Name: preparation of stable bicyclic aziridinium ions and their ring-opening for the synthesis of azaheterocycles
Uploaded: 2018-08-22T13:30:00.000+00:00
Duration: 11 min 45 s
Description: Watch this Scientific Journal Video about Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles at JoVE.com

This work was supported by the National Research Foundation of Korea (NRF-2012M3A7B4049645 and HUFS Research Fund (2018).

1. Synthesis of (6R)-1-[(R)-1-Phenylethyl)-1-Azoniabicyclo[4.1.0]Heptane Tosylate (4)
<ol>
	<li>Synthesis of 4-(R)-[1-(R)-1-phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (2)
	<ol>
		<li>Add 100 mg of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)12 (0.46 mmol, 1.0 equiv), 140 &#181;L of triethylamine (Et3N, 1.0 mmol, 2.2 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under nitrogen (N2) atmosphere.</li>
		<li>Add anhydrous dichloromethane (CH2Cl2, 5 mL) to the reaction flask using airtight syringe.</li>
		<li>Cool the reaction mixture at 0 &#176;C using ice bath and stir the mixture for 5 min.</li>
		<li>Add p-toluenesulfonic anhydride (164 mg, 0.50 mmol, 1.10 equiv) to the reaction mixture and stir for another 45 min.</li>
		<li>Warm the reaction mixture to room temperature (RT) and stir for 30 min.</li>
		<li>Monitor the reaction using a thin layer chromatography (TLC) by using hexanes:ethyl acetate (EtOAc) (1:1 v/v, retention factor Rf = 0.55) as an eluent.</li>
		<li>After the complete consumption of starting alcohol 1, quench the reaction mixture with water (5 mL). Extract the heterogeneous mixture with CH2Cl2 (3 x 15 mL), dry the combined organic layer over anhydrous sodium sulphate (Na2SO4) for 10 min and concentrate in vacuo using a rotary evaporator.</li>
		<li>Purify the crude product with flash column chromatography eluting with hexanes:EtOAc (2:1 to 1:2 v/v) to afford 165 mg (0.44 mmol, 96% yield) of 4-(R)-[1-(R)-1-phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (Rf = 0.55, hexanes:EtOAc (1:1 v/v)) as a viscous liquid.</li>
	</ol>
	</li>
	<li>Synthesis of (6R)-1-[(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate (4)
	<ol>
		<li>Transfer 5 mg of freshly prepared 2 in a NMR tube and add acetonitrile-d3 (CD3CN, 300 &#181;L).</li>
		<li>Keep the above solution at RT for 24 h to attain the complete conversion to (6R)-1-[(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate 4.</li>
		<li>Monitor the conversion of 2 to 4 by nuclear magnetic resonance (NMR) spectrum in CD3CN at different time points (10 min, 1, 5, 7 and 24 h).</li>
	</ol>
	</li>
</ol>
2. General Procedure for the Expansion of 1-Azoniabicyclo[4.1.0]Heptane Tosylate
<ol>
	<li>Use steps 1.1.1 to 1.1.7 for the preparation of corresponding tosylate 2.</li>
	<li>Add the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.</li>
	<li>Add anhydrous CH3CN (4.0 mL) to the reaction flask using airtight syringe.</li>
	<li>Add the corresponding nucleophile (1.37 mmol, 3.0 equiv) to the reaction mixture and stir for 8-15 h.</li>
	<li>Quench the reaction mixture with water (5 mL), extract with CH2Cl2 (3 x 15 mL), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with column chromatography by using hexanes:EtOAc (19:1 to 7:3 v/v) to afford pure ring expanded products. 
	NOTE: All compounds were synthesized using above procedure except 6j (entry j, Table 1). 
	Caution: Dried CH3CN is prepared by distilling it from calcium hydride (CaH2) under N2 atmosphere. Sodium cyanide is toxic among the most poisonous substances known and it is used under chemical fume hood with proper safety protection. Quenching of NaCN was performed with potassium permanganate (KMnO4) solution.</li>
</ol>
3. Synthesis of (S)-1-[(R)-1-Phenylethyl]azepan-3-ol (6j)
<ol>
	<li>Transfer 4-(R)-[1-(R)-1-Phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (100 mg, 0.27 mmol, 1.0 equiv), and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask fitted with reflux condenser.</li>
	<li>Add 1,4-dioxane (4 mL) to the reaction flask using syringe.</li>
	<li>Add 0.4 mL of 2.0 M sodium hydroxide solution (NaOH, 0.80 mmol, 3.0 equiv) to the reaction mixture and heat to reflux for 2.0 h.</li>
	<li>Quench the reaction mixture with water (4 mL), extract with CH2Cl2 (4 x 15 mL), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with column chromatography eluting with hexanes:EtOAc (2:1 to 1:1 (v/v)) (Rf = 0.60, hexanes:EtOAc (1:1 (v/v)) to afford 46 mg of (S)-1-[(R)-1-Phenylethyl]azepan-3-ol (0.21 mmol, 79% yield).</li>
</ol>
4. Synthesis of [(2R,3R,4R)-3,4-Bis(Benzyloxy)-1-(S)-1-Phenylethyl)Piperidin-2-Yl]Methyl Acetate (8):
<ol>
	<li>Transfer (3R,4R)-3,4-bis(benzyloxy)-4-[(R)-1-(S)-1-phenylethyl)aziridin-2-yl]butan-1-ol ( 7) (220 mg, 0.51 mmol, 1.0 equiv), 180 &#181;L of Et3N (1.27 mmol, 2.5 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under N2 atmosphere.</li>
	<li>Add anhydrous CH2Cl2 (4 mL) to the reaction flask using airtight syringe.</li>
	<li>Cool the reaction mixture at 0 &#176;C and stir for 5 min.</li>
	<li>Add p-toluenesulfonic anhydride (200 mg, 0.61 mmol, 1.20 equiv) to the reaction mixture and stir for another 45 min.</li>
	<li>Warm the reaction mixture to RT and stir for 30 min.</li>
	<li>Monitor the progress of reaction by TLC using hexanes:EtOAc (7:3 v/v, Rf = 0.60) as an eluent.</li>
	<li>After the complete consumption of alcohol 7, quench the reaction mixture with water (5 mL), extract with CH2Cl2 (3 x 15 mL), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Transfer the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.</li>
	<li>Add anhydrous CH3CN (4 mL) to the reaction flask using airtight syringe.</li>
	<li>Add 125 mg of sodium acetate (NaOAc, 1.53 mmol, 3.0 equiv) to the reaction mixture and stir for 12 h.</li>
	<li>Quench the reaction mixture with water (5 mL), extract with CH2Cl2 (3 x 15 mL), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with column chromatography by using hexanes: EtOAc (9:1 to 4:1 v/v) to afford pure compound 8 (200 mg, 83% yield).</li>
</ol>
5. Synthesis of (3R,4R)-3-Azido-1-[(R)-1-Phenylethyl]azepan-4-Ol (14):
<ol>
	<li>Transfer (R)-1-[(S)-1-(R)-1-phenylethyl)aziridin-2-yl]butane-1,4-diol (13) (235 mg, 1.0 mmol, 1.0 equiv), 0.35 mL of Et3N (2.50 mmol, 2.5 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under nitrogen atmosphere.</li>
	<li>Add anhydrous CH2Cl2 (8 mL, 0.12 M) to the reaction flask using airtight syringe.</li>
	<li>Cool the reaction mixture at 0 &#176;C and stir for 5 min.</li>
	<li>Add p-toluenesulfonic anhydride (359 mg, 1.10 mmol, 1.10 equiv) to the reaction mixture and stir for another 45 min.</li>
	<li>Monitor the progress of reaction by TLC using hexanes: EtOAc (1:1 v/v, Rf = 0.40) as an eluent.</li>
	<li>After the complete consumption of starting alcohol 13, quench the reaction mixture with water (10 mL), extract with CH2Cl2 (3 x 15 mL), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Add the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.</li>
	<li>Add anhydrous CH3CN (8 mL, 0.12 M) to the reaction flask using airtight syringe.</li>
	<li>Add 214 mg of NaOAc (3.30 mmol, 3.30 equiv) to the reaction mixture and stir for 12 h.</li>
	<li>Quench the reaction mixture with water (10 mL), extract with CH2Cl2 (15 mL x 3 times), dry the combined organic layer over anhydrous Na2SO4 and concentrate in vacuo using a rotary evaporator.</li>
	<li>Purify the crude product with column chromatography by using hexanes: EtOAc (9:1 to 4:1 v/v) to afford pure compound 14 (133 mg, 51% yield).</li>
</ol>
6. Characterization of All Products
<ol>
	<li>Characterize all the new compounds by 1H, 13C NMR spectroscopy and high-resolution mass spectrometry (HRMS).</li>
</ol>

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The authors declare no competing financial interests.

Piperidine and azepane are two most abundant azaheterocycles in many life-saving drugs and antibiotics including various biologically active natural products16. In order to access both enantiopure piperidine (5) and azepane (6) with diverse substituents, we develped an efficient synthetic method through the formation of 1-azoniabicyclo[4.1.0]heptane tosylate from entiopure 2-(4-hydroxybutyl)aziridne followed by regiospecific nucleophilic attack either at the bridg...

Among three membered cyclic compounds, aziridine has similar ring strain energy as cyclopropane and oxirane to afford various nitrogen-containing cyclic and acyclic compounds via ring opening1,2,3. However, the characteristics and reactivity of aziridine depend on the substituent of ring nitrogen. Aziridine with an electron-withdrawing group at the ring nitrogen4, is called &#34;activated aziridine&#34;, which is activated to react with the incoming nucleophile without any additional activating reagent. On the other hand, &#34;non-activated aziridine&#34; with electron-donating substituent at nitrogen is quite stable and inert to the nucleophiles, unless it is activated as an aziridinium ion as Ia (Figure 1a)5,6,7. The ring opening of a non-activated aziridine depends on various factors such as the substituents at C2 and C3 carbon of aziridine, the electrophile to activate the aziridine ring and the incoming nucleophile. The isolation and characterization of an aziridinium ion is not possible due to its high reactivity towards ring-opening reaction by nucleophiles, but its formation and characteristics were observed spectroscopically with a non-nucleophilic counter anion5,8,9,10. The regio- and stereoselective ring-opening reaction of aziridinium ion by a suitable nucleophile yields nitrogen-containing acyclic valuable molecules (Pi and Pii)5,6,7,8,9,10.
Similarly, a bicyclic aziridinium ion (Ib) is possibly generated via the removal of the leaving group by the nucleophilic attack of ring nitrogen of aziridine in intramolecular fashion (Figure 1b). Then, this intermediate undergoes ring-expansion with the incoming nucleophile via the release of ring strain. The formation and stability of bicyclic aziridinium ion are dependent on many factors such as the substituents, the size of the ring, and solvent medium9. The regio- and stereoselectivity of the aziridine ring-expansion is a pivotal aspect of its synthetic utility, which depends on the nature of the substituents in the starting substrate and the characteristics of applied nucleophile.
In our early study, we succeeded to prepare 1-azoniabicyclo [3.1.0]hexane tosylate Ib (n = 1) whose subsequent ring-expansion resulted in the formation of a pyrrolidine and a piperidine (Piii and Piv, n = 1, Figure 1)8. As a part of our continuing study on the bicyclic aziridinium ion chemistry, we describes herein the formation of 1-azoniabicyclo [4.1.0]heptane tosylate Ib (n = 2) as a representative example. This was prepared from 2-(4-toluensulfonyloxybutyl)aziridine and its ring-expansion was trigged by a nucleophile to afford valuable piperidine and azepane (Pi and Pii, n = 2, Figure 1) with diverse substituents around the ring11. The ring-expansion of enantiopure aziridine 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1) resulted in the asymmetric synthesis of substituted azaheterocycles which are applicable to build biologically active molecules with piperidine and azepane skeleton. This synthetic protocol has been applied for various compounds ranging from simple 2-cyanomethylpiperidine 5f, 2-acetyloxymethylpiperidine 5h and 3-hydroxyazepane 6j to more complex molecules including natural products such as fagomine (9), febrifugine analogue (12) and balanol (15) in optically pure forms11.

<table><tbody><tr><td>Thin Layer Chromatography (TLC)</td><td>Merck</td><td>100390</td><td></td></tr><tr><td>UV light</td><td>Sigma-Aldrich</td><td>Z169625-1EA</td><td></td></tr><tr><td>Bruker AVANCE III HD (400 MHz) spectrometer</td><td>Bruker</td><td>NA</td><td></td></tr><tr><td>JASCO P-2000</td><td>JASCO</td><td>P-2000</td><td>For optical rotation</td></tr><tr><td>High resolution mass spectra/ MALDI-TOF/TOF Mass Spectrometry</td><td>AB SCIEX</td><td>4800 Plus&amp;nbsp;</td><td>High resolution mass spectra</td></tr><tr><td>(2R)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&amp;ndash;)-menthol ester, 98%</td><td>Sigma-Aldrich</td><td>57,054-0</td><td></td></tr><tr><td>(2S)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&amp;ndash;)-menthol ester</td><td>Sigma-Aldrich</td><td>57,051-6</td><td></td></tr><tr><td>Triethylethylamine</td><td>DAEJUNG</td><td>8556-4400-1L</td><td>CAS No: 121-44-8</td></tr><tr><td>Dichloromethane</td><td>SAMCHUN</td><td>M0822-18L</td><td>CAS No: 75-09-2</td></tr><tr><td>p-Toluenesulfonic anhydride</td><td>Sigma-Aldrich</td><td>259764-25G</td><td>CAS No: 4124-41-8</td></tr><tr><td>n-Hexane</td><td>SAMCHUN</td><td>H0114-18L</td><td>CAS No: 110-54-3</td></tr><tr><td>Ethyl acetate</td><td>SAMCHUN</td><td>E0191-18L</td><td>CAS No: 141-78-6</td></tr><tr><td>Sodium sulfate</td><td>SAMCHUN</td><td>S1011-1kg</td><td>CAS No: 7757-82-6</td></tr><tr><td>Acetonitrile-d3</td><td>Cambridge Isotope Laboratories, Inc</td><td>15G-744-25g</td><td>CAS No: 2206-26-0</td></tr><tr><td>Acetonitrile</td><td>SAMCHUN</td><td>A0127-18L</td><td>CAS No: 75-05-8</td></tr><tr><td>1,4-Dioxane</td><td>SAMCHUN</td><td>D0654-1kg</td><td>CAS No: 123-91-1</td></tr><tr><td>Sodium hydroxide</td><td>DUKSAN</td><td>A31226-1kg</td><td>CAS No: 1310-73-2</td></tr><tr><td>Sodium acetate</td><td>Alfa Aesar</td><td>11554-250g</td><td>CAS No: 127-09-3</td></tr><tr><td>Lithium aluminum hydride</td><td>TCI</td><td>L0203-100g</td><td>CAS No: 16853-85-3</td></tr><tr><td>Tetrahydrofuran</td><td>SAMCHUN</td><td>T0148-18L</td><td>CAS No: 109-99-9</td></tr><tr><td>Sodium azide</td><td>D.S.P</td><td>703301-500g</td><td>CAS No: 26628-22-8</td></tr><tr><td>Cesium fluoride</td><td>aldrich</td><td>18951-0250-25g</td><td>CAS No: 13400-13-0</td></tr><tr><td>Tetrabutylammonium bromide</td><td>aldrich</td><td>426288-25g</td><td>CAS No: 1643-19-2</td></tr><tr><td>Sodium iodide</td><td>aldrich</td><td>383112-100g</td><td>CAS No: 7681-82-5</td></tr><tr><td>Sodium cyanide</td><td>Acros Organics</td><td>424301000-100g</td><td>CAS No: 143-33-9</td></tr><tr><td>Sodium thiocyanate</td><td>aldrich</td><td>467871-250g</td><td>CAS No: 540-72-7</td></tr><tr><td>Sodium methoxide</td><td>aldrich</td><td>156256-1L</td><td>CAS No: 124-41-4</td></tr><tr><td>Benzylamine</td><td>Alfa Aesar</td><td>A10997-1000g</td><td>CAS No: 100-46-9</td></tr><tr><td>Phenol</td><td>TCI</td><td>P1610-500g</td><td>CAS No: 108-95-2</td></tr><tr><td>Sodium benzoate</td><td>Alfa Aesar</td><td>A15946-250g</td><td>CAS No: 532-32-1</td></tr><tr><td>Chloroform-d</td><td>Cambridge Isotope Laboratories, Inc</td><td>DLM-7TB-100S/16H-239, 100g</td><td>CAS No: 865-49-6</td></tr><tr><td>Dimethyl sulfoxide-d6</td><td>Cambridge Isotope Laboratories, Inc</td><td>DLM-10-25, 25g</td><td>CAS No: 2206-27-1</td></tr><tr><td>Methanol</td><td>SAMCHUN</td><td>M0585-18L</td><td>CAS No: 67-56-1</td></tr><tr><td>Ninhydrin</td><td>Alfa Aesar</td><td>A10409-250g</td><td>CAS No: 485-47-2</td></tr><tr><td>Phosphomolybdic acid hydrate</td><td>TCI</td><td>P1910-100g</td><td>CAS No: 51429-74-4</td></tr><tr><td>p-Anisaldehyde</td><td>aldrich</td><td>A88107-5g</td><td>CAS No: 123-11-5</td></tr></tbody></table>

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.

The reaction of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)12 with p-toluenesulfonic anhydride and triethylamine in CH2Cl2 at room temperature for 1.0 h yielded the corresponding 2-(4-tosyloxybutyl)aziridine 2 in 96% yield11. 1H NMR (400 MHz) spectrum of compound 2 in CD3CN at different time intervals shows th...

Watch this Scientific Journal Video about Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles at JoVE.com

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

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.

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

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Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

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8.3K Views.  North Eastern Regional Institute of Science and Technology. 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.

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

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 ...

Activating Molecules, Ions, and Solid Particles with Acoustic Cavitation

The chemical and physical effects of ultrasound arise not from a direct interaction of molecules with sound waves, but rather from the acoustic cavitation: the nucleation, growth, and implosive collapse of microbubbles in liquids submitted to power ultrasound. The violent implosion of bubbles leads to the formation of chemically reactive species and to the emission of light, named sonoluminescence. In this manuscript, we describe the techniques allowing study of extreme intrabubble conditions and chemical reactivity of acoustic cavitation in solutions. The analysis of sonoluminescence spectra of water sparged with noble gases provides evidence for nonequilibrium plasma formation. The photons and the "hot" particles generated by cavitation bubbles enable to excite the non-volatile species in solutions increasing their chemical reactivity. For example the mechanism of ultrabright sonoluminescence of uranyl ions in acidic solutions varies with uranium concentration: sonophotoluminescence dominates in diluted solutions, and collisional excitation contributes at higher uranium concentration. Secondary sonochemical products may arise from chemically active species that are formed inside the bubble, but then diffuse into the liquid phase and react with solution precursors to form a variety of products. For instance, the sonochemical reduction of Pt(IV) in pure water provides an innovative synthetic route for monodispersed nanoparticles of metallic platinum without any templates or capping agents. Many studies reveal the advantages of ultrasound to activate the divided solids. In general, the mechanical effects of ultrasound strongly contribute in heterogeneous systems in addition to chemical effects. In particular, the sonolysis of PuO2 powder in pure water yields stable colloids of plutonium due to both effects.

Acoustic cavitation in liquids submitted to power ultrasound creates transient extreme conditions inside the collapsing bubbles, which are the origin of unusual chemical reactivity and light emission, known as sonoluminescence. In the presence of noble gases, nonequilibrium plasma is formed. The "hot" particles and the photons generated by collapsing bubbles are able to excite species in solution.

The chemical and physical effects of ultrasound arise not from a direct interaction of molecules with sound waves, but rather from the acoustic ...

Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants

We describe a general synthesis of 1,2-azaborines using standard air-free techniques and protein complex preparation with T4 lysozyme mutants by vapor diffusion. Oxygen- and moisture-sensitive compounds are prepared and isolated under an inert atmosphere (N2) using either a vacuum gas manifold or a glove box. As an example of azaborine synthesis, we demonstrate the synthesis and purification of the volatile N-H-B-ethyl-1,2-azaborine by a five-step sequence involving distillation and column chromatography for the isolation of products. T4 lysozyme mutants L99A and L99A/M102Q are expressed with Escherichia coli RR1 strain. Standard protocols for chemical cell lysis followed by purification using carboxymethyl ion exchange column affords protein of sufficiently high purity for crystallization. Protein crystallization is performed in various concentrations of precipitant at different pH ranges using the hanging drop vapor diffusion method. Complex preparation with the small molecules is carried out by vapor diffusion method under an inert atmosphere. X-ray diffraction analysis of the crystal complex provides unambiguous structural evidence of binding interactions between the protein binding site and 1,2-azaborines.

A protocol for the synthesis of 1,2-azaborines and the preparation of their protein complexes with T4 lysozyme mutants is presented.

We describe a general synthesis of 1,2-azaborines using standard air-free techniques and protein complex preparation with T4 lysozyme mutants by vapor ...

Biochemistry

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 &#176;C in the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 &#176;C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control.
Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by 1H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by 1H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity.

A protocol for the diastereoselective one-pot preparation of cis-N-Ts-iodoaziridines is described. The generation of diiodomethyllithium, addition to N-Ts aldimines and cyclization of the amino gem-diiodide intermediate to iodoaziridines is demonstrated. Also included is a protocol to rapidly and quantitatively assess the most appropriate stationary phase for purification by chromatography.

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. ...

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

This protocol describes the use of amide coupling reactions of isonicotinic acid and diaminoalkanes to form bridging ligands suitable for use in the synthesis of multinuclear platinum complexes, which combine aspects of the anticancer drugs BBR3464 and picoplatin.

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating &#945;-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-&#946; inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

In this study, we prepare both enantiomers of aziridine-2-carboxylate, which are used in the asymmetric synthesis of alkaloids, including biemamide B and D, and (-)-epiallo-isomuscarine.

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of ...

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring systems is challenging. An efficient methodology to synthesize these compounds was recently published that described the solid phase synthesis in four steps rather than the previously reported five steps. The advantage of this shorter synthesis is the elimination of the use of toxic reagents. Low-loading Regenerating Michael (REM) linker-based resin was found to be crucial in the synthesis as high-loading versions prevented the addition of reagents containing bulky phenyl and aromatic side chains. The colorimetric 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to examine the cytotoxicity of micromolar concentrations of these novel spirocyclic molecules in vitro. MTT is readily available commercially and produces relatively fast, reliable results, making this assay ideal for these spirocyclic heterocycles. Orthogonal ring structures as well as furfurylamine (a precursor in the synthesis method containing a similar 5-member ring motif) were tested.

Here, we describe a bioassay using 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) to test previously synthesized spirocyclic oximes.

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring ...

Biology

Preparation of 1&deg; Amines: Azide Synthesis

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum hydride, or by catalytic hydrogenation to primary amines. The driving force for such reactions is the elimination of nitrogen gas.
Azide synthesis also works with other electrophiles like epoxides to produce amino alcohols through stereoselective ring-opening reactions. Alkyl azides have an explosive nature and must be carefully handled.

Preparation of 1&amp;deg; Amines: Azide Synthesis

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide ...

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

Summary

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Chapters in this video

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

Activating Molecules, Ions, and Solid Particles with Acoustic Cavitation

Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Preparation of 1° Amines: Azide Synthesis