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DOI: 10.1039/C5CC09137C
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Rhodium‐Catalyzed Tunable Oxidative Cyclization toward the Selective Synthesis of α‐Pyrones and Furans Received 00th January 20xx, Accepted 00th January 20xx
Jiaping Wu, Dongxu Wang, Yanjun Wan, and Cheng Ma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The rhodium(III)‐catalyzed tunable oxidative cyclization of readily available N‐tosylacrylamides and diazo compounds is presented, which offeres a novel method for the selective construction of fully substituted α‐pyrones and furans in a regiospecific manner by employing acylsulfonamide groups as a versatile in situ removable directing group.
a) Oxidative annulation of N-benzoylsulfonamide with Isocyanide by Zhu and Falck O O NTs H
cat. [Cp*RhLn ]
RNC
NTs
oxidant s
N R b) Olefinic C- H alkynylation of N-tosylacrylamides by Loh and co-wor kers O R1
During the past decades, the directing‐group‐assisted method has become as a pivotal strategy for transition‐metal‐catalyzed C−H bond func onaliza on to produce diversely substituted molecules.1 In this context, the rhodium(III)‐mediated tandem oxidative C–H functionalization/cyclization reactions, typically involving the directing group (DG), offer a promising tool for the construction of various heterocycles.2,3 While a large numbers of DGs allow for this class of transformations, the development of in situ convertible poly‐functional DGs4 is worthy of special attention on behalf of diversity‐oriented synthesis.5 It has been noticed that this class of DGs not only enhance the efficiency4b of metal‐catalyzed direct C−H bond activation but also provide several straightforward access to structurally complex and diverse molecules by cleaving their N−O,6 N−N,7 or C−N8 bonds, albeit usually containing worthless fragments of the DGs used. The acylsulfonamide group, a bioisostere of carboxylic acid in medicinal chemistry,9 has recently been found capable of promoting several transition‐metal‐catalyzed directed C–H bond functionalization reactions.10 For instance, Zhu and Falck in 2011 presented the rhodium‐catalyzed oxidative annulation of N‐benzoylsulfonamides and isocyanides through arene C–H bond activation (Scheme 1a).10b In 2014, Loh and co‐workers notably achieved the olefinic C−H alkynylation of acrylamides (Scheme 1b).10g Among these, the acylsulfonamide group was regarded as a weakly coordinating DG and rendered somewhat superiority in C−H activation comparing with other reported DGs. As a part of our continuing efforts in N‐tosylacrylamide
+
H
O NHTs
+
I
O R1
TIPS
NHTs
cat. [Cp*RhLn]
O
H
TIPS
c) Tunable C-C or C-N cleavages of acylsulfonamides for annulations (this work) O O O R1 R1 cat. [Cp*RhLn] O N2 NHTs or + R3 wit hout or with 2 4 2 R R3 R H CO2R exter nal oxidants CO2R4
R1
O
R3
R2
Scheme 1 Acylsulfonamide‐assisted RhIII‐catalyzed C−H functionalization.
CO2R4
chemistry,11 herein we wish to report an unexpected rhodium‐ catalyzed tunable oxidative cyclocondensation of readily available N‐tosylacrylamides and diazo compounds, providing access to the selective synthesis12 of full‐substituted α‐pyrones and furans (Scheme 1c). In this protocol, the acylsulfonamide groups formally serve as either an oxidizing DG6 or a traceless DG13 for the directed insertion of carbenoides14 into vinyl C–H bonds,15 respectively, through unprecedented in situ C–N and C–C cleavage under mild conditions.16 Our initial studies were devoted to the expendient synthesis of N‐tosyl acrylamides 1, which were commonly prepared from their carboxylic acid precursors.10f‐h To our delight, using our previously developed method for the assembly of eneyne‐ imides (1, R2 = alkynyl),11b a series of acrylamides 1 could be easily synthesized from simple aldehydes, terminal alkynes, and tosyl azide in good yields with high stereoselctivities by using tBuOLi as the base instead (Scheme 2 and ESI†).
+
R2CHO
R1
+
TsN3
CuI (10 mol%) Et4 NI (10 mol%) tBuOLi (3.0 equiv) 25 o C, CH2 Cl 2 then NH4Cl ( aq)
Scheme 2 Synthesis of N‐tosylacrylamides 1.
This journal is © The Royal Society of Chemistry 20xx
O R1 R2
NHTs
1 R1, R2 = alkyl, (hetero)aryl 71-90% yield (tr ans/cis > 95:5)
J. Name., 2013, 00, 1‐3 | 1
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The coupling of N‐tosylacrylamide 1a and diazoacetoacetate 2a was then investigated in methanol at 60 °C under N2 (Table 1). While no product formation was observed in the absence of any catalysts, the use of [Cp*RhCl2]2 (2.5 mol%) produced α‐ pyrone 3aa in 98% yield (Table 1, entries 1 and 2). Interestingly, the acylsulfonamide group formally served as an oxidizing DG using C−N bond as an internal oxidant without any need of additives, while known amide DGs usually required additional acids.8d,14k While alcoholic solvents like EtOH and tBuOH lead to a slight decrease in the product yield (Table 1, entries 3 and 4), other solvents such as DCE, PhMe, CH3CN, dioxane, DMF, and THF significantly lowered the yield of 3aa (see ESI† for details). Surprisingly, when 1.0 equiv of AgOAc was added, 3aa and furan 4aa was isolated in 64% and 30% yield, respectively (Table 1, entry 5). It was found that increasing the amounts of AgOAc to 2.0 equiv could sharply raise the yield of 4aa to 61% (Table 1, entry 6). Further attempts to improve the selectivity to 4aa using a set of common oxidants including Ag2CO3, Ag2O, and Cu(OAc)2 proved unsuccessful (Table 1, entries 7–9). Gratifyingly, an extra addition of 10 mol% AgSbF6 allowed the efficient formation of furan 4aa in 78% yield (Table 1, entry 10). In contrast, in the absence of Rh catalysts, only trace amounts of 3aa was formed without any detectable 4aa, suggesting that both cationic rodium species and Ag salts are required for the generation of furan 4aa (Table 1, entry 11). Furthermore, a radical scavenge of 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO, 2 equiv) would completely forbid the formation of 4aa but still forged 3aa in 93% yield, hinting that a radical‐mediated conversion was presumably involved in the C−C bond cleavage process leading to furan products (Table 1, entry 12).17 Substrate scopes of the RhIII‐catalyzed oxidative cyclization to α‐pyrones 3 under redox‐neutral conditions were evaluated (Scheme 3). A variety of N‐tosylacrylamides 1a–o underwent
ChemComm Accepted Manuscript
Published on 01 December 2015. Downloaded by University of Toronto on 03/12/2015 01:00:28.
COMMUNICATION
View OArticle Online O R
DOI: 10.1039/C5CC09137C R1
O
1
NHTs
+
N2
MeOH, 60 oC, 12 h, N2
CO2R4
R2 1
2
O
1
Ph CO2tBu
3aa R = Ph, 98% 3ba R1 = 4-MeOC6H4, 90% 3ca R1 = 4-FC6H4, 94% 3da R1 = 4-NO2C6H4, 90%
R2 CO2tBu O
O
O Ph
O
O O
O
O
Ph
Ph S
CO2tBu
CO2tBu
CO2tBu
MeO
3ma 95%
3la 97%
3ka 95% O Ph
O O
Ph
Ph
3oa 87%
O R3
Ph CO2R4
CO2Et
4
3ad R3 = Bu, 96% 3ae R3 = Ph, 86% 3af R3 = 4-ClC6H4, 83% 3ag R3 = 4-BrC6H4, 77% 3ah R3 = 4-NO2C6H4, 85%
3ab R = Et, 95%
O
3ac R4 = Me, 93%
S
O
Ph
O
Ph
O
O R3 CO2Me
CO2tBu 3na 83%
O Ph
O
CO2tBu
Ph
R3
3ea R2 = 2-MeC6H4, 90% 3fa R2 = 4-MeOC6H4, 93% 3ga R2 = 4-FC6H4, 85% 3ha R2 = 2,4-Cl2C6H3, 90% 3ia R2 = 4-BrC6H4, 86% 3ja R2 = 4-NO2C6H4, 92%
O Ph
O
S
R
2
CO2R4 3
O R1
O
2.5 mol% [Cp*RhCl2]2
R3
3ai R3 = 4-MeC6H4, 85% 3aj R3 = 4-FC6H4, 86% 3ak R3 = 4-ClC6H4, 81% 3al R3 = 4-BrC6H4, 77%
Ph
CO2Me Ph 3am 85%
Scheme 3 Substrate scopes for the formation of 3.
MeO
O
CO2Et 3fb 96%
the formal [3 + 3] cyclization with 2a smoothly to deliver the targeted products. Variation of R1 and R2 substituents showed that the benzene rings with an electron‐dona ng group (−OMe) or an electron‐withdrawing group (−NO2) as well as o‐methyl were well tolerated, producing the desired α‐pyrones in 80‐98% yield. The reaction conditions were compatible with Br and Cl groups, which are useful handles for further manipulations via transition‐metal‐catalyzed coupling reactions (3ha and 3ja). The 2‐thienyl and 2‐naphthyl analogues could be employed to afford the corresponding products (3ka, 3la, and 3oa) in high Table 1. Optimization of reaction conditionsa yield. Those N‐tosylacrylamides bearing alkyl or cyclohexenyl groups also showed good reactivity with synthetically excellent yields (3ma and 3na). Meanwhile, the reaction of a wide range of diazo compounds (2a–m) with 1a was tested. Differential substitution on the ester gave the desired products in high yield (3ab and 3ac). Diazo substrates containing a wide scope b Yield (%) of substituents like methyl, butyl, subsituted phenyl, and 2‐ Entry Additive (equiv) Solvent 3aa 4aa thienyl groups had no problem to form products 3ad–3am in c – MeOH – – 1 77‐98% yield. Pyrone 3fb bearing four different substituents 2 – MeOH 98 – could easily be construrcted in excellent yield. 3 – EtOH 92 – The formal [2 + 3] cyclization to furans 4 via sequential C–H 4 – tBuOH 90 – and C–C cleavage was next investigated (Scheme 4). A set of N‐ 5 AgOAc (1.0) MeOH 64 30 tosylacrylamides having various substituted aryl groups as the 6 AgOAc (2.0) MeOH 33 61 R1/R2 groups were well tolerated, giving the desired products 7 Ag2O (2.0) MeOH 35 58 (4aa–4ja) in 50‐78% yield along with some corresponding MeOH 40 45 8 Ag2CO3 (2.0) 9 Cu(OAc)2 (2.0) MeOH 78 15 pyrone products 3. It was found that employing n‐hexyl group 10 AgOAc (2.0)/ AgSbF6 MeOH 13 78 as the R1 was also applicable to furnish 4ma (54%). Moreover, c AgOAc (2.0)/ AgSbF6 MeOH
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Wu, D. Wang, Y. Wan and C. Ma, Chem. Commun., 2015, DOI: 10.1039/C5CC09137C.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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DOI: 10.1039/C5CC09137C
Journal Name COMMUNICATION
Published on 01 December 2015. Downloaded by University of Toronto on 03/12/2015 01:00:28.
Rhodium‐Catalyzed Tunable Oxidative Cyclization toward the Selective Synthesis of α‐Pyrones and Furans Received 00th January 20xx, Accepted 00th January 20xx
Jiaping Wu, Dongxu Wang, Yanjun Wan, and Cheng Ma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The rhodium(III)‐catalyzed tunable oxidative cyclization of readily available N‐tosylacrylamides and diazo compounds is presented, which offeres a novel method for the selective construction of fully substituted α‐pyrones and furans in a regiospecific manner by employing acylsulfonamide groups as a versatile in situ removable directing group.
a) Oxidative annulation of N-benzoylsulfonamide with Isocyanide by Zhu and Falck O O NTs H
cat. [Cp*RhLn ]
RNC
NTs
oxidant s
N R b) Olefinic C- H alkynylation of N-tosylacrylamides by Loh and co-wor kers O R1
During the past decades, the directing‐group‐assisted method has become as a pivotal strategy for transition‐metal‐catalyzed C−H bond func onaliza on to produce diversely substituted molecules.1 In this context, the rhodium(III)‐mediated tandem oxidative C–H functionalization/cyclization reactions, typically involving the directing group (DG), offer a promising tool for the construction of various heterocycles.2,3 While a large numbers of DGs allow for this class of transformations, the development of in situ convertible poly‐functional DGs4 is worthy of special attention on behalf of diversity‐oriented synthesis.5 It has been noticed that this class of DGs not only enhance the efficiency4b of metal‐catalyzed direct C−H bond activation but also provide several straightforward access to structurally complex and diverse molecules by cleaving their N−O,6 N−N,7 or C−N8 bonds, albeit usually containing worthless fragments of the DGs used. The acylsulfonamide group, a bioisostere of carboxylic acid in medicinal chemistry,9 has recently been found capable of promoting several transition‐metal‐catalyzed directed C–H bond functionalization reactions.10 For instance, Zhu and Falck in 2011 presented the rhodium‐catalyzed oxidative annulation of N‐benzoylsulfonamides and isocyanides through arene C–H bond activation (Scheme 1a).10b In 2014, Loh and co‐workers notably achieved the olefinic C−H alkynylation of acrylamides (Scheme 1b).10g Among these, the acylsulfonamide group was regarded as a weakly coordinating DG and rendered somewhat superiority in C−H activation comparing with other reported DGs. As a part of our continuing efforts in N‐tosylacrylamide
+
H
O NHTs
+
I
O R1
TIPS
NHTs
cat. [Cp*RhLn]
O
H
TIPS
c) Tunable C-C or C-N cleavages of acylsulfonamides for annulations (this work) O O O R1 R1 cat. [Cp*RhLn] O N2 NHTs or + R3 wit hout or with 2 4 2 R R3 R H CO2R exter nal oxidants CO2R4
R1
O
R3
R2
Scheme 1 Acylsulfonamide‐assisted RhIII‐catalyzed C−H functionalization.
CO2R4
chemistry,11 herein we wish to report an unexpected rhodium‐ catalyzed tunable oxidative cyclocondensation of readily available N‐tosylacrylamides and diazo compounds, providing access to the selective synthesis12 of full‐substituted α‐pyrones and furans (Scheme 1c). In this protocol, the acylsulfonamide groups formally serve as either an oxidizing DG6 or a traceless DG13 for the directed insertion of carbenoides14 into vinyl C–H bonds,15 respectively, through unprecedented in situ C–N and C–C cleavage under mild conditions.16 Our initial studies were devoted to the expendient synthesis of N‐tosyl acrylamides 1, which were commonly prepared from their carboxylic acid precursors.10f‐h To our delight, using our previously developed method for the assembly of eneyne‐ imides (1, R2 = alkynyl),11b a series of acrylamides 1 could be easily synthesized from simple aldehydes, terminal alkynes, and tosyl azide in good yields with high stereoselctivities by using tBuOLi as the base instead (Scheme 2 and ESI†).
+
R2CHO
R1
+
TsN3
CuI (10 mol%) Et4 NI (10 mol%) tBuOLi (3.0 equiv) 25 o C, CH2 Cl 2 then NH4Cl ( aq)
Scheme 2 Synthesis of N‐tosylacrylamides 1.
This journal is © The Royal Society of Chemistry 20xx
O R1 R2
NHTs
1 R1, R2 = alkyl, (hetero)aryl 71-90% yield (tr ans/cis > 95:5)
J. Name., 2013, 00, 1‐3 | 1
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The coupling of N‐tosylacrylamide 1a and diazoacetoacetate 2a was then investigated in methanol at 60 °C under N2 (Table 1). While no product formation was observed in the absence of any catalysts, the use of [Cp*RhCl2]2 (2.5 mol%) produced α‐ pyrone 3aa in 98% yield (Table 1, entries 1 and 2). Interestingly, the acylsulfonamide group formally served as an oxidizing DG using C−N bond as an internal oxidant without any need of additives, while known amide DGs usually required additional acids.8d,14k While alcoholic solvents like EtOH and tBuOH lead to a slight decrease in the product yield (Table 1, entries 3 and 4), other solvents such as DCE, PhMe, CH3CN, dioxane, DMF, and THF significantly lowered the yield of 3aa (see ESI† for details). Surprisingly, when 1.0 equiv of AgOAc was added, 3aa and furan 4aa was isolated in 64% and 30% yield, respectively (Table 1, entry 5). It was found that increasing the amounts of AgOAc to 2.0 equiv could sharply raise the yield of 4aa to 61% (Table 1, entry 6). Further attempts to improve the selectivity to 4aa using a set of common oxidants including Ag2CO3, Ag2O, and Cu(OAc)2 proved unsuccessful (Table 1, entries 7–9). Gratifyingly, an extra addition of 10 mol% AgSbF6 allowed the efficient formation of furan 4aa in 78% yield (Table 1, entry 10). In contrast, in the absence of Rh catalysts, only trace amounts of 3aa was formed without any detectable 4aa, suggesting that both cationic rodium species and Ag salts are required for the generation of furan 4aa (Table 1, entry 11). Furthermore, a radical scavenge of 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO, 2 equiv) would completely forbid the formation of 4aa but still forged 3aa in 93% yield, hinting that a radical‐mediated conversion was presumably involved in the C−C bond cleavage process leading to furan products (Table 1, entry 12).17 Substrate scopes of the RhIII‐catalyzed oxidative cyclization to α‐pyrones 3 under redox‐neutral conditions were evaluated (Scheme 3). A variety of N‐tosylacrylamides 1a–o underwent
ChemComm Accepted Manuscript
Published on 01 December 2015. Downloaded by University of Toronto on 03/12/2015 01:00:28.
COMMUNICATION
View OArticle Online O R
DOI: 10.1039/C5CC09137C R1
O
1
NHTs
+
N2
MeOH, 60 oC, 12 h, N2
CO2R4
R2 1
2
O
1
Ph CO2tBu
3aa R = Ph, 98% 3ba R1 = 4-MeOC6H4, 90% 3ca R1 = 4-FC6H4, 94% 3da R1 = 4-NO2C6H4, 90%
R2 CO2tBu O
O
O Ph
O
O O
O
O
Ph
Ph S
CO2tBu
CO2tBu
CO2tBu
MeO
3ma 95%
3la 97%
3ka 95% O Ph
O O
Ph
Ph
3oa 87%
O R3
Ph CO2R4
CO2Et
4
3ad R3 = Bu, 96% 3ae R3 = Ph, 86% 3af R3 = 4-ClC6H4, 83% 3ag R3 = 4-BrC6H4, 77% 3ah R3 = 4-NO2C6H4, 85%
3ab R = Et, 95%
O
3ac R4 = Me, 93%
S
O
Ph
O
Ph
O
O R3 CO2Me
CO2tBu 3na 83%
O Ph
O
CO2tBu
Ph
R3
3ea R2 = 2-MeC6H4, 90% 3fa R2 = 4-MeOC6H4, 93% 3ga R2 = 4-FC6H4, 85% 3ha R2 = 2,4-Cl2C6H3, 90% 3ia R2 = 4-BrC6H4, 86% 3ja R2 = 4-NO2C6H4, 92%
O Ph
O
S
R
2
CO2R4 3
O R1
O
2.5 mol% [Cp*RhCl2]2
R3
3ai R3 = 4-MeC6H4, 85% 3aj R3 = 4-FC6H4, 86% 3ak R3 = 4-ClC6H4, 81% 3al R3 = 4-BrC6H4, 77%
Ph
CO2Me Ph 3am 85%
Scheme 3 Substrate scopes for the formation of 3.
MeO
O
CO2Et 3fb 96%
the formal [3 + 3] cyclization with 2a smoothly to deliver the targeted products. Variation of R1 and R2 substituents showed that the benzene rings with an electron‐dona ng group (−OMe) or an electron‐withdrawing group (−NO2) as well as o‐methyl were well tolerated, producing the desired α‐pyrones in 80‐98% yield. The reaction conditions were compatible with Br and Cl groups, which are useful handles for further manipulations via transition‐metal‐catalyzed coupling reactions (3ha and 3ja). The 2‐thienyl and 2‐naphthyl analogues could be employed to afford the corresponding products (3ka, 3la, and 3oa) in high Table 1. Optimization of reaction conditionsa yield. Those N‐tosylacrylamides bearing alkyl or cyclohexenyl groups also showed good reactivity with synthetically excellent yields (3ma and 3na). Meanwhile, the reaction of a wide range of diazo compounds (2a–m) with 1a was tested. Differential substitution on the ester gave the desired products in high yield (3ab and 3ac). Diazo substrates containing a wide scope b Yield (%) of substituents like methyl, butyl, subsituted phenyl, and 2‐ Entry Additive (equiv) Solvent 3aa 4aa thienyl groups had no problem to form products 3ad–3am in c – MeOH – – 1 77‐98% yield. Pyrone 3fb bearing four different substituents 2 – MeOH 98 – could easily be construrcted in excellent yield. 3 – EtOH 92 – The formal [2 + 3] cyclization to furans 4 via sequential C–H 4 – tBuOH 90 – and C–C cleavage was next investigated (Scheme 4). A set of N‐ 5 AgOAc (1.0) MeOH 64 30 tosylacrylamides having various substituted aryl groups as the 6 AgOAc (2.0) MeOH 33 61 R1/R2 groups were well tolerated, giving the desired products 7 Ag2O (2.0) MeOH 35 58 (4aa–4ja) in 50‐78% yield along with some corresponding MeOH 40 45 8 Ag2CO3 (2.0) 9 Cu(OAc)2 (2.0) MeOH 78 15 pyrone products 3. It was found that employing n‐hexyl group 10 AgOAc (2.0)/ AgSbF6 MeOH 13 78 as the R1 was also applicable to furnish 4ma (54%). Moreover, c AgOAc (2.0)/ AgSbF6 MeOH
