We acknowledge generous start-up funds from the State University of New York at Stony Brook in support of this work. We also thank TOSOH F-Tech, Inc. for providing us TMSCF3 reagent for the synthesis of Togni reagent II.

1. Precursor Preparation: Synthesis of Methyl 4-(N-hydroxyacetamido)benzoate (1a)
<ol>
	<li>Reduction of methyl 4-nitrobenzoate.
	<ol>
		<li>Add 5.00 g of methyl 4-nitrobenzoate (27.6 mmol, 1.00 equiv), 159 mg of 5% Rhodium on carbon (Rh/C, 0.300 mol% Rh), and a magnetic stir-bar into an oven-dried 250 ml two-neck round-bottom flask (dried at 150 &#176;C for 18 hr). 
		NOTE: Reagents can be weighed out under ambient atmosphere. However, the reaction needs to be carried out under nitrogen atmosphere.</li>
		<li>Connect one neck of the flask to a nitrogen/vacuum manifold and cap the other neck with a septum. Perform three vacuum-refill cycles (i.e., pumping the air out of the flask and replacing the resulting vacuum with nitrogen gas) to replace the air in the flask with nitrogen gas.</li>
		<li>Add 138 ml anhydrous tetrahydrofuran (THF, 0.200 M) to the reaction flask using airtight syringe. Cool and stir the reaction mixture at 0 &#176;C for 15 min.</li>
		<li>Add 1.47 ml of hydrazine monohydrate (1.52 g, 30.4 mmol, 1.20 equiv) dropwise to the reaction mixture at 0 &#176;C using an airtight syringe. Monitor the reaction using a thin layer chromatography (TLC). Use hexanes:ethyl acetate (EtOAc) (4:1 v/v, Rf = 0.23) as an eluent to develop the TLC.</li>
		<li>When methyl 4-nitrobenzoate is completely consumed, filter the reaction mixture through a short pad of diatomaceous earth (i.e., Celite, 5 g) in a 60 ml frit Buchner funnel using vacuum filtration. Wash the filter with EtOAc (20 ml x 3 times). Concentrate the filtrate in vacuo using a rotary evaporator to afford the crude methyl 4-(N-hydroxyamino)benzoate, which is used directly without further purification.</li>
	</ol>
	</li>
	<li>Acetyl protection of methyl 4-(N-hydroxyamino)benzoate
	<ol>
		<li>Add 2.55 g of sodium bicarbonate (NaHCO3, 30.4 mmol, 1.20 equiv), all the crude methyl 4-(N-hydroxyamino)benzoate obtained from the previous step, and a stir-bar into an oven-dried 500 ml two-neck round-bottom flask.</li>
		<li>Cap one neck with a septum and connect another neck to a nitrogen/vacuum manifold. Perform three vacuum-refill cycles to replace the air in the flask with nitrogen gas.</li>
		<li>Add 138 ml anhydrous diethyl ether (Et2O, 0.200 M) to the reaction flask using an airtight syringe. Cool and stir the reaction mixture at 0 &#176;C for 15 min.</li>
		<li>Prepare a solution of acetyl chloride (2.17 ml, 2.39 g, 30.4 mmol, 1.20 equiv) in anhydrous Et2O (138 ml, 0.220 M). Add the solution to the reaction mixture at 0 &#176;C using a syringe pump at a rate of 10.0 ml/hr.</li>
		<li>At the end of the addition, filter the reaction mixture through a short pad of diatomaceous earth (i.e., Celite, 5 g) in 60 ml frit Buchner funnel using vacuum filtration. Wash the filter with EtOAc (20 ml x 3 times). Concentrate the filtrate in vacuo using a rotary evaporator.</li>
		<li>Purify the crude product with flash column chromatography35 eluting with hexanes:EtOAc (4:1 to 1:1 (v/v)) (Rf = 0.13, hexanes:EtOAc (4:1 (v/v)) to afford 5.31 g of methyl 4-(N-hydroxyacetamido)benzoate as a light yellow solid (25.4 mmol, 92% yield).</li>
	</ol>
	</li>
</ol>
2. Synthesis of Methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a)
<ol>
	<li>Add 2.00 g of methyl 4-(N-hydroxyacetamido) benzoate (1a) (9.56 mmol, 1.00 equiv), 311 mg of Cs2CO3 (0.956 mmol, 10.0 mol%), 3.63 g of Togni reagent II (11.5 mmol, 1.20 equiv), and a magnetic stir-bar into an oven-dried 250 ml round-bottom flask inside a glovebox (nitrogen atmosphere). 
	NOTE: This reaction can also be performed using Schlenk techniques outside the glovebox. 
	Caution: Pure Togni reagent II is impact and friction sensitive, open flames, sparks, and/or grinding should be avoided. Soft and polished tools should be used for manipulations. In addition, the reaction mixture should be stirred behind a safety shield.36</li>
	<li>Add 95.6 ml of dried and degassed chloroform (CHCl3, 0.100 M) to the reaction flask.</li>
	<li>Cap the flask with septum and stir the reaction mixture at 23 &#176;C under N2 atmosphere either inside or outside of the glovebox for 16 hr.</li>
	<li>Filter the reaction mixture through a filter funnel to remove any solid residue. Concentrate the filtrate in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with flash column chromatography eluting with hexanes:dichloromethane (CH2Cl2) (7:3 to 0:1 (v/v)) (Rf = 0.44 (CH2Cl2) to afford 2.51 g of methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (9.05 mmol, 95% yield). 
	NOTE: Togni reagent II is prepared according to the literature procedures37 and stored in the glovebox freezer at -35 &#176;C to maintain its quality over a long period of time. This reaction is oxygen sensitive. Although all the reagents can be weighed out under ambient atmosphere at RT, removal of all oxygen from the reaction flask is critical. Dried and degassed CHCl3 is prepared by distilling it from CaH2 under nitrogen atmosphere followed by performing a three cycles of the freeze-pump-thaw procedure.</li>
</ol>
3. Synthesis of Methyl 4-Acetamido-3-(trifluoromethoxy)benzoate via OCF3-migration (3a)
<ol>
	<li>Add 2.51 g methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (9.05 mmol, 1.0 equiv), a magnetic stir-bar, and 9.05 ml of MeNO2 (1.00 M) into a 50 ml pressure vessel. Cap the vessel with a screw cap.</li>
	<li>Stir the reaction mixture at 120 &#176;C behind the safety shield for 20 hr. 
	Caution: Impure nitromethane is explosive, so the reaction mixture should be stirred behind the safety shield.</li>
	<li>Cool the reaction mixture to RT.</li>
	<li>Transfer the reaction mixture to a 100 ml round-bottom flask.</li>
	<li>Concentrate the reaction mixture in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with flash column chromatography eluting with hexanes:EtOAc (9:1 to 7:3 (v/v)) (Rf = 0.51 hexanes:EtOAc (4:1 (v/v)) to afford 2.13 g of methyl 4-acetamido-3-(trifluoromethoxy)benzoate (7.69 mmol, 85%). 
	NOTE: This reaction can be carried out under ambient atmosphere. Nitrogen atmosphere is not required. A round-bottom flask equipped with a water condenser can be used as an alternative reaction apparatus.</li>
</ol>
4. Characterization of New Products
<ol>
	<li>Characterize all the new compounds by 1H, 13C NMR spectroscopy and high-resolution mass spectroscopy and use 19F NMR spectroscopy to characterize compounds containing fluorine atoms.34</li>
</ol>

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The authors declare no competing financial interests.

Due to the lack of a general and user-friendly procedure for the synthesis of trifluoromethoxylated arenes, many OCF3-containing aromatic compounds are extremely expensive.34 Our strategy displaces a broad functional group tolerance and provides an easy access to various trifluoromethoxylated arenes. These compounds could serve as valuable building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and materials.
Hydrazine was used as a hydrogen source for the rhodium-catalyzed reduction of nitroarenes. Its quality is one of the keys in obtaining the reduction products in high yields. The reduction yields dropped when a few-month old hydrazine was used. To ensure the reproducibility, we transferred some of the hydrazine from a large commercial bottle to a smaller 20 ml vial and used it from the 20 ml vial. In addition, we stored it in the refrigerator (4 &#176;C) to slow down the rate of decomposition. Moreover, slow addition of hydrazine is crucial in getting clean hydroxylamines in good yields.
The O-trifluoromethylation is a radical mediated process, so exclusion of oxygen from the reaction mixture is critical. Using un-degassed chloroform as the solvent or performing the reaction under ambient atmosphere resulted in lower yield. Our preliminary mechanistic studies shown that the OCF3-migration process involved thermally induced heterolytic cleavage of the N-OCF3 bond to generate a tight ion pair of nitrenium ion and trifluoromethoxide.34 Trifluoromethoxide attacks the ortho-position of the nitrenium ion followed by the tautomerization to afford the desired ortho-trifluoromethoxylated aniline derivatives. Formation of the nitrenium ion in electron deficient substrates is energetically disfavored and thus requires higher reaction temperature.
In summary, we reported a general and laboratory scale synthetic protocol for the regioselective synthesis of ortho-OCF3 aniline derivatives. This strategy has several unique features: (i) a wide range of functional groups and substitution patterns are tolerated; (ii) the operational simplicity of our protocol would render trifluoromethoxylation available to broader synthetic community; and (iii) the final products are novel and could be used as useful synthetic building blocks for life and materials science research. Some troubleshooting procedures are outlined here: (i) store the reduction product, aryl hydroxyl amine, in the freezer or immediately use it for the next step; (ii) monitor the reduction/protection reactions closely with TLC to avoid over reduction of nitroarenes or protection of N-hydroxyamines; (iii) exclusion of oxygen from the reaction mixtures is critical for the reduction of nitroarenes and O-trifluoromethylation; (iv) higher reaction temperature is needed for electron deficient arenes in the intramolecular OCF3-migration step.

The trifluoromethoxy (OCF3) group has made a profound impact on life and materials science research since the first synthesis of trifluoromethyl ether in 1935.2 Due to its unique combination of high electronegativity (&#967; = 3.7)3 and excellent lipophilicity (&#928;x = 1.04),4 the trifluoromethoxy group has found broad applications in medicine, agriculture, and materials industry.5-10 However, facile introduction of the OCF3 group into organic molecules, especially aromatic compounds, remains a major challenge in synthetic chemistry.
Over the last few decades, efforts to address this challenge led to the development of a handful of transformations for the synthesis of trifluoromethoxylated arenes.5-7,9-11 These include (i) chlorine/fluorine exchange on trichlorinated precursors;1,12-17 (ii) deoxyfluorination of fluoroformates;18 (iii) oxidative fluorodesulfurization;19-21 (iv) electrophilic trifluoromethylation of alcohols;22-25 (v) nucleophilic trifluoromethoxylation;26-30, (vi) transition metal-mediated trifluoromethoxylation of aryl borates and stannanes;31 and (vii) radical trifluoromethoxylation.32,33 Nevertheless, many of these approaches either suffer from poor substrate scope or require use of highly toxic and/or thermally labile reagents. Therefore, due to the lack of a general and user-friendly method to synthesize OCF3-containing compounds, the potential of the OCF3 group has not been fully exploited in chemistry.
As part of our interest in trifluoromethoxylation reactions,34 we describe herein a two-step protocol (i.e., radical&#160;O-trifluoromethylation and thermally induced OCF3-migration) for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) from methyl 4-(N-hydroxyacetamido)benzoate (1a). The strategy is easy-to-operate and applicable to the synthesis of a wide range of ortho-trifluoromethoxylated aniline derivatives.

<table><tbody><tr><td>5% Rhodium on carbon</td><td>Aspira Scientific</td><td>300835</td><td>5% wt% dry loading</td></tr><tr><td>Hydrazine monohydrate</td><td>Sigma-Alderich</td><td>13696HMV</td><td>Reagent grade, 98%</td></tr><tr><td>Acetyl chloride</td><td>Alfa Aesar</td><td>10176887</td><td>98%</td></tr><tr><td>Sodium bicarbonate</td><td>Fisher Scientific</td><td>134826</td><td>Chemical pure</td></tr><tr><td>Cesium carbonate</td><td>Alfa Aesar</td><td>12887</td><td>99.9%, metals basis</td></tr><tr><td>Togni Reagent II</td><td></td><td></td><td>Prepared according to the literature procedure (ref 37). Caution: Pure Togni reagent II is impact and friction sensitive, treat it with great care (see ref. 36).</td></tr><tr><td>Tetrahydrofuran</td><td>BDH</td><td>BDH1149-4LG</td><td>Distilled from deep purple sodium benzophenone ketyl.</td></tr><tr><td>Diethyl Ether</td><td>Fisher Scientific</td><td>148221</td><td>Distilled from deep purple sodium benzophenone ketyl.</td></tr><tr><td>Chloroform</td><td>Fisher Scientific</td><td>141739</td><td>Dried over CaH&lt;sub&gt;2&lt;/sub&gt; and distilled</td></tr><tr><td>Nitromethane</td><td>Alfa Aesar</td><td>J03z053</td><td>Dried over CaSO&lt;sub&gt;4&lt;/sub&gt; and distilled</td></tr><tr><td>Silica gel</td><td>SILICYCLE</td><td>60514</td><td>40-63 &amp;micro;m (230-400 mesh)</td></tr><tr><td>Celite</td><td>EMD</td><td>2012040674</td><td>Not acid washed</td></tr></tbody></table>

protocol for the synthesis of ortho-trifluoromethoxylated aniline derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 &#176;C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Methyl 4-(N-hydroxyacetamido)benzoate (1a) was synthesized in 92% isolated yield through a two-step procedure (i.e., reducing methyl 4-nitrobenzoate with hydrazine using 5% Rh/C as a catalyst to form methyl 4-(N-hydroxyamino)benzoate, followed by acetyl protection of the resulting hydroxylamine). O-Trifluoromethylation of 1a with Togni reagent II in the presence of catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded the desired 4-(N-(trifluoromethoxy)acetamido)benzoate (2a) in 95% isolated yield. This compound underwent thermally induced OCF3-migration in MeNO2 at 120 &#176;C to give the desired methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in 85% isolated yield.
The 1H, 13C, and 19F NMR spectrum of the final product 3a are depicted in Figure 1, Figure 2, and Figure 3, respectively. A distinguish quartet peak at 120.6 ppm with a large coupling constant (258.9 Hz) in 13C NMR spectra corresponds to the CF3 carbon. When the OCF3-migration takes place, a sharp change in the 19F NMR from -65 ppm (2a) to -58.1ppm (3a) is observed. The detail characterization data of 3a is reported as follow: Rf = 0.51 (hexanes/EtOAc 4:1 (v/v)). NMR Spectroscopy: 1H NMR (700 MHz, CDCl3, 25 &#176;C, &#948;): 8.56 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.56 (br. s, 1H), 3.92 (s, 3H), 2.27 (s, 3H). 13C NMR (175 MHz, CDCl3, 25 &#176;C, &#948;): 168.5, 165.6, 137.2, 134.7, 129.3, 125.8, 121.5, 120.8, 120.6 (q, J = 258.9 Hz), 52.5, 25.2. 19F NMR (376 MHz, CDCl3, 25 &#176;C, &#948;): -58.1 (s). Mass Spectrometry: HRMS (ESI-TOF) (m/z): calcd for C11H11NO4F3 ([M + H]+) 278.0640, found 278.0643.
This protocol is general and applicable to a wide array of aromatic compounds (Table 1). The reaction tolerates a broad spectrum of functional groups including ester (3a, 3d), ketone (3b), nitrile (3c), ethers (3e, 3m), halogens (3g - 3l), CF3 group (3m, 3n), amide (3o) and heterocycle substituent (3o). The halogen substituents, especially Br and I, are particularly useful because they provide synthetic handles for further functionalization. In addition, high levels of ortho- over para-selectivity are observed (3f, 3k - 3l). In the presence of two non-identical ortho positions, low levels of regiocontrol are obtained (3d, 3e, 3k, 3m). Furthermore, the reaction temperature for the OCF3-migration step depends on the electronic nature of arenes. Generally, more electron deficient arenes require higher reaction temperature.
<img alt="Figure 1" src="/files/ftp_upload/53789/53789fig1.jpg" />
Figure 1. 1H NMR spectrum of 3a. Chemical shift and relative integration of characteristic protons are labeled. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/53789/53789fig2.jpg" />
Figure 2. 13C NMR spectrum of 3a. Chemical shift of characteristic carbons is labeled. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/53789/53789fig3.jpg" />
Figure 3. 19F NMR spectrum of 3a. Chemical shift of characteristic fluorine is labeled using trifluorotoluene (-63.3 ppm) as internal reference. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Table 1" src="/files/ftp_upload/53789/53789table1highres.jpg" width="700" />
Table 1. Selected examples of trifluoromethoxylation of arenes. Reaction time: 11-48 hr. Cited yields and isomeric ratios are for OCF3-migration step (from 2 to 3) and of isolated material by flash column chromatography. [a] 50 &#176;C. [b] 120 &#176;C. [c] 140 &#176;C. [d] Less than 5% para-product was detected. THF = Tetrahydrofuran; AcCl = acetyl chloride. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789table1highres.jpg" target="_blank">Please click here to view a larger version of this table.</a>

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Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

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10.2K Views.  State University of New York at Stony Brook. An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Video: Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes &#945;v and &#945;5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document. The modifications described here involve terminally (N&#969;) alkylated and acetylated guanidine groups. For the synthesis, tailor-made precursor molecules are synthesized, which are then subjected to a reaction with an orthogonally deprotected amine to transfer the pre-modified guanidine group. For the synthesis of alkylated guanidines, precursors based on N,N&#8242;-Di-Boc-1H-pyrazole-1-carboxamidine are used to synthesize acylated compounds, the precursor of choice being a correspondingly acylated derivative of N-Boc-S-methylisothiourea, which can be obtained in one- and two-step reactions.

A protocol for the synthesis of alkyl-modified guanidines based on the use of the corresponding precursors is presented.

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. ...

Biochemistry

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Synthesis of Indoxyl-glycosides for Detection of Glycosidase Activities

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are rapidly oxidized, for example by atmospheric oxygen, to indigo type dyes. This reaction enables fast and easy screening in vivo without isolation or purification of enzymes, as well as rapid tests on agar plates or in solution (e.g., blue-white screening, micro-wells) and is used in biochemistry, histochemistry, bacteriology and molecular biology. Unfortunately the synthesis of such substrates proved to be difficult, due to various side reactions and the low reactivity of the indoxyl hydroxyl function. Especially for glucose type structures low yields were observed. Our novel approach employs indoxylic acid ester as key intermediates. Indoxylic acid esters with varied substitution patterns were prepared on scalable pathways. Phase transfer glycosylations with those acceptors and peracetylated glycosyl halides can be performed under common conditions in high yields. Ester cleavage and subsequent mild silver mediated glycosylation yields the peracetylated indoxyl glycosides in high yields. Finally deprotection is performed according to Zempl&#233;n.

Indoxyl glycosides are well-established and widely used tools for enzyme screening and enzyme activity monitoring. Especially for glucose type structures previous syntheses proved to be challenging and low yielding. Our novel approach employs indoxylic acid esters as precious intermediates to yield a considerable number of indoxyl glycosides in good yields.

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are ...

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile ...

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates

Maleimide-bearing bifunctional probes have been employed for decades for the site-selective modification of thiols in biomolecules, especially antibodies. Yet maleimide-based conjugates display limited stability in vivo because the succinimidyl thioether linkage can undergo a retro-Michael reaction. This, of course, can lead to the release of the radioactive payload or its exchange with thiol-bearing biomolecules in circulation. Both of these processes can produce elevated activity concentrations in healthy organs as well as decreased activity concentrations in target tissues, resulting in reduced imaging contrast and lower therapeutic ratios. In 2018, we reported the creation of a modular, stable, and easily accessible phenyloxadiazolyl methyl sulfone reagent &#8212; dubbed &#8216;PODS&#8217; &#8212; as a platform for thiol-based bioconjugations. We have clearly demonstrated that PODS-based site-selective bioconjugations reproducibly and robustly create homogenous, well-defined, highly immunoreactive, and highly stable radioimmunoconjugates. Furthermore, preclinical experiments in murine models of colorectal cancer have shown that these site-selectively labeled radioimmunoconjugates exhibit far superior in vivo performance compared to radiolabeled antibodies synthesized via maleimide-based conjugations. In this protocol, we will describe the four-step synthesis of PODS, the creation of a bifunctional PODS-bearing variant of the ubiquitous chelator DOTA (PODS-DOTA), and the conjugation of PODS-DOTA to the HER2-targeting antibody trastuzumab.

In this protocol, we will describe the synthesis of PODS, a phenyoxadiazolyl methyl sulfone-based reagent for the site-selective attachment of cargos to the thiols of biomolecules, particularly antibodies. In addition, we will describe the synthesis and characterization of a PODS-bearing bifunctional chelator and its conjugation to a model antibody.

Maleimide-bearing bifunctional probes have been employed for decades for the site-selective modification of thiols in biomolecules, especially antibodies. ...

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyl(tropone)iron

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyltroponeiron

Representative experimental procedures for the addition of amine nucleophiles to tricarbonyl(tropone)iron and subsequent demetallation of the resulting complexes are presented in detail.

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate ...

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

3-Aroyl-N-hydroxy-5-nitroindoles were synthesized by cycloaddition of 4-nitronitrosobenzene with a conjugated terminal alkynone in a one-step thermal procedure. Preparation of the nitrosoarene and of the alkynones were adequately reported and respectively through oxidation procedures on the corresponding aniline and on the alkynol.

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ...

Synthesis of pH Dependent Pyrazole, Imidazole, and Isoindolone Dipyrrinone Fluorophores using a Claisen-Schmidt Condensation Approach

Methine-bridged conjugated bicyclic aromatic compounds are common constituents of a range of biologically relevant molecules such as porphyrins, dipyrrinones, and pharmaceuticals. Additionally, restricted rotation of these systems often results in highly to moderately fluorescent systems as observed in 3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidin-3-ones, xanthoglows, pyrroloindolizinedione analogs, BODIPY analogs, and the phenolic and imidazolinone ring systems of Green Fluorescent Protein (GFP). This manuscript describes an inexpensive and operationally simple method of performing a Claisen-Schmidt condensation to generate a series of fluorescent pH dependent pyrazole/imidazole/isoindolone dipyrrinone analogs. While the methodology illustrates the synthesis of dipyrrinone analogs, it can be translated to produce a wide range of conjugated bicyclic aromatic compounds. The Claisen-Schmidt condensation reaction utilized in this method is limited in scope to nucleophiles and electrophiles that are enolizable under basic conditions (nucleophile component) and non-enolizable aldehydes (electrophile component). Additionally, both the nucleophilic and electrophilic reactants must contain functional groups that will not inadvertently react with hydroxide. Despite these limitations, this methodology offers access to completely novel systems that can be employed as biological or molecular probes.

The Claisen-Schmidt condensation reaction is an important methodology for the generation of methine-bridged conjugated bicyclic aromatic compounds. Through utilizing a base-mediated variant of the aldol reaction, a range of fluorescent and/or biologically relevant molecules can be accessed through a generally inexpensive and operationally simple synthetic approach.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

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