Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation

Article abstract of DOI:10.1021/acs.joc.7b00423

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.

Full text of DOI:10.1021/acs.joc.7b00423

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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
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Readily Accessible 1,2ꢀAmino Ether Ligands for
Enantioselective Intramolecular Carbolithiation
Hélène Guyon, Anne Boussonnière*, and Anne-Sophie Castanet*
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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
1. t-BuLi, L*
toluene, –78 °C
R2
Br
Z
R1
R1
MeO
NMe2
2. warm
Z
L*
3. MeOH
Z = NCH2CH=CH2,
NH, O, CH2
Inexpensive chiral ligands
High stereoselectivity (90:10 er to 95:5 er)
ABSTRACT. A new class of chiral 1,2ꢀamino ether ligands, readily accessible from naturally occurring
αꢀaminoꢀ or αꢀhydroxy 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 2,3ꢀdihydrobenzo[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
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the most widely used chiral promotor for this reaction, the outcome of the L1ꢀmediated intramolecular
carbolithiation is quite substrate dependent.8 Moreover, since the commercial availability of L1 has
significantly varied over the last decade, concerns about its longꢀterm, highꢀvolume 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 1,2ꢀamino ether ligands
and describe its application to intramolecular carbolithiation reactions.
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The last two decades have witnessed considerable progress in the chiral ligandꢀmediated
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 1,2ꢀamino ethers and most of the
investigations reported to date are restricted to the pseudoephedrineꢀ or ephedrineꢀderived ligands L5
and L6.8a,15
Figure 1. Selection of chiral bidentate ligands
Interestingly, amino ether L5 is more effective than the transꢀdiaminocyclohexane L3 or the diether
L4 in the asymmetric cyclization of 2ꢀ(N,Nꢀdiallylamino)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 fiveꢀmembered ring upon chelation with an organolithium
(chelate A, figure 2). In this chelate, the methyl substituent on the ether oxygen would be oriented trans
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to the adjacent phenyl group to minimize nonꢀbonding 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
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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 αꢀaminoꢀ or αꢀhydroxy 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 fineꢀtuning of the ligand structure.
R
Ph
R
Me
Me
Me
Me
N
N
Me
O
O
MeO
NMe2
Li
Li
Me
Me
L7
R'
R'
B
A
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). αꢀHydroxy acid 1a
was synthesized by diazotizationꢀhydrolysis of
ꢀleucine.20 This reliable and inexpensive reaction,
L
known to proceed via an αꢀlactone, 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), 1ꢀhydroxyꢀ1Hꢀbenzotriazole (HOBt), dimethylamine hydrochloride
and diisopropylethylamine (DIPEA).23 Elimination of the dicyclohexyl urea byꢀproduct 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 (CSPꢀGC). Oꢀmethylation 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
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steps) after bulbꢀtoꢀbulb distillation. Remarkably, this synthetic scheme is easily amenable to multiꢀ
gram quantities, as no purification by column chromatography is required.
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Scheme 1. Synthesis of amino ether L7a from -leucine
L
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The same synthetic sequence was applied for the synthesis of ligands L7b–h, demonstrating the
generality of the procedure (Table 1). ꢀvaline, ꢀisoleucine, ꢀtertꢀleucine and ꢀphenylalanine were
L
L
L
L
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 cyclohexylꢀ
substituted hydroxy acid ent-1h, which was the precursor of ligand ent-L7h (entry 7).
Table 1. Preparation of amino ether ligands L7b–h
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Entry
R
1 %a
1b, 66
1c, 79
1d, 67
1e, 90
–
2 % a
2b, 71
2c, 67
2d, 72
2e, 54
2fb
L7 % a
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7
iPr
L7b, 57
L7c, 69
L7d, 51
L7e, 58
L7f, 74
s-Bu
t-Bu
benzyl
CyCH2
Ph
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ent-1gc ent-2g, 37
ent-L7g, 65
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. ent-1h was obtained by hydrogenation of (R)ꢀmandelic acid
(61% yield).
d
In order to assess their utility, the ligands L7a–h were evaluated in the enantioselective carbolithiation
of N,Nꢀdiallylꢀ2ꢀbromoaniline (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
crossꢀcomparison of results, a uniform set of reaction conditions, previously reported by Bailey,8a was
employed. tꢀBuLi (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 CSPꢀGC analysis. b Ref. 8a
To our delight, ligands L7 were found to give highꢀyielding carbolithiation reactions,26 with
enantioselectivities higher or comparable to those reached with L18a or L5.8a The stereocontrol was
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marginally affected by the side chain of the amino ether ligand and the best stereoselectivity (94:6 er)
was achieved with the valineꢀderived ligand L7b. Furthermore, ligands L7 offered an efficient access to
either enantiomer of 1ꢀallylꢀ3ꢀmethylindoline (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 αꢀamino acids using a route devised from literature precedent
(reduction, EschweilerꢀClark methylation and etherification).29 As anticipated, moving the stereogenic
carbon further away from the ether function was detrimental to the stereoselectivity.
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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 tꢀBuLi 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 tꢀBuLi/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 (–)ꢀsparteineꢀmediated 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 tꢀBuLi and 1.2 equiv of L7b (entry 5). Under these reaction conditions, the second
equivalent of tꢀBuLi reacts with the tꢀBuBr generated in the bromineꢀlithium 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 tꢀ
BuLi.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 tꢀBuBr, good yields
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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).
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Table 3. Optimization of the reaction conditions for the L7b-promoted carbolithiation of 4 a
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T
tꢀBuLi/L7b
erc
(R:S)
94:6
Entry Solvent
5b (%)
(°C) (equiv.)
–40 2.2/2.2
1d
Et2O
Et2O
Et2O
79
2
–40 2.2/2.2
–60 2.2/2.2
95
69
97
29
63
81
81
94:6
93:7
95:5
86:14
95:5
95:5
92:8
3
4
Toluene –40 2.2/2.2
Toluene –40 2.2/1.2
5
6
Et2O
–40 1.2/1.2
7
Toluene –40 1.2/1.2
8e
Toluene –40 1.05/0.25
a
Reaction conditions: 4 was added to a solution of tꢀBuLi (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. Yields determined by gas chromatography. er determined by CSPꢀGC. d tꢀ
b
c
BuLi 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 nonꢀcatalytic conditions optimized in
Table 3. The L7bꢀpromoted carbocylization of N,N-diallylꢀ2ꢀbromoꢀ3ꢀmethylaniline (6) and Nꢀallylꢀ2ꢀ
bromoaniline (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
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Scheme 2. Preparation of indolines 8 and 9
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The enantioselective synthesis of 2,3ꢀdihydrobenzofurans by intramolecular cyclization of allyl oꢀ
lithioaryl ethers was next investigated (Scheme 3). This L1ꢀmediated 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 2ꢀbromoꢀ1ꢀ(3ꢀ
butenyl)benzene (12) was examined. The L1ꢀmediated 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 1,2ꢀamino ethers has been efficiently synthesized in a short and
scalable synthetic sequence from readily available and inexpensive αꢀaminoꢀ or αꢀhydroxy acids.
Stoichiometric or substoichiometric amounts of these chiral ligands can serve as effective promoters for
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enantioselective intramolecular carbolithiation reactions. The valineꢀderived ligand L7b affords the
highest stereoselectivities, outperforming (–)ꢀsparteine in the synthesis of enantioenriched indolines,
2,3ꢀdihydrobenzofurans, and indans.
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Experimental Section
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A- General Experimental Methods
All airꢀ and moistureꢀsensitive manipulations were performed under argon atmosphere with
anhydrous solvents in flameꢀdried glassware. The solvents (THF, CH2Cl2, Et2O, Toluene) were dried by
activated alumina column (glass technology GTS 100). Pentane was distilled from CaH2. tꢀBuLi was
purchased as 1.7 M solution in pentane and was titrated periodically against Nꢀbenzylbenzamide.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 : 32ꢀ63 Å). Analytical TLC was performed using Merk precoated silica gel 60 Fꢀ254 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 FTꢀIR spectrometer. Melting points were
measured on a Melting Point Bꢀ540 apparatus and are uncorrected. Optical rotations were measured on
Jasco Pꢀ2000 polarimeter using a quartz cell (l=10 cm), with a highꢀpressure sodium lamp (λ = 589 cm).
[α]D values are given in 10ꢀ1deg.cm2.gꢀ1. High Resolution Mass Spectrometry (HRMS) was performed
on a Waters Micromass GTC Premier spectrometer or Bruker MicroTOF QIII spectrometer.
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B. Synthesis of ligands L7a–h (Table 1 and scheme 1)
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Hydroxy acids 1a–e and ent-1h
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(S)-2-hydroxy-4-methylpentanoic acid (1a): general procedure GP1
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To a cooled (ice bath) solution of ꢀleucine (19.7 g, 150 mmol, 1 equiv) in 1M H2SO4 (300 mL) was
L
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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)ꢀ2ꢀhydroxyꢀ4ꢀ
methylpentanoic acid (1a) (12.08 g, 61%) as a white solid. [ꢀ]ꢂꢁꢃ –14.8 (c = 1.02, H2O) (lit.37
[ꢀ]ꢂꢁꢃ –12.7 (c = 1.0, H2O)). mp 70–73 °C (lit.38 mp 73–75 °C). 1H 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). 13C NMR (100 MHz, CDCl3) : 180.0, 68.9, 43.2, 24.5, 22.8, 21.5 (consistent with lit.38). The
δ
enantiomeric purity of 1a was verified by chiral stationaryꢀphase gas chromatography (CSPꢀGC) (30 m
× 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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)ꢀ2ꢀhydroxyꢀ3ꢀmethylbutanoic acid (1b) was prepared according to GP1 from ꢀvaline (30.0 g, 256
L
mmol). Standard workꢀup and recrystallization (petroleum ether/Et2O) afforded 1b (20.0 g, 66%) as a
white solid. [ꢀ]ꢂꢁꢂ +17.8 (c = 2.08, CHCl3) (lit.39 [ꢀ]ꢁꢂꢂ +19 (c = 2.08, CHCl3)). mp 63–65 °C (lit.39 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,
13
3H), 0.93 (d, J = 6.9 Hz, 3H). 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)
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(2S,3S)ꢀ2ꢀhydroxyꢀ3ꢀmethylpentanoic acid (1c) (5.22 g, 79%) was prepared according to GP1 from
isoleucine (6.56 g, 50 mmol). White solid. 1H NMR (400 MHz, CDCl3)
L
ꢀ
1
2
3
4
5
6
δ
: 4.18 (d, J = 3.8 Hz, 1H), 1.89
13
(m, 1H), 1.44–1.17 (m, 2H), 1.03 (d, J = 7.0 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). C NMR (100 MHz,
7
8
CDCl3)
δ
: 179.5, 74.8, 39.1, 23.9, 15.5, 11.9 (consistent with lit.38).
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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)-2-hydroxy-3,3-dimethylbutanoic acid (1d)
(S)ꢀ2ꢀhydroxyꢀ3,3ꢀdimethylbutanoic acid (1d) (3.39 g, 67%) was prepared according to GP1 from ꢀ
L
tertꢀleucine (5.00 g, 38.1 mmol). White solid. [ꢀ]ꢂꢁꢃ +10.6 (c = 1.0, MeOH) (lit.40 [ꢀ]ꢁꢂꢃ +3.9 (c = 1.0,
1
MeOH). H NMR (400 MHz, CDCl3)
δ
: 3.89 (s, 1H), 1.02 (s, 9H). 13C 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)ꢀ2ꢀhydroxyꢀ3ꢀphenylpropanoic acid (1e) (7.30 g, 90%) was prepared according to GP1 from ꢀ
L
phenylalanine (8.03 g, 48.6 mmol). White solid. [ꢀ]ꢂꢁꢃ –27.3 (c = 1.03, acetone) (lit.41 [ꢀ]ꢁꢂꢃ–27.5 (c =
1.0, acetone). mp 123–125 °C (lit.41 mp 122–123 °C). H NMR (400 MHz, CD3OD)
δ
: 7.26–7.23 (m,
1
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)
(consistent with lit.42).
δ: 177.8, 136.0, 129.6, 128.7, 127.3, 71.2, 40.3
(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)ꢀ2ꢀcyclohexylꢀ2ꢀhydroxyacetic acid
1
(ent-1h) as a grey solid (4.86 g, 61%). [ꢀ]ꢁꢂꢃ –10.4 (c = 0.98, MeOH). mp 125–127 °C. H NMR (400
MHz, DMSOꢀd6)
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–
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1.04 (m, 5H). 13C NMR (100 MHz, DMSOꢀd6)
(consistent with lit.43).
δ: 175.2, 74.2, 41.2, 28.8, 26.7, 25.8, 25.7, 25.6
1
2
3
4
5
6
Hydroxy amides 2a–h
7
8
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(S)-2-hydroxy-N,N,4-trimethylpentanamide (2a) : general procedure GP2
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
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38
39
40
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43
44
45
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47
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49
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51
52
53
54
55
56
57
58
59
60
To a solution of (S)ꢀ2ꢀhydroxyꢀ4ꢀmethylpentanoic acid (1a) (1.20 g, 8.9 mmol, 1 equiv),
dimethylamine hydrochloride (0.72 g, 8.9 mmol, 1 equiv) and 1ꢀhydroxyꢀ1Hꢀbenzotriazole (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)ꢀ2ꢀhydroxyꢀN,N,4ꢀtrimethylpentanamide (2a) (1.18 g, 84%) as a yellow solid. [ꢀ]ꢂꢁꢃ –17.8 (c =
1
1.03, CHCl3). mp 46–48 °C. H 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
13
Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). C 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 cmꢀ1. HRMS (CI+) for C8H17NO2 [M+H]+ :
calcd 160.1338 found 160.1329. The enantiomeric purity of 2a was verified by chiral stationaryꢀphase
gas chromatography (CSPꢀGC) (30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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)ꢀ2ꢀhydroxyꢀN,N,3ꢀtrimethylbutanamide (2b) was prepared according to GP2 from (S)ꢀ2ꢀhydroxyꢀ
3ꢀmethylbutanoic acid (1b) (8.25 g, 69.8 mmol). Bulbꢀtoꢀbulb distillation (150 °C, 50 mbar) delivered
2b (7.19 g, 71%) as a colorless oil. [ꢀ]ꢂꢁꢄ +51 (c = 1.06, CHCl3) (lit.23a [ꢀ]ꢁꢂꢄ +54 (c = 1.0, CHCl3)). 1H
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
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(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
: 174.0, 72.2, 36.6, 35.9, 31.3, 19.8, 15.1 (consistent with lit.23a).
1
2
3
4
(50 MHz, CDCl3)
δ
5
6
(2S,3S)-2-hydroxy-N,N,3-trimethylpentanamide (2c)
7
8
9
(2S,3S)ꢀ2ꢀhydroxyꢀN,N,3ꢀtrimethylpentanamide (2c) was prepared according to GP2 from (2S,3S)ꢀ2ꢀ
hydroxyꢀ3ꢀmethylpentanoic acid (1c) (5.22 g, 39.5 mmol). Standard workup and purification by
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/EtOAc: 60/40 → 20/80) gave 2c (4.25 g, 67%) as a colorless
1
oil. [ꢀ]ꢂꢁꢃ +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
13
(t, J = 7.4 Hz, 3H). C 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 cmꢀ1. HRMS (ESI+) for C8H17NO2 [M+Na]+: calcd
182.1151 found 182.1154.
(S)-2-hydroxy-N,N,3,3-tetramethylbutanamide (2d)
(S)ꢀ2ꢀhydroxyꢀN,N,3,3ꢀtetramethylbutanamide (2d) was prepared according to GP2 from (S)ꢀ2ꢀ
hydroxyꢀ3,3ꢀdimethylbutanoic 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. [ꢀ]ꢂꢁꢃ +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). 13C 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 cmꢀ1. HRMS (ESI+) for C8H17NO2 [M+Na]+: calcd 182.1151 found
182.1151.
(S)-2-hydroxy-N,N-dimethyl-3-phenylpropanamide (2e)
(S)ꢀ2ꢀhydroxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanamide (2e) was prepared according to GP2 from (S)ꢀ2ꢀ
hydroxyꢀ3ꢀphenylpropanoic 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
solid. [ꢀ]ꢂꢁꢃ +34.9 (c = 2.0, EtOH) (lit. 44 [ꢀ]ꢁꢂꢃ +37.3 (c = 2.0, EtOH). mp 63–65 °C (lit.44 mp 66 °C). 1H
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),
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2.91–2.84 (m, 2H), 2.78 (s, 3H). 13C NMR (100 MHz, CDCl3)
69.1, 42.0, 36.3, 35.9 (consistent with lit.44).
δ: 173.8, 137.0, 129.4, 128.5, 126.9,
1
2
3
4
5
6
(S)-3-cyclohexyl-2-hydroxy-N,N-dimethylpropanamide (2f)
7
8
9
A solution of (S)ꢀ2ꢀhydroxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanamide (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)ꢀ3ꢀcyclohexylꢀ2ꢀhydroxyꢀN,Nꢀdimethylpropanamide (2f) (2.2 g,
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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
100%) as a yellow oil. [ꢀ]ꢂꢁꢃ –16.9 (c = 1.06, CHCl3). 1H 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 cmꢀ1. HRMS (ESI+) for C11H21NO2 [M+Na]+: calcd
222.1464 found 222.1473.
(R)-2-hydroxy-N,N-dimethyl-2-phenylacetamide (ent-2g)
(R)ꢀ2ꢀhydroxyꢀN,Nꢀdimethylꢀ2ꢀphenylacetamide (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
1
(cyclohexane/EtOAc: 70/30 → 30/70) gave ent-2g (2.64 g, 37%) as a white solid. H 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). 13C NMR (100
: 172.6, 139.4, 129.2, 128.7, 127.7, 71.8, 36.6, 36.5 (consistent with lit.45).
MHz, CDCl3)
δ
(R)-2-cyclohexyl-2-hydroxy-N,N-dimethylacetamide (ent-2h)
(R)ꢀ2ꢀcyclohexylꢀ2ꢀhydroxyꢀN,Nꢀdimethylacetamide (ent-2h) was prepared according to GP2 from
(R)ꢀ2ꢀcyclohexylꢀ2ꢀhydroxyacetic 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
white solid. [ꢀ]ꢂꢁꢃ –43.3 (c = 0.99, CHCl3). mp 100–102 °C. 1H NMR (400 MHz, CDCl3)
δ: 4.21 (dd, J
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= 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
1
2
3
4
5
(m, 2H), 1.54–1.39 (m, 3H), 1.27–1.14 (m, 4H). 13C NMR (100 MHz, CDCl3)
36.1, 30.0, 26.7, 26.2, 26.1, 25.8 (consistent with lit. 46)
δ: 174.0, 72.3, 41.7, 36.8,
6
7
8
9
Methoxy amides 3a–h
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18
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30
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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57
58
59
60
(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)ꢀ2ꢀhydroxyꢀN,N,4ꢀtrimethylpentanamide (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)ꢀ2ꢀmethoxyꢀN,N,4ꢀtrimethylpentanamide (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). [ꢀ]ꢂꢁꢃ +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 cmꢀ1. HRMS (ESI ) for C9H19NO2 [M+H]+ : calcd
174.1489 found 174.1489. The enantiomeric purity of 3a was verified by chiral stationaryꢀphase gas
chromatography (CSPꢀGC) (30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylbutanamide (3b) was prepared according to GP3 from (S)ꢀ2ꢀ
hydroxyꢀN,N,3ꢀtrimethylbutanamide (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
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(cyclohexane/EtOAc : 70/30). [ꢀ]ꢁꢂꢃ –35.5 (c = 1.07, CHCl3). 1H NMR (400 MHz, CDCl3)
δ: 3.67 (d, J
1
2
3
4
5
6
= 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,
7
8
9
18.8. IR (neat) ν : 2931, 1639, 1398, 1099, 987 cmꢀ1. HRMS (CI+) for C8H17NO2 [M+H]+ : calcd
160.1338 found 160.1331.
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13
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16
17
18
19
20
21
22
23
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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
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57
58
59
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(2S,3S)-2-methoxy-N,N,3-trimethylpentanamide (3c)
Crude (2S,3S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylpentanamide (3c) was prepared according to GP3 from
(2S,3S)ꢀ2ꢀhydroxyꢀN,N,3ꢀtrimethylpentanamide (2c) (2.50 g, 15.7 mmol). An analytically pure sample
of 3c was obtained as a colorless oil by bulbꢀtoꢀbulb distillation (130 °C, 50 mbar). [ꢀ]ꢂꢁꢃ –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
13
(s, 3H), 1.83–1.69 (m, 2H), 1.22 (m, 1H), 0.92–0.86 (m, 6H). 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 cmꢀ1. HRMS
(ESI+) for C9H19NO2 [M+H]+: calcd 174.1489 found 174.1485.
(S)-2-methoxy-N,N,3,3-tetramethylbutanamide (3d)
Crude (S)ꢀ2ꢀmethoxyꢀN,N,3,3ꢀtetramethylbutanamide (3d) was prepared according to GP3 from (S)ꢀ
2ꢀhydroxyꢀN,N,3,3ꢀtetramethylbutanamide (2d) (2.64 g, 16.6 mmol). An analytically pure sample of 3d
was obtained as a beige solid by sublimation. [ꢀ]ꢂꢁꢃ –21.4 (c = 1.0, CHCl3). mp 66–68 °C. 1H NMR (400
MHz, CDCl3)
: 170.9, 87.4, 58.0, 37.6, 36.3, 35.5, 26.6. IR (neat) ν : 2969, 2924, 1641, 1354, 1102, 851 cmꢀ1.
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
HRMS (ESI+) for C9H20NO2 [M+H]+: calcd 174.1489 found 174.1494.
(S)-2-methoxy-N,N-dimethyl-3-phenylpropanamide (3e)
Crude (S)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanamide (3e) was prepared according to GP3 from
(S)ꢀ2ꢀhydroxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanamide (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
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(cyclohexane/EtOAc : 70/30). [ꢀ]ꢁꢂꢃ +0.5 (c = 0.98, CHCl3). H NMR (400 MHz, CDCl3)
δ
: 7.29–7.22
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(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). C
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NMR (100 MHz, CDCl3) : 171.1, 137.4, 129.4, 128.4, 126.7, 80.9, 56.9, 38.6, 36.4, 36.0. IR (neat) ν :
δ
2931, 1639, 1106, 702 cmꢀ1. HRMS (ESI+) for C12H17NO2 [M+Na]+: calcd 230.1151 found 230.1150.
(S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropanamide (3f)
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Crude (S)ꢀ3ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylpropanamide (3f) was prepared according to GP3
from (S)ꢀ3ꢀcyclohexylꢀ2ꢀhydroxyꢀN,Nꢀdimethylpropanamide (2f) (2.2 g, 11 mmol). An analytically pure
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sample of 3f was obtained as a colorless oil after removal of grease by filtration through a plug of silica
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gel (cyclohexane/EtOAc : 70/30). [ꢀ]ꢂꢁꢃ –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
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(m, 1H), 1.43 (m, 1H), 1.30–1.14 (m, 3H), 0.99–0.85 (m, 2H). 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 cmꢀ1.
HRMS (ESI+) for C12H23NO2 [2M+Na]+: calcd 449.3350 found 449.3351.
(R)-2-methoxy-N,N-dimethyl-2-phenylacetamide (ent-3g)
Crude (R)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ2ꢀphenylacetamide (ent-3g) was prepared according to GP3 from
(R)ꢀ2ꢀhydroxyꢀN,Nꢀdimethylꢀ2ꢀphenylacetamide (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). 13C NMR (100 MHz, CDCl3)
127.1, 83.6, 57.7, 36.7, 36.4 (consistent with lit.47).
δ: 170.3, 136.6, 128.9, 128.5,
(R)-2-cyclohexyl-2-methoxy-N,N-dimethylacetamide (ent-3h)
Crude (R)ꢀ2ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylacetamide (ent-3h) was prepared according to GP3
from (R)ꢀ2ꢀcyclohexylꢀ2ꢀhydroxyꢀN,Nꢀdimethylacetamide (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
of silica gel (cyclohexane/EtOAc : 70/30). [ꢀ]ꢂꢁꢃ +28.8 (c = 1.04, CHCl3). 1H 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),
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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,
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36.5, 36.1, 29.4, 29.1, 26.3, 26.0, 25.9. IR (neat) ν: 2924, 2853, 1639, 1398, 1112 cmꢀ1. HRMS (ESI+)
for C11H21NO2 [M+H]+: calcd 200.1645 found 200.1641.
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Amino ethers L7a–h
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(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)ꢀ2ꢀmethoxyꢀN,N,4ꢀtrimethylpentanamide (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 bulbꢀtoꢀbulb distillation (130 °C, 550 mbar) provided (S)ꢀ2ꢀmethoxyꢀN,N,4ꢀ
trimethylpentanꢀ1ꢀamine (L7a) (4.9 g, 79% from 2a ) as a colorless oil. [ꢀ]ꢂꢁꢃ –11.8 (c = 1.03, CHCl3).
1H 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). 13C 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 cmꢀ1. HRMS (ESI+) for C9H21NO [M+H]+ : calcd 160.1696 found
160.1701.
(S)-2-methoxy-N,N,3-trimethylbutan-1-amine (L7b)
(S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylbutanꢀ1ꢀamine (L7b) was prepared according to GP4 from crude (S)ꢀ2ꢀ
methoxyꢀN,N,3ꢀtrimethylbutanamide (3b) (49.5 mmol). Standard workup and bulbꢀtoꢀbulb distillation
(100 °C, 300 mbar) gave (S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylbutanꢀ1ꢀamine (L7b) (4.14 g, 57% from 2b) as
a colorless oil. [ꢀ]ꢂꢁꢃ +27.5 (c = 1.0, CHCl3). 1H 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)
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δ
: 84.0, 60.7, 57.9, 46.5, 29.7, 18.0, 17.9. IR (neat) ν: 2957, 2820, 2766, 1460, 1097, 1035 cmꢀ1. HRMS
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(CI+) for C8H19NO [M+H]+ : calcd 146.1545 found 146.1542.
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(2S,3S)-2-methoxy-N,N,3-trimethylpentan-1-amine (L7c)
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(2S,3S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylpentanꢀ1ꢀamine (L7c) was prepared according to GP4 from crude
(2S,3S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylpentanamide (3c) (25.6 mmol). Standard workup and bulbꢀtoꢀbulb
distillation (130 °C, 400 mbar) gave (2S,3S)ꢀ2ꢀmethoxyꢀN,N,3ꢀtrimethylpentanꢀ1ꢀamine (L7c) (2.3 g,
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69% from 2c) as a colorless oil. [ꢀ]ꢁꢂꢃ +14.1 (c = 1.03, CHCl3). 1H 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
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= 7.5 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 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 cmꢀ1. HRMS (CI+) for C9H21NO
[M+H]+ : calcd 160.1701 found 160.1699.
(S)-2-methoxy-N,N,3,3-tetramethylbutan-1-amine (L7d)
(S)ꢀ2ꢀmethoxyꢀN,N,3,3ꢀtetramethylbutanꢀ1ꢀamine (L7d) was prepared according to GP4 from crude
(S)ꢀ2ꢀmethoxyꢀN,N,3,3ꢀtetramethylbutanamide (3d) (16.6 mmol). Standard workup and bulbꢀtoꢀbulb
distillation (130 °C, 400 mbar) gave (S)ꢀ2ꢀmethoxyꢀN,N,3,3ꢀtetramethylbutanꢀ1ꢀamine (L7d) (1.35 g,
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51% from 2d) as a colorless oil. [ꢀ]ꢂꢁꢃ +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,
: 87.3, 62.0, 60.3, 46.4, 35.3, 26.3. IR (neat) ν : 2948, 2818, 2764, 1460, 1106, 1041 cmꢀ1.
CDCl3)
δ
HRMS (CI+) for C9H21NO [M+H]+ : calcd 160.1701 found 160.1698.
(S)-2-methoxy-N,N-dimethyl-3-phenylpropan-1-amine (L7e)
(S)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanꢀ1ꢀamine (L7e) was prepared according to GP4 from
crude (S)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanamide (3e) (10 mmol). Standard workup and bulbꢀ
toꢀbulb distillation (150 °C, 70 mbar) gave (S)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ3ꢀphenylpropanꢀ1ꢀamine (L7e)
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(1.12 g, 58% from 2e) as a colorless oil. [ꢀ]ꢂꢁꢃ +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),
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2.26–2.22 (m, 7H). C NMR (100 MHz, CDCl3) δ: 139.1, 129.7, 128.4, 126.3, 80.8, 62.9, 57.4, 46.5,
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38.8. IR (neat) ν : 2936, 2820, 2767, 1456, 1102, 1033, 726 cmꢀ1. HRMS (ESI+) for C12H19NO [M+H]+ :
calcd 194.1539 found 194.1541.
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(S)-3-cyclohexyl-2-methoxy-N,N-dimethylpropan-1-amine (L7f)
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(S)ꢀ3ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylpropanꢀ1ꢀamine (L7f) was prepared according to GP4 from
crude (S)ꢀ3ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylpropanamide (3f) (11 mmol). Standard workup and
bulbꢀtoꢀbulb distillation (150 °C, 70 mbar) gave (S)ꢀ3ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylpropanꢀ1ꢀ
amine (L7f) (1.62 g, 74% from 2f) as a colorless oil. [ꢀ]ꢂꢁꢃ +2.4 (c = 1.02, CHCl3). 1H NMR (400 MHz,
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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,
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1H), 1.75–1.67 (m, 5H), 1.45–1.11 (m, 6H), 0.98–0.87 (m, 2H). C 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 cmꢀ1. HRMS (CI+) for C12H25NO [M+H]+ : calcd 200.2014 found 200.2010.
(R)-2-methoxy-N,N-dimethyl-2-phenylethanamine (ent-L7g)
(R)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ2ꢀphenylethanamine (ent-L7g) was prepared according to GP4 from
crude (R)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ2ꢀphenylacetamide (ent-3g) (14.7 mmol). Standard workup and
bulbꢀtoꢀbulb distillation (150 °C, 70 mbar) gave (R)ꢀ2ꢀmethoxyꢀN,Nꢀdimethylꢀ2ꢀphenylethanamine
(ent-L7g) (1.71 g, 65% from ent-2g) as a colorless oil. [ꢀ]ꢂꢁꢃ –104 (c = 1.18, MeOH) (lit.43 [ꢀ]ꢁꢂꢃ 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). 13C 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 cmꢀ1. 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)ꢀ2ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylethanamine (ent-L7h) was prepared according to GP4
from crude (R)ꢀ2ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀdimethylacetamide (ent-3h) (24.2 mmol). Standard
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workup and bulbꢀtoꢀbulb distillation (130 °C, 100 mbar) gave (R)ꢀ2ꢀcyclohexylꢀ2ꢀmethoxyꢀN,Nꢀ
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dimethylethanamine (ent-L7h) (3.17 g, 70% from ent-2h) as a colorless oil. [ꢀ]ꢂꢁꢃ –12.3 (c = 1.01,
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CHCl3). H NMR (400 MHz, CDCl3)
δ: 3.39 (s, 3H), 3.05 (m, 1H), 2.36 (m, 1H), 2.30–2.24 (m, 7H),
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1.80–1.54 (m, 6H), 1.31–1.02 (m, 5H). 13C 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 cmꢀ1. HRMS (CI+)
for C11H23NO [M+H]+ : calcd 186.1858 found 186.1854.
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C. Synthesis of ligands L8a–b
(S)-1-methoxy-N,N-4-trimethylpentan-2-amine (L8a) : general procedure GP5
A mixture of (S)ꢀN,Nꢀdimethylleucinol49 (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 bulbꢀtoꢀ
bulb distillation (120 °C, 400 mbar) afforded (S)ꢀ1ꢀmethoxyꢀN,Nꢀ4ꢀtrimethylpentanꢀ2ꢀamine (L8a)
(4.53 g, 56%) as a colorless oil. [ꢀ]ꢂꢁꢃ +18.3 (c = 1.02, CHCl3). 1H 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 cmꢀ1.
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,Nꢀdimethylvalinol (3.0 g, 22.9 mmol) according to
GP5. Standard workup and bulbꢀtoꢀbulb distillation (100 °C, 400 mbar) gave (S)ꢀ1ꢀmethoxyꢀN,Nꢀ3ꢀ
trimethylbutanꢀ2ꢀamine (L8b) (1.59 g, 48 %) as a colorless oil. [ꢀ]ꢂꢁꢃ –4.6 (c = 1.03, CHCl3). 1H NMR
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(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
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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 cmꢀ1. HRMS (CI +) for C8H19NO [M+H]+ : calcd 146.1545 found 146.1539.
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D. Synthesis of bromoarenes 4, 6, 7, 10 and 12
N,Nꢀdiallylꢀ2ꢀbromoaniline (4)8a and N,Nꢀdiallylꢀ2ꢀbromoꢀ3ꢀmethylaniline (6)8a were synthesized by
N,Nꢀdiallylation of 2ꢀbromoaniline and 2ꢀbromoꢀ3ꢀmethylaniline. Nꢀallylꢀ2ꢀbromoaniline (7)15a was
prepared from 2ꢀbromoaniline. 2ꢀbromoꢀ4,6ꢀdimethylphenyl 2ꢀpropenyl ether (10)4 was synthesized
from 2ꢀbromoꢀ4,6ꢀdimethylphenol and allylbromide. 2ꢀbromoꢀ1ꢀ(3ꢀbutenyl)benzene (12)50 was
prepared by the reaction of 2ꢀbromobenzyl bromide51 and allylmagnesium bromide.
E. Screening of ligands (Table 2) – General procedure GP6
A solution of N,Nꢀdiallylꢀ2ꢀbromoaniline (4) (126 mg, 0.5 mmol, 1 equiv) in anhydrous Et2O (4 mL)
was cooled to –78 °C in a flameꢀdried Schlenk tube under argon. tꢀBuLi 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 CSPꢀGC analysis of an aliquot of the organic layer (30 m × 250 ꢀm × 0.25 ꢀm CPꢀ
ChirasilꢀDex 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.
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F. Optimized procedure for the carbolithiation of anilines 4, 6, 7, 10, 12 (Table 3, scheme 2 and
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scheme 3) – General procedure GP7
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6
7
8
A solution of ligand L7b (0.25–3.3 equiv) in anhydrous toluene (4 mL) was cooled to –78 °C in a
flameꢀdried Schlenk tube under argon. tꢀBuLi 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 constantꢀtemperature 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 CSPꢀGC analysis of an aliquot of the organic layer.
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(R)-1-allyl-3-methylindoline (5) (entry 5, table 3)
Following the general procedure GP7, L7b (160 mg, 1.1 mmol), tꢀBuLi (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 workꢀup, the yield
and enantiomeric ratio of 5 were determined by chiral stationaryꢀphase gas chromatography (CSPꢀGC)
(30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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
enantiomeric ratio of 95:5, [ꢀ]ꢁꢂꢅ –59.4 (c = 0.98, CH2Cl2) (lit.8b er = 93:7 : [ꢀ]ꢂꢁꢅ –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,
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3H). 13C NMR (100 MHz, CDCl3)
35.2, 18.6 (consistent with lit.3a).
δ: 151.8, 135.2, 134.2, 127.4, 123.1, 117.7, 117.2, 107.3, 61.3, 52.0,
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5
6
(R)-1-allyl-3,4-dimethylindoline (8)
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8
9
Following the general procedure GP7, L7b (160 mg, 1.1 mmol), tꢀBuLi (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 workꢀup, the yield
and enantiomeric ratio of 8 were determined by chiral stationaryꢀphase gas chromatography (CSPꢀGC)
(30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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
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enantiomeric ratio of 95:5, [ꢀ]ꢁꢂꢃ –117.3 (c = 0.33, CH2Cl2) (lit.8a er = 85:15, [ꢀ]ꢂꢁꢃ –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
13
Hz, 3H). 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), tꢀBuLi (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 workꢀup, the yield
and enantiomeric ratio of 9 were determined by chiral stationaryꢀphase gas chromatography (CSPꢀGC)
(30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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
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chromatography on silica gel (cyclohexane / CH2Cl2: 80/20 → 50 /50). Colorless oil. For an
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enantiomeric ratio of 92:8, [ꢀ]ꢂꢁꢃ –35.5 (c = 0.265, CHCl3) (lit.52 er = 99.5: 0.5 : [ꢀ]ꢂꢁꢃ –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 =
5
6
7
8
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
9
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(app. t, J = 8.6 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H). C 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), tꢀBuLi (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 workꢀup, the
yield and enantiomeric ratio of 11 were determined by chiral stationaryꢀphase gas chromatography
(CSPꢀGC) (30 m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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, [ꢀ]ꢁꢂꢃ – 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), tꢀBuLi (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 workꢀup, the yield and
enantiomeric ratio of 13 were determined by chiral stationaryꢀphase gas chromatography (CSPꢀGC) (30
m × 250 ꢀm × 0.25 ꢀm CPꢀChirasilꢀDex 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):
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(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, [ꢀ]ꢂꢁꢃ +7.5 (c =
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3
4
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
5
6
7
8
9
13
(m, 1H), 1.60 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). 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).
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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
*Eꢀmail : anne.boussonniere@univ-lemans.fr
*Eꢀmail : anne-sophie.castanet@univ-lemans.fr
ORCID
Anne Boussonnière : 0000ꢀ0002ꢀ1113ꢀ099X
AnneꢀSophie Castanet : 0000ꢀ0003ꢀ4704ꢀ4724
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
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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.
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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.
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Amino ethers L5 and L6, which differ only in the configuration at the stereogenic carbon center α
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to the ether moiety, exhibit opposite sense of stereoinduction in the asymmetric cyclization of 2ꢀ(N,Nꢀ
diallylamino)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.
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21 Winitz, M.; BlochꢀFrankenthal, L.; Izumiya, N.; Birnbaum, S. M.; Baker, C. G.; Greenstein, J. P. J.
Am. Chem. Soc. 1956, 78, 2423–2430.
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The enantiomeric purity of recrystallized 1a was verified by chiral stationaryꢀphase gas
chromatography (CSPꢀGC). 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.
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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.;
RodriguezꢀSolla, 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.
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