Assembly of functionalized carbocycles or N-heterocycles through a domino electrocyclization–[1,2] migration reaction sequence

The development of processes that streamline the synthesis of complex, functionalized carbocycles and heterocycles remains a hotly pursued topic because their scaffolds are present in a range of bioactive molecules and electronic materials. Although the Nazarov reaction has emerged to be useful in the synthesis of carbocycles and heterocycles, using an electrocyclization to trigger a migration remains underdeveloped. By constructing several bonds in one operation, domino reaction sequences are particularly effective at improving the efficiency of synthesis. The use of transition metal catalysts has the potential to render these processes stereoselective. This review examines the use of electrocyclization-[1,2] migrations to construct molecules and is organized by the type of ring constructed and the order of the two steps in this process.


Introduction
The development of a methodology to streamline the synthesis of complex, functionalized carbocycles and N-heterocycles continues to motivate synthetic chemists because of the prevalence of these scaffolds in molecules that exhibit exciting biological or electronic activity.Electrocyclization reactions are

Navendu Jana
Navendu Jana is currently a 4 th year graduate student who is pursuing his PhD under the powerful transformations in organic synthesis that have been exploited to construct new C-C and new C-N bonds in a stereospecific manner.2][3][4][5][6][7][8][9] The Nazarov reaction is often catalyzed by a Brønsted-or Lewis acid, coordination of which generates the requisite oxyallyl cation 2, which undergoes a stereospecific 4π-electron-5-atom electrocyclization to generate the C-C bond.Elimination of a proton produces the cyclopentadiene 4, which furnishes the cyclopentenone product 5 upon hydrolysis.][12][13][14][15][16][17][18][19][20][21] In contrast to the legion of reports surrounding the development of the Nazarov cyclization, replacing one of the carbon-atoms in the pentadienyl cation with a nitrogen-atom has received less attention because of the challenges associated with generating and controlling the azapentadienyl cationic reactive intermediate.Illustrating the difficulties in overcoming these challenges, one of the first aza-Nazarov reactions was reported by Klumpp and co-workers in 2007-64 years after Nazarov's seminal report. 22They reported that upon exposure to super acidic F 3 CSO 3 H, N-acyliminium ions, such as 6, were transformed into pyrrolidinones via super electrophile 7 (Scheme 2).Since their report, processes have emerged that unlock the required electrophilic nitrogen from azide-, [23][24][25][26] imino-, [27][28][29][30][31] and azirine groups. 32,335][36][37][38][39][40] The most common approach is to intercept this intermediate with a nucleophile before deprotonation or elimination occurs.For example, West and co-workers reported an interrupted Nazarov reaction in 1999. 35They reported that exposure of divinyl ketone 9 to TiCl 4 produced 11 through the cationic olefin polycyclization of the oxyallyl cation 10 (Scheme 3).Because these cascade processes have been recently reviewed, [40][41][42][43][44][45][46] we have chosen to focus the current review on intercepting the oxyallyl cation with a [1,2] migration.While the majority of these domino reactions have been initiated with a 4π-electron-5-atom electrocyclization, we do discuss the use of 6π-electron-6-atom electrocyclizations to trigger these sequences.
We have divided this review on electrocyclization-[1,2] migration domino reactions into three parts (Scheme 4).The first part focuses on domino reactions where a 4π-electron-5-atom-or 6π-electron-6-atom electrocyclization generates an intermediate that engages in a [1,2] migration to create densely functionalized cycloalkenones.In the second part, we describe the related processes in which the [1,2] migration triggers an electrocyclization.The final section focuses on electrocyclization- [1,2] migration sequences that form a C-N bond in the electrocyclization step.Altogether, these domino reactions efficiently construct densely functionalized carbocyclic and heterocyclic scaffolds.Our goal in this review is to connect these apparent disparate reactions by their common mechanistic elementary steps.
Denmark and Hite were the first to systematically study a Nazarov cyclization- [1,2] migration sequence in vinyl dienyl ketones (Scheme 6). 54They reported that exposure of vinyl dienyl ketone 27 to stoichiometric amounts of ferric chloride produces the unusual α-vinyl cyclopentenone 28 instead of the expected cyclopentenone, which was observed by Peel and Johnson with tin-substituted vinyl dienyl ketones. 10Denmark and Hite's domino reaction proved to be general with a variety of cyclohexenyl dienyl ketones transformed into cyclopentenones 28 irrespective of the substituent or substitution pattern on the dienyl-or vinyl component.Alkyl dienyl ketones or phenyl dienyl ketones (e.g.27e and 27f ), however, were inert to reaction conditions.
On the basis of these reactivity trends and 13 C-labeling experiments, the mechanism for α-vinyl cyclopentenone formation was proposed by Denmark and Hite to occur through an electrocyclization- [1,2] migration reaction (Scheme 7).Coordination of the ketone to the Lewis acid FeCl 3 triggers an electrocyclization of the pentadienyl cation 30.This conrotatory closure appears to be favored because it occurs via the linearly conjugated dienyl moiety instead of the cross-conjugated divinyl ketone.The resulting allylic cation then undergoes a [1,2] vinyl migration to yield the α-vinyl cyclopentenone after dissociation of the Lewis acid.This mechanism, however, does not account for the lack of reactivity of phenyl dienyl ketone 27f.Its inertness was speculated to originate either from an inability to access the dienyl cation or the availability of competitive decomposition pathways.
Building on reports from the Denmark group that employed the trimethylsilyl group to accelerate Nazarov electrocyclizations, [55][56][57] Kuroda and co-workers reported a domino electrocyclization-ring expansion sequence of β,β-disubstituted divinyl ketones (Scheme 8). 58They showed that exposure of α-(trimethylsilylmethyl) divinyl ketone 32 to an excess amount of ferric chloride produced cyclopentenone 33. 59The authors proposed that the cyclopentenone product was formed through a conrotatory Nazarov cyclization of 34 that produces spirocycle 35, which undergoes a ring expansion to form the observed product.In support of their proposed mechanism, the authors reported that the electrocyclization product spiro- [4,4]-nonane 35 could be isolated at −30 °C if the reaction time was shortened to 2 hours.Ring expansion of 35 occurred upon warming the reaction mixture to room temperature.This domino reaction was limited to divinyl ketones such as 32.
Increasing the size of the β,β-cycloalkane substituent in 37 resulted in the formation of spiro- [4,5]-decane 38 even if the reaction temperature was increased.
When ferric chloride was substituted with a stronger Brønsted acid, 60 a relief of ring strain was no longer required to trigger the [1,2] alkyl shift.Hayashi and co-workers reported that exposure of divinyl ketone 39 to concentrated sulfuric acid produced cyclopentenone 41 instead of the expected 40 (Scheme 9). 61The authors proposed that 43 was formed from protonation of the Nazarov cyclization product 42.The resulting cation triggers a [1,2] methyl shift to produce the thermodynamically more stable allylic cation 44.Tautomerization then produces the observed cyclopentenone product.
Brønsted-and Lewis acid-catalyzed electrocyclization-ring contraction domino reactions were reported by Chiu and Li in their investigations toward building the hydroazulene core embedded in the natural product guanacastepene A. 62 When divinyl ketone 45 was exposed to methanolic sulfuric acid, the desired Nazarov cyclization product 46 was obtained.Changing the identity of the acid promoter affected the outcome of the reaction.When sulfuric acid or triflic acid was employed, ring-contraction to afford 47 became competitive with elimination to generate 46.Boron Lewis acids also were able to control the outcome of the process: exposure of divinyl ketone 45 to BF 3 •OEt 2 produced 46 as the only product in quantitative yield.Substituting BCl 3 as the Lewis acid induced a subsequent ring contraction to produce spirocycle 47 as the major product.Chiu and Li reported that the domino electrocyclization- [1,2] ring contraction is not limited to cycloheptenyl dienone 45.Cyclohexenyl dienone reacts similarly-albeit less selectively-to produce the mixture of three different products (49, 50 and 51).The best yield of the spirocyclic product was obtained using trifluoromethanesulfonic acid along with the [1,2] methyl shift product 51.The overall reactivity trend indicates that the combination of a Lewis-or Brønsted acid and a non-coordinating solvent prefers a ring contraction product, whereas in the presence of a Lewis basic solvent, elimination circumvents the migration to produce the expected Nazarov product (Scheme 10).
Based on these reactivity trends, the authors proposed a mechanism to rationalize the reaction outcome (Scheme 11).Irrespective of the identity of the acid promoter, they posited that the reaction occurs through a common oxyallyl cation intermediate 52, which is formed by acid-mediated Nazarov electrocyclization.When a Lewis base (e.g.MeOH or Et 2 O) is present, elimination occurs to produce the expected Nazarov product 49 after tautomerization ( path a).When the Lewis base is absent, the rate of elimination is reduced to enable a [1,2]-migration to form the more stabilized oxyallyl cation intermediate 54 ( path b).Subsequent deprotonation and tautomerization affords the product 50.When the smaller cyclohexenyl substituted divinyl ketone was examined, the increase in strain during the ring contraction from six-to fivemembered rings induces path c to occur.The process involves a [1,2]-hydride shift followed by a second [1,2] methyl shift to give intermediate 56.Tautomerization of 56 followed by dissociation of acid affords 51.
Recently, the Frontier group reported a Cu-catalyzed Nazarov cyclization- [1,2] migration reaction that results in the formation of unusual spirocycles. 63They found that the reaction outcome could be controlled by the identity of the Cu(II) complex (Scheme 12).Employing 10 mol% of Cu(OTf ) 2 produced expected bicyclic ketone 58 as a single diastereomer. 64n an attempt to achieve an asymmetric version of this reaction, copper bisoxazoline 60 was examined as a catalyst.In addition to forming 58, the authors observed the formation of spirocycle 59 as a by-product in 40% ee.As the catalyst loading of 60 was increased, the amount of spirocycle increased to become the only product observed once a stoichiometric amount of 60 was added.In contrast, simply increasing the amount of Cu(OTf ) 2 did not change the identity of the major product.The authors posited that spirocycle 59 might be formed as a consequence of the SbF 6 counterion, and they found that when either stoichiometric amounts of AgSbF 6 or Cu(SbF 6 ) 2 were added spirocycle 59 was the major (or only) product formed.Exposure of dienyl ketone 57 to either 10 mol% of AgSbF 6 or Cu(SbF 6 ) 2 , however, led to the formation of bicycle 58 as the major product.
To explore the scope of spirocycle formation, the Frontier group examined the copper bisoxazoline-promoted cyclization of a variety of dienyl ketones (Table 1).The authors found that only the Z-isomer of the starting dienone reacts under reaction conditions. 65,66They noticed that the identity of the spirocycle product was dependent on the nature of the β-substituent: while dienyl ketones with β-alkyl or sterically congested arenes produce spirocycle 62 (entries 1 and 2), an additional [1,2]  migration occurred with a β-4-methoxyphenyl group to  produce spirocycle 63c (entry 3).In addition to ring contractions, Frontier and co-workers reported that acyclic dienyl ketones were competent substrates in their domino reaction to produce cyclopentenone 62d with good yield and excellent enantioselectivity (entry 4).
The authors proposed that their transformation proceeded through the Lewis acid-promoted electrocyclization- [1,2]  domino reaction outlined in Scheme 13.Coordination of the copper(II) salt to dienyl ketone 64 triggers a conrotatory 4π-electron-5-atom electrocyclization to form the oxyallyl cation 65.When substoichiometric amounts of the Lewis acid was employed, elimination through path a is favored to afford ketone 66.When stoichiometric amounts of the Lewis acid is present, a [1,2] shift ( path b) occurs instead to afford spirocycle 67, which undergoes a second [1,2] shift to afford either 68 or 69.The migratory aptitude of the second shift depends upon the steric-and electronic nature of the migrating group.While the sterically congested trimethoxybenzene favors a hydride shift, the smaller 4-methoxybenzene preferentially migrates over a hydride shift presumably because the requisite phenonium ion can be formed.The authors rationalize that the [1,2] hydride shift occurs in the propyl-substituted dienone because the propyl group does not suitably stabilize the carbocation intermediate.
Control of the reaction outcome by catalyst loading was explained by the authors to result from binding of the transition metal complex to the keto-and ester functionality.When substoichiometric quantities of the catalyst are used, the unbound substrate and the product will exist, and these free carbonyl oxygens will accelerate the elimination step.Instead, when the concentration of Lewis acid is increased, both carbonyl oxygens are bound to enable the [1,2] shift to occur.The author's assertion was grounded in their observations: (1) using a Lewis basic solvent such as THF favored the elimination pathway; and (2) using Brønsted acids such as HBF 4 , HNTf 2 , or HSbF 6 afforded cyclopentanones 66. 65 In order to reduce the copper catalyst loading in their domino cyclization-migration reaction, Frontier and coworkers examined the effect of additives on their domino cyclization-migration reaction (Scheme 14). 67They anticipated that metal salts with non-coordinating anions might attenuate the Lewis basicity of the carbonyl group towards the copper catalyst and could be easily exchangeable with the catalyst.In line with their hypothesis, they found that the amount of the copper catalyst, (MeCN) 5 Cu(SbF 6 ) 2 , could be reduced to 10 mol% if 0.90 equiv. of NaBAr 4 F was added to enable the formation of cyclopentenone 59 from dienyl ketone 57.In contrast, the expected Nazarov product 58 was obtained when LiPF 6 (1 equiv.) was added to the reaction mixture.Other additives, such as LiClO 4 , Mg(OTf ) 2 , NaBPh 4 , and NaPF 6 , led to a mixture of products.The success of NaBAr 4 F was attributed to the non-coordinating nature of its counterion and its solubility in dichloromethane solvent relative to the other salts examined.The authors note that the unique ability of NaBAr 4 F to suppress the elimination pathway suggests that only one of the two carbonyl's Lewis basicity must be quashed.The scope of the author's reaction mirrored that of the stoichiometric copper results (Scheme 15).By examining a series of dienyl ketones 70, they found that the identity of the cyclopentenone product was controlled by the steric-and electronic nature of the R 2 -substituent: a [1,2] hydride shift was observed with the bulky trimethoxyphenyl group to afford 71a or 71b, whereas smaller electron-donating groups such as the phenyl group or a thiophene migrates selectively over the hydride shift (72c and 72d).In every substrate examined by the authors, the reaction outcome was comparable to that of stoichiometric copper catalyst conditions.
In the search for different metal catalysts to promote their electrocyclization-migration domino reaction process, Eisenberg, Frontier and co-workers reported that the copper(II) salt could be replaced with a chiral iridium(III) complex (Scheme 16). 68The complex that worked best in the author's reaction was iridium(III) bishexafluoroantimonate catalyst 73 bearing a chiral (R)-(+)-BINAP ligand and an exchangeable diethylisopropylidine malonate (DIM) unit.While Nazarov cyclizations could be triggered by as little as 2 mol% of Ir(III)-73, 69-71 catalysis of the analogous electrocyclization- [1,2] shift reaction required 10 mol% of iridium.In contrast to the previous results using copper, the addition of 1 equivalent of NaBAr 4 F as an additive a mixture of 58 and spirocycle 59 was obtained.The ratio of spirocycle could be improved to 1 : 11 by adding 1 equivalent of ZnI 2 instead, but the improved selectivity was accompanied by a drop in yield.The authors ascribe a similar mechanism for this transformation as with the copper catalyst.
Frontier and co-workers found that changing the electronic nature of the β-substituent on the divinyl ketone substrate changes the outcome of the reaction (Scheme 17). 72The authors reported that replacing the electron-rich C5-substituent in 74 with an electron-poor group produces a 4-alkylidene cyclopentenone 75-where the second [1,2] shift was circumvented by deprotonation.The optimal conditions for formation of 75 were found to be a stoichiometric amount of (MeCN) 5 Cu(SbF 6 ) 2 and an atmosphere of oxygen.In comparison with the author's other reported domino electrocyclization-migration reactions, higher temperatures were also required.The scope of the author's transformation proved to be broad tolerating electron-deficient arenes bearing ester-, nitro-and trifluoromethyl groups.These results indicate that the second [1,2] migration is disfavored because the electronwithdrawing C5 group could not provide stabilization of the intermediate.The reactivity of the electron-neutral 74e, however, suggests that obviating destabilizing steric interactions also play an important role.The formation of alkylidene 75e was rationalized in that the second [1,2]-shift could not occur because the suprafacial phenyl migration from C5 to C1 would create destabilizing steric interactions in 76.
Based on their experimental data, a mechanism for the transformation involving a Cu-mediated oxidation was proposed to account for alkylidene formation (Scheme 18).Coordination of the copper Lewis acid to dienone 74d triggers alcohol 81, 73 which the authors reported could be isolated from incomplete reactions.Dehydration then produces alkylidene cyclopentenone 75d.
In addition to the steric-and electronic nature of the migrating group and the counterion affecting the chemoselectivity, Frontier and co-workers reported that the outcome of their domino electrocyclization-migration reaction was also affected by the copper(II) ligand (Scheme 19). 74A systematic study of common ligands for copper(II) revealed the dependency of the [1,2] aryl migration step on the Cu(II) ligand.When an acetonitrile Cu(II) complex was employed, dienone 82 was converted to the Nazarov product 83 without any observed [1,2] migration events.Switching the ligand from acetonitrile to a chiral bisoxazoline ligand inhibits the elimination pathway; instead a cyclization-rearrangement pathway was exclusively favored.While bisoxazoline L1 or L2 provides a mixture of 84 and 85, exclusive formation of 84 was achieved by using the tert-butyl-bisoxazoline Cu-L3 complex.The authors attribute this product selectivity to the ability of L1-Cu and L2-Cu complexes to disrupt the second [1,2]-C5-aryl group migration.This disruption enables a hydride shift to occur to produce cyclopentenone 85.In contrast, the overlap of the C5-aryl group with the C1 cation is not disrupted with the L3-Cu complex so the second [1,2] aryl shift occurs smoothly to form cyclopentenone 84 as the major product.
Frontier and co-workers applied this ligand-controlled chemoselectivity in the synthesis of the enokipodines (Scheme 20). 74The enokipodines are natural products isolated from the mushroom Flammulina velutipes, and they possess antibacterial activity toward Gram-positive bacteria.Frontier and co-workers envisioned that the scaffold embedded in these sesquiterpenes could be synthesized from their domino electrocyclization-migration reaction sequence after oxidation of the migrating C5-aryl ring.Initial attempts toward this scaffold using 2,5-dimethoxy-substituted dienone 88a, however, were not successful because of the steric bulk of the C5 substituent, which led to a mixture of products.The authors were able to synthesize enokipodine B starting from dienone 88b, which was easily prepared by condensing β-ketoester 86 with aryl aldehyde 87.Exposure of dienone 88b to 1 equivalent of tert-butyl-bisoxazoline L3-Cu produced cyclopentenone 89 in 72% as a single diastereomer.Both the methylcarboxylate and the enone functionality were excised by exposing 89 to conditions developed by Agosta and coworkers. 75Demethylation followed by oxidation with Fremy's salt furnished enokipodin B. The power of the author's method is revealed in the efficiency of this total synthesis: this natural product was assembled in only six-steps from the starting enone in 34% overall yield.Domino 6π-electron-electrocyclization-migration processes.In contrast to domino reaction sequences where a Nazarov reaction initiated a migration, triggering this shift with a 6π-electron-electrocyclization is significantly rare.Liu and coworkers reported that these domino reactions could be promoted from terminal aryl acetylenes using a ruthenium catalyst to isomerize the alkynyl group to a metal alkylidene (Scheme 21). 76In 2004, they reported that an E-and Z-mixture View Article Online of o-ethynyl styrenes 92 could be converted to naphthalenes 93 by using 10 mol% of a Tp-Ru complex.Using isotopically labeled substrates in order to identify the substitution pattern of the naphthalene, the authors were able to confirm that a [1,2] halogen shift occurred after the electrocyclization step.While both bromine-and iodine migration could be triggered, reduced yields were obtained for [1,2] bromine migration.They reported that while their reaction tolerates methoxy groups without adversely affecting the yield, the presence of fluorine slightly attenuates the yield of the naphthalene (compare 93a and 93b with 93c).The authors also reported that this electrocyclization-migration reaction is not limited to aromatic substrates: cyclohexenyl enyne 92f was smoothly converted to tetrasubstituted benzene 93f.
Liu and co-workers proposed a catalytic cycle to account for naphthalene formation from o-ethynyl styrenes (Scheme 22). 76oordination of the terminal acetylene to the cationic ruthenium complex triggers a [1,2] hydride migration to form vinylidene 94.Although this species could directly insert into the Z-C-I bond to form the product, the authors proposed that a 6π-electron-electrocyclization of the vinylidene occurs.The resulting Ru-carbene 95 undergoes a [1,2] iodine shift to produce the η 2 -ruthenium arene complex 96.Dissociation of the catalyst regenerates the catalyst and forms the observed naphthalene product.
[1,2]-Migration followed by electrocyclization: Rautenstrauch rearrangement Inverting the order of the electrocyclization and migration steps of the domino reaction has emerged as a great strategy to assemble complex, functionalized cyclopentenes or five-membered heteroaromatic compounds from acetylenes.These transformations are generally triggered by a π-Lewis acid catalyst.Over the next few sections, we detail the similarities and differences between these reaction sequences.
In 1984, Rautenstrauch developed a Pd(II)-catalyzed rearrangement of propargyl acetate to efficiently access cyclopentenones (Scheme 23). 77When exposed to a PdCl 2 (MeCN) 2 catalyst, 1-ethynyl-2-propenyl acetates 97 rearranged to form 1,4-cyclopentadienyl acetates 98, which hydrolyzed to produce 99.The reaction tolerated different alkyl substituents including large cycloalkanes.A limitation of the domino reaction sequence was revealed in the poor reactivity of propargyl acetates that contained substituents on the terminus of either the acetylene or alkene moieties.
To account for the transformation of propargyl acetates into cyclopentenones, the mechanism outlined in Scheme 24 was proposed.Coordination of the enyne to the palladium(II) catalyst initiates a [1,2] acetoxy shift to generate the oxocarbenium ion 101, which is in equilibration with palladium carbene 102.This divalent species then undergoes a 4π-electron-5-atom electrocyclization to produce cyclopentadiene 98a, which upon hydrolysis generates cyclopentenone 99a.In support of their proposed mechanism, the authors reported that when N-phenyl phthalimide was added to the reaction mixture, The Frontier group reported an advancement to the Rautenstrauch rearrangement by developing a method that enabled the incorporation of substituents on both the acetylene-and vinyl moieties (Table 2). 78They reported that functionalized propargyl acetates 104 could be transformed into cyclopentenones upon exposure to only 2.5 mol% of PdCl 2 in acetonitrile.This transformation could be catalyzed using HgCl 2 as well, but diminished yields were obtained.Using PdCl 2 , the scope of the reaction was explored.The effect of changing the identity of the vinyl substituent is illustrated in entries 1 and 2: switching from a phenyl-to an isopropyl substituent attenuated the yield of the cyclopentenone.Adding a carboxylate substituent to the terminus of the acetylene changed the identity of the product to a pentasubstituted cyclopentadiene (entries 3 and 4).When the acetylenic substituent was changed to an alkyl group the yield of the cyclopentadiene diminished (entry 5).The authors reported that the reaction was dependent on the number of methylenes between the benzyl ether and the acetylene: increasing from one-to three methylene units resulted in no reaction.Although Pd(II)-ether complexes are rare, the authors interpreted this result to indicate the importance of chelation to the oxygen of the benzyl ether to trigger the domino reaction.
0][81][82][83][84] Ohe and co-workers reported that indenes 108 could be accessed from terminal propargyl acetates such as 107 through a Pt-catalyzed [1,2] acetoxy-electrocyclization. 80Higher yields of indenes were observed from electron-rich secondary propargyl acetates such as 107.While catalysis of tertiary progargyl acetates occurred at lower reaction temperatures, the reaction was not selective leading to a mixture of indenes 110a and 110b in every substrate investigated.The regioselectivity of indene formation was dependent on the electronic nature of the aryl substituent with electronrich or electron-poor groups leading to an erosion of selectivity.
Using a gold catalyst, the Wang group reported that sulfur migration was also possible. 81They showed that gold(I) or gold(III)chloride triggered the transformation of propargyl sulfides into indenes 112a and 112b (Scheme 26).In contrast to the Ohe report, this domino reaction sequence preferred the formation of the more substituted indene.Wang and co-workers proposed that the mixture of indenes resulted from a nonselective hydride migration of 113 that terminated the reaction sequence.
In the same study, Wang and co-workers reported that replacing the aryl sulfide with a dithioacetal improved the selectivity of indene formation (Scheme 27). 81Exposure of phenyl-substituted propargyl dithiolane 114 to 5 mol% of AuCl catalyzed a ring expansion of the dithiolane to afford 1,2dithioindene 115.Their reaction tolerated both halogen-and phenyl substituents on the aryl moiety.Further, the acetylene could be substituted with either aryl-or alkyl groups without  attenuation of the yield of the reaction.Changing the identity of the aryl moiety to a furan, however, reduced the efficiency of their process to produce 115f in only 43% with a significant amount of the starting material recovered.
In 2012, a solution to regioselectivity was published by Clark and Zhao (Scheme 28). 82They reported a platinum-catalyzed reaction of propargyl allyl carbonates that generated either indene 117a or 117b depending on the reaction conditions.In the presence of PtI 2 , the more substituted indene was formed when DBU was employed as a base.When DBU was excluded and platinum tetrachlorinate was used as the catalyst, the less substituted indene product was formed exclusively at room temperature.
A further advancement to generate highly functionalized indenes and N-heteroaromatic compounds from propargyl acetates was reported by Sarpong and co-workers (Scheme 29). 83The authors reported that the combination of 10 mol% of PtCl 2 (PPh 3 ) 2 and 20 mol% of iodosobenzene was able to trigger the formation of a broad range of functionalized carbocycles and heterocycles 119 from readily accessible propargyl acetates.The scope of their transformation is illustrated in that not only are indenes accessible from aryl propargyl acetates (e.g.119a and 119b), but also the arene moiety can be replaced with an N-tosyl-protected indole or pyrrole to afford functionalized N-heterocycles 119c or 119d without diminishment of the yield of the domino reaction sequence.In comparison with indene or heteroarene formation, the construction of cyclopentadienes was more limited.In order for the domino reaction sequence to be high yielding, an acetylenic carboxylate group was required.Substitution of this group with a more electron rich group, such as an alkyl-, phenyl-or silyl group had a deleterious effect on the reaction outcome.Further, while exposure of enyne 120 to reaction conditions led to the formation of bicycle 121b as the only product, increasing the size of the cycloalkenyl substituent from cyclopentene to cyclohexene led to a mixture of 123a and 123b.
A mechanism was proposed by the authors to explain the reaction outcome (Scheme 30). 83They posited that the Pt(II)catalyst initiates a [1,2] acetoxy migration via acetoxonium 126 to form platinum carbene 127.The authors propose that this metal divalent species could insert into the aryl C-H bond to afford the product.Alternatively, this C-H bond functionalization could occur stepwise through a 4π-electron-5-atom electrocyclization followed by a [1,5] hydride shift, which would also afford the indene product.While the exact role of iodosobenzene in this transformation remains unclear, the authors hypothesized that the oxidation of either platinum or phosphine helps in generating active metal catalysts.
A major limitation of this domino reaction was its inability to form chiral, non-racemic products.In 2006, Toste and coworkers reported that this limitation could be overcome by using enantioenriched propargyl pivolates (Table 3). 85Subjecting chiral, non-racemic 128 to 5 mol% of (Ph 3 P)AuSbF 6 at −20 °C resulted in formation of cyclopentenones 129 with good transfer of chirality.The non-coordinating SbF 6 counterion was critical to the success of this transformation.Switching to triflate resulted in a loss of enantioselectivity.Their reaction conditions could be used to access a range of substituted cyclopentenones from a variety of acyclic and cyclic sub-strates.Changing the ring size of the cycloalkenyl moiety did not affect the efficiency or selectivity of this transformation.
To account for the chirality transfer, the authors proposed a mechanism with a helical catalytic intermediate (Scheme 31). 85The authors posited that the formation of enantioenriched cyclopentenones indicated that a metal carbene was not being formed since its formation would destroy the chiral information embedded in the molecule by breaking the C-O bond.Accordingly, Toste and co-workers proposed that coordination of the Au(I) catalyst to the terminal acetylene triggered a [1,2] pivaloate migration that proceeded via helical 131 to afford cyclopentene 129a.The helical intermediate 131 enables efficient transfer of the chiral information because the new C-C bond forms concomitantly with the breaking of the C-O bond.
The formation of the C-C bond via a helical transition state was supported by a computational study on this reaction (Scheme 32). 86de Lera and co-workers identified helical transition state 131 where C-O bond scission occurred slightly before C-C bond formation.Their study revealed a significant difference in stability between pentadienyl cations 133 and 134: the (P)-anti 133 was found to be 4.38 kcal mol −1 which is more stable than the (M)-syn 134 to favor the formation of (S)-129a through the anti-helical transition state 131.
In 2015, the first enantioselective catalysis of the Rautenstrauch rearrangement was reported by Toste and co-workers (Scheme 33). 87In order to achieve this transformation, the  Toste group developed conditions where a nitrogen-atomassisted Nazarov cyclization was able to dominate over the chiral transfer process.They were able to achieve this by changing the aryl moiety to an indole and substituting the pivaloate group with an acetal.Upon exposure to chiral gold(I) complexes, heterocyclic propargyl acetals such as 135 could be transformed into enantioenriched cyclopenta[b]indoles 137.
Their transformation tolerates a range of functionality on the indole moiety, but the enantioselectivity was slightly diminished when 4-substituted indoles were employed (e.g.137d).This loss in enantioselectivity was attributed by the authors to result from steric repulsion between the methyl substituents.
The authors reported that their transformation could even be extended to other electron-rich heterocycles such as pyrrole to provide N-heterocycles such as 137g.
In order to account for the ability of the chiral gold(I) catalyst to override the chiral information embedded in the indole starting material, the authors proposed the catalytic cycle illustrated in Scheme 34. 87Coordination of the cationic gold species with the alkyne increases its electrophilicity to initiate attack by the proximal acetal.The C-O bond in the resulting oxonium ion 139 fragments to produce the oxocarbenium ion 140.The stereocenter in 140 is ablated when the electron-rich indole expels acetaldehyde to produce the pentadienyl cation 141, which undergoes an enantioselective Nazarov cyclization to form 142, where the stereoselectivity of C-C bond formation is controlled by the chiral, non-racemic phosphine ligand.Dissociation of the cationic gold complex from 142 produces the N-heterocycle 136a, which is hydrolyzed to produce the cyclopenta[b]indole 137a.Domino 6π-electron-Rautenstrauch processes.While generation of a metal vinylidene intermediate by a [1,2] acetate or a [1,2] sulfide migration has emerged as a common tactic to construct new C-C bonds, initiating the electrocyclization with a [1,2] halogen migration is less common.The resulting pro-ducts would contain an activated sp 2 -C-I bond that could be further functionalized by using cross-coupling reactions.In 2002, 88 Iwasawa and co-workers addressed this gap in their report of a tungsten-catalyzed reaction of ortho-alkynylstyrenes to produce functionalized α-iodonaphthalenes 145 (Scheme 35).While the use of stoichiometric amounts of tungsten led to higher yields, the authors reported that their transformation could be catalyzed with as little as 10-20 mol% of the tungsten catalyst to access a range of trisubstituted naphthalenes.Their reaction tolerates a broad range of R 1 -substituents including alkyl-, aryl-and silyl ethers without diminishing the yield of the naphthalene.The yield of their transformation was attenuated when either an R 1 -carboxylate-or α,β-disubstituted o-alkenyl substituted substrates was employed.The presence of the central arene appears to be critical, exposure of dienyne to reaction conditions led to only 34% of tetrasubstituted benzene 145f.
Based on the reactivity patterns of their substrates, the authors proposed a potential mechanism to account for the regioselectivity of their transformation (Scheme 36). 88Coordination of tungsten pentacarbonyl with the iodoacetylene triggers a [1,2] iodide shift to produce tungsten vinylidene 146.6π-Electrocyclization of 146 produces tungsten carbene 147, which undergoes a [1,2] hydride shift to form 148. Dissociation of the catalyst generates α-iodonaphthalene 145a.

Domino electrocyclization-migration processes involving C-N bond formation
In comparison with Nazarov-[1,2] migration processes, domino reactions in which the electrocyclization forms a C-N bond are very rare.In our opinion, this sequence was first reported in a 1969 report by Sundberg and co-workers, 89,90 who observed the conversion of β-phenyl-β-methyl-ortho-nitrostyrene to 2-methyl-3-phenyl indole (Scheme 37).Their reaction exhibits excellent migratorial selectivity in favor of a [1,2]  phenyl shift to produce 150.Indole formation was not dependent on the nitrostyrene isomer: both E-and Z-isomers were converted to the product with nearly equal yield.Building on work by Cadogan and co-workers, 91 Sundberg and Kotchmar proposed that indole formation occurred through a phosphitemediated deoxygenation of the nitroarene to afford nitroso-or nitrene 153, which underwent a cyclization to afford 154.Formation of this cation triggers a [1,2] phenyl shift to afford 3Hindole 155, which tautomerizes (with an additional deoxygenation if necessary) to afford 2-methyl-3-phenyl indole.
3][94][95][96] Their study built on an observation of Yabe in 1980, 97 who reported that low temperature photolysis of ortho-substituted biarylazides such as 156 produced an N-methylcarbazole 158 byproduct arising from methyl migration in addition to azine formation.The results of Moody, Rees and co-workers revealed that these migrations were a general phenomenon: irradiation of β,β-disubstituted 3-azido-2-alkenylthiophene azide 159 produced thienopyrrole 160 where C-N bond formation was accompanied by a [1,2] migration of one of the β-substituents.In addition to the selective acyl migration pictured in Scheme 38, the authors reported that sulfur groups-including sulfides and sulfoxides-also migrated in preference to the ethyl carboxylate group.The authors also found that sulfide and sulfoxide migration was competitive with C-H bond amination: 94 photolysis of thiophene azide 161 produced a mixture of thienopyrroles 162 and 163 in favor of sulfide or sulfoxide migration.In contrast to the preference of sulfides and sulfoxides, which engage in [1,2] shift reactions, the analogous sulfone produced only the C-H bond amination product, 163c.When the thiophene azide moiety was replaced with an aryl azide (164) exclusive migration of the methyl sulfide was observed to afford indole 165 as the only product. 96he mechanism for this transformation was postulated by the authors to occur through an electrocyclization- [1,2]  migration sequence (Scheme 39).Photolysis of thiophene azide 166 produces nitrene 169, which participates in a 4π-electron-5-atom electrocyclization to produce thiophenefused 2H-pyrrole 170.A [1,2] shift of the migrating group (MG) produces 3H-pyrrole 171.The thieno[3,2-b]pyrrole product 168 is formed through either a photochemically allowed [1,3]  hydrogen shift or two successive "dark" [1,5] shifts.When R = H, thienopyrrole 167 could be generated by a C-H bond amination: insertion of the nitrene into the sp 2 -C-H bond or a twostep H-atom abstraction-radical recombination.On the basis of established reactivity trends in 2H-indenes, [98][99][100][101] the authors proposed that the C-H bond amination products are formed through an electrocyclization- [1,5] hydrogen migration mechanism.The difference in migration ability of sulfide and sulfoxide versus the inertness of sulfone was rationalized through the use of the lone pair of electrons on sulfur to form an episulfonium ion 172, which could fragment to afford the [1,2] shift product.
In 2006, the Driver group reported that Rh 2 (II)-carboxylates catalyze the formation of indoles from vinyl-or aryl azides (Scheme 40). 23,24Their mechanistic experiments indicated that C-H bond amination occurred in a step-wise fashion with C-N bond formation preceding C-H bond scission. 25After coordination of the azide to the rhodium catalyst, extrusion of N 2 occurs to form rhodium nitrene 176.Because dinitrogen loss is accelerated by electron rich ortho-substituents, the authors suggested that significant delocalization of the positive charge occurs in the adjacent π-system.This delocalization facilitates C-N bond formation through a 4π-electron-5-atom electrocyclization, which forms 178.A [1,5] hydride shift then affords the product N-heterocycle after dissociation of the rhodium catalyst.In support of this step-wise mechanism, exposure of β,β-diphenylstyryl azide 179 to reaction conditions afforded 2,3-diphenylindole 180. 24he migratorial aptitude of β-substituents was investigated by the Driver group by examining the reactivity of styryl azides towards Rh 2 (II)-carboxylate catalysts.The first set of intramolecular competition experiments compared the reactivity of aryl-and alkyl groups to participate in the [1,2] shift (Scheme 41). 102Exposure of a series of β,β-disubstituted styryl azides 181 to Rh 2 (O 2 CC 7 H 15 ) 2 triggered the formation of 2,3disubstituted indole 182.In every substrate examined, a [1,2]  aryl shift occurred exclusively to afford the product irrespective of the electronic nature of the migrating aryl group or the stereochemistry of the starting styryl azide.The reaction was not affected by the size of the ring expansion, and even acetophenone-derived substrates could be converted to 2-methyl-3-aryl indole 182d.To account for the selectivity of 2-alkyl-3-arylindole formation, the authors proposed the catalytic cycle outlined in Scheme 42.Coordination of the rhodium catalyst to the azide promotes the extrusion of N 2 to form rhodium N-aryl nitrene 185, which undergoes a 4π-electron-5-atom electrocyclization to produce 186.The selective [1,2] aryl migration is rationalized through the formation of phenonium ion 187.This shift forms 3H-indole 188, which tautomerizes to form the observed indole product.In support of this catalytic cycle, the authors obtained and examined a series of β,β-diaryl substituted styryl azides.The ratio of indoles was analyzed using the Hammett equation and the resulting ρ-value of −1.49 (versus σ para values) supports the formation of the phenonium ion.
The Driver group next investigated the effect of distal substitution in styryl azides on controlling the migratorial preference of the β-substituent (Scheme 43). 103The authors proposed that a γ-heteroatom might control the selectivity of the [1,2] shift reaction by using its lone pair of electrons to trigger C-C bond heterolysis and stabilize the build up of positive charge in the migration.In line with their assertion, exposure of styryl azides such as 192 to reaction conditions produced only tetrahydrocarbolines 194-the product of exclusive aminomethylene migration.The scope of this reaction appeared broad: ring expansion to 5-, 6-and 7-membered heterocycles was tolerated and the reaction was unaffected by the electronic nature of the styryl azide.Their reaction, however, was sensitive to the steric environment around the azide.Introduction of an additional ortho-substituent dramatically reduced the yield of the transformation to afford indole 194g in only 34%.This reactivity was not confined to aminomethylene shifts: ethereal [1,2] shifts also occurred exclusively over alkyl groups to afford indole 194h.
Insight into the mechanism of the [1,2] aminomethylene shift came from the reactivity of proline-derived styryl azide 195 (Scheme 44). 103Subjecting chiral, non-racemic 195 to reac- tion conditions produced the expected aminomethine shift product as a mixture of racemates.To account for the loss of optical activity, the authors proposed that the shift occurs via the iminium ion 199.Double crossover experiments revealed that this iminium ion does not escape the solvent sheath.Further, the reactivity of this substrate established that aminomethine migration was preferred over the alternative [1,2]  phenyl migration.
The Driver group reported the electrocyclization-[1,2] nitro shift domino reaction of styryl azides (Scheme 45). 104In contrast to the thermolysis of β-nitro-substituted styryl azides, 105 which afforded 2-nitroindoles 201, the presence of Rh 2 (esp) 2 changed the reaction outcome to produce only 3-nitroindoles 202.While this reaction was insensitive to the electronic environment of the aryl azide moiety, an additional ortho-substituent led to formation of 2-substituted nitroindoles 201 as the major product.The ratio of 2-nitroindole increased as the ortho-substituent became more electron-withdrawing.The additional ortho-substituent could lead to dissociation of the Rh 2 (II)-carboxylate catalyst to result in N-aryl nitrene formation to mirror the results reported by Gribble and Pelkey in the thermolysis of β-nitrostyryl azides. 105n addition to nitro-group migration, the authors also examined the migratorial aptitude of other electron withdrawing groups. 104Acyl-and benzoyl groups were found to migrate preferentially to afford only 3-substituted indoles.The authors also reported that the [1,2] sulfone shift was competitive with a [1,5]-hydride shift.For the sulfones, a mixture of 2-and 3-substituted products was observed.In contrast to their expectations, the ratio of indoles was not dependent on the electronic nature of the migrating aryl sulfone-in each example a 90 : 10 ratio of 3-to 2-substituted indole was observed.Exposure of a β-amide-substituted styryl azide 208 to reaction conditions also afforded a mixture of 2-and 3-substituted indoles (77 : 23).Esters did not migrate affording only the 2-carboxylate-substituted indole (Scheme 46).
To place their results in context with other potential migrating groups, the authors performed several intra-molecular competition experiments using β,β-disubstituted styryl azides (Scheme 47). 104Subjecting β-sulfonyl-β-phenyl substituted styryl azide to reaction conditions produced only the 3-sulfonyl substituted indole 212.Exposure of a β-amideβ-phenyl styryl azide resulted in exclusive amide migration to afford indole 214.To compare the migratorial aptitude of nitro-and benzoyl groups, styryl azide 215 was tested.Only nitro-group migration occurred to produce indole 216.
Electrocyclization-[1,2]-amide shift domino reactions of β,β-disubstituted styryl azides can also be promoted using CuI (Scheme 48). 106Zhang and co-workers reported that photolysis of styryl azide 217 in the presence of a stoichiometric amount of CuI triggered ring expansion through the exclusive migration of the amide to form 2,3-disubstituted indole 218.The authors reported that reducing the amount of CuI reduced the yield of indole formation.The reaction tolerated a broad range of functionality including esters and NH-amides without attenuation of indole yield.Similar to the results of Driver and The authors reported a domino reaction mechanism to account for the formation of 3H-indoles (Scheme 52).Coordination of the Rh 2 (II) carboxylate catalyst to the azide triggers extrusion of N 2 to form rhodium N-aryl nitrene 230, which undergoes electrocyclization to form 231. From the cation 231, two [1,2] shifts are possible.As predicted from the author's earlier results, an alkyl shift would go through a transition state in which a partial positive charge is generated next to the carboxylate substituent 233.In contrast, if the carboxylate group migrated, a more stable iminium ion (232) would be generated.Dissociation of the rhodium catalyst would then generate the product.
If stability of the iminium ion controlled the selectivity of the [1,2] migration step, it was anticipated that changing the identity of the β-substituent to an electron-donating substituent should change the outcome of the reaction.In line with their hypothesis, exposure of β-alkoxy styryl azide 234 to reaction conditions triggered aryl migration to produce oxindole 236 after acid-mediated hydrolysis of 3H-indole 235 (Scheme 52).
Next, the authors reported that increasing the steric environment around the o-alkenyl substituent could override the innate reactivity preference of the substrate (Scheme 53). 111When aryl azides containing an ortho-[2.2.1] substituent were exposed to reaction conditions, carboxylate migration to the nitrogen-atom was observed as the major product instead of the carbon atom to result in the formation of indole 239.Adding methyl substituents to the bridgehead eliminated the formation of 3H-indole 241 to result in only 242.While this preference did not depend on the electronic nature of the aryl azide, simply moving one of the allylic substituents to the homoallylic position resulted in observation of 3H-indole 244 as the minor product.The authors proposed that the [1,2] migration selectivity resulted from minimizing the destabilizing steric interactions between the bridgehead methyl groups and the aryl moiety.
Driver and co-workers have recently reported that domino cyclization-migration reactions can be achieved from the Pd(II)-catalyzed reduction of ortho-substituted nitrostyrenes (Scheme 54). 112The authors turned their attention from aryl azides to nitrostyrenes because the latter require fewer steps to synthesize and the nitro-functional group is not as dangerous to introduce as an azide.The authors reported that β-phenyl trisubstituted nitrostyrenes-available in one step from crosscoupling commercially available 2-nitrophenylboronic acid with the vinyl triflate derived from 2-phenylcyclohexanonecould be transformed into spirocycle 247 through exposure to 10 mol% of ( phen)Pd(OAc) 2 and Mo(CO) 6 as the source of CO.Their transformation tolerated a range of electron-releasing and electron-withdrawing functionality on the nitroarene without attenuation of the yield of 247.Only when an additional ortho-substituent was introduced did the efficiency of N-heterocycle formation plummet.Similar to their results with ortho-substituted aryl azides, the authors reported that when the identity of the β-substituent was changed to carboxylate that 3H-indoles 248 were produced.This transformation also tolerated heteroatoms in the ortho-alkenyl group and exhibited slightly higher stereoselectivity than the analogous aryl azide substrate.For example, substrates with either an allylic-or homoallylic substituent were transformed into the 3H-indole with 90 : 10 ratio of diastereomers.
The authors proposed a catalytic cycle to account for 3Hindole formation that involved the cyclization of a metal nitrosoarene as the key step (Scheme 55).Thermolysis of Mo(CO) 6 produced carbon monoxide required for ( phen)Pd(OAc) 2 to reduce the nitro group to a nitrosoarene.Cyclization of the resulting metal nitrosoarene 249 could occur by nucleophilic attack of the ortho-alkenyl unit or a 6-electron-electrocyclization.The formation of the C-N bond by the latter pericyclic step was implicated by Houk and co-workers in their compu-tation study of Pd(II)-catalyzed carbazole formation from biphenyl nitroarenes. 113,114The resulting cation 250 triggers a [1,2] shift to form 3H-indole N-oxide 251.Metal-mediated reduction of the N-O bond produces the N-heterocycle product and regenerates the catalyst.The authors concluded from a series of mechanistic experiments that the palladium catalyst functions to reduce the nitrostyrene to the nitrosoarene.Molybdenum carbonyl is competent to mediate the remaining steps of the transformation.

Summary and outlook
Significant progress has been made in the development of domino reactions that assemble functionalized cycloalkanes or N-heterocycles through an electrocyclization-[1,2] migration sequence.Despite this progress, we believe that domino reaction sequences involving electrocyclization and [1,2] migration steps are still at a nascent stage and with significant challenges remaining.Although many methods assemble fivemembered rings, sequences that construct six membered rings through 6π-electron-6-atom electrocyclizations remain rare.Even though tremendous progress has been made by the Frontier and Toste groups to achieve the synthesis of chiral, non-racemic cycloalkanes, stereoselective formation of C-N bonds has lagged.These gaps in the synthetic literature will be plugged as our mechanistic understanding of the underpinning principles that govern each of the elementary steps increases.We eagerly anticipate these future reports that address these challenges to increase the accessibility of functionalized N-heterocycles and carbocycles.

Scheme 11
Scheme 11 Potential mechanism for electrocyclization-ring contraction process.

Scheme 14
Scheme 14 Examination of additives to reduce the Cu(II)-catalyst loading.

a
Scheme 16 Development of Ir(III)-catalyzed domino cyclizationmigration reaction.

Scheme 20
Scheme 20 Total synthesis of enokipodin B.

Scheme 25
Scheme 25 Formation of substituted indenes using the Rautenstrauch rearrangement.

Scheme 30
Scheme 30 Potential mechanism to account for product formation.

Scheme 46 Scheme 45
Scheme 46 Preference for electron-poor groups to migrate over hydrogen.

Scheme 53
Scheme 53 Effect of increasing the steric environment on the reaction outcome.

Table 1
Scope of the spirocyclization reaction

Table 3
Development of the chiral, non-racemic variant of the Rautenstrauch rearrangement Scheme 31 Mechanism to explain the origin of chirality transfer.Scheme 32 Computational study that supports synchronous C-O bond scission and C-C bond formation.