FULL PAPER DOI: 10.1002/asia.201402363
One-Pot Consecutive Catalysis by Integrating Organometallic Catalysis with Organocatalysis Samaresh Chandra Sau, Sudipta Raha Roy, and Swadhin K. Mandal*[a] Dedicated to Prof. Herbert W. Roesky on the occasion of his 79th birthday
Abstract: The present study integrates two types of catalysis, namely, organometallic catalysis and organocatalysis in one reaction pot. In this process, the product of the first catalytic cycle acts as catalytic component for next catalytic cycle. The abnormal N-heterocyclic carbene–copper-based organometallic catalyst acts as an efficient catalyst for a click reaction to provide triazole, which, in turn, acts as an efficient organocatalyst for different organic transformations, for example, aza-Michael addition and multicomponent reactions, in a consecutive fashion in the same reaction pot.
Introduction
next catalytic cycle within the same reaction pot (Figure 1 C).[4] Recently, we demonstrated a new synthetic route that combined two different catalytic centers in the same heterobimetallic catalyst by assembling zirconium and calcium moieties through an oxygen center, which acted in a dual fashion by catalyzing the intramolecular hydroamination reaction of primary and secondary aminoalkenes activated by calcium and zirconium centers, respectively (Figure 1 D).[5] Enders and co-workers controlled four stereocenters in a triple-cascade organocatalytic reaction, in which two substrates, A and B, reacted with each other to generate a new substrate, E, which further reacted with the third sub-
In recent years, there have been emerging trends in integrating multiple catalytic cycles in one pot.[1] In these multicatalytic processes, the product(s) of the first catalytic cycle has been used as substrate(s) of the subsequent catalytic cycle. In this way, the concepts of “tandem”, “merged”, “cascade”, or “relay” catalysis were introduced.[1–6] For example, Goldman and co-workers showed the development of highly productive, well-defined, tandem catalytic systems for the metathesis of n-alkanes.[2] A pincer iridium complex results in alkane dehydrogenation to produce an olefin in the first step, which subsequently acts as a substrate for the olefin metathesis process by using a Schrock-type metathesis catalyst in the same reaction pot in tandem fashion (Figure 1 A). MacMillan and Nicewicz merged photoredox catalysis with organocatalysis for direct asymmetric alkylation of aldehydes, in which two different catalysts (catalysts C and D) in the same reaction pot acted on two different substrates (substrates A and B), simultaneously leading to the final product (Figure 1 B).[3] Grubbs and co-workers showed a more direct approach with the use of a triple relay catalysis system that coupled palladium-catalyzed oxidation, acid-catalyzed hydrolysis, and ruthenium-catalyzed reduction cycles, in which the product of one reaction acted as the substrate for the
Figure 1. Recently reported multicatalytic processes.[2–6]
[a] S. C. Sau,+ Dr. S. R. Roy,+ Dr. S. K. Mandal Department of Chemical Sciences Indian Institute of Science Education and Research-Kolkata, Mohanpur 741252 (India) E-mail: [email protected] Homepage: http://www.iiserkol.ac.in/ ~ swadhin.mandal/index.htm
strate, C, present in the same reaction pot (Figure 1 E).[6] In this way, the development of an asymmetric, organocatalytic, triple-cascade reaction for the synthesis of tetrasubstituted cyclohexene carbaldehydes was possible.[6] In these catalytic processes (Figure 1 A, B, C, and E), the first catalytic step generates the product, which acts as a sub-
[+] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402363.
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Keywords: domino reactions · multicomponent reactions · one-pot synthesis · organocatalysis · organometallic catalysis
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Results and Discussion
strate for the next catalytic cycle. However, in none of these processes has the product of the first catalytic cycle been used as a catalyst for the next cycle. Interestingly, many biological processes utilize a catalytic array of reactions in which the product of the first process acts as a catalyst (enzyme) for the next process. For example, muscle cells respond to epinephrine (adrenaline) by breaking down glycogen into glucose, thereby providing the source of energy for our muscular activity. The breakdown of glycogen is catalyzed by the enzyme glycogen phosphorylase. In this process, the first enzyme, phosphorylage kinase, acts on glycogen phosphorylase to generate the activated glycogen phosphorylase (AGP; Figure 2 A) and the in situ generated AGP then acts as an enzyme for the next biochemical reaction to catalyze the conversion of glycogen into gluocose-1-phosphate. Thus, in this particular process, AGP is the product of the first catalytic (enzymatic) process, which itself acts as the catalyst (enzyme) for the second transformation in a consecutive fashion (Figure 2 A).
We recently reported the catalytic activity of complex 2 in the Huisgen cycloaddition of azides and alkynes at room temperature.[7a] As part of our continuing interest in developing catalysts with aNHCs,[7] imidazolium salt IA (Scheme 1) was employed herein as an aNHC precursor to
Scheme 1. Synthetic route leading to aNHC copper(I) complex 1.
prepare copper(I) bromo complex 1. Complex 1 was prepared by treatment of IA with potassium bis(trimethylsilyl)amide and copper bromide in tetrahydrofuran (THF). During the reaction, the color of the reaction mixture changed from colorless to green. Analytically pure compound 1 was obtained by recrystallization of the dried reaction mixture from dichloromethane/pentane mixture to yield light-green crystals of 1 in nearly 70 % yield. Complex 1 was characterized by NMR spectroscopy, X-ray crystallography, and elemental analysis. The 1H NMR spectrum of 1 featured the absence of the singlet at d = 8.8 ppm arising from C5(H) of imidazolium salt IA, which confirmed the abnormal mode of the N-heterocyclic carbene binding to the copper(I) ion. The 13C NMR spectrum revealed a singlet at d = 154.8 ppm, which was assigned to the C-5 carbon resonance bound to the copper(I) center; this value was comparable to that of reported copper carbene complex 2, in which a metal-bound carbene carbon appeared at d = 159.4 ppm in the 13C NMR spectrum.[7a] Finally, the molecular structure determined by X-ray crystallography (see the Supporting Information) confirmed the atom connectivity of 1 as that depicted in Scheme 1. The geometry around the copper ion was linear, which highlighted the abnormal mode of N-heterocyclic carbene binding in 1. Herein, catalyst 1 was used as the organometallic catalyst to yield 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature in very short reaction times. Furthermore, the triazole was used as an organocatalyst, after in situ activation, for aza-Michael addition reactions. A number of methods with stoichiometric or catalytic amounts of Lewis acids, such as metal chlorides, chlorates, nitrates, acetates, and triflates, have been reported for the aza-Michael addition reaction.[8] As a proof of concept, we began the study by testing the catalytic activity of the in situ generated triazole as an organocatalyst for the aza-Michael addition reaction in the same reaction pot. We performed optimization studies by adopting click catalysis conditions with different azide substrates and catalysts 1 and 2; the N-methylaniline (6 a) and methyl acrylate substrates (7 a) were kept fixed for
Figure 2. A) Conversion of glycogen to glucose-1-phosphate in a consecutive manner, in which the action of the enzyme phosphorylase kinase produces the AGP, which itself subsequently acts as an enzyme for the conversion of glycogen to glucose-1-phosphate. B) Integration of organometallic catalysis with organocatalysis, in which the product of the first organometallic catalytic step acts as an organocatalyst for the next catalytic cycle.
This study demonstrates the integration of two types of catalysis, namely, organometallic catalysis and organocatalysis, in one reaction pot. In this process, we have used an abnormal N-heterocyclic carbene (aNHC)–copper-based organometallic catalyst in the first catalytic step, resulting in an organic product, which, in turn, is utilized as an organocatalyst (after activation) for the next catalytic process in a consecutive fashion in the same reaction pot (Figure 2 B). We have been able to establish this concept for a number of chemical transformations. As a part of our ongoing interest in developing catalysts from aNHCs,[7] complexes 1 and 2 (Figure 2 B) were used herein as organometallic catalysts. Catalyst 1 was prepared by following the synthetic method adopted for the preparation of 2[7a] (see the Supporting Information for details).
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methyl iodide in DMSO. Following this alkylation step, the use of 6 a and 7 a in the same reaction pot afforded the expected aza-Michael addition product 8 a in 81 % yield (Table 1, entry 3) after 5 h at 70 8C. The use of organometallic catalyst 2 instead of 1 also led to a similar yield of 8 a (Table 1, entry 4). When a control reaction was carried out with 1 mol % of the isolated triazolium salt as the organocatalyst in DMSO, it also led to a similar yield of the azaEntry Azide Catalyst Triazole, time, Triazolium salt, time [h], Time [h], yield [%] yield [%] yield of 8 a[b] [%] Michael addition product (85 %; Table 1, entry 5), reveal1 3a 1 4 a, 10 min, 99 –, –, – 5, 20[c] 2 – – 4 a, –, – –, –, – 5, 25[c,d] ing that the triazolium salt 3 3a 1 4 a, 10 min, 99 5 a, 12, 81 5, 81 acted as the organocatalyst for 4 3a 2 4 a, 10 min, 99 5 a, 12, 81 5, 81 the aza-Michael addition step. 5 – – –, –, – 5 a, –, – 5, 85[d] To check the generality of this 6 3b 1 4 b, 6 h, 99 5 b, 12, 75 4.5, 87 7 3c 1 4 c, 4 h, 99 5 c, 12, 70 4, 88 protocol, we also successfully 8 3a – –, –, – –, –, – 5, 9 optimized our study by starting 9 – 1 –, –, – –, –, – 5, 8[d] with sterically more demanding 10 – – –, –, – –, –, – 5, 10[d] [d,e] azide substrates (Table 1, en11 – – –, –, – 5 a’, –, – 5, 10 tries 6 and 7). The triazolium [a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), catalyst 1/2 (1 mg, 1 mol %), 10 min– salts 1-(2,6-dimethylphenyl)-36 h, 25 8C; DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a), 12 h, 90 8C; amine (100 equiv) and a,bmethyl-4-phenyl-1H-1,2,3-triaunsaturated carbonyl compound (120 equiv with respect to 5 a), 5–12 h, 70 8C. [b] Isolated yield of product after chromatography. [c] Reaction performed in neat conditions. [d] Reaction was carried out without phenylzol-3-ium (5 b) and 1-mesityl-3acetylene. [e] 5 a’ = 3-methyl-1,4,5-triphenyl-1H-1,2,3-triazol-3-ium iodide. methyl-4-phenyl-1H-1,2,3-triazol-3-ium (5 c) were produced from the organometallic catalysis step followed by salt formation; these products acted as the aza-Michael reaction step. The results of the optimizaorganocatalysts for the aza-Michael addition step in subsetion studies are shown in Table 1. quent reactions (Table 1, entries 6 and 7). The isolated yield The optimization study for the synthesis of b-ketoamine of the final product is above 85 % although the click catalytby one-pot integration of organometallic catalysis (click reic step takes longer time (4–6 h) in these cases (Table 1, enaction) with organocatalytic aza-Michael addition was achtries 6 and 7) because of the sterically demanding substituieved as follows: 1,4-Diphenyl-1H-1,2,3-triazole (4 a) was ents on the starting azide substrates. The total time required obtained in 99 % yield after 10 min (Table 1, entry 1) in the to obtain the final product after two consecutive catalytic presence of 1 mol % of 1 as the catalyst and phenyl azide steps increased from 17 to 22.5 h. From the optimization (3 a) with phenylacetylene as the substrates under solventstudies, it was clear that the desired compound 8 a was obfree conditions at room temperature. After the first organotained in high yield after performing multiple catalytic steps metallic catalysis step, triazole 4 a was formed in nearly in the same reaction pot by this protocol (Table 1). quantitative yield. We performed the aza-Michael reaction We also performed a number of control reactions in the same reaction pot by adding 6 a and 7 a to afford the (Table 1, entries 8–11) to understand the reaction sequence. expected product, methyl-3-(phenylamino)propanoate (8 a), First, the aza-Michael reaction was attempted in DMSO in in only 20 % yield after 5 h at 70 8C (Table 1, entry 1). The the presence of phenylacetylene and 3 a in the reaction in situ generated triazole acted as an organocatalyst and the medium to check if any unreacted click reaction substrates loading of triazole was maintained at 1 mol %. A similar obcatalyzed the aza-Michael step. However, it afforded the exservation was made when a control aza-Michael addition repected product of aza-Michael addition (Table 1, entry 8) in action was performed in a separate catalytic run by using only 9 % yield. In another control reaction, the aza-Michael isolated triazole under a catalyst loading of 1 mol % (25 %; step was attempted with 6 a and 7 a as substrates in the presTable 1, entry 2). To improve the yield of the aza-Michael ence of the catalyst 1 alone in DMSO under similar reaction reaction step, we increased the Lewis acidity of the triazole condition, which also led to a similar yield of the aza-MiC5 proton by converting the triazole into its corresponding chael addition product (Table 1, entry 9). This result clearly triazolium salt through N-alkylation in the presence of Table 1. Optimization studies for the integration of organometallic catalysis (click reaction) with organocatalysis (aza-Michael addition).[a]
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protocol worked when we applied ethyl acrylate and butyl demonstrates that the presence of the organometallic cataacrylate instead of methyl acrylate (7 a) to give the products lyst (1) alone in the reaction medium does not affect the in good yield (Scheme 2, compounds 8 i and 8 j). aza-Michael step. Subsequently, a blank reaction was atThe scope of the organocatalysis step was further extendtempted with only aza-Michael substrates 6 a and 7 a in ed for carrying out the multicomponent reaction (MCR) DMSO under similar reaction conditions; this resulted in beyond the aza-Michael addition reaction. The MCR stratonly about 10 % of aza-Michael product formation (Table 1, egy is an important class of reaction, in which three or more entry 10). All of these findings from the control experiments easily accessible components react in one pot to form made us confident that the first step was catalyzed by an ora single product, which incorporates essentially all of the ganometallic catalyst (1), whereas the last step was an orgamolecular frameworks of the starting materials.[9] The heternocatalytic step that required the presence of the product from the first catalytic cycle (Table 1, entry 3). In a prelimiocyclic scaffolds comprising 2,4,5-trisubstituted imidazoles nary effort to understand the mechanistic pathway for the can be synthesized from MCRs; this can result in comorganocatalytic transformation, it was anticipated that 1,4pounds with versatile pharmacological actions.[10] There has substituted 1,2,3-triazole with an acidic proton at the C-5 been enormous interest among synthetic chemists to develposition of the ring may initiate electrophilic activation of op synthetic methodologies for the construction of these the carbonyl moiety, as observed previously for imidazoleheterocyclic scaffolds, generally prepared by the reaction of based organocatalysts activating the carbonyl moiety.[8e,g,i] It a 1,2-diketone with an aldehyde and ammonium acetate in the presence of a protic or Lewis acid catalyst under microis evident from Table 1 that the C5 proton, by converting wave/ultrasonic/classical heating.[11] Most of these synthetic the triazole into its corresponding triazolium salt through Nalkylation, speeds up the aza-Michael addition reaction sigmethods suffer from drawbacks, such as laborious and comnificantly (compare Table 1, entries 1 and 3). To confirm the plex workup and purification procedures, the generation of role of the Lewis acidity of the C5 proton as an important significant amounts of waste materials, strongly acidic condifactor in catalysis, we designed consecutive catalysis with tions, the occurrence of side reactions, low yields, the use of a triazole in which the C5 proton was replaced with expensive and moisture-sensitive reagents/catalysts, special a phenyl group (5 a’) to afford the aza-Michael addition efforts for the preparation of the starting materials, and the use of auxiliary reagents. These drawbacks necessitate the product (Table 1, entry 11) in only 10 % yield. This clearly indicates that the presence of the C5 proton is very important for the organocatalytic reaction (5 a’; Table 1, entry 11). To check the broader substrate scope and generality of this protocol, a wide range of amines, including aromatic and aliphatic amines, were screened under these optimized reaction conditions (Table 1, entry 3). The results are summarized in Scheme 2. Several substituted aromatic amines were examined in the reaction with 7 a. For aromatic amines, the reactions with 6 a, aniline, and mphenylenediamine went smoothly to afford the desired products (Scheme 2, 8 a–c) in high yields. Imidazole and substituted imidazole survived under the reaction conditions (Scheme 2, compounds 8 d–f). Aliphatic amines, such as morpholine and benzylamine, were also successfully used to obtain good yields in the azaMichael reaction within the same reaction pot (Scheme 2, Scheme 2. Synthesis of b-ketoamine by integrating an organometallic click step with an organocatalytic azacompounds 8 g and 8 h). The Michael addition reaction within the same reaction pot.
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improvement of the methodolo- Table 2. Optimization of the one-pot integration of organometallic catalysis (click reaction) with an organoca[a] gies for a new catalytic proce- talytic MCR for the synthesis of 2,4,5-trisubstituted imidazole. dure leading to the convenient synthesis of 2,4,5-trisubstituted imidazole. The MCR was attempted to synthesize 2,4,5-trisubstituted imidazole by adding benzil (9), aldehyde, and ammonium acetate in a consecutive catalysis fashion in the same reaction Entry Azide Catalyst Triazole, time [min], Triazolium salt, time [h], Time [h], pot. In this reaction sequence, yield [%] yield [%] yield of 11 a[b] [%] we kept the first two steps ex- 1 3a 1 4 a, 10, 99 –, –, – 1, 37 actly the same as those depicted 2 – – 4 a, –, – –, –, – 1, 41[c] 3a 1 4 a, 10, 99 5 a, 12, 81 1, 91 earlier (Table 1 and Scheme 2) 3 – – –, –, – 5 a, –, – 1, 95[c] and the last step of aza-Michael 4 5 3a – –, –, – –, –, – 1, 8 condition was replaced with 6 – 1 –, –, – –, –, – 1, 5[c] MCR conditions. We performed 7 – – –, –, – –, –, – 1, 6[c] a number of control experi- [a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), 1 (1 mg, 1 mol %), 10 min, 25 8C; ments (Table 2) to make sure DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a; yield of 4 a is 99 %), 12 h, 90 8C; aldehyde that the reaction protocol fol- (100 equiv), benzil (100 equiv), and ammonium acetate (200 equiv with respect to 5 a; yield of 5 a is 81 %) in lowed similar working princi- the same reaction pot at 110 8C to maintain a 1 mol % catalytic loading of 5 a. [b] Isolated yield of product ples as those established for the after chromatography. [c] Reaction carried out without phenylacetylene. aza-Michael reaction coupled with a click reaction. The optimization study for the synthesis of 2,4,5-trisubstituted tallic catalyst (1), whereas the last step was an organocataimidazole by one-pot integration of organometallic catalysis lytic step that required the presence of the product from the (click reaction) with organocatalytic MCR was performed as first catalytic cycle (Table 2, entry 3). In this process, the follows: After the first step of organometallic catalysis yieldproduct of the click reaction acts as an organocatalyst for ed triazole 4 a quantitatively, we performed the MCR in the the MCR step to form the final product. same reaction pot by adding 9, benzaldehyde (10 a), and amTo find the broader scope of this reaction sequence, we monium acetate to afford the expected product, 2,4,5-tritested different types of aldehydes in the MCR step phenyl-1H-imidazole (Table 2, entry 1), in 37 % yield after (Scheme 3). The reactions of different substituted aromatic 1 h at 110 8C in DMSO. However, when we performed the reaction in the presence of isolated 4 a, we found that 11 a formed in 41 % (Table 2, entry 2) yield. Furthermore, increasing the Lewis acidity of 4 a by alkylation with methyl iodide (Table 2, entry 3), to form 5 a, significantly improved the yield of the final product to 91 %. A similar yield (95 %; Table 2, entry 4) was obtained when a control reaction was performed with 1 mol % of pure triazolium salt (5 a) as the organocatalyst in DMSO. The desired product 11 a was obtained in only 8 % yield when the reaction was performed without any catalyst 1 (Table 2, entry 5), but only in the presence of the substrates of the click reaction. In another control reaction, when the MCR step was attempted with 9, 10 a, and ammonium acetate as the substrates in the presence of catalyst 1 alone in DMSO under similar reaction conditions, this led to only about 5 % conversion in the MCR step (Table 2, entry 6). This result excludes the possibility of the involvement of catalyst 1 in the MCR step. Subsequently, a blank reaction was attempted with only MCR substrates 9, 10 a, and ammonium acetate in DMSO under similar reaction conditions; this resulted in only a trace amount of MCR product formation (6 %; Table 2, entry 7). Scheme 3. Synthesis of 2,4,5-trisubstituted imidazole by integrating an orAll of these findings from the control experiments made us ganometallic click step and an organocatalytic MCR in the same reaction pot. confident that the first step was catalyzed by an organome-
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aldehydes with either electron-withdrawing or -donating groups were effective in yielding the corresponding imidazole derivatives (Scheme 3). During this one-pot integration, it was observed that different functional groups survived under the reaction conditions, resulting in a library of 2,4,5trisubstituted imidazoles (Scheme 3). To broaden the scope of the methodology adopted during this consecutive integration of organometallic and organocatalysis, we show that it is possible to synthesize a variety of 1,4-dihydropyrimidinones. The 1,4-dihydropyrimidinone moiety has versatile pharmacophoric features and exhibits a broad range of biological activities, such as antibacterial, anti-inflammatory, fungicidal, calcium channel modulator, a1a-adrenergic receptor antagonist, mitotic kinesin inhibitor, and anticancer.[12] Therefore, there has been long-lasting interest from synthetic chemists towards the development of newer methodologies for this class of compounds, which comprises a three-component reaction involving an aldehyde, a b-ketoester/b-diketone, and urea.[13] Similar to the previous study, we also performed a number of control experiments (Table 3) to support the consecutive catalysis protocol for the synthesis of 1,4-dihydropyrimidinones in one pot. The optimization study for the synthesis of 1,4-dihydropyrimidinones by one-pot integration of organometallic catalysis (click reaction) with an organocatalytic MCR was achieved as follows: After the first step of organometallic catalysis yielded triazole 4 a quantitatively, we performed the MCR in the same reaction pot by adding 10 a, urea, and ethyl acetoacetate to afford the expected product, 1,4-dihydropyrimidinone (Table 3, entry 1), in 24 % yield after 1.5 h at 110 8C in DMSO. When we performed this reaction in the presence of 4 a isolated in a separate catalytic run, we found
that 14 a was formed in a similar yield (29 %; Table 3, entry 2). Furthermore, increasing the Lewis acidity of 4 a by alkylation with methyl iodide (Table 3, entry 3) to give 5 a significantly improved the yield of the final product to 92 %. A similar observation was obtained when a control reaction was performed with 1 mol % of the isolated triazolium salt as a catalyst in DMSO in the MCR (95 %; Table 3, entry 4). The desired product 14 a was obtained in only 8 % yield when the reaction was carried out without any catalyst 1 (Table 3, entry 5), in the presence of the substrates of the click reaction. In another control reaction, when the MCR step was attempted with 10 a, urea, and ethyl acetoacetate as substrates in the presence of catalyst 1 in DMSO under similar reaction conditions, it led to a similar yield (5 %) of the MCR step (Table 3, entry 6). Subsequently, a blank reaction was attempted with only MCR substrates 10 a, urea, and ethyl acetoacetate in DMSO under similar reaction conditions; this resulted in only trace amounts of MCR product formation (7 %; Table 3, entry 7). In this process, the product of the click reaction also acts as an organocatalyst for the MCR step to form the final product. All of these findings from the control experiments made us confident that the first step was catalyzed by an organometallic catalyst (1), whereas the last step was an organocatalytic step that required the presence of the product from the first catalytic cycle (Table 3, entry 3). From these studies, it was clear that the desired compound 14 a was obtained in high yield after performing multiple catalytic steps in the same reaction pot in a consecutive way. Under the standardized condition, various functionalized aldehydes were treated with b-dicarbonyl and urea to obtain the corresponding 1,4-dihydropyrimidinones. The results of this reaction protocol are summarized in Scheme 4. In all cases, the reaction proceeded smoothly to afford the corresponding 1,4-dihydropyrimidiTable 3. Optimization of the one-pot integration of organometallic catalysis (click reaction) with organocatalysis (MCR), leading to the synthesis of 1,4-dihydropyrimidinones.[a] nones in excellent yield (83– 93 %) after very short reaction times. The reaction is compatible with a variety of functional groups, such as halogens and alkoxy groups. The reaction leads to excellent yields for aldehydes containing electronwithdrawing and -donating Entry Azide Catalyst Triazole, time [min], Triazolium salt, time [h], Time [h], groups. Both the b-keto ester [b] yield [%] yield [%] yield of 14 a [%] and b-diketones react smoothly 1 3a 1 4 a, 10, 99 –, –, – 1.5, 24 with urea/thiourea and alde[c] 2 – – 4 a, –, – –, –, – 1.5, 29 hyde to give the corresponding 3 3a 1 4 a, 10, 99 5 a, 12, 81 1.5, 92 [c] dihydropyrimidinone derivative. 4 – – –, –, – 5 a, –, – 1.5, 95 5 6 7
3a – –
– 1 –
–, –, – –, –, – –, –, –
–, –, – –, –, – –, –, –
1.5, 8 1.5, 5[c] 1,5, 7[c]
[a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), compound 1 (1 mg, 1 mol %), 10 min, 25 8C; DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a; yield of 4 a is 99 %), 12 h, 90 8C; aldehyde (100 equiv), urea (100 equiv), and 1,3-dicarbonyl compound (100 equiv with respect to 5 a; yield of 5 a is 81 %) in the same reaction pot at 110 8C to maintain a 1 mol % catalytic loading of 5 a. [b] Yield of product isolated after chromatography. [c] Reaction carried out without phenylacetylene.
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Conclusion We have been able to integrate organometallic catalysis and organocatalysis in the same reac-
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tained by using Q-Tof Micromass, Waters, instrument. Elemental analyses were performed on a PerkinElmer 2400, Series II, CHNS/O analyzer. The melting points were measured in sealed glass tubes on a Bchi B-540 melting point apparatus. Analytical TLC was performed on a Merck 60 F254 silica gel plate (0.25 mm thickness). NMR spectra were recorded on a JEOL ECS 400 MHz spectrometer and on a Bruker Avance 500 MHz spectrometer. All chemical shifts were reported in ppm by using tetramethylsilane as a reference. Chemical shifts (d) downfield from the reference standard were assigned positive values. Salt IA (Scheme 1),[7] 3 a,[14] 2,6-dimethylazide,[14] and mesitylazide[14] were prepared according to procedures reported in the literature.
Synthesis of complex 1 Under an argon atmosphere, THF (10 mL) was added at 80 8C to a mixture of 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenyl-imidazolium salt (308 mg, 0.50 mmol), copper(I) bromide (72 mg, 0.5 mmol), and potassium bis(trimethylsilyl)amide (200 mg, 1 mmol). After 30 min at 80 8C, the mixture was warmed to room temperature and stirred for 12 h. Solvent was evaporated under reduced pressure and the residue was extracted with dichloromethane (3 20 mL). The analytically pure, light-green compound was obtained (240 mg, 0.41 mmol, 70 %) by recrystallization from CH2Cl2/pentane. M.p. 223–225 8C; 1H NMR (400 MHz, CDCl3, 25 8C): d = 7.66 (t, J = 8.4 Hz, 1 H), 7.55 (t, J = 8 Hz, 1 H), 7.40–7.38 (m, 8 H), 7.25–7.23 (m, 2 H), 7.16 (t, J = 8.4 Hz, 2 H), 6.95 (d, J = 7.6 Hz, 2 H), 2.52–2.49 (m, 2 H), 2.44–2.38 (m, 2 H), 1.43 (d, J = 6.9 Hz, 6 H), 0.93 (d, J = 6.8 Hz, 6 H), 0.86 ppm (t, J = 6.1 Hz, 12 H); 13C NMR (100 MHz, [D6]DMSO, 25 8C): d = 154.8, 146.9, 144.9, 114.5, 138.7, 133.1, 132.7, 132.5, 130.9, 130.7, 129.3, 129.0, 128.7, 128.4, 126.0, 125.9, 124.8, 120.6, 28.6, 28.2, 24.5, 23.8, 23.3, 22.8 ppm; elemental analysis calcd (%) for C39H44BrCuN2 : C 68.46, H 6.48, N 4.09; found: C 69.30, H 6.88, N 4.17.
Scheme 4. Synthesis of 1,4-dihydropyrimidinones by integrating an organometallic click step followed by MCR conditions in the same reaction pot.
Synthesis of 5a’
tion pot, in which the product of the first catalytic cycle acts as the catalyst for the second catalytic step. Thus, in this protocol, the catalyst is generated in situ. We applied this onepot methodology to perform different types of reaction sequences, which established the scope of this concept in various reaction protocols. In the first step, the organometallic catalyst acted as an efficient catalyst for the click reaction to provide a triazole, which, after activation through an alkylation step, acted as an efficient organocatalyst for an aza-Michael addition reaction, leading to b-aminocarbonyl compounds. For MCRs, these led to the synthesis of a variety of 2,4,5-trisubstituted imidazoles and 1,4-dihydropyrimidinone compounds in a consecutive fashion within the same reaction pot. Thus, unlike previous multicatalytic processes in which the substrates of the first catalytic cycle act as the substrate for next catalytic cycle, we have been able to develop a process in which the product acts as a catalyst for the next cycle to mimic the function of certain enzymes.
Diphenylacetylene (1.73 mmol), 3 a (1.57 mmol), and 2 (10 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction was allowed to proceed at 70 8C for 5 h. After the appropriate period of time, the reaction was quenched by dissolving the reaction mixture in dichloromethane (10 mL). Subsequently, a simple aqueous workup was carried out, and the crude product was purified by flash chromatography on silica gel to yield NMR-pure 1,4,5-triphenyl-1H-1,2,3-triazole (4 a’; 85 % yield). Subsequently, 1,4,5-triphenyl-1H-1,2,3-triazole (4 a’; 1 equiv) was dissolved in acetonitrile (10 mL) and methyl iodide (10 equiv) was added. Then the mixture was heated to reflux for 24 h. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (15 mL) and precipitated by the addition of ethyl ether (50 mL). The yellow precipitate was collected by filtration to give product 5 a’ as a brown solid after evaporation under reduced pressure (82 % yield). M.p. 210–212 8C; 1 H NMR ([D6]DMSO, 500 MHz, 25 8C): d = 7.66–7.59 (m, 10 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 8 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 2 H), 4.34 ppm (s, 3 H); 13C NMR (CDCl3, 125 MHz, 25 8C): d = 141.19, 141.17, 141.0, 134.1, 131.5, 131.04, 130.98, 130.7, 129.5, 129.3, 128.9, 126.4, 122.3, 122.1, 39.5 ppm; HRMS (ESI): m/z: calcd for C21H18N3 : 312.1495 [M I] + ; found: 312.1525.
Experimental Section
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a as a solid product (yield of 4 a is 99 %). After complete formation of product 4 a, the alkylation step was done in same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to give 3-methyl-1,4-diphenyl-1H-1,2,3-triazol-3-ium iodide (5 a; 81 % yield). The aza-Michael addition reaction was carried out by adding amine (100 equiv) and a,b-unsaturated carbonyl compound (120 equiv with respect to 5 a (considered to be 80 % yield)) in the same pot at
General Procedure for the Synthesis of b-Ketoamine by Integrating an Organometallic Click Step and Organocatalytic Aza-Michael Addition in the Same Reaction Pot
General considerations All manipulations were performed under a dry, oxygen-free atmosphere (argon) by using standard Schlenk techniques or inside a glove box maintained below 0.1 ppm of O2 and H2O, utilizing oven-dried (130 8C) glassware after evacuation that was hot prior to use. All solvents were distilled from Na/benzophenone prior to use. All chemicals were purchased from Sigma–Aldrich and used as received. The HRMS data were ob-
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70 8C to maintain 1 mol % catalytic loading of 5 a. For compound 8 h, the aza-Michael addition reaction proceeded by adding amine (100 equiv) and a,b-unsaturated carbonyl compound (240 equiv with respect to 5 a) in the same pot at 70 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted in CH2Cl2 and purified by flash column chromatography (hexane/ethyl acetate) to obtain the corresponding aza-Michael addition product. All reported yields were those of product isolated and were an average of at least two runs.
[2] [3] [4] [5]
General Procedure for the Synthesis of 2,4,5-Trisubstituted Imidazole by Integrating an Organometallic Click Step and Organocatalytic MCR in the Same Reaction Pot
[6] [7]
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a in quantitative yield. After complete formation of product 4 a, the alkylation step was performed in the same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to give 5 a (81 % yield). The MCR was further carried out by adding aldehyde (100 equiv), benzil (100 equiv), and ammonium acetate (200 equiv with respect to 5 a) in the same pot at 110 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted with CH2Cl2 and was purified by recrystallization from EtOH. All reported yields were those of product isolated and were an average of at least two runs.
[8]
General Procedure for the Synthesis of 1,4-Dihydropyrimidinones by Integrating an Organometallic Click Step and Organocatalytic MCR in the Same Reaction Pot [9]
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a. After complete formation of product 4 a, the alkylation step was performed in the same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to obtain 5 a (81 % yield). The MCR was further carried out by adding aldehyde (100 equiv), urea (100 equiv), and 1,3-dicarbonyl compound (100 equiv with respect to 5 a) in the same reaction pot at 110 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted with CH2Cl2 and purified by recrystallization from EtOH. All reported yields were those of product isolated and were an average of at least two runs.
[10]
[11]
Acknowledgements S.K.M. thanks SERB (DST), New Delhi for financial support. S.C.S. thanks the UGC, New Delhi, for a research fellowship. S.R.R. thanks the CSIR for an RA fellowship. We also acknowledge the NMR spectroscopy and X-ray facilities of IISER-Kolkata. [12] [1] a) S. T. Scroggins, Y. Chi, J. M. J. Frchet, Angew. Chem. Int. Ed. 2010, 49, 2393 – 2396; Angew. Chem. 2010, 122, 2443 – 2446; b) J. Jiang, X. Guan, S. Liu, B. Ren, X. Ma, X. Guo, F. Lv, X. Wu, W. Hu, Angew. Chem. Int. Ed. 2013, 52, 1539 – 1542; Angew. Chem. 2013, 125, 1579 – 1582; c) F. Nahra, Y. Mac, D. Lambin, O. Riant, Angew. Chem. Int. Ed. 2013, 52, 3208 – 3212; Angew. Chem. 2013, 125, 3290 – 3294; d) Y. Ye, M. S. Sanford, J. Am. Chem. Soc. 2012, 134, 9034 – 9037; e) L. Ren, T. Lei, J.-X. Ye, L.-Z. Gong, Angew. Chem. Int. Ed. 2012, 51, 771 – 774; Angew. Chem. 2012, 124, 795 – 798; f) M. Terada, Y. Toda, Angew. Chem. Int. Ed. 2012, 51, 2093 – 2097; Angew. Chem. 2012, 124, 2135 – 2139; g) S. Guo, Y. Xie, X.
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[13]
[14]
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Hu, C. Xia, H. Huang, Angew. Chem. Int. Ed. 2010, 49, 2728 – 2731; Angew. Chem. 2010, 122, 2788 – 2791; h) D. Fuchs, G. Rousseau, L. Diab, U. Gellrich, B. Breit, Angew. Chem. Int. Ed. 2012, 51, 2178 – 2182; Angew. Chem. 2012, 124, 2220 – 2224. A. S. Goldman, A. H. Roy, Z. Huang, R. Ahuja, W. Schinski, M. Brookhart, Science 2006, 312, 257 – 260. D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77 – 80. G. Dong, P. Teo, Z. K. Wickens, R. H. Grubbs, Science 2011, 333, 1609 – 1612. A. Mukherjee, S. Nembenna, T. K. Sen, S. P. Sarish, P. K. Ghorai, H. Ott, D. Stalke, S. K. Mandal, H. W. Roesky, Angew. Chem. Int. Ed. 2011, 50, 3968 – 3972; Angew. Chem. 2011, 123, 4054 – 4058. D. Enders, M. R. M. Httl, C. Grondal, G. Raabe, Nature 2006, 441, 861 – 863. a) S. C. Sau, S. Raha Roy, T. K. Sen, D. Mullangi, S. K. Mandal, Adv. Synth. Catal. 2013, 355, 2982 – 2991; b) T. K. Sen, S. C. Sau, A. Mukherjee, A. Modak, S. K. Mandal, D. Koley, Chem. Commun. 2011, 47, 11972 – 11974; c) S. C. Sau, S. Santra, T. K. Sen, S. K. Mandal, D. Koley, Chem. Commun. 2012, 48, 555 – 557; d) T. K. Sen, S. C. Sau, A. Mukherjee, P. K. Hota, S. K. Mandal, B. Maity, D. Koley, Dalton Trans. 2013, 42, 14253 – 14260. a) G. Bartoli, M. Bosco, E. Marcantoni, M. Pertrini, L. Sambri, E. Torregiani, J. Org. Chem. 2001, 66, 9052 – 9055; b) L. Fadini, A. Tongi, Chem. Commun. 2003, 30 – 32; c) N. Srivastava, B. K. Banik, J. Org. Chem. 2003, 68, 2109 – 2111; d) N. Yamagiwa, H. Qin, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 13419 – 13427; e) S. Raha Roy, A. K. Chakraborti, Org. Lett. 2010, 12, 3866 – 3869; f) H.-M. Yang, L. Li, F. Li, K.-Z. Jiang, J.-Y. Shang, G.-Q. Lai, L.-W. Xu, Org. Lett. 2011, 13, 6508 – 6511; g) Z. Yacob, J. Shah, J. Leistner, J. Liebscher, Synlett 2008, 2342 – 2344; h) Q. Kang, Y. Zhang, Org. Biomol. Chem. 2011, 9, 6715 – 6720; i) A. Aggarwal, N. L. Lancaster, A. R. Sethi, T. Welton, Green Chem. 2002, 4, 517 – 520. a) E. J. Corey, D. A. Clark, G. Goto, A. Marfat, C. Mioskowski, B. Sameulson, S. Hammerson, J. Am. Chem. Soc. 1980, 102, 1436 – 1439; b) J. R. Luly, N. Yi, J. Soderquist, H. Stein, J. Cohen, T. J. Perun, J. J. Plattner, J. Med. Chem. 1987, 30, 1609 – 1616; c) A. Dçmling, Chem. Rev. 2006, 106, 17 – 89; d) P. Wipf, C. R. J. Stephenson, K. Okumura, J. Am. Chem. Soc. 2003, 125, 14694 – 14695; e) S. Gandhi, B. List, Angew. Chem. Int. Ed. 2013, 52, 2573 – 2576; Angew. Chem. 2013, 125, 2633 – 2636. a) J. G. Lombardino, E. H. Wiseman, J. Med. Chem. 1974, 17, 1182 – 118; b) L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey, S. M. Hannick, L. Gherke, R. B. Credo, Y. H. Hui, K. Marsh, R. Warner, J. Y. Lee, N. Zielinsky-Mozng, D. Frost, S. H. Rosenberg, H. L. Sham, J. Med. Chem. 2002, 45, 1697 – 1711. a) R. B. Sparks, A. P. Combs, Org. Lett. 2004, 6, 2473 – 2475; b) J. Boehm, J. Smietana, M. Sorenson, R. Garigipati, T. Gallagher, P. Sheldrake, J. Bradbeer, A. Badger, J. Laydon, J. Lee, L. Hillegass, D. Griswold, J. Breton, M. Chabot-Fletcher, J. Adams, J. Med. Chem. 1996, 39, 3929 – 3937; c) M. Bilodeau, A. Cunningham, J. Org. Chem. 1998, 63, 2800 – 2801; d) S. E. Wolkenberg, D. D. Wisnoski, W. H. Leister, Y. Wang, Z. Zhao, C. W. Lindsley, Org. Lett. 2004, 6, 1453 – 1456; e) F. Ijaz, S. Noreen, M. N. Khan, S. Naureen, M. A. Khan, M. A. Munawar, A. M. R. Bernardino, Asian J. Chem. 2012, 24, 5114 – 5116; f) S. Raha Roy, P. S. Jadhavar, K. Seth, K. K. Sharma, A. K. Chakraborti, Synthesis 2011, 2261 – 2267. a) M. Kidwai, S. Saxena, M. K. R. Khan, S. S. Thukral, Eur. J. Med. Chem. 2005, 40, 816 – 819; b) P. Kumar, B. R. Sankar, G. Nasir, R. B. Baig, S. Chandrashekaran, Eur. J. Med. Chem. 2009, 44, 4192 – 4198. a) R. O. M. A. De Souza, E. T. da Penha, H. M. S. Milagre, S. J. Garden, P. M. Esteves, M. N. Eberlin, O. A. C. Antunes, Chem. Eur. J. 2009, 15, 9799 – 9804; b) Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386 – 16387; c) C. O. Kappe, Acc. Chem. Res. 2000, 33, 879 – 888. S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov, V. V. Fokin, Org. Lett. 2010, 12, 4217 – 4219. Received: April 11, 2014 Published online: August 14, 2014
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One-Pot Consecutive Catalysis by Integrating Organometallic Catalysis with Organocatalysis Samaresh Chandra Sau, Sudipta Raha Roy, and Swadhin K. Mandal*[a] Dedicated to Prof. Herbert W. Roesky on the occasion of his 79th birthday
Abstract: The present study integrates two types of catalysis, namely, organometallic catalysis and organocatalysis in one reaction pot. In this process, the product of the first catalytic cycle acts as catalytic component for next catalytic cycle. The abnormal N-heterocyclic carbene–copper-based organometallic catalyst acts as an efficient catalyst for a click reaction to provide triazole, which, in turn, acts as an efficient organocatalyst for different organic transformations, for example, aza-Michael addition and multicomponent reactions, in a consecutive fashion in the same reaction pot.
Introduction
next catalytic cycle within the same reaction pot (Figure 1 C).[4] Recently, we demonstrated a new synthetic route that combined two different catalytic centers in the same heterobimetallic catalyst by assembling zirconium and calcium moieties through an oxygen center, which acted in a dual fashion by catalyzing the intramolecular hydroamination reaction of primary and secondary aminoalkenes activated by calcium and zirconium centers, respectively (Figure 1 D).[5] Enders and co-workers controlled four stereocenters in a triple-cascade organocatalytic reaction, in which two substrates, A and B, reacted with each other to generate a new substrate, E, which further reacted with the third sub-
In recent years, there have been emerging trends in integrating multiple catalytic cycles in one pot.[1] In these multicatalytic processes, the product(s) of the first catalytic cycle has been used as substrate(s) of the subsequent catalytic cycle. In this way, the concepts of “tandem”, “merged”, “cascade”, or “relay” catalysis were introduced.[1–6] For example, Goldman and co-workers showed the development of highly productive, well-defined, tandem catalytic systems for the metathesis of n-alkanes.[2] A pincer iridium complex results in alkane dehydrogenation to produce an olefin in the first step, which subsequently acts as a substrate for the olefin metathesis process by using a Schrock-type metathesis catalyst in the same reaction pot in tandem fashion (Figure 1 A). MacMillan and Nicewicz merged photoredox catalysis with organocatalysis for direct asymmetric alkylation of aldehydes, in which two different catalysts (catalysts C and D) in the same reaction pot acted on two different substrates (substrates A and B), simultaneously leading to the final product (Figure 1 B).[3] Grubbs and co-workers showed a more direct approach with the use of a triple relay catalysis system that coupled palladium-catalyzed oxidation, acid-catalyzed hydrolysis, and ruthenium-catalyzed reduction cycles, in which the product of one reaction acted as the substrate for the
Figure 1. Recently reported multicatalytic processes.[2–6]
[a] S. C. Sau,+ Dr. S. R. Roy,+ Dr. S. K. Mandal Department of Chemical Sciences Indian Institute of Science Education and Research-Kolkata, Mohanpur 741252 (India) E-mail: [email protected] Homepage: http://www.iiserkol.ac.in/ ~ swadhin.mandal/index.htm
strate, C, present in the same reaction pot (Figure 1 E).[6] In this way, the development of an asymmetric, organocatalytic, triple-cascade reaction for the synthesis of tetrasubstituted cyclohexene carbaldehydes was possible.[6] In these catalytic processes (Figure 1 A, B, C, and E), the first catalytic step generates the product, which acts as a sub-
[+] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402363.
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Keywords: domino reactions · multicomponent reactions · one-pot synthesis · organocatalysis · organometallic catalysis
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Results and Discussion
strate for the next catalytic cycle. However, in none of these processes has the product of the first catalytic cycle been used as a catalyst for the next cycle. Interestingly, many biological processes utilize a catalytic array of reactions in which the product of the first process acts as a catalyst (enzyme) for the next process. For example, muscle cells respond to epinephrine (adrenaline) by breaking down glycogen into glucose, thereby providing the source of energy for our muscular activity. The breakdown of glycogen is catalyzed by the enzyme glycogen phosphorylase. In this process, the first enzyme, phosphorylage kinase, acts on glycogen phosphorylase to generate the activated glycogen phosphorylase (AGP; Figure 2 A) and the in situ generated AGP then acts as an enzyme for the next biochemical reaction to catalyze the conversion of glycogen into gluocose-1-phosphate. Thus, in this particular process, AGP is the product of the first catalytic (enzymatic) process, which itself acts as the catalyst (enzyme) for the second transformation in a consecutive fashion (Figure 2 A).
We recently reported the catalytic activity of complex 2 in the Huisgen cycloaddition of azides and alkynes at room temperature.[7a] As part of our continuing interest in developing catalysts with aNHCs,[7] imidazolium salt IA (Scheme 1) was employed herein as an aNHC precursor to
Scheme 1. Synthetic route leading to aNHC copper(I) complex 1.
prepare copper(I) bromo complex 1. Complex 1 was prepared by treatment of IA with potassium bis(trimethylsilyl)amide and copper bromide in tetrahydrofuran (THF). During the reaction, the color of the reaction mixture changed from colorless to green. Analytically pure compound 1 was obtained by recrystallization of the dried reaction mixture from dichloromethane/pentane mixture to yield light-green crystals of 1 in nearly 70 % yield. Complex 1 was characterized by NMR spectroscopy, X-ray crystallography, and elemental analysis. The 1H NMR spectrum of 1 featured the absence of the singlet at d = 8.8 ppm arising from C5(H) of imidazolium salt IA, which confirmed the abnormal mode of the N-heterocyclic carbene binding to the copper(I) ion. The 13C NMR spectrum revealed a singlet at d = 154.8 ppm, which was assigned to the C-5 carbon resonance bound to the copper(I) center; this value was comparable to that of reported copper carbene complex 2, in which a metal-bound carbene carbon appeared at d = 159.4 ppm in the 13C NMR spectrum.[7a] Finally, the molecular structure determined by X-ray crystallography (see the Supporting Information) confirmed the atom connectivity of 1 as that depicted in Scheme 1. The geometry around the copper ion was linear, which highlighted the abnormal mode of N-heterocyclic carbene binding in 1. Herein, catalyst 1 was used as the organometallic catalyst to yield 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature in very short reaction times. Furthermore, the triazole was used as an organocatalyst, after in situ activation, for aza-Michael addition reactions. A number of methods with stoichiometric or catalytic amounts of Lewis acids, such as metal chlorides, chlorates, nitrates, acetates, and triflates, have been reported for the aza-Michael addition reaction.[8] As a proof of concept, we began the study by testing the catalytic activity of the in situ generated triazole as an organocatalyst for the aza-Michael addition reaction in the same reaction pot. We performed optimization studies by adopting click catalysis conditions with different azide substrates and catalysts 1 and 2; the N-methylaniline (6 a) and methyl acrylate substrates (7 a) were kept fixed for
Figure 2. A) Conversion of glycogen to glucose-1-phosphate in a consecutive manner, in which the action of the enzyme phosphorylase kinase produces the AGP, which itself subsequently acts as an enzyme for the conversion of glycogen to glucose-1-phosphate. B) Integration of organometallic catalysis with organocatalysis, in which the product of the first organometallic catalytic step acts as an organocatalyst for the next catalytic cycle.
This study demonstrates the integration of two types of catalysis, namely, organometallic catalysis and organocatalysis, in one reaction pot. In this process, we have used an abnormal N-heterocyclic carbene (aNHC)–copper-based organometallic catalyst in the first catalytic step, resulting in an organic product, which, in turn, is utilized as an organocatalyst (after activation) for the next catalytic process in a consecutive fashion in the same reaction pot (Figure 2 B). We have been able to establish this concept for a number of chemical transformations. As a part of our ongoing interest in developing catalysts from aNHCs,[7] complexes 1 and 2 (Figure 2 B) were used herein as organometallic catalysts. Catalyst 1 was prepared by following the synthetic method adopted for the preparation of 2[7a] (see the Supporting Information for details).
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methyl iodide in DMSO. Following this alkylation step, the use of 6 a and 7 a in the same reaction pot afforded the expected aza-Michael addition product 8 a in 81 % yield (Table 1, entry 3) after 5 h at 70 8C. The use of organometallic catalyst 2 instead of 1 also led to a similar yield of 8 a (Table 1, entry 4). When a control reaction was carried out with 1 mol % of the isolated triazolium salt as the organocatalyst in DMSO, it also led to a similar yield of the azaEntry Azide Catalyst Triazole, time, Triazolium salt, time [h], Time [h], yield [%] yield [%] yield of 8 a[b] [%] Michael addition product (85 %; Table 1, entry 5), reveal1 3a 1 4 a, 10 min, 99 –, –, – 5, 20[c] 2 – – 4 a, –, – –, –, – 5, 25[c,d] ing that the triazolium salt 3 3a 1 4 a, 10 min, 99 5 a, 12, 81 5, 81 acted as the organocatalyst for 4 3a 2 4 a, 10 min, 99 5 a, 12, 81 5, 81 the aza-Michael addition step. 5 – – –, –, – 5 a, –, – 5, 85[d] To check the generality of this 6 3b 1 4 b, 6 h, 99 5 b, 12, 75 4.5, 87 7 3c 1 4 c, 4 h, 99 5 c, 12, 70 4, 88 protocol, we also successfully 8 3a – –, –, – –, –, – 5, 9 optimized our study by starting 9 – 1 –, –, – –, –, – 5, 8[d] with sterically more demanding 10 – – –, –, – –, –, – 5, 10[d] [d,e] azide substrates (Table 1, en11 – – –, –, – 5 a’, –, – 5, 10 tries 6 and 7). The triazolium [a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), catalyst 1/2 (1 mg, 1 mol %), 10 min– salts 1-(2,6-dimethylphenyl)-36 h, 25 8C; DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a), 12 h, 90 8C; amine (100 equiv) and a,bmethyl-4-phenyl-1H-1,2,3-triaunsaturated carbonyl compound (120 equiv with respect to 5 a), 5–12 h, 70 8C. [b] Isolated yield of product after chromatography. [c] Reaction performed in neat conditions. [d] Reaction was carried out without phenylzol-3-ium (5 b) and 1-mesityl-3acetylene. [e] 5 a’ = 3-methyl-1,4,5-triphenyl-1H-1,2,3-triazol-3-ium iodide. methyl-4-phenyl-1H-1,2,3-triazol-3-ium (5 c) were produced from the organometallic catalysis step followed by salt formation; these products acted as the aza-Michael reaction step. The results of the optimizaorganocatalysts for the aza-Michael addition step in subsetion studies are shown in Table 1. quent reactions (Table 1, entries 6 and 7). The isolated yield The optimization study for the synthesis of b-ketoamine of the final product is above 85 % although the click catalytby one-pot integration of organometallic catalysis (click reic step takes longer time (4–6 h) in these cases (Table 1, enaction) with organocatalytic aza-Michael addition was achtries 6 and 7) because of the sterically demanding substituieved as follows: 1,4-Diphenyl-1H-1,2,3-triazole (4 a) was ents on the starting azide substrates. The total time required obtained in 99 % yield after 10 min (Table 1, entry 1) in the to obtain the final product after two consecutive catalytic presence of 1 mol % of 1 as the catalyst and phenyl azide steps increased from 17 to 22.5 h. From the optimization (3 a) with phenylacetylene as the substrates under solventstudies, it was clear that the desired compound 8 a was obfree conditions at room temperature. After the first organotained in high yield after performing multiple catalytic steps metallic catalysis step, triazole 4 a was formed in nearly in the same reaction pot by this protocol (Table 1). quantitative yield. We performed the aza-Michael reaction We also performed a number of control reactions in the same reaction pot by adding 6 a and 7 a to afford the (Table 1, entries 8–11) to understand the reaction sequence. expected product, methyl-3-(phenylamino)propanoate (8 a), First, the aza-Michael reaction was attempted in DMSO in in only 20 % yield after 5 h at 70 8C (Table 1, entry 1). The the presence of phenylacetylene and 3 a in the reaction in situ generated triazole acted as an organocatalyst and the medium to check if any unreacted click reaction substrates loading of triazole was maintained at 1 mol %. A similar obcatalyzed the aza-Michael step. However, it afforded the exservation was made when a control aza-Michael addition repected product of aza-Michael addition (Table 1, entry 8) in action was performed in a separate catalytic run by using only 9 % yield. In another control reaction, the aza-Michael isolated triazole under a catalyst loading of 1 mol % (25 %; step was attempted with 6 a and 7 a as substrates in the presTable 1, entry 2). To improve the yield of the aza-Michael ence of the catalyst 1 alone in DMSO under similar reaction reaction step, we increased the Lewis acidity of the triazole condition, which also led to a similar yield of the aza-MiC5 proton by converting the triazole into its corresponding chael addition product (Table 1, entry 9). This result clearly triazolium salt through N-alkylation in the presence of Table 1. Optimization studies for the integration of organometallic catalysis (click reaction) with organocatalysis (aza-Michael addition).[a]
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protocol worked when we applied ethyl acrylate and butyl demonstrates that the presence of the organometallic cataacrylate instead of methyl acrylate (7 a) to give the products lyst (1) alone in the reaction medium does not affect the in good yield (Scheme 2, compounds 8 i and 8 j). aza-Michael step. Subsequently, a blank reaction was atThe scope of the organocatalysis step was further extendtempted with only aza-Michael substrates 6 a and 7 a in ed for carrying out the multicomponent reaction (MCR) DMSO under similar reaction conditions; this resulted in beyond the aza-Michael addition reaction. The MCR stratonly about 10 % of aza-Michael product formation (Table 1, egy is an important class of reaction, in which three or more entry 10). All of these findings from the control experiments easily accessible components react in one pot to form made us confident that the first step was catalyzed by an ora single product, which incorporates essentially all of the ganometallic catalyst (1), whereas the last step was an orgamolecular frameworks of the starting materials.[9] The heternocatalytic step that required the presence of the product from the first catalytic cycle (Table 1, entry 3). In a prelimiocyclic scaffolds comprising 2,4,5-trisubstituted imidazoles nary effort to understand the mechanistic pathway for the can be synthesized from MCRs; this can result in comorganocatalytic transformation, it was anticipated that 1,4pounds with versatile pharmacological actions.[10] There has substituted 1,2,3-triazole with an acidic proton at the C-5 been enormous interest among synthetic chemists to develposition of the ring may initiate electrophilic activation of op synthetic methodologies for the construction of these the carbonyl moiety, as observed previously for imidazoleheterocyclic scaffolds, generally prepared by the reaction of based organocatalysts activating the carbonyl moiety.[8e,g,i] It a 1,2-diketone with an aldehyde and ammonium acetate in the presence of a protic or Lewis acid catalyst under microis evident from Table 1 that the C5 proton, by converting wave/ultrasonic/classical heating.[11] Most of these synthetic the triazole into its corresponding triazolium salt through Nalkylation, speeds up the aza-Michael addition reaction sigmethods suffer from drawbacks, such as laborious and comnificantly (compare Table 1, entries 1 and 3). To confirm the plex workup and purification procedures, the generation of role of the Lewis acidity of the C5 proton as an important significant amounts of waste materials, strongly acidic condifactor in catalysis, we designed consecutive catalysis with tions, the occurrence of side reactions, low yields, the use of a triazole in which the C5 proton was replaced with expensive and moisture-sensitive reagents/catalysts, special a phenyl group (5 a’) to afford the aza-Michael addition efforts for the preparation of the starting materials, and the use of auxiliary reagents. These drawbacks necessitate the product (Table 1, entry 11) in only 10 % yield. This clearly indicates that the presence of the C5 proton is very important for the organocatalytic reaction (5 a’; Table 1, entry 11). To check the broader substrate scope and generality of this protocol, a wide range of amines, including aromatic and aliphatic amines, were screened under these optimized reaction conditions (Table 1, entry 3). The results are summarized in Scheme 2. Several substituted aromatic amines were examined in the reaction with 7 a. For aromatic amines, the reactions with 6 a, aniline, and mphenylenediamine went smoothly to afford the desired products (Scheme 2, 8 a–c) in high yields. Imidazole and substituted imidazole survived under the reaction conditions (Scheme 2, compounds 8 d–f). Aliphatic amines, such as morpholine and benzylamine, were also successfully used to obtain good yields in the azaMichael reaction within the same reaction pot (Scheme 2, Scheme 2. Synthesis of b-ketoamine by integrating an organometallic click step with an organocatalytic azacompounds 8 g and 8 h). The Michael addition reaction within the same reaction pot.
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improvement of the methodolo- Table 2. Optimization of the one-pot integration of organometallic catalysis (click reaction) with an organoca[a] gies for a new catalytic proce- talytic MCR for the synthesis of 2,4,5-trisubstituted imidazole. dure leading to the convenient synthesis of 2,4,5-trisubstituted imidazole. The MCR was attempted to synthesize 2,4,5-trisubstituted imidazole by adding benzil (9), aldehyde, and ammonium acetate in a consecutive catalysis fashion in the same reaction Entry Azide Catalyst Triazole, time [min], Triazolium salt, time [h], Time [h], pot. In this reaction sequence, yield [%] yield [%] yield of 11 a[b] [%] we kept the first two steps ex- 1 3a 1 4 a, 10, 99 –, –, – 1, 37 actly the same as those depicted 2 – – 4 a, –, – –, –, – 1, 41[c] 3a 1 4 a, 10, 99 5 a, 12, 81 1, 91 earlier (Table 1 and Scheme 2) 3 – – –, –, – 5 a, –, – 1, 95[c] and the last step of aza-Michael 4 5 3a – –, –, – –, –, – 1, 8 condition was replaced with 6 – 1 –, –, – –, –, – 1, 5[c] MCR conditions. We performed 7 – – –, –, – –, –, – 1, 6[c] a number of control experi- [a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), 1 (1 mg, 1 mol %), 10 min, 25 8C; ments (Table 2) to make sure DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a; yield of 4 a is 99 %), 12 h, 90 8C; aldehyde that the reaction protocol fol- (100 equiv), benzil (100 equiv), and ammonium acetate (200 equiv with respect to 5 a; yield of 5 a is 81 %) in lowed similar working princi- the same reaction pot at 110 8C to maintain a 1 mol % catalytic loading of 5 a. [b] Isolated yield of product ples as those established for the after chromatography. [c] Reaction carried out without phenylacetylene. aza-Michael reaction coupled with a click reaction. The optimization study for the synthesis of 2,4,5-trisubstituted tallic catalyst (1), whereas the last step was an organocataimidazole by one-pot integration of organometallic catalysis lytic step that required the presence of the product from the (click reaction) with organocatalytic MCR was performed as first catalytic cycle (Table 2, entry 3). In this process, the follows: After the first step of organometallic catalysis yieldproduct of the click reaction acts as an organocatalyst for ed triazole 4 a quantitatively, we performed the MCR in the the MCR step to form the final product. same reaction pot by adding 9, benzaldehyde (10 a), and amTo find the broader scope of this reaction sequence, we monium acetate to afford the expected product, 2,4,5-tritested different types of aldehydes in the MCR step phenyl-1H-imidazole (Table 2, entry 1), in 37 % yield after (Scheme 3). The reactions of different substituted aromatic 1 h at 110 8C in DMSO. However, when we performed the reaction in the presence of isolated 4 a, we found that 11 a formed in 41 % (Table 2, entry 2) yield. Furthermore, increasing the Lewis acidity of 4 a by alkylation with methyl iodide (Table 2, entry 3), to form 5 a, significantly improved the yield of the final product to 91 %. A similar yield (95 %; Table 2, entry 4) was obtained when a control reaction was performed with 1 mol % of pure triazolium salt (5 a) as the organocatalyst in DMSO. The desired product 11 a was obtained in only 8 % yield when the reaction was performed without any catalyst 1 (Table 2, entry 5), but only in the presence of the substrates of the click reaction. In another control reaction, when the MCR step was attempted with 9, 10 a, and ammonium acetate as the substrates in the presence of catalyst 1 alone in DMSO under similar reaction conditions, this led to only about 5 % conversion in the MCR step (Table 2, entry 6). This result excludes the possibility of the involvement of catalyst 1 in the MCR step. Subsequently, a blank reaction was attempted with only MCR substrates 9, 10 a, and ammonium acetate in DMSO under similar reaction conditions; this resulted in only a trace amount of MCR product formation (6 %; Table 2, entry 7). Scheme 3. Synthesis of 2,4,5-trisubstituted imidazole by integrating an orAll of these findings from the control experiments made us ganometallic click step and an organocatalytic MCR in the same reaction pot. confident that the first step was catalyzed by an organome-
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aldehydes with either electron-withdrawing or -donating groups were effective in yielding the corresponding imidazole derivatives (Scheme 3). During this one-pot integration, it was observed that different functional groups survived under the reaction conditions, resulting in a library of 2,4,5trisubstituted imidazoles (Scheme 3). To broaden the scope of the methodology adopted during this consecutive integration of organometallic and organocatalysis, we show that it is possible to synthesize a variety of 1,4-dihydropyrimidinones. The 1,4-dihydropyrimidinone moiety has versatile pharmacophoric features and exhibits a broad range of biological activities, such as antibacterial, anti-inflammatory, fungicidal, calcium channel modulator, a1a-adrenergic receptor antagonist, mitotic kinesin inhibitor, and anticancer.[12] Therefore, there has been long-lasting interest from synthetic chemists towards the development of newer methodologies for this class of compounds, which comprises a three-component reaction involving an aldehyde, a b-ketoester/b-diketone, and urea.[13] Similar to the previous study, we also performed a number of control experiments (Table 3) to support the consecutive catalysis protocol for the synthesis of 1,4-dihydropyrimidinones in one pot. The optimization study for the synthesis of 1,4-dihydropyrimidinones by one-pot integration of organometallic catalysis (click reaction) with an organocatalytic MCR was achieved as follows: After the first step of organometallic catalysis yielded triazole 4 a quantitatively, we performed the MCR in the same reaction pot by adding 10 a, urea, and ethyl acetoacetate to afford the expected product, 1,4-dihydropyrimidinone (Table 3, entry 1), in 24 % yield after 1.5 h at 110 8C in DMSO. When we performed this reaction in the presence of 4 a isolated in a separate catalytic run, we found
that 14 a was formed in a similar yield (29 %; Table 3, entry 2). Furthermore, increasing the Lewis acidity of 4 a by alkylation with methyl iodide (Table 3, entry 3) to give 5 a significantly improved the yield of the final product to 92 %. A similar observation was obtained when a control reaction was performed with 1 mol % of the isolated triazolium salt as a catalyst in DMSO in the MCR (95 %; Table 3, entry 4). The desired product 14 a was obtained in only 8 % yield when the reaction was carried out without any catalyst 1 (Table 3, entry 5), in the presence of the substrates of the click reaction. In another control reaction, when the MCR step was attempted with 10 a, urea, and ethyl acetoacetate as substrates in the presence of catalyst 1 in DMSO under similar reaction conditions, it led to a similar yield (5 %) of the MCR step (Table 3, entry 6). Subsequently, a blank reaction was attempted with only MCR substrates 10 a, urea, and ethyl acetoacetate in DMSO under similar reaction conditions; this resulted in only trace amounts of MCR product formation (7 %; Table 3, entry 7). In this process, the product of the click reaction also acts as an organocatalyst for the MCR step to form the final product. All of these findings from the control experiments made us confident that the first step was catalyzed by an organometallic catalyst (1), whereas the last step was an organocatalytic step that required the presence of the product from the first catalytic cycle (Table 3, entry 3). From these studies, it was clear that the desired compound 14 a was obtained in high yield after performing multiple catalytic steps in the same reaction pot in a consecutive way. Under the standardized condition, various functionalized aldehydes were treated with b-dicarbonyl and urea to obtain the corresponding 1,4-dihydropyrimidinones. The results of this reaction protocol are summarized in Scheme 4. In all cases, the reaction proceeded smoothly to afford the corresponding 1,4-dihydropyrimidiTable 3. Optimization of the one-pot integration of organometallic catalysis (click reaction) with organocatalysis (MCR), leading to the synthesis of 1,4-dihydropyrimidinones.[a] nones in excellent yield (83– 93 %) after very short reaction times. The reaction is compatible with a variety of functional groups, such as halogens and alkoxy groups. The reaction leads to excellent yields for aldehydes containing electronwithdrawing and -donating Entry Azide Catalyst Triazole, time [min], Triazolium salt, time [h], Time [h], groups. Both the b-keto ester [b] yield [%] yield [%] yield of 14 a [%] and b-diketones react smoothly 1 3a 1 4 a, 10, 99 –, –, – 1.5, 24 with urea/thiourea and alde[c] 2 – – 4 a, –, – –, –, – 1.5, 29 hyde to give the corresponding 3 3a 1 4 a, 10, 99 5 a, 12, 81 1.5, 92 [c] dihydropyrimidinone derivative. 4 – – –, –, – 5 a, –, – 1.5, 95 5 6 7
3a – –
– 1 –
–, –, – –, –, – –, –, –
–, –, – –, –, – –, –, –
1.5, 8 1.5, 5[c] 1,5, 7[c]
[a] Reaction conditions: phenylacetylene (0.17 mmol), azide (0.15 mmol), compound 1 (1 mg, 1 mol %), 10 min, 25 8C; DMSO (5 mL), methyl iodide (5 equiv with respect to 4 a; yield of 4 a is 99 %), 12 h, 90 8C; aldehyde (100 equiv), urea (100 equiv), and 1,3-dicarbonyl compound (100 equiv with respect to 5 a; yield of 5 a is 81 %) in the same reaction pot at 110 8C to maintain a 1 mol % catalytic loading of 5 a. [b] Yield of product isolated after chromatography. [c] Reaction carried out without phenylacetylene.
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Conclusion We have been able to integrate organometallic catalysis and organocatalysis in the same reac-
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tained by using Q-Tof Micromass, Waters, instrument. Elemental analyses were performed on a PerkinElmer 2400, Series II, CHNS/O analyzer. The melting points were measured in sealed glass tubes on a Bchi B-540 melting point apparatus. Analytical TLC was performed on a Merck 60 F254 silica gel plate (0.25 mm thickness). NMR spectra were recorded on a JEOL ECS 400 MHz spectrometer and on a Bruker Avance 500 MHz spectrometer. All chemical shifts were reported in ppm by using tetramethylsilane as a reference. Chemical shifts (d) downfield from the reference standard were assigned positive values. Salt IA (Scheme 1),[7] 3 a,[14] 2,6-dimethylazide,[14] and mesitylazide[14] were prepared according to procedures reported in the literature.
Synthesis of complex 1 Under an argon atmosphere, THF (10 mL) was added at 80 8C to a mixture of 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenyl-imidazolium salt (308 mg, 0.50 mmol), copper(I) bromide (72 mg, 0.5 mmol), and potassium bis(trimethylsilyl)amide (200 mg, 1 mmol). After 30 min at 80 8C, the mixture was warmed to room temperature and stirred for 12 h. Solvent was evaporated under reduced pressure and the residue was extracted with dichloromethane (3 20 mL). The analytically pure, light-green compound was obtained (240 mg, 0.41 mmol, 70 %) by recrystallization from CH2Cl2/pentane. M.p. 223–225 8C; 1H NMR (400 MHz, CDCl3, 25 8C): d = 7.66 (t, J = 8.4 Hz, 1 H), 7.55 (t, J = 8 Hz, 1 H), 7.40–7.38 (m, 8 H), 7.25–7.23 (m, 2 H), 7.16 (t, J = 8.4 Hz, 2 H), 6.95 (d, J = 7.6 Hz, 2 H), 2.52–2.49 (m, 2 H), 2.44–2.38 (m, 2 H), 1.43 (d, J = 6.9 Hz, 6 H), 0.93 (d, J = 6.8 Hz, 6 H), 0.86 ppm (t, J = 6.1 Hz, 12 H); 13C NMR (100 MHz, [D6]DMSO, 25 8C): d = 154.8, 146.9, 144.9, 114.5, 138.7, 133.1, 132.7, 132.5, 130.9, 130.7, 129.3, 129.0, 128.7, 128.4, 126.0, 125.9, 124.8, 120.6, 28.6, 28.2, 24.5, 23.8, 23.3, 22.8 ppm; elemental analysis calcd (%) for C39H44BrCuN2 : C 68.46, H 6.48, N 4.09; found: C 69.30, H 6.88, N 4.17.
Scheme 4. Synthesis of 1,4-dihydropyrimidinones by integrating an organometallic click step followed by MCR conditions in the same reaction pot.
Synthesis of 5a’
tion pot, in which the product of the first catalytic cycle acts as the catalyst for the second catalytic step. Thus, in this protocol, the catalyst is generated in situ. We applied this onepot methodology to perform different types of reaction sequences, which established the scope of this concept in various reaction protocols. In the first step, the organometallic catalyst acted as an efficient catalyst for the click reaction to provide a triazole, which, after activation through an alkylation step, acted as an efficient organocatalyst for an aza-Michael addition reaction, leading to b-aminocarbonyl compounds. For MCRs, these led to the synthesis of a variety of 2,4,5-trisubstituted imidazoles and 1,4-dihydropyrimidinone compounds in a consecutive fashion within the same reaction pot. Thus, unlike previous multicatalytic processes in which the substrates of the first catalytic cycle act as the substrate for next catalytic cycle, we have been able to develop a process in which the product acts as a catalyst for the next cycle to mimic the function of certain enzymes.
Diphenylacetylene (1.73 mmol), 3 a (1.57 mmol), and 2 (10 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction was allowed to proceed at 70 8C for 5 h. After the appropriate period of time, the reaction was quenched by dissolving the reaction mixture in dichloromethane (10 mL). Subsequently, a simple aqueous workup was carried out, and the crude product was purified by flash chromatography on silica gel to yield NMR-pure 1,4,5-triphenyl-1H-1,2,3-triazole (4 a’; 85 % yield). Subsequently, 1,4,5-triphenyl-1H-1,2,3-triazole (4 a’; 1 equiv) was dissolved in acetonitrile (10 mL) and methyl iodide (10 equiv) was added. Then the mixture was heated to reflux for 24 h. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (15 mL) and precipitated by the addition of ethyl ether (50 mL). The yellow precipitate was collected by filtration to give product 5 a’ as a brown solid after evaporation under reduced pressure (82 % yield). M.p. 210–212 8C; 1 H NMR ([D6]DMSO, 500 MHz, 25 8C): d = 7.66–7.59 (m, 10 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 8 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 2 H), 4.34 ppm (s, 3 H); 13C NMR (CDCl3, 125 MHz, 25 8C): d = 141.19, 141.17, 141.0, 134.1, 131.5, 131.04, 130.98, 130.7, 129.5, 129.3, 128.9, 126.4, 122.3, 122.1, 39.5 ppm; HRMS (ESI): m/z: calcd for C21H18N3 : 312.1495 [M I] + ; found: 312.1525.
Experimental Section
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a as a solid product (yield of 4 a is 99 %). After complete formation of product 4 a, the alkylation step was done in same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to give 3-methyl-1,4-diphenyl-1H-1,2,3-triazol-3-ium iodide (5 a; 81 % yield). The aza-Michael addition reaction was carried out by adding amine (100 equiv) and a,b-unsaturated carbonyl compound (120 equiv with respect to 5 a (considered to be 80 % yield)) in the same pot at
General Procedure for the Synthesis of b-Ketoamine by Integrating an Organometallic Click Step and Organocatalytic Aza-Michael Addition in the Same Reaction Pot
General considerations All manipulations were performed under a dry, oxygen-free atmosphere (argon) by using standard Schlenk techniques or inside a glove box maintained below 0.1 ppm of O2 and H2O, utilizing oven-dried (130 8C) glassware after evacuation that was hot prior to use. All solvents were distilled from Na/benzophenone prior to use. All chemicals were purchased from Sigma–Aldrich and used as received. The HRMS data were ob-
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70 8C to maintain 1 mol % catalytic loading of 5 a. For compound 8 h, the aza-Michael addition reaction proceeded by adding amine (100 equiv) and a,b-unsaturated carbonyl compound (240 equiv with respect to 5 a) in the same pot at 70 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted in CH2Cl2 and purified by flash column chromatography (hexane/ethyl acetate) to obtain the corresponding aza-Michael addition product. All reported yields were those of product isolated and were an average of at least two runs.
[2] [3] [4] [5]
General Procedure for the Synthesis of 2,4,5-Trisubstituted Imidazole by Integrating an Organometallic Click Step and Organocatalytic MCR in the Same Reaction Pot
[6] [7]
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a in quantitative yield. After complete formation of product 4 a, the alkylation step was performed in the same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to give 5 a (81 % yield). The MCR was further carried out by adding aldehyde (100 equiv), benzil (100 equiv), and ammonium acetate (200 equiv with respect to 5 a) in the same pot at 110 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted with CH2Cl2 and was purified by recrystallization from EtOH. All reported yields were those of product isolated and were an average of at least two runs.
[8]
General Procedure for the Synthesis of 1,4-Dihydropyrimidinones by Integrating an Organometallic Click Step and Organocatalytic MCR in the Same Reaction Pot [9]
Phenylacetylene (0.17 mmol), 3 a (0.15 mmol), and 1 (1 mg, 1 mol %) were loaded in a 25 mL Schlenk flask. The reaction mixture was stirred for 10 min at room temperature to give 4 a. After complete formation of product 4 a, the alkylation step was performed in the same reaction pot by adding DMSO (5 mL) and methyl iodide (5 equiv with respect to 4 a) and the reaction mixture was stirred for 12 h at 90 8C to obtain 5 a (81 % yield). The MCR was further carried out by adding aldehyde (100 equiv), urea (100 equiv), and 1,3-dicarbonyl compound (100 equiv with respect to 5 a) in the same reaction pot at 110 8C to maintain 1 mol % catalytic loading of 5 a. After an appropriate period of time, the reaction was quenched by dissolving the reaction mixture in water (20 mL). Subsequently, the final compound was extracted with CH2Cl2 and purified by recrystallization from EtOH. All reported yields were those of product isolated and were an average of at least two runs.
[10]
[11]
Acknowledgements S.K.M. thanks SERB (DST), New Delhi for financial support. S.C.S. thanks the UGC, New Delhi, for a research fellowship. S.R.R. thanks the CSIR for an RA fellowship. We also acknowledge the NMR spectroscopy and X-ray facilities of IISER-Kolkata. [12] [1] a) S. T. Scroggins, Y. Chi, J. M. J. Frchet, Angew. Chem. Int. Ed. 2010, 49, 2393 – 2396; Angew. Chem. 2010, 122, 2443 – 2446; b) J. Jiang, X. Guan, S. Liu, B. Ren, X. Ma, X. Guo, F. Lv, X. Wu, W. Hu, Angew. Chem. Int. Ed. 2013, 52, 1539 – 1542; Angew. Chem. 2013, 125, 1579 – 1582; c) F. Nahra, Y. Mac, D. Lambin, O. Riant, Angew. Chem. Int. Ed. 2013, 52, 3208 – 3212; Angew. Chem. 2013, 125, 3290 – 3294; d) Y. Ye, M. S. Sanford, J. Am. Chem. Soc. 2012, 134, 9034 – 9037; e) L. Ren, T. Lei, J.-X. Ye, L.-Z. Gong, Angew. Chem. Int. Ed. 2012, 51, 771 – 774; Angew. Chem. 2012, 124, 795 – 798; f) M. Terada, Y. Toda, Angew. Chem. Int. Ed. 2012, 51, 2093 – 2097; Angew. Chem. 2012, 124, 2135 – 2139; g) S. Guo, Y. Xie, X.
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[14]
Swadhin K. Mandal et al.
Hu, C. Xia, H. Huang, Angew. Chem. Int. Ed. 2010, 49, 2728 – 2731; Angew. Chem. 2010, 122, 2788 – 2791; h) D. Fuchs, G. Rousseau, L. Diab, U. Gellrich, B. Breit, Angew. Chem. Int. Ed. 2012, 51, 2178 – 2182; Angew. Chem. 2012, 124, 2220 – 2224. A. S. Goldman, A. H. Roy, Z. Huang, R. Ahuja, W. Schinski, M. Brookhart, Science 2006, 312, 257 – 260. D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77 – 80. G. Dong, P. Teo, Z. K. Wickens, R. H. Grubbs, Science 2011, 333, 1609 – 1612. A. Mukherjee, S. Nembenna, T. K. Sen, S. P. Sarish, P. K. Ghorai, H. Ott, D. Stalke, S. K. Mandal, H. W. Roesky, Angew. Chem. Int. Ed. 2011, 50, 3968 – 3972; Angew. Chem. 2011, 123, 4054 – 4058. D. Enders, M. R. M. Httl, C. Grondal, G. Raabe, Nature 2006, 441, 861 – 863. a) S. C. Sau, S. Raha Roy, T. K. Sen, D. Mullangi, S. K. Mandal, Adv. Synth. Catal. 2013, 355, 2982 – 2991; b) T. K. Sen, S. C. Sau, A. Mukherjee, A. Modak, S. K. Mandal, D. Koley, Chem. Commun. 2011, 47, 11972 – 11974; c) S. C. Sau, S. Santra, T. K. Sen, S. K. Mandal, D. Koley, Chem. Commun. 2012, 48, 555 – 557; d) T. K. Sen, S. C. Sau, A. Mukherjee, P. K. Hota, S. K. Mandal, B. Maity, D. Koley, Dalton Trans. 2013, 42, 14253 – 14260. a) G. Bartoli, M. Bosco, E. Marcantoni, M. Pertrini, L. Sambri, E. Torregiani, J. Org. Chem. 2001, 66, 9052 – 9055; b) L. Fadini, A. Tongi, Chem. Commun. 2003, 30 – 32; c) N. Srivastava, B. K. Banik, J. Org. Chem. 2003, 68, 2109 – 2111; d) N. Yamagiwa, H. Qin, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 13419 – 13427; e) S. Raha Roy, A. K. Chakraborti, Org. Lett. 2010, 12, 3866 – 3869; f) H.-M. Yang, L. Li, F. Li, K.-Z. Jiang, J.-Y. Shang, G.-Q. Lai, L.-W. Xu, Org. Lett. 2011, 13, 6508 – 6511; g) Z. Yacob, J. Shah, J. Leistner, J. Liebscher, Synlett 2008, 2342 – 2344; h) Q. Kang, Y. Zhang, Org. Biomol. Chem. 2011, 9, 6715 – 6720; i) A. Aggarwal, N. L. Lancaster, A. R. Sethi, T. Welton, Green Chem. 2002, 4, 517 – 520. a) E. J. Corey, D. A. Clark, G. Goto, A. Marfat, C. Mioskowski, B. Sameulson, S. Hammerson, J. Am. Chem. Soc. 1980, 102, 1436 – 1439; b) J. R. Luly, N. Yi, J. Soderquist, H. Stein, J. Cohen, T. J. Perun, J. J. Plattner, J. Med. Chem. 1987, 30, 1609 – 1616; c) A. Dçmling, Chem. Rev. 2006, 106, 17 – 89; d) P. Wipf, C. R. J. Stephenson, K. Okumura, J. Am. Chem. Soc. 2003, 125, 14694 – 14695; e) S. Gandhi, B. List, Angew. Chem. Int. Ed. 2013, 52, 2573 – 2576; Angew. Chem. 2013, 125, 2633 – 2636. a) J. G. Lombardino, E. H. Wiseman, J. Med. Chem. 1974, 17, 1182 – 118; b) L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey, S. M. Hannick, L. Gherke, R. B. Credo, Y. H. Hui, K. Marsh, R. Warner, J. Y. Lee, N. Zielinsky-Mozng, D. Frost, S. H. Rosenberg, H. L. Sham, J. Med. Chem. 2002, 45, 1697 – 1711. a) R. B. Sparks, A. P. Combs, Org. Lett. 2004, 6, 2473 – 2475; b) J. Boehm, J. Smietana, M. Sorenson, R. Garigipati, T. Gallagher, P. Sheldrake, J. Bradbeer, A. Badger, J. Laydon, J. Lee, L. Hillegass, D. Griswold, J. Breton, M. Chabot-Fletcher, J. Adams, J. Med. Chem. 1996, 39, 3929 – 3937; c) M. Bilodeau, A. Cunningham, J. Org. Chem. 1998, 63, 2800 – 2801; d) S. E. Wolkenberg, D. D. Wisnoski, W. H. Leister, Y. Wang, Z. Zhao, C. W. Lindsley, Org. Lett. 2004, 6, 1453 – 1456; e) F. Ijaz, S. Noreen, M. N. Khan, S. Naureen, M. A. Khan, M. A. Munawar, A. M. R. Bernardino, Asian J. Chem. 2012, 24, 5114 – 5116; f) S. Raha Roy, P. S. Jadhavar, K. Seth, K. K. Sharma, A. K. Chakraborti, Synthesis 2011, 2261 – 2267. a) M. Kidwai, S. Saxena, M. K. R. Khan, S. S. Thukral, Eur. J. Med. Chem. 2005, 40, 816 – 819; b) P. Kumar, B. R. Sankar, G. Nasir, R. B. Baig, S. Chandrashekaran, Eur. J. Med. Chem. 2009, 44, 4192 – 4198. a) R. O. M. A. De Souza, E. T. da Penha, H. M. S. Milagre, S. J. Garden, P. M. Esteves, M. N. Eberlin, O. A. C. Antunes, Chem. Eur. J. 2009, 15, 9799 – 9804; b) Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386 – 16387; c) C. O. Kappe, Acc. Chem. Res. 2000, 33, 879 – 888. S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov, V. V. Fokin, Org. Lett. 2010, 12, 4217 – 4219. Received: April 11, 2014 Published online: August 14, 2014
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