Dialkyl diazomalonates in transition-metal-free, thermally promoted, diastereoselective wolff β-lactam synthesis

Article abstract of DOI:10.1055/s-0040-1707811

Metal-free, thermally promoted synthesis of 3-alkoxy-3-alkoxycarbonyl-2-azetidinones via the Wolff-Staudinger β-lactam synthesis using dialkyl diazomalonates is described. The reaction appears fairly general and delivers only one diastereomer.

Full text of DOI:10.1055/s-0040-1707811

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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J. Synofzik et al.
Letter
Synlett
Dialkyl Diazomalonates in Transition-Metal-Free, Thermally
Promoted, Diastereoselective Wolff -Lactam Synthesis
Judith Synofzik
Olga Bakulina
Dmitry Dar’in
Grigory Kantin
AlkO2C
AlkO
R1CHO
+
R2NH2
1) PhCl, reflux, 2 h
O
0
0
0
0-0
0
0
2-4
9
3
0-
0
7
3
9
2)
N2
N
0
0
0
0-0
0
0
2-0
4
1
3-
7
4
1
3
R1
R2
AlkO2C
CO2Alk
16 examples
25–82%
single diastereomer!
Mikhail Krasavin*
0
0
0
0-0
0
0
2-
0
2
0
0-4
7
7
2
reflux, 20 h
Saint Petersburg State University, Saint Petersburg 199034,
Russian Federation
m.krasavin@spbu.ru
Alk = Me, Et, iPr, tBu, Bn
R1, R2 = alkyl or aryl (no bulky groups!)
Received: 03.04.2020
Accepted after revision: 04.05.2020
Published online: 19.05.2020
R1
R1CHO
+
N
1) toluene
reflux, 3 h
R1
R3
AlkO2C
R2
O
R2
N
+
DOI: 10.1055/s-0040-1707811; Art ID: st-2020-b0190-l
(a)
R3
2)
N2
C
O
R2NH2
Abstract Metal-free, thermally promoted synthesis of 3-alkoxy-3-
alkoxycarbonyl-2-azetidinones via the Wolff-Staudinger -lactam syn-
thesis using dialkyl diazomalonates is described. The reaction appears
fairly general and delivers only one diastereomer.
R3
AlkO2C
CO2Alk
reflux, 20–24 h
1
3
2
O
R1
Key words -lactam, diazomalonates, Wolff rearrangement, metal-
free, thermal
R1CHO
+
N
1) high-boiling
solvent, reflux
R1
R2
O
R2
N
+
(b)
AlkO
AlkO
2)
N2
C
O
-Lactams (2-azetidinones) can be confidently regarded
as privileged motifs in drug design.1 Recently, we described
a one-pot, three component, generally diastereoselective
synthesis of polysubstituted -lactams 1 from in situ
formed imines and readily available -acyl--diazoacetate
esters 2.2 The reaction essentially represented the first ex-
ample of metal-free generation of specifically substituted
ketenes 3 bearing an alkoxy carbonyl function via the ther-
mally initiated3 Wolff rearrangement (Scheme 1, a). Consid-
ering the obvious attractiveness of this metal-free approach
to the earlier reported alternatives involving Rh(II) carben-
es4 and the general prominence of -lactams in antibacteri-
al drug design5 (as well as other therapeutic areas6) we con-
sidered an opportunity to expand this methodology to in-
clude other types of readily available diazo compounds. In
particular, dialkyl diazomalonates 4, if found workable in
the same atom-economic transformation (presumably, via
the intermediacy of alkoxy-substituted ketenes 5), would deliv-
er 3-alkoxy-3-alkoxycabonyl-2-azetidinones 6 (Scheme 1, b).
The latter represent exceedingly rare type of substituted
-lactams. Several related representatives have been pre-
pared from diazo Meldrum’s acid via photolytically gener-
ated carbene7 or Rh(II) carbene species8 but have not been
prepared in library fashion. Considering the high variability
of the imine component, the ready commercial9 and syn-
R2NH2
AlkO2C
AlkO2C
AlkO2C
CO2Alk
5
6
continued
reflux
4
Scheme 1 The thermally promoted Wolff-Staudinger -lactam synthe-
sis (a) reported earlier2 and (b) investigated in this work
thetic availability (vide infra) of dialkyl diazomalonates 4,
we set off to investigate their three-component, catalyst-
free10 reaction which would make the method particularly
suitable for generating arrays of these compounds in diver-
sity-controlled manner for subsequent biotarget interro-
gation.6
There are a few isolated examples in the literature de-
scribing generation of ketenes 5 from diazomalonate deriv-
atives 4 under photolytic11 or gas-phase pyrolysis12 condi-
tions; however, these reports did not convey the synthetic
utility of this transformation. In order to identify workable
conditions that would lead to the envisioned transforma-
tion 4 → 6, dimethyl diazomalonate (4a) was introduced
into the solution of (E)-N-ethyl-1-(p-tolyl)methanimine
(prepared in a separate step from p-tolualdehyde and ethyl-
amine) in various highly boiling solvents at various ratios,
temperatures, and time regimens (Table 1). Not unexpect-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Synofzik et al.
Letter
Synlett
edly, dialkyl malonates 4 are more stable toward thermal
decomposition compared to -acyl--diazoacetate esters 2
and, thus, prolonged (20 h) reflux in toluene (Table 1, entry
1) only led to incomplete conversion. Switching to xylene
(Table 1, entry 2) and to chlorobenzene (Table 1, entry 3)
using only 1.1 equiv of 4a led to some improvement of the
yield of the target product 6a. However, the optimal isolat-
ed yield of 6a (65% of a single diastereomer) was achieved
with 2 equiv of 4a (Table 1, entry 5), and these conditions
were adopted to study the reaction scope using dialkyl dia-
zomalonates 4a–e conveniently prepared on multigram
scale from respective dialkyl malonates using the previous-
ly described SAFE diazo transfer procedure,13 except for the
sterically hindered 4d which required using a different di-
azo transfer reagent (Figure 1).14
cases, with no signals from the opposite diastereomer de-
tectable in the crude H NMR spectrum) are provided in
1
Scheme 2.16 The origin17 of the observed excellent diastere-
oselectivity is likely similar to the one previously rational-
ized for the generally diastereoselective formation of lac-
tams 1.2 The relative stereochemistry, corresponding to the
trans relationship between the R group and the alkoxy sub-
stituent was confirmed by the single-crystal X-ray analysis
of the representative compound 6i (Figure 2).
Table 1 Conditions Finding for the Preparation of 6a
N
Et
OMe
O
O
O
MeO2C
N
MeO
OMe
Et
N2
4a
6a
Figure 2 Single-crystal X-ray structure of compound 6i
(CCDC1975681, thermal ellipsoids are shown at 50% probability; see
Supporting Information for details)
Entry 4a (equiv) Solvent
Temp (°C) Time (h) Yield of 6a (%)
1
2
3
4
5
6
1.1
1.1
1.1
1.5
2.0
3.0
toluene
xylene
PhCl
110
150
130
130
130
130
20
6
<20% conversion
As to the reactivity pattern illustrated by examples in
Scheme 2, migration of the tert-butoxy substituent preced-
ing the formation of the ketene intermediate appears to be
least efficient (cf. compound 6o), likely for steric reasons.
Steric bulk is the likely reason for no product 6k obtained
with tert-butylamine (same result was observed for lactams
12). Electron-withdrawing groups in the aldehyde portion
appear to be disfavored (compare 6p with 6q as well as 6g).
In conclusion, we have described the first metal-free,
thermally promoted synthesis of 3-alkoxy-3-alkoxycarbon-
yl-2-azetidinones via the Wolff -lactam synthesis using
dialkyl diazomalonates. The reaction appears fairly general
and displays remarkable diastereoselectivity. The com-
pounds obtained are exceedingly rare in the public domain
while belonging to the privileged -lactam class. Being able
to prepare them in diversity-controlled, library format will
undoubtedly promote and facilitate their biological annotation.
24
38
51
65
63
16
20
20
20
PhCl
PhCl
PhCl
O
O
O
O
O
O
MeO
OMe
EtO
OEt
iPrO
O
OiPr
N2
N2
N2
4c, 73%10
4a, 70%10
4b, 79%10
O
O
O
tBuO
OtBu
BnO
OBn
N2
4d, 71%11
N2
4e, 79%10
Figure 1 Dialkyl diazomalonates 4a–e employed in this work
Funding Information
In the majority of cases, the amine and the aldehyde
were combined in equimolar amounts in chlorobenzene,
refluxed with CaCl2 tube serving as a condenser for 2 h to
ensure the complete formation of the intermediate imine,
whereupon dialkyl diazomalonate was introduced and the
refluxing continued for 20 h.15 In some cases, however,
imine was either preformed due to volatility of one of the
reaction components or because it was available off-the-
shelf at the time. The structures and yields of the -lactam
products (obtained as the single diastereomer shown in all
This research was supported by the Russian Foundation for Basic Re-
search (Grant No. 20-03-00922).
R
u
si
a
n
F
o
u
n
d
ati
o
n
for
B
asi
c
R
esearc
h
(20-03-0
0
9
2
2)
Acknowledgment
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.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
J. Synofzik et al.
Letter
Synlett
AlkO2C
AlkO
R1CHO
1) PhCl, reflux, 2 h
O
+
2)
R2NH2
N2
N
R1
R2
AlkO2C
4a–e
reflux, 20 h
CO2Alk
6a–q
OMe
OMe
OMe
OMe
OMe
O
O
MeO2C
O
O
O
MeO2C
MeO2C
MeO2C
MeO2C
OMe
N
N
N
N
N
Et
O2N
Et
MeO
OMe
Cl
EtO
F
Me
6d, 47%a
6a, 65%a
OMe
6b, 29%
6c, 54%
6e, 44%
OMe
OMe
OMe
O
MeO2C
O
MeO2C
MeO
O
MeO2C
O
MeO2C
N
N
N
OMe
N
EtO2C
OMe
6g, 46%a
OMe
6i, 72%
MeO
OMe
6h, 52%
OMe
6f, 40%
OMe
F3C
OEt
OEt
O
O
EtO2C
EtO2C
O
MeO2C
O
MeO2C
N
N
N
N
Me
O
O
Cl
Me
6l, 66%a
Me
6k, 0%
6m, 82%
F
F
6j, 65%
OBn
O
OiPr
OiPr
OtBu
iPrO2C
iPrO2C
O
O
BnO2C
tBuO2C
O
O
N
N
N
Cl
N
OMe
S
6p, 68%a
6q, 32%
MeO
O2N
MeO
6n, 42%a
6o, 25%
MeO
Scheme 2 Synthesis of racemic -lactams 6a–q.15,16 a Reaction was conducted with a preformed imine.
Supporting Information
(7) Tsuno, T.; Kondo, K.; Sugiyama, K. J. Heterocycl. Chem. 2006, 43,
21.
(8) Golubev, A. A.; Smetanin, I. A.; Agafonova, A. V.; Rostovskii, N.
V.; Khlebnikov, A. F.; Starova, G. L.; Novikov, M. S. Org. Biomol.
Chem. 2019, 17, 6821.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707811.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(9) 70 various dialkyl diazomalonates are listed as commercially
available in SciFinder® according to the search performed on
February 16, 2020.
(10) Egorova, K. S.; Ananikov, V. P. Organometallics 2017, 36, 4071.
(11) Zeller, K.-P. Chem.-Ztg. 1973, 97, 37.
(12) Richardson, D. C.; Hendrick, M. E.; Jones, M. J. Am. Chem. Soc.
1971, 93, 3790.
(13) Dar'in, D.; Kantin, G.; Krasavin, M. Chem. Commun. 2019, 55,
5239.
References and Notes
(1) (a) Fernandes, R.; Amador, P.; Prudencio, C. Rev. Med. Microbiol.
2013, 24, 7. (b) McGeary, R. P.; Tan, D. T. C.; Schenk, G. Future
Med. Chem. 2017, 9, 673.
(2) Synofzik, J.; Dar’in, D.; Novikov, M. S.; Kantin, G.; Bakulina, O.;
Krasavin, M. J. Org. Chem. 2019, 84, 12101.
(3) Ohno, M.; Itoh, M.; Ohashi, T.; Eguchi, S. Synthesis 1993, 793.
(4) (a) Subba Reddy, B. V.; Karthik, G.; Rajasekaran, T.; Antony, A.;
Sridhar, B. Tetrahedron Lett. 2012, 53, 2396. (b) Mandler, M. D.;
Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Org. Lett. 2014, 16, 740.
(c) Chen, L.; Wang, K.; Shao, Y.; Sun, J. Org. Lett. 2019, 21, 3804.
(d) Chen, L.; Zhang, L.; Shao, Y.; Xu, G.; Zhang, X.; Tang, S.; Sun, J.
Org. Lett. 2019, 21, 4124.
(5) (a) Fernandes, R.; Amador, P.; Prudencio, C. C. Rev. Med. Micro-
biol. 2013, 24, 7. (b) McGeary, R. P.; Tan, D. T. C.; Schenk, G.
Future Med. Chem. 2017, 9, 673.
(14) Chany, A.-C.; Marx, L. B.; Burton, J. W. Org. Biomol. Chem. 2015,
13, 9190.
(15) General Procedure for the Preparation of Lactams 6a–p
In a 25 mL round-bottom flask, amine (0.8 mmol, 1.0 equiv) and
aldehyde (0.9 mmol, 1.1 equiv) were dissolved in 10 mL of chlo-
robenzene and refluxed with azeotropic removal of water. After
1 h, half of the solvent was distilled off and 2-diazomalonates
4a–e (1.6 mmol, 2.0 equiv) was added. The mixture was then
refluxed overnight, and the reaction progress was followed via
TLC. When no more diazo compound was detectable (20–24 h),
the solvent was evaporated in vacuo, and the resulting mixture
was purified by column chromatography on silica gel with a
(6) Veinberg, G.; Potorocina, I.; Vorona, M. Curr. Med. Chem. 2013,
21, 393.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
J. Synofzik et al.
Letter
Synlett
linear gradient (0–20%) of acetone in n-hexane (total volume of
eluent, 450 mL) to provide pure compounds 6a–p. In case of
volatile aldehyde or amine, they were reacted in chlorobenzene
at room temperature overnight in the presence of 4 Å MS. The
latter was filtered off before proceeding with the addition of 4
and heating. Compounds 6a,d,g,l,n,p were prepared with the
use of presynthesized imines.
NMR (400 MHz, CDCl3):  = 7.21 (d, J = 8.7 Hz, 2 H), 7.01–6.68
(m, 2 H), 4.63 (s, 1 H), 4.08 (dq, J = 8.9, 7.0 Hz, 1 H), 3.92 (dq, J =
10.8, 7.1 Hz, 1 H), 3.81 (s, 3 H), 3.78–3.63 (m, 1 H), 2.93 (s, 3 H),
1.30 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3):  = 166.3, 165.0, 160.1, 128.6, 124.4, 113.9,
95.2, 67.8, 64.1, 61.4, 55.3, 27.4, 15.4, 13.8 ppm. HRMS (ESI-
TOF): m/z [M + Na]+ calcd for C23H27NNaO7: 452.1680; found:
452.1683.
(16) Characterization Data of Representative Compounds
Compound 6i: white powder (231 mg, 72%); mp 113–115 °C. 1H
NMR (400 MHz, CDCl3):  = 7.30 (d, J = 8.9 Hz, 2 H), 6.95 (d, J =
8.5 Hz, 1 H), 6.87–6.82 (m, 2 H), 6.49 (d, J = 2.4 Hz, 1 H), 6.35 (d,
J = 8.5 Hz, 1 H), 5.50 (s, 1 H), 3.89 (s, 3 H), 3.78 (d, J = 2.0 Hz, 6 H),
3.75 (s, 3 H), 3.39 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3):  =
166.3, 161.2, 161.1, 158.6, 156.5, 130.5, 128.6, 119.0, 114.4,
112.4, 104.0, 98.5, 94.5, 60.1, 55.9, 55.8, 55.5, 55.3, 51.9 ppm.
Compound 6n: yellow oil (206 mg, 42%). 1H NMR (400 MHz,
CDCl3):  = 7.51–7.46 (m, 2 H), 7.42–7.26 (m, 8 H), 7.24–7.01 (m,
2 H), 6.80 (d, J = 8.0 Hz, 2 H), 5.35–5.09 (m, 2 H), 4.94 (d, J = 12.2
Hz, 1 H), 4.86–4.77 (m, 2 H), 4.54 (d, J = 18.0 Hz, 1 H), 3.81 (s, 3
H), 3.74 (s, 3 H), 3.65 (d, J = 18.0 Hz, 1 H) ppm. 13C NMR (101
MHz, CDCl3):  = 167.9, 165.9, 164.8, 160.2, 137.0, 134.7, 128.6,
128.4, 128.4, 128.3, 128.2, 128.0, 123.6, 114.1, 95.7, 70.3, 67.1,
66.4, 55.2, 52.5, 41.3 ppm. HRMS (ESI-TOF): m/z [M + Na]+ calcd
for C28H27NNaO7: 512.1680; found: 512.1700.
HRMS (ESI-TOF): m/z [M
+
Na]+ calcd for C21H23NaNO7:
424.1367; found: 424.1378.
Compound 6l: yellow powder (202 mg, 66%); mp 97–99 °C. H
1
(17) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006, 128, 6060.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D