Palladium-catalyzed intramolecular C(sp2)-H imidoylation for the synthesis of six-membered N-heterocycles

Article abstract of DOI:10.1021/jo502731n

A new strategy for the construction of phenanthridine and isoquinoline scaffolds, starting from arenes containing a pending isocyanide moiety under palladium catalysis, has been developed. This process involves sequential intermolecular isocyanide inserti

Full text of DOI:10.1021/jo502731n

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Article
Palladium-Catalyzed Intramolecular C(sp2)-H Imidoylation
for the Synthesis of Six-Membered N-Heterocycles
Jing Li, Yimiao He, Shuang Luo, Jian Lei, Jian Wang, Zeqiang Xie, and Qiang Zhu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2015
Downloaded from http://pubs.acs.org on January 23, 2015
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Palladium-Catalyzed Intramolecular C(sp2)-H Imidoylation for
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the Synthesis of Six-Membered N-Heterocycles
Jing Li, Yimiao He, Shuang Luo, Jian Lei, Jian Wang, Zeqiang Xie, and Qiang Zhu*
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou
510530, China
E-mail address of the corresponding author: zhu_qiang@gibh.ac.cn.
R1
Pd(OAc)2 (5 mol %), PPh3 (10 mol %)
R1
K2CO3 (1.2 equiv), PivOH (0.6 equiv)
toluene, 100 oC, Ar, slow addition in 1 h
+
RX
NC
N
R2
ABSTRACT: A new strategy for the construction of phenanthridine and isoquinoline scaffolds, starting from arenes con-
taining a pending isocyanide moiety under palladium catalysis, has been developed. This process involves sequential in-
termolecular isocyanide insertion to an aryl palladium(II) intermediate and intramolecular aromatic C-H activation as key
steps. Alkyl palladium(II) intermediate lacking βꢀhydrogen is also applicable to this reaction, generating unique bisheter-
ocyclic scaffolds with three C-C bonds being formed consecutively.
INTRODUCTION
The versatility of isocyanide in generating molecular complexity has been adequately demonstrated in Ugi and related
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multicomponent reactions (MCRs) since 1960’s. In the past decade, another important and unique reactivity of isocya-
nide has been increasingly recognized, that is palladium-catalyzed imidoylation process.2 Similar to carbon monoxide
(CO) as its isoelectronic equivalent, isocyanide can undergo migratory insertion to a Pd(II) intermediate, followed by sub-
stitution with various nucleophiles and reductive elimination to generate amidines,3a amides,3b,4 ketimines,5 imidates, or
thiomidates6 accordingly. This palladium-catalyzed imidoylation reaction is particularly powerful in construction of het-
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erocyclic skeletons through non-functionalized or functionalized isocyanide strategies. In non-functionalized isocyanide
approach, only the terminal carbon of isocyanide is consisted in the constructed heterocyclic ring by reacting isocyanide
with molecules either bearing two nucleophiles7 or containing a nucleophile and a precursor of Pd(II) intermediate ready
for isocyanide insertion.8 In functionalized isocyanide strategy, however, the isocyanide substrate not only participates in
migratory insertion, but also provides inbuilt functional groups which can react with the imidoyl palladium intermediate
further (Scheme 1).9 As a result, the isocyanide nitrogen is included in the cyclized product as a ring member. Therefore,
this strategy for heterocycle synthesis takes full advantage of RNC in having a diversifiable R group over CO. For instance,
in 2002, Takahashi reported a three-component coupling reaction of aryl iodides, o-alkenylphenyl isocyanides and sec-
ondary amines (Scheme 1). 9a In this reaction, the imidoyl palladium intermediate was trapped by the ortho styrenic moie-
ty followed by nucleophilic substitution and reductive elimination to build indole scaffold. Ten years later, Takemoto re-
ported a Pd-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp3)-H activation, leading to in-
dole derivatives as well (Scheme 1).9b Very recently, we used α-isocyanoacetamides as a novel class of functionalized iso-
cyanide for the synthesis of C2 diversified oxazoles9c as well as 2,2’-bisoxazoles.9d Herein, we would like to report a se-
quential process using arene-containing isocyanides as substrates to construct six-membered N-heterocycles including
phenanthridines10 and isoquinolines via intramolecular aromatic C-H activation as a key step (Scheme 1).
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Scheme 1. Functionalized Isocyanide in Palladium-Catalyzed Imidoylative Cyclization
2-Isocyano-1,1'-biphenyls were originally selected as idea substrates in testing the hypothesis. In recent years, reactions
using 2-isocyano-1,1'-biphenyls as radical acceptors to form multi-substituted phenanthridines have been frequently re-
ported. Some carbon centered radicals including aryl,11 CF3,12 alkyl,13 acyl,14 and alkoxycarbonyl15 radicals as well as heteroa-
tom-centered ones16 were applied to react with 2-isocyano-1,1'-biphenyls, forming various imidoyl radical intermediates
for the following intramolecular homolytic aromatic substitution (HAS) process.17 In these radical based reactions, how-
ever, no examples of corresponding alkenylation or alkynylation were realized. Given the fruitfulness of Pd chemistry, we
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anticipated that an alternative palladium-catalyzed imidoylation process would provide a new approach to multi-
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substituted six-membered N-heterocycles by using arene-containing isocyanides as a new class of functionalized isocya-
nides.
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RESULTS AND DISCUSSION
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Our initial effort was focused on using 2-isocyano-5-methyl-1,1'-biphenyl as a model substrate in a reaction with iodoben-
zene under palladium catalysis. Unfortunately, unstable products derived from consecutive isocyanide insertion were
obtained. This unwanted side reaction was probably due to the unfavorable reaction distance between the phenyl ring
and the Pd catalyst after isocyanide insertion. To circumvent multi isocyanide insertion, an additional substituent at the
C3 position of the 2-isocyano-1,1'-biphenyl substrate was introduced to force the Pd center in a position closer to the
pending phenyl ring. Indeed, when 2-isocyano-3,5-dimethyl-1,1'-biphenyl 1a (0.2 mmol scale) was chosen in a reaction
with iodobenzene 2a in the presence of Pd(OAc)2 (5 mol %), Ad2PnBu (10 mol %), and 1.2 equivalents of Cs2CO3 in toluene
at 100 °C, 2,4-dimethyl-6-phenylphenanthridine 3a was formed in 20% yield (entry 1, Table 1). When Cs2CO3 was replaced
by CsOPiv, the reaction was improved significantly to give 3a in 78% yield (entry 2). It was found that the influence of
phosphine ligand on the reaction efficiency was minimal (entries 3-6). Since CsOPiv was highly hygroscopic, in-situ for-
mation of CsOPiv by mixing Cs2CO3 and PivOH was preferred, which indeed gave a slightly improved result (entry 7).18
K2CO3 was proved the base of choice among the bases screened (entries 8-10). The reaction proceeded equally well in 0.5
mmol scale in the same amount of solvent (1.5 mL), and the product 3a was isolated in 90% yield (entry 11). It is notable
that in all of these cases, slow addition of a solution of 1a in toluene via a syringe pump to a pre-stirred reaction mixture is
applied to achieve maximum and reproducible result (see experimental section for details).
Table 1. Optimization of the Reaction Conditionsa
entry
base
ligand
additive
yieldb
20%
1
Cs2CO3
CsOPiv
Ad2PnBu
Ad2PnBu
2
78%
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3
CsOPiv
CsOPiv
CsOPiv
CsOPiv
Cs2CO3
CsF
Cy3P
dppe
PPh3
BINAP
PPh3
PPh3
PPh3
PPh3
PPh3
78%
76%
77%
78%
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PivOH
84%
80%
88%
trace
90%
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8
PivOH
PivOH
PivOH
PivOH
9
K2CO3
Na2CO3
K2CO3
10
11c
aReaction conditions: 1a (0.2 mmol, 1.0 equiv, in 1 mL of toluene), 2a (0.3 mmol, 1.5 equiv), Pd(OAc)2 (5 mol %), ligand (10
o
b
mol %), base (1.2 equiv), additive (0.6 equiv), toluene (0.5 mL), 100 C, Ar, syringe pump addition within 1 h. Isolated yield of
3a. c 1a (0.5 mmol), in the same amount of solvent (0.5 + 1 mL).
With the optimal conditions in hand, we first investigated the scope of halides in this Pd-catalyzed imidoylative cycliza-
tion reaction with 1a (Scheme 2). Aryliodides bearing a variety of functional groups including electron-withdrawing NO2,
methoxycarbonyl, Br, and Cl as well as electron-donating methyl at the para position gave the corresponding products 3b-
3f in yields ranging from 66 to 71%. 3-Methylphenyl iodide reacted smoothly with 1a to give 3g in 76% yield, while a me-
thyl group located at the ortho position of phenyl iodide affected the product formation significantly (3h, 50%). Phe-
nylbromide could also be used in this reaction, furnishing the same product 3a in 66% yield. Besides, alkenylated phenan-
thridine derivative 3i was also accessible by employing the corresponding vinyl bromide19 as a substrate, albeit in only 19%
yield. Unfortunately, a reaction between 1a and bromoethynylbenzene under otherwise identical conditions couldn’t yield
the desired product.
Scheme 2. Scope of Halidesa
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aReaction conditions: 1a (0.5 mmol, 1.0 equiv, in 1 mL of toluene), 2 (0.75 mmol, 1.5 equiv), Pd(OAc)2 (5 mol %), PPh3 (10
mol %), PivOH (0.6 equiv), K2CO3 (1.2 equiv), toluene (0.5 mL), 100 oC, Ar, syringe pump addition within 1 h. Isolated yields of 3
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were reported. bCorresponding bromide was used.
Then the reaction was investigated using various substituted 2-isocyano biphenyls (Scheme 3). Changing the substituent
on the 2-position from methyl to chloride also gave the desired product 3k in 75% yield. The reaction was not sensitive to
the electronic nature of substituents on the non-isocyano bearing aromatic ring, delivering F, CF3, and Me substituted 6-
phenyl phenanthridines 3l-3m in good yields. 2-Isocyano-3,5,2’-trimethyl-1,1'-biphenyl furnished 3o in a surprisingly high
yield (92%). Unfortunately, poor regio-selectivity was obtained for meta CF3 substituted 2-isocyano biphenyl (3p and 3p’).
C-H bond in a heteroaromatic ring could also be activated by the imidoyl palladium(II) intermediate, giving benzofu-
ro[3,2-c]quinolone derivative 3q in an excellent 96% yield.
Scheme 3. Scope of 2-Isocyano Biphenyls a
aReaction conditions: 1 (0.5 mmol, 1.0 equiv, in 1 mL of toluene), 2a (0.75 mmol, 1.5 equiv), Pd(OAc)2 (5 mol %), PPh3 (10
mol %), PivOH (0.6 equiv), K2CO3 (1.2 equiv), toluene (0.5 mL), 100 oC, Ar, syringe pump addition within 1 h. Isolated yields of 3
were reported.
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Scheme 4. Cascade Imidoylative Cyclizationa
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aStandard conditions, isolated yields of 5 and 3r.
It was anticipated that alkyl Pd(II)-intermediate lacking βꢀhydrogen was also applicable to this reaction to generate alkyl
substituted phenanthridine derivatives. Therefore, a cascade process involving oxidative addition of Pd(0) to aryl iodides
4 linking a 2-propene moiety and alkene insertion, followed by imidoylative cyclization, was investigated (Scheme 4). In-
deed, a range of unique bisheterocyclic scaffolds with a methylene tether were obtained in moderate to good yields (5a-
5d). When 2-iodophenyl methacrylate was used, the desired intramolecular alkene insertion to aryl Pd(II) intermediate
did not take place, furnishing aryl substituted phenanthridine 3r in 51% yield. Satisfyingly, when the terminal alkene was
one more carbon away from the aryl ring in a benzyl ether substrate, the cascade reaction occurred again (5e, 77%). It was
notable that three C-C bonds were formed consecutively in this one-pot reaction, enabling to install indolinone, indoline,
or isochromane to phenanthridine with high step and bond-forming efficiency.
To extend this Pd-catalyzed functionalized isocyanide strategy to other six-membered heterocycle synthesis, vinyl isocya-
nides 6 were used as substrates under the same reaction conditions (Scheme 5).20 Ethyl 4-methyl(ethyl)-1-
phenylisoquinoline-3-carboxylates 7a-b were prepared smoothly starting from the corresponding vinyl isocyanides. 1,4-
Diaryl isoquinolines 7c-d were also accessible by employing this method in acceptable yields.
Scheme 5. Synthesis of Isoquinolinesa
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R2
R2
R1
EtOOC
R1
EtOOC
1
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7
standard conditions
+
PhI
NC
N
7
Ph
6
2a
Cl
Cl
EtOOC
N
Ph
EtOOC
N
Ph
EtOOC
N
Ph EtOOC
N
Ph
8
7d, 54%
7a, 77%
7b, 53%
7c, 58%
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aStandard conditions, isolated yields of 7.
To gain insight into the reaction mechanism, intramolecular kinetic isotope effect was investigated using 2,6-diphenyl
1
aryl isocyanide 8 with one of the phenyl rings fully deuterium labeled. The ratio of 9 to 10, determined by H NMR, was
about 5.6:1, which indicated that C-H cleavage might be a rate-limiting step.
Scheme 6. Mechanistic study
A plausible mechanism of this imidoylative cyclization process was depicted in Scheme 6.5 Initial oxidative addition of
aryl halide to Pd(0) affords aryl Pd(II) intermediate A. Then, coordination and migratory insertion of the isocyano moiety
to intermediate A generates imidoyl palladium species B and B’. The steric hindrance of the ortho methyl group helps the
presence of conformer B in the equilibrium. Next, activation of the C(sp2)-H bond aided by the coordinated pivalate
through a concerted metalation deprotonation (CMD) intermediate C gives palladacycle D.21 Finally, reductive elimina-
tion delivers the cyclized phenanthridine product 3 and regenerates Pd(0) for the next catalytic cycle. However, an elec-
trophilic aromatic substitution process involving intermediate C’ cannot be excluded.
Scheme 7. Possible mechanism
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CONCLUSION
In summary, we have demonstrated the feasibility of functionalized isocyanide strategy in palladium-catalyzed imidoy-
lation in heterocycle synthesis. In this imidoylative cyclization process, 2-isocyano-1,1'-biphenyls as well as Z-2-
isocyanostyrenes react smoothly with arylhalides to generate aryl substituted six-membered phenanthridines and iso-
quinolines, respectively. Aryliodides bearing ortho alkenes by a variety of N or O linkage are also applied in this reaction.
Therefore, a process including alkene insertion, migratory insertion of isocyanide, and intramolecular C(sp2)-H activation
takes place sequentially, allowing to install other heterocycles to phenanthridine by a methylene tether. Three C-C bonds
are formed consecutively, representing high bond-forming efficiency of the reaction. Mechanistic study suggests that
C(sp2)-H activation is likely a rate-determining step.
EXPERIMENTAL SECTION
General Information. Reactions were monitored using thin-layer chromatography (TLC) on commercial silica gel plates
(GF254). Solvents for flash column chromatography (FC), crystallization and extractions have been distilled once. Visuali-
zation of the developed plates was performed under UV light (254 nm). Flash column chromatography was performed on
1
13
silica gel (200-300 mesh). H and C NMR spectra were recorded on a 400 or 500 MHz spectrometer. Chemical shifts (δ)
1
13
were reported in ppm referenced to an internal tetramethylsilane standard for H NMR. Chemical shifts of C NMR are
reported relative to CDCl3 (δ 77.0). Coupling constants, J, were reported in Hertz unit (Hz). High resolution mass spectra
(HRMS) were obtained on an ESI-LC-MS/MS spectrometer.
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General Procedure A: An oven-dried 25 mL Schlenk tube was charged with Pd(OAc)2 (0.025 mmol, 5.6 mg), PPh3 (0.05
mmol, 13.1 mg), K2CO3 (0.6 mmol, 84 mg), PivOH (0.3 mmol, 31 mg), and the tube was refilled with Ar for 3 times. Then a
solution of aryl(vinyl) halide 2 (0.75 mmol) in 0.5 mL of toluene was added. After the mixture was stirred at 100 oC for 0.5
h, 2-isocyano-1,1'-biphenyl 1 (0.5 mmol) was dissolved in 1.0 mL of toluene and the solution was added via a syringe pump
within 1 h. The crude reaction mixture was extracted with ethyl acetate (20 mL × 3) and washed with brine (20 mL). The
organic phase was concentrated in vacuum and the product 3 was purified by flash chromatography using ethyl acetate
and petroleum ether (1:100) as an eluent.
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General Procedure B: An oven-dried 25 mL Schlenk tube was charged with Pd(OAc)2 (0.025 mmol, 5.6 mg), PPh3 (0.05
mmol, 13.1 mg), K2CO3 (0.6 mmol, 84 mg), PivOH (0.3 mmol, 31 mg), and the tube was refilled with Ar for 3 times. Then,
o
0.5 mL of toluene was added, and the mixture was stirred at 100 C for 0.5 h. To this mixture, a solution of aryliodide 4
containing an ortho pending alkene moiety (0.75 mmol) in 0.5 mL of toluene was added. Besides, a solution of 2-isocyano-
3,5-dimethyl-1,1'-biphenyl (1a, 0.5 mmol, 103.6 mg) in 0.5 mL of toluene was introduced via a syringe pump within 1 h. The
crude reaction mixture was extracted with ethyl acetate (20 mL × 3) and washed with brine (20 mL). The organic phase
was concentrated in vacuum and the product 5 was purified by flash chromatography using ethyl acetate and petroleum
ether (1:50) as an eluent.
General Procedure C: An oven-dried 25 mL Schlenk tube was charged with Pd(OAc)2 (0.01 mmol, 2.3 mg), PPh3 (0.02
mmol, 5.3 mg), K2CO3 (0.24 mmol, 33 mg), PivOH (0.12 mmol, 12 mg), and the tube was refilled with Ar for 3 times. Then a
o
solution of PhI (2a, 0.3 mmol, 61.8 mg) in 0.5 mL of toluene was added. The mixture was stirred at 100 C for 0.5 h, fol-
lowed by adding a solution of vinyl isocyanide 6 (0.2 mmol) in 1.0 mL of toluene via a syringe pump within 1 h. The reac-
tion mixture was extracted with ethyl acetate (20 mL × 3) and washed with brine (20 mL). The organic phase was concen-
trated in vacuum and the product 7 was purified by flash chromatography using ethyl acetate and petroleum ether (1:100)
as an eluent.
2,4-dimethyl-6-phenylphenanthridine (3a)22
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75 mmol,
1
1.5 equiv) according to the general procedure A. Isolated as a white solid (128 mg, 0.45 mmol), yield: 90%. H NMR (400
MHz, CDCl3): δ 8.68 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.82-7.78 (m, 3H), 7.60-7.49 (m, 4H), 7.45 (s,
13
1H), 2.85 (s, 3H), 2.60 (s, 3H); C NMR (125 MHz, CDCl3): δ 158.3, 140.9, 137.8, 136.1, 133.6, 131.2, 130.2, 129.8, 128.5, 128.4,
128.1, 126.6, 124.8, 123.3, 122.4, 119.3, 21.9, 18.2; FTIR: νmax/cm-1 3047, 2910, 1566, 1517, 1442, 1360, 1319, 955, 850, 778, 761, 700,
672, 582; HRMS (ESI-TOF): calcd for C21H17N (M+H+) 284.1434; found: 284.1436; mp: 123-125 oC.
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2,4-dimethyl-6-(4-nitrophenyl)phenanthridine (3b)
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Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-iodo-4-nitrobenzene (187 mg,
0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a pale yellow solid (111 mg, 0.35 mmol), yield: 70%.
1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 8.4 Hz, 2H), 8.27 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.99 (d, J
8
9
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= 8.8 Hz, 2H), 7.85 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.49 (s, 1H), 2.83 (s, 3H), 2.62 (s, 3H); C NMR (125 MHz,
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CDCl3): δ 155.7, 147.9, 146.7, 140.8, 138.1, 137.1, 133.6, 131.6, 131.1, 130.3, 127.5, 127.1, 124.2, 123.5, 123.5, 122.8, 119.4, 22.0, 18.1; FTIR:
νmax/cm-1 3069, 2919, 1597, 1517, 1348, 1319, 852, 773, 694, 584; HRMS (ESI-TOF): calcd for C21H16N2O2 (M+H+) 329.1285;
found:329.1285; mp: 213-215 oC.
methyl 4-(2,4-dimethylphenanthridin-6-yl)benzoate (3c)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and methyl 4-iodobenzoate (196 mg,
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0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (120 mg, 0.35 mmol), yield: 70%. H
NMR (400 MHz, CDCl3): δ 8.68 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 8.88 (d, J =
8.0 Hz, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.46 (s, 1H), 3.98 (s, 3H), 2.83 (s, 3H), 2.60 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 167.0, 157.1, 144.8, 140.9, 138.0, 136.6, 133.6, 131.4, 130.3, 130.1, 130.0, 129.5, 128.0, 126.8, 124.5, 123.4, 122.6, 119.3,
52.2, 22.0, 18.2; FTIR: νmax/cm-1 3070, 2919, 1724, 1609, 1434, 1321, 1288, 1103, 777, 704; HRMS (ESI-TOF): calcd for C23H19NO2
(M+H+) 342.1489; found: 342.1489; mp: 191-193 oC.
6-(4-bromophenyl)-2,4-dimethylphenanthridine (3d)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-bromo-4-iodobenzene (212 mg,
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0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (126 mg, 0.35 mmol), yield: 69%. H
NMR (400 MHz, CDCl3): δ 8.69 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.69 (m, 4H), 7.59
(t, J = 7.2 Hz, 1H), 7.46 (s, 1H), 2.83 (s, 3H), 2.60 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 157.0, 140.9, 139.3, 137.8, 136.4, 133.6,
131.8, 131.4, 130.0, 128.1, 126.8, 124.5, 123.3, 122.9, 122.6, 119.3, 22.0, 18.2; FTIR: νmax/cm-1 3070, 2920, 1485, 1370, 1361, 1317, 1912,
841, 831, 794, 767, 583; HRMS (ESI-TOF): calcd for C21H16BrN (M+H+) 362.0539; found: 362.0539; mp: 176-178 oC.
6-(4-chlorophenyl)-2,4-dimethylphenanthridine (3e)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-chloro-4-iodobenzene (178 mg,
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0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (120 mg, 0.36 mmol), yield: 71%. H
NMR (400 MHz, CDCl3): δ 8.67 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.75 (d, J =
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8.4 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 2.83 (s, 3H), 2.59 (s, 3H); C NMR (125 MHz,
CDCl3): δ 157.0, 140.8, 138.8, 137.8, 136.4, 134.6, 133.6, 131.5, 131.3, 130.0, 128.4, 128.1, 126.8, 124.6, 123.3, 122.6, 119.3, 22.0, 18.2;
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FTIR: νmax/cm-1 3072, 2919, 1488, 1362, 1318, 1090, 834, 795, 763; HRMS (ESI-TOF): calcd for C21H16ClN (M+H+) 318.1044;
found: 318.1046; mp: 187-189 oC.
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2,4-dimethyl-6-(p-tolyl)phenanthridine (3f)
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Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-iodo-4-methylbenzene (164 mg,
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0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (99 mg, 0.33 mmol), yield: 66%. H
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NMR (400 MHz, CDCl3): δ 8.66 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 6.8 Hz, 1H), 7.71 (d, J =
8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.84 (s, 3H), 2.59 (s, 3H), 2.47 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 158.3, 141.0, 138.3, 137.8, 137.6, 136.0, 133.6, 131.2, 130.2, 130.1, 129.9, 129.8, 128.9, 128.6, 128.2, 126.5, 124.9, 123.2,
122.4, 119.3, 22.0, 21.4, 18.3; FTIR: νmax/cm-1 3069, 2914, 1449, 1361, 1318, 1181, 845, 797, 769, 582; HRMS (ESI-TOF): calcd for
C22H19N (M+H+) 298.1590; found: 298.1593; mp: 139-141 oC.
2,4-dimethyl-6-(m-tolyl)phenanthridine (3g)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-iodo-3-methylbenzene (163 mg,
0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a pale yellow solid (113 mg, 0.38 mmol), yield: 76%.
1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.60-7.53
(m, 3H), 7.45-7.41 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 2.84 (s, 3H), 2.59 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 158.5,
141.0, 140.4, 137.8, 137.7, 136.0, 133.5, 131.2, 130.8, 130.2, 129.8, 129.2, 128.6, 128.5, 128.4, 128.2, 128.0, 127.3, 126.6, 126.5, 124.9,
123.3, 122.4, 122.3, 119.3, 22.0, 21.6, 18.3; FTIR: νmax/cm-1 3075, 2911, 1570, 1357, 1318, 849, 792, 779, 766, 706; HRMS (ESI-TOF):
calcd for C22H19N (M+H+) 298.1590; found: 298.1591; mp: 133-135 oC.
2,4-dimethyl-6-(o-tolyl)phenanthridine (3h)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-iodo-2-methylbenzene (163 mg,
0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a pale yellow solid (75 mg, 0.25 mmol), yield: 50%.
1H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.80-7.76 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53-7.49 (m,
1H), 7.45 (s, 1H), 7.42-7.32 (m, 4H), 2.81 (s, 3H), 2.60 (s, 3H), 2.15 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.0, 140.9, 139.8,
137.9, 136.8, 136.1, 133.1, 131.1, 130.4, 130.0, 129.9, 129.8, 128.4, 128.2, 126.7, 125.6, 125.5, 123.4, 122.3, 119.3, 21.9, 20.0, 18.4; FTIR:
νmax/cm-1 3049, 2915, 1573, 1452, 1361, 1317, 854, 778, 760, 737, 726; HRMS (ESI-TOF): calcd for C22H19N (M+H+) 298.1590;
found: 298.1592; mp: 145-147 oC.
(Z)-6-(1-fluoro-2-(naphthalen-2-yl)vinyl)-2,4-dimethylphenanthridine (3i)
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Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and (E)-2-(2-bromo-2-
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2
fluorovinyl)naphthalene (188 mg, 0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as an orange solid
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(35 mg, 0.10 mmol), yield: 19%. H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 9.2 Hz, 1H), 8.23 (d, J =
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10.0 Hz, 1H), 7.98-7.95 (m, 1H), 7.91-7.83 (m, 4H), 7.73-7.69 (m, 1H), 7.53-7.48 (m, 3H), 7.01 (d, J = 38.4 Hz, 1H), 2.91 (s, 3H),
2.62 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 158.8 (d, J = 265.0 Hz, 1C), 149.3 (d, J = 30.6 Hz, 1C), 140.5, 138.0, 137.3, 133.6, 133.5,
132.8 (d, J = 1.6 Hz, 1C), 131.4, 131.1 (d, J = 3.6 Hz, 1C), 130.2, 129.0, 128.9, 128.3, 128.1, 127.6, 127.4, 127.2, 127.14, 127.07, 126.3,
126.2, 124.1, 123.9 (d, J = 3.6 Hz, 1C), 122.5, 119.4, 112.61, 112.56, 22.1, 18.2; FTIR: νmax/cm-1 3052, 2917, 1367,1313, 1165, 905, 817,
766, 748, 482; HRMS (ESI-TOF): calcd for C27H20FN (M+H+) 378.1653; found: 378.1654; mp:195-197 oC.
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4-methyl-6-phenylphenanthridine (3j)23
Prepared from 2-isocyano-3-methyl-1,1'-biphenyl (97 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75 mmol, 1.5
equiv) according to the general procedure A. Isolated as a white solid (106 mg, 0.40 mmol), yield: 79%. 1H NMR (400 MHz,
CDCl3): δ 8.68 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H),7.82-7.79 (m, 3H), 7.61-7.49 (m, 6H), 2.89
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.2, 142.6, 140.3, 138.2, 133.9, 130.2, 130.1, 129.4, 128.6, 128.5, 128.4, 128.2, 126.8, 126.4,
124.7, 123.4, 122.5, 119.7, 18.4; FTIR: νmax/cm-1 3059, 2957, 1567, 1467, 1361, 750, 689, 668; HRMS (ESI-TOF): calcd for C20H15N
(M+H+) 270.1277; found: 270.1278; mp:137-139 oC.
4-chloro-2-methyl-6-phenylphenanthridine (3k)
Prepared from 3-chloro-2-isocyano-5-methyl-1,1'-biphenyl (114 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75
mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (113 mg, 0.38 mmol), yield: 75%. 1H NMR
(400 MHz, CDCl3): δ 8.65 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.86-7.81 (m, 3H), 7.70 (s, 1H), 7.63 (t, J =
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8.0 Hz, 1H), 7.58-7.50 (m, 3H), 2.61 (s, 3H); C NMR (125 MHz, CDCl3): δ 160.5, 139.6, 138.4, 136.8, 134.2, 133.1, 130.7, 130.5,
130.3, 128.9, 128.8, 128.3, 127.5, 125.2, 125.1, 122.4, 120.5, 21.7; FTIR: νmax/cm-1 3048, 2914, 1360, 1317, 855, 829, 779, 762, 702,673;
HRMS (ESI-TOF): calcd for C20H14ClN (M+H+) 304.0888; found: 304.0886; mp:189-191 oC.
2,4,8-trimethyl-6-phenylphenanthridine (3l)
Prepared from 2-isocyano-3,4',5-trimethyl-1,1'-biphenyl (111 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75 mmol,
1
1.5 equiv) according to the general procedure A. Isolated as a white solid (126 mg, 0.43 mmol), yield: 85%. H NMR (400
MHz, CDCl3): δ 8.54 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.81-7.78 (m, 1H), 7.62-7.48 (m, 4H), 7.40 (s, 1H), 2.83 (s,
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3H), 2.57 (s, 3H), 2.48 (s, 3H); C NMR (125 MHz, CDCl3): δ 158.0, 140.7, 140.6, 137.8, 136.5, 136.0, 131.6, 131.5, 130.8, 130.2,
128.3, 128.2, 127.8, 125.0, 123.4, 122.4, 119.1, 22.0, 21.7, 18.3; FTIR: νmax/cm-1 3050, 2919, 2850, 1565, 1524, 1441, 1365, 1315, 818, 766,
700, 581; HRMS (ESI-TOF): calcd for C22H19N (M+H+) 298.1590; found: 298.1592; mp:147-149 oC.
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8-fluoro-2,4-dimethyl-6-phenylphenanthridine (3m)
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Prepared from 4'-fluoro-2-isocyano-3,5-dimethyl-1,1'-biphenyl (113 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75
mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (131 mg, 0.44 mmol), yield: 87%. 1H NMR
(400 MHz, CDCl3): δ 8.67-8.66 (m, 1H), 8.17 (s, 1H), 7.80-7.77 (m, 3H), 7.58-7.50 (m, 4H), 7.44 (s, 1H), 2.83 (s, 3H), 2.59 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 161.0 (d, J = 246.9 Hz, 1C), 157.4 (d, J = 4.1 Hz, 1C), 140.7, 139.9, 138.0, 136.6, 131.1, 130.2 (d,
J = 1.8 Hz, 1C), 130.0, 128.6, 128.3, 126.0 (d, J = 7.9 Hz, 1C), 125.0 (d, J = 8.4 Hz, 1C), 122.9, 119.2, 119.03, 118.99, 112.8, 112.6, 22.0,
18.2; FTIR: νmax/cm-1 3057, 2917, 1524, 1372, 1315, 1196, 875, 824, 765, 693, 580; HRMS (ESI-TOF): calcd for C21H16FN (M+H+)
302.1340; found: 302.1343; mp:147-149 oC.
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2,4-dimethyl-6-phenyl-8(trifluoromethyl)phenanthridine (3n)
Prepared from 2-isocyano-3,5-dimethyl-4'-(trifluoromethyl)-1,1'-biphenyl (138 mg, 0.5 mmol, 1.0 equiv) and iodobenzene
(153 mg, 0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (145 mg, 0.42 mmol), yield:
83%. 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 7.97-7.94 (m, 1H), 7.80-7.78 (m, 2H),
7.60-7.52 (m, 3H), 7.49 (s, 1H), 2.83 (s, 3H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 158.0, 141.6, 139.5, 138.2, 136.9, 132.4,
130.2, 128.9, 128.5, 128.4 (q, J = 32.9 Hz, 1C), 125.9 (q, J = 4.1 Hz, 1C), 125.6 (q, J = 3.2 Hz, 1C), 124.1 (q, J = 273.5 Hz, 1C), 124.0,
123.5, 122.4, 119.5, 21.9, 18.2; FTIR: νmax/cm-1 3056, 2920, 1372, 1330, 1303, 1225, 1162, 1119, 828, 769; HRMS (ESI-TOF): calcd for
C22H16F3N (M+H+) 352.1308; found:352.1309; mp:142-144 oC.
2,4,10-trimethyl-6-phenylphenanthridine (3o)
Prepared from 2-isocyano-2',3,5-trimethyl-1,1'-biphenyl (111 mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75 mmol,
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1.5 equiv) according to the general procedure A. Isolated as a white solid (137 mg, 0.46 mmol), yield: 92%. H NMR (400
MHz, CDCl3): δ 8.46 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.63 (d, J = 4.0 Hz, 1H), 7.55-7.53 (m, 3H), 7.51-7.43
(m, 2H), 3.15 (s, 3H), 2.86 (s, 3H), 2.59 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.0, 141.9, 141.1, 137.7, 135.2, 134.8, 134.1, 133.2,
130.5, 130.2, 128.2, 128.1, 127.3, 126.5, 126.0, 124.7, 124.2, 27.1, 22.3, 18.9; FTIR: νmax/cm-1 3051, 2915, 1442, 1379, 1362, 1322, 845,
779, 766, 700; HRMS (ESI-TOF): calcd for C22H19N (M+H+) 298.1590; found: 298.1591; mp:161-163 oC.
2,4-dimethyl-6-phenyl-9(trifluoromethyl)phenanthridine (3p)
Prepared from 2-isocyano-3,5-dimethyl-3'-(trifluoromethyl)-1,1'-biphenyl (138mg, 0.5 mmol, 1.0 equiv) and iodobenzene
(153 mg, 0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (67 mg, 0.19 mmol), yield:
38%. 1H NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.80-7.76 (m, 3H), 7.59-7.54 (m, 3H),
7.51 (s, 1H), 2.85 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 157.6, 141.3, 139.8, 138.2, 137.1, 133.3, 132.1, 131.3 (q, J = 32.7
Hz, 1C), 130.1, 129.5, 128.8, 128.3, 126.1, 124.1 (q, J = 272.7 Hz, 1C), 122.8, 122.5 (q, J = 3.2 Hz, 1C), 120.0 (q, J = 4.0 Hz, 1C), 119.2,
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21.9, 18.1; FTIR: νmax/cm-1 3063, 2920, 1349, 1316, 1161, 1152, 1119, 1072, 771, 703; HRMS (ESI-TOF): calcd for C22H16F3N (M+H+)
352.1308; found: 352.1309; mp: 187-189 oC.
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2,4-dimethyl-6-phenyl-7(trifluoromethyl)phenanthridine (3p’)
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Another isomer 3p’ was isolated as a white solid (57 mg, 0.15 mmol), yield: 30%. 1H NMR (400 MHz, CDCl3): δ 8.86 (d, J =
8.0 Hz, 1H), 8.17 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 4.0 Hz, 2H), 7.46-7.42 (m, 4H), 2.81 (s,
3H), 2.59 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 155.9, 143.6 (q, J = 1.8 Hz, 1C), 140.0, 137.5, 136.6, 135.5, 131.9, 129.3, 128.5, 128.4
(q, J = 31.5 Hz, 1C), 128.3, 127.6 (q, J = 6.2 Hz, 1C), 127.5, 126.2, 123.8 (q, J = 274.4 Hz, 1C), 121.7, 120.5, 119.0, 22.0, 17.7; FTIR:
νmax/cm-1 3058, 2919, 1298, 1185, 1128, 1112, 1092, 822, 776, 700; HRMS (ESI-TOF): calcd for C22H16F3N (M+H+) 352.1308; found:
352.1306; mp:199-201 oC.
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2,4-dimethyl-6-phenyl-9H-cyclopenta[4,5]furo[3,2-c]quinolonep (3q)
Prepared from 2-(2-isocyano-3,5-dimethylphenyl)benzofuran (120mg, 0.5 mmol, 1.0 equiv) and iodobenzene (153 mg, 0.75
mmol, 1.5 equiv) according to the general procedure A. Isolated as a white solid (151 mg, 0.48 mmol), yield: 96%. 1H NMR
(400 MHz, CDCl3): δ 8.04-8.01 (m, 3H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62-7.54 (m, 3H), 7.46 (t, J = 8.0 Hz,
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2H), 7.28-7.24 (m, 1H), 2.87 (s, 3H), 2.58 (s, 3H); C NMR (125 MHz, CDCl3): δ 158.4, 156.0, 153.1, 144.7, 140.4, 137.6, 136.2,
132.1, 129.3, 129.1, 128.5, 126.7, 123.3, 123.2, 122.3, 117.4, 115.9, 114.1, 111.8, 21.8, 18.4; FTIR: νmax/cm-1 3050, 2916, 1589, 1489, 1446,
1355, 1319, 1185, 1120, 851, 775, 745, 694; HRMS (ESI-TOF): calcd for C23H17NO (M+H+) 324.1383; found: 324.1383; mp:185-187
oC.
3-((2,4-dimethylphenanthridin-6-yl)methyl)-1,3-dimethylindolin-2-one (5a)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and N-(2-iodophenyl)-N-
methylmethacrylamide (227 mg, 0.75 mmol, 1.5 equiv) according to the general procedure B. Isolated as a yellow solid (162
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mg, 0.43 mmol), yield: 85%. H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H),
7.75-7.71 (m, 1H), 7.64-7.60 (m, 1H), 7.22 (s, 1H), 7.16-7.12 (m, 1H), 7.04-7.02 (m, 1H), 6.84-6.80 (m, 2H), 4.11 (d, J = 16.8 Hz,
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1H), 4.04 (d, J = 16.8 Hz, 1H), 3.30 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 1.58 (s, 3H); C NMR (125 MHz, CDCl3): δ 181.1, 154.0,
143.5, 140.3, 137.0, 135.4, 134.8, 132.5, 130.6, 129.7, 126.9, 126.7, 125.5, 125.2, 123.1, 122.5, 121.9, 121.8, 119.1, 107.9, 47.1, 40.8, 27.3,
26.4, 21.7, 18.2; FTIR: νmax/cm-1 3046, 2962, 1704, 1612, 1491, 1467, 1450, 1376, 1313, 791, 752; HRMS (ESI-TOF): calcd for
C26H24N2O (M+H+) 381.1961; found: 381.1963; mp:174-176 oC.
1-benzyl-3-((2,4-dimethylphenanthridin-6-yl)methyl)-3-methylindolin-2-one (5b)
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Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and N-benzyl-N-(2-
iodophenyl)methacrylamide (283 mg, 0.75 mmol, 1.5 equiv) according to the general procedure B. Isolated as a yellow
solid (87 mg, 0.19 mmol), yield: 38%. 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.09 (s,
1H), 7.73 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.23(s, 1H), 7.17-7.15 (m, 3H), 7.12-7.11 (m, 3H), 7.02 (t, J = 7.6 Hz, 1H),
6.83 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.32 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.17 (d, J = 16.4 Hz, 1H),
4.02 (d, J = 16.4 Hz, 1H), 2.49 (s, 3H), 2.34 (s, 3H), 1.66 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 180.9, 154.1, 142.4, 140.3, 137.1,
136.4, 135.5, 134.7, 132.7, 130.7, 129.7, 128.6, 127.3, 127.1, 126.9, 126.8, 125.8, 125.3, 123.2, 122.4, 122.3, 121.9, 119.1, 108.9, 47.6, 43.6,
40.8, 27.2, 21.2, 18.2; FTIR: νmax/cm-1 3060, 2914, 1718, 1613, 1489, 1464, 1340, 1305, 1168, 790, 746; HRMS (ESI-TOF): calcd for
C32H28N2O (M+H+) 457.2274; found: 457.2278; mp:174-176 oC.
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3-((2,4-dimethylphenanthridin-6-yl)methyl)-1-methacryloyl-3-methylindolin-2-one (5c)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and N-(2-iodophenyl)-N-
methacryloylmethacrylamide (266 mg, 0.75 mmol, 1.5 equiv) according to the general procedure B. Isolated as a white
solid (154 mg, 0.36 mmol), yield: 71%. 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.12 (d,
J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.78-7.74 (m, 1H), 7.68-7.64 (m, 1H), 7.25-7.21 (m, 1H), 7.10-7.08 (m, 1H), 7.03-6.99 (m, 1H),
5.40 (s, 1H), 5.37 (s, 1H), 4.21 (d, J = 16.0 Hz, 1H ), 4.13 (d, J = 16.0 Hz, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.05 (s, 3H), 1.67 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 180.3, 171.2, 153.0, 141.7, 140.2, 139.7, 137.2, 135.7, 134.6, 132.6, 131.0, 129.9, 127.3, 126.9, 125.1, 125.0,
124.7, 123.2, 122.6, 121.1, 119.8, 119.1, 115.7, 47.0, 41.2, 28.3, 21.7, 18.9, 18.4; FTIR: νmax/cm-1 3075, 2965, 1766, 1681, 1480, 1451, 1352,
1311, 1259, 1150, 790, 751; HRMS (ESI-TOF): calcd for C29H26N2O2 (M+H+) 435.2067; found: 435.2065; mp: 227-229 oC.
6-((1,3-dimethylindolin-3-yl)methyl)-2,4-dimethylphenanthridine (5d)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 2-iodo-N-methyl-N-(2-
methylallyl)aniline (215 mg, 0.75 mmol, 1.5 equiv) according to the general procedure B. Isolated as a pale yellow oil (86
mg, 0.24 mmol), yield: 47%. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.70
(t, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.63 (t, J = 8.0 Hz, 1H),
6.51 (d, J = 8.0 Hz, 1H), 3.78-3.74 (m, 2H), 3.54 (d, J = 14.8 Hz, 1H), 4.22 (d, J = 8.8 Hz, 1H), 2.84 (s, 3H), 2.76 (s, 3H), 2.56 (s,
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3H), 1.56 (s, 3H); C NMR (125 MHz, CDCl3): δ 156.5, 152.2, 140.5, 138.9, 137.2, 135.5, 132.6, 130.9, 129.5, 127.7, 126.6, 126.3,
126.2, 123.1, 122.4, 122.3, 119.3, 117.6, 107.3, 68.2, 44.4, 43.2, 35.8, 24.6, 21.9, 18.6; FTIR: νmax/cm-1 3020, 2952, 2803, 1605, 1489,
1460, 1450, 1372, 1361, 1300, 849, 795, 777; HRMS (ESI-TOF): calcd for C26H26N2 (M+H+) 367.2169; found: 367.2169.
2-(2,4-dimethylphenanthridin-6-yl)phenyl methacrylate (3r)
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Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 2-iodophenyl methacrylate (216 mg,
0.75 mmol, 1.5 equiv) according to the general procedure A. Isolated as a pale yellow oil (93 mg, 0.26 mmol), yield: 51%. 1H
NMR (400 MHz, CDCl3): δ 8.65 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.80-7.76 (m, 1H), 7.67-7.65 (m, 1H),
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7.60-7.53 (m, 2H), 7.45-7.40 (m, 3H), 5.65 (s, 1H), 5.25 (s, 1H), 2.78 (s, 3H), 2.60 (s, 3H), 1.56 (s, 3H); C NMR (125 MHz,
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CDCl3): δ 165.3, 155.1, 149.0, 140.9, 138.0, 136.4, 135.4, 133.0, 132.8, 131.7, 131.2, 130.0, 129.4, 128.3, 126.7, 126.6, 125.6, 125.3, 123.4,
123.1, 122.2, 119.3, 22.0, 18.2, 17.9; FTIR: νmax/cm-1 3068, 2923, 1737, 1447, 1363, 1319, 1294, 1196, 1130, 773, 758; HRMS (ESI-TOF):
calcd for C25H21NO2 (M+H+) 368.1645; found: 368.1647.
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2,4-dimethyl-6-((4-methylisochroman-4-yl)mthyl)phenanthridine (5e)
Prepared from 2-isocyano-3,5-dimethyl-1,1'-biphenyl (104 mg, 0.5 mmol, 1.0 equiv) and 1-iodo-2-(((2-
methylallyl)oxy)methyl)benzene (216 mg, 0.75 mmol, 1.5 equiv) according to the general procedure B. Isolated as a pale
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yellow oil (141 mg, 0.39 mmol), yield: 77%. H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J =
8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 5.02 (t, J = 14.8 Hz, 1H), 4.92 (d, J = 14.8 Hz, 1H), 4.29 (d, J = 11.6 Hz, 1H), 3.84 (d, J = 14.0
Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.64 (d, J = 11.2 Hz, 1H), 2.86 (s, 3H), 2.60 (s, 3H), 1.47 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 156.6, 142.2, 140.5, 137.3, 135.6, 133.7, 132.7, 130.9, 129.4, 126.5, 126.5, 126.5, 125.8, 124.0, 123.1, 122.3, 119.3, 74.3, 69.1, 44.0, 38.0,
23.5, 21.9, 18.4; FTIR: νmax/cm-1 3071, 2921, 1578, 1490, 1453, 1363, 1097, 773, 795, 745; HRMS (ESI-TOF): calcd for C26H25NO
(M+H+) 368.2009; found: 368.2009.
ethyl 4-methyl-1-phenylisoquinoline-3-carboxylate (7a)24
Prepared from ethyl (Z)-2-isocyano-3-phenylbut-2-enoate (43 mg, 0.2 mmol, 1.0 equiv) and iodobenzene (61 mg, 0.3 mmol,
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1.5 equiv) according to the general procedure C. Isolated as a pale yellow solid (45 mg, 0.16 mmol), yield: 77%. H NMR
(400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.71-7.68 (m, 2H), 7.61-7.57 (m, 1H),
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7.54-7.46 (m, 3H), 4.50 (q, J = 8.0 Hz, 2H), 1.45 (t, J = 8.0 Hz, 3H); C NMR (125 MHz, CDCl3): δ 168.0, 158.7, 142.1, 139.1,
136.6, 130.3, 130.2, 128.6, 128.3, 128.2, 127.9, 126.9, 124.3, 61.6, 14.32, 14.27; FTIR: νmax/cm-1 3039, 2921, 1713, 1374, 1331, 1309, 1238,
1214, 1057, 772, 762, 704; HRMS (ESI-TOF): calcd for C19H17NO2 (M+H+) 292.1332; found: 292.1334; mp: 92-94 oC.
ethyl 4-ethyl-1-phenylisoquinoline-3-carboxylate (7b)
Prepared from ((Z)-1,1-diisocyanobut-1-en-2-yl)benzene (46 mg, 0.2 mmol, 1.0 equiv) and iodobenzene (61 mg, 0.3 mmol,
1.5 equiv) according to the general procedure C. Isolated as a pale yellow solid (33mg, 0.11 mmol), yield: 53%. 1H NMR (400
MHz, CDCl3): δ 8.19 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.79-7.75 (m, 1H), 7.70-7.68 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H),
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7.53-7.45 (m, 3H), 4.49 (q, J = 8.0 Hz, 2H), 3.27 (q, J = 8.0 Hz, 2H), 1.46-1.42(m, 6H); C NMR (125 MHz, CDCl3): δ 167.9,
158.8, 141.9, 139.1, 135.7, 132.5, 130.3, 130.2, 128.6, 128.4, 128.3, 127.7, 127.3, 124.1, 61.6, 21.6, 15.4, 14.3; FTIR: νmax/cm-1 2966, 1716,
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1445, 1372, 1309, 1286, 1256, 1208, 1160, 1071, 1052, 774, 705; HRMS (ESI-TOF): calcd for C20H19NO2 (M+H+) 306.1489; found:
306.1486; mp:91-93 oC.
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ethyl 1,4-diphenylisoquinoline-3-carboxylate (7c)25
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Prepared from (Z)-ethyl 2-isocyano-3,3-diphenylacrylate (55 mg, 0.2 mmol, 1.0 equiv) and iodobenzene (61 mg, 0.3 mmol,
1.5 equiv) according to the general procedure C. Isolated as a pale yellow solid (41 mg, 0.12 mmol), yield: 58%. 1H NMR
(400 MHz, CDCl3): δ 8.17 (d, J = 8.0 Hz, 1H), 7.78-7.41 (m, 13H), 4.12 (q, J = 8.0 Hz, 2H), 0.98 (t, J = 8.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 167.5, 160.3, 142.3, 138.9, 136.4, 136.1, 131.9, 130.5, 130.2, 130.0, 128.8, 128.5, 128.3, 128.2, 128.1, 128.0, 127.7,
127.0, 126.5, 61.2, 13.7; FTIR: νmax/cm-1 3061, 2977, 1732, 1723, 1401, 1384, 1227, 1185, 1113, 782, 758, 700, 672; HRMS (ESI-TOF):
calcd for C24H19NO2 (M+H+) 354.1489; found: 354.1487; mp:108-110 oC.
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ethyl 7-chloro-4-(4-chlorophenyl)-1-phenylisoquinoline-3-carboxylate (7d)
Prepared from (Z)-4,4'-(2,2-diisocyanoethene-1,1-diyl)bis(chlorobenzene) (70 mg, 0.2 mmol, 1.0 equiv) and iodobenzene
(61 mg, 0.3 mmol, 1.5 equiv) according to the general procedure C. Isolated as a pale yellow oil (46 mg, 0.11 mmol), yield:
54%. 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.75-7.73 (m, 2H), 7.63-7.49 (m, 7H), 7.36-7.32 (m, 2H), 4.16 (q, J = 8.0 Hz,
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2H), 1.07 (t, J = 8.0 Hz, 3H); C NMR (125 MHz, CDCl3): δ 166.9, 159.7, 142.4, 138.2, 134.7, 134.53, 134.46, 134.1, 131.6, 131.3,
130.6, 130.1, 129.2, 128.7, 128.6, 128.1, 127.7, 126.6, 61.5, 13.8; FTIR: νmax/cm-1 3060, 2980, 1721, 1495, 1300, 1222, 1173, 1087, 841,
701, 533, 521; HRMS (ESI-TOF): calcd for C24H17Cl2NO2 (M+H+) 422.0709; found: 422.0708.
ASSOCIATED CONTENT
Supporting Information
Proton and carbon NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: zhu_qiang@gibh.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the National Science Foundation of China (21402203, 21472190) for financial support of this work.
REFERENCES
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(13) Selected examples for alkyl radical: (a) Jiang, H.; Cheng, Y. Z.; Wang, R. Z.; Zheng, M. M.; Zhang, Y.; Yu, S. Y. Angew. Chem., Int.
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Dai, Q.; Yu, J.–T.; Feng, X. M.; Jiang, Y.; Yang, H. T.; Cheng, J. Adv. Synth. Catal. 2014, 356, 3341.
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(14) Selected examples for acyl radical: (a) Leifert, D.; Daniliuc, C. G.; Studer, A. Org. Lett. 2013, 15, 6286; (b) Liu, J.; Fan, C.; Yin, H. Y.;
Qin, C.; Zhang, G. T.; Zhang, X.; Yi, H.; Lei, A. W. Chem. Commun. 2014, 50, 2145; (c) Tu, H.-Y.; Liu, Y.-R.; Chu, J.-J.; Hu, B.-L.; Zhang, X.-
G. J. Org. Chem. 2014, 79, 9907.
(15)Selected examples for alkoxycarbonyl radical: (a) Li, X. Q.; Fang, M. W.; Hu, P. Z.; Hong, G.; Tang, Y. C.; Xu, X. S. Adv. Synth. Catal.
2014, 365, 2103; (b) Pan, C. D.; Han, J.; Zhang, H. L.; Zhu, C. J. J. Org. Chem. 2014, 79, 5374; (c) Wang, G.; Chen, S.-Y.; Yu, X.-Q. Tetrahe-
dron Lett. 2014, 55, 5338.
(16) Selected examples for P-radical: (a) Zhang, B.; Daniliuc, C. G.; Studer, A. Org. Lett. 2014, 16, 250; (b) Gao, Y. Z.; Wu, J.; Xu, J.;
Wang, X. R.; Tang, G.; Zhao, Y. F. Asian J. Org. Chem. 2014, 3, 691; (c) Li, Y. W.; Qiu, G. Y. S.; Ding, Q. P.; Wu, J. Tetrahedron 2014, 70,
4652; Selected example for Si-radical: (d) Zhu, H.; Guo, S. J.; Cheng, J.; Yu, J.-T. Chem. Commun. 2014, 50, 10864.
(17) Selected Reviews: (a) Bolton, R.; Williams, G. H. Chem. Soc. Rev. 1986, 15, 261; (b) Studer, A. in Radicals in Organic Synthesis, Vol.
2, 1st ed. (Eds. : P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, pp. 62-80 ; (c) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev.
2007, 36, 1803; (d) Vaillard, S. E.; Schulte, B.; Studer, A. in Modern Arylation Methods (Ed.: L. Ackermann), Wiley-VCH, Weinheim, 2009,
pp. 475-511; (e) Yanagisawa, S.; Itami, K. ChemCatChem 2011, 3, 827; (f) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018.
(18) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570.
(19) Schneider, C.; Masi, D.; Couve-Bonnaire, S.; Pannecoucke, X.; Hoarau, C. Angew. Chem., Int. Ed. 2013, 52, 3246.
(20) (a) Jiang, H.; Cheng, Y.Z.; Wang, R. Z.; Zhang, Y.; Yu, S. Y. Chem. Commun., 2014, 50, 6164; (b) Cheng, Y. Z.; Yuan, X. A.; Jiang, H.;
Wang, R. Z.; Ma, J.; Zhang, Y.; Yu, S. Y. Adv. Synth. Catal. 2014, 356, 2859; (c) Wang, H.; Yu, Y.; Hong, X. H.; Xu, B. Chem. Commun. 2014,
50, 13485.
(21) (a) Lafrance M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754; (b) Garcıa-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A.M. J. Am. Chem. Soc. 2006, 128, 1066.
(22) Gu, L. J.; Jin, C.; Liu, J. Y.; Ding, H. Y.; Fan, B. M. Chem. Commun. 2014, 50, 4643.
(23) Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774.
(24) Cappelli, A.; Anzini, A.; Vomero, S.; De Benedetti, P. G.; Menziani, M. C.; Giorgi, G.; Manzoni, C. J. Med. Chem. 1997, 40, 2910.
(25) Wang, H.; Yu, Y.; Hong, X. H.; Xu, B. Chem. Commun. 2014, 50, 13485.
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