Additive-free radical cascade reaction of oxime esters: Synthesis of pyrroline-functionalized phenanthridines

Article abstract of DOI:10.1021/acs.joc.0c01532

A variety of dihydropyrrole-functionalized phenanthridines were efficiently synthesized by the metal-free, radical cascade cyclization reaction of 2-isocyanobiphenyls with γ,δ- unsaturated oxime esters. The C-N/C-C/C-C bonds were formed via the oil bath method in a one-pot procedure with broad substrate applicability. The radical process was supported by kinetic isotope effect studies and radical inhibition studies.

Full text of DOI:10.1021/acs.joc.0c01532

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Article
Additive-Free Radical Cascade Reaction of Oxime Esters#
Synthesis of Pyrroline-Functionalized Phenanthridines
Yijie Xue, Dengqi Xue, Qian He, Qianwei Ge, Wei Li, and Liming Shao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01532 • Publication Date (Web): 11 Sep 2020
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Additive-Free Radical Cascade Reaction of Oxime Esters：
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Synthesis of Pyrroline-Functionalized Phenanthridines
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Yijie Xue,+ Dengqi Xue,+†,‡ Qian He,† Qianwei Ge,† Wei Li,† Liming Shao*,†,‡
†
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†School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi-tech
Park, Pudong, Shanghai 201203, China
‡State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan
Road, Shanghai 200032, China
*E-mail: limingshao@fudan.edu.cn
+These authors contributed equally to this work
Table of Contents/Abstract Graphic:
R3
O
R4
R5
CN
N
N
N
R6
R7
R2
O
N
R6
R1
R7
1,2-dichlorobenzene
180 °C, 35 min
R3
H
R4 R5
R1
R2
one-step strategy
35 examples
yields up to 83%
radical pathway
metal-free
no ligand
ABSTRACT: A variety of dihydropyrrole-functionalized phenanthridines were
efficiently synthesized by the metal-free, radical cascade cyclization reaction of
2-isocyanobiphenyls with γ, δ-unsaturated oxime esters. The C−N/C−C/C−C bonds
were formed via the oil bath method in a one-pot procedure with broad substrate
applicability. The radical process was supported by kinetic isotope effect studies and
radical inhibition studies.
INTRODUCTION
Phenanthridine as a versatile bioactive molecule has attracted extensive
attention.1 Meanwhile, pyrrolines are one of the most important moieties in
pharmaceutical and natural products.2 Consequently, various methodologies for
preparing phenanthridine3 and pyrroline4 compounds have been developed in
recent years. Compounds with these two fragments may possess potential
biological and pharmacological activities; however, there has been little
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investigation into developing an efficient method for the synthesis of
pyrroline-functionalized phenanthridines.
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The use of iminyl radicals appears highly promising because of their wide
application in the synthesis of heterocycles.5 Reductive cleavage of the N−O bond in
oxime esters or ethers enables the efficient and facile generation of iminyl radicals
under transition metal-catalyzed,6 light irradiation,7 microwave irradiation8 or thermal
conditions.9 Although a number of functional groups have been introduced into
pyrrolines by iminyl radicals in cascade reactions with unactivated alkenes, these
transformations require transition-metal catalysts.10 To the best of our knowledge, the
use of an additive-free system for such a synthesis remains unexplored (Scheme 1a).
Designing a reaction protocol without the aid of catalysts toward developing a simple,
waste-free, and cost-effective method still remains a challenge.11 The use of
isocyanides as radical acceptors to directly and efficiently construct heterocycles has
been widely recognized.12 Thus, we believe that a free-radical cascade cyclization
reaction of γ, δ-unsaturated oxime esters with 2-isocyanobiphenyls should enable the
concise synthesis of various pyrroline-functionalized phenanthridines. This strategy
involves the one-pot formation of C−N/C−C/C−C bonds (Scheme 1b).
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Scheme 1. Previous work of the use of oxime esters-tethered alkenes in
cyclization reactions and strategies for this work.
(a) Imino-functionalization of oxime esters:
R
O
R5
R4
FG
O
[TM]
N
R4
N
FG-X
R1
R1
R5
[TM]=[Cu], [Ni], [Fe], [Pd]
R2 R3
R2 R3
, -unsaturated oxime esters
FG=Br, SCF3, SCN, CN, N3, SO2R, COAr, Ar, NHAr
functionalized pyrrolines
(b) Cascade cyclization of oxime esters with isocyanide (this work):
R6
R
O
CN
R4
R5
R7
O
N
R4
R6
N
N
R1
R5
1,2-dichlorobenzene
180 °C, 35 min
R2 R3
R1
R7
R2 R3
RESULTS AND DISCUSSION
The 2-pyridyl group was a good leaving group to N-O bond cleavage of oxime
ester,10e so the reaction of 2-isocyanobiphenyl (1a) with the oxime ester 2a-2-Py
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was investigated initially (Table 1). To our delight, the desired product
pyrroline-functionalized phenanthridine (3aa) was obtained in 62% yield at 190
°C in oil-bath heating (entry 1). Then, the effect of the temperature on the
reaction rate was investigated (entries 1–4). The reaction at 160 °C gave only
traces of the product and extending the reaction time to 24 h improved the yield
to 50% (entry 5). The yield was increased to 67% at 180 °C for 60 min. An
extensive screening of reaction times (entries 6–8) revealed that a reaction time
of 35 min gave the best results of all the reaction times investigated. It should
be noted that changing the amount of oxime ester resulted in a decreased yield
of the target product (3aa) (entries 9 and 10). Altering the solvent (entries 11–
13) or the N-based leaving groups (entries 14–17) did not improve the yield of
the target product (3aa). Performing the reaction under an air atmosphere or in
the presence of water led to a lower yield of the product (3aa) (entries 18–19).
It should be noted that the reaction could also be easily conducted on a gram
scale without appreciable loss of yield (entry 20). The reaction generated the
equivalent yield with new glassware and stir bar, which could exclude the
existence of trace amounts of metals (entry 21).
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Under the optimized reaction conditions, the scope of the oxime ester in this
cascade
sequence
was
investigated
(Table
2).
The
desired
pyrroline-functionalized phenanthridine derivatives (3aa–3ar) were produced
smoothly. The electronic properties and the position of the substituents on the
benzene rings of the oxime ester had little or no impact on the transformation,
with moderate to good yields observed (3aa–3ah). Pyridine and naphthalene
substituents on the oxime ester afforded the products with acceptable yields
(3ai–3ak). Removal of the di-methyl group from the oxime ester led to a low
yield of the product 3al. This was presumably because of the lack of the
Thorpe-Ingold effect.13 Introduction of a di-methyl group to the alkene of the
oxime ester also worked well (3am). A series of spirocyclic products could be
obtained conveniently (3an–3ap). When γ, δ-unsaturated oxime esters bearing
a cyclohexene moiety were reacted, the corresponding products were obtained
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as single diastereoisomers (3aq and 3ar). These two examples (3aq and 3ar)
indicate that the trapping of the cyclization-derived carbon radical from the less
sterically hindered exo direction was preferred.
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Table 1. Modification of the typical reaction conditionsa
R
O
N
CN
N
N
O
time, solvent,
temp, Ar
1a
2a
3aa
Entry
R
t
Solvent
(ml)
T
yield
(%)b
62
(min)
60
(°C)
190
180
170
160
160
180
180
180
180
180
180
180
180
180
180
180
180
180
1
2
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
Me
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
Xylene
DMF
60
67
3
60
61
4
60
Trace
50
5
1440
30
6
70
7
35
78
8
40
74
9c
10d
11
12
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15
16
17
18e
35
11
35
51
35
54
35
46
35
NMP
44
35
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
18
t-Bu
Ph
35
36
35
23
C6F5
2-Py
35
50
35
14
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19f
20g
21h
2-Py
2-Py
2-Py
35
35
35
o-DCB
o-DCB
o-DCB
180
180
180
68
72
76
9
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), solvent (1 mL), 180 °C (oil
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b
c
d
bath), 35 min, Ar, unless otherwise noted. Isolated yields. 2a (0.3 mmol). 2a (0.9
e
f
g
mmol). Under air conditions. Water (15 μL) was added. 3 mmol scale of substrate
was used. hNew stir bar and tube were used.
Table 2. Scope of γ, δ-unsaturated oxime esters.a
R1
R2
R3
O
CN
N
N
N
R4
R5
o-DCB,
O
N
R4
180 °C, 35 min
R1
R5
R2 R3
1a
2a-r
3aa-ar
N
R
N
N
N
N
N
3ab
: R=p-F, 71%
: R=p-Cl, 75%
: R=p-Br, 63%
: R=p-OCH3, 69%
: R=p-CH3, 74%
3ac
3ad
3ae
N
3af
3ag
3ah
: R=o-Cl, 70%
: R=m-Cl, 76%
b
3aa
, 78%
3ai
: 73%
N
N
N
N
N
N
N
N
3aj
, 68%
3ak
, 49%
3al
3am
, 34%
, 68%
N
N
n
N
N
H
H
H
N
H
N
H
H
3an
3ao
3ap
: n=1, 73%
: n=2, 72%
: n=3, 60%
c, d
c, d
3aq
3ar
, 61%, dr >95:5
, 64%, dr >95:5
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), solvent (1 mL), 180 °C (oil
b
c
bath), 35 min, Ar. Isolated yields. The determination of the ratio of diastereoisomer
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d
is based on H NMR. The configuration of diastereomer was confirmed by coupling
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constants of 1H NMR and NOE.
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2‑Isocyanobiphenyl compounds bearing various substituents were also subjected to
the optimized conditions with 2a, delivered the corresponding products (3ba–3qa) in
acceptable yields (Table 3). Substrates bearing electron-donating or
electron-withdrawing groups on 2‑isocyanobiphenyl reacted with 2a to afford the
corresponding products 3ba–3ma in yields of 38%–82%. When two nonequivalent
ortho hydrogen atoms were present on the isonitrile phenyl moiety, two isomers 3ja
and 3ja’ were isolated in good yields but with poor regioselectivity. The
ortho-methylbiphenylisonitrile afforded a lower yield (3ka, 38%). Slightly
lower yields were obtained in the reaction of 2a with naphthyl derivative and
phenanthryl derivative (3oa, 3pa). In addition, we found that heteroaryl
isocyanides were also suitable substrates in this annulation reaction (3na, 3qa).
To gain insight into the mechanism of the reaction, intermolecular
competition experiments were performed (Scheme 2). No kinetic isotope
effects (KIE, kH/kD = 1.0) were found upon using a 1:1 mixture of 1a and
[D5]-1a under the standard reaction conditions. Therefore, the reaction may
proceed via a free-radical process which was similar to mechanisms proposed
in previous reports.10e,12d,14 In addition, a radical trapping experiment was
conducted (Scheme 3). The addition of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) shut down the reaction, giving TEMPO-trapped pyrroline 4 in 27%
yield, which indicated that the reaction was inhibited by TEMPO and an iminyl
radical might be involved in the process.
To account for the process of the cascade sequence, we proposed a possible
reaction mechanism (Scheme 4).10 The reaction is initiated by oxime ester 2 to
generate an iminyl radical by heating, the iminyl radical then undergoes 5-exo-trig
cyclization to produce the C-centered radical B. The reactive center of B forms an
intermolecular C−C bond with 2-isocyanobiaryl 1, which gives the imidoyl radical C.
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Table 3. Scope of isocyanidesa
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7
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9
N
N
O
N
N
NC
o-DCB,
R2
O
R1
180 °C, 35 min
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R1
R2
1b-q
2a
3ba-qa
N
N
N
N
N
b
3ba
3ca
3da
3ea
3fa
: X=CH3, 83%
: X=Ph, 66%
: X=OCH3, 65%
: X=Br, 60%
X
N
: X=Cl, 82%
3ga
: X=COOCH3, 70%
: X=CN, 41%
3ha
3ia
: X=CF3, 69%
3ja
3ja'
, 40%
, 38%
N
N
N
N
N
N
N
N
N
Cl
3ka
, 38%
3la
3ma
, 65%
, 76%
3na
, 47%
N
N
N
N
N
N
S
3oa
, 61%
3pa
, 70%
3qa
, 24%
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), solvent (1 mL), 180 °C (oil
bath), 35 min, Ar. bIsolated yields.
Scheme 2. KIE studies
CN
H
1a
N
N
N
N
(0.15 mmol)
O
N
typical reaction
conditions
N
D
D
O
NC
D
kH/kD=1:1
D
D
D
D
D
2a
D
3aa
3aa'
1a
[D-5]- (0.15 mmol)
yield: 72%
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Scheme 3. Radical trapping experiment
5
6
7
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9
O
N
CN
N
N
N
N
o-DCB,
O
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60
180 °C, 35 min
TEMPO(3 eq)
O
N
1a
2a
4
3aa
, trace
, 27%
Subsequent cyclization results in the cyclohexadienyl radical D. The picolinoyl
radical abstracts one H from the intermediate D to form compound 3 and picolinic
acid.15 Meanwhile, the intermediate D is oxidized by oxime ester 2 through a single
electron transfer (SET) mechanism to give the cation intermediate E, followed by
deprotonation to generate compound 3.
Scheme 4. Possible mechanism
R1
N
R2
O
radical
5-exo-trig
N
R1
R2
R3
heating
O
N
R4
R4
R5
N
R3
R4
R1
R5
2
B
A
R2 R3
R5
CN
C-radical
intermolecular
addition
R7
O
N
R6
O
1
R1
R2
R3
R1
R2
R3
R1
R2
R3
C-radical
intramolecular
N
N
N
N
R4
R5
R4
R5
H
R4
R5
homolytic
armatic
N
N
substitution
O
R6
R6
R6
R7
N
R7
R7
OH
3
D
C
H
R1
R2
N
2
+
O
N
R3
R1
R2
R3
R4
O
N
N
R4
R5
R5
A
H
R6
R7
E
CONCLUSION
In conclusion, we have developed an efficient approach for the rapid
construction of a pyrroline-functionalized phenanthridine structure. This
approach does not require any catalysts or additives, which makes this method
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economical and at the same time simplifies the operation. Further applications
of this transformation are in progress in our group.
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EXPERIMENTAL SECTION
9
General Information. Purchased reagents were used without further purification.
All the reactions that require heating were heated in oil bath. 1H and 13C spectra were
recorded on Varian 400 MHz and Bruker 600 MHz. Chemical shifts are reported in
ppm using tetramethylsilane as internal standard. ESI-HRMS (high resolution mass
spectrometry) spectra were obtained on AB SCIEX TRIPLE TOF 5600+ mass
spectrometer.
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General Procedure for Synthesize of Isocyanides 1a-1q.12g,12h,16 Step 1:
Pd(PPh3)4 (0.05 equiv.), aryl boronic acid (1.5 equiv.), 2-bromoaniline (1.0 equiv.),
K3PO4·7H2O (3 equiv) and THF (2 mL per mmol) were added subsequently in
two-neck flask under argon atmosphere. The reaction mixture was stirred at 100 ºC
for 12 h. Upon completion of the reaction, the resulting mixture was cooled to room
temperature and filtered through a short path of silica gel, eluting with CH2Cl2. The
volatile compounds were removed in vacuo and the residue was purified by column
chromatography on silica gel, using petroleum ether and ethyl acetate (80 : 1- 50 : 1)
as the eluent. Step 2: New aniline (1.0 equiv.) and THF (2 mL per mmol) were added
into a flask and cooled to 0 °C. Acetic formic anhydride (2.0 equiv.), which was
prepared from the reaction of acetic anhydride with formic acid (1.1 equiv.) at 55 °C
for 2 h, was added dropwise into the reaction mixture at 0 °C. After the addition was
completed, the mixture was warmed to room temperature and stirred for 1 h. Then,
the mixture was treated with saturated solution of NaHCO3 and extracted with EtOAc
three times. The extract was dried and concentrated under vacuum to give formamide.
These materials were used for the subsequent dehydration without further purification.
Step 3: NEt3 (5.0 equiv.), formamide (1.0 equiv.), THF (1.5 mL per mmol) were
added to an oven-dried two-neck flask under argon atmosphere. After cooling the
reaction mixture to 0 °C, POCl3 (2.0 equiv.) was added via syring pump for a period
of 2 h. After the addition was complete, the resulted mixture was stirred at 0 °C for an
additional 1 h. Then, the mixture was quenched with saturated solution of NaHCO3
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and extracted with CH2Cl2 (25 mL x 3). The combined organic layer was dried with
Na2SO4, filtered and evaporated followed by a silica gel column chromatography,
using petroleum ether and ethyl acetate (100 : 1- 80 : 1) as the eluent.
9
General Procedure for Synthesize of γ, δ-Unsaturated Oxime Esters.
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General procedure for the preparation of 2a-C6F5, 2a-t-Bu, 2a-2l and 2n-q.10e,17
Step 1: A solution of corresponding ketone (1.0 equiv.), t-BuOK (1.5 equiv.) and
3-bromoprop-1-ene (3-bromocyclohex-1-ene for 2q) (1.5 equiv.) in t-BuOH (1 mL
per mmol) was heated at reflux under argon atmosphere. The mixture was monitored
by TLC. The reaction mixture was concentrated in vacuo. The crude mixture was
solubilized in EtOAc, washed three times with water (10 mL/mmol), dried with
Na2SO4 and concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel, using petroleum ether and ethyl acetate (100 :
1- 70 : 1) as the eluent. Step 2: A solution of H2NOH·HCl (2.0 equiv.) and NaOAc
(2.0 equiv.) in EtOH (2 mL/mmol) was stirred at room temperature. Then, appropriate
ketone (1.0 equiv.) was added via a syringe. The mixture was heated at 80 ºC for 1 h.
After cooling to room temperature, the reaction mixture was concentrated in vacuo.
The crude mixture was solubilized in EtOAc, washed with water (10 mL/mmol) and
brine (10 mL/mmol), dried with Na2SO4. Purification by column chromatography on
silica gel to give the corresponding oxime, using petroleum ether and ethyl acetate
(70 : 1- 50 : 1) as the eluent. Step 3: A solution of appropriate oxime (1.0 equiv.),
picolinic acid (1.1 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC·HCl) (1.1 equiv.), N,N-dimethyl-4-aminopyridine (DMAP)
(0.05 equiv.) and CH2Cl2 (2 mL/mmol). The reaction mixture was stirred at room
temperature for 24 h. Then, 1 N NaOHaq (10 mL/mmol) was added. The mixture was
extracted with EtOAc (40 mL x 2). The combined organic layer was washed with
brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The
residue was subjected to silica gel column chromatography to afford the
corresponding oxime ester, using petroleum ether and ethyl acetate (10 : 1- 8 : 1) as
the eluent.
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General procedure for the preparation of 2a-Me, 2a-Ph.18 Steps 1) and 2) are same
as above-mentioned. Step 3: A mixture of ketoxime (1.0 equiv.) and NEt3 (2.0 equiv.)
in DCM (3mL/mmol) at room temperature was added dropwise benzoyl chloride or
acetyl chloride (1.2 equiv.). After stirring overnight, the mixture was concentrated in
vacuo until the ketoximes were consumed monitored by TLC. The residual was
extracted from water (30mL) with ethyl acetate (30mL ×3) and the combined extracts
were washed with saturated brine, and dried with Na2SO4, filtered, and removed
under reduced pressure. The crude product was purified through silica gel column
chromatography to give the corresponding oxime ester, using petroleum ether and
ethyl acetate (10 : 1) as the eluent.
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General procedure for the preparation of 2m.19 Step 1: A solution of
diisopropylamine (1.1 equiv.) and n-BuLi (1.05 equiv.) in THF was stirred at 0 ºC for
30 min under argon atmosphere. Then isobutyronitrile (1.0 equiv.) was slowly added.
After stirring for 1 h, 1-bromo-3-methylbut-2-ene (1.2 equiv.) was added dropwise
and the reaction mixture was allowed to warm up to room temperature while stirring
overnight. The reaction was quenched with saturated aqueous NH4Cl solution, then
extracted three times with EtOAc. The organic phase was washed with water and
brine, and dried over Na2SO4. After filtration, the solvent was evaporated to give a
crude mixture, which was purified by flash column chromatography, using petroleum
ether and ethyl acetate (5 : 1) as the eluent. Step 2: A solution of
2,2,5-trimethylhex-4-enenitrile (1.0 equiv.) in anhydrous diethyl ether (Et2O) (1
mL/mmol) was cooled to 0 °C under argon atmosphere and PhMgBr (1.5 equiv.) was
slowly added to the reaction flask. Then, the mixture was stirred overnight in a sealed
tube at 60 ºC. After cooling down to 0 ºC, reaction was quenched with 3 N HCl (aq.)
and warmed up for 4 h to finish the hydrolysis. The crude mixture was then extracted
with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The crude
product was purified by flash column chromatography to give the ketone, using
petroleum ether and ethyl acetate (100 : 1) as the eluent. Steps 3) and 4) are same as
above-mentioned.
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General procedure for the preparation of 2r.10g Step 1: To a solution of the ethyl
3-oxo-3-phenylpropanoate (1.0 equiv.) in anhydrous THF (5 mL/mmol) was added
NaH (1.0 equiv., 60% dispersion in mineral oil). The mixture was stirred at room
temperature until gas evolution ceased (10 minutes). The 3-bromocyclohex-1-ene (1.1
equiv.) was then added via syringe and the mixture was heated at 50 ºC for 16 hours.
The mixture was cooled to room temperature and THF (2 mL/mmol), MeOH (1
mL/mmol), water (1 mL/mmol) and KOH (5.0 equiv.) were added. The mixture was
then heated at reflux for 16 hours. After cooling to room temperature, the mixture was
acidified with aq. 1 M HCl (8 mL/mmol) and extracted with Et2O (20 mL/mmol). The
organic extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated
in vacuo. Purification by column chromatography on silica gel to give the ketone,
using petroleum ether and ethyl acetate (100 : 1) as the eluent. Steps 2), and 3) are
same as above-mentioned.
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General Procedure for Synthesize of Compounds 3. 2-Isocyanobiaryls 1 (1
equiv., 0.3 mmol), γ, δ-unsaturated oxime esters 2 (2 equiv., 0.6 mmol) and
o-dichlorobenzene (1 mL) were added to a 5 mL reaction tube, equipped with a stirrer
bar. Then the tube was charged with argon and sealed. The mixture was heated in oil
bath to stirred at 180 °C for 35 min. After cooled to room temperature, the reaction
mixture was purified with chromatography column on silica gel directly (PE/EtOAc:
10/1) to afford the desired products 3.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenanthridine
(3aa). 3aa (85.4 mg, 78%) was obtained as a yellow oil after purification by column
chromatography (petroleum ether/ethyl acetate = 10/1). 1H NMR (400 MHz, CDCl3) δ
8.70 – 8.63 (m, 1H), 8.57 (d, J = 7.4 Hz, 1H), 8.50 – 8.43 (m, 1H), 8.20 – 8.13 (m,
1H), 7.90 – 7.81 (m, 2H), 7.73 (s, 3H), 7.40 (d, J = 4.3 Hz, 3H), 4.80 (s, 1H), 4.30 (d,
J = 14.0 Hz, 1H), 3.44 – 3.32 (m, 1H), 2.19 – 2.10 (m, 2H), 1.97 – 1.85 (m, 1H), 1.35
13
(dd, J = 7.6, 5.1 Hz, 6H). C{1H} NMR (151 MHz, CDCl3) δ 179.8, 159.7, 143.7,
134.8, 132.9, 130.3, 129.7, 129.4, 128.5, 128.1, 127.9, 127.2, 126.7, 126.4, 125.7,
123.7, 122.3, 121.9, 67.8, 50.5, 48.2, 42.9, 27.3, 26.1. HRMS (ESI) m/z: [M + H]+
Calcd for C26H25N2 365.2012; Found 365.2014.
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6-((5-(4-fluorophenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
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6
nthridine (3ab). 3ab (81.5 mg, 71%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
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MHz, CDCl3) δ 8.65 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 8.2 Hz,
1H), 8.15 (d, J = 7.9 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.1 Hz, 4H), 7.63
(t, J = 7.4 Hz, 1H), 7.06 (t, J = 8.2 Hz, 2H), 4.76 (d, J = 6.7 Hz, 1H), 4.24 (dd, J =
14.0, 4.8 Hz, 1H), 3.36 (dd, J = 13.6, 9.6 Hz, 1H), 2.12 (dd, J = 12.5, 6.5 Hz, 1H),
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1.97 – 1.81 (m, 1H), 1.34 (d, J = 10.9 Hz, 6H). C{1H} NMR (151 MHz, CDCl3) δ
178.6, 163.6 (d, J = 241.6 Hz), 159.7, 143.7, 132.9, 130.9 (d, J = 3.0 Hz), 130.4,
130.0 (d, J = 7.6 Hz), 129.7, 128.5, 127.3, 126.7, 126.4, 125.7, 123.8, 122.4, 122.0,
115.2 (d, J = 21.1 Hz), 67.7, 50.4, 48.4, 42.9, 27.3, 26.1. HRMS (ESI) m/z: [M + H]+
Calcd for C26H24FN2 383.1918; Found 383.1921.
6-((5-(4-chlorophenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3ac). 3ac (89.8 mg, 75%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
80.2-80.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.67 (t, J = 8.4 Hz, 1H), 8.58 (d, J = 8.0
Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.76 – 7.62
(m, 4H), 7.36 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 9.1 Hz, 1H), 4.78 (s, 1H), 4.24 (d, J =
4.9 Hz, 1H), 3.40 (s, 1H), 2.14 (s, 1H), 2.01 – 1.81 (m, 1H), 1.34 (t, J = 7.9 Hz, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 178.9, 159.6, 135.8, 133.0, 130.6, 129.4, 128.6,
128.5, 127.3, 126.9, 126.6, 125.7, 123.8, 122.4, 122.0, 67.7, 50.5, 48.3, 42.6, 27.3,
26.1. HRMS (ESI) m/z: [M + H]+ Calcd for C26H24ClN2 399.1623; Found 399.1619.
6-((5-(4-bromophenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3ad). 3ad (83.8 mg, 63%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
108.9-111.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 7.9 Hz, 1H), 8.58 (d, J =
7.8 Hz, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.91 – 7.84 (m, 1H),
7.74 (t, J = 7.6 Hz, 2H), 7.64 (dd, J = 20.8, 7.6 Hz, 3H), 7.52 (d, J = 7.9 Hz, 2H), 4.79
(s, 1H), 4.31 – 4.17 (m, 1H), 3.39 (s, 1H), 2.15 (dd, J = 12.2, 6.5 Hz, 1H), 1.94 – 1.86
13
(m, 1H), 1.34 (d, J = 6.5 Hz, 6H). C{1H} NMR (151 MHz, CDCl3) δ 178.8, 159.6,
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133.5, 133.0, 131.4, 130.5, 129.6, 128.6, 127.3, 126.8, 126.6, 125.7, 124.1, 123.8,
122.4, 122.0, 67.8, 50.5, 48.3, 42.6, 27.3, 26.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C26H24BrN2 443.1117; Found 443.1114.
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6-((5-(4-methoxyphenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phe
nanthridine (3ae). 3ae (81.7 mg, 69%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
133.5-135.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 7.3 Hz, 1H), 8.57 (d, J =
7.2 Hz, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 7.1 Hz,
1H), 7.74 (s, 4H), 7.65 (d, J = 6.4 Hz, 1H), 6.90 (d, J = 7.0 Hz, 2H), 4.75 (s, 1H), 4.28
(d, J = 13.5 Hz, 1H), 3.85 (d, J = 9.4 Hz, 3H), 3.35 (s, 1H), 2.18 – 2.04 (m, 1H), 1.94
– 1.86 (m, 1H), 1.37 (d, J = 18.0 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 179.0,
160.9, 159.8, 143.8, 132.9, 130.4, 129.8, 129.7, 128.5, 127.3, 126.9, 126.4, 125.8,
123.8, 122.4, 122.0, 113.6, 67.3, 55.3, 50.3, 48.5, 43.0, 27.5, 26.3. HRMS (ESI) m/z:
[M + H]+ Calcd for C28H27N2O2 423.2067; Found 423.2071.
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6-((4,4-dimethyl-5-(p-tolyl)-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenanthridine
(3af). 3af (84.0 mg, 74%) was obtained as a yellow oil after purification by column
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chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400 MHz, CDCl3)
δ8.66 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.15 (d, J
= 8.0 Hz, 1H), 7.86 (s, 1H), 7.77 – 7.58 (m, 5H), 7.20 (d, J = 6.2 Hz, 2H), 4.79 (s,
1H), 4.33 (d, J = 12.1 Hz, 1H), 3.42 – 3.29 (m, 1H), 2.38 (s, 3H), 2.12 (dd, J = 11.4,
6.3 Hz, 1H), 1.96 – 1.85 (m, 1H), 1.36 (d, J = 12.3 Hz, 6H). 13C{1H} NMR (151
MHz, CDCl3) δ 179.0, 158.6, 142.7, 131.9, 129.4, 128.7, 128.0, 127.9, 127.5, 127.1,
126.3, 125.8, 125.4, 124.7, 122.8, 121.3, 120.9, 66.3, 49.4, 47.2, 41.8, 26.4, 25.2,
20.4. HRMS (ESI) m/z: [M + H]+ Calcd for C27H27N2 379.2169; Found 379.2171.
6-((5-(2-chlorophenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3ag). 3ag (83.8 mg, 70%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.67 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.47 (d, J = 8.0 Hz,
1H), 8.16 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 7.4 Hz, 1H), 7.74 (s, 4H), 7.64 (t, J = 7.4
Hz, 1H), 7.40 (s, 2H), 4.80 (s, 1H), 4.30 (dd, J = 13.7, 4.9 Hz, 1H), 3.37 (dd, J = 13.9,
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9.5 Hz, 1H), 2.13 (dd, J = 12.7, 6.5 Hz, 1H), 1.91 (dd, J = 12.6, 8.7 Hz, 1H), 1.36 (d,
J = 9.6 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 179.8, 159.7, 134.9, 133.1,
132.7, 130.9, 129.9, 129.5, 129.2, 128.8, 127.6, 127.0, 126.7, 126.1, 125.6, 123.8,
122.4, 122.0, 69.5, 53.4, 53.0, 45.8, 26.6, 25.8. HRMS (ESI) m/z: [M + H]+ Calcd for
C26H24ClN2 399.1623; Found 399.1624.
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6-((5-(3-chlorophenyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3ah). 3ah (90.9 mg, 76%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
98.0-100.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 7.6 Hz, 1H), 8.56 (d, J =
7.0 Hz, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.86 (s, 1H), 7.80 –
7.68 (m, 3H), 7.65 (d, J = 6.1 Hz, 1H), 7.57 (d, J = 6.1 Hz, 1H), 7.36 (s, 1H), 7.31 (d,
J = 7.3 Hz, 1H), 4.79 (s, 1H), 4.23 (d, J = 13.8 Hz, 1H), 3.48 – 3.30 (m, 1H), 2.15 (d,
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J = 5.9 Hz, 1H), 1.90 (t, J = 10.6 Hz, 1H), 1.34 (s, 6H). C{1H} NMR (151 MHz,
CDCl3) δ 178.6, 159.6, 143.6, 136.6, 134.3, 133.0, 130.5, 129.7, 129.5, 129.4, 128.6,
128.2, 127.3, 126.8, 126.5, 125.9, 125.7, 123.8, 122.4, 122.0, 68.0, 50.6, 48.2, 42.7,
27.2, 26.1. HRMS (ESI) m/z: [M + H]+ Calcd for C26H24ClN2 399.1623; Found
399.1622.
6-((4,4-dimethyl-5-(pyridin-2-yl)-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenanth
ridine (3ai). 3ai (80.0 mg, 73%) was obtained as a yellow oil after purification by
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column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400 MHz,
CDCl3) δ 8.67 (d, J = 8.2 Hz, 1H), 8.59 (dd, J = 11.5, 6.5 Hz, 2H), 8.46 (d, J = 8.2 Hz,
1H), 8.18 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.78 –
7.61 (m, 4H), 7.27 (d, J = 4.6 Hz, 1H), 4.84 (q, J = 8.2, 7.5 Hz, 1H), 4.23 (dd, J =
14.0, 5.5 Hz, 1H), 3.43 (dd, J = 14.0, 9.1 Hz, 1H), 2.16 (dd, J = 12.8, 7.1 Hz, 1H),
1.90 (dd, J = 12.8, 8.4 Hz, 1H), 1.48 (d, J = 13.4 Hz, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 179.2, 159.7, 153.8, 148.4, 143.6, 136.1, 133.0, 130.4, 129.7, 128.6, 127.2,
126.9, 126.5, 125.8, 124.1, 123.8, 123.4, 122.4, 122.0, 68.4, 50.8, 47.9, 42.9, 27.3,
26.0. HRMS (ESI) m/z: [M + H]+ Calcd for C25H24N3 366.1965; Found 366.1968.
6-((4,4-dimethyl-5-(naphthalen-1-yl)-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3aj). 3aj (84.6 mg, 68%) was obtained a yellow oil after purification by
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column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.: 79.1-81.0 °C.
1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J = 8.3, 3.4 Hz, 1H), 8.57 (dd, J = 8.3, 3.3
Hz, 1H), 8.50 (dd, J = 8.4, 3.3 Hz, 1H), 8.18 (dd, J = 11.3, 3.5 Hz, 2H), 7.92 – 7.82
(m, 5H), 7.74 (dq, J = 8.6, 5.4, 5.0 Hz, 2H), 7.65 (dd, J = 8.0, 3.1 Hz, 1H), 7.51 (dd, J
= 6.2, 3.5 Hz, 2H), 4.97 – 4.71 (m, 1H), 4.32 (dt, J = 14.2, 4.2 Hz, 1H), 3.46 (d, J =
3.3 Hz, 1H), 2.17 (ddd, J = 12.9, 6.7, 3.3 Hz, 1H), 1.96 (td, J = 8.9, 4.2 Hz, 1H), 1.44
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(dd, J = 5.3, 3.2 Hz, 6H). C{1H} NMR (151 MHz, CDCl3) δ 179.7, 159.8, 143.7,
133.8, 132.9, 132.8, 132.0, 130.4, 129.7, 128.7, 128.6, 127.9, 127.7, 127.6, 127.3,
126.9, 126.8, 126.5, 126.3, 125.8, 125.6, 123.8, 122.4, 122.0, 67.8, 53.4, 48.4, 42.9,
27.5, 26.3.
HRMS (ESI) m/z: [M + Na]+ Calcd for C30H26N2Na 437.1988; Found 437.1987.
6-((4,4-dimethyl-5-(naphthalen-2-yl)-3,4-dihydro-2H-pyrrol-2-yl)methyl)phena
nthridine (3ak). 3ak (60.9 mg, 49%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.: 90.2-92.2 °C.
1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.2 Hz, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.52
(d, J = 8.2 Hz, 1H), 8.28 – 8.12 (m, 2H), 7.88 (dt, J = 17.6, 8.7 Hz, 5H), 7.75 (q, J =
8.2 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 – 7.46 (m, 2H), 5.03 – 4.74 (m, 1H), 4.34
(dd, J = 14.0, 4.8 Hz, 1H), 3.44 (dd, J = 13.8, 9.5 Hz, 1H), 2.20 (dd, J = 12.6, 6.7 Hz,
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1H), 1.97 (dd, J = 12.5, 8.9 Hz, 1H), 1.45 (d, J = 4.0 Hz, 6H). C{1H} NMR (151
MHz, CDCl3) δ 179.8, 159.7, 149.5, 143.7, 133.9, 133.0, 132.9, 130.4, 129.7, 128.7,
128.6, 127.9, 127.7, 127.3, 126.9, 126.5, 126.3, 125.8, 125.6, 123.8, 122.4, 122.0,
67.7, 50.6, 48.4, 42.8, 27.6, 26.4. HRMS (ESI) m/z: [M + H]+ Calcd for C30H27N2
415.2169; Found 415.2169.
6-((5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenanthridine (3al). 3al
(34.3 mg, 34%) was obtained as a yellow solid after purification by column
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chromatography (petroleum ether/ethyl acetate = 10/1); m.p.: 101.1-103.0 °C. H
NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.47 (d,
J = 8.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.93 – 7.83 (m, 3H), 7.73 (d, J = 6.0 Hz,
2H), 7.65 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 6.8 Hz, 3H), 5.01 (s, 1H), 4.23 (d, J = 12.3
Hz, 1H), 3.33 (d, J = 10.1 Hz, 1H), 3.11 (s, 1H), 2.99 (d, J = 7.3 Hz, 1H), 2.24 (s,
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1H), 2.04 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 159.6, 132.9, 130.5, 129.7,
128.6, 128.5, 128.0, 127.3, 126.9, 126.5, 125.7, 123.8, 122.4, 122.0, 42.3, 35.0, 29.7,
28.3. HRMS (ESI) m/z: [M + H]+ Calcd for C24H21N2 337.1699; Found 337.1698.
6-(2-(4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl)phenanth
ridine (3am). 3am (80.1 mg, 68%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
122.2-124.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 8.3 Hz, 1H), 8.71 (d, J =
8.1 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.76 (s,
2H), 7.73 – 7.59 (m, 3H), 7.41 (s, 3H), 5.21 (s, 1H), 2.08 (s, 3H), 1.65 (s, 5H), 1.35 (s,
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3H), 1.19 (s, 3H). C{1H} NMR (151 MHz, CDCl3) δ 164.7, 142.8, 134.0, 130.4,
129.4, 128.4, 128.2, 128.1, 127.9, 126.6, 126.2, 124.8, 123.4, 123.0, 121.6, 50.2, 47.4,
44.0, 28.2, 26.7, 23.6. HRMS (ESI) m/z: [M + H]+ Calcd for C28H29N2 393.2325;
Found 393.2323.
6-((5-phenyl-6-azaspiro[3.4]oct-5-en-7-yl)methyl)phenanthridine (3an). 3an
(82.5 mg, 73%) was obtained as a yellow solid after purification by column
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chromatography (petroleum ether/ethyl acetate = 10/1); m.p.: 109.1-110.7 °C. H
NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.43 (d,
J = 8.2 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.82 (dd, J = 17.2, 8.6 Hz, 3H), 7.71 (q, J =
8.9, 8.3 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.43 (s, 3H), 4.79 – 4.62 (m, 1H), 4.22 (dd,
J = 14.0, 4.6 Hz, 1H), 3.30 (dd, J = 13.8, 9.9 Hz, 1H), 2.75 – 2.66 (m, 1H), 2.58 –
2.51 (m, 1H), 2.47 (dd, J = 12.8, 6.7 Hz, 1H), 2.19 (dd, J = 12.8, 7.2 Hz, 1H), 2.13 –
1.97 (m, 3H), 1.96 – 1.84 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 178.1, 159.7,
143.7, 135.1, 132.9, 130.3, 129.8, 129.4, 128.5, 128.3, 127.8, 127.3, 126.8, 126.4,
125.7, 123.8, 122.4, 121.9, 68.2, 55.1, 47.0, 42.5, 32.2, 32.0, 16.4. HRMS (ESI) m/z:
[M + H]+ Calcd for C27H25N2 377.2012; Found 377.2013.
6-((1-phenyl-2-azaspiro[4.4]non-1-en-3-yl)methyl)phenanthridine(3ao).
3ao
(84.3 mg, 72%) was obtained as a yellow oil after purification by column
chromatography (petroleum ether/ethyl acetate = 10/1). 1H NMR (400 MHz, CDCl3) δ
8.65 (d, J = 8.0 Hz, 1H), 8.56 (d, J = 7.9 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.16 (d, J
= 8.0 Hz, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.68 (ddd, J = 25.9, 18.1, 7.4 Hz, 5H), 7.39 (s,
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3H), 4.75 (s, 1H), 4.30 (dd, J = 13.8, 4.7 Hz, 1H), 3.35 (dd, J = 13.5, 9.8 Hz, 1H),
2.16 (dd, J = 12.4, 6.4 Hz, 1H), 1.91 – 1.53 (m, 9H). 13C{1H} NMR (151 MHz,
CDCl3) δ 179.2, 159.8, 143.8, 134.8, 132.9, 130.3, 129.8, 129.4, 128.5, 128.2, 128.1,
128.0, 127.3, 126.8, 126.4, 125.8, 123.8, 122.4, 121.9, 68.5, 60.9, 48.1, 42.9, 37.7,
36.4, 25.7, 25.3. HRMS (ESI) m/z: [M + H]+ Calcd for C28H27N2 391.2169; Found
391.2170.
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6-((1-phenyl-2-azaspiro[4.5]dec-1-en-3-yl)methyl)phenanthridine (3ap). 3ap
(72.8 mg, 60%) was obtained as a yellow oil after purification by column
chromatography (petroleum ether/ethyl acetate = 10/1). 1H NMR (400 MHz, CDCl3) δ
8.68 (d, J = 8.1 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.20 (d, J
= 7.5 Hz, 1H), 7.89 (t, J = 7.3 Hz, 1H), 7.71 (dt, J = 32.4, 7.3 Hz, 5H), 7.43 (s, 3H),
4.88 (s, 1H), 4.40 (s, 1H), 3.43 (s, 1H), 2.43 (s, 1H), 1.84 (s, 2H), 1.70 – 1.51 (m, 6H),
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1.42 – 1.27 (m, 2H), 1.16 (d, J = 11.7 Hz, 1H). C{1H} NMR (151 MHz, CDCl3) δ
180.9, 159.7, 143.7, 135.8, 132.9, 130.4, 129.8, 129.0, 128.5, 128.1, 128.0, 127.3,
126.8, 126.4, 125.7, 123.8, 122.4, 122.0, 68.5, 56.6, 43.3, 40.9, 35.7, 32.3, 25.6, 23.3,
23.0. HRMS (ESI) m/z: [M + H]+ Calcd for C29H29N2 405.2325; Found 405.2327.
6-((3aR*,7S*,7aS*)-3,3,3a,7,7a-pentamethyl-2-phenyl-3a,4,5,6,7,7a-hexahydro-
3H-indol-7-yl)phenanthridine (3aq). 3aq (77.6 mg, 64%) was obtained as a yellow
oil after purification by column chromatography (petroleum ether/ethyl acetate =
10/1). 1H NMR (600 MHz, CDCl3) δ 8.65 (dd, J = 8.3, 1.1 Hz, 1H), 8.54 (dd, J = 8.2,
1.4 Hz, 1H), 8.37 – 8.32 (m, 1H), 8.16 (dd, J = 8.1, 1.3 Hz, 1H), 7.80 (ddd, J = 8.2,
6.9, 1.3 Hz, 1H), 7.68 (dddd, J = 22.3, 7.8, 5.8, 2.1 Hz, 4H), 7.60 (ddd, J = 8.3, 6.9,
1.4 Hz, 1H), 7.36 (dd, J = 5.2, 2.1 Hz, 3H), 4.95 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 5.2
Hz, 1H), 2.71 (dt, J = 9.9, 6.2 Hz, 1H), 2.07 – 1.95 (m, 2H), 1.78 (ddd, J = 11.0, 8.2,
4.8 Hz, 1H), 1.54 (tddd, J = 17.9, 10.4, 8.1, 4.8 Hz, 2H), 1.47 (s, 4H), 1.32 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 180.1, 163.9, 143.6, 135.8, 133.1, 130.1, 129.9,
129.2, 128.2, 128.1, 127.7, 127.1, 126.2, 126.1, 125.0, 123.4, 122.5, 121.8, 70.3, 53.3,
49.0, 41.6, 28.5, 25.3, 23.7, 21.7, 20.3. HRMS (ESI) m/z: [M + H]+ Calcd for
C29H29N2 405.2325; Found 405.2324.
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6-((3aR*,7S*,7aS*)-3a,7,7a-trimethyl-2-phenyl-3a,4,5,6,7,7a-hexahydro-3H-in
dol-7-yl)phenanthridine (3ar). 3ar (68.9 mg, 61%) was obtained as a yellow oil
after purification by column chromatography (petroleum ether/ethyl acetate = 10/1).
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 9.0 Hz, 1H), 8.60 – 8.52 (m, 1H), 8.30 –
8.21 (m, 1H), 8.22 – 8.13 (m, 1H), 7.86 – 7.57 (m, 6H), 7.40 (d, J = 9.6 Hz, 3H), 4.90
(s, 1H), 4.12 (s, 1H), 3.14 (d, J = 15.2 Hz, 2H), 2.90 (d, J = 13.1 Hz, 1H), 2.07 – 1.83
(m, 3H), 1.62 (s, 2H), 1.50 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.8, 143.7,
133.1, 130.0, 128.4, 128.3, 127.8, 127.0, 126.3, 126.2, 125.2, 123.5, 122.4, 121.9,
73.8, 53.4, 40.9, 36.8, 29.0, 27.1, 20.2. HRMS (ESI) m/z: [M + H]+ Calcd for
C27H25N2 377.2012; Found 377.2015.
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6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-8-methylphena
nthridine (3ba). 3ba (94.2 mg, 83%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.47 (t, J = 7.6 Hz, 2H), 8.21 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 7.74
(d, J = 5.9 Hz, 3H), 7.64 (d, J = 6.9 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H), 7.19 (s, 1H),
4.77 (s, 1H), 4.30 (d, J = 10.5 Hz, 1H), 3.44 – 3.22 (m, 1H), 2.57 (s, 3H), 2.11 (s, 1H),
1.94 – 1.82 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ
180.3, 158.1, 142.1, 136.5, 131.6, 129.9, 129.3, 128.1, 127.4, 127.3, 127.3, 125.6,
125.5, 124.7, 122.9, 121.3, 120.8, 66.2, 49.5, 46.9, 41.2, 26.3, 25.3, 20.8. HRMS (ESI)
m/z: [M + H]+ Calcd for C27H27N2 379.2169; Found 379.2172.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-8-phenylphena
nthridine (3ca). 3ca (87.2 mg, 66%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.74 – 8.66 (m, 2H), 8.58 (t, J = 8.2 Hz, 1H), 8.21 – 8.05 (m, 2H),
7.75 (q, J = 9.9, 8.6 Hz, 3H), 7.67 (s, 3H), 7.53 – 7.47 (m, 2H), 7.46 – 7.29 (m, 4H),
4.79 (s, 1H), 4.31 (d, J = 7.3 Hz, 1H), 3.57 – 3.33 (m, 1H), 2.20 – 2.12 (m, 1H), 1.95
– 1.86 (m, 1H), 1.34 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 180.1, 160.0, 143.6,
142.0, 140.1, 132.0, 129.7, 129.7, 129.1, 128.5, 128.2, 128.0, 127.8, 127.6, 126.6,
126.2, 125.1, 123.7, 123.0, 122.0, 67.8, 50.5, 48.3, 43.0, 27.3, 26.1. HRMS (ESI) m/z:
[M + H]+ Calcd for C32H29N2 441.2325; Found 441.2327.
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6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-8-methoxyphen
anthridine (3da). 3da (76.9 mg, 65%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
123.0-125.5 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.8 Hz, 1H), 8.48 (d, J =
8.0 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.80 – 7.71 (m, 3H), 7.64 (dt, J = 21.3, 7.1 Hz,
2H), 7.49 (d, J = 9.1 Hz, 1H), 7.41 (s, 3H), 4.83 (s, 1H), 4.29 (d, J = 13.8 Hz, 1H),
3.99 (s, 3H), 3.34 (dd, J = 13.9, 9.9 Hz, 1H), 2.18 (dd, J = 12.3, 6.4 Hz, 1H), 1.95 –
1.87 (m, 1H), 1.36 (d, J = 5.9 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 180.8,
158.9, 158.5, 142.5, 130.1, 129.5, 128.4, 128.2, 127.6, 127.3, 127.0, 126.6, 124.1,
123.9, 121.5, 121.3, 106.9, 67.1, 55.8, 50.6, 48.1, 42.6, 27.4, 26.2. HRMS (ESI) m/z:
[M + H]+ Calcd for C27H27N2O 395.2118; Found 395.2120.
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8-bromo-6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenan
thridine (3ea). 3ea (79.8 mg, 60%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
145.3-146.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.52 (d, J = 8.4 Hz, 2H),
8.14 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.83 – 7.70 (m, 3H), 7.65 (t, J = 7.6
Hz, 1H), 7.42 (s, 3H), 4.77 (s, 1H), 4.11 (s, 1H), 3.39 (dd, J = 14.1, 8.4 Hz, 1H), 2.22
(s, 1H), 1.92 – 1.86 (m, 1H), 1.40 (d, J = 5.2 Hz, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 158.8, 143.6, 133.6, 131.7, 129.9, 129.7, 128.9, 128.3, 128.1, 127.2, 126.9,
124.2, 123.2, 121.8, 121.3, 67.5, 50.5, 48.4, 42.8, 27.3, 26.2. HRMS (ESI) m/z: [M +
H]+ Calcd for C26H24BrN2 443.1117; Found 443.1114.
8-chloro-6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenan
thridine (3fa). 3fa (98.1 mg, 82%) was obtained as a yellow oil after purification by
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column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400 MHz,
CDCl3) δ 8.56 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 9.3 Hz, 2H), 8.14 (d, J = 8.1 Hz, 1H),
7.84 – 7.70 (m, 4H), 7.64 (t, J = 7.4 Hz, 1H), 7.40 (s, 3H), 4.82 – 4.67 (m, 1H), 4.09
(dd, J = 13.9, 5.7 Hz, 1H), 3.37 (dd, J = 13.8, 8.3 Hz, 1H), 2.19 (dd, J = 12.5, 6.5 Hz,
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1H), 1.98 – 1.81 (m, 1H), 1.43 – 1.31 (m, 6H). C{1H} NMR (151 MHz, CDCl3) δ
178.9, 157.9, 142.7, 133.6, 132.1, 130.3, 129.9, 128.8, 128.6, 127.8, 127.2, 127.0,
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125.8, 125.5, 123.0, 122.2, 120.8, 66.7, 49.5, 47.4, 41.8, 26.2, 25.1. HRMS (ESI) m/z:
[M + H]+ Calcd for C26H24ClN2 399.1623; Found 399.1620.
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Methyl-6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenant
hridine-8-carboxylate (3ga). 3ga (88.7 mg, 70%) was obtained as a yellow solid
after purification by column chromatography (petroleum ether/ethyl acetate = 10/1);
m.p.: 161.9-164.1 °C. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.69 (d, J = 8.5 Hz,
1H), 8.58 (d, J = 8.1 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.77
(dd, J = 17.8, 7.1 Hz, 3H), 7.67 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 6.8 Hz, 3H), 4.89 –
4.75 (m, 1H), 4.25 (dd, J = 14.2, 5.8 Hz, 1H), 4.02 (s, 3H), 3.44 (dd, J = 13.9, 8.7 Hz,
1H), 2.21 (dd, J = 12.5, 6.4 Hz, 1H), 1.95 – 1.84 (m, 1H), 1.38 (s, 6H). 13C{1H} NMR
(151 MHz, CDCl3) δ 179.0, 165.6, 159.3, 143.5, 135.0, 133.6, 129.2, 128.9, 128.6,
128.6, 128.3, 127.6, 127.2, 127.0, 125.8, 124.4, 122.1, 121.6, 121.5, 66.7, 51.4, 49.5,
47.5, 41.7, 26.3, 25.1. HRMS (ESI) m/z: [M + H]+ Calcd for C28H27N2O2 423.2067;
Found 423.2071.
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6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenanthridine-
8-carbonitrile (3ha). 3ha (47.9 mg, 41%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
104.1-106.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.71 (d, J = 8.6 Hz, 1H),
8.54 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.82 (t, J =
7.4 Hz, 1H), 7.71 (d, J = 12.6 Hz, 3H), 7.45 – 7.34 (m, 3H), 4.83 – 4.56 (m, 1H), 4.02
(dd, J = 13.9, 6.8 Hz, 1H), 3.49 – 3.41 (m, 1H), 2.31 – 2.24 (m, 1H), 1.92 – 1.84 (m,
1H), 1.39 (d, J = 7.5 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 179.2, 158.4,
143.7, 134.6, 133.3, 132.0, 130.5, 129.4, 129.3, 129.0, 128.8, 127.3, 126.9, 126.3,
124.4, 122.5, 121.5, 121.5, 117.7, 109.6, 66.7, 49.5, 47.6, 41.7, 26.2, 25.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C27H24N3 390.1965; Found 390.1966.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-8-(trifluoromet
hyl)phenanthridine (3ia). 3ia (89.5 mg, 69%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
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Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H),
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7.75 – 7.63 (m, 3H), 7.37 (d, J = 6.7 Hz, 3H), 4.81 – 4.70 (m, 1H), 4.12 (dd, J = 14.2,
6.5 Hz, 1H), 3.46 (dd, J = 14.2, 7.7 Hz, 1H), 2.26 (dd, J = 12.7, 6.6 Hz, 1H), 1.89 (dd,
J = 12.6, 9.1 Hz, 1H), 1.39 (d, J = 7.3 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ
207.0, 180.1, 160.0, 144.4, 135.2, 134.5, 129.9, 129.7, 128.9 (q, J = 32.6 Hz), 128.2,
127.9, 127.0, 126.2, 125.3, 125.1, 124.7 (d, J = 4.4 Hz), 123.4, 123.3, 122.8, 122.3,
67.8, 50.5, 48.6, 42.6, 27.2, 26.1. HRMS (ESI) m/z: [M + H]+ Calcd for C27H24F3N2
433.1886; Found 433.1889.
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6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-7-methylphena
nthridine (3ja). 3ja (45.4 mg, 40%) was obtained as a yellow oil after purification by
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column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400 MHz,
CDCl3) δ 8.56 (s, 2H), 8.12 (s, 1H), 7.82 (s, 2H), 7.70 (s, 2H), 7.63 (s, 1H), 7.53 (s,
1H), 7.44 (s, 3H), 4.95 (s, 1H), 4.71 (s, 1H), 3.51 (s, 1H), 3.11 (s, 3H), 2.39 (s, 1H),
13
1.80 (s, 1H), 1.40 (s, 6H). C{1H} NMR (151 MHz, CDCl3) δ 159.2, 142.3, 137.1,
134.6, 132.0, 129.9, 129.0, 128.5, 126.5, 126.2, 123.8, 122.3, 120.9, 67.4, 50.3, 48.6,
29.7, 27.5, 26.7, 26.3. HRMS (ESI) m/z: [M + H]+ Calcd for C27H27N2 379.2169;
Found 379.2166.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-9-methylphena
nthridine (3ja’). 3ja’ (43.1 mg, 38%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.55 (d, J = 7.6 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.16
(d, J = 7.5 Hz, 1H), 7.73 (s, 3H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H),
7.40 (s, 3H), 4.77 (s, 1H), 4.28 (d, J = 14.4 Hz, 1H), 3.42 – 3.25 (m, 1H), 2.65 (d, J =
7.2 Hz, 3H), 2.09 (d, J = 6.7 Hz, 1H), 1.97 – 1.83 (m, 1H), 1.35 (d, J = 11.7 Hz, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 180.2, 159.5, 143.5, 141.0, 134.5, 133.2, 129.7,
129.4, 129.1, 128.5, 128.2, 128.1, 126.8, 126.3, 123.8, 123.7, 122.1, 122.0, 67.7, 50.6,
48.1, 42.7, 27.3, 26.1, 22.3. HRMS (ESI) m/z: [M + H]+ Calcd for C27H27N2 379.2169;
Found 379.2168.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-10-methylphen
anthridine (3ka). 3ka (43.1 mg, 38%) was obtained as a yellow oil after purification
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by column chromatography (petroleum ether/ethyl acetate = 10/1). H NMR (400
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MHz, CDCl3) δ 8.73 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 6.8 Hz,
1H), 7.66 (d, J = 4.9 Hz, 4H), 7.59 – 7.48 (m, 2H), 7.33 (s, 3H), 4.73 (s, 1H), 4.27 (d,
J = 13.1 Hz, 1H), 3.39 – 3.21 (m, 1H), 3.09 (d, J = 14.4 Hz, 3H), 2.05 (dd, J = 11.2,
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6.4 Hz, 1H), 1.93 – 1.72 (m, 1H), 1.28 (d, J = 12.2 Hz, 6H). C{1H} NMR (151
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MHz, CDCl3) δ 179.1, 158.9, 143.7, 134.5, 133.7, 133.5, 131.4, 128.9, 128.6, 127.2,
127.1, 127.0, 126.8, 126.1, 125.7, 125.6, 124.6, 124.2, 124.2, 66.6, 49.5, 47.2, 42.4,
26.3, 25.9, 25.1. HRMS (ESI) m/z: [M + H]+ Calcd for C27H27N2 379.2169; Found
379.2172.
2-chloro-6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)phenan
thridine (3la). 3la (90.9 mg, 76%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
115.3-117.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.2 Hz, 1H), 8.52 (s, 1H),
8.47 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.77 (t, J =
7.6 Hz, 1H), 7.72 (d, J = 5.5 Hz, 2H), 7.66 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 6.5 Hz,
3H), 4.78 (d, J = 6.0 Hz, 1H), 4.24 (dd, J = 14.2, 5.0 Hz, 1H), 3.35 (dd, J = 14.0, 9.4
Hz, 1H), 2.15 (dd, J = 12.7, 6.8 Hz, 1H), 1.88 (dd, J = 12.6, 8.7 Hz, 1H), 1.36 (d, J =
13
5.7 Hz, 6H). C{1H} NMR (151 MHz, CDCl3) δ 180.1, 160.1, 142.2, 134.7, 132.2,
131.9, 131.3, 130.7, 129.6, 129.0, 128.2, 128.0, 128.0, 126.9, 125.9, 124.9, 122.4,
121.6, 67.6, 50.6, 48.3, 42.9, 27.4, 26.2. HRMS (ESI) m/z: [M + H]+ Calcd for
C26H24ClN2 399.1623; Found 399.1626.
6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)-2,4-dimethylph
enanthridine (3ma). 3ma (76.5 mg, 65%) was obtained as a yellow oil after
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purification by column chromatography (petroleum ether/ethyl acetate = 10/1). H
NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.20 (s,
1H), 7.80 (d, J = 6.5 Hz, 3H), 7.69 (t, J = 7.1 Hz, 1H), 7.43 (s, 4H), 4.98 (s, 1H), 4.37
(d, J = 15.0 Hz, 1H), 3.46 – 3.28 (m, 1H), 2.85 (s, 3H), 2.58 (s, 3H), 2.35 (dd, J =
13
12.5, 6.2 Hz, 1H), 1.89 (dd, J = 12.4, 8.3 Hz, 1H), 1.40 (s, 6H). C{1H} NMR (151
MHz, CDCl3) δ 156.5, 140.6, 137.3, 135.6, 132.8, 130.9, 129.8, 128.3, 128.1, 127.0,
126.1, 125.5, 123.3, 122.6, 119.4, 67.2, 50.5, 48.6, 42.5, 27.6, 26.3, 21.9, 18.3. HRMS
(ESI) m/z: [M + H]+ Calcd for C28H29N2 393.2325; Found 393.2328.
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5-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)benzo[c][2,7]nap
hthyridine (3na). 3na (51.5 mg, 47%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
9
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109.7-110.1 °C. H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.95 (s, 1H), 8.54 (s,
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1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.72 (d, J = 15.1 Hz, 3H), 7.39 (s, 3H),
4.83 (s, 1H), 4.22 (s, 1H), 3.51 (s, 1H), 2.24 (s, 1H), 1.91 (s, 1H), 1.40 (s, 6H). 13C{1H}
NMR (151 MHz, CDCl3) δ 206.9, 159.6, 150.9, 148.4, 145.1, 137.9, 130.8, 130.0,
128.3, 128.1, 127.1, 122.5, 121.8, 120.9, 115.5, 67.5, 53.4, 50.5, 48.4, 27.3, 26.1.
HRMS (ESI) m/z: [M + H]+ Calcd for C25H24N3 366.1965; Found 366.1968.
5-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)benzo[i]phenant
hridine (3oa). 3oa (75.9 mg, 61%) was obtained as a yellow solid after purification
by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
162.4-164.9 °C. 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J = 8.5 Hz, 1H), 8.64 (dd, J =
8.2, 4.1 Hz, 2H), 8.19 (dd, J = 17.2, 8.6 Hz, 2H), 8.04 (d, J = 7.8 Hz, 1H), 7.75 (dq, J
= 24.9, 8.7, 7.9 Hz, 6H), 7.39 (d, J = 5.0 Hz, 3H), 5.19 (s, 1H), 4.82 (dd, J = 15.0, 4.1
Hz, 1H), 3.67 (dd, J = 15.0, 10.0 Hz, 1H), 2.17 (dd, J = 12.6, 6.7 Hz, 1H), 1.59 – 1.44
(m, 1H), 1.35 (s, 3H), 1.27 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 179.9, 158.2,
143.8, 135.1, 133.7, 133.4, 131.8, 130.3, 129.4, 129.3, 128.9, 128.9, 128.7, 128.2,
128.1, 128.0, 127.9, 127.8, 127.1, 126.5, 126.3, 123.2, 123.2, 122.5, 120.3, 68.1, 50.4,
48.7, 48.6, 27.4, 26.1. HRMS (ESI) m/z: [M + H]+ Calcd for C30H27N2 415.2169;
Found 415.2172.
5-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)dibenzo[i,k]phe
nanthridine (3pa). 3pa (97.6 mg, 70%) was obtained as a yellow solid after
purification by column chromatography (petroleum ether/ethyl acetate = 10/1); m.p.:
191.8-193.2 °C. 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 7.7 Hz, 1H), 8.71 (dt, J =
17.0, 8.0 Hz, 4H), 8.21 (d, J = 8.3 Hz, 1H), 7.86 – 7.64 (m, 7H), 7.61 (d, J = 7.1 Hz,
1H), 7.35 (s, 3H), 5.17 (s, 1H), 4.55 (s, 1H), 3.58 (s, 1H), 2.05 (s, 1H), 1.48 – 1.38 (m,
1H), 1.34 (s, 3H), 1.22 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ179.7, 157.1,
145.5, 134.7, 134.4, 132.3, 130.7, 129.8, 129.4, 129.0, 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.2, 127.0, 126.9, 125.7, 123.7, 123.6, 123.4, 122.5, 68.5, 50.2, 48.4,
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46.6, 27.2, 26.0. HRMS (ESI) m/z: [M + H]+ Calcd for C34H29N2 465.2325; Found
465.2328.
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6-((4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)methyl)benzo[4,5]thieno
[3,2-c]quinoline (3qa). 3qa (30.2 mg, 24%) was obtained as a yellow oil after
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purification by column chromatography (petroleum ether/ethyl acetate = 10/1). H
NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.15 (d,
J = 7.5 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 6.6 Hz, 3H), 7.62 (d, J = 8.2
Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.42 (s, 3H), 4.94 (s, 1H), 4.64 (d, J = 13.4 Hz, 1H),
3.63 – 3.45 (m, 1H), 2.18 (s, 1H), 2.02 – 1.96 (m, 1H), 1.38 (d, J = 19.9 Hz, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 180.5, 155.9, 147.1, 144.2, 139.0, 135.5, 134.9,
129.6, 129.5, 129.3, 128.2, 128.0, 127.8, 126.4, 126.2, 125.6, 125.3, 123.8, 123.2,
123.0, 66.7, 50.7, 48.2, 45.5, 27.4, 26.2. HRMS (ESI) m/z: [M + H]+ Calcd for
C28H25N2S 421.1733; Found 421.1734.
Gram-Scale Synthesis of 3aa. 2-Isocyanobiaryls 1a (1 equiv., 3 mmol), γ,
δ-unsaturated oxime esters 2a (2 equiv., 6 mmol) and o-dichlorobenzene (10 mL)
were added to a 50 mL reaction tube, equipped with a stirrer bar. Then the tube was
charged with argon and sealed. The mixture was heated in oil bath to stirred at 180 °C
for 35 min. After cooled to room temperature, the reaction mixture was purified with
chromatography column on silica gel directly (PE/EtOAc: 10/1) to afford the desired
products 3aa as a yellow oil. 788.4 mg, 72% yield.
The kinetic isotope effect study between 1a and [D5]-1a. [D5]-1a (0.5 equiv.,
0.15 mmol), 1a (0.5 equiv., 0.15 mmol), γ, δ-unsaturated oxime esters 2a (2 equiv.,
0.6 mmol) and o-dichlorobenzene (1 mL) were added to a 5 mL reaction tube,
equipped with a stirrer bar. Then the tube was charged with argon and sealed. The
mixture was heated in oil bath to stirred at 180 °C for 35 min. After cooled to room
temperature, the reaction mixture was purified with chromatography column on silica
gel directly (PE/EtOAc: 10/1) to afford the mixture of products 3aa and 3aa’ (79.3
1
mg, 72%). H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 8.1
Hz, 2H), 8.47 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.85 (t, J = 7.6 Hz, 1H),
7.72 (t, J = 6.8 Hz, 7H), 7.63 (t, J = 7.5 Hz, 2H), 7.39 (d, J = 5.3 Hz, 6H), 4.79 (p, J =
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8.7 Hz, 2H), 4.28 (dd, J = 14.1, 5.1 Hz, 2H), 3.36 (dd, J = 14.0, 9.5 Hz, 2H), 2.11 (dd,
J = 12.7, 6.7 Hz, 2H), 1.90 (dd, J = 12.5, 8.8 Hz, 2H), 1.35 (d, J = 10.3 Hz, 12H).
Radical Inhibition Studies. 1a (1 equiv., 0.3 mmol), γ, δ-unsaturated oxime esters
2a (2 equiv., 0.6 mmol), TEMPO (3 equiv., 0.9 mmol) and o-dichlorobenzene (1 mL)
were added to a 5 mL reaction tube, equipped with a stirrer bar. Then the tube was
charged with argon and sealed. The mixture was heated in oil bath to stirred at 180 °C
for 35 min. After cooled to room temperature, the reaction mixture was purified with
chromatography column on silica gel directly (PE/EtOAc: 10/1) to afford the mixture
of products 4 as a yellow oil. And almost no 3aa was observed. 1H NMR (400 MHz,
CDCl3) δ 7.70 (s, 2H), 7.38 (s, 3H), 4.17 (d, J = 35.0 Hz, 2H), 3.96 (s, 1H), 2.06 (s,
1H), 1.90 (s, 1H), 1.52 – 1.33 (m, 12H), 1.18 – 1.03 (m, 8H). MS (ESI) m/z: 315.2 [M
+ H]+.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI:
1H and 13C NMR spectra for new compounds, and 2D NMR spectra (PDF)
ACKNOWLEDGMENTS
Financial support was provided by the National Natural Science Foundation
of China (No. 81673292 and 81973162) for financial support.
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