Modular and Stereoselective Approach to Highly Substituted Indole/Pyrrole-Fused Diazepanones

Article abstract of DOI:10.1021/acs.joc.1c00303

A one-pot synthetic method for indole/pyrrole-fused 1,4-diazepanone scaffolds has been developed. This method involves a sequential amide coupling/intramolecular aza-Michael addition of 1H-indole/pyrrole-2-carboxylic acids with Morita-Baylis-Hillman-deriv

Full text of DOI:10.1021/acs.joc.1c00303

pubs.acs.org/joc
Article
Modular and Stereoselective Approach to Highly Substituted
Indole/Pyrrole-Fused Diazepanones
Shutao Wang, Siyu Wang, Shaoli Song, Qiansong Gao, Chunxi Wen, Zhuoqi Zhang, Lianyou Zheng,*
and Jinbao Xiang*
Cite This: J. Org. Chem. 2021, 86, 6458−6466
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ABSTRACT: A one-pot synthetic method for indole/pyrrole-fused 1,4-diazepanone scaffolds has been developed. This method
involves a sequential amide coupling/intramolecular aza-Michael addition of 1H-indole/pyrrole-2-carboxylic acids with Morita−
Baylis−Hillman-derived allylamines. The readily available starting materials, good stereoselectivity, and gram-scale synthesis make
this method valuable for the construction of highly substituted fused heterocycles containing the 1,4-diazepanone moiety.
one-pot synthetic method for pyrrole-fused 1,4-diazepanones
based on the condensation of N-Boc amino acids with furans
containing aminoalkyl groups.8 Recently, Xiao’s group
developed an N-alkylation-initiated redox-neutral [5+2]
annulation of 3-alkylindoles with o-aminobenzaldehydes via a
cascade N-alkylation/dehydration/[1,5]-hydride transfer/Frie-
del−Crafts alkylation sequence to access indole-1,2-fused 1,4-
benzodiazepines.9 Despite this progress, more efficient and
straightforward synthetic strategies for such heterocyclic
scaffolds are still highly desirable.
Aza-Michael addition is one of the most important tools for
the construction of the C−N bond.10 In particular, domino or
cascade reactions involving intramolecular aza-Michael addi-
tions are well developed and have been applied to the
construction of various N-containing heterocycles.11 The
chemo- and stereoselective intermolecular aza-Michael addi-
tions of indoles or pyrroles to electron-deficient alkenes have
been reported by several groups.12 Compared with inter-
molecular reactions, intramolecular aza-Michael addition of
indoles or pyrroles seems more valuable for the construction of
fused polycyclic scaffolds. However, only a few examples of
such reactions have been reported so far. Bandini13 and You14
reported base- or acid-catalyzed intramolecular aza-Michael
INTRODUCTION
■
1,4-Diazepanones make up a highly attractive class of
privileged scaffolds in drug discovery and constitute the core
structures of many significant pharmaceuticals, including
benzodiazepine anxiolytics (e.g., Diazepam, Mexazolam,
etc.),1 the non-nucleoside reverse transcriptase inhibitor
Nevirapine,2 and benzodiazepine receptor antagonist Fluma-
zenil.3 Consequently, a diversity of polycyclic fused hetero-
cycles containing a 1,4-diazepanone moiety have been
developed.4 In particular, indole/pyrrole-1,2-fused 1,4-diazepi-
nones and their derivatives, which contain privileged indole/
pyrrole and 1,4-diazepinone skeletons, have attracted particular
attention due to their potential bioactivities. For instance, they
have been reported to exhibit activities as myeloid cell
leukemia-1 (Mcl-1) inhibitors,5 ribosomal S6 kinase (RSK)
inhibitors,6 and non-nucleoside HIV-1 reverse transcriptase
inhibitors7 (Figure 1).
Despite their bioactive significance, only a few synthetic
methods have been developed to access these scaffolds over
the past several decades. In 2018, Uchuskin’s group reported a
Received: February 7, 2021
Published: April 28, 2021
Figure 1. Selected bioactive compounds containing indole/pyrrole-
fused 1,4-diazepinone frameworks.
https://doi.org/10.1021/acs.joc.1c00303
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additions of indoles or pyrroles with tethered α,β-unsaturated
esters or ketones as Michael acceptors, and these reactions
proceeded through a 5- or 6-exo-trig cyclization to give five- or
six-membered rings (Scheme 1a). 7-endo-trig cyclization with a
Supporting Information for details). After tedious attempts, we
found that both K2CO3 and K3PO4 were suitable bases for this
reaction. Using 0.6 equiv of K2CO3 or K3PO4 and DMSO as
the solvent, the cyclization reaction proceeded smoothly at
room temperature to afford the desired product 4a as the
single isomer in 80% (10 h, with K2CO3) or 91% (3 h, with
K3PO4) yield, respectively. Other bases such as Cs2CO3,
Na2CO3, and DBU were not efficient for this reaction. It was
also found that the solvents had a strong influence on the
reaction. The nonprotonic polar solvent DMSO was key to the
successful reaction. Other solvents such as THF, CH3CN, and
CH2Cl2 failed to afford any products, which was in agreement
with the reported results from Bandini’s group.13 As a result,
K2CO3 and K3PO4 were identified as the suitable bases while
DMSO was identified as the key solvent to promote this
cyclization reaction.
Scheme 1. Synthesis of Indole/Pyrrole-Fused Heterocycles
The structure of compound 4a was clearly characterized by
NMR spectra, HRMS spectra, and single-crystal X-ray analysis.
Furthermore, X-ray analysis of 4a showed that the phenyl and
ester substituent are in a trans configuration, which exhibited
the high stereoselectivity of this intramolecular cyclization
reaction (see the Supporting Information).
To simplify the experimental operation and make our
strategy more efficient and practical, a one-pot procedure for
the desired products 4 was carried out on the basis of the
aforementioned conditions. Thus, the coupling of 1H-indole-2-
carboxylic acid 1a with allylamine 2a was performed in DMSO
following the conditions in Scheme 2. Compound 1a was
completely converted into intermediate 3a after being stirred at
room temperature for 2.5 h (monitored by TLC). Then base
was added into the reaction mixture under a nitrogen
atmosphere without any other treatment. However, no desired
product 4a formed when the reaction was performed for 24 h
at room temperature with 0.6 equiv of K2CO3, which was
different from the result in the stepwise reaction (Table 1,
entry 1).
nitrogen as the nucleophile to form seven-membered N-
containing heterocycles is still underdeveloped.15 To the best
of our knowledge, there have been no reports to date about the
intramolecular aza-Michael additions of indoles/pyrroles
through a 7-endo-trig cyclization to form fused seven-
membered N-containing polycycles.
Morita−Baylis−Hillmann (MBH) adducts have been
extensively used as synthons to construct highly functionalized
carbo- or heterocycles.16 Of these MBH adduct derivatives,
allylamines 2, which can be easily prepared from cheap and
readily available starting materials such as aldehydes, activated
alkenes, primary amines, etc., are very attractive as versatile
synthons due to their diversified functional groups. In our
previous work, we have developed an intramolecular iminium
ion cyclization reaction of MBH-derived allylamines with
aldehydes for the facile synthesis of dihydropyrroles.17 As a
continuation of this work, here we will report a simple one-pot
strategy for indole/pyrrole-1,2-fused 1,4-diazepanone scaffolds
via a sequential amide coupling/intramolecular aza-Michael
addition starting from 1H-indole/pyrrole-2-carboxylic acids 1
and MBH allylamines 2 (Scheme 1b). We envisioned that this
strategy would provide a modular and straightforward
approach for highly substituted indole/pyrrole-fused poly-
cycles.
Therefore, the base amount as well as reaction temperature
was further examined. The results showed that an increased
temperature and a higher loading of base could promote this
a
Table 1. Optimization of the One-Pot Reaction Conditions
RESULTS AND DISCUSSION
■
First, we investigated the stepwise synthesis conditions for the
construction of indole-fused 1,4-diazepanone derivatives. The
coupling of 1H-indole-2-carboxylic acid 1a and allylamine 2a
(E-configured) under the conventional conditions (HOBt,
EDCI, and Et3N in DMF at room temperature) afforded amide
intermediate 3a in 98% yield (Scheme 2). Furthermore, the
intramolecular cyclization of 3a was explored and various
organic or inorganic bases and solvents were screened (see the
b
entry
base (equiv)
t (°C)
time (h)
yield (%)
c
1
2
3
4
5
6
7
8
9
K2CO3 (0.6)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (4.0)
K3PO4 (3.0)
Cs2CO3 (3.0)
rt
rt
24
24
20
7.5
3
17
3
4
0
0
c
80
80
80
50
80
80
80
trace
75
83
trace
75
Scheme 2. Stepwise Investigation of the Synthesis of Indole-
Fused 1,4-Diazepanone 4a
c
0
3
54
a
Reaction conditions: (1) 1a (0.2 mmol), 2a (0.24 mmol), HOBt
(0.24 mmol), EDCI (0.24 mmol), and Et3N (0.3 mmol) in anhydrous
DMSO (2 mL) at room temperature for 3 h; (2) base added and the
mixture stirred at the indicated temperature under a N2 atmosphere.
b
c
Isolated yields. Only intermediate 3a could be observed by TLC.
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cyclization. The reaction performed at 80 °C with 3.0 equiv of
K2CO3 gave the best result, and product 4a was obtained in
83% yield (Table 1, entry 5). It was also found that K3PO4 was
not efficient in the one-pot reactions while Cs2CO3 led to a
lower yield (Table 1, entries 8 and 9). With the optimized
conditions (Table 1, entry 5) in hand, we next investigated the
general applicability of the one-pot amide coupling/intra-
molecular aza-Michael cyclization reaction. At first, the
substrate scope of allylamines 2 was explored (Scheme 3). A
led to better yields compared with those for electron-
withdrawing substituents (e.g., 4f and 4i vs 4g, 4h, and 4j).
Additionally, it was also found that the substituents could affect
the stereoselectivity of products. The electron-donating groups
gave the trans single isomer (e.g., 4f and 4i), while strong
electron-withdrawing groups such as NO2 or ester led to a
mixture of trans and cis isomers (e.g., 4h/4h′ and 4j/4j′).
Allylamine 2 bearing a 2-naphthyl group at R1 was also suitable
for the reaction, producing trans isomer 4k in 42% yield. For
Z-configured allylamine 2l (EWG = -CN), the desired cyclized
products were obtained in 86% total yield as a mixture of anti
and syn diastereoisomers (4l and 4l′, 1:1 ratio), which could be
separated by column chromatography.
a,b
Scheme 3. Substrate Scope of MBH-Derived Allylamines
In addition to aromatic groups, aliphatic aldehyde-derived
allylamines 2 (R1 = H, alkyl, or cycloalkyl) were also suitable
substrates for this one-pot reaction, affording the desired
products in moderate to good yields (e.g., 4m−4q). It was
interesting that in these reactions only trans isomers were
obtained as the single products despite the substrates with a Z-
and E-configured mixture. We envision that it is probably
because the unstable cis products formed in the reactions can
convert in situ into the more stable trans isomers under basic
conditions.
Then the substrate scope of indole-2-carboxylic acid
derivatives was explored to undergo the cyclization reaction
with allylamine 2a (Scheme 4). The electron-donating MeO
a,b
Scheme 4. Substrate Scope of Indole 2-Carboxylic Acids
a
All reactions were carried out with 1a (0.2 mmol) and 2 (0.24
mmol) in anhydrous DMSO (2 mL) under the optimized conditions.
The E configuration of allylamines 2 was used unless indicated
b
c
otherwise. Isolated yields. trans/cis ratios based on isolated
products. Z-configured allylamine 2l was used. A mixture of E-
and Z-configured allylamine with different ratios was used.
d
e
variety of allylamines 2 bearing diverse substituents at R1 and
R2 could precede the cyclization reactions with 1H-indole-2-
carboxylic acid 1a, giving the desired indole-fused 1,4-
diazepanones 4 in moderate to good yields with excellent
trans stereoselectivities in most cases. Alkyl substituents on the
nitrogen atom at R2, including Bu, 2-methoxylethlyl, i-Pr, and
Bn, were compatible with the reaction, affording the
corresponding products 4b−4e, respectively, in 35−64% yields
with exclusive trans stereoselectivity. Notably, the reaction
yields were significantly affected by the steric hindrance of the
substituents on allylamine 2 at R2. For example, bulky
substituents such as i-Pr or Bn groups gave lower yields of
products compared with less hindered Me, Bu, or 2-
methoxyethyl groups. The low yields were presumably ascribed
to the steric hindrance that decreased the reactivity in the first
amide coupling step. In fact, allylamines with a more hindered
t-Bu or inert Ph group at R2 failed to give any products under
the current conditions (the results are not listed).
a
All reactions were carried out with 1 (0.2 mmol) and 2a (0.24
mmol) in anhydrous DMSO (2 mL) under the optimized conditions.
b
Isolated yields.
group at the C5 or C6 position on 1H-indole-2-carboxylic
acids did not influence the reaction, and desired products 4r
and 4s could be obtained in good yields (74% and 78%,
respectively). The electron-withdrawing NO2 group at the C5
position was also compatible with this reaction but with a
slightly decreased yield (4t, 55%). In addition, we further
expanded the substrate scope by replacing the indole unit with
pyrrole-2-carboxylic acid, and desired cyclized product 4u
could also be obtained, although in a lower yield. Likewise, all
of the indicated products in Scheme 4 were determined to be
in the trans configuration by comparison of the NMR spectra
data with those of 4a, which indicated this reaction had
excellent stereoselectivities.
Then the electronic effect of the substituents on the phenyl
ring at R1 was studied. The results show that both electron-
donating and -withdrawing substituents were compatible with
the reaction. Electron-donating substituents on the phenyl ring
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removed, dried using anhydrous Na2SO4, filtered, and concentrated to
yield the Baylis−Hillman acetate, which was directly used in the next
step. In step 3, to the solution of the crude Baylis−Hillman acrylate
(2.5 mmol, 1.0 equiv) in THF (3 mL) was added dropwise over 15
min a stirred solution of amine (5.0 mmol, 2.0 equiv) in THF (12
mL) at 0 °C, and then the mixture was warmed to room temperature
and stirred for 30 min. The volatiles was removed in vacuo, and
saturated aqueous NaHCO3 (10 mL) was added. The mixture was
extracted with EtOAc (3 × 20 mL). The combined EtOAc layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Purification
by flash column chromatography on silica gel afforded the desired
products.
To demonstrate the synthetic practicability of this current
methodology, a gram-scale reaction of indole-2-carboxylic acid
1a and allylamine 2a was carried out under the optimized
conditions, and desired product 4a was obtained in 76% yield
(Scheme 5). This indicated that the one-pot reaction was easy
to scale up to give the annulated products without significant
decreases in the yields.
Scheme 5. Gram-Scale Synthesis of 4a
The alkene configurations of the allylamines described above were
determined by comparing the shift value of the β-vinylic proton in 1H
NMR spectra with reported values. Among them, allylamines 2b−2k
(R1 = aryl groups, and EWG = -CO2Me) deriving from aromatic
aldehydes were E-configured.18 2l (R1 = Ph, and EWG = -CN) was Z-
configured.19 2n−2q (R1 = alkyl or cycloalkyl groups) derived from
aliphatic aldehydes were inseparable mixtures of Z- and E-configured
CONCLUSIONS
■
1
isomers, and the ratios were determined on the basis of H NMR
In conclusion, we have developed a one-pot method to
construct indole/pyrrole-fused 1,4-diazepanone scaffolds. This
method involves a sequential amide coupling/intramolecular
aza-Michael reaction starting from 1H-indole/pyrrole-2-
carboxylic acids and MBH-derived allylamines, which can be
accessed via aldehydes, activated alkenes, and primary amines.
Readily available and cheap starting materials, good stereo-
selectivity, and gram-scale synthesis make this method useful
for the preparation of highly substituted fused 1,4-diazepanone
derivatives.
spectra.20
Spectral Data. Methyl (E)-2-{[(2-Methoxyethyl)amino]methyl}-
3-phenyl-acrylate (2c). This compound was prepared via the general
procedure as a pale yellow oil (418 mg, 67% total yield), eluting with
1
petroleum ether/ethyl acetate (5:1): H NMR (300 MHz, CDCl3) δ
7.81 (s, 1H), 7.52−7.43 (m, 2H), 7.39−7.30 (m, 3H), 3.82 (s, 3H),
3.62 (s, 2H), 3.48 (t, J = 5.7 Hz, 2H), 3.34 (s, 3H), 2.79 (t, J = 5.4 Hz,
2H), 2.01 (br.s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.1,
141.5, 134.8, 130.5, 129.3, 128.5, 128.2, 71.6, 58.4, 51.7, 48.5, 45.4;
HRMS (ESI-TOF) calcd for C14H20NO3+ [M + H]+ 250.1438, found
250.1439.
Methyl (E)-4-{2-[(Butylamino)methyl]-3-methoxy-3-oxoprop-1-
en-1-yl}benzoate (2j). This compound was prepared via the general
procedure as a pale yellow oil (344 mg, 45% total yield), eluting with
EXPERIMENTAL SECTION
■
General Experimental Information. Allylamines 2a, 2b, and
2d−2i as known compounds were prepared according to the
procedure reported by our group.17 Anhydrous DMSO was applied,
and other solvents and reagents were used as supplied by commercial
sources without further purification. Flash column chromatography
was carried out on silica gel G (200−300 mesh). All reactions were
monitored by TLC, which was performed on precoated aluminum
sheets of silica gel 60 (F254). Melting points were measured using a
SGW X-4 apparatus and were uncorrected. NMR spectra were
1
petroleum ether/ethyl acetate (8:1): H NMR (300 MHz, CDCl3) δ
8.06 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H), 3.93
(s, 3H), 3.84 (s, 3H), 3.54 (s, 2H), 2.60 (t, J = 6.9 Hz, 2H), 1.66
(br.s, 1H), 1.51−1.41 (m, 2H), 1.40−1.25 (m, 2H), 0.91 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.2, 166.6, 140.4,
140.3, 139.7, 132.7, 130.1, 129.6, 129.4, 52.1, 49.2, 45.9, 32.0, 20.4,
+
13.9; HRMS (ESI-TOF) calcd for C17H24NO4 [M + H]+ 306.1700,
found 306.1691.
1
recorded on a Varian spectrometer (300 MHz for H NMR and 75
Methyl (E)-2-[(Butylamino)methyl]-3-(naphthalen-2-yl)acrylate
(2k). This compound was prepared via the general procedure as a
pale yellow oil (394 mg, 53% total yield), eluting with petroleum
MHz for 13C{1H} NMR). The chemical shifts are reported in parts
per million (δ) with TMS as the internal standard and CDCl3 or
DMSO-d6 as the solvent. Multiplicities are indicated as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doubled
doublet; br.s, broad singlet. Coupling constants (J values) where
noted are in hertz. The HRMS spectra were recorded using a
quadrupole time-of-flight mass spectrometer and ESI positive
ionization source.
1
ether/ethyl acetate (10:1): H NMR (300 MHz, CDCl3) δ 8.02 (s,
1H), 7.96 (s, 1H), 7.86−7.81 (m, 3H), 7.59 (dd, J = 8.5, 1.2 Hz, 1H),
7.51−7.48 (m, 2H), 3.85 (s, 3H), 3.65 (s, 2H), 2.66 (t, J = 7.0 Hz,
2H), 1.76 (br.s, 1H), 1.55−1.44 (m, 2H), 1.42−1.32 (m, 2H), 0.91 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.6, 141.8,
133.2, 133.1, 132.7, 131.1, 129.5, 128.4, 128.0, 127.6, 126.9, 126.8,
126.4, 52.0, 49.4, 46.1, 32.1, 20.5, 14.0; HRMS (ESI-TOF) calcd for
General Experimental Procedure for the Synthesis of
Allylamines (2c and 2j−2q). The allylamines were prepared by
three-step continuous reactions via a modified reported procedure17
as follows. In step 1, a mixture of the aldehyde (10.0 mmol, 1.0
equiv), methyl acrylate or acrylonitrile (10.5 mmol, 1.05 equiv), and
DABCO (1.12 g, 10.0 mmol, 1.0 equiv) without solvent was stirred at
0 °C to room temperature for 7−14 days. After the reaction had
reached completion, the mixture was diluted with diethyl ether (25
mL) and then washed with a 0.5 M HCl solution (3 × 30 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to yield the Baylis−Hillman
alcohol without further purification. In step 2, to a solution of Et3N
(695 μL, 5.0 mmol, 1.0 equiv), Ac2O (473 μL, 5.0 mmol, 1.0 equiv),
and 4-dimethylaminopyridine (DMAP) (61 mg, 0.5 mmol, 0.1 equiv)
in 25 mL of dichloromethane was added the crude Baylis−Hillman
alcohol (5.0 mmol, 1.0 equiv) prepared as described above at 0 °C,
and the resulting mixture was stirred for 30 min. After the reaction
had reached completion, the mixture was washed with 20 mL of an
aqueous saturated solution of NaHCO3. The organic phase was
+
C19H24NO2 [M + H]+ 298.1802, found 298.1805.
(Z)-2-[(Butylamino)methyl]-3-phenylacrylonitrile (2l).19 This
compound was prepared via the general procedure as a pale yellow
oil (391 mg, 73% total yield), eluting with petroleum ether/ethyl
1
acetate (10:1): H NMR (300 MHz, CDCl3) δ 7.78−7.74 (m, 2H),
7.47−7.34 (m, 3H), 7.10 (s, 1H), 3.57 (d, J = 1.4 Hz, 2H), 2.64 (t, J =
6.9 Hz, 2H), 1.61 (br.s, 1H), 1.55−1.42 (m, 2H), 1.43−1.22 (m, 2H),
0.91 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 143.7,
133.3, 130.2, 128.8, 128.7, 118.4, 110.6, 53.7, 48.1, 32.1, 20.3, 13.9;
+
HRMS (ESI-TOF) calcd for C14H19N2 [M + H]+ 215.1543, found
215.1533.
Methyl 2-[(Butylamino)methyl]acrylate (2m). This compound
was prepared via the general procedure as a pale yellow oil (86 mg,
20% total yield), eluting with petroleum ether/ethyl acetate (1:1). It
was found to be unstable and was used for the next reaction
immediately after silica gel chromatography purification. The NMR
spectra were not measured.
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Methyl-2-[(butylamino)methyl]but-2-enoate (2n). An inseparable
mixture of E- and Z-configured isomers (2:1 E:Z based on H NMR
2a (243 mg, 1.2 mmol, 1.2 equiv) and triethylamine (208 μL, 1.5
mmol, 1.5 equiv) were then added immediately. After the addition,
the reaction mixture was stirred for an additional 3 h. The reaction
mixture was diluted with EtOAc (30 mL), washed successively with a
1 N HCl solution, saturated NaHCO3, and brine, and dried over
anhydrous Na2SO4. After the solvent had been removed in vacuo, the
crude product was purified by column chromatography on silica gel
(2:1 petroleum ether/ethyl acetate) to provide amide intermediate 3a
(0.314 g, 98% yield) as a white solid: mp 115−116 °C; 1H NMR (300
MHz, CDCl3) δ 9.62 (br.s, 1H), 7.98 (s, 1H), 7.62 (d, J = 8.0 Hz,
1H), 7.44−7.30 (m, 7H), 7.12 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H), 4.86
(s, 2H), 3.81 (s, 3H), 3.11 (br.s, 3H); 13C{1H} NMR (75 MHz,
DMSO-d6) δ 167.2, 163.1, 142.3, 135.8, 134.1, 130.2, 129.4, 129.1,
128.6, 128.0, 126.9, 123.2, 121.4, 119.6, 112.0, 104.5, 52.1, 52.1, 45.3;
HRMS (ESI-TOF) calcd for C21H21N2O3+ [M + H]+ 349.1547, found
349.1551.
Synthesis of Indole-Fused 1,4-Diazepanone (4a) in a
Stepwise Manner. To a solution of amide intermediate 3a (70
mg, 0.2 mmol, 1.0 equiv) in 2 mL of DMSO was added K2CO3 (17
mg, 0.12 mmol, 0.6 equiv). The reaction mixture was stirred at room
temperature for 10 h under a nitrogen atmosphere. After the reaction
had reached completion, the resulting solution was diluted with
EtOAc (20 mL), washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified
by silica gel column chromatography and eluted with petroleum
ether/ethyl acetate (2:1) to furnish the desired product 4a (56 mg,
80% yield).
1
spectra) was obtained via the general procedure as a pale yellow oil
(264 mg, 57% total yield), eluting with petroleum ether/ethyl acetate
1
(2:1). NMR data for the E isomer: H NMR (300 MHz, CDCl3) δ
7.00 (q, J = 7.2 Hz, 1H), 3.74 (s, 3H), 3.46 (s, 2H), 2.63−2.47 (m,
2H, overlapped), 1.88 (d, J = 7.2 Hz, 3H), 1.72 (br.s, 1H), 1.54−1.19
(m, 4H, overlapped), 0.91 (t, J = 7.2 Hz, 3H, overlapped); 13C{1H}
NMR (75 MHz, CDCl3) δ 167.9, 140.1, 131.0, 51.6, 48.6, 44.5, 32.1,
20.4, 14.3, 13.9. Selected NMR data for the Z isomer: 1H NMR (300
MHz, CDCl3) δ 6.21 (q, J = 7.3 Hz, 0.49H), 4.35 (t, J = 7.0 Hz,
0.36H), 3.78 (s, 1.5H), 3.46 (s, 2H), 3.41−3.34 (m, 1H), 2.02 (d, J =
7.2 Hz, 1.5H); 13C{1H} NMR (75 MHz, CDCl3) δ 139.4, 130.7, 53.1,
51.1, 48.4, 15.6; HRMS (ESI-TOF) calcd for C10H20NO2+ [M + H]+
186.1489, found 186.1491.
Methyl-2-[(butylamino)methyl]hex-2-enoate (2o). An insepara-
1
ble mixture of E- and Z-configured isomers (5:3 E:Z based on H
NMR spectra) was obtained via the general procedure as a pale yellow
oil (174 mg, 35% total yield), eluting with petroleum ether/ethyl
1
acetate (3:1). NMR data for the E isomer: H NMR (300 MHz,
CDCl3) δ 6.88 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.45 (s, 2H), 2.54 (t,
J = 6.9 Hz, 2H, overlapped), 2.32−2.22 (m, 2H), 1.72 (br.s, 1H,
overlapped), 1.52−1.39 (m, 2H), 1.38−1.26 (m, 2H, overlapped),
1.07 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H, overlapped); 13C{1H}
NMR (75 MHz, CDCl3) δ 168.1, 146.8, 129.4, 51.6, 48.6, 44.8, 32.1,
21.9, 20.4, 13.9, 13.3. Selected NMR data for the Z isomer: 1H NMR
(300 MHz, CDCl3) δ 6.07 (t, J = 7.4 Hz, 1H), 3.76 (s, 3H), 3.38 (m,
1H), 2.55 (t, J = 7.2 Hz, 2H, overlapped), 2.53−2.44 (m, 2H,
overlapped), 1.72 (br.s, 1H), 1.52−1.39 (m, 2H), 1.38−1.26 (m, 2H,
overlapped), 1.04 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H,
overlapped); 13C{1H} NMR (75 MHz, CDCl3) δ 129.2, 53.1, 51.2,
48.4, 32.1, 22.9, 13.8; HRMS (ESI-TOF) calcd for C11H22NO2+ [M +
H]+ 200.1645, found 200.1654.
When K3PO4 (0.6 equiv) was used instead of K2CO3, the reaction
reached completion in 3 h, and a 91% yield of product 4a was
obtained.
General Procedure for the One-Pot Amide Coupling/
Intramolecular Aza-Michael Addition for the Synthesis of
Compounds 4. A nitrogen-flushed Schlenk flask, equipped with a
magnetic stirring bar and a rubber septum, was charged with 1H-
indole/pyrrole-2-carboxylic acid 1 (0.2 mmol, 1.0 equiv), HOBt (32
mg, 0.24 mmol, 1.2 equiv), and EDCI (46 mg, 0.24 mmol, 1.2 equiv)
in dried DMSO (2 mL). After the mixture had been stirred at room
temperature for 25 min, the prepared MBH-derived allylamine 2
(0.24 mmol, 1.2 equiv) and triethylamine (42 μL, 0.3 mmol, 1.5
equiv) were added immediately to the mixture. After the addition, the
reaction mixture was stirred for an additional 3 h to form the amide
intermediate. Under a nitrogen atmosphere, K2CO3 (83 mg, 0.6
mmol, 3.0 equiv) was added directly to the reaction mixture. The
mixture was heated in an oil bath to 80 °C and reacted until amide
intermediate 3 had been completely consumed as judged by TLC.
After completion, the resulting solution was diluted with EtOAc (20
mL), washed with water and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by silica gel
column chromatography, and elution with petroleum ether/ethyl
acetate or petroleum ether/diethyl ether furnished the desired
product 4.
( )-trans-Methyl 2-Methyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-
1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4a). This compound
was prepared via the general procedure as a white solid (58 mg, 83%
yield), eluting with petroleum ether/ethyl acetate (2:1): mp 188−189
°C; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 1H), 7.53 (d,
J = 8.4 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.27−7.16 (m, 5H), 6.79 (d,
J = 7.8 Hz, 2H), 6.68 (s, 1H), 4.07−4.01 (m, 1H), 3.94−3.85 (m,
1H), 3.78 (s, 3H), 3.62 (dd, J = 14.7, 5.0 Hz, 1H), 2.92 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 171.7, 163.8, 140.6, 138.3, 133.6,
Methyl-2-[(butylamino)methyl]-3-cyclohexyl-acrylate (2p). An
inseparable mixture of E- and Z-configured isomers (1:1 E:Z based
on 1H NMR spectra) was prepared via the general procedure as a pale
yellow oil (133 mg, 25% total yield), eluting with petroleum ether/
ethyl acetate (5:1). NMR data for the E isomer: 1H NMR (300 MHz,
CDCl3) δ 6.71 (d, J = 10.1 Hz, 1H), 3.74 (s, 3H), 3.45 (s, 2H), 2.57−
2.51 (t, J = 6.9 Hz, 3H, overlapped), 1.81−1.57 (m, about 7H,
overlapped), 1.51−1.02 (m, about 8H, overlapped), 0.90 (t, J = 7.2
Hz, 3H, overlapped). Selected NMR data for the Z isomer: 1H NMR
(300 MHz, CDCl3) δ 5.87 (d, J = 9.7 Hz, 1H), 3.75 (d, J = 4.2 Hz,
3H), 3.37 (d, J = 1.1 Hz, 2H). NMR data for the isomer mixture:
13C{1H} NMR (75 MHz, CDCl3) δ 168.3, 167.9, 150.1, 149.8, 127.9,
127.5, 53.0, 51.5, 51.1, 48.3, 48.0, 44.9, 38.0, 37.5, 32.6, 32.2, 32.0,
31.9, 25.8, 25.6, 25.5, 25.3, 20.3, 13.8; HRMS (ESI-TOF) calcd for
+
C15H28NO2 [M + H]+ 254.2115, found 254.2109.
Methyl-2-[(butylamino)methyl]-3-cyclopropyl-acrylate (2q). An
inseparable mixture of E- and Z-configured isomers (4:3 E:Z based on
1H NMR spectra) was prepared via the general procedure as a pale
yellow oil (264 mg, 50% total yield), eluting with petroleum ether/
ethyl acetate (3:1). NMR data for the E isomer: 1H NMR (300 MHz,
CDCl3) δ 6.24 (d, J = 10.8 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 2H), 2.60
(t, J = 6.9 Hz, 2H), 1.80 (br.s, 1H, overlapped), 1.80−1.69 (m, 1H,
overlapped), 1.53−1.32 (m, 4H, overlapped), 1.02−0.88 (m, 5H,
overlapped), 0.67−0.62 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ
167.9, 150.6, 127.5, 51.5, 48.6, 45.2, 32.1, 20.5, 13.9, 11.6, 8.8.
Selected NMR data for the Z isomer: 1H NMR (300 MHz, CDCl3) δ
5.39 (d, J = 10.7 Hz, 1H), 3.78 (s, 3H), 3.36 (s, 2H), 2.54 (t, J = 6.9
Hz, 2H), 1.80−1.69 (m, 1H, overlapped), 1.53−1.32 (m, 4H,
overlapped), 1.02−0.88 (m, 5H, overlapped), 0.53−0.49 (m, 2H);
13C{1H} NMR (75 MHz, CDCl3) δ 151.0, 126.9, 53.0, 51.2, 48.4,
128.8, 127.5, 126.8, 124.8, 124.4, 122.2, 120.8, 110.1, 109.2, 56.8,
+
52.7, 49.9, 49.5, 34.6; HRMS (ESI-TOF) calcd for C21H21N2O3 [M
+ H]+ 349.1547, found 349.1541.
+
32.1, 20.4, 13.9, 12.1, 8.7; HRMS (ESI-TOF) calcd for C12H22NO2
( )-trans-Methyl 2-Butyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-
[1,4]diazepino[1,2-a]indole-4-carboxylate (4b). This compound was
prepared via the general procedure as a white solid (49 mg, 63%
yield), eluting with petroleum ether/ethyl acetate (10:1): mp 105−
106 °C; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 1H), 7.51
(d, J = 8.4 Hz, 1H), 7.39−7.10 (m, 6H), 6.81 (d, J = 7.4 Hz, 2H),
6.69 (s, 1H), 3.97−3.87 (m, 1H), 3.86−3.77 (m, 1H), 3.79 (s, 3H),
[M + H]+ 212.1645, found 212.1647.
Preparation of Indole Amide Intermediate 3a. To a solution
of 1H-indole-2-carboxylic acid (161 mg, 1.0 mmol, 1.0 equiv) in DMF
(10 mL) were added HOBt (162 mg, 1.2 mmol, 1.2 equiv) and EDCI
(230 mg, 1.2 mmol, 1.2 equiv). After the mixture had been stirred at
room temperature for 25 min, the prepared MBH-derived allylamine
6462
https://doi.org/10.1021/acs.joc.1c00303
J. Org. Chem. 2021, 86, 6458−6466

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3.64 (dd, J = 14.5, 4.9 Hz, 1H), 3.41−3.30 (m, 1H), 3.26−3.17 (m,
1H), 1.55−1.30 (m, 2H), 1.25−1.05 (m, 2H), 0.84 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.8, 163.7, 140.9, 138.1,
134.0, 128.8, 127.4, 126.8, 124.9, 124.4, 122.1, 120.8, 110.1, 109.2,
56.7, 52.8, 51.6, 47.8, 47.3, 30.1, 20.0, 13.8; HRMS (ESI-TOF) calcd
56.2, 52.9, 51.6, 47.8, 47.4, 30.2, 20.0, 13.8; HRMS (ESI-TOF) calcd
+
for C24H26ClN2O3 [M + H]+ 425.1626, found 425.1619.
( )-trans-Methyl 2-Butyl-5-(3-nitrophenyl)-1-oxo-2,3,4,5-tetra-
hydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4h) and
( )-cis-Methyl 2-Butyl-5-(3-nitrophenyl)-1-oxo-2,3,4,5-tetrahydro-
1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4h′). They were
prepared via the general procedure and purified by flash column
chromatography (2:1 petroleum ether/diethyl ether). The total yield
was 40%. The more polar trans isomer, 4h, was obtained as a pale
yellow oil (28 mg, 32% yield), and the less polar cis isomer, 4h′, as a
pale yellow oil (7 mg, 8% yield).
+
for C24H27N2O3 [M + H]+ 391.2016, found 391.2016.
( )-trans-Methyl 2-(2-Methoxyethyl)-1-oxo-5-phenyl-2,3,4,5-tet-
rahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4c). This
compound was prepared via the general procedure as a pale yellow
oil (50 mg, 64% yield), eluting with petroleum ether/ethyl acetate
(2:1): 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.52
(d, J = 8.4 Hz, 1H), 7.37−7.14 (m, 6H), 6.82 (d, J = 8.1 Hz, 2H),
6.73 (s, 1H), 4.22−4.16 (m, 1H), 4.04−3.96 (m, 1H), 3.91−3.70 (m,
2H), 3.77 (s, 3H), 3.34−3.27 (m, 1H), 3.17 (s, 3H), 3.15−3.05 (m,
1H), 2.97−2.90 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 172.3,
164.0, 141.2, 138.1, 133.7, 128.7, 127.2, 126.7, 124.9, 124.4, 122.1,
120.8, 110.0, 108.9, 71.4, 58.6, 56.6, 52.6, 51.4, 49.7, 47.8; HRMS
1
Spectral data for trans isomer 4h: H NMR (300 MHz, CDCl3) δ
7.76 (dd, J = 8.2, 1.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.51−7.49
(m, 1H), 7.39−7.26 (m, 2H), 7.20−7.15 (m, 1H), 7.10 (t, J = 7.8 Hz,
1H), 6.95 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 6.30 (d, J = 1.9 Hz, 1H),
4.19−4.05 (m, 1H), 3.87 (s, 3H), 3.81−3.71 (m, 1H), 3.16−2.92 (m,
2H), 2.07 (dd, J = 14.5, 5.1 Hz, 1H), 1.71−1.54 (m, 2H), 1.41−1.30
(m, 2H), 0.96 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 170.8, 160.9, 147.5, 139.3, 134.6, 132.0, 131.9, 131.5, 128.9, 124.5,
123.9, 123.0, 121.4, 121.2, 109.7, 98.7, 70.9, 52.9, 50.0, 40.6, 29.8,
28.5, 19.9, 13.7; HRMS (ESI-TOF) calcd for C24H26N3O5+ [M + H]+
436.1867, found 436.1872.
+
(ESI-TOF) calcd for C23H25N2O4 [M + H]+ 393.1809, found
393.1812.
( )-trans-Methyl 2-Isopropyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-
1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4d). This compound
was prepared via the general procedure as a white solid (30 mg, 40%
yield), eluting with petroleum ether/ethyl acetate (10:1): mp 148−
149 °C; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 7.7 Hz, 1H), 7.51
(d, J = 8.3 Hz, 1H), 7.34−7.14 (m, 6H), 6.81 (d, J = 8.0 Hz, 2H),
6.72 (s, 1H), 4.57−4.43 (m, 1H), 3.87−3.78 (m, 1H), 3.81 (s, 3H),
3.76−3.69 (m, 1H), 3.61−3.52 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H),
0.92 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.9,
163.8, 141.1, 138.0, 134.2, 128.8, 127.3, 126.7, 124.8, 124.4, 122.1,
120.8, 110.0, 109.3, 56.6, 53.3, 52.8, 45.0, 41.7, 19.7, 19.6; HRMS
1
Spectral data for cis isomer 4h′: H NMR (300 MHz, CDCl3) δ
8.02 (dd, J = 8.1, 1.2 Hz, 1H), 7.92−7.90 (m, 1H), 7.77 (d, J = 8.0
Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.35−7.25 (m, 2H), 7.27−7.18 (m,
1H), 7.15 (dd, J = 8.3, 1.0 Hz, 1H), 6.97 (s, 1H), 6.26 (d, J = 1.5 Hz,
1H), 4.16−4.00 (m, 1H), 3.90 (s, 3H), 3.50−3.39 (m, 1H), 3.13−
2.99 (m, 1H), 2.77 (dd, J = 14.5, 9.0 Hz, 1H), 2.43 (dd, J = 14.5, 4.5
Hz, 1H), 1.82−1.60 (m, 2H), 1.48−1.31 (m, 2H), 0.97 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.2, 160.4, 148.2, 140.1,
135.0, 133.2, 132.2, 132.0, 129.4, 124.4, 123.8, 123.4, 121.8, 121.3,
110.6, 99.0, 72.1, 53.1, 48.6, 40.0, 29.9, 28.7, 20.0, 13.6; HRMS (ESI-
+
(ESI-TOF) calcd for C23H25N2O3 [M + H]+ 377.1860, found
+
TOF) calcd for C24H26N3O5 [M + H]+ 436.1867, found 436.1865.
377.1852.
( )-trans-Methyl 2-Benzyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-
1H-[1,4]diazepino-[1,2-a]indole-4-carboxylate (4e). This compound
was prepared via the general procedure as a white solid (30 mg, 35%
yield), eluting with petroleum ether/ethyl acetate (10:1): mp 185−
186 °C; 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 1H), 7.48
(d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.34−7.28 (m, 1H), 7.27−7.14 (m,
7H), 6.99 (dd, J = 7.7, 1.8 Hz, 2H), 6.75−6.71 (m, 2H), 6.67 (s, 1H),
4.66 (d, J = 14.6 Hz, 1H), 4.34 (d, J = 14.6 Hz, 1H), 3.82−3.72 (m,
1H), 3.71 (s, 3H), 3.67−3.54 (m, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 171.8, 164.0, 141.0, 138.2, 136.4, 133.6, 128.9, 128.7, 128.4,
127.6, 127.4, 126.8, 124.9, 124.6, 122.2, 121.0, 110.1, 109.7, 56.7,
( )-trans-Methyl 2-Butyl-5-(2-methoxyphenyl)-1-oxo-2,3,4,5-tet-
rahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4i). This
compound was prepared via the general procedure as a white solid
(42 mg, 50% yield), eluting with petroleum ether/ethyl acetate (8:1):
mp 133−134 °C; 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz,
1H), 7.49 (d, J = 8.4 Hz, 1H), 7.34−7.26 (m, 2H), 7.21−7.13 (m,
2H), 6.87−6.83 (m, 2H), 6.74 (t, J = 7.5 Hz, 1H), 6.51 (d, J = 7.7 Hz,
1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.70−3.60 (m, 1H), 3.58−3.45 (m,
2H), 3.40−3.26 (m, 1H), 1.59−1.42 (m, 1H), 1.40−1.26 (m, 2H),
1.21−1.06 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 172.3, 163.7, 155.3, 138.0, 134.7, 129.8, 128.8, 126.8,
125.3, 124.2, 121.9, 121.0, 120.7, 110.5, 110.3, 109.2, 55.3, 54.0, 52.5,
52.1, 48.4, 47.5, 30.0, 19.9, 13.8; HRMS (ESI-TOF) calcd for
+
52.7, 51.3, 50.3, 47.0; HRMS (ESI-TOF) calcd for C27H25N2O3 [M
+ H]+ 425.1860, found 425.1861.
+
C25H29N2O4 [M + H]+ 421.2122, found 421.2122.
( )-trans-Methyl 2-Butyl-5-(4-methoxyphenyl)-1-oxo-2,3,4,5-tet-
rahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4f). This
compound was prepared via the general procedure as a pale yellow
oil (54 mg, 64% yield), eluting with petroleum ether/ethyl acetate
(8:1): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 7.4 Hz, 1H), 7.51
(d, J = 8.4 Hz, 1H), 7.33−7.26 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H),
6.80−6.69 (m, 4H), 6.63 (s, 1H), 3.95−3.78 (m, 2H), 3.78 (s, 3H),
3.70 (s, 3H), 3.66 (dd, J = 14.4, 4.5 Hz, 1H), 3.40−3.22 (m, 2H),
1.58−1.32 (m, 2H), 1.30−1.15 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 171.9, 163.7, 158.7, 138.1, 134.0,
( )-trans-Methyl 2-Butyl-5-[4-(methoxycarbonyl)phenyl]-1-oxo-
2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate
(4j) and ( )-cis-Methyl 2-Butyl-5-[4-(methoxycarbonyl)phenyl]-1-
oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxy-
late (4j′). The compounds were prepared via the general procedure
and purified by flash column chromatography (4:1 petroleum ether/
diethyl ether). The total yield was 30%. The more polar trans isomer,
4j, was obtained as a pale yellow oil (16 mg, 18% yield), and the less
polar cis isomer, 4j′, as a pale yellow oil (11 mg, 12% yield).
1
Spectral data for trans isomer 4j: H NMR (300 MHz, CDCl3) δ
132.9, 126.8, 126.1, 124.3, 122.1, 120.8, 114.1, 110.1, 109.2, 56.3,
55.1, 52.7, 51.3, 47.8, 47.4, 30.1, 20.0, 13.8; HRMS (ESI-TOF) calcd
7.75 (dt, J = 8.0, 0.9 Hz, 1H), 7.70−7.65 (m, 2H), 7.45−7.38 (m,
1H), 7.37−7.31 (m, 1H), 7.26−7.19 (m, 1H), 6.92 (s, 1H), 6.79−
6.72 (m, 2H), 6.25 (d, J = 1.8 Hz, 1H), 4.19−4.04 (m, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 3.72−3.64 (m, 1H), 3.11−2.93 (m, 2H), 1.96 (dd,
J = 14.1, 3.6 Hz, 1H), 1.69−1.53 (m, 2H), 1.44−1.29 (m, 2H), 0.95
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 170.9, 166.7,
160.9, 143.3, 132.2, 132.1, 131.8, 129.4, 128.6, 128.1, 124.3, 124.0,
121.3, 109.8, 98.6, 71.0, 52.7, 51.9, 50.5, 40.5, 29.8, 28.7, 19.9, 13.7;
HRMS (ESI-TOF) calcd for C26H29N2O5+ [M + H]+ 449.2071, found
449.2070.
+
for C25H29N2O4 [M + H]+ 421.2122, found 421.2117.
( )-trans-Methyl 2-Butyl-5-(4-chlorophenyl)-1-oxo-2,3,4,5-tetra-
hydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4g). This
compound was prepared via the general procedure as a white solid
(35 mg, 41% yield), eluting with petroleum ether/ethyl acetate (8:1):
mp 131−132 °C; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz,
1H), 7.50 (d, J = 8.4 Hz, 1H), 7.36−7.30 (m, 1H), 7.29 (s, 1H),
7.23−7.15 (m, 3H), 6.73 (dd, J = 8.8, 0.9 Hz, 2H), 6.65 (s, 1H),
3.99−3.76 (m, 2H), 3.80 (s, 3H), 3.68−3.60 (m, 1H), 3.39−3.20 (m,
2H), 1.55−1.30 (m, 2H), 1.30−1.05 (m, 2H), 0.86 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.6, 163.5, 139.6, 138.0,
133.7, 133.4, 129.0, 126.8, 126.3, 124.6, 122.3, 121.1, 110.0, 109.6,
1
Spectral data for cis isomer 4j′: H NMR (300 MHz, CDCl3) δ
7.92 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 8.3,
7.0, 1.3 Hz, 1H), 7.20 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.20−7.07 (m,
3H), 6.97 (s, 1H), 6.20 (d, J = 1.5 Hz, 1H), 4.16−3.99 (m, 1H), 3.89
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https://doi.org/10.1021/acs.joc.1c00303
J. Org. Chem. 2021, 86, 6458−6466

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(s, 3H), 3.83 (s, 3H), 3.47−3.37 (m, 1H), 3.09−2.94 (m, 1H), 2.77
(d, J = 14.4, 8.7 Hz, 1H), 2.37 (dd, J = 14.4, 4.6 Hz, 1H), 1.71−1.63
(m, 2H), 1.44−1.35 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 171.4, 166.7, 160.5, 143.7, 133.1, 132.3, 131.9,
129.8, 128.6, 128.6, 124.3, 123.7, 121.2, 110.6, 98.7, 72.0, 52.9, 52.0,
49.0, 39.9, 29.8, 29.1, 19.9, 13.6; HRMS (ESI-TOF) calcd for
= 7.3 Hz, 1H), 3.73 (s, 3H), 3.70−3.66 (m, 1H), 3.65−3.59 (m, 2H),
3.57−3.47 (m, 1H), 3.17 (dd, J = 11.1, 6.3 Hz, 1H), 1.76−1.58 (m,
2H), 1.46 (d, J = 7.2 Hz, 3H), 1.50−1.37 (m, 2H), 0.99 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.8, 164.2, 137.3, 132.5,
126.8, 124.1, 122.1, 120.5, 109.8, 109.2, 52.6, 50.8, 49.8, 48.0, 47.3,
+
30.3, 24.2, 20.3, 13.8; HRMS (ESI-TOF) calcd for C19H25N2O3 [M
+
C26H29N2O5 [M + H]+ 449.2071, found 449.2071.
+ H]+ 329.1860, found 329.1852.
( )-trans-Methyl 2-Butyl-5-(naphthalen-2-yl)-1-oxo-2,3,4,5-tet-
rahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4k). This
compound was prepared via the general procedure as a pale yellow
solid (37 mg, 42% yield), eluting with petroleum ether/ethyl acetate
( )-trans-Methyl 2-Butyl-1-oxo-5-propyl-2,3,4,5-tetrahydro-1H-
[1,4]diazepino[1,2-a]indole-4-carboxylate (4o). This compound
was prepared via the general procedure as a white solid (36 mg,
51% yield), eluting with petroleum ether/ethyl acetate (10:1): mp
77−78 °C; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H),
7.50 (d, J = 8.4 Hz, 1H), 7.35−7.28 (m, 1H), 7.20 (s, 1H), 7.16−7.10
(m, 1H), 5.24 (dd, J = 10.4, 6.0 Hz, 1H), 3.73 (s, 3H), 3.68−3.60 (m,
2H), 3.60−3.44 (m, 2H), 3.22 (dd, J = 11.7, 8.7 Hz, 1H), 1.98−1.77
(m, 2H), 1.74−1.56 (m, 2H), 1.48−1.35 (m, 2H), 0.99 (t, J = 7.5 Hz,
3H), 0.52 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
171.9, 164.2, 138.6, 132.3, 126.4, 124.2, 122.1, 120.4, 110.0, 109.2,
56.1, 52.5, 49.9, 47.9, 47.3, 32.1, 30.3, 20.3, 13.8, 11.0; HRMS (ESI-
1
(5:1): mp 139−140 °C; H NMR (300 MHz, CDCl3) δ 7.77−7.63
(m, 4H), 7.55 (d, J = 8.4 Hz, 1H), 7.44−7.37 (m, 2H), 7.45−7.26 (m,
3H), 7.22−7.13 (m, 1H), 6.93 (dd, J = 8.7, 2.1 Hz, 1H), 6.84 (s, 1H),
4.08−4.00 (m, 1H), 3.92−3.82 (m, 1H), 3.80 (s, 3H), 3.67 (dd, J =
15.0, 4.8 Hz, 1H), 3.40−3.15 (m, 2H), 1.30−1.10 (m, 2H), 1.05−
0.84 (m, 2H), 0.73 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 171.9, 163.7, 138.3, 138.2, 134.1, 133.1, 132.5, 129.0, 128.2,
127.4, 126.9, 126.5, 126.2, 124.5, 123.8, 123.1, 122.3, 120.9, 110.2,
109.5, 57.0, 52.9, 51.5, 47.9, 47.5, 30.2, 20.0, 13.7; HRMS (ESI-TOF)
+
TOF) calcd for C20H27N2O3 [M + H]+ 343.2016, found 343.2020.
+
calcd for C28H29N2O3 [M + H]+ 441.2173, found 441.2165.
( )-trans-Methyl 2-Butyl-5-cyclohexyl-1-oxo-2,3,4,5-tetrahydro-
1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4p). This compound
was prepared via the general procedure as a pale yellow oil (36 mg,
( )-trans-2-Butyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-[1,4]-
diazepino[1,2-a]indole-4-carbonitrile (4l) and ( )-cis-2-Butyl-1-
oxo-5-phenyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-4-
carbonitrile (4l′). The compounds were prepared via the general
procedure and purified by flash column chromatography (2:1
petroleum ether/diethyl ether). The total yield was 86%. The more
polar trans isomer, 4l, was obtained as a colorless oil (31 mg, 43%
yield), and the less polar cis isomer, 4l′, as a colorless oil (31 mg, 43%
yield).
1
46% yield), eluting with petroleum ether/ethyl acetate (10:1): H
NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.5
Hz, 1H), 7.33−7.28 (m, 1H), 7.17 (s, 1H), 7.15−7.10 (m, 1H), 4.93
(d, J = 11.0 Hz, 1H), 3.72 (s, 3H), 3.68−3.52 (m, 4H), 3.48−3.40
(m, 1H), 1.99 (d, J = 11.9 Hz, 1H), 1.85−1.56 (m, 6H), 1.49−1.11
(m, 6H), 0.99 (t, J = 7.5 Hz, 3H), 0.54−0.46 (m, 2H); 13C{1H} NMR
(75 MHz, CDCl3) δ 172.2, 164.2, 138.8, 132.8, 126.3, 124.1, 122.1,
120.4, 110.2, 108.7, 59.9, 52.5, 48.1, 47.2, 46.6, 44.5, 30.9, 30.3, 29.5,
1
Spectral data for trans isomer 4l: H NMR (300 MHz, CDCl3) δ
7.80 (d, J = 8.1 Hz, 1H), 7.47−7.35 (m, 2H), 7.30−7.25 (m, 1H),
7.23−7.08 (m, 3H), 6.99 (s, 1H), 6.91−6.81 (m, 2H), 6.06 (d, J = 1.6
Hz, 1H), 4.31−4.05 (m, 1H), 3.85−3.67 (m, 1H), 3.58−3.48 (m,
1H), 2.60 (dd, J = 13.8, 11.1 Hz, 1H), 1.95 (dd, J = 13.7, 3.9 Hz, 1H),
1.90−1.68 (m, 2H), 1.48−1.40 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 160.8, 134.9, 132.4, 132.2, 131.8,
128.8, 128.6, 127.5, 124.9, 124.4, 121.8, 117.9, 109.6, 99.5, 69.8, 41.2,
37.8, 30.3, 30.0, 20.0, 13.7; HRMS (ESI-TOF) calcd for C23H24N3O+
[M + H]+ 358.1914, found 358.1913.
+
26.0, 25.8, 25.3, 20.3, 13.9; HRMS (ESI-TOF) calcd for C24H33N2O3
[M + H]+ 397.2486, found 397.2480.
( )-trans-Methyl 2-Butyl-5-cyclopropyl-1-oxo-2,3,4,5-tetrahy-
dro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4q). This com-
pound was prepared via the general procedure as a white solid (77
mg, 60% yield), eluting with petroleum ether/ethyl acetate (10:1):
mp 144−145 °C; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz,
1H), 7.38 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.20 (s, 1H),
7.12 (t, J = 7.5 Hz, 1H), 4.46 (d, J = 10.5 Hz, 1H), 3.71 (s, 3H),
3.70−3.50 (m, 4H), 1.81−1.60 (m, 2H), 1.48−1.38 (m, 2H), 1.36−
1.24 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H), 0.69−0.56 (m, 1H), 0.43−
0.32 (m, 2H), 0.22−0.15 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3)
δ 171.8, 164.5, 137.9, 132.8, 126.7, 124.2, 122.1, 120.4, 109.5, 108.8,
60.1, 52.6, 50.6, 47.7, 47.3, 30.3, 20.3, 19.3, 13.9, 5.3, 4.2; HRMS
1
Spectral data for cis isomer 4l′: H NMR (300 MHz, CDCl3) δ
7.91 (dd, J = 8.4, 1.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.41 (ddd, J =
8.4, 7.1, 1.2 Hz, 1H), 7.34−7.22 (m, 4H), 7.15−7.05 (m, 2H), 7.01
(s, 1H), 5.98 (s, 1H), 4.15−4.00 (m, 1H), 3.50 (ddd, J = 10.6, 4.5, 1.3
Hz, 1H), 3.20−3.15 (m, 1H), 2.58 (dd, J = 13.9, 4.5 Hz, 1H), 2.29
(dd, J = 13.9, 10.6 Hz, 1H), 1.82−1.60 (m, 2H), 1.50−1.35 (m, 2H),
0.98 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.5,
135.0, 133.3, 132.0, 131.6, 129.0, 128.6, 127.7, 125.1, 123.7, 121.7,
118.9, 111.9, 99.7, 71.3, 40.5, 37.1, 30.3, 30.0, 20.0, 13.6; HRMS
(ESI-TOF) calcd for C23H24N3O+ [M + H]+ 358.1914, found
358.1914.
+
(ESI-TOF) calcd for C21H27N2O3 [M + H]+ 355.2016, found
355.2019.
( )-trans-Methyl 9-Methoxy-2-methyl-1-oxo-5-phenyl-2,3,4,5-
tetrahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4r). This
compound was prepared via the general procedure as a white solid
(56 mg, 74% yield), eluting with petroleum ether/ethyl acetate (2:1):
Methyl 2-Butyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-
a]indole-4-carboxylate (4m). This compound was prepared via the
general procedure as a pale yellow oil (32 mg, 51% yield), eluting with
1
mp 71−72 °C; H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 9.1 Hz,
1H), 7.31−7.15 (m, 4H), 7.12 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 8.7
Hz, 1H), 6.79 (d, J = 7.4 Hz, 2H), 6.59 (s, 1H), 4.10−3.91 (m, 2H),
3.86 (s, 3H), 3.78 (s, 3H), 3.61 (dd, J = 14.2, 4.4 Hz, 1H), 2.92 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.8, 163.8, 154.8, 140.7,
133.9, 133.6, 128.9, 127.5, 127.1, 124.8, 115.6, 111.1, 108.8, 102.7,
57.0, 55.7, 52.8, 49.9, 49.5, 34.7; HRMS (ESI-TOF) calcd for
1
petroleum ether/ethyl acetate (5:1): H NMR (300 MHz, CDCl3) δ
7.65 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.31 (ddd, J = 8.3,
7.0, 1.2 Hz, 1H), 7.15−7.11 (m, 1H), 7.10 (d, J = 0.9 Hz, 1H), 4.77
(dd, J = 14.7, 4.5 Hz, 1H), 4.37 (dd, J = 14.7, 6.6 Hz, 1H), 3.74 (s,
3H), 3.75−3.63 (m, 1H), 3.65−3.44 (m, 2H), 3.53−3.37 (m, 1H),
3.32−3.24 (m, 1H), 1.71−1.59 (m, 2H), 1.48−1.34 (m, 2H), 0.98 (t,
J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 171.5, 164.6,
136.9, 134.3, 126.7, 124.1, 122.1, 120.3, 109.7, 107.0, 52.4, 47.6, 47.4,
+
C22H23N2O4 [M + H]+ 379.1652, found 379.1651.
( )-trans-Methyl 8-Methoxy-2-methyl-1-oxo-5-phenyl-2,3,4,5-
tetrahydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4s).
This compound was prepared via the general procedure as a white
solid (59 mg, 78% yield), eluting with petroleum ether/ethyl acetate
(2:1): mp 62−63 °C; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.7
Hz, 1H), 7.32−7.14 (m, 4H), 6.92 (s, 1H), 6.87−6.80 (m, 3H), 6.57
(s, 1H), 4.10−3.87 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.61 (dd, J =
14.5, 4.9 Hz, 1H), 2.90 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
171.8, 163.9, 158.3, 140.4, 139.4, 132.6, 128.9, 127.5, 124.9, 122.9,
121.0, 111.6, 109.6, 93.1, 56.8, 55.5, 52.8, 49.6, 49.5, 34.6; HRMS
+
45.8, 41.9, 30.4, 20.2, 13.8; HRMS (ESI-TOF) calcd for C18H23N2O3
[M + H]+ 315.1703, found 315.1705.
( )-trans-Methyl 2-Butyl-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-
[1,4]diazepino[1,2-a]indole-4-carboxylate (4n). This compound was
prepared via the general procedure as a colorless oil (34 mg, 52%
1
yield), eluting with petroleum ether/ethyl acetate (5:1): H NMR
(300 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz,
1H), 7.35−7.30 (m, 1H), 7.19 (s, 1H), 7.16−7.11 (m, 1H), 5.52 (q, J
6464
https://doi.org/10.1021/acs.joc.1c00303
J. Org. Chem. 2021, 86, 6458−6466

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
+
(ESI-TOF) calcd for C22H23N2O4 [M + H]+ 379.1652, found
379.1647.
Jinbao Xiang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China; orcid.org/0000-0002-2628-3075;
Email: jbxiang@jlu.edu.cn
( )-trans-Methyl 2-Methyl-9-nitro-1-oxo-5-phenyl-2,3,4,5-tetra-
hydro-1H-[1,4]diazepino[1,2-a]indole-4-carboxylate (4t). This
compound was prepared via the general procedure as a light yellow
solid (43 mg, 55% yield), eluting with petroleum ether/ethyl acetate
(2:1): mp 222−223 °C; 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J =
2.3 Hz, 1H), 8.21 (dd, J = 9.3, 2.3 Hz, 1H), 7.60 (d, J = 9.3 Hz, 1H),
7.40 (s, 1H), 7.33−7.20 (m, 3H), 6.82 (d, J = 7.3 Hz, 2H), 6.70 (s,
1H), 4.16−4.03 (m, 1H), 3.88−3.82 (m, 1H), 3.80 (s, 3H), 3.71 (dd,
J = 15.0, 5.4 Hz, 1H), 2.93 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 171.4, 162.7, 142.6, 140.5, 139.1, 136.8, 129.1, 128.0, 125.9, 124.7,
119.6, 119.3, 119.3, 110.5, 57.4, 53.0, 49.4, 49.1, 34.7; HRMS (ESI-
Authors
Shutao Wang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China; orcid.org/0000-0003-4895-2687
Siyu Wang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Shaoli Song − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
+
TOF) calcd for C21H20N3O5 [M + H]+ 394.1397, found 394.1405.
( )-trans-Methyl 2-Methyl-1-oxo-5-phenyl-2,3,4,5-tetrahydro-
1H-pyrrolo[1,2-a][1,4]diazepine-4-carboxylate (4u). This com-
pound was prepared via the general procedure as a white solid (22
mg, 37% yield), eluting with petroleum ether/ethyl acetate (2:1): mp
1
141−142 °C; H NMR (300 MHz, CDCl3) δ 7.44−7.30 (m, 3H),
7.18−7.15 (m, 2H), 6.87 (dd, J = 3.9, 1.8 Hz, 1H), 6.43 (dd, J = 3.0,
1.8 Hz, 1H), 6.11 (dd, J = 3.9, 2.7 Hz, 1H), 5.85 (d, J = 7.5 Hz, 1H),
3.80−3.63 (m, 3H), 3.71 (s, 3H), 3.03 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 171.8, 164.4, 137.4, 129.0, 128.7, 128.6, 127.4, 124.5,
115.7, 108.3, 61.0, 52.5, 51.1, 50.4, 35.0; HRMS (ESI-TOF) calcd for
Qiansong Gao − The Center for Combinatorial Chemistry
and Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
+
C17H19N2O3 [M + H]+ 299.1390, found 299.1383.
Gram-Scale Synthesis of Compound 4a. A sealed bottle was
charged with 1H-indole-2-carboxylic acid 1a (967 mg, 6.0 mmol, 1.0
equiv), HOBt (973 mg, 7.2 mmol, 1.2 equiv), and EDCI (1.38 g, 7.2
mmol, 1.2 equiv) in dried DMSO (30 mL). After the mixture had
been stirred at room temperature for 25 min, the prepared MBH-
derived allylamine 2a (1.48 g, 7.2 mmol, 1.2 equiv) and triethylamine
(1.25 mL, 9.0 mmol, 1.5 equiv) were added immediately. After the
addition, the reaction mixture was stirred for an additional 3 h to form
the amide intermediate. Under a nitrogen atmosphere, K2CO3 (2.49
g, 18 mmol, 3.0 equiv) was added directly to the reaction mixture.
The mixture was heated in an oil bath to 80 °C and stirred for 20 h.
After the reaction had reached completion, the resulting solution was
diluted with EtOAc (100 mL), washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The crude material was
purified by column chromatography, using 2:1 petroleum ether/ethyl
acetate as the eluent to afford the desired product 4a as a white solid
(1.59 g, 76% yield).
Chunxi Wen − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Zhuoqi Zhang − The Center for Combinatorial Chemistry and
Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00303
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Sci-Tech Development
Project of Jilin Province in China (20200801039GH), the
“Chunhui Plan” Cooperative Research Project of the Ministry
of Education of China, the Foundation of Jilin Educational
Committee (JJKH20211225KJ and JJKH20211229KJ), and
the Outstanding Young Teacher Training Program of Jilin
University.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00303.
Experimental details, characterization data for all new
compounds, copies of NMR spectra, and X-ray crystallo-
graphic analysis of 4a (PDF)
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■
Corresponding Authors
Lianyou Zheng − The Center for Combinatorial Chemistry
and Drug Discovery of Jilin University, The School of
Pharmaceutical Sciences, Jilin University, Changchun, Jilin
130021, P. R. China; orcid.org/0000-0002-7304-6734;
Email: lianyouzh@jlu.edu.cn
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https://doi.org/10.1021/acs.joc.1c00303
J. Org. Chem. 2021, 86, 6458−6466

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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