Amino acid-catalyzed cascade [3+2]-cycloaddition/hydrolysis reactions based on the push-pull dienamine platform: Synthesis of highly functionalized NH-1,2,3-triazoles

Article abstract of DOI:10.1002/chem.200801325

The synthesis of NH-1,2,3-triazole products from simple starting materials through [3+2]-CA/H reactions under amino acid catalysis was investigated. The coupling of an organic azide with in situ generated push-pull dienamines led to protected 1.2.3-triazoles. Protected 1,2,3-triazoles were obtained under the standard reaction conditions. The amine or amino acid catalyzed cascade reaction was also investigated after successful demonstration of cascade EA/E and [3+2]-CA/H. A series of substituted Hagemann's esters were reacted with 0.5 equivalents of azides catalyzed by 20 mol% at 25°C in DMSO. It was observed that the cascade reactions proceeds in good yields with high selectivity using proline as the catalyst.

Full text of DOI:10.1002/chem.200801325

COMMUNICATION
DOI: 10.1002/chem.200801325
Amino Acid-Catalyzed Cascade [3+2]-Cycloaddition/Hydrolysis Reactions
Based on the Push–Pull Dienamine Platform: Synthesis of Highly
A
Functionalized NH-1,2,3-Triazoles
Dhevalapally B. Ramachary,* Kinthada Ramakumar, and Vidadala V. Narayana[a]
1,2,3-Triazoles are an important class of heterocycles,
which display very large spectrum of biological activities
and are widely used as pharmaceuticals and agrochemicals.[1]
Compounds containing 1,2,3-triazoles have also found indus-
trial applications as corrosion inhibitors, lubricants, dyes,
and photostabilizers.[1] As such, the development of new and
more general methods for their preparation is of significant
interest.[2] The conventional method to triazoles is the Huis-
gen 1,3-dipolar cycloaddition of alkynes with azides. Recent
discovery of the novel technology of CuI-catalyzed [3+2]-
cycloaddition reactions of terminal alkynes with organic
azides provided a general route to a variety of 1,4-disubsti-
tuted 1,2,3-triazoles in good yields, and it has become a
paradigm of a “click chemistry” reaction.[3] The advent of
click reaction technology triggered a burst of activity in the
synthesis of a huge variety of differently substituted 1,2,3-tri-
azoles as in vitro and in vivo conditions.[4]
Recently, the copper-catalyzed azide–alkyne click reaction
has proven extremely valuable for attaching small molecular
probes to various biomolecules in a test tube or on immobi-
lized cells.[5] However, its use in the labeling of biomolecule
in living cells or organisms is not feasible because the reac-
tion conditions require a cytotoxic copper catalyst.[5]
As part of our program to engineer direct organocatalytic
cascade reactions,[6] herein we have report the discovery of a
copper-free, novel and green technology for the synthesis of
highly substituted a-diazo compounds and NH-1,2,3-tria-
zoles using organocatalytic cascade enamine amination/elim-
ination (EA/E) and [3+2]-cycloaddition/hydrolysis ([3+2]-
CA/H) reactions from commercially available activated
enones, azides and amines/amino acid [Eq. (1)]. In this com-
munication, we report to the best of knowledge for the first
time an organocatalytic approach for the synthesis of NH-
1,2,3-triazole products.
Over the last few years, we have been interested in
amine-mediated in situ generation and application of novel
push–pull dienamines/push–pull dienols [A and B, see
Eq. (2)] in cascade reactions from Hagemannꢀs esters with
À
nitrogen-containing species for the formation of C N
bonds.[7] During our search for new coupling species for
such processes, we decided to explore the potential ability
of organic azides to participate in an amine/amino acid-cata-
lyzed coupling reaction. We expected that the coupling of
an organic azide with in situ generated push–pull dien-
amines would lead to protected 1,2,3-triazoles. However,
protected 1,2,3-triazoles were not detected, but instead NH-
1,2,3-triazoles were obtained under the standard reaction
conditions. This unexpected result of the cascade reaction
represents a novel methodology for the preparation of NH-
1,2,3-triazoles and a new reactivity for amino acid catalysts.
Herein, we report our findings regarding these new amino
acid-catalyzed cascade reactions.
[a] Prof. Dr. D. B. Ramachary, K. Ramakumar, V. V. Narayana
School of Chemistry
University of Hyderabad
Hyderabad-500046 (India)
Fax : (+91)40-23012460
E-mail: ramsc@uohyd.ernet.in
We initiated our preliminary studies of the cascade EA/E
or [3+2]-CA/H reactions by screening a number of both
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801325.
Chem. Eur. J. 2008, 14, 9143 – 9147
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9143

Table 1. Preliminary study for the reaction optimization.[a]
known and new organocatalysts for the amination of Hage-
mannꢀs ester 1a by 0.5 to 1.0 equivalents of p-toluenesulfon-
yl azide (TsN3) 2a; some representative results are shown in
Table 1. Interestingly, reaction of 1a with 1.0 equiv of 2a in
DMSO under 20 mol% of glycine (3a) catalysis furnished
the cascade [3+2]-CA/H product NH-1,2,3-triazole 6aa as
single product with only 25% yield (Table 1, entry 1). The
same reaction with 20 mol% of l-proline (3b) catalysis also
furnished the NH-1,2,3-triazole 6aa as single product with
55% yield (Table 1, entry 2). Interestingly, reaction of 1a
with 1.0 equiv of 2a under diamine 3c catalysis generated
the cascade EA/E diazo-product 4aa with 83% yield in
DMSO and there are no products from the cascade [3+2]-
CA/H sequence (Table 1, entry 3). Secondary amines such
as piperidine (3d), morpholine (3e), and pyrrolidine (3 f)
catalysts also furnished the cascade EA/E diazo-product 4aa
with good yields in DMSO solvent (entries 4, 5 and 6). Pri-
mary amine, benzylamine (3g) also catalyzed the formation
of cascade diazo-product 4aa in very good yield (entries 7–
9). Benzylamine-catalyzed cascade EA/E reactions are sol-
vent-dependent reactions, which work well in aprotic polar
solvents, such as DMSO, DMF and NMP: only <15% con-
version is observed in other solvents, such as EtOH,
CH3CN, CHCl3, THF, H2O and [bmim]BF4 (Table 1, en-
tries 11–12). Addition of 20 mol% of simple tertiary amines,
such as Et3N (3h), Me2NCH2CH2OH (3i), DBU (3j),
DABCO (3k) and DMAP (3l) as the catalyst in DMSO at
258Cfor 1.5 h furnished the cascade EA/E diazo-product
4aa as single compound in 65–77% yields as shown in
Table 1, entries 13–17. We envisioned the optimized condi-
tion to be 258Cin DMSO under 20–40 mol% benzylamine
(3g) catalysis to furnish the highly substituted diazo-product
4aa in 83–90% yield (Table 1, entries 7–9).
Entry
Catalyst 3
[20 mol%]
t[h]
Yield[%][b]
A
4aa
5aa
6aa
1
2
3
4
5
6
7
glycine (3a)
proline (3b)
diamine (3c)[c]
piperidine (3d)
morpholine (3e)
pyrrolidine (3 f)
benzylamine (3g)
3g
3g
3g
3g
3g
Et3N (3h)
Me2NCH2CH2OH (3i)
DBU (3j)
DABCO (3k)
DMAP (3l)
96
24
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
25
55
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.75
0.75
0.75
1.0
0.75
0.75
0.70
0.75
0.75
0.75
1.5
83
83
73
67
83
85
90
80
70
80
65
71
58
77
67
8[d]
9[e]
10[f]
11[g]
12[h]
13
14
15
16
17
1.5
1.5
1.5
1.5
[a] Reactions were carried out in solvent (0.3m) with 1.0 equiv of 1a rela-
tive to the 2a in the presence of 20 mol% of catalyst 3. Ts=p-toluenesul-
fonyl; [b] Yield refers to the column-purified product. [c] (S)-1-(2-Pyrro-
lidinylmethyl)pyrrolidine (3c). [d] 30 mol% of 3g was used. [e] 40 mol%
of 3g was used. [f] 2.0 equiv of 1a was used. [g] DMF used as solvent. [h]
NMP used as solvent.
Table 2. Reaction optimization for the NH-1,2,3-triazole synthesis.
Reaction of 1a with 2a under amino acid 3b catalysis fur-
nished the interesting [3+2]-CA/H cascade product 6aa as
single product (Table 1, entry 2). To improve the reaction
yield, we screened a number of reaction conditions for the
coupling of Hagemannꢀs ester 1a by 0.5 to 1.0 equiv of 2a
under 3b catalysis; some representative results are shown in
Table 2. Reaction of 1a with 1.0 equiv 2a in EtOH under
20 mol% 3b catalysis furnished 6aa as single product with
only 30% yield (Table 2, entry 1). Interestingly, same reac-
tion in MeOH furnished the unhydrolyzed 1,2,3-triazole 5aa
as single product with 35% yield (Table 2, entry 2). Reac-
tion of 1a with 1.0 equiv of 2a under 3b catalysis in DMSO
at 708Cfor 5 h furnished 6aa in 65% yield (Table 2,
entry 4). Increasing the catalyst 3b loading from 20 to
50 mol% or substrate 1a loading from 1.0 to 2.0 equiv, yield
of cascade product 6aa increased drastically from 55 to 90/
94% at 258Cfor 24 h in DMSO solvent as shown in Table 2,
entries 5–6 and 10–11. Interestingly, amino acid catalyzed
cascade [3+2]-CA/H reactions are also solvent dependent
reactions and performed well in aprotic polar solvents such
as DMSO, DMF and NMP; only <15% conversion is ob-
served in other solvents such as CH3CN, CHCl3, THF, H2O
and c-C6H12 (Table 2, entries 7–9). Cascade reaction of 1a
with 2a under 3b catalysis in DMF at 258Cfor 24 h fur-
Entry
0.5m
Solvent
Ester 1a
[equiv]
T [8C]
t [h]
Yield [%][a]
G
5aa
6aa
1
2
3
4
EtOH
MeOH
DMSO
DMSO
DMSO
DMSO
DMF
NMP
NMP
DMSO
DMSO
DMSO
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
0.5
25
25
25
70
25
25
25
25
25
25
80
80
120
120
24
5
24
24
24
24
19
24
5
–
30
-
35
–
55
65
76
90
10
10
10
94
91
75
–
–
–
5[b]
6[c]
7
55
60
70
–
8
9
10
11
12
–
–
5
[a] Yield refers to the column purified product. [b] Proline 3b was used
as 40 mol%. [c] Proline 3b was used as 50 mol%.
nished the unhydrolyzed 1,2,3-triazole 5aa in 55% yield ac-
companying with product 6aa in 10% yield as shown in
Table 2, entry 7. Same cascade reaction in NMP as solvent
furnished the products 5aa and 6aa in 60 and 10% yield, re-
spectively (Table 2, entry 8). We envisioned the optimized
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Chem. Eur. J. 2008, 14, 9143 – 9147

Highly Functionalized Triazoles
COMMUNICATION
conditions to be addition of 2.0 equiv of 1a to 2a under
20 mol% 3b catalysis in DMSO or NMP at 258Cfor 24 h to
furnish the cascade products 6aa and 5aa in 94 and 70%
yield, respectively (Table 2, entry 9 and 10). Structure and
regiochemistry of 4-methyl-1-(toluene-4-sulfonyl)-6,7-dihy-
dro-1H-benzotriazole-5-carboxylic acid ethyl ester (5aa) and
zoles 5ka, la and ma in 50, 70 and 65% yield, respectively,
as shown in Table 3, entries 11–13. But unfortunately we are
not observed the enantioselectivity in the 3b-mediated cas-
cade reaction of 6-substituted Hagemannꢀs esters 1 with 2a.
Fascinatingly, reaction of 3,4-dihydro-1H-naphthalen-2-one
(1n) with azides 2a or 2b at 258Cfor 1 h in DMSO under
amino acid catalysis furnished the expected 1,2,3-triazoles
5na/5nb in combination with 6na/6nb in almost quantitative
yields with excellent regioselectivity as shown in Table 3.
Regiochemistry of cascade products 5na–nb/6na–nb was
4-methyl-6,7-dihydro-1H-benzotriazole-5-carboxylic
acid
ethyl ester (6aa) was also confirmed by X-ray structure
analysis as shown in Figures S1 and S2 (see Supporting In-
formation).[8]
After successful demonstra-
tion of cascade EA/E and [3+
Table 3. Chemically diverse libraries of NH-1,2,3-triazoles 6.
2]-CA/H reactions from 1a
with 2a under amine or amino
acid-catalysis, we also investi-
gated the amine or amino acid
catalyzed cascade reaction of
1a with the other azides such
MsN3 (2b), N3CO2Et (2c), 4-
NO2C6H4SO2N3 (pNBSA) (2d),
Entry
1
Product
Yield [%][a]
Entry
8
Product
Yield [%][a]
2-NO2C6H4SO2N3
(oNBSA)
(2e), BnN3 (2 f) and TMSN3
(2g), but the diazotization or
NH-1,2,3-triazole formation of
the 1a was inferior compared
to 2a as shown in Table S1, en-
tries 1–7 (see Supporting Infor-
mation).
With the optimized reaction
conditions in hand, the scope of
the amino acid- and amine-cat-
alyzed [3+2]-CA/H and EA/E
cascade reactions was investi-
gated. A series of substituted
Hagemannꢀs esters 1a–m was
reacted with 0.5 equivalents of
azides 2a–b catalyzed by
20 mol% of 3b at 258Cin
DMSO (Table 3). Both aliphat-
ic and aromatic substituted Ha-
94
70
2
3
90
90
9
65
55
10
4
5
6
65
75
80
11
12
13
50
70
65
gemannꢀs esters
1 were fur-
nished the expected NH-1,2,3-
triazoles 6 with excellent yields
(Table 3). Yields of the cascade
[3+2]-CA/H products 6 were
increased by the prolonging re-
actions time up to 24 h and also
water content of the DMSO
solvent. These are ideal exam-
ples for the biomimetic solvent
induced cascade chemistry in
organic reactions. For example,
proline-mediated reaction of
simple Hagemannꢀs esters 1k, l
and m with 2a in DMSO at
258Cfor 1 h furnished the ex-
14[b]
80
80
7
70
15[b,c]
[a] Yield refers to the column-purified product. For the entries 1–10, reaction time is 12–24 h and for the en-
tries 11–15, time is 0.75–1.0 h. [b] In both reactions, 15–20% of corresponding hydrolyzed NH-1,2,3-triazole
pected unhydrolyzed 1,2,3-tria- 6na/6nb were isolated. [c] 2b was used instead of 2a.
Chem. Eur. J. 2008, 14, 9143 – 9147
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9145

D. B. Ramachary et al.
confirmed by NMR analysis and also finally confirmed by
X-ray structure analysis on 5na (see Figure S3, Supporting
Information).[8] Cascade products 5na/6na would be very in-
teresting model analogues for the studies of inhibitors of
hMetAP2 as shown in Equation (2).
We also generated the highly functionalized diversity ori-
ented library of cascade EA/E products 4 under primary
amine catalysis. The results in Table 4 demonstrate the
broad scope of this novel green methodology covering a
structurally diverse group of Hagemannꢀs esters 1a–g and
2a generally with very good yields compared with tertiary
amine catalysis. Cascade EA/E reaction of Hagemannꢀs
esters 1a–g, 2a under 3g catalysis furnished diazo products
4aa–4ga in good yields (Table 4). Structure and regiochem-
istry of cascade EA/E products 4 was also confirmed by X-
ray structure analysis on 4ba (Figure S4, see Supporting In-
formation).[8]
amino acid 3b with Hagemannꢀs ester 1a generates the
push–pull dienamine 14,[7b] which on treatment with 2a fur-
nish the selectively 7a-(2-carboxy-pyrrolidin-1-yl)-4-methyl-
1-(toluene-4-sulfonyl)-3a,6,7,7a-tetrahydro-1H-benzotria-
zole-5-carboxylic acid ethyl ester (16) via concerted [3+2]-
cycloaddition, which may transform into product 5aa
through rapid elimination of 3b. Possible weak interactions
from acid group in transition state 15 will be the driving
force to undergo concerted [3+2]-cycloaddition compare to
8/11 transition states. The solvent (DMSO) induced in situ
hydrolysis of resulting 1,2,3-triazole 5aa gives to the NH-
1,2,3-triazole 6aa in good yields as shown in Scheme 1. This
in situ hydrolysis step is totally influenced by the water con-
tent of the DMSO solvent and not in the workup stage.
In summary, we have first time developed the synthesis of
NH-1,2,3-triazole products 5 and 6 from simple starting ma-
terials via [3+2]-CA/H reactions under amino acid catalysis.
The cascade reaction proceeds in good yields with high se-
lectivity using proline as the catalyst. Furthermore, we have
The possible reaction mechanism for the synthesis of cas-
cade products 4, 5 and 6 through reaction of Hagemannꢀs
ester 1a, 2a and amine/amino
acid 3 is illustrated in Scheme 1.
Table 4. Chemically diverse libraries of diazo-products 4.[a]
The reaction mechanism can be
divided into three categories (I,
II and III) as catalyzed by three
different amines as shown in
Scheme 1. In the first category
(I), reaction of tertiary amines
with Hagemannꢀs ester 1a gen-
erates the push–pull dienol 7
based on reaction conditions.[7b]
Reaction of push–pull dienol 7
with 2a furnish the selectively
amination product 9, which will
give product 10 via keto–enol
tautomerism by treatment with
basic amine. Rearrangement
followed by elimination of tolu-
ene-4-sulfonamide of 10 con-
verted into highly substituted
diazo-product 4aa. In the
second category (II), reaction
of primary amine 3g with Ha-
gemannꢀs ester 1a generates
the push–pull dienamine 11,[7b]
which on treatment with 2a
furnish the selectively amina-
tion product 12, which will
transform into product 13 via
imine–enamine tautomerism by
treatment with basic amine.
Rearrangement followed by
elimination of toluene-4-sulfo-
namide of 13 and hydrolysis of
resulting imine gives to the
highly substituted diazo-prod-
uct 4aa. In the third category
90% (4aa)
80% (4ba)
65% (4ca)
50% (4da)
50% (4 fa)
70% (4ga)
[a] Yield refers to the column-purified product.
(III), reaction of secondary Scheme 1. Proposed reaction mechanism.
9146
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Highly Functionalized Triazoles
COMMUNICATION
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demonstrated the bio-mimetic solvent induced hydrolysis in
amino acid-catalyzed cascade reactions. Further work is in
progress to develop asymmetric version of cascade [3+2]-
CA/H reactions.
Experimental Section
Experimental procedures, characterization data for new products, and
complete details about the synthesis of new products are available in the
Supporting Information.
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Acknowledgements
This study was supported by the Department of Science and Technology
(DST), New Delhi. K.R.K. and V.V.N. thank Council of Scientific and In-
dustrial Research (CSIR), New Delhi for their research fellowships. We
thank Dr. P. Raghavaiah for X-ray structural analysis.
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Keywords: cascade
organocatalysis · push–pull dienamine · triazoles
reactions
·
cycloaddition
·
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[8] CCDC 689189 (5aa), 689190 (6aa), 690284 (5na) and 689188 (4ba)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: July 1, 2008
Published online: September 2, 2008
Chem. Eur. J. 2008, 14, 9143 – 9147
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9147