Synthesis of Bi(hetero)aryls via Sequential Oxidation and Decarboxylation of Benzylamines in a Batch/Fully Automated Continuous Flow Process

Article abstract of DOI:10.1002/ejoc.201800223

Catalytic dehydrogenative cross-coupling of two C–H bonds represents a green strategy in view of the atom- and step-economy. However, the challenge is to discover a new innovative bond strategy, especially for the direct coupling between Csp²–H

Full text of DOI:10.1002/ejoc.201800223

A Journal of
Accepted Article
Title: Synthesis of bi(hetero)aryls via sequential Oxidation and
Decarboxylation of Benzyl amines in a Batch/Fully Automated
Continuous Flow Process
Authors: Bhushan Mahajan, Dnyneshwar Aand, and Ajay K. Singh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800223
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800223
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of bi(hetero)aryls via sequential Oxidation and
Decarboxylation of Benzyl amines in a Batch/Fully Automated
Continuous Flow Process
Bhushan Mahajan, Dnyaneshwar Aand, Ajay K. Singh*
In chemical sciences, one of the major goals is to enhance the
Abstract: Catalytic dehydrogenative cross-coupling of two
synthetic efficiency by developing rapid and straightforward
access to synthetically important molecules.[11] In this context,
BzA form a class of compounds which are readily available,
inexpensive with huge industry usage. Additionally, it can be
synthesized using a variety of initial substrates and reaction
pathways, including hydrogenation of aromatic nitrile or amination
of aromatic aldehyde or aromatic methyl chloride.[12]
C−H bonds represents a green strategy in view of the atom-
and step-economy. However, the challenge is to discover a
new innovative bond strategy, especially for the direct
coupling between Csp2-H and benzyl amines (BzAs).
A
series of biaryls and bi(hetero)aryls were prepared from
commercially available substituted BzAs, AgNO3, cheap
K2S2O8 as anoxidant and benzene/pyridines as the coupling
source in batch and flow process. In batch reaction is
somewhat problematic in terms of safety (peroxide in
organic environment, high temperature above the boiling
point of the solvent and substrate, pressure, toxic pyridines),
we havechosen a convincing automated flow-setup to
perform it in a controlled and safe manner to one-pot
synthesis of biaryls. The mechanistic studies revealed that
the current protocol involves radical-initiation, multi-step
BzA oxidation and subsequent decarboxylative coupling for
the generation of biaryls.
Introduction
Scheme 1. Introduction of methylamine as new coupling group.
Transition metal-catalyzed cross coupling reactions are widely
used in organic synthesis and are now more useful as it has now
been melded with an award-winning green chemistry
technology.[1] The reaction is one of the several cross-coupling
strategies (Minisci,[2] Stille,[3] Suzuki–Miyaura,[4] Negishi,[5]
Hiyama–Denmark[6] and Kumada[7] typically to form biaryls, which
are common intermediates in drug synthesis.[8] These innovative
strategies have been able to create safer and eco-friendly
processes that avoid organic solvents, excess reagents, high
temperatures, and follow a shorter route to directly convert C−H
bonds to various valuable C−C and C−heteroatom bonds (e.g.,
C−halide, C−O, C−N, C-Si, and C−S).[9]Among the methods for
C−C bond formation, catalytic dehydrogenative cross-coupling of
two C−H bonds represents an ideal strategy in view of the atom-
and step-economy.[10] However, this pathway is highly
challenging and therefore there is a strong need for discovering
new innovative bond disconnection strategy, especially for the
direct coupling between Csp2-H and BzAs.
Conventionally, BzA have generally been transformed to
either a corresponding amide, acid, quinazolines, or for nitrogen
protection as well as pharmaceuticals intermediate.[13] Herein we
report the first protocol for biaryls and bi(hetero)aryls synthesis
via sequential oxidation and decarboxylation of BzA (Scheme 1).
Conceptually, usage of BzA to undergo tandemmulti-step
oxidation to yield corresponding carboxylic acid and subsequent
decarboxylative arylation appears to be straightforward but is
challenging; for this involves optimization of several parameters
including temperature, pressure, solvents, the suitable catalyst
and others. Additionally, in general, multi-step transformation
reactions are marred with the dramatic reduction in overall
efficiency owing to cumulative loss of product yield ineach
purification step. Therefore, to carry out multi-step reaction
sequences
poses
a
stiff
challenge
for
synthetic
tandem
chemists.[14] In general, one-pot
catalytic reaction,[15] combined with automation flow process
minimizes additional workup or column chromatography of
intermediates formed during multi-step reactions, thereby,
avoiding stop-and-go syntheses as well as generation and
separation of unwanted chemicals, while maximizing
time, energy-, environmental, economic and material-efficiency
with overall process simplicity.
[*] Bhushan Mahajan, Dnyneshwar Aand, Dr. A. K. Singh.
Division of Organic Synthesis and Process Chemistry,
CSIR-Indian Institute of Chemical Technology,
Hyderabad-500007, India.
Herein, we report the successful development of a new tandem
catalytic approach involving innovative bond disconnection
strategy which combines the radical- initiated, multi-step alkyl-
oxidation and subsequent decarboxylative coupling of Csp2-H
and BzA (Scheme 1). In batch reaction is somewhat problematic
in terms of safety (peroxide in organic environment, high
E-mail: ajaysingh015@gmail.com;
ajaysingh015@iict.res.in
Supporting information for this article is available on the
1
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
temperature above the boiling point of the solvent and substrate,
pressure, toxic pyridines), we have chosen an automated
continuous flow methodology enables a variety of BzAs to act as
arylating agents.
Assured of the catalytic feasibility of the Ag(I) for practical
applications, we next investigated the solvent effects. Only MeCN
was a good solvent to complete the conversion in the arylation of
BzA at 120ꢀ°C for 10ꢀh, whereas DMSO, DMF, DCM, ethylacetate,
methanol, acetone, hexane, diethylehther and dimethylacetamide
failed to produce the desired product in any appreciable yield.
Moreover, to our surprise we could see formation of 23% of
biphenyl product, when water was employed as a solvent.[16]
Temperature screening showed that selective arylation, with a
94% yield of biphenyl, was achieved after continuing the reaction
for 10ꢀh at 120ꢀ°C.[16]
Results and Discussion
Day by day molecular complexity is increasing and urgently
needed new transformation reaction to convert BzA to arylation
reaction. To begin with and to validate our hypothesis we had
chosen to use precursors BzA (1) and benzene (2) to yield
biphenyl (3), as model reaction with an aim to optimize reaction
conditions and parameters in batch system (Table 1). For
instance, we noted that monitoring several parameters, such as
steric and electronic structures of ancillary ligands, led to good
biphenyl selectivity (Table 1). At first, 0.25 mmol of 1 and an
excess of 2 (5 mmol), were taken in 1 mL of CH3CN a kept at 120
oC for 10 h in the presence of AgCN (30 mol%) and K2S2O8 (6
equiv) (entry 1). Unfortunately, with varied combination of this
combination of reactants/catalyst and the reaction conditions,
poor yield of biphenyl (~5%) was observed. In order to find the
suitable catalyst for the arylation reaction, several silver salts such
as AgOAc, AgCl, AgTFA, AgBF4, Ag2O, AgNO3, Ag2SO4, and
AgO were screened for their activity. Except for AgCl, the reaction
proceeded smoothly in most of the silver (I) salts, providing a
qualitative yield of biphenyl in CH3CN (Table 1, entries 2-8).
Additionally, replacing K2S2O8 with other oxidants led to sharp
decline in biphenyl yield (entry 11-13). With this background and
entire process optimization (oxidant, benzene), we found that a
mixture of 30 mol% AgNO3 and AgO, led to 94% yield of the
desired biphenyl product (Table 1, entry 7,9 &10).[16] Note that
AgNO3 was the catalyst of choice among AgNO3 and AgO due to
economic factors.
Scheme 2. Scope of BzA.
Reaction condition: (a) substituted BzA (0.25 mmol), CH3CN (1
mL), benzene (5 mmol) at 120 °C, time 10 h, K2S2O8 (1.5 mmol),
AgNO3 (30 mol%); (b) BzA (0.125 mmol); (c) substituted BzA
(0.25 mmol), CH3CN (1 mL), pyridine (5 mmol) at 120 °C; time 10
h, K2S2O8 (1.5 mmol), AgNO3 (30 mmol); TFA (1 mmol), Yields
refer to isolated yields and regioisomers determined by GC-MS
(data error is within ±1.5 %).
Table 1. Evaluation of reaction conditions.a
Entry
1
2
3
4
5
6
7
8
[Ag] cat.
AgCN
AgOAc
AgCl
AgTFA
AgBF4
Ag2O
AgNO3
Ag2SO4
AgO
AgNO3
AgNO3
AgNO3
AgNO3
oxidant
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHP
Yield (%)[b]
With the optimized reaction conditions in hand for BzAas
coupling group, the substrate scope with respect to BzA was
evaluated (Scheme 2). Under standard conditions, various ortho-
, meta-, para- substituted, as well as disubstituted BzA gave the
desired cross-coupling product in moderate and good yields. The
reaction tolerated a variety of electron-withdrawing substituents
such as fluoro (3b), chloro (3c), bromo (3d, 3j, 3l), iodo (3e),
cyano (3f) nitro (3h), phenyl (3i, 3k, 3m) groups and electron
donating group methoxy (3g). Not only for benzenes, arylation
reaction was found to be applicable to pyridine systems, but
reaction conditions were to be slightly modified to obtain
satisfactory yields.[16] As similar to Minisci reactions with alkyl
carboxylic acids, arylation occurred preferentially at the C2-
position ofpyridines based substrates, over the C3- and C4-
positions (4a–4d).[9a] The reaction selectivity exhibited by all
substituted pyridines can be predicted using guidelines put
forward by Baran et al.[17] To further broaden the reaction scope,
pryidine replaced with other heterocyclic compound such as
indole and benzofuran syste. Unfortunately, low yields of
corresponding arylation product with a complex mixture of
inseparable byproducts were obtained.[16]
5
82
<1
37
24
42
94 (86)[c]
73
9
94
<1
10
7
3
10[d]
11
12
13
H2O2
O2
[a] Reaction conditions: BzA (1, 0.25 mmol), anhydrous benzene
(2, 5 mmol), CH3CN (1 mL), K2S2O8 (1.5 mmol), AgNO3 (30 mol
%) for 10 h. [b] Yields are determined by GC analysis with internal
standard dodecane, at least three measurements were taken to
obtain an average yield. [c] Yields in small bracket indicated
isolated yield. [d] Runs the reaction without 1.
2
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
Figure 2. Time profile for BzA to biphenyl product in batch
system. Reactant (0.25 mmol); benzene (5 mmol); CH3CN (1mL);
catalyst AgNO3 (30 mol%); K2S2O8 (1.5 mmol); time varied; yield
calculation based on GC-MS.
changed to the reserved second catalytic cartridge. Meanwhile,
the first cartridge was refilled and reused thereafter.[16] This
continuous process resulted in the automatic removal of unused
or generated toxic or harmful chemicals or unutilized reactants
contribute strongly towards reducing tedious work up procedure
along with zero exposure to harmful pyridines and benzene and
their derivatives. In view of previous studies for quenching of a
chemical activity,[18] and removal of unwanted chemicals by
extraction,[19]an aqueous solution (flow rate = 1 mLmin-1) was
infused through a T-junction to mix with the organic mixture
flowing out of the catalyst cartridge. Reaction waste (excess
benzene/pyridines and excess of CH3CN) was preferentially
dissolve in water during the integrated process of 4 min mixing,
which led to the easier work-up procedure. For extraction of
synthesized bi(hetero)aryls, we infused highly volatile
dichloromethane (DCM, flow rate = 100Lmin-1) and liquid–liquid
extraction for 3 min via droplet microfluidics was adapted
(Supplementary Movie 1). This autonomous separation was
achieved under the microseparator by a simple principle that the
hydrophobic DCM containing product could preferentially wet and
penetrate through the PTFE membrane, while the non-wetting
CH3CN + benzene /water is unable to penetrate the PTFE
membrane.[19] Figure 1, reveals that the fully automated serial
process can deliver various bi(hetero)aryls products in excellent
yields over 66% (3a’–4b’), in 174ꢀmin by the fully automated
system (bi(hetero)aryls synthesis (165ꢀmin), solvent exchange (4
min), extraction (3 min), separation (1 min). In contrast, the
traditional batch methods require 24-40ꢀh, to produce these
substituted bi(hetero)aryls.
Figure 1. Synthesis of bi(hetero)aryls in continuous manner; (a)
Feed stock solution molar ratio (BzA: anhydrous benzene:
CH3CN (0.1: 2.0: 9.7). Pack-bed catalyst cartridge [K2S2O8 (15
mmol, 4.05 gm), AgNO3 (0.6 mmol)] at 120 oC. catalyst cartridge
diameter 7.5 mm and length 3 cm; (b) Feed stock solution molar
ratio (BzA: pyridine: CH3CN: TFA (0.1: 2.0: 9.7: 0.4). Pack-bed
catalyst cartridge (K2S2O8 (15 mmol, 4.05 gm), AgNO3 (0.6
o
mmol)) at 120 C. catalyst cartridge inner diameter 7.5 mm and
length 3 cm. Yields are determined by GC analysis with internal
standard dodecane, at least three measurements were taken to
obtain an average yield.
Batch reaction is somewhat problematic in terms of safety
(peroxide in organic environment, high temperature above the
boiling point of the solvent and substrate, pressure, toxic
pyridines), we have chosen a convincing flow-setup to perform it
in a controlled manner. The catalytic performance and efficacy of
continuous flow method were evaluated by a similar model
reaction as discussed above for the synthesis of biaryls by
infusing a solution containing reactants and solvent in the molar
ratio [BzA: anhydrous benzene: CH3CN (0.1: 2: 9.7)]. In general,
reaction performance was found to be dependent on the flow rate
(residence time), reactor pressure, and the concentrations of
reactants, as summarized in the Supporting Table 1.[16] After
extensive optimization, 92% yield of biphenyl (3a) was obtained
in 165 min (3.63 times faster than batch reaction due to we were
unable to control sealed tube reactor pressure at high
Step 1. Self-cross-coupling reaction.
o
temperature (120 C) above the boiling point of the solvent
CH3CN (82oC) and substrate benzene (80 oC) of residence time
at 120 °C and 17.2 bar, resulting in ∼0.028 mmol
h−1 productivity.[16]
The concept for a fully autonomous serial green process for the
synthesis of bi(hetero)aryls, as shown in Figure 1. Two catalyst
cartridges were alternatively used for desired biaryls synthesis.[16]
One catalytic cartridge could work efficiently for at least 80 h,
Step 2. Competition experiment.
where
upon
feed
solution
flow
direction
was
3
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
pathway. To ensure that a free radical redox reaction pathway is
operative, we replaced K2S2O8 by a typical radical initiator tert-
butyl hydroperoxide (TBHP) without changing the reaction
conditions where we observed the cross-coupled product in 14%
yield.[16] Next, the lower level ca.1.33-1.36 rates of kinetic isotope
effect were seen in both parallel reactions and competitive
reactions, indicating that C−H bond cleavage is not participating
in the rate-determining step (Scheme 3, step 6).
Step 3. Quenching with radical scavenger.
Scheme 4. Proposed mechanism for arylation.
Step 4. Direct cross-coupling with benzaldehyde.
Step 5. Direct cross-coupling with benzamide.
Step 6. Direct cross-coupling with benzoic acid.
Step7. Kinetic isotope effect.
Based on previous reports and our experimental evidence, a
plausible reaction mechanism is depicted in Scheme 4. In the first
step, Ag(I) is oxidized to Ag(II) species and the continuity of the
redox reactions led to the formation of phenylmethanimine (5) and
again the combination of redox and hydrolysis reaction led to the
formation of benzamide (10) and benzaldehyde (6). The formation
of benzaldehyde, benzamide, and benzoic acid (7) was
unequivocally detected during GC measurements and can also
be seen in the reaction time-profile in the earlier stages of the
reaction Figure 3. A control reaction again confirmed that
benzaldehyde, benzamide and benzoic acid were formed during
the reaction.[16] Next, self-condensation of benzaldehyde and BzA
gave N-benzylidene-1-phenylmethanamine (8). In the next step,
the redox reaction led to the formation of N-benzylbenzamide (9,
detected by GC analysis) and again consecutive redox processes
generated benzoic acid (7). Ensuing redox reactions oxidizes the
benzoic acid (7), leading to decarboxylation and aryl radical
generation. Eventually, the coupling between the aryl radical (11)
and arene produced the desired arylated product (3) through the
oxidation of cyclohexadienyl radical intermediate (12).
Scheme 3. Control experiments: Standard reaction condition:
K2S2O8 (1.5 mmol, 405.5 mg), reactant (0.25 mmol), AgNO3 (30
mol%), benzene (5.0 mmol), CH3CN (1 ml) at 120 oC for 10h
reaction time, 4 ml Ace pressure tube. Yields are determined by
GC-MS analysis with internal standard dodecane, at least three
measurements were taken to obtain an average yield.
In order to elucidate the reaction mechanism, several control
experiments were performed.[16] The mechanism of
decarboxylation by silver-catalyzed probably follows a pathway
similar to that suggested previously by Singh et al.[9]In the
beginning of the reaction, silver(I) salt is oxidized to a silver(III)
species by the generated persulfate anion and subsequently,[9e]
Ag(III) oxidized BzA to benzoic acid via multi-step pathways as
proposed in Scheme 3. Sequential multistep oxidation, we have
observed in the early stage of reaction (2-6 h), and again we were
confirming by control experiments (Scheme 3, step 1). To get
mechanistic insight in more details, additional experiments were
performed (Scheme 3, step 2). Under standard conditions,
electron-withdrawing substituent p-nitro BzA gave slightly better
arylation product yield but vice versa for electron-donating
substituent p-methoxy BzA and their lower kinetics (0.91-1.01)
indicating that sequential multi-step oxidation is not participating
in rate-determining step. We then looked for the possibilities of a
free-radical pathway and verification of its origin. For this purpose,
we added radical scavengers like tetramethylpiperidine N-oxide
(TEMPO) or tert-butyl-4-methyl phenol (BHT) to the reaction
mixture under identical reaction conditions. As expected, we
could not get any desired product. This implies that the current
cross-coupling reactions may be proceeding via a free radical
Conclusion
In summary, we have developed novel tandem catalyzed
innovative bond strategy, combined with radical-initiated, multi-
step BzA oxidation and subsequent decarboxylative coupling for
the direct coupling between Csp2-H and BzAs. This catalytic
protocol and automated continuous flow process would enable a
variety of BzAs to act as arylating reagents without pre-activation
and is compatible with a broad range of functional groups. In
future, this tandem catalyzed innovative bond strategy will enable
to direct replacement of BzA to make new bond such as C-C, C-
4
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
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Acknowledgments. A.K.S. thanks to Department of Science and
Technology, New Delhi (Govt. of India) (DST), New Delhi, for the
INSPIRE Faculty Award and Early Carrier Research award.
Financial assistance received from the DST, by sponsoring
project
no.
DST/INSPIRE/04/2016/000247
and
ECR/2017/000208are gratefully acknowledged. We gratefully
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Keywords: C-C coupling• BzA • Continuous Flow Process •
Tandem catalysis• Bi(hetero)aryls
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10.1002/ejoc.201800223
European Journal of Organic Chemistry
COMMUNICATION
Layout 2:
COMMUNICATION
Bhushan Mahajan, Dnyneshwar Aand, Ajay K.
Singh *
Page No. – Page No.
Title: Synthesis of bi(hetero)aryls via
sequential Oxidation and Decarboxylation
of Benzyl amines in
a Batch/Fully
Automated Continuous Flow Process
Text for Table of Contents
Herein we report the first protocol for synthesis of biaryls and bi(hetero)aryls via sequential
oxidation and decarboxylation of benzylamines in a batch/fully automated continuous flow
proecess.In batch reaction is somewhat problematic in terms of safety, we have chosen a convincing
automated flow-setup to perform it in a controlled and safe manner one-pot synthesis of biaryls and
bi(hetero)aryls.
6
This article is protected by copyright. All rights reserved.