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COMMUNICATION oxidation of α-(alkylideneamino)nitriles to imides by molecular oxygen under mild basic conditions
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Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012, Accepted 00th January 2012
Yu Zhang, Ling Pan,* Yunjia Zou, Xianxiu Xu and Qun Liu*
DOI: 10.1039/x0xx00000x www.rsc.org/
We reveal here the unique reactivity of α(alkylideneamino)nitriles toward molecular oxygen. Thus, α(alkylideneamino)nitriles can serve as the imide building block for the efficient synthesis of imides in the absence of transition metals under extremely mild conditions. α-(Alkylideneamino)nitriles 3, which can be prepared via a threecomponent Strecker reaction (an aldehyde, an amine and cyanide ion, to give α-aminonitriles 1)1,2 followed by condensation with another aldehyde 23 or an imine,4a are useful building blocks in organic synthesis (Scheme 1).1-7 In the presence of a suitable base, anion 4 from deprotonation of α-(alkylideneamino)nitriles 3 can undergo Mannich-type reactions with imines to afford α,β-diaminonitrile derivatives4a or undergo [3+2] cycloaddition with nitroolefins to furnish substituted pyrroles.5 In general, the reaction of anion 4 with enones 5 gives 1,4-adducts 6 via Michael-type addition under basic conditions, which leads further to substituted 3,4-dihydro-2Hpyrrole-2-carbonitriles 7 through acid-promoted hydrolysis/cyclization of 6 along with the release of aldehyde 2 (Scheme 1).3a On the other hand, α-iminonitriles 8 can be prepared through one-pot three-component IBX/TBAB-mediated oxidative Strecker reaction (IBX: 2-iodoxybenzoic acid; TBAB: tetrabutylammonium bromide)2 and 8 can be further converted to amides 9 by alumina-promoted hydrolysis followed by cyanide elimination.6 In addition, the corresponding amides 9’ can be obtained by direct oxidation of N,N-dialkyl-α-aminonitrile 1’ using DMSO (in the presence of ButOK or KOH under an argon atmosphere),7a NiO2-H2O7b and m-CPBA (metachloroperoxybenzoic acid)7c as oxidants, respectively (Scheme 1). In our recent research on the [5+1],8 [6+1],9 and [7+1]10 carbocyclization reactions using active methylene compounds as C1 nucleophilic components, it was found that mediated by K2CO3 in DMSO at room temperature under oxygen atmosphere, the reaction of α-(alkylideneamino)nitrile 3 (R1 = H) with α,β-unsaturated
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ketones could lead to the formation of double oxidation products via 1,4-adducts 6 through a tandem process using molecular oxygen as the oxidant.9b This result reveals a new property of α(alkylideneamino)nitriles, the reactivity toward molecular oxygen under basic conditions. The utilization of economically and ecologically friendly molecular oxygen as oxidant is a highly attractive topic in organic synthesis,11 especially in one-pot reactions12 and in the absence of transition metals and radical initiators.13 On the other hand, one-pot reactions are efficient and cost-effective as they allow for more than one transformation in a single synthetic sequence.12,14 In this context, however, examples of the incorporation of molecular oxygen into organic compounds in the absence of transition metals or radical initiators are rare.13 We reveal here that α-(alkylideneamino)nitriles 3 containing an acidic
Scheme 1 Reactivity profile of α-(alkylideneamino)nitriles.
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methylene group can serve as the alkamido(oxo)methanide equivalent (Scheme 1) in the presence of molecular oxygen (as oxidant) and a base, as in their conjugate addition to enones to form γ-ketoimides under very mild reaction conditions (vide infra),15,16a which, alternatively, can be prepared, for example, via Michael reaction of enones with protected hydroxyl malononitriles as acyl anion equivalent.16,17
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Table 1 One-pot reactions of 1a, 2a and 5a under different conditionsa
significantly different reactivity between α-(alkylideneamino)nitrile 3a and glycine imine 11 was observed. Under identical conditions as View 5a Article Online in Table 1, entry 8, the reaction of glycine imine 11 with gave 1DOI: 10.1039/C4CC06481J pyrroline 12 and no the corresponding oxidation product 10aa could be detected.18 The above results (entries 2, 3, 6-8 and10) reveal for the first time that the 1,4-adduct, α-(alkylideneamino)nitrile 6a, exhibits the ability to activate molecular oxygen13 and enables the straightforward synthesis of γ-ketoimides 10 from simple starting materials under extremely mild reaction conditions in a tandem process12,14,15,16a via probably a tandem Csp3–H oxidation/cyanide elimination sequence of 6a (vide infra). Having thus found an effective and practical protocol for the aerobic synthesis of γketoimides,15,16a we next investigated the scope of the double oxidation reaction. The efficiency of the selected aldehydes 2a–e for the one-pot synthesis of γ-ketoamides was then examined (Table 2). We were pleased to find that, under optimal reaction conditions as in Table 1, entry 8, aromatic aldehydes 2a–d, having phenyl (entry 3), electro-deficient (entries 1 and 2) and electro-rich (entry 4) aromatic groups, can afforded the desired imides 10aa–10da in high yields. In the case of aliphatic aldehyde (pivalaldehyde 2e), imide 10ea was also produced in high yield (entry 5). Table 2 Synthesis of imides 10aa–eaa
Entry 1 2 3 4 5 6 7c 8c 9c 10 c,d 11e
Solvent DMF DMF DMF DMF THF DMSO DMSO DMSO DMSO DMSO DMSO
Base (equiv.) DBU (2.0) K2CO3 (2.0) Et3N (2.0) KOH (2.0) K2CO3 (2.0) K2CO3 (2.0) K2CO3 (1.0) K2CO3 (0.5) K2CO3 (0.2) K2CO3 (0.5) K2CO3 (0.5)
air/O2 /N2 air air air air air air O2 O2 O2 O2 N2
t (h) 36 24 24 24 24 2.0 1.5 12 24 4.5 24
Yieldb (%) 7a (97%) 10aa (10%) 10aa (20%) 7a (95%) 7a (95%) 10aa (30%) 10aa (81%) 10aa (90%) 7a (30%) 10aa (72%) 7a (95%)
a Reactions were carried out at room temperature with mole ratio of 1a/2a/5a = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields. c Reactions were carried out under an oxygen atmosphere (O2 balloon). d Mole ratio of 1a/2a/5a = 1.0:1.0:1.2. e Under a nitrogen atmosphere.
In the present research, it was found that the desired 1,4-adduct 6a was formed exclusively, by performing the model reaction of α(alkylideneamino)nitrile 3a (generated in-situ from αaminoacetonitrile hydrochloride, 4-chlorobenzaldehyde 2a and Et3N) with 4-chlorochalcone 5a at room temperature in open air for 36 h using DBU (1,8-diazabicycloundec-7-ene) as the base in the solvent, DMF. Upon silica gel column chromatography, 6a was transformed directly to 3,4-dihydro-2H-pyrrole-2-carbonitrile 7a in excellent yield along with the release of 4-chlorobenzaldehyde 2a (Table 1, entry 1).3a This result is in accordance with our previous observations for the reaction of glycine imines with enones.18b Surprisingly, imide 10aa was isolated in 10% yield from the reaction mixture of 3a with 5a under the same conditions as above but with K2CO3 as the base (entry 2).19 Further investigation showed that the formation of 10aa was apparently base and solvent dependent (entries 2-5) and K2CO3 in DMSO was found to be the suitable choice (entry 6). It was also found that, under an oxygen atmosphere, 10aa was obtained in high yields within shorter reaction times at a lower base loading (entries 7 and 8). In comparison, under a nitrogen atmosphere, adduct 6a and its further transformation to 7a upon silica gel column chromatography was observed (entry 11). These observations indicate that molecular oxygen is the sole source of oxygen in product 10aa (entries 2, 3, 6-8 and 10). Furthermore, the
2 | J. Name., 2012, 00, 1‐3
Entry 1 2 3 4 5
R 4-ClC6H4 4-BrC6H4 Ph 4-MeC6H4 t-Bu
t (h) 12 9 26 27 12
10 aa ba ca da ea
Yieldb (%) 90 78 84 83 75
a Reactions were carried out under an oxygen atmosphere with mol ratio of 1a/2/5a = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields.
Imide derivatives have numerous applications in biological, medicinal, synthetic, and polymer chemistry.20-25 Usually, imides are prepared by condensation reactions of amides with acylating reagents or activated carboxylic acid derivatives, which greatly limits the substrate scope and increases waste and inefficiency.24 Although several alternative approaches, including Pd-catalyzed cross coupling of organoborons with methyl NPd-catalyzed [methoxy(methylthio)methylene]-carbamate,20 aminocarbonylation of aryl bromides,21 α-methylene oxidation of amides with stoichiometric or excess amounts of F-TEDA-PF6 (chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-borate), derived from Selectfluor through replacement of BF4 by PF6),22a DMP (Dess-Martin Periodinane: 1,1,1tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one),22b pyridine-N-oxide22c or periodic acid,22d oxidation of oxazoles with ceric ammonium nitrate,23 photochemical aerobic oxidation of lactams or secondary benzamides,24 and copper-catalyzed oxidation of arene-fused cyclic amines25 have been developed, the synthesis of imides from simple starting materials is far from straightforward. Promoted by the successful preparation of imides 10aa–10ea using selected aromatic and aliphatic aldehydes 2a–e as the aldehyde components (Table 2), the one-pot reaction of α-aminoacetonitrile 1a, 4-chlorobenzaldehyde 2a with selected enones 5 was further investigated to examine the efficiency of enone components (Table 3). As a result, all the desired imides 10ab–10am were obtained in
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good to excellent yields with this operationally simple procedure from a broad range of enones 5b–m bearing an aroyl (Table 3, entries 1-8 and 11) or an acetyl (Table 3, entries 9 and 10) as R1CO group; an aryl (Table 3, entries 1-3, and 6-9), alkyl (Table 3, entries 4 and 10) or H (Table 3, entry 11) as R2 group; and H (Table 3, entries 1-10) or phenyl (Table 3, entry 11) as R3 group, respectively. In the case of cyclohex-2-enone as the Michael acceptor, the desired product 10am was obtained in high yield under identical conditions as above (Table 3, entry 12). Clearly, the excellent functional group tolerance for both aldehydes 2 (Table 2) and enones 5 (Table 3) allows the reaction to access a variety of imides starting from three simple starting materials, i.e. an α-aminoacetonitrile, an aldehyde and an enone, in one-pot under very mild transition metal-free conditions with molecular oxygen as the sole oxidant.
aldehyde and an enone (Table 1);3a,18 (ii) deprotonation of 6 under basic conditions giving α-cyanocarbanion I and subsequent C–H Article Online oxidation by molecular oxygen (I → III) leading toView intermediate DOI: 10.1039/C4CC06481J 6,13 7,16 (iii) cyanide elimination (IV→V) followed by Strecker IV; reaction (V→VI/VI’);1,2,6a,27 and (iv) sequential oxidation (VI/VI’→ VII) and cyanide elimination, similar to the above process, finally to produce imides 10 (VII→10).
Scheme 3 Proposed mechanism. Entry 1 2 3 4 5 6 7 8 9 10 11 12 13c
R1 R2 Ph 4-MeC6H4 Ph 4-MeOC6H4 Ph 3,4-O2CH2C6H3 Ph Me Ph H 4-BrC6H4 4-MeC6H4 4-BrC6H4 4-ClC6H4 4-BrC6H4 4-FC6H4 Me 4-ClC6H4 Me Me Ph H (CH2)3 Ph 4-ClC6H4
R3 H H H H H H H H H H Ph H H
10 ab ac ad ae af ag ah ai aj ak al am aa
t (h) 24 25 10 24 24 14 8 7 6 24 18 16 12
Yieldb (%) 84 82 88 60 70 85 89 88 85 72 52 83 81
a Reactions were carried out under an oxygen atmosphere with mol ratio of 1a/2a/5 = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields. c Upon scale-up to 15 mmol of 5a.
It was found that high-yielding one-pot reaction of 1a, 2a and 5a can be executed on the milligram scale and up to the gram scale. For example, a 90% isolated yield of imide 10aa was obtained with 1a (0.6 mmol), 2a (0.6 mmol) and 5a (0.5 mmol) (Table 2, entry 1), and upon scale-up to 15 mmol of 5a, an 81% yield (5165 mg) of 10aa was produced (Table 3, entry 13). The efficiency and generality of the practical one-pot imide synthesis was further demonstrated by using cinnamoyl ketene dithioacetals, a kind of versatile intermediates in organic synthesis,26 as the enone component. Under similar reaction conditions as above (Table 2 and 3), the one-pot reaction of 1a, 2a with selected cinnamoyl ketene dithioacetals 5n–p gave the corresponding imides 10an–10ap in high yields leaving the ketene dithioacetal moiety intact (Scheme 2).
Scheme 2 Synthesis of imides 10an–ap.
On the basis of the above experimental results (Tables 1-3 and Scheme 2) and related reports,1,2,3a,6,7,13,18,27 a mechanism, involving twice-Csp3–H oxidation/cyanide elimination, for the formation of imides 10 is proposed (Scheme 3) via firstly, (i) the formation of a 1,4-adduct 6 from the one-pot reaction of an α-aminoacetonitrile, an
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Generally, a single-electron transfer (SET) process between intermediate I and triplet oxygen (to form the superoxide anion radical and a radical intermediate, Scheme 3, I → IV) would be involved in aerobic C–H oxidation by molecular oxygen.13a,b In our present experiments, however, none the corresponding hydroperoxide intermediate (for example III) could be obtained by performing the model reaction of 1a, 2a and 5a under optimal conditions (Table 1, entry 8) at either room temperature or 0 oC. In the reaction, only the 1,4-adduct 6aa as the intermediate product and imide 10aa as the final product were observed (under an 18O2 atmosphere, 10aaO18 was observed, for details, please see ESI). In addition, the reaction could not be inhibited in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) even up to 15 equivalents. In these cases, 10aa was obtained in 93% (TEMPO, 2.0 eq) and 89% yields (TEMPO, 15 eq), respectively.
Scheme 4 Synthesis of imides 13–15.
The one-pot synthesis of imides 10 also provides a very convenient access to 1,4-dicarbonyl compounds, such as γ-ketoimide derivatives.15,16a Importantly, it was further revealed that the imides, 4-chloro-N-propionylbenzamide 13, 4-chloro-N-(2phenylacetyl)benzamide 14 and (E)-N-but-2-enoyl-4chlorobenzamide 15, could also be prepared in good yields from the corresponding reactions of (E)-2-(4chlorobenzylideneamino)acetonitrile 3a with selected alkyl halides such as ethyl bromide, benzyl bromide and allyl bromide, respectively (Scheme 4). For the formation of imide 15, C=C double bond migration should occur under basic conditions. Significantly, the aerobic synthesis of imides mentioned above (Tables 2, 3 and Schemes 2 and 4) is broad in scope without the need for functional group activation, protection and deprotection.16,17,20-25,27,28
Conclusions
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Table 3 Synthesis of imides 10aa-ama
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4 | J. Name., 2012, 00, 1‐3
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In conclusion, the unique reactivity of α(alkylideneamino)nitriles toward molecular oxygen has been revealed for the first time. α-(Alkylideneamino)nitriles can sever as the alkamido(oxo)methanide equivalent (imide building block) and enables the efficient synthesis of a wide variety of imides in good to excellent yields under extremely mild reaction conditions from simple starting materials. This practical procedure has been successfully applied to 5 grams scale sequential one-pot synthesis of imides. Further studies are in progress. Financial support of this research by the National Natural Sciences Foundation of China (21172030, 21272034 and 21202015), the Project-sponsored by SRF for ROCS, SEM is greatly acknowledged.
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Double oxidation of α-(alkylideneamino)nitriles to imides by molecular oxygen under mild basic conditions Yu Zhang, Ling Pan,* Yunjia Zou, Xianxiu Xu and Qun Liu* Department of Chemistry, Northeast Normal University, Changchun 130024, China
α-(Alkylideneamino)nitriles are reactive toward molecular oxygen, which enables them to serve as the imide building block under mild basic conditions.
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Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012, Accepted 00th January 2012
Yu Zhang, Ling Pan,* Yunjia Zou, Xianxiu Xu and Qun Liu*
DOI: 10.1039/x0xx00000x www.rsc.org/
We reveal here the unique reactivity of α(alkylideneamino)nitriles toward molecular oxygen. Thus, α(alkylideneamino)nitriles can serve as the imide building block for the efficient synthesis of imides in the absence of transition metals under extremely mild conditions. α-(Alkylideneamino)nitriles 3, which can be prepared via a threecomponent Strecker reaction (an aldehyde, an amine and cyanide ion, to give α-aminonitriles 1)1,2 followed by condensation with another aldehyde 23 or an imine,4a are useful building blocks in organic synthesis (Scheme 1).1-7 In the presence of a suitable base, anion 4 from deprotonation of α-(alkylideneamino)nitriles 3 can undergo Mannich-type reactions with imines to afford α,β-diaminonitrile derivatives4a or undergo [3+2] cycloaddition with nitroolefins to furnish substituted pyrroles.5 In general, the reaction of anion 4 with enones 5 gives 1,4-adducts 6 via Michael-type addition under basic conditions, which leads further to substituted 3,4-dihydro-2Hpyrrole-2-carbonitriles 7 through acid-promoted hydrolysis/cyclization of 6 along with the release of aldehyde 2 (Scheme 1).3a On the other hand, α-iminonitriles 8 can be prepared through one-pot three-component IBX/TBAB-mediated oxidative Strecker reaction (IBX: 2-iodoxybenzoic acid; TBAB: tetrabutylammonium bromide)2 and 8 can be further converted to amides 9 by alumina-promoted hydrolysis followed by cyanide elimination.6 In addition, the corresponding amides 9’ can be obtained by direct oxidation of N,N-dialkyl-α-aminonitrile 1’ using DMSO (in the presence of ButOK or KOH under an argon atmosphere),7a NiO2-H2O7b and m-CPBA (metachloroperoxybenzoic acid)7c as oxidants, respectively (Scheme 1). In our recent research on the [5+1],8 [6+1],9 and [7+1]10 carbocyclization reactions using active methylene compounds as C1 nucleophilic components, it was found that mediated by K2CO3 in DMSO at room temperature under oxygen atmosphere, the reaction of α-(alkylideneamino)nitrile 3 (R1 = H) with α,β-unsaturated
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ketones could lead to the formation of double oxidation products via 1,4-adducts 6 through a tandem process using molecular oxygen as the oxidant.9b This result reveals a new property of α(alkylideneamino)nitriles, the reactivity toward molecular oxygen under basic conditions. The utilization of economically and ecologically friendly molecular oxygen as oxidant is a highly attractive topic in organic synthesis,11 especially in one-pot reactions12 and in the absence of transition metals and radical initiators.13 On the other hand, one-pot reactions are efficient and cost-effective as they allow for more than one transformation in a single synthetic sequence.12,14 In this context, however, examples of the incorporation of molecular oxygen into organic compounds in the absence of transition metals or radical initiators are rare.13 We reveal here that α-(alkylideneamino)nitriles 3 containing an acidic
Scheme 1 Reactivity profile of α-(alkylideneamino)nitriles.
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methylene group can serve as the alkamido(oxo)methanide equivalent (Scheme 1) in the presence of molecular oxygen (as oxidant) and a base, as in their conjugate addition to enones to form γ-ketoimides under very mild reaction conditions (vide infra),15,16a which, alternatively, can be prepared, for example, via Michael reaction of enones with protected hydroxyl malononitriles as acyl anion equivalent.16,17
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Table 1 One-pot reactions of 1a, 2a and 5a under different conditionsa
significantly different reactivity between α-(alkylideneamino)nitrile 3a and glycine imine 11 was observed. Under identical conditions as View 5a Article Online in Table 1, entry 8, the reaction of glycine imine 11 with gave 1DOI: 10.1039/C4CC06481J pyrroline 12 and no the corresponding oxidation product 10aa could be detected.18 The above results (entries 2, 3, 6-8 and10) reveal for the first time that the 1,4-adduct, α-(alkylideneamino)nitrile 6a, exhibits the ability to activate molecular oxygen13 and enables the straightforward synthesis of γ-ketoimides 10 from simple starting materials under extremely mild reaction conditions in a tandem process12,14,15,16a via probably a tandem Csp3–H oxidation/cyanide elimination sequence of 6a (vide infra). Having thus found an effective and practical protocol for the aerobic synthesis of γketoimides,15,16a we next investigated the scope of the double oxidation reaction. The efficiency of the selected aldehydes 2a–e for the one-pot synthesis of γ-ketoamides was then examined (Table 2). We were pleased to find that, under optimal reaction conditions as in Table 1, entry 8, aromatic aldehydes 2a–d, having phenyl (entry 3), electro-deficient (entries 1 and 2) and electro-rich (entry 4) aromatic groups, can afforded the desired imides 10aa–10da in high yields. In the case of aliphatic aldehyde (pivalaldehyde 2e), imide 10ea was also produced in high yield (entry 5). Table 2 Synthesis of imides 10aa–eaa
Entry 1 2 3 4 5 6 7c 8c 9c 10 c,d 11e
Solvent DMF DMF DMF DMF THF DMSO DMSO DMSO DMSO DMSO DMSO
Base (equiv.) DBU (2.0) K2CO3 (2.0) Et3N (2.0) KOH (2.0) K2CO3 (2.0) K2CO3 (2.0) K2CO3 (1.0) K2CO3 (0.5) K2CO3 (0.2) K2CO3 (0.5) K2CO3 (0.5)
air/O2 /N2 air air air air air air O2 O2 O2 O2 N2
t (h) 36 24 24 24 24 2.0 1.5 12 24 4.5 24
Yieldb (%) 7a (97%) 10aa (10%) 10aa (20%) 7a (95%) 7a (95%) 10aa (30%) 10aa (81%) 10aa (90%) 7a (30%) 10aa (72%) 7a (95%)
a Reactions were carried out at room temperature with mole ratio of 1a/2a/5a = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields. c Reactions were carried out under an oxygen atmosphere (O2 balloon). d Mole ratio of 1a/2a/5a = 1.0:1.0:1.2. e Under a nitrogen atmosphere.
In the present research, it was found that the desired 1,4-adduct 6a was formed exclusively, by performing the model reaction of α(alkylideneamino)nitrile 3a (generated in-situ from αaminoacetonitrile hydrochloride, 4-chlorobenzaldehyde 2a and Et3N) with 4-chlorochalcone 5a at room temperature in open air for 36 h using DBU (1,8-diazabicycloundec-7-ene) as the base in the solvent, DMF. Upon silica gel column chromatography, 6a was transformed directly to 3,4-dihydro-2H-pyrrole-2-carbonitrile 7a in excellent yield along with the release of 4-chlorobenzaldehyde 2a (Table 1, entry 1).3a This result is in accordance with our previous observations for the reaction of glycine imines with enones.18b Surprisingly, imide 10aa was isolated in 10% yield from the reaction mixture of 3a with 5a under the same conditions as above but with K2CO3 as the base (entry 2).19 Further investigation showed that the formation of 10aa was apparently base and solvent dependent (entries 2-5) and K2CO3 in DMSO was found to be the suitable choice (entry 6). It was also found that, under an oxygen atmosphere, 10aa was obtained in high yields within shorter reaction times at a lower base loading (entries 7 and 8). In comparison, under a nitrogen atmosphere, adduct 6a and its further transformation to 7a upon silica gel column chromatography was observed (entry 11). These observations indicate that molecular oxygen is the sole source of oxygen in product 10aa (entries 2, 3, 6-8 and 10). Furthermore, the
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Entry 1 2 3 4 5
R 4-ClC6H4 4-BrC6H4 Ph 4-MeC6H4 t-Bu
t (h) 12 9 26 27 12
10 aa ba ca da ea
Yieldb (%) 90 78 84 83 75
a Reactions were carried out under an oxygen atmosphere with mol ratio of 1a/2/5a = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields.
Imide derivatives have numerous applications in biological, medicinal, synthetic, and polymer chemistry.20-25 Usually, imides are prepared by condensation reactions of amides with acylating reagents or activated carboxylic acid derivatives, which greatly limits the substrate scope and increases waste and inefficiency.24 Although several alternative approaches, including Pd-catalyzed cross coupling of organoborons with methyl NPd-catalyzed [methoxy(methylthio)methylene]-carbamate,20 aminocarbonylation of aryl bromides,21 α-methylene oxidation of amides with stoichiometric or excess amounts of F-TEDA-PF6 (chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-borate), derived from Selectfluor through replacement of BF4 by PF6),22a DMP (Dess-Martin Periodinane: 1,1,1tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one),22b pyridine-N-oxide22c or periodic acid,22d oxidation of oxazoles with ceric ammonium nitrate,23 photochemical aerobic oxidation of lactams or secondary benzamides,24 and copper-catalyzed oxidation of arene-fused cyclic amines25 have been developed, the synthesis of imides from simple starting materials is far from straightforward. Promoted by the successful preparation of imides 10aa–10ea using selected aromatic and aliphatic aldehydes 2a–e as the aldehyde components (Table 2), the one-pot reaction of α-aminoacetonitrile 1a, 4-chlorobenzaldehyde 2a with selected enones 5 was further investigated to examine the efficiency of enone components (Table 3). As a result, all the desired imides 10ab–10am were obtained in
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good to excellent yields with this operationally simple procedure from a broad range of enones 5b–m bearing an aroyl (Table 3, entries 1-8 and 11) or an acetyl (Table 3, entries 9 and 10) as R1CO group; an aryl (Table 3, entries 1-3, and 6-9), alkyl (Table 3, entries 4 and 10) or H (Table 3, entry 11) as R2 group; and H (Table 3, entries 1-10) or phenyl (Table 3, entry 11) as R3 group, respectively. In the case of cyclohex-2-enone as the Michael acceptor, the desired product 10am was obtained in high yield under identical conditions as above (Table 3, entry 12). Clearly, the excellent functional group tolerance for both aldehydes 2 (Table 2) and enones 5 (Table 3) allows the reaction to access a variety of imides starting from three simple starting materials, i.e. an α-aminoacetonitrile, an aldehyde and an enone, in one-pot under very mild transition metal-free conditions with molecular oxygen as the sole oxidant.
aldehyde and an enone (Table 1);3a,18 (ii) deprotonation of 6 under basic conditions giving α-cyanocarbanion I and subsequent C–H Article Online oxidation by molecular oxygen (I → III) leading toView intermediate DOI: 10.1039/C4CC06481J 6,13 7,16 (iii) cyanide elimination (IV→V) followed by Strecker IV; reaction (V→VI/VI’);1,2,6a,27 and (iv) sequential oxidation (VI/VI’→ VII) and cyanide elimination, similar to the above process, finally to produce imides 10 (VII→10).
Scheme 3 Proposed mechanism. Entry 1 2 3 4 5 6 7 8 9 10 11 12 13c
R1 R2 Ph 4-MeC6H4 Ph 4-MeOC6H4 Ph 3,4-O2CH2C6H3 Ph Me Ph H 4-BrC6H4 4-MeC6H4 4-BrC6H4 4-ClC6H4 4-BrC6H4 4-FC6H4 Me 4-ClC6H4 Me Me Ph H (CH2)3 Ph 4-ClC6H4
R3 H H H H H H H H H H Ph H H
10 ab ac ad ae af ag ah ai aj ak al am aa
t (h) 24 25 10 24 24 14 8 7 6 24 18 16 12
Yieldb (%) 84 82 88 60 70 85 89 88 85 72 52 83 81
a Reactions were carried out under an oxygen atmosphere with mol ratio of 1a/2a/5 = 1.2:1.2:1.0 upon 0.6 mmol of 1a. b Isolated yields. c Upon scale-up to 15 mmol of 5a.
It was found that high-yielding one-pot reaction of 1a, 2a and 5a can be executed on the milligram scale and up to the gram scale. For example, a 90% isolated yield of imide 10aa was obtained with 1a (0.6 mmol), 2a (0.6 mmol) and 5a (0.5 mmol) (Table 2, entry 1), and upon scale-up to 15 mmol of 5a, an 81% yield (5165 mg) of 10aa was produced (Table 3, entry 13). The efficiency and generality of the practical one-pot imide synthesis was further demonstrated by using cinnamoyl ketene dithioacetals, a kind of versatile intermediates in organic synthesis,26 as the enone component. Under similar reaction conditions as above (Table 2 and 3), the one-pot reaction of 1a, 2a with selected cinnamoyl ketene dithioacetals 5n–p gave the corresponding imides 10an–10ap in high yields leaving the ketene dithioacetal moiety intact (Scheme 2).
Scheme 2 Synthesis of imides 10an–ap.
On the basis of the above experimental results (Tables 1-3 and Scheme 2) and related reports,1,2,3a,6,7,13,18,27 a mechanism, involving twice-Csp3–H oxidation/cyanide elimination, for the formation of imides 10 is proposed (Scheme 3) via firstly, (i) the formation of a 1,4-adduct 6 from the one-pot reaction of an α-aminoacetonitrile, an
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Generally, a single-electron transfer (SET) process between intermediate I and triplet oxygen (to form the superoxide anion radical and a radical intermediate, Scheme 3, I → IV) would be involved in aerobic C–H oxidation by molecular oxygen.13a,b In our present experiments, however, none the corresponding hydroperoxide intermediate (for example III) could be obtained by performing the model reaction of 1a, 2a and 5a under optimal conditions (Table 1, entry 8) at either room temperature or 0 oC. In the reaction, only the 1,4-adduct 6aa as the intermediate product and imide 10aa as the final product were observed (under an 18O2 atmosphere, 10aaO18 was observed, for details, please see ESI). In addition, the reaction could not be inhibited in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) even up to 15 equivalents. In these cases, 10aa was obtained in 93% (TEMPO, 2.0 eq) and 89% yields (TEMPO, 15 eq), respectively.
Scheme 4 Synthesis of imides 13–15.
The one-pot synthesis of imides 10 also provides a very convenient access to 1,4-dicarbonyl compounds, such as γ-ketoimide derivatives.15,16a Importantly, it was further revealed that the imides, 4-chloro-N-propionylbenzamide 13, 4-chloro-N-(2phenylacetyl)benzamide 14 and (E)-N-but-2-enoyl-4chlorobenzamide 15, could also be prepared in good yields from the corresponding reactions of (E)-2-(4chlorobenzylideneamino)acetonitrile 3a with selected alkyl halides such as ethyl bromide, benzyl bromide and allyl bromide, respectively (Scheme 4). For the formation of imide 15, C=C double bond migration should occur under basic conditions. Significantly, the aerobic synthesis of imides mentioned above (Tables 2, 3 and Schemes 2 and 4) is broad in scope without the need for functional group activation, protection and deprotection.16,17,20-25,27,28
Conclusions
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Table 3 Synthesis of imides 10aa-ama
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ChemComm Accepted Manuscript
In conclusion, the unique reactivity of α(alkylideneamino)nitriles toward molecular oxygen has been revealed for the first time. α-(Alkylideneamino)nitriles can sever as the alkamido(oxo)methanide equivalent (imide building block) and enables the efficient synthesis of a wide variety of imides in good to excellent yields under extremely mild reaction conditions from simple starting materials. This practical procedure has been successfully applied to 5 grams scale sequential one-pot synthesis of imides. Further studies are in progress. Financial support of this research by the National Natural Sciences Foundation of China (21172030, 21272034 and 21202015), the Project-sponsored by SRF for ROCS, SEM is greatly acknowledged.
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DOI: 10.1039/C4CC06481J
Double oxidation of α-(alkylideneamino)nitriles to imides by molecular oxygen under mild basic conditions Yu Zhang, Ling Pan,* Yunjia Zou, Xianxiu Xu and Qun Liu* Department of Chemistry, Northeast Normal University, Changchun 130024, China
α-(Alkylideneamino)nitriles are reactive toward molecular oxygen, which enables them to serve as the imide building block under mild basic conditions.
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E-mail: [email protected]; [email protected]
