI-TOF) m/z [M + H] Calcd for

C H F N 351.1667; Found 351.1669.

(2S,3R)-2-(2,6-Dichlorobenzyl)-3-(2,6-dichlorophenyl)-2,3,4,5-

tetrahydro-1H-benzo[b][1,4]diazepine (3j). Prepared according to

the general procedure and puriﬁed by column chromatography on

silica gel and eluted with petroleum ether/ethyl acetate (13:1) to

aﬀord a yellow oil (19 mg, yield 43%), with er 88.5:11.5 (HPLC,

Daicel Chiralcel AD-H column, 80:20 hexane/2-propanol, 1 mL/min,

254 nm; t = 9.7 min; t_R₂= 27.3 min); [α]_D= +31° (c 0.04,

CH Cl ). H NMR (400 MHz, CDCl ) δ 7.43 (d, J = 8.0 Hz, 1H),

for C H Cl N 383.1076; Found 383.1071.

22 21

(

2S,3R)-2-(4-Bromobenzyl)-3-(4-bromophenyl)-2,3,4,5-tetrahy-

dro-1H-benzo[b][1,4]diazepine (3f). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a

yellow oil (31 mg, yield 66%), with er 94:6 (HPLC, Daicel Chiralcel

AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t

.7 min; t_R₂= 11.6 min); [α]_D= +88° (c 0.04, CH Cl ). H NMR

(400 MHz, CDCl ) δ 7.50 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.3 Hz,

(

H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 6.83−6.73

m, 1H), 6.67 (t, J = 6.7 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H), 3.89 (dd, J

13.3, 4.4 Hz, 1H), 3.78−3.20 (m, 3H), 3.11 (dd, J = 13.3, 5.4 Hz,

H), 2.85 (dt, J = 9.3, 4.7 Hz, 1H), 2.76 (dd, J = 14.4, 2.7 Hz, 1H),

7.33 (dd, J = 18.1, 8.0 Hz, 3H), 7.16 (dt, J = 11.7, 8.0 Hz, 2H), 6.77

(ddt, J = 21.7, 14.4, 7.2 Hz, 3H), 6.40 (d, J = 7.5 Hz, 1H), 4.32 (td, J

= 10.3, 2.8 Hz, 1H), 4.23 (td, J = 9.5, 2.9 Hz, 1H), 3.90 (dd, J = 12.5,

10.0 Hz, 3H), 3.44−3.29 (m, 2H), 2.84 (dd, J = 13.7, 2.6 Hz, 1H).

2.53 (dd, J = 14.4, 11.0 Hz, 1H). C{ H} NMR (101 MHz, CDCl )

C{ H} NMR (101 MHz, CDCl ) δ 141.8, 139.2, 137.3, 136.3,

δ 142.6, 139.7, 138.0, 137.4, 131.8, 130.6, 129.7, 121.4, 120.7, 120.6,

20.5, 119.5, 118.2, 62.0, 52.2, 51.9, 40.3. HRMS (ESI-TOF) m/z [M

134.9, 134.6, 130.2, 128.8, 128.6, 128.5, 128.4, 122.1, 121.4, 121.2,

119.6, 57.2, 52.6, 49.2, 35.7. HRMS (ESI-TOF) m/z [M + H] Calcd

for C H Cl N 451.0297; Found 451.0290.

22 19

Preparation of Chiral 2,3-Disubstituted 1,5-BDPs with

Diﬀerent o-DPAs (3k−3t). To a tube were added a solution of

diﬀerent o-DPA (0.2 mmol, 1.0 equiv), 4 Å MS (50 mg), acid catalyst

5f (7.5 mg, 10 μmol, 0.05 equiv), and 1 mL of mixed solvent

(CH CN:CHCl = 1:1); the tube was sealed with a septum,

benzo[b][1,4]diazepine (3g). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(

24 mg, yield 70%), with er 87:13 (HPLC, Daicel Chiralcel AD-H

column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t = 5.8 min;

t_R₂= 16.2 min; [α]_D= +26° (c 0.04, CH Cl ). H NMR (400 MHz,

evacuated, and backﬁlled with nitrogen three times. Next, phenyl-

acetaldehyde (0.3 mmol, 1.5 equiv) was dissolved in 1 mL of mixed

solvent (CH CN:CHCl = 1:1), which was added into the above

CDCl ) δ 7.48 (d, J = 7.0 Hz, 1H), 7.27−7.22 (m, 2H), 7.18 (dd, J =

.4, 3.4 Hz, 5H), 6.78 (t, J = 7.0 Hz, 1H), 6.69 (dd, J = 12.9, 6.8 Hz,

H), 6.41−6.30 (m, 1H), 3.73 (dd, J = 13.2, 4.1 Hz, 2H), 3.69−3.53

solution by syringe under a nitrogen atmosphere, and it was stirred at

15 °C overnight. Next, the reaction mixture was concentrated. The

desired product was isolated by column chromatography on silica gel

(eluent: petroleum ether/ethyl acetate = 15/1−8/1). The enantio-

meric ratio of the product was determined by HPLC analysis. X-ray

quality crystals were obtained by slow evaporation of solvent from a

saturated solution in hexanes. This compound was further

characterized by X-ray crystallography.

(2S,3R)-2-Benzyl-7,8-diﬂuoro-3-phenyl-2,3,4,5-tetrahydro-1H-

benzo[b][1,4]diazepine (3k). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(23 mg, yield 66%), with er 96:4 (HPLC, Daicel Chiralcel AD-H

(

m, 2H), 3.29 (ddd, J = 9.7, 7.0, 4.2 Hz, 1H), 3.07 (dd, J = 13.2, 7.0

Hz, 1H), 2.78 (dd, J = 14.4, 2.5 Hz, 1H), 2.60 (dd, J = 14.4, 11.2 Hz,

H), 2.48 (s, 3H), 2.12 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ

41.5, 140.6, 139.0, 136.9, 136.7, 135.9, 130.8, 130.5, 129.3, 126.8,

26.5, 126.3, 126.1, 121.5, 120.8, 119.9, 118.6, 61.2, 52.4, 47.9, 37.7,

0.5, 19.4. HRMS (ESI-TOF) m/z [M + H] Calcd for C H N

43.2169; Found 343.2165.

2S,3R)-2-(2-Chlorobenzyl)-3-(2-chlorophenyl)-2,3,4,5-tetrahy-

(

dro-1H-benzo[b][1,4]diazepine (3h). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a

yellow oil (20 mg, yield 53%), with er 95:5 (HPLC, Daicel Chiralcel

column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t = 9.6 min;

AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t

t_R₂= 17.0 min; [α]_D= +38° (c 0.04, CH Cl ). H NMR (400 MHz,

2 2

.1 min; t_R₂= 11.8 min); [α]_D= +33° (c 0.04, CH Cl ). H NMR

CDCl ) δ 7.39 (d, J = 4.2 Hz, 4H), 7.36−7.32 (m, 2H), 7.29 (s, 2H),

(

400 MHz, CDCl ) δ 7.76 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.8 Hz,

7.15 (d, J = 7.2 Hz, 2H), 6.48 (dd, J = 11.2, 7.7 Hz, 1H), 6.07 (dd, J =

11.2, 7.8 Hz, 1H), 3.76 (dd, J = 13.3, 4.0 Hz, 1H), 3.68−3.37 (m,

3H), 3.09 (dd, J = 13.3, 6.8 Hz, 1H), 2.93−2.76 (m, 2H), 2.49 (dd, J

H), 7.36−7.29 (m, 2H), 7.19 (t, J = 7.4 Hz, 4H), 6.77−6.70 (m,

H), 6.68−6.60 (m, 2H), 6.38 (d, J = 7.3 Hz, 1H), 3.96 (dq, J = 9.3,

.4 Hz, 2H), 3.68 (dt, J = 9.0, 4.5 Hz, 3H), 3.14 (dd, J = 13.4, 4.6 Hz,

= 14.2, 11.3 Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ 144.6 (C-

H), 2.95−2.84 (m, 2H). C{ H} NMR (101 MHz, CDCl ) δ 140.9,

F, J = 227.3 Hz), 144.4 (C-F, J = 227.3 Hz), 142.6, 138.2, 135.9

(C-F, J = 7.1 Hz), 135.8 (C-F, J = 7.1 Hz), 135.2 (C-F, J

6.1 Hz), 135.1 (C-F, J = 6.1 Hz), 128.9, 128.8, 128.7, 127.9, 127.1,

127.0, 108.1 (C-F, J = 19.2 Hz), 107.2 (C-F, J = 20.2 Hz),

C‑F C‑F

38.0, 136.6, 131.0, 129.8, 129.4, 128.7, 128.1, 127.7, 127.1, 126.9,

C‑F

21.0, 120.2, 119.2, 118.0, 61.0, 51.0, 46.8, 38.1. HRMS (ESI-TOF)

C‑F

m/z [M + H] Calcd for C H Cl N 383.1076; Found 383.1072.

(

2S,3R)-2-(3-Fluorobenzyl)-3-(3-ﬂuorophenyl)-2,3,4,5-tetrahy-

62.41, 53.22, 52.80, 40.61. F NMR (376 MHz, CDCl ) δ −147.8,

dro-1H-benzo[b][1,4]diazepine (3i). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (15:1) to aﬀord a

yellow oil (20 mg, yield 56%), with er 94.5:5.5 (HPLC, Daicel

Chiralcel AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254

−147.9, −148.7, −148.8. HRMS (ESI-TOF) m/z [M + H] Calcd for

C H F N 351.1667; Found 351.1667.

(2S,3R)-2-Benzyl-7,8-dichloro-3-phenyl-2,3,4,5-tetrahydro-1H-

benzo[b][1,4]diazepine (3l). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(23 mg, yield 60%), with er 93.5:6.5 (HPLC, Daicel Chiralcel AS-H

nm; t_R₁= 7.5 min; t_R₂= 15.8 min; [α]_D= +30° (c 0.04, CH Cl ). H

NMR (400 MHz, CDCl ) δ 7.38−7.31 (m, 1H), 7.30 (d, J = 4.7 Hz,

H), 7.19 (t, J = 7.3 Hz, 2H), 7.05−6.89 (m, 3H), 6.85 (d, J = 9.8 Hz,

column, 98:2 hexane/2-propanol, 1 mL/min, 254 nm; t = 18.7 min;

H), 6.77 (t, J = 7.4 Hz, 1H), 6.69 (dd, J = 16.1, 7.8 Hz, 2H), 6.33 (d,

t_R₂= 26.5 min; [α]_D= +28° (c 0.04, CH Cl ). H NMR (400 MHz,

J = 7.6 Hz, 1H), 3.91 (dd, J = 13.3, 4.3 Hz, 1H), 3.77−3.23 (m, 2H),

CDCl ) δ 7.44−7.38 (m, 3H), 7.38−7.31 (m, 3H), 7.30−7.25 (m,

.14 (dd, J = 13.3, 5.6 Hz, 1H), 2.91 (dt, J = 9.4, 4.8 Hz, 1H), 2.82

2H), 7.18−7.07 (m, 2H), 6.69 (s, 1H), 6.32 (s, 1H), 3.87 (dd, J =

13.4, 4.4 Hz, 1H), 3.83−3.69 (m, 2H), 3.55 (s, 1H), 3.14 (dd, J =

13.4, 5.5 Hz, 1H), 2.86 (ddd, J = 14.3, 8.1, 4.0 Hz, 2H), 2.52 (dd, J =

(dd, J = 14.4, 2.6 Hz, 1H), 2.58 (dd, J = 14.4, 11.1 Hz, 1H). C{ H}

NMR (101 MHz, CDCl ) δ 163.1 (C-F, J = 246.4 Hz), 163.0 (C-

F, J = 247.5 Hz), 145.9 (C-F, J = 7.1 Hz), 141.0 (C-F, J

C‑F

14.5, 11.0 Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ 143.1,

C‑F

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39.8, 138.3, 138.2, 128.9, 128.8, 128.7, 127.9, 127.1, 127.0, 123.1,

column, 95:5 hexane/2-propanol, 1 mL/min, 254 nm; t = 10.1 min;

22.2, 120.0, 118.8, 62.1, 52.6, 51.9, 40.7. HRMS (ESI-TOF) m/z [M

t_R₂= 13.5 min; [α]_D= +15° (c 0.04, CH Cl ). H NMR (400 MHz,

2 2

H] Calcd for C H Cl N 383.1076; Found 383.1077.

CDCl ) δ 7.33 (dt, J = 12.1, 5.9 Hz, 1H), 7.28−7.15 (m, 3H), 7.06−

(

2S,3R)-2-Benzyl-7,8-dibromo-3-phenyl-2,3,4,5-tetrahydro-1H-

6.97 (m, 1H), 6.94 (t, J = 6.5 Hz, 2H), 6.85 (d, J = 9.7 Hz, 1H), 6.69

(d, J = 7.3 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H),

4.05 (dd, J = 13.4, 4.4 Hz, 1H), 3.89−3.35 (m, 3H), 3.19 (dd, J =

13.4, 4.5 Hz, 1H), 2.98−2.77 (m, 2H), 2.59 (dd, J = 14.3, 11.0 Hz,

benzo[b][1,4]diazepine (3m). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(

24. mg, yield 52%), with er 94.5:5.5 (HPLC, Daicel Chiralcel AS-H

1H), 2.20 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 163.1 (C-

column, 98:2 hexane/2-propanol, 1 mL/min, 254 nm; t = 12.2 min;

F, J = 246.4 Hz), 163.0 (C-F, J = 248.5 Hz), 146.2 (C-F, J

7.1 Hz), 141.1 (C-F, J = 8.1 Hz), 137.8, 137.7, 130.2 (C-F, J

C‑F

t_R₂= 15.5 min; [α]_D= +41° (c 0.04, CH Cl ). H NMR (400 MHz,

C‑F

CDCl ) δ 7.44−7.37 (m, 3H), 7.34 (dd, J = 9.4, 7.7 Hz, 2H), 7.28 (d,

8.1 Hz), 130.1 (C-F, J = 8.1 Hz), 124.6, 124.5 (C-F, J = 3.0

C‑F C‑F

J = 9.7 Hz, 3H), 7.16−7.08 (m, 2H), 6.86 (s, 1H), 6.48 (s, 1H), 3.88

Hz), 123.83 (C-F, J = 3.0 Hz), 123.2, 119.6, 117.7, 115.7 (C-F,

C‑F

(

dd, J = 13.4, 4.5 Hz, 1H), 3.84−3.70 (m, 2H), 3.55 (s, 1H), 3.14

J_C_‑_F= 20.2 Hz), 114.7 (C-F, J = 21.2 Hz), 113.8 (C-F, J

21.2 Hz), 113.7 (C-F, J = 21.21 Hz), 62.0, 52.3, 51.3, 40.5, 17.8.

F NMR (376 MHz, CDCl ) δ −112.8, −112.9. HRMS (ESI-TOF)

m/z [M + H] Calcd for C H F N 365.1824; Found 365.1817.

C‑F

dd, J = 13.3, 5.3 Hz, 1H), 2.92−2.77 (m, 2H), 2.52 (dd, J = 14.5,

C‑F

1.0 Hz, 1H). ¹³C{ H} NMR (101 MHz, CDCl ) δ 143.2, 140.5,

39.0, 128.9, 128.8, 128.7, 127.9, 127.1, 127.0, 122.9, 121.8, 62.0,

2.4, 51.8, 40.7. HRMS (ESI-TOF) m/z [M + H] Calcd for

(

2S,3R)-(2S,3R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-methyl-

C H Br N 471.0066; Found 471.0076.

2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (3r). Prepared ac-

(

2S,3R)-2-Benzyl-7-chloro-3-phenyl-2,3,4,5-tetrahydro-1H-

cording to the general procedure, but the reaction temperature was

benzo[b][1,4]diazepine (3n). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

°C, and puriﬁed by column chromatography on silica gel and eluted

with petroleum ether/ethyl acetate (15:1) to aﬀord a yellow oil (14

mg, yield 35%), with er 87.5:14.5 (HPLC, Daicel Chiralcel AD-H

(

20 mg, yield 57%), with er 94.5:5.5 (HPLC, Daicel Chiralcel AS-H

column, 95:5 hexane/2-propanol, 1 mL/min, 254 nm; t = 12.6 min;

column, 98:2 hexane/2-propanol, 1 mL/min, 254 nm; t = 13.0 min;

t_R₂= 15.2 min; [α]_D= +25° (c 0.04, CH Cl ). H NMR (400 MHz,

CDCl ) δ 7.37 (q, J = 8.6 Hz, 4H), 7.28 (d, J = 1.3 Hz, 2H), 7.06 (d, J

t_R₂= 17.7 min; [α]_D= +30° (c 0.04, CH Cl ). H NMR (400 MHz,

CDCl ) δ 7.44−7.29 (m, 8H), 7.14 (d, J = 7.1 Hz, 2H), 6.68 (dd, J =

= 8.3 Hz, 2H), 6.68 (d, J = 7.1 Hz, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.21

(d, J = 7.0 Hz, 1H), 4.03 (dd, J = 13.4, 4.5 Hz, 1H), 3.76 (td, J = 11.0,

3.1 Hz, 3H), 3.15 (dd, J = 13.4, 4.6 Hz, 1H), 2.89−2.74 (m, 2H), 2.54

.3, 2.3 Hz, 1H), 6.56 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 2.3 Hz, 1H),

.83 (dd, J = 13.3, 4.3 Hz, 1H), 3.77−3.68 (m, 1H), 3.59 (s, 1H),

.11 (dd, J = 13.3, 6.0 Hz, 1H), 2.86 (ddd, J = 17.1, 12.0, 4.2 Hz, 2H),

(dd, J = 14.5, 11.0 Hz, 1H), 2.18 (s, 3H). C{ H} NMR (101 MHz,

.52 (dd, J = 14.4, 11.1 Hz, 1H). C{ H} NMR (101 MHz, CDCl )

CDCl ) δ 142.2, 137.8, 137.7, 136.9, 132.6, 132.4, 130.1, 129.4, 128.8,

δ 143.2, 139.8, 138.7, 138.3, 128.9, 128.8, 128.7, 127.9, 127.0, 126.9,

124.5, 119.5, 117.6, 62.1, 52.0, 51.4, 40.1, 17.8. HRMS (ESI-TOF)

24.9, 120.8, 119.2, 119.0, 62.0, 53.0, 52.4, 40.8. HRMS (ESI-TOF)

m/z [M + H] Calcd for C H Cl N 397.1233; Found 397.1236.

m/z [M + H] Calcd for C H Cl N 349.1466; Found 349.1447.

(2S,3R)-2-Benzyl-6,8-dimethyl-3-phenyl-2,3,4,5-tetrahydro-1H-

benzo[b][1,4]diazepine (3s). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (15:1) to aﬀord a yellow oil

(19 mg, yield 56%), with er 91:9 (HPLC, Daicel Chiralcel AD-H

(

2S,3R)-2-Benzyl-7-bromo-3-phenyl-2,3,4,5-tetrahydro-1H-

benzo[b][1,4]diazepine (3o). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(

23 mg, yield 58%), with er 92.5:7.5 (HPLC, Daicel Chiralcel AD-H

column, 98:2 hexane/2-propanol, 1 mL/min, 254 nm; t = 10.7 min;

column, 80:20 hexane/2-propanol, 1 mL/min, 254 nm; t = 11.3

t_R₂= 15.6 min; [α]_D= +25° (c 0.04, CH Cl ). H NMR (400 MHz,

min; t_R₂= 36.1 min); [α]_D= +33° (c 0.04, CH Cl ). H NMR (400

MHz, CDCl ) δ 7.39 (q, J = 8.1, 7.5 Hz, 4H), 7.35−7.26 (m, 4H),

CDCl ) δ 7.45−7.35 (m, 4H), 7.32 (q, J = 6.1, 5.2 Hz, 3H), 7.28−

7.23 (m, 1H), 7.16 (d, J = 7.0 Hz, 2H), 6.52 (s, 1H), 6.02 (s, 1H),

3.90 (dd, J = 13.2, 4.3 Hz, 1H), 3.71 (td, J = 11.0, 2.9 Hz, 1H), 3.11

(dd, J = 13.2, 6.0 Hz, 1H), 2.94−2.79 (m, 2H), 2.53 (dd, J = 14.4,

.14 (d, J = 7.2 Hz, 2H), 6.86−6.78 (m, 1H), 6.51 (d, J = 8.2 Hz,

H), 6.43−6.37 (m, 1H), 3.84 (dd, J = 13.3, 4.2 Hz, 1H), 3.78−3.47

(

m, 3H), 3.12 (dd, J = 13.3, 5.8 Hz, 1H), 2.94−2.76 (m, 2H), 2.52

11.1 Hz, 1H), 2.17 (s, 3H), 2.12 (s, 3H). C{ H}NMR (101 MHz,

dd, J = 14.2, 11.1 Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ

CDCl ) δ 143.7, 138.7, 138.6, 136.2, 129.1, 128.9, 128.7, 128.6, 128.1,

43.3, 140.0, 139.3, 138.3, 128.9, 128.8, 128.7, 127.9, 126.9, 126.8,

126.8, 126.6, 124.9, 123.9, 118.4, 62.1, 53.5, 52.4, 40.9, 20.4, 17.8.

23.6, 121.7, 119.4, 111.9, 62.0, 52.9, 52.3, 40.8. HRMS (ESI-TOF)

m/z [M + H] Calcd for C H BrN 393.0961; Found 393.0963.

HRMS (ESI-TOF) m/z [M + H] Calcd for C H N 343.2169;

Found 343.2165.

(

2S,3R)-2-Benzyl-6-methyl-3-phenyl-2,3,4,5-tetrahydro-1H-

(2S,3R)-2-Benzyl-8-bromo-6-methyl-3-phenyl-2,3,4,5-tetrahy-

dro-1H-benzo[b][1,4]diazepine (3t). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (12:1) to aﬀord a

yellow oil (26 mg, yield 64%),with er 96.5:3.5 (HPLC, Daicel

Chiralcel AD-H column, 80:20 hexane/2-propanol, 1 mL/min, 254

benzo[b][1,4]diazepine (3p). Prepared according to the general

procedure and puriﬁed by column chromatography on silica gel and

eluted with petroleum ether/ethyl acetate (13:1) to aﬀord a yellow oil

(

21 mg, yield 65%), with er 94.5:5.5 (HPLC, Daicel Chiralcel AD-H

column, 98:2 hexane/2-propanol, 1 mL/min, 254 nm; t = 12.3 min;

t_R₂= 18.7 min; [α]_D= +43° (c 0.04, CH Cl ). H NMR (400 MHz,

CDCl ) δ 7.48−7.42 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.31 (td, J =

.4, 2.0 Hz, 3H), 7.27−7.21 (m, 1H), 7.19−7.11 (m, 2H), 6.68 (d, J =

.4 Hz, 1H), 6.53 (t, J = 7.6 Hz, 1H), 6.19 (dd, J = 7.8, 1.4 Hz, 1H),

.00 (dd, J = 13.3, 4.4 Hz, 1H), 3.78 (ddd, J = 11.0, 9.5, 3.0 Hz, 3H),

.16 (dd, J = 13.3, 5.4 Hz, 1H), 2.94−2.80 (m, 2H), 2.54 (dd, J =

4.4, 11.0 Hz, 1H), 2.19 (s, 3H). C{ H} NMR (101 MHz, CDCl )

δ 143.8, 138.7, 138.4, 128.9, 128.7, 128.6, 128.1, 126.8, 126.6, 124.5,

23.0, 119.5, 117.8, 62.2, 53.1, 51.9, 40.8, 17.8. HRMS (ESI-TOF)

nm; t_R₁= 7.9 min; t_R₂= 8.8 min; [α]_D= +28° (c 0.04, CH Cl ). H

2 2

NMR (400 MHz, CDCl ) δ 7.41 (dd, J = 13.4, 7.1 Hz, 4H), 7.32 (d, J

= 6.9 Hz, 4H), 7.13 (d, J = 6.9 Hz, 2H), 6.78 (s, 1H), 6.30 (s, 1H),

3.97 (dd, J = 13.6, 3.4 Hz, 1H), 3.85−3.56 (m, 3H), 3.16 (dd, J =

13.2, 4.4 Hz, 1H), 2.90−2.83 (m, 2H), 2.59−2.48 (m, 1H), 2.14 (s,

3H). C{ H} NMR (101 MHz, CDCl ) δ 143.5, 139.6, 138.4, 137.4,

128.9, 128.8, 128.7, 128.0, 126.9, 126.8, 126.2, 125.2, 119.8, 110.8,

62.0, 52.6, 51.7, 40.8, 17.7. HRMS (ESI-TOF) m/z [M + H] Calcd

for C23H24BrN 407.1117; Found 407.1115.

m/z [M + H] Calcd for C H N 329.2012; Found 329.2019.

2-Benzyl-1H-benzo[d]imidazole (4a). Prepared according to the

general procedure and puriﬁed by column chromatography on silica

gel and eluted with petroleum ether/ethyl acetate (5:1) to aﬀord a

(

2S,3R)-(2S,3R)-2-(3-Fluorobenzyl)-3-(3-ﬂuorophenyl)-6-methyl-

,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (3q). Prepared ac-

cording to the general procedure, but the reaction temperature was

white solid (8 mg, yield 38%, mp 243−244 °C). H NMR (400 MHz,

°C, and puriﬁed by column chromatography on silica gel and eluted

with petroleum ether/ethyl acetate (12:1) to aﬀord a yellow oil (12

mg, yield 33%), with er 86.5:13.5 (HPLC, Daicel Chiralcel AD-H

(DMSO-d ) δ 12.29 (s, 1H), 7.48 (s, 2H), 7.33 (d, J = 6.4 Hz, 4H),

7.27−7.21 (m, 1H), 7.13 (dd, J = 5.9, 3.1 Hz, 2H), 4.18 (s, 2H).

C{ H} NMR (101 MHz, (DMSO-d ) δ 154.0, 138.1, 129.2, 128.9,

116

J. Org. Chem. 2021, 86, 5110−5119

The Journal of Organic Chemistry

https://pubs.acs.org/10.1021/acs.joc.0c03064

Article

27.0, 121.7, 35.4. HRMS (ESI-TOF) m/z [M + H]⁺Calcd for

C H N 209.1073; Found 209.1075.

Large-Scale Synthesis of 3a. To a tube were added a solution of

o-DPA (1.0 mmol, 1.0 equiv), 4 Å MS (250 mg), acid catalyst 5f (37

mg, 50 μmol, 0.05 equiv), and 5 mL of mixed solvent

Notes

The authors declare no competing ﬁnancial interest.

(

CH CN:CHCl₃= 1:1); the tube was sealed with a septum,

ACKNOWLEDGMENTS

evacuated, and backﬁlled with nitrogen three times. Next, phenyl-

acetaldehyde (1.5 mmol, 1.5 equiv) was dissolved in 5 mL of mixed

solvent (CH CN:CHCl = 1:1), which was added into the above

■

This work was supported ﬁnancially by the Youth Innovation

Promotion Association CAS (2018402) and the West Light

Foundation of the Chinese Academy of Sciences (25E0C304).

solution by syringe under a nitrogen atmosphere, and it was stirred at

5 °C overnight, Next, the reaction mixture was concentrated. The

desired product was isolated by column chromatography on silica gel

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ASSOCIATED CONTENT

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■

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AUTHOR INFORMATION

■

Corresponding Authors

Guang-xun Li − Natural Products Research Center, Chengdu

Institution of Biology, Chinese Academy of Science, Chengdu,

Sichuan 610041, China; orcid.org/0000-0001-6782-

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066 ; Email: Ligx@cib.ac.cn

Zhuo Tang − Natural Products Research Center, Chengdu

Institution of Biology, Chinese Academy of Science, Chengdu,

Sichuan 610041, China; orcid.org/0000-0002-5845-

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Institution of Biology, Chinese Academy of Science, Chengdu,

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Ding-qiang Fu − Natural Products Research Center, Chengdu

Institution of Biology, Chinese Academy of Science, Chengdu,

Sichuan 610041, China

Xiao-kang Nie − Natural Products Research Center, Chengdu

Institution of Biology, Chinese Academy of Science, Chengdu,

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Xin Cui − Natural Products Research Center, Chengdu

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