Reactions of α-haloacroleins with azides: Highly regioselective synthesis of formyl triazoles

Article abstract of DOI:10.1039/c9gc01129c

A general metal-free route to 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles was developed. α-Haloacroleins reacted with organic azides in a DMSO/H₂O mixture solvent at room temperature to produce 1,4-disubstituted triazoles (up to 99%) with exclusive regioselectivities. This protocol is convenient and scalable with a broad substrate scope including aliphatic and aromatic azides. The resulting triazoles exhibited an aldehyde group at the C4 position and demonstrated synthetic utilizations. One 1,2,3-triazole compound containing diastereotopic protons was also identified.

Full text of DOI:10.1039/c9gc01129c

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DOI: 10.1039/C9GC01129C
ARTICLE
Reactions of -Haloacroleins with Azides: Highly Regioselective
Synthesis of Formyl Triazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Dongsheng Zhang, Yingzhu Fan, Zhongliang Yan, Yi Nie, Xingquan Xiong, and Lizhu Gao*
DOI: 10.1039/x0xx00000x
A general metal-free route to 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles was developed. -Haloacroleins
reacted with organic azides in DMSO/H2O mixture solvent at room temperature to produce 1,4-disubstituted triazoles (up
to 99%) with exclusive regioselectivities. This protocol is convenient and scalable with a broad substrate scope including
aliphatic and aromatic azides. The resulting triazoles exhibited an aldehyde group at the C4 position and demonstrated
synthetic utilizations. One 1,2,3-triazole compound containing diastereotopic protons was also identified.
esters and reaction produced 1,4,5-trisubstitued triazoles well
(Scheme 1bI).9c While -methoxyl--unsaturated esters were
used, products were 1,4-disubstituted triazole (Scheme 1bII).9d
Introduction
1,2,3-Triazoles are nitrogen heteroarenes with numerous
applications in medicinal chemistry1 and material science.2
They serve as key synthetic intermediates for various
important transformations in organic synthesis.3 Over the past
few decades, practical and efficient procedures to prepare
highly functionalized 1,2,3-triazoles have attracted enormous
interest. Within the context of triazole assembly,
regioselectivity control has received considerable attention in
organic chemistry. Transition metals, especially copper
catalyzed azide−alkyne cycloaddition (CuAAC), work well and
have been studied extensively.4 However, owing to substrate
limitations and the potential toxicity of transition metals in
chemical biology,5 metal-free synthetic methodologies for
1,2,3-triazoles continue to expand.6
In 2017, they again generated impressive NHC-catalyzed cross-
coupling reactions from -substituted acroleins with alkyl and
aryl azides, producing triazoles with high regioselectivities
(Scheme 1c).9e However, both catalytic system required an
elevated reaction temperature. Given that 1,2,3-triazoles have
already exhibited numerous important applications (especially
in biochemical research), a non-catalyzed protocol variant that
is scalable with a broad substrate scope and even compatible
with aqueous and ambient conditions is highly desirable.
a) Ramachary's work
R1
N
R2
O
DBU, RT
+
Ar N3
R1
N
DMSO, 30 min
Ar
N
R2
Developed methods include strain-promoted azide–olefin
cycloaddition,7
I) R1 = H, R2 = alkyl, aryl
II) R1 = H, R2 = aryl
Ramachary−Bressy−Wang
cycloaddition,8
enolate-mediated azide-alkyne cycloaddition,9 azide-free
reaction10, and other reactions.11 Although several metal-free
variants have been reported, general approaches towards 1,4-
disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles remain
rare. To date, three relevant synthetic procedures have been
reported. In 2014, Ramachary et al. presented an elegant
synthesis of 1,4-disubstituted triazoles from enolizable
aldehydes in high yields (Scheme 1aI).9a Later, they extended
this methodology to trisubstituted triazoles starting with
enolizable ketones (Scheme 1aII).9b Nevertheless, the azides
were limited to aryl in both cases, and the R2 group was
limited to aryl in the latter case. Meanwhile, Wang et al.
developed an DBU catalyzed protocol with -unsaturated
b) Wang's work
O
R4
N
COOR2
DBU
CHCl3, 80 oC
R3-N3
R1
OR2
+
N
R3
N
I) R1 = OMe, R1 = R4
/
II) R1 = OMe, R4 = H
R1
c) Wang's work
CHO
CO2R3
NHC
R3OH
R2 N3
+
N
N
R1
R2
N
THF, Cs2CO3, DQ
80 oC, 24 h
R1 = H, alkyl, aryl
d) This work
R1
N
CHO
Br
CHO
RT
R2 N3
+
N
R2
College of Materials Science & Engineering, Huaqiao University, Xiamen, 361021,
China. E-mail: lizhugao@hqu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data, and crystallographic data (CIF). CCDC 1864100. For ESI and
R1
N
R1 = H, alkyl, aryl R2 = alkyl, aryl
Scheme 1 Metal-free routes to 1,4-disubstitued and 1,4,5-trisubstituted 1,2,3-triazoles.
crystallographic
data
in
CIF
or
other
electronic
format
see
DOI: 10.1039/x0xx00000x
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Page 2 of 6
ARTICLE
1,3-Dipolar cycloaddition between an azide and alkene
Journal Name
Table 1 Optimization reaction of -haloacroleins with organic azidesa
View Article Online
DOI: 10.1039/C9GC01129C
with subsequent elimination reaction represents a route to
1,2,3-triazole; however, this method remains largely
undeveloped due to the weak reactivity of alkene.12 Only a few
non-metal-catalyzed regioselective examples have been
reported.13 In addition, formyl triazoles are highly valuable
intermediates for further transformation and have been used
frequently as key intermediates in the construction of many
bioactive compounds.9c,9d,14-16 Studies have found them to
exhibit high bioactivity;14 however, regioselective synthesis of
formyl triazoles in modern organic synthesis remains
challenging.17 In the total synthesis of bioactive compounds,
formyl triazoles are often generated either from the oxidation
of hydroxymethylated triazole prepared in the CuAAC reaction
of propargyl alcohol with azides,15 or from cycloaddition of
-acetylenic aldehydes with sodium azide without
regioselectivity.16 In light of the versatile synthetic potential of
formyl triazoles in biochemistry, we present the first example
of a straightforward and general approach leading to
regioselective synthesis of 1,4-disubstituted and 1,4,5-
trisubstituted formyl-1,2,3-triazoles without metal (Scheme
1d).
CHO
R
CHO
RT
BnCH2N3
+
N
N
BnH2C
36 h
N
1
Entry
R
Solvent
Yieldb [%]
1
Br
CHCl3
Toluene
DMF
54
2
3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
32
74
44
62
52
44
14
8
4
CH3CN
DCE
5
6
EtOAC
1,4-Dioxane
MeOH
nBuOH
neat
7
8
9
10
11
12
13c
14
15d
16
17
18
19
26
86
70
78
95
71
78
82
89
91
DMSO
H2O
H2O + 10 mol% TBAB
DMSO:H2O = 7:3
DMSO:H2O = 7:3
DMSO:H2O = 9:1
DMSO:H2O = 3:2
DMSO:H2O = 7:3
DMSO:H2O = 7:3
Results and discussion
-Bromo acrolein, an excellent dienophile in cycloaddition18
with one of the best leaving groups of bromo anion, was
chosen as the substrate in this investigation. Initially, the
reaction between -bromo acrolein and phenethyl azide was
examined at room temperature in chloroform; 36 h later, the
resulting formyl triazole was isolated in 54% yield (Table 1,
entry 1). Under the same reaction conditions, several organic
solvents such as toluene, N,N-Dimethylformamide, acetonitrile,
and others were screened, and the reaction in DMSO provided
a better yield (Table 1, entries 2–11). The reaction performed
in H2O at room temperature for 36 h also provided formyl
triazole in 70% isolated yield (entry 12).19 This is an
encouraging result because the development of a reaction
method compatible with aqueous and ambient conditions
remains difficult but could facilitate the growth of biochemical
research.20 With 10 mol % tetrabuylammonium bromide (TBAB)
as the phase transfer catalyst, yield was enhanced to 78%
(entry 13). To further increase the yield, we tested the reaction
in a solvent mixture of DMSO with H2O at a 7:3 volume ratio.
To our delight, isolated yield was enhanced to 95% (entry 14).
Under same reaction conditions with -bromo acrolein as the
limiting reactant, yields was deceased to 71% (entry 15),
properly because boiling point of -bromo acrolein was
relatively low and it was prone to be polymerized. Upon
attempting to perform the reaction in DMSO/H2O at varied
ratios (entries 16 and 17), yields were also reduced. Then, we
examined the effect of the halo group on the result. -Chloro
acrolein and -indo acrolein demonstrated good results, but
yields were relatively low compared with -bromo acrolein
(entries 18 and 19). Finally, the optimization of reaction
parameters revealed the solvent mixture of DMSO with H2O
a
The reaction was performed in 200 μL of solvent (0.65 M) with acrolein (0.20
mmol) and azide (0.13 mmol), at room temperature for 36 h. b Isolated yield. c 72
h. d acrolein (0.13 mmol), azide (0.20 mmol).
(7:3 vol/vol) as an ideal medium, and -bromo acrolein as the
substrate for the desired transformation endowed adduct 1
with an essentially high yield (entry 14). Moreover, in all cases,
product 1 could be obtained exclusively in regioselectivity
according to crude NMR analysis.
After determining optimal reaction conditions, we applied
this methodology to the synthesis of 1,4-disubstituted 1,2,3-
triazole. As shown in Scheme 2, a diverse range of azides could
be used in the transformation to produce triazoles with high to
excellent yields (1-8, 14, 15). Compound 1 could be prepared
in gram-scale, and be collected by precipitation without
chromatography in 89% yield (please see SI). Product
configuration was assigned based on the single-crystal X-ray
analysis of 5 (Figure 1). Benzyl azide with strong withdrawing
groups on the phenyl ring produced the product in relatively
low yields (9 and 10). Secondary azide (especially cyclopentyl
azide and cyclohexyl azide) also produced reactions with good
to excellent results (11-13, 18). Remarkably, azides containing
various functional groups such as esters and alcohol were well
tolerated under standard conditions (16-20). This protocol
succeeded with bifunctional building blocks, which gave the
flexible bis(triazole) 21 in high yield. Moreover, short synthesis
of highly bioactive molecules (22-24) was achieved directly,1,14
albeit at a relatively high temperature due to the low reactivity
of aromatic azide.
2 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
CHO
bromo--alkyl acrolein with phenethyl azide, wVeiewapArpticlileeOdnline-
bromo--phenyl acroleins in this reaction. -Bromo--phenyl
Br
CHO
RT, 36 h
R N3
+
DOI: 10.1039/C9GC01129C
N
DMSO/H2O (7/3)
N
R
N
acroleins were conjugated substance, thus reactions should
performed with mild heating to facilitate cycloaddition step
(Scheme 4). As shown in Scheme 3, various -bromo--phenyl
acroleins, irrespective of the electron-donating groups or
electron-withdrawing groups at the o, m, and p positions, all
led to the desired products (29-35). Interestingly, two protons
on each -CH2- group in compound 30 were determined to be
diastereotopic according to NMR analysis (see SI).21
1
2
3
4
, 99%
, 95%
, 88%
, 90%
7
, 97%
5
6
8
, 98%
, 96%
, 96%
CF3
R
CHO
Br
CHO
RT
BnCH2N3
+
O2N
CHCl3
N
N
BnH2C
R
N
nHep
F3C
9
10
11
12
, 82%
, 88%
, 84%
, 90%
nOct
15
a
25
25,
26
27
, 62%
, 21%
80%
, 78%
O
Ph
EtO
16
a
Cl
13
14
, 88%
, 77%
, 82%
, 86%
Cl
30
b
b
b
O
28
29
31
, 81%
, 60%
, 80%
, 66%
O
O
HO
tBuO
EtO
Cl
F
H3CO
BnO
17
a
a
a
18
20
, 91%
, 82%
19
, 75%
, 60%
b
c
b
32
33
34
35
, 44%
, 82%
, 61%
, 76%
Scheme 3 Preparation of 1,4,5-trisubstitued 1,2,3-triazoles. Conditions: acrolein
(0.26 mmol), azide (0.13 mmol), CHCl3 (200 μL), RT, 48–72 h; see SI for details.
a DMSO/H2O (7:3 vol/vol) was used as solvent. b 40 oC. c 50 oC.
OMe
b
c
c
c
21
, 83%
22
, 80%
23
, 81%
24
, 78%
The presumed reaction mechanism is illustrated in
Scheme 4 and is similar to previous reports.13 First, in the
presence of an electro-withdrawing bromo group, acrolein was
activated and LUMO energy was reduced, thereby facilitating a
cycloaddition reaction with organic azide to afford the
intermediate 36 regioselectively. Then one molecular of HBr
was eliminated, providing the resulting products with high
yields.
Scheme 2 Preparation of 1,4-disubstitued 1,2,3-triazoles. Conditions: acrolein
(0.20 mmol), azide (0.13 mmol), DMSO/H2O (7/3 vol/vol, 200 μL), RT, 36 h.
a
b
Isolated yield. Anhydrous DMSO was used as solvent. Acrolein (0.39 mmol),
c
azide (0.13 mmol), 300 μL of solvent. Acrolein (0.26 mmol), azide (0.13 mmol),
40 oC, 48 h.
O
R1
N
5
CCDC 1864100
CHO
H
CHO
Br
- HBr
H
N
Figure 1 X-ray crystal structure of 5.
R1
Br
N
N
N
N
R2
R1
N
R2
N
N
Given the excellent results from the preparation of 1,4-
disubstituted 1,2,3-triazoles, we applied this synthetic
methodology to the synthesis of 1,4,5-trisubstituted 1,2,3-
triazoles. When -bromo--ethyl acrolein was employed as
the substrate in DMSO/H2O at room temperature for 48 h, the
reaction proceeded rather slowly and only a 21% yield of 25
was isolated. Fortunately, the isolated yield of 25 could be
dramatically improved by performing the reaction using
chloroform as the solvent. Under optimized conditions, -
methyl, long-chain heptyl, and sterically hindered cyclohexyl
azides resulted in products with good to high yields (26-28).
Encouraged by the results observed in the reaction of -
R2
36
Scheme 4 Presumed reaction mechanism.
To further demonstrate the utility of this methodology,
we prepared 25 in gram-scale (Caution: Reaction was
exothermic! Azide should be added slowly into the acrolein
solution). Additional transformations into other bioactive
molecule analogues1,13 are illustrated in Scheme 5. Triazole 21
could be reduced and oxidized easily to alcohol 37 and acid 38,
respectively, in high yields; it could also be transformed into
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
o
Mingoia, A. Terenzi, A. Martorana, G. BaronVeiewanArdticleAO. nMline.
hydrozone in MeOH for 6 h at 60 C as E and Z isomers at a
ratio of 2.3:1. A reaction with benzylamine followed by a
reduction resulted in -benzyl amino triazole 40. Condensation
with N-benzyl hydroxyl-amine hydrochloride in ethanol
directly produced N-benzyl nitrone derivative 41. Coupling
with methylenetriphenylphosphine in THF for 4 h at room
temperature afforded 42.
Almerico, Eur. J. Org. Chem., 2014, 3289.
DOI: 10.1039/C9GC01129C
2
3
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Br
CHO
PhCH2CH2N3
+
Et
7 mmol
10 mmol
Et
Et
COOH
4
OH
RT, 48 h
CHCl3
b
79%
N
N
N
BnH2C
N
BnH2C
N
N
a
c
37
38
Bn
NH
Et
CHO
Et
N
Et
O
d
HN
N
N
N
N
BnH2C
5
6
BnH2C
25
N
N
N
N
BnH2C
Ph
N
, 1.268 g
f
39
e
40
Bn
Et
N
Et
O
N
N
BnH2C
N
N
N
BnH2C
N
41
42
Scheme 5 Synthetic transformations. (a) NaBH4, MeOH, -40 oC, 2 h, 95% yield; (b)
Pinnick oxidation, overnight, 91% yield; (c) Benzoyl hydrazine, MeOH, 60 oC, 6 h, 93%
yield; (d) i. Benzylamine, MeOH, RT, 6 h; ii. NaBH4, MeOH, 0 oC, 1 h, 91% yield; (e) N-
Benzylhydroxylamine hydrochloride, NaHCO3, EtOH, 60 oC, 3 h, 92% yield; (f) Ph3PCH3I,
KOtBu, THF, RT, 4 h, 88% yield.
7
Conclusions
We have discovered a metal-free regioselective synthesis
route to 1,4-disubstitued and 1,4,5-trisubstitued 1,2,3-triazoles
was developed. The reaction demonstrated an broad substrate
scope and produced 1,4-disubstitued triazoles at room
temperature in in DMSO/H2O mixture solvent. The resulting
products exhibited an aldehyde group at the C4 position of
1,2,3-triazole, which could undergo versatile transformations.
One 1,2,3-triazole containing diastereotopic protons was
identified. We believe this strategy could be highly valuable in
various fields.
8
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
9
This work was supported by the Scientific Research Funds and
Subsidized Project for Postgraduates’ Innovative Fund in
Scientific Research of Huaqiao University. We also thank
Instrumental Analysis Center of Huaqiao University for their
kind help.
Notes and references
1
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A metal-free route to 1,4-disubsituted and 1,4,5-trisubstituted formDyOlI: 10.1039/C9GC01129C
triazoles was developed. One 1,2,3-triazole containing diastereotopic
protons was identified.