A new, chiral bis-benzothiazine ligand

Article abstract of DOI:10.1021/ol016546n

Equation presented The synthesis and application of a new, chiral bis-benzothiazine ligand are described.

Full text of DOI:10.1021/ol016546n

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3321-3323
A New, Chiral Bis-Benzothiazine Ligand
Michael Harmata* and Sunil K. Ghosh
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211
harmatam@missouri.edu
Received August 8, 2001
ABSTRACT
The synthesis and application of a new, chiral bis-benzothiazine ligand are described.
The development of new chiral ligands for transition metal-
catalyzed organic reactions is at the forefront of research in
synthetic organic chemistry.1 Such studies have not only
potentially very important practical ramifications but also
provide for new insights into the chemistry of metals and
their interactions with organic substrates.
modialdehydes. We thus set out to synthesize a bis-
benzothiazine that could serve as a ligand.
Among the various classes of donor ligands that have been
introduced are those bearing two N atoms,2 some of which
have had a major impact on catalytic asymmetric synthesis.3
A subset of this class of ligands are the bis-sulfoximines,
and they are the subject of this paper. The utility of
sulfoximine-based ligands is only currently being realized.4
We recently reported that the reaction of sulfoximine 1
with 2-bromobenzaldehyde 2 under conditions reported by
Bolm for C-N bond formation (Buchwald-Hartwig reac-
tion) afforded the benzothiazine 3 in good yield (Scheme
1).5,6 In this reaction, both carbon-nitrogen and carbon-
carbon bond formation occurred in a single operation. We
anticipated that more complex structures could be prepared
by this method and demonstrated that bis-benzothiazines 4
and 5 could be synthesized from the corresponding dibro-
At the time we began our work, the synthesis of bis-
sulfoximines using the Buchwald-Hartwig approach was not
known. Recently, however, Bolm and co-workers reported
that 1,2-dibromobenzene afforded the bis-sulfoximine 8 in
good yield using the Buchwald-Hartwig reaction (Scheme
2) and that 8 was an exceptional ligand in the copper-
catalyzed Diels-Alder reaction of ethyl glyoxalate and 1,3-
cyclohexadiene.7
Scheme 1
(1) Handy, S. T. Curr. Org. Chem. 2000, 4, 363-395.
(2) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33,
497-526.
(3) For example, see: Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1-45.
(4) For leading references, see: Reggelin, M.; Zur, C. Synthesis 2000,
1-64.
(5) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419-
21.
(6) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 37, 5731-34.
10.1021/ol016546n CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/15/2001

in Table 1. The reactions were conducted at reflux temper-
atures using 2.5 mol % of the palladium source, 10 mol %
ligand, 3 equiv of BSA, and catalytic potassium acetate. The
first eight entries of Table 1 show that solvent effects are
important in the reaction. Relatively nonpolar solvents
afforded good yields and enantiomeric excesses while
reaction in dichloromethane and acetonitrile afforded only
racemic material in moderate yield. For the most part, it
appeared that the source of palladium was not significant,
except when a phosphine ligand was present that could
compete with the chiral ligand and thereby produce nearly
racemic product.
Scheme 2
With these results in hand, we prepared the ligand 8 and
evaluated its ability to serve as a ligand in these reactions.
Interestingly, only low yields and low enantiomeric excesses
were observed (Table 1, entries 15 and 16).13 A monodentate
ligand (3b) gave low yields of product with low ee (Table
1, entry 17).
Helmchen has suggested that the evaluation of ligands for
asymmetric allylation extend beyond the model system 11.14
We thus tested our ligand in the reaction of racemic
cyclohexenyl acetate with dimethyl malonate as shown in
Scheme 4.15 Using either enantiomer of 10, the product was
We prepared both enantiomers of bis-benzothiazine 10
using the procedure we reported earlier starting with the
dialdehyde 9 (Scheme 3).8,9 The choice of sulfoximine 6 was
Scheme 3
Scheme 4
based on its ready availability in enantiomerically pure
form.10
With both enantiomers of 10 in hand, we decided to
examine its utility as a ligand and chose to examine the
palladium-catalyzed asymmetric allylic alkylation reaction,
a standard in the evaluation of many new ligands.11,12
Treatment of racemic 1,3-diphenylallyl acetate with dimethyl
malonate in the presence of bistrimethylsilyl acetamide
(BSA) afforded alkylation product in good yield and with
reasonable enantiomeric excess. The results are summarized
obtained in only moderate yields with a moderate degree
(60% ee) of enantioselectivity (Scheme 4).
In summary, we have shown that the bis-benzothiazine
10 is an effective ligand in asymmetric allylic alkylation
reactions. The modular approach used in the synthesis of
(11) For leading references, see: Trost, B. M.; Lee, C. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
Chapter 8E.
(7) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830-31.
(8) The dialdehyde 9 was prepared by oxidation of the corresponding
p-xylene, a known compound. See: Gronowitz, S.; Hansen, G. Ark. Kemi
1967, 27, 145-151.
(12) General Procedure for the Palladium-Catalyzed Allylic Substitu-
tion of rac-1,3-Diphenyl-2-propenyl Acetate with Dimethyl Malonate.
A solution of ligand (0.02 mmol, 10 mol %) and Pd compound (2.5 mol
%) in dry solvent (2 mL) was stirred at room temperature for 1 h. This
solution was treated successively with a solution of rac-1,3-diphenyl-2-
propenyl acetate (0.2 mmol), dimethyl malonate (0.6 mmol), N,O-bis-
(trimethylsilyl)acetamide (0.6 mmol), and a catalytic amount of anhydrous
potassium acetate. The reaction mixture was refluxed for a given time (see
Table 1). The reaction mixture was cooled to room temperature, diluted
with diethyl ether (10 mL), and washed with saturated aqueous ammonium
chloride. The organic phase was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexanes/ether ) 4/1) to give the product. The enantiomeric excess was
determined by 1H NMR spectroscopy in the presence of the enantiomerically
pure shift reagent Eu(hfc)3. Splitting of the signals for one of the two
methoxy groups was observed.
(9) Preparation of (R,R)-10 and (S,S)-10. A dry 100 mL flask equipped
with a magnetic stirring bar and a reflux condenser was charged with Pd2-
dba3 (75 mg, 0.08 mmol, 10 mol %), rac-BINAP (76 mg, 0.12 mmol, 15
mol %), and toluene (40 mL). Dialdehyde 9 (240 mg, 0.82 mmol) was
added, followed by the (R)-6 (635 mg, 4.10 mmol, 5 equiv) and cesium
carbonate (800 mg, 2.46 mmol, 3 equiv). The mixture was then heated in
an oil bath at 110 °C for 48 h. After being cooled to ambient temperature,
the solution was diluted with dichloromethane, filtered through a pad of
Celite, and concentrated in vacuo to give a brown oil. Purification of the
product by flash chromatography afforded (R,R)-10 as an orange solid (230
mg, 68%). Mp: 277-286 °C. 1H NMR (250 MHz, CDCl3): δ 7.92-7.89
(m, 4 H), 7.66 (d, J ) 9.7 Hz, 2 H), 7.60-7.47 (m, 6H), 7.02 (s, 2H), 6.41
(d, J ) 9.7 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): δ 141.7, 139.8, 138.0,
133.1, 129.4, 128.7, 120.7, 117.3, 110.4. Anal. Calcd for C22H16N2O2S2:
(13) At room temperature, neither 8 nor 10 was an effective ligand for
the allylic alkylation reaction. Little progress was noted in the conversion
of 11 to 13 even after 13 days (TLC). The reaction using 8 was also not
productive at elevated temperatures in toluene, benzene and dichlo-
romethane.
C, 65.32; H, 3.99; N, 6.92. Found: C, 65.57; H, 4.22; N, 6.82. [R]589
:
-1316.1 (c ) 1.13, CHCl3). Data for (S,S,)-10. Same procedure as above.
Anal. Calcd for C22H16N2O2S2: C, 65.32; H, 3.99; N, 6.92. Found: C,
65.45; H, 4.04; N, 6.74. [R]589: +1316.6 (c ) 1.05, CHCl3).
(10) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909-912.
(14) Helmchen, G. J. Organomet. Chem. 1999, 576, 203-214.
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Org. Lett., Vol. 3, No. 21, 2001

Table 1. Reaction of Racemic 1,3-Diphenylallyl Acetate with Dimethyl Malonate in the Presence of Chiral Ligands under Various
Conditions
timea
(h)
yieldb
(%)
eec
entry
ligand
Pd source
solvent
(%)
configd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(R,R)-10
(S,S)-10
(R,R)-10
(S,S)-10
(R,R)-10
(S,S)-10
(R,R)-10
(R,R)-10
(R,R)-10
(S,S)-10
(S,S)-10
(R,R)-10
(S,S)-10
(R,R)-10
(S,S)-8
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd2dba3
Pd2dba3
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
THF
THF
5
3.5
3
80
90
90
85
85
70
30
45
75
69
67
68
90
79
31
30
15
80
80
82
82
78
78
0
S
R
S
R
S
R
e
benzene
benzene
toluene
toluene
CH2Cl2
CH3CN
THF
THF
THF
THF
THF
3
3.5
3.5
4
5
0
e
3.5
3.5
7.5
7.5
5
5
5
4
6
86
86
73
73
16
6
0
0
28
S
R
R
S
R
S
e
Pd(PPh3)4
[Pd(allyl)Cl]2
Pd2dba3
THF
THF
THF
THF
(S,S)-8
(R)-3b
e
R
[Pd(allyl)Cl]2
a All reactions were performed at reflux. b Isolated yield. c Determined by 1H NMR using Eu(hfc)3 as shift reagent. d The absolute configuration was
determined by comparing the specific rotation with the literature value. e Product was racemic.
our and Bolm’s ligand should make possible the high
throughput synthesis for the evaluation and optimization of
steric and electronic effects in ligands of this type. Future
studies on the application of 10 and related ligands in
asymmetric synthesis is in progress. Results will be reported
in due course.
Acknowledgment. This work was supported by the
Petroleum Research Fund, administered by the American
Chemical Society, to whom we are grateful. We thank the
National Science Foundation for partial support of the NMR
(PCM-8115599) facility at the University of Missouris
Columbia and for partial funding for the purchase of a 500
MHz spectrometer (CHE-89-08304). We thank Mr. Gary
Bohnert for his assistance.
(15) Procedure for the Palladium-Catalyzed Allylic Substitution of
rac-Cyclohexenyl Acetate with Dimethyl Malonate. A solution of 10 (14.4
mg, 0.035 mmol, 10 mol %) and [Pd(allyl)Cl]2 (3.26 mg, 0.008, 2.5 mol
%) in dry THF (2 mL) was stirred at room temperature for 1 h. This solution
was treated successively with a solution of rac-cyclohexenyl acetate (50
mg, 0.35 mmol), dimethyl malonate (125 µL, 1.07 mmol), N,O-bis-
(trimethylsilyl)acetamide (267 µL, 1.07 mmol), and a catalytic amount of
anhydrous potassium acetate. The reaction mixture was refluxed for 4 h.
The reaction mixture was cooled to room temperature, diluted with diethyl
ether (10 mL), and washed with saturated aqueous ammonium chloride.
The organic phase was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (hexanes/ether
) 4/1) to give the product. The enantiomeric excess was determined by 1H
NMR spectroscopy in the presence of enantiomerically pure shift reagent
Eu(hfc)3 by integration of the signals of the methine proton signal of the
malonate moiety.
Supporting Information Available: Procedure for the
synthesis of (R)-3b. Spectral data for 3b, 10, 13, and 15 as
well as examples of spectral and specific rotation data for
selected examples from Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016546N
Org. Lett., Vol. 3, No. 21, 2001
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