Ammonium persulfate activated DMSO as a one-carbon synthon for the synthesis of methylenebisamides and other applications

Article abstract of DOI:10.1039/c5ra21801b

Activation of DMSO to work as an economical and environmentally benign one-carbon synthon has been achieved by using a bench-top reagent ammonium persulfate for general and efficient access to symmetrical methylenebisamides from primary amides. This methodology was used to achieve a three-component Mannich reaction using acetophenone, saccharin and DMSO to furnish a β-amino ketone. It also provided a metal-free synthesis of thiadiazole and bis(phenyl)methane. Effectively, this method uses DMSO as a safer surrogate to formaldehyde. A mechanism for methylenebisamide formation involving radical intermediates has been proposed based on mechanistic studies.

Full text of DOI:10.1039/c5ra21801b

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Ammonium persulfate activated DMSO as the one-carbon synthon for the synthesis of
methylenebisamides and other applications
Pankaj S. Mahajan, Subhash D. Tanpure, Namita A. More, Jayant M. Gajbhiye, and Santosh B. Mhaske*
CSIR-National Chemical Laboratory, Division of Organic Chemistry, Pune 411 008, India
*Corresponding Author: sb.mhaske@ncl.res.in
Abstract:
Activation of DMSO to work as an economical and environmentally benign one-carbon
synthon has been achieved by using a bench-top reagent ammonium persulfate for a general
and efficient access to symmetrical methylenebisamides from primary amides. This
methodology was used to achieve a three-component Mannich reaction using acetophenone,
saccharin and DMSO to furnish β-amino ketone. It also provided a metal-free synthesis of
thiadiazole and bis(phenyl)methane. Effectively, this method uses DMSO as a safer surrogate
to formaldehyde. A mechanism for methylenebisamide formation involving radical
intermediates has been proposed based on mechanistic studies.
Introduction
The sulfonium salts generated in situ by the activation of DMSO using various electrophiles for
the “Swern oxidation” class of reactions are one of the most important synthetic
transformations.1 Similarly activation of DMSO to serve as a one-carbon synthon or for other
useful organic transformations has been a subject of contemporary interest (Figure 1).2 Organic
solvents such as CHCl3, DMF or DMSO, are becoming increasingly utilized as a reagent in
synthetic transformations.3 We were mainly interested in the transformation of primary amides to
1

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methylenebisamides using DMSO as a one-carbon synthon, because bisamides are of
considerable interest in the synthesis of peptidomimetic compounds,4 natural products5 and
potential key intermediates for the synthesis of bioactive compounds.6,7 In particular, they are
key fragments for the introduction of gem-diaminoalkyl residues in retro-inverso pseudopeptide
derivatives
synthesized
for
structure-activity
relationship
studies.8
Generally,
methylenebisamides are prepared (Figure 2) by the reaction of amides or nitriles with
formaldehyde using strong acid catalysts.7,9 Hexamethylenetetramine10 and activated DMSO
have been also used instead of formaldehyde.11 A review of literature shows that
methylenebisamides can be obtained in low yields by activation of DMSO using various
electrophiles.11 Li et al reported the synthesis of methylenebisamides in good to fair yields from
amides by using 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride) and 2,4-dichloro-6-
methoxy[1,3,5]triazine to activate DMSO.12
However, the development of a general synthetic process to bisamides is still
challenging.13 During the C-H activation studies on primary amide substrates using Pd as
catalyst, ammonium persulfate (APS) as an oxidant and small amount of DMSO (5% v/v), we
noticed the formation of bisamides. In view of their importance in bioorganic, natural product
and medicinal chemistry research and our interest in the development of facile synthetic
processes, we planned to explore our observation to establish a general method for the synthesis
of bisamides from primary amides using DMSO activated by APS as a new approach. It is an
effort to replace formaldehyde, acids and other corrosive/toxic reagents to make a greener
process.
2

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Results and discussion
Permutations and combinations of solvents, reagents and their mole ratios at varying
temperatures (Table 1) provided the optimum reaction condition, wherein heating the 1,4-
dioxane solution of benzamide (1, 1 equiv) in the presence of APS (2 equiv) and DMSO (6
equiv) smoothly furnished the methylenebisamide 2 in quantitative yield (Scheme 1). We
planned for the substrate scope study on varyingly substituted aromatic/aliphatic amides. The
benzamides substituted with -CF3, -Br and -I at the ortho-position of the amide furnished the
corresponding bisamides 3-5 respectively in good yields. The benzamides with electron
withdrawing m-NO2 functionality provided methylenebisamide 6 in 65% yield. The effect of
electron donating and withdrawing substituents at the para-position was also studied. The alkyl
substituted bisamides 7 and 8 were obtained in good to excellent yields and the methoxy
substituted bisamide 9 formed equally well. However, the yield of bisamide 10 from the p-NO2
substituted benzamide was similar to the yield of the m-NO2 substituted bisamide 6. These
observations suggest that under the developed protocol the reactivity of aromatic amides with
electron donating groups is high as compared to the electron withdrawing substituents. p-Chloro
benzamide too gave the corresponding bisamide 11 in good yield. The polyaromatic bisamide 12
was obtained in good yield from 2-naphthamide, though in lower yield than bisamide 2.
However, 3-hydroxybenzamide and p-toluenesulfonamide remained unreactive and the
corresponding bisamides 13 and 14 were not observed at all (figure 3). Amides 15 and 17 did not
furnish the expected bisamides (Scheme 2). Under the standard protocol phthalamide (15) was
converted to pthalimide (16) in quantitative yield. Benzothioamide (17) was converted to
diphenylthiadiazole 18 in excellent yield. This example represents an efficient and simple
alternative protocol for the formation of thiadiazoles from thioamides.14 Probably, both the
3

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reactions followed the APS-DMSO mediated deaminative and desulfurative cyclization pathway
respectively, and their mechanism may be similar to our previous report on dehydrative
cyclization of amic acids to imides.15
The suitability of symmetrical heteraromatic methylenebisamides was studied.
Thiophene-2-carboxamide provided bisamide 19 in high yield; however, quinoline-3-
carboxamide did not furnish bisamide 20, plausibly due to oxidation of the highly basic
quinoline nitrogen (Figure 4).
The synthesis of non-aromatic methylenebisamides was examined using the usual procedure
(Figure 5). Cinnamamide, an α,β-unsaturated amide worked well to provide the bisamide 21 in
good yield. Formation of various bisamides 22-24 from the corresponding arylacetamides was
feasible in good to moderate yields.
Short and long chain aliphatic amides 25 and 26 were examined as substrates; however, complex
mixture of products rather than methylenebisamides was obtained (Figure 6). We assumed that
the instability of the generated radical intermediate might be the reason, hence the reaction was
performed on trichloroacetamide, however the expected product 27 was not observed. The exact
reason for the failure of aliphatic amides to provide bisamides under these conditions is obscure
(Figure 6). Li et al also reported difficulties in preparing aliphatic bismethyleneamides from
aliphatic amides.12
During the course of our studies Sun et al reported an interesting multicomponent Mannich
reaction of a ketone, saccharine and DMSO using RuCl3 and Selectfluor® (Figure 1).2e We
performed our standard reaction on their substrates, compounds 28 and 29, and found that the
desired β-amino ketone 30 was obtained in moderate yield (Scheme 3). Further optimization of
our standard protocol might improve the efficiency of this multicomponent reaction. Application
4

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of Mannich reaction under similar condition and formation of bisamide with N-methyl
benzamide did not work.
Performing the reaction with amide 1 as substrate in the presence of free radical scavengers such
as TEMPO or BHT resulted in only trace amounts of bismethyleneamide 2 (Scheme 4). This
result suggests that the reaction proceeds via mechanism involving the formation of free radicals.
The source of methylene unit was confirmed to be DMSO by performing isotopic labelling
experiment using DMSO-d6 (Scheme 5). The deuterium labelled methylenebisamide 2a was
identified by 1H NMR and HRMS-ESI.
Two noteworthy publications appeared during the compilation of this manuscript, wherein the
activation of DMSO was achieved using NH4I to synthesize β‑alkoxy methyl sulphides by a
multicomponent reaction2c and substituted pyridines from ketones and ammonium acetate.16 We
repeated our reaction on benzamide (1) by using NH4I instead of APS, however there was no
reaction at all, thus suggesting a different mode of activation in our process.
Formation of a formaldehyde equivalent intermediate during the reaction was confirmed
by performing the standard reaction on 1,3,5-trimethoxybenzene (31) to obtain methylene
inserted product 32. Diarylmethanes of this type are important because of their presence in
supramolecular architectures, pharmaceuticals, and biologically active compounds (Scheme 6).20
We have previously proved that APS oxidizes DMSO to form dimethyl sulfone (DMS) in
1,4-dioxane.15 Taking that into consideration we envisaged formation of the sulfonyl compound
34 as a probable intermediate formed by the reaction of amide with DMSO/DMS radical species.
Reaction of benzamide (1) using DMS instead of DMSO under the standard protocol also
furnished the desired bisamide 2 (Scheme 7).
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For indirect evidence, the thio compound 33 was prepared as per the literature procedure19 and
reacted with p-methoxybenzamide in the presence of APS. The expected unsymmetrical
methylenebisamide 35 was obtained as a major product, which confirms our both hypothesis;
oxidation of thio compound 33 to form sulfonyl intermediate 34 and its further elimination and
reaction with another amide to furnish unsymmetrical bisamide 35. Formation of symmetrical
bisamide 9 and benzamide (1) as minor products were also observed, which probably suggests
that the formation of compound 34 and its conversion to DMS radical and benzamide (1) is a
reversible reaction (Scheme 8). Bisamide 2 was not observed under this condition probably
because of low temperature of the reaction and less reactivity of benzamide (1) as compared to p-
methoxybenzamide.
A plausible mechanism has been depicted in figure 7 based on all the above observations and
literature precedence.20b,21 Formation of methane sulfonic acid is also known.21a
In summary, we have developed an efficient protocol for the conversion of primary
amides to the corresponding symmetrical methylenebisamides by using environmentally benign
DMSO as the source of the methylene unit. The activation of DMSO was achieved by using
APS, a commonly used oxidant. The scope of the developed protocol is wide and it avoids the
use of formaldehyde, strong acids and transition-metal catalysts. Application of the protocol to a
three component Mannich reaction was demonstrated. It is also applicable in the synthesis of
thiadiazoles and bis(phenyl)methane. A plausible mechanism of the protocol has been proposed
and supported by mechanistic studies. Currently, we are exploring the other synthetic
applications of this interesting reagent combination.
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Experimental section
All reagents and solvents were used as received from commercial sources unless otherwise
noted. All amides were procured from commercial sources and used as it is. All experiments
were carried out under air atmosphere. Pre-coated plates (silica gel 60 PF254, 0.25 mm or 0.5
mm) were utilized for thin layer chromatography (TLC). Column chromatographic purifications
were carried out on flash silica-gel (240–400 mesh) using petroleum ether and ethyl acetate as
1
13
eluents. The H, C NMR spectra were recorded on 200/400/500 MHz, and 50/100/125 MHz
NMR spectrometers, respectively in CDCl3/DMSO-d6. Chemical shifts were reported as δ values
from standard peaks. Melting points are uncorrected. Mass spectra were taken on LC-MS (ESI)
mass or GC-MS mass spectrometer. HRMS were scanned on Quadrupole-Orbitrap Mass
Spectrometer available at our institutional facility.
General procedure for the synthesis of methylenebisamides
A solution of amide (50 mg, 1 equiv), ammonium persulfate [(NH4)2S2O8] (2 equiv) and DMSO
o
(6 equiv) in 1,4-dioxane (2 mL) was heated at 100 C in a round bottom flask, equipped with a
stirring bar and water condenser, until the reaction was complete as indicated by thin layer
chromatography. After completion, the reaction mixture was filtered through a cotton plug and
1,4-dioxane was removed under vacuum. The residue was then dissolved in ethyl acetate (10
mL) and washed with warm water (4 mL) and brine (3 mL x 2). The organic layer was dried over
anhydrous sodium sulfate and the crude product was purified by flash column chromatography to
furnish corresponding methylenebisamides in good to excellent yields.
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Acknowledgments
P.S.M. thanks CSIR-New Delhi for the research fellowship. S.B.M. gratefully acknowledges
generous financial support from DST, CSIR-ORIGIN, CSIR-OSDD New Delhi as well as CSIR-
NCL (start-up grant).
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Figure 1. Recent advances demonstrating application of activated DMSO
Figure 2. Traditional routes to methylenebisamides and this work
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Table 1. Optimization studiesa
Entry
Oxidant/DMSO
Solvent
(2 mL)
dioxane
dioxane
dioxane
-
Temp/Time Yield
(equiv)
(oC/h)
(%)b
1
APS (1)/ 4
APS (1)/ -
100/18
100/18
100/04
100/18
100/10
100/18
100/18
100/09
100/06
100/12
100/06
100/06
100/06
100/06
100/06
100/06
111/06
100/06
38
2
00
3
- / 4
00
4
APS (1)/ excess
APS (2)/ excess
APS (2)/ 4
APS (3)/ 4
APS (2)/ 5
APS (2)/ 6
APS (1)/ 6
APS (2)/ 10
K2S2O8 (2)/ 6
tBuO-OtBu
cDBPO (2)/ 6
PhI(OAc)2 (2)/ 6
OxoneTM
trace
05
5
-
6
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
88
7
71
8
94
9
98
10
11
12
13
14
15
16
17
18
40
97
35
00
trace
trace
17
APS (2)/ 6
58
APS (2)/ 6
water
07
b
c
aAll reactions were performed on 50 mg scale of amide 1 in a round bottom flask equipped with a water condenser; Isolated yields. DBPO-
dibenzoyl peroxide
Scheme 1. Protocol optimized on benzamide (1)
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[aThe ratio for amide: APS:DMSO = 1:3:9]
Figure 3. Scope of aromatic amides
Scheme 2. Different products than expected bisamides
Figure 4. Heteroaromatic bisamides
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Figure 5. Cinnamide and aryacetamides.
Figure 6. Aliphatic amides did not work
Scheme 3. Application to a multicomponent Mannich reaction
Scheme 4. Radical trapping experiment.
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Scheme 5. Isotopic labelling experiment
Scheme 6. Demonstration of DMSO as a formaldehyde equivalent
Scheme 7. Reaction using dimethyl sulfone instead of DMSO
Scheme 8. Intermediate 34 is a plausible intermediate in the key reaction
Figure 7. Plausible mechanism
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Table of Contents entry
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