1448
D. Jaspers, S. Doye
LETTER
Chem. Int. Ed. 1998, 37, 3389; Angew. Chem. 1998, 110,
3571. (d) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron
Lett. 1999, 40, 6193. (e) Hartung, C. G.; Breindl, C.;
Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157.
(f) Beller, M.; Breindl, C.; Seijas, J. A.; Vázquez-Tato,
M. P.; Martínez, M. M. Synlett 2001, 875. (g) Beller, M.;
Breindl, C. Chemosphere 2001, 43, 21. (h) Horrillo-
Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell, V. Eur.
J. Org. Chem. 2007, 3311.
H
N
1
2 mol% KOH
+
DMSO–hexane
reflux, 6 h
(Dean–Stark
apparatus)
H2N
3a (82%, 9 g)
2
(4) For selected examples of base-catalyzed intramolecular
hydroaminations, see: (a) Ates, A.; Quinet, C. Eur. J. Org.
Chem. 2003, 1623. (b) Martínez, P. H.; Hultzsch, K. C.;
Hampel, F. Chem. Commun. 2006, 2221. (c) Ogata, T.;
Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.;
Tomioka, K. Tetrahedron Lett. 2007, 48, 6648. (d) Quinet,
C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Markó,
I. E. Tetrahedron 2008, 64, 1077.
Scheme 2 Practical example for the addition of p-toluidine (2) to
styrene (1) using a Dean–Stark apparatus. Reaction conditions: sty-
rene (50 mmol), p-toluidine (80 mmol), KOH (1 mmol), DMSO–
hexane (1:1, 50 mL), 95 °C (oil bath), 6 h.
In summary, we have shown that KOH is a suitable cata-
lyst for the addition of various arylamines to styrenes to
produce pharmaceutically interesting b-arylethylamines.
Various styrenes, primary and secondary arylamines, as
well as phenylhydrazine could be converted into the cor-
responding products in moderate to good yields. Finally,
we have shown that the KOH-catalyzed hydroamination
is feasible for practical purposes without using Schlenk
technique. For this purpose, commercially available start-
ing materials and undried DMSO were used in a Dean–
Stark apparatus with hexane as entrainer.
(5) Kumar, K.; Michalik, D.; Garcia Castro, I.; Tillack, A.;
Zapf, A.; Arlt, M.; Heinrich, T.; Böttcher, H.; Beller, M.
Chem. Eur. J. 2004, 10, 746.
(6) Gaylord Chemical Company, L.L.C. http://
Bulletin102B.pdf (accessed Jan 28, 2011).
(7) General Procedure Exemplified by the Reaction of
Styrene (1) with p-Toluidine (2)
An oven-dried Schlenk tube equipped with a Teflon
stopcock and a magnetic stirring bar was transferred to a
nitrogen-filled glove box and charged with p-toluidine (343
mg, 3.2 mmol), styrene (208 mg, 2.0 mmol), dry DMSO (1.0
mL), and KOH (99.99% from Sigma-Aldrich, 6 mg, 0.1
mmol, 5 mol%). The tube was sealed, and the resulting
mixture was heated to 70 °C for 4 h. After the tube had been
cooled to r.t. the reaction mixture was poured into an aq
NaOH solution (1 M, 10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried
(MgSO4) and concentrated under vacuum in the presence of
Celite®. Finally, the crude product was purified by flash
chromatography (light PE–EtOAc, 20:1) to give amine 3a
(359 mg, 1.7 mmol, 85%) as a pale yellow oil. 1H NMR (500
MHz, CDCl3): d = 2.22 (s, 3 H), 2.86 (t, JH,H = 7.1 Hz, 2 H),
3.33 (t, JH,H = 7.1 Hz, 2 H), 3.46 (s, 1 H, NH), 6.51 (d,
JH,H = 8.2 Hz, 2 H), 6.97 (d, JH,H = 8.0 Hz, 2 H), 7.16–7.23
(m, 3 H), 7.26–7.31 (m, 2 H) ppm. 13C NMR (126 MHz,
DEPT, CDCl3): d = 20.3 (CH3), 35.4 (CH2), 45.3 (CH2),
113.1 (CH), 126.3 (CH), 126.5 (C), 128.5 (CH), 128.7 (CH),
129.7 (CH), 139.3 (C), 145.7 (C) ppm. IR (neat): n = 3404,
3025, 2918, 2861, 1615, 1519, 1318, 1259, 1182, 1080,
1031, 808, 699 cm–1. HRMS (70 eV): m/z calcd for C15H17N:
211.1361; found: 211.1365.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft for financial sup-
port of our research.
References and Notes
(1) For recent reviews, see: (a) Müller, T. E.; Beller, M. Chem.
Rev. 1998, 98, 675. (b) Brunet, J. J.; Neibecker, D. In
Catalytic Heterofunctionalization; Togni, A.; Grützmacher,
H., Eds.; Wiley-VCH: Weinheim, 2001, 91. (c) Bytschkov,
I.; Doye, S. Eur. J. Org. Chem. 2003, 935. (d) Pohlki, F.;
Doye, S. Chem. Soc. Rev. 2003, 32, 104. (e) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(f) Doye, S. Synlett 2004, 1653. (g) Odom, A. L. Dalton
Trans. 2005, 225. (h) Hultzsch, K. C. Adv. Synth. Catal.
2005, 347, 367. (i) Hultzsch, K. C. Org. Biomol. Chem.
2005, 3, 1819. (j) Severin, R.; Doye, S. Chem. Soc. Rev.
2007, 36, 1407. (k) Brunet, J.-J.; Chu, N.-C.; Rodriguez-
Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711. (l) Lee, A. V.;
Schafer, L. L. Eur. J. Inorg. Chem. 2007, 2243. (m)Müller,
T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem.
Rev. 2008, 108, 3795.
(2) For a review on base-catalyzed hydroaminations, see:
Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv.
Synth. Catal. 2002, 344, 795.
(3) For selected examples of base-catalyzed intermolecular
hydroaminations, see: (a) Lehmkuhl, H.; Reinehr, D.
J. Organomet. Chem. 1973, 55, 215. (b) Beller, M.; Breindl,
C. Tetrahedron 1998, 54, 6359. (c) Beller, M.; Breindl, C.;
Riermeier, T. H.; Eichberger, M.; Trauthwein, H. Angew.
(8) Under comparable conditions, much lower yields were
obtained with toluene (<5%), 1,4-dioxane (<5%), THF
(9%), and DME (9%).
(9) A base-catalyzed addition of the DMSO anion to styrene has
been reported: Walling, C.; Bollyky, L. J. Org. Chem. 1964,
29, 2699.
(10) Azeotropic data of H2O–hexane: TAz = 61.6 °C,
PAz = 101.33 kPa; ywater = 0.2110. See: Lide, D. R.
Handbook of Chemistry and Physics, 87th ed.; CRC Press:
Boca Raton, 2006, 6–161.
Synlett 2011, No. 10, 1444–1448 © Thieme Stuttgart · New York