N-alkylations of NH-sulfoximines and NH-sulfondiimines with alkyl halides mediated by potassium hydroxide in dimethyl sulfoxide

Article abstract of DOI:10.1002/adsc.201400193

A general method for the N-alkylation of NH-sulfoximines and NH-sulfondiimines has been developed, employing alkyl bromides with KOH in DMSO at room temperature. A variety of previously inaccessible N-alkylated sulfoximines and sulfondiimines was prepared in good to excellent yields (up to 97%). As an application, the conditions were used to access the biologically active Suloxifen.

Full text of DOI:10.1002/adsc.201400193

UPDATES
DOI: 10.1002/adsc.201400193
N-Alkylations of NH-Sulfoximines and NH-Sulfondiimines with
Alkyl Halides Mediated by Potassium Hydroxide in Dimethyl
Sulfoxide
Christine M. M. Hendriks,+a Rebekka A. Bohmann,+a Marina Bohlem,a
and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675; e-mail: carsten.bolm@oc.rwth-aachen.de
+
Both authors contributed equally.
Received: February 28, 2014; Revised: March 14, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400193.
Abstract: A general method for the N-alkylation of
NH-sulfoximines and NH-sulfondiimines has been
developed, employing alkyl bromides with KOH in
DMSO at room temperature. A variety of previous-
ly inaccessible N-alkylated sulfoximines and sulfon-
diimines was prepared in good to excellent yields
(up to 97%). As an application, the conditions were
used to access the biologically active Suloxifen.
drous conditions (Scheme 1, method A).[10] Further-
more, long reaction times are required for reasonable
conversions which often depend on the steric and
electronic properties of the individual substrate, re-
sulting in a limitation of the product scope. In several
cases, a two-step protocol involving an acylation/re-
duction sequence proved advantageous (Scheme 1,
method B).[11]
While sulfoximines are monoaza analogues of sul-
fones, sulfondiimines can be regarded as diaza ana-
logues of the latter. Although already discovered in
1964,[12] sulfondiimines are still difficult to prepare.
Only few approaches towards these interesting mole-
cules have been reported,[13] and this lack of general
accessibility has limited the number of their synthetic
applications.[14] With the goal to facilitate the synthe-
Keywords: N-alkylation; metal-free reactions; sul-
fondiimines; sulfoximines; superbase; synthetic
methods
Sulfoximines have been applied with great success in sis of sulfondiimines and to broaden the substrate
asymmetric synthesis,[1] and more recently, much at- scope, we have recently focused attention on these at-
tention has been focused on the bioactive profiles of tractive high-valent sulfur compounds.[15] N-Monosub-
such compounds.[2,3] In drug development, N-methyl- stituted sulfondiimines 3 appear to be particularly in-
and N-alkylamino-substituted sulfoximines have teresting because N-functionalization of 3 is a high-
proved to be attractive.[4,5] For the synthesis of the potential strategy for introducing molecular diversity.
former, several methods have been introduced includ-
ing methylations of NH-sulfoximines 1 under Esch-
ACHTUNGTRENNUNG
weiler–Clark conditions[6] and alkylations of such
compounds with strong methyl-transfer agents such as
trimethyloxonium salts[7] and “magic methyl” (methyl
fluorosulfate).[8] For the introduction of longer alkyl
chains, however, these simple N-functionalization
strategies have remained largely unsuccessful[9] pre-
sumably due to the low nucleophilicity of the sulfox-
ACHTUNGTRENNUNGimine nitrogen atom. Thus, nucleophilic substitution
reactions of sulfoximines with alkyl halides commonly
involve the use of strong bases such as alkali metal
hydrides (MH) or butyllithium in combination with
Scheme 1. Representative procedures for the N-alkylation of
phase-transfer catalysts (PTC) under strictly anhy- sulfoximines 1 and sulfondiimines 3.
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Christine M. M. Hendriks et al.
Table 1. Conditions for the N-alkylation reaction of sulfoxi-
mine 1a and sulfondiimine 3a with n-butyl halides.[a]
Along those lines, we have already developed N-ary-
lation[16] and N-alkenylation reactions of NH-sulfon-
diimines[16b] leading to a broad product portfolio. As
in the chemistry of sulfoximines, N-alkylations of NH-
sulfondiimines are difficult, and to date only few ex-
amples have been reported. Those include the prepa-
ration of N-alkylamino sulfondiimines by deprotona-
tion of NH-sulfondiimines with sodium hydride fol-
lowed by alkylations of the resulting anions with alkyl
halides at elevated temperature.[17] A general, mild
method for the preparation of N-alkylated sulfondi-
Entry
X
T [8C] Yield of 2a[b] [%] Yield of 4a[b] [%]
1
2
3
4
5
Br r.t.
r.t.
Cl r.t.
Br 60
Br 90
83
95
62
83
80
84
ACHTUNGTRENNUNG
I
79
73[c]
59
lenged by the preparative difficulties, we decided to
search for an alkylation strategy allowing specific con-
versions of NH-derivatives of sulfoximines and sul-
fondiimines. The success of this investigation is re-
ported here.
Initially, an early experimental observation report-
ed by Heaney and Ley in 1973 caught our atten-
tion.[18] They found KOH in DMSO to be a superb re-
56
[a]
Reaction conditions: alkyl halide (1.5 equiv.), KOH
(2.0 equiv.), DMSO, 4 h, argon atmosphere.
After flash column chromatography.
[b]
[c]
Reaction performed for 6 h.
agent combination for N-alkylations of indoles and DMSO was performed. The exclusive formation of
pyrroles with alkyl halides, providing the desired N-al- (R)-2a confirmed the expected stereospecificity of the
kylated products in high yields. Apparently, the reac- N-alkylation. Although not explicitly confirmed ex-
tions proceeded through N-metallated intermediates perimentally, we assume an identical reaction course
which required strongly ionizing solvents to be reac- for the analogous N-functionalizations of sulfondi-
tive enough for the subsequent nucleophilic substitu-
ACHTUNGTRENNUNG
tion reactions with the alkyl halides.[19–21] We antici-
pated an analogous reactivity profile in N-alkylations scope with respect to the alkyl halides was investigat-
of sulfoximines and sulfondiimines. To our delight, ed. Considering the results summarized in Table 1 and
this hypothesis was confirmed. Starting from NH-sul- taking into account factors such as cost, accessibility
foximine 1a and NH-sulfondiimine 3a alkylations with and environmental impact, alkyl bromides were
n-butyl bromide (1.5 equiv.) in combination with chosen as electrophiles for the intended N-alkylation
KOH (2 equiv.) in DMSO afforded the corresponding reactions. Again, NH-sulfoximine 1a and NH-sulfon-
N-butylated products 2a and 4a in yields of 83% and diimine 3a served as representative substrates. As the
84%, respectively (Table 1, entry 1).[22] The transfor- data in Table 2 reveal, the established N-alkylation
mations occurred at room temperature, and the protocol proved general, and in most cases the N-al-
common reaction time was 4 h.
kylated products were obtained in good to excellent
Employing n-butyl iodide as alkylating agent raised yields. Commonly, the N-alkylated sulfoximines 2
the yield of 2a (from 83% to 95%), but lowered it were obtained in slightly higher yields than the corre-
slightly for 4a (from 84% to 79%; Table 1, entry 2). sponding sulfondiimines 4. We attribute this fact, as
Also n-butyl chloride could be used for the N-alkyla- discussed before, to the lower stability of the sulfon-
tions, but in these cases the yields were lower even diimine derivatives under the strongly basic reaction
after an extended reaction time (6 h instead of 4 h; conditions.
Table 1, entry 3). Performing the reactions at ambient
All N-alkylations with linear alkyl bromides pro-
temperature proved optimal for conversions of both ceeded well irrespective of the chain length affording
1a and 3a. Raising the temperature to 608C or 908C the corresponding sulfoximines 2 and sulfondiimines 4
had almost no effect in alkylations of sulfoximine 1a in yields ranging from 80% to 89% and 64% to 80%,
with n-butyl bromide to give 2a. In contrast, the respectively (Table 2, entries 1–4). For the introduc-
yields of 4a were lower under those modified condi- tion of the N-octadecyl group the alkyl iodide was
tions, presumably due to an accelerated partial de- used and 2f and 4f were obtained in 92% and 70%,
composition of the starting material (Table 1, entries 4 respectively (Table 2, entry 5). A decrease in yield
and 5).
was observed when certain branched alkyl bromides
Commonly, the sulfur reagents were employed as were applied (Table 2, entries 6–9). In such transfor-
racemates. In order to ensure the stereochemical in- mations the position of the methyl substituent was im-
tegrity of the transformation, an N-butylation of portant as, for example, reflected by the yields of sul-
enantiopure (R)-1a with n-butyl bromide and KOH in foximines 2g–i. Whereas N-isopropyl derivative 2g
2
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N-Alkylations of NH-Sulfoximines and NH-Sulfondiimines with Alkyl Halides
Table 2. Conditions for the N-alkylation reaction of sulfox-
imine 1a and sulfondiimine 3a with various alkyl brom
ides.[a]
70% and 88% (Table 2, entries 15 and 16). In this
context, the formation of N-benzyl sulfondiimine 4p
(Table 2, entry 15) is of particular interest because
this compound had proven to be difficult to prepare
by other means.[16] Finally, citronellyl bromide was ap-
plied leading to sulfoximine 2r and sulfondiimine 4r
in 97% and 65% yield, respectively (Table 2,
entry 17). As the sulfur-containing starting materials
were used as racemates, diastereomeric products (in
ca. 1:1 ratios) were obtained in these cases.[23]
G
ACHTUNGTRENNUNG
Entry
R
2/4 Yield of Yield of
[b] [%] [b] [%]
2
4
To further investigate the newly devised method,
conversions of diversely substituted sulfoximines
1 and sulfondiimines 3 were studied. As alkylating
agents, 11-bromo-1-undecene and n-butyl bromide
were selected. The results are summarized in Table 3
and Table 4. To our delight, all substituent combina-
tions on sulfur (alkyl/aryl, dialkyl, and diaryl) were
tolerated well, and from both 1 and 3 the correspond-
ing N-alkylated products 5–9 and 10–16 were ob-
tained in high yields. Although different alkylating
agents were used, the reactions of the sulfoximines
appeared to lead to slightly higher yields than those
performed with the analogous sulfondiimine deriva-
tives (for example, Table 3, entry 3 versus Table 4,
entry 1). Methoxy and bromo substituents on the S-
aryl groups remained intact (Table 3, entries 1 and 2
as well as Table 4 entries 4 and 5), which might prove
useful for subsequent functionalizations.
A variety of S-aryl-S-alkyl sulfondiimines with
a phenyl, a 4-methoxyphenyl (PMP), or a tosyl group
on the second imine nitrogen reacted well with n-
butyl bromide as alkylating agent affording the corre-
sponding N-butylated products 10–15 in good to high
yields (Table 4, entries 1–6). The N’-substituent did
not have a major effect on the alkylation behaviour
as illustrated by the comparison between the yields of
À
1
2
3
CH2CH3
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
87
89
80
82
92
14
34
95
83
79
81
83
83
93
75
88
72
80
76
64
70
0
À
ACHTUNGTRENNUNG(CH2)6CH3
À
(CH2)11CH3
À
4
ACHTUNGTRENNUNG(CH2)13CH3
5[c]
6
ACHTUNGTRENNUNG(CH2)17CH3
À
CH
À
G
7
8
9
10
11
12
13
14
15
16
ACHTUNGTRENNUNG
38[d]
79
73
72
72
78
88
69
70
80
À
À
T
ACHTUNGTRENNUNG
À
G
À
CH2CH=CH2
À
ACHTUNGTRENNUNG(CH2)3CH=CH2
(CH2)9CH=CH2
À
À
ꢀ
CH2C CH
CH2C CCH2CH3
À
ꢀ
À
CH2C6H5
À
ACHTUNGTRENNUNG(CH2)3C6H5
17
r
97[e]
65[e]
[a]
Reaction conditions: alkyl bromide (1.5 equiv.), KOH
(2.0 equiv.), argon atmosphere.
After flash column chromatography.
Reaction performed with iodide.
Reaction performed for 9 h.
[b]
[c]
[d]
[e]
The product was isolated as a mixture of diastereomers.
was only formed in 14% yield, the respective data for phenyl-substituted 4a (84%, Table 1, entry 1) and
isobutyl- and isoamyl-containing products 2h and 2i tosyl-containing 12 (79%, Table 4, entry 3). Alkylating
were better (34% and 95% yield, respectively). Anal- the S,S-diimine of tetrahydrothiophene as a represen-
ogous observations were made in N-alkylations of sul-
fondiimine 3a with branched alkyl bromides, targeting
products 4g–i (Table 2, entries 6–8). A variety of unsa-
Table 3. N-Alkylation reactions of sulfoximines 1b–j.[a]
turated substituents could be introduced, and in these
cases no structural limitations were apparent (Table 2,
entries 10–14). Both N-alkenylated and N-alkynylated
products were formed in good to high yields starting
from sulfoximine 1a as well as sulfondiimine 3a. In all
cases, the unsaturated moieties remained intact. The
high yield (88%) in the preparation of N-propargylic
sulfondiimine 4n (Table 2, entry 13) is particularly
noteworthy because it demonstrates the superiority of
the new protocol over the existing technology apply-
ing a combination of KH and propargylic bromide in
THF which provided 4n in only 68% yield.[15] The use
of two aryl-substituted alkyl bromides (benzyl bro-
mide and 3-phenylpropyl bromide) afforded the ex-
pected products (2p, 2q and 4p, 4q) in yields between
Entry Starting R1
Material
R2
Product,
Yield [%][b]
1
2
3
4
5
1b
1c
1d
1e
1f
4-Br-C6H4
4-MeO-C6H4 Me
Ph
Ph
Me
Me
5, 83
6, 87
cyclopropyl 7, 91
Ph
Me
8, 88
9, 88
[a]
Reaction conditions: 11-bromo-1-undecene (1.5 equiv.),
KOH (2.0 equiv.), argon atmosphere.
After column chromatography.
[b]
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Christine M. M. Hendriks et al.
Table 4. N-Alkylation reactions of sulfondiimines 2b–h.[a]
Entry R1
R2
R3
Product,
Yield [%][b]
1
Ph
Ph
Ph
cyclopropyl Ph
10, 75
Scheme 3. Protection of sulfoximine 1e with a photo-cleava-
ble protecting group and regeneration of the starting materi-
al.
2[c]
3
Me
Me
4-MeOC6H4 11, 78
tosyl
12, 79
13, 85
14, 79
15, 83
16, 94
4
5
6
7
4-MeOC6H4 Me
4-BrC6H4
4-MeC6H4
Ph
Me
Me
Ph
Ph
was then shown that the photolabile nitrobenzyl pro-
tecting group could be cleaved under irradiation with
tetrahydrothiophene
Ph
[a]
Reaction conditions: n-butyl bromide (1.5 equiv.), KOH UV light in dioxane regenerating sulfoximine 1e in
(2.0 equiv.), argon atmosphere.
After flash column chromatography.
Reaction performed with 12-bromo-1-dodecene.
64% yield after 5 h.
[b]
[c]
In summary, we have developed a general protocol
for the N-alkylation of both NH-sulfoximines and
NH-sulfondiimines, employing alkyl bromides with
KOH in DMSO at room temperature. This cost-effec-
tive and operationally simple method proved suitable
tative S,S-dialkyl sulfondiimine provided 16 in 94% for the synthesis of a variety of N-alkylated sulfox-
yield (Table 4, entry 7). imines and sulfondiimines in good to excellent yields
AHCTUNGTRENNUNG
Finally, two applications of the newly devised N-al- (up to 97%). In terms of application, the protocol has
kylation method with KOH in DMSO were investi- been used for the preparation of the biologically
gated. The first focused on the preparation of N-ami- active Suloxifen and a related sulfondiimine. In addi-
noalkylated S,S-diphenyl sulfoximines[3,5a–c] and sul- tion, using the same method, a light-cleavable N-pro-
fondiimines,[17] which have been reported to exhibit tecting group was introduced into a sulfoximine, and
significant spasmolytic activity. In this context, Suloxi- subsequently cleaved with UV-light.
fen (17) proved particularl< interesting as it exhibit-
ed both oral and parental spasmolytic and antiasth-
matic effects.[5a–c] To our delight, the KOH/DMSO Experimental Section
method was also applicable here providing Suloxifen
(17), albeit in low yield (25%), in a single step by re- General Procedure for the Synthesis of N-Alkylated
acting sulfoximine 1e with 1-bromo-2-(diethylamine)- Sulfoximines and Sulfondiimines
ethane hydrobromide (Scheme 2). An analogous reac-
tion of sulfondiimine 2a gave 18 in 17% yield.
Into an argon-flushed Schlenk tube were added NH-sulfox-
AHCTUNGTREGiNNNU mine 1 (1 equiv.) or NH-sulfondiimine 3 (1 equiv.) and po-
The second application was followed with the wider
vision to introduce a light-cleavable N-protecting
group into sulfoximine chemistry. Following this idea
and applying the KOH/DMSO protocol developed
before, sulfoximine 1e was reacted with ortho-nitro-
benzyl bromide (for 5 h at 608C) to give 19 in 57%
yield (Scheme 3).[24] Confirming the original idea, it
tassium hydroxide (2 equiv.). The mixture was dissolved in
DMSO (1.5 mLmmolÀ1) and stirred for 5 min. Then, the
alkyl bromide (1.5 equiv.) was added, and the reaction mix-
ture was stirred for 3 to 6 h at room temperature. Water
(6 mL) was added and the mixture was extracted with DCM
(3ꢁ8 mL). The combined organic layers were dried over an-
hydrous magnesium sulfate, and the solvents were removed
under reduced pressure. Finally, the product was purified by
flash column chromatography.
Acknowledgements
R.A.B. acknowledges the Deutsche Forschungsgemeinschaft
(IRTG 1628, SeleCa) for financial support. We thank Dr.
Daniel Priebbenow and Dr. Vincent Bizet (both RWTH
Aachen University) for proof-reading of the manuscript and
Marcus Frings for the HPLC measurements (RWTH Aachen
University).
Scheme 2. Synthesis of Suloxifen (17) and a related sulfon-
diimine 18.
4
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Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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UPDATES
Christine M. M. Hendriks et al.
2010, 352, 2892–2898; b) A. Beyer, C. M. M. Reucher,
C. Bolm, Org. Lett. 2011, 13, 2876–2879; c) H. Baars,
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strate combinations, applications of lower reagent
amounts might also lead to high product yields.
[23] To confirm our assumption that bromoarenes and bro-
moalkenes could not be applied, couplings of bromo-
benzene and b-bromostryrene with sulfoximine 1a were
attempted. Both reactions remained unsuccessful, and
no coupling product was obtained.
[22] The use of over-stoichiometric amounts of the alkyl
halide and KOH resulted from observations made in
our previous work (ref.[21]), where it ensured high sub-
strate conversions. Although not investigated here
again, we assume that, depending on the specific sub-
[24] C. M. M. Reucher, Master Thesis, RWTH Aachen Uni-
versity, 2011.
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asc.wiley-vch.de
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
N-Alkylations of NH-Sulfoximines and NH-Sulfondiimines
with Alkyl Halides Mediated by Potassium Hydroxide in
Dimethyl Sulfoxide
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Christine M. M. Hendriks, Rebekka A. Bohmann,
Marina Bohlem, Carsten Bolm*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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These are not the final page numbers!