Oxone-Mediated Mild Removal of an Azine Protecting/Directing Group for Applications in Organic Synthesis

Abstract

Azine derivatives of carbonyl compounds are used as protecting groups and have recently been utilized as directing groups in C–H activation. The stability of the azine functional group limits its application in areas where its subsequent removal is desirable. We herein report a mild and efficient method for removal of an azine group using Oxone as a green oxidant in the presence of an acetone/water solvent system. Carbonyl regeneration occurs in high yields from a range of aldazine and ketazine derivatives. A gram-scale synthesis and removal of the azine directing group from an ortho-functionalized azine are performed to extend the application of this methodology.

Carbonyl groups have been explored widely in synthetic organic chemistry. The nucleophilicity of the carbonyl carbon has been exploited to achieve diverse functional group interconversions. Moreover, the carbonyl handle has become central to the synthesis of many heterocyclic scaffolds.[1] Azines are a class of compounds that have a >C=N–N=C< functional group. These α-diimines are synthesized conveniently from two molecules of the corresponding carbonyl compound and a hydrazine equivalent.[2] Numerous methods for the synthesis of azines have been reported in literature due to their applications as chemical building blocks for synthesis, their tendency to form complexes with metals and their wide spectrum of biological activities.[2] Moreover, azines offer unique structural features due to their ability to exhibit geometrical and conformational isomerism, as well as tautomerism wherever structurally possible. This leads to polymorphism in most symmetrical and unsymmetrical azines, enabling applications in materials science.[3]

Azines have also been used as carbonyl protecting groups due to their many desirable properties like ease of isolation and identification as well as their economic synthesis.[2] They exhibit excellent stability to cleavage, being considerably higher compared to imines.[4] This however limits their application as carbonyl protecting groups as harsh conditions are required for regeneration of the carbonyl compound. Several synthetic efforts have been made in this direction. Reagents such as CrO₃ supported on NaHSO₄·H₂O,[5] SeO₂,[6] 3-carboxypyridinium chlorochromate,[7] N-benzoylperoxycarbamic acid,[8] a silica sulfuric acid heterogenous system,[9] triethylammonium chlorochromate,[10] Zr(HSO₄)₄ in wet SiO₂,[11] cerium(IV) ammonium nitrate,[12] HOF·CH₃CN,[13] tribromoisocyanuric acid/wet SiO₂,[14] KMnO₄/montmorillonite K10[15] and Fe(ClO₄)₃ [16] have been used for azine deprotection.

Recently, the azine functional group has been explored as a directing group for ortho activation of aromatic C–H bonds.[3] Rhodium, ruthenium and cobalt complexes have been reported to complex efficiently with the azine moiety and activate the ortho position of these carbonyl derivatives. Numerous transformations, including alkylation,[17] carbenoid insertion,[18] vinylation and thioetherification,[19] amidation,[20] [21] [22] allylation[23] and acylation[24] have been realized using azines as directing groups. Some of the C–H activation reports also involve the preparation of isoquinoline scaffolds using rhodium[25] and cobalt[26] complexes. A few reports have described removal of the azine directing group (DG) post-functionalization by reflux in the presence of 4 M HCl.[18] [20] In another report, the use of an ortho-alkylated compound led to the formation of a small amount of the corresponding cyanide, derived from the azine functional group, when using a ruthenium carbonyl.[27]

The search for mild and high yielding protocols for the removal of azine groups remains an active area of research. Oxone is a commercially available formulation of peroxymonopersulfate stabilized as a triple salt (2KHSO₅·KHSO₄·K₂SO₄). The HSO₅ ^– anion is the active oxidizing species in this triple salt, which is used in a wide variety of oxidative transformations. It is stable, cheap, non-toxic and a green alternative to its acid counterpart H₂SO₅ (Caro’s acid), which is prepared by the reaction of sulfuric acid with hydrogen peroxide. Oxone has been used for the oxidation of C–H bonds, the oxidative functionalization of olefins, the oxidation of various functional groups and also in protection–deprotection chemistry. The use of Oxone for the deprotection of oximes to the corresponding carbonyl compound has been reported by Bose and Srinivas.[28] Herein, we report a robust route for the oxidation of azines to the corresponding carbonyl compounds using Oxone in acetone/water.

Table 1 Optimization of the Reaction Conditions

Entry	Solvent	Oxidant (equiv)	Time (min)	Yield
1	acetone/H2O	Oxone (2)	30	43%
2	acetone/H2O	Oxone (3)	20	70%
3	acetone/H2O	Oxone (4)	15	73%
4	acetone/H2O	Oxone (5)	12	82%
5	acetone/H2O	Oxone (6)	9	90%
6	acetone/H2O	Oxone (7)	9	90%
7	acetone/H2O	Oxone (8)	9	91%
8	THF/H2O	Oxone (6)	120	–
9	MeCN/H2O	Oxone (6)	120	–
10	DMF/H2O	Oxone (6)	120	–
11	DMSO/H2O	Oxone (6)	120	–
12	EtOH/H2O	Oxone (6)	120	–
13	–	Oxone/MgSO4 (6)	120	–
14	acetone/H2O	DTBP (6)	120	–
15	acetone/H2O	K2S2O8 (6)	120	37%

The azines were readily synthesized by the reaction of 2 equivalents of the corresponding carbonyl compound with 1 equivalent of hydrazine hydrate. The high stability of the azine group was reflected in the use of harsh reaction conditions for its removal, as discussed in recent reports on the use of azines as directing groups.[18] [20] Moreover, in many reports,[17,19] ^, [21–24] removal of the DG had not been executed due to this challenge. We hence set out to identify a milder route to remove the azine DG to make the C–H functionalization strategy more practically applicable. A literature investigation led us to peroxymonopersulfate,[28] a green oxidant used for a variety of organic transformations. We thus explored different solvents for the conversion of model substrates (acetophenone azine and benzaldazine) using Oxone as the oxidant. To our delight the reaction proceeded smoothly with short reaction times when acetone and water were used as solvents in a 1:1 ratio (Table [1]). Almost all the synthesized azines were deep yellow in color due to the presence of a conjugated chromophore. Oxidation of the azine functional group to the corresponding carbonyl could hence be visually monitored. In most of the literature reports, Oxone has been employed as a 1:1 acetone/water or acetonitrile/water solution in oxidative organic transformations. In order to study the role of the solvent in the reaction, we examined the reaction of the azine in a 1:1 v/v solution of acetonitrile/water (Table [1], entry 9). However, the azine was left unconsumed, even after a tenfold increase in the reaction time. To establish unequivocally the role of the solvent in the oxidative transformation, we screened other compatible solvents including THF, DMF, DMSO and ethanol in aqueous 1:1 v/v solutions (Table [1], entries 8, 10, 11 and 12). To our surprise, we did not observe any trace of the deprotected carbonyl compound when using these solvents and the starting azine remained unconsumed. We also explored a mechanochemical deprotection using a solventless strategy (Table [1], entry 13), but to no avail.

From these screening experiments, we concluded that the role of the solvent was crucial to the reaction, as not even traces of the product were isolated at high oxidant loadings in other solvents. The use of other oxidants like di-tert-butyl peroxide (DTBP) did not yield the desired product and left the starting material unconsumed (Table [1], entry 14), whereas potassium persulfate (K₂S₂O₈) only afforded the carbonyl compound in 37% yield (Table [1], entry 15). We then screened the number of equivalents of Oxone and found that 6 equivalents in acetone/water (1:1) were optimal for this transformation (Table [1], entry 5). All further experiments were performed using these optimized conditions.

To evaluate the application of the method in synthetic chemistry, we studied the substrate scope of the transformation (Scheme [1]). We used the optimized reaction conditions on different o-, m- and p-substituted aldazines and ketazines.[29] The robustness of the synthetic protocol can be seen in its tolerance of diverse functional groups. We were delighted to obtain high yields of the corresponding carbonyl compounds in most cases.[30] [31] In general, the reactions of aldazines were faster than those of ketazines. It is also notable to mention that the solubility of the azine in acetone was found to influence the reaction time more than the electron availability.

Those substrates that had high solubility in acetone required shorter reaction times, whereas substrates with low solubility showed considerably longer reaction times (see the Supporting Information). The reaction times are typically very short, with some of the azines being converted in less than 10 minutes. With such a high reactivity, the effect of electron availability was predicted to be insignificant.

We next performed some control experiments to collect mechanistic evidence. On increasing the number of equivalents of the oxidant, we were able to see a faster consumption of acetophenone azine by GC-MS (see Figure S1 in the Supporting Information). However, a splitting in the peak of acetophenone was observed. On evaluation of the mass spectrum, we were able to map the molecular weight and the fragmentation pattern to the reduced compound 1-phenylethanol (Table [2]). It was unusual to observe nearly 20% of the alcohol according to GC-MS (see Figure S1 in the Supporting Information) while using an oxidant on the corresponding azine substrate. As the boiling points of acetophenone and 1-phenylethanol are identical, their retention times on GC were very similar leading to insufficient resolution of the peaks.

Table 2 Mechanistic Experiments: Screening the Equivalents of Oxone for the Oxidation of Acetophenone Azine^a

Entry	Equiv of Oxone	Yields
		A	B	Azine
1	2	61.61%	9.98%	28.41%
2	3	63.41%	9.49%	27.1%
3	4	76.85%	17.79%	5.36%
4	5	77.59%	22.41%	–
5	6	97.02%	–	2.98%

^a Conditions: Acetophenone azine (1 mmol) in acetone was added dropwise to Oxone in H₂O. A 100 μL aliquot of the reaction mixture was drawn after 10 min and injected into the GC-MS. The area percentages of reaction products are reported.

To confirm the formation of an alcohol, we performed a control experiment on benzalazine at low temperature (Scheme [2]). Due to a larger difference in the boiling points between benzaldehyde and benzyl alcohol, we expected to see well-resolved peaks for these two compounds if formed. We were surprised to find a significant amount of benzyl alcohol in addition to benzaldehyde (see Figure S2 in the Supporting Information), proving their formation unequivocally. At higher equivalents of the oxidant, the alcohol peak gradually disappeared, and under the optimized conditions we could trace only the carbonyl compound by GC-MS. We believe that the oxidation process proceeds via in situ formation of dimethyldioxirane (DMDO). This is evident from the role of acetone as a solvent. Other solvents failed to even give traces of the product.

Acetone is known to be oxidized to DMDO in buffered Oxone solutions at low temperature and its ability to oxidize bisimines to bisoxaziridines has previously been reported.[32] The produced DMDO is then proposed to similarly oxidize the imine bonds in the azine to bisoxaziridines, which can either open up concertedly (Path I, Scheme [3]) or sequentially (Path II, Scheme [3]) to release molecular nitrogen and regenerate the carbonyl compound. At a stoichiometric concentration of the oxidant or at low temperature, we conceive the formation of a monooxaziridine, which on ring opening yields a carbonyl compound and a diazo fragment. Further, this diazo fragment can then produce the corresponding alcohol by elimination of a nitrogen molecule during its reaction with water (see Scheme [2]).

Due to the wide substrate scope, we explored the application of the developed method for the deprotection of an ortho-substituted azine, which happens to be the product of ortho-C–H functionalization. We synthesized an ortho-substituted azine in two steps from 2-aminoacetophenone by acetylation followed by condensation with hydrazine hydrate to yield 2′-(N-acetylamino)acetophenone azine. Application of the developed deprotection protocol yielded 2′-(N-acetylamino)acetophenone, with the azine directing group quantitatively removed (isolated yield 87%) (Scheme [4]). To further establish the proof of concept, we also attempted the gram-scale deprotection of the azine group from 3′-nitroacetophenone azine. The reaction successfully afforded the corresponding 3′-nitroacetophenone in 88% isolated yield, proving the robustness of the method (Scheme [5]).

The broad substrate scope of this method along with use of mild reaction conditions warrants its addition to the list of existing strategies for deprotection and exploration of C–H activation protocols involving removal of the directing group.

Acetophenone azines have been used for direct ortho-C–H amidation. To extend the application of our synthetic procedure to removal of a directing group post C–H activation, we first functionalized acetophenone azine by reacting it with the masked amide source dioxozolone, using a Cp*Co(CO)₂ complex. The reaction proceeded smoothly to yield the ortho-functionalized product (Scheme [6]). This product was treated with Oxone in aqueous acetone and the corresponding ortho-functionalized acetophenone was isolated, purified using column chromatography, and characterized by NMR spectroscopy. This experiment hence confirms the application of our synthetic methodology for the removal of an azine directing group post C–H activation.

In conclusion, we have reported a robust and mild method for removal of a highly stable azine protecting and directing group to yield the corresponding carbonyl compounds in high yields. The broad substrate scope of the method has been demonstrated by using a range of electron-donating and electron-withdrawing substituents on the azine starting materials. The protocol can also be utilized in the removal of an azine directing group post C–H functionalization. A gram-scale reaction and the removal of the DG from an activated substrate validate our claims. We are confident that this method will lead to further exploration of azine DGs in C–H functionalization due to the efficient removal strategy reported herein.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors would like to thank Jai Hind College Autonomous for the Central Instrumentation Facility (CIF) and the National Centre for Nanosciences and Nanotechnology for the facilities to carry out the research work. We also acknowledge the Department of Chemistry, IIT Bombay for the characterization data of the products.

• References and Notes

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• 21 Mishra NK, Oh Y, Jeon M, Han S, Sharma S, Han SH, Um SH, Kim IS. Eur. J. Org. Chem. 2016; 4976
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• 23 Wen J, Wu A, Miao Y, Zhu J. Tetrahedron Lett. 2015; 56: 5512
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• 24 Kianmehr E, Seifinoferest B, Afaridoun H. Eur. J. Org. Chem. 2020; 4925
• 25 Han W, Zhang G, Li G, Huang H. Org. Lett. 2014; 16: 3532
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• 26 Deshmukh DS, Yadav PA, Bhanage BM. Org. Biomol. Chem. 2019; 17: 3489
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• 27 Dönnecke D, Wunderle J, Imhof W. J. Organomet. Chem. 2004; 689: 585
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• 28 Hussain H, Green IR, Ahmed I. Chem. Rev. 2013; 113: 3329
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• 29 Azine Directing Group Removal; General Procedure A round-bottomed flask was charged with Oxone (1.74 g, 6 equiv) in H₂O (7.5 mL). A solution of the corresponding azine-protected carbonyl substrate (0.95 mmol) in acetone (7.5 mL) was added dropwise to the flask and the resulting mixture was allowed to stir at room temperature until completion of reaction (monitored by TLC). The reaction was quenched by adding H₂O (20 mL) and extracted using ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained product was dried under vacuum.
• 30 3-(Trifluoromethyl)benzaldehyde (2i) Time required for conversion: 40 min. ¹H NMR (400 MHz, CDCl₃): δ = 10.00 (d, J = 1.0 Hz, 1 H), 8.06 (s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 190.82, 136.82, 132.74, 130.69, 129.79, 126.23, 124.88, 122.14. MS (ESI): m/z = 174.03.
• 31 3,4,5-Trimethoxyacetophenone (2o) Time required for conversion: 90 min. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.24 (s, 2 H), 3.85 (s, 6 H), 3.73 (s, 3 H), 2.58 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ = 197.04, 141.93, 132.32, 105.81, 60.24, 56.10, 26.69. MS (ESI): m/z = 210.07.
• 32 Bigdeli MA, Nikje MM. A, Heravi MM. Phosphorus, Sulfur Silicon Relat. Elem. 2010; 177: 2309
  Search in Google Scholar

Corresponding Author

Publication History

Received: 02 February 2025

Accepted after revision: 08 May 2025

Accepted Manuscript online:
08 May 2025

Article published online:
03 July 2025

© 2025. Thieme. All rights reserved

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• References and Notes

• 1 Dickens TK, Warren SG. Chemistry of the Carbonyl Group: A Step-by-Step Approach to Understanding Organic Reaction Mechanisms. John Wiley & Sons; Hoboken: 2018
  Search in Google Scholar
• 2 Safari J, Gandomi-Ravandi S. RSC Adv. 2014; 4: 46224
  Search in Google Scholar
• 3 Chourasiya SS, Kathuria D, Wani AA, Bharatam PV. Org. Biomol. Chem. 2019; 17: 8486
  Search in Google Scholar
• 4 Dascalu AE, Halgreen L, Torres-Huerta A, Valkenier H. Chem. Commun. 2022; 58: 11103
  Search in Google Scholar
• 5 Shirini F, Mamaghani M, Rahmanzadeh A. ARKIVOC 2007; (i): 34
  Search in Google Scholar
• 6 Dekova BY, Evers MJ, Christiaens LR, Guillaume MR. Bull. Soc. Chim. Belg. 1987; 96: 219
  Search in Google Scholar
• 7 Mohammadpoor altork I, Pouranshirvani Sh. Synth. Commun. 1996; 26: 1
  Search in Google Scholar
• 8 Paredes R, Bastos H, Montoya R, Chavez AL, Dolbier WR, Burkholder CR. Tetrahedron 1988; 44: 6821
  Search in Google Scholar
• 9 Zolfigol MA, Poor-Baltork IM, Mirjalili BF, Shirini F, Salehzadeh S, Keypour H, Ghorbani-Choghamarani A, Zebarjadian MH, Mohammadi K, Hazar A. Phosphorus, Sulfur Silicon Relat. Elem. 2003; 178: 2735
  Search in Google Scholar
• 10 Nanjundaswamy HM, Pasha MA. Synth. Commun. 2006; 36: 3161
  Search in Google Scholar
• 11 Shirini F, Zolfigol MA, Safari A, Mohammadpoor-Baltork I, Mirjalili BF. Tetrahedron Lett. 2003; 44: 7463
  Search in Google Scholar
• 12 Giurg M, Młochowski J. Synth. Commun. 1999; 29: 4307
  Search in Google Scholar
• 13 Carmeli M, Rozen S. Tetrahedron Lett. 2006; 47: 763
  Search in Google Scholar
• 14 Habibi D, Zolfigol MA, Faraji AR, Rahmani P. Monatsh. Chem. 2012; 143: 809
  Search in Google Scholar
• 15 Mohammadpoor-Baltork I, Khodaei MM, Hajipour AR, Aslani E. Monatsh. Chem. 2003; 134: 539
  Search in Google Scholar
• 16 Kumar H, Kaur B, Kumar B. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1991; 30: 869
  Search in Google Scholar
• 17 Lim YG, Koo BT. Tetrahedron Lett. 2005; 46: 385
  Search in Google Scholar
• 18 Yu Y, Kuai C, Chauvin R, Tian N, Ma S, Cui X. J. Org. Chem. 2017; 82: 8611
  Search in Google Scholar
• 19 Wen J, Wu A, Wang M, Zhu J. J. Org. Chem. 2015; 80: 10457
  Search in Google Scholar
• 20 Vu HM, Yong JY, Chen FW, Li XQ, Shi GQ. J. Org. Chem. 2020; 85: 4963
  Search in Google Scholar
• 21 Mishra NK, Oh Y, Jeon M, Han S, Sharma S, Han SH, Um SH, Kim IS. Eur. J. Org. Chem. 2016; 4976
• 22 Ban T, Vu HM, Zhang J, Yong JY, Liu Q, Li XQ. J. Org. Chem. 2022; 87: 5543
  Search in Google Scholar
• 23 Wen J, Wu A, Miao Y, Zhu J. Tetrahedron Lett. 2015; 56: 5512
  Search in Google Scholar
• 24 Kianmehr E, Seifinoferest B, Afaridoun H. Eur. J. Org. Chem. 2020; 4925
• 25 Han W, Zhang G, Li G, Huang H. Org. Lett. 2014; 16: 3532
  Search in Google Scholar
• 26 Deshmukh DS, Yadav PA, Bhanage BM. Org. Biomol. Chem. 2019; 17: 3489
  Search in Google Scholar
• 27 Dönnecke D, Wunderle J, Imhof W. J. Organomet. Chem. 2004; 689: 585
  Search in Google Scholar
• 28 Hussain H, Green IR, Ahmed I. Chem. Rev. 2013; 113: 3329
  Search in Google Scholar
• 29 Azine Directing Group Removal; General Procedure A round-bottomed flask was charged with Oxone (1.74 g, 6 equiv) in H₂O (7.5 mL). A solution of the corresponding azine-protected carbonyl substrate (0.95 mmol) in acetone (7.5 mL) was added dropwise to the flask and the resulting mixture was allowed to stir at room temperature until completion of reaction (monitored by TLC). The reaction was quenched by adding H₂O (20 mL) and extracted using ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained product was dried under vacuum.
• 30 3-(Trifluoromethyl)benzaldehyde (2i) Time required for conversion: 40 min. ¹H NMR (400 MHz, CDCl₃): δ = 10.00 (d, J = 1.0 Hz, 1 H), 8.06 (s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 190.82, 136.82, 132.74, 130.69, 129.79, 126.23, 124.88, 122.14. MS (ESI): m/z = 174.03.
• 31 3,4,5-Trimethoxyacetophenone (2o) Time required for conversion: 90 min. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.24 (s, 2 H), 3.85 (s, 6 H), 3.73 (s, 3 H), 2.58 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ = 197.04, 141.93, 132.32, 105.81, 60.24, 56.10, 26.69. MS (ESI): m/z = 210.07.
• 32 Bigdeli MA, Nikje MM. A, Heravi MM. Phosphorus, Sulfur Silicon Relat. Elem. 2010; 177: 2309
  Search in Google Scholar

• Supplementary Material