Oxidative C-S bond cleavage reaction of DMSO for C-N and C-C bond formation: New Mannich-type reaction for β-amino ketones

Article abstract of DOI:10.1039/c4ra14249g

A novel oxidative C-S bond cleavage reaction of DMSO for N-methylation and subsequent C-C bond formation is described. A series of aryl ketones as well as acetone derivatives could be selectively converted into the corresponding β-amino ketones. Mechanistic studies suggested that N-methylation between imine and DMSO was involved in the reaction.

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Oxidative C–S Bond Cleavage Reaction of DMSO for C–N and C–C
Bond Formation: New Mannichꢀtype Reaction for βꢀamino Ketones
Kai Sun,* Yunhe Lv, Zhonghong Zhu, Liping Zhang, Hankui Wu, Lin Liu, Yongqing Jiang, Beibei Xiao and
Xin Wang*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A novel oxidative C–S bond cleavage reaction of DMSO for
Nꢀmethylation course and subsequent C–C bond formation is
described. A series of aryl ketones as well as acetone
10 derivatives could be selectively converted into the
corresponding βꢀamino ketones. Mechanistic studies
suggested that Nꢀmethylation course between imine and
DMSO was involved in the reaction.
βꢀamino carbonyl compounds are important biological molecules
15 as well as useful synthetic intermediates for various pharmacyꢀ
euticals and natural products.1 The most classic method for the
preparation of βꢀamino carbonyl compounds is the threeꢀ
component mannich reaction with aldehydes, amines, and a C−H
acidic carbonyl compounds, which has been employed numerous
20 times as a key step in natural product synthesis as well as in
medicinal chemistry (eqn 1).2 In recent years, oxidative mannich
reactions, originating from readily available tertiary amines,3
emerges as a powerful method for preparation βꢀamino carbonyl
compounds with the aid of metal catalyst and oxidant (eqn 2).4
25 However, some substrate limitations and side reactions limits its
wide application. Alternative methods for preparation βꢀamino
carbonyl compounds suffer from multiple steps such as michael
addition reaction between ketene and amine component, or the
substitution reaction of βꢀhalo/hydroxyl ketones with nucleophilic
30 nitrogen sources.5
and give the key enamine or methyl amine intermediate through
50 the Nꢀmethylation course.
Based on this assumption, our initial investigations focused on
the effect of various solvents with selectfluor as an oxidant and
Cu(OTf)2 as the catalyst, which was an efficient combination for
Nꢀmethylation reaction in previous report.7 To our delight, DMF,
55 N,Nꢀdimethylacetamide (DMA), DMSO and Nꢀmethylꢀ2ꢀ
pyrrolidone (NMP) were all effective amine methylation source
Scheme 1 Diverse methyl source in mannich reantion
In the past decades, the common polar solvents DMF and
DMSO was widely used as a multipurpose building block and has
played an important role in organic synthesis.6 Recently, zhang
group reported the first Nꢀmethylation reaction between N–H
35 bonds of amidines and methyl C(sp3)–H bonds of DMSO and
DMF.7 Subsequently, Xiao group also reported the Nꢀmethylation
of amines and nitro compounds with DMSO.8 It is well known
that methylation of amines is a general transformation in organic
synthesis9 and many methods for preparation of methylated
40 amines have beem developed.10,11 However, Nꢀmethylation
course using DMF and DMSO as methyl source is rare and to the
best of our knowledge, using the common solvents DMF and
DMSO in mannich reaction as a methyl source has never been
reported. As part of our continuing interest in construction of C–
45 N bonds directly from C–H bonds,12 we proposed that the
indispensable formaldehyde analogues in mannich reactions may
be replaced with the cheap and lowꢀtoxic solvents DMF/DMSO
60 and gave the derised product 2a in moderate yields. However, no
reaction occurred with N,Nꢀdiethylacetamide (DEA) as the
corresponding methy source (Scheme 1). After detailed
screenings revealed that RuCl3 was the best catalyst and DMSO
was the suitable choice as methyl source and solvent. In the
65 presence of additive Na2CO3, the yield of 2a could be increased
to 91% (see ESI). It is highlight that this newꢀtype mannich
reaction may be a breakthrough compared to conventional
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Table 1: Scope of the mannich reaction. a, b
synthesis, as well as F, Cl, Br, CN can be converted into various
functional groups under ambient conditions. Similarly smooth
coupling was observed for aromatic ketones bearing substitution
groups at different positions such as 2ꢀCl, 3ꢀCl, 4ꢀCl and 2ꢀMe, 3ꢀ
25 Me, 4ꢀMe, and no previous yield disparity was abversed. (Table 1,
2bꢀ2g). The multisubstituted substrate 1r, 1s and 1t can also
provide the desired products 2r, 2s and 2t in high yields (91%,
O
O
O
81% and 96%). Furthermore, the
fused
bicyclic
Nsacc
Nsacc
Nsacc
Nsacc
Nsacc
acetylnaphthalene 1u, 1v and heterocyclic ketones 1w were all
30 effective substrates under these conditions, the yields of the
corresponding 2u, 2v and 2w were up to 91%, 87% and 81%,
respectively.
2a, 3 h, 91%
2b, 3 h, 93%
2c, 3 h, 91%
O
O
O
Cl
Nsacc
Nsacc
Nsacc
Nsacc
The substrate scope of this reaction can be extended to
propiophenone derivatives such as propiophenone (4a), 1ꢀ(4ꢀ
35 chlorophenyl)propanꢀ1ꢀone (4b) and 1ꢀ(pꢀtolyl)propanꢀ1ꢀone (4c),
the desired products could be obtained in 96%, 93% and 91%
yields. It is highlight that the potential of this reaction for
catalytic asymmetric mannichꢀtype reaction might promote more
research interests in this area.13 In addition, the present catalytic
40 system was amenable to the reaction of alkyl ketone compounds
3d, 3e and 3f, gave the corresponding products 4d, 4e and 4f in
high yields (97%, 95, and 88%), respectively. To our delight, this
reaction was also applicable to other acidic C−H compounds such
as nitromethane and nitroethane, the desired products were
45 obtained in 84% and 79% yields. It is noteworthy that this new
reaction not only expanded the methyl source in mannich reaction
but also enriched the content of the mannich synthetic
methodology.
Cl
2d
, 3 h, 95%
2e
, 5 h, 96%
2f
, 5 h, 92%
O
O
NO2
O
O2N
Cl
2g, 5 h, 92%
2h, 10 h, 89%
2i, 10 h, 84%
O
O
O
Nsacc
Nsacc
Nsacc
MeO
Ph
2j,
2k
2n
O
2l
3 h,93%
O
, 3 h,91%
O
, 3 h,87%
O
Nsacc
Nsacc
Nsacc
F
Br
NC
2m
2o
, 5 h, 88%
, 5 h, 93%
O
, 5 h, 81%
O
O
Nsacc
Nsacc
O
Nsacc
Table 2: Scope of the mannich reaction. a, b
F3C
2p
2q
, 3 h, 96%
2r
, 5 h, 82%
, 3 h, 91%
Nsacc
O
O
O
S
RuCl3, 1.10-phen
selectflour, Na2CO3
O
O
O
O
R1
Cl
O
N
NH
O
F3C
R1
R2
+
Nsacc
Cl
Cl
DMSO, 120 o
C
S
R2
Nsacc
O
O
3
4
50
CF3
O
2s
2t
, 10 h, 96%
2u
, 3 h, 91%
, 10 h, 81%
O
O
O
Nsacc
Nsacc
Nsacc
Nsacc
Cl
Nsacc
O
4a, 3 h, 96%
4b, 3 h, 93%
4c, 3 h, 91%
O
2v,
2w,
3 h, 87%
3 h, 81%
O
O
O
Nsacc
4f
, 3 h,88%
Nsacc
Nsacc
3 h, 95%
aRaction conditions: 1 (0.5 mmol), saccharin (1.0 mmol), RuCl3
(5 mol%), 1,10ꢀphen (0.025 mmol), selectflour (1.0 mmol),
Na2CO3 (1.0 mmol) and DMSO (2 mL) at 120 oC for 3ꢀ10 h.
bYield of the isolated products.
4d
4e,
, 3 h, 97%
5
Nsacc
Nsacc
O2N
NO2
4g, 3 h, 84%
4h, 3 h, 79%
aRaction conditions: 3 (0.5 mmol), saccharin (1.0 mmol), RuCl3
mannich reaction with toxic formaldehyde analogues as an
10 indispensable methyl source.
(5 mol%), 1,10ꢀphen (0.025 mmol), selectflour (1.0 mmol),
o
b
Na2CO3 (1.0 mmol) and DMSO (2mL) at 120 C for 3 h. Yield
With the optimal conditions in hand, we continued to evaluate
the substrate scope of this method for the synthesis of various βꢀ
amino ketones. Different aryl ketones are subjected to react with
saccharin and the results are summarized in Table 1.
15 Functionalgroup compatibility was quite broad as those
demonstrated with both electronꢀrich Me, MeO, cyclohexy, Ph
and ꢀdeficient F, Cl, Br, CN, CF3, NO2 and ester groups which
were obtained in good to excellent yields (2a−2q). The results of
this work are significant considering that the ester unit may be
20 used as a readily manageable protecting group in organic
55 of the isolated products.
The mechanism of this reaction was then studied. First, radical
inhibitor BHT (2,6ꢀdiꢀtertꢀbutꢀylꢀ4ꢀmethylphenol) was introduced
into the reaction mixture, the reaction progress were completely
60 suppressed and an unexpected methyl imidated product H derived
from BHT was isolated in 73% yield [eqn. (4)]. When TEMPO
(2,2,6,6ꢀtetraꢀmethylꢀpiperidꢀidineꢀNꢀoxyl) was added, the
reaction was suppressed severely and the yield of 2d decreased
2
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Scheme 2 Plausible mechanism of this reaction.
from 92% to 18%. There results suggesting that radical
intermediate may be involved during the transforming.
Intermolecular kinetic isotope effect (KIE, KH/KD) was then
carried out, leading to more insight into the mechanism. Thus,
equimolar amounts of DMSO and DMSOꢀd6 was added as the
solvent, after 0.5 h, one proton of methylene adjacent to nitrogen
atom was replaced by deuterium atom [eqn. (5)]. Longer reaction
time to 3 h, approximate 1:1 protons of the both methylene were
replaced by deuterium atoms [eqn. (6)]. These results clearly
O
O
O
O
O
O
S
RuCl3, selectflour
ref (equiv 7)
S
H+
S
NH
N
N
5
S
S
O
O
O
HO
O
C
I
O
R
O
S
O
O
O
O
H+
R
S
N
N
C-S bond cleavage
10 show that the new methylene adjacent to nitrogen arise from
DMSO and ketoꢀenol tautomerism of ketone is involved during
this reaction. To get further envidence about the mechanism, the
C(sp3)–H imidate product 2ꢀ((methylsulfinyl)ꢀmethyl)benzo[d]isꢀ
othiazolꢀ3(2H)ꢀone 1,1ꢀdioxide C was isolated by the reaction of
15 DMSO with saccharin [eqn. (7)]. Its structure was confirmed by
1H and 13C NMR spectra (see ESI). A stoichiometric reaction
between 1ꢀ(pꢀtolyl)ethanone 1d and the possible intermediate C
was also performed. To our delight, after 2 h, we obtained the
desired product 2d in 94% yield [eqn. (8)]. This result signified
20 the C–N bond formation reaction between sulfonamide and
methyl C(sp3)–H bonds of DMSO was involved and compound C
is a temporary intermediate in this reaction.
O
O
II
processes. Considering its excellent reaction efficiency and wide
45 substrate scope, the strategy would be highly desirable for
convinent synthesis of βꢀamino ketone derivatives, which were
widely exit in natural products. Further application of the reaction
is currently underway in our lab.
Notes and references
50 College of Chemistry and Chemical Engineering, Anyang Normal
University, Anyang 455000, P. R. China
E-mail:sunk468@nenu.edu.cn
wangx933@126.com
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
55 DOI: 10.1039/b000000x/
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4
25
Based on the above experimental results, a possible mechanism
is proposed for the present catalytic recycle (Scheme 2): The first
step is likely to be an oxidative amination process by RuCl3 and
F+ (selectflour) combination, thus affording the intermediate C.14
30 Subsequently C−S bond cleavage in the presence of H+ delievers
the enamine intermediate II.15 Finally, carbonꢀcarbon bond
formation between II and tautomer of ketone delivers the aimed
products.
In summary, we have succeeded in developing a newꢀtype
35 mannich reaction between ketone methyl C(sp3)–H bonds and N–
H bond of saccharin with the addition of DMSO as one carbon
bridging group for the first time. Detail mechanism study
revealed that Nꢀmethylation between saccharin and DMSO was
involved during this procedure, which is an important
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