Hexafluoroisopropanol-Mediated Redox-Neutral α-C(sp3)-H Functionalization of Cyclic Amines via Hydride Transfer

Article abstract of DOI:10.1021/acs.joc.9b02606

Hexafluoroisopropanol has been demonstrated as the versatile promoter for redox-neutral α-C(sp³)-H functionalization of cyclic amines via the cascade [1,5]-hydride transfer/cyclization strategy. A wide range of cyclic amines are functionalized

Full text of DOI:10.1021/acs.joc.9b02606

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Article
Hexafluoroisopropanol-Mediated Redox-Neutral #-C(sp3)#
H Functionalization of Cyclic Amines via Hydride Transfer
Yao-Bin Shen, Lin-Xuan Wang, Yun-Ming Sun, Feng-Ying Dong, Liping Yu, Qing Liu, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02606 • Publication Date (Web): 11 Dec 2019
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Hexafluoroisopropanol-Mediated Redox-Neutral α-C(sp3)‒H
Functionalization of Cyclic Amines via Hydride Transfer
Yao-Bin Shen,†,∥, Lin-Xuan Wang†,∥, Yun-Ming Sun,† Feng-Ying Dong,† Li-Ping Yu,*, § Qing
Liu,┴ Jian Xiao*,†,‡
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†School of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
‡School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
§School of Landscape Architecture and Forestry, Qingdao Agricultural University, Qingdao, 266109, China.
┴College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao
266590, China.
Corresponding author: Li-Ping Yu and Jian Xiao
E-mail address: lipingyu99@163.com; chemjianxiao@163.com
Graphic Abstract
EWG
EWG
O
R3
R3
N
R1
R2
N
R1
R2
EWG
EWG
HFIP
HFIP
HN
O
H
9 examples
15 examples
R3
N
R1
R2
Ph
Ph
R2
N
N
N
R2NH2
HFIP
R3
R3
NH
Ph
Ph
HFIP
N
R1
R2
N
R1
R2
operational simplicity
wide substrate scope
additive-free conditions
16 examples
8 examples
Abstract: Hexafluoroisopropanol has been demonstrated as the versatile promoter for
redox-neutral α-C(sp3)‒H functionalization of cyclic amines via the cascade [1,5]-hydride
transfer/cyclization strategy. A wide range of cyclic amines are functionalized into bioactive
tetrahydroquinolines, quinazolines, benzoxazines, and benzotriazepines in moderate to excellent
yields. This protocol features additive-free conditions, operational simplicity, and wide substrate
scope.
INTRODUCTION
Functionalized cyclic amines are ubiquitous in biologically active compounds of synthetic and
natural origins.1 To target these scaffolds, the direct α-C(sp3)‒H functionalization of cyclic amines
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has proved to be an efficient way, which circumvents the prefunctionalization of amine feedstocks
and streamlines the synthetic routes.2,3 Remarkably, the cascade [1,5]-hydride transfer/cyclization
has attracted considerable interest for the direct α-C(sp3)‒H functionalization of cyclic amines due
to its inherent redox-neutral nature, environmental sustainability as well as high efficiency of
constructing molecular complexity and diversity (Scheme 1a).3 By utilizing various hydride
acceptors, the inert α-C(sp3)‒H bonds of cyclic amines are converted into C‒C, C‒N, and C‒O
bonds, thus providing access to different varieties of bioactive frameworks.4‒9 Nevertheless, these
transformations commonly necessitate not only the cumbersome prefabrication of substrates with
hydride acceptors but also the employment of strong Lewis acids or Brönsted acids, which limit
the widespread application of current hydride transfer strategy. Therefore, it is quite imperative to
achieve the redox-neutral α-C(sp3)‒H functionalization of cyclic amines just from two
independent starting materials under the additive-free conditions.
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Scheme 1. The Redox-Neutral α-C(sp3)‒H Functionalization of Cyclic Amines via Hydride
Transfer
a) Acid-catalyzed -C(sp3)–H functionalization of cyclic amines via hydride transfer

Y
H
Y
H
H
X
X
Y
acid
cyclization
X
R3
R3
R3
[1,5]-HT
R2
N
R1
R2
N
R1
R2
N
R1
X = C, N, O; Y = electron-withdrawing group
b) Our previous work: introduction of HFIP into aromatization-driven hydride transfer reaction
OH
R2
H
O
R2
R2
O
[1,5]-HT
H
R3
R3
H
R3
R2
O
dearomative
cyclization
HFIP
N
R1
R2
N
R1
N
R1
R2
c) This work: HFIP-mediated -C(sp3)–H functionalization of cyclic amines via hydride transfer

EWG
EWG
O
C
R3
HFIP
HFIP
R3
R2
N
R1
R2
N
R1
EWG
O
EWG
H
R3
Ph
R2
Ph
HN
NH
N
R1
R2
R2
R2
N
N
N
H2N
R3
R3
Ph
HFIP
Ph
N
R1
N
R1
HFIP
R2
The fluorinated alcohols, i.e. hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE), have
been demonstrated as magic reaction medium and promoters for organic synthesis, featuring high
hydrogen-bonding donor ability, weak hydrogen-bonding acceptor ability and weak acidity.10
Taking advantage of their unique characteristics, miscellaneous fluorinated alcohols-mediated
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reactions have been developed, such as nucleophilic substitution reactions, annulation reactions,
and epoxidation reactions.11‒12 Recently, our group innovatively employed HFIP as both promoter
and solvent for the realization of aromatization-driven cascade [1,5]-hydride transfer/cyclization
reactions, accomplishing the cascade dearomatization/rearomatization/dearomatization sequence
for the first time (Scheme 1b).4b‒c Inspired by these intriguing outcomes, we envisage that HFIP
might be an efficient promoter for the general hydride transfer reactions with different hydride
acceptors under the additive-free conditions. Herein, we report that HFIP acts as the versatile
promoter and solvent for hydride transfer-involved redox-neutral α-C(sp3)‒H alkylation,
amination, and etherification of cyclic amines, divergently furnishing bioactive
tetrahydroquinolines, quinazolines, benzoxazines, and benzotriazepines (Scheme 1c).
RESULTS AND DISCUSSION
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Initially, we focused on the HFIP-mediated redox-neutral α-C(sp3)‒H alkylation reaction
between o-aminobenzaldehydes and active methylene compounds, which allowed the rapid
construction of tetrahydroquinolines via the cascade Knoevenagel condensation/[1,5]-hydride
transfer/6-endo cyclization process (Table 1).4 Solvent screening by comparing HFIP with other
solvents manifested that HFIP exhibited the highest efficiency (see Supporting Information), and
the substrate scope of these transformations was shown in Table 1. In detail,
2-(pyrrolidin-1-yl)benzaldehydes with various substituents reacted smoothly with 1,3-indanedione,
providing spiro tetrahydroqunoline compounds 3a‒d in 70‒91% yields. Additionally,
2-(piperidin-1-yl)benzaldehyde and 2-(azepan-1-yl)benzaldehyde were well-tolerated in the
reaction system to deliver products 3e and 3f in 74% and 71% yields, respectively. It was noted
that various kinds of active methylene compounds, such as 1,3-cyclohexanedione, barbituric acid,
Meldrum’s acid, 3-phenyl-5-isoxazolone, and malononitrile, were suitable substrates to afford
3g‒l in 71‒98% yields, which revealed the generality of this protocol. Moreover, biologically
significant skeletons of 4-hydroxycoumarin and indolin-2-one were also compatible, delivering
the corresponding adducts 3m and 3n in good yields. Gratifyingly, the synthesis of PNU-286607
3o via this protocol was also successfully achieved in a one-pot manner.13
Table 1. Scope of HFIP-Mediated Redox-Neutral α-C(sp3)‒H Alkylation of Cyclic Amines
for the Synthesis of Tetrahydroquinolinesa
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O
EWG
EWG
EWG
4
5
6
7
H
HFIP
rt
R1
R1
+
N
3
EWG
2
N
1
O
O
O
8
OMe
9
O
O
O
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N
Cl
N
N
b
3a
3b
3c
, 77%
, 91%
, 70%
O
O
O
Br
O
O
N
O
N
N
3d
, 85%
3e
3f
, 71%
, 74%
Me
Me
H
N
O
O
O
O
NH
O
O
O
N
N
N
b
3g
3h
3i
, 93%
, 95%
, 77%
Me
Me
O
CN
CN
O
O
O
N
O
N
Ph
N
O
N
3l
O
, 71%
3j
, 87%
3k
, 98%, dr 1.2:1
O
HN
H
NH
O
N
O2N
O
H
O
Me
O
N
N
O
O
N
Me
c
3m
, 53%, dr 2.4:1
3n
b
, 70%, dr >20:1
3o
, 54%, dr >20:1
PNU-286607
aReaction conditions (unless other indicated): 1 (0.1 mmol) and 2 (0.12 mmol) in 1 mL of HFIP at room
temperature. Isolated yields after column chromatography; dr was determined by 1H NMR analysis. bAt 40 °C. cAt
120 °C.
Afterward, we turned our attention towards the HFIP-mediated redox-neutral α-C(sp3)‒H
amination of o-aminobenzaldehydes with primary amines for the buildup of quinazolines via the
cascade condensation/[1,5]-hydride transfer/6-endo cyclization sequence (Table 2).5 As shown in
Table 2, reactions of 2-(pyrrolidin-1-yl)benzaldehydes with aniline worked well, giving rise to
products 5a‒d in moderate to excellent yields. The low yield of 5b might be ascribed to the fact
that the stabilization effect of electron-donating group would weaken the ability of the in situ
generated imine to initiate the [1,5]-hydride transfer. Pleasingly, anilines bearing different
substituents afforded 5e‒j in good yields. Apart from anilines, benzyl and aliphatic amines were
also found to be viable substrates and furnished 5k‒m in 62‒80% yields. Notably, the target
products 5n and 5o were obtained even when amines were varied to sulfamides. More importantly,
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3-aminopropanoic acid could efficiently participate in the reaction to furnish 5p in 86% yield,
which indicated the potential of this methodology in the late-stage functionalization of amino
acids.
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Table 2. Scope of HFIP-Mediated Redox-Neutral α-C(sp3)‒H Amination of Cyclic
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Amines for the Synthesis of Quinazolinesa
O
R2
N
H
HFIP
rt
R1
R1
R2-NH2
+
N
N
1
4
5
N
N
N
Cl
N
N
Me
N
b
5a
, 92%
5b
, 40%
5c
, 70%
R
Br
N
N
N
Cl
N
N
N
5e
c
, R = OH, 68%
5d
, 82%
5g
, 81%
c
5f
, R = OMe, 57%
I
F
Me
N
N
N
NO2
N
S
N
N
CF3
b,c
b,c
b
5h
5i
, 80%
, 76%
5j
, 69%
Me
N
N
N
Me
N
Me
N
N
d
d
5k
5l
5m
, 62%
, 70%
, 80%
Me
O
O
CF3
CO2H
S
N
S
N
N
O
O
N
N
N
5n
5o
5p
, 86%
, 61%
, 36%
aReaction conditions: 1 (0.1 mmol) and 4 (0.12 mmol) in 1 mL of HFIP at room temperature. Isolated yields after
column chromatography. bAt 40 °C.c4 (0.2 mmol). dAt 60 °C.
Then the substrate scope of HFIP-mediated redox-neutral α-C(sp3)‒H etherification of
o-aminobenzaldehydes for the synthesis of benzoxazines was examined, as shown in Table 3.6
o-Aminobenzaldehydes
carrying
five-membered
pyrrolidine,
six-membered
tetrahydroisoquinoline, and seven-membered hexamethyleneimine could undergo the cascade
[1,5]-hydride transfer/6-endo cyclization process and afforded products 6a‒c in moderate yields.
In addition, the introduction of electronically diverse substituents, including methoxy, fluoro,
chloro, bromo, cyano, and nitro groups, were all well-tolerated, and the corresponding adducts
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6d‒i were obtained in 44‒87% yields. Notably, the higher yields of substrates bearing
electron-withdrawing groups might result from the fact that the electron-withdrawing groups
would enhance the capability of the aldehyde moiety to trap the hydride.
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Table 3. Scope of HFIP-Mediated Redox-Neutral α-C(sp3)‒H Etherification of Cyclic
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Amines for the Synthesis of Benzoxazinesa
O
O
HFIP
R1
H
R1
120 o
C
N
N
1
6
O
O
O
N
N
N
6a
6b
6c
, 47%
, 48%
, 53%
OMe
F
O
N
O
O
N
N
Cl
6d
6e
6f
, 77%
, 44%
, 63%
Br
O2N
O
O
O
N
NC
N
N
6g
6i
, 58%
, 72%
6h
, 87%
aReaction conditions: 1 (0.1 mmol) in 1 mL of HFIP at 120 °C. Isolated yields after column chromatography.
It has been known that in contrast to that of six-membered cycles, the synthesis of
seven-membered cycles is much more challenging on account of their higher ring strain energy.
Subsequently, we explored the HFIP-mediated redox-neutral α-C(sp3)‒H amination of
o-aminobenzaldehydes with 1,2-diphenylhydrazine for the assembly of benzotriazepines via the
cascade condensation/[1,5]-hydride transfer/7-endo cyclization sequence (Table 4).5a In general, a
variety of o-aminobenzaldehydes successfully took part in these reactions with
1,2-diphenylhydrazine, and products 8a‒h were delivered in 35‒81% yields. For instance, neither
electron-donating (methoxy and methyl) nor electron-withdrawing (trifluoromethyl, chloro, and
bromo) substituents on the phenyl rings had obvious influence on the transformations,
demonstrating the excellent functional group tolerance. Pleasingly, the change of pyrrolidine to
cis-hexahydroisoindole and tetrahydroisoquinoline was also feasible, and benzotriazepines 8g and
8h were provided in 44% and 81% yields, respectively.
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Table 4. Scope of HFIP-Mediated Redox-Neutral α-C(sp3)‒H Amination of Cyclic Amines
5
6
for the Synthesis of Benzotriazepinesa
7
8
9
O
Ph
H
N
N
HFIP
rt
H
R1
R1
N
Ph
+
Ph
Ph
N
H
N
8
N
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1
7
Ph
Ph
Ph
N
N
N
Ph
N
Ph
N
N Ph
Me
MeO
Cl
N
N
N
8a
8c
, 42%
8b
, 35%
Ph
, 47%
Ph
N
N
Ph
N
N
Ph
Ph
N
N Ph
Br
F3C
N
N
N
8d
, 51%
8f
8e
, 52%
, 47%
Ph
Ph
N
N
N
N
Ph
Ph
N
N
8g
8h
, 81%
, 44%, dr >20:1
aReaction conditions: 1 (0.1 mmol) and 7 (0.15 mmol) in 1 mL of HFIP at room temperature. Isolated yields after
column chromatography; dr was determined by 1H NMR analysis.
To broaden the application of this strategy in the construction of seven-membered skeletons, the
HFIP-mediated redox-neutral α-C(sp3)‒H etherification of 2-(pyrrolidin-1-yl)benzaldehyde with
phenylhydroxylamine was also conducted, affording benzoxadiazepine 10 in 30% yield via the
tandem condensation/[1,5]-hydride transfer/7-endo cyclization process (Scheme 2).5f It was noted
that the condensation between two substrates could facilely furnish the 1,3-dipole, however, the
following hydride transfer/ring closure cascade was rather difficult to achieve.
Scheme 2. HFIP-Mediated Redox-Neutral α-C(sp3)‒H Etherification of Cyclic Amines for
the Synthesis of Benzoxadiazepine
Ph
O
N
H
HFIP
H
O
+
N
100 o
12 h
C
Ph
OH
N
N
1a
9 (0.12 mmol)
10, 30%
(0.1 mmol)
To illustrate the practical utility of the HFIP-mediated redox-neutral α-C(sp3)‒H
functionalization of cyclic amines via hydride transfer, the large-scale reactions were carried out,
as shown in Scheme 3. These reactions proceeded smoothly and gave the corresponding products
3a, 5a, 6h and 8h in good yields.
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Scheme 3. Large-Scale Synthesis
5
O
O
O
6
7
8
9
HFIP
H
+
a)
rt, 0.5 h
N
O
N
O
1a
3a
2a
, 0.98 g, 81% yield
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O
HFIP
H
N
N
+
b)
H2N
rt, 6 h
N
1a
5a
4a
, 0.78 g, 78% yield
O
O
N
H
HFIP
c)
NC
NC
N
120 oC, 24 h
6h
, 0.54 g, 60% yield
1r
H
Ph
N
O
H
HFIP
rt, 0.5 h
N
Ph
N
Ph
+
Ph
N
H
N
d)
N
1l
7
8h
, 0.92 g, 78% yield
Based on the experimental results, HFIP was apparently found to be the versatile promoter for
the hydride transfer-enabled redox-neutral α-C(sp3)‒H functionalization of cyclic amines, which
might be ascribed to the unique properties of HFIP. On one hand, the strong hydrogen bond donor
ability could activate substrates and enhance their reactivity via the hydrogen-bonding clusters. On
the other hand, the cationic species stabilization ability could help stabilize the transition state and
in situ generated iminium ion.
CONCLUSION
In summary, we developed the HFIP-mediated redox-neutral α-C(sp3)‒H functionalization of
cyclic amines via cascade [1,5]-hydride transfer/cyclization strategy. By using
electron-withdrawing alkene, imine, aldehyde, and 1,3-dipole as hydride acceptors, the inert
α-C(sp3)‒H bonds of cyclic amines were divergently functionalized to C‒C, C‒N, and C‒O bonds,
thereby readily furnishing various kinds of tetrahydroquinolines, quinazolines, benzoxazines, and
benzotriazepines in moderate to excellent yields. Moreover, an example for the synthesis of
benzoxadiazepine was presented as well, albeit with the lower yield. This method featured
additive-free conditions, operational simplicity, and wide substrate scope. We believed that the
success of HFIP in diverse hydride transfer reactions would not only provide a distinctive
C(sp3)-H functionalization toolbox for the one-step construction of diverse biologically important
skeletons, but also push forward the application of HFIP in organic synthesis.
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Experimental Section
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All commercially available reagents, unless otherwise indicated, were used without further
purification. Reactions were monitored by thin layer chromatography (TLC) with 0.2 mm silica
gel-coated HSGF 254 plates, visualized by UV light at 254 or 365 nm. Products were isolated and
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purified by column chromatography on 200‒300 mesh silica gel. H, 13C, and 19F NMR spectra
1
were recorded on a Bruker AMX 500 (500 MHz for H NMR, 125 MHz for 13C NMR and 470
MHz for 19F NMR) spectrometer at room temperature. The chemical shifts (δ) were reported in
ppm with respect to an internal standard, tetramethylsilane (0 ppm), and the solvent. Coupling
constants (J) were given in Hertz. Splitting patterns of apparent multiplets associated with an
averaged coupling constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), dd (doublet of doublets) and br (broadened). All 13C spectra were recorded with
broadband proton decoupling. HRMS were performed on a Waters XEVO QTOF mass
spectrometer.
General Procedure for the Synthesis of o-Aminobenzaldehydes 1.4g-h, 5a-b
An oven-dried round-bottomed flask was charged with 2-chloro/fluorobenzaldehydes (1.0
equiv, 10 mmol), secondary amines (1.2 equiv, 12 mmol), K2CO3 (2.0 equiv, 20 mmol), and DMF
(50 mL). The reaction mixture was stirred vigorously and refluxed in oil bath for 12 h and
monitored by TLC. Upon consumption, the mixture was cooled to room temperature and diluted
with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined extracts were
washed with brine (3 x 50 mL), dried by anhydrous Na2SO4, filtered, and concentrated under
reduced pressure and the residue was purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc) to afford o-aminobenzaldehydes 1. Starting
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materials 1n‒r were new compounds and characterized as follows.
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General Procedure for the Synthesis of Products 3.
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An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (1.0 equiv, 0.1 mmol),
methylene compounds 2 (1.2 equiv, 0.12 mmol), and HFIP (1 mL). The reaction mixture was
stirred vigorously at the indicated temperature in oil bath and monitored by TLC. After the
consumption of 1, the reaction mixture was concentrated under reduced pressure and then purified
by flash column chromatography (column chromatography eluent, petroleum ether/EtOAc) to
afford products 3.
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General Procedure for the Synthesis of Products 5.
An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (1.0 equiv, 0.1 mmol),
primary amines 4 (1.2 equiv, 0.12 mmol), and HFIP (1 mL). The reaction mixture was stirred
vigorously at the indicated temperature in oil bath and monitored by TLC. After the consumption
of 1, the reaction mixture was concentrated under reduced pressure and then purified by flash
column chromatography (column chromatography eluent, petroleum ether/EtOAc) to afford
products 5.
General Procedure for the Synthesis of Products 6.
An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (0.1 mmol) and HFIP
(1 mL). The reaction mixture was stirred vigorously at 120 °C in oil bath and monitored by TLC.
After the consumption of 1, the reaction mixture was concentrated under reduced pressure and
then purified by flash column chromatography (column chromatography eluent, petroleum
ether/EtOAc) to afford products 6.
General Procedure for the Synthesis of Products 8.
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An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (1.0 equiv, 0.1 mmol),
1,2-diphenylhydrazine 7 (1.5 equiv, 0.15 mmol), and HFIP (1 mL). The reaction mixture was
stirred vigorously at room temperature and monitored by TLC. After the consumption of 1, the
reaction mixture was concentrated under reduced pressure and then purified by flash column
chromatography (column chromatography eluent, petroleum ether/EtOAc) to afford products 8.
Procedure for the Synthesis of Product 10.
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An oven-dried reaction tube was charged with 2-(pyrrolidin-1-yl)benzaldehyde 1a (0.1 mmol,
17.5 mg), phenylhydroxylamine 9 (0.12 mmol, 13.1 mg), and HFIP (1 mL). The reaction mixture
was stirred vigorously at the 120 °C in oil bath for 12 h and monitored by TLC. After the
consumption of 1, the reaction mixture was concentrated under reduced pressure and then purified
by flash column chromatography (column chromatography eluent, petroleum ether/EtOAc =
500:1) to afford product 10 as yellow oil in 30% yield (8.0 mg).
Procedure for the Large-Scale Synthesis of 3a.
An oven-dried round-bottomed flask was charged with 2-(pyrrolidin-1-yl)benzaldehyde 1a (4
mmol, 700 mg), 1,3-indanedione 2a (4.8 mmol, 700 mg), and HFIP (40 mL). The reaction mixture
was stirred vigorously at room temperature for 0.5 h and monitored by TLC. After the
consumption of 1a, the reaction mixture was concentrated under reduced pressure and then
purified by flash column chromatography (column chromatography eluent, petroleum
ether/EtOAc = 50:1) to afford product 3a as yellow solid in 81% yield (982 mg).
Procedure for the Large-Scale Synthesis of 5a.
An oven-dried round-bottomed flask was charged with 2-(pyrrolidin-1-yl)benzaldehyde 1a (4
mmol, 700 mg), aniline 4a (4.8 mmol, 447 mg), and HFIP (40 mL). The reaction mixture was
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stirred vigorously at room temperature for 6 h and monitored by TLC. After the completion of 1a,
the reaction mixture was concentrated under reduced pressure and then purified by flash column
chromatography (column chromatography eluent, petroleum ether/EtOAc = 100:1) to afford
product 5a as white solid in 78% yield (777 mg).
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Procedure for the Large-Scale Synthesis of 6h.
An oven-dried round-bottomed flask was charged with 3-(azepan-1-yl)-4-formylbenzonitrile 1r
(4 mmol, 912 mg) and HFIP (40 mL). The reaction mixture was stirred vigorously at 120 °C in oil
bath for 24 h and monitored by TLC. After the completion of 1r, the reaction mixture was
concentrated under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc = 120:1) to afford product 6h as white solid in
60% yield (544 mg).
Procedure for the Large-Scale Synthesis of 8h.
An
oven-dried
round-bottomed
flask
was
charged
with
2-(3,4-dihydroisoquinolin-2(1H)-yl)benzaldehyde 1l (3 mmol, 711 mg), 1,2-diphenylhydrazine 7
(4.5 mmol, 828 mg), and HFIP (30 mL). The reaction mixture was stirred vigorously at room
temperature for 0.5 h and monitored by TLC. After the completion of 1l, the reaction mixture was
concentrated under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc = 800:1) to afford product 8h as white solid in
76% yield (920 mg).
2-(azepan-1-yl)-6-methoxybenzaldehyde (1n). Yellow solid; 1.47 g, 63% yield; mp 67–69 °C;
column chromatography eluent, petroleum ether/EtOAc = 100:1; 1H NMR (500 MHz, CDCl3) δ
10.28 (s, 1H), 7.31–7.27 (m, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H),
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3.36–3.31 (m, 4H), 1.80‒1.74 (m, 4H), 1.64‒1.59 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ
189.1, 162.9, 155.5, 134.3, 114.7, 110.2, 100.2, 55.9, 54.9 (2C), 28.4 (2C), 28.1 (2C); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H20NO2 234.1489; found 234.1493.
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2-(azepan-1-yl)-6-fluorobenzaldehyde (1o). Yellow oil; 1.65 g, 68% yield; column
chromatography eluent, petroleum ether/EtOAc = 100:1; 1H NMR (500 MHz, CDCl3) δ 10.21 (s,
1H), 7.34‒7.28 (m, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.49 (dd, J = 10.7, 8.1 Hz, 1H), 3.38–3.33 (m,
4H), 1.83‒1.76 (m, 4H), 1.65‒1.58 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 186.8 (d, J = 8.6
Hz), 165.2 (d, J = 256.5 Hz), 155.0 (d, J = 4.1 Hz), 134.4 (d, J = 12.3 Hz), 114.0 (d, J = 7.3 Hz),
113.2 (d, J = 3.0 Hz), 104.4 (d, J = 21.6 Hz), 54.9 (2C), 28.3 (2C), 28.0 (2C); 19F NMR (470 MHz,
CDCl3) δ ‒117.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H17FNO 222.1289; found
222.1288.
2-(azepan-1-yl)-3-chlorobenzaldehyde (1p). Yellow solid; 1.68 g, 71% yield; mp 55–58 °C;
column chromatography eluent, petroleum ether/EtOAc = 200:1; 1H NMR (500 MHz, CDCl3) δ
10.54 (s, 1H), 7.73 (dd, J = 7.6, 0.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H),
3.36‒3.16 (m, 4H), 1.81‒1.70 (m, 8H); 13C{1H} NMR (125 MHz, CDCl3) δ 192.8, 153.9, 136.5,
136.3, 135.5, 126.7, 126.3, 54.6 (2C), 30.5 (2C), 28.0 (2C); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C13H17ClNO 238.0993; found 238.0990.
2-(azepan-1-yl)-5-bromobenzaldehyde (1q). Yellow oil; 2.16 g, 77% yield; column
chromatography eluent, petroleum ether/EtOAc = 200:1; 1H NMR (500 MHz, CDCl3) δ 10.02 (s,
1H), 7.74 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.9, 2.2 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 3.40–3.23
(m, 4H), 1.80‒1.67 (m, 4H), 1.65‒1.56 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 188.7, 153.7,
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135.7, 131.9, 126.5, 119.2, 110.7, 54.8 (2C), 27.5 (2C), 26.7 (2C); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C13H17BrNO 282.0488; found 282.0484.
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3-(azepan-1-yl)-4-formylbenzonitrile (1r). Yellow solid; 1.66 g, 73% yield; mp 68–70 °C;
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column chromatography eluent, petroleum ether/EtOAc = 50:1; H NMR (500 MHz, CDCl3) δ
10.13 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 3.48–3.38 (m, 4H),
1.88‒1.79 (m, 4H), 1.71–1.63 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 189.8, 154.2, 132.0,
127.9, 121.4, 120.9, 118.6, 116.9, 55.2 (2C), 28.4 (2C), 27.9 (2C); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C14H17N2O 229.1335; found 229.1336.
1',2',3',3a'-tetrahydro-5'H-spiro[indene-2,4'-pyrrolo[1,2-a]quinoline]-1,3-dione
(3a).4h
Yellow solid; 27.6 mg, 91% yield; mp 146–147 °C; column chromatography eluent, petroleum
1
ether/EtOAc = 50:1; H NMR (500 MHz, CDCl3) δ 8.04–7.96 (m, 1H), 7.87–7.76 (m, 3H), 7.17
(t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.68–6.56 (m, 2H), 3.87 (dd, J = 10.2, 5.6 Hz, 1H),
3.61–3.54 (m, 1H), 3.33–3.22 (m, 2H), 2.80 (d, J = 16.1 Hz, 1H), 2.00–1.89 (m, 2H), 1.88–1.80
(m, 1H), 1.32–1.23 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 202.7, 199.7, 143.9, 142.5,
141.4, 136.0, 135.5, 128.6, 127.8, 123.1, 123.0, 117.9, 115.6, 110.7, 61.2, 51.4, 47.4, 34.3, 28.1,
23.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18NO2 304.1332; found 304.1343.
6'-methoxy-1',2',3',3a'-tetrahydro-5'H-spiro[indene-2,4'-pyrrolo[1,2-a]quinoline]-1,3-dione
(3b). Yellow solid; 23.3 mg, 70% yield; mp 208–209 °C; column chromatography eluent,
1
petroleum ether/EtOAc = 20:1; H NMR (500 MHz, CDCl3) δ 8.01‒7.95 (m, 1H), 7.87–7.77 (m,
3H), 7.13 (t, J = 8.2 Hz, 1H), 6.32 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 3.82 (dd, J = 10.0,
5.6 Hz, 1H), 3.73 (s, 3H), 3.57 (td, J = 8.4, 2.5 Hz, 1H), 3.33 (dd, J = 16.2, 8.8 Hz, 1H), 3.10 (d, J
= 16.9 Hz, 1H), 2.88 (d, J = 16.9 Hz, 1H), 1.97–1.82 (m, 3H), 1.34–1.24 (m, 1H); 13C{1H} NMR
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(125 MHz, CDCl3) δ 203.0, 200.0, 157.4, 144.7, 142.5, 141.5, 135.8, 135.4, 127.6, 123.1, 123.0,
106.2, 104.6, 98.3, 60.4, 55.3, 51.4, 47.6, 28.2, 27.8, 23.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C21H20NO3 334.1438; found 334.1436.
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8'-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[indene-2,4'-pyrrolo[1,2-a]quinoline]-1,3-dione
(3c). Yellow solid; 25.9 mg, 77% yield; mp 169–170 °C; column chromatography eluent,
1
petroleum ether/EtOAc = 30:1; H NMR (500 MHz, CDCl3) δ 8.03–7.98 (m, 1H), 7.92–7.81 (m,
3H), 6.90 (d, J = 7.8 Hz, 1H), 6.64–6.51 (m, 2H), 3.86 (dd, J = 10.4, 5.6 Hz, 1H), 3.54 (t, J = 8.4
Hz, 1H), 3.32–3.19 (m, 2H), 2.77 (d, J = 16.2 Hz, 1H), 2.05–1.89 (m, 2H), 1.84 (dt, J = 11.6, 5.8
Hz, 1H), 1.31–1.25 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 202.3, 199.5, 144.7, 142.4,
141.3, 136.1, 135.6, 133.3, 129.4, 123.2, 123.1, 116.4, 115.3, 110.5, 61.0, 51.1, 47.4, 33.8, 28.0,
23.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17ClNO2 338.0942; found 338.0942.
7'-bromo-1',2',3',3a'-tetrahydro-5'H-spiro[indene-2,4'-pyrrolo[1,2-a]quinoline]-1,3-dione
(3d). Yellow solid; 32.4 mg, 85% yield; mp 178–180 °C; column chromatography eluent,
petroleum ether/EtOAc = 30:1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 6.0 Hz, 1H), 7.90–7.81
(m, 3H), 7.23 (d, J = 8.6 Hz, 1H), 7.09 (s, 1H), 6.45 (d, J = 8.7 Hz, 1H), 3.84 (dd, J = 10.2, 5.6
Hz, 1H), 3.57‒3.51 (m, 1H), 3.27–3.20 (m, 2H), 2.75 (d, J = 16.3 Hz, 1H), 2.00–1.88 (m, 2H),
1.89–1.80 (m, 1H), 1.33–1.22 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 202.2, 199.6, 142.9,
142.4, 141.3, 136.1, 135.7, 131.0, 130.4, 123.3, 123.1, 120.0, 112.2, 107.2, 61.2, 50.9, 47.6, 33.8,
28.1, 23.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17BrNO2 382.0437; found 382.0441.
2',3',4',4a'-tetrahydro-1'H,6'H-spiro[indene-2,5'-pyrido[1,2-a]quinoline]-1,3-dione
(3e).
Yellow solid; 23.5 mg, 74% yield; mp 178–180 °C; column chromatography eluent, petroleum
ether/EtOAc = 50:1; 1H NMR (500 MHz, CDCl3) δ 8.01–7.96 (m, 1H), 7.96–7.90 (m, 1H), 7.86–
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7.80 (m, 2H), 7.16 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.69 (t, J
= 7.3 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.36 (dd, J = 11.7, 2.3 Hz, 1H), 3.24 (d, J = 16.2 Hz,
1H), 2.86–2.71 (m, 2H), 1.77–1.67 (m, 2H), 1.61 (ddt, J = 13.6, 8.6, 4.1 Hz, 1H), 1.50–1.40 (m,
1H), 1.41–1.28 (m, 1H), 1.21‒1.09 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 202.4, 199.8,
145.8, 142.3, 141.3, 136.1, 135.6, 129.2, 127.6, 123.4, 123.3, 120.4, 117.8, 113.4, 59.6, 55.2, 49.0,
33.0, 28.7, 25.1, 24.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20NO2 318.1489; found
318.1488.
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6a,7,8,9,10,11-hexahydro-5H-spiro[azepino[1,2-a]quinoline-6,2'-indene]-1',3'-dione
(3f).
Yellow solid; 23.5 mg, 71% yield; mp 169–171 °C; column chromatography eluent, petroleum
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ether/EtOAc = 50:1; H NMR (500 MHz, CDCl3) δ 8.02‒7.89 (m, 2H), 7.89–7.75 (m, 2H), 7.13
(t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.68 (t, J = 7.3 Hz, 1H),
3.80–3.65 (m, 1H), 3.49 (dd, J = 11.2, 4.0 Hz, 1H), 3.35–3.19 (m, 1H), 3.11 (d, J = 17.0 Hz, 1H),
3.01 (d, J = 17.0 Hz, 1H), 2.01‒1.89 (m, 1H), 1.80‒1.72 (m, 1H), 1.69‒1.49 (m, 4H), 1.47‒1.39
(m, 1H), 1.38‒1.30 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 201.0, 201.0, 145.5, 141.8,
141.7, 135.6, 135.5, 129.0, 127.1, 123.3, 123.1, 118.8, 116.8, 112.8, 62.2, 54.2, 50.7, 30.6, 29.7,
29.4, 27.4, 26.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H22NO2 332.1645; found
332.1651.
1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2-a]quinoline]-2,6-dione (3g).4h
White solid; 25.0 mg, 93% yield; mp 140–142 °C; column chromatography eluent, petroleum
ether/EtOAc = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.11 (td, J = 8.2, 1.4 Hz, 1H), 6.92 (d, J = 7.3
Hz, 1H), 6.53 (td, J = 7.3, 0.7 Hz, 1H), 6.49 (d, J = 8.1 Hz, 1H), 3.97 (dd, J = 10.1, 6.0 Hz, 1H),
3.55 (t, J = 8.2 Hz, 1H), 3.29–3.19 (m, 1H), 3.12 (s, 2H), 2.86 (ddd, J = 16.1, 10.4, 5.7 Hz, 1H),
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2.73 (ddd, J = 16.2, 10.4, 6.1 Hz, 1H), 2.61 (dddd, J = 16.2, 6.2, 5.0, 1.1 Hz, 1H), 2.44–2.35 (m,
1H), 2.18–2.10 (m, 1H), 2.09–1.92 (m, 3H), 1.91‒1.81 (m, 1H), 1.74–1.65 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 210.0, 205.3, 144.4, 128.3, 128.1, 116.1, 114.8, 110.8, 60.9, 60.6,
47.9, 39.9, 39.0, 38.8, 27.4, 24.3, 17.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H20NO2
270.1489; found 270.1496.
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4,4-dimethyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2-a]quinoline]-2,6-
dione (3h).4h White solid; 28.2 mg, 95% yield; mp 158–159 °C; column chromatography eluent,
petroleum ether/EtOAc = 50:1; 1H NMR (500 MHz, CDCl3) δ 7.11 (t, J = 7.7 Hz, 1H), 6.90 (d, J
= 7.3 Hz, 1H), 6.51 (t, J = 7.3 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.02 (dd, J = 10.3, 5.9 Hz, 1H),
3.53 (t, J = 8.2 Hz, 1H), 3.22 (ddd, J = 10.4, 8.7, 6.5 Hz, 1H), 3.15 (d, J = 15.4 Hz, 1H), 3.08 (d, J
= 15.3 Hz, 1H), 2.90 (d, J = 15.1 Hz, 1H), 2.76 (d, J = 14.6 Hz, 1H), 2.48 (dd, J = 15.1, 2.6 Hz,
1H), 2.19 (dd, J = 14.6, 2.6 Hz, 1H), 2.11–2.03 (m, 2H), 2.02–1.92 (m, 1H), 1.73 (qd, J = 10.9, 7.3
Hz, 1H), 1.14 (s, 3H), 0.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 209.4, 205.1, 144.4,
128.5, 128.0, 115.9, 114.7, 110.7, 60.0, 59.9, 52.4, 52.2, 47.9, 40.8, 30.7, 30.4, 27.3, 26.7, 24.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H24NO2 298.1802; found 298.1807.
1',2',3',3a'-tetrahydro-2H,5'H-spiro[pyrimidine-5,4'-pyrrolo[1,2-a]quinoline]-2,4,6(1H,3H)-t
rione (3i).4h Pale yellow solid; 21.9 mg, 77% yield; mp 237–239 °C; column chromatography
eluent, petroleum ether/EtOAc = 2:1; 1H NMR (500 MHz, (CD3)2SO) δ 11.53 (s, 1H), 11.25 (s,
1H), 7.06 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.58 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 8.0
Hz, 1H), 3.66 (dd, J = 8.9, 6.2 Hz, 1H), 3.51 (td, J = 8.8, 4.0 Hz, 1H), 3.29 (d, J = 16.6 Hz, 1H),
3.22–3.06 (m, 2H), 2.14–2.05 (m, 1H), 2.02–1.89 (m, 2H), 1.67–1.54 (m, 1H); 13C{1H} NMR
(125 MHz, (CD3)2SO) δ 172.6, 169.3, 150.7, 143.8, 128.3, 127.0, 120.0, 115.8, 111.4, 63.3, 48.5,
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47.9, 35.0, 27.9, 23.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H16N3O3 286.1186; found
286.1194.
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2',2'-dimethyl-1,2,3,3a-tetrahydro-5H-spiro[pyrrolo[1,2-a]quinoline-4,5'-[1,3]dioxane]-4',6'-
dione (3j). White solid; 26.2 mg, 87% yield; mp 188–189 °C; column chromatography eluent,
petroleum ether/EtOAc = 30:1; 1H NMR (500 MHz, CDCl3) δ 7.17 (t, J = 7.7 Hz, 1H), 7.04 (d, J =
7.4 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 3.96 (dd, J = 8.9, 6.3 Hz, 1H), 3.62
(td, J = 8.5, 2.8 Hz, 1H), 3.55 (d, J = 16.2 Hz, 1H), 3.30 (dd, J = 16.0, 8.8 Hz, 1H), 3.13 (d, J =
16.3 Hz, 1H), 2.19 (dtd, J = 9.5, 6.7, 2.9 Hz, 1H), 2.08–1.94 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H),
1.71‒1.62 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.1, 164.2, 143.2, 128.3, 127.8, 117.0,
116.1, 111.6, 104.8, 64.7, 47.9, 47.3, 36.5, 30.0, 28.5, 28.2, 23.2; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H20NO4 302.1387; found 302.1384.
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3-phenyl-1',2',3',3a'-tetrahydro-5H,5'H-spiro[isoxazole-4,4'-pyrrolo[1,2-a]quinolin]-5-one
(3k).4h White solid; 31.2 mg, 98% yield, dr 1.2:1; mp 111–113 °C; column chromatography
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eluent, petroleum ether/EtOAc = 200:1; H NMR (500 MHz, CDCl3, major diastereomer) δ
7.75‒7.67 (m, 1H), 7.51–7.46 (m, 1H), 7.28–7.22 (m, 1H), 7.13–7.01 (m, 4H), 6.71‒6.45 (m, 1H),
6.21 (d, J = 8.1 Hz, 1H), 3.70 (dd, J = 9.3, 6.3 Hz, 1H), 3.54 (d, J = 17.0 Hz, 1H), 3.29–3.20 (m,
2H), 2.59 (dd, J = 16.7, 8.1 Hz, 1H), 2.16–1.87 (m, 3H), 1.62–1.53 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3 major diastereomer) δ 178.3, 166.2, 142.0, 129.6, 127.4, 127.2, 127.1, 127.0 (2C),
126.2 (2C), 116.3, 115.8, 110.3, 61.4, 49.6, 45.3, 33.7, 26.5, 21.9; 1H NMR (500 MHz, CDCl3,
minor diastereomer) δ 7.75‒7.67 (m, 1H), 7.54 (ddd, J = 6.3, 3.7, 1.2 Hz, 1H), 7.51–7.46 (m, 1H),
7.19 (t, J = 7.7 Hz, 1H), 7.13–7.01 (m, 3H), 6.71‒6.45 (m, 1H), 6.62 (d, J = 8.1 Hz, 1H), 4.05 (dd,
J = 9.4, 6.0 Hz, 1H), 3.65–3.57 (m, 2H), 3.38 (td, J = 8.9, 7.2 Hz, 1H), 3.06 (d, J = 16.4 Hz, 1H),
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2.16–1.87 (m, 3H), 1.62–1.53 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3, minor diastereomer)
δ174.3, 168.5, 142.3, 130.6, 128.3 (2C), 128.0, 127.2, 126.7, 126.6 (2C), 115.6, 113.6, 110.5,
59.0, 47.8, 47.0, 32.7, 27.6, 22.2,; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2O2
319.1441; found 319.1451.
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1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoline-4,4(5H)-dicarbonitrile (3l). White solid; 15.8 mg,
71% yield; mp 140–141 °C; column chromatography eluent, petroleum ether/EtOAc = 100:1; 1H
NMR (500 MHz, CDCl3) δ 7.23 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.4 Hz,
1H), 6.61 (d, J = 8.2 Hz, 1H), 3.84 (dd, J = 8.6, 6.1 Hz, 1H), 3.62–3.52 (m, 2H), 3.52–3.41 (m,
2H), 2.56 (ddd, J = 14.3, 7.2, 2.0 Hz, 1H), 2.33–2.25 (m, 1H), 2.25‒2.15 (m, 1H), 2.15–2.04 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 142.2, 129.5, 129.3, 117.8, 115.3, 113.8, 113.3, 112.4,
63.1, 48.1, 38.5, 34.2, 30.2, 23.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H14N3 224.1182;
found 224.1187.
1',2',3',3a'-tetrahydro-5'H-spiro[chromane-3,4'-pyrrolo[1,2-a]quinoline]-2,4-dione
(3m).4h
Yellow solid; 16.9 mg, 53% yield, dr 2.4:1; mp 152–153 °C; column chromatography eluent,
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petroleum ether/EtOAc = 80:1; H NMR (500 MHz, CDCl3, major diastereomer) δ 7.98 (dd, J =
7.8, 1.5 Hz, 1H), 7.71–7.65 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.26–7.19 (m, 1H), 7.16 (t, J = 7.4
Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.72–6.56 (m, 2H), 3.86 (dd, J = 9.3, 5.5 Hz, 1H), 3.63‒3.51
(m, 2H), 3.39–3.32 (m, 1H), 3.07 (d, J = 16.4 Hz, 1H), 2.05–1.90 (m, 3H), 1.67–1.60 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3, major diastereomer) δ 192.7, 164.9, 155.3, 143.2, 137.4, 128.4,
127.6, 127.2, 125.0, 118.4, 117.7, 117.3, 116.3, 111.3, 63.9, 55.2, 47.5, 36.3, 28.1, 23.5; 1H NMR
(500 MHz, CDCl3, minor diastereomer) δ 7.74 (dd, J = 7.9, 1.6 Hz, 1H), 7.65–7.61 (m, 1H), 7.26–
7.19 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.72–6.56 (m, 2H), 4.07 (dd, J =
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8.9, 6.5 Hz, 1H), 3.63–3.51 (m, 2H), 3.39–3.32 (m, 1H), 3.14 (d, J = 16.1 Hz, 1H), 2.17 (ddd, J =
11.9, 6.1, 3.4 Hz, 1H), 2.05–1.90 (m, 2H), 1.67–1.60 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3,
minor diastereomer) δ 189.6, 170.2, 154.2, 143.7, 136.6, 128.2, 127.9, 127.1, 125.3, 119.3, 117.2,
116.2, 111.3, 63.9, 54.4, 48.1, 37.9, 27.8, 23.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H18NO3 320.1281; found 320.1295.
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1',2',3',3a'-tetrahydro-5'H-spiro[indoline-3,4'-pyrrolo[1,2-a]quinolin]-2-one (3n). Yellow
solid; 20.3 mg, 70% yield, dr >20:1; mp 250–252 °C; column chromatography eluent, petroleum
ether/EtOAc = 10:1; 1H NMR (500 MHz, (CD3)2SO) δ 10.63 (s, 1H), 7.20‒7.07 (m, 2H), 6.99 (d,
J = 7.2 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.62–6.51 (m, 2H), 6.21 (d, J =
7.4 Hz, 1H), 3.71 (dd, J = 9.8, 5.7 Hz, 1H), 3.48 (t, J = 8.2 Hz, 1H), 3.16 (d, J = 15.6 Hz, 1H),
3.10 (dd, J = 16.5, 9.1 Hz, 1H), 2.59 (d, J = 15.7 Hz, 1H), 1.94‒1.83 (m, 1H), 1.83–1.70 (m, 2H),
0.81‒0.70 (m, 1H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ 179.9, 144.1, 142.6, 130.0, 129.8,
128.3, 128.2, 124.5, 121.9, 118.5, 115.7, 110.4, 109.8, 62.5, 47.6, 46.2, 37.1, 27.2, 23.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O 291.1492; found 291.1492.
2',4'-dimethyl-8'-nitro-1',2',4',4a'-tetrahydro-2H,6'H-spiro[pyrimidine-5,5'-[1,4]oxazino[4,3-
a]quinoline]-2,4,6(1H,3H)-trione (3o).13 Yellow solid; 20.2 mg, 54% yield, dr >20:1; mp 208–
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209 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; H NMR (500 MHz,
(CD3)2SO) δ 11.89 (s, 1H), 11.58 (s, 1H), 7.98 (dd, J = 9.2, 2.7 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H),
7.03 (d, J = 9.4 Hz, 1H), 4.30 (dd, J = 13.5, 1.7 Hz, 1H), 3.92 (d, J = 9.0 Hz, 1H), 3.68–3.50 (m,
3H), 2.99 (dd, J = 13.7, 10.8 Hz, 1H), 2.87 (d, J = 14.9 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.95 (d,
J = 6.4 Hz, 3H); 13C{1H} NMR (125 MHz, (CD3)2SO) δ 171.6, 168.2, 151.0, 149.9, 136.2, 125.2,
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124.5, 119.6, 111.2, 72.6, 71.6, 62.9, 53.2, 51.5, 37.5, 19.0, 18.6; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H19N4O6 375.1229; found 375.1233.
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yield; mp 82–84 °C; column chromatography eluent, petroleum ether/EtOAc = 100:1; H NMR
(500 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.14 (t, J = 7.4 Hz, 2H),
6.96 (d, J = 7.3 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.64 (dd, J = 8.2, 5.3
Hz, 1H), 4.39 (d, J = 14.9 Hz, 1H), 4.12 (d, J = 14.9 Hz, 1H), 3.46 (td, J = 8.7, 3.0 Hz, 1H), 3.38
(dd, J = 16.3, 8.4 Hz, 1H), 2.10–2.03 (m, 1H), 2.02–1.94 (m, 1H), 1.95–1.86 (m, 1H), 1.78–1.69
(m,1H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.3, 142.5, 127.9 (2C), 126.8, 124.9, 124.2 (2C),
123.7, 119.8, 115.2, 110.3, 75.7, 56.3, 46.1, 30.9, 21.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H19N2 251.1543; found 251.1546.
8-methyl-4-phenyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5b). Colorless oil; 10.6
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mg, 40% yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; H NMR (500
MHz, CDCl3) δ 7.30 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.85 (d,
J = 7.5 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 6.36 (s, 1H), 4.62 (dd, J = 8.2, 5.3 Hz, 1H), 4.35 (d, J =
14.8 Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 3.44 (td, J = 8.7, 3.1 Hz, 1H), 3.37 (dd, J = 16.4, 8.3 Hz,
1H), 2.30 (s, 3H), 2.11–2.02 (m, 1H), 2.01–1.84 (m, 2H), 1.77‒1.66 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ 150.4, 143.4, 137.5, 128.9 (2C), 125.8, 125.2 (2C), 124.7, 118.1, 117.0, 112.1,
76.7, 57.1, 47.1, 31.9, 22.3, 21.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21N2 265.1699;
found 265.1698.
8-chloro-4-phenyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5c). White solid; 19.9
mg, 70% yield; mp 88–90 °C; column chromatography eluent, petroleum ether/EtOAc = 150:1; 1H
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NMR (500 MHz, CDCl3) δ 7.31 (t, J = 7.6 Hz, 2H), 7.18–7.13 (m, 3H), 6.85 (d, J = 7.9 Hz, 1H),
6.59 (d, J = 7.9 Hz, 1H), 6.47 (s, 1H), 4.64 (dd, J = 8.5, 5.2 Hz, 1H), 4.32 (d, J = 15.0 Hz, 1H),
4.05 (d, J = 15.0 Hz, 1H), 3.43 (td, J = 8.6, 2.0 Hz, 1H), 3.32 (dd, J = 16.7, 8.5 Hz, 1H), 2.08–2.01
(m, 1H), 2.00–1.96 (m, 1H), 1.95–1.86 (m, 1H), 1.76–1.66 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 149.8, 144.4, 133.3, 129.1 (2C), 126.9, 125.4 (2C), 125.1, 119.0, 115.6, 110.7, 76.7,
56.9, 47.0, 32.0, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18ClN2 285.1153; found
285.1149.
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7-bromo-4-phenyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5d). White solid; 26.9
mg, 82% yield; mp 87–89 °C; column chromatography eluent, petroleum ether/EtOAc = 150:1; 1H
NMR (500 MHz, CDCl3) δ 7.31 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.18‒7.12 (m, 3H),
7.05 (s, 1H), 6.37 (d, J = 8.6 Hz, 1H), 4.62 (dd, J = 8.2, 5.3 Hz, 1H), 4.34 (d, J = 15.2 Hz, 1H),
4.04 (d, J = 15.2 Hz, 1H), 3.42 (td, J = 8.5, 2.2 Hz, 1H), 3.35‒3.28 (m, 1H), 2.08–2.01 (m, 1H),
2.00‒1.94 (m, 1H), 1.94–1.84 (m, 1H), 1.76‒1.66 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
149.7, 142.5, 130.5, 129.1 (2C), 128.5, 125.4 (2C), 125.1, 122.7, 112.7, 107.8, 76.7, 56.8, 47.1,
31.9, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18BrN2 329.0648; found 329.0647.
4-(1,2,3,3a-tetrahydropyrrolo[1,2-a]quinazolin-4(5H)-yl)phenol (5e). White solid; 18.1 mg,
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68% yield; mp 120–123 °C; column chromatography eluent, petroleum ether/EtOAc = 8:1; H
NMR (500 MHz, (CD3)2SO) δ 9.30 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 2H), 6.96
(d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.58 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H),
4.55 (dd, J = 7.8, 4.7 Hz, 1H), 4.26 (d, J = 14.8 Hz, 1H), 3.87 (d, J = 14.8 Hz, 1H), 3.51–3.46 (m,
1H), 3.22 (q, J = 8.1 Hz, 1H), 1.99–1.91 (m, 1H), 1.92–1.82 (m, 2H), 1.62–1.51 (m, 1H); 13C{1H}
NMR (125 MHz, (CD3)2SO) δ 155.1, 143.8, 141.9, 127.9, 126.9 (2C), 126.2, 121.4, 115.9 (2C),
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115.7, 111.2, 77.3, 57.3, 47.7, 32.2, 22.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19N2O
267.1492; found 267.1495.
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mg, 57% yield; mp 66–68 °C; column chromatography eluent, petroleum ether/EtOAc = 100:1; 1H
NMR (500 MHz, CDCl3) δ 7.17–7.09 (m, 3H), 6.95 (d, J = 7.3 Hz, 1H), 6.87–6.83 (m, 2H), 6.63
(td, J = 7.4, 0.8 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.57 (dd, J = 8.3, 5.0 Hz, 1H), 4.36 (d, J = 14.9
Hz, 1H), 4.01 (d, J = 14.9 Hz, 1H), 3.79 (s, 3H), 3.46 (td, J = 8.6, 2.7 Hz, 1H), 3.39–3.33 (m, 1H),
2.01–1.83 (m, 3H), 1.73–1.64 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 157.1, 143.4, 143.1,
127.8, 126.8 (2C), 126.0, 120.8, 116.0, 114.2 (2C), 111.2, 77.2, 57.6, 55.4, 47.1, 31.9, 22.3;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21N2O 281.1648; found 281.1647.
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4-(3-chlorophenyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5g). White solid; 23.0
mg, 81% yield; mp 70–71 °C; column chromatography eluent, petroleum ether/EtOAc = 400:1; 1H
NMR (500 MHz, CDCl3) δ 7.21 (t, J = 8.0 Hz, 1H), 7.17–7.11 (m, 2H), 7.08 (ddd, J = 8.0, 2.0, 0.9
Hz, 1H), 7.03 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.70–6.63 (m, 1H), 6.54 (d,
J = 8.0 Hz, 1H), 4.59 (dd, J = 8.3, 5.3 Hz, 1H), 4.36 (d, J = 14.9 Hz, 1H), 4.11 (d, J = 14.9 Hz,
1H), 3.44 (td, J = 8.7, 3.3 Hz, 1H), 3.37 (q, J = 8.4 Hz, 1H), 2.11 (dddd, J = 12.3, 7.6, 5.4, 2.5 Hz,
1H), 2.00 (dddd, J = 14.2, 11.7, 6.0, 3.5 Hz, 1H), 1.96–1.86 (m, 1H), 1.72 (ddt, J = 12.0, 10.8, 8.3
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 151.6, 143.5, 134.4, 129.9, 128.0, 126.0, 124.8,
124.5, 123.1, 120.6, 116.6, 111.6, 76.4, 56.9, 47.1, 31.8, 22.2; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H18ClN2 285.1153; found 285.1147.
4-(4-iodophenyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5h). White solid; 28.6 mg,
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76% yield; mp 72–74 °C; column chromatography eluent, petroleum ether/EtOAc = 150:1; H
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NMR (500 MHz, CDCl3) δ 7.63–7.56 (m, 2H), 7.14 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H),
6.93–6.87 (m, 2H), 6.66 (td, J = 7.4, 0.8 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.60 (dd, J = 8.4, 5.3
Hz, 1H), 4.37 (d, J = 15.0 Hz, 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.43 (td, J = 8.7, 3.3 Hz, 1H), 3.36
(q, J = 8.4 Hz, 1H), 2.08 (dddd, J = 12.3, 7.5, 5.4, 2.5 Hz, 1H), 1.98 (dddt, J = 13.1, 7.7, 5.8, 2.9
Hz, 1H), 1.94–1.85 (m, 1H), 1.70 (ddt, J = 12.0, 10.8, 8.3 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 149.9, 143.5, 138.0 (2C), 128.0, 127.1 (2C), 125.9, 120.5, 116.5, 111.5, 88.5, 76.4, 56.9,
47.0, 31.7, 22.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18IN2 377.0509; found 377.0508.
4-(3-nitrophenyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5i). Yellow oil; 23.6 mg,
80% yield; column chromatography eluent, petroleum ether/EtOAc = 150:1; 1H NMR (500 MHz,
CDCl3) δ 7.96–7.88 (m, 2H), 7.45–7.40 (m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.00 (dd, J = 7.5, 1.4
Hz, 1H), 6.70 (td, J = 7.4, 0.8 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.68 (dd, J = 8.4, 5.4 Hz, 1H),
4.46 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 3.47–3.37 (m, 2H), 2.22 (dddd, J = 12.5, 7.9,
5.4, 2.8 Hz, 1H), 2.08–1.91 (m, 2H), 1.74 (ddt, J = 12.1, 10.3, 8.5 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ 151.1, 148.8, 143.6, 130.1, 129.6, 128.2, 125.9, 120.5, 118.3, 118.2, 117.1, 111.8,
76.0, 56.1, 46.8, 31.5, 22.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18N3O2 296.1394;
found 296.1398.
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4-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-
a]quinazoline (5j). Colorless oil; 27.3 mg, 69% yield; column chromatography eluent, petroleum
ether/EtOAc = 400:1; 1H NMR (500 MHz, CDCl3) δ 7.27‒7.22 (m, 1H), 7.14 (t, J = 7.7 Hz, 1H),
6.98‒6.90 (m, 2H), 6.65 (t, J = 7.4 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 4.83–4.75 (m, 1H), 4.50 (d, J
= 15.3 Hz, 1H), 4.05 (d, J = 15.3 Hz, 1H), 3.45 (td, J = 8.5, 3.1 Hz, 1H), 3.33 (dd, J = 16.5, 8.2
Hz, 1H), 3.17 (q, J = 9.3 Hz, 2H), 2.41 (s, 3H), 2.13‒2.04 (m, 1H), 2.03–1.87 (m, 2H), 1.68–1.59
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(m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 158.8 (d, J = 248.9 Hz), 143.5, 139.0 (d, J = 8.1
Hz), 135.0 (d, J = 11.1 Hz), 132.0 (d, J = 2.9 Hz), 127.9, 127.6 (d, J = 3.4 Hz), 126.0, 125.3 (q, J
= 275.4 Hz), 119.9, 118.0 (d, J = 21.6 Hz), 116.4, 111.5, 75.9, 56.1, 46.9, 37.5 (q, J = 32.1 Hz),
30.6, 22.3, 20.2; 19F NMR (470 MHz, CDCl3) δ ‒66.15, ‒121.39; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C20H21F4N2S 397.1356; found 397.1358.
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4-benzyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5k).5i Colorless oil; 16.4 mg, 62%
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yield; column chromatography eluent, petroleum ether/EtOAc = 50:1; H NMR (500 MHz,
CDCl3) δ 7.37 (d, J = 7.1 Hz, 2H), 7.34–7.29 (m, 2H), 7.28–7.23 (m, 1H), 7.07 (t, J = 7.6 Hz, 1H),
6.80 (d, J = 7.3 Hz, 1H), 6.55 (td, J = 7.3, 0.7 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.14 (dd, J = 8.4,
5.3 Hz, 1H), 3.92 (d, J = 13.1 Hz, 1H), 3.66 (d, J = 14.8 Hz, 1H), 3.54 (d, J = 14.8 Hz, 1H), 3.42
(td, J = 8.6, 2.6 Hz, 1H), 3.37 (dt, J = 16.1, 8.0 Hz, 1H), 3.31 (d, J = 13.1 Hz, 1H), 2.30–2.24 (m,
1H), 2.14–2.07 (m, 1H), 2.03–1.84 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 142.2, 137.3,
128.0 (2C), 127.3 (2C), 126.6, 126.1, 125.4, 118.4, 114.7, 109.4, 77.4, 55.5, 53.5, 45.6, 30.8, 21.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21N2 265.1699; found 265.1706.
4-butyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5l). Colorless oil; 16.1 mg, 70%
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yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; H NMR (500 MHz,
CDCl3) δ 7.08 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.59 (td, J = 7.4, 0.7 Hz, 1H), 6.41 (d,
J = 8.0 Hz, 1H), 3.97–3.91 (m, 2H), 3.55 (d, J = 14.5 Hz, 1H), 3.39 (td, J = 8.7, 2.3 Hz, 1H), 3.32
(dt, J = 16.2, 8.1 Hz, 1H), 2.72–2.65 (m, 1H), 2.27–2.18 (m, 2H), 2.12–2.05 (m, 1H), 1.98–1.88
(m, 1H), 1.83–1.74 (m, 1H), 1.64–1.54 (m, 2H), 1.44–1.31 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 143.2, 127.7, 126.4, 119.6, 115.7, 110.4, 78.6, 54.6, 52.2,
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46.5, 31.8, 29.5, 22.4, 20.9, 14.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H23N2 231.1856;
found 231.1859.
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4-isobutyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5m).5i Colorless oil; 18.4 mg,
80% yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; 1H NMR (500 MHz,
CDCl3) δ 7.08 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.58 (td, J = 7.3, 0.7 Hz, 1H), 6.41 (d,
J = 8.0 Hz, 1H), 3.97 (dd, J = 8.8, 5.3 Hz, 1H), 3.87 (d, J = 14.8 Hz, 1H), 3.57 (d, J = 14.7 Hz,
1H), 3.40–3.30 (m, 2H), 2.29 (dd, J = 12.3, 9.2 Hz, 1H), 2.20–2.12 (m, 1H), 2.11–2.03 (m, 2H),
1.97–1.82 (m, 2H), 1.79–1.69 (m, 1H), 0.97‒0.90 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ
143.4, 127.6, 126.4, 119.8, 115.6, 110.3, 78.6, 60.5, 55.3, 46.5, 31.7, 26.4, 22.2, 21.4, 21.0;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H23N2 231.1856; found 231.1862.
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4-tosyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline (5n). White solid; 20.0 mg, 61%
yield; mp 130–131 °C; column chromatography eluent, petroleum ether/EtOAc = 30:1; 1H NMR
(500 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 7.7 Hz, 1H),
6.92 (d, J = 7.4 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 4.68 (d, J = 15.0 Hz,
1H), 4.30 (dd, J = 8.3, 5.8 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.29–3.24 (m, 1H), 3.15 (dd, J =
16.4, 8.5 Hz, 1H), 2.44–2.37 (m, 2H), 2.36 (s, 3H), 2.11–2.03 (m, 1H), 1.91–1.80 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 144.0, 142.9, 135.0, 129.8 (2C), 128.5, 127.9 (2C), 126.2,
118.7, 117.4, 111.9, 74.4, 49.8, 46.6, 32.3, 22.4, 21.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H21N2O2S 329.1318; found 329.1314.
4-((trifluoromethyl)sulfonyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazolin (5o). Colorless
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oil; 11.0 mg, 36% yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; H
NMR (500 MHz, CDCl3) δ 7.21 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.80 (t, J = 7.5 Hz,
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1H), 6.65 (d, J = 8.1 Hz, 1H), 4.80 (t, J = 6.7 Hz, 1H), 4.69‒4.60 (m, 2H), 3.39 (t, J = 7.0 Hz, 2H),
2.48–2.36 (m, 2H), 2.23–2.12 (m, 1H), 2.02–1.90 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
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143.1, 128.9, 125.8, 119.9 (q, J = 321.9 Hz), 119.6, 118.8, 113.4, 75.1, 49.4, 46.5, 30.9, 21.6; 19
F
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NMR (470 MHz, CDCl3) δ ‒75.59; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H14F3N2O2S
307.0723; found 307.0721.
3-(1,2,3,3a-tetrahydropyrrolo[1,2-a]quinazolin-4(5H)-yl)propanoic acid (5p). Colorless oil;
21.2 mg, 86% yield; column chromatography eluent, DCM/methanol = 10:1; 1H NMR (500 MHz,
CDCl3) δ 10.16 (s, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H),
6.46 (d, J = 8.1 Hz, 1H), 4.26 (t, J = 6.3 Hz, 1H), 4.05 (d, J = 15.1 Hz, 1H), 3.91 (d, J = 15.0 Hz,
1H), 3.38 (t, J = 6.9 Hz, 1H), 3.31 (dd, J = 15.5, 7.7 Hz, 1H), 2.96 (dt, J = 13.1, 6.7 Hz, 1H), 2.74
(dt, J = 12.6, 6.2 Hz, 1H), 2.58 (t, J = 6.4 Hz, 2H), 2.31–2.20 (m, 1H), 2.11–1.87 (m, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 174.7, 142.3, 128.4, 127.0, 116.9, 116.8, 111.2, 77.6, 53.3,
46.7, 46.1, 31.3, 30.0, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H19N2O2 247.1441;
found 247.1441.
1,2,3,3a-tetrahydro-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazine (6a).6c Colorless oil; 8.4 mg, 48%
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yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; H NMR (500 MHz,
CDCl3) δ 7.14 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.68 (d, J =
8.1 Hz, 1H), 4.96–4.90 (m, 2H), 4.75 (d, J = 14.4 Hz, 1H), 3.63–3.57 (m, 1H), 3.25 (dd, J = 15.9,
7.8 Hz, 1H), 2.37–2.28 (m, 1H), 2.10–2.01 (m, 1H), 1.98–1.88 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 143.2, 127.7, 124.6, 121.6, 117.9, 115.2, 89.4, 68.2, 49.7, 32.4, 22.5; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C11H14NO 176.1070; found 176.1071.
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4b,13-dihydro-6H,12H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (6b). White solid; 12.6 mg,
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53% yield; mp 138–139 °C; column chromatography eluent, petroleum ether/EtOAc = 200:1; H
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8.1 Hz, 1H), 7.04–6.94 (m, 2H), 5.41 (s, 1H), 5.22 (d, J = 14.7 Hz, 1H), 4.97 (d, J = 14.7 Hz, 1H),
3.55 (td, J = 11.3, 3.7 Hz, 1H), 3.49–3.42 (m, 1H), 3.14 (ddd, J = 16.0, 10.7, 5.3 Hz, 1H), 2.91 (dt,
J = 16.0, 3.6 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 146.0, 135.3, 133.4, 128.7, 128.3,
128.3, 127.3, 126.4, 126.3, 125.0, 121.7, 121.2, 84.4, 68.3, 46.2, 29.8; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C16H16NO 238.1226; found 238.1221.
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6a,7,8,9,10,11-hexahydro-5H-benzo[4,5][1,3]oxazino[3,2-a]azepine (6c). Colorless oil; 9.6
mg, 47% yield; column chromatography eluent, petroleum ether/EtOAc = 300:1; 1H NMR (500
MHz, CDCl3) δ 7.12 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.73 (t,
J = 7.4 Hz, 1H), 4.94 (d, J = 14.4 Hz, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.74–4.67 (m, 1H), 3.59 (dd,
J = 15.2, 8.3 Hz, 1H), 3.20 (dd, J = 15.2, 7.7 Hz, 1H), 2.12–2.02 (m, 1H), 1.97–1.88 (m, 1H),
1.85–1.76 (m, 2H), 1.74–1.64 (m, 2H), 1.60–1.50 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
145.5, 127.2, 124.4, 122.4, 117.8, 115.1, 88.1, 67.5, 47.6, 33.7, 30.2, 29.5, 22.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H18NO 204.1383; found 204.1388.
4-methoxy-6a,7,8,9,10,11-hexahydro-5H-benzo[4,5][1,3]oxazino[3,2-a]azepine
(6d).
Colorless oil; 10.3 mg, 44% yield; column chromatography eluent, petroleum ether/EtOAc =
200:1; 1H NMR (500 MHz, CDCl3) δ 7.09 (t, J = 8.2 Hz, 1H), 6.47 (d, J = 8.3 Hz, 1H), 6.31 (d, J
= 8.1 Hz, 1H), 4.85 (d, J = 15.2 Hz, 1H), 4.78 (d, J = 15.2 Hz, 1H), 4.60 (dd, J = 8.1, 5.0 Hz, 1H),
3.78 (s, 3H), 3.57 (dd, J = 15.2, 9.1 Hz, 1H), 3.22 (dd, J = 15.2, 6.9 Hz, 1H), 2.14–2.05 (m, 1H),
1.92–1.85 (m, 1H), 1.84–1.78 (m, 2H), 1.75–1.64 (m, 2H), 1.56–1.46 (m, 2H); 13C{1H} NMR
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(125 MHz, CDCl3) δ 155.9, 147.2, 127.4, 111.4, 109.0, 100.1, 87.9, 64.4, 55.2, 48.2, 33.4, 30.8,
29.7, 22.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H20NO2 234.1489; found 234.1485.
4-fluoro-6a,7,8,9,10,11-hexahydro-5H-benzo[4,5][1,3]oxazino[3,2-a]azepine (6e). Pale yellow
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oil; 13.9 mg, 63% yield; column chromatography eluent, petroleum ether/EtOAc = 500:1; H
NMR (500 MHz, CDCl3) δ 7.06 (dd, J = 15.2, 8.0 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 6.41 (t, J =
8.7 Hz, 1H), 4.92 (d, J = 14.9 Hz, 1H), 4.84 (d, J = 14.9 Hz, 1H), 4.66 (dd, J = 7.1, 4.8 Hz, 1H),
3.59 (dd, J = 15.4, 7.9 Hz, 1H), 3.22 (dd, J = 15.1, 7.9 Hz, 1H), 2.10–2.02 (m, 1H), 1.99–1.91 (m,
1H), 1.85–1.75 (m, 2H), 1.72–1.61 (m, 2H), 1.60–1.50 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 159.5 (d, J = 240.5 Hz), 147.6 (d, J = 7.8 Hz), 128.2 (d, J = 10.1 Hz), 110.4 (d, J = 2.6
Hz), 110.1 (d, J = 19.6 Hz), 104.2 (d, J = 20.8 Hz), 88.3, 63.2 (d, J = 6.0 Hz), 48.0, 33.9, 30.5,
29.8, 22.9; 19F NMR (470 MHz, CDCl3) δ ‒121.18; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H17FNO 222.1289; found 222.1291.
1-chloro-6a,7,8,9,10,11-hexahydro-5H-benzo[4,5][1,3]oxazino[3,2-a]azepine (6f). Pale yellow
1
oil; 18.2 mg, 77% yield; column chromatography eluent, petroleum ether/EtOAc = 300:1; H
NMR (500 MHz, CDCl3) δ 7.23 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.7 Hz, 1H), 6.81 (d, J = 7.5 Hz,
1H), 4.89 (d, J = 15.0 Hz, 1H), 4.82 (d, J = 15.0 Hz, 1H), 4.51 (t, J = 15.5 Hz, 1H), 3.33 (dd, J =
14.6, 11.6 Hz, 1H), 3.01 (m, 1H), 2.34–2.26 (m, 1H), 2.19–2.08 (m, 1H), 1.98–1.90 (m, 1H),
1.85–1.52 (m, 4H), 1.43–1.31 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 145.4, 129.5, 128.5,
128.0, 123.1, 122.7, 89.0, 67.1, 49.1, 33.9, 30.6, 30.4, 22.3; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C13H17ClNO 238.0993; found 238.0994.
3-bromo-6a,7,8,9,10,11-hexahydro-5H-benzo[4,5][1,3]oxazino[3,2-a]azepine (6g). Colorless
1
oil; 20.2 mg, 72% yield; column chromatography eluent, petroleum ether/EtOAc = 300:1; H
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