Direct access to 1,4-disubstituted 1,2,3-triazoles through organocatalytic 1,3-dipolar cycloaddition reaction of α,β-unsaturated esters with azides

Article abstract of DOI:10.1039/c5ra19038j

DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition reactions of α,β-unsaturated esters with azides have been developed. This strategy generates 1,4-disubstituted 1,2,3-triazoles in high yields with high regioselectivities. It is demonstrated that some of these products can be transformed into important pharmaceutical agents.

Full text of DOI:10.1039/c5ra19038j

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DOI: 10.1039/C5RA19038J
Wenjun Li, Yepeng
Luan, Jian Wang
O
N
N
N
DBU (10 mol%)
CHCl3, 80oC, 24h
N3
R2
OR1
+
R2
O
CO2R1
3
1
2
18 examples, 82-94% yield
Direct Access to
1,4-Disubstituted
1,2,3-Triazole
through
DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition reactions of α, β-unsaturated esters with
azides have been developed. This strategy could generate 1,4-disubstituted 1,2,3-triazoles in high
yields and high level of regioselectivities. It is demonstrated that some of these products can be
transformed into pharmaceutical important agents.
Organocatalytic
1,3-Dipolar
Cycloaddition
Reaction of α,
β-Unsaturated Ester
with Azide

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ARTICLE TYPE www.rsc.org/xxxxxx | XXXXXXXX
Direct Access to 1,4-Disubstituted 1,2,3-Triazole through OrganocatalVyietwiAcrticle Online
1,3-Dipolar Cycloaddition Reaction of α, β-Unsaturated Ester witDhOI: 1A0.1z03i9d/Ce5RA19038J
Wenjun Li,*a Xiao Zhou,a Yepeng Luana and Jian Wang*b
Received (in XXX, XXX) 1st January 200X, Accepted 1st January 200X
First published on the web 1st January 200X
DOI: 10.1039/b000000x
5
DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition
reactions of α, β-unsaturated esters with azides have been
developed. This strategy could generate 1,4-disubstituted 1,2,3-
triazoles in high yields and high level of regioselectivities. It is
demonstrated that some of these products can be transformed
10 into pharmaceutical important agents.
The 1,2,3-triazole core is a privileged scaffold that is featured in a
abundant number of bioactive molecules and they have exhibited
considerably biological activities.1 As showed in Fig 1,
Tazobactam has been identified as -lactum antibiotic
15 tazobactum.2 Cefatrizine could exhibit antibacterial activity.3
Rufinamide is an anticonvulsant drug developed in 2004 by
Novartis pharmaceutical company.4 It is normally used to treat
Lennox-Gastaut syndrome and other disorders. 1,2,3-Triazole
moieties can also behave as an antimicrobial agent.5
20
The widely used protocol to synthesize 1,2,3-triazole is the
Huisgen 1,3-dipolar cycloaddition.6 However, this method
requires high temperatures and proceed with limited
regioselectivity. In recent years, chemists have developed metal-
catalyzed (copper,7 ruthenium,8 iridium9) azide–terminal alkyne
25 cycloaddition (AAC). Although this strategy could provide a mild
and efficient synthesis of 1,4-disubstituted 1,2,3-triazoles, the
metal ions are potentially toxic for living organisms and could
induce degradation of viruses.10 In recent years, Ramachary,11
Bressy12 and our group13 independently reported the
30 organocatalytic regioselective synthesis of 1,4,5-trisubstituted
1,2,3-triazoles through in situ enamine intermediate. This
methodology provides a novel pathway to generate 1,2,3-triazoles
in high yields and regioselectivities. However, these approaches
are restricted to ketone or cyclic enone substrates and can only
35 produce 1,4,5-trisubstituted 1,2,3-triazoles. Inspired by the
Fig 2: Exploration of 1,4-Disubstituted 1,2,3-Triazoles.
40 success of the 1,4,5-trisubstituted 1,2,3-triazole synthesis,14 our
efforts are moved to another highly important class of 1,4-
disubstituted 1,2,3-triazoles. As exemplified in Figure 1,
rufinamide and antimicrobial agent have been identified as very
important pharmaceuticals. In the beginning, we speculate that
45 the reaction of ethyl acrylate 1c with azide 2a would give the 1,4-
disubstituted 1,2,3-triazole 3ca under standard conditions.
Surprisingly, the product arising from this reaction was
undesirable pyrazoline 4 (Fig 2). In this transformation (Fig 2),
the postulated mechanism suggested that the cycloaddition
50 intermediate A of acrylate 1c and azide 2a would undergo an
arrangement to generate the diazoester intermediate C,15 which
further react with second acrylate 1c to finally form undesirable
pyrazoline 4. In order to achieve the triazole structure, we behave
to circumvent the ring opening step to avoid the conversion
55 between B and C. After being confronted with this challenge, a
thermodynamic control strategy has been taken to solve above
problem. As indicated in Figure 2 (this design), we can bear a
suitable leaving group (LG) on C5 position, which probably
stimulates the competitive elimination reaction to eventually
60 induce the reaction to directly construct the desire product 1,4-
Fig 1: Examples of important 1,2,3-triazoles.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

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disubstituted 1,2,3-triazoles driven by the force of electron 30 Table 2: Synthesis of 1,4-Disubstituted 1,2,3-Triazoles.a
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delocalization and aromaticity.
DOI: 10.1039/C5RA19038J
O
N
N
N3
Cat.V (10 mol%)
CHCl3, 80oC, 24h
R2
N
We began our initial investigation by employing active α, β-
unsaturated esters 1a and phenyl azide 2a in the precence of
various amine or phosphine catalysts. The screening results
indicated that tertiary amine V was the best catalyst for this
reaction (Table 1, entry 5). Other amine catalysts (I-IV, VI-VIII)
can also give the desired product but the yields were not very
high (Table 1, entries 1-4, 6-8). While if we utilized
OR1
+
R2
CO2R1
O
1
2
3
5
N
N
N
N
N
N
N
N
N
Ph
CO2Me
CO2Me
Cl
F
CO2Me
3aa, 90% yield
3ac, 91% yield
3ab, 87% yield
N
N
N
N
N
N
N
N
N
CO2Me
Br
CO2Me PhO
CO2Me
MeO
10 triphenylphosphine IX as the catalyst, no desired product was
obtained (Table 1, entry 9). After identifying the catalyst V as
the best catalyst, we next further screened the reaction mediums
to improve yield. Further experimental results revealed that the
solvent was one of the crucial factors for this reaction. The
15 efficency of reaction exhibited great difference between different
solvents. For instance, when we conducted the reaction in DMF
or DMA, the solvent gave the positive influence on the reaction
and the yields of desired product 3aa were improved to 61% and
63% (Table 1, entries 10-11). However, when we changed the
20 solvents as methanol, toluene and CH3CN, only moderate yields
(42%, 53% and 56%) were observed (Table 1, entries 12-14). To
our delight, when we utilized THF as the reaction medium, the
yield would increase to 89% remarkably (Table 1, entry 15).
Further experiment revealed that CHCl3 was the best solvent for
3ad, 93% yield
3ae, 89% yield
3af, 92% yield
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
n-C7H15
Cl
F
3ag, 88% yield
3ah, 85% yield
3ai, 94% yield
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
F
Cl
Br
3aj, 91% yield
3ak, 82% yield
3al, 91% yield
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
Cl
CO2Me
N
Cl
3am, 87% yield
3ao, 88% yield
3an, 85% yield
N
N
N
N
N
N
Ph
Ph
N
N
N
Ph
CO2Me
CO2Et
3ap, 87% yieldb
3aq, 85% yieldb
3ba 92% yield
25 Table 1: Optimization of the Reaction Conditions.a
a Reaction conditions: A mixture of 1 (0.10 mmol), 2 (0.20 mmol) and V
(10 mol%) in CHCl3 (0.3 mL) was stirred at 80 oC for 24h. b neat, 80 oC,
48 h.
35 this transformation. When we conducted the reaction using
CHCl3 as the solvent, the excellent yield (93%) was observed
(Table 1, entry 16). Further extensive screening of temperature
indicated that decreased T oC led to a slow conversion (entry 17,
o
50 C, 53%, 48 h). It is worth to note that lowering the catalyst
40 loading to 10 mol% resulted in a longer reaction time (24h) with
the yield of product 3aa maintained (Table 1, entry 18). Further
reducing the catalyst loading to 5 mol% would reduce the
decrease of yield to 82% after 48h (Table 1, entry 19). Finally,
optimization of reaction parameters led us to identify DBU as a
45 superb catalyst and CHCl3 as an ideal medium for the desired
transformation to give adduct 3aa in essentially high yield.
Moreover, adduct 3aa could be obtained in absolute
regioselectivity, which may be contributed to the energy
coincidence of frontier molecular orbital between α, β-
50 unsaturated esters 1a and phenyl azide 2a.
With the optimized conditions in hand, the generality of
substrate scope of 1,4-disubstituted 1,2,3-triazole synthesis was
explored. As shown in table 2, a diverse set of azides involves in
the transformation to produce the 1,4-disubstituted 1,2,3-triazoles
55 in high to excellent yields. After obtaining the product 3aa in
90% yield, various aryl azides, regardless of electron-donating
groups or electron-withdrawing groups in o, m, p-position, all led
to the desire products 3aa–am (Table 2, 82–94%). To our delight,
aryl azides, which contained naphthalene ring and heterocyclic
60 rings, could be also general for this transformation to afford the
desired products 3an and 3ao in 85% and 88% yields respectively.
It is worth to note that alkyl azides also afforded expected
Entry
1
2
3
4
5
6
7
8
Cat.
I
II
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
t/h
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
48
24
48
Yieldb(%)
38
41
45
37
54
21
31
28
<5
61
63
42
53
56
89
93
53
90
III
IV
V
VI
VII
VIII
IX
V
V
V
V
V
9
10
11
12
13
14
15
16
17c
18d
19e
DMA
MeOH
Toluene
CH3CN
THF
CHCl3
CHCl3
CHCl3
CHCl3
V
V
V
V
V
82
a Reaction conditions: A mixture of 1a (0.10 mmol), 2a (0.20 mmol) and
catalyst (20 mol%) in the solvent (0.3 mL) was stirred at 80 OC for 18h. b
Isolated yield. The reaction was conducted at 50 C. d 10 mol% catalyst
c
o
used. e 5 mol% catalyst used.
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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Page 4 of 5
adducts in high chemical yields, but under neat condition (3ap 30 1a to form zwitterion D. Next addition of zwitterion intermediate
View Article Online
DOI: 10.1039/C5RA19038J
and 3aq, 87% and 85%, respectively). The configuration of the
products was assigned based on single-crystal X-ray analysis of
3ad.16
To further demonstrate the utility of this methodology, we have
performed a late-stage modification on several triazole analogues.
As shown in scheme 1, isonicotinoyl hydrazide 6 exhibited
antimycobacterial activity against mycobacterium tuberculosis
H37Rv Strain.17 DIBAL-H reduction of 3aa followed with an
D to phenyl azide 2a forms intermediate E. Elimination of E
allows to produce intermediate F, which undergoes a cascade
sequence of electrocyclization and subsequent elimination to
finally generate the cycloaddition product 3aa.
In summary, a DBU-catalyzed organocatalytic 1,3-dipolar
cycloaddition of active α, β-unsaturated ester to azide has been
5
35
developed.
This
methodology
provides
a
straight-
forward pathway to generate 1,4-disubstituted 1,2,3-triazoles,
which exhibit considerably biological activities, in high yields
10 efficient PCC oxidation to yield the key intermediate aldehyde 5
(85% overall yield, 2 steps). Then aldehyde 5 reacted with 40 and regioselectivities. Compared with the metal-based catalytic
isonicotinohydrazide (INH) at room temperature for 3 h to yield
the desired isonicotinoyl hydrazide 6 in 82% yield.
AAC systems, this methodology makes an important
complementary. Notably, the reaction proceeds efficiently by a
simple and cheap catalyst. Considering the ready availability of
the starting materials (α, β-unsaturated esters) and the operational
45 simplicity, we believe that this work will draw more research
interests in organocatalytic synthesis of substituted 1,2,3-triazoles
and other biologically active heterocycles. Such studies are
actively under way in our laboratory, and more results will be
reported in due course.
15
Scheme 1. Synthesis of Isonicotinoyl Hydrazide 6.
50 Notes and references
a
School of Pharmacy, Qingdao University, Qingdao, 266021, E-mail:
liwenjun324@163.com
b Department of Chemistry, National University of Singapore, Block S15,
Level 5,
3
Science Drive 3, Singapore 117543, E-mail:
55 wangjian1999@hotmail.com
General procedure for 1,3-dipolar cycloaddtions of α,β-unsaturated esters
with azides: To a solution of CHCl3 (0.3 mL) were added α,β-unsaturated
esters 1 (0.10 mmol), azides 2 (0.20 mmol) and catalyst V (0.01 mmol).
The reaction mixture was stirred at 80 oC for 24h and then the solvent was
60 removed under vacuum. The residue was purified by silica gel
chromatography to yield the desired product 3.
Scheme 2. Synthesis of Rufinamide.
After accomplishing the above synthesis, we embarked on the
total synthesis of rufinamide, an anticonvulsant drug. The
Acknowledgment. We thank the financial support from Qingdao
University and National University of Singapore (Academic Research
Grant: R143000480112, R143000443112).
65 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/b000000x/
20 synthetic route to rufinamide started with the DBU–catalyzed
[3+2] reaction (Scheme 2). Azide 7 reacted with α, β-unsaturated
ester 1a to give triazole 8 in 85% yield (approximately 80oC and
72 h). Next, ammonolysis of triazole 8 gave the corresponding
rufinamide (89% yield, rt, 24 h).
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