Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines

Article abstract of DOI:10.1021/acs.joc.6b02846

A practical and efficient method for divergent synthesis of 3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-triazines via unexpected rhodium-catalyzed O-H insertion/rearrangement/conditions-controlled intramolecular cyclization and oxidation reaction under mild conditions has been developed. Notably, it is the first example for the synthesis of 1,2,4-triazines with different substituted-patterns via a common intermediate with excellent chemoselectivities by the reaction of N-acylhydrazones as aze-[3C] or [4C] synthons with N-sulfonyl-1,2,3-triazoles as aze-[2C] synthons. Furthermore, this method allows direct access to di(het)aryl ketone frameworks containing 1,2,4-triazine moiety for the first time, serving as a versatile building block for the synthesis of other useful heterocyclic skeletons, such as pyridine or pyridazinone-fused triazine in excellent yields.

Full text of DOI:10.1021/acs.joc.6b02846

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Article
Unexpected O-H insertion of Rhodium-Azavinylcarbenes
with N-acylhydrazones: Divergent Synthesis of 3,6-
disubstituted- and 3,5,6-trisubstituted-1,2,4-Triazines
Jiang Meng, Min Wen, Shiwei Zhang, Peiwen Pan, Xingxin Yu, and Wei-Ping Deng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02846 • Publication Date (Web): 17 Jan 2017
Downloaded from http://pubs.acs.org on January 18, 2017
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Unexpected O-H insertion of Rhodium-Azavinylcarbenes
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with
N-acylhydrazones: Divergent Synthesis of
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3,6-disubstituted- and 3,5,6-trisubstituted-1,2,4-Triazines
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Jiang Meng, Min Wen, Shiwei Zhang, Peiwen Pan, Xingxin Yu* and WeiꢀPing Deng*
Shanghai Key Laboratory of New Drug Design & School of Pharmacy, East China University
of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
ABSTRACT: A practical and efficient method for divergent synthesis of 3,6ꢀdisubstitutedꢀ
and
3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazines
via
unexpected
rhodiumꢀcatalyzed
OꢀH
insertion/rearrangement/conditionsꢀcontrolled intramolecular cyclization and oxidation
reaction under mild conditions has been developed. Notably, it is the first example for the
synthesis of 1,2,4ꢀtriazines with different substitutedꢀpatterns via a common intermediate with
excellent chemoselectivities by the reaction of Nꢀacylhydrazones as azeꢀ[3C] or [4C]
synthons with Nꢀsulfonylꢀ1,2,3ꢀtriazoles as azeꢀ[2C] synthons. Furthermore, this method
allows direct access to diꢀ(het)aryl ketone frameworks containing 1,2,4ꢀtriazine moiety for the
first time, serving as versatile building block for the synthesis of other useful heterocyclic
skeletons, such as pyridine or pyridazinoneꢀfused triazine in excellent yields.
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INTRODUCTION
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Aromatic heterocycles are highly important structural units found in a large number of
biologically active natural products, pharmaceutical compounds and functional materials.1
Among them, those nitrogenꢀcontaining heterocycles are the most indispensable structural
motifs with great value in organic syntheses. 1,2,4ꢀTriazines and its derivatives are a
wellꢀknown class of azaheterocycles for their broad spectrum of biological activities and
natural occurrences (Figure 1).2 Taking Lamictal for example, as a member of the sodium
channel blocking class of antiepileptic drugs, it has been used in the treatment of epilepsy,
bipolar disorder and so on for a long time. Apart from these impressive biological properties,
1,2,4ꢀtriazines have been widely used as 2ꢀazadienes in the inverse electron demanded
DielsꢀAlder reactions to build important heterocyclic skeletons.3 Moreover, 1,2,4ꢀtriazines are
also used as key metal coordinating ligands and fluorescent sensor.4
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Figure 1. Selected natural products and pharmaceutical compounds.
Given the wide usefulness of 1,2,4ꢀtriazines and its derivatives, considerable efforts have
been devoted to the development of improved methods for their synthesis (Figure 2).5 To date,
several efficient methods are available for their construction. The mainstay for the synthesis
of substituted 1,2,4ꢀtriazine is the condensation of a 1,2ꢀdicarbonyl equivalent or its precursor
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with an amidrazone.5 However, many of these reported methods have drawbacks such as
tedious substrate preparation procedure, harsh reaction conditions, limited substrates scope
and especially low regioselectivity.5 Therefore, the development of a more convenient and
regiospecific methodology is highly desired.
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Figure 2. Previous methods for the construction of 1,2,4ꢀtriazines.
Multiꢀheteroatom heterocycles are of very considerable significance particularly in
medicinal chemistry, for example analogues of the pyrimidine and purine nucleosides have
been extensively studied.1 In recent years, the rhodiumꢀcatalyzed denitrogenative
transformations of readily accessible Nꢀsulfonylꢀ1,2,3ꢀtriazoles have led to a new family of
synthetic methods toward a variety of valuable organic molecules.6ꢀ11 As shown, the in situ
generated rhodiumꢀazavinylcarbene (RhꢀAVC) displays diverse reactivities, which could be
used as [1C]ꢀ/[2C]ꢀ/azeꢀ[3C]ꢀsynthon (Figure 3a), especially for the synthesis of
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nitrogenꢀcontaining heterocycles. But up to now, its potential as a azeꢀ[2C]ꢀsynthon remains
untouched.9b And also, there was, to the best of our knowledge, rare method developed for
synthesis of important heterocycles containing more than two heteroatoms in
rhodiumꢀazavinylcarbene chemistry owing to the challenge of choosing an appropriate
substrate.6ꢀ11 With our research interests in azaheterocycle synthesis and
Nꢀsulfonylꢀ1,2,3ꢀtriazoles chemistry,12 we have reported a novel and efficient route for the
construction of oxaꢀbridged 2,5ꢀepoxyꢀ1,4ꢀbenzoxazepines via Rh(II)ꢀcatalyzed reaction of
Nꢀsulfonylꢀ1,2,3ꢀtriazoles and salicylaldehydes.12b We envisaged that the triazoles could be
used to construct multiꢀheteroatom heterocycles according to the high nucleophilicity feature
of nitrogen atom in RhꢀAVC (Figure 3a).
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Formal 1,3ꢀinsertions of the RhꢀAVC into NꢀH bonds of amides, ambiphilic βꢀenamino
esters, 9Hꢀcarbazoles have been achieved (Figure 3b).13aꢀc Meanwhile, hydrazones have been
widely used to react with olefins via [3+2] cycloaddition to form pyrazolidines. Inspiringly,
hydrazone may be the possible substrate for the construction of 1,2,4ꢀtriazine via a formal
[3+3] cycloaddition owing to its feature containing two nitrogen atoms (Figure 3c). Herein,
we describe a novel method for the divergent synthesis of 3,6ꢀdisubstitutedꢀ and
3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazines via an unexpected OꢀH insertion of RhꢀAVC with
Nꢀacylhydrazones rather than the initial hypothesis (Figure 3d).
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Figure 3. Rhodiumꢀcatalyzed reactions of Nꢀsulfonyl 1,2,3ꢀtriazoles.
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RESULTS AND DISCUSSION
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We initiated our studies by testing the reactions of different types of hydrazones with
triazole 1a (Scheme 1). Disappointingly, the desired cycloaddition product was not detected,
and there were even no reactions taking place in most cases. Surprisingly, when hydrazone 2a
was used, an unexpected product 3aa was obtained in 57% yield. We reasoned that the
hydroxy tautomer of benzoylhydrazone is easily formed under the reaction conditions and
then could been captured by RhꢀAVC through OꢀH insertion rather than the assumed NꢀH
insertion.13c Interestingly, 3aa would degenerate after a long time exposing to air or remaining
in NMR tube to form the expected 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazine 4aa. The encouraging
results promoted us to do a further study of this transformation.
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Scheme 1. Initial findings.
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Table 1. Optimization of reaction conditions for the synthesis of
3,6-disubstituted-1,2,4-triazine 4aa.a
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entry
1d
solvent
CHCl3
CHCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Rh (II)
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(piv)4
Rh2(oAc)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
T1(°C)/t1(h)
75/3.5
75/3.5
75/3.5
100/3.5
65/3.5
75/4
3aa(%)b
57
4aa(%)c
ꢀꢀ
ꢀꢀ
2
66
3
69
ꢀꢀ
4
47
ꢀꢀ
5
68
ꢀꢀ
6
67
ꢀꢀ
7
75/3
69
ꢀꢀ
8
75/3
53
ꢀꢀ
9
75/3
NP
56
ꢀꢀ
10
75/3
ꢀꢀ
11e
12e
13 e,f
14e,g
15e,f,h
16e,f,i
17e,f,j
18e,f,k
19e,f,l
75/1
69
ꢀꢀ
75/4
70
ꢀꢀ
75/1
75
ꢀꢀ
75/1
75
ꢀꢀ
75/1
75
68
68
< 10
trace
67
75/1
75
75/1
75
75/1
75
75/1
75
aConditions: Under N2, 1a (0.24 mmol), 2a (0.2 mmol), Rh(II) (2 mol%), and solvent (1.0 mL) were
heated at 75°C until 2a was consumed, then the next step was conducted. Isolated yields. cIsolated
b
yields based on intermediate 3. d1 equiv. 1a was used. e5 mol% Rh(II) was used. f1.4 equiv. 1a was
used. g1.5 equiv. 1a was used. h20 mol% pꢀTsOH was added, 2 mL THF was used as the solvent, T2
= 30°C, t2 = 4 h. iThe intermediate 3aa was directly exposed to air, T2 = 30°C, t2 > 72 h. j20 mol%
CF3COOH was used instead of pꢀTsOH. k20 mol% PhCOOH was used instead of pꢀTsOH. 50
l
mol% FeCl3 was used instead of pꢀTsOH. NP = No Product.
With the initial results in hand, we first focused on the improvement of rhodiumꢀcatalyzed
reaction of triazole 1a with hydrazone 2a. Slightly increasing the amount of triazole 1a, the
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yield of 3aa was improved to 66% (Table 1, entry 2). Using 1,2ꢀdichloroethane (DCE) as the
solvent instead of CHCl3 provided 3aa in 69% yield (Table 1, entry 3). An attempt to increase
the temperature to 100 °C resulted in a lower yield, while decreasing the temperature to 65 °C
or prolonging the reaction time did not give a better result (Table 1, entries 4ꢀ6). Shorting the
reaction time to 3 h did not deteriorate the result and based on this, different Rh(II)ꢀcatalysts
were examined (Table 1, entries 7ꢀ9). It was found that Rh2(oct)4 was still the optimal choice,
while Rh2(piv)4 gave a lower yield and Rh2(oAc)4 afforded a mixture. The optimal reaction
conditions for 3aa were finally obtained by increasing the catalyst loading to 5 mol% and
using 1.4 equiv. triazole 1a (Table 1, entries 10ꢀ14). Key step for the formation of
3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazine 4aa, we think, is the hydrolysis of 3aa. So, 20 mol% pꢀTsOH
as additive promoting hydrolysis was added after the rhodiumꢀcatalyzed reaction in the
oneꢀpot process. The desired product could be obtained but with an impurity difficult to
separate. With these information in mind, a novel twoꢀstep method to form
3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazine 4aa was set up after optimization (Table 1, entries 15ꢀ19).
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Table 2. Synthesis of 3,6-disubstituted-1,2,4-triazines 4.a
entry
substrate 1/ 2 (R1/R2)
1a/ 2a (Ph/ Ph)
t(h)b
3(%)c
4(%)d
4aa/ 68
4ab/ 77
4ac/ 81
4ad/ 68
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2
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4
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1
1
2
3aa/ 75
3ab/ 91
3ac/ 77
3ad/ 60
1a/ 2b (Ph/ 2ꢀMeꢀPh)
1a/ 2c (Ph/ 2ꢀFꢀPh)
1a/ 2d (Ph/ 3ꢀMeꢀPh)
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1a/ 2e (Ph/ 3ꢀCF3ꢀPh)
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2
3ae/ 42
3af/ 69
3ag/ 67
3ah/ 0
4ae/ 38
4af/ 84
4ag/ 60
4ah/ ꢀꢀe
4ai/ ꢀꢀf,g
4aj/ 43
4ba/ 67
4ca/ 58
4da/ 52
4ea/ 68
4fa/ 57
4ga/ 66
4ha/ 56
4ia/ 68
4ja/ 61
4ka/ 73
4la/ 56
4ma/ 57
6
1a/ 2f (Ph/ 4ꢀMeꢀPh)
1a/ 2g (Ph/ 4ꢀFꢀPh)
7
1.5
30
1
8
1a/ 2h (Ph/ 4ꢀPyridinyl)
1a/ 2i (Ph/ Me)
9
3ai/ 78
3aj/ 70
3ba/ 76
3ca/ 81
3da/ 80
3ea/ 76
3fa/ 83
3ga/ 69
3ha/ 68
3ia/ 72
3ja/ 73
3ka/ 61
3la/ 55
3ma/ 92
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1a/ 2j (Ph/ Benzyl)
2
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1b/ 2a (4ꢀBrꢀPh / Ph)
1c/ 2a (4ꢀClꢀPh / Ph)
1d/ 2a (4ꢀFꢀPh / Ph)
1e/ 2a (4ꢀMeꢀPh / Ph)
1f/ 2a (4ꢀMeOꢀPh / Ph)
1g/ 2a (3ꢀMeOꢀPh/ Ph)
1h/ 2a (3ꢀBrꢀPh/ Ph)
1i/ 2a (2ꢀMeOꢀPh/ Ph)
1j/ 2a (2ꢀClꢀPh/ Ph)
1k/ 2a (3,4,5ꢀ(MeO)3ꢀPh/ Ph)
1l/ 2a (3ꢀThienyl / Ph)
1
1.5
1
1.5
1
1
1.5
1
3
1.5
1
1m/ 2a (NꢀPhSO2ꢀ3ꢀindolyl/ Ph)
1
aStandard conditions without changes. Reaction time of step one. Isolated yields based on substrates 2. Isolated yields
based on intermediates 3. eNo product, substrate 1a degraded. fIntermediate 3ai was stable under standard conditions. gA
mixture was obtained when raising the temperature to 75°C or 50 mol% FeCl3 was used as additive at 50°C.
b
c
d
After that, our next step was to explore the generality of this approach to assemble a range
of 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazines under the established optimal reaction conditions. As
indicated in Table 2, various substituted Nꢀbenzoylhydrazones 2aꢀ2g reacted smoothly with
the triazole 1a in moderate to excellent yields to afford 3aaꢀ3ag, while 4ꢀpyridinyl substituted
hydrazone 2h did not give the target 3ah (Table 2, entries 1ꢀ8). It should be noted that
Nꢀbenzoylhydrazones 2bꢀ2c with substituents at the orthoꢀposition gave better results (Table 2,
entries 2ꢀ3). Further transformations of 3 to 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazines 4 were completed
very well under the standard conditions, except for that one with strong electronꢀwithdrawing
group (Table 2, entry 5). Reactions with methylꢀ and benzylꢀ substituted Nꢀacylhydrazones
2iꢀ2j also successfully provided the intermediates 3aiꢀ3aj, but the methylꢀsubstituted one was
rather stable to be hydrolyzed (Table 2, entries 9ꢀ10). After testing the limitation of
Nꢀacylhydrazones 2, we moved forward to examine varying substitution patterns for various
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triazoles 1. As shown, the results revealed that C4 arylsubstituted triazoles 1bꢀ1k afforded
corresponding products in both rhodiumꢀcatalyzed and hydrolysis steps in good yields, which
were insignificantly affected by positions or electronic properties of the substituents (Table 2,
entries 11ꢀ20).14 The reactions still proceeded smoothly affording products 4la and 4ma in
good yields when C4 heteroarylꢀsubstituted triazoles 1l and 1m were used (Table 2, entries
21ꢀ22).
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Table 3. Optimization of reaction conditions for the synthesis of
3,5,6-trisubstituted-1,2,4-triazines 5.a
entry
1
solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
base
T2(°C) /t2(h)
75/ 0.2
rt/ 16
5aa/6aa(%)b
24/10
DBU/ 1eq
DBU/ 1eq
DBU/ 2eq
Et3N/ 3eq
2
25/11
3
rt/ 22
ꢀꢀ/10
4c
rt/ 144
30/ 36
30/ 36
30/ 36
46/ <5
45/ <5
43/ <5
48/ <5
5d
DBU/ 0.2 eq
DBU/ 0.2 eq
DBU/ 0.2 eq
6d,e
7d,f,g
aConditions: Under N2, 1a (0.24 mmol), 2a (0.2 mmol), Rh2(oct)4 (2 mol%), and solvent (1.0 mL) were
b
c
heated at 75 °C until 2a was consumed, then the next step was conducted. Isolated yields. 1 eq Et3N was
d
added every 48 h for three times. No additional oxidant was added. After 2a consumed, the solution was
cooled to 30 °C, then 0.2 equiv. DBU was added. After stirring 12 h for cyclization, 2 equiv. DDQ was added
for oxidation, 24 h. e1 equiv. PIDA was used instead of DDQ. f5 mol% Rh2(oct)4 was used. g1.4 equiv. 1a was
used.
Meanwhile, we wondered that base would promote the intramolecular cyclization reaction
by deprotonation of 3. To test our hypothesis, 1 equivalent DBU was added after the
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rhodiumꢀcatalyzed reaction. As expected, 3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazines 5aa (Xꢀray) was
obtained in 24% yield along with unexpected 6aa in 10% yield after silic gel
column chromatographic separation.15 Decreasing the reaction temperature to ambient
temperature, the reaction provided nearly the same result but with a longer reaction time
(Table 3, entries 1ꢀ2). 2 equivalent DBU would obviously deteriorate the reaction and made
5aa degraded (Table 3, entry 3). After screening of different bases, we found that inorganic
bases could not catalyze the cyclization reaction since the blocking of byproduct formed in
rhodiumꢀcatalyzed step in oneꢀpot manner. Moreover, bases like Cs2CO3, KOH, NaOH and
LDA were also not compatible with 5aa and made it degraded, while K2CO3 catalyzed the
cyclization reaction smoothly in twoꢀstep process affording 1,4,5,6ꢀtetrahydroꢀ1,2,4ꢀtriazines
7 in good yields and diastereoselectivities with trace amounts of 5 (Scheme 2). Also, we
found that catalytic amount of DBU was enough to catalyze the cyclization step and
stoichiometric Et3N were equally effective, albeit with a longer reaction time. It is noteworthy
that the oxidation process of amine in 7 to imine is key step for producing 5.16 So, additional
oxidants were screened for the improvement of synthesis of 3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazines
5aa, and 2 equivalent DDQ was optimal for the oxidation process (Table 1, entry 5).
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Scheme 2. Synthesis of 1,4,5,6-tetrahydro-1,2,4-triazines 7.
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Table 4. Synthesis of 3,5,6-trisubstituted-1,2,4-triazines 5.a
aStandard conditions without changes. b0.3 equiv. DBU was used as the base.
c1 equiv. Et3N was used as the base.
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Next, attention was paid to test the scope of this protocol with various triazoles 1 and
hydrazones 2, and the results are presented in Table 4. All examined substrates were
effectively transformed to the desired products 5 in moderate to good yields. But, methylꢀ
substituted Nꢀacylhydrazone 2i and benzylꢀ substituted Nꢀacylhydrazone 2j were not suitable
substrates for this transformation, as only trace amounts of the desired products were
observed. However, fullꢀsubstituted 1,2,4ꢀtriazoles 6ai and 6aj were successfully obtained in
acceptable yields (Scheme 3). Notably, when C4 arylsubstituted triazoles with
electronꢀdonating groups or heteroarylꢀsubstituted triazoles were used, stoichiometric Et3N
was a better choice to promote cyclization step for preparation of 5ga, 5ia, 5ka, 5la and 5ma.
And also, no additive was needed in the reaction of tricyclicꢀtriazole 1n with hydrazones 2a
and 2b, and 3ꢀsubstitutedꢀnaphtho[2,1ꢀe][1,2,4]triazines 8na and 8nb were obtained in good
yields (Scheme 4). This method is, in our knowledge, the first case to access the
5ꢀacylꢀsubstitutedꢀ1,2,4ꢀtriazines directly. It should be mentioned that diaryl or hetaryl ketone
frameworks are of great important that can be found in several currently marketed drugs or
compounds under clinical evaluation.17
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Scheme 3. Synthesis of 1,2,4-triazoles 6ai and 6aj.
N
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Ts
O
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N
1) 5 mol% Rh2(oct)4, DCE, 75 °C, 1 h
O
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COOEt
N
+
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2) Base, 30 °C, 12 h
3) DDQ, 30 °C, 24 h
COOEt
H
Ph
Ph
6ai 20 mol% DBU: 21%
1a
R = Me
R = Bn
2i
2j
6aj
20 mol% DBU: 30%
100 mol%TEA: 22%
Scheme 4. Synthesis of 3-substituted-naphtho[2,1-e][1,2,4]triazines 8na and 8nb.
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On the basis of the known Nꢀsulfonylꢀ1,2,3ꢀtriazole chemistry and the above outcomes, a
plausible mechanism for this divergent transformation is delineated in Scheme 5. The
azavinyl carbene first reacts with the hydroxy tautomer of Nꢀacylhydrazone 2a via an initial
OꢀH insertion to form the putative intermediate I and releases the Rh(II)ꢀcatalyst, which will
enter the next catalytic cycle to initiate the reaction. Then, intermediate I undergoes
intramolecular rearrangement to afford intermediate 3aa. 3aa as the key intermediate can
undergo different routes to yield diversified products: a) after a hydrolysis process, 3aa can
transform into intermediate II. Then intramolecular condensation/ aromatization processes
take place successively to yield 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazine 4aa; b) under basic conditions,
1,4,5,6ꢀtetrahydroꢀ1,2,4ꢀtriazine 7aa is first obtained through the intramolecular cyclization
reaction, then with the help of additional oxidant or air, the desired
3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazine 5aa is afforded through oxydehydrogenation/aromatization
steps; c) intermediate 3aa partly degrades in the presence of base followed by intramolecular
cyclization reaction to give intermediate III, which gives rise to 1,2,4ꢀtriazole 6aa after
oxidation.
Scheme 5. Proposed reaction pathway.
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Finally, to demonstrate the further applications of the 1,2,4ꢀtriazines for preparing useful
heterocyclic skeletons, condensation reaction and inverse electron demand DielsꢀAlder
reaction of 5aa were examined respectively (Scheme 6). As a result, reaction of 1,2,4ꢀtriazines
5aa with hydrazine hydrate at 85 °C in ethanol was performed smoothly to afford desired
product 9aa in nearly quantitative yield, while the reaction with 2,5ꢀnorbornadiene in toluene
gave ethyl 2ꢀbenzoylꢀ6ꢀphenylnicotinate 10aa with αꢀaryl pyridyl ketone moiety in 88% yield
at 120 °C for 4 h. Notably, αꢀaryl pyridyl ketone derivatives are useful intermediates in the
syntheses of various natural products and drugs, which have drawn wide attention.18 This
method here provides a new perspective for their preparation.
Scheme 6. Further transformation of 5aa.
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CONCLUSION
In summary, we have described an unexpected OꢀH insertion of αꢀimino carbenes derived
from readily accessible Nꢀsulfonylꢀ1,2,3ꢀtriazoles with Nꢀacylhydrazones. Followed by
intramolecular rearrangement/acid or basicꢀcatalyzed intramolecular cyclization and oxidation
reaction, it provides a facile protocol for the divergent synthesis of 3,6ꢀdisubstitutedꢀ and
3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazines with excellent chemoselectivities in moderate to good
yields under mild conditions. To the best of our knowledge, it constitutes the first example for
the synthesis of 1,2,4ꢀtriazines with different substitutedꢀpatterns from a common
intermediate, which greatly enriches compound libraries of 1,2,4ꢀtriazine scaffolds with
potential medicinal utilities, and the first example for the construction of multiꢀheteroatom
heteroaromatic rings using Nꢀsulfonylꢀ1,2,3ꢀtriazoles as azeꢀ[2C] synthons. Importantly, this
research describes an unprecedented application of Nꢀacylhydrazones as azeꢀ[3C] or [4C]
synthons differing from the traditional to construct azaheterocycles, which might be of
potential use for the synthesis of other useful skeletons. Moreover, transformations of the
3,5,6ꢀtrisubstitutedꢀ1,2,4ꢀtriazine products was demonstrated by hydrazine condensation
reaction and inverse electron demand DielsꢀAlder reaction, providing structurally important
azaheterocycles such as pyridine or pyridazinoneꢀfused triazine in excellent yields. Further
studies on the construction of other pharmaceutically important heterocycles and biological
assessment are in progress.
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EXPERIMENTAL SECTION
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General Information
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All reactions were carried out using standard Schlenk techniques under nitrogen
atmosphere unless otherwise stated. CHCl3, 1,2ꢀdichloroethane(DCE) were dried with CaH2.
THF and Toluene were dried with sodium (Na). Reactions were monitored by thin layer
chromatography (TLC) carried out on 0.20ꢀ0.3 mm silica gel plates (GF254) using UV light
as the visualizing agent. Silica gel (200ꢀ300 mesh) was used for column chromatography.
NMR spectra were recorded on 400M instrument and calibrated using residual undeuterated
1
solvent as an internal reference (CHCl3 @ 7.26 ppm H NMR, 77.16 ppm 13C NMR). The
following abbreviations (or combinations thereof) were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Highꢀresolution mass spectra
(HRMS) were recorded on QꢀTOF LC/MS system. Melting points were obtained in
open capillary tubes using
a
micro melting point apparatus which were
uncorrected. Rh(II) acetate, Rh(II) octanoate were purchased from Adamasꢀbeta. Rh2(piv)4
were prepared using literature procedures.19 Nꢀsulfonylꢀ1,2,3ꢀtriazoles20ꢀ22 and
Nꢀacylhydrazones were prepared according to the literature procedures.23ꢀ25
General procedure for synthesis of 3,6-disubstituted-1,2,4-triazines 4
To an ovenꢀdried Schlenk tube was added 0.28 mmol (1.4 equiv.)
Nꢀsulfonylꢀ1,2,3ꢀtriazoles, 0.20 mmol (1.0 equiv.) Nꢀacylhydrazones and 0.01 mmol (5 mol%)
Rh(II), successively. The Schlenk tube was sealed with a Rubber plug and the atmosphere was
replaced using standard Schlenk techniques under nitrogen atmosphere. Then 1 mL dried
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solvent was added and the reaction mixture was heated at 75 °C, with vigorous stirring, for
1ꢀ3 h. Once hydrazones consumed, the reaction mixture was cooled to ambient temperature.
Then reaction mixture was purified by flash chromatography (petroleum ether/ethyl acetate=
5:1~3:1) to provide the intermediate. The intermediate was then dissolved in 2 mL dried THF
and 20 mol % pꢀTsOH was added. The resulting solution was stirred at 30 °C for 4 h. After
reaction, solvent was evaporated and the residue was purified by flash chromatography
(petroleum ether/ ethyl acetate = 10:1~5:1) to afford the desired product.
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3,6-diphenyl-1,2,4-triazine (4aa): yellow solid, 24 mg, 51% yield, mp: 148ꢀ150 °C (literature:
158ꢀ160 °C)26; 1H NMR (400 MHz, Chloroformꢀd) δ 9.06 (s, 1H), 8.65ꢀ8.53 (m, 2H), 8.17ꢀ8.15 (m, 2H),
7.63ꢀ7.51 (m, 6H). 13C NMR (100 MHz, Chloroformꢀd) δ 162.5, 155.2 146.6, 134.7, 133.4, 131.8, 131.0,
129.5, 129.1, 128.3, 126.8; IR(KBr): ṽ = 3049, 2957, 2923, 2853, 1964, 1905, 1655, 1636, 1599, 1452,
1405, 1320, 1178, 1087, 1025, 764, 583 cmꢀ1; HRMS (EIꢀTOF): calcd for, C15H11N3 [M]+, 233.0953; found,
233.0950.
6-phenyl-3-(o-tolyl)-1,2,4-triazine (4ab): yellow solid, 35 mg, 70% yield, mp: 125ꢀ127 °C (literature:
118ꢀ120 °C)27; 1H NMR (400 MHz, Chloroformꢀd) δ 9.11 (s, 1H), 8.20ꢀ8.18 (m, 2H), 8.03 (d, J = 7.5 Hz,
1H), 7.62ꢀ7.58 (m, 3H), 7.46ꢀ7.42 (m, 1H), 7.38 (t, J = 7.2 Hz, 2H), 2.68 (s, 3H); 13C NMR (100 MHz,
Chloroformꢀd) δ 165.4, 154.4, 146.1, 138.3, 134.8, 133.3, 131.8, 131.0, 130.9, 130.5, 129.5, 126.9, 126.3,
21.7; IR(KBr): ṽ = 3053, 2959, 2923, 2853, 1968, 1915, 1600, 1578, 1495, 1439, 1401, 1329, 1127, 1080,
988, 932, 821, 767, 725, 694, 590 cmꢀ1; HRMS (EIꢀTOF): calcd for, C16H13N3 [M]+, 247.1109; found,
247.1110.
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3-(2-fluorophenyl)-6-phenyl-1,2,4-triazine (4ac): yellow solid, 31 mg, 62% yield, mp: 118ꢀ120 °C; H
NMR (400 MHz, Chloroformꢀd) δ 9.13 (s, 1H), 8.28ꢀ8.23 (m, 1H), 8.20ꢀ8.17 (m, 2H), 7.62ꢀ7.52 (m, 4H),
7.35 (t, J = 7.6 Hz, 1H), 7.30ꢀ7.26 (m, 1H); 13C NMR (100 MHz, Chloroformꢀd) δ 161.9 (d, J = 5.4 Hz),
161.6 (d, J = 257.3 Hz), 154.9, 146.3, 133.1 (d, J = 23.3 Hz), 133.0, 131.8, 131.2, 129.5, 126.9, 124.6 (d, J
= 3.9 Hz), 123.6 (d, J = 9.6 Hz), 117.2 (d, J = 22.1 Hz); IR(KBr): ṽ = 3059, 2924, 2853, 1974, 1914, 1611,
1580, 1495, 1452, 1407, 1322, 1233, 1115, 1081, 1040, 831, 769, 696 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C15H10N3F [M]+, 251.0859; found, 251.0860.
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6-phenyl-3-(m-tolyl)-1,2,4-triazine (4ad): yellow solid, 20mg, 41% yield, mp: 108ꢀ110°C; 1H NMR (400
MHz, Chloroformꢀd) δ 9.05 (s, 1H), 8.42 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.18ꢀ8.16 (m, 2H), 7.60ꢀ7.57 (m,
3H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ
162.6, 155.1, 146.5, 138.8, 134.7, 133.4, 132.6, 130.9, 129.5, 128.9, 128.8, 126.8, 125.5, 21.7; IR(KBr): ṽ
= 3046, 2922, 2852, 1961, 1898, 1816, 1598, 1493, 1431, 1395, 1331, 1090, 1039, 922, 781, 693 cmꢀ1;
HRMS (EIꢀTOF): calcd for, C16H13N3 [M]+, 247.1109; found, 247.1108.
6-phenyl-3-(3-(trifluoromethyl)phenyl)-1,2,4-triazine (4ae): yellow solid, 10 mg, 16% yield, mp:
1
156ꢀ158 °C; H NMR (400 MHz, Chloroformꢀd) δ 9.11 (s, 1H), 8.89 (s, 1H), 8.80 (d, J = 7.9 Hz, 1H),
8.19ꢀ8.17 (m, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.63ꢀ7.60 (m, 3H); 13C NMR (100
MHz, Chloroformꢀd) δ 161.4, 155.8, 146.7, 135.6, 133.1, 131.6 (q, J = 32.6 Hz), 131.4, 131.4, 129.6, 129.6,
128.2 (q, J = 3.7 Hz), 126.9, 125.2 (q, J = 3.8 Hz), 124.1 (q, J = 272.3 Hz); IR(KBr): ṽ = 3059, 2924, 2853,
1654, 1613, 1579, 1441, 1396, 1346, 1315, 1271, 1168, 1112, 1068, 923, 803, 693 cmꢀ1; HRMS (EIꢀTOF):
calcd for, C16H10N3F3 [M]+, 301.0827; found, 301.0828.
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6-phenyl-3-(p-tolyl)-1,2,4-triazine (4af): yellow solid, 29 mg, 58% yield, mp: 161ꢀ163 °C; 1H NMR (400
MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.48 (d, J = 8.1 Hz, 2H), 8.17ꢀ8.15 (m, 2H), 7.60 ꢀ7.57 (m, 3H), 7.37
(d, J = 8.0 Hz, 2H), 2.46 (s, 3H).28 13C NMR (100 MHz, Chloroformꢀd) δ 162.6, 154.9, 146.5, 142.3, 133.5,
132.1, 130.9, 129.8, 129.5, 128.3, 126.7, 21.7; IR(KBr): ṽ = 3031, 2920, 2853, 1926, 1739, 1654, 1607,
1507, 1442, 1404, 1331, 1181, 1086, 1033, 795, 687, 581 cmꢀ1; HRMS (EIꢀTOF): calcd for, C16H13N3 [M]+,
247.1109; found, 247.1108.
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3-(4-fluorophenyl)-6-phenyl-1,2,4-triazine (4ag): yellow solid, 21 mg, 40% yield, mp: 176ꢀ178 °C; H
NMR (400 MHz, Chloroformꢀd) δ 9.05 (s, 1H), 8.62ꢀ8.59 (m, 2H), 8.17ꢀ8.15 (m, 2H), 7.62ꢀ7.58 (m, 3H),
7.27ꢀ7.22 (m, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 165.4 (d, J = 252.3 Hz), 161.7, 155.1, 146.6,
133.3, 131.1, 130.9 (d, J = 3.1 Hz), 130.5 (d, J = 8.8 Hz), 129.5, 126.8, 116.2 (d, J = 21.9 Hz); IR(KBr): ṽ
= 3054, 2923, 2853, 1972, 1912, 1600, 1509, 1442, 1407, 1227, 1155, 1084, 1040, 846, 806, 762, 701, 586
cmꢀ1; HRMS (EIꢀTOF): calcd for, C15H10N3F [M]+, 251.0859; found, 251.0858.
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3-benzyl-6-phenyl-1,2,4-triazine (4aj): yellow solid, 15 mg, 30% yield, mp: 143ꢀ145 °C; H NMR (400
MHz, Chloroformꢀd) δ 8.93 (s, 1H), 8.10ꢀ7.98 (m, 2H), 7.59ꢀ7.50 (m, 3H), 7.43 (d, J = 7.4 Hz, 2H), 7.33 (t,
J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.51 (s, 2H); 13C NMR (100 MHz, Chloroformꢀd) δ 167.5, 155.4,
147.0, 137.3, 133.3, 130.9, 129.5, 129.4, 128.9, 127.1, 126.9, 43.5; IR(KBr): ṽ = 3058, 2925, 2853, 1720,
1636, 1562, 1495, 1437, 1406, 1318, 1080, 1047, 1004, 919, 758, 694 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C16H13N3 [M]+, 247.1109; found, 247.1110.
6-(4-bromophenyl)-3-phenyl-1,2,4-triazine (4ba): yellow solid, 32 mg, 51% yield, mp: 144ꢀ146 °C
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(literature: 201 °C)28; H NMR (400 MHz, Chloroformꢀd) δ 9.05 (s, 1H), 8.59ꢀ8.57 (m, 2H), 8.05 (d, J =
8.5 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.58ꢀ7.56 (m, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.7,
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154.3, 146.3, 134.6, 132.8, 132.3, 131.9, 129.1, 128.4, 128.2, 125.9; IR(KBr): ṽ = 3050, 2924, 2853, 1737,
1654, 1636, 1561, 1459, 1404, 1380, 1309, 1165, 1091, 617 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C15H10N3Br79 [M]+, 311.0058; found, 311.0060.
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6-(4-chlorophenyl)-3-phenyl-1,2,4-triazine (4ca): yellow solid, 25 mg, 47% yield, mp: 148ꢀ151 °C
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(literature: 197ꢀ198 °C)26; H NMR (400 MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.59ꢀ8.57 (m, 2H), 8.13 –
8.10 (m, 2H), 7.58ꢀ7.55 (m, 5H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.7, 154.2, 146.3, 137.5, 134.6,
131.9, 131.8, 129.8, 129.1, 128.3, 127.9; IR(KBr): ṽ = 3056, 2922, 1920, 1673, 1596, 1489, 1448, 1412,
1326, 1236, 1089, 1009, 841, 749, 692, 581 cmꢀ1; HRMS (EIꢀTOF): calcd for, C15H10N3Cl35 [M]+,
267.0563; found, 267.0565.
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6-(4-fluorophenyl)-3-phenyl-1,2,4-triazine (4da): yellow solid, 21 mg, 42% yield, mp: 137ꢀ139 °C; H
NMR (400 MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.59ꢀ8.57 (m, 2H), 8.19ꢀ8.16 (m, 2H), 7.58ꢀ7.56 (m, 3H),
7.30ꢀ7.26 (m, 2H); 13C NMR (100 MHz, Chloroformꢀd) δ 164.8 (d, J = 251.8 Hz), 162.5, 154.3, 146.3,
134.7, 131.9, 129.6 (d, J = 3.3 Hz), 129.1, 128.8 (d, J = 8.6 Hz), 128.3, 116.7 (d, J = 22.0 Hz); IR(KBr): ṽ
= 3066, 2922, 2852, 1738, 1703, 1601, 1512, 1451, 1414, 1327, 1239, 1161, 1106, 1033, 842, 753, 689
cmꢀ1; HRMS (EIꢀTOF): calcd for, C15H10N3F [M]+, 251.0859; found, 251.0858.
3-phenyl-6-(p-tolyl)-1,2,4-triazine (4ea): yellow solid, 26 mg, 52% yield, mp: 158ꢀ160 °C (literature:
156ꢀ157 °C)26; 1H NMR (400 MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.60ꢀ8.57 (m, 2H), 8.08ꢀ8.06 (m, 2H),
7.58ꢀ7.55 (m, 3H), 7.40ꢀ7.38 (m, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.3 , 155.1 ,
146.4, 141.5, 134.9, 131.7, 130.6, 130.2, 129.0, 128.2, 126.7, 21.6; IR(KBr): ṽ = 3056, 2922, 2853, 1917,
1776, 1614, 1601, 1563, 1447, 1408, 1329, 1189, 1085, 1036, 988, 830, 750, 690 cmꢀ1; HRMS (EIꢀTOF):
calcd for, C16H13N3 [M]+, 247.1109; found, 247.1110.
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6-(4-methoxyphenyl)-3-phenyl-1,2,4-triazine (4fa): yellow solid, 25 mg, 47% yield, mp: 165ꢀ167 °C
(literature: 161ꢀ164 °C)27; 1H NMR (400 MHz, Chloroformꢀd) δ 9.02 (s, 1H), 8.58ꢀ8.55 (m, 2H), 8.13 (d, J
= 8.7 Hz, 2H), 7.56ꢀ7.55 (m, 3H), 7.09 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H); 13C NMR (100 MHz,
Chloroformꢀd) δ 162.1, 161.9, 154.7, 146.0, 134.9, 131.6, 129.0, 128.2, 128.1, 125.7, 114.9, 55.6; IR(KBr):
ṽ = 3043, 2923, 2852, 1971, 1923, 1655, 1605, 1512, 1407, 1296, 1255, 1179, 1040, 988, 840, 755, 692
cmꢀ1; HRMS (EIꢀTOF): calcd for, C16H13N3O [M]+, 263.1059; found, 263.1061.
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6-(3-methoxyphenyl)-3-phenyl-1,2,4-triazine (4ga): yellow solid, 24 mg, 46% yield, mp: 128ꢀ130 °C; 1H
NMR (400 MHz, Chloroformꢀd) δ 9.06 (s, 1H), 8.60ꢀ8.58 (m, 2H), 7.82ꢀ7.81 (m, 1H), 7.68ꢀ7.65 (m, 1H),
7.59ꢀ7.55 (m, 3H), 7.49 (t, J = 8.0 Hz, 1H), 7.11 (ddd, J = 8.3, 2.6, 0.8 Hz, 1H), 3.93 (s, 3H); 13C NMR
(100 MHz, Chloroformꢀd) δ 162.6, 160.6, 154.9, 146.7, 134.7 , 134.7, 131.8, 130.5, 129.1, 128.3, 118.9,
117.4, 111.6, 55.6; IR(KBr): ṽ = 3065, 2923, 2852, 1604, 1582, 1494, 1457, 1405, 1328, 1253, 1205,1085,
1047, 891, 780, 687 cmꢀ1; HRMS (EIꢀTOF): calcd for, C16H13N3O [M]+, 263.1059; found, 263.1058.
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6-(3-bromophenyl)-3-phenyl-1,2,4-triazine (4ha): yellow solid, 24 mg, 38% yield, mp: 123ꢀ125 °C; H
NMR (400 MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.60ꢀ8.58 (m, 2H), 8.35 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.58ꢀ7.55 (m, 3H), 7.47 (t, J = 7.9 Hz, 1H); 13C NMR (100 MHz, Chloroformꢀd)
δ 162.9, 153.9, 146.5, 135.4, 134.5, 133.9, 132.0, 130.9, 129.8, 129.1, 128.4, 125.2, 123.7; IR(KBr): ṽ =
3064, 2954, 2923, 2852, 1949, 1634, 1564, 1446, 1407, 1319, 1089, 904, 788, 687 cmꢀ1; HRMS (EIꢀTOF):
calcd for, C15H10N3Br79 [M]+, 311.0058; found, 311.0060.
6-(2-methoxyphenyl)-3-phenyl-1,2,4-triazine (4ia): yellow solid, 26 mg, 49% yield, mp: 159ꢀ161 °C; 1H
NMR (400 MHz, Chloroformꢀd) δ 9.26 (s, 1H), 8.60ꢀ8.57 (m, 2H), 8.13 (dd, J = 7.7, 1.7 Hz, 1H),
7.58ꢀ7.55 (m, 3H), 7.51 (ddd, J = 8.4, 7.5, 1.8 Hz, 1H), 7.18 (td, J = 7.6, 0.9 Hz, 1H), 7.07 (d, J = 8.3 Hz,
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1H), 3.93 (s, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 161.6, 157.5, 155.1, 150.5, 135.1, 132.3, 131.6,
130.9, 128.9, 128.2, 122.8, 121.7, 111.5, 55.8; IR(KBr): ṽ = 3057, 3004, 2924, 2853, 1753, 1658, 1601,
1494, 1457, 1406, 1270, 1179, 1088, 1020, 743, 685 cmꢀ1; HRMS (EIꢀTOF): calcd for, C16H13N3O [M]+,
263.1059; found, 263.1060.
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6-(2-chlorophenyl)-3-phenyl-1,2,4-triazine (4ja): yellow solid, 24 mg, 45% yield, mp: 140ꢀ142 °C
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(literature: 89ꢀ90 °C)26; H NMR (400 MHz, Chloroformꢀd) δ 9.10 (s, 1H), 8.63ꢀ8.60 (m, 2H), 7.88ꢀ7.86
(m, 1H), 7.59ꢀ7.55 (m, 4H), 7.52ꢀ7.48 (m, 2H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.3, 155.9, 150.0,
134.6, 133.2, 132.6, 132.0, 131.9, 131.6, 130.5, 129.1, 128.5, 127.8; IR(KBr): ṽ = 3095, 3059, 2923, 2853,
1739, 1654, 1560, 1452, 1402, 1164, 1085, 1057, 1031, 765, 687 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C15H10N3Cl35 [M]+, 267.0563; found, 267.0568.
3-phenyl-6-(3,4,5-trimethoxyphenyl)-1,2,4-triazine (4ka): yellow solid, 29 mg, 45% yield, mp:
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129ꢀ131 °C; H NMR (400 MHz, Chloroformꢀd) δ 9.03 (s, 1H), 8.59ꢀ8.57 (m, 2H), 7.57ꢀ7.54 (m, 3H),
7.41 (s, 2H), 3.99 (s, 6H), 3.95 (s, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.3, 154.6, 154.1, 146.3,
140.8, 134.6, 131.8, 129.0, 128.5, 128.2, 103.9, 61.1, 56.5; IR(KBr): ṽ = 3051, 2992, 2926, 2852, 1654,
1589, 1507, 1458, 1399, 1350, 1132, 995, 882, 751, 690 cmꢀ1; HRMS (EIꢀTOF): calcd for, C18H17N3O3
[M]+, 323.1270; found, 323.1271.
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3-phenyl-6-(thiophen-3-yl)-1,2,4-triazine (4la): yellow solid, 15 mg, 31% yield, mp: 150ꢀ152 °C; H
NMR (400 MHz, Chloroformꢀd) δ 8.98 (s, 1H), 8.57ꢀ8.55 (m, 2H), 8.18ꢀ8.17 (m, 1H), 7.88 (d, J = 4.9 Hz,
1H), 7.57ꢀ7.55 (m, 4H); 13C NMR (100 MHz, Chloroformꢀd) δ 162.1, 151.8, 146.4, 135.7, 134.8, 131.7,
129.1, 128.2, 127.8, 125.8, 125.6; IR(KBr): ṽ = 3082, 2957, 2922, 2852, 1965, 1908, 1654, 1600, 1528,
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[M]+, 239.0517; found, 239.0518.
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3-(3-phenyl-1,2,4-triazin-6-yl)-1-(phenylsulfonyl)-1H-indole (4ma): yellow solid, 43 mg, 52% yield, mp:
241ꢀ243 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 9.04 (s, 1H), 8.58ꢀ8.53 (m, 3H), 8.30 (s, 1H), 8.07 (d, J
= 8.1 Hz, 1H), 7.98 (d, J = 7.7 Hz, 2H), 7.60ꢀ7.55 (m, 4H), 7.51ꢀ7.39 (m, 4H); 13C NMR (100 MHz,
Chloroformꢀd) δ 161.8, 152.2, 146.9, 137.8, 135.6, 134.8, 134.6, 131.8, 129.7, 129.0, 128.2, 127.7, 127.1,
126.1, 125.9, 124.7, 123.2, 116.8, 113.6; IR(KBr): ṽ = 3143, 3055, 2923, 2853, 1602, 1566, 1546, 1444,
1411, 1370, 1334, 1285, 1173, 1140, 1107, 1088, 1024, 999, 750, 686, 593 cmꢀ1; HRMS (EIꢀTOF): calcd
for, C23H16N4O2S [M]+, 412.0994; found, 412.0996.
General procedure for synthesis of 3,5,6-trisubstituted-1,2,4-triazines 5
To an ovenꢀdried Schlenk tube was added 0.28 mmol (1.4 equiv.) Nꢀsulfonylꢀ1,2,3ꢀtriazoles,
0.20 mmol (1.0 equiv.) Nꢀacylhydrazones and 0.01 mmol (5 mol%) Rh(II), successively. The
Schlenk tube was sealed with a Rubber plug and the atmosphere was replaced using standard
Schlenk techniques under nitrogen atmosphere. Then 1 mL dried solvent was added and the
reaction mixture was heated at 75 °C, with vigorous stirring, for 1ꢀ3 h. Once hydrazones
consumed, the reaction mixture was cooled to 30 °C and 20 mol % DBU or 100 mol% TEA
was added. About 12 h later, the intermediate was consumed, then DDQ 0.4 mmol (2.0 equiv.)
was added. The resulting solution was stirred for further 24 h. After reaction, solvent was
evaporated and the residue was purified by flash chromatography (petroleum ether/ ethyl
acetate = 10:1~5:1) to afford the desired product.
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Ethyl 5-benzoyl-3-phenyl-1,2,4-triazine-6-carboxylate (5aa): yellow solid, 31 mg, 46% yield, mp:
119ꢀ121 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.63 (d, J = 7.5 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.69
(t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.55 (q, J = 7.6 Hz, 4H), 4.43 (q, J = 7.1 Hz, 2H), 1.31 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.3, 163.6, 162.6, 157.1, 146.4, 134.8, 134.2, 133.4,
133.4, 130.1, 129.6, 129.3, 129.1, 63.4, 13.9; IR(KBr): ṽ = 3061, 2986, 2925, 2853, 1973, 1749, 1720,
1685, 1596, 1450, 1388, 1307, 1279, 1201, 1046, 968, 861, 779, 692 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C19H15N3O3 [M]+, 333.1113; found, 333.1112.
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Ethyl 5-benzoyl-3-(o-tolyl)-1,2,4-triazine-6-carboxylate (5ab): yellow solid, 38 mg, 55% yield, mp:
80ꢀ82 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.16 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.68 (t,
J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.47 (t, J = 7.1 Hz, 1H), 7.37 (t, J = 6.9 Hz, 2H), 4.44 (q, J = 7.1
Hz, 2H), 2.68 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.2, 166.4, 162.6,
156.5, 145.6, 139.7, 134.8, 134.2, 133.2, 132.3, 131.9, 131.9, 130.1, 129.1, 126.5, 63.4, 22.2, 13.9;
IR(KBr): ṽ = 3066, 2964, 2925, 2853, 1988, 1723, 1684, 1597, 1507, 1369,, 1289, 1211, 1109, 966, 877,
776, 710, 657 cmꢀ1; HRMS (EIꢀTOF): calcd for, C20H17N3O3 [M]+, 347.1270; found, 347.1271.
Ethyl 5-benzoyl-3-(2-fluorophenyl)-1,2,4-triazine-6-carboxylate (5ac): yellow solid, 33 mg, 47% yield,
mp: 106ꢀ108 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.28 (td, J = 7.7, 1.5 Hz, 1H), 7.93 (d, J = 7.4 Hz,
2H), 7.69 (t, J = 7.5 Hz, 1H), 7.62ꢀ7.52 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.29ꢀ7.24 (m, 1H), 4.44 (q, J =
7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 189.9, 162.9 (d, J = 5.7 Hz),
162.5, 162.0 (d, J = 260.7 Hz), 156.5, 146.4, 134.9, 134.4 (d, J = 8.8 Hz), 134.1, 132.4, 130.7, 130.2, 129.1,
129.0, 124.7 (d, J = 3.9 Hz), 122.4 (d, J = 9.1 Hz), 117.5 (d, J = 21.8 Hz), 63.4, 13.9; IR(KBr): ṽ = 3068,
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2980, 2924, 2853, 1986, 1725, 1679, 1611, 1498, 1452, 1385, 1286, 1208, 1110, 1065, 967, 772, 713, 652
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cmꢀ1; HRMS (EIꢀTOF): calcd for, C19H14N3O3F [M]+, 351.1019; found, 351.1018.
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Ethyl 5-benzoyl-3-(m-tolyl)-1,2,4-triazine-6-carboxylate (5ad): yellow solid, 26 mg, 37% yield, mp:
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95ꢀ97 °C; H NMR (400 MHz, Chloroformꢀd) δ 8.43ꢀ8.41 (m, 2H), 7.89 (d, J = 7.6 Hz, 2H), 7.69 (t, J =
7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.47ꢀ7.43 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.3, 163.7, 162.6, 157.1, 146.2, 139.1, 134.8, 134.3,
134.2, 133.3, 130.1, 130.0, 129.2, 129.1, 126.8, 63.3, 21.6, 13.9; IR(KBr): ṽ = 3066, 2995, 2924, 2854,
1713, 1682, 1598, 1511, 1450, 1378, 1287, 1218, 1122, 1035, 971, 798, 709, 645 cmꢀ1; HRMS (EIꢀTOF):
calcd for, C20H17N3O3 [M]+, 347.1270; found, 347.1271.
Ethyl 5-benzoyl-3-(3-(trifluoromethyl)phenyl)-1,2,4-triazine-6-carboxylate (5ae): yellow solid, 13 mg,
17% yield, mp: 104ꢀ106 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.88 (s, 1H), 8.83 (d, J = 7.9 Hz, 1H),
7.88 (d, J = 7.8 Hz, 3H), 7.71 (t, J = 7.9 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.31 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.0, 162.5, 162.4, 157.3, 146.9, 134.9, 134.2,
134.1, 132.6, 131.9 (q, J = 33.0 Hz), 130.1, 129.9, 129.7 (q, J = 3.5 Hz), 129.2, 126.3 (q, J = 3.9 Hz), 123.8
(d, J = 272.7 Hz), 63.5, 13.9; IR(KBr): ṽ = 3085, 2982, 2920, 2850, 1723, 1686, 1597, 1511, 1450, 1394,
1272, 1173, 1123, 971, 818, 697, 645 cmꢀ1; HRMS (EIꢀTOF): calcd for, C20H14N3O3F3 [M]+, 401.0987;
found, 401.0984.
Ethyl 5-benzoyl-3-(p-tolyl)-1,2,4-triazine-6-carboxylate (5af): yellow solid, 29 mg, 42% yield, mp:
130ꢀ132 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.51 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 7.9 Hz,2H), 7.68 (t,
J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H),
1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.4, 163.6, 162.7, 157.1, 146.1, 144.3,
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134.7, 134.3, 130.7, 130.1, 130.1, 129.6, 129.9, 63.2, 21.9, 13.9; IR(KBr): ṽ = 3067. 2992, 2924, 2855,
1981, 1720, 1677, 1608, 1502, 1449, 1371, 1288, 1208, 1178, 1045, 963, 814, 725, 653 cmꢀ1; HRMS
(EIꢀTOF): calcd for, C20H17N3O3 [M]+, 347.1270; found, 347.1272.
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Ethyl 5-benzoyl-3-(4-fluorophenyl)-1,2,4-triazine-6-carboxylate (5ag): yellow solid, 28 mg, 40% yield,
mp: 170ꢀ172 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.67ꢀ8.63 (m, 2H), 7.88 (d, J = 7.5 Hz, 2H), 7.69 (t,
J = 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.27ꢀ7.21 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.2, 166.2 (d, J = 255.3 Hz), 162.7, 162.5, 157.2, 146.2,
134.8, 134.2, 131.9 (d, J = 9.2 Hz), 130.1, 129.6 (d, J = 3.0 Hz), 129.1, 116.5 (d, J = 22.0 Hz), 63.4, 13.9;
IR(KBr): ṽ = 3069, 2924, 2853, 1721, 1675, 1598, 1509, 1375, 1285, 1208, 1154, 1110, 1046, 965, 877,
788, 652 cmꢀ1; HRMS (EIꢀTOF): calcd for, C19H14N3O3F [M]+, 351.1019; found, 351.1020.
Ethyl 5-(4-bromobenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ba): yellow solid, 33 mg, 40% yield,
mp: 144ꢀ146 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.62ꢀ8.59 (m, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.68 (d,
J = 8.5 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 189.3, 163.5, 162.6, 156.5, 146.4, 133.4, 133.2, 133.0,
132.5, 131.4, 130.4, 129.5, 129.3, 63.4, 14.0; IR(KBr): ṽ = 3096, 2989, 2936, 2867, 1720, 1682, 1584,
1507, 1375, 1285, 1211, 1126, 1070, 967, 879, 779, 703, 672 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C19H14N3O3Br79 [M]+, 411.0219; found, 411.0218.
Ethyl 5-(4-chlorobenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ca): yellow solid, 28 mg, 38% yield,
mp: 148ꢀ151 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.61 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H),
7.63 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.35 (t,
J = 7.1 Hz, 1H); 13C NMR (100 MHz, Chloroformꢀd) δ 189.1, 163.6, 162.7, 156.6, 146.5, 141.5, 133.4,
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133.3, 132.6, 131.4, 129.5, 129.5, 129.3, 63.4, 14.0; IR(KBr): ṽ = 3096, 2968, 2923, 2852, 1720, 1683,
1586, 1508, 1377, 1284, 1211, 1115, 1089, 1044, 967, 779, 703, 672 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C19H14N3O3Cl35 [M]+, 367.0724; found, 367.0726.
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Ethyl 5-(4-fluorobenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5da): yellow solid, 31 mg, 44% yield,
mp: 137ꢀ139 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.63ꢀ8.60 (m, 2H), 7.96ꢀ7.92 (m, 2H), 7.65ꢀ7.61 (m,
1H), 7.56 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 8.6 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, Chloroformꢀd) δ 188.8, 166.8 (d, J = 258.4 Hz), 163.5, 162.7, 156.7, 146.5, 133.4, 133.3,
132.9 (d, J = 9.7 Hz), 130.8 (d, J = 2.9 Hz), 129.5, 129.3, 116.5 (d, J = 22.3 Hz), 63.4, 14.0; IR(KBr): ṽ =
3074, 2985, 2929, 1921, 1721, 1680, 1596, 1507, 1373, 1285, 1242, 1211, 1160, 971, 837, 691, 608 cmꢀ1;
HRMS (EIꢀTOF): calcd for, C19H14N3O3F [M]+, 351.1019; found, 351.1021.
Ethyl 5-(4-methylbenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ea): yellow solid, 28 mg, 39% yield,
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mp: 158ꢀ160 °C; H NMR (400 MHz, Chloroformꢀd) δ 8.62ꢀ8.61 (m, 1H), 7.78 (d, J = 7.2 Hz, 1H),
7.61ꢀ7.60 (m, 1H), 7.56ꢀ7.55 (m, 1H), 7.33 (d, J = 7.0 Hz, 1H), 4.46ꢀ4.39 (m, 1H), 2.46 (s, 1H), 1.33ꢀ1.29
(m, 1H); 13C NMR (100 MHz, Chloroformꢀd) δ 189.9, 163.5, 162.6, 157.2, 146.5, 146.1, 133.4, 133.3,
131.8, 130.2, 129.8, 129.5, 129.2, 63.3, 22.1, 13.9; IR(KBr): ṽ = 3064, 2973, 2924, 1723, 1677, 1603, 1505,
1376, 1286, 1211, 1123, 1045, 966, 879, 773, 692 cmꢀ1; HRMS (EIꢀTOF): calcd for, C20H17N3O3 [M]+,
347.1270; found, 347.1271.
Ethyl 5-(4-methoxybenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5fa): yellow solid, 33 mg, 45%
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yield, mp: 165ꢀ167 °C; H NMR (400 MHz, Chloroformꢀd) δ 8.63ꢀ8.61 (m, 2H), 7.89ꢀ7.86 (m, 2H),
7.64ꢀ7.60 (m, 1H), 7.57ꢀ7.53 (m, 2H), 7.02ꢀ6.98 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.32 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 188.9, 164.9, 163.5, 162.7, 157.2, 146.7, 133.5, 133.2,
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132.6, 129.5, 129.3, 127.4, 114.5, 63.2, 55.8, 13.9; IR(KBr): ṽ = 3082, 2987, 2932, 2836, 1724, 1671, 1598,
1511, 1454, 1387, 1323, 1269, 1173, 1125, 1023, 968, 856, 777, 694, 610 cmꢀ1; HRMS (EIꢀTOF): calcd for,
C20H17N3O4 [M]+, 363.1219; found, 363.1218.
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Ethyl 5-(3-methoxybenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ga): yellow solid, 35 mg, 48%
yield, mp: 128ꢀ130 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.63ꢀ8.61 (m, 2H), 7.62 (t, J = 7.3 Hz, 1H),
7.57ꢀ7.54 (m, 3H), 7.40 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.22 (dd, J = 8.2, 2.0 Hz, 1H), 4.44 (q,
J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 190.1, 163.6,
162.6, 160.2, 157.1, 146.3, 135.5, 133.4, 133.3, 130.1, 129.5, 129.3, 123.4, 121.6, 113.3, 63.3, 55.7, 13.9;
IR(KBr): ṽ = 3070, 2989, 2958, 2922, 1720, 1683, 1596, 1512, 1466, 1385, 1285, 1194, 1109, 998, 767,
692 cmꢀ1; HRMS (EIꢀTOF): calcd for, C20H17N3O4 [M]+, 363.1219; found, 363.1221.
Ethyl 5-(3-bromobenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ha): yellow solid, 25 mg, 30% yield,
mp: 123ꢀ125 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.62 (d, J = 7.4 Hz, 2H), 8.06 (s, 1H), 7.81 (d, J =
7.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.9 Hz,
1H), 4.46 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 188.9, 163.6,
162.6, 156.5, 146.3, 137.6, 135.9, 133.5, 133.2, 132.7, 130.6, 129.6, 129.3, 128.7, 123.5, 63.5, 14.0;
IR(KBr): ṽ = 3068, 2924, 2853, 1970, 1716, 1684, 1567, 1509, 1425, 1373, 1309, 1286, 1207, 1123, 1045,
782, 723, 670 cmꢀ1; HRMS (EIꢀTOF): calcd for, C19H14N3O3Br79 [M]+, 411.0219; found, 411.0214.
Ethyl 5-(2-methoxybenzoyl)-3-phenyl-1,2,4-triazine-6-carboxylate (5ia): yellow solid, 25 mg, 34%
yield, mp: 159ꢀ161 °C; 1H NMR (400 MHz, Chloroformꢀd) δ 8.62ꢀ8.60 (m, 2H), 8.23 (dd, J = 7.8, 1.7 Hz,
1H), 7.65ꢀ7.57 (m, 2H), 7.55ꢀ7.51 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.42 (q, J =
7.1 Hz, 1H), 3.45 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformꢀd) δ 188.8, 163.7,
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