An azide and acetylene free synthesis of 1-substituted 1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2020.152483

This paper details a simple and efficient 3-component synthesis of 1-substituted 1,2,3-triazoles using a primary amine, 2,2-dimethoxyacetaldehyde and tosylhydrazide. The reaction proceeds in good to excellent yields using either aliphatic or aromatic amine substrates and is tolerant of a wide range of functional groups including electron-rich and deficient aryl groups, terminal alkynes, ketones and highly sterically encumbered amines.

Full text of DOI:10.1016/j.tetlet.2020.152483

Journal Pre-proofs
An azide and acetylene free synthesis of 1–substituted 1,2,3-triazoles
Sarah J.M. Patterson, Peter R. Clark, Glynn D. Williams, Nicholas C.O.
Tomkinson
PII:
S0040-4039(20)30964-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152483
TETL 152483
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 July 2020
17 September 2020
21 September 2020
Please cite this article as: Patterson, S.J.M., Clark, P.R., Williams, G.D., Tomkinson, N.C.O., An azide and
acetylene free synthesis of 1–substituted 1,2,3-triazoles, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/
j.tetlet.2020.152483
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An azide and acetylene free synthesis of 1-substituted 1,2,3-triazoles
Sarah J. M. Patterson, a Peter R. Clark,*a,b Glynn D. Williamsa,c and Nicholas C. O. Tomkinsonb
a. Chemical Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK
b. Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
c. Current address: API Chemistry, Aptuit, 111 Innovation Dr, Milton, Abingdon, OX14 4RZ
This paper details a simple and efficient 3-component of sulfur-fluoride exchange (SuFEx) reagents and the valuable
synthesis of 1-substituted 1,2,3-triazoles using a primary transformations these reagents offer is undeniable, the
amine, 2,2-dimethoxyacetaldehyde and tosylhydrazide. The liberation of noxious gases (SO2) and poor cost and atom
reaction proceeds in good to excellent yields using either efficiency render these reactions less desirable to large-scale
aliphatic or aniline substrates and is tolerant of a wide range synthetic procedures. Moreover, the use of organic azides
of functional groups including electron-rich and deficient aryl remains essential for each of these procedures. These species
groups, terminal alkynes, ketones and highly sterically often require preparation and the high energetics associated
encumbered amines.
with azides would necessitate significant process understanding
on a larger scale.
1-Substituted triazoles are prevalent bioactive substrates,
exemplified by their occurrence in important pharmaceutical
compounds. Tazobactam 1 is a beta-lactamase inhibitor used to
treat a variety of bacterial infections1 and IMG-7289 2 is an
irreversible LSD1 inhibitor currently in Phase 2b clinical trials for
the treatment of patients with myelofibrosis and myeloid
leukaemia (Figure 1).2 The presence of N-alkyl and N-aryl
1,2,3-triazoles in pharmaceutical compounds suggests that the
development of new, efficient methodologies to synthesise
these functionalities will be of great value to chemical
industries.
Azide-alkyne cycloaddition
Azide and ESF
b)
a)
OH
R
N3
R
N3
SO2F
TMS
3
CaC2
4
COOH
Use of azide reagents
Liberates noxious gases
Use of azide reagents
Transition metal required
Alklyation or cross coupling
Sakai reaction
d)
c)
TsHN
N
N
N
+
R
X
NH
Cl
H2N
R
H
X = Br, I
5
6
7
Cl
N
N
Regioselectivity concerns
Transition metal required
Two-step process
N
Chlorinated reagent
O
O
H
H
N
S
e) This work:
N
N
H
N
N
O
O
N
N
O
N
F
O
MeO
+
TsNHNH2
+
H2N
R
N
R
OH
NMe
H
O
8
9
OMe
1
2
Tazobactam
Figure 1 Examples of biologically active 1I,M2,G3--7t2r8i9azoles
Figure
2 7Common methods for 1-
substituted triazole synthesis
A direct method for the synthesis of 1-substituted triazoles is
the copper(I) azide-alkyne cycloaddition reaction (CuAAC) with
an organic azide 3 and acetylene gas (Figure 2a).3,4 Acetylene is
a flammable and explosive gas and as such, powerful
engineering solutions have been developed to overcome the
safety hazards associated with this methodology.5 An additional
challenge with this approach is the fact that acetylene can react
with a copper(I) source to produce the heat and shock-sensitive
explosive copper acetylide.6 Therefore, it is unsurprising that
safer, indirect alternatives for this transformation have been
developed. The protecting groups utilised are often C(CH3)2OH,
trimethylsilyl- and carboxyl-, as well as the inorganic source of
acetylene, calcium carbide. These species have proven to be
valuable synthetic precursors to access triazole products (Figure
2a).7-10 Whilst these are easier to handle than acetylene, the
products require an extra synthetic step to remove the handle,
increasing the length of the synthesis and inevitably resulting in
a loss of yield. To this end, Moses recently presented a traceless
alternative using ethenesulfonyl fluoride (4, ESF) to give triazole
products which could be isolated without the need for
protecting groups (Figure 2b).11 Whilst the growing popularity
An alternative to the use of azides is to use the preformed
parent heterocycle, 1,2,3-triazole (5), to access 1-substituted
triazoles. This species is known to participate in SN2 reactions or
metal
catalysed
cross-couplings
(Figure
2c).12, 13
Whilst effective, these reactions tend to offer poor
regioselectivity, leading to mixtures of 1-substituted and
2-substituted products that can be difficult to separate.
Harada and Singh have both reported an adaption of the Sakai
reaction14, 15 showing that dichlorohydrazone 6 can react with a
primary amine 7 to furnish 1-substituted triazoles (Figure
2d).16, 17 However, the use of halogenated reagents and the
requirement to prepare and isolate a potentially hazardous
hydrazone intermediate (6) is undesirable. There remains an
unmet challenge for the direct, one-pot synthesis of
1-substituted triazoles from a primary amine.
Recently, both ourselves and
simultaneously reported that α-ketoacetals could be used as
effective triazole precursors through one-pot, three-
component synthesis leading to a simple method for the
a
group from Pfizer
a

preparation of 4-, 1,4-, 1,5- and 1,4,5-substituted triazole
products.18, 19 We believed that this method would be
applicable to a novel procedure to access 1-substituted
1,2,3-triazoles. Within this work we describe our findings which
show the use of readily available 2,2-dimethoxyacetaldehyde 8
as a precursor to this important heterocycle through the
reaction with p-toluene sulfonylhydrazide (9) and a primary
amine (7, Figure 2e).
3
4
5
6
7
75
75
75
75
30
AcOH (1.0)
MsOH (1.0)
AcOH (0.1)
AcOH (5.0)
AcOH (1.0)
16
16
16
16
72
78[b] (76)
2
72
74
54
Table 1 Optimisation of the presented transformation
[a] solution yield calculated using 1,3,5-trimethoxybenzene by 1H NMR
spectroscopy. [b] solution yield calculated as an average of 3 experiments. The
yield in parenthesis was the isolated yield of one experiment after
chromatographic purification.
Condensation of p-toluene sulfonylhydrazide 9 with an aqueous
solution of dimethoxyacetaldehyde 8 proceeded smoothly in
methanol to give the intermediate hydrazone 10 after 2 hours.20
Addition of benzylamine (11) directly to the reaction mixture
and heating the resulting solution in a sealed tube at 75 °C for
16 hours gave 65% N-benzyltriazole 12 (Entry 1, Table 1).
Surprisingly, in contrast to literature observations,18 addition of
triethylamine (1.1 equiv) lowered the yield of 12 to 57% (Entry
2). Examination of the literature surrounding the Sakai reaction
suggests that chlorovinyldiazene 13 is a potential intermediate
in the transformation.21 The mass of the analogous enol ether
diazene intermediate 14 was observed as a fragment ion of
hydrazone 10 in an LCMS experiment (m/z = 241.1 in the MS
ES+). Despite being unable to isolate a clean sample of
compound 14, the presence of a fragment ion consistent in
mass with this species (m/z = 241) suggests that it could play an
important role in the reaction mechanism. To promote collapse
of acetal 10 to enol ether 14, Entry 3 details the result of an
experiment performed in the presence of 1 equivalent of acetic
acid, which led to a 78% solution yield of the triazole 12. The
stronger acid, methanesulfonic acid, almost entirely shut down
the desired reaction pathway (2% 12, 16 h, Entry 4) suggesting
the process is pH sensitive. This remains in contrast to our
previous work which showed that the yield of the desired
triazole product proved to be pH independent.18 0.1 equivalents
of acetic acid resulted in only a slight decrease in yield of the
desired triazole (72% yield Entry 5), whilst increasing the acetic
acid loading to 5 equivalents did not prove beneficial (Entry 6,
74%). Finally, we observed that lower temperatures resulted in
lower yields of triazole 12 after prolonged reaction times (54%
at 30 °C, 72 h, Entry 7).22 With these observations, the
conditions shown in Entry 3 were scaled up and we isolated 76%
We next turned our attention to aniline nucleophiles,
speculating that less basic primary amines would prove to be
effective substrates under the acidic reaction conditions
(Scheme 1). Using aniline (15) as the coupling partner gave an
excellent yield of 1-phenyl triazole (97% yield). Further
exploration of anilines revealed that halogenated substrates
(fluoro-, chloro-, bromo- and iodo-anilines) gave the triazole
products 16–19 (71–82%) and the trisubstituted aniline
substrate 20 gave the triazole product in 90% yield. Both
electron-rich (methoxy 21 90%, dimethylamino 22 78%) and
electron-deficient systems (acetophenone 23 95%, methyl ester
24 98%, nitro 25 81% yield) were also tolerated within the
transformation. Sterically encumbered 2,6-dimethylaniline 26
provided access to the triazole product in 82% yield showing a
high level of steric tolerance within the amine partner.
Aminophenol 27 afforded an 84% yield of the triazole product
in which the phenol did not require protection. Amino-
pyridines 28 and 29 also proved effective within the
transformation providing the expected products in 38% and
64% yield respectively. Next, we explored some simple aliphatic
amines including propargylamine 30 (33%), cyclohexylamine 31
(54%) and hexylamine 32 (57%) which all provided the expected
triazole products.23 Further optimisation of the standard
reaction conditions should allow for further development of the
scope of this transformation.
NHTs
O
N
R
R
N
NH2
TsNHNH2
N
MeO
MeO
N
H
H
AcOH (1.0 equiv)
75 °C, 16 h
MeOH
rt, 2 h
OMe
OMe
of triazole 12.
8
10
, quant.
H2N
NHTs
O
11
BnNH2
(1.1 equiv)
9
N
TsNHNH2
N
BnN
MeO
H2N
MeO
H2N
MeOH
rt, 2 h
N
Additive
H
H
H2N
H2N
8
OMe
N
10
12
OMe
F
Cl
11
15
16
17
75%
NTs
NTs
76%
97%
82%
90%
N
H2N
F
R
H
H2N
H2N
Cl 13
OMe 14
Intermediate proposed
in the Sakai reaction
Br
I
OMe
Exact Mass: 240.06
via
18
19
20
21
25
75%
78%
78%
95%
90%
81%
H2N
H2N
H2N
H2N
O
Entry
Temperature
(°C)
Additive
(equiv)
Time
(h)
12 yield[a]
NMe2
CO2Me
NO2
22
23
24
98%
1
2
75
75
none
16
16
65[b]
57[b]
OH
H2N
N
H2N
H2N
N
H2N
Et3N (1.1)
26
27
28
29
82%
84%
38%
H2N
67%
H2N
H2N
30
31
32
57%
33%
54%

Scheme 1 Scope of the developed method, showing the amine In conclusion, an operationally simple azide, halogen and
starting materials utilised. Percentages shown correspond to acetylene free synthesis of 1-substituted-1,2,3-triazoles has
the isolated yield of the corresponding triazole product after been developed. The reaction involves the condensation of
column chromatography.
2,2-dimethoxyacetaldehyde 8 with p-toluene sulfonylhydrazide
9 and reaction of the resultant hydrazone with a primary amine
As an exemplification of this method, we isolated 13.35 g of the 7 under mildly acidic conditions. The transformation tolerates a
product derived from methyl 4-aminobenzoate 24 in 85% yield wide range of functional groups, including alkynes, ketones,
after a simple precipitative workup (Scheme 2). This triazole alcohols, esters and halides. The developed method presents a
product can then be used to prepare the irreversible LSD1 regiospecific alternative to literature processes that avoids the
inhibitor, IMG-7289 (2) in 6 steps using known literature use of both azides and acetylene derivatives, as well as
transformations.24 The high-yielding nature of the providing a transition-metal free route to these valuable
transformation highlights the practical utility of this method to compounds. This important new method will therefore have
synthesise biologically active 1-substituted triazoles on a applications in the synthetic community when the use of azides
preparative scale.
and acetylene are discouraged.
H2N
N
N
N
Acknowledgements
NHTs
N
CO2Me
, 1.1 equiv
24
MeO
H
The authors thank GlaxoSmithKline for funding and chemical
resources (PRC, SJMP) and the EPSRC for funding via Prosperity
Partnership EP/S035990/1. The authors thank J. Hayes for his
early work and for helpful discussions during the preparation of
this manuscript.
CO2Me
, 13.35 g, 85%
AcOH (1 equiv)
reflux, 18 h
OMe
10
24a
N
N
N
H
N
6 steps
N
H
(Literature)
O
Conflicts of interest
There are no conflicts to declare
O
N
F
NMe
2
IMG-7289
Scheme 2 Triazole formation on a multi-gram scale
A
potential mechanism for this 3-component coupling
procedure is outlined in Scheme 3. Hydrazone 10 can eliminate
an equivalent of methanol to form enoldiazene intermediate
14. This species can undergo a 1,4-addition with the primary
amine, analogous to the Sakai reaction forming hemiaminal
intermediate 33.14, 15, 20 This species is then primed to lose a
second equivalent of methanol leading to enaminediazene 34.
Under the acidic reaction conditions, protonation of this species
can be invoked, enabling an addition-elimination sequence to
form the triazole product 35 after elimination of p-toluene
sulfinate (36).25
Notes and references
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R1
O
6
NH
R1NH2, AcOH
S
N
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N
O
OMe
10
H
35
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OMe
7
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8
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O
S
R1
Ts
N
N
N
HN
34
O
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OMe
±H+
+H+
-MeOH
14
Ts
R1
NH HN
N
OMe
33
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Scheme 3 A proposed mechanism for the transformation

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,
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20 Full consumption of p-toluene sulfonylhydrazide was
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temperature. The consumption of this peak coincided with
the formation of a single new species which was consistent
in mass with hydrazone 10 by LCMS analysis.
21 R. Hanselmann, G. E. Job, G. Johnson, R. Lou, J. G. Martynow
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quantities of hydrazone 10, indicated by both HPLC and
LCMS.
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amines could be due to the increased basicity of an aliphatic
amine when compared to an aromatic amine. Under the
reaction conditions using acetic acid, the aliphatic amine will
remained protonated, which would result in a lower
concentration of free amine in the reaction mixture to
participate in the desired transformation.
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