Improved solubility and stability of trialkylammonium selenocarboxylate in organic solvents for efficient amidation with azides

Article abstract of DOI:10.1016/j.tetlet.2006.04.144

Trialkylammonium selenocarboxylate, formed in situ from the reaction of diacyl diselenide with piperidine in the presence of diisopropylethylamine, was found to react readily at room temperature with electron-deficient azides to form amides in excellent yields. The trialkylammonium selenocarboxylate salt formed has good solubility and stability in organic solvents. The enhanced stability allowed mild heating to improve the amidation yields with electron-rich azides.

Full text of DOI:10.1016/j.tetlet.2006.04.144

Tetrahedron Letters 47 (2006) 4609–4613
Improved solubility and stability of trialkylammonium
selenocarboxylate in organic solvents for efficient amidation
with azides
Prathima Surabhi, Xinghua Wu and Longqin Hu*
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers,
The State University of New Jersey, Piscataway, NJ 08854, USA
Received 7 April 2006; revised 25 April 2006; accepted 27 April 2006
Available online 19 May 2006
Abstract—Trialkylammonium selenocarboxylate, formed in situ from the reaction of diacyl diselenide with piperidine in the pres-
ence of diisopropylethylamine, was found to react readily at room temperature with electron-deficient azides to form amides in
excellent yields. The trialkylammonium selenocarboxylate salt formed has good solubility and stability in organic solvents. The
enhanced stability allowed mild heating to improve the amidation yields with electron-rich azides.
Ó 2006 Elsevier Ltd. All rights reserved.
Amide bonds are usually formed through the reaction of
an activated carboxylic acid with a free amine. However,
not all functional groups are compatible with the pres-
ence of a free amine. One such example is the decompo-
sition of 4-aminobenzyl esters due to 1,6-elimination.1,2
An alternative amidation method is to react thio acids
with azides to form amides through a thiatriazoline
intermediate without involving the amine intermedi-
ates.3–6 We and others have reported recently that sele-
nocarboxylates react with azides to form amide bonds
in a similar fashion to thio acids.2,7 Selenocarboxylates
have greater reactivity as compared to thio acids. The
enhanced reactivity of selenocarboxylates would acceler-
ate the reaction, shorten the reaction time, and poten-
tially lower the reaction temperature. For our initial
efforts,2 we used potassium selenocarboxylates to react
with azides because alkali metal salts of selenocarboxyl-
ates were known to be relatively stable.8 However, to
better solubilize potassium selenocarboxylates and
potassium methoxide used to prepare selenocarboxyl-
ates,9 we used DMSO as a co-solvent for the reaction.
The mild oxidizing property of DMSO accelerated the
decomposition of selenocarboxylates, which adversely
affected the yield of product formation. Using an HPLC
assay, we found that the half-life of selenocarboxylate
was only 25 min under the mixed solvent conditions of
DMSO and ethyl acetate at room temperature.2 With
electron-deficient azides and excess (2 equiv) potassium
selenocarboxylate, the reaction was fast and the short
half-life of selenocarboxylate did not present a problem.
When electron-rich azides were used, the reactions
under the same conditions required longer time to
complete. The poor stability of selenocarboxylate under
these reaction conditions led to much lower conversion
yields. Our efforts then focused on the use of organic
amine salts of selenocarboxylates, and on finding condi-
tions to improve the solubility and stability of seleno-
carboxylates and to increase the reaction yields with
electron-rich azides. Here, we report the preparation of
diisopropylethylammonium benzeneselenocarboxylate
(4) as a model substrate and its subsequent direct amida-
tion with azides in a much improved set of reaction
conditions.
In our previous method,2 diacyl selenides were used to
prepare selenocarboxylates. Here, we used a diacyl disel-
enide instead, as diacyl diselenides are more stable than
diacyl selenides. As shown in Scheme 1, dibenzoyl disel-
enide (2) was prepared from benzoyl chloride (1) upon
treatment with LiAlHSeH in THF and subsequent oxi-
dation with iodine and potassium iodide.10,11 The di-
benzoyl diselenide was easily purified by silica gel flash
column chromatography and can be stored for several
months at ꢀ20 °C without significant decomposition.
To prepare selenocarboxylate, dibenzoyl diselenide was
*
Corresponding author. Tel.: +1 732 445 5291; fax: +1 732 445
6312; e-mail: LongHu@rutgers.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.144

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P. Surabhi et al. / Tetrahedron Letters 47 (2006) 4609–4613
conditions. However, the presence of too much water
O
O
O
1. LiAlHSeH
2. I2/KI
would adversely affect the solubility of the organic
azides in the reaction medium, resulting in heterogeneity
of the reaction mixture. Even for the electron-deficient
4-nitrophenyl azide (6), it took 3 h for the reaction to
complete in 50% aqueous methanol and isopropanol
(entries 1 and 2, Table 1). When acetonitrile was used,
the solubility of the azide improved and the reaction
was complete within 1 h in 50% acetonitrile (entry 3,
Table 1). The same reaction, if run in neat acetonitrile,
took less than 30 min to complete (entry 4, Table 1).
Mixed solvents of chloroform and methanol slowed
down the amidation reaction and lowered the yield
(entry 5, Table 1). Hence, neat acetonitrile was selected
as the solvent of choice for the amidation reaction.
Se2
Cl
THF
HN
1
2
+ DIEA
CH3CN
Se +
O
N
3
O
O
H
N
R
N3-R
Se
N
H
5
4
The stability of DIEA benzeneselenocarboxylate in
acetonitrile was measured using an HPLC assay via
the reaction of selenocarboxylate with p-toluenesulfonyl
azide (13), the fastest amidation reaction in Table 2.
When DIEA benzeneselenocarboxylate (4) was incu-
bated with 2 equiv of p-toluenesulfonyl azide (13) in aceto-
nitrile at room temperature or 55 °C, a complete and
quantitative amidation was achieved in less than
5 min, as monitored by HPLC.12 To monitor the stabil-
ity of DIEA benzeneselenocarboxylate (4), dibenzoyl
diselenide (2) was mixed with 1.2 equiv of DIEA and
1.2 equiv of piperidine at room temperature under an
argon atmosphere. The DIEA benzeneselenocarboxylate
formed was then allowed to stand at room temperature
or at 55 °C and aliquots were combined with 2 equiv of
p-toluenesulfonyl azide (13). The amide product, N-(p-
toluenesulfonyl) benzamide (28), was analyzed to deter-
mine the amount of DIEA benzeneselenocarboxylate
that remained in solution. Figure 1 shows the stability
of DIEA benzeneselenocarboxylate at 25 °C and
55 °C. The half-life of DIEA benzeneselenocarboxylate
was found to be 11.3 h at 25 °C. This is an improvement
of 27 times in stability if compared to the half-life of
25 min under our previous conditions of using DMSO
as a co-solvent.2 Even when the temperature was raised
to 55 °C, the half-life of the selenocarboxylate was 1.4 h
under our present conditions.
Scheme 1. In situ generation of benzeneselenocarboxylate and
subsequent amidation with azides.
dissolved in acetonitrile and then treated under an argon
atmosphere with 1 equiv of diisopropylethylamine
(DIEA) and 1 equiv of piperidine to form the selenium
metal, the stable N-benzoylpiperidine (3) and diisoprop-
ylethylammonium benzeneselenocarboxylate (4). The
DIEA benzeneselenocarboxylate (4) was used directly
without purification to react with various azides to form
amide products 5 in a one-pot process. Since azides do
not react with diacyl diselenide, they can be dissolved to-
gether prior to the addition of DIEA and piperidine to
simplify the operation and to improve the product
yields. Because of the increased stability of DIEA benzene-
selenocarboxylate, as discussed later, we were also able
to decrease the amount of selenocarboxylate from the
earlier 2 equiv excess to only 1.2 equiv for electron-defi-
cient azides.
We selected 4-nitrophenyl azide (6), one of the most
electron-deficient aromatic azides that reacted quickly
with selenocarboxylate, to explore different solvent sys-
tems for the amidation reaction. As shown in Table 1,
aqueous organic solvents containing 50% water (entries
1–3) gave good yields of the amide product suggesting
that the amidation reaction does not require anhydrous
After we confirmed the increased stability of DIEA benz-
eneselenocarboxylate under our new reaction condi-
tions, a variety of azides (6, 8–22) were used to explore
the effect of this improved stability on the amidation
reaction.13 For electron-deficient azides, we found as
shown in Table 2 that using 1.2 equiv of selenocarboxyl-
ate was sufficient to give excellent conversion rates to the
corresponding amides with isolated yields between 87%
and 96%. For electron-rich azides that are less reactive,
2 equiv of selenocarboxylate and mild heating were used
to obtain good yields based on azides. The position of
substitution on the phenyl azide also affects the rate of
amidation. When the nitro group was in the para
position (entry 1, Table 2), the reaction was complete
within 30 min. When the nitro group was moved to
the ortho position, the reaction was slower and required
1 h to complete (entry 2, Table 2), suggesting the pres-
ence of steric effects in addition to the electronic effects
on the amidation reaction. Since DIEA selenocarboxyl-
Table 1. Effect of solvents on reaction time and yielda
O
NO2
NO2
O
Ph
Ph
DIEA
Se2
O
+
piperidine
25 °C
Ph
N
H
7
N3
6
2
Entry
Solvent system
Time (h)
Yieldb (%)
1
2
3
4
5
CH3OH/H2O (1:1, v/v)
(CH3)2CHOH/H2O (1:1,v/v)
CH3CN/H2O (1:1, v/v)
CH3CN (neat)
3
3
1
0.5
2
75
73
83
95
78
CHCl3/CH3OH (1:1, v/v)
a General conditions: 4-nitrophenyl azide 6 (0.2 mmol), dibenzoyl
diselenide (0.24 mmol), DIEA (0.24 mmol), and piperidine
2
(0.24 mmol) in the given solvent system at room temperature.
b Isolated yield (%).

P. Surabhi et al. / Tetrahedron Letters 47 (2006) 4609–4613
Table 2. Amidation reaction of selenocarboxylates with azidesa
4611
Entry
Azide starting material
Amide product
Selenocarboxylateb
(equiv)
Temperature
(°C)
Time (h)
0.5
Yieldc (%)
O
O2N
N3
1
1.2
1.2
25
25
95
93
O2N
NH
6
7
O
N3
NO2
NH
NO2
2
1.0
8
23
O
Cl
N3
3
4
1.2
1.2
25
25
2.0
1.0
95
96
Cl
NH
9
24
O
NC
N3
NC
NH
10
25
O
O
O
5
6
7
8
1.2
1.2
1.2
1.2
25
25
25
25
2.0
1.0
0.08
3.0
87
89
96
88
N3
NH
MeO
11
MeO
26
O
O
O
N3
NH
HO
12
HO
27
O
SO2N3
SO2 NH
13
28
O
O
O
PhO P N3
OPh
PhO P NH
OPh
14
29
O
9
2.0
2.0
55
55
12d
51
81
NH
O
N3
O
15
16
30
31
O
N3
10
6.0
NH
O
MeO
H2N
N3
11
12
13
14
2.0
2.0
2.0
2.0
55
55
55
55
6.0
6.0
65
54
56
78
MeO
H2N
NH
17
32
O
N3
NH
18
33
O
12d
N3
NH
O
HO
19
20
HO
34
35
N3
6.0
NH
HO
F
HO
F
(continued on next page)

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P. Surabhi et al. / Tetrahedron Letters 47 (2006) 4609–4613
Table 2 (continued)
Entry
15
Azide starting material
Amide product
Selenocarboxylateb
(equiv)
Temperature
(°C)
Time (h)
12d
Yieldc (%)
O
N3
2.0
55
37
HO
NH
F
HO
21
F
36
O
N3
16
2.0
55
6.0
68
NH
AcO
22
AcO
37
a General conditions: azide (0.2 mmol), diacyl diselenide (0.24 or 0.4 mmol), DIEA (0.24 or 0.4 mmol), piperidine (0.24 or 0.4 mmol), acetonitrile
(8 mL).
b Equiv of selenocarboxylate formed in situ.
c Isolated yield (%) of the amide product.
d Reactions were left overnight (ꢁ12 h) for convenience.15
inductive effects (rI = 0.50) at the meta position, and has
both electron-withdrawing inductive and electron-
1.0
donating resonance effects at the ortho/para positions
0.8
0.6
0.4
0.2
0.0
ðr0R ¼ ꢀ0:31Þ.14 Apparently due to the electron-donat-
ing resonance effect of the fluoro substituent in the ortho
position, delocalization of the negative charge on the
nitrogen in the transition state was probably hindered,
thereby lowering the reaction yield.2
Directly introducing electron-withdrawing groups adja-
cent to azido, such as sulfonyl and phosphoryl, gave
excellent yields of N-acyl sulfonamide 28 and N-acyl
phosphoramide 29 with only 1.2 equiv of selenocarboxy-
late (entries 7 and 8, Table 2). Reaction of sulfonyl azide
with selenocarboxylate was the fastest reaction with a
near quantitative yield (entry 7, Table 2). Acyl azide,
such as benzoyl azide (15), gave poorer yield. With
2 equiv of selenocarboxylate, the isolated yield was only
51% at 55 °C. This was due to the instability of the acyl
azide itself that led to a side reaction, Curtius rearrange-
ment, during the amidation process. Consistent with the
mechanism proposed,2 the reaction is compatible with
the presence of free amines and alcohols (entries 12–
15, Table 2). The formation of 4-benzoylaminobenzyl
acetate (37) from 4-azido benzyl acetate (22, entry 16,
Table 2) indicated the formation of amide without the
prior reduction of azide to its corresponding amine, as
we reported previously.2
0
10
20
30
40
50
Time (h)
Figure 1. Stability of DIEA benzeneselenocarboxylate at 25 °C (d)
and 55 °C (m) as monitored by conversion to N-(p-toluenesulfonyl)
benzamide (28) in an HPLC assay.
ate is more stable in acetonitrile than the corresponding
potassium salt in the previous DMSO-containing sol-
vent system, we were able to raise the reaction tempera-
ture to 55 °C to further speed up the amidation reactions
for less reactive azides. The phenyl azide and p-meth-
oxyphenyl azide gave amidation yields of only 25%
and 7%, respectively, in the DMSO-containing solvent
system.2 Under our new conditions, the same azides
gave much improved yields of 81% and 65%, respec-
tively (entries 10 and 11, Table 2).
To summarize, we developed a new set of conditions to
increase the solubility and stability of selenocarboxylates.
The half-life of the selenocarboxylate was increased by
27-fold at room temperature. Excellent yields were
obtained with electron-deficient azides, and much
improved yields were obtained with electron-rich azides
upon mild heating. Thus, these new conditions represent
a significant improvement over the earlier conditions
used to couple selenocarboxylates with azides.
The effect of fluoro substitution on aromatic azide is
also interesting. Electron-withdrawing groups are ex-
pected to stabilize the transition state through delocal-
ization of the negative charge on the nitrogen, and
thus facilitate amidation.2 Fluorine substitution at the
meta position, as in compound 20, improved the amida-
tion yield from 56% to 78% (entries 13 vs 14, Table 2).
However, when fluoro substitution was moved to the
ortho position, the yield of the corresponding amide
was reduced to only 37% (entry 15, Table 2). This was
surprising, but could be explained by the different elec-
tronic effects of fluoro substitution at the meta and
ortho/para positions. Fluorine has electron-withdrawing
Acknowledgments
We gratefully acknowledge the financial support of a
research grant from the State of New Jersey Commission

P. Surabhi et al. / Tetrahedron Letters 47 (2006) 4609–4613
4613
10. Ishihara, H.; Koketsu, M.; Fukuta, Y.; Nada, F. J. Am.
Chem. Soc. 2001, 123, 8408–8409.
11. Koketsu, M.; Nada, F.; Hiramatsu, S.; Ishihara, H. J.
Chem. Soc., Perkin Trans. 1 2002, 737–740.
12. For the stability assay, the best azide substrate was used in
excess to ensure fast and quantitative consumption of all
selenocarboxylate at a given time point.
on Cancer Research and a research scholar grant from
the American Cancer Society (to L.H.). We thank Profes-
sors Lawrence Williams and Spencer Knapp for helpful
discussions.
References and notes
13. General procedure for the preparation of amides: Diacyl
diselenide (0.24 mmol) and azide (0.2 mmol) were dis-
solved in deaerated acetonitrile (5 ml) and stirred at room
temperature under an argon atmosphere. To this was
added DIEA (0.24 mmol), followed by piperidine
(0.24 mmol). The mixture was stirred at room temperature
or heated at 55 °C depending on the azide. The reaction
was monitored using TLC and LCMS. Upon completion,
the mixture was concentrated and dissolved in ethyl
acetate and filtered through a celite pad to remove
selenium powder. The ethyl acetate phase was washed
with aqueous saturated NaHCO3, water and concentrated
to dryness. The crude product was then purified by silica
gel flash column chromatography.
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