Unexpected Rearrangement of Dilithiated Isoindoline-1,3-diols into 3

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Unexpected Rearrangement of Dilithiated Isoindoline-1,3diols into 3-Aminoindan-1-ones via N-Lithioamino-ArylCarbenes: A Combined Synthetic and Computational Study Magdalena Ciecha#ska, Andrzej Jó#wiak, Ryszard Boleslaw Nazarski, and Ewa A. Skorupska J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01217 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 28, 2019

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The Journal of Organic Chemistry

Unexpected Rearrangement of Dilithiated Isoindoline-1,3diols into 3-Aminoindan-1-ones via N-Lithioamino-ArylCarbenes: A Combined Synthetic and Computational Study Magdalena Ciechańska,† Andrzej Jóźwiak,† Ryszard B. Nazarski,*,‡, and Ewa A. Skorupska† †

Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 Łódź, Poland Theoretical and Structural Chemistry Group, Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 163/165, 90-236 Łódź, Poland ‡

ABSTRACT: The reaction of 2-aryl-3-hydroxyisoindolin-1-ones with the s-BuLiTMEDA system in THF at 78 oC, affording a series of diastereomeric 3-aminoindan-1-ones via a novel rearrangement of the isoindolinone scaffold, is reported. It is proposed that -elimination of LiOH from the transient N,O-dilithiated hemiaminal carbenoids leads to the formation of singlet carbenes followed by their trapping via an intramolecular CH insertion. An alternative explanation based on an intramolecular Mannich reaction seems to be less probable. A mechanistic-type study that combines spectroscopic data of the products and calculation results, with a special focus on the diverse lithiated intermediates that are most likely to engage in the title process (particularly those with internal Li-bonds), is presented. The MP2 approach, involving also the NPA and QTAIM data, provided insight into structures and properties of all these species. Two reaction routes A and B appeared to be possible for the postulated carbene mechanism. An unusual metamorphosis of the CCN atom triad, from a near sp 1-azaallene-type in more stable non-carbene Li enolates to a roughly sp2 type in their carbene keto tautomers, is recognized in one of these pathways (route B). Dominant forms of resonance structures for the aforementioned tautomeric systems that have sevenmembered quasi rings stabilized by Li+ ions bridging the N- and carbonyl O-atoms, are indicated. Large computational difficulties arising from a huge impact of internal Li+ complexation on conformational preferences and electronic properties of carbonyl group-bearing lithium derivatives are also discussed. The new -keto carbene species under study belong to a subclass of acyclic amino-aryl-carbenes (AAACs).

INTRODUCTION All studies directed toward unraveling the mechanism of any organic reaction require unequivocal spectroscopic identification of a vast majority of products, whereas theoretical calculations are needed to have reliable insight into molecular geometries and electronic structures of reactive shortlived intermediate (IM) and, if possible, transition state (TS) species together with relative energy data about all chemically reasonable elementary reaction steps involved in the process of interest. The use of post-Hartree-Fock ab initio or density functional theory (DFT) approaches is mandatory in these cases; the latter cost-effective methods being especially relevant for medium and largesized systems. 2-Substituted 3-hydroxyisoindolin-1-ones (1) are the main starting materials in the synthesis of 2,3-dihydro-1H-isoindol-1-ones of type 2 that constitute versatile building blocks of many bioactive molecules.1 Moreover, some lactams of this kind are known to have wide-ranging pharmacologic properties,2 including the recently studied potential antiproliferative2c or pro-apoptotic2d activity in 1

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therapeutic treatment of human cancers.2bd Therefore, new syntheses of these pharmacophoric systems remain of substantial importance. As to the chemistry of α-hydroxy-γ-lactams 1, they react with Grignard or alkyllithium reagents to give products with structures that depend on the specific character of both isoindolinone and organometallic reactants employed.3 For instance, metalation at the 7-ring position or addition to the carbonyl group (C=O) occurs in their reaction with 2.3 equiv of sec-buthyllithium solvated4 by N,N,N′,N′-tetramethyl-1,2-ethylenediamine (s-BuLiTMEDA system). Thus, in the case of racemic substrates 1a-c bearing 2-aryl groups, hydrolysis of O,O’dilithiated isoindoline-1,3-diols that are initially formed provides corresponding pairs of diastereomeric γ-lactams 2a-c3e (Scheme 1). Surprisingly, diastereomeric 3-aminoindan-1-ones (IUPAC name: 3-amino-2,3-dihydroinden-1ones, 3a-c) were also isolated in a more detailed study of the aforementioned reaction, recognized as products of a hitherto unknown reorganization of the isoindolinone skeleton. Furthermore, it was established that the reaction outcome is influenced by changes in the room temperature (rt) reaction time and by the presence of substituents R2R5 in substrates 1b and 1c. Herein, several cases where a transformation of this kind takes place are reported. Our mechanistic proposals relating to this internal process are based on a joint use of experimental (spectroscopic) structural information, and first of all, quantum mechanical methods briefly outlined above. The classic multi-step synthetic approach to 3-aminoindan-1-one derivatives involves the final five-membered ring closure accomplished by an electrophilic aromatic substitution.5 Their synthesis from 2-acetylbenzaldehydes and secondary amines in acidic conditions was reported very recently.6 Compounds of this type are useful synthetic intermediates toward the 1-aminoindane unit embedded in many important systems of biological activity.5,6 Scheme 1. Two different types of products of the reaction of s-BuLi with compounds 1 O R4 N R1 R3 R2

1) s-BuLi (2.3 eq) TMEDA, THF 78oC rt 2) H2O, H+

*

R4

*

2

*

R3 O

R2 1

N R1 +

R3

OH 1

O R4

2

4

a: R = Ph, R  R = H b: R1 = Ph, R2  R4 = OMe c: R1 = 4-R5-C6H4, R2  R5 = OMe

*

N R1

R2 3 H

Thus, four following and not separable issues were especially addressed in this work: (i) unequivocal identification of three newly synthesized β-amino ketones 3, mainly based on an interpretation of their NMR spectra, (ii) modeling of molecular structures of the diverse possible intermediates involved in the rearrangement, (iii) evaluation of reaction energies for all rational elementary chemical reaction steps, and (iv) analysis of calculated topological properties of selected bonds in different IM lithium species, with all the computations (ii-iv) done at the MP2 level of theory.

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A study of this kind that focuses on the explanation of the impact of changing the reaction conditions and substituent effect of groups R2R5 on the distribution of such type of products has not yet been published. The in situ generation of N-lithiated acyclic amino-aryl-carbene (AAAC) species by -elimination of LiOH and an unprecedented conformation/tautomerism-dependent metamorphosis of the molecular and electronic structure of the CCN atom triad, from a near sp digonal 1-azaallene-type in more stable lithium enolate carbene precursors to ~sp2 trigonal type in their Li+ complexed keto tautomers [along one of the two pathways (route B)], were also not proposed to date. Additionally, the natural bond orbital (NBO) method7 and quantum theory of ‘Atoms in Molecules’ (QTAIM)8 were applied to find answers to certain closely associated questions. As an aside, this is a ninth paper of one of the authors on assigning structures to diastereomeric systems by analysis of their NMR spectra.9

METHODOLOGY With the aim to validate the rearrangement mechanism, as laid out in Figure 1, a B3LYP/6311+G(d,p) computational study of structural and energetic aspects concerning all elementary steps engaged in the formation of products 3a-c and, especially, their different lithiated precursors was carried out with the Gaussian 09 suite of programs.10 The diffuse functions are necessary to correct accounting for anionic species and unshared (lone) pairs of electrons on heteroatoms.11 More expanded bases including core correlating functions were in fact recommended for calculations on lithium species,12 but they were not used here because of other simplifications adopted (vide infra). Overall, the aforementioned DFT method has been shown to give accurate descriptions of comparable molecular systems.12b The results of Ramachandran et al.13 suggested, however, that B3LYP is not a suitable DFT functional for handling with lithium carbenoids. Therefore, selected low-energy IM species were subjected to geometry reoptimization without any constrains at the MP2/6-311+G(d,p) level of theory (hereafter referred to as MP2 level), which was used recently for some small-sized carbenes.14 The Cartesian coordinates of the best (energetically most preferable) conformers of all the considered systems are given in Table S6 of Supporting Information (SI) as reliable representations of entire families of closely related conformations being in dynamic equilibrium. Their 3D molecular views were generated using the Chemcraft program.15 On the whole, we have focused on finding the most stable structures of lithiated intermediates that are assumed to be formed during the course of the title rearrangement. Hence final calculations were performed for both R and S configurations of a chiral center at the site of CH insertion. However, convergence issues were encountered for some cases, due to a relatively large size (e.g., species stemming from 1c, C22H27Li2NO6, 415.3 g mol1) and, especially, quite substantial structural freedom of these branched systems arising from conformational isomerizations by rotation around CC or CN bonds and from inversion at the N atom. Consequently, relatively flat potential energy surfaces plagued with shallow local minima were usually analyzed. A far more essential problem was the presence of diverse mono- and dilithium IM species. Indeed, such systems have an enormously large tendency to undergo a wide variety of oligomerization and dynamic restructuring in all states of aggregation,4,13,16 as well as participating 3

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in different types of Li-bonded complexes, Li+ adducts and/or Li-bridged structures.4,16,17 In the present case, these specific features of lithium species make very difficult performing standard (geometrically unconstrained) calculations, such as energy minimizations, TS searching and so on, by forcing the systems under study to adopt certain unwanted conformations that are stabilized by intramolecular NLi+O bridges. On the other hand, the competition of THF and TMEDA molecules as external electron donors with internal complexation of a Li+ ion most likely exists in the reaction medium employed.17c,i NMR experimental evidences for the Li-bond dependent conformational switch taking place in solutions of some carbonyl group-bearing lithium salts and leading to the formation of seven-membered Li+-bridged quasi-ring systems (via structural alterations assisted by Li-bond reorganizations) were provided by Robert’s group.17s,t Fortuitously, corresponding intermolecular interactions could be neglected, because complexation of Li+ by TMEDA, as a chelating additive, effectively breaks down such super structures. Thus, potential influence of TMEDA was omitted for simplicity (except the case of LiOH and its aggregation states, vide infra), despite the known formation of related mono- and, especially, bidentate complexes with lithiated systems.17d,k,p In turn, the impact of THF as Licoordinating ethereal solvent was only roughly mimicked by the standard IEF-PCM18 implicit solvation model that is also applied in other similar investigations,17g,s despite its known shortcomings.13,17q,19 However, the computational cost of an explicit use of surrounding THF molecules,17x to ensure tetracoordination17f around each Li+ in lithium species under consideration, would be too prohibitive. The considerable ionicity of the LiN/O bonds, and therefore high positive and negative charges in different lithium bonds, could be a probable reason for the failure of several intrinsic reaction coordinate (IRC) calculations performed within the IEF-PCM scheme. A close enough situation, rationalized by a relatively high charge on the system under study, was found in mechanistic considerations on sulfate hydrolysis of the phosphate anion.20 Some associated issues on bonding interactions and charge distribution in IM species analyzed here were solved with resort to additional computations conducted with the NBO7 and QTAIM8 methods. In the later approach, introduced by Bader’s group, a question about a ‘shared’ covalent or ‘closed-shell’ non-covalent character of atom-atom interactions is answered in a topological analysis of electron charge density  at (3,1) bond critical points (BCPs), denoted with BCP as a subscript, because BCP correlates well with a covalent bond order.8 A crucial information arises also from the Laplacian of BCP (2BCP) and total local electron energy density, HBCP = GBCP + VBCP, where GBCP and VBCP are the local kinetic and potential energy densities, respectively.8,21 The negative value of 2BCP shows that there is a concentration of  at the BCP, indicating the covalent nature of the bond. On the contrary, positive 2BCPs, revealing a depletion of  along the bond path, are typical of closed-shell interactions, e.g., ionic, highly polar covalent or weak hydrogen bonds.8 It is commonly thought that if both 2BCP and HBCP values are negative/positive, then covalent/non-covalent bonding occurs, while its partial covalency or intermediate-bonded interactions are believed for 2BCP > 0 but HBCP < 0.21,22 Equal information is available from the – GBCP/VBCP ratio. Its values < 0.5 and > 1 generally indicate a covalent and non-covalent bonding, respectively; the interaction is intermediate for –GBCP/VBCP  (0.5:1).22a,c Valuable information is 4

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also provide by the electron delocalization index values, DI(A,B)s, playing a role of bond indices for the AB bonds of interest. A full QTAIM numerical analysis was performed with AIMAll software package,23 by applying MP2 wave functions generated using Gaussian 09.10 With regard to Weinhold’s NBO analysis, the 3.1 and 6.0 versions of the NBO program (the latter connected to Gaussian 0910a) have been employed. All further details on methodology are described in the Theoretical section of SI.

RESULTS AND DISCUSSION Experimental and Initial Mechanistic Results. The conditions and most relevant results of treatment of 3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1a) with the s-BuLi in THF solution in the presence of TMEDA as a reaction activator,4 are listed in Table 1; all details are given in the Experimental Section. This reaction carried out at 78 oC for 1.5 h resulted in exclusive formation of two diastereomers of 3-sec-butyl-2-phenyl-2,3-dihydro-1H-isoindol-1-one (2a), after allowing to reach rt over 0.5 h and quenching with water3e (Table 1, entry 1). In sharp contrast, hydrolysis after 24.5 h gave two new diastereomeric β-amino indanones 3a as main products identified in the mixture. Their chemical structure was unambiguously established by interpretation of MS, IR and especially 2D-NMR data and was additionally supported by deuterium isotope effects of type nC(D) observed for 3a; see the NMR Data Analysis section of SI. Further lengthening of the rt reaction time to 96.5 h did not practically affect the yield of 2a and 3a (Table 1, entry 3). Moreover, it was found that the products distribution is modified to some degree by substituents R2R5 in the starting materials employed. Thus, the presence of mesomerically electron-donating methoxy (MeO) groups in aryl units of 1b and 1c greatly facilitates formation of 3b and 3c (cf. entries 4 and 5 of Table 1). Relatively large amounts of unreacted substrates 1a-c (~2530%) can be rationalized in part by the TMEDA-mediated lithiation of THF, followed by ether cleavage and subsequent processes, taking place mostly at temperatures above 40 oC.16f,24 In other words, some quantity of s-BuLi is most likely consumed by an undesirable side reaction with THF. Similar recovery of starting materials was observed for the other close reactions.3e Table 1.

The products of reaction of compounds 1 with the s-BuLi/TMEDA system in THF a

Entry

Substrate

1 2 3 4 5

1a 1a 1a 1b 1c

Total time, h b 2 26 98 2 2

Recovered substrate 1, % 18 19 21 23 32

Yield of 2, % 75 26 21 32 24

Yield of 3, % 0 38 40 39 39

a

Very similar results were obtained when the reaction mixture were at the same time treated with chlorotrimethylsilane; see Experimental Section. b Intensive stirring for 1.5 h at 78 oC and warming to rt at least over 0.5 h.

Undoubtedly, compounds 2a and 3a originated from cis and trans isomers of dilithiated 1H-2,3dihydroisoindole-1,3-diols, Acis/trans, formed by treatment of the parent (unsubstituted) hydroxylactams 1a with 2.3 equiv of the s-BuLi/TMEDA system (Figure 1). One could suppose that with the elongation of rt reaction time these lithium alkoxides can undergo five-membered ring 5

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opening via tautomerization of their hemiketal moieties, proven by Tomooka et al.,17i to form N,Odilithiated -keto species B as classical carbenoids.25 The opposite reversible conversion, from openchain ketones to cyclic alkoxy lithium salts, was reported by Epsztajn et al.26 In the case under study, an endergonic AB reaction step is most likely followed by -elimination of LiOH from chemically unstable hemiaminal-type carbenoids B to yield an N-lithioamino aryl carbene C. This latter species can be considered as a new example of relatively stable AAACs27 (Scheme 2) known to undergo an intramolecular insertion reaction into an aliphatic CH bond with the formation of five-membered carbocycles.27a,d O O rt Li Li - LiOH N N Ph (route B) Ph Li H O Cb(keto) ((17.2)){0} Bdb (11.6)((0))

O

O

N Ph OH

1a

s-BuLi (2.3 eq) TMEDA, THF, -78oC to rt

(route B)

Li N Ph

(route A) O

Li

H

Acis (0)

O

Li

. Li

N

H Ph

C {0.2}[13.45]

rt

rt - LiOH

C-H bond insertion O

O

OH

Li

N Ph N E

rt - LiOH (route A)

Bb (15.6)[0]

+2 H2O, -2 LiOH

Ph

O

rt

N Ph

N

Cb(enol) {-2.0}

O

Li

Li

conformational alternation (route B)

conformational alternation

rt O

.

..

OH

O

H

Ph Li

B - H2O

N Ph Li Dtrans {-36.2}[-23.0]) + H2O, - LiOH O

tautomerization N Ph F

OH

N Ph O

2a

3a H

N Ph

Figure 1. Proposed mechanism for the origin of products 2a and 3a. Relative Go298 data, in kcal mol1, are given in (), [], (()) and {} as reaction energies of individual elementary steps, by using the reactants Acis, Bb, Bdb and Cb(keto) as ‘reference species’, respectively. These energy data were determined at the MP2/6-311+G(d,p) level for the best conformations found; see also text and Table 2 (numerical values). Dashed-line arrows represent the reaction path suggested initially. All the LiN/O bonds are shown traditionally.

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The irreversible liberation of LiOH was recognized for scarce lithium (bio)organic molecules or their Li+ adducts in the gas-phase.12b,17n,28 We were surprised to not find any such papers dealing with its release into non-aqueous reaction media. A notable exception is the formal 1,2- and 1,4elimination of LiOH from a complex lithium alkoxide in THF solution described by Vigalok et al.29 Similar 1,1-elimination of p-toluenesulfonic acid (TsOH) in THF at 20 oC with concomitant generation of alk-1-ynyl-hetaryl-carbenes was only noticed briefly.30 The strongly resonancestabilized tosylate (TsO) anion is a weak base and thus a very good leaving group. In sharp contrast, the lithium monoxide ion (LiO) is one of strongest known bases and exhibits a very high proton affinity.31 For this reason, a release of two oppositely charged parts of LiOH into the reaction medium in a classical two-step base-catalyzed process,32 consisting of a rapid removal of the proton, followed by a slow loss of the remaining anionic part, is unlikely. Therefore, a single concerted or quasi-concerted step of their -elimination can be suggested (for its very schematic depiction, see formula B in Figure 1) as an intramolecular variant of the concerted mechanism proposed by Hine and Langford for haloforms containing two fluorine atoms.32a,b Scheme 2. Carbenes 4 and their three main Lewis structures 4A-4C R4

R3

R4

R3

.. .. N

2

R1 2

..

N

4A

.

R1

R

R

R4

R3 Me

Me

4B a: R1  R4 = t-Bu b d: R1 = i-Pr, t-Bu or 1-Ad, R2 = R4 = CF3, R3 = H

R2 4C

N

Me

R1

The first reported AAAC species 4a-d (Scheme 2) with a singlet ground state far below the triplet are stable at rt, both in solution and in the solid state.27 The dominant factor in stabilizing these systems seems to be an extensive -electron donation from the lone pair on an adjacent planar N atom into the formally vacant p orbital of a divalent :C atom violating the octet rule.33 Furthermore, their amino units act as strong σ-electron attractors. As a result of this ‘push-pull’ mesomeric-inductive synergistic effect,34 the aryl units in AAACs of type 4 and their analogues27b,d are considered only as spectator substituents in relation to the carbene center27a,c,d that tune its electronic environment through mesomeric, inductive or steric effects and so regulate the stability/reactivity of the whole system. The bonding in carbenes 4a-d is reasonably approximated by the ylide structure 4B27a,c,35 based on a geometric consideration of the single-crystal X-ray structure determined for 4a.27a In this context, it is noteworthy that the modulating character of aryl units (and thus also of their substituents) in carbenes 4 is in line with similar behavior observed for MeO group-bearing substrates 1b and 1c (vide supra). However, an extra stabilization of carbene sites was anticipated for the species of type C studied here, due to accumulation of a large negative charge on their α-N atoms arising from a high degree of ionic nature of the NLi bond. Accordingly, it could be expected that the resultant electron-deficient carbene center in C inserts spontaneously into the nucleophilic CH bond at an asymmetric carbon of the distant sec-butyl 7

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group, as is the case for a tert-butyl CH of the substituent R2/R4 in compound 4a.27a The final quenching of the so-obtained N-lithium species D, by proton source during aqueous workup, affords a mixture of two diastereomers of the 1,5-CH insertion product 3a. Thus, it was envisioned that the reasonable reaction sequence, which explains the formation of ‘coproducts’ 3a from 1a via the intermediate lithium derivatives A-D, is shown in Figure 1. The obvious2a,36 IM species E and F involved in the primary reaction pathway leading to ‘normal’ products 2a are also given for completeness. An alternative explanation of the transformation of Li-bond-free carbenoids B to species D by a cascade of reactions ending with an intramolecular Mannich reaction between the imine group and the carbanionic site suggested by one of the reviewers seems much less likely, mainly due to very low electrophilicity of imine carbon in corresponding IM species under strongly alkaline conditions employed. For all details, new calculation results obtained within the conceptual DFT framework and related discussion, see the Non-Carbene Route section of SI. Geometry and Energy. All usual calculation attempts to find minima on energy hypersurfaces relating to putative carbenoids B with uncomplexed lithioalkoxy (OLi+) groups were uniformly fruitless. The lack of success in carrying this search was apparently due to favorable interaction of the Li+ ion with a neighboring N atom. Consequently, our efforts resulted in the location of various bonded forms, Bbs, stabilized by intramolecular amine coordination to Li+ achieved within the formed four-membered quasi-ring systems (Figure S21); simultaneously, the simplest reaction route A was traced in this way (Figure 1). The attempts to reach TS structures linked with these IMs yielded several TS structures, named BTSs. It was obvious that a deeper knowledge of such TSs would be of fundamental importance in shedding light on -elimination of LiOH en route to in situ generation of a free carbene C (= 6a). As a matter of fact, in view of an impact of the presence of MeO groups in substrates 1 on the reaction rate and products distribution (vide supra), one could suppose that LiOH loss is the slowest (rate-determining) elementary step of the whole rearrangement under study. Thus, its liberation would be an irreversible step of the latter of two competing reaction pathways, i.e., 12 or 3, considered in the spirit of Schlosser coupled equilibria.37 Unfortunately, numerous IRC calculations attempted by starting from different structures BTS were ineffective.

Scheme 3. Carbenoids 5 of type Bdb and Li-bond-free AAAC species 6 of type C under study O 4

4

R

R

O 3

R2

H

5a-d

Li2 N R1 Li1 O

R

.

R3 R2

6a-d

H

N Li2

R1

a: R1 = Ph, R2 - R4 = H b: R1 = Ph, R2 - R4 = OMe c: R1 = 4-R5-C6H4, R2 - R5 = OMe d: R1 = Ph, R2 = H, R3 = R4 = OMe

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Gratifyingly, however, optimization of the BTS geometries has led us to the location of several doubly bonded rotamers of the -keto carbenoid B, named hereafter species Bdb, with an additional stabilized complexation of the Li+ ion by the C=O group (Scheme 3). Thus, seven-membered quasirings are formed in this way with Li2 bridging the N- and carbonyl O-atoms. At the same time, the NLi1 distance becomes lengthened, especially for 5a (= Bdb); related geometric data for species 5a-d are given in Table S3. Consequently, the lithium bond (Li-bond) involving Li1 is a lot weaker than this in Bb; for discussion, please see the Carbenoids Bb vs. Bdb section of SI. The best-found conformation of species Bdb is depicted in Figure 2. A close inspection of this structure and an arrangement of regrouping atoms O, Li and N in the formula Acis (Figure 1) can raise the question whether doubly-Li-bonded species Bdb are not rotamers formed directly from the initial adducts of type A. This hypothesis seems to be a highly probable one. The internally bonded forms of -keto amino carbene C, i.e., species Cb(keto) (cf. Figure 3 and Scheme 4), with identical N,O-donor assistance were also located starting from some promising geometries of the free carbene C. As shown in Table S2, the carbonyl O atom of such Li+ complexes Bdb and Cb(keto) carries a negative charge, little increased relative to that in parent species Bb and C. The formation of different quasiring systems stabilized by Li-bonding was evidenced in DFT modeling of various pathways relating to some ring-enlarging reactions.17i The energy of conformational change from Cb(keto) to a Li-bondfree species C accompanied by Li-bond breaking is practically negligible (rG = 0.2 kcal mol1). The second, multistep reaction route B toward generation of the carbene C active in the 1,5-CH insertion was outlined in this manner.

Figure 2. The calculated lowest-energy conformation of Bdb (= 5a). Atom color coding: O, red; N, blue; Li, magenta; C, darkly grey; H, gray. The four carbon atoms form the planar part of a seven-membered chelate ring.

All the aforementioned internally Li-bond stabilized forms Cb of a species C were found to be more stable than the best-found form of its unstabilized CarCcarbonyl or CarCc rotamer, namely, a Li-bond-free carbene C (= 6a) with the CCcN angle of 109.7o and an easily accessible CH bond of the s-Bu group (Figure 4). This carbene bond angle, c, is smaller than that of 121.0o found for 4a.27a,c The above result for 6a, CcN bond length of 1.320 Å and diminished negative NPA atomic charge at an almost planar N atom (0.87 e, N = 356.8o; Tables S2 and S3) are consistent with a resonance hybrid of two Lewis structures A’ and B’, with a dominant participation of the former (Scheme 4). An introduction of three OMe groups into the C-aryl moiety leads to only small 9

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changes in these geometric features. Thus, c = 113.8o, N = 350.3o and similar CcN bond length/charge values were found for the best conformation of 6c. Such a structure of the carbene center in species 6a-c concerns also related systems Cb(keto) that are Li-bonded rotamers of free carbenes of type C.

Figure 3. 3D views of the best MP2/6-311+G(d,p) optimized conformations of carbene precursors Cb(keto) (top) and Cb(enol) (bottom). Atom color coding as in Figure 2. The four C atoms form an almost planar part of a 7-membered chelate ring.

It is worth pointing out that the structure of the CCN triad in the Li+-bridged species Cb depends on the conformation of a seven-membered ring and aliphatic chain as well as on the orientation of the N-aryl unit. Indeed, several middle states between O-bonded Cb(keto)s (presumably formed directly from the carbenoids Bdb in a fast kinetically-controlled step) and their N-coordinated enolate counterparts Cb(enol)s as thermodynamic products bearing a sp digonal azaallene unit of the ortho-chinoid-like -conjugated system, were found in the calculations. All these IM species are likely to play a role in the cascade of structural changes including breaking and de novo formation of Li-bonds in the stepwise route B and are similar to those proposed in the chelate-assisted conducted-tour mechanisms studied by Haeffner et al.17g More detailed depictions of these species are shown in Figure 3 and Scheme 4; for some related key atomic charges and geometric parameters, see Tables S2 and S3. 10

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The Journal of Organic Chemistry

Figure 4. The lowest-energy conformation of a free carbene C; atom color coding as in Figure 2. The distance between :C and C/H atoms of the tertiary CH bond is of 3.132/2.384 Å.

Scheme 4. Lewis formulae of main participants of the keto-enolate tautomerism of species C

O

.. N

O Ph

A'

.. N B'

O Li N

Li Ph

O Li

I

Cb(keto)

.N

Ph

Ph

II Cb(enol)

Thus, one can speak about a unique keto-enolate dynamic tautomeric equilibrium (Scheme 4) in which the best conformation of Cb(enol) has the CarCN angle of 170.5o. At first sight, such a result seems to be in agreement with a linear or near-linear geometry anticipated for the zwitterionic allene-type form 4C. Nevertheless, as already mentioned above, this kind of structure does not coincide with a large negative charge localized on the N atom and relatively large positive charge, +0.5 e, on Cc in the CCN triad (Table S2). Therefore, the predominance of a linear azaallene form II and some minor contribution of a bent zwitterion I38 to the resonance structure of Cb(enol) can be proposed. The above tautomerism-dependent structures of our Li+-bridged AAAC precursors, with the more stable enolates Cb(enol)s as conjugate bases of Cb(keto)s, were not proposed to date. Similar structural dependence is, however, a well-known phenomenon inter alia for N-confused porphyrinoids.39 The equilibrium geometry of a large fragment of Cb(enol) is analogous to that determined by the single-crystal X-ray diffraction study of a certain ketenimine.40 Moreover, nonlinearity (168.8−170.5o) of the C=C=N chain found for five different conformations of Cb(enol) is in agreement with the belief that such geometry, CCN of 170−176o, is an intrinsic property of ketenimines.38b,41 Finally, a word is in order about the used terminology. In brief, all the species Cb are considered as ‘structurally blocked’ (Li-bond stabilized) carbene precursors as opposed to a Libond-free carbene C, that is its rotamer(s) with a coordinatively unsaturated Li+ ion, and so being capable of inserting into a proximal C−H bond. 11

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Energetics for the lowest-energy forms of the systems under study are gathered in Table 2, whereas their key geometric parameters are summarized in Table S3. Standard molar Gibbs free energy data calculated at 298 K were used as the most reliable measures of thermodynamic stability of these IM species, LiOH and the by-product J in simulated THF solution. It can be considered that differences in such Go298 data provide driving forces of elementary steps engaged in the rearrangement of interest. Owing to relative large simplifications employed (cf. Methodology), it can be supposed that the accuracy of these energy data is within  1.5 kcal mol1. This conclusion is roughly in line with similar energies a priori expected for two conversions reflecting formation of an internal Li-bond accompanied by necessary conformational changes, namely, BbBdb vs. CCb(keto) (rG = 4.0 vs. 0.2 kcal mol1). The problem of evaluation of reaction energies and estimation of their uncertainties is still relevant, particularly for large-system reactions proceeding through a series of intermediates.42 Table 2. Energy data for key intermediates or products and various elementary chemical steps involved in the mechanism under study, calculated at the IEF-PCM(THF)-MP2/6-311+G(d,p) level a Speciesb Acis Atrans B Bb {Bb  LiOH}d,e Bdb = 5a [Bdb  LiOH]d,e Cb(keto) Cb(enol) C = 6a Dcis Dtrans F (3S,2’R)-2af (3S,2’S)-2af (2R,3R)-3a (cis) (2S,3R)-3a (trans) Jg LiOH

Go298, a.u. -915.008960 -915.005796 c -914.984084 {-831.754237} -914.990469 [-831.760622] -831.733190 -831.736407 -831.732804 -831.783719 -831.790936 -824.828998 -824.865438 -824.864409 -824.844939 -824.845936 -824.821664 -83.229847

rGo298, kcal moll 0 1.99  15.61 [0] 11.60 ((0)) 1.3, indicating some participation of C=N double bond, were found for internally Li-bonded species Cb(keto) and Cb(enol) (Table 3). The majority of findings outlined above give credibility to the notion that an expected outflow of electron density from aryl rings to the CCN atom triads in species 5b and 5c really takes place. More negative charges on their N atoms are particularly important in this case (Table S2). In other words, these calculations seem to support our thought that the presence of the OMe groups in substrates 1 accelerates the formation of carbene precursors Cb(keto) by a facilitated LiOH loss from carbenoids Bdb (or direct generation of C from Bb). An enlarged tendency to liberate LiOH from 15

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gas-phase adducts of Li+ with N-aryl-benzamides was also attributed to the presence of electron-rich p-methoxyphenyl units.17n Boche and Lohrenz (BL) wrote17e that (i) the stability of carbenes :CR1R2 increases strongly with the donor qualities of groups Rn (what was confirmed by more recent theoretical results14a) and that (ii) only comparatively stable carbenes with two donor substituents are formed from carbenoids CR1R2XY by α-elimination of XY. After the discovery of AAACs,27a it became apparent that one adjacent N atom is enough for such stabilization.48 (Later isolation49 of carbene without an αnitrogen, explained50 in the framework of QTAIM approach, modified this stability criterion further.) The proposed carbenoids of type Bb and Bdb meet both requirements of BL very well. Thus, it seems that it was the main reason why α-elimination of LiOH to generate free carbenes was not reported to date. Furthermore, one can suppose that the presence of electron-releasing OMe groups in the C-aryl unit of carbenes 6 and their precursors 5 counterbalances the deactivating effect of the CO-s-Bu group. This conclusion follows the analysis of changes in atomic charges within the carbonyl groups on going from 5a to 5b via 5d, and from 5a to 5c (Table S2). Hence, such aryl units in carbenes 6 should be thought as stabilizing electron-donating substituents and not as playing only a spectator role, as recognized for carbenes 4a-d (especially, for those bearing electron-withdrawing CF3 groups) and their analogues.27a,c,d All the above discussion relate to a stepwise route B of the rearrangement in question, because methoxy-functionalized intermediates of type Bdb and Cb(keto) are relatively conformationally rigid systems. In fact, owing to internal Li-bonds, these species are much easier to molecular modeling and topological parameters calculation. There is no reason, however, to think that analogous conclusions do not concern an alternative reaction route A. In closing, a more general aspect is worth of noting. Atomic charges considered in Table S2 show that bonding between Li+ and N or O atoms is highly ionic in all IM species. Indeed, the Li+ ion bear high positive charge close to +1, whereas both heteroatoms have large negative charges. A perusal of Table S4 reveals that BCPs for LiN/O bonds are insignificant, showing a small covalent contribution to the Li-bonding. The positive 2BCP and HBCP values unequivocally indicate an ionic nature of these interactions as well. A high degree of ionicity of the Li bonding was also found in a recent NBO and QTAIM study.17w All these results indicate that heteroorganic lithium derivatives under study, existing in O-donor solvents most likely as contact (tight) ion pairs with solvated Li+ counterions, are highly ionic systems, and that their structures symbolically represented by R1R2NLi+ and especially ROLi+ are much more apt than their traditional formulas with the NLi and OLi bonds; see, e.g., Scheme 4. Undoubtedly, their oversimplified description as ‘naked’ anions is also inadequate and misleading and should be avoided.

CONCLUSIONS We have described a study of a serendipitous variant of the reaction between compounds 1 and sBuLi in THF solution at 78 oC with TMEDA as a disaggregating agent, which was found as leading to a hitherto-unknown rearrangement of the isoindolinone scaffold. In comparison to 16

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previous results, new diastereomeric β-amino indanones 3 were predominantly isolated along with ‘normal’ products 2 under slightly changed experimental conditions. The formation of the former systems is rationalized in the framework of an intramolecular insertion of N-lithiated AAAC species of type C into the tertiary aliphatic CH bond. Two alternative or competitive routes A and B of their in situ generation, respectively, from the carbenoids of type Bb and Bdb, are suggested. All proposals for the formation of products 3 and their different lithium precursors produced in this way are corroborated by extensive electronic-structure calculations carried out at the MP2 level, including additional use of the NBO and QTAIM methods. Special attention was paid to evaluate structural and topological properties of intramolecular Li-bonds in various intermediate systems under study. Another mechanism of the observed rearrangement, based on an intramolecular Mannich reaction in strongly alkaline media, seems less likely. To summarize our main results and conclusions: 1) The process in question consists of a cascade of sequential equilibria, of which the majority are energetically unfavorable. An irreversible LiOH loss from hemiaminal-type carbenoids Bb and/or Bdb (bearing one or two quasi-ring systems involving N,O-coordination to Li+) is presumably a critical stage in driving the whole process to completion. Therefore, it is also most likely to be the rate-determining step of this reaction occurring only at an extended rt time or with supporting assistance of electron-releasing OMe groups in substrates 1. 2) The Li-bonded keto carbenes Cb(keto) are suggested to exist in dynamic tautomeric equilibrium with more stable lithium enolates, Cb(enol)s. The transformation of structure of the CCN atom triad from ~sp2 trigonal type in keto AAACs to a near sp digonal 1-azaallene-type in their noncarbene enolate tautomers was found computationally (involving NBO and QTAIM results). The contributing resonance structures of both these tautomeric families are proposed. All internally Li-bonded Cb states, considered here as carbene precursors, are more stable that the Li-bond-free species C operating in the 1,5-CH insertion reaction. 3) According to MP2 results, the crucial step en route to generation of a free carbene C has an estimated cost of rG < 13.45 and < 17.4 kcal mol1, by starting from carbenoids Bb and Bdb, respectively. In turn, the formation energy of Bb is quite high (rG = 15.6 kcal mol1). Thus, the two above values, 15.6 and < 17.4 kcal mol1, are the greatest calculated reaction energies (not energetic barriers) within the rearrangement route A and B, respectively. 4) Computational evidences suggest that the expected outflow of electron density from aryl rings to the CCN atom triad in species 5b,c and 6b,c functionalized with OMe groups, does indeed take place. Consequently, these aryl units in carbenes 6b,c should be thought as stabilizing electron-donating substituents and not as only playing a spectator role, as was identified by the Bertrand group for the AAAC systems 4a-d and their congeners. 5) The great advantage of formulas R1R2NLi+ and ROLi+ for highly ionic N- and O-lithio systems over their frequent symbolic representations (with explicit NLi and OLi linkages) was clearly revealed in the analysis of NPA and QTAIM data for the lithium derivatives under study. 6) Serious difficulties in geometrically unconstrained molecular modeling and TS searching were encountered for all lithium intermediates bearing the carbonyl group (due to strong internal 17

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complexation of Li+ by the C=O oxygen) leading to the adoption of unwanted and undesirable Li-bridged conformations by these species. Such calculation problems were not reported to date. Finally, we would like to highlight the great synergy between modern experimental methods and current theoretical computations. Indeed, today’s spectroscopic techniques (especially solution NMR) provide key pieces of encoded structural information mainly on ground states of chemical systems and/or their ensembles, while electron correlation calculations also offer a variety of details about their high-energy states that are not available for observation. Only the joint use of these two complementary approaches allows us to shape proposals for interactions between such systems, including mechanistic hypotheses and other related issues. All the above points 15 are the best proof of this belief.

EXPERIMENTAL SECTION General Information. All reagents and commercially available materials were used without additional purification unless otherwise stated. n-Butyllithium (2.5 M solution in hexanes) and secbutyllithium (1.4 M solution in cyclohexane) were purchased from Aldrich and were analyzed immediately before use by applying the double titration procedure51 with 1,2-dibromoethane in heptane solution (second step). N,N,N’,N’-tetramethyl-1,2-ethylenediamine (TMEDA; Aldrich, 99.5%) was distilled prior to use and stored over KOH pellets. Chlorotrimethylsilane (purity 99%) was obtained from Fluka. Tetrahydrofuran (POCH, pure) was distilled from sodium benzophenone ketyl prior to use. Reagents and solvents were handled by using standard syringe techniques. All the air- and moisturesensitive reactions were carried out under an argon atmosphere. Analytical thin-layer chromatography (TLC) was conducted on Merck silica-gel plates (Kieselgel 60 F254, layer thickness 0.2 mm) with UV detection at 254 and/or 365 nm. Gravitational column chromatography (GCC) separations and purifications were performed on silica gel 60 (0.063–0.100 mm) from Merck. 1H and 13C{1H} NMR spectra were obtained at ~300 K for solutions in DMSO-d6 with a Bruker Avance III spectrometer at a frequency of 600.3 MHz (1H) and 150.9 MHz (13C), respectively, by using standard pulse sequences. Chemical shifts are reported as  values given downfield from tetramethylsilane (TMS), although the spectra were calibrated against the 1H signal of residual DMSO-d5 and 13C signal of the solvent as internal references (H = 2.50 ppm and C = 39.52 ppm, respectively).52,53 All NMR spectra were processed with the TopSpin 4.0.5 program;54 their copies are presented in SI. Prior to Fourier transformation, the collected FID’s were zero-filled to 128, 256 or even 512K data points to enhance the digital resolution of the spectra. The splitting patterns are presented as follows: br = broad, m = multiplet, p = pseudo, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, and so on. Coupling constants, JHHs, in hertz (Hz) are quoted as obtained from first-order analysis. In turn, the figures in parentheses following C data refer to the number of directly attached hydrogens (13) as revealed by the DEPT technique. An extra [2C] annotation means the double-intensity signals due to a double amount of such 13C nuclei. All diastereomeric mixtures afforded two sets of the 1H signals from major and minor components, the relative intensities of which indicated diastereomer ratios. In some instances, NMR signals were assigned with the help of 2D experiments (COSY, HMQC and HMBC); for details see the NMR Data Analysis section of SI. These assignments were fully confirmed by deuterium isotope effects of type nC(D) observed for some 13C nuclei in proximity to the NH proton of 3a.53,55 Infrared (IR) spectra were taken in KBr disks on a Thermo Nicolet Nexus FT-IR spectrometer; absorption frequencies are given in cm1. Low-resolution electron impact mass spectra (EI MS) were recorded on a Finnigan MAT 95 double-focusing magnetic sector spectrometer at 70 eV ionization energy. Ion mass-to-charge (m/z) ratios are reported as values in atomic mass units; selected peaks are given only. Melting points (mp's) were determined on a Boëtius microscope hot stage and are 18

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uncorrected. The analyses were carried out on a Vario EL III instrument (Elementar Analysensysteme GmbH). Synthesis of Substrates. All 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones (1a-c) were prepared in 0.01 mol scale from the corresponding amides, according to the previously used procedure.3e 3-Hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1a). Colorless solid (2.15 g, 95% yield): mp 171–172 oC (from methanol) [lit.56 mp 167–168 oC (hexane-CHCl3)]. IR (KBr, cm1): 1693 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.82-7.77 (m, 3H, 2,6-PhH & IsoindH), 7.72 (td, J = 7.3, 1.0 Hz, 1H, IsoindH), 7.695 (d, J = 7.3 Hz, 1H, IsoindH), 7.61 (td, J = 7.3, 1.0 Hz, 1H, IsoindH), 7.455 (pt, J = 7.9 Hz, 2H, 3,5-PhH), 7.23 (pt, J = 7.4 Hz, 1H, 4-PhH), 6.88 (d, J = 10.0 Hz, 1H, exchangeable with D2O, C3-OH), 6.545 (d, J = 10.0 Hz, 1H, C3-H). 13C{1H} NMR (150 MHz, DMSO-d6): 165.5, 144.4, 137.5, 132.8 (1), 131.3, 129.7 (1), 128.7 (1)[2C], 124.7 (1), 123.7 (1), 122.9 (1), 122.4 (1)[2C], 82.0 (1). 3-Hydroxy-4,5,6-trimethoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1b). Colorless solid (2.21 g, 70% yield): mp 128–130 oC (EtOAc/hexane, 1/1 v/v). IR (KBr, cm1): 1674 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.78 (pd, J = 7.6 Hz, 2H, 2,6-PhH), 7.43 (pt, J = 8.0 Hz, 2H, 3,5-PhH), 7.20 (pt, J = 7.4 Hz, 1H, 4-PhH), 7.12 (s, 1H, C7-H), 6.77 (d, J = 10.4 Hz, 1H, exchangeable, C3-OH), 6.63 (d, J = 10.4 Hz, 1H, C3-H), 4.02 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.80 (s, 3H, OCH3). 13C{1H} NMR (150 MHz, DMSO-d6): 165.0, 155.3, 149.2, 144.6, 137.5, 128.7 [2C], 127.3, 127.3, 124.6, 122.1 [2C], 101.25, 80.6, 60.6, 60.25, 56.4. Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43; N, 4.44%; Found: C, 64.74; H, 5.49; N, 4.29%. 3-Hydroxy-4,5,6-trimethoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one (1c). Colorless solid (1.80 g, 52% yield): mp 142–144 oC (EtOAc/hexane, 8/2 v/v) [lit.3e 142–144 oC]. IR (KBr, cm1): 1676 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.60 (pd, J = 9.1 Hz, 2H, ArH), 7.10 (s, 1H, C7-H), 7.00 (pd, J = 9.1 Hz, 2H, ArH), 6.70 (d, J = 10.3 Hz, 1H, exchangeable, C3-OH), 6.49 (d, J = 10.3 Hz, 1H, C3-H), 4.00 (s, 3H, OCH3), 3.89 (br s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.77 (s, 3H, OCH3). 13 C{1H} NMR (150 MHz, DMSO-d6): 164.8, 156.6, 155.2, 149.2, 144.4, 130.3, 127.45, 127.25, 124.5 [2C], 113.9 [2C], 101.2, 81.0, 60.6, 60.2, 56.35, 55.3. General Procedure for the Reaction of Isoindol-1-ones with sec-Butyllithium. To a vigorously stirred solution of appropriate compound 1 (3.0 mmol) and TMEDA (7.0 mmol) in THF (70 mL) s-BuLi (7.0 mmol) was added at 78 oC. The solution was kept at 78 oC for 1.5 h, treated with chlorotrimethylsilane57 (7.0 mmol), stirred for 10 min and allowed to come to rt over 0.5 h. In three cases (Table 1, entries 1, 4 and 5) after this time, the reaction mixture was quenched by addition of water (20 mL). In two other cases (Table 1, entries 2 and 3) water was added after 24.5 and 96.5 hrs, respectively. The mixture was adjusted to pH ~2 with concd hydrochloric acid, and then the organic layer was separated. The aqueous phase was extracted with a mixture of CHCl3 and THF (1/1 v/v) (3  20 mL). The combined organic solutions were concentrated under reduced pressure after drying over MgSO4. The residue was separated on a silica gel column. Colorless products 2 and 3 were thus isolated as inseparable mixtures of their two diastereomers. Reaction of 3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1a) (Table 1, entry 1). TLC (CHCl3) of the organic layer indicated the presence of two components (Rf = 0.15 and 0.03). The firsteluted fraction (Rf = 0.15) was identified as a 2.1:1 diastereomeric mixture of 3-sec-butyl-2-phenyl-2,3dihydro-1H-isoindol-1-one (2a) (0.60 g, 75%): mp 142–144 oC (hexane) [lit.3e 142–144 oC (hexane)]. IR (KBr, cm1): 1680 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.81 [pd, J = 7.6 Hz, 0.3H, IsoindH (minor)], 7.79 [pd, J = 7.6 Hz, 0.7H, IsoindH (major)], 7.70–7.59 (m, 4.0H, 2  IsoindH & ArH), 7.59– 7.54 (m, 1.0H, IsoindH), 7.50–7.44 (m, 2.0H, ArH), 7.28–7.24 (m, 1.0H, 4-ArH), 5.56 [d, J = 3.2 Hz, 0.3H, C3-H (minor)], 5.22 [d, J = 2.7 Hz, 0.6H, C3-H (major)], 1.95–1.87 [m, 0.7H, CHCH3 (major)], 19

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1.87–1.81 [m, 0.3H, CHCH3 (minor)], 1.78–1.70 [m, 0.3H, CH2CH3 (minor)], 1.48–1.40 [m, 0.3H, CH2CH3 (minor)], 1.02 [d, J = 7.1 Hz, 2.0H, CHCH3 (major)], 0.99–0.91 [t, J = 7.4 Hz & m, 1.7H, CH2CH3 (minor) & CH2CH3 (major)], 0.60 [t, J = 7.4 Hz, 2.0H, CH2CH3 (major)], 0.44–0.35 [m, 0.7H, CH2CH3 (major)], 0.26 [d, J = 6.8 Hz, 1.0H, CHCH3 (minor)]. 13C{1H} NMR (150 MHz, DMSO-d6) major isomer: 166.4, 143.9, 137.5, 132.2, 132.0 (1), 128.9 (1)[2C], 128.4 (1), 125.55 (1), 124.35 (1)[2C], 123.5 (1), 123.3 (1), 64.8 (1), 36.3 (1), 23.1 (2), 15.0 (3), 11.7 (3); minor isomer: 166.2, 142.9, 137.1, 132.7, 131.9 (1), 129.0 (1)[2C], 128.5 (1), 125.4 (1), 123.9 (1)[2C], 123.7 (1), 123.4 (1), 63.7 5 (1), 35.7 (1), 25.7 (2), 12.3 (3), 12.1 (3). The second-eluted fraction (Rf = 0.03) turned out to be starting material 1a (0.12 g, 18%). Reaction of 3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1a) (Table 1, entries 2 and 3). TLC (CHCl3) of the organic layer indicated the presence of three components (Rf = 0.20, 0.15 and 0.03). The first-eluted fraction (Rf = 0.20) was identified as a 1.4:1 diastereomeric mixture of 2-ethyl-2-methyl3-phenylaminoindan-1-one (3a) (0.30 g, 38% - Table 1, entry 2; 0.32 g, 40% - entry 3): mp 95–96 oC (hexane). IR (KBr, cm1): 3383 (R1R2NH), 1705 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.76–7.71 (m, 1.0H, C5-H), 7.70–7.67 (dd, J = 7.7, 7.6 Hz, 0.95H, C7-H), 7.64–7.60 (dd, J = 9.0, 8.1 Hz, 1.0H, C4H), 7.54–7.50 (dt, J = 7.2, 6.9 Hz, 1.0H, C6-H), 7.14–7.09 (m, 2.0H, PhH), 6.86 [pd, 1.2H, J = 7.9 Hz, PhH (major)], 6.83 [pd, 0.8H, J = 7.9 Hz, PhH (minor)], 6.60–6.56 (m, 1.0H, 4-PhH), 6.07 [d, J = 10.1 Hz, 0.5H, C3-NH (major)], 5.98 [d, J = 10.4 Hz, 0.3H, C3-NH (minor)], 5.15 [d, J = 10.3 Hz, 0.4H, C3H (minor)], 5.12 [d, J = 10.0 Hz, 0.6H, C3-H (major)], 1.78–1.72 [m, 0.4H, CH2CH3 (minor)], 1.65–1.58 [m, 0.4H, CH2CH3 (minor)], 1.54–1.47 [m, 0.6H, CH2CH3 (major)], 1.40–1.34 [m, 0.6H, CH2CH3 (major)], 1.28 [s, 1.8H, C2-CH3 (major)], 0.99 [s, 1.2H, C2-CH3 (minor)], 0.82 [t, J = 7.5 Hz, 1.3H, CH2CH3 (minor)], 0.73 [t, J = 7.5 Hz, 1.8H, CH2CH3 (major)]. 13C{1H} NMR (150 MHz, DMSO-d6) major isomer: 207.3, 153.2, 148.9, 134.9 (1), 134.7, 129.0 (1)[2C], 128.65 (1), 125.8 (1), 122.7 (1), 116.1 (1), 112.35 (1)[2C], 61.1 (1), 54.3, 27.1 (2), 20.85 (3), 8.6 (3); minor isomer: 208.7, 154.0, 148.9, 135.2 (1), 134.6, 129.0 (1)[2C], 128.8 (1), 126.5 (1), 122.7 (1), 116.2 (1), 112.4 (1)[2C], 57.5 (1), 54.3, 30.5 (2), 19.1 (3), 8.85 (3). For complete assignment of NMR signals, see Table S1. EI MS (70 eV, m/z): 265.1 (M+, 13.7%), 236.1 (100.0%), 173.1 (85.4%). Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28%; Found: C, 81.54; H, 7.20; N, 5.34%. The second-eluted fraction (Rf = 0.15) was identified as a diastereomeric mixture of 3-sec-butyl-2-phenyl-2,3-dihydro-1H-isoindol-1-one (2a) with spectral characteristics identical to those described above (0.21 g, 26% - Table 1, entry 2; 0.17 g, 21% - entry 3). The third-eluted fraction (Rf = 0.03) was found to be starting material 1a (0.13 g, 19% - Table 1, entry 2; 0.14 g, 21% - entry 3). Reaction of 3-hydroxy-4,5,6-trimethoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one (1b) (Table 1, entry 4). TLC (CHCl3/EtOAc, 95/5 v/v) of the organic layer indicated the presence of three components (Rf = 0.54, 0.25 and 0.09). The first-eluted fraction (Rf = 0.54) was identified as a 1.7:1 diastereomeric mixture of 2-ethyl-4,5,6-trimethoxy-2-methyl-3-phenylaminoindan-1-one (3b) (0.42 g, 39%): mp 176–178 oC (hexane/EtOAc, 8/2 v/v). IR (KBr, cm1): 3352 (R1R2NH), 1710 and 1702 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.11–7.06 (m, 2.0H, PhH), 7.01 (s, 1.0H, C7-H), 6.72 [pd, J = 8.0 Hz, 0.8H, PhH (minor)], 6.69 [pd, J =8.0 Hz, 1.3H, PhH (major), 6.54–6.50 (m, 1.0H, 4-PhH), 5.88 [d, J = ~8.7 Hz, 0.3H, C3-NH (minor)], 5.87 [d, J = ~9.2 Hz, 0.6H, C3-NH (major)], 4.97 [d, J = 9.6 Hz, 0.6H, C3-H (major)], 4.95 [d, J = 9.5 Hz, 0.4H, C3-H (minor)] 3.871 and 3.867 (two overlapping br s, 3.0H, OCH3), 3.83 [s, 1.9H, OCH3 (major)], 3.82 [s, 1.1H, OCH3, (minor)], 3.75 [s, 1.9H, OCH3 (major)], 3.68 [s, 1.1H, OCH3, (minor)], 1.71–1.62 [m, 0.6H, CH2CH3 (major)], 1.60–1.50 (m, 1.4H, CH2CH3 (major & 2  minor)], 1.21 [s, 1.1H, C2-CH3 (minor)], 1.00 [s, 1.9H, C2-CH3 (major)], 0.80 [t, J = 7.5 Hz, 1.1H, CH2CH3 (minor), 0.77 [t, J = 7.5 Hz, 1.9H, CH2CH3 (major). 13C{1H} NMR (150 MHz, DMSO-d6) major isomer: 207.9, 155.1, 150.7, 148.55, 147.9, 138.4, 130.6, 128.9 (1)[2C], 115.4 (1), 111.9 (1)[2C], 100.2 (1), 60.5 (3)[2C], 60.3 (3), 56.85 br m (1), 56.2 (3)[2C], 54.1, 32.0 (2), 17.6 (3), 8.9 (3); minor isomer: 207.5, 154.9, 150.8, 148.6, 147.95, 138.1, 130.2, 128.9 (1)[2C], 115.3 (1), 111.7 (1)[2C], 100.3 (1), 60.5 (3), 60.2 (3), 59.6 br m (1), 56.2 (3), 53.0, 26.1 (2), 22.9 (3), 8.9 (3). EI MS (70 20

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eV, m/z): 355.2 (M+, 16.7%), 326.1 (50.8%), 262.1 (100.0%). Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94%; Found: C, 70.99; H, 7.05; N, 4.01%. The second-eluted fraction (Rf = 0.25) was identified as a 1.7:1 diastereomeric mixture of 3-sec-butyl-5,6,7-trimethoxy-2-phenyl-2,3-dihydro-1Hisoindol-1-one (2b) (0.34 g, 32%): mp 115–117 oC (hexane), IR (KBr, cm1): 1680 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.58–7.55 [pd, J = 8.1 Hz, 0.80H, PhH (minor)], 7.54–7.51 [pd, J = 7.9 Hz, 1.25H, PhH (major)], 7.46–7.41 (m, 2.0H, PhH), 7.25–7.20 (m, 1.0H, 4-PhH), 6.97 [s, 0.6H, C4-H (major)], 6.88 [s, 0.4H, C4-H (minor)], 5.35 [d, J = 2.8 Hz, 0.4H, C3-H (minor)], 5.335 [d, J = 2.2 Hz, 0.6H, C3-H (major)], 3.952 [s, 1.1H, OCH3 (minor)], 3.948 [s, 1.8H, OCH3 (major)], 3.91 [s, 2.9H, OCH3 (both)], 3.755 [s, 1.1H, OCH3 (minor)], 3.750 [s, 1.8H, OCH3 (major)], 1.94–1.87 [m, 0.6H, CHCH3 (major)], 1.85–1.78 [m, 0.4H, CHCH3 (minor)], 1.70–1.62 [m, 0.4H, CH2CH3 (minor)], 1.43–1.35 [m, 0.4H, CH2CH3 (minor)], 1.06–0.98 [m, 0.65H, CH2CH3 (major)], 0.92 [t, J = 7.4 Hz, 1.2H CH2CH3 (minor)], 0.89 [d, J = 7.1 Hz, 1.9H, CHCH3 (major)], 0.66 [t, J = 7.4 Hz, 1.9H CH2CH3 (major)], 0.57– 0.48 [m, 0.6H, CH2CH3 (major)], 0.35 [d, J = 6.8 Hz, 1.1H, CHCH3 (minor)]. 13C{1H} NMR (150 MHz, DMSO-d6) major isomer: 164.7, 157.05, 150.9, 142.05, 141.25, 137.9, 128.7 [2C], 125.3, 124.7 [2C], 116.6, 102.2, 63.9, 62.2, 60.9, 56.3, 37.3, 24.0, 14.2, 11.8; minor isomer: 164.4, 156.9, 151.0, 141.4, 140.8, 137.4, 128.8 [2C], 125.0, 124.1 [2C], 117.1, 102.45, 63.25, 62.2, 60.9, 56.3, 36.3, 25.2, 12.4, 12.4. Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94%. Found: C, 70.93; H, 7.11; N, 3.91%. The thirdeluted fraction (Rf = 0.09) turned out to be starting material 1b (0.22 g, 23%). Reaction of 3-hydroxy-4,5,6-trimethoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one (1c) (Table 1, entry 5). TLC (CHCl3/EtOAc, 8/2 v/v) of the organic layer indicated the presence of three components (Rf = 0.64, 0.40 and 0.19). The first-eluted fraction (Rf = 0.64) was identified as a 2.4:1 diastereomeric mixture of 2-ethyl-4,5,6-trimethoxy-3-(4-methoxyphenylamino)-2-methylindan-1-one (3c); (0.45 g, 39%): mp 93–96 oC (CHCl3/EtOAc, 8/2 v/v). IR (KBr, cm1): 3352 (R1R2NH), 1711 (C=O). 1H NMR (600 MHz, DMSO-d6): 6.99 (two overlapping s, 1.0H, C7-H), 6.75–6.71 (m, 2.0H, ArH), 6.69–6.66 [m, 0.6H, ArH (minor)], 6.66–6.63 [m, 1.4H, ArH (major)], 5.48 [br d, J = 9.5 Hz, 0.9H, C3-NH (both)], 4.88 [d, J = 9.5 Hz, 0.7H, C3-H (major)], 4.85 [d, J = 9.4 Hz, 0.3H, C3-H (minor)], 3.865 and 3.861 (two partially overlapping s, 3.0H, OCH3), 3.825 [s, 2.1H, OCH3 (major)], 3.81 and [s, 0.9H, OCH3 (minor)], 3.76 [s, 2.1H, OCH3 (major)], 3.68 [s, 0.9H, OCH3 (minor)], 3.653 and 3.650 (two partially overlapping s, 2.9H, OCH3), 1.67–1.60 [m, 0.8H, CH2CH3 (major)], 1.57–1.50 [m, 1.3H, CH2CH3 (major & 2  minor)], 1.19 [s, 0.9H, C2-CH3 (minor)], 1.00 [s, 2.1H, C2-CH3 (major)], 0.80 [t, J = 7.5 Hz, 0.9H, CH2CH3 (minor)], 0.76 [t, J = 7.5 Hz, 2.1H, CH2CH3 (major)]. 13C{1H} NMR (150 MHz, DMSO-d6) major isomer: 208.1, 155.0, 150.7, 150.4, 147.8, 142.9, 138.6, 130.5, 114.6 (1)[2C], 112.8 (1)[2C], 100.1 (1), 60.5 (3), 60.3 (3), 57.8 (1)[2C], 56.1 (3), 55.3 (3)[2C], 54.2, 32.0 (2), 17.6 (3), 8.9 (3); minor isomer: 207.6, 154.9, 150.8, 150.3, 147.9, 142.9, 138.3, 130.15, 114.6 (1)[2C], 112.7 (1)[2C], 100.3 (1), 60.6 (3), 60.2 (3), 57.8 (1), 56.1 (3), 55.3 (3), 53.1, 26.2 (2), 22.8 (3), 8.9 (3). EI MS (70 eV, m/z): 385.2 (M+, 21.5%), 356.2 (12.6%), 263.1 (100.0%). Anal. Calcd for C22H27NO5: C, 68.55; H, 7.06; N, 3.63%; Found: C, 68.50; H, 7.00; N, 3.69%. The second-eluted fraction (Rf = 0.40) was identified as a 2.0:1 diastereomeric mixture of 3-sec-butyl-5,6,7-trimethoxy-2-(4-methoxyphenyl)2,3-dihydro-1H-isoindol-1-one (2c); (0.28 g, 24%): mp 109–111 oC (after GCC; eluent: CHCl3/EtOAc, 8/2 v/v). IR (KBr, cm1): 1679 (C=O). 1H NMR (600 MHz, DMSO-d6): 7.43 [pd, J = 8.9 Hz, 0.7H, ArH (minor)], 7.395 [pd, J = 8.9 Hz, 1.3H, ArH (major)], 7.00 and 6.99 (2  pd, J = ~8.7, 8.7 Hz, 2.0H, ArH), 6.96 [s, 0.7H, C4-H (major)], 6.87 [s, 0.3H, C4-H (minor)], 5.22 [br d, J = 2.8 Hz, 0.4H, C3-H (minor)], 5.21 [br d, J = 2.0 Hz, 0.6H, C3-H (major)], 3.955 and 3.951 (two overlapping s, 3.0H, OCH3), 3.90 (s, 3.0H, OCH3), 3.78 (s, 3.0H, OCH3), 3.755 [s, 1.0H, OCH3 (minor)], 3.75 [s, 1.9H, OCH3 (major)], 1.93– 1.85 [m, 0.7H, CHCH3 (major)], 1.82–1.74 [m, 0.3H, CHCH3 (minor)], 1.66–1.58 [m, 0.3H, CH2CH3 (minor)], 1.43–1.33 [m, 0.3H, CH2CH3 (minor)], 1.09–0.98 [m, 0.7H, CH2CH3 (major)], 0.90 [t, J = 7.4 Hz, 1.0H CH2CH3 (minor)], 0.86 [d, J = 7.0 Hz, 2.1H, CHCH3 (major)], 0.68 [t, J = 7.3 Hz, 2.1H CH2CH3 (major)], 0.60–0.51 [m, 0.7H, CH2CH3 (major)], 0.37 [d, J = 6.8 Hz, 1.0H, CHCH3 (minor)]. 13 C{1H} NMR (150 MHz, DMSO-d6) major isomer: 164.8, 156.9 br, 156.8, 150.8, 142.1, 141.2 br, 21

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130.75, 126.4 (1)[2C], 116.7, 113.9 (1)[2C], 102.1 (1), 64.2 (1), 62.15 (3), 60.85 (3), 56.3 (3), 55.2 (3), 37.35 (1), 24.1 (2), 14.0 (3), 11.8 (3); minor isomer: 164.4, 156.7 br, 156.65, 150.9, 141.3 br, 140.8, 130.2, 125.9 (1)[2C], 117.2, 114.0 (1)[2C], 102.4 (1), 63.7 (1), 62.2 (3), 60.9 (3), 56.3 (3), 55.2 (3), 36.3 (1), 25.05 (2), 12.5 (3), 12.3 (3). Anal. Calcd for C22H27NO5: C, 68.55; H, 7.06; N, 3.63%; Found: C, 68.51; H, 7.09; N, 3.59%. The third-eluted fraction (Rf = 0.19) was found to be starting material 1c (0.33 g, 32%).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxxxx Copies of 1H, 13C and some 2D NMR spectra, complete signal assignments for 3a, calculation details and results (including NPA and QTAIM data) with discussion, a series of additional calculations carried out within the conceptual DFT framework, Cartesian coordinates, energy data and vibrational frequencies for the MP2- optimized geometries of all the studied systems  Schemes S1-S5, Tables S1-S7 and Figures S1-S24 (PDF).

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Magdalena Ciechańska: 0000-0001-6510-1716 Andrzej Jóźwiak: 0000-0001-7314-904X Ryszard B. Nazarski: 0000-0001-5063-3912 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS R.B.N. gratefully thanks to Dr. Jasper Adamson (NICPB, Tallinn, Estonia) for improving the English style and to Dr. Piotr Matczak (University of Lodz) for helpful discussion on an early draft of this article and his suggestion to use the concept of reactivity indices. This work was supported in part by Grant-in-Aid for Scientific Research from the University of Lodz within the Faculty grant 'Basic research'. This research was also supported by the computer facilities of the ACC Cyfronet (AGH University of Science and Technology, Kraków, Poland) within the PL-Grid Infrastructure (the Prometheus supercomputer)  all computational grants to R.B.N.

DEDICATION Dedicated to the memory of Professor Romuald M. Skowroński (19262013).

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REFERENCES (1) See, e.g., (a) Manoharan, R.; Jeganmohan, M. Synthesis of isoindolinones via a rutheniumcatalyzed cyclization of N-substituted benzamides with allylic alcohols. Chem. Commun. 2015, 51, 2929–2932. (b) Meng, J.-L.; Jiao, T.-Q.; Chen, Y.-H.; Fu, R.; Zhang, S.-S.; Zhao, Q.; Feng, C.-G.; Lin, G.-Q. Synthesis of chiral isoindolinones via asymmetric propargylation/lactamization cascade. Tetrahedron Lett. 2018, 59, 1564–1567. (c) Zhang, Y.; He, L.; Shi, L. Asymmetric hydrogenolysis of racemic 3-substitued-3-hydroxyisoindolin-1-ones employing SPINOL-derived chiral phosphoric acid. Tetrahedron Lett. 2018, 59, 1592–1595. (d) Wang, Q.; Shi, P.; Zeng, R. Copper(I) reagentpromoted hydroxytrifluoromethylation of enamides: flexible synthesis of substituted-3-hydroxy-2aryl-3-(2,2,2-trifluoro-1-arylethyl)isoindolin-1-one. RSC Adv. 2018, 8, 25961–25965. (2) (a) Takahashi, I.; Hatanaka, M. Recent Progress of Phthalimidine Syntheses. Heterocycles 1997, 45, 2475–2499. (b) Hardcastle, I. R.; Liu, J.; Valeur, E.; Watson, A.; Ahmed, S. U.; Blackburn, T. J.; Bennaceur, K.; Clegg, W.; Drummond, C.; Endicott, J. A.; Golding, B. T.; Griffin, R. J.; Gruber, J.; Haggerty, K.; Harrington, R. W.; Hutton, C.; Kemp, S.; Lu, X.; McDonnell, J. M.; Newell, D. R.; Noble, M. E. M.; Payne, S. L.; Revill, C. H.; Riedinger, C.; Xu, Q.; Lunec, J.; Lunec, J. Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: StructureActivity Studies Leading to Improved Potency. J. Med. Chem. 2011, 54, 1233–1243. (c) Mondal, C.; Halder, A. K.; Adhikari, N.; Saha, A.; Saha, K. D.; Gayen, S.; Jha, T. Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. Eur. J. Med. Chem. 2015, 90, 860–875. (d) Grigoreva, T. A.; Novikova, D. S.; Petukhov, A. V.; Gureev, M. A.; Garabadzhiu, A. V.; Melino, G.; Barlev, N. A.; Tribulovich, V. G.; Proapoptotic modification of substituted isoindolinones as MDM2-p53 inhibitors. Bioorg. Med. Chem. Lett. 2017, 27, 5197– 5202. (3) (a) Ismail, M. F.; Enayat, E. I.; El-Bassiouny, F. A. A.; Younes, H. A. Reactions of 2,3-Diaryl-3hydroxyphthalimidines with Grignard Reagents and Hydrazine Hydrate. Gazz. Chim. Ital. 1990, 120, 677–678. (b) Metallinos, C.; Nerdinger, S.; Snieckus, V. N-Cumyl Benzamide, Sulfonamide, and Aryl O-Carbamate Directed Metalation Groups. Mild Hydrolytic Lability for Facile Manipulation of Directed Ortho Metalation Derived Aromatics. Org. Lett. 1999, 1, 1183–1186. (c) Ciechańska, M.; Jóźwiak, A.; Ścianowski, J. Synthesis of Selenium Derivatives of 3-Hydroxy-2substituted-2,3-dihydroisoindol-1-ones. Phosphorus, Sulfur, and Silicon 2009, 184, 1502–1507. (d) Achmatowicz, M.; Thiel, O. R.; Wheeler, P.; Bernard, C.; Huang, J.; Larsen, R. D.; Faul, M. M. Practical Synthesis of a p38 MAP Kinase Inhibitor. J. Org Chem. 2009, 74, 795–809. (e) Jóźwiak, A.; Ciechańska, M. The Behavior of 2-Substituted-3-hydroxyisoindolinones in the Reaction with sec-Butyllithium. J. Heterocycl. Chem. 2014, 51, 357–362. (4) (a) Bauer, W.; Winchester, W. R.; Schleyer, P. v. R. Monomeric Organolithium Compounds in Tetrahydrofuran: tert-Butyllithium, sec-Butyllithium, “Supermesityllithium”, Mesityllithium, and Phenyllithium. Carbon-Lithium Coupling Constants and the Nature of Carbon-Lithium Bonding. Organometallics 1987, 6, 2371–2379. (b) Snieckus, V. Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics. Chem. Rev. 1990, 90, 879–933. (c) Moene, W.; Vos, M.; Schakel, M.; de Kanter, F. J. J.; Schmitz, R. F.; Klumpp, G. W. Reactivity of Ether- and Amine-Complexed Dimers and Tetramers of Alkyllithiums towards Triphenylmethane. Chem. - Eur. J. 2000, 6, 225–236. (d) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions. Angew. Chem. Int. Ed. 2004, 43, 2206–2225. (e) Chadwick, S. T.; Ramirez, A.; Gupta, L.; Collum, D. B. n-Butyllithium/N,N,N′,N′Tetramethylethylenediamine-Mediated Ortholithiations of Aryl Oxazolines: Substrate-Dependent Mechanisms. J. Am. Chem. Soc. 2007, 129, 2259−2268. (5) See e.g., (a) Dallemagne, P.; Rault, S.; Pilo, J. C.; Foloppe, M. P.; Robba, M. One-Pot Cyclization of Alkoxy-3-Aminoindan-1-ones. Tetrahedron Lett. 1991, 32, 6327−6328. (b) Wu, Y-J. Michael 23

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(39) (a) Harvey, J. D.; Ziegler, C. J. Developments in the metal chemistry of N-confused porphyrin. Coord. Chem. Rev. 2003, 247, 1–19. (b) Toganoh, M.; Furuta, H. Blooming of confused porphyrinoids—fusion, expansion, contraction, and more confusion. Chem. Commun. 2012, 48, 937–954. (40) Mackert, P. J.; Hafner, K.; Nimmerfroh, N.; Banert, K. Synthesis, Structure and Reactivity of Cyclopenta-annulated 1,2,3,4-Tetrazines. Chem. Ber. 1994, 127, 1479–1488. (41) (a) Kuipers, W.; Kanters, J. A.; Schouten, A. Structure of 1,4-Phenylenebis(3,3diphenylketenimine). Acta Cryst., Sect. C 1989, 45, 482–485. (b) Wolf, R.; Stadtmüller, S.; Wong, M. W.; Barbieux-Flammang, M.; Flammang, R.; Wentrup, C. Novel Heterocumulenes: Bisiminopropadienes and Linear Ketenimines. J. Am. Chem. Soc. 1995, 117, 6789–6790. (42) (a) Simm, G. N.; Reiher, M. Systematic Error Estimation for Chemical Reaction Energies. J. Chem. Theory Comput. 2016, 12, 2762−2773. (b) Dandu, N. K.; Reed, J. A.; Odoh, S. O. Performance of Density Functional Theory for Predicting Methane-to-Methanol Conversion by a Tri-Copper Complex. J. Phys. Chem. C 2018, 122, 1024−1036. (c) Simm, G. N.; Reiher, M. Error-Controlled Exploration of Chemical Reaction Networks with Gaussian Processes. J. Chem. Theory Comput. 2018, 14, 5238−5248. (43) Burk, P.; Sillar, K.; Koppel, I. A. Gas-phase basicities and proton affinities of alkali metal oxides and hydroxides. A theoretical study. J. Mol. Struct.: THEOCHEM 2001, 543, 223–231. (44) (a) Shibasaki, M.; Kanai, M.; Matsunaga, S. Chiral, Poly(Rare-Earth Metal) Complexes in Asymmetric Catalysis. Aldrichim. Acta 2006, 39, 31–39. (b) Linghu, X.; Wong, N.; Iding, H.; Jost, V.; Zhang, H.; Koenig, S. G.; Sowell, C. G.; Gosselin, F. Development of a Practical Synthesis of ERK Inhibitor GDC-0994. Org. Process Res. Dev. 2017, 21, 387−398. (45) See, e.g., (a) Pugh, J. K.; Streitwieser, A. The CN Rotation Barrier of the Lithium Enolate of Acetamide: An ab Initio and Density Functional Theory Investigation. J. Org. Chem. 2001, 66, 1334–1338. (b) Ryu, I.; Maddaluno, J. Aspects of the synthesis, structure and reactivity of lithium enolates in The chemistry of organolithium compounds: R-Li, Rappoport, Z.; Marek, I. Eds.; John Wiley & Sons, Ltd.: Chichester, 2006; Vol. 2, pp 525–646. (c) Pandit, S.; De, D.; De, B. R. The Li+ affinities of a series of substituted crotonaldehyde in the ground state: A DFT study. J. Mol. Struct.: THEOCHEM 2007, 819, 160–162. (46) (a) Mujika, J. I.; Matxain, J. M.; Eriksson, L. A.; Lopez X. Resonance Structures of the Amide Bond: The Advantages of Planarity. Chem. - Eur. J. 2006, 12, 7215–7224. (b) Glover, S. A.; Rosser, A. A. Reliable Determination of Amidicity in Acyclic Amides and Lactams. J. Org. Chem. 2012, 77, 5492−5502 and references therein. (47) Certain differences were found in the NPA values of natural charge calculated with two versions of the NBO program, see Table S1. For instance, atomic charges for Li7 in species 5a, 5d and 5b are decreasing and increasing according to the 3.1 and 6.0 version of NBO, respectively. The comparison with related QTAIM charges is not fully univocal, but the decreasing trend is rather reproduced. (48) (a) Lavallo, V.; Mafhouz, J.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Synthesis, Reactivity, and Ligand Properties of a Stable Alkyl Carbene. J. Am. Chem. Soc. 2004, 126, 8670– 8671. (b) Schuster, O.; Yang, L.; Raubenheimer, H. G.; Albrecht, M. Beyond Conventional NHeterocyclic Carbenes: Abnormal, Remote, and Other Classes of NHC Ligands with Reduced Heteroatom Stabilization. Chem. Rev. 2009, 109, 3445–3478. (49) Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Cyclopropenylidenes: From Interstellar Space to an Isolated Derivative in the Laboratory. Science 2006, 312 (5774), 722–724. (50) Johnson, L. E.; DuPré, D. B. Mechanism of the Electronic Stabilization of the 3MR and Divalent Carbon of Bis(diisopropylamino)cyclopropenylidene. J. Phys. Chem. A 2007, 111, 11066–11073. (51) Gilman, H.; Cartledge, F. K. The Analysis of Organolithium Compounds. J. Organomet. Chem. 1964, 2, 447–454. 29

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(52) (a) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29, 2176–2179. (b) Babij, N. R.; McCusker, E. O.; Whiteker, G. T.; Canturk, B.; Choy, N.; Creemer, L. C.; De Amicis, C. V.; Hewlett, N. M.; Johnson, P. L.; Knobelsdorf, J. A.; Li, F.; Lorsbach, B. A.; Nugent, B. M.; Ryan, S. J.; Smith, M. R.; Yang, Q. NMR Chemical Shifts of Trace Impurities: Industrially Preferred Solvents Used in Process and Green Chemistry. Org. Process Res. Dev. 2016, 20, 661−667. (c) NMR Solvent Data Chart  Cambridge Isotope Laboratories, Inc., Andover, MA 01810 USA; http://www2.chem.umd.edu/nmr/reference/isotope_solvent.pdf (accessed Feb 10, 2019). (53) 1H NMR signals of residual H2O52 and, occasionally, of HOD52c (due to partial H/D exchange of NH protons in the samples under analysis) were also found at 3.33  0.03 and 3.28 ppm, respectively. In the latter case, DMSO-d6 used had to contain traces of residual D2O. As a result, minor amounts of NH/D-exchanged coproducts (3a, in particular) were formed in this way; for details on four NH/ND isomeric species of 3a, see Figure S9. The 13C NMR spectrum of the same solution of 3a revealed the presence of two incomplete series of weak resonance lines showing small deuterium-induced isotope effects on 13C chemical shifts [up to 2C(D) = 0.069 ppm for Cipso in the major diastereomer (Table S1)],55 which were attributed to both ND isotopomers of this amino ketone. Analogous 13C NMR lines of the OD isotopomers originating from some alcohols ROH were reported recently.52b (54) TopSpin 4.0.5 (version of August 08, 2018) - The Next Generation in NMR Software, 2018 Bruker, BioSpin GmbH. (55) The notation applied is in accordance with: Hansen, P. E. Isotope effects in nuclear shielding, Prog. NMR Spectrosc. 1988, 20, 207–255. (56) Mali, R. S.; Yeola, S. N. A Novel Synthesis of N-Substituted-3-carboethoxymethylphthalimidines. Synthesis, 1986, 755–757. (57) Chlorotrimethylsilane was used as a detector for the possible ortho-metalation reaction.58 However, in no case was this process observed. This application of (CH3)3SiCl did not change the distribution of products 2 and 3 in relation to analogous experiments carried out without its use. (58) (a) West, R.; Jones, P. C. Polylithiation. II. Polylithiation of Toluene and the Formation of Poly(trimethylsilyl)toluenes. J. Am. Chem. Soc. 1968, 90, 2656–2661. (b) Wakefield, B. J. The Chemistry of Organolithium Compounds, Pergamon Press: Oxford, 1974, pp 260–264 and references therein.

Table of Contents / Graphic Abstract O

O R N Ar R R

OH

(1) s-BuLi / TMEDA, THF, 78oC to rt

.

(2) 2698 hrs at rt loss of LiOH (route A or B) R = H or OMe

Li

N

O H2O

H

H+

Ar

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H

N H

Ar