One stone two birds: Construction of polysubstituted benzenes from the same starting material and precatalyst by switching the active sites of catalyst with different additives

Article abstract of DOI:10.1039/c1cc15835j

Two different tetrasubstituted benzenes were selectively constructed from the same starting materials by tuning the active sites of the Grubbs second generation catalyst (GC-II) with CuI or AgOTf as the additive.

Full text of DOI:10.1039/c1cc15835j

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COMMUNICATION
One stone two birds: construction of polysubstituted benzenes from the
same starting material and precatalyst by switching the active sites of
catalyst with different additivesw
Chun Feng,ab Xin Wang,b Bi-Qin Wang,*a Ke-Qing Zhao,*a Ping Hua and Zhang-Jie Shi*b
Received 20th September 2011, Accepted 10th November 2011
DOI: 10.1039/c1cc15835j
Two different tetrasubstituted benzenes were selectively constructed
from the same starting materials by tuning the active sites of the
Grubbs second generation catalyst (GC-II) with CuI or AgOTf as
the additive.
In previous studies, the enyne metathesis followed by Diels–
Alder cycloaddition and oxidation is a well-known strategy to
construct the core structure of benzene derivatives.7 With the
Grubbs(II) catalyst, the understanding of mechanism indicated
that the dissociation of phosphine ligand to release one co-
ordinating site is essential to initiate the enyne metathesis and
both carbene and Cl are spectator ligands to support the
catalyst to keep its reactivity and stability.8 Thus, proper
additives to assist the dissociation of PCy3 enhance the rate
of metathesis (path a). On the other hand, the assembly of two
alkynes and one alkene might also go through the oxidative
cyclometallation followed by the annulation in the presence
of stoichiometric or catalytic amount of transition metals.9
Various catalysts can promote such transformations10 while
Ru(II) species exhibited high catalytic ability.11 The intrinsic
understanding of this pathway implied that the requirement of
such an annulation by oxidative cyclometallation is two co-
ordinating sites of Ru center, which could interact with both
unsaturated species (path b). Therefore, we envisioned that
different additives result in completely different active species
from the same Grubbs-II catalyst with either one or two
coordinating sites and trigger different catalytic pathways to
produce structurally unique products (Scheme 1).
Polyfunctionalized arene is an important structural unit in
synthetic drugs and useful materials.1 In general, two strategies
have been considered to approach the construction of polysub-
stituted benzene. One is direct functionalization of existing benzene,
for example, classic Friedel–Crafts reaction2 and recently developed
transition-metal-catalyzed direct C–H functionalizations.3
The other one is the assembly of several small fragments to
construct the benzene core structure.4 Owing to this strategy,
transition-metal-mediated [2+2+2] annulation5 is one of the
most efficient and suitable methods with high atom and step
economy.6 Herein we demonstrated a new concept to construct
different polysubstituted benzenes from the same starting
materials and precatalysts. The catalytic pathways to produce
different products are triggered by different additives based on
the understanding of the catalyst structure and our rationale
design to switch the catalytic active sites (Scheme 1).
With the idea in mind, we started searching for an efficient
model to prove our concept (Table 1). The treatment of
diphenylacetylene (1a) with Grubbs-II catalyst in the absence
of additives gave the mixed product of 3a (22%) from enyne
metathesis and non-metathesis product 4a (48%) (Table 1,
entry 1). It was reasoned that two competitive pathways were
involved (paths a and b). In previous reports, Cu(I) salt was
considered as a good additive to facilitate the dissociation of
PCy3 in different transformations.12 To our delight, the proper
amount of CuI indeed promoted both the efficiency and selec-
tivity to produce 1,2,4,5-tetrasubstituted benzene 3a (entry 7),
which was produced through enyne metathesis/Diels–Alder
annulation/dehydro-genative oxidation sequence.
Scheme 1 Rational design to approach different products from the
same materials and precatalysts by switching the active sites.
a College of Chemistry and Material Sciences,
Sichuan Normal University, Chengdu, Sichuan 610066, China.
E-mail: wangbiqin1964@126.com; Fax: +86-28-84767868;
Tel: +86-28-84767868
Different Ag salts were further investigated to switch the
pathway. Only AgOTf showed the credible effect to tune the
reaction to the completely different direction and 1,2,3,4-tetra-
substituted benzene 4a was produced from the same starting
materials in good efficiency and exclusive selectivity (Table 1,
entry 17). Notably, the catalyst loading was increased to
15.0 mol% to approach the high efficacy. Moreover, the reaction
b 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
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15835j
c
356 Chem. Commun., 2012, 48, 356–358
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Table 1 Tunable pathway to produce different products from the
same starting materials
Table 2 CuI-promoted enyne metathesis–DA–oxidation sequence to
produce 1,2,4,5-polysubstituted benzenea
Grubbs II Additive
(mol%)
DMAD T/
(equiv.) 1C
4aa
Entry (mol%)
3aa (%) (%)
1
5.0
5.0
5.0
5.0
5.0
5.0
10.0
10.0
5.0
5.0
5.0
5.0
5.0
10.0
10.0
15.0
15.0
—
5
80
22
18
16
59
59
69
85
85
25
18
21
7
48
8
7
6
6
2b
3b
4b
5
CuCI (5.0)
CuBr (5.0)
CuI (2.5)
2.5
2.5
2.5
4.0
5.0
5.0
7.0
2.5
2.5
2.5
5.0
4.0
4.0
4.0
4.0
5.0
5.0
80
80
80
80
80
80
80
80
80
80
80
CuI (5.0)
6
7
8
CuI (10.0)
CuI (5.0)
CuI (5.0)
o5
5
5
5
7
6
25
42
58
62
55
71
75
9b
10
11
12
13
14
15
16
17c
AgCI (5.0)
AgBr (5.0)
AgOMs (5.0)
AgBF4 (5.0)
AgOTf (10.0)
AgOTf (20.0)
AgOTf (20.0)
AgOTf (30.0)
AgOTf (30.0)
AgOTf (30.0)
100 o5
100 o5
110 o5
110 o5
110 o5
110 o5
18c,d 15.0
The reactions were performed in a 0.125 mmol scale of 1a and 2.5 mL
b
toluene was used.a Isolated yield. 0.25 mmol 1a and 5 mL toluene
c
d
was used. Step 1: reaction time 12 h. 5 mL toluene was used.
temperature is also critical to promote the efficiency. Notably,
the formation of a cyclometallation product catalyzed by a
decomposition species of the precatalyst could not be rooted out.
Subsequently, we set out to test the different substrates for
the formation of polyfunctionalized benzenes (Table 2). In the
presence of CuI, various diarylacetylenes were tested and the
desired products 3 were produced in good to excellent yields.
Both symmetric and unsymmetric alkynes with either electron-
donating group or electron-withdrawing group are compatible.
The presence of halogen and O-containing groups offered a
great chance for further functionalizations.13 Notably, dialkyl-
acetylenes also showed great reactivity by using 5 mol%
Grubbs-II catalyst even in the absence of CuI. The presence
of an acetoxyl/benzyloxyl group at the propargylic position
produced benzylic functionalized polysubstituted benzene, which
could be further utilized to construct more complicated structures
and even fused ring systems.14 Starting from TMS-substituted
acetylene, the TMS group will be equipped at the formed
benzene ring, which also offered the potential for further
functionalization.15 Moreover, arylalkylacetylene is also a good
substrate (3q). Notably, 1,4-quinone is suitable as a partner,
which led to the polyfunctionalized naphthalene product (3r).
Different diarylacetylene derivatives were also submitted to
construct 1,2,3,4-tetrasubstituted benzene derivatives by tuning
the reaction pathway (Table 3). Both electronic (4a–4h) and
steric (4i and 4j) factors did not affect the efficiency obviously.
Similarly, C–X groups survived well (4d–4f and 4i), which could
be further transformed into different functionalities.13 Hetero-
cycles, for example thiophenyl group (4k), are suitable while the
efficiency is slightly decreased. Similarly, 1,4-quinone as a reac-
tion partner affords 1,4-naphthalenyldione as a product (4l).
a
b
Average isolated yields of at least two runs. The reactions were
carried out in the 0.125 mmol scale of 1 and 2.5 mL toluene was used.
c
The reactions were carried out in the 0.5 mmol scale of 1 with 5 mol%
d
Grubbs-2 in the absence of CuI and 5 mL toluene was used. DDQ
e
(1.2 equiv.), 100 1C, 24 h. 2 equivalent of 1,4-quinone was used.
Later on, preliminary mechanistic studies were conducted.
When the 2 : 1 mixture of Grubbs(II) catalyst and CuI was
stirred in toluene at room temperature, the in situ 31P NMR
studies indicated the slight shift of the corresponding complex
adducts, which might arise from the electronic similarity of the
complexes Ru-PCy3 and Cu-PCy3. However, the large shift of
31P NMR indicated the generation of new cationic Ru(II) com-
plexes B when the Grubbs(II) catalyst was treated with two
equivalents of AgOTf in toluene at 90 1C for 0.5 h (Scheme 2).16
We made full efforts to isolate the metallocyclopentene
intermediate C by heating diphenylacetylene (1a) and the active
species B under various conditions but finally failed. Notably,
the formation of C was indirectly proved by the subsequent
insertion of DMAD, followed by reductive elimination to
afford the corresponding cyclohexadiene D (Scheme 3).
In conclusion, we have demonstrated that the Grubbs(II)
catalyst serves as a precursor for two distinct annulation
reactions by a one stone, two birds strategy. By switching
the catalytic active sites with CuI or AgOTf, different multi-
functionalized benzene derivatives were selectively produced
from the same starting materials. Not only does this rational
design offer the efficient methods to construct a complicated
aromatic system, but also provided a conceptually new thinking
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Chem. Commun., 2012, 48, 356–358 357

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Table 3 AgOTf-promoted annulation to produce 1,2,3,4-polysubsti-
tuted benzenea
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a
All the reactions were carried out in the scale of 0.125 mmol of 1 and
the average isolated yields of at least two runs were reported.
b
5.0 equiv. of 1,4-quinone was used instead of DMAD.
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Scheme 2 The determination of the active species A and B in the
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about the current catalytic systems, which might lead to the
new discovery based on the same precatalyst. Further studies to
deliver such an efficient design to other systems are under way.
Support of this work by NSFC (No. 20872104, 21072140) is
gratefully acknowledged.
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16 For 31P NMR spectrum, see ESIw.
c
358 Chem. Commun., 2012, 48, 356–358
This journal is The Royal Society of Chemistry 2012