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DOI: 10.1039/C5CC05058H
Jo ournal Naame COMMU C NICATIO ON
Copper-Catalyzed Oxidativ C ve C–H/C C–H Cros s-Couplin ng of B Benzamid hiophenees es and Th Received 00th January 20xx, Accepted 00th January 20xx
Shheng Zhao, Jun Yuan, Yi-C Chen Li, Bing--Feng Shi*
Published on 06 July 2015. Downloaded by Université Laval on 06/07/2015 11:17:22.
DOII: 10.1039/x0xx000000x www w.rsc.org/
Abstract: A C Copper-catalyzzed oxidative C–H/C–H crosscou upling of benzaamides and thiiophenes has been b developed d. This rea action exibits b broad substratte scope and ex xcellent tolera nce of fun nctional groupss. The directin ng group could d be readily rem moved to afford a 2-thienyylbenzoic acidss. Arylated A thiophhenes have attrracted intensivee attention ownning to their significant vvalues in natuural products, pharmaceuticalls and adv vanced materiaals.1 Although transition meetal-catalyzed crosscou upling reactionss have providedd an efficient and a reliable acccess to these structural motifs, it sufferedd from the mullti-step preparattion of the starting aromaatic fragments and a the generattion of stoichioometric amount of toxic by-products.2 Undoubtedly, the oxidative crosscou upling betweenn simple arenees and thiophen nes via doublee C-H cleaavage would bbe the most atttractive strateg gy to constructt those scaaffolds by avooiding the preefunctionalizatio on of both sttarting matterials and therrefore making the synthetic routes r more effficient and d atom-econom mical.3,4 In 20100, You5a and Zh hang6a indepenndently reported the Pd-ccatalyzed crosss-coupling betw ween thiophenees and sev veral electron--deficient N-hheterocycles or perfluoroaarenes. Theereafter, the P Pd-catalyzed oxidative o cross--coupling of vvarious (hetero)arenes witth thiophenes have h been exten nsively studied by the sam me groups andd others (Schem me 1a).5-7 Reccently, the oxiidative cou upling of thiophenes with eleectronically distinct heteroarennes or aren nes bearing chhelation groupss has been exp panded to the uuse of rho odium catalyst8 and rutheniuum8c by the Glorius, G You annd Su gro oups (Scheme 1a). However, these establish hed methods m mainly rely y on the use off noble-metal caatalysts, such ass palladium, rhhodium and d ruthenium. Thhe developmennt of novel cataalytic systems bby the usee of cheap, abunndant, first-row w metal catalystts, such as coppper, to exeecute the dehydr drogenative aryllation would be highly desirab le. Since S the pioneering work by Yu Y and Chatan ni on the Cu-meediated C–H H functionalizaation of 2-arylppyridines,9 sign nificant progreess has
Dep partment of Chemisstry, Zhejiang Univversity, 38 Zheda Rd., Hangzhou 3100027, Chin na. E‐mail: [email protected] † Fo ootnotes rela ng to o the tle and/or a authors should app pear here. Elecctronic Supplementary Information (ESI) available: [dettails of any supplementary inform mation available should be included h here]. See DOI: 10.1039/x0xx000 000x
been achieved in th he construction of C-C and C-heteroatom C boonds cataly yzed by copper.10,11 However, the copper-cataalyzed oxidativve CH/C-H H diaryl cross-coupling reactiion remains larrgely undeveloped. In 20 012, Zhang,12a You12b, Wanng12c and Bolm m12d independeently reported the copper-catalyzed deh ehydrogenative cross-couplingg of two electron-deficiient (hetero)arrenes with distinctly d diffeerent electrronic characteriistics. The Miuura group reporrted several elegant exam mples of cross-coupling betweeen heteroarenes containing accidic C-H bonds and arenes bearing diirecting groups.13 Although thhese metho ods are efficient, one of thee coupling parttners is limitedd to (heterro)arenes containing acidic C––H bonds, such as azoles, azinee NTo the best of oxidees, and perfluo oroarenes.12,13 T o our knowledge, coppeer-catalyzed deehydrogenative cross-coupling with thiopheenes has never n been achieved, largely because thioph henes are electtronrich and a are more prone to oxidatiive homocoupliing in the preseence of co opper catalysts.14 As part of oour continuing efforts on coppperN,N-bidentate auxiliary,15,16 we cataly yzed C-H activation with N presented a Cu-cattalyzed oxidatiive C–H/C–H cross-couplingg of 1 benzaamides and thio ophenes using (pyridin-2-yl)issopropyl (PIP)17 as directting group (Sch heme 1b). It is worth noting that t this is the first exam mple of Cu-cataalyzed direct C C–H arylation with electron--rich arenees. A) A Previous work: Nob ble-Metal-Catalyzed D Dehydrogenative Aryla ation with Thiophenes X
X
H Y
Y
X=N Y = N, O, S
+
DG
S
Pd, Rh, Ru H
ref 5-8
S
DG
H
S
B) B This work: Copper-C Catalyzed Dehydrogeenative Arylation with Thiophenes T O
O Ar/ Het
N H H
N PIP
Cu
+ H
S
N H
Ar/ Het
PIP
S
cheap metal: coppe er non-acidic arenees: thiophenes and benzothiophenes b removable DG broad substrate -sccope: 24 examples gram scale
Schem me 1. Transittion-metal-catallyzed dehydro ogenative arylaation with thiophenes t
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We commenced the investigation by the optimization of reaction conditions using benzamide 1a and 2-methylthiophene 2a as the model substrates. After fully screening of the copper catalysis and the accessible oxidants, we were delighted to obtain the desired product 3a in 37% yield in the presense of CuOAc (0.2 equiv) as optimal catalysis, AgNO3 (2.0 equiv) as oxidant and Li2CO3 (3.0 equiv) as base (Table 1, entry 1). Consistent with previous reports,11 the Cu/Ag catalytic system exhibited superior efficiency in current transformation. We also found that the yield could be improved by increasing the amount of AgNO3 (entry 2). Then we investigated the influence of the amount of CuOAc. We observed that the yields were reduced when the amount of CuOAc was increased, largely because of the formation of unwanted hydroxylation product6a and the homocoupling of thiophene (entries 3-5). Subsequently, various Lewis acids were examined to tune the reactivity and Zn(OAc)2 was found to be the best (entries 6-8). To our delight, by simply turning the amount of AgNO3 and Zn(OAc)2, the desired product 3a was obtained in 78% yield under the following optimal conditions: 20 mol% CuOAc, 3.0 equiv of Li2CO3, 1.2 equiv of Zn(OAc)2 and 4.0 equiv of AgNO3 in DMF (0.3 M) under N2 at 120 oC for 24 h (entry 13). The control experiment showed that copper is crucial for this reaction (entry 15). The use of excess amount of thiophene (3 equiv) was crucial for the efficiency of this reaction, might due to the homocoupling of thiophene (Table S10).
positions of benzamides (Scheme 2, 3a-3j). Both electron-donating View Article Online 10.1039/C5CC05058H (fluoro, chloro, iodo, trifluoromethyl, DOI: methoxycarbonyl) and electron-withdrawing (methoxy and alkyl) substituents on aryls, were compatible with this protocol. meta-Alkoxy substrates exclusively reacted at the sterically more hindered position, indicating that the alkoxy group probably have a coordinating effect with the copper catalyst (3d). Besides, the 2-naphthamide substrate also proceeded well in this reaction and reacted with 2a regioselectively at the 3-position, which is generally considered as the more electronic-rich position (3k). Moreover, some representative heterocyclic substrates, including pyridines and thiophenes, were also well tolerated, furnishing the biologically important biheteroaryl motifs in moderate yields (3l-3o). However, only moderate yields were obtained (30%-39%), largely due to the competitive coordination of heteroatom with the copper catalyst. Unfortunately, other electron-rich heterocycles, such as furans and indoles, didn’t react under the optimized reaction conditions. O
O N H
R
PIP
H
CuOAc, Li2CO3 Zn(OAc)2, AgNO3
S
H
S
3
2a
S
O
S
O
PIP
N H
O
PIP
N H
N H CF3
F 3a, 78%
S
3b, 41%
S
O
O
N H
S N H
O
PIP
N H Cl
F 3e, 50%
3d, 52%
S
O N H
PIP
3c, 32%
O
PIP
O
S
PIP
N H S
R
DMF,120 ºC, 24 h
1
Table 1. Optimization of the reaction conditions
3f, 42%
S
O
PIP
N H
O
PIP
N H
MeOOC
I
3h, 67%
3g, 40%
3i, 75%
O S
N H
O N H
PIP
S
S
S
3l, 30%
N H
S
O
PIP S
N H
O N H
N
3k, 46%
O S
PIP
S
3j, 79%
O
PIP S
N H
Cl 3m, 39%
a
Reaction conditions: 1a (0.15 mmol), CuOAc, AgNO3 (x equiv), 2a (3 equiv), Li2CO3 (3 equiv) and Lewis acid in DMF (0.5 mL) for 24 h. b 1H NMR yield using CH2Br2 as the internal standard. cIsolated yield.
With the optimized reaction conditions in hand, we next examined the scope of benzamides using 2-methylthiophene as coupling partner. As shown in Scheme 2, the reaction could proceed well with a series of substituents at the ortho-, meta-, and para-
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3n, 35%
3o, 30%
PIP
PIP
PIP
PIP
Scheme 2. The scope of benzamides. Reaction conditions: 1 (0.15 mmol), 2a (3.0 equiv), CuOAc (0.2 equiv), Li2CO3 (3.0 equiv), Zn(OAc)2 (1.2 equiv) and AgNO3 (4.0 equiv) in DMF (0.5 mL) for 24 h, isolated yield.
The scope of various thiophene coupling partners were next examined (Scheme 3). A series of thiophenes bearing both electronrich and electron-deficient groups could afford the orthoheteroarylated products regioselectively in moderate to excellent yields (Scheme 3). 2-Acylthiophene only gave the corresponding
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product 4h in 20% yield only, probably due to the strong electronwithdrawing of the acyl group (4h). Halides such as chloride and bromide, which are useful for further synthetic transformations, were well tolerated under the reaction conditions and no cross-coupling between thiophenes was observed (4c and 4d). Surprisingly, oxidative coupling at the β-position of thiophene could also proceed, provided that no α-hydrogen was presented (2,5-dichlorothiophene, 4i, 62% yield). Meanwhile, 3-substituted thiophenes were tested as the coupling partners (4j and 4k). The 3-methyl thiophene only reacted at the 5-position, probably due to the steric effect of the methyl group (4j). However, 3-methoxythiophene gave a mixture of the desired products at both the 2- and 5-positions, which could be easily separated by chromatography. Interestingly, arylation happened predominantly at the 5-position, probably due to the coordinating effect of the methoxy group (4ka, 28% and 4kb, 50%).
N H
PIP H
CuOAc, Li2CO3 Zn(OAc)2, AgNO3
S
H
X
1a
N H
DMF,120 ºC, 24 h
S 3
2
S
O N H
PIP
N H
4a, 55%
Br S
O
PIP
N H
4b, 81%
S
O N H
4e, 67%
4d, 77%
N H
PIP
S
O
4f, 90%
O
PIP
N H
N H
4g, 85%
PIP
4h, 20%
MeO
S S
O N H 4i, 62%
PIP
O S
Cl Cl
N H
4c, 81%
O
PIP
Scheme 5. Mechanistic Investigations
O
PIP
Ph
OMe S
S
O
PIP
X
Cl S
To gain further insight into the mechanism of thisView oxidative C– Article Online 10.1039/C5CC05058H H/C–H cross-coupling reaction, a series of DOI: deuteration experiments were conducted. The intermolecular KIE for cross dehydrogenative coupling is 3.0 while the intramolecular KIE is 1.9, indicating that C–H activation procedure is either rate-determining step or the ratedetermining step is prior to C–H cleavage.18
O
O
PIP
S
O N H
4j, 58%
PIP
MeO O N H
S
O N H
PIP
4ka, 28%
PIP
Although the detailed mechansim is not clearly understood, a tentative reaction pathway was proposed in Scheme 6 based on the precedents.11,19 First, Cu(I) is in situ oxidized to Cu(II), which coordinates with the directing group. Subsequent ortho-C–H activation affords the Cu(II)-complex A. Then the Cu(III)-aryl intermediate B was formed after oxidation or disproportionation.11 The electrophilic copper intermediate B reacts with thiophene via an electrophilic aromatic substitution (SEAr) parthway to generate Cu(III)-intermediate C. Reductive elimination gives the desired product 3a and Cu(I) to finish the catalytic cycle. Although the exact role of Zn(OAc)2 is unclear at this stage, we hypothesized that it might facilitate the SEAr step.
4kb, 50%
Scheme 3. The scope of thiophenes. Reaction conditions: 1a (0.15 mmol), 2 (3.0 equiv), CuOAc (0.2 equiv), Li2CO3 (3.0 equiv), Zn(OAc)2 (1.2 equiv) and AgNO3 (4.0 equiv) in DMF (0.5 mL) for 24 h, isolated yield. Finally, a gram-scale reaction was conducted using 2methylthiophene as the coupling partner. This cross dehydrogenative coupling was found to be applicable and afforded the product 3a in 71 % yield (1.08 g). Additionally, the PIP directing group could be readily removed. As shown in Scheme 4, nitrosylation of the secondary amide followed by hydrolysis in the presence of LiOH and H2O2 gave the corresponding 2-heterobenzoic acid 5 in good yield (85%).17 This acid product 5 could be potentially used as a synthetic intermediate for further application.
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Scheme 6. Plausible reaction mechanism
In summary, we have developed a copper-catalyzed oxidative C– H/C–H cross-coupling of benzamides bearing PIP directing group with various thiophenes. This strategy is scalable and a wide range of functional groups were compatible, providing an efficient protocol for the construction of valuable arylated thiophenes. Moreover, the directing group could be easily removed after the
Scheme 4. Gram scale synthesis and removal of the directing group
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coupling reaction, which gave the corresponding 2-thienylbenzoic acids in good yield.
9 10
Acknowledgements Financial support from the National Basic Research Program of China (2015CB856600), the NSFC (21422206, 21272206, J1210042), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.
11
Notes and references
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A copper-catalyzed oxidative C–H/C–H cross-coupling of benzamides and thiophenes is described.
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DOI: 10.1039/C5CC05058H
Jo ournal Naame COMMU C NICATIO ON
Copper-Catalyzed Oxidativ C ve C–H/C C–H Cros s-Couplin ng of B Benzamid hiophenees es and Th Received 00th January 20xx, Accepted 00th January 20xx
Shheng Zhao, Jun Yuan, Yi-C Chen Li, Bing--Feng Shi*
Published on 06 July 2015. Downloaded by Université Laval on 06/07/2015 11:17:22.
DOII: 10.1039/x0xx000000x www w.rsc.org/
Abstract: A C Copper-catalyzzed oxidative C–H/C–H crosscou upling of benzaamides and thiiophenes has been b developed d. This rea action exibits b broad substratte scope and ex xcellent tolera nce of fun nctional groupss. The directin ng group could d be readily rem moved to afford a 2-thienyylbenzoic acidss. Arylated A thiophhenes have attrracted intensivee attention ownning to their significant vvalues in natuural products, pharmaceuticalls and adv vanced materiaals.1 Although transition meetal-catalyzed crosscou upling reactionss have providedd an efficient and a reliable acccess to these structural motifs, it sufferedd from the mullti-step preparattion of the starting aromaatic fragments and a the generattion of stoichioometric amount of toxic by-products.2 Undoubtedly, the oxidative crosscou upling betweenn simple arenees and thiophen nes via doublee C-H cleaavage would bbe the most atttractive strateg gy to constructt those scaaffolds by avooiding the preefunctionalizatio on of both sttarting matterials and therrefore making the synthetic routes r more effficient and d atom-econom mical.3,4 In 20100, You5a and Zh hang6a indepenndently reported the Pd-ccatalyzed crosss-coupling betw ween thiophenees and sev veral electron--deficient N-hheterocycles or perfluoroaarenes. Theereafter, the P Pd-catalyzed oxidative o cross--coupling of vvarious (hetero)arenes witth thiophenes have h been exten nsively studied by the sam me groups andd others (Schem me 1a).5-7 Reccently, the oxiidative cou upling of thiophenes with eleectronically distinct heteroarennes or aren nes bearing chhelation groupss has been exp panded to the uuse of rho odium catalyst8 and rutheniuum8c by the Glorius, G You annd Su gro oups (Scheme 1a). However, these establish hed methods m mainly rely y on the use off noble-metal caatalysts, such ass palladium, rhhodium and d ruthenium. Thhe developmennt of novel cataalytic systems bby the usee of cheap, abunndant, first-row w metal catalystts, such as coppper, to exeecute the dehydr drogenative aryllation would be highly desirab le. Since S the pioneering work by Yu Y and Chatan ni on the Cu-meediated C–H H functionalizaation of 2-arylppyridines,9 sign nificant progreess has
Dep partment of Chemisstry, Zhejiang Univversity, 38 Zheda Rd., Hangzhou 3100027, Chin na. E‐mail: [email protected] † Fo ootnotes rela ng to o the tle and/or a authors should app pear here. Elecctronic Supplementary Information (ESI) available: [dettails of any supplementary inform mation available should be included h here]. See DOI: 10.1039/x0xx000 000x
been achieved in th he construction of C-C and C-heteroatom C boonds cataly yzed by copper.10,11 However, the copper-cataalyzed oxidativve CH/C-H H diaryl cross-coupling reactiion remains larrgely undeveloped. In 20 012, Zhang,12a You12b, Wanng12c and Bolm m12d independeently reported the copper-catalyzed deh ehydrogenative cross-couplingg of two electron-deficiient (hetero)arrenes with distinctly d diffeerent electrronic characteriistics. The Miuura group reporrted several elegant exam mples of cross-coupling betweeen heteroarenes containing accidic C-H bonds and arenes bearing diirecting groups.13 Although thhese metho ods are efficient, one of thee coupling parttners is limitedd to (heterro)arenes containing acidic C––H bonds, such as azoles, azinee NTo the best of oxidees, and perfluo oroarenes.12,13 T o our knowledge, coppeer-catalyzed deehydrogenative cross-coupling with thiopheenes has never n been achieved, largely because thioph henes are electtronrich and a are more prone to oxidatiive homocoupliing in the preseence of co opper catalysts.14 As part of oour continuing efforts on coppperN,N-bidentate auxiliary,15,16 we cataly yzed C-H activation with N presented a Cu-cattalyzed oxidatiive C–H/C–H cross-couplingg of 1 benzaamides and thio ophenes using (pyridin-2-yl)issopropyl (PIP)17 as directting group (Sch heme 1b). It is worth noting that t this is the first exam mple of Cu-cataalyzed direct C C–H arylation with electron--rich arenees. A) A Previous work: Nob ble-Metal-Catalyzed D Dehydrogenative Aryla ation with Thiophenes X
X
H Y
Y
X=N Y = N, O, S
+
DG
S
Pd, Rh, Ru H
ref 5-8
S
DG
H
S
B) B This work: Copper-C Catalyzed Dehydrogeenative Arylation with Thiophenes T O
O Ar/ Het
N H H
N PIP
Cu
+ H
S
N H
Ar/ Het
PIP
S
cheap metal: coppe er non-acidic arenees: thiophenes and benzothiophenes b removable DG broad substrate -sccope: 24 examples gram scale
Schem me 1. Transittion-metal-catallyzed dehydro ogenative arylaation with thiophenes t
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We commenced the investigation by the optimization of reaction conditions using benzamide 1a and 2-methylthiophene 2a as the model substrates. After fully screening of the copper catalysis and the accessible oxidants, we were delighted to obtain the desired product 3a in 37% yield in the presense of CuOAc (0.2 equiv) as optimal catalysis, AgNO3 (2.0 equiv) as oxidant and Li2CO3 (3.0 equiv) as base (Table 1, entry 1). Consistent with previous reports,11 the Cu/Ag catalytic system exhibited superior efficiency in current transformation. We also found that the yield could be improved by increasing the amount of AgNO3 (entry 2). Then we investigated the influence of the amount of CuOAc. We observed that the yields were reduced when the amount of CuOAc was increased, largely because of the formation of unwanted hydroxylation product6a and the homocoupling of thiophene (entries 3-5). Subsequently, various Lewis acids were examined to tune the reactivity and Zn(OAc)2 was found to be the best (entries 6-8). To our delight, by simply turning the amount of AgNO3 and Zn(OAc)2, the desired product 3a was obtained in 78% yield under the following optimal conditions: 20 mol% CuOAc, 3.0 equiv of Li2CO3, 1.2 equiv of Zn(OAc)2 and 4.0 equiv of AgNO3 in DMF (0.3 M) under N2 at 120 oC for 24 h (entry 13). The control experiment showed that copper is crucial for this reaction (entry 15). The use of excess amount of thiophene (3 equiv) was crucial for the efficiency of this reaction, might due to the homocoupling of thiophene (Table S10).
positions of benzamides (Scheme 2, 3a-3j). Both electron-donating View Article Online 10.1039/C5CC05058H (fluoro, chloro, iodo, trifluoromethyl, DOI: methoxycarbonyl) and electron-withdrawing (methoxy and alkyl) substituents on aryls, were compatible with this protocol. meta-Alkoxy substrates exclusively reacted at the sterically more hindered position, indicating that the alkoxy group probably have a coordinating effect with the copper catalyst (3d). Besides, the 2-naphthamide substrate also proceeded well in this reaction and reacted with 2a regioselectively at the 3-position, which is generally considered as the more electronic-rich position (3k). Moreover, some representative heterocyclic substrates, including pyridines and thiophenes, were also well tolerated, furnishing the biologically important biheteroaryl motifs in moderate yields (3l-3o). However, only moderate yields were obtained (30%-39%), largely due to the competitive coordination of heteroatom with the copper catalyst. Unfortunately, other electron-rich heterocycles, such as furans and indoles, didn’t react under the optimized reaction conditions. O
O N H
R
PIP
H
CuOAc, Li2CO3 Zn(OAc)2, AgNO3
S
H
S
3
2a
S
O
S
O
PIP
N H
O
PIP
N H
N H CF3
F 3a, 78%
S
3b, 41%
S
O
O
N H
S N H
O
PIP
N H Cl
F 3e, 50%
3d, 52%
S
O N H
PIP
3c, 32%
O
PIP
O
S
PIP
N H S
R
DMF,120 ºC, 24 h
1
Table 1. Optimization of the reaction conditions
3f, 42%
S
O
PIP
N H
O
PIP
N H
MeOOC
I
3h, 67%
3g, 40%
3i, 75%
O S
N H
O N H
PIP
S
S
S
3l, 30%
N H
S
O
PIP S
N H
O N H
N
3k, 46%
O S
PIP
S
3j, 79%
O
PIP S
N H
Cl 3m, 39%
a
Reaction conditions: 1a (0.15 mmol), CuOAc, AgNO3 (x equiv), 2a (3 equiv), Li2CO3 (3 equiv) and Lewis acid in DMF (0.5 mL) for 24 h. b 1H NMR yield using CH2Br2 as the internal standard. cIsolated yield.
With the optimized reaction conditions in hand, we next examined the scope of benzamides using 2-methylthiophene as coupling partner. As shown in Scheme 2, the reaction could proceed well with a series of substituents at the ortho-, meta-, and para-
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3n, 35%
3o, 30%
PIP
PIP
PIP
PIP
Scheme 2. The scope of benzamides. Reaction conditions: 1 (0.15 mmol), 2a (3.0 equiv), CuOAc (0.2 equiv), Li2CO3 (3.0 equiv), Zn(OAc)2 (1.2 equiv) and AgNO3 (4.0 equiv) in DMF (0.5 mL) for 24 h, isolated yield.
The scope of various thiophene coupling partners were next examined (Scheme 3). A series of thiophenes bearing both electronrich and electron-deficient groups could afford the orthoheteroarylated products regioselectively in moderate to excellent yields (Scheme 3). 2-Acylthiophene only gave the corresponding
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product 4h in 20% yield only, probably due to the strong electronwithdrawing of the acyl group (4h). Halides such as chloride and bromide, which are useful for further synthetic transformations, were well tolerated under the reaction conditions and no cross-coupling between thiophenes was observed (4c and 4d). Surprisingly, oxidative coupling at the β-position of thiophene could also proceed, provided that no α-hydrogen was presented (2,5-dichlorothiophene, 4i, 62% yield). Meanwhile, 3-substituted thiophenes were tested as the coupling partners (4j and 4k). The 3-methyl thiophene only reacted at the 5-position, probably due to the steric effect of the methyl group (4j). However, 3-methoxythiophene gave a mixture of the desired products at both the 2- and 5-positions, which could be easily separated by chromatography. Interestingly, arylation happened predominantly at the 5-position, probably due to the coordinating effect of the methoxy group (4ka, 28% and 4kb, 50%).
N H
PIP H
CuOAc, Li2CO3 Zn(OAc)2, AgNO3
S
H
X
1a
N H
DMF,120 ºC, 24 h
S 3
2
S
O N H
PIP
N H
4a, 55%
Br S
O
PIP
N H
4b, 81%
S
O N H
4e, 67%
4d, 77%
N H
PIP
S
O
4f, 90%
O
PIP
N H
N H
4g, 85%
PIP
4h, 20%
MeO
S S
O N H 4i, 62%
PIP
O S
Cl Cl
N H
4c, 81%
O
PIP
Scheme 5. Mechanistic Investigations
O
PIP
Ph
OMe S
S
O
PIP
X
Cl S
To gain further insight into the mechanism of thisView oxidative C– Article Online 10.1039/C5CC05058H H/C–H cross-coupling reaction, a series of DOI: deuteration experiments were conducted. The intermolecular KIE for cross dehydrogenative coupling is 3.0 while the intramolecular KIE is 1.9, indicating that C–H activation procedure is either rate-determining step or the ratedetermining step is prior to C–H cleavage.18
O
O
PIP
S
O N H
4j, 58%
PIP
MeO O N H
S
O N H
PIP
4ka, 28%
PIP
Although the detailed mechansim is not clearly understood, a tentative reaction pathway was proposed in Scheme 6 based on the precedents.11,19 First, Cu(I) is in situ oxidized to Cu(II), which coordinates with the directing group. Subsequent ortho-C–H activation affords the Cu(II)-complex A. Then the Cu(III)-aryl intermediate B was formed after oxidation or disproportionation.11 The electrophilic copper intermediate B reacts with thiophene via an electrophilic aromatic substitution (SEAr) parthway to generate Cu(III)-intermediate C. Reductive elimination gives the desired product 3a and Cu(I) to finish the catalytic cycle. Although the exact role of Zn(OAc)2 is unclear at this stage, we hypothesized that it might facilitate the SEAr step.
4kb, 50%
Scheme 3. The scope of thiophenes. Reaction conditions: 1a (0.15 mmol), 2 (3.0 equiv), CuOAc (0.2 equiv), Li2CO3 (3.0 equiv), Zn(OAc)2 (1.2 equiv) and AgNO3 (4.0 equiv) in DMF (0.5 mL) for 24 h, isolated yield. Finally, a gram-scale reaction was conducted using 2methylthiophene as the coupling partner. This cross dehydrogenative coupling was found to be applicable and afforded the product 3a in 71 % yield (1.08 g). Additionally, the PIP directing group could be readily removed. As shown in Scheme 4, nitrosylation of the secondary amide followed by hydrolysis in the presence of LiOH and H2O2 gave the corresponding 2-heterobenzoic acid 5 in good yield (85%).17 This acid product 5 could be potentially used as a synthetic intermediate for further application.
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Scheme 6. Plausible reaction mechanism
In summary, we have developed a copper-catalyzed oxidative C– H/C–H cross-coupling of benzamides bearing PIP directing group with various thiophenes. This strategy is scalable and a wide range of functional groups were compatible, providing an efficient protocol for the construction of valuable arylated thiophenes. Moreover, the directing group could be easily removed after the
Scheme 4. Gram scale synthesis and removal of the directing group
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coupling reaction, which gave the corresponding 2-thienylbenzoic acids in good yield.
9 10
Acknowledgements Financial support from the National Basic Research Program of China (2015CB856600), the NSFC (21422206, 21272206, J1210042), and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.
11
Notes and references
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A copper-catalyzed oxidative C–H/C–H cross-coupling of benzamides and thiophenes is described.
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