Fused Catechol Ethers from Gold(I)-Catalyzed Intramolecular Reaction of Propargyl Ethers with Acetals

Article abstract of DOI:10.1021/acs.orglett.5b03522

Selective gold(I)-catalyzed rearrangement of aromatic methoxypropynyl acetals leads to fused catechol ethers (1,2-dialkoxynapthalenes) in excellent yields. Furthermore, this process extends to the analogous heterocyclic and aliphatic substrates. Alkyne activation triggers nucleophilic addition of the acetal oxygen that leads to an equilibrating mixture of oxonium ions of similar stability. This mixture is "kinetically self-sorted" via a highly exothermic cyclization. Selective formation of 1,2-dialkoxy naphthalenes originates from chemoselective aromatization of the cyclic intermediate via 1,4-elimination of methanol.

Full text of DOI:10.1021/acs.orglett.5b03522

Letter
pubs.acs.org/OrgLett
Fused Catechol Ethers from Gold(I)-Catalyzed Intramolecular
Reaction of Propargyl Ethers with Acetals
Kamalkishore Pati, Gabriel dos Passos Gomes, Trevor Harris, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S
* Supporting Information
ABSTRACT: Selective gold(I)-catalyzed rearrangement of
aromatic methoxypropynyl acetals leads to fused catechol
ethers (1,2-dialkoxynapthalenes) in excellent yields. Further-
more, this process extends to the analogous heterocyclic and
aliphatic substrates. Alkyne activation triggers nucleophilic
addition of the acetal oxygen that leads to an equilibrating mixture of oxonium ions of similar stability. This mixture is “kinetically
self-sorted” via a highly exothermic cyclization. Selective formation of 1,2-dialkoxy naphthalenes originates from chemoselective
aromatization of the cyclic intermediate via 1,4-elimination of methanol.
lkynes have the same redox state as carbonyl compounds
and, thus, offer a “back door” entry into the rich field
Zhang et al. reported carboalkoxylation with efficient chirality
transfer from enantioenriched benzylic ethers and N,O-acetals.5e,f
Pd- and Pt-catalyzed cycloisomerizations of o-alkynylbenzaldehyde
acetals and thioacetals to functionalized indenes were described
by Yamamoto.5i Recently, we reported Au-catalyzed cyclo-
isomerization of aryl propargyl ethers that opened synthetic
access to substituted biaryls with a functionalized naphthalene
core.6 There have been several examples of Au-assisted for-
mation of aromatic cores.7
In this work, we report the synthesis of fused catechol ethers
via a room-temperature gold-catalyzed cycloisomerization
reaction. Fused catechols can be found in a number of bio-
logically active natural products and pharmaceuticals.8
Since the known synthetic routes to 1,2-dialkoxy-substituted
fused polyaromatics generally start with the preassembled
1,2-dialkoxybenzenes and concentrate on the assembly of the
second ring, such approaches are limited in scope (Figure S2).9
Herein, we describe a new strategy that will directly produce
the 1,2-dialkoxy substituted ring at a cyclic scaffold via a high-
yielding transformation at ambient temperature. This strategy
allows efficient preparation of a variety of such compounds via a
unified synthetic approach.
A
of carbonyl chemistry. However, despite the high energy
(thermodynamic “metastability”) of the alkyne moiety, their
π-bonds are relatively strong and unreactive.1 The notable
alkynophilicity of electron-deficient gold species is frequently
used for overcoming this kinetic hurdle. In this scenario, the
“carbonyl chemistry of alkynes” is unlocked via nucleophilic
addition of heteroatoms that converts alkynes into enols,
enamines, and their equivalents.2 Furthermore, the combina-
tion of the carbon-rich character of alkynes and the variety of
available stereoelectronic approaches to control cyclizations3
opens attractive routes for the preparation of functionalized
conjugated molecules and materials.4
Several Au-catalyzed cycloisomerizations of acetylene acetals
reported in the literature illustrate the diversity of this chemistry
(Figure 1).5 Toste and co-workers reported synthesis of indenyl
The substrates 1 were prepared in good yields from
2-bromobenzaldehydes. The first step included formation of
acetals via treatment with trimethoxyorthoformate. The acetals
were transformed into the requisite propagylic substrates 1 in
two additional steps shown in Scheme 1. Ortho formylation
was followed by reaction with ethynyl magnesium bromide with
the in situ addition of methyl iodide to produce the library
of o-methoxyprop-2-ynyl acetal benzenes in 70−85% yields.
The scope of prepared substrates is shown in Table 2.
Next, we investigated the influence of Lewis acids in the
transformation of o-methoxypropynyl acetal benzene 1a into
1,2-dimethoxynapthalene 2a. The screening was carried out in
Figure 1. (Left) The earlier metal-catalyzed reactions of conjugated
acetylenic acetals. (Right) Two approaches to substituted naphtha-
lenes from propargylic ethers developed in our lab.
ethers by intramolecular carboalkoxylation of alkynes.5a Liu et al.
disclosed a transformation of allenyl acetals into 5-alkylidene-
cyclopent-2-en-1-ones.5b Synthesis of highly substituted
piperidines has been developed by the Rhee group,5c whereas
Received: December 22, 2015
© XXXX American Chemical Society
A
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Letter
a
Scheme 1. Synthesis of Acetylenic Acetals
Table 2. Substrate Scope
dichloroethane (DCE) at room temperature using 5 mol % cata-
lyst. All triflates, PPh3AuOTf, LAuOTf (L = P(t-Bu)2(o-biphenyl),
and IPrAuOTf provided the 1,2-dimethoxynapthalene 2a in
good yields. Decrease in the nucleophilic nature of an anion
(PPh3AuX with X = SbF6, NTf2, Table 1, entries 4 and 5) had
Table 1. Screening of Catalysts and Solvents
ab
,
c
entry
catalyst (mol %)
conditions
yield
1
2
3
4
5
6
7
8
9
10
LAuCl/AgOTf (5)
PPh3AuCl/AgOTf (5)
IPrAuCl/AgOTf (5)
PPh3AuCl/AgSbF6 (5)
PPh3AuCl/AgNTf2 (5)
PPh3AuCl/AgNTf2 (5)
PPh3AuCl/AgNTf2 (5)
PPh3AuCl/AgNTf2 (2)
AgNTf2 (10)
DCE, 25 min, rt
DCE, 30 min, rt
DCE, 25 min, rt
DCE, 25 min, rt
DCE, 20 min, rt
DCM, 35 min, rt
Toluene, 40 min, rt
DCE, 45 min, rt
DCE, 2 h, rt
78%
74%
75%
84%
91%
64%
85%
90%
a
Isolated yields after filtration through a small silica plug.
d
1g, 1k revealed that the propargylic ether group remains a
bystander whereas each of the alkoxy groups from the acetal
participates in the reaction cascade; one of them migrates
whereas the other one is eliminated in the aromatization pro-
cess.10 The structures of the final products were confirmed with
the combination of NMR spectroscopy techniques, and, in the
case of compound 2k (Scheme 2), with X-ray crystallography.11
nd
PPh3AuCl (5)
DCE, 1 h, rt
nd
a
IPr = 1,3-bis(diisopropylphenyl)imidazole-2-ylidine, L = P(t-Bu)2-
(o-biphenyl), Tf = trifluoromethane sulfonyl. Substrate 0.1 M solu-
tion. Yields reported after passed over small silica plug. nd = no
desired product (only acetal deprotection observed).
b
c
d
only a minor effect on the reaction time and yield of 2a. Use of
dichloromethane and toluene as solvents slightly decreased the
yield of 2a and increased the reaction time (entries 6 and 7,
respectively). The reaction was slower when 2 mol % catalyst
was used, but the yield remained acceptable (90%). The
activation of the Au−Cl bond with cationic Ag salts was
essential, since no reaction was observed with LAuCl alone. As
expected, AgNTf2 was inefficient if the Au salts were absent
(Table 1, entries 9 and 10). PPh3AuNTf2 gave the best results,
providing 2a in 91% yield (entry 5). In most cases, reaction
mixtures were very clean and pure products can be obtained via
simple filtration through silica plug followed by evaporation of
the solvent.
With these optimized reaction conditions in hand, we
investigated the substrate scope. The gold-catalyzed cyclo-
isomerization of additional o-propargyl ether acetals 1a−1j
under the optimized conditions (Table 2) illustrates that this
process is fully compatible with alkoxy and halogen substituents
at the aryl ring. The reaction also tolerates heteroaromatics (2h)
and works well with partially saturated cyclic substrates (2i).
These results highlight the scope and selectivity of this method.
We have also varied the alkoxy groups at the propargylic
position by comparing the methoxy, ethoxy, and benzyloxy
substituents. All of these alkoxy groups are compatible with this
reaction cascade. Furthermore, the rearrangement of substrates
Scheme 2. Control Experiments Illustrate the OR Moiety
Transposition and ORTEP Representation of the Product
Computational Analysis. We used the hybrid PBE012 DFT
functional, reported to give a good description of gold
complexes.13 The 6-311+G(d,p) Gaussian basis set was
employed for C, P, O, and H atoms, while the Def2-TZVP14
basis set, including Effective Core Potential (ECP), was used
for Au atoms. Further details are provided in the Supporting
Information (SI).
The intramolecular nucleophilic addition of the acetal at the
activated Au−alkyne complex leads to the regioselective tran-
sformation of the alkyne into an activated enol ether/oxonium
intermediate B. According to our computational data, this step
and the following formation of the benzylic carbocation C are
slightly endergonic (Scheme 3).
The relatively low barriers for the intercoversion of oxonium
ions of similar energies suggest that this situation can be treated
B
DOI: 10.1021/acs.orglett.5b03522
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Letter
cyclization via the C−C bond formation. The latter step
provides kinetic self-sorting to the pool of dynamically inter-
converting species via conversion of one of the pool components
into a much more stable six-membered cyclic intermediate D.
The key cation that undergoes an irreversible ring closure
depleting and self-sorting the pool arises from an unusual
directing element, coordination of the cationic center at the Au
end of the Au−C σ-bond (Scheme 4). This interaction is too
strong to be accurately estimated by the NBO perturbation
analysis, but this dynamically formed Au−C contact is
comparable in magnitude to a chemical bond.20 Note that the
carbon at this point is both pyramidalized and depleted of most
of its cationic character. In a highly exothermic and irreversible
step, this species “slips” over from Au- to C-coordination via a
very low (0.2 kcal/mol) transition state that provides the six-
membered ring of the product (Scheme 5).
The central part of the cascade that converts the heterocyclic
cation B into its carbocyclic isomer D corresponds to a
Au-catalyzed version of Petasis−Ferrier rearrangement.21
Selective elimination of methanol22 from the cyclic carbocation
yields the target 1,2-dimethoxy naphthalenes upon aromatiza-
tion. This step involves selective cleavage of the more acidic
C1−H bond communicating stereoelectronically with the
cationic Au catalyst through the alkene π-system. The
Au-catalyst transfer from the product to the alkyne moiety of a
new starting material is exergonic by 2 kcal/mol, and thus, the
catalytic cycle restarts.
Scheme 3. Proposed Mechanism
as a “pool of equilibrating cations”,15 self-sorted via their relative
reactivity. One can consider such a system as an example of
Dynamic Covalent Chemistry (DCC)16−18 in Au-catalyzed
transformations. In this scenario, the system can take advantage
of the “error-checking” in DCC where fast equilibration allows
covalent bonds to form, break, and reform reversibly before
converging on one of many possible products.19
The pre-equilibration steps lead to the transfer of one of the
acetal OR groups that accomplishes two goals: (1) transform
the alkyne into an enol ether and (2) convert an acetal in an
activated electrophile (the oxonium ion). The favorable com-
bination of two appropriately positioned reaction partners of
complementary polarities results in a fast and irreversible
In summary, we have developed an efficient approach for the
synthesis of fused catechol ethers via Au(I)-catalyzed intra-
molecular reaction of propargyl ethers and acetals under mild
conditions. Both alkoxy groups of acetal functionality serve a
distinct mechanistic purpose: one acts as an internal nucleo-
phile, whereas the other one enables a facile elimination
pathway needed for the final aromatization step.
Scheme 4. Calculated Geometry of C′ and D′ with the NBO
Charges and Key Stereodefining Groups (Shown in Blue)
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03522.
1
Full synthetic procedures, H NMR, 13C NMR, X-ray
structure, computational details (PDF)
Scheme 5. Calculated Gibbs Energy Surface for the Proposed Reaction Mechanism
C
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Letter
M. O.; Durst, T.; Charron, M.; Wright, J. S. Chem. Res. Toxicol. 2006,
19, 1221.
(9) (a) Adams, D. R.; Duncton, M. A. J. Synth. Commun. 2001, 31,
2029. (b) Huang, K. S.; Wang, E. C. Tetrahedron Lett. 2001, 42, 6155.
(c) Mukherjee, C.; De, A. Synlett 2002, 2002, 325.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: alabugin@chem.fsu.edu.
Notes
(10) Selective elimination of the OMe group via a radical pathway is
another valuable strategy for terminating reaction cascades via an
aromatizing step. For an example where OMe serves as a traceless
directing group, see: Pati, K.; dos Passos Gomes, G.; Harris, T.;
Hughes, A.; Phan, H.; Banerjee, T.; Hanson, K.; Alabugin, I. V. J. Am.
Chem. Soc. 2015, 137, 1165.
(11) The crystallographic data for compound 2k, CCDC 1435948.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Center www.ccdc.cam.ac.uk/data_request/cif.
(12) (a) Perdew, J. P.; Ernzerhof, M.; Burke, K. J. Chem. Phys. 1996,
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(13) (a) Kang, R. H.; Chen, H.; Shaik, S.; Yao, J. N. J. Chem. Theory
Comput. 2011, 7, 4002. (b) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg,
H. J. Chem. Phys. 2010, 132, 154104. (c) Grimme, S.; Ehrlich, S.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation (CHE-
1465142) for support of this research. We are also grateful to
Mr. Mark Silver for X-ray crystallographic analysis, under-
graduate students C. G. Michas and Ana Phelan for their
assistance in several experiments, and FSU Research Comput-
ing Center for the allocation of computational resources.
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