Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]tri-azolo[1,5-d][1,4]diazepine derivatives by [3+ + 2]-cyclo-addition/rearrangement reactions

Article abstract of DOI:10.3762/bjoc.14.155

Two new series of tricyclic heterocycles, namely 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 and the related neutral, free bases 13 were synthesized from 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 and nitriles 9 in the presence of aluminium chloride by the [3⁺ + 2]-cycloaddition reaction of the in situ generated azocarbenium intermediates 14 followed by a ring-expansion rearrangement. In the rearrangement reaction, the phenyl substituent in the initially formed spiro-triazolium adducts 16 underwent a [1,2]-migration from C(3) to the electron-deficient N(2). This led to the ring expansion from 6-membered piperidine to 7-membered diazepine furnishing the tricyclic 1,2,4-triazole-fused 1,4-benzodiazepines.

Full text of DOI:10.3762/bjoc.14.155

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]tri-
azolo[1,5-d][1,4]diazepine derivatives by [3+ + 2]-cyclo-
addition/rearrangement reactions
Lin-bo Luan, Zi-jie Song, Zhi-ming Li and Quan-rui Wang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1826–1833.
Department of Chemistry, Fudan University, 2005 Songhu Road,
Fudan University, Shanghai 200438, People’s Republic of China
doi:10.3762/bjoc.14.155
Received: 02 April 2018
Accepted: 04 June 2018
Published: 18 July 2018
Email:
Quan-rui Wang* - qrwang@fudan.edu.cn
* Corresponding author
Associate Editor: I. R. Baxendale
Keywords:
© 2018 Luan et al.; licensee Beilstein-Institut.
License and terms: see end of document.
1,4-benzodiazepine (BDZ); cyclization; hydrazones; oxidation;
rearrangement
Abstract
Two new series of tricyclic heterocycles, namely 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 and the
related neutral, free bases 13 were synthesized from 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 and nitriles 9 in
the presence of aluminium chloride by the [3+ + 2]-cycloaddition reaction of the in situ generated azocarbenium intermediates 14
followed by a ring-expansion rearrangement. In the rearrangement reaction, the phenyl substituent in the initially formed spiro-
triazolium adducts 16 underwent a [1,2]-migration from C(3) to the electron-deficient N(2). This led to the ring expansion from
6-membered piperidine to 7-membered diazepine furnishing the tricyclic 1,2,4-triazole-fused 1,4-benzodiazepines.
Introduction
Heterocyclic compounds comprising a 1,4-benzodiazepine anxiety, insomnia and withdrawal symptoms from alcohol and/
(BDZ) ring have been a topic of continued interest as they ex- or drug abuse by Hoffmann-La Roche since the 1960’s. Benzo-
hibit a wide spectrum of drug-like profiles such as good anti- diazepines are thus categorized as a privileged heterocyclic
convulsant activity against acutely elicited seizure, particularly system that is the structural basis of a large number of drugs as
for the central nervous system [1-5]. Many biologically active defined by Evans about 30 years ago [7-12]. Later, more
small molecules with such a core structure have been marketed detailed research revealed that improved biological activities,
for the treatment of various diseases, mostly as psychotropic metabolic stability and other profiles could be achieved when a
substances [6]. Thus, for example, chlordiazepoxide (Librium) third heterocycle, especially a 1,2,4-triazolo moiety, was at-
and the benzodiazepine diazepam (Valium) have been a seda- tached to the seven-membered ring as part of 1,4-benzodi-
tive and hypnotic medication and marked for the treatment of azepine [13,14]. Among various reported 1,2,4-triazole-annu-
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lated 1,4-benzodiazepines, triazolam (I), estazolam (II), alpra- work, motivated to achieve structural diversity and potential bi-
zolam (III) and pyrazolam (IV) are prominent examples of such ological profile improvement of 1,4-benzodiazepines, we wish
clinically drugs having enhanced effects on the neurotrans- to describe the synthesis of unprecedented tricyclic hetero-
mitter γ-aminobutyric acid (GABA) at the GABAA receptor and cycles, i.e., 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-
low toxicity (Figure 1) [15].
d][1,4]diazepinium salts 10 and the related neutral free base de-
rivatives 13 via the cationic [3+ + 2]-cycloaddition/rearrange-
Although 1,4-benzodiazepines are widely prescribed medicines, ment reactions using the bicyclic 4-acetoxy-4-azo-1,2,3,4-
side effects like drowsiness, drug resistance, addiction and with- tetrahydroquinolines 8/12 as the key starting material.
drawal potential are detrimental [16]. Consequently, the devel-
opment of expedient synthetic protocols to access new members Results and Discussion
of 1,4-benzodiazepine derivatives has long been the subject of The required N-acylated 2,3-dihydro-4(1H)-quinolones 6 were
considerable interest aiming at the discovery of biologically generally prepared following a literature method with the acid-
active and drug-like compounds [17-30].
catalysed Fries rearrangement of N-arylazetidin-2-ones of the
general form 4 [43,44]. As illustrated in Scheme 1, the prepara-
Over the past years, we have been engaged in the synthesis of tion starts from the related anilines 1 which were acylated with
novel 1,2,4-triazolo heterocycles annulated to benzoazepine or 3-bromopropionyl chloride (2) to afford amides 3. Upon basic
heteroazepine derivatives by a tandem [3+ + 2]-cycloaddition/ treatment with t-BuONa, the amides 3 were converted to the
rearrangement between 1-aza-2-azoniaallenium ions with cyclized β-propiolactams 4. In the presence of triflic acid, the
nitriles [31-34]. In the [3+ + 2]-cycloaddition, α-acetoxyazo Fries rearrangement occurred smoothly to yield the dihydro-
intermediates are initially transformed into an azocarbenium quinolinones 5, which were then converted to 1-acetyl-2,3-dihy-
ion. Subsequently, it takes part in a cationic cycloaddition reac- droquinolin-4(1H)-ones 6 by reaction with acetyl chloride in
tion with the triple bond of a nitrile followed by a rearrange- 36–56% overall yields (Scheme 1, see Supporting Information
ment reaction [35-39]. This type of ionic cycloaddition–rear- File 1 for details).
rangement protocol proved to be quite general and has also been
conducted intramolecularly for a tethered olefin moiety by The phenylhydrazones 7 were readily acquired by condensation
Brewer and co-workers in recent years [40-42]. In the present of the quinolones 6 and phenylhydrazine with a catalytic
Figure 1: Examples of marketed pharmaceutical 1,2,4-triazolobenzodiazepines.
Scheme 1: Preparation of N-acylated 2,3-dihydro-4(1H)-quinolones 6.
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amount of AcOH in refluxing n-propyl alcohol. Subsequently, 2-chloroacetonitrile which gave a low yield (37%) of 10f from
the hydrazones 7 were converted into the 4-acetoxy-1-acetyl-4- the reaction with 8a. This type of reaction worked also well
phenylazo-1,2,3,4-tetrahydroquinolines 8 via the oxidation with with 3-methoxypropanenitrile to provide salt 10e in 88% yield.
hypervalent iodine(III) reagent PhI(OAc)2 (Scheme 2) [45]. The Similarly, 2-phenylacetonitrile participated in the reaction
electron-withdrawing N-acetyl functionality in compounds 8 smoothly to give 10g in 73% yield.
was introduced to conceal the basicity of the N(1) atom, thus
avoiding the plausible disturbance in the following cationic As mentioned above, with the purpose to obtain stable tricyclic
polar cycloaddition/rearrangement reaction.
1,2,4-triazolodiazepinium salts 10, the anion AlCl3(OAc)− in
the initially formed products was replaced with a suitable
After the accomplishment of the synthesis of key intermediates counter ion such as chloride, trifluoroacetate and picrate, which
8, we tried to apply the well-documented protocol in this labo- proved to be a useful way to facilitate the isolation of the target
ratory for the synthesis of the target tricyclic heterocycles [46]. salts 10.
Thus, the α-acetoxyazo compound 8a was allowed to react with
acetonitrile in the presence of AlCl3 as a Lewis acid at low tem- In order to further explore the scope and generality in view of
perature (−40 °C) in dry CH2Cl2 for a period of 0.5 h. Then the nitriles, the strategy was also probed with aromatic nitriles 9
reaction mixture was gradually warmed to room temperature that were reacted with 8 under the same reaction conditions.
and kept at this temperature for an additional hour. The work-up The nucleophilicity of the N atom in aromatic nitriles should be
afforded successfully the 5,6-dihydro-4H-benzo[b][1,2,4]tri- lower than that of aliphatic ones owing to the conjugation of the
azolo[1,5-d][1,4]diazepinium salt 10a as a white solid in triple bond with the benzene ring. To our delight, compound 8a
81% yield. It is noteworthy to mention that the counter ion in reacted smoothly with benzonitrile to give the 2-phenyl-substi-
the product had been changed from anion AlCl3(OAc)− to tuted benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium picrate
picrate anion. This variation proved to be quite beneficial for 10h in 83% yield. Then the effect of the electronic nature of
the formation of stable salts.
benzonitriles was examined with benzonitriles carrying differ-
ent functionalities. It was disclosed that various electron-donat-
Encouraged by the above success, we then examined the ing and electron-withdrawing groups on the benzene ring were
protocol’s efficacy by applying different kinds of nitriles. As compatible with the reaction conditions furnishing the desired
can be seen from Scheme 3, most of the expected tricyclic products 10i–r in good yields. This indicated that the nucleophi-
benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 were licity of the nitrogen atom of nitrile 9 is strong enough to over-
produced readily from the corresponding acetoxyazo com- ride the electronic effect of the substituent in the benzene ring.
pounds 8 and the corresponding nitriles 9. Moderate to good However, when nicotinonitrile was employed, the reaction was
yields of 10a–g were obtained with aliphatic nitriles, except for unsuccessful, and the expected product 10s could not be identi-
Scheme 2: Synthesis of α-acetoxyazo compounds 8a–g. Reaction conditions: for synthesis of 8a: 7a (10.42 mmol), PhI(OAc)2 (12.50 mmol), AcOH
(10 mL); for synthesis of 8b–g: 7b–g (0.71 mmol), PhI(OAc)2 (0.85 mmol), AcOH (1 mL). bIsolated yield. cRatio of E/Z isomers was not determined.
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Scheme 3: Synthesis of tricyclic benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10. Reaction conditions: substrate 8 (0.25 mmol) in CH2Cl2
(2 mL), nitrile 9 (0.35 mmol), AlCl3 (0.35 mmol), CH2Cl2 (5 mL), −40 °C for 0.5 h, then room temperature for 1 h under an atmosphere of N2. bIsolated
yields.
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Beilstein J. Org. Chem. 2018, 14, 1826–1833.
fied in the reaction mixture. We speculate that this could be due result could be attributed to the increased steric hindrance in
to the stronger electron density at the N atom in the pyridine nitrile moiety.
ring that interferes with the action of the Lewis acid.
As can be seen from Scheme 3, equally satisfactory results
By employment of 8a as a model substrate, we next turned our could be obtained from the reaction of other acetoxyazo com-
attention to determine possible steric effects with o-, m- and pounds 8 with several different substituents on the benzene ring,
p-methyl-substituted benzonitriles. The tested reactions as exemplified by the synthesis of 10b,c,l–o. These results
proceeded well to give the products 10t–v with comparable demonstrated the broad scope of the present strategy for the
good yields, respectively. This indicated that there was no preparation of novel tricyclic heterocycles 10. Based on the
obvious steric impact on the reaction with monosubstituted success in the synthesis of the triazolobenzodiazepinium salts
benzonitriles. On the other hand, from disubstituted benzo- 10, we then turned our efforts to access the N(1)-unsubstituted
nitriles including 2-fluoro-4-methylbenzonitrile and 2-methyl-4- neutral tricyclic heterocycles. To this end, the phenylhydra-
chlorobenzonitrile, the tricyclic benzo[b][1,2,4]triazolo[1,5- zones 7 were replaced by the ethoxycarbonylhydrazone 11, in
d][1,4]diazepinium salts 10w and 10x were obtained in moder- which the ethoxycarbonyl group was hoped to be removable by
ate yields of 76% and 67%, respectively. However, one limita- hydrolysis [34]. As presented in Scheme 4, ethyl carbazate was
tion was observed for the reaction between 8a and 2,6- used to prepare the hydrazone 11 by condensation with 2,3-
dimethylbenzonitrile in which the cyano group is flanked by dihydro-4(1H)-quinolone 6a [46]. However, it was odd that the
two substituents in the ortho-positions. Under the same condi- oxidation using the hypervalent iodine(III) reagent PhI(OAc)2
tions, the reaction failed to give the desired product 10y. This as described for phenylhydrazones 7 failed to produce the ex-
Scheme 4: Synthesis of N(1)-unsubstituted benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepines 13. Reaction conditions: a) compound 11 (1.20 mmol),
Pb(OAc)4 (1.44 mmol), CH2Cl2 (10 mL) to give the crude compound 12. b) (i) compound 12 (1.20 mmol, calculated via theory yield), nitrile
(1.68 mmol), AlCl3 (1.68 mmol), CH2Cl2 (5 mL), −40 °C for 0.5 h, then at rt for 1 h under N2; (ii) ice water (1 mL); 0 °C, 5 min. Isolated yields are
given.
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Beilstein J. Org. Chem. 2018, 14, 1826–1833.
pected α-acetoxy-ethoxycarbonyl compound 12. Instead, the bear a diazenium function where the electron-deficient N(2)
hydrazone 11 remained intact and was recovered. Therefore, we displayed the feature of a latent nitrenium ion. The subsequent
switched to a stronger oxidant, Pb(OAc)4. To our pleasure, [1,2]-shift after cationic Huisgen-type cycloaddition occurs with
hydrazone 11 was successfully oxidized to provide the required complete regioselectivity to N(2) not to N(4). Meanwhile, there
azoester 12. However, NMR analysis revealed that compound are two possible migrating moieties: the aromatic side competes
12 was impure and contained also some cyclized byproduct with the aliphatic side. It has been reported that the migratory
[47]. Furthermore, it was discovered that compound 12 was tendency of substituents prefer those with a higher ability to
quite unstable and tended to degrade when it was subjected to accommodate the respective carbocations [46]. As anticipated,
chromatographic separation. Based on this, we planned to use it was the phenyl moiety not the aliphatic moiety that moves
the product mixture resulting from the oxidation of hydrazone from C(3) to N(2) to furnish the isolated products. This rear-
11 directly for the following reaction with nitriles 9 in the pres- rangement falls into the uncommon class of migration of a sub-
ence of AlCl3. We were pleased to observe that the reaction stituent from a carbon atom to an electron-deficient nitrogen
proceeded as expected under the usual reaction conditions and atom [50].
the desired products 13 were obtained after quenching with
H2O at 0 °C. As can be seen from Scheme 4, both aliphatic and The assignment of the structures for all of 5,6-dihydro-4H-
aromatic nitriles worked similarly.
benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 and the
free base counterparts 13 was made on the basis of spectroscop-
In light of the experimental achievements and preceding theo- ic analysis. To further support our assignment, we were able to
retical work, we rationalized the synthesis with a proposed acquire X-ray crystal structures of 10k as well as of 13e, which
mechanism as outlined in Scheme 5 with the α-acetoxyphenyl- indisputably confirm their structures [51]. For these two com-
azo compound 8a serving as a model substrate. In this pathway, pounds, the ORTEP pictures are shown in Figure 2 and
the reaction is initiated by AlCl3 coordination with the acetate Figure 3, respectively.
moiety of 8a to generate the azocarbenium ion 14 as a reactive
intermediate, which cannot be isolated by now [31]. Then, the Conclusion
nitrogen atom of the nitrile approaches to the central electron- In summary, an appealing series of 1,2,4-triazole-fused
deficient carbon atom in 14 to form a Ritter-type nitrilium salt 1,4-benzodiazepines 10 and 13 were prepared via the
15 [48]. Salt 15 then undergoes a concerted but asynchronous [3+ + 2]-cycloaddition reaction followed by a cationic [1,2]-re-
cyclization [49] to afford the initial spiro-substituted adduct 16, arrangement reaction. The procedure is general and has several
which has a strong proclivity for ring expansion to occur. Ac- advantages such as ready availability of starting materials, good
cordingly, the 6-membered piperidine ring was enlarged flexibility in terms of substitution, and an unprecedented fusion
to the 7-membered diazepine ring giving the isolated pattern of the produced heterocycles. In view of the fact that the
benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 via constructed 1,2,4-triazolobenzodiazepines represent a class of
[1,2]-shift. It is noteworthy that the intermediate products 16 N-containing fused heterocycles with a new type of scaffold
Scheme 5: Mechanistic rationale for the [3+ + 2]-cycloaddition/rearrangement reaction.
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Beilstein J. Org. Chem. 2018, 14, 1826–1833.
ORCID® iDs
Lin-bo Luan - https://orcid.org/0000-0002-5413-0850
Zhi-ming Li - https://orcid.org/0000-0001-5471-8462
Quan-rui Wang - https://orcid.org/0000-0001-7593-9176
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