New chiral benzothiazine ligand and its use in the synthesis of a chiral receptor

Article abstract of DOI:10.1021/jo060175c

The development of chiral ligands to direct the course and stereoselectivity of many catalytic asymmetric reactions is an important area of interest for many research groups. As part of a program examining the chemistry of 2,1-benzothiazines, we have prep

Full text of DOI:10.1021/jo060175c

1,4-additions to enones,4 palladium-catalyzed C-allylation,1a,5
vanadium-catalyzed sulfide oxidation,6 copper-catalyzed Diels-
Alder and hetero Diels-Alder reactions,7 copper-catalyzed 1,4-
additions,8 copper-catalyzed Mukaiyama-type aldol reactions,9
and iridium-catalyzed imine hydrogenation.1b The sulfoximine
functional group continues to have promise as a convenient
source of chirality that can be useful in catalytic reaction
chemistry and stoichiometric chemistry2 and shows promise in
the development of materials for other applications.10
New Chiral Benzothiazine Ligand and Its Use in
the Synthesis of a Chiral Receptor
Michael Harmata,*,† Nathan L. Calkins,†
Russell G. Baughman,‡ and Charles L. Barnes†
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211, and Department of Chemistry,
Truman State UniVersity, KirksVille, Missouri 63501
The intention of this work was to build a molecule that would
serve as the foundation for a family of ligands generally
applicable to both catalysis and molecular recognition. We chose
1 as our target, anticipating that the hydroxyl group would be
a useful appendage for further functionalization.
harmatam@missouri.edu
ReceiVed January 25, 2006
The synthesis of 1 could be achieved by a simple protection
of the commercially available 2-bromo-3-hydroxybenzaldehyde
under basic conditions to give the protected phenol 2 in 94%
yield. Another route to 2 was recently reported in which the
conversion of 3-methoxymethoxybenzaldehyde to 2 was achieved
in 83% yield, via the Comins method11 using a sequence of in
situ protection/ortho-lithiation.12 We next used our benzothiazine
synthesis2 to achieve the direct formation of benzothiazine 4 in
89% yield using enantiomerically pure sulfoximine 3. An
attempt to directly form 1 via the coupling of the commercially
available phenol with sulfoximine 3 gave no evidence for the
formation of 1. The deprotection of 4 was achieved quantita-
tively by treatment with i-PrOH/HCl/THF (2:1:1)13 to give
benzothiazine 1 (Scheme 1). Upon vapor diffusion of hexane
into an ethyl acetate solution containing 1, crystals suitable for
X-ray analysis were formed.14
The development of chiral ligands to direct the course and
stereoselectivity of many catalytic asymmetric reactions is
an important area of interest for many research groups. As
part of a program examining the chemistry of 2,1-benzo-
thiazines, we have prepared a new chiral benzothiazine
ligand. This ligand can be made in as few as three steps
from commercially available starting materials. Presented
herein is the synthesis of the ligand along with the synthesis
of a chiral molecular receptor that potentially presages a new
class of chiral molecular tweezers.
The preparation of ligands in an inexpensive, quick, and
efficient manner is of considerable interest to both academic
and industrial research. As frameworks for the development of
both chiral catalysts and molecular receptors, chiral ligands that
can be easily obtained can have a high impact. Our goal is to
design a family of ligands based on the 2,1-benzothiazines, in
particular, those that contain sulfoximine functionality as the
source of chirality. We have reported some progress in this area,
but in the context of both catalysis and receptor chemistry, much
more needs to be done.1
We attempted to synthesize different P-N ligands by reacting
1 with a variety of P(III) reagents. Although in general it
appeared that a reaction took place, the products appeared to
be hydrolytically quite labile and attempted isolation or trapping
(3) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 5, 482.
(4) Bolm, C.; Felder, M.; Muller, J. Synlett 1992, 439.
(5) Bolm, C.; Kaufmann; Zehnder, M.; Neuburger, M. Tetrahedron Lett.
1996, 37, 3985.
The synthesis of sulfoximine-containing molecules in both
racemic and nonracemic forms is a well-developed area where
high yields and high reproducibility are noteworthy.2 In addition
to our work, the use of chiral sulfoximine-based ligands has
been studied extensively by Bolm.1b,3-6 In all cases, the ligands
show moderate to excellent enantioselectivity in many asym-
metric reactions. The variety of reactions containing sulfox-
imine-based ligands ranges from nickel-catalyzed asymmetric
(6) Bolm, C.; Bienewald, F.; Harms, K. Synlett 1996, 775.
(7) (a) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (b) Bolm,
C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett. 2003, 5, 427.
(8) Kinahan, T. C.; Tye, H. Tetrahedron: Asymmetry 2001, 12, 1255.
(9) Langer, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984.
(10) (a) Harmata, M. Chiral Molecular Tweezer Review. Acc. Chem.
Res. 2004, 37, 862. (b) Hamel, A.; Hollatz, C.; Schier, A.; Schmidbaur, H.
Naturforsch 2000, 55b, 889. (c) Takata, T.; Nakamura, K.; Endo, T.
Macromolecules 1996, 29, 2696. (d) Beecher, J. E.; Durst, T.; Frechet, J.
M. J.; Godt, A.; Pangborn, A.; Robello, D. R.; Willand, C. S.; Williams,
D. J. AdV. Mater. 1993, 5, 632. (e) Schmidbaur, H.; Kammel, G. J.
Organomet. Chem. 1968, 14, P28.
(11) (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078. (b)
Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54, 3730.
(12) Kaiser, F.; Schwink, L.; Velder, K.; Schmalz, H. Tetrahedron 2003,
59, 3201.
(13) Yardley, J. P.; Fletcher, H., III. Synthesis 1976, 244.
(14) The X-ray crystal structure and its packing diagram of 1 are available
in the Supporting Information.
† University of MissourisColumbia.
‡ Truman State University.
(1) (a) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321. (b) Moessner,
C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 45, 1.
(2) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581. (b) Harmata, M.;
Hong, X. Tetrahedron Lett. 2005, 46, 3847. (c) Harmata, M.; Hong, X.;
Barnes, C. L. Org. Lett. 2004, 6, 2201. (d) Harmata, M.; Hong, X. J. Am.
Chem. Soc. 2003, 125, 5754. (e) Reggelin, M.; Zur, C. Synthesis 2000, 1.
10.1021/jo060175c CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
3650
J. Org. Chem. 2006, 71, 3650-3652

SCHEME 1
SCHEME 2
SCHEME 3
We were somewhat disappointed that complex 7 formed with
6 functioning as a tridentate ligand using only a single
benzothiazine for binding.15b The metal was unable to bind to
both sulfoximine nitrogens but rather bound to the ether in two
five-membered ring chelates with the pyridine-N and sulfox-
imine-N as shown in the X-ray structure (see Supporting
Information, Figure 1). This result gave new insight to the
possibilities of the ligand and some insight as to the reason the
molecules were having trouble packing in the crystal lattice.
Using both sulfoximines as ligands is sterically disfavored,
regardless of the metal. It is likely that the unbound benzo-
thiazine in structures such as 7 makes packing into a crystal
lattice difficult, hence the small number of crystalline materials
obtained. Therefore, if we remove the unbound benzothiazine,
it might be replaced with another group, such as a flat aromatic
ring, to produce materials of higher crystallinity that could
function as chiral molecular tweezers. We are investigating this
idea.
The chiral scaffold embodied in 1 can be potentially modi-
fied in many ways, including hydroxyl functionalization and
carbanion formation and alkylation, among others. This should
make it highly suitable for the generation of large numbers of
related chiral ligands for use in both asymmetric synthesis and
the generation of chiral species for molecular recognition and
supramolecular chemistry. In addition, fundamental insight into
the chemistry of these hetereocycles and the sulfoximine
functional group will result from such studies. Further work in
this area is in progress, and results will be reported in due course.
with metals was ultimately unsuccessful. However, the func-
tionalization of 1 with a P(V) reagent was quite straightforward.
For example, reaction of 1 with diphenylphosphinic chloride
gave phosphinic ester 5 in 91% yield as shown in Scheme 2.
This compound was stable and easy to isolate and purify and
was structurally characterized by both spectral and X-ray
analysis.
We subsequently became interested in building systems that
could serve as metal binders and possibly assemble into larger
chiral arrays, such as helices.15 We thus reacted enantiomerically
pure 1 with 2,6-bis(chloromethyl)pyridinium chloride16 in the
presence of NaH in DMF, obtaining ligand 6 in 89% yield after
chromatography, as shown in Scheme 3. To test the metal
binding abilities of this ligand, we mixed it with a number of
metal salts, particularly with the aim of obtaining a crystalline
material that could be characterized by X-ray analysis. Of the
metal salts chosen for this study,17 most formed noncrystalline
insoluble precipitates or oils; only the cadmium iodide complex
7 afforded X-ray quality crystals. Attempts to obtain a crystalline
sample of the free ligand or a simple (e.g., protonated) derivative
were unsuccessful.
Experimental Section
2-Bromo-3-(methoxymethoxy)benzaldehyde (2). 2-Bromo-3-
hydroxybenzaldehyde (1.0 g, 4.97 mmol) was dissolved in THF
(10 mL) along with triethylamine (3.4 mL, 24.8 mmol), NaI (0.372
g, 2.48 mmol) and a stirbar, resulting in a dark orange solution
which was then flushed with dry N2 gas. MOMCl (0.751 mL, 9.94
mmol) was added dropwise resulting in the formation of a
precipitate. The reaction was allowed to stir further until TLC
showed completion (1 h) (Rf ) 0.72 in 50% EtOAc/hexanes; short
UV dark spot). The reaction was taken up in water (10 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concentrated
(15) (a) Seitz, M.; Kaiser, A.; Stempfhuber, S.; Zabel, M.; Reiser, O.
Inorg. Chem. 2005, 44, 4630. (b) Seitz, M.; Kaiser, A.; Stempfhuber, S.;
Zabel, M.; Reiser, O. J. Am. Chem. Soc. 2004, 126, 11426. (c) Seitz, M.;
Kaiser, A.; Stempfhuber, S.; Zabel, M.; Schutz, M.; Reiser, O. Angew.
Chem., Int. Ed. 2004, 44, 242.
(16) (a) Lamture, J. B.; Zhou, Z. H.; Kumar, A. S.; Wensel, T. G. Inorg.
Chem. 1995, 34, 864. (b) Xinyan, W.; Yongbin, H.; Chengtai, W. Wuhan
UniV. J. Nat. Sci. 1996, 1, 105. (c) Nick, B.; Pietzsch, H.; Tisato, F.; Maina,
T.; Leibnitz, P.; Spies, H.; Chiotellis, E. Inorg. Chim. Acta 2000, 304, 26.
(17) A table listing the metal salts examined can be found in Table 1 of
the Supporting Information.
J. Org. Chem, Vol. 71, No. 9, 2006 3651

in vacuo. Purification by flash chromatography, 25% EtOAc/
hexanes, yielded 2 (1.13 g, 93%) as a yellow-orange semisolid.
Spectral data corresponded to that reported in the literature.12
(R)-8-(Methoxymethoxy)-2-S-oxa-2-S-phenyl-2,1-benzothi-
azine (4). Compound 2 (1.00 g, 4.08 mmol), Pd(OAc)2 (45% Pd,
0.046 g, 0.204 mmol), rac-BINAP (0.191 g, 0.306 mmol), R-
methylphenyl sulfoximine 3 (0.759 g, 4.89 mmol), and Cs2CO3
(2.12 g, 6.51 mmol) in toluene (80 mL) were combined in a flask
which was flushed with dry N2 for several minutes. A reflux
condenser and a N2 balloon were added, and the mixture was stirred
at reflux temperature (120 °C) for 48 h. The solution was then
cooled to room temperature, diluted with dichloromethane, filtered
through a plug of Celite, and concentrated in vacuo. The dark brown
semisolid was purified by flash chromatography (40% EtOAc/
hexanes, Rf ) 0.60 in 50% EtOAc/hexanes) to afford 4 (1.17 g,
89%) as a yellow-orange semisolid. 1H NMR: (300 MHz, CDCl3)
δ 3.53 (s, 3H), 5.33 (q, J ) 5.6 Hz, 2H), 6.38 (d, J ) 9.8 Hz, 1H),
6.96 (t, J ) 7.8 Hz, 1H), 7.07 (dd, J ) 7.8 Hz, J ) 1.2 Hz, 1H),
7.34 (dd, J ) 7.8 Hz, J ) 1.2 Hz, 1H), 7.50-7.62 (m, 3H), 7.63
(d, J ) 9.8 Hz, 1H), 7.89 (d, J ) 7.2 Hz, 1H). 13C NMR: (300
MHz, CDCl3) δ 56.1, 95.5, 110.4, 117.1, 118.4, 119.7, 123.4, 128.8,
129.1, 133.2, 136.4, 138.5, 141.6, 149.6. IR (NaCl, cm-1) 3020,
1605, 1547, 1434, 1284, 1250, 1153, 1104, 1044, 992, 669. HRMS
calcd for C16H15NO3SNa [M + Na]+, 324.0664; found, 324.0661.
(R)-8-(Hydroxy)-2-S-oxa-2-S-phenyl-2,1-benzothiazine (1). Com-
pound 4 (2.43 g, 8.06 mmol) was added to a solution of 2-propanol
(32.1 mL, 419 mmol), HCl (12.1 N, 16.6 mL, 201 mmol), and
THF (17.05 mL, 209 mmol). The mixture was stirred at room
temperature until completion was observed by TLC (3 h). The
mixture was diluted with water (20 mL) and extracted by ether (3
× 20 mL). The comibined organic layers were washed with 5%
(w/w) NaHCO3 and brine, dried (MgSO4), and concentrated in
vacuo. The remaining yellow-orange solid afforded 2.06 g of phenol
1 which was pure by NMR and TLC (Rf ) 0.68 in 50% EtOAc/
hexanes; brown/orange long UV spot) in >99% yield. Mp 146-
147 °C. The solid can be purified by flash chromatography in 50%
EtOAc/hexanes. 1H NMR: (250 MHz, CDCl3) δ 6.37 (d, J ) 9.7
Hz, 1H), 6.7 (s, 1H), 6.95 (d, J ) 4.7 Hz, 2H), 7.10 (p, J ) 4.6
Hz, 1H), 7.54-7.67 (m, 3H), 7.67 (d, J ) 9.7 Hz, 1H), 7.88 (d, J
) 6.8 Hz, 1H). 13C NMR: (250 MHz, CDCl3) δ 110.2, 114.9,
115.7, 120.2, 120.4, 128.8, 129.1, 133.2, 133.6, 138.7, 141.3, 148.5.
IR (NaCl, cm-1) 3460, 3022, 1620, 1592, 1550, 1440, 1278, 1223,
1244, 1206, 1190, 1101, 992, 792, 729, 588, 426. HRMS calcd for
C14H11NO2SNa [M + Na]+, 280.0402; found, 280.0399.
purification (50% EtOAc/hexanes, then EtOAc; Rf ) 0.23 in 50%
EtOAc/hexanes) gave 5 (0.0953 g, 91%) as a yellow semisolid. 1H
NMR: (250 MHz, CDCl3) δ 6.37 (d, J ) 9.8 Hz, 1H), 6.86 (t, J
) 7.9 Hz, 1H), 7.08 (d, J ) 7.8 Hz, 1H), 7.30-7.50 (m, 5H), 7.54-
7.65 (m, 4H), 7.71 (d, J ) 7.9 Hz, 1H), 7.88 (d, J ) 6.6 Hz, 2H),
8.02 (d, J ) 7.5 Hz, 2H), 8.07 (d, J ) 7.3 Hz, 2H). 13C NMR:
(250 MHz, CDCl3) δ 110.6, 117.5, 119.5, 123.9, 123.9, 125.9,
128.0, 128.2, 128.5, 128.7, 129.0, 129.8, 130.5, 131.9, 132.0, 132.1,
132.8, 133.3, 138.3, 138.3, 141.6, 143.3.31P NMR (250 MHz,
CDCl3): δ 32.1. IR (NaCl, cm-1) 3064, 2998, 2927, 2361, 2340,
1609, 1592, 1545, 1444, 1440, 1289, 1131, 1104, 1037, 994, 877,
748, 695, 666.
(R,R)-2,6-Bis(dimethyl-8-O-2-(S)-oxa-2-S-phenyl-2,1-benzothi-
azine)pyridine (6). Benzothiazine 1 (0.106 g, 0.414 mmol) in DMF
(10 mL) was treated with NaH (60% in mineral oil, 0.026 g, 0.6587
mmol) at 0 °C, resulting in a dark red solution. After 5 min, the
2,6-bis(chloromethyl)pyridinium chloride (0.040 g, 0.188 mmol)
was added as a solid. The reaction was allowed to warm to room
temperature and was stirred until completion by TLC (20 h) (Rf )
0.15 in 50% EtOAc/hexanes). The reaction was quenched with
water (5 mL) and extracted by dichloromethane (3 × 5 mL). The
organic extracts were washed with water (5 mL), dried (MgSO4),
and concentrated in vacuo. The remaining crude oil was purified
by flash chromatography in (50% EtOAc/hexanes; 80% EtOAc/
hexanes) to afford 6 (0.073 g, 89%) as an off-white solid. Mp 123-
1
124 °C. H NMR: (250 MHz, CDCl3) δ 5.42 (s, 4 H), 6.35 (d, J
) 9.8 Hz, 2H), 6.6 (t, J ) 7.6 Hz, 2H), 6.95 (d, J ) 7.6 Hz, 4H),
7.47-7.66 (m, 11H), 7.89 (d, J ) 6.6 Hz, 4H). 13C NMR: (250
MHz, CDCl3) δ 71.6, 110.3, 115.3, 117.0, 119.6, 120.0, 122.3,
128.8, 129.05, 133.2, 136.1, 137.6, 138.5, 141.7, 150.8, 157.0. IR
(NaCl, cm-1) 3015, 1605, 1546, 1464, 1449, 1432, 1284, 1256,
1223, 1206, 1105, 1090, 993, 792, 729, 426. HRMS calcd for
C35H27N3O4S2Na [M + Na]+, 640.1335; found, 680.1362.
Cd Complex (7). Compound 6 (0.0244 g, 0.00394 mmol) was
dissolved in dichloromethane (1 mL) and added to a flask containing
CdI2 (0.0217 g, 0.00592 mmol) in methanol (1 mL) and a stirbar.
After flushing with dry N2, the solution was heated to reflux (40
°C) for 3 h and then cooled to room temperature. The flask was
capped and allowed to stand for 48 h during which off-white spikes
formed. The crystals were filtered to afford 7 (0.0354 g, 84%) as
an off-white solid. Mp 191.5-192.5 °C. The structure was
established by X-ray crystal analysis.
Acknowledgment. We thank the Petroleum Research Fund,
administered by the American Chemical Society, for funding
this work. We also thank Frontier Scientific Inc. for the generous
donation of 2-bromo-3-hydroxybenzaldehyde.
(R)-8-(P-oxa-P-Diphenyl)-2-S-oxa-2-S-phenyl-2,1-benzothi-
azine (5). A flask was charged with benzothiazine 1 (0.0587 g,
0.228 mmol) and flushed with dry argon. THF (1.5 mL) was added,
and the solution was cooled to -78 °C. n-BuLi (2.20 M in hexanes,
0.114 mL, 0.250 mmol) was added dropwise, affording a dark
brown solution. This solution was stirred further for 5 min at -78
°C, and then diphenylphosphinic chloride (0.522 mL, 0.273 mmol)
was added. The reaction was warmed to room temperature and
stirred overnight. MeOH (2 mL) was added, and the solvent was
removed in vacuo to afford a yellow oil. Flash chromatographic
1
Supporting Information Available: Copies of H NMR, 13C
NMR, 31P NMR, HRMS, and IR for all new compounds as well as
X-ray structure data for the benzothiazine 1, phosphine oxide 5,
and cadmium metal complex 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO060175C
3652 J. Org. Chem., Vol. 71, No. 9, 2006