Catalytic asymmetric aziridination of enol derivatives in the presence of chiral copper complexes to give optically active α-amino ketones

Article abstract of DOI:10.1002/(SICI)1099-0690(200002)2000:3<557::AID-EJOC557>3.0.CO;2-B

A series of acyclic and cyclic enol derivatives 1 has been transformed into the corresponding α-amino-functionalized ketones 2 by means of enantioselective catalytic aziridination with chiral Cu complexes, prepared in situ from [Cu(MeCN)₄]PF

Full text of DOI:10.1002/(SICI)1099-0690(200002)2000:3<557::AID-EJOC557>3.0.CO;2-B

FULL PAPER
Catalytic Asymmetric Aziridination of Enol Derivatives in the Presence of
Chiral Copper Complexes to give Optically Active α-Amino Ketones
Waldemar Adam,*[a] Konrad Johann Roschmann,[a] and Chantu Ranjan Saha-Möller[a]
Keywords: Amino ketones / Homogeneous catalysis / Aziridination / Copper / EnolsAmino ketones / Homogeneous
catalysis / Aziridination / Copper / Enols
A series of acyclic and cyclic enol derivatives 1 has been
transformed into the corresponding α-amino-functionalized
ketones 2 by means of enantioselective catalytic aziridination
with chiral Cu complexes, prepared in situ from
[Cu(MeCN)4]PF6 and the optically active ligands 3, by using
(N-tosylimino)iodobenzene (PhINTs) as a nitrogen source.
The best enantioselectivities (ee values of up to 52%) have
been achieved for the electronically deactivated enol acetate
1aδ, but the incorporation of steric bulk and the substitution
pattern at the enol double bond do not improve the ee values.
The cyclic substrates react considerably less readily (only up
to 45% conversion) compared to their acyclic counterparts
(complete consumption). A transition structure is suggested
for the asymmetric Cu-catalyzed aziridination of the enol
acetate 1aδ in the presence of the chiral ligand 3b that could
account for the sense of the (R)-configured product 2a.
Introduction
tive examples involving the Cu-catalyzed asymmetric azirid-
ination of styrene and cinnamate derivatives by employing
the C2-symmetric ligands 3a and 3b as chiral auxiliaries
have been independently developed by Evans[8b] and by Ja-
cobsen.[9a]
The amino functionality is ubiquitous and is of immense
importance in natural products, in drugs, as well as in build-
ing blocks in organic synthesis.[1] Since most of these com-
pounds possess at least one chiral center, it is of general
interest to develop synthetic methods for their preparation
in enantiomerically enriched form.
An attractive target molecule is Cathinone, or (–)-(2S)-2-
amino-1-phenylpropanone, the main active component of
fresh leaves of Catha edulis, which shows cardiovascular
biological activity.[2] Moreover, its reduction to the corres-
ponding β-amino alcohol furnishes a valuable chiral auxili-
ary for use in asymmetric catalysis.[3]
Following the aziridination of enol derivatives (X ϭ OR,
Scheme 1), ring-opening of the aziridine intermediate af-
fords the corresponding α-amino ketone. For this purpose,
a few stoichiometric methods are available, allowing the en-
antio- or diastereoselective α-amination of ketones.[5,7c,7d]
For example, Komatsu and co-workers[7c] and Jørgensen et
al.[7d] have recently used optically active nitridomangane-
se(V) complexes to good effect in the stoichiometric azirid-
ination of enols (ee values of up to 79%). However, as far
as we are aware, no catalytic asymmetric nitrene transfers
to enol derivatives have hitherto been reported.
An elegant way of introducing a nitrogen atom into a
molecule is by means of aziridination, in which a nitrene or
a
nitrenoid species is transferred onto the olefin
(Scheme 1).[4] A convenient way of generating a nitrene is
either by photolysis or thermolysis of an azide,[5] while ox-
aziridines[6] serve as efficient thermal sources for nitrenoid-
type aza functionalization.
The aim of this study was to employ the Evans[8b] and
the Jacobsen method[9a] for Cu-catalyzed asymmetric amin-
ation of enol derivatives of propiophenone bearing silyl,
methyl, and acetyl groups (1aα–δ, cf. Table 1) in order to
generate optically active Cathinone derivatives. It was of in-
terest to vary the steric bulk and the electronic properties
of the enol substrate so as to allow optimization of the en-
antioselectivity of this catalytic aza functionalization.
Scheme 1. Aziridination of olefins (X ϭ R or Ar) and enol deriva-
tives (X ϭ OR)
In order to achieve metal-mediated nitrogen transfer, ni-
tridomanganese(V) complexes may be activated by p-tolu-
enesulfonic or trifluoroacetic anhydride,[7] or in situ gener-
ated
copper
and
rhodium
nitrene
complexes
(MϭN–SO2Ar) may be utilized.[8–10] Notable enantioselec-
Results
[a]
Institute of Organic Chemistry, University of Würzburg,
Am Hubland, D-97074 Würzburg, Germany
Fax: (internat.) ϩ49-931/888-4756
The enol derivatives 1a–d were prepared from the corres-
ponding ketones according to literature methods.[11] The Z-
configured acyclic enol derivatives 1aα–bβ (for structures,
E-mail: adam@chemie.uni-wuerzburg.de
Internet: http://www.organik.chemie.uni-wuerzburg.de
Eur. J. Org. Chem. 2000, 557Ϫ561
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0303Ϫ0557 $ 17.50ϩ.50/0
557

W. Adam, K. J. Roschmann, C. R. Saha-Möller
FULL PAPER
Table 1. Copper-catalyzed aziridination of the enol derivatives 1a–d[a] tained by using 5 mol-% of [Cu(MeCN)4]PF6 as the copper
source and 5.5 or 6.0 mol-% of ligand 3a or 3b in CH2Cl2
at –40 °C (entries 1 and 2). At lower temperatures (–70 °C),
no conversion of the enol derivative 1aα was observed after
5 h using ligand 3a, while with ligand 3b the reaction was
appreciably retarded (ca. 95% conversion only after 10 h)
without any significant increase in enantioselectivity (data
not shown) as compared with that of the reaction at –40 °C
(entry 2). Both the conversion and the enantioselectivity in
the aziridination of silyl enol ether 1aα with PhINTs in the
presence of ligand 3a or 3b were decreased when
CuOTf
1/2 C6H6 or Cu(OTf)2 was used instead of
[Cu(MeCN)4]PF6 as the copper source (data not shown).
Therefore, all subsequent catalytic asymmetric aziridina-
tions of the enol derivatives 1aβ–d were carried out with
[Cu(MeCN)4]PF6 under the optimized reaction conditions
(CH2Cl2, –40 °C).
To assess the effect of the steric bulk of the silyloxy group
on the enantioselectivity, the catalytic aziridination of the
TBDMS-substituted enol ether 1aβ was investigated. For
this substrate, a decrease in the ee values to 12–13% was
observed (entries 3 and 4), as compared with the 16–18%
obtained for the enol ether 1aα, which is functionalized
with the sterically less demanding TMS group (entries 1
and 2).
[a]
A 1.0:0.6:0.05 molar ratio of 1:PhINTs:CuPF6 was employed,
Once it had been established that the steric demand of
[b]
rection temperature –40 °C. –
5.5 mol-% of chiral ligand 3a or
6.0 mol-% of 3b was used. – Referred to the amount of PhINTs the R3 substituent has no significant effect on the enanti-
[c]
consumed, determined by 1H NMR analysis, error ca. ±5%. –
oselectivity, its electronic influence was tested by carrying
[d]
Enantiomeric excess of amino ketone 2, determined by HPLC
analysis on a chiral column, error ca. ±2%. – [e] After acid-catalysed
hydrolysis of the aziridine 4 with HCl/MeOH to the amino ketone
2a, the ee values of aziridine (ϩ)-4 are 28% and 53%, respectively.
out asymmetric aziridinations of the methyl enol ether 1aγ
and the enol acetate 1aδ. Remarkably higher ee values (28%
and 52%) were achieved for the less electron-rich enol acet-
ate 1aδ (entries 7 and 8) compared to the more electron-
rich methyl enol ether 1aγ (ca. 10%, entries 5 and 6). Both
substrates 1aγ and 1aδ preferentially afforded the (R)-con-
figured α-amino ketone 2a in the presence of the chiral li-
gand 3a (cf. entries 5 and 7), while in the case of ligand 3b
the sense of the enantioselectivity with these substrates was
reversed (cf. entries 6 and 8). Fortunately, the aziridine 4 of
the enol acetate 1aδ persisted under the reaction conditions,
which permitted its isolation. Subsequent hydrolysis by
treatment with methanolic HCl to give the α-amino ketone
2a proceeded without loss of optical purity.
see Table 1) were obtained almost exclusively (Z/E Ͼ 95:5)
under optimized reaction conditions. Racemic samples of α-
tosylamino ketones 2a–c were prepared by copper-catalyzed
aziridination of the corresponding enols 1a–c according to
a literature method,[8c] while derivative 2d was obtained by
tosylation of the corresponding amino ketone hydro-
chloride.[12]
The copper-catalyzed asymmetric aziridinations of the
enols 1a–d with N-tosyl-iminoiodobenzene (PhINTs) were
carried out using the C2-symmetric ligands diimine 3a and
bis(oxazoline) 3b as sources of chirality (Scheme 2). The re-
sults are summarized in Table 1.
To evaluate whether the substitution pattern of the R1
and R2 groups of the enol derivative has an influence on
the enantioselectivity, the silyl enol ethers 1bα and 1bβ,
which, in contrast to the substrates 1aα and 1aβ, bear the
methyl group in the α- and the phenyl group in the β posi-
tion with respect to the silyloxy functionality, were reacted
with PhINTs under the optimized catalytic conditions. Sim-
ilar ee values (ca. 20%) were observed for the TMS-substi-
tuted derivatives 1aα and 1bα (entries 1, 2, 9, and 10). For
the TBDMS-substituted silyl enol ether 1bβ, slightly higher
ee values (21% and 27%) were observed (entries 11 and 12),
compared to 12% and 13% seen with 1aβ (entries 3 and 4).
Scheme 2. Copper-catalyzed asymmetric amination of enol deriva-
ives 1
The reaction conditions were optimized with regard to Moreover, the sense of the enantioselectivity was reversed
degree of conversion and enantioselectivity by employing in the case of the TBDMS-substituted derivatives 1aβ (ent-
the trimethylsilyl enol ether 1aα as a model substrate. The ries 3 and 4) and 1bβ (entries 11 and 12). Whereas the for-
best results (conversion Ͼ 90%, ee value 16–18%) were ob- mer preferentially produced the (S)-configured amino ke-
558
Eur. J. Org. Chem. 2000, 557Ϫ561

Catalytic Assymetric Aziridination of Enol Derivatives
FULL PAPER
tone 2a, the (R)-enantiomer of 2b was preferentially formed the catalytic aziridination of the enol derivates 1a–d seems
from 1bβ.
to be intrinsic to the nitrogen-transfer process.
In contrast to the acyclic enol derivatives 1aα–bβ (entries
The ee values in Table 1 reveal that neither the substitu-
1–12), for the cyclic substrates 1c,d only poor conversion tion pattern of the substrate 1 (entries 1, 2, 9, and 10) nor
(up to 45%) to the corresponding α-amino ketones 2c,d was the steric bulk of silyloxy groups (entries 1–4) has an appre-
observed (entries 13–16). With these cyclic derivatives, cop- ciable effect on the enantioselectivity of Cu-catalyzed aziri-
per-catalyzed decomposition of PhINTs to tosyl amide pre- dination of these enol derivatives. However, the electronic
vailed over aziridination, which, surprisingly, has not been property of the substituent on the oxygen atom of the enol
observed in the absence of chiral ligands.
substrate does influence the degree of enantioselectivity. For
The absolute configurations of amino ketones 2a,b were example, considerably higher ee values of up to 52% (entries
determined by independent synthesis (cf. SchemeS)-2a was 7 and 8) were obtained for the more electron-deficient enol
prepared by tosylation of (1R,2S)-norephedrine and sub- acetate 1aδ as compared to only ca. 10% for the methoxy
sequent Jones oxidation,[13] while the α-amino ketone (ϩ)- derivative 1aγ (entries 5 and 6). Let us now attempt to ra-
(S)-2b was obtained in 96% ee from (S)-phenylglycine by tionalize these electronic effects on the enantioselectivity.
tosylation and subsequent reaction with MeLi.[14]
For the Jacobsen–Katsuki epoxidation of chromene de-
rivatives, it has been reported[15a] that methoxy-substituted
salen ligands give rise to higher ee values than their nitro-
substituted counterparts. This has been explained in terms
of stabilization of the electrophilic, oxygen-transferring
oxo-Mn(III) species by the electron-donating methoxy sub-
stituent, which decreases the reactivity of the oxo complex.
According to the Hammond postulate, a less reactive re-
agent favors a late, more product-like transition state,[15b]
which, for a reaction without substrate–reagent precoor-
dination, implies a more ordered transition structure. Thus,
stronger steric interactions are operative during the encoun-
ter of the substrate and reagent and a higher selectivity is
to be expected. In analogy to the Jacobsen–Katsuki epoxid-
ation, we propose that in the asymmetric aziridination of
the less electron-rich, less reactive enol acetate 1aδ, a more
ordered, product-like transition state is involved. Hence, the
enantioselectivity in the case of the more electron-deficient
enol acetate 1aδ is significantly higher than that seen with
the methyl enol ether 1aγ. Indeed, the electron-deficient cin-
namates are aziridinated with ee values of up to 85%,[8b][9b]
Scheme 3. Synthesis of authentic samples of (S)-2a and (S)-2b
Discussion
As mentioned in the Results Section, Cu-catalyzed asym- which substantiates the aforementioned rationale for the
metric aziridination of the enol derivatives 1a–d with observed electronic effect on the enantioselectivity of the
PhINTs yielded the corresponding α-amino ketones 2a–d catalytic asymmetric aziridination.
with poor to moderate enantiomeric excesses (ee values up
It remains to suggest a likely transition structure for the
to 52%, Table 1). In control experiments using the silyl enol Cu-catalyzed aziridination of the enol acetate 1aδ (chosen
ether 1aα as a model substrate in the absence of the Cu as a model substrate in view of the highest ee value of 52%)
catalyst, under otherwise identical reaction conditions, no in the presence of the chiral ligand 3b, that would account
PhINTs was consumed, from which it can be concluded for the sense of the (R)-configured α-amino ketone 2a
that the non-catalytic reaction is not responsible for the low (entry 8). A monomeric, trigonal-planar nitrene–cop-
enantioselectivity. Furthermore, when a stoichiometric per(III) complex was initially suggested by Jacobsen and
amount of the chiral Cu complex prepared from CuPF6 and co-workers[9b] for the asymmetric aziridination of styrene
the chiral ligand 3a was employed in the aziridination of derivatives, and was later applied by Uemura and Taylor[16]
the enol ether 1aα, no significant increase in the ee value to Cu-catalyzed sulfimide formation. Assuming that this
was observed (data not shown) as compared to that ob- active Cu complex holds true for our nitrogen transfer, we
tained under catalytic conditions. These results imply that propose the trajectory shown in Figure 1, where the plane
the low enantioselectivity of this asymmetric aziridination a of the substrate double bond attacks the plane b of the
is not due to a competing reaction catalyzed by the copper Cu–N bond in a perpendicular orientation.
source [Cu(MeCN)4]PF6. Since no loss of optical purity
To minimize steric interactions, the enol acetate orients
was observed when the enantiomerically pure (R)-config- itself in such a way that its phenyl group points away from
ured α-tosylamino ketone 2a was exposed to the standard the chiral ligand of the complex and is anti to the Ts group
reaction conditions, product racemization may also be ex- of the nitrene, as shown in the uppermost-left structure in
cluded as a possible reason for the low ee values of the α- Figure 1. A similar substrate approach has been proposed
amino ketones 2a–d. Thus, the low enantiodifferentiation in by Pfaltz et al.[17] for the Cu-catalyzed asymmetric cyclo-
Eur. J. Org. Chem. 2000, 557Ϫ561
559

W. Adam, K. J. Roschmann, C. R. Saha-Möller
FULL PAPER
tially, as is indeed observed experimentally. This trajectory
also correctly accounts for the stereoselectivity observed by
Evans[8b] in the aziridination of cinnamate esters.
In conclusion, while Cu-catalyzed asymmetric aziridin-
ation of the electron-rich silyl enol ethers 1a–d proceeds
with low enantioselectivity, appreciable ee values (up to
52%) have been achieved with the less electron-rich enol
acetate 1aδ. A late transition state is proposed for the asym-
metric aziridination of this less reactive substrate, where en-
hanced steric interactions with the chiral ligand 3b and the
tosyl amide group dictate preferential formation of the (R)-
configured α-amino ketone 2a.
Experimental Section
General Remarks: IR: Perkin–Elmer model 1605 FT-IR spectro-
photometer. – 1H NMR (250 MHz): Bruker AC 250 (CHCl3 at δ ϭ
7.26 as internal standard). – 13C NMR (63 MHz): Bruker AC 250
(CHCl3 at δ ϭ 77.0 as internal standard). – Melting points: Büchi
B-545 apparatus (uncorrected values). – Column chromatography
was performed on silica gel (32–63 µm mesh, Merck). – HPLC:
Kontron Instruments pump system 322, UV detection on a Kon-
tron UVIKON 720 LC micro spectrophotometer; optical rotations
detected with an IBZ Meßtechnik GmbH Chiralyser. – Optical ro-
tations: Perkin–Elmer 241 MC polarimeter.
Asymmetric Aziridination of Enol Derivatives 1a–d: A solution of
18.6 mg (50.0 µmol) of [Cu(MeCN)4]PF6 and 23.6 mg (55.0 µmol)
of ligand 3a or 20.1 mg (60.0 µmol) of ligand 3b in 4 mL CH2Cl2
was stirred for 15 min. at room temp. (ca. 20 °C) under an atmo-
sphere of argon. To this mixture, a solution of 1.00 mmol of the
appropriate enol ether 1a–d in 0.5 mL of CH2Cl2 and about 0.5 g
Figure 1. Proposed trajectories for the approach of enol acetate 1aδ
in asymmetric aziridination with the catalyst system CuPF6/3b;
plane a relates to the substrate and plane b to the bis(oxazoline)
complex.
˚
of molecular sieves 4 A were added and the resulting mixture was
stirred for 15 min. at room temp. After cooling to –40 °C, 250 mg
(670 µmol) of PhIϭNTs was added in small portions over a period
of 5 min. The resulting suspension was stirred until a clear, green
solution was obtained (typically after 3 to 5 h), which was then
passed through a short column of neutral Al2O3 (ca. 15 g), eluting
with 200 mL of EtOAc. Removal of the solvent (30 °C, 10 mbar)
Table 2. HPLC conditions for the amino ketone
1
afforded a colorless oil, which was subjected to H NMR analysis
Com-
pound
Column
Flow
[mL/min]
Retention time
[min]
[a]
to assign its structure (comparison with authentic racemic samples)
and to determine the degree of conversion (relative to the PhINTs
consumed, using dimethyl 1,3-benzenedicarboxylate as an internal
standard). The enantiomerically enriched amino ketones 2a–d were
analyzed by HPLC on chiral columns (Table 2).
2a
2b
2c
2d
4
Chirapak AS
Chirapak AS
Chiracel OB-H
Chirapak AS
Chirapak AS
0.5
0.2
0.5
0.5
0.5
29.5 (S), 33.1 (R)
64.8 (R), 68.1 (S)
28.2 (ϩ), 33.7 (–)
40.3 (ϩ), 44.0 (–)
17.5 (2S,3R),
21.9 (2R,3S)[b]
Preparation of Racemic Samples of 2d and 4
[a]
3-{[(4-Methylphenyl)sulfonyl]amino}-4-chromanone (2d): A sample
of 124 mg (621 µmol) of 3-amino-4-chromanone hydrochloride was
dissolved in 3 mL of pyridine and the solution was cooled to 0 °C.
After the addition of 133 mg (700 µmol) of tosyl chloride, the reac-
tion mixture was stirred at room temp. (ca. 20 °C) for 21 h. After
removal of the solvent (30 °C, 10 mbar), the residue was treated
with 10 mL of a mixture of ice and 2  HCl. The orange precipitate
thus formed was collected, washed with cold ethanol, and dried
over P4O10 (156 mg, 79%). Double recrystallization from ethanol
yielded 61.8 mg (31%) of 2d as colorless needles; m.p. 129–130 °C. –
IR (KBr): ν˜ ϭ 3264 cm–1 (NH), 3030 (CH), 2889 (CH), 1696 (Cϭ
O), 1647 (CϭC), 1608, 1578, 1480, 1345, 1216, 1168, 961, 820. –
1H NMR: δ ϭ 2.40 (s, 3 H), 3.98–4.25 (m, 2 H), 4.89 (dd, J ϭ
A mixture of n-hexane and ethanol (80:20) was used as eluent.
[b]
The configuration was assigned following acid-catalyzed hydro-
lysis to give the known optically active 2a.
ropanation of styrene. For our proposed trajectory, two op-
tions are possible, namely frontside or backside attack of
the substrate. Frontside attack should be favored over back-
side attack, since in the latter a repulsive steric interaction
would be operative between the NTs moiety and a phenyl
group of the ligand. Therefore, in the asymmetric Cu-cata-
lyzed aziridination of the enol acetate 1aδ, the (R)-config-
ured α-amino ketone (R)-2a should be formed preferen- 5.2 Hz, J ϭ 15.4 Hz, 1 H), 5.76 (br. s, 1 H, NH), 6.96 (d, J ϭ
560 Eur. J. Org. Chem. 2000, 557Ϫ561

Catalytic Assymetric Aziridination of Enol Derivatives
8.4 Hz, 1 H), 7.03 (d, J ϭ 7.2 Hz, 1 H), 7.32 (d, J ϭ 7.9 Hz, 2 H), This work was supported by the Deutsche Forschungsgemeinschaft
FULL PAPER
7.50 (t, J ϭ 7.3 Hz, 1 H), 7.79 (t, J ϭ 6.2 Hz, 1 H), 7.81 (d, J ϭ
8.2 Hz, 2 H). – 13C NMR: δ ϭ 21.5, 54.8, 70.4, 118.0, 118.8, 121.9,
127.3, 127.5, 130.0, 135.1, 137.0, 144.2, 161.8, 188.6. – C16H15NO4S
(317.4): calcd. C 60.55, H 4.76, N 4.41, S 10.10; found C 60.46, H
4.70, N 4.35, S 9.95.
(Sonderforschungsbereich 347 “Selektive Reaktionen metallakti-
vierter Moleküle’’) and the Fonds der Chemischen Industrie. We
thank Prof. T. Patonay (Debrecen, Hungary) for generous gifts of
4-chromanone and 3-amino-4-chromanone hydrochloride.
[1]
Comprehensive Organic Chemistry, Vol. 5 (Exec. Eds.: D. Bar-
(Z)-3-Methyl-1-[(4-methylphenyl)sulfonyl]-2-phenyl-2-
aziridinol Acetate (4): To a solution of 176 mg (1.00 mmol) of enol
acetate 1aδ and 336 mg (900 µmol) of (N-tosylimino)iodobenzene
in 7 mL of MeCN at 0 °C was added a solution of 29.8 mg
(80.0 mmol) of [Cu(MeCN)4]PF6 in 3 mL of acetonitrile and the
mixture was stirred for ca. 2 h. It was then passed through a short
column of neutral Al2O3 (ca. 15 g) and eluted with 200 mL of
EtOAc. After removal of the solvent (30 °C, 10 mbar), purification
of the crude product by flash chromatography (PE/EtOAc, 8:1, ϩ
1% NEt3) yielded 234 mg (75%) of 4 as a colorless powder; m.p.
103–104 °C. – IR (KBr): ν˜ ϭ 3056 cm–1 (CH), 2979 (CH), 1753
(CϭO), 1679, 1595, 1451, 1334, 1209, 1160, 1089, 1001, 956, 816. –
1H NMR: δ ϭ 1.33 (d, J ϭ 5.8 Hz, 3 H), 2.03 (s, 3 H), 2.42 (s, 3
H), 3.79 (q, J ϭ 5.8 Hz, 1 H), 7.22–7.39 (m, 5 H), 7.53 (d, J ϭ
7.8 Hz, 2 H), 7.60 (d, J ϭ 8.3 Hz, 2 H). – 13C NMR: δ ϭ 12.6,
20.8, 21.5, 44.7, 79.1, 127.6, 127.9, 129.1, 129.4, 129.8, 131.5, 135.9,
144.3, 168.3. – C18H19NO4S (345.4): calcd. C 62.59, H 5.54, N 4.06,
S 9.28; found C 62.64, H 5.61, N 3.78, S 9.35.
ton, W. D. Ollis; Ed.: E. Haslam), Pergamon Press, Oxford,
1979, part 22, p. 21; part 23, p. 177; part 28, p. 867; part 30,
p. 1043.
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(S)-2-{[(4-Methylphenyl)sulfonyl]amino}propiophenone (2a): To a
solution of 893 mg (2.92 mmol) of (1R,2S)-[N-(4-methylphenyl)sul-
fonyl]norephedrine in 60 mL of acetone at 0 °C was added 0.95 mL
(2.09 mmol, 1.07 equiv.) of Jones’ reagent (2.2 ) and the reaction
mixture was stirred for 15 min. at room temp. After the addition
of 5 mL of ethanol, the mixture was diluted with 90 mL of distilled
water, extracted with ethyl ether (4 ϫ 50 mL), and the combined
extracts were dried over Na2SO4. After removal of the solvent (30
°C, 10 mbar), flash chromatography of the residue on silica gel
(hexane/EtOAc, 5:1) yielded 480 mg (54%) of a colorless powder
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1
P. Müller, C. Baud, Y. Jacquier, M. Moran, I. Nägeli, J.
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Phys. Org. Chem. 1996, 9, 341–347. –
P. Müller, C. Baud,
H), 4.94 (quint., J ϭ 7.4 Hz, 1 H), 5.92 (d, J ϭ 7.9 Hz, 1 H, NH),
7.14 (d, J ϭ 8.7 Hz, 2 H), 7.41 (t, J ϭ 7.5 Hz, 2 H), 7.56 (t, J ϭ
7.3 Hz, 1 H), 7.69 (d, J ϭ 8.3 Hz, 2 H), 7.73 (d, J ϭ 7.2 Hz, 2 H). –
13C NMR: δ ϭ 20.9, 21.3, 53.2, 126.9, 128.4, 128.7, 129.5, 133.2,
134.0, 137.0, 143.4, 198.0. – [α]2D0 ϭ ϩ62.6 (CHCl3, c ϭ 1.00).
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(2b): To
a solution of 763 mg (2.50 mmol) of (S)-α-{[(4-
[12]
methylphenyl)sulfonyl]amino}benzeneacetic acid and 1.17 mL
(7.75 mmol) of TMEDA in 12.5 mL of THF at –78 °C was added
6.20 mL (7.75 mmol) of MeLi in Et2O (1.25 ). After stirring for
1 h at –78 °C, the reaction mixture was allowed to warm to room
temp. and stirred for a further 2 h. It was then cooled by means of
an ice-bath and poured into 75 mL of ice-cold 2  H3PO4 solution.
The resulting mixture was extracted with EtOAc (3 ϫ 20 mL), the
combined organic layers were washed with aq. NaHCO3 solution
(3 ϫ 20 mL) and brine (2 ϫ 20 mL), and dried over Na2SO4. Re-
moval of the solvent (30 °C, 10 mbar) and subsequent flash chro-
matography of the residue on silica gel (hexane/EtOAc, 4:1) yielded
75.0 mg (10%) of 2b as a colorless powder (ee 96%); m.p. 139–140
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[13b]
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[16]
[17]
[18]
1
°C (ref.[18] 142 °C). – H NMR: δ ϭ 1.91 (s, 3 H), 2.26 (s, 3 H),
4.94 (d, J ϭ 5.0 Hz, 1 H), 5.98 (d, J ϭ 4.9 Hz, 1 H, NH), 6.99–
7.41 (m, 9 H). – 13C NMR: δ ϭ 21.1, 26.2, 66.3, 127.2, 128.4, 129.0,
135.4, 137.6, 143.6, 202.6. – [α]2D0 ϭ ϩ258.4 (CHCl3, c ϭ 1.00).
M. Regitz, Chem. Rev. 1965, 98, 1210–1224.
Received July 20, 1999
Acknowledgments
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561