Synthesis of substituted azulenes via Pt(II)-Catalyzed ring-expanding cycloisomerization

Article abstract of DOI:10.1021/ol502270q

Substituted azulenes, valuable structures for electronic devices and pharmaceuticals, have been synthesized by the platinum(II)-catalyzed intramolecular ring-expanding cycloisomerization of 1-en-3-yne with ortho-disubstituted benzene. This novel method provides an alternative route for the efficient synthesis of substituted azulenes. The reaction mechanism of selected catalytic transformations was explored using density functional calculations.

Full text of DOI:10.1021/ol502270q

Letter
pubs.acs.org/OrgLett
Synthesis of Substituted Azulenes via Pt(II)-Catalyzed Ring-
Expanding Cycloisomerization
Kazuteru Usui,* Kensuke Tanoue, Kosuke Yamamoto, Takashi Shimizu, and Hiroshi Suemune*
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
S
* Supporting Information
ABSTRACT: Substituted azulenes, valuable structures for electronic devices and
pharmaceuticals, have been synthesized by the platinum(II)-catalyzed intra-
molecular ring-expanding cycloisomerization of 1-en-3-yne with ortho-disub-
stituted benzene. This novel method provides an alternative route for the efficient
synthesis of substituted azulenes. The reaction mechanism of selected catalytic
transformations was explored using density functional calculations.
zulene (C10H8) and its derivatives, which are brilliant blue
nonbenzenoid aromatic hydrocarbons, have attracted
expansion.7a,11 Finally, a subsequent [1,2]-H shift of D could
afford substituted azulene F (Scheme 1). This is a rare example
A
much attention because of their remarkable electronic and
optical properties. Significantly, azulene exhibits a large dipole
moment (1.08 D) due to its ability to shift electron density
from the seven-membered ring toward the five-membered
ring.1 Hence, azulene possesses a donor−acceptor character
that may be exploited in advanced functional electronic,
optoelectronic, and electrochromic devices.2 Azulenes have
also been utilized as building blocks for a broad range of
pharmaceutically active compounds. Some synthetic azulene
analogues possess antioxidative,3 anticancer,4 and anti-inflam-
matory activities.5 Because of the wide variety of applications,
the development of a simple and efficient synthesis of azulene
derivatives would be very useful.
Scheme 1. Synthetic Strategy for the Construction of
Substituted Azulenes
Traditional methods for the construction of an azulene
scaffold include long, low-yielding synthetic procedures that in
many cases do not afford the desired substitution patterns.6
Although sophisticated synthetic methodologies for the
introduction of functional groups on the seven-membered
ring have been reported recently,6a,7 it is imperative to develop
facile synthetic methods for novel substitution motifs in order
to extend the applications of azulenes.
π-Acidic, metal-catalyzed skeletal rearrangements of alkyne
derivatives have attracted considerable attention as efficient
methods to facilitate the atom-economical construction of
complex molecules.8 Matsuda and co-workers reported the
synthesis of azulenophenanthrenes by the platinum-catalyzed
skeletal rearrangement of 2,2′-di(arylethynyl)biphenyls.9 We
recently reported that azulene-fused helicenes are formed as a
minor product through the synthetic study of 1-functionalized
[5]helicenes by Pt(II)- catalyzed cycloisomerization, presum-
ably via a cyclopropyl platinum carbene intermediate.10
Therefore, we sought to develop a new strategy toward the
construction of azulene skeletons by Pt(II)-catalyzed cyclo-
isomerization. We envisioned that substrate A, with an ortho-
disubstituted benzene bearing a lateral 1-en-3-yne unit, could
undergo Pt(II)-catalyzed cyclization of the ipso-carbon on the
phenyl ring to produce C. Cyclopropyl platinum carbene C
of a Pt(II)-induced intramolecular ipso-cyclization of an 1-en-3-
yne. In this paper, we describe the successful realization of this
concept, the Pt(II)-catalyzed ring expanding cycloisomerization
of 1 to give substituent azulene derivative 2. To our knowledge,
this is the first Pt(II)-catalyzed ring-expanding cycloisomeriza-
tion method to prepare substituted azulenes.
As a model for this study, easily accessible substrate 1a with
an embedded 1-en-3-yne moiety was subjected to Pt(II)-
catalyzed cycloisomerization (Table 1). In the presence of
PtCl2 (10 mol %) or PtCl4 (10 mol %),12 the reaction of 1a
proceeded at 80 °C in toluene to give the desired 5,9-dimethyl-
1,2,3,4-tetrahydrobenzo[a]azulene 2a in low yield (entries 1
and 2).7d,13 Use of PtCl2(H2O) slightly increased the yield
(28%, entry 3).14 Treatment of 1a with PtCl2 (10 mol %)
under an atmosphere of CO (1 atm)15 led to an improved yield
of 2a (56%, entry 4). Next, the influence of phosphane ligands
(2 equiv compared to PtCl2) such as PPh3, P-t-Bu3, P(OPh)3,
Received: July 31, 2014
could yield D with a 7-memberd ring through a Buchner ring
̈
© XXXX American Chemical Society
A
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Organic Letters
Letter
Table 1. Cycloisomerization of 1a: Investigation of Reaction
Conditions
Scheme 2. Scope of the Platinum(II)-Catalyzed Ring-
a
a
Expanding Cyclisomerization
b
yield (%)
entry
catalyst
PtCl2
additive
none
none
2a
1a
1
2
3
4
5
6
7
8
17
18
28
56
5
PtCl4
c
PtCl2
H2O
PtCl2
CO (1 atm)
PPh3
PtBu3
PtCl2
45
84
PtCl2
16
PtCl2
P(OPh)3
P(C6F5)3
COD
trace
d
PtCl2
93 (86)
e
9
PtCl2
37
23
47
<1
46
19
f
10
[PtCl2(C2H4)]2
[PtCl2(C2H4)]2
none
f
11
P(C6F5)3
a
Reaction conditions: reaction was performed with 1a (0.38 mmol)
and Pt catalyst (10 mol %) in toluene (1.5 mL) at 80 °C for 12 h.
b
c
Yield of isolated product. Reaction was performed in wet toluene.
d
e
Yield in parentheses refers to the ratio of Pt:ligand = 1:1. Reaction
f
carried out for 12 h at room temperature. The catalyst loading was 5
mol %. Reaction carried out for 1 h at room temperature. COD = 1,5-
cyclooctadiene.
and P(C6F5)3 was examined (entries 5−8). In contrast to the
phosphane-free conditions (entries 1−3), the reaction was
retarded and gave diminished yields (entries 5−7). Interest-
ingly, the addition of strongly π-accepting ancillary phosphine
ligand P(C6F5)3 led to a drastic increase in the yield of 2a to
93% (entry 8).16 The use of COD as an additive gave 2a at
room temperature, but in a poor yield (37%, entry 9). Although
the use of Zeise’s dimer ([PtCl2(C2H4)]2) by itself was
ineffective (entry 10), the combination of Zeise’s dimer and
catalytic amounts of P(C6F5)3 (2 equiv, based on monomeric
Pt) improved the yield of the reaction (47%, entry 11). Thus,
the use of PtCl2 (10 mol %) and P(C6F5)3 in toluene at 80 °C
was found to be the most efficient and was subsequently used
as the standard condition.
a
b
Isolated yield. 58% of 1h was recovered.
With the optimized reaction conditions in hand, we screened
the scope of alkynes for the cycloisomerization (Scheme 2).17
A
variety of derivatives bearing different substituents at the ortho-
position of the phenyl ring (R1 = R3 = Et, R2 = H (1b), R1 = R3
= OMe, R2 = H (1c), R1 = R2 = R3 = Me (1d)) were well-
tolerated, affording the products in high yields (84−93%).
When using an unsymmetric alkyne 1e (R1 = Me, R2 = H, R3 =
OMe), a highly regioselective cycloisomerization occurred on
the ipso carbon of the methyl group side. This observed
regioselectivity would be attributed to the higher electron
density at ipso carbon atom (C2′) of alkyne 1e (Figure S3,
Supporting Information). The structure of 2e was unambigu-
ously confirmed by X-ray crystallographic analysis (Figure 1).18
In addition, we found that the cycloalkenyl ring size had an
influence on the reaction. Although 1f and 1g bearing a 8- or 7-
membered ring showed almost the same yield (94−99%) as
that of 1a with a 6-membered ring, 1h with a small 5-
membered ring was converted in very low yield (2%) into the
corresponding 2h. The differences in reactivity should be
Figure 1. X-ray crystallographic structure of 2e.
primarily attributed to increasing of the θ angle (see within a
square dotted line, Scheme 2). Moreover, 2i was also
successfully formed, which might expand the scope of the
products.
To gain insight into the reaction mechanism and to
rationalize how the P(C6F5)3 ligand influences the reaction, a
computational DFT study was carried out using the B3PW91
hybrid functional with Gaussian 09 programs (LANL2DZ for
Pt atom and 6-31G* for other atoms).19 The computed energy
profile of the favored pathway between 1a and 2a is illustrated
in Figure 2 and shows the relative Gibbs free-energies in the gas
phase. For both Pt(II) catalytic systems, the reactions begin
with coordination of Pt to the alkyne framework forming a π-
complex IM1a/b, which is much more exergonic for ligand-free,
B
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Organic Letters
Letter
In conclusion, we have developed a platinum(II)-catalyzed
intramolecular ring-expanding cycloisomerization for the syn-
thesis of substituted azulenes from 1-en-3-yne with ortho-
disubstituted benzene, using phosphine ligands for the Pt
catalyst. It is a simple and efficient method for constructing
substituted azulenes. We believe that this method should
provide a new approach toward functional azulene synthesis.
Further studies regarding the expansion of the substrate scope
are in progress in our laboratories and will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details including synthesis, characterization data
(1H and 13C NMR, IR, and mass spectrometry), and
computational methods. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: usui@phar.kyushu-u.ac.jp.
*E-mail: suemune@phar.kyushu-u.ac.jp.
Figure 2. Computational investigation of the cycloisomerization
pathway. The relative free energies (kcal mol−1, at 298 K) for
stationary points were calculated using B3PW91 with the 6-31G* basis
set for P, F, C, and H and LANL2DZ for Pt. Most of the hydrogen
atoms have been omitted for clarity. IM = intermediate, TS =
transition state.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid for
Scientific Research (C) from the Japan Society for the
Promotion of Science (No. 25410096) and Platform for
Drug Discoverty, Informatics, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
IM1a (−41.9 kcal mol−1 for PtCl2 vs −5.3 kcal mol−1 for
(C6F5)3P·PtCl2).20a The next ipso-cyclization step would give
the cyclopropyl platinum carbene IM2a/b via TS1a/b, involving
energy barriers of 10.6 and 13.2 kcal mol−1, respectively.21 The
formation of IM2a from IM1a is exothermic at −10.5 kcal
mol−1, whereas the conversion of IM1b → IM2b is slightly
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D
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