Efficient method to prepare diethylphosphonacetamides

Article abstract of DOI:10.1016/j.tetlet.2010.07.125

An efficient and versatile synthetic method is described to synthesize diethylphosphonacetamides in a single step.

Full text of DOI:10.1016/j.tetlet.2010.07.125

Tetrahedron Letters 51 (2010) 5154–5156
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient method to prepare diethylphosphonacetamides
a
a
b
a
Federico Scaravelli a, , Sergio Bacchi , Luca Massari , Ornella Curcuruto , Pieter Westerduin ,
*
William Maton a
a Chemical Development Department, GlaxoSmithKline Medicines Research Centre, via Fleming 4, 37135 Verona, Italy
b Analytical Chemistry Department, GlaxoSmithKline Medicines Research Centre, via Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and versatile synthetic method is described to synthesize diethylphosphonacetamides in a
Received 28 June 2010
Revised 19 July 2010
Accepted 21 July 2010
Available online 25 July 2010
single step.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diethylphosphonacetamides
T3P
Amide coupling
Horner–Wadsworth–Emmons Agents
Phosphonacetamides are very useful intermediates for access-
ing ,b-unsaturated amides as synthetic precursors in natural
coupling agents in order to improve the reaction profile. Boronic
acids and T3P were screened and the results are shown in Table 1.
The formation of 2 was achieved with the use of T3P. Notably,
the use of triethylamine at room temperature did not lead to com-
plete conversion (Table 1, entry 5) and, moreover, the removal of
the base did not have an impact on the reaction behaviour (Table
1, entry 6). The conversion was improved by heating the reaction
mixture to reflux (Table 1, entry 7) and it was brought to comple-
tion by increasing the amount of the coupling agent (Table 1, entry
8). After a mild basic aqueous wash, which allowed the selective
removal of the by-products of the T3P, 2 was isolated as a white so-
lid in 93% yield.
We explored the scope and versatility of the coupling reaction
involving T3P, without a base as additive, by applying this unprec-
edented methodology to a wide range of substrates containing NH
group. The results are summarized in Table 2. Reactions were first
carried out at room temperature to confirm the need for heating;
as a general trend, the reaction takes place immediately after the
a
product synthesis.1 The routine method to prepare phosphonaceta-
mides is the Arbuzov reaction.2 This method is also applied in the
literature to prepare the diethylphosphonacetamides 23 from
(1R,2S)-(+)-10,2-camphorsultam. However, the Arbuzov synthesis
is a two-step route and does not allow for adequate diversity of
the amide side chains, mainly due to the limited availability of
the amines. Another widely reported approach describes the syn-
thesis of phosphonacetamides starting from the commercially
available diethylphosphonoacetic acid 1 via a peptide coupling
procedure, using carbodiimides with or without additives such as
HOBT and 4-DMAP.4 Also Melmam and co-worker5 described an
efficient acylation of sterically hindered alcohols of diethylphos-
phonoacetic acid through ketene intermediates promoted by the
presence of DCC.
In our view, the latter approach is the most suitable for a large-
scale synthesis.
Herein, we report an efficient, simple and practical method for
accessing diethylphosphonacetamides using 1-propanephosphonic
acid cyclic anhydride (T3P) as the coupling reagent.
In the initial attempts, the camphorsultam was treated with
DCC and a solution of diethylphosphonoacetic acid 1 in dichloro-
methane at room temperature, leading to the formation of a
complex mixture within which the desired product 2 was identi-
fied. These promising results encouraged us to investigate other
HN
O
P
O
O
P
O
S
O
O
O
N
O
OH
O
T3P in EtOAc
O
S
O
O
1
2
* Corresponding author. Tel.: +39 045 821 8074; fax: +39 045 821 8117.
E-mail addresses: federico.scaravelli@gmail.com, federico.2.scaravelli@gsk.com
(F. Scaravelli).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.125

F. Scaravelli et al. / Tetrahedron Letters 51 (2010) 5154–5156
5155
Table 1
Coupling reagents screening via Scheme 1
Entry
Coupling agents
Conditions
Results
1
2
3
4
5
6
7
8
DCC
DCC (1.1 equiv), DCM, 20 °C
Complex mixture
No reaction
No reaction
No reaction
Incomplete conversion
Incomplete conversion
B(OH)3
PhB(OH)2
2-BrPhB(OH)2
T3P
T3P
T3P
B(OH)3 (0.2 equiv), toluene, Dean–Stark
PhB(OH)2 (0.2 equiv), toluene, Dean–Stark
2-BrPhB(OH)2 (0.2 equiv), toluene, Dean–Stark
T3P (1.1 equiv), Et3N (2 equiv), EtOAc, 20 °C
T3P (1.1 equiv), EtOAc, 20 °C
T3P (1.1 equiv), EtOAc, 80 °C
T3P (1.1 equiv + 0.35 equiv), EtOAc, 80 °C
Almost complete conversion
Complete conversion
T3P
amide and oxazolidinone7 were successfully converted into the
corresponding diethylphosphonacetamides (Table 2, entries 13
and 14).
A representative procedure using benzylamine is described.
Diethylphosphonoacetic acid (3.08 mmol, 1.1 equiv) was added to
a solution of benzylamine (2.8 mmol, 1 equiv) in ethyl acetate
Table 2
Preparation of diethylphosphonacetamides with T3P
R1
HN
O
P
O
O
P
O
R2
R1
O
O
N
OH
O
O
T3P in EtOAc
R2
(3 mL) under nitrogen.
A solution of T3P in ethyl acetate
º
80 C
(50 wt %, 4.06 mmol, 1.45 equiv) was added dropwise over 5 min.
The resulting solution was heated to 80 °C and stirred overnight.
The reaction progression was followed by HPLC or LC/MS. After
cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (3 mL) and water (3 mL). The biphasic system
was then basified to pH 6 with 12 N aqueous NaOH, stirred for
1 h, then the two layers were allowed to settle and separate. The
organic layer was washed with water (3 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to a so-
lid which was triturated with heptane to yield 640 mg of benzyl
diethylphosphonacetamides (80%).11
Entry Amine
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Benzylamine8
80a
56a
53b
91b
84b
40a
iso-Propylamine
tert-Butylamine9
(1R)-1-Phenylethanamine
2-Phenylcyclohexylamine
(2S)-2-{Diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine
(2S)-2-{Diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidinec 70a
Aniline
89b
83a
78b
58a
85b
93a
80a
3,5-Bis(trifluoromethyl)aniline
2-Aminopyridine
6-Amino-5-iodo-3-pyridinecarbonitrile
5-Fluoro-3-methyl-2-pyridinamine
(1R,2S)-(+)-10,2-Camphorsultam
(4R)-4-Phenyl-1,3-oxazolidin-2-one10
In conclusion, we have developed an efficient, simple and prac-
tical synthesis of diethylphosphonacetamides using T3P as the
coupling agent.
a
Isolated as a solid.
b
Acknowledgements
Isolated as an oil, contaminated by triethylphosphono acetate already present
in the purchased diethylphosphonoacetic acid.
c
Reaction carried out at 20 °C.
We thank Stefano Provera and Lucilla Turco for the NMR
support.
addition of the coupling agent but it tends to stall until heated to
80 °C. Generally, the resulting diethylphosphonacetamides were
obtained in moderate to high yields. The variability was probably
due to the solubilities of the final compounds in water, which
cause partial losses in the aqueous media used during the work-
up. This appeared to be of particular relevance for alkyl primary
amines (Table 2, entries 2 and 3). As a matter of fact, we included
in our investigation one of the widely known organic catalysts,
Jørgensen’s (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrroli-
dine6 (Table 2, entry 6). Even if it reacted well, the isolated product
was exclusively 3 resulting from the –OTMS elimination and con-
sequent loss of the chirality. When the reaction was carried out un-
der milder condition (Table 2, entry 7) no elimination occurred but
TMS hydrolysis to 4 was observed. The highly hindered OH did not
interfere and the reaction proceeded selectively on the nitrogen.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.125 and new
chemical entities can be downloaded from http://www.elsevier.
com/wps/find/journaldescription.cws_home/233/description#
description.
References and notes
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O
P
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O
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O
O
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3
4
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F. Scaravelli et al. / Tetrahedron Letters 51 (2010) 5154–5156
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11. 1H NMR (400 MHz, CDCl3): d (ppm) 7.19–7.42 (m, 5H), 7.09 (br s, 1H), 4.47 (d,
J = 5.71 Hz, 2H), 4.00–4.20 (m, 4H), 2.89 (d, J = 20.64 Hz, 2H), 1.31 (td, J = 7.03,
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C
13H20NO4P [M+H]+: 286.1208; found:
286.1219.