Bis azide-triphenylphosphine as a reagent for esterification at room temperature

Article abstract of DOI:10.1016/j.tetlet.2015.10.073

Modified Staudinger reaction is a well-established reaction for the amide synthesis from organic azides and carboxylic acids in the presence of phosphorous reagents. In contrary to this, it is notable that bis azide in the presence of triethylphosphite or trimethylphosphite does not afford the expected bis amides but affords the ethyl or methyl esters of the carboxylic acids respectively. This serendipitous observation when further investigated results in the discovery of bis azide-triphenylphosphine as an efficient reagent for esterification at room temperature.

Full text of DOI:10.1016/j.tetlet.2015.10.073

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Bis azide–triphenylphosphine as a reagent for esterification at room
temperature
Murugan Dinesh, Sivasubramaniyan Archana, Raja Ranganathan, Murugan Sathishkumar,
⇑
Alagusundaram Ponnuswamy
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Modified Staudinger reaction is a well-established reaction for the amide synthesis from organic azides
and carboxylic acids in the presence of phosphorous reagents. In contrary to this, it is notable that bis
azide in the presence of triethylphosphite or trimethylphosphite does not afford the expected bis amides
but affords the ethyl or methyl esters of the carboxylic acids respectively. This serendipitous observation
when further investigated results in the discovery of bis azide–triphenylphosphine as an efficient reagent
for esterification at room temperature.
Received 16 September 2015
Revised 21 October 2015
Accepted 22 October 2015
Available online xxxx
Keywords:
Bis azide
Ó 2015 Elsevier Ltd. All rights reserved.
Trialkylphosphite
Triphenylphosphine
Ester synthesis
New reagent
Introduction
search for an effective and simple esterifying agent becomes
essential.
The esterification is an extensively used fundamental reaction
in synthetic organic chemistry. Mineral acids,1 catalyst2 and vari-
ous electrophilic activators like DCC,3 DEAD/Ph3P,4 Ph3P/NBS,5
Me2NSO2Cl/DMAP,6 Ph3PO/(FSO2)2O7 and Ph3PBr2/DMAP8 have
been employed to achieve effective esterification. These method-
ologies are associated with disadvantages such as anhydrous and
tedious reaction procedures, long reaction time, high temperature,
expensive reagents, excess of alcohol and toxic solvents. Hence, the
Aza-ylides, the nitrogen analogues (R3P@NR) of phosphorous
ylides (R3P@CR) referred to as iminophosphoranes or phosp-
hazenes are versatile intermediates in organic synthesis. Their
pronounced basicity and the readily polarizable P@N bond have
paved the way for the well-established and documented reactions
such as Aza-Wittig reaction,9–13 Modified Staudinger reaction14
and Staudinger ligation.15–17 Additionally, the application of
iminophosphorane in co-ordination chemistry18a,b polymer
O
TEP
O
TEP
R
R
OEt
O
O
R
OH
TMP
TPP
O
TMP
TPP
R
N
H
N
H
R
OMe
N3
N3
Expected
NO REACTION
Unexpected
Scheme 1. Serendipitous observation leading to the present investigation.
⇑
Corresponding author.
E-mail address: ramradkrish@yahoo.co.in (A. Ponnuswamy).
http://dx.doi.org/10.1016/j.tetlet.2015.10.073
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dinesh, M.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.073

2
M. Dinesh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
OH
P(OR)3
O
Optimization of the reaction conditions in the synthesis of ester (3n)
R
n N3
N3
solvent-free, rt
O
O
N3
N3
O
TEP,
or rt
where R=Et
n=2; 20 min; 67%
n=3; 10 min; 80%
n=4; 15 min; 72%
where n=3, R= Me 78 %
R= Et 80 %
OEt
Solvent/solvent-free
O
3n
OH
Yielda (%)
Scheme 2. Scope of bis azides–trialkylphosphite as reagents for esterification.
Entry
Solvent
Time (h)
Temperature (°C)
1
2
3
4
5
Benzene
Toluene
Xylene
Mesitylene
Solvent-free
8
5
1
80
56
63
70
78
80
110
135
160
rt
Recently we have reported the solvent-free protocol for the syn-
thesis of amide via the modified Staudinger reaction,that is, trap-
ping the iminophosphorane generated insitu from organic azide
and triphenylphosphine (TPP)24 or triethylphosphite (TEP)25 or
trimethylphosphite (TMP) with carboxylic acids under solvent-free
condition. The expeditious methodology eradicated a number of
limitations that were associated with analogous solution-
phase26,27 preparations of amides.
30 (min)
20 (min)
Reaction conditions: 1,3-diazidopropane (0.5 mmol), triethylphosphite (1.0 mmol)
and phenyl acetic acid (1.0 mmol) in solvent (5 ml) or solvent-free condition were
stirred at the temperature for the time mentioned in the table.
a
Isolated yield.
chemistry19–21 and catalysis22,23 is commendable. In view of this,
further investigation involving iminophosphoranes is gaining
importance. We herein submit the report on the versatile applica-
bility of bis-iminophosphorane (generated in situ from Bis azide
and triphenylphosphine) as an efficient reagent for esterification.
Results and discussion
While transposing the solvent-free protocol for the bis amide
synthesis, we noted that in contrary to the above, bis azides on
Table 2
Scope of solvent-free esterification using trialkylphosphites
O
O
P(OR)3
R
N3 3 N3
Ar
O
solvent-free, rt
Ar
OH
R=Me
=Et
O
O
O
O
O
O
O
O
Cl
Cl
3b (75%)
3a (74%)
3c (72%)
3d (77%)
O
O
O
O
O
O
O
O
Cl
Cl
3e (73%)
NO2
3h (77%)
3f (75%)
O
3g (75%)
O
O2N
O
O
O
O
O
O2N
O
O
N
N
NO2
3j (75%)
3l (78%)
O
3k (75%)
3i (72%)
O
O
O
O
O
O
O
O
O
3n (80%)
O
O
3p (77%)
3o (74%)
3m (78%)
O
O
O
O
O
H2N
3t (73%)
H2N
3s (76%)
3r (78%)
3q (74%)
O
O
O
O
OH
3v (74%)
OH
3u (76%)
Reaction conditions: 1,3-diazidopropane (0.5 mmol), trimethylphosphite/triethylphosphite (1.0 mmol) and car-
boxylic acid (1.0 mmol) were stirred at room temperature for 20 min.
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M. Dinesh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
R
R
R
O
P
R
R1
N
R
O
P
R
O
R
O
O
R
R
R
O
R
R
O
R
R
O
O
O
O
O
O
O
N
O
O
P
O
H
N
P
O
N3
N3
H
P
N
R
N
H
H
P
O
O
R1
O
O
N
H
H
R
H
H
H
H
P(OCH2R)3
-N2
R
H
H
R
R1COOH
R1COO
H
H
H
H
H
H
H
H
Bis iminophosphorane
Alkyloxyphosphonium ion
R
O
R1
O
R
R1
O
R
O
P
R
R
R
O
R
R
R1
O
O
O
O
O
R
O
O
R
O
P
O
O
H N
Dealkylation
P
O
O
NH
R
R
O
P
R1COO
N
R
H
NH
R
O
R
O
R
O
P
O
P
Where R = H or CH3
O
O
N
N
H
H
Scheme 3. Proposed mechanism for esterification using trialkylphosphites.
Table 3
Scope of solvent-free esterification using triphenylphosphine
O
N3
N3
O
R
OH
solvent free
rt,10 mins
Ph
P
R
O
R1
R1 OH
R1=
Ph
Ph
O
O
O
O
O
O
Cl
5c (80%)
5a (81%)
5b (79%)
O
O
O
O
O
O
Cl
5f (81%)
O
5d (81%)
5e (83%)
O
O
O
O
O
O
5i (77%)
5h (81%)
5g (78%)
O
O
O
7
O
7
O
O
O
5l (83%)
5k (85%)
5j (80%)
Reaction conditions: To
a
mixture of triphenylphosphine (1.0 mmol), 2-phenylethanol/cinnamyl alcohol
(1.0 mmol) and carboxylic acid (1.0 mmol), 1,3-diazidopropane (0.5 mmol) was added slowly in a drop wise
manner (to avoid accumulation of azide) and the mixture was stirred at room temperature for 10 min.
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4
M. Dinesh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Ph
P
Ph
Ph
N
Ph
Ph
Ph
N3
H
N3
H
Ph
P
P
H
H
N
Ph
Ph
H
H
Bis iminophophorane
- N2
H
H
path B
path A
R
OH
RCOOH
RCOOH
R
OH
Ph
P
R
R
O
Ph
Ph
HO
R
O
R
O
O
Ph
R
O
R
Ph
O
Ph
O
R
OH
Ph
R
P
Ph
H
H N
P
H
O
N
H
Ph
Ph
O
Ph
H
O
H
P
N
N
H
Ph
H
H
H
H
H
(II)
H
(I)
H
deacylation
O
dealkylation
O
O
O
R
R
P
R
O
O
R
R
O
R
R
O
R
O
O
Ph
Ph
Ph
O
P
Ph
Ph
O
Ph
P
Ph
Ph
Ph
P
Ph
Ph
H2N
Ph
NH2
H
NH2
H
NH2
H
H
H
H
H
H
NH2
H2N
H2N
NH2
Scheme 4. Proposed mechanism for esterification using triphenylphosphine.
treatment with two equivalents of phosphorus reagent (TPP or TEP
or TMP) and two equivalents of carboxylic acid do not afford the
bis amide (Scheme 1), the expected product.
(obtained from trialkylphosphite and bis azide) of the bis
iminophosphorane results in the formation of the corresponding
alkyloxyphosphonium ion which then leads to the formation
Instead, in the above attempt while using phosphorus reagents
viz TEP and TMP, the ethyl ester and methyl ester of the carboxylic
acid were obtained respectively in excellent yields. Further, inves-
tigation related to the serendipitous observation resulted in the
discovery of bis azide–TPP as an efficient reagent for esterification.
The findings in this regard are presented in the forthcoming pages.
At the outset the effect of solvent and solvent-free condition in the
esterification was investigated, the results of which are summa-
rized (Table 1).
It is evident from the screening that solvent-free condition
(entry 5) is more efficient in the sense that esterification occurs at
room temperature in just 20 min. Further, it was noted that the bis
azide viz 1,3-diazidopropane is more efficient than 1,2-diazidoethane
and 1.4-diazidobutane in the esterification (Scheme 2).
of the ester in an intramolecular manner or via
intermediate.
a cyclic
However, for the preparation of various esters, the corre-
sponding trialkylphosphites have to be prepared. To overcome
this difficulty, it was envisaged to use TPP and alcohol as the
substitute for trialkylphosphite. To our delight, this presump-
tion turned out to the successful,that is, under solvent-free con-
dition, various carboxylic acids and alcohols coupled rapidly at
room temperature in few minutes to afford the corresponding
esters (5a–5l45–54 Table 3) in the presence of bis azide–TPP
as the reagent.
(Scheme 4).
A
plausible mechanism is present vide
Herein, initial protonation of the bis iminophosphorane leading
to the formation of the reactive phosphonium ions which would
have been trapped either by alcohol (pathway A) or by the car-
boxylate ion (pathway B) to afford the corresponding intermedi-
ates I and II respectively. Subsequently, I and II would afford the
ester via dealkylation and deacylation.
The simple requirements such as stoichiometric quantity of
alcohol and carboxylic acid, very short reaction time
(10–20 min), room temperature and solvent-free condition while
using bis azide–TPP as an esterifying reagent in the present
investigation show its significance.
The broad scope of the optimized protocol for the synthesis of a
library of esters (3) has been established (Table 2).
Esters (3a–3v)28–44 of various carboxylic acids have been
obtained in good yields using TEP and TMP by optimized proce-
dure. A plausible mechanism is presented vide (Scheme 3). Herein,
it is notable that formation of the ester is through the dealkylation
of TMP or TEP by the carboxylate ion.
Apparently, the mechanism initiated by the initial
protonation of the nitrogen of one of the iminophosphoranes
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M. Dinesh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
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Supplementary data
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