Tandem synthesis of 1-formyl-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2017.10.023

A tandem method for preparing 4-formyl-1,2,3-triazoles via a two-step one-pot acetal cleavage/CuAAC reaction was developed. Using this method, 4-formyl-1,2,3-triazole analogs with both electron-withdrawing and electron-donating substituents were prepared in good yield and purity. Expansion of this method to a three-step tandem reaction that incorporates an additional step of azide substitution was also successful, circumventing the need for organic azide isolation. This one-pot method, noteworthy in its simplicity and mild conditions, utilizes practical, readily available reactants and relies on protic solvent to promote acid-catalyzed acetal cleavage.

Full text of DOI:10.1016/j.tetlet.2017.10.023

Accepted Manuscript
Tandem synthesis of 1-formyl-1,2,3-triazoles
James T. Fletcher, Joseph A. Christensen, Eric M. Villa
PII:
S0040-4039(17)31302-3
https://doi.org/10.1016/j.tetlet.2017.10.023
TETL 49385
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 July 2017
7 October 2017
9 October 2017
Please cite this article as: Fletcher, J.T., Christensen, J.A., Villa, E.M., Tandem synthesis of 1-formyl-1,2,3-triazoles,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.023
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TOC Figure

Tandem synthesis of 1-formyl-1,2,3-triazoles
James T. Fletcher*, Joseph A. Christensen, Eric M. Villa
Department of Chemistry, Creighton University, 2500 California Plaza, Omaha, NE 68178, U.S.A.
Abstract - A tandem method for preparing 4-formyl-1,2,3-triazoles via a two-step one-pot
acetal cleavage/CuAAC reaction was developed. Using this method, 4-formyl-1,2,3-triazole
analogs with both electron-withdrawing and electron-donating substituents were prepared
in good yield and purity. Expansion of this method to a three-step tandem reaction that
incorporates an additional step of azide substitution was also successful, circumventing the
need for organic azide isolation. This one-pot method, noteworthy in its simplicity and
mild conditions, utilizes practical, readily available reactants and relies on protic solvent to
promote acid-catalyzed acetal cleavage.
Keywords
Acetal
Aldehyde
Click chemistry
Tandem reaction
1,2,3-Triazole

Among the many attractive features of the Sharpless-Meldal copper-catalyzed azide-
alkyne cycloaddition (CuAAC) reaction1–4 is its remarkable chemical orthogonality. Not
only does this allow CuAAC reactions to be employed in a diverse range of chemical
environments, but it also facilitates the development of tandem reactions around this bond
forming process.5 Examples include substitution,6–8 desilylation,9,10 decarboxylation,11
cross-coupling,12 oxidation,13 and condensation,14 along with combinations thereof.
Establishing reliable tandem CuAAC methods enables the efficient preparation of 1,2,3-
triazole-containing molecules, which have shown value in diverse fields including
coordination compounds,15–17 chemosensors,18 bioimaging agents,17,19 and polymeric
materials.20,21
Analogs of the 4-formyl-1,2,3-triazole motif have recently been reported to display
enzyme inhibitory,22 anti-cancer23,24 antileishmanial25 and anti-tuberculosis activity.26,27
With the aldehyde group an attractive handle for synthetic diversification, such compounds
have also served as synthons for preparing bioimaging,28 anti-cancer,23,24 and anti-
tuberculosis26,27 agents. Likewise, 4-imino-1,2,3-triazoles formed from amine
condensation reactions have been shown to be useful for constructing novel coordination
compounds.29–31
Several published methods are known for preparing 4-formyl-1,2,3-triazoles. The
direct synthesis from propynal has been reported,32 but is impractical due to this reagent’s
low boiling point and lack of commercial availability. A two-step method of CuAAC reaction
with propargyl alcohol followed by oxidation of the hydroxymethylated triazole
intermediate with reagents such as CrO324 or MnO230 is effective but limited to substituents
that can withstand such oxidants, and is environmentally unfriendly. Advances in this

approach using organic oxidants23,33 and polymer-immobilized two-component catalysis34
methods have recently been reported. Lastly, two-step methods using CuAAC reactions
with commercially available acetal-protected propargyl aldehydes followed by
deprotection of the formyl group via acid-catalyzed hydrolysis are known,35,36 but are
limited to substituents tolerant of strong acids such as HCl or TFA.
Examples of tandem click reactions involving acetal cleavage leading to aldehyde-
functionalized products are lacking. The aim of this investigation was therefore to develop
a reliable, mild and straightforward tandem CuAAC method to prepare 4-formyl-1,2,3-
triazoles directly from practical, commercially available precursors. In addition, exploring
the amenability of such conditions for expansion into three- and four-step tandem CuAAC
reactions was desired. This included the evaluation of the pre-CuAAC reaction step of azide
substitution, of interest because it allows the circumvention of organic azide isolation,37
and the post-CuAAC reaction step of imine-forming condensation, of interest in
coordination chemistry applications.29–31
During an initial study aiming to prepare 4-formyl-1,2,3-triazole compounds using a
stepwise approach, common room temperature aqueous CuAAC conditions were used to
click aryl azides with propargyl aldehyde diethyl acetal. As described in Table 1, it was
observed that these product mixtures contained minor but significant amounts of
deprotected 1-aryl-4-formyl-1,2,3-triazole products in addition to the expected diethyl
acetal product analogs, as determined by 1H NMR spectroscopy. This inspired the study
reported herein, aiming to determine whether aqueous CuAAC conditions could be
optimized towards producing deprotected formyl analogs in what would be a two-step
tandem cleavage/CuAAC reaction.

It was believed that the protic solvent environment of these conditions was
adequately acidic to promote measurable acetal cleavage, albeit slowly. With the goal of
enhancing the rate of deprotection relative to the initial observations, three parameters
were evaluated: temperature, solvent and triazole substituent identity. As summarized in
Table 1, a simple increase in the reaction temperature from room temperature to 70o C
resulted in a remarkable increase in deprotected product yields. This effect was consistent
for analogs possessing representative electron-withdrawing and electron-donating
substituents.
Table 1
Evaluation of temperature for two-step tandem reactiona
Entry
1
2
3
4
5
6
7
8
R =
Temp.
r. t.
r. t.
r. t.
r. t.
ID
Yield 1 (%)
ID
Yield 2 (%)
NO2
CF3
H
CH3
OCH3
NEt2
NO2
CF3
H
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
83
70
56
67
60
83
0
0
0
0
0
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
15
28
43
31
38
0
81
95
88
97
93
95
r. t.
r. t.
70o C
70o C
70o C
70o C
70o C
70o C
9
10
11
12
CH3
OCH3
NEt2
0
a Reaction conditions: azide (1.0 mmol), alkyne (1.0 mmol), CuSO4 (0.2 mmol), sodium
ascorbate (0.4 mmol) in 1:1 t-BuOH:H2O (10 ml) under air for 24 h.

1H NMR provides a straightforward method for quantitatively monitoring the
progress of acetal cleavage. For the series of compounds studied, the acetal α-proton
resonates between 5.6 and 5.9 ppm. After deprotection of the aldehyde functionality, this
proton shifts downfield to between 10.1 and 10.4 ppm. Likewise, the triazole proton shifts
downfield from 7.7-8.0 ppm to 8.3-8.5 ppm. Both 1H signals appear as singlets, and
integration of the peak area of these two characteristic resonances allows for
determination of reaction progress. An example of the distinguishing signals between
acetal and aldehyde products for the conversion of 1f to 2f is illustrated in Figure S1.
Table 2
Evaluation of alcohol solvents for two-step tandem reactiona
Entry
Solvent
MeOH
EtOH
i-PrOH
t-BuOH
t-BuOH:H2O
Yield 1d (%)
Yield 2d (%)
9
14
30
49
97
1
2
3
4
5
85
79
69
8
0
a Reaction conditions: azide (1.0 mmol), alkyne (1.0 mmol), CuSO4 (0.2 mmol), sodium
ascorbate (0.4 mmol) in solvent (10 ml) under air for 24 h.
Because CuAAC reactions using the CuSO4/sodium ascorbate catalyst system are
tolerant to a wide range of solvents, a survey of alcohol solvents was completed. As
summarized in Table 2, this evaluation showed that the progress of the desired two-step
tandem reaction varied considerably with alcohol solvent identity. The ideal solvent

condition among those surveyed was 1:1 H2O:t-BuOH. Hence, these conditions were
utilized in subsequent reaction development efforts for this investigation.
An evaluation of this tandem acetal cleavage/CuAAC reaction’s compatibility with
an additional azide substitution step was completed (Table 3). Simple addition of sodium
azide and either allyl bromide or benzyl bromide reactants to the standard aqueous CuAAC
reaction conditions resulted in both allylated and benzylated triazole products. Similar to
the aryl azide studies, at low temperature a mixture of major acetal products and minor
formyl products were observed. At high temperature, pure formyl analogs were obtained
in good yield and purity, establishing a reliable three-step tandem method for preparing 1-
substituted-4-formyl-1,2,3-triazole compounds.
Table 3
Evaluation of temperature for three-step tandem reactiona
Entry
R =
Allyl
Benzyl
Allyl
Temp.
r. t.
r. t.
70o C
70o C
ID
Yield 1 (%)
ID
Yield 2 (%)
4
13
71
67
1
2
3
4
1g
1h
1g
1h
76
73
0
2g
2h
2g
2h
Benzyl
0
a Reaction conditions: organic bromide (1.0 mmol), sodium azide (1.0 mmol), alkyne (1.0
mmol), CuSO4 (0.2 mmol), sodium ascorbate (0.4 mmol) in 1:1 t-BuOH:H2O (10 ml) under
air for 24 h.
Crystals of 2d and 2f suitable for structural analysis were grown from slow
evaporation of methylene chloride solutions. As shown in Figure S2, the dihedral angle

between the phenyl and triazole rings of 2d is 0.6o and the dihedral angle between its
formyl group and triazole ring is 5.5o. Figure S3 illustrates similar structural
characteristics for 2f, where the dihedral angle between aromatic rings is 22.9o and the
dihedral angle between the formyl group and triazole ring is 3.8o. The bond angles of the
diethylamino nitrogen atom clearly indicate its sp2 hybridization and conjugation with the
benzene ring. Collectively, the largely coplanar neighboring π-systems of these molecules
support the ability of peripheral para-phenyl groups to communicate electronically with
the remote 4-formyltriazole units and exert substituent effects in this family of compounds.
In order to measure the extent by which para-phenyl substituent identity at the 1-
position of the triazole is able to influence the electrophilicity of the formyl group at the 4-
position, solvolysis studies were performed in CD3OD. Degree of solvation was measured
by integration of aldehyde vs. acetal 1H NMR signals, along with corresponding triazole
singlets. As summarized in Table S1, a trend of increasing degree of solvation was
observed as electron-withdrawing strength of the 1-aryl substituent increased. This clearly
demonstrates the ability of para phenyl substituents to influence the remote carbonyl
position via electronic effects through the benzene and triazole aromatic systems.
With the goal of developing a three-step tandem reaction that includes a
condensation step leading to 4-imino-1,2,3-triazole products, a survey of condensation
efficiency between 4-formyl-1,2,3-triazoles and aryl amines using aqueous tandem click
conditions was completed (Table 4). This initial study employed matching para functional
groups between the triazole and aryl amine reactants, which were treated under high
temperature aqueous click solvent conditions. Following isolation from the reaction
solvent by extraction, the resulting mixtures were analyzed by 1H NMR in order to define

the spontaneity of the condensation relative to functional group identity. With the
exception of the nitro-substituted analog, each derivative was capable of forming
significant quantity of imine product despite the use of an aqueous 1:1 H2O:t-BuOH solvent
system.
Table 4
Evaluation of substituent identity on direct condensationa
Entry
R =
ID
Ratio 2 (%)
ID
Ratio 4 (%)
1
2
3
4
5
6
NO2
CF3
H
CH3
OCH3
NEt2
2a
2b
2c
2d
2e
2f
100
57
38
45
33
13
4a
4b
4c
4d
4e
4f
0
43
62
55
67
87
a Reaction conditions: 2 (1.0 mmol), amine (1.0 mmol) in 1:1 t-BuOH:H2O (10 ml) under air
for 24 h.
Encouraged by these results, three-step tandem reactions incorporating acetal
cleavage, CuAAC and condensation were attempted by simple addition of all reagents at the
onset of the reaction. Having demonstrated the individual compatibility of these reactants
with each of the three steps in this sequence, it was expected that the electron-rich systems
would produce the largest ratio of 4-imino-1,2,3-triazole products. Surprisingly, it was
observed for these three-step tandem reactions that as the electron-donating ability of the
substituents increased the amount of acetal-containing products increased (Table 5).

Table 5
Evaluation of substituent and addition time on three-step tandem condensationa
Entry R =
Add time
0
0
0
0
0
0
20 h
20 h
20 h
20 h
ID
Ratio (%) ID
Ratio (%)
100
56
22
12
10
0
100
61
25
ID
Ratio (%)
0
1
2
3
NO2
CF3
H
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
0
0
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
4a
4b
4c
4d
4e
4f
44
67
44
45
10
0
39
75
90
83
100
11
44
45
90
0
4
5
6
7
8
9
CH3
OCH3
NEt2
NO2
CF3
H
0
0
0
0
10
11
12
CH3
OCH3 20 h
NEt2 20 h
10
17
0
0
a Reaction conditions: organic azide (1.0 mmol), alkyne (1.0 mmol), CuSO4 (0.2 mmol),
sodium ascorbate (0.4 mmol) in 1:1 t-BuOH:H2O (10 ml) under air for 24 h. Amine (1.0
mmol) added either at reaction onset or after 20 h of stirring.
Considering the requirements of each step of the sequence, it was proposed that the
increasingly basic nature of the electron-rich aryl amine reactants was interfering with the
ability of the solvent system to generate sufficient acidity to promote acetal cleavage.
While the electron-poor nitro analog showed successful deprotection but failed to
condense, analogs of increasing electron density showed the disparate outcome of both
stalling at the acetal cleavage stage and proceeding to successful condensation. Under the
conditions studied, none of the utilized analogs were capable of establishing a balance of
sufficient nucleophilicity to promote spontaneous condensation together with insufficient
basicity to allow solvent-promoted acid-catalyzed acetal cleavage.

A simple solution to this issue was a time-delayed introduction of aryl amine into
the reaction mixture. When added at the 20 h time point (not optimized) instead of at the
reaction onset, no acetal products were observed and the ratio of formyl and imino
products closely resembled that in the one-step condensation studies. While optimization
of this reaction was not a focus of this study, it appears that a three-step tandem approach
for preparing 4-imino-1,2,3-triazoles from commercially available reactants is indeed
feasible if a time-delayed introduction of reagents were to be employed. It is noteworthy
that a four-step tandem reaction also including an azide substitution step analogous to that
shown in Scheme 3 was attempted, but failed due to cross-reaction between the organic
bromides and aryl amine reactants.
In conclusion, a mild and effective method has been established to prepare 4-
formyl-1,2,3-triazoles from commercially available reactants via a two-step tandem acetal
cleavage/CuAAC transformation.[38] Using this method, 4-formyl-1,2,3-triazole analogs
with both electron-withdrawing and electron-donating substituents at the 1-position can
be prepared in good yield and purity. It is proposed that the simplicity of this tandem
method will be useful for efficiently preparing a wide range of 1-substituted-4-formyl-
1,2,3-triazoles. Expansion of this method to a three-step tandem reaction that incorporates
an additional step of azide substitution was also successful, circumventing the need for
organic azide isolation.
While condensation reactions converting 4-formyl-1,2,3-triazoles into 4-imino-
1,2,3-triazoles were effective even in an aqueous environment, a three-step tandem
reaction incorporating an additional step of condensation leading to imine analogs was
successful only when a time-delayed introduction of amine was used. This incompatibility

is likely due to the acid-catalyzed nature of the acetal cleavage step. Future work will focus
on more closely investigating the parameters of the imine-forming condensation reaction
and using tandem methods to prepare new 4-imino-1,2,3-triazole motifs for applications in
coordination chemistry.
Acknowledgments
This publication was made possible by grants from the National Institute for General
Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of
Health (NIH), and its contents are the sole responsibility of the authors and do not
necessarily represent the official views of NIGMS or NIH. JAC acknowledges Creighton
University’s Baumann Family Scholarship for financial support.
Supplementary data
Supplementary data related to this article can be found at _______. Crystallographic
information for the SC-XRD analysis of 2e and 2f can be found in the Supplementary data.
Crystallographic data for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre: 2e as CCDC 1565067 and 2f as 1565068. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: despoit@ccdc.cam.ac.uk).
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(38) General procedure for cleavage/CuAAC. To a 20 mL screw-top vial was added (in
order) CuSO4 (0.032 g, 0.2 mmol), L-ascorbic acid sodium salt (0.079 g, 0.4 mmol),
water (5 mL), t-butyl alcohol (5 mL), aryl azide reactant (1.0 mmol) and propargyl
aldehyde diethyl acetal (0.158 mL, 1.1 mmol). The vial was then capped and stirred
at either room temperature or 70⁰ C for 24 hr. The reaction mixture was then
extracted between CH2Cl2 and 5% NH4OH (aq). The organic layer was separated,
dried with MgSO4 and gravity filtered. The solvent was removed via rotary
evaporation to give the isolated product or product mixture used for NMR analysis.
Further purification was accomplished by silica gel chromatography using either
CH2CH2 or 20:1 CH2CH2:ethyl acetate eluent.

Highlights:
•
•
•
•
A tandem, two-step acetal cleavage/CuAAC method was developed.
Acetal cleavage is promoted by protic solvent at moderate temperature.
A tandem, three-step substitution/acetal cleavage/CuAAC reaction was successful.
Tandem imine formation was successful only with a time-delayed amine addition.