Iron-catalysed tandem cross-dehydrogenative coupling (CDC) of terminal allylic C(sp3) to C(sp2) of styrene and benzoannulation in the synthesis of polysubstituted naphthalenes

Article abstract of DOI:10.1039/c2cc17330a

A novel iron-catalysed tandem cross-dehydrogenative coupling and benzoannulation process was developed for the synthesis of biologically and synthetically important polysubstituted naphthalene derivatives from simple 1,2-aryl-propenes and styrenes in moderate to good yields. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17330a

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COMMUNICATION
Iron-catalysed tandem cross-dehydrogenative coupling (CDC) of terminal
allylic C(sp3) to C(sp2) of styrene and benzoannulation in the synthesis of
polysubstituted naphthalenesw
Hua Liu,a Li Cao,a Jia Sun,a John S. Fosseyab and Wei-Ping Deng*a
Received 24th November 2011, Accepted 12th January 2012
DOI: 10.1039/c2cc17330a
A novel iron-catalysed tandem cross-dehydrogenative coupling
and benzoannulation process was developed for the synthesis of
biologically and synthetically important polysubstituted naphthalene
derivatives from simple 1,2-aryl-propenes and styrenes in moderate
to good yields.
Since the pioneering work of Li and co-workers,1 the direct
formation of C–C bonds from different C–H bonds under
Fig. 1 Known CDC reactions of double activated sp3 C–H.
oxidative conditions, termed cross-dehydrogenative coupling
(CDC), has emerged as an exciting research area in organic
synthesis.2 The advantages of this strategy encompass high
efficiency and environmental benignancy by avoiding the use
of either organohalides/halide surrogates or organometallic
reagents. Electrophilic substrates for these CDC reactions
feature the presence of either heteroatoms (such as N, O and S)1,3
or aryl/vinyl groups a- to the C(sp3)–H4 to be oxidized and
coupled. C(sp3)–H bonds adjacent to nitrogen have been used
as the electrophilic components, with benzylic or allylic
C(sp3)–H bonds also attracting much attention due to their
importance in organic synthesis. For example, Li and co-workers
reported the first example of FeCl2-catalyzed selective CDC of a
benzylic C–H bond with 1,3-dicarbonyl compounds.4a Bao and
co-workers described a DDQ mediated oxidative coupling of
allylic C–H bonds with 1,3-dicarbonyl methylenic compounds.4b
Shi and co-workers reported the direct functionalisation of
benzylic C–H bonds with arene and vinyl acetates via iron-
catalysis.4c It is noteworthy that, in most cases, the benzylic
and allylic C–H bonds are doubly activated by diaryl (S-I) or
aryl/vinyl groups (S-II) (Fig. 1), which might facilitate the
formation of the active carbocation in the oxidative step. The
C–C bond formation via the oxidative activation of allylic
C–Hs without other activating components are mainly cyclic
alkenes,5 and those of an acyclic system have rarely been
reported.6 Recently, Shi and co-workers reported a direct allylic
alkylation via a Pd(II)-catalysed allylic C–H activation regime and
subsequent coupling with an active methylenic C–H bond. In their
system,7 exclusive terminal regioselectivities were observed when
allylbenzene (S-II) was used as a substrate, and 1-aryl-1-propene
(S-III) was completely inactive. Therefore, despite the success of
C–heteroatom coupling through oxidative allylic C–H activation
of monoactivated C–H bonds of 1-aryl-1-propene,8 C–C bond
formation via terminal allylic C–H (S-III) oxidative activation is
still an extremely attractive but challenging task.
Herein, a novel tandem cross-dehydrogenative coupling
(CDC) of terminal allylic C(sp3) to C(sp2) of styrene and
benzoannulation for the synthesis of polysubstituted naphthalenes
is described. To the best of our knowledge, this methodology
represents the first successful example of coupling of terminal allylic
C(sp3) to C(sp2) of styrene via unconventional reaction mode.
Initially, model substrate 1a with an allylic methyl group syn to
a 1-phenyl group was designed to test the possibility of terminal
allylic sp3 C–H activation. With 1a in hand, we planned to
explore direct intramolecular CDC through a Friedel–Crafts type
process to generate indene compound 2 upon allylic C–H bond
activation. To our surprise, however, 1a reacted smoothly in the
presence of 20 mol% FeCl3 to afford an unexpected product 3 in
41% yield, rather than the desired product 2 (Scheme 1).
A hypothetical reaction pathway was therefore proposed to
account for the formation of product 3 (see ESIw), which can
be considered as an iron-catalyzed CDC reaction of a mono-
activated allylic C–H bond with an alkene.4d,9 Encouraged by
this finding, we further speculated about the possibility for the
C–C bond coupling of in situ generated carbocation species with
simple styrene instead of 1a. Gratifyingly, when 1a (1.0 equiv.)
and styrene (1.5 equiv.) were mixed in nitromethane in the
presence of DDQ (2.0 equiv.) and FeCl3 (0.2 equiv.) at room
temperature, a polysubstituted naphthalene 6aa was obtained
in 68% yield instead of cyclopentene 3 (Scheme 2).
a School of Pharmacy and Shanghai Key Laboratory of Functional
Materials Chemistry, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: weiping_deng@ecust.edu.cn
b School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, B15 2TT, UK. E-mail: j.s.fossey@bham.ac.uk
w Electronic supplementary information (ESI) available: General
experimental procedure and the copies of 1H and 13C NMR for all
new products. See DOI: 10.1039/c2cc17330a
c
2674 Chem. Commun., 2012, 48, 2674–2676
This journal is The Royal Society of Chemistry 2012

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in the synthesis of both biologically active compounds and
p-conjugated functional materials.12
In order to understand the generality and scope of this
remarkable process, a systematic screening of reaction conditions
was performed which provided optimal reaction conditions as
follows: substrate 1 (1 eq.)/styrene (2 eq.)/DDQ (2.5 eq.)/FeCl3
(0.1 eq.)/CH3NO2/50 1C. Under these optimised reaction
conditions, polysubstituted naphthalene 6aa was obtained in
80% yield (see ESIw). Next, a series of substituted substrates
were investigated (Table 1). It was found that substrates with
strong electron-donating substituents on either Ar1 or Ar2
gave no product (entries 6 and 7), and other weakly electron-
donating and electron-withdrawing substituents on either Ar1
or Ar2 gave moderate to good yields of the corresponding
naphthalene (entries 2–5, 8 and 9). Moreover, substrates with
different substituents on Ar1 or Ar2 gave exclusive regioselectivity
of newly formed naphthalenes fused to the Ar2 group to afford
the corresponding products with the R2 group mostly at
position 6 of the naphthalene backbone (entries 2–4, 8 and 9).
However, the reaction of 1e with an electron-withdrawing
bromo substituent at the meta position was relatively
complicated and sluggish due to the ortho- and para-directing
deactivating bromine, affording a 1 : 1 mixture of ortho- and
para-product 6ea and 6ea0 in 56% of overall yield (entry 5).
Further investigation of substituent effects on both Ar1 and
Ar2 furnished the corresponding products in similar yields to
those of monosubstituted substrate 1 (entries 10–13). Interestingly,
it was found that substrates 1f and 1g with a para-methoxy
group on different aryl rings gave no desired product, the
reasons for this observation remain unclear. However, substrate
1m, bearing an electron-withdrawing bromo substituent on
Scheme 1 Model CDC reaction of 1a.
Scheme 2 The synthesis of naphthalene 6aa via a tandem CDC.
To the best of our knowledge, this is the first example of
tandem iron-catalyzed CDC10 of monoactivated allylic sp3
C–H with styrene to afford a polysubstituted naphthalene
skeleton. Although, many efforts have been made to develop
synthetic methods to access polysubstituted naphthalenes,11 most
synthetic methodologies involve rare/noble metal catalysts such as
Au, Rh, Ru, Pd, etc. and prefunctional starting materials such
as aryl halides, aryl boronates, aryl aldehyde, etc. Therefore,
efficient and practical synthetic protocols are still urgently
required to satisfy the increasing applications of naphthalenes
Table 1 The synthesis of naphthalenes 6 via a tandem CDC processa
Entry
Ar1/Ar2
R1
R2
Yieldb [%]
1
2
3
4
5
6
7
8
Ph, Ph (1a)
H (5a)
H
H
H
H
H
H
H
H
H
H
H
H
4-OMe (5b)
4-Me (5c)
4-Br (5d)
4-Cl (5e)
4-F (5f)
H
H
6-Me
6-Cl
6-Br
7-Br/5-Br
6-OMe
H
H
H
6-Br
80
66
70
61
56c
Ph, 4-MePh (1b)
Ph, 4-ClPh (1c)
Ph, 4-BrPh (1d)
Ph, 3-BrPh (1e)
Ph, 4-OMePh (1f)
4-OMePh, Ph (1g)
4-MePh, Ph (1h)
4-BrPh, Ph (1i)
4-MePh, 4-BrPh (1j)
4-BrPh, 4-MePh (1k)
4-BrPh, 4-BrPh (1l)
4-BrPh,3-Br-4-OMePh (1m)
Ph, Ph (1a)
e
—
—
e
70
63
67
9
10
11
12
13
14
15
16
17
18
19
6-Me
6-Br
6-OMe-7-Br/6-OMe-5-Br
62
62d
43c
e
—
H
H
H
H
H
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, 2-naphthyl (1n)
33
70
74
71
30
f
—
a
Optimised reaction conditions were employed as follows: substrate 1 (0.3 mmol)/styrene (0.6 mmol)/DDQ (0.75 mmol)/FeCl3 (0.03 mmol)/
b
c
d
CH3NO2 (2 mL)/50 1C. Isolated yield. A mixture of regioisomers (1 : 1) was obtained. The yield is calculated based on recovered starting
material. A mixture of unidentified products was observed. An anthracene derivative, 1-methyl-2,4-diphenylanthracene, was obtained.
e
f
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2674–2676 2675

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Notes and references
1 (a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810;
(b) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 6968;
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2 For recent reviews on cross-dehydrogenative coupling (CDC), see:
(a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335 and the references
therein; (b) C. J. Scheuermann, Chem.–Asian J., 2010, 5, 436;
(c) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215.
3 For selected examples of activation of sp3 C–H bond adjacent to
heteroatoms, see: (a) Y. Zhang and C.-J. Li, Angew. Chem., Int. Ed.,
2006, 45, 1949; (b) Z. Li, D. S. Bohle and C.-J. Li, Proc. Natl. Acad.
Sci. U. S. A., 2006, 103, 8928; (c) L. Zhao and C.-J. Li, Angew. Chem.,
Int. Ed., 2008, 47, 7075; (d) W. Tu, L. Liu and P. E. Floreancig,
Angew. Chem., Int. Ed., 2008, 47, 4184; (e) Z. Li, R. Yu and H. Li,
Angew. Chem., Int. Ed., 2008, 47, 7497; (f) H. Li, Z. He, X. Guo,
W. Li, X. Zhao and Z. Li, Org. Lett., 2009, 11, 4176; (g) C. M.
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5 (a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 56;
(b) D. Ramesh, U. Ramulu, S. Rajaram, P. Prabhakar and
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Fig. 2 Proposed reaction pathway for iron-catalysed tandem CDC.
each aryl ring, was found to give a mixture (1 : 1 ratio) of
products 6ma and 6ma0 in moderate yield (entry 13, 43% of
overall yield).
Next, a series of styrenes with either electron-withdrawing
or donating groups were investigated. Most styrenes afforded
the corresponding polysubstituted naphthalenes in moderate to
good yields (entries 15–18). Similar to methoxy containing
substrates 1f–g, styrene 5b bearing an electron-donating methoxy
group was also found to give no desired product (entry 14).
Gratifyingly, when substrate 1n was synthesised by replacing Ar2
with a naphthyl motif, and employed for this novel CDC process,
a trisubstituted anthracene derivative 6na was obtained in 30%
yield (entry 19).
7 S. Lin, C.-X. Song, G.-X. Cai, W.-H. Wang and Z.-J. Shi, J. Am.
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In order to understand the mechanism, this model reaction
was performed again with an additional 2.0 equiv. of TEMPO,
and the formation of 6aa was completely inhibited, which implies
that a radical species may be involved in this reaction (Fig. 2).
In conclusion, we have demonstrated a novel iron-catalysed
tandem cross-dehydrogenative coupling and benzoannulation
process for the synthesis of biologically and synthetically
important polysubstituted naphthalene derivatives from simple
1,2-aryl-propenes and styrenes in moderate to good yields. In
this system, a highly controlled reaction regioselectivity was
observed to give either cyclopentene or polysubstituted
naphthalenes as a result of including or excluding styrene.
Therefore, we believe that this new synthetic strategy will allow
access to various functionalised naphthalenes, anthracenes and
even more complicated aromatic ring systems, which would be
of great benefit to synthesis and materials science. Further
studies on the application of this protocol to the synthesis of
more complicated aromatic ring systems and their physical
properties are in the progress.
This work was supported by the Fundamental Research Funds
for the Central Universities, the Natural Science Foundation of
China (No. 21172068, 21050110426). We also thank Prof. Ning
Jiao and Shuli You for helpful discussion.
c
2676 Chem. Commun., 2012, 48, 2674–2676
This journal is The Royal Society of Chemistry 2012