Palladium-catalyzed C-N cross-coupling of N'-monosubstituted sulfondiimines with aryl bromides

Article abstract of DOI:10.1002/adsc.201200754

A general method for the N-arylation of sulfondiimines with aryl bromides using tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) as catalyst system was developed. A new benzothiazine was obtained, and a protocol for the cleavage of para-methoxyphenyl (PMP) groups in PMP-protected sulfondiimines has been found, which provides access to synthetically useful NH-derivatives, that are difficult to prepare by other means. Copyright

Full text of DOI:10.1002/adsc.201200754

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DOI: 10.1002/adsc.201200754
À
Palladium-Catalyzed C N Cross-Coupling of N’-Monosubstituted
Sulfondiimines with Aryl Bromides
Mathieu Candy,a Rebekka Anna Bohmann,a and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675; e-mail: carsten.bolm@oc.rwth-aachen.de
Received: August 23, 2012; Revised: September 17, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200754.
Abstract: A general method for the N-arylation of
sulfondiimines with aryl bromides using tris(dibenz-
ACHTUNGTRENNUNGylideneacetone)dipalladium(0) [Pd2ACHTUNGTREN(NGUN dba)3] and 2-di-
cyclohexylphosphino-2’,6’-diisopropoxybiphenyl
(RuPhos) as catalyst system was developed. A new
benzothiazine was obtained, and a protocol for the
cleavage of para-methoxyphenyl (PMP) groups in
PMP-protected sulfondiimines has been found,
which provides access to synthetically useful NH-
derivatives, that are difficult to prepare by other
means.
copper-catalyzed N-arylation of 1a with an aryl iodide
[Eq. (2)].[10] Although the yield of the corresponding
product (2l) was only moderate, it allowed a structural
diversification of the core unit, which was difficult to
achieve by other means.
Keywords: aryl bromides; cross-coupling; N-aryla-
tion; palladium catalysis; sulfondiimines
Sulfondiimines are high-valent sulfur compounds first
described by Cogliano and Braude in 1964,[1] and
since their discovery, they have received only minimal
Despite this first success, the development of an im-
interest in the scientific community. The synthetic proved and more general N-arylation of sulfondii-
access to sulfondiimines has been considered arduous, mines appeared desirable. Here, we report a major
and the structural diversity of the reported products advance along those lines and describe the palladium-
remained low.[2] As a consequence, only a very limited catalyzed cross-coupling reactions of N-monosubsti-
number of examples describing the utility of these tuted sulfondiimines of type 1a with aryl bromides.
compounds exist.[3–5] Interestingly, this is the sharp
Taking the encouraging initial result [Eq. (2)] as
contrast to the structurally related sulfoximines, which starting point, we first focused our attention on
nowadays represent core units of well-established copper-catalyzed Ullmann-type cross-couplings using
chiral ligands and auxiliaries[6] and which have experi- sulfondiimine 1a and iodobenzene as test substrates.
enced growing interest in medical[7] and crop-protec- To our disappointment, none of applied systems led
tion applications.[8]
to a significant breakthrough,[11] and the desired prod-
Recently, we described a novel method for the uct (2a) was only obtained in low to moderate yield
preparation of sulfondiimines by NCS-mediated oxi- (ꢀ54%).[10–12] With a stoichiometric amount of copper
dative imination of sulfiliminium salts [Eq. (1)].[9] The the yield of 2a could be raised to 76%.[11] In order to
mild conditions tolerate many functional groups, and search for a more efficient method, we decided to
the method is particularly convenient for the synthesis change the metal and to explore palladium-catalyzed
of chiral S-aryl-S-alkyl derivatives.
cross-coupling reactions.
In the same study,[9] derivatizations of the second
Inspired by the methods developed for N-arylations
nitrogen atom of N-monosubstituted sulfondiimine 1a of sulfoximines, analogous conditions were applied to
were investigated. Particularly noteworthy is the first the model cross-coupling reaction of sulfondiimine 1a
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Palladium-Catalyzed C N Cross-Coupling of N’-Monosubstituted Sulfondiimines
Table 1. Optimization of the palladium-catalyzed N-arylation of N-phenyl-S-methyl-S-phenyl sulfondiimine (1a).
Entry
Base
Ligand
Temp. [8C]
Reaction time [h]
Yield [%][a]
1[b]
2[c]
3
4
5
t-BuOK
Cs2CO3
t-BuONa
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
IPr
80
36
36
12
24
24
24
24
12
20
0
BINAP
BINAP
BINAP
BINAP
DPPF
DPPE
RuPhos
RuPhos
110
110
100
100
100
100
100
110
19
30
67
0
20
0
6
7
8
90
86
9[d]
[a]
After flash column chromatography.
[b]
[c]
[d]
Use of Pd
Use of Pd
CHTUNGTRENNUNG
U
Use of 1.5 equiv. of bromobenzene, 1.6 equiv. of Cs2CO3, 2.5 mol% of Pd2ACHTNUGTRNEUNG(dba)3 and 7.5 mol% of RuPhos.
with bromobenzene (Table 1). Nolanꢁs procedure em- of sulfoximines with aryl chlorides,[16] noticably im-
ploying a combination of Pd2A(dba)3 and IPr as ligand proved the yield of 2a (90%; Table 1, entry 8). The
in dioxane at 808C[13] led to no reaction (Table 1, combination of Pd
2A(dba)3 and RuPhos also allowed us
entry 1). The use of Pd(OAc)2 as metal source and to reduce the amounts of both reagents and catalyst
CTHUNGTRENNUNG
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
BINAP as ligand in the presence of Cs2CO3 gave only without significantly affecting the yield of 2a. Thus
a low conversion (Table 1, entry 2). Better results with 1.5 equiv. of bromobenzene (instead of 2 equiv.)
were observed with a Pd2ACHTNUGTRNE(UGN dba)3/BINAP combination and 1.6 equiv. of Cs2CO3 (instead of 2 equiv.) together
and either t-BuONa or Cs2CO3 could be used as base with 2.5 mol% (instead of 4 mol%) of the metal com-
(30% versus 67% yield, albeit under slightly different plex and 7.5 mol% (instead of 8 mol%) of the ligand,
reaction conditions; Table 1, entries 3 and 4). At least 2a was obtained in 86% yield (Table 1, entry 9).
in part, the lower yield in the reaction with the stron-
With the goal of elucidating the substrate scope,
ger base t-BuONa was due to a base-induced degra- the optimized reaction conditions were applied in
dation of the starting material. Apparently, compared cross-coupling reactions of 1a with various aryl bro-
to sulfoximines, sulfondiimines were less tolerant to mides (Scheme 1). Generally, the expected products
strong basic reaction conditions and high tempera- were obtained in good yields, and the functional
tures. Furthermore, the nucleophilicity of the depro- group tolerance was high. Thus, also thioether 2g as
tonated nitrogen was lower. Subsequent screenings of well as acetyl-, nitro-, and cyano-substituted products
solvents and palladium sources led to no improve- 2h, 2l and 2m, respectively, were isolated in good to
ment. Noteworthy, the use of Cs2CO3 has proven cru- high yields. The electron density on the aryl bromide
cial. K2CO3 was ineffective (Table 1, entry 5).
Finally, the influence of the ligand was studied.[11] tions typically proceeded faster with electron-poor
Catalysts composed of combinations of Pd2A(dba)3 and substrates. In contrast, sterics played a dominant role.
had no major impact on the yields, although the reac-
CTHUNGTRENNUNG
bidentate phosphines DPPF or DPPE gave only low While meta- or para-substituted aryl bromides reacted
or no conversions (Table 1, entries 6 and 7). In con- readily, ortho-substituted ones led to a major decrease
trast and to our delight, the use of Buchwaldꢁs in yield. For instance, the N-3-methoxyphenyl deriva-
RuPhos,[15] which was recently used for the arylation tive 2c was obtained in 85% yield, whereas the analo-
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Scheme 2. Reactions of N-phenyl-S-methyl-S-phenyl sulfon-
diimine (1a) with 2-bromobenzaldehyde.
the heterocycle 3 (73% after 20 h at 1108C) could se-
lectively be obtained.
Next, the reaction conditions were applied in N-ar-
ylations of various sulfondiimines (Scheme 3). Gener-
ally, S-aryl-S-alkyl substrates reacted smoothly. For
example, cyclopropyl derivative 2r was obtained by
arylation of the corresponding NH-sulfondiimine with
bromobenzene in 92% yield. Triaryl derivatives 2s
and 2t were prepared in 75% and 71% yield, respec-
tively. The N-arylation with 2-bromopyridine and the
conversion of an N-butyl-substituted derivative pro-
ceeded well too, providing products 2u and 2v in 70%
Scheme 1. Cross-coupling reactions of N-phenyl-S-methyl-
S-phenyl sulfondiimine (1a) with various aryl bromide.
gous N-2-methoxyphenyl-substituted compound 2d
was only accessed in 58% yield. Along the same line,
bromomesitylene gave 2p in 79% yield, but the steri-
cally more demanding 2,4,6-tri-tert-butylbromoben-
zene did not react at all. The same argument ex-
plained the reactivity difference observed in couplings
with 1- and 2-bromonaphthalene affording 2k and 2j,
respectively. The 2-nitrophenyl derivative 2l was ob-
tained in a moderate yield of 42%, and full conver-
sion of the sulfondiimine could not even be reached
after 20 h. Finally, also pyridine derivatives 2n and 2o
could be prepared in good yields.
Noteworthy is the cross-coupling reaction of 1a and
2-bromobenzaldehyde, because heterocycle 3 was iso-
lated (Scheme 2). Apparently, it resulted from a subse-
quent intramolecular addition of the deprotonated
methyl group to the formyl moiety followed by dehy-
dration. Benzothiazine 3 represents the first example
of a new class of heterocyclic sulfondiimines. Its for-
mation was not surprising considering the similar be-
haviour of sulfoximines.[17,18] After further optimiza-
tion of the reaction conditions, both the cross-cou-
Scheme 3. Palladium-catalyzed N-arylation of N’-substituted
sulfondiimines. (The circles indicate which aryl group origi-
pling product 2q (80% yield after 5 h at 908C) and nated from the aryl bromide.)
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Palladium-Catalyzed C N Cross-Coupling of N’-Monosubstituted Sulfondiimines
Experimental Section
General Procedure for the N-Arylation of
Sulfondiimines
In a glove-box a dry Schlenk tube was charged with
Pd2ACTHNUTRGNE(UNG dba)3 (23 mg, 2.5 mol%) and RuPhos (35 mg,
7.5 mol%). The flask was then removed from the glove-box
and dry toluene (5 mL) was added followed by Cs2CO3
(521 mg, 1.6 mmol, 1.6 equiv.), the aryl bromide (1.5 mmol,
1.5 equiv.) and the sulfondiimine (1.0 mmol, 1.0 equiv.). The
reaction mixture was kept at 1108C for 20 h. After cooling
to room temperature saturated NH4Cl solution (20 mL) was
added, the product was extracted with ethyl acetate (3ꢂ
10 mL). The combined organic layers were then washed
with brine (20 mL), dried over MgSO4 and concentrated.
The product was purified by flash column chromatography.
Scheme 4. Oxidative deprotection of N-PMP sulfondiimines.
and 76% yield, respectively. As representative for an
S,S-dialkyl sulfondiimine, an N-arylated tetrahydro-
thiophene derivative was chosen, and from its reac-
tion with bromobenzene 2w was obtained in 78%
yield after only 5 h. When the first nitrogen carried
an electron-withdrawing group (here tosyl), degrada-
tion occurred. Thus, the attempt to prepare 2x re-
mained unsuccessful (after 5 h at 908C).
Acknowledgements
This work was supported by the Fonds der Chemischen In-
dustrie and, in part, by the Excellence Initiative of the
German federal and state governments (Seed Funds at
RWTH Aachen University). M.C. acknowledges support by
the Alexander von Humboldt foundation. We also thank Dr.
D. Priebbenow and I. Thomꢀ (both RWTH Aachen Universi-
The N-para-methoxyphenyl (PMP) derivatives 2r,
2u, and 2w, which were obtained by the cross-coupling ty) for helpful discussions and proof reading.
strategy in good to high yields, proved particularly
useful for subsequent transformations. The precursors
for the cross-coupling were easily accessed from the
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