Electrochemical synthesis of 1,2,4-triazole-fused heterocycles

Article abstract of DOI:10.1039/c7gc03739b

A reagent-free intramolecular dehydrogenative C-N cross-coupling reaction has been developed under mild electrolytic conditions. In this atom- and step-economical one-pot process, valuable 1,2,4-triazolo[4,3-a]pyridines and related heterocyclic compounds could be synthesized efficiently from commercially available aliphatic or (hetero)aromatic aldehydes and 2-hydrazinopyridines. Various functional groups are compatible with this metal- and oxidant-free protocol which can be carried out on a gram scale easily. This novel method was applied to the synthesis of one of the top-selling drugs Xanax and late stage functionalization for generating chemical diversity in biologically relevant lead molecules.

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Electrochemical Synthesis of 1,2,4-Triazole-Fused Heterocycles
Zenghui Ye,a Mingruo Ding,a Yanqi Wu,b Yong Li,a Wenkai Huaa and Fengzhi Zhang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
group tolerance, and innate scalability.[5]
A
reagent-free intramolecular dehydrogenative C–N cross-
coupling reaction has been developed under mild electrolytic
conditions. In this atom- and step-economic one-pot process,
valuable 1,2,4-triazolo[4,3-a]pyridines and related heterocyclic
compounds could be synthesized efficiently from commercially
available aliphatic or (hetero)aromatic aldehydes and 2-
hydrazinopyridines. Various functional groups are compatible with
Triazolopyridines
and
the
related
triazole-fused
poly(hetero)aromatic structures are privileged scaffolds of
numerous biological active compounds and functional materials
(Scheme 1a).[6] A wide range of biological activities have been
reported with this skeleton, such as antiproliferative,[7]
antipsychotic,[8] antibacterial[9] and anti-depressant etc.[10]
this metal- and oxidant-free protocol which can be carried out on Previously, the triazolopyridine scaffold 1 were mainly constructed
by the intramolecular cyclization of 2-pyridylhydrazone[11] or N-
gram scale easily. This novel method was applied to the synthesis
(pyridin-2-yl)benzohydrazide 2[12] starting from 2-chloropyridine
of one of the top selling drugs Xanax and late stage
(Scheme 1b). Another complementary approach involves the
functionalization for generating chemical diversity of biologically
relevant lead molecules.
intermolecular 1,3-dipolar cycloaddition between the N-heterocycle
3
and N-tosylhydrazone 4.[13] However, most of the existing
protocols still have drawbacks: 1) harsh reaction conditions; 2) the
use of expensive catalysts or superstoichiometric amounts of
oxidizing agents; 3) limited substrate scopes or scalability; 4) low
chemo-selectivity. Therefore, it’s desirable to develop
complementary approaches for the fast and efficient synthesis of
these valuable 1,2,4-triazole-fused heterocycles.
Introduction
The construction of the carbon-nitrogen (C−N) bonds in an efficient
and sustainable fashion is a long-standing challenge for the organic
chemists due to the prevalence of complicated nitrogen-containing
natural products, functional materials, and pharmaceutical
agents.[1] Although the conventional transition-metal (TM)
catalyzed C−N cross-coupling reactions have been used widely for
the C−N bond formaꢀon, these methods normally require extra
steps to pre-functionalize the starting materials which would
consume resources and generate stoichiometric amounts of
harmful byproducts.[2] To address this issue, significant progress
have been achieved in TM-catalyzed direct C−H aminaꢀon.[3] While
these methods are relatively step- and atom-economical, most of
the protocols still require expensive TM catalysts and
superstoichiometric amounts of external oxidants under harsh
conditions.[4] Therefore, it’s highly important to develop metal- and
oxidant-free C−N bond forming methods for the preparation of
biologically active nitrogen-containing compounds, which would
possess many advantages over traditional reagent-based
transformations, such as mild reaction conditions, highly functional
Electroorganic synthesis which is a versatile and environmentally
friendly synthetic tool has attracted renewed interest.[14] Recently,
electrochemical anodic oxidation has been successfully employed in
the cross-dehydrogenative coupling (CDC) for the construction of C-
N bonds.[15] In 2014, Little group reported an electrochemically
promoted oxidative amination of benzoxazoles with secondary
amines.[16] In 2017, Xu group developed an efficient anodic
cyclization of amidines for the synthesis of benzimidazoles.[17] Very
recently, the same group reported the synthesis of N-
heteroaromatic products through anodic condensation between
biaryl aldehydes and NH3.[18] With our continued interest in
developing green organic reactions for the synthesis of
heterocycles,[19] herein we reported an efficient one-pot synthesis
of various functionalized 1,2,4-triazolo[4,3-a]pyridines and related
heterocycles by a C−N bond forming reaction under metal- and
oxidant-free undivided electrosynthetic conditions (Scheme 1c).
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Table 1 Optimization of electrochemical conditions [a]
Entry
Substrate
Variation from standard
conditions
Yield
(%)[b]
R.T. (25 oC)
50 oC
1
2a
40
48
98
0
2
2a
3[c]
2a
None
Scheme 1. Functionalized 1,2,4-triazolo[4,3-a]heterocycles and
their synthesis.
No current
MeCN
4
2a
Results and discussion
5
2a
68
31
56
6
5a + 6a
5a + 6a
5a + 6a
5a + 6a
5a + 6a
5a + 6a
5a + 6a
5a + 6a
(a) EtOH, 2.24 F/mol
(b) MeCN, 2.24 F/mol
The electrochemical reaction was performed under constant
current conditions in a simple undivided cell equipped with a
normal graphite rod anode and a Pt plate cathode. First, we
investigated the electrochemically promoted oxidative cyclization
with hydrazone 2a as the substrate, which was prepared in 89%
yield through the condensation of 2-hydrazinopyridine 5a and
benzaldehyde 6a. Utilizing n-Bu4NBF4 as the electrolyte, the mixture
of acetonitrile and H2O as the co-solvent,20 the desired cyclized
product 7a could be obtained in 40% yield under 10 mA constant
current at room temperature (Table 1, entry 1). It was found that
the yield could be improved with increased temperature (Table 1,
entry 2-3). Gratifingly, the triazolopyridine product 7a could be
obtained in 98% yield by conducting the reaction at 70 °C (Table 1,
entry 3). Decreasing the constant current to 7 mA with the same
electricity gave the product in 85% yield (Table 1, entry 3). No
product was obtained in the absence of an electric current (Table 1,
entry 4). The yield was dropped significantly to 68% if acetonitrile
was used as the single solvent (Table1, entry 5).
7
8
(b) MeCN/EtOH, 2.24 F/mol 70
9
2.24 F/mol
None
74
86
10
34
37
10
11
12
13
C (+) | C (-)
Pt (+) | Pt (-)
LiClO4 as electrolyte
aOne-pot reaction conditions: (i) 5a (0.5 mmol), 6a (1.2 equiv),
MeCN (5 mL), rt or heat; (ii) C (+) | Pt (-), n-Bu4NBF4 (1.0 equiv),
MeCN/H2O (4/1 mL), 70 oC, air atmosphere, undivided cell.
bIsolated yield. cThe yield was 85% when I = 7 mA.
With optimized reaction conditions in hand, the substrate scopes
of this novel one-pot transformation were probed next. By reacting
substituted 2-hydrazinopyridine 5 with various aromatic aldehydes
Next, we investigated the sequential one-pot synthesis of
triazolopyridine 7a without the isolation of intermediate 2a. After
the first condensation was completed, the electrodes, n-Bu4NBF4
and solvents were added directly to the reaction system to continue
for the electrochemically promoted dehydrocyclization. The
influence of the solvents was studied first (Table 1, entries 6-9). It
was found the yield could be improved to 74% by using MeCN and
H2O as the co-solvents (Table 1, entry 9). By increasing the
electricity to 2.98 F/mol the yield could be further improved to 86%
(Table 1, entry 10). By changing the other electrodes or electrolytes
resulted much poorer yields of the product (Table 1, entries 11-13).
under the optimized conditions,
a series of 3-aryl[1,2,4]-
triazolo[4,3-a]pyridines and related heterocyclic derivatives were
prepared efficiently (Table 2). Both the aromatic and
heteroaromatic aldehydes (such as furan 7f, thiazole 7g, pyridine 7h
and indole 7i) have proven to be viable substrates. Notably,
medicinally privileged pyrazine (7m), pyridazine (7n) and
quinolones (7o-q) have also been successfully coupled with
aldehydes affording the valuable cyclized products in good yields.
For example, the compound 7dg could be used for the OLED
material,[10f] and compound 7q shows good inhibitory activity
against several bacterial strains.[9] It is worth to mention that
various functional groups including halogen (7da-db), free alcohol
(7dc), highly electron-donating (7dd-df) or withdrawing groups (7c,
7dg-dh and 7q) were tolerated under the reaction conditions, which
could be used for further transformations.
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to 100 mA with the same 2.98 F/mol of charge, the reaction of 5a
with different aromatic aldehydes 6 furnished the desired cyclized
products 7a-c in good yields respectively (Scheme 2). These results
highlight the operational simplicity, safe procedure, simple workup
and ease of product isolation of this newly developed method.
Table 2 Substrate scopes with aromatic aldehydes.
R1
R1
N
NHNH2
N
X
ArCHO, MeCN
X
N
N
then C (+) Pt (ꢀ), I = 10 mA
nBu4BF4, MeCN/H2O, 70 °C
5
Ar
7
X = C or N
24 examples, up to 94% yield
7da, R = Cl, 65%
7db, R = Br, 64%
7dc, R = OH, 62%
N
N
N
N
N
N
N
N
N
N
N
N
7dd,
R = OMe, 84%
Me
7de, R = NEt2, 85%
7df, R = NHCOMe 75%
F3C
R
7a
, 86%
N
7b, 84%
7c, 87%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
S
Scheme 2 Gram scale synthesis of triazolopyridines.
N
CN
CO2Me
7dg, 54%
7e, 94%
7dh,
7g, 50%
Cl
70%
7f, 76%
To further understand this reaction we carried out the following
experiments (Scheme 5). First we treated the phenylhydrazine 9
with benzaldehyde 6a under the optimized conditions, only the
hydrazone product 10 was isolated in 90% yield without detection
of the cyclized product 11 (Scheme 3, eq 1). No cyclized product
was detected as well by reacting 2-hydrazinopyridine 5a with
ketone 12 (Scheme 3, eq 2). 2-Hydrazinyl pyrimidine 14a was then
tested, interestingly the reaction can be carried out at r.t. and gave
the desired cyclized product 15a in 76% yield (Scheme 3, eq 3).
However, the 2-hydrazinyl-4-methylpyrimidine 14b afforded an
inseparable mixture of 15b in 67% yield, with the cyclization mainly
taking place at the nitrogen far away from the methyl substituent.
When the radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT,
1.0 equiv.) was added into the reaction system, the desired product
7a was only isolated in 16% yield (Scheme 3, eq 4). The reaction
was inhibited completely in the presence of 2.0 equiv. BHT. By
adding 2,2,6,6-tetramethyl-1-piperidinyloxy(TEMPO, 1.0 equiv. or
2.0 equiv.) into the reaction, 7a was isolated only in 31% and 25%
yield respectively under 2.24 F/mol electricity with large amounts of
starting material 2a recovered. If the electricity was increased to 5.22
F/mol the reaction was completed and gave the cyclized product 7a
only in 54% yield in the presence of 2.0 equiv. TEMPO. These
experimental results implied that the reaction might involve a radical
pathway.
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
F3C
N
N
H
7h
, 41%
7i, 75%
7j, 90%
7k, 53%
7l
, 88%
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cl
N
O
NO2
7m
, 76%
7n, 85%
7o, 75%
7p
, 71%
7q, 55%
This C−H/N−H cross-coupling reaction also showcased a broad
scope with respect to the aliphatic and unsaturated aldehydes
(Table 3). Various aldehydes with cyclopropyl (8a), linear aliphatic
alkanyl (8b-e), benzyl (8f), vinyl (8g), bicycloheptenyl (8h) or
piperidinyl (8i) group were effective affording the desired cyclized
products in good yields. The Boc protecting group remained
untouched because of the neutral electrochemical condition. It is of
note that compound 8j has been demonstrated good antimicrobial
activity for monocotyledonous plants.[10g] Other N-containing
heterocyclic substrates such as quinolone and pyridazine worked as
well affording the corresponding medicinally important products
8m and 8n.
Table 3 Substrate scopes with aliphatic aldehydes.
The scalability of this electrochemical dehydrogenative C–N
cross-coupling was then evaluated by performing 10 mmol scale
reaction, which was conducted using inexpensive graphite rod
electrodes in a beaker open to air. Increasing the constant current
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H
N
H
[1,2,4]triazolo[4,3-ɑ]pyridine 7b was used as the substrate probably
because of the relatively rigid multi-substituted biaryl linkage.
Reacting the 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-ɑ]-pyridine 7c
with iodide 16b afforded the mono-arylated product 17cb in 89%
yield as single product, which might useful for the modulation of
beta-secretase enzyme activity and for the treatment of Alzheimer’s
disease.[23] To our knowledge this is the first example of direct
arylation by employing the triazolopyridine as the directing group.
N
CHO
N
+
NHNH2
N
(1)
Ph
N
+
standard conditions
standard conditions
Ph
11, 0%
10
, 90%
9
6a
H
N
NHNH2
+
O
(2)
(3)
N
Ph
12
N
Ph
5a
13, 88%
R
N
CHO
N
R
N
N
R
N
NHNH2
N
+
N
Scheme 5 Directed arylation of triazolopyridines
N
N
+
N
standard conditions
Ph
Ph
room temperature
14a, R = H
14b, R = Me
Finally we applied our method for the synthesis of alprazolam
which is one of the most prescribed medicines in the US in 2010 for
the treatment of anxiety disorders under the trade name Xanax
(Scheme 6).[24] The key intermediate 20 was prepared from 19
according to the known procedure in 50% yield over 4 steps.[25]
Treatment of 20 and acetaldehyde under our standard
electrochemical conditions gave the desired product Xanax 21a in
60% yield, which was normally obtained in much lower yield over a
two-step procedure under harsh conditions.[24d] By employing this
metal- and oxidant-free green protocol, the late stage
functionalization of 20 for generating chemical diversity of
biologically relevant lead molecules could be easily achieved as well.
For example, by using both aliphatic and aromatic aldehydes, the
other analogues of Xanax 21b and 21c could be prepared in 55%
and 52% yield respectively.
6a
15a, 76%
15b, 67% (1.7:1)
N
N
H
N
N
N
(4)
N
standard conditions
I = 10 mA
2a
additive
electricity
7a
BHT (1.0 equiv)
BHT (2.0 equiv)
TEMPO (1.0 equiv)
TEMPO (2.0 equiv)
TEMPO (2.0 equiv)
2.24 F/mol
2.24 F/mol
2.24 F/mol
2.24 F/mol
5.22 F/mol
16%
trace
31%
25%
54%
Scheme 3 Control experiments.
Based on the experimental results and literature reports,[21]
a
plausible mechanism was proposed in Scheme 4. The condensation
of 2-hydrazinopyridine 5a and benzaldehyde 6a gave the hydrazone
2a which has a tautomer I. Subsequent deprotonation by hydroxide
generated from cathodic reduction of water would produce a
nitrogen ion intermediate II. Single-electron transfer (SET) oxidation
of II by the anode might form a nitrogen radical intermediate III.
Followed by the intramolecular radical addition, anodic oxidation
and deprotonation the final product 7a could be obtained via the
intermediate IV. At the same time, concomitant cathodic reduction
of water can release hydrogen gas as the by-product.
R
N
N
NHNH2
N
N
1) ClCH2COCl
2) HMTM, NH4OAc
NH2
O
RCHO
N
N
Cl
Cl
Cl
standard
3) Lawesson's reagent
4) N2H4 — H2O
conditions
50% overall yield
21a, R = Me, 60%
21b, R = Bn, 55%
20
19
21c
, R = Ph, 52%
Scheme 6 Synthesis of Xanax and its biologically relevant analogues
through late stage functionalization.
eꢀ
Conclusions
eꢀ
N
N
N
N
OHꢀ
eꢀ
In conclusion, we have developed an environmentally friendly,
atom- and step-economic one-pot electrochemical reaction
protocol to synthesize valuable 1,2,4-triazolo[4,3-a]pyridines and
related heterocycles. Commercially available aromatic, aliphatic and
a,β-unsaturated aldehydes could be used as substrates. Neither
metal catalysts nor chemical oxidants were needed in this simple
transformation, and various functional groups are compatible with
this mild conditions. The further transformations of the products
were successfully achieved for the first time by direct arylation
using the triazolopyridine as the directing group. Importantly, this
reaction could be conducted on a gram scale, and applied for the
synthesis of one of the most selling drugs Xanax and its biologically
relevant analogues. Further applications of this method and the
biologically screening of those valuable heterocyclic products are
ongoing in our lab, which will be reported in due course.
II
N
N
N
N
N
1/2 H2
NH
7a
I
eꢀ
eꢀ
H
H2O
H2
O
N
N
OHꢀ
2a
N
N
NHNH2
OHC
N
N
N
H
N
N
6a
5a
IV
III
Scheme 4 Proposed mechanism.
To further demonstrate the applicability of our novel method, we
successfully carried out a direct arylation of the 1,2,4-triazolo[4,3-
a]pyridine product 7 with aryl iodide 16 under Ru-catalyzed
condition (Scheme 5).[22] The reaction between unsubstituted
triazolopyridine 7a with aryl iodide 16a or 16b gave a mixture of
mono-arylated and bis-arylated products (17 and 18) respectively.
There is no arylated product formed if the 3-(o-tolyl)-
Acknowledgements
This research was supported by Zhejiang Provincial Natural Science
Foundation of China for Distinguished Young Scholars under grant
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No. LR15H300001. We aslo thank the Zhejiang Provincial Thousand-
Talent Program and Zhejiang University of Technology for financial
support.
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The authors declare no conflict of interest.
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Table of Contents
Electrochemical Synthesis of 1,2,4-Triazole-Fused
Heterocycles
Z. Ye, Mingruo Ding, Y. Wu, Y. Li, W. Hua and F. Zhang*
A reagent free electrochemical synthesis of valuable 1,2,4-triazolo[4,3-a]pyridines and related heterocycles was
developed.