Palladium-based kinetic resolution of racemic tosylaziridines

Article abstract of DOI:10.1055/s-2002-34221

Dicationic Pd(II) complexes with chiral pyridine bis(oxazoline) ligands are catalysts for kinetic resolution of racemic styrene tosylazirdines, Treatment of styrene tosylaziridine with 0.5 equivalents of alcohol in the presence of the chiral Pd catalyst a

Full text of DOI:10.1055/s-2002-34221

1688
LETTER
Palladium-based Kinetic Resolution of Racemic Tosylaziridines
P
alladium-base
d
K
inetic
a
R
esolution-Hung Leung,*a Wing-Leung Mak,a Eddie Y. Y. Chan,a Tony C. H. Lam,a Wing-Sze Lee,b Hoi-Lun Kwong,b
Lam-Lung Yeung*a
a
Department of Chemistry and Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and
Synthesis, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
E-mail: chleung@ust.hk; E-mail: chyeungl@ust.hk
b
Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
Fax +852(2358)1594
Received 23 August 2002
Treatment of racemic substituted styrene tosylaziridine
(X-STA) with 0.5 equivalents of alcohol in the presence
of 10 mol% of S-1 at 0 °C resulted in isolation of 2-alkoxy
tosylamide 4 in 22–41% yield along with the minor prod-
uct 2-hydroxy tosylamide 5 (Table 1).11 The formation of
4 with high regioselectivity is in contrast with the
Co(salen)-catalyzed alcoholysis of styrene oxide, in
which a mixture of regioisomeric products were pro-
duced.5 Thus, methanolysis of STA with S-1 led to isola-
tion of 4 (34% yield, 46% ee) and 5 (8% yield, 26% ee),
and recovery of STA (58% yield, 50% ee) (entry 1). Sim-
ilar yields and ee’s were obtained for the reaction with the
Phpybox complex S-2. When 0.8 equiv of MeOH was
used, STA was recovered in lower yield (34%) but higher
ee (76%) (entry 2). Aliphatic aziridines such as cyclohex-
ene aziridine did not react under these conditions. It seems
likely that the hydroxy group in 5 was derived from the
moisture of solvent and substrate rather than the aquo
ligand in S-1 because similar amounts of 5 were obtained
when different loadings of S-1 were used. An attempt
to eliminate 5 by addition of molecular sieves (4 Å) to the
reaction mixture was unsuccessful. The Pd catalyst ap-
peared to be deactivated by molecular sieves and no alco-
holysis was observed. Methanolysis with non-aqua
complexes such as [Pd(S-Prpybox)(MeCN)]2+ and
[Pd(Prpybox)(CF3SO3)2] was found to be less stereo-
selective (ee of 4 < 20%) than that with 1. Other [M(S-
Rpybox)]2+ complexes (e.g. M = Cu, Pt) are not active in
aziridine ring opening.
Abstract: Dicationic Pd(II) complexes with chiral pyridine bis(ox-
azoline) ligands are catalysts for kinetic resolution of racemic sty-
rene tosylazirdines. Treatment of styrene tosylaziridine with 0.5
equivalents of alcohol in the presence of the chiral Pd catalyst af-
fords -alkoxy tosylamide with ee up to 71%.
Key words: palladium, kinetic resolution, aziridine, asymmetric,
alcoholysis
Aziridines are versatile building blocks for nitrogen-con-
taining compounds.1 Of synthetic significance is nucleo-
philic ring opening of aziridines by alcohols to give -
alkoxy amides.2 Recently, Jacobsen and coworkers dem-
onstrated that Co(salen) complexes can catalyze highly
enantioselective ring opening of epoxides by water and al-
cohols.3 Significantly, the Co(salen)-based ring opening
reactions have been successfully used for kinetic resolu-
tion of racemic terminal epoxides with excellent stereose-
lectivity and efficiency.4,5 This prompted us to investigate
into a similar approach to kinetic resolution of racemic
aziridines via their enantioselective alcoholysis. Although
metal-catalyzed asymmetric cleavage of aziridines by thi-
ols,6 azide7 and Grignard reagents8 has been well devel-
oped, there are no reports on catalytic asymmetric
alcoholysis of aziridines. We are particularly interested in
Pd-based alcoholysis due to the recent findings that Pd(II)
complexes are capable of catalyzing C–O bond forming
reactions,9 apparently via Pd alkoxide intermediates. We
herein report on our preliminary results of kinetic resolu-
tion racemic tosylaziridines with chiral dicationic Pd(II)
complexes [Pd(S-Rpybox)(H2O)][BF4]2 (S-Rpybox = 2,6-
bis[(4S)-(+)-alkyl-2-oxazolin-2-yl]pyridine)10 (Figure 1).
Using water as nucleophile, ring opening of STA afforded
5 as the sole product in 16% ee (entry 5). It appears that
the stereoselectivity for aziridine alcoholysis increases as
the steric demand of alcohol increases. For example, the
krel value12 increases from ca. 3.4 for MeOH to 7.7 for
i-PrOH. However, the reaction was very slow when either
t-BuOH or [Pd(S-Bupybox)(H2O)][BF4]2 was used. Simi-
lar to the acid-catalyzed alcoholysis of styrene oxides,13
the substituent X on the phenyl ring has a profound influ-
ence on both the rate and selectivity of the alcoholysis of
X-STA. Thus, methanolysis of electron-rich 4-MeSTA
was fast and non-selective (entry 8) whereas that of 4-
ClSTA was slower but more selective (krel 7.2) (entry
10). The rate of alcoholysis was found to decrease in the
order 4-FSTA > STA > 3-FSTA > 4-CF3STA, indicating
that the reactive intermediate may carry partial positive
[BF4]2
O
O
R = i-Pr 1
= Ph
= t-Bu 3
N
2
N
Pd
N
H2O
R
R
[Pd(S-Rpybox)(H2O)][BF4]2
Figure 1
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1688,1690,ftx,en;D10502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Palladium-based Kinetic Resolution of Racemic Tosylaziridines
1689
Table 1 Pd-Catalyzed Asymmetric Alcoholysis of Styrene Tosylaziridinesa
Ts
Ts
ROH
10 mol% Pd cat.
HO
NHTs
N
N
RO
NHTs
2
+
+
CH2Cl2, 0 o
C
X
X
X
X
5
4
X-STA
(±)
Entry
X
ROH
Catalyst
Time/ h
% Yieldb (% eec)
d
Recovered X-STA 4 [krel
]
5
1
2
H
MeOH
S-1
S-1
S-2
R-1
S-1
S-1
S-1
S-1
S-1
S-1
S-1g
S-1
S-1
S-1
3
5
5
5
5
2
2
1
1
3
3
2
5
5
58 (50, S)
34 (76, S)
49 (33, S)
52 (33, R)
56 (27, S)
48 (47, S)
63 (35, S)
43 (0)
34 (46, S) [3.4]
57 (31, S) [2.7]
41 (43, S) [3.3]
34 (42, R) [3.0]
–
8 (26, S)
9 (17, S)
H
MeOHe
MeOH
MeOH
H2O
3
H
10 (33, S)
13 (8, R)
41 (16, S)
11 (13, S)
9 (36, S)
10 (0)
4
H
5
H
6
H
EtOH
39 (55, S) [4.8]
28 (71, S) [7.7]
33 (0) [1]
7
H
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
8f
9
4-Me
4-F
4-Cl
4-Cl
4-Br
4-CF3
3-F
58 (30, S)
69 (29, S)
51 (14, S)
62 (48, S)
95 (3, S)
90 (7, S)
31 (43, S) [3.0]
22 (71, S) [7.2]
43 (66, S) [7.9]
29 (69, S) [7.2]
5 (N.D.h)
10 (19, S)
5 (32, S)
6 (25, S)
4 (2, S)
10
11
12
13
14
N.D.
9 (58, S) [4.0]
N.D.
a Aziridine (0.27 mmol), Pd catalyst (0.027 mmol) and ROH (0.14 mmol) in CH2Cl2 (1 mL) at 0 °C.
b Isolated yield (based on starting aziridine).
c Determined by chiral HPLC analysis using a (S,S) WHELK-O column. Absolute configuration determined by optical rotation.
d See ref.12
e 0.8 equiv of MeOH used.
f Run at –10 °C.
g 20 mol% catalyst used.
h Not determined.
charge at the benzylic position, which also accounts for lieve that the first step of the catalytic cycle involves the
the observed C2-selectivity for the aziridine ring opening. binding of STA to Pd and ring opening of aziridine to give
Furthermore, given the stereoselectivitiy of the alcoholy- a Pd-bound cationic intermediate 7 that possibly has a
sis it is reasonable to assume that the intermediate is a Pd- metallacycle-like structure with substantial Pd-C2 inter-
bound cationic species (vide infra) instead of free benzylic action (Scheme 1). A similar metallacycle intermediate
carbocation. Recently, -aryl amides were prepared by the has previously been proposed for Rh-catalyzed carbony-
reaction of tosylaziridines with electron-rich arenes in the lation of aziridines.16 Concerted nucleophilic attack at C2
presence of In(OTf)3,14 which presumably also involves by alcohol gives the 2-alkoxy ring-opening product with
similar cationic intermediates. Non-labile [Pd(S-Prpy- inversion of configuration.
box)Cl][BF4] is not an active catalyst, suggesting that a
vacant coordination site on Pd for binding to aziridine or
alcohol is an important step for the catalysis. However, we
rule out the possibility of nucleophilic attack on aziridine
by Pd(II) alkoxide because no reaction was found between
S-1 and ROH in the absence of STA under the experimen-
tal conditions, although refluxing S-1 in MeOH yielded a
Pd(I) dimer [Pd2(S-Prpybox)2][BF4]2 6,15 presumably via
reductive elimination of a Pd–OMe intermediate. We be-
Proposed mechanism
Ts
Pd NTs
RO
Ph
NHTs
N
Pd2+
ROH
2
1
- Pd2+
Ph
Ph
7
Pd = [Pd(Rpybox)]
Scheme 1
Synlett 2002, No. 10, 1688–1690 ISSN 0936-5214 © Thieme Stuttgart · New York

1690
W.-H. Leung et al.
LETTER
A preliminary kinetic study17 showed that the Pd-catal-
yzed alcoholysis is first order in the Pd catalyst and zero
order in alcohol, suggesting that the rate-determining step
is Pd-mediated ring opening of aziridine instead of nu-
cleophilic attack by alcohol. This is in contrast with the
Jacobsen’s Cr(salen)-catalyzed ring opening of epoxides,
which is second order in the Cr catalyst.3
(6) Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. J. Chem. Soc.,
Chem. Commun. 1994, 2699.
(7) Li, Z.; Fernández, H.; Jacobsen, E. N. Org. Lett. 1999, 1,
1611.
(8) Muller, P.; Nury, P. Org. Lett. 1999, 1, 439.
(9) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 3395. (b) Hartwig, J. F. Acc. Chem. Res.
1998, 31, 852.
(10) Asymmetric aldol reaction of methyl isocyanate with
benzaldehyde catalysed by [Pd(S-Prpybox)(MeCN)][BF4]2
has been reported: Nesper, R.; Pregosin, P. S.; Puentener, K.;
Woerle, M. Helv. Chim. Acta 1993, 76, 2239.
In summary, we have developed a new method for kinetic
resolution of racemic styrene tosylaziridines based on
chiral Pd catalysts. To our knowledge, this is the first
report on Pd-catalyzed ring opening of aziridines. This re-
action has potential applications to the synthesis of chiral
-alkoxy amides. Efforts are being made to improve the
stereoselectivity factor for the kinetic resolution by tuning
the metal and/or ligand of catalyst.
(11) Typical procedure for Pd-catalyzed alcoholysis of styrene
tosylaziridine: To a mixture of aziridine (50 mg, 0.18 mmol)
and S-1 (12 mg, 0.018 mmol) in CH2Cl2 (1 mL) was added
dried MeOH (4 L, 0.09 mmol) under nitrogen at 0 °C. The
mixture was stirred at that temperature for 1–5 h and purified
by flash chromatography (silica gel, 50% ether–hexane).
Spectroscopic data for PhCH(OMe)CH2NHTs: 1H NMR
(400 MHz, acetone-d6): 7.90 (d, J = 8.0 Hz, 2 H), 7.53 (d,
J = 8.0 Hz, 2 H), 7.45 (m, 5 H), 6.65 (s, br, 1 H), 4.35 (dd,
J = 8.8, 4.4 Hz, 1 H), 3.20 (m, 2 H), 3.25 (s, 3 H), 2.56 (s,
3 H); 13C NMR (100 MHz, acetone-d6): 143.5, 140.0,
139.0, 130.1, 129.1, 128.7, 127.6, 127.3, 83.0, 56.8, 50.2,
21.3; MS (+CI) m/z (relative intensity): 306 (M + H+, 18),
274 (M – OMe+, 100). Anal. Calc. for C16H19NOS3 (305.39):
C, 62.93; H, 6.27; N, 4.59. Found: C, 62.91; H, 6.35; N, 4.54.
(12) The krel values were calculated using the equation krel = ln[1
– c(1+ee)]/ln[1 – c(1 – ee)] where ee and c are the
enantiomeric excess and conversion of the product,
respectively. See for example: Eliel, E. L.; Wilen, S. H.;
Mander, L. M. Stereochemistry of Organic Compounds;
Wiley: New York, 1994, 395.
Acknowledgement
This work has been supported by the Hong Kong Research Grants
Council (project no.: HKUST6125/01P), the Hong Kong University
of Science and Technology, and the Areas of Excellence Scheme
established under the University Grants Committee of the Hong
Kong Special Administrative Region, China (project no.: AoE-P-
10/01-1).
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Synlett 2002, No. 10, 1688–1690 ISSN 0936-5214 © Thieme Stuttgart · New York