Synthesis of triazoles via regioselective reactions of aryl azides with cyanoacetyl pyrroles and indoles

Article abstract of DOI:10.1055/s-0028-1087992

Novel 5-aminotriazoles are prepared by the cycloaddition reactions of aryl azides with cyanoacetyl pyrroles and indoles. The regioselectivity of these reactions is discussed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087992

PAPER
1297
Synthesis of Triazoles via Regioselective Reactions of Aryl Azides with
Cyanoacetyl Pyrroles and Indoles
Synthesis of
T
riazo
a
les via Reg
z
ioselective
a
Reactionsriy T. Pokhodylo, Vasyl S. Matiychuk, Mykola D. Obushak*
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla and Mefodiya str. 6, Lviv 79005, Ukraine
Fax 0038(322)971668; E-mail: obushak@in.lviv.ua
Received 26 November 2008; revised 11 December 2008
O
O
N
Abstract: Novel 5-aminotriazoles are prepared by the cycloaddi-
tion reactions of aryl azides with cyanoacetyl pyrroles and indoles.
The regioselectivity of these reactions is discussed.
R3
R2
N–
N
R1
Key words: triazoles, cycloadditions, regioselectivity, pyrroles,
indoles
N
N
N
N
O
O
N
N
R1
R1
R3
R2
R2
R3
Functionalized 1,2,3-triazoles have a broad spectrum of
biological activity even though they do not occur in natu-
ral compounds.1 The antibiotic Cefatrizine is a represen-
tative example of the cephalosporins and is an effective
drug against pathogenic organisms of the respiratory tract,
tissue and skin.2,3 Triazole derivatives are also used as an-
ticonvulsants.4 They show anti-HIV-1 activity5 and are in-
hibitors of glycogen synthase kinase 3 (GSK-3) which
plays an important role in the treatment of Alzheimer’s
disease and type 1 and 2 diabetes.6 Antagonists of GABA
receptors,7,8 agonists of muscarinic receptors,9
neuroleptics10 and compounds showing cytotoxic,11
antihistamine12 and antiproliferative action are found
among 1,2,3-triazole derivatives.13
Scheme 1 Formation of regioisomers in reactions of azides with un-
symmetrical 1,3-diketones
Herein, we describe a study of the regioselectivity be-
tween possible attack of the N-1 nitrogen atom of an azido
group on the carbonyl or nitrile groups of cyanoacetyl
pyrroles and cyanoacetyl indoles. It is known that cy-
anoacetic acid and its derivatives can serve as building
blocks for 1,2,3-triazole synthesis. However, replacement
of the hydroxy group with alkyl or aryl substituents results
in problems of regioselectivity. Cyclization can take place
at either the nitrile (path A) or the carbonyl group (path B)
and the formation of two regioisomers is possible
(Scheme 2). Obviously, the nature of the R2 group will in-
fluence the direction of cyclization. The presence of an
electron-donor substituent increases the probability of ni-
trogen attack on the nitrile group leading to the formation
of a 5-amino-1H-1,2,3-triazole (path A). In contrast, an
electron-withdrawing group should favor formation of the
regioisomeric carbonitrile (path B).
The most general and versatile synthesis of 1,2,3-triazoles
involves pericyclic addition of organic azides to 1,3-dipo-
larophiles such as alkynes.14 A problem associated with
concerted 1,3-dipolar cycloadditions is that unsymmetri-
cal alkynes can give rise to two isomeric products, the
separation of which is necessary. Moreover, organic
azides undergo base-catalyzed condensation reactions
with activated methylene compounds possessing neigh-
boring carbonyl or nitrile groups to form 1,2,3-triazoles.
In such reactions, high regioselectivities were obtained
with the exception of reactions of azides with unsymmet-
rical 1,3-diketones. For example, in the reaction of benzyl
azides or azidopyrimidines with benzoylacetone15,16 mix-
tures of two regioisomers were obtained as a result of at-
tack of the azido nitrogen on either one of the two
carbonyl groups (Scheme 1). The different nature of the
substituents on benzoylacetone (Me and Ph) does not al-
low the regioselectivity to be predicted. No investigation
of the conditions under which regioselectivity can be
achieved in these systems has been reported.
R1
B
O
N
+
–
N
N
N
R2
NaOMe
MeOH
+
–
N
N
N
N
R1
A
O
R2
A
B
N
N
N
N
O
N
R1
N
R1
N
R2
R2
NH2
I
II
Scheme 2 Formation of regioisomers I and II
SYNTHESIS 2009, No. 8, pp 1297–1300
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1087992; Art ID: Z25808SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9
Taking into account these facts we selected electron-do-
nating pyrrole and indole derivatives 2a–c as reaction
partners for cyclization with aryl azides. It was estab-

1298
N. T. Pokhodylo et al.
PAPER
O
N3
1a: R1 = H
R2
R1
R2
+
1b: R1 = 4-Me
1c: R1 = 4-Cl
2a
2b
2c
N
N
H
1
2
NaOMe
MeOH
1d: R1 = 4-NO2
N
Me
N
N
O
N
N
N
N
N
R2
R1
R1
N
R2
NH2
H
3a–h
Scheme 3 Regioselective reactions between aryl azides 1 and nitriles 2
Table 1 Triazoles 3a–h (continued)
lished that the reactions between aryl azides 1 and nitriles
2 occurred in the presence of sodium methoxide in meth-
anol at room temperature leading to the formation of 5-
amino-1H-1,2,3-triazoles 3 (Scheme 3 and Table 1).
When aryl azides 1a–c were reacted with 3-oxo-3-(1H-
pyrrol-2-yl)propanenitrile 2a or 3-(1-methyl-1H-pyrrol-
2-yl)-3-oxopropanenitrile 2b, the corresponding 1,2,3-tri-
azoles 3a–d were obtained after precipitation from the re-
action medium upon addition of a few drops of water.
Reactions of azides 1a–d with 3-(1H-indol-3-yl)-3-oxo-
propanenitrile 2c under the same conditions gave 1,2,3-
triazoles 3e–h which precipitated in good yields from the
reaction medium in one hour. The advantage of these re-
actions is that they occur at room temperature to afford
pure products. Regioisomeric 1,2,3-triazoles of type II
were not formed in these reactions.
Entry
Product
Yield (%)
O
Me
N
N
N
3d
77
N
NH2
O
N
N
N
3e
72
NH
NH2
O
Table 1 Triazoles 3a–h
N
Entry
Product
Yield (%)
70
N
NH
3f
79
85
86
N
NH2
O
N
H
N
N
3a
N
NH2
Me
O
O
N
N
H
N
N
N
NH
N
3g
N
NH2
3b
3c
74
81
NH2
Me
Cl
O
O
N
H
N
N
N
N
N
NH
NH2
N
NH2
3h
Cl
NO2
Synthesis 2009, No. 8, 1297–1300 © Thieme Stuttgart · New York

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Synthesis of Triazoles via Regioselective Reactions
1299
3-HPyr), 7.40 (d, 2 H, 3J = 8.4 Hz, 3,5-HAr), 7.49 (d, 2 H, 3J = 8.4 Hz,
2,6-HAr), 7.59 (br s, 1 H, 5-HPyr), 11.69 (br s, 1 H, NH).
On the other hand, when 3-oxo-3-phenylpropanenitrile, 13C NMR (100 MHz, DMSO-d6): d = 21.3 (Me), 110.5 (CHPyr),
Our results correlate well with the abovementioned influ-
ence of the R2 substituent on the direction of cyclization.
118.2 (CHPyr), 124.9 (2 × CHAr), 125.5 (CTriazole), 127.3 (CHPyr),
130.7 (2 × CHAr), 130.8 (CPyr), 132.5 (CAr), 139.5 (CAr), 147.1
(CTriazole), 174.9 (CO).
MS (CI): m/z (%) = 268 (100%) [M + H+].
which was anticipated to form regioisomer II, was reacted
with aryl azides mixtures of regioisomers were obtained
in poor yields (<10%) under the same conditions as those
described for compounds 3a–d. Increasing the reaction
temperature led to a decrease in the triazole yields. More-
over, aryl amines, the products of reduction of the azido
group, were detected.
Anal. Calcd for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C,
62.81; H, 4.73; N, 26.06.
[5-Amino-1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl](1H-pyrrol-
2-yl)methanone (3c)
Yield: 81%; white crystals; mp 262–263 °C (EtOH).
Many indole and pyrrole derivatives are biologically ac-
tive and these systems are often fragments of natural com-
pounds and amino acids.17 Therefore, the reported
reaction represents a new method to compounds of poten-
tial pharmacological activity. Furthermore, the keto and
amine groups present in these compounds provide scope
for possible additional structural modifications.
1H NMR (400 MHz, DMSO-d6): d = 6.21 (m, 1 H, 4-HPyr), 6.84 (s,
2 H, NH2), 7.04 (br s, 1 H, 3-HPyr), 7.40 (d, 2 H, 3J = 8.8 Hz, 3,5-
3
HAr), 7.49 (d, 2 H, J = 8.8 Hz, 2,6-HAr), 7.60 (br s, 1 H, 5-HPyr),
11.69 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 110.5 (CHPyr), 118.2 (CHPyr),
125.5 (CTriazole), 126.9 (2 × CHAr), 127.3 (CHPyr), 130.4 (2 × CHAr),
130.8 (CPyr), 134.0 (CAr), 134.2 (CAr), 147.1 (CTriazole), 174.9 (CO).
In conclusion, we have reported the first example of regio-
selective base-catalyzed condensation reactions of azides
with active methylene compounds which enables access
to novel 1,2,3-triazole derivatives.
MS (CI): m/z (%) = 288 (100%) [M + H+].
Anal. Calcd for C13H10ClN5O: C, 54.27; H, 3.50; N, 24.34. Found:
C, 54.49; H, 3.27; N, 24.47.
Melting points were measured with an Electrothermal melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on a Varian Mercury 400 instrument (400 MHz for 1H, 100
MHz for 13C, DMSO-d6 as solvent). The 1H and 13C chemical shifts
are reported in ppm relative to TMS or the deuterated solvent as in-
ternal reference. Mass spectra were obtained using an Agilent 1100
series LC/MSD in API-ES/APCI ionization mode. Compounds
2a–c were prepared according to the literature procedure.18
(5-Amino-1-phenyl-1H-1,2,3-triazol-4-yl)(1-methyl-1H-pyrrol-
2-yl)methanone (3d)
Yield: 77%; white crystals; mp 150–151 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): d = 4.00 (s, 3 H, Me), 6.14 (dd, 1
H, 3J = 4.0, 3J = 2.4 Hz, 4-HPyr), 6.91 (s, 2 H, NH2), 7.05 (br s, 1 H,
3-HPyr), 7.53 (m, 1 H, 4-HAr), 7.61 (d, 4 H, 3J = 8.0 Hz, 2,3,5,6-HAr),
7.85 (dd, 1 H, 3J = 4.0, 4J = 1.6 Hz, 5-HPyr).
13C NMR (100 MHz, DMSO-d6): d = 37.9 (Me), 108.5 (CHPyr),
121.5 (CHPyr), 124.9 (2 × CHAr), 127.8 (CTriazole), 129.4 (CHPyr),
129.7 (CHAr), 130.3 (2 × CHAr), 131.8 (CPyr), 135.0 (CAr), 147.2
(CTriazole), 176.4 (CO).
Synthesis of Triazoles; General Procedure
Oxopropanenitrile 2 (10.0 mmol) was added to a solution of
NaOMe (540 mg, 10.0 mmol) in dry MeOH (20 mL). Next, a solu-
tion of aryl azide 1 (10.0 mmol) in dry MeOH (5 mL) was added
dropwise and the mixture was stirred in the dark for 24 h. The re-
sulting suspension was filtered and the solid product was washed
with H2O and MeOH to give triazole 3 as a white, crystalline solid.
The addition of a few drops of H2O was necessary to precipitate tri-
azoles 3a–d.
MS (CI): m/z (%) = 268 (100%) [M + H+].
Anal. Calcd for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C,
62.75; H, 5.02; N, 26.44.
(5-Amino-1-phenyl-1H-1,2,3-triazol-4-yl)(1H-indol-3-yl)meth-
anone (3e)
Yield: 72%; white crystals; mp 278–279 °C (EtOH–H2O).
(5-Amino-1-phenyl-1H-1,2,3-triazol-4-yl)(1H-pyrrol-2-
yl)methanone (3a)
Yield: 70%; white crystals; mp 146–147 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): d = 6.22 (br s, 1 H, 4-HPyr), 6.93
(s, 2 H, NH2), 7.06 (br s, 1 H, 3-HPyr), 7.53 (br s, 1 H, 5-HPyr), 7.60–
7.67 (m, 5 H, HAr), 11.73 (br s, 1 H, NH).
1H NMR (400 MHz, DMSO-d6): d = 6.91 (s, 2 H, NH2), 7.19 (m, 2
H, 5,6-HInd), 7.49 (dd, 1 H, 3J = 5.9, 4J = 2.9 Hz, 4-HInd), 7.53 (t, 1
H, 3J = 6.8 Hz, 4-HAr), 7.62 (t, 2 H, 3J = 6.8 Hz, 3,5-HAr), 7.68 (d, 2
H, 3J = 6.8 Hz, 2,6-HAr), 8.41 (dd, 1 H, 3J = 5.9, 4J = 2.9 Hz, 7-HInd),
9.04 (s, 1 H, 2-HInd), 11.82 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 112.7 (CHInd), 114.9 (CInd),
122.1 (2 × CHInd), 123.3 (CHInd), 124.9 (2 × CHAr), 127.0 (CInd),
128.5 (CTriazole), 129.7 (CAr), 130.4 (2 × CHAr), 135.1 (CAr), 135.4
(CHInd), 136.6 (CInd), 146.6 (CTriazole), 181.4 (CO).
13C NMR (100 MHz, DMSO-d6): d = 110.5 (CHPyr), 118.2 (CHPyr),
124.9 (2 × CHPh), 125.5 (CTriazole), 127.3 (CHPyr), 129.8 (CHAr),
130.2 (CPyr), 130.4 (2 × CHAr), 135.0 (CAr), 147.1 (CTriazole), 174.9
(CO).
MS (CI): m/z (%) = 304 (100%) [M + H+].
MS (CI): m/z (%) = 254 (100%) [M + H+].
Anal. Calcd for C17H13N5O: C, 67.32; H, 4.32; N, 23.09. Found: C,
67.25; H, 4.40; N, 23.21.
Anal. Calcd for C13H11N5O: C, 61.65; H, 4.38; N, 27.65. Found: C,
61.46; H, 4.60; N, 27.51.
[5-Amino-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl](1H-indol-
3-yl)methanone (3f)
Yield: 79%; white crystals; mp 285–286 °C (EtOH–H2O).
[5-Amino-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl](1H-pyr-
rol-2-yl)methanone (3b)
Yield: 74%; white crystals; mp 186–187 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): d = 2.46 (s, 3 H, Me), 6.83 (s, 2 H,
1H NMR (400 MHz, DMSO-d6): d = 2.46 (s, 3 H, Me), 6.21 (dd, 1
3
H, 3J =3.6, 3J = 2.0 Hz, 4-HPyr), 6.82 (s, 2 H, NH2), 7.04 (br s, 1 H,
NH2), 7.17 (m, 2 H, 5,6-HInd), 7.40 (d, 2 H, J = 7.8 Hz, 3,5-HAr),
4
7.47 (dd, 1 H, 3J = 6.8, J = 2.9 Hz, 4-HInd), 7.50 (d, 2 H, 3J = 7.8
Synthesis 2009, No. 8, 1297–1300 © Thieme Stuttgart · New York

1300
N. T. Pokhodylo et al.
PAPER
Hz, 2,6-HAr), 8.40 (dd, 1 H, 3J = 6.8, 4J = 2.9 Hz, 7-HInd), 9.04 (s, 1
H, 2-HInd), 11.81 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 21.3 (Me), 112.7 (CHInd),
114.9 (CInd), 122.1 (2 × CHInd), 123.2 (CHInd), 124.8 (2 × CHAr),
127.0 (CInd), 128.5 (CTriazole), 130.7 (2 × CHAr), 132.6 (CAr), 135.4
(CHInd), 136.5 (CInd), 139.4 (CAr), 146.6 (CTriazole), 181.4 (CO).
References
(1) Finley, K. T. Triazoles 1,2,3, In The Chemistry of
Heterocyclic Compounds, Vol. 39; Weissberger, A.; Taylor,
E. C., Eds.; Wiley: New York, 1980, 1.
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MS (CI): m/z (%) = 338 (100%) [M + H+].
Anal. Calcd for C18H15N5O: C, 68.13; H, 4.76; N, 22.07. Found: C,
68.21; H, 4.58; N, 21.95.
[5-Amino-1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl](1H-indol-
3-yl)methanone (3g)
Yield: 85%; white crystals; mp >300 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): d = 7.00 (s, 2 H, NH2), 7.18 (m, 2
H, 5,6-HInd), 7.48 (dd, 1 H, 3J = 6.8, 4J = 2.9 Hz, 4-HInd), 7.64 (d, 2
(7) Bascal, Z.; Holden-Dye, L.; Willis, R. J.; Smith, S. W. G.;
Walker, R. J. Parasitology 1996, 112, 253.
(8) Biagi, G.; Giorgi, I.; Livi, O.; Lucacchini, A.; Martini, C.;
Scartoni, V. J. Pharm. Sci. 1993, 82, 893.
3
3
H, J = 8.8 Hz, 3,5-HAr), 7.65 (d, 2 H, J = 8.8 Hz, 2,6-HAr), 8.40
(dd, 1 H, 3J = 6.8, 4J = 2.9 Hz, 7-HInd), 9.03 (s, 1 H, 2-HInd), 11.83
(s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 112.7 (CHInd), 114.8 (CInd),
122.1 (CHInd), 122.2 (CHInd), 123.2 (CHInd), 126.9 (2 × CHAr), 127.0
(CInd), 128.5 (CTriazole), 130.4 (2 × CHAr), 134.0 (CAr), 134.2 (CAr),
135.5 (CHInd), 136.6 (CInd), 146.8 (CTriazole), 181.2 (CO).
(9) Moltzen, E. K.; Pedersen, H.; Bøgesø, K. P.; Meier, E.;
Frederiksen, K.; Sanchez, C.; Lembøl, K. L. J. Med. Chem.
1994, 37, 4085.
(10) Chakrabarti, J. K.; Hotten, T. M.; Pullar, I. A.; Steggles,
D. J. J. Med. Chem. 1989, 32, 2375.
(11) Sanghvi, Y. S.; Bhattacharya, B. K.; Kini, G. D.;
Matsumoto, S. S.; Larson, S. B.; Jolley, W. B.; Robins,
R. K.; Revankar, G. R. J. Med. Chem. 1990, 33, 336.
(12) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A.
J. Med. Chem. 1986, 29, 2262.
(13) Hupe, D. J.; Boltz, R.; Cohen, C. J.; Felix, J.; Ham, E.;
Miller, D.; Soderman, D.; Van Skiver, D. J. Biol. Chem.
1991, 266, 10136.
MS (CI): m/z (%) = 339 (100%) [M + H+].
Anal. Calcd for C17H12ClN5O: C, 60.45; H, 3.58; N, 20.73. Found:
C, 60.19; H, 3.55; N, 20.82.
[5-Amino-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl](1H-indol-3-
yl)methanone (3h)
Yield: 86%; white crystals; mp >300 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): d = 7.14 (m, 2 H, 5,6-HInd), 7.26
(s, 2 H, NH2), 7.48 (d, 1 H, 3J = 6.8 Hz, 4-HInd), 7.98 (d, 2 H, 3J =
8.8 Hz, 3,5-HAr), 8.40 (d, 1 H, 3J = 6.8 Hz, 7-HInd), 8.44 (d, 2 H, 3J =
8.8 Hz, 2,6-HAr), 9.01 (d, 1 H, 3J = 2.4 Hz, 2-HInd), 11.86 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): d = 113.0 (CHInd), 114.6 (CInd),
116.6 (2 × CHAr), 122.0 (CHInd), 122.7 (CHInd), 123.7 (CHInd), 126.0
(2 × CHAr), 126.8 (CInd), 131.9 (CTriazole), 136.8 (CHInd, CInd), 140.3
(CAr), 147.7 (CTriazole), 149.0 (CAr), 181.6 (CO).
(14) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Rev. 2005,
74, 339.
(15) Cottrell, I. F.; Hands, D.; Houghton, P. G.; Humphrey, G. R.;
Wright, S. H. B. J. Heterocycl. Chem. 1991, 28, 301.
(16) Krivopalov, V. P.; Nikolaenkova, E. B.; Sedova, V. F.;
Mamaev, V. P. Chem. Heterocycl. Compd. 1983, 19, 1116.
(17) Sundberg, R. J. Indoles, In Best Synthetic Methods: Key
Systems and Functional Groups; Meth-Cohn, O., Ed.;
Academic Press: London, 1996.
MS (CI): m/z (%) = 349 (100%) [M + H+].
(18) Slätt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760.
Anal. Calcd for C17H12N6O3: C, 58.62; H, 3.47; N, 24.13. Found: C,
58.28; H, 3.58; N, 24.04.
Synthesis 2009, No. 8, 1297–1300 © Thieme Stuttgart · New York