Efficient synthesis of 2-substituted-1,2,3-triazoles

Article abstract of DOI:10.1021/ol8006748

(Chemical Equation Presented) In this three-component reaction, alkynes undergo a copper(I)-catalyzed cycloaddition with sodium azide and formaldehyde to yield 2-hydroxymethyl-2H-1,2,3-triazoles, which are useful intermediates that can be readily converte

Full text of DOI:10.1021/ol8006748

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3171-3174
Efficient Synthesis of
2-Substituted-1,2,3-triazoles
Jarosław Kalisiak, K. Barry Sharpless, and Valery V. Fokin*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
fokin@scripps.edu
Received March 24, 2008
ABSTRACT
In this three-component reaction, alkynes undergo a copper(I)-catalyzed cycloaddition with sodium azide and formaldehyde to yield
2-hydroxymethyl-2H-1,2,3-triazoles, which are useful intermediates that can be readily converted to polyfunctional molecules. The hydroxymethyl
group can also be removed, providing convenient access to NH-1,2,3-triazoles. The reaction is experimentally simple and readily scalable.
The 1,3-dipolar cycloaddition of organic azides and
alkynes, a direct route to 1,2,3-triazoles,1 is usually slow and
not regioselective. Catalytic azide-alkyne cycloaddition
methods for the synthesis of 1,4- (copper(I)-catalyzed)2 or
1,5-disubstituted (ruthenium(II)-catalyzed)3 1,2,3-triazoles
provide reliable means for the assembly of diversely
substituted 1,2,3-triazoles under mild conditions and with
excellent regioselectivity. However, a general, simple, and
scalable method for the synthesis of the 2H-isomers is still
not available.
Although 2-substituted-2H-1,2,3-triazoles can be obtained
by alkylation of NH-1,2,3-triazoles with suitable electrophilic
reagents, a mixture of the isomeric products is often pro-
duced.4 Another common route to the 2H-1,2,3-triazoles, the
oxidative cyclization of bishydrazones or bissemicarbazones,
is limited to the synthesis of 2-aryl-substituted 1,2,3-tri-
azoles.5 In 2002, Yamamoto and co-workers reported an
elegant three-component Pd-catalyzed synthesis of 2-allyl-
1,2,3-triazoles.6 The proposed mechanism involves the initial
formation of a 1-allylpalladium-1,2,3-triazole complex, which
may subsequently rearrange to the 2H isomer. Similar
behavior was observed by Iddon et al. during the hydrolysis
of a mixture of 1H- and 2H- MOM-alkylated 4,5-dibromo-
1,2,3-triazoles, where only the 2-hydroxymethyl isomer was
obtained.7 These results suggest that the 2-hydroxymethyl
derivative of 4,5-dibromo-1,2,3-triazole is thermodynamically
more stable than its 1-substituted isomer and that there is a
dynamic equilibrium between the N-hydroxymethyl triazole,
formaldehyde, and the NH-triazole.8
Here we present a three-component, one-pot synthesis of
2-hydroxymethyl-2H-1,2,3-triazoles.9 These compounds are
versatile intermediates that can be used for the preparation
of 2-chloromethyl-2H-1,2,3-triazoles and NH-1,2,3-triazoles,
(1) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984.
(5) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. ReV. 2005, 74, 339.
(6) (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahedron Lett.
2002, 43, 9707. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 7786.
(2) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(7) Iddon, B.; Nicholas, M. J. Chem. Soc., Perkin Trans. 1 1996, 1341.
(8) N-Hydroxymethyl derivatives of other heterocycles are known to
rearrange: (a) Katritzky, A. R.; Perumal, S.; Savage, G. P. J. Chem. Soc.
Perkin Trans. 2 1990, 921. (b) Alkorta, I.; Elguero, J.; Jagerovic, N.;
Fruchier, A.; Yap, G. P. A. J. Heterocycl. Chem. 2004, 41, 285.
(9) (a) Ladyzhnikova, T. D.; Manue´l, D. V.; Altukhov, K. V. Russ. J.
Org. Chem. 1993, 29, 1249. (b) Quiclet-Sire, B.; Zard, S. Z. Synthesis 2005,
3319.
(3) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(b) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680. (c)
Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.;
Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, in press.
(4) Tome, A. C. In Science of Synthesis; Storr, R. C., Gilchrist, T. L.,
Eds.; Thieme: Stuttgart, New York, 2004; Vol. 13, pp 415.
10.1021/ol8006748 CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society

an important class of heterocycles with pharmacophoric
properties.10
Table 1. One-Pot Synthesis of N-Hydroxymethyl-1,2,3-triazoles
In our method, formaldehyde, sodium azide, and a terminal
alkyne react in a one-pot two-reaction sequence under slightly
acidic (pH ) 6.5) conditions. Azidomethanol (HO-CH2-N3),
formed in situ from protonated formaldehyde and sodium azide,
is a likely intermediate.11 Its subsequent copper(I)-catalyzed
reaction with the alkyne provides the 1-hydroxymethyl-1H-
1,2,3-triazole product. However, the instability of this derivative
and its equilibrium with the NH-triazole and formaldehyde
results in the rearrangement of the 1-hydroxymethyl triazole to
the thermodynamically more stable 2-hydroxymethyl isomer.12
Thus, the net result of a sequence that begins with phenylacety-
lene, formaldehyde, and sodium azide is the regioisomeric
mixture of 1- and 2-hydroxymethyl-4-phenyl-1,2,3-triazole
products 1(a+b) (Scheme 1).
entry
AcOH (equiv)
solventa
yield (%)b
1
2
3
4
5
6
7
none
0.6
1.5
1.5
1.5
1.5
1.5
H2O
H2O
H2O
none
10
48
84
92
H2O/DMSO (1:1)
H2O/DMF (1:1)
H2O/dioxane (1:1)
92
H2Oc/dioxane (1:1)
1.3c
a A 37% solution of formaldehyde in water was used. b Combined yield
of 1a and 1b. c No formaldehyde was added; NH-triazole 1c was the product.
Scheme 1. Synthesis of 2-Substituted-2H-1,2,3-triazoles
product as the 1,4-disubstituted-1,2,3-triazole was determined
by HMQC and HMBC experiments. As demonstrated for the
Examination of different reaction parameters (Table 1)
revealed that the best yields of the triazole were obtained
under slightly acidic conditions (entries 1-3). Due to the toxic
and explosive nature of the hydrazoic acid, we opted to use the
relatively weak acetic acid to conduct the reaction (CH3COOH,
pKa(H2O) ) 4.76, pKa(DMSO) ) 12.3 cf. HN3, pKa(H2O) )
4.72, pKa (DMSO) ) 7.9). The best results were obtained using
a formalin/1,4-dioxane (1:1) mixture as the solvent system,
which provided 1(a+b) in 92% yield (entry 6). The reaction
was successfully scaled up to 1 mol, and the product 1(a+b)
was isolated by simple extractive workup in 92% yield (157
g). The structure of 1a was unambiguously confirmed by X-ray
crystallographic analysis (Figure 1).
The scope of the one-pot method was then tested on a
gram scale using several alkynes.13 As shown in Table 2,
mixtures of the 1- and 2-hydroxymethyl triazole products
were obtained with yields ranging from 67% to 95%.
In all cases, the 2-substituted product was formed predomi-
nantly, as confirmed by the characteristic 13C NMR chemical
shift of the hydroxymethylene carbon. The identity of the minor
Figure 1. X-ray structure of 1a.
product mixture 12(a+b), the heteronuclear correlation experi-
ments showed a strong interaction between the protons of the
methylene group of the minor isomer with the C-5 carbon of
the triazole ring, which was expected for the 1,4-isomer (see
Supporting Information for details).
(13) General experimental procedure as exemplified for the synthesis
of 1. CAUTION: any experiments that may result in the formation of
hydrazoic acid should be performed in a well-Ventilated fume hood and
behind a blast shield. Sodium azide should not be mixed with strong
acids. A mixture of 37% HCHOaq (736 mL, 9.8 mol, 10 equiv), glacial
AcOH (84 mL, 1.47 mol, 1.5 equiv), and 1,4-dioxane (736 mL) was
stirred for 15 min, and NaN3 (95.6 g, 1.47 mol, 1.5 equiv) was added,
followed by phenylacetylene (100 g, 0.98 mol). At this point the pH of
the reaction mixture was 6.5. After an additional 10 min of stirring,
sodium ascorbate (38.8 g, 0.196 mol, 20 mol %) was added, followed
by CuSO4 solution (7.8 g, 0.049 mol, 5 mol %) in 40 mL of H2O.
CAUTION: the reaction was exothermic, and although it achieVed
maximum temperature of 56 °C after 15 min without cooling, the use of
an ice-water bath is recommended. The mixture was stirred for 18 h at
rt and then diluted with H2O (3000 mL) and extracted using CHCl3 (3
× 500 mL). Combined organic layers were filtered through Celite to
remove solids, dried over MgSO4, filtered, and concentrated on a rotary
evaporator to give yellowish solid (157.5 g, 91.8%). The crude product
was sufficiently pure to be used without further purification. The
analytically pure sample was obtained as white solid (mp ) 115-116
°C) by recrystallization from CHCl3 or EtOAc/hexanes (1:1).
(10) (a) Woerner, F. P.; Reimlinger, H. Chem. Ber. 1970, 103, 1908.
(b) Journet, M.; Cai, D.; Kowal, J. J.; Larsen, R. D. Tetrahedron Lett. 2001,
42, 9117. (c) Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.;
Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C. K.; Smith,
W. W.; Janson, C. A.; Ryan, M. D.; Zhang, G. F.; Johanson, K. O.;
Kirkpatrick, R. B.; Ho, T. F.; Fisher, P. W.; Mattern, M. R.; Johnson, R. K.;
Hansbury, M. J.; Winkler, J. D.; Ward, K. W.; Veber, D. F.; Thompson,
S. K. J. Med. Chem. 2005, 48, 5644.
(11) We also considered the possibility of the Cu(I)-catalyzed cycload-
dition of HN3 and phenylacetylene to give the NH-triazole, which could
subsequently react with formaldehyde (cf. Scheme 4). However, when H2O
was used instead of 37% formaldehyde solution (Table 1, entry 7), only
NH-triazole 1c was obtained in low 1.3% yield.
(12) Deprotection of the O-benzyl derivative of 1b led to a mixture of
1a and NH-triazole 1c (see Suporting Information).
3172
Org. Lett., Vol. 10, No. 15, 2008

sors for the corresponding NH-triazoles. Therefore, basic
hydrolysis with sodium hydroxide, reduction with sodium
borohydride, and oxidation with manganese dioxide provide
three complementary routes to the NH-triazoles. As illustrated
in Table 2, all 13 NH-triazole products could be obtained in
good yield using at least one of these reagents.
Table 2. Synthesis of N-Hydroxymethyl-1,2,3-triazoles and
NH-1,2,3-Triazoles
Existing syntheses of NH-triazoles usually use an azide
with a suitable protecting group, which is removed after the
1,2,3-triazole heterocycle is assembled.16 In our approach,
azidomethanol serves as a “protected” azide which is formed
in situ from inexpensive and readily available reagents,
formaldehyde and sodium azide. The reaction can be readily
performed on multigram scale (for example, 123 g of 1c was
obtained using this protocol).
To illustrate other facets of the reactivity and utility of
N-hydroxymethyl triazoles, two representative compounds
1(a+b) and 2(a+b) were converted to the corresponding 2H-
chloromethyl derivatives 1417 and 1518 (Scheme 2). Their
electrophilic properties are revealed by reactions with nu-
cleophiles, such as phenoxides and sodium azide. For exam-
ple, they could be readily converted to aryl ethers 18 or to
2-azidomethyl-1,2,3-triazoles 16 and 17.
Scheme 2. Synthesis of 2-Substituted-2H-1,2,3-triazoles
Additional proof that N-chloromethyl-1,2,3-triazole 14 and
N-azidomethyl derivative 16 are 2H isomers comes from the
Pd-catalyzed arylation of the bistriazole 19 with bromoben-
zene using a method recently developed by Gevorgyan and
co-workers.19 The di- and monoarylated products (20 and
21) were obtained in 24% and 60% yields, respectively
(Scheme 3). The preferred formation of the monoarylated
product 21 suggests that the 2,4-disubstituted triazole is less
reactive in the Pd-catalyzed arylation than the 1,4-isomer.
a Ratio of isomers was determined by integration of the triazole proton.
b Hydroxymethylene carbon signals; all 13C NMR spectra were recorded
in d6-DMSO. c NaOH. d NaBH4. e MnO2.
Basic hydrolysis of N-hydroxymethyl derivatives of various
heterocycles is generally facile and leads to the parent NH-
compounds.14 Additionally, N-hydroxymethyl triazoles can be
deprotected under reductive15 or oxidative conditions. Therefore,
isomeric mixtures of products 1-13(a+b) can serve as precur-
(16) (a) Shainyan, B. A.; Meshcheryakov, V. I. Russ. J. Org. Chem.
2001, 37, 1797. (b) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem.
2004, 3789. (c) Kamijo, S.; Huo, Z.; Jin, T.; Kanazawa, C.; Yamamoto, Y.
J. Org. Chem. 2005, 70, 6389. (d) Loren, J. C.; Krasin´ski, A.; Fokin, V. V.;
Sharpless, K. B. Synlett 2005, 2847. (e) Yap, A. H.; Weinreb, S. M.
Tetrahedron Lett. 2006, 47, 3035.
(14) (a) Dhanak, D.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1986,
2181. (b) Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007,
9, 1165.
(15) For example, reaction of the 1H-hydroxymethyl benzotriazole with
NaBH4 provides exclusively 1H-benzotriazole: Gaylord, N. G.; Kay, D. J.
J. Org. Chem. 1958, 23, 1574.
(17) 1-(Chloromethyl)-4-phenyl-1H-1,2,3-triazole was obtained as a side
product in 21% yield.
(18) NH-triazole 2c (50%) accounts for the mass balance.
Org. Lett., Vol. 10, No. 15, 2008
3173

exclusively to symmetrical 2H-hydroxymethyl products 26 and
27, respectively (Scheme 4). Chlorination of the hydroxyl group
of 26 and 27 was successfully achieved using PCl5 on up to
60 g scale. 2H-chloromethyl-1,2,3-triazoles 28, 29, and 30 are
versatile electrophiles. Their reaction with NaN3 gives 2H-
azidomethyl derivatives 31, 32, and 33. 2H-Azidomethyl
derivatives 32 and 33 can be readily functionalized at all three
positions using known methods. For example, 2H-azidomethyl
triazole 32 reacted with 1-ethynyl-2-nitrobenzene to form
bistriazole derivative 34 in 95% yield (Scheme 5). Subsequent
aminolysis of methyl esters with propargylamine gave bis(pro-
pargyl) amide 35, a substrate poised to undergo a next round
of alkyne transformations.
Scheme 3. Pd-Catalyzed Arylation of Bistriazole 19
Synthesis of N-hydroxymethyl 1,2,3-triazoles can also be
accomplished by the reaction of the NH-triazoles with
paraformaldehyde or formaldehyde. Thus, the simplest parent
NH-triazole 22 gave a mixture of 2H- and 1H-derivatives
25a and 25b in a 7:3 ratio (Scheme 4). In an earlier account,20
only formation of the 2H-isomer was reported, possibly an
Scheme 5. Transformations of Azidomethyl Triazole 32
1
artifact of insufficient H NMR resolution. Nevertheless, the
reaction of the regioisomeric mixture of 25(a+b) and meth-
anesulfonyl chloride gave, after distillation, pure 2H-chlorom-
ethyl derivative 28. The scope of the method was probed using
4,5-dimethyl dicarboxylate- (23) and 4,5-dibromo-1,2,3-triazole
Scheme 4. Hydroxymethylation of NH-1,2,3-Triazoles
In conclusion, 2H-hydroxymethyl-1,2,3-triazoles are now
readily accessible from sodium azide, formaldehyde, and
alkynes using a simple one-pot process. Alternatively, they
can be prepared by hydroxymethylation of NH-triazoles with
formaldehyde. Hydroxymethyl triazoles are versatile precur-
sors to a broad variety of 2H- substituted 1,2,3-triazoles as
well as NH-triazoles, which are important classes of het-
erocycles in medicinal chemistry and materials science.
Acknowledgment. We thank Dr. J. E. Hein, Ms. J.
Raushel, and Mr. Sen-Wai Kwok (The Scripps Research
Institute) for helpful discussions and critical reading of the
manuscript. Financial support from the National Institutes
of Health, National Institute of General Medical Sciences
(GM28384), the Skaggs Institute for Chemical Biology, and
the W. M. Keck Foundation is gratefully acknowledged.
(24) as starting materials. The reactions of 23 and 24 with
formaldehyde proceeded smoothly at room temperature leading
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org.
Lett. 2007, 9, 2333.
(20) Vereshchagin, L. I.; Maksikova, A. V.; Tikhonova, L. G.; Buzilova,
S. R.; Sakovich, G. V. Chem. Heterocycl. Compd. 1981, 17, 510.
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