Radical Addition/Insertion/Cyclization Cascade Reaction to Assemble Phenanthridines from N-Arylacrylamide Using Cyano as a Bridge under Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.7b01447

A radical addition/nitrile insertion/homolytic aromatic substitution (HAS) cascade reaction to prepare 6-quaternary alkylated phenanthridines was developed. The addition of the active methylene radicals which were generated from 2-bromoacetonitrile, ethyl 2-bromoacetate, 2-bromo-N,N-dimethylacetamide, or 2-bromo-1-phenylethan-1-one to carbon-carbon double bonds of N-arylacrylamides followed by the cyano-participating sequential cyclization produced a series of phenanthridines in moderate to good yields under photoredox catalysis.

Full text of DOI:10.1021/acs.joc.7b01447

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Article
Radical Addition/Insertion/Cyclization Cascade Reaction
to Assemble Phenanthridines from N-Arylacrylamide
Using Cyano as A Bridge under Photoredox Catalysis
Yulan Yu, Zhiqiang Cai, Weiwen Yuan, Ping Liu, and Peipei Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01447 • Publication Date (Web): 19 Jul 2017
Downloaded from http://pubs.acs.org on July 19, 2017
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Radical Addition/Insertion/Cyclization Cascade Reaction to
Assemble Phenanthridines from N-Arylacrylamide Using Cyano as A
Bridge under Photoredox Catalysis
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Yulan Yu, Zhiqiang Cai, Weiwen Yuan, Ping Liu,* and Peipei Sun*
School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control, Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing 210023, China
sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
ABSTRACT: A radical addition/nitrile insertion/HAS cascade reaction to prepare 6ꢀquaternary
alkylated phenanthridines was developed. The addition of the active methylene radicals which
generated from 2ꢀbromoacetonitrile, ethyl 2ꢀbromoacetate, 2ꢀbromoꢀN,Nꢀdimethylacetamide or
2
ꢀbromoꢀ1ꢀphenylethanꢀ1ꢀone to carbonꢀcarbon double bonds of Nꢀarylacrylamides followed by
the cyanoꢀparticipated sequential cyclization produced a serial of phenanthridines in moderate to
good yields under photoredox catalysis.
■
INTRODUCTION
1
Phenanthridine motifs are widespread in natural products and demonstrate diverse biological
2
3
4
activities such as anticancer and antitumor, antimalarial, antituberculosis and cytotoxic
5
activities. They are also an important class of organic compounds in a wide range of materials
6
applications. As a consequence, many protocols have been developed for the construction of
phenanthridines over the past decades. Among them, approaches based on cascade reaction are the
most widely used because of their economy and efficiency. Many means, including azaꢀWittig
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8
cyclizations, [2+2+2] cycloaddition, palladiumꢀcatalyzed crossꢀcoupling cascade annulation
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reactions, acidꢀmediated modified Pictet−Spengler reactions, annulation with arynes,
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In(OTf) ꢀcatalyzed cascade reaction with alkynylbenzaldehydes and alkynylanilines,
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3
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nitrogenation of 2ꢀacetylbiphenyls and oxidative Robinsonꢀtype annulation have been
employed for this purpose.
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Cascade radical reactions provided a new approach for the assembly of diversified substituted
phenanthridines. In 1995, Nanni and coꢀworkers firstly described a cascade reaction between
2
ꢀisocyanobiphenyl and 2ꢀcyanopropyl radical stemmed from AIBN to access 6ꢀsubstituted
phenanthridines, in which the imidoyl radical A underwent a homolytic aromatic substitution
15
(
HAS) (Scheme 1a). Since then the 2ꢀisocyanobiphenyls appear to be the most versatile
acceptors for various radicals initiated by oxidants or photocatalysts in the field of phenanthridines
1
6
synthesis. Oxime derivatives, in which the N−O bond could be broken under heating, photo or
microwave radiation to form iminyl radicals, were also employed as alternative substrates to
17
furnish phenanthridines (Scheme 1b). As a versatile functional group, cyano is playing an
important role in the construction of diverse heterocycles. Although the biarylꢀ2ꢀcarbonitriles
could be readily obtained, so far only treating them with organometallic reagents via anionic
18
cyclization could generate the phenanthridines. Indeed, the direct intermolecular radical cyano
insertion is not easy to occur, whereas the intramolecular cyano insertion is available and several
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excellent protocols to build nitrogen containing heterocycles via this strategy were developed. In
this work, we wish to report an active methylene radicals initiated cascade reaction. Through the
intramolecular carbon−carbon double bond and cyanoꢀparticipated radical addition and cyclization,
the functionalized phenanthridines were synthesized under visibleꢀlight photocatalysis (Scheme
1c).
Scheme 1. Typical Radical Cyclization to Construct Phenanthridine and Our Strategy
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■ RESULTS AND DISCUSSION
With this strategy in mind, we designed
Nꢀ(2ꢀcyanoꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀyl)ꢀNꢀmethylmethacrylamide (1a) as the reactant and treated it with
ꢀbromoacetonitrile (2a) under photoredox catalysis (Table 1). Initially, the reaction was
performed in the presence of 2 mol % facꢀIr(ppy) in DMSO under argon atmosphere upon
irradiation with 5 W blue LEDs at room temperature for 32 h. To our delight, a cyclization product
3ꢀ(4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile (3a)
a
polyfunctional compound
2
3
was obtained in 25% yield (entry 1). Encouraged by this result, we then screened the reaction
conditions. The reaction did not take place in the absence of the photocatalyst (entry 2) or in a
dark environment (entry 3). When conducted in the open air, the reaction also could not perform
successfully (entry 4). Further screening the additives revealed that the presence of base (2 equiv)
such as NaHCO
improve the reaction yields, and Na
optimized base, the solvent was then examined, and the mixed solvent (DMSO/CH
mL) turned out to be more effective and provided 3a in 81% yield (entries 12–18). In addition, a
series of photocatalysts were tested and facꢀIr(ppy) gave the best result (entries 15, 19–22).
3
, NaOAc, Na
2
CO
3
, Na
2
HPO
gave the highest yield of 74% (entries 5–11). With the
CN = 1 : 1, 2
4 2 4
, K HPO , DBU or DABCO could drastically
2
CO
3
3
3
Furthermore, upon irradiation of 23 W CFL light instead of blue LEDs, no improved yield was
obtained (entry 23).
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Table 1. Optimization of Reaction Conditions
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entry
photocatalyst
base
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
yield (%)
25
1
2
facꢀIr(ppy)
–
3
–
–
0
b
3
facꢀIr(ppy)
3
–
0
c
4
facꢀIr(ppy)3
–
trace
69
5
facꢀIr(ppy)
facꢀIr(ppy)
facꢀIr(ppy)
facꢀIr(ppy)
3
3
3
3
NaHCO
NaOAc
3
6
63
7
Na
2
CO
3
74
8
2
Na HPO
4
65
9
facꢀIr(ppy)3
K HPO4
2
61
10
facꢀIr(ppy)
facꢀIr(ppy)
facꢀIr(ppy)
facꢀIr(ppy)
3
3
3
3
DBU
50
11
DABCO
53
1
2
3
Na
2
2
CO
3
3
3
CH CN
72
1
Na
CO
DMF
63
14
facꢀIr(ppy)3
fac-Ir(ppy)
Na CO3
EtOAc
68
2
d
15
16
17
3
Na
2
CO
3
DMSO/CH
3
CN
81
d
facꢀIr(ppy)
facꢀIr(ppy)
facꢀIr(ppy)
eosin Y
3
3
3
Na
Na
Na
2
2
2
CO
CO
CO
3
DMSO/DMF
75
d
3
DMSO/EtOAc
76
d
18
3
3
CH CN/DMF
73
d
19
20
21
Na CO3
DMSO/CH CN
45
2
3
d
Ru(bpy) Cl
3 2
Na
Na
Na
Na
2
2
2
2
CO
CO
CO
CO
3
3
3
3
DMSO/CH
DMSO/CH
DMSO/CH
DMSO/CH
3
3
3
3
CN
CN
CN
CN
30
d
3
Ru(bpy) (PF
6
)
2
28
d
22
Ir(ppy)
2
(dtbbpy)PF
6
25
d,e
2
3
facꢀIr(ppy)
3
72
a
Reaction conditions (unless otherwise specified): 1a (0.2 mmol), 2a (0.6 mmol), base (0.4
mmol), photocatalyst (2 mol %) and solvent (2 mL) were carried out in a sealed tube under Ar
atmosphere upon irradiation of 5 W blue LEDs for 32 h. In the dark. Under air. Mixed
solvent with a ratio of 1:1 (v/v) was used. Using 23 W CFL.
b
c
d
e
With the optimized reaction conditions in hand, the substrate scope was investigated and the
corresponding results were summarized in Scheme 2. The Nꢀarylacrylamides 1 with a variety of
substituents on the aromatic ring A were firstly employed as the reactants. The reactions of
substrates 1 with either electronꢀdonating or electronꢀwithdrawing groups on the paraꢀ, metaꢀ or
orthoꢀposition of the aromatic ring A performed well with 2ꢀbromoacetonitrile and gave the
desired phenanthridines (3a–3s) in 58–84% yields. The structure of product 3g was determined by
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an Xꢀray diffraction analysis (CCDC number: 1541486). For the metaꢀmethyl substituted material
1n, the cascade cyclization could take place at either 2ꢀ or 6ꢀposition and gave the two products 3n
and 3n’ (76%, 3:1). The reactions of the substrates with two substituents such as 3,5ꢀdimethyl or
3,5ꢀdichloro on the aromatic ring A also readily provided the corresponding products in good
yields (3o, 3p). It was found that the benzodioxole group had no obvious impact on the reactivity
and afforded the expected siteꢀselective product 3q in 75% yield. From the substrates bearing
biphenyl, αꢀnaphthyl or βꢀnaphthyl on the aromatic ring B, several novel pentacyclic
phenanthridines were obtained (3t–3v). For the βꢀnaphthyl substituted reactant 1v, the cyclization
selectively took place on the adjacent αꢀposition to produce 3v probably due to orienting effect.
However, the thienyl substituted Nꢀarylacrylamide 1w gave the desired thieno[3,2ꢀc]isoquinoline
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2
derivative 3w in poor yield (33%) under our current conditions. Next, different substituent R on
nitrogen atom of 1 such as nꢀbutyl, iꢀbutyl and benzyl were evaluated and the corresponding
products were obtained in good yields (3x–3z, 3aa–3ac). Gratifyingly, when the substrate 1ad
bearing phenyl at the αꢀposition of carbonyl, the space congested 6ꢀquaternary alkylated
phenanthridines 3ad was isolated in 65% yield. In addition, if 2ꢀchloroacetonitrile was used
instead of 2ꢀbromoacetonitrile, the product 3a was obtained with a lower yield of 58%.
a
Scheme 2. Photo-Induced Cascade Synthesis of 3
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2 3 3
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), Na CO (0.4 mmol), facꢀIr(ppy) (2 mol %),
DMSO/MeCN (1:1, v/v, 2 mL), upon irradiation with 5 W blue LEDs under Ar atmosphere at
b
room temperature for 32 h. 2ꢀChloroacetonitrile was used instead of 2a.
Furthermore, some other active bromomethylene compounds ethyl 2ꢀbromoacetate (2b),
2
ꢀbromoꢀN,Nꢀdimethylacetamide (2c) and 2ꢀbromoꢀ1ꢀphenylethanꢀ1ꢀone (2d) were employed to
react with Nꢀarylacrylamides under the standard conditions (Scheme 3). The Nꢀarylacrylamides 1
bearing both electronꢀdonating and electronꢀwithdrawing groups on the paraꢀposition of aromatic
ring A were proven to be suitable for this cascade process with ethyl 2ꢀbromoacetate since they
could provide the desired products (4a–4e) in moderate to high yields.
2
ꢀBromoꢀN,Nꢀdimethylacetamide, as well as 2ꢀbromoꢀ1ꢀphenylethanꢀ1ꢀone were also suitable
reaction partners for this similar transformation under the photoredox conditions (4f–4k).
a
Scheme 3. Photo-Induced Cascade Synthesis of 4
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O
N
B
fac-Ir(ppy)3, Na2CO3
O
4
R1
R1
N
+
BrCH R
2
A
CN
DMSO/CH3CN
Ar, rt, 32 h
N
R4 = COOEt (2b)
CON(CH3)2 (2c)
COPh (2d)
R4
1
5 W blue LEDs
4
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a
2 3 3
Reaction conditions: 1 (0.2 mmol), 2(bꢀd) (0.6 mmol), Na CO (0.4 mmol), facꢀIr(ppy) (2
mol %), DMSO/MeCN (1:1, v/v, 2 mL), upon irradiation with 5 W blue LEDs under Ar
atmosphere at room temperature for 32 h.
For further demonstrating the synthetic utility of this methodology, we tried to convert the
cyano group of the cyclization product 3a into some other functional groups. When the
o
cyanomethylated product 3a was treated with conc. H SO in methanol at 90 C for 12 h,
2
4
hydrolyzation and esterification occurred to afford the product 5a in excellent yield (95%).
Furthermore, the compound 3a could be easily hydrolyzed to generate
ꢀ(4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanamide (6a) in
the presence of H (30% in water) and K CO in 50% yield (Scheme 4).
3
2
O
2
2
3
Scheme 4. Transformation of Cyclization Product 3a
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To gain insight into the mechanism of this cascade reaction, several control experiments were
carried out as shown in Scheme 5. When the model reaction was performed in the presence of
radical scavenge 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO, 4 equiv), no product 3a was
found (Scheme 5, eq. 1). Another radical scavenger 1,1ꢀdiphenylethylene (7a) could successfully
trap the cyanomethyl radical under the standard reaction conditions to produce a coupling product
4
,4ꢀdiphenylbutꢀ3ꢀenenitrile (8a) in 78% yield (Scheme 5, eq. 2). Based on these findings, we
presumed that this cyclization reaction most likely proceeded via a radical pathway.
Scheme 5. Control Experiments
The proposed reaction mechanism for the photoredox conversion of Nꢀarylacrylamide 1a
with 2ꢀbromoacetonitrile (2a) into 6ꢀquaternary alkylated phenanthridine 3a is shown in Scheme 6.
*
Initially, the photocatalyst [facꢀIr(III)(ppy) ] was irradiated to the excited state [facꢀIr(III)(ppy) ] ,
3
3
+
3
which was oxidative quenched by 2a with the generation of a [facꢀIr(IV)(ppy) ] complex and a
2
0
cyanomethyl radical E. Subsequently, addition of the cyanomethyl radical to the carbonꢀcarbon
double bond of 1a led to alkyl radical C, followed by a regioselective addition to the cyano via
19e
6
ꢀexoꢀdig to give iminyl radical D (path a), which then underwent intramolecular homolytic
aromatic substitution to give the radical intermediate F. It should be pointed that under our
reaction conditions, no radical addition to the orthoꢀcarbon of the benzene ring occurred to result
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in corresponding oxindole derivatives (path b). A singleꢀelectron oxidation of F by
+
[
facꢀIr(IV)(ppy)
3
]
regenerated the photocatalyst and simultaneously produced the cation
intermediate G. Finally, G underwent deprotonation to yield the desired product 3a.
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Scheme 6. Plausible Reaction Mechanism
■
CONCLUSIONS
In summary, we developed the radical addition/nitrile insertion/HAS cascade reaction to
construct phenanthridines. The addition of the active methylene radicals from 2ꢀbromoacetonitrile,
ethyl 2ꢀbromoacetate or 2ꢀbromoꢀN,Nꢀdimethylacetamide to carbonꢀcarbon double bonds of
Nꢀarylacrylamides resulted in 6ꢀquaternary alkylated phenanthridines in moderate to good yields
under photoredox catalysis. The advantage of our method is that it proceeds with easily available
material, broad substrate scope, low loading of catalyst, and generates highly complex polycyclic
scaffold in one step. Most importantly, we anticipate that the Nꢀarylacrylamides with orthoꢀcyano
group as a bridge are good precursors and could therefore be applied to synthesize phenanthridine
derivatives with diverse radicals based on this strategy.
■ EXPERIMENTAL SECTION
General Remarks. All reactions were run in a sealed tube with a Teflon lined cap under
ambient Ar. Chemicals were commercially available from chemical suppliers and were used
2
1
without purification. NꢀArylacrylamides 1 were prepared according to the literature procedures.
1
13
The NMR spectra were recorded at 400 MHz ( H) and 100 MHz ( C) in CDCl
3
or DMSOꢀd
6
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5
5
5
5
6
using TMS as an internal standard. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of triplet, td
=
triplet of doublet, q = quartet, m = multiplet, ddd = doublet of doublet of doublet. QꢀTOF was
used for the HRMS measurement. Melting points are uncorrected.
0
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General Procedure for Synthesis of Products 3 and 4. NꢀArylacrylamide 1 (0.2 mmol),
2
3 2 3
ꢀbromoacetonitrile (72.0 mg, 42 µL, 0.6 mmol), facꢀIr(ppy) (2 mol %, 2.6 mg), Na CO (42.4
mg, 0.4 mmol) were added to the mixed solvents DMSO and acetonitrile (1:1, v/v, 2 mL). Then
the reaction mixture was stirred under Ar atmosphere upon irradiation of 5 W blue LEDs for 32 h.
After completion of the reaction, the resulting solution was extracted with EtOAc (15 × 3 mL),
and the combined organic layers were washed with brine (15 mL), dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using
hexane/ethyl acetate (5:1) to afford the pure products 3. The products 4 were synthesized
according to the general produce of products 3 except ethyl 2ꢀbromoacetate (100.2 mg, 67 µL, 0.6
mmol), 2ꢀbromoꢀN,Nꢀdimethylacetamide (99.6 mg, 0.6 mmol) or 2ꢀbromoꢀ1ꢀphenylethanꢀ1ꢀone
(118.8 mg, 0.6 mmol) was used.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile (3a).
o
1
Yellow solid (51.1 mg, 81% yield); mp 130–132 C; H NMR (400 MHz, CDCl ) δ (ppm) 8.54
3
(dd, J = 8.2, 1.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.17 (dd, J = 8.2, 0.9 Hz, 1H), 7.86 (t, J = 8.1
Hz, 1H), 7.78 (t, J = 6.9 Hz, 1H), 7.68 (t, J = 8.3 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 3.61 (s, 3H),
1
3
3.02–2.75 (m, 2H), 2.30–2.26 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.6,
3
157.4, 144.8, 138.4, 133.5, 132.2, 129.9, 129.4, 127.1, 122.8, 122.7, 119.4, 116.5, 112.0, 111.2,
+
50.8, 34.3, 30.4, 30.0, 13.7; HRMS (ESI) m/z: calcd for C20
18
H N
3
O [M + H] 316.1444, found
316.1443.
3ꢀ(9ꢀEthylꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
o
1
(
3b). Yellow solid (52.2 mg, 76% yield); mp 135–136 C; H NMR (400 MHz, CDCl
3
) δ (ppm)
8
.47 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.56 (d, J
=
8.4 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 3.62 (s, 3H), 3.03–2.76 (m, 4H), 2.28 (t, J = 8.2 Hz, 2H),
13
1
3
.71 (s, 3H), 1.43 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.7, 157.3, 146.0,
145.0, 138.3, 133.6, 132.1, 128.0, 127.9, 122.6, 120.7, 119.4, 116.4, 111.8, 110.7, 50.8, 34.3, 30.5,
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3
3
0.0, 28.9, 15.4, 13.7; HRMS (ESI) m/z: calcd for C H N O [M + H] 344.1757, found
22 22 3
44.1757.
ꢀ(9ꢀ(tertꢀButyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propane
1
nitrile (3c). Yellow oil (58.6 mg, 79% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.50 (d, J = 8.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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35
36
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39
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.7, 2.1 Hz,
1
3
1
1
3
H), 7.24 (d, J = 7.9 Hz, 1H), 3.62 (s, 3H), 3.06–2.78 (m, 2H), 2.29 (t, J = 8.0 Hz, 2H), 1.72 (s,
13
3
H), 1.52 (s, 9H); C NMR (100 MHz, CDCl ) δ (ppm) 172.7, 157.3, 152.9, 144.9, 138.3, 133.4,
32.1, 125.7, 125.6, 122.3, 120.5, 119.5, 116.4, 111.8, 110.7, 50.8, 35.1, 34.3, 31.3, 30.5, 30.0,
+
3.8; HRMS (ESI) m/z: calcd for C24
H
26
N
3
O [M + H] , 372.2070 found 372.2073.
ꢀ(9ꢀMethoxyꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenit
o
1
rile (3d). Yellow solid (56.6 mg, 82% yield); mp 126–127 C; H NMR (400 MHz, CDCl ) δ
3
(ppm) 8.42 (d, J = 9.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.56 (s, 1H),
7.32 (dd, J = 9.0, 2.7 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 4.04 (s, 3H), 3.61 (s, 3H), 3.02–2.75 (m,
13
2H), 2.30–2.25 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.6, 160.7, 157.8,
1
3
3
46.6, 138.4, 133.7, 132.2, 123.8, 119.5, 118.5, 116.9, 116.1, 111.2, 110.0, 109.3, 55.7, 50.8, 34.3,
+
20 3 2
0.5, 30.0, 13.7; HRMS (ESI) m/z: calcd for C21H N O [M + H] 346.1550, found 346.1550.
ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ9ꢀphenoxyꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenit
1
rile (3e). Yellow oil (52.9 mg, 65% yield); H NMR (400 MHz, CDCl ) δ (ppm) 8.52 (d, J = 9.0
3
Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.49–7.45(m,
1
3
3H), 7.28–7.20 (m, 4H), 3.62 (s, 3H), 2.96–2.72 (m, 2H), 2.28–2.23 (m, 2H), 1.68 (s, 3H);
C
NMR (100 MHz, CDCl ) δ (ppm) 172.6, 158.9, 158.3, 156.1, 146.3, 138.4, 133.5, 132.4, 130.1,
3
124.4, 124.3, 120.1, 119.5, 119.4, 118.4, 116.3, 115.6, 111.5, 110.5, 50.8, 34.3, 30.4, 30.0, 13.7;
+
HRMS (ESI) m/z: calcd for C26
22
H N
O
3 2
[M + H] 408.1707, found 408.1705.
3ꢀ(4,6ꢀDimethylꢀ9ꢀ(methylthio)ꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propan
o
1
enitrile (3f). Yellow solid (55.6 mg, 77% yield); mp 147–149 C; H NMR (400 MHz, CDCl ) δ
3
(ppm) 8.38 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H),
7
3
1
.53 (dd, J = 8.7, 2.1 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 3.61 (s, 3H), 3.02–2.75 (m, 2H), 2.69 (s,
13
H), 2.29–2.25 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.5, 158.1, 145.4,
3
41.1, 138.4, 133.5, 132.3, 125.9, 124.3, 122.8, 119.9, 119.4, 116.3, 111.7, 110.7, 50.8, 34.2, 30.5,
+
30.0, 15.2, 13.8; HRMS (ESI) m/z: calcd for C21
H N
20 3
OS [M + H] 362.1322, found 362.1319.
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ꢀ(9ꢀFluoroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitril
o
1
e (3g). Yellow solid (49.3 mg, 74% yield); mp 148–150 C; H NMR (400 MHz, CDCl
.53 (dd, J = 9.1, 5.8 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.80 (dd, J = 9.7,
2.7 Hz, 1H), 7.44 (ddd, J = 9.0, 8.2, 2.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 3.62 (s, 3H), 3.00–2.74
3
) δ (ppm)
8
0
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2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
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4
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6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
(m, 2H), 2.30–2.25 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.4, 163.0 (d, J
=
247.9 Hz), 159.0, 146.1 (d, J = 12 Hz), 138.5, 133.3, 132.6, 124.7 (d, J = 9.6 Hz), 119.6 (d, J =
1
5
3
3
.9 Hz), 119.3, 116.3 (d, J = 23.8 Hz), 116.3, 114.2 (d, J = 20.3 Hz), 111.7 (d, J = 1.1 Hz), 111.0,
+
0.8, 34.2, 30.4, 30.0, 13.7; HRMS (ESI) m/z: calcd for C H FN O [M + H] 334.1350 , found
20
17
3
34.1347.
ꢀ(9ꢀChloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitril
o
1
e (3h). Yellow solid (54.5 mg, 78% yield); mp 160–162 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
8
.45 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.89 (t, J = 8.1 Hz, 1H),
7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 3.62 (s, 3H), 2.99–2.74 (m, 2H), 2.30–
13
2.25 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.4, 159.0, 145.4, 138.6,
1
1
3
35.1, 133.1, 132.7, 129.0, 127.6, 124.1, 121.3, 119.2, 116.4, 112.0, 111.4, 50.9, 34.2, 30.5, 30.1,
+
3.7; HRMS (ESI) m/z: calcd for C20
3
H17ClN O [M + H] 350.1055, found 350.1057.
ꢀ(9ꢀBromoꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitril
o
1
e (3i). Yellow solid (56.6 mg, 72% yield); mp 175–176 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
8
7
.40 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.89 (t, J = 8.1 Hz, 1H),
.77 (dd, J = 8.8, 2.1 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 3.62 (s, 3H), 2.99–2.74 (m, 2H), 2.30–
13
2.26 (m, 2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.4, 158.9, 145.6, 138.6,
3
133.2, 132.7, 132.2, 130.3, 124.2, 123.3, 121.7, 119.2, 116.4, 112.0, 111.5, 50.9, 34.2, 30.5, 30.1,
+
13.7; HRMS (ESI) m/z: calcd for C20
H
17BrN
3
O [M + H] 394.0550, found 394.0552.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ9ꢀ(trifluoromethyl)ꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)pr
o
1
opanenitrile (3j). Yellow solid (61.3 mg, 80% yield); mp 176–177 C; H NMR (400 MHz, CDCl )
3
δ (ppm) 8.67 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.96 (t, J = 8.1 Hz, 1H),
7
2
1
.87 (dd, J = 8.6, 1.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 3.64 (s, 3H), 3.03–2.77 (m, 2H), 2.33–
13
.28 (m, 2H), 1.72 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.3, 159.4, 144.1, 138.7,
3
32.9, 132.7, 131.4 (q, J = 32.7 Hz), 127.4 (q, J = 4.1 Hz), 125.2, 124.0 (q, J = 270.7 Hz), 123.9,
122.9 (q, J = 3.2 Hz), 119.1, 116.8, 112.6, 112.3, 50.9, 34.1, 30.6, 30.1, 13.7; HRMS (ESI) m/z:
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+
calcd for C H F N O [M + H] 384.1318, found 384.1317.
21
17
3
3
3
ꢀ(4,6ꢀDimethylꢀ9ꢀ(methylsulfonyl)ꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)pro
o
1
3
panenitrile (3k). Yellow solid (57.4 mg, 73% yield); mp 170–171 C; H NMR (400 MHz, CDCl )
δ (ppm) 8.74–8.71 (m, 2H), 8.35 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.97 (t, J = 8.1 Hz,
1H), 7.40 (d, J = 8.0 Hz, 1H), 3.63 (s, 3H), 3.21 (s, 3H), 3.00–2.74 (m, 2H), 2.36–2.23 (m, 2H),
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
1
1
3
.70 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.2, 160.2, 144.1, 140.8, 138.8, 133.3, 132.4,
29.8, 126.6, 124.6, 123.9, 119.1, 117.0, 113.0, 112.8, 51.0, 44.6, 34.1, 30.6, 30.1, 13.7; HRMS
+
(
ESI) m/z: calcd for C H N O S [M + H] 394.1220, found 394.1219.
2
1
20
3
3
6
ꢀ(2ꢀCyanoethyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridineꢀ9ꢀcarbonitr
o
1
ile (3l). Yellow solid (47.6 mg, 70% yield); mp 223–224 C; H NMR (400 MHz, CDCl
3
) δ (ppm)
.64 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 8.1 Hz, 1H),
.87 (dd, J = 8.5, 1.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 3.64 (s, 3H), 3.02–2.76 (m, 2H), 2.38–
8
7
13
3
2.24 (m, 2H), 1.72 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.2, 160.1, 143.9, 138.8,
134.8, 133.2, 132.5, 128.4, 126.1, 124.1, 119.0, 118.4, 116.9, 112.8, 112.7, 112.7, 51.0, 34.1, 30.6,
+
3
0.1, 13.7; HRMS (ESI) m/z: calcd for C21
Ethyl
ꢀ(2ꢀcyanoethyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridineꢀ9ꢀcarboxyla
H
17
N
4
O [M + H] 341.1397, found 341.1401.
6
o
1
te (3m). Yellow solid (44.9 mg, 58% yield); mp 154–156 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
8
.83 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.27 (dd, J = 8.5, 1.6
Hz, 1H), 7.91 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.62 (s, 3H),
13
3.03–2.76 (m, 2H), 2.32–2.28 (m, 2H), 1.71 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl ) δ (ppm) 172.4, 166.2, 158.6, 144.2, 138.6, 132.9, 132.7, 131.7, 131.1, 127.0, 126.0, 123.0,
3
119.2, 117.0, 112.5, 112.2, 61.5, 50.9, 34.1, 30.5, 30.1, 14.4, 13.7; HRMS (ESI) m/z: calcd for
+
C
H
23 22
N
O
3 3
[M + H] 388.1656, found 388.1657.
3
ꢀ(4,6,8ꢀTrimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile (3n)
and 3ꢀ(4,6,10ꢀtrimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
o
1
(
3n’). White solid (50.0 mg, 76% yield); mp 130–131 C; H NMR (400 MHz, CDCl
.42–8.35 (m, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.09 (s, 0.22H), 7.85 (t, J = 8.1 Hz, 1H), 7.67–7.56
m, 1.72H), 7.25 (d, J = 7.9 Hz, 1H), 3.63 (s, 3H), 3.04–2.97 (m, 1H), 2.89 (s, 2.18H), 2.84–2.77
3
) δ (ppm)
8
(
13
3
(m, 1H), 2.66 (s, 0.72H), 2.33–2.28 (m, 2H), 1.71 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm)
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72.7, 172.7, 156.3, 155.8, 143.4, 143.2, 138.4, 138.3, 137.7, 137.1, 133.8, 133.2, 131.9, 131.9,
31.2, 130.0, 129.6, 126.8, 122.7, 122.6, 122.2, 120.5, 119.5, 116.8, 116.5, 111.8, 111.0, 110.9,
1.0, 50.7, 34.4, 34.3, 30.7, 30.3, 30.0, 30.0, 22.0, 18.3, 13.7, 13.7; HRMS (ESI) m/z: calcd for
+
C
H
21 20
N
3
O [M + H] 330.1601, found 330.1603.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3ꢀ(4,6,8,10ꢀTetramethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
o
1
(3o). Yellow solid (46.7 mg, 68% yield); mp 100–101 C; H NMR (400 MHz, CDCl
3
) δ (ppm)
8
1
2
1
1
3
.29 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.22 (d, J = 7.9 Hz,
H), 3.61 (s, 3H), 3.03–2.96 (m, 1H), 2.85 (s, 3H), 2.83–2.76 (m, 1H), 2.60 (s, 3H), 2.33–2.27 (m,
13
H), 1.71 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.8, 154.7, 141.8, 138.3, 137.3, 136.6,
33.5, 131.9, 131.6, 122.5, 120.0, 119.5, 116.8, 111.9, 110.7, 50.9, 34.5, 30.6, 30.0, 22.0, 18.2,
+
3.7; HRMS (ESI) m/z: calcd for C H N O [M + H] 344.1757, found 344.1758.
22
22
3
ꢀ(8,10ꢀDichloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propan
o
1
enitrile (3p). White solid (59.8 mg, 78% yield); mp 183–185 C; H NMR (400 MHz, CDCl
(ppm) 8.41 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.92 (t, J = 8.1 Hz, 1H), 7.84–7.83 (m,
H), 7.34 (d, J = 7.9 Hz, 1H), 3.63 (s, 3H), 3.04–2.73 (m, 2H), 2.40–2.35 (m, 2H), 1.73 (s, 3H);
3
) δ
1
13
3
C NMR (100 MHz, CDCl ) δ (ppm) 172.4, 158.6, 139.6, 138.8, 135.5, 133.0, 132.4, 132.3,
129.9, 125.0, 121.2, 119.2, 116.7, 112.3, 51.0, 34.2, 30.5, 30.1, 13.7; HRMS (ESI) m/z: calcd for
+
C H Cl N O [M + H] 384.0665, found 384.0664.
2
0
16
2
3
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀ[1,3]dioxolo[4,5ꢀb]pyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)pr
o
1
opanenitrile (3q). Yellow solid (53.9 mg, 75% yield); mp 178–180 C; H NMR (400 MHz,
CDCl ) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.16
3
(d, J = 7.8 Hz, 1H), 6.16 (d, J = 1.1 Hz, 2H), 3.60 (s, 3H), 2.97–2.72 (m, 2H), 2.31–2.17 (m, 2H),
13
1.69 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.7, 154.9, 150.0, 148.3, 142.5, 138.2, 133.3,
131.6, 119.4, 118.8, 116.3, 111.5, 109.9, 107.3, 102.0, 99.6, 50.4, 34.5, 30.3, 30.0, 13.7; HRMS
+
(
ESI) m/z: calcd for C21
H
18
3
N O
3
[M + H] 360.1343, found 360.1342.
3ꢀ(11ꢀMethoxyꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propaneni
o
1
trile (3r). Yellow solid (57.3 mg, 83% yield); mp 120–121 C; H NMR (400 MHz, CDCl
ppm) 9.31 (dd, J = 8.7, 0.5 Hz, 1H), 7.88–7.84 (m, 2H), 7.73 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 7.8
Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 4.17 (s, 3H), 3.63 (s, 3H), 3.02–2.75 (m, 2H), 2.30 (t, J = 7.9 Hz,
3
) δ
(
1
3
3
2H), 1.70 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.3, 158.3, 157.7, 146.5, 137.8, 133.5,
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32.0, 129.0, 122.6, 122.4, 119.5, 113.8, 112.4, 111.0, 108.1, 56.0, 50.5, 34.1, 30.3, 30.1, 13.7;
+
HRMS (ESI) m/z: calcd for C21
20
H N
O
3 2
[M + H] 346.1550, found 346.1551.
3ꢀ(11ꢀChloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitr
o
1
ile (3s). Yellow solid (58.6 mg, 84% yield); mp 124–125 C; H NMR (400 MHz, CDCl
3
) δ (ppm)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9.60 (dd, J = 8.7, 0.6 Hz, 1H), 8.11 (dd, J = 8.1, 1.4 Hz, 1H), 7.91–7.87 (m, 1H), 7.74 (dd, J = 7.7,
1
2
1
1
3
.5 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 3.63 (s, 3H), 3.01–2.74 (m, 2H),
1
3
3
.32–2.28 (m, 2H), 1.67 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.1, 158.1, 146.8, 138.1,
32.8, 131.6, 131.0, 130.8, 129.7, 128.6, 121.0, 120.7, 119.3, 112.8, 112.1, 50.5, 33.9, 30.3, 30.2,
+
3.7; HRMS (ESI) m/z: calcd for C20
H
17ClN
3
O [M + H] 350.1055, found 350.1052.
ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ9ꢀphenylꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitri
o
1
le (3t). White solid (46.2 mg, 59% yield); mp 213–215 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
8
.61 (d, J = 8.6 Hz, 1H), 8.44 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.96 (dd, J = 8.5, 2.0 Hz, 1H),
7.91–7.84 (m, 3H), 7.57–7.54 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 3.64 (s,
13
3H), 3.07–2.79 (m, 2H), 2.31 (t, J = 8.0 Hz, 2H), 1.74 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
(ppm) 172.6, 158.0, 145.1, 142.2, 140.0, 138.5, 133.4, 132.3, 129.0, 128.0, 127.7, 127.4, 126.3,
123.2, 121.9, 119.4, 116.6, 112.0, 111.1, 50.8, 34.2, 30.5, 30.0, 13.8; HRMS (ESI) m/z: calcd for
+
C H
26 22
N
3
O [M + H] 392.1757, found 392.1759.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀbenzo[a]pyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitril
o
1
e (3u). Orange solid (59.9 mg, 82% yield); mp 114–116 C; H NMR (400 MHz, CDCl
.07 (d, J = 8.3 Hz, 1H), 8.81 (d, J = 8.5 Hz, 1H), 8.12–8.05 (m, 3H), 7.89 (t, J = 8.1 Hz, 1H),
7.75 (t, J = 7.3 Hz, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 3.66 (s, 3H), 3.08–2.80
3
) δ (ppm)
9
13
3
(m, 2H), 2.31 (t, J = 7.8 Hz, 2H), 1.74 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.5, 156.6,
144.8, 138.2, 133.5, 133.2, 131.8, 130.5, 129.7, 128.9, 128.0, 127.6, 126.9, 126.6, 121.3, 119.6,
+
20 3
119.4, 113.3, 110.4, 50.5, 34.3, 30.3, 30.2, 13.8; HRMS (ESI) m/z: calcd for C24H N O [M + H]
366.1601, found 366.1603.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀbenzo[c]pyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitril
o
1
e (3v). Yellow solid (50.4 mg, 69% yield); mp 171–173 C; H NMR (400 MHz, CDCl
3
) δ (ppm)
.43 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 9.1 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 9.0 Hz,
H), 8.01 (d, J = 7.4 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.85–7.81 (m, 1H), 7.78–7.74 (m, 1H), 7.26
9
1
1
3
(d, J = 7.8 Hz, 1H), 3.66 (s, 3H), 3.18–2.87 (m, 2H), 2.32 (t, J = 7.9 Hz, 2H), 1.82 (s, 3H);
C
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (100 MHz, CDCl ) δ (ppm) 172.7, 156.0, 142.0, 138.4, 133.7, 133.5, 132.0, 131.5, 128.0,
3
127.7, 127.2, 124.9, 120.1, 119.8, 119.4, 116.9, 112.7, 110.4, 51.0, 34.9, 30.8, 30.0, 13.8; HRMS
+
(
ESI) m/z: calcd for C24
H
20
N
3
O [M + H] 366.1601, found 366.1601.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀbenzo[de]thieno[3,2ꢀb][1,6]naphthyridinꢀ6ꢀyl)propanenitr
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
ile (3w). Yellow solid (21.2 mg, 33% yield); mp 145–147 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
7
2
1
.83–7.69 (m, 4H), 7.16 (dd, J = 7.1, 1.5 Hz, 1H), 3.62 (s, 3H), 3.01–2.78 (m, 2H), 2.25–2.20 (m,
1
3
3
H), 1.74 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 172.6, 155.8, 139.9, 138.7, 132.6, 132.3,
28.3, 125.9, 119.2, 117.4, 111.2, 109.8, 50.5, 34.9, 30.9, 30.0, 13.8; HRMS (ESI) m/z: calcd for
+
C H
18 16
N
3
OS [M + H] 322.1009, found 322.1007.
3ꢀ(4ꢀButylꢀ6ꢀmethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
1
(
3x). Yellow oil (48.6 mg, 68% yield); H NMR (400 MHz, CDCl ) δ (ppm) 8.52 (dd, J = 8.3, 0.9
3
Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.79–7.74 (m,
1H), 7.68–7.64 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.28–4.09 (m, 2H), 3.04–2.74 (m, 2H), 2.32–
1
3
2.27 (m, 2H), 1.81–1.73 (m, 2H), 1.68 (s, 3H), 1.56–1.47 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H);
NMR (100 MHz, CDCl ) δ (ppm) 172.3, 157.5, 144.7, 137.4, 133.7, 132.2, 129.8, 129.4, 127.1,
22.9, 122.6, 119.5, 116.4, 112.2, 111.2, 50.7, 42.5, 33.9, 30.5, 28.9, 20.3, 13.9, 13.7; HRMS (ESI)
C
3
1
+
24 3
m/z: calcd for C23H N O [M + H] 358.1914, found 358.1912.
3ꢀ(4ꢀButylꢀ6,9ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
1
(
3y). Yellow oil (54.9 mg, 74% yield); H NMR (400 MHz, CDCl
H), 8.25 (d, J = 8.3 Hz, 1H), 7.98 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.51 (dd, J = 8.4, 1.6 Hz, 1H),
7.22 (d, J = 8.0 Hz, 1H), 4.28–4.10 (m, 2H), 3.04–2.75 (m, 2H), 2.62 (s, 3H), 2.32–2.27 (m, 2H),
3
) δ (ppm) 8.42 (d, J = 8.4 Hz,
1
13
1.81–1.73 (m, 2H), 1.68 (s, 3H), 1.54–1.49 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 172.3, 157.4, 144.8, 139.7, 137.4, 133.8, 132.1, 129.3, 128.9, 122.4, 120.5, 119.5,
116.2, 112.0, 110.7, 50.7, 42.5, 33.9, 30.6, 28.9, 21.6, 20.3, 13.9, 13.7; HRMS (ESI) m/z: calcd for
+
C H
24 26
N
3
O [M + H] 372.2070, found 372.2070.
3ꢀ(4ꢀButylꢀ9ꢀchloroꢀ6ꢀmethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propane
1
nitrile (3z). Yellow oil (59.5 mg, 76% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.43 (d, J = 8.8
Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.59 (dd, J =
.8, 2.2 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 4.28–4.10 (m, 2H), 3.01–2.73 (m, 2H), 2.32–2.26 (m,
8
13
2H), 1.80–1.72 (m, 2H), 1.67 (s, 3H), 1.56–1.46 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H); C NMR (100
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8
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MHz, CDCl ) δ (ppm) 172.1, 159.0, 145.2, 137.6, 135.1, 133.4, 132.7, 128.9, 127.6, 124.1, 121.4,
3
119.3, 116.2, 112.2, 111.5, 50.8, 42.6, 33.8, 30.6, 28.8, 20.3, 13.9, 13.7; HRMS (ESI) m/z: calcd
+
3
for C23H23ClN O [M + H] 392.1524, found 392.1525.
3ꢀ(4ꢀIsobutylꢀ6ꢀmethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(3aa). Yellow oil (57.9 mg, 81% yield); H NMR (400 MHz, CDCl ) δ (ppm) 8.56 (dd, J = 8.3,
3
1
.0 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.80 (ddd,
J = 8.3, 7.1, 1.3 Hz, 1H), 7.70 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.25–4.20
(
m, 1H), 3.99–3.94 (m, 1H), 3.10–2.76 (m, 2H), 2.34–2.25 (m, 3H), 1.69 (s, 3H), 1.05 (dd, J = 6.7,
13
2
1
.9 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.8, 157.4, 144.5, 137.8, 133.8, 132.1, 129.8,
29.5, 127.2, 122.9, 122.6, 119.6, 116.4, 112.2, 111.7, 50.9, 49.1, 33.4, 31.0, 26.4, 20.3, 20.2, 13.7;
+
HRMS (ESI) m/z: calcd for C H N O [M + H] 358.1914, found 358.1914.
23
24
3
3
ꢀ(4ꢀBenzylꢀ6ꢀmethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
o
1
3
(3ab). Yellow solid (68.1 mg, 87% yield); mp 133–135 C; H NMR (400 MHz, CDCl ) δ (ppm)
8.55 (dd, J = 8.2, 0.8 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.1
Hz, 1H), 7.76–7.69 (m, 2H), 7.40–7.36 (m, 2H), 7.33–7.28 (m, 3H), 7.19 (d, J = 7.9 Hz, 1H), 5.69
(
d, J = 16.2 Hz, 1H), 5.23 (d, J = 16.2 Hz, 1H), 3.18–2.85 (m, 2H), 2.40 (t, J = 7.8 Hz, 2H), 1.81
1
3
(
s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 172.9, 157.2, 137.6, 136.0, 133.7, 132.2, 129.8,
1
1
3
29.5, 129.0, 127.5, 127.3, 126.3, 122.9, 122.6, 119.4, 116.7, 112.3, 112.2, 51.0, 46.4, 33.7, 30.9,
+
3.8; HRMS (ESI) m/z: calcd for C26
H
22
N
3
O [M + H] 392.1757, found 392.1758.
ꢀ(4ꢀBenzylꢀ6,9ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrl
o
1
e (3ac). Yellow solid (67.3 mg, 83% yield); mp 129–131 C; H NMR (400 MHz, CDCl ) δ (ppm)
3
8.43 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.54 (dd, J
= 8.4, 1.2 Hz, 1H), 7.40–7.31 (m, 5H), 7.14 (d, J = 7.9 Hz, 1H), 5.69 (d, J = 16.1 Hz, 1H), 5.22 (d,
13
J = 16.1 Hz, 1H), 3.12–2.84 (m, 2H), 2.65 (s, 3H), 2.39 (t, J = 8.0 Hz, 2H), 1.80 (s, 3H); C NMR
100 MHz, CDCl ) δ (ppm) 173.0, 157.1, 144.8, 139.9, 137.5, 136.1, 133.7, 132.1, 129.3, 129.0,
27.5, 126.3, 122.4, 120.6, 119.5, 116.5, 111.9, 111.8, 51.0, 46.4, 33.7, 30.9, 21.7, 13.8; HRMS
(
3
1
+
(
24 3
ESI) m/z: calcd for C27H N O [M + H] 406.1914, found 406.1913.
3
ꢀ(4ꢀMethylꢀ5ꢀoxoꢀ6ꢀphenylꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanenitrile
1
(
3ad). Yellow oil (49.0 mg, 65% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.60 (d, J = 8.0 Hz,
1H), 8.34–8.32 (m, 2H), 7.88–7.83 (m, 2H), 7.76 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H),
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.18–7.16 (m, 3H), 7.08–7.05 (m, 2H), 3.64 (s, 3H), 3.53–3.46 (m, 1H), 3.30–3.23 (m, 1H), 2.59–
13
.54 (m, 2H); C NMR (100 MHz, CDCl
3
) δ (ppm) 170.4, 155.3, 144.3, 142.1, 138.4, 133.5,
32.4, 130.1, 129.6, 128.8, 127.7, 127.6, 126.3, 123.0, 122.7, 119.8, 116.6, 113.1, 111.4, 59.2,
+
32.9, 30.4, 14.4; HRMS (ESI) m/z: calcd for C25
H N
20 3
O [M + H] 378.1601, found 378.1604.
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4
5
6
7
8
9
0
1
2
3
4
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6
7
8
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Ethyl 3ꢀ(4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanoate (4a).
o
1
Yellow solid (55.0 mg, 76% yield); mp 83–84 C ; H NMR (400 MHz, CDCl
3
) δ (ppm) 8.54 (d, J
=
8.2 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.77 (t,
J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.96–3.90 (m, 2H), 3.61 (s, 3H),
13
2
.83–2.60 (m, 2H), 2.28–2.05 (m, 2H), 1.82 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 173.5, 172.9, 158.8, 144.8, 138.7, 133.3, 131.9, 129.9, 129.2, 126.8, 122.7, 122.6,
116.2, 112.2, 110.9, 60.3, 50.7, 36.3, 30.5, 29.9, 28.5, 14.1; HRMS (ESI) m/z: calcd for
+
C
H
22 23
N
O
2 3
[M + H] 363.1703, found 363.1704.
Ethyl 3ꢀ(9ꢀ(tertꢀbutyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)
1
propanoate (4b). Yellow oil (61.1 mg, 73% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.48 (d, J
=
8.7 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.6,
1
2
.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.61 (s, 3H), 2.83–2.61 (m, 2H),
13
.28–2.05 (m, 2H), 1.83 (s, 3H), 1.50 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl ) δ (ppm) 173.6, 172.9, 158.6, 152.6, 144.9, 138.7, 133.2, 131.8, 125.6, 125.2, 122.2, 120.4,
3
116.1, 112.0, 110.4, 60.3, 50.6, 36.4, 35.1, 31.3, 30.5, 29.8, 28.6, 14.1; HRMS (ESI) m/z: calcd for
+
26 31 2 3
C H N O [M + H] 419.2329, found 419.2328.
Ethyl 3ꢀ(4,6ꢀdimethylꢀ5ꢀoxoꢀ9ꢀphenoxyꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)
1
propanoate (4c). Yellow oil (54.5 mg, 60% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.51 (d, J
= 9.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.47–7.42 (m, 3H),
7
2
.24 (t, J = 7.4 Hz, 1H), 7.20–7.18 (m, 3H), 3.95 (q, J = 6.9 Hz, 2H), 3.60 (s, 3H), 2.79–2.57 (m,
1
3
3
H), 2.25–2.02 (m, 2H), 1.79 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl ) δ
(ppm) 173.5, 172.2, 159.9, 158.6, 156.3, 146.3, 138.9, 133.3, 132.1, 130.1, 124.2, 124.2, 119.9,
119.1, 118.4, 115.8, 115.8, 111.6, 110.2, 50.9, 37.2, 36.1, 35.3, 29.9, 29.7, 28.5; HRMS (ESI) m/z:
+
calcd for C H N O [M + H] 455.1965, found 455.1966.
28
27
2
4
Ethyl 3ꢀ(9ꢀchloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)
1
propanoate (4d). Yellow oil (63.4 mg, 80% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.34 (d, J
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J = 8.7, 1.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 3.90 (q, J = 7.1 Hz, 2H), 3.57 (s, 3H), 2.79–2.56(m,
1
3
2H), 2.27–2.03 (m, 2H), 1.77 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ
(ppm) 173.2, 172.7, 160.3, 145.4, 138.8, 134.8, 132.8, 132.4, 128.9, 127.2, 123.9, 121.2, 116.0,
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49
50
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52
53
54
55
56
57
58
59
60
2 3
112.0, 111.1, 60.3, 50.7, 36.3, 30.4, 29.9, 28.3, 14.1; HRMS (ESI) m/z: calcd for C22H22ClN O
+
[
M + H] 397.1314, found 397.1313.
Ethyl 6ꢀ(3ꢀethoxyꢀ3ꢀoxopropyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthri
1
dineꢀ9ꢀcarboxylate (4e). Yellow oil (47.8 mg, 55% yield); H NMR (400 MHz, CDCl ) δ (ppm)
3
8
.86 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.29 (dd, J = 8.6, 1.5 Hz, 1H), 7.91
t, J = 8.1 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.93 (q, J = 7.1 Hz, 2H),
.62 (s, 3H), 2.86–2.60 (m, 2H), 2.29–2.06 (m, 2H), 1.82 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H), 1.13 (t,
(
3
13
3
J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 173.3, 172.8, 166.4, 160.0, 144.3, 138.9,
132.7, 132.4, 131.8, 130.9, 126.7, 125.9, 122.8, 116.7, 112.7, 111.9, 61.4, 60.4, 50.8, 36.1, 30.4,
+
29.9, 28.5, 14.4, 14.1; HRMS (ESI) m/z: calcd for C25
27
H N
2
O
5
[M + H] 435.1915, found
435.1915.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)ꢀN,Nꢀdimethylpropan
1
amide (4f). Yellow oil (56.3 mg, 78% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.54 (d, J = 7.4
Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.76 (t, J =
7
2
.6 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.89–2.81 (m, 4H),
1
3
3
.76 (s, 3H), 2.64–2.56 (m, 1H), 2.30–2.10 (m, 2H), 1.77 (s, 3H); C NMR (100 MHz, CDCl ) δ
(ppm) 173.6, 172.2, 159.0, 144.8, 138.8, 133.3, 131.9, 129.8, 129.2, 126.7, 122.8, 122.6, 116.1,
24 3 2
112.2, 110.8, 50.9, 37.2, 35.9, 35.2, 29.9, 29.7, 28.7; HRMS (ESI) m/z: calcd for C22H N O [M
+
+ H] 362.1863, found 362.1863.
3ꢀ(9ꢀ(tertꢀButyl)ꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)ꢀN,Nꢀdi
o
1
methylpropanamide (4g). Yellow solid (66.8 mg, 80% yield); mp 184–185 C ; H NMR (400
MHz, CDCl ) δ (ppm) 8.46 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 0.9 Hz, 1H),
.81 (t, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.7, 2.0 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H),
.90–2.83 (m, 4H), 2.78 (s, 3H), 2.65–2.57 (m, 1H), 2.30–2.07 (m, 2H), 1.77 (s, 3H), 1.48 (s, 9H);
3
7
2
13
3
C NMR (100 MHz, CDCl ) δ (ppm) 173.7, 172.2, 158.8, 152.6, 145.0, 138.7, 133.2, 131.7,
125.7, 125.1, 122.2, 120.4, 116.1, 112.0, 110.4, 50.9, 37.2, 36.0, 35.3, 35.0, 31.3, 29.8, 29.7, 28.9;
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5
5
5
5
5
6
+
HRMS (ESI) m/z: calcd for C H N O [M + H] 418.2489, found 418.2489.
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32
3
2
3
ꢀ(9ꢀChloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)ꢀN,Nꢀdimeth
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ylpropanamide (4h). Yellow oil (59.3 mg, 75% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.42
(d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H),
7.56 (dd, J = 8.8, 2.2 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.59 (s, 3H), 2.86 (s, 3H), 2.83–2.75 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
4
3
H), 2.61–2.53 (m, 1H), 2.30–2.08 (m, 2H), 1.74 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm)
1
73.4, 172.1, 160.6, 145.4, 138.9, 134.8, 132.9, 132.4, 128.9, 127.2, 124.0, 121.3, 116.0, 112.1,
+
1
11.1, 51.0, 37.2, 35.9, 35.3, 29.9, 29.6, 28.5; HRMS (ESI) m/z: calcd for C H ClN O [M + H]
22 23 3 2
396.1473, found 396.1474.
3
ꢀ(11ꢀChloroꢀ4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)ꢀN,Nꢀd
1
imethylpropanamide (4i). Yellow oil (56.9 mg, 72% yield); H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.53 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H),
7.59 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.59 (s, 3H), 2.87–2.80 (m, 4H), 2.75 (s, 3H),
1
3
2.59–2.52 (m, 1H), 2.28–2.08 (m, 2H), 1.73 (s, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 173.1,
1
3
72.1, 159.7, 146.8, 138.5, 132.6, 131.4, 130.9, 130.4, 129.6, 128.4, 120.6, 113.0, 111.8, 50.6,
+
3 2
7.2, 35.7, 35.3, 30.1, 29.5, 28.5; HRMS (ESI) m/z: calcd for C22H23ClN O [M + H] 396.1473,
found 396.1475.
9
ꢀ(tertꢀButyl)ꢀ4,6ꢀdimethylꢀ6ꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)ꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ5(6
1
H)ꢀone (4j). Yellow oil (59.4 mg, 66% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.49 (d, J =
8
.7 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.87–7.81 (m, 3H), 7.76 (dd, J =
8.7, 2.1 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.40–7.33 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 3.63 (s,
13
3H), 3.03–2.73 (m, 4H), 1.82 (s, 3H), 1.50 (s, 9H); C NMR (100 MHz, CDCl
3
) δ (ppm) 199.6,
173.7, 158.8, 152.6, 145.0, 138.7, 136.7, 133.3, 132.8, 131.8, 128.3, 128.2, 125.7, 125.2, 122.2,
1
20.4, 116.1, 112.0, 110.4, 51.0, 35.5, 35.1, 31.3, 29.9, 29.1; HRMS (ESI) m/z: calcd for
+
C H
30 31
N
O
2 2
[M + H] 451.2380, found 451.2383.
9
ꢀChloroꢀ4,6ꢀdimethylꢀ6ꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)ꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ5(6H)ꢀo
o
1
ne (4k). White solid (53.9 mg, 63%); mp 140–142 C; H NMR (400 MHz, CDCl
3
) δ (ppm) 8.43
(
dd, J = 8.8, 1.5 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 1.1 Hz, 1H), 7.87 (t, J = 7.8 Hz,
1
H), 7.79–7.77 (m, 2H), 7.60–7.56 (m, 1H), 7.50–7.46 (m, 1H), 7.37–7.33 (m, 2H), 7.27 (d, J =
13
3
8.0 Hz, 1H), 3.62 (s, 3H), 2.95–2.69 (m, 4H), 1.80 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm)
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99.4, 173.4, 160.5, 145.4, 139.0, 136.6, 134.9, 133.0, 132.8, 132.4, 129.0, 128.4, 128.1, 127.3,
123.9, 121.3, 116.1, 112.1, 111.1, 51.1, 35.5, 34.8, 29.9, 28.6; HRMS (ESI) m/z: calcd for
+
C
H
26 22
N
O
2 2
[M + H] 429.1364, found 429.1362.
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The Hydrolyzation and Esterification of 3a. To a stirred solution of 3a (157.7 mg, 0.5
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
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48
49
50
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52
53
54
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56
57
58
59
60
mmol) in MeOH (4 mL) in a sealed tube was added H
2
3
O (4 drops), CH COOH (1 mL) and conc.
o
H
2
SO
4
(1.5 mL). The reaction mixture was heated at 90 C for 24 h. After cooling to room
temperature, the reaction mixture was slowly quenched with saturated aqueous NaHCO
and extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (15
mL), dried over anhydrous MgSO , and concentrated in vacuo. The residue was purified by silica
gel chromatography using hexane/ethyl acetate (5:1) to afford the pure product 5a.
3
to pH 8
4
Methyl
3ꢀ(4,6ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanoate
1
(
5a). Yellow oil (66.1 mg, 95% yield); H NMR (400 MHz, CDCl
3
) δ (ppm) 8.53 (d, J = 8.1 Hz,
1H), 8.28 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.76 (t, J = 7.5 Hz,
1H), 7.66 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 3.48 (s, 3H), 2.88–2.61 (m,
1
3
2
1
3
3
H), 2.30–2.06 (m, 2H), 1.81 (s, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 173.4, 173.3, 158.7,
44.7, 138.7, 133.3, 132.1, 129.8, 129.3, 126.8, 122.7, 122.6, 116.3, 112.1, 110.9, 51.5, 50.7, 36.1,
+
0.3, 29.9, 28.7; HRMS (ESI) m/z: calcd for C21
H N
21 2
O
3
[M + H] 349.1547, found 349.1546.
22
The Hydrolyzation and Amidation of 3a. To a stirred solution of 3a (157.7 mg, 0.5 mmol)
2 2 2 3
in DMSO (2 mL) was added H O (30% in water, 0.5 mL) and K CO (69.1 mg, 0.5 mmol) at 0
o
C. Then the reaction mixture was stirred at room temperature for 12 h. After completion of the
reaction, the reaction mixture was diluted with H O (15 mL) and extracted with EtOAc (15 mL ×
2
4
3). The combined organic phases were washed with brine (15 mL), dried over anhydrous MgSO ,
filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using
hexane/ethyl acetate (5:1) to afford the pure product 6a.
3ꢀ(4,6ꢀDimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrido[4,3,2ꢀgh]phenanthridinꢀ6ꢀyl)propanamide
(6a).
o
1
White solid (33.3 mg, 50% yield); mp 150–151 C; H NMR (400 MHz, DMSO–d
6
) δ (ppm) 8.75
(d, J = 7.6 Hz, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.08 (dd, J = 8.2, 0.9 Hz, 1H), 7.94 (t, J = 8.1 Hz,
1H), 7.79 (t, J = 7.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.66
1
3
(
s, 1H), 3.52 (s, 3H), 2.47–2.30 (m, 2H), 1.91–1.84 (m, 1H), 1.70 (s, 3H), 1.67–1.59 (m, 1H); C
6
NMR (100 MHz, DMSO–d ) δ (ppm) 173.6, 173.0, 159.7, 144.7, 138.8, 133.1, 133.0, 129.8,
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6
1
29.7, 127.3, 123.7, 122.9, 116.7, 112.2, 112.0, 50.5, 38.6, 31.1, 30.0, 28.1; HRMS (ESI) m/z:
+
calcd for C20
20 3
H N O
2
[M + H] 334.1550, found 334.1552.
23
o
1
4
,4ꢀDiphenylbutꢀ3ꢀenenitrile (8a). Yellow solid (34.2 mg, 78% yield); mp 90–91 C; H NMR
(400 MHz, CDCl ) δ (ppm) 7.48–7.39 (m, 3H), 7.34–7.31 (m, 3H), 7.26–7.20 (m, 4H), 6.06 (t, J =
7.4 Hz, 1H), 3.18 (d, J = 7.4 Hz, 2H); C NMR (100 MHz, CDCl
29.4, 128.8, 128.4, 128.2, 128.2, 127.5, 118.2, 115.5, 18.4.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
3
) δ (ppm) 147.5, 140.7, 138.0,
1
■
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
Copies of H NMR and C NMR spectra for all products, and the crystal structure of 3g (PDF).
■
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Project 21672104,
2
1502097), the Key International (Regional) Joint Research Program of NSFC (Grant No.
1420102002), the Natural Science Foundation of the Education Department of Jiangsu province
2
(15KJB150015), and the Priority Academic Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Hailong Liu for the determination of HRMS.
■
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