Consecutive hydrazino-Ugi-azide reactions: Synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

Article abstract of DOI:10.3762/bjoc.13.256

Isocyanide-based multicomponent reactions (IMCRs) allow the construction of relatively complex molecules through a one-pot synthesis. The combination of IMCRs in a consecutive or sequential fashion further extends the complexity of the molecules obtained. Herein, we report the efficient application of this approach to the synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi-azide four-component reaction; second a hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to excellent yields. The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles.

Full text of DOI:10.3762/bjoc.13.256

Consecutive hydrazino-Ugi-azide reactions: synthesis
of acylhydrazines bearing 1,5-disubstituted tetrazoles
Angélica de Fátima S. Barreto*, Veronica Alves dos Santos
and Carlos Kleber Z. Andrade*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2596–2602.
Laboratório de Química Metodológica e Orgânica Sintética, Instituto
de Química, Universidade de Brasília, 70910-970, Brasília-DF, Brazil
doi:10.3762/bjoc.13.256
Received: 28 August 2017
Accepted: 14 November 2017
Published: 05 December 2017
Email:
Angélica de Fátima S. Barreto* - angelfsb@yahoo.com.br;
Carlos Kleber Z. Andrade* - ckleber@unb.br
Associate Editor: T. P. Yoon
* Corresponding author
© 2017 Barreto et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
acylhydrazines; consecutive Ugi reactions; 1,5-disubstituted
tetrazoles; isocyanide-based multicomponent reactions (IMCRs);
Ugi-azide reaction
Abstract
Isocyanide-based multicomponent reactions (IMCRs) allow the construction of relatively complex molecules through a one-pot
synthesis. The combination of IMCRs in a consecutive or sequential fashion further extends the complexity of the molecules ob-
tained. Herein, we report the efficient application of this approach to the synthesis of acylhydrazines bearing 1,5-disubstituted tetra-
zoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi-azide four-component reaction; second a
hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to
excellent yields. The products synthesized herein contain functional groups within their structures that can be easily modified to
obtain new acylhydrazino 1,5-disubstituted tetrazoles.
Introduction
Tetrazoles are extensively studied, useful non-natural hetero- range of pharmacological activities. For instance, cilostazol
cyclic skeletons with the highest nitrogen content among the (anti-inflammatory), pentylenetetrazol (circulatory and respira-
stable heterocycles [1,2]. The tetrazole-ring system has a variety tory stimulant) and nojiritetrazole (antidiabetic) are drugs con-
of applications in organic chemistry, coordination chemistry, taining the 1,5-disubstituted tetrazole nucleus, along with the
and agriculture and, in particular, it displays a wide range of pharmaceutically important tetrazoles losartan and valsartan,
biological properties such as analgesic, anti-inflammatory, which are used as angiotensin receptor blockers (Figure 1) [8].
antiviral, anticancer, among others [3-5].
In recent years, the synthesis of 1,5-disubstituted tetrazoles has
The tetrazole nucleus most widely described in the literature is attracted the attention of several research groups around the
the 1,5-disubstituted tetrazole [6,7] because it presents a wide world not only for their important pharmacological activities
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Figure 1: Tetrazole-containing drugs.
but also for being an excellent mimic of the cis-amide bond. ic negamycin, active against Gram-negative bacteria [25],
Furthermore, they can be used to pre-organize the amide bonds among others [26]. Furthermore, trisubstituted acylhydrazines
of peptides [9].
were found to serve as tertiary amide bioisosters [27]. There-
fore, it is highly desirable to have a method that allows an easy
Most methods for the synthesis of tetrazoles have limitations incorporation of hydrazino groups into more complex mole-
that include multistep syntheses of starting materials and/or the cules. In this respect, Dömling et al. have recently described the
use of expensive reagents. The most commonly used synthesis synthesis of α-hydrazino amides using N-hydroxyimides as the
of 1,5-disubstituted tetrazoles are intermolecular cycloaddition acid component in Ugi reactions [28].
reactions and isocyanide-based multicomponent reactions
(IMCRs). Indeed, the Ugi-multicomponent reaction using As part of our continuing efforts in using consecutive multi-
TMSN3 (trimethylsilyl azide) as acid component, originally re- component reactions to obtain novel molecules in a reduced
ported by Ugi in 1961 [10], is one of the best and most general number of steps [29-31], herein we describe a concise and effi-
methods for the synthesis of 1,5-disubstituted tetrazoles due to cient strategy for the synthesis of acylhydrazino bistetrazoles
the intrinsic generation of molecular diversity [11-15]. As the through hydrazino-Ugi-azide reactions in only three steps.
Ugi reaction also requires an amine component, we envisaged During the course of our work, Dömling et al. reported the syn-
that reactions of hydrazino compounds (RNHNH2) with thesis of hydrazinotetrazoles through a different approach
TMSN3 could furnish useful compounds bearing both the focused on their postcyclization strategy [32].
hydrazino and the tetrazole moieties.
Results and Discussion
The term ‘hydrazino-Ugi’ was first proposed for the synthesis Two multicomponent reactions were used for the synthesis of
of hydrazinopeptides [16] in 2010. The application of consecu- acylhydrazino bis(1,5-disubstituted tetrazoles) as outlined in
tive hydrazino-Ugi reactions has also been described in the lit- Scheme 1. The approach presented here is initially based on a
erature [17]. Besides this, the introduction of the hydrazino hydrazino-Ugi-azide reaction, followed by a hydrazinolysis step
group into several classes of compounds presents several advan- and a second hydrazine-Ugi-azide reaction to provide the
tages. For instance, hydrazinopeptides comprise a class of desired acylhydrazino bis(1,5-disubstituted tetrazoles). Recently
peptidomimetics with promising biological and conformational we have reported the synthesis of acylhydrazino-peptomers by a
activities [18-21]. It is worth mentioning that in such com- similar strategy [31].
pounds the so-called "hydrazino-turns" are formed through
intramolecular hydrogen bonding between the hydrazino The hydrazides 2a–c were prepared by the reaction of esters 1,
groups. The resulting unique secondary structures can improve 4 and 6 with hydrazine monohydrate, following a known proce-
the proteolytic stability of these compounds [22]. An acylhy- dure (Scheme 2) [31].
drazine (hydrazide) was first reported in Ugi reactions back in
1961 [23] and also some natural products contain this moiety, To access the acylhydrazino-tetrazoles, the hydrazides 2a–c
such as the vitamin B6 antagonist linatine [24] and the antibiot- were subjected to a multicomponent reaction comprising an
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Scheme 1: Synthesis of acylhydrazino bis(1,5-disubstituted tetrazoles) through two hydrazino-Ugi-azide reactions and a hydrazinolysis step.
Scheme 2: Synthesis of hydrazides 2a–c. Reagents and conditions: (i) N2H4·H2O, EtOH, reflux, 2–3 h; (ii) CH3I, NaHCO3, DMF, rt, 46 h; (iii) (Boc)2O,
NaOH, dioxane/H2O, overnight [31].
aldehyde or ketone 7a–h, trimethylsilyl azide (TMSN3, 8), Next, a second hydrazino-Ugi-azide reaction was carried out to
methyl isocyanoacetate (9) and ZnCl2 (10 mol %) in trifluoro- obtain the acylhydrazino bistetrazoles. For this purpose, we
ethanol (TFE) at room temperature for 24 h. The presence of chose hydrazine tetrazole 10j to continue the synthesis, as it
catalytic amounts of zinc chloride as Lewis acid in this reaction was obtained in excellent yield, it shows distinct NMR spectra
had already been reported to improve the yields [33]. Indeed, and offers the possibility of further functionalization after
initial studies without the catalyst afforded the desired products removal of the Boc protecting group. Therefore, compound 10j
10a in only 28% yield (120 °C, 30 min, MW, TFE) and 10j in was subjected to hydrazinolysis with hydrazine monohydrate as
68% yield (rt, 24 h, TFE). As solvent, TFE was found to be the already described to give the corresponding hydrazide 11
best choice for the reactions. The results summarized in (Scheme 5). The latter compound was then subjected to the
Scheme 3 show that various ketones and aldehydes generated hydrazine-Ugi-azide reaction with different ketones, to yield the
the respective products under the optimized conditions when corresponding acylhydrazino bis(1,5-disubstituted tetrazoles)
acetyl hydrazide (2a) was employed, albeit in moderate yields 12a–d in moderate to good yields (45–70%). At this stage, only
(30–53%). Nevertheless, the yields were considerably higher symmetrical ketones were used to facilitate the product charac-
for Cbz-glycine hydrazide (2b) and Boc-glycine hydrazide (2c) terization by NMR analysis. Indeed the 1H and 13C NMR spec-
when compared to 2a (Scheme 4).
tra were in full agreement with the proposed structures. Of note
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Scheme 3: Synthesis of acylhydrazino 1,5-disubstituted tetrazoles 10a–h through multicomponent reactions involving 2a.
Scheme 4: Synthesis of acylhydrazino 1,5-disubstituted tetrazoles 10i–m through multicomponent reactions involving 2b or 2c.
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Scheme 5: Synthesis of acylhydrazino bis(1,5-disubstituted tetrazoles) 12a–d.
are the characteristic C=N tetrazole resonances that are ob- after ester cleavage and/or Boc deprotection. So, further
served between 155–158 ppm in the 13C NMR spectra. In addi- Ugi/Ugi-azide reactions allow elongating the acylhydrazino
tion, HRMS data supported the product structures.
bis(1,5-disubstituted tetrazoles) main chain (Scheme 6). For
instance, the ester terminus can be submitted to another hydrazi-
The obtained acylhydrazino bis(1,5-disubstituted tetrazoles) nolysis to install a new tetrazole nucleus after an Ugi-azide
12a–d can be further functionalized on either or both termini reaction.
Scheme 6: Possible postmodification reactions of the acylhydrazino bis(1,5-disubstituted tetrazoles) 12a–d.
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15.Maleki, A.; Sarvary, A. RSC Adv. 2015, 5, 60938–60955.
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In summary, the approach developed herein allows the synthe-
sis of a wide range of hydrazino bis(1,5-disubstituted tetrazoles)
in only three steps. The procedure offers several advantages,
such as high atom-economy, a simple synthetic procedure with
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pounds allow further modification reactions.
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Supporting Information
Supporting Information File 1
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Detailed experimental procedures, NMR and mass spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-256-S1.pdf]
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