Enantiopure Methyl- and Phenyllithium: Mixed (Carb-)Anionic Anisyl

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

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Enantiopure Methyl- and Phenyllithium: Mixed (Carb-)Anionic Anisyl Fencholate-Aggregates Vanessa Grote, Jörg-Martin Neudörfl, and Bernd Goldfuss* Department of Chemistry, University of Cologne, Greinstrasse 4−6, 50939 Cologne, Germany

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S Supporting Information *

ABSTRACT: Methyl- and phenyllithium aggregates with enantiopure anisyl fencholate units form after reaction of organolithium reagent with (+)-anisyl fenchol in hydrocarbon and some ethereal solvents. These carbanionic aggregates are characterized by X-ray crystal analyses and exhibit both 3:1 stoichiometry and distorted cubic Li4O3C1 cores, in which three lithium ions coordinate the carbanion (i.e., methylide or phenylide). These three lithium ions define a Lewis acidic surface (Li3), binding the carbanion and expanding with the steric demand of the carbanion (i.e., from Me: 2.62 Å2, over n-Bu: 2.65 Å2 (previous work) to Ph: 2.79 Å2). Methylation and phenylation reactions of various prochiral aldehydes employing these methyllithium and phenyllithium aggregates yield alcohols with up to 44% ee. To rationalize the formation of the mixed (carb-)anionic aggregates, aggregate formation energies, describing co-condensations of RLi (R = Me, Ph, n-Bu) and lithium fencholates, are computed for the 3:1 and 2:2 stoichiometries. These computed aggregate formation energies point to preferences for 3:1 over 2:2 aggregates, as it is also apparent from experimental aggregate formations, confirmed by X-ray crystal analyses. In close analogy to the X-ray crystal structures, the computed Li3 surfaces increase with increasing steric demand of the carbanions. The chiral, mixed (carb-)anionic RLi-fencholate aggregates hence adapt to different carbanion sized and arise not only with small (Me) or primary carbanions (n-Bu) but even with the larger secondary phenyl anion.

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INTRODUCTION

mediators, even catalytic, enantioselective RLi-additions were reported.22 A variety of enantiopure fenchols (1a−f) and n-BuLi form spontaneously mixed (carb-)anionic aggregates (3−10, Figure 1). Compositions of these chiral carbanionic aggregates do not arise from the stoichiometries of the reactants, but they are inherently controlled by the structures of the fencholate-units, yielding mixed anionic aggregates of 3:1,5,10 2:2,9,19 or 4:29 compositions (Figure 1). Steric effects of the fencholate units were found to compete with electrostatic interactions in cubic Li4O3C1 versus Li4O2C2 cores.9 Lithiation of N,N-dimethylamino benzyl fenchol (1g) with nBuLi yields pure dimer 1119 without carbanion incorporation (Figure 1).23 However, n-BuLi-lithiations of anisyl- (1b) or phenyl fenchol (1a), form lithium fencholates (2b, 2a), which do not yield the corresponding pure lithium alkoxides but aggregate with n-BuLi and form mixed (carb-)anionic aggregates 810 and 7,5 both with 3:1 composition (Figure 1). In n-BuLi lithium anisyl fencholate 8,10 three lithium ions coordinate the n-butylide ion. Methoxy groups coordinate these lithium cations, while the diagonally situated lithium ion is partially “naked” and has only contacts to the three oxide ions of the Li4O3C1 core in 8.10 The formation of 7 shows that the coordinating ortho-OMe function (i.e., X = H (1a)) instead of OMe (1b, Figure 1) is dispensable for the spontaneous self-

Organolithium compounds are frequently used in organic syntheses as strong bases for lithiations1 and as powerful nucleophiles for C−C bond formations.2 Despite the fact that nbutyllithium (n-BuLi) and other organolithium compounds are extensively employed reagents, comparatively few chirally modified organolithium complexes have been structurally characterized.3,4 Structural analyses of enantiopure n-BuLi aggregates in solution4−7 and in the solid state5,6,8−10 can provide explanations for reactivities and selectivities.11 Structural elucidations of these aggregates can also be crucial for a more rational design of new and more efficient chiral organolithium compounds for asymmetric syntheses.12 Stalke’s group has reported solid-state structures of n-BuLi and MeLi;13 structures of methyllithium (MeLi)414 and phenyllithium (PhLi)415 without coordinating solvents are also known. Strohmann et al. analyzed MeLi and PhLi complexes with (−)-sparteine, forming structures with 2:2 or 4:2 compositions.16 The synthesis of efavirenz,17 a reverse transcriptase inhibitor of the HI-virus,6,18 provides a prominent example for an application of a mixed (carb-)anionic pseudoephedrine aggregate. Here, chirally modified carbanions enable enantioselective alkylations of prochiral electrophiles (e.g., aldehydes).9,19 Hilmersson’s group performed enantioselective alkylations with MeLi, n-BuLi, and PhLi at −116 °C, with up to 98% ee.20 Williard et al. reported ee’s up to 83% for n-BuLi with pivaldehyde.21 Besides stoichiometric employments of chiral © XXXX American Chemical Society

Received: October 7, 2018

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DOI: 10.1021/acs.organomet.8b00724 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

two “naked” lithium cations in the Li4O2C2 cores next to the carbanionic n-butylide groups. These two lithium cations therefore engage in Li−H−C-agostic interactions with αCHunits of the n-butylide moieties (3, 4, or 5,9,19 Figure 1). This different coordination mode (i.e., nonagostic vs agostic) of the n-butylide-anion is apparent in 2:2 versus 3:1 mixed (carb-)anionic fencholate aggregates. Enantioselectivities of nbutylide additions to benzaldehyde are higher for the 2:2 aggregates than for the 3:1 aggregates (i.e., for 2:2-aggregate 4 with up to 76% ee versus 3:1-aggregate 8 with up to 14% ee).9 NMR studies of 3, 4, and 7 (Figure 1) show that their solid-state structures (based on X-ray analyses) of mixed 2:2 n-butylide fencholate aggregates also appear in toluene solution.5 The surprising formation of the mixed n-butylide aggregate 6, now with a unique 2:4 composition, demonstrates that the stoichiometric variability of mixed (carb-)anionic fencholates can exceed the more frequently observed 3:1 or 2:2 aggregates (Figure 1). In this work, we now introduce methylide and phenylide as new carbanionic components in enantiopure lithium fencholates.

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RESULTS AND DISCUSSION

Syntheses and Structural Characterizations of 9 and 10 (Figure 1). Mixed anionic (+)-(1S,2S,4R)-anisyl fencholate MeLi aggregate (9, Figure 2) and anisyl fencholate PhLi aggregate (10, Figure 3) both form after reaction of (+)-fenchone based fenchol (1S,2S,4R)-anisyl fenchol (2b, Figure 1) with methyllithium or phenyllithium and subsequent spontaneous self-aggregation. X-ray analyses of single crystals

Figure 1. Mixed (carb-)anionic aggregate formation of hitherto described (3−8)5,9,10,12 and new (this work: 9, 10) organolithium aggregates, composed of organolithiums n-BuLi, MeLi, or PhLi and fencholates 2a−g in 2:2, 2:4 or 3:1 stoichiometry. Only lithium fencholate 2g23 forms noncarbanionic dimer 11.19

aggregation to a mixed (carb-)anionic fencholate aggregate with n-BuLi.5 The introduction of bulky substituents (i.e., t-Bu or silyl groups in 1d, 1e, or 1f; Figure 1) leads after reaction with n-BuLi to mixed anionic aggregates of 2:2 composition (3, 4, or 5, Figure 1).9,19 Computations show that interfencholate repulsions of bulky-substituted fencholates intrinsically favor such 2:2 compositions over the parent 3:1 stoichiometries in mixed (carb-)anionic aggregates.9 In contrast to 3:1 aggregates, X-raycrystal structure analyses shown that the 2:2 complexes exhibit

Figure 2. X-ray crystal structure of the MeLi mixed (carb-)anionic aggregate 9 (ORTEP 3).24 Hydrogen atoms have been omitted for clarity, with exception of those attached to the carbanion CH3 (F2 = 1.036, R = 0.0429, the Li3 Lewis acidic surface is 2.62 Å2). B


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Organometallics

Table 1. Selected Distances (Å), Areas (Å2), and Angles (deg) Taken from X-ray Crystal Structures of Mixed (Carb-)Anionic Aggregates 8,9,10 9, and 10 (Figure 1) atoms Li1−C1 Li2−C1 Li3−C1 Ø Li1−O4 Li2−O6 Li3−O2 Ø Li1−O3(Me) Li2−O5(Me) Li3−O1(Me) Ø Li4−C1d Lewis acidic surface area (Li1−Li2−Li3)e torsion angles θ(MeO−Ar)e −19.4 −19.7 −32.6 Ø −23.9 torsion angles φ(Fen−Ar)e 51.2 49.5 46.6 Ø 49.1

89,10,a 2.211 2.225 2.195 2.210 1.992 1.958 2.005 1.985 1.987 1.982 2.025 1.998 3.708 2.65

9b

2.242 2.233 2.234 2.236 1.916 1.972 1.976 1.955 1.963 1.987 1.985 1.978 3.761 2.62 22.7 24.0 21.0 22.6 −49.5 −50.9 −51.0 −50.5

10c 2.315 2.295 2.328 2.313 1.925 1.926 1.923 1.925 2.007 1.976 2.036 2.006 3.806 2.79 14.8 23.3 32.6 23.6 −51.7 −46.1 −51.9 −49.9

a

n-BuLi aggregate (8), based on (−)-fenchone; CCDC 1295527.10 MeLi aggregate (9), based on (+)-fenchone; CCDC 1858793;25 Figure 2. cPhLi aggregate (10), based on (+)-fenchone; CCDC 1858794;25 Figure 3. dSpace diagonal of the cubic center. eSee also Figure 4. b

Figure 3. X-ray crystal structure of the PhLi mixed (carb-)anionic aggregate 10 (ORTEP 3).24 Hydrogen atoms have been omitted for clarity, with exception of those attached to the carbanion C6H5 (F2 = 1.013, R = 0.0320, the Li3 Lewis acidic surface is 2.79 Å2).

reveal for both aggregates 3:1 stoichiometries of the lithium fencholate/organolithium ratio and distorted cubic Li4O3C1 cores (Figures 2 and 3). A comparison of 9 and 10 with previously reported n-BuLiaggregate 8 (Figure 1) is intriguing (Table 1).10 The cubic Li4O3C1 cores of 8,10 9 (Figure 2), and 10 (Figure 3) each exhibit three lithium cations which bind the carbanionic moiety and are each coordinated by a methoxy group of the fencholate unit (Figures 1−3). The fourth lithium cation (labeled Li4) is positioned diagonal to the carbanionic unit and exhibits only contacts to the three oxygen anions of the Li4O3C1 core (Figures 2 and 3, Table 1). The average Li−C distances are shortest for the n-BuLi aggregate 8 (2.210 Å), longer for the MeLi aggregate 9 (2.236 Å), and longest for PhLi aggregate 10 (2.313 Å, Table 1). Hence, in all three mixed anionic aggregates (8,10 9, 10), the carbanionic moiety is coordinated by three lithium ions (Figures 2 and 3). These three lithium ions (Li3) generate a Lewis acidic surface, on which the carbanion R (R = Me, Ph, n-Bu) is positioned (marked green in Figure 4a, Table 1).9 The size of this Li3 Lewis acidic surface, binding electrostatically the carbanion R, increases with the steric demand of the carbanion: The small methylid in 9 generates a Li3 surface of 2.62 Å2, while the n-butylid in 810 increases Li3 to 2.65 Å2. Likewise, the secondary phenylid in 10 expands Li3 to 2.79 Å2 (Table 1). All three carbanionic aggregates (i.e., 8−10) exhibit each Omethoxy coordination of the anisyl moiety to the Li-ions, which

Figure 4. (a) Lewis acidic surface of three Li-cations Li1−Li2−Li3 (bold green lines) coordinating carbanions R (i.e., R = Me (Figure 2), n-Bu,10 and Ph (Figure 3)), in mixed anionic aggregates and (b) torsions angles of methoxy-aryl θ(MeO-Ar) and fenchyl-aryl-units φ(Fen-Ar) (cf. Table 1).

bind the carbanion. The average Li−O(Me) distances are 1.998 Å (8), 1.978 Å (9), and 2.006 Å (10, Figure 2, Table 1). In all three structures, the Li ions, which are positioned diagonally relative to the carbanion R, are only three-coordinated by alkoxides of the fencholates (2b) of the cubic Li4O3C1 core. These “naked” Li ions exhibit no further coordination to external ligand. Enantioselective Alkylations with 9 and 10. Mixed (carb-)anionic aggregates 9 and 10 (Figures 2 and 3) were C


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Organometallics employed in alkylations with prochiral aldehydes (12a−i), yielding chiral alcoholic products (13a−n, Tables 2 and 3, Table 2. Enantioselective Methylations of Prochiral Aldehydes at −78°C in Toluene Using the in Situ Generated Mixed Anionic Aggregate 9 as Methylation Reagent (cf. Figure 5) entry

aldehyde → alcohol

1 2 3 4 5 6 7 8 9 10

benzaldehyde (12a) → 13a benzaldehyde (12a) → 13a benzaldehyde (12a) → 13a benzaldehyde (12a) → 13a 1-naphthaldehyde (12b) → 13b 1-naphthaldehyde (12b) → 13b 1-naphthaldehyde (12b) → 13b 9-anthracenaldehyde (12c) → 13c 4-tolualdehyde (12d) → 13d 4-methoxybenzaldehyde (12e) → 13e 4-(trifluoromethyl)-benzald. (12f) → 13f 4-fluorobenzaldehyde (12g) → 13g

11 12

T [h]

yield [%]a

ee [%] (config)b

2 2 22 4 2 3 23 2 2 6

20e 3c 22d 38e 10e 13 14 61 33e 17

41 (R) 36 (R)c 25 (R)d 36 (R) 36 (R) 26 (R) 9 (R) 6 (n.d.) 44 (S) 7 (R)

2

76

1 (n.d.)

2

57e

5 (n.d.)

Figure 6. Yields of methylations with in situ generated 9 yielding 1phenylethanol (13a) at temperatures −78, −20, or −5 °C, determined by chiral GC (Lipodex E) using dodecane (1 mmol L−1) as internal standard (Figure 5).

preceding crystallization (Tables 2 and 3).9,19 The methylations of benzaldehyde derivatives with mixed anionic aggregate 9 (Figure 1 and 2) were performed in toluene at −78, −20, and −5 °C and were quenched with methanol and 9% (w/w) HCl solution (Figure 6). At−78 °C, the methylation of benzaldehyde with 9 appears to be completed after 2 h (Figure 6). With lower reaction temperatures higher yields of 1-phenylethanol (13a) are observed (Figure 6). The lower yields for methylations with 9 at higher temperatures and longer reaction times (Figure 6) can be explained by Cannizzaro background reactions, yielding benzylic alcohols.26 While methylations with aggregate 9 provide enantioselectivities up to 44% (Table 2, entry 9), with aggregate 10 phenylations were obtained only up to 19% ee (Table 3, entry 8). Computational Studies on 9 and 10 (Figure 1). To explain the formations of mixed (carb-) anionic aggregates 9 and 10 (Figure 2 and 3), aggregate formation energies are computed via virtual co-condensations of MeLi or PhLi and lithium fencholates (Figure 7). In these virtual co-condensations, aggregate compositions of 3:1 (found experimentally for 9 and 10, cf. Figures 2 and 3) and of the alternative 2:2 stoichiometry (cf. Figure 1) are considered. The parent phenyl fencholate (2a) as well as anisyl fencholate (2b, Figure 1) are employed for computing these virtual aggregate formations (Figure 7). Computed aggregate-formation energies (based on M06-2XD3/6-311++G**//rB3LYP-D3(BJ)/def2SVP) of all 3:1 species show higher stabilities than of the corresponding 2:2 aggregates, each for MeLi and PhLi and also each for phenyl fencholate (2a) as well as the anisyl fencholate (2b) (Table 4, Figure 7) at 25 °C. This reflects the higher electrostatic stabilization with more (i.e., three) alkoxide ions in Li4O3C1 (in 3:1 aggregates) rather than less (i.e., two) in Li4O2C2 cores (in 2:2 aggregates). This computed and also experimentally observed preference of the 3:1 stoichiometry for 9 and 10 (cf. X-ray crystal structures, Figures 2 and 3) emphasizes, that the less sterically demanding anisyl fencholate 2b governs the 3:1 composition regardless of the carbanion (i.e., not only for nbutylide in 89 but also for methyl (in 9) and phenyl (in 10) anions). Only with bulky (e.g., silyl-) substituents in fencholates are 2:2 stoichiometries observed (Figure 1), which therefore can be also envisioned for methyl- and phenyl- anions. The hitherto experimentally unknown phenyl fencholates with MeLi (14) and PhLi (15, Figure 7) can therefore be predicted to also form 3:1 aggregates, similar to 9 and 10 (Figures 2 and 3).

a

Isolated yields after column chromatography; cf. Supporting Information section. bThe ee was determined by HPLC;28 cf. Supporting Information section 3. cWith isolated crystals of aggregate 9, not in situ generated. dAt −95 °C. eContains traces of anisyl fenchol 1b.

Table 3. Enantioselective Phenylations of Prochiral Aldehydes at −78°C in Toluene for 2 h Using the in Situ Generated Mixed Anionic Aggregate 10 as Phenylation Reagent (cf. Figure 5) entry

aldehyde → alcohol

1 2 3 4 5

1-naphthaldehyde (12b) → 13h 9-anthracenaldehyde (12c) → 13i 4-tolualdehyde (12d) → 13j 4-methoxybenzaldehyde (12e) → 13k 4-(trifluoromethyl)-benzald. (12f) → 13l 4-fluorobenzaldehyde (12g) → 13m acetaldehyde (12h) → 13a pivaldehyde (12i) → 13n

6 7 8

yield [%]a

ee [%] (config.)b

61 79 77c 84 87

18 (S) 11 (n.d.) 6 (S) 2 (R) 1 (n.d.)

85 24 68c

0 (n.d.) 17 (R) 19 (R)

a

Isolated yields after column chromatography; cf. Supporting Information. bThe ee was determined by HPLC;28 cf. Supporting Information section 3. cContains traces of anisyl fenchol 1b.

Figures 5 and 6). As 1H,7Li-HOESY experiments show, fencholate-based mixed (carb-)anionic aggregates form in hydrocarbon solutions similar structures like in the solid state (cf. X-ray structures in Figures 2 and 3),5,27 mixed (carb)anionic aggregates 9 and 10 are employed in situ and without

Figure 5. Enantioselective methyl- and phenylations of (benz-)aldehydes (12a−i) with mixed anionic aggregate 9 or 10 (Figure 1, R = Me, Ph) yielding chiral alcoholic products 13a−g (R = Me, Table 2) and 13a,h−n (R = Ph, Table 3). D


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Organometallics

Figure 7. Computed aggregate formation energies via virtual co-condensation of lithium phenyl- or lithium anisyl fencholate (2a,b) in gas phase with RLi (R = n-Bu, Me, Ph), resulting in 3:1 or 2:2 mixed (carb-)anionic aggregates (cf. Table 4).

Table 4. Computed Absolute Energies and Relative Aggregate Formation Energies (cf. Figure 7) at 25°Ca entry 1 2 3 4 5 6 7 8 9 10 11 12

mixed anionic aggregate (ratio, X) 75 (3:1 H) 16 (2:2 H) 15 (3:1 H) 18 (2:2 H) 14 (3:1 H) 17 (2:2 H) 810 (3:1 OMe) 19 (2:2 OMe) 10 (3:1 OMe) (cf. X-ray) 21 (2:2 OMe) 9 (3:1 OMe) (cf. X-ray) 20 (2:2 OMe)

R

absolute energies in Hartreea

aggregate formation energies Δkcal mol−1 (ΔHartree)

n-Bu n-Bu Ph Ph Me Me n-Bu n-Bu Ph

−2280.588143 −1739.590325 −2354.393743 −1888.462271 −2162.685621 −1505.036491 −2624.145097 −1967.440641 −2697.980897

−185.7 (−0.295933) −169.6 (−0.270289) −185.3 (−0.25248) −173.8 (−0.276990) −185.9 (−0.296324) −168.7 (−0.268828) −175.5 (−0.280000) −166.8 (−0.265753) −194.0 (−0.309123)

Ph Me

−2117.505536 −2506.248398

−170.3 (−0.271410) −179.9 (−0.285432)

Me

−1731.610724

−164.0 (−0.261332)

Table 5. Computed and Experimental Li3 Lewis Acidic Surface Areas [Å2] in Mixed (Carb-)Anionic Aggregates (cf. Figures 4 and 7)a structure

Li3 surfacesb

3:1 phenyl fenchole-aggregate (R = Me) (14) 3:1 phenyl fenchole-aggregate (R = n-Bu) (7)5 3:1 phenyl fenchole-aggregate (R = Ph) (15) 3:1 anisyl fenchole-aggregate (R = Me) (9)c 3:1 anisyl fenchole-aggregate (R = n-Bu) (8)10 3:1 anisyl fenchole-aggregate (R = Ph) (10)c

2.57 2.57 2.66 2.54 2.58 2.69

cf. X-rayc 2.60 2.62 2.65 2.79

M06-2X-D3/6-311++G**//B3LYP-D3(BJ)/def2SVP for 25 °C. Lewis acidic surface [Å2], formed by Li1−Li2−Li; cf. Figure 4. c Measured at −173 °C; Table 1. a

b

pseudo-C3 propeller-like arrangement and enable enantioselective alkylations of prochiral carbonyl compounds (i.e., aldehydes). With methyllithium 9 and phenyllithium 10 aggregates, a broad range of aldehydes can be reduced enantioselectively in up to 44% ee and with recyclable chiral mediator 1b. Computations of aggregate formation energies show that all 3:1 aggregates with methylide, n-butylide, or phenylide anions as well as with phenyl fencholate or with anisyl fencholate are favored over the corresponding 2:2 aggregates. The computations predict that the hitherto experimentally unknown phenyl fencholate aggregates 14 and 15 (Figure 7) with incorporated MeLi or PhLi should form aggregates with 3:1 ratio. In such 3:1-mixed carbanionic aggregates, three lithium ions act as chiral tridentate Lewis acid, binding the carbanionic group. X-ray crystal analyses show that these Li3 surfaces increase with the steric demand of the carbanion (i.e., Me, 2.62 Å2 < n-Bu, 2.65 Å2 (previous work) < Ph, 2.79 Å2). This Li3 expansion in parallel to the size of the carbanion is also found in computed model structures. The Li3 Lewis acidic surface of mixed anionic fencholate aggregates apparently adapts to different carbanions and is therefore capable to bind and chirally modify not only small, primary carbanions, but even the larger secondary phenyl anion.

a

Absolute energies of RLi’s and free lithium alkoxide ligands (1a,b). M06-2X-D3/6-311++G**//rB3LYP-D3(BJ)/def2SVP. MeLi = −47.38090; n-BuLi = −165.28303; PhLi = −239.08971; 2a = −705.002928; 2b = −819.527354.

The computed Lewis acidic surfaces in the mixed anionic aggregates, formed by the three Li-ions binding the carbanions, expand with increasing size of carbanion R, as it was also observed experimentally (Figure 4, Table 1). These Li3 surfaces are computed to be 2.54 Å2 for Me-aggregate 9, 2.58 Å2 for n-Buaggregate 8, and 2.69 Å2 for Ph-aggregate 10 (Table 5).

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CONCLUSIONS Two new enantiopure, mixed (carb-) anionic aggregates containing methyllithium 9 and phenyllithium 10 are efficiently accessible via reaction of (+)-anisyl fenchol (synthesized from (+)-fenchone) and the organolithium systems methyllithium or phenyllithium as well as subsequent spontaneous selfaggregation in hydrocarbon solvents. These aggregates exhibit 3:1 stoichiometry with distorted cubic Li4O3C1 cores. The chiral fencholate units and the 3:1 stoichiometry and give rise to a E


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Organometallics

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The reaction was allowed to warm to room temperature and stirred for further 1.5 h. Methanol (3.0 mL) was added and the mixture was stirred for additional 10 min. The mixture was concentrated in vacuo. 3.0 mL 9% (w/w) hydrochloric acid was added to resolve the suspension and the mixture was stirred for additional 10 min. After separation of the organic phase, the aqueous phase was extracted three times with 1 mL DCM, the organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was purified via column chromatography. HPLC was used to determine the ee%.9 HPLC spectra are shown in Supporting Information section 3,28 and NMR spectra are given in Supporting Information section 4. Additionally, all temperature screening reactions were performed in toluene for 4 h in the presence of 1 mmol L−1 dodecane as internal standard after 30 min equilibration of the aggregate 9. Samples were taken at 10, 20, 60, 120, and 240 min, with an argon purged 500 μL syringe, the exact volume was read shortly before hydrolysis, respectively. GC-FID was used to determine the conversion equipped with a Lipodex E column.26c GC-FID spectra are shown in Supporting Information section 2. General Procedure for the Synthesis of Racemic Standards with MeLi (13a−i). MeLi (0.92 mL, 1.48 mmol, 1.5 equiv) was added via syringe to absolute toluene (2 mL) at −78 °C and was stirred for 30 min. Then, 1.0 equiv of aldehyde (12a−i) was added, and the reaction was stirred for additional 30 min, holding the temperature. The reaction was allowed to warm to room temperature and stirred for a further 1.5 h. Methanol (5.0 mL) was added, and the mixture was stirred for additional 10 min. The mixture was concentrated in vacuo. The orangeyellow residue was dissolved in 5.0 mL of 9% (w/w) hydrochloric acid, and the mixture was stirred for additional 10 min. After separation of the organic phase, the aqueous phase was extracted with DCM (3 × 5 mL), the organic layers were combined and the solvent was evaporated under reduced pressure. The resulting crude product had a yellowish oil characteristic and was purified via column chromatography, yielding the product as clear colorless oil.32 HPLC spectra are shown in Supporting Information section 3, and NMR spectra are given in Supporting Information section 4. General Procedure for the Synthesis of Racemic Standards with PhLi (13a,h−n). PhLi (0.78 mL, 1.48 mmol, 1.5 equiv) was added via syringe to absolute toluene (2 mL) at −78 °C and stirred for 30 min. Then, 1.0 equiv of aldehyde (12b−i) was added, and the reaction was stirred for additional 30 min, keeping the temperature. The reaction was allowed to warm to room temperature and stirred for further 1.5 h. Methanol (5.0 mL) was added and the mixture was stirred for additional 10 min. The mixture was concentrated in vacuo. The orange-yellow residue was dissolved in 5.0 mL of 9% (w/w) hydrochloric acid, and the mixture was stirred for additional 10 min. After separation of the organic phase, the aqueous phase was extracted with DCM (3 × 5 mL), the organic layers combined, and the solvent evaporated under reduced pressure. The resulting crude product had a yellowish sediment characteristic and was purified via column chromatography, yielding the product as a clear colorless solid.32 HPLC spectra are shown in Supporting Information section 3, and NMR spectra are given in Supporting Information section 4. (1S,2S,4R)-2-(2-Methoxyphenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1b). At a temperature of 0 °C, n-BuLi (42.0 mL, 2.5 M, 105 mmol, 1.1 equiv) was transferred via syringe in a 250 mL Schlenk-flask containing TMEDA (15.9 mL, 105 mmol, 1.1 equiv). Then, anisole (11.0 mL, 100 mmol, 1.0 equiv) was added. The reaction was allowed to warm to room temperature and stirred for further 12 h. (+)-Fenchone (16.0 mL, 100 mmol, 1.0 equiv) was added at 0 °C. The reaction was allowed to warm to room temperature and stirred for a further 2 days. dest. H2O (15 mL) was used to hydrolyze the reaction mixture. After separation of the organic phase, the aqueous phase was extracted three times with n-hexane (15 mL), the organic layers combined and dried over Na2SO4, and the solvent evaporated under reduced pressure. The excess educts were extracted by distillation at 0.8 mbar and 110 °C. The residue was recrystallized from n-pentane three times. The product yielded was a white solid (19.4 g, 75%). Rf = 0.617 (90% n-hexane, 10% ethyl acetate). Mp = 64 °C. [α]20 D + 78° (c = 0.05 g/100 mL in n-hexane). 1H NMR (300 MHz, CDCl3) δ 7.51 (dd, J =

EXPERIMENTAL SECTION

General. All reactions were carried out under an argon atmosphere using Schlenk techniques. Solvents were dried by standard methods and freshly distilled prior to use. Nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance-300 (Bruker, 300 MHz) using CDCl3 as solvent. NMR chemical shifts in parts per million (ppm) were referenced to tetramethylsilan (TMS). Signal multiplicities are given as singlet (s), doublet (d), doublet of doublet (dd), doublet of quartet (dq), triplet (t), and multiplet (m). MestReNova 9.0 was used to evaluate the data. Mass spectra were recorded on a Varian GC-MS4000 equipped with a J&W Scientific DB-5ht column or a Varian CP-Sil 8 LB/MS column. X-ray diffraction were recorded on Bruker D8 with kappa geometry and copper microfocus-source. The X-ray diffraction analysis was measured at −173 °C under perfluorinated polyether (Fomblin); structures were solved with SHELXT29 and refined using SHELXL.30 Disordered solvent was modeled with Platon SQUEEZE.31 Pictures were generated with ORTEP 3 (1.0.3).24 HPLC analytics were performed using a La Chrome Elite L-2130 pump, UV detector L-2400, and chromaster 5310 column oven (HITACHI) equipped with Chiracel OJ, OB-H, OD-H or AD-H columns (Daicel Chemical Industries, Ltd.). Solvents for HPLC analysis were commercially obtained as HPLC-grade (Fisher Scientific). All HPLC measurements were compared to a reference standard of the racemate. Temperature was adjusted by a cryostat JULABO F25-MA (JULABO GmbH, Seelbach, Germany). Silica gel for chromatography (0.035−0.070 mm; 60 Å, nitrogen flushed) was purchased from Acros Organics. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 aluminum sheets (Merck), visualized using UV fluorescence 254 nm and stained with potassium permanganate. GC-spectra were recorded on an HP 6890 gas chromatograph (Hewlett-Packard Company), equipped with a Lipodex E column (Machery-Nagel, 0.25 mm × 25 m, 25 μm), an Agilent 7683 split injector (Agilent), and a flame-ionization detector (Agilent, FID) using dodecane (Acros Organics) as internal standard. MeLi (Acros Organics, 1.6 M in diethyl ether, product number: 188751000), PhLi (Sigma-Aldrich, 1.9 M in di-n-butyl ether, product number: 593230), n-BuLi (Sigma-Aldrich, 2.5 M in n-hexane, product number: 230707), and (+)-fenchone (Alfa Aesar, product number: L15938) were commercially obtained and used without further purification. The aldehydes benzaldehyde (Fluka, PCode: 101248687, Lot #BCBH5564 V), 4-methoxybenzaldehyde (Fluka, PCode: 10440, analysis number: 346128/1 596), 1-naphthaldehyde (Acros Organics, Code: 128091000, Lot: A0262921), 4-tolualdehyde (Sigma-Aldrich, PCode: 1002275318, Lot # MKBX3490 V), 4(trifluoromethyl)-benzaldehyde (Sigma-Aldrich, PCode: 101893072, Lot #STBG9890), 4-fluorobenzaldehyde (Sigma-Aldrich, PCode: 101866630, Lot #MKBZ4651 V), 9-anthracenaldehyde (Alfa Aesar, Code: A11258, Lot: 18480A), iso-butyraldehyde (Alfa Aesar, PCode: 8.01556.0100, Lot: S7249356 724), and pivaldehyde (Alfa Aesar, Code: A15013/L02892, Lot: 10157266) were commercially obtained and used without further purification, if not stated otherwise. Crystallization of (3:1 Ratio) Lithium Anisyl Fencholate·MeLi (9) and (3:1 Ratio) Lithium Anisyl Fencholate·PhLi (10). Anisyl fenchole (1b, 651 mg, 2.5 mmol, 3.0 equiv) was put into a 10 mL Schlenk-flask and dried in vacuo for 60 min. Then, it was solved in absolute diethyl ether (0.3 mL) via syringe. MeLi or PhLi (3.3 mmol, 4.0 equiv) was added to the solution at −78 °C and stirred for additional 30 min, keeping the temperature. For diffusion crystallization, the solution was covered in n-hexane; a trough is used to cover the solution. Slow diffusion is used to gain colorless crystals by cooling down the solvent to low temperatures (storage at −20 °C). X-ray crystal structures are shown in Supporting Information section 1. General Procedure for Enantioselective Alkylation of Various Aldehydes (13a−i). In a 250 mL Schlenk flask, toluene (100 mL) was purged with argon for 60 min. After that, toluene (2.0 mL) was transferred via syringe to a 10 mL Schlenk-flask, containing anisyl fenchole (1b, 650 mg, 2.5 mmol, 3.0 equiv). 2.1 mL MeLi or 1.8 mL PhLi (3.3 mmol, 4.0 equiv) was added to the solution via syringe at −78 °C and stirred for 30 min, respectively. After equilibrating the reaction mixture 1.0 equiv aldehyde (12a−i, 0.83 mmol) was added and the reaction was stirred for additional 30 min, keeping the temperature. F


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reagents to the CN-double bond. Tetrahedron: Asymmetry 1997, 8 (12), 1895−1946. (d) Denmark, S. E.; Nicaise, O. J.-C. Ligand-mediated addition of organometallic reagents to azomethine functions. Chem. Commun. 1996, No. 9, 999. (e) Seebach, D. Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures. Angew. Chem., Int. Ed. Engl. 1988, 27 (12), 1624−1654. (f) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D. Enantioselective aldol and Michael additions of achiral enolates in the presence of chiral lithium amides and amines. Synthesis 1993, 1993 (12), 1271. (g) Seebach, D. Stereospecificity in Chemistry and Biochemistry. Proc. Robert A. Welch Found. Conf. Chem. Res. 1984, No. 27, 93−145. (h) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Structure−Nucleophilicity Relationships for Enamines. Chem. - Eur. J. 2003, 9 (10), 2209−2218. (i) Minegishi, S.; Mayr, H. How Constant Are Ritchie’s “Constant Selectivity Relationships”? A General Reactivity Scale for n-, π-, and σ-Nucleophiles. J. Am. Chem. Soc. 2003, 125 (1), 286−295. (j) Mayr, H.; Kempf, B.; Ofial, A. R. πNucleophilicity in carbon−carbon bond-forming reactions. Acc. Chem. Res. 2003, 36 (1), 66−77. (k) Mayr, H.; Patz, M.; Gotta, M. F.; Ofial, A. R. Reactivities and selectivities of free and metalcoordinated carbocations. Pure Appl. Chem. 1998, 70 (10), 1993. (2) (a) Briggs, T. F.; Winemiller, M. D.; Xiang, B.; Collum, D. B. Solution Structures of the Mixed Aggregates Derived from Lithium Acetylides and a Camphor-Derived Amino Alkoxide. J. Org. Chem. 2001, 66 (19), 6291−6298. (b) Bremand, N.; Marek, I.; Normant, J. F. Diastereoselective “contra-Michael″ addition of (−)-sparteineorganolithiumcomplexes to secondary chiral cinnamyl amides. Tetrahedron Lett. 1999, 40 (17), 3383−3386. (c) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. 3-Aminopyrrolidine lithium amide in enantioselective addition of organolithium compounds onto aromatic aldehydes. Tetrahedron: Asymmetry 1997, 8 (10), 1519−1523. (d) Goldfuss, B. Enantioselective Addition of Organolithiums to C = O Groups and Ethers; Springer, Heidelberg, 2003. (e) Hoppe, D.; Hense, T. Enantioselective synthesis with lithium/(−)-sparteine carbanion pairs. Angew. Chem., Int. Ed. Engl. 1997, 36 (21), 2282−2316. (f) Hoppe, D.; Kaiser, B.; Stratmann, O.; Fröhlich, R. A Highly Enantiomerically Enriched α-Thiobenzyl Derivative with Unusual Configurational Stability. Angew. Chem., Int. Ed. Engl. 1997, 36 (24), 2784−2786. (3) (a) Kronenburg, C. M. P.; Rijnberg, E.; Jastrzebski, J. T. B. H.; Kooijman, H.; Spek, A. L.; van Koten, G. Stereochemical Aspects of Enantiopure and Racemic Organolithium Aggregates Li4Ar4 {Ar = C6H4[CH(Me)NMe2]-2}. Eur. J. Org. Chem. 2004, 2004 (1), 153−159. (b) Nichols, M. A.; Williard, P. G. Solid-state structures of nbutyllithium-TMEDA,-THF, and-DME complexes. J. Am. Chem. Soc. 1993, 115 (4), 1568−1572. (c) Barnett, N. D. R.; Mulvey, R. E.; Clegg, W.; O’Neil, P. A. Butyllithium Cubane Tetramers Linked by LiTMEDA-Li Bridges in an Infinite, Zig-Zag Chain Arrangement: First Crystallographic Study of a Simple Butyl Compound of an Early Main Group Element. J. Am. Chem. Soc. 1993, 115 (4), 1573−1574. (d) Kottke, T.; Stalke, D. Crystal handling at low temperatures. Angew. Chem. 1993, 105 (4), 619−621. (e) Marsch, M.; Harms, K.; Lochmann, L.; Boche, G. [nBuLi · LiOtBu]4, Solid-State Structure of an nButyllithium−Lithium tert-Butoxide Complex. Angew. Chem., Int. Ed. Engl. 1990, 29 (3), 308−309. (4) Hilmersson, G.; Malmros, B. Mixed Dimer and Mixed Trimer Complexes of nBuLi and a Chiral Lithium Amide. Chem. - Eur. J. 2001, 7 (2), 337−341. (5) Goldfuss, B.; Steigelmann, M.; Loschmann, T.; Schilling, G.; Rominger, F. A Dispensable Methoxy Group? Phenyl Fencholate as a Chiral Modifier of n-Butyllithium. Chem. - Eur. J. 2005, 11 (13), 4019− 4023. (6) Xu, F.; Reamer, R. A.; Tillyer, R.; Cummins, J. M.; Grabowski, E. J. J.; Reider, P. J.; Collum, D. B.; Huffman, J. C. Highly Enantioselective 1,2-Addition of Lithium Acetylide-Ephedrate Complexes: Spectroscopic Evidence for Reaction Proceeding via a 2:2 Tetramer, and X-ray Characterization of Related Complexes. J. Am. Chem. Soc. 2000, 122 (45), 11212−11218.

7.8, 1.6 Hz, 1H), 7.20−7.09 (m, 1H), 6.95−6.82 (m, 2H), 5.13 (s, 1H), 3.86 (s, 3H), 2.45 (dddd, J = 12.2, 8.7, 5.3, 2.5 Hz, 1H), 2.22 (dq, J = 10.3, 2.3 Hz, 1H), 1.79−1.60 (m, 2H), 1.44−1.32 (m, 1H), 1.30 (s, 3H), 1.25 (dd, J = 10.2, 1.4 Hz, 1H), 1.14 (dd, J = 12.7, 4.2 Hz, 1H), 1.10 (s, 3H), 0.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 157.99, 132.87, 129.06, 127.10, 119.94, 111.21, 85.56, 55.40, 52.69, 50.25, 44.94, 40.96, 33.59, 29.54, 24.85, 22.61, 18.43. NMR spectra are given in Supporting Information section 4.10,33

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COMPUTATIONAL SECTION

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ASSOCIATED CONTENT

All computed structures were fully optimized and characterized by frequency computation as minima (NIMAG = 0) by using the program GAUSSIAN16.34 The hybrid density functional method (B3LYPD3(BJ)), including Grimme’s dispersion (D3)35 and Becke-Johnsondamping (BJ),36 restricted B3LYP-D3(BJ)/def2SVP was used for geometry optimization and frequency calculations of these strong polar aggregates. To determine single points the Minnesota functional M062X and high basis set 6-311++G** were used. Polarization functions on heavy atoms and hydrogen, as well as diffuse functions on heavy atoms are also included. S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00724. GC, HPLC, and NMR spectra (PDF) DFT geometries (XYZ) Accession Codes

CCDC 1858793 and 1858794 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bernd Goldfuss: 0000-0002-1814-8818 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the computing center of the University of Cologne (RRZK) for providing CPU time on the DFG-funded supercomputer CHEOPS, as well as for support. We also thank the German Science Foundation DFG, Bayer AG, BASF AG, Wacker AG, Evonik AG, Raschig GmbH, Symrise GmbH, Solvay GmbH, the OMG group, and INEOS-Köln for support. We would like to thank Wakemakers.com and Florian Grote for construction of the TOC-picture.

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REFERENCES

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Enantiopure Methyl- and Phenyllithium: Mixed (Carb-)Anionic Anisyl

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