No.175 No.175

ResearchResearch ArticleArticle

Silver-Catalyzed CO2 Incorporation Reactions

Tohru Yamada

Department of Chemistry, Keio Univeristy 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, Japan

Abstract: Silver-catalyzed reactions are some of the important methodologies in organic chemistry. For the sequential carboxylation and cyclization of alkyne derivatives, such as propargyl alcohols and amines, using carbon dioxide, silver catalysts show significant reactivity under mild conditions unlike other transition metals. Related silver-catalyzed C–C bond forming reactions with carbon dioxide have also provided the synthetic methods of the corresponding carboxylic acid derivatives.

Keywords: Carbon dioxide, Silver catalyst, Alkyne, Cyclic carbonate, Heterocycle

1. Introduction principle of combustion of fossil fuels, metabolism of life body, fuel cells, etc. The challenges of the future are not to merely Although the authenticity of temperature data which is the reduce carbon dioxide emissions, but to convert the energy from basis of "global warming theory" that the average temperature fossil fuel base to various resources, although much attention on of the earth is rising unprecedented is suspected, it is fact carbon dioxide due to a powerful greenhouse effect. In industry, that the concentration of carbon dioxide in the atmosphere is because carbon dioxide is provided abundantly on reasonable increasing. There is no choice but to commit a cause for human cost and it is non-toxic in itself, research as an organic synthetic activity that depends on energy from fossil fuels. In chemistry, resource is also active. The commercial production of salicylic oxidation of hydrocarbons releases energy to exhaust the most acid by the Kolbe-Schmitt reaction is one of the most famous oxidized carbon dioxide ultimately. This is the unique and basic practical processes, and recently synthesis of dimethyl carbonate

NaBH , EtOH, HO 4 O

NaBH2(OEt) O O cat. Ph Ph Ph Ph N N N N Co Co O O O O O O O O MPAC

Ph Ph N N Co O OH N N O O O O Co H R R O O O O AMAC Highly Enantioselective

Scheme 1. Enantioselective borohydride reduction

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by reaction with methanol has been reported. Cyclic carbonates for enantioselective cyclopropanation of styrene derivatives obtained from the reaction of epoxide and carbon dioxide are with diazoacetates.2 During mechanistic researches, density expected as polymer precursors such as polycarbonate, as functional calculations on the hetero-Diels–Alder reaction aprotic polar solvents or synthetic intermediates. However, these catalyzed by 3-oxobutylideneaminatocobalt complexes revealed reactions require severe reaction conditions of high pressure that axial coordination of an aldehyde as a Lewis base induces and high temperature including supercritical conditions due to a spin transition in the catalytic cycle.3 The Lewis acidity of the stability of carbon dioxide, and are limited to the industrial the complex is increased, and the enantioselectivity improved. production purpose of simple compounds. The reactions Based on these considerations, in the presence of a catalytic under milder conditions are required for advanced molecular amount of optically active cobalt complexes and amine bases, transformation such as synthesis of more complicated structure racemic glycidols reacted with gaseous carbon dioxide to with high stereoselectivity. afford the optically active cyclic carbonate along with the From our research group, optically active cobalt(II) optically active starting epoxide4 (Scheme2). The alternating complexes with a conventional reductant; sodium borohydride, copolymerization of propylene oxide/ alkylene oxide and carbon have been proposed as an effective system for the catalytic dioxide has been developed.5 The ratio-controlled incorporation enantioselective reduction of ketone and imine derivatives to of the poly(alkylene carbonate) units could improve the thermal afford the corresponding secondary alcohols and amines in high- properties, such as the glass-transition temperature and thermal to-excellent yields with high enantioselectivities1 (Scheme 1). degradation temperature, of the obtained polycarbonates6 These cobalt complexes could be employed as the catalyst (Scheme 3).

2 mol%

(R) O EtO N N OEt O Co H O O O O O O Ph2N 86% ee (49% yield) Ph N 2 1 mol% (R) Et2N SiMe3 H O Ph N 87% ee (49% recovery) CO2 (7 atm) 2 (S) S = 32

Scheme 2. Enantioselective CO2 fixation catalyzed by cobalt complex

0.05 mol%

(R) EtO N N OEt Co O O O O O O O OBz + CO2 R O R 0.05 mol% n Ph3PNPPh3 >99% carbonate Cl

Scheme 3. Polycarbonate with cobalt complex catalyst

2. Silver-Catalyzed Carboxylation of Propargyl under mild reaction conditions (Scheme 4). The exo-alkenyl Alcohols cyclic carbonates were obtained as the sole isomers and the geometry of the C–C double bond was confirmed to be the Z In 2007, we reported the silver-catalyzed carboxylation isomer by X-ray single crystal structure analysis or NOE. These and cyclization of propargyl alcohols under mild reaction results suggested that the silver catalyst activates the C–C triple conditions.7,8,9 The study indicated that the combined use of bond from the opposite side of the carbonate to promote anti- silver acetate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) addition through 5-exo-dig cyclization. was an efficient catalyst system for the incorporation of In the reactions mentioned above, the silver-catalyzed carbon dioxide into various propargyl alcohols to afford the reaction of propargyl alcohols with carbon dioxide selectively corresponding cyclic carbonates in high-to-excellent yields, afforded the corresponding cyclic carbonates in a toluene though other transition-metals including copper, gold, rhodium, solution (path a in Scheme 4), while in DMF, the corresponding mercury, platinum, and palladium were not effective at room a,b-unsaturated carbonyl compounds, generated via a Meyer– temperature. It was also noted that this catalytic system could be Schuster type reaction, were detected. In polar solvent, the applied to the aryl- and alkyl-substituted internal alkynes even b-carbon of propargyl alcohol would be alternatively attacked

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to promote the [3,3]-sigmatropic rearrangement into the allene- 3. Carboxylation with C–C Bond Formation enolate. The a,b-unsaturated carbonyl compounds would result from the release of carbon dioxide10 (path b in Scheme 4). 3-1. Cobalt-Catalyzed Reductive Carboxylation The computational approach for the reaction mechanism was performed.11 As a model substrate, 2-methyl-3-pentyn-2- In the presence of a catalytic amount of bis(acetylacetonato) ol was adopted for the representative of propargylic alcohol, cobalt(II), the reductive carboxylation of a,b-unsaturated and 1-methyl-1,4,5,6-tetrahydropyrimidine for the DBU base. carbonyl compounds with carbon dioxide was studied. From The calculations suggested that carboxylate with silver catalyst this laboratory, the combined use of cobalt(II) complexes with would be formed as an active species, although the reaction various reductants, such as 2-propanol,13 silanes,14 and sodium pathway was not clear. We then analyzed the cyclization borohydride,15 was examined. Isayama and Mukaiyama reported mechanism from the active species. Although the activation the reductive aldol reaction from a,b-unsaturated nitriles energy between the two pathways did not reverse in the catalyzed by bis(acetylacetonato)cobalt(II) and phenylsilane in calculation of the model substrate, this observation shows that 1989.16 The reaction mechanism is presumed to be as follows: the polarity of the solvent was crucial for the ratio between the phenylsilane could act on the cobalt complex as a reducing cyclic carbonate and the enone, and this tendency was consistent agent to generate “cobalt hydride.” Its 1,4-addition to an a,b- with the fact that the carbonate was preferentially obtained unsaturated nitrile would afford the corresponding cobalt enolate in the nonpolar solvent, while the enone was predominantly equivalent, which would produce the cobalt alkoxide of the formed in the polar solvent. aldol adduct by a nucleophilic attack on the electrophile such as On the basis of the reaction mechanism, we developed aldehydes and ketones. The screening of various reducing agent the asymmetric carbon dioxide incorporation into bispropargyl revealed that diethylzinc effectively afforded the corresponding alcohols with desymmetrization by the combination of a-carboxylates in high yield and high regioselectivity from a,b- silver acetate and the chiral Schiff base ligand L* to afford unsaturated nitriles17 and N-methylanilides.18 the corresponding cyclic carbonates with good-to-excellent enantiomeric excess12 (Scheme 5).

O O OH Ag+ O a O path a b O 3 1 O 2 R CO2 R3 in toluene R 1 R 2 3 R DBU R1 R R2 R Ag+ Cyclic Carbonates path b [3,3]-sigmatropic in DMF rearrangement

O OCO O O O R3 1 R 3 R R1 R2 R2 Enones

Scheme 4. Reaction pathways of propargylic alcohol with CO2

O O cat. OH AgX O O cat. O Chiral ligand : L* R1 O 2 2 2* 1 R 1 CO2 1 R 1 R R R R + R 1 L* Ag / L* R Me Me NN

N N

Scheme 5. Enantioselective chemical incorporation of CO2 into bispropargylic alcohols

2 2 cat. Co(acac) R R2 R 2 1 Co CO2 TMSCHN2 COOMe R1 R R1 CN Et2Zn CN (1 atm) CN THF, 20 °C H α-selective carboxylation

Scheme 6. Cobalt-catalyzed reductive carboxylation

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3-2. C–C Bond formation between Enolate and lactones that are not easily decarboxylated. In this section, Carbon Dioxide the silver-catalyzed C–C bond forming carboxylation and cyclization reactions are described. Enolate has been a Propargyl alcohols and propargyl amines were converted to promising reagent for the C–C bond forming reactions in the corresponding cyclic carbonates and oxazolidinones in the organic chemistry. The reactions of an enolate with carbon presence of silver catalyst. To incorporate carbon dioxide into dioxide produce the corresponding b-ketocarboxylic acids. Due organic molecules, the formation of C–C bonds between the to its thermodynamic instability, however, b-ketocarboxylic acid substrate and carbon dioxide is important. Cyclization following would easily revert to the starting material.19 Therefore, careful C–C bond forming carboxylation can afford the corresponding treatment or subsequent reduction of the product was required.

CO2 + O 2 2 O O O O O R2 R2 Ag R R Ag+ Base 1 1 1 R1 R R O R O 2 3 C R3 2 R R R 3 R3 O O R2 R R2 5-exo 6-endo

Scheme 7. C–C Bond formation with CO2

Table 1. Examination of reaction conditions 20 mol% O Metal Salt O O 2.0 eq. Base CO Ph 2 Ph O (1.0 MPa) Solvent 30 °C, 48 h Ph Ph Entry Metal Salt Base Solvent Yield / %a N 1 none DBU DMSO 0 N 2 Pd(OAc)2 DBU DMSO trace DBU 3 Cu(OTf) DBU DMSO 0 2 NH 4 CuBr DBU DMSO 0 5 AuCl DBU DMSO 0 Me2N NMe2 TMG 6 (Ph3P)AuCl DBU DMSO trace 7 AgOAc DBU DMSO 22 N 8 AgOBz DBU DMSO 40 N N 9 AgOBz TMG DMSO 7 H 10 AgOBz TBD DMSO 3 TBD 11 AgOBz MTBD DMSO 48 N 12 AgOBz MTBD DMF 72 N N 13b AgOBz MTBD DMF 91 Me a Isolated yield. b 4 eq. MTBD, 25 °C. MTBD

20 mol% AgOBz CO (1.0 MPa) O O O R2 R2 2 4.0 eq. MTBD 1 O R1 R 3 DMF, 25 °C 2 R R 3 R2 R O O O O O O O O Ph O Ph O Ph O OMe Ph O

Me CF 91% 90% 87% 90% 3 O O O O O O O O Ph O Ph O O O

Me Ph F3C Ph 77% Ph 83% 84% 79% O O O O O O O O Ph O Ph O O Ph O

Ph Ph Ph Ph 74% 36% 58% 59%

Figure 1. Silver-catalyzed CO2 incorporation with C–C bond formation

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A tandem reaction for the conversion of b-ketocarboxylic acid was not an effective base for this reaction. In the preliminary into a stable compound is one of the most reasonable methods examination of solvents, nonprotic polar solvents were found to for the reaction of an enolate and carbon dioxide. We reported promote the reaction smoothly. Several nonprotic polar solvents that b-ketocarboxylate was trapped by the silver-activated C–C were next examined. As a result, DMF was found to be the most triple bond to afford the corresponding stable 5-membered suitable as the reaction in this solvent afforded the product in lactone in a one-pot synthesis (Scheme 7). the highest yield. Under the optimized conditions the product Several metal catalysts were investigated for the reaction was obtained in 91% yield at 25 °C in 48 h.20 of the model substrate, in DMSO in the presence of DBU (2.0 A good scope of substrates under the optimized reaction equiv) under 1.0 MPa CO2 pressure (Table 1). The reactions conditions was indicated (Figure 1). Both aromatic and aliphatic did not proceed in the absence of the metal salt. Palladium, ketones were suitable for this reaction. copper, and gold(I) salts, which were expected to activate the Interestingly, during the reaction optimization of the alkyne- C–C triple bond, hardly worked for this reaction. Among the containing aliphatic ketones, not only the corresponding lactone catalysts tested, a silver salt was the most effective catalyst for derivatives, but also furan derivatives containing a carboxyl this reaction to produce the g-lactone. Taking into account the group were detected. Based on the structure of the furan, it acidity of a proton of the substrate, several bases were screened. was assumed that the ketone carbonyl of the b-ketocarboxylic In the previous work, amidine-type bases such as DBU were acid was trapped on the C–C triple bond activated by the silver effectively employed to afford the cyclic carbonates in high catalyst unlike in our previous studies. This result inspired us to yield. Based on these results, various amine bases, such as TBD examine the C–C bond forming reaction with carbon dioxide to and MTBD, were examined. When MTBD was employed as successively construct a carboxyl group and a furan skeleton. a base, the product was obtained in good yield, whereas TBD It was postulated that dihydro-isobenzofuran derivatives

O O O O O CO2 O O n n n + R R R Ag Lactone

OX O O OH O R CO2 O O

n n n + R R Ag Furan X= H or baseH

Scheme 8. Silver-catalyzed cyclization affords furan derivatives

O 10 mol% R3 O AgOAc 3 CO2 (1.0 MPa) OMe R 2.0 equiv DBU CH3I R1 R1 O esterification CH3CN, 30 °C R2 R2 O O O O O 95:5 88:12 OMe MeO OMe OMe OMe OMe O O O O O MeO F 92% Ph 91% Ph 90% Ph 95% 62% O O O O

OMe OMe OMe OMe O O O O

87% Me 87% CF3 89% 91% MeO O O O Me O OMe OMe O O 73%(DMSO) 47%(DMSO) Ph Ph

Figure 2. Silver-catalyzed cyclization of several o-alkynylacetophenones

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bearing a carboxyl group could be obtained by the 5-exo-dig medicinal compounds. Though allylsilane compounds have regioselective cyclization of o-alkynyl-acetophenone and carbon the additional potential for carbon dioxide incorporation, few dioxide using the silver-catalytic system (Scheme 8). systems involving the Lewis acid mediated carboxylation Unfortunately, the purification of the product was not have been reported. The present reaction was promoted successful using the standard methods, such as back extraction by a silver salt and CsF to afford the corresponding and silica gel column chromatography, though the product 2-furanones and 2-pyrones in good-to-high yields22 could be isolated by recrystallization. In order to obtain the (Scheme 9). corresponding ester, esterification was attempted. It was found When aromatic ring-substituted alkynes were used, that the carboxylate could be esterified with methyl iodide in a 2-furanone derivatives were selectively obtained via 5-exo-dig one-pot synthesis to give the corresponding methyl ester in 92% cyclization, whereas the reaction of the alkyl-substituted alkynes yield.21 The substrate scope of the silver-catalyzed cyclization produced 2-pyrone derivatives with high selectivity (Figure 3). under the optimized reaction conditions was shown in Figure 2. Tetronic acids, or 4-hydroxy-5H-furan-2-ones, are found The geometries of the two C–C double bonds were suggested to in a range of natural products and are considered as important be Z isomers based on NOE experiments. scaffolds for the construction of bioactive and pharmaceutical Recently, the silver-catalyzed cascade carboxylation compounds. Although several methods for the synthesis of their and cyclization of the trimethyl(2-methylenebut-3-yn-1-yl)- derivatives have been reported, multiple steps are generally silane derivatives were developed. The allylsilane compound required. In this section, we report that a readily prepared is one of the useful reagents for new C–C bond formation. conjugated ynone has been employed as a carbon nucleophile to For example, Hosomi–Sakurai allylation has been used synthesize tetronic acid derivatives using CO2 in the presence of to provide homoallyl alcohols, which are an important a silver catalyst (Scheme 10). framework for the total synthesis of natural products and

O O O SiR3 cat. + O + Ag F H O P O CO2, CsF 1 1 R R R1 (Z) 1 Ag+ R Furanone Pyrone Scheme 9. Carboxylation of allylsilanes

10 mol% (IPr)AgCl O O Me Si 1.5 equiv CsF 3 + CO2 O O (1 MPa) 1.2 equiv R MeOH DMF, 40 °C, 24 h R R O O O O O O O O O O

CF3 CN 78% 80% 73% N 78% 92% O O O O O O O Me O COOEt Me 72% O 74% 78%(95:5) 76%(94:6) O O O O O O 66% O 43% O 18% O 43% O 77% OMe O O O O (88:12) Me (60:40) (56:44) (75:25) O O O O O 9% 29% O 65% 15% Ph OMe Me 14% Figure 3. Carboxylation of allylsilanes

O O R2 R2 R2 Base CO O 2 O 2 1 R O O O R R1 R1 1 R Ag+ OH Tetronic acid Scheme 10. Preparation of teronic acid

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Various organic bases were examined first. Under 2.0 cyclohexyl groups were examined, 6-endo-dig cyclization MPa pressure of CO2, the ynone was treated with organic occurred versus the 5-exo-dig cyclization to afford the tetronic bases in the presence of a catalytic amount of silver acetate in acids and the hydroxypyrones (Figure 4). 1,2-dichloromethane. When triethylamine or N-methylimidazole This protocol was applied to the synthesis of aspulvinone was employed, no reaction occurred, and the ynone was E (Scheme 11). The internal alkyne, which is a precursor for quantitatively recovered. The use of 1,5,7-triazabicyclo[4.4.0]- the CO2 incorporation reaction, was prepared from the reaction dec-5-ene (TBD), DBU, and 7-methyl-1,5,7-triazabicyclo[4.4.0]- of ethyl (4-methoxyphenyl)acetate with the lithium acetylide, dec-5-ene (MTBD) were found effective against the 5-exo-dig generated from (4-methoxyphenyl)acetylene with n-BuLi. cyclization to afford the tetronic acid in 74%, 86%, and 90% The silver-catalyzed intramolecular cyclization involving the 23 yields, respectively. CO2 fixation proceeded to afford the corresponding product in The optimized conditions were applied to various ynones. 73% yield. After demethylation, aspulvinone E was obtained The substrates bearing phenyl, o-tolyl, m-tolyl, and p-tolyl in 98% isolated yield. Overall, the synthesis of aspulvinone groups were converted to the corresponding tetronic acids in E was achieved in three steps from commercially available 92%, 88%, 74%, and 87% yield, respectively. When substrates materials. In one previous report, six steps including Dieckmann with no substituent or bearing an n-hexyl group were employed, cyclization were required to synthesize aspulvinone E. the 5-exo-dig cyclization proceeded to afford the corresponding Therefore, our protocol can be regarded as noteworthy in terms tetronic acids in 95% and 97% yield, respectively. On the other of step-economy. hand, when the reactions of substrates bearing isopropyl and

10 mol% AgOAc O O CO2 (2.0 MPa) 4.0 equiv R2 MTBD O 1 R2 CH2Cl2 R R1 25 °C, 24 h OH O O O O Me O O O O Ph Me Me Me Me Me OH 92% Me OH 88% OH 74% OH 87% O O O MeO NC O O O Me Me Ph

OH >99% OH 62% OH 95% O O O O O O O O Ph Ph Ph Ph Ph OH OH OH OH 97% 88% 77% 75%

Figure 4. Preparation of various tetronic acid derivatives

OMe O MeO EtO

2.0 qeuiv n-BuLi THF 2.4 equiv BF3•OEt2 -78 °C

OMe 20 mol%AgOAc CO2 (2.0 MPa) O MeO 4.0 equiv MTBD O OMe O CH3CN, 40 °C 72 h OH MeO BBr3 O HO O OH

OH Aspulvinone E

Scheme 11. Facile approach to Aspulvinone E

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3-3. Rearrangement for Hydroxylquinolin-2-one and catalyzed by the silver catalyst. In the second step, the Tetramic Acid benzoxazine would immediately be deprotonated by the DBU base to generate the isocyanate and the enolate from the C–O It was found that a silver catalyst successfully promoted bond cleavage of the carbamate functionality. The enolate the incorporation of CO2 into o-alkynylanilines to afford the would then attack the carbon atom of the isocyanate to afford corresponding benzoxazine-2-ones bearing (Z)-exo-olefin via the 1,3-diketone intermediate, which would produce the 6-exo-dig cyclization at the activated C–C triple bond.24 corresponding 4-hydroxyquinolin-2(1H)-one after enolization. 18 During the optimization for the primary o-alkynylaniline, a Isotopic labeling experiments with C O2 were conducted to side-product was detected. Based on several analytical results, reveal that the quinoline contained carbon dioxide. In addition, such as X-ray single crystal structure analysis, 1H NMR, 13C in situ IR measurement of the reaction of the benzoxazin-2-one NMR and mass spectrometry, the side-product was identified and DBU was carried out. After DBU was added to the THF to be 4-hydroxyquinolin-2(1H)-one. The possible reaction solution of the benzoxazine, absorption at 2150 cm-1 assigned as mechanism is shown in Scheme 13. isocyanate group was observed. This result would also support First, the corresponding benzoxazin-2-one would be the proposed reaction mechanism (Figure 5). generated from the o-alkynylaniline and carbon dioxide

Ag+ R R cat. Ag R (Z) CO2 O R R R Base O NH N N O R R O R Benzoxazine-2-one

Scheme 12. Silver-catalyzed CO2 incorporation into o-alkynylanilines

10 mol% AgNO + Ph Ph 3 Ag Ph CO2 (1 atm) 1.0 eq. DBU O O DMSO, 60 °C NH2 N N O 24 h H O H DBU Ph O OH Ph Ph O N N O N O C H H O 4-Hydroxyquinolin-2(1H)-one Scheme 13. Rearrangement reaction via isocyanate

Ph Ph OH Ph O 1.0 eq. DBU O N O THF, -78 °C N N O H C H O Benzoxazine Isocyanate Hydroxyquinoline

Figure 5. Isocyanate absorption region (2150 cm-1) was detected by in situ IR measurement

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Under the optimized reaction conditions, various o-alky- Candida fungi. In addition, spirotetramat has been used as nylaniline derivatives were applied to the C–C bond-forming an agricultural chemical.28 This rearrangement mentioned- carbon dioxide incorporation reaction. The reactivity of the above was expected to be applicable to five-membered ring enolate intermediates was not influenced by steric or electronic compounds to enable synthesis of tetramic acid derivatives from effect. Various substrates could be subjected to the optimized the corresponding primary propargylic amines (Scheme 14). reaction conditions and smoothly transformed into the The optimized reaction conditions were applied to reactions corresponding quinoline derivatives in high yields25 (Figure 6). involving various primary propargylic amine derivatives29 The cyclization and rearrangement system was applied to (Figure 7). In the presence of 0.5 mol% of AgNO3 and 2.0 propargyl amines for the synthesis of tetramic acid. Tetramic equiv of DBU under atmospheric pressure of carbon dioxide acid structures are found in natural products known for their in MeCN, various propargylic amines were converted into the biological activity. For example, reutericyclin26 inhibits Gram- corresponding tetramic acids in high yield. positive bacteria, and discodermide27 inhibits the growth of

2 R OH 10 mol% AgNO 3 R2 1.0 eq. R1 DBU 1 CO2 R NH2 (1.0 MPa) DMSO, 60 °C N O 24 h H OH OH OH OH Ph Me Ph F Ph F3C Ph

N O N O N O N O H 97% H 82% H 98% H 90% OH OH OH OH Ph Ph

Me N O N O N O N O H H H H 84% Me 85% 75% 69% OMe NO OH OH OH OH 2 N N O N O N O N O H H H H 96% 98% 98% 97%

Figure 6. CO2 Incorporation through intramolecular rearrangement with o-alkynylanilines

O cat. Ag+ O NH2 C CO2 O O R2 N H N 3 DBU R1 R1 1 R 3 3 R 2 R 2 R (Z) R DBU R

O O R1 R1 NH NH O R3 HO R3 R2 R2 Tetramic acid

Scheme 14. CO2 Incorporation and intramolecular rearrangement into propargylic amines

cat. O AgNO3 1 NH2 R 2 DBU R CO2 NH 3 MeCN, 60 °C R1 R (1.0 atm) HO R3 R2 O O2N Me Ph O O O NH HO NH NH NH 96% HO HO HO 90% 85% 90% O O O Ph Ph NH NH NH HO HO Me HO 84% Me 90% Et 91%

Figure 7. CO2 Incorporation into various propargylic amines

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3-4. Three-Component Reaction of for alkenes and alkynes for halocyclization, such as Propargylic Amines for Preparation of (E)- halolactonization. Therefore, it was a concern that, without Halovinyloxazolidinones silver catalysts, NIS itself promoted the cyclization to afford the oxazolidinone. In the absence of AgOAc, the oxazolidinone The oxazolidinone preparation from carbon dioxide is was obtained in 10% yield along with a 20% yield of the imine. one of the most attractive synthetic methods. We reported The imine was supposed to be produced by the oxidation of that carbon dioxide incorporation into various propargylic benzylamine by the iodonium ion. When iodine was employed amines proceeded to give the corresponding oxazolidinone instead of NIS, the reaction did not afford the oxazolidinone at derivatives in high yields under mild reaction conditions, i.e., all. It was assumed that the iodo-cyclization pathway was not 2 mol% of AgOAc and 1.0 atm of carbon dioxide. Through dominant in the present silver-catalyzed reaction and that the the reaction, a vinylsilver intermediate was expected to be vinylsilver intermediate could be trapped by the iodonium ion stereoselectively generated as a result of the anti-addition of to stereoselectively afford corresponding (E)-oxazolidinones.31 carbamate to the C–C triple bond activated by silver salts. It The scope of the substrates was investigated under the optimized is reasonable to assume that the silver ion in the intermediate reaction conditions (Figure 8). would be stereospecifically replaced by a proton to produce Next the bromination was examined. Initially, (Z)-alkenyloxazolidinone and regenerate the silver catalyst. N-bromosuccinimide was employed under the similar This plausible mechanism suggested that in the presence of reaction conditions as iodination reaction. However, the appropriate electrophiles (E+), the C(vinyl)–Ag bond could be corresponding (E)-bromovinyloxazolidinone was not stereospecifically trapped by the electrophiles instead of the obtained at all and the corresponding imine was isolated in proton to afford the corresponding oxazolidinones containing 18% yield. In order to suppress the imine formation, various the C(vinyl)–E bond with high geometry control (Scheme 15). organic bases were examined. It was found that the use of For the initial screening, the propargylic amine was 1,1,3,3-tetramethylguanidine (TMG) afforded the brominated employed as the starting material using 10 mol% AgOAc in product. After screening of reaction solvents, when CH3CN was DMSO under a 2.0 MPa CO2 atmosphere. The halonium ions employed for this reaction, the yield and selectivity significantly were first examined using the corresponding succinimides. In increased to 68% with the formation of the protonated product the case of N-chlorosuccinimide and N-bromosuccinimide, in 2% yield. The N-aryl guanidine substituted by an electron- the corresponding oxazolidinone was not obtained. When withdrawing group such as the 4-CF3 and 4-CN groups, gave N-iodosuccinimide (NIS) was employed, the propargylic amine the brominated product selectively. With the optimized reaction was completely consumed in 24 h to produce the oxazolidinone conditions, the scope of the propargylic amines for the silver- bearing the iodovinyl group in 92% yield.30 catalyzed three-component reaction was next examined using 32 The halonium ion is typically employed as an activator the 4-CNC6H4-TMG (Figure 9).

cat. + O O O 4 Ag NHR 4 O + O CO2 O NR 5-exo NR4 E NR4 3 1 1 R 3 R R R2 R 3 3 R1 R2 R2 R R2 R R1 Ag E Ag+ vinylsilver intermediate

Scheme 15. Three-component reaction of propargylic amine, CO2 and electrophile

10 mol% O NHR4 AgOAc 1.0 eq. N-iodosuccinimide O 3 NR4 R + CO2 1 (E) R2 (2.0 MPa) DMSO (0.15 M) R R1 2 R3 25 °C, 24 h I R O O O O O F3C O Me O MeO O NBn NBn NBn NBn Me Me Me I Me I Me I Me Me Me 92% 89% 91% 91% I O O O O O O O O NBn NBn NBn NPMB Me Me Me Me I I Me I I Me 96% 95% 86% 92%

Figure 8. Three-components iodination of propargylic amines

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10 mol% AgOAc CN 1.0 equiv O p-CNC6H4TMG NHnPr NBS 1.0 equiv p-CNC H TMG O CO 6 4 NnPr N Me + 2 1 (E) MeCN, 25 °C R 1 Me (2.0 MPa) R 24 h Me Me N NMe Br Me 2 2 O O O

O F3C O O NnPr NnPr NnPr

F C Me MeMe MeMe 3 Me 72%Br 57% Br 69% Br O O O O Me O O NC O Cl O NnPr NnPr NnPr NnPr

MeMe Me MeMe MeMe MeMe 61% Br 70% Br 62% Br 67% Br O O O MeO O O O NnPr NnPr NnPr

Me Me S Me Br Me Br Me Br Me 56% 72% 60%

Figure 9. Three-components bromination of propargylic amines

4. Conclusion of the acetoacetic ester synthesis method. It was shown that decarboxylation could be sufficiently suppressed by stabilizing Initially, I considered carbon dioxide was an inactive with lactone formation by an appropriate trap of thermally molecule due to its high thermodynamic stability, but the unstable β-ketocarboxylic acid with the alkyne activated in reactions introduced in this paper are performed under rather the presence of the silver catalyst. In other reactions, though it mild conditions at the maximum 2 MPa CO2 pressure and 60 should be considered that the silver catalyst or the organic base °C. In addition, the nucleophilic addition reaction with carbon could activate carbon dioxide, the cyclization step was effective dioxide sufficiently proceeded not only with an alcoholic to suppress decarboxylation. oxygen atom or a nitrogen atom of an amino group but also Carbon dioxide is a safe and inexpensive C1 synthesis with the enolate generated by an organic base or the carbanion unit. Conventionally, highly toxic compounds such as phosgene equivalent generated from an organic silane compound in the have been applied to the same purpose. I hope that the above- presence of a fluoride ion, to afford the corresponding cyclized mentioned reactions will replace those dangerous processes for products. In particular, the reaction between an enolate and the synthesis of heterocyclic compounds. carbon dioxide is a reverse reaction of the decarboxylation step

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Intoduction of the author:

Tohru Yamada Professor, Department of Chemistry, Keio Univeristy

[Education & Professional Career] 1987 Ph.D., The University of Tokyo, Japan, Doctoral Mentor: Prof. Teruaki Mukaiyama; 1987–1997 Mitsui Petrochemical Industries, Ltd. Basic Research Laboratories; 1997–2001 Associate professor of Department of Chemistry, Keio University; 2002-present Professor of Department of Chemistry, Keio University. [Award] 1993 Chemical Society of Japan Award for Young Chemist, 2010 SSOCJ Nissan Chemical Industries Award for Novel Reaction & Method 2009. [Research Interests] Organic synthesis, Asymmetric reaction [Contact] E-mail: [email protected]

TCI Related Products B1844 (R)-MPAC [= (1R,2R)-N,N'-Bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-1,2-diphenylethylenediaminato Cobalt(II)] 100mg B1845 (S)-MPAC [= (1S,2S)-N,N'-Bis[3-oxo-2-(2,4,6-trimethylbenzoyl)butylidene]-1,2-diphenylethylenediaminato Cobalt(II)] 100mg B2314 (R)-AMAC [= (1R,2R)-N,N'-Bis(2-acetyl-3-oxo-2-butenylidene)-1,2-dimesitylethylenediaminato Cobalt(II)] 100mg B2315 (S)-AMAC [= (1S,2S)-N,N'-Bis(2-acetyl-3-oxo-2-butenylidene)-1,2-dimesitylethylenediaminato Cobalt(II)] 100mg

D1270 DBU (= 1,8-Diazabicyclo[5.4.0]-7-undecene) 25g 100g 500g T0148 TMG (= 1,1,3,3-Tetramethylguanidine) 25mL 100mL 500mL T1982 TBD (= 1,5,7-Triazabicyclo[4.4.0]dec-5-ene) 5g 25g M1443 MTBD (= 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) 1g 5g B0656 NBS (= N-Bromosuccinimide) 25g 100g 500g 13