α-Acyl-α-diazoacetates in Transition-Metal-Free β-Lactam Synthesis

Article abstract of DOI:10.1021/acs.joc.9b02030

Thermally promoted reaction of α-acyl-α-diazoacetates with imines has been investigated. The transformation, earlier reported predominantly under transition metal catalyzed conditions, delivers α-alkoxycarbonyl-substituted β-lactams with outstanding diastereoselectivity. DFT calculations performed in order to evaluate energetically feasible reaction pathways revealed the intermediacy of 1,3-oxazin-4-one intermediates hitherto never implicated in the Staudinger synthesis of β-lactams.

Full text of DOI:10.1021/acs.joc.9b02030

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Article
alpha-Acyl-alpha-diazoacetates in Transition-
Metal-Free beta-Lactam Synthesis
Judith Synofzik, Dmitry Dar'in, Mikhail Sergeevich Novikov,
Grigory Kantin, Olga Bakulina, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02030 • Publication Date (Web): 21 Aug 2019
Downloaded from pubs.acs.org on August 22, 2019
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-Acyl--diazoacetates in Transition-Metal-Free -Lactam Synthesis
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Judith Synofzik, Dmitry Dar’in, Mikhail S. Novikov, Grigory Kantin, Olga Bakulina, and Mikhail
Krasavin*
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Saint Petersburg State University, Saint Petersburg 199034, Russia
no bulky or
acceptor groups
alkyl or
(hetero)aryl
1) toluene
reflux, 3 h
Dean-Stark
trap
O
R''
R'
R
RCHO
R'NH2
N
+
2)
N2
not sterically
demanding or
from 'enolizable'
aldehydes
YO2C
R''
CO2Y
O
28 examples
45-89%
reflux, 20-24 h
Y = Me or Et
ABSTRACT: Thermally promoted reaction of -acyl--diazoacetates with imines has been
investigated. The transformation, earlier reported predominantly under transition metal catalyzed
conditions, delivers -alkoxycarbonyl-substituted lactams with outstanding diastereoselectivity.
DFT calculations performed in order to evaluate energetically feasible reaction pathways revealed the
intermediacy of 1,3-oxazin-4-one intermediates hitherto never implicated in the Staudinger synthesis
of -lactams.
INTRODUCTION
Thermally promoted cyclocondensation of imines with various dicarboxylic acid anhydrides 1a-c
(exemplifying only a portion of the feasible reagent scope1) has been a prolific source of
polysubstituted lactam carboxylic acids 2a-c and their derivatives dubbed the Castagnoli-Cushman
reaction.2 In these practically convenient transformations, carried out at ambient or, more frequently,
elevated temperatures, anhydrides 1a-c essentially manifest themselves as 1,3-, 1,4- and 1,5-dipolar
synthons 3a-c, delivering - and -lactams3 (including heteroatom-containing variants of the latter4) as
well as recently reported -lactams,5 respectively. Retrosynthetic analysis of similarly substituted -
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lactams 4, however, breaks them down to imines and difficult-to-obtain and unstable6 malonic
anhydrides 5. The latter, being essentially synthetic equivalents of 1,2-dipolar synthons 6, can be
visualized as ketenes 7 obtainable, in principle, via the Wolff rearrangement of respective -acyl--
diazoacetates 8 (Figure 1).
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The literature analysis revealed that the overwhelming majority of reported -lactam syntheses which
exploit the disconnection in question, involve generating ketenes such as 7 via Rh(II) carbenes7 which,
in our view, somewhat tarnishes this approach compared to the convenience and practical simplicity of
the catalyst-free Castagnoli-Cushman chemistry. Considering that there are also examples involving
thermally8 and photochemically9 generated ketenes 7 in the literature, we set off to investigate the
feasibility of thermally promoted cyclocondensation of -acyl--diazoacetates 8 with imines as an
entry into -lactam scaffold. In light of the prominence of -lactams in antibacterial drug design10 (as
well as other target areas11) and the recently described approach to various diazo compounds in array
fashion,12 a practically simple, catalyst-free method toward this classical cores would be highly
beneficial both from early discovery and process chemistry prospective.13 Herein, we present the
results of these studies.
Figure 1. Polysubstituted lactam carboxylic acid derivatives of various sizes accessed via
condensation reactions of imines.
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-, - and -lactams:
3
4
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8
O
O
O
R'
R
R'
N
N
O
+
X
X
R
X
O
Y = H
CO2Y
CO2Y
9
2a-c
1a-c
3a-c
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a
b
c
X = direct bond ( ); CH2, O, S, NR ( ); o-phenylene, (CH2)2 ( )
-lactams:
O
R'
N
O
O
R'
R
O
"
"
N
+
R''
R
R''
CO2Y
CO2Y
R''
O
Y = alkyl
YO2C
4
5
6
O
.
O
CO2Y
R''
R''
N2
8
7
RESULTS AND DISCUSSION
The initial attempt to realize the thermal cyclocondensation of methyl -acetyl--diazoacetate (8a)
with an imine generated in situ turned out to be successful and was performed as follows. Benzylamine
and p-tolualdehyde were reacted in refluxing toluene for 3 h (with a Dean-Stark trap to allow
separation of water to drive the imine formation forward) at which point diazo compound 8a was
added and after additional 24 h, anticipated -lactam compound 4a was isolated as a single cis-
diastereomer as was confirmed by single-crystal X-ray analysis. Such a remarkable diastereoselectivity
drew our attention and needed to be understood from the mechanistic perspective (vide infra). A
somewhat lower yield of 4a (66%) was obtained in a microwave-promoted reaction of 8a with the
same preformed imine, however, over a substantially shorter period of time (1 h). Considering the
clear yield advantage offered by conventional heating, such a procedure was employed throughout the
subsequent study aimed at evaluating the scope of various amine/aldehyde combinations in thermally
promoted cyclocondensation with diazo compounds 8a-l involving the Wolff rearrangement of the
latter (Figure 2).
Figure 2. -Acyl--diazoacetates 8 employed in this study.
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O
O
O
O
CO2Me
CO2Et
CO2Bu-t
CO2Me
CO2Me
O
Me
8a
Me
Me
Et
N2
N2
N2
N2
8b
8c
8d
5
6
7
8
9
O
O
O
CO2Et
CO2Et
CO2Et
t-Bu
N2
N2
N2
N2
8e
8g
8f
8h
10
11
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O
O
O
OMe O
CO2Me
CO2Et
CO2Et
CO2Me
N
N2
S
N2
N2
N2
F
8i
8j
8l
8k
To our delight, the -lactams 4 successfully synthesized in this study, were obtained almost
exclusively (except for compounds 4e-f) as a single diastereomer which was confirmed by single X-
ray crystallography to have the carboxylic ester (CO2Y) and the aldehyde-derived R group on the same
face of the -lactam ring (Table 1). The imine procedure had to be modified slightly when either the
aldehyde or the amine were volatile and did not permit the imine formation in refluxing toluene. In
these cases, the imine was pre-formed by reacting the aldehyde and the amine at room temperature in
the presence of 4Ǻ molecular sieves and filtering the latter off.
Table 1. -Lactams 4 investigated in this study.
1) toluene
reflux, 3 h
O
R'
R
Dean-Stark trap
N
R''
YO2C
RCHO + R'NH2
O
2)
CO2Y
4
R''
8
N2
reflux, 20-24 h
Yield,
%
Entry
1
8
Product
Entry
18
8
Product
Yield, %
81
Me
O
Me
O
MeO2C
MeO2C
N
N
Ph
8a
86a
8a
Ph
4a
4r
Me
Me
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Me
MeO2C
O
Me
MeO2C
O
N
4
5
6
7
8
9
OMe
N
Ph
2
3
8a
8a
86
19
20
8a
8a
65
4b
4s
Me
MeO
Me
MeO2C
MeO
O
O
MeO2C
10
11
12
13
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15
16
17
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N
53d
N
0
Ph
S
OMe
4t
4c
N
Me
MeO2C
O
N
O
EtO2C
H
4
8a
Ph
Ph
71
21
8j
50a,d
N
4d
F
4u
Me
MeO2C
O
O
MeO2C
OMe
5
6
8a
8a
57b
57c
22
23
8d
8b
0d
N
N
F
4e
4v
Me
EtO2C
O
Me
MeO2C
O
N
N
51d,e
Ph
Me
4w
4f
F3C
Me
MeO2C
Me
EtO2C
O
O
N
70d
60d
0d
24
25
26
27
8b
8b
8e
8e
71
89
N
7
8
8a
8a
8a
8a
SBu-t
4g
4x
N
Me
Me
MeO2C
Me
EtO2C
O
O
N
N
4y
4h
MeO
Me
Me
MeO2C
O
O
EtO2C
N
S
9
82
N
S
4i
4z
Me
Me
MeO2C
O
O
EtO2C
Me
O
N
10
61a
N
63d
4j
4aa
OMe
Me
Ph
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Me
MeO2C
O
O
MeO2C
N
N
11
12
8a
8a
0
28
29
8g
8h
45f
76
4k
4ab
CF3
Me
Cl
OMe
10
11
12
13
14
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17
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Me
MeO2C
O
O
EtO2C
57d
N
Me
N
O
4l
4ac
F
O
EtO2C
O
13
14
8h
8k
87
71
30
31
8i
8j
68d,g
MeO2C
N
Ph
N
Ad
4m
4ad
Me
MeO
N
OMe
O
O
MeO2C
EtO2C
EtO2C
77c
N
N
Ph
4ae
4n
Me
OMe
F
S
O
EtO2C
O
MeO2C
15
8i
85
32
8l
65%
N
Ph
N
Ph
4af
4o
Me
Me
N
Me
O
N
t-BuO2C
O
O
EtO2C
16
17
8j
8f
73
33
34
8c
8a
0h
Ph
N
Ph
Ph
4ag
4p
Me
Me
MeO2C
O
MeO2C
0
0i
N
N
O
4q
4ah
Me
aStructure confirmed by single-crystal X-ray analysis. Contains traces of the other diastereomer. dr 8.2:1.0.
b
c
d
Imine prepared in a separate step. eAdditional 1.0 equiv. of 8c was added after 9 h. fAdditional 0.5 equiv. of 8g
g
h
was added after 18 h. Ad = 1-adamantyl. Enamide by-product 12 isolated in 22% yield and characterized.
iEnamide and malonic monoamide were the observed by-products (not isolated).
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The successful Wolff rearrangement (with subsequent ‘trapping’ of the ketene intermediate with
imine) apparently involved not only migration of primary and secondary alkyl (e. g., Me, Et, i-Pr) but
also cyclopropyl as well as various (hetero)aryl groups. The reaction was remarkably sensitive to the
steric effects in the aldehyde and the amine portion (cf. 4c, 4v, 4ag - and 4i, respectively, which failed
to form) as well as electronic effects in the amine portion - cf. attempted preparation of 4k where
introducing electron-withdrawing group at the aniline made the formation of -lactam ring ineffective.
The failure of compound 4q to form is likely attributable to the reluctance of 8f to enter the Wolff
rearrangement, as could be preliminarily concluded based on the absence of a typical ketene-derived
anilide 10 when 8f was reacted under the same conditions with p-toluidine (Scheme 1).
10
11
12
13
14
15
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17
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Scheme 1. Evidence for ineffective Wolff rearrangement of 8f.
O
NH2
O
CO2Et
t-Bu
EtO2C HN
toluene
reflux, 20-24 h
N2
8f
10
, 0%
A substantial limitation of the reaction scope discovered in the course of these studies was the inability
of enolizable -C-H imines to give the expected -lactam products (cf. 4ag). In this case, the principal
products (derived, presumably, from betaine 11) are enamide 12 and malonic monoamide 13 (not
isolated) thought to be the product of hydrolysis of 12 by adventitious water (Scheme 2). Similar
outcome was observed in the attempt to prepare compound 4ah.
Scheme 2. Reaction of an enolizable -C-H imine with compound 8c under thermal conditions.
4ag
8c
c-HexCHO + BnNH2
X
O
.
- H2O
Me
N
CO2t-Bu
Me
Bn
CO2t-Bu
Me
CO2t-Bu
Bn
O
N
O
Me
CO2t-Bu
+
O
HN
Bn
N
Bn
H
H
13
11
12
, 22%
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The apparent sensitivity of the -lactam formation to the availability of the imine nitrogen atom for
acylation (in steric as well as electronic sense) and the failure to obtain -lactams from -C-H imines
argues for the importance of the stepwise formation of the -lactam ring involving acylation (rather
than concerted [2+2]-cycloaddition). Moreover, it allows drawing an almost exact analogy between the
-lactam syntheses described herein and the Castagnoli-Cushman reaction of succinic anhydride (an
exemplary dicarboxylic acid anhydride) which proceeds with ‘non-enolizable’ imines under nearly the
same conditions as described herein, to give -lactams 2a via N-acylation/intramolecular Mannich
sequence14 and fails to give 2a with -C-H imines, delivering enamides 144,15 (similar to 12) instead
(Scheme 3).
10
11
12
13
14
15
16
17
18
19
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Scheme 3. Mechanistically relevant formation of -lactams 2a and enamides 14.
O
N R'
intramolecular
Mannich
O
HO2C
R
R'
N
O
R'
R
2a
N
R
HO
O
acylation
R = -C-H
O
O
alkyl
O
R'
N
O
R''
14
OH
In order to verify the validity of this mechanistic interpretation, preliminarily devised from the
experimental facts, as well as to understand the origin of the high diastereoselectivity observed in the
formation of -lactams 4, we performed DFT calculations of the possible reaction pathways (Scheme
4) and the associated energy profiles (Figure 3) for the interaction of imine 15 and ketene 7a (derived
from diazo compound 8a) en route to -lactam RS,SR-4l.
Scheme 4. Plausible mechanistic interpretation for the formation of compound RS,SR-4l
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OMe
OMe
H
Me
O
TS1endo
TS3
Me
O
OMe
TS4
Me
OMe
O
O
O
N
Me
N
Me
Ph
O
H
N
Me
H
O
Me
Ph
C
Ph
-16
O
Ph
-17
-17
eq
H
,
ax
E endo
7a
endo
N
TS5
Ph
Me
15
10
11
12
13
14
15
16
17
18
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OMe
O
H
Ph
Me
Ph
H
H
O
Me
O
Me
O
OMe
TS1exo
C
O
TS6
Me
MeO
O
exo
7a
O
OMe
Me
-16'
N
N
N
O
Me
-16
Me
,
Z endo
,
-16
E exo
,
Z endo
TS2
TS7
Ph
OMe
Me
O
N
O
Me
4l
RS,SR-
Imine 15 can approach ketene 7a from endo or exo directions leading, via TS1endo and TS1exo transition
states, to two alternative betaine adducts – E,endo-16 and E,exo-16, respectively. The free energy
levels of TS1endo and TS1exo are very close. However, E,endo-16 betaine adduct is substantially lower
in energy compared to E,exo-16. Rotation around the C=N bond in betaine E,exo-16 results in the
direct formation of lactam RS,SR-4l proceeding via transition state TS2. However, the energy of TS2 is
overly high for this pathway to be realized under the reaction conditions. Alternatively, the more stable
E,endo-16 betaine adduct can be converted into RS,SR-4l. Such a reaction pathway turns out to be
energetically more favorable, despite its multistep character. Indeed, this transformation includes the
successive formation of oxazinones ax-17 and eq-17 which are nearly equal in energy and differ only
by the axial and equatorial position of the phenyl group. Subsequent evolution of oxazinone eq-17
proceeds with ring opening to give betaine Z,endo-16 (Z arrangement of the Ph and Me groups) which
undergoes a sigma-bond rotation of the methoxycarbonyl group (passing through a surprisingly high
energy barrier TS6) and finally cyclizes, via TS7, to give the sole observed diastereomer RS,SR-4l,
with the highest negative free energy change of all the above elementary steps.
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Figure 3. Energy profile (Gibbs free energies) obtained by DFT wb97xd/cc-pvtz calculations (PCM,
toluene, 383 K) for cycloaddition of imine 15 to ketene 7a.
Besides rationalizing the formation of the sole observed diastereomer of 4l, these DFT calculations
reveal the following significant mechanistic clue. Oxazinones analogous to 17 are commonly isolable
products in the reactions of imines with acyl ketenes derived from -diazo--diketones.7a,16 However,
their formation has never been implicated in the observed Staudinger-type reactions of imines. The
mechanistic picture involving the formation of the oxazinone intermediate can potentially unify the
two types of reactions – those of ketenes 7 derived from -acyl--diazoacetates 8 - and of ketenes 19
formed via the Wolff rearrangement of -diazo--diketones 18. If oxazinones 20 are indeed the true
intermediates in both cases, their propensity to give -lactams via ring opening and 1,4-recyclization
can be attributed to the destabilization by the R2 alkoxy substituent while alkyl-substituted oxazinones
20 are stable, isolable adducts (Figure 4).
Figure 4. Plausible unified mechanistic interpretation for the reactions of imines with ketenes.
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R4
N
R4
N
O
.
O
O
R1
R3

R2
O
R3
O
O
R1
R2
O
Wolff
rearragement
O
R1
R1
N2
N
R3
R4
R2
R2
20
2
8
, R = OAlkyl
2
7
, R = OAlkyl
2
18
, R = Alkyl
R2 = OAlkyl: unstable
R2 - Alkyl: stable
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, R - Alkyl
The proposed mechanistic interpretation requires further investigation. Preliminarily, we synthesized
oxazinone 20a and attempted to observe its transformation under forcing conditions. However, the
only observed product was the starting imine 21 and not the -lactam in question (Scheme 5).
Scheme 5. Preparation and attempted thermal transformation of oxazinone 20a.
N2
Ph
Me
Me
O
O
O
toluene, 180 oC
Me
Me
N
O
O
N
Ph
N
Ph
X
MeOC
toluene
reflux, 2.5 h
20 h
Me
21
20a
, 33%
In summary, we have investigated thermally-promoted reaction of -acyl--diazoacetates with imines
which proceeds via the Wolff rearrangement and formation of the respective ketenes. The reaction is
conveniently conducted with imines prepared in situ or in a separate step in refluxing toluene and
delivers densely substituted -lactams with remarkable diastereoselectivity. Compared to the majority
of the literature reports involving such transformations, the approach does not involve generating a
transition metal (Rh(II)) carbene and is, therefore, more amenable to pharmaceutical production. The
reaction can be viewed as a mechanistic congener of the Castagnoli-Cushman reaction of imines and
cyclic anhydrides and suffers from similar side-reactions and limitations. Mechanistic analysis of
energetically feasible reaction pathways using DFT calculations revealed the intriguing intermediacy
of oxazinone species which are known as stable and isolable products in reactions on imines with
ketenes derived from -diazo--diketones. The transformation of oxazinone intermediates into -
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lactams via ring opening/ring closure requires further experimental investigation which is currently
4
5
underway in our laboratories.
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EXPERIMENTAL SECTION
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General information. NMR spectra were acquired with a 400 MHz Bruker Avance III spectrometer
(400.13 MHz for 1H and 100.61 MHz for 13C) in CDCl3 and were referenced to residual solvent proton
signals (δH = 7.26) and solvent carbon signals (δC = 77.16). Melting points were determined with a
melting point apparatus Stuart SMP 50 in open capillary tubes. Mass spectra were acquired with a
Bruker maXis HRMS-ESI-qTOF spectrometer (electrospray ionization mode, positive ions detection).
X-ray single crystal analyses were performed on Agilent Technologies «Xcalibur» and «Supernova»
diffractometers with monochromated Mo Kα or Cu Kα radiation, respectively. The temperature was
kept at 129 (4a) or 100 K (4j, 4u) during data collection. Using Olex2, the structure was solved with
the olex2.solve structure solution program using Charge Flipping and refined with the olex2.refine
refinement package using Gauss-Newton minimization17. Column chromatography was carried out on
silica gel grade 60 (0.040−0.063 mm) 230−400 mesh. Diazocompounds 8 were prepared according to
SAFE-protocol18. Aldehydes, amines and solvents were obtained from commercial sources and were
used without further purification.
General procedure for preparation of lactams 4
In a 25 mL round-bottom flask, an amine (0.8 mmol, 1 eq.) and an aldehyde (0.9 mmol, 1.1 eq.) were
dissolved in 10 mL toluene and refluxed with azeotropic removal of water. After one hour, half of the
solvent was distilled off and an α-acyl-α-diazoacetate (8a-l, 1.0 mmol, 1.2 eq.) was added. The mixture
was then refluxed overnight and the reaction progress was followed via TLC. When no more diazo
compound was detectable (20-24h), the solvent was evaporated in vacuo and the resulting mixture was
purified by column chromatography on silica gel with a linear gradient (0-20%) of acetone in hexane
(total volume of eluent - 450 mL) to provide pure compounds 4.
(±) (3R,4S)-Methyl 1-benzyl-3-methyl-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4a): yield 222 mg,
1
86%; white powder; mp 112,5-114,0 C; H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 3H), 7.21 –
7.16 (m, 4H), 7.15 – 7.07 (m, 2H), 5.01 (d, J = 14.9 Hz, 1H), 4.21 (s, 1H), 3.92 (d, J = 14.9 Hz, 1H),
3.35 (s, 3H), 2.37 (s, 3H), 1.63 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 169.1, 167.2, 138.6,
135.1, 130.8, 129.2, 128.9, 128.5, 127.9, 126.8, 66.7, 65.5, 51.7, 44.6, 21.2, 17.2 ppm; HRMS (ESI-
TOF) m/z: [M+Na]+ Сalcd for C20H21NO3Na 346.1414; Found 346.1419.
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(±) (2S,3R)-Methyl 1-benzyl-2-(4-methoxyphenyl)-3-methyl-4-oxoazetidine-3-carboxylate (4b): yield
234 mg, 86%; light yellow powder; mp 134 – 136 C; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m,
3H), 7.19 – 7.14 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 4.99 (d, J = 14.9 Hz, 1H), 4.20 (s, 1H), 3.92 (d, J =
14.9 Hz, 1H), 3.83 (s, 3H), 3.37 (s, 3H), 1.63 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 169.1,
167.1, 160.0, 135.1, 128.9, 128.5, 128.2, 127.9, 125.6, 113.9, 66.7, 65.3, 55.3, 51.8, 44.5, 17.1 ppm;
HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C20H21NNaO4 362.1363; Found 362.1367.
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(±) (2S,3R)-Methyl 1-benzyl-2-(4-fluorophenyl)-3-methyl-4-oxoazetidine-3-carboxylate (4d): yield
187 mg, 71%; white powder; mp 84 − 86 C; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m, 3H), 7.26
– 7.11 (m, 4H), 7.06 (t, J = 8.6 Hz, 2H), 4.99 (d, J = 14.9 Hz, 1H), 4.22 (s, 1H), 3.93 (d, J = 14.9 Hz,
13
1H), 3.36 (s, 3H), 1.63 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 168.8, 166.9, 162.9 (d, J =
248.1 Hz), 134.9, 129.7 (d, J = 3.2 Hz), 129.0, 128.6 (d, J = 8.3 Hz), 128.5, 128.0, 115.6 (d, J = 21.7
Hz), 66.8, 64.9, 51.8, 44.7, 17.1 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C19H18FNNaO3
350.1163; Found 350.1175.
(±) (2R,3R)-Methyl 1-benzyl-2-(2-fluorophenyl)-3-methyl-4-oxoazetidine-3-carboxylate (4e): yield
1
154 mg, 57%; yellow powder; mp 71 − 72 C; H NMR (400 MHz, CDCl3) δ 7.31 – 7.22 (m, 5H),
7.17 – 7.04 (m, 3H), 7.03 – 6.91 (m, 1H), 4.94 (d, J = 14.8 Hz, 1H), 4.51 (s, 1H), 3.92 (d, J = 14.9 Hz,
13
1H), 3.24 (s, 3H), 1.59 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 168.9, 167.3, 161.1 (d, J =
248.2 Hz), 135.0, 130.3 (d, J = 8.3 Hz), 129.1, 128.6, 128.2, 127.4 (d, J = 3.5 Hz), 124.0 (d, J = 3.8
Hz), 121.9 (d, J = 13.1 Hz), 115.7 (d, J = 20.9 Hz), 66.7, 59.0 (d, J = 5.0 Hz), 51.9, 45.3, 16.9 ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Сalcd for C19H19FNO3 328.1343; Found 328.1353.
(±) (3R,4S)-Methyl 1-benzyl-3-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidine-3-carboxylate (4f):
1
yield 172 mg, 57%; light yellow powder; mp 79 − 81 C; H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
8.2 Hz, 2H), 7.44 – 7.29 (m, 5H), 7.17 (dd, J = 7.1, 2.2 Hz, 2H), 5.02 (d, J = 14.9 Hz, 1H), 4.28 (s,
13
1H), 3.95 (d, J = 14.8 Hz, 1H), 3.32 (s, 3H), 1.66 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ
168.5, 166.8, 138.3, 134.6, 131.0 (q, J = 32.6 Hz), 129.0, 128.5, 128.2, 127.3, 125.5 (q, J = 3.8 Hz),
123.8 (q, J = 272.3 Hz), 67.0, 64.9, 51.9, 45.0, 17.2 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C20H18F3NNaO3 400.1131; Found 400.1144.
(±) (3R,4S)-Methyl 1-ethyl-3-methyl-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4g): yield 146 mg,
1
70%; light yellow powder; mp 43 − 45 C; H NMR (400 MHz, CDCl3) δ 7.17 (s, 4H), 4.45 (s, 1H),
3.66 (dq, J = 14.7, 7.4 Hz, 1H), 3.33 (s, 1H), 3.06 (dq, J = 14.3, 7.2 Hz, 1H), 2.36 (s, 3H), 1.70 (s, 3H),
13
1.16 (t, J = 7.3 Hz, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 169.2, 167.1, 138.7, 131.3, 129.2,
126.7, 66.3, 65.9, 51.7, 35.5, 21.2, 17.5, 12.6 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C15H19NNaO3 284.1257; Found 284.1261.
(±) (3R,4S)-Methyl 1-cyclohexyl-3-methyl-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4h): yield 150 mg,
60%; beige powder; mp 68 - 70 C; 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.1 Hz, 2H), 7.16 (d, J
= 8.0 Hz, 2H), 4.41 (s, 1H), 3.44 (ddd, J = 15.3, 7.7, 3.8 Hz, 1H), 3.34 (s, 3H), 2.35 (s, 3H), 2.09 –
2.03 (m, 1H), 1.92 – 1.84 (m, 1H), 1.83 – 1.76 (m, 1H), 1.72 – 1.64 (m, 2H), 1.66 (s, 3H), 1.62 – 1.56
13
(m, 1H), 1.34 – 1.02 (m, 4H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 169.3, 167.4, 138.6, 132.5,
129.0, 126.8, 65.7, 65.5, 53.1, 51.7, 31.2, 30.5, 25.19, 25.17, 25.0, 21.2, 17.7 ppm; HRMS (ESI-TOF)
m/z: [M+H]+ Сalcd for C19H26NO3 316.1907; Found 316.1904.
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(±) (3R,4S)-Methyl 1-(4-methoxyphenyl)-3-methyl-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4j): yield
1
164 mg, 61%; beige powder; mp 173 − 175 C; H NMR (400 MHz, CDCl3) δ 7.42 – 7.23 (m, 2H),
7.20 – 7.05 (m, 4H), 6.92 – 6.70 (m, 2H), 4.85 (s, 1H), 3.78 (s, 3H), 3.32 (s, 3H), 2.35 (s, 3H), 1.81 (s,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 163.8, 156.3, 138.7, 131.0, 130.5, 129.2, 126.7,
118.6, 114.3, 66.3, 65.9, 55.5, 51.8, 21.2, 17.6 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C20H21NNaO4 362.1363; Found 362.1380.
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(±) (3R,4S)-methyl 1,3-dimethyl-2-oxo-4-phenylazetidine-3-carboxylate (4l): yield 133 mg, 57%;
yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.30 (m, 3H), 7.25 (dd, J = 7.9, 1.7 Hz, 2H), 4.42 (s,
13
1H), 3.28 (s, 3H), 2.92 (s, 3H), 1.72 (s, 3H).ppm; C{1H} NMR (101 MHz, CDCl3) δ 169, 167.3,
134.0, 128.8, 128.6, 126.7, 68.3, 67.2, 51.7, 27.6, 17.4 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Сalcd for
C13H16NO3 234.1125; Found 234.1126.
(±) (3R,4S)-Ethyl 1-benzyl-2-oxo-3-phenyl-4-(p-tolyl)azetidine-3-carboxylate (4m): yield 279 mg,
1
87%; light yellow powder; mp 89,5 – 91,5 C; H NMR (400 MHz, CDCl3) δ 7.76 – 7.55 (m, 2H),
7.41 – 7.30 (m, 3H), 7.24 – 7.18 (m, 7H), 7.10 – 7.01 (m, 2H), 4.98 (d, J = 15.0 Hz, 1H), 4.75 (s, 1H),
13
3.96 (d, J = 15.0 Hz, 1H), 3.86 – 3.68 (m, 2H), 2.37 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H) ppm; C{1H}
NMR (101 MHz, CDCl3) δ 167.2, 165.2, 139.0, 135.1, 135.0, 131.1, 129.6, 128.9, 128.7, 128.4, 128.2,
127.9, 127.6, 127.3, 74.1, 66.0, 61.6, 44.6, 21.3, 13.7 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C26H25NNaO3 422.1727; Found 422.1730.
(±) (3R,4S)-Methyl 1-benzyl-3-(2-methoxyphenyl)-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4n): yield
1
233 mg, 71%; beige powder; mp 124 − 125 C; H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 7.7, 1.7
Hz, 1H), 7.38 – 7.31 (m, 3H), 7.26 – 7.19 (m, 5H), 7.10 – 7.06 (m, 2H), 7.03 – 6.94 (m, 2H), 4.99 (d, J
= 15.1 Hz, 1H), 4.90 (s, 1H), 3.97 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 3.41 (s, 3H), 2.40 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 167.4, 165.3, 157.5, 138.4, 135.0, 130.9, 129.6, 128.8, 128.7,
128.38, 128.35, 128.0, 127.6, 123.9, 120.7, 111.9, 72.9, 64.4, 55.3, 52.0, 44.3, 21.3 ppm; HRMS (ESI-
TOF) m/z: [M+Na]+ Сalcd for C26H25NNaO4 438.1676; Found 438.1692.
(±) (3R,4S)-Methyl 1-benzyl-3-(4-fluorophenyl)-2-oxo-4-(p-tolyl)azetidine-3-carboxylate (4o): yield
1
286 mg, 86%; white powder; mp 77,5 – 79,5 C; H NMR (400 MHz, CDCl3) δ 7.85 – 7.48 (m, 2H),
7.29 – 7.19 (m, 7H), 7.14 – 7.03 (m, 4H), 5.04 (d, J = 15.0 Hz, 1H), 4.70 (s, 1H), 3.99 (d, J = 15.0 Hz,
13
1H), 3.39 (s, 3H), 2.42 (s, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 167.7, 164.9, 162.7 (d, J =
247.7 Hz), 139.3, 134.8, 130.7, 130.7, 129.7, 129.4 (d, J = 8.1 Hz), 128.9, 128.4, 128.0, 127.1, 115.7
(d, J = 21.6 Hz), 73.4, 66.3, 52.4, 44.7, 21.4 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C25H22FNNaO3 426.1476; Found 426.1478.
(±) (3R,4S)-Ethyl 1-benzyl-2-oxo-3-(pyridin-3-yl)-4-(p-tolyl)azetidine-3-carboxylate (4p): yield
1
233 mg, 73%; light orange powder; mp 90,5 − 92C; H NMR (400 MHz, CDCl3) δ 8.93 – 8.85 (m,
1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H),
7.28 – 7.22 (m, 7H), 7.10 – 7.05 (m, 2H), 5.01 (d, J = 15.0 Hz, 1H), 4.73 (s, 1H), 3.99 (d, J = 15.0 Hz,
1H), 3.88 – 3.69 (m, 2H), 2.40 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (101 MHz,
CDCl3) δ 166.5, 164.0, 149.4, 148.9, 139.3, 135.0, 134.6, 131.0, 130.3, 129.6, 128.9, 128.3, 128.0,
127.2, 123.3, 72.0, 65.6, 61.9, 44.7, 21.2, 13.6 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C25H24N2NaO3 423.1679; Found 423.1682.
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(±) (3R,4S)-Methyl 3-methyl-2-oxo-1-phenyl-4-(p-tolyl)azetidine-3-carboxylate (4r): yield 250 mg,
81%; white powder; mp 162 − 164C; 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.25 (m, 4H), 7.25 – 6.88
(m, 5H), 4.89 (s, 1H), 3.33 (s, 3H), 2.35 (s, 3H), 1.82 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ
168.7, 164.3, 138.7, 137.4, 130.4, 129.2, 129.1, 126.6, 124.2, 117.3, 66.2, 65.9, 51.9, 21.2, 17.6 ppm;
HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C19H19NNaO3 332.1257; Found 332.1262.
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(±) (2S,3R)-Methyl 2-cyclopropyl-1-(4-methoxybenzyl)-3-methyl-4-oxoazetidine-3-carboxylate (4s):
yield 150 mg, 65%; light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.6 Hz, 2H), 6.83 (d, J
= 8.6 Hz, 2H), 4.64 (d, J = 15.0 Hz, 1H), 4.09 (d, J = 15.0 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.33 (d,
J = 9.8 Hz, 1H), 1.45 (s, 3H), 0.85 – 0.66 (m, 1H), 0.55 – 0.46 (m, 1H), 0.46 – 0.37 (m, 1H), 0.09 –
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0.01 (m, 1H), -0.00 – -0.08 (m, 1H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 170.2, 166.5, 159.2,
129.5, 127.7, 114.1, 68.3, 62.9, 55.2, 52.2, 43.8, 16.8, 8.5, 3.9, 1.0 ppm; HRMS (ESI-TOF) m/z:
[M+H]+ Сalcd for C17H22NO4 304.1543; Found 304.1540.
(±) (3R,4R)-Methyl 1-cyclopropyl-3-methyl-2-oxo-4-(thiophen-2-yl)azetidine-3-carboxylate (4t): yield
114 mg, 53%; yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 5.0, 1.1 Hz, 1H), 7.07 (d, J = 3.4
Hz, 1H), 7.02 (dd, J = 5.0, 3.6 Hz, 1H), 4.58 (s, 1H), 3.46 (s, 3H), 2.67 – 2.60 (m, 1H), 1.64 (s, 3H),
1.12 – 1.03 (m, 1H), 0.84 – 0.62 (m, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 169.0, 167.3,
137.9, 127.1, 126.7, 126.0, 66.3, 63.4, 52.0, 23.8, 17.2, 5.5, 5.1 ppm; HRMS (ESI-TOF) m/z: [M+H]+
Сalcd for C13H16NO3S 266.0845; Found 266.0846.
(±)
(1S,9bS)-Ethyl
2-oxo-1-(pyridin-2-yl)-2,4,5,9b-tetrahydro-1H-azeto[2,1-a]isoquinoline-1-
1
carboxylate (4u): yield 122 mg, 50%; light yellow crystalline powder; mp 151 − 153 C; H NMR
(400 MHz, CDCl3) δ 8.97 (d, J = 2.4 Hz, 1H), 8.76 – 8.49 (m, 1H), 8.07 (dt, J = 8.0, 2.0 Hz, 1H), 7.39
(dd, J = 8.0, 4.8 Hz, 1H), 7.30 (dq, J = 7.2, 3.9, 3.1 Hz, 3H), 7.25 – 7.18 (m, 1H), 4.95 (s, 1H), 4.24
(ddd, J = 13.6, 6.6, 1.3 Hz, 1H), 3.76 (dq, J = 10.8, 7.1 Hz, 1H), 3.64 (dq, J = 10.8, 7.1 Hz, 1H), 3.27
(ddd, J = 15.9, 11.9, 6.4 Hz, 1H), 3.07 (ddd, J = 13.6, 11.8, 4.1 Hz, 1H), 2.81 (dd, J = 15.8, 4.0 Hz,
1H), 0.77 (t, J = 7.2 Hz, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 166.7, 164.8, 149.4, 149.2,
13
135.3, 135.3, 130.6, 130.2, 129.7, 128.2, 127.0, 127.0, 123.3, 71.5, 61.9, 59.9, 37.6, 28.7, 13.2 ppm;
HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C19H18N2NaO3 345.1210; Found 345.1207.
(±) (2S,3R)-ethyl 1,3-dimethyl-2-(naphthalen-1-yl)-4-oxoazetidine-3-carboxylate (4w): yield 120 mg,
1
51%; yellow oil; H NMR (400 MHz, CDCl3) δ 7.96 – 7.86 (m, 2H), 7.83 (dd, J = 7.4, 2.0 Hz, 1H),
7.61 – 7.45 (m, 4H), 5.24 (s, 1H), 3.62 – 3.41 (m, 2H), 3.05 (s, 3H), 1.93 (s, 3H), 0.52 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 167.8, 133.7, 131.3, 130.1, 128.9, 128.9, 126.7,
126.1, 124.9, 123.8, 122.6, 66.9, 65.1, 60.8, 28.2, 17.5, 13.3 ppm; HRMS (ESI-TOF) m/z: [M+Na]+
Сalcd for C18H19NNaO3 320.1257; Found 320.1260.
(±) (3R,4S)-ethyl 1-(2-(tert-butylthio)ethyl)-3-methyl-2-oxo-4-(pyridin-3-yl)azetidine-3-carboxylate
(4x): yield 198 mg, 71%; orange powder; mp 65,5 − 67 C; 1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J
= 4.8, 1.7 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.61 (dt, J = 7.9, 2.0 Hz, 1H), 7.32 – 7.28 (m, 1H), 4.67 (s,
1H), 3.90 (dt, J = 14.3, 6.7 Hz, 1H), 3.85 – 3.67 (m, 2H), 3.09 (dt, J = 14.4, 6.6 Hz, 1H), 2.83 (dt, J =
13.2, 6.7 Hz, 1H), 2.69 (dt, J = 12.9, 6.6 Hz, 1H), 1.76 (s, 3H), 1.30 (s, 9H), 0.91 (t, J = 7.1 Hz, 3H)
13
ppm; C{1H} NMR (101 MHz, CDCl3) δ 168.1, 166.9, 150.1, 148.8, 134.5, 130.3, 123.3, 66.8, 64.9,
61.3, 42.7, 40.9, 30.9, 26.8, 17.6, 13.7 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for
C18H26N2NaO3S 373.1556; Found 373.1559.
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(±) (2S,3R)-Ethyl 1-benzyl-2-(4-methoxyphenyl)-3-methyl-4-oxoazetidine-3-carboxylate (4y): yield
314 mg, 89%; light yellow powder; mp 69 − 71C; 1H NMR (400 MHz, CDCl3) δ 7.32 (td, J = 5.3, 2.4
Hz, 3H), 7.23 – 7.12 (m, 4H), 6.92 – 6.81 (m, 2H), 4.99 (d, J = 14.8 Hz, 1H), 4.20 (s, 1H), 3.93 (d, J =
13
14.9 Hz, 1H), 3.89 – 3.69 (m, 5H), 1.62 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H) ppm; C{1H} NMR (101
MHz, CDCl3) δ 168.6, 167.3, 160.0, 135.2, 128.9, 128.5, 128.3, 127.9, 125.8, 113.9, 66.6, 65.3, 61.1,
55.3, 44.5, 17.2, 13.8 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C21H23NNaO4 376.1519;
Found 376.1531.
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(±) (3R,4R)-ethyl 3-isopropyl-2-oxo-1,4-di(thiophen-2-yl)azetidine-3-carboxylate (4z): yield 238 mg,
1
82%; light orange powder; mp 69 − 71 C; H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 4.9, 1.4 Hz,
1H), 7.26 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 – 6.99 (m, 2H), 6.95 (dd, J = 5.1, 3.5 Hz, 1H), 6.87 (d, J = 3.4
Hz, 1H), 5.10 (d, J = 15.5 Hz, 1H), 4.72 (s, 1H), 4.20 (d, J = 15.5 Hz, 1H), 3.92 (q, J = 7.1 Hz, 2H),
13
2.36 (hept, J = 6.7 Hz, 1H), 1.16 – 1.04 (m, 9H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 167.8,
165.1, 138.1, 136.8, 127.7, 127.3, 127.1, 126.4, 126.0, 125.9, 75.8, 61.0, 56.9, 38.2, 30.9, 19.2, 17.4,
13.8 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C18H21NNaO3S2 386.0855; Found 386.0855.
(±) ((3R,4S)-ethyl 3-isopropyl-2-oxo-4-((E)-1-phenylprop-1-en-2-yl)-1-(2-(p-tolyloxy)ethyl)azetidine-
1
3-carboxylate (4aa): yield 219 mg, 63%; yellow oil; H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.6,
6.7 Hz, 2H), 7.28 – 7.22 (m, 3H), 7.10 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.53 (s, 1H), 4.26
(s, 1H), 4.20 – 3.98 (m, 5H), 3.37 (ddd, J = 14.6, 7.8, 3.3 Hz, 1H), 2.39 (hept, J = 6.6 Hz, 1H), 2.31 (s,
13
3H), 1.90 (d, J = 1.3 Hz, 3H), 1.25 – 1.12 (m, 9H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 168.7,
166.4, 156.0, 136.9, 132.4, 130.5, 130.0, 128.9, 128.2, 127.2, 126.8, 114.2, 74.9, 65.6, 65.2, 61.0, 39.9,
31.1, 20.5, 19.3, 17.6, 16.7, 14.2 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C27H33NNaO4
458.2302; Found 458.2304.
(±)
(2S,3R)-methyl
2-(4-chlorophenyl)-3-cyclopropyl-1-(4-methoxyphenethyl)-4-oxoazetidine-3-
1
carboxylate (4ab): yield 149 mg, 45%; yellow oil H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.5 Hz,
2H), 7.10 (d, J = 2.3 Hz, 2H), 7.08 (d, J = 2.4 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.38 (s, 1H), 3.88 (dt,
J = 14.4, 7.4 Hz, 1H), 3.81 (s, 3H), 3.36 (s, 3H), 3.12 (dt, J = 14.0, 7.0 Hz, 1H), 2.82 (t, J = 7.2 Hz,
2H), 1.54 (tt, J = 8.3, 5.3 Hz, 1H), 0.91 – 0.80 (m, 1H), 0.65 – 0.48 (m, 2H), 0.42 – 0.27 (m, 1H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 164.1, 158.5, 134.7, 132.8, 129.8, 129.5, 128.8, 128.3,
114.1, 71.7, 64.6, 55.3, 51.8, 41.5, 33.0, 12.8, 2.4, 1.4 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd
for C23H24ClNNaO4 436.1286; Found 436.1283.
(±) (2R,3R)-ethyl 1-allyl-2-(furan-2-yl)-4-oxo-3-phenylazetidine-3-carboxylate (4ac): yield 167 mg,
1
76%; yellow oil; H NMR (400 MHz, CDCl3) δ 7.77 – 7.66 (m, 2H), 7.50 (dd, J = 1.9, 0.8 Hz, 1H),
7.47 – 7.34 (m, 3H), 6.58 – 6.42 (m, 2H), 5.70 (dddd, J = 17.1, 10.2, 7.1, 5.3 Hz, 1H), 5.20 – 5.04 (m,
2H), 4.99 (s, 1H), 4.22 (ddt, J = 15.6, 5.3, 1.6 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.60 (ddt, J = 15.7,
13
7.2, 1.3 Hz, 1H), 1.09 (t, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 167.1, 164.4,
148.5, 143.4, 134.7, 130.8, 128.7, 128.3, 127.3, 119.1, 110.8, 109.9, 72.9, 61.8, 59.9, 43.3, 13.8 ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Сalcd for C19H20NO4 326.1387; Found 326.1380.
(±) (2S,3R)-methyl 1-(adamantan-1-yl)-3-(4-fluorophenyl)-2-(4-methoxyphenyl)-4-oxoazetidine-3-
1
carboxylate (4ad): yield 254 mg, 68%; white crystalline powder; mp 133 − 135 C; H NMR (400
MHz, CDCl3) δ 7.13 – 6.97 (m, 3H), 6.86 – 6.74 (m, 3H), 6.73 – 6.58 (m, 2H), 5.39 (s, 1H), 3.79 (s,
3H), 3.75 (s, 3H), 2.07 – 2.02 (m, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.64 (d, J = 3.0 Hz, 6H) ppm; 13C{1H}
NMR (101 MHz, CDCl3) δ 169.9, 163.8, 161.9 (d, J = 246.8 Hz), 159.5, 130.3 (d, J = 8.1 Hz), 129.3,
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128.8 (d, J = 3.3 Hz), 128.6, 114.9 (d, J = 21.5 Hz), 113.4, 71.0, 61.6, 56.22, 55.2, 53.2, 40.8, 36.0,
29.1 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Сalcd for C28H30FNNaO4 486.2051; Found 486.2051.
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(±) (2R,3R)-Diethyl 1-(4-methoxyphenyl)-4-oxo-3-(pyridin-3-yl)azetidine-2,3-dicarboxylate (4ae):
yield 246 mg, 77%; light yellow oil; H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 2.4 Hz, 1H), 8.63 –
1
8.56 (m, 1H), 7.93 – 7.71 (m, 1H), 7.37 – 7.29 (m, 3H), 6.92 (d, J = 9.0 Hz, 2H), 5.36 (s, 1H), 4.38 –
4.28 (m, 2H), 3.94 – 3.71 (m, 5H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 (td, J = 7.2, 0.9 Hz, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 166.8, 158.4, 157.1, 149.9, 149.2, 135.7, 130.1, 127.8,
123.3, 118.6, 114.5, 69.8, 63.3, 62.0, 60.8, 55.5, 14.0, 13.7 ppm; HRMS (ESI-TOF) m/z: [M+H]+
Сalcd for C21H23N2O6 399.1551; Found 399.1550.
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(±) (3S,4S)-Ethyl-1-benzyl-2-oxo-3-(thiophen-2-yl)-4-(p-tolyl)azetidine-3-carboxylate (4af)
Yield 210 mg, 65 %, yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 5.2, 1.3 Hz, 1H), 7.30 –
7.25 (m, 4H), 7.21 (s, 4H), 7.16 (dd, J = 7.1, 2.4 Hz, 2H), 7.02 (dd, J = 5.1, 3.6 Hz, 1H), 5.06 (d, J =
15.0 Hz, 1H), 4.62 (s, 1H), 4.02 (d, J = 15.0 Hz, 1H), 3.87 – 3.78 (m, 2H), 2.39 (s, 3H), 0.99 (t, J = 7.2
13
Hz, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 166.4, 164.2, 139.1, 136.0, 134.8, 130.3, 129.4,
128.8, 128.5, 127.9, 127.1, 126.7, 126.3, 126.1, 71.5, 68.0, 61.8, 44.8, 21.2, 13.6.ppm; HRMS (ESI-
TOF) m/z: [M+Na]+ Сalcd for C24H23NO3SNa 428.1291; Found 428.1293.
tert-Butyl 3-(benzyl(cyclohexylidenemethyl)amino)-2-methyl-3-oxopropanoate (12)
Column chromatography was carried out using neutral alumina. Yield 69 mg, 22%; light yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.05 (m, 5H), 5.75 (s, 1H), 4.83 (d, J = 14.0 Hz, 1H), 4.44 (d, J =
14.1 Hz, 1H), 3.63 (q, J = 7.1 Hz, 1H), 2.08 (t, J = 5.6 Hz, 2H), 2.05 – 1.91 (m, 2H), 1.63 – 1.48 (m,
13
6H), 1.43 (s, 9H), 1.34 (d, J = 7.1 Hz, 3H) ppm; C{1H} NMR (101 MHz, CDCl3) δ 170.7, 170.1,
144.6, 137.2, 128.9, 128.3, 127.2, 120.1, 81.1, 51.3, 44.5, 33.0, 28.0, 27.9, 27.8, 26.6, 26.2, 13.7 ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Сalcd for C22H31NO3Na 380.2196; Found 380.2199.
3-Benzyl-5,6-dimethyl-2-(p-tolyl)-2H-1,3-oxazin-4(3H)-one (20a): A solution of 3-diazopentane-2,4-
dione (151 mg, 1.2 mmol) and imine 21 (209 mg, 1.0 mmol) in dry toluene (2 mL) was refluxed for
2.5 h. After evaporation of volatiles the residue was subjected to flash column chromatography on
silica gel (eluent – acetone in n-hexane from 5% to 40%). Yield 103 mg, 33%; white solid; mp 92 − 94
C; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.23 (m, 3H), 7.21 – 7.15 (m, 6H), 5.99 (s, 1H), 5.32 (d, J =
13
15.4 Hz, 1H), 3.86 (d, J = 15.4 Hz, 1H), 2.39 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H) ppm; C{1H} NMR
(101 MHz, CDCl3) δ 164.5, 158.7, 139.4, 137.3, 133.1, 129.1, 128.5, 127.8, 127.32, 127.27, 105.6,
86.7, 46.7, 21.2, 17.3, 10.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Сalcd for C20H22NO2 308.1645;
Found 308.1651.
ASSOCIATED CONTENT
Supporting Information
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Copies of H and 13C NMR spectra, crystallographic data, computational details. This material is
available free of charge via the Internet at http://pubs.acs.org. CCDC 1938173 (4a), 1938204 (4j) and
1939763 (4u) contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: m.krasavin@spbu.ru
ORCID
Olga Bakulina: 0000-0002-4930-0739
Dmitry Dar’in: 0000-0002-0413-7413
Mikhail Krasavin: 0000-0002-0200-4772
Mikhail S. Novikov: 0000-0001-5106-4723
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Foundation for Basic Research (project grant 18-33-
20194). We thank the Research Centre for Magnetic Resonance, the Center for Chemical Analysis and
Materials Research and the Centre for X-ray Diffraction Methods of Saint Petersburg State University
Research Park for obtaining the analytical data.
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