A novel straightforward synthesis of 2,4-disubstituted-1,3,5-triazines via aerobic copper-catalyzed cyclization of amidines with DMF

Article abstract of DOI:10.1021/ol501493h

A novel straightforward synthesis of both symmetrical and unsymmetrical 2,4-disubstituted-1,3,5-triazines via aerobic copper-catalyzed cyclization of amidines with DMF as a one-carbon synthon has been developed. The presented method allows synthesizing the products that are currently inaccessible or challenging to prepare with the advantages of operational simplicity, broad substrate scope, and no need for prefunctionalized reagents, making it a highly practical approach to access various 2,4-disubstituted-1,3,5-triazines.

Full text of DOI:10.1021/ol501493h

Letter
pubs.acs.org/OrgLett
A Novel Straightforward Synthesis of 2,4-Disubstituted-1,3,5-
triazines via Aerobic Copper-Catalyzed Cyclization of Amidines with
DMF
Xiaowen Xu,†,‡ Min Zhang,*,† Huanfeng Jiang,† Jia Zheng,† and Yiqun Li*,‡
†School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641,
People’s Republic of China
‡Department of Chemistry, Jinan University, Guangzhou 510632, People’s Republic of China
S
* Supporting Information
ABSTRACT: A novel straightforward synthesis of both
symmetrical and unsymmetrical 2,4-disubstituted-1,3,5-tria-
zines via aerobic copper-catalyzed cyclization of amidines
with DMF as a one-carbon synthon has been developed. The
presented method allows synthesizing the products that are currently inaccessible or challenging to prepare with the advantages
of operational simplicity, broad substrate scope, and no need for prefunctionalized reagents, making it a highly practical approach
to access various 2,4-disubstituted-1,3,5-triazines.
Scheme 1. Methods Accessing 2,4-Disubstituted-1,3,5-
triazines
ryl-substituted 1,3,5-triazines constitute a significant
important class of nitrogen-containing heterocycles that
A
exhibit diverse biological activities.1 In addition, these
compounds could serve as chelating ligands for the preparation
of organometallic materials,2 liquid crystals,3 and transition-
metal catalysts.4 Despite their multiple functions, there are only
a few methods reported for the synthesis of this type of
compound. During the past decades, much attention has been
focused on developing alternative methods to access sym-
metrical 2,4,6-triaryl-1,3,5-triazines.5−7 Nevertheless, the syn-
thesis of 2,4-disubstituted-1,3,5-triazines still remains now as
before a challenging goal. Conventionally, such a goal can be
realized by the cyclization reactions of aryl amidines with
special prefunctionalized formylating reagents such as diimino
salt,8a N-[(dimethylamino)methylene]benzamidine,8b N-carba-
moyl benzamidine,8c and α-methoxymethylene Meldrum’s
acid8d (Scheme 1, eqs 1−4). However, these methods suffer
either harsh reaction conditions such as high temperature
(180−185 °C) or low product yields and limited substrate
scope that is restricted to the synthesis of only symmetrical 2,4-
diaryl-1,3,5-triazines. Moreover, the prefunctionalization steps
could constantly increase the complexity of the workup
procedure and result in a detrimental influence on the
environment. Hence, the development of efficient methods
for direct synthesis of 2,4-disubstituted-1,3,5-triazines from
easily available feedstock is of significant importance.
performed at 90 °C for 14 h by using Cs2CO3 as the base,
CuI/pyridine (L1) as the catalyst system, and O2 as the oxidant.
Unexpectedly, we observed, instead of the anticipated imidazole
product, the 2,4-diphenyl-1,3,5-triazine 2a in 18% yield (Table
1, entry 1). Interestingly, the reaction in absence of ethylene
glycol gave a higher product yield (standard conditions: Table
1, entry 2). However, replacing DMF with ethylene glycol as
the reaction solvent failed to yield even a trace of 2a (Table 1,
entry 3), indicating DMF is an essential component while
ethylene glycol was not involved in the formation of 2a and the
C−H unit at position-6 of 2a might come from DMF. Then,
Herein, we wish to report a novel straightforward synthesis of
both symmetrical and unsymmetrical 2,4-disubstituted-1,3,5-
triazines via aerobic copper-catalyzed cyclization of amidines
with DMF, a one-carbon supplier (Scheme 1, eq 5).
Actually, our initial intention was to develop a dehydrogen-
ative synthesis of imidazoles from amidines with abundant and
sustainable alcohols9 using a cost-effective copper catalyst.10
Thus, the reaction of benzamidine hydrochloride 1a with
ethylene glycol in N,N-dimethylformamide (DMF) was
Received: May 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501493h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Optimized Reaction Conditions
Scheme 2. Synthesis of Symmetrical 2,4-Diaryl-1,3,5-
triazines
b
entry
change of the initial conditions
2a, yield (%)
1
2
3
4
5
6
7
8
addition of 1 equiv of ethylene glycol
standard conditions
18
43
ethylene glycol instead of DMF
DMSO instead of DMF
19
15
DMA instead of DMF
no CuI
N2 instead of O2
without L1 (pyridine)
29
<40
36
c
9
L2 or L3 or L4 or L5 or L6
10
11
12
13
14
15
16
17
15 mol % instead of 20 mol % CuI
25 mol % instead of 20 mol % CuI
K3PO4 or K2CO3 or DABCO instead of Cs2CO3
NEt3 (2 equiv) instead of Cs2CO3
NEt3 (3 equiv) instead of Cs2CO3
NEt3 (2 equiv), 100 °C instead of Cs2CO3, 90 °C
NEt3 (2 equiv), 80 °C instead of Cs2CO3, 90 °C
CuBr or CuCl or Cu(OAc)2 or CuCl2 with NEt3
41
<20
85
85
68
65
<15
a
a
Isolated yield.
Reaction conditions: Unless otherwise stated, the reaction of amidine
hydrochloride 1a (1 mmol), catalyst (20 mol %), base (2 mmol),
solvent (2.0 mL), pyridine ligand (40 mol %) was performed at 90 °C
b
under 1 atm O2 atmosphere for 14 h. NMR yield using mesitylene as
bearing electron-withdrawing groups being able to more easily
undergo the deammoniation reaction, leading to partial
formation of benzonitriles. Gratifyingly, nicotinamidine 1l and
isonicotinamidine 1m could also be transformed in combina-
tion with DMF into the 2,4-dipyridyl products (Scheme 2, 2l,
2m). These examples demonstrate the potential of the
methodology for further construction of various 2,4-diheter-
oaryl products. However, the homocoupling of acetamidine 1n
failed to give even trace of desired product. It is conceivable
that the alkyl amidines disfavor the formation of essential
intermediates owing to lack of aryl stabilizing groups.
Noteworthy, all of the obtained products possess a non-
substituted C−H unit at position 6, providing the potential for
further elaboration of complex molecules via direct C−H bond
functionalization.12 Moreover, owing to the aryl groups are
ortho to the nitrogen atom of the 1,3,5-triazine, they could serve
as C∧N or C∧N∧C ligands for the preparation of organometallic
materials13 and especially pincer complexes.14
Subsequently, we turned our attention to synthesize
unsymmetrical 2,4-disubstituted-1,3,5-triazines with the syn-
thetic protocol. By employing different combinations of aryl
amidines (for the reactant molar amount, see Supporting
Information, Table S1), all of the cross-coupling reactions
underwent efficient cyclization to afford the desired products in
moderate to good yields. Similar to the results described in
Scheme 2, the electron-rich amidines gave the products in
relatively higher yields (Scheme 3, 2n and 2o) than the
electron-poor ones (Scheme 3, see 2p−2t). Interestingly, the
reactions of 1 equiv of aryl amidines with 4 equiv of
acetamidine 1n could also be transformed into the desired 2-
aryl-4-alkyl-triazine products in reasonable yields (Scheme 3,
see 2u and 2v). Hence, the examples presented herein have
demonstrated the first straightforward synthesis of unsym-
metrical 2,4-disubstituted-1,3,5-triazines, offering an important
basis for the further elaboration of various C∧N or C∧N∧C
types of organometallic complexes or materials.13,14
an internal standard. DMSO: dimethyl sulfoxide; DMA: N,N-
dimethylacetamide. Bidentate nitrogen ligand: 20 mol %.
c
when representative one-carbon suppliers11a−d (DMSO, DMA)
were tested, product 2a could also be detected but in relatively
lower yields (Table 1, see entries 4 and 5). Further, it was
shown that the copper catalyst, O2, and pyridine ligand (L1)
were essential in the formation of 2a (Table 1, entries 6−8).11e
Among various nitrogen ligands tested (see Supporting
Information, Scheme S1), pyridine (L1) was the most effective
one (Table 1, entries 2 and 9), and a decrease or increase of
catalyst loading would decrease the product yields (Table 1,
entries 10 and 11). Furthermore, we examined several inorganic
and organic bases (Table 1, entries 12 and 13), and the use of
NEt3 led to exclusive formation of 2a in 85% yield. However, an
increase NEt3 amount failed to improve the product yield
(Table 1, entry 14). Finally, we chose NEt3 and DMF as the
preferred base and solvent, respectively. Both increase and
decrease of reaction temperatures resulted in decreased product
yields (Table 1, entries 15 and 16), and other copper catalysts
were proven to be inferior to CuI (Table 1, entry 17). Thus, the
optimal reaction conditions can be as indicated in entry 13 of
Table 1.
With the optimized reaction conditions in hand, we then
examined the generality and the limitations of the synthetic
protocol. First, we focused on the synthesis of symmetrical 2,4-
diaryl-1,3,5-triazines by testing a variety of aryl amidines 1 (see
Supporting Information, Scheme S2). As shown in Scheme 2,
all of the reactions proceeded smoothly and furnished the
desired products in moderate to good yields upon isolation. It
was found that electron-donating groups (i.e., -Me, -OMe)
containing amidines afforded the products in higher yields
(Scheme 2, 2b−2d) than the electron-deficient ones (i.e., -F
and -CF3) (Scheme 2, 2e−2k). By means of GC and GC−MS
analyses, this phenomenon can be rationalized as the amidines
B
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Letter
Scheme 3. Synthesis of Unsymmetrical 2,4-Diaryl-1,3,5-
triazines and 2-Aryl-4-alkyl-1,3,5-triazines
Scheme 5. Possible Pathway for the Formation of Product 2
then proceeds by direct insertion into the C(sp3)-H bond of
DMF to afford intermediate D.17,18 The N-protonation of D
would facilitate the C−N bond cleavage of the diaminomethyl
moiety of E and produce an iminium cation F by eliminating
one molecule of N-methyl formamide. The electrophilic
addition of F to amidine 1′ and subsequent tautomerization
give intermediate G. Then, intramolecular nucleophilic addition
of amino group to the imino center of G would generate
aminals H. Finally, the thermodynamic favorable deammonia-
tion of H and O2-promoted dehydrogenative aromatization
steps would afford desired product 2.
In summary, we have developed a novel straightforward
synthesis of 2,4-disubstituted-1,3,5-triazines from easily avail-
able amidines with DMF as a one-carbon supplier. By
employing a CuI/pyridine catalyst system and molecular O2,
both symmetrical 2,4-diaryl- and unsymmetrical 2,4-diaryl, 2-
aryl-4-alkyl products could be furnished efficiently. The
presented method allows synthesizing the products that are
currently inaccessible or challenging to prepare with the
advantages of operational simplicity, broad substrate scope,
and no need for prefunctionalized reagents, making it a highly
practical approach for the synthesis of various 2,4-disubstituted-
1,3,5-triazines. On the basis of the importance of 2,4-
disubstituted-1,3,5-triazines in biological, material, and coordi-
nation chemistry, the presented method has the potential to be
frequently employed for various applications.
a
b
Isolated yield. Reaction time: 24 h.
In order to determine how the C−H unit at position-6 of the
obtained products is provided (for detailed information, see
Supporting Information, Scheme S3), the reaction of 1b with
carbonyl 13C-labeled DMF did not afford 13C-labeled product
2ba (Scheme 4, eq 1). Further, the reaction with DMF-d7 gave
Scheme 4. Verification Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
both deuterated and nondeuterated products (2b, 2bb) with a
comparable D/H ratio (49:8) (Scheme 4, eq 2). These results
strongly support the methyl group of DMF serve as the C−H
supplier. The formation of product 2b (1H NMR: δ 9.12 ppm)
is the result of base-induced partial H/D exchange of 2bb,
suggesting H+ is produced during the catalytic process.
However, the formation of 2b and 2bb were totally suppressed
upon addition of 4 equiv of radical scavenger (TEMPO), and
product 2bc via TEMPO-trapped hydrogen radical was
observed exclusively in 35% yield (Scheme 4, eq 3), which is
1.4 equiv of 1b, implying the reaction undergoes a dual single-
electron oxidation process on amidine 1b, and an iminium
cation intermediate derived from oxidation of DMF is less
favored.15
Detailed experimental procedures including spectroscopic and
analytical data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: minzhang@scut.edu.cn.
*E-mail: tlyq@jnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Based on our experimental results and some related
research,16 a possible reaction pathway is depicted in Scheme
5. Initially, highly reactive nitrene intermediate C (copper
nitrene complex) is generated via a sequential dual single-
electron oxidation of amidine (Scheme 5, from 1 to C), which
The authors are grateful to the funds of the National Natural
Science Foundation of China (21101080), Natural Science
Foundation of Jiangsu Province (BK2011144), Fundamental
Research Funds for the Central Universities of China
(2014ZZ0047), and Distinguished talent program of SCUT.
C
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