Efficient synthesis of fused 1,2,3-triazolo-δ-lactams using Huisgen [3 + 2] dipolar cycloaddition "click-chemistry" in water

Article abstract of DOI:10.1246/cl.2007.592

A general approach for the quick synthesis of various 1,2,3-triazolo- δ-lactams has been described, which involves the Huisgen [3 + 2] dipolar cycloaddition of azides derived from different amino acids with dimethyl acetylenedicarboxylate in water followe

Full text of DOI:10.1246/cl.2007.592

592
Chemistry Letters Vol.36, No.5 (2007)
Efficient Synthesis of Fused 1,2,3-Triazolo-ꢀ-lactams
Using Huisgen [3 + 2] Dipolar Cycloaddition ‘‘Click-chemistry’’ in Water
Indresh Kumar and Chandrashekhar V. RodeÃ
Homogeneous Catalysis Division, National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune 411008, India
(Received January 30, 2007; CL-070115; E-mail: cv.rode@ncl.res.in)
A general approach for the quick synthesis of various 1,2,3-
N
N
N
N
X
triazolo-ꢀ-lactams has been described, which involves the
Huisgen [3 + 2] dipolar cycloaddition of azides derived from
different amino acids with dimethyl acetylenedicarboxylate in
water followed by cyclization.
N
X
X
N
NPg
N
MeO2C
CO2Me
COOH
NH
CO2Me
O
N3
Small nitrogen heterocycles containing amine and amine-
derived functionality are frequently found in a wide variety of
natural and non-natural compounds of biological significance.1
1,3-Dipolar cycloaddition reaction between alkyne and azide de-
veloped by Huisgen2 is the most popular reaction because the re-
sulting five-membered substituted 1,2,3-triazole heterocyclic
ring has a wide range of industrial applications such as dyes,
photostabilizers, agrochemicals3 as well as in the designing of
new drugs.4 This cycloaddition is typically carried out at higher
temperature which usually gives a mixture of 1,4- and 1,5-sub-
stituted regioisomeric triazole products. The remarkable stability
of triazole ring to the metabolic transformations like oxidation,
reduction, both acidic and basic hydrolysis enhances its utility
as a connecting group.5 It is known that electron-withdrawing
group on alkyne moiety enhances the rate of irreversible cyclo-
addition reaction and recently termed as ‘‘click chemistry.’’6
Medium sized ring lactams are important building blocks for
the synthesis of bioactive molecules. Recently, a number of ꢀ-
lactams (piperazone) 1 have been synthesized and evaluated as
potent elastases inhibitors.7 Similarly lactum based, both mono-
cyclic and bicyclic piperazinone 2 building blocks as constrained
peptidomimetics have been synthesized.8 The synthesis of
various 1,2,3-triazolo[1,5-a]quinoxaline compounds 3 and their
binding to benzodiazepine and adenosine receptors have also
X
NPg
α-Amino-acids
Scheme 1. Reterosynthetic analysis of fused 1,2,3-triazolo-ꢀ-
lactams.
been studied.9 As a continuation of our interest in developing
different strategies based on the amino acids as a chiral starting
materials for the synthesis of bioactive compounds,10 We report
here the first general approach for the synthesis of fused 1,2,3-
triazolo-ꢀ-lactams 4 using Huisgen [3 + 2] dipolar cycloaddi-
tion reaction between activated alkyne and azides derived from
different amino acids in water as a ‘‘click-chemistry’’ reaction
followed by cyclization. The retro synthetic analysis of our strat-
egy is shown in Scheme 1. We established our methodology
starting with various commercially available amino acids. As
shown in Scheme 2, L-serine 5 was easily transformed into the
corresponding alcohol 6 following a reported procedure.11 The
amino alcohol 6 was subjected to the tosyl protection with tosyl
chloride/Et3N in dry DCM at 0 ꢀC for 4 h, followed by
nucleophilic substitution with NaN3 in 1,4-dioxane/DMSO at
CO2Me
Ref. 11
O
OH (a)
NBoc
O
N3
L-Serine
+
NBoc
Ts
5
6
7
8
CO2Me
N
O
CO2Me
O
R
N
N
N
HO
N
N
Ph
N
N
(c)
(b)
(a)
O
R
HN
NBoc
HN
N
MeO2C
CO2Me
CO2Me
O
Boc
9
10
1
2
N
N3
N
N
N
N
HN
N
N
N
R3
CO2Me
X
N
O
N
R1
11
N
O
Scheme 2. (a) (i) TsCl (1.1 equiv.), Et3N (1.2 equiv.), dry
DCM, 0 ꢀC, 4 h (ii) NaN3 (2.2 equiv.), 1,4-Dioxane/DMSO
(10:1), 65 ꢀC, 6 h, 85% in two steps. (b) Dimethyl acetylenedi-
carboxylate 8 (1.1 equiv.), H2O, 70 ꢀC, 1 h, 95% yield (c) (i)
TFA (2.5 equiv.), dry DCM, 6 h, (ii) MeOH/DMSO (5:1), reflux,
3.5 h, 78% in two steps.
CO2Me
O
R2
3
4
X= OH, N3, CH2, Ph,
CH3, CH(CH3)2
Figure 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.5 (2007)
593
N
CO2H
N
N
N
Ref. 11
OH
N
(c)
N
N3
(a)
(b)
NCbz
MeO2C
N
NH
NCbz
NCbz
CO2Me
CO2Me
O
12
13
14
15
16
N
N
N
N
CO2H
NH2
N
N
R
(c)
N3
(a)
(b)
R
OH
NHCbz
R
R
HN
R
CbzHN
NHCbz
CO2Me
MeO2C
CO2Me
O
17a, R= Ph
17b, R= CH3
17c, R= CH(CH3)2
18
19
20
21
Scheme 3. (a) (i) TsCl (1.1 equiv.), Et3N (1.2 equiv.), dry DCM, 0 ꢀC, 4 h (ii) NaN3 (2.2 equiv.), 1,4-Dioxane/DMSO (10:1), 65 ꢀC,
6 h, 87% in two steps. (b) Dimethyl acetylenedicarboxylate 8 (1.1 equiv.), H2O, 70 ꢀC, 1 h, quantitative yield (c) (i) Pd/C (10 mol %),
H2 (1 atm), MeOH, rt, 2 h (ii) reflux, 4 h, yield mentioned in the text.
65 ꢀC for 24 h to provide azido-derivative 7 with 85% yield in
two steps. Our next aim was to carry out the Huisgen [3 + 2]
dipolar cycloaddition of azido compound 7 with an activated
alkyne in water. For this purpose, a mixture of 7 and dimethyl
acetylenedicarboxylate 8 were heated in water at 70 ꢀC for 1 h
to provide cycloadduct 9 in 95% yield after passing through a
small bed of silica gel. In order to achieve the synthesis of cor-
responding fused 1,2,3-triazolo-ꢀ-lactam 10, the sequential de-
protection of N-Boc and acetonide moiety followed by cycliza-
tion were successfully carried out in a single-pot two-step proce-
dure using TFA/DCM at rt for 4 h followed by refluxing in
MeOH/DMSO to provide bicyclic compound 10 with 78% yield
after chromatographic purification. Further conversion of hybrid
compound 10 into its corresponding azido derivative 11 was
carried out with 88% yield in two steps, similar to the previous
one as shown in Scheme 2.
Amino acid L-proline 12 containing pyrrolidine ring
was transformed into its corresponding N-Cbz protected alcohol
13 following the standard procedure. The resulting alcohol
was then transformed into its corresponding azido compound
14 using the sequence of tosyl protection/azide substitution
by single-pot two-step procedures with excellent yield. The
[3 + 2] dipolar cycloaddition reaction of compound 14 was
carried out with 1.1 mol equiv. of 8 in water at 70 ꢀC for 1 h to
provide its corresponding cycloadduct 15 in almost quantitative
yield.
In order to achieve the synthesis of its corresponding fused
tricycilc triazolo-ꢀ-lactum 16, the sequential deprotection of
N-Cbz and further cyclization was successfully carried out with
one-pot two-step procedure using Pd/C (10 mol %) in MeOH
under hydrogen atmosphere at rt for 2 h followed by refluxing
for 4 h to provide 16 with 80% yield. Similarly, the other amino
acids like L-phenylalanine 17a, L-valine 17b and L-leucine 17c
were transformed into their corresponding azido derivatives
19. The [3 + 2] dipolar cycloaddition of these azides with 8 in
water under similar conditions, followed by intramolecular cyc-
lization leads to the synthesis of different corresponding bicyclic
triazolo-ꢀ-lactams 21 in excellent yields (Scheme 3). All the new
compounds were fully characterized by spectroscopic means.12
In summery, we have developed an efficient and general
route for the synthesis of new class of various triazolo-ꢀ-lactams
in few steps from azides derived from amino acids. The main
strength of this approach is that it allows the use of wide variety
of existing amino acids as starting materials for the synthesis of
various triazolo-ꢀ-lactams.
Mr. Indresh Kumar thanks, CSIR New Delhi, for the award
of senior research fellowship.
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Published on the web (Advance View) March 29, 2007; doi:10.1246/cl.2007.592