Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iridium-Catalyzed Three-component Coupling Reaction of Carbon Dioxide, Amines, and Sulfoxonium Ylides Huanfeng Jiang,* Hao Zhang, Wenfang Xiong, Chaorong Qi, Wanqing Wu, Lu Wang, and Ruixiang Cheng Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
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S Supporting Information *
ABSTRACT: The first iridium-catalyzed three-component coupling reaction of carbon dioxide, amines, and sulfoxonium ylides has been developed, providing an efficient and straightforward method for the construction of a range of structurally diverse O-βoxoalkyl carbamates in moderate to excellent yields. This novel protocol features the use of readily available substrates, wide substrate scope, and good functional group tolerance. Moreover, the phosgene-free strategy was successfully applied to the synthesis of a potential antitumor agent.
O
as safe alternatives to diazo compounds in transition metalcatalyzed carbon−carbon bond- and carbon−heteroatom bond-forming reactions.9,10 However, to the best of our knowledge, the use of sulfoxonium ylides for the construction of organic carbamates has not yet been reported. As our continuous effort in the development of efficient methods for the transformation of carbon dioxide into carbamates,11 we envisioned that a direct route to O-β-oxoalkyl carbamates might be achieved by transition metal-catalyzed threecomponent coupling between CO2, amines, and sulfoxonium ylides (Scheme 1). The reaction pathway was hypothesized as follows: initially, sulfoxonium ylide reacts with metal catalyst to give a metal−carbene intermediate D, which would be attacked
rganic carbamates are important structural motifs in numerous biologically active natural products,1 pharmaceutical reagents,2 and agricultural chemicals.3 For example, these O-β-oxoalkyl carbamate compounds A−C are known as potential antihypertensives, anti-infective agent, and antiinflammatory agent (Figure 1). 4 In addition, organic
Scheme 1. Hypothetical New Pathway for the Synthesis of O-β-Oxoalkyl Carbamates
Figure 1. Representative drugs containing O-β-oxoalkyl carbamate motifs.
carbamates can be used as important intermediates, protecting groups, and starting materials in organic synthesis chemistry.5 Classically, organic carbamates are prepared from highly toxic phosgene or their derivatives as starting material, which may cause serious environmental and operational problems.6 During the past decades, carbon dioxide (CO2) has attracted increasing attention as raw material for the synthesis of different valuable chemicals because CO2 is not only a greenhouse gas but also an abundant, safe, and renewable C1 source.7 Due to the wide applications of organic carbamates in various fields, the development of new and efficient methods for the synthesis of these compounds by using CO2 as an alternative to phosgene is therefore of great significance.8 Sulfoxonium ylides, which are bench-stable compounds and safer to be synthesized, have recently been extensively explored © XXXX American Chemical Society
Received: January 7, 2019
A
DOI: 10.1021/acs.orglett.9b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
catalyst
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21d 22
[Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)OMe]2 Ir(ppy)3 [Cp*IrCl2]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2 [Ir(COD)Cl]2
base DABCO DABCO DABCO DABCO DABCO DABCO DABCO TMG DBU TBD K2CO3 TMG TMG TMG TMG TMG TMG TMG TMG TMG TMG
additive
AgBF4 AgSbF6 Ag3PO4 Ag2CO3 Ag3PO4 Ag3PO4 Ag3PO4 Ag3PO4 Ag3PO4 Ag3PO4
ligand
solvent
yield (%)b
L1 L2 L3 L4 L4 L4
toluene toluene toluene toluene toluene DCE DMSO t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH t-BuOH
14 24 20 n.d. n.d. 18 n.d. 32 34 18 trace 19 56 32 60 42 48 65 64 78 89 (84c) n.d.
a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), CO2 (3 MPa), catalyst (5 mol %), base (0.9 mmol), solvent (3 mL), additive (20 mol %), ligand (10 mol %), 100 °C, 12 h. bYields were determined by GC−MS using dodecane as internal standard. cIsolated yield. dBase (0.6 mmol).
nucleophilically by in situ generated carbamate anion E to generate intermediate F. Finally, the protonation of F gives the desired product.12 With this hypothesis in mind, we then chose sulfoxonium ylide (1a) and diethylamine (2a) as the model substrates for the optimization of the reaction conditions, and the results were summarized in Table 1. To our delight, when the reaction was conducted in the presence of 5 mol % of [Ir(COD)Cl]2 as the catalyst and 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base in toluene at 100 °C for 12 h, the expected 2-oxo-2phenylethyl diethylcarbamate (3aa) was obtained in 24% yield (Table 1, entry 2). Other iridium catalysts including [Ir(COD)OMe]2, Ir(ppy)3, and [Cp*IrCl2]2 were also examined, but they showed lower or no reactivity for the reaction (entries 3−5). Solvent screening showed that the use of t-BuOH as the solvent could improve the yield of 3aa to 32% (entries 6−8). Further exploration with various organic and inorganic bases revealed that 1,1,3,3-tetramethylguanidine (TMG) was more efficient than DABCO, while 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD), and K2CO3 gave inferior results (entries 9−12). Moreover, it was found that the reaction could be facilitated by introducing catalytic amount of AgBF4 and delivered the desired product in 56% yield (entry 13), which might be due to the in situ generation of a cationic iridium catalytic species. Encouraged by these results, a series
of silver salts including AgSbF6, Ag3PO4, and Ag2CO3 were further investigated, and Ag3PO4 proved to be the best choice (entries 14−16). In order to further improve the reaction efficiency, we evaluated the effect of ligand on the reaction. Pleasingly, the addition of 2,9-dimethyl-4,7-diphenyl-1,10phenanthroline (L4) led to an obvious increase in yield (entries 17−20). Finally, 3aa could be obtained in 84% yield upon isolation when 2 equiv of the base was employed (entry 21). One more control experiment confirmed that the reaction could not occur in the absence of Ir(I) catalyst (entry 22). With the optimized reaction conditions in hand, the substrate scope of sulfoxonium ylides for the iridium-catalyzed three-component reaction was first investigated by using 2a as the coupling partner (Scheme 2). Gratifyingly, a variety of sulfoxonium ylide derivatives could undergo the reaction smoothly to give the desired products (3aa−3oa) in moderate to high yields. Both electron-donating and -withdrawing groups, such as alkyl (Me, Et, and t Bu), methoxy, dimethylamino, halide (F, Cl, and Br), trifluoromethoxy, trifluoromethyl-thio, and trifluoromethyl, at the para positions of the benzene ring of the substrates could be well tolerated. The structure of the product 3ja was unambiguously confirmed by means of X-ray crystallographic analysis. Substrates with a substituent at the meta position of the aryl ring could also work well to give the corresponding products in high yields. Unfortunately, sulfoxonium ylide 1p, bearing a substituent at B
DOI: 10.1021/acs.orglett.9b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Sulfoxonium Ylidesa
Scheme 3. Scope of Aminesa
a
Reaction conditions: 1a (0.3 mmol), 2 (1.5 mmol), CO2 (3 MPa), [Ir(COD)Cl]2 (5 mol %), L4 (10 mol %), Ag3PO4 (20 mol %), TMG (0.6 mmol), t-BuOH (3 mL), 100 °C, 12 h. Isolated yield.
1a on a 3 mmol scale with 2a gave the desired product 3aa in 57% yield upon isolation (Scheme 4a). Second, compound 6, a Scheme 4. Synthetic Applications a
Reaction conditions: 1 (0.3 mmol), 2a (1.5 mmol), CO2 (3 MPa), [Ir(COD)Cl]2 (5 mol %), L4 (10 mol %), Ag3PO4 (20 mol %), TMG (0.6 mmol), t-BuOH (3 mL), 100 °C, 12 h. Isolated yield.
the ortho position, could not take part in the reaction, which indicated that steric hindrance has significant impact on the reaction. Besides monosubstituted sulfoxonium ylides, the disubstituted substrate 1q could also react well with 2a and CO2 to furnish the corresponding product 3pa in 75% yield. Moreover, sulfoxonium ylides containing a naphthalene or thiophene moiety were all suitable substrates for the transformation, delivering the desired products (3ra−3sa) in good yields. Notably, the reaction was not limited to aryl and heteroaryl sulfoxonium ylides. Alkenyl, linear, and cycloalkyl substituted substrates could also enter into the reaction and furnished the corresponding product (3ta−3wa) in moderate yields, revealing the wide substrate scope of our protocol. Subsequently, the scope of amines was examined for the transformation. As can be seen from Scheme 3, different acyclic secondary amines, including symmetric and asymmetric ones, underwent smooth reaction with sulfoxonium ylide 1a and CO2 to give rise to the corresponding products (3ab− 3ah) in moderate or excellent yields. Furthermore, various cyclic secondary amines could also take part in the reaction without difficulty, giving rise to the desired products (3ai− 3ak) in satisfactory yields. However, primary amines 2l and aniline 2m could not afford the desired products but gave a mixture of unidentified products under the standard conditions. Encouraged by the above results, we turned our attention to the synthetic applications of our protocol. First, the reaction of
potential antitumor agent,13 could be synthesized conveniently by using the present method via a three-step procedure starting from steroid carboxylic acid 4.14 On the basis of the above-mentioned observations and previous literatures,15−17 a plausible mechanism of the reaction was proposed in Scheme 5. Initially, an active cationic Ir(I) species G was generated with the assistance of Ag salts and ligand, which reacted with sulfoxonium ylide 1a to give an iridium carbene complex H. Then, H underwent nucleophilic attack by carbamate anion I, which was generated from the reaction of amine 2a with CO2, leading to the formation of complex J. Protonolysis of the Ir−alkyl bond of complex J by C
DOI: 10.1021/acs.orglett.9b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
Scheme 5. Possible Reaction Mechanism
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank the National Program on Key Research Project (2016YFA0602900), the National Natural Science Foundation of China (21572071 and 21420102003), and the Guangdong Natural Science Foundation (2017A030313054) for financial support.
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ammonium ion gave the final product 3aa and regenerated the active catalyst. In summary, we have developed an iridium-catalyzed threecomponent reaction of CO2, amines, and sulfoxonium ylides, offering a direct and efficient method for the synthesis of a range of O-β-oxoalkyl carbamates in moderate to excellent yields. This new protocol features the use of readily available substrates, wide substrate scope, and good functional group tolerance. Moreover, the phosgene-free strategy was successfully applied to the synthesis of a potential antitumor agent. Further investigations to extend the utility of this reaction and to deepen our mechanistic understanding of this transformation are ongoing in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00072. Experimental procedures, condition screening table, characterization data, and copies of NMR spectra for all products (PDF) Accession Codes
CCDC 1883154 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Huanfeng Jiang: 0000-0002-4355-0294 Chaorong Qi: 0000-0003-4776-2443 Wanqing Wu: 0000-0001-5151-7788 D
DOI: 10.1021/acs.orglett.9b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
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DOI: 10.1021/acs.orglett.9b00072 Org. Lett. XXXX, XXX, XXX−XXX
