C-C bond cleavage: Metal-free-catalyzed reaction of Betti bases with various heterocycles under microwave irradiation

Article abstract of DOI:10.1080/00397911.2016.1239740

The reaction of Betti bases with various heterocycles in the presence of p-toluenesulphonic acid (PTSA) under microwave irradiation gives bis(heterocycle)methanes through benzyl transfer. The reaction proceeds via the cleavage of C-N bond followed by C-C

Full text of DOI:10.1080/00397911.2016.1239740

C-C Bond cleavage: Metal-free-catalyzed reaction of Betti bases with various
heterocycles under microwave irradiation
Mohit L. Deb1,, B-Shriya Saikia1, Kongkona Borah1, Pranjal K. Baruah1
1Department of Applied Sciences, GUIST, Gauhati University, Guwahati, Assam, India
Corresponding author Mohit L. Deb E-mail: mohitdd.deb@gmail.com;
baruah.pranjal@gmail.com
Abstract
The reaction of Betti bases with various heterocycles in presence of p-toluenesulphonic
acid (PTSA) under microwave irradiation gives bis(heterocycle)methanes through benzyl
transfer. The reaction proceeds via the cleavage of C-N bond followed by C-C bond. The
metal-free cleavage of C-C bond, which is in fact a C-dearylation, is rarely reported in
the literature.
Graphical Abstract
KEYWORDS: C-C bond cleavage, metal-free, C-dearylation, benzyl transfer, Betti base
INTRODUCTION
1

The cleavage or activation of C-C bond has attracted much attention in recent years due
to its great potential in organic synthesis. Although considerable progresses have been
made, due to the non-reactive nature of C-C bond in comparison to C-H bonds, much
work needs to be done. Transition metal catalyzed C-C bond cleavage/activation
reactions have become a challenging and hot area of research.[1] These reactions are
intriguing to chemists as it requires neutral reaction condition and many functional
groups are tolerated. This property is highly desirable because it allows selective C-C
bond activation in structurally complex molecules, and its utility is demonstrated in the
synthesis of many natural products.[2] Nature has been able to perform several oxidative
C-C cleavage reactions through various metalloenzymes.[3] Usually iron is found as the
cofactor, however, copper and nickel are also found. Although metal catalyzed C-C bond
cleavage is well documented, but examples of metal-free variant of this important
reaction are rare.[4] The use of toxic and expensive metal catalyst for C-C bond cleavage
limits its application and hence methods using transition metal-free approaches are
gaining importance for synthetic transformations. Furthermore, C-dearylation is much
more important in synthetic organic chemistry. Many metal catalyzed dearylation were
reported in the literature, but most of them are N- and O-dearylation.[5] Since the cleavage
of C-aryl bond is difficult, only few reports are available regarding the C-dearylation.[6]
The synthesis of bis(heterocycle)methanes have attracted great attention because of their
many importance in medicines[7] and use as intermediates in organic synthesis.[8]
Therefore, various methods have been developed for their synthesis.[9] Although, this
paper describes the synthesis of many bis(heterocycle)methanes, but the prime focus of
2

the paper is the metal-free C-dearylation and hence benzyl transfer. To the best of our
knowledge, this is the first report of Betti base [10] as benzyl transfer agent. Although a
few instances of benzyl transfer was previously observed in other cases, but they are
either metal catalyzed or O/N/S-benzyl transfer.[11]
RESULTS AND DISCUSSIONS
Very recently we have reported a preliminary study of the p-toulenesulfonic acid (PTSA)
catalyzed reaction between Betti bases and indoles under classical heating method in
toluene.[12] Encouraged by this result, we planned to carry out the reaction under
microwave irradiation to further improve the yield of 3 and reduce the reaction time.[13]
We chose the reaction of 1a with 2a affording 3a as the representative reaction for the
optimization of the condition. Different Bronsted/Lewis acid catalysts and solvents were
screened for the reaction. However, PTSA (20 mol %) in CH3CN at 100 °C gave us best
result (entry 9, Table 1). Increase in the catalyst loading has no affect on the product
yield, whereas decreasing the loading decrease the yield remarkably (entry 11, Table 1).
The use of stronger acids like TFA and triflic acid lowered the yield, possibly due to the
decomposition of the product (entries 6 & 7, Table 1).
We next explored Betti bases having different tertiary amine moieties to observe the
effect on the product yield under the optimized condition. We noticed that Betti base
having pyrrolidine moiety gave the best result compared to others (entry 2, Table 2).
Therefore, we continued our rest of the reactions using the Betti bases of pyrrolidine.
3

To generalize the method, we have investigated the reaction using various derivatives of
Betti bases having pyrrolidine and indoles (Scheme 1). Electron-withdrawing group on
‘R’ of Betti base increased the product yield whereas electron-donating group
diminished. When R = H, the reaction gave low yield and this particular reaction was
purely an instance of methylene (-CH2-) transfer (3i, Scheme 1), which is rarely reported
in the literature.14 We also investigated the reaction using phenolic betti bases, but
obtained lower yield of 3 as expected (Scheme 1). In order to extend the scope of the
reaction, we used other heterocyclic nucleophiles like 5-pyrazolones, 6-aminouracils and
4-hydroxycoumarins. To our delight, we obtained the respective
bis(heterocycle)methanes in all the cases (Scheme 2). When “R” is electron-withdrawing
group, the product yield increases in all the cases (Scheme 2).
As we isolated traces of 3'a from our model reaction, a plausible mechanism for the
reaction is proposed (Scheme 3). PTSA first helps to eliminate the tert-amine moiety of
Betti base by protonating nitrogen, which generates o-quinone methide (A).[15]
Subsequently a molecule of indole attacks A, producing 3-(α,α-diarylmethyl) indole (3').
In presence of PTSA, naphthol ring of 3' gets protonated and eliminated as free naphthol
through the formation of alkylideneindoleninium ion (C). Then another molecule of
indole attacks C producing bis(indolyl)methanes 3.
From the mechanism we hypothesized that if a molecule can attain 3'-type structural unit,
can be denaphtholated in presence of indole and acid catalyst. To validate our thought,
we performed couple of new reactions taking 2-hydroxy-1-naphthaldehyde (4, 1.0 mmol)
4

and indole (3.0 mmol) or 2-methylindole (3.0 mmol) in presence of PTSA under
optimized condition (Scheme 4). Much to our delight, we obtained tris(indolyl)methanes
(TIM) in both the cases. Therefore, the most possible mechanistic pathway for the
formation of TIM is proposed (Scheme 5).
CONCLUSIONS
In summary, the application of Betti base as benzyl group transfer agent is reported for
the first time through the formation of bis(heterocycle)methanes. We used heterocycles
like indole, 5-pyrazolone, 6-aminouracil, 4-hydroxycoumarin. As the reaction proceeds
through dearylation of naphthol or phenol ring, the reaction also reveals a metal-free C-
dearylation strategy. The strategy is also applicable to 2-hydroxy-1-naphthaldehyde
which gives tris(heterocycle)methanes. The reaction is catalyzed by PTSA which is an
inexpensive and easily available catalyst. Moreover, the reaction was carried out in
microwave, which substantially reduces the reaction time compared to conventional
method. We proposed a tentative mechanistic pathway and justified.
EXPERIMENTAL
General Experimental Procedure For The Synthesis Of 3
1 (1.0 mmol), 2 (2.0 mmol) and p-TsOH.H2O (20 mol %, 38 mg) were irradiated in a
closed vessel by employing CH3CN (0.5 mL) as solvent inside a microwave reactor at
100 oC for specified time. After completion of the reaction which was monitored by TLC,
solvent was removed in rotavapor and the crude mixture was purified by column
chromatography using hexane/ethyl acetate as the eluent to give the desired product 3.
5

The same procedure has been followed for the synthesis of 5 (where 1:3 ratios of
substrates were taken).
Microwave Instrumentation
All microwave reactions were carried out in a Synthos 3000 (Anton Paar) microwave
reactor. The multitude microwave has a twin magnetron (2.45 GHz) with maximum
output power of 1400 W. The output power can be controlled in unpulsed control mode
over whole power which is adjustable in 1 W increment. A 68xxx series microprocessor
system control is used to measure power, pressure, time and temperature during the
reaction. The temperature and pressure were monitored throughout the reaction by an
infrared detector. The temperature can be measured from 0 to 280 °C with uncertainty
±1%. The pressure can be measured from 0 to 86 bar with uncertainty ±0.2 bar.
SUPPORTING INFORMATION
Full experimental detail and characterization of the products. This material can be found
via the ‘‘Supplementary Content’’ section of this article’s webpage.
ACKNOWLEDGEMENTS
MLD is thankful to Science and Engineering Research Board (SERB), India, for financial
support (Grant No. SB/FT/CS-073/2014) under Fast Track Scheme. PKB is thankful to
DST, New Delhi, (Grant No. SB/FT/CS-100/2012) for financial support.
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Table 1. Optimization of the reaction condition[a]
Entry Catalyst (mol %) Solvent Temp. (°C) Time (min) Yield[b] (%)
1
HCl-4N ( 20)
H2SO4-4N (20)
AcOH (20)
TNBA (20)
PTSA (20)
TFA (20)
Toluene 110
Toluene 110
Toluene 110
Toluene 110
Toluene 110
Toluene 110
Toluene 110
Toluene 100
CH3CN 100
CH3CN 100
CH3CN 100
CH3CN 100
10
10
12
10
7
40
25
10
15
60
45
40
62
75
70
55
72
30
42
Trace
2
3
4
5
6
7
7
Triflic acid (20)
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (10)
PTSA (30)
PTSA (20)
PTSA (20)
PTSA (20)
7
8
7
9
7
10
11
12
13
14
15
8
7
7
EtOH
DMF
H2O
100
100
100
7
8
10
[a] Unless otherwise mentioned, all the reactions were performed by using 1a' (1.0 mmol,
277 mg) and 2a (2.0 mmol, 234 mg).
11

[b] Products were purified by column chromatography and yields are for the isolated
products.
12

Table 2 Optimization of the amine moiety of Betti bases for the reaction[a]
Entry
Yield 3a (%)[b]
1
2
3
75
86
60
4
5
33
55
[a] Unless otherwise mentioned, all the reactions were performed by using 1(1.0 mmol)
and 2a (2.0 mmol, 234 mg).
[b] Products were purified by column chromatography and yields are for the isolated
products.
13

Scheme 1. Reaction of Betti bases with indoles to synthesize bis(indolyl)methanes
14

Scheme 2. Substrate scope for the reaction of Betti bases with various heterocycles
15

Scheme 3. Tentative mechanism for the formation of 3,3-bis(indolyl)methanes
16

Scheme 4. Synthesis of TIM through denaphtholation
17

Scheme 5. Mechanism for the formation of TIM
18