A Scalable Metal-, Azide-, and Halogen-Free Method for the Preparation of Triazoles

Article abstract of DOI:10.1002/anie.201915944

A scalable metal-, azide-, and halogen-free method for the synthesis of substituted 1,2,3-triazoles has been developed. The reaction proceeds through a 3-component coupling of α-ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional-group tolerance with respect to both the α-ketoacetal and amine coupling partners, providing access to 4-, 1,4-, 1,5-, and 1,4,5-substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3-triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.

Full text of DOI:10.1002/anie.201915944

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Accepted Article
Title: A Scalable, Metal-, Azide- and Halogen-Free Method for the
Preparation of Triazoles
Authors: Peter Clark, Glynn D. Williams, Jerome F. Hayes, and
Nicholas C. O. Tomkinson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915944
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10.1002/anie.201915944
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A Scalable, Metal-, Azide- and Halogen-Free Method for the
Preparation of Triazoles
Peter R. Clark,*[a][b] Glynn D. Williams,[a] Jerome F. Hayes,[a] and Nicholas C. O. Tomkinson[b]
Abstract: A scalable, metal-, azide- and halogen-free method for
the synthesis of substituted 1,2,3-triazoles has been developed.
The reaction proceeds through a 3-component coupling of
α-ketoacetals, tosyl hydrazide, and a primary amine. Functional
group tolerance is outstanding in both the -ketoacetal and amine
coupling partners providing access to 4-, 1,4-, 1,5-, and 1,4,5-
substituted triazoles in excellent yield. This robust method results
in densely functionalised 1,2,3-triazoles that remain challenging
to prepare by azide-alkyne cycloaddition (AAC, CuAAC, RuAAC)
methods and can be scaled in either batch or flow reactors.
Methods for the chemoselective reaction of either aliphatic
amines or anilines are also described revealing some of the
potential of this novel and highly versatile transformation.
catalyst prevents the use of AAC technology in live cells. To
address this shortfall, strain promoted azide-alkyne cycloaddition
(SPAAC) has been developed providing an invaluable method to
conjugate biologically relevant targets.[8] Both cycloaddition
strategies require the use of an azide coupling partner.
Replacement of the azide with a primary amine nucleophile, the
most common commercially available nitrogen containing
substrate, is of great interest to the synthetic community.[9]
The 1,2,3-triazole motif is an important heterocycle with
applications in chemical biology, materials chemistry,
agrochemicals and pharmaceuticals.[1] This scaffold is highly
prevalent in experimental drug candidates and several marketed
drug molecules which are used to treat varied clinical
indications.[2] Examples include the monosubstituted antibiotics
Tazobactam 1 and Cefatrizine 2, the disubstituted anticonvulsant
Rufinamide
3
and the trisubstituted oncology candidate
JNJ-54175446 4 which is currently in clinical trials[3] (Figure 1a).
The diversity in substitution of 1–4 shows there is a strong
demand for robust methods to access all possible substitution
patterns of this heterocyclic core.
The most common method to access 1,2,3-triazoles is the
Huisgen [3+2] cycloaddition between azide 5 and an alkyne 6
coupling partners.[4] It has been shown that this cycloaddition
process can be accelerated with transition metal catalysts.[5] Of
great relevance in this area are the CuAAC and RuAAC click
reactions, pioneered by Sharpless and Meldal, which deliver the
1,4- and 1,5-regioisomeric products respectively (Figure 1b).[5–6]
These transformations have revolutionised chemical biology by
providing a robust, efficient and versatile tool that has been
applied to solve many challenges within the field.[7] Whilst the
cycloaddition approach is undoubtedly important to prepare this
class of heterocycle, the requirement for a transition metal
[a]
Mr. Peter R. Clark, Dr. Glynn D. Williams and Dr. Jerome F. Hayes,
Chemical Development
Figure 1. a) Marketed and experimental drugs containing the 1,2,3-triazole
motif. b) Methods to synthesise 1,2,3-triazoles. c) One-pot method for the
preparation of 1,2,3-triazoles.
GlaxoSmithKline
Gunnels Wood Road, Stevenage, SG1 2NY, UK
Email: peter.r.clark@gsk.com
In 1986 Sakai reported the synthesis of substituted 1,2,3-triazoles
11 through the reaction of an α,α-dichloroketone 10,
tosylhydrazide and a primary amine (Figure 1b).[10] The scope of
this transformation was explored by Westermann[11] and
demonstrated on scale by Hanselmann,[12] providing a novel
process to form this heterocyclic core. However, several
[b]
Mr. Peter R. Clark and Prof. Dr. Nicholas C. O. Tomkinson
Department of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral Street, Glasgow, G1 1XL, UK
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915944
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limitations exist with this methodology. These include the
requirement to isolate and purify the α,α-dichlorohydrazone
intermediate resulting in a two-step synthesis of the triazole and
the necessity to use a potentially mutagenic halogenated
reagent/intermediate. Due to these challenges, this methodology
has seen a limited uptake to date. To address some of these
problems oxidative variants have been developed (12→13),[13]
however, they suffer from additional drawbacks providing an
opportunity for further development.
Table 1. Optimisation of triazole synthesis using ketoacetal, tosylhydrazide and
benzylamine.
We believed that under appropriate reaction conditions the
-ketoacetal functionality 14 could act as an effective surrogate
for the problematic ,-dichloroketone providing a significantly
more versatile method to prepare substituted 1,2,3-triazole
products (Figure 1c). Within this manuscript we show that
-ketoacetals 14 can be reacted with N-tosylhydrazide 15 and a
primary amine 16 in a 3-component coupling procedure to provide
access to mono-, di- and tri-substituted 1,2,3-triazoles in a robust
and efficient procedure. The reaction proved to be amenable to
scale-up and the protocol was successfully transferred to a flow
reactor.
Entry
Temperature T
Time t
Variations
21 yield[a]
1
2
3
4
rt
16 h
16 h
-
-
-
47%
75%
83%
84%
Reflux
120 °C
120 °C
20 min
20 min
BnNH2
(2.0 equiv)
5
6
7
120 °C
140 °C
140 °C
5 min
5 min
5 min
-
-
82%
89%
Reaction of -ketoacetal 17 (1.05 equiv) with tosylhydrazide 15
(1 equiv) in methanol for 5 minutes at room temperature gave the
hydrazone 18 (>98%). Selective hydrolysis of the acetal moiety
of 18 in the presence of the hydrazone group proved challenging
and we were unable to isolate an analytically pure sample of the
aldehyde 19. However, we were delighted to discover that
treatment of the crude methanolic solution containing 18 with
benzylamine 20 (1.1 equiv) at room temperature and stirring the
reaction mixture for a further 16 h gave the triazole 21 in 47% yield
(Table 1, Entry 1). Heating the reaction mixture at reflux for 16 h
increased the observed yield of 21 to 75% (Entry 2). Increasing
the temperature to 120 °C in a sealed reaction vessel gave the
product in 83% after 20 minutes (Entry 3) and shortening the time
to just 5 minutes gave the product in similar yield (Entry 5, 82%).
Increasing the number of equivalents of benzylamine (2.0 equiv)
had no significant effect on the reaction outcome (Entry 4, 84%),
however, raising the temperature to 140 °C gave the triazole
product in 89% after 5 minutes (Entry 6). Under the reaction
conditions (MeOH, 140 °C) the sulfinic acid co-product 22 was
converted to methyl 4-methylbenzenesulfonate 23 which had to
be separated from the triazole product 21 by column
chromatography.[14] Conducting the reaction in the presence of
triethylamine (1.1 equiv) shut down this pathway and allowed for
removal of the sulfinate salt through aqueous workup, simplifying
the purification of the product 21 (cf. Entry 6 vs 7). This simple
and effective protocol allowed access to the triazole 21 through
reaction of -ketoacetal 17, N-tosylhydrazide 15 and benzylamine
20 in a 1-pot procedure. This method provides a novel metal-,
azide- and halogen-free process for the preparation of this
important class of heterocyclic product.
Et3N
(1.1 equiv)
88%
(88% isolated)
[a]solution yield calculated using internal standard by 1H NMR spectroscopy.
A series of aliphatic amines were examined under the optimised
reaction conditions (Scheme 1). Linear aliphatic amines
(n-propyl- 24, methyl- 25), branched sterically encumbered
amines (isopropyl-, cyclopropyl, cyclohexyl and tertbutyl, 26–29)
and a fluorinated analogue (30) all proved suitable substrates to
deliver the N-alkyl triazole in excellent yields (79–98%). Products
that are challenging to prepare using an AAC strategy were also
readily accessible using our protocol. For example, using
ammonia as the nucleophile provided access to the NH triazole
31 in 78% isolated yield and the alkene and alkyne containing
amines 32 and 33 resulted in the corresponding triazole (85–87%).
Incorporation of tertiary amines into the amine substrate was also
possible, as exemplified by the diamine 34 (81%). A selection of
substituted benzylamines underwent clean conversion to the
N-benzyl triazole products, where the aromatic ring could tolerate
both electron-donating and electron-withdrawing groups,
including elaborate handles for further functional groups
interconversions (35–37). Heterocyclic amines (pyridyl-, furfuryl-,
azetidyl- and pyrazyl-, 38–41) all underwent cyclisation to
poly-heterocyclic systems in excellent yield (68-96%). Aniline
(42) was also a suitable nucleophilic coupling partner, furnishing
the N-aryl triazole (74%). Finally, optically active amino-alcohol
substrate 43 provided the desired triazole with no erosion in the
diastereochemical purity of the product. Whilst under the
standard reaction conditions the amino acid derivative 44 gave
the triazole product with a substantially reduced e.r., lowering the
reaction temperature to 75 °C (18 h) and addition of just 1
equivalent of NEt3 gave the product with a markedly higher e.r.
(98:2) in an excellent 84% isolated yield. It is worth noting that by
carrying out the reaction in the presence of NEt3, many the
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products in Scheme 1 did not require chromatographic purification
to afford analytically clean product, greatly increasing the
synthetic utility of this efficient transformation.
appropriate primary amine (1.1 equiv) and NEt3 (1.1 equiv) before
heating at 140 °C for 5 minutes. This array led to all twenty
triazoles (49-68) being isolated in good to excellent yields
(58 90%), showing a high level of tolerance of substitution at the
-
Scheme 1. Scope of primary amine substrate.
4-position of the triazole. The formation of the triazoles derived
from ammonia is of note as the dipolar cycloaddition of an alkyne
with inorganic azide (NaN3) represents a significant synthetic
challenge. Further, there are safety concerns due to the
energetics of sodium azide and the risk of forming hydrazoic
acid[16] highlighting the benefits of this process. The ability to use
our 3-component coupling procedure to access this class of
heterocycle therefore provides an effective and particularly
attractive complementary procedure to the AAC which should be
applicable in a process chemistry environment.
Scheme 2. Scope of α-ketoacetal substrate.
a2 equiv Et3N used. bReaction performed in a sealed tube (75 °C, Et3N 1 equiv,
18 h).
To explore the scope of the α-ketoacetal unit, homo-benzyl,
phenyl, cyclohexyl (Cy) and homo-allyl substrates (45–48) were
prepared
through
a
Grignard
addition
to
ethyl
2,2-diethoxyaceatete (See Supporting Information for full
experimental details).[15] Each substrate was then reacted with
five amines (benzylamine, aniline, methylamine, cyclohexylamine
and ammonia) in order to probe both steric and electronic effects
on the reaction (Scheme 2). Sterically encumbered α-ketoacetals
(phenyl 46 and cyclohexyl 47) reacted slower with tosylhydrazide
15, requiring up to 2 h for hydrazone formation, however, the
transformation proceeded in quantitative yield to give the
expected hydrazone which was treated directly with the
a2.2 equiv NH3 used in absence of NEt3.
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Scheme 3. a) Regiospecific access to 1,5-disusbtituted triazoles. b) Regiospecific access to 1,4,5-trisubstituted triazoles. a2 equiv ketoketal used. c) Scalable
access to 1,2,3-triazoles using flow or batch reactor. d) Chemoselective 1,2,3-triazole formation.
prepared[17] and used to furnish fused bicyclic triazoles,[18] the use
of small (<8 membered) cyclic alkynes remains a significant
synthetic challenge within the click chemistry protocol.
To further expand the process, we showed that 1,5-disubstituted
triazoles could also be prepared using this procedure starting from
2,2-diethoxypropanal 69, providing a complementary procedure
to RuAAC[6] to deliver 70–74 in good yield (68–77%, Scheme 3a).
This series of results suggests that α-ketal aldehydes will prove
to be general substrates to access 1,5-disubstituted triazoles with
high functional group tolerance under metal-, halogen- and azide-
free conditions.
To demonstrate the scalability of the procedure, we designed a
two-stage flow process for triazole formation (Scheme 3c).
Solutions of N-tosylhydrazide 15 and α-ketoacetal 17 were
reacted in a 20 mL reactor at ambient temperature, before
combining with a neat solution of both cyclohexylamine and
triethylamine. The solution was then passed through super-
heated tubing at 145 °C to allow the cyclisation to occur. From this
flow process we isolated 82% of triazole 28 on a 73-gram scale
over a processing time of 4.5 hours. This compared favourably
with a simple batch-process in which the cyclisation reaction
occurred under reflux, isolating 7.4 grams of triazole 28 in an 81%
yield after 16 hours. Each of these procedures highlights the
utility of the method to access 1,2,3-triazoles from α-ketoacetals
on a preparative scale.
Using -ketoketals as substrates we were also able to access
1,4,5-trisusbtituted triazoles using this procedure extending the
scope of the transformation (Scheme 3b). The triazoles 75 and
76 were isolated in 75% and 91% yields respectively through the
reaction of 3,3-dimethoxybutan-2-one under slightly modified
conditions. Of note is the fact that cyclic α-ketoketals were also
suitable substrates providing tetrahydrobenzotriaozles 77 and 78
in 79% and 87% yield respectively. This method is therefore
further complementary to AAC chemistry in which cyclohexyne
would be the alkyne required to deliver the product. Despite being
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[1]
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Finally, to further extend this process we developed a protocol
that could be used for the chemoselective reaction of either
primary aliphatic amines or primary anilines through simple
modification of the reaction conditions (Scheme 3c). Preparation
of the hydrazone 18 under standard conditions followed by
addition of the amino aniline 79 in the presence of NEt3 (1 equiv)
(140 °C, 5 min) gave the 1,4-triazole 80 (83%) which arose from
exclusive reaction of the more nucleophilic aliphatic amine. No
indication of a product from reaction through the aniline nitrogen
could be detected by examination of the crude reaction mixture
by either LCMS or 1H NMR analysis. However, reaction of 18 with
the diamine 79 in the presence of TFA (1 equiv, , 18 h) gave the
alternative triazole product 81 (87%) where triazole formation had
taken place exclusively on the aniline nitrogen.[19] This powerful
divergent strategy suggests this method will be applicable to
preparation of the triazole of choice through judicious choice of
both substrate and additive.
[2]
[3]
[4]
[5]
In conclusion, a scalable, metal-, azide- and halogen-free
multicomponent reaction to prepare substituted 1,2,3-triazoles
has been developed using readily available α-ketoacetals,
N-tosylhydrazide and a primary amine.[20] The procedure shows
excellent functional group tolerance and provides access to the
[6]
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The mechanism for the formation of 23 remains unclear.
However, no precautions were made to degas the
solvent or to inert the headspace of the reaction, and so
the presence of oxygen could facilitate this oxidative
transformation. Moreover, the spectroscopic and
analytical data of the isolated species match that of a
known sample of 23 and is concurrent with literature
substitution pattern of choice in
a regiospecific manner.
Conducting the reaction in the presence of NEt3 (1 equiv) allows
for the generation of p-toluenesulfinic acid as the sole co-product
of the transformation which can be removed by aqueous workup.
To extend the utility of the reaction further, 28 was prepared under
flow or batch reaction conditions highlighting the practical utility
and scalability of the method. This work addresses challenges
associated with the Sakai reaction by removing the need to isolate
a reactive and potentially genotoxic ,-dichlorohydrazone
intermediate and eliminating a problematic bishydrazone co-
product. Further, this methodology expands the scope of the
process by providing regiospecific access to all substitution
patterns of mono-, di- and tri-substituted 1,2,3-triazoles.
Chemoselectivity for primary aliphatic amines over anilines has
been observed, which has previously been unachievable using
,-dichloroketones. This selectivity can be reversed by carrying
out the reaction in the presence of TFA. Further research into this
intriguing method for the preparation of triazoles and its
application is ongoing in our laboratory.[21]
[8]
[9]
[10]
[11]
[12]
[13]
Acknowledgements
The authors thank GlaxoSmithKline for funding and chemical
resources (PRC) and the EPSRC for funding via Prosperity
Partnership EP/S035990/1. The authors thank L. Wilson for
proofreading of this manuscript.
[14]
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,2,3-triazole • azide-free • α-ketoacetals • amines •
heterocycles
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10.1002/anie.201915944
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COMMUNICATION
values. Y. Wang, L. Deng, Y. Deng, J. Han, J. Org.
Chem. 2018, 83, 4674-4680
reaction which could be removed by column
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[20]
[21]
After submission of our work, we became aware that the
Sutton group recently detailed a similar strategy to
access 1,2,3-triazoles. L. R. Zehnder, J. M. Hawkins, S.
C. Sutton. One-Pot, Metal- and Azide-Free Synthesis of
1,2,3-Triazoles from α-Ketoacetals and Amines, Synlett,
2019. DOI: 10.1055/s-0039-1691526
For a potential reaction mechanism, the authors refer
the reader to the previous work of Westermann and
Hanselmann [11-12] and the additional review article: C.
G. S. Lima, A. Ali, S. S. v. Berkel, B. Westermann, M.
Paixão, Chem. Commun, 2015, 51, 10784-10796.
Based on our current findings, the transformation
presented here follows a similar mechanistic pathway,
however current research is ongoing within our
laboratory to gain a more complete understanding.
[17]
[18]
[19]
We believe the TFA acts as a strong Brønsted acid and
protonates the more basic aliphatic amine, removing
this as a reactive partner. Owing to the acidic reaction
conditions, trace quantities of 23 were observed in this
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Peter R. Clark*,
Glynn D. Williams, Jerome F. Hayes
and Nicholas C. O. Tomkinson
Page No. – Page No.
A Scalable, Metal-, Azide- and
Halogen-Free Method for the
Preparation of Triazoles
Tri-component tri-azoles: We report a simple and efficient, redox neutral,
3-component synthesis of 1,2,3-triazoles from α-ketoacetals, N-tosylhydrazide and a
primary amine. The method allows access to all triazole substitution patterns, without
the requirement for azides, alkynes, halides, transition metals or oxidants.
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