Acknowledgement is made to the Donors of the American Chemical Society Petroleum Research Fund for support of this research. We acknowledge the Lafayette College Chemistry Department and the Lafayette College EXCEL Scholars program for financial support.

1. Synthesis of tricarbonyl(tropone)iron (1)19
<ol>
	<li>In an argon-atmosphere glovebox, weigh out 4.1 g of diiron nonacarbonyl into an oven-dried 20 mL vial. Cap the vial and remove it from the glovebox. 
	CAUTION: Prolonged storage of diiron nonacarbonyl leads to some deterioration to give triiron dodecacarbonyl and finely divided metallic iron20. This deterioration is evidenced by the presence of a black solid within the shiny orange diiron nonacarbonyl. The iron impurity is pyrophoric and can ignite upon exposure to air. Storing the diiron nonacarbonyl under argon at 2-8 &#176;C in a bottle sealed with electrical tape appears to minimize this deterioration. The pyrophoric iron impurities can be destroyed via addition of dilute hydrochloric acid.</li>
	<li>Add an oven-dried PTFE stir bar, 0.5 mL of tropone, and 10 mL of dry benzene to an oven-dried 50 mL round bottom flask. 
	NOTE: A round bottom flask with a 24/40 ground glass joint is preferred so that the solid diiron nonacarbonyl may be added rapidly with minimal spilling (see Step 1.5).</li>
	<li>Degas the contents of the round bottom flask via three freeze-pump-thaw cycles as follows.
	<ol>
		<li>Submerge the flask in a dry ice-acetone bath until the contents solidify completely. Then, with the flask still submerged in the cold bath, evacuate the flask under vacuum for 2-3 min.</li>
		<li>Allow the contents to thaw under static vacuum.</li>
		<li>Repeat steps 1.3.1 and 1.3.2 twice.</li>
		<li>After the final thaw, backfill the flask with argon and cover the flask with a rubber septum. Keep the flask under a positive pressure of argon.</li>
	</ol>
	</li>
	<li>Cover the flask with aluminum foil and commence vigorous magnetic stirring.</li>
	<li>Briefly remove the rubber septum and add the previously weighed diiron nonacarbonyl in a single portion and replace the septum.</li>
	<li>Immerse the flask in an oil bath at 55-60 &#176;C and stir for 30 min.</li>
	<li>After 30 min, remove the flask from the oil bath and allow to cool to room temperature.</li>
	<li>Isolate the tropone complex via alumina column chromatography as follows.
	<ol>
		<li>Pack a chromatography column (~30 mm diameter) with 12 cm of alumina (Activity II/III) and hexanes.</li>
		<li>Pipette the crude reaction mixture directly onto the alumina. Rinse the flask with a small amount (1-3 mL) of hexanes and add to the top of the column.</li>
		<li>Drain the column until the solvent is level with the top of the alumina and add ~2 cm of sand.</li>
		<li>Elute with hexanes until the blue-green band (triiron dodecacarbonyl) comes off the column.</li>
		<li>Elute with 1:1 hexanes:methylene chloride until the red-orange tropone iron complex elutes completely.</li>
		<li>Remove the solvent from the red-orange solution via rotary evaporation to obtain the tropone complex as a dark red oil that solidifies on standing. 
		NOTE: The tropone complex isolated in this fashion is occasionally contaminated with paramagnetic, iron-based impurities, as evidenced by severely broadened peaks in the 1H NMR spectrum. These impurities can be removed by redissolving the complex in methylene chloride&#160;and passing through a short plug of alumina, eluting with 1:1 hexanes:methylene chloride.</li>
	</ol>
	</li>
</ol>
2. Synthesis of tricarbonyl(5-ketocycloheptadienyl)iron tetrafluoroborate (2)21
<ol>
	<li>Add a PTFE magnetic stir bar, 432 mg of tricarbonyl(tropone)iron, and 10 mL of methylene chloride to a 50 mL round bottom flask.</li>
	<li>Cool the flask in an ice bath and commence vigorous magnetic stirring.</li>
	<li>Add 3.2 mL of concentrated sulfuric acid dropwise.</li>
	<li>Vigorously stir the mixture at 0 &#176;C for 30 min.</li>
	<li>To a separate 100 mL round bottom flask, add a PTFE stir bar, 2.0 g of anhydrous sodium carbonate, and 10 mL of methanol.</li>
	<li>Cool the flask containing the sodium carbonate mixture in an ice bath and vigorously stir it magnetically.</li>
	<li>Upon completion of the 30-min period (step 2.4), cease magnetic stirring. Two layers should form.</li>
	<li>Using a Pasteur pipette, transfer the viscous, brown lower layer to the rapidly stirring sodium carbonate suspension.</li>
	<li>Stir for ~5 min, and then carefully and slowly add 50 mL of deionized water. 
	CAUTION: Vigorous bubbling is involved in this step.</li>
	<li>Pour the mixture into a 250 mL separatory funnel and extract with methylene chloride (2x 50 mL).</li>
	<li>Sequentially wash the combined organic layers with water (50 mL) and brine (50 mL).</li>
	<li>Dry the organic layers over anhydrous magnesium sulfate.</li>
	<li>Remove the magnesium sulfate via gravity or vacuum filtration and concentrate the filtrate via rotary evaporation to obtain a red-brown oil. 
	NOTE: The protocol may be paused at this point.</li>
	<li>Add 3 mL of acetic anhydride to a 25 mL Erlenmeyer flask and cool it in an ice bath.</li>
	<li>Add 1 mL of 48% aqueous tetrafluoroboric acid to the cold acetic anhydride dropwise. 
	CAUTION: The addition is highly exothermic. However, the exotherm is readily contained by controlling the temperature and rate of addition.</li>
	<li>In a 100 mL round bottom flask submerged in an ice bath, add the mixture obtained from step 2.15 to the oil obtained in step 2.13.</li>
	<li>Agitate the mixture with a stainless steel spatula for 5 min. 
	NOTE: The mixture generally takes on a gummy consistency upon agitation and the color becomes lighter.</li>
	<li>Add 50 mL of diethyl ether to the mixture. Collect the resulting pale yellow solid via vacuum filtration using a Buchner funnel to obtain the cationic complex as its tetrafluoroborate salt.</li>
</ol>
3. Synthesis of aza-Michael adduct 4: Tricarbonyl[(2-5-h)-6-((2-phenylethyl)amino)cyclohepta-2,4-dien-1-one]iron
<ol>
	<li>Add a PTFE magnetic stir bar, 150 mg of tricarbonyl(tropone)iron (1), and 0.154 mL of phenethylamine to a 1-dram vial. Cap the vial under an air atmosphere and commence magnetic stirring. 
	NOTE: Phenethylamine will be oxidized by air upon prolonged storage resulting in a yellow-brown color. Phenethylamine should be distilled prior to use if it is not colorless.</li>
	<li>Monitor the reaction periodically by removing a small (~1 drop) aliquot from the reaction mixture, dissolving in CDCl3, and acquiring a 1H NMR spectrum. 
	NOTE: While this particular reaction is usually complete within 1 h, the reaction may be left to stir overnight.</li>
	<li>Upon disappearance of the signals for tricarbonyl(tropone)iron in the 1H NMR spectrum (see Representative Results and Figure 3 and Figure 4), purify the crude reaction mixture via chromatography on basic alumina (Activity II/III) as follows.
	<ol>
		<li>Pack a 30 mm diameter chromatography column with alumina (10-15 cm) and hexanes and apply the crude reaction mixture to the top of the column.</li>
		<li>Elute the column with 1:1 hexanes:diethyl either to remove the excess phenethylamine from the column. Monitor the elution via thin layer chromatography (TLC). 
		NOTE: The column was monitored using alumina TLC plates and a 1:1 diethyl ether:methylene chloride mixture as the mobile phase. If alumina TLC plates are not available, silica gel plates may be used (use 5% methanol in methylene chloride as the mobile phase).</li>
		<li>After the excess amine has finished eluting, change the eluting solvent to 1:1 diethyl ether:methylene chloride to elute the product. 
		NOTE: The title compound elutes as a yellow band.</li>
		<li>Combine the product-containing fractions (as judged by thin layer chromatography) and remove the solvent on a rotary evaporator to obtain the purified product as a dark yellow oil.</li>
	</ol>
	</li>
</ol>
4. Synthesis of tricarbonyl[(2-5-h)-6-(2-methylanilino)cyclohepta-2,4-dien-1-one]iron (3)
<ol>
	<li>Add a PTFE stir bar, 0.021 mL of o-toluidine, and 1.0 mL of diethyl ether to a 1-dram vial. Commence vigorous magnetic stirring.</li>
	<li>Carefully add 33 mg of the cationic complex to the mixture. Allow the suspension to stir for 12 h.</li>
	<li>Pour the reaction mixture into 5 mL of deionized water in a separatory funnel and extract the aqueous layter with 5 mL of ethyl acetate three times.</li>
	<li>Wash the combined organic layers with 10 mL of brine before drying over anhydrous sodium sulfate.</li>
	<li>Remove the sodium sulfate by gravity filtration and concentrate the filtrate via rotary evaporation to obtain the crude product.</li>
	<li>Purify the crude product via column chromatography on basic alumina using a gradient of 30-50% diethyl ether in hexanes to obtain the pure product as a yellow solid.</li>
</ol>
5. Protection of amine 4 as a tert-butyl carbamate
<ol>
	<li>Dissolve 76 mg of amine 4 in 2 mL of absolute ethanol in a 25 mL round bottom flask under air atmosphere.</li>
	<li>Add 104 mg of di-tert&#173;-butyl dicarbonate followed by 40 mg of solid sodium bicarbonate to the reaction mixture.</li>
	<li>Cap the flask with a rubber septum and sonicate the mixture for 1 h. 
	NOTE: This reaction may be allowed to run overnight.</li>
	<li>Filter the crude reaction mixture through a bed of diatomaceous earth using a Buchner funnel. Wash the diatomaceous earth with ethanol until no more brown-colored solution comes out the bottom of the funnel.</li>
	<li>Transfer the filtrate to a round bottom flask and concentrate on a rotary evaporator. Dissolve the resulting oil in ~2.5 mL of methylene chloride.</li>
	<li>Add ~1.3 g of silica gel to the solution and remove the methylene chloride on the rotary evaporator until a fine, free-flowing solid is obtained.</li>
	<li>Pack the silica gel into a 10 g silica cartridge for automated flash chromatography. 
	NOTE: An automated purification system was used in this protocol. However, conventional flash chromatography with silica gel may also be employed.</li>
	<li>Run the column using a gradient starting from 90:10 hexanes:ethylacetate and ending at 20:80 hexanes:ethyl acetate over a period of 20 min. Collect the fractions containing the product (as indicated by the major peak detected at 254 nm absorbance) in a round bottom flask. Evaporate the hexanes and ethyl acetate on a rotary evaporator to obtain the purified product as a yellow oil.</li>
</ol>
6. Synthesis of tert-butyl (6-oxocyclohepta-2,4-dien-1-yl)(2-phenylethyl) carbamate (6)
<ol>
	<li>In a 10 mL round bottom flask, dissolve 27 mg of iron complex 5 in 1 mL of methanol under air atmosphere and immerse the flask in an ice bath.</li>
	<li>Commence magnetic stirring and add 33 mg of cerium(IV) ammonium nitrate.</li>
	<li>After 30 min, add a second 33 mg portion of cerium(IV) ammonium nitrate, followed by a third 33 mg portion after an additional 30 min of stirring.</li>
	<li>After adding the third portion of cerium(IV) ammonium nitrate, dilute the reaction mixture with ethyl acetate (5 mL).</li>
	<li>Pour the mixture into a 30 mL separatory funnel containing 5 mL of saturated aqueous sodium bicarbonate. Separate the layers.</li>
	<li>Re-extract the aqueous layer with ethyl acetate (2x 5 mL). Dry the combined organic layers over anhydrous sodium sulfate.</li>
	<li>Remove the sodium sulfate via gravity or vacuum filtration and concentrate the filtrate on a rotary evaporator.</li>
	<li>Dissolve the crude product in ~2.5 mL of methylene chloride, add ~1.3 g of silica gel, and remove the solvent on a rotary evaporator.</li>
	<li>Pack the silica gel with the adsorbed crude product into a 10 g silica gel column for automated flash chromatography. 
	NOTE: An automated purification system was used in this protocol. However, conventional flash chromatography with silica gel may also be employed.</li>
	<li>Run the column using a gradient starting from 90:10 hexanes:ethylacetate and ending at 20:80 hexanes:ethyl acetate over a period of 20 min. Collect the fractions containing the product (as indicated by the major peak detected at 254 nm absorbance) in a round bottom flask. Evaporate the hexanes and ethyl acetate on a rotary evaporator to obtain the purified product as a pale brown oil.</li>
</ol>

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The authors have nothing to disclose.

Whether the solvent-free protocol involving direct addition to tricarbonyl(tropone)iron (Figure 2) or the indirect method utilizing the corresponding cationic complex as the electrophile (Figure 1) is to be employed depends on the amine substrate used. In general, the direct addition method is preferable since it requires fewer steps to generate the aza-Michael adducts from tropone and the overall yields are generally higher. However, this more direct m...

Structurally complex amines containing a seven-membered carbocyclic ring are common to a number of biologically active molecules. Notable examples include the tropane alkaloids1 and several members of the Lycopodium2, Daphniphyllum3, and monoterpenoid indole alkaloid4 families. However, such compounds are often more difficult to synthesize compared to compounds of similar complexity containing only five- or six-membered rings. Thus, we sought to develop a new avenue towards such compounds by attaching diverse amine nucleophiles to tropone5. The resulting adduct contains several functional handles for subsequent synthetic elaboration to diverse complex seven-membered ring-containing scaffolds that would be otherwise difficult to access.
While previous work with tropone6,7 suggests that it would not be suitable for such a transformation, the related organometallic complex tricarbonyl(tropone)iron8 (1, Figure 1) has proven to be a versatile synthetic building block that has been utilized in the synthesis of a number of natural products and complex molecules9,10,11,12,13. Furthermore, the uncomplexed double bond of tricarbonyl(tropone)iron has been shown to behave similar to an &#945;,&#946;-unsaturated ketone in reactions with, for example, dienes14,15, tetrazines16, nitrile oxides17, diazoalkanes8,10, and organocopper reagents11. Thus, we envisioned that an aza-Michael reaction of tricarbonyl(tropone)iron would provide an efficient entry to synthetically valuable aminated tropone derivatives.
Eisenstadt had previously reported that, following protonation of tricarbonyl(tropone)iron, the resulting cationic complex 2 (Figure 1) could undergo nucleophilic attack by aniline or tert-butylamine to produce aminated derivatives of the tropone iron complex.18 However, the synthetic potential of this method remains unrealized. Indeed, no additions of other amines had been reported, and the demetallation of those products was not explored in Eisenstadt&#8217;s report. We have adapted this protocol to demonstrate the addition of a wide variety of amine nucleophiles.
We also describe a method for direct aza-Michael additions to tricarbonyl(tropone)iron (Figure 2), which does not require synthesis of the cationic complex and generally proceeds in higher yields compared to the previously reported method. We also report herein a protocol for the demetallation of the resulting adducts. Overall, this protocol provides formal aza-Michael adducts of tropone in four steps from tropone (and three steps from the known iron complex).

<table><tbody><tr><td>10 g SNAP Ultra silica gel columns</td><td>Biotage</td><td></td><td>for automated column chromatography</td></tr><tr><td>Acetic anhydride</td><td>Fisher Scientific</td><td>A10-500</td><td></td></tr><tr><td>Acetone</td><td>Fisher Scientific</td><td>A-16S-20</td><td>for cooling baths</td></tr><tr><td>Acetonitrile-D3</td><td>Sigma Aldrich</td><td>366544</td><td></td></tr><tr><td>Benzene, anhydrous, 99.8%</td><td>Sigma Aldrich</td><td>401765</td><td></td></tr><tr><td>Biotage Isolera Prime</td><td>Biotage</td><td>ISO-PSF</td><td>for automated chromatography</td></tr><tr><td>Celite; 545 Filter Aid</td><td>Fisher Scientific</td><td>C212-500</td><td>diatomaceous earth</td></tr><tr><td>Cerium(IV) ammonium nitrate, ACS, 99+%</td><td>Alfa Aesar</td><td>33254</td><td></td></tr><tr><td>Chloroform-D</td><td>Acros</td><td>209561000</td><td></td></tr><tr><td>Di-tert-butyl dicarbonate, 99%</td><td>Acros</td><td>194670250</td><td></td></tr><tr><td>Ethyl acetate</td><td>Fisher Scientific</td><td>E145-4</td><td></td></tr><tr><td>Ethyl alcohol, absolute - 200 proof</td><td>Greenfield Global</td><td>111000200PL05</td><td></td></tr><tr><td>Ethyl ether anhydrous</td><td>Fisher Scientific</td><td>E138-1</td><td></td></tr><tr><td>Hexanes</td><td>Fisher Scientific</td><td>H302-4</td><td></td></tr><tr><td>iron nonacarbonyl 99%</td><td>Strem</td><td>26-2640</td><td>air sensitive, synonymous with diiron nonacarbonyl</td></tr><tr><td>Magnesium sulfate</td><td>Fisher Scientific</td><td>M65-500</td><td></td></tr><tr><td>Methanol</td><td>EMD Millipore</td><td>MX0475-1</td><td></td></tr><tr><td>Methylene chloride</td><td>Fisher Scientific</td><td>D37-4</td><td></td></tr><tr><td>MP alumina, Act. II-III acc. To Brockmann</td><td>MP Biomedicals</td><td>4691</td><td>for column chromatography</td></tr><tr><td>o-toluidine 98%</td><td>Sigma Aldrich</td><td>466190</td><td></td></tr><tr><td>Phenethylamine 99%</td><td>Sigma Aldrich</td><td>128945</td><td>distill prior to use if not colorless</td></tr><tr><td>Sodium bicarbonate</td><td>Fisher Scientific</td><td>S233-500</td><td></td></tr><tr><td>Sodium carbonate anhydrous</td><td>Fisher Scientific</td><td>S263-500</td><td></td></tr><tr><td>Sodium chloride</td><td>Fisher Scientific</td><td>S271-500</td><td>dissolved in deionized water to perpare a saturated aqueous solution</td></tr><tr><td>Sodium sulfate anhydrous</td><td>Fisher Scientific</td><td>S415-500</td><td></td></tr><tr><td>Sonicator</td><td>Branson</td><td></td><td>model 2510</td></tr><tr><td>Sulfuric acid</td><td>Fisher Scientific</td><td>A300C-212</td><td></td></tr><tr><td>Tetrafluoroboric acid solution, 48 wt.%</td><td>Sigma Aldrich</td><td>207934</td><td>aqueous solution</td></tr><tr><td>TLC Aluminium oxide 60 F254, neutral</td><td>EMD Millipore</td><td>1.05581.0001</td><td>for thin layer chromatography</td></tr><tr><td>Tropone 97%</td><td>Alfa Aesar</td><td>L004730-06</td><td>Light sensitive</td></tr></tbody></table>

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.

All novel compounds in this study were characterized by 1H and 13C NMR spectroscopy and high resolution mass spectrometry. Previously reported compounds were characterized by 1H NMR spectroscopy. NMR data for representative compounds are described in this section.
The 1H NMR spectrum of tricarbonyl(tropone)iron is shown in Figure 3. The protons of the &#951;4-diene ligand give rise to the signals at 6.39 ppm (...

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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.

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 ...

preparation-6-aminocyclohepta-24-dien-1-one-derivatives-via

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Education

JoVE Journal

JoVE Core

Chemistry

Organic Chemistry

Unit 1

Amines

Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

SCIENTISTS IN ACTION

7.9K 次观看.  Lafayette College. 该协议是合成氨化龙衍生物的一种有效方法。这些化合物可以作为合成中间体，用于合成结构复杂的胺。该技术的一个优点是，aza-Micheal 的添加可以在具有许多胺基材的无溶剂工艺中完成。这简化了反应设置和产品隔离。加入PTFE磁搅拌棒，150毫克三碳基龙铁和0.154毫升苯乙胺到一个德拉姆小瓶。将小瓶盖在空气大气中，开始磁搅拌。通过从反应混合物中去除少量等...

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

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.

高价碘鎓炔基三氟甲磺酸酯的生成Cyanocarbenes的合成应用

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

科研

化学

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.

修改和胍集团的官能通过量身定制的前兆

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

生物化学

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.

通过中级过氧化物的抗病毒四氢咔唑衍生物的合成光化学和酸催化CH官能（筹）

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 ...

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.

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.

协议的合成<em&gt;邻</em&gt; -trifluoromethoxylated苯胺类化合物

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

Accessing Valuable Ligand Supports for Transition Metals: A Modified, Intermediate Scale Preparation of 1,2,3,4,5-Pentamethylcyclopentadiene

A reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that derive from initial 2-bromo-2-butene lithiation followed by acid mediated dienol cyclization. The revised synthesis and purification of the ligand avoids the use of mechanical stirring while still permitting access to significant quantities (39 g) of Cp*H in good yield (58%). The procedure offers other additional benefits, including a more controlled quench of excess lithium during the production of the intermediate heptadienols and a simplified isolation of Cp*H of sufficient purity for metallation with transition metals. The ligand was subsequently used to synthesize [Cp*MCl2]2 complexes of both iridium and ruthenium to demonstrate the utility of the Cp*H prepared and purified by our method. The procedure outlined herein affords substantial quantities of a ubiquitous ancillary ligand support used in organometallic chemistry while minimizing the need for specialized laboratory equipment, thus providing a simpler and more accessible entry point into the chemistry of 1,2,3,4,5-pentamethylcyclopentadiene.

Reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented. The revised protocol for the synthesis and purification of the ligand minimizes the need for specialized laboratory equipment while simplifying reaction workups and product purification. Use of Cp*H in the synthesis of [Cp*MCl2]2 complexes (M = Ru, Ir) is also described.

访问有价值的配体为支持过渡金属:1,2,3,4,5-五甲基环戊二烯的一种改进，中级规模制备

A reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that ...

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.

准备n-(2-alkoxyvinyl) 磺胺从n-tosyl-1,2,3-triazoles 和随后转换为取代 Phthalans 和 Phenethylamines

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

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

α-伊米诺γ-乳胶酮和阿基地利酮吡唑酮有机催化环加花法高效构建药物样双环脚手架

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Preparation of SNS Cobalt(II) Pincer Model Complexes of Liver Alcohol Dehydrogenase

Chemical model complexes are prepared to represent the active site of an enzyme. In this protocol, a family of tridentate pincer ligand precursors (each possessing two sulfur and one nitrogen donor atom functionalities (SNS) and based on bis-imidazole or bis-triazole compounds) are metallated with CoCl2&#183;6H2O to afford tridentate SNS pincer cobalt(II) complexes. Preparation of the cobalt(II) model complexes for liver alcohol dehydrogenase is facile. Based on a quick color change upon adding the CoCl2&#183;6H2O to acetonitrile solution that contains the ligand precursor, the complex forms rapidly. Formation of the metal complex is complete after allowing the solution to reflux overnight. These cobalt(II) complexes serve as models for the zinc active site in liver alcohol dehydrogenase (LADH). The complexes are characterized using single crystal X-ray diffraction, electrospray mass spectrometry, ultra-violet visible spectroscopy, and elemental analysis. To accurately determine the structure of the complex, its single crystal structure must be determined. Single crystals of the complexes that are suitable for X-ray diffraction are then grown via slow vapor diffusion of diethyl ether into an acetonitrile solution that contains the cobalt(II) complex. For high quality crystals, recrystallization typically takes place over a 1 week period, or longer. The method can be applied to the preparation of other model coordination complexes and can be used in undergraduate teaching laboratories. Finally, it is believed that others may find this recrystallization method to obtain single crystals beneficial to their research.

Preparation of SNS CobaltII Pincer Model Complexes of Liver Alcohol Dehydrogenase

The preparation of SNS pincer cobalt(II) model complexes of liver alcohol dehydrogenase is presented here. The complexes can be prepared by reacting the ligand precursor with CoCl2&#183;6H2O and can then be recrystallized by allowing diethyl ether to slowly diffuse into an acetonitrile solution that contains the cobalt complex.

制备SNS钴（II）针质模型复合物肝酒精脱氢酶

Chemical model complexes are prepared to represent the active site of an enzyme. In this protocol, a family of tridentate pincer ligand precursors (each ...

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. Traditionally, they were synthesized through thermal cycloaddition reactions, whereas today, photocatalysis is preferred due to the mild and efficient conditions. With this focus, a new photocatalytic method for the synthesis of nitrogen-containing heterocycles is highly desired. Here, we report a protocol for the biosynthesis of cercosporin, which could function as a metal-free photocatalyst. We then illustrate cercosporin-photocatalyzed protocols for the synthesis of nitrogen-containing heterocycles 1,2,3-thiadiazoles through annulation of azoalkenes with KSCN, and synthesis of 1,4,5,6-tetrahydropyridazines [4+2] through cyclodimerization of azoalkenes under mild conditions, respectively. As a result, there is a new bridge between the microbial fermentation method and organic synthesis in a mild, cost-effective, environmentally friendly and sustainable manner.

New routes for the synthesis of nitrogen-containing heterocycles utilizing cercosporin as a metal-free photocatalyst were developed.

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

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