Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles from Ethenesulfonyl Fluoride and Organic Azides

Article abstract of DOI:10.1002/anie.201912728

The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.

Full text of DOI:10.1002/anie.201912728

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles
from Ethenesulfonyl Fluoride and Organic Azides
Authors: Marie-Claire Giel, Christopher J. Smedley, Emily R. R.
Mackie, Taijie Guo, Jiajia Dong, Tatiana P. Soares da Costa,
and John Edward Moses
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912728
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10.1002/anie.201912728
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Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles
from Ethenesulfonyl Fluoride and Organic Azides
Marie-Claire Giel,[a] Christopher J. Smedley,[a] Emily R. R. Mackie,[a] Taijie Guo,[b] Jiajia Dong,[b] Tatiana
P. Soares da Costa,[a] and John E. Moses*[a]
Abstract: The 1,2,3-triazole group is one of the most important
connective linkers and functional aromatic heterocycles in modern
chemistry. The boom in growth of 1,4-disubstituted triazole products, in
particular, since the early 2000’s, can be largely attributed to the birth of
click chemistry and the discovery of the Cu(I)-catalyzed azide-alkyne
cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit
important, 1-substituted-1,2,3-triazoles, has been surprisingly more
challenging. We report a straightforward and scalable click-inspired
protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic
azides and the bench stable acetylene-surrogate, ethenesulfonyl
fluoride (ESF). The new transformation tolerates a wide selection of
substrates and proceeds smoothly under metal-free conditions to give
the products in excellent yield. Under controlled acidic conditions, the
1-substituted-1,2,3-triazole products undergo
a Michael addition
reaction with a second equivalent of ESF to give the unprecedented 1-
substituted triazolium sulfonyl fluoride salts.
The 1,2,3-triazole group is an important aromatic heterocycle
system with a long history.[1] First reported by Pechmann in 1888,[1a]
triazoles have evolved to become one of the most successful
connective linkers[1m] and functional heterocyclic cores in modern
organic chemistry[2] — not least due to the pioneering work of
Huisgen,[1g] and subsequent discovery of the copper(I)-catalyzed
alkyne-azide cycloaddition (CuAAC) click[3] reaction.[1k,1l] The
weakly basic 1,2,3-triazole products (pKa = 9.3, pKb = 1.2)[4]
function as stable linkers that are resistant to metabolic
degradation, but moreover, through hydrogen bonding and dipole
interactions, 1,2,3-triazoles can associate effectively with biological
targets and may function as pharmacophores,[5,6] sharing both
topological and electronic features of amides.[7] Of particular
importance are the 1-substituted-1,2,3-triazoles — prevalent in
several drugs and clinical candidates,[8,9] including: PH-027 (1), a
potent derivative of the antimicrobial linezolid;[10,11] the ß-lactamase
inhibitor tazobactam (2);[12] the quinazolinamine based VEGF
receptor kinase inhibitor
[a]
[b]
M.-C. Giel, Dr. C. J. Smedley, E. R. R. Mackie, Dr. T. P. Soares da
Costa and Prof. Dr. J. E. Moses
La Trobe Institute for Molecular Science, La Trobe University
Melbourne, VIC 3086, Australia
E-mail: J.Moses@latrobe.edu.au
T. Guo and Prof. Dr. J. Dong
Key Laboratory of Organofluorine Chemistry
Center for Excellence in Molecular Synthesis
University of Chinese Academy of Sciences
Chinese Academy of Sciences
Figure 1. A) Representative examples of drugs comprising a 1-substituted-
1,2,3-triazole group; B) Representative examples of methods for the synthesis
of 1-substituted-1,2,3-triazoles; C) Comparison between acetylene, ESF and
ESCl; D) The reaction between organic azides and ESCl, and the development
of this work with ESF.
3;[13]
the
antiretroviral
7-(5-methyl-3-(1H-1,2,3-triazol-1-
345 Ling-Ling Road, Shanghai 200032 (P. R. China)
yl)imidazo[1,5-b]pyridazin-7-yl)-1- phenylheptan-1-one, 4[14] and
the HER-2 protein kinase inhibitor, mubritinib (5)[15] among others
(Figure 1A). Despite their significance, few direct methods are
available for their synthesis and, of those, a majority involve
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201912728
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COMMUNICATION
Scheme 1. A) Metal-free protocol for the synthesis of 1-substituted-1,2,3-triazoles from ESF and organic azides; B) Metal-free late-stage functionalization of a
selection of azide functionalized drugs and drug fragments with ESF to give the 1,2,3-triazole groups. C) Synthesis of 13gg. [a] Isolated yields; reactions performed
on 0.50 mmol scale of the azide and 0.75 mmol of ESF. [b] Reactions performed on 0.25 mmol scale of the organic azide and 0.38 mmol of ESF. [c] The compound
12gg was synthesized from chloramphenicol (15) following a modified literature procedure,[16,17] using Pd/C (10 mol%) under an atmosphere of H2 then using
tBuONO (1.50 eq) and TMSN3 (1.20 eq). The minimum inhibitory concentration (MIC) was determined using a broth microdilution method according to guidelines
defined by the Clinical Laboratory Standards Institute (See SI).
the 1,3-dipolar cycloaddition between organic azides and
acetylenic materials.[1h,1t]
Dimroth and Fester first reported (1910) that when heated
in a sealed pipe, phenyl azide and acetylene-saturated acetone
react to give 1-phenyl-1,2,3-triazole.[1c] Several analogous
protocols have since emerged,[1h,1s,1u] each requiring high
pressure and specialized apparatus to handle the potentially
dangerous acetylene methods
gas.[18] Representative
circumventing the direct use of acetylene include the reaction of
organic azides with: sodium acetylide;[1t] norbornadiene;[1j]
phase-vanishing fluorous system for in situ generation of
acetylene from calcium carbide,[1v] and a copper catalyzed
a
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10.1002/anie.201912728
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COMMUNICATION
approach using trimethylsilylacetylene (TMS-acetylene).[1i,1q] The
direct substitution of organic halides with 1H-1,2,3-triazole is
possible, although is disadvantaged by the tendency of 1H-1,2,3-
triazole to tautomerize to the 2H-1,2,3-triazole (Figure 1B).[1p,1r]
We report herein a straightforward click-inspired protocol for
the synthesis of 1-substituted-1,2,3-triazoles from organic azides
and ethenesulfonyl fluoride (ESF).[19] In contrast to earlier
methods, the new metal-free transformation eliminates the need
for potentially dangerous gases and specialized apparatus,
delivering the 1-substituted-1,2,3-triazole products exclusively.
The protocol also demonstrates a broader substrate scope to
reported literature which is often displayed with simple aromatic
and alkyl substrates.[1i, 1s-v] We demonstrate, for the first time, ESF
as a bench stable, safe and efficient acetylene surrogate for
application in 1,3-dipolar cycloaddition chemistry (Figure 1C). The
transformation meets many of the criteria of a click reaction,[3]
being: modular; wide in scope; high yielding; simple to perform
and using solvents that are easily removed.
The method performs well with a wide range of aromatic azides,[17]
including electron-rich (12a-e), electron-poor (12f-j), and the
sterically hindered aromatic azide (12b), and equally well with
benzyl and alkyl azides (12k-v) to give the corresponding 1-
substituted-1,2,3-triazole products in good to excellent yields
(Scheme 1). The chemoselective transformation tolerates
multiple functional groups, including alkynes (13e), esters (13g,
13u), ketones (13o), acetals (13s), sulfones (13p), sulfonamides
(13q), oxetanes (13v) and nitriles (13j), to name a few.
The potential of the new method was demonstrated in the
late-stage functionalization (LSF) of a selection of important
biologically active compounds.[29] The azide derivatives of a
selection of drug and drug-fragments were prepared[30] and
reacted with ESF following the new protocol (Scheme 1B and C).
The 1-substituted-1,2,3-triazoles (1, 13w
–
13gg) were
synthesized in mostly good yields (up to 92%) from a wide range
of azido modified drug and drug-fragments including antibiotics
and anti-cancer agents.[30]
The inspiration for the new method can be traced to a 1955
report by Rondestvedt and Chang describing the reaction
between ethenesulfonyl chloride (ESCl) and phenyl azide (6) to
give the [2:1]; [ESCl:azide] adduct product (9). The product was
unstable and hydrolyzed upon standing to the corresponding
sulfonate (10) (Figure 1D).[20] Even with an excess of phenyl
azide, the same product was consistently obtained. The reaction
was suggested to occur through a 1,3-dipolar cycloaddition of 6
and ESCl to give triazoline 7, followed by N-alkylation with a
second equivalent of ESCl to 8 — proton abstraction and
elimination of SO2 led to the triazole salt 9. It was also noted that
10 could be synthesized by heating 1-phenyl-1,2,3-triazole (11)
with ESCl; presumably via a direct Michael reaction pathway
(Figure 1D). While the reported method is not practical for the
synthesis of 1-substituted-1,2,3-triazoles due to the unavoidable
ring alkylation, we were intrigued by the potential role of ESCl as
surrogate for acetylene.[21]
Of particular note is 13gg; itself prepared in 75% yield from
the unstable azide derivative 12gg of chloramphenicol (15)
(Scheme 1C). Chloramphenicol inhibits the peptidyl transferase
activity of the bacterial ribosome and has been used extensively
with great effect in the treatment of severe bacterial infections.[31]
However, the occurrence of adverse side effects resulting from
the use of 15, including sometimes fatal aplastic anemia and bone
marrow suppression, have been linked to the metabolism of the
aromatic nitro-group and formation of reactive nitroso and N-
hydroxy- species.[32,33] When tested against a panel of pathogenic
Gram-positive bacteria, including: methicillin sensitive and
resistant Staphylococcus aureus (MSSA and MRSA,
respectively) and vancomycin susceptible and resistant
enterococci (VSE and VRE, respectively), the observed minimum
inhibitory concentrations (MICs) for 13gg were comparable to
those for chloramphenicol (15). This impressive retention of
activity suggests that replacement of the nitro-group with a
metabolically stable 1,2,3-triazole group is a valid strategy with
much potential (Figure 1C). Collectivity, the results demonstrate
the power of the new click-inspired reaction as a valuable tool for
the late-stage introduction of 1-substituted-1,2,3-triazoles for drug
discovery and development.
In related studies, we[22] and Fokin[23] independently
reported the 1,3-dipolar cycloaddition reaction between 1-
bromoethene-1-sulfonyl fluoride and organic azides to give the
corresponding
1-substituted-1H-1,2,3-triazole-4-sulfonyl
fluorides. No alkylation of the triazole ring by 1-bromoethene-1-
sulfonyl fluoride was observed, leading us to question whether
ESF could itself function as a practical acetylene surrogate in the
reaction with organic azides — without the interfering side
reactions (cf. ESCl).[24, 25] ESF offers many other advantages over
ESCl in terms of stability and properties (Figure 1C),[26] and has
been described as “the most perfect Michael acceptor ever
The metal-free protocol is also scalable and can be
performed in a one-pot synthesis directly from anilines through in
situ generation of the azide — hence avoiding the need to handle
potentially hazardous intermediates.[17] The 1,2,3-triazole
products 13f (79%), 13g (88%) and 13hh (73%) were each
isolated as single products on gram scale without need for
additional purification. While a lower yield (56%) of the triazole
[24, 27]
found”
Studies commenced by performing a reaction between ESF
and phenyl azide (6) following the method of Rondestvedt and
Chang (cf. ESCl)[20]: stirring in benzene at ambient temp for 5
hours in a sealed tube. Under these conditions, no products were
observed and starting materials fully recovered. However, raising
the reaction temperature to 100 °C and stirring for a further 5 h,
the 1-phenyl-1,2,3-triazole (11) was isolated in 47% yield along
with unreacted starting materials (See SI). Significantly, no
alkylated triazole product was detected. Further optimization
revealed the following protocol (Table 1, SI): 1.00 equivalent of
azide with 1.50 equivalents of ESF in EtOAc; stirring at 100 °C for
16 h in a sealed tube (for safety precautions see footnote 28).[28]
product 13ii was observed from the alkyl amine (16ii) via in situ
35]
diazotransfer to the azide starting material,[34,
the one-pot
synthesis from alkyl halides or alcohols (via the corresponding
azides) gave good yields of the 1,2,3-triazole products 13l (78%),
13u (61%) and 13jj (67%) (Scheme 2, See SI).
Rondestvedt and Chang demonstrated that 1-phenyl-1,2,3-
triazole (11) undergoes direct Michael addition to ESCl (reflux in
benzene, 6 h) to give the sulfonate adduct (10) in 99% yield
[presumed to arise through hydrolysis of the unstable sulfonyl
chloride (9).[20, 36] Under the equivalent conditions with ESF, we
o
observe no such reaction. However, upon heating at 100 C in
EtOAc with 3.00 equivalents of HCl for 4 hours, the triazole
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10.1002/anie.201912728
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COMMUNICATION
unfavorable steric clashes (cf. syn-addition).[38] However,this
regiochemical assignment could not be corroborated — under the
reaction conditions no evidence for the formation of 17 was
observed. We posit that in the case of ESF, the cycloaddition step
is rate limiting and that subsequent elimination of SO2 and HF
occurs rapidly through an Ei thermal syn-elimination mechanism.
This may explain the absence of any alkylated triazolium product
19, since under the high reaction temperature (cf. ESCl at r.t.), the
elimination of SO2/HF may be significantly faster than the Michael
reaction between ESF (cf. ESCl) and the triazoline intermediate
(18) (Figure 1C).[39, 40]
Scheme 2. One-pot gram scale synthesis of 1,2,3-triazoles directly from anilines
(i), alkyl amines (ii), halides (iii) and alcohols (iv). See SI for conditions i, ii, iii
and iv.
Scheme 4. Plausible concerted reaction pathway for the 1,3-dipolar thermal
cycloaddition reaction between ESF and organic azides.
addition products (14a-e) could indeed be obtained in good yield.
The controlled synthesis of these unprecedented 1-substituted
triazolium sulfonyl fluoride salts, enabled only through the
reaction with ESF, highlights the incredible versatility and duality
of this reagent as an acetylene surrogate and electrophile
(Scheme 3).
To rationalize the mechanism of the new reaction several
features were taken into account: that no additives or base are
required, and that solvent polarity does not appear to affect the
yield or reaction rate to any significant degree, ruling out large
build-up of charge in the transition state.[37] Collectively, these
observations support a concerted pathway proceeding through a
1,3-dipolar cycloaddition of ESF and the azide (12) to the 1,4-
disubstituted triazoline (17) (Scheme 4). The suggested anti-
regiochemistry of the initial cycloaddition product 17 is supported
by related 1,3-dipolar cycloaddition products between organic
azides and 1-bromoethene-1-sulfonyl fluoride,[22,23] and 1-
bromoethene-1-sulfonyl chloride,[20] and rationalized by the lower
energy transition state for the anti-addition pathway, which avoids
In conclusion, a new metal-free click-inspired synthesis of
1-substituted-1,2,3-triazoles has been established through a 1,3-
dipolar cycloaddition-elimination reaction between ethenesulfonyl
fluoride and organic azides. The straightforward and practical
metal-free method is wide in scope, has broad functional group
tolerance, good to excellent yielding (up to 98%) and often
requires no chromatographic purification. The reliable protocol
was successfully applied to the late-stage functionalization of a
selection of drugs and fragments, including the synthesis of the
stable chloramphenicol derivative, 13gg, which demonstrated
excellent activity against MSSA, MRSA, VSE and VRE. Under
acidic conditions, we demonstrate that the 1-substituted-1,2,3-
triazoles undergo Michael addition to ESF to give the
unprecedented addition products, demonstrating that ESF is a
more practical and superior reagent to ESCl.
Acknowledgements
We thank the ARC for support through a Future Fellowship (J.E.M.;
FT170100156) and a DECRA Fellowship (T.P.S.C.; DE190100806).
We acknowledge La Trobe University (M.-C. G) and the Grains
Research and Development Corporation (E.R. R.M.; 9176977) for
PhD scholarships. We acknowledge the National Natural Science
Foundation of China (NSFC 21672240, NSFC 21421002) the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB200203), the Key Research Program of Frontier
Sciences (CAS, grant no. QYZDB-SSWSLH-028) and Shanghai
Sciences and Technology Committee (18JC1415500, 18401933502)
for financial support (T.G and J.D).
Keywords: Metal-Free Click Chemistry
Acetylene Ethenesulfonyl Fluoride
Functionalization
•
1,2,3-triazole
•
•
•
Late-stage
Scheme 3. Synthesis of the 1,2,3-triazole derived salts 14a-e from ESF and 1-
substituted-1,2,3-triazoles.
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Note: Unless otherwise stated, all reactions were performed in a
sealed Biotage Microwave Reaction vial designed to withstand
pressures of up to 30 bar using 0.50 mL (0.25 mmol scale) or 1.00
mL of solvent (0.50 mmol scale) in a vial with a solvent capacity
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Marie-Claire Giel, Christopher J.
Smedley, Emily R. R. Mackie, Taijie
Guo, Jiajia Dong, Tatiana P. Soares da
Costa, John E Moses *
Page No. – Page No.
Metal-Free Synthesis of Functional 1-
Substituted-1,2,3-Triazoles from
Ethenesulfonyl Fluoride and Organic
Azides
A metal-free click-protocol for the synthesis of 1-substituted-1,2,3-triazoles from
organic azides and ethenesulfonyl fluoride (ESF) is described. The synthetic
value of the concerted reaction is reflected in the simplicity of the protocol and
demonstrated by the one-pot preparation of the triazole from the corresponding
amine, alkyl halide or alkyl alcohol performed on gram scale. The utility of this
method is shown in the late-stage modification of several drugs, including the
famous antibiotic chloramphenicol to give the new active antibiotic derivative.
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