Accessing benzooxadiazepines: Via formal [4 + 3] cycloadditions of aza- o -quinone methides with nitrones

Article abstract of DOI:10.1039/c8ob00201k

An unprecedented and efficient [4 + 3] cycloaddition of N-(ortho-chloromethyl)aryl amides with nitrones has been developed. This approach provides easy access to a series of seven-membered benzooxadiazepine derivatives in good to excellent yields (up to 99% yield) under mild reaction conditions.

Full text of DOI:10.1039/c8ob00201k

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Accessing benzooxadiazepines via formal [4+3] cycloadditions of
aza-o-quinone methides with nitrones
Yong-Sheng Zheng,a Liang Tu,a Li-Mei Gaoab, Rong Huang,a Tao Feng,a Huan Sun,a Wen-Xuan
Wang,a Zheng-Hui Liab* and Ji-Kai Liua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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An unprecedented and efficient [4+3] cycloaddition of N-(ortho-
chloromethyl)aryl amides with nitrones has been developed. This
approach provides easy access to a series of seven-membered
benzooxadiazepine derivatives in good to excellent yields (up to
99% yield) under mild reaction conditions.
Introduction
Seven-membered N-heterocycles are ubiquitous motifs found
in a broad range of biologically active natural products.
Especially, those of benzo-fused bicyclic structures play an
important role as pharmaceuticals in clinical use.1 Typical
examples are shown in Figure 1. For instance, diazepam, a
medication of benzodiazepine, is commonly used to treat a
range of neurological disease.2 Diltiazem, a calcium channel
blocker, is used to treat hypertension and angina.3
[4,1,3]benzoxadiazepine-5-ones are potential antibacterial
agents.4 Therefore, the search for efficient approaches to
construct seven-membered N-heterocycles has always been a
hot area of research in synthetic chemistry.5 Representative
synthetic strategies include [4+3] cycloaddition,6 [2+2+3]
cycloaddition,7 and [5+2] cycloaddition8. However, great
challenges with the construction of seven-membered rings
exist due to the enthalpic and entropic factors and non-
bonding interactions in the transition states.9 Moreover, the
construction of oxygen-containing seven-membered N-
heterocycles has received much less attention compared to
their nitrogen-heterocycles analogues. Therefore, the search
for reliable and practical methods to obtain structurally
diverse seven-membered nitrogen heterocycles remains highly
desirable.
membered N-heterocycles, reactions employing 1,3-dipolar
cycloadditions are probably the most straightforward method
and has received considerable attention with respect to atom
economy and efficiency. Nitrones, developed by Beckmann in
1890, are well-known reagents for 1,3-dipolar cycloadditions
leading to heterocycles by [3+2] cycloaddition with electron
rich alkenes.10 In addition to their classical reactivity as 1,3-
dipoles, nitrones are capable of reacting as electrophiles in
nucleophilic addition reactions.11 By comparsion, the [4+3]
cycloadditions of nitrones has received much less attention in
the synthesis of seven-membered heterocycles except for a
few examples,6c,12 probably because it is difficult to find
suitable electrophilic diene components.
Aza-o-quinone methides (aza-oQMs), first introduced by
Corey, are versatile synthons in various [4+n]
cycloadditions.13 The [4+3] cycloaddition reactions involving
aza-oQMs turned out to be a reliable entry to benzo-fused N-
heterocycles. For example, Chen and Xu reported the [4+3]
cycloadditions of aza-oQMs and isatins for the synthesis of
aza-spirocycloheptane.14 Du described the synthesis of 1,2,4-
triazepines via the [4+3] cycloaddition reaction of aza-oQMs
with azomethine imines.15 Enders reported [4+3] annulation
of aza-o-quinone methides with enals to synthesize 1,2-
diazepinones.5f The successful applications of aza-oQMs in
cyclizations inspired us to envision whether this class of
reactants could be used for constructing oxygen-containing
Among the established methods to construct seven-
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seven-membered N-heterocycles via
a
novel [4+3]
cycloaddition reaction between nitrones and aza-oQMs.
Results and discussion
We started our investigations by screening a series of solvents
of the cycloaddition of N-(ortho-chloromethyl)aryl amide 1a
with nitrone 2a
spirocycloheptane oxindole. As shown in Table 1, the [4+3]
cycloaddition proceeded smoothly, affording the
,
in order to construct an aza-
benzooxadiazepine 3aa in 83% yield after 36 h in CH2Cl2 in the
presence of Na2CO3 at room temperature (Table 1, entry 1).
The protonic solvent was found to have a dramatic impact on
the efficiency of the reaction (Table 1, entry 7). Notably,
dioxane was identified as optimal for the formation of 3aa
(Table 1, entry 9). Other bases (Table 1, entries 10–12) did not
lead to an improvement in the reaction efficiency. Endeavors
Entry
1
2
3
4
5
6
7
8
Base
Solvent
DCM
Toluene
DCE
CHCl3
THF
CH3CN
MeOH
DMF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Time (h)
30
30
40
48
46
46
48
36
36
36
36
36
36
36
36
Yield (%)b
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
TEA
83
82
87
90
94
83
49
87
94
83
53
40
78
94
95
9
Furthermore, nitrone bearing naphthyl ring (Table 2, 3ao) was
also good substrate for this reaction. Interestingly, nitrones
with sterically more bulky group on phenyl ring (Table 2, 3aj-
3ak, 3am-3an), exerted negligible effect on the reaction
efficiency. However, bulky groups directly linked to nitrogen of
nitrones had great influence on the yields (Table 2, 3ap-3ar).
The ketonitrone was not tolerated, and no reaction was
obseraved mainly due to the hindrance (Table 2, 3as). We also
tried to apply C-heterocycle and C-alkyl nitrones, the
corresponding products were detected by HRMS. However,
these cycloaddition products are very unstable and
decomposed quickly.
10
11
12
13
14d
15e
Na2CO3
Na2CO3
Na2CO3
on further improving the efficacy of the reaction by screening
the amount of base proved to be in vain (Table 1, entries 13–
15).
Next, we turned our attention to the scope of N-(ortho-
chloromethyl)aryl amides by reacting with nitrone (2a). As
shown in Table 3, good tolerance for diverse electron-donating
or electron-withdrawing groups at different positions on the
phenyl ring was observed. The corresponding seven-
membered N-heterocycles were generally produced in good to
excellent yields (Table 3, 3ba-3la except for 3ka). Incorporation
of methyl substituent at the ortho positions relative to the
sulfonanilide nitrogen atom slightly retarded the reaction
(Table 3, 3ha and 3ia). However, changing the methyl group
With the optimal reaction conditions established (Table 1,
entry 9), we next investigated the substrate scope of the
reaction by employing a variety of nitrones 2. As summarized
in Table 2, various nitrones could be smoothly transformed
into the corresponding [4+3] cycloaddition product in good to
excellent yields (78–99%) except for 3ar
. This [4+3]
cycloaddition can be extended to a variety of nitrones bearing
either electron-rich (Table 2, 3ab and 3ac) or electron-deficient
(Table 2, 3ad-3an) substituents on the phenyl ring, giving the
corresponding cycloaddition products in good yields.
2 | J. Name., 2012, 00, 1-3
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1q and 2a was conducted under the standard conditions, 1q
was recovered and no desired product was observed. Based on
the above results and previous related studies, a plausible
reaction pathway for the formation of oxygen-containing
seven-membered
chloromethyl)aryl amides and nitrones is proposed (Scheme 3).
Firstly, aza-o-quinone methides intermediate is generated in
N-heterocycles
from
N-(ortho-
A
situ from N-(ortho-chloromethyl)aryl amide 1a under the basic
conditions.13,16 And then, addition of nitrone to aza-o-quinone
methane gaves the intermediate
B, which will subsequently
take place a nucleophilic addition to generate the seven-
membered N-heterocycles.
with a methoxy group had significantly detrimental effects on
the reaction efficiency probably due to the steric effect (Table
3, 3ha vs 3ka). Variations of the substituents on sulfonyl group
were investigated and the corresponding products were
isolated in good yields (Table 3, 3ma-3pa).
Conclusions
In conclusion, we have demonstrated
a fomal [4+3]
cycloaddition of nitrones and aza-o-quinone methides,
generated in situ under basic conditions. With this developed
protocol, a wide range of oxygen-containing seven-membered
N-heterocycles were smoothly obtained in good yields (up to
99%) under mild reaction conditions. The large scale
experiment has also been conducted to demonstrate the
utility of this methodology. A plausible reaction pathway was
also proposed. The related bioassays are under investigation in
this laboratory and will be reported in due course.
To evaluate the practicability of the above methodology, the
preparation of compound 3aa was performed on a gram scale
(5.25 mmol of 1a and 3.50 mmol of 2a) under the optimized
conditions. As shown in Scheme 1, the preparative scale
reaction proceeded smoothly and gave the corresponding
product in 91% yield.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
To gain some insight into the reaction mechanism, a control
experiment was performed (Scheme 2). When the reaction of
We are grateful to the Key Projects of Technological
Innovation of Hubei Province (No. 2016ACA138), the National
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Table of Contents Graphic
Seven membered N-heterocycles were constructed through a formal [4+3] cycloadditions of
nitrones with in situ generated aza-o-quinone methides.