An efficient method for the preparation of N-formyl-imide via amidine using propylphosphonic anhydride (T3P)

Article abstract of DOI:10.1016/j.tetlet.2015.12.046

An efficient method for the preparation of N-formyl imide via amidine using propylphosphonic anhydride (T3P) has been described. Using this method many aryl, hetero aryl, alkyl as well as amino acid imides were synthesized in high yields.

Full text of DOI:10.1016/j.tetlet.2015.12.046

Accepted Manuscript
An Efficient Method for the Preparation of N-Formyl-Imide via Amidine using
Propylphosphonic Anhydride (T3P®)
M. Sambaiah, Ramakrishna Gudipati, K. Shiva Kumar, Satyanarayana Yennam,
Manoranjan Behera
PII:
S0040-4039(15)30461-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.046
TETL 47093
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 October 2015
3 December 2015
8 December 2015
Please cite this article as: Sambaiah, M., Gudipati, R., Shiva Kumar, K., Yennam, S., Behera, M., An Efficient
Method for the Preparation of N-Formyl-Imide via Amidine using Propylphosphonic Anhydride (T3P®),
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.046
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Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
An Efficient Method for the Preparation of N-Formyl-Imide via
Amidine using Propylphosphonic Anhydride (T3P®)
M. Sambaiaha, b, Ramakrishna Gudipatia, K. Shiva Kumarb, Satyanarayana Yennama &
Manoranjan Beheraa*
a Chemistry services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana State, India
bDepartment of Chemistry, GITAM University, Hyderabad Campus, Rudraram Village, Patancheru Mandal, Medak Dist.,Telangana State,
502329, India
Abstract: An efficient method for the preparation of N-formyl imide via amidine using propylphosphonic anhydride (T3P®) has been
described. Using this method many aryl, hetero aryl, alkyl as well as amino acid imides were synthesized in high yield.
Imides are compounds consisting of two carbonyl
groups bound to nitrogen atom.1 Imides are versatile
building blocks in the synthesis of nitrogen heterocycles.
2The imide moiety is also an important component in many
natural products that exhibit a broad range of activities
including immune-suppressants,3 cytotoxic anticancer
agents,4 antibiotics,5 and antifeedants.6 Cyclic imide moiety
and their derivatives play an integral part in various
important molecules such as thalidomide, isogranulatimide
and rebeccamycin etc.7 Unlike cyclic imides, where much is
known about their synthesis and reactivity, only few
methods have been reported for the preparation of acyclic
imides.8 N-formyl imides are acyclic imides where the
formyl group is attached to amide moieties which are useful
intermediates for natural product synthesis (Fig 1).9-13 Apart
from their biological activities, imide derivatives are useful
in the reactions involving Wittig reaction, condensation,
alkylation, acylation and cyclocondensation.14
Propylphosphonic anhydride (T3P) is a mild
peptide coupling reagents having low toxicity and low
allergenic potential.17 Recently, it has been used as a
versatility reagent in organic chemistry beyond peptide
synthesis.18 T3P is well known for conversion of carboxylic
acids and amides to nitriles,19 formation of Weinreb
amides,20 ester21 and isonitrile synthesis.19 T3P offers
several advantages over traditional reagents, such as broad
functional group tolerance, low epimerization tendency, as
easy work up due to water soluble by-products and non-
toxic in nature. There are quite a few examples, where in
T3P is utilized in dehydration chemistry and molecular
rearrangement.22-23 Recently, it has been used as a reagent
in the preparation of various heterocycles viz. quinolines,24
coumarins,25 indole synthesis,26 but its synthetic utility has
not been investigated in the synthesis of imide derivatives.
There is no report for the synthesis of imides using T3P in
the literature.
Marquez group has extensively studied the
Formylation of amide is a very useful process in
formylation of amide in order to make enamide.15-16 The
key to their approach lies in considering that the N-formyl
unit could potentially behave as a pseudo-aldehyde unit, as
opposed to a normal amide group. It was reasoned that the
nitrogen lone pair would be effectively delocalised into the
adjacent carbonyl group. This delocalization would render
the N-formyl group to being significantly more reactive
than a typical formamide. Despite the importance of N-
formyl imide in the natural product synthesis, there are very
few methods available for its synthesis.
synthetic organic chemistry.27 Many methods have been
developed for the preparation of imides,28 however most
available methods either employ sophisticated reagents or
provide only moderate yields. Also high temperature
condition and scrambling of the grouping to give
symmetrical imides are the limiting factors in this
methodologies.29 Classically, imides are prepared by the
reaction of amides with acyl chlorides, anhydrides and
carboxylic esters or acids. However, these methods are not
as straightforward as they seems to be the first glance and
several side reactions such as elimination to nitriles,
formation of triacyl amides or acyl group scrambling can
occur. Other procedure for the synthesis of acyclic imides
involves amino carboxylation of aryl bromides,30 reaction
of azalactone with oxygen/palladium31 and reaction of
pentafluorophenyl esters with deprotonated amides.32
Key words: N-formylation, Imide, T3P, amidine, DMF-DMA
Corresponding author: Manoranjan Behera
Email: Manoranjan.Behera@gvkbio.com

2
Tetrahedron Letters
Treatment of amides with reagents such as
aromatic rings and oxidative cleavage of both carbon–
carbon double bonds and carbon–carbon triple bonds.
Trudell et al., have reported that N-alkyl amides could be
oxidized to imides with chromium(VI) oxide and periodic
acid in the presence of acetic anhydride in acetonitrile.38 In
another report, silica sulfuric acid has been used as a
recyclable reagent for the one pot synthesis of acyclic
imides by reaction of aliphatic and aromatic nitriles with
acyclic carboxylic anhydrides.39 These reported methods
involve use of expensive reagents, harsh reaction
conditions, elevated temperature and sophisticated reagents.
So development of new methodologies for the synthesis of
imides is required.
dimethylacetals of amides,33 N,N-bis(trimethylsilyl)
formamide, α, α, α-trichloromethyl carbonyl compounds,34
diketenes35 or vinyl esters36 are few direct methods for the
synthesis of imides. The direct oxidation of N-alkyl amides
is the simplest and most straightforward method for the
preparation of imides. Unfortunately, most of the oxidations
cited in the literature suffers from a competitive N-
dealkylation and afford the corresponding imides only as
minor products. Only the RuO4 oxidation has been proven
to be synthetically useful for the preparation of imide
derivatives.37 However, the synthetic scope of the RuO4
oxidation is limited due to oxidative degradation of
During our research program on natural product
hybrid synthesis,39-42 we need to synthesize a number of N-
formyl imides with various degrees of substituents on
aromatic ring. Herein, we wish to report that
propylphosphonic anhydride (T3P®) can be used for the
preparation of N-formyl imide via amidine (Scheme 1).
The amidine 2a was prepared by condensation of
was converted back to 1a. We have observed similar results
using PPA for hydrolysis. Finally, intriguing by the use of
T3P for various conversions,5 we have treated compound 2a
with T3P in EtOAc reflux condition; the imide 3a was
formed cleanly in this condition and were able to isolate
compound 3a in 92% yield
To prove the generality of this method various
benzamide 1a with N,N-dimethylformamide-dimethylacetal
(DMF-DMA) in refluxing toluene (Scheme 1). Initially, the
hydrolysis of amidines was attempted using various
conditions (Table 1). Using concentrated HCl in THF for
hydrolysis, the starting material 2a was completely
consumed, but LC-MS analysis showed no desired product
3a. When we used 4M HCl in dioxane the compound 2a
different highly substituted aryl, hetero aryl, alkyl as well as
amino acid amides were examined and the results were
given in Table 2. Similar yields were observed for the
substrates having electron withdrawing groups (compounds
3k, 3l) as well as electron donating groups (compound 3b,
3f).It is noteworthy to mention here that previously
inaccessible furan analogues and thiophene analogues were

Tetrahedron Letters
3
synthesized in very good yield (compound 3o, 3p). We did
not observe the oxidation of aldehyde or degradation of
amidines in any of the examples. Alkyl amides (3n, 3q and
3r) were also converted to imides in good yield which are
not reported in the literature.
pentane to afford pure compound 2a (1.3 g, 90 %) as an off
white solid.
Typical experimental procedure for the preparation N-
formylbenzamide (3a). To a solution of compound 2a (200
mg, 1.13 mmol) in ethyl acetate (10 ml) was added T3P
(3.40 mmol, 1.02 ml) at 0°C and the reaction mixture was
Table 1. Different Conditions used for Hydrolysis of 2a
0
stirred at 80 C for 12 h. The progress of the reaction was
Reaction Conditions &
Product obtained (yield)a
Reaction Conditions &
Entry
Entry
Product obtained (yield)a
monitored by TLC (50% EtOAc/petroleum ether). After
completion of the reaction, water (50 ml) was added to the
reaction mixture and extracted with ethyl acetate thrice.
Combined the organic layers, washed with water, brine and
dried over Na2SO4. The solvent was evaporated to afford the
crude product. The crude product was charged on silica gel
column. Elution of the column with 30% EtOAc/ petroleum
ether gave the pure compound 3a (155 mg, 92 %) as an off
white solid
__________________________________________________________
O
O
1
5
6
NH2
NH2
1a
1a
HCl, THF, reflux (90%)
4M HCl, Dioxane, reflux (98%)
2
3
4
TFA, EtOAc,reflux (83%)
O
N
O
O
N
N
NH2
Conclusion:
5
1a
H3PO2, EtOAc, reflux (16%)
In summary, we have developed an efficient and
simple method for the preparation of N-formyl imide via
amidine using propylphosphonic anhydride (T3P®) in good
yield.
PPA, DMF, H2O, 80 °C (58%)
O
O
7
N
O
4
NH2
1a
H
3a
T3P, EtOAc, 80 °C (92%)
Acknowledgements:
NaIO4, DMF, H2O, 80 °C (77 %)
Authors are grateful to GVK Biosciences Pvt. Ltd.,
for the financial support and encouragement. Help from the
analytical department for the analytical data is appreciated.
We thank Dr. Sudhir Kumar Singh for his invaluable
support and motivation.
a The sturcture of the product was determine by crude LC-MS analysis only
Typical experimental procedure for the preparation
of(E)-N-(dimethylamino)methylene)benzamide (2a):To a
solution of benzamide 1a (1g, 8.26 mmol) in toluene (10
ml) was added DMF-DMA (5.7 ml, 24.79 mmol) at room
0
temperature and the reaction mixture was stirred at 100 C
for 12 h. The progress of the reaction was monitored by
TLC (50% EtOAc/ petroleum ether). After completion of
the reaction, toluene was evaporated to give the crude
product. The crude product was recrystallized with n-

4
Tetrahedron Letters
Table 2. Synthesis of N-formyl amide using T3P

Tetrahedron Letters
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TETRAHEDRON
LETTERS
Graphical Abstract
An Efficient Method for the Preparation of N-Formyl-
Imide via Amidine using Propylphosphonic Anhydride
(T3P®)
M. Sambaiaha,b , Ramakrishna Gudipatia, K. Shiva Kumarb, Satyanarayana Yennama & Manoranjan Behera*a