Base-oxidant promoted metal-free N-demethylation of arylamines

Article abstract of DOI:10.1007/s12039-016-1152-7

A metal-free oxidative N-demethylation of arylamines with triethylamine as a base and tert-butyl hydroperoxide (TBHP) as oxidant is reported in this paper. The reaction is general, practical, inexpensive, non-toxic, and the method followed is environmentally benign, with moderate to good yields. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1152-7

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1152-7
Base-oxidant promoted metal-free N-demethylation of arylamines
VINAYAK BOTLA, CHIRANJEEVI BARREDDI, RAMANA V DAGGUPATI and
CHANDRASEKHARAM MALAPAKA∗
I&PC Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad 500 007, India
e-mail: chandra@iict.res.in
MS received 17 June 2016; accepted 28 July 2016
Abstract. A metal-free oxidative N-demethylation of arylamines with triethylamine as a base and tert-butyl
hydroperoxide (TBHP) as oxidant is reported in this paper. The reaction is general, practical, inexpensive,
non-toxic, and the method followed is environmentally benign, with moderate to good yields.
Keywords. N, N-dialkylaniline; N-dealkylation; Triethylamine; tert-butyl hydroperoxide; metal-free.
1. Introduction
have been reported on N-dealkylation of alkyl and aryl
amines.5 Hence there is intense interest to look for
an efficient N-dealkylation of aryl amines under mild
conditions.
Reinventing organic transformations with less expen-
sive and environmentally benign methods which have
been otherwise successfully catalyzed by transition
metal complexes is attracting the attention of chemists.1
Many tertiary N-methylamines find place as part of nat-
ural products, pharmaceuticals, etc.2 Several new and
important pharmaceutical compounds can be obtained
by the oxidative N-dealkylation or modification of the
N-methylamine group of alkyl and aryl tertiary amines
present in alkaloids and drugs.2c,d Moreover, many ter-
tiary N-methylamines are known to have profound
pharmacological properties which have applications
as psycho-active agents, anticancer agents, in DNA
alkylation damage repair, cancer metastatic chemopre-
vention and also for drug metabolism.3 In classical
methods, enzymatic processes are mostly responsible
for this conversion in which metal complexes4 and
various oxidases or peroxidases, like horseradish per-
oxidase, lipogenase, cytochrome P-450, bleomycin,
methemoglobin, amine oxidase, and hydrogen perox-
ide with either dioxygen or peroxide as oxidant have
been employed.5 This reaction involves two alternative
mechanisms, one is a formal hydroxylation of a C–H
bond on the carbon adjacent to the heteroatom (HAT,
hydrogen atom transfer), and the other is a one-electron
oxidation of the heteroatom itself (SET, single elec-
tron transfer).6 A copper catalyzed oxidative demethy-
lation of N, N-dimethyl anilines in the presence of
TBHP has been reported.7 Alternatively a plethora of
expensive and less environmentally benign strategies
We have been engaged in iron-catalyzed reactions
and green technologies and recently reported the use
of iron(III) chloride for the C-H functionalization of
N, N-dialkylanilines resulting in the construction of
C-C and C-O bonds.8 As a part of our interest on
N, N-dialkylanilines and their derivatives, we strived
to develop a metal-free oxidative N-demethylation of
arylamines with triethylamine as a base and tert-butyl
hydroperoxide (TBHP) as oxidant (Scheme 1). This is
a generic, metal-free, practical, inexpensive, non-toxic
and environmentally benign method.
2. Experimental
2.1 Materials and Methods
All commercially available chemicals were used as
received. Triethylamine and tert-butyl hydroperoxide
(TBHP) were purchased from Sigma Aldrich. Thin-
layer chromatography plates were visualized by expo-
sure to UV light/iodine and/or by immersion in an
acidic staining solution of phosphomolybdic acid fol-
1
lowed by heating on a hot plate. H NMR spectra
were obtained on 300, 400 and 500 MHz, and 13C
NMR spectra 75, 100 and 125 MHz, spectrometers with
tetramethylsilane and chloroform-d1, respectively, as
the internal standard. Chemical shifts (δ) are reported
in ppm relative to the residual solvent signal (δ =
1
7.26 for H NMR and δ = 77.0 for 13C NMR). Data
1
∗For correspondence
for H NMR are reported as follows: chemical shift

Vinayak Botla et al.
Table 1. Optimization reaction conditionsa.
Entry
Oxidant
Base
Solvent % of Yieldb
1
2
3
TBHP
H2O2
DDQ
(C2H5)3N Toluene
(C2H5)3N Toluene
(C2H5)3N Toluene
71
–
–
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Benzyl peroxide (C2H5)3N Toluene
Trace
–
Scheme 1. Oxidative N-demethylation of arylamines.
K2S2O8
atm O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
(C2H5)3N Toluene
(C2H5)3N Toluene
13
54
58
69
70
56
69
–
–
68
–
26
–
14
22
22
–
NaOH
NaH
Toluene
Toluene
(multiplicity, coupling constant, number of hydrogens).
Multiplicity is abbreviated as follows: s (singlet), d
(doublet), dd (double doublet), t (triplet), q (quartet),
and m (multiplet).
Na2CO3 Toluene
K3PO4
KOAc
Toluene
Toluene
Nat-OBu Toluene
Pyridine Toluene
Imidazole Toluene
DIPEA Toluene
(C2H5)3N MeOH
2.2 General synthetic procedures
2.2a Preparation of N, N-dialkyl anilines from ani-
line: 4-Ethyl aniline (8.252 mmol) was dissolved in
50 mL of glacial acetic acid under inert N2 condition.
Paraformaldehyde (80.871 mmol) was added and the
contents were stirred for 15 min. Sodium cyanoborohy-
dride (38.785 mmol) was added as the next step and it
was stirred overnight at room temperature. The reaction
mixture was poured in the saturated Sodium hydrox-
ide solution, which contained crushed ice. Ethyl acetate
was added later and the upper layer was collected which
contained the compound and was further subjected to
solvent evaporation.
(C2H5)3N
THF
(C2H5)3N DCM
(C2H5)3N DMF
(C2H5)3N CH3CN
(C2H5)3N DiOxane
(C2H5)3N
H2O
solvents produced good yields and toluene was the best.
The next most suitable solvent was THF.
Then we turned our attention on the strength of
base and investigated the reaction output with sodium
carbonate, sodium hydroxide, potassium phosphate,
sodium hydride, potassium acetate, pyridine, imida-
zole, Dipea, sodium tert-butoxide and triethylamine.
(Table 1, entries 1, 7–15) Triethyl amine was found
to be the most efficient, followed by potassium phos-
phate. To optimize the reaction time, we conducted the
reaction under refluxing toluene and realized that reflux
for 3h was enough for a fruitful conversion. Oxidants,
DDQ and H2O2 failed to produce the desired prod-
uct even on continued reflux for long hours (30 h). In
the case of benzoyl peroxide, a trace amount of prod-
uct was formed after stirring for a longer period of
time. The reaction outcome was the same under dioxy-
gen or atmospheric conditions (Table 1, entries 1–6) in
the presence of TBHP. However the reaction did not
2.2b Procedure for N-demethylation from N, N-
dialkyl anilines: A round-bottom flask was charged
with N, N-dialkyl aniline dissolved in toluene solution,
under N2 condition. TBHP was added drop wise and
reaction was stirred for 2 min. Triethyl amine was added
thereafter, and then the contents of the reaction were
stirred for 3 h at 110◦C under inert N2 condition. The
reaction mixture was washed 2–3 times with H2O and
ethyl acetate. The upper organic layer was separated
and dried over sodium sulphate and then subjected to
rotavapour. The crude mixture was purified by column
chromatography on silica gel (60–120).
3. Results and Discussion
Our initial efforts on controlled demethylation of tert- proceed in the absence of TBHP. It is noteworthy to
anilines involved the optimization of various parame- mention that the oxidant TBHP and base triethylamine
ters such as base, oxidant and the solvent, etc., and are essential for demethylation reaction. The product
N, N-dimethyl aniline was chosen for the purpose. yield did not change significantly on the increase of
Among various polar (1, 4-Dioxane, DMF, DCM, the quantity of TBHP or triethylamine from 2 to 4
MeOH and H2O), semi-polar (THF, CH3CN, etc.) and equiv. indicating that 2 equiv. of the reagents are opti-
hydrocarbon solvents (Benzene, o-,m-,p- Xylenes and mum for a successful reaction. In the absence of base,
Toluene) tested (Table 1, entries 16–22), CH3OH, DCM the desired product did not form, though the starting
and H2O failed to effect this conversion. Hydrocarbon material was consumed completely. From the above

N-demethylation of arylamines
investigations it was concluded that the optimized con- moderate to good yields. The oxidative N-demethylation
dition for the demethylation reaction is to reflux a of aromatic amines with electron-withdrawing group
mixture of the tert-aniline in toluene in the presence of such as floro, chloro, bromo, iodo and trifluoromethyl
2 equiv. each of triethylamine and TBHP for 3 h.
on the ring gave moderate yields under the reaction
Under the optimized conditions, the substrate scope conditions (Entries 7–11). It is noteworthy that strong
for the selective N-demethylation of N, N-dialkyl ani- electron withdrawing CN or Nitro at the para posi-
lines was investigated and the results are shown in tion severely passivated the oxidative N-demethylation
Table 2. Methyl groups were removed chemoselec- (Entries 14 and 15) and produced no product even on
tively in the presence of other substitutions like N-allyl, prolonged reaction times, and the stating material was
N-benzyl, and N-ethyl anilines (Entries 17–19).
When N, N-diethylaniline was used as a substrate,
recovered almost completely.
Our efforts to extend this methodology to1-
trace amount of N-deethylation product was obtained methylmorpholine, 9-methyl-9H-carbazole were in
and most of the stating material remained unreacted vain. N-methyl aniline as a substrate was also found
(Entry 20). This may be due to the steric effect. Para- to be resistant (Scheme 2). To have an insight on the
and meta- substituted N, N-dimethylanilines converted reaction mechanism, we conducted the reaction under
into the corresponding N-demethylation products in the optimized conditions in the presence of the radical
Table 2. Substrate scope.
Entry
Substrate
Time (h)
product
% of yield
Entry
Substrate
Time (h)
product
% of yield
1
2
3
3
71
88
11
12
3
3
45
81
3
4
3
3
83
77
13
14
3
85
00
12
5
3
76
15
12
00
6
7
3
3
78
65
16
17
3
6
53
43
8
9
3
3
63
60
18
19
6
5
40
48
10
3
59
20
12
trace

Vinayak Botla et al.
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A promising protocol for metal-free oxidative N-
demethylation of arylamines with triethylamine as a
base and tert-butyl hydroperoxide (TBHP) as oxidant
was developed. The reaction is general, practical, inex-
pensive, non-toxic, and follows an environmentally
benign method, with moderate to good yields.
Supplementary Information (SI)
All the spectra are available at www.ias.ac.in/chemsci.
Acknowledgments
B V thanks UGC New Delhi for senior Research
Fellowship.

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