Regio- and diastereoselective synthesis of β-lactam-triazole hybrids via passerini/CuAAC sequence

Article abstract of DOI:10.1021/jo301113g

Passerini (P-3CR) and Passerini-Smiles reactions were investigated in azetidine-2,3-diones, affording the corresponding 3,3-disubstituted-β- lactams with complete diastereoselectivity in high yields. The study has been carried out using different isocyanides, carboxylic acids, and phenols showing the scope of both reactions. In addition, the regioselective synthesis of highly functionalized β-lactam-triazole hybrids has been developed via a Passerini/CuAAC sequence. Interestingly, the use of dialkynes/diazides or trialkynes/triazides as linkers in the CuAAC step has allowed the synthesis of C₂ and C₃ symmetric β-lactam-triazole hybrids, respectively.

Full text of DOI:10.1021/jo301113g

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Article
Regio- and Diastereoselective Synthesis of beta-
Lactam-Triazole Hybrids via Passerini/CuAAC Sequence
Benito Alcaide, Pedro Almendros, Cristina Aragoncillo,
Ricardo Callejo, María Pilar Ruiz, and Maria Rosario Torres
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301113g • Publication Date (Web): 19 Jul 2012
Downloaded from http://pubs.acs.org on July 21, 2012
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Regio- and Diastereoselective Synthesis of β-Lactam-Triazole Hybrids via Passerini/CuAAC
Sequence
Benito Alcaide,*, † Pedro Almendros,‡ Cristina Aragoncillo,† Ricardo Callejo,† M. Pilar Ruiz,† and M.
Rosario Torres§
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†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040ꢀMadrid, Spain,
‡Instituto de Química Orgánica General, IQOG, CSIC, Juan de la Cierva 3, 28006ꢀMadrid, Spain, and
§CAI Difracción de Rayos X, Facultad de Química, Universidad Complutense, 28040ꢀMadrid, Spain.
alcaideb@quim.ucm.es
ABSTRACT
NHR2
N
N
1) "P-3CR"
N3
N
N
O
1) "P-3CR"
R2NC
O
O
O
H
NHR2
N
NHR2
H
N
O
N
O
O
O
N
N
N
O
O
NHR2
O
O
O
CO2H
O
O
N
H
O
H
O
O
CO2H
R2NC
2) "CuAAC"
O
N
O
R1
N
O
N
N
H
N
O
R1
O
O
N
N
O
N
R1
R1
O
N
O
O
N
R1
2) "CuAAC"
N3
O
N
NHR2
N
O
N3
Cu(I)
1
O
O
NHR2
O
O
O
11
10
Cu(I)
N
H
H
N3
O
R1
O
O
N
R1
O
O
Passerini (Pꢀ3CR) and PasseriniꢀSmiles reactions were investigated in azetidineꢀ2,3ꢀdiones,
affording the corresponding 3,3ꢀdisubstitutedꢀβꢀlactams with complete diastereoselectivity in high
yields. The study has been carried out using different isocyanides, carboxylic acids and phenols showing
the scope of both reactions. In addition, the regioselective synthesis of highly functionalized βꢀlactamꢀ
triazole hybrids has been developed via a Passerini/CuAAC sequence. Interestingly, the use of
dialkynes/diazides or trialkynes/triazides as linkers in the CuAAC step has allowed the synthesis of C2
and C3 symmetric βꢀlactamꢀtriazole hybrids respectively.
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INTRODUCTION
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Multicomponent reactions (MCRs) are very powerful synthetic processes, which allow achieving
both complexity and diversity in a single and simple experimental step with high efficiency and atom
economy.1 The applicability of MCRs has been widely demonstrated in the synthesis of natural
products,2 and medicinal chemistry.3 In particular, isocyanide based MCRs (IMCRs) are specially
interesting due to the versatility of isocyanides in terms of functional group tolerance and the high levels
of chemoꢀ, regioꢀ, and stereoselectivity obtained.4 In particular, the impact of IMCRs is remarkable in
targetꢀoriented and diversityꢀoriented synthetic (TOS and DOS, respectively) strategies.5 Among them,
the Passerini threeꢀcomponent reaction (Pꢀ3CR) and the Ugi fourꢀcomponent reaction (Uꢀ4CR) are the
most classic and successful ones (Scheme 1). In the classical Passerini reaction, an isocyanide, a
carboxylic acid and either an aldehyde or a ketone react to yield an αꢀacyloxy carboxamide.6,7 This
methodology has been applied to the synthesis of potentially bioactive molecules.8 Particular attention
has been focused on the combination of the Pꢀ3CR with other synthetic reactions for the construction of
cyclic or more complex structures.1c
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Scheme 1. General Passerini (P-3CR) and Ugi (U-4CR) Reactions
R2 R3
O
O
O
NHR4
R4NC
P-3CR
U-4CR
+
+
R1
O
R1
OH
R2
R3
O
R2 R3
O
O
O
NHR4
R5NH2
R4NC
+
+
R1
+
R1
OH
R2
R3
N
R5
O
On the other hand, the concept of “click chemistry” coined by Sharpless and coꢀworkers in 2001
embraces the synthetic approach to use practical and reliable chemical transformations.9 The application
of “click chemistry” in many areas has been widely documented in the bibliography.10 The copper(I)
catalyzed Huisgen organic azides and terminal alkynes 1,3ꢀdipolar cycloaddition (CuAAC), to give 1,4ꢀ
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disubstituted 1,2,3ꢀtriazoles regioselectively, is undoubtedly on the top of click chemistry reactions.
This valuable transformation is playing an outstanding role in nearly all areas of contemporary
chemistry from drug discovery to material science.11 In addition, although the 1,2,3ꢀtriazole moiety is
not found in nature, there are synthetic molecules containing this unit with different interesting
biological activities.12 Besides, due to the stereoelectronic similarity between the 1,2,3ꢀtriazole core and
the amide bond, this heterocycle represents an isostere of the peptide bond with the advantage of being
stable to hydrolytic and proteolytic cleavage.13
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In connection with our ongoing project aimed at the asymmetric synthesis of nitrogenated
compounds,14 we became interested in the study of the Pꢀ3CR and the subsequent CuAAC in azetidineꢀ
2,3ꢀdiones in order to obtain βꢀlactamꢀtriazole hybrids15 with C2 and C3 symmetry.
RESULTS AND DISCUSSION
Passerini three-component reaction in azetidine-2,3-diones
The starting materials, optically pure azetidineꢀ2,3ꢀdiones 1a−c (Figure 1) were synthesized from
aromatic or aliphatic (R)ꢀ2,3ꢀOꢀisopropylideneglyceraldehyde derived imines by Staudinger reaction
with acetoxyacetyl chloride in the presence of Et3N, followed by sequential transesterification and
Swern oxidation, as previously reported.16
Figure 1. Starting Materials for the Passerini Reaction
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O
O
H
O
9
N
O
R1
10
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(+)-1a R1 = 4-MeOC6H4
(−)-1b R1 =
(−)-1c R1 = Bn
The initial survey was conducted with azetidineꢀ2,3ꢀdione (+)ꢀ1a, benzoic acid, and benzyl
isocyanide in dichloromethane at room temperature, affording αꢀacyloxy carboxamide (+)ꢀ2a as single
isomer in 92 % yield after 21h (entry 1, Table 1). Taking into account that Passerini reactions have been
shown to exhibit rate accelerations in more environmentally friendly solvents, such as water, compared
to organic solvents,17 we decided to test the above reaction in water and in a mixture of
acetonitrile/water (1:1). However, only conversions up to 85% were observed in both experiments by
1HꢀNMR after long reaction times (entries 2 and 3, Table 1). Thus, the scope of the Pꢀ3CR was explored
in dichloromethane using benzyl isocyanide, azetidineꢀ2,3ꢀdiones (−)ꢀ1b and (−)ꢀ1c, and carboxylic
acids. αꢀAcyloxy carboxamides 2b−h were obtained with complete synꢀdiastereoselectivity (with cis
configuration between the βꢀlactamic H4 and the amide group on C3) and the and moderate to excellent
yields in almost all cases (entries 4−10, Table 1). 2ꢀIodo and 2ꢀazido benzoic acids required longer
reaction times (22h and 16h, respectively), but diastereoselectivity values and yields were not affected
(entries 7 and 8, Table 1).
Table 1. Survey of the Passerini Reaction of Azetidine-2,3-diones 1a−c, Benzyl isocyanide, and
Carboxylic Acidsa
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R2
O
O
O
O
O
O
H
N
H
N
O
O
O
Solvent
BnNC
R2CO2H
+
+
Bn NH
rt
R1
O
R1
1
2
Entry
Substrate
R1
R2
Solvent
t (h)d
Product Conversion (%)e syn/antie yield
(%)f
16
17
18
19
20
21
22
23
24
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30
31
32
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1
2
3
(+)ꢀ1a
(+)ꢀ1a
(+)ꢀ1a
PMPb
PMPb
PMPb
Ph
Ph
Ph
CH2Cl2
H2O
21
48
24
(+)ꢀ2a
(+)ꢀ2a
(+)ꢀ2a
100
85
100:0
100:0
100:0
92
g
MeCN, H2O
(1:1)
85
g
(−)ꢀ1b
(+)ꢀ1a
(+)ꢀ1a
(+)ꢀ1a
(+)ꢀ1a
(+)ꢀ1a
(−)ꢀ1c
4
5
2ꢀpropenyl
PMPb
PMPb
PMPb
PMPb
PMPb
Bn
Ph
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
4
(−)ꢀ2b
(+)ꢀ2c
(+)ꢀ2d
(−)ꢀ2e
(−)ꢀ2f
(−)ꢀ2g
(−)ꢀ2h
100
100
100
100
100
100
100
100:0
100:0
100:0
100:0
100:0
100:0
100:0
71
95+
95+
89
Me
6
3ꢀbutynyl
2ꢀIꢀC6H4
2ꢀN3ꢀC6H4
6
7
22
16
3
8
90
c
9
PhtCH2
91
10
3ꢀbutynyl
3
53
aAll reactions were performed by using an azetidinꢀ2,3ꢀdione/carboxilic acid/isocyanide ratio of 1.00:1.05:1.10 mmol. PMP = 4ꢀ
b
MeOC6H4. Pht = Phtalimidoyl.
dReaction progress was followed by TLC. The conversion and the syn/anti ratio were determined
c
e
by integration of wellꢀresolved signals in the 1H NMR spectra (300 MHz) of the crude reaction mixtures before purification. fYield
of pure syn isomer after flash chromatography. gThe crude reaction was not purified.
Analogous results were observed when benzyl isocyanide was replaced by tꢀbutyl isocyanide and pꢀ
toluenesulfonyl methyl isocyanide (TosMIC), affording compounds (+)ꢀ2i and (+)ꢀ2j in 1 and 72h,
respectively, as single isomers in excellent yields (entries 1 and 2, Table 2). In order to minimize the
reaction time to obtain compound (+)ꢀ2j, we decided to carry out the reaction at 50 °C in a sealed tube.
However, the desired reduction of time was not observed (entry 3, Table 2). Then, we decided to use
acetonitrile as solvent. However, we did not get better results, in fact only a conversion of 85% was
observed after 72 h (entry 4, Table 2). Fortunately, when the reaction was studied in acetonitrile at
reflux temperature, compound (+)ꢀ2j was obtained in 89% yield after 3h (entry 5, Table 2). Similar
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results were observed when the reaction was carried out with acetic acid and 4ꢀpentynoic acid, affording
compounds (+)ꢀ2k and (+)ꢀ2l in 34% and 62 % yields respectively (entries 6 and 7, Table 2). Probably,
the 2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl group placed at C4 position of the βꢀlactam ring is affected under the
acidic conditions at reflux temperature, giving decomposition products from a complex crude reaction
(checked by TLC), causing the lower yield obtained in adduct (+)ꢀ2k. Analogously, compound (+)ꢀ2m
was isolated in 74% yield when the reaction was carried out in acetonitrile at reflux temperature (entry
8, Table 2).
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6
7
8
9
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Table 2. Passerini Reaction of Azetidine-2,3-dione (+)-1a, Carboxylic acids and other Isocyanidesa
R2
O
O
O
O
O
O
H
N
H
N
O
O
O
Solvent
R3NC
R2CO2H
+
+
R3 NH
Temperature
PMP
O
PMP
(+)-1a
2
Entry
R2
R3
tBu
Solvent/T (°C)
CH2Cl2/rt
t (h)e
1
Product
(+)ꢀ2i
(+)ꢀ2j
(+)ꢀ2j
(+)ꢀ2j
(+)ꢀ2j
(+)ꢀ2k
(+)ꢀ2l
(+)ꢀ2m
Conversion (%)f
syn/antif
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
Yield (%)g
1
2
3
4
5
6
7
8
3ꢀbutynyl
100
100
100
85
88
95+
97
h
Ph
Ph
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
PMPb
CH2Cl2/rt
72
72
72
3
CH2Cl2/50c
Ph
CH3CN/rt
Ph
CH3CN/reflux
CH3CN/reflux
CH3CN/reflux
CH3CN/refluxd
100
100
100
100
89
34
62
Me
22
3
3ꢀbutynyl
Ph
46
74
aAll reactions were performed by using an azetidinꢀ2,3ꢀdione/carboxilic acid/isocyanide ratio of 1.00:1.05:1.10 mmol. PMP = 4ꢀ
b
c
d
MeOC6H4. Reaction was carried out in a sealed tube. A second equivalent of pꢀmethoxyphenyl isocyanide was added after 12h.
eReaction progress was followed by TLC. The conversion and the syn/anti ratio were determined by integration of wellꢀresolved
f
1
g
signals in the H NMR spectra (300 MHz) of the crude reaction mixtures before purification. Yield of pure syn isomer after flash
chromatography. hThe crude reaction was not purified.
When the P3CR was studied with azetidineꢀ2,3ꢀdione (+)ꢀ1a, bromoacetic acid, and benzyl
isocyanide, the corresponding Passerini adduct (+)ꢀ2n and 3ꢀhydroxyꢀβꢀlactam (−)ꢀ3 were isolated
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(49% and 11% yields, respectively) after flash chromatography. Probably, compound (+)ꢀ2n is
unstable under the acidic conditions of the chromatography and gives its Oꢀdeprotected derivative (−)ꢀ
3. Taking advantage of the high reactivity of compound (+)ꢀ2n, we decided to carry out the Passerini
reaction followed by addition of non nucleophilic base N,N´ꢀdiisopropylethylamine (DIPEA),
affording spirocyclic βꢀlactam derivative (−)ꢀ4 in 56% yield (Scheme 2).
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9
10
11
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Scheme 2. Passerini Reaction of Azetidine-2,3-dione (+)-1a, Bromoacetic Acid, and Benzyl
Isocyanide. Synthesis of Spirocycle (−)-4
O
O
RO
i) BrCH2CO2H, BnNC
CH2Cl2, rt, 1.5h
H
N
O
BnHN
ii) Chromatography (SiO2)
O
PMP
(+)-2n, R = COCH2Br (100:0, 49%)
(−)-3, R = H (100:0, 11%)
O
O
H
N
O
O
PMP
O
(+)-1a
O
O
i) BrCH2CO2H, BnNC
CH2Cl2, rt, 1.5h
H
N
O
BnN
ii) DIPEA, CH2Cl2, rt, 2h
O
O
PMP
(−)-4 (56%)
Passerini-Smiles three-component reaction in azetidine-2,3-diones
The use of phenols instead of carboxylic acids is known as PasseriniꢀSmiles reaction,18 which
involves an irreversible Smiles rearrangement in place of the traditional Mumm acyl transfer of the
classical Passerini reaction, affording αꢀaryloxy amides. Knowing that Passerini reactions usually
require stronger acidic conditions than Ugi couplings, we decided to test the reaction of azetidineꢀ2,3ꢀ
dione (+)ꢀ1a and benzyl isocyanide with an electronꢀdeficient phenol as acidic partner, such as pꢀ
nitrophenol (entry 1, Table 3). Thus, the corresponding αꢀaryloxy amide (+)ꢀ5a was obtained in high
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yield and good diastereoselectivity. Analogous results were observed when the reaction was studied
with tꢀbutyl isocyanide (entry 2, Table 3), and when 4ꢀnitrophenol was replaced by 2ꢀhaloꢀ4ꢀ
nitrophenols (entries 3ꢀ5, Table 3), affording compounds 5b−e in good yields. Next, we examined the
reaction of azetidineꢀ2,3ꢀdione (+)ꢀ1a and benzyl isocyanide with oꢀnitrophenol, showing longer
reaction time and a complex reaction crude, probably due to steric hindrance (entry 6, Table 3).
Nevertheless, performing the reaction at 80 °C in a sealed tube allowed 100% conversion and 63%
isolated yield (entry 7, Table 3). However, these results were not improved by changing
dichloromethane by acetonitrile as solvent at reflux temperature or in a sealed tube at 80 °C (see
entries 8 and 9, Table 3).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
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41
42
43
44
45
46
47
48
49
50
51
52
53
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56
57
58
59
60
Table 3. Passerini-Smiles Reaction of Azetidine-2,3-dione (+)-1aa,b
R2
R1
O
O
OH
R2
O
O
O
H
N
H
N
O
R1
O
O
Solvent
R3NC
+
+
R3HN
Temperature
PMP
O
PMP
(+)-1a
5
Entry
R1
H
R2
R3
Solvent/T (°C)
CH2Cl2/rt
Time (h)d
53
Product
(+)ꢀ5a
(+)ꢀ5b
(+)ꢀ5c
(+)ꢀ5d
(+)ꢀ5e
(+)ꢀ5f
(+)ꢀ5f
(+)ꢀ5f
syn/antie
Conversion (%)
Yield (%)f
1
2
3
4
5
6
7
8
NO2
Bn
>95:5
>95:5
95:5
95:5
95:5
95:5
95:5
95:5
100
100
100
100
100
50
79
63
94
89
73
g
H
NO2 tꢀBu
NO2 Bn
NO2 tꢀBu
CH2Cl2/rt
46
Br
Br
I
CH2Cl2/rt
24
CH2Cl2/rt
24
NO2
H
Bn
Bn
Bn
Bn
CH2Cl2/rt
21
NO2
NO2
NO2
CH2Cl2/rt
168
168
26
H
CH2Cl2/80c
CH3CN/reflux
100
100
63
24
H
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NO2
H
Bn
CH3CN/80c
240
(+)ꢀ5f
95:5
100
25
5
6
7
8
9
aAll reactions were performed by using an azetidinꢀ2,3ꢀdione/phenol/isocyanide ratio of 1.00:1.05:1.10 mmol. bPMP = 4ꢀMeOC6H4.
d
e
cReaction was carried out in a sealed tube. Reaction progress was followed by TLC. The ratio was determined by integration of
1
f
wellꢀresolved signals in the H NMR spectra (300 MHz) of the crude reaction mixtures before purification. Yield of pure syn
isomer.gThe crude of reaction was not purified.
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CuAAC of Passerini Aducts
The combination of the βꢀlactam skeleton and the triazole ring is present in the cephalosporin
antibiotic cefatrizine,19 and in the βꢀlactamase inhibitor tazobactam.20 In addition, in the last few years
the synthesis of several 1,2,3ꢀtriazole linked βꢀlactams with interesting pharmacological activities has
been developed.15 Taking into account the appealing properties of βꢀlactamꢀtriazole hybrids, we were
interested in the study of the CuAAC methodology to our Passerini products. Although the most
common conditions of CuAAC use CuSO4 with sodium ascorbate (AscNa) as a reducing agent in
aqueous conditions, we were particularly interested in carrying out the CuAAC reaction in the same
solvent used for the Passerini reaction, in order to study both reactions in a one pot procedure. Thus, we
decided to use Cu(I) salts in anhydrous conditions to achieve our goal. First, we focused our attention in
the sequential synthesis of the desired triazole compound from the isolated Passerini adduct 2. Thus,
treatment of compound (+)ꢀ2d with tosylazide, CuI, and 2,6ꢀlutidine in dichloromethane at room
temperature afforded the corresponding βꢀlactam triazole hybrid (−)ꢀ6a in moderate yield (50%) and
total regioselectivity (Scheme 3).
Scheme 3. CuAAC of Passerini Adduct (+)-2d
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Ts
O
N
N
N
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O
O
O
O
O
O
O
CuI (0.1 equiv)
2,6-lutidine (2 equiv)
H
N
H
O
O
Ts N3
Bn NH
Bn NH
N
CH2Cl2, rt, 26h
O
PMP
O
PMP
(+)-2d
(−)-6a (50%)
The next step was to study a tandem reaction of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 4ꢀpentynoic acid,
benzyl isocyanide, and tosyl azide in presence of CuI and 2,6ꢀlutidine. However, under the reaction
conditions tested, βꢀlactamꢀtriazole hybrid (−)ꢀ6a was isolated after chromatography from a complex
reaction mixture in only 15% yield. Then, we decided to turn our attention to the study of the oneꢀpot
reaction, treating the crude Passerini adduct (total consumption of the starting azetidineꢀ2,3ꢀdione 1 as
checked by TLC) with tosyl azide, CuI, and 2,6ꢀlutidine. In the event, compound (−)ꢀ6a was isolated
in 80% yield (entry 1, Table 4). The use of other bases, such as Et3N, DIPEA, and K2CO3 did not
improve the yield of compound (−)ꢀ6a (entries 2ꢀ4, Table 4). Next, the oneꢀpot PasseriniꢀCuAAC was
studied with tꢀbutyl and benzyl isocyanide under the optimal reaction conditions, affording βꢀlactamꢀ
triazole hybrids (+)ꢀ6b and (+)-6c in 85% and 91% yield, respectively (entries 5 and 6, Table 4).
However, the best result for the synthesis of the βꢀlactamꢀtriazole hybrid (+)ꢀ6d was achieved using
the optimized conditions for its Passerini adduct (+)ꢀ2l (acetonitrile at reflux temperature) followed by
removal of the acetonitrile before carrying out the CuAAC step in dichloromethane (entry 7, Table 4).
Table 4. Synthesis of β-Lactam-Triazole Hybrids 6 via One-Pot Passerini/CuAAC Reactions
of Azetidine-2,3-dione (+)-1aa,b
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R2
N
N
N
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9
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O
O
O
O
O
O
i) CH2Cl2, rt
H
N
H
O
O
O
ii) R2N3, CuI, base
R1NC
+
+
R1 NH
CO2H
N
PMP
O
PMP
6
(+)-1a
Entry
R1
Bn
R2
Ts
Ts
Ts
Ts
Ts
Bn
Bn
Base
2,6ꢀlutidine
Et3N
t (h)e
6+4
Product
(−)ꢀ6a
(−)ꢀ6a
(−)ꢀ6a
(−)ꢀ6a
(+)ꢀ6b
(+)ꢀ6c
(+)ꢀ6d
yield (%)f
1
2
3
4
5
6
7
80
20
14
10
85
91
74
Bn
6+17
6+22
6+20
1+4
Bn
DIPEAc
Bn
K2CO3
tꢀBu
Bn
2,6ꢀlutidine
2,6ꢀlutidine
2,6ꢀlutidined
6+17
3+13
TsCH2
aAll Pꢀ3CR/CuAAC reactions were catalyzed by CuI (10 mol%) and performed by using an
azetidinꢀ2,3ꢀdione/carboxilic acid/isocyanide/azide/base molar ratio of 1.00:1.05:1.10:2.00:2.00.
bPMP = 4ꢀMeOC6H4. DIPEA = N,N´ꢀdiisopropylethylamine. Pꢀ3CR was carried out in MeCN
c
d
e
while the CuAAC was performed in dichloromethane. Reaction time of the Passerini and the
CuAAC steps. Reaction progress was followed by TLC. fYield of pure isolated compound.
When the optimum reaction conditions were applied to the reaction of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
3ꢀazidobenzoic acid, benzyl isocyanide, and phenylacetylene, βꢀlactamꢀtriazole hybrid (+)ꢀ7 was
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obtained in good yield (75%, Scheme 4).
Scheme 4. Synthesis of β-Lactam-Triazole Hybrid (+)-7 via One-Pot Passerini/CuAAC
Reactions of Azetidine-2,3-dione (+)-1a
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Ph
7
8
9
N
O
O
H
N
N
N
O
O
O
O
i) 2-Azido-benzoic acid, BnNC, CH2Cl2, rt, 16h
O
O
H
N
O
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ii)
, CuI (0.1 equiv), 2,6-lutidine (2 equiv), 48h
Ph
PMP
Bn NH
O
PMP
(+)-1a
(+)-7 (75%)
Taking into account that dimers have superior biological activity in comparison to their
monomers,21 we were interested in synthesizing dimeric structures22 via the designed
Passerini/CuAAC sequence using diazides or dialkynes. We examined the oneꢀpot reaction of
azetidineꢀ2,3ꢀdione (+)ꢀ1a in presence of 4ꢀpentynoic acid and benzyl isocyanide, followed by
addition of the corresponding bisꢀazide, affording C2 symmetric bis(βꢀlactam triazole) hybrids (+)ꢀ8a
and (+)ꢀ8b in good yields (87% and 74%, respectively, Scheme 5). Due to the high polarity of (+)ꢀ8a
and (+)ꢀ8b, these compounds were isolated by precipitation using cool hexanes followed by filtration.
Scheme 5. Synthesis of C2 Symmetric Bis(β-Lactam-Triazole) Hybrids (+)-8a and (+)-8b via
One-Pot Passerini/CuAAC Reactions of Azetidine-2,3-dione (+)-1a
O
N
N
N
O
H
N
O
O
O
O
O
O
O
N
O
O
N
i) 4-Pentynoic acid, BnNC, CH2Cl2, rt, 6h
ii) CuI (0.1 equiv), 2,6-lutidine (2 equiv),
N
H
H
O
O
O
O
PMP
N
N
PMP
PMP
, CH2Cl2, 20h (8a) / 25h (8b)
N3
N3
(+)-1a
NHBn
BnHN
O
=
(+)-8a (87%)
(+)-8b (74%)
=
Next, we were interested in studying the reaction by using dialkynes as linkers. However, when we
tested the reaction of azetidineꢀ2,3ꢀdione (+)ꢀ1a with 2ꢀazidoꢀbenzoic acid and benzyl isocyanide,
followed by addition of CuI/2,6ꢀlutidine and the corresponding dialkyne, a complex reaction mixture
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was observed. Fortunately, C2 symmetric bis(βꢀlactamꢀtriazole) derivatives (−)ꢀ9a and (+)ꢀ9b were
obtained by previous formation of the Passerini adduct and evaporation of the solvent, followed by
CuAAC (using the CuSO4ꢁ5H2O/AscNa system in dimethylformamide as solvent) (Scheme 6). Thus,
compounds (−)ꢀ9a and (+)ꢀ9b were isolated in 71% and 72% yields respectively, after precipitation
using cool hexanes.
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Scheme 6. Synthesis of C2 Symmetric Bis(β-Lactam-Triazole) Hybrids (−)-9a and (+)-9b
via Passerini/CuAAC Sequence Using a Dialkyne as Linker
i) 2-Azido-benzoic acid, BnNC, CH2Cl2, rt
ii) CuI (0.1 equiv), 2,6-lutidine (2 equiv), CH2Cl2
complex reaction mixture
O
O
H
O
i) 2-Azido-benzoic acid, BnNC, CH2Cl2, rt, 16h
N
O
O
O
N
N
N
N
O
O
PMP
ii) Evaporation of CH2Cl2
H
H
O
N
N
(+)-1a
O
O
iii) CuSO4·5H2O (0.1 equiv), AscNa (0.2 equiv),
O
O
O
O
N
N
PMP
(0.5 equiv), DMF, rt, 32h
PMP
NHBn
O
BnHN
O
=
iv) n-Hexane
O
(−)-9a (71%)
O
=
(+)-9b (72%)
O
Due to the importance of C3ꢀsymmetric derivatives containing the triazole ring in their structures,23
we decided to apply this protocol to the synthesis of tris(βꢀlactamꢀtriazole) derivatives, by using either
the corresponding triazides or trialkynes. However, the oneꢀpot reaction of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
4ꢀpentynoic acid, and benzyl isocyanide, followed by addition of CuI, 2,6ꢀlutidine, and 1,3,5ꢀ
tris(azidomethyl)benzene after formation of the Passerini adduct, gave a complex reaction mixture.
Once again, the problem was solved evaporating the dichloromethane after completion of the Passerini
reaction followed by CuAAC using the system Cu(II)/AscNa in dimethylformamide (Scheme 7).
Then, C3 symmetric tris(βꢀlactamꢀtriazole) hybrids 10a−c were obtained in moderate to good yields
after precipitation in cool hexanes. Analogously, when 2,4,6ꢀtris(propꢀ2ꢀynyloxy)ꢀ1,3,5ꢀtriazine was
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used as linker in the CuAAC, the expected C3 symmetric tris(βꢀlactamꢀtriazole) derivative (+)ꢀ11 was
7
8
obtained in excellent yield under similar reaction conditions (Scheme 8).
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Scheme 7. Synthesis of C3 Symmetric Tris(β-Lactam-Triazole) Hybrids 10a−c via
Passerini/CuAAC Sequence Using a Triazide as Linker
O
O
N
N
N
N
O
O
H
N
O
O
H
N
O
O
O
O
i) 4-Pentynoic acid, R2NC, CH2Cl2, rt,
N
N
O
NHR2
R2HN
6h (10a) / 3h (10b) / 1h (10c)
O
H
N
O
O
N
O
N
R1
R1
O
O
ii) Evaporation of CH2Cl2
N
iii) CuSO4·5H2O (0.15 equiv), AscNa (0.3 equiv),
R1
R2HN
O
N3
N3
(+)-1a R1 = PMP
(−)-1c R1 = Bn
O
O
N
H
R1
(0.33 equiv)
O
N3
O
DMF, rt, 16h (10a) / 21h (10b) / 23h (10c)
iv) n-Hexane
(−)-10a R1 = PMP, R2 = Bn (75%)
(−)-10b R1 = Bn, R2 = Bn (73%)
(+)-10c R1 = PMP, R2 = t-Bu (50%)
Scheme 8. Synthesis of C3-Symmetric Tris(β-Lactam-Triazole) Hybrid (+)-11 via
Passerini/CuAAC Sequence Using a Trialkyne as Linker
PMP
O
N
O
O
H
NHBn
O
O
O
O
i) 2-Azidobenzoic acid, BnNC, CH2Cl2, rt, 16h
ii) Evaporation of CH2Cl2
O
H
N
N
N
O
O
O
N
iii) CuSO4·5H2O (0.15 equiv), AscNa (0.3 equiv),
DMF, 47h
PMP
(+)-1a
O
N
O
N
N
N
N
(0.33 equiv)
O
N
O
N
N
O
N
N
O
N
N
O
O
O
O
O
H
H
O
O
iv) n-Hexane
O
O
N
N
BnHN
NHBn
PMP
PMP
(+)-11 (84%)
O
O
The diastereoselectivity in the Passerini reaction with azetidineꢀ2,3ꢀdiones 1 is explained by the
presence of a bulky chiral auxiliary at Cꢀ4, in which one face of the carbonyl group is blocked
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preferentially. Thus, the nucleophilic addition takes place to the less hindered face of the carbonyl
group affording Passerini adducts as single isomers.24 On the other hand, the simplicity of the proton
and carbon NMR spectra of bisꢀ and tris(βꢀlactamꢀtriazole) hybrids pointed to C2ꢀ and C3 symmetrical
structures. In addition, 1,4ꢀdisubstituted 1,2,3ꢀtriazoles were obtained regioselectively,25 which was
confirmed unequivocally by single crystal Xꢀray analysis of compound (+)ꢀ6b.26
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CONCLUSIONS
In conclusion, the present work demonstrates the diastereoselective synthesis of various 3,3ꢀ
disubstituted βꢀlactams via Passerini and PasseriniꢀSmiles reactions, with stereocontroled formation of
a new quaternary stereogenic centre in excellent optical purity and generally high yields. The Passerini
reaction was coupled with CuAAC using the corresponding alkynes or azides to afford a family of
monoꢀ bisꢀ and tris(βꢀlactamꢀtriazole) hybrids regioselectively. This Passerini/CuAAC synthetic
sequence represents a practical and efficient opportunity to obtain highly functionalized and complex
βꢀlactamꢀtriazole structures, which combine the interesting biological features of the βꢀlactam skeleton
and the 1,2,3ꢀtriazole moiety.
EXPERIMENTAL SECTION
1
13
General Methods. H and C NMR spectra were recorded on a 300 MHz spectrometer. NMR were
recorded in CDCl3 or C2D2Cl4 solutions. Chemical shifts are given in ppm relative to TMS (1H, 0.0
13
ppm), CDCl3 (13C, 77.0 ppm) or C2D2Cl4 (1H, 5.94 ppm; C, 75.5 ppm). NMR spectra of compounds
8−11 were recorded at high temperature (120ꢀ130°C) to resolve the multiplicity of the signals. High
resolution mass spectra were performed on a QTOF LC/MS spectrometer under electrospray mode
(ESI) technique unless otherwise stated. Specific rotation [α]D is given in 10–1 deg cm2 g–1 at 20 °C, and
the concentration (c) is expressed in grams per 100 mL. All commercially available compounds were
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used without further purification. Flash Sꢀ2 chromatography was performed by using silica gel 60
(230−400 mesh). Products were identified by TLC (Kieselgel 60Fꢀ254). UV light (λ = 254nm) and a
solution of phosphomolibdic acid in EtOH (1 g of phosphomolybdic acid hydrate, 100 mL EtOH) was
used to develop the plates.
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General Procedure for the Passerini Reaction. Synthesis of Compounds 2. Method A. To a solution
of azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous dichloromethane (5 mL), the corresponding carboxylic
acid (1.05 mmol) and the appropriate isocyanide (1.10 mmol) were sequentially added at room
temperature and under argon atmosphere. The reaction mixture was stirred until complete
disappearances of the starting material (TLC). Then, the mixture was diluted with CH2Cl2 (2 mL) and
NaHCO3 aq. sat. (1 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 x 2 mL), the
combined organic extracts were dried (MgSO4), and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography eluting with hexanes/ethyl acetate mixtures. Method
B. To a solution of azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous acetonitrile (5 mL), the corresponding
carboxylic acid (1.05 mmol) and TosMIC (1.10 mmol) were sequentially added at room temperature
and under argon atmosphere. The reaction mixture was stirred at reflux temperature until complete
disappearance of the starting material (TLC). Then, the mixture was diluted with CH2Cl2 (10 mL) and
NaHCO3 aq. sat. (4 mL) was added. The resulting reaction mixture was workedꢀup as indicated above
(Method A). Method C. To a solution of azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous acetonitrile (5
mL), the corresponding carboxylic acid (1.05 mmol) and pꢀmethoxyphenyl isocyanide (PMPNC) (1.10
mmol) were sequentially added, at room temperature and under argon atmosphere. The reaction mixture
was stirred at reflux temperature for 12 h. Then, a second equivalent of PMPNC was added and the
resulting mixture was stirred at reflux temperature until complete disappearance of the starting material
(TLC). After that, the resulting reaction mixture was workedꢀup as indicated above (Method B).
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Passerini Adduct (+)-2a. Method A. From 50 mg (0.17 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 84 mg
(92%) of compound (+)ꢀ2a was obtained as a colorless oil after purification by flash chromatography
5
6
7
8
9
1
(hexanes/ethyl acetate, 1:1). [α]D = + 28.7 (c 0.2, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 8.04ꢀ
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8.01 (m, 2H), 7.66 (m, 2H), 7.61ꢀ7.67 (m, 1H), 7.51ꢀ7.46 (m, 2H), 7.22ꢀ7.32 (m, 5H), 6.89 (m, 2H),
6.70 (t, J = 5.6 Hz, 1H), 4.92 (d, J = 7.5 Hz, 1H), 4.61 (dd, J = 15.0, 6.1 Hz 1H), 4.50 (q, J = 7.1 Hz,
1H), 4.44 (dd, J = 15.0, 5.4 Hz, 1H), 4.14 (dd, J = 8.8, 6.6 Hz, 1H), 4.03 (dd, J = 8.8, 6.9 Hz, 1H), 3.81
13
(s, 3H), 1.46 and 1.26 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.4, 164.3, 160.0, 157.2,
137.0, 134.3, 130.2, 130.1, 128.8, 128.7, 127.9, 127.6, 127.5, 120.7, 114.1, 110.2, 86.4, 75.2, 66.8, 64.1,
55.4, 43.9, 26.4, 25.1; IR (CHCl3, cmꢀ1): υ 3337, 1763, 1734, 1682; HRMS (ESI): for C30H31N2O7
+
(M+H)+ calcd 531.2126, found 531.2123.
Passerini Adduct (−)-2b. Method A. From 64 mg (0.28 mmol) of azetidineꢀ2,3ꢀdione (−)ꢀ1b, 94 mg
(71%) of compound (−)ꢀ2b was obtained as a colorless oil after purification by flash chromatography
1
(hexanes/ethyl acetate, 1:1). [α]D = − 50.8 (c 1.6, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 8.03ꢀ
8.00 (m, 2H), 7.63 (bt, J = 7.5 Hz, 1H), 7.47 (bt, J = 7.7 Hz, 2H), 7.22ꢀ7.29 (m, 5H), 6.52 (t, J = 5.6 Hz,
1H), 5.82 (dddd, J = 17.2, 10.2, 7.0, 4.8 Hz, 1H), 5.33 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 10.2 Hz, 1H),
4.46 (d, J = 7.6 Hz, 1H), 4.56 (dd, J = 15.1, 5.8 Hz, 1H), 4.44 (dd, J = 15.1, 5.5 Hz, 1H), 4.35 (q, J = 6.7
Hz, 1H), 4.28 (dd, J = 15.7, 4.8 Hz, 1H), 4.05 (dd, J = 9.1, 6.6 Hz, 1H), 3.95 (dd, J = 8.9, 5.7 Hz, 1H),
3.85 (dd, J = 15.6, 7.2 Hz, 1H), 1.43 and 1.28 (s, each 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.5,
164.5, 162.4, 137.2, 134.2, 130.7, 130.1, 128.73, 128.66, 127.9, 127.5, 127.4, 119.1, 110.0, 87.0, 75.1,
67.0, 62.0, 44.5, 43.8, 26.6, 25.0; IR (CHCl3, cmꢀ1): υ 3333, 1770, 1732, 1683; HRMS (ESI) for
+
C26H29N2O6 (M+H)+ calcd 465.2020, found 465.2038.
Passerini Adduct (+)-2c. Method A. From 36 mg (0.12 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 54 mg
(100%) of compound (+)ꢀ2c was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = + 44.2 (c 1.7, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.60
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(m, 2H), 7.37ꢀ7.25 (m, 5H), 6.88 (m, 2H), 6.83 (t, J = 5.8 Hz, 1H), 4.73 (d, J = 7.3 Hz, 1H), 4.59 (dd, J
= 14.9, 6.2 Hz, 1H), 4.41 (q, J = 7.0 Hz, 1H), 4.36 (dd, J = 14.9, 5.0 Hz, 1H), 4.16 (dd, J = 8.9, 6.7 Hz,
1H), 3.97 (dd, J = 8.9, 6.8 Hz, 1H), 3.80 (s, 3H), 2.19 (s, 3H), 1.48 and 1.35 (s, each 3H); 13CꢀNMR (75
MHz, CDCl3, 25 ºC) δ 168.5, 164.4, 160.0, 157.2, 137.0, 130.1, 128.7, 127.6, 127.6, 120.5, 114.1,
110.2, 86.0, 75.3, 66.6, 64.3, 55.4, 43.9, 26.4, 25.1, 20.6; IR (CHCl3, cmꢀ1) υ 3332, 1754, 1677; HRMS
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(ESI) for C25H29N2O7 (M+H)+ calcd 469.1969, found 469.1976.
Passerini Adduct (+)-2d. Method A. From 221 mg (0.76 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 384 mg
(100%) of compound (+)ꢀ2d was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = + 15.5 (c 0.6, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.59
(m, 2H), 7.34ꢀ7.24 (m, 5H), 6.92 (t, J = 5.7 Hz, 1H), 6.88 (m, 2H), 4.82 (d, J = 7.2 Hz, 1H), 4.57 (dd, J
= 14.8, 6.2 Hz, 1H), 4.41 (q, J = 6.9 Hz, 1H), 4.37 (dd, J = 14.9, 5.4 Hz, 1H), 4.16 (dd, J = 8.8, 6.7 Hz,
1H), 3.92 (dd, J = 8.8, 6.8 Hz, 1H), 3.80 (s, 3H), 2.72ꢀ2.67 (m, 2H), 2.56ꢀ2.51 (m, 2H), 1.89 (t, J = 2.6
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Hz, 1H), 1.47 and 1.33 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 169.5, 164.1, 159.7, 157.2,
137.0, 130.1, 128.7, 127.7, 127.6, 120.6, 114.0, 110.2, 86.3, 81.8, 75.0, 69.8, 66.7, 64.1, 55.4, 43.9,
+
33.0, 26.4, 25.1, 14.2; IR (CHCl3, cmꢀ1) υ 3295, 1758, 1678; HRMS (ESI) for C28H31N2O7 (M+H)+
calcd 507.2126, found 507.2124.
Passerini adduct (−)-2e. Method A. From 42 mg (0.14 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 84 mg
(89%) of compound (−)ꢀ2e was obtained as a colorless oil after purification by flash chromatography
(hexanes/ethyl acetate, 1:1). [α]D = − 1.3 (c 0.4, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 8.02 (dd,
J = 8.0, 0.9 Hz, 1H), 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.61 (m, 2H), 7.56 (td, J = 7.6, 1.1 Hz, 1H,), 7.37ꢀ
7.28 (m, 5H), 7.23 (td, J = 7.7, 1.8 Hz, 1H), 6.90 (m, 2H), 6.76 (t, J = 5.8 Hz, 1H), 5.00 (d, J = 6.6 Hz,
1H), 4.66 (dd, J = 14.8, 6.4 Hz, 1H), 4.53 (q, J = 6.8 Hz, 1H), 4.43 (dd, J = 14.9, 5.4 Hz, 1H), 4.12 (dd,
J = 8.8, 6.7 Hz, 1H), 3.99 (dd, J = 8.8, 6.9 Hz, 1H), 3.81 (s, 3H), 1.45 and 1.28 (s, each 3H); 13CꢀNMR
(75 MHz, CDCl3, 25 ºC) δ 164.3, 164.0, 159.6, 157.3, 141.7, 137.0, 133.7, 132.9, 131.7, 130.1, 128.8,
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128.1, 127.8, 127.7, 120.8, 114.1, 110.2, 94.4, 86.9, 74.9, 66.8, 63.8, 55.5, 44.1, 26.4, 25.2, IR (CHCl3,
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cmꢀ1) υ 3333, 1764, 1680; HRMS (ESI) for C30H30IN2O7 (M+H)+ calcd 657.1092, found 657.1094.
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Passerini Adduct (−)-2f. Method A. From 33 mg (0.11 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 58 mg
(90%) of compound (−)ꢀ2f was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = − 17.1 (c 1.5, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.95
(dd, J = 7.9, 1.5 Hz, 1H), 7.69 (m, 2H), 7.61 (td, J = 8.2, 1.6 Hz, 1H), 7.55 (t, J = 5.3 Hz, 1H), 7.38ꢀ7.29
(m, 5H), 7.21 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H,), 6.91 (m, 2H), 4.91 (d, J = 7.8 Hz, 1H), 4.63
(dd, J = 14.8, 5.8 Hz, 1H), 4.55 (q, J = 7.2 Hz, 1H), 4.51 (dd, J = 14.8, 5.1 Hz, 1H), 4.02 (dd, J = 8.8,
6.7 Hz, 1H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 3.82 (s, 3H), 1.31 and 1.48 (s, each 3H); 13CꢀNMR (75
MHz, CDCl3, 25 ºC) δ 164.2, 163.1, 159.4, 157.0, 140.1, 136.9, 134.7, 133.2, 130.4, 128.9, 127.85,
127.75, 125.0, 120.5, 119.9, 119.4, 114.1, 110.2, 86.9, 75.1, 66.6, 65.3, 55.4, 44.2, 26.5, 25.2; IR
+
(CHCl3, cmꢀ1) υ 3354, 2123, 1766, 1735, 1683; HRMS (ESI) for C30H30N5O7 (M+H)+ calcd 572.2140;
found 572.2143.
Passerini Adduct (−)-2g. Method A. From 40 mg (0.14 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 76 mg
(91%) of compound (−)ꢀ2g was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = − 13.2 (c 3.1, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.86
(AA'BB', 2H), 7.76 (AA'BB', 2H), 7.52 (m, 2H), 7.32ꢀ7.23 (m, 5H), 7.07 (bs, 1H), 6.86 (m, 2H), 5.00
(d, J = 6.4 Hz, 1H), 4.57 (s, 2H), 4.56 (dd, J = 14.8, 6.2 Hz, 1H), 4.41 (dd, J = 14.0, 6.3 Hz, 1H), 4.39
(q, J = 6.6 Hz, 1H), 4.12 (dd, J = 8.6, 6.9 Hz, 1H), 3.82 (dd, J = 9.0, 6.8 Hz, 1H), 3.79 (s, 3H), 1.43 and
1.37 (s, each 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 167.1, 165.6, 163.2, 159.1, 157.3, 137.0, 134.5,
131.7, 129.9, 128.6, 127.6, 127.5, 123.8, 121.0, 114.1, 110.2, 87.2, 74.4, 66.5, 63.4, 55.4, 44.0, 38.8,
+
26.3, 24.9; IR (CHCl3, cmꢀ1) υ 3342, 1764, 1722, 1683; HRMS (ESI) for C33H32N3O9 (M+H)+ calcd
614.2133, found 614.2132.
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Passerini Adduct (−)-2h. Method A. From 46 mg (0.17 mmol) of azetidineꢀ2,3ꢀdione (−)ꢀ1c, 44 mg
(53%) of compound (−)ꢀ2h was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = − 59.8 (c 1.1, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.37ꢀ
7.21 (m, 10H), 6.55 (t, J = 5.6 Hz, 1H), 4.94 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 5.7, 2H), 4.36ꢀ4.27 (m,
1H), 4.26 (d, J = 14.9 Hz, 1H), 4.10 (d, J = 7.4 Hz, 1H), 4.05 (dd, J = 9.0, 6.9 Hz, 1H), 3.76 (dd, J = 9.1,
5.4 Hz, 1H), 2.67ꢀ2.61 (m, 2H), 2.54ꢀ2.48 (m, 2H), 1.84 (t, J = 2.6 Hz, 1H), 1.33 and 1.32 (s, each 3H);
13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 169.6, 164.3, 162.4, 137.1, 134.4, 128.7, 128.7, 128.4, 127.9,
127.64, 127.61, 110.1, 86.8, 81.8, 74.7, 69.8, 66.6, 61.7, 45.7, 43.8, 32.9, 26.4, 24.9, 14.1; IR (CHCl3,
cmꢀ1) υ 3299, 1762, 1680; HRMS (ESI) for C28H31N2O6 (M+H)+ calcd 491.2177, found 491.2174.
+
Passerini Adduct (+)-2i. Method A. From 40 mg (0.14 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 58 mg
(88%) of compound (+)ꢀ2i was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = + 53.3 (c 1.0, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.63
(m, 2H), 6.89 (m, 2H), 6.17 (bs, 1H), 4.62 (d, J = 7.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 1H), 4.19 and 3.99
(dd, J = 8.8, 6.8 Hz, each 1H), 3.81 (s, 3H), 2.73ꢀ2.68 (m, 2H), 2.59ꢀ2.53 (m, 2H), 2.04 (t, J = 2.6 Hz,
13
1H), 1.49 (s, 3H), 1.36 (s, 9H), 1.33 (s, 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 169.3, 163.2, 160.1,
157.1, 130.2, 120.4, 114.0, 110.1, 86.4, 81.6, 75.3, 69.8, 66.7, 64.2, 55.4, 52.2, 33.0, 28.4, 26.4, 25.0,
+
14.1; IR (CHCl3, cmꢀ1) υ 3304, 1755, 1684; HRMS (ESI) for C25H33N2O7 (M+H)+ calcd 473.2282;
found 473.2303.
Passerini Adduct (+)-2j. Method A. From 48 mg (0.16 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 100 mg
(100%) of compound (+)ꢀ2j was obtained as a yellowish solid after purification by flash
chromatography (hexanes/ethyl acetate, 1:1). Method B. From 28 mg (0.10 mmol) of azetidineꢀ2,3ꢀ
dione (+)ꢀ1a, 52 mg (89%) of pure compound (+)ꢀ2j was obtained. Mp: 208−210 °C; [α]D = + 31.0 (c
1.4, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 8.07ꢀ8.01 (m, 2H), 7.68 (m, 2H), 7.67ꢀ7.60 (m, 1H),
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7.59 (m, 2H), 7.49 (m, 2H), 7.33 (t, J = 6.7 Hz, 1H), 7.11 (2H, m), 6.91 (m, 2H), 4.85 (dd, J = 14.2, 7.4
Hz, 1H), 4.59 (dd, J = 14.0, 6.8 Hz, 1H), 4.57 (d, J = 7.3 Hz, 1H), 4.38 (q, J = 6.9 Hz, 1H), 4.04 (dd, J =
8.9, 6.7 Hz, 1H), 3.83 (s, 3H), 3.79 (dd, J = 8.7, 6.8 Hz, 1H), 2.28 (s, 3H), 1.43 and 1.24 (s, each 3H);
13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.3, 164.0, 158.9, 157.2, 145.3, 134.5, 133.4, 130.2, 130.1,
129.9, 129.0, 128.9, 127.5, 120.5, 114.1, 110.2, 86.0, 75.0, 66.7, 63.7, 60.1, 55.5, 26.4, 25.0, 21.5; IR
(KBr, cmꢀ1) υ 3328, 1766, 1737, 1701; HRMS (ES) for C31H33N2O9S+ (M+H)+ calcd 609.1901, found
609.1894.
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Passerini Adduct (+)-2k. Method B. From 39 mg (0.13 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 24 mg
(34%) of compound (+)ꢀ2k was obtained as a white solid after purification by flash chromatography
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(hexanes/ethyl acetate, 2:1). Mp: 197−198 °C; [α]D = + 45.6 (c 1.0, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 ºC) δ 7.70 (m, 2H), 7.56 (m, 2H), 7.49 (t, 1H, J = 6.7 Hz), 7.16 (m, 2H), 6.90 (m, 2H), 4.86
(dd, J = 14.2, 7.5 Hz, 1H), 4.60 (dd, J = 14.1, 6.2 Hz, 1H), 4.40 (d, J = 7.4 Hz, 1H), 4.31 (q, J = 6.9 Hz,
1H), 4.05 (dd, J = 8.8, 6.6 Hz, 1H), 3.82 (s, 3H), 3.71 (dd, J = 8.8, 6.8 Hz, 1H), 2.20 (s, 3H), 2.31(s,
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3H), 1.32 and 1.45 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC): δ 168.6, 164.2, 158.9, 157.2,
145.4, 133.5, 130.0, 129.9, 128.9, 120.4, 114.1, 110.2, 85.7, 74.9, 66.5, 63.9, 60.2, 55.5, 26.4, 25.0,
21.6, 20.5; IR (KBr, cmꢀ1) υ 3324, 1761, 1699; HRMS (ESI) for C26H30N2NaO9S+ (M+Na)+ calcd
569.1564, found 569.1553.
Passerini Adduct (+)-2l. Method B. From 49 mg (0.17 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 60 mg
(62%) of compound (+)ꢀ2l was obtained as a yellowish oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = + 22.4 (c 2.0, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.71
(m, 2H), 7.56 (m, 2H), 7.22 (t, J = 7.1 Hz, 1H), 7.18 (m, 2H), 6.91 (m, 2H), 4.84 (dd, J = 14.2, 7.6 Hz,
1H), 4.53 (dd, J = 14.2, 6.1 Hz, 1H), 4.40 (d, J = 7.3 Hz, 1H), 4.32 (q, J = 6.8 Hz, 1H), 4.09 (dd, J = 8.8,
6.5 Hz, 1H), 3.83 (s, 3H), 3.71 (dd, J = 8.8, 6.3 Hz, 1H), 2.72 (t, J = 6.7 Hz, 2H), 2.60ꢀ2.55 (m, 2H),
13
2.32 (s, 3H), 2.14 (t, J = 2.6 Hz, 1H), 1.45 and 1.31 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ
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169.6, 163.9, 158.6, 157.2, 145.4, 133.3, 130.0, 129.0, 120.5, 114.0, 110.2, 85.9, 81.8, 74.7, 70.1, 66.5,
63.8, 60.1, 55.5, 32.9, 26.4, 25.0, 21.6, 14.2; IR (CHCl3, cmꢀ1) υ 3300, 1761, 1698; HRMS (ESI) for
C29H33N2O9S+ (M+H)+ calcd 585.1901, found 585.1910.
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Passerini Adduct (+)-2m. Method C. From 45 mg (0.15 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 61 mg
(74%) of compound (+)ꢀ2m was obtained as a colorless oil after purification by flash chromatography
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(hexanes/ethyl acetate, 1:1). [α]D = + 25.6 (c 0.3, CHCl3); HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 8.16
(bs, 1H), 8.09ꢀ8.06 (m, 2H), 7.64 (m, 2H), 7.67ꢀ7.63 (m, 1H), 7.54ꢀ7.49 (m, 2H), 7.44 (m, 2H), 6.93 (m,
2H), 6.84 (m, 2H), 4.94 (d, J = 7.8 Hz, 1H), 4.55 (q, J = 7.8 Hz, 1H), 4.20 (dd, J = 8.9, 6.7 Hz, 1H),
13
4.11 (dd, J = 8.8, 6.9 Hz, 1H), 3.82 and 3.78 (s, each 3H), 1.50 and 1.31 (s, each 3H); CꢀNMR (75
MHz, CDCl3, 25 ºC) δ 164.5, 162.0, 160.2, 157.2, 157.1, 134.3, 130.2, 130.1, 129.8, 128.8, 127.9,
122.1, 120.6, 114.2, 114.1, 110.3, 86.5, 75.4, 66.9, 64.4, 55.5, 55.4, 26.5, 25.2; IR (CHCl3, cmꢀ1) υ 3309,
+
1753, 1687; HRMS (ESI) for C30H31N2O8 (M+H)+ calcd 547.2075, found 547.2097.
P-3CR of Azetidine-2,3-dione (+)-1a with Benzyl Isocyanide and Bromoacetic Acid. Method A.
From 50 mg (0.17 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a, 46 mg (49%) of Passerini adduct (+)ꢀ2n and 8
mg (11%) of 3ꢀhydroxyꢀβꢀlactam (−)ꢀ3 were obtained after purification by flash chromatography
(hexanes/ethyl acetate, 1:1).
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Passerini Adduct (+)-2n. Colorless oil. [α]D = + 26.4 (c 1.8, CHCl3); HꢀNMR (300 MHz, CDCl3, 25
ºC) δ 7.60 (m, 2H), 7.36ꢀ7.24 (m, 5H), 6.89 (m, 2H), 6.90ꢀ6.85 (m, 1H), 4.77 (d, J = 7.3 Hz, 1H), 4.59
(dd, J = 14.3, 6.9 Hz, 1H), 4.42 (q, J = 6.7 Hz, 1H), 4.37 (dd, J = 14.8, 5.8 Hz, 1H), 4.24 (dd, J = 8.9,
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6.7 Hz, 1H), 3.97 (dd, J = 8.9, 6.6 Hz, 1H), 3.93 (s, 2H), 3.81 (s, 3H), 1.35 and 1.48 (s, each 3H); Cꢀ
NMR (75 MHz, CDCl3, 25 ºC) δ 164.9, 163.6, 159.1, 157.4, 136.8, 129.8, 128.8, 127.72, 127.69, 120.7,
114.1, 110.4, 86.7, 75.0, 66.7, 64.2, 55.5, 44.0, 26.4, 25.0, 24.3; IR (CHCl3, cmꢀ1) υ 3336, 1758, 1673;
+
HRMS (ESI) for C25H28BrN2O7 (M+H)+ calcd 547.1074, found: 547.1079.
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3-Hydroxy-β-Lactam (−)-3. White solid. Mp: 184−186 °C; [α]D = − 6.8 (c 0.4, CHCl3); 1HꢀNMR (300
MHz, CDCl3, 25 ºC) δ 7.54 (m, 2H), 7.36ꢀ7.20 (m, 5H), 7.01 (t, J = 5.8 Hz, 1H), 6.85 (m, 2H), 5.98 (bs,
1H), 4.61 (d, J = 6.1 Hz, 1H), 4.50 (dd, J = 15.6, 6.7 Hz, 1H), 4.45 (q, J = 6.7 Hz, 1H), 4.29ꢀ4.22 (m,
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2H), 3.79 (s, 3H), 3.77 (dd, J = 8.6, 6.1 Hz, 1H), 1.45 and 1.37 (s, each 3H); CꢀNMR (75 MHz,
CDCl3, 25 ºC) δ 167.1, 164.4, 157.2, 137.4, 130.0, 128.7, 127.7, 127.6, 120.7, 114.1, 110.2, 84.6, 75.9,
+
66.5, 65.5, 55.4, 43.4, 26.4, 25.2; IR (KBr, cmꢀ1) υ 3302, 1755, 1655; HRMS (ESI) for C23H27N2O6
(M+H)+ calcd 427.1864, found: 427.1861.
P-3CR-Base Promoted Cyclization Sequence. Synthesis of Spiro Compound (−)-4. To a solution of
azetidineꢀ2,3ꢀdione (+)ꢀ1a (58 mg, 0.20 mmol) in anhydrous dichloromethane (1 mL), bromoacetic acid
(29 mg, 0.21 mmol) and benzyl isocyanide (27 ꢀL, 0.22 mmol) were successively added, at room
temperature under argon. The reaction mixture was stirred at room temperature for 1.5h. Then, DIPEA
was added (36 ꢀL, 0.21 mmol) and the resulting mixture was stirred at room temperature for 2h. Then,
the mixture was diluted with CH2Cl2 (1 mL) and H2O (1 mL) was added. The aqueous layer was
extracted with CH2Cl2 (3 x 2 mL), the combined organic extracts were dried (MgSO4), and the solvent
was removed under reduced pressure. The residue was purified by flash chromatography eluting with
hexanes/ethyl acetate (3:1) affording 52 mg (56%) of compound (−)ꢀ4 as a colorless oil. [α]D = − 2.5 (c
0.5, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.63 (m, 2H), 7.34ꢀ7.28 (m, 5H), 6.89 (m, 2H), 5.16
(d, J = 16.5 Hz, 1H), 5.03 (s, 2H), 4.77 (d, J = 8.9 Hz, 1H), 4.61 (d, J = 16.7 Hz, 1H), 4.42 (dt, J = 8.7,
6.6 Hz, 1H), 4.20 (dd, J = 9.1, 6.9 Hz, 1H), 3.81 (s, 3H), 3.58 (dd, J = 9.1, 6.3 Hz, 1H), 1.53 and 1.34 (s,
13
each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 167.5, 165.4, 159.2, 157.2, 135.5, 129.9, 128.7, 128.3,
127.9, 120.3, 114.0, 110.4, 86.3, 75.9, 66.8, 66.3, 63.7, 55.4, 43.0, 26.5, 24.8; IR (CHCl3, cmꢀ1) υ 1755,
+
1692; HRMS (ESI) for C25H27N2O7 (M+H)+ calcd 467.1813, found 467.1808.
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General Procedure for the Passerini-Smiles Reaction. Synthesis of compounds 5. Method A. To a
solution of azetidineꢀ2,3ꢀdione (+)ꢀ1a (1 mmol) in anhydrous dichloromethane (5 mL), the
corresponding phenol (1.05 mmol) and the appropriate isocyanide (1.10 mmol) were sequentially added,
at room temperature and under argon atmosphere. The reaction mixture was stirred until complete
disappearances of the starting material (TLC). Then, the mixture was diluted with CH2Cl2 (2 mL) and
NaHCO3 aq. sat. (1 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The
organic extract was washed with NaHCO3 aq. sat. (3 x 2 mL), dried (MgSO4), and the solvent was
removed under reduced pressure. The residue was purified by flash chromatography eluting with
mixtures of hexanes/ethyl acetate. Method B. To a solution of azetidineꢀ2,3ꢀdione (+)ꢀ1a (1 mmol) in
anhydrous dichloromethane (5 mL), the appropriate phenol (1.05 mmol) and the corresponding
isocyanide (1.10 mmol) were sequentially added, at room temperature under argon atmosphere. The
reaction mixture was heated in a sealed tube at 80 °C until complete disappearance of the starting
material (TLC). The reaction mixture was allowed to cool to room temperature, diluted with CH2Cl2 (2
mL) and, then NaHCO3 aq. sat. (1 mL) was added. The resulting reaction mixture was workedꢀup as
indicated above (Method A).
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Passerini-Smiles Adduct (+)-5a. Method A. From 35 mg (0.12 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
52 mg (79%) of compound (+)ꢀ5a was obtained as a yellow solid after purification by flash
chromatography (hexanes/ethyl acetate, 3:2). Mp: 164−166 °C; [α]D = + 167.0 (c 0.4, CHCl3); 1HꢀNMR
(300 MHz, CDCl3, 25 ºC) δ 8.12 (m, 2H), 7.68 (m, 2H), 7.34 (m, 2H), 7.27ꢀ7.20 (m, 3H), 7.04ꢀ7.02 (m,
2H), 6.92 (m, 2H), 6.48 (t, 1H, J = 5.9 Hz), 4.59ꢀ4.50 (m, 2H), 4.46ꢀ4.41 (m, 1H), 4.28 (dd, J = 14.6,
5.4 Hz, 1H), 4.12 (dd, J = 8.9, 5.7 Hz, 1H), 3.85ꢀ3.81 (m, 1H), 3.83 (s, 3H), 1.54 and 1.37 (s, each 3H);
13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.4, 160.2, 159.3, 157.4, 143.6, 136.5, 129.8, 128.7, 128.0,
127.7, 125.7, 120.5, 118.3, 114.1, 110.4, 88.7, 76.0, 66.9, 65.7, 55.5, 43.8, 26.5, 24.8; IR (KBr, cmꢀ1) υ
+
3351, 1756, 1676; HRMS (ESI) for C29H30N3O8 (M+H)+ calcd 548.2027, found 548.2030.
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Passerini-Smiles Adduct (+)-5b. Method A. From 35 mg (0.12 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
39 mg (63%) of compound (+)ꢀ5b was obtained as a colorless oil after purification by flash
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chromatography (hexanes/ethyl acetate, 1:1). [α]D = + 142.0 (c 0.4, CHCl3); HꢀNMR (300 MHz,
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CDCl3, 25 ºC) δ 8.24 (m, 2H), 7.69 (m, 2H), 7.40 (m, 2H), 6.92 (m, 2H), 5.95 (bs, 1H), 4.57ꢀ4.50 (m,
1H), 4.46 (d, J = 8.0 Hz, 1H), 4.42 (dd, J = 8.7, 6.6 Hz, 1H), 4.10 (dd, J = 8.8, 6.1 Hz, 1H), 3.83 (s, 3H),
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1.54 and 1.37 (s, each 3H), 1.24 (s, 9H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 163.4, 160.7, 159.6,
157.4, 143.7, 130.0, 125.6, 120.5, 118.5, 114.1, 110.4, 89.0, 76.0, 66.9, 65.7, 55.5, 52.6, 28.4, 26.5,
24.8; IR (CHCl3, cmꢀ1) υ 3394, 1758, 1684; HRMS (ESI) for C26H32N3O8 (M+H)+ calcd 514.2184,
+
found 514.2191.
Passerini-Smiles Adduct (+)-5c. Method A. From 101 mg (0.35 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
205 mg (94%) of compound (+)ꢀ5c was obtained as a colorless oil after purification by flash
1
chromatography (hexanes/ethyl acetate, 1:1). [α]D = + 153.4 (c 2.0, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 ºC) δ 8.41 (d, J = 2.8 Hz, 1H), 8.01 (dd, J = 9.2, 2.8 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68
(m, 2H), 7.33ꢀ7.24 (m, 3H), 7.10ꢀ7.06 (m, 2H), 6.91 (m, 2H), 6.39 (t, J = 5.9 Hz, 1H), 4.71ꢀ4.64 (m,
2H), 4.50 (dd, J = 14.5, 6.1 Hz, 1H), 4.46 (d, J = 7.0 Hz, 1H), 4.39 (dd, J = 14.6, 5.8 Hz, 1H), 4.17ꢀ4.10
13
(m, 1H), 3.83 (s, 3H), 1.57 and 1.38 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.2, 159.4,
157.5, 156.4, 143.3, 136.6, 129.6, 129.1, 128.8, 128.0, 127.7, 124.3, 120.8, 117.4, 114.0, 112.3, 110.6,
89.3, 76.1, 67.4, 66.0, 55.4, 43.9, 26.7, 24.7; IR (CHCl3, cmꢀ1) υ 3347, 1757, 1680; HRMS (ESI) for
+
C29H29BrN3O8 (M+H)+ calcd 626.1133, found: 626.1137.
Passerini-Smiles Adduct (+)-5d. Method A. From 101 mg (0.35 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
183 mg (89%) of compound (+)ꢀ5d was obtained as a colorless oil after purification by flash
1
chromatography (hexanes/ethyl acetate, 1:1). [α]D = + 158.3 (c 3.2, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 ºC) δ 8.50 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.2, 2.6 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.70
(m, 2H), 6.92 (m, 2H), 5.84 (bs, 1H), 4.70ꢀ4.63 (m, 2H), 4.42ꢀ4.36 (m, 1H), 4.13ꢀ4.07 (m, 1H), 3.83 (s,
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3H), 1.58 and 1.38 (s, each 3H), 1.28 (s, 9H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 163.3, 159.8, 157.5,
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156.6, 143.4, 129.8, 129.2, 124.2, 120.8, 117.5, 114.1, 112.4, 110.5, 89.6, 76.0, 67.4, 66.1, 55.5, 52.8,
9
+
28.4, 26.6, 24.7; IR (CHCl3, cmꢀ1) υ 3405, 1758, 1689; HRMS (ESI) for C26H31BrN3O8 (M+H)+ calcd
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592.1289, found: 592.1285.
Passerini-Smiles Adduct (+)-5e. Method A. From 103 mg (0.35 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
174 mg (73%) of compound (+)ꢀ5e was obtained as a colorless oil after purification by flash
1
chromatography (hexanes/ethyl acetate, 1:1). [α]D = + 132.3 (c 0.8, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 ºC) δ 8.61 (d, J = 2.6 Hz, 1H), 8.04 (dd, J = 9.2, 2.8 Hz, 1H), 7.66 (m, 2H), 7.64 (d, J = 8.9
Hz, 1H), 7.28ꢀ7.26 (m, 3H), 7.11ꢀ7.08 (m, 2H), 6.91 (m, 2H), 6.35 (t, J = 5.7 Hz, 1H), 4.77ꢀ4.69 (m,
2H), 4.50 (dd, J = 14.6, 6.1 Hz, 1H), 4.46 (d, J = 8.2 Hz, 1H), 4.40 (dd, J = 14.8, 5.8 Hz, 1H), 4.15ꢀ4.09
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(m, 1H), 3.83 (s, 3H), 1.38 and 1.55 (s, each 3H); CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 164.3, 159.3,
158.8, 157.5, 143.4, 136.6, 135.2, 129.6, 128.8, 128.0, 127.7, 125.2, 121.0, 116.2, 114.0, 110.6, 89.5,
85.0, 75.8, 67.9, 65.9, 55.4, 43.9, 26.7, 24.8; IR (CHCl3, cmꢀ1) υ 3361, 1759, 1680; HRMS (ESI) for
C29H29IN3O8 (M+H)+ calcd 674.0994, found 674.1007.
+
Passerini-Smiles Adduct (+)-5f. Method B. From 32 mg (0.11 mmol) of azetidineꢀ2,3ꢀdione (+)ꢀ1a,
38 mg (63%) of compound (+)ꢀ5f was obtained as a colorless oil after purification by flash
chromatography (hexanes/ethyl acetate, 1:1). [α]D = + 66.1 (c 0.6, CHCl3); 1HꢀNMR (300 MHz, CDCl3,
25 ºC) δ 8.17 (d, J = 8.5 Hz, 1H), 7.71 (td, J = 8.8, 1.6 Hz, 1H), 7.70 (m, 2H), 7.53 (td, J = 8.0, 1.7 Hz,
1H), 7.23ꢀ7.07 (m, 4H), 7.09 (t, J = 5.6 Hz, 1H), 6.94ꢀ6.87 (m, 2H), 6.90 (m, 2H), 4.58ꢀ4.51 (m, 2H),
4.42 (d, J = 8.9 Hz, 1H), 4.34ꢀ4.28 (m, 1H), 4.32 (dd, J = 9.4, 6.6 Hz, 1H), 3.97 (dd, J = 9.4, 5.1 Hz,
1H), 3.82 (s, 3H), 1.55 and 1.34 (s, each 3H); 13CꢀNMR (75 MHz, CDCl3, 25 ºC) δ 165.1, 159.5, 157.3,
147.7, 140.1, 136.7, 134.6, 129.8, 128.7, 127.6, 127.4, 125.3, 123.6, 120.9, 119.7, 113.9, 110.4, 89.9,
76.1, 66.9, 65.9, 55.4, 43.7, 26.6, 24.6; IR (CHCl3, cmꢀ1) υ 3602, 1759, 1679; HRMS (ESI) for
+
C29H29N3NaO8 (M+Na)+ calcd 570.1847, found 570.1857.
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General Procedure for the CuAAC. Synthesis of β-Lactam-Triazole Hybrids 6. Method A. To a
solution of the appropriate Passerini adduct 2 (1 mmol) in anhydrous dichloromethane (3.2 mL), CuI
(0.10 mmol), 2,6ꢀlutidine (2 mmol) and tosylazide (2 mmol) were sequentially added, at room
temperature under argon atmosphere. The reaction mixture was stirred until complete disappearance of
the starting material (TLC). Then, the mixture was diluted with CH2Cl2 (6.4 mL) and NH4Cl aq. sat.
(3.2 mL) and stirred at room temperature for 30 min. The aqueous layer was extracted with CH2Cl2 (3 x
6 mL), the combined organic extracts were dried (MgSO4), and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography eluting with mixtures of hexanes/ethyl
acetate.
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General Procedure for the Passerini/CuAAC Sequence. Synthesis one-pot of β-Lactam Triazole
Hybrids 6−11. Method B. To a solution of the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous
dichloromethane (5 mL), the appropriate carboxylic acid (1.05 mmol) and the corresponding isocyanide
(1.10 mmol) were sequentially added, at room temperature under argon atmosphere. The reaction
mixture was stirred at the same temperature until complete disappearances of the azetidineꢀ2,3ꢀdione 1
(TLC). Then, CuI (0.10 mmol), 2,6ꢀlutidine (2 mmol) and the corresponding azide (2 mmol) were
sequentially added. The resulting mixture was stirred at room temperature until complete
disappearances of the corresponding Passerini adduct (TLC). After that, the reaction mixture was
diluted with CH2Cl2 (5 mL) and NH4Cl aq. sat. (3.3 mL) and stirred at room temperature for 30 min.
The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), the combined organic extracts were dried
(MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash
chromatography. Method C. To a solution of the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in
anhydrous acetonitrile (5 mL), 4ꢀpentynoic acid (1.05 mmol) and TosMIC (1.10 mmol) were
sequentially added, at room temperature under argon atmosphere. The reaction mixture was stirred at
reflux temperature until complete disappearances of the azetidineꢀ2,3ꢀdione 1 (TLC). Then, acetonitrile
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was evaporated under reduced pressure and CH2Cl2 (5 mL), CuI (0.10 mmol), 2,6ꢀlutidine (2 mmol),
and benzyl azide (2 mmol) were sequentially added, at room temperature under argon atmosphere. The
reaction mixture was stirred until complete disappearances of the Passerini adduct (TLC). Then, the
mixture was workedꢀup as indicated above (Method B). Method D. To a solution of the appropriate
azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous dichloromethane (5 mL), 2ꢀazidoꢀbenzoic acid (1.05
mmol) and benzyl isocyanide (1.10 mmol) were sequentially added, at room temperature under argon
atmosphere. The reaction mixture was stirred at room temperature until complete disappearance of the
azetidineꢀ2,3ꢀdione 1 (TLC). Then, CuI (0.10 mmol), 2,6ꢀlutidine (2 mmol), and phenyl acetylene (2
mmol) were sequentially added. The reaction mixture was stirred at room temperature until complete
disappearances of the Passerini adduct 2 (TLC). Then, the mixture was workedꢀup as indicated above
(Method B). Method E. To a solution of the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous
dichloromethane (5 mL), was added 4ꢀpentynoic acid (1.05 mmol) and benzyl isocyanide (1.10 mmol).
The reaction mixture was stirred at room temperature under argon atmosphere until complete
disappearance of the azetidineꢀ2,3ꢀdione 1 (TLC). Then, CuI (0.10 mmol), 2,6ꢀlutidine (2 mmol) and the
corresponding bisꢀazide (0.50 mmol) were sequentially added, at room temperature under argon
atmosphere. The reaction mixture was stirred until complete disappearances of the Passerini adduct
(TLC). Then, the mixture was workedꢀup as indicated above (Method B). Method F. To a solution of
the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous dichloromethane (5 mL), 2ꢀazido benzoic
acid (1.05 mmol) and benzyl isocyanide (1.10 mmol) were sequentially added, at room temperature
under argon atmosphere. The reaction mixture was stirred until complete disappearance of the azetidineꢀ
2,3ꢀdione 1 (TLC). Then, dichloromethane was evaporated under reduced pressure, and anhydrous DMF
(10 mL), CuSO4ꢁ5H2O (0.10 mmol), sodium ascorbate (0.20 mmol) and the corresponding bisꢀalkyne
(0.50 mmol) were sequentially added, at room temperature under argon atmosphere. The reaction
mixture was stirred until complete disappearances of the Passerini adduct (TLC). Then, H2O (7 mL) and
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ethyl acetate (10 mL) were added and the aqueous layer was extracted with AcOEt (3 x 5mL). The
organic layer was washed with H2O (2 x 10 mL), brine (10 mL), dried (MgSO4) and, the solvent was
removed under reduced pressure. The corresponding compound was precipitated with cool hexanes and
collected by filtration. Method G. To a solution of the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in
anhydrous dichloromethane (5 mL), 4ꢀpentynoic acid (1.05 mmol) and the appropriate isocyanide (1.10
mmol) were sequentially added, at room temperature under argon atmosphere. The reaction mixture was
stirred until complete disappearances of the azetidineꢀ2,3ꢀdione 1 (TLC). Then, dichloromethane was
evaporated under reduced pressure, and anhydrous DMF (10 mL), CuSO4ꢁ5H2O (0.15 mmol), sodium
ascorbate (0.30 mmol) and the corresponding trisꢀazide (0.33 mmol), were sequentially added, at room
temperature under argon atmosphere. The reaction mixture was stirred until complete disappearances of
the Passerini adduct (TLC). Then, the mixture was workedꢀup as indicated above (Method F). Method
H. To a solution of the appropriate azetidineꢀ2,3ꢀdione 1 (1 mmol) in anhydrous dichloromethane (5
mL), 2ꢀazido benzoic acid (1.05 mmol) and benzyl isocyanide (1.10 mmol) were sequentially added, at
room temperature under argon atmosphere. The reaction mixture was stirred until complete
disappearances of the azetidineꢀ2,3ꢀdione (TLC). Then, dichloromethane was evaporated at reduced
pressure, and anhydrous DMF (10 mL), CuSO4ꢁ5H2O (0.15 mmol), sodium ascorbate (0.30 mmol) and
the corresponding trisꢀalkyne (0.33 mmol), were added at room temperature under argon atmosphere.
The reaction mixture was stirred until complete disappearances of the Passerini adduct (TLC). Then, the
mixture was workedꢀup as indicated above (Method F).
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β-Lactam-Triazole Hybrid (−)-6a. Method A. From 39 mg (0.08 mmol) of Passerini adduct (+)ꢀ2d,
27 mg (50%) of compound (−)ꢀ6a was obtained as a white solid after purification by flash
chromatography (hexanes/ethyl acetate, 2:1). Method B. From 65 mg (0.22 mmol) of azetidineꢀ2,3ꢀ
dione (+)ꢀ1a, 125 mg (80%) of pure compound (−)ꢀ6a was obtained. Mp.: 75−77 °C; [α]D = −6.4 (c 0.5,
CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 ºC) δ 7.97ꢀ7.94 (m, 4H), 7.57 (m, 2H), 7.36ꢀ7.25 (m, 6H), 6.88
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