1,3,5-Triazinanes as Formaldimine Surrogates in the Ugi Reaction

Article abstract of DOI:10.1002/ejoc.202000569

In the present study, a new synthetic strategy towards N-acylated glycinamides was developed by the use of 1,3,5-triazinanes as formaldimine surrogates in the Ugi reaction. The targeted products were obtained in a combinatorial, diversity-oriented fashion in good yields. Further modifications allowed us to adapt this procedure for the one-pot two-step syntheses of a local anesthetic druglidocaine and several unsymmetrically substituted diketopiperazines.

Full text of DOI:10.1002/ejoc.202000569

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Multicomponent Reactions
1,3,5-Triazinanes as Formaldimine Surrogates in the Ugi
Reaction
Pavel Golubev,*[a] Natalia Guranova,[a] and Mikhail Krasavin[a]
Abstract: In the present study, a new synthetic strategy to- diversity-oriented fashion in good yields. Further modifications
wards N-acylated glycinamides was developed by the use of allowed us to adapt this procedure for the one-pot two-step
1,3,5-triazinanes as formaldimine surrogates in the Ugi reac- syntheses of a local anesthetic druglidocaine and several un-
tion. The targeted products were obtained in a combinatorial, symmetrically substituted diketopiperazines.
1,3,5-triazinanes were published[4] as well as iridium-catalyzed
1,3,5-Trisubstituted hexahydro-1,3,5-triazines, also referred to as
aminomethylation of conjugated enynes[5] and rhodium-cata-
1,3,5-triazinanes or triazacyclohexanes, were introduced by Re-
lyzed C3-aminomethylation of indoles.[6] Another common
transformation is the condensation of 1,3,5-triazinanes with
α-hydroxyimino ketones to form 1,4,5-trisubstituted imidazole
N-oxides. This reaction was a key step in the construction of
potent mitogen-activated protein kinase p38 inhibitors.[7] More-
over, these imidazole N-oxides were further modified to obtain
chiral nitrogen heterocycles[8] and chiral ionic liquids[9] or used
as 1,3-dipoles in cycloaddition reactions.[10] 1,3,5-Triazinanes
also served as a scaffold for peptide macrocycles – inhibitors of
coagulation factor XII with Ki values in the low nanomolar
infield in 1902[1] and are commonly used in organic synthesis as
stable, easily accessible formaldimine surrogates. For example,
1,3,5-triazinanes readily participate in the Lewis acid-
promoted cycloaddition reactions. Numerous variants of the lat-
ter published over the last 3 years include [n+2] (triazinane as
an imine surrogate), [n+4] or [n+2+2] (triazinane as a formal
1,4-dipole) and [n+3] (triazinane as a formal 1,3-dipole) cyclo-
additions.[2] In these reactions triazinanes were utilized as do-
nors of C-N, C-N-C, N-C-N or C-N-C-N fragments for the construc-
tion of 5-, 6-, 7- and 8-membered nitrogen heterocycles. In
2015, Krische and co-workers published a ruthenium-catalyzed range.[11] Unusual rhodium-catalyzed annulation of N-sulfonyl-
hydroaminomethylation of allenes and 1,3-dienes with 1,3,5-tri- 1,2,3-triazoles with 1,3,5-triazinanes was reported recently by
azinanes.[3] Later on, asymmetric Mannich-type reactions with Bao.[12] In this reaction triazinane acts as a formal donor of both
Scheme 1. Known synthetic transformations of 1,3,5-triazinanes and the reaction investigated in this work.
C-N-C and N-C-N fragments, and the final products are octa-
hydro-1H-purine derivatives (Scheme 1).
[a] Dr. P. Golubev, N. Guranova, Prof. Dr. M. Krasavin
Institute of Chemistry, Saint Petersburg State University,
26 Universitetsky prospect, Peterhof 198504, Russia.
E-mail: p.r.golubev@spbu.ru
http://www.krasavin-group.org
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000569.
Despite being a well-studied class of synthetic building
blocks and their resemblance of formaldimines, 1,3,5-triazin-
anes remain scarcely explored in multicomponent reactions
typical for imines. One rare example is the synthesis of 3-unsub-
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the only detectable reaction product, isolated in moderate to
stituted tetrahydroisoquinolinic acids via the Castagnoli–Cush- nearly quantitative yields. However, when pivalic acid was used,
man reaction of triazinanes with homophthalic anhydride.[13] iminoimidazoline 5 was isolated along with the targeted prod-
Surprisingly, however, there are no examples of the Ugi reaction uct 4o. Apparently, steric bulk around the carboxylic acid anion
involving 1,3,5-triazinanes as formaldimine surrogates in the lit- impedes its addition to the intermediate nitrilium ion, slowing
erature. Puzzled by this fact, we set off to fill this gap and report down the formation of an Ugi adduct. At the same time, a com-
the results of our findings herein.
peting reaction occurs either as an acid-promoted [2+2+2]
cycloaddition or as a stepwise addition of a second formaldim-
ine molecule to the nitrilium ion followed by ring closure (Fig-
ure 2).
Initially, 1,3,5-triphenyltriazinane, benzoic acid and tert-butyl
isocyanide were chosen as model substrates for the optimiza-
tion of the reaction conditions. Luckily, compound 4m was iso-
lated in nearly quantitative yield after stirring a solution of a
stoichiometric mixture of the three starting materials in di-
chloroethane for 12 h at 45 °C. Hence, no further optimization
was attempted, and these conditions were applied to all further
experiments. The reaction with isonicotinic acid (compound 4c)
was the only exception and was carried out in methanol due
to poor solubility of the acid in dichloroethane.
Next, a series of experiments were carried out with 16 triazin-
anes, 14 isocyanides and 21 acids to explore the reaction scope
(Scheme 2, Figure 1). In most cases, glycine derivative 4 was
Figure 2. Proposed mechanism of formation of compound 5.
Notably, with a proper choice of reagents, the presented
methodology can be applied for the synthesis of both small
glycine derivatives (such as 4b and 4g) and short peptoids (4e).
Scheme 2. Synthesis of glycinamides 4. Reactions carried out with
(0.6 mmol), 2 (0.2 mmol) and 3 (0.6 mmol).
1
Figure 1. Glycinamides synthesized in this work. aReaction carried out in MeOH for 36 h.
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stituted and monosubstituted phenyl rings, respectively, are not
As chloroacetic acid can be employed in the reaction, an
seen clearly in the 1H NMR spectra and therefore the “apparent”
coupling constants for observed “doublets” and “triplets” of the cor-
responding aromatic protons are given. DEPT spectra were used for
assignment of carbon atoms signals. Melting points were deter-
mined with a Stuart SMP30 instrument and are uncorrected. Mass
spectra were recorded with a Bruker Maxis HRMS-ESI-qTOF spec-
trometer (electrospray ionization mode).
intramolecular SN2-type ring closure can be envisioned in anal-
ogy to our previous report,[14] which would open a straightfor-
ward entry to 2,5-diketopiperazines, compounds of significant
importance in medicinal chemistry.[15] We applied the previ-
ously developed one-pot two-step protocol (Scheme 3) and
synthesized several diketopiperazines without isolation of inter-
mediate Ugi adducts in good overall yields (Figure 3).
General Procedure A. Synthesis of Glycinamides 4: A solution of
isocyanide (0.6 mmol) in 0.3 mL of dichloroethane and a solution
of carboxylic acid (0.6 mmol) in 0.3 mL of DCE were added sequen-
tially to a stirred solution (suspension) of triazinane (0.2 mmol) in
0.3 mL of DCE in a screw-cap vial. The reaction mixture was stirred
at 45 °C for 12–18 h (TLC monitored). After full consumption of the
starting material the solvent was evaporated and the residue was
separated by column chromatography on silica eluted with 3 % to
20 % acetone in CH2Cl2.
Scheme 3. Synthesis of diketopiperazines 6.
Due to poor solubility of isonicotinic acid synthesis of compound
4c was carried out in methanol following General procedure A.
General Procedure B. Synthesis of Diketopiperazines 6: Crude
glycinamides were prepared following the general procedure A. The
residue after evaporation of CHCl3 was dissolved in anhydrous THF,
then NaH (60 % in oil, 26 mg, 0.66 mmol) was added in portions
and the resulting suspension was stirred at 40 °C overnight. The
reaction was quenched with saturated aqueous NH4Cl and ex-
tracted with CH2Cl2. Organic extracts were dried with MgSO4, then
filtered and the solvent was distilled off. Diketopiperazines were
isolated by column chromatography using acetone/dichloro-
methane as eluent.
Figure 3. Diketopiperazines 6a–c synthesized in this work.
Finally, we noticed that one of the synthesized compounds
(glycinamide 4b) resembles a well-known local anesthetic drug
lidocaine. Earlier it was shown that a tertiary amide group in
Ugi adducts can be selectively and efficiently reduced with
BH3·SMe2 or BH3·THF.[16] To our delight, BH3·THF proved to be
efficient in present case as well, and we were able to obtain
lidocaine in a one-pot fashion without isolation of 4b in 65 %
overall yield (Scheme 4).
Acknowledgments
This research was supported by the Russian Science Foundation
(grant #19-73-00109). We thank the Research Centre for Mag-
netic Resonance and the Centre for Chemical Analysis and Ma-
terials Research of the Saint Petersburg State University Re-
search Park for obtaining the analytical data.
Keywords: Molecular diversity · Multicomponent reactions ·
Synthetic methods · 1,3,5-Triazinanes · Ugi reaction
Scheme 4. Synthesis of lidocaine.
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In conclusion, we have demonstrated that 1,3,5-triazinanes
can be successfully used as formaldimine surrogates in the Ugi
reaction to construct N2-acylated glycinamide derivatives and
short peptoids. Moreover, post-MCR modifications allowed us
to adapt the proposed method for one-pot synthesis of diketo-
piperazines and lidocaine. The practical simplicity and the avail-
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General Information: NMR spectroscopic data were recorded with
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Received: April 24, 2020
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Multicomponent Reactions
P. Golubev,* N. Guranova,
M. Krasavin .......................................... 1–5
1,3,5-Triazinanes as Formaldimine
Surrogates in the Ugi Reaction
1,3,5-Triazinanes were used as easily good to nearly quantitative yields. This
accessible, bench-stable formaldimine protocol was applied for one-pot two-
surrogates in the Ugi reaction for rapid step syntheses of lidocaine and several
assembly of glycinamide derivatives unsymmetrically substituted diketo-
with three elements of diversity, in piperazines.
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