Carbene Catalyzed Access to 3,6-Disubstituted α-Pyrones via Michael Addition/Lactonization/Elimination Cascade

Article abstract of DOI:10.1002/adsc.202100760

The first direct transition metal-free access to 3,6-disubstituted α-pyrones from α-chloro aldehydes and β-tosyl enones is reported. The reactions proceed via the Michael addition/lactonization/elimination cascade. The regioselective addition of NHC-bound enolates/homoenolates to the enones bearing a bulkier functionality such as tosyl group at the β-position has remained challenging. The 3,6-disubstituted α-pyrones could be converted to valuable products such as 1,2,3,4-tetrasubstituted benzenes, 1,4-disubstituted naphthalenes as well as anthracenes and 6,13-disubstituted dihydro-ethenopentacenes in a simple operation. (Figure presented.).

Full text of DOI:10.1002/adsc.202100760

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doi.org/10.1002/adsc.202100760
Carbene Catalyzed Access to 3,6-Disubstituted α-Pyrones via
Michael Addition/Lactonization/Elimination Cascade
Anil Kumar Khatana,+a, b Vikram Singh,+a Manoj Kumar Gupta,b and
Bhoopendra Tiwaria,*
a
Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road,
Lucknow-226014, India
E-mail: btiwari@cbmr.res.in
Department of Chemistry, Central University of Haryana, Mahendergarh-123031, Haryana, India
b
+
A. K. K. and V. S. contributed equally.
Manuscript received: June 18, 2021; Revised manuscript received: August 6, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100760
(Scheme 1a).[5] Despite this, their synthetic methods
are scarcely available. In 2010, Pale and co-workers
reported an elegant gold(I) catalyzed cycloisomeriza-
Abstract: The first direct transition metal-free
access to 3,6-disubstituted α-pyrones from α-chloro
aldehydes and β-tosyl enones is reported. The
reactions proceed via the Michael addition/lactoni-
zation/elimination cascade. The regioselective addi-
tion of NHC-bound enolates/homoenolates to the
enones bearing a bulkier functionality such as tosyl
group at the β-position has remained challenging.
tion of β-alkynylpropiolactones to produce 3,6-func-
tionalized α-pyrones (Scheme 1b).[6]
However, this transition metal-based method using
relatively unstable β-lactones as the substrate has
remained limited to a few substrates. It was found to
be unsuitable for α-aryl-substituted substrates (R1 =
The 3,6-disubstituted α-pyrones could be converted
Ar), whereas a poor yield was observed when R1 was
to valuable products such as 1,2,3,4-tetrasubstituted
not a methyl group (up to 33% yield). Therefore, the
benzenes, 1,4-disubstituted naphthalenes as well as
development of a new operationally simple organo-
anthracenes and 6,13-disubstituted dihydro-etheno-
catalytic method with a wide substrate scope is highly
pentacenes in a simple operation.
desired.
With our group’s core objective of developing
organocatalytic methods, we were interested to develop
Keywords: α-Pyrones; β-Tosyl enones; Cascade;
Carbenes
an N-Heterocyclic Carbene (NHC) catalyzed oxidant-
free method to access these valuable targets.[7,8] We
envisioned that enolates in reaction with the enones
bearing a leaving group would eventually produce 3,6-
α-Pyrones with a diverse backbone are highly abound disubstituted α-pyrones via the Michael addition-
in nature and pharmacologically active compounds.[1] lactonization-elimination cascade (Scheme 1c).[9] Ac-
They also serve as the versatile building blocks for cordingly, we chose to use the widely accessible α-
preparing complex targets due to multiple reactive chloro aldehydes and β-tosyl enones as the substrates.
sites.[2] Consequently, a considerable effort has been It is worth mentioning that enones bearing a bulkier β-
devoted on developing synthetic methods. Typically, substituent has remained challenging under carbene
they are accessed using transition metal-catalysts via catalysis. Very recently, Fu, Huang and co-workers
cycloaddition, ring expansion and annulation achieved [4+2] cycloaddition using β-trimethylsilyl
reactions.[3] Recently, several organocatalytic methods enones whereas the corresponding reaction with
have also been explored for the synthesis of α-pyrones phosphorylated enones was reported by our group.[10]
by Kwon, Smith, Chi and Studer.[4] 3,6-Disubstituted On the other hand, β-tosyl enones have yet remained
α-pyrones are essential skeleton in numerous marine beyond the scope of carbene catalysis.
natural products exhibiting potent biological activities
At the outset, we examined 2-chloro-3-phenyl-
like neuro-protective effects, NO production inhibition, propanal 1a and 1-phenyl-3-tosylprop-2-en-1-one 2a
antibacterial, pro-inflammatory factor inhibition, etc. as the model substrates for this cascade reaction in the
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Table 1. Optimization of the Reaction Condition.[a]
S. No.
NHC
Base
Solvent
Yield (%)[b]
1
2
3
4
5
6
7
8
A
B
C
D
D
D
D
D
D
D
D
D
D
D
–
DBU
DBU
DBU
DBU
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
toluene
CH2Cl2
CHCl3
(CH2Cl)2
CH2Cl2
CH2Cl2
0
12
23
54
51
38
65
72
54
76
97
91
90
65
0
TMG
DABCO
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14[c]
15
[a] Standard reaction condition, unless otherwise specified: 1a
(0.2 mmol), 2a (0.1 mmol), NHC A–D (20 mol%), Cs2CO3
(200 mol%), solvent (1.5 mL) at rt for 12 h.
Scheme 1. 3,6-Disubstitued α-Pyrones: Naturally Occurring
Bioactive Scaffolds and Synthetic Methods.
[b] Isolated yield of 3a.
[c] 100 mol% of Cs2CO3 used. DBU=1,8-Diazabicycloundec-
7-ene, DABCO=1,4-Diazabicyclo [2.2.2] octane, TMG=
1,1,3,3-Tetramethyl guanidine.
presence of DBU as a base in THF (Table 1). Different
NHC precatalysts were evaluated under this condition.
Among them, imidazolium salt A was found to be
ineffective and the thiazolium salt B gave the desired
product 3a in a trace amount (entries 1 and 2). The use NHC catalyst failed to produce the product (entry 15).
of pyrrolidinone-based triazolium salt C bearing The use of other enolate precursors like cinnamalde-
NÀ C6F5 group produced the desired product in 23% hyde and its saturated analogue in the presence of
yield (entry 3). Switching to the corresponding N-Mes 3,3’,5,5’-tetra-tert-butyldipheno-quinone as an oxidant,
protected catalyst D produced 3a in a decent yield of cyclopropanecarbaldehyde or 4-nitrophenyl-3-phenyl-
54% (entry 4). A higher yield with catalyst D in propanoate instead of 1a was found to be inefficient
comparison to C may be attributed to the irreversible under the optimized reaction condition.
addition of the former to 1a, thereby accelerating the
With a set of optimal reaction condition in hand, we
formation of the Breslow intermediate.[11] We next moved on to evaluate the scope of this NHC-catalyzed
screened various organic and inorganic bases using cascade reaction with respect to α-chloro aldehydes 1
catalyst D. The use of other organic bases such as in reaction with tosyl enone 2a (Table 2). The β-aryl
TMG and DABCO furnished 3a in a reduced yield aldehydes 1 with an electron-donating substituent such
(entries 5 and 6). Among the different inorganic bases as methyl or methoxy groups at para, meta or ortho-
employed, Cs2CO3 provided 3a in an improved yield position reacted well to produce 3b-3e in an excellent
of 72% (entries 7 and 8). We next tested different yield. Likewise, electron-withdrawing substituents on
solvents such as CH3CN, toluene, CH2Cl2, CHCl3 and the aryl ring were well tolerated, giving the desired α-
(CH2Cl)2 (entries 9–13). Gratifyingly, a number of pyrones in 89–91% yields (3f–3g). Replacing the β-
chlorinated solvents were found to be equally good for phenyl substituent with either a naphthyl or heteroaryl
this reaction and 3a was obtained in an excellent yield unit did not affect the yield (3h–3j). The reaction
of 97% in CH2Cl2 (entry 11). A reduced loading of condition was amenable to the presence of an
Cs2CO3 from 200 mol% to 100 mol% led to the unsaturated moiety, affording 3k in a good yield. We
formation of 3a with a diminished yield (65%, next investigated aliphatic aldehydes with a varied
entry 14). A control experiment in the absence of any carbon chain length. Pleasantly, chloro aldehydes
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Table 2. Scope of α-Chloro aldehydes.[a]
Table 3. Scope of β-Tosyl enones.[a]
[a] Standard reaction condition as in entry 11, Table 1. Yields
are the isolated yields after column chromatography.
[a] Standard reaction condition as in entry 11, Table 1. Yields
are the isolated yields after column chromatography.
derived from 4-phenyl butanal, pentanal and octanal a competing conjugated olefin functionality, reacted
led to the products 3l–3n in excellent yields. The use chemoselectively to furnish 3ad in 78% yield. A more
of 2-phenyl chloroacetaldehyde generated 3-aryl sub- sterically challenging β-phenyl substituted enone 2 did
stituted pyrone 3o, albeit with a slightly lower yield not react under this condition.
under the optimal reaction condition. A gram scale
synthesis (1.0 g, 3.5 mmol, of 2a) was also performed ing blocks for the preparation of molecules that are
to obtain 3a in 89% isolated yield. difficult to access otherwise. They were transformed to
The 3,6-disubstituted α-pyrones make unique build-
Encouraged by the scope of the reaction for a wide a variety of highly functionalized arenes and polyar-
range of chloro aldehydes, we next strived to expand omatic hydrocarbons (PAHs) (Scheme 2). For instance,
the generality of this cascade reaction using a variety the reaction of 3a with Lawesson’s reagent in toluene
of tosyl enones 2 in reaction with 1a (Table 3). The afforded 3,6-disubstituted pyran-2-thione 4a in 85%
electron-rich aryls, bearing a methyl substituent at yield. A highly substituted benzene 4b could be
ortho, meta or para-position, were well tolerated, obtained in 78% yield via Diels-Alder reaction of 3a
leading to the formation of α-pyrones in 87–94% with dimethylacetylene dicarboxylate, followed by
yields (3p–3r). A bulkier tert-butyl group on the ring decarboxylation. The treatment of 3a with a benzyne
did not affect the yield (92%, 3s). The enones precursor in CH3CN gave 5,8-disubstituted naphtho-
incorporating other high-electron donating groups like 1,3-dioxol 4c in 73% yield. Interestingly, the use of
methoxy, N,N-dimethylamine or even disubstitution on 2,3-naphthynes instead of sesamol-derived benzyne
the aryl ring smoothly converted to the pyrones in 83– provided a separable mixture of 1,4-disubstituted
93% yield (3t–3v). Behaving similar to electron-rich anthracene 4d and 6,13-disubstituted dihydroetheno-
aryls, the electron-deficient aryls loaded with flouro, pentacene 4d’.
chloro, bromo and nitro groups were also compatible
In conclusion, we have developed the first direct
under the reaction condition (3w–3z, 83–91% yield). organocatalytic method for the preparation of 3,6-
We subjected naphthyl as well as heteroaryl-derived disubstituted α-pyrones via Michael addition-lactoniza-
substrates to the standard condition to obtain 3aa–3ac tion-elimination cascade from α-chloro aldehydes and
in excellent yields. Pleasantly, the enones 2ad having β-tosyl enones. The sterically hindered β-tosyl enones
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Scheme 2. Transformation of 3a.
that remained beyond the scope of NHC-catalysis till
now, reacted smoothly to give the desired products in
good to excellent yield. This method greatly improves
the availability of the 3,6-functionalized pyrones,
hitherto limited to a few, in terms of substitution
pattern on the ring. The products could be easily
transformed to 1,2,3,4-tetrasubstituted benzenes, 5,8-
disubstituted naphtho-1,3-dioxol, 1,4-disubstituted an-
thracenes and 6,13-disubstituted dihydro-ethenopenta-
cenes in a simple operation. Further application of β-
tosyl enones under NHC catalysis is being explored in
our lab.
Experimental Section
General Procedure for the Synthesis of
3,6-Disubstituted α-Pyrones
To an oven-dried Schlenk tube equipped with a magnetic
stirring bar, was added NHC-pre-catalyst D (0.02 mmol,
20 mol%), β-tosyl enones 2 (0.1 mmol, 1.0 equiv.) under an
argon atmosphere. The tube was sealed with a septum,
evacuated and refilled with argon (3 cycles). Dichloromethane
(1.5 mL), α-chloro aldehyde 1 (0.2 mmol, 2.0 equiv.) and
Cs2CO3 (0.2 mmol, 2.0 equiv.) were added and the reaction
mixture was stirred at room temperature for 12 hours. After
completion of the reaction, the reaction mixture was concen-
trated under reduced pressure and the residue was subjected to
column chromatography using hexane/ethyl acetate as eluent to
afford the desired product 3.
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Carbene Catalyzed Access to 3,6-Disubstituted α-Pyrones via
Michael Addition/Lactonization/Elimination Cascade
Adv. Synth. Catal. 2021, 363, 1–6
A. K. Khatana, V. Singh, M. K. Gupta, B. Tiwari*