Gold-catalyzed dearomative spirocyclization of aryl alkynoate esters

Article abstract of DOI:10.1021/ol503022h

Aryl alkynoate esters undergo gold-catalyzed spirocyclization under mild conditions, affording spirolactones in high yields. This approach obviates the need for stoichiometric halogenating reagents typically employed for alkyne activation in related trans

Full text of DOI:10.1021/ol503022h

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Dearomative Spirocyclization of Aryl Alkynoate
Esters
Mark D. Aparece and Paul A. Vadola*
Department of Chemistry, DePaul University, 1110 West Belden Avenue, Chicago, Illinois 60614, United States
S
* Supporting Information
ABSTRACT: Aryl alkynoate esters undergo gold-catalyzed
spirocyclization under mild conditions, affording spirolactones
in high yields. This approach obviates the need for
stoichiometric halogenating reagents typically employed for
alkyne activation in related transformations. Water was found
to play a critical role in governing the product selectivity.
Anhydrous conditions lead selectively to coumarin products, as
has previously been observed for aryl alkynoate esters, while
the addition of 1 equiv of water leads selectively to spirocycle
formation.
pirocycles are a common structural pattern found at the core
species might enable a catalytic method for the spirocyclization
Sof numerous natural products of varying complexity. Their of aryl alkynoate esters.5
Our investigation began with the use of cationic gold
prevalence in medicinally and pharmaceutically desirable
compounds, as well as the synthetic challenges associated with
the construction of the highly substituted centers that character-
ize this motif, have made spirocycles an attractive target for
chemists.1 One commonly exploited mechanistic approach
among these synthetic methods is the dearomative spirocycliza-
tion of functionalized phenols and related alkoxyarenes. These
reactions typically proceed by the electrophilic activation of a
pendant functional group (alkyne in 1, Figure 1) triggering a
Friedel−Crafts-type nucleophilic attack of the arene leading to
C−C bond formation with concomitant dearomatization and
spirocycle formation (1 to 2, Figure 1).2−4
complexes. Such electrophiles have been employed for the π-
activation of alkynes,6 particularly the hydroarylation of alkynyl
arenes,7 with aryl alkynoate esters leading to coumarins via ortho-
cyclization (Table 1).8 Ester 4 was subjected to 5 mol % of
Table 1. Selective Spirocycle Formation
entry silver salt activator spirocycle 5 yield (%) coumarin 6 yield (%)
1
2
3
AgSbF6
AgBF4
AgOTf
39
53
93
48
19
Au(PPh3)Cl and AgSbF6 in a 1:1 mixture of dichloroethane and
1,4-dioxane. These conditions afforded a mixture of both the
ortho-cyclized coumarin 6 and the ipso-cyclized spirocyclic
lactone 5 in 48% and 39% yields, respectively. With this proof-
of-concept result we evaluated alternative silver salts with the
expectation that the counterion might impact the reactivity of the
gold catalyst in its activated form. Although a mixture was still
obtained, AgBF4 switched the selectivity of the cyclization,
favoring spirocyclization. Moreover, AgOTf led to complete
spirocycle selectivity, affording 5 in 93% yield after 5 h.
Figure 1. Electrophilic spirocyclization of aryl alkynoates.
Within this reaction paradigm, the halo-spirocyclization of
alkynyl arenes has recently emerged as a robust method for the
synthesis of halogenated spirocycles.4 This approach utilizes
electrophilic halogenating reagents as alkyne activators, under
basic conditions. While this approach can deliver high yields of
halo-spirocycles, the stoichiometric use of highly reactive
halogenating reagents and bases exhibits low atom economy
and has limited scope due to potential cross-reactivity of the
requisite reagents with other functional groups. We envisioned
the use of π-acidic metal complexes as alternatives to
stoichiometric electrophiles, with the anticipation that such
Optimization studies initially focused on the reaction solvent,
with the goal of eliminating the 1,4-dioxane (Table 2). We found
that DCE alone not only led to selective spirocyclization in a
Received: October 14, 2014
© XXXX American Chemical Society
A
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Letter
Table 2. Product Selectivity Dictated by Water
Table 3. Substitution at the Alkynyl Position
a
b,c
entry
solvent (0.05M)
water (equiv)
time
5 h
% yield 5:6
1
2
3
4
5
6
7
DCE/1,4-dioxane
DCE
93:0
20 min
6 h
91:0 (3)
6:85
DCE, anhydrous
DCE, anhydrous
1,4-dioxane
DCM
1
1
1
30 min
5 h
91:0 (3)
97:0
30 min
98:0 (trace)
15:61
DCM
6 h
a
b
Reactions conducted at room temperature. 1H NMR yields
determined using 4-nitrobenzaldehyde as an external standard.
c
Percent yield of β-keto ester shown in parentheses.
comparable 91% yield but did so with a reduction in reaction
time from 5 h to 20 min (entry 2). In an attempt to avoid
potential deactivation of the catalyst by water or oxygen, we next
ran our reaction with dry DCE, as opposed to our initial screen,
which employed benchtop solvent. Under these anhydrous
conditions the selectivity switched to favor the coumarin
product, which formed in 85% yield after 6 h (entry 3). These
results suggested the presence of water was critical for selective
spirocycle formation. Similar water-controlled product selectivity
has been observed in related transformations.4a
We were able to restore the spirocycle selectivity with the
addition of 1 equiv of water to our anhydrous DCE (entry 4).
These conditions gave the spirocycle in an identical 91% yield
after 20 min. Presumably, the success of our initial experiments
was the fortuitous result of using “wet” solvent. Moving forward,
1 equiv of water was added to all solutions prior to the addition of
the substrate. Most of the solvents screened led to mixtures of
spirocycle, coumarin, and β-keto ester arising from alkyne
hydration. We found benchtop dichloromethane (DCM) at 0.05
M concentration of substrate with 1 equiv of water to be the ideal
solvent conditions, yielding the spirocycle in 90% isolated yield.
We then turned our attention to the catalyst. Re-examination
of the initial catalyst screen (Table 1) showed similar selectivities
and yields (see the Supporting Information for complete screen).
AgOTf-activated Au(P(p-CF3Ph)3)Cl and (dppm)(AuCl)2 also
furnished the spirocycle selectively in high yield, but with longer
reaction times. Catalyst control experiments were conducted by
subjecting ester 4 to Au(PPh3)Cl and AgOTf independently. We
found that Au(PPh3)Cl failed to promote any reaction, while
AgOTf afforded 6% of the spirocycle after 24 h. We also
examined platinum salts (PtCl4, PtI4), which have been shown to
be competent catalysts for alkyne hydroarylation.8c,9 Surprisingly
these salts failed to promote any reaction.
a
reactions conducted at room temperature in DCM (0.05 M) with 1
b
equiv of H2O, 5 mol % of Au(PPh3)Cl, and AgOTf; Average yield of
three trials.
desilylated coumarin 14. Desilylation of TMS-alkynes has
previously been observed during gold catalysis and here likely
leads to the formation of substrate 11 in situ while sequestering
the water needed for spirocycle formation to trimethylsilanol.11
The more congested substrate 15, however, failed to undergo any
1
appreciable reaction, leading to a trace of spirocycle 16 by H
NMR along with 23% β-keto ester and 70% unreacted substrate.
The final substrate in this series was the β-bromo ester 17. We
expected the C−Br bond to be a potential pitfall, as oxidative
addition might occur, although oxidative addition at gold remains
rare.10 However, this substrate delivered a 74% yield of the β-
bromo spirocycle 18. We view this result as a complement to the
halogen-promoted methods, which yield α-halogenated spiro-
cycles.4b
We next directed our investigation to the aromatic ring of the
substrate (Table 4). The incorporation of methyl groups meta to
the ester in substrates 19 and 21 had little impact on the reaction,
yielding the methylated products 20 and 22 in 65% and 90%
yield, respectively. Substrate 23 with both ortho-positions
methylated led to trimethyl spirocycle 24 in quantitative yield,
while the monomethylated substrate 25 also led exclusively to
spirocyclization, affording 26 in 97% yield. The product
selectivity exhibited in these two reactions suggests that the
presence of an ortho-substituent, albeit a compact one, is not
enough to preclude spirocyclization nor promote ortho-
cyclization.
Our study of the substrate scope employed 5 mol % Au(PPh3)
Cl and AgOTf in DCM at 0.05 M with 1 equiv of water and began
with an examination of the tolerance for substitution on the
alkyne (Table 3). Ethylated substrate 7 performed comparably to
the methyl-bearing substrate 4, affording 8 in 86% yield. The
substantially bulkier phenyl substituent was also similarly
tolerated, affording the β-phenyl spirocycle 10 in 85%. Removing
the substituent altogether in substrate 11 resulted in a 74% yield
of the unsubstituted spirocycle 12.
To further test the steric allowance at the β-carbon we
prepared substrates 13 and 15. Surprisingly, 13 afforded the
desilylated product 12 in 25% yield along with 18% of the
Elaborating on this substrate and endeavoring to explore
possible electronic influences on the reaction, we prepared
substrate 27 with an o-methoxy group, which spirocyclized to
B
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Table 4. Substitution on the Aromatic Ring
Figure 2. Naphthyl alkynoate esters: (a) reactions conducted at room
temperature in DCM (0.05 M) with 1 equiv of H2O, 5 mol % of
Au(PPh3)Cl, and AgOTf; (b) average yield of three trials; (c) no
reaction (N.R.) was observed.
ester substituted substrate 40. Unfortunately, even after stirring
at 80 °C no reaction was observed. The additional ester likely
decreased the Lewis basicity of the alkyne, thereby inhibiting its
activation by the catalyst.
In regard to the mechanism of this transformation, we propose
the initial step to be formation of an alkyne−gold π-acid complex
(Figure 3, I). This alkyne activation induces a nucleophilic attack
a
reactions conducted at room temperature in DCM (0.05 M) with 1
b
equiv of H2O, 5 mol % of Au(PPh3)Cl, and AgOTf. Average yield of
three trials.
afford 28 in 92% yield. The success of this substrate prompted us
to investigate the potential spirocyclization of substrate 29 in
order to see whether the o-methoxy group alone could activate
the arene for nucleophilic attack. This substrate failed to undergo
cyclization, leading to a complex mixture, with β-keto ester 30 as
the only isolable product.
Investigations of electronic-withdrawing group influences
were carried out using substrates 31 and 33. Bromo arene 31
proved to be particularly reactive, affording bromo spirocycle 32
in 86% yield. The aldehyde-bearing substrate 33, however, led to
a mixture of products with the target spirocycle 34 being isolated
in 23% yield along with the related dimethyl acetal in 24% yield.
Interestingly, a new side product, coumarin 35, was observed and
isolated in 25% yield. This coumarin is distinct from those
discussed above (6 and 14) as it does not arise from
hydroarylation of the alkyne but rather through condensation
of the aldehyde substituent with the β-keto ester following alkyne
hydration.
Figure 3. Proposed spirocyclization mechanism.
of the arene forging the new C−C bond. The resulting spirocyclic
intermediate II then undergoes hydrolytic demethylation.
Protodemetalation of III leads to spirocycle formation and
catalyst regeneration. In the absence of water, however,
demethylation is not possible. Alternatively, a 1,2-alkyl shift
can occur, leading to bicyclic intermediate IV, which then
undergoes rearomatization followed by protodemetalation to
afford the coumarin product.
The dramatic differences we observed in the rates of formation
of the spirocycle versus the coumarin suggest that this 1,2-alkyl
shift is a slow process. While we cannot entirely rule out the
possibility of a direct hydroarylation mechanism (ortho-
cyclization), this would seem unlikely given the relative lack of
electron density at the ortho-carbon. Moreover, gold-catalyzed
hydroarylation of aryl alkynoate esters is typically rapid,
suggesting that ortho-cyclization is not inherently slower than
ipso-cyclization.8c
The final class of substrates we explored was inspired by the
recently discovered antifungal natural product perenniporide A
(Figure 2).12 The core benzo-fused spirocycle prompted us to
investigate the spirocyclization of naphthyl alkynoate esters.
Esters 36 and 38 were found to undergo spirocyclization to 37
and 39 in 89% and 77% yields, respectively. In a final
investigation of alkynyl substitution, we synthesized the methyl
In summary, we have demonstrated that the dearomative
spirocyclization of aryl alkynoate esters can be achieved by gold
catalysis to afford a broad scope of spirocyclic lactones in good to
C
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excellent yields in short reaction times under mild conditions,
requiring only water as a stoichiometric additive. The inclusion of
water and the presence of a p-methoxy group in the substrate are
crucial for the selective formation of the desired spirocyclic
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, H and 13C NMR, and HRMS data.
(9) (a) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 16, 6264−6267.
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This material is available free of charge via the Internet at http://
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(c) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859−
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8868. (d) Martín-Matute, B.; Nevado, C.; Cardenas, D. J.; Echavarren,
AUTHOR INFORMATION
Corresponding Author
A. M. J. Am. Chem. Soc. 2003, 125, 5757−5766. (e) Mamane, V.;
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Hannen, P.; Furstner, A. Chem.Eur. J. 2004, 10, 4556−4575.
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(f) Oyamada, J.; Kitamura, T. Tetrahedron 2006, 62, 6918−6925.
(g) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131, 16525−16528.
(h) Xia, Y.; Huang, G. J. Org. Chem. 2010, 75, 7842−7854.
(10) (a) Tamaki, A.; Kochi, J. K. J. Organomet. Chem. 1973, 64, 411−
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*E-mail: pvadola@depaul.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Mass Spectroscopy Laboratory of the University of
Illinois at Urbana−Champaign for HRMS analysis.
■
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(12) Feng, Y.; Wang, L.; Niu, S.; Li, L.; Si, Y.; Liu, X.; Che, Y. J. Nat.
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