Molecular iodine mediated oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups into aldehydes

Article abstract of DOI:10.1039/d0nj05832g

The oxidative cleavage of the C-N bond of aryl and heteroaryl (dimethylamino)methyl groups is achieved by employing molecular iodine as a mild oxidizing agent under ambient conditions in the presence of a mild base. The important reaction of C3 formylation of free NH and substituted indoles containing various substituents is accomplished from the corresponding Mannich bases. This methodology can also be extended for the synthesis of aryl and other heteroaryl aldehydes and ketones. Furthermore, the usefulness of the method is successfully demonstrated on a gram scale.

Full text of DOI:10.1039/d0nj05832g

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Molecular iodine mediated oxidative cleavage of
the C–N bond of aryl and heteroaryl
Cite this: New J. Chem., 2021,
5, 4152
(dimethylamino)methyl groups into aldehydes†
4
Received 30th November 2020,
Accepted 4th February 2021
Ketan S. Mandrekar and Santosh G. Tilve
*
DOI: 10.1039/d0nj05832g
rsc.li/njc
The oxidative cleavage of the C–N bond of aryl and heteroaryl formylation of indoles. Recently, Stodulski and co-workers synthe-
dimethylamino)methyl groups is achieved by employing molecular sized a series of indole-3-carboxaldehyde derivatives by visible-
iodine as a mild oxidizing agent under ambient conditions in the light-mediated oxygenation of 3-(dimethylaminomethyl)-indoles
(
10
presence of a mild base. The important reaction of C3 formylation bearing various substituents (Scheme 1b).
of free NH and substituted indoles containing various substituents The direct oxidation of tertiary amines to form the
is accomplished from the corresponding Mannich bases. This corresponding carbonyl compounds is less explored as
1
1
methodology can also be extended for the synthesis of aryl and compared to the alcohols. Iodine being a mild oxidizing
1
2
other heteroaryl aldehydes and ketones. Furthermore, the usefulness and environmentally benign reagent is explored to convert
1
3a–c
of the method is successfully demonstrated on a gram scale.
tertiary amines to their respective lactams.
Having excellent
affinity towards nitrogen, iodine serves as a reliable route to
1
3d
Carbonyl functionalization of indole compounds is an important form imines
either in the presence of a mild base or a
process to synthesize naturally occurring bioactive molecules co-oxidant, which are then transformed to amides. Alternatives
1
14a
14b
containing an indole motif. Many methods have been developed to molecular iodine, like PIDA
and TBAI,
have been
to introduce carbonyl groups to indoles bearing different studied to do a-oxygenation of tertiary amines. We envisioned
2
3
4
substituents. Vilsmeier–Haack, Rieche’s, Duff’s and Reimer– that substituted gramine prepared by Mannich reaction of sub-
5
Tiemann reactions are well known classical methods which are stituted indoles can be converted to indole-3-carboxaldehyde via
used to carry out such transformations. Due to their harsh iodine mediated oxidative cleavage of the C–N bond. In this
reaction conditions, low selectivity, and poor functional group process it was visualized that first imine formation would take
compatibility, chemists have further developed mild, effective, place by loss of the benzylic hydrogen followed by hydrolysis to
and regioselective carbonylation of indoles. Subjecting tertiary yield aldehyde.
6
a
6b–d
6e
amines to oxidants, such as Pb(OAc)
4
,
KMnO
4
,
MnO
2
,
To begin with, we treated parent gramine 1 with one equiv.
of molecular iodine in chloroform, followed by workup with aq.
6f
6g
6h
6i
chromic acid, HgOÁI
with K under visible-right irradiation, or bromination Na
reagents, such as cyanogen bromide, or N-bromosuccinimide,
2
,
Hg(OAc)
2
,
K
2
FeO
4
,
and Ru(bpy)
3
Cl
2
6
j
S O
2 2 8
2
S
2
O
3
which gave 12% of aldehyde 2a along with most of the
unreacted gramine (Table 1, entry 1). We reasoned that the
6k
6l
gives the corresponding aldehydes or ketones. One of the best iodide ion liberated in the reaction may not act as a better
among the rest to do C3 formylation of indoles is by oxidizing
7
the different C3 substituted groups like methanamines, and
8
methylene alcohols, into the corresponding carbonyl
compounds. Su et al. established an excellent method to
prepare indole-3-carboxaldehyde using N-methylaniline as a
9a
carbonyl source (Scheme 1a). Emulating his work, many groups
9
b
9c
9d,e
9f,g
have developed strategies using n-Bu
4
NI, KI, CuCl
2
I
2
,
Rose
9h
9i
Bengal or ceric ammonium nitrate (CAN) as catalysts for C3
School of Chemical Sciences, Goa University, Taleigao, Goa, 403206, India.
E-mail: stilve@unigoa.ac.in
†
Electronic supplementary information (ESI) available: Experimental procedure
Scheme 1 Intermolecular (a) and intramolecular (b) representation of
and data of compounds. See DOI: 10.1039/d0nj05832g
synthesis of 3-formyl or keto indoles.
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a
Table 1 Optimization of the reaction conditions
b
Sr.
Yield
(%)
Scheme 2 Screening of sec-amine groups of Mannich base.
no. Reagent
Oxidant Base
Solvent
1
2
3
4
I
I
I
I
2
2
2
2
(1 equiv.)
(1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
—
—
—
—
—
Na
Na
NaHCO
equiv.)
Cs
CHCl
(1 equiv.) CHCl
(1.5 equiv.) CHCl
3
3
3
3
12
35
65
45
2
CO
CO
3
Using the optimum conditions (entry 11), we prepared N-
methyl 2b and N-benzyl 2c indole-3-carboxaldehydes
(Scheme 3). Aldehydes bearing substituents like 5-OMe 2d, 6-
a
2
3
3
(1.5
CHCl
5
6
7
I
I
2
2
(1.1 equiv.)
(1.1 equiv.)
—
—
—
2
CO
3
(1.5 equiv.) CHCl
Ethanol
(1.5 equiv.) CHCl
3
49
N.R.
25
Cl 2e, 5-NO 2f, 2-methyl 2g, 2-phenyl 2h, 5-CN 2i and 2-COOEt
2
NaOH(1 equiv.)
Na
2j, were obtained from their respective gramines in excellent to
NIS (1.1
equiv.)
2
CO
3
3
good yields. Heterocyclic amines, 3-((dimethylamino)methyl)-4-
hydroxy-2H-chromen-2-one and N,N-dimethyl-1-(thiophen-2-yl)
methanamine were also converted to 4-hydroxy-2-oxo-2H-
chromene-3-carbaldehyde 2k and thiophene-2-carboxaldehyde
8
9
1
1
1
1
1
1
1
I
I
I
I
I
I
I
I
I
2
2
2
2
2
2
2
2
2
(1.1 equiv.)
(1.1 equiv)
(1.1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
(1.1 equiv.)
—
—
—
—
—
—
—
—
—
Na
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
(1.5 equiv.) DCE
(1.5 equiv.) Ethanol
(1.5 equiv.) THF
(1.5 equiv.) 1,4-Dioxane
(1.5 equiv.) Acetonitrile
(1.5 equiv.) THF:H
(1.5 equiv.) ACN:H
(1.5 equiv.) CHCl
(1.5 equiv.) 1,4-
53
45
69
81
46
46
37
29
62
0
1
2
3
4
5
6
2l, respectively, in moderate yields. Furthermore, to exploit the
2
O
feasibility of the reaction methodology, aryl compounds were
also subjected to this oxidative cleavage reaction. Mannich adducts
2
O
3 2
:H O
1
-((dimethylamino)methyl)naphthalen-2-ol, N,N-dimethyl veratry-
lamine, 2,3,4-trimethoxy-N,N-dimethylbenzenemethanamine and
-(3-methoxyphenyl)-N,N-dimethylmethanamine were transformed
Dioxane:H
THF
2
O
1
7
I
2
(1.1 equiv.) TBHP
—
N.R.
1
a
b
Reaction was carried out on 1 mmol of starting substrate. Isolated
into their aldehydes 2m, 2n, 2o and 2p, respectively, in good yields.
Ketones like benzophenone 2q and acetophenone 2r were also
synthesized from N,N-dimethyl-1,1-diphenylmethanamine and
N,N-dimethyl-1-phenylethanamine respectively.
To make the procedure a one pot method, a three component
reaction was carried out between indole, formaldehyde,
and dimethylamine; however it gave 2a in only 53% yield.
The use of an excess of iodine and base did not improve
yields.
conjugate base to abstract the methylene proton. Hence, we
thought of performing the reaction under basic conditions. The
reaction of 1 with one equiv. of iodine and one equiv. of Na CO
as a base increased the yield to 35% (entry 2). Increase in iodine
and base loading to 1.1 equiv. and 1.5 equiv. respectively,
2
3
furnished 2a in 65% (entry 3). Alternatives for Na
2 3
CO were
examined using NaHCO and Cs CO , but no substantial
3
2
3
change was seen in the yields (entries 4 and 5). Reaction with
a stoichiometric amount of NaOH failed to give the product
(entry 6). On the other hand, the use of NIS failed as an
alternative for iodine in deamination of 1 (entry 7). Furthermore,
other solvents were studied as a means to increase in the
productivity. Thus, we tried 1,2-dichloroethane as an alternative
for chloroform (entry 8), but chloroform remained the best.
Polar solvents like ethanol, tetrahydrofuran, 1,4-dioxane and
acetonitrile were tried (entries 9–12), from which 1,4-dioxane
served our purpose, giving 2a in 81% yield. To reduce the
aqueous workup step in the reaction and to achieve spontaneous
oxidative cleavage we studied aqueous–organic solvent mixtures.
Screening was carried out in THF:H O, ACN:H O, CHCl :H O
2
2
3
2
and 1,4-dioxane:H O solvent mixtures to observe any increase in
2
yield (entries 13–16). But unfortunately, none of the solvent
combinations achieved this goal. The use of a co-oxidant like
aq. TBHP in ethanol was examined, which did not result in any
product formation (entry 17).
Mannich bases using diethylamine and pyrrolidine were
prepared to study the generality of the reaction. It was found
that dimethylamine furnished the highest yield among all
others (Scheme 2).
Scheme 3 Oxidative cleavage of the C–N bond of (dimethylamino)-
methyl derivatives to aldehydes.
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the reaction yield substantially for the one pot procedure solvent has any role in the reaction. However, no change in
Scheme 4). the spectrum was observed to suggest its participation. Also no
Gram scale synthesis for the conversion of gramine to bis-indole formation was seen ruling out the possibility of
(
indole-3-carboxaldehyde provided 2a in 71% yield (Scheme 5). the formation of (1H-indol-3-yl)methanol and subsequent
The plausible mechanistic pathway for the product is oxidation.
depicted in (Scheme 6). We speculated that iodine might be
acting as a mild Lewis acid that coordinates with the nitrogen
of the dimethylamine. The base then might deprotonate the
Conclusions
coordinated amine to generate the iminium salt, which then A cheap, environmentally benign methodology was developed to
hydrolyses during the work up to deliver the aldehyde group. carry out oxidative cleavage of the C–N bond of the (dimethylamino)
To confirm the mechanism, we carried out the reaction in an
methyl group of indoles and aryl compounds. N-Deprotected
indoles were also successively a-oxygenated to give their carboxal-
dehydes in good yields. This methodology proved applicable to
NMR tube in CDCl as the solvent. As speculated, coordination
3
of iodine shifted the methylene protons downfield initially.
After a while, the signal due to the methylene protons other heterocyclic compounds. The one pot conversion of the aryl
disappeared and a salt was seen precipitated out in CDCl
due to its insolubility in the solvent. After removal of CDCl
DMSO-d
3
and heteroaryl systems to their corresponding aldehyde derivatives
was also feasible in moderate yield.
3
,
6
was added and the NMR was recorded, in which the
iminium salt proton was seen clearly. We also tried the reaction
in the presence of one equiv. of dioxane to check whether the
Author contributions
SGT was involved in overall supervision while KSM was involved
in project planning, execution, carrying out experiments and
manuscript writing.
Conflicts of interest
Scheme 4 Three component synthesis of indole-3-carboxaldehyde.
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the financial support from DST, New
Delhi (Grant No. EMR/2016/000091) and K. S. M. acknowledges
financial support through the UGC-NFOBC fellowship provided by
UGC, New Delhi.
Scheme 5 Gram scale synthesis of indole-3-carboxaldehyde.
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