N-Heterocyclic Carbene-Catalyzed Annulation of Ylides with Ynals: Direct Access to α-Pyrones

Article abstract of DOI:10.1002/asia.201800595

We herein report an N-Heterocyclic Carbene (NHC)-catalyzed annulation of ylides with ynals that provides an efficient protocol to make 4,6-disubstituted α-pyrones. This method affords a variety of α-pyrones in good to high yields as well as broad substrat

Full text of DOI:10.1002/asia.201800595

CHEMISTRY
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Accepted Article
Title: N-Heterocyclic Carbene-Catalyzed Annulation of Ylides with
Ynals: Direct Access to α-Pyrones
Authors: Jian Wang, ming lang, and qianfa jia
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N-Heterocyclic Carbene-Catalyzed Annulation of Ylides with
Ynals: Direct Access to α-Pyrones
Ming Lang,†[a] Qianfa Jia,†[a] and Jian Wang*[a]
Dedication ((optional))
group disclosed an elegant example of carbene-catalyzed
annulation of aroyl-substituted nitromethanes with enals,
afforded 4,6-disubstituted α-pyrones in moderate to good
yields.[17] Herein, we wish to report an efficient NHC-
catalyzed cycloaddition of heteroaromatic ylides with ynals
to assemble 4,6-disubstituted α-pyrones (Scheme 1c).
Abstract: We herein report an unprecedented NHC-catalyzed
annulation of ylides with ynals, providing an efficient protocol to
make 4,6-disubstituted α-pyrones. This method affords a
variety of α-pyrones in good to high yields as well as broad
substrate scope and good functional group tolerance
.
Scheme 1. Background for the synthesis of α-pyrones

-Pyones are frequently observed as the core in numerous
natural products and biologically important molecules
(Figure 1).[1] They have exhibited promising biological
activities, such as anti-HIV,[2] antimicrobial,[3] antifungal,[4]
telomerase
inhibition,[5]
pheromonal,[6]
androgen,[7]
cardiotonic,[8] neurotoxic[9] and phytotoxic effects.[10] In
medicinal chemistry, α-pyones often serve as convenient
precursors for the assembly of other medicinal important
structures.[11] Therefore, the development of an efficient
synthetic protocol for the construction of diversified α-
pyrone derivatives tends to be interesting and highly
demanded.
Figure 1. Representative biologically important α-pyrones
Our study commenced with an attempt using
isoquinolinium ylide 1a and 3-phenylpropiolaldehyde 2a as
model substrates. As indicated in Table 1, the initial
Over the past few years, N-heterocyclic carbenes
(NHCs) catalysed reactions have been broadly utilized in
organic synthesis.[12] NHC-bounded α,β-unsaturated acyl
azolium can be generated from redox reaction of the
Breslow intermediate derived from ynals since it was
discovered in 2006.[13] More recently, NHC-catalyzed
annulations of α,β-unsaturated acyl azoliums have been
reported to react with a variety of stable enols or enamines,
screening of NHC precatalysts
amount of product 3a was detected in the presence of
precatalyst . To our delight, precatalysts could
promote this reaction, but still afforded low to moderate
yields (Table 1, entries 2-4). Disappointedly, precatalyst
and also showed poor reactivities under the same
conditions (Table 1, entries 5 and 6). Building upon
precatalyst , we turned our attention to the effect of bases.
A-F found that only a trace
A
B-D
E
F
affording
functionalized
dihydropyranones
or
dihydropyridinones.[14] Despite these progresses, the
examples of organocatalytic synthesis of substituted α-
pyrones are still very scarce. The Kwon group reported a
phosphine catalyzed cyaloaddition of allenoates with
aldehydes to generate 6-substituted α-pyrones (Scheme
1a).[15] Then Smith and co-workers reported an efficient
synthesis of trifluoromethyl substituted α-pyrones catalysed
by an isothiourea (Scheme 1b).[16] Very recently, the Studer
D
A slightly enhanced yield was achieved in the use of
NaHCO3 as base (Table 1, entries 7-12). To further improve
reaction efficiency, we then focused on the examination of
other parameters, including solvents and ratio of starting
materials (Table 1, entries 13-21). Decreasing the catalyst
loading of precatalyst
D to 10 mol% led to a lower yield
(Table 1, entry 22). Finally, a combination of 1a (0.15 equiv),
2a (0.1 equiv), NaHCO3 (5.0 equiv), CHCl3 as medium, and
room temperature, was identified as the current optimal
condition.
[a]
M. Lang, Q.-F. Jia, Prof. Dr. J. Wang
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic
Phosphorous Chemistry & Chemical Biology (Ministry of Education)
Institution
Table 1. Optimization of reaction conditions[a]
Tsinghua University
E-mail: wangjian2012@tsinghua.edu.cn
Contributed equally
†
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Entry
Ylides
1a
Yield (%)[b]
1
2
73
78
34
53
68
45
82
1b
3
1c
4
1d
5
1e
6
1f
7c
1b
[a] If not further mentioned, the reaction was carried out
with 1a (0.15 mmol), 2a (0.10 mmol) and NaHCO3 (5.0
equiv) in CHCl3 (2.0 mL) was stirred at room temperature
for 48 h. [b] Isolated yield. [c] 4Å MS (50 mg) was added.
Entry
1
2
3
4
5
6
7
8
Cat.
A
B
C
D
E
Base
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Toluene
THF
Yield (%)b
trace
21
35
46
N.R.
N.R.
24
54
21
10
N.R.
N.R.
58
60
73
Table 3. Scope of ynals[a,b]
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaHCO3
Na2CO3
DBU
F
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
9
10
11
12
13c
14d
15e
16
17
18
19
20
21
22f
DMAP
DIPEA
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
8
trace
trace
N.R.
N.R.
N.R.
62
CH3CN
Et2O
1,4-Dioxane
CHCl3
[a] If not further mentioned, the reaction was carried out with 1a (0.10 mmol),
2a (0.15 mmol) and base (2.0 equiv) in the solvent (2.0 mL) was stirred at
room temperature for 24 h. [b] Isolated yield. [c] The reaction was stirred at
room temperature for 48 h. [d] NaHCO3 (5 equiv.) was used. [e] 1a:2a = 1.5:1.
[f] 10 mol% cat. D was used.
[a] If not further mentioned, the reaction was carried out with 1a (0.15
mmol), 2a (0.10 mmol), NaHCO3 (5.0 equiv) and 4Å MS (50 mg) in
CHCl3 (2.0 mL) was stirred at room temperature for 48 h. [b] Isolated
yield.
On the basis of current moderate yield (Table 1, entry
15, 73%), we then continued to improve the reaction
efficiency. Based on the proposed mechanism, the
reactivity of ylides may accelerate or slow the reaction. As
highlighted in Table 2, N-pyridinium, N-quinolinium and N-
imidazolium ylides were evaluated. It was observed that
yield was slightly increased when the substrate 1b
participated in the reaction (Table 2, entry 2). Pleasingly, α-
pyrone 3a could be achieved in a higher yield when 4 Å
molecular sieves were added additionally (Table 2, entry 7).
Having the optimized conditions in hand, we then
investigated the scope of ynals. As summarized in Table 3,
a number of 3-phenylpropiolaldehyde
2 were tested initially.
Interestingly, substituents have limited effects on reaction
efficiency. Both electron-withdrawing and -donating
substituents on the phenyl unit were tolerated (Table 3, 3b
-
m
). When phenyl ring was replaced by 2-naphthyl or 3-
Table 2. Effect of ylides[a]
thiophenyl group, reactions still could promote smoothly to
afford the corresponding products in good yields (Table 3,
3n and 3o, 76% and 78%, respectively). Disappointedly,
when

-alkyl enal 2p was used, no desired 3p was
-alkyl group may cause a
observed. We deduced that the

LUMO-raising of enal, that eventually preventing the
reaction to occur.
The scope of ylides was also evaluated (Table 4).
Pleasingly, this new protocol tolerated a wide range of
functional groups on the phenyl ring of ylides and provided
the corresponding products in moderate to good yields
(Table
4,
3q
-
w
).
Additionally,
1-(2-cyclopropyl-2-
oxoethyl)pyridin-1-ium bromide 1x was also found to be a
suitable partner and generated the desired product 3x in an
acceptable yield.
Table 4. Scope of ylides[a,b]
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As outlined in Scheme 4, a plausible mechanism is illustrated.
Briefly, NHC catalyst reacts with ynal to afford tetrahedral
intermediate I. After proton transfer, Breslow intermediate II is
generated, followed by a redox and protonation to form α,β-
[a] If not further mentioned, the reaction was carried out with 1a (0.15 mmol),
2a (0.10 mmol), NaHCO3 (5.0 equiv), and 4Å MS (50 mg) in CHCl3 (2.0 mL) at
room temperature for 48 h. [b] Isolated yield.
unsaturated acyl azolium III. Then, 1,4-addition of pyridinium ylide
In addition, we also explored the possibility to synthesize
1b’ to intermediate III generates adduct IV, which undergoes
elimination to afford intermediate V. A subsequent intramolecular
cyclization gives the desired α-pyrone 3a and liberates NHC catalyst
for next catalytic cycle.

-pyrones via a multicomponent reaction mode. Gratifyingly, 3a
was achieved in a moderate yield when in situ generated
pyridinium ylide reacted with 3-phenylpropiolaldehyde 2a
(Scheme 2). To highlight the utility of this transformation, we
undertook the derivatization of the 2-pyrone scaffold (Scheme 3).
4,6-Diphenylpyridin-2-yl 4-methylbenzenesulfonate
5
was
synthesized via a two-step procedure by reacting 4,6-diphenyl-
2H-pyran-2-one 3a with aqueous NH4OH, followed by O-
tosylation with TsCl to give the desired product in overall 72%. In
addition, the reaction of 3a with dimethyl but-2-ynedioate
Experimental Section
In CHCl3 (2 mL) were dissolved NHC precatalyst D, pyridinium ylide 1b
(0.15 mmol), alkynal 2a (0.1 mmol), NaHCO3 (0.5 mmol, 42 mg) and 4 Å
molecular sieves (50 mg). The reaction mixture was stirred at room
temperature for 48 h. The crude product was purified by column
chromatography on silica gel, eluted by hexane/EtOAc = 5:1 to afford 20
mg (82% yield) of the desired product 3a as white solid. 1H NMR (400
MHz, CDCl3) δ 7.96 – 7.87 (m, 2H), 7.70 – 7.64 (m, 2H), 7.56 – 7.48 (m,
6H), 6.99 (d, J = 1.4 Hz, 1H), 6.49 (d, J = 1.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 162.73, 160.39, 155.64, 136.05, 131.54, 130.97, 130.74,
129.28, 129.00, 126.77, 125.78, 109.28, 101.41. HRMS (ESI): exact
mass calculated for C17H12NaO2 [M+Na]+ required m/z 271.0735, found
m/z 271.0734.
(DMAD) could form multisubstituted benzene derivative
6 in 93%.
Scheme 2. Synthesis of -pyrone via a three-component reaction.
Scheme 3. Synthetic transformations.
Acknowledgements ((optional))
Generous financial supports for this work are provided by: the National
Natural Science Foundation of China (21672121), the “Thousand Plan”
Youth program of China, the Tsinghua University, the Bayer Investigator
fellow, the fellowship of Tsinghua-Peking centre for life sciences (CLS).
Keywords: N-heterocyclic carbene • organocatalysis • [3+3] •
pyrone • ylide
[1]
For selected reviews and examples on α-pyrones, see: a) J. Staunton.
In Comprehensive Organic Chemistry; D. H. Burton, W. D. Ollis, Eds.;
Pergamon: New York, 1979; 629; b) P. J. Brogden, C. D. Gabbutt; J. D.
Hepworth. In Comprehensive Heterocyclic Chemistry; A. R.
Katritzky; C. W. Rees, Eds.; Pergamon Press: Oxford, 1984; Vol. 3,
Scheme 4. Postulated mechanism.
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Part 2B, Chapter 2.22, 573; c) G. P. McGlacken; I. J. S. Fairlamb. Nat.
Prod. Rep. 2005, 22, 369; d) J. M. Dickinson. Nat. Prod. Rep. 1993,
10, 71; e) P. Fu, P. Liu, H. Qu, Y. Wang, D. Chen, H. Wang, J. Li, W.
Zhu. J. Nat. Prod. 2011, 74, 2219; f) D. Liu, X.M. Li, L. Meng, C.S. Li,
S.S. Gao, Z. Shang, P. Proksch, C.G. Huang, B.G. Wang. J. Nat. Prod.
2011, 74, 1787; g) M.C. Kim, O.W. Kwon, J.S. Park, S.Y. Kim, H.C.
Kwon. Chem. Pharm. Bull. 2013, 61, 511; h) J. S. Lee. Mar. Drugs.
2015, 13, 1581.
a) J. V. N. Vara Prasad, K. S. Para, E. A. Lunney, D. F. Ortwine, J. B. Jr
Dunbar, D. Ferguson, P. J. Tummino, D. Hupe, B. D.Tait, J. M.
Domagala, C. Humblet, T. N. Bhat, B. Liu, D. M. A. Guerin, E. T.
Baldwin, J. W. Erickon, T. K. Swayer. J. Am. Chem. Soc. 1994, 116,
6989; b) S. E. Hagen, J. V. N. Vara Prasad, F. E. Boyer, J. M. Domagala,
E. L. Ellsworth, C. Gjda, H. W. Hamilton, L. J. Markkoski, B. A.
Steinbangh, B. D. Tit, E. A. Lunney, P. J. Tummino, D. Fergnson, D.
Hupe, C. Nouhan, S. J. Gracheck, J. M. Saunders, S. Vander Roest. J.
Med. Chem. 1997, 40, 3707; c) C. J. Douglas, H. M. Sklenicka, H. C.
Shen, D. S. Mathias, S. I. Degen, G. M. Golding, C. D. Morgan, R. A.
Shih, K.L. Mueller, I. M. Seurer, E. W. Johnson, R. P. Hsung.
Tetrahedron. 1999, 55, 13683.
a) T. Yao, R. C. Larock. J. Org. Chem. 2003, 68, 5936; b) I. J. S.
Fairlamb, L. R. Marrison, J. M. Dickinson, F. J. Lu, J. P. Schmidt.
Bioorg. Med. Chem. 2004, 12, 4285.
a) A. Simon, R. W. Dunlop, E. L. Ghisalberti, K. Silvasithamparam, Soil
Biol. Biochem. 1988, 20, 263; b) K. Nagai, K. Kamigiri, H. Matsumoto,
Y. Kawano, M. Yamaoka, H. Shimoi, M. Watanabe, K. Suzuki. YM-
202204. Phoma sp. J. Antibiot. 2002, 55, 1036; c) A. Evidente, A.
Cabras, L. Maddau, S. Serra, A. Andolfi, A. Motta. J. Agri Biol. Chem.
2003, 51, 6957.
[12] For selected reviews, see: a) D. Enders and T. Balensiefer, Acc. Chem.
Res. 2004, 37, 534; b) D. Enders, O. Niemeier and A. Henseler, Chem.
Rev. 2007, 107, 5606; c) V. Nair, S. Vellalath and B. P. Babu, Chem.
Soc. Rev. 2008, 37, 2691; d) P. Dominguez de Maria and S.
Shanmuganathan, Curr. Org. Chem. 2011, 15, 2083; e) S. Ryan, L.
Candish and D. W. Lupton, Synlett. 2011, 2275; f) A. T. Biju, N. Kuhl
and F. Glorius, Acc. Chem. Res. 2011, 44, 1182; g) X. Bugaut and F.
Glorius, Chem. Soc. Rev. 2012, 41, 3511; h) J. Izquierdo, G. E. Hutson,
D. T. Cohen and K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 51,
11686; i) J. Douglas, G. Churchill and A. D. Smith, Synthesis. 2012,
2295; j) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev.
2013, 42, 4906; k) X.-Y. Chen and S. Ye, Org. Biomol. Chem. 2013, 11,
7991; l) S. De Sarkar, A. Biswas, R. C. Samanta and A. Studer, Chem-
Eur. J. 2013, 19, 4664; m) J. Mahatthananchai and J. W. Bode, Acc.
Chem. Res. 2014, 47, 696; n) M. N. Hopkinson, C. Richter, M.
Schedler, F. Glorius. Nature. 2014, 510, 485; o) D. M. Flanigan, F.
Romanov-Michailidis, N. A. White, T. Rovis. Chem. Rev. 2015, 115,
9307; p) K. Zhao, D. Enders. Angew. Chem. Int. Ed. 2017, 56, 3754.
[13] K. Zeitler, Org. Lett. 2006, 8, 637.
[14] For selected examples, see: a) J. Kaeobamrung, J. Mahatthananchai,
P. Zheng and J. W. Bode, J. Am. Chem. Soc. 2010, 132, 8810; b) S. D.
Sarkar and A. Studer, Angew. Chem. Int. Ed. 2010, 49, 9266; c) Z. Q.
Zhu and J. C. Xiao, Adv. Synth. Catal. 2010, 352, 2455; d) J.
Mahatthananchai, P. Zheng and J. W. Bode, Angew. Chem. Int. Ed.
2011, 50, 1673; e) Z.-Q. Zhu, X.-L. Zheng, N.-F. Jiang, X. Wan and J.-C.
Xiao, Chem. Commun. 2011, 47, 8670; f) A. Biswas, S. D. Sarkar, R.
Fröhlich and A. Studer, Org. Lett. 2011, 13, 4966; g) A. Biswas, S. De
Sarkar, L. Tebben and A. Studer, Chem. Commun. 2012, 48, 5190; h)
F. Romanov-Michailidis, C. Besnard and A. Alexakis, Org. Lett. 2012,
14, 4906; i) J. Mahatthananchai, J. Kaeobamrung and J. W. Bode,
ACS Catal. 2012, 2, 494; j) S. Lu, S. B. Poh, W.-Y. Siau and Y. Zhao,
Angew. Chem. Int. Ed. 2013, 52, 1731; k) Y. Lu, W. Tang, Y. Zhang, D.
Du and T. Lu, Adv. Synth. Catal., 2013, 355, 321; l) B. Zhou, Z. Luo
and Y. Li, Chem-Eur. J. 2013, 19, 4428; m) S. Bera, R. C. Samanta, C.
G. Daniliuc and A. Studer, Angew. Chem. Int. Ed. 2014, 53, 9622; n) B.
Wanner, J. Mahatthananchai and J. W. Bode, Org. Lett. 2011, 13,
5378; o) A. G. Kravina, J. Mahatthananchai and J. W. Bode, Angew.
Chem. Int. Ed. 2012, 51, 9433.
[2]
[3]
[4]
[5]
[6]
A. Kanai, T. Kamino, K. Kuramochi, S. Kobayashi. Org. Lett. 2003, 5,
2837.
a) X. Shi, W. S. Leal, Z. Liu, E. Schrader, J. Meinwald. Tetrahedron
Lett. 1995, 36, 71; b) F. Bellina, M. Biagetti, A. Carpita, R. Rossi.
Tetrahedron. 2001, 57, 2857.
[7] G. Schlingmann, L. Milne, G. T. Carter. Tetrahedron. 1998, 54, 13013.
[8] a) K. K. Chen, A. Kovarikova. J. Pharm. Sci. 1967, 56, 1535; b) Z. Liu, J.
Meinwald. J. Org. Chem. 1996, 61, 6693.
[9]
J. M. Dickinson. Nat. Prod. Rep. 1993, 10, 71.
[10] H. Sato, K. Konoma, S. Sakamura. Agric. Biol. Chem. 1981, 45, 1675.
[11] a) N. P. Shusherina, N. D. Dmitrieva, Levina, R. Y. Zhur. Obshchei
Khim. 1961, 31, 2794; b) W. H. Pirkle, M. Dines. J. Heterocyclic Chem.
1969, 6, 313; c) W. H. Pirkle, M. Dines. J. Org. Chem. 1969, 34, 2239;
d) S. Sib. Tetrahedron. 1975, 31, 2229; e) D. A. Griffin, J. C. S.
Stannton. Chem. Commun. 1975, 675.
[15] X. F. Zhu, A. P. Schaffner, R. C. Li, O. Kwon. Org. Lett. 2005, 7, 2977.
[16] P. P. Yeh, D. S. Daniels, D. B. Cordes, A. M. Slawin, A. D. Smith. Org.
Lett. 2014, 16, 964.
[17] S. Bera, A. Studer. Synthesis. 2017, 49, 121.
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Ming Lang, Qianfa Jia, and Jian Wang *
Page No. – Page No.
N-Heterocyclic Carbene-Catalyzed
Annulation of Ylides with Ynals:
Direct Access to α-Pyrones
We herein report an unprecedented NHC-catalyzed annulation of ylides with
ynals, providing an efficient protocol to make 4,6-disubstituted α-pyrones.
This method affords a variety of α-pyrones in good to high yields as well as
broad substrate scope and good functional group tolerance
.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.