Asymmetric synthesis of 1,3-diamines. II: Diastereoselective reduction of atropisomeric N-tert -butanesulfinylketimines

Article abstract of DOI:10.1021/jo1025767

Chiral, nonracemic o-aminobenzylamines were prepared in a highly diastereoselective reduction of atropisomeric N-tert-butanesulfinylketimines. The ortho-substituent ensures the distinct reactivity of atropisomers 4d-f. The free energy of activation for at

Full text of DOI:10.1021/jo1025767

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of 1,3-Diamines. II: Diastereoselective
Reduction of Atropisomeric N-tert-Butanesulfinylketimines
Marina Martjuga, Sergey Belyakov, Edvards Liepinsh, and Edgars Suna*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
S Supporting Information
b
ABSTRACT:
Chiral, nonracemic o-aminobenzylamines were prepared in a highly diastereoselective reduction of atropisomeric N-tert-
butanesulfinylketimines. The ortho-substituent ensures the distinct reactivity of atropisomers 4dꢀf. The free energy of activation
for atropisomerization of sulfinylimines 4dꢀf in THF-d8 was determined by NMR methods to range from 70.8 to 97.9 kJ/mol.
’ INTRODUCTION
Chiral, nonracemic R-methylbenzylamines have found nu-
merous applications in asymmetric synthesis.1 Introduction of an
ortho-substituent often enhances enantioselectivity and endows
this chiral entity with 1,3-bidentate properties, thus considerably
expanding the scope of potential applications. Thus, enantiopure
o-hydroxybenzylamines2 have been employed as chiral ligands
Figure 1. Target diamines 1 and 2.
for asymmetric addition of dialkyl zinc reagents to aldehydes3
and in the enantioselective reduction of ketones,4 whereas o-
between the reactivity and structure of N-tert-butanesulfinylketi-
methoxybenzylamines have been used in the design of highly
mines. In particular, we demonstrate herein the distinct reactivity of
efficient phosphoramidite ligands for Ir-catalyzed asymmetric
configurationally stable atropisomers of N-tert-butanesulfinylketi-
mines in the diastereoselective reduction with representative hy-
dride reducing agents.
allylic substitution reaction.5 Furthermore, chiral o-phosphino-
benzylamines are useful bidentate ligands for enantioselective
hydrogenation.6 Finally, o-aminobenzylamines have also been em-
ployed as efficient chiral catalysts7 and chiral reagents.8 However,
’ RESULTS AND DISCUSSION
even broader application of o-aminobenzylamines in asymmetric
synthesis has been hampered by lack of convenient methods for
Synthesis and Structural Analysis of Sulfinylimines 4aꢀf.
Following the procedure reported in the literature,12 heating of
their preparation.
ketones 3aꢀe13 with (RS)-tert-butanesulfinamide at 75 °C in the
Herein we report an efficient approach toward chiral, non-
racemic o-aminobenzylamines 1, 2 (Figure 1) via the diastereo-
presence of Ti(OEt)4 (Scheme 1) afforded sulfinylimines 4aꢀe.
selective reduction of N-tert-butanesulfinylketimines.9,10 This
Sulfinylimine 4f could not be synthesized in the reaction of ketone
study was stimulated by our recent demonstration of unusual
directing effects by the ortho-substituent in the diastereoselective
reduction of N-tert-butanesulfinylketimines.11 Thus, we showed
that the ortho-substituent controls the E/Z geometry of diaryl N-
tert-butanesulfinylketimines and established that there is a corre-
lation between facial selectivity of the reduction and the E/Z
geometry of the starting ketimines. Our new investigation reinforces
the observed correlation by increasing the structural diversity of
ketimines as well as provides additional insights into the relationship
3f with (RS)-tert-butanesulfinamide even under forcing condi-
tions (heating at 120 °C in Ti(OEt)4 without solvent). There-
fore, 4f was obtained from (Z)-4e by a deprotonationꢀalkylation
sequence (Scheme 1).
Sulfinylimines 4a,b were formed as E-isomers (entries 1 and 2,
Table 1) as evidenced by the X-ray crystallographic analysis. The
Received: December 28, 2010
Published: March 16, 2011
r
2011 American Chemical Society
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formation of E-sulfinylimines 4a,b is noteworthy because struc-
turally related ortho-substituted acetophenone imines favor the
opposite, i.e. Z-geometry.14 The preference for E-isomers of
sulfinylimines 4a,b was attributed to stabilization by an intramo-
lecular hydrogen bond between the nitrogen of the aniline and
that of the imino group, as evidenced by the 2.66ꢀ2.68 Å
distance15 between the two nitrogens in crystal lattices of
sulfinylimines 4a,b (see N1ꢀN2 distances in entries 1 and2,
Table 1). The intramolecular hydrogen bond enforces a syn-peripla-
nar relationship between the aniline ring and the CdN bond of
the imines 4a,b (see C1ꢀC2ꢀC3ꢀN2 torsion angles, Table 1),
and places the sulfoxide moiety in the trans position.16 As
anticipated, sulfinylimine 4c was obtained as E-isomer. Z-
geometry is unfavorable because of nonbonded steric interac-
tions between the ortho-substituent and the sulfinylimine
moiety in the conformationally fixed 2,3-dihydro-1H-indene
scaffold.
steric interactions between the bulky chiral auxiliary and the tert-
butyl group of the imine moiety. Hence, the stabilization by the
intramolecular hydrogen bond between the nitrogen of the
aniline and that of the sulfinyl group is overriden by steric
interactions in sulfinylimines (Z)-4dꢀe. In the observed Z
geometry, tert-butyl groups are positioned mutually trans with
respect to the CdN bond, and the ortho-substituted phenyl
moieties of imines 4dꢀf are twisted out of the CdN plane (see
C1ꢀC2ꢀC3ꢀN2 torsion angles, Table 1). Furthermore, sulfiny-
limine (Z)-4e exists as a 1:1 mixture of (M) and (P) atropisomers
in the crystal lattice, apparently because of a hindered rotation
about the aryl-imine axis. By intriguing contrast, individual
crystals of sulfinylimines (Z)-4d and (Z)-4f were obtained
exclusively as the (M)-atropisomers (see Table 1).
(E)-Sulfinylimines 4a,bwere the only species observed in THF-d8
and CDCl3 solutions at ambient temperature. The absence of
(Z)-4a,b isomers (within NMR detection limits) suggests a high
configurational stability of the E-isomers in various solvents,
apparently owing to the stabilizing effect of the intramolecular
hydrogen bond. On the other hand, sterically hindered sulfiny-
limines 4dꢀf existed solely as the (Z)-isomers in THF-d8 solution.
Furthermore, each of the sulfinylimines (Z)-4dꢀf appeared as
a mixture of (M) and (P) atropisomers. Thus, when a
single crystalline atropisomer (Z)-(M)-4d was dissolved in
Surprisingly, the structurally related sulfinylimines 4dꢀf
exist as Z-isomers in the crystalline form as evidenced by X-ray
analysis (entries 3ꢀ5, Table 1). Apparently, the E geometry
of sulfinylimines 4dꢀf is unfavorable due to the nonbonded
Scheme 1. Preparation of Sulfinylimines 4aꢀf
1
THF-d8 at room temperature, the H NMR spectrum of the
resulting suspension showed two sets of signals in a ratio of
78:22.17 Likewise, a 79:21 ratio of isomers was formed when the
crystalline 1:1 mixture of (Z)-4e atropisomers was dissolved in
THF-d8.
Crystalline atropisomer (Z)-(M)-4f displayed high configura-
tional stability in THF-d8 solution at ꢀ15 °C, and none of the
isomeric (Z)-(P)-4f was observed after 24 h. However, isomer-
ization to a 1:1 equilibrium mixture of atropisomers (Z)-(M)-4f
and (Z)-(P)-4f occurred within 6 h at room temperature.18
Remarkably, the atropisomers of (Z)-4f could be easily separated
by chromatography on silica gel. The individual atropisomers
(Z)-(M)-4f and (Z)-(P)-4f are stable in the crystalline form
at ꢀ18 °C for more than three weeks.
Table 1. Selected Crystallographic Parameters for Sulfinylketimines 4a,b,dꢀf
entry
imine (RS)-4
N1ꢀN2 (Å)
C1ꢀC2ꢀC3ꢀN2 torsion angle
C3ꢀN2ꢀSꢀO torsion angle
1
2
3
4
(E)-4a
(E)-4b
(Z)-4da
(Z)-4eb
2.683
2.658
ꢀ10.9
6.3
ꢀ138.9
ꢀ140.6
ꢀ77.9
ꢀ82.5
79.7 (P)
ꢀ84.1 (M)
ꢀ111.2c
ꢀ95.5 (P)
ꢀ102.0 (M)
ꢀ93.5c
5
(Z)-4fa
a Crystallized as individual (M)-atropisomer. b Crystallized as 1:1 mixture of (M):(P) atropisomers in the unit cell. c Average values of two molecules
crystallized in a unit cell.
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Table 2. Rate Constants and Free Energy of Activation for Atropisomerization of Sulfonylketimines (Z)-4dꢀf in THF-d8
ARTICLE
(P) f (M)
ΔGq258 (kJ/mol)
(M) f (P)
Δ(ΔGq258), kJ/mol
entry
imine
R
(M):(P) ratio, %
k, sꢀ1
k
ꢀ1, sꢀ1
ΔGq258 (kJ/mol)
1
2
3
(Z)-4d
(Z)-4e
(Z)-4f
NH2
22:78a
21:79a
1:1b
62 ꢁ 10ꢀ4
66 ꢁ 10ꢀ4
0.45 ꢁ 10ꢀ4
73.8
73.7
97.9c
221 ꢁ 10ꢀ4
247 ꢁ 10ꢀ4
0.45 ꢁ 10ꢀ4
71.1
70.8
97.9c
2.7
2.9
0
NHMe
NMe2
a Determined in THF-d8 at 258 K by NMR. b Determined in THF-d8 at 298 °C by NMR. c Corresponds to ΔGq298 (kJ/mol).
The structural assignment of atropisomers (Z)-4d,e in solution
was based on the differences in chemical shifts of H-3 and C-3
between the (M) and (P) atropisomeric series. Thus, the corre-
sponding signals in the case of stable atropisomer (Z)-(M)-4f19
appeared downfield compared with those in the isomeric
(Z)-(P)-4f, apparently due to the deshielding of the ortho-
position by the sulfoxide oxygen (see Newman projections in
the graphic of Table 2).20 Similar differences between the
chemical shifts of H-3 and C-3 were observed also for all
atropisomeric sulfinylimines (Z)-4dꢀf (Δδ[1H] = 0.03ꢀ0.05
ppm, Δδ[13C] = 1.5ꢀ2.6 ppm).21 Consequently, the major
atropisomers (Z)-4d,e in solution were assigned (P) geometry.
The predominance of (P) atropisomers of (Z)-4d,e in solution
was further supported by DFT calculations by using a B3LYP/6-
31G(d,p) basis set.22 Accordingly, (Z)-(P)-4e was calculated to
be more stable by 4.7 kJ/mol than the isomeric (Z)-(M)-4e.
To account for the observed fast interconversion of sulfinylimines
(Z)-4d,ein solutions, the free energy of activation and rate constants
for the atropisomerization of (Z)-4dꢀf were determined in THF-d8
by NMR methods.23 Barriers to the rotation around the aryl-imine
bond of (Z)-4d,e isomers in THF-d8 varied from 70.8 to 73.8 kJ/
mol (see Table 2), values that are comparable to the isomerization
barriers of related aryl ketimines.24 The observed ground-state
energy differences (ΔΔGq258) correlate well with the equilibrium
ratio of atropisomers in THF-d8 (Table 2). The atropisomerization
barrier for (Z)-4f in THF-d8 was determined to be 97.9 kJ/mol (see
Table 2), which is considerably higher than the interconversion
barriers for (Z)-4d,e and comparable to the atropisomerization
barriers of the most hindered (Z)-ketimines.25
previously reported correlation between the sense of asymmetric
induction and the favored E or Z configuration of the starting
imines 4aꢀf.11 Accordingly, the reduction of (E)-4aꢀc resulted
in formation of (RS,R)-5aꢀc whereas (Z)-4dꢀf afforded sulfi-
nylamides (RS,S)-5dꢀf.
The correlation between the facial selectivity of the reduction
and E or Z geometry of the starting ketimines implies the
involvement of a cyclic transition state for the reduction. Con-
sequently, a chelation-controlled reduction mechanism26 is pro-
posed, where borane or DIBAL forms an “ate” complex with
sulfinyl oxygen,27 ensuring the internal sulfoxide-mediated delivery
of hydride from the Si face (for (E)-4aꢀc) or from the Re face
(for imines (Z)-4dꢀf) of the CdN bond (Figure 2, TS-1). Less
likely is an alternative mechanism, where the NMe2 group of the
aniline controls the diastereoselectivity by forming a covalent
NꢀB bond with the BH3ꢀTHF or NꢀAl bond with DIBAL. In
the latter case, the internal hydride transfer from (Z)-(M)-4f
derived amidometallohydrides must occur from the Si face and
afford the reduction products with (R) configuration at the newly
created stereogenic center. In fact, (Z)-(M)-4f was reduced with
DIBAL to (RS,S)-5f with (S) configuration (99% conversion,
99:1 dr), and the outcome is consistent with the involvement of
sulfinyl oxygen in the transient “ate” complex (Figure 2, TS-1).
Notably, the isomeric sulfinylimine (Z)-(P)-4f was completely
unreactive in the reduction with DIBAL (Table 3, entries 16 vs
13). Thus, (Z)-(P)-4f did not react with BH3 THF at ꢀ15 °C
3
within 3 h, whereas (Z)-(M)-4f was reduced in 47% yield (dr =
99:1) (Table 3, entries 12 vs 15). After 22 h at ꢀ15 °C the
conversion of (Z)-(M)-4f increased to 88%, but (Z)-(P)-4f still
was not reduced.28 The reluctance of (Z)-(P)-4f to undergo
Diastereoselective Reduction of Sulfinylimines 4aꢀf. The
reduction by BH3 THF or DIBAL presumably results from
reduction of imines 4aꢀf was carried out by using BH3 THF or
3
3
steric shielding of the sulfinylimine Re face by the o-dimethyla-
mino group (TS-2, Figure 2) together with high configurational
stability of (Z)-4f atropisomers under the reduction conditions.29
Eventually, sulfinylimine (Z)-(P)-4f could be reduced with
DIBAL at ꢀ78 °C in THF (Table 3, conditions A and B, respectively).
Both reducing agents ensured excellent levels of diastereoselectivity.
Furthermore, the purity of the major diastereomers 5aꢀf could be
readily increased to >99:1 dr by flash column chromatography.
The relative configuration at the newly created asymmetric
carbon was determined for reduction products 5a,b,d,e as well as
for derivatives 6c and 7f by X-ray crystallographic analysis.
Sulfinylamides 5aꢀc were formed with the R absolute configuration
at the newly created asymmetric center, whereas reduction products
5dꢀf possessed the S configuration. These results reinforced
BH3 THF at room temperature (2 h, 75% conversion, 99:1
3
dr). In the latter case, however, isomerization of (Z)-(P)-4f to the
more reactive atropisomer (Z)-(M)-4f apparently took place.30
Steric hindrance of the Re-face presumably would also occur in
the structurally closely related sulfinylimines (Z)-(P)-4d,e (see
TS-2, Figure 2), rendering them unreactive under the reduction
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Table 3. Diastereoselective Reduction of tert-Butanesulfinylimines 4aꢀf
a Geometry of the CdN bond in crystalline material was determined by X-ray crystallographic analysis. b The E/Z ratio in THF-d8 was determined at
ꢀ15 °C by NOESY experiments. c Conditions A: BH3 THF (1.6 equiv), ꢀ78 °C, THF, 3 h. Conditions A1: BH3 THF (1.6 equiv), ꢀ15 °C, THF, 3 h.
3
3
Conditions B: DIBAL (3 equiv), ꢀ78 °C, THF, 3 h. d Determined by 1H NMR and HPLC assay for the crude reduction mixture. e Relative configuration
of the major diastereomer 5 was determined by X-ray crystallographic analysis. f Yield of major diastereomer. In parentheses: conversion of imines 4aꢀf.
g Relative configuration was determined by X-ray crystallographic analysis of (RS,R)-6c. h X-ray analysis was performed for the minor diastereomer (RS,
i
j
R)-5e. 96% yield and 99:1 dr was obtained in the reduction with DIBAL at room temperature. Relative configuration was determined by X-ray
crystallographic analysis of S-methyl sulfoximine (RS,S)-7f.
conditions. However, the differences in the reduction rates of
atropisomers (Z)-(M)-4d,e and (Z)-(P)-4d,e cannot be deter-
mined because fast atropisomerization occurs under the reduction
conditions.31 The fast isomerization of sulfinylimines (Z)-4d,e
apparently accounts for the excellent diastereoselectivities of the
reduction. Thus, the 99:1 diastereomer ratio of (RS,S)-5d,e
(Table 3, entries 7ꢀ10) exceeds the ∼4:1 equilibrium ratio of
(Z)-(P)-4d,e and (Z)-(M)-4f in solution (see Table 2).
The isomeric (E)-sulfinylimines 4aꢀc afforded sulfinylamides
(RS,R)-5aꢀc with the opposite, i.e. (R) absolute configuration
(Table 3). On the basis of our previous observations a cyclic
transition state involving internal sulfoxide-mediated delivery of
borane is proposed. The intramolecular hydrogen bond between
the aniline NꢀH and nitrogen of the imine stabilizes the favored E
conformation of sulfinylimines 4a,b in the transition state (TS-3).
Elaboration of Sulfinamides 5aꢀf To Target Diamines 1, 2.
Following the procedure reported previously,11 sulfinamides 5aꢀc
were treated with 4 N HCl in dioxane to obtain (R)-1aꢀc in
excellent yields (see Scheme 2). The cleavage of the chiral auxiliary
occurred without racemization of the newly created stereogenic
center. To access the corresponding N-methyl derivatives (R)-
2aꢀc, introduction of an N-methyl group at the benzylic nitrogen
was performed before the removal of the chiral auxiliary from (RS,
R)-5aꢀc. This allowed regioselective N-lithiation of sulfonamide
NꢀH in (RS,R)-5aꢀc with LiHMDS without interference by
aniline NꢀH, and subsequent addition of iodomethane gave the
desired (RS,R)-6aꢀc. On the other hand, a similar lithiation/
methylation sequence from sulfinamides (RS,S)-5dꢀf afforded
the S-methyl sulfoximines (RS,S)-7eꢀf instead of the anticipated
N-methyl sulfinamides (Scheme 2).32 This change from N- to S-
methylation was attributed to considerable steric hindrance near the
sulfinyl nitrogen in sulfinamides (RS,S)-5dꢀf. Therefore, the de-
sired (S)-2dꢀf were synthesized by an alternative sequence starting
with the desulfinylation of (RS,S)-5dꢀf to benzylamines (S)-1dꢀf,
followed by an N-formylationꢀreduction sequence (Scheme 2).
’ CONCLUSIONS
Synthesis of chiral, nonracemic o-aminobenzylamines
1 and 2 employed highly diastereoselective reduction of
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Figure 2. Transition states for the reduction of imines 4a,f.
Scheme 2. Elaboration of the Reduction Products 5aꢀf
tert-butanesulfinylimines as the key step. The configura-
tion of the newly created stereogenic center in the reduc-
tion products depended on E or Z geometry of the starting
tert-butanesulfinylketimines. Thus, reduction of (E)-imines
4aꢀc afforded (RS,R)-5aꢀc with the R configuration at the
newly created stereogenic center, whereas (Z)-4dꢀf were
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converted to sulfinylamides (RS,S)-5dꢀf with the S config-
uration. These results reinforce the previously reported
correlation between the sense of asymmetric induction and
E/Z geometry of the sulfinylimines.11
Sulfinylimines (Z)-4d,e exist in solution as rapidly equilibrating
mixtures of atropisomers. An individual atropisomer (Z)-(M)-4f
cooled to ꢀ78 °C, a solution of pivaloyl chloride (3.98 g, 33.04 mmol) in
THF (5 mL) was rapidly added, and the mixture was allowed to warm to
room temperature. After the solution was stirring for 2 h, aqueous
saturated 1 N HCl (150 mL) was added and product was extracted with
EtOAc (3 ꢁ 100 mL). Combined organic extracts were washed with
brine (30 mL), dried over Na2SO4, and concentrated (rotary evaporator).
Purification of the solid reside by column chromatography on silica gel
with gradient elution from 2% EtOAc/petroleum ether to 10% EtOAc/
petroleum ether yielded 6.05 g of N-[4-chloro-2-(2,2-dimethyl-1-
oxopropyl)phenyl]-2,2-dimethyl propanamide as a white solid (87%
yield); analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf
0.52. Pure material was obtained by crystallization from EtOAc/petro-
leum ether: mp 50ꢀ52 °C. IR (film, cmꢀ1) 3362 (NH), 1690 (CdO),
1507 (CdO); 1H NMR (400 MHz, CDCl3, ppm) δ 9.80 (1H, s), 8.37
(1H, d, J = 9.0 Hz), 7.65 (1H, d, J = 2.4 Hz), 7.38 (1H, dd, J = 9.0, 2.4
Hz), 1.33 (9H, s), 1.27 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ
211.0, 177.3, 136.5, 131.8, 127.8, 127.6, 127.41, 127.39, 127.3, 127.21,
127.19, 45.5, 39.9, 28.3, 27.4. Anal. Calcd for C16H22ClNO2: C, 64.97;
H, 7.50; N, 4.73. Found: C, 65.04; H, 7.64; N, 4.52.
could be reduced with DIBAL and BH3 THF under conditions
3
where the isomeric (Z)-(P)-4f was completely unreactive. The
reluctance of (Z)-(P)-4f to undergo reduction presumably results
from steric shielding of the sulfinylimine Re face by the ortho-
substituent in a cyclic transition state for the reduction. The distinct
reactivity of atropisomers together with the observed correlation
between the sense of asymmetric induction and E/Z geometry of
the sulfinylimines supports the hypothesis that sulfoxide oxygen
plays a major role in control of reduction diastereoselectivity.
’ EXPERIMENTAL SECTION
A suspension of N-[4-chloro-2-(2,2-dimethyl-1-oxopropyl)phenyl]-
2,2-dimethyl propanamide (4.36 g, 14.74 mmol; from above) in aqueous
6 N HCl (150 mL) was heated at 90 °C for 12 h. The resulting clear
solution was basified to pH 8 with aqueous saturated NH4OH and
extracted with EtOAc (3 ꢁ 75 mL). Combined organic extracts were
washed with brine (30 mL), dried over Na2SO4, and concentrated to
afford 2.93 g of 3d as a yellow solid (94% yield); analytical TLC on silica
gel, 1:10 EtOAc/petroleum ether, Rf 0.26. Pure material was obtained by
crystallization from hexane: mp 65ꢀ67 °C. IR (film, cmꢀ1) 3478
(NH2), 3357 (NH2), 1643 (CdO). 1H NMR (400 MHz, CDCl3, ppm)
δ 7.71 (1H, d, J = 2.4 Hz), 7.14 (1H, dd, J = 8.8, 2.4 Hz), 6.63 (1H, d, J =
8.8 Hz), 5.58 (2H, s), 1.38 (9H, s). 13C NMR (100.6 MHz, CDCl3,
ppm) δ 208.7, 147.8, 132.4, 129.5, 119.8, 119.5, 119.0, 44.8, 28.7, 28.6,
28.5. Anal. Calcd for C11H14ClNO: C, 62.41; H, 6.67; N, 6.62. Found:
C, 62.61; H, 6.66; N, 6.49.
Experimental Procedure for Synthesis of Ketones 3
1-[2-(Methylamino)phenyl]-1-ethanone (3b): To a solution
of 20-aminoacetophenone 3a (5.0 g, 37.0 mmol) in anhydrous DMF
(25 mL) was added K2CO3 (5.11 g, 37.0 mmol), followed by a solution
of MeI (5.25 g, 37.0 mmol) in anhydrous DMF (5 mL). After being
stirred for 48 h at room temperature the solution was diluted with water
(100 mL) and extracted with MeOtBu (3 ꢁ 75 mL). Combined organic
extracts were washed with water (50 mL) and brine (30 mL) and dried
over Na2SO4. Purification of the crude product by column chromatog-
raphy with gradient elution from 3% EtOAc/petroleum ether to 15%
EtOAc/petroleum ether afforded 3b as a yellow solid (2.7 g, 49% yield);
analytical TLC on silica gel, 1:10 EtOAc/petroleum ether, Rf 0.36. Pure
material was obtained by crystallization from petroleum ether: mp
37ꢀ39 °C. IR (film, cmꢀ1) 3325 (NH), 1635 (CdO); 1H NMR
(400 MHz, CDCl3, ppm) δ 8.77 (1H, s), 7.74 (1H, dd, J = 8.0, 1.2 Hz),
7.38 (1H, dd, J = 7.5, 1.2 Hz), 6.69 (1H, d, J = 8.5 Hz), 6.59 (1H, t, J =
7.5, 1.2 Hz), 2.91 (3H, d, J = 5.1 Hz), 2.58 (3H, s). 13C NMR (100.6
MHz, CDCl3, ppm) δ 200.7, 151.9, 135.0, 132.6, 117.5, 113.8, 111.2,
29.2, 27.8. Anal. Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found:
C, 72.29; H, 7.49; N, 9.34.
2,3-Dihydro-7-(methylamino)-1H-inden-1-one (3c): To a
solution of 7-amino-2,3-dihydro-1H-inden-1-one33 (3.19 g, 21.7 mmol)
in anhydrous DMF (25 mL) was added K2CO3 (3.0. g, 21.7 mmol),
followed by a solution of MeI (3.08 g, 21.7 mmol) in anhydrous DMF
(5 mL). After being stirred for 48 h at room temperature the solution was
diluted with water (100 mL) and extracted with MeOtBu (3 ꢁ 75 mL).
Combined organic extracts were washed with water (50 mL) and brine
(30 mL) and dried over Na2SO4. Purification of the crude product by
column chromatography with use of gradient elution from from 3%
EtOAc/petroleum ether to 20% EtOAc/petroleum ether afforded
product as a yellow solid (1.75 g, 50% yield); analytical TLC on silica
gel, 1:10 EtOAc/petroleum ether, Rf 0.20. Pure material was obtained by
crystallization from hexane: mp 96ꢀ98 °C. IR (film, cmꢀ1) 3365 (NH),
1680 (CdO); 1H NMR (400 MHz, CDCl3, ppm) δ 7.37 (1H, dd, J =
7.8, 7.8 Hz), 7.18 (1H, s), 6.60 (1H, dd, J = 7.3, 1.0 Hz), 6.41 (1H, d, J =
8.2 Hz), 3.03ꢀ2.98 (2H, m), 2.92 (3H, d, J = 5.2 Hz), 2.65ꢀ2.60 (2H,
m). 13C NMR (100.6 MHz, CDCl3, ppm) δ 207.9, 156.7, 149.5, 136.8,
119.9, 112.1, 106.6, 36.1, 29.0, 25.5. Anal. Calcd for C10H11NO: C, 74.51;
H, 6.88; N, 8.69. Found: C, 74.44; H, 6.92; N, 8.68.
1-[5-Chloro-2-(methylamino)phenyl]-2,2-dimethyl-1-propa-
none (3e): NaH (60% suspension in mineral oil, 389 mg, 16.22 mmol)
was washed under an argon atmosphere with anhydrous Et2O (2 ꢁ
10 mL) to remove the mineral oil, then suspended in anhydrous DMF
(5 mL) and cooled to 1ꢀ2 °C in an ice bath. A solution of N-[4-chloro-
2-(2,2-dimethyl-1-oxopropyl)phenyl]-2,2-dimethyl propanamide (4.0
g, 13.52 mmol; synthesized as described in the experimental for 3d)
in anhydrous DMF (15 mL) was added dropwise. When gas evolution
ceased, the ice bath was removed. After the mixture was stirred at
ambient temperature for 1 h, a solution of MeI (3.81 g, 27.04 mmol) in
anhydrous DMF (5 mL) was added. After being stirred for 5 h the
solution was diluted with water (75 mL) and extracted with MeOtBu
(3 ꢁ 50 mL). Combined organic extracts were washed with water(30 mL)
and brine (20 mL) and dried over Na2SO4. Purification by column
chromatography by using gradient elution from 10% EtOAc/petroleum
ether to 20% EtOAc/petroleum ether afforded N-[4-chloro-2-(2,2-
dimethyl-1-oxopropyl)phenyl]-N,2,2-trimethyl propanamide as a white
solid (3.59 g, 86% yield); analytical TLC on silica gel, 2:5 EtOAc/
petroleum ether, Rf 0.20. Pure material was obtained by crystallization
from EtOAc/petroleum ether: mp 83ꢀ85 °C. IR (film, cmꢀ1) 1689
(CdO), 1636 (CdO); 1H NMR (400 MHz, CDCl3, ppm) δ 7.40ꢀ7.35
(2H, m), 7.12ꢀ7.08 (1H, m), 3.34 (3H, s), 1.30ꢀ1.23 (18H, m). 13C
NMR (100.6 MHz, CDCl3, ppm) δ 209.5, 177.8, 141.9, 139.8, 131.6,
130.4, 130.1, 126.2, 44.4, 41.1, 39.2, 28.2, 28.0. Anal. Calcd for
C17H24ClNO2: C, 65.90; H, 7.81; N 4.52. Found C, 66.24; H, 7.89;
N, 4.37.
1-(2-Amino-5-chlorophenyl)-2,2-dimethyl-1-propanone (3d):
TMEDA (2.74 g, 23.6 mmol) was added to a cooled solution (ꢀ10 °C)
of N-(4-chlorophenyl)-2,2-dimethylpropanamide34 (5.0 g, 23.6 mmol)
in anhydrous THF (45 mL) under an argon atmosphere, followed by
dropwise addition of n-BuLi (2.2 M solution in hexane, 6.0 mL, 13.23
mmol). After stirring at ꢀ10 °C for 2 h, the yellow suspension was
A suspension of N-[4-chloro-2-(2,2-dimethyl-1-oxopropyl)phenyl]-
N,2,2-trimethyl propanamide (6.7 g, 21.6 mmol; from above) in aqueous
6 N HCl (75 mL) was heated at 90 °C for 12 h. The resulting clear
solution was basified to pH 8 with aqueous saturated NH4OH and
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The Journal of Organic Chemistry
ARTICLE
extracted with EtOAc (3 ꢁ 75 mL). Combined organic extracts were
washed with brine (30 mL), dried over Na2SO4, and concentrated to
afford product 3e as a yellow solid (4.58 g, 94% yield); analytical TLC on
silica gel, 1:10 EtOAc/petroleum ether, Rf 0.48. Pure material was
obtained by crystallization from EtOAc/petroleum ether: mp 57ꢀ59 °C.
IR (film, cmꢀ1) 3365 (NH), 1635 (CdO). 1H NMR (400 MHz, CDCl3,
ppm) δ 7.97 (1H, s), 7.81 (1H, d, J = 2.5 Hz), 7.26 (1H, dd, J = 9.0, 2.5
Hz), 6.65 (1H, d, J = 9.0 Hz), 2.85 (3H, s), 1.39 (9H, s). 13C NMR
(100.6 MHz, CDCl3, ppm) δ 208.6, 150.1, 133.1, 130.4, 117.81, 117.79,
113.1, 44.8, 29.7, 29.0. Anal. Calcd for C12H16ClNO: C, 63.85; H, 7.15;
N, 6.21. Found: C, 63.94; H, 7.21; N, 6.11.
(400 MHz, CDCl3, ppm) δ 9.23 (1H, s), 7.63 (1H, dd, J = 8.0, 1.0 Hz),
7.37ꢀ7.31 (1H, m), 6.69 (1H, d, J = 8.5 Hz), 6.65ꢀ6.59 (1H, m), 2.92
(3H, d, J = 5.0 Hz), 2.77 (3H, s), 1.29 (9H, s). 13C NMR (100.6 MHz,
CDCl3, ppm) δ 179.6, 151.3, 113.7, 131.1, 117.5, 114.2, 111.2, 56.2,
29.5, 22.2, 21.4. Anal. Calcd for C13H20N2OS: C, 61.87; H, 7.99; N,
11.10. Found: C, 62.02; H, 7.83; N, 11.09. [R]20 ꢀ164.5 (c 2.58,
D
EtOH).
N-[2,3-Dihydro-7-(methylamino)-1H-inden-1-yliden]-2-
methyl-(RS)-2-propanesulfinamide (4c): Following the gen-
eral procedure, ketone 3c (837 mg, 5.19 mmol) was converted into
sulfinylimine 4c. Purification of the crude product by column
chromatography by using gradient elution from 6% EtOAc/petro-
leum ether to 37% EtOAc/petroleum ether afforded product as a
yellow solid (471 mg, 34% yield); analytical TLC on silica gel, 2:5
EtOAc/petroleum ether, Rf 0.36. Pure material was obtained by
crystallization from hexane: mp 100ꢀ102 °C. IR (film, cmꢀ1) 3325
1-[5-Chloro-2-(dimethylamino)phenyl]-2,2-dimethyl-1-pro-
panone (3f): To a solution of ketone 3e (1.0 g, 4.43 mmol) in anhydrous
DMF (25 mL) was added K2CO3 (1.22 g, 8.86 mmol), followed by a
solution of MeI (1.26 g, 8.86 mmol) in anhydrous DMF (5 mL). After
being stirred at room temperature for 48 h the solution was diluted with
water (100 mL) and extracted with MeOtBu (3 ꢁ 75 mL). Combined
organic extracts were washed with water (50 mL) and brine (30 mL) and
dried over Na2SO4. Purification of the crude product by column
chromatography by using gradient elution from 5% CH2Cl2/petroleum
ether to 15% CH2Cl2/petroleum ether afforded product as a yellow oil
(754 mg, 71% yield); analytical TLC on silica gel, 1:10 EtOAc/
1
(NH), 1604 (CdN), 1068 (SdO). H NMR (400 MHz, CDCl3,
ppm) δ 7.64 (1H, s), 7.33 (1H, dd, J = 8.2, 7.4 Hz), 6.58 (1H, dd, J =
7.4, 0.8 Hz), 6.44 (1H, d, J = 8.2 Hz), 3.41ꢀ3.32 (1H, m), 3.06ꢀ2.95
(3H, m), 2.93 (3H, s), 1.29 (9H, s). 13C NMR (100.6 MHz, CDCl3,
ppm) δ 187.7, 153.6, 149.6, 135.6, 120.4, 111.5, 106.8, 56.1, 32.2,
29.3, 28.5, 22.2. Anal. Calcd for C14H20N2OS: C, 63.60; H, 7.62; N,
1
petroleum ether, Rf 0.60. IR (film, cmꢀ1) 1690 (CdO); H NMR
10.60. Found: C, 63.64; H, 7.54; N, 10.44. [R]20 ꢀ16.3 (c 0.93,
D
(400 MHz, CDCl3, ppm) δ 7.25 (1H, dd, J = 8.6, 2.5 Hz), 7.01 (1H, dd,
J = 8.6 Hz), 6.92 (1H, d, J = 2.5 Hz), 2.63 (6H, s), 1.19 (9H, s). 13C NMR
(100.6 MHz, CDCl3, ppm) δ 215.5, 149.1, 139.0, 129.2, 127.9, 125.9,
120.5, 44.9, 29.0, 27.4. HRMS-ESI (m/z) calcd for C13H18ClNO [M þ
H]þ 240.1155, found 240.1169.
EtOH).
N-[(Z)-1-(2-Amino-5-chlorophenyl)-2,2-dimethylpropylidene]-
2-methyl-(RS)-2-propanesulfinamide (4d): Following the general
procedure, ketone 3d (500 mg, 2.36 mmol) was converted into sulfinyli-
mine 4d. Purification of the crude product by column chromatography
by using gradient elution from 6% EtOAc/petroleum ether to 30%
EtOAc/petroleum ether afforded product as a white solid (520 mg, 75%
yield); analytical TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf 0.20.
Pure material was obtained by crystallization from petroleum ether: mp
116ꢀ118 °C. IR (film, cmꢀ1) 3442 (NH2), 3339 (NH2), 1586 (CdN),
1069 (SdO). 1H NMR for a mixture of atropisomers (Z)-(M)-4d and
(Z)-(P)-4d (400 MHz, CDCl3, ppm) δ 7.14ꢀ7.08 (1H, m), 6.93
(0.16H, d, J = 2.2 Hz), 6.73 (0.84H, d, J = 2.2 Hz), 6.65 (0.84H, d,
J = 8.6 Hz), 6.62 (0.16H, d, J = 8.6Hz), 3.74(2H, s), 1.26ꢀ1.21 (18H, m).
13C NMR for a mixture of atropisomers (Z)-(M)-4d and (Z)-(P)-4d
(100.6 MHz, CDCl3, ppm) δ 193.0, 142.1, 129.5, 129.4, 127.2, 126.3,
125.5, 122.7, 118.2, 116.2, 55.8, 43.3, 28.2, 28.0, 22.3, 21.7. Anal. Calcd
for C15H23ClN2OS: C, 57.22; H, 7.36; N, 8.90. Found: C, 57.28; H,
7.30; N, 8.81. [R]20D ꢀ56.6 (c 0.69, EtOH; determined for a mixture of
atropisomers (Z)-(M)-4d and (Z)-(P)-4d).
General Procedure for the Condensation of Ketones with
(RS)-tert-Butanesulfinamide. A mixture of appropriate ketone 3
(1.0 equiv), (RS)-tert-butanesulfinamide (1.0 equiv), and neat Ti(OEt)4
(Alfa Aesar, Vertec, 99þ%, 2.0 equiv) in a sealed Ace pressure tube was
stirred and heated for 12 h at 75 °C (ketones 3a,b,d,e) or 125 °C (ketone
3c) under an argon atmosphere. After cooling to room temperature, the
reaction mixture was poured into a mixture of brine (20 mL/mmol of
ketone 3) and EtOAc (20 mL/mmol of ketone 3). The resulting slurry
was stirred for 10 min and filtered throught a plug of Celite (3 ꢁ 5 cm),
then the filter cake was washed with EtOAc (50 mL/mmol of ketone 3).
The organic layer from the filtrate was washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column chroma-
tography on silica gel.
N-[(E)-1-(2-Aminophenyl)ethylidene]-2-methyl-(RS)-2-propa-
nesulfinamide (4a): Following the general procedure, ketone 3a (500mg,
3.7 mmol) was converted into sulfinylimine 4a. Purification of the crude
product by column chromatography by using gradient elution from 6%
EtOAc/petroleum ether to 100% EtOAc afforded product as a yellow solid
(776 mg, 88% yield); analytical TLC on silica gel, 1:1 EtOAc/petroleum
ether, Rf 0.24. Pure material was obtained by crystallization from EtOH: mp
189ꢀ191 °C. IR (film, cmꢀ1) 3400 (NH2), 3283 (NH2), 1457 (CdN),
1066 (SdO). 1H NMR (400 MHz, CDCl3, ppm) δ7.57 (1H, dd, J= 8.3, 1.1
Hz), 7.23ꢀ7.18 (1H, m), 6.69ꢀ6.63 (2H, m), 6.49 (2H, s), 2.91 (3H, s),
1.28 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ 179.6, 149.5, 132.9,
130.5, 118.3, 117.4, 116.1, 56.3, 22.3, 21.6. Anal. Calcd for C12H18N2OS: C
N-[(Z)-1-[5-Chloro-2-(methylamino)phenyl]-2,2-dimeth-
ylpropylidene]-2-methyl-(RS)-2-propanesulfinamide (4e):
Following the general procedure, ketone 3e (3.36 g, 14.90 mmol)
was converted into sulfinylimine 4e. Purification of the crude
product by column chromatography by using gradient elution from
6% EtOAc/petroleum ether to 20% EtOAc/petroleum ether af-
forded product as a white solid (3.66 g, 75% yield); analytical TLC
on silica gel, 1:1 EtOAc/petroleum ether, Rf 0.48. Pure material was
obtained by crystallization from Et2O: mp 154ꢀ156 °C. IR
(film, cmꢀ1) 3375 (NH), 1458 (CdN), 1053 (SdO). 1H NMR
for a mixture of atropisomers (Z)-(M)-4e and (Z)-(P)-4e (400 MHz,
CDCl3, ppm) δ 7.24ꢀ7.18 (1H, m), 6.90 (0.13H, d, J = 2.2 Hz), 6.70
(0.87H, d, J = 2.2 Hz), 6.63 (0.87H, d, J = 8.8 Hz), 6.57 (0.13H, d, J =
8.8 Hz), 3.79 (0.87H, q, J = 5.0 Hz), 3.17 (0.13H, q, J = 5.0 Hz), 2.84
(0.44H, d, J = 5.0 Hz), 2.77 (2.56H, d, J = 5.0 Hz), 1.24ꢀ1.19 (18H,
m). 13C NMR for a mixture of atropisomers (Z)-(M)-4e and
(Z)-(P)-4e (100.6 MHz, CDCl3, ppm) δ 193.3, 144.4, 129.6,
129.5, 126.8, 125.9, 125.3, 121.2, 112.3, 111.2, 55.7, 43.2, 30.9,
28.3, 28.1, 22.3, 21.7. Anal. Calcd for C16H25ClN2OS: C, 58.43; H,
60.47; H 7.61; N 11.75. Found: C 60.51; H 7.60; N 11.63. [R]20 ꢀ76.4 (c
D
0.97, EtOH).
N-[(E)-1-[2-(Methylamino)phenyl]ethylidene]-2-methyl-(RS)-
2-propanesulfinamide (4b): Following the general procedure, ke-
tone 3b (200 mg, 1.6 mmol) was converted into sulfinylimine 4b.
Purification of the crude product by column chromatography by using
gradient elution from 6% EtOAc/petroleum ether to 38% EtOAc/
petroleum ether afforded product as a yellow solid (241 mg, 60% yield);
analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf 0.39. Pure
material was obtained by crystallization from Et2O: mp 81ꢀ83 °C.
7.66; N, 8.52. Found: C, 58.39; H, 7.64; N, 8.44. [R]20 ꢀ33.4 (c
D
1
IR (film, cmꢀ1) 3223 (NH), 1543 (CdN), 1071 (SdO). H NMR
2.07, EtOH).
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The Journal of Organic Chemistry
ARTICLE
N-[(Z)-1-[5-Chloro-2-(dimethylamino)phenyl]-2,2-dimethyl-
propylidene]-2-methyl-(RS)-2-propanesulfinamide (4f): Sulfinyl
imine 4e (500 mg, 1.52 mmol) was dissolved in anhydrous DMF (5 mL)
and cooled to ꢀ20 °C under argon atmosphere. A solution of LiHMDS in
THF (1 M solution in THF, 1.67 mmol) was added dropwise and the
colorless solution was stirred at ꢀ20 °C for 1 h whereupon neat MeI (258
mg, 1.82 mmol) was added. After warming to room temperature and
stirring for 2 h, the mixture was diluted with water (30 mL) and extracted
with MeOtBu (3 ꢁ 50 mL). Combined organic extracts were dried over
Na2SO4 and concentrated. Purification of the crude product by column
chromatography by using gradient elution from 6% EtOAc/petroleum
ether to 38% EtOAc/petroleum ether afforded individual atropisomers35
(Z)-(M)-4f and (Z)-(P)-4f as white solids (totally 476 mg, 91% yield);
analytical TLC on silica gel, 2:5 EtOAc/petroleum ether Rf 0.56 (for
(Z)-(M)-4f) and Rf 0.48 (for (Z)-(P)-4f). Pure material was obtained by
crystallization from hexane: mp 76ꢀ78 °C. IR (film, cmꢀ1) 1489 (CdN),
1084(SdO). Anal. Calcd for C17H27ClN2OS: C, 59.54; H, 7.94; N, 8.17.
(1H, dd, J = 7.8, 1.0 Hz), 6.75 (1H, dd, J = 7.8, 7.8 Hz), 6.69 (1H, d, J = 7.8
Hz), 4.55(1H, dq, J=6.6, 2.1Hz), 4.27(2H, s), 3.40(1H, s), 1.59(3H, d,J=
6.6 Hz), 1.22 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ 144.6, 128.9,
126.8, 125.7, 118,0 116.6, 55.2, 49.8, 22.5, 19.8. Anal. Calcd for C12H20N2OS:
C, 59.96; H, 8.39; N, 11.65. Found: C, 60.0; H, 8.32; N, 11.63. Optical
rotation (99% de, HPLC/csp) [R]20D ꢀ147.7 (c 2.2, EtOH). HPLC/csp
assay: Daicel CHIRALPAK IB, 25 cm ꢁ 4.6 mm i.d., mobile phase 20% IPA/
80% Hex, flow rate 0.7 mL/min, detector UV 210 nm, retention time 8.5 min
((RS,R)-5a), major and 9.2 min ((RS,S)-5a), minor.
(RS)-N-(R)-1-[2-(Methylamino)phenyl]ethyl-2-methyl-2-pro-
panesulfinamide (5b): Following general procedure B for the reduc-
tion, sulfinylimine 4b (767 mg, 3.04 mmol) was converted into 5b. Purification
of the crude product by column chromatography by using gradient elution
from 6% EtOAc/petroleum ether to 42% EtOAc/petroleum ether afforded
product as a white solid (750 mg, 97% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf 0.20. Pure material was obtained by crystal-
lization fromEt2O: mp 81ꢀ83 °C. IR (film, cmꢀ1) 3380 (NH), 1046 (SdO);
1H NMR (400 MHz, CDCl3, ppm) δ 7.29ꢀ7.20 (2H, m), 6.75ꢀ6.64 (2H,
m), 4.89(1H, s), 4.51(1H, dq,J= 6.5, 2.1 Hz), 3.34 (1H, s), 2.87 (3H, s), 1.59
(3H, d, J = 6.5 Hz), 1.20 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ
146.8, 129.2, 126.5, 125.0, 116.1, 110.5, 55.2, 49.6, 30.3, 22.5, 19.9. Anal. Calcd
for C13H22N2OS: C, 61.38; H, 8.72; N, 11.01. Found: C, 61.39; H, 8.80; N,
10.97. Optical rotation (99% de, HPLC/csp) [R]20D ꢀ164.5 (c 2.58, EtOH).
HPLC/csp assay: Daicel CHIRALPAK IA, 25 cm ꢁ 4.6 mm i.d., mobile phase
10% IPA/90% Hex, flow rate 0.9 mL/min, detector UV 254 nm, retention time
5.8 min ((RS,R)-5b), major and 6.3 min ((RS,S)-5b), minor.
Found: C, 59.77; H, 7.99; N, 8.08. [R]20 ꢀ122.4 (c 0.96, EtOH;
D
determined for the mixture of atropisomers (Z)-(M)-4f and (Z)-(P)-4f).
(Z)-(M)-4f: 1H NMR (400 MHz, THF-d8, ppm) δ 7.35 (1H, dd, J =
8.7, 2.2 Hz), 7.18 (1H, d, J = 8.7 Hz), 7.08 (1H, d, J = 2.2 Hz), 2.63 (6H,
s), 1.21 (9H, s), 1.19 (9H, s). 13C NMR (100.6 MHz, THF-d8, ppm) δ
190.8, 149.2, 133.2, 129.2, 128.2, 128.9, 126.3, 120.7, 56,0 43.7, 42.4,
28.9, 21.7.
(Z)-(P)-4f: 1H NMR (400 MHz, THF-d8, ppm) δ 7.28 (1H, dd, J =
8.7, 2.5 Hz), 7.10 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 2.5 Hz), 2.72 (6H,
s), 1.22 (9H, s), 1.21 (9H, s). 13C NMR (100.6 MHz, THF-d8, ppm) δ
191.6, 149.2, 135.6, 129.0, 126.5, 126.3, 120.8, 55.7, 43.6, 42.4, 28.9, 21.5.
General Procedure A for the Reduction of N-tert-Butane-
(RS)-N-[(R)-7-(Methylamino)-2,3-dihydro-1H-inden-1-yl]-
2-methyl-2-propanesulfinamide (5c): Following general proce-
dure B for the reduction, sulfinylimine 4c (420 mg, 1.59 mmol) was
converted into 5c. Purification of the crude product by column chroma-
tography by using gradient elution from 6% EtOAc/petroleum ether to
20% EtOAc/petroleum ether afforded product as a white solid (398 mg,
94% yield); analytical TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf
0.26. Pure material was obtained by crystallization from hexane: mp
127ꢀ129 °C. IR (film, cmꢀ1) 3365 (NH), 3220 (NH), 1046 (SdO).
1H NMR (400 MHz, CDCl3, ppm) δ 7.19 (1H, dd, J = 7.8, 7.8 Hz), 6.58
(1H, d, J = 7.4 Hz), 6.45 (1H, d, J = 8.0 Hz), 5.07ꢀ5.02 (1H, m), 4.80
(1H, ddd, J = 8.0, 5.6, 2.7 Hz), 3.41 (1H, d, J = 5.6 Hz), 3.05 (1H, dt, J =
16.0, 8.0 Hz), 2.84 (3H, d, J = 4.3 Hz), 2.76 (1H, ddd, J = 16.0, 9.0, 3.6
Hz), 2.46ꢀ2.35 (1H, m), 2.07ꢀ1.98 (1H, m), 1.21 (9H, s). 13C NMR
(100.6 MHz, CDCl3, ppm) δ 146.1, 145.2, 130.3, 125.5, 112.4, 107.5,
59.1, 55.3, 35.0, 30.5, 30.0, 22.6. Anal. Calcd for C14H22N2OS: C, 63.12;
H, 8.32; N, 10.52. Found: C, 62.78; H, 8.32; N, 10.41. Optical rotation
sulfinyl Imines 4aꢀf with BH3 THF. Sulfinylimine 4 (1.0 equiv)
3
was dissolved in anhydrous THF (10 mL/mmol of imine 4) and cooled
to ꢀ78 °C under argon atmosphere. Borane THF complex (1.0 M
3
solution in THF, 1.6 equiv) was added dropwise and the resulting
solution was stirred at ꢀ78 °C for 3 h whereupon it was quenched at
ꢀ78 °C with brine (50 mL/mmol of imine 4). After the solution was
warmed to room temperature, EtOAc (50 mL/mmol of imine 4) was
added and the layers were separated. The organic phase was washed with
brine, dried over Na2SO4, and concentrated. An aliquot of the crude
product was submitted to 1H NMR and HPLC analysis to determine the
diastereoselectivity of the reduction. Diastereomerically pure product
was obtained after purification by column chromatography on silica gel.
General Procedure B for the Reduction of N-tert-Butane-
sulfinyl Imines 4aꢀf with DIBAL. Sulfinylimine 4 (1.0 equiv) was
dissolved in anhydrous THF (5.0 mL/mmol of imine 4) and the mixture
was cooled to ꢀ78 °C under argon atmosphere. Diisobutylaluminium
hydride (1.0 M solution in hexanes, 3.0 equiv) was added dropwise and
the resulting solution was stirred at ꢀ78 °C for 3 h whereupon it was
quenched at ꢀ78 °C with brine (12 mL/mmol of imine 4). After the
solution was warmed to room temperature, EtOAc (15 mL/mmol of
imine 4) was added and the layers were separated. The organic phase
was washed with brine, dried over Na2SO4, and concentrated. An aliquot
of the crude product was submitted to 1H NMR and HPLC analysis to
determine th diastereoselectivity of the reduction. Diastereomerically
pure product was obtained after purification by column chromatography
on silica gel.
(measured for a batch with 86% de, HPLC/csp) [R]20 ꢀ3.3 (c 1.0,
D
EtOH). HPLC/csp assay: Daicel CHIRALPAK IA, 25 cm ꢁ 4.6 mm i.d.,
mobile phase 5% IPA/95% Hex, flow rate 0.9 mL/min, detector UV
254 nm, retention time 6.2 min ((RS,R)-5c), major and 10.1 min ((RS,
S)-5c), minor.
(RS)-N-(S)-[1-(2-Amino-5-chlorophenyl)-2,2-dimethylpropyl]-
2-methyl-2-propanesulfinamide (5d): Following general procedure
B for the reduction, sulfinylimine 4d (1.80 g, 5.71 mmol) was converted
into 5d. Purification of the crude product by column chromatography by
using gradient elution from 6% EtOAc/petroleum ether to 100% EtOAc/
petroleum ether afforded product as a white solid (1.79 g, 99% yield);
analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf 0.19. Pure
material was obtained by crystallization from hexane: mp 147ꢀ149 °C.
IR (film, cmꢀ1) 3459 (NH), 3355 (NH2), 3245 (NH2), 1055 (SdO);
1H NMR (400 MHz, CDCl3, ppm) δ 7.17ꢀ7.13 (0.81H, m), 7.05ꢀ6.95
(1.19H, m), 6.62ꢀ6.48 (1H, m), 4.23 (0.78H, s), 4.04 (0.22H, s), 3.68
(0.25H, s), 3.66 (2H, s), 3.52 (0.75H, s), 1.27ꢀ1.18 (9H, m), 1.05ꢀ0.97
(9H, m). 13C NMR (100.6 MHz, CDCl3, ppm) δ 144.3, 133,0 129.6,
128.5, 127.9, 125.3, 122.9, 118.4, 117.8, 68.7, 58.8, 55.5, 55.3, 37.4, 36.6,
28.0, 26.5, 22.5. Anal. Calcd for C15H25ClN2OS: C, 56.85; H, 7.95; N,
8.84. Found: C, 56.91; H, 8.12; N, 8.78. Optical rotation (99% de,
(RS)-N-(R)-[1-(2-Aminophenyl)ethyl]-2-methyl-2-propanesul-
finamide (5a): Following general procedure B for the reduction, sulfiny-
limine 4a (839 mg, 3.52 mmol) was converted into 5a. Purification of the
crude product by column chromatography by using gradient elution from 6%
EtOAc/petroleum ether to 100% EtOAc afforded product as a white solid
(745 mg, 88% yield); analytical TLC on silica gel, 1:1 EtOAc/petroleum
ether, Rf 0.20. Pure material was obtained by crystallization from Et2O: mp
126ꢀ128 °C. IR (film, cmꢀ1) 3459 (NH2), 3369 (NH2), 3205 (NH), 1038
(SdO). 1H NMR (400 MHz, CDCl3, ppm) δ 7.22 (1H, d, J = 7.8 Hz), 7.13
2642
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The Journal of Organic Chemistry
ARTICLE
HPLC/csp) [R]20 ꢀ97.9 (c 1.07, EtOH). HPLC/csp assay: Daicel
NMR (400 MHz, CDCl3, ppm) δ 7.20 (1H, dd, J = 7.0, 1.5 Hz), 7.10
(1H, ddd, J = 7.8, 7.8, 1.5 Hz), 6.77 (1H, ddd, J = 7.8, 7.8, 1.5 Hz), 6.68
(1H, dd, J = 7.8, 1.0 Hz), 4.32 (1H, q, J = 7.0 Hz), 4.01 (2H, s), 2.56 (3H,
s), 1.63 (3H, d, J = 7.0 Hz), 1.10 (9H, s). 13C NMR (100.6 MHz, CDCl3,
ppm) δ 145.1, 128.5, 127.8, 125.9, 118.4, 116.6, 59.9, 57.5, 29.3, 23.6,
16.6. Anal. Calcd for C13H22N2OS: C, 61.38; H, 8.72; N, 11.01. Found:
D
CHIRALPAK IB, 25 cm ꢁ 4.6 mm i.d., mobile phase 10% IPA/90%
Hex, flow rate 0.9 mL/min, detector UV 254 nm, retention time 6.4 min
((RS,S)-5d), major and 7.8 min ((RS,R)-5d), minor.
(RS)-N-(S)-[1-[5-Chloro-2-(methylamino)phenyl]-2,2-dimeth-
ylpropyl]-2-methyl-2-propanesulfinamide (5e): Following gener-
al procedure B for the reduction, sulfinylimine 4e (658 mg, 2.0 mmol)
was converted into 5e. Purification of the crude product by column
chromatography by using gradient elution from 6% EtOAc/petroleum
ether to 80% EtOAc/petroleum ether afforded product as a white solid
(636 mg, 96% yield); analytical TLC on silica gel, 1:1 EtOAc/petroleum
ether, Rf 0.40. Pure material was obtained by crystallization from Et2O:
mp 101ꢀ103 °C. IR (film, cmꢀ1) 3390 (NH), 1057 (SdO); 1H NMR
(400 MHz, CDCl3, ppm) δ 7.17ꢀ7.10 (1.7H, m), 6.97ꢀ6.95 (0.3H, m),
6.56 (0.7H, d, J = 8.7 Hz), 6.49 (0.3H, d, J = 8.7 Hz), 5.35 (1H, s), 4.23
(0.7H, s), 4.06 (0.3H, s), 3.58 (0.3H, s), 3.51 (0.7H, s), 2.82 (2H, s), 2.73
(1H, s), 1.26ꢀ1.19 (9H, m), 1.02ꢀ0.97 (9H, m). 13C NMR (100.6
MHz, CDCl3, ppm) δ 147.4, 146.8, 132.8, 129.4, 128.6, 128.0 124.9,
121.3, 120.7, 111.7, 111.6, 69.0, 58.1, 55.5, 55.3, 37.1, 36.6, 31.2, 30.1,
28.1, 26.5, 22.6, 22.5. Anal. Calcd for C16H27ClN2OS: C, 58.07; H, 8.22;
N, 8.47. Found: C, 58.15; H, 8.22; N, 8.33. Optical rotation (99% de,
C, 61.41; H, 8.84; N, 10.93. Optical rotation [R]20 ꢀ14.9 (c 1.14,
D
EtOH).
(RS)-N-(R)-[1-[2-(Methylamino)phenyl]ethyl]-N,2-dimeth-
yl-2-propanesulfinamide (6b): Following the general procedure
for the alkylation, sulfinyl amide 5b (572 mg, 2.25 mmol) was converted
into 6b. Purification of the crude product by column chromatography by
using gradient elution from 6% EtOAc/petroleum ether to 60% EtOAc/
petroleum ether afforded product as a colorless oil (434 mg, 72% yield);
analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf 0.28. IR
(film, cmꢀ1) 3385 (NH), 1068 (SdO). 1H NMR (400 MHz, CDCl3,
ppm) δ 7.25ꢀ7.17 (2H, m), 6.74 (1H, ddd, J = 7.5, 7.5, 1.0 Hz), 6.65
(1H, dd, J = 7.5, 1.0 Hz), 4.48 (1H, s), 4.25 (1H, q, J = 6.8 Hz), 2.86 (3H,
s), 2.56 (3H, s), 1.64 (3H, d, J = 6.8 Hz), 1.07 (9H, s). 13C NMR (100.6
MHz, CDCl3, pmm) δ 147.5, 128.7, 127.5, 125.2, 116.7, 110.4, 60.4,
57.5, 30.5, 29.7, 23.6, 22.5, 16.5. HRMS-ESI (m/z) calcd for [M þ Na]þ
291.1507, found 291.1518. Optical rotation [R]20D ꢀ155.2 (c0.66, EtOH).
(RS)-N-(R)-[2,3-Dihydro-7-(methylamino)-1H-inden-1-yl]-
N,2-dimethyl-2-propanesulfinamide (6c): Following the general
procedure for the alkylation, sulfinyl amide 5c (321 mg, 1.21 mmol) was
converted into 6c. Purification of the crude product by column
chromatography on amine-functionalized silica by using gradient elution
from 6% EtOAc/petroleum ether to 60% EtOAc/petroleum ether
afforded product as a white solid (309 mg, 91% yield); analytical TLC
on silica gel, 2:5 EtOAc/petroleum ether, Rf 0.32. Pure material was
HPLC/csp) [R]20 ꢀ96.0 (c 1.01, EtOH). HPLC/csp assay: Daicel
D
CHIRALPAK IB, 25 cm ꢁ 4.6 mm i.d., mobile phase 5% IPA/95% Hex,
flow rate 0.9 mL/min, detector UV 254 nm, retention time 10.4 min
((RS,S)-5e), major and 8.2 min ((RS,R)-5e), minor.
(RS)-N-(S)-[1-[5-Chloro-2-(dimethylamino)phenyl]-2,2-di-
methylpropyl]-2-methyl-2-propanesulfinamide (5f): Follow-
ing general procedure B for the reduction, the individual (M)-atropi-
somer of sulfinylimine 4f (737 mg, 2.15 mmol) was converted into 5f.
Purification of the crude product by column chromatography by using
gradient elution from 6% EtOAc/petroleum ether to 40% EtOAc/
petroleum ether afforded product as a white solid (719 mg, 97% yield);
analytical TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf 0.32. Pure
material was obtained by crystallization from hexane: mp 75ꢀ77 °C. IR
obtained by crystallization from Et2O: mp 107ꢀ109 °C. IR (film, cmꢀ1
)
3408 (NH), 1054 (SdO). 1H NMR (400 MHz, CDCl3, ppm) δ 7.17
(1H, dd, J = 7.8, 7.8 Hz), 6.57 (1H, d, J = 7.8 Hz), 6.42 (1H, d, J = 7.8
Hz), 4.98 (1H, dd, J = 8.3, 6.3 Hz), 4.77 (1H, s), 2.94 (1H, ddd, J = 16.0,
9.4, 4.6 Hz), 2.84 (3H, s), 2.78ꢀ2.69 (1H, m), 2.44 (3H, s), 2.31 (1H,
dtd, J = 9.0, 4.6, 4.6 Hz), 2.08ꢀ1.99 (1H, m), 1.24 (9H, s). 13C NMR
(100.6 MHz, CDCl3, ppm) δ 147.1, 145.2, 129.9, 122.9, 112.7, 107.2,
69.5, 58.1, 30.3, 30.2, 30.1, 25.5, 23.9. Anal. Calcd for C15H24N2OS: C,
64.25; H, 8.63; N, 9.99. Found: C, 64.33; H, 8.75; N, 9.83. Optical
roation [R]20D ꢀ163.8 (c 1.71, EtOH).
1
(film, cmꢀ1) 3443 (NH), 3335 (NH); H NMR (400 MHz, CDCl3,
ppm) δ 7.22ꢀ7.16 (2H, m), 7.13ꢀ7.10 (1H, m), 4.98 (1H, d, J = 2.0
Hz), 3.51 (1H, s), 2.64 (6H, s), 1.22 (9H, s), 0.93 (9H, s). 13C NMR
(100.6 MHz, CDCl3, ppm) δ 153.2, 137.4, 129.7, 128.8, 127.9, 122.1,
59.1, 55.6, 45.4, 35.9, 26.4, 22.6. Anal. Calcd for C17H29ClN2OS: C,
59.19; H, 8.47; N, 8.12. Found: C, 59.23; H, 8.09; N, 8.05. Optical
rotation (99% de, HPLC/csp) [R]20D ꢀ8.8 (c 0.95, EtOH). HPLC/csp
assay: Daicel CHIRALPAK IB, 25 cm ꢁ 4.6 mm i.d., mobile phase 5%
IPA/95% Hex, flow rate 0.9 mL/min, detector UV 254 nm, retention
time 9.2 min ((RS,S)-5f), major and 12.3 min ((RS,R)-5f), minor.
General Procedure for the Alkylation of N-tert-Butanesul-
finyl Amides 5aꢀc. Sulfinyl amide 5 (1.0 equiv) was dissolved in
anhydrous DMF (3 mL/mmol of amide 5) and cooled to ꢀ20 °C under
argon atmosphere. A solution of LiHMDS in THF (1 M solution in
THF, 1.0 equiv) was added dropwise and the yellow solution was stirred
at ꢀ20 °C for 1 h whereupon neat MeI (2.0 equiv) was added. After
being warmed to room temperature and stirred for 2 h, the mixture was
diluted with water (30 mL/mmol of amide 5) and extracted with
MeOtBu. Combined organic extracts were dried (Na2SO4) and con-
centrated and the residue was purified by column chromatography on
silica gel.
(RS)-N-(R)-[1-(2-Aminophenyl)ethyl]-N,2-dimethyl-2-pro-
panesulfinamide (6a): Following the general procedure for the
alkylation, sulfinyl amide 5a (1.00 g, 4.17 mmol) was converted into
6a. Purification of the crude product by column chromatography by
using gradient elution from 10% EtOAc/petroleum ether to 100%
EtOAc/petroleum ether afforded product as a white solid (936 mg,
88% yield); analytical TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf
0.12. Pure material was obtained by crystallization from Et2O: mp
93ꢀ95 °C. IR (film, cmꢀ1) 3433 (NH2), 3343 (NH2), 1054 (SdO). 1H
(RS)-2-((1S)-1-[tert-Butyl(methyl)oxo-λ6-sulfanylidene]amino-
2,2-dimethylpropyl)-4-chloro-N-methylaniline (7e): Following the
general procedure for the alkylation, sulfinyl amide 5e (200 mg, 0.61 mmol)
was converted into 7e. Purification of the crude product by column
chromatography by using gradient elution from 5% EtOAc/petroleum ether
to 30% EtOAc/petroleum ether afforded product as a white solid (158 mg,
75% yield); analytical TLC on silica gel, 2:5 EtOAc/EtOAc, Rf 0.44. Pure
material was obtained by crystallization from hexanes: mp 134ꢀ136 °C. IR
(film, cmꢀ1) 3330 (NH), 1513 (NdS), 1231 (SdO). 1H NMR (400 MHz,
CDCl3,ppm) δ7.32 (0.2H, d, J= 2.6 Hz), 7.07ꢀ7.02 (1H, m), 6.89 (0.8H, d,
J = 2.6 Hz), 6.51 (0.2H, d, J = 8.6 Hz), 6.44 (0.8H, d, J = 8.6 Hz), 6.23 (1H, q,
J = 4.9 Hz), 4.07 (0.2H, s), 4.05 (0.8H, s), 2.84 (0.5H, s), 2.74 (2.5H, s), 2.42
(2.5H, s), 2.19 (0.5H, s), 1.47ꢀ1.41 (9H, m), 0.93ꢀ0.90 (9H, m). 1H NMR
(400 MHz, CDCl3, ppm) δ 147.9, 114.9, 130.9, 130.6, 129.4, 127.2, 127.1,
126.7, 119.4, 111.4, 111.1, 67.5, 59.4, 59.0, 56.6, 38.1, 37.4, 33.0, 31.1, 30.4,
27.8, 26.5, 23.7, 23.6. Anal. Calcd for C17H29ClN2OS: C, 59.19; H, 8.47; N,
8.12. Found: C, 59.43; H, 8.48; N, 7.99. [R]20D ꢀ10.4 (c 0.92, EtOH).
(RS)-2-((1S)-1-[tert-Butyl(methyl)oxo-λ6-sulfanylidene]amino-
2,2-dimethylpropyl)-4-chloro-N,N-dimethylaniline (7f): Following
the general procedure for the alkylation, sulfinyl amide 5f (185 mg, 0.54
mmol) was converted into 7f. Purification of the crude product by column
chromatography using gradient elution from 5% EtOAc/petroleum ether to
20% EtOAc/petroleum ether afforded product as a white foam (119 mg, 62%
yield); analytical TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf 0.56. IR
2643
dx.doi.org/10.1021/jo1025767 |J. Org. Chem. 2011, 76, 2635–2647

The Journal of Organic Chemistry
ARTICLE
1
(film, cmꢀ1) 1479 (NdS), 1239 (SdO). H NMR (400 MHz, CDCl3,
procedure, cleavage of the chiral auxiliary in sulfinyl amide 5d (448
ppm) δ 7.38 (1H, d, J = 2.2 Hz), 7.11 (1H, dd, J = 8.5, 2.2 Hz), 7.07 (1H, d,
J=8.5Hz),4.80(1H,s),2.63(6H,s),2.24(3H,s),1.44(9H,s),0.99(9H,s).
13C NMR (100.6 MHz, CDCl3, ppm) δ 151.5, 142.9, 129.8, 128.9, 127.0,
122.2, 59.8, 57.2, 45.5, 37.1, 34.6, 26.6, 23.7. HRMS-ESI (m/z) calcd for
C18H32N2OSCl [M þ H]þ 359.1924, found 359.1918. [R]20D þ3.9 (c 0.80,
EtOH).
mg, 1.41 mmol) afforded 1d HCl as a white solid (312 mg, 89% yield);
3
analytical TLC on silica gel, 9:1 CHCl3/MeOH, Rf 0.28. Pure material
was obtained by crystallization from MeOH/MeCN: mp 225ꢀ227 °C.
IR (free base 1d, film, cmꢀ1) 3352 (NH), 3334 (NH), 3321 (NH), 3253
(NH); 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.37 (3H, s), 7.25 (1H,
d, J = 2.4 Hz), 7.04 (1H, dd, J = 8.6, 2.4 Hz), 6.68 (1H, d, J = 8.6 Hz), 5.51
(2H, s), 4.34 (1H, s), 0.97 (9H, s). 13C NMR (100.6 MHz, DMSO-d6,
ppm) δ 146.4, 128.8, 127.7, 120.9, 119.1, 117.4, 56.0, 35.8, 26.2. Anal.
Calcd for C11H18Cl2N2: C, 53.02; H, 7.28; N, 11.24. Found: C, 52.96; H,
7.24; N, 11.19. Optical rotation [R]20D ꢀ66.9 (c 1.11, MeOH).
(1S)-1-[5-Chloro-2-(methylamino)phenyl]-2,2-dimethyl-
General Procedure for Cleavage of N-tert-Butanesulfinyl
Chiral Auxiliary. Sulfinyl amide 5aꢀf or 6aꢀc (1.0 equiv) was
dissolved in a 1:1 mixture of anhydrous 1,4-dioxane and anhydrous
MeOH (6 mL/mmol of amide), and anhydrous HCl in dioxane (4 M
solution in dioxane, 4.0 equiv) was added. After the mixture was stirred
at room temperature for 1 h, all volatiles were removed in vacuo, and the
residue was dissolved in water (20 mL/mmol of amide) and extracted
with EtOAc (10 mL/mmol of amide). The water layer was basified to
pH 8 with aqueous concentrated NH4OH and extracted with EtOAc.
Combined organic extracts were washed with brine, dried over Na2SO4,
and concentrated (rotary evaporator) to afford the 1,3-diamines. The
crude diamines were dissolved in anhydrous 1,4-dioxane and converted
into hydrochloric acid salts by dropwise addition of anhydrous HCl in
dioxane (4 M solution in dioxane, 1.0 equiv), followed by filtration of the
formed precipitate.
1-propanamine hydrochloride (1e HCl): Following the general
3
procedure, cleavage of the chiral auxiliary in sulfinyl amide 5e (371 mg,
1.12 mmol) afforded 1e HCl as a white solid (283 mg, 96% yield);
3
analytical TLC on silica gel, 9:1 CHCl3/MeOH, Rf 0.32. Pure material was
obtained by crystallization from MeOH/MeCN: mp 234ꢀ236 °C. IR
(free base 1e, film, cmꢀ1) 3313 (NH), 3230 (NH). 1H NMR (400 MHz,
DMSO-d6, ppm) δ 8.45 (3H, s), 7.32 (1H, d, J = 2.4Hz), 7.18 (1H, dd, J =
8.8, 2.4Hz), 6.54 (1H, d, J= 8.8 Hz), 5.89(1H, q, J = 4.3Hz), 4.45 (1H, s),
2.69 (3H, d, J = 4.3 Hz), 0.96 (9H, s). 13C NMR (100.6 MHz, DMSO-d6,
ppm) δ 146.9, 129.0, 127.7, 121.9, 118.8, 66.8, 55.5, 35.7, 30.6, 26.2. Anal.
Calcd for C12H20Cl2N2: C, 54.76; H, 7.66; N, 10.64. Found: C, 54.87; H,
7.70; N, 10.27. Optical rotation [R]20D ꢀ52.7(c 1.01, MeOH).
(1R)-1-(2-Aminophenyl)-1-ethanamine hydrochloride
(1a HCl): Following the general procedure, cleavage of the chiral
3
auxiliary in sulfinyl amide 5a (250 mg, 1.04 mmol) afforded 1a HCl as a
(1S)-1-[5-Chloro-2-(dimethylamino)phenyl]-2,2-dimethyl-1-
3
white solid (176 mg, 98% yield); analytical TLC on silica gel, 9:1
propanamine hydrochloride (1f HCl): Following the general pro-
3
CHCl3/MeOH, Rf 0.28. Pure material was obtained by crystallization
cedure, cleavage of the chiral auxiliary in sulfinyl amide 5f (262 mg, 0.76
from MeOH/MeCN: mp 125ꢀ127 °C. IR (free base 1a, film, cmꢀ1
)
mmol) afforded 1f HCl as a white solid (200 mg, 95% yield); analytical
3
3364 (NH2), 3359 (NH2), 3324 (NH2), 3294 (NH2). 1H NMR (400
MHz, DMSO-d6, ppm) δ 8.41 (2H, s), 7.33 (1H, dd, J = 7.8, 1.2 Hz),
7.06ꢀ6.99 (1H, m), 6.74ꢀ6.70 (1H, m), 6.66ꢀ6.60 (1H, m), 4.52 (1H,
q, J = 6.6 Hz), 1.44 (3H, d, J = 6.6 Hz). 13C NMR (100.6 MHz, CDCl3,
pmm) δ 145.4, 129.0, 126.3, 123.6, 117.3, 116.6, 44.9, 20.1. HRMS-ESI
TLC on silica gel, 9:1 CHCl3/MeOH, Rf 0.32. Pure material was obtained
by crystallization from MeOH/MeCN: mp 254ꢀ259 °C. IR (free base
1f, film, cmꢀ1) 3355 (NH), 3163 (NH). 1H NMR (400 MHz, DMSO-
d6, ppm) δ 8.64 (3H, s), 7.61 (1H, d, J = 2.4 Hz), 7.41 (1H, dd, J = 8.6,
2.4 Hz), 7.35 (1H, d, J = 8.6 Hz), 4.65 (1H, q, J = 5.7 Hz), 2.57 (6H, s),
0.93 (9H, s). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ 152.8, 134.5,
129.5, 128.7, 128.3, 123.9, 56.8, 45.6, 35.0, 26.6. Anal. Calcd for
C13H22Cl2N2: C, 56.32; H, 8.0; N, 10.10. Found: C, 56.33; H, 8.13;
N, 9.96. Optical rotation [R]20D þ78.7 (c 0.91, MeOH).
(m/z) calcd for C8H12N2 [M þ H]þ 137.1079, found 137.1094. [R]20
D
ꢀ7.1 (c 1.0, MeOH).
(1R)-1-[2-(Methylamino)phenyl]-1-ethanamine hydrochlor-
ide (1b HCl): Following the general procedure, cleavage of the chiral
3
auxiliary in sulfinyl amide 5b (250 mg, 0.98 mmol) afforded 1b HCl as a white
(1R)-1-(2-Aminophenyl)-N-methyl-1-ethanamine hydro-
3
solid (171 mg, 94% yield); analytical TLC on silica gel, 9:1 CHCl3/MeOH, Rf
0.12. Pure material was obtained by crystallization from MeOH/MeCN: mp
173ꢀ175 °C. IR (free base 1b, film, cmꢀ1) 3370 (NH), 3309 (NH), 3200
(NH); 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.39 (3H, s), 7.32 (1H, dd,
J= 7.7, 1.4 Hz), 7.22ꢀ7.12(1H,m),6.70ꢀ6.63(1H, m),6.62ꢀ6.53(1H, dd,
J = 8.2, 0.8 Hz), 5.63 (1H, s), 4.54 (1H, s), 2.70 (3H, s), 1.43 (3H, d, J = 6.7
Hz). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ 146.6, 129.5, 125.8, 123.7,
116.3, 100.6, 44.5, 30.5, 20.2. Anal. Calcd for C9H15N2Cl:C, 57.90;H,8.10;N,
15.01. Found: C, 57.88; H, 8.13; N, 14.85. Optical rotation [R]20D ꢀ19.1
(c 0.92, MeOH).
chloride (2a HCl). Following the general procedure, cleavage of the
3
chiral auxiliary in sulfinyl amide 6a (204 mg, 0.80 mmol) afforded
2a HCl as a white solid (165 mg, 91% yield); analytical TLC on silica
3
gel, 9:1 CHCl3/MeOH, Rf 0.12. Pure material was obtained by crystal-
lization from MeOH/MeCN: mp 184ꢀ186 °C. IR (free base 2a,
1
film, cmꢀ1) 3339 (NH), 3180 (NH). H NMR (400 MHz, DMSO-
d6, ppm) δ 8.45 (3H, s), 7.56 (1H, d, J = 7.8 Hz), 7.24ꢀ7.16 (1H, m),
7.04ꢀ6.88 (2H, m), 4.54 (1H, q, J = 6.5 Hz), 3.57 (1H, s), 2.42 (3H, s),
1.53 (3H, d, J = 6.5 Hz). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ
141.4, 129.9, 124.5, 121.3, 119.3, 52.3, 30.6, 19.0. HRMS-ESI (m/z)
calcd for C9H15N2 [M þ H]þ 151.1235, found 151.1261. Optical
rotation [R]20D ꢀ18.4 (c 0.84, MeOH).
(1R)-7-(Methylamino)-2,3-dihydro-1H-inden-1-amine hy-
drochloride (1c HCl): Following the general procedure, cleavage of
3
the chiral auxiliary in sulfinyl amide 5c (564 mg, 2.12 mmol) afforded
(1R)-N-Methyl-1-[2-(methylamino)phenyl]-1-ethanamine
1c HCl as a white solid (400 mg, 95% yield); analytical TLC on silica
hydrochloride (2b HCl). Following the general procedure, cleavage
of the chiral auxiliary in sulfinyl amide 6b (338 mg, 1.26 mmol) afforded
3
3
gel, 9:1 CHCl3/MeOH, Rf 0.20. Pure material was obtained by crystal-
lization from MeOH/MeCN: mp 175ꢀ177 °C. IR (free base 1c,
2b HCl as a white solid (235 mg, 93% yield); analytical TLC on silica
3
1
film, cmꢀ1) 3346 (NH), 3189 (NH). H NMR (400 MHz, DMSO-
gel, 9:1 CHCl3/MeOH, Rf 0.20. Pure material was obtained by crystal-
lization from MeOH/MeCN: mp 206ꢀ208 °C. IR (free base 2b,
d6, ppm) δ 8.22 (3H, s), 7.16 (1H, dd, J = 7.6, 7.6 Hz), 6.56 (1H, d, J =
7.4 Hz), 6.40 (1H, d, J = 8.0 Hz), 4.66 (1H, d, J = 7.0 Hz), 3.63 (1H, s),
3.16ꢀ3.06 (1H, m), 2.77ꢀ2.69 (1H, m), 2.72 (3H, s), 2.36ꢀ2.24 (1H,
m), 2.14ꢀ2.06 (1H, m). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ
146.6, 146.4, 131.3, 123.2, 122.7, 108.1, 53.0, 31.0, 30.5, 30.1. Anal.
Calcd for C10H15N2Cl: C, 60.45; H, 7.61; N, 14.10. Found: C, 60.45; H,
7.69; N, 13.85. Optical rotation [R]20D ꢀ77.7(c 0.87, MeOH).
1
film, cmꢀ1) 3286 (NH), 3200 (NH). H NMR (400 MHz, DMSO-
d6, ppm) δ 9.78 (1H, s), 8.99 (1H, s), 7.44 (1H, d, J = 7.5 Hz),
7.24ꢀ7.16 (1H, m), 6.71 (1H, dd, J = 7.5, 7.5 Hz), 6.63 (1H, d, J = 8.0
Hz), 4.55 (1H, q, J = 6.4 Hz), 3.84ꢀ3.09 (1H, br s), 2.70 (3H, s), 2.39
(3H, s), 1.49 (3H, d, J = 6.4 Hz). 13C NMR (100.6 MHz, DMSO-d6,
ppm) δ 147.0, 130.0, 126.9, 121.8, 116.9, 111.2, 51.9, 30.6, 30.6, 18.8.
HRMS-ESI (m/z) calcd for C10H17N2 [M þ H]þ 165.1392, found
165.1371. Optical rotation [R]20D ꢀ40.6(c 0.98, MeOH).
(1S)-1-(2-Amino-5-chlorophenyl)-2,2-dimethyl-1-pro-
panamine hydrochloride (1d HCl): Following the general
3
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ARTICLE
(1R)-N-Methyl-7-(methylamino)-2,3-dihydro-1H-inden-1-
amine hydrochloride (2c HCl). Following the general procedure,
cleavage of the chiral auxiliary in sulfinyl amide 6c (200 mg, 0.713 mmol)
(1S)-1-[5-Chloro-2-(dimethylamino)phenyl]-N,2,2-trimeth-
yl-1-propanamine hydrochloride (2f HCl): Following the general
procedure, N-formylation of (S)-1f (200 mg, 0.83 mmol) and subse-
3
3
afforded 2c HCl as a white solid (148 mg, 97% yield); analytical TLC
quent reduction with LiAlH4 afforded diamine 2f HCl as a white solid
3
3
on silica gel, 9:1 CHCl3/MeOH, Rf 0.12. Pure material was obtained by
crystallization from MeOH/MeCN: mp 192ꢀ194 °C. IR (free base 2c,
film, cmꢀ1) 3298 (NH), 3274 (NH). 1H NMR (400 MHz, DMSO-d6,
ppm) δ 9.08 (2H, s), 7.17 (1H, dd, J = 7.8, 7.8 Hz), 6.55 (1H, d, J = 7.4
Hz), 6.39 (1H, d, J = 7.8 Hz), 4.76ꢀ4.69 (1H, m), 3.33 (1H, s),
3.23ꢀ3.05 (1H, m), 2.80ꢀ2.63 (4H, m), 2.47 (3H, s), 2.30ꢀ2.16 (2H,
m). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ 147.3, 147.0, 131.7,
120.9, 112.5, 107.9, 60.6, 30.7, 30.3, 30.0, 28.6. Anal. Calcd for
C11H17N2Cl: C, 62.11; H, 8.06; N, 13.17. Found: C, 62.14; H, 7.98;
N, 13.15. Optical rotation [R]20D ꢀ148.5 (c 0.91, MeOH).
(157 mg, 65% yield); analytical TLC on silica gel, 9:1 CHCl3/MeOH,
Rf = 0.48. Pure material was obtained by crystallization from MeOH/
MeCN: mp 221ꢀ223 °C. IR (free base 2f; film, cmꢀ1) 3210 (NH). 1H
NMR (400 MHz, DMSO-d6, ppm) δ 9.42 (1H, s), 8.90 (1H, s), 7.74
(1H, s), 7.46 (2H, s), 4.70 (1H, s), 2.55 (6H, s), 2.38 (3H, s), 0.98 (9H,
s). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ 154.2, 132.3, 130.2,
129.6, 127.8, 125.3, 65.5, 46.0, 35.3, 33.2, 27.1. HRMS-ESI (m/z) calcd
for C14H24N2Cl [M þ H]þ 255.1628, found 255.1645. [R]20D þ4.2 (c
0.12, MeOH). Anal. Calcd for salt of 2f with picric acid, C20H26ClN5O7:
C, 49.64; H, 5.42; N, 14.47. Found: C, 49.63; H, 5.28; N, 14.44.
General Procedure for Synthesis of Diamines 2dꢀf. To a
solution of diamine 1dꢀf (1 equiv) in CH2Cl2 (5 mL/mmol of diamine
1dꢀf) at 0 °C under argon atmosphere was added dropwise neat DIC
(1.0 equiv). The mixture was stirred at 0 °C for 15 min, whereupon neat
HCOOH (1.0 equiv) was added slowly. After being stirred for 1.5 h at
0 °C, the solution was basified to pH 8 with aqueous saturated NH4OH,
extracted with EtOAc (3 ꢁ 35 mL), dried over Na2SO4, and evaporated.
The semisolid residue was treated with CH2Cl2 (5 mL/mmol of diamine
1dꢀf), the resulting precipitate was removed by filtration, and the filter
cake was washed with CH2Cl2. Combined filtrates were concentrated,
then the oily residue was dissolved in dry THF (5 mL/mmol of diamine
1dꢀf) and cooled to 0 °C under argon atmosphere. Lithium aluminum
hydride (1 M solution in THF, 3 equiv with respect to the diamine
1dꢀf) was added dropwise, and the resulting solution was heated under
reflux for 5 h. After the solution was cooled to 0 °C, the Fieser-type
workup36 (careful successive dropwise addition of water, 15% aqueous
NaOH solution, and additional water followed by filtration of a granular
inorganic precipitate) afforded the diamines 2dꢀf. Diamines 2dꢀf were
dissolved in anhydrous 1,4-dioxane and converted into hydrochloric acid
salts by dropwise addition of anhydrous HCl in dioxane (4 M solution in
dioxane, 1.0 equiv), followed by filtration of the formed precipitate.
(1S)-1-(2-Amino-5-chlorophenyl)-N,2,2-trimethyl-1-pro-
’ ASSOCIATED CONTENT
S
Supporting Information. Kinetics of the atropisomeriza-
b
tion of (Z)-4f; DFT computed relative energies of (P)-(Z)-4e
and (M)-(Z)-4e atropisomers; X-ray crystallographic data for
imines 4a,b,dꢀf and sulfinylamides 5a,b,e and 6c as well as
sulfoximine 7f (CIF files); and copies of H and 13C NMR
1
spectra for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: edgars@osi.lv.
’ ACKNOWLEDGMENT
This work was supported by the European Social Fund (No.
2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023). The authors
thank Artis Kinens for DFT calculations.
panamine hydrochloride (2d HCl): Following the general proce-
dure, N-formylation of (S)-1d (200 mg, 0.94 mmol) and subsequent
3
’ REFERENCES
(1) (a) Jaen, J. C. (S)-R-Methylbenzylamine. In Chiral Reagents for
Asymmetric Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 2003; p 406.
(b) Juaristi, E.; Escalante, J.; Leon-Romo, J. L.; Reyes, A. Tetrahedron:
Asymmetry 1998, 9, 715. (c) Juaristi, E.; Leon-Romo, J. L.; Reyes, A.;
Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
(2) For the application of the Betti base in asymmetric synthesis, see:
Cardellicchio, C.; Annunziata, M.; Capozzi, M.; Naso, F. Tetrahedron:
Asymmetry 2010, 21, 507 and references cited therein.
reduction with LiAlH4 afforded diamine 2d HCl as a white solid (156
3
mg, 63% yield); analytical TLC on silica gel, 9:1 CHCl3/MeOH, Rf 0.32.
Pure material was obtained by crystallization from MeOH/MeCN: mp
225ꢀ227 °C. IR (free base 2d, film, cmꢀ1) 3371 (NH), 3292 (NH), 3180
(NH). 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.19 (1H, s), 8.94 (1H, s),
7.41ꢀ7.36 (1H, m), 7.12ꢀ7.04 (1H, m), 6.77ꢀ6.69 (1H, m), 4.37 (1H, d,
J = 9.8 Hz), 3.88ꢀ2.78 (2H, s), 2.35ꢀ2.25 (3H, m), 1.01 (9H, s). 13C
NMR (100.6 MHz, DMSO-d6, ppm) δ 147.7, 129.3, 127.3, 119.6, 118.0,
117.9, 64.7, 35.9, 32.7, 26.6. HRMS-ESI (m/z) calcd for C12H20N2Cl [M þ
H]þ 227.1315, found 227.1297. [R]20D ꢀ16.4 (c 0.94, MeOH).
(3) (a) Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361. (b) Liu,
D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi,
M. C. K.; Chan, A. S. C. Org. Lett. 2001, 3, 2733. (c) Cimarelli, C.;
Palmieri, G.; Volpini, E. Tetrahedron: Asymmetry 2002, 13, 2417. (d)
Yang, X.-F.; Wang, Z.-H.; Koshizawa, T.; Yasutake, M.; Zhang, G.-Y.;
Hirose, T. Tetrahedron: Asymmetry 2007, 18, 1257. (e) Cimarelli, C.;
Palmieri, G. Chirality 2009, 21, 218 and references cited therein.
(4) (a) Lee, D.-S. Chirality 2007, 19, 148. (b) Cimarelli, C.; Fratoni,
D.; Palmieri, G. Chirality 2010, 22, 655.
(5) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int.
Ed. 2004, 43, 2426. (b) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky,
G.; Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957. (c) Polet, D.;
Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.—
Eur. J. 2006, 12, 3596. (d) Dahnz, A.; Helmchen, G. Synlett 2006, 697.
(6) (a) Wang, D.-Y.; Huang, J.-D.; Hu, X.-P.; Deng, J.; Yu, S.-B.;
Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2008, 73, 2011. (b) Qiu, M.; Hu, X.-
P.; Huang, J.-D.; Wang, D.-Y.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Zhenga,
Z. Adv. Synth. Catal. 2008, 350, 2683. (c) Zhou, X.-M.; Huang, J.-D.;
Luo, L.-B.; Zhang, C.-L.; Zheng, Z.; Hu, X.-P. Tetrahedron: Asymmetry
2010, 21, 420.
(1S)-1-[5-Chloro-2-(methylamino)phenyl]-N,2,2-trimethyl-1-
propanamine hydrochloride (2e HCl): Following the general pro-
3
cedure, N-formylation of (S)-1e (200 mg, 0.88 mmol) and subsequent
reduction with LiAlH4 afforded diamine 2e HCl as a white solid (190
3
mg, 78% yield); analytical TLC on silica gel, 9:1 CHCl3/MeOH, Rf 0.40.
Pure material was obtained by crystallization from MeOH/MeCN: mp
237ꢀ239 °C. IR (free base 2e; film, cmꢀ1) 3284 (NH), 3200 (NH). 1H
NMR (400 MHz, DMSO-d6, ppm) δ 9.05 (1H, s), 8.88 (1H, s), 7.34
(1H, d, J = 2.4 Hz), 7.20 (1H, dd, J = 8.8, 2.4 Hz), 6.57 (1H, d, J = 8.8
Hz), 5.84 (1H, s), 4.43ꢀ4.38 (1H, m), 2.66 (3H, s), 2.27 (3H, t, J = 5.0
Hz), 0.96 (9H, s). 13C NMR (100.6 MHz, DMSO-d6, ppm) δ 148.2,
129.6, 127.1, 119.3, 118.8, 112.4, 64.2, 35.9, 32.8, 30.7, 26.5. HRMS-ESI
(m/z) calcd for C13H22N2Cl [M þ H]þ 241.1472, found 241.1472.
[R]20D ꢀ52.1(c 0.83, MeOH). Anal. Calcd for salt of 2e with picric acid,
C19H24ClN5O7: C, 48.57; H, 5.15; N, 14.90. Found: C, 48.56; H, 5.00;
N, 14.98.
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ARTICLE
(7) Vedejs, E.; Kruger, A. W. J. Org. Chem. 1998, 63, 2792.
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Suna, E. J. Am. Chem. Soc. 2000, 122, 4602.
(9) For recent reviews on applications of tert-butylsulfinamide see:
(a) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res.
2008, 41, 831. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Pꢀerez-Luna, A.
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(22) Complete geometry optimization was carried out for aniline
(Z)-4e with hydrogen bonded THF molecule using B3LYP hybrid
density functional as implemented in Gaussian 03. A THF molecule was
introduced to minimize the putative intramolecular hydrogen bond in
(P)-atropisomer between N-H of aniline and oxygen of sulfinyl group. In
fact, the small difference between N-H chemical shifts of (P) and (M)
atropisomers in various solvents (Δδ(THF-d8) = 0.22 ppm; Δδ-
(CHCl3-d) = 0.6 ppm) confirms the absence of the intramolecular
hydrogen bond in solutions. A relative energy of (P) and (M) atropi-
somers of (Z)-4e was calculated by using the B3LYP/6-31G(d,p) basis
set (see the Supporting Information for details).
(10) For examples of diastereoselective reduction see: (a) Liu, G.;
Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
64, 1278. (b) Shaw, A. W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173.
(c) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276.
(d) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652. (e) Chelucci,
G.; Baldino, S.; Chessa, S.; Pinna, G. A.; Soccolini, F. Tetrahedron:
Asymmetry 2006, 17, 3163. (f) Zhao, C.-H.; Liu, L.; Wang, D.; Chen, Y.-J.
Eur. J. Org. Chem. 2006, 2977. (g) Colyer, J. T.; Andersen, N. G.; Tedrow,
J. S.; Soukup, T. S.; Faul, M. M. J. Org. Chem. 2006, 71, 6859. (h) Morton,
D.; Pearson, D.; Field, R. A.; Stockman, R. A. Chem. Commun. 2006, 1833.
(i) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211. (j)
Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem., Int. Ed.
2007, 46, 1290. (k) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. J. Org. Chem.
2007, 72, 626. (l) Watzke, A.; Wilson, R. M.; O’Malley, S. J.;Bergman, R. G.;
Ellman, J. A. Synlett 2007, 2383. (m) Denolf, B.; Mangelinckx, S.; T€ornroos,
K. W.; De Kimpe, N. Org. Lett. 2007, 9, 187. (n) Han, Z.; Koenig, S. G.;
Zhao, H.; Su, X.; Singh, S. P.; Bakale, R. P. Org. Process Res. Dev. 2007,
11, 726. (o) Liu, Z.-J.; Liu, J.-T. Chem. Commun. 2008, 5233. (p) Grajewska,
A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 557. (q)
Guijarro, D.; Pablo, O.; Yus, M. Tetrahedron Lett. 2009, 50, 5386. (r)
Leemans, E.; Mangelinckx, S.; De Kimpe, N. Synlett 2009, 1265. (s)
Guijarro, D.; Pablo, O.; Yus, M. J. Org. Chem. 2010, 75, 5266. (t) Guijarro,
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(23) A series of 2D EXSY spectra were acquired by using the phase-
sensitive NOESY pulse sequence to establish reasonable mixing times. A
mixing time of 1 s at T = 258 K was subsequently chosen for all 2D EXSY
experiments. The rate constants for chemical exchange were calculated
from the ratio of diagonal and exchange cross peaks as described in: (a)
Perrin, C. L.; Dwyer, T. G. Chem. Rev. 1990, 90, 935. (b) Gibson, K. R.;
Hitzel, L.; Mortishire-Smith, R. J.; Gerhard, U.; Jelley, R. A.; Reeve, A. J.;
Rowley, M.; Nadin, A.; Owens, A. P. J. Org. Chem. 2002, 67, 9354. See
also the Supporting Information (pp S5ꢀS6) for details. The exchange
rate constant for (Z)-4f, however, could not be determined from the 2D
EXSY (NOESY) spectra because of the very slow interconversion of
(Z)-4f isomers on the time scale of the NMR experiment. Instead,
isomerization kinetics of the individual pure atropisomer (Z)-(P)-4f was
measured at three different temperatures (T1 = 298 K, T2 = 313 K, and
T3 = 333 K). The Gibbs free energy of activation at T = 298 K was
calculated from the Eyring plot of the atropisomerization rate constants
vs inverse temperature (see the Supporting Information, pp S3ꢀS4, for
details).
(24) Free energies of activation for atropisomerization of ortho-
substituted acetophenone imines in toluene-d8 were found to be in the
range from 14.4 to 20.4 kcal/mol (60.2 to 85.4 kJ/mol): Boyd, D. R.;
Al-Showiman, S.; Jennings, W. B. J. Org. Chem. 1978, 43, 3335.
(25) The atropisomerization barrier of 102.9 kJ/mol (24.6 kcal/
mol) has been determined in DMSO-d6 for highly hindered tert-
butylketimines: Casarini, D.; Lunazzi, L.; Macciantelli, D. J. Chem.
Soc., Perkin Trans. 2 1992, 1363.
(11) Martjuga, M.; Shabashov, D.; Belyakov, S.; Liepinsh, E.; Suna,
E. J. Org. Chem. 2010, 75, 2357.
(12) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278.
(13) For preparation of ketones 3aꢀf, see the Experimental Section.
(14) Introduction of ortho-substituents in acetophenone imine
results in a marked change in isomeric preference from E to Z form
(with respect to the unsubstituted imine); see: Bjørgo, J.; Boyd,
D. R.; Watson, C. G.; Jennings, W. B. J. Chem. Soc., Perkin Trans. 2
1974, 757.
(26) A cyclic six-membered transition state has been proposed in the
reduction of sulfinylketimines with DIBAL: (a) Hose, D. R. J.; Mahon,
M. F.; Molloy, K. C.; Raynham, T.; Wills, M. J. Chem. Soc., Perkin Trans. 1
1996, 691. (b) Chelucci, G.; Baldino, S.; Chessa, S. Tetrahedron 2006,
62, 619.
(27) Atomic charge calculations have demonstrated considerable
negative charge on oxygen in sulfinylimines: Bharatam, P. V.; Uppal, P.;
Kaur, D. J. Chem. Soc., Perkin Trans. 2 2000, 43.
(15) Gilli, G. Molecules and Molecular Crystals. In Fundamentals of
Crystallography; Giacovazzo, C., Ed.; Oxford University Press: New
York, 2002; pp 590ꢀ595.
(28) Interestingly, neither isomer of (Z)-4f could be reduced with
BH3 THF at ꢀ78 °C (Conditions A: Table 3, entries 11 and 14).
(16) Stabilization of the E-isomer of ortho-substituted diaryl sulfi-
nylimines by the intramolecular hydrogen bond has been recently
demonstrated: see ref 11.
3
(29) Individual atropisomers (Z)-(P)-4f and (Z)-(M)-4f did not
undergo atropisomerization under the reduction conditions (BH3 THF
3
(1.6 equiv), ꢀ15 °C, THF-d8, 3 h) as evidenced by NMR (see the
(17) It is well-documented that in the solid state the rotational
barriers are larger than in solutions. For selected examples, see: (a)
Riddell, F. G.; Arumagam, S.; Harris, K. D. M.; Rogerson, M.; Strange,
J. H. J. Am. Chem. Soc. 1993, 115, 1881. (b) Casarini, D.; Lunazzi, L.;
Mazzanti, A. J. Org. Chem. 1998, 63, 9125. (c) Casarini, D.; Foresti, E.;
Lunazzi, L.; Mazzanti, A. Chem.—Eur. J. 1999, 5, 3501. (d) Anderson,
J. E.; Casarini, D.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2000, 65, 1729.
(e) Lunazzi, L.; Mazzanti, A.; Casarini, D.; De Lucchi, O.; Fabris, F.
J. Org. Chem. 2000, 65, 883.
(18) For NMR spectra see the Supporting Information, p S10.
(19) Configuration of (Z)-(M)-4f was confirmed by X-rays analysis.
(20) Syn-diaxial orientation between a sulfinyl group and a proton in
cyclic sulfoxides results in downfield shifts for the proton; see: (a) Harpp,
D. N.; John, G.; Gleason J. Org. Chem. 1971, 36, 1314. (b) Buchanan,
G. W.; Durst, T. Tetrahedron Lett. 1975, 16, 1683. For the related
shilding effects in 13C spetra see: Kato, A.; Numata, M. Tetrahedron Lett.
1972, 13, 203.
Supporting Information, p S7, for details).
(30) The atropisomerization barrier of 97.9 kJ/mol at 25 °C (see
Table 2) corresponds to an isomerization half-life (conversion of a pure
atropisomer (Z)-(P)-4f to a (P):(M)=75:25 mixture) of 4.3 h. In fact,
the actual (P)(M) isomerization rate is higher because the backward
(M)(P) transformation is suppressed due to the rapid reduction of the
more reactive atropisomer (Z)-(M)-4f immediate upon forming.
(31) In a control experiment pure crystalline atropisomer (Z)-(M)-
4d was added to precooled (ꢀ78 °C) THF-d8 and an 1H NMR
spectrum of the resulting suspension (at ꢀ45 °C) was acquired
immediately. Two sets of signals in a ratio of 78:22 were observed for
the dissolved fraction, showing that spontaneous atropisomerization
occurs in THF-d8 solution under the reduction conditions.
(32) The structure of (RS,S)-7d was confirmed by X-ray analysis (see
the Supporting Information).
(33) Prepared following the procedure described in the literature:
Nguyen, P.; Corpuz, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M. E.
J. Org. Chem. 2003, 68, 10195.
(21) For a list of chemical shifts see the Supporting Information
(Table S1, p S9).
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ARTICLE
(34) Prepared as described by: Pierce, M. E.; Parsons, R. L., Jr.;
Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam, Q.;
Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Morgan,
S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.; Frey, L.;
Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski,
E. J. J.; Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63, 8536.
(35) To avoid isomerization of individual atropisomers in eluate,
collected fractions were cooled to ꢀ78 °C (dry iceꢀacetone bath).
(36) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, 1967; Vol. 1, pp 581ꢀ595.
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