Anionic [4+3] heteroannulation of 2-azidoacrylates: A modular synthesis of 2-benzazepin-1-ones

Article abstract of DOI:10.1039/c2cc30279a

2-Azidoacrylates undergo [4+3] annulation with phthalides under anionic conditions at low temperatures to furnish 5-hydroxy-2-benzazepinones, the formation of which represents a new concept for the construction of azepines as well as a new reactivity of 2-azidoacrylates.

Full text of DOI:10.1039/c2cc30279a

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COMMUNICATION
Anionic [4+3] heteroannulation of 2-azidoacrylates: a modular synthesis
of 2-benzazepin-1-onesw
Bidyut Kumar Dinda, Amit Kumar Jana and Dipakranjan Mal*
Received 13th January 2012, Accepted 27th February 2012
DOI: 10.1039/c2cc30279a
2-Azidoacrylates undergo [4+3] annulation with phthalides under
anionic conditions at low temperatures to furnish 5-hydroxy-2-
benzazepinones, the formation of which represents a new concept
for the construction of azepines as well as a new reactivity of
2-azidoacrylates.
Table 1 Screening of bases for annulation
Benzazepines are regarded as privileged heterocyclic motifs in that
they occur in numerous pharmacologically active synthetic
molecules.1 They are also widespread in bioactive natural
products like Ribasine alkaloids.2 Compounds having these
motifs exhibit a range of neuroleptic and neurotropic activities.3
Galanthamine, which features a 2-benzazepine, is now marketed as
a hydrobromide salt for the treatment of neurodegenerative
disorders like Alzheimer’s disease.4 Consequently, the development
of practical and flexible synthetic methods for benzazepines in
general is in growing demand. The literature methods for
2-benzazepines include intramolecular Mitsunobu amination,5
ring closing metathesis,6 Friedel–Crafts reaction,7 Pictet–Spengler
reaction,8 Bischler–Napieralski reaction,9 Pummerer cyclization,10
7-endo-trig radical cyclization,11 reductive amination,12 ring
expansion,13 1,7-electrocyclization14 and Heck reaction.15
In conjunction with our interest in anionic [4+2] benzan-
nulations,16 we encountered an unprecedented result in the
reaction of azidoacrylate 1a with phthalide 2a, which resulted in
the formation of benzazepinone 3a (Table 1). The compelling
interest in the benzazepinones, the regiochemical integrity of the
benzannulation16 and the chemistry17 of vinyl azides prompted
us to scrutinize the reaction in more detail.
Entry
Bases
Conditions
Yield %
1
2
3
4
LTB/KHMDS
LDA
LHMDS
NaHMDS
À60 1C to rt
À78 1C to rt
À78 1C to rt
À78 1C to rt
0
45
90
13
Scheme 1 Oxidation and acetylation of azepinone 3a.
1
proton was absent in the H NMR spectrum. To confirm its
19
presence, benzazepinone 3a was oxidized with active MnO2
at rt to afford benzazepinedione 4 (Scheme 1). The signal of C4
hydrogen shifted downfield and appeared at d 6.89 ppm as a
sharp singlet.
When methyl 2-azidoacrylate18 (1a) was subjected to reaction
with phthalide 2a in the presence of t-BuOLi (LTB) in THF at
À60 1C to rt, an intractable mixture of products was obtained
along with recovered phthalide 2a. With LDA as the base, the
reaction turned deep red at À78 1C and furnished a brown
solid after acidic work-up. This was purified and found to be
benzazepinone 3a (45%). There was no indication of the
formation of the [4+2] annulation16 product i.e., 2-azido-1-
naphthol. The structure of 3a was established by analysis of
the IR, NMR and HRMS data. The resonance of the –OH
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India. E-mail: dmal@chem.iitkgp.ernet.in
w Electronic supplementary information (ESI) available. CCDC
862841–862843. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc30279a
Scheme 2 Proposed mechanism for the annulation.
Chem. Commun., 2012, 48, 3999–4001 3999
c
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Acetylation of 3a with acetic anhydride-pyridine accordingly
afforded O-acetylated product 5.
(1b) (Table 2, entry 1) which produced benzazepinone 3b in
85% yield. The patterns of the spectral data of 3b were in
consonance with those of 3a, confirming the initially proposed
structure. Our next motivation was to generalize the reaction
with various azidoacrylates keeping the donor phthalide
invariant (Table 2). First, we considered examining methyl
2-azidocrotonate (1c) to increase the number of substituents in
the product. Reaction of 1c with phthalide 2a in the presence
of LHMDS produced 4-methylbenzazepinone 3c (entry 2) as a
white solid. Although its 1H NMR spectrum was in accordance
with the proposed structure, the 13C NMR spectrum did not
reveal all the expected signals. This is perhaps due to rapid
equilibration with its tropylium-like cation. To further support
the structure, oxidation of a sample of 3c with MnO2 in
chloroform at rt was carried out to furnish benzazepinedione
12 (structure was confirmed by single crystal X-ray analysis,
see ESIw), spectral data including 13C NMR data of which
conformed to the structure. To validate the structure of
benzazepinone 3c by correlation with a known compound,
we attempted to reduce the olefinic bond of the azepinone ring
in 12 to obtain methyl 4-methyl-1,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[c]azepine-3-carboxylate.21 But, the reduction of
benzazepinone 12 with H2/Pd–C (10%) in methanol (Scheme 3)
at rt produced triply reduced benzazepinone 13 in 75% yield.
Similar was the result when benzazepinone 3c was subjected to
hydrogenation. In this case, benzazepinone 13 was obtained in
85% yield.
To improve the yield of the annulation reaction, KHMDS,
LDA, LHMDS and NaHMDS (Table 1, entries 1–4) were
examined in THF. LHMDS was found to be the most effective
base with respect to the yields of the annulation.
Mechanism. The formation of azepinone 3a can be
explained by the speculative mechanism shown in Scheme 2.
At low temperature, the incipient phthalide anion 6 adds to
azidoacrylate 1a in Michael mode to form new anion 7. The
enolate ion 7 then expels N2 to form imine anion 8 in a manner
similar to that of 2-azido esters.20 This, in turn, intramolecularly
attacks the lactone carbonyl, resulting in the formation of
7-membered lactam 9 (Path A). Finally, protonation followed
by tautomerization leads to the azepinone 3a via intermediate
10. Alternatively, the azido anion 7 can attack the lactone
carbonyl to give intermediate 11(Path B), which undergoes ring
cleavage and N2 expulsion to form 3a via 9.
Scope. In order to establish the scope of this unprecedented
reaction, we examined the reactivity of ethyl-2-azidoacrylate20
Table 2 [4+3] Heteroannulation of 2-azidoacrylates with phthalide
2a to 2-benzazepinones
Azido acrylate
Entry
Benzazepinone
Yield %
1
90a, 60b, 85a,e
Next, we turned to the 3-arylazidoacrylates to test their
applicability in the annulation. 3-Phenylazidoacrylate 1d
(Table 2, entry 3) produced the benzazepinone 3d in 65%
yield on annulation with phthalide 2a. The structure of
benzazepinone 3d was confirmed by analysis of X-ray data.
Entries 4–7 exemplify the types of substituted aryl groups
that can be placed in the azide acceptors. In all cases, the
annulation products were obtained in good yields. For substituted
arylazidoacrylates 1e–1h (entries 4–7), the reactions proceeded
2
75a, 80b
3
1d Y = H, Z = CH
65a, 80b
Scheme 3 Reduction of benzazepinones 3c and 12.
4
5
6
1e Y = r-OMe, Z = CH
1f Y = r-Me, Z = CH
1g Y = r-Cl, Z = CH
65a, 72b
75a, 78b
75a, 75b
Table 3 [4+3] Heteroannulation of substituted phthalides with
methyl 2-azidoacrylate (1a) to 2-benzazepinones
Phthalide
Entry
Benzazepinone Yield %
7
8
1h Y = m-NO2, Z = CH
1i Y = 6-OMe, Z = N
72a, 80b
70d
1
2
2b R2 = 6-OMe, Z = CH
68b
70a
2c R2 = 5,6-dimethoxy, Z = CH
9
65a
3
4
a
2d R2 = 5,6-O–CH2–O, Z = CH
70b
57b
2e R2 = H, Z = N
a
Yields of benzazepinones. b Yields of oxidized products. c MnO2,
CHCl3, rt. d Overall yield for two steps i.e. annulation followed by oxida-
tion. e Yield of compound 3b. f X-Ray crystal data are available in ESI.
b
Yield of benzazepinone. Overall yield for two steps i.e. annulation
c
followed by oxidation. MnO2, CHCl3, rt.
c
4000 Chem. Commun., 2012, 48, 3999–4001
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smoothly to provide the corresponding azepinones 3e–3h in
65, 75, 75 and 72% yields respectively. Benzazepinones 3d–3h
(entries 3–7) were fully characterized after oxidation to
benzazepinediones 14–18 respectively. It appears that the
substituents in the benzene ring of azidoacrylates have little
effects on the outcome of the reaction. We were interested in
the reactivity of 3-heteroarylazidoacrylate 1i (entry 8) to
discern whether ortho lithiation or nucleophilic substitution
interferes the annulation. The annulation of 1i gave regio-
selectively benzazepinone 3i with intact pyridine nucleus. The
hydroxy product 3i was fully characterized after oxidation to
benzazepinedione 19. For the annulations of entries 3–8, the
temperature of the reactions was maintained at À78 1C for
1.5 h after adding the azido acrylates to avoid their hydrolysis
and the yields significantly increased. The annulation is also
compatible with the azido cyclic ketone 1j (entry 9). The
reaction of phthalide 2a with 1j resulted in the formation of
tricyclicazepinone 3j, which may serve as the precursor for
dibenzoazepinones.
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Next we examined the reactivity of methoxy substituted
phthalides with azidoacrylate 1a (Table 3) in view of the
occurrence of methoxy substitutions in natural aromatic poly-
ketides. We were also interested in ruling out the possibility of
nuclear lithiation of methoxyphthalides (2b and 2c) (entries 1
and 2) under the annulation conditions. The reaction of these
phthalides with 1a afforded azepinones 3k and 3l respectively.
The azepinone 3k was fully characterized as its oxidized
derivative 20. The study was further extended to the reaction
of phthalide 2d with 1a (entry 3). This annulation led to the
formation of azepinone 3m. It was oxidized to benzazepinedione
21 and then fully characterized. Since heteronuclear systems are
susceptible towards nucleophilic addition, we inquisitively treated
azaphthalide 2e with azidoacrylate 1a (entry 4). Interestingly,
the reaction led to the formation of benzazepinones 3n which
were subjected to oxidation and then characterized. This
method can be useful for the synthesis of pyridinoazepinones
as antagonists of the nociceptin receptor, which is implicated
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In conclusion, the studies above have led to the development
of a modular and regiospecific method for the synthesis of
2-benzazepinones. It relies upon a previously unreported reaction
of vinyl azides. Full scope of the reaction is under further study.
Financial assistance of CSIR and UGC, New Delhi, is
greatly appreciated. We thank Professor G. Mani for solving
the X-ray structures.
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Chem. Commun., 2012, 48, 3999–4001 4001