Strategies for protecting and manipulating triazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.01.150

Aminotriazine derivatives are available in two steps by treating chlorotriazines with acid-labile benzylic amines including triphenylmethylamine, diphenylmethylamine, and 2,4-dimethoxybenzyl-amine (Dmb-amine), followed by deprotection using trifluoroaceti

Full text of DOI:10.1016/j.tetlet.2005.01.150

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2005–2008
Strategies for protecting and manipulating triazine derivatives
Emily Hollink, Eric E. Simanek* and David E. Bergbreiter*
Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
Received 26 January 2005; accepted 27 January 2005
Abstract—Aminotriazine derivatives are available in two steps by treating chlorotriazines with acid-labile benzylic amines including
triphenylmethylamine, diphenylmethylamine, and 2,4-dimethoxybenzyl-amine (Dmb-amine), followed by deprotection using triflu-
oroacetic acid. This high yielding (85–99%) protocol is a milder alternative to the traditional method that uses ammonia and high
temperature as a route to aminotriazine derivatives. The nucleophilic substitution reaction that installs the benzylic amine on mono-
chlorotriazine herbicide derivatives may be performed using conventional heating. Alternatively, a microwave reactor can be used to
decrease the reaction times 100-fold. The intermediates in these syntheses are soluble in a range of organic solvents and amenable to
chromatography. In some cases when dimethoxybenzyl groups are used, oligomerization of the dimethoxybenzyl side product upon
treatment with trifluoroacetic acid yields a precipitate that facilitates purification by simple filtration.
Ó 2005 Elsevier Ltd. All rights reserved.
Triazine chemistry has experienced a renaissance due to
the utility of melamine derivatives as precursors of a
variety of oligomers1 or polymers,2 as scavenging resins
in organic manipulations,3 as components of host–
guest4 and ÔsuperstructureÕ5 assemblies, as ligand scaf-
folds for catalysis,6 and in medicinal chemistry.7 The ap-
peal of the s-triazine core is largely due to the ease of
systematic substitution of the chloride atoms with amine
nucleophiles to generate a variety of structures. Consecu-
tive substitution reactions with good nucleophiles such
as primary or secondary amines proceed as a one-pot
procedure: the first substitution occurs at low tempera-
ture; the second substitution occurs slower, but at ambi-
ent temperature; and the third substitution typically
requires temperatures above 80 °C.
toward other nucleophiles often makes installation of
this NH2-group more preferable as the last step. In such
cases, installation of this NH2-group requires more forc-
ing conditions. Typically this involves ammonium
hydroxide (or ammonia), temperatures that exceed
100 °C, extended periods of time, and specially designed
glass bombs. Here, we describe an alternative simpler
strategy to install this group at any point in the
synthesis.
Benzylic groups such as the dimethoxybenzyl (Dmb)
and trityl groups are widely used as acid-labile protect-
ing groups for nitrogen substituents in synthesis. Exam-
ples of their utility are seen in syntheses of peptides,9
amides,10 2-acetamide glycosyl donors,11 amines,12 and
a variety of heterocycles such as 1,2,4-triazoles,13 1,2-
thiazetidine 1,1-dioxides,14 and maleimides.15 Dmb and
trityl groups have labile benzylic C–N bonds due to
the stability of the intermediate benzylic carbocation.
Here we describe the utility of these benzylic amines,
RNH2 in aminotriazine synthesis (Scheme 1). Here we
describe the utility of a two step sequence to yield
Many of these targets possess an NH2-group on the tri-
azine ring. Most syntheses of NH2-substituted triazines
continue to use the original procedures developed by
the American Cyanamide Co.8 Wherein cyanuric chlo-
ride is reacted with ammonia at low temperature to yield
amino-dichloro-s-triazine which in turn may be used to
prepare other NH2-substituted triazine derivatives.
However, this compoundÕs poor solubility and the more
modest reactivity of this monosubstituted triazine
Keywords: Triazine; Protecting group.
*
Corresponding authors. Tel.: +1 979 845 4242; fax: +1 979 84509452
(E.E.S.); tel.: +1 979 845 3437; fax: +1 979 84509452 (D.E.B.); e-mail
addresses: simanek@tamu.edu; bergbreiter@tamu.edu
Scheme 1. Synthesis of triazine derivatives using the benzylic amines
(RNH2) identified in Table 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.150

2006
E. Hollink et al. / Tetrahedron Letters 46 (2005) 2005–2008
aminotriazines: reaction with suitable benzylic amines
followed by mild acid-catalyzed deprotection. Scheme
1 shows the synthesis of the benzyl derivatives.
Table 1 reports the yield for the preparation of the de-
sired model compounds and the results of their treat-
ment with trifluoroacetic acid (TFA). Cleavage to
generate the desired 2,4-dipiperidinyl-6-amino-s-triazine
occurs only when triphenylmethylamine (tritylamine),
diphenylmethyl-amine, or 2,4-dimethoxybenzylamine
(Dmb-amine) were incorporated (5–7). As expected,
the ease of cleavage correlated with the presumed stabil-
ity of the intermediate carbocation. When a trityl cation
was generated from 7, the product formed in less than
5 min as indicated by a bright yellow solution. Genera-
tion of the deeply green diphenylmethyl cation from 6
took approximately 16 h. Cleavage of the Dmb group
from 5 to produce a violet solution requires 2 h. In this
example, the cleaved Dmb group underwent oligomeri-
zation,16 and as a result, chromatography was not re-
quired to separate the aminotriazine products from the
Dmb products. Instead, purification was achieved by
simple filtration.
Scheme 2. Preparation and manipulation of the benzylic amine
derivatives of herbicides.
Table 2. Optimization of the synthetic protocol to generate the
biologically relevant triazine derivatives suitable for treatment with
TFA
Compd
Solvent
Temperature/°C
Time
Isolated
yield/%
8
8
8
p-Dioxane
EtOH
DMA
80
70
70
2 d
3 d
94
70
99
12 h
8
8
8
p-Dioxane
EtOH
DMA
150
150
80
10 mina
5 mina
5 mina
98
99
99
9
9
9
9
p-Dioxane
p-Dioxane
EtOH
150
150
150
150
2 d
86
97
84
77
15 mina
10 mina
10 mina
Introducing the NH2-group last is the least attractive
route to aminotriazine derivatives as it requires the
harsher conditions of the American Cyanamide proce-
dure. Scheme 2 illustrates the utility of the reaction of
Dmb-amine with monochlorotriazines using two tri-
azine herbicides, atrazine (8) and turbutazine (9).
DMA
a Microwave experiments.
required for complete conversion to the product varied
with the solvent employed. Dimethylacetamide (DMA)
was the solvent of choice, affording product after only
12 h of heating. Other solvents such as THF, p-dioxane,
or ethanol required several days to completely convert
the monochlorotriazine herbicide to a Dmb-amine
derivative. However, a microwave reactor permitted
quantitative formation of the herbicide-containing prod-
uct in 5–15 min. This 100-fold decrease in reaction time
greatly facilitates this chemistry and represents one of
the first examples where this technology has been used
in aminotriazine synthesis. Microwave techniques have
become increasingly prevalent in literature.17 They have
also been used to prepare triazine derivatives; however,
in most cases this only involves assembly of the triazine
core.18 In this case, microwave technology enhances
Substitution of 8 or 9 with Dmb-amine proceeds in
acceptable yields using conventional methods (Table 2)
although the reaction times are long and vary only
slightly with solvent choice. Dimethylacetamide
(DMA) afforded product after 12 h of heating. The time
Table 1. Yields of intermediates, cleavage times, and products
Compd
R
Isolated Cleavage Yields observed
yield/% timea
(isolated)/%
1
2
73
99
12 h
12 h
0b (83)
0b (87)
0b (80)
nucleophilic
aromatic
substitution
of
the
monochlorotriazine.19
3
4
5
96
84
91
12 h
12 h
Successful installation of the Dmb-amine group on
monochlorotriazines led us to reexamine the use of trityl
amine. While our efforts demonstrated that cleavage of
the trityl group from a triazine derivative is more facile
than cleavage of the Dmb-amine, substitution of the
third chlorine atom of atrazine with tritylamine was
unsuccessful even with heating at 120 °C in p-dioxane
for 2 weeks. Reaction of atrazine with tritylamine in
DMA also failed to produce desired product using
microwave techniques (20 min at a temperature of
150 °C).
0b (87)
2 h
1 h
>99 (93)
70
6
7
Ph2HC–NH
Ph3C–NH
85
85
16 h
99 (63)c
5 min
99 (93)
a Refers to time required to affect the TFA cleavage.
b No cleavage of the benzylic amine was observed; rather, the TFA salt
was isolated and characterized.
c Although cleavage of the C–N bond appears to be quantitative as
monitored by 1H NMR spectroscopy, the isolated yield of this
product is low due to the formation of additional (unidentified) by-
products.
Removal of the Dmb group from 10 and 11 with TFA
afforded near-quantitative cleavage of the Dmb group
in 12 h. In these cases, chromatography was necessary

E. Hollink et al. / Tetrahedron Letters 46 (2005) 2005–2008
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Acknowledgments
This work was supported by the Robert A. Welch Foun-
dation (A-1121 (D.E.B.) and A-1439 (E.E.S.) and
USDA CSREES 2002-35102 12504). E.H. is grateful
for a post-doctoral fellowship from NSERC of Canada.
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Supplementary data
Synthetic details and characterization data. Supplemen-
tary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2005.01.150.
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