Name: facile preparation of (2z,4e)-dienamides by the olefination of electron-deficient alkenes with allyl acetate
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The authors have nothing to disclose.

Caution: Please consult all relevant material safety data sheets (MSDS) before use. All cross-coupling reactions should be performed in vials under a sealed argon atmosphere (1 atm).
1. Preparation of Butadienes by the Olefination of Acrylamides with Allyl Acetate
<ol>
	<li>Dry a screw-cap vial (8 mL) with a compatible magnetic stir bar in an oven at 120 &#176;C for over 2 h. Cool the hot vial to room temperature by blowing on it with inert gas before use.</li>
	<li>Use an analytical balance and weigh 3.7 mg (~3 mol %, ~0.005 mmol) of [Ru(p-cymene)Cl2]2 (brown powder) and 13.7 mg (20 mol%, 0.04 mmol) of AgSbF6 (white solid) into the above reaction vial. 
	NOTE: Since this is a new methodology, the cross-coupling reactions have been performed on a small scale for proof of concept to reduce waste formation. AgSbF6 is used as an additive that may abstract chloride to generate a cationic ruthenium complex for electrophilic C-H bond activation13. Other silver salts, such as Ag2CO3, have also been tested, but no product was detected. The weight of the catalyst ([Ru(p-cymene)Cl2]2) is not very accurate and is in the range of 3.4-3.9 mg.</li>
	<li>Add 1 mL of dry 1,2-dichloroethane to the reaction vial. 
	NOTE: The amount of solvent is flexible-1 mL of 1,2-dichloroethane is just about enough to meet the minimal requirement of volume for the cross-coupling reaction. However, a little more (~0.1 mL) solvent is also permissible for a reaction of this scale. 1,2-dichloroethane was dried over a 3-&#550; molecular sieve before its use.</li>
	<li>Use an analytical balance and add acrylamide (0.2 mmol, 1.0 equiv; solid or oil) to the above reaction vial.</li>
	<li>Use a micro-syringe to add 43 &#181;L (0.4 mmol, 2.0 equiv) of allyl acetate (a colorless liquid) to the above reaction vial. 
	NOTE: Here, an excess amount of allyl acetate is required to inhibit the homo-coupling of acrylamide and to ensure that the acrylamide is fully converted. The product yield decreases if less allyl acetate (1.5 equiv) is added. The addition of more allyl acetate (3.0 equiv) cannot further improve the yield. In practice, there is no observed homo-coupling of allyl acetate, and the residual allyl acetate could be recovered.</li>
	<li>Gently blow on the reaction vial with argon gas and cover the vial with a compatible screw-cap as quickly as possible. 
	NOTE: The vial should be covered with a screw-cap as quickly as possible because an inert atmosphere is crucial for the cross-coupling reaction. It is better to perform the above protocol in a glove box.</li>
	<li>Stir the reaction mixture at room temperature for an additional 5 min.</li>
	<li>Heat the reaction vial to 110 &#176;C in an oil bath with stirring for 16-18 h. 
	NOTE: Generally, a color change to dark red is an indication that the reaction is taking place.</li>
	<li>After cooling the vial down, use ethyl acetate:petroleum ether (2:1 or 1:3) mixtures as the solvent to develop the thin layer chromatography (TLC) plates to monitor the progress of the reaction by comparing the mixture to an acrylamide standard. 
	NOTE: Depending upon the nature of the starting materials, the reaction may not go to completion. Typical Rf values of the products and starting materials are in the range of 0.3 - 0.7. The acrylamide starting material has been observed as a lower running spot than the butadiene product.</li>
	<li>Dissolve the crude product in a minimum of DCM and load it onto a silica column wet with petroleum ether. Separate the cross-coupling product via column chromatography using a mixture of ethyl acetate:petroleum ether (1:100 to 1:4) as the eluent.
	<ol>
		<li>Collect the eluent in a separate flask, evaporate the solvent on a rotatory evaporator, and place it under a high vacuum for a minimum of 2 h.</li>
		<li>Obtain approximately 20-50 mg of product for characterization by NMR spectroscopy. 
		NOTE: The reaction mixture should be applied to column chromatography for purification directly after reaction completion.</li>
	</ol>
	</li>
</ol>
2. Characterization of Dienamides
<ol>
	<li>.Characterize and assess the purity of the final product using 1H and 13C NMR spectroscopy14. Typically, the chemical shift of the carbonyl carbon appears near 170 ppm on the 13C NMR spectrum. The three sp2 protons of the butadiene functional group are represented by characteristic peaks near 6.0 and 5.6 ppm.</li>
	<li>Use infrared spectroscopy14 to identify the characteristic carbonyl and C-C double-bond peak of the diene product.</li>
	<li>Determine the molecular mass of the product and further validate the identity using high-resolution mass spectrometry (HRMS)14.</li>
	<li>Determine the melting point of the solid products14.</li>
</ol>

<ol>
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N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Uniting+C1-Ammonium+Enolates+and+Transition+Metal+Electrophiles+via+Cooperative+Catalysis:+The+Direct+Asymmetric+&#945;-Allylation+of+Aryl+Acetic+Acid+Esters.">Uniting C1-Ammonium Enolates and Transition Metal Electrophiles via Cooperative Catalysis: The Direct Asymmetric &#945;-Allylation of Aryl Acetic Acid Esters.</a> J Am Chem Soc. 138 (16), 5214-5217 (2016).</li><li>Zell, D., Bu, Q., Feldt, M., Ackermann, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mild+C-H/C-C+Activation+by+Z-Selective+Cobalt+Catalysis.">Mild C-H/C-C Activation by Z-Selective Cobalt Catalysis.</a> Angew Chem Int Ed. 55 (26), 7408-7412 (2016).</li><li>Li, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=N-Acyl+Amino+Acid+Ligands+for+Ruthenium(II)-Catalyzed+meta-C-H+tert-Alkylation+with+Removable+Auxiliaries.">N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H tert-Alkylation with Removable Auxiliaries.</a> J Am Chem Soc. 137 (43), 13894-13901 (2015).</li><li>Li, F., Yu, C., Zhang, J., Zhong, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Olefination+of+Electron-Deficient+Alkenes+with+Allyl+Acetate:+Stereo-+and+Regioselective+Access+to+(2Z,4E)-Dienamides.">Olefination of Electron-Deficient Alkenes with Allyl Acetate: Stereo- and Regioselective Access to (2Z,4E)-Dienamides.</a> Org Lett. 18 (18), 4582-4585 (2016).</li><li>Lehman, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The student's lab companion: laboratory techniques for organic chemistry: standard scale and microscale. , (2008).</li></ol>

We gratefully acknowledge National Natural Science Foundation of China (NSFC) (Nos. 21502037, 21373073, and 21672048), the Natural Science Foundation of Zhejiang Province (ZJNSF) (No. LY15B020008), the PCSIRT (No. IRT 1231), and Hangzhou Normal University for financial support. G. Z. acknowledges a Qianjiang Scholar award from Zhejiang Province, China.

[Ru(p-cymene)Cl2]2 is a cheap, easily accessible, air-stable, and highly active Ru-based catalyst with excellent functional group tolerance that efficiently operates under mild reaction conditions to give C-H/C-H coupling butadiene products. Silver salt AgSbF6 was used as an additive that may abstract the chloride of [Ru(p-cymene)Cl2]2 to generate a cationic ruthenium complex for the following C-H bond activation. However, only &#945;-substituted and &#945;,&#946;-disubstituted acrylamides are suitable for this cross-coupling reaction. We also tested some other acrylamides, such as primary methacrylamide and N-benzyl methacrylamide, but both of them delivered no product. Also, &#946;-substituted acrylamide, such as crotonamide, and plain acrylamide without any substituent did not exhibit any reactivity, even at an elevated temperature. Moreover, allyl acetate proved to be the best coupling partner. We only demonstrated that the reaction can be scaled up to the gram-scale (0.5 g of 1a), with 62% isolated yield and good stereoselectivity (Z,Z/Z,E = 87/13). The reactions may be performed on a larger scale.
On the basis of these mechanistic studies and previous reports, we propose a possible mechanism (Figure 3). First, an active cationic ruthenium complex I was generated from [RuCl2(p-cymene)]2. Then, an acetic acid-assisted reversible C-H bond activation occurred by an electrophilic-type cycloruthenation, forming intermediate II. Subsequent coordination and the migratory insertion of allyl acetate delivered a seven-membered Ru (II) species IV. As coordination of the amide group may have prevented the syn&#946;-hydride elimination of the benzylic hydrogen atom by conformational restriction, the following &#946;-oxygen elimination was facile, producing allylation product 4 and regenerating the active Ru(II) complex I. The final butadiene 3 of the thermodynamically more stable product was formed via the migratory isomerization of the double bond with the help of the active [Ru] species.
Even though the described syntheses, as well as the coupling reaction protocols, are straightforward, some of the critical steps are listed here. Use newly purchased or properly stored AgSbF6, as it is hygroscopic. Store [Ru(p-cymene)Cl2]2 under an inert atmosphere. Use freshly distilled allyl acetate and store it under an inert atmosphere. Prepare the acrylamide freshly and store it under an inert atmosphere. Use dry 1,2-dichloroethane with high purity and store it over a 3-&#506; molecular sieve under an inert atmosphere. Dry all glassware in an oven at 120 &#176;C for more than 2 h and cooling them under an inert atmosphere before use. Perform the cross-coupling under an inert atmosphere; argon is the best choice.

Butadienes are widely occurring and are commonly found in many natural products, drugs, and bioactive molecules1. Chemists have made intense efforts to develop an efficient, selective, and practical synthetic methodology for the synthesis of 1,3-butadienes2,3. Recently, direct cross-couplings between two alkenes via double vinylic C-H bond activation was developed, representing an efficient strategy for the synthesis of butadienes, with high atomic and step economy. Among them, the palladium-catalyzed cross-coupling of two alkenes has attracted much attention, providing (E,E)-configured butadienes via alkenyl-Pd species4,5. For example, Liu&#39;s group developed a Pd-catalyzed butadiene synthesis by the direct cross-coupling of alkenes and allyl acetate (Figure 1 and Equation 3)4. Meanwhile, the functional group-directed cross-coupling between alkenes provided butadienes with excellent (Z,E)-stereoselectivity due to the olefinic C-H cyclometalation event, representing a complementary method6. To date, some directing groups, such as enolates, amides, esters, and phosphates, have been successfully introduced to the cross-coupling between alkenes, providing a series of valuable and functionalized 1,3-butadienes. However, the directed cross-coupling reaction has not been developed, as there are still limited directing groups in practical use. In particular, a stoichiometric amount of oxidant is usually required to maintain the catalytic cycle, which produces a large amount of organic and inorganic wastes. There are very limited examples using electron-rich alkenes as the coupling partner.
Allyl acetate and its derivatives have been deeply investigated in organic transformations as powerful allylation and olefination reagents, including catalyzed cross-coupling, Friedel-Crafts allylation of electron-rich arenes, and catalytic C-H activation of electron-deficient arenes (Figure 1 and Equation 1)7. More recently, the Loh group developed a rhodium(III)-catalyzed C-H allylation of electron-deficient alkenes with allyl acetates, creating 1,4-dienes (Figure 1 and Equation 2)8. Meanwhile, the Kanai group reported a dehydrative direct C-H allylation with allylic alcohols by using a Co(III) catalyst9. Interestingly, Snaddon and co-workers disclosed a novel cooperative catalysis-based method for the direct asymmetric &#945;-allylation of acyclic esters10. Very recently, the Ackermann group reported several novel allylation examples using inexpensive Fe, Co, and Mn catalysts11. These reports have made breakthroughs in allylation and olefination reactions, but double-bond migration and poor regioselectivity are usually inevitable and are not easily controlled. Hence, developing more efficient and selective reaction patterns of allyl acetates to construct valuable molecules is still highly desirable. With our interest in novel 1,3-butadiene synthesis via C-H olefination, we assumed that allyl acetate could be introduced to the directed allylation of electron-deficient alkenes, first delivering 1,4-diene. Then, the more thermodynamically stable 1,3-butadiene could be formed after the migratory isomerization of the C-C double bond7, forming the diene product that cannot be obtained by cross-coupling using electron-rich alkenes, such as propene, as coupling partner6. Here, we report an inexpensive Ru(III)-catalyzed olefinic C-H bond olefination of acrylamides with allyl acetates in the absence of any oxidant, which opens a novel synthetic route for the creation of (Z,E)-butadienes (Figure 1 and Equation 4)13.

<table><tbody><tr><td>Allyl Acetate</td><td>TCI</td><td>A0020</td><td>&gt;98.0%(GC), 25 mL package</td></tr><tr><td>Dichloro(p-cymene)ruthenium(II) dimer</td><td>TCI</td><td>D2751</td><td>&gt;95.0%(T), 5 g package</td></tr><tr><td>Silver hexafluoroantimonate</td><td>TCI</td><td>S0463</td><td>&gt;97.0%(T),&amp;nbsp; 5 g package</td></tr><tr><td>1,2-Dichloroethane</td><td>TCI</td><td>D0364</td><td>&gt;99.5%(GC), 500 g package</td></tr><tr><td>Rotavapor</td><td>EYELA</td><td>N-1200A</td><td>Use to dry solvent</td></tr><tr><td>Silica gel</td><td>Merck</td><td>107734</td><td>Silica gel 60 (0.063-0.2 mm), for column chromatoraphy</td></tr></tbody></table>

facile preparation of (2z,4e)-dienamides by the olefination of electron-deficient alkenes with allyl acetate

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high atomic and step economy. However, this functionality-directed cross-coupling reaction has not been developed, as there are still limited directing groups in practical use. In particular, a stoichiometric amount of oxidant is usually required, producing a large amount of waste. Due to our interest in novel 1,3-butadiene synthesis, we describe the ruthenium-catalyzed olefination of electron-deficient alkenes using allyl acetate and without external oxidant. The reaction of 2-phenyl acrylamide and allyl acetate was chosen as a model reaction, and the desired diene product was obtained in 80% isolated yield with good stereoselectivity (Z,E/Z,Z = 88:12) under optimal conditions: [Ru(p-cymene) Cl2]2 (3 mol %) and AgSbF6 (20 mol %) in DCE at 110 &#186;C for 16 h. With the optimized catalytic conditions in hand, representative &#945;- and/or &#946;-substituted acrylamides were investigated, and all reacted smoothly, regardless of aliphatic or aromatic groups. Also, differently N-substituted acrylamides have proven to be good substrates. Moreover, we examined the reactivity of different allyl derivatives, suggesting that the chelation of acetate oxygen to the metal is crucial for the catalytic process. Deuterium-labeled experiments were also conducted to investigate the reaction mechanism. Only Z-selective H/D exchanges on acrylamide were observed, indicating a reversible cyclometalation event. In addition, a kinetic isotope effect (KIE) of 3.2 was observed in the intermolecular isotopic study, suggesting that the olefinic C-H metalation step is probably involved in the rate-determining step.

Our efforts were focused on the preparation of 1,3-butadiene from acrylamide and allyl acetate.
Table 1 illustrates the optimization of conditions, including the screening of various additives and solvents, using [Ru(p-cymene)Cl2]2 as the catalyst. After screening a series of representative solvents, we were pleased to find that the product yield dramatically improved to 80%, with good selectivity (Z,E/Z,Z = 88:12). The cis-structure was confirmed by the NOESY NMR analysis, indicating that the amido group directed the C-C bond formation step in the catalytic cycle. The Z,E/Z,Z ratio was determined by the integration of 1H NMR. When the reaction was performed in 1,2-dichloroethane, only trace amounts of allylation product 4a (3a/4a = 95:5) were obtained (Table 1, entry 6). However, other solvents, such as tetrahydrofuran and t-amyl alcohol, greatly hindered the reaction, while strong polar solvents, such as acetonitrile and N,N-dimethylformamide, provided no product (Table 1, entries 1 - 5). Moreover, a lower temperature (90 &#176;C) resulted in decreased yield but facilitated the allylation process, while elevating the temperature (130&#176;C) enhanced the olefination process but caused a decreased yield, presumably due to degradation (Table 1, entries 7 and 8). The [Ru(p-cymene)Cl2]2 complex itself could not result in the corresponding butadiene 3a (Table 1, entry 9). Other additives, such as Ag2CO3, KPF6, and Cu(OAc)2, were also screened, but all of them failed to assist the ruthenium complex in forming the product (Table 1, entries 10-12).
In Table 2, the scope of the reaction was explored by submitting various acrylamides to the optimized conditions in the presence of allyl acetate 2a. Modest to excellent yields were obtained, with good regioselectivity and (Z,E/Z,Z) selectivity. As shown in Table 2, the differently N-substituted acrylamide 1 also reacted well with allyl acetate, providing the desired 1,3-butadienes with good stereoselectivity (Z,E/Z,Z up to 88:12) (3a-3f). This cross-coupling reaction also proceeded smoothly when performed on the gram-scale, as described in the synthesis of 3a, showing the robustness of this method. Secondary and primary amides were also tested, but none of them delivered the olefination or allylation product. Installation of the phenyl ring in the &#945;-position of acrylamide showed limited influence on the reaction. The desired product was isolated in 67% yield, with excellent regioselectivity (3g/4g = 97:3), but the stereoselectivity decreased slightly (Z,E/Z,Z = 83:17). Valuable functional groups, such as Br, F, or Me, could be well tolerated, although the product yields decreased when an electron-withdrawing group was introduced (Table 2, 3h-j). Larger aromatic rings, such as naphthalene-substituted acrylamide, also provided good results (Table 2, 3k). Other alkyl groups, such as benzyl and hexyl tethering substrates, were also reacted well, with good regioselectivity and Z/E selectivity (Table 2, 3l-o). The reactivity of &#945;,&#946;-disubstituted acrylamides 1 were also examined. Acrylamide 1, bearing a cyclopentenyl unit, reacted well, but the allylation product 4p increased remarkably. Interestingly, acrylamide embedded with a cyclohexenyl moiety exhibited excellent regio- and stereoselectivity, forming trace amount of 1,4-diene 4q.
In Table 3, the reactivity of different allyl derivatives was examined. Branched allyl acetates were also examined. &#945;- or &#946;-substituted allyl acetates were completely inert for cross-coupling, while &#947;-substituted allyl acetate afforded only trace product. Other allyl carboxylic esters, such as allyl hexanoate 2b, allyl methacrylate 2c, allyl phenoxyacetate 2d, and allyl 3,3,3-trifluoropropanoate 2e, were also tested, showing decreased reactivity comparing to allyl acetate 2a. In contrast, allyl methyl carbonate 2f was more inactive for olefination and allylation, forming product with only 24% yield. It is worth noting that allyl iodide 2g did not exhibit any reactivity towards acrylamide, suggesting that the chelation of acetate oxygen to the metal is crucial in the catalytic process.
Moreover, to investigate the reaction mechanism, two deuterium-labeled experiments were conducted (Figure 2). If the acrylamide 1g was subjected to a standard catalytic system in the presence of acetic acid-d4 (10.0 equiv) without allyl acetate, the cationic ruthenium species led to a Z-selective H/D exchange on acrylamide; an E-selective H/D exchange was not observed, thereby indicating a reversible cyclometallation event6,7,8. Moreover, a kinetic isotope effect (KIE) of kH/kD = 3.2 was observed in the intermolecular isotopic study, suggesting that the olefinic C-H bond metalation step is probably involved in the rate-determining step6.
<img alt="Table 1" src="/files/ftp_upload/55766/55766tbl1.jpg" /> 
Table 1: Optimization of Catalytic Conditions.
<img alt="Table 2" src="/files/ftp_upload/55766/55766tbl2.jpg" /> 
Table 2: Scope of Differently Substituted Acrylamides. 
<img alt="Table 3" src="/files/ftp_upload/55766/55766tbl3.jpg" /> 
Table 3: Scope of Different Allyl Derivatives. 
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/55766/55766fig1.jpg" /> 
Figure 1: Transition Metal-catalyzed Olefination and Allylation by C-H Activation with Allyl Derivatives. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/55766/55766fig2.jpg" /> 
Figure 2: Deuterium-labeled Experiments. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/55766/55766fig3.jpg" /> 
Figure 3: Proposed Mechanism for this Catalytic Olefination. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/55766/55766fig4.jpg" /> 
Figure 4: 1H NMR and 13C NMR Spectra for (2Z,4E)-2-methyl-1-(pyrrolidin-1-yl) hexa-2,4-dien-1-one (3a). This compound was prepared by the general procedure described above and was obtained as a yellow oil (28.6 mg, yield = 80%). 1H NMR (500 MHz, CDCl3): &#948; 6.00 - 5.87 (m, 2H), 5.76 - 5.66 (m, 1H), 3.54 (t, J = 7.0, 2H), 3.33 (t, J = 6.5 Hz, 2H), 1.93 (s, 3H), 1.92 -1.88 (m, 4H), 1.74 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): &#948; 170.46, 132.11, 130.79, 128.11, 127.62, 47.21, 45.05, 25.92, 24.52, 19.92, 18.22. HR-MS (ESI): m/z calculated for C11H17NO: [M+H]+180.1383, found: 180.1388. FTIR (KBr, cm-1): &#957; 3819, 3709, 3627, 3565, 2924, 1733, 1652, 1615, 1558, 1455. The Z/E ratio of the final products can be calculated from 1H NMR by the integration of olefinic protons on isomers. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/55766/55766fig5.jpg" /> 
Figure 5: 1H NMR and 13C NMR Spectra for (2Z,4E)-2-phenyl-1-(pyrrolidin-1-yl) hexa-2,4-dien-1-one (3g). This compound was prepared by the general procedure described above and was obtained as a yellow solid (32.3 mg, yield = 67%). 1H NMR (500 MHz, CDCl3): &#948; 7.41-7.21 (m, 5H), 6.58 (d, J = 11.0 Hz, 1H), 6.26-6.17 (m, 1H), 6.02-5.93 (m, 1H), 3.67 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 1.82-1.95 (m, 7H). 13C NMR (125 MHz, CDCl3): &#948; 168.48, 136.28, 135.83, 134.19, 128.78, 128.16, 127.70, 127.26, 125.40, 47.23, 45.18, 25.85, 24.58, 18.61. HR-MS (ESI): m/z calculated for C16H19NO [M+H]+ 242.1539, found: 242.1531. FTIR (KBr, cm-1): &#957; 3851, 3647, 3627, 3565, 2924, 1732, 1633, 1429, 966, 694. Melting point: 82-83 &#176;C. The Z/E ratio of the final products can be calculated from 1H NMR by the integration of olefinic protons on isomers. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/55766/55766fig6.jpg" /> 
Figure 6: 1H NMR and 13C NMR Spectra for (E)-(2-(prop-1-en-1-yl)cyclohex-1-en-1-yl)(pyrrolidin-1-yl)methanone (3q). This compound was prepared by the general procedure described above and was obtained as a yellow oil (25.4 mg, yield = 58%). 1H NMR (500 MHz, CDCl3) &#948; 5.98 (d, J = 15.5 Hz, 1H), 5.72 - 5.58 (m, 1H), 3.47 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 2.18-2.09 (m, 4H), 1.86-1.79 (m, 4H), 1.67 (d, J = 6.5 Hz, 3H), 1.59 (brs, 4H). 13C NMR (125 MHz, CDCl3): &#948; 170.53, 131.25, 129.92, 128.58, 124.04, 46.18, 43.99, 25.76, 24.89, 23.58, 23.37, 21.20, 21.17, 17.53. HR-MS (ESI): m/z calculated for C14H21NO [M+H]+: 220.1696, found: 220.1694. FTIR (KBr, cm-1): &#957; 3742, 3674, 3646, 3565, 2933, 1683, 1634, 1557, 1505, 1435. The Z/E ratio of the final products can be calculated from 1H NMR by the integration of olefinic protons on isomers. <a href="http://cloudflare.jove.com/files/ftp_upload/55766/55766fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/55766/55766fig7.jpg" /> 
Figure 7: NOESY NMR Analysis for (2Z,4E)-2-phenyl-1-(pyrrolidin-1-yl) hexa-2,4-dien-1-one (3g).

Watch this Scientific Journal Video about Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate at JoVE.com

Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

The ruthenium-catalyzed olefination of electron-deficient alkenes with allyl acetate is described here. By using aminocarbonyl as a directing group, this external oxidant-free protocol has high efficiency and good stereo- and regioselectivity, opening a novel synthetic route to (Z,E)-butadiene skeletons.

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high ...

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Organic Chemistry

Unit 1

Dienes, Conjugated Pi Systems, and Pericyclic Reactions

Alkene Structure and Reactivity

SCIENTISTS IN ACTION

7.3K Views.  Hangzhou Normal University.  De rutheniumgekatalyseerde olefinering van elektron-deficiënte alkenen met allylacetaat wordt hier beschreven. Door het gebruik van aminocarbonyl als een directe groep heeft dit externe oxidantvrije protocol hoge efficiëntie en goede stereo- en regioselectiviteit, waardoor een nieuwe synthetische route wordt geopend naar ( Z , E ) -butadiene skelet. 

Video: Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

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.

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

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 ...

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond&#8211;forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the &#945;-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

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 ...

Preparation of Alkynes: Alkylation Reaction

<h4>Introduction</h4>
Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for the synthesis of longer carbon-chain alkynes. For example, treatment of 1-propyne with sodium amide followed by reaction with ethyl bromide yields 2-pentyne.
<img alt="Alkyne alkylation reaction using NaNH2 and ethyl bromide, chemical equation diagram." src="/files/ftp_upload/11834/11834_PT_Figure_1.svg" style="text-align: center; height: 50px;" data-altupdatedat="1747908711000" data-alt="Figure1">
The reaction takes place in two steps:
1. The first step is the deprotonation of the terminal alkyne by the strong base forming an acetylide ion.
<img alt="Alkyne ionization reaction equation NaNH2, diagram shows acetylene converting to acetylide ion." src="/files/ftp_upload/11834/11834_PT_Figure_2.svg" style="text-align: center; height: 50px;" data-altupdatedat="1747908711000" data-alt="Figure2">
2. The second step is a nucleophilic substitution reaction in which the acetylide ion reacts with the alkyl halide to form a new C–C bond.
<img alt="Organic reaction mechanism, Na+ and Br- ion exchange, illustrates chemical synthesis process." src="/files/ftp_upload/11834/11834_PT_Figure_3.svg" style="text-align: center; height: 50px;" data-altupdatedat="1747908711000" data-alt="Figure3">
<h4>Reaction Mechanism —SN2 pathway </h4>
Acetylide ions are strong bases and can also function as good nucleophiles. The substitution reaction follows an SN2 pathway where the nucleophilic acetylide ion attacks the electrophilic carbon of the primary alkyl halide from the backside.
<img alt="Nucleophilic substitution reaction mechanism diagram with alkynes, NaBr formation, chemical process." src="/files/ftp_upload/11834/11834_PT_Figure_4.svg" style="text-align: center; height: 250px;" data-altupdatedat="1747908711000" data-alt="Figure4">
Since this is a concerted process, the nucleophilic attack and the departure of the leaving group takes place simultaneously to form the product with an inverted stereochemistry at the reaction center.
The reaction works best with unhindered alkyl halides like methyl halide and other primary halides. With secondary and tertiary alkyl halides, acetylide ions act as strong bases, in which case E2 elimination is the preferred pathway.
<h4>Application in organic synthesis </h4>
Alkylation of simple terminal alkynes is a useful method to extend the length of the carbon chain. Acetylene, a terminal alkyne, can be converted to a higher internal alkyne by repeated alkylation as shown below:
<img alt="Alkyne chain elongation via NaNH₂, CH₃Br; reaction equation diagram for organic synthesis." src="/files/ftp_upload/11834/11834_PT_Figure_5.svg" style="text-align: center; height: 50px;" data-altupdatedat="1747908711000" data-alt="Figure5">

Introduction
Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for ...

Alkynes

KEY TERMS AND CONCEPTS

Preparation of Alkynes: Dehydrohalogenation

<h4>Introduction</h4>
Alkynes can be prepared by dehydrohalogenation of vicinal or geminal dihalides in the presence of a strong base like sodium amide in liquid ammonia. The reaction proceeds with the loss of two equivalents of hydrogen halide (HX) via two successive E2 elimination reactions.
<img alt="Chemical reaction diagram, alkyne synthesis, 2NaNH2/NH3, hydrogen elimination, organic chemistry." src="/files/ftp_upload/11835/11835_PT_Figure_1.svg" style="text-align: center; height: 200px;" data-altupdatedat="1747908711000" data-alt="Figure1">
<h4>Reaction Mechanism – E2 pathway</h4>
Vicinal dihalides
In the first elimination step, the strong base abstracts the proton from the dihalide that is oriented anti to the leaving group. Since E2 reactions follow a concerted pathway, the abstraction of a proton and departure of the halide leaving group occur simultaneously to form a haloalkene.
<img alt="Birch reduction mechanism diagram, showing electron flow in organic compound reaction." src="/files/ftp_upload/11835/11835_PT_Figure_2.svg" style="text-align: center; height: 90px;" data-altupdatedat="1747908711000" data-alt="Figure2">
In the second elimination reaction, another equivalent of the strong base reacts with the haloalkene in a similar fashion to give the desired alkyne.
<img alt="Elimination reaction mechanism diagram, E2 mechanism, showing alkene formation from alkyl halide." src="/files/ftp_upload/11835/11835_PT_Figure_3.svg" style="text-align: center; height: 90px;" data-altupdatedat="1747908711000" data-alt="Figure3">
Geminal dihalides
Likewise, geminal dihalides, when treated with two equivalents of a sodium amide, undergo double dehydrohalogenation to give alkynes.
<img alt="Alkyne formation reaction; sodium amide abstracting proton; chemical equation diagram; synthesis method." src="/files/ftp_upload/11835/11835_PT_Figure_4.svg" style="text-align: center; height: 90px;" data-altupdatedat="1747908711000" data-alt="Figure4">
<img alt="Chemical reaction mechanism, arrow-pushing diagram, alkyne formation using sodium amide." src="/files/ftp_upload/11835/11835_PT_Figure_5.svg" style="text-align: center; height: 90px;" data-altupdatedat="1747908711000" data-alt="Figure5">
Terminal dihalides 
Dehydrohalogenation of terminal dihalides yields terminal alkynes as the final product. In the presence of a strong base like sodium amide, terminal alkynes get converted to acetylide ions. In such cases, a third equivalent of the base is required to complete the dehydrohalogenation of the remaining haloalkene.
<img alt="Hofmann elimination reaction; chemical equations diagram; synthesis process using NaNH2; alkyne formation." src="/files/ftp_upload/11835/11835_PT_Figure_6.svg" style="text-align: center; height: 70px;" data-altupdatedat="1747908711000" data-alt="Figure6">
Protonation of the acetylide ions with water or an aqueous acid completes the reaction.
<img alt="Organic reaction mechanism with sodium acetylide, water; diagram illustrating nucleophilic attack." src="/files/ftp_upload/11835/11835_PT_Figure_7.svg" style="text-align: center; height: 50px;" data-altupdatedat="1747908711000" data-alt="Figure7">
<h4>Application in Organic Synthesis</h4>
Dehydrohalogenation of vicinal dihalides is a useful intermediate step in the conversion of alkenes to alkynes. For example, chlorination of 1-propene gives 1,2-dichloropropane – a vicinal dihalide, which upon double dehydrohalogenation yields 1-propyne.
<img alt="Alkene to alkyne conversion diagram; chemical reaction mechanism, dichlorination, dehydrohalogenation." src="/files/ftp_upload/11835/11835_PT_Figure_8.svg" style="text-align: center; height: 60px;" data-altupdatedat="1747908711000" data-alt="Figure8">
Similarly, alkynes can also be synthesized from ketones via dehydrohalogenation of geminal dihalides. For example, treatment of acetone with phosphorous pentachloride yields 2,2-dichloropropane – a geminal dihalide, which undergoes double dehydrohalogenation to give 1-propyne.
<img alt="Organic synthesis mechanism; ketone to alkyne via substitution and elimination; chemical reaction diagram." src="/files/ftp_upload/11835/11835_PT_Figure_9.svg" style="text-align: center; height: 80px;" data-altupdatedat="1747908711000" data-alt="Figure9">

Introduction
Alkynes can be prepared by dehydrohalogenation of vicinal or geminal dihalides in the presence of a strong base like sodium amide in liquid ...

Preparation of Epoxides

<h4>Overview</h4>
Epoxides result from&#160;alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
<h4>Epoxidation with Peroxy Acids</h4>
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon&#8211;carbon double bond to an epoxide using the oxidizing agent&#160;meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O&#8211;O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to alkenes occurs with ease, thereby following syn addition. Hence, the epoxides are produced with the retention of the alkene configuration.
<h4>Epoxidation via Air Oxidation</h4>
Although peroxy-mediated epoxidation is the most common method for alkene oxidation, ethylene oxide is synthesized at the industrial scale via air oxidation by treating a mixture of ethylene and air in the presence of a silver catalyst.
<h4>Cyclization of Halohydrins</h4>
Cyclization of halohydrins of alkenes in the presence of a base also yields epoxides, and the reaction follows the SN2 substitution mechanism. Hence, the nucleophile&#8212;the oxygen anion&#8212;and the leaving group&#8212;the chloride ion&#8212;must orient anti to each other in the transition state to make the halohydrins cyclization feasible.
<img alt="Figure1" src="/files/ftp_upload/12094/12094Figure 1.svg" style="text-align: center; height: 260x;" />
In noncyclic halohydrins, this anti-relationship is achieved by an internal rotation. For instance, in 1-chloro-2-methyl-2-propanol, shown in Figure 1, the hydroxyl and the chloro group are not oriented anti to each other. To achieve the anti-relationship, the carbon-bearing chloro group undergoes an internal rotation, thereby making the nucleophile attack&#8212;from the backside of the C&#8211;X bond&#8212;and the ejection of the leaving group feasible. Thus, the epoxides formed via halohydrin cyclization also retain the alkene configuration.
Similarly, the cyclic halohydrins must undergo conformational changes to achieve the anti-relationship. For example, the halohydrin of cyclohexane, shown in Figure 2, undergoes a conformational change from diequatorial to diaxial to successfully form&#160;an epoxide.
<img alt="Figure2" src="/files/ftp_upload/12094/12094Figure 2.svg" style="text-align: center; height: 120px;" />

Preparation of Epoxides via Alkene Oxidation

Overview
Epoxides result from&#160;alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin ...

Ethers, Epoxides, Sulfides

Carboxylic Acids to Methylesters: Alkylation using Diazomethane

Carboxylic acids react with diazomethane in an ether solvent via alkylation at the carboxylate oxygen atom to give methyl esters of the corresponding acid with excellent yields.
<img alt="Esterification reaction: carboxylic acid with diazomethane formula, chemical process diagram." src="/files/ftp_upload/12349/12349_PT_Figure_1.svg" style="text-align: center; height: 60px;" data-altupdatedat="1747908711000" data-alt="Figure1">
Diazomethane is a yellow gas having a boiling point of −23 °C. It is conveniently prepared by the action of a base on N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulphonamide.
The esterification mechanism involves the protonation of diazomethane by the carboxylic acid to yield a carboxylate salt and methyldiazonium cation. The methyldiazonium cation is highly unstable due to the presence of N≡N, which functions as an excellent leaving group.
<img alt="Chemical reaction, Curtius rearrangement equations, molecular transformation diagram." src="/files/ftp_upload/12349/12349_PT_Figure_2.svg" style="text-align: center; height: 72px;" data-altupdatedat="1747908711000" data-alt="Figure2">
In the final alkylation step, an SN2 attack on the methyldiazonium ion by the carboxylate anion produces a methyl ester, along with the elimination of N2 gas.
<img alt="SN2 reaction mechanism diagram; nucleophile attack on carbonyl, forming new bond, expelling N2." src="/files/ftp_upload/12349/12349_PT_Figure_3.svg" style="text-align: center; height: 70px;" data-altupdatedat="1747908711000" data-alt="Figure3">
However, diazomethane is a potentially explosive gas and requires precautions during its handling and storage. It undergoes spontaneous detonation upon contact with rough or scratched surfaces. Therefore, flame-polished glassware and a blast shield are often recommended in reactions involving diazomethane. Moreover, diazomethane is highly toxic as well as carcinogenic.
Diazomethane decomposes in the presence of heat or light to generate carbenes and eliminate nitrogen.
<img alt="Chemical reaction diagram; azide decomposition to form methylene and nitrogen under heat or light." src="/files/ftp_upload/12349/12349_PT_Figure_4.svg" style="text-align: center; height: 52px;" data-altupdatedat="1747908711000" data-alt="Figure4">

Carboxylic acids react with diazomethane in an ether solvent&#160;via alkylation at the carboxylate oxygen atom&#160;to give&#160;methyl esters of the ...

Carboxylic Acids

Amines to Alkenes: Hofmann Elimination

Alkenes can be obtained from amines via an E2 elimination. The amine is first converted into a good leaving group, such as a quaternary ammonium salt. This is accomplished by treating the amine with an excess of alkyl halide, which results in a halide salt. Next, the halide salt is transformed into a hydroxide salt that functions as a base to enable elimination.
Under thermal conditions, the hydroxide can abstract a proton from the &#946; carbon; this generates an alkene with the simultaneous release of a neutral amine molecule. This elimination process is called the Hofmann elimination. For the elimination to occur, the &#946; proton and tertiary amine group must be positioned opposite or anti-periplanar to each other. This reaction yields the less substituted alkene as the major product, also known as the Hofmann product.

Alkenes can be obtained from amines via an E2 elimination. The amine is first converted into a good leaving group, such as a quaternary ammonium salt. ...

Amines

&alpha;-Alkylation of Ketones via Enolate Ions

Ketones with &#945; protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the &#945; carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the &#945;&nbsp;carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction of the positive counterpart of the base with the anionic oxygen, which restricts the approaching electrophile, making the reaction less favorable. Also, the product obtained through C-attack is more stable than that obtained through O-attack, as the stronger C=O &#960; bond is retained in the former, whereas a weaker C=C &#960; bond is preserved in the latter.
A subsequent reaction of the enolate with electrophiles such as alkyl halides produces an &#945;-alkylated ketone via the SN2 pathway. The &#945;-alkylation of ketones is achieved with the halides of primary alkyl, benzyl, and allylic groups. With secondary and tertiary alkyl halides, elimination predominates over substitution.

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

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