DOI: 10.1002/chem.201402070

Review

& C H Functionalization

Direct Metal-Catalyzed Regioselective Functionalization of Enamides Nicolas Gigant, Latitia Chausset-Boissarie, and Isabelle Gillaizeau*[a]

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Review development of the C H functionalization of enamides involving efficient and atom-economical routes. Syntheses of different heterocycles are classified based on the site reactivity of enamides and key mechanistic insights are given for each transformation.

Abstract: Enamides are stable enamine surrogates and provide key intermediates for the synthesis of small but complex nitrogen-containing compounds. Metal-catalyzed regioselective functionalization of enamides provides a rapid method to synthesize useful nitrogen containing heterocycles. This review discloses the recent progress made in the

Introduction

This review focuses on the activation of various enamide C H bonds. The article is organized by reaction types according to their regioselectivity (C2 vs. C3) and their reactivity (inter- vs. intramolecular). In each part, progress and new developments are highlighted with representative examples. We have also tried to emphasize the scope and the mechanisms for key reactions, while presenting successful applications in the synthesis of relevant natural compounds.

Over the past decade, enamides have emerged as a relevant functional group that has been involved in a variety of new synthetic transformations including natural product and bioactive molecule syntheses.[1] Enamides are stable enamine surrogates and provide key intermediates for the synthesis of small but complex nitrogen-containing compounds. The p-donating ability of the nitrogen atom renders enamides more electronrich than simple alkenes and they afford a means of activating carbon–carbon double bonds, giving them both nucleophilic and electrophilic properties. Indeed, the Ca-position is an electrophilic atom, whereas the Cb-position is a nucleophilic center and is prone to electrophilic attacks. The electronic bias can be controlled by adjusting the nitrogen-protecting group, which can be for instance an amide, a carbamate, or a sulfonamide (Scheme 1). Since the nitrogen atom is ubiquitous in nature

Direct C2 Intramolecular Functionalization Over recent years, the applicability of enamides to nitrogen heterocycle synthesis by means of an intramolecular Heck coupling has been well demonstrated. Beginning with the seminal work of Giggs and co-workers,[4] a wide variety of substrates has been synthesized. Later, Zhang and co-workers reported the a-regioselective intramolecular Heck reaction of N-acyl-2,3dihydro-4-pyridinone.[5] Interestingly the corresponding heterocycle was isolated with good yield with the hydrogenated coupling product (Scheme 2).

Scheme 1. Various types of enamides (EWG = electron-withdrawing group).

and living organisms, nitrogen-containing building blocks are of prime importance and enamides represent a powerful platform to introduce them into many synthetic compounds. In addition, there is still a need to produce diverse libraries of compounds starting from a common intermediate.[2] Therefore, the direct and selective functionalization of enamides remains an attractive challenge. To this end, the direct metal-catalyzed functionalization of C H bonds is perhaps one of the most effective pathways for streamlining chemical synthesis, avoiding tedious and expensive substrate preactivation steps.[3] Impressive progress has been reported during the past fifteen years, covering arenes, heterocycles, alkenes, or alkynes with a wide range of coupling partners. The C H activation field is now well-recognized for its high synthetic potential in the development of new methodologies with applications in total synthesis.

Scheme 2. Intramolecular Heck coupling of N-acyl-2,3-dihydro-4-pyridinone.

As proof of its utility, Hallberg and co-workers prepared some anabasine analogues.[6] The 5-exo-trig intramolecular cyclization was achieved with Pd(OAc)2, Et3N, and (R)-BINAP (BINAP = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) as ligand in acetonitrile, leading to a mixture of the three double-bond isomers in reasonable yields (Scheme 3). Reau and co-workers extended the methodology to cyclic sulfonamide precursors of aryl-substituted cyclic amines (Scheme 4).[7] The authors observed that with a-substituted sulfonamides the competitive isomerized product resulting from the double bond migration was isolated. Wipf and co-workers reported the first synthesis of the diazabicyclo[3.2.1]octane ring system through a palladium-catalyzed intramolecular process.[8] [Pd2(dba)3] (dba = dibenzylideneacetone); with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF was found to give a cyclization product with excellent yield and total a-regioselectivity (Scheme 5) .

[a] Dr. N. Gigant, Dr. L. Chausset-Boissarie, Prof. Dr. I. Gillaizeau Institut de Chimie Organique et Analytique, UMR 7311, CNRS Universit d’Orlans, rue de Chartres, 45067 Orlans cedex 2 (France) Fax: (+ 33) 2-38-41-72-81 E-mail: [email protected]

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Review

Scheme 7. Synthesis of 3-arylisoquinolines.

A significant extension in scope of the reaction was highlighted in the synthesis of tricyclic isoindolines by Maier and co-workers (Scheme 8).[12] This methodology benefits from fairly broad substituent compatibility and the cyclized products were obtained in good yield. The successful asymmetric Heck reaction for the formation of the indolizidine skeleton, the precursor of a large number of

Scheme 3. Synthesis of anabasine analogues.

Dr. Latitia Chausset-Boissarie studied chemistry at CPE Lyon (France). She received her Ph.D. in 2011 from the University of Geneva (Switzerland), under the supervision of Prof. E. P. Kndig, working on the total synthesis of Lythraceae alkaloids. She undertook postdoctoral research at the University of Bristol (UK) with Prof. V. K. Aggarwal on the novel application of enantioenriched borinic esters. She then joined the group of Prof. I. Gillaizeau to work on the functionalization of enamides. She is currently a research and teaching assistant at Paris Descartes University in the laboratory of Dr. F. Acher in bio-chemistry.

Scheme 4. Pd-catalyzed Heck cyclization of cyclic sulfonamides.

Scheme 5. Pd-catalyzed intramolecular Heck cyclization.

Dr. Nicolas Gigant was born in Vagney (France). He graduated from the National Graduate School of Chemical Engineering in Lille in 2009. He obtained his Ph.D. under the supervision of Prof. I. Gillaizeau at the Institut de Chimie Organique et Analytique in Orlans (France). His research focuses on the synthesis and reactivity of cyclic enamides for the development of new methodologies giving access to motifs frequently found in “privileged structures”. He is currently carrying out postdoctoral research at Stockholm University in the laboratory of Prof. J.-E. Bckvall in the area of green oxidation methodologies by means of a biomimetic approach.

Remarkably, the corresponding vinyl phosphate cyclized by means of an intramolecular Heck reaction although the yield was low (Scheme 6).

Prof. Isabelle Gillaizeau studied for her Ph.D. at Ren Descartes University (Paris V, France) under the supervision of Prof. H.-P. Husson and Dr. J. Royer, on the asymmetric synthesis of azabicyclo[n.2.1]alkanes according to the CN(R,S) method. She conducted postdoctoral research first (1998) at University College London (UK) with Prof. W. B. Motherwell, then at Ecole Polytechnique (1999) in Palaiseau (Paris, France) with Prof. S. Z. Zard and at the University of Nantes (France) with Dr. F. Odobel. In 2000, she joined the Institut de Chimie Organique et Analytique in Orlans as an assistant professor, and became a full professor in 2010. The research interests of her group lie mainly in the field of organic synthesis and especially in methodological studies in heterocyclic chemistry.

Scheme 6. Pd-catalyzed intramolecular allylic alkylation.

An interesting strategy for the synthesis of 3-arylisoquinoline alkaloids that rely on an intramolecular Heck cyclization of endocyclic enamides was explored by Orito and co-workers (Scheme 7).[9] The authors also used this Pd-catalyzed cyclization as the key step for the formation of a ring system characteristic of isoindolobenzazepine.[10] A similar strategy was developed for the synthesis of indoles.[11] Chem. Eur. J. 2014, 20, 1 – 18

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Review responding iodide compound was employed the level of enantioselectivity was lower.

Direct C2 Intermolecular Functionalization Interest in controlling regioselectivity for the Heck reaction of electron-rich olefins such as enamides has recently emerged. The first example of palladium-catalyzed direct arylation of enamides by naphthyl triflate was reported by Cabri and coworkers.[16] In the presence of Pd(OAc)2, Et3N, and 1,3-bis(diphenylphosphino) propane (dppp), enamides were coupled with naphthyl triflate in good yield with almost complete a-selectivity for the arylated products (Scheme 11).

Scheme 8. Synthesis of tricyclic isoindolines.

natural products, from prochiral enamides was reported by Shibasaki and co-workers (Scheme 9).[13] The indolizidine derivative was obtained as a mixture of two isomers, the use of

Scheme 11. Palladium-catalyzed arylation of enamides with naphthyl triflate.

The regioselectivity for the C2 position could be influenced mostly by the ligand and the leaving group present on the aromatic ring. In fact by using 1-naphthyl iodide as the coupling partner, both the regioselectivity and the reaction rate of the reaction decreased. Based on this observation the authors proposed that two competing pathways for the association–insertion step (Scheme 12) could be envisaged depending on the counterion X.[17]

Scheme 9. Enantioselective synthesis of indolizidine.

BPPFOH ((R)-a-[(S)-1’,2-bis(diphenylphosphino)ferrocenyl]ethyl alcohol) as ligand and an Ag-exchanged zeolite was crucial in achieving good enantiomeric excesses and excellent yields. Later, Sulikowski and co-workers also examined this reaction and based on some investigations the authors postulated that the enantiomeric discriminating step is the migratory insertion step.[14] Hallberg and Ripa reported an asymmetric Heck reaction allowing the formation of quaternary carbon centers. Various spirocyclic derivatives of tetrahydropyridines were obtained in presence of (R)-BINAP as chiral ligand with good enantiomeric excesses. However, the reaction suffered from low selectivity and low yield due to the simultaneous formation of a mixture of three isomers (Scheme 10).[15] Chiral phosphanyldihydro oxazole was found to suppress the formation of the isomer containing the double bond at the a-position of the nitrogen. By switching to a more hindered base (iPr2NEt), improvement in the regioselectivity was observed. Interestingly, while the cor-

Scheme 12. Proposed mechanism for the palladium-catalyzed arylation of enamides with naphthyl triflate.

When the counterion is a triflate, the Pd OTf bond is weak, and a tricoordinate 14-electron cationic complex is formed. The complexation of alkene into the vacant site leads to the 16-electron species in which the p-system is polarized. The migration of the aryl moiety (formally an anion) is then dependent on electronic factors and frontier orbital interactions. Moreover, the addition of silver or thallium salts, which act as

Scheme 10. Enantioselective synthesis of spirocyclic tetrahydropyridines.

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Review halide scavengers, can also promote the ionic pathway. With electron-rich olefins, such as enamides, a high selectivity for migration onto the carbon with the lowest charge density (C2 attack) was observed. In contrast, if the counterion is a halide, a neutral complex is generated after dissociation of one ligand, the regioselectivity is influenced by steric factors and the linear product is formed (Scheme 13).

Scheme 15. Palladium-catalyzed regioselective vinylation of enamides.

over, the reaction time was decreased by using microwave irradiation. Simultaneously, Skrydstrup and co-workers found that a,bunsaturated tosylates and mesylates were also suitable coupling partners for regioselective Heck coupling with enamides.[23] Tosylates and mesylates are significantly less expensive and toxic than triflates and therefore constitute valuable coupling partners. Under optimized conditions, 2-acylamino-1,3butadienes were obtained with good-to-excellent yields with complete a-regioselectivity. Even mesylate derivatives that are less reactive as electrophile than the corresponding tosylates proved to be suitable coupling partners. The authors proposed a cationic reaction mechanism to rationalize the high degree of regioselectivity (Scheme 16).

Scheme 13. Cationic and neutral pathways for the Heck mechanism.

Subsequently, the authors found that when 1,10-phenanthroline was used as the ligand instead of dppp, the same level of regioselectivity and yield was obtained under milder conditions.[18] Moreover, the catalyst decomposition was limited by the introduction of electron-poor olefins. Meek and co-workers extended the methodology to commercially available N-vinylacetamide.[19] Aryl-N-acyl enamides were obtained in moderate to good yields with a broad range of substituents (Scheme 14).

Scheme 16. Regioselective Heck coupling of a,b-unsaturated tosylates and mesylates with enamides.

Scheme 14. Palladium-catalyzed arylation of N-vinylacetamide with aryl triflate.

Following this seminal work, Skrydstrup and co-workers developed an alternative protocol using [Pd2(dba)3] and dppf (1,1’-bis(diphenylphosphino)ferrocene)) as catalytic system and N,N-diisopropylethylamine (DIPEA) as the base in the presence of dioxane, which leads to the desired functionalized enamides in high a-regioselectivity with good-to-excellent yields.[20] Larhed, Curran, and co-workers also applied this protocol to form dienamide precursors for the microwave-enhanced carbonylative generation of indanones.[21] In agreement with the work of Cabri, Hallberg and co-workers reported an attractive a-regioselective Heck vinylation of enamides (Scheme 15).[22] Fluorous-tagged 1,3-bis(diphenylphosphino)propanes (F-dppp) were used instead of the previous dppp to simplify the purification step. Even if the scope was limited, the ligand was easily removed by simple solid fluorous-phase separation from the reaction mixture and the same level of yield and regioselectivity was achieved. MoreChem. Eur. J. 2014, 20, 1 – 18

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After optimization of the previous conditions, Skrydstrup and co-workers reported the coupling of a range of electronpoor and electron-rich heteroaromatic tosylates with good to moderate yields and total a-regioselectivity (Scheme 17).[24] In 2005, Xiao and co-workers succeeded in developing a highly a-regioselective Heck arylation of enamides with activated and deactivated aryl bromide using a combination of 1butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4])/

Scheme 17. Palladium-catalyzed arylation of N-vinylacetamide with heteroaromatic tosylates.

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Review DMSO (1:1) as solvent.[25] Aryl bromides preferentially follow a neutral pathway, leading to a mixture of a- and b-substituted olefins and all the methodologies presented so far require a stoichiometric quantity of silver or thallium salt in order to achieve high a selectivity (Scheme 18). Importantly a stoichiometric amount of enamides and aryl bromides was used in this procedure.

Scheme 21. Heck arylation of enamides with [H2NiPr2].

gioselectivity were obtained with a range of aromatic and heteroaromatic rings bearing electron-donating or -withdrawing groups. Moreover, while aryl iodides were suitable coupling partners, only low yields were observed starting from aryl chlorides. Subsequent to their study on the use of a hydrogen bond donor in Heck arylation, Xiao and co-workers reported the first Heck arylation of enamides with aryl bromides in a cheap and environmentally friendly alcohol, such as ethylene glycol, without any halide scavengers or salt additives.[28] Under optimized conditions, products were obtained in excellent yields with complete a-regioselectivity (Scheme 22). The authors suggested that ethylene glycol, which is a good hydrogen-bond donor, acts as receptor for the halide anion and favors the formation of the cationic PdII–olefin intermediate.

Scheme 18. Ionic-liquid-promoted, highly a-regioselective, Heck arylation of aryl bromide.

From a mechanistic point of view, the authors proposed that the ionic liquid could promote the ionic pathway by facilitating the dissociation of halide anions from palladium (Scheme 19).

Scheme 19. Ionic liquids favor the generation of the Pd–olefin cation. Scheme 22. Heck arylation of enamides in ethylene glycol.

The same authors developed in 2006 a new protocol for the selective a-arylation of enamides.[26] Based on the observation that the arylation rate decreases with an enhance in the bromide concentration, Xiao suggested that the bromide anion may be scavenged by a possible hydrogen bonding between [HNEt3] + and Br (Scheme 20). They found that the same cata-

Finally, the authors firstly extended the methodology to the more challenging aryl chlorides.[29] They found that using an electron-rich ligand 4-MeO-dppf (1,3-bis[bis(4-methoxyphenyl) phosphino]propane) and KOH as the base in ethylene glycol led to high regioselectivity and good yields (Scheme 23). However, aryls bearing electron-withdrawing groups failed to react under these reaction conditions. Several years later and quite

Scheme 20. Possible hydrogen bonding between [HNEt3] + and Br favoring the PdII cation.

lyst and additive in the presence of a mixture of [HNEt3][BF4] and [bmim][BF4] led to the formation of the arylated product with excellent regioselectivity (a/b > 99:1) and good-to-excellent yields with a shorter reaction time. It is worth noting that the palladium loading could be lowered and the TOF (turnover frequency) and TON (turnover number) increased. Following this reasoning, the authors explored the use of the hydrogen-bond donor [H2NiPr2][BF4] as an additive for the reaction without [bmim][BF4] in DMF[26] or isopropanol[27] (Scheme 21). Interestingly, both high yields and complete a-re&

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Scheme 23. Heck arylation of enamides in ethylene glycol with aryl chlorides.

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Review recently, aryl iodides were also employed in the case of substituted enamides.[30] In 2004, Larhed expanded the scope of the Heck reaction by developing a regioselective oxidative Heck arylation of enamides with arylboronic acids using the rigid oxidatively stable neocuproine as the ligand (dmphen) and oxygen gas as an efficient palladium reoxidant.[31] Unlike the previously reported methodologies, the starting arylpalladium(II) intermediate was generated by transmetalation of an organometallic reagent. Based on experiments and DFT calculations, the authors proposed that the regioselective oxidative Heck arylation of acyclic enamides proceeds via a cationic p-complex intermediate. The regioselectivity of the coupling was influenced by the electronic character of arylboronic acids (Scheme 24). This method

also reported that the reaction was not compatible with aryl trifluoroborate or arylboronic acid, since they undergo rapid protodeborylation. Recently, Gillaizeau and co-workers reported an original direct mono- or diarylation reaction of cyclic enamides through a Pd-catalyzed decarboxylative cross-coupling process under mild conditions (Scheme 26).[33] Interestingly, performing the

Scheme 26. Mono- or diarylation reactions of cyclic enamides through a Pdcatalyzed decarboxylative cross-coupling process.

reaction with strong electroattractive protecting groups favored the double direct cross-coupling process, while less electroattractive protecting groups favored the mono cross-coupling reaction. Unfortunately the reaction is restricted to electron-rich ortho-methoxy-substituted benzoic acids. Although palladium, arguably the most versatile transition metal in catalysis, dominates the field of enamide functionalization, Skrydstrup developed a regioselective rhodium-catalyzed hydrosilylation of enamides, providing direct access to alkyl-aminosilanes (Scheme 27).[34] The potential of this method is highlighted by the fact that only one equivalent of silane derivative was required to efficiently achieve the reaction.

Scheme 24. Oxidative Heck arylation of enamides.

is compatible with substituted aryls bearing a range of electron-withdrawing and -donating substituents. The authors also noted that the reaction could proceed under microware irradiation with a slight loss of regioselectivity. Later, Park and co-workers revisited and dramatically improved this challenging chemistry by developing a stereoselective oxidative Heck reaction of highly substituted acyclic or cyclic enamides with arylboronates in the presence of potassium hydrogen fluoride as fluoride source, an electron-rich ligand (dicyclohexylphosphino)biphenyl (bpPCy2) and a catalytic amount of copper acetate in combination with oxygen as oxidant (Scheme 25).[32] This methodology has fairly broad substituent compatibility and generates enamides in moderate-toexcellent yields with complete Z stereoselectivity. The authors

Scheme 27. Hydrosilylation of enamides using silanes.

The first example of the intermolecular asymmetric Heck reaction of 2,3-dihydropyroles was reported by Hayashi.[35] Later reports of successful examples of the asymmetric Heck reaction were published by Tietze[36] and Pfaltz.[37] Interestingly, Dai and co-workers reported the use of a planar chiral diphosphine–oxazoline ferrocenyl ligand in combination with Pd(OAc)2 as an efficient catalytic system for the regio- and enantioselective Heck reaction of N-methoxycarbonyl-2-pyrro-

Scheme 25. Stereoselective synthesis of enamides by an oxidative Heck reaction. Chem. Eur. J. 2014, 20, 1 – 18

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Review functionalization) was initially expected, the unanticipated endo-product (C3 functionalization) was isolated in good yield under their best conditions. A range of highly polycyclic scaffolds were obtained thanks to this new selectivity. This approach was next extended to the total synthesis of natural products by Tozer’s group.[41] Maier disclosed the formation of spirocyclic compounds from Heck coupling starting from 4-alkyl-piperidones (Scheme 31).[42] Unfortunately, the reaction was not selective and three scaffolds were isolated: the corresponding debrominated starting material, the spiroimide, and the spiroamide. The mechanism remained unclear.

Scheme 28. Asymmetric Heck reaction of aryl triflates with enamides.

line (Scheme 28).[38] The regioselectivity of this process was strongly dependent on the polarity of the solvent and the palladium species. Quite recently the scope of the reaction was extended to aryl bromides (Scheme 29).[39] Various five-membered enamides were isolated with high enantioselectivity. Both alkylammonium salts and alcohol solvents were crucial in generating the cationic aryl–Pd species for enantioselective olefin insertion. The bisphosphine oxide bearing a spirobisindane skeleton was highly active and similar ligands gave low enantioselectivity.

Scheme 31. PdII-catalyzed formation of spirocyclic scaffolds.

Scheme 29. Asymmetric Heck reaction of aryl iodides with enamides.

Direct C3 Intramolecular Functionalization The use of metal for the direct C3 intramolecular functionalization of enamides has attracted considerable attention, and more particularly toward the Heck reaction. Among pioneers, Rigby described the endo-selective cyclization of enamides (Scheme 30).[40] While the exo-product (C2

Scheme 32. PdII-catalyzed formation of spirocyclic pentacyclic scaffolds.

After this promising work, his group also developed a domino sequence on cyclic enamides for the preparation of pentacyclic structures (Scheme 32).[43] Although the amount of debrominated enamide remained non-negligible, the desired difunctionalized products were finally isolated in satisfying yields. A final step of C H activation with concomitant HBr elimination was postulated. Rutjes and co-workers described the first example of RCM reactions (ring-closed metathesis) involving enamides (Scheme 33).[44] This methodology demonstrated its high versatility for the construction of five- and six-membered rings. The synthesis of aze-

Scheme 30. Cycloisomerization of enamides.

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Review cient in the majority of cases in the presence of only 1– 2 mol % of AgOTf. Regarding the conversion, the complex [Pt(dppb)(OH)]2[BF4]2 proved to be the most efficient in some cases, dramatically decreasing the reaction time. With this technique, enamide works as a nucleophilic component in the ring-forming process. The reaction was successfully carried out in the total synthesis of (+)-Fawcettidine as the key step. Simultaneously the same group studied PtII-catalyzed cyclizations starting from an electron-deficient alkyne at the C3 position on the cyclic core (Scheme 36).[48] The presence of metha-

Scheme 33. First examples of RCM involving enamides (EWG = electron-withdrawing group).

pane derivatives was not achieved, because of the isomerization of the double bond during the process, giving an unexpected new six-membered ring. After this seminal work, this reaction was extensively investigated to develop original nitrogen-containing building blocks[45] or precursors that would be useful in total synthesis.[46] In particular, Evano reported an elegant total synthesis of alkaloid Paliurine E.[46a] The final macrocyclization step was performed by an enamide ring-closing metathesis with a Grubbs’ second-generation catalyst (Scheme 34). Even minor, structural

Scheme 36. Sequential one-pot cyclization-reduction involving enamides (EWG = electron-withdrawing group).

nol was required to trap the iminium ion intermediate as well as “turnover” the catalyst. Moreover, a sequential one-pot cyclization-reduction sequence was tried in order to avoid the characterization of the complex diastereoisomeric mixture. In addition, Larhed’s group tested the synthesis of 3-acylamino-1-indanones under microwave heating (Scheme 37).[21] This

Scheme 34. Synthesis of Paliurine E by means of a RCM.

modifications on the starting enamide appeared to be very critical during the cyclization process. Dake and co-workers reacted cyclic ene-N-p-toluenesulfonamides bearing an electron-deficient alkyne at the C4 position and using catalytic PtII or AgI salts leading to the desired functionalized 2-azahydrindans (Scheme 35).[47] The cycloisomerization occurred under very mild conditions and was more effi-

Scheme 37. PdII-catalyzed carbonylative of enamides.

PdII-catalyzed carbonylative reaction involved an ortho-bromoaryl-substituted enamide in presence of molybdenum hexacarbonyl for the in situ generation of carbon monoxide. Both neutral and electron-rich o-halostyrene derivatives were tolerated by the reaction conditions. Finally, the Toste group reported very recently an efficient enantioselective cyclization of enamide-ynes as relevant building blocks for the synthesis of the kopsifoline core (Scheme 38).[49] The Pd complex [Pd{(R)-binaphane}(OTf)2] furnished the desired products in high enantioselectivity. Interestingly, the process was developed on a larger scale with a lower catalyst loading (1 mol %) and no erosion in enantioselectivity.

Scheme 35. Cycloisomerization of enamides. Chem. Eur. J. 2014, 20, 1 – 18

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Scheme 40. Proposed mechanism for the direct arylation of cyclic enamides with aryl boronic acid derivatives.

Scheme 38. Enantioselective cyclization of enamide–ynes (EWG = electronwithdrawing group).

Following a similar approach, Bckvall also reported an efficient oxidative Heck coupling of cyclic sulfonyl enamides with aryl boroxines for the synthesis of oxazolones.[52] An improvement of this method was obtained by Loh’s group with organosilane reagents toward a Hiyama-type coupling reaction (Scheme 41).[53] This methodology provided only

Direct C3 Intermolecular Functionalization Up till five years ago, the C3 intermolecular functionalization of enamides had almost never been investigated, since the prefunctionalization of enamides at the C3-position is complicated and no general methodology had been reported.[50] Direct C3 functionalization is therefore currently a very challenging subject with profound synthetic potential. Loh et al. developed the first direct arylation of cyclic enamides by means of PdII-catalyzed C H activation with organoboron reagents in 2009 (Scheme 39).[51] This strategy involved

Scheme 41. Direct arylation of cyclic enamides with organosilane derivatives.

the desired arylated products, avoiding the previous aromatized coupling products.[51] Note that AgF is both a simple fluoride activator of organosilane derivatives and an oxidant for the regeneration of the PdII active species in the catalytic cycle. A variety of enamides was obtained in high yields, except when ortho-substituted phenylsilanes or sterically encumbered enamides were employed. A series of DFT studies on the mechanism, solvent effect, and role of additive involving enamides and aryl siloxane were carried out by Fang’s group.[54] Three conclusions were established: the transmetalation step is the rate-determining step, AgF assists the transmetalation step by supplying HF and helping to recover the catalyst and, lastly, the role of the dioxane is to separate the product from the Pd ligand. Gillaizeau and co-workers also developed a copper-catalyzed direct arylation of cyclic enamides using diaryliodonium salts (Scheme 42).[55] The reaction demonstrated large functional group tolerance, good yields, and total regioselectivity with a C3-functionalization. Mechanistically a pre-formed CuIII-aryl species underwent electrophilic addition at the electron-rich C3-position of the enamide. Surprisingly, starting from a nonfunctionalized seven-membered derivative, the diarylated enamide was formed in a moderate yield when five equivalents of diaryiodonium salt were involved.

Scheme 39. Direct arylation of cyclic enamides with aryl boronic acid derivatives.

10 mol % Pd(OAc)2 in the presence of Cu(OTf)2 as the oxidant, and K2CO3 as the base in dioxane as the solvent. The corresponding C3-arylated substrates were isolated with good yields, accompanied by the aromatized coupling products. The authors suggested a mechanism involving the assistance of the acetamino group, stabilizing a six-membered palladacycle (Scheme 40). Traditional reductive elimination gave the desired arylated product and the Pd0 species. Finally, the latter was re-oxidized to PdII thanks to the involvement of CuII to complete the catalytic cycle. Two possible pathways for the formation of the aromatized product were proposed. The first may be based on the oxidation of the functionalized enamides. The second pathway postulates an initial oxidation of the starting material followed by both aromatic C H activation and C C formation. It should be stressed that the use of the base is crucial for this process. &

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Scheme 45. C H functionalization of enamides by using visible-light photoredox catalysis.

Scheme 42. Direct arylation of cyclic enamides with diaryliodonium salts (EWG = electron-withdrawing group).

cedure. First described by Fujiwara and Moritini, this type of reaction provides rapid access for the creation of C C bonds without prefunctionalized starting materials.[59] In their recent study, Loh’s group described the first Pd-catalyzed direct C H arylation of enamides with simple arenes (Scheme 46).[60] The

A series of sulfonated substrates were obtained in moderate yields by Loh’s group by means of a palladium-catalyzed sulfonylation of enamides using oxygen as the terminal oxidant (Scheme 43).[56] The palladium-catalyzed intermolecular acylation of enamides was also successfully applied for the synthesis of a diverse range of b-acyl enamide products (Scheme 44).[57] Two equiva-

Scheme 46. Direct arylation of acyclic enamides with simple arenes.

reaction required the use of Pd(OAc)2, Cu(OAc)2 as terminal oxidant in the presence of five equivalents of AcOH, and 40 equivalents of arene. Moreover, this protocol gave unprecedented access to highly substituted enamides with absolute regio and Z stereoselectivity. Regarding the scope of this transformation, the reaction conditions were applied to a large variety of enamides and arenes, although regioisomers were observed when nonsymmetric aromatic substrates were involved. In their discussion of mechanistic possibilities, the authors favored a carbopalladation mechanism. The formation of this process under acidic conditions is common in Fujiwara–Moritini coupling. Taking into account the fact that the reaction is slower without an acidic source and that the reactivity decreased when electron-deficient arenes were employed, an electrophilic palladation pathway is suggested. This study was extended and confirmed by primary kinetic isotope effect. Finally, a one-pot double arylation was carried out in a sequential manner by using a fresh quantity of catalyst, oxidant, and acid on completion of the first arylation (Scheme 47). AcOH is substituted by TFA for the synthesis of tetrasubstituted enamides, generating a better electrophilic palladium cation. The same approach was independently adopted by the group of Loh and Gillaizeau for the oxidative cross-coupling reaction of enamide using activated alkenes with a total E selectivity (Scheme 48).[61] These reactions used as catalyst 10 mol % of Pd(OAc)2, an oxidant in an acidic medium under oxygen at-

Scheme 43. Direct sulfonation of cyclic enamides.

Scheme 44. Direct acylation of enamides with various arylglyoxylic derivatives.

lents of arylglyoxylic derivatives were employed under very mild conditions. Although successfully applied for a large number of a-oxocarboxylic acids, the scope of the reaction is limited for N-(2H-chromen-4-yl)acetamide derivatives. Zhang and Yu developed an elegant direct C H functionalization of cyclic and acyclic enamides by using visible-light photoredox catalysis (Scheme 45).[58] This environmentally friendly method tolerates either alkylating, arylating, or trifluoromethylating reagents with an exclusive E configuration under a low iridium-catalyst loading. Mechanistically, an amido radical is suggested after addition of the alkyl radical onto the corresponding enamide. Another challenge for the direct functionalization of enamides was to establish an intermolecular dehydrogenative proChem. Eur. J. 2014, 20, 1 – 18

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Review ty of the process was not total, the major diastereoisomer was isolated under its Z form. Several styrene derivatives as well as the usual activated alkenes were tolerated regardless of their electronic properties, with high yields and good diastereoselectivity. Amide derivatives also represent an important class of compounds. In this view, Bergman and Ellman studied the preparation of b-enamide amides starting from enamides and isocyanates (Scheme 50).[65] This efficient strategy involved a RhIII complex and afforded the possibility of using chiral substrates,

Scheme 47. One-pot sequential arylation of enamide with arenes.

Scheme 48. PdII-catalyzed direct alkenylation of enamides with activated alkenes (EWG = electron-withdrawing group).

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Scheme 50. Direct amidation of enamides using isocyanates.

mosphere. Starting from an acetamide derivative—an X-ray structure confirmed the six-membered palladacycle—a hypothesis put forward for direct arylation.[51] Electron-rich enamides bearing a heteroatom (O, S) in theb-position were not reactive in the presence of acetic acid. However, this lack of reactivity was solved by involving both Ag2CO3 and pivalic acid. The preference for pivalic acid compared to acetic acid is explained by both a greater encumbrance and the increased basicity of its conjugate base.[62] In addition, Bckvall and co-workers reported a biomimetic aerobic oxidative coupling between enamides and acrylates with relatively low catalyst loading and a catalytic amount of electron-transfer mediators under ambient oxygen pressure.[63] Rhodium was also successfully employed by Glorius et al. in Fujiwara–Moritani coupling (Scheme 49).[64] While the selectivi-

thus increasing the synthetic potential of this methodology for the preparation of natural products and drugs. Unfortunately, an over-stoichiometric amount of enamides was employed. We can underline that the choice of temperature is the key point to control the selectivity of the reaction: while the desired amides are isolated at room temperature, pyrimidin-4-one derivatives are obtained when the process is carried out at high temperature due to a thermally spontaneous dehydration of the enamide amide intermediate. In view of the considerable interest that fluorine compounds have received in recent years due to their growing importance in science, Loh and co-workers recently reported an unprecedented work regarding the copper-catalyzed trifluoromethylation of acyclic enamides (Scheme 51).[66] This powerful method-

Scheme 49. RhII-catalyzed direct alkenylation of enamides with activated alkenes.

Scheme 51. Direct trifluoromethylation of acyclic enamides with Togni reagent.

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Review Guan[71] and Loh[72] using copper or palladium salts as the catalyst. In a recent communication, Guan and co-workers reported a FeCl3-catalyzed self-condensation of acyclic enamides (Scheme 54).[73] A series of Brønsted acid and Lewis acid cata-

ology allows the authors to incorporate fluorine atoms onto enamides by using the simple Togni reagent. THF proved to be the best solvent with total Z selectivity. Finally Glorius’s group disclosed a versatile pyrrole synthesis by using oxidative annulations of enamides (Scheme 52).[67] In-

Scheme 54. FeCl3-catalyzed self-condensation of enamides.

lysts were screened and none of them was more active than FeCl3. This general protocol proceeds under very mild reaction conditions and gave rapid access to nitrogen-containing quaternary carbon centers. The key step is certainly the isomerization of enamide into the ketamine before a nucleophilic addition of a second enamide on this newly formed intermediate.

Scheme 52. Regioisomeric controlled synthesis of pyrrole starting from enamides and alkynes.

volving a ruthenium catalyst and unactivated alkynes, N-protected pyrroles were obtained through the cleavage of N H/ C H bonds. Remarkably, a switch in reactivity was observed between an allylic sp3 C H activation and a vinylic sp2 C H activation. The ester function seems be crucial in activating the allylic sp3 C H bond and forming the regioisomeric pyrrole. With the same strategy, Ackermann and co-workers were also able to accomplish the process with total b-regioselectivity by using air as the terminal oxidant and decreasing the Cu(OAc)2·H2O loading to 30 mol % (Scheme 53).[68] In addition, an extension of the methodology was performed by Wang and co-workers. By adding a catalytic amount of AgSbF6 in the presence of methanol, the N-unsubstituted pyrroles were isolated.[69] An aqueous protocol was next optimized by Liu.[70] Alternative catalytic systems were also recently reported by

Direct Intramolecular Difunctionalization In this part, we outline examples dealing with the direct intramolecular difunctionalization of enamides. Work by Dominguez and co-workers led to the development of a Heck coupling of N-vinyl-2-iodobenzamides both at aand b-positions. They proposed that the control of regioselectivity is related to the more reactive Ar I bond triggering a 5exo-trig cyclization (Scheme 55).[74] Dake and co-workers developed a platinum(II)-catalyzed cyclization method to generate quaternary carbon centers starting from enamides as nucleophiles (Scheme 56).[48] By using an arylalkyne species, the iminium ion intermediate was trapped in a Friedel–Crafts/Pictet–Spengler-type process. Two isomers were isolated and this methodology was extended to the syn-

Scheme 55. Pd-catalyzed cyclization of enamides.

Scheme 56. Direct PtII-catalyzed cyclization.

Scheme 53. Synthesis of pyrroles starting from enamides and alkynes. Chem. Eur. J. 2014, 20, 1 – 18

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Review Direct Intermolecular Difunctionalization

thesis of more complex ring systems bearing an indole moiety for instance.[75] The potential of this elegant method was investigated by Zhai’s group toward the synthesis of the tetracyclic core of ent-nakadomarin A (Scheme 57).[76] In this example, the

This section highlights the different processes to access difunctionalized nitrogen-containing substrates starting from enamides in an intermolecular fashion. Nitrene chemistry represents an important tool for the introduction of a nitrogen atom in p-electron-rich olefins, such as enamides. Indeed, two elegant Cu- or Rh-catalyzed oxyamidations were simultaneously developed by the groups of Dodd, and Gillaizeau and Dauban (Scheme 59).[78] The method de-

Scheme 57. Synthesis of the tetracyclic core of ent-nakadomarin A.

tandem reaction was regiospecific (6-endo versus 5-exo) and stereospecific. Mechanistically, after nucleophilic attack of enamide on the PtCl2-activated alkyne, the iminium ion intermediate is trapped by the furan group before its re-aromatization, regenerating the catalyst and giving the desired scaffolds in a satisfying yield. After this seminal work dealing with cyclic enamides, Dake and co-workers examined the reactivity of acyclic enamides and arylalkynes towards intramolecular tandem addition/Friedel–Crafts reactions (Scheme 58).[77] Subjecting the starting ma-

Scheme 59. Oxyamidation of enamides using nitrenes (EWG = electron-withdrawing group).

scribed by Dodd and co-workers is based on the reactivity of aryl enamides in the presence of a nosylamine-derived iminoiodane in the presence of an alcohol. The reaction tolerated a large number of functional groups and the asymmetric version was also reported with satisfactory enantioselectivity by using a chiral box ligand. Dauban, Gillaizeau et al. showed that rhodium catalysts are more suitable for obtaining the corresponding alkoxyaminated products. This approach involved an in situ prepared iminoiodane thanks to the reactivity between TcesNH2 and PhI(OCOtBu)2. Even if results were excellent both in terms of efficiency and regioselectivity, total control of the diastereoselectivity of each substrate was not achieved. The precise mechanism is not yet fully understood; the authors tentatively suggest that an initial step of aziridination may be involved in the process. In their research program on the reactivity of enamides, Loh’s group has developed methodologies for the oxytrifluoro-

Scheme 58. Gold-catalyzed intramolecular tandem addition/Friedel–Crafts reactions.

terial to the previous conditions in the presence of PtII at 110 8C gave two regioisomers in 67 % yield in a 8:1 ratio. At lower temperature (80 8C), a third product was isolated as a diastereoisomeric mixture. Finally, triphenylphosphinegold(I) chloride appeared to be the best catalyst, yielding the two previous regioisomers in 86 % yield in a 13:1 ratio. A wide range of polycyclic nitrogen-containing frameworks was obtained in high yields and satisfactory selectivity.

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Review methylation of enamides employing Togni reagent (Scheme 60).[66] By using similar conditions to those employed for direct C3 trifluoromethylation, but by replacing THF with methanol, the difunctionalized skeletons were isolated. Unlike

Scheme 62. Pd-catalyzed difunctionalization of enamide to amino acetal.

difunctionalization with the concomitant formation of one C C and one C O bond. On the basis of their mechanism, the authors suggested a reduction of the PdII precatalyst by 2-PrOH, giving the active Pd0 species and a catalytic amount of triflic acid. Triflic acid can promote the C N bond cleavage before oxidative addition of aminal to the Pd0 species (Scheme 63). After reaction with the

Scheme 60. Direct oxytrifluoro-methylation of acyclic enamides with Togni reagent.

the previous case, the imine intermediate is trapped by methanol in situ and no product resulting from the elimination appeared during the process, giving the desired oxytrifluoromethylated products in high yields without any column chromatographic purification. Very recently, Zhou’s group described an elegant Pd-catalyzed asymmetric intermolecular cyclization of enamides with o-vinylphenyl triflate (Scheme 61).[79] Mechanistically, an alkyl-

Scheme 63. Plausible reaction mechanism for the Pd-catalyzed enamide difunctionalization.

double bond of the enamide, a new Pd–alkyl intermediate is formed that is immediately trapped by the free alcohol. Subsequent reductive elimination followed by the regeneration of the catalyst under its active form completes the catalytic cycle. Finally, photoredox-induced three-component synthesis of 1,2-difunctionalized amines have been developed by Masson. b-Alkylated a-carbamido ethers have been isolated as stable imine surrogates with wide substrate scope and good-to-excellent yields starting from diethyl bromomalonate and alcohols (Scheme 64).[81] A radical/cationic pathway is suggested for this reaction.

Scheme 61. Synthesis of a tricyclic scaffold through a domino reaction.

palladium intermediate is trapped by the vinyl bond to produce the desired tricyclic scaffolds through a domino reaction. This powerful methodology gives the key structure of the ( )martinellic acid in a single step. A disclosure by Huang outlines a palladium-catalyzed difunctionalization of N-boc-2,3-pyrroline to amino acetals with aminals and alcohols (Scheme 62).[80] Two diastereoisomers were obtained and two equivalents of enamide are involved during the process. This study represents the first example of enamide Chem. Eur. J. 2014, 20, 1 – 18

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Scheme 64. Photoredox-induced difunctionalization of enamides.

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[11] W.-I. Lee, J.-W. Jung, J. Sim, H. An, Y. G. Suh, Tetrahedron 2013, 69, 7211 – 7219. [12] G. Satyanarayana, M. E. Maier, Tetrahedron 2012, 68, 1745 – 1749. [13] a) S. Nukui, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1993, 34, 4965 – 4968; b) Y. Sato, S. Nukui, M. Sodeoka, M. Shibasaki, Tetrahedron 1994, 50, 371 – 382; c) S. Nukui, M. Sodeoka, H. Sasai, M. Shibasaki, J. Org. Chem. 1995, 60, 398 – 404. [14] K. Kiewel, M. Tallant, G. A. Sulikowski, Tetrahedron Lett. 2001, 42, 6621 – 6623. [15] L. Ripa, A. Hallberg, J. Org. Chem. 1997, 62, 595 – 602. [16] W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org. Chem. 1992, 57, 3558 – 3563. [17] a) W. Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2 – 7; see also, b) C. Amatore, E. Carr, A. Jutand, Acta. Chemica. Scand. 1998, 52, 100 – 106. [18] W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org. Chem. 1993, 58, 7421 – 7426. [19] P. Harrison, G. Meek, Tetrahedron Lett. 2004, 45, 9277 – 9280. [20] A. L. Hansen, T. Skrydstrup, J. Org. Chem. 2005, 70, 5997 – 6003. [21] X. Wu, P. Nilsson, M. Larhed, J. Org. Chem. 2005, 70, 346 – 349. [22] K. S. A. Vallin, Q. Zhang, M. Larhed, D. P. Curran, A. Hallberg, J. Org. Chem. 2003, 68, 6639 – 6645. [23] A. L. Hansen, T. Skrydstrup, Org. Lett. 2005, 7, 5585 – 5587. [24] T. M. Gøgsig, A. T. Lindhardt, M. Dekhane, J. Grouleff, T. Skrydstrup, Chem. Eur. J. 2009, 15, 5950 – 5955. [25] a) J. Mo, L. Xu, J. Xiao, J. Am. Chem. Soc. 2005, 127, 751 – 760; b) J. Mo, S. Liu, J. Xiao, Tetrahedron 2005, 61, 9902 – 9907; c) J. Ruan, J. Xiao, Acc. Chem. Res. 2011, 44, 614 – 626. [26] J. Mo, J. Xiao, Angew. Chem. 2006, 118, 4258 – 4263; Angew. Chem. Int. Ed. 2006, 45, 4152 – 4157. [27] Z. Liu, D. Xu, W. Tang, L. Xu, J. Mo, J. Xiao, Tetrahedron Lett. 2008, 49, 2756 – 2760. [28] Z. Hyder, J. Ruan, J. Xiao, Chem. Eur. J. 2008, 14, 5555 – 5566. [29] J. Ruan, J. A. Iggo, N. G. Berry, J. Xiao, J. Am. Chem. Soc. 2010, 132, 16689 – 16699. [30] Q. G. B. Deng, H. Zhang, J. Qin, Org. Lett. 2013, 15, 2022. [31] M. M. S. Andappan, P. Nilsson, H. von Schenck, M. Larhed, J. Org. Chem. 2004, 69, 5212 – 5218. [32] Y. Liu, D. Li, C.-M. Park, Angew. Chem. 2011, 123, 7471 – 7474; Angew. Chem. Int. Ed. 2011, 50, 7333 – 7336. [33] N. Gigant, L. Chausset-Boissarie, I. Gillaizeau, Org. Lett. 2013, 15, 816 – 819. [34] G. K. Min, T. Skrydstrup, J. Org. Chem. 2012, 77, 5894 – 5906. [35] a) F. Ozawa, T. Hayashi, J. Organomet. Chem. 1992, 428, 267 – 277; b) F. Ozawa, Y. Kobatake, T. Hayachi, Tetrahedron Lett. 1993, 34, 2505 – 2508. [36] L. F. Tieste, K. Thede, Synlett 2000, 1470 – 1472. [37] O. Loiseleur, M. Hayashi, N. Schmees, A. Pfaltz, Synthesis 1997, 1338 – 1345. [38] T. Tu, X.-L. Hou, L.-X. Dai, Org. Lett. 2003, 5, 3651 – 3653. [39] C. Wu, J. Zhou, J. Am. Chem. Soc. 2014, 136, 650 – 652. [40] J. H. Rigby, R. C. Hughes, M. J. Heeg, J. Am. Chem. Soc. 1995, 117, 7834 – 7835. [41] a) J. H. Rigby, M. E. Mateo, Tetrahedron 1996, 52, 10569 – 10582; b) S. E. Gibson, N. Guillo, R. J. Middleton, A. Thuilliez, M. J. Tozer, J. Chem. Soc. Perkin Trans. 1 1997, 447 – 456. [42] G. Satyanarayana, M. E. Maier, J. Org. Chem. 2008, 73, 5410 – 5415. [43] G. Satyanarayana, C. Maichle-Mçssmer, M. E. Maier, Chem. Commun. 2009, 1571 – 1573. [44] S. S. Kinderman, J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, Org. Lett. 2001, 3, 2045 – 2048. [45] For selected examples, see : a) M. Arisawa, Y. Terada, M. Nakagawa, A. Nishida, Angew. Chem. 2002, 114, 4926 – 4928; Angew. Chem. Int. Ed. 2002, 41, 4732 – 4734; b) M. L. Bennasar, T. Roca, M. Monerris, D. GarciaDiaz, J. Org. Chem. 2006, 71, 7028 – 7034; c) G. Liu, W.-Y. Tai, Y.-L. Li, F.-J. Nan, Tetrahedron Lett. 2006, 47, 3295 – 3298. [46] a) M. Toumi, F. Couty, G. Evano, J. Org. Chem. 2008, 73, 1270 – 1281; b) J. D. Katz, L. E. Overman, Tetrahedron 2004, 60, 9559 – 9568. [47] a) T. J. Harrison, G. D. Dake, Org. Lett. 2004, 6, 5023 – 5026; b) J. A. Kozak, R. D. Dake, Angew. Chem. 2008, 120, 4289 – 4291; Angew. Chem. Int. Ed. 2008, 47, 4221 – 4223. [48] T. J. Harrison, B. O. Patrick, G. D. Dake, Org. Lett. 2007, 9, 367 – 370.

As this review has shown, the number of new methodologies regarding the direct C H functionalization of enamides has dramatically increased from year to year. All these transformations provide rapid access to new and original nitrogen-containing compounds, affording the possibility of increasing structural diversity in a straightforward way starting from simple and common substrates. In addition, it is important to note that the synthesis of all these new molecules was previously not possible from traditional pathways. However, some limitations still subsist for almost all of the methods. For example, few of them are efficient for both cyclic and acyclic enamides. In addition, several reactions require relatively harsh reaction conditions and work with environmentally hostile reagents. Palladium appears to be the best catalyst, but the use of copper or iron salts would certainly become a better choice. We therefore anticipate that the chemistry of enamides will continue to be an attractive area in the coming decades. Future work could open up the possibility for the successful creation of new bonds through the direct functionalization of enamides with applications in all fields of chemistry.

Acknowledgements Financial support from the MESR (Ministre de l’Enseignement Suprieur et de la Recherche) to N.G., APR IA 2011 Rgion Centre to L.C.-B. and the LABEX SynOrg (ANR-11-LABX-0029) are gratefully acknowledged. Keywords: atom economy · C H enamides · heterocycles · metal catalysis

functionalization

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Chem. Eur. J. 2014, 20, 1 – 18

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Published online on && &&, 0000

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Review

REVIEW &C

Useful nitrogen-containing heterocycles can be rapidly synthesized from metal-catalyzed regioselective functionalization of enamides. This review discloses the progress made in the development of the direct C H functionalization of enamides involving efficient and atom-economical routes (see scheme; EWG = electron-withdrawing group).

H Functionalization

N. Gigant, L. Chausset-Boissarie, I. Gillaizeau* && – && Direct Metal-Catalyzed Regioselective Functionalization of Enamides

C H Functionalization Enamides have emerged as a relevant functional group that has been involved in a variety of new synthetic transformations including natural product and bioactive molecule syntheses. The p-donating ability of the nitrogen atom renders enamides more electron-rich than simple alkenes and they afford a means of activating carbon– carbon double bonds, giving them both nucleophilic and electrophilic properties. See the Review by Isabelle Gillaizeau et al. on page && for more details.

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Chem. Eur. J. 2014, 20, 1 – 18

www.chemeurj.org

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 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

Direct metal-catalyzed regioselective functionalization of enamides.

Enamides are stable enamine surrogates and provide key intermediates for the synthesis of small but complex nitrogen-containing compounds. Metal-catal...
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