104
E. F. Flegeau et al.
Letter
Synlett
electrophilic functional groups on the arene, as well as en-
compassing the use of both primary and secondary amines,
anilines, and amino acid derivatives.
mixture was filtered through Celite and the filter washed with ace-
tone until disappearance of the brown color. The organic solution was
then concentrated and the residue purified by flash chromatography
with silica gel under standard eluent mixtures [typically EtOAc in PE
(40–60 °C bp PE)]. The products were dried under high vacuum and
analyzed by NMR and IR spectroscopy and MS.
H
N
O
O
Pd(OAc)2
PAd2Bu
R2
R3
S
R3
I
O
S
2
N
R2
R1
R1
HNR3
Acknowledgment
Et3N
iPrOH, 75 °C
Ar
O
NaOCl (aq)
0 °C to r.t.
1
4
This work was supported by the EPSRC.
O
O
O
O
S
MeO
S
Pr
N
N
Supporting Information
H
H
MeO
4a, 63%
Supporting information for this article is freely available online at
4f, 64%
OMe
O
O
O
O
tal procedures and associated characterization data.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
S
OMe
OMe
S
N
N
H
H
MeS
MeO
References
4b, 70%
4g, 69%
O
O
(1) For example, see: (a) Teall, M.; Oakley, P.; Harrison, T.; Shaw, D.;
Kay, E.; Elliott, J.; Gerhard, U.; Castro, J. L.; Shearman, M.; Ball, R.
G.; Tsou, N. N. Bioorg. Med. Chem. Lett. 2005, 15, 2685.
(b) Harrak, Y.; Casula, G.; Basset, J.; Rosell, G.; Plescia, S.; Raffa,
D.; Cusimano, M. G.; Pouplana, R.; Pujol, M. D. J. Med. Chem.
2010, 53, 6560. (c) Smith, D. A.; Jones, R. M. Curr. Opin. Drug Dis-
covery Dev. 2008, 11, 72.
(2) For example, see: Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes,
M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A.
S. Org. Process Res. Dev. 2000, 4, 17.
O
O
S
S
N
H
N
Me
Me
4h, 48%
4c, 66%
O
S
O
CO2Me
O
O
N
MeO
S
N
N
H
MeS
4d, 89%a
4i, 73%
(3) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. In
Vogel's Textbook of Practical Organic Chemistry; Longman Scien-
tific and Technical: UK, 1989, 5th ed.
CO2H
O
O
O
O
MeO
S
MeO
S
N
N
H
H
(4) For example, see: Wright, S. W.; Hallstrom, K. N. J. Org. Chem.
2006, 71, 1080.
4e, 53%b
4j, 57%a,c
(5) For example, see: (a) Colombe, J. R.; DeBergh, J. R.; Buchwald, S.
L. Org. Lett. 2015, 17, 3170. For a review of sulfinates in synthe-
sis, see: (b) Aziz, J.; Messaoudi, S.; Alami, M.; Hamze, A. Org.
Biolmol. Chem. 2014, 12, 9743.
(6) For recent alternative sulfonamide syntheses, see: (a) Frost, C.
G.; Hartley, J. P.; Griffin, D. Synlett 2002, 1928. (b) Caddick, S.;
Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024.
(c) DeBergh, J. R.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2013, 135, 10638. (d) Johnson, M. G.; Gribble, M. W. Jr.;
Houze, J. B.; Paras, N. A. Org. Lett. 2014, 16, 6248. (e) Young, J.
M.; Lee, A. G.; Chandrasekaran, R. Y.; Tucker, J. W. J. Org. Chem.
2015, 80, 8417.
Scheme 3 Scope of the amine component in one-pot sulfonamide for-
mation. Reagents and conditions: Pd(OAc)2 (5 mol%), PAd2Bu (7.5 mol%),
DABSO (0.6 equiv), Et3N (3.0 equiv), i-PrOH (0.2 M), 75 °C, 16 h, then
amine (3 equiv), NaOCl (10.3% aq solution, 2 equiv), 0 °C to r.t., 45 min
to 3.5 h. a The reaction was performed on 4.23 mmol scale (1.0 g) of
starting aryl iodide. b Additional amine (3.0 equiv) and NaOCl (2.0
equiv) added after 2 h. c The solvent from first step was removed and
replaced by water. The ee of the methyl ester derivative was confirmed
by chiral HPLC to be >99%.
General Procedure for the Formation of Sulfonamides Using Mor-
pholine, Exemplified by the Preparation of 4-Tosylmorpholine 3a
(7) For a review of SO2 surrogates, see: Emmett, E. J.; Willis, M. C.
Asian J. Org. Chem. 2015, 4, 602.
An oven-dried glass reaction tube was charged with the relevant aryl
iodide (4-iodotoluene) (87 mg, 0.40 mmol, 1 equiv), DABSO (58 mg,
0.24 mmol), Pd(OAc)2 (5.0 mg, 20.0 μmol, 5 mol%), and CataCXium A
(11.0 mg, 31.6 μmol, 7.5 mol%), sealed with a rubber septum and
flushed with nitrogen. Under positive pressure of nitrogen, Et3N (168
μL, 1.20 mmol, 3 equiv), and anhydrous 2-PrOH (1.5 mL) were added
sequentially through the septum. The reaction mixture was then im-
mersed in a preheated oil bath at 75 °C for 16 h. The formation of the
ammonium sulfinate and the disappearance of the aryl iodide are
easily followed by HPLC. After cooling to r.t., the relevant amine (mor-
pholine) (104 μL, 1.20 mmol, 3 equiv) and previously titrated 10.31%
w/w aq NaOCl (0.47 mL, 0.80 mmol, 2 equiv) were added sequentially
through the septum and stirred at r.t. for 90 min until consumption of
the sulfinate was observed by HPLC. Upon completion, the reaction
(8) (a) Woolven, H.; González-Rodríguez, C.; Marco, I.; Thompson,
A. L.; Willis, M. C. Org. Lett. 2011, 13, 4876. (b) Emmett, E. J.;
Hayter, B. R.; Willis, M. C. Angew. Chem. Int. Ed. 2013, 52, 12679.
(c) Deeming, A. S.; Russell, C. J.; Hennessy, A. J.; Willis, M. C. Org.
Lett. 2014, 16, 150. From other laboratories: (d) Waldmann, C.;
Schober, O.; Haufe, G.; Kopka, K. Org. Lett. 2013, 15, 2954.
(e) Rocke, B. N.; Bahnck, K. B.; Herr, M.; Lavergne, S.; Mascitti,
V.; Perreault, C.; Polivkova, J.; Shavnya, A. Org. Lett. 2014, 16,
154. (f) Chun Chen, C.; Waser, J. Org. Lett. 2015, 17, 736.
(9) Deeming, A. S.; Russell, C. J.; Willis, M. C. Angew. Chem. Int. Ed.
2015, 54, 1168.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 101–105