Synthesis of β-Lactams via Enantioselective Allylation of Anilines with Morita-Baylis-Hillman Carbonates

Article abstract of DOI:10.1055/s-0039-1691570

Enantioenriched β-lactams are accessed via enantioselective allylation of anilines with Morita-Baylis-Hillman carbonates followed by a base-promoted cyclization. The resulting 3-methyleneazetidin-2-ones are amenable to diastereoselective functionalization

Full text of DOI:10.1055/s-0039-1691570

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
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Synthesis of -Lactams via Enantioselective Allylation of Anilines
with Morita–Baylis–Hillman Carbonates
You Zia
Markus Langea
Philipp Schülerb
Sven Krieckb
good control of
diastereoselectivity
Ar2
Ar1
O
Ar2
Ar1
(DHQD)2AQN
(10 mol%)
OBoc
NH
1. Sn(HMDS)2
2. H2, Pd/C
N
Ar2
CO2Me
NH2 Ar1
CO2Me
C6H12, rt
Matthias Westerhausenb
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0
0
0-
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2-1
5
2
0-2
4
0
1
up to 97% yield
up to 98:2 er
single isomer
up to 93% yield
Ivan Vilotijevic*a
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1-6
1
9
9-0
6
3
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a Institute of Organic Chemistry and Macromolecular Chemistry,
Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena,
Germany
ivan.vilotijevic@uni-jena.de
b Institute of Inorganic and Analytical Chemistry, Friedrich Schiller
University Jena, Humboldtstrasse 8, 07743 Jena, Germany
Published as part of the ISySyCat2019 Special Issue
Received: 14.11.2019
Accepted after revision: 20.12.2019
Published online: 16.01.2019
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DOI: 10.1055/s-0039-1691570; Art ID: st-2019-b0618-c
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Abstract Enantioenriched -lactams are accessed via enantioselective
allylation of anilines with Morita–Baylis–Hillman carbonates followed by
a base-promoted cyclization. The resulting 3-methyleneazetidin-2-ones
are amenable to diastereoselective functionalization to produce ana-
logues of biologically active -lactams. The use of nearly equimolar
quantities of the starting materials make this method efficient and
straightforward.
Penicillins 1
Cephalosporins 2
OMe
MeO
MeO
MeO
O
O
N
N
HO
Ph
MeO
MeO
Key words -lactams, allylic substitution, allylation, Lewis base catal-
ysis
Combretastatin A-4 analogue
Cholesterol absorption
(nM tubulin binding) 3
inhibitor 4
Lewis base
catalyst
OBoc
(b)
O
COOMe
COOMe
+
Ar1
Boc2O, base
-Lactams remain a central structural motif in modern
medicinal chemistry due to the widespread use of penicil-
lins, cephalosporins, carbapenems and monobactams (1
and 2) (Scheme 1, a).1 In addition to -lactam antibiotics
which inhibit bacterial cell wall biosynthesis, molecules
containing this structural motif exhibit a range of other bi-
ological activities including neuroprotective, antioxidant,
analgesic or immunomodulatory capabilities.2 For example,
a new class of -lactams (3 and 4) (Scheme 1, a) has been
identified as potent tubulin binders and therefore potential
anticancer agents.3 Although numerous synthetic ap-
proaches to -lactams have been reported,4 the continuing
cycle of discovery of new biological activities for -lactams
creates the need for the synthesis of molecules with new
substitution patterns and makes the development of new
methods and the improvement of known processes a wor-
thy endeavor.
Ar1
H
5
6
7
chiral
Lewis base
catalyst
Ar2
NH2
8
Ar2
Ar2
O
Ar2
O
NH
N
N
COOMe
Ar1
Ar1
Ar1
11
10
9
Scheme 1 (a) Bioactive -lactam analogues. (b) Proposed route for the
asymmetric synthesis of -lactams from aldehydes, acrylate and anilines.
thesis of -amino acids and their derivatives, -lactams. We
were particularly interested in the allylation of anilines,
which would allow access to structures of type 11, being
derivatives of biologically active compounds 3 and 4. The
products of N-allylations using MBH adducts 9 (Scheme 1,
b) appear to be perfectly equipped for this as they are a sin-
gle cyclization step away from the desired -lactams. The
presence of an exo-methylene in the resulting lactam 10
was seen as an excellent opportunity for further modifica-
tions of the scaffold in a diastereoselective manner, which
highlights the importance of efficiently constructing the
While developing the concept of latent nucleophiles in
Lewis base catalysis as a general method for enantioselec-
tive allylation of N-centered nucleophiles using cheap and
widely available Morita–Baylis–Hillman (MBH) adducts 7,5,6
we became interested in applying such reactions to the syn-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Zi et al.
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stereogenic center  to the nitrogen atom in 9. N-Allyl ani-
lines similar to 9 have been previously prepared via metal-
catalyzed allylic substitutions that are often burdened with
the issue of SN2 vs SN2′ selectivity,7 and via aza-MBH reac-
tions where the scope for the imine is usually very limited.8
An efficient organocatalytic method that circumvents these
problems would certainly be of interest in small-scale ex-
ploratory medicinal chemistry work.
Table 1 Optimization of the Conditions for the Asymmetric Allylation
of Anilinesa
Cl
OBoc
NH2
Cat. (10 mol%)
Solvent
COOMe
NH
+
COOMe
Cl
7a
8a
9a
Entry Catalyst
Solvent
Time (h) Yield (%)b ee (%)c
Lewis base catalyzed allylations of N-centered nucleo-
philes are normally limited in scope to those nucleophiles
that feature an acidic N–H that can be activated by a leaving
group released from a typical MBH adduct, usually a car-
1
2
DABCO
quinine
toluene
2
56
56
56
56
56
56
56
56
56
56
56
56
56
56
52
24
30
67
27
21
46
46
86
64
81
67
74
76
79
66
94 (94)
50
94
88
–
–30
25
84
9
toluene
carbonate/alcoholate.7g,9 Imides/carba-
3
cinchonidine
(DHQD)2AQN
(DHQD)2PHAL
(DHQD)2PYR
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
toluene
boxylate or
a
mates,7g,9b,d sulfonamides9c,e and sulfoximines,9h,i for exam-
ple, perform well in allylations using MBH carbonates. The
N-centered nucleophile in these reactions should also be
less nucleophilic than the catalyst in order to avoid compet-
ing reactivity with the catalyst itself. With these restric-
tions in mind and considering their low N–H acidity (pKa of
around 30 compared to a pKa of around 18 for the butoxide
generated upon degradation of a carbonate), predicting the
reactivity of anilines in (chiral) Lewis base catalyzed allyla-
tions is not straightforward.10
4
toluene
5
toluene
6
toluene
–18
79
84
75
88
82
86
86
87
87
89
87
88
84
88
7
THF
8
dioxane
9
CH2Cl2
10
11
12d
13e
14f
15g
16
17h
18i
19j
20j
PhCF3
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
Reactions of anilines and MBH adducts, catalyzed or
promoted with DABCO, produce racemic N-allyl anilines.11
These products easily undergo 3,3-sigmatropic rearrange-
ments, which proved useful in synthesis of N-heterocycles
such as quinolines and uracils.12 With the goal of develop-
ing an enantioselective coupling of anilines and MBH car-
bonates, our work commenced with the optimization of the
reaction conditions for the chiral Lewis base catalyzed al-
lylation of aniline 8a with MBH carbonate 7a (Table 1). Fo-
cus was placed on cinchona-alkaloid-based catalysts that
are often used for similar transformations.6c,13 The chiral
catalysts required significantly longer reaction times than
the reactions with DABCO. In our hands, the monomeric
cinchona catalysts failed to produce the desired products
with high enantioselectivity. Dimeric catalysts such as (DH-
QD)2AQN, (DHQD)2PHAL and (DHQD)2PYR were tested and
surprisingly showed distinctly divergent activities and en-
antioselectivities. (DHQD)2AQN was identified as a suitable
catalyst as it provided the desired product in good yield
with an enantiomeric ratio of 92:8. Further optimization
was focused on the catalyst loading and identification of
the optimum reaction solvent, reaction time, concentration
and temperature. The optimized conditions included reac-
tions in cyclohexane with 10 mol% of (DHQD)2AQN as the
catalyst at room temperature, with a 0.4 M concentration of
the electrophile.14
cyclohexane/PhCF3 56
cyclohexane
cyclohexane
cyclohexane
PhCF3
56
56
40
40
a Reaction conditions: Carbonate 7a (1 equiv), 4-chloroaniline (8a) (1.1
equiv), catalyst (10 mol%), rt, 0.2 M.
b NMR yield based on triphenylmethane as the internal standard, yield of iso-
lated product in parentheses.
c Determined by HPLC of the purified product.
d (DHQD)2AQN (5 mol%) was used.
e (DHQD)2AQN (15 mol%) was used.
f 4-Chloroaniline (1.0 equiv) was used.
g 4-Chloroaniline (1.3 equiv) was used.
h The concentration was 0.4 M.
i The concentration was 0.1 M.
j The reaction was heated to 40 °C.
line (1.1 equiv) was sufficient to drive the reactions to com-
pletion after 56 hours, allowing us to avoid the commonly
seen use of superstoichiometric quantities of electrophile.
The reactions reported here are thus greener and more effi-
cient.
Optimization studies were followed by an investigation
of the reaction scope for substituted anilines and MBH car-
bonates (Scheme 2). Halogen-substituted anilines gave the
corresponding allylation products 9a–f in excellent yields
and high enantioselectivities. The reactions showed gener-
ally broad tolerance for substituents on the aniline. Sub-
It is apparent that these reactions fit the kinetic resolu-
tion scenario where the two enantiomers of the racemic
MBH carbonate 7 react in an enantioconvergent manner to
produce one enantiomer of the substitution product 9 pre-
dominantly. It is noteworthy that only a slight excess of ani-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
Y. Zi et al.
Cluster
Synlett
strates with electron-donating (9h–j) and electron-with-
drawing (9k) substituents gave the desired products in
good yields.
turned our attention to the cyclization to form the exo-
methylene-containing -lactams, substituted 3-methylene-
azetidin-2-ones 10.
Extended -systems within the nucleophile were also
well tolerated (9l and 9m). The enantiomeric ratios re-
mained good for various combinations of reaction partners
with values of up to 94:6. The enantioselectivities observed
with bulkier nucleophiles like 2-naphthylamine and an or-
tho-substituted aniline were slightly lower (9f and 9l). The
steric bulk of the nucleophile also affected the yield when
an ortho-substituted nucleophile was used (9f). A series of
substituted MBH carbonates was used to assess the reaction
scope for the electrophilic partner. MBH carbonates carry-
ing halide substituents all performed well with respect to
both yield and enantioselectivity (9n–s) (Scheme 2). Even
an electrophile with an ortho-substituent performed well,
albeit with lower enantioselectivity (9r, 77%, 84:16 er).
Substrates with electron-donating and electron-withdraw-
ing substituents performed equally well in these reactions,
showing generally good functional group tolerance with
yields of up to 97% and enantiomeric ratios of up to 98:2.
The configuration of the major enantiomer in reactions cat-
alyzed by (DHQD)2AQN was assigned by comparison of
the optical rotations to those of the previously reported
material.7c With access to a variety of allylated anilines, we
The focus was placed on activation of the nucleophiles
with a strong base to effect cyclization. A brief optimization
of the reaction conditions corroborated the previous re-
ports that Sn(HMDS)2 gives the desired four-membered
rings with the highest yields. Cyclizations using Sn(HMDS)2
provided a small library of compounds with various N- and
C4-substituents, which included alkyl, halide and ether
substituents (including methyl ethers often present in the
tubulin-binding -lactams) (Scheme 3, a). Gratifyingly, the
cyclization reactions provided a variety of substituted -
lactams in good yields (43–95%) and were even able to ac-
commodate an ortho-substituted substrate carrying addi-
tional steric bulk close to the reactive center (10j, 89%). A
brief survey of the enantiomeric ratios for the products
showed that they matched those of the starting materials,
confirming that the stereogenic centers are not affected
during the cyclization process.
The final synthetic step to access analogues 11 was 1,4-
reduction. With a variety of methods to choose from,15 we
opted for simple hydrogenation over a palladium catalyst.
The reactions confidently produced the reduced products in
excellent yields across the set of substrates used to test the
R2
(DHQD)2AQN
(10 mol%)
OBoc
NH
COOMe
R2 NH2
COOMe
+
R1
cyclohexane, 56 h, r.t.
R1
7a
8
9
Cl
I
F
Br
Br
Br
NH
NH
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
Ph
Ph
Ph
9a, 94%, 93:7 er
9b, 92%, 93:7 er
9c, 81%, 94:6 er
9d, 90%, 93:7 er
9e, 83%,89:11 er
9f, 26%, 84:16 er
OMe
NH
NC
NH
MeO
NH
NH
NH
NH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
Ph
Ph
Ph
9g, 75%, 93:7 er
9h, 57%, 94:6 er
9i, 66%, 89:11 er
9j, 85%, 92:8 er
9k, 64%, 91:9 er
9l, 70%, 80:20 er
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
CO2Me
CO2Me
CO2Me
CO2Me
Br
CO2Me
NH
CO2Me
Cl
I
Br
Br
Ph
9m, 65%, 92:8 er
9n, 96%, 97:3 er
9o, 92%, 98:2 er
9p, 91%, 98:2 er
9q, 72%, 88:12 er
9r, 77%, 84:16 er
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
4-ClH4C6NH
CO2Me
CO2Me
O2N
CO2Me
CO2Me
MeO
CO2Me
CO2Me
F
MeO2C
9t, 97%, 91:9 er
9s, 90%, 95:5 er
9u, 72%, 96:4 er
9v, 81%, 95:5 er
9w, 59%, 91:9 er
9x, 92%, 97:3 er
Scheme 2 Enantioselective Lewis base catalyzed allylations of anilines using MBH carbonates
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
Y. Zi et al.
Cluster
Synlett
Ar1
Ar2
(a)
(b)
Ar1
Ar2
O
Ar1
O
Ar1
O
Pd/C, H2 (1 atm)
EtOAc, 30 min
Sn(HMDS)2
NH
N
N
N
CO2Me
toluene, 3 h, reflux
Ar2
Ar2
9
10
10
11
Cl
Br
Cl
MeO
O
O
MeO
N
O
O
O
N
O
O
O
O
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10a, 70%, 93:7 er 10d, 85%, 93:7 er 10g, 89%, 94:6 er 10h, 59%, 94:6 er
10i, 85%, 89:11 er 11a, 89%, 93:7 er 11g, 94%, 91:9 er
11h, quant.
11i, quant., 90:10 er
Cl
Cl
Cl
Cl
Cl
Cl
O
O
N
O
O
O
N
N
N
N
OMe
OMe
O
O
O
O
N
N
N
N
Ph
Ph
F
Ph
Ph
Cl
I
Br
10j, 89%, 94:6 er 10l, 89%, 76:24 er 10n, 82%, 97:3 er 10o, 43%, 97:3 er
10p, 70%, 98:2 er 11j, 93%, 94:6 er
11l, 79%
11n, quant.
11s, 72%, 97:3 er
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
O
O
N
O
N
N
O
N
O
N
N
N
N
Br
MeO
MeO
F
10q, 81%, 90:10 er 10s, 53%, 95:5 er 10v, 73%, 98:2 er 10w, 90%, 89:11 er 10x, 95%, 96:4 er
11v, 98%
11w, 93%
11x, 98%, 98:2 er
Scheme 3 (a) Cyclization to give exo-methylene-containing -lactams 10. (b) Diastereoselective hydrogenation of the exo-methylene group to pro-
duce -lactams 11.
reaction scope (Scheme 3, b). Furthermore, the hydrogena-
tion reactions proceeded with good control of the diastere-
oselectivity. Attempts to isomerize the reaction product un-
der basic conditions produced only minor quantities of the
trans-isomers, suggesting that the cis-diastereomer was
more stable, a fact that could be used to control otherwise
less diastereoselective transformations involving the exo-
methylene group in the resulting -lactams. The assign-
ment of the structures of the two diastereomers was based
Funding Information
Financial support from the Carl-Zeiss-Stiftung (Carl-Zeiss Foundation)
(endowed professorship to I.V.), Friedrich-Schiller-Universität Jena
and the State of Thuringia (graduate fellowship to M.L.) is gratefully
acknowledged. P.S. is grateful to the Deutsche Bundesstiftung Umwelt
(DBU) (German Environment Foundation) (Grant No. 20018/578) for a
generous Ph.D. grant.
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Acknowledgment
3
on JH–H coupling constants, which are consistent with the
dihedral angles in the low energy conformations for the
two isomers (5.9 Hz for cis-11a and 2.4 Hz for trans-11a).
The enantiomeric ratios of the isolated -lactams matched
those of the starting materials, showing that the stereogen-
ic center  to the nitrogen atom was not affected by the
two-step sequence.
We thank Dr. Peter Bellstedt and Dr. Nico Ueberschaar for their sup-
port with NMR and MS analysis.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691570.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
In conclusion, we have presented an efficient route for
the asymmetric synthesis of biologically relevant -lactams
that relies on enantioselective Lewis base catalyzed allyla-
tion of anilines to set the stereogenic centers.16 Considering
the high atom economy in the synthesis of MBH adducts,
the efficiency of the catalytic substitution reactions which
require nearly equimolar quantities of starting materials
and the simplicity of the cyclization/reduction se-
quence,17,18 this route represents an economical and green
tool for the synthesis of -lactams. The library of prepared
compounds will be evaluated for biological activity in due
course.
References and Notes
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Hinze, S. Chem. Eur. J. 2017, 23, 8473. (b) Schömberg, F.; Zi, Y.;
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Schömberg, F.; Seifert, F.; Görls, H.; Vilotijevic, I. Org. Biomol.
Chem. 2018, 16, 6341.
(16) Enantioselective Allylation of Anilines; General Procedure
Carbonate 7 (1 equiv), aniline 8 (1.1 equiv) and (DHQD)2AQN
(10 mol%) were added to a vial containing a stir bar. The vial
was evacuated and refilled with nitrogen 3 times. The reaction
mixture was then stirred at room temperature after adding
cyclohexane (0.4 M). After completion of the reaction, the
solvent was removed under reduced pressure. The crude
residue was purified by column chromatography (eluent: 5%
ethyl acetate in petroleum ether).
(8) (a) Shi, M.; Xu, Y. M. Angew. Chem. Int. Ed. 2002, 41, 4507.
(b) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127,
3680. (c) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem. Int.
Ed. 2007, 46, 4614. (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007,
2905. (e) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1.
Methyl
late (9a)
2-{[(4-Chlorophenyl)amino](phenyl)methyl}acry-
Yield: 28 mg (94%); pale yellow oil; 93:7 er (determined by
HPLC analysis) [Phenomenex Lux Cellulose-1, n-hexane/i-
PrOH = 95:5, 1.0 mL/min,  = 253 nm, tR (major) = 18.73 min, tR
1
(minor) = 14.92 min]. H NMR (300 MHz, CDCl3):  = 7.48–7.27
(9) (a) Li, J.; Wang, X.; Zhang, Y. Tetrahedron Lett. 2005, 46, 5233.
(b) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron: Asymmetry
2007, 18, 1990. (c) Sun, W.; Ma, X.; Hong, L.; Wang, R. J. Org.
Chem. 2011, 76, 7826. (d) Ma, G.; Sibi, M. P. Org. Chem. Front.
2014, 1, 1152. (e) Yao, L.; Wang, C.-J. Adv. Synth. Catal. 2015,
357, 384. (f) Kamlar, M.; Císařová, I.; Hybelbauerová, S.; Veselý,
J. Eur. J. Org. Chem. 2017, 1926. (g) Dočekal, V.; Šimek, M.;
Dračínský, M.; Veselý, J. Chem. Eur. J. 2018, 24, 13441. (h) Li, Z.;
Frings, M.; Yu, H.; Raabe, G.; Bolm, C. Org. Lett. 2018, 20, 7367.
(i) Li, Z.; Frings, M.; Yu, H.; Bolm, C. Org. Lett. 2019, 21, 3119.
(10) Bordwell, F. G.; Algrim, D. J. J. Am. Chem. Soc. 1988, 110, 2964.
(11) (a) Bakthadoss, M.; Srinivasan, J.; Selvakumar, R. Aust. J. Chem.
2014, 67, 295. (b) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H.
Synlett 2002, 173.
(m, 5 H), 7.18–7.04 (m, 2 H), 6.57–6.44 (m, 2 H), 6.40 (s, 1 H),
5.92 (s, 1 H), 5.39 (s, 1 H), 4.24 (s, 1 H), 3.72 (s, 3 H). 13C NMR (75
MHz, CDCl3):  = 166.58, 145.23, 140.21, 139.80, 129.07, 128.88,
128.01, 127.51, 126.37, 122.60, 114.63, 59.13, 52.06.
(17) Cyclization to -Lactams 10; General Procedure
To a solution of 9 (1.0 equiv) in toluene was added Sn[HMDS]2
(1.5 equiv). The mixture was refluxed for 2 h and the solution
then cooled and concentrated. The residue was purified by flash
chromatography on silica gel (eluent: 5% ethyl acetate in petro-
leum ether) to afford the desired product.
(R)-1-(3-Methoxyphenyl)-3-methylene-4-phenylazetidin-2-
one (10i)
Yield: 14 mg (85%); white solid. IR (ATR): 2927, 2360, 1743,
1597, 1492, 1454, 1369, 1249, 1114, 848, 752 cm–1 1H NMR
.
(12) (a) Chen, H.-Y.; Patkar, L. N.; Ueng, S.-H.; Lin, C.-C.; Lee, A. S.-Y.
Synlett 2005, 2035. (b) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tet-
rahedron 2005, 61, 1493. (c) Lee, C.-G.; Gowrisankar, S.; Kim, J.-
N. Bull. Korean Chem. Soc. 2005, 26, 481. (d) Kim, S.-C.;
Gowrisankar, S.; Kim, J.-N. Bull. Korean Chem. Soc. 2005, 26,
1001. (e) Pathak, R.; Madapa, S.; Batra, S. Tetrahedron 2007, 63,
451. (f) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahe-
dron Lett. 2008, 49, 1670.
(400 MHz, CDCl3):  = 7.46–7.32 (m, 5 H), 7.17 (t, J = 8.1 Hz, 1
H), 7.06 (t, J = 2.2 Hz, 1 H), 6.84 (dd, J = 8.0, 1.9 Hz, 1 H), 6.63
(dd, J = 8.2, 2.5 Hz, 1 H), 5.86 (t, J = 1.9 Hz, 1 H), 5.41 (d, J = 1.6
Hz, 1 H), 5.19 (d, J = 1.6 Hz, 1 H), 3.77 (s, 3 H). 13C NMR (101
MHz, CDCl3):  = 161.01, 160.13, 149.77, 138.68, 136.45, 129.92,
129.10, 128.81, 126.61, 111.01, 110.11, 109.41, 103.00, 63.72,
55.28. HRMS (EI): m/z [M]+ calcd for C17H15NO2: 265.1103;
found: 265.1094.
(13) (a) Du, Y.; Han, X.; Lu, X. Tetrahedron Lett. 2004, 45, 4967.
(b) Lin, A.; Mao, H.; Zhu, X.; Ge, H.; Tan, R.; Zhu, C.; Cheng, Y.
Adv. Synth. Catal. 2011, 353, 3301. (c) Pei, C.-K.; Zhang, X.-C.;
Shi, M. Eur. J. Org. Chem. 2011, 4479. (d) Liu, T. Y.; Xie, M.; Chen,
Y. C. Chem. Soc. Rev. 2012, 41, 4101. (e) Zhao, M.-X.; Chen, M.-X.;
Tang, W.-H.; Wei, D.-K.; Dai, T.-L.; Shi, M. Eur. J. Org. Chem. 2012,
3598. (f) Putaj, P.; Tichá, I.; Císařová, I.; Veselý, J. Eur. J. Org.
Chem. 2014, 6615.
(18) Reduction to -lactams 11; General Procedure
To a degassed ethyl acetate solution of 10 (1 equiv) was added
(10 mol%) Pd/C and the reaction flask was furnished with a H2
balloon. After stirring for 30 min, the reaction mixture was fil-
tered over Celite and evaporated. The crude residue was puri-
fied by flash column chromatography (eluent: 5% ethyl acetate
in petroleum ether).
(3S,4S)-1-(4-Chlorophenyl)-3-methyl-4-(naphthalen-2-yl)-
azetidin-2-one (11x)
(14) During the preparation of this manuscript, two independent
reports describing similar reactions of anilines and MBH car-
bonates were published. These methods use 10 mol% of -iso-
Yield: 25 mg (98%); white solid. IR (ATR): 2974, 1728, 1597,
1492, 1381, 1365, 1161, 1091, 813, 744 cm–1 1H NMR (300
.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
Y. Zi et al.
Cluster
Synlett
MHz, CDCl3):  = 7.92–7.77 (m, 3 H), 7.73–7.67 (m, 1 H), 7.53
(dt, J = 6.3, 3.4 Hz, 2 H), 7.37–7.28 (m, 3 H), 7.25–7.16 (m, 2 H),
5.35 (d, J = 6.0 Hz, 1 H), 3.80 (qd, J = 7.6, 5.9 Hz, 1 H), 0.93 (d,
J = 7.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3):  = 168.44, 136.28,
133.18, 132.13, 129.16, 128.80, 128.72, 127.89, 127.82, 126.66,
126.45, 126.22, 124.36, 118.34, 58.74, 49.79, 9.79. HRMS (EI):
m/z [M]+ calcd for C20H16ClNO: 321.0920; found: 321.0916.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F