Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Interception of Secondary Amide Ylide with Sulfonamides: CatalystControlled Synthesis of N‑Sulfonylamidine Derivatives Jijun Chen, Wenhao Long, Yonggang Yang,* and Xiaobing Wan* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China S Supporting Information *
ABSTRACT: A novel, secondary amide activation strategy has been developed through the in situ generation of ylides from amides and diazoacetates. Under the developed reaction conditions, Mncatalyzed ylide formation and interception reaction by sulfonamide delivered a variety of N-sulfonylamidines. Notably, when highly active Zn(OTf)2 was used as the catalyst, further N−H insertion products were obtained. In contrast with traditional methods, our amide activation strategy is distinguished by accessible starting material, inexpensive catalyst, and broad substrate scope.
S
Scheme 1. Selective Transformations of Secondary Amides with Metal Carbenes
econdary amides are common and readily available compounds, which are ubiquitous in proteins, polypeptides, and pharmaceuticals.1 Its transformations have also attracted considerable attention from chemists who wish to create useful functional groups, such as aldehydes, imines, etc.2 In recent years, metal−carbene activation of amides has been validated as a powerful platform for the transformation of amides.3,4 Specifically, tremendous efforts have been devoted to the diversification of tertiary amides for the synthesis of various cycloaddition products.5 In sharp contrast, the transformation of secondary amides with metal−carbenes has been less explored due to the unambiguous N−H insertions of amides.6 Recently, Fokin demonstrated that the sterically hindered secondary amides could undergo selective conversion through an O−H insertion followed by a rearrangement to deliver α-amine ketones (Scheme 1a).7 Another secondary amide activation process that relies on the tautomerism of 2-arylquinazolinone analogues has been achieved by several groups (Scheme 1b).8 In addition, Deng and Volla independently reported a rhodiumcatalyzed transformation of activated secondary amides with 1sulfonyl-1,2,3-triazoles (Scheme 1c).9 Although these works represent promising advances, it is still highly desirable to explore a novel strategy for the activation of secondary amides. Hu and others, in their pioneering works, have demonstrated ylides formation from diazo compounds and subsequent trapping by a variety of electrophiles.10 Very recently, we achieved the interception of tertiary amide ylides with sulfonamides as nucleophiles.11 However, to the best of our knowledge, the transformation of secondary amides via amide ylide pathway has not been reported to date, perhaps due to the unavoidable N−H insertion reactions.6−9 We thus conceived that the key to inhibit undesired N−H insertions relies on the choice of the catalyst and reaction conditions. After extensive screenings, a novel Mn-catalyzed interception of secondary amide ylides by sulfonamides was well established, leading to Nsulfonylamidines with high chemoselectivity (Scheme 1d, left). Interestingly, when highly active Zn(OTf)2 was used as the © XXXX American Chemical Society
catalyst, a variety of amidines containing ester groups were obtained through interception of the secondary amide ylide and a subsequent N−H insertion reaction sequence (Scheme 1d, right). We began our investigations with acetanilide 1a, ptoluenesulfonamide 2a, and ethyl diazoacetate 3a as substrates using our previous zinc-catalysis system.11 Not surprisingly, both N-sulfonylamidine 4a and N−H insertion product 5a were obtained in low yield and selectivity (see Table S1, entries 1−3). The structure of 4a and 5a was confirmed by NMR and singlecrystal analysis. Next, we evaluated various transition-metal species to tune the selectivity of this secondary amide activation reaction. After extensive screenings, we found Mn(ClO4)2· Received: March 16, 2018
A
DOI: 10.1021/acs.orglett.8b00867 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
extensive screenings, the yield of 5a could be increased to 81% by simultaneously increasing the amount of 3a and Zn(OTf)2 (Table S1, entry 17). Encouraged by the above results, we next explored the generality for the synthesis of 5 under zinc catalysis (Scheme 3). In general, secondary linear amide with various
6H2O, which is inexpensive and easy to handle, showed higher catalytic efficiency and selectivity compared with other metal salts, leading to N-sulfonylamidine 4a in 63% yield (Table S1, entry 8). We next prepared a variety of N-sulfonylamidines 4 from secondary amides and sulfonamides under the optimal conditions (Scheme 2). Pleasingly, various common secondary
Scheme 3. Substrate Scope for Synthesis of 5a
Scheme 2. Substrate Scope for Synthesis of 4a
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), 3a (0.4 mmol), and Mn(ClO4)2·6H2O (10 mol %) in C6H12 (0.5 mL) at reflux for 12 h under air, isolated yield.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), 3 (1.2 mmol), and Zn(OTf)2 (30 mol %) in C6H12 (0.5 mL) at reflux for 12 h under air, isolated yield. bZn(OTf)2 (40 mol %).
linear amides were well tolerated in this process (4a−j). NMethylformamide also worked well, leading to product 4k in 88% yield. Notably, secondary lactams were easily converted to the corresponding cyclic amidines 4l−q in moderate to excellent yields. The scopes of sulfonamides were investigated by using 2pyrrolidinone or AC-PHE-OME (N-Acetyl-L-phenylalanine methyl ester) as amide substrates. Both heteroaryl- and naphthyl-substituted sulfonamides work well to generate products 4r−t in satisfactory yields. Alkyl sulfonamides also reacted efficiently and provided products 4u−w with high yields. When oxy- and azo-sulfonamide were used as substrates, the desired products 4x and 4y were achieved in 65% and 78% yields, respectively. Notably, the exact structure of 4l was unambiguously established by X-ray analysis. As an extension of this work, we also attempted the synthesis of N-sulfonylamidines containing ester groups through the interception of secondary amide ylides with sulfonamides and a subsequent diazo compound N−H insertion reaction. After
substituents led to 5a−h in modest to high yields. Primary formamide afforded 5i with the reservation of one unreacted NH group. Notably, when enamide was used as the substrate, the desired product 5j was obtained in 50% yield. In addition, substituted pyrrolidinones gave N-sulfonylamidines 5k−m in satisfying yields. Unfortunately, ε- and δ-lactams were not suitable substrates under this conditions.12 Next, various sulfonamides were tested and gave the products 5n−r in moderate yields. As expected, various diazo esters proceeded smoothly to generate the corresponding N-sulfonylamidine derivatives 5t−y in good yields. Notably, the exact structure of 5k was confirmed by X-ray analysis. Further derivations of a range of bioactive compounds were conducted to highlight the synthetic utility of our method. Both rolipram13a and linezolid13b provided corresponding products in satisfactory yields (Scheme 4). In addition, amino acid B
DOI: 10.1021/acs.orglett.8b00867 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Late-Stage Modification of Bioactive Compoundsa,b
Scheme 6. Mechanistic Investigations
On the basis of the above observations and literature reports, we proposed a plausible catalytic cycle as shown in Scheme 7. Scheme 7. Proposed Reaction Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), 3a (0.4 mmol), and Mn(ClO4)2·6H2O (10 mol %) in C6H12 (0.5 mL) at reflux for 12 h under air, isolated yield. bReaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), 3a (1.2 mmol), and Zn(OTf)2 (30 mol %) in C6H12 (0.5 mL) at reflux for 12 h under air, isolated yield.
derivatives, such as ethyl L-pyroglutamate and AC-PHE-OME, furnished the desired products 6c, 7b, and 7d in moderate yields. Sulfonamide drugs, including topiramate,13c celecoxib,13d and zonisamide,13e also reacted smoothly to provide 6d−f and 7d−f in acceptable yields with high E/Z ratios. The synthetic practicality of this transformation was further supported by scale-up experiments, as shown in Scheme 5.
Initially, a transition-metal catalyst decomposes diazo compounds to form electrophilic carbenoid species I,14,15 which is then attacked by a secondary amide to give the key amide ylide intermediate II and its imine counterparts III.3,4 Then the nucleophilic addition of II or III by sulfonamide furnishes intermediate IV, which then affords intermediate V and regenerates the transition-metal catalyst.11,16 Intermediate V undergoes elimination to afford the desired N-sulfonylamidine 4 and ethyl 2-hydroxyacetate. Notably, when Zn(OTf)2 was used as the catalyst, further N−H insertion led to product 5 with high selectivity. In summary, a highly efficient secondary amide activation was well established, leading to N-sulfonylamidine derivatives in moderate to excellent yields. This protocol is distinguished by accessible starting material, inexpensive catalyst, broad substrate scope, ready scale-up ability, and late-stage application for biologically active compounds. Further investigations on amide activation are underway in our laboratory.
Scheme 5. Gram-Scale Reaction
A series of experiments were carried out to gain insight into the mechanisms of this transformation as shown in Scheme 6. 4-tertButylstyrene, a carbene scavenger, was subjected to the standard conditions; the cyclopropanation product 8 could be detected by GC (Scheme 6a), implying carbene intermediate was involved in this reaction. The reaction of secondary amide 1a with diazo compound 3a under zinc catalysis did not lead to a significant amount of N−H insertion product 9. In sharp contrast, the N−H insertion reaction of N-sulfonylamidine 4a occurred efficiently to give product 5a in excellent 98% yield. These results indicated that an amide ylide formation/intermation/insertion process was involved in this N-sulfonylamidine formation reaction.
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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.8b00867. Experimental procedures and full spectroscopic data for all new compounds (PDF) C
DOI: 10.1021/acs.orglett.8b00867 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Accession Codes
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CCDC 1827576, 1827580−1827581, and 1828634 contain 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 Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yonggang Yang: 0000-0003-0185-7471 Xiaobing Wan: 0000-0001-9007-2128 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and NSFC (21572148, 51673141, and 21272165).
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DOI: 10.1021/acs.orglett.8b00867 Org. Lett. XXXX, XXX, XXX−XXX
