Silver-Catalyzed tert-Butyl 3-Oxopent-4-ynoate π-Cyclizations: Controlling the Ring Size - Hydroxypyrone or Pulvinone Formation - By Counterion and Additive Optimization

Article abstract of DOI:10.1021/acs.orglett.8b03214

tert-Butyl 2,5-diaryl-3-oxopent-4-ynoates, obtained from arylacetylenes and the acid chloride of tert-butyl 2-phenylmalonate, represent strongly enolized β-ketoesters. Their C≡C bonds were activated by Ag(I) salts so that de-tert-butylating π-cyclizations

Full text of DOI:10.1021/acs.orglett.8b03214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed tert-Butyl 3‑Oxopent-4-ynoate π‑Cyclizations:
Controlling the Ring SizeHydroxypyrone or Pulvinone
Formationby Counterion and Additive Optimization
David Hermann and Reinhard Bruckner*
̈
Institut fu
̈
r Organische Chemie, Albert-Ludwigs-Universitat, Albertstr. 21, D-79104 Freiburg, Germany
̈
S
* Supporting Information
ABSTRACT: tert-Butyl 2,5-diaryl-3-oxopent-4-ynoates, ob-
tained from arylacetylenes and the acid chloride of tert-butyl
2-phenylmalonate, represent strongly enolized β-ketoesters.
Their CC bonds were activated by Ag(I) salts so that de-
tert-butylating π-cyclizations occurred. The latter followed a 6-
endo-dig mode giving 3,6-diaryl-4-hydroxy-2-pyrones, or a 5-
exo-dig mode giving (Z)-configured 2-aryl-4-(arylmethyli-
dene)tetronic acids (“pulvinones”). Perfectly selective pyrone
formations were induced by AgSbF6 in methanol and equally selective pulvinone formations by Ag2CO3 and DABCO in
acetonitrile.
wo-fold unsaturated 6-membered ring lactones (“2-
pyrones”) abound in nature.1 In contrast, 3,6-diaryl-2-
pyrones 1 (Figure 1) are rare and 3,6-diaryl-4-hydroxy-2-
includes synthesizing type-1 pyrones11 and type-4 furanones.
However, to the best of our knowledge, type-2 hydroxypyrones
have never been prepared in this manner and pulvinones 5 only
once (5a: Ar1 = Ar2 = Ph8e). The present study fills this void by
accessing, selectively, diarylhydroxypyrones 2 as well as
pulvinones 5 by silver-induced π-cyclizations of enol-containing
tert-butyl pent-2-en-4-ynoates 7 and/or their β-ketoester
tautomers keto-7 (Figure 2). This required conducting such
cyclizations 6-endo-dig-selectively12 (→ 2) and 5-exo-dig-
selectively12 (→ 5), respectively.
T
The preferred cyclization mode of pent-2-en-4-ynoic acids,
their salts or their esters are affected by the nature of their CO
bond,13 α,β-14 or δ-substituent,15 the attacking electrophile16
Figure 1. 3,6-Diaryl-2-pyrones (1), 3,6-diaryl-4-hydroxy-2-pyrones
(2), type-2 compounds 3 from a pesticide patent,4 (Z)-2-aryl-5-
(arylmethylidene)furan-2(5H)-ones (4), and pulvinones (5), to which
aspulvinone E (67a) belongs.
pyrones 2 (other than aryl-free 4-hydroxy-2-pyrones2) are even
rarer, both in nature (e.g., ref 3) and synthesis (like the pesticide
34). 3-Aryl-5-(arylmethylidene)furan-2(5H)-ones 4 are 5-
membered ring isomers of 3,6-diaryl-2-pyrones 1 and originate
rather from synthesis5 than from nature.6 Similarly, 3-aryl-5-
(arylmethylidene)-4-hydroxyfuran-2(5H)-ones 5or “pulvi-
nones”are 5-membered ring isomers of 3,6-diaryl-4-
hydroxy-2-pyrones 2. If (Z)-configured, they are well-known
naturally7e.g., aspulvinone E (67a)and synthetically.8 Some
have evoked interest by their bioactivity.9
Figure 2. Considering 3,6-diaryl-4-hydroxy-2-pyrones (2) and
pulvinones (5) or their respective β-ketolactone tautomers (keto-2,
keto-5) as de-tert-butylated π-cyclization products of CγCδ-
containing β-ketoesters keto-7 or their enols 7.
Unsaturated 6- and 5-membered ring lactones have been
synthesized, inter alia, by acid-, base-, or metal-promoted π-
cyclizatitions of pent-4-ynoic acids and their derivatives.10 This
Received: October 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
including its oxidation state, ligand, or counterion,17 the
solvent,18 “additives”,19 and the temperature.20 Therefore, the
outcome of such cyclizations is difficult to predict.21
yield was unaffected when the reaction time remained 16 h. It
sunk when we worked up after 8 h or less.
Choosing tert-butyl 5-arylpent-2-en-4-ynoates 7containing
0−24% of the tautomeric ketoester keto-7as our substrates,
we explored several accesses.22 We settled on acylating an excess
of the lithiated arylethynes 10 with the chloride 9 of mono-tert-
butyl phenylmalonate (8; Scheme 1); 9 was obtained from 8 in
Scheme 2. 6-Endo-dig Cyclizations of the tert-Butyl 5-
Phenylpent-2-en-4-ynoate 7a, Giving the 3,6-Diphenyl-4-
hydroxypyrone 2a: Effect of Catalyst Loading
Scheme 1. Synthesis of the Pent-2-en-4-ynoates 7a−7f from
the Arylacetylenes 10a−10f and the Chloride 9 of Mono-tert-
a
butyl Phenylmalonate
Under the conditions of Scheme 2, the tert-butyl 5-arylpent-2-
en-4-ynoates 7b−7f cyclized to the corresponding hydroxy-
pyrones 2b−2f with the same perfect selectivity as 7a (see
Scheme 3). Only the hydroxypyrone 2c was isolated by
Scheme 3. Optimized 6-endo-dig Cyclizations of the tert-Butyl
5-Arylpent-2-en-4-ynoates 7a−7f Giving the 3,6-Diaryl-4-
hydroxypyrones 2a−2f
a
Reaction conditions: (a) (COCl)2 (1.0−1.7 equiv), DMF (cat.),
CH2Cl2, room temperature, 30−90 min; evaporation of the volatiles
at 10−2 mbar; (b) 10a−10f (2.1−2.8 equiv), n-BuLi for 10a−10e and
MeLi for 10f (2.1−2.6 equiv), THF, −78 °C for 10a−10c,10e, 0 °C
for 10f, and −30 °C for 10d, 15−120 min; addition of 9 in THF, 30−
65 min.
situ. Alkyne lithiation in THF using n-BuLi or MeLi (for 10f, lest
Br/Li exchange interfered), acylation at −78 °C, quenching with
saturated aqeuous NH4Cl, extractive workup, and purification
by flash-chromatography on silica gel23 immediately thereafter
(for minimizing decomposition) afforded 43%−66% yields of
the tert-butyl 5-arylpent-2-en-4-ynoates 7a−7f.
extractive workup and purification by flash chromatography
on silica gel.23 The hydroxypyrones 2a, 2b, and 2d−2f were
poorly soluble, so they precipitated while their formation was
underway. We isolated them in yields of 80%−96% by
centrifugation, removing the supernatant, and triturating the
remaining solid successively with H2O, iPrOH, and n-pentane or
toluene.
As previously mentioned, tert-butyl 5-phenylpent-2-en-4-
ynoate (7a) and Ag2CO3 in CH3CN provided the highest
proportion of pulvinone 5a during our initial screening.
Nevertheless, some hydroxypyrone 2a formed as well. Its
proportion in the product amounted to 2%−7%, as a result of
somewhat scattering outcomes of seemingly identical experi-
ments (Scheme 4, first row, “no additive”). Aggravatingly, this
contaminant could not be removed from the desired pulvinone.
This forced us to vary the reaction parameters until we attained a
perfectly ring-size specific cyclization of our substrate. We
noticed that diluting the substrate without diluting the catalyst
decreased the proportion of the hydroxypyrone 2a. This led us
to speculate whether the basicity of the carbonate counterion
favored the desired 5-exo-dig vs the undesired 6-endo-dig
cyclization. As a consequence, we added 2 equiv of a base to
the original Ag2CO3/CH3CN system (Scheme 4). They were
composed of amines, a diamine (DABCO), an amidine (DBU),
We treated tert-butyl 5-phenylpent-2-en-4-ynoate (7a) with
six different Ag(I) salts in 10 different solvents and with AuCl or
AuCl3 in DMF. π-Cylizations always ensued, but mostly with
little ring-size control. The hydroxypyrone 2a resulted best from
an AgSbF6-induced cylization in CH3OH. The pulvinone 5a
formed best in the presence of Ag2CO3 in CH3CN. Ring-size
control was due to both the counterion and the solvent. For
instance, exposure of the ester 7a to AgSbF6 in CH3OHas
mentionedor in acetone gave the hydroxypyrone 2a
exclusively; 2a/5a mixtures resulted in (F3C)2CHOH or 1,3-
dimethyl-2-imidazolidinone (∼70:30) or CH3CN or DMF
(∼30:70). Similarly, the ester 7a and Ag2CO3 gave the
pulvinone 5a as the major product in CH3CNas mentione-
d(5a:2a = 93:7) or DMF (85:15); 5a was the minor product
in 1,3-dimethyl-2-imidazolidin-2-one (49:51), acetone (42:58),
CH3OH (34:66), or (F3C)2CHOH (20:80).
Regarding the conversion of our simplest tert-butyl 5-
arylpent-2-en-4-ynoates 7a into the hydroxypyrone 2a in
CH3OH, we decreased the amount of AgSbF6 from our
screening (20 mol %) to as little as 1 mol % (Scheme 2). The
B
DOI: 10.1021/acs.orglett.8b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. 5-Exo-dig Cyclizations of the tert-Butyl 5-
Phenylpent-2-en-4-ynoate 7a Giving Pulvinone (5a): Base
Effects
Scheme 7. Optimized 5-exo-dig Cyclizations of the tert-Butyl
5-Arylpent-2-en-4-ynoates 7a−7f Giving the Pulvinones 5a−
5f
a
The amount of pulvinone 5a was dependent on the concentration of
the reactants and the amount of Ag2CO3. Abbreviations: DBU, 1,8-
diazabicyclo[5.4.0]undec-7-ene; TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-
ene; and DABCO, 1,4-diazabicyclo[2.2.2]octane.
a guanidine (TBD), and K2CO3. Each base increased the
pulvinone/hydroxypyrone ratio, with the order being DBU <
i
TBD < Pr2NEt (Scheme 4, left table) < K2CO3 or HNEt2 or
NEt3 or DABCO (Scheme 4, right table). Also, each base, with
the exception of DABCO, caused a silver mirror or black flakes
(amorphous Ag?) to form during the 16 h of reaction time.
Moreover, DABCO gave the highest yield. Accordingly, our
further optimizations maintained the latter.
The more DABCO we applied to our substrate 7a, the higher
the yield of pulvinone 5a (see Scheme 5). It seemed as if ≥2
a
Obtained from ester 7d by employing 4 equiv of DABCO.
which 7a gave 5a. After 16 h, the crude pulvinones 5a−5f were
first extracted from ether into saturated aqueous NaHCO3 as an
anion. The aqueous phases were acidified (HCl) so that the
respective pulvinone 5a−5f re-formed as a yellow precipitate.
The latter was dissolved upon back-extraction with ether.
Removal of the volatiles provided pure pulvinones (58%−86%
yields).
Scheme 5. 5-Exo-dig Cyclizations of the tert-Butyl 5-
Phenylpent-2-en-4-ynoate 7a Giving Pulvinone (5a): Effect
of Varying Amounts of DABCO
The hydroxypyrone 2f (Scheme 3) and the pulvinone 5f
(Scheme 7) contain a C−Br bond. It originated from (4-
bromophenyl)acetylene and was introduced via tert-butyl 5-(4-
bromophenyl)pent-2-en-4-ynoate (7f; see Scheme 1). The
C−Br bonds were intended to allow late stage modifications of
the two lactones by Pd-catalyzed C,C or C,Het coupling
reactions. Their feasibility is illustrated in Scheme 8 by
Sonogashira−Hagihara couplings with hept-1-yne. They were
effected after protecting the OH group of the hydroxypyrone 2f
as methyl ether 11 and the OH group of the pulvinone 5f as
methyl ether 12. These compounds and hept-1-yne coupled,
affording the heptynylated pyrone ether 13 and the heptynylated
pulvinone ether 14 in excellent yields. It is unclear whether the
CC bond introduced in these couplings would have interfered
with the π-cyclizationswhich established the respective
hydroxypyrone and pulvinone scaffoldsif they had already
been present then. The modus procedendi of Scheme 8 avoids
such incertitudes.
equiv of DABCO precipitated this pulvinone from the reaction
mixture as a solid. Finally, we found that the amount of Ag2CO3
could be reduced to 0.01 equiv without affecting the yield after
16 h of reaction time (Scheme 6). However, in the absence of
Ag2CO3, 2 equiv of DABCO left the substrate 7a unaltered
under otherwise identical conditions throughout 6 /4 h. This
proves that DABCO alone cannot cyclize 7a at all.
Under the conditions of Scheme 6, the tert-butyl 5-arylpent-2-
en-4-ynoates 7b−7f cyclized giving the corresponding pulvi-
nones 5b−5f (Scheme 7) with the same perfect selectivities with
3
The pulvinone syntheses described here circumvent the
nonadoptability of our π-cyclization route to aryl-
(arylmethylidene)butenolides (“desoxypulvinones”) 165f to
yield the corresponding pulvinones, e.g., compound 5a (see
Scheme 9). This would have required the oxidation of the
respective hydroxybutanolide intermediates 15, e.g., compound
15a, which we accessed by π-cyclizing the type-17 substrate not
with Ag2CO3 in dimethylformamide (DMF),5f but with AgNO3
in 1,2-dimethoxyethane (DME).24
Scheme 6. 5-Exo-dig Cyclizations of the tert-Butyl 5-
Phenylpent-2-en-4-ynoate 7a Giving Pulvinone (5a): Effect
of Catalyst Loading
Sadamitsu et al. reached one pulvinone (5a) by an AgOTf-
mediated π-cyclization of the ketopentynoate 19, which was
generated in situ from the ynone 18 and CO2 (see Scheme 10).8e
Their access looks generalizable, but is more demanding than
C
DOI: 10.1021/acs.orglett.8b03214
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Letter
20) but 5-exo-dig-cyclizes with AgSbF6 (→22; see Scheme 11,
top):21b Ag2CO3 would act as a σ-Lewis acid and thereby induce
Scheme 8. Post-Cyclization Modifications of the
Hydroxypyrone 2f and the Pulvinone 5f by a Sonogashira−
a
Hagihara Couplings with Their C−Br Moieties
Scheme 11. Juxtaposition of the Salt-Dependent π-
Cyclizations of the Present Study (Center) and of Selected
Substrates from ref 21b (at the Top and Bottom)
a
Reagents and conditions: (a) Me2SO4 (1.93 equiv), K2CO3 (1.60
equiv), acetone, reflux, 3.5 h; (b) hept-1-yne (2.14 equiv),
i
PdCl2(PPh3)2 (0.02 equiv), CuI (0.05 equiv), Pr2NH/THF (1:2),
reflux, 4.5 h; (c) Me2SO4 (2.03 equiv), K2CO3 (1.69 equiv), acetone,
reflux, 1.5 h; (d) hept-1-yne (2.14 equiv), PdCl2(PPh3)2 (0.02 equiv),
i
CuI (0.04 equiv), Pr2NH/THF (1:2), reflux, 3 h.
Scheme 9. A π-Cyclization Route to
Aryl(arylmethylidene)butenolides 165f and Its
Nontransferability to Reaching the Pulvinone 5a
the formation of the hemiacetal “anion” 23, which cyclizes 6-
endo-dig selectively. AgSbF6 would act as a π-Lewis acid and thus
allow the resulting complex 24 to cyclize 5-exo-dig selectively.
Unfortunately, these cyclization modes of their substrate (21)
contrast with those of ours (7a; see Scheme 11, center). If the
preceding reasoning21b was correct, AgSbF6 should let the 7a-
based π-complex 25 cyclize, Ag2CO3/DABCO the 7a-based σ-
complex 26. But why would the resulting rings be oppositely
sized6-membered (2a) vs 5-membered (5a)than the rings
formed via Belmont’s π-complex 24 and σ-complex 23, which
are 5-membered (22) vs 6-membered (20)? Interestingly, the
Ag(I)-catalyzed π-cyclizations of the (alkynylaryl)aldehyde 28
display the identical ring-size/salt correlations (→ 27/29; see
Scheme 11, bottom)21b as our π-cyclizations (see Scheme 11,
center). Belmont et al. noticed the contrast to their 21-
cyclizations (see Scheme 11, top) but had no explanation.
In summary, we developed an access to 3,6-diaryl-4-
hydroxypyrones 2 and pulvinones 5 from tert-butyl 2,5-diaryl-
3-hydroxy-2-en-4-ynoates 7 as common precursors. The latter
stemmed from acylating arylacetylenes 10 with the chloride 9 of
tert-butyl phenylmalonate (8). These tert-butyl 2,5-diaryl-3-
hydroxy-2-en-4-ynoates 7 underwent perfectly regioselective 6-
ours (CO2 was pressurized at 20 bar) and more expensive (they
used 20 times as much Ag(I) as we did).
It would be nice if there was a rationale for the ring-size
selectivities that we observed. However, we cannot provide one.
Ag(I) can act both as a π-electrophile toward CC motifs and
as a σ-electrophile toward CO motifs.21c Both properties were
invoked by Belmont et al., independently, to explain why the
(alkynylaryl)aldehyde 21 6-endo-dig-cyclizes with Ag2CO3 (→
Scheme 10. Only π-Cyclization That Afforded a Pulvinone,
Namely the Parent Compound 5a, before Our Study8e
D
DOI: 10.1021/acs.orglett.8b03214
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Organic Letters
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̃
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03214.
■
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S
1
Experimental procedures, characterization data, H and
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hydroxypyrones 2a−2f, and pulvinones 5a−5f, along with
additional references to citations given as refs 10 and
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de.
ORCID
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Tetrahedron 2002, 58, 5023−5038. (b) Yao, T.; Larock, R. C. J. Org.
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M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857−2870. (c) See ref
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Reinhard Bruckner: 0000-0002-9028-8436
̈
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Deutsche Forschungsgemein-
schaft for supporting this work (Project No. BR 881-8). We
̈
̈
thank Pavlos Tzortzoglou (Universitat Freiburg, Institut fur
Organische Chemie) for skilled technical assistance.
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(7) (a) Ojima, N.; Takenaka, S.; Seto, S. Phytochemistry 1973, 12,
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Alvarez, R.; Aurrecoechea, J. M. Eur. J. Org. Chem. 2014, 2014, 6263−
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(8) For reviews, see: (a) Bruckner, R. Curr. Org. Chem. 2001, 5, 679−
̈
(20) Kumar, M. R.; Irudayanathan, F. M.; Moon, J. H.; Lee, S. Adv.
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(21) Ring-size switchable π-cyclizations: (a) By changing from acid to
base: see ref 16e. By changing the Ag(I) salt: (b) Godet, T.; Vaxelaire,
C.; Michel, C.; Milet, A.; Belmont, P. Chem. - Eur. J. 2007, 13, 5632−
718. (b) Rao, Y. S. Chem. Rev. 1976, 76, 625−694. (c) Rao, Y. S. Chem.
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(cf. Scheme 10) .
E
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Letter
5641. (c) Calculational analysis of counterion effects: Yamamoto, Y. J.
Org. Chem. 2007, 72, 7817−7831.
(22) We could not oxidize the β-hydroxypentynoic acid 17 (Ar1 = Ar2
= Ph; formula: Scheme 9) nor its tert-butyl ester to the corresponding β-
ketoacid or β-ketoester 7a, respectively. Attempted syntheses of 7a by
acylating the Li-enolate of tert-butyl phenylacetate with the chloride,
esters or activated esters of phenylpropiolic acid suffered from
competing Michael additions to the CC−CO motif.
(23) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923−
2925.
(24) Failing oxidants that did not affect the dehydration 15a → 16a
were MnO2, DDQ, the Dess−Martin periodinane, PDC, PCC, and
SeO2.
F
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