ortho-Quinone methides: TFA-mediated generation in water and trapping with lactams and styrenes

Article abstract of DOI:10.1016/j.tetlet.2015.04.072

Abstract A simple and efficient trifluoroacetic acid mediated protocol for ortho-amidomethylation of phenols in aqueous medium has been described. Developed protocol has a good substrate scope, involves mild reaction conditions, and products are obtained

Full text of DOI:10.1016/j.tetlet.2015.04.072

Accepted Manuscript
Ortho-quinone methides: TFA-mediated generation in water and trapping with
lactams and styrenes
Rohit Sharma, Sheenu Abbat, Ramesh Mudududdla, Ram A. Vishwakarma,
Prasad V. Bharatam, Sandip B. Bharate
PII:
S0040-4039(15)00709-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.072
TETL 46211
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2015
16 April 2015
18 April 2015
Please cite this article as: Sharma, R., Abbat, S., Mudududdla, R., Vishwakarma, R.A., Bharatam, P.V., Bharate,
S.B., Ortho-quinone methides: TFA-mediated generation in water and trapping with lactams and styrenes,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.072
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Ortho-quinone methides: TFA-mediated generation in
water and trapping with lactams and styrenes
Rohit Sharma,ab Sheenu Abbat,c Ramesh Mudududdla,ab Ram A. Vishwakarma,ab Prasad V. Bharatam,c* Sandip
B. Bharateab*
0.1% TFA in water
+
HN
(CH2)n
Aqueous medium
Short reaction times
Catalytic amount of TFA
O
R
+ HCHO
R
(CH2)n
N
OH
O
OH
N
(CH2)n
+
0.1% TFA in water
O
1

2
Tetrahedron Letters
journal homepage: www.els evier.com
Ortho-quinone methides: TFA-mediated generation in water and trapping with
lactams and styrenes
Rohit Sharma,ab Sheenu Abbat,c Ramesh Mudududdla,ab Ram A. Vishwakarma,ab Prasad V. Bharatam,c*
Sandip B. Bharateab*
a
Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
b
Academy of Scientific & Innovative Research (AcSIR), CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India
cDepartment of Pharmacoinformatics and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), SAS
Nagar, Punjab-160062
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient trifluroacetic acid mediated protocol for ortho-amidomethylation of
phenols in aqueous medium has been described. Developed protocol has a good substrate scope,
involves mild reaction conditions and products are obtained in good yields. The quantum
chemical calculations were performed in implicit solvent (water) conditions, which helped in
tracing the reaction mechanism and getting insights on the possible reaction pathway, which
involves the N-C bond formation and simultaneous hydrogen transfer to give final product. The
applicability of this protocol for one-pot synthesis of flavans from phenols, formaldehyde and
styrene has also been demonstrated.
Available online
Keywords:
DFT
TFA
2015 Elsevier Ltd. All rights reserved.
Vinylbenzenes
Amidomethylation
Organic reaction in water has been an important area of interest
in recent years to meet environmental considerations.1 The use of
water as a solvent contributes to environment friendly process.2
For environmentally friendly processes, the “best solvent” is no
solvent, but if required then water is recommended.3 In recent
years, the major focus of process industries is to use water as a
solvent rather than organic solvents.4 Mannich reaction is widely
used for C-C bond formation and for the synthesis of
enantiomerically enriched nitrogenous molecules including
amino acids and amino alcohols.5 It is a classical method for the
synthesis of β-amino ketones and aldehydes. Mannich reaction
has been widely used in the synthesis of drugs and natural
products containing nitrogen; due to which synthetic chemists are
attracted towards this reaction.6 A lot of synthetic routes are
reported for Mannich reaction including few reports on reaction
in aqueous medium.7 Many reported reactions have been carried
out in the presence of surfactant but normal phase separation is
difficult due to the formation of emulsion because of surfactant.8
In continuation to our previous methodology on ortho-
amidoalkylation of phenols using Silica-HClO4 as a catalyst and
acetonitrile as a reaction medium,9 we investigated this reaction
using water as a reaction medium. Thus herein, we report an
efficient, convenient and simple method for ortho-
amidomethylation of phenols using catalytic quantity of TFA in
water as a reaction medium in place of Silica-HClO4 (Figure 1).
The use of N-vinyl lactam also produced the same ortho-
amidoalkylated product 1 via tandem devinylation followed by
Mannich-type of condensation. Additionlly, herein we performed
quantum chemical calculations in implicit solvent (water)
conditions in order to get insights on the possible reaction
pathway.
+
HN (CH2)n
O
0.1% TFA in water
80 oC, 30 min
R
R
(CH2)n
+ HCHO
N
OH
O
OH
1
3
2
0.1% TFA in water
80 oC, 30 min
N
(CH2)n
+
O
Figure 1. TFA mediated ortho-amidomethylation of phenols in
aqueous medium.
In order to establish a green protocol for ortho-amidomethylation
of phenols, initially, a series of experiments were carried out
using water as solvent with addition of various acids like formic
acid, acetic acid and TFA (Table 1). In the presence of 10%
formic acid in water under reflux condition, reaction proceeded,
however there was only 60% conversion. Similarly, in case of
acetic acid, reaction was incomplete. However, in the presence of
*Corresponding author. Tel. +91-191-2585006; Fax: 91-191-2586333
E-mail: sbharate@iiim.ac.in (SBB); pvbharatam@niper.ac.in (PVB)

10% TFA in water, the reaction progress was better, producing
95% yield of the desired product. Further optimization of the
TFA loading and reaction time indicated that 0.1% TFA in water
for 0.5 h, was enough to get 95% yield of the product (entry 10 –
optimized condition). The control reaction in water in the
absence of acids does not proceed at all (entry 9). Next, we
performed the reaction of phenol (2a) with formaldehyde and N-
vinyl caprolactam using optimized reaction condition, which led
to the formation of amido-alkylated product 1a in 90% yield,
through an initial N-devinylation.
2d
4a
O
1e
O
OH
OH
N
N
6.
7.
92
86
5a
1a
2a
O
O
O
HO
O
OH
HO
O
OH
N
N
OH
O
OH
5b
2c
1d
a Reagents and conditions: phenol 2 (100 mg, 1.0 mmol), lactam
4 (1.2 mmol) or N-vinyl lactam 5 (1.5 mmol), formaldehyde 3
(3.0 mmol) in 0.1% TFA in water (10 mL); b isolated yield.
Table 1. Solvent and catalyst optimization studiesa
OH
O
O
OH
HN
N
HCHO
+
+
Next, the utility of this method for the synthesis of flavans was
also investigated (Figure 2).10 Reaction worked very well with
phenols as well as substituted phloroglucinols and styrenes
producing corresponding flavans 6a-f in 85 to 55% yields,
respectively.
2a
3
1a
Temp. (ºC) Time (h) %Yieldb
4a
Entry Reaction medium
1.
2.
3.
4.
5.
6.
7.
8.
10% AcOH in water 80
10% HCOOH in water 80
3
4
1
4
40
60
80
0
10% TFA in water
10% TFA in water
10% TFA in water
1% TFA in water
0.1% TFA in water
0.1% TFA in water
Water
80
25
25
80
80
80
80
80
R2
O
R2
OH
a
+
R1
16
2
2
1
24
0.5
0
+
R1
HCHO
80
80
78
0
7
6
3
2
O
9.
H
O
O
O
10.c
0.1% TFA in water
95
HO
O
HO
O
a
Reagents and conditions: phenol 2a (1.0 mmol), caprolactam 4a
H
O
(1.2 mmol), formaldehyde 3 (3.0 mmol); b isolated yield; c optimized
reaction condition. All % values in reaction medium column are
expressed as % v/v.
OH
OH
6c, 81%
O
O
O
6a, 55%
6b, 85%
O
H
O
O
O
H
O
O
H
Me
Me
HO
O
HO
HO
O
O
O
O
Next, we investigated the scope of this reaction for various
substituted phenols and lactams. The substituted phenols as well
as substituted phloroglucinols participated well in this reaction,
producing corresponding Mannich products 1a-e in excellent
yields in a 30 min reaction time (Table 2).
H
OH
6d, 84%
H
OH
H
OH
6f, 76%
6e, 80%
Figure 2. TFA catalyzed one-pot synthesis of flavans in aqueous
medium. Reagents and conditions: (a) phenol 2 (100 mg, 1.0 mmol),
styrene 7 (1.2 mmol), formaldehyde 3 (3.0 mmol) in 0.1% TFA in
water (10 mL). Isolated yields are shown after compound codes.
Table 2. Scope of the reaction.
Entry Phenol
Lactam
Product
% yieldb
95
O
O
OH
OH
N
HN
To understand the mechanism of TFA-mediated ortho-
amidomethylation of phenols, quantum chemical studies on the
reactants, intermediates, products and the important transition
states of the reaction path have been carried out using B3LYP/6-
311+G(d,p) method under implicit solvent (water) conditions.
Figure 3 shows the reaction scheme along with the ∆G values
and the activation barriers (Ea). Initially, the phenol 2b after
reacting with formaldehyde 3, gives O-quinone methide II. Next,
the coupling of intermediate II with lactam enol 4a1 proceeds via
N-C bond formation and simultaneous hydrogen transfer (II +
4a1) to give the final product 1c via TS1. The energy barrier for
the proposed pathway is 11.1 kcal/mol. This step is exoergic by
24.0 kcal/mol and hence is quite readily favorable on kinetic as
well as thermodynamic grounds.
1.
2.
3.
4.
1a
2a
2b
2b
4a
O
N
HN
H3C
H3C
85
82
90
O
OH
OH
OH
1b
4a
N
HN
O
H3C
H3C
OH
O
1c
4b
O
O
O
HO
O
OH
HO
O
OH
HN
N
O
OH
OH
In summary, we have developed an efficient, ecofriendly and
catalyst-free TFA mediated protocol for ortho-amidomethylation
of phenols. Flavans were also synthesized using this one-pot
protocol. Quantum chemical calculations helped in tracing the
reaction mechanism and provided further insights on possible
reaction pathways.
4a
2c
1d
CHO
O
H
O
HO
OH
HO
OH
HN
H
5.
88
N
OHC
O
OH
O
OH
3

4
Tetrahedron Letters
Figure 3. Reaction mechanism for the TFA-mediated ortho-methylation. The Gibbs free energy values at each step were calculated
using B3LYP/6-311+G (d,p) method under implicit solvent (water) conditions. All the energy values are given in kcal/mol.
Acknowledgements
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Supplementary material
Experimental details and spectral data scans. Supplementary data
associated with this article can be found, in the online version at
http://www.sciencedirect.com
8.
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