Palladium-Catalyzed Carbonylation in the Synthesis of N-Ynonylsulfoximines

Article abstract of DOI:10.1002/adsc.202001440

Palladium-catalyzed carbonylation reactions with Cr(CO)₆ as carbonyl source are key for the preparation of N-ynonylsulfoximines from NH-sulfoximines and bromoalkynes. The couplings proceed at room temperature with a wide range of substrate combinations affording the corresponding products in good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202001440

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DOI: 10.1002/adsc.202001440
Palladium-Catalyzed Carbonylation in the Synthesis of N-
Ynonylsulfoximines
Ding Ma,a Chenyang Wang,a Deshen Kong,a Yongliang Tu,a Peng Shi,a and
Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
Phone: (+49)-241-8094675
E-mail: Carsten.Bolm@oc.RWTH-Aachen.de
Manuscript received: November 18, 2020; Revised manuscript received: January 12, 2021;
Version of record online: January 21, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001440
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
serve as valuable intermediates in the preparation of
Abstract: Palladium-catalyzed carbonylation reac-
tions with Cr(CO)6 as carbonyl source are key for
the preparation of N-ynonylsulfoximines from NH-
sulfoximines and bromoalkynes. The couplings
biologically relevant products.[2]
In recent years, the chemistry of sulfoximines has
progressed from the use as “chemical chameleons for
asymmetric synthesis”[3–5] to promising applications in
proceed at room temperature with a wide range of
medicinal chemistry, crop protection, and material
substrate combinations affording the corresponding
sciences.[6] Surprisingly, combinations of ynones and
products in good yields.
sulfoximines as represented by scaffolds 2 have only
scarcely been reported. To the best of our knowledge,
Guin and coworkers were the first to report a single
Keywords: carbonylation; chromium hexacarbonyl;
palladium catalysis; sulfoximines; ynones
example of such compounds (molecule 2a) in 2016,[7]
and very soon after, we described compounds 2b and
2c as accidentally obtained oxidation products of the
corresponding N-propagylsulfoximines.[8,9] We now
Ynones have found numerous applications in organic targeted on an extension of the structural portfolio of
synthesis.[1] Derivatives with nitrogen substituents at such N-ynonylsulfoximines envisioning multi-compo-
the carbonyl group (2-ynamides or propiolamides 1, nent couplings involving metal-catalyzed carbonyla-
Figure 1) are particularly attractive because they can tion reactions. In this scenario, additionally required
components were simple bromoalkynes 3 and NH-
sulfoximines 4 which both are readily accessible or
commercially available (Scheme 1).
Carbonylation reactions are of tremendous impor-
tance for synthesizing carbonyl compounds.[10] The
high toxicity of gaseous carbon monoxide has led to
the development of significant technical advances such
as in-situ CO generation in two-chamber systems[11] or
Figure 1. Ynones, 2-ynamides or propiolamides 1, and N-
ynonylsulfoximines 2.
Scheme 1. Retrosynthesis for N-ynonylsulfoximines 2 by met-
al-catalyzed carbonylation reactions.
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flow protocols.[12] Furthermore, various CO surrogates
have been introduced.[13] Among the latter, metal
carbonyls play a significant role. Various complexes
can be applied as CO source including Co2(CO)8,
W(CO)6, and Mo(CO)6, just to name a few.[14] For the
preparation of 2-ynamides, Wu, Wu, and co-workers
demonstrated the applicability of Co2(CO)8, and start-
ing from mixture of bromoalkynes and amines, they
devised a palladium-catalyzed aminocarbonylation
leading to the desired products in good to high
yields.[15] A typical example is shown in Scheme 2
(top).
Table 1. Optimization of reaction conditions.[a]
entry base
ligand
metal
solvent
yield
(%)[b]
carbonyl
1
Cs2CO3 Xphos Co2(CO)8 MeCN
8
2
Cs2CO3 Xphos Co2(CO)8 1,4-dioxane 25
3
4
5
6
Cs2CO3 Xphos Co2(CO)8 DMF
Cs2CO3 Xphos Co2(CO)8 THF
Cs2CO3 Xphos Co2(CO)8 toluene
Cs2CO3 Xphos Fe2(CO)9 DMF
Cs2CO3 Xphos Mo(CO)6 DMF
28
trace
trace
17
27
35
58
46
34
11
Taking inspiration by Wu’s findings, we wondered
about an analogous carbonylation strategy with NH-
sulfoximines 4 as amino component, which we
7
8
9
Cs2CO3 Xphos Cr(CO)6
K2CO3 Xphos Cr(CO)6
Na2CO3 Xphos Cr(CO)6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
envisaged to provide N-ynonylsulfoximines
2
(Scheme 2, bottom). The successful implementation of
10
11
12
13
14
15[c]
this approach is reported here.[16,17]
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
Xphos Cr(CO)6
PPh3 Cr(CO)6
BINAP Cr(CO)6
The study was commenced with (bromoethynyl)-
benzene (3a) and S-methyl-S-phenylsulfoximine (4a)
as representative starting materials. To our disappoint-
ment, similar conditions as those reported by Wu, Wu,
and coworkers for their system (Scheme 2, top) proved
ineffective here. Thus, in the presence of a catalyst
derived from Pd(OAc)2 and Xphos (2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl) with Co2(CO)8
as carbonyl source and Cs2CO3 as base in acetonitrile
for 24 h at room temperature in air, the yield of product
2aa was only 8% (as determined by NMR spectro-
scopy with 1,1,2,2-tetrachlorethane as internal
standard; Table 1, entry 1). Using 1,4-dioxane or DMF
as solvent improved the yield of 2aa to 25% and 29%,
respectively. THF and toluene were not suitable
(Table 1, entries 2–5). With DMF as solvent, various
carbonyl sources were tested. Among Co2(CO)8,
Fe2(CO)9, Mo(CO)6, and Cr(CO)6 the latter complex
59
74
–
–
Cr(CO)6
Cr(CO)6
83
(76)[d]
82
16[c,e] K2CO3
17[c,e,f] K2CO3
–
–
Cr(CO)6
Cr(CO)6
DMF
DMF
61[d]
[a] Reaction conditions: 3a (0.4 mmol), 4a (0.2 mmol), Pd
(OAc)2 (0.02 mmol), ligand (0.02 mmol), metal carbonyl
([CO] 0.4 mmol), and base (0.4 mmol) in solvent (1.0 mL).
[b] Determined by 1H NMR analysis of the crude reaction
mixture using CHCl2CHCl2 as the internal standard.
[c] Reaction time of 36 h.
[d] Yield after isolation by column chromatography.
[e] Use of 0.002 mmol of Pd(OAc)2.
[f] Performed on a gram scale.
gave the best result providing 2aa in 35% yield dium catalysis was performed in the absence of a
(Table 1, entries 3, 6–8). Other base/phosphine combi- phosphine ligand. Thus now, 2aa was obtained in 74%
nations led to variable results (Table 1, entries 3, 9– yield (Table 1, entry 14). Extending the reaction time
13). In general, the use of K2CO3 instead of Cs2CO3 from 24 h to 36 h also had a positive effect, leading to
showed the best effects (Table 1, entry 8 versus 9), and 2aa in 83% yield (Table 1, entry 15). Isolating the
thus, several subsequent experiments applied this base. product by column chromatography afforded 2aa in
Another result came to our surprise: unexpectedly, the 76% yield. The palladium loading could be reduced
yield of 2aa significantly increased, when the palla- from 10 mol% to 1 mol% without significantly affect-
ing the yield (Table 1, entry 16). Finally, performing
the catalysis on a gram scale led to 2aa in 61% yield
after isolation by column chromatography (Table 1,
entry 17).j18]
Next, the substrate scope was evaluated. Scheme 3
summarizes the results. The standard conditions for the
test reactions performed on a 0.2 mmol scale involved
a 2:1 substrate ratio (for bromoalkyne and sulfoximine)
and the use of 1 mol% of Pd(OAc)2 in combination
with 0.33 equiv. of Cr(CO)6 and 2.0 equiv. of K2CO3 in
Scheme 2. Amidocarbonylation reported by Wu, Wu, and co-
workers (top);[15] envisaged synthesis of N-ynonylsulfoximines
2 (bottom).
DMF at ambient temperature for 36 h. In the first
series of experiments, the sulfoximine structure was
varied in carbonylation reactions with (bromoethynyl)-
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Scheme 4. Substrate scope – variation of the bromoalkyne;
yields after isolation by column chromatography.
Scheme 3. Substrate scope – variation of the sulfoximines;
yields after isolation by column chromatography.
products 2ba–2pa ranged from 41% for 4-nitro-
substituted compound 2ga to 91% for 3-methoxy-
containing product 2la. In average, substrates with
benzene (3a). In general, the couplings proceeded electron-donating groups gave slightly higher yields
well, and with S-aryl-S-methyl NH-sulfoximines prod- that those with electron-donating substituents. Compar-
ucts 2ab–ap were obtained in yields ranging from 33– ing the yields of the three fluoro-containing products
94%. Although stereoelectronic effects induced by 2da, 2ma, and 2pa shows the best result for 4-
substituents on the arene showed a low degree of substituted product 2da (83% yield). The two other
consistency, the reaction appeared to benefit from the products were both obtained in 69% yield. Finally,
presence of electron-donating groups, as reflected by cyclohexyl-substituted bromoalkyne 3q was tested,
the yield of 91% for 4-methoxy-containing product and also in this case, the carbonylation proceeded well
2ac. Electron-withdrawing groups on the arene seemed leading to the desired product 2qa in 76% yield.
to hamper the reaction outcome as exemplified by the
In light of the aforementioned experimental results
formation of 4-cyano-substituted 2ah, which was only and considering previous reports,[10,19] a tentative
obtained in 68% yield. Fluoro, chloro, and bromo mechanistic path for the presented carbonylation
substituents were well tolerated, independent of their reaction can be proposed (Scheme 5). At first, in-situ
position at the arene. The presence of a 4-nitro group generated palladium(0) oxidatively inserts into the
proved problematic, and only traces of product 2ai
were observed under standard conditions. Increasing
the catalyst loading from 1 mol% to 5 mol%, however,
gave 2ai in 45% yield. Comparing the results for the
three bromo-containing products 2af, 2am, and 3ap
revealed that steric effect played a role, but unexpect-
edly, ortho-substituted product 2ap gave the highest
yield (66%) in this series (versus 62% and 37% for
para- and meta-substituted compounds 2af and 2am,
respectively). Finally, S,S-diphenyl-NH sulfoximine
(4q) and dibenzothiophene sulfoximine (4r) were
applied, and also those couplings proceeded well
affording the corresponding products 2aq and 2ar in
85% and 63% yield, respectively.
Subsequently, the substrate scope with respect to
the bromoalkyne was explored. NH-sulfoximine 4a
was selected as representative coupling partner.
Scheme 4 summarizes the results. First, aryl-substi-
tuted bromoalkynes were applied. A wide range of
functional groups including alkyl, halo, and formyl
were tolerated in all three positions (para, meta, and
ortho) of the arene. The yields of the corresponding
Scheme 5. Proposed mechanism.
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CÀ Br bond of bromoalkyne 3 leading to palladium(II)
intermediate A. Subsequently, A reacts with CO
stemming from Cr(CO)6 to give acyl palladium
intermediate B. Ligand exchange of B with NH-
sulfoximine 4 followed by reductive elimination via C
provides product 2 and closes the catalytic cycle by
regeneration of the initial palladium(0) species.
Acknowledgements
D.M., C.W., D.K., Y.T. and P.S. are grateful to the China
Scholarship Council (CSC) for pre-doctoral stipends. The
authors also thank an anonymous reviewer for suggesting the
use of CO sources other than metal carbonlys (as detailed in
footnote 18). Open Access funding enabled and organized by
Projekt DEAL.
As starting point for exploring product functionali-
zations, brominations of N-ynonylsulfoximines 2aa,
2ab, 2ah, and 2an with bromosuccinimide (NBS)[20]
were studied (Scheme 6). Starting from 2aa, dibromi-
nated product 5a was obtained with an E/Z ratio of
1.2:1.0 in 92% yield. 4-Tolyl-containing derivative
2ab reacted analogously providing 5b in 85% yield
(E/Z=1.3:1.0). Presumably due to electronic and steric
effects, respectively, the yields of the corresponding
products resulting from conversions of 2ah and 2an
were lower. Thus, 5c stemming from 4-cyano-sub-
stituted 2ah was formed in only 67% yield, and for 5d
resulting from 2-methoxy-containing 2an the yield
was 57%. Also in these two cases, double bond
isomers were observed (for 5c: E/Z=1.6:1.0 and for
5d: E/Z=1.2:1.0).
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