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Ascorbic acid promoted [4 + 2] benzannulation:

Cite this: Org. Chem. Front., 2016, 3,
630
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a mild, operationally simple approach to the
synthesis of phenanthrenes†
Mei-jie Bu, Guo-ping Lu and Chun Cai*

Received 15th January 2016,
Accepted 19th March 2016
DOI: 10.1039/c6qo00020g
rsc.li/frontiers-organic
A mild, simple and metal-free radical [4 + 2] benzannulation for the generation of phenanthrenes has
been developed. A substoichiometric reductant, ascorbic acid (vitamin C), is harnessed as the radical
initiator. This method has a broad substrate scope, and various substituted phenanthrenes were obtained
in moderate to good yields at room temperature without irradiation.

Introduction In fact, arenediazonium ions generated in situ could be

reduced to aryl radicals by a “green” reducing reagent, L-threo-
Polycyclic aromatic hydrocarbons, especially phenanthrenes, ascorbic acid, through an inner-sphere mechanism under very
are a prominent class of compounds in organic chemistry. The
structure of phenanthrene could be found in diverse natural
products,1 pharmaceuticals,2 and functional materials.3 Thus,
many kinds of methods have been reported for the synthesis
of phenanthrenes over the past few decades.4 One of the
methods for their preparation is transition metal-catalyzed
[4 + 2] benzannulation of biaryl compounds with alkynes, and it Scheme 1 Ascorbic acid promoted [4 + 2] benzannulation with ortho-
amino-biaryls nitrosated in situ.
has drawn much attention.5 Other approaches, including intra-
molecular aryl–aryl bond formation from stilbene derivatives,6
ring-closing olefin metathesis,7 and cycloisomerization,8 Table 1 Reaction optimizationa
contribute as alternatives to provide phenanthrenes.
Arenediazonium salts can serve as precursors of highly reac-
tive aryl radicals in C–C bond forming reactions,9 and the
[4 + 2] benzannulation of biaryl diazonium salts with alkynes
could afford phenanthrenes efficiently from readily-available
starting materials.10 In 2012, Zhou’s report demonstrated an
eosin Y-catalyzed, visible light-induced synthesis of phenan- Entry Solvent 2a (equiv.) Additive Yield (%)b
threnes.11 In this chemistry, oxidative quenching of the photo- 1 CH3CN 3 — 58, 51,c 55d
excited photocatalyst with biaryl diazonium salts gives biaryl 2 CH3CN 5 — 63
radicals. After that, Studer and co-workers employed isoamyl 3 CH3CN 10 — 60
4 PhCF3 5 — 56
nitrite for in situ diazonium salt generation, Bu4NI as a radical 5 CH3OH 5 — 35
initiator for the formation of an aryl radicals, which undergo 6 DMSO 5 — 71
addition to alkynes and subsequent base-promoted homolytic 7 DMF 5 — 21
8 NMP 5 — 10
aromatic substitution (BHAS) to provide phenanthrenes.12 9 1,4-Dioxane 5 — 24
However, in these two protocols, either heating or irradiation 10 THF 5 — 5
is required for the transformation. 11 H2O 5 — 15
12 DMSO 5 NaOAc 29
13 DMSO 5 CsOAc 3
14e DMSO 5 — 18
15 f DMSO 3 — 73
Chemical Engineering College, Nanjing University of Science and Technology,
Nanjing, Jiangsu 210094, People’s Republic of China. a
Reaction conditions: 1a (0.2 mmol), 2a (excess), ascorbic acid
E-mail: c.cai@mail.njust.edu.cn (10 mol%), t-BuONO (1.5 equiv., 0.3 mmol), solvent (1 mL), additive
† Electronic supplementary information (ESI) available: Experimental procedures (1 equiv.), under N2, rt. b Isolated yields. c 8 h. d 24 h. e Without
for the synthesis, spectral data and NMR spectra. See DOI: 10.1039/c6qo00020g ascorbic acid. f DMSO (0.5 mL).

630 | Org. Chem. Front., 2016, 3, 630–634 This journal is © the Partner Organisations 2016

Organic Chemistry Frontiers
mild conditions. In this case, ascorbic acid indeed acts as a
reductant instead of a Lewis acid, for which solid evidence has
been reported by Bravo-Díaz and co-workers.13 This elegant
method has recently received much attention, and it was suc-
cessfully utilized by Martin and Carrillo for the metal-free C–H
arylation of (hetero)arenes.14 Later, our group reported an
ascorbic acid promoted synthesis of aryl sulfides,15 involving
Table 2 Ascorbic acid promoted [4 + 2] benzannulation: alkyne scopea
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a
Reaction conditions: 1a (0.2 mmol), 2 (1 mmol), ascorbic acid
(10 mol%), t-BuONO (0.3 mmol), DMSO (1 mL), under N2, rt, isolated
yield. b Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), ascorbic acid
(10 mol%), t-BuONO (0.3 mmol), DMSO (0.5 mL), under N2, rt,
isolated yield.
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the reaction of aryl radicals and disulfides. The strategy was
also applied by Ranu’s group for the oxidative arylation of vinyl-
arenes,16 which allows the assembly of 1,2-diarylated etha-
nones. We speculate that biaryl radicals generated by this
manner may react with alkynes to produce substituted phe-
nanthrenes via radical cascade processes. Herein, we wish to
report an ascorbic acid promoted [4 + 2] benzannulation with
ortho-amino-biaryls nitrosated in situ under mild conditions
without irradiation (Scheme 1).
Results and discussion
To test our hypothesis, biphenyl-2-amine (1a) was treated with
methyl propiolate (2a), ascorbic acid, and tert-butyl nitrite in
acetonitrile at room temperature for 12 hours under nitrogen
(Table 1, entry 1). To our delight, the substituted phenan-
Table 3 Ascorbic acid promoted [4 + 2] benzannulation: aminodiphe-
nyl scopea
a
Reaction conditions: 1 (0.2 mmol), 2c (1 mmol), ascorbic acid
(10 mol%), t-BuONO (0.3 mmol), DMSO (1 mL), under N2, rt, isolated
yield.
Org. Chem. Front., 2016, 3, 630–634 | 631

Research Article
threne was obtained in 58% yield along with biphenyl as the
main by-product,17 and the hydroamination product could not
be detected. The reaction time, amount of 2a and different sol-
vents were then screened to optimize the reaction conditions,
and the results are shown in Table 1. A reaction time of
12 hours, five equivalents of 2a and DMSO as the solvent pro-
vided the highest yield (Table 1, entry 6). Considering that the
innate chain might be a BHAS process,12 a base was tested as
an additive. However, the addition of a base resulted in an
obvious decrease of the yield (Table 1, entries 12 and 13). This
could be because diazonium salts are labile towards bases.
When the experiment was conducted in the absence of
ascorbic acid, the reaction became sluggish and only 18%
yield was obtained after a reaction time of 12 hours (Table 1,
entry 14). Although the amount of alkyne has been reduced
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compared to Studer’s protocol,12 five equivalents of alkyne is
still a large excess and this is a big obstacle for its practical
application. We tried to reduce the amount in some ways,18
and succeeded to obtain 73% yield with three equivalents of
2a by using 0.5 mL DMSO as the solvent.
With the optimal reaction parameters identified, various
alkynes were investigated to explore the scope of the [4 + 2]
benzannulation. As shown in Table 2, the reaction tolerated a
series of aryl alkynes besides methyl and ethyl propiolates.
A variety of aryl alkynes carrying electron-donating and -with-
Scheme 2 Scale-up experiment. Reaction conditions: 1a (4 mmol), 2c
(12 mmol), ascorbic acid (10 mol%), t-BuONO (6 mmol), DMSO (10 mL),
under N2, rt. Isolated yield.
Scheme 3 Proposed mechanism.
632 | Org. Chem. Front., 2016, 3, 630–634
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drawing substituents at the para position could successfully
react with 1a to afford products in good yields. Alkyloxy, acetyl,
trifluoromethyl, and carbon–halogen bonds remained intact
during the ascorbic acid promoted benzannulation. The yields
were almost the same obtained by the reactions of 1a with aryl-
acetylenes 2d, 2l and 2m respectively, indicating that the
steric effect is not significant. It is important to note that
heteroaryl alkynes 2o and 2p could provide the corresponding
products with good yields (3ao and 3ap). Cyclopropyl acetylene
(2q) and trimethylsilylacetylene (2r) could also serve as sub-
strates for this transformation, and moderate yields were
obtained by both of the reactions. This radical [4 + 2] benz-
annulation was also tested on two internal alkynes (2s, 2t),
however, low yields were obtained by both of the reactions.
Having established the scope of the broad scope of alkynes,
we next focused on varying the substituents on the amino-
biphenyl component (Table 3). The substituents, including
alkyl, alkyloxy, halo, cyano, trifluoromethyl and nitro, on both
aromatic rings were all tolerated in the benzannulation. The
reaction of phenylacetylene with substrate 1e gave a relatively
low yield, because of the low solubility of 1e in DMSO. meta-
Difluoro-biaryl amine (1h) worked well for the reaction.
However, when only one ortho hydrogen atom was available,
the yield turned out to be lower (3ic).
In order to further demonstrate the practicality and general-
ity of the ascorbic acid promoted [4 + 2] benzannulation,
biphenyl-2-amine (1a) and phenylacetylene (2c) were employed
in a gram-scale reaction, which could be effectively scaled up
with slightly lower efficiency, affording 3ac in 78% yield
(Scheme 2).
According to previous reviews by Studer and Curran,19
diverse radical cascade reactions, including BHAS, are grouped
under electron catalysis. So a possible mechanism of this
transformation with an electron-catalyzed innate cycle is
depicted in Scheme 3. In the first step, biaryl amine 1a is nitro-
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sated by tert-butyl nitrite to produce diazonium salt A. The
reaction was initiated upon the protonation of A by ascorbic
acid, resulting in the formation of diazonium salt B via the
change of the anion to ascorbate. The diazonium ion is
reduced by ascorbate through a single-electron transfer to
generate a biaryl radical C, an ascorbyl radical and nitrogen.
The ascorbyl radical could dismutate into dehydroascorbic
acid and ascorbic acid, which would react with another dizo-
nium salt A. Meanwhile, vinyl radical D is afforded by the
addition of an aryl radical C to alkyne, followed by an intra-
molecular radical cyclization to give cyclized radical intermedi-
ate E. Then, deprotonated by tert-butanolate, the conjugated
radical anion F is formed, and t-BuOH generated could
accelerate the dismutation of the ascorbyl radical.20 Finally,
product 3 was obtained after the formal liberation of an elec-
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tron from F. In this step, diazonium salt A is easily reduced by
this electron to give tert-butanolate and another radical C,
which completes the innate chain cycle. The possibility of
propagation by electron transfer from cyclohexadienyl radical
E to the diazonium salt A is small, based on the report by
Majek and Wangelin.21
Conclusions
In summary, we have described a mild, operationally simple,
and metal-free approach to generate phenanthrenes. In this
chemistry, various substituted phenanthrenes were obtained
from readily-prepared starting materials with a substoichio-
metric amount of ascorbic acid at room temperature. The
radical initiator ascorbic acid and its decomposition product
dehydroascorbic acid are both edible. The mildness of this
protocol makes it appealing for a variety of applications.
Experimental section
General procedure for the ascorbic acid promoted synthesis of
phenanthrenes
A 10 mL Schlenk tube with a magnetic stirring bar was
charged with L-ascorbic acid (0.1 equiv., 4 mg), ortho-amino-
biaryl (0.2 mmol) and alkyne (1.0 mmol, 5 equiv. or 0.6 mmol,
3 equiv.). The tube was evacuated and backfilled with dry nitro-
gen (this operation was repeated three times). DMSO (1 mL or
0.5 mL) was then added by a syringe. The mixture was stirred
vigorously for 1 minute before t-BuONO (0.3 mmol, 1.5 equiv.,
36 μL) was added via a syringe. After the resulting mixture was
stirred at r.t. for 12 hours, the reaction mixture was diluted
with water (10 mL) and extracted with diethyl ether (3 ×
10 mL). The combined organic layers were washed with brine,
dried over K2SO4, and concentrated in vacuo. Purification of
the crude product was achieved by column chromatography.
Acknowledgements
We gratefully acknowledge Natural Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776). This work was
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also supported by National Natural Science Foundation of
China (21476116, 21402093) and Chinese Postdoctoral Science
Foundation (2015M571761).
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