Synthesis of substituted biaryls through gold-catalyzed petasis-ferrier rearrangement of propargyl ethers

Article abstract of DOI:10.1002/ejoc.201402469

Au-catalyzed cycloisomerization of aryl propargyl ethers provides controlled transition from alkyne to carbonyl chemistry followed up by a Petasis-Ferrier rearrangement/aromatization cascade leading to substituted biaryls with functionalized naphthalene cores. An Au-catalyzed sequence of alkoxy group translocation, Petasis-Ferrier rearrangement, and aromatization transforms aryl propargyl ethers into substituted biaryls with functionalized naphthalene cores. Copyright

Full text of DOI:10.1002/ejoc.201402469

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402469
Synthesis of Substituted Biaryls through Gold-Catalyzed Petasis–Ferrier
Rearrangement of Propargyl Ethers
Kamalkishore Pati*[a] and Igor V. Alabugin*[a]
Keywords: Synthetic methods / Rearrangement / Cycloisomerization / Alkynes / Gold / Biaryls
Au-catalyzed cycloisomerization of aryl propargyl ethers pro-
vides controlled transition from alkyne to carbonyl chemistry
followed up by a Petasis–Ferrier rearrangement/aromatiza-
tion cascade leading to substituted biaryls with function-
alized naphthalene cores.
Introduction
Alkynes are convenient carbon-rich precursors for the
preparation of conjugated molecules and materials.[1] Not
only do they undergo cyclizations in a controllable and pre-
dictable way,[2] but they can also serve as synthetic equiva-
lents of carbonyl compounds.[3] The latter aspect is illus-
trated well by the elegant Au-catalyzed versions of the Pet-
asis–Ferrier rearrangement (PFR) that utilized homoprop-
argylic amines and amides as carbonyl precursors.[4] The
PFR is a valuable reaction that utilizes the dual reactivity of
enolate moieties for the preparation of functionalized cyclic
molecules.[5]
The known Au-catalyzed versions of this process rely on
the presence of an endocyclic heteroatom donor[4a,4b] and
are very useful for the preparation of biologically active het-
erocycles. However, these processes are not applicable for
the preparation of carbocycles. Furthermore, applications
of PFR for the preparation of aromatic compounds are
very rare.[6]
In this work we have leveraged the propensity of alkynes
to participate in well-choreographed metal-catalyzed trans-
formations[7,8] to develop the first example of alkyne con-
version into an aromatic system that proceeds through Au-
catalyzed PFR. We use an aromatic ring as an endocyclic
donor and complement this effect with a suitably positioned
exocyclic aryl donor (Figure 1).
This design provides a new strategy for the production
of substituted biaryls through de novo construction of one
of the aromatic rings from a readily available acyclic precur-
sor.[9] Substituted biaryls are widely used as ligands in metal
[a] Department of Chemistry and Biochemistry, Florida State
University,
Tallahassee, Florida 32306-4390, U.S.A
E-mail: alabugin@chem.fsu.edu
Figure 1. Top: two possible stabilization patterns for the Petasis–
Ferrier rearrangement. Center: use of endocyclic donors for the
preparation of heterocycles. Bottom: combination of these patterns
in the suggested reaction design.
kpati@chem.fsu.edu
http://www.chem.fsu.edu/~alabugin/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402469.
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Gold-Catalyzed Rearrangement of Propargyl Ethers
catalysis[10] and as building blocks for the synthesis of or-
ganic functional materials[11] and natural products.[12]
Although Brønsted-acid-catalyzed cycloisomerization of
similar alkynes bearing bis-acetoxy groups reported by Yu-
anhong produced indenyl ketones through an exo-closure
[Scheme 1, Equation (1)],[13] other literature precedents
were more encouraging. Toste and co-workers reported for-
mation of five-membered cycles through formal endo-dig
gold(I)-catalyzed carboalkoxylation [Equation (2)].[14] An
even closer precedent was provided in work by Echavarren,
who reported a gold(I)-catalyzed cyclization of 1-(prop-2-
yn-1-yl)-2-alkenylbenzenes substituted at the benzylic posi-
tion with alkoxy groups, giving 1,3-disubstituted naphthal-
enes. Interestingly, this transformation proceeded with con-
comitant fragmentation of the alkene and formation of an
Au vinylidene, as depicted in Equation (3).[15]
Scheme 2. Synthesis of propargylbenzyl methyl ethers.
Table 1. The range of prepared substrates.
Scheme 1. Related transformations of acetylenic aryl ethers (top)
and the present work (bottom).
Results and Discussion
We envisioned that if the cation were formed from a
benzylic ether, the cycloisomerization of o-(methoxyprop-
argyl)benzyl methyl ethers 1 should provide the biaryl prod-
ucts 2 in a more atom-economical way as shown in Equa-
tion (4). After the gold(I)-catalyzed alkyne activation,
methoxy migration should lead to benzyl carbocation for-
mation followed by cycloisomerization.
Table 2 shows the screening of Lewis acids for the trans-
The methyl aryl ether substrates 1a–1p for the prepara- formation of 2-propargylbenzyl methyl ether 1a into biaryl
tion of biaryls 2a–p were prepared in good yields from 2- 2a. The screening experiments were performed in CH2Cl2
bromobenzaldehydes. The first step included treatment with at room temperature with 5 mol-% catalyst. All three tri-
aryl Grignard reagents, followed by addition of methyl iod- flates – PPh3AuOTf, LAuOTf {L = P(tBu)2(o-biphenyl)},
ide to produce the library of 2-bromobenzyl methyl ethers and IPrAuOTf – gave good yields of the desired biaryl 2a.
S-a in 70–80% yields. These were transformed into alkynes An increase in the nucleofugal nature of the anion (LAuX
1 in two additional steps as shown in Scheme 2. The range with X = SbF6, NTf2) had little effect on the yield of 2a
of prepared methyl aryl ethers is shown in Table 1.
but reduced the reaction time (Entries 4 and 5). Use of
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K. Pati, I. V. Alabugin
SHORT COMMUNICATION
Table 2. Screening of catalysts and solvents.
dichloroethane (DCE) and toluene as solvents slightly de-
creased the yield of 2a (Entries 6 and 7, respectively). Acti-
vation of the Au–Cl bond with cationic Ag salts was essen-
tial: no reaction was promoted by LAuCl alone, or by
AgNTf2 in the absence of Au catalysts (Table 2, Entries 8
and 10). Heating in the presence of 10 mol-% Cu(OTf)2 led
to a complex mixture of products that did not contain 2a.
The reaction was slower with 2 mol-% catalyst loading.
Overall, P(tBu)2(o-biphenyl)AuNTf2 in CH2Cl2 at room
temperature was found to be the optimal choice, providing
2a in 90% yield (Entry 5).
In most cases the reaction mixtures were very clean, and
filtration through a silica plug followed by solvent evapora-
tion was the only required workup. No further purification
was necessary. Although reactants 1a–n were used as mix-
tures of diastereomers, subsequent reactions of these mix-
tures converged to single products (Table 3).
[a]
Entry Catalyst [mol-%]
Conditions
Yield[b]
1
2
3
4
5
6
7
8
PPh3AuCl/AgOTf (5) CH2Cl2, 15 min, r.t.
75%
85%
70%
80%
90%
85%
72%
n.r.[c]
n.d.p.
n.r.
LAuCl/AgOTf (5)
IPrAuCl/AgOTf (5)
LAuCl/AgSbF6 (5)
LAuCl/AgNTf2 (5)
LAuCl/AgNTf2 (5)
LAuCl/AgNTf2 (5)
AgNTf2 (10)
CH2Cl2, 5 min, r.t.
CH2Cl2, 10 min, r.t.
CH2Cl2, 5 min, r.t.
CH2Cl2, 5 min, r.t.
DCE, 5 min, r.t.
toluene, 30 min, r.t.
CH2Cl2, 3 h, r.t.
9
10
11
Cu(OTf)2 (10)
LAuCl (5)
LAuCl/AgNTf2 (5)
CH2Cl2, 1 h, r.t.
CH2Cl2, 1 h, r.t.
CH2Cl2, 30 min, r.t.
85%
The structures of the gold(I)-catalyzed transformation
products were confirmed by a combination of HSQC and
HMBC NMR spectroscopy techniques and, in the case of
compounds 2n and 2k, by X-ray crystallography[16] (Fig-
ure 2).
[a] L = P(tBu)2(o-biphenyl), IPr = 1,3-bis(diisopropylphenyl)imid-
azol-2-ylidine, Tf = trifluoromethanesulfonyl; substrate 0.1 m solu-
tion. [b] Yields reported after passage through a small silica plug.
[c] n.r.: no reaction. n.d.p.: no desired product.
Table 3. Reaction scope for the transformation of benzyl methyl ethers.
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Eur. J. Org. Chem. 2014, 3986–3990

Gold-Catalyzed Rearrangement of Propargyl Ethers
The above observations provide further support to the
suggested reaction mechanism, shown in Scheme 4. In the
first step, gold activates the alkyne for intramolecular nu-
cleophilic addition of the benzylic ether with the formation
of oxonium intermediate B. Ionization of the C–O bond
transforms the alkyne into an enol ether with the concomi-
tant generation of stabilized benzylic carbocation C. Con-
sistently with the proposed mechanism, introduction of an
acceptor R group (p-CF3–Ph) significantly slowed the cy-
cloisomerization process. Even after 16 hours, the reaction
had reached only 32% conversion. Intramolecular capture
of the carbocation leads to formation of six-membered cy-
clic intermediate D or DЈ, which leads to formation of bi-
aryl product 2 through loss of methanol.
Figure 2. ORTEP representations of 2n and 2k.
The rearrangement of substrates 1o and 1p, each contain-
ing two different alkoxy functionalities at the two benzylic
positions, revealed that the propargylic ether group is lost
whereas the other alkoxy group is retained, but translocated
to the former terminal alkyne position (Scheme 3).
The presence of a β-OR functionality activates the
naphthyl products for subsequent oxidative dimerizations,
paving the way for the preparation of larger polyaromatics
(Scheme 5).
Conclusions
In summary, we have developed a new approach to the
synthesis of biaryl derivatives from propargylbenzyl methyl
ethers through gold(I)-catalyzed cycloisomerization. This
cascade process involves regioselective transformation of
alkyne moieties into activated enol ethers through Au-cata-
lyzed Petasis–Ferrier rearrangement followed by aromatiza-
tion. The process proceeds under mild conditions and with
high efficiency. Alkoxy substitution in the products acti-
vates them for the highly regioselective oxidative dimeriza-
tion into tetranaphthyls.
Scheme 3. Control experiments illustrate the transposition of the
OR moiety.
Scheme 4. Three mechanistic modules in the cycloisomerization cascade.
Scheme 5. Oxidative dimerization of the dinaphthyl products.
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K. Pati, I. V. Alabugin
SHORT COMMUNICATION
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Acknowledgments
Financial support from National Science Foundation (NSF) (grant
number CHE-1213578) is gratefully acknowledged. We are also
grateful to Mr. Hoa Phan and Mr. T. G. Parker for their assistance
with X-ray crystallographic analysis and thank T. Harris for his
assistance in several experiments.
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Received: April 22, 2014
Published Online: May 27, 2014
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