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J. Iran. Chem. Soc., Vol. 4, No. 3, September 2007, pp. 364-369.

JOURNAL OF THE
Iranian
Chemical Society

2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium Tetrafluoroborate as an
Efficient Coupling Reagent for the Amidation and Phenylhydrazation of Carboxylic
Acids at Room Temperature
S. Balalaie*, M. Mahdidoust and R. Eshaghi-Najafabadi
Peptide Chemistry Research Group, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran

(Received 10 May 2006, Accepted 28 February 2007)

The synthesis of amides and phenylhydrazides from the reaction of corresponding carboxylic acids with primary aliphatic,
aromatic amines or phenylhydrazine in the presence of triethylamine or diisopropylethyl amine as a base using 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) proceeds smoothly under mild conditions to afford the
corresponding amides or phenylhydrazides in good to high yields in ethyl acetate at room temperature.

Keywords: Amidation, Phenylhydrazation, Coupling reagent, TBTU, Mild condition

INTRODUCTION of an amide bond [17]. In the last decades, some phosphonium


and uronium salts were used as coupling reagents for the
The amide functional group is important in organic and synthesis of peptides, such as 1-hydroxy benzotriazole (HOBt)
biological chemistry. Amides are important as pharmaceutical [18], HATU [19], HBTU, BOP, HOAt, TCTU, and HCTU
as well as agrochemicals [1]. In general, the formation of [20].
amide bond directly from carboxylic acids requires activation 2-[(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
of the carboxyl group. Activation of a carboxyl group can be tetrafluoroborate] (TBTU) has been widely used in carbon-
achieved either by conversion into more reactive functional nitrogen bond forming reactions for the synthesis of peptides
groups such as acyl halide, anhydride, acyl azide [2]. Coupling [21]. Meanwhile, polymer-supported TBTU (P-TBTU) has
reagents could be used for in-situ activation of the carboxyl been prepared using polystyrene to form an efficient solid-
group, such as: N,N-dicyclohexylcarbodiimide (DCC) [3],
supported reagent for peptide-coupling reactions [22].
TiCl4 [4], activated phosphate [5], Sn[N(TMS)2]2 [6], N-halo
Unfortunately, some of the reported methods suffer from
succinimide/Ph3P [7], Cl3CCN/Ph3P [8], ArB(OH)2 [9],
serious drawbacks such as lack of reagent availability, low
Lawesson’s reagent [10], Boc-odhbt (tert-butyl-3-[3,4-
yields, high temperatures, long reaction times, and tedious
dihydrobenzotriazin-4-one]yl carbonate) [11], Me2NSO2Cl
work-up procedures. TBTU has been used as efficient
and N,N-dimethylamine [12], SO2ClF [13], chloro-sulfonyl
coupling reagent for the synthesis of pharmaceutical peptides
isocyanate [14], tosyl chloride under solvent-free conditions
in our laboratories [23]. Now, we report the use of TBTU as a
[15], and 2-mercaptopyridine-1-oxide based uronium salts
mild and effective reagent for the direct reaction of carboxylic
[16]. Recently, novel reagents were reported for the synthesis
acids, primary amines and phenylhydrazines in the synthesis
*Corresponding author. E-mail: balalaie@kntu.ac.ir of amides and phenylhydrazides at room temperature.
Balalaie et al.

EXPERIMENTAL MHz, CDCl3) δ1.10-1.55 (m, 6H, 3CH2), 1.70-2.10 (m, 4H,
2CH2), 4.00 (m, 2H, H-Ar), 6.00 (brs, 1H, NH), 7.40-7.50 (m,
Melting points were recorded on a BÜCHI B-545 and 3H, H-Ar), 7.70-7.80 (m, 2H, H-Ar).
Electrothermal 9100 melting point apparatus and are N-Propyl benzamide (3c). m.p.: 81-82 °C; IR (KBr, Cm-1)
uncorrected. IR spectra were recorded on FTIR Mattson 1000 3300, 1626, 1540; 1H NMR (300MHz, CDCl3) δ 0.99 (t, 3H, J
(Unicam) and IR-460 Shimadzu spectrometers using KBr = 7.5 Hz, CH3), 1.65 (m, 2H, CH2), 3.43 (q, 2H, J = 7.5 Hz
disks. 1H NMR spectra were recorded on a Bruker Avance CH2), 6.26 (brs, 1H, NH), 7.4-7.53 (m, 3H, H-Ar), 7.8 (d, 2H,
DRX-300 FT-NMR spectrometer in CDCl3 using TMS as the J = 8.9 Hz, H-Ar).
internal standard. N-Ethyl benzamide (3d). m.p.: 68-69 °C; 1H NMR
(300MHz, CDCl3) δ 1.32 (t, 3H, J = 7.3 Hz, CH3), 3.55 (m,
General Procedure for the Synthesis of Amides (3a-p) 2H, CH2), 6.27 (brs, 1H, NH), 7.45-7.58 (m, 3H, H-Ar), 7.83
in the Presence of TBTU (d, 2H, J = 8.4 Hz, H-Ar).
TBTU (323 mg, 1 mmol) was added to a mixture of N-sec-butyl benzamide (3e). m.p.: 92 °C; IR (KBr, cm-1)
carboxylic acid (1 mmol) and triethylamine (0.27 ml, 2 mmol) 3300, 1660,1550; 1H NMR (300 MHz, CDCl3) δ 0.7 (t, 3H, J
in EtOAc (30 ml). The mixture was stirred for 10 min and the = 7.3 Hz , CH3), 1.23 (d, 3H, J = 7.3 Hz, CH3), 1.55 (m, 2H,
appropriate amine (2 mmol) was then added. After completion CH2), 4.20 (m, 1H, CH), 6.10 (brs, 1H, NH), 7.20-7.60 (m,
of the reaction, the mixture was washed with water and the 3H, H-Ar), 7.70-80 (m, 3H, H-Ar).
organic phase was separated and dried over anhydrous N-Isopropyl benzamide (3f). m.p.: 104 °C; IR (KBr,
MgSO4. After filtration and evaporation of the solvent at cm-1) 3295, 1624, 1526; 1H NMR (300 MHz, CDCl3) δ 1.27
reduced pressure, the crude product was purified by (d, J = 6.6 Hz, 6H, 2CH3), 4.30 (m, 1H, CH), 6.03 (brs, 1H,
crystallization in petroleum ether:dichloromethane (4:1) or n- NH), 7.27-7.52 (m, 3H, H-Ar), 7.76 (d, 2H, J = 8.0 Hz, H-Ar).
heptane:ethylacetate (5:1). Benzanilide (3g). m.p.: 159-161 °C [lit26 = 160-161 °C];
IR (KBr, cm-1) 3346, 1661, 1530; 1H NMR (300 MHz, CDCl3)
General Procedure for the Synthesis of δ 7.1-8 (m, 10H, H-Ar), 10.3 (brs, 1H, NH).
Phenylhydrazides (6a-f) in the Presence of TBTU N-Cyclohexyl-2,4,6-trimethyl benzamide (3h). m.p.
TBTU (323 mg, 1 mmol) was added to a mixture of (dec.) = 98 °C ; IR (KBr, cm-1) 3225, 1613, 1541; 1H NMR
carboxylic acid (1 mmol) and diisopropylethylamine (0.35 ml, (300 MHz, CDCl3) δ 1.07-2.66 (m, 10H, 5CH2), 2.03 (s, 3H,
2 mmol) in 30 ml acetonitrile. The mixture was stirred for 10 CH3), 2.29 (s, 6H, 2CH3), 4.00 (m, 1H, CH), 5.56 (brs, 1H,
min and then phenylhydrazine (2 mmol) was added. After NH), 6.48 (s, 2H, H-Ar).
completion of the reaction, the mixture was washed with N-Cyclohexyl-2-bromo-benzamide (3i). m.p.: 118-120
water, the organic phase of which was again washed with °C; 1H NMR (300 MHz, CDCl3)δ 1.00-2.20 (m, 10H, 5CH2),
water and dried with magnesium sulfate. After filtration and 4.00 (m, 1H, CH), 5.90 (brs, 1H, NH), 7.20-7.70 (m, 5H, H-
evaporation of the solvent at reduced pressure, the crude Ar).
product was purified by crystallization from EtOH (96%). N-Benzyl-phenyl acetamide (3j). m.p.: 119-120 °C [lit25 =
118-119 °C]; IR (KBr, cm-1) 3285, 1633, 1539; 1H NMR
Selected Data for Amides (3a-3p) and (300MHz, CDCl3) δ 3.6 (s, 2H, CH2), 4.43 (d, 2H, J = 5.8 Hz,
Phenylhydrazides (6a-f) CH2), 5.71 (brs, 1H, NH), 7.18-7.39 (m, 10H, Ar).
N-Benzyl benzamide (3a). m.p.: 103-106 °C [lit25 = 105- N-Isopropyl-phenyl acetamide (3k). m.p.: 102-104 °C;
106 °C]; IR (KBr, cm-1) 3350, 1650, 1550; 1H NMR (300 IR (KBr, cm-1) 3284, 1645, 1548; 1H NMR (300 MHz, CDCl3)
MHz, CDCl3) δ 4.60 (d, 2H, J = 7.5 Hz, CH3), 6.60 (brs, 1H, δ 1.06 (d, 3H, J = 6.5 Hz, CH2), 3.55 (s, 2H, CH2), 4.04-4.11
NH), 7.20-7.90 (m, 10H, H-Ar). (m, 1H, CH), 5.23 (brs, 1H, NH), 7.25-7.39 (m, 5H, H-Ar).
N-Cyclohexyl benzamide (3b). m.p.: 146 °C [lit14 = 145- N-(2-Methyl) phenyl acetamide (3l). m.p.: 161-161.7 °C;
147 °C]; IR (KBr, cm-1) 3300, 1620, 1515; 1H NMR (300 IR (KBr, cm-1) 3251, 1653, 1530; 1H NMR (300 MHz,

365
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium Tetrafluoroborate

CDCl3): δ 1.81 (s, 3H, CH3), 3.72 (s, 2H, CH2), 6.83-7.38 (m, should have the following characteristics: a) high efficiency,
8H, H-Ar), 7.81 (d, 1H, J = 7.9 Hz, H-Ar). b) works in stoichiometric quantities, and c) solubility in the
N-Phenyl phenylacetamide (3m). m.p.: 117-118 °C [lit13 currently-used solvents. TBTU is one of the most common
= 117.6 °C]; 1H NMR (300 MHz, CDCl3) δ 3.74 (s, 2H, CH2), coupling reagents and additives used in peptide chemistry.
7.08-7.5 (m, 10H, H-Ar). Scheme 1 shows the two tautomeric forms of TBTU, of which
N-Cyclohexyl4-methyl benzamide (3n). m.p.: 151 °C; 1H form I reacts with the carboxylate ion [20].
NMR (300 MHz, CDCl3) δ 1.1-1.98 (m, 10H, 5CH2), 2.32 (s, Introduced in the last decade, onium (phosphonium and
3H, CH3), 3.90 (m, 1H, CH), 5.85 (brs, 1H, NH), 7.15 (d, 2H, uronium) salts of hydroxyl benzotriazole derivatives have
J = 8.0 Hz, H-Ar), 7.57 (d, 2H, J = 8.0 Hz, H-Ar). been rapidly adapted for research purposes; however, only a
N-Cyclohexyl4-methoxy benzamide (3o). m.p.: 155 °C; few of them are compatible with the current industrial
1
H NMR (300 MHz, CDCl3) δ 1.00-2.20 (m, 10H, 5CH2), 3.90 requirements and synthetic strategies, thus few have been
(s, 3H, OCH3), 4.00 (m, 1H, CH), 6.9 (d, 2H, J = 9.0 Hz, H- applied to the industry. In the reaction of the carboxylate ion
Ar), 7.70 (d, 2H, J = 9.0Hz, H-Ar). with the onium salt, at least one equivalent base is essential. In
N-sec-butyl Fmoc-Tryptophamide (3p). m.p.: 158-159 this study, triethylamine or diisopropylethyl amine was used
°C; IR (KBr, cm-1) 3280, 1683, 1636. as a base in the esterification reaction. This procedure
4-Methyl-benzoic acid N-phenylhydrazide (6a). m.p.: describes a useful method for the preparation of amides and
167-169 °C; IR (KBr, cm-1) 3260, 1639, 1537; 1H NMR (300 phenylhydrazides from a variety of carboxylic acids using
MHz, CDCl3) δ 2.4 (s, 3H, CH3), 4.8 (brs, 1H, NH), 6.94 (m,
3H, H-Ar), 7.25 (d, 2H, J = 8.1 Hz, H-Ar), 7.75 (d, 2H, J = 8.1
Hz, H-Ar), 8.08 (brs, 1H, NH). N
2-Bromo-benzoic acid N-phenylhydrazide (6b). m.p.: N
N
O
168-170 °C; 1H NMR (300 MHz, CDCl3) δ 5.48 (brs, 1H, N
NH), 6.94-7.65 (m, 9H, H-Ar), 8.06 (brs, 1H, NH). N N
N N
3-Chloro-benzoic acid N-phenylhydrazide (6c). m.p.: BF4 BF4
N N
159 °C; 1H NMR (300 MHz, CDCl3) δ 6.10 (brs, 1H, NH),
6.94-7.82 (m, 9H, H-Ar), 8.70 (brs, 1H, NH). O

4-Methoxy benzoic acid N-phenylhydrazide (6e). m.p.: I II


178-179 °C; 1H NMR (300 MHz, CDCl3) δ 3.85 (s, 3H,
OCH3), 6.80 (brs, 1H, NH), 6.90 (d, 2H, J = 8.8 Hz, H-Ar), Scheme 1. Tautomeric forms of TBTU: 2-(1-H-benzotriazole-
1-y-l)-1,1,3,3-tetramethyluronium tetrafluoroborate
7.80 (d, 2H, J = 8.8 Hz, H-Ar), 6.90-7.27 (m, 5H, H-Ar), 8.7
(brs, 1H, NH).
Phenyl acetic acid N-phenylhydrazide (6f). m.p.: 171- O O
172 °C; 1H NMR (300 MHz, CDCl3) δ 3.49 (s, 2H, CH2), TBTU, R.T
+ R2-NH2 R2
6.63-6.69 (m, 3H, H-Ar), 7.09 (m, 2H, H-Ar), 7.24 (s, 5H, H- R1 OH TEA, EtOAc R1 N
H
Ar) 7.75 (brs, 1H, NH), 9.88 (brs, 1H, NH).
1 2 3
Scheme 2
RESULTS AND DISCUSSION

TBTU is an uronium salt that acts as a highly efficient O O


coupling reagent used in peptide chemistry for a wide variety + R2-NH-NH2
TBTU, R.T
of peptide sequences, including the synthesis of some R1 OH DIEA, EtOAc R1 NH-NH-R2
pharmaceutical peptides. From the industrial and
4 5 6
environmental point of view, an effective coupling reagent
Scheme 3

366
Balalaie et al.

TBTU as a coupling reagent. The high efficiency and ease of The reaction of benzoic acid derivatives and phenyl acetic
product isolation, prompted us to investigate its use for the acid using alkylamine derivatives, cyclohexylamine and
direct reaction of carboxylic acid derivatives and amines or aniline resulted in good yields as well. The scope of the
phenylhydrazine for the synthesis of appropriate amides and transformation was also investigated by reactions of a broad
phenylhydrazides at room temperature (Schemes 2 and 3). variety of carboxylic acids, especially those carrying bulky
Several carboxylic acids (benzoic acid derivatives, phenyl groups with a variety of primary amines. The work-up of the
acetic acid, and a protected amino acid) were readily reaction products is convenient, since the residual coupling
converted into the corresponding amides in good to high reagent TBTU is water soluble. Thus, the products are usually
yields (Table 1). The structures of all the products were isolated in pure form after a simple aqueous work- up
established from their physical and spectral (IR, 1H NMR) procedure, a promising advantage compared to the standard
data. The proposed mechanism for the activation process of DCC (dicyclohexylcarbodiimide) protocol.
carboxylic acid, followed by its nucleophilic reaction with In conclusion, we have introduced an effective coupling
amines and phenylhydrazines, is shown in Fig. 1 [18,20]. reagent, TBTU, for the amidation and phenylhydrazation of
Experimental results of the direct synthesis of carboxylic acid derivatives with amines and phenylhydrazine
phenylhydrazides 6a-f from various carboxylic acids, in good to high yields. The advantages of TBTU include
phenylhydrazine using TBTU as a coupling reagent at room stability, long shelf-life, solubility in common organic
temperature are listed in Table 2 Each of these reactions was solvents, and generation of HOBt (1-hydroxy benzotriazole), a
completed in 15-35 min. Primarily, the amidation of benzoic water-soluble by-product. The low toxicity of the by-products,
acid was performed as a model compound with benzylamine, ease of handling and its commercial availability, accompanied
and was completed within 30 min, with a 97% yield at room by the simple work-up of the reaction mixture, are the strong
temperature. advantages of the presented method.

Table 1. Direct Synthesis of Amides 3a-p from Carboxylic Acids and Primary
Amines using TBTU as a Coupling Reagent at Room Temperature

No R1 R2 Time Yield
(min) (%)a
a Ph PhCH2 30 97
b Ph Cyclohexyl 15 75
c Ph n-propyl 30 74
d Ph Et 30 57
e Ph sec-butyl 30 91
f Ph iso-propyl 30 62
g Ph Ph 15 88
h 2,4,6-Me3-C6H2- Cyclohexyl 35 53
i 2-Br-C6H4 Cyclohexyl 15 54
j PhCH2- PhCH2 15 57
k PhCH2- Cyclohexyl 15 71
l PhCH2- Cyclohexyl 15 89
m PhCH2- Ph 30 56
n 4-CH3-C6H4- Cyclohexyl 30 50
o 4-OCH3-C6H4- Cyclohexyl 15 51
p Fmoc-tryptophan sec-butyl 30 87
a
In all cases, yields refer to pure isolated products.

367
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium Tetrafluoroborate

N
N
O N
O
O N TEA N
N N
+ R1 O
R1 OH N N
BF4 N
N BF4 N
O BF4
I II
O
N
N
N

N
N
OH
N
O
N
R2 O
N + R1 N
H R2-NH2 O
N
R1

Fig. 1. Proposed mechanism for the amide bond formation through TBTU activation.

Table 2. Direct Synthesis of Phenylhydrazides 6a-f from Carboxylic Acid and


Phenylhydrazine using TBTU as a Coupling Reagent at Room Temperature

No R1 R2 Time Yield
(min) (%)a
a 4-Me-C6H4 Ph 20 89
b 2-Br-C6H4 Ph 15 60
c 2-Cl-C6H4 Ph 15 75
d 2,4,6-Me3-C6H2 Ph 15 53
e 4-CH3O-C6H4- Ph 15 61
f PhCH2 Ph 15 82
a
In all cases, yields refer to isolated pure products.

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