Synthesis of Polysubstituted Polycyclic Aromatic Hydrocarbons by Gold-Catalyzed Cyclization-Oxidation of Alkylidenecyclopropane-Containing 1,5-Enynes

Article abstract of DOI:10.1021/acscatal.7b00784

A gold-catalyzed tandem cyclization-oxidation of alkylidenecyclopropane-containing 1,5-enynes with 3,5-dibromo-pyridine N-oxide via a noncarbene model was developed, providing a range of synthetically valuable and useful arylacetaldehyde derivatives in mo

Full text of DOI:10.1021/acscatal.7b00784

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Article
Synthesis of Polysubstituted Polycyclic Aromatic
Hydrocarbons by Gold-Catalyzed Cyclization-Oxidation
of Alkylidenecyclopropane (ACP)-containing 1,5-Enynes
Liu-Zhu Yu, Yin Wei, and Min Shi
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 16 May 2017
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Synthesis of Polysubstituted Polycyclic Aromatic Hydrocarbons by Gold-Catalyzed
Cyclization-Oxidation of Alkylidenecyclopropane (ACP)-containing 1,5-Enynes
LiuꢀZhu Yu,a Yin Wei,b and Min Shi*a,b,c
9
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East
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China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
bState Key Laboratory of Organometallic Chemistry, University of Chinese Academy of Science, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
cState Key Laboratory and Institute of Elementoꢀorganic Chemistry, Nankai University, Tianjin 300071, People’s Republic of
China
ABSTRACT:
cyclization-oxidation
A
gold-catalyzed
of alkylidenecyclopropane
tandem
(ACP)-containing 1,5-enynes with 3,5-dibromo-pyridine
N-oxide via non-carbene model has been developed,
providing a range of synthetically valuable and useful
arylacetaldehyde derivatives in moderate to good yields
without oxidation of alkynes. Moreover, the
corresponding aldehydes can be further transformed
into polycyclic aromatic hydrocarbons (PAHs) in the
presence of catalytic amount of Lewis acid In(OTf)3. The
reaction represents an example of gold-catalyzed
halide-free Kornblum-type oxidation through the
oxidation of cyclopropane moiety.
KEYWORDS: gold catalysis, non-carbene model, alkylidenecyclopropane (ACP)-containing 1,5-enynes,
3,5-dibromo-pyridine N-oxide, polycyclic aromatic hydrocarbons (PAHs)
NꢀO oxides at goldꢀπꢀalkynes,6 followed by XꢀH insertions
(X = C, N, O),7 cyclopropanations,8 and annulation
INTRODUCTION
reactions.9 However, the carbene model can be also
Polycyclic aromatic hydrocarbons (PAHs) with
interpreted that cyclization preferentially occurs to form
annulated aromatic ring have attracted considerable
cyclopropyl gold carbene, followed by Oꢀtransfer from
pyridine Nꢀoxide.10 On the other hand, goldꢀcatalyzed
attention owing to their fascinating structural features and
wide application in organic, optical, and electronic
cyclization of 1,nꢀenynes has emerged as a powerful
materials.1 Additionally, they have also proven to be active
transformation to construct molecular complexity in an
semiconductor materials that have been utilized extensively
atomꢀ and stepꢀeconomic manner,11 and goldꢀcatalyzed
in organic fieldꢀeffect transistors (OFETs) and organic
oxidation of enynes also attracted much attention. In most
lightꢀemitting diode application.2 Strategies for the
preparation of PAHs include thermolysis of prefunctional
precursors, oxidative photocyclization, DielsꢀAlder
cases, all these reactions were proposed to occur via a
carbene mechanism in which the αꢀcarbonylꢀcarbenoids A
and B were preferentially formed. For example, Liu’s
reactions and metalꢀcatalyzed crossꢀcoupling and
group reported two oxidationꢀcyclizations of 1,5ꢀenynes
cycloaddition reactions.3 However, most methods often
with 8ꢀmethylquinoline Nꢀoxide, in which the success
suffer from poor yields, narrow substrate scope, harsh
relies on the proposed prior oxidation of alkyne moiety
reaction conditions and multistep syntheses. Therefore, the
(Scheme 1a).8b Thereafter, Zhang’s group reported an
effective and convenient approaches to highly substituted
PAHs remain challenging and urgently pursued.
enantioselective
goldꢀcatalyzed
intramolecular
oxidationꢀcyclopropanation of 1,5ꢀenynes using a novel
P,Nꢀbidentate ligand (Scheme 1a).8f Moreover, Zhang’s
group also developed a goldꢀcatalyzed highly diastereoꢀ
and enantioselective tandem oxidationꢀcyclopropanation
sequence of 1,6ꢀenynes with pyridine Nꢀoxide or
Since Zhang and coꢀworkers reported their pioneering
work for the goldꢀcatalyzed oxidation of alkyne with
pyridine Nꢀoxides,4 the utilization of αꢀoxo gold carbenes
formed from goldꢀcatalyzed oxidation of alkynes with
either pyridine Nꢀoxides or nitrones to construct
uncommon and useful carboꢀ and heterocyclic frameworks
have been intensively investigated.5 In most cases, the
oxidation preferentially occurs by an attack of highly basic
8ꢀmethylquinoline
Nꢀoxide
to
provide
densely
functionalized bicyclo[3.1.0]hexanes (Scheme 1b).8a,e
Herein, we wish to report a different reaction pathway via
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nonꢀcarbene
model
using
electronꢀrich
3a could further be improved to 76% upon changing the
alkylidenecyclopropane (ACP)ꢀcontaining 1,5ꢀenynes,12 in
which the cyclization preferentially occurs to form
intermediate C, which also resonates with cyclopropyl gold
carbine,10a and followed by a Kornblumꢀtype oxidation,
rather than oxygen transfer to cyclopropyl gold carbene
using pyridine Nꢀoxide (Scheme 1c). The entire process
represents goldꢀcatalyzed halideꢀfree and baseꢀfree
Kornblum oxidation as compared to a classical one.13
During our preparation this manuscript, a similar oxidation
has been reported using pyridine Nꢀoxide under Brønsted
acid catalysis, in which the halonium ion intermediate was
coordinated anion of gold complex to SbF6 (Table 1, entry
2). Further catalyst screening revealed that both NHC
carbeneꢀligated and electronꢀdeficient phosphineꢀligated
cationic gold catalysts were detrimental to the reaction
efficiency (Table 1, entries 3 and 6). An obvious change
was observed when a sterically bulky phosphine ligand was
used: sterically hindered (JohnPhos)Au(NCMe)SbF6 and
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t
Me4 BuXPhosAu(NCMe)SbF6 further improved the yield
to 80% and 78% yields, respectively (Table 1, entries 4 and
5). With AgSbF6 as a sole catalyst, the reaction became
sluggish and even prolonged reaction time did not produce
significant amounts of 3a (Table 1, entry 7). Next, we
examined the reaction outcome of other pyridine Nꢀoxide,
and astonishingly, only trace amount of 3a was detectable
when commercially available 2b and 2c were used as the
oxidants (Table 1, entries 8 and 9). Solvent effect was also
investigated, and it was identified that toluene was better
than other solvents such as 1, 4ꢀdioxane, MeCN, and DCE
(Table 1, entries 10ꢀ12). Raising the reaction temperature
attacked by pyridine Nꢀoxide via
a Kornblumꢀtype
mechanism.14 Moreover, the obtained products can be
easily transformed to polycyclic aromatic hydrocarbons
(PAHs) in the presence of a Lewis acid.
a) Gold-catalyzed oxidation-cyclization of 1,5-enynes (Liu's and Zhang's works)
H
R1
R1
R2 R1
O
NR3R4
o
NR3R4
O
to 95 C could improve the yield to 92%, along with the
oxidation
cyclization
A
O
Y
Au
R2 R1
formation of thermally induced [3+2] cycloaddition
product 4a in 3% yield (Table 1, entry 13). However,
further raising the reaction temperature to 110 oC, the
isolated yield of 3a was reduced to 86% along with an
improved yield of 4a (Table 1, entry 14). Moreover,
thermally induced product 4a was obtained in good yields
if raising the temperature to 120 oC without pyridine
Nꢀoxide for 12 h. No reaction occurred in the absence of
the gold catalyst, and only 4a was obtained in 19% yield
(Table 1, entry 15).
H
X
R1
H
Au
Au
H
X = NR3R4 (to A)
X = H (to B)
O
B
O
b) Gold-catalyzed oxidation-cyclization 1,6-enynes (Zhang's work)
O
Y
AuO
R2
R1
O
X
O
X
R1
R1
H
cyclization
oxidation
R2
O
O
R3
A
X
R3
R4
R4
X = N, O, C
c) Gold-catalyzed cyclization-oxidation of ACP-containing 1,5-enynes (This work)
R2
R2
O
Y
R2
OHC
R1
Au
Table 1. Optimization of reaction conditionsa
oxidation
R1
Au
cyclization
R1
Base-free !
Halide-free !
R3
R3
R2 = aryl
R3
C
a gold-catalyzed non-carbene process !
excellent chemoselectivities without oxidation of alkyne
access to polysubstituted arylacetaldehyde
broad substrate scope and functional group tolerance
further transformation into PAHs
Polycyclic aromatic
hydrocarbons (PAHs)
entry
catalyst
PPh3AuNTf2
Nꢀoxide solvent
yield
(%)b
70
Classical Kornblum-oxidation
1
2
3
2a
2a
2a
DCE
DCE
DCE
YX
O
X
Y
O
O
[Ag]
Y
n
n
n
R
R
R
Base
X = Halide
PPh3AuSbF6
76
54
H
X
Base
IPrAuSbF6
Scheme 1. Carbene vs nonꢀcarbene model.
4
5
6
(JohnPhos)Au(NCMe)SbF6
Me4 BuXPhosAu(NCMe)SbF6
2a
2a
2a
DCE
DCE
DCE
80
78
64
t
RESULTS AND DISCUSSION
(ArO)3PAuSbF6
AgSbF6
7c
2a
DCE
trace
Our studies commenced with easily available
1ꢀ(cyclopropylidene(phenyl)methyl)ꢀ2ꢀ(phenylethynyl)ben
zene 1a (0.15 mmol, 1.0 equiv) as the test substrate,
3,5ꢀdibromopyridineꢀNꢀoxide (1.5 equiv) as an oxidation
8
9
10
(JohnPhos)Au(NCMe)SbF6
(JohnPhos)Au(NCMe)SbF6
(JohnPhos)Au(NCMe)SbF6
2b
2c
2a
DCE
DCE
1,4ꢀdio
xane
trace
trace
47
reagent,
1,2ꢀdichloroethane (DCE) (1.5 mL) at 80 C under argon
atmosphere for h, giving the desired
and
PPh3AuNTf2
(0.05
equiv)
in
o
11
12
(JohnPhos)Au(NCMe)SbF6
(JohnPhos)Au(NCMe)SbF6
(JohnPhos)Au(NCMe)SbF6
(JohnPhos)Au(NCMe)SbF6
ꢀ
2a
2a
2a
2a
2a
toluene
MeCN
toluene
toluene
toluene
84
50
92 (3)
86 (8)
N D
8
13d e
14f,g
15d,e,h
2ꢀnaphthylacetaldehyde 3a in 70% yield without the
oxidation of alkyne (Table 1, entry 1). The isolated yield of
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a
All the reactions were carried out on a 0.15 mmol scale in
solvent (0.15 mL) at 80 oC for 8 h unless otherwise specified.
b
c
Isolated yield of 3a and 4a (in parentheses). The reaction
d
o
e
f
o
g
was carried out for 48 h. At 95 C. For 4 h. At 110 C.
For
9
h
2
h.
4a was isolated in 19% yield. Ar
=
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2,4ꢀdiꢀtertꢀbutylphenyl. DCE = 1,2ꢀdichloroethane.
Br
Br
N
N
O
2c
N
O
2b
O
2a
Having established the optimal reaction conditions, we
began to investigate the substrate scope of
orthoꢀalkynylarylꢀsubstituted
alkylidenecyclopropanes
(ACPs) carefully and the results are shown in Table 2.
When R1 is an aryl group, a variety of arylalkynes were
compatible and the reactions proceeded smoothly to furnish
the corresponding naphthylacetaldehydes 3aꢀ3g in good
yields ranging from 81% to 92% yield, accompanied by the
formation of thermally induced [3+2] cycloaddition
n
products in less than 3% yield. Cyclopropyl and butyl
alkynes were also compatible under the optimum
conditions, thus delivering 3h and 3i in 84% and 76%
yields, respectively. Moreover, thienyl alkyne 1j and
naphthyl alkyne 1k were also tolerable, thereby giving
products 3j and 3k in 83% and 86% yields, respectively.
Then, we examined the electronic effect and steric
hindrance of R2, when it was an aryl group:
metaꢀmethylꢀsubstituted and orthoꢀmethylꢀsubstituted
substrates 1l and 1m performed very well, affording 3k and
3m in good yields. However, the paraꢀsubstituted
naphthylacetaldehydes were not stable when they were
purified by silica gel flash chromatography. Thus the
corresponding alcohols were synthesized after oneꢀpot
treatment of the formed aldehydes with 2.0 equivalents of
NaBH4. All the reactions proceeded smoothly to furnish the
desired alcohols 3n’ꢀ3s’ in 70ꢀ84% yields regardless of
whether they have electronꢀrich or electronꢀdeficient
aromatic ring. Substrate 1t, replacing aryl group with a
methyl group, could also afford the corresponding aldehyde
3t in 87% yield. As for thienyl groupꢀsubstituted substrate
1v, the corresponding product 3v’ was also formed, albeit
in 36% yield. However, when R2 was nonꢀsubstituted, the
reaction system became complex, probably because of the
lower stability of carbocationic intermediate. Changing R3
to OMe group or Cl atom, the reactions still worked
efficiently and the products 3wꢀ3y were isolated in good
yields as well. Both phenyl rings substituted substrate 1z
was also tolerable, affording 3z in 81% yield. Finally, the
three annelated aldehyde 3A was also obtained in 93%
yield using naphthaleneꢀlinked substrate 1A. The structure
of 3w was confirmed by single crystal Xꢀray analysis.15
Next, we further investigated the substrate scope of this
thermally induced [3+2] cycloaddition reaction using a
series
of
orthoꢀalkynylarylꢀsubstituted
alkylidenecyclopropanes in toluene at 120 oC, and the
results are shown in Table 3. To our delight, the electronic
effect had no obvious effect on the reaction outcome and
the corresponding products 4a to 4B were obtained in
70ꢀ91% yields. To be noted, the thienyl group substituted
substrates 1j and 1v were also tolerable without erosion of
heterocyclic subunit, delivering the corresponding products
4j and 4v in 70% and 91% yields, respectively. However,
when R2 was nonꢀsubstituted, the reaction became sluggish.
Moreover, trimethylsilyl group protected substrate and
terminal alkyne substituted substrate gave the same product
4B in 64% and 52% yields in the presence of gold catalyst,
respectively. The structure of 4v has been also confirmed
by single crystal Xꢀray analysis.16
Table 2. Substrate scope for goldꢀcatalyzed
cyclizationꢀoxidation of ACPꢀcontaining enynesa,b
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Table 3. Substrate scope for thermally induced [3+2]
cycloaddition of 1a,b
Table 4. Substrate scope for In(OTf)3ꢀcatalyzed synthesis
of PAHs from 3a,b
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With
a
diverse
range
of
functionalized
naphthylacetaldehydes in hand, we then embarked on their
transformation into polycyclic aromatic hydrocarbons and
the results are shown in Table 4. Gratifyingly, a series of
tetraphenes 5 containing fourꢀfused aromatic rings were
readily prepared in the presence of catalytic amount of
o
Lewis acid In(OTf)3 (5 mol%) at 50 C in DCE from
naphthylacetaldehydes 3. Both electronꢀrich and
electronꢀdeficient substrates were compatible, thus
affording the corresponding annulated PAHs 5aꢀ5A in
84%ꢀ94%
yields.
Notably,
as
for
the
metaꢀmethylꢀsubstituted substrate 3l,
a
couple of
regioisomers were formed in 10:1 ratio, in which the
cyclization preferentially occurred at less hindered position
in 84% total yield, and heteroacene 5j and disubstituted
acene 5z were also obtained in 94% and 92% yields,
respectively. Moreover, the five annelated PAHs
benzo[a]tetraphene 5k and benzo[a]tetracene 5A were also
obtained at 80 oC in 67% and 53% yields, respectively. The
structures of 5a and 5b were confirmed by single crystal
Xꢀray analysis.17 It should be stressed here that product 5a
was exclusively obtained and another possible annulated
product 5a’ was not detected (Scheme 2).
Scheme 2. Rationalization of product selectivity
In order to account for why only product 5 was
exclusively obtained, we have done DFT calculations to
investigate the formation of product 5a and another
possible product 5a’. All DFT calculations were performed
with Gaussian 09 program.18 The reaction energy profiles
are depicted in Scheme 3. To be noted, all the intermediates
are hexaꢀcoordinated. Initially, coordination of In(OTf)3
catalyst to the substrate 3a generates complex Int1. The
complex Int1 undergoes a ketoꢀenol tautomerization to
give an enol intermediate Int2 via transition state TS1.
Subsequently, the intermediate Int2 can undergo two
possible reaction pathways to obtain products 5a or 5a’. In
Path 1, passing through TS2 with an energy barrier of 57.5
kcal/mol, the annulated intermediate Int3 is located, which
undergoes the Hꢀshift, leading to the product complex Int4.
In Path 2, passing through TS2’ with an energy barrier of
58.2 kcal/mol, the annulated intermediate Int3’ is located,
which undergoes the Hꢀshift, leading to the product
complex Int4’. The product complex Int4 is more stable
than the Int4’ by 6.3 kcal/mol. Kinetically, the Path 1 is
slightly favorable than the Path 2. The calculation results
indicate that the product 5a is thermodynamically favorable
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O
product, which may account for why it is obtained
exclusively in experiments (For details, see Scheme S1 in
the Supporting Information).
Br
N
O
Pd2(dba)3, XantPhos, Cs2CO3
+
toluene, 100 o
63%
C
N
H
7
8
9
5r, 0.2 mmol
6, Antitumor agent
TfO
HO
MeO
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Tf2
O
BBr3
CH2Cl2, 0 oC to rt
89%
CH2Cl2, 0 oC to rt
94%
5p
HOOC
MeOOC
Pd(OAc)2, CO, MeOH
DIPEA, DMSO, 80 o
86%
LiOH (aq)
THF/MeOH, rt
64%
C
O
N
7
NH
8, Anti-infective agent
Anti-inflammatory agent
Antitumor agent
Ref. [17]
Scheme 5. Further transformation to bioactive molecules
Scheme 3. DFT studies on the formation 5a
To demonstrate the necessity of the strained small ring,
two control experiments using 1,5ꢀenynes 9 and 11 having
no cyclopropane moiety were conducted under the
optimum reaction conditions, the desired aldehydes were
not formed. Instead, polysubstituted naphthalenes 1022 and
12 were furnished in excellent yields without the
involvement of 3, 5ꢀdibromoꢀpyridine Nꢀoxide, revealing
Furthermore, we also investigated oneꢀpot synthesis of
PAHs from the ACPꢀcontaining 1,5ꢀenynes with
3,5ꢀdibromoꢀpyridine Nꢀoxide. However, initial attempt
was not successful when Lewis acid catalyst In(OTf)3 was
added directly or used stepwise. We wondered the Lewis
acid was poisoned by coordinating with the formed
3,5ꢀdibromoꢀpyridine.4,8d Indeed, when the reaction
mixture was treated with methanesulfonic acid (1.5 equiv),4
oneꢀpot synthesis of PAHs 5 was realized (for details, see
Scheme S2 in the Supporting Information). Several PAHs
were also synthesized in a oneꢀpot manner in 62%ꢀ78%
yields (Scheme 4). The whole process represents
goldꢀcatalyzed oxidative dehydrogenation reaction of
ACPꢀcontaining 1,5ꢀenynes with 3,5ꢀdibromoꢀpyridine
Nꢀoxide for synthesis of PAHs.
that
cyclopropane
was
essential
for
this
cyclizationꢀoxidation sequence (Scheme 6). Furthermore,
the corresponding byproduct 3,5ꢀdibromoꢀpyridine was
also detected and characterized by GC/MS analysis (for the
details, see Scheme S3 in the Supporting Information).
Scheme 4. Oneꢀpot synthesis of PAHs 5
To further illustrate the synthetic value of this method,
two bioactive polycyclic molecules were prepared using
oneꢀpot prepared tetraphenes (Scheme 5). Antitumor 619
was obtained in 63% yield utilizing BuchwaldꢀHartwig
amination conditions. Compound 8, which exhibited
Scheme 6. Control experiments
On the basis of the previous reports on goldꢀcatalyzed
enynes cyclization5,11 and the mechanism of Kornblum
oxidation,13 a plausible mechanism is outlined in Scheme 7.
Initially, coordination of cationic AuI complex to the
alkyne moiety of 1a forms intermediate I, followed by a
6ꢀendoꢀdig cyclization to give intermediate II, because
benzene ring and electronꢀrich cyclopropane can stabilize
the formed carbon cation.12,23 Then intermediate II is
combined with external 3,5ꢀdibromoꢀpyridine Nꢀoxide to
antiꢀinfective,
antiꢀinflammatory,
and
antitumor
activities,20 could also be obtained using linear multistep
synthesis after condensation of the corresponding
carboxylic acid 7 (for details, see Scheme S3 in the
Supporting Information).21
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form a reactant complex III, which leads to ringꢀopening of
ORCID
ACP to form intermediate IV (electrophilically assisted
nucleophilic ring opening).24 Finally, deprotonation
Min Shi: 0000-0002-3747-5830
utilizing
the
released
3,5ꢀdibromoꢀpyridine
and
Notes
protodeauration sequence occur, thus furnishing the desired
naphthylacetaldehyde 3a.
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Ph
We are grateful for the financial support from the National
Basic Research Program of China (973)ꢀ2015CB856603,
the Strategic Priority Research Program of the Chinese
Academy of Sciences, Grant No. XDB20000000, the
National Natural Science Foundation of China (20472096,
21372241, 21572052, 20672127, 21421091, 21372250,
21121062, 21302203, and 20732008) and the Fundamental
Ph
AuL+
Ph
AuL
2a
Br
I
II
1a
Br
N
Ph
O
AuL+
3a + 3,5-dibromo-pyridine
Br
AuL
Ph
Research
Funds
for
the
Central
Universities
222201717003.
CHO
Ph
Br
Br
Br
N
O
III
REFERENCES
N
AuL
Ph
H
H
Ph
Ph
AuL
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V
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Scheme 7. A plausible mechanism for goldꢀcatalyzed
cyclizationꢀoxidation of ACPꢀcontaining 1,5ꢀenynes
CONCLUSION
In summary, we have disclosed a goldꢀcatalyzed
cycloisomerization and halideꢀfree Kornblum oxidation of
ACPꢀcontaining 1,5ꢀenynes with 3,5ꢀdibromoꢀpyridine
Nꢀoxide, providing a convenient access to functionalized
2ꢀnaphthylacetaldehydes, which are further transformed
into four/five annelated PAHs in the presence of Lewis
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acscatal.
1
Experimental procedures, characterization data, and H and
13C NMR spectra for new compounds (PDF).
Xꢀray data (CIF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for M.S.: mshi@mail.sioc.ac.cn.
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