Transition metal-free assembly of 1,3,5-triazines using ethyl bromodifluoroacetate as C1 source

Article abstract of DOI:10.1039/c9cc03534f

An efficient transition metal-free annulation of amidine with ethyl bromodifluoroacetate to access 2,4-disubstituted-1,3,5-triazines is firstly presented. The desired symmetric and unsymmetric 2,4-disubstituted-1,3,5-triazines were obtained in decent yields via multiple C-N bond formation, in which ethyl bromodifluoroacetate is harnessed as a unique C1 synthon via quadruple cleavage. This reaction is transition metal-free, oxidant-free and simple in operation, and only lowly toxic inorganic wastes are generated.

Full text of DOI:10.1039/c9cc03534f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Transition metal-free assembly of 1,3,5-triazines by using ethyl
bromodifluoroacetate as C1 source
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaoxia Yu, Yao Zhou, Xingxing Ma and Qiuling Song *
DOI: 10.1039/x0xx00000x
An efficient transition metal-free annulation of amidine with assemble the 1,3,5-triazines by organic chemists. However,
ethyl bromodifluoroacetate to access 2,4-disubstituted-1,3,5- transition-metal catalysts and oxidants were obligatory to
triazines is firstly presented. The desired symmetric and generate good yields of the desired 1,3,5-triazines for these
unsymmetric 2,4-disubstituted-1,3,5-triazines were obtained newly discovered carbon synthons.6 Given the characteristic
in decent yields via multiple C-N bonds formation, in which biological activity and coordination ability of 1,3,5-triazines as
ethyl bromodifluoroacetate is harnessed as unique C1 well as the sustainable chemistry, the development of a metal-
synthon via quadruple cleavage. This reaction features with free and facile protocol to streamline synthesis of 1,3,5-
transition metal-free, oxidant-free and simple operation, in triazines is still in demand.
which only low toxic inorganic wastes were generated.
1,3,5-triazines are indisputably present as one of the privileged
karyoskeletons in natural products and pharmaceutical
molecules.1 As showcased in Figure 1, a round of 1,3,5-
triazines have been found with good biological activities.2
Furthermore, 1,3,5-triazines could serve as promising ligands
in organic synthesis for the assembly of organometallic
materials, liquid crystals, and transition-metal catalysts.3
Conventionally, 1,3,5-triazines are achieved through the
cyclization reactions of amidines with a strand of formylating
reagents such as diimino salt, N-[(dimethylamino)
methylene]benzamidine, N-carbamoyl benzamidine, and α-
methoxymethylene Meldrum’s acid.4 However, these known
multi-step reactions suffer from the shortcomings such as
harsh reaction conditions, narrow substrate scope and low
yields. To address this drawback, myriads alternative synthetic
strategies have been established for the construction of 1,3,5-
triazines in the past few years.5 A sequence of novel C1
synthons have been developed for cyclizations of amidines to
Scheme 1. Novel methods using ethyl bromodifluoroacetate as
a carbon source
Ethyl bromodifluoroacetate has been extensively
employed as difluoroalkylating reagents in organic synthesis.7,8
An ample number of radical-involved transformations have
been developed using ethyl bromodifluoroacetate as radical
precursors via single cleavage of C-Br bond.7d-g,12 Despite of
these
undisputed
difluoroalkylation
of
ethyl
Figure 1. Representative examples of bioactive 1,3,5-triazines
bromodifluoroacetate, the transition metal-free quadruple
cleavage of ethyl bromodifluoroacetate is challenging and has
been sparsely documented (Scheme 2a).9,7b In 2018, our group
reported an efficient strategy for the assembly of β-
aminoenones by cross-coupling of in-situ generated
isocyanides, using ethyl bromodifluoroacetate as C1 source via
Institute of Next Generation Matter Transformation, College of Materials Science
& Engineering at Huaqiao University, P. R. China.
E-mail: qsong@hqu.edu.cn
†Electronic Supplementary Information (ESI) available: CCDCC 1913836. See
DOI: 10.1039/x0xx00000x
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Table 1. Screening of optimized reaction conditions
entries 13 and 14). Gladly, the isolated yield of 3a was slightly
increased to 86% when we reduced the amount of ethyl
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DOI: 10.1039/C9CC03534F
bromodifluoroacetate to 2.25 equivalents (Table 1, entry 15).
The yield of 1,3,5-triazine 3a was significantly decreased to 56%
when the reaction was carried out under air atmosphere
(Table 1, entry 16). Trace amount of targeted 3a was detected
when this cyclization reaction was performed without base
(Table 1, entry 17), which indicated that base was
indispensable for this transformation.
Having affirmed the optimized reaction conditions, we
then investigated the functional group compatibility and
substrate universality involved in this reaction. Firstly, a range
of amidines were inspected to assemble various symmetrical
2,4-disubstituted-1,3,5-triazines, which was summarized in
Scheme 2. Benzimidamides having electron-donating groups
were proved to be good candidates in this transformation,
enabling to produce the expected 2,4-diaryl-1,3,5-triazines 3b
and 3c in 80% and 76% yield, respectively. The structure of 3c
was accurately confirmed by X-ray single crystal diffraction.
Halo-substituted benzimidamides 1d
this reaction, delivering the desired 1,3,5-triazines 3d
-
1f were also amenable to
3f in
-
58%-83% yields. Compared with the electron-donating groups
substituted benzimidamides, the benzimidamides bearing
electron-withdrawing groups such as (NO2 and CF3)
demonstrated relatively low reactivity, which resulted in 3g
and 3h in moderate yields. In addition to para-substituted
quadruple cleavage.10 We also found that ethyl
bromodifluoroacetate could be utilized as the formylation
reagent, in which one C-N bond and one C-O bond were
formed under transition metal-free conditions (Scheme 2b).11
benzimidamides,
the
meta-
and
ortho-substituted
To
our knowledge, taking advantage of
ethyl
benzimidamides could work smoothly underlying the standard
conditions as well, providing the corresponding 1,3,5-triazines
3i-3m in 50%-77% yields. Aside from the aromatic amides, the
submitting of cyclopropanecarboximidamide 1n to this
transformation was also successful, leading to the formation of
2,4-dicyclopropyl-1,3,5-triazine 3n in 53% yield. Regrettably,
only trace amounts of desired product 3o was detected when
bromodifluoroacetate as C1 synthon to construct multiple C-N
bonds has yet to be explored. As our ongoing interest in
transformation of BrCF2COOEt,12 herein, we describe a simple
and green annulation of amidines to streamline synthesis of
1,3,5-triazines by using BrCF2COOEt as C1 synthon, which
represents the first example for using BrCF2COOEt to forge the
valuable 1,3,5-triazines under transition metal-free and
oxidant-free conditions (Scheme 1c).
We commenced our study with benzamidine
hydrochloride (1a) and ethyl bromodifluoroacetate (2a) as
benchmark substrates and carried out the reaction in
acetonitrile (CH3CN) at 100 °C for 12 hours by using Na2CO3 as
the base. To our delight and surprise, the 2,4-diphenyl-1,3,5-
triazine 3a was obtained in 78% yield (Table 1, entry 1).
Inspired by this result, we subsequently inspected the effect of
the different bases on this reaction (Table 1, entries 2-5).
Among the bases investigated, Na2CO3 was proved to be the
best choice, which exhibited higher reactivity than other bases,
such as K2CO3, tBuONa, K3PO4 and MeOK. Successively,
solvents screening for this transformation was executed (Table
1, entries 6-9). No desired product 3a was observed when the
reaction proceeded in ethylene glycol dimethyl ether.
Meanwhile, when other solvents were used instead of CH3CN,
no superior results were gained. After determining the
optimum base and solvent, the reaction temperature for this
metal-free synthesis of 1,3,5-triazine was then studied (Table 1,
entries 10-12). It was found that the isolated yield of 3a was
increased to 80% when reaction temperature was elevated to
110 °C (Table 1, entry 11). The attempt to shorten or extend
the reaction time failed to deliver better results (Table 1,
Scheme 2. Synthesis of symmetrical 2,4-disubstituted-1,3,5-
triazines
2 | J. Name., 2012, 00, 1-3
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pyrimidine-2-carboximidamide 1o was used as starting
material.
Table 2. Substrate scope of halodifluoromethyl compounds
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DOI: 10.1039/C9CC03534F
Inspired by the success for the construction of
symmetrical 2,4-disubstituted-1,3,5-triazines, we attempted
to synthesize unsymmetric 2,4-disubstituted 1,3,5-triazines by
utilizing two different amidines (Scheme 3). When the reaction
of 4-methylbenzimidamide 1b and 4-methoxybenzamidine 1c
was performed by using equimolar 1b and 1c, the yield of
unsymmetrical product 3bc was relatively low and symmetrical
product 3b was detected as the major product. To enhance the
yield of unsymmetrical 2,4-disubstituted 1,3,5-triazines, the
amount of two amidines was screened. Pleasurably, when the
reaction was conducted with 2 equiv of 1b and 1 equiv of 1c
,
the yield of unsymmetric product 3bc was increased to 51%
along with 40% yield of 3b. When 1b was replaced with 1f and
1g, unsymmetric 3cf and 3cg were obtained with yields of 50%
and 46%, respectively. Alternatively, the reaction of 1j and 1n
with 1a also delivered unsymmetric product 3aj, 3an in 45%
and 30% yield. To our surprise and delight, the reaction of 1a
with 4-fluorobenzamidine 1d afforded an unsymmetric
product 3ad with a high yield of 79%, with relatively low yield
(10%) of symmetrical 3a. The use of 1c and 1n instead of 1a to
react with 1d was also successful, which enabled to furhish the
unsymmetric 2,4-disubstituted 1,3,5-triazines 3dc and 3dn in
yield of 52% and 40%, respectively.
halodifluoromethyl compounds, sodium difluorochloroacetate
2f and N-phenyl difluorobromoacetamide 2g displayed lower
reactivity as carbon sources, resulting in the target product 3a
with 30% and 40% yields, respectively.
As summarized in Table 2, we also investigated other
halodifluoromethyl compounds and it was found that all of
them could serve as carbon sources to forge 2,4-substituted
1,3,5-triazine under the standard conditions by using
benzamidine 1a as cyclization reagent. In addition to ethyl
bromodifluoroacetate 2a, ethyl difluoroiodoacetate 2b and
ethyl difluorochloroacetate 2d were proved to be good C1
source in this transformation, enabling to deliver 3a in 75%
and 77% respectively. When difluorobromoacetic acid 2c was
used as C1 source, the yield of 3a could be isolated in 63%
yield. Diethyl difluorobromomethylphosphonate 2e and
difluorobromomethyl morpholinone 2h provided the
corresponding 2,4-diphenyl 1,3,5-triazine 3a in semblable
yields of 55% and 54%, respectively. Compared with other
To shed light on the reaction mechanism of this
transformation, several control experiments were executed
(Scheme 4). First,
a radical-trapping experiment was
conducted, the desired product 3a was also isolated in
moderate yields in the presence of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and 2,6-ditertbutyl-4-methylphenol
(BHT) as the radical inhibitors, which indicated a radical
pathway might not be involved in this transformation (Scheme
4a and 4b). Next, in order to capture the difluorocarbene, the
carbene scavenger benzimidazole
under standard conditions for 12 hours and N-
difluoromethylbenzimidazole was achieved in 56% isolated
4 was added to the reaction
5
yield, along with trace amount of 3a (Scheme 4c). Based on the
above experimental results, it could be speculated that
difluorocarbene (:CF2) was actually generated in-situ during
this transformation.
Based on our experimental results and previous work,6,9
a
plausible reaction mechanism for this synthesis of 1,3,5-
triazine is depicted in Scheme 5. First, with the assistance of
Base, BrCF2COOEt undergoes the saponification to produce
BrCF2COONa, which then suffers from the decarboxylation and
debromination to generate difluorocarbenedifluorocarbene
Scheme 3. Synthesis of unsymmetrical 2,4-diaryl-1,3,5-
triazines
Scheme 4. Control experiments for mechanistic studies
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J. Name., 2013, 00, 1-3 | 3
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Scheme 5 Plausible mechanism
(:CF2) in-situ.9 Successively, difluorocarbene is captured by
amidine
transformed to imine intermediate
process under the basic conditions. Subsequently, the active
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1
to afford intermediate
A
,
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elimination of one molecule of ammonia.
In summary, we have developed a facile and efficient
method for the synthesis of symmetric and unsymmetric 2,4-
disubstituted-1,3,5-triazines under transition metal-free and
external oxidant-free conditions with only low toxic inorganic
wastes generated. The annulation of amidines with ethyl
bromodifluoroacetate provided a range of 1,3,5-triazines in
decent yields via multiple C-N bonds formation, in which
quadruple cleavage of ethyl bromodifluoroacetate was
achieved by cleavage of two C-F bonds, one C-Br bond and one
C-COOEt bond in one-pot. This novel reactivity of ethyl
bromodifluoroacetate for the assembly of 1,3,5-triazines is
reported for the first time. Further studies for using ethyl
bromodifluoroacetate as unique C1 synthon are underway in
our laboratory.
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Financial support from the National Natural Science
Foundation (21772046) and the Natural Science Foundation of
Fujian Province (2016J01064) are gratefully acknowledged. We
also thank Instrumental Analysis Center of Huaqiao University
for analysis support. X. Y. thanks the Subsidized Project for
Cultivating Postgraduates' Innovative Ability in Scientific
Research of Huaqiao University.
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Conflicts of interest
The authors declare no competing financial interest.
8
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