Asymmetric mannich-type reaction of a chiral N-(tert-butylsulfinyl) ketimine with imines: Application to the synthesis of chiral 1,3-diamines

Article abstract of DOI:10.1002/ejoc.200600147

Deprotonation of the chiral N-(tert-butylsulfinyl) ketimine 1 followed by trapping with imines 2 afforded the β-amino imines 3 as the Mannich-type products in high diastereoselectivities (99:1 dr). As versatile synthons chiral β-amino imines 3 could be tr

Full text of DOI:10.1002/ejoc.200600147

FULL PAPER
DOI: 10.1002/ejoc.200600147
Asymmetric Mannich-Type Reaction of a Chiral N-(tert-Butylsulfinyl)
Ketimine with Imines: Application to the Synthesis of Chiral 1,3-Diamines
Cui-Hua Zhao,[a,b] Li Liu,[a] Dong Wang,*[a] and Yong-Jun Chen*[a]
Keywords: Asymmetric Mannich reaction / N-(tert-Butylsulfinyl) ketimine / Chiral β-amino imine / Chiral β-amino ketone /
Chiral 1,3-diamine
Deprotonation of the chiral N-(tert-butylsulfinyl) ketimine 1
followed by trapping with imines 2 afforded the β-amino
stereomeric excess by hydrolysis or reduction, respectively.
Moreover, the nucleophilic addition of organometallic
imines 3 as the Mannich-type products in high diastereo- reagents to chiral β-amino imines 3 could provide 1,1,3-tri-
selectivities (99:1 dr). As versatile synthons chiral β-amino
imines 3 could be transformed into enantiomeric β-amino
ketone and chiral syn- or anti-1,3-diamines with high dia-
substituted 1,3-diamines with high diastereoselectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
polysubstituted chiral 1,3-diamines by a diastereoselective
1,3-dipolar cycloaddition of azomethine imine ylide and
followed by electroreduction of the pyrazolidine intermedi-
ates.[10] Chiral 1,3-diamines can also be obtained by func-
tional-group transformation of optically active compounds
such as 1,3-diols[11] or β-amino nitriles[12] and β-amino iso-
cyanides.[13] Recently, Kobayashi reported the CuII-cata-
lyzed enantioselective addition of enamides to imino esters
and the transformation of the β-amino imines into chiral
1,3-diamines with good diastereoselectivities.[3d] Despite the
availability of such methods, it remains indispensable to
find new highly selective synthetic approaches to prepare
structural diverse chiral 1,3-diamines in comparison with
its analogues 1,2-diamines.
Chiral N-sulfinyl imines have attracted considerable
interests in organic synthesis.[14] The chiral N-sulfinyl group
can serve not only as a good chiral auxiliary but also acti-
vate the C=N bond of imines. Therefore, chiral N-sulfinyl
imines have been widely used in the nucleophilic addition
reaction.[15,16] Recently, Ellman reported the deprotonation
of N-sulfinyl ketimines to provide metalloenamines, which
were subsequently applied in a series of reactions with elec-
trophiles, such as α-alkylation,[17] Michael addition,[18] and
addition to aldehydes,[19] as well as the self-condensation
reactions of N-(tert-butylsulfinyl) aldimines.[4] In most
cases, high diastereoselectivities and good yields were
achieved by using metal salts and other additives after de-
protonation. Herein we would like to report an asymmetric
Mannich-type reaction of metalloenamines derived from
chiral N-(tert-butylsulfinyl) ketimine with imines.[20] The β-
amino imines thus obtained are versatile synthons that can
be transformed into chiral β-amino ketones or 1,3-di-
amines. The subsequent addition of organometallic regents
to β-amino imines provided chiral 1,1,3-trisubstituted 1,3-
diamines.
Introduction
The Mannich reaction is one of the most important reac-
tions in organic synthesis because it is not only a classic
method for carbon–carbon bond formation, but also able
to afford versatile synthetic intermediates in organic synthe-
sis. In general, the Mannich reaction involves the addition
of carbon nucleophiles to imines.[1] Most carbon nucleo-
philes used are enolates or enol ethers, and β-amino car-
bonyl compounds are obtained as the Mannich products.
However, as the important equivalent of enolates, α-carban-
ions derived from imines used in the Mannich reaction are
less noticed. Risch developed a synthetic method to 1,3-
diamines by means of the aminoalkylation of enamines or
imines with tertiary iminium salts,[2] followed by the re-
duction of the C=N double bond.[3] Nevertheless, there
were few efficient methods available to synthesize optically
active β-amino imines[3d,4] and 1,3-diamines[3d] until very
recently.
1,3-Diamines are important compounds or key structural
units in natural products,[5] pharmacologically active com-
pounds,[6] and chiral auxiliaries and ligands.[7] They have
been used in total synthesis, medicinal research, and asym-
metric synthesis. Chiral 1,3-diamines can be prepared by
regio- and stereoselective ring-opening of α-amino-substi-
tuted aziridines[8] or epoxides[9] with nucleophiles such as
amines. Bonin and Micouin et al. reported the synthesis of
[a] Center for Molecular Science, Institute of Chemistry, Chinese
Academy of Sciences,
Beijing 100080, China
[b] Graduate School of Chinese Academy of Sciences, Chinese
Academy of Sciences,
Beijing 100080, China
E-mail: yjchen@mail.iccas.ac.cn
dwang210@mail.iccas.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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C.-H. Zhao, L. Liu, D. Wang, Y.-J. Chen
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does not need any additives for high selectivity. This is
probably because the coordination of the lithium ion of
LDA with the nitrogen atom of the imine 2 is strong enough
to make the transition state of the Mannich reaction more
stable and reach a high diastereoselectivity [Figure 1(a)].
With the optimized reaction conditions in hand, we ex-
plored the scope of the substrates of the N-tosyl imines 2
(Table 2). As shown in Table 2, N-(p-substituted benzyl-
idene)-p-toluenesulfonamides with either electron-with-
drawing or -donating functional groups, such as –Cl (2b),
–NO2 (2c), –Me (2d), –MeO (2e) and N-(o-substituted
benzylidene)-p-toluenesulfonamides, such as –MeO (2f)
and –Br (2g) could react smoothly with metalloenamines
derived from N-(tert-butylsulfinyl) ketimine 1 to afford the
corresponding β-amino imines 3b–g in moderate to good
yields and in high diastereoselectivities (Ͼ99:1 dr). For the
furyl-substituted N-tosyl imine 2h, the reaction also gener-
ated the desired product in high yield and diastereoselectiv-
ity (Entry 8). It is worthy to mention that no 1,4-addition
was observed for N-cinnamylidene-p-toluenesulfonamide
(2i) (Entry 9). The electron-donating p-methoxyphenyl
group (PMP; 2j) is not favorable to the addition reaction
(Entry 10). Unfortunately, the N-tosyl imine 2k derived
from an aliphatic aldehyde also could not give the product
(Entry 11), perhaps due to the low electrophilicity of such
a substrate. In all cases, the NMR signals of these products
show that only one of the isomers was obtained (Ͼ99:1
dr).The absolute configuration of the formed β-amino
imine was assigned to be (Rs,S) by X-ray crystallographic
analysis of compound 3e (Figure 2). The observed stereo-
chemistry for the addition reaction is consistent with a
Zimmerman–Traxler-type six-membered-ring transition
state [Figure 1(a)].[19,21]
Results and Discussion
We initiated the study on the asymmetric Mannich-type
reaction of metalloenamines derived from (R)-N-(tert-bu-
tylsulfinyl) ketimine (R)-1 with the N-tosyl imine 2a by
screening solvents and bases (Scheme 1, Table 1). Com-
pound (R)-1 was deprotonated with a base, followed by
trapping with the imine 2a. The reaction proceeded
smoothly in the presence of LDA in THF to provide the
chiral β-amino imine 3a in 89% yield and Ͼ99:1 dr (En-
try 4). NaH could not deprotonate the N-sulfinyl imine 1
and the starting material was recovered (Entry 1). The use
of nBuLi resulted in a complex mixture, and the product
was obtained in only 45% yield. Although by the use of
nBuLi or LHMDS as the base, the reaction gave only low
to moderate yields, high diastereoselectivities of the product
3a were still observed (Ͼ99:1 dr) (Entries 2 and 3). THF
was found to be the best solvent (Entry 4). Both the yield
and the diastereoselectivity decreased when the reaction
was carried out in Et2O or toluene (Entries 5 and 6).
Contrary to the aldol-type reaction of trapping metallo-
enamines derived from chiral N-sulfinyl ketimines by alde-
hydes,[19] which requires an additional reagent (e.g. MgBr2)
to enable metal exchange which leads to better coordination
to the carbonyl group and hence to achieve high diastereo-
selectivity [Figure 1(b)], the present Mannich-type reaction
Hydrolysis of 3 in the presence of AcOH in MeOH/H2O
at 40 °C for 24 h provided important optically active β-
amino ketones 4 (Ͼ80%yield). Excellent diastereoselectivi-
ties of the addition reaction were further confirmed by chi-
ral HPLC analysis of the generated β-amino ketones 4[22]
(98–99% ee; Table 3).
It is well known that the C=N double bond of β-amino
imines can be easily reduced by NaBH4, DIBALH, or
NaCNBH3 to provide racemic 1,3-diamines. In Kobayashi’s
work, chiral β-amino imines could be reduced by LiAl-
H(OtBu)3 in the presence of LiI to generate the optically
active 1,3-diamine in good diastereoselectivity (syn/anti =
14:86).[3d] On the other hand, Ellman[19] reported the highly
Scheme 1.
Table 1. The Mannich-type reaction of N-(tert-butylsulfinyl) ket-
imine 1 with imine 2a.
Entry
Base
Solvent
Yield [%][a]
dr[b]
1
2
3
4
5
6
NaH
nBuLi
LHMDS
LDA
LDA
LDA
THF
THF
THF
THF
Et2O
n.r.
45
75
89
57
60
Ͼ99:1
Ͼ99:1
Ͼ99:1
64:36
64:36
toluene
1
[a] Isolated yield. [b] Determined by H NMR.
Figure 1. (a) Addition of a metalloenamine to an imine; (b) addition of a metalloenamine to an aldehyde.
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Synthesis of a Chiral 1,3-Diamines from a Chiral N-(tert-Butyl) Ketimine
Table 2. Addition of metalloenamines derived from 1 to imines 2.
FULL PAPER
1
[a] Isolated yield. [b] The diastereoselectivity was determined by H NMR.
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diastereoselective reduction of β-hydroxy-sulfinyl imine
with catecholborane or LiBHEt3, offering syn- and anti-1,3-
amino alcohols in Ͼ99:1 dr, respectively. Similarly β-amino-
sulfinyl imines 3 could be reduced with catecholborane to
give syn-1,3-diamines (syn-5) in moderate yields and high
diastereoselectivities (Ͼ99:1 dr; Table 4). Furthermore,
when β-amino imines 3 were reduced with LiBHEt3, chiral
anti-1,3-diamines (anti-5) were obtained, also in good yields
and high diastereoselectivities (Ͼ99:1 dr; Table 4). The syn
and anti selectivities in the reduction of β-amino imines 3
under the conditions by using catecholborane and LiBHEt3
as the reductants are the same as in the cases of β-hydroxy
imines observed by Ellman.[19] The chiral auxiliary could
be easily removed by treating syn- and anti-5a with 4  HCl
in MeOH/dioxane, followed by neutralization to afford
the chiral 1,3-diamines syn- and anti-6a, respectively
(Scheme 2).
Figure 2. ORTEP drawing of (Rs,S)-3e.
Table 3. Preparation of β-amino ketones 4 by hydrolysis of 3.
[a] Isolated yield. [b] Determined by chiral HPLC. [c] Not determined.
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Synthesis of a Chiral 1,3-Diamines from a Chiral N-(tert-Butyl) Ketimine
Table 4. Selective reduction of β-amino imines 3 with different reducing agents.
FULL PAPER
1
[a] Isolated yield. [b] Determined by H NMR.
The absolute configuration of the produced syn-1,3-di-
amines was assigned as (Rs,1R,3S) by X-ray crystallo-
graphic analysis of compound syn-5i. In order to under-
stand the origin of the stereochemistry of the reduction re-
action, the reduction of chiral β-amino ketone 4a, which
was obtained by the hydrolysis of β-amino imine 3a, was
To further demonstrate the utility of the chiral β-amino
carried out with catecholborane. It was found that the gen- imines 3 as versatile intermediates in organic synthesis, we
erated 1,3-amino alcohol 7 was formed only in a low dia- investigated the nucleophilic addition reaction of organo-
stereoselectivity (60:40 dr). This result demonstrated that metallic reagents with β-amino imines 3. It was found from
the stereoselectivity of the reduction of β-amino imines 3 screening several organometallic reagents that lithium enol-
was mainly controlled by the chiral N-sulfinyl group.
ates derived from ethyl acetate/LDA and benzylmagnesium
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C.-H. Zhao, L. Liu, D. Wang, Y.-J. Chen
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bromide could react with β-amino imines 3, respectively.
The results of the nucleophilic addition of Grignard rea-
The addition of lithium enolates to β-amino imines 3 pro- gents to β-amino imines 3 are shown in Table 6. Benzylmag-
vided the 1,1,3-trisubstituted 1,3-diamines 8 in good yields nesium bromide could react smoothly with aryl-β-amino
(Table 5). As shown in Table 5, the reactions of β-amino imines 3a, 3d–e, as well as styryl-β-amino imine 3i to afford
imines 3, except 4-chlorophenyl- and furyl-β-amino imines the chiral 1,3-diamines 9 in very high diastereoselectivities.
(3b and 3h) (Entries 2 and 7), with ethyl acetate/LDA exhib- The absolute configuration of the newly formed stereocen-
ited high diastereoselectivities (99:1 dr) without using any ter was assigned to be (S) based on the X-ray crystallogra-
additives such as ClTi(OiPr)3.[16]
phy data of compound 9e. The crystal structure of β-amino
Table 5. Addition of the enolate derived from ethyl acetate/LDA to 3.
1
[a] Determined by H NMR. [b] Isolated yield.
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Synthesis of a Chiral 1,3-Diamines from a Chiral N-(tert-Butyl) Ketimine
Table 6. Addition of a Grignard reagent to β-amino imines 3.
FULL PAPER
1
[a] Isolated yield. [b] Determined by H NMR.
documented that the addition of a Grignard reagent to sim-
ple sulfinyl aldimines without β-amino group occurred in
an anti-Cram mode, because the stereochemistry of the re-
action was consistent with a six-membered-ring transition
state which resulted from the coordination of the Mg ion
of the Grignard reagent to the oxygen atom of the sulfinyl
group [Figure 3(a)].[14b,15]
Scheme 2.
imine 3e showed that the distance between the nitrogen
atom of the amino group and oxygen atom of the sulfinyl
group is 2.876 Å, which indicates a hydrogen-bond interac-
tion between the hydrogen atom of the sulfonamido group
and the oxygen atom of sulfinyl group. The addition of ben-
zylmagnesium bromide to the β-amino imine 3e takes place
through a transition state fixed by an intramolecular Mg
complexation. The Grignard reagent attacks the sulfinimine
group from the Re face which is consistent with the model
of Yamamoto and results in the (S) configuration of the
new chiral center. [Figure 3(b)]. The stereochemistry is con-
Figure 3. Transition state in the addition of Grignard reagents to
sulfinyl imines.
Conclusions
We have developed a highly diastereoselective Mannich
sistent with the Cram rule. However, in contrary, it was reaction of metalloenamines derived from enantiopure N-
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MeOH was added 4.0  aqueous AcOH (8 mmol, 2 mL) and the
mixture was stirred at 40 °C until the hydrolysis was determined to
be complete by TLC. The mixture was reduced to half of its volume
under reduced pressure and a saturated aqueous solution of NaCl
was added. Then the mixture was extracted with CH2Cl2, dried
with Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel to afford
the β-amino ketones 4.[22]
(tert-butylsulfinyl) ketimine 1 with imines 2. Chiral β-amino
imines 3 were obtained in 99:1 dr, which could be used as
versatile synthons in organic synthesis: (1) hydrolysis of the
resulting β-amino imines 3 provided enantiomeric β-amino
ketones; (2) reduction of the β-amino imines 3 with dif-
ferent reducing agents gave selectively syn- or anti-1,3-di-
amines with high diastereoselectivities (99:1 dr); (3) nucleo-
philic addition of lithium enolate or benzylmagnesium bro-
mide to β-amino imines 3 afforded 1,1,3-trisubstituted 1,3-
diamines in good yields and with high diastereoselectivities.
(S)-1,3-Diphenyl-3-tosylamino-1-propanone (4a): 34 mg, 90%yield.
1
[α]2D0 –22.0 (c = 1.0, CHCl3). M.p. 106–107 °C. H NMR (CDCl3/
TMS, 300 MHz): δ = 2.49 (s, 3 H, CH3-Ts), 3.48 (dd, J = 6.1,
17.4 Hz, 1 H, H-CH2), 3.62 (dd, J = 5.1, 17.4 Hz, 1 H, H-CH2),
4.89–4.96 (m, 1 H, CH), 5.77 (d, J = 6.5 Hz, 1 H, NH), 6.98–7.24
(m, 7 H, Harom.), 7.48 (t, J = 7.5 Hz, 2 H, Harom.), 7.59 (t, J =
7.3 Hz, 1 H, Harom.), 7.68 (d, J = 7.8 Hz, 2 H, Harom.), 7.86 (d, J
= 7.8 Hz, 2 H, Harom.) ppm. 13C NMR(100 MHz): δ = 21.5, 44.7,
54.5, 126.7, 127.2, 127.7, 128.0, 128.6, 128.7, 129.5, 133.6, 136.4,
Experimental Section
General Remarks: IR spectra were recorded with a Perkin–Elmer
782 IR spectrometer. 1H NMR and 13C NMR spectra were ob-
tained in CDCl3 at room temperature with a Bruker DMX-300
(300 MHz) spectrometer. Chemical shifts are given in ppm relative
to tetramethylsilane (TMS). Mass spectra were recorded with a
Bruker APEX-2 spectrometer using the FAB technique. Elemental
analyses were performed with a Carlo Erba 1102 Element Analysis
instrument. Optical rotations were measured with a Perkin–Elmer
241 instrument (589 nm). HPLC analysis was performed with a
Shimadzu CTO_10ASVP instrument equipped with the stated chi-
ral columns. Melting points were measured with a Beijing-Taike X-
4 apparatus and are uncorrected. Unless otherwise noted, all rea-
gents were obtained from commercial suppliers and were used
without further purification.
137.3, 139.3, 143.3, 197.8 ppm. IR: ν = 3280, 1681, 1327,
˜
1158 cm–1. C22H21NO3S (379.12): calcd. C 69.63, H 5.58, N 3.69;
found C 69.51, H 5.60, N 3.54. HPLC (Daicel Chiralcel OD, hex-
ane/iPrOH, 9:1, flow rate 1.0 mL/min): tR(minor) = 23.04 min,
tR(major) = 29.91 min.
Typical Experimental Procedure for the Reduction of β-Amino
Imines 3 with Catecholborane: To a solution of a β-amino-sulfinyl
imine 3 (0.1 mmol) in THF (2 mL) was added catecholborane
(60 mg, 0.5 mmol) at –10 °C, and the mixture was stirred for 24 h.
To this mixture was added MeOH (1.0 mL) and a saturated solu-
tion of sodium potassium tartrate (1 mL). The resulting mixture
was stirred at room temperature for 1 h, then extracted with
CH2Cl2. The combined organic phases were dried with Na2SO4,
concentrated and purified by flash chromatography to provide the
syn-1,3-diamines syn-5.
Typical Experimental Procedure for the Mannich-Type Reaction of
N-(tert-Butylsulfinyl) Ketimine 1 with Imines 2: To a stirred solution
of 1 (23 mg, 0.2 mmol) in THF (2 mL) at –78 °C was added LDA
(0.11 mL, 2.0  in THF/hexane) dropwise. After the reaction solu-
tion had been stirred at –78 °C for 1 h, a solution of the imine 2
(0.4 mmol) in THF (2 mL) was added in one portion, and the mix-
ture was stirred at –78 °C for another 2 h. A saturated aqueous
solution of NH4Cl (5 mL) was then added to the mixture with stir-
ring. The mixture was warmed to room temperature, followed by
extraction with CH2Cl2. The combined organic phases were dried
with Na2SO4 and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography on silica gel to
afford the desired β-amino-sulfinyl imines 3.
(Rs,1R,3S)-N-(tert-Butylsulfinyl)-1-phenyl-3-(2-phenylvinyl)-3-(tos-
ylamino)propylamine (syn-5i): 36 mg, 71%yield. [α]2D0 = –37.3 (c =
1
1.0, CHCl3). M.p. 81–82 °C. H NMR (CDCl3/TMS, 300 MHz): δ
= 1.21 (s, 9 H, tBu), 1.95–1.99 (m, 1 H, H-CH2), 2.24 (s, 3 H, CH3-
Ts), 2.44–2.50 (m, 1 H, H-CH2), 3.99–4.04 (m, 2 H, CH, NH),
4.60–4.61 (m, 1 H, CH), 5.62 (dd, J = 7.7, 15.9 Hz, 1 H, CH=),
5.89 (d, J = 8.6 Hz, 1 H, NH), 6.06 (d, J = 15.9 Hz, 1 H, CH=),
6.99–7.02 (m, 2 H, Harom.), 7.10 (d, J = 8.0 Hz, 2 H, Harom.), 7.18–
7.22 (m, 3 H, Harom.), 7.28–7.34 (m, 5 H, Harom.), 7.65 (d, J =
8.3 Hz, 2 H, Harom.) ppm. 13C NMR (CDCl3/TMS, 75 MHz): δ =
21.3, 22.8, 42.5, 54.3, 56.2, 126.3, 127.3, 127.5, 127.7, 128.1, 128.3,
(Rs,S)-N-[3-(p-Methoxyphenyl)-1-phenyl-3-(tosylamino)propyl-
128.5, 128.8, 129.4, 131.4, 136.1, 138.4, 141.5, 143.1 ppm. IR: ν =
˜
idene]-2-methylpropanesulfinamide (3e): 96 mg, 94%yield. [α]2D0
=
3258, 3062, 1326, 1157 cm– 1 . HRMS (FAB): calcd. for
C28H34N2O3S2Na [M + Na] 533.1923; found 533.1899. The crystal
used for the X-ray study had the dimensions 0.66×0.53×0.38 mm.
Crystal data: C28H34N2O3S2, M = 510.69, monoclinic, space group
C2, a = 24.3114(16), b = 11.7896(7), c = 10.3552(7) Å, β =
105.9490(19)°, V = 2853.8(3) Å3, Z = 4, Dcalcd. = 1.189 g/cm3, Fo
= 1088, reflections collected: 3385, λ = 0.71073 Å.
+27.8 (c = 1.0, CHCl3). M.p. 134–135 °C. 1H NMR (CDCl3/TMS,
300 MHz): δ = 1.45 (s, 9 H, tBu), 2.25 (s, 3 H, CH3-Ts), 3.24 (dd,
J = 4.1, 13.4 Hz, 1 H, H-CH2), 3.26–3.74 (m, 4 H, OCH3, H-CH2),
4.56–4.63 (m, 1 H, CH–N), 6.64 (d, J = 8.3 Hz, 2 H, Harom.), 6.86
(d, J = 7.9 Hz, 2 H, Harom.), 7.10 (d, J = 8.3 Hz, 2 H, Harom.), 7.24
(d, J = 7.7 Hz, 2 H, Harom.), 7.44 (t, J = 7.3 Hz, 2 H, Harom.), 7.52–
7.61 (m, 2 H, NH, Harom.), 7.78 (d, J = 7.7 Hz, 2 H, Harom.) ppm.
13C NMR (CDCl3/TMS, 100 MHz): δ = 21.3, 22.9, 41.3, 54.7, 55.3,
59.0, 113.8, 126.6,127.5, 127.6, 128.7, 128.8, 132.1, 133.1, 136.5,
Typical Experimental Procedure for the Reducion of β-Amino Imines
3 with LiBHEt3: To a solution of β-amino-sulfinyl imines 3
(0.1 mmol) in THF (2 mL) at –78 °C was added LiBHEt3
(0.25 mmol, 1.0  in THF) and the solution was stirred at –78 °C
for 3 h. A saturated aqueous solution of NH4Cl was added to the
solution. Then the solution was warmed to room temperature fol-
lowed by extraction with CH2Cl2. The combined organic phases
were dried with Na2SO4, concentrated, and purified by flash
chromatography to provide anti-1,3-diamines anti-5.
138.6, 141.7, 159.0, 175.4 ppm. IR: ν = 3121, 1329, 1155 cm–1
.
˜
C27H32N2O4S2 (512.18): calcd. C 63.25, H 6.29, N 5.46; found C
63.24, H 6.34, N 5.28. The crystal used for the X-ray study had the
dimensions 0.57×0.42×0.18 mm. Crystal data: C27H32N2O4S2, M
= 512.67, orthorhombic, space group P212121, a = 10.4322(4), b =
13.6353(6), c = 18.3325(7) Å, V = 2607.73(18) Å3, Z = 4, Dcalcd.
=
1.308 g/cm3, Fo = 1092, reflections collected: 3354, λ = 0.71073 Å.
Typical Experimental Procedure for the Hydrolysis of β-Amino
Imines 3: To a 0.02  solution of β-amino imines 3 (0.1 mmol) in
(Rs,1S,3S)–N-(tert-Butylsulfinyl)-1,3-diphenyl-3-(tosylamino)pro-
pylamine (anti-5a): 39 mg, 81% yield. [α]2D0 = –32.3 (c = 1.0,
2984
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Synthesis of a Chiral 1,3-Diamines from a Chiral N-(tert-Butyl) Ketimine
FULL PAPER
1
CHCl3). M.p. 144–145 °C. HNMR (CDCl3/TMS, 400 MHz): δ = NMR (CDCl3/TMS, 100 MHz): δ = 13.3, 208, 22.3, 41.9, 44.1,
1.20 (s, 9 H, tBu), 2.30 (s, 3 H, CH3-Ts), 2.35–2.42 (m, 1 H, H- 55.1, 56.6, 59.9, 61.0, 125.9, 126.3, 126.4, 126.6, 127.3, 127.6, 127.7,
CH2), 2.50–2.57 (m, 1 H, H-CH2), 4.17 (d, J = 6.0 Hz, 1 H, NH),
128.3, 137.1, 140.5, 141.6, 141.8, 168.7 ppm. IR: ν = 3259, 3163,
˜
4.27–4.36 (m, 2 H, 2CH–N), 6.32 (d, J = 8.1 Hz, 1 H, NH), 6.94– 3063, 2980, 1720, 1599, 1494, 1454, 1330, 1159 cm–1. HRMS
6.96 (m, 2 H, Harom.), 7.00 (d, J = 8.3 Hz, 2 H, Harom., Harom.), (FAB): calcd. for C30H39N2O5S2 [M + H+] 571.2294, found
7.11–7.20 (m, 5 H, Harom.), 7.28–7.40 (m, 5 H, Harom.) ppm. 13C
NMR (CDCl3/TMS, 100 MHz): δ = 21.4, 22.6, 45.1, 55.5, 56.1,
57.2, 126.6, 127.0, 127.1, 127.5, 127.7, 128.6, 128.7, 129.1, 137.3,
571.2292.
General Procedure for Addition of Benzylmagnesium Bromide to β-
Amino Imines 3: In a flame-dried flask was placed the β-amino
imine 3 (1.0 equiv., 0.1 mmol) in THF (2 mL) and the solution was
cooled to –78 °C. The Grignard reagent (3.0 equiv., 0.3 mmol in
2 mL THF) was added dropwise to the solution and the conversion
was monitored by TLC. Then to the reaction mixture was added a
saturated aqueous NH4Cl solution and the mixture was warmed
to room temperature. The resulting suspension was diluted with
saturated aqueous NaCl and extracted with CH2Cl2. The organic
layers were combined, dried, and concentrated. The residue was
purified by flash column chromatography to give the desired prod-
ucts 9.
139.5, 141.2, 142.8 ppm. IR: ν = 3267, 3064, 1324, 1156 cm–1
.
˜
HRMS (FAB): calcd. for C26H33N2O3S2 [M + H+] 485.1927; found
485.1929.
Typical Experimental Procedure for the Cleavage of the Chiral Sulf-
inyl Auxiliary: Compound syn-5a (0.1 mmol) was treated with a 1:1
mixture (2 mL) of MeOH and 4.0  HCl in dioxane (2 mL) at room
temperature for 1 h. To the mixture was added a saturated aqueous
Na2CO3 solution and the mixture was extracted with CH2Cl2. The
combined organic portions were dried with Na2SO4, concentrated
under reduced pressure and recrystallized from CH2Cl2/hexane to
give syn-6a as a white solid in 89% yield. According to the same
procedure, compound anti-5a gave compound anti-6a.
N-[1-(4-Methoxyphenyl)-3-(2-methylpropylsulfinylamino)-3,4-di-
phenylbutyl]-4-methyl-benzenesulfonamide (9e): 43 mg, 71% yield.
[α]2D0 = +51.3 (c = 1.0, CHCl3). M.p. 185–186 °C. 1H NMR (CDCl3/
TMS, 300 MHz): δ = 1.36 (s, 9 H, H-tBu), 2.24 (s, 3 H,CH3-Ts),
2.37 (d, J = 15.6 Hz, 1 H, H-CH2), 2.80 (t, J = 15.6 Hz, 1 H, H-
CH2), 3.24 (d, J = 13.7 Hz, 2 H, CH2), 3.70 (s, 3 H, O–CH3), 4.38–
4.44 (m, 1 H, CH), 5.01 (s, 1 H, NH), 6.44–6.52 (m, 4 H, Harom.),
6.81–6.85 (m, 4 H, Harom.), 6.95–7.06 (m, 3 H, NH, Harom.), 7.12–
7.18(m, 4 H, Harom.), 7.38–7.41(m, 4 H, Harom.) ppm. 13C NMR
(CDCl3/TMS, 75 MHz): δ = 21.3, 23.1, 47.0, 48.5, 54.7, 55.2, 57.3,
64.5, 113.5, 126.2, 126.5, 126.7, 127.3, 127.5, 127.7, 128.6, 130.9,
133.6, 135.4, 138.4, 141.2, 141.7, 158.5. IR 3297, 3088. 2925, 1611,
1512, 1454, 1331, 1159 cm–1. HRMS (FAB): calcd. for
C34H41N2O4S2 [M + H+] 605.2502, found 605.2488. The crystal
used for the X-ray study had the dimensions 0.50×0.40×0.25 mm.
Crystal data: C34H40N2O4S2, M = 604.80, orthorhombic, space
group P21, a = 12.088(2), b = 12.327(3), c = 22.612(5) Å, V =
3313.4(11) Å3, Z = 4, Dcalcd. = 1.212 g/cm3, Fo = 1288, reflections
collected 21574, λ = 0.71073 Å.
(1S,3R)–1,3-Diphenyl-3-(tosylamino)propylamine (syn-6a): 34 mg,
89%yield. [α]2D0 = –26.0 (c = 1.0, CHCl3). M.p. 150–151 °C.
1HNMR (CDCl3/TMS, 300 MHz): δ = 1.88–2.01 (m, 2 H, CH2),
2.36 (s, 3 H, CH3-Ts), 3.75 (br., 1 H, CH), 4.42–4.47 (m, 1 H, CH),
7.10–7.32 (m, 12 H, Harom.), 7.54 (d, J = 8.1 Hz, 2 H, Harom.) ppm.
13C NMR (CDCl3/TMS, 100 MHz): δ = 21.4, 44.9, 55.2, 58.6,
125.6, 126.5, 127.1, 127.4, 128.2, 128.5, 128.8, 129.0, 137.5, 141.4,
142.6, 145.5 ppm. IR: ν = 3357, 3302, 3061, 3030 cm–1. HRMS
˜
(FAB): calcd. for C22H25N2O2S [M + H+] 381.1631 found 381.1634.
(1S,3S)-1,3-Diphenyl-3-(tosylamino)propylamine (anti-6a): 35 mg,
92% yield. [α]2D0 = –32.0 (c = 1.0, CHCl3). M.p. 129–130 °C.
1HNMR (CDCl3/TMS, 300 MHz): δ = 1.98–2.02 (m, 2 H, CH2),
2.36 (s, 3 H, CH3-Ts), 3.87 (br., 1 H, CH), 4.52(t, J = 5.5, 1 H,
CH), 7.07–7.11 (m, 5 H, Harom.), 7.16–7.19 (m, 4 H, Harom.), 7.21–
30 (m, 3 H, Harom.),7.54 (d, J = 8.3 Hz, 2 H, Harom.) ppm. 13C
NMR (CDCl3/TMS, 100 MHz): δ = 21.4, 44.6, 52.6, 56.0, 125.7,
126.4, 126.9, 127.1, 127.2, 128.3, 128.7, 129.2, 137.8, 140.6, 142.7,
145.5 ppm. IR: ν = 3278, 3061, 3030 cm–1. C H N O S (380.15):
˜
CCDC-601459 (3e), -601460 (9e) and -601461 (syn-5i) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
22 24
2
2
C 69.44, H 6.36, N 7.36; found C 69.05, H 6.30, N 7.36
Typical Experimental Procedure for Addition of the Enolate of Ethyl
Acetate to β-Amino Imines 3: To a stirred solution of ethyl acetate
(3.0 equiv., 0.3 mmol) in THF (2 mL) at –78 °C was added LDA
(0.33 mmol, 0.16 mL, 2.0  in THF/hexane) dropwise by a syringe.
After the reaction solution was stirred for 30 min, a solution of β-
amino imine 3 (0.1 mmol, 1.0 equiv.) in THF(2 mL) was added in
one portion, and the reaction mixture was stirred at –78 °C for
another 2 h. A saturated aqueous solution of NH4Cl (5 mL) was
then added to the mixture with stirring. The mixture was warmed
up to room temperature, followed by extraction with CH2Cl2. The
combined organic phases were dried with Na2SO4 and the solvent
was removed under reduced pressure. The residue was purified by
flash chromatography on silica gel to afford the desired products
8.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China, and the Chinese Academy of Sciences for financial support.
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Eur. J. Org. Chem. 2006, 2977–2986
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2985

C.-H. Zhao, L. Liu, D. Wang, Y.-J. Chen
FULL PAPER
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Received: February 21, 2006
Published Online: May 9, 2006
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