Base-Mediated [3 + 4]-Cycloaddition of Anthranils with Azaoxyallyl Cations: A New Approach to Multisubstituted Benzodiazepines

Article abstract of DOI:10.1021/acs.orglett.9b02118

A new [3 + 4] cycloaddition of azaoxyallyl cations and anthranils has been achieved for rapid access to multisubstituted benzodiazepine derivatives. A variety of anthranils and α-halo hydroxamates were both effective substrates with simple operations unde

Full text of DOI:10.1021/acs.orglett.9b02118

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Base-Mediated [3 + 4]-Cycloaddition of Anthranils with Azaoxyallyl
Cations: A New Approach to Multisubstituted Benzodiazepines
†
,‡,§
†
†
†
†,‡,§
,†,‡,§
Juan Feng,
Meng Zhou, Xuanzi Lin, An Lu, Xiaoyi Zhang,
and Ming Zhao*
†
School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
‡
Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of
Ministry of Education of China, Beijing, China
§
Beijing Laboratory of Biomedical Materials, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University
of Chemical Technology), Ministry of Education, Beijing, China
*
S Supporting Information
ABSTRACT: A new [3 + 4] cycloaddition of azaoxyallyl
cations and anthranils has been achieved for rapid access to
multisubstituted benzodiazepine derivatives. A variety of
anthranils and α-halo hydroxamates were both effective
substrates with simple operations under transition-metal-free
conditions. The intriguing features of this method include its
mild nature of the reaction conditions, high efficiency, broad
substrate scope, and wide functional group compatibility.
itrogen heterocycles are widespread structural motifs in
Scheme 1. Base Mediated [3 + 4] Cycloadditions with
Azaoxyallyl Cations
N
bioactive natural products, therapeutic agents, agro-
1
chemicals, and material molecules with significant activities.
In particular, benzodiazepines, a member of the family of
privileged scaffold, occupy a significant place in pharmaceutical
2
ingredients. As representative examples shown in Figure 1,
SB-214857 (lotrafiban), a potent glycoprotein IIb/IIIa
3
receptor antagonist, displays antithrombotic activity. Diaze-
2a
pam, commercially known as Valium, is used to treat anxiety.
Abbemycin, isolated from Streptomyces sp. AB-999F-52, is an
4
antibiotic. TRAIL (tumor necrosis factor-related apoptosis-
inducing ligand)-resistance could be overcome by use of
5
fuligocandin B. Circumdatin D and E are two quinazolino-
benzodiazepine alkaloids isolated from the fungus Aspergillus
6
ochraceus. Given the rich biological profiles of the seven-
membered nitrogen heterocycles in organic synthesis and
medical chemistry, the development of a novel method to
access benzodiazepine and related scaffolds remains highly
desirable.
[
3 + 4]-Cycloaddition reaction is an efficient strategy to
7
assemble seven-membered rings. In recent years, azaoxyallyl
Figure 1. Selected biologically active molecules with the benzodia-
zepine unit.
Received: June 20, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02118
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Anthranils
b
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
Na CO
NaOH
NaHCO3
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
1
35
77
trace
94
74
37
52
59
77
2
3
0.5
24
0.5
1
3
2
K CO
2
3
Cs CO
2
3
t-BuOK
DBU
Et N
9
1
3
DMAP
10
11
12
13
14
15
16
17
18
K CO3
2
0.5
24
0.5
24
24
24
24
6
41
K CO3
2
i-PrOH
MeOH
THF
trace
NR
trace
15
26
70
K CO3
2
K CO3
2
K CO3
2
dioxane
toluene
CH Cl
K CO3
2
K CO3
2
2
2
K CO3
2
CH CN
80
trace
3
K CO3
2
DMF
24
a
The reactions were carried out with 0.2 mmol of 1a and 0.4 mmol of
a in 1.5 mL of solvent with 0.4 mmol of base at room temperature.
2
b
Isolated yield. HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-dimethylaminopyridine,
TFE = 2,2,2-trifluoroethanol, NR = No Reaction, THF = tetrahydro-
furan, DMF = N,N-dimethylformamide.
8
cations, as 1,3-dipoles, have been widely applied in [3 + 1]-,
[
9
10
3 + 2]-, and [3 + 3]- cycloaddition reactions. Because of
their high reactivity profile, an azaoxyallyl cationic intermediate
has also recently emerged as a three-atom component in the [3
1
1
+
4]- cycloaddition reaction for synthesis of seven-membered
a
All reactions were performed with anthranil 1 (1.0 equiv) with α-
halo hydroxamate 2a (2.0 equiv) and K CO (2.0 equiv) dissolved in
N-heterocycles. Jeffrey and co-workers had a continuing
interest in this emerging area of research. In 2011, Jeffrey
disclosed the first [3 + 4]-cycloaddition reaction to construct
2
3
b
HFIP (7.5 M) at rt for 0.5−1.5h. Isolated yield.
11a
seven-membered azacycles (Scheme 1a). Subsequently, an
aza-[3 + 4] cycloaddition of diaza-oxyallyl cationic inter-
mediates to furnish ureas has been realized by the same group
under metal-free conditions. Herein, we described our work on
the aforementioned reaction.
1
1b
(Scheme 1b).
Following these successes, Jeffrey’s group
further developed the intramolecular [3 + 4] cycloaddition of
We commenced our investigations by using anthranil (1a)
and α-halo hydroxamate (2a) as standard substrates (Table 1).
Initially, it was found that Na CO was effective in promoting
aza-oxyallylic cations with furans or N-Boc-pyrroles (Scheme
1
1c
1
c). However, to the best of our knowledge, cycloaddition
of anthranils with aza-oxyallylic cations, especially in the [3 +
]-cycloaddition toward the construction of benzodiazepine
2
3
this transformation, affording our designed [3 + 4] cycloadduct
in 35% yield in HFIP (Table 1, entry 1). The structure of 3a
was determined by X-ray crystallographic study (CCDC
4
derivatives, has not yet been reported.
13
Recently, we have successfully developed a [3 + 2]
cycloaddition reaction of azaoxyallyl cations and 1,2-benzisox-
azoles, which enabled the efficient construction of oxazolines
1923224). Then, a systematic condition optimization was
performed. As shown, among the several commonly used
inorganic and organic bases, K CO was proven to be the best
2
3
9
i
derivatives. Inspired by this approach, we observed that
anthranils have been widely used as synthetically important
and useful motifs for the synthesis of pharmaceuticals and
functional molecules due to their unique electronic proper-
choice, affording 3a in an excellent yield of 94% (Table 1,
entries 2−9). Next, the effect of solvent was examined. By
performing the reaction under TFE, the yield of 3a sharply
decreased to 41% (Table 1, entry 10). Both i-PrOH and
MeOH gave inferior results (Table 1, entries 11−12). Finally,
it turned out that the yields failed to be enhanced compared
with HFIP after evaluating a range of other solvents, including
THF, dioxane, toluene, CH Cl , CH CN, and DMF (Table 1,
1
2
ties. It was envisioned that anthranils could serve as potential
12a,f,g
precursors for cycloaddition as four-atom components.
We postulated that cycloaddition of aza-oxyallylic cations with
anthranils could be employed as a powerful method to prepare
seven-membered heterocycles bearing an oxa-bridged ring
2
2
3
entries 13−18).
B
DOI: 10.1021/acs.orglett.9b02118
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of α-Halo Hydroxamates ,
a b
Scheme 5. Proposed Reaction Mechanism
confirmed the chemical structure of 3j (CCDC 1923225).
Some other anthranils possessing trifluoromethyl or cyanide
aryl substituents have showed comparable efficiency. We found
that 3-(naphthalen-2-yl)benzo[c]isoxazole also behaved well,
providing benzodiazepine derivative 3m in 60% yield. When
the R -substituent was a pyrimidine group, this reaction also
2
smoothly proceeded to provide the desired product with a
relatively lower yield. However, when the anthranil bearing a H
atom at the C-3 position was tested, no desired product was
12a
obtained (structures not shown).
a
All reactions were performed with anthranil 1 (1.0 equiv) with α-
We then moved toward investigating the reactivity of an α-
halo hydroxamates partner. As depicted in Scheme 3,
substrates (2b−2e) with variation of protecting groups on
the nitrogen atom tend to provide benzodiazepine derivatives
in 85−97% yields (3o−3r). Additionally, cyclohexyl-substi-
halo hydroxamate 2 (2.0 equiv) and K CO (2.0 equiv) dissolved in
HFIP (7.5 M) at rt for 0.5−1.5h. Isolated yield.
2
3
b
Scheme 4. Synthetic Applications
3
tuted hydroxamate afforded 3s in 75% yield. When the R and
4
R groups were different alkyl chains, the N-benzyloxy α-
bromoamides 2g yielded product 3t with a diastereomeric ratio
(
d.r. = 7:1) in 60% combined yield. However, the cyclo-
addition reaction did not take place with N-benzyl-2-bromo-2-
methylpropanamide as the substrate, which might arise from
10f,11d,13
the low stability of the azaoxyallyl cation.
Moreover,
some other combinations of anthranils and α-halohydrox-
amates were also compatible, providing functionalized
benzodiazepine derivatives (3v−3x) in excellent yields.
In order to address the viability and potential synthetic
application of this [3 + 4] cycloaddition, gram-scale reactions
and several chemical transformations of product 3a were
carried out. The product was obtained in 94% (1.2 g scale) and
9
0% (5.8 g scale) yields, respectively (Scheme 4A). This result
indicates that there is no loss of efficiency during the scale-up
operation of the present methodology.
We found that both the N−O bond and the benzyl group of
a were readily transformed through hydrogenation with Pd/C
3
Under the optimal conditions, the generality of anthranils 1
were examined (Scheme 2). The cycloaddition reactions could
endure anthranils (1b−1c, 1e−1f) bearing various halide
substituents (5-Cl, 5-Br, 6-Cl, 6-F), affording products in high
yields (96−99%). In addition, electron-donating methyl group
substituted substrate 1d reacted smoothly to give 3d in 91%
yield. Anthranils with an ethyl group (1g and 1h) and a
bromomethyl group (1i) at the C-3 position afforded [3 + 4]-
cycloadducts (3g, 3h and 3i) in excellent yields. Moreover, the
R2 substituent could be replaced by various aryl rings. For
substrate 3j bearing a phenyl group, the desired product was
obtained in 95% yield. The X-ray diffraction analysis firmly
in methanol solvent (Scheme 4B). Hydrogenation in ethyl
acetate could be completed to provide 5 without cleavage of
the N−O bond. X-ray analysis of product 5 determined its
chemical structure (CCDC 1923226). Under more strenuous
conditions, when 3a was treated with Mo(CO) , N-
6
unprotected 6 could be achieved through deprotection of the
benzyl group and cleavage of the N−O bond. In addition, the
N−O bond could also be cleaved by zinc under acidic
conditions, providing 7 in 71% yield.
A plausible mechanism of the above transformation is
proposed in Scheme 5. First, azaoxyallyl cation intermediate A
was formed from α-halohydroxamate 2a in the presence of
C
DOI: 10.1021/acs.orglett.9b02118
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K CO . Next, anthranil 1a reacted with intermediate A
(4) Hochlowski, J. E.; Andres, W. W.; Theriault, R. J.; Jackson, M.;
2
3
McAlpine, J. B. J. Antibiot. 1987, 40, 145−148.
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cycloadduct 3a was observed through intramolecular nucleo-
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Ishibashi, M.; Sunazuka, T.; Izuhara, T.; Sugahara, K.; Tsuruda, K.;
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In summary, aza-oxyallyl cations generated in situ and
anthranils undergo a [3 + 4] cycloaddition to provide
synthetically useful benzodiazepine derivatives in average
good yields. The new method was both concise and mild,
which exhibited good functional group tolerance. More
importantly, the process was performed without addition of a
transition-metal catalyst, which further rendered the approach
attractive and valuable. The application of the cycloaddition
reaction in the synthesis of biological benzodiazepine
molecules is ongoing in our laboratory.
(
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ASSOCIATED CONTENT
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CCDC 1923224−1923226 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
*
R. Org. Lett. 2012, 14, 5764−5767. (c) Acharya, A.; Eickhoff, J. A.;
Jeffrey, C. S. Synthesis 2013, 45, 1825−1836. (d) Barnes, K. L.;
Koster, A. K.; Jeffrey, C. S. Tetrahedron Lett. 2014, 55, 4690−4696.
E-mail: maozhao@126.com.
(
e) Acharya, A.; Eickhoff, J. A.; Chen, K.; Catalano, V. J.; Jeffrey, C. S.
ORCID
Org. Chem. Front. 2016, 3, 330−334. (f) Di, X.; Wang, Y.; Wu, L.;
Zhang, Z.; Dai, Q.; Li, W.; Zhang, J. Org. Lett. 2019, 21, 3018−3022.
Juan Feng: 0000-0002-7224-2696
Notes
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12) (a) Lei, X.; Gao, M.; Tang, Y. Org. Lett. 2016, 18, 4990−4993.
(
b) Skaria, M.; Sharma, P.; Liu, R.-S. Org. Lett. 2019, 21, 2876−2879.
(c) Kardile, R. D.; Kale, B. S.; Sharma, P.; Liu, R.-S. Org. Lett. 2018,
0, 3806−3809. (d) Zeng, Z.; Jin, H.; Sekine, K.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2018, 57,
The authors declare no competing financial interest.
2
ACKNOWLEDGMENTS
■
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935−6939. (e) Zeng, Z.; Jin, H.; Rudolph, M.; Rominger, F.;
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of China (2018ZX097201003) and the National Science
Foundation of China (81703332).
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2018, 57, 16549−16533.
(f) Ren, J.; Pi, C.; Wu, Y.; Cui, X. Org. Lett. 2019, 21, 4067−4071.
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DOI: 10.1021/acs.orglett.9b02118
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