Transition Metal-Free Oxidative Radical Decarboxylation/Cyclization for the Construction of 6-Alkyl/Aryl Phenanthridines

Article abstract of DOI:10.1021/acs.joc.5b01518

A radical cascade decarboxylation/cyclization of 2-isocyanobiphenyls with aliphatic carboxylic acids as well as aromatic carboxylic acids under the transition metal-free conditions was reported. This process, which included formation of two new C-C bonds and cleavage of C-COOH bonds, afforded a novel and environmentally friendly approach to producing 6-alkyl/aryl phenanthridines with moderate to good yields.

Full text of DOI:10.1021/acs.joc.5b01518

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Note
Transition-metal-free oxidative radical decarboxylation/
cyclization for the construction of 6-alkyl/aryl phenanthridines
Shichao Lu, Yaling Gong, and Demin Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01518 • Publication Date (Web): 24 Aug 2015
Downloaded from http://pubs.acs.org on August 25, 2015
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Transition-metal-free oxidative radical decarboxylation/cyclization for the
construction of 6-alkyl/aryl phenanthridines
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Shichao Lu,*, †, ‡, § Yaling Gong,§ and Demin Zhou†
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†
‡
§
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38
Xueyuan Road, Beijing 100191, People’s Republic of China
National Institute of Biological Sciences (NIBS), 7 Science Park Rd., ZGC life science park, Beijing 102206, People’s
Republic of China
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Road,
Xicheng Dist., Beijing 100050, People’s Republic of China
E-mail: lushichao@nibs.ac.cn (Corresponding author)
Abstract A radical cascade decarboxylation/cyclization of 2-isocyanobiphenyls with
aliphatic carboxylic acids as well as aromatic carboxylic acids under the
transition-metal-free conditions was reported. This process, which included formation of
two new C–C bonds and cleavage of C–COOH bonds, afforded a novel and
environmentally friendly approach to producing 6-alkyl/aryl phenanthridines with moderate
to good yields.
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Phenanthridine skeletons have attracted considerable attention because of their
pharmaceutical and bioactive properties such as antiviral, antibacterial, antitumoral,
cytotoxic, and DNA inhibitory properties.1 Therefore, the development of new and efficient
methods for the preparation of phenanthridines and their derivatives is very important. In
recent years, the radical-driven oxidative coupling methodology has been established as a
powerful strategy to prepare these compounds with atom- and step-economical features. In
2012, Chatani’s group reported the first example of the synthesis of 6-alkyl/aryl
phenanthridines by Mn(acac)3-mediated oxidative cyclization of 2-isocyanobiphenyls with
organoboron reagents as radical precursors.2 Subsequently, several groups have successively
reported their efforts for the construction of 6-alkyl or 6-aryl phenanthridines through the
reaction of 2-isocyanobiphenyls with corresponding radical precursors, such as simple
ethers,3 alkanes,4 alcohols,4a 2-bromide ethyl esters,5 and 1,3-dicarbonyl compounds,6 aryl
sulfonyl chlorides,7 and aryl amines8 under radical conditions. Although these methods have
their own specific applications, they still suffer from limited reaction scope, harsh reaction
conditions, and the necessity of using transition-metal catalysts. Very recently, Zhu et al.
reported a metal-free approach to access 6-aryl/alkyl phenanthridines that utilizes acyl
peroxides as radical precursor,9 which appears to be an environmentally friendly method.
However, most of acyl peroxides are commercially unavailable. Thus, further developments
for more practical and general alkylation/arylation methodologies are quite desired.
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Carboxylic acids (or their salts) are readily available, stable, cheap, and structurally
diverse substrates that are widely employed to form carbon–carbon and carbon–heteroatom
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bonds.10 These reactions present potential advantages, such as high selectivity and atom
economy, as well as the release of non-toxic CO2. However, the C–COOH bond cleavage
usually requires a toxic transition-metal catalytic system (e.g., palladium, copper, silver,
etc.).11 Thus, the decarboxylative cross-coupling of carboxylic acids under
transition-metal-free conditions remains a challenge.12 In view of this, we disclose
transition-metal-free radical oxidative decarboxylation/cyclization in aqueous solution
which provides a simple and general protocol for valuable 6-alkyl/aryl phenanthridines.
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Initially, the model reaction of 2-isocyano-biphenyl 1a and 2,2-dimethylbutanoic acid 2a
was employed to screen the reaction conditions, and the results are shown in Table 1. When
1a (1.0 equiv) was treated with 2a (2.0 equiv) in the presence of AgNO3 (20 mol %) and
K2S2O8 (3.0 equiv) under an argon atmosphere in CH3CN/H2O (2 mL) (v/v = 1/1) at 80 °C
for 1 h, no desired product was observed (Table 1, entry 1). Then, other silver catalysts (e.g.,
Ag2O, AgF, Ag2CO3) were tested respectively (Table 1, entries 2–4). Delightedly, the
desired product 3a was obtained in 18% yield in the presence of Ag2CO3, although the
majority of the starting material 1a was converted to a hydrolysis byproduct (Table 1, entry
4). We next tried to add 1.0 equiv of K2CO3 to the reaction system to improve the stability
of 1a (Table 1, entry 5), and the yield of the target product significantly increased to 54%.
Different amounts of K2CO3 were employed, among which 1.5 equiv of K2CO3 provided
the satisfactory yield (70%) (Table 1, entry 6). But on the other hand, this reaction might be
suppressed with the excess amount of K2CO3 (Table 1, entry 7). Surprisingly, the reaction
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can achieve a highest yield of 74% in the absence of Ag2CO3 (Table 1, entry 8). Both
decreasing temperature and exposure to air negatively affected the reaction (Table 1, entries
9–10). In addition, we attempted to examine the effects of different solvent systems on the
model reaction (Table 1, entries 11–17), but none of the other solvent systems were
effective for this transformation. These results showed that the optimized conditions were
3.0 equiv of K2S2O8 with 1.5 equiv of K2CO3 in CH3CN/H2O (v/v = 1/1) at 80 °C under Ar
for 1 h.
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Table 1 Optimization of the reaction conditionsa
entry
1
catalyst
AgNO3
Ag2O
AgF
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
—
solvent (v/v)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
CH3CN/H2O (1/1)
H2O
base (equiv)
—
yieldb
0%
2
—
0%
3
—
0%
4
—
18%
54%
70%
32%
74%
62%
54%
0%
5
K2CO3 (1.0)
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
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9c
10d
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—
—
—
—
CH3CN
0%
—
DMSO/H2O (1/1)
DMF/H2O (1/1)
THF/H2O (1/1)
acetone /H2O (1/1)
dioxane/H2O (1/1)
18%
<5%
0%
—
—
—
0%
—
<5%
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (20
mol%), K2S2O8 (0.6 mmol), K2CO3 (0.3 mmol), solvent (2.0 mL),
80 °C, under Ar for 1 h. bIsolated yield. cUnder air. dAt 60 °C.
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We next investigated the scope and generality of the reaction under optimized conditions.
The results are summarized in Table 2. First, we evaluated the reactivity of
2-isocyanobiphenyl 1a toward aliphatic carboxylic acids (Table 2, 3a–3k). Notably, the
transition-metal-free system can be successfully applied to tertiary and secondary
carboxylic acids (Table 2, 3a–3h). It is worth noticing that aliphatic carboxylic acids that
contain a cyclopropyl, ether and Boc group, respectively, provided the desired products in
good yields, demonstrating the mild nature of the reaction conditions. Delightedly, when
primary alkyl carboxylic acids such as propanoic acid and phenylacetic acid were employed
as reactants, the desired products could be achieved in moderate yields (Table 2, 3i and 3j).
Comparatively, acetic acid, as a radical precursor, provided a trace amount of the
corresponding products, which is possibly due to the difficulty to generate methyl radical or
capture methyl radical by 1a (Table 2, 3k). Furthermore, the oxidative cyclization of
different 2-isocyanobiphenyls with 2a was investigated (Table 2, 3l–3q). Results showed
that the method was successfully amenable to a wide range of 2-isocyanobiphenyls bearing
different functional groups, such as F, OMe, COOMe, and Me (Table 2, 3l–3p), and
produced moderate to good yields. In addition, heterocyclic 2-isocyanobiphenyl was also
favored in this system and afforded the corresponding product in 42% yield (Table 2, 3q).
We next attempted to apply the method to the reaction of 2-isocyanobiphenyl and aromatic
carboxylic acids (Table 2, 3r–3v). Previous studies proved that aromatic carboxylic acids
had more difficulty in generating radicals for radical decarboxylation/coupling than
aliphatic carboxylic acids. To our delight, aromatic carboxylic acids were also found to be
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suitable for the transformation and showed satisfactory tolerance with halogen groups,
which provided useful components for further transformations through traditional
cross-coupling reactions (Table 2, 3t and 3u).
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Table 2 Scope of oxidative cyclization of different isocyanobiphenyls 1 and carboxylic
acids 2a,b
product, yield
3a, 74%
product, yield
3b, 77%
product, yield
product, yield
3d, 67%
3c, 55%
3e, 71%
3f, 65%
3g, 66%
3k, trace
3h, 53%
3i, 55%
3j, 64%
3l, 68%
3m, 77%
3q, 42%
3o, 64%
3s, 46%
3p, 73%
3t, 37%
3n, 65%
3r, 48%
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3u, 35%
3v, 43%
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), K2S2O8 (0.6 mmol), K2CO3 (0.3 mmol),
CH3CN/H2O (2 mL, v/v = 1/1), 80 °C, under Ar for 1 h. bIsolated yield.
The green system was further applied to 6-trifluoromethyl-phenanthridines (Scheme 1),
which have recently caught the attention of chemists13 because of its significant effects on
the chemical, physical, and biological properties of compounds after the introduction of a
trifluoromethyl group.14 In an initial experiment, CF3COOH was subjected to the reaction
system, but no desired products was observed. However, when CF3SO2Na (Langlois reagent)
was used as the CF3 radical source, the radical cyclization reaction proceeded smoothly in
moderate yield under optimized reaction conditions. The present process with cheap CF3
reagents and cost-effective oxidants provided a novel and practical approach for obtaining
CF3-containing phenanthridines.
Scheme 1 Further applications
In order to obtain insights into reaction mechanism, TEMPO (2.0 equiv) as a radical
scavenger was employed under standard reaction conditions (Scheme 2). As a result, the
reaction was completely supressed, which could indicate that this transformation involved
radical intermediates.
Scheme 2 Radical trapping experiment
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A plausible reaction pathway is proposed in Scheme 3 based on the above observation
and reported literature.15 First, 2,2-dimethylbutanoic acid anion I is converted into radical II
in the presence of sulfate anion radicals by homolytic cleavage of K2S2O8. Subsequently,
the radical II is selectively added to the isocyanide 1a, which provides the imidoyl radical
III that can form the intermediate IV through an intramolecular radical cyclization. Finally,
further oxidation of IV by another sulfate radical produces the corresponding carbocation,
which loses a proton under basic conditions to provide the desired product 3a.
Scheme 3 Postulated reaction pathway
In conclusion, we have successfully developed a general and practical protocol for the
synthesis of phenanthridine derivatives by a transition-metal-free radical cascade
decarboxylation/cyclization reaction. The novel method presents the major advantages of a
broad substrate scope, good functional-group tolerance, and environmentally benign
character. Further studies on the reaction mechanism and the extension of the substrate’s
scope are currently underway in our laboratory.
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Experimental Section
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General Procedure for Synthesis of 2-Isocyanobiphenyls. 2-Isocyanobiphenyls were
prepared according to the reported method,16 including 2-isocyano-1,1'-biphenyl (1a),16
4'-fluoro-2-isocyano-1,1'-biphenyl (1b),17 2-isocyano-4'-methoxy-1,1'-biphenyl (1c),16
methyl 2'-isocyano-[1,1'-biphenyl]-4-carboxylate (1d),16 2-isocyano-5-methyl-1,1'-biphenyl
(1e),17 5-fluoro-2-isocyano-1,1'-biphenyl (1f),18 and 4-(2-isocyanophenyl)pyridine (1g).
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4-(2-isocyanophenyl)pyridine (1g). H NMR (400 MHz, CDCl3) δ 8.76 – 8.73 (m, 2H),
7.55 – 7.42 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 150.4, 144.9, 136.2, 130.4, 130.2,
129.8, 128.4, 123.9. HRMS (ESI-TOF) calcd for C12H9N2 [M + H]+ (181.0766), found
181.0769.
General procedure for synthesis of 6-alkyl/aryl phenanthridines. The mixture of
2-isocyanobiphenyl 1a (0.20 mmol), carboxylic acid 2a (0.40 mmol), and K2CO3 (0.30
mmol) in CH3CN/H2O (2.0 mL, v/v = 1/1) was treated with K2S2O8 (0.60 mmol). The
o
reaction was allowed to stir at 80 C for 1 h under an Ar atmosphere. Upon completion as
shown by TLC, water (5 mL) was added to the reaction mixture. Then, the reaction mixture
was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 200:1) to
afford 3a in 74% yield.
6-(tert-pentyl)phenanthridine (3a). Colorless oil, 36.8 mg, 74% yield. 1H NMR (400 MHz,
CDCl3) δ 8.70 – 8.67 (m, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.52 (dd, J = 8.2, 1.1 Hz, 1H), 8.13
(d, J = 7.9 Hz, 1H), 7.81 – 7.75 (m, 1H), 7.72 – 7.67 (m, 1H), 7.66 – 7.58 (m, 2H), 2.21 (qd,
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J = 7.6, 0.4 Hz, 2H), 1.69 (d, J = 0.6 Hz, 6H), 0.73 (td, J = 7.5, 1.0 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 166.0, 143.3, 134.1, 130.7, 129.6, 128.6, 128.0, 126.7, 126.4, 125.1, 123.6,
123.3, 121.9, 44.3, 35.8, 29.6, 9.9. HRMS (ESI-TOF) calcd for C18H20N [M + H]+
(250.1590), found 250.1588.
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6-(tert-butyl)phenanthridine (3b).19 Colorless oil, 36.2 mg, 77% yield. H NMR (400
MHz, CDCl3) δ 8.66 (d, J = 8.3 Hz, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H),
8.12 (d, J = 8.0 Hz, 1H), 7.78 – 7.72 (m, 1H), 7.71 – 7.65 (m, 1H), 7.65 – 7.56 (m, 2H),
1.72 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 166.8, 143.0, 134.1, 130.4, 129.4, 128.5, 128.4,
126.6, 126.1, 124.4, 123.5, 123.1, 121.7, 40.3, 31.3. HRMS (ESI-TOF) calcd for C17H18N
[M + H]+ (236.1434), found 236.1430.
6-(1-methylcyclopropyl)phenanthridine (3c). Colorless oil, 25.6 mg, 55% yield. 1H NMR
(400 MHz, CDCl3) δ 8.73 – 8.62 (m, 2H), 8.55 (dd, J = 8.1, 1.3 Hz, 1H), 8.20 (d, J = 6.4 Hz,
1H), 7.87 – 7.81 (m, 1H), 7.75 – 7.68 (m, 2H), 7.66 – 7.60 (m, 1H), 1.67 (s, 3H), 1.25 (t, J =
13
5.2 Hz, 2H), 1.05 (t, J = 5.2 Hz, 2H). C NMR (100 MHz, CDCl3) δ 164.5, 133.7, 130.6,
130.1, 128.9, 127.9, 127.3, 127.0, 125.4, 124.1, 122.8, 122.2, 30.1, 25.7, 14.1. HRMS
(ESI-TOF) calcd for C17H16N [M + H]+ (234.1277), found 234.1273.
1
6-(1-methylcyclohexyl)phenanthridine (3d). Colorless oil, 37.0 mg, 67% yield. H NMR
(400 MHz, CDCl3) δ 8.69 – 8.61 (m, 2H), 8.51 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H),
7.74 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 2.63 – 2.54 (m,
2H), 1.96 – 1.87 (m, 2H), 1.69 (s, 3H), 1.68 – 1.59 (m, 4H), 1.57 – 1.48 (m, 1H), 1.48 –
1.40 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 166.5, 143.3, 134.5, 130.5, 129.5, 128.7,
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128.4, 126.7, 126.1, 124.8, 123.6, 123.4, 121.9, 43.9, 39.5, 27.6, 26.9, 23.4. HRMS
(ESI-TOF) calcd for C20H22N [M + H]+ (276.1747), found 276.1741.
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6-cyclobutylphenanthridine (3e). Colorless oil, 33.1 mg, 71% yield. H NMR (400 MHz,
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CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.11 (d,
J = 8.2 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.74 – 7.67 (m, 1H), 7.67 – 7.57 (m, 2H), 4.40 (p, J =
8.6 Hz, 1H), 2.83 – 2.69 (m, 2H), 2.59 – 2.47 (m, 2H), 2.27 – 2.16 (m, 1H), 2.03 – 1.92 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 163.4, 144.1, 133.2, 130.4, 130.2, 128.8, 127.4, 126.6,
126.4, 125.1, 123.9, 122.8, 122.2, 40.2, 27.6, 18.8. HRMS (ESI-TOF) calcd for C17H16N [M
+ H]+ (234.1277), found 234.1275.
6-cyclohexylphenanthridine (3f).20 Colorless oil, 33.9 mg, 65% yield. 1H NMR (400 MHz,
CDCl3) δ 8.63 (d, J = 8.3 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.14 (d,
J = 8.1 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.72 – 7.65 (m, 2H), 7.62 – 7.57 (m, 1H), 3.65 –
3.57 (m, 1H), 2.12 – 2.04 (m, 2H), 2.01 – 1.80 (m, 5H), 1.63 – 1.52 (m, 2H), 1.50 – 1.40 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 165.6, 144.2, 133.3, 130.2, 128.7, 127.4, 126.4, 125.9,
125.0, 123.6, 122.9, 122.1, 42.3, 32.6, 27.2, 26.6. HRMS (ESI-TOF) calcd for C19H20N [M
+ H]+ (262.1590), found 262.1587.
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6-(tetrahydro-2H-pyran-4-yl)phenanthridine (3g). Colorless oil, 34.7 mg, 66% yield. H
NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 7.5 Hz, 1H), 8.31 (d, J =
8.2 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.71 (q, J = 6.5 Hz, 2H), 7.63
(t, J = 7.5 Hz, 1H), 4.20 (dd, J = 11.4, 2.6 Hz, 2H), 3.87 (t, J = 11.3 Hz, 1H), 3.74 (td, J =
12.1, 2.0 Hz, 2H), 2.42 – 2.27 (m, 2H), 2.00 – 1.92 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
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163.3, 157.4, 144.1, 133.5, 130.4, 128.9, 127.6, 126.8, 125.5, 124.8, 123.7, 123.1, 122.2,
68.6, 39.5, 32.3. HRMS (ESI-TOF) calcd for C18H18NO [M + H]+ (264.1383), found
264.1377.
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tert-butyl 3-(phenanthridin-6-yl)piperidine-1-carboxylate (3h). Colorless oil, 38.4 mg,
53% yield. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.2 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H),
8.35 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.70 (t, J = 7.6
Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 4.60 – 4.15 (m, 2H), 3.80 – 3.65 (m, 1H), 3.35 – 3.25 (m,
1H), 2.95 – 2.80 (m, 1H), 2.27 – 2.07 (m, 2H), 1.93 – 1.69 (m, 2H), 1.51 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 162.1, 155.2, 143.9, 133.3, 130.5, 130.3, 128.8, 127.7, 126.8, 125.7,
124.9, 123.7, 123.0, 122.2, 79.8, 50.0, 44.5, 40.7, 30.8, 28.9, 25.9. HRMS (ESI-TOF) calcd
for C23H27O2N2 [M + H]+ (363.2067), found 363.2058.
6-ethylphenanthridine (3i).21 Yellow oil, 22.8 mg, 55% yield. 1H NMR (400 MHz, CDCl3)
δ 8.63 (d, J = 8.2 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.13 (dd, J =
8.2, 1.1 Hz, 1H), 7.85 – 7.79 (m, 1H), 7.73 – 7.65 (m, 2H), 7.64 – 7.58 (m, 1H), 3.41 (q, J =
7.6 Hz, 2H), 1.51 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.2, 143.7, 132.9,
130.3, 129.5, 128.6, 127.2, 126.2, 125.0, 123.6, 122.5, 121.9, 29.3, 13.5. HRMS (ESI-TOF)
calcd for C15H14N [M + H]+ (208.1126), found 208.1129.
6-benzylphenanthridine (3j).21 Yellow solid, 34.4 mg, 64% yield, m.p. 101 – 103 °C . 1H
NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.7 Hz, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.19 (t, J =
7.7 Hz, 2H), 7.78 – 7.71 (m, 2H), 7.67 – 7.61 (m, 1H), 7.59 – 7.53 (m, 1H), 7.31 (d, J = 7.6
Hz, 2H), 7.26 – 7.20 (m, 2H), 7.15 (t, J = 7.2 Hz, 1H), 4.76 (s, 2H). 13C NMR (100 MHz,
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CDCl3) δ 160.1, 143.6, 139.1, 133.2, 130.3, 129.8, 128.6, 128.5, 127.3, 127.0, 126.6, 126.3,
125.3, 123.9, 122.4, 121.9, 43.0. HRMS (ESI-TOF) calcd for C20H16N [M + H]+ (270.1283),
found 270.1285.
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8-fluoro-6-(tert-pentyl)phenanthridine (3l). Colorless oil, 36.3 mg, 68% yield. H NMR
(400 MHz, CDCl3) δ 8.69 – 8.63 (m, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.27 – 8.21 (m, 1H),
8.13 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6, 1H), 7.57 – 7.51 (m, 1H),
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2.17 (qd, J = 7.4, 1.5 Hz, 2H), 1.67 (d, J = 1.7 Hz, 6H), 0.73 (td, J = 7.5, 1.7 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 165.2 (d, J = 3.6 Hz), 160.6 (d, J = 244.4 Hz), 142.9, 130.8,
128.6, 127.2, 126.1 (d, J = 7.6 Hz), 125.6 (d, J = 8.6 Hz), 123.2, 121.7, 118.8 (d, J = 23.5
Hz), 112.8 (d, J = 22.2 Hz), 44.3, 35.7, 29.4, 9.9. HRMS (ESI-TOF) calcd for C18H19NF [M
+ H]+ (268.1496), found 268.1491.
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8-methoxy-6-(tert-pentyl)phenanthridine (3m). Colorless oil, 43.0 mg, 77% yield. H
NMR (400 MHz, CD3OD) δ 8.68 (d, J = 9.1 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.05 – 8.02
(m, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.50 – 7.45 (m, 1H), 3.98 (s, 3H),
2.24 (q, J = 7.5 Hz, 2H), 1.69 (s, 6H), 0.71 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz,
CD3OD) δ 166.6, 159.9, 144.3, 131.9, 130.1, 129.2, 128.6, 127.9, 126.6, 125.6, 123.2, 121.4,
110.7, 56.8, 45.8, 37.1, 30.5, 10.7. HRMS (ESI-TOF) calcd for C19H22ON [M + H]+
(280.1696), found 280.1692.
methyl 6-(tert-pentyl)phenanthridine-8-carboxylate (3n). Colorless oil, 40.0 mg, 65%
yield. 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.54 (d, J = 8.2
Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.64 (t, J =
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7.6 Hz, 1H), 4.04 (s, 3H), 2.25 (q, J = 7.4 Hz, 2H), 1.72 (s, 6H), 0.73 (t, J = 7.5 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 167.2, 166.6, 143.9, 137.3, 130.7, 130.4, 129.9, 129.5, 127.7,
127.2, 124.4, 123.6, 123.0, 122.5, 52.9, 44.5, 36.2, 29.8, 9.9. HRMS (ESI-TOF) calcd for
C20H22O2N [M + H]+ (308.1645), found 308.1641.
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2-methyl-6-(tert-pentyl)phenanthridine (3o). Colorless oil, 33.7 mg, 64% yield. H NMR
(400 MHz, CD3OD) δ 8.72 (d, J = 8.3 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.37 (s, 1H), 7.94
(d, J = 8.3 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.60 – 7.66 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 2.57
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(s, 3H), 2.24 – 2.15 (m, 2H), 1.65 (d, J = 1.1 Hz, 6H), 0.68 (td, J = 7.5, 1.0 Hz, 3H). C
NMR (100 MHz, CD3OD) δ 165.7, 142.4, 137.5, 134.8, 131.0, 130.8, 130.5, 128.6, 127.1,
125.9, 124.4, 124.1, 122.4, 44.9, 36.4, 29.8, 21.9, 9.9. HRMS (ESI-TOF) calcd for C19H22N
[M + H]+ (264.1747), found 264.1742.
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2-fluoro-6-(tert-pentyl)phenanthridine (3p). Colorless oil, 39.0 mg, 73% yield. H NMR
(400 MHz, CDCl3) δ 8.63 (d, J = 8.5 Hz, 1H), 8.54 (d, J = 8.3 Hz, 1H), 8.16 – 8.08 (m, 2H),
7.78 (t, J = 7.6 Hz, 1H), 7.69 – 7.63 (m, 1H), 7.45 – 7.38 (m, 1H), 2.20 (q, J = 7.4 Hz, 2H),
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1.67 (s, 6H), 0.72 (t, J = 7.4 Hz, 3H). C NMR (100 MHz, CDCl3) δ 165.3, 161.5 (d, J =
244.4 Hz), 140.0, 133.6 (d, J = 4.1 Hz), 132.7 (d, J = 8.9 Hz), 129.8, 128.1, 127.1, 125.1,
124.9 (d, J = 9 Hz) 123.5, 117.5 (d, J = 23.9 Hz), 106.9 (d, J = 23.1 Hz), 44.3, 35.8, 29.5,
9.9. HRMS (ESI-TOF) calcd for C18H19NF [M + H]+ (268.1496), found 268.1491.
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5-(tert-pentyl)benzo[c][2,7]naphthyridine (3q). Colorless oil, 21.0 mg, 42% yield. H
NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.88 (s, 1H), 8.51 (dd, J = 8.1, 0.7 Hz, 1H), 8.45
(d, J = 4.9 Hz, 1H), 8.22 – 8.11 (m, 1H), 7.84 – 7.77 (m, 1H), 7.72 – 7.63 (m, 1H), 2.23 (q,
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J = 7.5 Hz, 2H), 1.70 (s, 6H), 0.75 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.2,
151.2, 147.2, 144.5, 139.3, 131.0, 130.9, 127.4, 122.4, 121.5, 120.4, 116.7, 44.4, 36.2, 29.6,
9.8. HRMS (ESI-TOF) calcd for C17H19N2 [M + H]+ (251,1543), found 251.1538.
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6-phenylphenanthridine (3r).22 Pale yellow solid, 24.5 mg, 48% yield, m.p. 68 °C. H
NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 8.1 Hz, 1H), 8.26 (d, J =
8.1 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.79 – 7.72 (m, 3H), 7.71 – 7.66
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(m, 1H), 7.64 – 7.50 (m, 4H). C NMR (100 MHz, CDCl3) δ 161.6, 144.0, 140.0, 133.8,
130.9, 130.6, 130.1, 129.3, 129.2, 129.1, 128.8, 127.5, 127.3, 125.6, 124.1, 122.5, 122.3.
HRMS (ESI-TOF) calcd for C19H14N [M + H]+ (256.1121), found 256.1119.
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6-(p-tolyl)phenanthridine (3s).19 Pale yellow solid, 24.7 mg, 46% yield, m.p. 106 °C. H
NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.3 Hz, 1H), 8.61 (d, J = 8.1 Hz, 1H), 8.26 (d, J =
7.9 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.78 – 7.72 (m, 1H), 7.71 – 7.58
(m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.6, 144.0,
139.0, 137.0, 133.9, 130.5, 130.0, 129.43, 129.37, 129.2 127.4, 127.2, 125.6, 124.0, 122.5,
122.3, 21.8. HRMS (ESI-TOF) calcd for C20H16N [M + H]+ (270.1277), found 270.1274.
6-(3-bromophenyl)phenanthridine (3t). Pale yellow solid, 24.6 mg, 37% yield, m.p. 137 –
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139 °C. H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 8.3 Hz, 1H), 8.64 (dd, J = 8.0, 0.7 Hz,
1H), 8.27 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.93 – 7.86 (m, 2H), 7.79 (td, J = 8.0,
0.8 Hz 1H), 7.72 (td, J = 8.0, 0.8 Hz 1H), 7.69 – 7.63 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 159.6, 143.4, 133.7, 132.8, 132.0, 131.1, 130.2, 130.0, 129.2,
128.7, 128.6, 127.54, 127.48, 125.0, 124.0, 122.8, 122.5, 122.1. HRMS (ESI-TOF) calcd for
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C19H13NBr [M + H]+ (334.0226), found 334.0226.
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6-(4-bromo-2-chlorophenyl)phenanthridine (3u). Pale yellow solid, 25.6 mg, 35% yield,
m.p. 173 – 175 °C. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.3 Hz, 1H), 8.64 (d, J = 8.1
Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.82 – 7.66 (m, 4H), 7.66 – 7.58
(m, 2H), 7.43 (d, J = 8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 158.2, 143.7, 140.5, 134.2,
133.4, 132.8, 131.5, 131.4, 130.6, 129.4, 128.5, 128.0, 127.9, 125.3, 124.5, 122.6, 122.5,
121.2. HRMS (ESI-TOF) calcd for C19H12NBrCl [M + H]+ (367.9836), found 367.9837.
8-fluoro-6-(p-tolyl)phenanthridine (3v). Pale yellow solid, 24.7 mg, 43% yield, m.p. 115
– 117 °C. 1H NMR (400 MHz, CDCl3) δ 8.70 (dd, J = 9.1, 5.3 Hz, 1H), 8.56 (d, J = 8.1 Hz,
1H), 8.28 (s, 1H), 7.82 – 7.73 (m, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.66 – 7.58 (m, 3H), 7.39 (d,
J = 7.9 Hz, 2H), 2.49 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.4 (d, J = 246 Hz), 160.5,
139.2, 130.4, 129.7, 129.5, 129.0, 127.5, 126.7 (d, J = 8.5 Hz), 125.0 (d, J = 8.3 Hz), 123.4,
121.9, 120.1, 113.6 (d, J = 20.9 Hz), 21.4. HRMS (ESI-TOF) calcd for C20H15NF [M + H]+
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(288.1183), found 288.1179.
Experimental Procedure for Synthesis of 6-Trifluoromethyl-phenanthridine (3w).
Following procedure for synthesis of 6-alkyl/aryl phenanthridines, 3w was obtained by
employing CF3SO2Na as radical precursor instead of carboxylic acid 2a in 58% yield.
6-(trifluoromethyl)phenanthridine (3w).16 Pale yellow solid, 28.6 mg, 58% yield, m.p. 62
oC. 1H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 8.4 Hz, 1H), 8.67 – 8.63 (m, 1H), 8.29 (d, J
= 8.4 Hz, 1H), 8.19 – 8.14 (m, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.82 – 7.74 (m, 3H). 13C NMR
(100 MHz, CD3OD) δ 147.3 (q, J = 32.4 Hz), 142.8, 135.3, 132.9, 131.6, 130.63, 130.58,
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129.4, 126.6 (q, J = 3.3 Hz), 126.3, 124.0, 123.6, 123.3 (q, J = 274.6 Hz), 122.6. HRMS
(ESI-TOF) calcd for C14H9NF3 [M + H]+ (248.0682), found 248.0678.
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Experimental Procedure for Mechanistic Studies with TEMPO. To a mixture of
2-isocyanobiphenyl 1a (0.20 mmol), carboxylic acid 2a (0.40 mmol), and K2CO3 (0.30
mmol), TEMPO (0.40 mmol) in CH3CN/H2O (2.0 mL, v/v = 1/1) was added K2S2O8 (0.60
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o
mmol). The reaction was allowed to stir at 80 C for 1 h under an Ar atmosphere. After
completion of the reaction, no desired product was detected by LC-MS.
Acknowledgments
The research is financially supported by the Beijing Postdoctoral Research Foundation
and the Ministry of Science and Technology, China (2014CB849600).
Supporting Information
1H and 13C NMR spectra for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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