Name: versatile co2 transformations into complex products: a one-pot two-step strategy
Uploaded: 2019-11-09T14:00:00
Duration: 7 min 36 s
Description: Watch this Scientific Journal Video about Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy at JoVE.com

S. D. thanks R&#233;gion Midi-Pyr&#233;n&#233;es and Universit&#233; F&#233;d&#233;rale de Toulouse for doctoral fellowship. D. Z. thanks Chinese Scholarship Council for doctoral fellowship. A. M. thanks COLFUTURO for doctoral fellowship. S. B. thanks the ANR programme JCJC &#34;ICC&#34; and Prof. A. Leon for fruitful discussion.

CAUTION: Please consult material safety data sheets (MSDS) of the chemicals before use. Please use appropriate safety practices when performing the following reactions and personal protective equipment. A special attention must be dedicated to the use of the vacuum line and gas pressure system.
1. Synthesis of compound 2 from CO2 in a nuclear magnetic resonance (NMR) tube
<ol>
	<li>Stock solution of Fe(H)2(dmpe)2: dissolve 4.6 mg of Fe(H)2(dmpe)221,22 in 1 mL of tetrahydrofuran (THF)-d8. 
	NOTE: dmpe = 1,2-bis(dimethylphosphino)ethane</li>
	<li>In a glove box, charge an NMR tube with 15.9 mg of 9-borabicyclo[3.3.1]nonane (9-BBN) and 100 &#181;L of a stock solution of Fe(H)2(dmpe)2 (1 mol%).</li>
	<li>Add 0.5 mL of tetrahydrofuran (THF)-d8.</li>
	<li>Close the tube and bring it outside the glove box.</li>
	<li>Connect the tube to a gas system and place it at 25 &#176;C for 15 min to equilibrate the temperature of the solution inside the tube. 
	NOTE: The gas system connects the CO2 bottle to both the vacuum line and the NMR tube. The connections are with Teflon tube and Swadgelock connectors (see Figure 1 for a scheme of the setup). This system enables to add the pressure defined at the regulator at the desired temperature.</li>
	<li>Add 1 atm of CO2.</li>
	<li>Leave for 3 min under a dynamic pressure of CO2 and close the tube.</li>
	<li>Leave the tube at 25 &#176;C for 45 min. 
	NOTE: At this step bis(boryl)acetal 1 is generated inside the NMR tube in 85% yield (see representative results for the NMR analysis).</li>
	<li>Stock solution of amine: dissolve 177.3 mg of 2,6-(diisopropyl)phenylamine in 1 mL of THF-d8.Once compound 1 is generated, open the NMR tube inside a glove box and add 55 &#181;L of a stock solution of the 2,6-(diisopropyl)phenylamine, corresponding to 1 equivalent of the generated bis(boryl)acetal 1.</li>
	<li>Close the tube and hand shake it for 10 s.</li>
	<li>After 20 min, confirm the formation of imine 2 by 1H NMR analysis (Figure 2). Use hexamethylbenzene (roughly 10 mol% vs 9-BBN) as an internal standard to determine the NMR yield.</li>
</ol>
2. Synthesis of compound 3 from CO2 in a Fisher Porter
<ol>
	<li>Charge a Fisher Porter with 320 mg of 9-BBN, 9.4 mg of Fe(H)2(dmpe)2 and a magnetic stirring bar21,22.</li>
	<li>Add 10 mL of THF.</li>
	<li>Close the Fisher Porter and bring it outside the glove box.</li>
	<li>Place it at 25 &#176;C for 15 min to equilibrate the temperature of the solution.</li>
	<li>Connect the Fisher Porter to the gas system and add 1 atm of CO2. 
	NOTE: The gas system connects the CO2 bottle to both the vacuum line and the Fisher Porter. The connections are with Teflon tube and Swadgelock connectors (see Figure 1 for a scheme of the setup). This system enables to add the pressure defined at the regulator at the desired temperature.</li>
	<li>Leave for 3 min under a dynamic pressure of CO2, close the tube and stir it at 25 &#176;C for 45 min. 
	NOTE: This stage corresponds to the selective generation of bis(boryl)acetal 1 from CO2 hydroboration in 85% yield.</li>
	<li>After 45 min, open the Fisher Porter in a glove box and add a solution of 380 mg of triazol-5-ylidene in 6 mL of THF.</li>
	<li>Outside the glove box, charge the Fisher Porter with 3 atm of CO2.</li>
	<li>Stir the solution at 60 &#176;C for 60 min under a dynamic pressure of 3 atm of CO2.</li>
	<li>Let the solution cool down to room temperature.</li>
	<li>Remove the volatiles under vacuum and wash the residue with 3x 2 mL of diethylether (Et2O) at 0 &#176;C to obtain CO2 adduct 3 as a white powder (Figure 3).</li>
	<li>To generate monocrystals, place a concentrated THF/pentane solution at -37 &#176;C for 24-48 h.</li>
</ol>
3. Synthesis of compound 4 from CO2 in a Fisher Porter
<ol>
	<li>In a glove box, charge a Fisher Porter tube with 159 mg of 9-BBN, 4.7 mg (1 mol%) of Fe(H)2(dmpe)2 and a magnetic stirring bar.</li>
	<li>Add 5 mL of THF.</li>
	<li>Close the Fisher Porter and bring it outside the glove box.</li>
	<li>Place it at 25 &#176;C for 15 min to equilibrate the temperature of the solution.</li>
	<li>Connect the Fisher Porter to the gas system and add 1 atm of CO2.</li>
	<li>Leave 3 min under a dynamic pressure of CO2, close the Fisher Porter and stir it at 25 &#176;C for 45 min. 
	NOTE: This stage corresponds to the selective generation of bis(boryl)acetal 1 from CO2 hydroboration in 85% yield.</li>
	<li>After the generation of 1, open the Fisher Porter in a glove box and add 54 mg of triazol-5-ylidene.</li>
	<li>Outside the glove box, stir the solution at 80 &#176;C for 40 min to generate a mixture of compounds containing compound 4.</li>
	<li>Remove the solvent and dissolve part of the residue in 0.6 mL of THF-d8.</li>
	<li>Filtrate the solution with a syringe equipped with a PTFE filter (0.2 &#181;m) and place it in an NMR tube for analysis. Use hexamethylbenzene (roughly 10 mol% vs 9-BBN) as an internal standard to determine the NMR yields.</li>
</ol>
4. Alternative synthesis of compound 4 from d,l-Glyceraldehyde
<ol>
	<li>In a glove box, charge a Schlenk tube with 50 mg of d,l-Glyceraldehyde, 135 mg of 9-BBN and a magnetic stirring bar.</li>
	<li>Add 4 mL of THF. 
	CAUTION: Upon dissolution of the compound, H2 evolution occurs.</li>
	<li>Close the Schlenk with a septum and stick a needle into it to allow the constant release of H2 formed.</li>
	<li>Stir the white suspension at room temperature for 24 h inside the glove box.</li>
	<li>Add 165 mg of triazol-5-ylidene.</li>
	<li>Stir 3 h at room temperature. All residues solubilize during that time.</li>
	<li>Remove the volatiles under vacuum.</li>
	<li>Solubilize the residue in a minimum amount of Et2O (1 mL) and place the solution at -37 &#176;C for 12 h.</li>
	<li>Compound 4 precipitates. Remove the filtrate by filtration and dry the precipitate under vacuum.</li>
	<li>Isolate compound 4 as a white powder in 72% yield.</li>
</ol>

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The authors have nothing to disclose.

Herein, we present the one-pot two-step versatile transformations of CO2 into complex products. The first step of the method concerns the selective 4 e- reduction of CO2 with a hydroborane reductant. This step is critical because selectivity toward the 4 e- reduction is challenging. Very few systems have been reported that describe the selective generation of bis(boryl)acetal23,24,25. In our case, an iron hydride complex catalyzes this selective 4 e- reduction of CO2 with 9-BBN, affording compound 1, under mild conditions (25 &#176;C) and with very short reaction time (45 min) (Figure 2)18. Our study shows that the reaction conditions are very important. In our hand, each attempt to change the concentration, solvent, CO2 pressure and temperature led to the decrease of the yield in compound 1. A longer reaction time is also detrimental because it leads to over-reduction to the methanol level or evolution of the bis(boryl)acetal into several oligomeric compounds. From our experience, it is necessary to verify the outcome of this reduction step by in situ 1H NMR characterization. The reproducibility of the method needs to be probed over several runs.
The in situ condensation reaction of the intermediate 1 with a bulky aniline gives rise to the corresponding imine 2 (Figure 2). This is a straightforward method and compound 2 is readily formed in a high yield (83%). This reaction can also be used to probe the efficiency of the reduction step. This method is the only method enabling the synthesis of imine function from CO2. Moreover, intermediate 1 was proved to be a versatile source of methylene in various condensation reactions leading to the formation of C-N, C-O, C-C and C=C bonds18. This method thus offers a straightforward way of using CO2 as a surrogate of formaldehyde in condensation reactions26.
Intermediate 1 reacts with Ender&#39;s carbene to afford compounds 3 or 4, depending on the reaction conditions (Figure 3)20. With the support of in-depth experimental and theoretical study, we were able to explain the observed reactivity. In this case, compound 1 does not react as formaldehyde since boryl moieties remain in compounds 3 and 4. This feature arises from the formation of an unprecedented O-Borylated Breslow intermediate (Figure 3)27,28,29,30,31,32. This intermediate is not observed experimentally but may act as a bifunctional Lewis acid/Lewis base activator toward CO2 to afford compound 3 or leads to the homocoupling of two more carbon centers to afford compound 4. In both products, chiral centers are generated and in the case of compound 4, the two chiral centers, C2 and C3, are obtained in a diastereoselective manner, thanks to the presence of the bridging boryl fragment.
The advances presented herein were possible thanks to the one-pot two-step method employed and to the high and versatile reactivity of intermediate 1 generated from the selective 4e- reduction of CO2. Following a similar method to further improve the scope and the complexity of the synthesized molecules, on-going works are dedicated i) to tune the properties of bis(boryl)acetal in using other hydroborane reductants and ii) to probe different coupling conditions in using other organo-catalysts.

In light of the large interest in using CO2 as a sustainable carbon source1,2,3, the purpose of the method is to transform CO2 into a variety of value-added products.
Intense researches aim at functionalizing CO24,5 or reducing it into formic acid (2 e- reduction), carbon monoxide (2 e- reduction), methanol (6 e- reduction) or methane (8 e- reduction)1,6. The interception of the 2 e- reduction product with amine, notably, gives rise to formamide and methylamine7,8,9. These areas of research are the most advanced so far. However, the scope of accessible functions and the added value of products formed compared to the starting materials remains rather minimal.
To circumvent this limitation, we focused i) on the 4 e- reduction of CO2 and ii) on applying a one-pot two-step procedure. The interest of the one-pot two-step procedure is to limit compatibility issues between the two steps and consequently to broaden the type of reactivity which could be conducted after the first step of reduction. We targeted the 4 e- reduction of CO2 because formaldehyde -the simplest 4 e- reduction product- is a particularly reactive and versatile carbon source10,11. It is used in condensation reaction as a methylene source and can be polymerized into carbohydrates. The latter -called formose reaction- is an impressive transformation generating carbon chain and chiral carbon centers solely from formaldehyde and is of high interest for synthetic-12,13 and prebiotic-chemistry14,15,16.While we are able to observe free formaldehyde from CO2 hydroboration17, its selective generation under homogeneous conditions is still unprecedented. Instead of formaldehyde, we developed the synthesis of bis(boryl)acetal compound 1 from the selective double hydroboration of CO218,19.
In one-pot two step processes we prove herein that, in the same pot, this intermediate 1 i) reacts as a surrogate of formaldehyde in condensation reactions18 or ii) gives rise to a modified formose-type reaction20. In this latter reaction, C-C coupling and chiral carbon centers are obtained.

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	<tbody>
		<tr>
			<td>Wilmad quick pressure valve NMR tube 5 mm diam.</td>
			<td>Sigma-Aldrich</td>
			<td>Z562882-1EA</td>
			<td></td>
		</tr>
		<tr>
			<td>Filtre-seringue PTFE hydrophobe &#216; 25 mm pores 0,22 &#181;m</td>
			<td>UGAP</td>
			<td>2528593</td>
			<td></td>
		</tr>
		<tr>
			<td>Fisher Porter</td>
			<td>Home made system</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>9-borabicyclo[3.3.1]nonane dimer</td>
			<td>Sigma-Aldrich</td>
			<td>178713</td>
			<td></td>
		</tr>
		<tr>
			<td>FeCl2 (anhydrous)</td>
			<td>Strem</td>
			<td>MFCD00011004</td>
			<td></td>
		</tr>
		<tr>
			<td>d,l-Glyceraldehyde</td>
			<td>Sigma-Aldrich</td>
			<td>G5001</td>
			<td></td>
		</tr>
		<tr>
			<td>2,6-(diisopropyl)phenylamine</td>
			<td>Sigma-Aldrich</td>
			<td>374733</td>
			<td></td>
		</tr>
		<tr>
			<td>dimethylphosphinoethane</td>
			<td>Strem</td>
			<td>MFCD00008511</td>
			<td></td>
		</tr>
		<tr>
			<td>Tetrahydrofuran</td>
			<td>Carlo Erba</td>
			<td></td>
			<td>solvent</td>
		</tr>
		<tr>
			<td>Diethyl ether</td>
			<td>Carlo Erba</td>
			<td></td>
			<td>solvent</td>
		</tr>
		<tr>
			<td>Pentane</td>
			<td>Carlo Erba</td>
			<td></td>
			<td>solvent</td>
		</tr>
		<tr>
			<td>Tetrahydrofuran D8</td>
			<td>Eurisotop</td>
			<td>D149FE</td>
			<td></td>
		</tr>
	</tbody>
</table>

versatile co2 transformations into complex products: a one-pot two-step strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Successful generation of bis(boryl)acetal compound 1 is assessed by 1H NMR analysis with the characteristic methylene pick at 5.54 ppm in THF-d8 (Figure 4a). Successful generation of compound 2 is assessed by 1H NMR analysis with the characteristic AB signal (&#948; = 7.73 (d, 1H, 2JH-H = 18.4 Hz, CH2), 7.30 (d, 1H, 2JH-H = 18.4 Hz, CH2) for the two inequivalent protons of the methylene in THF-d8 (Figure 4b). Successful generation of compound 3 is assessed by 1H NMR analysis in THF-d8 (Figure 4c). The most notable signals are the CHCO2 at 5.34 ppm, and the CH of the BBN fragment at 0.26 and -0.65 ppm. Successful generation of compound 4 is assessed by 1H NMR analysis in THF-d8. As shown in Figure 4d, compound 4, in situ generated from CO2, is notably characterized by a doublet at 4.64 ppm (3JH-H = 7.9 Hz, H3) and a pseudo-t at 3.36 (2JH-H = 9.7 Hz, 3JH-H = 9.5 Hz, 1H, H1b). In the isolated compound 4 from d,l-Glyceraldehyde, the four proton signals of the C3 chain are clearly observed (Figure 4e) and the three carbon atoms of the chain are characterized in the 13C{1H} NMR analysis at 76.9 (C2), 74.0(C3) and 71.5(C1) ppm (Figure 5).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60348/60348fig1.jpg" /> 
Figure 1: Gas system. Scheme of the gas system enabling the addition of a defined pressure of CO2 at a given temperature. <a href="https://www.jove.com/files/ftp_upload/60348/60348fig1large.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/60348/60348fig2a.jpg" /> 
Figure 2: Reductive functionalization of CO2. Synthesis of compounds 1 and 2. <a href="https://www.jove.com/files/ftp_upload/60348/60348fig2large.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/60348/60348fig3a.jpg" /> 
Figure 3: Carbene-mediated C-C bond formation. Synthesis of compounds 3 and 4. <a href="https://www.jove.com/files/ftp_upload/60348/60348fig3large.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/60348/60348fig4a.jpg" /> 
Figure 4: 1H NMR analyses of compound 1-4, recorded at room temperature in THF-d8. (A) In situ generated compound 1, (B) in situ generated compound 2, (C) isolated compound 3, (D) in situ generated compound 4 from CO2, (E) isolated compound 4 from d,l-Glyceraldehyde. <a href="https://www.jove.com/files/ftp_upload/60348/60348fig4large.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/60348/60348fig5a.jpg" /> 
Figure 5: Representative characterization of compound 4 isolated from d,l-Glyceraldehyde. 13C{1H} NMR analysis recorded at room temperature in THF-d8; inlet: zoom of the C1-C3 area. <a href="https://www.jove.com/files/ftp_upload/60348/60348fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy at JoVE.com

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

This protocol is significant because we can control the full electron reduction of CO2 and we can use the product form as a reactive and versatile intermediate in one-pot cascade reactions. Thanks to the crucial CO2 reduction step and cascade strategy, this technique and reverse probing of the intermediate reactivity leading to the synthesis of carbon compound from CO2 for the first step. The reaction mixture preparation is a meticulous process that involves multiple additions to a reaction vessel inside the glove box, CO2 pressurization, and a strict time and temperature control.This cascade strategy requires subsequent reaction steps, the use of a glove box and gas handling, all of which are easier to understand through visual demonstration. For synthesis of compound two, charge an NMR tube with 15.9 milligrams of nine BBN, 130 microliters of a 10%molar hexamethyl benzene as an internal standard, and 100 microliters of a 1%molar iron catalyst solution in deuterated tetrahydrofuran. Add 0.37 milliliters of additional deuterated tetrahydrofuran to the tube before closing the tube and connecting it to a gas system outside of the glove box.Place the NMR tube in a 25 degree Celsius bath for 15 minutes. Then add one atmosphere of carbon dioxide for three minutes before closing the tube for a 45-minute incubation at 25 degree Celsius. During the equilibration, prepare a stock solution by mixing 189 microliters of freshly distilled 2, 6-diisopropylethylamine, and 811 microliters of fresh deuterated tetrahydrofuran.When compound one has been generated, open the NMR tube inside the glove box, and add 55 microliters of the prepared 2, 6-diisopropylethylamine solution to the tube. Then close and shake the tube for 10 seconds. After 20 minutes, confirm the formation of imine 2 by proton NMR analysis and determine the NMR yield by comparison of the signal to the internal standard.For synthesis of compound three, charge the reaction vessel containing a magnetic stirring bar with 9.4 milligrams of iron catalyst, 320 milligrams of 9-BBN, And 10 milliliters of tetrahydrofuran inside a glove box. After closing the reaction vessel, remove it from the glove box for connection to the gas system. Add one atmosphere of carbon dioxide to the vessel for three minutes before closing the vessel for a 45-minute stirring incubation at 25 degree Celsius.At the end of the reaction, open the reaction vessel in the glove box, and add a solution 380 milligrams of triazol-5-ylidene in six milliliters of tetrahydrofuran to the mixture. Then charge the reaction with three atmospheres of carbon dioxide and stirring for 60 minutes at 60 degrees Celsius. At the end of the reaction, when the solution has cooled to room temperature, remove the volatiles under vacuum and wash the residue three times with two milliliters of diethyl ether at zero degrees Celsius to obtain carbon dioxide adduct three as a white powder.For compound four synthesis in a glove box, charge a new reaction vessel containing a magnetic stir bar with 159 milligrams of 9-BBN, 10%molar hexamethyl benzene as an internal standard, and 4.7 milligrams of iron catalyst followed by the addition of five milliliters of tetrahydrofuran. Place the closed vessel outside of the glove box for a 15-minute equilibration at 25 degree Celsius before connecting the vessel to the gas system for three minutes under a dynamic pressure of one atmosphere carbon dioxide. At the end of the pressurization, close the vessel for a 45-minute stirring incubation at 25 degrees Celsius.When compound one has been generated, open the reaction vessel in the glove box, and add 54 milligrams of triazol-5-ylidene. Outside of the glove box, stir the solution at 80 degrees Celsius for 40 minutes to generate mixture of compounds containing compound four, and remove the solvent under vacuum. Then dissolve part of the residue in 0.6 milliliters of deuterated tetrahydrofuran, and strain the solution through a syringe equipped with a 0.2 micrometer polytetrafluoroethylene filter into an NMR tube for analysis.A successful generation of bis(boryl)acetal compound one, as assessed by proton NMR analysis, results in a characteristic methylamine peak at 5.4 parts per million in deuterated tetrahydrofuran. A successful generation of compound two presents a characteristic AB peak set at 7.30 parts per million for the two inequivalent methylamine protons in deuterated tertrahydrofuran. In a successful generation of compound three, the most notable signals are the methene peak connected to the carbene at 5.34 parts per million and the methene peaks of the BBN fragment at 0.26 and minus 0.65 parts per million.A successful synthesis of compound four in situ generated from carbon dioxide is notably characterized by a doublet at 4.64 parts per million in a pseudo-triplet at 3.36 parts per million. The aliphatic C3 chain of the isolated compound four from DL-glyceraldehyde is characterized in proton NMR by four proton signals, and in carbon 13 NMR by three carbon signals. The reduction steps are sensitive to changes in the protocol, and the reproducibility must be probed notably by the reproductive synthesis of compound two in good yield.Please be sure to check the safety sheets for any hazardous material and gases to take precaution regarding handling of gases, and to avoid the building of overpressure.

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