LETTER
Sulfoximine Acylation
363
Huang, C.; Chen, Y.; Zheng, P.; Gao, X.; Ying, W. Synlett
2008, 2051. (d) Harmata, M.; Rayanil, K.-O.; Gomes, M.
G.; Zheng, P.; Calkins, N. L.; Kim, S.-Y.; Fan, Y.; Bumbu,
V.; Lee, D. R.; Wacharasindhu, S.; Hong, X. Org. Lett. 2005,
7, 143. (e) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581.
(f) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125,
5754. (g) Harmata, M.; Pavri, N. Angew. Chem. Int. Ed.
1999, 38, 2419. (h) Harmata, M.; Claassen, R. J. III
Tetrahedron Lett. 1991, 32, 6497. (i) Harmata, M.
Thus, the reaction of 10 with 1 was examined under con-
ditions that give rather poor yields when boric acid was
used a catalyst as illustrated in Table 3 (entry 1). Phenyl-
boronic acid offered no improvement at the same catalyst
loading, but both 24 and 25 gave 11 in much improved
yield, with 25 functioning as the best catalyst at that (still
rather high) loading.5a Given that no dramatic improve-
ment was observed, we decided not to pursue this line of
investigation further.
Tetrahedron Lett. 1989, 30, 437.
(3) (a) Hwang, K. J.; Logusch, E. W. Tetrahedron Lett. 1987,
28, 4149. (b) Bolm, C.; Hackenberger, C. P. R.; Simic, O.;
Verrucci, M.; Müller, D.; Bienewald, F. Synthesis 2002,
879. (c) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger,
C. P. R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13,
3207. (d) Hackenberger, C. P. R.; Raabe, G.; Bolm, C.
Chem. Eur. J. 2004, 10, 2942. (e) Cho, G. Y.; Okamura, H.;
Bolm, C. J. Org. Chem. 2005, 70, 2346.
Table 3 Catalyst Variation is the Acylation of 1
O
O
NH
cat. (0.4 equiv)
Ph
Ph
N
S
Ph
S
O
1
Me
+
toluene, 0.32 M
115 °C, 24 h
HO
Ph
Me
Ph
Ph
10
O
11
(4) (a) Barajas, J. G. H.; Mendez, L. Y. V.; Kouznetsov, V. V.;
Stashenko, E. E. Synthesis 2008, 377. (b) Maki, T.;
Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645.
(c) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith,
G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348, 813.
(d) Tang, P. Org. Synth. 2005, 81, 262. (e) Latta, R.;
Springsteen, G.; Wang, B. Synthesis 2001, 1611.
(5) (a) Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int.
Ed. 2008, 47, 2876. (b) Ishihara, K.; Ohara, S.; Yamamoto,
H. Org. Synth. 2003, 79, 176.
(6) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(7) Marcelli, T. Angew. Chem. Int. Ed. 2010, 49, 6840.
(8) Typical Procedure: A flame-dried, 50-mL single-neck
round-bottomed flask was equipped with a Dean–Stark trap
topped with a reflux condenser fitted with nitrogen inlet, and
a Teflon-coated magnetic stirring bar. The reaction vessel
was charged with racemic 1 (1 g, 6.45 mmol), carboxylic
acid (7.09 mmol, 1.1 equiv), boric acid (310 mg, 0.8 equiv,
5.12 mmol) and toluene (20 mL, 0.32 M). The apparatus
(save the condenser) was wrapped in aluminum foil to
prevent heat loss. The reaction mixture was heated at reflux
for 24 h, and H2O (ca. 0.1 mL) was collected in the Dean–
Stark trap. The remaining volume of toluene in the flask
was ca. 10 mL, corresponding to approximately 0.645 M
concentration of the reactants. The mixture was allowed to
cool at ambient temperature and worked up in one of two
ways.
Entry
Catalyst
Yield (%)
1
2
B(OH)3
15
13
PhB(OH)2
B(OH)2
3
4
35
45
N
24
25
B(OH)2
I
In conclusion, we have demonstrated that boric acid is ca-
pable of mediating the N-acylation of a sulfoximine in
good to high yield.8 Catalyst loading and activity are still
issues to be resolved, but the method is effective and can
be used in a mild process for selective N-acylation of sulf-
oximines.9,10
Supporting Information for this article is available online at
The reaction mass was dissolved in EtOAc (50 mL) and
washed with sat. NaHCO3 (3 × 50 mL) solution to remove
any unreacted carboxylic acid and boric acid present. The
collected organic layer was washed once with 3 N HCl (50
mL), followed by brine (50 mL). The organic layers were
collected, dried with MgSO4 and filtered and the solvent was
removed under vacuum. The crude product was pure in
many cases and did not need further purification.
In an alternative workup, the reaction mass was dissolved in
EtOAc (50 mL) and washed with brine (50 mL) and the
organic layer was dried with MgSO4 and filtered and the
solvent was removed under vacuum. The crude product was
purified by flash column chromatography using 20–40%
EtOAc–hexanes mixtures to afford pure product.
Acknowledgment
The authors thank the donors to the Harmata Research Fund
(Merck) and the National Science Foundation for support. Thanks
to Dr. Charles. L. Barnes for providing the X-ray crystallography
data. Thanks to Professor Dennis G. Hall (Alberta) for a gift of com-
pound 25.
References and Notes
(1) (a) Worch, C.; Mayer, A. C.; Bolm, C. Synthesis and Use of
Chiral Sulfoximines, In Organosulfur Chemistry in
(9) Data for selected compounds: Compound 3: crystalline
white solid; Rf 0.48 (40% EtOAc–hexanes); mp 94.5–98 °C;
yield: 80%. IR (KBr): 3313, 3056, 2943, 2916, 1667, 1488,
1205, 981, 830, 744 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.86 (d, J = 7.5 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.54 (t,
J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 6.98–6.93 (m, 3
H), 4.67 (s, 2 H), 3.38 (s, 3 H). 13C NMR (125 MHz, CDCl3):
d = 177.3, 158.2, 138.2, 133.9, 129.6, 129.3, 127.0, 121.1,
Asymmetric Synthesis; Toru, T.; Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2008, 209–229. (b) Okamura, H.; Bolm,
C. Chem. Lett. 2004, 33, 482. (c) Harmata, M. Chemtracts
2003, 16, 660. (d) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) (a) Harmata, M.; Rayanil, K.-O.; Espejo, V. R.; Barnes, C.
L. J. Org. Chem. 2009, 74, 3214. (b) Harmata, M.; Cai, Z.;
Chen, Y. J. Org. Chem. 2009, 74, 5559. (c) Harmata, M.;
Synlett 2011, No. 3, 361–364 © Thieme Stuttgart · New York