Synthesis of 6-substituted phenanthridines by metal-free, visible-light induced aerobic oxidative cyclization of 2-isocyanobiphenyls with hydrazines

Article abstract of DOI:10.1039/c3gc42517g

Irradiation of hydrazines with visible-light in the presence of organic dye eosin B generates various types of functional radicals, which are trapped by 2-isocyanobiphenyls to give 6-substituted phenanthridines. the Partner Organisations 2014.

Full text of DOI:10.1039/c3gc42517g

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Synthesis of 6-substituted phenanthridines by
metal-free, visible-light induced aerobic oxidative
cyclization of 2-isocyanobiphenyls with
hydrazines†
Cite this: DOI: 10.1039/c3gc42517g
Received 11th December 2013,
Accepted 29th January 2014
DOI: 10.1039/c3gc42517g
Tiebo Xiao, Linyong Li, Guoliang Lin, Qile Wang, Ping Zhang, Zong-wan Mao* and
Lei Zhou*
www.rsc.org/greenchem
Irradiation of hydrazines with visible-light in the presence of
organic dye eosin B generates various types of functional radicals,
which are trapped by 2-isocyanobiphenyls to give 6-substituted
phenanthridines.
A practical synthesis of phenanthridines is of considerable
interest in the fields of organic and pharmaceutical chem-
istry,1 since this basic skeleton is widespread in naturally
occurring alkaloids and exhibits interesting biological activi-
ties.2 Recently, a cascade radical pathway involving C-radical
addition to 2-isocyanobiphenyls and subsequently intramole-
cular homolytic aromatic substitution has been developed,
which allows the rapid assembly of a phenanthridine frame-
work with high efficiency.3 For example, Chatani and co-
workers demonstrated a Mn(III)-mediated annulation of 2-iso-
cyanobiphenyls with boronic acid under heating conditions.3a
We3b and Studer3c independently reported the synthesis of
6-trifluoromethyl phenanthridines through a CF3 radical. Very
recently, the reaction of 2-isocyanobiphenyls with aromatic
Scheme 1 Radical generation upon visible-light irradiation using an
organic dye as the photoredox catalyst and our design.
t
aldehydes using BuOOH as an oxidant was also developed by
Studer.3d Each of these methods has its own specific appli-
cations, but remains associated with certain disadvantages
such as harsh reaction conditions, use of environmentally
unfriendly oxidants and limited reaction scope.
As a result of its natural abundance, the use of visible-light
as a driving force for green organic synthesis has received
much scientific and technological interest in recent years.4
Although tris(bipyridine) ruthenium and iridium complexes
have been proved to be powerful photosensitizers in a wide
range of organic transformations, organic dyes, which are
cheap and easy to modify, would be attractive alternatives com-
pared to metal-based photoredox catalysts.5 Recently, organic
dye has gained considerable attention as an initiator for the
generation of aryl radicals from aryl diazonium salts under
visible-light conditions (Scheme 1).4g Our group also reported
an eosin Y-catalyzed, visible light-induced [4 + 2] benzannula-
tion of biaryl diazonium salts with alkynes.6 However, diazo-
nium salts usually need to be freshly prepared from anilines
using stoichiometric amounts of nitrite salts or other oxidants.
In addition, radicals other than aryl radicals are less explored
because of the limited availability of the corresponding diazo-
nium salts.
On the other hand, the oxidative degradation of hydrazines
that leads to radical species has been essentially known for a
long time.7 Various types of radicals including alkyl,8 aryl,9
acyl,10 alkoxycarbonyl,11 and sulfonyl radicals12 could be
generated from their hydrazine precursors. However, many of
these radical reactions were carried out in the presence of
toxic transition metals. Despite the use of oxygen as an
oxidant, usually with a catalytic amount of copper or iron as
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xingang
West Road, Guangzhou 510275, China. E-mail: zhoul39@mail.sysu.edu.cn;
Tel: +86 20-84110217
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc42517g
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the promoter,9f,g,11,12 there is still no report on the employ- rates (see Table S1 in the ESI†). Varying the solvents proved
ment of photoredox catalysts to initiate the formation of DMSO to be optimal (Table 1, entries 5–9). Further optimi-
radical species from hydrazines. Herein we wish to report the zations revealed that this reaction proceeded more efficiently
use of organic dye eosin B as an efficient initiator for gen- in the presence of inorganic base, and the use of K2CO3
eration of radical species from hydrazines upon visible-light gave the best result (Table 1, entries 10–12). Although the
irradiation in the open air, which were trapped by 2-isocyano- slow generation of radical species from hydrazines with only
biphenyls to give a series of 6-substituted phenanthridines in O2 was reported,9f,g less than 10% yield of product was
good yields (Scheme 1).13
detected in the absence of eosin B, and 85% of phenyl hydra-
At the outset, a solution of 2-isocyanobiphenyl (1a) and zine remained unreacted after the reaction mixture was stirred
phenyl hydrazine (2a) in DMSO was irradiated with a 5 W blue at room temperature for 72 h (Table 1, entry 13). This result
LED in the presence of eosin Y at room temperature. We were indicates that eosin B significantly accelerates this reaction as
delighted to find that the desired phenanthridine 3a was a promoter.15 However, when CuI or FeBr3 was employed as a
obtained in 25% yield (Table 1, entry 1). A survey of organic catalyst, the reaction resulted in complex mixtures and only a
dyes demonstrated that eosin B is the best choice of photo- trace amount of phenanthridine 3a was obtained (Table 1,
redox catalysts, which may be attributed to its stronger absorp- entries 14 and 15). In the control experiments, the reaction
tion ability in the range of blue light (Table 1, entries 1–4).14 was found to be completely shut down without the irradiation
The reactions irradiated with household light bulbs or green of light or under a nitrogen atmosphere (Table 1, entries
LED strips provided somewhat diminished yields and slower 16 and 17).
With the optimized reaction conditions in hand, we next
explored the scope of the reaction with 2-isocyanobiphenyl (1a)
and a variety of hydrazines. First, different substituted phenyl
hydrazines were examined, and they were found to undergo
Table 1 Optimization of reaction conditionsa
the reactions with 1a smoothly to give 6-arylated phenanthri-
dine derivatives 3a–i in good yields. The reaction tolerates
various functional groups including methyl, methoxy, trifluoro-
methyl, and halogen (F, Cl, Br) present in the aryl hydrazines.
As shown in Table 2, ortho-, para-, and meta-substituted toyl
hydrazines all worked well in the present system to afford the
phenanthridines in good yields. Besides, 2-chloro-6-hydrazino-
pyridine was also suitable for the reaction, yielding the desired
product 3j in 83% yield. To further expand the scope of the
reaction, alkyl hydrazines were employed as substrates under
optimized reaction conditions. We were delighted to find that
the reactions of 2-isocyanobiphenyl (1a) with methylhydrazine,
tert-butylhydrazine and cyclohexylhydrazine can furnish the
corresponding phenanthridines 3k–m in good to excellent
yields. Similarly, a benzoyl group (3n) and an ester group (3o)
Entry
Catalyst
Solvent
Base
Yieldb (%)
were successfully introduced onto the 6-position of phenan-
thridines, albeit with low efficiency.
1
2
3
4
5
6
7
8
Eosin Y
Eosin B
RB
DMSO
DMSO
DMSO
DMSO
DMF
MeCN
CH2Cl2
1,4-Dioxane
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
None
None
None
None
None
None
None
None
25
64
55
13
61
45
30
28
33
89
62
74
<10
11
Trace
<10
0
Next, the scope of 2-isocyanobiaryl compounds was exam-
ined. As shown in Table 3, the isocyanides bearing either
an electron-rich or an electron-deficient substituent on the
4′-position of the aromatic ring all underwent the reactions
smoothly to give the corresponding 6-phenyl phenanthridines
3p–s in similar yields. When the meta-methyl derivative was
employed, the reaction afforded two regioisomers 3t and 3t′ in
a ratio of 1 : 2. The reaction was not significantly affected by
the substituent on the aromatic ring attached to isocyanides,
such as methyl, phenyl, trifluoromethyl groups, leading to
the phenanthridines 3u–w in yields of 82%, 85% and 69%
respectively.
MB
Eosin B
Eosin B
Eosin B
Eosin B
Eosin B
Eosin B
Eosin B
Eosin B
None
CuI
FeBr3
Eosin B
Eosin B
9
None
10
11
12
13
14
15
16c
17d
K2CO3
Na2CO3
K2HPO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
In conclusion, we have described the use of organic dye
eosin B as the initiator for the generation of radical species
from hydrazines upon visible-light irradiation in the open
air. Through the radical cyclization of 2-isocyanobiphenyls
with hydrazines under environmentally friendly conditions,
a 2-Isocyanobiphenyl 1a (0.2 mmol), phenyl hydrazine 2a (0.6 mmol),
base (3 equiv.), solvent (1 mL), and catalyst (5 mol%), rt in the open
air for 18 h. b Yields were determined by 1H-NMR analysis using
CH3NO2 as an internal standard. c The reaction was carried out in the
absence of light. d Under the protection of nitrogen.
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Table 2 Reaction scope of hydrazinesa,b
Table 3 Reaction scope of isocyanidesa,b
a All the reactions were carried out under the same conditions as
described in Table 2. b Isolated yield. c The ratio was determined by
1H-NMR.
Acknowledgements
We thank the National Natural Science Foundation of China
(grant no. 21202207 and J1103305), the Research Fund for
Guangzhou Peal River New Star of Science and Technology
(grant no. 2013J2200017) and the Program for Changjiang
Scholars and Innovative Research Team in University of China
(grant no. IRT1298) for the financial support.
a All the reactions were carried out using 2-isocyanobiphenyl 1a
(0.2 mmol), hydrazines 2 (0.6 mmol), K2CO3 (3 equiv.), DMSO (1 mL),
and eosin B (5 mol%) at room temperature in the open air with the
irradiation of a 5 W blue LED for 18 h. b Isolated yield. c Hydrazine
hydrochlorides were directly used as the substrates.
Notes and references
the reaction allows the rapid assembly of a phenanthridine
framework, a common structural unit present in a wide variety
of naturally occurring alkaloids. Various functional groups
including aryl, alkyl, acyl, and ester were introduced onto the
6-position of phenanthridines in good to excellent yields.
Instead of ruthenium and iridium based photosensitizers,
the reaction proceeded under metal-free conditions using an
inexpensive and easily available organic dye as a photoredox
catalyst. These advantages may make this method find poten-
tial applications in the synthesis of 6-substituted phenanthri-
dines. Further investigations on the mechanistic details
and related radical processes are currently underway in our
laboratory.
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