Selective product formation in the Pd-catalyzed cyclization of unsaturated amide and carboxylic acid derivatives is an intriguing and challenging task. We recently discovered that the oxidative intramolecular Pd(II)-catalyzed amination or oxylation of unsaturated N-sulfonyl carbamates, N-sulfonyl carboxamides and carboxylic acids takes place through the involvement of cyclic (usually, 5- or 6-membered) aminopalladated (AmPIs) or oxypalladated (OxPI) intermediates. Such cyclic intermediates can undergo a variety of transformations such as distocyclic β-H elimination, oxidative acetoxylation or intramolecular carbopalladation, depending upon the substrate and/or the reaction conditions. In the absence of appropriate reaction pathways, the cyclic nucleopalladated intermediates (NuPIs) simply engage in an inconsequential equilibrium with the initial substrate and other transformations occur such as allylic C–H activation or, in the particular case of allyl carbamates, [3,3]-sigmatropic rearrangement.
When an alkene coordinates to a PdX2 complex, the electronic character of the olefin π-system changes enabling two main and mutually excluding reaction paths, namely nucleopalladation [1–6] or C–H allylic activation [7–12] to provide an electrophilic η3-allylpalladium complex. Other reactions and intermediates are also accessible depending upon the nature of the starting alkene and/or the reaction conditions (Scheme 1) .
These transformations are normally oxidative and therefore require an oxidant to regenerate the active metal catalyst. The oxidant can intervene after the formation of product and convert Pd(0) back into Pd(II) (Scheme 2, left) or assist product formation through oxidation of an intermediate organometallic Pd(II) species to a more reactive Pd(IV) species (Scheme 2, right) [14–17].
Many studies on the role of the oxidant have been published. However, a complete understanding of the rules governing the path selection lacks. Accordingly, we decided to undertake a systematic investigation of the Pd(II)-catalyzed cyclization of unsaturated N-sulfonyl carboxamides (1a), carboxylic acids (1b), and N-sulfonyl carbamates (1c) in the presence of a variety of terminal oxidants (Scheme 3) . This study has permitted a correlation of reaction pathway with substrate type and reaction conditions.
Substrates with internal alkenes
Based on a series of preliminary experiments, optimal reaction conditions were defined for the nitrogen containing substrates [protocol A: Pd(OAc)2 10 mol%, (PhSOCH2)2 15 mol%, phenylbenzoquinone (PhBQ) 1.07 equiv, AcOH (0.2 M), 45°C, 24 h] and the unsaturated carboxylic acids [protocol A′: Pd(OAc)2 10 mol%, (PhSOCH2)2 15 mol%, PhBQ 1.07 equiv, NaOAc 1 equiv, DCM (0.5 M), 45°C, 24 h]. Submission of N-tosyl (E)-hex-4-enamide 1a3i and of hex-4-enoic acid 1b3i to these optimized reaction conditions gave 5-vinyl pyrrolidone 2a3i, and 5-vinyl γ-butyrrolactone 2b3i (Scheme 4, top), respectively .
On the other hand, the same reactions with PhI(OAc)2 as oxidant [protocol B for 1a3i: Pd(OAc)2 10 mol%, (PhSOCH2)2 15 mol%, PhI(OAc)2 2.1 equiv, AcOH (0.2 M), 45°C, 24 h; protocol B′ for 1b3i: Pd(OAc)2 10 mol%, (PhSOCH2)2 15 mol%, PhI(OAc)2 2.1 equiv, NaOAc 1 equiv, DCM (0.5 M), 45°C, 24 h] gave rise to inseparable mixtures; 5-vinyl- and β-styryl-pyrrolidones 3a3i (same as 2a3i) and 3′a3i were obtained from 1a3i and 5-vinyl-, 5-(β-styryl)- and 5-(1-iodo-ethyl)-γ-butyrrolactones 3b3i (same as 2b3i), 3′b3i, and 3″b3i were obtained from 1b3i (Scheme 4, bottom).
Substrates with terminal alkenes
N-sulfonyl carbamates , N-sulfonyl carboxamides , and carboxylic acids [22, 23] bearing terminal double bonds were also considered and gave similar results. In particular, reaction of N-tosyl but-3-en-1-yl carbamate 1c4t and its homolog N-tosyl pent-4-en-1-yl carbamate 1c5t according to protocol A provided 4-vinyl-1-tosyl-1,3-oxazolidin-2-one 2c4t and 1-tosyl-4-vinyl-1,3-oxazinan-2-one 2c5t, respectively. The expected products were also obtained from N-tosyl hex-5-en-amide 1a4t, and N-tosyl hept-6-en-amide 1a5t. Similarly, cyclization of the unsaturated carboxylic acids hex-5-enoic acid 1b4t and hept-6-enoic acid 1b5t furnished 5-vinyl γ-lactone 2b4t (same as 2b3i) and 6-vinyl δ-lactone 2b5t (Scheme 5).
A very different outcome was observed when PhI(OAc)2 was the oxidant (protocol B). Here, heterocycles resulting from a formal alkene 1,2-aminoacetoxylation were obtained (Scheme 6). In the case of the carbamates and the carboxamides with a three atom bridge between the nucleophile and the double bond, random mixtures of 6-exo and 7-endo products were detected.
Rationalization of the results
Although confusing at first glance, all the results obtained can be explained through an initial equilibration between the substrate and the nucleopalladated intermediate (NuPI). The fate of the NuPI depends upon the substrate and the reaction conditions, particularly the nature of the oxidizing agent. For substrates having a three atom bridge between the nucleophile and the unsaturation (Scheme 4, top), the intermediate 5-membered-ring NuPI  can easily undergo distocyclic dehydropalladation  in the presence of PhBQ (protocols A/A′) to provide vinylpyrrolidones or lactones (Scheme 7). Such a β-elimination is favored by the presence of three easily accessible equivalent hydrogen atoms.
The fact that these same products were generated in the presence of PhI(OAc)2 (protocol B/B′) indicates that the oxidation of NuPI does not compete with this very facile β-H elimination. However, further reactions occurred to furnish the styryl heterocycles 3′a3i and 3′b3i, as a result of a Mizoroki–Heck process and, in the case of the carboxylic acids, the iodolactone 3″b3i via a potential PhI(OAc)2 promoted iodolactonisation (Scheme 8).
For substrates bearing a terminal unsaturation, we believe that the NuPI intermediate still forms in a rapid and reversible equilibrium [26–31] but that β-H elimination, only possible through a proxicyclic path, is disfavored . Therefore, protocol A/A′ leads predominately to irreversible C–H activation before nucleophilic attack, to provide the product  (Scheme 9).
We believe that the proxicyclic dehydropalladation of carbamates and carboxamides is disfavored by electronic effects as well as geometric constraints. Indeed, in AcOH solvent, the nitrogen atom of AmPI can be protonated, thereby rendering β-H elimination more difficult. Furthermore, interaction between the Pd atom and one of the two oxygen atoms of the sulfonyl moiety may impede the synperiplanar H-C-C-Pd arrangement, required in the β-H elimination step (Scheme 10).
However, in the presence of PhI(OAc)2 (protocol B/B′), oxidation of the NuPI intermediate can occur, opening up a new product manifold. The oxidation to either a Pd(IV) [34, 35] or a dimeric Pd(III) intermediate apparently occurs, followed by reductive elimination [14–17]. This process is much faster than the C–H activation observed in the presence of PhBQ (Scheme 11).
Carbopalladation as a means to trap the elusive NuPIs
According to this proposed mechanism, substrates possessing a terminal unsaturation are expected to reversibly form an off-cycle NuPI under reaction conditions A/A′ as a result of a forbidden proxicyclic β-H elimination (Scheme 12, left). One clever way to demonstrate the existence of such elusive intermediate would be to incorporate an additional unsaturation into the substrate, so as to enable an easy intramolecular carbopalladation/dehydropalladation sequence, according to a domino process [36, 37] (Scheme 12, right).
Indeed, submission of N-tosyl 3-vinylhept-5-enamide 1a′3t to cyclization protocol A afforded the fused pyrrolidin-2-one 2a′3t as a single diastereoisomer in 10% yield (40% when using 26 mol% of Pd(OAc)2) (Scheme 13, right). Under the same conditions, 3-vinylhept-5-enoic acid 1b′3t gave a mixture of the expected bicyclic γ-lactone 2b′3t and the dienic δ-lactone 2b″3t. We surmised that the poor Pd turnover for carboxamide 1a′3t was due to an unfavorable equilibrium in the reductive elimination step, AcO[Pd]H⇆[Pd(0)]+AcOH, due to the acidic conditions. Repeating the reaction under basic aerobic conditions [protocol A″: Pd(OAc)2 (0.1 equiv), NaOAc (2 equiv), DMSO, O2, 80°C, 24 h] provided the desired product 2a′3t in an improved yield of 40%.
Interestingly, whereas the reaction cascade consisting of 5-exo aminopalladation and carbopalladation was stereo- and regio-selective for the carboxamide, transformation of the carboxylic acid substrate was characterized by two unselective and competing reactions: 5-exo oxypalladation/carbopalladation and 6-exo oxypalladation/distocyclic dehydropalladation sequence (Scheme 14). Despite the moderate Pd turnover, these catalytic domino sequences are of synthetic interest and unequivocally confirm the involvement of the postulated cyclic NuPIs.
The special case of allylic carbamates
Reaction of prop-3-enyl N-tosylcarbamate 1c3t according to protocol A (but using CH2Cl2 instead of AcOH), gave only the allyl-N-tosyl amine 2c′3t in 54% yield. Here again, a rapid and reversible equilibrium with an off-cycle cyclic AmPI could be present but, in this particular case, the substrate undergoes a facile [3,3]-sigmatropic rearrangement [38–43] followed by decarboxylation  (Scheme 15).
Substrate 1c3i is an intriguing probe as it can undergo both aminopalladation as well as the [3,3]-sigmatropic rearrangement sequence. Using protocol A″ (protocol A was ineffective), a mixture of 4-vinyl oxazolidinone 2c3i (2.5%), N-tosyl 3-aminobutene 2c′3i (7%) and 4-acetoxy-3-tosylamino butene 2″c3i (12%) was obtained. This is not totally unexpected and reflects a balanced competition between the [3,3]-sigmatropic rearrangement and the distocyclic β-H elimination pathways. Worthy of note is the BAL-type  cleavage of the oxazolidinone ring by the acetate anion at high temperature (protocol A″ @ 80°C). This leads to the aminoacetoxy derivative 2c″3i after decarboxylation (Scheme 16).
The present account provides the first unified mechanistic scheme for the Pd(II)-catalyzed oxidative cyclization of unsaturated carbamates, carboxamides and carboxylic acids. The formation of a cyclic NuPI appears always possible, although it may or may not lie on the path of product generation. In particular, these intermediates can occur along several reaction pathways such as distocyclic β-H elimination, oxidative acetoxylation, or carbopalladation. On the other hand, in the absence of the above transformations, the NuPI may participate in an equilibrium with the initial substrate, potentially leading to [3,3]-sigmatropic rearrangements or allylic C–H activation of olefinic substrates.
A collection of invited papers based on presentations at the 19th European Symposium on Organic Chemistry (ESOC-19), Lisbon, Portugal, 12–16 July 2015.
The authors would like to thank the organizers of ESOC-19 (2015) and particularly the chairperson, Prof. Amélia Pilar Rauter. They also warmly thank all students who participated in this exciting project, whose names are quoted in the reference section. CNRS, UPMC, and Labex Michem are acknowledged for financial support. Support through CMST COST Action, CM1205 (CARISMA) is also gratefully acknowledged. Finally, we are grateful to Dr. Allan Cunningham (BASF Schweiz AG) for helpful discussions.
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