O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00090-4

The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.

Full text of DOI:10.1016/S0040-4039(02)00090-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1661–1664
O-Succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as
efficient reagents in active ester synthesis
Miguel A. Baile´n, Rafael Chinchilla, David J. Dodsworth and Carmen Na´jera*
Departamento de Qu´ımica Orga´nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 20 November 2001; accepted 11 January 2002
Abstract—The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetra-
fluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxy-
succinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was
observed. © 2002 Elsevier Science Ltd. All rights reserved.
The generation of N-hydroxysuccinimide (HOSu)-
derived active esters is an important step in the activa-
tion of the carboxylic acid function, and has been
employed profusely for the generation of the amide
bond in peptide synthesis,1 and also for reduction of
acids to alcohols2 or for the synthesis of tetramic acids.3
These esters are generally isolable and easy to purify,
an important point when final highly pure peptides are
required. Moreover, HOSu esters are fairly stable in
aqueous solutions,1a allowing their generation from
water-soluble or rather insoluble carboxylic acids. Typi-
cally, DCC has been used as the initial coupling
reagent, in spite of problems related to removing the
urea by-product, formation of acylisoureas and Lossen
rearrangements.4 Moreover, the use of this DCC–
HOSu methodology frequently produces unacceptable
levels of racemization in peptide synthesis.1h In order to
avoid the use of DCC, a number of activated deriva-
tives of HOSu have been developed, such as the car-
bonate 1,5 prepared from HOSu and trichloromethyl
chloroformate, or by reaction of O-trimethylsilyloxy-
succinimide and phosgene. In addition, the oxalate 2,6
prepared from HOSu and oxalyl chloride, and the
phosphate 3,7 derived from HOSu and diphenylphos-
phochlorhydrate can be used for the generation of
hydroxysuccinimido esters as well as the combination
chlorophosphate/HOSu/base.8 They have also been iso-
lated via transesterification reactions mediated by
polystyrene-supported 1-hydroxybenzotriazole-derived
esters.9 Furthermore, a 1,1,3,3-tetramethylurea (TMU)-
derived uronium salt such as O-succinimidyl-1,1,3,3-tet-
ramethyluronium tetrafluoroborate (4, TSTU) has been
employed for the in situ preparation of these type of
esters.10
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
O
1
2
O
O
N
O
-
O
BF4
PhO
P
PhO
N
O
+
O
NMe2
Me2N
O
4
3
Recently, we have studied the synthetic applications of
thiouronium salts derived from 2-mercaptopyridone-1-
oxide and ureas as peptide coupling reagents11 and for
the synthesis of primary amides12 and hydroxamates.13
In these studies we have also been searching for an
alternative to the use of TMU which, in spite of its
reported toxicity,14 is probably the most frequently
employed urea in peptide coupling reagent synthesis.1h
In this way, we have found that the common solvent
1,3-dimethylpropyleneurea (DMPU, 5) can be
employed as a safer and economical alternative for the
preparation of these thiouronium salts.11b,c,13 Therefore,
it was assumed that DMPU could be suitable for the
synthesis of new N-hydroxysuccinimide-derived uro-
nium salts related to TSTU (4), useful in the prepara-
tion of active esters. In this paper we report the
Keywords: active esters; N-hydroxysuccinimide; uronium salts; amino
acids; ureas.
* Corresponding author. Fax: +34 96 5903549; www.ua.es/
dept.quimorg; e-mail: cnajera@ua.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00090-4

1662
M. A. Baile´n et al. / Tetrahedron Letters 43 (2002) 1661–1664
O
Cl
1. (COCl)2, DMF cat.
CH2Cl2
synthesis of new uronium salts derived from N-hydroxy-
succinimide and DMPU11c and their use as efficient
active ester-forming reagents.
Z-
+
MeN
NMe
MeN
NMe
2. KPF6 or NaBF4
MeCN
6a: Z = PF6
6b: Z = BF4
The uronium salts O-succinimidyl-1,3-dimethyl-1,3-
trimethyleneuronium hexafluorophosphate (7a, HSDU)
and the corresponding tetrafluoroborate (7b, TSDU)
were prepared following a one-pot procedure, which
implied reaction of DMPU (5) with oxalyl chloride and
a catalytic amount of DMF (Scheme 1). The correspond-
ing chlorouronium salts were treated with potassium
hexafluorophosphate or sodium tetrafluoroborate to
afford crude salts 6a and 6b,11b,c and subsequently with
N-hydroxysuccinimide in the presence of triethylamine.
The uronium salts HSDU (7a) and TSDU (7b) were
obtained in 54 and 64% overall yield, respectively, as
white crystalline solids which could be stored at ambient
temperature for months without appreciable decomposi-
tion.
5
O
OH
N
O
O
N
Z-
O
O
+
NMe
MeN
Et3N
7a, 7b
Scheme 1.
O
O
O
7
These new uronium salts were employed for the synthesis
of N-succinimidyl active esters 8 (Scheme 2). Thus,
reaction of 7a or 7b with a carboxylic acid function in
the presence of triethylamine as base, in DMF as solvent
and at room temperature afforded pure crude esters 8 (1H
and 13C NMR) after aqueous work-up (Table 1).
N
Et3N, DMF
R
OH
R
O
O
8
Scheme 2.
Table 1. Preparation of succinimide-derived active esters employing HSTU (7a) or TSTU (7b)
Entry
Acid
Reagent
Active ester
Time (h)
Yielda,b (%)
Mpc (°C)
[h]2D5c
(c 2.0, dioxane)
1
2
PhCO2H
PhCO2H
(E)-PhCHꢀCHCO2H
7a
7b
7b
7b
PhCO2Su
PhCO2Su
(E)-PhCHꢀCHCO2Su
0.5
0.5
0.5
0.5
80 (88)
89 (88)
86 (86)
51 (47)
134–136
134–136
180–183
170–172
3
4d
5
7b
1
73
131–133
6
7
8
9
10
11
12
13
14
15
16
CbzGlyOH
CbzGlyOH
BocGlyOH
BocGlyOH
CbzAlaOH
BocAlaOH
CbzValOH
BocValOH
FmocValOH
BocLeuOH
BocAibOH
7a
7b
7a
7b
7b
7b
7b
7b
7b
7b
7b
CbzGlyOSu
CbzGlyOSu
BocGlyOSu
BocGlyOSu
CbzAlaOSu
BocAlaOSu
CbzValOSu
BocValOSu
FmocValOSu
BocLeuOSu
BocAibOSu
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
85 (86)
87 (86)
88 (62)
88 (62)
84 (65) [97]
87 (71) [81]
84 (53) [100]
86 (74) [89]
85
114–115 (113–114)
114–115 (113–114)
165–166 (168–170)
164–165 (168–170)
120–121 (123–123.5)
143–144 (143–144)
114–115 (117–117)
126–127 (128–129)
−37 (−37.2)
−49 (−49)
−25 (−25.1)
−36 (−37)
−25
e
–
80 (48) [83]
73
113–114 (116)
166–167
−42 (−41.8)
a Isolated pure crude compounds (1H, 13C NMR) after work-up.
b In parenthesis, yields obtained using DCC overnight (Ref. 17). In brackets, yields obtained using carbonate 1 (Ref. 5).
c For crude products. In parenthesis, reported values (Ref. 17).
d A mixture of THF/water (2/1 v/v) was used as solvent.
e White foam (Ref. 18).

M. A. Baile´n et al. / Tetrahedron Letters 43 (2002) 1661–1664
1663
Typically, the reactions were completed in 30 min, the
final isolated yields being high in most of the studied
cases. In general, the use of reagent 7b afforded similar
or higher yields than when 7a was employed, therefore
the use of the former was preferred. For example,
benzoic acid gave 89% yield using 7b and 80% using 7a
(Table 1, entries 1 and 2), whereas a similar 88% yield
was reported in 4 h reaction time when DCC in the
presence of a polymeric 1-hydroxybenzotriazole (P-
HOBt) was used.8 Using the later DCC–P-HOBt com-
bination, an 86% yield of the active ester from cinnamic
acid was obtained in 7 h,8 whereas an identical yield
was obtained in just 0.5 h using 7b (Table 1, entry 3). A
problematic starting material, such as 2-aminonicotinic
acid afforded a 51% yield using 7b, but only a 47% in
24 h reaction time when DCC was used15 (Table 1,
entry 4). In this case, a mixture of THF/water was used
as solvent due to the solubility of the starting acid in
water, thus proving the effectivity of reagent 7b in
aqueous conditions. In addition, 1-pyrenebutanoic acid
gave a 73% yield of the corresponding active ester,
which has recently been used for protein immobiliza-
tion via p-stacking16 (Table 1, entry 5). Also, different
N-Cbz-, N-Boc- and N-Fmoc-protected amino acids
were transformed into their corresponding active esters
(Table 1, entries 6–16). In most cases, yields were
considerably higher in 0.5 h reaction time using 7 than
when using DCC overnight,17 and generally comparable
to the use of carbonate 1,5 no appreciable racemization
being detected after comparison of their optical rota-
tion values (see Table 1, entries 10–15). Even a hindered
amino acid such as N-Boc-aminoisobutyric acid (Aib)
afforded a good yield of the corresponding active ester
in 1 h reaction time (Table 1, entry 16).
was dissolved in MeCN (40 mL) and KPF6 (for 7a, 8.8
g, 48 mmol) or NaBF4 (for 7b, 5.27 g, 48 mmol) were
added. The mixture was stirred at room temperature
for 24 h and to the resulting suspension was added
N-hydroxysuccinimide (5.1 g, 40 mmol). Triethylamine
(6.7 mL, 48 mmol) was added dropwise keeping the
temperature below 25°C and the resulting suspension
was stirred at room temperature for 5 h and at 45°C for
1 h. The solution was filtered through a plug of Celite,
the solvents were evaporated (15 Torr) and the uronium
salts 7a and 7b were obtained after crystallization with
MeOH/isopropanol (7a: 8.0 g, 75%; 7b, 8.0 g, 57%).
HSDU (7a): mp 171–172°C (EtOH). w (cm−1): 1755,
1697, 849. lH (DMSO-d6): 2.02–2.06 (m, 2H), 2.86 (s,
4H), 3.20 (s, 6H), 3.57 (t, J=6.1, 4H). lC (DMSO-d6):
20.0, 25.7, 38.2, 49.0, 158.0, 171. Anal. calcd for
C10H16N3OPF6: C, 32.34; H, 4.35; N, 11.32. Found: C,
32.32; H, 4.44; N, 11.18.
TSDU (7b): mp 105–106°C (MeOH/i-Pr-OH). w (cm−1)
1739, 1693, 1040. lH (DMSO-d6): 2.00–2.08 (m, 2H),
2.86 (s, 4H), 3.19 (s, 6H), 3.56 (t, J=6.1, 4H). lC
(DMSO-d6): 20.0, 25.7, 38.2, 49.0, 158.0, 171.0. Anal.
calcd for C10H16N3O3BF4: C, 38.32; H, 5.15; N, 13.42.
Found: C, 38.16; H, 5.14; N, 12.94.
A typical procedure for synthesis of 8
To a solution of the carboxylic acid (1 mmol) in DMF
(5 mL) was added triethylamine (0.14 ml, 1 mmol) and
reagent 7a or 7b (1 mmol). The resulting mixture was
stirred at room temperature for 0.5 or 1 h. Saturated
NaCl was added (50 mL) and the solution was
extracted with AcOEt (3×25 mL). The organics were
washed with 2N HCl (2×10 mL) (except for entry 4,
Table 1), saturated NaHCO3 (2×10 mL) and water
(6×10 mL). The organic layer was dried (Na2SO4),
filtered off and the solvent was evaporated (15 Torr)
affording esters 8, after trituration of the residue in
water followed by filtration.
We also explored the utility of these reagents in the
formation of amide bonds. For example, the reaction of
benzoic acid with n-butylamine in the presence of
TSDU (7b) for 4 h in DMF at room temperature
afforded 89% yield of the amide after extractive work-
up when all the reaction components were mixed at
once. A similar 86% yield was isolated when the acid
was allowed to form the active ester in situ by reaction
with TSDU (7b) for 0.5 h before addition of the amine
and reaction for 4 h.
Acknowledgements
We conclude that uronium salts derived from N-
hydroxysuccinimide and non-toxic DMPU are efficient
reagents for the preparation of succinimidyl-derived
active esters in a rapid, high-yielding and racemization-
free fashion.
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica (project no. 1FD97-0721)
of the Ministerio de Educacio´n y Cultura (MEC) and
ASAC Pharmaceutical International S. A. for financial
support.
Procedure for synthesis of 7
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each treatment. The obtained crude chlorouronium salt
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