Water-mediated C-H activation of arenes with secure carbene precursors: The reaction and its application

Article abstract of DOI:10.1039/c9cc05804d

A water-mediated C-H activation using sulfoxonium ylides is reported, providing a general, green and step-economic approach to construct a C-C bond and varieties of useful N-heterocycle scaffolds. Notably, the "water-mediated" activation, in contrast to that in organic solvents, shows great potential in pharmaceutical, biochemistry and chemical industries.

Full text of DOI:10.1039/c9cc05804d

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Received 00th January
20xx,
Water-Mediated C-H Activation of Arenes with Secure Carbene
Precursors: the Reaction and its Application
Ruifang Nie,† Ruizhi Lai,† Songyang Lv, Yingying Xu, Li Guo, Qiantao Wang* and Yong Wu*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A water-mediated C-H activation using sulfoxonium ylides is by coupling and cyclization with the introduced functional
reported, providing a general, green and step-economic approach groups. Unsurprisingly, most of C-H activations were reacted in
to construct C-C bond and varieties of useful N-heterocycle organic solvents, with limited exceptions. Among the
scaffolds. Notably, the “water-mediated”, in contrast to that of in exceptions, diazo reagents as carbene precursors has been used
organic solvent, shows
pharmaceutical, biochemistry and chemical industries.
a great potential in developing in water-mediated C-H functionalization successfully (Scheme
1a).6 The diazo reagents, however, can cause safety issues in
large scale processes due to their instability and the risk of
potential exothermic reactions linked releasing of nitrogen gas.
This greatly limited its application. In recent years, α-carbonyl
sulfoxonium ylides as safer alternative reagents to diazo
compounds has been optimized in laboratory and industry
scales.7 Typically, these reagents are well-behaved crystalline
solids that demonstrate high stability and serve as carbene
precursors that do not generate gas by-products. In recent
years, C-H activation of sulfoxonium ylides with different
directing groups (DG) in organic solvents were independently
reported by many groups.8 These methodologies composed a
powerful toolbox to afford N-heterocycles such as lactones,
lactams, isoquinolines, azolopyrimidines, indazoles, indoles and
etc. Despite the application of sulfoxonium ylides is constantly
expanding, this secure carbene precursor has not detached
Conventionally, organic synthesis relies heavily on organic
solvents, which are usually used in vast quantity in comparison
with that of the reactants. As a result, the bulk of chemical
waste was the toxic organic solvents. Therefore, limiting or
avoiding the use of organic solvents could effectively reduce the
amount of chemical waste and meet the growing needs for
sustainable chemistry across academic and industrial fields.1 To
achieve this goal, one way would be developing solvent-free
processes, but solvents also play an immense role in bringing
the reaction equilibrium and rates under control or even be a
partner to improve the catalyst in many reactions.2 Alternative
solvents were also developed,3 but none of them are as “green”
as water given its abundance, cost-efficiency, environment
compatibility, non-toxicity and non-flammability.
Transition-metal-catalysed successive activation and
functionalization of C-H bonds is at the heart of synthetic
innovations for the development of C-C bond cross-coupling
processes because it does not require pre-functionalizing the
a. Diazo as carbene precursors in water-mediated C-H activations
NHAc
H
N
O
[Cp*Rh2Cl2]2, CsOAc
N
R3
NHAc
R1
R2
R2
R1
+
HOAc, H2O
N2
R3
substrate
and
is
highly
regioselective.4
C-H
O
O
X
R2
activation/annulation represents one of the hottest topics in
recent years,5 because it does not only specifically functionalize
the inert C-H bonds but also forms varieties of cyclic compounds
Rh2L4
H2O
N
R2
X
(X = PO(OEt)2, SO2Ph, Ac, CO2Et)
N
N2
H
n
n
R1
R1
O
Tp(CF3)2,BrAg(thf)
H2O
H
CH2
CH2
O
CO2Et
+
R
EtO
+
CO2Et
R
R
N2
O
Sichuan Engineering Laboratory for Plant-Sourced Drug and Research Center for
Drug Industrial Technology, Key Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, West China School of Pharmacy, Sichuan
University, Chengdu, 610041, China.
b. This work
DG
R1
DG
O
O
[Cp*Rh(OAc)2]
H O
R1
S
+
R2
, 100 oC, 6-24 h
R2
Email: wyong@scu.edu.cn (Yong Wu); qwang@scu.edu.cn (Qiantao Wang)
2
H
† R.N. and R.L. contributed equally.
3, 5
1, 4
2
Electronic Supplementary Information (ESI) available: general information,
experimental procedures, characterization data and spectra data. See
DOI:10.1039/x0xx00000x
DG = directing groups
Scheme 1 Water-mediated C-H activation
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Table 2 Scope of arenes and sulfonium ylidesa
from the organic solvent system yet, and the study about non-
organic solvent mediated reactions was underexploited. Thus,
the study of sulfoxonium ylides in “green” solvents would be of
great interest. Recently, our group were interested in the
diversified reactivities of sulfoxonium ylides.8d Meanwhile, our
group were committed to the study of non-organic solvent
mediated C-H activation for a long time.9 Herein, as a result, we
reported our most recent work in water-mediated sp2 C-H
activation of arenes with sulfoxonium ylides (Scheme 1b).
View Article Online
DOI: 10.1039/C9CC05804D
DG
DG
O
O
S
R
[Cp*Rh(OAc)2]
R1
R1
+
R2
H2O, 100 °C, 6 h
O
3
1
2
3a
, R = H, 86%
3b
3c
3d
3e
, R = 2-Me, 76%
, R = 3-Me, 80%
, R = 3-CF3, 77%
, R = 4-OMe, 88%
, R = 4-Me, 85%
N
N
N
Ph
Ph
Ph
R
S
O
O
O
3f
3g
3h
, R = 4-Cl, 86%
3j
,77%
N
b
, R = 4-NO2, 53%
3i
, 94%
The
reactions
of
2-phenylpyridine
1a
and
N
dimethyloxosulfonium benzoylmethylide 2a in the presence of
N
N
N
N
o
N
Ph
[Cp*RhCl2]2/AgSbF6 and non-organic solvents at 100 C were
Ph
Ph
Ph
O
initially investigated (Table S1 in ESI). Fortunately, the reaction
proceeded smoothly in water providing the desired product 3a
with a 82% isolated yield (Table 1, entry 1). Notably,
[Cp*Rh(OAc)2] was obviously favoured as the catalyst to
generate product 3a with a 86% isolated yield, and more green
without any additives (Table 1, entries 2-5). Excessive
temperature will cause serious side-reactions of ylides, and
decreasing the temperature also reduced starting material
conversion.
O
O
O
O
O
b
b
3n
, 55%
3m
, 78%
3l
3k
, 54%
, 77%
Ph
N
N
N
O
O
O
b
b
b
3o
, 52%
3p
, 31%
3q
,85%
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*Rh(OAc)2] (5 mol%), H2O (1.5
ml), under air. Desired product 3 was isolated by column chromatography on silica
With the optimized reaction conditions in hand, the substrate gel (eluent: PE/EA = 50/1). bReaction time 24 hours.
scope of 2-phenylpyridines was examined (Table 2).10
methoxy and halogen substituted S-aryl-S-methylsulfoximines
Unsubstituted 2-phenylpyridine gave a 86% isolated yield of 3a.
Introduction of electron-donating and -withdrawing as well as
halogen groups into different positions of the benzene ring was
fully tolerated (3b-3h). When the phenyl moiety was replaced
with β-naphthyl, thienyl, indole ring and 1,3-benzodioxole
groups, the desired products 3i-3l still owned moderate to
excellent yields. Notably, 3k was obtained as an reverse-steric
effect regioisomeric product, and it may because the reaction
was dominated by the electrical effect. Pyrimidine, pyrazole and
isoquinoline were also seemed to be good directing groups
affording 3m-3o. In addition to aromatic sulfonium ylides,
aliphatic sulfonium ylides also exhibited good reactivity, and
expanded the application of the reaction (3p and 3q).
To better define the scope of this strategy, the coupling of
NH-sulfoximine with sulfoxonium ylides was also examined
(Table 3).11 The sulfoxonium ylide was not limited to aryl
substitution, and the yields were comparably high when iso-
propyl and tert-butyl substituted sulfoxonium ylides were used
(5a-5c). To further demonstrate the substrates scope, methyl,
coupled with dimethyloxosulfonium pivaloylmethylide
respectively to give the corresponding products 5d-5g with 70-
91% yields. In addition, S-aryl-S-isopropylsulfoximine, S-
diarylsulfoximine and even S-phenyl-S-benzylsulfoximine all
coupled smoothly to give 1,2-benzothiazines 5h-5j with 66-89%
yields.
Encouraged by these initial experimental results, we sought
to further explore this water-mediated C-H activation in order
to increase the scope of this strategy to a greater extent.
Isoquinolines and its related derivatives are the well-known
nitrogen-containing heterocyclic compounds that pose broad-
spectrum biological activities, and have been widely used in
pharmaceutical, agricultural and chemical industries.12 More
efficient and environment-friendly synthesis of isoquinoline
compounds is of great interest for the general chemistry field.
Obviously, the emergence of C-H activation/annulation coincide
with this requirement (Scheme 2a).13 However, the previous
works have not detached from the organic solvent system yet,
and have limitations in practical application due to the substrate
complexity. Therefore, we hope to achieve the synthesis of 3-
Table 1 Optimization of the reaction conditionsa
Table 3 Synthesis of 1,2-benzothiazinesa
O
O
S
N
N
Rh cat.
+
solvent
100 oC, 6 h
R2
O
R2
O
O
O
S
S
S
[Cp*Rh(OAc)2]
N
NH
O
+
R1
R1
R3
H2O, 100 °C, 24 h
R3
2a
1a
3a
2
5
4
Entry
Catalyst
[Cp*RhCl2]2/AgSbF6
[Cp*Rh(MeCN)3](SbF6)2
[Rh(COD)Cl]2
[Cp*Rh(OAc)2]
[Cp*RhCl2]2/AgOAc
Solvent
H2O
H2O
H2O
H2O
Yieldb
82%
78%
trace
86%
85%
R
O
5h, R = i-Pr, 30%
O
5a
5b
5c
, R = Ph, 35%
, R = i-Pr, 90%
, R = t-Bu, 91%
S
S
5i
,
,
R = Ph, 91%
R = Bn, 62%
1
2
3
4
5
N
N
5j
R
O
S
5d
5e
, R = 4-Me, 91%
, R = 4-OMe,89%
R = 4-F, 70%
, R = 2-OMe,85%
N
R
5f
,
5g
H2O
aUnless otherwise noted, all the reactions were carried out using: 2-phenylpyridine
1a (0.2 mmol), dimethyloxosulfonium benzoylmethylide 2a (0.4 mmol), Rh cat. (5
mol%), AgSbF6 (20 mol%), solvent(1.5 ml), under air. bIsolated yields.
aReaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), [Cp*Rh(OAc)2] (5 mol%), H2O (1.5
ml), under air. Desired product 5 was isolated by column chromatography on silica
gel (eluent: PE/EA = 50/1).
2 | J. Name., 2012, 00, 1-3
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a. Isoquinolines synthesis based on C-H activation/annulation (previous works)
R1
yield, but 2-thiophenemethylamine afforded 7n with a lower
yield. This contrast may be caused by the different conjugation
View Article Online
DOI: 10.1039/C9CC05804D
R1
R3
R4
RhIII / CoIII / RuIII / PdII /MnI
R2
N
N
N
H
+
of the substrates. α-Substituted benzylamines gave the 1-
substituted isoquinolines 7o and 7p both in 95% yield. Next, the
scope of sulfoxonium ylides was studied. Both the electron-
donating and-withdrawing groups of the phenyl ring were
adapted well, affording 8a-8g in moderate to good yields. When
the phenyl ring was replaced by a naphthalene ring, 8h was
obtained with a good yield. However, when the phenyl ring was
replaced by a furan ring or aliphatic chain, 8i-8k was obtained
with lower yields. The different results may be due to the
conjugation change.
Isoquinolines are ubiquitous scaffolds found in numerous
natural products (Scheme 3a).14 Based on our recent work on
the synthesis of natural products such as berberine,15 B-homo
Palmatine16 and decumbenine B,17 we noted that the easily
available primary amines and sulfoxonium ylides could be the
most suitable combination to form natural products and the
related derivatives. For example, conjectured from the
retrosynthetic analysis, decumbenine B can be easily obtained
through two steps of C-H activation from 1,3-benzodioxol-5-
methanamine and dimethyloxosulfonium 1,3-benzodioxol-5-
formylmethylide (Scheme 3b). As the biologically active
isoquinolines were successfully obtained, we tried to use this
methodology for the total synthesis of natural products.
Decumbenine B and Palmatine are both isoquinoline alkaloids
existing in nature. Applying our methodology, intermediate A
was easily obtained, and can easily transformed to
decumbenine B through our established protocol (Scheme 3c,
Base / Acid
Organic Solvents
R5
R3 / R5
R4
R1
Alkyne / Alkene
R1
O
R3
COOR4
RhIII / CoIII / IrIII
R2
N
H
+
+
Base / Acid
Organic Solvents
N2
R3
COOR4
Diazo Compounds
R1
R1
X
O
O
S
[RhCp*(MeCN)3](SbF6)2
Zn(OTf)2, DCE
X
N
NH
R3
R3
Sulfoxonium Ylides
b. Our work
R2
R2
H
O
O
S
[Cp*Rh(OAc)2]
N
NH2
R1
R1
+
, 100 oC, 24 h
R3
H O
2
R3
7, 8
6
2
Scheme 2 Synthesis of isoquinoline via C-H activation
phenylisoquinolines by the water-mediated C-H activation
strategy (Scheme 2b).
To our delight, the coupling of benzylamine 6a and
dimethyloxosulfonium 2,6-dimethoxyl-1-benzoylmethylide 2b
afforded the desired product 7a with a 81% yield. Various
benzylamine derivatives and analogues were tested following
this method, and the results were summarized in Table 4. Both
electron-donating groups (methyl, methoxy and dimethoxy)
and electron-withdrawing groups (fluoro, chloro, bromo, and
trifluoromethyl) were well tolerated, giving the corresponding
isoquinolines in moderate to good yields (7b-7l). It was
noteworthy that 7l was obtained as a reverse steric effect
regioisomeric product, possibly because of the dominance of
the electrical effect. Naphthylamine afforded 7m with a good
a. Isoquinolines scaffolds found in natural products
O
O
N
O
O
N
N
Table 4 Synthesis of isoquinoline derivativesa
O
O
O
R2
O
OH
O
O
R2
O
O
O
O
S
[Cp*Rh(OAc)2] 5 mol%
H2O, 100 oC 24 h
Decumbenine B
Palmatine
Berberine
N
NH2
+
R1
R1
R3
b. Retrosynthetic analysis of decumbenine B
HO
R3
7-8
6
2
N
H
N
O
O
S
N
O
O
N
O
HCHO
R
NH2
O
O
N
O
O
O
+
H
O
O
O
O
O
O
O
O
O
O
A
B
C
Decumbenine B
decumbenine B
O
c. Synthesis of
7m
7l
, 73%
R
, 74%
7a
, R= H, 81%
, R= 2-Me, 80%
, R= 2-F, 40%
, R= 2-CF3, 89%
, R= 3-Me, 67%
, R= 4-Me, 56%
O
O
S
7b
7c
7d
7e
7f
7g
7h
7i
7j
S
N
O
N
O
OH
N
O
NH2
N
C
(HCHO)n
(2)
O
, R= 4-OMe, 43%
O
O
O
O
(1)
O
, R= 4-F, 30%
, R= 4-Cl, 40%
, R= 4-Br, 71%
O
O
B
O
O
O
A
7n
7o, R= Me, 95%
, R= Ph, 95%
, 30%
O
O
Decumbenine B
7p
7k
, R= 4-CF3, 86%
Palmatine
d. Synthesis of
N
N
O
O
O
O
O
N
O
S
O
O
O
O
O
O
N
R
, MeOH
N2
NH2
E
O
8i
, 33%
N
8h
,75%
(3)
(4)
8a
8b
8c
8d
8e
,R=H, 56%
O
F
D
, R= 2-Me, 68%
, R= 2-Cl, 66%
, R= 3-Cl, 52%
, R= 3-OMe, 57%
R= 4-Me, 49%
, R= 3,5-diMe, 46%
O
N
O
Cl-
O
O
O
O
N
8f
,
N
OMe
O
(5) hydroxymethylation
(6) cyclization
8k
, 46%
8j
, 32%
8g
aReaction conditions: 6 (0.2 mmol), 2 (0.4 mmol), [Cp*Rh(OAc)2] (5 mol%), H2O (1.5
ml), under air. Desired product 7 or 8 was isolated by column chromatography on
silica gel (eluent: PE/EA = 20/1).
O
Palmatine
G
O
O
Scheme 3 Synthesis of natural products.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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NH2
NH2
3
4
(a) B. H. Lipshutz, F. Gallou, S. Handa, ACS Sustainable Chem.
[Cp*Rh(OAc)2]
HOAc
View Article Online
Eng., 2016, 4, 5838; (b) R. A. Sheldon, Green Chem., 2005, 7,
6a
DOI: 10.1039/C9CC05804D
267.
O
Ph
V
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NH
Rh
NH
Rh
heat - H2O
Cp*
Cp*
I
O
Ph
NH
Ph
IV
S
O
5
6
VI
O
Ph
2a
heat - H2
NH
NH
Rh
Rh
Cp*
Cp*
Ph
N
S
O
R
Ph
III
O
O
II
7a
7
8
9
DMSO
Scheme 4 Possible mechanism
see ESI for details).17 Similarly, intermediate F was also obtained,
and then transformed to Palmatine following previous works
(Scheme 3d, see ESI for details).18 Thus, a more simple, green
and efficient synthesis strategy of isoquinolines natural
products was developed.
Benzylamines as C-H activation substrates had two possible
paths according to previous related studies.13b-c,19 In order to
gain the insight into the reaction mechanism, a series of
experiments was conducted (for details, see ESI). Based on the
results, a possible mechanism for this protocol was shown in
Scheme 4. Initially, cyclometalation of benzylamine 6a gives a
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I.
Coordination
of
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dimethyloxosulfonium benzoylmethylide 2a generates a Rh(III)
alkyl species II, and the subsequent α-elimination of DMSO from
species II affords a reactive rhodium α-oxo carbene species III.
Subsequently, intermediate III underwent migratory insertion
of the Rh-C bond to generate a six-membered rhodacyclic
intermediate IV. After that, protonation of IV delivered the
alkylated imine V and released the active catalyst. Then, under
heating, the alkylated imine V takes part in the intra-molecular
annulation of amino and carbonyl to furnish ring closure leading
to 1,2-dihydroisoquinoline VI. Eventually, the aromatization of
1,2-dihydroisoquinoline VI provides the final product
isoquinoline 7a by the extrusion of H2.
In summary, we report the example of water-mediated C-H
activation of arenes with sulfoxonium ylides. This work
develops a green and sustainable approach to construct C-C
bond without any organic solvents or additives. Furthermore,
this methodology has been used to synthesis natural products
successfully, indicating its great potential in developing green
chemistry in chemical synthesis and drug design.
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Financial support from NSFC (grant number 81373259,
81573286 and 81602954) are gratefully acknowledged.
There are no conflicts to declare.
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Notes and references
1
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4 | J. Name., 2012, 00, 1-3
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