NIS-catalyzed oxidative cyclization of alcohols with amidines: A simple and efficient transition-metal free method for the synthesis of 1,3,5-triazines

Article abstract of DOI:10.1039/c5ob01835h

An efficient method for the synthesis of 1,3,5-triazines by NIS-catalyzed oxidative cyclization of alcohols with amidines has been developed. The reaction works smoothly under transition-metal free and phosphine-free conditions to afford a wide range of 1,3,5-triazine derivatives in moderate to good yields. The synthetic methodology was achieved via in situ oxidation of alcohols to aldehydes.

Full text of DOI:10.1039/c5ob01835h

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NIS-Catalyzed Oxidative Cyclization of Alcohols with Amidines: A
Simple and Efficient, Transition-Metal Free Method for The
Synthesis of 1,3,5-triazines
eceived 00th January 20xx,
Accepted 00th January 20xx
Abhishek R. Tiwari, Akash T. and Bhalchandra M. Bhanage*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient method for the synthesis of 1,3,5-triazines by NIS- reaction of aryl methanols and amidines.11 However, this
catalyzed oxidative cyclization of alcohols with amidines has method requires costly ruthenium-phosphine complex as a
been developed. The reaction works smoothly under transition- catalyst which is difficult to prepare and needs a long reaction
metal free and phosphine-free conditions to afford a wide range time. In recent times, Zhang et al. reported another method for
of 1,3,5-triazine derivatives in moderate to good yields. The synthesis of 1,3,5-triazines via Cu(OAc)2-catalyzed aerobic
synthetic methodology was achieved via in situ oxidation of oxidative coupling of alcohols and amidines.12 But, this method
alcohol to aldehyde.
uses less environmentally benign Cu(OAc)2 as a catalyst, needs
a long reaction time and reflux condition. Considering the
1,3,5-triazine and its derivatives are a class of nitrogen- pharmaceutical importance of 1,3,5-triazines and limitations of
containing six-membered heterocyles that exhibit a wide range these reported methods, it is highly desirable to develop an
of
biological and medicinal applications such as economically and environmentally benign method under
antimalarial,1b agents,1c transition-metal free and mild reaction conditions. Very
antitumor
antimicrobial,1a
antituberculosis1d and inhibition of photosynthetic electron recently, we have shown the synthesis of 1,3,5-trianzes from
transport (PET) and binding.1e They are also used as chelating benzylamines and amidines under transition-metal free
ligands for the preparation of organometallic materials,2 condition.13 It will be interesting to report another alternate
transition-metal catalysts,3 liquid crystals,4 and fluorescent method for the synthesis of 1,3,5-triazines from benzylalcohols
brighteners.5 In spite of these important biological, medicinal and amidines under transition-metal free conditions at a lower
and catalytic functions, there are only a few known procedures reaction temperature.
for the synthesis of 1,3,5-triazines. Conventionally, they were
Recently, iodine has gained considerable attention as a non-
synthesized by transition metal-catalyzed coupling reaction of toxic, non-metallic, inexpensive, and easily available catalyst
halogenated 1,3,5-triazines,6 and the cyclotrimerization reaction for various organic transformations.14 However, to the best of
of nitriles.7 Nevertheless, the former method requires the our knowledge, there is no report on the oxidative cyclization
transition-metal palladium (Pd), less-environmentally benign of primary alcohols with amidines to 1,3,5-triazines in the
halogenated substrates, produces stoichiometric amounts of NIS/DMSO system under green conditions. In continuation of
undesirable waste, and the latter usually needs an excess of our ongoing work on transition-metal free approach in organic
amines as co-catalysts. Alternatively, these compounds were synthesis;13,15 herein, we report
a simple and efficient,
also obtained by cyclization of aromatic aldehydes with transition-metal free NIS-catalyzed oxidative cyclization of
amidines.8 However, the use of aldehydes have several alcohols with amidines. Noteworthily, the reaction proceeds
disadvantages such as aldehydes could undergo
a
without the need of oxygen at 100 oC for 16 h.
decarbonylation reaction under harsh conditions,9 oxidation of
active aldehyde groups leading to the formation of unwanted
by-products, hence requiring inert conditions.10 Recently, Xie
and co-workers, reported a new method for the synthesis of aryl
substituted 1,3,5-triazines based on ruthenium-catalyzed
Ru-Complex Catalyst
110 oC, Base, DMSO, 16 h
NH -HC
Previous work11,12
OH
R1
Cu(OAc)2 - H2O
R2
NH2
110 oC, Base, toluene (reflux)
air, 24 h
10 mol% NIS
This work
100 oC, Base. DMSO, 16 h
Scheme 1 Synthesis of 1,3,5-triazines from alcohols and amidines.
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Table 1Optimization of reaction conditionsa
results as they gave low yield of 3a (Table 1, entry 15). The use
of 1.0 mmol of Cs2CO3 proved to be essential. Decreasing the
amount of the base to 0.5 mmol led to a significant reduction in
the yield of 3a (Table 1, entry 16). However, only trace
amounts of 3a was formed when the reaction was carried out in
the absence of base (Table 1, entry 17). Addition of DMC led to
a decrease in the yield of 3a (table 1, entry 18). No formation of
product was obtained when the reaction was carried out in
DMF (table 1, entry 19). Thus, standard conditions are: NIS (10
mol%), Cs2CO3 (1.0 mmol) at 100 oC for 16 h.
Entry
Iodine-source
(mol%)
Solvent
Temp (oC)
/Time (h)
Yieldb
(%)
I2 (20 mol%)
I2 (20 mol%)
I2 (20 mol%)
I2 (20 mol%)
I2 (20 mol%)
I2 (20 mol%)
I2 (20 mol%)
I2 (15 mol%)
I2 (10 mol%)
I2 (5 mol%)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1
2
80/24
90/24
65
78
To check the substrate applicability of this protocol, a series
of substituted benzylalcohols (1) and amidines (2) were
3
100/24
110/24
100/20
100/16
100/14,12
100/16
100/16
100/16
100/16
100/16
100/16
100/16
100/16
100/16
100/16
85
investigated under the optimized reaction conditions and
corresponding results are shown in Table 2. All the substrates
examined, provided excellent to good yields (table 2, entries 1-
17). Firstly, the reactions of benzamidine hydrochloride (2a) in
combination with different substituted benzylalcohols were
examined. Electron donating groups such as –Me and –OMe
4
86
5
85
6
85
7
72,61
84
8
9
84
provided corresponding products 3ba, 3ca and 3da in very
10
11
12
13
14
15
16
17
66
good yields (table 2, entries 2-4). Strong electron-withdrawing
group (–NO2) containing benzylalcohols could be transformed
into the corresponding products efficiently (table 2, entries 5
and 6). The reactions with halo-substituted benzylalcohols such
as -Cl and -F proceeded smoothly affording the desired
products 3ga-3ia in good yields (table 2, entries 7-9). An
apparent substitution effect was also studied on amidine
NIS (10 mol%)
TBAI (10 mol%)
I2O5 (10 mol%)
KI (10 mol%)
NIS (10 mol%)
NIS (10 mol%)
NIS (10 mol%)
NIS (10 mol%)
88
-
-
81
41,c65d
60e
tracef
hydrochlorides. The reaction of 1a
methylbenzamidine hydrochloride (2b), afforded 1,3,5-triazines
3ab 3db and 3gb) in moderate to good yields (table 2, entries
10-12), while the reaction of 1d with -bromobenzamdine
, 1d and 1g favoured with p-
DMSO :
DMC (1:1)
DMF
18
19
100/16
100/16
36
-
NIS (10 mol%)
(
,
a Reaction conditions: benzyl alcohol (1a, 0.5 mmol), benzamidine hydrochloride (2a,
p
1.0 mmol), Cs2CO3, (1.0 mmol), solvent (2 mL). b GC Yields. c Use of Na2CO3 instead of
hydrochloride (2c) furnished moderate yield of 3dc (table 2,
entry 13). Further, heteroaryl primary alcohols such as pyridin-
2-ylmethanol (1j), pyridin-3-ylmethanol (1k), furfuryl alcohol
Cs2CO3. d Use of K2CO3 instead of Cs2CO3. e 0.5 mmol Cs2CO3. Reaction was carried
f
out in the absence of base.
(
1l) and (5-methylfuran-2-yl)methanol (1m) proceeded well
We initiated our study by choosing benzylalcohol (1a) and
benzamidine hydrochloride (2a) as model substrates for the
optimization of reaction conditions, which include solvent,
iodine source, Cs2CO3, temperature and time. As per our
under optimized reaction conditions (table 2, entries 14-17).
Furthermore, the reaction between cinnamyl alcohol (1m) and
benzamidine hydrochloride (2a) was investigated. Interestingly,
it did not give the expected 1,3,5-triazine product, instead an
unexpected intra-molecular cyclized product
obtained in a very good yield.
expectation, the reaction of benzylalcohol
(
1a)
and
(4na) was
benzamidine hydrochloride (2a) with I2 (20 mol%) afforded the
desired product 1,3,5-triazine (3a) in 65% yield at 80 oC in
DMSO for 24 h (table 1, entry 1). To our delight, increase in
the reaction temperature led to a significant increase in the yield
o
of desired product 3a providing 78% and 85% yields at 90 C
and 100 oC respectively (table 1, entries 2 and 3). Further
increase in temperature didn’t have significant effect on the
yield of 3a (table 1, entry 4). Next, reaction time studies
revealed that the reaction time could be reduced from 24 to 16 h
giving 84% yield of 3a (table 1, entries 5-7). The dosages of I2
were also studied and it was found that 10 mol% I2 gave the
highest yield of 84% (table 1, entries 8-10). Also, various
iodine-containing non-metal sources such as NIS, TBAI, I2O5,
KI and TBAI were tested (table 1, entries 11-14). Only NIS and
KI were found to be active for this reaction. Relatively, NIS
provided better yield than I2 (table 1, entry 11). In the next set
of experiments, various inorganic bases such as Na2CO3 and
K2CO3 were screened, unfortunately they did not show better
Scheme 2 Intra-molecular cyclization of cinnamyl alcohol (1n) and benzamidine
hydrochloride (2a)
Recently, Wei and co-workers have shown that DMSO
could convert HI to I2.14h Keeping this in mind, a plausible
reaction mechanism has been illustrated in Scheme 3. The
reaction is believed to take place via in situ oxidation of benzyl
alcohols to corresponding aldehyde (A) in the presence of
iodine source (Scheme 3a). In the meantime, the amidine 2’ is
neutralized by base from its hydrochloride salt 2. Then, the in
situ generated aldehyde (A) reacts with amidine 2’ to form an
imine intermediate azadiene B (Scheme 3c). Consequentially,
another molecule of amidine 2’ reacts with B to give C. Finally,
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Table 2 NIS-catalyzed oxidative cyclization of benzyl alcohols with benzamidine
hydrochlorides under optimized reaction conditionsa
Entry
1
R1
H
R2
H
Product (3)
Yieldb (%)
88
3aa
2
3
p-Me
o-Me
H
H
H
3ba
3ca
3da
3ea
3fa
88
41
90
63
74
81
83
77
71
76
70
66
4
p-OMe
Scheme 3 A plausible reaction mechanism
5
p
-NO2
H
the desired product 3 is formed via dehydrogenative aromatization of
C, which is promoted by DMSO. This illustrated mechanism is
similar to previous reports.11,12
6
m
-NO2
H
Conclusions
7
p
-Cl
H
3ga
3ha
3ia
In summary, a transition metal-free method for the synthesis of
1,3,5-triazines from benzyl alcohols and amidines has been
developed. The developed methodology is requires only
catalytic amount of NIS at lower reaction temperature. Various
1,3,5-triazine derivatives were synthesized in moderate to good
yields.
8
m
-Cl
H
9
p
-F
H
10
11
12
13
H
p
p
p
-Me
-Me
-Me
3ab
3db
3gb
3dc
Acknowledgement
p
p
-OMe
The author (Abhishek R. Tiwari) is greatly thankful to the UGC
(University Grant Commissions), New Delhi, India for
providing a Basic Science Research (BSR) fellowship.
p
-Cl
-OMe
p
-Br
H
Notes and references
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