
==== Front
J Org Chem
J Org Chem
jo
joceah
The Journal of Organic Chemistry
0022-3263
1520-6904
American Chemical Society

39155458
10.1021/acs.joc.4c01054
Article
In Situ-Generated Formamidine as a Carbon/Nitrogen Source for Enaminone Formation: One-Pot Synthesis of Functionalized 4-Acyl-1,2,3-triazoles
Lin Jia-Xin ∇†
Chen You-Xin ∇†
Chien Min-Cheng †
Chen Hsiang-Jou †
https://orcid.org/0000-0002-2697-4845
Lai Chian-Hui ‡
https://orcid.org/0000-0001-8438-5873
Liang Chien-Fu *†
† Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan
‡ Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan
* lcf0201@dragon.nchu.edu.tw
19 08 2024
06 09 2024
89 17 1217012175
30 04 2024
14 08 2024
07 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

N,N-Dimethylformamide was reacted with hexamethyldisilazane to generate an N,N-dimethylformimidamide intermediate; thereafter, a reaction with acetophenones/β-diketones was induced to form enaminones. The one-pot synthetic protocol described in this paper can be applied to synthesize 1,4-disubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles, in which organic azides are used as substrates under optimized conditions. Furthermore, this protocol uses readily available materials, is nearly free of solvent, can be applied to gram-scale operations, and leads to the formation of structurally diverse products with favorable yields.

National Chung-Hsing University 10.13039/501100004946 NA Ministry of Education, Taiwan NA NA National Science and Technology Council 10.13039/501100020950 NSTC 112-2113-M-005-005 document-id-old-9jo4c01054
document-id-new-14jo4c01054
ccc-price
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pmcIntroduction

Functionalized 1,2,3-triazoles play a critical role in numerous biological processes, especially in organic scaffolding, and they are frequently utilized in therapeutic medications.1 In addition, 4-acyl-1,2,3-triazoles are crucial N-heterocycles used in many fields, such as chemical synthesis,2 biology,3 medicinal chemistry,4 supramolecular chemistry,5 and materials science.6 However, synthesizing 4-acyl-1,2,3-triazoles is challenging. They are typically synthesized through the copper-catalyzed azide–alkyne cycloaddition of ynones, acetylenic carbinols, or acetylenic iminium salts to organic azides7 and the cyclization/oxidation of enones.8 These synthetic preparation methods can be tedious and have considerable limitations, including the risk of polymerization of ynones or enones and the lack of commercial availability of ynones/acetylene carbinols. Therefore, to overcome these limitations, the development of alternative methods under feasible and optimal conditions is highly desirable. In the literature, alternative methods that use readily available reagents to ensure optimal reaction conditions have been reported, such as an enaminone-based cycloaddition/elimination strategy,9 base-promoted cycloaddition of NH-based secondary enaminones and tosyl azide through the Regitz diazo transfer process,10 Lewis acid/base-catalyzed aerobic oxidative intermolecular cycloaddition of α/β-unsaturated or β/γ-unsaturated ketones,11 and copper-catalyzed C–C bond cleavage/reformation and cycloaddition from β-alkyl nitroalkanes.12 Despite their effectiveness, most of these methods require environmentally unfriendly agents or harsh conditions, such as high-cost catalysts, oxidative additives, corrosive reagents, substantial quantities of toxic solvents, and microwave/high operating temperatures, or their durations are long. Hence, developing direct, rapid, and environmentally friendly methods for the formation of 4-acyl-1,2,3-triazoles is an urgent need.

Some advances have been made in the direct synthesis of 4-acyl-1,2,3-triazoles, such as Cu-catalyzed oxidative dehydrogenation/cycloaddition of α-alkyl ketone with N,N-dimethylformamide (DMF) as a C1 donor (Scheme 1a)13 and Cu/TEMPO-catalyzed tandem multiple oxidative dehydrogenation/cycloaddition of β-alkyl ketone (Scheme 1b).14 Although these strategies have been used to successfully synthesize 4-acyl-1,2,3-triazoles using readily available aryl alkyl ketones, they require expensive transition metal catalysts and oxidants. In a previous study, as an alternative method, the authors proposed DMF as a C1 source for the formation of N-sulfonyl/aryl formamidine.15 On the basis of our success in utilizing DMF as a C1 source, as a method for the synthesis of 4-acyl-1,2,3-triazoles, we hypothesize that the direct condensation of α-methyl ketone with stoichiometric amounts of DMF would generate enaminones in situ. In the work presented here, we report a one-pot synthetic protocol for directly converting α-methyl ketones into enaminones under metal-free and oxidant-free conditions, and in this reaction, several functionalized azides are used as substrates to produce 1,4-disubstituted 1,2,3-triazoles (Scheme 1c). Moreover, this protocol can be applied for enaminone formation by using β-diketones as substrates to produce 1,4,5-trisubstituted 1,2,3-triazoles (Scheme 1c).

Scheme 1 Direct Strategies for the Synthesis of 4-Acyl-1,2,3-triazoles

Results and Discussion

In this study, we optimized the formation of 4-acyl-1,2,3-triazoles by using methyl phenyl ketones (1a) and phenyl azides (3a) with stoichiometric amounts of hexamethyldisilazane (HMDS) and DMF under heating conditions (Table 1). Initially, 4 equiv of HMDS and DMF agents were employed, which resulted in poor conversion (entry 1). However, a previous study produced enaminone in situ by using aryl methyl ketone with the dimethyl acetal of DMF in the presence of acidic additives, which exhibited increased reactivity;16 thus, reaction conversion can be optimized through this approach. Accordingly, in this study, the reaction conditions for the one-pot multicomponent synthetic protocol were optimized using catalytic amounts of acidic additives, improving the yield. The following acidic additives were employed: camphorsulfonic acid (CSA), boron trifluoride diethyl etherate (BF3·OEt2), pyridinium p-toluenesulfonate (PPTS), lanthanum(III) trifluoromethanesulfonate [La(OTf)3], and p-toluenesulfonic acid (Table 1, entries 2–6, respectively). We observed that the reaction proceeded favorably in the presence of a PPTS catalyst (entry 4), with a yield of 78% for the cycloaddition product (4aa). Therefore, PPTS was selected as the acid catalyst for further reactions. Subsequently, 3 and 5 equiv of HMDS and DMF agents were utilized to determine the optimal quantity of these reactants (Table 1, entries 7 and 8, respectively). The results revealed that entry 4 was the minimum amount of HMDS and DMF agents required for optimal activity. Additionally, when the amount of the PPTS catalyst was reduced 5-fold under optimized conditions, yields of 86% were obtained (entry 9). Moreover, when the quantities of phenyl azides (3a) were reduced to 1.2 equiv, the yield decreased (entry 10). Furthermore, we optimized the reaction temperature. Higher temperatures resulted in higher reaction yields, and the results revealed that the reaction proceeded most favorably at 120 °C (entry 11). Moreover, to investigate the formation of the enaminone intermediate using DMF as a C1 source, we utilized β-diketone (2a) under these optimized acid and temperature conditions. Although we expected to obtain 4,5-diacyl-1,2,3-triazole, we instead obtained a 4-acyl-1,2,3-triazole product. This product was a 1,4,5-trisubstituted 4-acyl-1,2,3-triazole (5aa), which was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. This result suggests that the reaction route for the formation of the enaminone intermediate from β-diketone may differ from that of the α-methyl ketone. Nevertheless, after systematically evaluating the optimized conditions (entries 12–15), we found that the reaction proceeded favorably with reduced amounts of HMDS and DMF agents in the absence of the PPTS catalyst, providing a yield of 91% of the desired 1,4,5-trisubstituted 1,2,3-triazole (5aa) (entry 15).

Table 1 Optimized Conditions

entrya	HMDS (equiv)	DMF (equiv)	acid (equiv)	T (°C)	yieldb (%)	
1	4	4	–	100	trace	
2	4	4	CSA (0.5)	100	66	
3	4	4	BF3·OEt2 (0.5)	100	trace	
4	4	4	PPTS (0.5)	100	78	
5	4	4	La(OTf)3 (0.01)	100	72	
6	4	4	PTSA (0.5)	100	73	
7	3	3	PPTS (0.5)	100	68	
8	5	5	PPTS (0.5)	100	76	
9	4	4	PPTS (0.1)	100	86	
10c	4	4	PPTS (0.1)	100	69	
11	4	4	PPTS (0.1)	120	92	
12d	4	4	PPTS (0.1)	120	54	
13d	4	4	–	120	53	
14d	3	3	–	120	70	
15d	2	2	–	120	91	
a For the reactions, 1a (0.83 mmol, 1.0 equiv) and 3a (2.0 equiv) were reacted under a nitrogen atmosphere.

b Isolated yield.

c With 1.2 equiv of phenyl azide 3a.

d Using 2a (0.89 mmol, 1.0 equiv) as a reactant.

Subsequently, the optimized conditions for the direct one-pot multicomponent reaction were employed in the synthesis of a series of functionalized 4-acyl-1,2,3-triazoles, which involved the reaction of HMDS and DMF agents with diverse aryl methyl ketones (1a–1r) and organic azides (3a–3t) (Scheme 2). In the synthesis with aryl azides bearing electron-donating groups [methyl, ethyl, tert-butyl, octyl, methoxy, or naphthyl (3a–3i and 3r)], the desired products (4aa–4ai and 4ar, respectively) were formed in 53–92% yields. Furthermore, a reaction with aryl azides having electron-withdrawing groups (F, Cl, Br, I, NO2, or CO2Me, 3j–3q/3t) resulted in yields of 64–99%. Moreover, aryl azides bearing ortho-substituted groups (3d, 3o, and 3t) produced 4ad, 4ao, and 4at in 64%, 99%, and 76% yields, respectively. These results indicate that steric effects had a limited influence on the reactivity of aryl azides. Additionally, under optimized conditions, benzyl azide (3s) achieved a satisfactory yield of product 4as. Subsequently, we applied the optimized conditions to functionalized aryl methyl ketones 1b–1r with phenyl azides (3a) (Scheme 2). Various functionalized aryl methyl ketones were converted into the corresponding 4-acyl-1,2,3-triazole adducts (4ba–4ra, respectively), with reaction yields of 60–94%. The ease of reaction conversion and the high yields for the aryl system indicate its high functional group tolerance; chloro (4ba–4da), fluoro (4ea), bromo (4fa), iodo (4ga), nitro (4ha), trifluoro (4ia), methyl (4ja–4la), methoxy (4ma), thiophene (4na), furan (4oa), and naphthyl (4pa) products were all obtained at comparably high yields under optimized conditions. Moreover, substrates 1q and 1r, which contained disubstituted electron-donating and -withdrawing motifs in the aryl system, generated products 4qa and 4ra in 66% and 60% yields, respectively. However, this method proved to be unsuccessful in 1,4-disubstituted triazole formation using alkyl azide (4aw). According to a previous study of 4-acyl-1,2,3-triazole formation from an enaminone intermediate under metal-free conditions,9 the major issues for such reactions are the high reaction temperatures under microwave operating conditions required for the formation of the enaminone intermediate and the requirement of substantial amounts of toxic solvents in the cycloaddition step. The method proposed in this study overcomes these limitations and provides a green synthetic protocol for synthesizing 4-acyl-1,2,3-triazole.

Scheme 2 Formation of 4-Acyl-1,2,3-triazoles Using Various Aryl Methyl Ketones and Azides

For the reactions, 1 (0.40–0.83 mmol, 1.0 equiv), HMDS (4.0 equiv), DMF (4.0 equiv), 3 (2.0 equiv), and PPTS (0.1 equiv) were stirred at 120 °C under a nitrogen atmosphere for 12 h.

Reaction time of 2 h.

For the reaction, 1a (0.50 mmol for 3p or 0.83 mmol for 3s, 1.0 equiv), HMDS (4.0 equiv), and DMF (4.0 equiv) were stirred at 120 °C; after reaction for 8 h, 3p or 3s (2 equiv) was added to the reaction mixture for an additional 12 h.

Reaction time of 4 h.

With 3.0 equiv of phenyl azide.

Reaction time of 6 h.

The reaction produced enaminone 12 in 42% yield, including some unrecognized spots.

We subsequently attempted to use β-diketone to perform cycloaddition under optimized conditions and obtained 1,4,5-trisubstituted 4-acyl-1,2,3-triazole derivatives (Scheme 3), indicating the broad application of the protocol proposed in this study for the formation of 4-acyl-1,2,3-triazole through the in situ generation of enaminone intermediates. Furthermore, we performed cycloaddition reactions of β-diketones (2a–2d) with a range of functionalized aryl azides (3a–3q, 3u, and 3v) under optimized conditions. This transformation method produced yields of 35–98% for the desired products (5aa–5aq, 5au, 5av, 5ba–5da, 5be–5de, and 5bk–5dk). However, treatment of the ortho-substituted aryl azide (3d) with 2a under optimized conditions formed 5ad, with a reaction yield of only 35%; this may be caused by steric hindrance. These results revealed that the reaction yields of aryl azides bearing electron-withdrawing substituents (3j–3q and 3u) were higher than those of aryl azides bearing electron-donating substituents (3b–3i and 3v). In a previous study of 1,3-dipolar cycloaddition,9c organic azides behaved as electrophiles, which demonstrated that the azides with electron-withdrawing groups induce rapid reactions and thus produce superior yields. Accordingly, we also tested the DMF/HMDS method developed in the study presented here on 1,3-dicarbonyl derivatives (2e–2g), which have been infrequently used in previous studies.7−14,16 Our results revealed that the method developed in the study presented here exhibits high functional group tolerance with respect to the resulting products, specifically the 5-methyl (5ek), 4-ester (5fk), and 4-amide (5gk) 1,2,3-triazole compounds. However, this method proved to be unsuccessful for 1,4,5-trisubstituted triazole formation using an alkyl azide (5aw).

Scheme 3 Formation of 4-Acyl-1,2,3-triazoles Using Various β-Diketones and Azides

For the reactions, 2 (0.50–0.89 mmol, 1 equiv), 3 (2 equiv), HMDS (2 equiv), and DMF (2 equiv) were stirred at 120 °C under a nitrogen atmosphere for 12 h.

For the reaction, 2a (0.89 mmol, 1 equiv), 3b (2 equiv), HMDS (2 equiv), and DMF (2 equiv) were stirred at 120 °C; after reaction for 6 h, 3b (2 equiv) was add to the reaction mixture for an additional 6 h.

The reaction afforded 2a (40% conversion) and produced intermediate 15 in 90% yield (recovery yield).

In the next phase of the study, we employed methyl phenyl ketone (1a), β-diketone (2a), and phenyl azide (3a) for the synthesis of 4-acyl-1,2,3-triazole as a means of enhancing the scalability of the proposed synthetic method. Subsequently, we verified the approach in gram-scale synthesis with yields of 78% and 70% for products 4aa and 5aa, respectively (Scheme 4a). Inspired by the broad applicability of this methodology, we further exemplified this by synthesizing a bis-triazole 7 [81% (Scheme 4b)]. The practical potential of the 4-acyl-1,2,3-triazole structure may lie in the synthesis of key pharmaceutical compounds. The structure of compound 11 is a crucial suppressor of estrogen-related receptor α for the therapeutic treatment of breast cancer.3a Under optimal conditions, it was smoothly converted into N-Boc-protected 4-acyl-1,2,3-triazole 10. Subsequently, the Boc protecting group of compound 10 was replaced with an amino group, yielding ERRα suppressor compound 11 [61% (Scheme 4c)].

Scheme 4 Gram-Scale Reaction and Synthetic Applications

To clarify the reaction mechanism, we conducted control experiments (Scheme 5). As expected, methyl phenyl ketone (1a) was converted into N,N-dimethyl enaminones (12) under HMDS/DMF-mediated conditions with a yield of 93%. Subsequently, N,N-dimethyl enaminone (12) was reacted with phenyl azide (3a) under the same reaction conditions, producing 4aa in 94% yield (Scheme 5a). Moreover, we applied our developed protocol for deuteration on enaminone formation.17 These results indicate that a DMF agent can serve as a carbon source for the generation of 1,4-disubstituted 1,2,3-triazole. For comparison, in the absence of the HMDS agent under optimized conditions, we observed that compound 1a was recovered without producing N,N-dimethyl enaminones (12) (Scheme 5b). Additionally, given the success of the reaction for the formation of enaminone, the generality of this protocol was further examined. The application of this approach to N,N-diethylformamide led to the formation of enaminone derivative 13, with a good yield [71% (Scheme 5c)]. Moreover, to further determine the applicability scope of this method for enaminone synthesis, we conducted the reaction using a sequential one-pot process. The results revealed that this approach was efficient for the formation of NH-enaminone (14) [63% (Scheme 5d)]. Next, we observed that the β-diketone (2a) was successfully converted into the enaminone derivative (15) with a good yield [78% (Scheme 5e)]. Moreover, we observed that the β-diketone (2a) reacted under HMDS/DMF-mediated conditions to generate a β-aminoenone intermediate (15); thereafter, intermediate 15 was reacted with phenyl azide (3a) under optimized conditions, producing 5aa in 46% yield (Scheme 5f). According to the literature report,18 1,3-dipolar cycloaddition of β-diketones with azides in the presence of basic conditions led to the 1,2,3-triaole, in which the enolate was generated from β-diketones under basic conditions upon reaction with azides. For comparison, we performed a reaction using HMDS in the presence of toluene as a solvent. The results revealed that the desired product (5aa) was provided in 33% yield and confirmed that it may produce enolate from β-diketone and react with azide under basic conditions (Scheme 5g). Additionally, we observed that in the absence of the DMF agent under optimized conditions, compound 2a was recovered without producing β-aminoenones (15) (Scheme 5h).

Scheme 5 Control Experiment and Proposed Mechanism

On the basis of the results of the control experiment and the literature we reviewed,9c,15,18 we suggest plausible mechanisms for the synthesis of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles (Scheme 5i). One report suggested that a DMF agent can initially be reacted with HMDS under heating conditions to generate N,N-dimethylformimidamide intermediate A,15 which can then be used as a carbon/nitrogen source for the formation of enaminones. For the synthesis of 1,4-disubstituted 1,2,3-triazole, N,N-dimethylformimidamide intermediate A subsequently reacts with tautomer B under catalytic amounts of PPTS and heating conditions, resulting in the formation of enaminone intermediate C after the loss of a molecule of ammonia. Enaminone intermediate C reacts with an azide through inverse-electron-demand [3+2] cycloaddition with complete regioselectivity, producing 1,4-disubstituted 1,2,3-triazole 4 (Scheme 5i).9c Next, according to our previous study, we verified that transamidination of a sulfonyl amide with N,N-dimethylformimidamide intermediate A occurs through hydrogen bonding.15 On the basis of these results, we suggest that the reaction for 1,4,5-trisubstituted 1,2,3-triazole synthesis is initiated through an intermolecular two-point hydrogen bonding system between N,N-dimethylformimidamide intermediate A and tautomer D to generate β-aminoenone intermediate E. Subsequently, the formation of 1,4,5-trisubstituted 1,2,3-triazole 5 from β-aminoenone intermediate E and aryl azide follows a mechanism similar to that underlying the formation of 1,4-disubstituted 1,2,3-triazoles (Scheme 5i). There is an alternative route in which the aryl azide undergoes 1,3-dipolar cycloaddition with the enolate intermediate (G) arising from the tautomerization of β-diketone under basic conditions, which produces the cycloaddition adduct (H). Finally, the dehydration process gives rise to 1,4,5-trisubstituted 1,2,3-triazoles (Scheme 5i).

Conclusions

In conclusion, by employing readily available aryl methyl ketones and β-diketones as starting materials, we synthesized 1,4-disubstituted 4-acyl-1,2,3-triazoles and 1,4,5-trisubstituted 4-acyl-1,2,3-triazoles without using metal catalysts or oxidants. In the involved reactions, a DMF agent reacted with HMDS to generate an N,N-dimethylformimidamide intermediate in situ, which was then utilized as a carbon/nitrogen source for the formation of enaminones. Thereafter, a reaction with organic azides was induced to produce 4-acyl-1,2,3-triazoles. Additionally, the proposed method was successfully employed in the gram-scale synthesis of the desired products and effectively synthesized the enaminone derivatives and an analogue of a crucial pharmaceutic compound. Moreover, the conditions for this synthetic protocol are environmentally friendly (free of metal, free of oxidants, and nearly free of solvents), and the protocol can be applied for the formation of diverse functionalized 4-acyl-1,2,3-triazoles. Thus, the HMDS-mediated enaminone formation protocol described in this study is suitable for a wide range of applications in synthesizing diverse cycloaddition products.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01054.Descriptions of experimental procedures for compounds and analytical characterization (PDF)

Supplementary Material

jo4c01054_si_001.pdf

Author Contributions

∇ J.-X.L. and Y.-X.C. contributed equally to this work.

The authors declare no competing financial interest.

Acknowledgments

Financial support from the National Science and Technology Council, Taiwan (Grant NSTC 112-2113-M-005-005), is gratefully acknowledged. This work is also financially supported by the “Innovative Center on Sustainable Negative-Carbon Resources” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The authors also acknowledge the support from National Chung Hsing University.
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For selected examples, see:

a Xie Y.-Y. ; Wang Y.-C. ; Qu H.-E. ; Tan X.-C. ; Wang H.-S. ; Pan Y.-M. Regioselective Synthesis of ß-Aryl Enaminones and 1,4,5-Trisubstituted 1,2,3-Triazoles from Chalcones and Benzyl Azides. Adv. Synth. Catal. 2014, 356 , 3347 10.1002/adsc.201400315.
b Li W. ; Wang J. Lewis Base Catalyzed Aerobic Oxidative Intermolecular Azide-Zwitterion Cycloaddition. Angew. Chem., Int. Ed. 2014, 53 , 14186 10.1002/anie.201408265.
c Li W. ; Du Z. ; Huang J. ; Jia Q. ; Zhang K. ; Wang J. Direct access to 1,2,3-triazoles through organocatalytic 1,3-dipolar cycloaddition reaction of ally ketones with azides. Green Chem. 2014, 16 , 3003 10.1039/C4GC00406J.
Zheng L. ; Yi T. ; Fang R. ; Zhou Z. ; Wang C. ; Chen Y. Cascade C–C bond cleavage/reformation and cycloaddition for the synthesis of 4-acyl-1,2,3-triazoles from ß-alkyl nitroalkanes and organic azides. Org. Chem. Front. 2023, 10 , 5260 10.1039/D3QO01086D.
Liu Y. ; Nie G. ; Zhou Z. ; Jia L. ; Chen Y. Copper-Catalyzed Oxidative Cross-Dehydrogenative Coupling/Oxidative Cycloaddition: Synthesis of 4-Acyl-1,2,3-Triazoles. J. Org. Chem. 2017, 82 , 9198 10.1021/acs.joc.7b01429.28749668
Huang L. ; Zheng L. ; Zhou Z. ; Chen Y. Copper-catalyzed multiple oxidation and cycloaddition of aryl-alkyl ketones (alcohols) for the synthesis of 4-acyl- and 4-diketo-1,2,3-triazoles. Chem. Commun. 2022, 58 , 3342 10.1039/D1CC06477K.
Chou Y.-C. ; Lin W.-H. ; Lin X.-Y. ; Kuo C.-L. ; Zeng W.-Q. ; Lu I.-C. ; Liang C.-F. Hexamethyldisilazane-Mediated Amidination of Sulfonamides and Amines with Formamides. J. Org. Chem. 2022, 87 , 15327 10.1021/acs.joc.2c01902.36302512
Xie Y.-B. ; Ye S.-P. ; Chen W.-F. ; Hu Y.-L. ; Li D.-J. ; Wang L. Brønsted-Acid-Catalyzed Multicomponent One-Pot Reaction: Efficient Synthesis of Polysubstituted 1,2-Dihydropyridines. Asian J. Org. Chem. 2017, 6 , 746 10.1002/ajoc.201700127.
For detailed studies of deuterated enaminone formation, see the Supporting Information.

a Chen J. ; Liang T. ; Zhao H. ; Lin C. ; Chen L. ; Zhang M. Silver-Mediated Three-Component Cycloaddition Reaction for Direct Synthesis of 1-N-Vinyl-Substituted 1,2,3-Triazoles. Org. Biomol. Chem. 2019, 17 , 4843 10.1039/C9OB00686A.31033976
b Cicco L. ; Perna F. M. ; Falcicchio A. ; Altomare A. ; Messa F. ; Salomone A. ; Capriati V. ; Vitale P. 1,3-Dipolar Cycloaddition of Alkanone Enolates with Azides in Deep Eutectic Solvents for the Metal-Free Regioselective Synthesis of Densely Functionally 1,2,3-Triazoles. Eur. J. Org. Chem. 2022, 2022 , e202200843 10.1002/ejoc.202200843.
