Synthesis of 1,2-dihydro-1,3,5-triazine derivativesviaCu(ii)-catalyzed C(sp3)-H activation ofN,N-dimethylethanolamine with amidines

Article abstract of DOI:10.1039/d0cc03820b

1,2-Dihydro-1,3,5-triazines and symmetrical 1,3,5-triazines were obtained in up to 81% yields from amidines andN,N-dimethylethanolamine catalyzed by CuCl₂. The reaction involves three C-N bond formations during the oxidative annulation process

Full text of DOI:10.1039/d0cc03820b

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Synthesis of 1,2-dihydro-1,3,5-triazines derivatives via Cu(II)-
catalyzed C(SP3)-H activation of N,N-dimethylethanolamine with
amidines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Min Yana,b, Renchao Maa, Rener Chena, Lei Wanga, Zhiming Wanga and Yongmin Maa,b*
1,2-Dihydro-1,3,5-triazines and symmetrical 1,3,5-triazines were the synthesis of 1,2-dihydro-1,3,5-triazines by condensation of
obtained in up to 81% yields from amidines and N,N- 1,3,5-triazapenta-1,3-dienes with aldehydes/ketones but with
dimethylethanolamine catalyzed by CuCl2. The reaction involves low yields.19a Eckert-Maksic et al. used guanidines and two
three C-N bond formations during the oxidative annulation equivalents
of
N,N’-diphenylcarbodiimide
or
N,N’-
process and the mechanism was proposed. This efficient synthesis diisopropylcarbodiimide to construct the 1,2-dihydro-1,3,5-
of 1,2-dihydro-1,3,5-triazines was developed for the first time.
triazine scaffold.19b Hulme et al. developed a microwave-
assisted protocol for the transformation of dihydrotriazines
from aldehydes and aryl amidines.20 Recently, Zhao et al.
found copper supported on octahedral manganese oxide
molecular sieve being an efficient catalyst for the synthesis of
1,2-dihydro-1,3,5-triazines directly from alcohols and
amidines.21 Chang et al. presented a direct annulation of N-
benzimidazolyl amidines with aldehydes for the formation of
ortho-fused 1,3,5-triazines.22 However, the existing methods
suffer from the disadvantages of harsh reaction conditions,
low yields and not readily accessible raw materials. Thus,
simple and efficient approaches to dihydrotriazines in a user-
friendly manner remain highly demanded.
In 2008 and 2009 respectively, Buchwald and Shi
independently reported the transformation of benzimidazoles
from amidines under oxygen catalyzed by Cu(II) or Pd(II) using
DMSO as the reaction medium (Scheme 1a).23 With an
addition of Selectfluor, DMSO acts not only as a solvent, also
as a methylene donor and as a consequence, 3,4-dihydroquin-
-azolines or quinazolines were performed successfully (Scheme
Transition-metal-catalyzed C-H activation is one of the
hotspots in the field of organic synthesis with the concern
about environmental impact and concept of atom and step
economy.1 For example, C-H activation/cyclization performs
activation of the inert C-H bonds followed by cyclization with
an introduced functional group.1h,2 Oxidative functionalization
of the C-H bond adjacent to nitrogen via cross-
dehydrogenative coupling (CDC) is greatly successful and has
attracted organic chemist’s attentions in recent years.3
However, cleavage of C-N bond is the least explored due to its
relative stability.4 This C-N bond cleavage of N,N-
dimethylaniline5,
N,N-dimethylbenzylamine6,
N,N,N’,N’-
tetramethylethylenediamine7, N,N-dimethyl aliphatic amide8
or N-methylpyrrolidone (NMP)9 is usually catalyzed by Ru10,
Pd11, Cu12 or Fe13 to offer one carbon source.
1,3,5-Triazines represent an important class of nitrogen-
containing heterocycle. Compounds containing the triazine
motif have widespread applications in pharmaceutical and
agriculture industries, material science and organic synthesis.14
1,2-Dihydro-1,3,5-triazines, one derivative of 1,3,5-triazine
species, have been extensively studied in the last few years
due to their broad biological activity such as antitumor15,
1b).24
Our
previous
work
shows
that
N,N-
dimethylethanolamine (DMEA) can offer one carbon donor.25
As part of our continuing interest in using DMEA as the carbon
antibacterial16,
anti-inflammatory17
and
antimalarial18
Scheme 1. Previous and present work for annulation of amidines.
previous work:
properties. Consequently, the development of effective
methods for constructing the dihydrotriazine skeleton has
attracted considerable attention. Wurthwein et al. reported
Cu(II) or Pd(II)
O2, additive
DMSO or NMP
H
N
NH
Ar
(a)
(b)
N
H
Ar
Ar
Ref 23
N
Cu(II), oxidant
DMSO, DMF,
DMA or NMP
H2
C
C
N
NH
N
NH
a. Institute of Advanced Studies and School of Pharmaceutical and Chemical
Engineering, Taizhou University, 1139 Shifu Avenue, Taizhou, 318000, P R China
b. School of Pharmaceutical Science, Zhejiang Chinese Medical University,
Hangzhou, 310053, P R China
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
or
N
H
Ref 24
Ar
N
Ar
this work:
NH
Ar
Ar
N
H2
C
C
N
Ph
NH
N
Ar
OH
N
N
Cu(II)
N
C
N
(c)
+
H2
N
Ar
N
Ar
Ar
H
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synthon, we were wondering whether DMEA can offer a carb- were employed for the reaction. Having exhibitedVtiehweArsticcolepOenlionef
DOI: 10.1039/D0CC03820B
on to perform the annulation reaction for the synthesis of 3,4- the amidines with substituents on the N-aryl side, the
dihydroquinazolines or quinazolines in same manner as DMSO amidines with substituents on the benzimidamide side (1j-1q)
did. Unfortunately, the target quinazolines were not under the optimized reaction conditions were next studied.
successfully formed. 1H NMR data also ruled out the possibility Similarly, amidines bearing with an EDG gave appreciably
of the production of 3,4-dihydroquinazoline derivative. On the higher yields compared to those with an EWG (3j-3p) and a di-
basis of its structural analysis and spectra, a novel 1,2-dihydro- substituted analogue provided only a moderate yield (3q). To
1,3,5-triazine derivatives was assigned (Scheme 1c). Here we further explore the universality of the reaction, amidines with
report the details.
substituents on both the N-aryl and the benzimidamide sides
We started by selecting N-phenylbenzimidamide (1a) as the were also examined. Not surprisingly, moderate yields (38-64%)
model substrate. The effect of different carbon sources, of the desired products (3r-3x) were achieved with two
solvents, catalysts and temperatures on the product yields exceptions which gave delighted yields (73% for 3y and 81%
were investigated (see SI Table S1). After tedious optimization for 3z). Unfortunately, heterocyclic analogues such as furan-2-
experiments, the optimal reaction condition is: N- yl and thiophen-3-yl substituted amidines did not work for the
phenylbenzimidamide (1a, 0.5 mmol), DMEA (0.5 mL) and reaction. It is also noteworthy that the expected products
CuCl2 (15 mol%) at 80oC under air atmosphere for 36h.
were not successfully afforded when one of the aryl groups
Having affirmed the optimized reaction conditions, the scope was replaced with an aliphatic group, such as using N-(tert-
of the reaction with a range of amidines 1 was investigated. butyl)benzimidamide, N-benzylbenzimidamide and N-
We first employed the amidines with different substituents on phenylacetimidamide as the starting materials.
the N-aryl side (1a-1i) as substrates and the results are Encouraged by these promising results, we further applied this
presented in Table 1. In general, the presence of an electron- method to assemble various symmetrical 2,4-disubstituted-
donating group (EDG) or electron-withdrawing group (EWG) at 1,3,5-triazines
(5)
started
from
N-unsubstituted
either ortho-, meta- or para- position was well tolerated and benzimidamides (4) (Table 2). A series of amidines 4a-4i
moderate to good yields of 3 were obtained. The position of bearing either an EDG or an EWG on the phenyl ring could be
both EDG and EWG on the aromatic ring had no significant employed in the reaction, to afford the corresponding
influence on the yield (group of 3b, 3d, 3e and 3g). However, symmetrical heterocycles in moderate yields. Similar to the
the electronic nature of the aromatic moiety appreciably aforementioned results, amidines with an EDG gave relatively
influenced on the yield. For instance, the average yield of 3c higher yields of 5 compared to those with an EWG (5b-c vs 5d-
and 3f which containing an EDG is 70%, whereas the average h). On the other hand, ortho-substituted aryl amidine afforded
yield of 3b, 3d, 3e and 3g which containing an EWG is 54% only. much lower yield compared to meta- and para-substituted
In addition, moderate yields were achieved when di- analogues (5d vs 5e-h). This phenomenon is different from the
substituted benzimidamide (1h) and naphthyl amidine (1i) results mentioned above for the conversion of N-substituted
amidines. In addition, heterocyclic amidines was also tolerated
in this reaction and the desired product 2,4-di(pyridin-4-yl)-
1,3,5-triazine (5i) was achieved in a moderate yield. Again,
Table 1. Substrate scope of amidinesa,b
R1
R2
when the aromatic group of the amidine was substituted with
an aliphatic group such as ethyl, the desired product failed to
be afforded.
NH
R1
N
N
15 mol% CuCl2
8
N
+
N
H
OH
R2
N
R2
0
o
1
2
3
To gain an insight into the reaction mechanism, some
controlled experiments were carried out. A radical inhibitor
c
C
3a
, R = H, 65%; 61%
,
3b
, R = 2-Ph, 56%
, R = 3-Me, 77%
R
3c
3d
N
N
3
6
, R = 3-Ph, 54%
, R = 3-Cl, 53%
, R = 4-OMe, 62%
N
N
3e
3f
N
Table 2. Synthesis of symmetrical 2,4-disubstituted-1,3,5-triazinesa
3i
, 46%
N
h
3g
3h
R = 4-F, 54%
, R = 3,4-Cl2, 30%
N
N
HCl
NH
CuCl2,Cs2CO3
90oC, 10 h
3j
3k
, R = 2-Me, 61%
, R = 3-Me, 79%
N
R
+
Ar
N
Ar
OH
Ar
NH2
3l
3m
3n
3o
3p
3q
, R = 3-F, 48%
N
N
N
N
3r
, R = 3-Me, 64%
, R = 4-Et, 76%
, R = 4-Cl, 45%
, R = 4-F, 47%
R = 4-CF3, 41%
3s
3t
, R = 3-Cl, 44%
, R = 4-F, 42%
5
4
2
N
N
R
R
Entry
Product
5a
Ar
C6H5
Yield(%)b
66
, R = 3-Me,4-F, 32%
1
2
3
4
5
6
7
8
9
R
5b
5c
5d
5e
5f
5g
5h
5i
3-CH3-C6H4
4-CH3-C6H4
2-F-C6H4
3-Br-C6H4
4-Cl-C6H4
4-Br-C6H4
3,4-F2-C6H3
4-pyridin
53
51
18
36
41
38
29
58
Cl
Et
N
N
N
N
3u
3v
3w
, R = 2-Ph, 51%
, R = 3-Cl, 39%
, R = 4-F, 38%
F
F
N
N
3x
, 57%
Et
N
N
N
N
N
3z
, 81%
N
3y
, 73%
F3C
CF3
F
F
aReaction conditions: 1 (0.5 mmol), CuCl2 (0.15 equiv), in DMEA (0.5 mL) at 80 C
for 36 h; bIsolated yield; cReaction performed in 6 mmol scale.
o
aReaction conditions: 4 (0.5 mmol), CuCl2 (0.15 equiv), Cs2CO3 (2.0 equiv) in DMEA
(0.5 mL) at 90 oC for 10 h. bIsolated yield.
2 | J. Name., 2012, 00, 1-3
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O2
H
O2
Cu+
OH
N
O
N
Scheme 2 Control experiments
O
N
N
Cu2+
Cu2+
Cu2+
View Article Online
DOI: 10.1039/D0CC03820B
O
C
B
A
2
Cu2+
+
O
O2
Cu2+
N
OH
NH
NH
Ar
N
H
CuCl2, TEMPO (2 equiv.)
80oC, in air, 36 h
path
A
HN
N
+
HN
Ar
(1)
no product
condensation
C
N
H
OH
R
N
Ar
N
-RNH2
R
R
D
N
Ar
N
N
1a
[O]
N
N
2
NH2
NH
E
NH
Ar
when
Ar
R = H
Cu2+
O
R
R
Ar
N
Ar
N
Ar
N
Ar
path B
N
H
Ar
5
HN
N
HN
N
1
or
4
3
C
1' or 4'
1
4
R
R
=
=
Ar
H
R
R
Ar
R
N
N
Ar
RNH2
OH
F
N
G
NH
H
+
N
N
CuCl2
Cu2+
N
+
N
H
OH
N
(2)
80oC, in O2, 24 h
1a
2
3a
, 66%
cheme 3 Proposed reaction mechanism
NH
the benzonitrile was fully recovered after the reaction
(Scheme 2, eq. 5).
standard conditions
N
+
(3)
(4)
no product
N
H
OH
1a
2'
Thus, the reaction mechanism for the annulation of the
amidines with DMEA to obtain 1,2-dihydro-1,3,5-triazine
derivatives was proposed based on the aforesaid results and
literature reports25, 28(Scheme 3). Initially, DMEA coordinates
with Cu2+ to form an intermediate A which performs a Fenton-
like reaction29 to generate radical cation B. Removal of one
proton from intermediate B leads to a reactive iminium ion C.
Intermediate C couples with D which is performed by a
condensation of compound 1 or 4 to afford the corresponding
intermediate E (path A). Finally, intermediate E is annulated by
removing N-methylethanolamine to give the final product 3,
regenerating copper salt for the next cycle. There is another
possible pathway where intermediate C couples with 1 or 4 to
afford intermediate F. F was nucleophilically attacked by 1 or 4
to form intermediate G, which followed by annulation to
achieve the product 3 (path B). When N-unsubstituted
amidines were employed as the starting material, 3 could be
further oxidized in air to form an aromatic product 5.
In summary, we have successfully developed a novel copper-
mediated oxidative annulation for the synthesis of 1,4,6-
triaryl-1,2-dihydro-1,3,5-triazines and symmetrical 2,4-diaryl
1,3,5-triazines. All of the 1,4,6-triaryl-1,2-dihydro-1,3,5-
triazines are new compounds. DMAE was employed as a one
carbon synthon in the reaction and the corresponding
products are different from that using DMSO, DMF, DMA or
NMP as the carbon source, rendering the method very
attractive. Further studies utilizing this DMAE/metal salt
system for the construction of various C-C and C-N bond
formations are ongoing in our lab.
NH
N
N
CuCl2
+
DMSO / DMF
N
H
N
80oC, in air, 36 h
1a
6
, <20%
NH
N
N
CuCl2
Ph
N
+
Ph
PhCN
+
N
H
OH
N
(5)
80oC, in air, 36h
2
1a
3a
, 36%
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) was added to
the reaction system and the product yield was dramatically
diminished and no product was observed when the amount of
TEMPO reached 2 equivalents (Scheme 2, eq. 1). This obvious
inhibiting effect indicates that the reaction may undergo a
radical pathway. In addition, when the reaction was carried
out under oxygen atmosphere, although the product yield was
not significantly improved, the starting material 1a was mostly
consumed after 24 h reaction time, implied that oxygen
atmosphere could accelerate the reaction process (Scheme 2,
eq. 2). The kinetic studies were carried out under air and O2
atmosphere, respectively, as illustrated in SI Figure S1. In the
first 25 h, the yields of 3 in O2 are much higher than those in
air in the same reaction time. After 25 h, the reaction
continued to afford 3 in air until the peak levelled to stable
values, while yield of 3 in O2 started to decrease slowly, most
likely due to an over-oxidization of the resulting product.
When the DMEA was replaced by N,N-diethylethanolamine,
the reaction failed under such standard conditions, indicating
that DMEA is critical to provide a carbon source for the
annulation reaction (Scheme 2, eq. 3). On the other hand,
when DMEA was replaced with DMSO or DMF which was used
as a methylene donor widely, the desired 1,3,5-triazine was
not obtained. Instead, DMSO/DMF was employed only as a
solvent and 1,2,4-triazole (6) was afforded in less than 20%
yield (Scheme 2, eq. 4). This result is similar to the literature
report, where the reaction of amidines and benzonitriles was
Financial support from the Leading Innovative and
Entrepreneur Team Introduction Program of Zhejiang (No.
2019R01005) is gratefully acknowledged.
Conflicts of interest
There are no conflicts to declare
catalysed by Cu(OAc)2 or CuI27. However, it is inconsistent
26
.
with Buchwald’s report23a that 2-aryl benzimidazoles were
achieved from amidines in DMSO catalysed by Cu(OAc)2.
Considering that the reaction consumes 2 moles of 1 and the
product 3 was achieved along with the byproduct aryl amine,
based on the concept of atom economy, we attempted to
replace 2 moles of 1a with amidine and benzonitrile at one
mole respectively. However, the reaction was less efficient and
Notes and references
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J. Name., 2013, 00, 1-3 | 3
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A
D
r
OI: 10.1039/D0CC03820B
Ar
N
C
R
N
NH
N
N
N
N
OH
cat. Cu(II)
or
N
+
R
HC
H2C
N
Ar
N
Ar
N
Ar
Ar
H
R = Aryl
R = Aryl, 26 examples
up to 81% yield
R = H, 9 examples
up to 66% yield
This efficient synthesis of 1,2-dihydro-1,3,5-triazine derivatives was developed for the first time
using N,N-dimethylethanolamine as a new carbon donor.