Exploring α-chromonyl nitrones as 1,5-dipoles

Article abstract of DOI:10.1055/s-0031-1290070

N-Phenyl-C-chromonyl nitrones 1 and the allenoate zwitterion 2, generated by addition of phosphine to acetylenedicarboxylates, undergo a cascade reaction sequence involving an unprecedented [5+3] annulation followed by deoxygenative rearrangement leading to dihydropyridine-fused benzopyrones. Unusual electronic control by the N-substituents of 1 directs the annulation pathway, leading to two different ring-systems. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290070

LETTER
227
Exploring a-Chromonyl Nitrones as 1,5-Dipoles
a
-Chromonyl
Nitro
a
nes as 1,5-
t
D
ipole
h
s
rin Wittstein,a,b Ana B. García,a Markus Schürmann,c Kamal Kumar*a,b
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
c
Technische Universität Dortmund, Fachbereich Chemie, Chemische Biologie, 44221 Dortmund, Germany
Technische Universität Dortmund, Anorganische Chemie, 44221 Dortmund, Germany
Received 17 October 2011
in, we report the first case of trapping nitrone 1 as a 1,5-
dipole in a cascade sequence of annulation–rearrangement
reaction with a phospha-zwitterion derived from dimethyl
acetylenedicarboxylate (DMAD), leading to novel dihy-
Abstract: N-Phenyl-C-chromonyl nitrones 1 and the allenoate
zwitterion 2, generated by addition of phosphine to acetylenedicar-
boxylates, undergo a cascade reaction sequence involving an un-
precedented [5+3] annulation followed by deoxygenative
rearrangement leading to dihydropyridine-fused benzopyrones. Un- dropyridine fused benzopyrones.
usual electronic control by the N-substituents of 1 directs the annu-
lation pathway, leading to two different ring-systems.
O
R1
R2
R3
Keywords: nitrones, dipolar cycloadditions, acetylene carboxy-
lates, cascade reactions, zwitterions
4
R2O
O
PR1
N
O
C
2
O
CO2R2
2
1
(1,3-dipole OR 1,5-dipole)
Ring systems form the core of many natural products and
drug molecules and provide the spatial arrangement for
interacting with proteins and other macromolecules.1 Al-
though the biological relevance of scaffolds that exist in
natural products or privileged frameworks of drugs (for
instance, benzodiazepines) makes them useful starting
points for compound library synthesis,2 there is always a
demand and scope for novel molecular architectures in
medicinal chemistry and drug discovery reasearch.3 Con-
sequently, new annulation reactions that provide access to
new ring systems are highly desirable. We have been ex-
ploring the annulation chemistry of electronically similar
substrates with the expectation that this might provide in-
teresting and novel scaffolds that are amenable to the syn-
thesis of focused compound collections.4 For instance, we
have recently developed a [4+2] annulation between elec-
tron-deficient oxadienes and electron-poor acetylenes,
leading to tricyclic benzopyrones.4a–c In a continuation of
this program, and seeking access to unprecedented ring-
systems based on the privileged benzopyrone scaffold, we
wanted to examine whether the two dipoles, a nitrone 15
and a zwitterion 26 (generated in situ by addition of phos-
phine to acetylenedicarboxylates; Figure 1) would under-
go an annulation reaction.
1a; R1 = R3 = Me, R2 = H
1b; R1 = Cl, R2 = R3 = Me
1c; R1 = Me, R2 = H, R3 = Bn
1d; R1 = R2 = H, R3 = Bn
O
N
R
R
1e; R1 = Cl, R2 = H, R3 = Bn
1f; R1 = Me, R2 = H, R3 = Ph
1g; R1 = Cl, R2 = Me, R3 = Ph
1h; R1 = R2 = H, R3 = Ph
3
(1,3-dipole)
R = aryl or alkyl
1i; R1 = i-Pr, R2 = H, R3 = Ph
Figure 1 Dipolar species used to probe reactivity
However, rearrangement of nitrones 1 to products 4 and 5
is quite facile (Scheme 1)9 and, in the absence of reactive
partners, could prove to compete strongly with the envis-
aged annulation/cycloaddition reactions.
O
H
O
H
intramolecular
rearrangement
O
H
NHR
1
+
O
O
O
N
R
4
5
Scheme 1 Rearrangement of nitrone 1 yields 4 and 5
Although [3+2] cycloaddition reactions of nitrone 1 with
electron-deficient olefines have been reported, similar at-
tempts with electron-poor alkynes remain unprecedented.
Before employing the zwitterion 2 with nitrone 1, a reac-
tion of N-methylnitrone 1a with DMAD in dichlo-
romethane at room temperature was attempted
(Scheme 2); this led to the formation of [3+2] adduct 6a
(35% yield; Table 1, entry 1) along with the nitrone rear-
rangement products 4 and 5. No trace of a plausible [5+2]
cycloadduct was observed. Increasing the reaction tem-
perature led only to increased amounts of the rearranged
products (Table 1, entry 2).
Similar to nitrones 3, benzopyrone nitrones of type 1 have
been reported to undergo [3+2] cycloadditions with both
electron-rich and electron-deficient olefins.5 We were cu-
rious to realize the potential of nitrone 1 as a 1,5-dipole in
annulation chemistry because this would provide novel
ring-systems embodying the benzopyrone scaffold. In
general, a 1,5-dipolar cycloaddition/annulation reaction
of any conjugated nitrone7 remains unprecedented.8 Here-
SYNLETT 2012, 23, 227–232
x
x.
x
x.
2
0
1
1
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290070; Art ID: B56411ST
© Georg Thieme Verlag Stuttgart · New York

228
K. Wittstein et al.
LETTER
Me
O
N
O
O
CO2Me
MeO2C
CO2Me
Me
Me
Me
4
N
O
CH2Cl2
CO2Me
2
O
O
1a
6a
Scheme 2
corresponding imines.4a–c,10 Therefore, we were expecting
a similar addition of allenoate 2 on the C2 of nitrone 1,
which may trap it as a 1,5-dipole. To this end, reactions of
zwitterion 2, generated by different Lewis base nucleo-
philes (Table 1, entries 3–8), were attempted with 1. Em-
ploying triphenylphosphine neither provided the [5+2]
adduct nor enhanced the yield of 6a (Table 1, entries 3 and
4). Electron-poor phosphine (PhCF3)3P was as good as
Ph3P at yielding 6a (entry 5) but did not provide any [5+2]
cycloadduct. In contrast, electron-rich phosphine and ter-
tiary amine DABCO did not provide any cycloadduct at
all (Table 1, entries 6 and 7). Garicia-Tellado and co-
workers had reported an ‘on-water’ [3+2] cycloaddition
of nitrones with allenoate 2.11 However, in our hands,
these reaction conditions also failed to yield any cyclo-
adduct of DMAD with 1 (Table 1, entry 8).
Table 1 [3+2] Cycloaddition of Nitrone 1 with DMAD
Entry
Additive (equiv)
–
Temp
r.t.
Yield 6a (%)a
1
2
3
4
5
6
7
8
35
15
30
32
30
–
–
40 °C
r.t.
Ph3P (0.2)
Ph3P (1.2)
r.t.
(PhCF3)3P (1.2)
(NMe2)3P (1.2)
DABCO (1.3)
Ph3P (1.2) + H2O (3 M LiOH)
r.t.
r.t.
r.t.
–
r.t.
–
a Isolated yield.
N-Methyl- and N-benzyl-C-chromonyl nitrones also pro-
vided the corresponding [3+2] cycloadducts with acety-
lenedicarboxylates (Scheme 3). Interestingly, while N-
methyl nitrones provided only moderate yields of adducts
6a and 6b, reactions of N-benzyl nitrones were both clean-
er and higher yielding (6c–e). It should be noted that most
Zwitterionic nucleophiles, generated by addition of phos-
phines to acetylenecarboxylates or allenic esters, often
add to the highly electrophilic C2 position of conjugated
chromone systems, including 3-formylchromone and its
Alkyl
O
O
O
N
R3O2C
CO2R3
R1
R2
Alkyl
R1
R2
CO2R3
(2.0 equiv)
N
O
CO2R3
CH2Cl2
r.t., 48 h
O
O
(1)
(6)
Me
Bn
Me
O
O
N
O
O
O
O
N
N
Cl
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Me
O
O
O
6a (35%)
6b (13%)
6c (22%)
Bn
O
Bn
O
O
N
O
N
CO2Me
Cl
CO2Et
CO2Me
6d (80%)
CO2Et
O
O
6e (58%)
nOe
O
O
O
N
N
O
Ha
O
CO2Me
CO2Me
CO2Me
CO2Me
7 (5+2 adduct; not formed)
Ha
O
6d (3+2 adduct)
Scheme 3 [3+2] Cycloaddition of N-alkyl-C-chromonyl nitrones with acetylenedicarboxylates
Synlett 2012, 23, 227–232
© Thieme Stuttgart · New York

LETTER
a-Chromonyl Nitrones as 1,5-Dipoles
229
of the spectroscopic data fits well with both of the molec- rangement of nitrone 1 remained the favored transforma-
ular structures of [3+2] (6) and [5+2] adducts (7), render- tion and could not be avoided. Other substituted nitrones
ing structural assignment quite difficult. However, a were also successfully employed to yield novel dihydro-
strong NOE interaction between the Ha proton with the pyridine-fused benzopyrones in moderate yields
benzylic protons in 6d favored the formation of [3+2] ad- (Scheme 4c).13–15
ducts (Scheme 3). Furthermore, a carbon signal for the
Formation of cycloadduct 8 in the above reactions was
vinylogous ester (C4 appearing at d = 176.5 ppm) and C2
quite an unexpected result. We considered whether triph-
(d = 155 ppm) clearly indicated the intact chromone moi-
enylphospine had induced any deoxygenation16 of nitrone
ety in 6d.5a
leading to an azadiene 9 that might involve DMAD to
To our surprise, when N-phenyl nitrone 1f was employed form 8. In separate experiments, treatment of 1g with
in the reaction with DMAD, no [3+2] cycloaddition prod- triphenylphosphine under the annulation reaction condi-
uct was obtained. Anticipating an addition of nucleophilic tions and also in the presence of acceptor diethyl azodicar-
zwitterion 2 to 1f, the reaction was attempted with a cata- boxylate (DEAD) did not result in any deoxygenation
lytic amount (20 mol%) of triphenylphosphine. However, (Scheme 4b), which thus ruled out this reaction pathway.
only trace amounts of a new addition product was ob-
tained. The yield of the latter increased with the amounts
of PPh3 and reached a maximum using 1.2 equivalent of
phosphine (Scheme 4). The structure of this adduct was
A plausible mechanism for the formation of adduct 8 is
depicted in Scheme 5. We assume that the two dipoles, for
instance, nitrone 1f and zwitterion 2 derived from DMAD
and triphenylphosphine, add initially in a [5+3] annula-
unambiguously established by X-ray crystallographic
tion (either in a concerted or stepwise manner) yielding an
analysis to be a dihydropyridine fused benzopyrone
eight-membered-ring intermediate 10. Larger rings facili-
(8a).12 Other nucleophiles presented in Table 1, however,
tate hydride shifts17 and a 1,3-hydride shift in 10 provides
failed to deliver 8a under a range of reaction conditions
intermediate 11. The latter eliminates phosphine oxide
(using 20 mol% to 2.0 equivalents; from room tempera-
leading to imine 12, which eventually undergoes 6p elec-
trocyclization to yield the tricyclic benzopyrone 8a
(Scheme 5).
ture to 50 °C; and up to 72 h reaction time) and only nitro-
ne rearranged products were obtained. Furthermore,
electron-rich tributylphosphine did not yield 8a at all.
To gain further insights into this cascade annulation–
Dichloromethane proved to be the solvent of choice
rearrangement sequence, the deuterium labeled nitrone
among the solvents tested (toluene, THF, MeCN, MeOH,
1h-d2 (see the Supporting Information) was treated with
DMAD and triphenylphosphine and the expected deuter-
ated adduct 8b-d2 was obtained in 21% yield (Scheme 6).
Although 75% of the deuterium at C3 (the highly acidic a-
H2O/LiOH) in the triphenylphosphine-mediated synthesis
of dihydropyridine-fused benzopyrone 8a and provided a
moderate yield of 8a. However, the intramolecular rear-
a)
O
O
DMAD (2.0 equiv)
Ph3P (1.2 equiv)
Me
Ph
Me
Ph
N
O
N
CO2Me
CH2Cl2, r.t., 18 h
O
O
H
CO2Me
1f
8a
Ph3P (1.2 equiv),
CH2Cl2, r. t., 18 h
OR
O
Cl
Ph
N
b)
c)
1g
Ph3P (1.2 equiv)
DEAD (1.2 equiv),
CH2Cl2, r.t., 48 h
Me
O
O
9a
O
O
Me
Ph
Ph
N
N
CO2Me
CO2Me
O
H
H
CO2Me
CO2Me
8a (36%)
8b (24%)
O
O
O
i-Pr
Ph
Cl
Ph
N
N
CO2Me
CO2Me
O
Me
H
H
CO2Me
CO2Me
8c (27%)
8d (23%)
Scheme 4 Synthesis of dihydropyridine-fused benzoypyrones through phosphine-mediated annulation
© Thieme Stuttgart · New York
Synlett 2012, 23, 227–232

230
K. Wittstein et al.
LETTER
O
PPH3
O
O
O
C
N
Me
Me
MeO
CO2Me
O
N
O
2
PPh3
[5+3]
O
Z-1f
CO2Me
MeO2C
10
1,3-H shift
O
O
N
Me
Me
phosphine oxide
elimination
N
O
PPh3
H
O
CO2Me
O
CO2Me
MeO2C
CO2Me
11
12
6π-cyclization
O
Me
N
H
O
CO2Me
CO2Me
8a
8a
Scheme 5 Proposed reaction mechanism for the cascade annulation leading to dihydropyridine-fused benzopyrones 8
position next to an ester and a nitrogen) was exchanged tained with N-aryl-C-chromonyl nitrones 1f–i clearly sup-
with protons during silica gel column chromatographic ports its preferred Z-configuration. We assume that the Z-
purification, the experiment provided ample evidence for configuration of 1f–i facilitates the initial [5+3] annula-
the suggested 1,3-hydride shift occurring after [5+3] an- tion, leading to intermediate 10, which eventually pro-
nulation.
vides benzopyrones 8 (Scheme 5).
The non-catalytic [3+2] cycloaddition of N-alkyl nitrones In summary, for the first time, conjugated N-phenyl-C-
1a–e with acetylenedicarboxylates seems to be driven by chromonyl nitrones were trapped as 1,5-dipoles in a reac-
a HOMO(nitrone):LUMO(acetylenedicarboxylates) interaction18 that tion with nucleophilic zwitterions generated by addition
favors 1,3-dipolar cycloaddition. However, the different of triphenylphosphine to acetylenedicarboxylates. N-Sub-
reactivity of N-phenyl-C-chromonyl nitrones 1f–i could stituents of nitrones 1 display amazing electronic control
originate from the differing electronic nature of N-aryl ni- over the mode of cycloaddition/annulation reactions.
trones as well as their preferred Z-configuration.5a,19 It is Whereas the N-alkyl-substituted nitrones 1a–e follow a
noteworthy that the facile rearrangement of nitrones 1 be- non-catalytic [3+2] cycloaddition path, the corresponding
gins with an intramolecular 1,5-cyclization9 that is clearly N-phenyl analogues undergo a phosphine-mediated cas-
facilitated by a Z-configuration of 1. Larger amounts of cade reaction sequence of [5+3] annulation–rearrange-
rearranged products 4 and 5 (or moderate yields of 8) ob- ment and yielded novel dihydropyridine fused
DMAD (2.0 equiv)
O
O
D
O
O
D
1
Ph3P (1.2 equiv)
CH2Cl2
r.t., 48 h
N
O
N
H(D)
purification
(silica gel)
3
D
CO2Me
CO2Me
1h-d2
100% deuterated
8b-d2 (21%)
C1-D: 100% deuterated
C3-D: 25% deuterated
Scheme 6 Cascade annulation of DMAD with deuterated nitrone 1h-d2 provides evidence for the proposed 1,3-hydride shift
Synlett 2012, 23, 227–232
© Thieme Stuttgart · New York

LETTER
a-Chromonyl Nitrones as 1,5-Dipoles
231
(9) (a) Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett.
1998, 39, 6547. (b) Ghosh, T.; Bandyopadhyay, C.
Tetrahedron Lett. 2004, 45, 6169.
benzopyrones 8. We believe that these results might be in-
triguing for further exploration of conjugated nitrones as
1,5-dipoles and their applications in organic synthesis.
(10) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org. Lett.
2000, 2, 2023.
(11) González-Cruz, D.; Tejedor, D.; de Armas, P.; Moralesa, E.
Q.; García-Tellado, F. Chem. Commun. 2006, 2798.
(12) Crystallographic data for 8a has been deposited at the
Cambridge Crystallographic Data Centre (CCDC-848674).
Copies of the data can be obtained free of charge at
www.ccdc.cam.uk/data_request/cif or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ [fax: +44 (1223)336033; e-mail:
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This research work was supported by the Max Planck Gesellschaft.
We thank Dr M. G. Sankar, MPI, Dortmund for his help in some
control experiments.
deposit@ccdc.cam.ac.uk]
(13) Representative procedure for the synthesis of dihydro-
pyridine fused benzopyrones 8a: To a solution of nitrone 1f–
i (94 mg, 0.34 mmol) in anhydrous CH2Cl2 (10 mL) was
added dimethyl acetylenedicarboxylate (83 mL, 0.67 mmol,
2 equiv), followed by triphenylphosphine (88 mg, 0.4 mmol,
1.2 equiv). The resulting mixture was stirred at r.t. for 48 h.
The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography
(EtOAc–petroleum ether, 15–18%) to give 8a (48 mg, 0.12
mmol, 36% yield) as a yellow solid
(14) Compound 8a: Rf = 0.35 (EtOAc–petroleum ether, 40%); mp
226–236 °C; 1H NMR (400 MHz, CDCl3): d = 8.31 (d,
J = 1.8 Hz, 1 H), 7.87 (d, J = 1.9 Hz, 1 H,), 7.51–7.44 (m,
2 H), 7.41–7.34 (m, 4 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.10 (d,
J = 1.7 Hz, 1 H), 3.87 (s, 3 H), 3.74 (s, 3 H), 2.39 (s, 3 H);
13C NMR (100 MHz, CDCl3): d = 175.54, 170.29, 164.85,
156.97, 154.45, 147.13, 143.13, 135.75, 133.75, 129.83,
127.71, 125.89, 121.47, 120.24, 117.34, 105.59, 84.38,
61.98, 53.11, 51.62, 20.64; HRMS (ESI): m/z [M + H]+ calcd
for C23H20NO6: 406.12851; found: 406.12806
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(s, 1 H), 7.48 (dd, J = 7.7 Hz, 2 H), 7.40–7.32 (m, 3 H), 7.21
(s, 1 H), 6.10 (d, J = 1.7 Hz, 1 H), 3.87 (s, 3 H), 3.74 (s,
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442.08659; found: 442.08630
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