A Ugi Straightforward Access to Bis-β-lactam Derivatives

Article abstract of DOI:10.1002/ejoc.201900678

THe Ugi reaction of β-amino acids with aromatic aldehydes affords β-lactams which may be used as starting materials in a second β-lactam formation following a base triggered diiodomethane addition. The sequence may be conducted in a one-pot fashion afford

Full text of DOI:10.1002/ejoc.201900678

DOI: 10.1002/ejoc.201900678
Communication
Multicomponent Reactions
A Ugi Straightforward Access to Bis-ꢀ-lactam Derivatives
Cristina Cheibas,[a] Marie Cordier,[b] Yanyan Li,[c] and Laurent El Kaïm*[a]
Abstract: THe Ugi reaction of ꢀ-amino acids with aromatic al- diiodomethane addition. The sequence may be conducted in
dehydes affords ꢀ-lactams which may be used as starting mate- a one-pot fashion affording a straightforward access to bis-ꢀ-
rials in a second ꢀ-lactam formation following a base triggered lactams.
Introduction
case, the resulting ꢀ-lactams feature an amino substituent on
the core ꢀ-lactam in agreement with the structure of most natu-
ral bioactive ꢀ-lactams.[3] This new approach towards this im-
portant family of heterocycles is not the first involving a Ugi
reaction as the use of ꢀ-amino acids in the so called Ugi 4-
center 3-component coupling is well recognized as an elegant
access to ꢀ-lactams (U-4C-3C, Scheme 1).[4] In order to explore
further the scope of our diiodomethane cyclocondensation and
harness it to more sensitive substrates towards basic conditions,
we decided to combine both approaches as a means to reach
bis-ꢀ-lactams A in a straightforward manner (Scheme 1).
The chemistry of ꢀ-lactams has been largely been driven by
their recognition as powerful drugs against bacterial infec-
tion.[1] The early apparition of resistance together with the dis-
closure of ꢀ-lactamase inhibitors have even increased the ef-
forts devoted to these structures. We recently disclosed a very
efficient access to the ꢀ-lactam core under diiodomethane ad-
dition onto diamide anions (Scheme 1).[2] We further demon-
strated that this reaction could be easily performed on relatively
acidic Ugi adducts obtained from aromatic aldehydes. In this
Results and Discussion
Bis-ꢀ-lactams A were first reported by Sharma et al. in 1980[5]
and later studied by Ojima et al. as well as other groups.[6] The
interest for these structures was associated with their potential
biological activities together with their use as synthetic inter-
mediates.
Disclosed preparations of bis-ꢀ-lactams involved [2+2] cyclo-
additions of imines with ketenes using a previously formed
ꢀ-lactam bearing a ketene or an imine tether. In all these ap-
proaches, several steps are required to prepare the starting
bactam with the functionality required for the final cycloaddi-
tion. An example from Ojima's work is displayed in Scheme 2.[6a]
Scheme 1. Ugi reactions and ꢀ-lactams.
[a] Laboratoire de Synthèse Organique (LSO), CNRS, Ecole Polytechnique,
ENSTA ParisTech-UMR 7652, Institut Polytechnique de Paris,
828 Bd des Maréchaux, 91128 Palaiseau. France
E-mail: .laurent.elkaim@ensta-paristech.fr
[b] Laboratoire de Chimie Moléculaire, UMR 9168, CNRS, Ecole Polytechnique,
Institut Polytechnique de Paris,
Scheme 2. Ojima's procedure towards bis ꢀ-lactams A.
91128, Palaiseau Cedex, France
Most reported U-4C-3C couplings involve the use of ꢀ-amino
acids with stoichiometric amount or slight excess of the two
other reagents in methanol at room temperature. In some
cases, water as solvent or cosolvent improves both kinetics and
yields.[4d] With the aim of performing one-pot reactions at a
[c] Unité Molécules de Communication et Adaptation des Microorganismes
(MCAM), Muséum national d'Histoire naturelle, CNRS, CP 54,
57 rue Cuvier, 75005 Paris, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900678.
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Communication
later stage of the study, we decided to focus on the conditions
reported by Dömling et al. in 2015.[4g] Their use of microwave
conditions allowed them to reach moderate to good yields of
ꢀ-lactams under stoichiometric conditions and within one hour
time. These conditions were selected to prepare a set of ꢀ-
lactams 4 from isocyanides 1, aldehydes 2 and ꢀ-amino acids
3 (Scheme 3). With this new family of Ugi ꢀ-lactams 4 in hand,
we next examined the second ꢀ-lactam formation. These
strained heterocycles are known to be rather sensitive toward
base triggered ring-opening. In the case of our previous
NaH-CH2I2 based ꢀ-lactam formation, the apparent stability of
the latter was partly explained by the presence of bulky substit-
uents on the cycle which could lower the nucleophilic attacks
at the carbonyl lactam function. This is not the case with 4 and
a potential ring opening of the ꢀ-lactam moiety of 4 was ex-
pected to be a threat for the success of the following step.
Scheme 4. U-4C-3C towards ꢀ-lactams 4.
pot sequence. Thus, after performing the Ugi reaction, the
methanol was evaporated followed by DMSO addition and sub-
sequent addition of sodium hydride and diiodomethane. Under
these conditions the bis-lactam 5i was directly obtained in a
45 % isolated yield (Scheme 5) which compares positively with
the 60 % and 61 % isolated yield of the two steps with purifica-
tion of the intermediate lactam 4i.
Scheme 3. U-4C-3C towards ꢀ-lactams 4.
However when 4a was treated with 2.5 equiv. of NaH in
DMSO and let to react at r.t. for 3 hours (Scheme 4), we were
pleased to observe the formation of 5a in a moderate 53 %
isolated yields. All lactams 4 behaved similarly affording the
expected lactams 5 in moderate yields. Compared with our pre-
vious study working with less sensitive Ugi adducts, the reac-
tion affords lower yields which can be mainly explained by the
sensitivity of the ꢀ-lactams ring under these conditions. In
agreement with these considerations, the lower yields observed
with 5e and 5h were associated with the longer reaction time
(6 and 7 hours respectively). The structure of the bis-lactam was
confirmed by a single-crystal X-ray analysis of 5g.[7]
Scheme 5. One-pot Ugi access to ꢀ-lactams 5.
In order to raise further the interest of the sequence, and
having in mind a potential loss of material during the interme-
With this more efficient sequence in hand, we decided to
diate chromatography on rather acidic silica, we decided to ex- examine the behavior of a substituted ꢀ-amino acid in relation
amine the ability to achieve the preparation of 5 under a one- with diastereoselectivity issues. Indeed, the interest of limiting
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Communication
Cq), apparent multiplicity, coupling constants and integration
where relevant. Analytical TLC was performed with Merck silica gel
plates, pre-coated with silica gel 60 F254 (0.2 mm). Visualisation
was effected by quenching of UV fluorescence (λmax = 254 nm or
360 nm) and by staining with potassium permanganate or vanillin
TLC stain solutions, followed by heating. Flash chromatography em-
ployed ASTM (70–230 mesh) silica gel. Reactions were conducted
under a positive pressure of dry nitrogen. Anhydrous solvents were
obtained from commercial sources. Commercially available chemi-
cals were used without further purification. IR spectra were re-
corded on a Perkin Elmer FT 1600 Spectrometer with wavelengths
in cm–1. Melting points were measured on a Stuart SMP3 melting
point apparatus and are uncorrected. High resolution mass spectra
were recorded on a JEOL JMSGCmatell spectrometer. Monowave
300 produced by Anton Paar was used for the microwave condi-
tions.
the first part of the study to the use of ꢀ-alanine 3a was mainly
associated with the lack of potential mixtures of diastereomers
obtained in both steps of the sequence.
With substituted ꢀ-alanines, the Ugi reaction was expected
to afford a very low diastereomeric excess as observed in previ-
ous studies using 3-phenyl-ꢀ-alanine 3b.[8] This was indeed the
case when 3b and cyclohexyl isocyanide were added to 4-
phenylbenzaldehyde or 3-naphthaldehyde. NMR of the crude
mixtures revealed in both cases a ratio of diastereomers close
to 1:1. Interestingly, the following deprotonation is expected to
destroy part of these information leading to possible improve-
ment of the overall selectivity after two steps. This was indeed
the case with 5k and 5l (Scheme 5) as when the intermediate
mixtures were treated under the basic conditions required for
the second ꢀ-lactam formation, a strong improvement of the
diastereoselectivity was observed with a 94:6 mixture in the Synthesis of 1a: Methyl 2-allyl-2-isocyanopent-4-enoate (1a):[12]
To a solution of methyl α-isocyanoacetate (0.5 mL, 5.0 mmol,
1.0 equiv.) in MeCN (10 mL, 0.5 ) were added, K2CO3 (3.0 g,
case of naphthyl-substituted lactam 5k. A single-crystal X-ray
analysis of the major isomer of 5k[9] suggests that a π stacking
effect between the phenyl and the naphthyl rings might be at
the origin of the control of the selectivity.
Antibacterial activity of the synthetic compounds were
tested against Escherichia coli MC4100, Staphylococcus aureus
subsp. aureus ATCC6538 and Micrococcus luteus ATCC9341 strain
by soft-agar overlay technique. None of them was active on
the Gram-negative bacterium E. coli. Some compounds showed
weak activity toward S. aureus (5i, 5f) or M. luteus (5e).
M
22.0 mmol, 4.4 equiv.), triethylbenzylammonium chloride (57 mg,
5 mol-%) and allyl bromide (1.7 mL, 20.0 mmol, 4 equiv.). The reac-
tion mixture was stirred at 72 °C for 6 hours. After completion, the
reaction mixture was cooled to room temperature, quenched with
a saturated aqueous solution of NaHCO3 and extracted with DCM
(3 times). The combined organic layers were washed with brine (1
time), dried with MgSO4, filtered and concentrated under reduced
pressure. The crude mixture was purified by column chromatogra-
phy (PE/Et2O = 95:5) to afford the compound 1a (860 mg, 4.8 mmol,
yield 96 %). Aspect: yellow solution. Rf: 0.26 (PE/Et2O = 95:5). 1H
NMR (400 MHz, CDCl3) δ = 5.83–5.73 (m, 2H), 5.25–5.19 (m, 4H),
3.78 (s, 3H), 2.68–2.62 (dd, J = 13.9, 7.1 Hz, 2H), 2.57–2.52 (dd, J =
13.9, 7.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ = 168.4, 159.8, 129.9,
121.2, 67.7 (t, J = 7.0 Hz), 53.3, 42.6. HRMS: calculated for C10H13NO2:
Conclusions
The present study demonstrates further the efficiency of Ugi
reactions for the preparation of ꢀ-lactams as well as the robust-
ness of the CH2I2 based ꢀ-lactam formation. Two consecutive
ꢀ-lactam formation may be achieved in one pot conditions
leading to a fast assembly of bis ꢀ-lactams. These methods
based on Ugi reaction open access to these families of impor-
tant heterocycles without the traditional use of [2+2] cycloaddi-
tion processes.[10] Further improvements could be probably
brought in the first Ugi step of the sequence using water[4d] or,
as recently disclosed, trifluoroethanol as solvent.[11] The ob-
served activity of some compounds against Gram-positive bac-
teria, although poor, would set the starting point to further
improvements such as the use of an N-benzyl removable group
followed by deprotection and functionalization towards poten-
tially more active monobactams.
179.0946, found 178.0664. IR (thin film): ν = 3083, 2956, 2136, 1745,
˜
1438, 1220, 1153, 993, 926, 663 cm–1
.
Synthesis of 4a to 4i
General Procedure A:[4g]To a dried microwave tube was added
aldehyde 2 (1.0 mmol, 1 equiv.), MeOH (1.0 , 1 mL) followed by ꢀ-
M
amino acid 3 (1.0 mmol, 1 equiv.), and the isocyanide 1 (1.0 mmol,
1 equiv.). The tube was filled with nitrogen before heating under
microwave condition to 120 °C, 100 W for 1 hour. After completion,
the solvent was removed under reduced pressure and the crude
mixture purified by column chromatography on silica gel to afford
the desired 4a– 4i.
Methyl 2-Allyl-2-[2-(4-chlorophenyl)-2-(2-oxoazetidin-1-yl)acet-
amido]pent-4-enoate (4a): Following general procedure A, the
synthesis was carried out with 4-chlorobenzaldehyde (141 mg,
1.0 mmol, 1 equiv.), ꢀ-alanine (89 mg, 1.0 mmol, 1 equiv.) and 1a
(179 mg, 1.0 mmol, 1 equiv.). The crude mixture was purified by
column chromatography (PE/Et2O = 60:40 to 40:60) to afford the
compound 4a (200 mg, 0.51 mmol, yield 51 %). Aspect: yellow solid,
Experimental Section
General Considerations: NMR spectra were recorded at 298 K us-
ing a Bruker AVANCE 400 spectrometer. 1H NMR spectra were re- m.p. 86–88 °C. Rf: 0.26 (PE/Et2O = 3:7) 1H NMR (400 MHz, CDCl3)
corded at 400 MHz and residual solvent peaks were used as an δ = 7.35–7.28 (m, 4H), 6.75 (s, 1H), 5.59–5.38 (m, 2H), 5.36 (s, 1H),
internal reference (CDCl3 δ = 7.26). Data are reported as follows:
chemical shift in ppm, apparent multiplicity (s = singlet, d = dou-
blet, dd = doublet of doublet, dt = doublet of triplet, t = triplet,
m = multiplet or overlap of nonequivalent resonances), coupling
constants, integration. 13C NMR spectra were recorded at 100 MHz
and residual solvent peaks were used as an internal reference
(CDCl3 δ = 77.16). Data are reported as follows: chemical shift in
ppm, multiplicity deduced from DEPT experiments (CH3, CH2, CH,
5.08–4.98 (m, 4H), 3.73 (s, 3H), 3.56–3.53 (m, 1H), 3.14–3.11 (m, 1H),
3.10–3.05 (dd, J = 14.0, 7.2 Hz, 2H), 3.03–2.97 (m, 1H), 2.89–2.83 (m,
1H), 2.57–2.52 (dd, J = 14.0, 7.2 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ = 173.0, 167.8, 167.2, 134.8, 132.9, 131.8, 131.8, 129.9, 129.3,
119.7, 119.6, 64.4, 59.2, 53.0, 39.1, 39.0, 38.9, 36.5. HRMS: calculated
for C20H23ClN2O4: 390.1346, not found, fragment: 195.0444.
IR (thin film): ν = 3312, 3076, 2954, 1733, 1681, 1641, 1492, 1227,
˜
922 cm–1
.
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Communication
N-Cyclohexyl-2-(4-fluorophenyl)-2-(2-oxoazetidin-1-yl)acet-
amide (4b): Following general procedure A, the synthesis was car-
ried out with 4-fluorobenzaldehyde (0.11 mL, 1.0 mmol, 1 equiv.),
1H), 6.79–6.77 (d, J = 7.9 Hz, 1H), 5.60 (s, 1H), 3.83–3.74 (m, 1H),
3.72–3.68 (m, 1H), 3.22–3.19 (m, 1H), 3.04–2.99 (m, 1H), 2.91–2.85
(m, 1H), 1.92–1.85 (m, 2H), 1.69–1.62 (m, 2H), 1.59–1.54 (m, 1H),
ꢀ-alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 1.37–1.27 (m, 2H), 1.18–1.05 (m, 3H). 13C NMR (101 MHz, CDCl3) δ =
95 % (0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified
by column chromatography (PE/Et2O, 60:40 to 20:80) to afford the
compound 4b (170 mg, 0.56 mmol, yield 56 %). Aspect: white solid,
168.1, 167.0, 150.3, 147.9, 135.5, 130.3, 129.3, 128.2, 128.1, 127.7,
127.4, 57.6, 49.0, 39.3, 36.5, 32.9, 32.8, 25.5, 24.8, 24.8. HRMS: calcu-
lated for C20H23N3O2: 337.1790, found 337.1801, 212,0946. IR (thin
1
m.p. 105–108 °C. Rf: 0.19 (PE/Et2O = 2:8). H NMR (400 MHz, CDCl3)
film): ν = 3293, 3054, 2929, 2853, 1732, 1656, 1538, 1248, 753,
˜
δ = 7.36–7.32 (m, 2H), 7.08–7.03 (m, 2H), 6.24–6.23 (d, J = 7.0 Hz,
1H), 5.33 (s, 1H), 3.79–3.70 (m, 1H), 3.62–3.59 (m, 1H), 3.18–3.14 (m,
1H), 3.02–2.96 (m, 1H), 2.89–2.83 (m, 1H), 1.89–1.82 (m, 2H), 1.70–
1.55 (m, 3H), 1.38–1.27 (m, 2H), 1.18–1.03 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ = 168.1, 167.6, 164.0–161.6 (d, J = 248.8 Hz),
130.9 (d, J = 3.3 Hz), 130.1–130.0 (d, J = 8.3 Hz), 116.2–116.0 (d, J =
21.6 Hz), 59.3, 48.8, 39.1, 36.3, 32.8, 32.8, 25.5, 24.8, 24.8. HRMS:
calculated for C17H21FN2O2: 304.1587, not found, fragment:
731 cm–1
.
2-(4-Chlorophenyl)-N-cyclohexyl-2-(2-oxoazetidin-1-yl)acet-
amide (4f): Following general procedure A, the synthesis was car-
ried out with 4-chlorobenzaldehyde (141 mg, 1.0 mmol, 1 equiv.),
ꢀ-alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide
95 % (0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified
by column chromatography (PE/Et2O = 60:40 to 10:90) to afford the
compound 4f (211 mg, 0.66 mmol, yield 66 %). Aspect: yellow solid,
m.p. 127–130 °C. Rf: 0.42 (Et2O). 1H NMR (400 MHz, CDCl3) δ = 7.35–
7.28 (m, 4H), 6.36–6.34 (d, J = 7.6 Hz, 1H), 5.34 (s, 1H), 3.77–3.69 (m,
1H), 3.63–3.60 (m, 1H), 3.19–3.15 (m, 1H), 3.01–2.95 (m, 1H), 2.89–
2.83 (m, 1H), 1.86–1.82 (m, 2H), 1.70–1.63 (m, 2H), 1.59–1.56 (m, 1H),
1.37–1.26 (m, 2H), 1.17–1.06 (m, 3H). 13C NMR (101 MHz, CDCl3) δ =
168.1, 167.4, 134.7, 133.5, 129.6, 129.3, 59.3, 48.8, 39.2, 36.4, 32.8,
25.5, 24.8, 24.7. HRMS: calculated for C17H21ClN2O2: 331.1532, not
178.0669. IR (thin film): ν = 3295, 3069, 2930, 2854, 1731, 1651,
˜
1540, 1507, 1224, 731 cm–1
.
N-Cyclohexyl-2-(2-oxoazetidin-1-yl)-2-(pyridin-3-yl)acetamide
(4c): Following general procedure A, the synthesis was carried out
with 3-pyridinecarboxaldehyde (0.09 mL, 1.0 mmol, 1 equiv.), ꢀ-ala-
nine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
(0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
column chromatography (PE/AcOEt = 40:60 to 0:100; DCM/MeOH =
95:5) to afford the compound 4c (177 mg, 0.62 mmol, yield 62 %).
Aspect: colorless oil. Rf: 0.36 (DCM/MeOH = 9.5:0.5). 1H NMR
(400 MHz, CDCl3) δ = 8.55–8.53 (dd, J = 4.8, 1.9 Hz, 1H), 8.52–8.51
(d, J = 1.9 Hz, 1H), 7.74–7.72 (dt, J = 7.9, 1.9 Hz, 1H), 7.31–7.27 (dd,
J = 7.9, 4.8, 1H), 7.01–6.99 (d, J = 7.8 Hz, 1H), 5.44 (s, 1H), 3.74–3.67
(m, 1H), 3.67–3.63 (m, 1H), 3.22–3.18 (m, 1H), 3.00–2.94 (m, 1H),
2.88–2.83 (m, 1H), 1.85–1.78 (m, 2H), 1.68–1.53 (m, 3H), 1.32–1.25
(m, 2H), 1.13–1.04 (m, 3H). 13C NMR (101 MHz, CDCl3) δ = 168.0,
166.9, 149.7, 149.4, 135.7, 131.2, 123.9, 57.1, 48.8, 39.3, 36.4, 32.7,
32.7, 25.4, 24.8, 24.7. HRMS: calculated for C16H21N3O2: 287.1634,
found, fragment: 194.0376. IR (thin film): ν = 3296, 3064, 2929, 2853,
˜
1732, 1656, 1538, 1490, 1249, 1091, 802 cm–1
.
N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-oxoazetidin-1-yl)acet-
amide (4g): Following general procedure A, the synthesis was car-
ried out with 4-chlorobenzaldehyde (141 mg, 1.0 mmol, 1 equiv.),
ꢀ-alanine (89 mg, 1.0 mmol, 1 equiv.) and tert-butyl isocyanide
(0.11 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
column chromatography (PE/Et2O = 60:40 to 40:60) to afford the
compound 4g (181 mg, 0.62 mmol, yield 62 %). Aspect: yellow oil.
Rf: 0.37 (PE/Et2O = 2:8). 1H NMR (400 MHz, CDCl3) δ = 7.33–7.28 (m,
4H), 6.57 (s, 1H), 5.45 (s, 1H), 3.68–3.65 (m, 1H), 3.15–3.14 (m, 1H),
2.97–2.92 (m, 1H), 2.82–2.78 (m, 1H), 1.29 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ = 167.9, 167.7, 134.4, 133.8, 129.5, 129.2, 58.7, 51.7, 39.1,
36.2, 28.5. HRMS: calculated for C15H19ClN2O2: 294.1135, not found,
found 287.1644. IR (thin film): ν = 3301, 3055, 2931, 2855, 2246,
˜
1736, 1659, 1542, 908, 726 cm–1
.
N-Cyclohexyl-2-(naphthalen-2-yl)-2-(2-oxoazetidin-1-yl)acet-
amide (4d): Following general procedure A, the synthesis was car-
ried out with 2-naphthaldehyde (156 mg, 1.0 mmol, 1 equiv.), ꢀ-
alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
(0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
column chromatography (PE/Et2O = 60:40 to 0:100) to afford the
compound 4d (231 mg, 0.69 mmol, yield 69 %). Aspect: yellow solid,
fragment: 194.0372. IR (thin film): ν = 3322, 3056, 2969, 1732, 1677,
˜
732 cm–1
.
N-(tert-Butyl)-2-(2-oxoazetidin-1-yl)-2-(p-tolyl)acetamide (4h):
Following general procedure A, the synthesis was carried out with
4-methylbenzaldehyde (0.12 mL, 1.0 mmol, 1 equiv.), ꢀ-alanine
(89 mg, 1.0 mmol, 1 equiv.) and tert-butyl isocyanide (0.11 mL,
1.0 mmol, 1 equiv.). The crude mixture was purified by column chro-
matography (PE/Et2O = 60:40 to 30:70) to afford the compound 4h
(200 mg, 0.73 mmol, yield 73 %). Aspect: white solid, m.p. 140–
1
m.p. 146–150 °C. Rf: 0.4 (Et2O). H NMR (400 MHz, CDCl3) δ = 7.81–
7.76 (m, 4H), 7.47–7.43 (m, 3H), 6.79–6.77 (d, J = 7.9 Hz, 1H), 5.67
(s, 1H), 3.79–3.72 (m, 1H), 3.71–3.67 (m, 1H), 3.16–3.13 (m, 1H), 2.97–
2.91 (m, 1H), 2.81–2.75 (m, 1H), 1.85–1.81 (m, 2H), 1.64–1.50 (m, 3H),
1.31–1.22 (m, 2H), 1.11–1.03 (m, 3H). 13C NMR (101 MHz, CDCl3) δ =
168.1, 167.8, 133.3, 133.1, 132.4, 129.0, 128.2, 127.8, 127.6, 126.7,
126.7, 125.6, 59.8, 48.7, 39.1, 36.4, 32.8, 25.5, 24.8, 24.8. HRMS: calcu-
1
144 °C. Rf: 0.18 (PE/Et2O = 4:6). H NMR (400 MHz, CDCl3) δ = 7.22–
7.20 (d, J = 8.1 Hz, 2H), 7.15–7.13 (d, J = 8.1 Hz, 2H), 6.21 (s, 1H),
5.35 (s, 1H), 3.64–3.61 (m, 1H), 3.09–3.06 (m, 1H), 2.94–2.89 (m, 1H),
2.78–2.72 (m, 1H), 2.31 (s, 3H), 1.28 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ = 168.3, 167.8, 138.3, 132.1, 129.7, 128.1, 59.2, 51.6, 38.8,
36.1, 28.6, 21.2. HRMS: calculated for C16H22N2O2: 287.1634, not
lated for C21H24N2O2: 336.1838, found 336.1830. IR (thin film): ν =
˜
3296, 3056, 2927, 2853, 1731, 1651, 1543, 1247, 753, 732 cm–1
.
found, fragment: 174.0914. IR (thin film): ν = 3321, 2966, 2922, 1731,
˜
N-Cyclohexyl-2-(2-oxoazetidin-1-yl)-2-(quinolin-3-yl)acetamide
(4e): Following general procedure A, the synthesis was carried out
with 3-quinolinecarboxaldehyde (157 mg, 1.0 mmol, 1 equiv.), ꢀ-
alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
(0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
column chromatography (PE/AcOEt = 60:40 to 0:100) to afford the
1678, 1666, 1541, 1361, 1245, 1223, 577 cm–1
.
2-([1,1′-Biphenyl]-4-yl)-N-cyclohexyl-2-(2-oxoazetidin-1-yl)acet-
amide (4i): Following general procedure A, the synthesis was car-
ried out with 4-biphenylaldehyde (182 mg, 1.0 mmol, 1 equiv.), ꢀ-
alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
(0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
compound 4e (163 mg, 0.48 mmol, yield 48 %). Aspect: yellow oil.
1
Rf: 0.2 (PE/EA = 2:8) H NMR (400 MHz, CDCl3) δ = 8.84–8.83 (d, J = column chromatography (PE/Et2O = 40:60 to 3:7) to afford the com-
2.3 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.09–8.07 (d, J = 8.5 Hz, 1H),
7.82–7.80 (dd, J = 8.5, 0.8 Hz, 1H), 7.75–7.71 (m, 1H), 7.59–7.55 (m,
pound 4i (219 mg, 0.60 mmol, yield 60 %). Aspect: yellow oil. Rf: 0.2
(PE/Et2O = 4:6). 1H NMR (400 MHz, CDCl3) δ = 7.60–7.56 (t, J =
Eur. J. Org. Chem. 0000, 0–0
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4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
7.9 Hz, 4H), 7.46–7.42 (t, J = 7.8 Hz, 4H), 7.38–7.34 (m, 1H), 6.36–
6.34 (d, J = 7.8 Hz, 1H), 5.45 (s, 1H), 3.82–3.75 (m, 1H), 3.69–3.66 (m,
1H), 3.24–3.21 (m, 1H), 3.03–2.98 (m, 1H), 2.90–2.85 (m, 1H), 1.92–
1.89 (m, 2H), 1.70–1.65 (m, 2H), 1.60–1.56 (m, 1H), 1.38–1.29 (m, 2H),
Et2O = 20:80 to 0:100; EP/EA = 50:50 to 30:70) to afford the com-
pound 5c (94 mg, 0.31 mmol, yield 35 %). Aspect: yellow oil. Rf: 0.23
1
(PE/EA = 5:5). H NMR (400 MHz, CDCl3) δ = 8.68 (s, 1H), 8.60–8.59
(m, 1H), 7.81–7.79 (d, J = 7.9 Hz, 1H), 7.34–7.31 (m, 1H), 4.42–4.41
1.18–1.10 (m, 3H). 13C NMR (101 MHz, CDCl3) δ = 168.1, 167.8, 141.5, (d, J = 5.6 Hz, 1H), 3.64–3.56 (m, 1H), 3.51–3.50 (d, J = 5.6 Hz, 1H),
140.4, 134.0, 129.0, 128.6, 127.8, 127.7, 127.2, 59.6, 48.8, 39.1, 36.4,
32.8, 25.5, 24.8, 24.8.
3.36–3.33 (m, 1H), 3.14–3.12 (m, 1H), 3.01–2.88 (m, 2H), 1.95–1.92
(d, J = 12 Hz, 1H), 1.84–1.74 (m, 3H), 1.62–1.58 (d, J = 12 Hz, 1H),
1.42–1.22 (m, 4H), 1.16–1.06 (m, 1H). 13C NMR (101 MHz, CDCl3) δ =
167.2, 163.3, 150.1, 148.3, 134.7, 131.6, 123.8, 69.1, 51.6, 49.6, 38.8,
36.8, 30.6, 30.5, 25.2, 24.7. HRMS: calculated for C17H21N3O2:
Synthesis of 5a to 5i
General Procedure B, following the literature report:[2]The Ugi
product 4 (1 equiv.) was disolved in a solution of anhydrous DMSO
299.1634, not found, fragment: 174.0782. IR (thin film): ν = 3330,
˜
2929, 2854, 1736, 1668, 1365, 711 cm–1
.
(0.5
M) under nitrogen. Then, NaH (2.5 equiv.) was added and a
emulsion was observed until complete dissolution of the base. After
15 min, CH2I2 (1.5 equiv.) was added. The reaction mixture was
stirred vigorously at room temperature for some hours under nitro-
gen. After completion, the organic layers were extracted with DCM
(three times). The combined organic layers were washed with brine
(two times), dried with MgSO4, filtered and concentrated under re-
duced pressure. The crude mixture was purified by column chroma-
tography (× 10 silica mass) to afford 5a–5i.
1′-Cyclohexyl-3′-(naphthalen-2-yl)-[1,3′-biazetidine]-2,2′-dione
(5d): Following general procedure B, the synthesis was carried out
with 4d (209 mg, 0.6 mmol, 1 equiv.), NaH (62 mg, 1.6 mmol,
2.5 equiv.) and CH2I2 (0.08 mL, 0.9 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for three and a
half hours under nitrogen. The crude mixture was purified by col-
umn chromatography (PE/Et2O = 70:30 to 40:60) to afford the com-
pound 5d (112 mg, 0.32 mmol, yield 54 %). Aspect: yellow solid,
m.p. 90 °C. Rf: 0.25 (PE/Et2O = 8:2). 1H NMR (400 MHz, CDCl3) δ =
8.01–8.00 (d, J = 1.6 Hz, 1H), 7.90–7.83 (m, 3H), 7.52–7.50 (m, 3H),
4.58–4.57 (d, J = 5.6 Hz, 1H), 3.70–3.63 (m, 1H), 3.57–3.56 (d, J =
5.6 Hz, 1H), 3.36–3.33 (m, 1H), 3.10–3.06 (m, 1H), 3.01–2.95 (m, 1H),
2.92–2.86 (m, 1H), 2.01–1.97 (m, 1H), 1.86–1.72 (m, 3H), 1.63–1.60
(m, 1H), 1.46–1.27 (m, 4H), 1.18–1.10 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ = 167.3, 164.4, 133.2, 133.1, 133.0, 129.2, 128.4, 127.8,
126.8, 126.8, 126.1, 124.5, 71.1, 51.3, 49.6, 38.7, 36.6, 30.6, 30.5, 25.3,
24.8. HRMS: calculated for C22H24N2O2: 348.1838, not found, frag-
Methyl 2-Allyl-2-[3′-(4-chlorophenyl)-2,2′-dioxo-(1,3′-biazet-
idin)-1′-yl]pent-4-enoate (5a): Following general procedure B, the
synthesis was carried out with 4a (182 mg, 0.47 mmol, 1 equiv.),
NaH (46 mg, 1.2 mmol, 2.5 equiv.) and CH2I2 (0.06 mL, 0.7 mmol,
1.5 equiv.). The reaction mixture was stirred vigorously at room tem-
perature for three hours under nitrogen. The crude mixture was
purified by column chromatography (DCM/Et2O = 100:0 to 90:10)
to afford the compound 5a (101 mg, 0.25 mmol, yield 53 %). Aspect
1
orange oil. Rf: 0.18 (DCM). H NMR (400 MHz, CDCl3) δ = 7.41–7.35
ment: 223.0997. IR (thin film): ν = 3337, 3055, 2927, 2853, 1735,
(m, 4H), 5.79–5.64 (m, 2H), 5.18–5.09 (m, 4H), 4.57–4.55 (d, J =
5.9 Hz, 1H), 3.73 (s, 3H), 3.70–3.69 (d, J = 5.9 Hz, 1H), 3.38–3.34 (m,
1H), 3.17–3.13 (m, 1H), 3.01–2.95 (m, 1H), 2.93–2.88 (m, 1H), 2.87–
2.70 (m, 4H). 13C NMR (101 MHz, CDCl3) δ = 171.0, 167.1, 164.5,
134.8, 134.1, 131.5, 131.4, 129.3, 128.3, 120.2, 120.2, 70.3, 66.0, 53.3,
52.7, 39.2, 39.0, 38.8, 36.7. HRMS: calculated for C21H23ClN2O4:
˜
1363, 748 cm–1
.
1′-Cyclohexyl-3′-(quinolin-3-yl)-[1,3′-biazetidine]-2,2′-dione
(5e): Following general procedure B, the synthesis was carried out
with 4e (186 mg, 0.6 mmol, 1 equiv.), NaH (56 mg, 1.4 mmol,
2.5 equiv.) and CH2I2 (0.07 mL, 0.8 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for six hours
under nitrogen. The crude mixture was purified by column chroma-
tography (PE/Et2O = 40:60 to 0:100; PE/AcOEt = 40:60) to afford the
compound 5e (53 mg, 0.15 mmol, yield 28 %). Aspect: orange oil.
Rf: 0.12 (Et2O). 1H NMR (400 MHz, CDCl3) δ = 8.96–8.95 (d, J = 2.3 Hz,
1H), 8.34–8.33 (d, J = 2.3 Hz, 1H), 8.13–8.11 (d, J = 8.2 Hz, 1H), 7.87–
7.84 (dd, J = 8.2, 1.1 Hz, 1H), 7.78–7.73 (m, 1H), 7.61–7.57 (m, 1H),
4.58–4.57 (d, J = 5.8 Hz, 1H), 3.69–3.63 (m, 1H), 3.62–3.60 (d, J =
5.8 Hz, 1H), 3.39–3.36 (m, 1H), 3.15–3.12 (m, 1H), 3.04–2.98 (m, 1H),
2.96–2.90 (m, 1H), 2.01–1.97 (m, 1H), 1.85–1.72 (m, 3H), 1.65–1.60
(m, 1H), 1.38–1.27 (m, 4H), 1.19–1.11 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ = 167.2, 163.6, 149.4, 148.0 134.3, 130.4, 129.4, 128.6, 128.3
127.6, 127.4, 69.3, 51.6, 49.5, 38.9, 36.9, 30.6, 30.6, 25.2, 24.8. HRMS:
calculated for C21H23N3O2: 349.1790, not found, fragment: 224.0951.
402.1346, not found, fragment: 207.0450. IR (thin film): ν = 3078,
˜
2954, 2923, 1737, 1370, 1219 cm–1
.
1′-Cyclohexyl-3′-(4-fluorophenyl)-[1,3′-biazetidine]-2,2′-dione
(5b): Following general procedure B, the synthesis was carried out
with 4b (141 mg, 0.46 mmol, 1 equiv.), NaH (48 mg, 1.2 mmol,
2.5 equiv.) and CH2I2 (0.06 mL, 0.7 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for five hours
under nitrogen. The crude mixture was purified by column chroma-
tography (PE/Et2O = 80:20 to 40:60) to afford the compound 5b
(68 mg, 0.21 mmol, yield 47 %). Aspect: yellow oil. Rf: 0.13 (PE/
1
Et2O = 4:6). H NMR (400 MHz, CDCl3) δ = 7.45–7.42 (m, 2H), 7.08–
7.04 (m, 2H), 4.42–4.41 (d, J = 5.6 Hz, 1H), 3.63–3.56 (m, 1H), 3.46–
3.44 (d, J = 5.6 Hz, 1H), 3.31–3.28 (m, 1H), 3.08–3.05 (m, 1H), 2.98–
2.92 (m, 1H), 2.88–2.82 (m, 1H), 1.95–1.92 (m, 1H), 1.83–1.70 (m, 3H),
1.62–1.57 (m, 1H), 1.41–1.22 (m, 4H), 1.16–1.06 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ = 167.1, 164.1, 164.0–161.5 (d, J = 248.2 Hz),
131.6–131.5 (d, J = 3.3 Hz), 128.9–128.8 (d, J = 8.3 Hz), 116.1–115.9
(d, J = 21.7 Hz), 70.2, 51.4, 49.8, 38.6, 36.6, 30.5, 30.5, 25.2, 24.7.
HRMS: calculated for C18H21FN2O2: 316.1587, not found, fragment:
IR (thin film): ν = 2931, 2854, 1742, 1671, 1370, 754 cm–1
.
˜
3′-(4-Chlorophenyl)-1′-cyclohexyl-[1,3′-biazetidine]-2,2′-dione
(5f): Following general procedure B, the synthesis was carried out
with 4f (100 mg, 0.3 mmol, 1 equiv.), NaH (31 mg, 1.8 mmol,
2.5 equiv.) and CH2I2 (0.04 mL, 0.45 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for four hours
under nitrogen. The crude mixture was purified by column chroma-
tography (PE/Et2O = 50:50 to 40:60) to afford the compound 5f
191.0747. IR (thin film): ν = 2931, 2855, 1737, 1602, 1509, 1403,
˜
1365, 1224 cm–1
.
1′-Cyclohexyl-3′-(pyridin-3-yl)-[1,3′-biazetidine]-2,2′-dione (5c):
Following general procedure B, the synthesis was carried out with (49 mg, 0.15 mmol, yield 49 %). Aspect: yellow oil. Rf: 0.24 (PE/
1
4c (255 mg, 0.9 mmol, 1 equiv.), NaH (88 mg, 2.2 mmol, 2.5 equiv.)
and CH2I2 (0.11 mL, 1.3 mmol, 1.5 equiv.). The reaction mixture was
Et2O = 4:6). H NMR (400 MHz, CDCl3) δ = 7.40–7.34 (m, 4H), 4.42–
4.41 (d, J = 5.6 Hz, 1H), 3.62–3.55 (m, 1H), 3.45–3.44 (d, J = 5.6 Hz,
stirred vigorously at room temperature for six hours under nitrogen. 1H), 3.32–3.29 (m, 1H), 3.09–3.06 (m, 1H), 2.99–2.93 (m, 1H), 2.89–
The crude mixture was purified by column chromatography (PE/
2.83 (m, 1H), 1.94–1.91 (m, 1H), 1.82–1.73 (m, 3H), 1.61–1.58 (m, 1H),
Eur. J. Org. Chem. 0000, 0–0
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5 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
1.34–1.22 (m, 4H), 1.15–1.09 (m, 1H). 13C NMR (101 MHz, CDCl3) δ = removed under reduced pressure, and the obtained oil was disolved
167.2, 163.9, 134.8, 134.2, 129.3, 128.4, 70.3, 51.4, 49.7, 38.7, 36.6,
30.6, 30.5, 25.2, 24.7. HRMS: calculated for C17H21ClN2O2: 332.1292,
in a solution of anhydrous DMSO (0.5 M) under nitrogen. Then, NaH
(2.5 equiv.) was added and a emulsion was observed until complete
dissolution of the base. After 15 min, CH2I2 (1.5 equiv.) was added.
The reaction mixture was stirred vigorously at room temperature
for five hours under nitrogen. The organic layers were extracted
with DCM (three times). The combined organic layers were washed
with brine (two times), dried with MgSO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by column
chromatography (× 10 silica mass) to afford 5i–5l.
not found, fragment: 207.0454. IR (thin film): ν = 3316, 2929, 2854,
˜
1737, 1666, 1491, 1401, 1364, 1091, 1013 cm–1
.
1′-(tert-Butyl)-3′-(4-chlorophenyl)-[1,3′-biazetidine]-2,2′-dione
(5g): Following general procedure B, the synthesis was carried out
with 4g (330 mg, 1.1 mmol, 1 equiv.), NaH (108 mg, 2.7 mmol,
2.5 equiv.) and CH2I2 (0.14 mL, 1.7 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for four and a
half hours under nitrogen. The crude mixture was purified by col-
umn chromatography (PE/Et2O = 90:10 to 50:50) to afford the com-
pound 5g (144 mg, 0.47 mmol, yield 43 %). Aspect: orange crystals,
m.p. 87–88 °C. Rf: 0.18 (PE/Et2O = 4:6). 1H NMR (400 MHz, CDCl3)
3′-([1,1′-Biphenyl]-4-yl)-1′-cyclohexyl-[1,3′-biazetidine]-2,2′-di-
one (5i): Following general procedure C, the synthesis was carried
out with 4-biphenylaldehyde (182 mg, 1.0 mmol, 1 equiv.), ꢀ-alanine
(89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
δ = 7.42–7.34 (m, 4H), 4.41–4.39 (d, J = 5.7 Hz, 1H), 3.42–3.41 (d, J = (0.13 mL, 1.0 mmol, 1 equiv.). The crude mixture was purified by
5.7 Hz, 1H), 3.34–3.30 (m, 1H), 3.09–3.06 (m, 1H), 3.00–2.94 (m, 1H),
2.89–2.84 (m, 1H), 1.34 (s, 9H). 13C NMR (101 MHz, CDCl3) δ = 167.2,
163.5, 134.8, 134.4, 129.3, 128.4, 69.5, 53.8, 49.4, 38.7, 36.7, 27.6.
HRMS: calculated for C16H19ClN2O2: 306.1135, not found, fragment:
column chromatography (PE/Et2O = 70:30 to 50:50) to afford the
compound 5i (169 mg, 0.45 mmol, yield 45 %). Aspect: orange oil.
Rf: 0.18 (PE/Et2O = 4:6). 1H NMR (400 MHz, CDCl3) δ = 7.63–7.52 (m,
6H), 7.45–7.42 (m, 2H), 7.37–7.33 (m, 1H), 4.50–4.48 (d, J = 5.6 Hz,
207.0446. IR (thin film): ν = 2971, 2905, 1737, 1680, 1492, 1365, 1H), 3.68–3.61 (m, 1H), 3.55–3.53 (d, J =5.6 Hz, 1H), 3.38–3.34 (m,
˜
1092, 1013 cm–1
.
1H), 3.17–3.13 (m, 1H), 3.01–2.95 (m, 1H), 2.93–2.87 (m, 1H), 2.00–
1.96 (m, 1H), 1.88–1.85 (m, 1H), 1.81–1.72 (m, 2H), 1.64–1.60 (m, 1H),
1.49–1.25 (m, 5H). 13C NMR (101 MHz, CDCl3) δ = 167.2, 164.3, 141.6,
140.3, 134.5, 128.9, 127.7, 127.7, 127.3, 127.1, 70.7, 51.3, 49.8, 38.7,
36.6, 30.6, 30.5, 25.2, 24.8. HRMS: calculated for C24H26N2O2:
1′-(tert-Butyl)-3′-(p-tolyl)-[1,3′-biazetidine]-2,2′-dione (5h): Fol-
lowing a modified version of general procedure B, the synthesis
was carried out with 4h (160 mg, 0.6 mmol, 1 equiv.), NaH (90 mg,
2.3 mmol, 3.75 equiv.) and CH2I2 (0.11 mL, 1.4 mmol, 2.25 equiv.).
The reaction mixture was stirred vigorously at room temperature
for seven hours under nitrogen. The crude mixture was purified by
column chromatography (PE/Et2O = 70:30 to 40:60) to afford the
compound 5h (55 mg, 0.19 mmol, yield 33 %). Aspect: yellow solid,
374.1994, not found, fragment: 249.1149. IR (thin film): ν = 3478,
˜
3030, 2929, 2853, 1736, 1666, 1486, 1400, 1363, 1262, 1006, 761,
729 cm–1
.
1′-Cyclohexyl-3′-(4-methoxyphenyl)-[1,3′-biazetidine]-2,2′-di-
one (5j): Following a modified version of general procedure C, the
synthesis was carried out with p-anisaldehyde (0.12 mL, 1.0 mmol,
1 equiv.), ꢀ-alanine (89 mg, 1.0 mmol, 1 equiv.) and cyclohexyl iso-
cyanide 95 % (0.13 mL, 1.0 mmol, 1 equiv.). After the addition of
NaH and CH2I2, the reaction mixture was stirred vigorously at 50 °C
for three hours under nitrogen. The crude mixture was purified by
column chromatography (PE/Et2O = 80:20 to 20:80) to afford the
compound 5j (134 mg, 0.41 mmol, yield 41 %). Aspect: orange oil.
Rf: 0.31 (PE/Et2O = 2:8). 1H NMR (400 MHz, CDCl3) δ = 7.39–7.35 (m,
2H), 6.91–6.87 (m, 2H), 4.42–4.41 (d, J = 5.5 Hz, 1H), 3.78 (s, 3H),
3.63–3.55 (m, 1H), 3.45–3.44 (d, J = 5.5 Hz, 1H), 3.28–3.24 (m, 1H),
3.06–3.03 (m, 1H), 2.95–2.89 (m, 1H), 2.86–2.80 (m, 1H), 1.96–1.92
1
m.p. 110 °C. Rf: 0.38 (PE/Et2O = 3:7). H NMR (400 MHz, CDCl3) δ =
7.36–7.34 (d, J = 8.2 Hz, 2H), 7.21–7.19 (d, J = 8.2 Hz, 2H), 4.44–4.43
(d, J = 5.5 Hz, 1H), 3.44–3.43 (d, J = 5.5 Hz, 1H), 3.33–3.29 (m, 1H),
3.09–3.05 (m, 1H), 2.99–2.93 (m, 1H), 2.88–2.83 (m, 1H), 2.35 (s, 3H),
1.35 (s, 9H). 13C NMR (101 MHz, CDCl3) δ = 167.3, 164.2, 138.7, 132.9,
129.7, 126.9, 69.9, 53.7, 49.5, 38.6, 36.5, 27.7, 21.3. HRMS: calculated
for C17H22N2O2: 286.1681, not found, fragment: 187.0992. IR (thin
film): ν = 2969, 2924, 1737, 1365 cm–1
.
˜
3′-([1,1′-Biphenyl]-4-yl)-1′-cyclohexyl-[1,3′-biazetidine]-2,2′-di-
one (5i): Following general procedure B, the synthesis was carried
out with 4i (192 mg, 0.53 mmol, 1 equiv.), NaH (90 mg, 1.3 mmol,
2.5 equiv.) and CH2I2 (0.065 mL, 0.8 mmol, 1.5 equiv.). The reaction
mixture was stirred vigorously at room temperature for five hours
under nitrogen. The crude mixture was purified by column chroma-
tography (DCM/Et2O = 95:5) to afford the compound 5i (120 mg,
0.32 mmol, yield 61 %). Aspect: orange oil. Rf: 0.25 (DCM/Et2O =
(m, 1H), 1.82–1.70 (m, 3H), 1.60–1.57 (m, 1H), 1.44–1.22 (m, 5H). 13
C
NMR (101 MHz, CDCl3) δ = 167.1, 164.6, 159.8, 128.3, 127.7, 114.3,
70.4, 55.4, 51.2, 49.8, 38.5, 36.4, 30.5, 30.5, 25.3, 24.8. HRMS: calcu-
lated for C19H24N2O3: 328.1787, not found, fragment: 203.0940.
IR (thin film): ν = 2923, 2853, 1737, 1680, 1513, 1365, 1247,
˜
1
9:1). H NMR (400 MHz, CDCl3) δ = 7.63–7.52 (m, 6H), 7.45–7.42 (m,
1179 cm–1
.
2H), 7.37–7.33 (m, 1H), 4.50–4.48 (d, J = 5.6 Hz, 1H), 3.68–3.61 (m,
1H), 3.55–3.53 (d, J =5.6 Hz, 1H), 3.38–3.34 (m, 1H), 3.17–3.13 (m,
1H), 3.01–2.95 (m, 1H), 2.93–2.87 (m, 1H), 2.00–1.96 (m, 1H), 1.88–
1.85 (m, 1H), 1.81–1.72 (m, 2H), 1.64–1.60 (m, 1H), 1.49–1.25 (m, 5H).
13C NMR (101 MHz, CDCl3) δ = 167.2, 164.3, 141.6, 140.3, 134.5,
128.9, 127.7, 127.7, 127.3, 127.1, 70.7, 51.3, 49.8, 38.7, 36.6, 30.6,
30.5, 25.2, 24.8. HRMS: calculated for C24H26N2O2: 374.1994, not
1′-Cyclohexyl-3′-(naphthalen-2-yl)-4-phenyl-[1,3′-biazetidine]-
2,2′-dione (5k): Following a modified version of general procedure
C, the synthesis was carried out with 2-naphthaldehyde (156 mg,
1.0 mmol, 1 equiv.), DL-3-Amino-3-phenylpropionic acid (165 mg,
1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 % (0.13 mL,
1.0 mmol, 1 equiv.). After the addition of NaH and CH2I2, the reac-
tion mixture was stirred vigorously at 50 °C for three hours under
nitrogen. The crude mixture was purified by column chromatogra-
phy (PE/Et2O = 90:10 to 0:100) to afford the compound 5k (220 mg,
0.52 mmol, yield 52 %). Mixture of diastereomers: dr 94:6. Aspect:
orange solid, m.p. 135–137 °C. Rf: 0.34 (PE/Et2O = 3:7). 1H NMR
(400 MHz, CDCl3) δ = (C-Hmajor isomer) 7.77–7.59 (m, 4H), 7.51–7.44
(m, 2H), 7.30–7.27 (m, 1H), 7.05–6.98 (m, 3H), 6.92–6.90 (m, 2H),
4.54–4.53 (dd, J = 5.5, 2.5 Hz, 1H), 4.38–4.37 (d, J = 5.3 Hz, 1H), 3.71–
3.64 (m, 1H), 3.70–3.69 (d, J = 5.3 Hz, 1H), 3.44–3.39 (dd, J = 15.1,
found, fragment: 249.1149. IR (thin film): ν = 3478, 3030, 2929, 2853,
˜
1736, 1666, 1486, 1400, 1363, 1262, 1006, 761, 729 cm–1
.
One Pot Synthesis of 5i to 5l
General Procedure C: To a dried microwave tube was added alde-
hyde 2 (1.0 mmol, 1 equiv.), ꢀ-amino acid 3 (1.0 mmol, 1 equiv.),
isocyanide 1 (1.0 mmol, 1 equiv.) and MeOH (1.0 M, 1 mL). The tube
was filled with nitrogen before heating under microwave condition
to 120 °C, 100 W for 1 hour. After completion, the solvent was
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Communication
ganic Chemistry of ꢀ-Lactams (Ed.: G. I. Georg), VCH Publishers, New York,
1993, ppp. 1–368; c) A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008,
108, 3988–4035; d) C. R. Pitts, T. Lectka, Chem. Rev. 2014, 114, 7930–
7953.
5.5 Hz, 1H), 2.91–2.87 (dd, J = 15.1, 2.5 Hz, 1H), 2.09–2.06 (m, 1H),
1.84–1.63 (m, 5H), 1.37–1.29 (m, 3H), 1.20–1.11 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ = (Cmajor isomer) 167.4, 164.6, 138.5, 133.0, 132.7,
131.6, 128.3, 128.2, 128.1, 128.1 127.5, 127.4, 126.7, 126.6, 126.3,
125.4, 70.9, 55.2, 51.4, 50.4, 46.0, 30.5, 30.5, 25.4, 24.8, 24.8. HRMS:
calculated for C28H28N2O2: 424.2151, not found, fragment: 299.1306.
[2] A. Zidan, J. Garrec, M. Cordier, A. M. El Naggar, N. E. A. El-Sattar, A. K. Ali,
M. A. Hassan, L. El Kaïm, Angew. Chem. Int. Ed. 2017, 56, 12179–12183;
Angew. Chem. 2017, 129, 12347.
[3] For reviews on monobactams see: a) R. B. Sykes, D. P. Bonner, Rev. Infect.
Dis. 1985, 7, 579–593; b) L. Decuyper, M. Jukic, I. Sosic, A. Zula, M. D'hoo-
ghe, S. Gobec, Med. Res. Rev. 2018, 38, 426–503.
IR (thin film): ν = 3319, 3057, 2929, 2854, 1732, 1661, 1362, 1346,
˜
745, 697 cm–1
.
3′-([1,1′-Biphenyl]-4-yl)-1′-cyclohexyl-4-phenyl-[1,3′-biazet-
idine]-2,2′-dione (5l): Following a modified version of general pro-
cedure C, the synthesis was carried out with 4-biphenylaldehyde
(182 mg, 1.0 mmol, 1 equiv.), DL-3-Amino-3-phenylpropionic acid
(165 mg, 1.0 mmol, 1 equiv.) and cyclohexyl isocyanide 95 %
(0.13 mL, 1.0 mmol, 1 equiv.). After the addition of NaH and CH2I2,
the reaction mixture was stirred vigorously at 50 °C for three hours
under nitrogen. The crude mixture was purified by column chroma-
tography (PE/Et2O = 98:2 to 30:70) to afford the compound 5l
(145 mg, 0.32 mmol, yield 32 %). Mixture of diastereomers: dr
0.85:0.15. Aspect: yellow solid, m.p. 60–65 °C. Rf: 0.25 (PE/Et2O =
4:6). 1H NMR (400 MHz, CDCl3) δ = (C-Hmajor isomer) 7.41–7.33 (m,
4H), 7.29–7.26 (m, 1H), 7.22–7.15 (m, 4H), 7.09–7.00 (m, 3H), 6.88–
6.87 (d, J = 7.7 Hz, 2H), 4.45–4.44 (m, 1H), 4.26–4.24 (d, J = 4.8 Hz,
1H), 3.57–3.52 (m, 1H), 3.55–3.54 (d, J = 4.8 Hz, 1H), 3.32–3.27 (dd,
J = 15.0, 5.4 Hz, 1H), 2.79–2.75 (d, J = 15.0 Hz, 1H), 1.97–1.94 (m,
1H), 1.73–1.63 (m, 3H), 1.55–1.52 (m, 1H), 1.29–1.14 (m, 4H), 1.09–
1.04 (m, 1H). 13C NMR (101 MHz, CDCl3) δ = (Cmajor isomer) 167.4,
164.7, 141.4, 140.6, 138.7, 133.1, 128.9, 128.4, 128.4, 128.0, 127.6,
127.1, 126.9, 126.8, 70.6, 55.1, 51.4, 50.2, 45.9, 30.5, 30.4, 25.4, 24.8.
HRMS: calculated for C30H30N2O2: 450.2307, not found, fragment:
[4] a) I. Ugi, Angew. Chem. Int. Ed. Engl. 1982, 21, 810–819; Angew. Chem.
1982, 94, 826. For selected applications: b) J. E. Baldwin, R. Y. Chan,
J. D. Sutherland, Tetrahedron Lett. 1994, 35, 5519–5522; c) S. Gedey, J.
Van der Eycken, F. Fulöp, Org. Lett. 2002, 4, 1967–1969; d) M. C. Pirrung,
K. D. Sarma, Tetrahedron 2005, 61, 11456–11472; e) G. Kulsi, A. Ghorai,
P. Chattopadhyay, Tetrahedron Lett. 2012, 53, 3619–3622; f) N. Takenaga,
K. Fukazawa, M. Maruko, K. Sato, Heterocycles 2015, 90, 113–120; g) C. G.
Neochoritis, J. Zhang, A. Dömling, Synthesis 2015, 47, 2407–2413;
h) S. Shaabani, C. G. Neochoritis, A. Twarda-Clapa, B. Musielak, T. A. Holak,
A. Dömling, Med. Chem. Commun. 2017, 8, 1046–1052.
[5] S. D. Sharma, P. K. Gupta, J. Bindra, Sunita, Tetrahedron Lett. 1980, 21,
3295–3298.
[6] a) N. Hatanaka, I. Ojima, J. Chem. Soc., Chem. Commun. 1981, 344–346;
b) I. Ojima, T. Yamato, K. Nakahashi, Tetrahedron Lett. 1985, 26, 2035–
2038; c) I. Ojima, K. Nakahashi, S. M. Brandstadter, N. Hatanaka, J. Am.
Chem. Soc. 1987, 109, 1798–1805; d) I. Ojima, M. Zhao, T. Yamato, K.
Nakahashi, J. Org. Chem. 1991, 56, 5263–5277.
[7] CCDC 1900062 (for 5g) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[8] For poorly selective U-4C-3C using 3-aryl ꢀ-alanines see: ref (4d), (4h).
For a diastereoselective ꢀ-lactam formation using chiral isocyanides in
U-4C-3C see: T. M. Vishwanatha, N. Narendra, V. V. Sureshbabu, Tetrahe-
dron Lett. 2011, 52, 5620–5624.
[9] CCDC 1900062 (for 5k) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
325.1458. IR (thin film): ν = 3285, 3058, 3030, 2928, 2853, 1739,
˜
1658, 1364, 1343, 762, 730, 695 cm–1
.
Acknowledgments
The authors thanks ENSTAParisTech, Polytechnique and the
CNRS for financial support.
[10] If ꢀ-amino acids are often prepared through ring-opening of ꢀ-lactams
resulting from [2+2] cycloadditions, direct Mannich type preparations
from malonic acids and aldehydes are available (see ref [4h] for some
preparations).
[11] G. Rainoldi, G. Lesma, C. Picozzi, L. L. Presti, A. Silvani, RSC Adv. 2018, 8,
34903–34910.
[12] A. Clemenceau, Q. Wang, J. Zhu, Org. Lett. 2017, 19, 4872–4875.
Keywords: Β-Lactams · Ugi reaction · Amide dianions ·
Multicomponent reactions · Diiodomethane
[1] For reviews on ꢀ-lactams, see: a) Beta-Lactams, Novel Synthetic Pathways
and Applications (Ed.: B. K. Banik), Springer, 2013, pp. 1–419; b) The Or-
Received: May 9, 2019
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Communication
Multicomponent Reactions
C. Cheibas, M. Cordier, Y. Li,
L. El Kaïm* ............................................ 1–8
A Ugi Straightforward Access to Bis-
ꢀ-lactam Derivatives
Ugi reactions at the cutting edge of ꢀ- tions towards bis-ꢀ-lactam derivatives
lactams synthesis: consecutive cycliza- from ꢀ-amino acids derivatives
DOI: 10.1002/ejoc.201900678
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