Reactivity of Arynes toward Functionalized Alkenes: Intermolecular Alder-Ene vs. Addition Reactions

The selectivity between two different manifolds of reactions of arynes reacting with functionalized alkenes is described. Arynes generated from bis-1,3-diynes react with various trisubstituted and 1,1-disubstituted alkenes including methallyl amine, prenyl azide, and methacrylic acid, providing mainly addition products of the polar heteroatom functionalities over the Alder-ene products of the alkene segment. The selectivity, however, intricately depends on the substituent pattern of the alkene. Except for the most reactive 2-propenyl group-containing aldehyde, α,β-unsaturated aldehydes generally participated in an addition reaction, generating chromene derivatives.

In order to expand the scope and utility of aryne-based transformations, obtaining comprehensive information about the reactivity of arynes with structurally diverse alkenes containing a heteroatom functionality would be desirable.Thus, we explored the intermolecular Alder-ene reaction of arynes with alkenes containing a polar functional group 6 such as amine, azide, carboxylic acid and aldehyde.It was found that the addition reaction of these alkenes generally outcompeted the Alder-ene reaction (Table 1).The aryne generated from symmetrical tetrayne 1 reacted with N-methallyl The difference in the product distribution between these two reactions is probably the consequence of the small nucleophilicity difference of the nitrogen center.The reaction of prenyl azide (3:1 isomeric mixture) generated cycloadduct 3c derived from a primary azide in 76% yield and a trace amount of its regioisomer (entry 3).Methacrylic acid provided a mixture of both ene-product 2d (33%) and addition product 3d (40%) (entry 4). 7While the reaction with methacrolein afforded exclusively Alder-ene product 2e, the corresponding butyl-substituted aldehyde generated a 1:1 mixture of Alder-ene product 2f and 2H-chromene 8 derivative 3f (entry 5 and 6).
A proposed mechanism for the formation of 2H-chromene is shown in Scheme 2. 8,9 The overall sequence of events is initiated by the association of the formyl group with an electrophilic aryne moiety to form zwitterionic intermediate I-1, which can be further stabilized another resonance form I-2. Ring closure of intermediate 1-1 to form oxacyclobutene I-3 followed by its cycloreversion will generate I-4.Finally, the Z-isomer of I-4 undergoes 6π−electrocyclization to generate 2H-chromene 3 while the Eisomer reverts back to I-4.The DFT calculated energy profiles corroborate the facile nature of this reaction pathway (see Supporting Information).Having seen the change of product distribution caused by the slight structural change in the reacting aldehydes, we further explored the generality of the reaction by employing structurally diversified α,β-unsaturated aldehydes (Table 2).While mono-and disubstituted acrolein such as crotonaldehyde and tiglic aldehyde efficiently generated 2H-chromenes 3g and 3h (entries 1 and 2), β,β-dimethyl acrolein afforded the highest yield of product 3i (entry 3).Also, the reaction involving hexa-2,4-dienal afforded 3j in excellent yield probably due to the development a bisallylic carbocationic character when the initial adduct formed in the reaction pathway (entry 4).The reactions involving cycloalkenyl carboxaldehydes are similar to that of α,β-dimethyl acrolein, generating 3k and 3l in 56% and 62% yield, respectively (entries 5 and 6).Because cycloalkylidenyl carboxaldehydes have the same substituent pattern as that of β,β-dimethyl acrolein spirocyclic products 3m-3o were generated in good yields (entries 7-9).11 Scheme 2. Proposed mechanism for the reaction of an aryne with an α,β-unsaturated aldehyde to form 2H-chromene From these reactions, a general trend has emerged: α,βunsaturated aldehydes undergo an addition reaction most favorably to generate 2H-chromene derivatives (3g-3o) and the efficiency of the reaction decreases with the α-alkyl substituent whereas it increases with the β-alkyl substituent.This trend can be correlated with the stabilizing effect of the developing β-carbocationic character by the β-alkyl substituent 12 in intermediate I-2 in Scheme 2. On the other hand, the α-alkyl substituent may increase the steric hindrance of the aldehyde when it interacts with an aryne counterpart during the conversion of I-2 to I-3.
With the reactivity trend of simple α,β-unsaturated aldehydes in hand, we next examined the reactions of structurally more elaborated α,β-unsaturated aldehydes (Table 3).Perillylaldehyde containing a 4-isopropenyl group on cyclohexenyl carboxaldehyde provided both the Alder-ene product 2p and the aldehyde addition product 3p in 24% and 34% yield, respectively (entry 1).On the other hand, β-methyl cyclopentenyl carboxaldehyde with a β,βdialkyl substituent pattern afforded exclusively the addition product 3q in 55% yield (entry 2) where the isopropenyl group remained unreacted.The different product distribution from these two aldehydes clearly reflects the aforementioned general trend of aldehyde reactivity.The substituent pattern of geranial also correlates with the general reactivity trend, exclusively providing 3r in 62% yield without an Alder-ene product (entry 3).Similarly, the citronellal-derived dialdehyde afforded product 3s (46%) wherein the α,β-unsaturated aldehyde moiety solely participated in the reaction and the saturated aldehyde portion remained intact (entry 4).Finally, dialdehyde containing an α-and a β-methyl substituent afforded chromene 3t (72%) through the participation of only the βmethyl substituted α,β-unsaturated aldehyde moiety (entry 5).
To diversify the pool of carbonyl groups that can react with arynes, other electron-rich carbonyl compounds were also examined (Table 4).As expected the reactions of aldehyde with no possibility of Alder-ene reaction such as acrolein and 4dimethylaminocinnamaldehyde afforded 2H-chromene derivatives 3u and 3v in good yields (entries 1 and 2).The reaction with βdiethylaminocinnamaldehyde afforded 3x, which is the This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3 Please do not adjust margins Please do not adjust margins consequence of hydrolysis of the initially formed amino-substituted product during purification on silica gel (entry 3).A β-alkoxysubstituted enal afforded 5,6-spiroketal derivative 3y in excellent yield (entry 4). 13Dimethylacrylamide and the corresponding thioamide 14 also participated in the reaction to generate chroman-4-one 3za and thiochroman-4-one 15 3zb in 56% and 51% yield, respectively (entries 5 and 6).An aryne species generated from ester-tethered triyne also reacts with β,β-dimethyl acrolein to afford 3aa in excellent yield (entry 7).Interestingly, the benzyne generated from 1-trimethylsilyl-2-phenyl triflates with fluoride 16 or from aprotic diazotization of anthranilic followed by thermal decomposition of the diazonium carboxylate in the presence of Table 3.The selectivity between Alder-ene and addition reactions of structurally elaborated aldehydes a Tetrayne 1 (20-50 mg), alkene (5 equiv), toluene 90 °C.b Isolated yield.
c Ene reaction product (2p) with the isoprenyl group was also obtained in 24% yield.d For easier purification, the crude product was treated with NaBH 4 and the corresponding alcohol was isolated and oxidized to 3s with yield referring to final isolated yield.perillylaldehyde afford only the Alder-ene product 2pa in 75% and 42% yield without forming 2H-chromene derivative (entry 8).This is in sharp contrast to the reactivity of the aryne species generated from tetrayne 1 via the hexadehydro Diels-Alder reaction, which preferentially engaged in the reaction with the same aldehyde to generate 2H-chromene derivatives 3p as the major product and Alder-ene product 2p as the minor product (entry 1 in Table 3).
To gain further insight into the reactivity and selectivity of different manifolds of reactions with arynes, we carried out DFT calculations (Scheme 3). 9 As a representative reaction, we used the reaction between the aryne generated from symmetric tetrayne 1 and α,β-unsaturated tiglic aldehyde (Scheme 3).In the calculations, the transition state energies of competing Alder-ene and aldehyde addition reaction were compared.The Alder-ene reaction proceeds through a single transition state TS1 (11.7   (1.2 kcal/mol).These calculated results clearly show that the interaction of the lone pair electrons of the aldehyde with the aryne is kinetically much more favorable to generate the relatively unstable zwitterionic intermediate compared to the abstraction of the allylic hydrogen to form the final Alder-ene product.For the reaction of β,γ-unsaturated aldehyde, the energy of transition state TS2′ is higher than TS2 by 5.6 kcal/mol, which corroborates the lack of the reactivity of saturated aldehydes towards the addition reaction to form oxacyclobutenes.

Scheme 3. DFT calculations for the reaction between an aryne and tiglic aldehyde and its deconjugated form
In summary, we have explored the reactions of arynes with functionalized alkenes focusing on the selectivity between Alderene and addition reaction manifolds.The reactions of 1,1disubstituted alkenes containing a polar functional group such as methallyl amine, prenyl azide, and methacrylic acid, provide addition products of the polar heteroatom functionalities predominantly over the Alder-ene reaction of the alkene moiety.The selectivity trend, however, intricately depends on the substituent patterns of the alkene moiety.The addition reaction of α,β-unsaturated aldehyde is generally much more favorable and efficient than Alder-ene reaction.Except for 2-propenyl groupcontaining aldehyde such as methacrolein, all α,β−unsaturated aldehydes examined in this study preferentially participated in the addition reaction of the formyl group to generate 2H-chromene derivatives in high yields.DFT calculations show that the preferred mode of addition of α,β-unsaturated aldehyde is a kinetically favorable process compared to the corresponding Alder-ene reaction.Other electron-rich carbonyl compounds such as dimethyl acrylamide and acrylthioamide also participated in the addition reaction to generate chroman-4-one and thiochroman-4-one.It was observed that the structure of arynes and the method of their generation as well, have a significant impact on the reactivity and selectivity between different manifolds of reactions.This implies

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kcal/mol) to generate final ene reaction product (-67.0kcal/mol).On the other hand, the aldehyde addition occurs via a multiple-step process, where the This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | Please do not adjust margins Please do not adjust margins