DFT Mechanistic Study on Tandem Sequential [4 + 2]/[3 + 2] Addition Reaction of Cyclooctatetraene with Functionalized Acetylenes and Nitrile Imines

Received: 11 February 2019 Revised: 16 May 2019 Accepted: 22 May 2019 DOI: 10.1002/poc.3992

RESEARCH ARTICLE

DFT mechanistic study on tandem sequential [4 + 2]/[3 + 2] addition reaction of cyclooctatetraene with functionalized acetylenes and nitrile imines

Ernest Opoku | Richard Tia | Evans Adei

Theoretical and Computational Chemistry Abstract Laboratory, Department of Chemistry, Kwame Nkrumah University of Science The mechanistic pathways for the tandem sequential [4 + 2] / [3 + 2] and and Technology, Kumasi, Ghana [3 + 2]/[4 + 2] cycloaddition reaction of functionalized‐acetylenes with

Correspondence cyclooctatetraene (COTE) and nitrile imines for the formation of the Richard Tia, Theoretical and biologically‐active tricyclic cyclobutane‐condensed pyrazoline systems, and Computational Chemistry Laboratory, the subsequent cycloreversion/thermolysis of these adducts, have been studied Department of Chemistry, Kwame ‐ ‐ ‐ Nkrumah University of Science and using density functional theory (DFT) at the M06 2X/6 31G(d) and 6 311G(d,p) Technology, Kumasi, Ghana. levels with the aim of providing mechanistic rationale for the regioselectivities Email: [email protected]; and stereoselectivities. Along the [4 + 2] / [3 + 2] addition sequence, it has [email protected] been found that the initial 6π‐electrocyclic ring‐closure of the COTE is the Funding information rate‐determining step irrespective of the type of substituent on the parent acet- National Council for Tertiary Education, ylene or the nitrile imine. The mechanistic channels along the [4 + 2] / [3 + 2] Republic of Ghana, Grant/Award Num- ber: TALIF/KNUST/3/0008/2005 addition sequence show that the addition of the dipole across the unsubstituted olefinic bond in the cyclohexadiene moiety in the endo fashion is the most favored, which is in agreement with experimentally observed selectivity. The results show that the thermolysis proceeds with relatively high activation barriers toward formation of the monocyclic pyrazolines among other products. The decomposition of the tandem adducts has been found to be controlled solely by kinetic factors. An exploration of a [3 + 2] / [4 + 2] addition sequence as a mechanistic possibility reveals that in contrast to the [4 + 2] / [3 + 2] addition sequence, the Diels‐Alder addition step is the rate‐determining. The [3 + 2] / [4 + 2] addition order is found as an approach with better selectivity as it leads to formation of only tandem adducts where the nitrile imines are attached to the substituted olefinic bond in the cyclohexadiene subunit. The results show that the monocyclic pyrazolines obtained from the thermolysis of the [4 + 2] / [3 + 2] tandem adducts could easily be obtained from a direct 1,3‐dipolar addition of the alkynes with the dipoles which has been found to proceed rapidly with low activation barriers. The results are rationalized with perturbation molecular orbital theory.

KEYWORDS cyclooctatetraene, mechanistic study, nitrile imine, pyrazole, pyrazoline, tandem addition

1 | INTRODUCTION

Cycloaddition reactions have become a powerful synthetic tool employed in the rapid construction of complex molecules from simpler ones. This widespread recogni- tion of cycloaddition reactions as a synthetic approach is due to its predictability in the formation of various bonds, rings, and stereocenters in a single conversion, which is – crucial for high synthetic efficiency. [1 5] Modern synthetic designs require the ability to carry out multiple chemical transformations in a single step in order to achieve a higher synthetic efficiency. Tandem reactions as a synthetic approach which allows for construction of several chemical transformations in a single step without the need to isolate intermediates have thus become an important method in the synthetic tool kit. [6,7] SCHEME 1 Tandem sequential [4 + 2]/[3 + 2] cycloaddition of cyclooctatetraene with dimethyl acetylenedicarboxylate and a Denmark and Thorarenson[8] have categorized tandem nitrile imines by Bianchi and coworkers[18] cycloaddition reactions into three, comprising tandem cas- cade, consecutive, and sequential cycloadditions reactions, dipoles with the tricyclic diester for the synthesis of respectively. In tandem sequential cycloadditions, two isoxazolidines and its derivatives. reactive components are employed to initiate the reaction Tandem sequential [4 + 2]/[3 + 2] of any leading to formation of an intermediate. The intermediate sequence/order has been extensively utilized by Denmark is expected to have the required chemical functionalities and his team in the construction of complex heterocycles which is poised to undergo a further transformation with such as daphnilactone rings and azapropellanes among a third reactive component to yield the final product. It others, an indication of the power of this synthetic should be noted that no change in reaction conditions is approach.[8,9,16,19] Pyrazoline and isoxazolidine derivatives required and isolation of the intermediate is not a are among some of the natural products that can also be necessity.[7,9] synthesized by employing the tandem sequential [4 + 2]/ The usefulness of tandem sequential addition reactions [3 + 2] of any sequence/order by making use of the appro- is epitomized by its extensive applications in the syntheses priate reactive components. Due to their useful potentials, of diverse natural products. The work of Danishefsky and many studies in recent times have been devoted toward the his team has made use of tandem sequential cycloaddition syntheses of pyrazolines and its derivatives. For instance, for the syntheses of vernolepin and vernomenin[10] in ear- one‐pot synthesis of pyrazoline derivatives obtained from lier studies. In recent years, Sears and co‐workers[1,11] have alkyl dihalides and primary amines as well as hydrazines employed this synthetic strategy toward construction of has been reported by Ju and co‐workers.[20] In similar vindolein. Several studies in the literature have made use works, Cui and his team have reported a domino reaction of tandem sequential cycloaddition stratagem for diverse of 2‐acylaziridines with the Huisgen zwitterions which fur- – synthetic applications.[12 16] nishes 2‐pyrazolines.[21] Bianchi and his coworkers have reported an intriguing Despite all the progress, the only method available for tandem sequential [4 + 2]/[3 + 2] cycloaddition involving the synthesis of cyclobutane‐condensed pyrazoline the use of cyclooctatetraene (COTE).[17,18] Reaction of systems is the Bianchi's tandem sequential [4 + 2]/[3 + 2] COTE with dimethyl acetylenedicarboxylate affords an cycloaddition of COTE with dimethyl unusual tricyclic product that arises from an initial acetylenedicarboxylate and a nitrile imine. However, there [4 + 2] cycloaddition (Scheme 1). Subsequent reaction is no mechanistic study on the tandem sequential [4 + 2]/ of the Diels‐Alder adduct intermediate with a nitrile [3 + 2] addition reaction of COTE with dimethyl imine[18] affords a mixture of tandem cycloadducts acetylenedicarboxylate and a nitrile imine to establish the (pyrazolines) a, b, and c in the ratio 1:1:2.8 as shown in reactivity and the origin of the regioselectivities and Scheme 1. The thermolysis of the tandem adducts toward stereoselectivities of the reaction. In addition, no study the formation of monocyclic pyrazolines and their has reported the effects of substituents on the mechanistic corresponding synthetic intermediates were also pathways of the tandem Diels‐Alder/1, 3‐dipolar cycload- described. Their study offers the synthetic prospects of dition of COTE with functionalized‐acetylenes and nitrile cyclobutane‐condensed heterocyclic systems. In an analo- imines. Also, no experimental nor theoretical study has gous study by Bianchi et al,[17] nitrones were used as been carried out on the synthetic possibility of changing OPOKU ET AL. 3of14 the addition sequence to a [3 + 2]/[4 + 2] cycloaddition of software packages at the M06‐2X level of theory with the the dimethyl acetylenedicarboxylate with nitrile imines 6‐31G(d) and 6‐311G(d,p) basis sets. The M06‐2X func- and COTE to ascertain how it affects product outcomes tional developed by Zhao and Truhlar[24] is a hybrid and selectivities. This mechanistic understanding is very meta‐generalized gradient approximation (meta‐GGA) crucial toward the syntheses of cyclobutane‐condensed established to be effective at computing thermochemical tricyclic pyrazolines of high selectivity and efficiency for and kinetic parameters, especially where nonlocal disper- – improved activity. sion interactions play a role.[25 27] In reactions involving Herein, density functional theory (DFT) calculations predominantly C―C bond, forming and breaking occurs; are employed to elucidate the mechanism of the tandem M06‐2X generally avoids systematic errors associated with sequential [4 + 2]/[3 + 2] cycloaddition reaction of energetic barrier heights with, for instance, B3LYP.[28] COTE with functionalized‐acetylenes and nitrile imines Houk and coworkers have compared energetics at the 6‐ toward the formation of tricyclic pyrazolines (Scheme 31G(d) basis set with single point calculations at 6‐ 2). Our aim is to shed light on the molecular level 311G(d,p) basis set and established that the size of the basis mechanistic details of the reaction. The different reactiv- set does not affect the conclusions[29]. The polarizable con- ity of the cyclobutene and cyclohexadiene double bonds tinuum model (PCM) was employed to model the effects of in the Diels‐Alder adduct intermediate of this reaction solvents in the reactions.[30] toward 1,3‐dipoles will be evaluated. This study also The initial geometries of the structures were built explores the subsequent cycloreversions/fragmentations using Spartan's graphical model builder and minimized of the tricyclic pyrazolines toward formation of various interactively using the sybyl force field.[31] Transition products as shown in Scheme 3. The effects of state structures were computed by first obtaining guess changing the addition sequence to a [3 + 2]/[4 + 2] input structures. This was done by constraining specific cycloaddition on selectivity and product outcomes will internal coordinates of the molecules (bond lengths, bond also be explored as shown in Scheme 4. Furthermore, angles, dihedral angles) while fully optimizing the this study will investigate the effects of substituents on remaining internal coordinates. This procedure offers reactivity, regioselectivities, and stereoselectivities of appropriate guess transition state input geometries which the reaction as clearly illustrated in Schemes 2, 3, and 4. are then submitted for full transition state calculations without any geometry or symmetry constraints. Full har- 2 | COMPUTATIONAL DETAILS monic vibrational frequencycalculations were carried out AND METHODOLOGY to verify that each transition state structure had a Hessian matrix with only a single negative eigen value, character- All the DFT computations were performed using the Spar- ized by an imaginary vibrational frequency along the tan′14[22] and Gaussian 09[23] Molecular Modeling respective reaction coordinates. Intrinsic reaction

SCHEME 2 Proposed reaction pathways for study of [4 + 2] / [3 + 2] addition reaction of cyclooctatetraene with functionalized‐acetylenes and nitrile imines 4of14 OPOKU ET AL.

SCHEME 3 Proposed scheme of study for the thermal decomposition/retro‐Diels‐Alder addition of the [4 + 2] / [3 + 2] tandem tricyclic pyrazolines

SCHEME 4 Proposed reaction pathways for study of [3 + 2] / [4 + 2] addition reaction of functionalized‐acetylenes with nitrile imines and cyclooctatetraene coordinate calculations were then performed to ensure synthetic analogues are also discussed in Section 3.7. that each transition state smoothly connects the reactants Finally, the possibility of reversing the order of addition – and products along the reaction coordinate.[32 34] for a [3 + 2]/4 + 2] addition sequence is discussed in Sec- tion 3.8.

3 | RESULTS AND DISCUSSION 3.1 | [4 + 2] / [3 + 2] tandem sequential The results of the [4 + 2] / [3 + 2] tandem sequential addi- addition reaction of the parent tion reaction of the parent (unsubstituted) acetylene with (unsubstituted) acetylene with COTE and dimethyl nitrile imine are discussed in Section cyclooctatetraene and dimethyl nitrile 3.1. Sections 3.2 and 3.3 looks at the results of the [4 + 2] imine / [3 + 2] tandem sequential addition reaction of substituted‐acetylenes with COTE and diphenyl nitrile Scheme 2 outlines the proposed pathways for the reaction imine. The effects of substituents on COTE reactivity are of functionalized‐acetylenes with COTE and selected also outlined in Section 3.4. Sections 3.5 and 3.6 account nitrile imines. We reason that the reaction will most for the investigation of the regioselectivities and likely proceed by an initial 6π electrocyclic ring closure stereoselectivities of the reaction, respectively. Results on of the COTE X through TS1 to generate a bicyclic inter- thermal decomposition of the tandem adducts to other mediate, bicyclo [4, 2, 0] octa‐2, 4, 7‐triene (Int1)[35] OPOKU ET AL. 5of14

FIGURE 1 Zero point energy corrected Gibbs free energy profile of the [4 + 2]/ [3 + 2] addition of unsubstituted acetylene with COTE and dimethyl nitrile imine at the M06‐2X with the 6‐31G(d) basis set. − Relative energies in kcalmol 1. All bond distances are measured in Å containing the 1,3‐butadiene moiety. The in situ gener- activation barrier of 28.5 kcal/mol leading to the formation ated bicyclic intermediate Int1 undergoes a [4 + 2] of a less stable bicyclic intermediate Int1 with a reaction Diels‐Alder cycloaddition with the functionalized‐ energy of +6.5 kcal/mol. The bicyclic intermediate Int1 acetylenes (Y) through transition state TS2 to yield a tri- undergoes a [4 + 2] Diels‐Alder cycloaddition reaction cyclic dipolarophile intermediate Int2. The highly through transition state TS2‐H with an activation barrier strained tricyclic Int2 dipolarophile undergoes a further of 10.5 kcal/mol, leading to a tricyclic dipolarophile inter- 1,3‐dipolar cycloaddition with the selected nitrile imines mediate Int2‐H with a reaction energy of −56.00 kcal/mol. (Z). The [3 + 2] cycloaddition step may occur across Although Int2‐H is very stable, subsequent 1,3‐dipolar either the cyclobutene or cyclohexadiene double bonds addition with Z2 occurs rapidly with relatively low activa- of the Diels‐Alder adduct in various isomeric fashions to tion barriers, along the six proposed regio‐isomeric and yield their corresponding cyclobutane‐condensed tricyclic stereo‐isomeric transition states. The regioselective addi- pyrazoline derivatives (Pdt isomers) through their respec- tion across the cyclobutene double bond in the Int2‐H tive TS3 isomers. The latter part of this study investigates may occur via TS3AEndo‐H and TS3AExo‐H stereoiso- the thermolysis/fragmentation and retro‐Diels‐Alder mers found to have activation barriers of 13.2 and reaction of the tricyclic pyrazoline systems (Pdt isomers) through transition states (TS4 isomers) to their corresponding monocyclic pyrazolines and other synthetic analogues as labeled PdtF isomers in Scheme 2. Figure 1 shows the zero‐point‐corrected Gibbs free energy profile as well as the geometries of the stationary points (minima and maxima) relevant to the proposed scheme of study of the [4 + 2] / [3 + 2] addition of the parent (unsubstituted) acetylene with COTE and dimethyl imine (Z2). For purposes of computational expense, we chose dimethyl nitrile imines (Z2) as a surrogate for diphenyl nitrile imine (Z1) in some instances as illustrated in Figure 2. As shown in Figure 2, the molecular orbital coefficients of the reactive carbon and nitrogen of the dipole are similar in both instances, but the charge separa- tion is slightly lower in Z1 compared with Z2. From FIGURE 2 Optimized geometries of the selected 1,3‐dipoles Figure 1, it can be seen that the initial 6π‐electrocyclic ring employed in this study at the M06‐2X with the 6‐31G(d) basis set. closure proceeds through transition state TS1‐ with an Atomic color code (blue = nitrogen, gray = carbon) 6of14 OPOKU ET AL.

9.7 kcal/mol, respectively. The regioselective addition across the substituted double bond (where R1 = H, in the 31G(d) ‐ 97.4 129.3 119.7 118.3 131.8 137.5 136.9 142.1 130.1 case of acetylene) of the cyclohexadiene moiety occurs − − − − − − − − − via two proposed distereoselective transition states TS3BEndo‐H and TS3BExo‐H with activation barriers of 8.8 and 11.5 kcal/mol, respectively. Again, the regiose- 2X with the 6 ‐ 100.9 131.9 122.7 122.0 136.4 141.7 151.5 133.2 − − − − − − − lective addition across the unsubstituted olefinic bond of − the cyclohexadiene unit of the dipolarophile may occur through the proposed distereoselective transition states 76.6 132.0 122.5 116.4 131.6 138.4 138.9 149.7 148.1 124.8 TS3CEndo‐H and TS3CExo‐H with activation barriers − − − − − − − − − of 8.1 and 14.3 kcal/mol, respectively. Thus, the )/kcal/mol rxn TS3CEndo‐H pathway is the most favored followed by ‐ ‐

TS3BEndo H and TS3AExo H, respectively, which 72.8 131.4 122.3 114.1 130.4 137.1 128.8 149.4 124.5 − − − − − − − − agrees with the product outcomes in the experimental − study of Bianchi and coworkers.[18] The corresponding tricyclic pyrazoline products (Pdt isomers) have compara- 132.1 122.9 121.0 133.5 140.1 102.2 139.8 143.3 132.6 − − − − − − − − ble reaction energies as can be seen in Figure 1 and Table 1 − . The effects of temperature and solvent on the reaction 99.2 129.3 119.9 118.4 131.2 138.3 138.2 141.0 of the parent acetylene with COTE and Z2 were investi- 131.2 − − − − − − − − gated by increasing the reaction temperature to 413.15 K − in toluene. Although there are slight variations in the 56.0 47.0 44.7 55.8 73.2 25.5 71.2 62.3 63.6 − − − − − − − − energetic barriers, the trends remain unchanged (see − Table 1). Based on this observation, it can be said that temperature and solvent do not play a significant role in deter-

mining product outcomes in this reaction. Therefore, the acetylenes with cyclooctatetraene and dimethyl nitrile imine at the M06 ‐ gas phase calculations at the standard 298.15 K are deemed adequate for the reactions studied.

3.2 | [4 + 2] / [3 + 2] tandem sequential

addition reaction of dimethyl +7.7 +14.0 +5.4 acetylenedicarboxylate with COTE and diphenyl nitrile imine ‐

Based on the results obtained from the reaction of the parent (unsubstituted) acetylene with COTE and dimethyl nitrile imine, we extended the studies to substituted acetylenes. This section of the study explores the Diels‐

‐ 1

Alder/1,3 dipolar cycloaddition reaction of dimethyl − acetylenedicarboxylate with COTE and diphenyl nitriles, the same reaction components used by Bianchi and coworkers [18] in their experimental study. The geometries of all the reactants, intermediates, products, and transition states as well as their relative energies are reported on Figures 3 and S1. The bicyclic intermediate Int1 obtained from the initial 6π‐electrocyclic ring closure undergoes a rapid [4 + 2] Diels‐Alder cycloaddition reaction with the Y‐Ester through an asynchronous concerted transition state Energetics of the tandem [4 + 2] / [3 + 2] cycloaddition reaction of functionalized TS2‐Ester with a very small activation barrier of TS1 TS2 TS3AEndo+27.3 TS3AExo +12.3 TS3BEndo+28.5 +13.1 TS3BExo +14.8 TS3CEndo +13.5 TS3CExo Int1+28.5 +8.9 Int2 +11.7 +13.7 PdtAEndo +5.0 PdtAExo +8.2 PdtBEndo PdtBExo +11.3+28.5 PdtCEndo +8.0 PdtCExo +3.7+28.5 +19.3 +13.9 +17.0 +10.1 +10.5 +2.4 +10.8 +12.0 +5.6 +1.9 +1.8 +8.2 +16.0 +6.5 +8.0 +6.5 +20.2 +5.7 +6.5 +4.5 +15.0 +8.9 +6.5 +6.5 3 ) 3 H +28.5 +1.4 +19.4 +14.8 +3.0 +8.8 +2.4 +18.1 +6.5

‐ 2 3 2

1.1 kcal/mol. TS2 Ester leads to the formation of COTE 3 * 1 [4 + 2]/[3 + 2] TandemSubstituent Addition H +28.5 +17.0 +13.7 Activation Energy(G*)/kcal/mol +9.7 +8.8 +11.5 +8.1 +14.3 +6.5 Reaction Energy(G H CH OH +28.5 +11.0CO +10.7 +5.2(CH +0.8 +2.0 +0.7 +8.3 +6.5 CN +28.5 +1.5 +12.1 +4.2 +2.8 +3.6 +3.5 +7.2 +6.5 R NH dimethyl acetylenedicarboxylate adduct Int2‐Ester with CF basis set. All energies are measured in kcalmol TABLE 1 *Energetics at 413.15 K in toluene. All other calculations were carried out at 298.15 K in gas phase. OPOKU ET AL. 7of14

FIGURE 3 Zero point energy corrected Gibbs free energy profile of the [4 + 2]/ [3 + 2] addition of dimethyl acetylenedicarboxylate with COTE and diphenyl nitrile imine at the M06‐2X with the 6‐31G(d) basis set. Relative energies in − kcalmol 1. All bond distances are measured in Å a reaction energy of −66.4 kcal/mol. Subsequent 1,3‐ reaction (TS3) clearly agree with product outcomes dipolar addition reaction of the diphenyl nitrile imine observed by Bianchi et al.[18] Z1 to Int2‐Ester may occur via six proposed regio‐ In order to check the suitability of the 6‐31G(d) basis isomeric and stereo‐isomeric transitions states (scheme 2). set for this study, we employed triple zeta basis sets 6‐ Addition across the cyclobutene‐subunit olefenic bond 311G(d,p) and 6‐311++G(d,p) for the same reaction of has barriers of 8.6 and 6.6 kcal/mol for TS3AEndo‐Ester dimethyl acetylenedicarboxylate with COTE and Z1, and TS3AExo‐Ester, respectively. and the results are reported in Table 2. Although slight The regioselective addition of Z1 across the Y‐ester‐ variations in the energetics are observed, the energetic substituted double bond of the cyclohexadiene‐subunit trends remain similar to that obtained with the 6‐ occurs via transition states TS3BEndo‐Ester and 31G(d) basis set. Therefore, we conclude that the 6‐ TS3BExo‐Ester activation barriers of 0.4 and 2.4 kcal/ 31G(d) basis set employed for the study is sufficient to mol, respectively. Also, addition across the unsubstituted address the issues of interest as earlier observed else- double bond of the cyclohexadiene‐subunit occurs via where.[26] Hence, for the rest of our study in this work transition states TS3CEndo‐Ester and TS3CExo‐Ester the 6‐31G(d) basis set is employed. with activation barriers of 2.0 and 8.5 kcal/mol, respectively. Based on the forgoing energetic trends, it can be said that among all the six proposed transition states 3.3 | [4 + 2] / [3 + 2] tandem sequential at the selectivity step (TS3AEndo‐Ester, TS3AExo‐Ester, addition reaction of substituted acetylenes TS3BEndo‐Ester, TS3BExo‐Ester, TS3CEndo‐Ester with COTE and dimethyl nitrile imines and TS3CExo‐Ester), TS3CEndo‐Ester is the most favored, followed by TS3Bndo‐Ester and TS3AExo‐ To investigate the effects of substituents on the reaction Ester, respectively. It should also be noted that all the six pathways and product outcomes, varying substituents

TS3‐isomeric transition states occurs in a highly asynchro- are introduced at position R1 on the parent acetylene nous concerted fashion as it can be seen from Figure S1. (see Scheme 1). The results obtained under this section From Table 2, it can be seen that the cyclobutane‐ of our study are reported in Table 1. It should be noted condensed tricyclic pyrazoline products obtained are that for simplicity of computations, dimethyl nitrile imine very stable enough to be isolable, as their stability (Z2) is employed as the 1,3‐dipole throughout this section relative to the starting reactants range from −128.8 to of the study. −151.5 kcal/mol. Considering the stability of the In order to establish the effects of electron‐donating products which make the reactions most likely nonrevers- groups (EDG) on this reaction pathways, we employed ible, it is most likely that thermodynamic factors are not CH3, OH, and NH2‐substituted acetylenes. In all the three the determining factors for product outcomes. Hence, the cases, a general decrease in the TS2 (Diels‐Alder addition outcome of this reaction is solely driven by kinetic factors. step) activation barriers compared with the parent reac-

Indeed, the energetic trends in the selectivity step of this tion is observed. In the case of CH3‐substituted acetylene, 8of14 OPOKU ET AL. ‐ Y (CH3)2, it is discovered that at the selectivity step (TS3), TS3CEndo‐Methyl is the most favored, followed by 120.7 131.9 137.9 TS3AExo‐Methyl and TS3CExo‐Methyl. Also, for Y − − − (OH)2, it is realized that TS3CEndo‐Hydroxy is the most 2X with the 6 ‐ favored, followed by TS3BEndo‐Hydroxy and TS3CExo‐ ‐ Hydroxy, respectively, which also shows a unique selec- 124.6 140.8 − − tivity. Again, for Y (NH2)2, it is established that TS3CEndo‐Amino is the most favored followed by ne at the M06 TS3CExo‐Amino and TS3AExo‐Amino, respectively, 116.0 129.1 133.9 − − − implying a unique selectivity. This study was then extended to electron‐withdraw-

ing‐substituted acetylenes. Here, for Y (CO2H)2, it is seen ‐ 113.5 127.2 132.3 that at the selectivity step, TS3CEndo Acid is the most − − − )/kcal/mol favored followed by TS3BEndo‐Acid and TS3BExoo‐ rxn Acid, respectively. This energetic trend is in agreement 125.7 136.3 141.9 with that observed for Y (OH)2. Furthermore, for Y − − − (CN)2, it is found that TS3BEndo‐Cyano is the most favored followed by TS3CEndo‐Cyano and TS3AExo‐

Cyano, respectively. Also, for Y (CF3)2, it is observed that 124.3 135.3 140.9 TS3BEndo‐Fluoromethyl is the most preferred pathway − Reaction Energy(G − − followed by TS3CEndo‐Fluoromethyl and TS3BExo‐ 55.1 56.9 66.4 Fluoromethyl, respectively. − − − When a bulky substituent Y[(CH3)3]2 is introduced, it is observed that there is a marginal increase in the TS2‐ Isobutane activation energy compared with the parent reaction, and this could be attributed to steric hindrance. At the selectivity step (TS3), it is realized that TS3CEndo‐ Isobutane is the most preferred pathway followed by TS3AExo‐Isobutane and TS3CExo‐Isobutane, respectively. It should be noted that despite all the unique ener- 7.8 14.8 8.5 getic trends for all the substituents considered in this work, it is found that the TS3CEndo which transforms 1 − ‐ to PdtCEndo isomer is the most favored mechanistic pathway in most cases. Clearly, this observation proposes a general favorable selectivity toward the TS3CEndo isomer. This observation could be seen as an ample reason Bianchi and coworkers[18] obtained the PdtBEndo‐ Ester, which arises from TS3CEndo‐Ester as the highest tandem adduct yield.

3.4 | Effects of substituents on COTE reactivity

Based on the results obtained as discussed in the pre- ceding sections, it can be seen that the initial 6π‐

+28.6 0.4 14.3 12.1 7.8 electrocyclic ring closure is the rate‐determining step

311G(d,p) basis sets. All energies are measured in kcalmol (rds) irrespective of the reaction components. Spurred ‐ Energetics of the tandem [4 + 2] / [3 + 2] cycloaddition reaction of dimethyl acetylenedicarboxylate with cyclooctatetraene and diphenyl nitrile imi by this observation, we probed how introducing varying substituents on the COTE may affect the rds activation ‐ * 311++G(d,p) 311G(d,p) +28.5 +0.9 +11.3 +9.55 +2.9 +14.8 +2.6 +11.4 +8.2 31G(d) +28.5 +1.1 +8.6 +6.63 +0.4barrier. +2.4 +2.0 We employed +8.5 +6.5 various electron donating groups ‐ ‐ ‐ 6 [4 + 2]/[3 + 2] TandemActivation Addition Energy(G*)/kcal/mol 6 Basis set6 TS1 TS2 TS3AEndo TS3AExo TS3BEndo TS3BExo TS3CEndo TS3CExo Int1 Int2 PdtAEndo PdtAExo PdtBEndo PdtBExo PdtCEndo PdtCExo 31G(d) and 6 TABLE 2 *Energetics at 298.15 K in toluene. All other calculations were carried out at 298.15 K in gas phase. (EDG), electron‐withdrawing groups (EWG) as well as OPOKU ET AL. 9of14 sterically bulky groups on the COTE, and the results for all the considered substrates are reported in Table 3.

It was discovered that introducing (OCH3)2 and [N (CH3)2]2 on the COTE reduces the activation barrier albeit marginally, leading to a less stable Int1 compared with the parent reaction (see Table 3.) For EWGs includ- ing CONH2,SO2H, and CN‐substituted COTE, we see relatively lower activation barriers for the CONH2 and SO2H compared with the parent acetylene. However, CN‐ substituted COTE gives almost the same activation barrier as the parent acetylene. CONH2 and CN‐substituted acetylenes lead to a relatively less stable Int1 compared with the parent. For SO2H, we find that it leads to formation of a marginally stable Int1 compared with the parent reaction. The optimized transition state structures of all the substituted COTE considered in this section are shown in Figure 4 for clarity sake. FIGURE 5 Frontier molecular orbital interactions in the 1,3‐ cycloaddition reaction of Int2‐Ester and Z1 at the M06‐2X with the 6‐31G(d) basis set 3.5 | Investigation of the origin of regioselectivity between the HOMO of the dipole and the LUMO of the In this section, the frontier molecular orbital (FMO) theory dipolarophile because that gives the closest energy, an is invoked to rationalize the regioselectivity and reactivity indication of a normal electronic demand cycloaddition of the 1,3‐dipolar cycloaddition of Int2‐Ester and Z1. For reaction. A graphical plot of the HOMO of Z1 and LUMO a better visualization of the FMO approach, we have of Int2‐Ester is shown in Figure 6. depicted the possible interactions in Figure 5. The energy Analyses of the molecular orbital coefficients in the − obtained for HOMOdipole − LUMOdipolarophile is 5.631 eV reaction centers show that, for the dipole N2 = 0.342 ‐ − and that of HOMOdipolarophile − LUMOdipole is 7.383 eV. and C7 = +0.339. For the Int2 Ester,C1 = 0.208, − − − The analyses show that the dominant interactions occur C2 = 0.220, C5 = 0.088, C6 = 0.047 while C9 = −0.200 and C10 = −0.200. According to Houk's [36] TABLE 3 Effects of substituents on energetics of the 6π‐ rule, electrocyclic ring closure step at the M06‐2X 6‐31G(d) basis set. All for a normal electronic demand cycloaddition reaction, − energies are measured in kcalmol 1 the addition will occur between atoms with the highest molecular orbital coefficients because that will lead to Substituent on COTE TS1 Int1 the greatest stabilization. Based on the magnitude of the H +28.5 +6.5 molecular orbital coefficients, addition of the dipole ‐ ‐ O (CH3)2 +26.9 +14.7 across C9 C10 in the dipolarophile (Int2 Ester) is the most favored. Thus, the results of the molecular orbital coeffi- N (CH3)2 +25.6 +15.5 cients analysis are consistent with the activation barriers CONH2 +22.6 +9.8 as well as the experimentally observed trends. The vari- SO H +24.2 +5.9 2 ous atomic labels of Z1 and Int2‐Ester are shown in CN +28.1 +12.2 Figure 7 for clarity purposes.

FIGURE 4 Optimized transition state geometries of substituted COTE at 6π‐electrocyclic ring closure step at the M06‐2X with the 6‐ 31G(d) basis set. All bond distances are measured in Å. Atomic color code (red = oxygen, blue = nitrogen, gray = carbon, yellow = sulfur) 10 of 14 OPOKU ET AL.

FIGURE 6 Graphical display of the HOMO (A) and LUMO (B) of Z1 and Int2‐Ester respectively at the M06‐2X with the 6‐31G(d) basis set

has an energy of 6.63 eV, TS3AExo‐Ester = 5.90 eV, TS3BEndo‐Ester = 5.86 eV, TS3BExo‐Ester = 6.00 eV, TS3CEndo‐Ester = 5.77 eV, and TS3CExo‐ Ester = 5.96 eV. Thus, the HOMO − LUMO energy gaps suggest that TS3CEndo‐Ester would have the most stabi- lizing interaction followed by TS3BEndo‐Ester. Hence, the observed end/exo selectivities. In light of the selectivities in the TS3‐isomers, the differ- ‐ FIGURE 7 Graphical display of atomic labels on Int2 Ester (A) ent reactivities of the double bonds and the different inter- and Z1 (B), respectively. Hydrogen atoms are ignored for the sake of actions between the Int2‐Ester and Z1 moieties could be clarity another important reason that results in the selectivities. In this case, noncovalent interactions may play a dominant – In this present work, analysis of the molecular orbital role as observed elsewhere [38 40] in similar scenarios. coefficients has been employed to rationalize the regioselectivities in the reaction. In addition, the Parr functions[37] are good indexes to explain the reactivity of 3.7 | Thermal the reaction centers. decomposition/retro‐Diels‐Alder addition of the [4 + 2] / [3 + 2] tandem adducts

3.6 | Investigation of the origin of This section of our study investigates the thermal decom- stereoselectivity position of the tricyclic pyrazolines obtained from the [4 + 2] / [3 + 2] tandem sequential cycloaddition (see As can be seen from Scheme 2, at the [3 + 2] cycload- Scheme 3) as reported in the experimental work of Bianchi dition step, each regioisomer has two possible transition et al.[18] In accordance to our proposed scheme of study, we states leading to six different tandem adducts. Based on investigate the thermal decomposition of PdtAEndo and the activation energies, it has been established that irre- PdtAExo to generate monocyclic pyrazoline (PdtFA1) spective of the substituent on the parent acetylene, and barralene (PdtFA2) as well as the thermal TS3CEndo is mostly the preferred route. decomposition/retro‐Diels‐Alder addition of PdtBEndo We employed perturbation molecular orbital (PMO) and PdtBExo toward the formation of monocyclic theory to rationalize this observation. Figure 8 shows the pyrazoline derivative (PdtB1) and bicyclo[2.2.0]octa‐ graphical illustration of the HOMOs of all the six possible 2,5,7‐triene (PdtFB2). We also extended our probe to the transition state structures for ester‐substituted acetylene thermal decomposition of PdtCEndo and PdtCExo to reaction. It can be seen that there is a migration of the elec- PdtFA1 and a disubstituted bicyclo[4.2.0]octa‐2,4,7‐triene tron density from the dipole to the dipolarophile. (PdtFC). TS3BEndo‐Ester shows the greatest electron density Figure 9 shows the optimized geometries as well as migrating from the dipole to the dipolarophile, an indica- relative energies of all the stationary points involved in tion of a favorable interaction. This observation could be the thermolysis/fragmentation of the [4 + 2]/[3 + 2] tan- due to secondary orbital interactions at the transition state dem adducts obtained from the cycloaddition of dimethyl and other reasons that will be apparent in a moment. acetylenedicarboxylate with COTE and diphenyl nitrile Consideration of the HOMO − LUMO gap for all the imine at 513.13 K in toluene as employed in the experi- six possible transition states shows that TS3AEndo‐Ester mental work. OPOKU ET AL. 11 of 14

FIGURE 8 Graphical depiction of the HOMOs of TS3AEndo‐Ester (A), TS3AExo‐Ester (B), TS3BEndo‐Ester (C) and TS3BExo‐Ester (D), TS3CEndo‐Ester (E), TS3CExo‐Ester (F) at the M06‐2X with the 6‐31G(d) basis set. Hydrogen atoms are ignored for clarity sake

From the profile, it can be seen that the decomposition (see Scheme 4) is reported. Follow‐up [4 + 2] addition of TS4AEndo‐Ester and TS4AExo‐Ester occurs through of Int1B to Int1 through TS3BEndo and TS3BExo to an activation barrier of +79.47 and + 82.82 kcal/mol, furnish PdtBEndo and PdtBExo is also explored. respectively. Also, TS4BEndo‐Ester and TS4BExo‐Ester We have arbitrarily selected the reaction of Z1 with are found to have activation barriers of +38.17 and Y‐Ester and Int1 via the [3 + 2] / [4 + 2] addition +35.17 kcal/mol, respectively. Also, TS4CEndo‐Ester sequence to ascertain the feasibility and suitability of and TS4CExo‐Ester are found to have activation energies this mechanistic route. Figure 10 shows the geometries of +40.23 and +39.49 kcal/mol, respectively. Table 4 dis- of all the stationary points on the potential energy sur- plays the energetics of the thermolytic cleavage involved face of the [3 + 2]/[4 + 2] addition of diphenyl nitrile in all the substrates considered in this section. imine with dimethyl acetylenedicarboxylate and COTE to yield tricyclic pyrazolines. When the results are compared with the [4 + 2] / [3 + 2] addition sequence 3.8 | Can a change in addition sequence (Figure 3), it is seen that the present [3 + 2] / [4 + 2] affect reactivity and selectivity? addition sequence has improved selectivity as it occurs through only the TS3BEndo‐Ester and TS3BExo‐Ester This section of the study explores the synthetic possibility to form PdtBEndo‐Ester and PdtBExo‐Ester, of [3 + 2] / [4 + 2] addition sequence and the plausible respectively. However, it should be noted that higher product outcomes. The initial dipolar cycloaddition activation barriers at the Diels‐Alder step along the between Y‐Ester and Z1 is explored on the potential present [3 + 2] / [4 + 2] addition sequence are observed energy surface. The formation of Int1B through TS1B (TS3BEndo‐Ester = 45.3 kcal/mol and TS3BExo‐ 12 of 14 OPOKU ET AL.

FIGURE 9 Zero point energy corrected Gibbs free energy profile of the thermolysis of the [4 + 2]/[3 + 2] tandem adducts obtained from the addition of dimethyl acetylenedicarboxylate with COTE and diphenyl nitrile imine at the M06‐2X with the 6‐31G(d) basis set at 513.13 K in toluene. Relative energies in − kcalmol 1. All bond distances are measured in Å. All energies are relative to the respective reactants

TABLE 4 Energetics on the thermolysis of the [4 + 2] / [3 + 2] tandem adducts at the M06‐2X with the 6‐31G(d) basis set. All energies are − measured in kcalmol 1. All energies are relative to the respective reactants

Thermolysis of [4 + 2]/[3 + 2] Tandem Adducts

Substituent Activation Energy(G*)/kcal/mol Reaction Energy(Grxn)/kcal/mol

R1 R2 TS4AEndo TS4AExo TS4BEndo TS4BExo TS4CEndo TS4CExo PdtF(A1 + A2) PdtF(B1 + B2) PdtF(A1 + C)

HCH3 +57.3 +69.7 +33.5 +34.9 +40.6 +44.0 −119.4 −114.8 −113.6

CH3 CH3 79.8 +74.8 +35.0 +33.0 +43.0 +80.0 −115.2 −109.9 −107.7

OH CH3 ‐ +69.2 +49.2 +44.2 +40.9 +39.7 −134.7 −127.6 −136.7

NH2 CH3 ‐ +84.0 +40.7 +39.8 +41.2 +40.5 −124.4 −120.3 −124.7

*NH2 CH3 +45.1 +83.7 +40.4 +39.2 +36.8 +44.6 −127.5 −120.3 −125.3

COOH CH3 +79.2 +80.5 +26.2 +32.1 +49.9 +40.2 −138.1 −133.8 −131.8

CO2Me Ph +79.3 +82.7 +37.9 +35.8 +40.5 +38.1 −123.6 −112.2 −116.9

*CO2Me Ph +79.5 +82.8 +38.2 +35.8 +40.2 +39.5 −124.8 −112.3 −116.5

CN CH3 +78.6 +79.7 +29.4 +28.5 +37.5 +39.5 −127.1 −119.7 −118.7

CF3 CH3 +79.7 +81.1 +37.4 +31.8 +38.8 +38.8 −133.8 −127.5 −127.7

(CH3)3 CH3 +81.2 +80.8 +31.5 +28.3 +51.5 +49.3 −98.1 −89.3 −83.1

*Energetics at 573.15 K in toluene. All other calculations were carried out at 298.15 K in gas phase.

Ester = 47.3 kcal/mol); it is still argued that it is the [3 + 2] / [4 + 2] addition order will be a better best pathway for obtaining PdtBEndo‐Ester and approach based on selectivity concerns. It is also noted PdtBExo‐Ester because of improved selectivity. The that, along this [3 + 2] / [4 + 2] addition sequence, observation so far suggests that for the formation of Int1B which is obtained via a low activation barriers PdtBEndo‐Ester and PdtBExo‐Ester isomers, the corresponds to one of the products (PdtFB1) which OPOKU ET AL. 13 of 14

FIGURE 10 Zero point energy corrected Gibbs free energy profile of the [3 + 2]/[4 + 2] addition of diphenyl nitrile imine with dimethyl acetylenedicarboxylate and COTE and at the M06‐2X with the 6‐31G(d) basis set. − Relative energies in kcalmol 1. All bond distances are measured in Å

Bianchi et al[18] sought to obtain via the thermolysis of investigated. Fragmentation of all the tandem adducts their [4 + 2] / [3 + 2] tandem adducts found to proceed of all the substrates considered in this work has been with higher activation barriers. Hence, this observation found to proceed with higher activation energies. The comes as a convenient approach toward obtaining initial 6π‐electrocyclic ring closure of the COTE has been PdtFB1 derivatives. found as the rate‐determining step irrespective of the substrate considered. Introduction of different substituents on the COTE shows variable effects on the energet- 4 | CONCLUSIONS ics at the 6π‐electrocyclic ring closure step. Finally, the mechanistic possibility of a [3 + 2] / A comprehensive theoretical study on the tandem [4 + 2] addition sequence involving the same reaction sequential [4 + 2] / [3 + 2] cycloaddition reaction of components is explored. The results suggest this route functionalized‐acetylenes with COTE and nitrile imines as a novel, convenient, and a direct approach, although for the formation of varied pyrazolines is reported. The with relatively high activation barriers, toward obtaining regioselectivities and stereoselectivities are studied by PdtBEndo and PdtBExo products. Also, the Int1B means of an exploration of the potential energy surface obtained via the [3 + 2] / [4 + 2] addition sequence cor- and FMO theory at the DFT/M06‐2X with the 6‐31G(d) responds to one the key five‐membered analogues and 6‐311G(d,p) basis sets. The [3 + 2] cycloaddition step obtained from the thermolysis of the [4 + 2] / [3 + 2] tan- along the tandem sequential [4 + 2] / [3 + 2] cycloaddi- dem adducts. Because formation of Int1B has been found tion pathways, six reactive pathways, has been character- to proceed with low activation barriers, it is concluded ized in accordance with the regio‐chemistry and stereo‐ that employing this addition sequence for the formation chemistry at this step. An FMO analysis shows a normal of Int1B is a better and convenient route. It is expected electronic demand character for the reaction. The transi- that this theoretical exploration will serve as a guide for tion states have been found to proceed through asyn- future experiments. chronous concerted addition pathways. This study has shown that incorporating solvent and temperature effects ACKNOWLEDGEMENTS does not affect the conclusions. Again, it is established that the use of either the 6‐31G(d) or 6‐311G(d,p) basis The authors are very grateful to the National Council for sets does not affect the energetic trends. DFT study on Tertiary Education, Republic of Ghana, for a research the thermolysis of the [4 + 2] / [3 + 2] tandem adducts grant under the Teaching and Learning Innovation Fund to subsequent monocyclic and bicyclic adducts is also (TALIF/KNUST/3/0008/2005), and to South Africa's 14 of 14 OPOKU ET AL.

Centre for High Performance Computing for access to Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. additional computing resource. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. COMPETING INTEREST Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, The authors declare that there is no conflict of interests R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. whatsoever regarding the publication of this manuscript. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, revision b. 01, Gaussian Inc., Wallingford, CT ORCID 2009 6492. [24] Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157. Ernest Opoku https://orcid.org/0000-0002-4271-6838 [25] S. N. Pieniazek, K. N. Houk, Angew. Chem. Int. Ed. 2006, 45, Richard Tia https://orcid.org/0000-0003-1043-8869 1442. [26] R. S. Paton, J. L. Mackey, W. H. Kim, J. H. Lee, S. J. REFERENCES Danishefsky, K. N. Houk, J. Am. Chem. Soc. 2010, 132, 9335. [27] R. S. Paton, S. E. Steinhardt, C. D. Vanderwal, K. N. Houk, [1] J. E. Sears, D. L. Boger, Acc. Chem. Res. 2016, 49, 241. J. Am. Chem. Soc. 2011, 133, 3895. [2] D. A. Margeti, P. A. Tro, M. R. B. Johnston, Mini. Rev. Org. [28] S. E. Wheeler, A. Moran, S. N. Pieniazek, K. N. Houk, J. Phys. Chem. 2011, 8, 49. Chem. 2009, 113, 10376. [3] S. Karlsson, H.‐E. Högberg, Org. Prep. Proced. Int. 2001, 33, 103. [29] S. N. Pieniazek, F. R. Clemente, K. N. Houk, Angew. Chem. Int. [4] H. Pellissier, Chem. Rev. 2012, 113, 442. Ed. 2008, 47, 7746. [5] H. Pellissier, Adv. Synth. Catal. 2012, 354, 237. [30] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999. [6] P. J. Parsons, C. S. Penkett, A. J. Shell, Chem. Rev. 1996, 96, 195. [31] M. Clark, R. D. Cramer, N. Van Opdenbosch, J. Comput. Chem. [7] R. A. Bunce, Science 1995, 51, 13103. 1989, 8, 10. [8] S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96, 137. [32] E. Opoku, R. Tia, E. Adei, J. Chem. 2016, 2016, 10. [9] S. E. Denmark, R. Y. Baiazitov, J. Org. Chem. 2006, 71, 593. [33] R. Tia, E. Adei, Comput. Theor. Chem. 2011, 971,8. [10] S. Danishefsky, P. F. Schuda, T. Kitahara, S. J. Etheredge, [34] E. Fosu, R. Tia, E. Adei, Tetrahedron 2016, 72, 8261. J. Am. Chem. Soc. 1977, 99, 6066. [35] E. Vogel, H. Kiefer, W. Roth, Angew. Chem. Int. Ed. 1964, 6, 442. [11] J. E. Sears, T. J. Barker, D. L. Boger, Org. Lett. 2015, 17, 5460. [36] K. N. Houk, Acc. Chem. Res. 1975, 11, 361. [12] J. D. Winkler, Chem. Rev. 1996, 96, 167. [37] L. R. Domingo, P. Pérez, J. A. Sáez, RSC Adv. 2013, 3,5. [13] L. F. Tietze, J. Heterocycl. Chem. 1990, 1, 47. [38] Y. Wang, S.‐R. Zhang, Y. Wang, L.‐B. Qu, D. Wei, Org. Chem. [14] K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun. Front. 2018, 5,13. 2003, 5, 551. [39] Y. Wang, Y. Qiao, D. Wei, M. Tang, Org. Chem. Front. 2017, 4, 10. [15] C. Chapman, C. Frost, Synthesis (Stuttg). 2007, 1,1. [40] Y. Wang, D. Wei, W. Zhang, ChemCatChem 2018, 10(2). [16] S. E. Denmark, R. Y. Baiazitov, S. T. Nguyen, Tetrahedron 2009, 65, 6535. [17] G. Bianchi, A. Gamba, R. Gandolfi, Tetrahedron 1972, 28, SUPPORTING INFORMATION 1601. Additional supporting information may be found online [18] G. Bianchi, R. Gandolfi, P. Grünanger, Tetrahedron 1973, 29, in the Supporting Information section at the end of the 2405. article. [19] S. E. Denmark, D. S. Middleton, J. Org. Chem. 1998, 63, 1604. [20] Y. Ju, R. S. Varma, J. Org. Chem. 2006, 71, 135. [21] S. L. Cui, J. Wang, Y.‐G. Wang, Org. Lett. 2008, 10, 13. [22] Wavefunction, Spartan 14' v.1.1.8, Wavefunction 2014. How to cite this article: Opoku E, Tia R, Adei E. [23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. DFT mechanistic study on tandem sequential Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, [4 + 2]/[3 + 2] addition reaction of G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. cyclooctatetraene with functionalized acetylenes Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. and nitrile imines. J Phys Org Chem. 2019;32:e3992. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. https://doi.org/10.1002/poc.3992 Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F.