Preparation of Phenanthridines from o-Cyanobiaryls via Addition of Organic Lithiums to Nitriles and Imino Radical Cyclization with Iodine

Article abstract of DOI:10.1021/acs.joc.8b01688

Simple treatment of 2-cyanobiaryls with methyllithium, ethylmagnesium bromide, butyllithium, phenyllithium, p-methylphenyllithium, etc., followed by the reaction with water and then with molecular iodine at 60 °C provided efficiently 6-methyl-, 6-ethyl-, 6-butyl-, 6-phenyl, 6-(p-methylphenyl)phenanthridines, etc., in good yields, respectively. Here, imines formed through the addition of carbanion onto the nitriles reacted with molecular iodine to form N-iodoimines smoothly, and their warming treatment induced the formation of imino radicals that smoothly cyclized onto the aryl group to give 6-alkyl- and 6-arylphenanthridines.

Full text of DOI:10.1021/acs.joc.8b01688

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Article
Preparation of Phenanthridines from o-Cyanobiaryls via Addition of
Organic Lithiums to Nitriles and Imino Radical Cyclization with Iodine
Atsushi Kishi, Katsuhiko Moriyama, and Hideo Togo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01688 • Publication Date (Web): 17 Aug 2018
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Preparation of Phenanthridines from o-
Cyanobiaryls via Addition of Organic Lithiums to
Nitriles and Imino Radical Cyclization with Iodine
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† †‡
Atsushi Kishi , Katsuhiko Moriyama , Hideo Togo*
†
†Graduate School of Science and ‡Molecular Chirality Research Center,
Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
togo@faculty.chiba-u.jp
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
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ABSTRACT:
X
X
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N
1) RLi or RMgBr
CN
R
2) H2O
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3) I2, K2CO3
60 °C, 2 h
33 examples
up to 96%
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X = H, CH3, OMe, Cl
R = CH3, C2H5, C4H9, C6H5, C6H4CH3-p,
C6H4OCH3-p, C6H4Cl-p
Simple treatment of 2-cyanobiaryls with methyllithium, ethylmagnesium bromide, butyllithium,
phenyllithium, p-methylphenyllithium, etc., followed by the reaction with water and then with
molecular iodine at 60 °C provided efficiently 6-methyl-, 6-ethyl-, 6-butyl-, 6-phenyl, 6-(p-
methylphenyl)phenanthridines, etc. in good yields, respectively. Here, imines formed through the
addition of carbanion onto the nitriles reacted with molecular iodine to form N-iodoimines
smoothly, and their warming treatment induced the formation of imino radicals that smoothly
cyclized onto the aryl group to give 6-alkyl- and 6-arylphenanthridines.
INTRODUCTION
Phenanthridine is an important nitrogen-containing heteroaromatic base that is found in some
natural products and biologically active alkaloids bearing antibacterial and antitumoral properties,
1
functional materials, and pharmaceuticals. In addition, it is well known that phenanthridines and
bis-phenanthridines exhibit strong affinity for DNA through intercalation, because of their having
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pH-induced positive charge, high polarizability, and high electron affinity, as shown in Fig. 1.
R2
O
H
H
N
N
O
R1 =
Me
R1, R2 =
Et
N
N
O
N
Me
H
H
N
NH2
N
R1
R1
(trisphaeriidine)
NH NH
Fig. 1 Phenanthridines Having Specific Binding Ability to DNA
Naturally occurring benz[c]phenanthridines and their N-methyl ammonium salts also exhibit
3
biological activities, such as antitumor activity. Therefore, synthetic studies of the phenanthridine
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core have been carried out extensively. Under transition-metal-free conditions, the reductive
construction of phenanthridines from o-(o’-nitrophenyl)benzaldehydes with zinc in acetic acid
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6
4a
under refluxing conditions and the preparation of 6-alkylphenanthridines by the condensation of
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4b
o-aminobiphenyl with cyclic ketones / aza-triene-electrocyclization / ring-fisson at 250~300 °C
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were reported. As the most popular method, the radical-mediated cyclization of 2-isocyanobiaryls
via imino carbon-centered radical (Scheme 1, eq. 1) has been extensively studied, and some
examples are as follows: the preparation of 6-(trifluoromethyl)phenanthridines from 2-
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5a 5b
isocyanobiaryls with Togni reagent and with TMSCF3 and PhI(OAc)2 (DIB); and the preparation
5c
of 6-alkylphenanthridines or 6-arylphenanthridines from 2-isocyanobiaryls with BPO in CCl4,
5d
with PhSO2CF2H, DIB, and t-BuONa, and with azobis(isobutyronitrile) (AIBN).
5e
As
photochemical methods, the preparation of 6-alkylphenanthridines or 6-arylphenanthridines from
6a
6b
2-isocyanobiaryls with a-bromoacetate ester and fac-Ir(ppy)3, with ArSO2Cl and Eosin Y, with
6c
6d
THF, TBHP, and [Ru(bpy)3]Cl2, with NH2NHCO2R, Eosin Y, and TBHP, with RfI and N,N,N’,N’-
6e
tetra(ethyl)ethylenediamine, and with ArBr and N,N-di(isopropyl)ethylamine was also reported.
6f
As examples of transition-metal-catalyzed formation of 6-substituted phenanthridines from 2-
7a
isocyanobiaryls, the reactions with ArB(OH)2 and Mn(acac)2, with ArCH=O, TBHP, and FeCl3,
7b
7c 7d
with ether, TBHP, and Fe(acac)2, with R2P(=O)H and Mn(OAc)2, and with RCO2H, K2S2O8, and
7e 5~7
Ag2CO3, are known. Most of those reactions proceed via the formation of imino carbon-centered
radicals and their cyclization onto the aromatic ring, as shown in Scheme 1 (eq. 1).
<Isonitrile Method> Many methods were reported recently
•
N
N
N
•
C
R
R
C:
Imino carbon-centered
radical
R•
[O]
1)
N
R
<Nitrile Method> This work
C
C
•
R
R
NH
N
R:
N
Imino nitrogen-centered
radical
[O]
•
2)
N
N
R
R
Scheme 1. Construction of Phenanthridine Core
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Other methods for the preparation of the phenanthridine core are as follows: the preparation of 6-
phenylphenanthridines from benzophenone O-aroyl oximes, O-(trimethylsilyl)phenyl triflate, and
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6
8a
[{(allyl)PdCl}2]; the preparation of phenanthridines from N-aryl-(2-iodobenzyl)amines under
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9
8b
irradiation with Hg-lamp; the preparation of 6-(t-butylamino)phenanthridines from 2-
8c
aminobiaryls, t-BuNC, and Co(acac)2; the preparation of phenanthridines from 2-bromobenzyl
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8d
bromide, N-aryl methanesulfonamides, and Pd(O2CCF3)2;
the preparation of 6-
8e
thioarylphenanthridines from 2-biaryl isothiocyanates, diaryliodonium salts, and CuCl; the
8f
preparation of 9-acylphenanthridines from 1,5-diyne-3-enes, 2-alkynylanilines, PdCl2, and CuI;
8g
and the electrosynthesis of phenanthridines from biaryl-2-carboaldehydes and ammonia.
On the other hand, synthetic studies of phenanthridine via imino nitrogen-centered radical
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(Scheme 1, eq. 2) are extremely limited. Typically, the cascade formation of the phenanthridine
core from N-(2-cyano-[1,1’-biaryl-3-yl]-N-methylmethacrylamide with a-bromoacetonitrile in the
9f
presence of fac-Ir(ppy)3 through the addition of a cyanomethyl radical to the olefinic group, and
with trifluoromethanesulfonyl chloride in the presence of Ru(phen)2Cl2 through the addition of a
9g
trifluoromethyl radical to the olefinic group, both of which are followed by 6-endo-trig
cyclization of the formed carbon-centered radicals onto the nitrile groups and then the cyclization
of the formed imino nitrogen-centered radicals onto the phenyl rings under visible-light irradiation
conditions, respectively, was reported very recently. As a related reaction to that shown in eq. 2,
the preparation of phenanthridines by the visible-light irradiation of biaryl-2-carboaldehyde O-
aroyl oximes in the presence of fac-Ir(ppy)3 through N-O bond cleavage and formation of the
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imino nitrogen-centered radical, followed by the cyclization onto the aromatic ring was reported.
As regards the synthesis of 6-aryl- and 6-alkylphenanthridines from 2-cyanobiaryls, the reactions
of 2-bromo-2’-cyanobiaryls with RMgBr in the presence of Cu2O at 100 °C via an intramolecular
11a
coupling reaction on copper atom between imino nitrogen and C-Br groups and with LiEt3BH at
11b
100 °C via a SNAr pathway onto the bromoaryl group by the formed imino anion group were also
reported.
Thus, to the best of our knowledge, the synthesis of phenanthridines from 2-cyanobiaryls based on
eq. 2 has been little studied. Here, we would like to report a simple preparation of 6-alkyl- and 6-
arylphenanthridines from 2-cyanobiaryls with alkyllithiums or aryllithiums, followed by the
reaction with water and then molecular iodine through the formation of imino nitrogen-centered
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radical and its cyclization onto the aromatic ring based on eq. 2 under transition-metal-free
conditions.
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RESULTS AND DISCUSSION
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First, to research the chemical behavior of imines with iodines based on our synthetic studies of
molecular iodine and related iodine reagents, such as N-iodosuccinimide (NIS) and 1,3-diiodo-5,5-
12
dimethylhydantoin (DIH), phenylimine 1Ad (1.0 mmol), which was prepared from the reaction of
2-cyano-4’-methylbiphenyl 2A with PhLi, was treated with NIS (1.1 equiv.) in 1,2-dichloroethane
(DCE, 4.0 mL) under irradiation with a tungsten lamp (200 W) for 1 h to give 3-methyl-6-
phenylphenanthridine 3Ad in 37% yield together with recovered imine 1Ad in 51% yield, as
shown in Table 1 (entry 1). When phenylimine 1Ad was treated with NIS (2.1 equiv.) under the
same conditions, the yield of phenanthridine 3Ad was increased to 56% (entry 2). When the
solvent was changed from DCE to THF, acetonitrile, benzene, 1,4-dioxane, and diethyl ether
under the same conditions, THF showed the best result, giving phenanthridine 3Ad in 77% yield
(entry 3 in entries 3~7). Then, methylimine 1Aa, ethylimine 1Ab, and p-methylphenylimine 1Ae
were treated with NIS (2.1 equiv.) using the same conditions as those in entry 3 to provide 3,6-
dimethylphenanthridine 3Aa, 6-ethyl-3-methylphenanthridine 3Ab and 3-methyl-6-(4’-
methylphenyl)phenanthridine 3Ae in 71%, 68%, and 85% yields, respectively (entries 8~10). On
the other hand, when the reaction of phenylimine 1Ad with NIS (2.1 equiv.) in THF was carried
out at 60 °C for 1 h instead of the irradiation with a tungsten lamp (200 W), the yield of 3-methyl-
6-phenylphenanthridine 3Ad was slightly increased to 80% (entry 11 and entry 3). Thus, warming
conditions at 60 °C were better than irradiation conditions at room temperature. When DIH (1.1
equiv.) was used instead of NIS (2.1 equiv.), 3-methyl-6-phenylphenanthridine 3Ad was obtained
in 80% yield (entry 12). However, NIS and DIH were rather expensive, and therefore, the
cyclization of phenylimine 1Ad with molecular iodine was studied. Treatment of phenylimine
1Ad with I2 (1.5 equiv.) in THF at 60 °C for 5 h gave 3-methyl-6-phenylphenanthridine 3Ad in
31% yield together with the recovery of starting phenylimine 1Aa (entry 13). When the oxidative
cyclization of phenylimine 1Ad was carried out in the presence of I2 (1.5 equiv.) and K2CO3 (3.0
equiv.) in THF at 60 °C for 5 h, the yield of 3-methyl-6-phenylphenanthridine 3Ad was increased
to 88% (entry 14). Moreover, the reaction of phenylimine 1Ad (1.0 mmol) with I2 (1.5 equiv.) and
K2CO3 (3.0 equiv.) was carried out in a 9:1 mixture (4.0 mL) of THF and water at 60 °C, and a 1:1
mixture (4.0 mL) of THF and water at 60 °C, 3-methyl-6-phenylphenanthridine 3Ad was obtained
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in 79% and 95% yields, respectively (entries 15, 16). Thus, the treatment of phenylimine 1Ad
(1.0 mmol) with I2 (1.5 equiv.) and K2CO3 (3.0 equiv.) in a 1:1 mixture (4.0 mL) of THF and water
at 60 °C for 1.5 h gave 3-methyl-6-phenylphenanthridine 3Ad in the best yield (entry 16).
The structure of 3-methyl-6-phenylphenanthridine 3Ad was supported by X-ray crystallographic
analysis, as shown in Table 1.
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Based on those results, the direct transformation of 2-cyano-4’-methylbiphenyl 2A (1.0 mmol)
into 3-methyl-6-phenylphenanthridine 3Ad was carried out by the reaction with PhLi, followed by
the reaction with water, and then with I2 (1.5 equiv.) and K2CO3 (3.0 equiv.) in a 1:1 mixture of
THF (4.0 mL) and water (4.0 mL) at 60 °C for 2 h to give 3-methyl-6-phenylphenanthridine 3Ad
in 96% yield, as shown in Table 2 (entry 1). As a gram-scale experiment, the treatment of
compound 2A (6.0 mmol) under the same procedure and conditions provided compound 3Ad in
98% yield, as shown in Table 2 (entry 1). When the present reaction with 2A was carried out in
the presence of 2,6-di-t-butyl-p-cresol (BHT, 3.0 equiv.) and 4-hydroxy-2,2,6,6-
Table 1. Optimization for Reaction Conditions from Imines 1A to
Phenanthridines 3A.
CH3
CH3
Reagent
NH
N
Solvent,
Time, Conditon
R
R
3Ad
1A
3A
1Aa: R = CH3, 1Ab: R = C2H5, 1Ad: R = C6H5, 1Ae: R = C6H4CH3-p
1
Entry
Reagent
Solvent
Time (h)
Condition
Yield (%)
W-hνꢀ
W-hνꢀ
1
2
DCE
DCE
37 (51)b (3Ad)
56 (3Ad)
1Ad NIS (1.1 equiv.)
1
1
"
"
"
"
"
"
NIS (2.1 equiv.)
NIS (2.1 equiv.) THF
NIS (2.1 equiv.) CH3CN
1
1
1
1
1
1
1
1
1
1
5
W-hνꢀ
W-hνꢀ
W-hνꢀ
W-hνꢀ
W-hνꢀ
W-hνꢀ
W-hνꢀ
W-hνꢀ
60 °C
60 °C
60 °C
3
4
77 (3Ad)
54 (3Ad)
50 (3Ad)
74 (3Ad)
55 (3Ad)
71 (3Aa)
68 (3Ab)
85 (3Ae)
80 (3Ad)
80 (3Ad)
31 (3Ad)
NIS (2.1 equiv.)
NIS (2.1 equiv.)
5
benzene
dioxane
6
NIS (2.1 equiv.) ether
7
1Aa NIS (2.1 equiv.) THF
1Ab NIS (2.1 equiv.) THF
1Ae NIS (2.1 equiv.) THF
1Ad NIS (2.1 equiv.) THF
8
9
10
11
12
13
"
"
"
DIH (1.1 equiv.) THF
I2 (1.5 equiv.)
THF
THF
c
14
I2, K2CO3
5
60 °C
88 (3Ad)
b
"
"
THF:H2O = 9:1
THF:H2O = 1:1
15
16
I2, K2CO3
I2, K2CO3
3.5
1.5
60 °C
60 °C
79 (3Ad)
95 (3Ad)
b
a The mixture was irradiated with a tungsten lamp (200 W) at 30 °C for 1 h.
b 1Ad was recovered. c I2 (1.5 equiv.) and K2CO3 (3.0 equiv.) were used.
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rd
tetramethylpiperidine-1-oxy radical (4-hydroxy-TEMPO, 3.0 equiv.) at the 3 step under the same
4
5
6
procedure and conditions, the yield of 3-methyl-6-phenylphenanthridine 3Ad was 0%,
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9
and 32% together with phenylimine 1Ad in 58% yield, respectively (entries 2, 3). Here, 3
equivalents each of BHT and 4-hydroxy-TEMPO was used to retard the rapid intramolecular
cyclization of the imino group to the p-methylphenyl group to form phenanthridine 3Ad. Thus,
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rd
these results indicate that the 3 reaction step for the construction of phenanthridine 3Ad from
phenylimine 1Ad with I2 is a radical-mediated reaction. Practically, the formation of N-
iodophenylimine 1Ad-I was observed by the reaction of phenylimine 1Ad and NIS, and the
thermal treatment of N-iodophenylimine 1Ad-I at 60 °C in THF gave 3-methyl-6-
phenylphenanthridine 3Ad in 77% yield.
Table 2. Transformation of Nitrile 2A to 6-Phenylphenanthridine
3Ad
CH3
CH3
1)
PhLi (2.0 equiv.)
THF
0 °C, 15 min 1st step
N
2nd step
2) H2O (4.0 mL)
CN
3)
Reagents
Additive
2A
3Ad
3rd step
60 °C, 2 h
Entry
Reagents
Additive
Yield (%)
96 (98d)
a
1
2
3
4
5
I2, K2CO3
I2, K2CO3
I2, K2CO3
-
a
BHT (3.0 equiv.)
4-OH-TEMPO (3.0 equiv.)
0
32 (58e)
0 (85f)
0 (49g)
a
NBSb
NCSc
-
-
a I2 (1.5 equiv.) and K2CO3 (3.0 equiv.) were used.
b NBS (2.1 equiv.) was used. c NCS (2.1 equiv.) was used.
d Reaction was carried out with 2A (6.0 mmol).
e Yield of phenylimine 1Ad. f Yield of N-bromophenylimine.
g Yield of N-chlorophenylimine.
On the other hand, when the present reactions of 2A with N-bromosuccinimide (NBS) and N-
rd
chlorosuccinimide (NCS) instead of NIS at the 3 step were carried out under the same procedure
and conditions, phenanthridine 3Ad was not obtained at all in both reactions, and N-
bromophenylimine 1Ad-Br and N-chlorophenylimine 1Ad-Cl were obtained in 85% and 49%
yields, respectively, together with hydrolyzed 2-benzoyl-4’-methylbiphenyl after quenching with
aq. Na2SO3. Here, the same treatment of phenylimine 1Ad with NBS and NCS generated N-
bromophenylimine 1Ad-Br and N-chlorophenylimine 1Ad-Cl in quantitative yields, respectively.
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However, the same thermal treatment of 1Ad-Br and 1Ad-Cl at 60 °C in THF did not generate 3-
methyl-6-phenylphenanthridine 3Ad at all.
5
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8
Based on those results, the one-pot transformation of 2-cyano-4’-methylbiphenyl 2A (1.0 mmol)
with methyllithium (a), ethylmagnesium bromide (b), n-butyllithium (c), phenyllithium (d), p-
methylphenyllithium (e), p-methoxyphenyllithium (f), and p-chlorophenyllithium (g) at 0 °C in
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60
st
nd
THF (4.0 mL, 1 step); and the addition of water (4.0 mL) (2 step), and the reaction with I2 (1.5
rd
equiv.) and K2CO3 (3.0 equiv.) at 60 °C for 2 h (3 step) were carried out to give 3,6-
dimethylphenanthridine
methylphenanthridine
3Aa,
3Ac,
6-ethyl-3-methylphenanthridine
3-methyl-6-phenylphenanthridine
3Ab,
3Ad,
6-butyl-3-
3-methyl-6-(4’-
methylphenyl)phenanthridine 3Ae, 6-(4’-methoxyphenyl)-3-methylphenanthridine 3Af, and 6-(4’-
chlorophenyl)-3-methylphenanthridine 3Ag in good yields, respectively, as shown in Scheme 2.
Similarly, the same treatment of 2-cyanobiaryls 2 (1.0 mmol), such as 2-cyanobiphenyl 2B, 2-
cyano-4’-methoxybiphenyl 2C, and 4’-chloro-2-cyanobiphenyl 2D, with methyllithium (a),
ethylmagnesium bromide (b), n-butyllithium (c), phenyllithium (d), p-methylphenyllithium (e), p-
st
methoxyphenyllithium (f), and p-chlorophenyllithium (g) at 0 °C in THF (1 step), the addition of
nd
water (4.0 mL) (2 step); and the reaction with I2 (1.5 equiv.) and K2CO3 (3.0 equiv.) at 60 °C for 2
rd
h (3 step) were carried out to give 6-substituted phenanthridines 3Ba~3Bg, 6-substituted 3-
methoxyphenanthridines 3Ca~3Cg, and 6-substituted 3-chlorophenanthridines 3Da~3Dg in good
yields, respectively (Scheme 2). 2-Cyano-3’-methylbiphenyl 2E could be also used under the
same procedure and conditions to form 4-methyl-6-phenylphenanthridine 3Ed in 67% yield
(Scheme 2).
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Scheme 2. Scope for Transformation of 2-Cyanobiaryls 2 to Phenanthridines 3
2
3
4
5
6
7
8
X
X
RLi, THF
0 °C − r.t., 15 min
H2O (4.0 mL)
1)
1st step
2nd step
2)
3)
N
CN
I2 (1.5 equiv.)
K2CO3 (3.0 equiv.)
R
9
3rd step
60 °C, 2 h
2
3
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A: X = CH3, B: X = H, C: X = OCH3, D: X = Cl
a: R = CH3, b: R = C2H5, c: R = C4H9, d: R = C6H5,
e: R = C6H4CH3-p, f: R = C6H4OCH3-p, g: R = C6H4Cl-p
Product, Yield
N
N
N
N
3Aa (93%)
3Ab (82%)a
3Ac (67%)
3Ad (96%)
N
N
N
N
OMe
Cl
3Ae (87%)
3Af (83%)
3Ag (84%)
3Ba (86%)
N
N
N
N
3Bb (84%)a
3Bc (83%)
3Bd (95%)
3Be (68%)
OMe
OMe
N
N
N
N
OMe
Cl
3Bf (81%)
3Bg (64%)
3Ca (71%)
3Cb (54%)a
OMe
OMe
OMe
OMe
N
N
N
N
OMe
3Cc (61%)
3Cd (79%)
3Ce (78%)
3Cf (69%)
OMe
Cl
Cl
Cl
N
N
N
N
Cl
3Cg (59%)
3Da (74%)
3Db (59%)a
3Dc (72%)
Cl
Cl
Cl
Cl
N
N
N
N
OMe
Cl
3Dd (82%)
3De (89%)
3Df (76%)
3Dg (96%)
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2
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N
4
5
6
3Ed (67%)b
7
8
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a C2H5MgBr was used instead of C2H5Li. NIS (2.1 equiv.) was used instead
of I2 and K2CO3. The mixture was irradiated with a tungsten lamp (200 W) at
30 °C for 1 h. b 2-Cyano-3’-methylbiphenyl 2E was used.
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Scheme 3. Preparation of Phenanthridines 3B from 2-Bromobiphenyl 4B
1)
nBuLi (1.5 equiv.)
1st step
-50 °C, 30 min
R = C6H5
= C6H4CH3-p 71% (3Be)
92% (3Bd)
THF
N
48% (3Bf)
Br
= C6H4OCH3-p
= C6H4Cl-p
= C6H4Br-p
= (CH3)2CH
R
2)
RCN (1.0 equiv.)
70% (3Bg)
2nd step
40% (3Bh)a
71% (3Bi)
58% (3Bj)
0% (79%)b
H2O (4.0 mL)
3)
4)
3B
4B
3rd step
I2 (1.5 equiv.)
K2CO3 (3.0 equiv.)
= c-C6H11
= (CH3)3C
60 °C, 2 h
4th step
b
a nBuLi (1.1 equiv.) was used. Yield of 2-cyanobiphenyl.
st
On the other hand, the one-pot treatment of 2-bromobiphenyl 4B with n-butyllithium (1 step) and
nd
nitriles (2 step), such as benzonitrile, p-methylbenzonitrile, p-methoxybenzonitrile, p-
chlorobenzonitrile, p-bromobenzonitrile, isobutyronitrile, cyclohexanecarbonitrile, and
rd
pivalonitrile, followed by quenching with water (4 mL, 3 step), and the reaction with I2 (1.5
th
equiv.) and K2CO3 (3.0 equiv.) at 60 °C for 2 h (4 step) gave 6-phenylphenanthridine (3Bd), 6-(4’-
methylphenyl)phenanthridine (3Be), 6-(4’-methoxyphenyl)phenanthridine (3Bf), 6-(4’-
chlorophenyl)phenanthridine
(3Bg),
6-[4’-bromophenyl]phenanthridine
(3Bh),
6-
isopropylphenanthridine (3Bi), and 6-cyclohexylphenanthridine (3Bj) in good to moderate
yields, respectively, as shown in Scheme 3. However, when pivalonitrile was used under the same
procedure and conditions, 6-t-butylphenanthridine (3Bk) was not obtained at all and instead, 2-
cyanobiphenyl was obtained in 79% yield.
A possible reaction pathway for the present one-pot preparation of phenanthridines 3 from 2-
cyanobiaryls 2 is shown in Scheme 4. 2-Cyanobiaryl 2 reacts with alkyllithium or aryllithium to
form an imino anion that is converted into imine 1 by quenching with water. Treatment of imine 1
with I2 in the presence of K2CO3 gives N-iodoimine I that smoothly generates reactive imino
nitrogen-centered radical II. Once imino nitrogen-centered radical II is formed, it rapidly cyclizes
onto the aromatic ring to form stabilized radical III that would be smoothly oxidized to
phenanthridine 3 by I2. Practically, N-iodoimine 1Ad-I could be observed by the reaction of
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phenylimine 1Ad and NIS, and the thermal treatment of N-iodoimine 1Ad-I at 60 °C generated
phenanthridine 3Ad. In addition, the present cyclization was completely retarded by the addition
of BHT (3.0 equiv.) and the yield of phenanthridine was decreased by the addition of 4-hydroxy-
TEMPO (3.0 equiv.). Moreover, treatment of N-iodo compound derived from 2-biphenyl t-butyl
imine formed from the reaction of 2-biphenyllithium and pivalonitrile at 60 °C did not generate 6-
t-butylphenanthridine (3Bk) at all (Scheme 3) and instead, 2-cyanobiphenyl was obtained in good
yield. This result suggests that b-cleavage of the formed imino radical would occur to form 2-
cyanobiphenyl and stable t-butyl radical that would react with molecular iodine to form t-butyl
iodide. Very recently, the b-cleavage of cyclic imino radicals to form cyano derivatives was
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60
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reported. On the other hand, the same treatment of phenylimine 1Ad with NBS and NCS via N-
bromophenylimine and N-chlorophenylimine did not generate phenanthridine at all under
warming conditions or irradiation with a tungsten lamp.
H2O
X
X
X
C
C
C
NH
N:
R
R
N
R:
1
2
I2
(-KI)
K2CO3
60 °C
(-KHCO3)
X
X
X
•
N
C
C
N
N•
I
R
R
R
III
II
I
1/2 I2
I-
I•
X
N
R
3
Scheme 4. Possible Reaction Pathway
CONCLUSION
Treatment of 2-cyanobiaryls with alkyllithiums and aryllithiums, followed by the reaction with
water and then with molecular iodine and K2CO3 at 60 °C for 2 h provided the corresponding 6-
alkylphenanthridines and 6-arylphenanthridines in good yields, respectively, through the
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formation of imino nitrogen-centered radicals and their cyclization onto the aromatic ring. We
believe that the present method would be useful not only for the preparation of 6-substituted
phenanthridines from 2-cyanobiaryls but also for the synthetic use of the imino nitrogen-centered
radical.
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EXPERIMENTAL SECTION
1
General: H NMR spectra were measured on 500 MHz spectrometers. Chemical shifts were
recorded as follows: chemical shift in ppm from internal tetramethylsilane on the d scale,
multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad), coupling
13
constant (Hz), integration, and assignment. C NMR spectra were measured on 125 MHz
spectrometers. Chemical shifts were recorded in ppm from the solvent resonance employed as the
internal standard (deuterochloroform at 77.0 ppm). Characteristic peaks in the infrared (IR)
-1
spectra were recorded in wavenumber, cm . High-resolution mass spectra were measured with
Thermo Fisher Scientific Exactive Orbitrap mass spectrometers.
Melting points were
uncorrected. Thin-layer chromatography (TLC) was performed using 0.25 mm silica gel plates
(60F-254). The products were purified by column chromatography on silica gel 60 (63–200 mesh).
Typical Procedure for Transformation of Imines 1A into Phenanthridines 3A: To a solution of
phenylimine 1Ad (1.0 mmol, 271.13mg) in a mixture of THF (2.0 mL) and water (2.0 mL) were
added I2 (1.5 mmol, 380.7 mg) and K2CO3 (3.0 mmol, 414.6mg). The obtained mixture was stirred
for 1.5 h at 60 °C under argon atmosphere. Saturated Na2SO3 aqueous solution (20 mL) was added
to the reaction mixture and the product was extracted with EtOAc (10 mL × 3). The organic layer
was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was
purified by silica-gel column chromatography (eluent: n-hexane:EtOAc = 6:1) to give 3-methyl-6-
phenylphenanthridine 3Ad (255.1 mg, 95%).
Typical Procedure for Transformation of o-Cyanobiaryls into Phenanthridines: To a solution
of 2-cyano-4'-methylbiphenyl 2A (1.0 mmol, 193.2 mg) in THF (4.0 mL) was added PhLi (2.0
°
mmol, 1.88 mL) at 0 C. The obtained mixture was stirred for 15 min at room temperature under
argon atmosphere. H2O (4.0 mL) was added to the mixture, and then I2 (1.5 mmol, 380.7 mg) and
K2CO3 (3.0 mmol, 414.6 mg) were added to the mixture at 0 °C, and the obtained mixture was
stirred for 2 h at 60 °C. Saturated Na2SO3 aqueous solution (20 mL) was added to the reaction
mixture and the product was extracted with EtOAC (10 mL × 3). The organic layer was purified by
silica-gel column chromatography (eluent: n-hexane:EtOAc = 6:1) to give 3-methyl-6-phenyl-
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phenanthridine 3Ad (258.5 mg 96%).
3,6-Dimethylphenanthridine (3Aa): Yield: 193.5 mg (93%); yellow solid; Mp: 92-93 °C; IR
5
6
-1
(neat) 1585, 1486, 1375, 822, 724, 628 cm ; H-NMR (400 MHz, CDCl3): δ = 2.57 (s, 3H), 3.04 (s,
1
7
8
9
3H), 7.44-7.47 (m, 1H), 7.65-7.68 (m, 1H), 7.80 (t, 1H, J = 8.4 Hz) 7.90 (s, 1H), 8.21 (d, 1H, J =
13
1
8.0 Hz), 8.43 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 8.0 Hz); C{ H}NMR (100 MHz, CDCl3): δ =
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21.5, 23.3, 121.3, 121.6, 122.0, 125.5, 126.4, 126.7, 127.9, 128.9, 130.2, 132.5, 138.6, 143.7,
+
158.7; HRMS (ESI) Calcd for C15H14N [M+H] = 208.1121, Found = 208.1120.
6-Ethyl-3-methylphenanthridine (3Ab): Yield: 182.7 mg (82%); yellow solid; Mp: 80-81 °C; IR
-1
1
(neat) 1585, 1485, 1373, 818, 763, 727 cm ; H-NMR (400 MHz, CDCl3): δ = 1.50 (t, 3H, J = 7.8
Hz), 2.58 (s, 3H), 3.39 (q, 2H, J = 7.8 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.80
(t, 1H, J = 8.0 Hz), 7.92 (s, 1H), 8.23 (d, 1H, J = 8.4 Hz), 8.41 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J =
13
1
8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 13.2, 21.2, 29.2, 120.9, 121.3, 121.9, 124.6, 125.7,
+
126.3, 127.5, 128.9, 129.7, 132.5, 138.2, 143.6, 162.6; HRMS (ESI) Calcd for C16H16N [M+H] =
222.1277, Found = 222.1272.
6-Butyl-3-methylphenanthridine (3Ac): Yield: 168.5 mg (67%); yellow solid; Mp: 38-39 °C; IR
-1
1
(neat) 2954, 1584, 1486, 817, 760, 727 cm ; H-NMR (400 MHz, CDCl3): δ = 1.00 (t, 3H, J = 7.8
Hz), 1.50-1.60 (m, 2H), 1.87-1.92 (m, 2H), 2.57 (s, 3H), 3.35 (t, 2H, J = 8.0 Hz), 7.43 (d, 1H, J =
8.4 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.79 (t, 1H, J = 7.8 Hz), 7.92 (s, 1H), 8.22 (d, 1H, J = 8.4 Hz),
13
8.41 (d, 1H, J = 8.4 Hz), 8.58 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 14.0, 21.5,
1
23.1, 31.7, 36.1, 121.2, 121.6, 122.2, 124.8, 126.2, 126.6, 127.8, 129.1, 130.1, 132.9, 138.5, 143.7,
+
162.3; HRMS (ESI) Calcd for C18H20N [M+H] = 250.1590, Found = 250.1591.
3-Methyl-6-phenylphenanthridine (3Ad): Yield: 258.5 mg (95%); yellow solid; Mp: 110-111 °C;
-1
1
IR (neat) 1559, 1444, 1362, 771, 700, 668 cm ; H-NMR (400 MHz, CDCl3): δ = 2.61 (s, 3H), 7.50-
7.60 (m, 5H), 7.71-7.74 (m, 2H), 7.84 (t, 1H, J = 8.4 Hz), 8.05 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz),
13
8.51 (d, 1H, J = 8.4 Hz), 8.67 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 21.5, 121.3,
1
121.6, 121.9, 124.8, 126.6, 128.3 (2C), 128.5, 128.6, 128.8, 129.6 (2C), 129.8, 130.4, 133.4, 138.9,
+
139.8, 143.8, 161.2; HRMS (ESI) Calcd for C20H16N [M+H] = 270.1277, Found = 270.1274.
3-Methyl-6-(4’-methylphenyl)phenanthridine (3Ae): Yield: 246.5 mg (87%); white solid; Mp:
-1
1
90-91 °C; IR (neat) 1482, 1360, 1325, 820, 759, 726 cm ; H-NMR (400 MHz, CDCl3): δ = 2.47 (s,
3H), 2.59 (s, 3H), 7.36 (d, 2H, J = 8.4 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.56 (t, 1H, J = 8.0 Hz), 7.63
(d, 2H, J = 8.4 Hz), 7.81 (t, 1H, J = 8.0 Hz), 8.03 (s, 1H), 8.11 (d, 1H, J = 8.4 Hz), 8.47 (d, 1H, J =
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8.4 Hz), 8.64 (d, 1H, J = 8.8 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 21.3, 21.5, 121.3, 121.6,
1
121.9, 124.9, 126.5, 128.5, 128.9, 129.0 (2C), 129.6 (2C), 129.8, 130.3, 133.4, 137.0, 138.4, 138.8,
5
6
+
143.9, 161.2; HRMS (ESI) Calcd for C21H18N [M+H] = 284.1434, Found = 284.1429.
7
8
9
6-(4’-Methoxyphenyl)-3-methylphenanthridine (3Af): Yield: 236.6 mg (83%); yellow solid; Mp:
-1
1
154-155 °C; IR (neat) 1249, 1173, 1021, 835, 730, 506 cm ; H-NMR (400 MHz, CDCl3): δ = 2.60
(s, 3H), 3.92 (s, 3H), 7.09 (d, 2H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.59 (t, 1H, J = 8.0 Hz),
7.70 (d, 2H, J = 8.8 Hz), 7.84 (t, 1H, J = 8.0 Hz), 8.03 (s, 1H), 8.14 (d, 1H, J = 8.0 Hz), 8.49 (d, 1H,
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J = 8.8 Hz), 8.66 (d, 1H, J = 8.0 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 21.5, 55.4, 113.8 (2C),
1
121.2, 121.7, 122.0, 124.9, 126.5, 128.4, 128.8, 129.7, 130.3, 131.1 (2C), 132.3, 133.5, 138.9,
+
144.1, 160.0, 160.8; HRMS (ESI) Calcd for C21H18NO [M+H] = 300.1383, Found = 300.1383.
6-(4’-Chlorophenyl)-3-methylphenanthridine (3Ag): Yield: 260.8 mg (84%); yellow solid; Mp:
-1
1
170-171 °C; IR (neat) 1479, 1361, 827, 759, 725 cm ; H-NMR (400 MHz, CDCl3): δ = 2.60 (s,
3H), 7.52-7.61 (m, 4H), 7.66-7.69 (m, 2H), 7.82-7.86 (m, 1H), 8.03 (d, 2H, J = 9.6 Hz), 8.50 (d,
13 1
1H, J = 8.8 Hz), 8.66 (d, 1H, J = 8.8 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 21.5, 121.3, 121.7,
122.0, 124.6, 126.7, 128.3, 128.6 (2C), 128.8, 129.8, 130.5, 131.1 (2C), 133.4 134.7, 138.2, 139.1,
+
143.7, 159.8; HRMS (ESI) Calcd for C20H15ClN [M+H] = 304.0888, Found = 304.0888.
6-Methylphenanthridine (3Ba): Yield: 166.8 mg (86%); yellow solid; Mp: 80-81 °C; IR (neat)
-1
1371, 1239, 750, 720, 503 cm ; H-NMR (400 MHz, CDCl3): δ = 3.05 (s, 3H), 7.63 (t, 1H, J = 8.4
1
Hz), 7.68-7.73 (m, 2H), 7.85 (t, 1H, J = 8.4 Hz), 8.11 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 8.4 Hz),
13
8.55 (d, 1H, J = 8.4 Hz), 8.63 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 23.3, 121.8,
1
122.2, 123.6, 125.7, 126.2, 126.4, 127.2, 128.5, 129.2, 130.3, 132.4, 143.5, 158.7; HRMS (ESI)
+
Calcd for C14H12N [M+H] = 194.0964, Found = 194.0958.
6-Ethylphenanthridine (3Bb): Yield: 174.2 mg (84%); yellow solid; Mp: 56-57 °C; IR (neat)
-1
1584, 1373, 1268, 748, 723 cm ; H-NMR (400 MHz, CDCl3): δ = 1.51 (t, 3H, J = 7.8 Hz), 3.41 (q,
1
2H, J = 7.8 Hz), 7.61 (t, 1H, J = 8.4 Hz), 7.67-7.73 (m, 2H), 7.82 (t, 1H, J = 8.4 Hz), 8.12 (d, 1H, J
13
1
= 8.4 Hz), 8.26 (d, 1H, J = 8.4 Hz), 8.54 (d, 1H, J = 8.4 Hz), 8.64 (d, 1H, J = 8.4 Hz); C{ H}NMR
(100 MHz, CDCl3): δ = 13.1, 29.1, 121.7, 122.2, 123.4, 124.9, 125.9, 126.0, 127.0, 128.3, 129.3,
+
130.0, 132.6, 143.5, 162.9; HRMS (ESI) Calcd for C15H14N [M+H] = 208.1121, Found = 208.1117.
6-Butylphenanthridine (3Bc): Yield: 197.3 mg (83%); yellow oil; IR (neat) 2955, 1584, 1485,
-1
1362, 753, 723 cm ; H-NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6 Hz), 1.52-1.61 (m, 2H),
1
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1.87-1.95 (m, 2H), 3.38 (t, 2H, J = 8.2 Hz), 7.62 (t, 1H, J = 7.6 Hz), 7.67-7.73 (m, 2H), 7.84 (t, 1H,
J = 7.6 Hz), 8.12 (d, 1H, J = 8.4 Hz), 8.26 (d, 1H, J = 8.4 Hz), 8.55 (d, 1H, J = 8.4 Hz), 8.65 (d, 1H,
5
6
13 1
J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 13.9, 23.0, 31.7, 36.2, 121.7, 122.2, 123.4, 125.0,
7
8
9
126.0, 126.1, 126.9, 128.3, 129.4, 130.0, 132.6, 143.5, 162.2; HRMS (ESI) Calcd for C17H18N
+
[M+H] = 236.1434, Found = 236.1433.
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59
60
6-Phenylphenanthridine (3Bd): Yield: 243.6 mg (95%); yellow solid; Mp: 99-101 °C; IR (neat)
-1
1
1360, 1137, 960, 1758, 695 cm ; H-NMR (400 MHz, CDCl3): δ = 7.50-7.65 (m, 4H), 7.67-7.78 (m,
4H), 7.85 (t, 1H, J = 7.6 Hz), 8.10 (d, 1H, J = 8.4Hz), 8.23 (d, 1H, J = 8.4 Hz), 8.61 (d, 1H, J = 8.4
13
Hz), 8.70 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 121.8, 122.1, 123.6, 125.1,
1
126.8, 127.0, 128.3 (2C), 128.6, 128.7, 128.8, 129.6 (2C), 130.2, 130.4, 133.3, 139.7, 143.7,
+
161.1;HRMS (ESI) Calcd for C19H14N [M+H] = 256.1121, Found = 256.1121.
6-(4’-Methylphenyl)phenanthridine (3Be): Yield: 185.6 mg (68%); white solid; Mp: 80-82 °C;
-1
IR (neat) 1357, 960, 822, 754, 726 cm ; H-NMR (400 MHz, CDCl3): 2.48 (s, 3H), 7.37 (d, 2H, J =
1
8.4 Hz), 7.59-7.70 (m, 4H), 7.75 (t, 1H, J = 7.6 Hz), 7.86 (t, 1H, J = 7.6 Hz), 8.14 (d, 1H, J = 8.4
13
1
Hz), 8.24 (d, 1H, J = 8.4 Hz), 8.62 (d, 1H, J = 8.4 Hz), 8.70 (d, 1H, J = 8.4 Hz); C{ H}NMR (100
MHz, CDCl3): δ = 21.3, 121.8, 122.1, 123.6, 125.2, 126.7, 127.0, 128.7, 128.9, 129.0 (2C), 129.6
+
(2C), 130.2, 130.4, 133.3, 136.9, 138.5, 143.7, 161.2; HRMS (ESI) Calcd for C20H16N [M+H] =
270.1277, Found = 270.1273.
6-(4’-Methoxyphenyl)phenanthridine (3Bf): Yield: 232.7 mg (81%); yellow solid; Mp: 144-146
-1
°C; IR (neat) 1509, 1247, 1171, 1028, 828, 759 cm ; H-NMR (400 MHz, CDCl3): δ = 3.92 (s, 3H),
1
7.09 (d, 2H, J = 8.4 Hz), 7.60-7.77 (m, 5H), 7.82 (t, 1H, J = 8.4 Hz), 8.16 (d, 1H, J = 8.4 Hz), 8.23
13
1
(d, 1H, J = 8.4 Hz), 8.60 (d, 1H, J = 8.4 Hz), 8.70 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz,
CDCl3): δ = 55.4, 113.8 (2C), 121.8, 122.1, 123.5, 125.2, 126.6, 127.0, 128.7, 128.8, 130.2, 130.3,
+
131.1 (2C), 132.2, 133.4, 143.8, 160.3, 160.8; HRMS (ESI) Calcd for C20H16NO [M+H] = 286.1226,
Found = 286.1227.
6-(4’-Chlorophenyl)phenanthridine (3Bg): Yield: 186.3 mg (64%); yellow solid; Mp: 151-152
-1
°C; IR (neat) 1359, 1089, 1014, 829, 752, 722 cm ; H-NMR (400 MHz, CDCl3): δ = 7.51-7.56 (m,
1
2H), 7.62-7.79 (m, 5H), 7.88 (t, 1H, J = 7.6 Hz), 8.07 (d, 1H, J = 8.8 Hz), 8.23 (d, 1H, J = 8.4 Hz),
13
8.63 (d, 1H, J = 8.4 Hz), 8.72 (d, 1H, J = 8.8 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 122.0,
1
122.3, 123.7, 124.4, 127.1, 127.4, 128.4, 128.6 (2C), 128.9, 130.3, 130.6, 131.1 (2C), 133.4, 134.8,
+
138.1, 143.6, 159.9; HRMS (ESI) Calcd for C19H13ClN [M+H] = 290.0731, Found = 290.0728.
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6-(4’-Bromophenyl)phenanthridine (3Bh): Yield: 133.6 mg (40%); yellow solid; Mp: 160-162
-1
1
°C; IR (neat) 1482, 1389, 1010, 823, 754, 723 cm ; H-NMR (400 MHz, CDCl3): δ = 7.52 (m, 1H),
5
6
7.61-7.78 (m, 6H), 7.85-7.90 (m, 1H), 8.06 (d, 1H, J = 8.0 Hz), 8.23 (d, 1H, J = 8.0 Hz), 8.63 (d,
7
8
13
1
1H, J = 8.0 Hz), 8.71 (d, 1H, J = 8.0 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 121.9, 122.3, 123.1,
9
123.7, 124.8, 127.1, 127.2, 128.4, 128.9, 130.2, 130.6, 131.3 (2C), 131.5 (2C), 133.4, 138.6, 143.6,
10
11
12
13
14
15
16
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18
19
20
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22
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24
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
159.9; HRMS (ESI) Calcd for C19H13BrN [M+H] = 334.0226 , Found = 334.0227.
6-Isopropylphenanthridine (3Bi): Yield: 157.2 mg (71%); colorless oil; IR (neat) 2964, 1582,
-1
1
1006, 756, 724, 677 cm ; H-NMR (400 MHz, CDCl3): δ =1.51 (d, 6H, J = 6.8 Hz), 3.99 (m, 1H),
7.60 (t, 1H, J = 7.6 Hz), 7.65-7.71 (m, 2H), 7.80 (t, 1H, J = 7.6 Hz), 8.14 (d, 1H, J = 7.6 Hz), 8.30
13
(d, 1H, J = 8.4 Hz), 8.53 (d, 1H, J = 8.4 Hz), 8.64 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz,
1
CDCl3): δ = 22.6 (2C), 31.4, 121.7, 122.5, 123.3, 124.6, 125.6, 126.1, 127.0, 128.3, 129.8 (2C),
+
132.9, 143.7, 166.7; HRMS (ESI) Calcd for C16H16N [M+H] = 222.1277 , Found = 222.1278.
6-Cyclohexylphenanthridine (3Bj): Yield: 228.6 mg (87%); yellow oil; IR (neat) 2927, 2852,
-1
1
1581, 1447, 987, 756, 725 cm ; H-NMR (400 MHz, CDCl3): δ = 1.11-2.14 (m, 10H), 3.61 (m,
1H), 7.59 (t, 1H, J = 7.6 Hz), 7.69 (m, 2H), 7.80 (t, 1H, J = 8.4 Hz), 8.13 (d, 1H, J =8.4 Hz), 8.31
13
(d, 1H, J = 8.4 Hz), 8.53 (d, 1H, J = 8.4 Hz), 8.65 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz,
1
CDCl3): δ = 13.9, 26.2, 26.8 (2C), 32.2 (2C), 41.9, 121.7, 122.5, 123.2, 124.6, 125.5, 126.1, 127.0,
+
128.3, 129.8, 132.9, 143.8, 165.2; HRMS (ESI) Calcd for C19H20N [M+H] = 262.1590 , Found =
262.1590.
3-Methoxy-6-methylphenanthridine (3Ca): Yield: 136.1 mg (71%); yellow solid; Mp: 78-79 °C;
-1
1
IR (neat) 1616, 1484, 1213, 1030, 843, 755 cm ; H-NMR (400 MHz, CDCl3): δ = 3.04 (s, 3H), 3.89
(s, 3H), 7.26 (dd, 1H, J = 8.8, 2.8 Hz), 7.52 (d, 1H, J = 2.8 Hz), 7.62 (t, 1H, J = 7.6 Hz), 7.80 (t,
1H, J = 7.6 Hz), 8.19 (d, 1H, J = 8.4 Hz), 8.42 (d, 1H, J = 8.8 Hz), 8.52 (d, 1H, J = 8.4 Hz);
13
1
C{ H}NMR (100 MHz, CDCl3): δ = 23.0, 55.2, 108.9, 116.9, 117.3, 121.4, 122.8, 124.5, 125.7,
+
126.1, 130.1, 132.3, 144.8, 158.9, 159.7; HRMS (ESI) Calcd for C15H14NO [M+H] = 224.1070,
Found = 224.1067.
6-Ethyl-3-methoxyphenanthridine (3Cb): Yield: 129.2 mg (54%); yellow solid; Mp: 45-46 °C;
-1
1
IR (neat) 1597, 1492, 1447, 1025, 746, 693 cm ; H-NMR (400 MHz, CDCl3): δ = 1.49 (t, 3H, J =
7.8 Hz), 3.37 (q, 2H, J = 7.8 Hz), 3.96 (s, 3H), 7.20-7.23 (m, 1H), 7.52 (d, 1H, J = 2.8 Hz), 7.56 (t,
1H, J = 7.6 Hz), 7.73 (t, 1H, J = 7.6 Hz), 8.18 (d, 1H, J = 8.4 Hz), 8.36 (d, 1H, J = 9.2 Hz), 8.47 (d,
13
1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 13.6, 29.3, 55.4, 109.2, 117.1, 117.4, 121.8,
1
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123.0, 123.8, 125.9, 126.0, 130.1, 132.9, 145.2, 159.9, 163.6; HRMS (ESI) Calcd for C16H16NO
+
[M+H] = 238.1226, Found = 238.1226.
5
6
7
8
9
6-Butyl-3-methoxyphenanthridine (3Cc): Yield: 162.4 mg (61%); yellow oil; IR (neat) 2956,
-1
1
1615, 1214, 1038, 750, 724 cm ; H-NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6 Hz), 1.56 (m,
2H), 1.90 (m, 2H), 3.35 (t, 2H, J = 8.0 Hz), 3.97 (s, 3H), 7.23-7.26 (m, 1H), 7.53 (d, 1H, J = 2.8
Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.76 (t, 1H, J = 7.8 Hz), 8.20 (d, 1H, J = 8.8 Hz), 8.39 (d, 1H, J = 8.8
10
11
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44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz), 8.50 (d, 1H, J = 8.8 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 14.0, 23.1, 31.9, 36.2, 55.4,
1
109.2, 117.2, 117.5, 121.8, 123.0, 124.1, 125.9, 126.2, 130.2, 133.0, 145.2, 160.0, 163.0; HRMS
+
(ESI) Calcd for C18H20NO [M+H] = 266.1539, Found = 266.1537.
3-Methoxy-6-phenylphenanthridine (3Cd): Yield: 226.1 mg (79%); yellow solid; Mp: 107-108
-1
1
°C; IR (neat) 1617, 1203, 1035, 768, 706, 673 cm ; H-NMR (400 MHz, CDCl3): δ = 3.98 (s, 3H),
7.32 (dd, 1H, J = 9.2, 2.8 Hz), 7.50-7.59 (m, 4H), 7.66 (d, 1H, J = 2.8 Hz), 7.71-7.74 (m, 2H), 7.81
(t, 1H, J = 7.8 Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.50 (d, 1H, J = 9.2 Hz), 8.60 (d, 1H, J = 8.0 Hz);
13
1
C{ H}NMR (100 MHz, CDCl3): δ = 55.3, 109.7, 117.5, 117.9, 121.4, 122.9, 124.0, 125.7, 128.2
(2C), 128.4, 128.6, 129.5 (2C), 130.3, 133.6, 139.6, 145.1, 160.0, 161.4; HRMS (ESI) Calcd for
+
C20H16NO [M+H] = 286.1226, Found = 286.1225.
3-Methoxy-6-(4’-methylphenyl)phenanthridine (3Ce): Yield: 234.2 mg (78%); white solid; Mp:
-1
1
118-120 °C; IR (neat) 1203, 1039, 821, 760, 721, 599cm ; H-NMR (400 MHz, CDCl3): δ = 2.48
(s, 3H), 3.98 (s, 3H), 7.32 (dd, 1H, J = 2.8, 9.2 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.54 (t, 1H, J = 8.0
Hz), 7.61-7.65 (m, 3H), 7.81 (t, 1H, J = 8.0 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.50 (d, 1H, J = 9.0 Hz),
13
1
8.59 (d, 1H, J = 8.0 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 21.2, 55.3, 109.7, 117.5, 117.7,
121.4, 122.9, 124.1, 125.7, 128.7, 128.9 (2C), 129.4 (2C), 130.2, 133.4, 136.8, 138.2, 145.2, 159.9,
+
161.5; HRMS (ESI) Calcd for C21H18NO [M+H] = 300.1383, Found = 300.1379.
3-Methoxy-6-(4’-methoxyphenyl)phenanthridine (3Cf): Yield: 218.9 mg (69%); white solid;
-1
1
Mp: 141-143 °C; IR (neat) 1607, 1244, 1027, 832, 766 cm ; H-NMR (400 MHz, CDCl3): δ = 3.92
(s, 3H), 3.98 (s, 3H), 7.07-7.11 (m, 2H), 7.31 (dd, 1H, J = 8.4, 2.8 Hz), 7.55 (t, 1H, J = 7.8 Hz),
7.64 (d, 1H, J = 2.4 Hz), 7.68-7.71 (m, 2H), 7.82 (t, 1H, J = 7.8 Hz), 8.13 (d, 1H, J = 8.4 Hz), 8.50
13
(d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 55.1, 55.2,
1
109.6, 113.6 (2C), 117.3, 117.6, 121.4, 122.8, 124.5, 125.6, 128.6, 130.1, 130.9 (2C), 132.1, 133.4,
+
145.2, 159.8, 159.9, 161.0; HRMS (ESI) Calcd for C21H18NO2 [M+H] = 316.1332, Found =
316.1331.
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6-(4’-Chlorophenyl)-3-methoxyphenanthridine (3Cg): Yield: 191.4 mg (59%); white solid; Mp:
-1
143-145 °C; IR (neat) 1617, 1204, 1044, 757, 719, 502 cm ; H-NMR (400 MHz, CDCl3): δ = 3.98
1
5
6
(s, 3H), 7.33 (dd, 1H, J = 8.4, 2.8 Hz), 7.52-7.69 (m, 6H), 7.84 (t, 1H, J = 7.2 Hz), 8.02 (d, 1H, J =
7
8
13 1
8.4 Hz), 8.51 (d, 1H, J = 8.4 Hz), 8.61 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ =
9
55.5, 110.0, 117.7, 118.3, 121.7, 123.1, 123.9, 126.1, 128.4 , 128.6 (2C), 130.7, 131.0 (2C), 133.6,
10
11
12
13
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48
49
50
51
52
53
54
55
56
57
58
59
60
+
134.8, 138.2, 145.2, 160.2, 160.3; HRMS (ESI) Calcd for C20H15ClNO[M+H] = 320.0837, Found =
320.0834.
3-Chloro-6-methylphenanthridine (3Da): Yield: 170.1 mg (74%); yellow solid; Mp: 120-122 °C;
-1
IR (neat) 1370, 876, 755, 727, 720, 627 cm ; 1H-NMR (400 MHz, CDCl3): δ = 3.04, (s, 3H), 7.58
(dd, 1H, J = 8.0 Hz, 2.4 Hz), 7.72 (t, 1H, J = 7.6 Hz), 7.86(t, 1H, J = 7.6 Hz), 8.01 (d, 1H, J = 2.4
13
1
Hz), 8.23 (d, 1H, J = 8.0 Hz), 8.46 (d, 1H, J = 8.0 Hz), 8.57 (d, 1H, J = 8.0 Hz); C{ H}NMR (100
MHz, CDCl3): δ = 23.3, 122.1 (2C), 123.2, 125.7, 126.6, 126.7, 127.5, 128.6, 130.8, 130.9, 134.1,
+
144.3, 160.2; HRMS (ESI) Calcd for C14H11ClN [M+H] = 228.0575, Found = 228.0573.
3-Chloro-6-ethylphenanthridine (3Db): Yield: 143.9 mg (59%); yellow solid; Mp: 100-102 °C;
-1
1
IR (neat) 1583, 1476, 1080, 771, 750, 727 cm ; H-NMR (400 MHz, CDCl3): δ = 1.50 (t, 3H, J =
7.6 Hz), 3.78 (q, 2H, J = 7.6 Hz), 7.54 (m, 1H), 7.69 (t, 1H, J = 7.6 Hz), 7.82 (t, 1H, J = 7.6 Hz),
8.10 (d, 1H, J = 2.0 Hz), 8.24 (d, 1H, J = 8..4 Hz), 8.41 (d, 1H, J = 8.8 Hz), 8.53 (d, 1H, J = 8.8
13
1
Hz); C{ H}NMR (100 MHz, CDCl3): δ = 13.2, 29.2, 122.0, 122.3, 123.2, 124.8, 126.1, 126.6,
+
127.4, 128.7, 130.1, 132.2, 134.0, 144.6, 164.3; HRMS (ESI) Calcd for C15H13ClN [M+H] =
242.0731, Found = 242.0731.
3-Chloro-6-butylphenanthridine (3Dc): Yield: 195.5 mg (72%); yellow solid; Mp: 62-64 °C; IR
-1
1
(neat) 2952, 1478, 1078, 885, 752, 726 cm ; H-NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6
Hz), 1.53-1.59 (m, 2H), 1.94-1.86 (m, 2H), 3.37 (t, 2H, J = 8.0 Hz), 7.57 (dd, 1H, J = 9.2, 2.4 Hz),
7.71 (t, 1H, J = 8.0 Hz), 7.85 (t, 1H, J = 8.0 Hz), 8.12 (d, 1H, J = 2.4 Hz), 8.26 (d, 1H, J = 8.4 Hz),
13
8.45 (d, 1H, J = 9.2 Hz), 8.58 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 14.1, 23.0,
1
31.4, 36.0, 121.9, 122.2, 123.1, 124.9, 126.2, 126.5, 127.3, 128.7, 130.4, 132.2, 133.9, 144.3,
+
163.6; HRMS (ESI) Calcd for C17H17ClN [M+H] = 270.1043, Found = 270.1044.
3-Chloro-6-phenylphenanthridine (3Dd): Yield: 238.7 mg (82%); yellow solid; Mp: 132-134 °C;
-1
1
IR (neat) 1443, 1360, 1074, 765, 668 cm ; H-NMR (400 MHz, CDCl3): δ = 7.51-7.65 (m, 5H),
7.70-7.75 (m, 2H), 7.87 (t, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 9.2 Hz). 8.24 (d, 1H, J = 2.4 Hz), 8.53
13
(d, 1H, J = 9.2 Hz), 8.64 (d, 1H, J = 8.8 Hz); C{ H}NMR (100 MHz, CDCl3): δ = 122.1, 122.2,
1
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123.3, 125.1, 127.4 (2C), 128.4 (2C), 128.9, 129.0, 129.5, 129.6 (2C), 130.9, 133.0, 134.4, 139.3,
+
144.4, 162.4; HRMS (ESI) Calcd for C19H13ClN [M+H] = 290.0731, Found = 290.0730.
5
6
7
8
9
3-Chloro-6-(4’-methylphenyl)phenanthridine (3De): Yield: 272.9 mg (89%); white solid; Mp:
-1
1
128-129 °C; IR (neat) 1078, 905, 819, 746, 719, 671 cm ; H-NMR (400 MHz, CDCl3): δ = 2.48 (s,
3H), 7.37 (d, 2H, J = 8.0 Hz), 7.65-7.10 (m, 4H), 7.86 (t, 1H, J = 8.0 Hz), 8.15 (d, 1H, J = 8.4 Hz),
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
13
8.22 (d, 1H, J = 2.0 Hz), 8.52 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H, J = 8.4 Hz); C{ H}NMR (100 MHz,
1
CDCl3): δ = 21.4, 122.0, 122.1, 123.2, 125.1, 127.2, 127.3, 129.1 (3C), 129.4, 129.6 (2C), 130.8,
+
133.0, 134.3, 136.4, 138.9, 144.4, 162.4; HRMS (ESI) Calcd for C20H15ClN [M+H] = 304.0888,
Found = 304.0887.
3-Chloro-6-(4’-methoxyphenyl)phenanthridine (3Df): Yield: 244.8 mg (76%); white solid; Mp:
-1
1
133-135 °C; IR (neat) 1360, 1248, 1031, 828, 761, 598 cm ; H-NMR (400 MHz, CDCl3): δ = 3.92
(s, 3H), 7.10 (d, 2H, J = 8.8 Hz), 7.61-7.72 (m, 4H), 7.88 (t, 1H, J = 8.4 Hz), 8.18 (d, 1H, J = 8.4
13
Hz), 8.21 (d, 1H, J = 2.4 Hz), 8.52 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H, J = 8.4 Hz), C{ H}NMR (100
1
MHz, CDCl3): δ = 55.3, 113.8 (2C), 121.9, 122.0, 123.2, 125.1, 127.1, 127.2, 129.0, 129.3, 130.7,
+
131.2 (2C), 131.7, 132.9, 134.2, 144.4, 160.2, 161.9; HRMS (ESI) Calcd for C20H15ClNO [M+H] =
320.0837, Found = 320.0836.
3-Chloro-6-(4’-chlorophenyl)phenanthridine (3Dg): Yield: 313.2 mg (96%); white solid; Mp:
-1
1
210-212 °C; IR (neat) 1359, 1078, 831, 765, 722 cm ; H-NMR (400 MHz, DMSO-d6): δ = 7.72 (d,
2H, J = 8.4 Hz), 7.83-7.93 (m, 4H), 8.13 (d, 1H, J = 8.4 Hz), 8.19 (t, 1H, J = 8.4 Hz), 8.26 (d, 1H, J
13
= 2.0 Hz), 8.97 (d, 1H, J = 9.2 Hz), 9.02 (d, 1H, J = 8.4Hz); C{ H}NMR (100 MHz, CDCl3 and
1
CF3CO2H): δ = 121.1, 123.1, 123.2, 123.3, 124.6, 127.4, 130.0 (2C), 130.7, 131.3 (2C), 131.8,
+
132.2, 133.3, 135.8, 138.1, 139.0, 140.4, 160.6; HRMS (ESI) Calcd for C19H12Cl2N [M+H] =
324.0341, Found = 324.0340.
4-Methyl-6-phenylphenanthridine (3Ed): Yield: 181.7 mg (67%); pale yellow solid; Mp: 108-
110 °C; IR (neat) 1566, 1466, 1360, 744, 687, 667 cm-1; 1H-NMR (400 MHz, CDCl3): δ = 2.88 (s.
3H), 7.50-7.62 (m, 6 H), 7.80-7.84 (m, 3 H), 8.18 (d, 1H, J = 8.4 Hz), 8.46 (d, 1H, J = 8.0 Hz), 8.69
(d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 18.4, 119.6, 122.4, 123.4, 124.7, 126.4,
126.8, 128.2 (2C), 128.5, 129.4, 130.1, 130.2 (2C), 133.8, 140.2, 142.5, 159.2; HRMS (ESI) Calcd
for C20H16N [M+H]+ = 270.1277, Found = 270.1278.
Crystal Data of 3-methyl-6-phenylphenanthridine 3Ad: Recrystalized from a mixture of ethyl
acetate and hexane. Formula: C20H15N, Crystal Color: colorless, Crystal Dimensions: 0.20 0.20
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0.20 mm3, Crystal Shape: Needle, Bravais Lattice: Monoclinic, Space Group: P 1 21/n 1’, a =
9.6849(8) Å, b = 14.6284(11) Å, c = 20.1462(16) Å, a = 90 °, b = 98.8224(11) °, g = 90 °, V =
2820.4(4) Å3, Z = 8, rcalc = 1.269 g cm-3, F(000) = 1136, µ(MoKa) = 0.073 mm-1, T = 173 K,
Reflections Collected 16048, 6431 independent reflections with I>2s (2qmax = 27.51 °), 381
parameters were used for the solution of the structure, R1 = 0.0484, wR2 = 0.1148, GOF = 1.043.
Crystallographic data (excluding structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC-1853388. Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [Fax: int. code + 44(1223)336-033; E-mail:
deposit@ccdc.cam.ac.uk].
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AUTHOR INFORMATION
Corresponding Author
*E-mail: togo@faculty.chiba-u.jp
ORCID
Hideo Togo: 0000-0002-3633-7292
Katsuhiko Moriyama: 0000-0001-8443-3599
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
http://pubs.acs.org. NMR charts of all phenanthridines 3, and X-ray analytical data of 3Ad.
ACKNOWLEDGEMENTS
Financial support in the form of a Grant-in–Aid for Scientific Research (No. 18K05118) from
the Ministry of Education, Culture, Sports, Science, and Technology in Japan is gratefully
acknowledged.
REFERENCES
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