I2/K2S2O8 Mediated Direct Oxidative Annulation of Alkylazaarenes with Amidines for the Synthesis of Substituted 1,3,5-Triazines

Article abstract of DOI:10.1002/ejoc.201901737

A direct method for the synthesis of heteroaryl-substituted 1,3,5-triazines from readily available methyl-azaarenes and amidines has been developed. The present method involves iodine mediated cascade aerobic C(sp³)–H oxidative amination and following condensation, cyclization with amidine. Both of methyl quinoline, pyridine and benzothiazole derivatives could be well tolerated to react with various amidines leading to corresponding products in good to excellent yields.

Full text of DOI:10.1002/ejoc.201901737

A Journal of
Accepted Article
Title: I2/K2S2O8 Mediated Direct Oxidative Annulation of
Alkylazaarenes with Amidines for the Synthesis of Substituted
1,3,5-Triazines
Authors: Jun Zhang, Tingting Zheng, and Jidong Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901737
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901737
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10.1002/ejoc.201901737
European Journal of Organic Chemistry
COMMUNICATION
I2/K2S2O8Mediated Direct Oxidative Annulation of Alkyl azaarenes
with Amidinesfor the Synthesis of Substituted 1,3,5-Triazines
Jun Zhang,*[a] Tingting Zheng,[a] and Jidong Zhang*[b]
Abstract: A direct method for the synthesis of heteroaryl substituted
1,3,5-triazines from readily available methyl-azaarenes and amidines
has been developed. The present method involves iodine mediated
cascade aerobic C(sp3)–H oxidative amination and following
condensation, cyclization with amidine. Both of methyl quinoline,
pyridine and benzothiazole derivates could be well tolerated to react
with various amidines leading to corresponding products in good to
excellent yields.
Traditionally, the symmetrically 2,4,6-substituted 1,3,5-
triazines could be prepared through the cyclotrimerization of
nitriles.[11] For the 1,3,5-triazines bearing three different
substituents, the common preapration processes are based on
the sequential coupling of each substituent with halogenated
1,3,5-triazines.[12] The domino cyclization of isothiocyanates with
aryl amidines is also an effective method to polysubstituted 1,3,5-
triazine derivatives.[13] Not long ago, a microwave-assisted cyclo
condensation of 4H-pyrido[1,3]oxazin-4-ones with amidines was
established leading to asymmetry2,4,6-substituted 1,3,5-triazines
bearing pyridyl as well.[14] More recently, a novel visible light
promoted the three-component reaction of isothiocyanates,
amidines and guanidines were developed by Guo for the
construction of amino-containing unsymmetrical trisubstituted
1,3,5-triazines.[15] In addition, transition metal and visible light
catalyzed cascade amination of 1,1-dibromoalkenes,[16a]
alcohol[16b] or perfluoroalkyl halides[16c] with biguanides to 1,3,5-
triazines were also effective methods to introduce various
substitutes. In contrast, the formal [3+2+1] annulation of
aldehydes with amidines is of particular interets and widely
adopted in rapid assembly of triazine skeletons due to its
convergent and step-economical features.[17] Based on this
strategy, researchers have tried various carbon synthons in
cyclization with amidines to improve the synthesis of 1,3,5-
triazines and achieved a lot of progresses over the past decades.
In previous work, transition-metal Ru,[18a] Cu(II)[18b] and
hypervalent iodine[18c] catalyzed aerobic oxidative coupling of
alcohols with amidine were respectively developed leading to
2,4,6-triaryl-1,3,5-triazines via aldehydes intermediate. Similarly,
polythene glycol mediated aerobic oxidative tandem cyclization of
benzylamines with amidines[19a] and oxidative C(sp3)–H amination
of tertiary amines with amidines using Cu(II)[19b] or iodine[19c] as
catalysts were also further established as novel strategies for the
synthesis of polysubstituted 1,3,5-triazine. As an alternative, other
carbon synthons such as aryl acetic acids, styrenes, isatins and
alkyl ethers were also developed as C1 coupling precursors
introduced to this strategy.[20]
Introduction
Recently, the 1,3,5-triazines have attracted much attentions and
widely used as core skeleton introduced to functional
supramolecular organic frame exhibiting various founion such as
photoredox catalysts,[1] transfer hydrogenation catalysts,[2] gas
absorption,[3] magnetism,[4] semiconductor.[5] A large number of
small molecules bearing 1,3,5-triazine fragments usually possess
a broad spectrum of biological activities such as antitumor,[6a,b]
anti-inflammatory,[6c,d] antibacterial,[6e] antiviral[6f] and play a
significant role in the discovering of active lead compounds.
Moreover, this scaffold exhibits extensive applications in
preparation of high performance chelating ligands,[7] liquid
crystals,[8] molecular probes,[9] photoelectric materials. [10] (Figure
1)
Figure 1. Selected examples of functional molecular bearing 1,3,5-triazine.
[a]
Dr. Jun Zhang
Ministry of Education Key Laboratory of Synthetic and Natural
Functional Molecule
College of Chemistry & Materials Science
Northwest University
Xi'an. Shaanxi 710127, P. R. China
E-mail: ws1003m@163.com
https://orcid.org/0000-0001-8598-3752
Dr. Jidong Zhang
[b]
School of Chemistry & Chemical Engineering
Ankang University
Ankang. Shaanxi 725000, P. R. China
E-mail: akuzjd@aku.edu.cn
http://hx.aku.edu.cn/info/news/content/4790.htm
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synthesis of 1,3,5-triazines via direct oxidative amination.
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10.1002/ejoc.201901737
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Despite these previous reactions synthetic exhibit high
efficiency, a simple and direct method for the construction of
triazine containing biheteroaryls is still needed in consideration of
tedious synthetic process, expensive substrates of above
methods. Comparing with inaccessible heteroaryl aldehyde, the
alkylazaarenes have been widely used as the carbon source in
organic synthesis as their cheap, easily available features.[21]
With a certain oxidant, the methyl group attached to the aryl ring
could be oxidized in-situ to aldehyde and involved in further
transformations. To date, copper,[22] elemental sulfur[23] and iodine
reagent[24] were successively selected as the catalysts to promote
aerobic oxidative C-N, C-S bonds coupling of alkylazaarenes to
construct various heterocycles. Nevertheless, to the best of our
knowledge, there is still no report using alkylazaarenes as the C-
1 carbon source to the oxidative cyclization with amidines to 1,3,5-
triazine. In 2015, Guo reported TBHP mediated oxidative C(sp3)–
H amination of methylarenes[25] with amidine for the synthesis of
1,3,5-triazines (Scheme 1, eq. a). However, this protocol needed
an excessive amount of methyl arenes as solvent which limited its
wide application in heterocyclic substrates. As a green and
recyclable catalyst, molecular iodine had attracted much attention
in the C(sp3)-H functionalization of alkylazaarenes for the
construction of various heterocycles including quinazolinones,[24a-
K2S2O8 did not improve the yield of t1 at all (Table 1, entry 6).
Some other iodine sources were also investigated to promote the
reaction. However, neither of NH4I, NIS, TBAI lead to a higher
yield of product and only KI showed comparable efficiency (Table
1, entries 7-10). Following, the optimal loading amount of iodine
was also explored and 50 mol % iodine was found to be ideal
leading to a 70% yield of t1 (Table 1, entry 12).
Table 1. Optimization of reaction conditions.a
Base
(equiv.)
Entry
[ I ] (mol %)
Oxidant
Solvent
Yieldb
1
2
I2 (30%)
I2 (30%)
I2 (30%)
I2 (30%)
I2 (30%)
I2 (30%)
KI (30%)
NH4I (30%)
NIS (30%)
TBAI (30%)
I2 (20%)
I2 (50%)
I2 (75%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
I2 (50%)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (4)
Cs2CO3 (5)
Na2CO3 (4)
K2CO3 (4)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
20
50
K2S2O8
TBHP
3
35
4
DTBP
25
5
TBPB
21
b]
imidazo[1,5-a]-pyridines,[24e] 1,2,4-triazolo[4,3-a]pyridines[24f]
6
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
38c, 49d
45
and so on. Recently, Bhanage and group utilized molecular iodine
as catalyst to facilitate the C(sp3)-H amination of acetophenone[26]
and developed a practical methodology for the synthesis of 1,3,5-
triazines (Scheme 1, eq. b). Therefore, we considered that iodine
promoted oxidative C(sp3)-H amination of alkylazaarenes with
amidines would be feasible and disclosed a novel route for the
synthesis of 1,3,5-triazines bearing heterocycles (Scheme 1, eq.
c).
7
8
30
9
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
20
45
70
Results and Discussion
70
72
At the outset of this study, we employed the reaction of 2-methyl
quinoline (a1) and benzamidine hydrochloride (b1) as the model
to optimize the reaction conditions for this tandem oxidative
cycloaddition (Table 1). Base on previous iodine promoted
78
74
oxidative cycloaddition of amidines with tertiary amines[19c] or
34
[26]
methyl ketones
and our preliminary exploration of reaction
conditions (Table s1), iodine combining with DMSO might be the
suitable catalytic system in the presence of Cs2CO3. However,
an excessive amount of iodine did not significantly improve the
desirable transformation, hence, we conducted the reaction using
30 mol % iodine as a catalyst with the addition of Cs2CO3 in
DMSO, firstly (Table 1, entry 1). Fortunately, the reaction mixture
converted to desired 1,3,5-triazine t1 in 20% yield when heated at
120°C for 24h. In consideration of the fast recovery of iodine might
promote the oxidation of a1 and then improve the reaction yield,
we subsequently investigated the effect of oxidants and found it
is essential for the current catalytic system. Then, a series of
different oxidants including K2S2O8, TBHP, DTBP, TBPB were
successively screened, and K2S2O8 exhibited the best activity
(Table 1, entry 2-5). It is encouraging that the reaction was
significantly improved and the yield increased to 50% with the
addition of K2S2O8 (2.0 equiv.). Further increase or decrease of
68
KOH(4)
38
CsOH(4)
40
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
NMP
48
Toluene
PhCl
20
25
DMSO/PhCl
(1:1)
Cs2CO3 (4)
24
25
I2 (50%)
K2S2O8
90
DMSO/PhCl
(1:1)
78e, 85f
Cs2CO3 (4)
I2 (50%)
K2S2O8
a Reaction condition: a1 (0.5 mmol), b1 (1.1 mmol), oxidant (1.0 mmol) and base
(1.0 mmol) in 5.0 mL solvent, reacted at 120°C for 24 h.b Products were obtained
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10.1002/ejoc.201901737
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COMMUNICATION
in isolated yields based on a1. c 1 equiv. K2S2O8 was used. d 3 equiv. K2S2O8
based on the excited-state intramolecular proton transfer, the 2-
methyl quinoline with hydroxy at the C8 position was also
examined. However, no target molecular was observed at all, both
of increasing reaction time and temperature (t8). Besides the 2-
methyl-quinolines, the optimized reaction conditions can also be
extended to the oxidative amination of other methyl azaarenes.
Gratifyingly, both of 4-methyl quinoline, 1-methyl isoquinolines
derivates smoothly underwent the oxidative cycloaddition with b1,
giving the corresponding products t9, and t12 in 82% and 88%
yields, respectively. It was surprising that Cl- at the C-2 position
of 4-methyl quinoline was also tolerated well and led to the
corresponding products t10 in good yield (74%). When 3-methyl
quinoline was employed as a substrate, unfortunately, no reaction
was observed under the present reaction condition. 2-
Methylquinoxaline which contains another nitrogen atom was
suitable for the protocol to obtain t13 in 76% yield. The reaction
was further successfully applied to sulfur containing five-member
heterocycle substrates. The 2-methyl benzothiazole is proved to
be suitable for this oxidative cyclization reaction and transformed
into corresponding products t14 in satisfied yield. However, when
2-methylbenzoxazole was employed as a substrate, no reaction
was observed either at a higher and lower temperature (t15). In
addition, 2-methyl pyridines, 4-methyl pyridines all turned out to
be suitable substrates for this transformation, leading to the
corresponding products t16, t18 in 79% and 62% yields,
respectively. Similar to 3-methyl quinoline, 3-methylpyridine did
not react at all under the standard condition.
was used.eReaction performed at 110°C. f Reaction performed at 130°C.
Moreover, with the increase of Cs2CO3, the transformation was
gradually enhanced and achieved a satisfying yield of 78% when
4 equivalents of Cs2CO3 was added. Subsequently, the screening
of optimal base was conducted while only K2CO3 exhibited a
satisfied promotion to the reaction (Table 1, entries 16-18). In
addition, the results of solvent effects showed that both DMF,
NMP, toluene and chlorobenzene were unsuitable for the current
reaction system (Table 1, entries 19-22). Nevertheless, the result
exhibited that a significant enhancement in yield was achieved
when the reaction was conducted in a mixed solvent. With the
combination of DMSO and PhCl (1:1), the reaction gratifyingly
proceeded and gave the product in excellent yield (Table 1, entry
23). Finally, Increasing or decreasing reaction temperature could
be of no advantage to the conversion of reactants, resulting in
lower yield (Table 1, entry 25)
Table 2. Scope of methyl azaarene derivatives.a
Table 3. Scope of amidine hydrochlorides.a
a Reaction condition: a (0.5 mmol), b1 (1.1 mmol), K2S2O8 (1.0 mmol) and
Cs2CO3 (2.0 mmol) were stirred in DMSO (2.5 mL)/PhCl (2.5 mL) at 120°C
for 24 h. Products were obtained in isolated yields based on a.
a Reaction condition: a1 (0.5 mmol), b (1.1 mmol), K2S2O8 (1.0 mmol) and
Cs2CO3 (2.0 mmol) were stirred in DMSO (2.5 mL)/PhCl (2.5 mL) at 120°C
for 24 h. Products were obtained in isolated yields based on a1.
With the optimized conditions in hand, the scope of 2-
aminobenzamides was firstly investigated. As shown in Table 2,
substrates with electron-withdrawing groups or electron-donating
groups can react smoothly to afford the corresponding products
in good to excellent yields (t1-18). In general, the electronic nature
of substituents showed no significant impact on the yields of target
molecules. Both 2-methyl quinoline bearing F, Cl, Br, CH3, OCH3
on C-6 and C-7 position could lead to the desired products (t3-7)
up to about 92% yield. The C-4 chlorine on 2-methyl quinoline well
compatible with a current catalytic system with a slight decrease
of yield (t2). Considering the wide application of fluorescent dyes
To further demonstrate the applicability of the reaction, we
next investigated the generality of the current procedure by testing
various amidine hydrochlorides with 2-methyl quinoline (a1). A
wide range of amidine including phenyl, aromatic heterocycles,
alkyl substituted derivates could reacted with a1 smoothly to give
the corresponding 1,3,5-triazines. Firstly, a series of functional
groups on the phenyl ring of benzamidines including CH3, OCH3,
F, Cl, Br and CF3 were tested and tolerated well providing the
corresponding products in good to excellent yields. In generally,
the benzamidines bearing electron-donating group on the
benzene ring showed better reactivity and provided higher yields
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Following, to confirm the active intermediate of 2-methyl quinoline
(a1), the reaction was conducted in the absence of benzamidine.
It was found that most of a1 could be transformed into quinoline-
2-carbaldehyde under the standard condition (Scheme 2b). In the
presence of iodine, the oxidation of a1 could be quickly initiated
in 0.5 h and transform into quinoline-2-carbaldehyde (A2) via the
key intermediate 2-iodomethyl-quinoline (A1) in the presence of
DMSO. With the increase of reaction time, the intermediate A1
gradually disappeared, the main product A2 achieved an 84%
yield after stirring of 3h. These results indicated that intermediate
A1 acted as a crucial intermediates during the oxidative process
while the A2 might be active species in the cyclization process.
Besides, the oxidation of a1 to A2 would be completely inhibited
with the remove of iodine or K2S2O8 (Scheme 2c). Moreover,
single b1 was treated with the standard condition, however, only
21% yield of benzoic acid was obtained in the absence of a1
(Scheme 2d). Subsequently, the reaction of quinoline-2-
carbaldehyde with benzamidine was also investigated and gave
the product t1 in excellent yield which further verified the
important role of A2 (Scheme 2e). Notably, the transformation of
A2 with b1seemed entirely unaffected without iodine. This result
indicated that the iodine catalyst played an important role in the
oxidative in-situ aldehyde generation process while had no
obvious promotion and suppression during the condensation and
cyclization steps. In addition, when the reaction of A2 with b1 was
performed at 90°C, the aldimine (B1) was proved to the main
product and an only trace amount of t1 was observed (Scheme
2f). However, the intermediate B1 would be gradually
disappeared and converted into t1 with an additional stirring of 6
h when the temperature was further raised to 120°C.
than electron-rich ones. It was found that the substrates bearing
electron-donating groups like Me or OCH3 on para and meta
position were highly suitable and provided the desired products
(t23 and t26-27) in excellent isolated yields. Both of the halide
substituents on para, meta position were tolerated, providing the
respective target products (t19-21 and t24-t25) in 76-85% yields.
Furthermore, the amidines bearing strong electron-withdrawing
CF3 group was also employed, while the reaction became
sluggish giving the corresponding product in 70% yields. When
the ortho substituted benzamidine was tested, a slight steric effect
was observed and inhibited the reaction. Even so, the desired
product t28 was successfully obtained in 68% yield and further
confirmed by X-ray crystallography. The reaction of a1 with the
polysubstituted benzamidines was also feasible and afforded
corresponding product t29 in 70% yields. In addition, 2-
thienylamidine was confirmed to be an efficient substrate for this
reaction, leading to the triazine t30 bearing three heterocycles in
79% yield. Gratifyingly, when cyclopropane carboxamidine was
subjected to this reaction, dicyclopropyl-substituted 1,3,5-
triazines t31 were successfully obtained in a moderate yield.
Scheme 2. Several control experiments for mechanism studies.
Scheme 3. Proposed reaction mechanism.
In order to clarify the mechanism of this reaction, a series of
control experiments were carried out as shown in Scheme 2. First,
the radical inhibition experiments were performed to investigate
the reaction by addition of excess 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) or 2,6-di-tertbutyl-4-methyl phenol (BHT).
The results showed that both of TEMPO and BHT have
significantly influences on the yields of t1 (Scheme 2a). Thus, a
radical mechanism could be included during the transformation.
Based on these results and previous reports, a plausible
mechanism was proposed and illustrated in Scheme 3 using the
reaction of 2-methyl quinoline with benzamidine as an example.
Initially, 2-methyl quinoline underwent nucleophilic substitution
with iodine to afford the intermediate 2-iodomethyl-quinoline (A1)
via the more active enamine. The intermediate A1 would be
rapidly oxidized to quinoline-2-carbaldehyde (A2) via Kornblum
oxidation in the presence of DMSO. Then, the condensation of
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Angew Chem Int Ed Engl. 2018, 57, 8316-8320; b) D. Schwarz, Y. Noda,
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quinoline-2-carbaldehyde with benzamidine hydrochloride (b1)
was initiated to afford imine (B1) with the promotion of Cs2CO3.
Subsequently, in the presence of an excessive base, the
nucleophilic addition of b1 with B1 was achieved and provided an
intermediate B2. Finally, B2 could be rapidly transformed into C1
which underwent oxidation to the desired product 1,3,5-triazine.
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Conclusions
In summary, we have developed a novel and practical strategy for
the construction of biheteroaryls bearing quinoline and 1,3,5-
triazine ring. Compared with literature procedures, the reaction
showed advantages such as cheap starting materials, transition
metal-free and good functional group tolerance. The current
catalytic system performed via a tandem oxidative in-situ
aldehyde generation, amination, condensation and cyclization
utilized a catalytic amount of molecular iodine as catalyst in the
presence of oxidant. The mild reaction conditions make it suitable
for a wide range of methyl quinoline, methylpyridine and methyl
benzothiazole as aldehyde precursors leading to respectively
substituted 1,3,5-triazines. To the best of our knowledge, this is
the first direct method for the synthesis of 2-heteroaryl substituted
1,3,5-triazines with methyl-azaarenes. We believe that the
present methodology would have wide applications in organic
synthesis, medicinal chemistry and materials science fields.
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Experimental Section
The general experimental procedure is as follows: To an oven-dried
reaction vessel charged with 2-methyl quinoline (a1, 0.5 mmol, 72.5 mg),
amidine hydrochloride (b1, 1.1 mmol, 171.6 mg), iodine (50 mol %, 0.25
mmol, 63.5 mg), K2S2O8 (1.0 mmol, 270.3 mg), Cs2CO3 (2.0 mmol, 651.6
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mg) was added. Then,
a mixture of dried DMSO (2.5 mL) and
chlorobenzene (2.5 mL) was used as the solvent. The vessel was sealed
and heated to 120°C for 24 h. The reaction progress was monitored using
TLC. After completion of the reaction, the reaction mixture was cooled to
room temperature. The resulting mixture was diluted with brine (50 mL)
and extracted with dichloromethane (20 mL) three times. The organic
phase was dried over anhydrous Na2SO4, filtered and evaporated on a
rotary evaporator to get the crude product. The crude product was purified
by silica gel column chromatography (eluent: 15:1 petroleum ether/ethyl
acetate). Other 1,3,5-triazine derivates were prepared according to similar
procedure to t1.
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Acknowledgments
This work was supported by the Key Projects of Shaanxi
Provincial Science & Technology Department (No.2018PT-31),
Major Scientific Research Projects of the Leading Industry of
Ankang city (2016AKZDCY002).
Keywords: azaarenes • biheteroaryls • C(sp3)-H amination •
cyclization • Kornblum oxidation
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Key Topic*
J. Zhang* [a] T. T.Zheng, [a] J. D. Zhang*
[b]
Page 1. – Page 7.
I2/K2S2O8 Mediated Direct Oxidative
Annulation of Alkylazaarenes with
Amidines for the Synthesis of Sub-
stituted 1,3,5-triazines
A simple and direct approach to 1,3,5-triazines based biheteroaryls from methyl-
azaarenes and amidines has been developed, providing the target products with up
to 92%. The transformation is achieved via I2/K2S2O8 catalyzed in-situ aldehyde
generation of methyl-azaarenes and cascade amination, cyclization.
*C(sp3)–H functionalization, biheteroaryls
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