Regioselective rapid synthesis of fully substituted 1,2,3-triazoles mediated by propargyl cations

Article abstract of DOI:10.1021/ol402387w

Regioselective rapid triazole syntheses at low temperature are described. Organic azides and propargyl cations generated by acids gave fully substituted 1H-1,2,3-triazoles. Most reactions could be performed in 5 min at not only rt but also -90 C. Both terminal and internal alkynes were acceptable, and the sterically bulky substituents could afford the products smoothly. Various types of three-component coupling reactions were demonstrated, and the presence of allenylaminodiazonium intermediates was indicated.

Full text of DOI:10.1021/ol402387w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Rapid Synthesis
of Fully Substituted 1,2,3-Triazoles
Mediated by Propargyl Cations
Huan Zhang, Hiroki Tanimoto,* Tsumoru Morimoto, Yasuhiro Nishiyama, and
Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology
(NAIST), 8916-5 Takayamacho, Ikoma, Nara 630-0192, Japan
tanimoto@ms.naist.jp
Received August 20, 2013
ABSTRACT
Regioselective rapid triazole syntheses at low temperature are described. Organic azides and propargyl cations generated by acids gave fully
substituted 1H-1,2,3-triazoles. Most reactions could be performed in 5 min at not only rt but also ꢀ90 °C. Both terminal and internal alkynes were
acceptable, and the sterically bulky substituents could afford the products smoothly. Various types of three-component coupling reactions were
demonstrated, and the presence of allenylaminodiazonium intermediates was indicated.
AzideꢀAlkyne Cycloadditions (AAC) to produce 1,2,3-
triazoles have been extensively developed since the copper-
catalyzed conditions (CuAAC) were reported.1 Due to their
numerous applications especially in chemical biology,2
ligand/material design,3 and pharmaceuticals,4 many groups
have reported mild, rapid, and Cu-free triazolations
(Scheme 1).5 Recently, AAC using reactive strained alkynes
have been well-utilized in chemical biology,6 and CꢀC triple
bond activations with carbonyls furnish [3 þ 2] reactions
under milder conditions compared to general alkynes.7
However, CuAAC and metal-activated AAC are limited to
mostly terminal alkynes, and most of the reported methods
including classical Huisgen reactions require rt or higher with
a long reaction time.8,9 More recently, 1,2,3-triazoles have
been focused on as synthetic precursors of functionalized
compounds recently.10,11 Therefore, novel methods of rapid
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r
10.1021/ol402387w
XXXX American Chemical Society

triazole synthesis should be studied, which allow use of
internal and acyclic alkynes at rt or below.
Scheme 1. Strategies of AzideꢀAlkyne Cycloaddions and Our
We have recently developed a method for the synthesis
of cyclic unsaturated imines by way of the reactions with
allyl cations from allyl alcohols and organic azides.12
Based on the conjugated carbocation chemistry, we herein
report a rapid synthesis of highly substituted 1H-1,2,3-
triazoles from propargyl cations and organic azides, which
can accept both terminal and internal alkynes under low
temperature and multicomponent coupling reactions.
Approach
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~
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J. C.; Sletten, E. M.; Houk, K. N.; Bertozzi, C. R. J. Am. Chem. Soc.
2012, 134, 9199–9208. (b) Friscourt, F.; Fahrni, C. J.; Boons, G.-J.
J. Am. Chem. Soc. 2012, 134, 18809–18815. (c) Debets, M. F.; van Berkel,
S. S.; Dommerholt, J.; Dirks, A. J.; Rutjes, F. P. J. T.; van Delft, F. L.
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J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. J. Am. Chem. Soc. 2008,
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^
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2013, 24, 684–689. For carbenes, see: (g) Sawoo, S.; Dutta, P.; Chakraborty,
A.; Mukhopadhyay, R.; Bouloussa, O.; Sarkar, A. Chem. Commun. 2008,
5957–5959.
Ourstrategyfor triazolesynthesisisshownineq1. Using
propargyl cations prepared from alcohols, reactions with
azides at C3 could generate the allenylaminodiazonium
intermediates powerful enough to form triazole rings
immediately. Although it is known that allenyl azides
gradually cyclize into triazoles at rt,13 the chemistry of
these diazonium compounds have been not reported to the
best of our knowledge. However, we expected that these
unstable species could achieve rapid transformations at
ambient temperature. Due to the strong reactivities of both
propargyl cations and diazonium intermediates, trisubsti-
tuted triazoles functinalized with additional nucleophiles
could be obtained. Although concerted [3 þ 2] reactions
would deliver both 1H- and 3H-triazoles, deactivation of
the C2 position by a delocalized carbocation can avoid this
pathway and yield products selectively.
Our plan is challenging from the following viewpoints: (1)
with azides, an sp2 carbocation (C1) is more reactive than the
desired sp carbocation (C3)14aꢀc to produce unsaturated
imines by a Schmidt reaction15 or propargyl azides;13
(2) MeyerꢀSchuster rearrangement producing enones would
be competitive;14d To avoid the reaction at C1 by steric
and electronic influences,16 we designed diphenyl propargyl
(8) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles 2003,
60, 1225–1239. (b) Croatt et al. reported triazolation at ꢀ78 °C with
lithium acetylides and sulfonyl azides. See ref 5c.
(9) Even in the presence of azides and acids, the [3 þ 2] reaction of
ynone 11 required a few hours at ambient temperature (eq 3).
~
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14670–14673. (h) Selander, N.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134,
2477–2480. (i) Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M. J. Am.
Chem. Soc. 2012, 134, 194–196. For reviews, see: (j) Gulevich, A. V.;
Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084–
3213. (k) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012,
51, 862–872.
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Ed. 2012, 51, 13054–13057. (b) Miura, T.; Funakoshi, Y.; Morimoto,
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17443.
(13) (a) Fotsing, J. R.; Banert, K. Eur. J. Org. Chem. 2005, 3704–
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K. Chem. Ber. 1989, 122, 911–918. (d) Banert, K.; Hagedorn, M. Angew.
Chem., Int. Ed. Engl. 1989, 25, 1675–1676. And see also ref 1a.
B
Org. Lett., Vol. XX, No. XX, XXXX

alcohol 1a for the initial study of reaction conditions, and the
reactions were quenched with a saturated sodium bicarbon-
ate aqueous solution in order to produce triazolylalkanols,
recently reported as new synthetic precursors (Table 1).11
Scheme 2. Scope of Substituents on Alkynes and Azidesa
Table 1. Optimization of Reaction Conditions
BnN3
(equiv)
reagent
(equiv)
temp
(°C)
t
yield
(%)a
entry
(min)
1
2
3
4
5
6
7
8
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.5
1.5
1.5
1.5
1.5
TsOH H2O (1.2)
rt
rt
rt
rt
rt
rt
rt
ꢀ20
ꢀ60
ꢀ78
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
ꢀ90
20
10
120
5
5
10
1
5
5
5
5
5
5
120
5
5
11
79
0
3
MsOH (1.2)
TMSCl (1.2)
FeCl3 (1.2)
Sc(OTf)3 (1.2)
Cu(OTf)2 (1.2)
0
52
47
90
92
80
97
99
90
94
16
60
88
97
BF3 OEt2 (1.2)
3
3
3
BF3 OEt2 (1.2)
9
BF3 OEt2 (1.2)
10
11
12
13
14
15
16b
17c
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.05)
TMSOTf (0.2)
TBSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.2)
5
a Isolation yield. b Performed in toluene. c High dilution conditions
(0.005 M).
Tosylic acid gave a desired triazole 2a, but the Meyerꢀ
Schuster rearrangement product was major probably
due to its solubility and the presence of water of hydrates
(entry 1).12b,17,18 On the other hand, mesylic acid could
produce 2a in 10 min in good yield (entry 2). Although the
conditions are effective at rt, further investigations on
reagents were continued to improve the reaction speed
and availability under low temperatures. Trimethylsilyl
chloride (TMSCl) and ferric chloride only afforded a
MeyerꢀSchuster rearrangement ketone (entries 3ꢀ4).18
Scandium triflate and copper triflate worked to yield 2a
in moderate yield (entries 5ꢀ6), and a boron trifluoride
ether complex worked well resulting in an excellent yield
(entry 7). This reagent could complete the reaction in 1 min
and was powerful enough to perform the reaction at ꢀ60 °C
(entries 8ꢀ9). Further cooling conditions were achieved with
a Isolation yield. b 2.1 equiv of TMSOTf was used. c Along with 7% of deTBS
triazole. d Performed at ꢀ60 °C. e 10 min reaction. f 2.5 equiv of TMSOTf.
TMSOTf, and the desired transformation was successfully
demonstrated even at ꢀ90 °C, close to the melting point of
the solvent (entries 10ꢀ11). It should be noted that these
reaction conditions could afford 2a in almost quantitative
yield in only 5 min at ꢀ90 °C. Reducing the equivalence of
benzyl azide and an acid reagent could also give similar
results (entries 12ꢀ13). Unfortunately, catalytic conditions
were ineffective probably due to the basicity of the resulting
triazoles (entry 14). The use of TBSOTf also worked, but not
as well as TMSOTf (entry 15). Instead of dichloromethane,
toluene could work as an efficient solvent (entry 16). It is
noteworthy that high dilution conditions did not reduce
the efficiency of the reaction (entry 17). TfOH, MgBr2,
Ti(OiPr)4, TiCl4, or Yb(OTf)3 was not effective.
(14) (a) Naredla, R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905–
6948. (b) Bauer, E. B. Synthesis 2012, 44, 1131–1151. (c) Egi, M.; Kawai,
T.; Umemura, M.; Akai, S. J. Org. Chem. 2012, 77, 7092–7097. (d)
Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–438.
(15) Pearson, W. H.; Fang, W.-k. J. Org. Chem. 1995, 60, 4960–4961.
(16) (a) Yan, W.; Ye, X.; Weise, K.; Petersen, J.; Shi, X. Chem.
Commun. 2012, 48, 3521–3523. (b) Yin, G.; Zhu, Y.; Zhang, L.; Lu, P.;
Wang, Y. Org. Lett. 2011, 13, 940–943. (c) Ishikawa, T.; Okano, M.;
Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635–4642. (d) Grecian, S.;
With optimal conditions determined, our focus was
directed toward studying the substrates (Scheme 2), and
the reaction temperature was set to ꢀ90 °C. From inves-
tigating the substituents on alcohols R1 and R2, electron-
deficient aryl 2b was found to be effective as a phenyl
ꢀ
Desai, P.; Mossman, C.; Poutsma, J. L.; Aube, J. J. Org. Chem. 2007, 72,
9439–9447.
(17) TsOH H2O worked enough in the intramolecular reactions.
3
(18) Associated MeyerꢀSchuster reaction products were obtained as
an inseparable mixture with unidentified byproducts. Thus, we did not
isolate them to calculate yields.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Three-Component Coupling Reactions
Scheme 4. Intramolecular Reaction
To develop the efficiency of our method, we conducted
various types of three-component coupling reactions
(Scheme 3). Double [3 þ 2] reaction with dialkyne 5
furnished 6a under condition A, and the reagent control
(condition B) could also smoothly produce 6b, a sequen-
tially coupled product. Not only a hydroxy group but also
other fuctional groups could be introduced by changing
quenching methods. These were actually demonstrated to
yield 7aꢀd by the addition of trapping reagents.23 The
successive propargylation and azidation can also provide
new junctures with other molecules through AAC reac-
tions. With diethylamine and indole, a tertiary amine and
quaternary carbon center was successfully constructed in
one pot. Since the use of TMSOTf slightly increased the
yield of 2a, the resulting silanols or triflates would also be
hydroxy group sources.
The presence of the envisaged allenylaminodiazonium
intermediates was suggested by the intramolecular reaction
in Scheme 4.17 2-Methoxyphenyl secondary alcohol 8 was
transformed to bicyclic triazole 9 and benzofuranylpyrroline
10. Since 10 was not obtained from 9, 10 would be generated
from 100 through umpolung cyclization of an allenamine
derivative24 followed by demethylation of the oxonium ion.
In conclusion, we have developed regioselective rapid
azideꢀalkyne cycloaddition to produce fully substituted
1H-1,2,3-triazoles. Use of propargyl cations derived from
corresponding alcohols by acids or silylation reagents produced
triazoles within 5ꢀ10 min through regioselective azidations.
The cycloaddition reactions were performable not only at
room temperature but also at ꢀ90 °C. Various types of
three-component coupling reactions were demonstrated, and
the presence of allenylaminodiazonium intermediates was in-
dicated. Our method can provide an extension of the prepara-
tion of triazoles and their uses in synthetic organic chemistry.
group, despite electron-donative aryl 2c in low yield.
Methylphenyl alcohol 1d gave 2d0 in moderate yield as a
dehydrated product. In the case of benzyl alcohol 1e,
aldehyde 2e0 was obtained probably through [3 þ 2]
followed by Schmidt reactionꢀhydrolysis.14 Diethyl 1f
did not afford products 2f in the intermolecular reactions,
and fluorenyl alcohol 1g was labile under acid conditions.
Upon further research of R3, we found that despite con-
jugated alkyne 1i and propargyl acetate 1m resulted in fair
yields, secondary alkyl 1h, alkoxy methyl 1kꢀl, and methoxy-
carbonyl 1n afforded triazoles in good to excellent yields.
Interestingly, terminal alkyne 1j was also acceptable in giving
disubstituted triazole 2j, and the propargylic alkyne was
selectively reacted in the case of 1p.19 Even sterically bulky
compound 1q could give [3 þ 2] product 2q immediately. In the
case of trityl compound 3 (eq 2), triazolation followed by the
FriedelꢀCrafts reaction occurred to give tricyclic product 4.20
From screening R4 in organic azides, it was revealed that
although electrophilic azide and conjugated azide did not
produce products, primary and tertiary azides afforded
trisubstituted triazoles 2rꢀs, and 2w. In contrast to unreac-
tive phenyl azide, sterically hindered 2,6-diisopropylpheny-
lazide successfully gave desired 2v due to the stronger
nucleophilicity of its azide moiety than phenylazide as re-
ported by Hosoya et al.21 It should be noted that all triazoles
were obtained as single isomers even in the case of ester 2o.22
(19) (a) Doak, B. C.; Scanlon, M. J.; Simpson, J. S. Org. Lett. 2011,
13, 537–539. (b) Luu, T.; McDonald, R.; Tykwinski, R. R. Org. Lett.
2006, 8, 6035–6038.
(20) (a) Although excess use of TMSOTf could afford 4 at ꢀ90 °C in
99% yield, the consumption of starting material was irreproducible. (b)
Triazolylalkanol by [3 þ 2] (no FriedelꢀCrafts reaction) was not observed.
(21) Yoshida, S.; Shiraishi, A.; Kanno, K.; Matsushita, T.; Johmoto,
K.; Uekusa, H.; Hosoya, T. Sci. Rep. 2011, 1, 82.
Acknowledgment. We acknowledge the research sup-
port fellowship of NAIST for H.Z. We also thank
Ms. Mika Yamamura, Ms. Yuriko Nishiyama, Ms.Yoshiko
Nishikawa (HRMS measurement), and Mr. Shohei Katao
(X-ray crystallographic analysis) of NAIST.
(22) The regiochemistry of the resulting triazoles were determined by
NOEs and/or X-ray crystallographic analyses. CIF files of triazoles 2b,
2h, 2j, 2q, 2s, 4, and 7d (CCDC 950501ꢀ950506 and 956342) are
available free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information Available. Reaction procedures,
preparations, and analytical data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Conversions of 2a to 7aꢀd were not observed under the same
conditions.
(24) Gronnier, C.; Kramer, S.; Odabachian, Y.; Gagosz, F. J. Am.
Chem. Soc. 2012, 134, 828–831.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX