10.1002/anie.201802483
Angewandte Chemie International Edition
COMMUNICATION
Table 4: Transformations of benzazocinones (+)-3a and (–)-11[a]
MeO2C
MeO2C
MeO2C
Mgo (20 equiv),
CH3
CH3
MeO2C
NH4Cl (20 equiv)
MeOH/THF (2:1)
O
O
0 → 23 oC, 5 h
MeO2C
MeO2C
O
N
Ts
N
CH3
R2
H
(74% yield)
N
(+)-3a
(-)-11
DBU, µW
80 ℃
Nuc
O
CH3
O
14 or 15
LiAlH(Ot-Bu)3 (2 equiv)
THF, -78 →23°C, 23 h
(45%, dr 1:1)
µW or 23 °C
O
N
R1
N
R1
(+)-3a: R1 = Ts
16 (R2 = Et, Bn, NH2)
(−)-11: R1 = H
O
O
OHC CO2Me
MeO2C
OMe
NaBH4 (1.2 equiv)
spiroglutarimide
benzazocinone
Nuc
initial adduct
MeOH, 20 min
(74%, dr 1:1)
CH3
O
CH3
O
NHEt
NHTs
12
O
NHTs
13
Et
N
H3C
CO2Me
O
EtNH2
(+)-3a
O
CH3
O
Scheme 5. Detosylation and d-lactone formation from benzazocinone (+)-3a
N
N
Ts
Ts
(−)-14a
(22 h, dr 3.6:1)[b]
(65% yield of the major;
11% yield of the minor)
16a
(14 h, 62% yield, dr 6.7:1)[f]
We next explored addition of various nucleophiles to both
the tosylated and detosylated benzazocinones, (+)-3a and (–)-11.
Ring opening of benzazocinone (+)-3a with EtNH2 afforded
isoquinolinone analogue 14a (65%) proceeding through
presumed ring-cleavage of the benzazocinone ring followed by
intramolecular lactamization with moderate diastereoselectivity
(dr. 3.6:1). On the other hand, addition of benzyl amine delivered
only the ring-opened amide (–)-15a in 90% yield, without
lactamization, when conducted at room temperature (75 h) or
with microwave heating (1 h). Subsequent treatment of the
amides 14a and 15a with DBU afforded spiroglutarimides 16a
and 16b (62% and 72% respectively) with some degree of
diastereotopic group (methyl ester) selectivity (6.7:1 and 7:1,
respectively). Addition of hydrazine to the detosylated
benzazocinone (–)-11 directly afforded the spiroglutarimide (+)-
16c (30% yield) and confirmed by X-ray analysis. Finally,
treatment of benzazocinone with MeOH, in a similar manner to
reaction with ethylamine, led to ring cleavage and lactamization
delivering esters 14b (dr 1:1).
O
MeO2C CO2Me
Ph
N
NHBn
O
BnNH2
CH3
O
(+)-3a
CH3
NHTs
(−)-15a
O
N
Ts
16b
(6 h, 72% yield, dr 7:1)[f]
(1 h, 90% yield)[c]
(75 h, 90% yield)[b]
O
H2N
O
N
CH3
not
observed
H2NNH2
(−)-11
(+)-3a
O
NH
(+)-16c
(8 h, 30% yield)[g]
CO2Me
H3C
MeO2C
O
MeOH
N
Ts
14b
(3 h, 78% yield, dr 1.4:1)[d,e]
(63 h, 85% yield, dr 1.2:1)[b,e]
[a] Isolated yields are indicated for all reactions and relative stereochemistry was assigned
by comparison with the structure of (+)-16c which was confirmed by X-ray analysis (inset,
ORTEP representation of single-crystal X-ray structure; thermal ellipsoids are shown at
50% probability.). [b] The reaction was performed at 23 ℃ without microwave irradiation [c]
The reaction was performed using microwave irradiation at 100 ℃. [d] The reaction was
performed using microwave irradiation at 70 ℃. [e] DBU was added to this reaction. [f] 4 Å
MS were added. [g] The reaction was performed at 105 ℃ in the absence of DBU.
In conclusion, we developed
method for the asymmetric synthesis of medium-sized
heterocycles including azepanones, benzazepinones,
a direct, organocatalytic
azocanones and benzazocinones. These are prepared from
commodity acid chlorides and readily available amino malonates
through
the
intermediacy
of
chiral
a,b-unsaturated
Keywords: medium-ring compounds •Michael addition •
acylammonium salts. The organocascade involves a Michael
addition-proton transfer-medium-sized ring lactamization. An
unexpected tricyclic indoline (+)-5a’ was prepared through
organocatalysis•enantioselectivity• medicinal chemistry
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a
tetrahedral intermediate during the
organocascade process. Addition of various nucleophiles to the
derived benzazocinone led to simple cleavage of the medium
sized-ring but also subsequent d-lactam formation delivering
isoquinolinones
spiroglutarimides. An additional stereocenter, including
and
spirolactamization
leading
to
a
quaternary carbon center, was introduced onto the
benzazocinone ring through a deallylative decarboxylation or
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decarboxylative
allylation,
respectively. The
described
methodology expands the utility of unsaturated acylammonium
salts to the synthesis of medium-sized nitrogen heterocycles.
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