Efficient and atom-economic synthesis of α-substituted β-chromonyl-α,β-unsaturated carbonyls through molecular rearrangement

Article abstract of DOI:10.1055/s-0029-1219176

Under mild acidic conditions [4+2] cycloadducts of 3-formylchromones and acetylenecarboxylates rearrange to yield -substituted - chromonyl-,-unsaturated carbonyl compounds in excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219176

LETTER
403
Efficient and Atom-Economic Synthesis of a-Substituted b-Chromonyl-
a,b-unsaturated Carbonyls through Molecular Rearrangement
S
a
ynthesis of
a-Sub
i
stituted
v
-
b
-chromon
e
yl-
a
,
b
-unsa
k
turated Carbonyls Khedkar,a Wei Liu,a,b Heiko Dückert,a,b Kamal Kumar*a
Max Planck Institut für Molekulare Physiologie, Otto-Hahn Str. 11, 44227 Dortmund, Germany
Fax +49(231)1332496; E-mail: Kamal.Kumar@mpi-dortmund.mpg.de
b
Technische Universität Dortmund, Fachbereich Chemie, 44221 Dortmund, Germany
Received 23 October 2009
for the Wittig reaction is one limitation, the facile addition
of carbon nucleophile to highly electrophilic C-2 carbon
of the 3-formylchromones (1) leading to chromone ring
opening3 makes them hard substrates for condensation re-
actions too. Moreover, atom-economic alternatives to al-
dol condensation and Wittig olefination are always
desired. Recently, we discovered a novel phosphine-
catalyzed [4+2]-annulation reaction between 3-formyl-
chromones 1 and electron-deficient acetylene carboxy-
lates 2.5a However, during attempts to resolve the
enantiomers of the adduct 3 using chiral HPLC, partial
transformation of 3 into another compound was observed.
Suspecting that the trifluoroacetic acid (TFA) present in
the solvent system was responsible for this transforma-
tion, pure adduct 3a was treated overnight with 1% TFA
in dichloromethane. A simple silica gel column chromato-
graphic purification of the crude reaction mixture yielded
the dimethyl-2-oxo-3-[(4-oxo-4H-chromene-3-yl)meth-
ylene]succinate (4a) in 55% yield (Scheme 1).
Abstract: Under mild acidic conditions [4+2] cycloadducts of
3-formylchromones and acetylenecarboxylates rearrange to yield
a-substituted-b-chromonyl-a,b-unsaturated carbonyl compounds in
excellent yields.
Key words: benzopyrones, rearrangements, cascade reactions,
acetylenecarboxylates
Benzopyrone scaffold is one of the privileged molecular
frameworks embodied by many natural products display-
ing diverse biological activities.1 It had inspired chemists
to generate compound libraries based on benzopyrone and
related molecular architectures for medicinal chemistry
and chemical biology investigations.2 To get an easy ac-
cess to a large number of diverse molecules based on ben-
zopyrone scaffold, the substrates should be either
commercially available or accessible by efficient synthet-
ic processes. For instance, commercially available substi-
tuted 3-formylchromones3 have been extensively
employed in the synthesis of skeletally diverse compound
collections.4 In the same context, benzopyrone-substitut-
ed olefins can be regarded as important precursors for
generating diverse hetero- and carbocyclic molecules.4d
These olefins in principle can be obtained either by Wittig
olefination of chromone aldehydes with phosphorus
ylides or by an aldol condensation reaction with active
methylene carbonyls under basic reaction conditions.
However, if the availability of the desired phosphoranes
Further, we observed that increasing the concentration of
TFA to 10% in dichloromethane could complete the reac-
tion in half an hour and yielding 4a quantitatively. On the
other hand catalytic amounts of the TFA could not com-
plete the reaction even after 48 hours. Although, BF3·OEt2
completed the reaction within ten minutes with slightly re-
duced yield of 4a, we preferred to use the milder reaction
conditions with TFA for this transformation.6
O
O
R1
R1
R2
R5O2C
R4
4
O
O
2
2
toluene, Ph3P (cat.)
R2
O
2
O
R4
CO2R5
r.t.
R3
R3
ref. 5a
3
1
O
O
O
2´
4
O
10% TFA , 30 min
CO2Me
CO2Me
2
O
CO2Me
CO2Me
O
3a
4a
Scheme 1
SYNLETT 2010, No. 3, pp 0403–0406
1
2.
0
2.
2
0
1
0
Advanced online publication: 07.01.2010
DOI: 10.1055/s-0029-1219176; Art ID: G31909ST
© Georg Thieme Verlag Stuttgart · New York

404
V. Khedkar et al.
LETTER
Structure of the product 4a was corroborated by spectro- Table 1 Rearrangement of the Adducts 3 to 4a
scopic analysis.7–9 Whereas the mass analysis revealed 4a
O
O
to be isomeric to the substrate, disappearance of singlet
R3O2C
O
R1
R4
peak for C2-H of 3a and appearance of one for an olefinic
O
R1
proton (in aromatic region) in 1H NMR spectrum suggest-
R2
O
R4
CO2R3
ed the rearrangement of the adduct 3. Further, appearance
of a doublet at d = 8.32 ppm for one proton (with long-
range coupling to another proton at d = 7.50 ppm) in the
1H NMR spectrum (for C2-H of 4a) and the appearance of
C-4 at d = 174 ppm10 in the 13C NMR spectrum indicated
the intact chromone moiety with an a,b-unsaturated
carbonyl branch on C-3. The ketone carbonyl of the
ketoesters moiety appeared at d = 180.8 ppm in the 13C
NMR spectrum confirming the structure to be 4a.
R2
O
3
4
Entry
1
R1
H
R2
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
R3
R4
Yield of 4 (%)b
4a 99
4b 94
4c 98
Me
Me
Me
Et
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
H
2
Cl
i-Pr
i-Pr
Me
H
3
The reaction yielded the conjugated ketoesters decorated
with a substituted benzopyrone moiety in excellent yields
(Table 1, entries 1–7). Interestingly, when 3h supporting
only one ester moiety was treated with TFA, conjugated
aldehyde 4h was obtained in very good yield (entry 8,
Table 1).8 Substrates 3i–n yielded the corresponding b-
chromonyl acrylates 4i–n in acceptable yields (entries 9–
14, Table 1). Further, employing the adduct 3o supporting
a phenyl group yielded the corresponding phenyl ketone
4o9 in good yield (entry 15, Table 1).
4
4d 98
4e 91
5
Et
6
Et
4f 97
7
Cl
H
Et
4g 91
4h 87
4i 94
8
Me
Me
Me
t-Bu
Me
Me
Me
Et
9
Cl
Me
H
H
10
11
12
13
14
15
H
4j 92
The NMR spectra and LC-MS analysis clearly indicated
the formation of a single isomer of 4. The configuration of
the molecules 4 was elucidated with the help of 1D NOE
NMR experiments. Selective irradiation of the aldehydic
proton in 4m led to enhancement of the signal for C1¢-H.
On irradiating the latter, a clear enhancement for the C2-
H (and vice versa) was observed, thus establishing the Z-
configuration to the molecule (Figure 1, A). Similar NOE
effects were observed in the case of ketoester 4f. While ir-
radiation of C2-H in 4f resulted in signal enhancement for
C1¢-H; the latter on irradition led to the signal enhance-
ment for C2-H besides a weak signal enhancement for the
methylene(-OCH2Me) proton of ketoester (established by
HMBC and HSQC NMR experiments, Figure 1, B). Thus,
E-configuration was assigned to the ketoesters 4a–g.
H
4k 98
4l 88
i-Pr
Cl
Br
H
H
H
4m 82
4n 83
4o 89
H
Ph
a Reaction conditions: 10% TFA in CH2Cl2, 30 min, r.t.
b Isolated yields after flash column chromatography.
after a single-bond rotation to avoid the steric proximity
of the ester functionality to the benzopyrone ring. Alterna-
tively, the Claisen ring opening of 6 would yield the iso-
mer of observed product 4¢ which could isomerize via
acid-catalyzed tautomerism to 7 before transforming to 4
(Scheme 2).11
(A)
(B)
O
O
MeO2C
O
EtO2C
O
O
O
H
In order to make a direct access to the products 4 employ-
ing commercially available 3-formylchromones, a one-
pot, two-step procedure was developed. To this end, 3-
formylchromone was treated with dimethylacetylene-di-
carboxylate (DMAD) and triphenylphosphine to yield the
[4+2] adduct 4a. After completion of the reaction (TLC),
it was quenched by slow addition a solution of 10% TFA
in dichloromethane at low temperature (0–4 °C) and stir-
ring the solution at room temperature for three to four
hours (TLC).
Cl
1´
H
1´
H
2
NOE
O
H
O
H
NOE
(E)-4f
(Z)-4m
Figure 1
Mechanistically, we assume that the [4+2] adducts 3 act as
push–pull system under acidic conditions. Facilitated by
the formation of aromatic pyrilium cation, the chromone
ring would open up yielding 5 which undergoes intramo-
lecular addition of the phenol leading to cyclic allyl vinyl
ether 6 formation. The latter could undergo protonation
and ring opening of the dihydropyran ring forming an ex-
tended enol 7 which tautomerize to the observed product
Although, by this method we could avoid the purification
of adducts 3, the yields of the rearrangement products 4
were clearly compromised (Scheme 3).
In summary, we have discovered a very efficient, easy,
and atom-economic cascade synthesis of benzopyrone-
Synlett 2010, No. 3, 403–406 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Substituted-b-chromonyl-a,b-unsaturated Carbonyls
405
O
O
+
O
O
H+
chromone
ring opening
R1
CO2R2
O
R1
CO2R2
OH
5
3
H+
O
O
O
O
R1
H+
CO2R2
OH
CO2R2
protonation and
ring opening
O
R1
+
6
7
isomerization
Claisen ring
opening
O
O
O
CO2R2
R1
R2O2C
O
R1
O
O
4´
4
Scheme 2 Cascade rearrangement of adducts 3 to 4
O
O
R2O2C
O
i) R2O2C
Ph3P (40 mol%), r.t., 8 h
CO2R2
R1
CO2R2
O
R1
ii) 10% TFA in CH2Cl2, r.t., 3–4 h
O
O
3
4a; R1 = H, R2 = Me (55%)
4d; R1 = i-Pr, R2 = Me (57%)
4e; R1 = Me, R2 = Et (59%)
Scheme 3 One-pot synthesis of 4 from commercially available 3-formylchromones
substituted acrylates and oxosuccinates. The significance
of this methodology could be realized from the fact that
other possible routes to these molecules should be multi-
step and tedious considering the reactivity of 3-formyl-
chromones.3,12 The reactive aldehyde and ketoester
functionalities in the molecules 4 would always compete
with substrates in alternative routes.13 We are currently
exploring the applications of these molecules in com-
pound library syntheses which shall be reported in the
near future.
References and Notes
(1) (a) Veitch, N. G.; Grayer, R. J. Nat. Prod. Rep. 2008, 25,
555. (b) Harborne, J. B.; Williams, C. A. Nat. Prod. Rep.
1995, 12, 639. (c) Harborne, J. B.; Williams, C. A. Nat.
Prod. Rep. 1998, 15, 631. (d) Harborne, J. B.; Williams,
C. A. Nat. Prod. Rep. 2001, 18, 310. (e) Williams, C. A.;
Grayer, R. J. Nat. Prod. Rep. 2004, 21, 539. (f) Ferreira, D.;
Slade, D.; Marais, J. P. J. In Flavonoids: Chemistry,
Biochemistry and Applications; Andersen, O. M.; Markham,
K. R., Eds.; CRC Press: Boca Raton, 2006, 553–616.
(g) Veitch, N. C. Nat. Prod. Rep. 2007, 24, 417.
(h) Reynaud, J.; Guilet, D.; Terreux, R.; Lussignol, M.;
Walchshofer, N. Nat. Prod. Rep. 2005, 22, 504.
Acknowledgment
(i) Mackova, Z.; Koblovska, R.; Lapcik, O. Phytochemistry
2006, 67, 849. (j) Flavonoids: Chemistry, Biochemistry and
Applications; Andersen, O. M.; Markham, K. R., Eds.; CRC
Press: Boca Raton, 2006. (k) The Flavonoids: Advances in
Research since 1986; Harborne, J. B., Ed.; Chapman and
Hall: London, 1994. (l) The Science of Flavonoids;
Authors are grateful to Max Planck Gesellschaft for the financial as-
sistance and Prof. H. Waldmann, MPI Dortmund, for his support
and encouragement.
Grotewold, E., Ed.; Springer: New York / London, 2006.
(m) Maurya, R.; Yadav, P. P. Nat. Prod. Rep. 2005, 22, 400.
Synlett 2010, No. 3, 403–406 © Thieme Stuttgart · New York

406
V. Khedkar et al.
LETTER
(2) Selected reports: (a) Dahlen, K.; Wallen, E. A. A.; Grotli,
M.; Luthman, K. J. Org. Chem. 2006, 71, 6863. (b) Bhat,
A. S.; Whetstone, J. L.; Brueggemeier, R. W. J. Comb.
Chem. 2000, 2, 597. (c) Patil, N. T.; Huo, Z.; Yamamoto, Y.
Tetrahedron 2007, 63, 5954.
CHO), 8.66 (d, J = 0.8 Hz, 1 H), 8.28–8.24 (m, 2 H), 7.73 (d,
J = 0.8 Hz, 1 H), 7.52–7.44 (m, 2 H), 3.89 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d = 189.3, 174.8, 165.6, 158.4, 155.8,
140.8, 134.5, 133.8, 126.4, 126.3, 123.6, 118.4, 118.3, 52.6.
ESI-HRMS: m/z calcd for C14H11O5 [M + H+]: 259.06010;
found: 259.06017.
(3) (a) Sabitha, G. Aldrichimica Acta 1996, 29, 15. (b) Ghosh,
C. K.; Patra, A. J. Heterocycl. Chem. 2008, 45, 1529.
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Choudhary, M. Bioorg. Med. Chem. 2009, 17, 2983.
(b) Sersen, F.; Loos, D.; Mezesova, L.; Lacova, M. Med.
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Anticancer Res. 2008, 28, 277. (d) Dang, A.; Miller, D. O.;
Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233.
(e) Kawase, M.; Tanaka, T.; Kan, H.; Tani, S.; Nakashima,
H.; Sakagami, H. In Vivo 2007, 21, 829. (f) Barath, Z.;
Radics, R.; Spengler, G.; Ocsovszki, I.; Kawase, M.;
Motohashi, N.; Shirataki, Y.; Shah, A.; Molnar, J. In Vivo
2006, 20, 645.
(9) Spectroscopic Data for the Phenyl Ketone 4o
Yellow solid; mp 171–173 °C; Rf = 0.45 (cyclohexane–
EtOAc, 6:4). 1H NMR (400 MHz, CDCl3): d = 8.18–8.16
(dd, J = 1.3, 8.4 Hz, 1 H), 8.15 (d, J = 1.0 Hz, 1 H), 8.05 (d,
J = 1.0 Hz, 1 H), 7.93–7.91 (dd, J = 1.3, 8.4 Hz, 1 H), 7.63
(td, J = 7.8 Hz, 1 H), 7.55–7.35 (m, 5 H), 7.28–7.25 (m, 1 H),
4.25–4.19 (q, J = 7.1 Hz, 2 H), 1.17 (t, J = 7.1 Hz, 3 H). 13
NMR (100 MHz, CDCl3): d = 194.5, 175.2, 164.3, 156.2,
155.8, 140.6, 136.1, 134.1, 133.8, 132.9, 129.8, 129.0,
C
128.7, 128.5, 126.1, 125,7, 123.5, 119.0, 118.1, 61.5, 13.9.
ESI-HRMS: m/z calcd for C21H17O5 [M + H+]: 349.10705;
found: 349.10719.
(5) (a) Waldmann, H.; Khedkar, V.; Dückert, H.; Schürmann,
M.; Oppel, I. M.; Kumar, K. Angew. Chem. Int. Ed. 2008, 47,
6869. (b) Terzidis, M. A.; Dimitriadou, E.; Tsoleridis, C. A.;
Stephanidou-Stephanatou, J. Tetrahedron Lett. 2009, 50,
2174.
(10) (a) Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett.
1998, 39, 6547. (b) Ishar, M. P. S.; Singh, G.; Kumar, K.;
Singh, R. Tetrahedron 2000, 56, 7817.
(11) The authors appreciate the comments from one of the
referees regarding the mechanistic postulations.
(6) General Procedure for the Rearrangement of the
Adducts 3 to 4
(12) Neo, A. G.; Carrillo, R. M.; Barriga, S.; Momán, E.;
Marcaccini, S.; Marcos, C. F. Synlett 2007, 327.
TFA (1 mL in 5 mL CH2Cl2) was added slowly dropwise to
the CH2Cl2 solution (5 mL) of the tricyclic benzopyrones 3
(1 mmol). The reaction mixture was stirred at r.t. for 30 min
under argon. The reaction was monitored by TLC using
cyclohexane–EtOAc (7:3) as eluent. After evaporation of the
solvent, the crude product was purified by column chroma-
tography on silica gel with cyclohexane–EtOAc as the
eluent.
(13) An alternative synthesis of 4 by a Wittig olefination of 3-
formylchromone would require the corresponding ketoester
or aldehydic phosphoranes which are not commercially
available and require multistep synthesis and also remain
susceptible to self-olefination and polymerization reaction.
The same is true for the alternative aldol condensation
strategy to provide 4 by reacting chromone aldehydes with
ketoester 7. Using our previously reported methodology14 to
condense 1,3-dicarbonyls with 3-formylchromone, we could
observe self-condensation products of 7 but not any
formation of 4a (Scheme 4).
(7) Spectroscopic Data for the Ketoester 4a
Yellow solid; mp 177–178 °C; Rf = 0.33 (cyclohexane–
EtOAc, 6:4). 1H NMR (400 MHz, CDCl3): d = 8.32 (d,
J = 0.7 Hz, 1 H), 8.21–8.19 (dd, J = 1.6, 8.0 Hz, 1 H), 7.63
(td, J = 1.6, 7.8 Hz, 1 H), 7.50 (d, J = 0.7 Hz, 1 H), 7.49–7.47
(dd, J = 1.0, 7.4 Hz, 1 H), 7.43 (td, J = 1.0, 7.4 Hz, 1 H), 3.98
(s, 3 H), 3.82 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
180.8, 174.0, 164.8, 161.1, 159.6, 155.7, 134.6, 132.9,
131.6, 126.7, 126.2, 123.3, 118.3, 118.0, 53.1, 52.6. ESI-
HRMS: m/z calcd for C16H13O7 [M + H+]: 317.06558; found:
317.06568.
O
MeO2C
CO2Me
7
3a
4a (not formed)
NaOAc, Ac2O, 80 °C
Scheme 4
(8) Spectroscopic Data for the Aldehyde 4h
Yellow solid; mp 120–122 °C; Rf = 0.39 (cyclohexane–
EtOAc, 6:4). 1H NMR (400 MHz, CDCl3): d = 9.71 (s, 1 H,
(14) Waldmann, H.; Kühn, M.; Liu, W.; Kumar, K. Chem.
Commun. 2008, 1211.
Synlett 2010, No. 3, 403–406 © Thieme Stuttgart · New York

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