Organocatalytic synthesis of densely functionalized oxa-bridged 2,6-epoxybenzo[: B] [1,5]oxazocine heterocycles

Article abstract of DOI:10.1039/c8cc02565g

Metal-free addition of salicylhydrazones to electron deficient internal alkynes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) to yield oxa-bridged 2,6-epoxybenzo[b][1,5]oxazocine heterocycles was achieved. The demonstrated protocol proceeds through an o-quinone methide formation, aza-Michael addition, stereoselective protonation, enamine promoted aromatization, O,O-acetalization and O,N-aminalization sequence to provide privileged heterocycles in good yields with high diastereoselectivities.

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Organocatalytic synthesis of densely
functionalized oxa-bridged 2,6-
Cite this:DOI: 10.1039/c8cc02565g
epoxybenzo[b][1,5]oxazocine heterocycles†
Received 30th March 2018,
Accepted 11th May 2018
Ramani Gurubrahamam, ‡ Koppanathi Nagaraju‡ and Kwunmin Chen
*
DOI: 10.1039/c8cc02565g
rsc.li/chemcomm
Metal-free addition of salicylhydrazones to electron deficient inter-
nal alkynes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) to
yield oxa-bridged 2,6-epoxybenzo[b][1,5]oxazocine heterocycles
was achieved. The demonstrated protocol proceeds through an
o-quinone methide formation, aza-Michael addition, stereoselective
protonation, enamine promoted aromatization, O,O-acetalization and
O,N-aminalization sequence to provide privileged heterocycles in
good yields with high diastereoselectivities.
The privileged O,O-acetal and N,O-aminal scaffolds are com-
mon in the pharmaceutical industry and are found in myriad
1
natural products and biologically active skeletons. The
demand for accessing these diverse architectures continues to
2
inspire the development of novel strategies. Additionally,
developing protocols that are operationally simple and can
provide complex skeletons containing fragile ketal-derived
aminal ether (a OCOCN-bond) linkages with functional groups
that can be further derivatized is of great importance. Recently,
transition metal catalysed strategies have been developed to
build this diacetal linkage using salicylaldehyde derivatives as
Fig. 1 Metal-mediated construction of aza-bridged (a) and oxa-bridged
(
b and c) skeletons and the organocatalytic strategy from 2-oxo-3-
butynoates and salicylhydrazones.
3
,4
precursors.
For instance, Shi and co-workers developed a
Rh(II) catalysed intramolecular cycloisomerization technique to complex architectures has received much attention in transition
5,6
construct aza-bridged benzodioxepine derivatives (Fig. 1, eqn metal catalysis. In this scenario, we wondered if a metal-free
3
(
a)). In a similar fashion, an O,O,N-linked skeleton could be strategy could be used to access epoxy-bridged azaheterocyclic
effectively constructed through the cyclization of a-imino skeletons by utilizing 2-oxo-3-butynoates as bis-electrophiles.
carbenes generated in situ from tosyl triazoles (Fig. 1, eqn Analogously, environmentally benign metal-free strategies
4
a,b
7–10
(b)).
Alternatively, the oxa-bridged core skeleton can be were developed for electron deficient alkynes.
Alkynal and
accessed from the cycloaddition of azomethine ylides to ethyl ynone precursors are a challenging class of electron deficient
diazoacetate in the presence of a copper(II) trifluoroacetoacetate internal alkynes, where the incoming nucleophiles could add either
4
c,d
(Cu(tfacac)
2
) catalyst (Fig. 1, eqn (c)).
The use of alkynes and across the triple bond to provide unsaturated carbonyls or at the
their derivatives as useful substrates for accessing diverse carbonyl site to generate propargylic alcohols in which the alkyne
component would be intact unless an additional electrophilic
9,11
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow reagent was used.
To the best of our knowledge, harnessing
Road, Taipei 11677, Taiwan, Republic of China. E-mail: kchen@ntnu.edu.tw;
the chemoselectivity of the reaction of internal alkynes with a labile
carbonyl site, such as in 2-oxo-3-butynoates, under metal-free con-
ditions, is relatively rare. On the other hand, salicylhydrazones
have been explored by utilizing either their free hydroxyl group or
their amine functionality as a nucleophilic partner; however,
Fax: +886-2-2932-4249
†
Electronic supplementary information (ESI) available. CCDC 1819727 (3p). For
12
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc02565g
‡
Equally contributed to this work.
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Table 1 Optimization of the cascade process
a
b
c
Entry
Catalyst
Solvent
t (h)
dr
Yield (%)
1
2
3
4
5
6
7
8
9
DABCO
DBU
DMAP
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
36
36
24
36
36
36
36
36
36
36
36
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
81
35
76
44
24
12
11
79
34
46
96
PPh
TMG
Et
3
3
N
2 3
K CO
DABCO
DABCO
DABCO
DABCO
EtOH
CHCl
DCM
10
1
3
d
1
a
All reactions were carried out with 0.2 mmol of 1a, 0.24 mmol of 2a
(
1.2 equiv.) and 10 mol% of the base in the given solvent at ambient
b
1
temperature. dr was determined from crude H-NMR analysis.
c
d
Isolated yield. Reaction was carried out with 1.5 equiv. of 2a.
literature precedent, which also reports the use of the electrophilic
13,14
imine, is scarce.
From this perspective, we were inspired by
the anomalous reactivity of salicylhydrazone towards 2-oxo-3- Fig. 2 Substrate scope.
butynoates, in which the electrophilic imine acts as a nucleophile
1
5,16
in the facile o-quinone methide formation.
As a result, as part of
17
our development of organocatalytic reactions of activated alkynes,
electron-withdrawing groups on the aryl group of either the
we established a triple cascade reaction sequence between 2-oxo-3- salicylaldehyde component or the hydrazine component of the
butynoates and salicylhydrazones using DABCO as a catalyst. salicylhydrazones afforded good to excellent yields and
The initial optimization was carried out with salicylhydrazone required relatively shorter reaction times at ambient tempera-
1
a and 2-oxo-3-butynoate 2a under DABCO catalysis in DCM as ture. This could be attributed to the facile formation of o-
the solvent at ambient temperature. To our delight, the desired quinone methide with electron-deficient salicylhydrazides. The
cascade product 3a was obtained in good yield with excellent O-isopropyl substituent in ynoate performed better than the
diastereoselectivity (81% yield, 419 : 1 dr) (Table 1, entry 1). We other O-alkyl substitutions (tert-butyl, Bn and allyl; 3j–3m) and
observed that DMAP provided a better yield of the desired product the methoxy phenyl group enhanced the reactivity of the
than other organic bases (DBU, DMAP, PPh
were screened for this reaction (up to 76% yield, entries 2–6). We temperature (40 1C) to obtain good yields for 3j–3m and 3r,
also examined the applicability of an inorganic base (K CO ) in the where the substrates do not contain electron-withdrawing
3 3
, TMG and Et N) that reaction (3b vs. 3e). The reactions required a slightly higher
2
3
cascade process; however, it resulted in a poor yield (11%, entry 7). groups on the aryl moiety of the salicylhydrazones or
Furthermore, we attempted to improve the yield by varying the electron-donating groups on the aryl moiety of the 2-oxo-3-
solvent under DABCO catalysis at ambient temperature. Fortu- butynoates 2 (Fig. 2). The relative configuration of the cascade
nately, among the solvents that were screened, we obtained the products was tentatively assigned from the X-ray crystal struc-
1
8
desired product 3a in a comparable yield (up to 79%) with good ture of the heterocycle 3p.
0
diastereoselectivity in THF (Table 1, entries 8–10). To our surprise,
a poor yield was observed with a similar chlorinated solvent, CHCl
Interestingly, when sterically hindered (E)-N -(1-(2-hydroxy-
3
phenyl)ethylidene)benzohydrazide was used as the starting material,
(
2
46% yield, entry 10). Finally, we increased the loading of electrophile the desired products 3y and 3z were obtained in moderate to good
a (1.5 equiv.) to improve the yield of the desired heterocycle 3a. yields (44 and 60%, respectively) and with excellent diastereoselec-
Gratifyingly, an excellent yield with satisfactory diastereoselectivity tivities (419 : 1 dr).
up to 96% yield, 419 : 1 dr) was achieved (Table 1, entry 11). We attempted to extend this protocol to a salicylimine that
(
With the optimized conditions in hand, we turned our atten- was derived from salicylaldehyde and p-anisidine, and we obtained
tion to the scope of substrates with different substituents on the desired heterocycle with excellent diastereoselectivity, albeit, in
salicylhydrazones 1 and 2-oxo-3-butynoates 2 in the presence of a moderate yield (3s, 40% yield, 419 : 1 dr). The current protocol
DABCO (Fig. 2). In most of the cases, the desired heterocycles 3 were suffers from a few limitations as 1,3-diphenylprop-2-yn-1-one
obtained in good to excellent yields with satisfactory diastereo- did not yield any of the desired products with N-benzoyl salicylhy-
selectivities. As expected, we noticed that substrates with drazide
under
the
optimized
reaction
conditions.
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a reversible acetalization process with the proximal carbonyl group
to generate alkoxide species 8. Furthermore, the resulting iminium-
alkoxide species is susceptible to facile O,N-aminalization to
2
generate desired cascade products 3 with good diastereoselectivities.
Although the proposed mechanism is tentative, the plausibility of
a concerted path for all off-cycle transformations (aromatization,
O,O-acetalization and O,N-aminalization) cannot be ruled out as it
is a possible outcome of the simple reorganization of the mole-
cular structure that does not involve an atom transfer (Fig. 3).
In conclusion, an organocatalytic method was developed for
Scheme 1 A gram-scale reaction of the cascade process.
Similarly, the hydrazone derived from N-(2-formylphenyl)acetamide
did not furnish any desired product with 2a. Presumably, this could electron deficient internal alkynes by exploiting a unique activation
be attributed to the delocalization of a nitrogen lone pair over the mode in which a nucleophilic Brønsted base is not directly bound
acyl group, resulting in it being unavailable for the in situ formation to the internal alkyne, unlike traditional nucleophilic phosphine/
19
of o-quinone methide imine. Finally, we examined the efficacy of tertiary amine catalysis. Additionally, an unexpected intriguing
the optimized conditions for a gram-scale synthesis of 3b, and to our reactivity pattern in the reaction of salicylhydrazones with 2-oxo-
delight, we obtained the desired product in a desirable yield 3-butynoates was observed and has the potential to inspire further
(up to 96%) and diastereoselectivity (419 : 1 dr) (Scheme 1).
developments. The current protocol has provided a wide range of
The putative mechanism is depicted in Fig. 3. We presume functionalized heterocycles containing privileged ketal derived
that salicylhydrazide 1 forms the o-quinone methide derivative aminal ether linkages as a core skeleton in good yields (up to
4
under Brønsted base catalysis, which would undergo an 99%) with excellent diastereoselectivities (419 : 1 dr).
aza-Michael addition with 2-oxo-3-butynoates 2 to generate
We thank the Ministry of Science and Technology of the
intermediate allenic enolate species 5. The facial differentiation Republic of China (MOST 106-2113-M-003-013-) for financial
of these allenic species for protonation is crucial for delivering support of this work.
2
0
either the (Z)- or (E)-adduct as the major product. Gratifyingly,
the sterically bulky enaminone arm successfully shields its face
from protonation, making the intermolecular protonation of Conflicts of interest
the opposite face preferred, and this selective protonation
leads to the formation of bis-enaminone 6. Consequently,
There are no conflicts to declare.
bis-enaminone 6 underwent enamine-promoted aromatization
to provide transient phenoxide species 7, which would undergo
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