An organocatalytic azide-aldehyde [3+2] cycloaddition: High-yielding regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/anie.201406721

An organocatalytic azide-aldehyde [3+2] cycloaddition (organo-click) reaction of a variety of enolizable aldehydes is reported. The organo-click reaction is characterized by a high rate and regioselectivity, mild reaction conditions, easily available subs

Full text of DOI:10.1002/anie.201406721

Angewandte
Chemie
DOI: 10.1002/anie.201406721
1,2,3-Triazoles
An Organocatalytic Azide–Aldehyde [3+2] Cycloaddition: High-
Yielding Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles**
Dhevalapally B. Ramachary,* Adluri B. Shashank, and S. Karthik
Abstract: An organocatalytic azide–aldehyde [3+2] cyclo-
addition (organo-click) reaction of a variety of enolizable
aldehydes is reported. The organo-click reaction is character-
ized by a high rate and regioselectivity, mild reaction
conditions, easily available substrates with simple operation,
and excellent yields with a broad spectrum of substrates. It
constitutes an alternative to the previously known CuAAC,
Figure 1. Potential applications based on the 1,2,3-triazoles.
RuAAC, and IrAAC click reactions.
1,4-Disubstituted 1,2,3-triazoles have emerged as an
important class of organic compounds, displaying a vast
spectrum of properties and are widely used as pharmaceut-
icals.[1] Many 1,2,3-triazoles have found medicinal applica-
tions, such as HIV protease inhibitors, anticancer drugs,
antituberculosis drugs, antifungal agents, antibacterial drugs,
histone deacetylase inhibitors, and bioorthogonal probes, and
are also used as corrosion inhibitors, lubricants, dyes, and
photostabilizers (Figure 1).[1] Thus, the development of green
methods for the preparation of these compounds is of
significant interest.[2]
The regioselective formation of 1,4- and 1,5-disubstituted
1,2,3-triazoles can be accomplished by copper-catalyzed
azide-alkyne [3+2] cycloaddition (CuAAC) reactions
[Eq. (a), Scheme 1],[3] and ruthenium-catalyzed azide-alkyne
[3+2] cycloaddition (RuAAC) reactions, respectively.[4]
Recently, a strain-promoted [3+2] cycloaddition reaction of
substituted cyclooctyne with aryl azides was reported to
furnish 1,4,5-trisubstituted 1,2,3-triazoles [Eq. (b), Scheme 1],
which have become good bioorthogonal probes.[5] Very
Scheme 1. Background and design of the enolate-mediated organo-
catalytic azide–aldehyde [3+2] cycloaddition reaction.
recently, an enamine-mediated amino acid or amine catalyzed
[3+2] cycloaddition reaction of different carbonyl compounds
(enones, b-keto esters, ketones, and enals) with aryl azides
was reported to furnish 1,4,5-trisubstituted 1,2,3-triazoles in
good yields [Eq. (c), Scheme 1].[6]
CuAAC only gave 1,4-disubstituted 1,2,3-triazoles, and the
remaining two methods gave 1,4,5-trisubstituted 1,2,3-tria-
zoles. Even though the CuAAC reaction has become a para-
digm of the “click reaction”, its use for the labeling of
biomolecules in live cells is prohibited because of the
cytotoxicity of the copper catalyst.[3d,5a–c] Alkynes used in
CuAAC or RuAAC click reactions are more expensive than
the corresponding aldehydes. For example, the price of
phenylacetylene is $76 for 100 mL, whereas that of phenyl-
acetaldehyde is only $33 for 100 mL. These obstacles inspired
us to develop a novel green method for the high-yielding
regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles
based upon enolate-mediated organocatalytic azide–alde-
hyde [3+2] cycloaddition (organo-click) reaction from com-
mercially available enolizable aldehydes, aryl azides, and
a catalytic amount of a tertiary amine [Eq. (d), Scheme 1].
Although simple enolizable aldehydes and active methylenes
In all the above three methods, the authors either used
expensive or not commercially available alkynes, or less
reactive carbonyl compounds other than simple aldehydes as
the starting materials along with aryl azides. Furthermore,
[*] Prof. Dr. D. B. Ramachary, A. B. Shashank, S. Karthik
Catalysis Laboratory, School of Chemistry, University of Hyderabad
Hyderabad-500 046 (India)
E-mail: ramsc@uohyd.ernet.in
ramchary.db@gmail.com
Homepage: http://chemistry.uohyd.ernet.in/~dbr/
[**] We thank DST (New Delhi) for financial support. A.B.S. and S.K.
thank CSIR (New Delhi) and UGC (New Delhi) for their senior
research fellowships, respectively.
Supporting information for this article (including experimental
procedures and analytical data for all new compounds) is available
on the WWW under http://dx.doi.org/10.1002/anie.201406721.
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were previously used in reactions with aryl azides to furnish
1,2,3-triazoles through the formation of enolates or enamines
with strong bases/amines, further development is required
because the known protocols require an excess amount of
amine/base and harsh reaction conditions.[7] Herein, we
present the organocatalytic enolate-mediated synthesis of
1,2,3-triazoles from aldehydes and aryl azides.
using 1.0 equiv of 2a was not so successful in promoting the
high-yielding organo-click reaction (Table 1, entries 5, 6, and
7). These results clearly support our hypothesis of the
formation of reactive enolates. The use of less basic tertiary
amines, such as DABCO (3e), DMAP (3 f), and Et3N (3g),
resulted in the formation of 1,2,3-triazole 4aa with moderate
yields compared to the use of 3d (Table 1, entries 8 to 10), and
no reaction was observed without the catalyst in DMSO for
24 h at 258C (Table 1, entry 13). The same reaction catalyzed
by 10 mol% of non-amine bases K2CO3 and tBuOK also
furnished the 1,2,3-triazole 4aa in moderate to good yields
(Table 1, entries 11,12). The DBU-promoted organo-click
reaction is dependent on the solvent, as it works well in
aprotic polar solvents such as DMSO and DMF, but in other
solvents, such as EtOH and H2O, less than 5% of the product
is formed (results not shown in the Table). The optimized
conditions for the reaction comprise the catalysis by 10 mol%
of 3d at 258C in DMSO to furnish the single 1,2,3-triazole 4aa
in 95% yield from 1a and 2a (Table 1, entry 4).
With the optimized conditions in hand, the scope and
generality of the DBU-catalyzed organo-click reactions were
investigated. A variety of functionalized azides 2b–r were
reacted with 1a for 0.5 h (Table 2). Interestingly, aryl azides
2b—o, which contain functional groups, such as NO2, CO2Et,
CN, CF3, CHO, halogen, alkyl, and OMe, at different
positions of the aromatic ring, furnished the expected 1,2,3-
triazoles 4ab–ao in excellent to good yields within 0.5 h
(Table 2). The yields of products 4ab–ao were dependent on
the substituent at the para position of 2, increasing with
electron-withdrawing groups, and slightly decreasing with
We initiated our preliminary optimization of the organo-
click reaction by screening a number of known simple
organocatalysts for the click reaction of phenylacetaldehyde
(1a) with 1.0 to 1.5 equiv of phenyl azide (2a) (Table 1).
Interestingly, the reaction of 1a with 1.5 equiv of 2a in DMSO
catalyzed by 10 mol% of proline (3a) furnished the product
4aa as a single regioisomer in moderate yield (53%; Table 1,
entry 1). The same reaction catalyzed by 10 mol% of diethyl
amine (3b) or pyrrolidine (3c) did not furnish the 1,2,3-
triazole 4aa, but 1a is consumed completely (Table 1,
entries 2 and 3). After obtaining discouraging results for the
enamine-mediated reaction with catalysts 3a–c, we inves-
tigated the reaction via enolates, which were formed in situ
with tertiary amines 3d–g. Intriguingly, the reaction of 1a with
1.5 equiv of 2a in DMSO catalyzed by 10 mol% of DBU (3d)
at 258C for 0.5 h furnished 4aa in 95% yield (Table 1,
entry 4). Deviations from these reaction conditions by switch-
ing the solvent to DMF, using 5 mol% of 3d as the catalyst, or
Table 1: Optimization of reaction conditions.[a]
Table 2: Azide substrate scope.[a]
Entry
Catalyst
Catalyst
t
[h]
Yield
pKa[b]
4aa [%][c]
1
3a (10 mol%)
3b (10 mol%)
3c (10 mol%)
3d (10 mol%)
3d (10 mol%)
3d (5 mol%)
3d (10 mol%)
3e (10 mol%)
3 f (10 mol%)
3g (10 mol%)
K2CO3 3h (10 mol%)
tBuOK 3i (10 mol%)
–
10.64
10.84
11.31
12
12
12
12
8.8
9.2
10.75
10.33
29.4
–
24
53
–
–
2[d]
3[d]
4
0.5
0.5
0.5
0.5
0.5
0.5
24
24
10
0.5
0.5
24
Entry
Substrate 2
Yield (4) [%][b]
95
70
70
75
45
40
45
65
87
–
5[e]
6
1
2
3
4
5
6
7
8
2b (FG=2-NO2)
2c (FG=4-NO2)
2d (FG=4-CO2Et)
2e (FG=4-CN)
2 f (FG=4-CF3)
2g (FG=3-CHO)
2h (FG=4-F)
2i (FG=4-Cl)
2j (FG=3-Cl)
2k (FG=4-Br)
2l (FG=2-Br)
2m (FG=4-Me)
2n (Ar=1-naphthyl)
2o (FG=4-OMe)
2o (FG=4-OMe)
2p (R=PhCH2)
2q (R=EtCO2)
2r (R=Ts)
93 (4ab)
95 (4ac)
93 (4ad)
95 (4ae)
95 (4af)
90 (4ag)
90 (4ah)
95 (4ai)
93 (4aj)
93 (4ak)
90 (4al)
85 (4am)
90 (4an)
75 (4ao)
80 (4ao)
15 (4ap)
60 (4aq)
– (4ar)
7[f]
8
9
10
11
12
13
9
10
11
12
13
14
15[c]
16[c]
17[c,d]
18
[a] Reactions were carried out in solvent (0.5m) with 1.5 equiv of 2a
relative to 1a (0.5 mmol) in the presence of 5–10 mol% of the catalyst.
[b] pKa values refer to the conjugate acid of the amine/base. [c] Yields of
products purified by column chromatography on silica gel. [d] 1a was
consumed completely. [e] DMF was used as solvent. [f] 1.0 equiv of 2a
was used relative to 1a (0.5 mmol). Entry in bold marks optimized
reaction conditions.
[a] Reactions were carried out in DMSO (0.5m) with 1.5 equiv of 2b–r
relative to 1a (0.5 mmol) in the presence of 10 mol% of 3d. [b] Yields of
products purified by column chromatography on silica gel. [c] Catalyzed
by tBuOK at RT for 1–3 h. [d] Decarboxylated 1H-1,2,3-triazole 4aq was
obtained.
2
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alkyl and electron-donating groups. For example, the DBU-
catalyzed organo-click reactions of aryl azides 2m and 2o
with 1a furnished the expected 1,2,3-triazoles 4am and 4ao in
85% and 75% yield, respectively (Table 2, entries 12 and 14).
Interestingly, the reaction of 1a with 2o catalyzed by
10 mol% of the more basic 3i furnished 4ao in a slightly
improved yield (80%, Table 2, entry 15). On the other hand,
the 3d-catalyzed organo-click reaction of 1a with alkyl, acyl,
and tosyl azides 2p–r did not furnish the expected products 4,
but the same reactions catalyzed by 3i gave 4ap in less than
15% and decarboxylated product 4aq in 60% yield, respec-
tively, while 4ar was not formed at all (Table 2, entries 16–18).
The structures of organo-click products 4ab–aq were con-
firmed by NMR and X-ray structure analysis on 4ab, as shown
in Figure S1 (see the Supporting Information).[8]
hydes 1q–x, which have less acidic a-methylene groups
compared to 2-arylacetaldehydes 1a–p (Table 4). Surpris-
ingly, the DBU-catalyzed reaction of 3-phenylpropanalde-
hyde (1q) with 2c furnished the expected 1,2,3-triazole 4qc in
95% yield (Table 4, entry 1). In a similar manner, the DBU-
catalyzed reaction of butyraldehyde (1r) with 2c furnished
the 1,2,3-triazole 4rc in 70% yield (Table 4, entry 3). We
tested six more aliphatic aldehydes 1q–w as substrates for the
organo-click reaction with 2c/2e, and obtained the expected
1,2,3-triazoles 4 in good to excellent yields (Table 4, entries 2–
Table 4: Aldehyde substrate scope: other aldehydes.[a]
After investigating the effects of the electronic factors of
substrates 2 on the [3+2] cycloaddition reaction, we next
turned our attention to the reaction scope with different 2-
arylacetaldehydes 1b–p in the organo-click reaction with
PhN3 2a (Table 3). In this reaction, 1b–p containing different
functional groups, such as NO2, halogen, alkyl, heteroaryl,
and OMe, were used as substrates in the organocatalytic
synthesis of the single isomers of 1,2,3-triazoles 4ba–pa,
which were obtained in excellent to good yields within 0.5 h
(Table 3). These results demonstrate the broad scope of this
novel methodology, covering a structurally diverse group of 2-
arylacetaldehydes 1b–p and phenyl azide 2a. Many of the
organo-click products 4 were obtained in very good yields
compared to other routes (Table S1, see the Supporting
Information).
Entry
Substrate 1 (R)
2
Yield (4) [%][b]
1
2
3
4
5
6
7
8
1q (PhCH2)
1q (PhCH2)
1r (MeCH2)
1s (MeCH2CH2)
1t (MeCH2CH2CH2)
1u (MeCH2CH2CH2CH2)
1v (CH3)
1w (H)
1x (1,3-isoindoledione)
1q (PhCH2)
2c
2e
2c
2c
2c
2c
2c
2c
2c
2a
2 f
2k
95 (4qc)
90 (4qe)
70 (4rc)
75 (4sc)
75 (4tc)
80 (4uc)
80 (4vc)
80 (4wc)
– (4xc)
9
10[c]
11[d]
12[c]
60 (4qa)
65 (4qf)
60 (4qk)
1q (PhCH2)
1q (PhCH2)
[a] Reactions were carried out in DMSO (0.5m) with 1.5 equiv of 2
relative to 1q–x (0.5 mmol) in the presence of 10 mol% of 3d. [b] Yields
of products purified by column chromatography on silica gel. [c] Cata-
lyzed by tBuOK at RT for 1 h. [d] Catalyzed by DBU at RT for 0.5 h and at
608C for 1 h.
To further understand the importance of the electronic or
acidic nature of the a-methylene group of aldehydes 1 in the
organo-click reaction, we investigated simple aliphatic alde-
Table 3: Aldehyde substrate scope: 2-arylacetaldehydes.[a]
8). Surprisingly, the reaction of 2-succinimidoacetaldehyde
(1x) with 2c catalyzed by 3d or 3i did not give the desired
product (Table 4, entry 9). The organo-click reaction of 3-
phenylpropanaldehyde (1q) with less reactive aryl azides 2a,
2 f, and 2k catalyzed by 3d or 3i at 258C for 1 h furnished the
1,2,3-triazoles 4qa–qk in 60–65% yields (Table 4, entries 10–
12). The industrial scope of this reaction was investigated by
performing the syntheses of 1,2,3-triazoles 4aa and 4ag on
a gram scale without compromising the reaction rates, yields,
and purity of the products [Eq. S1,S2, see the Supporting
Information].
The possible mechanism for the regioselective synthesis of
4 from 1 and 2 catalyzed by 3d is illustrated in Scheme 2. The
reaction of catalyst 3d (pKa = 12) with aldehyde 1 generates
enolate 5, which on in situ treatment with probably the major
contributing mesomeric structure of Ar-N3 2’ selectively
furnishes the adduct 1,2,3-triazolines 6 through a concerted
[3+2] cycloaddition or stepwise amination–cyclization reac-
tion.[7] Adduct 6 further transforms into the 1,2,3-triazole 4
through the rapid elimination of water induced by the basic
nature of 3d.
Entry
Ar-CH2CHO 1
Yield (4) [%][b]
1
2
3
4
5
6
7
8
1b (Fg=2-NO2)
1c (Fg=4-F)
1d (Fg=4-Cl)
1e (Fg=2-Cl)
1 f (Fg=4-Br)
1g (Fg=2-Br)
1h (Fg=4-Me)
1i (Fg=2-Me)
1j (Ar=2-naphthyl)
1k (Ar=1H-indol-3-yl)
1l (Ar=thiophen-2-yl)
1m (Fg=4-OMe)
1n (Fg=3-OMe)
1o (Fg=2-OMe)
1p (Fg=3,4-(OMe)2)
90 (4ba)
90 (4ca)
90 (4da)
90 (4ea)
95 (4 fa)
92 (4ga)
93 (4ha)
90 (4ia)
95 (4ja)
75 (4ka)
88 (4la)
90 (4ma)
80 (4na)
90 (4oa)
75 (4pa)
9
10
11
12
13
14
15
[a] Reactions were carried out in DMSO (0.5m) with 1.5 equiv of 2a
relative to 1b–p (0.5 mmol) in the presence of 10 mol% of 3d. [b] Yields
of products purified by column chromatography on silica gel.
In summary, we have developed the metal-free DBU-
catalyzed regioselective synthesis of 1,4-disubstituted 1,2,3-
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[3] For CuAAC click reactions, see: a) C. W. Tornøe, C. Christensen,
M. Meldal, J. Org. Chem. 2002, 67, 3057 – 3064; b) V. V. Rostovt-
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[4] For RuAAC and IrAAC click reactions, see: a) L. Zhang, X.
Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharpless, V. V.
Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127, 15998 – 15999; b) L. K.
Rasmussen, B. C. Boren, V. V. Fokin, Org. Lett. 2007, 9, 5337 –
5339; c) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H.
Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130,
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Scheme 2. Mechanism of the organo-click reaction.
triazoles 4 from the simple aldehydes 1 and aryl azides 2
through a [3+2] cycloaddition reaction. This organo-click
reaction proceeds with a high rate and selectivity within 0.5 h
at room temperature, giving the desired products in very good
yields. Further work is in progress to develop organocatalytic
enolate-mediated [3+2] cycloaddition reactions.
Received: June 30, 2014
Published online: && &&, &&&&
[5] For strain-promoted AAC reactions, see: a) N. J. Agard, J. A.
Preschner, C. R. Bertozzi, J. Am. Chem. Soc. 2004, 126, 15046 –
15047; b) N. J. Agard, J. M. Baskin, J. A. Prescher, A. Lo, C. R.
Bertozzi, ACS Chem. Biol. 2006, 1, 644 – 648; c) J. M. Baskin,
C. R. Bertozzi, QSAR Comb. Sci. 2007, 26, 1211 – 1219; d) J. A.
Johnson, J. M. Baskin, C. R. Bertozzi, J. T. Koberstein, N. J. Turro,
Chem. Commun. 2008, 3064 – 3066; e) E. M. Sletten, C. R.
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Keywords: 1,2,3-triazoles · aldehydes · azides · click chemistry ·
organocatalysis
.
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4
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[8] CCDC 1005119 (4ab) contains the supplementary crystallo-
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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Angewandte
Communications
Communications
1,2,3-Triazoles
D. B. Ramachary,* A. B. Shashank,
S. Karthik
&&&& — &&&&
Metal-free click: A variety of commercially
available aldehydes was used in the
metal-free organo-click reaction with aryl
azides to obtain 1,4-disubstituted 1,2,3-
triazoles. The method constitutes an
alternative to previously known metal-
catalyzed azide–alkyne cycloaddition
reactions (AAC), such as CuAAC, RuAAC,
and IrAAC. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene; DMSO=dimethyl
sulfoxide.
An Organocatalytic Azide–Aldehyde
[3+2] Cycloaddition: High-Yielding
Regioselective Synthesis of 1,4-
Disubstituted 1,2,3-Triazoles
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!