Neocuproine-KOtBu promoted intramolecular cross coupling to approach fused rings

Article abstract of DOI:10.1039/c1cc13907j

Polycycles can be produced with different linkages (A, B = O, N, C, S) by constructing biaryl C-C bonds via neocuproine-KO^tBu promoted cross coupling between C-Xs and C-Hs.

Full text of DOI:10.1039/c1cc13907j

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COMMUNICATION
Neocuproine–KOtBu promoted intramolecular cross coupling to approach
fused ringsw
Chang-Liang Sun,a Yi-Fan Gu,a Wei-Ping Huanga and Zhang-Jie Shi*ab
Received 30th June 2011, Accepted 20th July 2011
DOI: 10.1039/c1cc13907j
Polycycles can be produced with different linkages (A, B = O,
N, C, S) by constructing biaryl C–C bonds via neocuproine–KOtBu
promoted cross coupling between C–Xs and C–Hs.
of high toxicity. In 2008, Itami and co-workers first reported a
KOtBu-promoted intermolecular cross coupling of electron-
deficient nitrogen heterocycles with aryl iodides.6 Later on,
our and other groups reported transition-metal-free couplings
of arenes with aryl halides, respectively, which were promoted
by KOtBu together with a catalytic amount of phenanthroline
derivatives or DMEDA.7 Hayashi also reported a KOt
Bu-promoted coupling of aryl chlorides with styrenes.8 These
processes were proven to undergo a radical pathway,9 which
provides a new efficient and low-toxic process for the generation
of aryl radicals, which can be further utilized in the intra-
molecular aromatic substitution (Scheme 1). We started searching
for the proper conditions to realize such a reasonable goal.
6H-benzo[c]chromene was selected as the first target molecule
in our initiating investigation since it is a typical fused heterocycle
and broadly exists in many organic molecules. (2-Iodobenzyl)-
phenylether was prepared as the substrate 1a. Starting from
the conditions used in our previous report,7b we found the
desired cyclization product 6H-benzo[c]chromene 2a in the
product mixture, as well as a dehalogenative byproduct 3a
and another byproduct 4a via intermolecular aromatic
substitution with benzene. To inhibit the production of 4a, other
solvents were tested instead of benzene. However, among
different solvents, benzene was still the best to afford the
cyclization product in 75% yield (Table 1, entry 6). The
use of other solvents, such as toluene, mesitylene, dioxane,
diglyme, and DMF, gave a complete conversion of the 1a but
larger amounts of dehalogenative byproduct 3a were produced
(Table 1, entries 1–5).
Polycycles are fundamental scaffolds in organic compounds
and broadly exist in natural products, bioactive molecules and
synthetic drugs.1 The synthesis of polycyclic compounds has
been widely studied. Among the fused rings, fused-heterocyclic
compounds are of great importance and are broadly applied in
different aspects.2 Many methods have been developed to
build up the fused-heterocyclic compounds. In recent decades,
the most important strategy to approach heterocyclic fused
rings has been the transition-metal-catalyzed intramolecular
cross-coupling, especially the palladium-catalyzed intramolecular
coupling of carbon–hydrogen bonds and carbon–halogen
bonds (Scheme 1, path a).3 Besides, intramolecular homolytic
aromatic substitution (IHAS) with aryl radicals was an efficient
competitive method to synthesize such kinds of structures by
avoiding the use of late transition metal catalysts (Scheme 1,
path b).4 In recent years, a direct transition-metal-free intra-
molecular arylation of phenols was reported by Daugulis and
Bajracharya to afford 6H-benzo[c]chromenes presumably via a
benzyne pathway.5 In this communication, we systematically
reported a neocuproine–KOtBu promoted intramolecular
cross coupling to approach fused rings via an IHAS process.
In traditional intramolecular homolytic aromatic substitution,
aryl radicals were usually generated from aryl halides promoted
by AIBN and R3SnH or R3SiH, which have obvious drawbacks
Among different phenanthroline derivatives, neocuproine
(2,9-dimethyl-1,10-phenanthroline) was the most effective
(Table 1, entry 6) and bathophen (bathophenanthroline, 4,7-
diphenyl-1,10-phenanthroline) was also very efficient and 2a
was produced only in a slightly lower yield (Table 1, entry 8).
While 1,10-phenanthroline showed an obvious decrease in the
yield of 2a (Table 1, entry 7). The use of NO2-phen (5-nitro-1,10-
phenanthroline) caused a decomposition of the substrate and
only 12% of 2a was obtained (Table 1, entry 9). The use of
DMEDA, TMEDA and 2,20-bipyridine resulted in low
conversions of 1a (Table 1, entries 10–12). It was noteworthy
that all of these conditions could not completely suppress the
generation of two byproducts 3a and 4a.
Scheme 1 Two major strategies to construct fused-heterocyclic compounds.
a Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry and Green Chemistry
Center, Peking University, Beijing 100871, China.
E-mail: zshi@pku.edu.cn; Fax: +86 10-6276-0890;
Tel: +86 10-6276-0890
b State Key Laboratory of Organometallic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13907j
Under the conditions of entry 6 in Table 1, we tested
(2-iodobenzyl)arylethers bearing different substituents (Table 2).
c
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Chem. Commun., 2011, 47, 9813–9815 9813

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Table 1 Condition screening of the intramolecular radical
aromatic substitutiona
Table 2 Intramolecular radical aromatic substitution for 6H-
benzo[c]chromene derivativesa
Substrates
Productsb
R = H, X = I, 2a, 74%
X = Br, 2a, 64%
R = Me, X = I, 2b, 75%
X = Br, 2b, 65%
R = Bu, X= I, 2c, 82%
R = Ph, X = I, 2d, 63%
X = Br, 2d, 46%
Yield Yield Yield
Conversion of 2ab of 3ab of 4ab
t
Entry Ligand
Solvent
of 1ab (%) (%)
(%)
(%)
1
2
3
4
5
6
7
8
Neocuproine Toluene
499
47
30
25
19
21
75
62
72
12
16
9
40
62
72
66
74
11
7
—
—
—
—
—
13
13
R = F, X = I, 2e, 66%
X = Br, 2e, 68%
R = Cl, X = I, 2f, 71%
X = Br, 2f, 57%
Neocuproine Mesitylene 499
Neocuproine Dioxane 499
Neocuproine Dioxane 499
Neocuproine DMF
Neocuproine Benzene 499
Phen Benzene 499
Bathophen Benzene 499
499
R = OMe, X = I,
2g, o10%
R = Me, X = I, 2h, 60%
X = Br, 2h, 39%
R = Bn, X = I, 2i, 62%
8
15
9
NO2-phen
DMEDAc
TMEDAd
bipy
Benzene 499
o5
o5
o5
o5
o5
o5
o5
o5
o5
o5
10
11
12
13
Benzene
Benzene
Benzene
Benzene
o5
X = Br, 2i, 55%
18
13
o5
X = I, 2j, 51%
—
o5
o5
a
All the reactions were carried out on the scale of 0.5 mmol 1a; 0.5 equiv.
of ligands, 2.5 equiv. of KOtBu and 4 mL solvent were added in sealed
b
Schlenk tubes and the reactants were heated at 100 1C for 24 h. The
yields were GC yields with n-dodecane as the internal standard.
X = I, 2a, 62%
X = Br, 2a, 65%
c
d
DMEDA = N,N0-dimethylethylenediamine. TMEDA = N,N0-
tetramethylethylenediamine.
a
All the reactions were carried out on the scale of 0.5 mmol of 1 and
b
in 4 mL benzene at 100 1C for 24 h. The yields of all the products
were isolated yields.
(2-Iodobenzyl)(4-tolyl)ether, (2-iodobenzyl)(4-tert-butyl phenyl)-
ether, and (2-iodobenzyl)(4-biphenyl)ether gave the corresponding
product 6H-benzo[c]chromenes in high yields (2b, 2c and 2d).
Fluoro and chloro groups were tolerated well in this condition
and 2-fluoro 6H-benzo[c]chromene (2e) and 2-chloro 6H-
benzo[c]chromene (2f) were obtained in good yield. (2-Iodo-
benzyl)(2-tolyl)ether and (2-iodobenzyl)(2-benzylphenyl)ether also
underwent this process smoothly and afforded the corresponding
products (2h, 2i) in good efficacy. While (2-iodobenzyl)-
(2-anisyl)-ether did not work well in this condition and only
a trace amount was detected (2g). We considered that the
aromatic ring with two alkoxy groups was too electron-rich to
survive. (2-Bromobenzyl)(1-naphthyl)ether gave a b-cyclization
product in 51% yield (2j). When (2-iodophenyl)benzylether
was subjected to this reaction, the corresponding product 2a
could also be obtained in good yield. Aryl bromides were
further tested in the reaction. Compared with the corres-
ponding aryl iodides, most of the aryl bromides reacted in
relatively lower yields. These results indicated a lower reactivity
of aryl bromides in such an intramolecular radical aromatic
substitution process.
afforded the cyclization product 6H-benzo[c]thiochromene
(6b) in 63% yield. We also tried N-(2-iodobenzyl)aniline as
the substrate, however, the desired cyclization product 5,
6-dihydrophenanthridine (6c) was not obtained. It seems that
the unprotected secondary aniline could not survive in this
process. We further tried alkyl, phenyl and acyl protected
anilines. N-(2-Iodobenzyl)-N-methylaniline afforded the cycliza-
tion product N-methyl-5,6-dihydrophenanthridine (6d) in 78%
yield. While N-(2-iodobenzyl)-N-phenylpivalamide gave the
corresponding product 6e in 27% yield (1,10-phenanthroline
was used) and N-(2-iodobenzyl)-4-methyl-N-phenylbenzenesul-
fonamide gave no desired product 6f at all. Similarly, aryl
bromides could also be introduced in this process with slightly
lower yields. For example N-(2-bromobenzyl)-N-methylaniline
gave the cyclization product N-methyl-5,6-dihydrophenanthri-
dine (6d) in 76% yield. N,N-Dibenzyl-2-bromoaniline gave the
cyclization product 6g in 76% yield. Unfortunately, when phenyl
2-iodobenzoate was subjected to the reaction, no cyclization
product 6H-benzo[c]chromen-6-one (6h) was obtained and the
substrate was decomposed under these conditions.
We also tested various substrates for constructing other fused-
heterocyclic compounds (Table 3). From the 1-iodo-2-phenethyl-
benzene, the cyclization product 9,10-dihydrophananthrene (6a)
was obtained in 77% while the corresponding 1-bromo-
2-phenethylbenzene gave the same product in 65%. The sub-
strate benzyl(2-bromophenyl)sulfane could also work well and
Although 6H-benzo[c]chromen-6-one could not be synthesized
by this method, it can be easily obtained from the simple oxidation
of 6H-benzo[c]chromene. For example, when 6H-benzo[c]-
chromene (6a) was oxidized by PCC in CH2Cl2 at the reflux
c
9814 Chem. Commun., 2011, 47, 9813–9815
This journal is The Royal Society of Chemistry 2011

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Table 3 Intramolecular radical aromatic substitution for
other fused-heterocyclic compoundsa
Substrates
Productsb
X = I, 6a, 77%
X = Br, 6a, 65%
Scheme 2 A proposed mechanism of this process.
6b, 63%
examined to process this cyclization and different fused
heterocycles were built up in good to excellent yields. This
reaction provides a simple, efficient, transition-metal-free
method for the synthesis of fused-heterocyclic structures by
avoiding the use of transition metal catalysts. Further application
of this method is being explored in the lab.
X = I, R = H, 6c, o5%
X = Br, R = H, 6c, o5%
X = I, R = Me, 6d, 78%
X = Br, R = Me, 6d, 76%
X = I, R = Piv, 6e, 27%c
X = I, R = Ts, 6f, o5%
Notes and references
1 A. Bjoerseth, Handbook of Polycyclic Aromatic Hydrocarbons,
Marcel Dekker, New York, NY, 1983.
6g, 76%
2 T. Eicher and S. Hauptmann, The Chemistry of Heterocycles,
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X = I, 6h, o5%
X = Br, 6h, o5%
a
All the reactions were carried out on the scale of 0.5 mmol of 5 and in
b
4 mL benzene at 100 1C for 24 h. The yields of all the products were
isolated yields. 0.4 equiv. of 1,10-phenanthroline, instead of neo-
cuproine, was added in these reactions.
c
temperature, 6H-benzo[c]chromen-6-one was obtained in a
high yield (eqn (1)).10
ð1Þ
A possible mechanism is described in Scheme 2. The complex
of KOtBu with neocuproine is considered as a radical precursor.
After a single electron transfer (SET) process with substrate 1,
a radical anion 7 is generated, which further undergoes a
dehalogenation to generate an aryl radical 8 to initiate the
radical process. An intramolecular aromatic substitution of
aryl radical 8 occurs to produce a radical 9 or 10. The
formation of radical 9 is more favored than 10 since 5-exo
annulation is highly preferred to 6-endo in the radical cyclization
process. The thermodynamically stable radical 10 can be
formed via a rearrangement of radical 9. After a deprotona-
tion with the assistance of KOtBu, another radical anion 11 is
generated. Then a radical chain transfer9 occurs between 11
and substrate 1, resulting in the formation of final cyclization
product 2 and the regeneration of radical anion 7.
7 (a) W. Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He,
H. Wang, F. Y. Kwong and A. Lei, J. Am. Chem. Soc., 2010,
132, 16737; (b) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou,
X.-Y. Lu, K. Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat.
Chem., 2010, 2, 1044; (c) E. Shirakawa, K.-i. Itoh, T. Higashino
and T. Hayashi, J. Am. Chem. Soc., 2010, 132, 15537.
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2011, 50, 4671.
9 A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018.
10 W. R. Bowman, E. Mann and J. Parr, J. Chem. Soc., Perkin Trans.
1, 2000, 2991.
In conclusion, we successfully realized an intramolecular
radical substitution to construct 6H-benzo[c]chromene derivatives
and other fused-heterocyclic compounds.11 Various linkages were
11 When this manuscript was prepared, a report with similar results
appeared: D. S. Roman, Y. Takahashi and A. B. Charette, Org.
Lett., 2011, 13, 3242.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9813–9815 9815