Cycloadditions of noncomplementary substituted 1,2,3-triazines

Article abstract of DOI:10.1021/ol502436n

The scope of the [4 + 2] cycloaddition reactions of substituted 1,2,3-triazines, bearing noncomplementary substitution with electron-withdrawing groups at C4 and/or C6, is described. The studies define key electronic and steric effects of substituents impacting the reactivity, mode (C4/N1 vs C5/N2), and regioselectivity of the cycloaddition reactions of 1,2,3-triazines with amidines, enamines, and ynamines, providing access to highly functionalized heterocycles.

Full text of DOI:10.1021/ol502436n

Letter
pubs.acs.org/OrgLett
Cycloadditions of Noncomplementary Substituted 1,2,3-Triazines
Erin D. Anderson, Adam S. Duerfeldt, Kaicheng Zhu, Christopher M. Glinkerman, 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: The scope of the [4 + 2] cycloaddition
reactions of substituted 1,2,3-triazines, bearing noncomple-
mentary substitution with electron-withdrawing groups at C4
and/or C6, is described. The studies define key electronic and
steric effects of substituents impacting the reactivity, mode
(C4/N1 vs C5/N2), and regioselectivity of the cycloaddition
reactions of 1,2,3-triazines with amidines, enamines, and ynamines, providing access to highly functionalized heterocycles.
nverse-electron-demand Diels−Alder reactions of electron-
deficient heterocyclic azadienes often provide a powerful
used to predictably enhance their reactivity (R = CO2Me > Ph >
H) without impacting either the intrinsic mode (across C4/N1)
or regioselectivity of the 1,2,3-triazine cycloaddition reaction.
The rate of reactions for each dienophile class was also shown to
follow a now predicable trend (amidine > ynamine > enamine)
and the reactivity of 3, bearing a strong C5 electron-withdrawing
group (CO2Me), extended to an even larger and remarkable
range of additional dienophiles.13 The efficiency with which
amidines were found to react with 1−4 to provide pyrimidines
was unique and suggested that this reaction might exhibit an even
broader scope.
In studies first examined in the total synthesis of (−)-pyr-
imidoblamic acid and P-3A, we successfully employed the
reaction of amidines with two 1,2,3-triazines (7 and 9) bearing
differentiated substitution at the 4,6- and 4,5,6-positions that
represent noncomplementary substitution sites for promoting
the [4 + 2] cycloaddition reactions.16 This success provided the
incentive to more comprehensively investigate the reactivity of
such 1,2,3-triazines with 5−9 (Figure 2). At the onset of these
studies, it was not clear if 5−9 would behave analogously to 1−4
or if the addition of the electron-withdrawing substituents at the
C4 and/or C6 positions would sterically slow the reactions or
electronically redirect the mode of cycloaddition (C4/N1 vs C5/
N2). Intuitively, one might expect the 4-substituted (5), 4,6-
disubstituted (6−7), and 4,5,6-trisubstituted (8−9) 1,2,3-
I
approach to the preparation of highly substituted heteroaromatic
systems not easily accessed by conventional means.1 The most
widely recognized of such heterocyclic azadienes are the 1,2,4,5-
tetrazines,2 1,2,4-triazines,3 1,3,5-triazines,4 1,3,4-oxadiazoles,5
and 1,2-diazines.6 Subject to the impact of substituents that
modulate their reactivity, alter their mode of reaction, and control
their reaction regioselectivity, they have been shown to react with
a variety of electron-rich or strained dienophiles to provide not
only six-membered heterocyclic ring systems but also five-
membered heteroaromatics,7 many of which represent core
elements present in natural products.8−11 Recently, we disclosed
studies on the cycloaddition reactions of 1,2,3-triazine (1)12 and
the 5-substituted 1,2,3-triazines 2−413 bearing complementary
substitution that enhance their reactivity, reinforce an intrinsic
mode and regioselectivity of cycloaddition, and substantially
expand the scope of such reactions (Figure 1).14,15 Herein, we
Figure 1. Selected Diels−Alder reactions of 1,2,3-triazines.
report an examination of 4-substituted, 4,6-disubstituted, and
4,5,6-trisubstituted 1,2,3-triazines as additional participants in
inverse-electron-demand Diels−Alder reactions, defining the
steric and electronic effects of the noncomplementary placement
of electron-withdrawing substituents on the scope of such
cycloaddition reactions.
Figure 2. 1,2,3-Triazines examined.
The 1,2,3-triazines 1−4 participate in inverse-electron-
demand Diels−Alder reactions in which the C5 substituent was
Received: August 16, 2014
Published: September 15, 2014
© 2014 American Chemical Society
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triazines to exhibit increased electrophilic character at the C5-
position. The preparation of 7 and 9, enlisting an oxidative ring
expansion (I2, KHCO3, 68 and 73% respectively) of the
corresponding N-aminopyrazoles, was conducted as disclosed,16
and 1,2,3-triazines 5, 6, and 8 were prepared in an analogous
fashion by N-amination of the starting pyrazoles followed by
oxidative ring expansion using NaIO414 (5, 73%) or I215 (6, 46%;
8, 66%; Supporting Information).
The initial dienophiles examined as the cycloaddition partners
for the 1,2,3-triazines 5−9 were amidines. The reactions of 5 with
the amidines at room temperature were monitored (TLC), and
although product formation appeared complete after 15 min, the
reaction mixtures were stirred for 1 h at 25 °C (0.3 M, CH3CN)
to ensure complete conversion. Aromatic, benzylic, and aliphatic
amidines were effective reaction partners for 5, providing the 2-
substituted-4-carbomethoxypyrimidines in good yields (68−
98%) without further optimization and without the appearance of
competitive reaction products (Figure 3).
preclude the cycloaddition reaction, and despite the non-
complementary electronic and steric bias, the C4/N1 (vs C5/
N2) cycloaddition mode was not altered.
Similarly, the fully substituted 1,2,3-triazines 8 and 9 were
subjected to [4 + 2] cycloaddition with the amidines. Not only do
they bear noncomplementary substitution at either of the
reacting C4 centers but they also contain a nonactivating
substituent at C5. Both 1,2,3-triazines reacted to provide the
product pyrimidines in moderate to good yields (19−66%)
without optimization (Figure 5). Expectedly, these 1,2,3-triazines
Figure 5. Reaction of 1,2,3-triazines 8 and 9 with amidines.
exhibited a lower reactivity and required longer reaction times
(CH3CN, 25 °C, 16 h) and, in one instance, an elevated
temperature to complete product formation. Again, the unsym-
metrical 1,2,3-triazine 9, bearing the larger t-Bu ester, consistently
provided the pyrimidines in a more pronounced 2−3-fold higher
yield, although theorigin ofthis moreeffective behavior of9 is not
yet understood.
Pairwise competition studies comparing the reactivity of the
1,2,3-triazines with amidine 10b revealed that they follow the
trend of 3 > 6 > 5 > 8 and 1 in which the complementary C5
substitution with a single electron-withdrawing substituent
provides the most reactive 1,2,3-triazine (3 > 6), that the
noncomplementary 4,6-disubstitution with the two electron-
withdrawing groups is more activating than C4 monosubstitution
(6 > 5) despite the additional steric bias, that 8 was the least
reactive of the substituted 1,2,3-triazines despite the diactivation
substitution, and that not only 3 but also 5 and 6 were more
reactive than 1,2,3-triazine (1) itself.
Figure 3. Reaction of 1,2,3-triazine 5 with amidines.
The behavior of the 4,6-disubstituted 1,2,3-triazines 6 and 7
was especially interesting. With the exception of the phenyl-
amidine 10a, the benzylic and aliphatic amidines provided the
pyrimidine products in good to excellent yields (51−89%,
CH3CN, 25 °C, 4 h), and the unsymmetrical 1,2,3-triazine 7,
bearing the larger t-Bu ester, consistently provided higher yields
than the symmetrical 1,2,3-triazine 6 (Figure 4). Unlike reactions
of 1,2,3-triazine 5, which proceeded within 1 h, both 6 and 7
showed more gradual product formation over 4 h. Notably,
substitution of the 1,2,3-triazine reacting C4 center did not
The reactions of three enamines with the 1,2,3-triazines 5, 6,
and 8 were examined (Scheme 1). The reaction of methyl 1,2,3-
triazine-4-carboxylate (5) proceeded with cycloaddition only
across C6/N3 and with a regioselectivity where the nucleophilic
carbon of the enamine adds to C6, providing exclusively the
pyridine products in good yields (Scheme 1). Although nitrogen
evolution was often observed upon mixture of the reactants at
room temperature, indicating a rapid [4 + 2] cycloaddition
followed by loss of N2, complete reaction required higher
reaction temperatures (60 °C, CHCl3) in the presence of 4 Å
molecular sieves (MS)3c to promote the slower aromatization
step with the elimination of pyrrolidine.
The more substituted and symmetrical 1,2,3-triazines 6 and 8
behaved similarly with enamine addition across C4/N1 (C6/N3)
to provide exclusively the pyridine products, albeit in reactions
that progressed to completion at a slower rate. Examined in detail
Figure 4. Reaction of 1,2,3-triazines 6 and 7 with amidines.
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Scheme 1
Scheme 3
CHCl3, 1 h) to provide predominately (5 and 8, >8:1) or
exclusively (6) the pyridazine products 23, 25, and 26 (64−85%)
in excellent yields and derived from cycloaddition across C5/N2
with the nucleophilic carbon of the ynamine attaching to C5.
This preferential C5/N2 mode of cycloaddition not only
represents a switch in the mode of cycloaddition relative to their
reactions with amidines and enamines but also that of the
ynamine cycloadditions observed with 1 and the C5 activated
1,2,3-triazines 2−4, where only C4/N1 cycloaddition is
observed. In the case of 5, where C6 is unsubstituted and
sterically accessible, and 8, where C5 is substituted and sterically
less accessible, a small amount of C4/N1 (C6/N3) cycloaddition
is observed, resulting in the minor pyridine products 24 and 27
(0−12%). Unlike their behavior toward amidines and enamines,
the C4 and C4/C6 substitution with electron-withdrawing
groups redirects the mode of cycloaddition (C5/N2 vs C4/N1)
as well as enhances the reactivity of the 1,2,3-triazines relative to 1
toward ynamines by virtue of this now complementary
substitution. Just as interesting, the initial ynamine-derived C5/
N2 cycloadduct derived from 5 exclusively undergoes a retro-
Diels−Alder loss of HCN (vs MeO2CCN) providing a single
pyridazine product.
Scheme 2
with the fully substituted 1,2,3-triazine 8, its reaction with
enamines 16a and 16c at 25 °C led to an instantaneous color
change, the observable evolution of N2, consumption of 8 within
15−30 min, and the generation of the isolated unaromatized
cycloadducts 20 (77%) and 21 (57%) in excellent conversions
(Scheme 2).
The extension of the reaction at higher temperatures (60 °C)
for longer periods of time (12 h) even in the presence of 4 Å MS3c
was insufficient to promote completion of the aromatization step.
However, the addition of strong acid catalysts (HOAc, 12 h, 54%;
MeSO3H, 2 h, 67%)3c or m-CPBA (N-oxide formation, 0 °C, 1 h,
78%) to the reaction mixtures, following the consumption of 8
upon addition of 16a (40 min, 25 °C), led to effective
aromatization to provide the pyridine product. Notably and
despite the noncomplementary substitution, the mode of
cycloaddition with enamines (C4/N1 vs C5/N2) was not
altered, and they exhibited an enhanced reactivity relative to
1,2,3-triazine (1) but diminished relative to 3 bearing the
complementary C5 substitution.
A competition study comparing the reactivity of 5, 6, and 8
toward ynamine 22a (1.2 equiv, 22 °C, CHCl3, 30 min) defined a
clear trend (6 > 5 > 8) where the now complementary C4 and C6
disubstitution (CO2Et) electronically enhances the reactivity of 6
relative to 5 bearing a single electron-withdrawing group
(CO2Me), and the C5 methyl substitution of 8 sterically slows
the cycloaddition relative to not only 6 but also 5, despite the C4/
C6 disubstitution activation of 8 (Figure 6).
Although not comprehensively explored and unlike methyl
1,2,3-triazine-5-carboxylate (3),13 which bears a complementary
activating C5 electron-withdrawing substituent, additional
electron-rich alkenes (ketene acetals, enol ethers) and alkynes
(ethoxyacetylene) failed to effectively react with 5−9.
The [4 + 2] cycloaddition reactions of 5, 6, and 8 with
ynamines proved especially interesting (Scheme 3). The
reactions proceeded rapidly at room temperature (22 °C,
A systematic study of the cycloaddition reactions of 1,2,3-
triazines substituted with noncomplementary C4 and/or C6
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Figure 6. Ynamine competition study.
electron-withdrawing groups was conducted. Such substituents
were found to enhance the reactivity of the 1,2,3-triazine (5−9 >
1) despite the noncomplementary electronic and steric effects.
Remarkably, the mode of cycloaddition for amidines and
enamines relative to 1 was not altered (C4/N1), whereas that
of ynamines was redirected to C5/N2. Significantly, the studies
provide additional heterocyclic azadienes, complementary to the
1,2,4- and 1,3,5-triazines, that participate in effective cyclo-
addition reactions, extending the range of accessible heterocyclic
ring systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: boger@scripps.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Institutes of Health (CA042056). A.S.D. was an American
Cancer Society postdoctoral fellow (2012−2014, PF-12-122-01-
CDD).
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