Synthesis of naphthalenes via platinum-catalyzed hydroarylation of aryl enynes?

Article abstract of DOI:10.1021/ol302437v

An efficient synthetic method of functionalized naphthalenes having hydrogen, alkyl, alkenyl, aryl, or heteroaryl groups on the 4-position and ethoxycarbonyl group on the 2-position was developed through selective Pt-catalyzed 6-endo intramolecular hydroa

Full text of DOI:10.1021/ol302437v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Naphthalenes via
Platinum-Catalyzed Hydroarylation
of Aryl Enynes†
Dongjin Kang, Jinsik Kim, Susung Oh, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
phlee@kangwon.ac.kr
Received September 2, 2012
ABSTRACT
An efficient synthetic method of functionalized naphthalenes having hydrogen, alkyl, alkenyl, aryl, or heteroaryl groups on the 4-position and
ethoxycarbonyl group on the 2-position was developed through selective Pt-catalyzed 6-endo intramolecular hydroarylation of ethyl (E)-2-ethynyl/
alkynyl cinnamates.
Transition-metal-catalyzed hydroarylation of alkynes
has quite recently emerged as an efficient and atom-economic
methodology for the construction of functionalized aro-
matic compounds and styrene derivatives.1 Moreover, the
importance of its intramolecular reaction has been widely
recognized as a possible approach to cyclic vinylarene
frameworks.2 Since Fujiwara et al. first reported transi-
tion-matal-catalyzed intramolecular hydroarylation of
alkynes in 2000,3 a large number of transition-metal cata-
lysts have been developed to date for this transformation.1,4
Research efforts have been focused on catalytic efficiency
and regioselectivity, whereas little attention has been paid
to the scope and types of performable substrates. Accord-
ingly, the development of new substrates in hydroaryla-
tion is as important as the transition-metal catalyst and
ligand for the synthesis of valuable organic compounds
such as annulated arene carbocycles and heterocycles.
† Dedicated to Prof. Kwan Soo Kim, Yonsei University, on the occasion of
his honorable retirement.
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r
10.1021/ol302437v
XXXX American Chemical Society

Until now, a variety of substrates having linkers such
as ethylene (ÀCH2CH2À),5 ester,6 N-tosyl,7 amide,8 ether,9
diethyl malonate,10 ynamide,11 and arene12 between the
arene and alkyne have been used in hydroarylation reactions
(Figure 1).
Scheme 1. Transition-Metal-Catalyzed Intramolecular Hydro-
arylation of Aryl Enynes
of new and efficient methodologies for the regioselective
synthesis of polysubstituted naphthalenes has attracted
much attention.15 In this regard, we envisioned that treat-
ment of ethyl (E)-2-alkynyl cinnamates with a variety of
catalysts would give naphthalenes. Moreover, because
there are two nucleophilic centers in ethyl (E)-2-alkynyl
cinnamates, we envisaged that a sharp reversal of the
selectivity or reaction pathway would be achieved by varing
the catalysts. Rossi et al. reported that 3-[l-(aryl)methyl-
idene]- and 3-(1-alkylidene)-3H-furan-2-ones have been
synthesized by cyclization of the corresponding (E)-2-
(1-alkynyl)-3-aryl/alkylpropenoic acids in the presence of
Ag- or Pd-catalysts.16 Although Burton et al. described
a synthetic method for synthesizing naphthalenes via
Sonogashira reaction of R-bromocinnamates followed
by electrocyclization of in situ generated allene intermedi-
ates, catalyzed by DBU, the reaction conditions are very
harsh (NMP, 200 °C).17 Also, because isomerization of
enynes to allenes is necessary to obtain hydroarylated
products, tert-butyl- or phenyl-substituted aryl enynes
did not produce naphthalenes. To overcome the inherent
problems of the previously reported method, and develop
a new reaction pathway to naphthalenes that depended
on variation of the catalyst, we describe herein our results
on the selective hydroarylation reaction of a number of
aryl enynes with Au- and Pt-catalysts (Scheme 1).
Figure 1. Substrates for intramolecular hydroarylation.
Recently, we developed a stereoselective synthetic method
for securing ethyl (E)-2-ethynyl/alkynyl cinnamates via
DABCO-catalyzed elimination, or a sequential Sonogashira
cross-coupling with allenyl acetates.13 Because polysubsti-
tuted naphthalenes have played an important role in the
chemical and pharmaceutical industries,14 the development
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We initiated our investigation using ethyl (E)-2-ethynyl
cinnamate 1a13 (Table 1). Although 1a did not react with
AuCl3 (5 mol %) and AgOTf (15 mol %), the hydroary-
lated product 2a was obtained in 20% yield in 6-endo mode
with AuCl3/AgOTf or Ph3PAuCl/AgBF4 (5 mol % each)
in the presence of trifluoromethanesulfonic acid (TfOH,
5 mol %) (entries 1À3). To check the possibility of cycliza-
tion by a protic acid, we attempted the cyclization in the pres-
ence of TfOH (1 equiv) and found that 2a was not produced
(entry 4). Pt(PPh4)4 (5 mol %) and PtCl2(PPh3)2 (5 mol %)
also did not give the cyclized product (entries 5 and 6), while
PtCl2 (5 mol %) provided 2a in 70% yield (entry 7). Of
the hydroarylation reactions screened, the best results were
obtained with PtCl4 (5 mol %) in toluene at 110 °C for
10 min, which selectively produced 2a (87%) (entry 8).
Toluene was the best solvent among the several examined
(toluene, DCM, acetonitrile, and DCE) (enties 8À11).
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to a wide range of
ethyl (E)-2-ethynyl cinnamate derivatives 1, and the results
Rubio, E.; Gonzalez, J. M. Chem. Commun. 2005, 2008. (b) Pastine, S. J.;
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Y.; Xu, J.; Burton, D. J. J. Org. Chem. 2006, 71, 7780.
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hedron 1999, 55, 8263.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Intramolecular Hydroarylation
Table 2. Pt-Catalyzed Intramolecular Hydroarylationa
cat.a
additive
temp time yield
entry
(mol %)
(mol %) solvent (°C)
(h)
(%)b
1
AuCl3/AgOTf
DCE
DCE
DCE
DCE
80
50
25
25
5
0
2
AuCl3/AgOTf
TfOH
TfOH
TfOH
5
20c
20c
0d
0
3
Ph3PAuCl/AgBF4
24
0.3
12
12
2
4
5
Pt(PPh4)4
PtCl2(PPh3)2
PtCl2
toluene 110
toluene 110
toluene 110
toluene 110
CH2Cl2 40
CH3CN 80
6
0
7
70
87
80
64
68
8
PtCl4
0.2
4.5
14
0.2
9
PtCl4
10
11
PtCl4
PtCl
DCE
80
a Au and Pt (5 mol % each) were used. AgOTf (15 mol %) and AgBF4
(5 mol %) were used. b Isolated yields. c TfOH (10 mol %) was used.
d TfOH (1 equiv) was used.
aresummarized inTable2. Varying the electron demandof
the substituents on the phenyl ring did not diminish the
efficiency of cyclization. Treatment of enyne 1b having an
acetoxy group on the phenyl ring with PtCl4 (5 mol %)
selectively gave the 6-endo hydroarylated product 2b in
74% yield after heating in toluene at 110 °C for 20 min
(entry 1). When aryl enyne 1c, having a 3-methoxy group,
was employed as the substrate, theoretically, there could
have been two possible products from two different cycli-
zation directions of the corresponding enyne. It was not
surprising therefore that ethyl 7-methoxy-2-naphthoate
2ca and 5-methoxy-2-naphthoate 2cb were obtained in
71% and 10% yields, respectively (entry 2). Under the
optimized reaction conditions, enyne 1d smoothly cyclized
to produce ethyl 5,7-dimethoxy-2-naphthoate 2d in 70%
yield (entry 3). In contrast, enyne 1e having a 3,4-methy-
lenedioxy group underwent cyclization to produce 6,7-
(methylenedioxy)naphthoate 2e in 75% yield as the sole
product, even though two products were possible (entry 4).
Moreover, cyclization proceeded smoothly counter-intuitively
with enynes having an electron-withdrawing group on the
phenyl ring. Aryl enynes 1fÀh having a chloride, bromide,
and iodide group gave the desired naphthalenes 2fÀh in
6-endo mode in good yields, without loss of halogen func-
tionality (entries 5À7). Electron-poor arenes possessing a
4-methoxycarbonyl group (1i) took part in the hydroaryla-
tion reaction, giving rise to the desired product 2i in 75%
yield (entry 8). When enyne 1j having a 2-furyl group was
subjected to the reaction conditions, 5-ethoxycarbonylben-
zofuran 2j was obtained in 67% yield (entry 9).
a Reactions were carried out with 5 mol % PtCl4 in toluene at 110 °C
within 30 min. b Isolated yields.
activities (Scheme 2).18 Under the optimum reaction con-
ditions, phenyl enyne having a 4-n-butylphenyl group on
the distal alkynyl carbon gave the cyclized product in 10%
yield. In addition, 3,5-dimethoxyphenyl enyne having a
4-ethoxycarbonylphenyl group provided a 23% yield in
toluene at 110 °C after 18 h. These results indicate that the
reactivity of hydroarylation of aryl enynes having an aryl
grouponthe distal alkynylcarbon is lower thanthat ofaryl
enynes 1 having a terminal alkynyl group. On the basis of
these results, we next turned our attention to the hydro-
arylation of 3,5-dimethoxyphenyl enynes bearing a phenyl,
aryl with electron-donating substituents, alkyl, or alkenyl
group on the distal alkynyl carbon. Gratifyingly, an aryl
enyne having a phenyl group underwent cyclization to
selectively produce the desired product 4a in 72% yield in
toluene at 110 °C after 3 h. The presence of the 4-n-butyl
With this new protocol developed, we subsequently
examined a variety of aryl enynes with internal alkynyl
groups instead of terminal ones for the Pt-catalyzed in-
tramolecular hydroarylation, because arylnaphthalene lig-
nans occur widely in nature and exhibit various biological
(18) (a) Foley, P.; Eghbali, N.; Anastas, P. T. J. Nat. Prod. 2010, 73,
811. (b) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75. (c) Ward, R. S. Nat.
Prod. Rep. 1995, 12, 183.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Pt-Catalyzed Intramolecular Hydroarylation of Aryl
Enynesa
Scheme 3. Plausible Reaction Mechanism
Scheme 4. Deuterium Incorporation in Pt-Catalyzed Hydro-
arylation
a Reactions were carried out with 5 mol % PtCl4 in toluene at 110 °C.
Addition of 10 mol % D2O to toluene provided 2a in 70%
yield with 57% d-incorporation, indicating that the present
reaction might proceed through activation of the alkyne by
the Pt-catalyst and that C might be formed (Scheme 4).
In summary, we have developed an efficient synthetic
method for securing functionalized naphthalenes with
hydrogen, alkyl, alkenyl, aryl, or heteroaryl groups on
the 4-position and an ethoxycarbonyl group on the 2-posi-
tion through Pt-catalyzed selective 6-endo hydroarylation
of ethyl (E)-2-ethynyl/alkynyl cinnamates. Of special im-
portance, because aryl enynes having a nonisomerizable
group on the distal alkynyl carbon were smoothly con-
verted to naphthalenes via Pt-catalyzed hydroarylation
incorporated deuterium, the present reaction likely pro-
ceeds via arylplatinum intermediates. This method could
pavethewaytosyntheticallyvaluableprocessesfor synthe-
sizing a wide range of naphthalene derivatives.
group had little effect on either the reaction rate (3 h) or the
product yield (4b, 73%). Likewise, aryl enynes having a
methoxyphenyl group on the distal alkynyl carbon effi-
ciently cyclized with 5 mol % PtCl4 to afford 4c and 4d in
70% and 72% yields, respectively. We were pleased to find
that a 3,5-dimethoxy enyne possessing a 4-tert-butyl-1-
cyclohexenyl group successfully engaged in the hydro-
arylation reaction. When a cyclization reaction was carried
out with an aryl enyne with a 2-thienyl in the presence of
5 mol % PtCl4, the desired naphthalene 4f was obtained
in 69% yield. Under the optimum reaction conditions,
3,5-dimethoxy enynes having an n-butyl or 3-phenylpropyl
group on the distal alkynyl carbon were smoothly converted
to the corresponding naphthalenes 4g and 4h. Chloride and
nitrile groups are tolerable in the Pt-catalyzed hydroaryla-
tion reaction. However, ethyl (E)-2-(1-hexyn-1-yl)cinnamate
was not cyclized even in the presence of TfOH.
Although the mechanism of the present reaction has not
been fully established, a possible pathway for intramo-
lecular Pt-catalyzed hydroarylation is shown in Scheme 3.
Because aryl enynes 1 and 3 cannot be isomerized to an
allene, the mechanism of the present reaction is different
from that of hydroarylation via isomerization of enynes to
allenes.17 Thus, the reaction would be initiated by activa-
tion of the alkynyl group by the Pt-catalyst and followed
by 6-endo cyclization to afford zwitterionic intermediate
arylplatinum B. Aromatization to arylplatinum C and sub-
sequent protonation would provide naphthalene 2 and 4.
Acknowledgment. This work was supported by the
NCRL (2012-0001245) and BRL program (2009-0087013)
funded by the National Research Foundation of Korea. We
thank Dr. Sung Hong Kim at the KBSI (Daegu) for
obtaining the HRMS data. P.H. thanks Profs. S. Chang
(KAIST) and E. J. Yoo (KNU) for helpful discussions.
Supporting Information Available. 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX