KOt-Bu/DMF promoted intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones: An efficient synthesis of phenanthrenes

Article abstract of DOI:10.1039/c5ra07188g

A new synthesis of phenanthrene derivatives has been achieved through intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones promoted by KOt-Bu/DMF. A free radical reaction pathway is proposed.

Full text of DOI:10.1039/c5ra07188g

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KOt-Bu/DMF promoted intramolecular cyclization of 1,1'-
biphenyl aldehydes and ketones: an efficient synthesis of
phenanthrenes
Received 00th January 20xx,
Accepted 00th January 20xx
Yan-yan Chen, Niu-niu Zhang, Lin-miao Ye, Jia-hua Chen, Xiang Sun, Xue-jing Zhang, Ming Yan*
DOI: 10.1039/x0xx00000x
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cyclization of 1,1'ꢀbiphenyl aldehydes and ketones promoted by
KOtꢀBu/ DMF.
A new synthesis of phenanthrene derivatives has been achieved
through intramolecular cyclization of 1,1'-biphenyl aldehydes and
Initially, we examined the reaction of 2'ꢀbenzylꢀ(1,1'ꢀ
biphenyl)ꢀ2ꢀcarbaldehyde 1a and the results are summarized in
Table 1. The expected phenanthrene 2a was obtained in a good
yield when the reaction was carried out in DMF with 3.0
equivalents of KOtꢀBu at 90 oC (Table 1, entry 1). The excellent
yield was kept while the reaction temperature was decreased to
room temperature (Table 1, entry 2). The reaction in DMSO gave
54% yield of 2a combined with 9ꢀmethylꢀ10ꢀphenylꢀ
phenanthrene (32% yield). This side product was generated via
the further reaction of 2a with DMSO (Table 1, entry 3).14 The
similar transformation was previously reported by Russell and
Weiner.15 The replacement of DMF with DMA led to a lower
yield (Table 1, entry 4). Other reaction solvents such as THF,
ketones promoted by KOt-Bu/DMF.
A free radical reaction
pathway is proposed.
Phenanthrenes have attracted great attention over the past
years because of their important applications in biological
studies1 and materials science.2 A number of synthetic methods
of phenanthrenes have been developed.3 The classical methods
such as carbocyclic ring expansion or cyclization of stilbenes,
suffer from the harsh conditions and limited substrate scope. In
recent years, the cyclizations of biphenyl substrates have been
widely used to synthesize phenanthrenes. Fabbri and coꢀworkers
reported the synthesis of phenanthrenes by ringꢀclosing
metathesis of 2,2′ꢀdivinylbiphenyls.4 Wang and coꢀworkers
found that TsNHNH2 promotes the intramolecular cyclization of
2′ꢀbenzoylꢀbiphenylꢀ2ꢀcarbaldehyde to give phenanthrenes.5 The
[4+2] cycloadditions of alkynes or bis(pinacolatoboryl)alkenes
with biphenyl reactants including 2,2′ꢀhalogenated biphenyls,6 2ꢀ
Table 1 Intramolecular cyclization of 1aa.
biphenylmagnesium
bromide,7
2ꢀphenylbenzoylchloride,8
biphenyl tosylhydrazones9 and biphenyldiazonium salts10, were
also used for the synthesis of phenanthrenes. Phenanthrenes can
also be prepared by intramolecular cyclization of 2ꢀalkynyl
biphenyl compounds.11 Koning and coꢀworkers found that the
combination of KOtꢀBu/DMF and UV light irradiation could
promote the intramolecular cyclization of 2ꢀalkyl benzaldehydes
to give naphthalenes and phenanthrenes.12 In recent years, we
developed a series of KOtꢀBu/DMF promoted radical coupling
reactions of tertiary amines, amides with alkenes, alkynes and
ketones.13 In these reactions, KOtꢀBu/DMF can readily initiate
the formation of αꢀamino alkyl radicals without UVꢀlight
irradiation. We speculate that KOtꢀBu/DMF also promotes the
generation of diarylmethyl radicals. The subsequent reaction
with carbonyl compounds will provide an attractive method for
the synthesis of phenanthrenes. In this paper, we report an
efficient synthesis of phenanthrenes via intramolecular
entry
1c
2
3
4
5
6
7
8
solvent
base (equiv)
yieldb (%)
DMF
DMF
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOtꢀBu (3.0)
KOMe (3.0)
NaOMe (3.0)
KOH (3.0)
93
92
54
82
0
0
0
0
90
87
89
0
93
85
89
DMSO
DMA
THF
CH2Cl2
CH3CN
Dioxane
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
14
K2CO3 (3.0)
KOtꢀBu (1.0)
KOtꢀBu (0.5)
KOtꢀBu (1.0)
DMF
DMF
15d
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China. E-mail:
yanming@mail.sysu.edu.cn
a
Reaction conditions: 1a (0.2 mmol), base, solvent (2.0
b
mL), room temperature, argon atmosphere, 1 h. Isolated
yields. c Reaction was carried out at 90 °C. Reaction was
d
Electronic Supplementary
DOI: 10.1039/x0xx00000x
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(ESI)
available:
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carried out in the dark.
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Table 3 Intramolecular cyclization of substrates 3a-3ka.
dichloromethane, acetonitrile and dioxane are incompatible with
the reaction (Table 1, entries 5ꢀ8). The complete decomposition
of the substrate 1a was observed in these solvents, but no product
Table 2 Intramolecular cyclization of substrates 1a-1pa.
entry
R3
R4
product
yieldb
(%)
91
88
80
86
94
90
84
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeO
Ph
4a
4b
4c
4d
4e
4f
2ꢀMeꢀPh
4ꢀFꢀPh
4ꢀMeOꢀPh
4ꢀCF3ꢀPh
Me
entry
R1
R2
H
H
H
H
H
product
2a
yieldb (%)
1
2
3
4
5
6
Ph
93
70
81
73
87
50
cycloꢀPr
Ph
4g
4h
2ꢀMeꢀPh
3ꢀMeꢀPh
4ꢀMeOꢀPh
4ꢀFꢀPh
2b
65
2c
9
4i
81
2d
2e
10
11
4j
63
0
2f
4k
7
8
2g
2h
70
65
a
Reaction conditions: 3a-3k (0.2 mmol), KOtꢀBu (0.2 mmol),
DMF (2.0 mL), argon atmosphere, 80 oC, 1 h. b Isolated yields.
2a could be isolated from the reaction mixture. Other bases such
as KOMe, NaOMe and KOH are also applicable, but lower
yields were obtained (Table 1, entries 9ꢀ11). Weaker base such
as K2CO3 is completely inefficient (Table 1, entry 12). The effect
of KOtꢀBu loading was also examined. The excellent yield was
still kept even 1.0 equivalent of KOtꢀBu was used (Table 1, entry
13). The further decrease of KOtꢀBu loading led to a loss of yield
(Table 1, entry 14). A control experiment in the dark was carried
out. No substantial effect on the yield was observed (Table 1,
entry 15) .
9c
MeO
H
H
2i
33
21
83
86
80
94
10d
11
12
13
14
H
2j
Ph
5ꢀMe
4ꢀMeO
4ꢀCl
2k
2l
Ph
Ph
2m
2n
With the optimal reaction conditions in hand, a number of
1,1'ꢀbiphenylꢀ2ꢀcarbaldehyde derivatives were examined and the
results are summarized in Table 2. The substitution at the 2′ꢀ
benzyl group with 2ꢀmethyl, 3ꢀmethyl, 4ꢀmethoxy and 4ꢀfluoro is
tolerable, but lower yields were obtained (Table 2, entries 2ꢀ5).
The replacement of phenyl with vinyl, amino, and benzoxy are
also acceptable. The products 2fꢀ2h were obtained in moderate
yields (Table 2, entries 6ꢀ8). The replacement with methoxy
group led to a low yield (Table 2, entry 9). The reaction of
2'ꢀmethylꢀbiphenylꢀ2ꢀcarbaldehyde 2j gave phenanthrene in a
poor yield (Table 2, entry 10).12 The results implicate that the
activation of benzyl position with aryl or heteroatom substitution
is crucial. On the other hand, the substitution at the phenyl ring
with 5ꢀmethyl, 4ꢀmethoxy and 4ꢀchloro led to the slight loss of
yield (Table 2, entries 11ꢀ13). The reaction of 2ꢀnaphthyl derived
benzaldehyde 1n provided the expected product 2n in an
excellent yield (Table 2, entry 14). The substrates 1oꢀ1p with
heteroaryl backbones are also applicable. The corresponding
15
16
2o
2p
68
50
a Reaction conditions: 1aꢀ1p (0.2 mmol), KOtꢀBu (0.2 mmol),
b
DMF (2.0 mL), argon atmosphere, room temperature, 1 h.
Isolated yields. Reaction was carried out at 80 oC for 2 h.
c
d
Yield determined by 1H NMR.
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products were obtained in moderate yields (Table 2, entries 15ꢀ
16).
The reaction of 1,1'ꢀbiphenyl derived ketones were also
examined at an elevated reaction temperature and the results are
summarized in Table 3. To our delight, various diaryl ketones
and aryl alkyl keones are suitable substrates. The expected
phenanthrenes 4aꢀ4g were obtained in good yields (Table 3,
entries 1ꢀ7). Methoxy substituted ketones 3h provided the
product in a moderate yield (Table 3, entry 8). The reaction of
pyrrolidinꢀ2ꢀone derived substrate 3i gave the product 4i in a
good yield (Table 3, entry 9).
α, βꢀUnsaturated ketone is also
applicable. The 10ꢀstyrylphenanthrene 4j was obtained in a
moderate yield (Table 3, entry 10). The reaction of substrate 3k
did not afford the expected 1,2ꢀdiphenylꢀnaphthalene (Table 3,
entry 11). The 1,1'ꢀbiphenyl backbone seems to be necessary for
the reaction.
In 2009, Sliwka and coꢀworkers reported that the observation
of radical intermediates in the basic DMF and DMSO solution
via the EPR analysis.16 We examined the reaction of 1a in the
presence of radical scavengers BQ (benzoquinone) and DPPH
(1,1ꢀdiphenylꢀ2ꢀpicrylhydrazylradical). The reaction was found
to be inhibited significantly (Scheme 1). To further explore the
reaction mechanism, the EPR analysis of the solutions of KOtꢀ
Bu/DMF, 1a in KOtꢀBu/DMF and triphenylmethane in KOtꢀ
Bu/DMF, were carried out respectively (Figure 1). Weak EPR
signal was observed in the solution of KOtꢀBu/DMF. Strong
signal was observed in the solution of 1a in KOtꢀBu/DMF. More
intensive signal was found in the solution of triphenylmethane in
KOtꢀBu/DMF. The results approve the possible generations of
Scheme 2 Tentative reaction mechanism.
DMF radical, diphenylmethyl radical from substrate 1a, and
highly stable triphenylmethyl radical.
Based on our previous studies,13
a tentative reaction
mechanism is proposed in Scheme 2. DMF is deprotonated by
KOtꢀBu to give the carbamoyl anion. After a singleꢀelectron
transfer (SET) step, the carbamoyl radical A is generated. The
radical A abstracts a hydrogen from substrate 1a to generate
diaryl radical C. An intramolecular radical addition gives the
oxygen radical D. After the abstraction of a hydrogen from DMF
or 1a, the primary product E is formed. The subsequent
dehydration provides the final product 2a.17
Scheme 1 Controlled experiments with radical scavengers.
Conclusions
In summary, we have developed an efficient intramolecular
cyclization of 1,1'ꢀbiphenyl aldehydes or ketones promoted by
KOtꢀBu/DMF. The reaction could be carried out under mild
reaction conditions. A number of phenanthrenes were prepared in
moderate to good yields. A radical reaction pathway is proposed.
This finding provides a practical synthesis of phenanthrenes from
1,1'ꢀbiphenyl aldehydes or ketones.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21202208, 21172270, 21472248), Guangdong Engineering
Research Center of Chiral Drugs, and Major Scientific and
Technological Project of Guangdong Province (No.
2011A080300001) for the financial support of this study. We
Figure 1 EPR spectra, (a) KOtꢀBu/DMF; (b) 1a in KOtꢀBu/DMF;
(c) triphenylmethane in KOtꢀBu/DMF.
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also thank Mr. Guꢀping Hu at the department of chemistry, Sun 12 (a) C. B. de Koning, J. P. Michael and A. L. Rousseau,
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X. J. Zhang and M. Yan, J. Org. Chem., 2014, 79, 8557; (d) W.
T. Wei, Y. Liu, L. M. Ye, R, H. Lei, X. J. Zhang and M. Yan,
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