Multicomponent reactions stereo- and regioselective three-component reaction in water: Synthesis of triazole substituted β-lactams via click chemistry

Article abstract of DOI:10.2174/157017811795038430

Three-component reaction in water was used to prepare a series of triazole substituted trans-β-lactams from the corresponding trans-4-acetoxy-lactam, sodium azide, and alkynes via a Cu(I)-catalyzed click chemistry with base free. This highly stereo- and r

Full text of DOI:10.2174/157017811795038430

Letters in Organic Chemistry, 2011, 8, 163-169
163
Multicomponent Reactions Stereo- and Regioselective Three-Component
Reaction in Water: Synthesis of Triazole Substituted ꢀ-Lactams Via Click
Chemistry
Ming Lei*, Wang-Ze Song, Zu-Jin Zhan, Sun-Liang Cui and Fang-Rui Zhong
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. China
Received January 07, 2010: Revised January 01, 2011: Accepted January 01, 2011
Abstract: Three-component reaction in water was used to prepare a series of triazole substituted trans-ꢀ-lactams from the
corresponding trans-4-acetoxy-lactam, sodium azide, and alkynes via a Cu(I)-catalyzed click chemistry with base free.
This highly stereo- and regioselective procedure is simple, clean and efficient.
Keywords: Three-component reaction, ꢀ-lactam, (3R,4R)-4-acetoxy-3-[(R)-1-((tert-butyldimethyl-silyl)oxy)-ethyl]-2-
azetidinone, click reaction, triazole, stereo- and regioselective reaction.
INTRODUCTION
diverse heterocycles [12], we developed a stereo- and
regioselective method for the synthesis of triazole substituted
ꢀ-lactams via copper-catalyzed three-component click
reaction of 4-acetoxy ꢀ-lactam, sodium azide and alkynes.
ꢀ-Lactam (azetidinones) derivatives are important
compounds that attract significant research interests from
both synthetic and pharmaceutical areas [1, 2]. The ꢀ-lactam
nucleus is considered to be a general lead-structure for the
design and synthesis not only of new antibacterial products,
such as carbapenems, carbacephems, and monobactams [3],
but also of new inhibitors of enzymes containing a serine
nucleophile in their active site, like ꢀ-lactamases [4], human
leukocyte elastase [5] and cholesterol absorption inhibitors
[6]. Therefore the search for new functionalized ꢀ-lactam
with potential clinical usefulness would be continued. Owing
to the presence of several stereocenters whose correct
configuration is crucial for pharmacological activity; there is
a need for highly stereoselective syntheses of these
molecules.
RESULTS AND DISCUSSION
Initially, (3R,4R)-4-acetoxy-3-[(R)-1-((tert-butyldimethyl-
silyl)oxy)-ethyl]-2- azetidinone (1), a convenient source of a
labile azetidinone which has taken part in coupling reactions
with nucleophiles leading to many novel systems of
biological interest [13], was used to react with sodium azide
in CH3CN. We were pleased to find that 4-azide substituted
trans-ꢀ-lactam 2 was formed in nearly quantitative yield
(Scheme 1) with 4-position stereo configuration retention
[14]. Compared with Kita’s method, ZnI2 catalyzed
substitution of trans-4-sulfinylazetidin-2-one with trimethyl-
silyl azide [15], the present method provided a practical and
convenient route to trans-4-azido-3-(1’-tert-butyldimethyl-
silyoxy)ethyl 2-azetidinone, which is the key intermediate of
a new class of ꢀ-lactam derivatives bearing 4-heterofunction
scaffolds. Fortunately, water could be used to take place of
CH3CN as a clean medium and afforded 2 in 95% yield.
The copper catalyzed Huisgen 1, 3-dipolar cycloadditions
of organic azides with terminal alkynes for the synthesis of
triazoles [7] has been widely used in various fields, ranging
from bioorganic and medicinal chemistry to materials
science for its remarkable efficiency and high regioselec-
tivity [8]. Recently, a novel family of saccharide/ ꢀ-lactam
hybrids for lectin inhibition has been built via click reaction
which displayed full anomer and configuration control [9].
J = 1.0 Hz
TBDMSO
TBDMSO
H
H
H
H
N3
Nowadays, the multicomponent reactions (MCRs) invo-
lving domino processes with at least three different simple
substrates have emerged as a powerful strategy [10]. These
methodologies allow molecular complexity and diversity to
be created by the facile formation of several new covalent
bonds in a one-pot transformation quite closely approaching
the concept of an ideal synthesis. Also, the MCRs are
particularly well-adapted for combinatorial synthesis [11].
As a part of our program aiming at new approaches to
OAc
+
CH3CN, reflux, 5h
or H2O, 70 ˚C, 4h
NaN3
NH
NH
O
O
2
1
95% isolated yield
Scheme 1. Stereoselective synthesis of 4-azide substituted trans-ꢀ-
lactam 2.
As we envisioned that a Cu(I)-catalyzed click reaction of
2 with terminal alkyne would lead to triazole substituted ꢀ-
lactams. Phenylacetylene 3a was used to identify the
optimum reaction condition (Table 1). The best result was
obtained in presence of a catalytic amount of CuI (5 mol%)
*Address correspondence to this author at the Department of Chemistry of
Zhejiang University, 38 Zheda Road, Hangzhou, 310027 Zhejiang, China;
Tel:+86 571 87952359; Fax: +86 571 87953816;
E-mail: leiming@zju.edu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

164 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Lei et al.
Table 1. Optimization of Conditions for the Click Reactiona
TBDMSO
N
N
H
H
Conditions
Ph
N
2
+
Ph
NH
O
3a
4a
Entry
Catalystc
Solvent
Time (h)
Yield (%)d
1
2
CuI
CuI
THF
CH3CN
CH3CN
CH3CH2OH
CH2Cl2
Toluene
CH3CN
CH3CN
H2O
7.5
4
64
95
3b
4
CuI
14
6
94
CuI
90
5
CuI
24
24
24
24
3
Trace
Trace
Trace
90
6
CuI
7
none
CuCl
CuI
8
9
95
aAll reaction were carried out on a 1 mmol scale; 1.1 equiv. of 3a was used in 10 ml solvent at 70oC unless other state. bAt room temperature. c5 mol%. dIsolated yield based on 2.
in CH3CN at 70oC with 95% yield (Table 1, entry 2). At
room temperature, the reaction led to slight yield decreasing
and time prolonging (Table 1, entry 3). Regarding to solvent,
EtOH performed fairly well (Table 1, entries 4), while THF,
CH2Cl2 and toluene were less effective (Table 1, entries 1, 5
and 6). It was also found that CuI, as the catalyst, was crucial
for the reaction while CuCl worked in lower activity. It is
noteworthy that the present click reaction proceeded without
base addition. Most importantly, in water, the reaction
successfully carried out in high yield (95%). Combined with
the step for preparation of 2 in water, this result suggests a
one-pot two step procedure for the synthesis of triazole
substituted ꢀ-lactams.
Furthermore, the crude product could be obtained by simple
filtration.
Inspired by these excellent results we expanded the scope
of the reaction regarding the terminal alkynes which
containing various functionalities. As shown in Table 2, all
of the substrates gave clean reactions under mild conditions
and tolerated functional groups, such as hydroxyl,
cyclopropyl, ester, ether, amide groups. No significant
difference was observed for alkynes substituted with alkyl,
phenyl, electron-donating or electron-withdrawing group.
The yields remained good to excellent, and regioselectivity
was exclusive: only 1,4-regioisomeric products were formed.
The structure of the product was confirmed by X-ray
crystallographic analysis of 4i, in which the configuration of
3 and 4 position was shown as trans definitely (Fig. 1).
Although organic azides are stable against most reaction
conditions, the compounds of low molecular weight or those
containing several azides tend to be explosive and are
difficult to handle [16]. Thus, some procedures for the
generation of azide in situ followed by azide-alkyne
cycloaddition have been reported [11a, 17]. With the success
in hand, therefore, we probed a modular synthesis of
triazoles applying a MCRs protocol (Scheme 2). As
expected, in water without isolation of azide 2, the reaction
smoothly afforded the corresponding product 4a in excellent
yield (95%) in shortened time (Table 2, entry 1).
In addition, for the TBDMS-free derivative of 1, (3R,4R)-
4-acetoxy-3-((R)-1- hydroxyethyl)azetidin-2-one 5, the
procedure also gave the corresponding product 6 in 93%
yield (Scheme 3).
Our mechanistic proposals are depicted in Scheme 4. The
nucleophilic component, NaN3, also as a base, underwent the
reaction with 1 to yield 2 via acyliminium intermediate (A)
[15b]. Subsequently, a click reaction with Cu(I) acetylide B
TBDMSO
H
H
OAc
CuI (5 mol%)
NaN3
+
Ph
+
4a
NH
H2O, 70 oC
O
95% Isolated yield
1
3a
Scheme 2. One-pot three-component synthesis of 4a.

Synthesis of Triazole Substituted ꢀ-Lactams Via Click Chemistry
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
165
Table 2. One-Pot Synthesis of Triazole Substituted ꢀ-Lactams in Water from 1, Sodium Azide and Alkynes 3a
R
TBDMSO
TBDMSO
N
H
H
H
H
OAc
N
N
CuI(5 mol%)
H2O, 70 oC
NaN
R
+
+
3
NH
NH
O
O
3
1
4
Entry
Alkyne
Time (h)
Product
4a
Yield (%)b
1
3
3
3
95
Et
2
3
4b
4c
96
96
MeO
C4H9
4
5
6
6
4d
4e
90
90
6
7
8
6
6
6
4f
4g
4h
88
92
90
HO
HO
O
9
6
4i
90
MeO
O
10
11
6
6
4j
90
88
EtO
O
4k
O
O
NH
12
4
4l
90
aAll reaction were carried out on a 1 mmol scale; equiv molar of 1, sodium azide and alkyne were used with 5 mol% CuI in 10 ml water at 70oC. bIsolated yield based on 1.
Fig. (1). X-ray crystallographic analysis of 4i.

166 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Lei et al.
Et
OH
H
OH
H
N
H
H
OAc
+
N
N
CuI (5 mol%)
H2O, 70 oC, 4h
+
NaN3
Et
NH
NH
O
O
5
6
93% isolated yield
Scheme 3. Synthesis of triazole substituted ꢀ-lactam 6 from 5.
N3
TBDMSO
TBDMSO
TBDMSO
Na
N3
H
H
H
H
H
OAc
N3
OAc
NaN3
NH+
NH
N
NH
O
H
O
O
NaOAc
A
2
1
R
3
R
N
Cu(I)
R
[Cu]
1
TBDMSO
-H+
N
B
H
H
+H+
N
NH
R
N
O
C
N
R
[Cu]
4
TBDMSO
[Cu]
H
TBDMSO
C
N
N
H
H
H
N
N
NH
NH
O
O
D
C
Scheme 4. Mechanism for the three-component synthesis.
generated from alkyne 3 in the presence of CuI as catalyst to
afford triazolyl copper species D via metallocycle C,
followed by a protonation to furnish triazole substituted ꢀ-
lactams [18]. Herein, water appears to be an ideal solvent
capable of supporting Cu(I) acetylide B in its reactive state,
especially when it is formed in situ [18b]. So this three-
component reaction performed smoothly in water in high
yields.
spectra were recorded at 125 MHz. Optical rotations were
measured on Perkin Elmer Model 341 with the solvent
indicated. Melting points were measured on a WRS-1B
digital melting point apparatus. Infrared spectra were
recorded as thin film or in KBr. MS spectra were recorded
with ESI ionization source.
Representative Experimental Procedure for the Synthesis
of Compound 2
In conclusion, we have developed
a stereo- and
regioselective method for the preparation of triazole
substituted trans-ꢀ-lactams from trans-4-acetoxy ꢀ-lactam,
sodium azide and alkynes in water in high yields (88~96%).
This three-component procedure, via Cu(I)-catalyzed click
reaction with base free, does not require isolation of the
azide intermediates and proves to be experimentally simple
and efficient.
In a 100ml single necked flask, the mixture of compound
1 (10 mmol, 2.87 g) and sodium azide (15 mmol，9.75 g) in
30ml CH3CN was stirred and refluxed for 5h. The progress
of the reaction was monitored by TLC using ethyl
acetate/hexane (1:3) as eluent. After completion, CH3CN
was removed under vacuum. Then the residue was dissolved
in 80ml of ethyl acetate/H2O (5:3), the organic layer was
separated and the aqueous layer was extracted with ethyl
acetate (2ꢁ20 ml). The combined organic layer was dried
over anhydrous sodium sulfate and concentrated under
vacuum. The residue was purified by flash silica gel
EXPERIMENTAL
All chemicals were reagent grade and used as purchased.
1H NMR spectra were recorded at 500 MHz. 13C NMR

Synthesis of Triazole Substituted ꢀ-Lactams Via Click Chemistry
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
167
chromatography eluting with EtOAc-ether (1:5) afforded
2.57 g of compound 2 in 95% yield.
403.2[M+H+]. IR (KBr): 3384, 2958, 1778, 1254, 830 cm-1.
1H NMR (CDCl3): ꢀ = 7.94 (1H, s), 7.71-7.73 (2H, m), 6.93-
6.97 (1H, br s, -NH), 6.31 (1H, d, J = 0.9 Hz, 4-H), 4.35 (1H,
m), 3.83 (3H, s), 3.54 (1H, m, 3-H), 1.26 (3H, t, J = 6.4Hz),
0.90 (9H, s), 0.12 and 0.11 (total 6H, each s). 13C NMR
(CDCl3): ꢀ = 166.6, 160.1, 148.8, 127.3, 122.9, 116.4, 114.6,
68.7, 64.3, 63.3, 55.5, 25.9, 22.4, 18.2, -4.0, -4.9. Anal.
Calcd for C20H30N4O3Si: C, 59.67; H, 7.51; N, 13.92. Found:
C, 59.62; H, 7.54; N 13.90.
White solid; [ꢀ]D20 = +38.0 (c 0.10, CH3CN); mp 70.9-
71.2 ˚C [15b]. MS (ESI): m/z 292.9[M+Na+]. IR (KBr):
3174, 2105, 1770 cm-1. 1H NMR (CDCl3): ꢀ = 6.38 (1H, br s,
-NH), 5.02 (1H, s, 4-H), 4.24 (1H, m), 3.18 (1H, dd, J = 3.7,
1.6 Hz, 3-H), 1.27 (3H, d, J = 6.4Hz), 0.88 (9H, s), 0.08 and
0.01 (total 6H, each s). 13C NMR (CDCl3): ꢀ = 166.8, 66.7,
65.4, 64.2, 25.9, 22.6, 18.1, -4.1, -4.9.
Compound 4d
Yield 90%; White solid; [ꢀ]D20 = +22.0 (c 0.10, CH3CN);
Representative Experimental Procedure for the Synthesis
of Compound 4a from Compound 2
mp 70.6-71.1 ˚C. MS (ESI): m/z 375.2[M+Na+],
1
353.0[M+H+]. IR (KBr): 3209, 1778, 1750, 1358cm-1. H
In a 25ml single necked flask, the mixture of compound 2
(270 mg, 1 mmol), phenylacetylene (112 mg, 1.1 mmol) and
CuI (0.05 mmol, 9.6 mg) in 10ml H2O was stirred at 70 ˚C
under N2 The progress of the reaction was monitored by TLC
using ethyl acetate/hexane (1:3) as eluent. After completion
the reaction, the crude product was obtained by filtration and
was purified by flash silica gel chromatography eluting with
EtOAc-ether (1:5) afforded 353mg of compound 4a in 95%
yield.
NMR(CDCl3): ꢀ = 7.54 (s, 1H), 6.87 (1H, br s, -NH), 6.26
(d, J = 1.2 Hz, 1H), 4.34 (dd, 1H, J = 6.35, 2.9 Hz), 3.51 (m,
1H, 3-H), 2.73 (t, 2H, J = 7.7Hz), 1.64-1.67 (m, 2H), 1.36-
1.41 (m, 2H), 1.26 (d, 3H, J = 6.4Hz), 0.95 (t, 3H, J =
7.4Hz), 0.89 (s, 9H), 0.11 and 0.09 (total 6H, each s). 13C
NMR (CDCl3): ꢀ = 166.7, 149.7, 118.2, 68.4, 64.3, 63.1,
31.6, 25.9, 25.6, 22.5, 22.4, 18.2, 14.0, -4.0, -4.9. Anal.
Calcd for C17H32N4O2Si: C, 57.92; H, 9.15; N, 15.89. Found:
C, 57.99; H, 9.10; N 15.89.
White solid; [ꢀ]D20 = +92.5 (c 0.10, CH3CN); mp 114.6-
115.4 ˚C. MS (ESI): m/z 395.2[M+Na+], 373.1[M+H+]. IR
Compound 4e
1
(KBr): 3315, 1794, 1768, 1646, 1555, 1464cm-1. H NMR
Yield 90%; White solid; [ꢀ]D20 = +49.7 (c 0.10, CH3CN);
mp 133.0-133.7 ˚C. MS (ESI): m/z 359.2[M+Na+],
337.2[M+H+. IR (KBr): 3448, 1783, 1652, 1558, 1341cm-1.
1H NMR (CDCl3): ꢀ = 7.50 (s,1H), 6.71 (1H, br s, -NH),
6.25 (s, 1H), 4.34-4.32 (dd, 1H, J = 6.4, 2.8 Hz), 3.49 (m,
1H, 3-H), 1.96 (m, 1H), 1.25 (d, 3H, J = 6.4 Hz), 0.99-0.95
(m, 2H), 0.88 (s, 9H), 0.84-0.87 (m, 2H), 0.11 and 0.10 (total
6H, each s).
(CDCl3): ꢀ = 8.04 (1H, s), 7.82 (2H m), 7.44-7.35 (3H, m),
6.89 (1H, br s, -NH), 6.34 (1H, s, 4-H),4.35 (1H, m), 3.56
(1H, m, 3-H), 1.28 (3H, d, J = 6.4Hz), 0.90 (9H, s), 0.12 and
0.11 (total 6H, each s). 13C NMR (CDCl3): ꢀ = 166.6, 148.9,
130.2, 129.2, 128.8, 126.0, 117.2, 68.8, 64.3, 63.4, 25.9,
22.4, 18.2, -4.0, -4.9. Anal. Calcd for C19H28N4O2Si: C,
61.26; H, 7.58; N, 15.04. Found: C, 61.27; H, 7.53; N 15.10.
13C NMR (CDCl3): ꢀ = 166.5, 151.6, 117.2, 68.5, 64.3,
63.1, 26.0, 22.4, 18.2, 8.1, 7.0, -4.0, -4.9. Anal. Calcd for
C16H28N4O2Si: C, 57.11; H, 8.39; N, 16.65. Found: C, 57.09;
H, 8.39; N 16.61.
Representative Experimental Procedure for One-Pot
Synthesis of Compound 4a from Compound 1 in Water
In a 25ml single necked flask, the mixture of compound 1
(287 mg, 1 mmol), phenylacetylene (102 mg, 1 mmol),
sodium azide 2 (1 mmol，65 mg) and CuI (0.05 mmol, 9.6
mg) in 10ml H2O was stirred at 70 ˚C under N2. The progress
of the reaction was monitored by TLC using ethyl
acetate/hexane (1:3) as eluent. After completion the reaction,
the crude product was obtained by filtration and was purified
by flash silica gel chromatography eluting with EtOAc-ether
(1:5) afforded 354mg of 4a in 95% yield.
Compound 4f
Yield 88%; White solid; [ꢀ]D20 = +31.0 (c 0.10, CH3CN);
mp133.8-134.5 ˚C. MS (ESI): m/z 375.2[M+Na+],
353.2[M+H+]. IR (KBr): 2961, 2936, 1780, 1047, 846 cm-1.
1H NMR (CDCl3): ꢀ = 7.55 (1H, s), 7.02 (1H, br s, -NH),
6.24 (1H, s, 4-H), 4.35 (1H, m), 3.52 (1H, m, 3-H),1.34 (9H,
s), 1.28 (3H, d, J = 6.4Hz), 0.89 (9H, s), 0.09 and 0.10 (total
6H, each s). 13C NMR (CDCl3): ꢀ = 166.7, 158.8, 116.4,
68.3, 64.4, 63.2, 31.1, 30.5, 25.9, 22.5, 18.2, -4.0, -4.9. Anal.
Calcd for C17H32N4O2Si: C, 57.92; H, 9.15; N, 15.89. Found:
C, 57.89; H, 9.18; N 15.84.
Compound 4b
Yield 96%; White solid; [ꢀ]D20 = +69.0 (c 0.10, CH3CN);
mp 51.8-53.4 ˚C. MS (ESI): m/z 423.2[M+Na+],
401.2[M+H+]. IR (KBr): 3448, 2960, 1786, 1259, 846 cm-1.
1H NMR (CDCl3): ꢀ = 7.99 (1H, s), 7.73-7.75 (2H, m), 7.26-
7.27 (2H, m), 6.81 (1H, br s, -NH), 6.34 (1H, d, J = 1.13 Hz,
4-H), 4.35 (1H, m), 3.56 (1H, m, 3-H), 2.69 (q, 2H), 1.25-
1.29 (6H, m), 0.92 (9H, s),0.13 and 0.12 (total 6H, each s).
13C NMR (CDCl3): ꢀ = 166.6, 149.1, 145.1, 128.7, 127.6,
126.0, 116.8, 68.8, 64.4, 63.4, 28.9, 25.9, 22.5, 18.2, 15.7, -
4.0, -4.9. Anal. Calcd for C21H32N4O2Si: C, 62.96; H, 8.05;
N, 13.99. Found: C, 62.92; H, 8.02; N 13.93.
Compound 4g
Yield 92%; White solid; [ꢀ]D20 = +31.8 (c 0.10, CH3CN);
mp: 124.0-125.8 ˚C. MS (ESI): m/z 349.2[M+Na+],
1
327.2[M+H+]. IR (KBr): 3392, 1777, 1445, 1142 cm-1. H
NMR (CDCl3): ꢀ = 7.82 (1H, s), 7.39 (1H, br s, -NH), 6.22
(1H, s, 4-H, 4-H), 4.73 (2H, s), 4.31-4.33 (m, 1H), 3.70 (1H,
br, -OH), 3.48 (1H, s, 3-H), 1.25 (3H, d, J = 6.3Hz), 0.89
(9H, s), 0.10 and 0.09 (total 6H, each s). 13C NMR (CDCl3):
ꢀ = 166.9, 148.7, 120.1, 68.4, 64.3, 63.4, 56.2, 25.9, 22.5,
18.2, -4.1, -4.9. Anal. Calcd for C14H26N4O3Si: C, 51.51; H,
8.03; N, 17.16. Found: C, 51.48; H, 7.99; N 17.10.
Compound 4c
Yield 96%; White solid; [ꢀ]D20 = +73.0 (c 0.10, CH3CN);
mp 147.6-148.9 ˚C. MS (ESI): m/z 425.2[M+Na+],

168 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Lei et al.
Compound 4h
148.3, 139.1, 130.7, 129.8, 121.5, 120.1, 117.9, 117.2, 68.4,
64.3, 63.4, 36.7, 25.9, 22.4, 19.8, 18.1, -4.0, -4.9. Anal.
Calcd for C23H35N5O3Si: C, 60.36; H, 7.71; N, 15.30. Found:
C, 60.30; H, 7.69; N 15.35.
Yield 90%; White solid; [ꢀ]D20 = +39.6 (c 0.10, CH3CN);
mp 137.3-137.9 ˚C. MS (ESI): m/z :377.2[M+Na+]. IR
(KBr): 3217, 1776, 1752cm-1. 1H NMR (CDCl3): ꢀ = 7.72 (s,
1H), 6.80 (1H, br s, -NH), 6.26 (1H, d, J = 0.95Hz, 4-H),
4.33-4.35 (1H, m), 3.52 (1H, dd, J = 2.7, 1.9 Hz, 3-H), 2.69
(1H, br s, -OH), 1.64 (6H, s), 1.27 (3H, d, J = 6.3Hz), 0.90
(9H s,), 0.11 and 0.10 (total 6H, each s). 13C NMR (CDCl3):
ꢀ = 166.5, 156.8, 117.1, 68.8, 68.5, 64.3, 63.3, 30.6, 25.9,
22.5, 18.2, -4.0, -4.9. Anal. Calcd for C16H30N4O3Si: C,
54.21; H, 8.53; N, 15.80. Found: C, 54.12; H, 8.54; N 15.73.
Compound 6
20
Yield 93%; White solid; [ꢀ]D = +73.5 (c 0.10,
CH3CN); mp: 184.0-184.2 ˚C. MS (ESI): m/z 309.2[M+Na+],
287.2[M+H+]. IR (KBr): 3448, 2960, 1786, 1259, 846 cm-1.
1H NMR (d -DMSO): ꢀ = 9.04 (1H, br s, -NH), 8.87 (1H, s),
6
7.78 (2H, d, J = 7.9), 7.29 (2H, d, J = 7.9), 6.15 (1H, s, 4-H),
5.19 (1H, -OH), 4.05 (1H, m), 3.64 (1H, m, 3-H), 2.61-2.66
(q, 2H, J = 7.5Hz), 1.17-1.22 (6H, m). 13C NMR (d6-
DMSO): ꢀ = 167.0, 147.5, 144.2, 128.7, 128.4, 125.7, 119.8,
67.2, 63.5, 63.3, 28.4, 22.1, 15.9. Anal. Calcd for
C15H18N4O22: C, 62.92; H, 6.34; N, 19.57. Found: C, 62.81;
H, 6.38; N 19.61.
Compound 4i
Yield 90%; White solid; [ꢀ]D20 = +25.5 (c 0.10, CH3CN);
mp: 139.4-140.6 ˚C. MS (ESI): m/z 376.9[M+Na+]. IR
(KBr): 2951, 1788, 1745, 1374, 1214, 1042 cm-11H NMR
(CDCl3): ꢀ = 8.41 (1H, s),7.08 (1H, br s, -NH), 6.35 (1H, s,
4-H), 4.34-4.35 (1H, m), 3.95 (3H, s,-OCH ), 3.56 (1H, m,
3
3-H), 1.28 (3H, d, J = 6.4Hz), 0.88 (9H, s),0.11 and 0.10
ACKNOWLEDGEMENT
(total 6H, each s). 13C NMR (CDCl3): ꢀ = 166.1, 161.0,
140.8, 125.7, 68.9, 64.3, 63.7, 52.6, 25.9, 22.4, 18.1, -4.0, -
4.9. Anal. Calcd for C15H26N4O4Si: C, 50.82; H, 7.39; N,
15.81. Found: C, 50.97; H, 7.35; N 15.87.
We thank Dr. W. Xu for his X-ray crystallographic
analysis.
Compound 4j
REFERENCES AND NOTES
Yield 90%; White solid; [ꢀ]D20 = +22.0 (c 0.10, CH3CN);
mp: 142.1-143.9 ˚C. MS (ESI): m/z 390.9[M+Na+]. IR
(KBr): 2936, 1790, 1739, 1209, 1040cm-1. 1H NMR
(CDCl3): ꢀ = 8.39 (1H, s), 7.14 (1H, br s, -NH), 6.34 (1H, s,
4-H), 4.41 (2H, q, J = 7.2Hz), 4.34-4.35 (1H, m), 3.54 (1H,
m, 3-H), 1.40 (3H, t, J = 7.2Hz), 1.27 (3H, d, J = 6.4Hz),
0.87 (9H, s), 0.10 and 0.08 (total 6H, each s). 13C NMR
(CDCl3): ꢀ = 166.2, 160.6, 141.0, 125.6, 68.9, 64.3,
63.6,61.8, 25.9, 22.4, 18.1, 14.5, -4.0, -4.9. Anal. Calcd for
C16H28N4O4Si: C, 52.15; H, 7.66; N, 15.20. Found: C, 52.13;
H, 7.62; N 15.22.
[1]
(a) Chemistry and Biology of ꢀ-Lactam Antibiotics; Morin, R.B.;
Gorman, M. Eds.; Academic Press: New York, 1982; (b) The
Organic Chemistry of ꢀ-Lactams; Georg, G.I. Ed.; Verlag Chemie:
New York, 1993 and references therein; (c) Neuhaus, F.C.;
Georgopapadaku, N. H. In: Emerging Targets in Antibacterial and
Antifungal Chemotherapy; Sutcliffe, J.; Georgopapadakou, N.H.
Eds.; Chapman and Hall: New York, 1992.
(a) Staub, I.; Sieber, S.A. ꢁ-Lactam probes as selective chemical-
proteomic tools for the identification and functional
characterization of resistance associated enzymes in MRSA. J. Am.
Chem. Soc., 2009, 131, 6271-6276; (b) Brandi, A.; Cicchi, S.;
Cordero, F.M. Novel syntheses of azetidines and azetidinones.
Chem. Rev., 2008, 108, 3988-4035; (c) Alcaide, B.; Almendros, P.;
Aragoncillo, C. ꢁ-Lactams: versatile building blocks for the
stereoselective synthesis of non-ꢁ-lactam products. Chem. Rev.,
2007, 107, 4437-4492; (d) Zhang, X.J.; Hsung, R.P.; Li, H.Y.;
Zhang, Y.; Johnson W.L.; Figueroa, R. A highly stereoselective
synthesis of chiral alpha-amino-ꢁ-lactams via the Kinugasa
reaction employing ynamides. Org. Lett., 2008, 10, 3477-3479.
Kidwai, M.; Sapra, P.; Bhushan, K.R. Synthetic strategies and
medicinal properties of ꢁ-lactams. Curr. Med. Chem., 1999, 6, 195-
215.
Bulychev, A.; Bellettini, J.R.; O’Brien, M.; Crocker, P. J.;
Samama, J.P.; Miller, M.J.; Mobashery, S. N-sulfonyloxy-ꢁ-lactam
inhibitors for ꢁ-lactamases. Tetrahedron, 2000, 56, 5719-5728.
(a) Page, M.I.; Laws, A.P. The chemical reactivity of ꢁ-lactams, ꢁ-
sultams and ꢁ-phospholactams. Tetrahedron, 2000, 56, 5631-5637;
(b) Buynak, J.D.; Rao, A.S.; Ford, G.P.; Carver, C.; Adam, G.;
Geng, B.; Bachmann, B.; Shobassy, S.; Lackey, S. 7-
Alkylidenecephalosporin esters as inhibitors of human leukocyte
elastase. J. Med. Chem., 1997, 40, 3423-3433 and references cited
therein.
[2]
Compound 4k
Yield 88%; Pale yellow solid. [ꢀ]D20 = +28.0 (c 0.10,
CH3CN); mp: 79.1-80.9 ˚C. MS (ESI): m/z 432.9[M+Na+],
410.9[M+H+]. IR (CH2Cl2): 3262, 2951, 1788, 1462, 1132,
832 cm-1. 1H NMR (CDCl3): ꢀ = 7.84 (1H, s), 7.31 (1H, br s,
-NH), 6.26 (1H, s, 4-H), 4.86 (1H, m), 4.73-4.74 (1H, m),
4.61 (1H, m), 4.32-4.34 (1H, m), 3.89 (1H, m), 3.53 (1H, m),
1.60-1.73 (2H, m), 1.52-1.60 (4H, m), 1.25 (3H, t, J =
6.4Hz), 0.89 (9H, s), 0.11 and 0.10 (total 6H, each s).
13C NMR (CDCl3): ꢀ = 166.7, 146.2, 120.4, 98.6, 68.3,
64.2, 63.2, 62.5, 60.6, 30.5, 25.8, 25.4, 22.4, 19.5, 18.1, -4.1,
-4.9. Anal. Calcd for C19H34N4O4Si: C, 55.58; H, 8.35; N,
13.65. Found: C, 55.52; H, 8.40; N 13.58.
[3]
[4]
[5]
[6]
Kværnø, L.; Werder, M.; Hauser, H.; Carreira, E.M. Synthesis and
in vitro evaluation of inhibitors of intestinal cholesterol absorption.
J. Med. Chem., 2005, 48, 6035-6053.
Huisgen, R. In: 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984.
(a) Park, I.S.; Kwon, M.S.; Kim, Y.; Lee, J.S.; Park, J.
Heterogeneous copper catalyst for the cycloaddition of azides and
alkynes without additives under ambient conditions. Org. Lett.,
2008, 10, 497-500; (b) Kumar, A.; Pandey, P.S. Anion recognition
by 1,2,3-triazolium receptors: application of click chemistry in
anion recognition. Org. Lett., 2008, 10, 165-168; (c) Geng, J.;
Lindqvist, J.; Mantovani, G.; Haddleton, D.M. Simultaneous
copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and
Compound 4l
Yield 90%; White solid; [ꢀ]D20 = +48.2 (c 0.10, CH3CN);
mp: 95.1-97.2 ˚C. MS (ESI): m/z 479.9[M+Na+],
457.8[M+H+]. IR (KBr): 3317, 2958, 2930, 1775, 1376,
[7]
[8]
1
1252cm-1. H NMR (CDCl3): ꢀ = 8.02(1H, s), 8.01 (1H, s),
7.94 (1H, s), 7.79 (1H, br s, -NH), 7.57-7.59 (1H, m), 7.47-
7.49 (1H,m), 7.27-7.32 (1H, m), 6,27 (1H,s, 4-H), 4.33-4.35
(1H, m), 3.57 (1H, m, 3-H), 2.58 (1H, m), 1.26 (3H, t, J =
6.3Hz), 1.24 (6H, m, J = 6.8Hz), 0.85 (9H, s), 0.10 and 0.09
(total 6H, each s). 13C NMR (CDCl3): ꢀ = 176.3, 166.8,

Synthesis of Triazole Substituted ꢀ-Lactams Via Click Chemistry
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
169
living radical polymerization. Angew. Chem. Int. Ed. Engl., 2008,
47, 4180-4183; (d) Moses, J.E.; Moorhouse, A.D. The growing
applications of click chemistry. Chem. Soc. Rev., 2007, 36, 1249-
1262; (e) Fournier, D.; Hoogenboom, R.; Schubert, U.S. Clicking
polymers: a straightforward approach to novel macromolecular
architectures. Chem. Soc. Rev., 2007, 36, 1369-1380; (f) Lutz, J.F.
1,3-Dipolar cycloadditions of azides and alkynes: a universal
ligation tool in polymer and materials science. Angew. Chem. Int.
Ed. Engl., 2007, 46, 1018-1025; (g) Leigh, D.A.; Aucagne, V.
Chemoselective formation of successive triazole linkages in one
pot: "Click-click" chemistry. Org. Lett., 2006, 8, 4505-4507; (h)
Such, G.K.; Quinn, J.F.; Quinn, A.; Tjipto, E.; Caruso, F. Assembly
of ultrathin polymer multilayer films by click chemistry. J. Am.
Chem. Soc., 2006, 128, 9318-9319.
Palomo, C.; Aizpurua, J. M.; Balentová, E.; Azcune, I.; Santos, J.I.;
Jiménez-Barbero, J.; Cañada, J.; Miranda, J.I. "Click" saccharide/ꢀ-
lactam hybrids for lectin inhibition. Org. Lett., 2008, 10, 2227-
2230.
Forsome recent reviews of MCRs, (a) Ganem, B. Strategies for
innovation in multicomponent reaction design. Acc. Chem. Res.,
2009, 42, 463-472; (b) Ramón, D.J.; Yus, M. Asymmetric
multicomponent reactions (AMCRs): The new frontier. Angew.
Chem. Int. Ed. Engl., 2005, 44, 1602-1634; (c) Zhu, J. Recent
developments in the isonitrile-based multicomponent synthesis of
heterocycles. Eur. J. Org. Chem., 2003, 1133-1150,
doi:10.1002/ejoc.200390167.
catalyzed multicomponent reaction: facile access to functionalized
5-arylidene-2-imino-3-pyrrolines. Org. Lett., 2007, 9, 5023-5025;
(c) Cui, S.L.; Lin, X.F.; Wang, Y.G. Novel and efficient synthesis
of iminocoumarins via copper-catalyzed multicomponent reaction.
Org. Lett., 2006, 8, 4517-4520.
(a) Berks, A. H. Preparations of two pivotal intermediates for the
synthesis of 1-ꢀ-methyl carbapenem antibiotics. Tetrahedron, 1996,
52, 331-375; (b) Singh, G.S. ꢀ-Lactams in the new millennium.
Part I: monobactams and carbapenems. Mini-Rev. Med. Chem.,
2004, 4, 69-92.
[13]
[14]
[15]
The value of coupling constants of the H3 and H4 (ca. 1.0Hz) is in
agreement with that of the trans-lactam ring.
(a) Kita, Y.; Shibata, N.; Yoshida, N.; Tohjo, T.
A novel
substitution-reaction of 4-sulfinylazetidin-2-one with silylated
heteronucleophiles-an efficient synthesis of 4-heterofunction
substituted 3-(1-hydroxy)ethylazetidin-2-ones. Tetrahedron Lett.,
1991, 32, 2375-2378; (b) Kita, Y.; Shibata, N.; Yoshida, N.; Tohjo,
T. An efficient synthesis of 4-heterofunction-substituted 3-(1-
hydroxy) ethylazetidin-2-ones from 3-(1-hydroxy) ethyl-4-
[9]
[10]
phenylsulfinylazetidin-2-one
by
reaction
with
silylated
heteronucleophiles. Chem. Pharm. Bull., 1992, 40, 1733-1736.
Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Organic azides:
An exploding diversity of a unique class of compounds. Angew.
Chem. Int. Ed. Engl., 2005, 44, 5188-5240.
[16]
[17]
(a) Ackermann, L.; Potukuchi, H.K.; Landsberg, D.; Vicent, R.
Copper-catalyzed "click" reaction/direct arylation sequence:
Modular syntheses of 1,2,3-triazoles. Org. Lett., 2008, 10, 3081-
3084; (b) Chittaboina, S.; Fang, X.; Wang, Q. One-pot synthesis of
triazole-linked glycoconjugates. Tetrahedron Lett., 2005, 46, 2331-
2336; (c) Feldman, A.K.; Colasson, B.; Fokin, V.V. One-pot
synthesis of 1,4-disubstituted 1,2,3-triazoles from in situ generated
azides. Org. Lett., 2004, 6, 3897-3899; (d) Sharghi, H.; Khalifeh,
R.; Doroodmand, M.M. Copper nanoparticles on charcoal for
multicomponent catalytic synthesis of 1,2,3-triazole derivatives
from benzyl halides or alkyl halides, terminal alkynes and sodium
azide in water as a "green" solvent. Adv. Synth. Catal., 2009, 351,
207-218; (e) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Cu-
FeCl3-mediated one-pot multicomponent reaction leading to N-
aryl- and N-alkyltriazoles in water. Synlett, 2007, 10, 1591-1594.
(a) Bock, V.D.; Hiemstra, H.; van Maarseveen, J.H. Cu-I-catalyzed
[11]
(a) Appukkuttan, P.; Dehaen, W.; Fokin, V.V.; Van der Eycken, E.
A
microwave-assisted click chemistry synthesis of 1,4-
disubstituted 1,2,3-triazoles via copper(I)-catalyzed three-
a
component reaction. Org. Lett., 2004, 6, 4223-4225; (b) Liéby-
Muller, F.; Constantieux, T.; Rodriguez, J. Multicomponent
domino reaction from ꢀ-ketoamides: Highly efficient access to
original polyfunctionalized 2,6-diazabicyclo[2.2.2]
octane
cores. J. Am. Chem. Soc., 2005, 127, 17176-17177; (c) Byk, G.;
Kabha, E. Anomalous regioselective four-member multicomponent
Biginelli reaction II: one-pot parallel synthesis of spiro
heterobicyclic aliphatic rings. J. Comb. Chem., 2004, 6, 596-603;
(d) Sha, F.; Huang, X. A multicomponent reaction of arynes,
isocyanides, and terminal alkynes: highly chemo- and
regioselective synthesis of polysubstituted pyridines and
isoquinolines. Angew. Chem. Int. Ed. Engl., 2009, 48, 3458-3461;
(e) Zhu, W.; Mena, M.; Jnoff, E.; Sun, N.; Pasau, P.; Ghosez, L.
Multicomponent reactions for the synthesis of complex piperidine
scaffolds. Angew. Chem. Int. Ed. Engl., 2009, 48, 5880-5883.
(a) Tao, X.L.; Lei, M.; Wang, Y.G. Ionic liquid supported synthesis
of ꢀ-lactam library in ionic liquid batch. Tetrahedron Lett., 2007,
48, 5143-5146; (b) Cui, S.L.; Wang,J.; Wang, Y.G. Copper-
[18]
alkyne-azide "click" cycloadditions from
a mechanistic and
synthetic perspective. Eur. J. Org. Chem. 2006, 51-68,
doi:10.1002/ejoc.200500483; (b) Fokin, V. V.; Hein, J. E. Copper-
catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new
reactivity of copper (I) acetylides. Chem. Soc. Rev., 2010, 39,
1302-1315.
[12]