Synthesis and Reactivity of o-Enoyl Arylisocyanides: Access to Phenanthridine-8-Carboxylate Derivatives

Article abstract of DOI:10.1002/adsc.201800606

Various o-enoyl arylisocyanides were prepared from readily available reactants and found to undergo a double annulation with glutaconate to provide straightforward access to phenanthridine-8-carboxylates and hydrophenanthridine-8-carboxylates under mild aerobic conditions. In this domino transformation, two rings and three bonds were successively created. A mechanism involving tandem [3+3]-annulation/intramolecular cyclization/ demethoxycarbonylation/aerobic oxidative aromatization sequence was proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201800606

Title: Synthesis and Reactivity of o-Enoyl Arylisocyanides: Access to
Phenanthridine-8-Carboxylate Derivatives
Authors: Jinxiong Cai, Zhongyan Hu, Yifei Li, Jun Liu, and Xianxiu Xu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800606
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10.1002/adsc.201800606
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis and Reactivity of o-Enoyl Arylisocyanides: Access to
Phenanthridine-8-Carboxylate Derivatives
Jinxiong Cai,a,b Zhongyan Hu,a,b,* Yifei Li,b Jun Liu,b and Xianxiu Xua,*
a
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized
Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of
Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China
xuxx677@sdnu.edu.cn
b
Jilin Province Key Laboratory of Organic Functional Molecular Design and Synthesis, Department of Chemistry,
Northeast Normal University, Changchun 130024, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Various o-enoyl arylisocyanides were prepared
from readily available reactants and found to undergo a
double annulation with glutaconate to provide
straightforward access to phenanthridine-8-carboxylates
and hydrophenanthridine-8-carboxylates under mild
aerobic conditions. In this domino transformation, two
rings and three bonds were successively created. A
mechanism
involving
tandem
[3+3]-
annulation/intramolecular
cyclization/
demethoxycarbonylation/aerobic oxidative aromatization
sequence was proposed.
Keywords: o-enoyl arylisocyanides; double annulation;
phenanthridines; aerobic oxidation; glutaconate
Phenanthridine framework exists in a large number of
natural products, pharmacological agents, and
functional molecules.[1] Given their significance, great
effort has been devoted to developing new methods
for the synthesis of these tricyclic heterocycles during
the past several decades.[2,3] Among these methods,
the construction of phenanthridines from the domino
reactions of readily accessible functionalized
isocyanides has lately attracted enormous attention.[3-
6] Recently, the tandem insertion/cyclization of ortho-
isocyanobiphenyls with various radicals has become a
popular method for the synthesis of a wide range of 6-
functionalized phenanthridines (Scheme 1, eq 1).[3,4]
In 2014, Ji, Wang[5a] and Jiang[5b] groups
independently reported elegant syntheses of 6-amino
phenanthridine derivatives via Co- or Pd-catalyzed
oxidative isocyanide insertion with 2-aryl anilines
(Scheme 1, eq 2). These isocyanide-based synthetic
strategies rely on the closure of the central pyridine
ring and provide the phenanthridines bearing a variety
of substituents on the 6-position. Very recently, we
Scheme 1. Synthesis of phenanthridines from isocyanides
2-isocyanochalcones with active methylene ketones
for the expedient synthesis of 6-H-phenanthridines
(Scheme 1, eq 3).[6] In this domino transformation, the
tricyclic phenanthridine scaffolds were efficiently
created by the successive formation of the central
pyridine and one of the benzene rings.
Isocyanides are useful synthons in the synthesis of
heterocycles.[7] Great progress has been made in this
reported
a
DBU-catalyzed aerobic oxidative
Robinson-type double annulation of
1
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10.1002/adsc.201800606
Advanced Synthesis & Catalysis
area in the past several decades.[8] Along with our stirred at room temperature in air for 0.5 h, dihydro
continuous interest in isocyanide chemistry[9] and the phenanthridine-8-carboxylate 3a[23] was obtained in
importance of phenanthridine carboxylic acid 81% yield (Table 1, entry 1). The reaction at 45 °C
derivatives,[10] we initiated a project towards the gave a higher yield of 3a (93%) than those at room
preparation of functionalized arylisocyanides and temperature or 60 °C (Table 1, entries 2 and 3).
their application in the synthesis of phenanthridine Decreasing the amount of DBU to 10 mol% and 20
carboxylates. Although several o-functionalized mol% led to lower yields of product 3a (Table 1,
arylisocyanides, such as o-alkenyl,[11] alkynyl,[12] entries 4 and 5). Different solvents such as 1,4-
acyl,[13]
aryl,[3,14]
cyano,[15]
and
halo,[16] dioxane, THF, DMF, and CH2Cl2 were also screened.
methoxycarbonyl[17]
aminocarbonyl However, these solvents gave slightly lower yields of
arylisocyanides,[18] have been employed for the 3a compared to acetonitrile (Table 1, entries 6−9 vs
synthesis of diverse class of benzo-fused heterocycles, 2). Bases such as NaOH, K2CO3, and t-BuOK were
to our knowledge, the synthetic utility of o-enoyl then tested. 3a was also obtained in slightly lower
arylisocyanides have barely been exploited.[19] We yield (Table 1, entries 10−12 vs 2). To our delight,
recently reported the only transformation of o-enoyl when the reaction time was prolonged to 24 h, the
arylisocyanides, i.e., o-cinnamoyl phenylisocyanide, aromatized phenanthridine-8-carboxylate 4a was
as
functionalized
arylisocyanides
in
the obtained in 90% yield (Table 1, entry 13). However,
chemoselective [4+2] annulation of two different the reaction under oxygen atmosphere gave a slightly
isocyanides.[9a] However, in this reaction, the lower yield of 4a (Table 1, entry 14).
cinnamoyl group was intacted. We envisioned that the
reactive enoyl functional group could bestow new Table 1. Screening of Reaction Conditions[a]
reactivities to theses substrates, especially in domino
reactions. Herein, we report the preparation of a
variety of o-enoyl arylisocyanides and their double
annulation with glutaconate for the efficient
construction of both phenanthridine-8-carboxylate
entry base
solvent
T
T.
Yield (%)[b]
and dihydro phenanthridine-8-carboxylate derivatives
in a single operation under mild aerobic conditions
(Scheme 1, eqs 4 and 5). Two rings and three bonds
were successively created and one C–C bond was
cleavaged in this domino transformation.
(ºC) (h)
3a
4a
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
NaOH
K2CO3
CH3CN RT
CH3CN 45
CH3CN 60
CH3CN 45
CH3CN 45
dioxane 45
0.5
0.5
0.5
0.5
0.5
1.5
1
81
2
93
3
89
A series of o-enoyl arylisocyanides 1 were easily
prepared from 1-(2-aminophenyl)prop-2-en-1-one
derivatives 5[20] by a routine procedure involving
amine formylation and dehydration[21] (Scheme 2).
4
76[c]
88[d]
80
5
6
7
THF
45
45
45
79
8
DMF
DCM
0.5
1
89
9
87
10
11
12
13
14
CH3CN 45
CH3CN 45
1
71
1
74
t-BuOK CH3CN 45
1
68
DBU
CH3CN 45
24
90
82[e]
DBU
CH3CN 45
24
[a] Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol),
base (30 mol%), solvent (2 mL), air atmosphere.
[b]Yield of isolated products.
[c] 10 mol% DBU was used.
[d] 20 mol% DBU was used.
[e] Under O2 atmosphere.
Scheme 2. Synthesis of o-enoyl arylisocyanides 1. Yields
of isolated products in two steps.
With the optimal conditions at hand, we first
examined the substrate scope for the aromatic
phenanthridine-8-carboxylate 4 (Table 1, entry 11).
As shown in Scheme 3, this domino double
annulation/aerobic oxidation reaction tolerates a wide
range of o-enoyl arylisocyanides 1 bearing various
electronically and sterically different R1 groups, such
as para- (Scheme 3, 1b−h), meta- (Scheme 3, 1i), or
Employing o-cinnamoyl arylisocyanide 1a and
methyl glutaconate 2 as model substrates, we
surveyed the reaction conditions (Table 1). When a
mixture of isocyanide 1a (0.3 mmol), 2 (1.2 equiv),
and DBU[22] (0.3 equiv) in acetonitrile (2 mL) was
2
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10.1002/adsc.201800606
Advanced Synthesis & Catalysis
ortho-substituted aryl (Scheme 3, 1j and 1k), di- and this domino reaction, and the dihydrophenanthridine
(Scheme 3, 1l–n), trisubstituted aryl (Scheme 3, 1o), 3a-j were obtained in high to excellent yields.
1- and 2-naphthyl (Scheme 3, 1p and 1q), heteroaryl Furthermore, 5-chloro and -bromo as well as 4-chloro
(Scheme 3, 1r–t) and vinyl groups (Scheme 3, 1u). substituted isocyanide 1v, 1w and 1y also gave the
The steric and electronic effects of substituents on the corresponding dihydrophenanthridines 3k–m in good
phenyl ring seem to have no obvious effect on the yields.
transformation (Scheme 3, 1a–k). In addition, 5-
chloro and -bromo, as well as 4-fluoro and -chloro,
substituted isocyanides 1v–1y also gave the
corresponding phenanthridines 4v–y in good yields.
Notably, this reaction is high yielding and gave
products 4 in high to excellent yields (74–95%).
Scheme 4. Synthesis of dihydrophenanthridines 3.
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol) and
DBU (30 mol%) in CH3CN (2 mL) at 45 ºC for 0.5 h;
yields of isolated products.
On the basis of previous[6] and present observations
as well as literature precedent,[20a,27] a plausible
pathway for this domino reaction is proposed in
Scheme 5 (exemplified by the generation of 3a and
4a). First, in the presence of DBU, Michael addition
Scheme 3. Synthesis of phenanthridines 4.
of glutaconate 2 to the enone moiety of isocyanide 1a
occurs to produce intermediate I,[20a,27] which was
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol) and
detected by high-resolution mass spectra ([M+Na]+ =
DBU (30 mol%) in CH3CN (2 mL) at 45 ºC for 24 h; yields
of isolated products.
414.1323, Figure S1). Intermediate I undergoes 1,3-
proton shift and isomerization to generate the anion
III. Then intramolecular condensation of III takes
Hydrophenanthridine derivatives are valuable
molecules because they exhibited promising
biological activities[24] and have been used as a key
intermediate for the synthesis of the natural product[25]
as well as pharmaceutical agents.[26] Thus, the scope
place to give the cyclohexa-1,3-diene IV, which
undergoes deprotonation and isomerization to
generate anion VI, following by intramolecular
cyclization and protonation to form the tricyclic
intermediate
VIII.[6]
Subsequent
isomerization and
demethoxycarbonylation,[6]
of
preparation
of
dihydrophenanthridine-8-
carboxylates 3 was also explored under the optimal
conditions (Table 1, entry 2). As depicted in Scheme
4, a wide range of o-enoyl arylisocyanides 1 with
different R1 groups such as electron-neutral (Scheme
4, 3a), electron-poor (Scheme 4, 3b and 3d) and
electron-rich aryl (Scheme 4, 3c and 3e), naphthyl
(Scheme 4, 3f and 3g), heteroaryl (Scheme 4, 3h and
3i) and vinyl groups (Scheme 4, 3j) were tolerated in
protonation afforded the hydrophenanthridine 3a.
Finally, aerobic oxidative aromatization of 3a by air
afforded phenanthridine 4a.
To test the practicability of the present double
annulation, 5 mmol scale synthesis was performed.
As shown in Scheme 6, 1.433
hydrophenanthridine 3a and 1.393
g
g
of
of
3
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10.1002/adsc.201800606
Advanced Synthesis & Catalysis
phenanthridine 4a were obtained, when isocyanide 1a and high to excellent product yields. Further studies
(5 mmol) and glutaconate 2 (6 mmol) were treated on the domino reaction of functionalized isocyanides
under the optimized reaction conditions, respectively.
are ongoing.
Experimental Section
Typical Procedure for the Synthesis of Imidazole 4a
To a solution of (E)-1-(2-isocyanophenyl)-3-phenylprop-2-
en-1-one (1a) (0.3 mmol, 70 mg) and dimethyl glutaconate
2 (0.36 mmol, 0.046 mL) in CH3CN (2 mL) at 45 ºC, DBU
(0.09 mmol, 0.014 mL) was added. After stirred the
resulting mixture for 24 h in the open air, the substrate 1a
was consumed as indicated by TLC. Then the mixture was
cooled to room temperature, poured into water (50 mL) and
the resulting mixture was extracted with dichloromethane
(3×20 mL). The organic layer was washed with brine (20
mL), dried over MgSO4 and concentrated. Purification of
the crude product by flash column chromatography (silica
gel; petroleum ether: ethyl acetate = 10:1) gave 4a (84.5
1
mg, 90% yield) as a white solid. m. p. 190-192 ºC. H
NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 7.41–7.54 (m, 5H),
7.71 (t, J = 7.5 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 8.23 (d, J
= 7.9 Hz, 1H), 8.58 (d, J = 11.2 Hz, 3H), 9.37 (s, 1H); 13C
NMR (151 MHz, CDCl3) δ 52.2, 122.6, 123.2, 124.2, 124.6,
127.4,
127.7,
128.1,
128.4,
129.6,
130.1,
130.3,131.2,133.9,140.9, 144.3, 145.2, 153.1, 167.9.
+
HRMS (ESI-TOF) calculated for C21H15NNaO2 ([M+Na]
+): 336.0995, Found: 336.0999.
Acknowledgments
Financial support of this research provided by the NSFC
(21672034), the Natural Sciences Foundation of Jilin Province
(20160101330JC) is gratefully acknowledged.
Scheme 5. Proposed mechanism.
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10.1002/adsc.201800606
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
UPDATE
Synthesis and Reactivity of o-Enoyl
Arylisocyanides: Acess to Phenanthridine-8-
Carboxylate Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Jinxiong Cai,a,b Zhongyan Hu,a,b,* Yifei Li,b Jun
Liu,b and Xianxiu Xua,*
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