C2-symmetric bissulfoximines in palladium-catalyzed allylic alkylations

Article abstract of DOI:10.1055/s-2001-18756

C₂-Symmetric bissulfoximines 2 have been used as chiral ligands in palladium-catalyzed asymmetric allylic alkylations. With 2c enantioselectivities of up to 98% ee have been achieved in the reaction of 1,3-diphenylpropenyl acetate with malonates as nucleophiles.

Full text of DOI:10.1055/s-2001-18756

1878
LETTER
C2-Symmetric Bissulfoximines in Palladium-catalyzed Allylic Alkylations
C
-symmetric Bis
a
sulfoximin
r
es sten Bolm,* Oliver Simi , Marc Martin
2
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Str. 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.RWTH-Aachen.de
Received 29 July 2001
Table 1 Synthesis of Ethylene-bridged Bissulfoximines 2a–d via
an Acylation Reduction Sequence
Abstract: C2-Symmetric bissulfoximines 2 have been used as
chiral ligands in palladium-catalyzed asymmetric allylic alkyla-
tions. With 2c enantioselectivities of up to 98% ee have been
achieved in the reaction of 1,3-diphenylpropenyl acetate with mal-
onates as nucleophiles.
O
O
O
O
O
a)
b)
NH
S
2
R2
S
N
N
S
R2
R1
R1
R1
Key words: asymmetric catalysis, allylic alkylation, enantioselec-
tivity, palladium, sulfoximines
R2
4
3
a) (COCl)2 (0.5 equiv), DMAP (cat.), CH2Cl2, 0 °C. b) BH3•THF, CH2Cl2.
Entry R1
R2
Yields of Yields of Bissulfox-
4 [%] 4 2 [%] imine
Since their discovery by Bentley and Whitehead,1 sulfox-
imines have emerged as versatile reagents in organic syn-
thesis.2 Their application ranges from the use as chiral
auxiliaries3 and ligands4 in catalysis to incorporations as
modules in pseudopeptidic structures.5 Recently, we in-
troduced a new aryl-bridged C2-symmetric bissulfox-
imine 1 and demonstrated its potential as ligand in highly
enantioselective copper(II)-catalyzed hetero Diels–Alder
reactions.6 As part of the ongoing study we now found that
structurally related bissulfoximines 2 having an alkyl
backbone can be applied in palladium-catalyzed allylic
alkylations7 furnishing products with very high enantio-
meric excesses (Figure 1).
3
1
2
3
4
Me
Ph
Ph
Ph
Me
90
88
85
93
68
66
65
69
2a
2b
2c
2d
i-Pr
c-Pen
2-MeO-Ph
The best results (93% ee at 0 °C) were obtained with bis-
sulfoximine 2c having a cyclopentyl group as aliphatic
substituent at sulfur (entries 3 and 7). Using the S,S-enan-
tiomer of 2c led to R-configurated 7 predominately. Low-
ering the reaction temperature had a positive effect on the
ee of 7. To our surprise use of 2d gave 7 only with 8% ee.
This result was unexpected, because in the previously
studied HDA reaction, catalyses with 2d gave products
with > 90% ee. Along with the low ee in the reaction with
2d a remarkable high reactivity was observed. Thus in this
case the conversion was complete after 2 hours, whereas
in catalyses with 2a–c reaction times of several days were
required to afford 7 in high yield. Raising the reaction
temperature to 50 °C effected an increase in yield at sig-
nificantly shorter reaction times, but lowered the ee of 7
(entries 8 and 9).
O
O
O
O
S
N
N S
R2
R1
S
N
N S
Ph
Me
R1
R2
Me
Ph
1
2
Figure 1
The syntheses of the new alkyl-bridged C2-symmetric bis-
sulfoximines 2 followed a synthetic strategy described
earlier.8 Thus, treatment of the corresponding sulfoximine
39 with oxalyl chloride followed by borane reduction of
the carbonyl groups of the resulting bridged compounds 4
gave the desired bissulfoximines 2 in good yields
(Table 1).
With the notion that an increased steric bulk at the sulfur
atoms of 2 would be beneficial for the enantioselectivity
of the catalysis, we attempted to prepare bis(tert-butyl)-
substituted bissulfoximine 2e according to the synthetic
strategy described above (coupling of two sulfoximines
with oxalyl chloride followed by borane reduction).
Whereas the first step starting from (S)-S-tert-butyl-S-
phenyl sulfoximine (3e)9 proceeded well to give 4e, the
subsequent selective reduction of the two carbonyl groups
failed. Instead of the desired bissulfoximine 2e compound
8 was obtained in 60% yield.12,13 Finally, 2e became ac-
cessable on another route involving a double deprotona-
tion of 2b followed by alkylation of the intermediate
dianion with iodomethane (50% yield) (Figure 2).
The potential of the new bissulfoximines to serve as
ligands in Pd-catalyzed nucleophilic substitution reac-
tions was first investigated with 1,3-diphenylpropenyl
acetate (5) and dimethylmalonate (6) as substrates. In all
catalyses the yield of 7 was good ( 72%) and the enantio-
selectivities ranged from 8 to 93% ee (Table 2).10,11
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1878,1880,ftx,en;G16601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
C2-Symmetric Bissulfoximines in Allylic Alkylations
1879
Table 2 Enantioselective allylic Alkylation of 1,3-Diphenylprope-
nyl Acetate using Bissulfoximines 2a–da
Table 3 Use of substituted Malonates in the enantioselective allylic
Alkylation of 1,3-Diphenylpropenyl Acetate (5)
OAc
Ph
(R'O2C)2CR
H
(MeO2C)2C
OAc
Ph
[Pd(allyl)Cl]2 (5 mol%)
[Pd(allyl)Cl]2, ligand,
10 mol% 2c, cat. KOAc
CH2(CO2Me)2 (6),
Ph
Ph Ph
Ph
Ph
Ph
5
10
KOAc, BSA, CH2Cl2
nucleophile, BSA, CH2Cl2
7
5
a: R = R' = Me
b: R = NHAc, R' = Et
Entry
Ligand
Yield
[%]
Temp
[°C]
Time
ee of 7
[%]
Entry Nucleophile
Yield
[%]
Temp
[°C]
Time
[h]
ee of 10
[%]
1
2a
2b
2c
2d
2a
2b
2c
2c
2c
73
78
78
99
70
72
75
99
99
r.t.
r.t.
r.t.
r.t.
0
5 d
5 d
72
76
90
8
2
1
2
MeCH(CO2Me)2,
(9a)
79
45
30
94a
98b
3
5 d
AcNHCH(CO2Et)2, 89
45
96
4
2 h
(9b)
a Determined by 1H NMR using 15 mol% Eu(hfc)3.
5
11 d
11 d
11 d
1.5 h
2 h
76
81
93
84
82
b Determined by HPLC using a chiral column (Chiralcel OJ;
6
0
heptane:i-PrOH = 3:1).
7
0
To our delight we found that with methyl malonic acid
dimethylester (9a) the corresponding substitution product
(S)-10a had 94% ee. Use of the acetamido derivative 9b
afforded (S)-10b with 98% ee.14,15
8c
9d
+50
+50
a Conditions: [Pd(allyl)Cl]2 (5 mol%), ligand (10 mol%), 3 equiv
BSA, 3 equiv malonate, cat. KOAc.
In summary, we demonstrated the use of C2-symmetric
bissulfoximines as ligands in the palladium-catalyzed
asymmetric alkylations and achieved enantioselectivities
of up to 98% ee.
b Determined by HPLC using a chiral column (Chiralcel AD;
heptane:i-PrOH = 95:5).
c 7.5 mol% of [Pd(allyl)Cl]2.
d 5 mol% of 2c and 2.5 mol% of [Pd(allyl)Cl]2 was used.
Acknowledgement
O
N
O
N
O
O
O
O
We are grateful to the Fonds der Chemischen Industrie and DFG
(SFB 380) for financial support. M.M. thanks DFG (Graduierten-
kolleg 440) for a predoctoral fellowship. C. Böing is acknowledged
for experimental contributions.
BH3•THF, CH2Cl2
S
NH HN S
S
S
tBu
Ph
Ph
Ph
Ph
tBu
Ph
8
4e
n-BuLi (2 equiv),
THF, 0 °C, 30 min;
then MeI (2 equiv)
O
S
O
S
O
O
References
N
N
S
N
N S
tBu
iPr
Ph
(1) Whitehead, J. K.; Bentley, H. R. J. Chem. Soc. 1952, 1572.
(2) Reviews: (a) Johnson, C. R. Aldrichimica Acta 1985, 18, 3.
(b) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341. (c) Pyne,
S. G. Sulfur Rep. 1992, 12, 57. (d) Reggelin, M.; Zur, C.
Synthesis 2000, 1.
iPr
tBu
Ph
Ph
2b
2e
Figure 2
(3) Selected examples: (a) Pyne, S. G.; Dong, Z.; Skelton, B.
W.; White, A. W. J. Org. Chem. 1997, 62, 2337.
Contrary to our expectations, use of 2e as ligand in the de-
scribed allylic alkylation with 5 and 6 did not improve the
catalysis at all. Thus, even after one week reaction time
only 15% conversion of 5 was observed and finally 7 was
isolated as a racemate. Most likely, the attack of the inter-
mediate Pd-allyl complex by the nucleophile is sterically
too hindered due to the presence of the bulky tert-butyl
groups in 2e, which in consequence causes the low con-
version compared to the catalyses with the other bissul-
foximines.
(b) Reggelin, M.; Heinrich, T.; Angew. Chem. Int. Ed. 1998,
37, 2883; Angew. Chem. 1998, 110, 3005. (c) Bosshammer,
S.; Gais, H.-J. Synthesis 1998, 919. (d) Paquette, L. A.; Gao,
Z.; Ni, Z.; Smith, G. F. J. Am. Chem. Soc. 1998, 120, 2543.
(e) Harmata, M.; Kahraman, M.; Jones, D. E.; Pavri, N.;
Weatherwax, S. E. Tetrahedron 1998, 54, 9995.
(4) (a) Bolm, C.; Felder, M.; Müller, J. Synlett 1992, 439.
(b) Bolm, C.; Felder, M. Tetrahedron Lett. 1993, 34, 6041.
(c) Bolm, C.; Müller, J.; Schlingloff, G.; Zehnder, M.;
Neuburger, M. J. Chem. Soc., Chem. Commun. 1993, 182.
(d) Bolm, C.; Seger, A.; Felder, M. Tetrahedron Lett. 1993,
34, 8079. (e) Bolm, C.; Felder, M. Synlett 1994, 655.
(f) Bolm, C.; Müller, P. Tetrahedron Lett. 1995, 36, 1625.
(g) Bolm, C.; Müller, P. Acta Chem. Scand. 1996, 50, 305.
(5) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett.
1997, 38, 1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D.
Chem.– Eur. J. 2001, 7, 1118.
Since bissulfoximine 2c gave the best results in the catal-
ysis, we also studied its use in the reaction of 1,3-diphe-
nylpropenyl acetate (5) with other malonates. Table 3
summarizes the most significant results.
(6) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830.
Synlett 2001, No. 12, 1878–1880 ISSN 0936-5214 © Thieme Stuttgart · New York

1880
C. Bolm et al.
LETTER
(7) Reviews: (a) Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993, 325. (b) Trost, B.
M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(c) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999, 833. (d) Helmchen, G. J.
to 0 °C bistrimethylsilylamide (BSA) (165 L, 137 mg, 0.68
mmol), dimethylmalonate (77 L, 89 mg, 0.68 mmol) and a
catalytic amount of potassium acetate were added and the
reaction monitored by TLC. After consumption of the
starting material (Table 2, entry 7) the product was directly
purified by column chromatography, (silica, petroleum
ether–Et2O, 3:1, Rf = 0.35) furnishing 7 (56 mg, 0.17 mmol,
75%) as a colorless solid.
Organomet. Chem. 1999, 576, 203. (e) Trost, M. B.; Lee, C.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000.
(11) For the use of a C1-symmetric sulfoximine-containing ligand
in this reaction, see: Bolm, C.; Kaufmann, D.; Zehnder, M.;
Neuburger, M. Tetrahedron Lett. 1996, 37, 3985.
(12) Similar compounds have recently been used in asymmetric
Cu-catalyzed [4+2] cycloadditions: Owens, T. D.;
Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 1539.
(13) The absolute configuration of 8 has not been determined, but
we assume that the reduction of 4e proceeds with retention
of configuration at sulfur as shown.
(14) For the assignment of the absolute configurations of 10a and
10b, see: (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1993, 32, 566; Angew. Chem.; 1993, 105: 614.
(b) Vysko il, .; Smr ina, M.; Hanu , V.; Polá ek, M.;
Ko ovsk , P. J. Org. Chem. 1998, 63, 7738.
(15) Attempts to employ cyclohexenyl acetate as substrate
(together with 6) resulted in the formation of corresponding
product with only 20% ee.
(8) Bolm, C.; Bienewald, F.; Harms, K. Synlett 1996, 775.
(9) Both enantiomers of S-methyl-S-phenyl-sulfoximine (3a)
are commercially available (Lancaster). To prepare 3a in
enantiopure form on a large scale, we recommend the
improved protocol described in: Brandt, J.; Gais, H.-J.
Tetrahedron: Asymmetry 1997, 6, 909. Sulfoximines 3b, 3c,
and 3e were prepared from TMS-protected (S)-S-methyl-S-
phenyl-sulfoximine via a metalation/alkylation sequence.
The synthesis of 3d followed the procedure described in
ref.4g (MSH imination of the corresponding enantiopure
sulfoxide).
(10) In a typical experiment [Pd(C3H5)Cl]2 (4.0 mg, 0.011 mmol)
and 2c (10.0 mg, 0.023 mmol) were dissolved in 2 mL of
CH2Cl2 under an argon atmosphere and the resulting pale
yellow solution was stirred for 30 min at r.t. To this solution
was added 1,3-diphenylpropenyl acetate (57 mg, 0.23 mmol)
and stirring was continued for further 10 min. After cooling
Synlett 2001, No. 12, 1878–1880 ISSN 0936-5214 © Thieme Stuttgart · New York