Intramolecular hydrogen bonding-assisted cyclocondensation of α-diazoketones with various amines: A strategy for highly efficient Wolff 1,2,3-triazole synthesis

Article abstract of DOI:10.1039/c2cc33157h

A catalytic and highly efficient Wolff's cyclocondensation of α-diazoketones with aromatic and aliphatic amines has been realized for the first time by utilizing the strategy of an intramolecular hydrogen bonding-activating carbonyl group. This approach successfully solved the challenging problem of poor condensation efficiency in Wolff 1,2,3-triazole synthesis, and constitutes a powerful method for the synthesis of highly functionalized 1,2,3-triazoles. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc33157h

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COMMUNICATION
Intramolecular hydrogen bonding-assisted cyclocondensation of
a-diazoketones with various amines: a strategy for highly efficient Wolff
1,2,3-triazole synthesisw
Zikun Wang,a Xihe Bi,*bc Peiqiu Liao,b Rui Zhang,a Yongjiu Lianga and Dewen Dong*ab
Received 2nd May 2012, Accepted 23rd May 2012
DOI: 10.1039/c2cc33157h
A catalytic and highly efficient Wolff’s cyclocondensation of
a-diazoketones with aromatic and aliphatic amines has been realized
for the first time by utilizing the strategy of an intramolecular
hydrogen bonding-activating carbonyl group. This approach
successfully solved the challenging problem of poor condensation
efficiency in Wolff 1,2,3-triazole synthesis, and constitutes a
powerful method for the synthesis of highly functionalized 1,2,3-
triazoles.
Since the seminal discovery of Wolff 1,2,3-triazole synthesis in
1902 through the cyclocondensation of a-diazo carbonyl
compounds with primary amines,1 the Wolff’s cyclocondensation
has become one of the most important synthetic approaches to
1,2,3-triazoles,2 which are a class of heterocycles with unique
Fig. 1 Wolff 1,2,3-triazole synthesis.
chemical characteristics, interesting pharmacological properties
and a broad range of uses in industrial applications.3 Compared
Additionally, the yields of the reactions are highly dependent
to the current most popular Huisgen’s cycloaddition of alkynes
with organic azides,4 Wolff’s cyclocondensation has displayed
the following superior advantages with regards to fabricating a
triazole ring, including: (1) Wolff’s cyclocondensation is a
regiospecific reaction that does not require specific catalysts
such as copper,5 rhodium6 or Pd–Cu bimetallic catalysts7 to
prevent the formation of regioisomers; (2) carbonyl compounds,
the precursor for a-diazocarbonyls, and amines are abundant,
readily available and cheap.
on the amine derivative used, and low yields are often observed for
aliphatic and aromatic amines.11 During our study on the synthetic
utilities of b-oxoamides, we have noted the effect of intramolecular
hydrogen bonding that played a critical role in intramolecular
cyclization reactions.12 Inspired by this finding, we envisaged that
the hydrogen bonding effect could promote the condensation
between the carbonyl group of a-diazo-b-oxoamides with amines
by activating the carbonyl group, thereby realizing a highly efficient
Wolff 1,2,3-triazole synthesis (Fig. 1b).
However, the poor condensation efficiency of the carbonyl
group with aliphatic and aromatic amines, a key step in Wolff’s
cyclocondensation, has seriously hindered the practicality of this
classic reaction in organic synthesis, and become a challenging
problem. To address this issue, non-catalytic reaction conditions
and highly reactive reactants are usually required (Fig. 1a), for
example, the presence of stoichiometric amounts of Lewis acids
(e.g., TiCl4),8 the use of protonic acids (e.g., HOAc) as solvents,
the utility of highly electrophilic a-diazoaldehydes,9 and highly
nucleophilic hydroxylamine and hydrazine, and their derivatives.10
This hypothesis was confirmed by an initial examination of
the cyclocondensation of a-diazoacetoacetamide with aniline
catalyzed by 20 mol% of FeCl3. To our delight, triazole 2b1
was formed efficiently and isolated in 71% yield (Table 1,
entry 1). The structure of 2b1 was unambiguously confirmed
by X-ray crystallography (for details, please see supporting
informationw). Further condition screening for the reaction
parameters, including the type of catalyst, reaction temperature
and solvent, disclosed that they all influenced the cyclization
reaction to some extent (entries 2–11). Finally, the conditions
listed in entry 7 using iron salt (20 mol% FeCl2) as a catalyst were
found to be optimal and therefore selected for the next investiga-
tions.13 Interestingly, the cyclocondensation reaction proceeded
smoothly even in water in the presence of 10 mol% tetrabutyl
ammonium bromide (TBAB), although the reaction required
more time and gave 2a1 in a slightly lower yield (72%) (entry 12).
To confirm the crucial role of intramolecular hydrogen bonding
in the catalytic cyclocondensation reaction, representative
a Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, Changchun, 130022, China. E-mail: dwdong@ciac.jl.cn
b Department of Chemistry, Northeast Normal University, Changchun,
130024, China. E-mail: bixh507@nenu.edu.cn
c State Key Laboratory and Institute of Elemento-organic Chemistry,
Tianjin 300071, China
w Electronic supplementary information (ESI) available: experimental
procedures, analytical data, and spectra copies of all compounds. See
DOI: 10.1039/c2cc33157h
c
7076 Chem. Commun., 2012, 48, 7076–7078
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Table 1 Condition screening
Table
2
Synthesis of 1,2,3-triazoles 2a by varying a-diazo-
b-oxoamides
Entry Cat.
Temp. (1C) Solvent
Time (h) Yielda (%)
Entry
1
R1
R2
2a
Yielda (%)
1
2
3
4
5
6
7
8
FeCl3
SnCl4
TiCl4
p-TsOH
Fe(acac)3 80
Fe(OTf)3 80
FeCl2
—
FeCl2
FeCl2
FeCl2
FeCl2
80
80
80
80
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
10
11
10
15
13
13
10
20
20
10
71
79
60
28
62
68
85
Trace
68
81
15
72
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
2-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
2,4-diMeC6H3
4-CF3C6H4
2-Pyridyl
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
Ph
2a2
2a3
2a4
2a5
2a6
2a7
2a8
2a9
2a10
2a11
2a12
76
87
74
86
72
79
75
77
83
80
67
80
80
50
80
80
80
9
10
11
12b
9
10
11
1j
1k
1l
Toluene 20
H2O 15
Ph
a
b
Isolated yields. TBAB (10 mol%) was added.
a
Isolated yields.
a-diazocarbonyls were subjected to optimal conditions
(Scheme 1). a-Diazocarbonyls lacking amide groups, such as
the acyclic and cyclic a-diazo-b-dicarbonyls S1 and S2 did not
result in any reaction in the presence of 20 mol% FeCl2. The
examination on a-diazo-b-oxoamides that could not form
intramolecular hydrogen bonding showed that the cyclic a-diazo-
b-oxoamide S3 did not react with aniline, while N-protected acyclic
a-diazo-b-oxoamide S4 decomposed itself leaving the aniline intact
in the mixture. These results provided the most direct evidence
that the intramolecular hydrogen bonding interaction between
the amide and the carbonyl group was essential for the
catalytic Wolff 1,2,3-triazole synthesis.
(e.g. 2-pyridyl) and fused aromatic (e.g. 2-naphthyl) amines all
reacted efficiently with 1a to afford 1,2,3-triazoles 2b1–2b7 in
good to high yields. The reaction efficacy was further evaluated
by the reactions of 1a with a wide range of aliphatic amines
containing representative functional groups, such as long-chain
alkyl, cyclopropyl, ester, Boc-protected amino, hydroxyl, alkenyl,
alkynyl and chiral amine groups. All reactions proceeded
smoothly and produced highly functionalized 1,2,3-triazoles
2b8–2b18 in good yields. Also, highly reactive amines such as
methylhydrazine and O-methylhydroxylamine afforded high
yields of 1,2,3-triazoles 2b19 and 2b20. Notably, these useful
functional groups introduced onto the triazole core provided
the possibility for further modification. For example, the
triazole 2b15 (R3 = CH2CH2OH) was used as precursor to
several 1,2,3-triazole-containing kinase inhibitors.14
We used standard conditions and iron catalysis and then
examined the scope of the reaction by the variation of a-diazo-
b-oxoamides (Table 2). Substrates with various R1 groups,
including the electron-donating and electron-withdrawing
group substituted phenyl ring and the heteroaromatic ring
(e.g. 2-pyridyl), all reacted efficiently with aniline to afford
corresponding triazoles 2a2–2a10 in good to high yields
(entries 1–9). Similarly, the variation of the R2 group from a
methyl group to bulk substituents such as n-Pr and Ph also
gave the desired triazoles 2a11 and 2a12, even though the yield
of 2a12 was moderate (67%) (entries 10 and 11).
NH-1,2,3-triazoles are an important group of triazole
derivatives.3,15 They have interesting biological activities such
Table 3 Synthesis of 1,2,3-triazoles 2b by varying aminesa
Next, the reactivity of the amines was scrutinized in detail.
The variation of the amines in the cyclocondensation with
a-diazo-b-oxoamide 1a showed that the scope of the reaction
was quite broad (Table 3). Aromatic amines with electron-donating
and electron-withdrawing substituents on aniline, heteroaromatic
a
Isolated yields.
Scheme 1 Probing the effect of hydrogen bonding.
c
This journal is The Royal Society of Chemistry 2012
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Table 4 Synthesis of NH-1,2,3-triazoles 2ca
Notes and references
1 (a) L. Wolff, Justus Liebigs Ann. Chem., 1902, 325, 129;
(b) L. Wolff, Justus Liebigs Ann. Chem., 1912, 394, 23.
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of Synthesis, ed. R. C. Storr and T. L. Gilchrist, Thieme, Stuttgart,
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a
Isolated yields.
3 S. G. Agalave, S. R. Maujan and V. S. Pore, Chem.–Asian J., 2011,
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as the ability to inhibit indoleamine 2,3-dioxygenase (IDO)
and VIM-2 metallo-b-lactamase.16 Previous protocols for the
synthesis of NH-1,2,3-triazoles by the Wolff cyclocondensation of
a-diazoaldehydes with NH4OAc in acetic acid (HOAc) suffered
from low yields (20%–50%).11 With the aim of examining the
generality of our method, we carried out the reactions of several
a-diazo-b-oxoamides with NH4OAc. To our delight, the desired
NH-1,2,3-triazoles 2c1–2c5 were isolated with excellent yields
(Table 4). It is worth mentioning that the 1,2,3-triazole products
2a, 2b and 2c all contain an amide group and previous studies
have described its transformation into a more reactive carboxylic
acid.17 In this way, the amide group on the 1,2,3-triazole products
not only promotes the condensation but is also a potentially
useful functional group.
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Considering the importance of bidentate flexible ligands
containing two 1,2,3-triazole units in coordination chemistry,
we next investigated the cyclocondensation of a-diazo-
b-oxoamides 1h/1k with 1,6-hexanediamine under the FeCl2-
catalyzed conditions.18 As expected bis-triazoles 3a and 3b
were isolated in 74% and 71% yields, respectively (eqn (1)).
The yields were calculated based on the 1,6-hexanediamine.
11 O. Sezer, K. Dabak, A. Akar and O. Anac, Helv. Chim. Acta, 1996,
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C. Valdes, G. Beltran, M. Escribano and F. Aznar, Angew. Chem.,
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ð1Þ
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In summary, the catalytic Wolff cyclocondensation has been
realized for the first time by utilizing the strategy of an
intramolecular hydrogen bonding-activating carbonyl group,
thereby successfully addressing the challenging problem that
poor reaction efficiency existed in the Wolff cyclocondensation
of a-diazoketones with aromatic and aliphatic amines. The
reaction scope is quite broad and constitutes a powerful route
to highly functionalized 1,2,3-triazoles.
Financial supports by National Natural Science Foundation
of China (21172211, 21172029), ‘‘Hundred Talents Program’’ of
the Chinese Academy of Sciences.
18 J. D. Crowley and D. A. McMorran, Top. Heterocycl. Chem.,
2012, 28, 31–83.
c
7078 Chem. Commun., 2012, 48, 7076–7078
This journal is The Royal Society of Chemistry 2012