Palladium-catalyzed intramolecular α-arylation of sulfoximines

Article abstract of DOI:10.1016/j.jorganchem.2003.07.004

The palladium-catalyzed cyclization of N-(2-bromobenzyl)- and N-(2-bromobenzoyl)-sulfoximines affords six-membered heterocycles in moderate to good yield. In both cases, the α-arylations of the sulfoximine methyl groups are catalyzed by combination of Pd(

Full text of DOI:10.1016/j.jorganchem.2003.07.004

Journal of Organometallic Chemistry 687 (2003) 444ꢀ450
/
www.elsevier.com/locate/jorganchem
Palladium-catalyzed intramolecular a-arylation of sulfoximines
Carsten Bolm *, Hiroaki Okamura, Marinella Verrucci
Institut fur Organische Chemie der RWTH Aachen, Professor-Pirlet-Straße 1, D-52056 Aachen, Germany
¨
Received 10 June 2003; received in revised form 29 July 2003; accepted 29 July 2003
Dedicated to Professor Dr. J. P. Geneˆt on occasion of his 60th birthday
Abstract
The palladium-catalyzed cyclization of N-(2-bromobenzyl)- and N-(2-bromobenzoyl)-sulfoximines affords six-membered
heterocycles in moderate to good yield. In both cases, the a-arylations of the sulfoximine methyl groups are catalyzed by
combination of Pd(OAc)2 and rac-BINAP in the presence of a base such as Cs2CO3 or K2CO3.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Arylation; Catalysis; Cyclization; Palladium; Sulfoximine
1. Introduction
Thus, the heterocyclization reaction depicted in
Scheme 1 relies on the high efficiency of both the
palladium-catalyzed intermolecular N-arylation of the
sulfoximine [4,5] and the subsequent intramolecular ring
close involving a formal CH-activation [6]. We now
wondered, if such cyclization reaction would also occur
with other substrates that lack the N-aryl-sulfoximine
nitrogen bond. As starting materials we envisaged the
use of benzylated and benzoylated sulfoximines 5 and 6,
respectively. Those compounds are readily available
[7,8] and would lead to interesting heterocyclic products
7 and 8, respectively, which could eventually serve as
useful building blocks for the synthesis of biologically
active sulfoximines [9,10] and chiral ligands for asym-
metric catalysis [5] (Scheme 2).
The palladium-catalyzed a-arylation of carbonyl
compounds was first reported in 1997 [1] and since
then it has been developed to an important method for
CꢀC bond formations [2]. The scope of this reaction
/
covers a wide range of substrates such as ketones, esters,
amides, nitriles and other compounds having acidic a-
hydrogens. Recently, we reported on the first palladium-
catalyzed a-arylation of sulfoximines, which allowed the
preparation of six- to eight-membered heterocyclic ring
systems in a most straighforward manner [3]. A typical
example is shown in Scheme 1. In the presence of
catalytic amounts of Pd(OAc)2 or [Pd2dba3] in combina-
tion with rac-BINAP as ligand and sodiumꢀtert-
/
Here, we report on the realization of this concept.
butoxide as base, 1,9-dibromonaphthaline (1) reacts
with sulfoximine 2 to give cyclized product 3 in 99%
yield. Mechanistic studies (using 2,2?-dibromobiphenyl
as substrate) revealed that the transformation involves
two steps which occur sequentially. First, the sulfox-
imine is N-arylated to afford intermediate 4, which then
cyclizes to give 3 through activation of the acidic
protons of the sulfoximine methyl group. Both steps
are palladium-catalyzed and proceed without detectable
racemization at the stereogenic sulfur atom.
2. Results and discussion
N-(2-Bromobenzyl)-sulfoximines (5a,c) and N-(2-
bromobenzoyl)-sulfoximines (6aꢀd) were prepared by
/
derivatization of NH-sulfoximine (2) with the corre-
sponding 2-bromobenzyl bromide or 2-bromobenzoyl
chloride, respectively. Compounds 5b and 5d were
derived from the reduction of 6b and 6d, respectively.
A metallation/alkylation sequence using n-butyliodide
as electrophile afforded 5e from 5a. The results of the
* Corresponding author. Fax: ꢁ49-241-809-2391.
E-mail address: carsten.bolm@oc.rwth-aachen.de (C. Bolm).
/
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2003.07.004

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palladium-catalyzed cyclization reactions are summar-
ized in Tables 1 and 2.
For the optimization of the reaction protocol 5a was
used as substrate. Confirming the overall concept we
found that with Pd(OAc)2 as metal source, rac-BINAP
as ligand, and cesium carbonate as base in toluene under
reflux a smooth intramolecular C-arylation of 5a
occurred affording the corresponding sulfoximine-con-
taining heterocycle after 16 h in 93% yield (Table 1,
entry 1). Other bases could also be applied, but the
yields were lower. For example, potassium carbonate
afforded the product in 88% yield, and the stronger base
sodium tert-butoxide led to decomposition and none of
the product was obtained. Nitro-substituted 5b was also
a good substrate for the cyclization reaction (Table 1,
entry 4). However in this case and in contrast to the
general trend, K2CO3 proved to be a better base than
Cs2CO3. Compound 5c bearing an electron-donating
Scheme 1.
substituent (Table 1, entries 5ꢀ
/
8) was less reactive than
the previously mentioned substrates, and in order to
Scheme 2.
Table 1
Palladium-catalyzed cyclization reactions of benzylated sulfoximines 5 a

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C. Bolm et al. / Journal of Organometallic Chemistry 687 (2003) 444ꢀ450
/
Table 2
Palladium-catalyzed cyclization reactions of benzoylated sulfoximines 6 a
achieve a high product yield with the Pd(OAc)2-based
catalyst an extended reaction time was required (91%
after 3 days). The catalyst derived from PdCl2 showed a
rather low activity (Table 1, entry 7), and, much to our
surprise, use of [Pd2dba3], which previously had been
applied successfully in a-arylations, gave rise to an
ineffective catalyst (Table 1, entry 8). Pyridine-derived
5d proved to be an excellent substrate for the hetero-
cyclization, and its palladium-catalyzed ring closure
afforded the corresponding product in 92% yield.
Particularly noteworthy is the conversion of 5e, since
for the first time the cyclization of a methylene carbon a
to the sulfoximine was achieved. Even though the yield
of the cyclized product was only 40% and a 1:1 mixture
of diastereomers was obtained, this transformation sets
the basis for further investigations directed towards the
synthesis of higher branched and more functionalized
derivatives.
with a mixture of Pd(OAc)2, rac-BINAP, and K2CO3
and gave the cyclized product stemming from 6a in 62%
yield (Table 2, entry 1). Changing the base to NaOt-Bu,
KHMDS or LHMDS, as well as using [Pd2dba3] as
metal source or phosphines such as PPh3 or P(t-Bu)3 as
ligands, afforded the product in very low yield at best.
N-Benzoyl sulfoximine 6b bearing an electron-with-
drawing nitro group on the arene did not undergo
cyclization at all, whereas 6c having a more electron-rich
aromatic ring led to the heterocyclic product in 74%
yield (Table 2, entries 4 and 5, respectively). In the light
of the reaction behavior of pyridine 5d, which under-
went smooth cyclization under standard reaction con-
ditions (Table 1, entry 9), the low reactivity of 6d was
surprising. The yield of the desired product 7d was only
16%, and prolonged reaction time decreased the yield,
probably due to the decomposition of the product under
the reaction conditions.
Next, reactions with N-benzoylated sulfoximines 6 as
starting materials were investigated. In general, the
reactivity of these substrates was lower than those of
5, and the reaction scope was rather limited. Table 2
summarizes the results. The best catalysis was observed
A comparison of the data presented in Tables 1 and 2
reveals that structural details of the substrates have a
major impact on their reactivity. As found previously,
acylated sulfoximines are prone to undergo cleavage
reactions at the carbonyl imine bond [11]. Thus in

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reactions with 6, this cleavage could result in loss of
starting material and decomposition of the correspond-
ing product. Tables 1 and 2 also suggest that N-
benzoylated sulfoximines 6 are less reactive towards
cyclization reaction than their N-benzylated counter-
parts 5. This observation can be attributed to two
factors: The presence of an sp2-hydridized carbon as
linking unit between the sulfoximine and the arene part
of 6, which hampers the cyclization for steric reasons,
and the electron-withdrawing capability of the carbonyl
group in 6, which reduces the nucleophilicity of the
intermediate carbanion. The requirement of fine-tuned
electronic properties has also been observed in inter-
molecular a-arylations of sulfones, where highly nucleo-
philic carbanions were found to be unreactive [12].
Entirely unsuccessful were direct palladium-catalyzed
arylations of sulfoxides with haloarenes [13]. In our
study, the importance of electronic factors was further
apparent when comparing the cyclizations of 6b and 6c.
For the former compound a smooth palladium insertion
into the aryl halide bond can be expected due to the
presence of the electron-withdrawing nitro substituent
on the arene. The same group, however, slows down the
subsequent cyclization step (of intermediate 9), which
requires a most nucleophilic carbanion at the sulfox-
imine methyl group. In this particular case, the second
factor is so dominate that no heterocycle formation
occurs (Table 2, entry 4).
4. Experimental
4.1. General
1H- and 13C-NMR (400 and 100 MHz, respectively)
spectra were recorded in CDCl3 using TMS as an
internal standard on an Inova 400 spectrometer (or a
Gemini 300 for 13C-NMR only). Chemical shifts are
given in ppm and spinꢀspin coupling constants, J, are
/
given in Hz. IR spectra were recorded on a Perkin Elmer
FTIR as KBr pellets. MS spectra were measured on a
Varian MAT 212 and HRMS as well as SIMS-FAB
spectra on a Finnigan MAT 95 mass spectrometer.
Sulfoximine 2 was prepared according to literature
protocols [14].
4.2. Preparation of 5a and 5c
To a suspension of KH (48 mg, 1.2 mmol) in DME
(10 ml), methylphenylsulfoximine (2, 155 mg, 1.0 mmol),
Bn4NBr (16 mg, 0.05 mmol), and 2-bromobenzylbro-
mide (375 mg, 1.5 mmol) or 2-bromo-5-methoxybenzyl-
bromide (420 mg, 1.5 mmol) were added at room
temperature (r.t.). After stirring for ca. 16 h, water (20
ml) was added, and the mixture was extracted with
CH2Cl2 (3ꢂ20 ml). The combined organic layers were
/
dried over MgSO4, filtered, and concentrated, and the
resulting product was purified by chromatography using
silica gel as stationary phase.
4.2.1. Compound 5a
Colorless oil, 91% yield; Rf 0.46 (pentane: AcOEtꢃ
/
1
1:2); H-NMR (CDCl3): d 7.99ꢀ
(d, Jꢃ7.7 Hz, 1H, Ar), 7.68ꢀ7.56 (m, 3H, Ar), 7.50 (d,
Jꢃ8.0 Hz, Ar), 7.34 (t, Jꢃ7.7 Hz, Ar), 7.11 (t, Jꢃ8.0
Hz, 1H, Ar), 4.28 (d, Jꢃ15.7 Hz, 1H, CH2), 4.12 (d,
Jꢃ
15.7 Hz, CH2), 3.21 (s, 3H, CH3); 13C-NMR
(CDCl3): d 140.2 (C), 139.4 (C), 133.0 (C), 132.2
(CH), 129.5 (CHꢂ3), 128.6 (CHꢂ2), 128.0 (CH),
/
7.96 (m, 2H, Ar), 7.75
/
/
/
/
/
Apparently, the electronic factors are more balanced
in 6c. There, the palladium insertion reaction is more
difficult, but the electron-donating capability of the
methoxy substituent increases the nucleophilicity of
intermediate carbanion, and the cyclization reaction
affords the product in good yield (Table 2, entry 5).
/
/
/
/
127.4 (CH), 123.1 (C), 47.5 (CH2), 45.5 (CH3); IR
(neat): n 1443, 1227, 1144, 980, 747 cmꢄ1; MS (EI), m/z
(relative intensity): 325 ([Mꢁ
2]ꢁ, 13), 323 ([M]ꢁ, 12);
/
HRMS for C14H14NOSBr, Calc. [M]ꢁ 322.9980. Found
[M]ꢁ 322.9978.
3. Conclusion
4.2.2. Compound 5c
A new synthesis of sulfoximine-based heterocycles by
palladium catalyzed intramolecular a-arylations has
been developed. The reaction scope has been investi-
gated, and the relevant factors for an efficient catalytic
process have been identified. Since sulfoximines have
widely been recognized as most interesting reagents,
auxiliaries and ligands in organic synthesis, the newly
developed protocol expands the currently existing ap-
plication repertoire of this highly useful heteroatomic
molecular fragment by novel facettes.
White powder, 94% yield; m.p. 96ꢀ
(pentane: AcOEtꢃ
1:1); 1H-NMR (CDCl3): d 7.96ꢀ
7.90 (m, 2H, Ar), 7.63ꢀ7.50 (m, 3H, Ar), 7.35ꢀ7.32
(m, 2H, Ar), 6.62 (dd, Jꢃ3.2, 8.7 Hz, 1H, Ar), 4.19 (d,
/
98 8C; Rf 0.65
/
/
/
/
/
Jꢃ
/
15.8 Hz, 1H, CH2), 4.03 (d, Jꢃ15.8 Hz, 1H, CH2),
/
3,79 (s, 3H, CH3), 3.17 (s, 3H, CH3); 13C-NMR
(CDCl3): d 159.1 (C), 141.3 (C), 139.3 (C), 133.1
(CH), 132.7 (CH), 129.5 (CHꢂ
115.2 (CH), 113.7 (CH), 113.3 (C), 55.5 (CH3), 47.5
(CH2), 45.3 (CH3); IR (KBr): n 1470, 1439, 1296, 1225,
/
2), 128.6 (CHꢂ2),
/

448
C. Bolm et al. / Journal of Organometallic Chemistry 687 (2003) 444ꢀ450
/
1142, 743 cmꢄ1; MS (EI), m/z (relative intensity): 355
([Mꢁ
2]ꢁ, 33), 353 ([M]ꢁ, 29); Calc. for
C13H13N2OSBr: C, 50.86; H, 4.55; N, 3.95. Found C,
IR (CHCl3): n 2956, 1443, 1263, 1227, 1142, 750 cmꢄ1
MS (EI) m/z (relative intensity): 338 ([MꢄC3H7ꢁ
2]ꢁ,
6), 336 ([Mꢄ
C3H7]ꢁ, 6); HRMS for C18H22NOSBr,
Calc. [M]ꢁ 379.0605. Found [M]ꢁ 379.0605.
;
/
/
/
/
51.18; H, 4.92; N, 3.87%.
4.3. Preparation of 5b and 5d
4.5. Preparation of 6aꢀd
/
BH3×
/
SMe2 (890 ml, 2.0 mmol) was added to a solution
Et3N (167 ml, 1.2 mmol), and a catalytic amount of
DMAP, the aromatic acid chloride (1.1 mmol) were
added to a CH2Cl2 (10 ml) solution of methylphenyl-
sulfoximine (2, 155 mg, 1.0 mmol) at r.t. The reaction
mixture was stirred for 5 h, and poured into water (20
of 6b (383 mg, 1.0 mmol) or 6d (339 mg, 1.0 mmol) in
THF (10 ml) at 0 8C, and the reaction temperature was
allowed to rise to r.t. After stirring for ca. 16 h, an
aqueous solution of NaOH (0.1 N, 10 ml) was added
and the whole mixture was extracted with CH2Cl2 (3ꢂ
/
ml). The mixture was extracted with CH2Cl2 (3ꢂ20 ml),
/
20 ml). The combined organic layers were dried over
MgSO4, filtered, and the resulting product was purified
by chromatography using silica gel as stationary phase.
and the combined organic layers were dried over
MgSO4, filtered, and concentrated. The resulting pro-
duct was purified by chromatography using silica gel as
stationary phase.
4.3.1. Compound 5b
Pale brown powder, 91% yield; m.p. 131ꢀ
0.47 (ether); 1H-NMR (CDCl3): d 8.66 (m, 1H, Ar),
8.00ꢀ7.91 (m, 3H, Ar), 7.70ꢀ7.56 (m, 4H, Ar), 4.28 (d,
Jꢃ
/
133 8C; Rf
4.5.1. Compound 6a
White powder, 84% yield; m.p. 88.5ꢀ
/
90.5 8C; Rf 0.58
1
/
/
(AcOEt); H-NMR (CDCl3): d 8.15ꢀ
7.81 (dd, Jꢃ
Ar), 7.34 (dt, Jꢃ
7.7 Hz, 1H, Ar), 3.50 (s, 3H, CH3); 13C-NMR (CDCl3):
d 174.7 (C), 138.1 (Cꢂ2), 133.8 (CH), 133.5 (CH),
131.0 (CH), 130.4 (CH), 129.5 (CHꢂ2), 127.1 (CHꢂ
/
8.10 (m, 2H, Ar),
/
16.7 Hz, 1H, CH2), 4.06 (d, Jꢃ
/
16.7 Hz, 1H, CH2),
3.27 (s, 3H, CH3); 13C-NMR (CDCl3): d 147.4 (C),
/
1.7, 7.7 Hz, 1H, Ar), 7.74ꢀ
/7.59 (m, 4H,
/
1.4, 7.7 Hz, 1H, Ar), 7.25 (dt Jꢃ
/1.7,
142.7 (C), 138.9 (C), 133.4 (CH), 133.0 (CH), 129.9 (C),
2), 124.1 (CH), 122.6
129.7 (CHꢂ
/
2), 128.5 (CHꢂ
/
/
(CH), 47.0 (CH2), 45.4 (CH3); IR (KBr): n 1517, 1344,
1260, 1224, calcd. [M]ꢁ 323.9932. Found [M]ꢁ
323.9932.
/
/
2), 126.9 (CH), 120.1 (C), 44.3; IR (KBr): n 1635, 1297,
1256, 1216, 1144, 979, 744 cmꢄ1; MS (EI), m/z (relative
intensity): 324 ([Mꢀ
/
CH3ꢁ
/
2]ꢁ, 1), 322 ([MꢄCH3]ꢁ, 1);
Calc. for C14H12NO2SBr: C, 49.72; H, 3.58; N, 4.14.
Found C, 49.78; H, 3.53; N, 4.00%.
/
4.4. Preparation of 5e
To a solution of LDA (1.2 mmol) in THF (10 ml), a
solution of 5a (324 mg, 1.0 mmol) in THF (5 ml) was
4.5.2. Compound 6b
added at ꢄ
/
78 8C. After stirring for 30 min at this
Yellowish powder, 89% yield; m.p. 167.5ꢀ
/
168.5 8C; Rf
1
temperature, n-BuI (138 ml, 1.2 mmol) was added and
the reaction temperature was allowed to rise to r.t. After
stirring for ca. 16 h, H2O (20 ml) was added and the
0.32 (Hexane: AcOEtꢃ
/
1:1); H-NMR (CDCl3): d 8.69
(d, Jꢃ
/
2.7 Hz, 1H, Ar), 8.13ꢀ
/
8.07 (m, 3H, Ar), 7.83ꢀ
/
7.60 (m, 4H, Ar), 3.52 (s, 3H, CH3); 13C-NMR (CDCl3):
d 172.5 (C), 146.8 (C), 139.3 (C), 137.8 (C), 135.1 (CH),
mixture was extracted with CH2Cl2 (3 ꢂ
/
20 ml). The
combined organic layers were dried over MgSO4,
filtered, and concentrated, and the resulting product
was purified by chromatography using silica gel as
stationary phase.
134.4 (CH), 129.9 (CHꢂ
125.6 (CH), 125.3 (CH), 44.3 (CH3); IR (CHCl3): n
1635, 1515, 1344, 1300, 1217, 1153, 972 cmꢄ1; MS (EI),
/
2), 128.1 (C), 127.2 (CHꢂ2),
/
m/z (relative intensity): 369 ([Mꢄ
/
CH3ꢁ
2]ꢁ, 0.7), 367
/
([Mꢄ
/
CH3]ꢁ, 0.6); Calc. for C14H11N2O4SBr: C, 43.88;
H, 2.89; N, 7.31. Found C, 43.77; H, 3.00; N, 7.25%.
4.4.1. Compound 5e
Yellowish powder, 82% yield; m.p. 68ꢀ
(AcOEt); 1H-NMR (CDCl3): d 7.87 (bd, Jꢃ
Ar), 7.75 (br d, Jꢃ7.7 Hz, 1H, Ar), 7.64ꢀ7.52 (m, 3H,
Ar), 7.46 (dd, Jꢃ1.2, 7.8 Hz, 1H, Ar), 7.31 (dt, Jꢃ1.2,
7.4 Hz, 1H, Ar), 7.07 (br t, Jꢃ7.7 Hz, 1H, Ar), 4.25 (d,
Jꢃ15.9 Hz, 1H, CH2), 4.10 (d, Jꢃ15.9 Hz, 1H, CH2),
3.36ꢀ3.16 (m, 2H, CH2), 1.88ꢀ1.77 (m, 1H, CH2), 1.73ꢀ
1.61 (m, 1H, CH2), 1.38ꢀ1.23 (m, 4H, CH2ꢀCH2ꢀ), 0.85
(t, Jꢃ
7.0 Hz, 3H, CH3); 13C-NMR (CDCl3): d 132.8
(CH), 131.9 (CH), 129.2 (CHꢂ2), 129.1 (CHꢂ2),
/
70 8C; Rf 0.73
/
7.1 Hz, 2H,
4.5.3. Compound 6c
/
/
White powder, 91% yield; m.p. 95ꢀ
/
97 8C; Rf 0.54
1
/
/
(AcOEt); H-NMR (CDCl3): d 8.14ꢀ
7.74ꢀ7.60 (m, 3H, Ar), 7.48 (d, Jꢃ
(d, Jꢃ3.0 Hz, 1H, Ar), 6.82 (dd, Jꢃ3.0, 8.7 Hz, 1H,
/
8.10 (m, 2H, Ar),
8.7 Hz, 1H, Ar), 7.33
/
/
/
/
/
/
/
/
/
/
Ar), 3.80 (s, 3H, CH3), 3.48 (s, 3H, CH3); 13C-NMR
/
/
/
(CDCl3): d 174.9 (C), 158.6 (C), 139.1 (C), 138.3 (C),
134.4 (CH), 134.1 (CH), 129.7 (CHꢂ
2), 117.7 (CH), 115.4 (CH), 110.6 (C), 55.6 (CH3), 44.2
(CH3); IR (KBr): n 1627, 1573, 1469, 1403, 1317, 1260,
1217, 1116, 975 cmꢄ1; MS (EI), m/z (relative intensity):
/
/
2), 127.3 (CHꢂ
/
/
/
127.7 (CH), 127.1 (CH), 122.8 (CH), 56.8 (CH2), 47.0
(CH2), 30.3 (CH2), 22.3 (CH2), 22.1 (CH2), 13.7 (CH3);

C. Bolm et al. / Journal of Organometallic Chemistry 687 (2003) 444ꢀ
/
450
449
369 ([Mꢁ
/
2]ꢁ, 22), 367 ([M]ꢁ, 18); Calc. for
CH2), 4.50 (d, Jꢃ
/
15.8 Hz, 1H, CH2), 4.20 (d, Jꢃ
/
15.8
Hz, 1H, CH2); 13C-NMR (CDCl3): d 147.5 (C), 139.8
(C), 139.4 (C), 135.9 (C), 133.9 (CH), 130.2 (CH), 129.4
C15H14NO3SBr: C, 48.92; H, 3.83; N, 3.81. Found C,
48.97; H, 3.92; N, 3.81%.
(CHꢂ
/
2), 129.1 (CHꢂ2), 122.1 (CH), 121.7 (CH), 53.9
/
4.5.4. Compound 6d
(CH2), 48.8 (CH2); IR (KBr) 1521, 1345, 1228, 1189,
1124, 733 cmꢄ1; MS (EI), m/z (relative intensity): 288
([M]ꢁ, 15); HRMS of C14H12N2O3S, Calc. [M]ꢁ
288.0569. Found [M]ꢁ 288.0569.
White powder, 71% yield; m.p. 73.5ꢀ
(AcOEt); 1H-NMR (CDCl3): d 8.44 (dd, Jꢃ
1H, Ar), 8.17 (dd, Jꢃ1.9, 7.7 Hz, 1H, Ar), 8.13ꢀ
/
74.5 8C; Rf 0.39
1.9, 4.7 Hz,
8.08
4.7,
/
/
/
(m, 2H, Ar), 7.76ꢀ
/
7.62 (m, 3H, Ar), 7.30 (dd, Jꢃ
/
7.7 Hz, 1H, Ar), 3.50 (s, 3H, CH3); 13C-NMR (CDCl3):
4.6.3. Compound 7c
d 172.6 (C), 150.3 (CH), 148.5 (C), 139.4 (CH), 137.8
(C), 134.0 (CH), 132.7 (C), 129.6 (CHꢂ
2), 122.0 (CH), 44.2 (CH3); IR (KBr): n 1636, 1396,
1276, 1216, 1154, 1056, 975 cmꢄ1; MS (EI), m/z
Pale brown powder; m.p. 120ꢀ
tane: AcOEtꢃ
1:1); 1H-NMR (CDCl3): d 7.72ꢀ
2H, Ar), 7.48 (tt, Jꢃ1.2, 7.4 Hz, 1H, Ar), 7.40ꢀ
2H, Ar), 6.88 (d, Jꢃ8.2 Hz, 1H, Ar), 6.80 (d, Jꢃ
Hz, 1H, Ar), 6.68 (dd, Jꢃ2.7, 8.2 Hz, 1H, Ar), 4.63 (d,
Jꢃ15.6 Hz, 1H, CH2), 4.53 (d, Jꢃ15.6 Hz, 1H, CH2),
15.1 Hz, 1H,
/
121 8C; Rf 0.28 (pen-
7.67 (m,
7.35 (m,
2.7
/
2), 127.1 (CHꢂ
/
/
/
/
/
/
/
(relative intensity): 325 ([Mꢄ
([Mꢄ
CH3]ꢁ, 0.7); HRMS for C13H11N2O2SBr, Calc.
[MꢄCH3ꢁ CH3ꢁ
2]ꢁ 324.9470. Found [Mꢄ 2]ꢁ
324.9480.
/
CH3ꢁ
/
2]ꢁ, 0.7), 323
/
/
/
/
/
/
/
/
4.26 (d, Jꢃ
/
15.1 Hz, 1H, CH2), 3.97 (d, Jꢃ
/
CH2), 3.74 (s, 3H, CH3); 13C-NMR (CDCl3): d 159.5
(C), 140.3 (C), 139.7 (C), 133.3 (CH), 130.0 (CH), 129.0
4.6. Typical reaction procedure for the palladium-
catalyzed cyclization reaction
(CHꢂ4), 120.5 (C), 112.7 (CH), 112.2 (CH), 55.4
/
(CH3), 53.6 (CH2), 49.5 (CH2); IR (KBr) 1604, 1498,
1445, 1262, 1231, 1118, 841, 797 cmꢄ1;MS (EI), m/z
(relative intensity): 273 ([M]ꢁ, 3); Calc. for
C15H15NO2S: C, 65.91; H, 5.53; N, 5.12. Found C,
66.18; H, 5.52; N, 5.00%.
rac-BINAP (33 mg, 0.05 mmol), K2CO3 (276 mg, 2.0
mmol) or Cs2CO3 (652 mg, 2.0 mmol), and the substrate
(0.5 mmol) were added toluene (5 ml) to the mixture of
Pd(OAc)2 (5.6 mg, 0.025 mmol) and the resulting
suspension was stirred and heated to 100 8C. After the
reaction time indicated in Tables 1 and 2, the reaction
mixture was cooled to r.t., and water (10 ml) was added.
4.6.4. Compound 7d
Colorless oil; Rf 0.22 (AcOEt); H-NMR (CDCl3): d
1
8.45 (dd, Jꢃ
Ar), 7.64ꢀ7.46 (m, 4H, Ar), 7.27 (dd, Jꢃ
1H, Ar), 4.80 (d, Jꢃ16.6 Hz, 1H, CH2), 4.70 (d, Jꢃ
16.6 Hz, 1H, CH2), 4.58 (d, Jꢃ16.0 Hz, 1H, CH2), 4.32
(d, Jꢃ
16.0 Hz, 1H, CH2); 13C-NMR (CDCl3): d 148.4
(C), 148.1 (CH), 139.7 (C), 134.3 (CH), 133.7 (CH),
132.9 (C), 129.3 (CHꢂ2), 128.8 (CHꢂ2), 123.1 (CH),
/
1.6, 4.8 Hz, 1H, Ar), 7.91ꢀ/7.87 (m, 2H,
The mixture was extracted with CH2Cl2 (3ꢂ20 ml), and
/
/
/
4.8, 7.7 Hz,
the combined organic layers were dried over MgSO4,
filtered, and concentrated. The resulting product was
purified by chromatography using silica gel as station-
ary phase.
/
/
/
/
/
/
4.6.1. Compound 7a
1
56.2 (CH2), 47.6 (CH2); IR (CHCl3) 1440, 1234, 1139,
1119, 752 cmꢄ1; MS (EI), m/z (relative intensity): 244
([M]ꢁ, 63%); HRMS for C13H12N2OS, Calc. [M]ꢁ
244.0670, Found 244.0671.
White powder; m.p. 88ꢀ
/
90 8C; Rf 0.43 (AcOEt); H-
NMR (CDCl3): d 7.81 (m, 1H, Ar), 7.78 (m, 1H, Ar),
7.58 (br t, Jꢃ7.4 Hz, 1H, Ar), 7.46 (br t, Jꢃ7.4 Hz,
2H, Ar), 7.34 (br d, Jꢃ4.0 Hz, 2H, Ar), 7.25 (m, 1H,
Ar), 7.06 (br d, Jꢃ7.4 Hz, 1H, Ar), 4.77 (d, Jꢃ15.8 Hz,
1H, CH2), 4.68 (d, Jꢃ15.8 Hz, 1H, CH2), 4.41 (d, Jꢃ
15.3 Hz, 1H, CH2), 4.13 (d, Jꢃ
15.3 Hz, 1H, CH2); 13C-
NMR (CDCl3): d 140.3 (C), 138.2 (C), 133.4 (CH),
129.9 (CHꢂ5), 128.6 (C), 128.1 (CH), 127.0 (CH),
/
/
/
/
/
/
/
4.6.5. Compound 7e
/
Colorless oil; Rf 0.26 (pentane: AcOEtꢃ
NMR (CDCl3): d 7.90ꢀ6.90 (m, 18H, Ar), 4.90 (d, Jꢃ
15.9 Hz, 1H, CH2), 4.77 (d, Jꢃ16.8 Hz, 1H, CH2), 4.72
(d, Jꢃ16.8 Hz, 1H, CH2), 4.65 (d, Jꢃ15.9 Hz, 1H,
CH2), 4.10ꢀ4.00 (m, 2H, CHꢂ2), 2.50 (m, 1H, CH2),
1.80ꢀ1.18 (m, 11H, CH2), 0.84 (t, Jꢃ7.2 Hz, 3H, CH3),
0.78 (t, Jꢃ
6.9 Hz, 3H, CH3); 13C-NMR (CDCl3):
d137.8 (C), 137.7 (C), 133.3ꢀ125.8 (Cꢂ4, CHꢂ18),
/
1:1); 1H-
/
/
/
/
126.7 (CH), 54.0 (CH2), 49.1 (CH2); IR (CHCl3) 1652,
1241, 1190, 1120, 753 cmꢄ1; MS (EI), m/z (relative
intensity): 243 ([M]ꢁ, 25); HRMS for C14H13NOS,
Cacl. [M]ꢁ 243.0718. Found [M]ꢁ 243.0717.
/
/
/
/
/
/
/
/
/
/
4.6.2. Compound 7b
63.3 (CH), 62.7 (CH), 50.2 (CH2), 49.1 (CH2), 29.7
(CH2), 29.2 (CH2), 29.0 (CH2), 28.2 (CH2), 14.0 (CH3),
13.9 (CH3); IR (CHCl3) 2957, 1446, 1236, 1126, 752, 695
cmꢄ1; MS (EI), m/z (relative intensity): 299 ([M]ꢁ, 6%);
HRMS of C13H12N2OS, Calc. [M]ꢁ 299.1344. Found
299.1343.
White powder: m.p. 165ꢀ
AcOEtꢃ
1:1); 1H-NMR (CDCl3): d 8.22 (d, Jꢃ
1H, Ar), 8.12 (dd, Jꢃ2.4, 8.4 Hz, 1H, Ar), 7.86ꢀ
(m, 2H, Ar), 7.64 (tt, Jꢃ1.2, 7.4 Hz, 1H, Ar), 7.55ꢀ
(m, 2H, Ar), 7.20 (d, Jꢃ
/
166 8C; Rf 0.30 (pentane:
/
/
2.4 Hz,
/
/
7.80
7.47
/
/
/
8.4 Hz, 1H, Ar), 4.83 (s, 2H,

450
C. Bolm et al. / Journal of Organometallic Chemistry 687 (2003) 444ꢀ450
/
4.6.6. Compound 8a
References
White powder, m.p. 148ꢀ
1H-NMR (CDCl3): d 8.31 (m, 1H, Ar), 8.17ꢀ
2H, Ar), 7.77 (t, Jꢃ7.6 Hz, 1H, Ar), 7.66 (t, Jꢃ
2H, Ar), 7.58ꢀ7.53 (m, 2H, Ar), 7.25 (m, 1H, Ar), 4.60
(d, Jꢃ15.4 Hz, 1H, CH2), 4.50 (d, Jꢃ15.4 Hz, 1H,
CH2); 13C-NMR (CDCl3): d 167.5 (C), 136.6 (C), 135.2
(CH), 132.9 (CH), 130.2 (CH), 130.0 (CHꢂ3), 129.3
2), 128.8 (C), 127.3 (C), 53.4 (CH2);
IR (KBr) 1639, 1311, 1279, 1148, 1131, 982 cmꢄ1; MS
(EI), m/z (relative intensity): 257 ([M]ꢁ, 83%); Calc. for
C14H11NO2S: C, 65.36; H, 4.31; N, 5.44. Found C,
65.36; H, 4.40; N, 5.30%.
/
149 8C; Rf 0.43 (AcOEt);
8.13 (m,
7.6 Hz,
[1] (a) M. Palucki, S.L. Buchwald, J. Am. Chem. Soc. 119 (1997)
11108;
/
/
/
(b) B.C. Hamann, J.F. Hartwig, J. Am. Chem. Soc. 119 (1997)
12382;
/
/
/
(c) T. Satoh, Y. Kawamura, M. Miura, M. Nomura, Angew.
Chem. Int. Ed. Engl. 36 (1997) 1740;
(d) For early intramolecular a-arylations of ketones, see: H.
Muratake, A. Hayakawa, M. Natsume, Tetrahedron Lett. 38
(1997) 7577;
/
(CH), 128.8 (CHꢂ
/
(e) H. Muratake, M. Natsume, Tetrahedron Lett. 38 (1997) 7581.
[2] Review: D.A. Culkin, J.F. Hartwig, Acc. Chem. Res. 36 (2003)
234.
[3] C. Bolm, M. Martin, L. Gibson, Synlett (2002) 832.
[4] (a) C. Bolm, J.P. Hildebrand, Tetrahedron Lett. 39 (1998) 5731;
(b) C. Bolm, J.P. Hildebrand, J. Org. Chem. 65 (2000) 169.
[5] (a) For the use of N-arylated sulfoximines in asymmetric
catalysis, see: C. Bolm, O. Simic, M. Martin, Synlett (2001) 1878.;
(b) C. Bolm, O. Simic, J. Am. Chem. Soc. 123 (2001) 3830;
(c) C. Bolm, M. Martin, O. Simic, M. Verrucci, Org. Lett. 5 (2003)
427;
4.6.7. Compound 8c
Yellow powder, m.p. 192.5ꢀ
1H-NMR (CDCl3): d 8.20ꢀ
8.10 (m, 2H, Ar), 7.81ꢀ
(m, 4H, Ar), 7.15 (d, Jꢃ8.4 Hz, 1H, Ar), 7.06 (dd, Jꢃ
2.7, 8.4 Hz, 1H, Ar), 4.55 (d, Jꢃ15.1 Hz, 1H, CH2),
4.44 (d, Jꢃ
15.1 Hz, 1H, CH2), 3,87 (s, 3H, CH3); 13C-
NMR (CDCl3): d 167.6 (C), 160.5 (C), 136.3 (C), 134.9
(CH), 130.3 (CH), 129.8 (C), 129.7 (CHꢂ2), 128.6
(CHꢂ2), 120.2 (CH), 118.9 (C), 113.2 (CH), 55.7
/
194 8C; Rf 0.41 (AcOEt);
/
/
7.60
/
/
(d) C. Bolm, M. Martin, G. Gescheidt, C. Palivan, D. Neshcha-
din, H. Bertagnolli, M.P. Feth, A. Schweiger, G. Mitrikas, J.
Harmer, J. Am. Chem. Soc. 125 (2003) 6222.
/
/
[6] (a) For other intramolecular heterocyclizations involving N-
arylated sulfoximines, see: M. Harmata, N. Pavri, Angew.
Chem. Int. Ed. Engl. 38 (1999) 2419;
/
/
(b) M. Harmata, S.K. Ghosh, Org. Lett. 3 (2001) 3321;
(c) M. Harmata, X. Hong, J. Am. Chem. Soc. 125 (2003) 5754.
[7] For a recent review on sulfoximines, see: M. Reggelin, C. Zur,
Synthesis (2000) 1.
(CH3), 52.6 (CH2); IR (KBr) 1655, 1603, 1493, 1323,
1281, 1236 cmꢄ1; MS (EI), m/z (relative intensity): 287
([M]ꢁ, 41%); Calc. for C15H13NO3S: C, 62.70; H, 4.56;
N, 4.87. Found C, 62.62; H, 4.80; N, 4.62%.
[8] Sulfoximines bearing non-aromatic acyl groups can reductively be
transferred into the corresponding N-alkyl derivatives. For a
recent study on this topic, see: C. Bolm, C.P.R. Hackenberger, O.
Simic, M. Verrucci, D. Muller, F. Bienewald, Synthesis (2002)
¨
879.
4.6.8. Compound 8d
Yellow oil; Rf 0.23 (AcOEt); H-NMR (CDCl3): d
1
[9] (a) L.L. Muldoon, L.S.L. Walker-Rosenfeld, C. Hale, S.E.
Purcell, L.C. Bennett, E.A. Neuwelt, J. Pharmacol. Exp. Ther.
296 (2001) 797;
8.72 (dd, Jꢃ
Hz, 1H, Ar), 8.20ꢀ
1H, Ar), 7.69 (t, Jꢃ
7.9 Hz, 1H, Ar), 4.83 (d, Jꢃ
Jꢃ
15.8 Hz, 1H, CH2); 13C-NMR (CDCl3): d 167.0 (C),
153.0 (CH), 138.6 (C), 137.6 (CH), 136.2 (C), 135.2
(CH), 130.0 (CHꢂ2), 128.6 (CHꢂ2), 125.0 (CH),
/
1.7, 4.7 Hz, 1H, Ar), 8.59 (dd, Jꢃ
8.16 (m, 2H, Ar), 7.81 (t, Jꢃ
7.4 Hz, 2H, Ar), 7.53 (dd, Jꢃ
15.8 Hz, 1H, CH2), 4.59 (d,
/
1.7, 7.9
7.4 Hz,
4.7,
/
/
(b) P.J. Harvison, T.I. Kalman, J. Med. Chem. 35 (1992) 1227.
[10] (a) For sulfoximine-based transition-state analogue inhibitors and
pseudopeptides, see: W.L. Mock, J.-T. Tsay, J. Am. Chem. Soc.
111 (1989) 4467;
/
/
/
/
(b) W.L. Mock, J.Z. Zhang, J. Biol. Chem. 266 (1991) 6393;
(c) C. Bolm, J.D. Kahmann, G. Moll, Tetrahedron Lett. 38 (1997)
1169;
/
/
125.3 (C), 55.3 (CH2); IR (CHCl3) 1656, 1302, 1235,
1146, 982, 752 cmꢄ1; MS (EI), m/z (relative intensity):
258 ([M]ꢁ, 62); HRMS for C13H11N2O2S, calcd. [M]ꢁ
258.0463. Found 258.0463.
(d) C. Bolm, G. Moll, J.D. Kahmann, Chem. Eur. J. 7 (2001)
1118;
(e) C. Bolm, D. Muller, C.P.R. Hackenberger, Org. Lett. 4 (2002)
¨
893.
[11] C. Bolm, D. Muller, C. Dalhoff, C.P.R. Hackenberger, E.
¨
Weinhold, Bioorg. Med. Chem. Lett., in press.
[12] A.N. Kashin, A.V. Mitin, I.P. Beletskaya, R. Wife, Tetrahedron
Lett. 43 (2002) 2539.
Acknowledgements
[13] N. Rodrigues, A. Cuenca, C. Ramirez de Arellano, M. Medio-
Simo´n, G. Asensio, Org. Lett. 5 (2003) 1705.
[14] (a) R. Fusco, F. Tericoni, Chim. Ind. (Milan) 47 (1965) 61;
(b) C.R. Johnson, C.W. Schroeck, J. Am. Chem. Soc. 95 (1973)
7418;
The Deutsche Forschungsgemeinschaft within the
SFB 380 and the Fonds der Chemischen Industrie are
gratefully acknowledged for financial support. H.O.
thanks the Alexander von Humboldt-Stiftung for a
postdoctoral fellowship.
(c) C.S. Shiner, A.H. Berks, J. Org. Chem. 53 (1988) 5542;
(d) K. Mori, F. Toda, Chem. Lett. (1988) 1997.;
(e) J. Brandt, H.-J. Gais, Tetrahedron: Asymmetry 6 (1997) 909.