Copper-catalyzed N-alkynylations of sulfoximines with bromoacetylenes

Article abstract of DOI:10.1021/ol5016898

N-Alkynylated sulfoximines have been obtained by copper-catalyzed cross-coupling reactions starting from NH-sulfoximines and bromoacetylenes in moderate to good yields. The reaction conditions are mild, and the substrate scope is wide.

Full text of DOI:10.1021/ol5016898

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed N‑Alkynylations of Sulfoximines with
Bromoacetylenes
Xiao Yun Chen, Long Wang, Marcus Frings, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: N-Alkynylated sulfoximines have been obtained
by copper-catalyzed cross-coupling reactions starting from
NH-sulfoximines and bromoacetylenes in moderate to good
yields. The reaction conditions are mild, and the substrate
scope is wide.
ulfoximines have come a long way since their discovery in
1950.1 Starting as a structural oddity, the sulfonimidoyl
readily available bromoalkynes 5 were known to undergo
alkynylating cross-couplings in related systems,13,14 they
became our first-choice reagents in the search for an improved
and safe(r) synthetic access to 3. The realization of this idea is
presented here.
S
unit, which consists of a central sulfur atom bound to an
oxygen, a nitrogen, and two (mostly differently substituted)
carbon atoms, is now found in many areas of contemporary
chemistry.2 Those include classical auxiliary-supported asym-
metric synthesis,3 ligand-assisted (stereoselective) metal
catalysis,4 and organocatalysis.5 Furthermore, sulfoximines are
present in other fields where, for example, they have shown
promising bioactivities being relevant in medicinal or
agricultural chemistry.6
Realizing that N-alkynylated sulfoximines 3 could be
regarded as chiral analogues of ynamides and thus offer rich
prospects for sequential functionalizations,7 this essentially
unfathomed type of compound piqued our interest.8
For the initial phase of the project, S-methyl-S-phenyl-
sulfoximine (1a) and 1-bromo-2-phenylacetylene (5a) were
chosen as substrates, which we expected to provide N-
alkynylated sulfoximine 3a after the coupling. Because of the
particular properties of the sulfoximines, an extensive screening
of reaction conditions was necessary to get the first positive
results. Ultimately, a slightly modified procedure of Hsung’s
original protocol13d as described by Yorimitsu, Oshima, and co-
worker15 for the coupling of aryl sulfonamides with 1-
bromoalkynes worked best (Scheme 1, eq 3). It involved the
use of CuSO4·5H2O (10 mol %), 1,10-phenanthroline (phen,
20 mol %), and K2CO3 (2 equiv), which were applied in
toluene at 60 °C. In this manner, product 3a was obtained in
64% yield after 24 h (Table 1, entry 1). Control reactions
confirmed that no product was formed in the absence of either
the copper salt or the ligand. Next, the reactivities of different
Cu(I) and Cu(II) salts were tested (entries 2−6). Neither the
oxidation state nor the presence or absence of coordinated
water had a distinct impact on the product formation, and in all
cases, product 3a was obtained in similar yields (58−68%).
Since the use of anhydrous Cu(OAc)2 provided the highest
yield (entry 4), it was chosen for the following studies. Raising
or lowering the reaction temperature from 60 to 80 °C or
40 °C, respectively, as well as utilizing a catalytic amount of
pyridine instead of 1,10-phenanthroline resulted in diminished
yields of 3a (entries 7−9). Next, the effects of base, reaction
time, solvent, and substrate ratio were investigated (entries 10−
25).
To date, only two synthetic approaches are known (Scheme
1, eqs 1 and 2).9−12 Both are copper-catalyzed oxidative cross-
Scheme 1. Synthetic Approaches toward N-Alkynylated
Sulfoximines 3
coupling reactions starting from NH-sulfoximines 1. They differ
in the required coupling partners, which are either terminal
alkynes 2 or propiolic acids 4. In both reactions, dioxygen (pure
or in form of air) is used as terminal oxidant at elevated
temperature (70 and 80 °C), which raises safety concerns in
large-scale applications. We hypothesized that sequential
processes with decoupled oxidation/cross-coupling steps
could reduce this potential danger in the preparation of 3. As
Compared to K2CO3 (68% yield of 3a, Table 1, entry 4), all
other bases proved less efficient (Table 1, entries 10−16). To
our surprise, this was also true for the reactions with Na2CO3
and Cs2CO3, which led to 3a in only 8% and 6% yield,
Received: June 11, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5016898 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Development of Optimal Reaction Conditions
Scheme 2. Scope of the Copper-Catalyzed N-Alkynylation of
Sulfoximines 1 with Bromoacetylenes 5
entry
copper salt
base
solvent
toluene
time (h) yield (%)
1
2
3
4
5
6
CuSO4·5H2O
CuSO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
t-BuOK
KOH
24
24
24
24
24
24
24
48
24
24
24
24
24
24
48
48
48
72
48
48
48
48
48
48
48
64
58
60
68
65
67
48
44
31
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
Cu(OAc)2·H2O
Cu(OAc)2
CuCl2
CuI
b
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
c
8
d
9
10
11
12
13
14
15
16
17
18
19
20
21
6
2
5
pyridine
KOAc
51
0
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
30
72
74
50
55
8
17), the general applicability of the protocol using various
sulfoximines 1 and bromoacetylenes 5 was explored (Scheme
2). First, arylbromoacetylenes with an electron-donating or
-withdrawing group at the 2-, 3-, or 4-position of the arene were
coupled with sulfoximine 1a. Irrespective of the substitution
pattern, the reactions proceeded well leading to the
corresponding products (3b−l) in moderate to high yields.
Although no clear reactivity trend was observed, it appeared as
if reactions with halo-substituted substrates gave the best results
as reflected by the high yields (71−86%) of products 3c, 3d, 3f,
3j, and 3k (Scheme 2). An electron-withdrawing nitro group
seemed to hamper the coupling, and the yields of 3g and 3l
were lower (46% and 43%, respectively) compared to the
unsubstituted product 3a (72%). Whereas methyl groups on
the arene had essentially no effect (3b: 74%, 3h: 71%),
methoxy substituents gave nonuniform results (3e: 62%, 3i:
34%).17
Finally, a triisopropylsilyl- and a β-styrenyl-substituted
bromoacetylene were applied in the coupling with sulfoximine
1a. These reactions proceeded well, and the corresponding
products, 3m and 3n, were obtained in 61% and 24% yields,
respectively. The former result is of particular interest because
cleavage of the silyl substituent could prove useful for the
synthesis of a monosubstituted terminal.
With the goal to evaluate the applicability of other
sulfoximines, products 3o−t were targeted (Scheme 2).
Probably because of the low solubility of S,S-dimethyl
sulfoximine (1b) in toluene, N-alkynylated 3o was obtained
in only 26% yield. In light of the analogous experiment with
sulfoximine 1a as starting material, which led to 3c in 85%
yield, this result was disappointing. Higher yields were achieved
in couplings of other sulfoximine/alkyne combinations. For
example, applying S,S-diphenyl sulfoximine (1c) in a coupling
with (2-bromoethynyl)-4-bromobenzene led to 3p in 71%
yield. Both the alkyl as well as the aryl substituent of the
sulfoximine could be modified as reflected by the syntheses of
N-alkynylated products 3q−t, which were obtained in yields
ranging from 47% to 64%. Analyzing these data in detail
suggested that steric effects dominated over electronic ones.
1,4-dioxane
DMF
e
22
toluene
toluene
toluene
toluene
60
73
62
50
f
23
g
24
h
25
a
Conditions used: 1a (0.6 mmol), 5a (0.5 mmol), copper salt (0.05
mmol, 10 mol %), base (1.25 mmol), stirred in solvent (1 mL) under
argon at 60 °C for indicated time. Conducted at 80 °C. Conducted
b
c
d
at 40 °C. With 20 mol % of pyridine instead of 1,10-phenanthroline.
e
f
Use of 1a (0.5 mmol) and 5a (0.75 mmol). Use of 1a (0.75 mmol)
g
h
and 5a (0.5 mmol). Performed in air. Performed with 0.025 mmol
(5 mol %) of Cu(OAc)2.
respectively (Table 1, entries 10 and 11).16 The only
noteworthy yields of 3a were obtained from reactions with
pyridine or K3PO4 instead of K2CO3 providing 3a in 51% and
30% yield, respectively (Table 1, entries 14 and 16). Prolonging
the reaction time from 24 h to 48 h and 72 h increased the yield
of 3a from 68% to 72% and 74%, respectively (Table 1, entries
4, 17, and 18). Considering this only minor change, the
evaluation of the substrate scope (Scheme 2) was later done
with a reaction time of 48 h. With respect to the solvent,
toluene proved superior to DCE, 1,4-dioxane, and DMF, which
all gave 3a in lower yields (Table 1, entries 4, 19−21). Varying
the ratio of 1a and 5a showed that using a slight excess of the
sulfoximine was beneficial for the yield of 3a (Table 1, entries 4,
22, and 23). Finally, it is important to note that the coupling
could be performed in air (instead of argon as inert
atmosphere; Table 1, entry 24) and that the catalyst loading
could be reduced from 10 to 5 mol % (Table 1, entry 25).
Although compared to the standard conditions (Table 1, entry
4) the yields of 3a were slightly lower (62% and 50%,
respectively, versus 68%), these observations might prove
valuable for a possible scale-up of the coupling process.
Having identified optimal conditions for the coupling of 1a
and 5a to give 3a with respect to yield per time (Table 1, entry
B
dx.doi.org/10.1021/ol5016898 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008; p 209. (d) Han, Z (S);
Reeves, D. C.; Krishnamurthy, D.; Senanayake, C. H. In Comprehensive
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As noted in our previous work, N-alkynylated sulfoximines 3
were prone to undergo acid-catalyzed hydroysis providing N-
acylsulfoximines.9 Furthermore, we reported a (Z)-selective
reduction of 3a to the corresponding N-vinylsulfoximine10 and
demonstrated thermal [2 + 2]-cycloadditions leading to
cyclobutenone derivatives.10,11 It was now decided to attempt
an oxidative transformation (Scheme 3). To this end, N-
Yamamoto, H., Eds.; Elsevier: Amsterdam, 2012; p 560. (e) Lucking,
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Scheme 3. Transformation of N-Alkynyl Sulfoximine 3a into
Diketo Derivative 6 under Oxidative Conditions
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described by Al-Rashid, Hsung, and co-workers for the
formation of α-ketoimides from ynamides.18 The ruthenium-
catalyzed oxidation of the triple bond with NaIO4 worked very
well providing diketo derivative 6 in excellent yield (91%).
In conclusion, we have developed an alternative approach
toward N-alkynylated sulfoximines avoiding the use of
potentially hazardous gaseous dioxygen. The copper-catalyzed
transformations proceed under mild reaction conditions
involving the use of readily available bromoacetylenes in
combination with diversely substituted NH-sulfoximines. In an
initial experiment, an efficient ruthenium-catalyzed oxidative
transformation of the C−C-triple bond into an α-diketo moiety
was demonstrated.
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ASSOCIATED CONTENT
■
Hillisch, A.; Reichel, A.; Wengner, A. M.; Siemeister, G.
ChemMedChem 2013, 8, 1067.
S
* Supporting Information
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H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P.
Acc. Chem. Res. 2014, 47, 560.
(8) Banert, K.; Hagedorn, M.; Wutke, J.; Ecorchard, P.;
Schaarschmidt, D.; Lang, H. Chem. Commun. 2010, 46, 4058.
(9) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.-F.; Bolm, C.
Angew. Chem., Int. Ed. 2013, 52, 3478.
Experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carsten.bolm@oc.rwth-aachen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) Priebbenow, D. L.; Becker, P.; Bolm, C. Org. Lett. 2013, 15,
6155.
(11) For initial synthetic applications of 3, see: Pirwerdjan, R.;
Priebbenow, D. L.; Becker, P.; Lamers, P.; Bolm, C. Org. Lett. 2013,
15, 5397.
X.Y.C. is grateful to the China Scholarship Council (CSC) for a
predoctoral stipend. Christine Hendriks and Ying Cheng (both
RWTH Aachen University) are kindly acknowledged for
providing samples of sulfoximines 1. We also cordially thank
Prof. Dr. Jun Wang (School of Chemistry and Chemical
Engineering, Sun Yat-Sen University, China) for stimulating
discussions.
(12) An early example of an alkynylated sulfoximine can be found in
the literature: Tanaka, R.; Yamabe, K. J. Chem. Soc., Chem. Commun.
1983, 329. However, as demonstrated by Professor Banert (TU
Chemnitz), the proposed structure was incorrect. For a clarification,
see: Banert, K.; Hagedorn, M.; Wutke, J.; Ecorchard, P.;
Schaarschmidt, D.; Lang, H. Chem. Commun. 2010, 46, 4058.
(13) For selected examples, see: (a) Frederick, M. O.; Mulder, J. A.;
Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.;
Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (b) Dunetz, J. R.;
Danheiser, R. L. Org. Lett. 2003, 5, 4011. (c) Hirano, S.; Tanaka, R.;
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(e) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
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