Organocatalytic 1,3-Dipolar Cycloaddition Reaction of β-Keto Amides with Azides - Direct Access to 1,4,5-Trisubstituted 1,2,3-Triazole-4-carboxamides

Article abstract of DOI:10.1002/ejoc.201600157

Organocatalytic [3+2] 1,3-dipolar cycloaddition reactions of β-keto amides with azides catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been developed. This strategy generates 1,4,5-trisubstituted 1,2,3-triazole-4-carboxamides in high yields and

Full text of DOI:10.1002/ejoc.201600157

DOI: 10.1002/ejoc.201600157
Full Paper
Nitrogen Heterocycles
Organocatalytic 1,3-Dipolar Cycloaddition Reaction of ꢀ-Keto
Amides with Azides – Direct Access to 1,4,5-Trisubstituted 1,2,3-
Triazole-4-carboxamides
Xiao Zhou,[a] Xianhong Xu,[a] Kun Liu,[a] Hua Gao,[a] Wei Wang,[a] and Wenjun Li*[a]
Abstract: Organocatalytic [3+2] 1,3-dipolar cycloaddition reac- in high yields and regioselectivities at room temperature. The
tions of ꢀ-keto amides with azides catalyzed by 1,8-diazabi- reaction conditions have been optimized, and the scope of the
cyclo[5.4.0]undec-7-ene (DBU) have been developed. This strat- ꢀ-keto amide and azide have been investigated. A mechanism
egy generates 1,4,5-trisubstituted 1,2,3-triazole-4-carboxamides for the reaction is also proposed.
Introduction
low chemical yield.[10] In 2002, the groups of Meldal[11] and
Sharpless[12] independently developed copper-catalyzed azide–
alkyne cycloaddition (CuAAC). The CuAAC reaction provides a
mild pathway to the synthesis of 1,4-disubstituted 1,2,3-tri-
azoles owing to its wide applicability and efficiency. Unlike the
successful use of terminal alkynes in CuAAC reactions, the reac-
tions of internal alkynes for the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles remain a challenge. Although ruthenium-based
catalytic systems (RuAAC)[13] and iridium-based catalytic sys-
tems (IrAAC)[14] have overcome the obstacles to some extent,
the development of efficient, atom-economic, and green cata-
lytic systems remains in great demand.[15,16] More recently, the
Ramachary,[17] Bressy,[18] and Wang groups[19] independently re-
ported organocatalytic [3+2] cycloaddition reactions through
enamine intermediates. This method provides practical access
to highly substituted 1,2,3-triazoles, and the substrate scope
has been extended to ketones, aldehydes, ꢀ-keto esters, α,ꢀ-
unsaturated aldehydes, α,ꢀ-unsaturated ketones, and α,ꢀ-unsat-
urated esters. Although great progress has been achieved, the
extension of the substrate scope and the diversity of the 1,2,3-
triazole products is still largely required.
The 1,2,3-triazole core is an important scaffold in a large num-
ber of bioactive molecules.[1] 1,2,3-Triazoles are one of the most
important classes of heteroaromatic compounds and exhibit
various biological activities.[2] Of the compounds shown in Fig-
ure 1, carboxyamidotriazole (CAI) exhibits anticancer activity,[3]
cefatrizine exhibits antibacterial activity,[4] tetracyclic 1,2,3-tri-
azoles exhibit good serine protease inhibition activity,[5] and
the sulfur-containing triazole is a potential herbicide with anti-
fungal activity.[6] Moreover, the application of triazole chemistry
is not limited to drug discovery but also extends to numerous
other scientific fields, such as bioconjugation,[7] materials sci-
ence,[8] and polymer chemistry.[9]
In 2012, Dong and Bi reported a catalytic and highly efficient
Wolff cyclocondensation of α-diazoketones with amines with
FeCl2 as the catalyst in reactions of 10 h at 80 °C.[20] Although
this method provides a powerful route to 1,4,5-trisubstituted 4-
amide-1,2,3-triazoles, a high reaction temperature is required,
and the metal ions are potentially toxic to living organisms.
Later, Alves reported an enamine-mediated [3+2] cycloaddition
reaction between ꢀ-keto amides and azidophenyl arylselenides
for the synthesis of (arylselanyl)phenyl-1H-1,2,3-triazole-4-
carboxamides [Scheme 1, Reaction (1)].[21] However, the restric-
tion of the substrate of this method to azidophenyl arylselenide
has largely limited its application. More recently, Ramachary re-
ported an amine-catalyzed enolate-mediated click reaction to
furnish 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles
at room temperature [Scheme 1, Reaction (2)].[17c,17d] Inspired
by this work, we report herein our new discovery regarding the
organocatalytic enolate-mediated [3+2] cycloaddition reactions
Figure 1. Examples of important 1,2,3-triazoles.
The most powerful protocol for the synthesis of 1,2,3-tri-
azoles is the Huisgen 1,3-dipolar cycloaddition, which is ther-
mally induced to give the adduct in poor regioselectivity and
[a] School of Pharmacy, Qingdao University,
Qingdao, 266021, People's Republic China
E-mail: liwenjun324@163.com
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600157.
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Scheme 1. Reaction design.
of ꢀ-keto amides with azides to generate 1,4,5-trisubstituted
1,2,3-triazole-4-carboxamides in high yields and high regiose-
lectivities [Scheme 1, Reaction (3)].
Table 1. Optimization studies.[a]
Results and Discussion
Our preliminary experiments began with the enamine-medi-
ated [3+2] cycloaddition reaction of ꢀ-keto amide 1a with phe-
nyl azide (2a) in the presence of secondary amines (I–IV) with
dimethyl sulfoxide (DMSO) as the solvent. The preliminary ex-
periments indicated that moderate yields were obtained in the
presence of catalysts I–III (Table 1, Entries 1–3). However, the
desired product was not obtained with proline as the catalyst
(Table 1, Entry 4). As Ramachary and co-workers developed an
enolate-mediated [3+2] cycloaddition reaction to furnish 1,4-
disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles in high
yields and regioselectivities,[17c–17f] we switched our attention
to the enolate intermediate formed in situ with tertiary amines.
After extensive screening of commonly used tertiary amines,
we found that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was
the most efficient catalyst for this [3+2] cycloaddition reaction.
In the presence of 0.2 equiv. of DBU, 74 % yield of 3aa was
obtained after 12 h at room temperature (Table 1, Entry 8).
The use of less-basic tertiary amines, such as Et3N (V) and 1,4-
diazabicyclo[2.2.2]octane (DABCO, VI) afforded the adduct in
moderate yields (Table 1, Entries 5 and 6). However, only an
11 % yield of 3aa was observed in the presence of 20 mol-% of
4-(dimethylamino)pyridine (DMAP, VII; Table 1, Entry 7). Further
investigation revealed that solvents also played a key role in
this transformation. Moderate yields were obtained when the
reactions were conducted in N,N-dimethylformamide (DMF),
CH3CN, and tetrahydrofuran (THF; Table 1, Entries 9–11). How-
ever, when methanol, toluene, and dioxane were employed as
the solvents, we observed low yields of 3aa after 12 h (Table 1,
Entry
Cat.
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
36
25
51
41
<5
33
47
11
74
78
72
45
<5
18
24
95
82
72
90
84
9
10
11
12
13
14
15
16[c]
17[d]
18[e]
19[f]
CH3CN
THF
MeOH
toluene
dioxane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
[a] Reaction conditions: a mixture of 1a (0.10 mmol), 2a (0.20 mmol), and
catalyst (20 mol-%) in the solvent (0.3 mL) was stirred at room temperature
for 12 h. [b] Isolated yield. [c] 1a/2a = 1.0:1.5. [d] 1a/2a = 1.0:1.2. [e] 10 mol-
% catalyst used. [f] 5 mol-% catalyst used.
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Entries 12–14). To our delight, when we conducted the reaction properties, the corresponding products could be obtained in
in CHCl3, the product was obtained in excellent yield (Table 1, good-to-excellent yields (Table 2, 3aa–3ao, 84–96 % yields). No-
Entry 15). After identifying CHCl3 as the best solvent for this tably, azides with a naphthalene or heterocyclic ring also exhib-
process, we considered the 1a/2a ratio for this reaction; 82 and ited high reactivities to afford the corresponding products 3ap
72 % yields were obtained when the amount of 2a was de- and 3aq in 87 and 88 % yields, respectively. However, when
creased to 1.5 and 1.2 equiv. (Table 1, Entries 16 and 17). A alkyl azides participated in this transformation, poor yields were
decreased catalyst loading of 10 mol-% afforded the product observed (Table 2, 3ar–3as, <5 % yield).
3aa in 90 % yield in a reasonable time (Table 1, Entry 18). A
further decrease of the catalyst loading to 5 mol-% still afforded
a good chemical yield over a prolonged reaction time (Table 1,
Entry 19). Finally, the best result was achieved by performing
the reaction in the presence of 10 mol-% of catalyst VIII with
1a/2a = 2:1 in CHCl3 at room temperature for 24 h.
Encouraged by the above results, the generality of the ꢀ-
keto amide was also evaluated. As shown in Table 3, ꢀ-keto
amides with various substituents, including electron-donating
groups and electron-withdrawing groups were all compatible
under the optimal reaction conditions (Table 3, 3ba–3ha, 76–
91 % yields). To our delight, if the methyl group was replaced
With the optimized reaction conditions in hand, we then in- by a phenyl group, the reaction generated the product 3ia in
vestigated the scope of the ꢀ-keto amides 1 and azides 2. As 62 % yield in the presence of 10 mol-% of catalyst VIII at 80 °C
summarized in Table 2, the reaction is general for aromatic az- for 24 h. Notably, when the reaction was performed with N,N-
ides 2a–2q; no matter what the substitution pattern was or if dimethyl-3-oxobutanamide (1j) with 2a, the corresponding
the substituent had electron-donating or electron-withdrawing product 3ja was obtained in 65 % yield after 24 h at 80 °C.
Table 2. Scope of azides.[a]
[a] Reaction conditions: a mixture of 1a (0.10 mmol), 2a–2s (0.20 mmol), and VIII (10 mol-%) in CHCl3 (0.3 mL) was stirred at room temperature for 24 h.
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Table 3. Scope of ꢀ-keto amides.[a]
[a] Reaction conditions: a mixture of 1b–1j (0.10 mmol), 2a (0.20 mmol), and VIII (10 mol-%) in CHCl3 (0.3 mL) was stirred at room temperature for 24 h. [b]
The reaction was conducted at 80 °C for 24 h.
Scheme 2. Proposed reaction mechanism.
As shown in Scheme 2, a plausible mechanism has been pro- 1,2,3-triazoles and other biologically active heterocycles. Fur-
posed to explain the reaction process. First, the reaction of ꢀ- ther work is in progress in our laboratory, and more results will
keto amide 1a with catalyst VIII generates the enolate 4. Then, be reported in due course.
the enolate 4 reacts with azide 2a to afford the intermediate 5
through [3+2] cycloaddition. Finally, the rapid elimination of
Experimental Section
General: The H and 13C NMR spectra were recorded with a Bruker
water induced by the catalyst VIII transforms intermediate 5
into the final product 3aa. Notably, the cycloaddition provides
a method for the rapid synthesis of highly substituted 1,2,3-
triazoles in high regioselectivities.
1
ACF300 spectrometer (500 and 125 MHz). The 1H chemical shifts
are reported in ppm downfield from tetramethylsilane and are refer-
enced to residual protium in the NMR solvent (CDCl3: δ = 7.26 ppm).
The 13C chemical shifts are reported in ppm downfield from tetra-
methylsilane and are referenced to the resonances of the solvent
(CDCl3: δ = 77.16 ppm). The data are represented as follows: chemi-
cal shift, integration, multiplicity (br. = broad, s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet), coupling constants in
Hz. All high-resolution mass spectra were obtained with a Finnigan/
MAT 95XL-T mass spectrometer. For TLC, Merck precoated TLC plates
(Merck 60 F254) were used, and the compounds were visualized
with a UV light at 254 nm. Flash chromatography separations were
performed with Merck 60 mesh (0.040–0.063 mm) silica gel.
Conclusions
A versatile enolate-mediated organocatalytic 1,3-dipolar cy-
cloaddition reaction between ꢀ-keto amides and azides has
been developed. This reaction generates various 1,4,5-trisubsti-
tuted 1,2,3-triazole-4-carboxamides in high yields and regiose-
lectivities. Notably, the reaction proceeds efficiently in the pres-
ence of a simple and cheap catalyst at room temperature. Con-
sidering the large variety and ready availability of the starting
materials and the operational simplicity, we believe that this
work will have a wide practical use and will draw more research
General Procedure for the 1,3-Dipolar Cycloaddition Reaction
of ꢀ-Keto Amides with Azides: To a solution of CHCl3 (0.3 mL)
interest to the organocatalytic synthesis of highly substituted were added ꢀ-keto amide 1 (0.10 mmol), aryl azide 2 (0.20 mmol),
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and catalyst VIII (0.01 mmol). The reaction mixture was stirred at
room temperature for 24 h, and then the solvent was removed
under vacuum. The residue was purified by silica gel chromatogra-
phy to yield the desired product. However, if alkyl azides were used,
the desired product was not obtained.
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article): Analytical data for all prepared compounds and intermedi-
1
ates with copies of the H and 13C NMR spectra.
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The authors acknowledge the financial support from the start-
up grant from Qingdao University and the National Natural Sci-
ence Foundation of China (NSFC) (grant number 21502043).
Keywords: Click chemistry · Azides · Cycloaddition ·
Enolates · Nitrogen heterocycles
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Received: February 15, 2016
Published Online: March 21, 2016
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