Metal-free C-C, C-O, C-S and C-N bond formation enabled by SBA-15 supported TFMSA

Article abstract of DOI:10.1039/c9cc08389h

The construction of intermolecular C-C, C-O, C-S and C-N bonds between diazo compounds and acyclic and cyclic 1,3-dicarbonyl compounds, thiophenol and alkynes was developed by using TFMSA@SBA-15, thus providing a metal-free and eco-friendly platform for f

Full text of DOI:10.1039/c9cc08389h

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DOI: 10.1039/C9CC08389H
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Metal-free C-C, C-O, C-S and C-N Bond Formation Enabled by SBA-
15 Supported TFMSA
Xiangyan Yi,a,b Jiajun Feng,a,b Fei Huang*a,b, and Jonathan Bayldon Baell*b,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
industries (< ppm level).13 Consequently, as a mean to
improve applicability and maneuverability, the research
on utilization of organic molecular as a substitute for
metal catalysts will be significant. We targeted a new
protic acid as the activator of diazo. Based on
achievements in Lewis acids14 and Brønsted acid15
activation of diazo compounds. We questioned whether
trifluoromethanesulfonic acid (strongest protic acid,
TFMSA) could be used to meditate C-C, C-O, C-S and C-N
bonds formation. In addition, we envisioned that the
higher catalytic efficiency can be exhibited through
immobilizing the protic acid on mesoporous silica,
according to excellent physical properties of this
material and the high oxophilicity of Si helps to the
formation of six-membered cyclic structure that
increases the electrophilicity of proton in protic acid.16
Guided by this den idea, herein we would like to
elaborate the development of such TFMSA@SBA-15
(only 2 mol%) catalyst catalyzed four chemical bonds
The intermolecular C-C, C-O, C-S and C-N bonds construction
between diazo compounds and acyclic, cyclic 1,3-dicarbonyl
compounds, thiophenol, alkynes were developed by using a
TFMSA@SBA-15, thus providing a metal-free and eco-friendly
platform for forging those chemical bonds.
C-C and C-X (X = O, C, N) bonds exist widely in drug or
bioactive molecules.1 A wide range of transition-metal
catalyzed insertion reactions between diazo compounds
and various nucleophiles forging those chemical bonds
above have become indispensable to organic synthetic
field.2 In this regard, the most used metal catalysts are
Rh3 and Cu,4 which were first developed to promote the
formation of metal-carbenoid intermediates. Metal
carbene species can undergo corresponding
transformations, forming C-C, C-O, C-S and C-N bonds.
Subsequently, transition metal complexes and salts like
Fe,5 Ru,6 Pd,7 Sc,8 In,9 Au,10 Ag11 and Ir12 have been
employed as activator of diazo to catalyze formation of
those chemical bonds. Although the process of those
reactions can be controlled by sophisticated metal, the
cost of preparation of metal catalysts and ligands raise
serious barrier in economy. Meanwhile, the issue of
transition-metal residue contained in metal catalysts
allows those protocols are limited in the pharmaceutical
Well established the activation methods of diazo
Transition metals
C-C, C-O, C-S, C-N bond formation
N2
Lewis acids
R1 R2
C-O bond formation
diazo
Brønsted acids
C-O bond formation
This work
Protic acid
a. School of Food Science and Pharmaceutical Engineering, Nanjing Normal
University, Nanjing, 210023, China.
N2
C-C, C-O, C-S, C-N bond formation
R1 R2
b. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816,
China.
diazo
Mesoporous silica
c. Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria 3052, Australia.
Metal-free and Heterogeneous catalyst
E-mail: huangfei0208@yeah.net, jonathan.baell@monash.edu
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1 Intermolecular C-C, C-O, C-S and C-N bonds
construction by pervious contributions and this work.
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construction between diazo compounds and acyclic, isolated yields in C-C (80%), C-O (95%), C-S (85%) and C-
View Article Online
cyclic 1,3-dicarbonyl compounds, thiophenol, alkynes.
N (88%) bond products, respectivelyD(OFIi:g1.02.10b3)9./TCh9CeCr0e8f3o8r9eH,
Our investigation began with a search for a it was concluded that TFMSA@SBA-15 (2 mol%) was the
nonmetallic catalyst for intermolecular C-C, C-O, C-S and best catalyst for those reactions (TON=50).
C-N bonds formation through diazo compounds. We
Next, the morphology of TFMSA@SBA-15 were
examined the activity of various protic acids toward the observed by scanning electron microscopy (SEM). As
reactions between ethyl 2-diazoacetate (1a) and 5- shown in (Fig. 2c), an overall perspective of
methylcyclohexane-1,3-dione (2a) to check the TFMSA@SBA-15 can be seen clearly and it presents
feasibility of C-O bond formation (see SI for detail). The ordered mesoporous channels. Fluorine and sulfur
results are displayed in (Fig. 1a). The reaction mentioned elements were confirmed via EDS. In addition, the
above did not deliver the desired results with high yield transmission electron microscope images (Fig. 2c)
in the presence of acids such as AcOH, CSA, TFA and demonstrated that strongly acidic condition didn’t cause
MsOH. However, the use of some strong acids like TsOH, structural damage to the highly ordered mesoporous
H2SO4, HCl and HClO4 gave the product (3a) remarkably channels.
better yield. Gratifyingly, when TFMAS (pKa =-14) was
The binding mode between TFMSA and SBA-15 was
used as a catalyst, the isolated yield of product (3a) further analysed by flourier transform infrared (FT-IR) in
reached the highest. These results also revealed that the (Fig. 2d). For the pure SBA-15 samples, two peaks were
correlation between catalytic activity of acid and its pKa observed at 807 cm-1 and 1078 cm-1, which can be
value, strong protic acid was necessary for giving the attributed to Si-O bond group in samples. After
best results, whereas weak acid was ineffective with treatment with TFMAS, a band was observed at 641 cm-1
starting material unchanged.
thatarise from stretching vibration of the sulfonic group.
Moreover, a redshift in the symmetric stretching
vibration band from 1078 to 1046 cm-1 was observed,
simultaneously, another redshift ranging from 807 to
796 cm-1 was observed. Thus, we deduce that the
adsorption of TFMSA on SBA-15 preferentially occurred
through Si-O binging16 during the preparation
TFMSA@SBA-15 process.
O
O
N2
R1 R2
1
O
O
R3
R4
TFMSA@SBA-15
DCE, 60 o
C-C bond
R3
Ph
R4
C
R1 R2
3
2
O
O
O
O
O
O
O
O
O
Ph
CO2Et
Ph
Ph
CO2Et
Ph
Ph
Ph
Ph
OiBu
CO2Et
F
O
3a
[80% 1 h]
[77% 1 gram-scale]
3b
3c
3d
[75% 2 h]
[87% 7 h]
[68% 5 h]
3a
O
O
O
O
O
O
Ph
Ph
CO2Et
Fig. 1 (a) Screening various protic acids with different pKa in C-
O bond formation. (b) Study on TFMSA@SBA-15 in C-C, C-O, C-
S and C-N bonds formation reactions. (c) TFMSA@SBA-15 SEM
images and TEM images. (d) FT-IR spectra of SBA-15 and
TFMSA@SBA-15. Reaction condition see SI for details.
Ph
Ph
O
Ph
Ph
OBn
O
O
3e
3f
3g
[65% 2 h]
[77% 2 h]
[74% 5 h]
3a
X-ray structure of
O
O
O
O
Ph
Ph
CO2Et
N
CO2Et
To minimize the catalyst amount, as well as the
improvement of acid operation, a heterogeneous
catalyst, TFMSA@SBA-15, was prepared by immobilizing
TFMSA on solid support (SBA-15). Improved results were
obtained in each model reactions, affording excellent
3h
3i
[trace 2 h]
[trace 2 h]
Scheme 2 Intermolecular C-C bonds formation through α-diazo
compounds. Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol),
TFMSA@SBA-15 (2 mol%), DCE (3 mL), 60 oC, isolated yield.
2 | J. Name., 2012, 00, 1-3
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R5
With the advent of this efficient heterogeneous
View Article Online
N2
SH
TFMSA@SBA-15
S
DOI: 10.1039/C9CC08389H
R5
R1 R2
solvent-free
catalytic system, we investigated the scope of the
reaction between α-diazoesters and acyclic 1,3-
dicarbonyl substrates firstly. A variety of α-diazoesters
with either OMe, F, or isobutyl, allyl, benzyl
phenyldiazoacetates, were successfully formed the
desired C-C bond products in 68-87% yields. It was noted
that the presence of an electron-withdrawing group in
the phenyl ring increased the yield to 87% (3b). Electron-
donating group, such as methoxy, decreased the yield
(3c). 2-Naphthyl-diazoacetates also afforded the
corresponding products (3g) in 65% isolated yield, while
lower reactivity was observed for heteroaryl system (3h)
and alkyl 1.3-diketone (3i).
R1 R2
6
7
C-S bond
1
S
4 min
solvent-free
5 min
Ph
CO2Et
1a+6a
1a+6a
7a+6a
7a
[85% 5 min]
[80% 1 gram-scale]
7a
S
S
CO2Et
O
S
S
OBn
CO2Et
Ph
H
CO2Et
O
F
7b
7e
[70% 30 min]
[82% 5 min]
7c
7d
MeO
[78% 5 min]
[70% 50 min]
Cl
S
S
S
S
OiBu
O
Ph
Ph
Ph
CO2Et
Ph
CO2Et
O
O
a
7i
[75% 20 min]
7f
7g
7h
[77% 20 min]
[72% 30 min]
[65% 50 min]
Scheme 4 Intermolecular C-S bonds formation through α-diazo
compounds. Reaction conditions: 1 (0.5 mmol), 6 (1.5 mmol),
TFMSA@SBA-15 (2 mol%), rt, isolated yield, aDCE (3 mL).
R1
N2
TFMSA@SBA-15
DCE, 60 o
O
O
O
R2
R1 R2
C
O
To our delight, this catalyst applied to those
reactions between various alkynes and α-diazo
compounds as well. In general, good yields (70-93%)
were obtained in this 1,3-dipolar cycloaddition reaction.
Presumably due to hindered aryl migration,
phenyldiazoacetate (9e) afforded relatively poor yield
compared with ethyl diazoacetate (9a). The highest TOF
is up to 600 h-1.
C-O bond
4
5
1
H
H
H
O
O
CO2Et
O
O
CO2Et
5d
[80% 3 h]
O
O
CO2Et
O
O
CO2Et
5b
5c
[95% 12 h]
F
[85% 12 h]
CF3
5a
[95% 5 h]
5a
[90% 1 gram-scale]
OMe
O
O
CO2Et
O
O
CO2Et
O
O
CO2Et
5e
5f
5g
[80% 12 h]
[88% 12 h]
[95% 7 h]
5d
X-ray structure of
R1
N2
R2
OBn
O
OiBu
R6
TFMSA@SBA-15
R6
O
O
O
O
O
O
O
O
DCE, 60 o
C
R1 R2
O
O
CO2Et
O
N
HN
1
8
C-N bond
9
5i
5j
5k
[85% 12 h]
[86% 12 h]
[85% 12 h]
5h
[49% 7 h]
CO2Et
CO2Et
Scheme 3 Intermolecular C-O bonds formation through α-diazo
compounds. Reaction conditions: 1 (0.5 mmol), 4 (1.5 mmol),
TFMSA@SBA-15 (2 mol%), DCE (3 mL), 60 oC, isolated yield.
O
O
O
O
CO2Et
CO2Et
CO2Et
O
O
O
N
N
N
HN
HN
9a
HN
N
HN
9b
9c
9d
[88% 8 h]
[68% 8 h]
[63% 8 h]
[93% 8 h]
9a
[83% 1 gram-scale]
Ph
O
O
N2
Interestingly, TFMSA@SBA-15 exclusively furnished
the C-O bond product for cyclic 1,3-dicarbonyl
substrates, without formation of the C-C bond products.
The results may be attributed to the different enol forms
of acyclic diketone (cis-enol) and cyclic diketone (trans-
enol).11
Then TFMSA@SBA-15 was also proved be an
efficient catalyst for solvent-free C-S bond formation in
room temperature between α-diazoester and
thiophenol in the scheme 4. Not only substituted
phenyldiazoacetates but also ethyl diazoacetate could
participate in S-H insertion reaction to give products
with moderate to good yield (65-85%) in 5-50 mins.
O
O
CO2Et
same condition
Ph
Ph
CO2Et
1a
N
HN
9e
N
HN
9f
8a
[70% 8 h]
[74% 8 h]
Scheme 5 Intermolecular C-N bonds formation through α-diazo
compounds. 1 (0.55 mmol), 8 (0.5 mmol), TFMSA@SBA-15 (2
mol%), DCE (3 mL), 60 oC, isolated yield.
As an indication of the possible potential of this
catalytic system, those reactions were carried out on the
1 g scale and the catalyst can be reused 4 times (see SI
for detail). Based on related precedents11,15-18 and the
structure of catalyst, a plausible mechanism was
proposed. Firstly, α-diazo compound activated by
protonation of the carbon atom in C-N bond.11,17
Meanwhile, carbocation is nucleophilic attacked by
acyclic, cyclic 1,3-dicarbonyl substrates, thiophenol to
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J. Name., 2013, 00, 1-3 | 3
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form C-C,11 C-O15, C-S bond and regenerate the catalyst.
Particularly, there is a 1,3-diplor cycloaddition for C-N
bond formation between α-diazo compounds and
alkynes after protonation of alkynes.18
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3
4
C-C, C-O and C-S bond formation
Nu1
N2
Nu
N
N
N
N
O
H
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
TFMSA@SBA-15
O
O
O
O
S
S
HO CF3
O
CF3
O
O
OH
Ph
TFMSA@SBA-15
1,5-aryl
Ph
1,3-H shift
CO2Et
CO2Et
1,3-DC
N
HN
N
N
N2
Ph
CO2Et
C-N bond formation
Nu1=acyclic and cyclic 1,3-dicarbonyl substrates, thiophenol
5
Scheme 6 Possible mechanism.
In conclusion, for the first we have demonstrated
that organic acid is able to catalyse the insertion and
cycloaddition reactions between diazo compounds and
acyclic, cyclic 1,3-dicarbonyl substrates, thiophenol,
alkynes. Employing catalyst loadings as low as 2 mol%,
good yield was obtained in those reactions of formation
C-C, C-O, C-S and C-N bond, when TFMSA was
immobilized on SBA-15. Particularly, the reaction of S-H
insertion reaction proceeds under solvent-free
conditions and remarkably short time with high yields.
We believe that this work may open for new possibility
of organic molecular catalyzed insertion and
cycloaddition reactions, offering a green and feasible
entry to industrial application.
6
7
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We are grateful to the National Natural Science
Foundation of China (21901124), Natural Science
Foundation of the Jiangsu Higher Education Institutions
of China (19KJB150032), China Postdoctoral Science
Foundation (2019M651809).
Conflicts of interest
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