Direct Synthesis of β-Aminoenals through Reaction of 1,2,3-Triazine with Secondary Amines

Article abstract of DOI:10.1021/acs.orglett.7b01543

Simple and direct nucleophilic addition of secondary amines, including imidazole, to 1,2,3-triazine under mild reaction conditions (THF, 25-65 °C, 12-48 h), requiring no additives, cleanly provides β-aminoenals 4 in good yields (21 examples, 31-79%). The

Full text of DOI:10.1021/acs.orglett.7b01543

Letter
pubs.acs.org/OrgLett
Direct Synthesis of β‑Aminoenals through Reaction of 1,2,3-Triazine
with Secondary Amines
Ryan E. Quinones, Christopher M. Glinkerman, Kaicheng Zhu, and Dale L. Boger*
̃
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Simple and direct nucleophilic addition of
secondary amines, including imidazole, to 1,2,3-triazine under
mild reaction conditions (THF, 25−65 °C, 12−48 h), requiring
no additives, cleanly provides β-aminoenals 4 in good yields (21
examples, 31−79%). The reaction proceeds by amine nucleophilic addition to C4 of the 1,2,3-triazine, in situ loss of N2, and
subsequent imine hydrolysis to provide 4.
he inverse electron demand Diels−Alder reaction of
electron-deficient heterocyclic azadienes has been em-
triazines. In our studies on the cycloaddition of 1,2,3-triazine
with pyrrolidine enamines, we occasionally observed that the
pyrrolidine liberated in the aromatization step consumed the
starting triazine. Thus, secondary amines were chosen as a
representative class of nucleophiles with which to examine this
reactivity with the parent 1,2,3-triazine (1). Herein we describe
studies on this intrinsic electrophilic reactivity of 1,2,3-triazine
and its effective use in reactions with secondary amines,
providing β-aminoenals (β-enaminals) 4 (Figure 1). Formally,
reagent 1 behaves in such reactions as an equivalent of 2 or as a
stable alternative to the unmanageable malondialdehyde (3) in
reactions toward secondary amines.
T
ployed as powerful methodology for the synthesis of complex
heterocyclic targets.1 Extensive efforts have now detailed the
wide range of cycloaddition reactions and applications of
1,2,4,5-tetrazines,2 1,2,4-triazines,3 1,3,5-triazines,4 1,3,4-oxadia-
zoles,5 and 1,2-diazines.6 These reactions have been, and
continue to be, inspired by their synthetic applications, enabling
concise routes to challenging target molecules with the rapid
construction of highly substituted or functionalized heterocyclic
cores.7−10 Recent applications of 1,2,4,5-tetrazines in bio-
orthogonal reactions have capitalized on their unusually rapid
and efficient cycloaddition reactions with select dienophiles.11
We recently described a series of such studies on 1,2,3-
triazines, an untapped class of heterocyclic azadienes, exploring
their synthesis, defining the scope of their cycloaddition
reactions with various classes of dienophiles, and illustrating
pronounced substituent electronic effects on their reactivity,
regioselectivity, or mode of cycloaddition.12 The exploration
and development of the 1,2,3-triazine cycloaddition reactions
were inspired by their projected use in total syntheses of natural
products, which now include dihydrolysergic acid,13 pyrimido-
blamic acid,14 P-3A,14 and methoxatin.15
Nucleophilic addition of secondary amines to 1,2,3-triazine
was found to proceed under mild, easily reproducible reaction
In the course of our studies, the susceptibility of the more
reactive 1,2,3-triazines toward nucleophiles was noted. Much
like studies of the heterocycle itself, prior investigations on the
addition of nucleophiles to 1,2,3-triazine (1) are limited. The
C4 addition of methoxide has been reported, the addition of
Grignard reagents at C4 (PhMgBr) or C5 (MeMgI) has been
disclosed, and the reaction of a lithium reagent (PhLi) at C4
has been described.16 C4 and C6 disubstitution (methyl) on
1,2,3-triazine has been reported to redirect the addition of a
nucleophile to C5 and, remarkably, N2 as well.16 Like the work
detailed herein, C4 addition in these studies has been reported
to proceed with in situ loss of nitrogen (N2) and hydrolysis of
the resulting imine, providing the corresponding α,β-unsatu-
rated aldehyde.
Figure 1. Addition of secondary amines to 1,2,3-triazine.
Received: May 20, 2017
As part of our continuing interest in heterocyclic azadienes,
we elected to investigate this underexplored reactivity of 1,2,3-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01543
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Organic Letters
Letter
conditions. In initial surveys of the reaction, it was found to be
relatively insensitive to the choice of nonprotic solvent and
proceeded at room temperature without the need of additives,
such as a base. Only addition at C4 was observed, and this was
followed by in situ loss of N2 without detection (MS, 1H NMR)
of a dihydro-1,2,3-triazine intermediate. The intermediate imine
was observable by mass spectrometry (MS) of the reaction
mixture, and hydrolysis to the corresponding aldehyde was also
observable by MS over time by the use of “wet” THF as the
reaction solvent. However, the initial dihydro adduct was not
observed, nor was competitive addition at C5 (MS, 1H NMR).
Interestingly, a second condensation of excess amine onto the
product was also detected (MS), and it is conceivable that
further manipulation at this step, such as reductive amination,
could provide a route to additional products.
As shown in Figure 2, 1 reacts with a variety of secondary
amines to provide 4 in good yields. Although some amines
required elevated temperatures (65 °C) to drive the reaction to
completion, final yields were seemingly not impacted. The
reactions were halted once full consumption of 1 was observed
by 1H NMR spectroscopy, with isolation of the product
achieved simply by direct chromatographic purification of the
concentrated reaction mixture. Although the reactions detailed
in Figure 2 were conducted in reagent-grade (not anhydrous)
THF under otherwise anhydrous conditions, the reaction of 1
with pyrrolidine under a range of THF−H2O conditions
provided 4m in comparable or even higher yields [THF (53%),
1% H2O−THF (87%), 5% H2O−THF (85%), 10% H2O−THF
(80%), 50% H2O−THF (59%)]. This indicates that the
presence of water does not impede the reaction, does not
competitively consume starting 1,2,3-triazine or the product β-
aminoenal, and may be used to facilitate hydrolysis of the
product imine under the reaction conditions and further
improve the conversion. Notably, imidazole (THF, 65 °C, 48
h) participated effectively in this reaction. Less nucleophilic
secondary arylamines (secondary anilines) failed to effectively
participate in the reaction, and a primary amine preferentially
produced the diaddition product 5 resulting from amine
addition to two molecules of 1,2,3-triazine (eq 1). Finally, no
evidence of the participation of the product β-aminoenals 4 in
subsequent cycloaddition reactions with 1 was detected under
the reaction conditions.
Figure 2. Reaction of 1,2,3-triazine with secondary amines. Notes:
aThe reaction was conducted at 60 °C. bThe reaction was conducted at
c
65 °C. The reaction was conducted at 50 °C.
derived from the reaction of dibenzylamine with 1 confirmed
the structure (4h) and trans olefin configuration (Figure 3b).17
The C4 versus C5 preference for the site of secondary amine
nucleophilic attack, like that established for heterocycles in
general, can be rationalized as arising from the preferential
delocalization of the resulting anion onto two (vs one) ring
nitrogens. This site (C4) also constitutes the most electron-
deficient center of the reacting molecular orbital (LUMO) of 1,
but it is not the center that bears the largest LUMO molecular
orbital coefficient.16
A general, effective, and simple synthesis of β-aminoenals
based on the nucleophilic addition of secondary amines to
1,2,3-triazine (1) has been detailed. It complements the existing
methods based on condensation with malondialdehyde or its
equivalents (1,1,3,3-tetramethoxypropane),19 hydroamination
of propargylic aldehyde,18 or dehydrogenative amination of
The reactions proceed cleanly, exclusively generating the
trans-β-aminoenals. The products from symmetrical secondary
amines, highlighted in Figure 2, display distinguishable signals
for the amine Cα protons, indicative of restricted rotation on
the NMR time scale due to amine conjugation with the enal.
The products generated from addition of unsymmetrical
1
secondary amines also display distinguishable rotameric H
NMR signals (1−3:1), including the aldehyde signal itself.
Although prior disclosures18−20 of such β-aminoenals have
characterized them as inseparable cis/trans isomers because of
1
this doubling of the H NMR signals, variable-temperature
(25−45 °C) 1H NMR spectroscopy revealed smooth
coalescence of the rotameric, not geometrically isomeric,
resonances (Figure 3a). A single-crystal X-ray structure of the
−
DNP-hydrazone (isolated as the HSO4 salt) of the aldehyde
B
DOI: 10.1021/acs.orglett.7b01543
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Letter
ORCID
Dale L. Boger: 0000-0002-3966-3317
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Institutes of Health (CA042056), the award of an NSF
fellowship (NSF/DGE-1346837, C.M.G.), and the award of a
Turner B. and Lesly Starr Shelton Endowment Scholarship
(C.M.G.). We thank Dr. Rheingold (UCSD) for the X-ray
structure. We dedicate this article to Professor A. Padwa
(Emory University) on the occasion of his 80th birthday.
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Figure 3. (a) VT H NMR spectra (DMSO-d6) of 4u showing the
coalescence of aldehyde rotamer peaks with increasing temperature.
(b) X-ray crystal structure of the DNP-hydrazone derived from 4h,
−
isolated as the HSO4 salt, showing the trans olefin configuration.
acrolein.20 It is likely that this general electrophilic character of
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01543.
1
Full experimental details and H and 13C NMR spectra
(PDF)
Crystallographic data for the DNP-hydrazone derived
from 4h (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: boger@scripps.edu.
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