Readily Accessible 1,2-Amino Ether Ligands for Enantioselective

Subscriber access provided by Fudan University

Note

Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation Hélène Guyon, Anne Boussonnière, and Anne-Sophie Castanet J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00423 • Publication Date (Web): 10 Apr 2017 Downloaded from http://pubs.acs.org on April 11, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation Hélène Guyon, Anne Boussonnière*, and Anne-Sophie Castanet* Université du Maine and CNRS UMR 6283, Institut des Molécules et Matériaux du Mans, Faculté des Sciences et Techniques, avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France

Table of contents

Br

1. t-BuLi, L* toluene, –78 °C

Z

2. warm 3. MeOH

R1

R2 R1

Z = NCH2CH=CH2, NH, O, CH 2

Z

MeO L*

NMe2

Inexpensive chiral ligands High stereoselectivity (90:10 er to 95:5 er)

ABSTRACT. A new class of chiral 1,2-amino ether ligands, readily accessible from naturally occurring α-amino- or α-hydroxy acids, was found to provide high levels of both conversion and stereocontrol (up to 95:5 er) in intramolecular carbolithiation reactions, outperforming the benchmark ligand (–)sparteine. The ligand could be used in a substoichiometric amount (0.25 equiv) without significant loss of enantioselectivity.

The intramolecular addition of organolithiums to unactivated alkenes offers an attractive strategy for building functionalized carbocyclic and heterocyclic systems.1 This approach has found numerous synthetic applications,2 including the preparation of indolines,3 2,3-dihydrobenzo[b]furans,4 and indans.5 Enantiofacially selective cyclization of an olefinic aryllithium can be performed by conducting the reaction in the presence of a chiral bidentate ligand.6 Although the natural alkaloid (–)-sparteine7 (L1) is

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 32

the most widely used chiral promotor for this reaction, the outcome of the L1-mediated intramolecular carbolithiation is quite substrate dependent.8 Moreover, since the commercial availability of L1 has significantly varied over the last decade, concerns about its long-term, high-volume supply9 have highlighted the need for new classes of versatile and efficient chiral ligands. Toward this goal, we describe hereafter the development of a new family of readily accessible chiral 1,2-amino ether ligands and describe its application to intramolecular carbolithiation reactions. The last two decades have witnessed considerable progress in the chiral ligand-mediated enantioselective organolithium reactions.10 Tertiary diamines and diethers have been widely used as chiral promoters in these transformations.11 Besides (–)-sparteine (L1), representative examples include O’Brien’s (+)-sparteine surrogate L2,12 Alexakis’ diamine L3,13 and Tomioka’s diether L414 (Figure 1). In contrast, limited attention has been paid to chiral bidentate 1,2-amino ethers and most of the investigations reported to date are restricted to the pseudoephedrine- or ephedrine-derived ligands L5 and L6.8a,15

Figure 1. Selection of chiral bidentate ligands Interestingly, amino ether L5 is more effective than the trans-diaminocyclohexane L3 or the diether L4 in the asymmetric cyclization of 2-(N,N-diallylamino)phenyllithium and provides stereoselectivities matching those of (–)-sparteine.8a However, since pseudoephedrine can be diverted to manufacture illicit drugs, its sale is highly regulated in some countries,16 complicating its use in industrial and academic research.17 On the basis of works of Tomioka18 and Alexakis,13a it seems reasonable to speculate that amino ether L5 would form a five-membered ring upon chelation with an organolithium (chelate A, figure 2). In this chelate, the methyl substituent on the ether oxygen would be oriented trans


2

Page 3 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


to the adjacent phenyl group to minimize non-bonding interactions. This would relay the chirality of the carbon backbone to the ligating ether, bringing a chiral environment close to the lithium atom. Therefore, the enantioinduction generated from L5 would be mainly controled by the stereogenic carbon center located α to the ether moiety.19 These considerations led us to question whether the second stereogenic carbon center, α to the NMe2 group, could be “removed” while preserving a good stereocontrol (chelate B, figure 2). To answer this question, we intended to evaluate amino ethers L7 in intramolecular carbolithiation reactions. We envisioned that these ligands could be easily synthesized from inexpensive naturally occurring α-amino- or α-hydroxy acids. In contrast to pseudoephedrine and (–)-sparteine, these starting materials are readily available and would provide a wide array of R side chains, enabling the fine-tuning of the ligand structure. Ph O Me

Me

R

Me N N O Li Li Me Me Me Me R' R' B A

R NMe2

MeO L7

Figure 2. Five-membered chelates A and B and new amino ether ligands L7 Route to ligands L7 was optimized with the isobutyl derivative L7a (Scheme 1). α-Hydroxy acid 1a was synthesized by diazotization-hydrolysis of L-leucine.20 This reliable and inexpensive reaction, known to proceed via an α-lactone, affords overall retention of configuration via a double inversion.21 Recrystallization from petroleum ether/ diethyl ether afforded enantiomerically pure hydroxy acid 1a in 61% yield.22 Conversion of acid 1a to amide 2a was accomplished by treatment with dicyclohexylcarbodiimide (DCC), 1-hydroxy-1H-benzotriazole (HOBt), dimethylamine hydrochloride and diisopropylethylamine (DIPEA).23 Elimination of the dicyclohexyl urea by-product by filtration followed by an aqueous NaHCO3 wash provided amide 2a, which was sufficiently pure for use in the next step (84% yield). The absence of racemization was verified by gas chromatography on a chiral stationary phase (CSP-GC). O-methylation of 2a (NaH, MeI) delivered crude methoxyamide 3a,24 which was reduced with an excess of LiAlH4.25 Amino ether L7a was isolated in 79% yield (over two


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 32

steps) after bulb-to-bulb distillation. Remarkably, this synthetic scheme is easily amenable to multigram quantities, as no purification by column chromatography is required. Scheme 1. Synthesis of amino ether L7a from L-leucine

The same synthetic sequence was applied for the synthesis of ligands L7b–h, demonstrating the generality of the procedure (Table 1). L-valine, L-isoleucine, L-tert-leucine and L-phenylalanine were employed as starting materials for the synthesis of ligands L7b–e (entries 1–4). The preparation of ligand L7f involved the reduction of the benzyl group of hydroxyamide 2e as the key step of the synthesis (entry 5). Ligand ent-L7g, bearing a phenyl substituent, was prepared from commercially available (R)-mandelic acid (ent-1g) (entry 6). Hydrogenation of ent-1g provided the cyclohexylsubstituted hydroxy acid ent-1h, which was the precursor of ligand ent-L7h (entry 7). Table 1. Preparation of amino ether ligands L7b–h


4

Page 5 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Entry

R

1 %a

2 %a

L7 % a

1

iPr

1b, 66

2b, 71

L7b, 57

2

s-Bu

1c, 79

2c, 67

L7c, 69

3

t-Bu

1d, 67

2d, 72

L7d, 51

4

benzyl

1e, 90

2e, 54

L7e, 58

5

CyCH2

–

2fb

L7f, 74

6

Ph

ent-1gc

ent-2g, 37

ent-L7g, 65

7

Cy

ent-1hd

ent-2h, 79

ent-L7h, 70

a

isolated yields. b 2f was obtained by hydrogenation of 2e with H2, Rh/C (quant. yield). c (R)-mandelic acid (ent-1g) is commercially available. d ent-1h was obtained by hydrogenation of (R)-mandelic acid (61% yield). In order to assess their utility, the ligands L7a–h were evaluated in the enantioselective carbolithiation of N,N-diallyl-2-bromoaniline (4) and their efficiencies were compared to those previously obtained with ligands L1 and L5, the best ligands reported so far for this transformation (Table 2). To assist cross-comparison of results, a uniform set of reaction conditions, previously reported by Bailey,8a was employed. t-BuLi (2.2 equiv) and the chiral ligand (2.2 equiv) were added to an ethereal solution of 4 at –78 °C. The resulting mixture was incubated at –40 °C for 3 h before being quenched with methanol at –78 °C. Table 2. Screening of Ligandsa

a

Yields and er determined by CSP-GC analysis. b Ref. 8a

To our delight, ligands L7 were found to give high-yielding carbolithiation reactions,26 with enantioselectivities higher or comparable to those reached with L18a or L5.8a The stereocontrol was ACS Paragon Plus Environment

5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 32

marginally affected by the side chain of the amino ether ligand and the best stereoselectivity (94:6 er) was achieved with the valine-derived ligand L7b. Furthermore, ligands L7 offered an efficient access to either enantiomer of 1-allyl-3-methylindoline (5)27 as ligand ent-L7h, which is readily synthesized from (R)-mandelic acid, produced equally high, but opposite, stereoselectivity compared to L7b.28 To further confirm that the relay of chirality from the stereogenic carbon to the ether oxygen was crucial to the stereocontrol imparted by ligands L7, we also evaluated their regioisomeric analogs L8a–b. These amino ethers were prepared from α-amino acids using a route devised from literature precedent (reduction, Eschweiler-Clark methylation and etherification).29 As anticipated, moving the stereogenic carbon further away from the ether function was detrimental to the stereoselectivity. We next focused on further optimizing reaction conditions for ligand L7b (Table 3). The reverse addition, i.e. adding 4 to a preformed complex of t-BuLi and L7b, had a beneficial effect on the reaction yield (entries 1 and 2). Lowering the temperature to –60 °C failed to improve the selectivity and considerably decreased the cyclization rate (entry 3). Toluene and diethyl ether gave the same level of stereocontrol when 2.2 equiv of t-BuLi/L7b complex were used (entry 4). Asymmetric carbolithiation reactions involving catalytic amounts of chiral ligand have been scarcely described in the literature,6,30 and the cyclization of the aryllithium derived from 4 under substoichiometric conditions was highly challenging. In agreement with previous results on (–)-sparteine-mediated carbolithiation of 4,8b poor yield (29%) and moderate enantioselectivity (86:14 er) were obtained when the reaction was conducted with 2.2 equiv of t-BuLi and 1.2 equiv of L7b (entry 5). Under these reaction conditions, the second equivalent of t-BuLi reacts with the t-BuBr generated in the bromine-lithium exchange to give isobutene, isobutane and lithium bromide.31 This lithium salt probably traps one equivalent of chiral ligand via preferential complexation. To address this problem, we therefore used only 1.2 equiv of tBuLi.32 Gratifyingly, a full conversion of the starting material was observed when the reaction was conducted in the presence of 1.2 equiv of L7b and excellent stereoselectivities (95:5 er) were restored both in toluene and in diethyl ether (entries 6 and 7). Although a small amount of the aryllithium generated in the exchange is probably quenched by proton abstraction from the t-BuBr, good yields ACS Paragon Plus Environment

6

Page 7 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


were obtained, especially in toluene (81%). Pleasingly, it was possible to further decrease the amount of ligand L7b to 0.25 equiv while preserving a good yield (81%) and an efficient stereocontrol (92:8 er) (entry 8). Table 3. Optimization of the reaction conditions for the L7b-promoted carbolithiation of 4 a

Et2O

T (°C) –40

t-BuLi/L7b (equiv.) 2.2/2.2

79

erc (R:S) 94:6

2

Et2O

–40

2.2/2.2

95

94:6

3

Et2O

–60

2.2/2.2

69

93:7

4

Toluene

–40

2.2/2.2

97

95:5

5

Toluene

–40

2.2/1.2

29

86:14

6

Et2O

–40

1.2/1.2

63

95:5

7

Toluene

–40

1.2/1.2

81

95:5

8e

Toluene

–40

1.05/0.25

81

92:8

Entry

Solvent

1d

5b (%)

a

Reaction conditions: 4 was added to a solution of t-BuLi (n equiv) and L7b (n’ equiv) in the specified solvent at –78 °C. The resulting mixture was incubated at T °C for 3 h before being quenched with methanol at –78 °C. b Yields determined by gas chromatography. c er determined by CSP-GC. d tBuLi and L7b were added to a solution of 4. e 16 h at –40 °C. We then turned our attention to substrate generality using the non-catalytic conditions optimized in Table 3. The L7b-promoted carbocylization of N,N-diallyl-2-bromo-3-methylaniline (6) and N-allyl-2bromoaniline (7) was first examined (Scheme 2). Whereas Bailey has shown that (–)-sparteine (L1) struggles to cyclize the aryllithiums derived from 68a and 7,15a amino ether L7b delivered indolines 8 and 927 in high yields and stereoselectivities (>92:8 er). 33,34


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 32

Scheme 2. Preparation of indolines 8 and 9

The enantioselective synthesis of 2,3-dihydrobenzofurans by intramolecular cyclization of allyl olithioaryl ethers was next investigated (Scheme 3). This L1-mediated reaction was pioneered by Barluenga who obtained compound 11 from 10 in 47% yield and with an er of 89.5:10.5.4 Once again, ligand L7b was a useful alternative to (–)-sparteine as it afforded dihydrobenzofuran 11 with a slightly improved enantioselectivity (95:5 er).34,35 Finally the more challenging substrate 2-bromo-1-(3butenyl)benzene (12) was examined. The L1-mediated carbolithiation of the aryllithium derived from 12, which was reported by Bailey, is only moderately stereoselective (71:29 er).8b Remarkably, ligand L7b provided a significant boost in enantioselectivity (93:7 er),34 further demonstrating that this ligand has the potential to fill voids left by (–)-sparteine in the field of enantioselective carbolithiation. Scheme 3. Preparation of 2,3-dihydrobenzofuran 11 and indan 13

In summary, a new family of chiral 1,2-amino ethers has been efficiently synthesized in a short and scalable synthetic sequence from readily available and inexpensive α-amino- or α-hydroxy acids. Stoichiometric or substoichiometric amounts of these chiral ligands can serve as effective promoters for ACS Paragon Plus Environment

8

Page 9 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


enantioselective intramolecular carbolithiation reactions. The valine-derived ligand L7b affords the highest stereoselectivities, outperforming (–)-sparteine in the synthesis of enantioenriched indolines, 2,3-dihydrobenzofurans, and indans. Experimental Section A- General Experimental Methods All air- and moisture-sensitive manipulations were performed under argon atmosphere with anhydrous solvents in flame-dried glassware. The solvents (THF, CH2Cl2, Et2O, Toluene) were dried by activated alumina column (glass technology GTS 100). Pentane was distilled from CaH2. t-BuLi was purchased as 1.7 M solution in pentane and was titrated periodically against N-benzylbenzamide.36 Other commercially available reagents were used without further purification, unless otherwise indicated. Flash column chromatography was carried out using Merk Kieselgel 60 silica gel (particle size : 32-63 Å). Analytical TLC was performed using Merk precoated silica gel 60 F-254 sheets with spot detection under UV light or using potassium permanganate stain or cerium ammonium molybdate stain. 1H and 13C NMR spectra were recorded on a BRUKER DPX 200 or on a BRUKER Advance 400 spectrometer. Coupling constants J are reported in Hertz (Hz). Multiplicity is indicated as follow, s (singlet), d (doublet), t (triplet), q (quartet), sext (sextuplet), sept (septuplet), oct (octuplet), dd (doublet of doublet), bs (broad singlet), m (multiplet) and “app.” stands for apparent. IR spectra were recorded neat or as thin films using a Nicolet Avatar 370 DTGS FT-IR spectrometer. Melting points were measured on a Melting Point B-540 apparatus and are uncorrected. Optical rotations were measured on Jasco P-2000 polarimeter using a quartz cell (l=10 cm), with a high-pressure sodium lamp (λ = 589 cm). [α]D values are given in 10-1deg.cm2.g-1. High Resolution Mass Spectrometry (HRMS) was performed on a Waters Micromass GTC Premier spectrometer or Bruker MicroTOF QIII spectrometer.


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 32

B. Synthesis of ligands L7a–h (Table 1 and scheme 1) Hydroxy acids 1a–e and ent-1h (S)-2-hydroxy-4-methylpentanoic acid (1a): general procedure GP1 To a cooled (ice bath) solution of L-leucine (19.7 g, 150 mmol, 1 equiv) in 1M H2SO4 (300 mL) was added dropwise a solution of sodium nitrite (62.1 g, 900 mmol, 6 equiv) in H2O (180 mL). The mixture was stirred at 0 °C for 2 h and allowed to stand at room temperature overnight. After extraction with EtOAc (6 × 60 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum pressure. Recrystallization from petroleum ether/Et2O afforded (S)-2-hydroxy-437 methylpentanoic acid (1a) (12.08 g, 61%) as a white solid. [] –14.8 (c = 1.02, H2O) (lit. 38 1 [] –12.7 (c = 1.0, H2O)). mp 70–73 °C (lit. mp 73–75 °C). H NMR (400 MHz, CDCl3) δ: 5.28 (bs,

1H), 4.29 (dd, J = 8.5, 4.7 Hz, 1H), 1.91 (sept, J = 6.8 Hz, 1H), 1.69–1.57 (m, 2H), 0.97 (d, J = 6.8 Hz, 6H).

13

C NMR (100 MHz, CDCl3) δ: 180.0, 68.9, 43.2, 24.5, 22.8, 21.5 (consistent with lit.38). The

enantiomeric purity of 1a was verified by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; Carrier gas : helium, 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C; Oven temp. : 90 °C (hold 2 min.) to 180 °C at 3 °C/min): (R)-1a tR = 5.4 min, (S)-1a tR = 5.7 min . (S)-2-hydroxy-3-methylbutanoic acid (1b) (S)-2-hydroxy-3-methylbutanoic acid (1b) was prepared according to GP1 from L-valine (30.0 g, 256 mmol). Standard work-up and recrystallization (petroleum ether/Et2O) afforded 1b (20.0 g, 66%) as a 39 39 white solid. [] +17.8 (c = 2.08, CHCl3) (lit. [] +19 (c = 2.08, CHCl3)). mp 63–65 °C (lit. mp

65–66 °C). 1H NMR (200 MHz, CDCl3) δ: 4.16 (d, J = 3.4 Hz, 1H), 2.16 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H).

13

C NMR (50 MHz, CDCl3) δ: 179.4, 74.9, 32.0, 18.8, 15.9 (consistent

with lit.39). (2S,3S)-2-hydroxy-3-methylpentanoic acid (1c)


10

Page 11 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(2S,3S)-2-hydroxy-3-methylpentanoic acid (1c) (5.22 g, 79%) was prepared according to GP1 from Lisoleucine (6.56 g, 50 mmol). White solid. 1H NMR (400 MHz, CDCl3) δ: 4.18 (d, J = 3.8 Hz, 1H), 1.89 (m, 1H), 1.44–1.17 (m, 2H), 1.03 (d, J = 7.0 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

13

C NMR (100 MHz,

CDCl3) δ: 179.5, 74.8, 39.1, 23.9, 15.5, 11.9 (consistent with lit.38). (S)-2-hydroxy-3,3-dimethylbutanoic acid (1d) (S)-2-hydroxy-3,3-dimethylbutanoic acid (1d) (3.39 g, 67%) was prepared according to GP1 from L40 tert-leucine (5.00 g, 38.1 mmol). White solid. [] +10.6 (c = 1.0, MeOH) (lit. [] +3.9 (c = 1.0,

MeOH). 1H NMR (400 MHz, CDCl3) δ: 3.89 (s, 1H), 1.02 (s, 9H).

13

C NMR (100 MHz, CDCl3) δ:

178.8, 78.5, 35.4, 26.0 (consistent with lit.40). (S)-2-hydroxy-3-phenylpropanoic acid (1e) (S)-2-hydroxy-3-phenylpropanoic acid (1e) (7.30 g, 90%) was prepared according to GP1 from L41 phenylalanine (8.03 g, 48.6 mmol). White solid. [] –27.3 (c = 1.03, acetone) (lit. [] –27.5 (c =

1.0, acetone). mp 123–125 °C (lit.41 mp 122–123 °C). 1H NMR (400 MHz, CD3OD) δ: 7.26–7.23 (m, 4H), 7.18 (m, 1H), 4.91 (bs, 2H), 4.33 (dd, J = 8.0, 4.4 Hz, 1H), 3.09 (dd, J = 14.0, 4.4 Hz, 1H), 2.89 (dd, J = 14.0, 8.0 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 177.8, 136.0, 129.6, 128.7, 127.3, 71.2, 40.3 (consistent with lit.42). (R)-2-cyclohexyl-2-hydroxyacetic acid (ent-1h) A solution of (R)-mandelic acid (9.40 g, 62 mmol, 1 equiv) in MeOH (50 mL) was charged in a Parr bomb. After the addition of AcOH (0.62 mL) and 5% Rh/C (1.8 g), the bomb was sealed and pressurized to 55 bars with hydrogen. The reaction mixture was stirred at room temperature for 3 days. After filtration through a pad of celite, the filtrate was dried over Na2SO4. Concentration under reduced pressure and purification by recrystallization (toluene) gave (R)-2-cyclohexyl-2-hydroxyacetic acid 1 (ent-1h) as a grey solid (4.86 g, 61%). [] –10.4 (c = 0.98, MeOH). mp 125–127 °C. H NMR (400

MHz, DMSO-d6) δ: 12.28 (bs, 1H), 4.94 (bs, 1H), 3.73 (d, J = 4.3 Hz, 1H), 1.70–1.51 (m, 6H), 1.22–


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1.04 (m, 5H).

Page 12 of 32

13

C NMR (100 MHz, DMSO-d6) δ: 175.2, 74.2, 41.2, 28.8, 26.7, 25.8, 25.7, 25.6

(consistent with lit.43). Hydroxy amides 2a–h (S)-2-hydroxy-N,N,4-trimethylpentanamide (2a) : general procedure GP2 To a solution of (S)-2-hydroxy-4-methylpentanoic acid (1a) (1.20 g, 8.9 mmol, 1 equiv), dimethylamine hydrochloride (0.72 g, 8.9 mmol, 1 equiv) and 1-hydroxy-1H-benzotriazole (1.36 g, 8.9 mmol, 1 equiv) in THF (4.4 mL) was added diisopropylethylamine (1.5 mL, 8.9 mmol, 1 equiv) dropwise at –20 °C under argon. After 2 min, dicyclohexylcarbodiimide (1.92 g, 9.3 mmol, 1.05 equiv) was added at once. The mixture was allowed to stir at room temperature overnight. The formed precipitate was filtered through a pad of celite and washed with EtOAc (10 mL). The combined filtrates were washed with NaHCO3 (2 × 10 mL), dried over Na2SO4, and concentrated under vacuum to give pure (S)-2-hydroxy-N,N,4-trimethylpentanamide (2a) (1.18 g, 84%) as a yellow solid. [] –17.8 (c = 1.03, CHCl3). mp 46–48 °C. 1H NMR (400 MHz, CDCl3) δ: 4.39 (ddd, J = 9.6, 7.4, 2.4 Hz, 1H), 3.62 (d, J = 7.4 Hz, 1H), 3.00 (s, 3H), 2.97 (s, 3H), 1.99 (m, 1H), 1.43 (m, 1H), 1.31 (m, 1H), 1.0 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 175.0, 66.5, 44.0, 36.3, 35.9, 24.6, 23.7, 21.3. IR (neat) ν: 3335, 2948, 2864, 1626, 1119, 1078 cm-1. HRMS (CI+) for C8H17NO2 [M+H]+ : calcd 160.1338 found 160.1329. The enantiomeric purity of 2a was verified by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; Carrier gas : helium, 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C; Oven temp. : 130 °C (hold 2 min.) to 160 °C at 3 °C/min): (R)-2a tR = 3.98 min, (S)-2a tR = 4.16 min . (S)-2-hydroxy-N,N,3-trimethylbutanamide (2b) (S)-2-hydroxy-N,N,3-trimethylbutanamide (2b) was prepared according to GP2 from (S)-2-hydroxy3-methylbutanoic acid (1b) (8.25 g, 69.8 mmol). Bulb-to-bulb distillation (150 °C, 50 mbar) delivered 23a 1 2b (7.19 g, 71%) as a colorless oil. [] [] +51 (c = 1.06, CHCl3) (lit. +54 (c = 1.0, CHCl3)). H

NMR (200 MHz, CDCl3) δ: 4.26 (dd, J = 7.4, 2.9 Hz, 1H), 3.59 (d, J = 7.4 Hz, 1H), 3.01 (s, 3H), 3.00 ACS Paragon Plus Environment

12

Page 13 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(s, 3H), 1.90 (ddd, J = 6.8, 6.8, 2.9 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H). 13C NMR (50 MHz, CDCl3) δ: 174.0, 72.2, 36.6, 35.9, 31.3, 19.8, 15.1 (consistent with lit.23a). (2S,3S)-2-hydroxy-N,N,3-trimethylpentanamide (2c) (2S,3S)-2-hydroxy-N,N,3-trimethylpentanamide (2c) was prepared according to GP2 from (2S,3S)-2hydroxy-3-methylpentanoic acid (1c) (5.22 g, 39.5 mmol). Standard workup and purification by chromatography on silica gel (cyclohexane/EtOAc: 60/40 → 20/80) gave 2c (4.25 g, 67%) as a colorless 1 oil. [] +45.1 (c = 1.03, CHCl3). H NMR (400 MHz, CDCl3) δ: 4.26 (d, J = 3.4 Hz, 1H), 3.56 (bs,

1H), 3.01 (s, 3H), 3.00 (s, 3H), 1.62 (m, 1H), 1.35 (m, 1H), 1.19 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 174.1, 72.4, 38.5, 36.7, 36.0, 22.3, 16.3, 11.8. IR (neat) ν : 3427, 2963, 2935, 1639, 1374, 1108, 1043 cm-1. HRMS (ESI+) for C8H17NO2 [M+Na]+: calcd 182.1151 found 182.1154. (S)-2-hydroxy-N,N,3,3-tetramethylbutanamide (2d) (S)-2-hydroxy-N,N,3,3-tetramethylbutanamide (2d) was prepared according to GP2 from (S)-2hydroxy-3,3-dimethylbutanoic acid (1d) (6.12 g, 46.3 mmol). Purification by sublimation (60 °C, 20 1 mbar) delivered 2d (5.31 g, 72%) as a white solid. [] +67.5 (c = 1.06, CHCl3). mp 50–52 °C. H

NMR (400 MHz, CDCl3) δ: 4.19 (d, J = 9.4 Hz, 1H), 3.33 (d, J = 9.4 Hz, 1H), 3.04 (s, 3H), 3.00 (s, 3H), 0.97 (s, 9H).

13

C NMR (100 MHz, CDCl3) δ: 173.9, 74.0, 37.9, 36.6, 35.8, 25.9. IR (neat) ν : 3382,

2952, 1631, 1326, 1076, 853 cm-1. HRMS (ESI+) for C8H17NO2 [M+Na]+: calcd 182.1151 found 182.1151. (S)-2-hydroxy-N,N-dimethyl-3-phenylpropanamide (2e) (S)-2-hydroxy-N,N-dimethyl-3-phenylpropanamide (2e) was prepared according to GP2 from (S)-2hydroxy-3-phenylpropanoic acid (1e) (7.3 g, 43.9 mmol). Standard workup and purification by chromatography on silica gel (cyclohexane/EtOAc: 50/50) gave 2e (4.7 g, 54%) as a yellow 44 44 1 solid. [] +34.9 (c = 2.0, EtOH) (lit. [] +37.3 (c = 2.0, EtOH). mp 63–65 °C (lit. mp 66 °C). H

NMR (400 MHz, CDCl3) δ: 7.31–7.21 (m, 5H), 4.58 (m, 1H), 3.75 (d, J = 8.4 Hz, 1H), 2.96 (s, 3H), ACS Paragon Plus Environment

13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2.91–2.84 (m, 2H), 2.78 (s, 3H).

13

Page 14 of 32

C NMR (100 MHz, CDCl3) δ: 173.8, 137.0, 129.4, 128.5, 126.9,

69.1, 42.0, 36.3, 35.9 (consistent with lit.44). (S)-3-cyclohexyl-2-hydroxy-N,N-dimethylpropanamide (2f) A solution of (S)-2-hydroxy-N,N-dimethyl-3-phenylpropanamide (2e) (2.2 g, 11 mmol) in a mixture of EtOH (11 mL), H2O (1.5 mL) and AcOH (1.5 mL) was charged to a Parr bomb and treated with 260 mg of 5% Rh/C. The bomb was sealed and pressurized to 50 bars with hydrogen. The reaction was then stirred at 50 °C for 60 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and washed with 10% aq. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to give (S)-3-cyclohexyl-2-hydroxy-N,N-dimethylpropanamide (2f) (2.2 g, 1 100%) as a yellow oil. [] –16.9 (c = 1.06, CHCl3). H NMR (400 MHz, CDCl3) δ: 4.38 (m, 1H), 3.58

(bs, 1H), 2.95 (s, 3H), 2.91 (s, 3H), 1.91 (m, 1H), 1.69–1.61 (m, 5H), 1.34–1.10 (m, 5H), 0.97–0.83 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 175.3, 66.1, 42.9, 36.4, 36.1, 34.6, 34.1, 32.4, 26.7, 26.5, 26.2. IR (neat) ν : 3423, 2922, 2849, 1639, 1378, 1074 cm-1. HRMS (ESI+) for C11H21NO2 [M+Na]+: calcd 222.1464 found 222.1473. (R)-2-hydroxy-N,N-dimethyl-2-phenylacetamide (ent-2g) (R)-2-hydroxy-N,N-dimethyl-2-phenylacetamide (ent-2g) was prepared according to GP2 from (R)mandelic acid (6.10 g, 40 mmol). Standard workup and purification by chromatography on silica gel (cyclohexane/EtOAc: 70/30 → 30/70) gave ent-2g (2.64 g, 37%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.38–7.30 (m, 5H), 5.17 (s, 1H), 4.71 (bs, 1H), 3.00 (s, 3H), 2.75 (s, 3H).

13

C NMR (100

MHz, CDCl3) δ: 172.6, 139.4, 129.2, 128.7, 127.7, 71.8, 36.6, 36.5 (consistent with lit.45). (R)-2-cyclohexyl-2-hydroxy-N,N-dimethylacetamide (ent-2h) (R)-2-cyclohexyl-2-hydroxy-N,N-dimethylacetamide (ent-2h) was prepared according to GP2 from (R)-2-cyclohexyl-2-hydroxyacetic acid (ent-1h) (4.86 g, 30.7 mmol). Standard workup and purification by chromatography on silica gel (cyclohexane/EtOAc: 70/30 → 30/70) gave ent-2h (4.50 g, 79%) as a 1 white solid. [] –43.3 (c = 0.99, CHCl3). mp 100–102 °C. H NMR (400 MHz, CDCl3) δ: 4.21 (dd, J


14

Page 15 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


= 7.5, 3.0 Hz, 1H), 3.55 (d, J = 7.5 Hz, 1H), 3.01 (s, 3H), 2.99 (s, 3H), 1.81–1.75 (m, 2H), 1.65–1.62 (m, 2H), 1.54–1.39 (m, 3H), 1.27–1.14 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 174.0, 72.3, 41.7, 36.8, 36.1, 30.0, 26.7, 26.2, 26.1, 25.8 (consistent with lit. 46) Methoxy amides 3a–h (S)-2-methoxy-N,N,4-trimethylpentanamide (3a) : general procedure GP3 Methyl iodide (4.4 mL, 70.7 mmol, 1.7 equiv) and NaH (60% in mineral oil, 2.8 g, 70.7 mmol, 1.7 equiv) were successively added to a solution of (S)-2-hydroxy-N,N,4-trimethylpentanamide (2a) (6.62 g, 41.6 mmol, 1 equiv) in THF (120 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature prior to the addition of saturated NH4Cl(aq) (50 mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude (S)-2-methoxy-N,N,4-trimethylpentanamide (3a), which was used in the next step without further purification. An analytically pure sample of 3a was obtained as a colorless oil after removal of grease by filtration through a plug of silica gel (cyclohexane/EtOAc : 1 70/30). [] +3.1 (c = 1.06, CHCl3). H NMR (400 MHz, CDCl3) δ: 4.07 (dd, J = 9.5, 4.2 Hz, 1H),

3.31 (s, 3H), 3.10 (s, 3H), 2.97 (s, 3H), 1.83 (m, 1H), 1.70 (m, 1H), 1.40 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 172.3, 79.8, 57.2, 41.2, 36.6, 36.3, 24.9, 23.4, 22.0. IR (neat) ν: 2931, 1639, 1398, 1104 cm-1. HRMS (ESI +) for C9H19NO2 [M+H]+ : calcd 174.1489 found 174.1489. The enantiomeric purity of 3a was verified by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; Carrier gas : helium, 1.5 mL/min; Injector : set at 220 °C ; Detector : FID set at 230 °C; Oven temp. : 90 °C (hold 2 min.) to 180 °C at 3 °C/min): (S)-3a tR = 9.2 min, (R)-3a tR = 9.3 min. (S)-2-methoxy-N,N,3-trimethylbutanamide (3b) Crude (S)-2-methoxy-N,N,3-trimethylbutanamide (3b) was prepared according to GP3 from (S)-2hydroxy-N,N,3-trimethylbutanamide (2b) (7.19 g, 49.5 mmol). An analytically pure sample of 3b was obtained as a colorless oil after removal of grease by filtration through a plug of silica gel ACS Paragon Plus Environment

15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 32

1 (cyclohexane/EtOAc : 70/30). [] –35.5 (c = 1.07, CHCl3). H NMR (400 MHz, CDCl3) δ: 3.67 (d, J

= 7.6 Hz, 1H), 3.32 (s, 3H), 3.13 (s, 3H), 2.99 (s, 3H), 2.01 (oct, J = 6.9 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.5, 87.1, 57.4, 36.5, 36.1, 30.8, 18.9, 18.8. IR (neat) ν : 2931, 1639, 1398, 1099, 987 cm-1. HRMS (CI+) for C8H17NO2 [M+H]+ : calcd 160.1338 found 160.1331. (2S,3S)-2-methoxy-N,N,3-trimethylpentanamide (3c) Crude (2S,3S)-2-methoxy-N,N,3-trimethylpentanamide (3c) was prepared according to GP3 from (2S,3S)-2-hydroxy-N,N,3-trimethylpentanamide (2c) (2.50 g, 15.7 mmol). An analytically pure sample of 3c was obtained as a colorless oil by bulb-to-bulb distillation (130 °C, 50 mbar). [] –47.1 (c = 1.03, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 3.73 (d, J = 8.7 Hz, 1H), 3.32 (s, 3H), 3.14 (s, 3H), 2.99 (s, 3H), 1.83–1.69 (m, 2H), 1.22 (m, 1H), 0.92–0.86 (m, 6H).

13

C NMR (100 MHz, CDCl3) δ: 170.9,

87.4, 58.0, 37.6, 36.3, 35.5, 26.6, 15.0, 10.9. IR (neat) ν : 2963, 2933, 1639, 1398, 1099 cm-1. HRMS (ESI+) for C9H19NO2 [M+H]+: calcd 174.1489 found 174.1485. (S)-2-methoxy-N,N,3,3-tetramethylbutanamide (3d) Crude (S)-2-methoxy-N,N,3,3-tetramethylbutanamide (3d) was prepared according to GP3 from (S)2-hydroxy-N,N,3,3-tetramethylbutanamide (2d) (2.64 g, 16.6 mmol). An analytically pure sample of 3d 1 was obtained as a beige solid by sublimation. [] –21.4 (c = 1.0, CHCl3). mp 66–68 °C. H NMR (400

MHz, CDCl3) δ: 3.80 (s, 1H), 3.31 (s, 3H), 3.16 (s, 3H), 3.00 (s, 3H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 170.9, 87.4, 58.0, 37.6, 36.3, 35.5, 26.6. IR (neat) ν : 2969, 2924, 1641, 1354, 1102, 851 cm-1. HRMS (ESI+) for C9H20NO2 [M+H]+: calcd 174.1489 found 174.1494. (S)-2-methoxy-N,N-dimethyl-3-phenylpropanamide (3e) Crude (S)-2-methoxy-N,N-dimethyl-3-phenylpropanamide (3e) was prepared according to GP3 from (S)-2-hydroxy-N,N-dimethyl-3-phenylpropanamide (2e) (2.0 g, 10 mmol). An analytically pure sample of 3e was obtained as a colorless oil after removal of grease by filtration through a plug of silica gel 1 (cyclohexane/EtOAc : 70/30). [] +0.5 (c = 0.98, CHCl3). H NMR (400 MHz, CDCl3) δ: 7.29–7.22


16

Page 17 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(m, 5H), 4.28 (dd, J = 7.5, 6.3 Hz, 1H), 3.30 (s, 3H), 3.05–3.01 (m, 2H), 2.94 (s, 3H), 2.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.1, 137.4, 129.4, 128.4, 126.7, 80.9, 56.9, 38.6, 36.4, 36.0. IR (neat) ν : 2931, 1639, 1106, 702 cm-1. HRMS (ESI+) for C12H17NO2 [M+Na]+: calcd 230.1151 found 230.1150. (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropanamide (3f) Crude (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropanamide (3f) was prepared according to GP3 from (S)-3-cyclohexyl-2-hydroxy-N,N-dimethylpropanamide (2f) (2.2 g, 11 mmol). An analytically pure sample of 3f was obtained as a colorless oil after removal of grease by filtration through a plug of silica 1 gel (cyclohexane/EtOAc : 70/30). [] –15.4 (c = 1.19, CHCl3). H NMR (400 MHz, CDCl3) δ: 4.10

(dd, J = 9.6, 4.0 Hz, 1H), 3.30 (s, 3H), 3.09 (s, 3H), 2.96 (s, 3H), 1.80 (m, 1H), 1.73–1.63 (m, 5H), 1.51 (m, 1H), 1.43 (m, 1H), 1.30–1.14 (m, 3H), 0.99–0.85 (m, 2H).

13

C NMR (100 MHz, CDCl3) δ: 172.4,

79.1, 57.3, 39.9, 36.6, 36.4, 34.3, 32.8, 26.7, 26.4, 26.3. IR (neat) ν : 2920, 2851, 1641, 1398, 1112 cm-1. HRMS (ESI+) for C12H23NO2 [2M+Na]+: calcd 449.3350 found 449.3351. (R)-2-methoxy-N,N-dimethyl-2-phenylacetamide (ent-3g) Crude (R)-2-methoxy-N,N-dimethyl-2-phenylacetamide (ent-3g) was prepared according to GP3 from (R)-2-hydroxy-N,N-dimethyl-2-phenylacetamide (ent-2g) (2.64 g, 14.7 mmol). An analytically pure sample of ent-3g was obtained as a colorless oil after removal of grease by filtration through a plug of silica gel (cyclohexane/EtOAc : 70/30). 1H NMR (400 MHz, CDCl3) δ: 7.44–7.31 (m, 5H), 4.99 (s, 1H), 3.41 (s, 3H), 2.93 (s, 3H), 2.88 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ: 170.3, 136.6, 128.9, 128.5,

127.1, 83.6, 57.7, 36.7, 36.4 (consistent with lit.47). (R)-2-cyclohexyl-2-methoxy-N,N-dimethylacetamide (ent-3h) Crude (R)-2-cyclohexyl-2-methoxy-N,N-dimethylacetamide (ent-3h) was prepared according to GP3 from (R)-2-cyclohexyl-2-hydroxy-N,N-dimethylacetamide (ent-2h) (4.5 g, 24.3 mmol). An analytically pure sample of ent-3h was obtained as a yellow oil after removal of grease by filtration through a plug 1 of silica gel (cyclohexane/EtOAc : 70/30). [] +28.8 (c = 1.04, CHCl3). H NMR (400 MHz, CDCl3)

δ: 3.73 (d, J = 7.9 Hz, 1H), 3.31 (s, 3H), 3.13 (s, 3H), 2.98 (s, 3H), 1.98 (m, 1H), 1.77–1.69 (m, 3H), ACS Paragon Plus Environment

17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 32

1.65 (m, 1H), 1.52 (m, 1H), 1.24–0.98 (m, 5H). 13C NMR (100 MHz, CDCl3) δ: 171.5, 86.7, 57.5, 40.4, 36.5, 36.1, 29.4, 29.1, 26.3, 26.0, 25.9. IR (neat) ν: 2924, 2853, 1639, 1398, 1112 cm-1. HRMS (ESI+) for C11H21NO2 [M+H]+: calcd 200.1645 found 200.1641. Amino ethers L7a–h (S)-2-methoxy-N,N,4-trimethylpentan-1-amine (L7a) : general procedure GP4 To a suspension of LiAlH4 (4.4 g, 116.1 mmol, 3 equiv) in dry Et2O (70 mL) at 0 °C was added a solution of crude (S)-2-methoxy-N,N,4-trimethylpentanamide (3a) (38.7 mmol, 1 equiv) in dry Et2O (140 mL). The reaction mixture was refluxed overnight, cooled to 0 °C and diluted with Et2O (50 mL). After the portionwise addition of Na2SO4.10H2O (3 equiv), the resulting mixture was stirred at room temperature for 1 h. The solids were removed by filtration through a pad of celite and were washed with Et2O (50 mL). The filtrate was dried over Na2SO4 and diethyl ether was removed by simple distillation. Purification by bulb-to-bulb distillation (130 °C, 550 mbar) provided (S)-2-methoxy-N,N,4trimethylpentan-1-amine (L7a) (4.9 g, 79% from 2a ) as a colorless oil. [] –11.8 (c = 1.03, CHCl3). 1

H NMR (400 MHz, CDCl3) δ: 3.37 (s, 3H), 3.33 (m, 1H), 2.41 (dd, J = 12.7, 6.7 Hz, 1H), 2.25 (s, 6H),

2.21 (dd, J = 12.7, 4.6 Hz, 1H), 1.73 (m, J = 6.7 Hz, 1H), 1.43 (m, 1H), 1.28 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H).

13

C NMR (100 MHz, CDCl3) δ: 77.6, 63.8, 56.8, 46.4, 42.3, 24.9, 23.4, 22.8. IR (neat) ν :

2954, 2820, 2766, 1460, 1100, 1045 cm-1. HRMS (ESI+) for C9H21NO [M+H]+ : calcd 160.1696 found 160.1701. (S)-2-methoxy-N,N,3-trimethylbutan-1-amine (L7b) (S)-2-methoxy-N,N,3-trimethylbutan-1-amine (L7b) was prepared according to GP4 from crude (S)-2methoxy-N,N,3-trimethylbutanamide (3b) (49.5 mmol). Standard workup and bulb-to-bulb distillation (100 °C, 300 mbar) gave (S)-2-methoxy-N,N,3-trimethylbutan-1-amine (L7b) (4.14 g, 57% from 2b) as 1 a colorless oil. [] +27.5 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ: 3.38 (s, 3H), 3.08 (m, 1H),

2.36 (m, 1H), 2.27–2.23 (m, 7H), 1.93 (m, 1H), 0.90 (d, J = 7.0 Hz, 6H). 13C NMR (100 MHz, CDCl3)


18

Page 19 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


δ: 84.0, 60.7, 57.9, 46.5, 29.7, 18.0, 17.9. IR (neat) ν: 2957, 2820, 2766, 1460, 1097, 1035 cm-1. HRMS (CI+) for C8H19NO [M+H]+ : calcd 146.1545 found 146.1542. (2S,3S)-2-methoxy-N,N,3-trimethylpentan-1-amine (L7c) (2S,3S)-2-methoxy-N,N,3-trimethylpentan-1-amine (L7c) was prepared according to GP4 from crude (2S,3S)-2-methoxy-N,N,3-trimethylpentanamide (3c) (25.6 mmol). Standard workup and bulb-to-bulb distillation (130 °C, 400 mbar) gave (2S,3S)-2-methoxy-N,N,3-trimethylpentan-1-amine (L7c) (2.3 g, 1 69% from 2c) as a colorless oil. [] +14.1 (c = 1.03, CHCl3). H NMR (400 MHz, CDCl3) δ: 3.37 (s,

3H), 3.17 (m, 1H), 2.37 (m, 1H), 2.25–2.19 (m, 7H), 1.72 (m, 1H), 1.41 (m, 1H), 1.17 (m, 1H), 0.92 (t, J = 7.5 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ: 82.9, 60.3, 57.3, 46.5, 36.1,

25.6, 14.0, 12.3. IR (neat) ν : 2963, 2818, 2766, 1460, 1095, 1037 cm-1. HRMS (CI+) for C9H21NO [M+H]+ : calcd 160.1701 found 160.1699. (S)-2-methoxy-N,N,3,3-tetramethylbutan-1-amine (L7d) (S)-2-methoxy-N,N,3,3-tetramethylbutan-1-amine (L7d) was prepared according to GP4 from crude (S)-2-methoxy-N,N,3,3-tetramethylbutanamide (3d) (16.6 mmol). Standard workup and bulb-to-bulb distillation (130 °C, 400 mbar) gave (S)-2-methoxy-N,N,3,3-tetramethylbutan-1-amine (L7d) (1.35 g, 1 51% from 2d) as a colorless oil. [] +10 (c = 1.03, CHCl3). H NMR (400 MHz, CDCl3) δ: 3.50 (s,

3H), 2.86 (dd, J = 6.4, 3.9 Hz, 1H), 2.35–2.32 (m, 2H), 2.25 (s, 6H), 0.90 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 87.3, 62.0, 60.3, 46.4, 35.3, 26.3. IR (neat) ν : 2948, 2818, 2764, 1460, 1106, 1041 cm-1. HRMS (CI+) for C9H21NO [M+H]+ : calcd 160.1701 found 160.1698. (S)-2-methoxy-N,N-dimethyl-3-phenylpropan-1-amine (L7e) (S)-2-methoxy-N,N-dimethyl-3-phenylpropan-1-amine (L7e) was prepared according to GP4 from crude (S)-2-methoxy-N,N-dimethyl-3-phenylpropanamide (3e) (10 mmol). Standard workup and bulbto-bulb distillation (150 °C, 70 mbar) gave (S)-2-methoxy-N,N-dimethyl-3-phenylpropan-1-amine (L7e) 1 (1.12 g, 58% from 2e) as a colorless oil. [] +8.3 (c = 1.03, CHCl3). H NMR (400 MHz, CDCl3) δ:

7.30–7.18 (m, 5H), 3.51 (m, 1H), 3.36 (s, 3H), 2.82 (d, J = 6.0 Hz, 2H), 2.37 (dd, J = 13.2, 7.0 Hz, 1H), ACS Paragon Plus Environment

19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2.26–2.22 (m, 7H).

13

Page 20 of 32

C NMR (100 MHz, CDCl3) δ: 139.1, 129.7, 128.4, 126.3, 80.8, 62.9, 57.4, 46.5,

38.8. IR (neat) ν : 2936, 2820, 2767, 1456, 1102, 1033, 726 cm-1. HRMS (ESI+) for C12H19NO [M+H]+ : calcd 194.1539 found 194.1541. (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropan-1-amine (L7f) (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropan-1-amine (L7f) was prepared according to GP4 from crude (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropanamide (3f) (11 mmol). Standard workup and bulb-to-bulb distillation (150 °C, 70 mbar) gave (S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropan-11 amine (L7f) (1.62 g, 74% from 2f) as a colorless oil. [] +2.4 (c = 1.02, CHCl3). H NMR (400 MHz,

CDCl3) δ: 3.37–3.34 (m, 4H), 2.41 (dd, J = 12.9, 6.8 Hz, 1H), 2.25 (s, 6H), 2.20 (dd, J = 12.9, 4.7 Hz, 1H), 1.75–1.67 (m, 5H), 1.45–1.11 (m, 6H), 0.98–0.87 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 77.0, 63.9, 56.8, 46.5, 40.9, 34.5, 34.2, 33.6, 26.8, 26.6, 26.5. IR (neat) ν : 2922, 2851, 2818, 2766, 1451, 1104, 1045 cm-1. HRMS (CI+) for C12H25NO [M+H]+ : calcd 200.2014 found 200.2010. (R)-2-methoxy-N,N-dimethyl-2-phenylethanamine (ent-L7g) (R)-2-methoxy-N,N-dimethyl-2-phenylethanamine (ent-L7g) was prepared according to GP4 from crude (R)-2-methoxy-N,N-dimethyl-2-phenylacetamide (ent-3g) (14.7 mmol). Standard workup and bulb-to-bulb distillation (150 °C, 70 mbar) gave (R)-2-methoxy-N,N-dimethyl-2-phenylethanamine 43 (ent-L7g) (1.71 g, 65% from ent-2g) as a colorless oil. [] –104 (c = 1.18, MeOH) (lit. [] for

(S)-enantiomer : +118 (c = 1.18, MeOH). 1H NMR (400 MHz, CDCl3) δ: 7.37–7.28 (m, 5H), 4.26 (dd, J = 9.3, 3.3 Hz, 1H), 3.21 (s, 3H), 2.69 (dd, J = 13.3, 9.3 Hz, 1H), 2.28 (s, 6H), 2.25 (dd, J = 13.3, 3.3 Hz, 1H).

13

C NMR (100 MHz, CDCl3) δ: 141.1, 128.6, 127.9, 126.9, 82.2, 67.0, 57.0, 46.2. IR (neat) ν :

2939, 2820, 2767, 1454, 1106, 1065, 1026, 758, 702 cm-1. HRMS (CI+) for C11H17NO [M+H]+ : calcd 180.1388 found 180.1383 (consistent with lit. 48). (R)-2-cyclohexyl-2-methoxy-N,N-dimethylethanamine (ent-L7h) (R)-2-cyclohexyl-2-methoxy-N,N-dimethylethanamine (ent-L7h) was prepared according to GP4 from crude (R)-2-cyclohexyl-2-methoxy-N,N-dimethylacetamide (ent-3h) (24.2 mmol). Standard ACS Paragon Plus Environment

20

Page 21 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


workup and bulb-to-bulb distillation (130 °C, 100 mbar) gave (R)-2-cyclohexyl-2-methoxy-N,Ndimethylethanamine (ent-L7h) (3.17 g, 70% from ent-2h) as a colorless oil. [] –12.3 (c = 1.01, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 3.39 (s, 3H), 3.05 (m, 1H), 2.36 (m, 1H), 2.30–2.24 (m, 7H), 1.80–1.54 (m, 6H), 1.31–1.02 (m, 5H).

13

C NMR (100 MHz, CDCl3) δ: 83.6, 60.9, 57.8, 46.3, 40.1,

28.6, 28.3, 26.7, 26.5. IR (neat) ν : 2924, 2853, 2818, 2764, 1452, 1102, 1045, 849 cm-1. HRMS (CI+) for C11H23NO [M+H]+ : calcd 186.1858 found 186.1854. C. Synthesis of ligands L8a–b (S)-1-methoxy-N,N-4-trimethylpentan-2-amine (L8a) : general procedure GP5 A mixture of (S)-N,N-dimethylleucinol49 (7.4 g, 51 mmol, 1 equiv) and NaH (6.12 g, 153 mmol, 3 equiv) in dry Et2O (78 mL) was stirred under argon at room temperature for 4 h. Dimethyl sulfate (2.9 mL, 30.3 mmol, 0.6 equiv) in dry Et2O (10 mL) was added dropwise to the reaction mixture and the suspension was stirred at room temperature overnight. The excess of NaH was carefully quenched with saturated aqueous NH4Cl (15 mL). The aqueous phase was extracted with Et2O (4 × 20 mL). The combined extracts were dried over Na2SO4 and the solvent was distilled off. Purification by bulb-tobulb distillation (120 °C, 400 mbar) afforded (S)-1-methoxy-N,N-4-trimethylpentan-2-amine (L8a) 1 (4.53 g, 56%) as a colorless oil. [] +18.3 (c = 1.02, CHCl3). H NMR (400 MHz, CDCl3) δ: 3.44 (dd,

J = 9.9, 7.2, 1H), 3.34 (s, 3H), 3.26 (dd, J = 9.9, 4.1 Hz, 1H), 2.69 (m, 1H), 2.29 (s, 6H), 1.61 (sept, J = 6.7 Hz, 1H), 1.30 (m, 1H), 1.09 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ: 72.8, 61.0, 58.9, 40.9, 36.1, 25.5, 23.1, 22.6. IR (neat) ν : 2956, 2926, 2868, 2825, 2779, 1460, 1115 cm-1. HRMS (CI+) for C9H21NO [M+H]+ : calcd 160.1701 found 160.1696. (S)-1-methoxy-N,N-3-trimethylbutan-2-amine (L8b) The title compound L8b was prepared from (S)-N,N-dimethylvalinol (3.0 g, 22.9 mmol) according to GP5. Standard workup and bulb-to-bulb distillation (100 °C, 400 mbar) gave (S)-1-methoxy-N,N-31 trimethylbutan-2-amine (L8b) (1.59 g, 48 %) as a colorless oil. [] –4.6 (c = 1.03, CHCl3). H NMR


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 32

(400 MHz, CDCl3) δ: 3.45–3.43 (m, 2H), 3.31 (s, 3H), 2.32 (s, 6H), 2.15 (m, 1H), 1.86 (sept, J = 6.6 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 70.4, 69.4, 58.6, 42.1, 27.8, 21.2, 19.4 (consistent with lit.29). IR (neat) ν : 2956, 2928, 2872, 2825, 2779, 1462, 1110 cm-1. HRMS (CI +) for C8H19NO [M+H]+ : calcd 146.1545 found 146.1539. D. Synthesis of bromoarenes 4, 6, 7, 10 and 12 N,N-diallyl-2-bromoaniline (4)8a and N,N-diallyl-2-bromo-3-methylaniline (6)8a were synthesized by N,N-diallylation of 2-bromoaniline and 2-bromo-3-methylaniline. N-allyl-2-bromoaniline (7)15a was prepared from 2-bromoaniline. 2-bromo-4,6-dimethylphenyl 2-propenyl ether (10)4 was synthesized from 2-bromo-4,6-dimethylphenol and allylbromide. 2-bromo-1-(3-butenyl)benzene (12)50 was prepared by the reaction of 2-bromobenzyl bromide51 and allylmagnesium bromide. E. Screening of ligands (Table 2) – General procedure GP6 A solution of N,N-diallyl-2-bromoaniline (4) (126 mg, 0.5 mmol, 1 equiv) in anhydrous Et2O (4 mL) was cooled to –78 °C in a flame-dried Schlenk tube under argon. t-BuLi in pentane (1.1 mmol, 2.2 equiv) was added dropwise and a beige precipitate formed. After 10 min at –78 °C, a solution of ligand (1.1 mmol, 2.2 equiv) in anhydrous Et2O (1 mL) was added dropwise to give a homogeneous pale yellow solution. After 10 min at –78 °C, the reaction vessel was transferred to a –40 °C cooling bath (the yellow color deepened) and the mixture was stirred at this temperature for 3 h. After being cooled to –78 °C, the reaction mixture was quenched with 1 mL of deoxygenated dry MeOH and was allowed to reach room temperature. An aqueous saturated NH4Cl solution (5 mL) was added and the organic layer was dried over MgSO4. The yields and the enantiomeric ratios, summarized in Table 2, were determined by CSP-GC analysis of an aliquot of the organic layer (30 m × 250 µm × 0.25 µm CPChirasil-Dex CB column; carrier gas : helium : 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C; Oven temp. : 115 °C (hold 14 min) to 180 °C at 20 °C/min: (S)-5 tR = 12.8 min, (R)-5 tR = 13.1 min.


22

Page 23 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


F. Optimized procedure for the carbolithiation of anilines 4, 6, 7, 10, 12 (Table 3, scheme 2 and scheme 3) – General procedure GP7 A solution of ligand L7b (0.25–3.3 equiv) in anhydrous toluene (4 mL) was cooled to –78 °C in a flame-dried Schlenk tube under argon. t-BuLi in pentane (1.05–3.3 equiv) was added dropwise and an intense yellow solution formed. A solution of bromoarene (4, 6, 7, 10 or 12, 0.5 mmol, 1 equiv) in anhydrous toluene (1 mL) was then added dropwise and the mixture was stirred for an additional 10 min at –78 °C. The reaction vessel was then transferred to a constant-temperature bath maintained at the specified temperature (–40 °C, +5 °C or 20 °C) and stirred for 1–6 h. The reaction mixture was then recooled to –78 °C, quenched by the addition of 1 mL of deoxygenated dry MeOH, and allowed to reach room temperature. An aqueous saturated NH4Cl solution (5 mL) was added, the phases were separated, and the organic layer was dried over MgSO4. The yields and the enantiomeric ratios were determined by CSP-GC analysis of an aliquot of the organic layer. (R)-1-allyl-3-methylindoline (5) (entry 5, table 3) Following the general procedure GP7, L7b (160 mg, 1.1 mmol), t-BuLi (0.72 mL, 1.52 M in pentane, 1.1 mmol) and 4 (126 mg, 0.5 mmol) were reacted at –40 °C for 3 h. After standard work-up, the yield and enantiomeric ratio of 5 were determined by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; carrier gas : helium ; 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 115 °C (hold 14 min.) to 180 °C at 20 °C/min): (S)-5 tR = 12.8 min, (R)-5 tR = 13.1 min. An analytically pure sample of 5 was obtained by flash chromatography on silica gel (cyclohexane / CH2Cl2: 100/0 → 85/15). Colorless oil. For an 8b

enantiomeric ratio of 95:5, []

–59.4 (c = 0.98, CH2Cl2) (lit. er = 93:7 : [] –50.6 (c = 0.97,

CH2Cl2)).1H NMR (400 MHz, CDCl3) δ: 7.08–7.04 (m, 2H), 6.68 (td, J = 7.4, 0.9 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 5.90 (ddt, J = 17.2, 10.2, 6.0 Hz, 1H), 5.28 (app. dq, J = 17.2, 1.7 Hz, 1H), 5.18 (app. dq, J = 10.2, 1.7 Hz, 1H), 3.78 (app. ddt, J = 15.1, 6.0, 1.7 Hz, 1H), 3.61 (app. ddt, J = 15.1, 6.0, 1.7 Hz, 1H), 3.55 (app. t, J = 8.6 Hz, 1H), 3.28 (m, J = 7.5 Hz, 1H), 2.85 (app. t, J = 8.6 Hz, 1H) 1.30 (d, J = 6.8 Hz, ACS Paragon Plus Environment

23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 32

3H). 13C NMR (100 MHz, CDCl3) δ: 151.8, 135.2, 134.2, 127.4, 123.1, 117.7, 117.2, 107.3, 61.3, 52.0, 35.2, 18.6 (consistent with lit.3a). (R)-1-allyl-3,4-dimethylindoline (8) Following the general procedure GP7, L7b (160 mg, 1.1 mmol), t-BuLi (0.73 mL, 1.50 M in pentane, 1.1 mmol) and 6 (133 mg, 0.5 mmol) were reacted at –40 °C for 3 h. After standard work-up, the yield and enantiomeric ratio of 8 were determined by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; carrier gas : helium ; 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 115 °C (hold 14 min.) to 180 °C at 20 °C/min): (R)-8 tR = 16.1 min, (S)-8 tR = 16.2 min. An analytically pure sample of 8 was obtained by flash chromatography on silica gel (cyclohexane / CH2Cl2: 100/0 → 85 /15). Brown oil. For an 8a enantiomeric ratio of 95:5, [] –117.3 (c = 0.33, CH2Cl2) (lit. er = 85:15, [] –110 (c = 0.33,

CH2Cl2)). 1H NMR (400 MHz, CDCl3) δ: 6.98 (t, J = 7.7 Hz, 1H), 6.47 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.89 (ddt, J = 17.2, 10.3, 6.0 Hz, 1H), 5.26 (app. dq, J = 17.2, 1.6 Hz, 1H), 5.17 (app. dq, J = 10.3, 1.6 Hz, 1H), 3.79 (app. ddt, J = 15.3, 6.0, 1.6 Hz, 1H), 3.57 (app. ddt, J = 15.3, 6.0, 1.6 Hz, 1H), 3.36 (app. t, J = 8.4 Hz, 1H), 3.27 (m, 1H), 3.09 (dd, J = 8.4, 2.7 Hz, 1H), 2.25 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ: 151.2, 134.3, 133.7, 133.4, 127.5, 119.5, 117.1, 105.0, 60.8,

51.9, 34.2, 19.1, 18.2 (consistent with lit.8a). (R)-3-methylindoline (9) Following the general procedure GP7, L7b (218 mg, 1.5 mmol), t-BuLi (1.0 mL, 1.50 M in pentane, 1.5 mmol) and 7 (106 mg, 0.5 mmol) were reacted at +5 °C for 6 h. After standard work-up, the yield and enantiomeric ratio of 9 were determined by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; carrier gas : helium ; 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 115 °C (hold 14 min.) to 180 °C at 20 °C/min): (S)-9 tR = 9.6 min, (R)-9 tR = 9.8 min. An analytically pure sample of 9 was obtained by flash ACS Paragon Plus Environment

24

Page 25 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chromatography on silica gel (cyclohexane / CH2Cl2: 80/20 → 50 /50). Colorless oil. For an 52 enantiomeric ratio of 92:8, [] –35.5 (c = 0.265, CHCl3) (lit. er = 99.5: 0.5 : [] –30.2 (c = 0.25,

CHCl3)). 1H NMR (400 MHz, CDCl3) δ: 7.08 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 3.69 (app. t, J = 8.6 Hz, 1H), 3.59 (bs, 1H), 3.36 (m, 1H), 3.11 (app. t, J = 8.6 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 151.2, 134.4, 127.3, 123.4, 118.7, 109.6, 55.5, 36.7, 18.6 (consistent with lit.52). (R)-3-methyl-5,7-dimethyl-2,3-dihydrobenzofuran (11) Following the general procedure GP7, L7b (160 mg, 1.1 mmol), t-BuLi (0.72 mL, 1.55 M in pentane, 1.1 mmol) and 10 (120 mg, 0.5 mmol) were reacted at –40 °C overnight. After standard work-up, the yield and enantiomeric ratio of 11 were determined by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; carrier gas : helium ; 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 70 °C (hold 90 min.) to 180 °C at 20 °C/min): (R)-11 tR = 76.3 min, (S)-11 tR = 79.4 min. An analytically pure sample of 11 was obtained by flash chromatography on silica gel (Petroleum ether / CH2Cl2: 100/0 → 80/20). Colorless oil. For an 1 enantiomeric ratio of 95:5, [] – 5.0 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ: 6.79 (s, 1H),

6.75 (s, 1H), 4.65 (app. t, J = 8.7 Hz, 1H), 4.03 (dd, J = 8.7, 7.6 Hz, 1H), 3.49 (m, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 156.0, 131.6, 129.8, 129.7, 121.7, 119.1, 78.4, 36.9, 20.8, 19.3, 15.1 (consistent with lit.4). (S)-1-methylindan (13) Following the general procedure GP7, L7b (160 mg, 1.1 mmol), t-BuLi (0.72 mL, 1.53 M in pentane, 1.1 mmol) and 12 (106 mg, 0.5 mmol) were reacted at rt for 1 h. After standard work-up, the yield and enantiomeric ratio of 13 were determined by chiral stationary-phase gas chromatography (CSP-GC) (30 m × 250 µm × 0.25 µm CP-Chirasil-Dex CB column; Carrier gas : helium ; 1.5 mL/min ; Injector : set at 220 °C ; Detector : FID set at 230 °C, Oven temp. : 70 °C (hold 22 min.) to 180 °C at 20 °C/min): ACS Paragon Plus Environment

25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 32

(S)-13 tr = 19.4 min, (R)-13 tr = 20.2 min. An analytically pure sample of 13 was obtained by flash chromatography on silica gel (pentane). Colorless oil. For an enantiomeric ratio of 93:7, [] +7.5 (c = 0.8, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.30–7.10 (m, 4H), 3.18 (m, 1H), 2.95–2.68 (m, 2H), 2.30 (m, 1H), 1.60 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ: 148.8, 143.9, 128.5,

126.1, 124.3, 123.2, 39.4, 34.8, 31.5, 19.9 (consistent with lit. 8b).

ASSOCIATED CONTENT Supporting Information. Selected spectra and chromatograms. This material is available free of charge via Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors *E-mail : [email protected] *E-mail : [email protected] ORCID Anne Boussonnière : 0000-0002-1113-099X Anne-Sophie Castanet : 0000-0003-4704-4724 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We gratefully acknowledge the French Ministry of Research and Technologies for a fellowship granted to H.G. and the CNRS and Université du Maine for financial support. We also thank Frédéric Legros for the technical support, Corentin Jacquemmoz for the NMR analyses, and Patricia Gangnery and Emmanuelle Mebold for the HRMS analyses. REFERENCES AND NOTES ACS Paragon Plus Environment

26

Page 27 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1


(a) Fañanás, F. J.; Sanz, R. Intramolecular Carbolithiation Reactions. In The chemistry of

organolithium compounds (2 parts), Rappoport, Z., Marek, I., Eds.; Wiley Interscience: Chichester, 2006; pp 295–379. (b) Minko, Y.; Marek, I. Advances in Carbolithiation. In Lithium Compounds in Organic Synthesis, Luisi, R., Capriati, V., Eds.; Wiley-VCH: Weinheim, 2014; pp 329–350. 2

(a) Hogan, A.-M. L.; O'Shea, D. F. Chem. Commun. 2008, 3839–3851. (b) Mealy, M. J.; Bailey, W.

F. J. Organomet. Chem. 2002, 646, 59–67. (c) García-Calvo, O.; Coya, E.; Lage, S.; Coldham, I.; Sotomayor, N.; Lete, E. Eur. J. Org. Chem. 2013, 1460–1470. 3

(a) Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596–2597. (b) Zhang, D.; Liebeskind, L. S.

J. Org. Chem. 1996, 61, 2594–2595. (c) Bailey, W. F.; Salgaonkar, P. D.; Brubaker, J. D.; Sharma, V. Org. Lett. 2008, 10, 1071–1074. 4

Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C. Chem.—Eur. J. 2005, 11, 5397–5407.

5

Bailey, W. F.; Daskapan, T.; Rampalli, S. J. Org. Chem. 2003, 68, 1334–1338.

6

For a review, see Gómez-SanJuan, A.; Sotomayor, N.; Lete, E. Beilstein J. Org. Chem. 2013, 9,

313–322. 7

(a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282–2316. (b) Chuzel, O.; Riant, O.

Top. Organomet. Chem. 2010, 15, 59–92. 8

(a) Mealy, M. J.; Luderer, M. R.; Bailey, W. F.; Sommer, M. B. J. Org. Chem. 2004, 69, 6042–6049.

(b) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787–6788. 9

Tanoury, G. J.; Chen, M.; Dong, Y.; Forslund, R.; Jurkauskas, V.; Jones, A. D.; Belmont, D. Org.

Process Res. Dev. 2014, 18 (10), 1234–1244.


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

10

Page 28 of 32

(a) Hodgson, D. M.; Stent, M. A. H Top. Organomet. Chem. 2003, 5, 1–20 . (b) Clayden, J.

Organolithiums: Selectivity for Synthesis, Elsevier Science & Technology Books, 2002. (c) HarissonMarchand, A.; Maddaluno, J. Advances in the Chemistry of Chiral Lithium Amides. In Lithium Compounds in Organic Synthesis; Luisi, R, Capriati, V., Eds.; Wiley-VCH: Weinheim, 2014; pp 297– 328. 11

(a) Iguchi, M.; Yamada, K.-I.; Tomioka, K. Top. Organomet. Chem. 2003, 5, 37–59. (b) Kizirian,

J.-C. Chem. Rev. 2008, 108, 140–205. 12

(a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002, 124,

11870–11871. (b) Dearden, M. J.; McGrath, M. J.; O'Brien, P. J. Org. Chem. 2004, 69, 5789–5792. (c) O'Brien, P. Chem. Commun. 2008, 655–667. 13

(a) Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron Lett. 2003, 44, 8893–8895. (b) Kizirian,

J.-C.; Cabello, N.; Pinchard, L.; Caille, J.-C.; Alexakis, A. Tetrahedron 2005, 61, 8939–8946. (c) Stead, D.; O'Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409–1412. 14

(a) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111 (21), 8266–8268. (b) Shindo,

M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1992, 114 (22), 8732–8733. (c) Perron, Q.; Alexakis, A. Adv. Synth. Catal. 2010, 352 (14–15), 2611–2620. 15

(a) Bailey, W. F.; Luderer, M. R.; Mealy, M. J. Tetrahedron Lett. 2003, 44, 5303–5305. (b)

Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron: Asymmetry 2001, 12, 2077–2082. 16

Pseudoephedrine is included in Table I of the 1988 United Nations Convention against Illicit Traffic

in Narcotic Drugs and Psychotropic Substances calling for the strictest levels of control. The trade of pseudoephedrine is prohibited in Colombia and Mexico, and is highly regulated in the United States.


28

Page 29 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


17

Morales, M. R.; Mellem, K. T.; Myers, A. G. Angew. Chem., Int. Ed. 2012, 51, 4568–4571.

18

Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351–9357.

19

Amino ethers L5 and L6, which differ only in the configuration at the stereogenic carbon center α

to the ether moiety, exhibit opposite sense of stereoinduction in the asymmetric cyclization of 2-(N,Ndiallylamino)phenyllithium. See ref 8a. 20

(a) Shin, I.; Lee, M.-R.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem. 2000, 65, 7667–7675.

(b) Bauer, T.; Gajewiak, J. Tetrahedron 2004, 60, 9163–9170. 21

Winitz, M.; Bloch-Frankenthal, L.; Izumiya, N.; Birnbaum, S. M.; Baker, C. G.; Greenstein, J. P. J.

Am. Chem. Soc. 1956, 78, 2423–2430. 22

The enantiomeric purity of recrystallized 1a was verified by chiral stationary-phase gas

chromatography (CSP-GC). See Supporting Information. 23

(a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C. J. Org. Chem. 2000, 65, 3034–3041. (b)

Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–10852. 24

Alternatively, enantiomerically pure methoxyamide 3a can be prepared by deprotonation/

methylation of 1a (83% yield) followed by amide synthesis (74 % yield). 25

(a) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith, A. D.;

Rodriguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5, 1961–1969. (b) Davies, S. G. ; Huckvale, R.; Lorkin, T. J. A. ; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1591–1593. (c) Davies, S. G. ; Huckvale, R.; Lee, J. A.; Lorkin, T. J. A. ; Roberts, P. M.; Thomson, J. E. Tetrahedron 2012, 68, 3263–3275.


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

26

Page 30 of 32

Whatever the ligand L7 used, the starting material was entirely consumed. The only significant

impurity in the crude reaction mixtures was the debrominated derivative resulting from the protonation of the aryllithium prior to the cyclization. 27

The absolute configuration of the carbolithiation product was assigned by optical rotation

comparison with literature data. See the experimental part. 28

(S)-5 is also potentially accessible by using the opposite enantiomer of L7b, which can be easily

prepared from commercially available “unnatural” D-valine. 29

Ramírez, A.; Lobkovsky, E.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15376–15387.

30

Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am. Chem. Soc. 1995, 117, 8853–8854.

31

Seebach, D. ; Neumann, H. Chem. Ber. 1974, 107, 847–853.

32

Waldmann, C.; Schober, O.; Haufe, G.; Kopka, K. Org. Lett. 2013, 15, 2954–2957.

33

Ligand 7b gives higher enantioselectivity than the pseudoephedrine-derived ligand L5 as the L5-

mediated asymmetric cyclization of 7, followed by the sequential addition of EtOH and allylbromide onto the bislithiated cyclic intermediate, delivered the 1,3-disubstituted indoline with an enantiomeric ratio of 84:16. See ref 15a. 34

Yields and er determined by CSP-GC.

35

The absolute configuration of the major enantiomers of 11 and 13 was tentatively assigned on the

assumption that the L7b-mediated ring-closure of 10 and 12 proceeded with the same facial selectivity as did the cyclization of 4, 6, and 7 in the presence of L7b. 36

Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542, 281–283.


30

Page 31 of 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


37

Guette, J.-P.; Spassky, N. Bull. Soc. Chim. Fr. 1972, 4217–4224.

38

Poterała, M.; Plenkiewicz, J. Tetrahedron: Asymmetry 2011, 22, 294–299.

39

Li, W. R.; Ewing, W. R.; Harris, B. D.; Joullie, M. M. J. Am. Chem. Soc. 1990, 112, 7659–7672.

40

Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56,

2499–2506. 41

Larissegger-Schnell, B.; Glueck, S. M.; Kroutil, W.; Faber, K. Tetrahedron 2006, 62, 2912–2916.

42

Lakshminarayana, N.; Rajendra Prasad, Y.; Gharat, L.; Thomas, A.; Ravikumar, P.; Narayanan, S.;

Srinivasan, C. V.; Gopalan, B. Eur. J. Med. Chem. 2009, 44, 3147–3157. 43

Baker, G. L.; Jing, F.; Smith, M. R. Cyclic alkyl substituted glycolides and poly-lactides therefrom.

US20070142461A1, 2007. 44

Schurig, V.; Hintzer, K.; Leyrer, U.; Mark, C.; Pitchen, P.; Kagan, H. B. J. Organomet. Chem.

1989, 370, 81–96. 45

46

Kolasa, T.; Miller, M. J. J. Org. Chem. 1987, 52, 4978–4984. Dong, L.; Guo, C.; Hong, Y.; Johnson, M. C.; Kephart, S. E.; Li, H.; McAlpine, I. J.; Tikhe, J. G.;

Yang, A.; Zhang, J. Preparation of carbonylaminopyrrolopyrazoles as PAK4 kinase inhibitors. WO2007072153A2, 2007. 47

Priyadarshini, S.; Joseph, P. J. A.; Kantam, M. L., RSC Adv. 2013, 3, 18283–18287.

48

Inoue, I.; Shindo, M.; Koga, K.; Kanai, M.; Tomioka, K. Tetrahedron: Asymmetry 1995, 6, 2527–

2533. 49

Davidson, T. A.; Mondal, K.; Yang, X. J. Colloid Interface Sci. 2004, 276, 498–502.


31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 32

50

Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056–2057.

51

Torun, T.; Robinson, T. W.; Krzykawski, J.; Purkiss, D. W.; Bartsch, R. A. Tetrahedron 2005, 61,

8345–8350. 52

Gotor-Fernández, V.; Fernández-Torres, P.; Gotor, V. Tetrahedron: Asymmetry 2006, 17, 2558–

2564.


32

Readily Accessible 1,2-Amino Ether Ligands for Enantioselective

Recommend Documents