Single-Flask Multicomponent Synthesis of Highly Substituted α-Pyrones via a Sequential Enolate Arylation and Alkenylation Strategy

Article abstract of DOI:10.1021/acs.orglett.6b02969

Trisubstituted α-pyrones are obtained by a Pd-catalyzed three-component, single-flask operation via an α-arylation, subsequent α-alkenylation, alkene isomerization, and dienolate lactonization. A variety of coupling components under mild conditions afforded isolated yields of up to 93% of the pyrones with complete control of regioselectivity. Metal dependence was noted for three of the steps of the pathway. Utility of the pyrone products was demonstrated by further transformations providing convenient access to polyaromatic compounds, exhibiting broad molecular diversity.

Full text of DOI:10.1021/acs.orglett.6b02969

Letter
pubs.acs.org/OrgLett
Single-Flask Multicomponent Synthesis of Highly Substituted
α‑Pyrones via a Sequential Enolate Arylation and Alkenylation
Strategy
Michael Grigalunas, Olaf Wiest, and Paul Helquist*,†
†
†,‡
†
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46566, United States
‡
Lab of Computational Chemistry and Drug Design, School of Chemical Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen 518055, China
*
S Supporting Information
ABSTRACT: Trisubstituted α-pyrones are obtained by a Pd-
catalyzed three-component, single-flask operation via an α-arylation,
subsequent α-alkenylation, alkene isomerization, and dienolate
lactonization. A variety of coupling components under mild
conditions afforded isolated yields of up to 93% of the pyrones
with complete control of regioselectivity. Metal dependence was
noted for three of the steps of the pathway. Utility of the pyrone products was demonstrated by further transformations
providing convenient access to polyaromatic compounds, exhibiting broad molecular diversity.
α-Pyrones are valuable heterocycles found in many biologically
1
2
active compounds and are versatile synthetic building blocks
3
for further transformations. Because of the importance of α-
pyrones, several synthetic procedures have been reported for
4
their synthesis using either conventional organic or organo-
5
metallic reactions. Typical approaches involve intramolecular
or intermolecular ring-forming processes, but often require
multistep syntheses to obtain the necessary substrates, resulting3
in limitations on facile access to molecularly diverse α-pyrones.
Furthermore, a number of procedures employ harsh reaction
conditions, have a limited substrate scope, and are non-
regiospecific, leading to an undesired mixture of regioisomers
Figure 1. Proposed multicomponent pathway to α-pyrones.
5a−d,6
or to a predominance of an undesired isomer.
Thus, there
lactonization to afford an α-pyrone 6. Herein we report the
successful implementation of this approach to a diverse range of
trisubstituted α-pyrones under mild conditions from simple,
readily available starting materials, and we demonstrate the
utility of the resulting pyrones in various further trans-
formations.
is a clear need for improved methods to access more readily a
diverse array of these compounds. With the growing need to
explore chemical space for medicinal and material science
purposes, multicomponent reactions that present an avenue for
facile access to molecular diversity while decreasing the number
of individual operations and eliminating the need for isolation
7
−9
To approach the development of the multicomponent
sequence systematically, we needed to take into account
whether the basic and metal-catalyzed conditions required for
the α-arylation and α-alkenylation reactions were suitable for
the final steps of E/Z-isomerization and lactonization. Based on
and purification of intermediates are especially desirable.
To provide facile and modular access to molecularly diverse
α-pyrones, we set out to design a multicomponent, single-flask
approach to α-pyrones employing a sequence of ketone α-
arylation, α-alkenylation, and E/Z-isomerization/lactonization.
While each individual reaction is known, incorporating all three
reactions into a single-flask operation would streamline access
to highly substituted α-pyrones. Our envisioned multi-
component approach (Figure 1) would begin with a Pd-
9a,11c
conditions from our previous α-alkenylation studies,
we
subjected unsaturated ketone (5a) to Pd (dba) (0.5 mol %),
2
3
Q-Phos (1 mol %), and LiOt-Bu (2 equiv) in THF at 22 °C.
The desired α-pyrone 6a was obtained but only in a moderate
yield after 3 h (Table 1, entry 1). We then examined whether
the absence of a catalytic amount of Pd (dba) and Q-Phos has
10
catalyzed coupling of a methyl ketone 1 with an aryl halide 2.
Under the basic reaction conditions, the α-arylated product 3
would be deprotonated and, after the addition of a β-
bromoacrylate 4 to the reaction mixture, a further coupling
2
3
positive or negative consequences for the isomerization and
1
1
would occur. The α-alkenylated intermediate 5 would
Received: October 1, 2016
undergo deprotonation followed by E/Z-isomerization and
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02969
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Organic Letters
Letter
Table 1. Optimization and Identification of the Active
Catalyst for Isomerization/Lactonization of 5a
reaction mixture. Overall, these results suggest that both a Pd-
catalyzed α-alkenylation and a non-Pd-catalyzed Michael
addition followed by elimination are feasible, but that the Pd-
mediated process is more favorable, and that the isomerization/
lactonization is faster than the alkenylation step. Several other
examples of obtaining α-pyrones starting from α-substituted
ketones (essentially a two-component rather than three-
component procedure) can be found in the Supporting
Information.
With an understanding of the latter steps, we were able to
14
incorporate an initial α-arylation reaction to achieve the
envisioned multicomponent sequence. The resulting procedure
consists of adding an aryl bromide (1 equiv) to a solution of
LiO-tBu (4 equiv), Pd (dba) (0.5 mol %), Q-Phos (1 mol %),
2
3
and a methyl ketone (1 equiv) at 22 or 40 °C. After TLC
indicates full consumption of the starting ketone (1−4 h), a β-
bromoacrylate (1.05 equiv) is added to the reaction mixture,
which is stirred for 15 h at 22 or 40 °C. Following workup, the
crude reaction mixtures are in many cases sufficiently pure for
synthetic purposes (see Supporting Information). The reaction
proved to be robust, reproducible, and easily conducted.
The scope was established for a range of methyl ketones
undergoing reaction with 4-bromo-N,N-dimethylaniline and 4a
a
b
Reported in mol %. Yield based on NMR internal standard.
cyclization. α-Alkenyl ketone 5a was subjected to LiO-tBu in
THF, affording again only a moderate yield (entry 2). When
Pd(OAc) (1 mol %) was used as a Pd(II) rather than a Pd(0)
source, a nearly quantitative yield of 6a was obtained (entry 3).
The basis for examining the effect of Pd(II) is that, in the
envisioned multicomponent reaction, a Pd(II) species would be
produced upon oxidative addition of either an aryl or alkenyl
halide. Indeed, incorporating 5 mol % of alkenyl bromide 4a in
the presence of LiO-tBu, Pd (dba) , and Q-Phos resulted again
2
(
Figure 3). Electron-rich to slightly electron-deficient aryl
2
3
in a nearly quantitative yield of 6a (entry 4). These results
suggest that a Pd(II) catalyst, whether generated in situ from
Pd(0) or added initially as a Pd(II) salt, is beneficial for the
isomerization/lactonization portion of the envisioned sequence.
In a related pathway for pyridine synthesis, thermal isomer-
ization and cyclization were observed at higher temperatures
1
1e
(
70−120 °C) but without a role of Pd being invoked,
whereas, in other systems, alkene isomerization has been shown
12
to be catalyzed by Pd(II).
With conditions for isomerization and cyclization established,
we next examined incorporation of the α-alkenylation step.
Since enolates have been found to undergo alkenylation with
highly activated α,β-unsaturated electrophiles such as alkylide-
nemalonate derivatives by a nonmetal-catalyzed addition/
4a,b,13
elimination pathway,
we compared the reactions of our
less activated bromoacrylate substrate in the absence and
presence of a Pd catalyst. A very low yield of α-pyrone 6a was
obtained when the reaction was conducted with α-aryl ketone
3
a, β-bromoacrylate 4a (1.05 equiv), and LiOt-Bu (3 equiv) in
THF in the absence of Pd catalyst. When Pd (dba) (0.5 mol
2
3
%
) and Q-Phos (1 mol %) were included, a 93% yield of 6a was
obtained after 10 h at 22 °C and a nearly quantitative yield after
6 h (Figure 2). For the experiments in Figure 2, the
alkenylated intermediate 5a was not observed in the crude
1
Figure 3. Investigation of the three-component synthesis of α-pyrones
using methyl ketones with aryl or alkenyl bromides and
bromoacrylates. Reactions were conducted on a 0.5 mmol scale.
a
b
Isolated yields are reported. Conducted on a 4.5 mmol scale. The
c
Figure 2. Examination of reaction conditions for the combination of
second part of the sequence was conducted at 40 °C. The entire
reaction sequence was conducted at 40 °C. The corresponding ethyl
a
d
α-alkenylation and subsequent isomerization/lactonization. Yield
based on NMR internal standard.
acrylate was employed.
B
DOI: 10.1021/acs.orglett.6b02969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketones give excellent yields of the desired α-pyrones (6b, 6a,
and 6c). A more electron-deficient aryl ketone results in
moderate yields when conducted at either 22 or 40 °C (6d).
The more sterically hindered o-tolyl ketone gives a high yield of
6
6
e at 22 °C. The aliphatic 2-pentanone affords a good yield of
f and is regioselective at the initially unsubstituted α-carbon
for both coupling steps. The multicomponent reaction
sequence is amenable to scale-up, producing 1.30 g (85%) of
6
a.
Next, a variety of aryl bromides was used with acetophenone
and β-bromoacrylate 4a. Electron-rich aryl bromides give
excellent yields of 6a and 6g, while an electron-neutral substrate
gives a moderate yield of 6h. Aryl bromides that were even
slightly more electron-deficient than bromobenzene react
poorly, even at 40 °C, and result in low yields (6i) or no
detectable quantity of the desired α-pyrones. The α-arylated
ketone is isolated as the major product in these cases.
Electronic effects were again apparent during the study of
hindered aryl bromides. When 2-bromotoluene is employed at
40 °C, a moderate yield of 6j is obtained, whereas the use of a
more electron-rich but still sterically hindered aryl bromide
results in higher yields at 40 °C (6k). An electron-rich α-
methoxy acrylate affords a good yield of 6l, while a moderate
yield is obtained with a phenyl-substituted acrylate (6m).
Several α-pyrones are obtained in high yields when both the
methyl ketone and the aryl bromide are electron-rich due to
varying methoxy substitution patterns (6n−q). The efficiency
of the three-component sequence is comparable to the two-
component process as illustrated in the formation of 6a by the
two procedures (Figures 2 and 3). The three-component
coupling can be applied to the synthesis of alkenyl-substituted
α-pyrones (6r and 6s) by sequential use of two different alkenyl
bromides.
Figure 4. Further reactions of initially obtained α-pyrones. (i)
PhI(OCOCF ) (1.1 equiv), BF ·OEt (2.2 equiv), DCM, −40 °C. (ii)
3 2 3 2
PhI(OCOCF ) (1.1 equiv), BF ·OEt (2.2 equiv), DCM, −40−22
3
2
3
2
1
1
°
(
°
C, 12 h. (iii) R CCR (3 equiv), 1,2-dichlorobenzene, 200 °C, 48 h.
iv) PhI(OCOCF ) (2.1 equiv), BF ·OEt (4.2 equiv), DCM, −40
C, 5 h. (v) AcOH, H SO , 120 °C, 24 h. Isolated yields are shown. X-
3
2
3
2
2
4
ray diffraction structures are shown for 10a and 11 without hydrogens
for clarity (red = O, green = F). Yield is based on PhI(OCOCF ) as
a
3
2
the limiting reagent.
conditions. The utility of the resulting α-pyrones is
demonstrated in further transformations to access polyaromatic
compounds, which have several applications in organic
chemistry, supramolecular chemistry, polymers, and materials
science. Furthermore, a two-component procedure may also be
employed starting with substituted ketones (see Supporting
Information). Extensions of the sequential reactions and other
pathways for derivatization of the products are subjects of
further investigations in our laboratory.
With facile access to richly substituted α-pyrones, we have
performed a brief, preliminary survey of some of their further
transformations (Figure 4) to demonstrate utility of these
diverse compounds. We focused on generation of highly
substituted, extended aromatic systems, which are of significant
15
interest for their physical and material properties. A high yield
of pyranophenanthrene 7 is obtained by intramolecular
16
oxidative coupling of 6n. When α-pyrone 6o is subjected to
similar conditions, the initial intramolecular coupling is
followed by a subsequent intermolecular coupling to afford
an unexpected bis(pyranophenanthrene) 8 as the major
product. Diels−Alder cycloadditions and decarboxylatio-
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02969.
2a,d,f,13a
n
produce highly substituted teraryls 9a and 9b in
excellent yields from α-pyrone 6q. When subjected to BF3·
Crystallographic data (CIF, CIF)
Full experimental procedures, copies of spectral data, and
X-ray crystal structures (PDF)
OEt /PhI(OCOCF ) conditions, these teraryls yield fused
2
3 2
tetracyclic compounds 10a and 10b in high yields. Subjecting
b to 2.1 equiv of iodonium salt and 4.2 equiv of BF ·OEt2
9
3
provides another unexpected result whereby aryl−aryl oxidative
coupling is accompanied by lactonization to afford 11 in
excellent yield. The structures of 10a and 11 were confirmed by
X-ray diffraction. Finally, acid promoted electrophilic cycliza-
tion of a 5-alkenyl α-pyrone 6s affords dihydronaphthopyrone
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: phelquis@nd.edu.
Notes
1
2 in high yield.
In conclusion, we have demonstrated that highly substituted
The authors declare no competing financial interest.
α-pyrones are produced efficiently by an α-arylation/α-
alkenylation/ketone enolate coupling strategy in a single-flask
operation. Pd was found to have beneficial roles in all of the key
steps of the sequence. A range of electronically and structurally
diverse substrate combinations gives molecularly diverse α-
pyrones with absolute control of regioselectivity under mild
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1058075 and CHE-1261033) and the National Institutes
of Health (1R01NS092653). We thank Prof. Dr. P.-O. Norrby
(AstraZeneca) for valuable discussions, Prof. Dr. K. Henderson
C
DOI: 10.1021/acs.orglett.6b02969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Notre Dame) for sharing equipment, and Dr. A. Oliver (Notre
Letter
(
Zhou, J. Angew. Chem., Int. Ed. 2013, 52, 4906. (c) Grigalunas, M.;
Ankner, T.; Norrby, P.-O.; Wiest, O.; Helquist, P. Org. Lett. 2014, 16,
970. (d) Grigalunas, M.; Ankner, T.; Norrby, P.-O.; Wiest, O.;
Dame) for X-ray data collection and structure determination.
3
Helquist, P. J. Am. Chem. Soc. 2015, 137, 7019. (e) Hardegger, L. A.;
Habegger, J.; Donohoe, T. J. Org. Lett. 2015, 17, 3222.
(12) (a) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67,
4627. (b) Franzoni, I.; Poblador-Bahamonde, A. I. Organometallics
2016, 35, 2955. For citation of other examples, see the following
reviews: (c) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170.
DEDICATION
■
This paper is dedicated to Professor Robert M. Carlson on the
occasion of his 75th birthday and upon completion of 50 years
of service on the faculty of the University of Minnesota Duluth.
(
d) Hassam, M.; Taher, A.; Arnott, G. E.; Green, I. R.; Van Otterlo, W.
A. L. Chem. Rev. 2015, 115, 5462.
13) (a) Boger, D. L.; Mullican, M. D. J. Org. Chem. 1984, 49, 4033.
b) Kumar, V.; Singh, F. V.; Parihar, A.; Goel, A. Tetrahedron Lett.
009, 50, 680.
14) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553.
15) (a) Cheng, Y.-J.; Yang, S.-H.; Hsu, C.-S. Chem. Rev. 2009, 109,
868. (b) Li, C.; Liu, M.; Pschirer, N. G.; Baumgarten, M.; Mullen, K.
REFERENCES
■
(
1) (a) Sunazuka, T.; Omura, S. Chem. Rev. 2005, 105, 4559.
b) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
c) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
(
(
(
2
(
Prinsep, M. R. Nat. Prod. Rep. 2013, 30, 237.
2) (a) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111. (b) Sun, C.-L.; Furstner, A. Angew. Chem.,
Int. Ed. 2013, 52, 13071. (c) Shin, H.-S.; Jung, Y.-G.; Cho, H.-K.; Park,
H.-K.; Cho, C.-G. Org. Lett. 2014, 16, 5718. (d) Okura, K.; Tamura,
R.; Shigehara, K.; Masai, E.; Nakamura, M.; Otsuka, Y.; Katayama, Y.;
Nakao, Y. Chem. Lett. 2014, 43, 1349. (e) Khatri, A. I.; Samant, S. D.
RSC Adv. 2015, 5, 2009. (f) Gan, P.; Smith, M. W.; Braffman, N. R.;
Snyder, S. A. Angew. Chem., Int. Ed. 2016, 55, 3625.
(
(
̈
(
5
̈
Chem. Rev. 2010, 110, 6817. (c) Jin, T.; Zhao, J.; Asao, N.; Yamamoto,
Y. Chem. - Eur. J. 2014, 20, 3554. (d) Bunz, U. H. F. Acc. Chem. Res.
2
1
015, 48, 1676. (e) Hammer, B. A. G.; Mu
̈
llen, K. Chem. Rev. 2016,
16, 2103. (f) Lungerich, D.; Reger, D.; Holzel, H.; Riedel, R.; Martin,
̈
M. M. J. C.; Hampel, F.; Jux, N. Angew. Chem., Int. Ed. 2016, 55, 5602.
16) (a) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.;
(
3) For reviews of α-pyrones, see: (a) Goel, A.; Ram, V. J.
Tetrahedron 2009, 65, 7865. (b) Lee, J. S. Mar. Drugs 2015, 13, 1581.
4) (a) Goel, A.; Taneja, G.; Raghuvanshi, A.; Kant, R.; Maulik, P. R.
Org. Biomol. Chem. 2013, 11, 5239. (b) Miura, T.; Fujioka, S.;
Takemura, N.; Iwasaki, H.; Ozeki, M.; Kojima, N.; Yamashita, M.
Synthesis 2014, 46, 496. (c) Yeh, P.-P.; Daniels, D. S. B.; Cordes, D. B.;
Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2014, 16, 964. (d) Liu, W.;
Zhao, G. Org. Biomol. Chem. 2014, 12, 832.
(
Kita, Y. Tetrahedron 2009, 65, 10797. (b) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215. (c) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014,
(
1
14, 9219. (d) Narayan, R.; Matcha, K.; Antonchick, A. P. Chem. - Eur.
J. 2015, 21, 14678.
(
5) (a) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2
009, 74, 6295. (b) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K.
Org. Lett. 2012, 14, 930. (c) Li, Q.; Yan, Y.; Wang, X.; Gong, B.; Tang,
X.; Shi, J.; Xu, H. E.; Yi, W. RSC Adv. 2013, 3, 23402. (d) Yu, Y.;
Huang, L.; Wu, W.; Jiang, H. Org. Lett. 2014, 16, 2146.
(
e) Moghaddam, F. M.; Mirjafary, Z.; Javan, M. J.; Motamen, S.;
Saeidian, H. Tetrahedron Lett. 2014, 55, 2908. (f) Manikandan, R.;
Jeganmohan, M. Org. Lett. 2014, 16, 652. (g) Tian, P.-P.; Cai, S.-H.;
Liang, Q.-J.; Zhou, X.-Y.; Xu, Y.-H.; Loh, T.-P. Org. Lett. 2015, 17,
1
̈
636. (h) Preindl, J.; Jouvin, K.; Laurich, D.; Seidel, G.; Furstner, A.
Chem. - Eur. J. 2016, 22, 237. (i) Faizi, D. J.; Issaian, A.; Davis, A. J.;
Blum, S. A. J. Am. Chem. Soc. 2016, 138, 2126.
(
5
(
6) (a) Larock, R. C.; Han, X.; Doty, M. J. Tetrahedron Lett. 1998, 39,
713. (b) Wang, Y.; Burton, D. J. J. Org. Chem. 2006, 71, 3859.
7) For reviews on multicomponent reactions, see: (a) Vlaar, T.;
Ruijter, E.; Orru, R. V. A. Adv. Synth. Catal. 2011, 353, 809. (b) Tietze,
L. F. Domino Reactions: Concept for Efficient Organic Synthesis; Wiley-
VCH: 2014.
(
8) For recent examples of multicomponent tandem reactions, see:
(
a) Chen, J.; Palani, V.; Hoye, T. R. J. Am. Chem. Soc. 2016, 138, 4318.
(
b) Paioti, P. H. S.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2016,
1
(
(
38, 2150.
9) For recent examples of multicomponent sequential reactions, see:
a) Grigalunas, M.; Norrby, P.; Wiest, O.; Helquist, P. Angew. Chem.,
Int. Ed. 2015, 54, 11822. (b) Deeming, A. S.; Russell, C. J.; Willis, M.
C. Angew. Chem., Int. Ed. 2016, 55, 747. (c) Battilocchio, C.; Feist, F.;
Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.;
Ley, S. V. Nat. Chem. 2016, 8, 360. (d) Wolters, A. T.; Hornillos, V.;
Heijnen, D.; Giannerini, M.; Feringa, B. L. ACS Catal. 2016, 6, 2622.
(
e) Yugandhar, D.; Kuriakose, S.; Nanubolu, J. B.; Srivastava, A. K.
Org. Lett. 2016, 18, 1040. (f) Liu, C.; Zeng, Z.; Chen, R.; Jiang, X.;
Wang, Y.; Zhang, Y. Org. Lett. 2016, 18, 624.
(
2
3
10) (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed.
010, 49, 676. (b) Novak, P.; Martin, R. Curr. Org. Chem. 2011, 15,
233. (c) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org. Biomol.
́
Chem. 2015, 13, 4367. (d) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.;
Seechurn, C. C. C. J.; Colacot, T. J. Eur. J. Org. Chem. 2015, 2015, 38.
(
11) (a) Ankner, T.; Cosner, C. C.; Helquist, P. Chem. - Eur. J. 2013,
1
9, 1858. (b) Huang, Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.;
D
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Org. Lett. XXXX, XXX, XXX−XXX