Efficient palladium-catalyzed N-arylation of a sulfoximine with aryl chlorides

Article abstract of DOI:10.1039/c1cc12444g

The efficient N-arylation of a sulfoximine with aryl chlorides was developed by using Pd₂(dba)₃ as a catalyst and various ligands. The reactions using RuPhos as a ligand afforded the coupled products in fair to excellent yields.

Full text of DOI:10.1039/c1cc12444g

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COMMUNICATION
Efficient palladium-catalyzed N-arylation of a sulfoximine with aryl
chlorideswz
Nattawut Yongpruksa, Nathan L. Calkins and Michael Harmata*
Received 26th April 2011, Accepted 16th May 2011
DOI: 10.1039/c1cc12444g
The efficient N-arylation of a sulfoximine with aryl chlorides
was developed by using Pd2(dba)3 as a catalyst and various
ligands. The reactions using RuPhos as a ligand afforded the
coupled products in fair to excellent yields.
The N-arylation of sulfoximines has been of interest over the
past decade because the products of the process are important
as chiral ligands1 and heretofore unknown heterocycles.2
From a more fundamental point of view, the study of such
reactions affords the opportunity to learn more about the
chemical behavior of the sulfoximine nitrogen atom, which is
neither a typical amine or amide nitrogen.3
Scheme 1 N-Arylation of a sulfoximine with 2-bromobenzaldehyde.
using microwave methodology and found that N-arylation
could be achieved in yields ranging from 31–94%.11 The lower
yields in this approach were typically associated with aromatic
chlorides bearing electron-donating groups.
Our interest in the N-arylation of NH-sulfoximines began
with a study demonstrating the N-arylation of 1 and o-bromo-
benzaldehyde to afford benzothiazine 3 (Scheme 1).4
Though yields could be improved by using chloroaromatics
as solvents in the reaction, this solution left much to be
desired. Further, our microwave apparatus was constrained
to the preparation of relatively small batches of product.
We wondered if changes in the ligand used in the process could
improve the N-arylation of aryl bromides and/or chlorides and if a
procedure that could be run without excessive concern about air
or moisture might be developed.
The process represents a general method for accessing chiral,
enantiomerically pure 2,1-benzothiazines. For that and other
work,5 we made use of an N-arylation protocol introduced by
Bolm,6 who showed that treatment of simple aryl bromides with
sulfoximine 4 in the presence of a palladium source, racemic
BINAP, and a base, afforded N-arylated sulfoximines in good
to excellent yields.
We began our work with an investigation of the N-arylation of
4 using bromobenzene. The experiments were conducted by
combining reagents in an undried, but ultimately sealed tube,
and heating for 12 h at 110 1C. The results are shown in Scheme 2.
A sealed tube system was used in anticipation of our using aryl
chlorides in the process, since this would mimic the reactions we
had performed with aryl chlorides in the past using microwave
irradiation.11
The N-arylation of sulfoximines has been reported using aryl
bromides, iodides and sulfonate esters under palladium, copper,
nickel and iron catalysis.7,8 Aryl boronic acids have been used as
arylating agents with copper as well.9 More recently, certain azoles
and polyfluoroarenes have been used for N-arylation via C–H
activation with catalysis by copper salts.10
As can be seen, bidentate ligands were preferred in this
reaction, with some exceptions as represented by dppf and
others.12 Monodentate phosphine ligands were also poor
performers. The three best monodentate ligands were tricyclo-
hexylphosphine, t-Bu-XPhos and BippyPhos,13 while other
simple phosphines were ineffective.12
While the arylation of sulfoximines with aryl chlorides
would be economically and practically attractive, efforts in
this direction have only been reported sparingly. We applied
the Bolm catalyst system to the arylation of sulfoximine 4
Several palladium sources were examined in order to probe
counterion/ligand effects in the process. RuPhos was chosen
for most of these studies as the phosphine ligand. The results
are summarized in Table 1.
Department of Chemistry, University of Missouri, Columbia, MO,
65211, USA. E-mail: HarmataM@missouri.edu;
Fax: +1 573-882-2754; Tel: +1 573-882-1097
In general, Pd0 species afforded higher yields than Pd(II)
species as can be seen from a comparison of entry 5 with
entries 1–3 of Table 1. It is interesting to note that Pd(PPh3)4
was a viable Pd source (Table 1, Entry 4). In the absence
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all new compounds. See DOI:
10.1039/c1cc12444g
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7665–7667 7665

latter species being derived from an impurity in 8. No products
derived from 7 were found (Scheme 3).
Scheme 2 Ligand optimization.
Scheme 3 Competition experiment.
of RuPhos, this metal complex did not lead to Buchwald–Hartwig
coupling, suggesting dynamic ligand exchange enabling access to a
catalytically active species containing RuPhos. Since BrettPhos
has recently been established as a superior ligand in the Buchwald–
Hartwig amination reaction,14 we tested it, but it was not superior
to RuPhos (Table 1, entry 6). Carbene ligands, such as PEPPSI-I
and II have also found extensive use in metal-catalyzed reactions.15
However, neither catalyst gave useful results in the synthesis of 6
(Table 1, entries 7–8).
Table 2 N-arylation of sulfoximine 4 with aryl chlorides
Time
Conda (h) Product
Yield
(%)
EntrySubstrate
We also studied the effect of a base on the reaction and the
results are summarized in the supporting information.z
The first aryl chloride examined was chlorobenzene (under
reaction conditions described in Table 1, entry 5, at 135 1C
for 6 h), which afforded only trace amounts of sulfoximine 6.
We increased the amount of catalyst to 5% and ligand to 10%,
but the yield of the product was still low (3%) compared
directly to the bromobenzene experiment (Table 1).
1
2
A
B
12
24
40
97
3
4
5
6
A
12
24
24
36
10
12
17
19
Ab
A
A
7
B
24
88
The low reactivity of the aryl chloride was not surprising. We
nevertheless performed
a competition experiment between
8
C
48
60
p-bromotoluene and 4-ethylchlorobenzene with 4. This afforded
sulfoximines 9 and 10 in 83% and 5% yields, respectively, the
Table 1 Effect of Pd sources on coupling reaction
9
B
B
24
24
99
77
10
Entry
Pd Source
Ligand
Yield (%)
1
2
3
4
Pd(OAc)2
PdCl2
PdCl2
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
PEPPSI-I
PEPPSI-II
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
BrettPhos
—
55
71
56a
61
92b
57b
6
11
B
12
77
5
6
7c
8c
—
28
12
13
B
48
48
93
73
a
b
10 mol% AgSbF6 added. 2.5 mol% catalyst added. 5 mol%
c
D
catalyst, 1.6 equiv Cs2CO3, toluene, 115 1C, 12 h.
14
D
48
77
a
A: 1.2 equiv 4, 2.5% Pd2(dba)3, 7.5% RuPhos, 1.4 equiv Cs2CO3;
B: 1.2 equiv 4, 5% Pd2(dba)3, 10% RuPhos, 1.4 equiv Cs2CO3; C: 2.2 equiv
4, 10% Pd2(dba)3, 10% RuPhos, 3.2 equiv Cs2CO3; D: 2.2 equiv 4,
b
5% Pd2(dba)3, 10% RuPhos, 3.2 equiv Cs2CO3. 5 mol% RuPhos
c
was used. (R)-4 was used.
c
7666 Chem. Commun., 2011, 47, 7665–7667
This journal is The Royal Society of Chemistry 2011

However, we were aware that the coupling process we had
discovered was qualitatively faster than that which used
BINAP. We therefore wondered if the coupling reaction with
aryl chlorides might work under conditions that were more
demanding. This turned out to be the case (Table 2).
Notes and references
1 For example, see: (a) C. Bolm, J.-C. Frison, J. Le Paih,
C. Moessner and G. Raabe, J. Organomet. Chem., 2004,
689, 3767; (b) C. Bolm, M. Verrucci, O. Simic, P. G. Cozzi,
G. Raabe and H. Okamura, Chem. Commun., 2003, 2826;
(c) C. Bolm and O. Simic, J. Am. Chem. Soc., 2001, 123, 3830.
2 C. Bolm, M. Martin and L. Gibson, Synlett, 2002, 832.
3 For example, see: (a) C. P. R. Hackenberger, G. Raabe and
C. Bolm, Chem.–Eur. J., 2004, 10, 2942; (b) C. R. Johnson and
O. M. Lavergne, J. Org. Chem., 1993, 58, 1922.
4 M. Harmata and N. Pavri, Angew. Chem., Int. Ed., 1999, 38, 2419.
5 (a) M. Harmata and S. K. Ghosh, Org. Lett., 2001, 3, 3321;
(b) M. Harmata and X. Hong, J. Am. Chem. Soc., 2003, 125, 5754;
(c) M. Harmata, X. Hong and C. L. Barnes, Org. Lett., 2004, 6, 2201;
(d) M. Harmata and X. Hong, Org. Lett., 2005, 7, 3581.
6 C. Bolm and J. P. Hildebrand, Tetrahedron Lett., 1998, 39, 5731.
7 (a) C. Bolm and J. P. Hilderbrand, J. Org. Chem., 2000, 65, 169;
(b) J. Sedelmeier and C. Bolm, J. Org. Chem., 2005, 70, 6904;
(c) G. Y. Cho, P. Remy, J. Jansson, C. Moessner and C. Bolm,
Org. Lett., 2004, 6, 3293; (d) A. Correa and C. Bolm, Adv. Synth.
Catal., 2008, 350, 391.
Variations in procedures generally involved changing amounts
of catalyst and ligand, as well as occasional increases in the amount
of 4 used for coupling. Entries 1 and 2 illustrate that chloride
coupling is possible and can result in near quantitative yields to
afford an N-arylated sulfoximine, provided sufficient amounts of
palladium and ligand are present.16 Chloride 12 presented some
difficulties but once again with only a slight increase in catalyst
loading, good yields of coupling product 13 could be obtained.
Interestingly, o-dichlorobenzene (14) afforded the bis-coupling
product 15 in 60% yield (Table 2, entry 8). This ligand was
first reported by Bolm as a product of the corresponding
dibromide17 and it has been used in a number of interesting
catalytic, asymmetric processes, with variable results.18 Its
accessibility from 14 should broaden interest in its further
application or modification.
8 J. Rudolph and C. Bolm, Synthesis, 2000, 911.
9 C. Moessner and C. Bolm, Org. Lett., 2005, 7, 2667.
10 M. Miyasaka, K. Hirano, T. Satoh, R. Kowalczyk, C. Bolm and
M. Miura, Org. Lett., 2011, 13, 359.
We expected that aryl chlorides bearing additional electron-
withdrawing groups would couple with greater facility than those
without and this was apparently the case. Both 16 and 18 gave
good yields of the corresponding coupling products 17 and 19
(Table 2, entries 9–10). We expected and found that o-chlorobenzo-
phenone (20) successfully reacted with 4 to afford benzothiazine 21
in 77% yield (Table 2, entry 11). We thought that fluorine
substitution would be a problem with aldehyde 22, but even in
the presence of excess 4 the fluorinated benzothiazine 23 was
obtained in excellent yield with no evidence of fluoride
displacement under the reaction conditions (Table 2, entries
12–13). Finally, the dapsone analogue 25 was produced from
the dichloride 24.
11 M. Harmata, X. Hong and S. K. Ghosh, Tetrahedron Lett., 2004,
45, 5233.
12 Please see the supporting information for more results from the
ligand studyz.
13 (a) S. Yu, A. Haight, B. Kotecki, L. Wang, K. Lukin and D. R. Hill,
J. Org. Chem., 2009, 74, 9539; (b) G. J. Withbroe, R. A. Singer and
J. E. Sieser, Org. Process Res. Dev., 2008, 12, 480; (c) B. J. Kotecki,
D. P. Fernando, A. R. Haight and K. A. Lukin, Org. Lett., 2009, 11, 947.
14 M. R. Biscoe, B. P. Fors and S. L. Buchwald, J. Am. Chem. Soc.,
2008, 130, 6686.
15 (a) C. Valente, M. E. Belowich, N. Hadei and M. G. Organ, Eur. J.
Org. Chem., 2010, 4343; (b) J. Nasielski, N. Hadei, G. Achonduh,
E. A. B. Kantchev, C. J. O’Brien, A. Lough and M. G. Organ,
Chem.–Eur. J., 2010, 16, 10844; (c) M. G. Organ, M. Abdel-
Hadi, S. Avola, N. Hadei, J. Nasielski, C. J. O’Brien and
C. Valente, Chem.–Eur. J., 2007, 13, 150; (d) E. A. B. Kantchev,
C. J. O’Brien and M. G. Organ, Aldrichimica Acta, 2006,
39, 97.
16 For comparison purposes, when the reaction was conducted
at reflux (Pd2(dba)3, 10% RuPhos, toluene) for 48 h, the
yield of 11 was 48%. When the reaction was conducted
with BINAP in a sealed tube for 48 h (135 1C) the yield of 11
was 25%.
17 C. Bolm and O. Simic, J. Am. Chem. Soc., 2001, 123, 3830.
18 (a) V. Cadierno, J. Diez, S. E. Garcia-Garrido, J. Gimeno and
A. Pizzano, Polyhedron, 2010, 29, 3380; (b) C. Bolm, M. Martin,
G. Gescheidt, C. Palivan, T. Stanoeva, H. Bertagnolli, M. Feth,
A. Schweiger, G. Mitrikas and J. Harmer, Chem.–Eur. J., 2007,
13, 1842; (c) C. Bolm, M. Martin, O. Simi and M. Verrucci, Org.
Lett., 2003, 5, 427.
In conclusion, we have found a catalyst system that
facilitates the N-arylation of sulfoximine 4 with aryl chlorides.
These results suggest that this methodology will be useful for
the generation of N-aryl sulfoximines from both aryl
bromides and chlorides. Further studies of this chemistry are
in progress and results will be reported in due course.
This work was supported by the National Science Founda-
tion and the donors to the Harmata Research Fund (Merck).
We thank Professor Michael Organ (York University) for a gift
of PEPPSI ligands. We thank Drs Anthony R. Haight and
Brian J. Kotecki (Abbott) for a gift of bippyPhos.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7665–7667 7667