Chemoselective reaction of aryl azides with ethyl 3-oxo-4- (triphenylphosphor- anylidene) butanoate

Article abstract of DOI:10.1007/s10593-010-0452-y

The reaction of aryl azides with ethyl 3-oxo-4-(triphenylphosphoranylidene) butanoate has been studied under different conditions and it was found that the reaction occurs chemoselectively to form one of two possible isomers. Novel (1H-1,2,3-triazol-5-yl)

Full text of DOI:10.1007/s10593-010-0452-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
CHEMOSELECTIVE REACTION
OF ARYL AZIDES WITH ETHYL
3-OXO-4-(TRIPHENYLPHOSPHOR-
ANYLIDENE)BUTANOATE
N. T. Pokhodylo1, V. S. Matiychuk1, and M. D. Obushak1*
The reaction of aryl azides with ethyl 3-oxo-4-(triphenylphosphoranylidene)butanoate has been studied
under different conditions and it was found that the reaction occurs chemoselectively to form one of two
possible isomers. Novel (1H-1,2,3-triazol-5-yl)acetic acids have been synthesized.
Keywords: azides, 1H-1,2,3-triazole, heterocyclizations, chemoselectivity.
Following the recent discovery of biological activity and other practically useful properties amongst
many 1,2,3-triazole derivatives the amount of work relating to these compounds and to satisfactory synthetic
methods has grown (as seen in reviews discussing these topics [1-5]).
One basic method for constructing a 1,2,3-triazole ring is the reaction of azides with acetylenes or
activated methylene compounds [1-5]. The cycloaddition of azides to acetylenes is generally used in the
synthesis of triazole fragments with identical substituents in positions 4 and 5 since the use of unsymmetrical
alkynes potentially leads to formation of two regioisomers. The reaction of azides with activated methylene
compound anions (generally containing a CO or CN group near the carbanion center) or phosphorus ylides with
a keto group in the α-position shows higher regioselectivity as a result of a closely controlled distribution of
charges [3]. However, in such reactions secondary processes are possible, e.g. a diazo exchange with reduction
of the azide group to an amino group [3]. It should be noted that reactions of azides with compounds having
several potential carbanion centers have not been reported in the literature.
In this publication we report the results of a study of the reaction of aryl azides with ethyl 3-oxo-
4-(triphenylphosphoranylidene)butanoate (1). Through a marked polarization of the C=P bond in such ylides the
negative charge is localized on an oxygen atom and a 1,3-dipolar cycloaddition of azide to the enol form of ylide
1b occurs with a subsequent loss of triphenylphosphine oxide [6]. It should be noted that a non-synchronous
anion mechanism involving addition in the first stage of the terminal nitrogen atom of the azide group to ylide
1a and subsequent attack at the carbonyl group gives a similar result. It should also be noted that an alternative
reaction route via attack of the ylide fragment by the azide group is possible. In a series of examples
phosphazines and diazo compounds are generated as a result of a 1,3-dipolar addition of azide to the strongly
polarized C=P bond rather than the C=C bond [6].
_______
* To whom correspondence should be addressed, e-mail: obushak@in.lviv.ua.
1 Ivan Franko Lviv National University, Lviv 79005, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1823-1827, December, 2009.
Original article submitted December 21, 2008; revision submitted October 22, 2009.
0009-3122/09/4512-1469©2009 Springer Science+Business Media, Inc.
1469

The structure of the deprotonated compound 1 can be represented by the resonance structures 2a,b [7]
implying a possible electrophilic attack at both reaction centers (positions 2 and 4).
_
+
Ph3P
+
OEt
OEt
OEt
Ph3P
Ph3P
O
O
O
O
O
H
O
_
O
1
1a
1b
_
+
_
_
+
OEt
OEt
Ph3P
Ph3P
O
O
O
2a
2b
Hence in treating ylide 1 with the aryl azides 3 attack of the azide group can occur at position 2 or 4.
The study [8] reports the reaction of compound 1 with C-electrophiles at position 2. In our case the electrophilic
center is the terminal nitrogen atom of the azide group.
We have studied the reaction of azides 3 with ylide 1 in various solvents and bases including benzene,
Et3N in benzene, NaH in benzene, NaOMe in methanol, and KOH in DMSO. It was found that carrying out the
reaction in benzene gave the triazolylacetates 4a-d which underwent hydrolysis to acids 5a-d without their
separation.
N3
O
O
+
Ph3P
OEt
R
1
3a–d
N
N
N
N
O
O
N
N
NaOH
H2O
OEt
OH
–Ph3PO
5a–d
4a–d
R
R
O
O
N
N
N
NaOH,
H2O
OEt
N
OH
N
PPh3
N
–Ph3PO
Me
R
6a–c
R
7a–c
3–7 а R = H, b R = Ме, c R = Cl, d R = NO2
The reaction occurred by the same route if base (Et3N or NaH) was added to the reaction mixture.
However, in the case of NaH the yields of compound 5 were somewhat decreased and, by contrast, use of
triethylamine increased the reaction rate and the yields (Table 1). In all cases the reactions were carried out at
room temperature with some exothermic effect. A decrease in the yield of triazole 5d in the presence of base is
related to concurrent reduction reactions of the starting 4-nitrophenyl azide 3d as has been noted in the literature
[9].
1470

TABLE 1. Yields of Compounds 5a-d under Different Reaction Conditions*
Yield, %
Compound
Et3N
in benzene
NaH
in benzene
NaOMe
in methanol
KOH
in DMSO
benzene
5a
5b
5c
5d
56
57
64
71
74
77
80
65
49
54
58
36
7*2
8*2
13*3
—
—
—
—
—
_______
* Reaction carried out at 75-80ºC in methanol at reflux temperature.
*2 Acids 7a,b were obtained in trace amounts.
*4 Compound 7c (6%) also observed.
Attempts to change the reaction route and to prepare compounds 6 were unsuccessful. The influence of
concurrent reactions became more marked with increase in the basicity of the medium. The use of strongly basic
media (NaOMe in methanol or KOH in DMSO) led to tarring of the reaction mixture. Only in the single example of
the use of the 4-chlorophenyl azide 3c and with the reaction carried out in methanol in the presence of MeONa was
a low yield of the ester 6c obtained and this was identified as the acid 7c [10] formed as a result of hydrolysis of the
Ph3P=CH group. Use of 1H NMR spectroscopy also showed trace amounts of the acids 7a,b.
In all the experiments the reaction products were analyzed by chromato-mass spectrometry. Aromatic
amines were identified as secondary products.
A specific drawback of the synthetic methods using phosphorus ylides is that the reaction product has to
be separated from triphenylphosphine oxide which is formed during the reactions. Hence the method discussed
here can conveniently be used in the synthesis of triazolyl-containing acids and amines which can be readily
separated via a water soluble salt.
It should be noted that the triazolylacetic acids 5a-d are quite stable and survive heating in solution to
80ºC without decarboxylation (which is noted for similarly structured acids [11]).
Thus it was shown that cyclization of acyl azides with ethyl 3-oxo-4-(triphenylphosphoranylidene)-
butanoate occurs chemoselectively. The novel (1H-1,2,3-triazol-5-yl)acetic acids obtained are promising
reagents for organic synthesis.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Unity Plus400 (400 MHz) instrument using DMSO-d6 and
with TMS as internal standard. Mass spectra were taken on an Agilent 1100 LC/MSD chromato-mass
spectrometer using chemical ionization.
The starting ylide 1 was synthesized by reaction of 4-chloroacetoacetic ester with triphenylphosphine
and subsequent treatment with base [12]. Azides 3a-d were prepared by method [13].
Synthesis of (1-Aryl-1H-1,2,3-triazol-5-yl)acetic Acids 5a-d (General Method). Aryl azide 2
(0.1 mol) and triethylamine (14 ml) were added with stirring to a solution of ylide 1 (3.9 g, 0.1 mol) in benzene
(50 ml). The reaction mixture was heated for 2 h, a solution of NaOH (14%, 50 ml) was added, and the product
was heated for a further 2 h. The separated aqueous layer was washed with a small amount of benzene and
acidified. The precipitated acid 5 formed was filtered off and recrystallized from ethanol.
The remaining experiments (see Table 1) were carried out similarly using equimolar amounts of
reagents and base in the corresponding solvent (50 ml).
1
(1-Phenyl-1H-1,2,3-triazol-5-yl)acetic Acid (5a). Yield 74%; mp 128-129ºC. H NMR spectrum, δ,
ppm (J, Hz): 3.77 (2H, s, CH2); 7.48-7.64 (5H, m, H Ph); 7.73 (1H s, H Tr); 12.50 (1H, br. s, COOH). Mass
spectrum, m/z (Irel, %): 204 [M+H]+. Found, %: C 58.88; H 4.51; N 20.57. C10H9N3O2. Calculated, %: C 59.11;
H 4.46; N 20.68.
1471

1
[1-(4-Methylphenyl)-1H-1,2,3-triazol-5-yl]acetic Acid (5b). Yield 77%; mp 149-150ºC. H NMR
spectrum, δ, ppm (J, Hz): 2.44 (3H, s, CH3); 3.72 (2H, s, CH2); 7.37 (4H, m, H Ar); 7.70 (1H, s, H Tr); 12.67
(1H, br. s, COOH). Mass spectrum, m/z (Irel, %): 218 [M+H]+. Found %: C 60.76; H 5.23; N 19.22. C11H11N3O2.
Calculated, %: C 60.82; H 5.10; N 19.34.
1
[1-(4-Chlorophenyl)-1H-1,2,3-triazol-5-yl]acetic Acid (5c). Yield 80%; mp 185-186ºC. H NMR
spectrum, δ, ppm (J, Hz): 3.80 (2H, s, CH2); 7.57 (2H, d, J = 8.8, H-3,5 Ar); 7.61 (2H, d, J = 8.8, H-2,6 Ar);
7.73 (1H, s, H Tr); 12.68 (1H, br. s, COOH). Mass spectrum, m/z (Irel, %): 238 [M+H]+. Found, %: C 50.30;
H 3.27; N 17.75. C10H8ClN3O2. Calculated, %: C 50.54; H 3.39; N 17.68.
1
[1-(4-Nitrophenyl)-1H-1,2,3-triazol-5-yl]acetic Acid (5d). Yield 65%; mp 219-220ºC. H NMR
spectrum, δ, ppm (J, Hz): 3.80 (2H, s, CH2); 7.73 (1H, s, H Tr); 8.03 (2H, d, J = 8.8, H-3,5 Ar); 8.46 (2H, d,
J = 8.8, H-2,6 Ar); 12.68 (1H, br. s, COOH). Mass spectrum, m/z (Irel, %): 249 [M+H]+. Found, %; C 48.31;
H 3.02; N 22.39. C10H8N4O4. Calculated, %: C 48.39; H 3.25; N 22.57.
5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (7a). Yield 2%; mp 147-148ºC [14-16].
5-Methyl-1-(4-methylphenyl)-1H-1,2,3-triazole-4-carboxylic acid (7b). Yield 2%; mp 183-184ºC [16].
1-(4-Chlorophenyl)-5-methyl-1,2,3-triazole-4-carboxylic acid (7c). Yield 6%; mp 213-214ºC
[15, 16].
REFERENCES
1.
2.
3.
4.
5.
M. V. Gil, M. J. Arévalo, and Ó. López, Synthesis, 1589 (2007).
M. Rodriquez and M. Taddei, Top Heterocycl. Chem., 213 (2006).
V. P. Krivopalov and O. P. Shkurko, Usp. Khim., 74, 369 (2005).
A. R. Katritzky, Y. Zhang, and S. K. Singh, Heterocycles, 60, 1225 (2003).
A. E. Koumbis and J. K. Gallo, Curr. Org. Chem., 7, 771 (2003).
M. Regiltz, M. Tawfik, and H. Heydt, Synthesis, 805 (1979).
6.
7.
H. Feist and P. Langer, Synthesis, 3877 (2008).
8.
M. L. Gelmi and D. Pocar, Synthesis, 453 (1992).
9.
K. M. Pietrusiewicz and J. Monkiewicz, J. Org. Chem., 48, 788 (1983).
H.-S. Dong and B. Wang, J. Chin. Chem. Soc., 52, 103 (2005).
C. R. Jacobson and E. D. Amstutz, J. Org. Chem., 18, 1183 (1953).
L. Benati, P. C. Montevecchi, and P. Spagnolo, Gazz. Chim. Ital., 122, 249 (1992).
R. S. Shreiber (editor), Organic Synthesis, Vol. 31, Wiley, New York (1951), p. 14.
O. Dimroth, Liebigs Ann. Chem., 364, 183 (1909).
10.
11.
12.
13.
14.
15.
16.
H. El. Khadem, H. A. R. Mansour, and M. H. Meshreki, J. Chem. Soc. (C), 1329 (1968).
X.-W. Sun , P.-F. Xu , and Z.-Y. Zhang, Magn. Reson. Chem., 36, 459 (1998).
1472