Greener and expeditious synthesis of 1,4-disubstituted 1,2,3-triazoles from terminal acetylenes and in situ generated α-azido ketones

Article abstract of DOI:10.1055/s-0028-1087556

A convenient and mild protocol for the one-pot regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous PEG 400 has been reported. The methodology involves the one-pot reaction of α-bromo ketones, sodium azide, and terminal acetylenes cata

Full text of DOI:10.1055/s-0028-1087556

LETTER
399
Greener and Expeditious Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from
Terminal Acetylenes and in situ Generated a-Azido Ketones
S
ynthesis of 1,4-D
a
isubstituted
l
1,2,3-
i
T
riazol
p
es Kumar,* Gautam Patel, V. Buchi Reddy
Chemistry Group, Birla Institute of Technology and Science, Pilani 333031, India
Fax +91(1596)244183; E-mail: dalipk@bits-pilani.ac.in
Received 7 August 2008
tensively studied by Huisgen et al.7 Recently, Sharpless
and co-workers have reported remarkable high-yielding
syntheses of 1,2,3-triazoles with excellent regioselectivi-
ty.1b
Abstract: A convenient and mild protocol for the one-pot regiose-
lective synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous
PEG 400 has been reported. The methodology involves the one-pot
reaction of a-bromo ketones, sodium azide, and terminal acetylenes
catalyzed by Cu(I) in aqueous PEG 400 at room temperature. Prom-
inent features of our approach are mild reaction conditions, use of
readily available a-bromo compounds, aqueous PEG 400 as a be-
nign reaction medium, avoiding the isolation of labile a-azido ke-
tones, simple workup, and good yields.
a-Bromo ketones can be easily prepared by the selective
a-bromination of the appropriate acetyl compound.8 Iso-
lation and purification of some a-azido ketones from the
reaction of a-bromo ketones and sodium azide is difficult
due to incomplete conversion.9 Therefore, a method
which avoids the isolation and handling of a-azido ke-
tones via in situ generation from the reaction of a-bromo
ketones with sodium azide is highly attractive and safe. In
our efforts to prepare a novel and diverse library of 1,4-
disubstituted 1,2,3-triazoles, we report herein a one-pot
synthesis of these interesting compounds using Cu(I)-
catalyzed reaction of a-bromo ketones, terminal acety-
lenes, and sodium azide in aqueous PEG 400 at room tem-
perature (Scheme 1).10
Key words: 1,2,3-triazoles, a-bromo ketones, click chemistry,
a-azido ketones
The 1,2,3-triazole, a five-membered, nitrogen-containing
heterocycle, is often encountered as a structural unit of
compounds possessing diverse biological activities in-
cluding herbicidal, fungicidal, antibacterial, antiallergic,
selective b3 adrenergic receptor agonism, anti-HIV, and
anti-convulsant.1 Many 1,2,3-triazoles are also used as
dyes, optical brightners, agrochemicals, photographic ma-
terials, and corrosion inhibitors.1c–1e,2 Stability towards
metabolic degradation and capability of hydrogen-bond
formation make 1,2,3-triazoles an attractive connecting
unit to discover novel biologically interesting chemical
entities.3
NaN3
R2
N
O
N
N
O
Na ascorbate (10 mol%)
R2
Br
R1
R1
CuSO4 (5 mol%)
PEG–H2O, r.t., 30 min
Scheme 1 Synthesis of 1,2,3-triazoles 2
Organic reactions in environmentally benign media have
attracted significant interest among researchers due to the
detrimental impact of toxic and volatile solvents on the
environment.4 In the past, without losing reaction effi-
ciency, chemists have demonstrated the utility of benign
alternative solvents such as ionic liquids, water, and poly-
ethylene glycol (PEG) as a replacement for toxic and vol-
atile organic solvents.5 Multicomponent reactions (MCR)
involving sequential reactions among three or more sub-
strates have emerged as a powerful synthetic strategy to
achieve diversely substituted organic compounds.6 Owing
to many advantages in terms of molecular complexity, op-
erational simplicity, isolation and handling of intermedi-
ates, purification, and atom economy, MCR comply with
most of the stringent requirements of green chemistry.
We first tested the three-component reaction involving a-
bromo ketones, sodium azide, and phenylacetylene in var-
ious solvents such as water, DMF, DMSO, and PEG 400
and their different combinations in the presence of the
Cu(I) at room temperature. After varying the reaction con-
ditions, it was found that aqueous PEG 400 (1:1) is the
solvent of choice for this three-component reaction.
Under these optimized conditions, reaction of a-bromo
acetophenone, sodium azide, and phenylacetylene result-
ed in the exclusive formation of 1-phenyl-2-(4-phenyl-
1H-1,2,3-triazol-1-yl)ethanone (2a) in 90% yield at room
temperature in 30 minutes. The IR spectrum of 2a
(Table 1) displayed a strong band at about 1690 cm–1 in-
1
In the past, various methods were developed for the syn-
thesis of 1,2,3-triazoles. Of the existing procedures, the
1,3-dipolar cycloaddition reaction of azides with alkynes
is a very useful organic transformation which has been ex-
dicating the presence of a ketone group. The H NMR
spectrum of 2a displayed a distinct singlet at d = 8.19 ppm
for the triazolyl C5–H proton. The mass spectra of this
compound exhibits the molecular ion peak at m/z = 264.3
[M + H]+, which is in agreement with the calculated value.
SYNLETT 2009, No. 3, pp 0399–0402
x
x.
x
x.
2
0
0
9
Advanced online publication: 06.02.2009
DOI: 10.1055/s-0028-1087556; Art ID: D29108ST
© Georg Thieme Verlag Stuttgart · New York

400
D. Kumar et al.
LETTER
Table 1 Synthesis of 1,4-Disubstituted 1,2,3-Triazoles 2
Table 1 Synthesis of 1,4-Disubstituted 1,2,3-Triazoles 2
(continued)
Product
Yield (%)a
90
Product
Yield (%)a
85
N
N
N
O
N
N
O
N
N
2a
2b
2m
2n
Me
Me
Me
N
N
O
N
O
N
N
81
80
88
F
Me
N
O
N
N
Me
N
O
N
N
2c
2d
2e
2f
86
90
85
86
84
2o
2p
F
N
SO2Ph
N
O
N
N
N
O
77
78
79
75
N
Me
N
Me
O
Me
N
N
O
Me
N
2q
2r
2s
N
O
N
N
N
Me
Me
N
N
N
N
N
O
O
N
NC
N
Cl
N
O
N
MeO
N
Me
N
N
Br
2g
a Yields refer to pure and isolated products.
MeO
Encouraged by the success with initial efforts, we decided
to extend the scope of this one-pot protocol by choosing
various a-halo compounds and terminal acetylenes.
N
N
O
O
N
N
2h
2i
87
85
All the a-bromo ketones, a-bromoacetonitrile, a-bromo-
N,N-dimethylacetamide, and terminal acetylenes reacted
smoothly to afford diverse 1,4-disubstituted 1,2,3-tria-
zoles 2b–s in good yields (Table 1). Regioselective syn-
theses of 1,4-disubstituted 1,2,3-triazole analogues with
diverse functionalities further demonstrates the usefulness
of this protocol. After completion of the reaction, the
products were isolated by simple filtration or percolating
the crude product through a bed of silica gel. All the prod-
ucts were characterized by IR, NMR, and MS data.
Cl
N
N
Me
Cl
O
N
N
N
2j
86
81
N
O
O
N
To check the reusability of the catalyst and aqueous PEG
400 system, after the removal of product 2a, the solution
obtained was recycled for successive reactions. Almost
similar results were obtained in the second and third suc-
cessive recycles in terms of product yield and reaction
time.
2k
N
Me
N
N
N
2l
83
Formation of 1,4-disubstituted 1,2,3-triazoles 2 probably
involve first in situ generation of a-azido ketones by the
reaction of a-bromo ketone with sodium azide. Subse-
Synlett 2009, No. 3, 399–402 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
401
Ph
N
O
O
N
N
Na ascorbate (10 mol%)
O
NaN3
Ph
N3
Br
PEG–H2O
r.t., 20 min
CuSO4 (5 mol%)
r.t., 10 min
Ph
Ph
Ph
Scheme 2 Stepwise synthesis of 1,2,3-triazoles 2
Alfah, M. A.; Jibril, I.; Marii, F. M.; Ali, A. A. S.
quently, cycloaddition reaction of a-azido ketones and
terminal acetylenes generates 2. Higher solubility of reac-
tants in aqueous PEG 400 and formation of PEG 400–
sodium cation complex may be responsible for the faster
reaction.11 The reaction pathway was further unambigu-
ously confirmed by the preparation of 2 from the reac-
tion of a-azidoacetophenone with phenylacetylene
(Scheme 2).
J. Heterocycl. Chem. 1989, 26, 1461. (d) Scriven, E. F. V.;
Turnbull, K. Chem. Rev. 1988, 88, 297. (e) Maksikova, A.
V.; Serebryakova, E. S.; Tikhonova, L. G.; Vereshagin, L. I.
Chem. Heterocycl. Compd. 1980, 1284. (f) Kacprzak, K.
Synlett 2005, 943. (g) Lubineau, A.; Auge, J.; Queneau, Y.
Synthesis 1994, 741. (h) Li, C. J.; Chan, T. H. Organic
Reactions in Aqueous Media; New York: Wiley, 1997.
(i) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751.
(3) (a) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R.
J. Am. Chem. Soc. 2004, 126, 15366. (b) Dalvie, D. K.;
Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.;
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(c) Speers, A. E.; Cravatt, B. F. Chem. Biol. 2004, 11, 535.
(d) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.;
Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125,
9588.
(4) (a) Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev. 2008,
1546. (b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res.
2008, 41, 629. (c) Adams, D. J.; Dyson, P. J.; Tavener, S. J.
Chemistry in Alternative Reaction Media; Wiley:
Chichester, 2004. (d) Matlack, A. S. Introduction to Green
Chemistry; Marcel Dekker Inc.: New York, 2001.
(5) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
(6) Zhu, J.; Bienayme, H. Multicomponent Reactions, 1st ed.;
Wiley-VCH: Weinheim, 2005.
In summary, we have developed a rapid and high yielding
one-pot regioselective synthesis of 1,4-disubstituted
1,2,3-triazoles in aqueous PEG 400 system at room tem-
perature. Use of easily available a-bromo ketones, a-
bromoacetonitrile, a-bromo-N,N-dimethylacetamide, and
terminal acetylenes makes this protocol very useful for the
preparation of diverse 1,4-disubstituted 1,2,3-triazoles.
Simple experimentation, solvent and catalyst reusability,
benign reaction solvent, mild reaction conditions, and
high yields make this method attractive.
Acknowledgment
We thank DRDO, New Delhi, for financial support (Project No.
ERIP/0505034/M/01).
(7) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984, 1–176. (b)Padwa,
A. In Comprehensive Organic Synthesis, Vol. 4; Trost,
B. M., Ed.; Pergamon: Oxford, 1991, 1069–1109.
(c) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward,
J. J.; Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5,
1559.
References and Notes
(1) (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today
2003, 8, 1128. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2001, 40, 2004. (c) Gil, M. V.;
Arevalo, M. J.; Lopez, O. Synthesis 2007, 1589. (d) Moses,
J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
(e) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. V. Eur. J.
Org. Chem. 2006, 51. (f) Genin, M. J.; Allwine, D. A.;
Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.; Garmon,
S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson,
D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenco,
G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H.
J. Med. Chem. 2000, 43, 953. (g) Pagliai, F.; Pirali, T.;
Grosso, E. D.; Brisco, R. D.; Tron, G. C.; Sorba, G.;
Genazzani, A. A. J. Med. Chem. 2006, 49, 467. (h) Brik,
A.; Muldoon, J.; Lin, Y. C.; Elder, J. H.; Goodsell, D. S.;
Olson, A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C. H.
ChemBioChem 2003, 4, 1246. (i) Brockunier, L. L.;
Parmee, E. R.; Ok, H. O.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom,
G. J.; MacIntyre, D. E.; Tota, L.; Wyvratt, M. J.; Fischer, M.
H.; Weber, A. E. Bioorg. Med. Chem. Lett. 2000, 10, 2111.
(j) Velazquez, S.; Alvarez, R.; Perez, C.; Gago, F.;
(8) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.;
Horaguchi, T. Chem. Commun. 2004, 470.
(9) (a) Marsh, F. D. J. Org. Chem. 1972, 37, 2966. (b) Priebe,
H.; Braathen, G. O.; Klaeboe, P.; Neelsen, C.; Priebe, H.
Acta Chem. Scand. Ser. B 1984, 38, 895. (c) Smith, P. A. S.
Derivatives of Hydrazine and Other Hydronitrogens Having
N–N Bonds; Benjamin-Cummings: Reading (MA), 1983,
263.
(10) General Procedure
To a solution of a-halo compound 1 (1.0 mmol), NaN3 (1.2
mmol), and terminal acetylene (1.0 mmol) in aq PEG 400 (2
mL) was added sodium ascorbate (19.8 mg, 10 mol%) and 1
M CuSO4 (50 mL, 5 mol%) solution. The reaction mixture
was allowed to stir at r.t. for 30 min. After the reaction was
complete, as indicated by TLC, the solid product was
filtered, washed, and dried to afford pure product.
Analytical Data for Selected Compounds
Compound 2a:7c IR (KBr): 1690 (CO) cm–1. 1H NMR (200
MHz, CDCl3): d = 8.04–8.00 (2 H, m), 7.95 (1 H, s), 7.89–
7.84 (2 H, m), 7.73–7.65 (1 H, m), 7.59–7.31 (5 H, m), 5.91
(2 H, s). 13C NMR (50 MHz, CDCl3): d = 195.0 (CO), 152.4,
139.0, 138.2, 134.5, 133.5, 133.2, 132.7, 132.5, 130.1,
126.4, 59.9. MS (EI): m/z calcd for C16H14N3O [M + H]+:
264.1; found: 264.3.
De Clercq, E.; Balzarini, J.; Camarasa, M. J. Antiviral Chem.
Chemother. 1998, 9, 481..
(2) (a) Fan, W. Q.; Katritzky, A. R. In Comprehensive
Heterocyclic Chemistry II, Vol. 4; Katritzky, A. R.; Rees,
C. W.; Scriven, C. W. V., Eds.; Oxford: Elsevier, 1996,
1–126. (b) Thibault, R. J.; Takizawa, K.; Lowenheilm, P.;
Helms, B.; Mynar, J. L.; Frechet, J. M. J.; Hawker, C. J.
J. Am. Chem. Soc. 2006, 128, 12084. (c) Abu-Orabi, S. T.;
Compound 2h: IR (KBr): 1680 (CO) cm–1. 1H NMR (400
MHz, DMSO-d6): d = 8.53 (1 H, s), 8.11 (2 H, d, J = 8.0 Hz),
Synlett 2009, No. 3, 399–402 © Thieme Stuttgart · New York

402
D. Kumar et al.
LETTER
7.88 (2 H, d, J = 8.0 Hz), 7.70 (2 H, d, J = 8.0 Hz), 7.48–7.45
(2 H, m), 7.37–7.35 (1 H, m), 6.27 (2 H, s). 13C NMR (100
MHz, DMSO-d6): d = 191.4 (CO), 146.3, 139.2, 132.8,
130.7, 130.1, 129.1, 128.9, 127.9, 125.1, 123.0, 56.0. MS
(EI): m/z calcd for C16H13ClN3O [M + H]+:298.0747; found:
297.9593.
50.8. MS (EI): m/z calcd for C11H12N3O2 [M + H]+: 218.1;
found: 218.3.
Compound 2q: IR (KBr): 1651 (CO) cm–1. 1H NMR (300
MHz, CDCl3): d = 8.03 (1 H, s), 7.85–7.83 (2 H, m), 7.44–
7.39 (2 H, m), 7.39–7.30 (1 H, m), 5.23 (2 H, s), 3.46–3.39
(4 H, m), 1.25 (3 H, t, J = 7.15 Hz), 1.15 (3 H, t, J = 7.10
Hz). 13C NMR (75 MHz, CDCl3): d = 164.0 (CO), 148.0,
130.7, 128.8, 128.1, 125.8, 121.4, 50.9, 42.0, 41.0, 14.4,
12.8. MS (EI): m/z calcd for C14H19N4O [M + H]+: 259.2;
found: 259.3.
Compound 2l: IR (KBr): 1720 (CO) cm–1. 1H NMR (400
MHz, DMSO-d6): d = 8.56 (1 H, s), 7.85 (2 H, d, J = 8.0
Hz), 7.47–7.44 (2 H, m), 7.35–7.32 (1 H, m), 5.76–5.71
(1 H, m), 2.75–2.67 (1 H, m), 2.45–2.32 (3 H, m), 2.11–2.09
(1 H, m), 1.96–1.92 (2 H, m), 1.76–1.68 (1 H, m). 13C NMR
(100 MHz, DMSO-d6): d = 204.1 (CO), 145.9, 130.8, 128.9,
127.8, 125.0, 121.3, 66.8, 40.4, 33.4, 26.4, 23.6. MS (EI):
m/z calcd for C14H16N3O [M + H]+: 242.1293; found:
242.0473.
Compound 2r: IR (KBr): 2286 (CN) cm–1. 1H NMR (200
MHz, CDCl3): d = 8.00 (1 H, s), 7.86–7.81 (2 H, m), 7.51–
7.38 (3 H, m), 5.40 (2 H, s). 13C NMR (50 MHz, CDCl3):
d = 149.6, 129.9, 129.4, 129.3, 126.3, 120.3, 113.1, 38.0. MS
(EI): m/z calcd for C10H9N4 [M + H]+: 185.1; found: 185.2.
Compound 2s: IR (KBr): 1693 (CO) cm–1. 1H NMR (300
MHz, DMSO-d6): d = 7.86 (2 H, d, J = 8.49 Hz), 7.68 (2 H,
d, J = 8.49 Hz), 7.51 (1 H, s), 5.79 (2 H, s), 3.65–3.58 (2 H,
m), 2.96–2.91 (2 H, m), 2.24–2.15 (2 H, m). 13C NMR (75
MHz, CDCl3): d = 189.7 (CO), 146.8, 132.7, 132.6, 130.0,
129.6, 123.0, 55.3, 44.2, 31.8, 22.7. MS (EI): m/z calcd for
C13H14BrClN3O [M + H]+: 342.0; found: 342.0.
Compound 2o: IR (KBr): 1685 (CO) cm–1. 1H NMR (400
MHz, DMSO-d6): d = 9.17 (1 H, s), 8.61 (1 H, s), 8.20 (2 H,
d, J = 8.0 Hz), 8.15 (1 H, d, J = 8.0 Hz), 8.02 (1 H, d, J = 8.0
Hz), 7.90 (2 H, d, J = 8.0 Hz), 7.80–7.76 (1 H, m), 7.69–7.65
(2 H, m), 7.49–7.33 (5 H, m), 6.26 (2 H, s). 13C NMR (100
MHz, DMSO-d6): d = 187.9 (CO), 146.3, 136.3, 135.4,
134.8, 133.9, 130.7, 130.2, 128.9, 127.9, 127.3, 126.8,
126.2, 125.2, 125.1, 123.2, 122.0, 117.5, 113.1, 56.0. MS
(EI): m/z calcd for C24H19N4O3S [M + H]+: 443.1178; found:
443.0073.
(11) (a) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D.
Green Chem. 2005, 7, 64. (b) Zaslavsky, B. Y. Aqueous
Two-Phase Partitioning: Physical Chemistry and
Bioanalytical Applications; Marcel Dekker: New York,
1995. (c) Yalkowsky, S. H.; Banerjee, S. Aqueous
Solubility: Methods of Estimation for Organic Compounds;
Marcel Dekker: New York, 1992.
Compound 2p: IR (KBr): 1759 (CO) cm–1. 1H NMR (300
MHz, CDCl3): d = 7.92–7.82 (3 H, m), 7.42–7.27 (3 H, m),
5.21 (2 H, s), 3.80 (3 H, s). 13C NMR (75 MHz, CDCl3): d =
166.8 (CO), 148.2, 130.4, 128.9, 128.3, 125.8, 121.1, 53.0,
Synlett 2009, No. 3, 399–402 © Thieme Stuttgart · New York

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