Diversity-oriented synthesis of N,N-dimethylamino-substituted azoles employing TBTU

Article abstract of DOI:10.1016/j.tetlet.2018.05.075

A convenient, diversity-oriented approach for the transformation of readily available amidoximes, o-hydroxyarylamines, acyl hydrazines, carboximidohydrazides and thiohydrazides into their respective N,N-dimethylamino-substituted azoles is described. The method is particularly suitable for array chemistry application as it employs a stable, solid reagent TBTU.

Full text of DOI:10.1016/j.tetlet.2018.05.075

Accepted Manuscript
Diversity-oriented synthesis of N,N-dimethylamino-substituted azoles employ-
ing TBTU
Alexey Lukin, Natalya Kalinchenkova, Tatiana Vedekhina, Nikolay Zhurilo,
Mikhail Krasavin
PII:
S0040-4039(18)30700-7
https://doi.org/10.1016/j.tetlet.2018.05.075
TETL 50022
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
24 April 2018
23 May 2018
25 May 2018
Please cite this article as: Lukin, A., Kalinchenkova, N., Vedekhina, T., Zhurilo, N., Krasavin, M., Diversity-oriented
synthesis of N,N-dimethylamino-substituted azoles employing TBTU, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.05.075
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Diversity-oriented synthesis of N,N-dimethylamino-substituted
azoles employing TBTU
Alexey Lukin,a Natalya Kalinchenkova,a Tatiana Vedekhina,a Nikolay Zhurilo,a and Mikhail
Krasavinb,*
aLomonosov Institute of Fine Chemical Technologies, Moscow Technological University, 86
Vernadskogo Prospekt, Moscow, 117571 Russian Federation
bSaint Petersburg State University, Saint Petersburg, 199034 Russian Federation
* Corresponding author.
Phone: +7 931 361 7872, fax: +7 812 428 6939, e-mail: mkrasavin@spbu.ru
URL: https://krasavin-group.org
Abstract: A convenient, diversity-oriented approach for the transformation of readily
available amidoximes, o-hydroxyarylamines, acyl hydrazines, carboximidohydrazides and
thiohydrazides into their respective N,N-dimethylamino-substituted azoles is described. The
method is particularly suitable for array chemistry application as it employs a stable, solid
reagent TBTU.
Keywords: dimethylamino group; azoles; acylation; guanidine formation; diversity-oriented
synthesis; fragment-based drug discovery.
Organic compounds that are based on privileged1 heterocyclic cores, which possess increased
solubility and low molecular weight, are of particular interest for fragment-based drug
discovery (FBDD).2 Indeed, privileged character increases the chances of identifying, via
initial screening, the starting affinity points for further fragment evolution; high solubility
allows testing the fragments at high enough concentration to detect binding to protein targets
and low molecular weight provides sufficient room for fragment growth and subsequent
medicinal chemistry optimization within the limits of druglikeness.3 Various azole moieties
are omnipresent in organic compounds endowed with diverse biological activities and are
often included in fragment screening libraries.4 As an alternative to the costly protein/ligand
X-ray crystallography platform,5 NMR-based approaches6 have been employed as a time- and
cost-efficient way to identify fragment hits, ever since the conceptual introduction of FBDD
in 1996.7 Methyl groups bound to a heteroatom, a (hetero)aromatic ring or a carbonyl group

1
that give a standalone, uncoupled signal in the H NMR spectrum and thus facilitate NMR
fragment screening, are desired structural elements in a fragment library.8 N,N-
Dimethylamino-substituted azoles combine the above-mentioned features (privileged core and
‘NMR screening-friendly’ methyl groups) with the solubilizing character of the nitrogen
atom. Herein, we describe a new and convenient method for the preparation of such
compounds, many of them fragment-like,9 in a diversity-oriented fashion from readily
available
precursors
and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
tetrafluoroborate (TBTU).
Scheme 1. Serendipitously discovered transformation of 1a into 2a and the structures of
TBTU and Vilsmeier salt.
In the course of preparing an array of 1,2,4-oxadiazoles from amidoximes and carboxylic
acids via TBTU activation as described in the literature,10 the carboxylic acid coupling partner
was not added to the reaction mixture by accident. This resulted in the conversion of
amidoxime 1a into 5-(dimethylamino)-1,2,4-oxadiazole 2a which was isolated in 63% yield.
This transformation is quite similar to the known cyclization of amidoximes to 1,2,4-
oxadiazoles brought about by the action of Vilsmeier salt (Scheme 1).11 Since Vilsmeier salt
needs to be prepared prior to use12 and cannot be stored and used as an off-the-shelf reagent,
we viewed TBTU as being a potentially attractive alternative, particularly for small-scale
parallel chemistry applications where the convenience of using a stable, solid reagent is likely
to be of importance.13 Considering that no such application of TBTU or its analogs (e. g.,
HATU or HBTU) had been described in the literature, we set off to investigate the substrate
scope of the newly identified reaction.
Since the use of Vilsmeier salt has been applied to the synthesis of other azoles besides 5-
(dimethylamino)-1,2,4-oxadiazoles such as 2a, including various benzazoles,14-15 we included
o-hydroxyarylamines 3a-f in the selection of substrates hoping to obtain the corresponding
arene-fused 1,3-oxazoles 4a-f. In addition, although no such reaction had been described in

the literature neither for Vilsmeier salt nor for TBTU or its analogs, we also attempted to
transform acyl hydrazines 5a-d, carboximidohydrazides 7a-b and thiohydrazides 9a-d into
1,3,4-oxadiazoles 6a-d, 1,2,4-triazoles 8a-b and 1,3,4-thiadiazoles 10a-d, respectively
(Scheme 2). As evident from the data presented in Table 1, the reaction with TBTU readily
transformed all these substrates into the respective N,N-dimethylamino-substituted azoles.
Scheme 2. Synthesis of N,N-dimethylamino-substituted azoles investigated in this work.
Prior to performing the substrate scope investigation, we briefly examined variations of the
reaction time and temperature as well as the substrate-to-DIPEA and substrate-to-TBTU ratios
and found the conditions shown in Scheme 2 to be optimal.16 Except for the transformation of
acyl hydrazines 5 into the respective 1,3,4-oxadiazoles 6 (Table 1, entries 13-16), which
required heating the reaction mixture at reflux for 4 h, all reactions were performed at ambient
temperature for 10 h. The isolated yields obtained after chromatographic purification of the
azole product were moderate to very good. With respect to molecular weight, the majority of
compounds obtained are rule-of-three compliant (MW < 300), which makes them suitable
tools for FBDD.9 The method was found to be compatible with a range of protecting groups
such as Boc (Entries 2 and 4) as well as trityl and acetonide (Entry 5).
Table 1. Preparation of N,N-dimethylamino-substituted azoles 2, 4, 6, 8 and 10.
Isolated
Entry
Substrate
Product
MW
yield (%)

1
2
267
296
63
69
3
4
197
268
43
27
5
594
55
6
7
8
190
229
176
45
87
63

9
196
239
185
61
75
64
10
11
12
162
296
233
207
61
20
68
70
13a
14a
15a
16a
223
189
79
43
17

18
19
20
189
284
262
79
59
55
21
282
325
85
63
22
aReaction was conducted at reflux for 4 h.
From the mechanistic perspective, it is likely that the reaction is initiated by the known18
formation of guanidine intermediate 11 which undergoes intramolecular addition-elimination
leading to formation of the azole ring (Scheme 3).
Scheme 3. Plausible mechanism for azole formation.

In summary, we have developed a convenient, diversity-oriented approach for the
transformation of readily available amidoximes, o-hydroxyarylamines, acyl hydrazines,
carboximidohydrazides and thiohydrazides into their respective N,N-dimethylamino-
substituted azoles using a unified synthetic procedure. The method represents a practical
alternative to the use of Vilsmeier salts. The transformation has been applied to acyl
hydrazines, carboximidohydrazides and thiohydrazides for the first time. The majority of
compounds obtained via this method are rule-of-three compliant and can be considered
practical tools for fragment-based drug discovery, particularly by NMR-based techniques.
Acknowledgements
This research was supported by the Russian Science Foundation (project grant 14-50-00069).
Mass-spectrometry studies were performed at the Centre for Chemical and Materials Research
of Saint Petersburg State University Research Park.
References and notes
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Yet. Wiley and Sons, 2018. 560 pp.
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46, 3–26.
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Med. Chem. 2005, 48, 403-413.
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1599-1610.
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599-606.
16. General procedure for the synthesis of N,N-dimethylamino azoles 2, 4, 6, 8 and 10 – The
substrate (1.40 mmol) was dissolved in CH2Cl2 (10 mL) and treated with TBTU (1.54 mmol)
with stirring. Diisopropylethylamine (DIPEA, 2.80 mmol) was added dropwise and the
reaction was stirred at r. t. for 10 h (heated at reflux for 4 h in the case of substrates 5a-d).
The reaction mixture was washed with 5% aq. citric acid, 5% aq. K2CO3, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 05% methanol in chloroform as eluent.
17. Zhurilo, N. I.; Chudinov, M. V.; Matveev, A. V.; Smirnova, O. S.; Konstantinova, I. D.;
Miroshnikov, A. I.; Prutkov, A. N.; Grebenkina, I. E.; Pulkova, N. V.; Shvets, V. I. Bioorg.
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1185-1193.

Diversity-oriented synthesis of N,N-dimethylamino-substituted
azoles employing TBTU
Alexey Lukin, Natalya Kalinchenkova, Tatiana Vedekhina, Nikolay Zhurilo, and Mikhail
Krasavin*





TBTU was found to give 5-(dimethylamino)-1,2,4-oxadiazoles from amidoximes
The transformation was found applicable to a variety of substrates
The method offers a practical alternative to the use of Vilsmeier salt
Compounds obtained can be considered tools for fragment-based drug discovery
19.