A Novel Approach to Substituted α-Carbamoyl Phosphonates: Useful Reagents for the Horner-Wadsworth-Emmons Olefination

Article abstract of DOI:10.1055/s-0040-1707200

α-Carbamoyl phosphonates are useful reagents for the Horner-Wadsworth-Emmons olefination of aldehydes en route to medicinally relevant polysubstituted acrylamides. A new synthetic approach to these reagents has been developed. The methodology relies on the microwave-promoted Wolff rearrangement of α-acyl-α-diazophosphonates with trapping of the ketene intermediate in situ with various amines.

Full text of DOI:10.1055/s-0040-1707200

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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A. Inyutina et al.
Letter
Synlett
A Novel Approach to Substituted -Carbamoyl Phosphonates:
Useful Reagents for the Horner–Wadsworth–Emmons Olefination
Anna Inyutinaa
Evgeny Chupakhina,b
Dmitry Dar’in*a
Mikhail Krasavin*a,b
R2 R3
O
N
H
R4CHO
R1 R2
N
O
(EtO)2(O)P
0
0
0
0-
0
0
0
1-5
2
8
4-4
7
4
8
R1
R4
(EtO)2(O)P
R3
R3
N
toluene
140 °C, MW
1 h
N2
1 = Me, Ph,
c-Pr, c-Hex
0
0
0
0-
0
0
0
2-0
4
1
3-7
4
1
3
NaH, THF
r.t.
R1 R2
O
0
0
0
0-0
0
0
2-
0
2
0
0-4
7
7
2
R
12 examples
34–66%
a Saint Petersburg State University, Saint Petersburg, 199034,
Russian Federation
m.krasavin@spbu.ru
one pot
d.dariin@spbu.ru
b Immanuel Kant Baltic Federal University, Kaliningrad, 236016,
Russian Federation
Received: 14.05.2020
Accepted after revision: 15.06.2020
Published online: 20.07.2020
cancer cells, we required a convenient entry into simple
substituted acrylamides 1 (or ‘piper-amides’ i.e., ,-unsat-
urated amides bearing resemblance to the components of
plant genus Piper8), which would allow for a flexible varia-
tion of the peripheral diversity elements (R1/2, R3, and R4).
Such a facility in substituent variation is required to fine-
tune the electrophilicity of 1 from electronic as well as ste-
ric perspectives and to achieve selective targeting of the
catalytic selenocysteine (Sec-SeH) residue (ionized at physi-
ological pH) of TrxR over cysteines (Cys-SH) abundantly
present in proteins.9 Retrosynthetically, acrylamides 1 can
be disconnected, with the Horner–Wadsworth–Emmons
DOI: 10.1055/s-0040-1707200; Art ID: st-2020-b0288-l
Abstract -Carbamoyl phosphonates are useful reagents for the
Horner–Wadsworth–Emmons olefination of aldehydes en route to me-
dicinally relevant polysubstituted acrylamides. A new synthetic ap-
proach to these reagents has been developed. The methodology relies
on the microwave-promoted Wolff rearrangement of -acyl--diazo-
phosphonates with trapping of the ketene intermediate in situ with var-
ious amines.
Key words Michael acceptors, -diazo--oxophosphonates, Wolff re-
arrangement, ketene trapping, Horner–Wadsworth–Emmons olefina-
tion, one-pot procedure
(HWE) olefination in mind, to 2-phosphonamides
2
(Scheme 1).10 The latter, in turn, can be obtained either via
amidation of -phosphono-N-hydroxysuccinimidyl esters
311 or through a somewhat cumbersome sequence com-
prising the Arbuzov reaction of -bromoacetamide 4 and
subsequent -alkylation with R1Hal.12 For our purposes,
however, we considered an entirely different disconnection
of 2; namely, down to their diazo precursors 5, the simplest
of which (5a, R1 = Me) is known as the Ohira–Bestmann re-
agent.13 Such a disconnection was inspired by our recent
success involving closely related -diazo--oxosulfones in
thermally promoted Wolff rearrangement in the presence
of aromatic amines, which gave rise to -sulfonyl acetani-
lides.14 Indeed, the Wolff rearrangement of -diazo phos-
phonates has been realized under Rh(II)-catalyzed15 as well
as thermally promoted16 conditions, with O-nucleophile
trapping of the resulting ketene intermediate 6. This pro-
vided an additional encouragement for us to investigate the
new approach to phosphonamides 2 (intended for the use
in the Horner–Wadsworth–Emmons olefination of alde-
hydes) from -diazo phosphonates 5 under practically con-
venient, catalyst-free conditions (Scheme 1). Herein, we
would like to provide the details of this investigation.
The so-called ‘Michael acceptors’ (electron-deficient
olefins capable of reacting with nucleophiles via conjugate
or Michael addition) are often regarded as cautionary
structural features in bioactive compound design because
of their potentially nonspecific reactivity towards nucleop-
hilic centers in proteins, which can generate false positive
response in biological assays.1 At the same time, the reac-
tivity of Michael acceptors towards cysteines has been suc-
cessfully exploited in medicinal chemistry, particularly for
the design of targeted covalent inhibitors.2 It is also notable
that in the natural product domain, unrivaled by its success
as a source of drug leads, Michael acceptor motifs are fre-
quently encountered3 and could be responsible for the anti-
neoplastic activity displayed by such naturally occurring
compounds.4 The selective cytotoxic activity displayed by
Michael acceptors towards cancer cells could be attribut-
able to their interaction with the components of critical cell
survival mechanisms (such as ubiquitin proteasome sys-
tem5 or thioredoxin system6).
In our medicinal chemistry program7 directed at devel-
oping anticancer small-molecule inhibitors of thioredoxin
reductase (TrxR), a redox defense enzyme overexpressed in
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Inyutina et al.
Letter
Synlett
R1
O
(EtO)2(O)P
ref. 11
O
N
O
3
R4
O
R4
R1
O
N
R1
C
Wolff
rearrangement
HWE
R3
R1
Cys
Sec
SH
Se
N
this work
R3
(EtO)2(O)P
(EtO)2(O)P
X
N
(EtO)2(O)P
N
O
R2
R1
Δ
R2
5
6
O
O
O
2
1
ref. 12
Br
R3
N
O
R2
4
Scheme 1 ‘Piper-amides’ 1 and retrosynthetic approaches to their phosphonamide precursors 2
Initially, we screened the reaction conditions for the ke-
tene generation from 5a and trapping it with aniline under
microwave irradiation.17 As detailed in Table 1, the opti-
mum results (entry 2) from the standpoint of the yield of
product 2a, reaction time and the reagent expenditure
were obtained with 1.2 equiv of 5a at 140 °C in toluene. The
reaction could also be conducted under conventional heat-
ing (reflux in toluene, entry 3) with no detriment to the
yield, albeit with markedly longer reaction time.
aliphatic amines,14 products 2g and 2l were successfully ob-
tained, albeit in somewhat lower yields. This could be due
to the higher nucleophilicity of aliphatic amines, which can
lead to degradation of the starting -diazo--oxophospho-
nates 5 via deacylation. Also notable is the successful use of
deactivated anilines (to give 2f and 2i) as well as of o-amin-
ophenol (to give 2h).
Having established the new approach to phos-
phonamides 2, we were keen to test them in HWE olefina-
tion reactions (although this is a transformation well estab-
lished for 210). To this end, reagents 2a–c and 2j–k were
treated with a slight excess of sodium hydride in the pres-
ence of various aldehydes in THF at room temperature.11
The reactions were complete in 1–3 hours according to the
Table 1 Condition Screening for the Preparation of Phosphonamide 2aa
N2
CH3
PhNH2
CH3
NHPh
(EtO)2(O)P
5a
(EtO)2(O)P
toluene
T (°C), time
MW
O
O
2a
R2 R3
O
N
H
O
Entry
5a (equiv)
T (°C)
Time (h)
Yield (%)b
R3
(EtO)2(O)P
(EtO)2(O)P
R1
N
toluene
140 °C, MW
1 h
1
1.1
1.2
1.2
1.2
1.5
1.2
1.2
1.2
140
140
110
140
140
110
130
150
1
54
64
63
57
67
65
65
60
R1 R2
N2
5a, R1 = Me; 5b, R1 = Ph;
5c, R1 = c-Pr; 5d, R1 = c-Hex
2
1
2a–l
3c
4d
5
6.5
1
Br
O
O
O
O
O
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
1
N
H
N
H
NHPh
CH3
CH3
CH3
6
5
2a, 64%
2b, 66%
2c, 57%
7
2
F
8
0.75
O
O
O
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
a Reactions were performed on a 0.5 mmol scale.
NHPh
N
N
H
b Yield after isolation of 2a by flash column chromatography.
c Reaction was conducted under conventional heating.
d Reaction was conducted in 1,4-dioxane.
Ph
Ph
O2N
CH3
2d, 54%
2e, 64%
2f, 47%
O
O
O
The optimum conditions thus identified were then ap-
plied to -diazo--oxophosphonates 5a–d (all prepared on
gram scale from the respective active-methylene -oxo-
phosphonates by using the sulfonyl-azide-free or SAFE di-
azo transfer protocol in aqueous medium18) in combination
with a range of aromatic as well as aliphatic amines
(Scheme 2).19
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
N
N
N
H
H
Ph
Ph
OH
O
CH3
2g, 48%
2h, 55%
2i, 66%
CH3
O
O
O
(EtO)2(O)P
(EtO)2(O)P
N
H
NHPh
N
Ph
H
CH3
CH3
The yields of products 2a–l were quite uniform, irre-
spective of the nature of the migrating group (R1) or the
trapping amine. In contrast to the similar transformation of
the closely related -diazo--oxosulfones, which failed for
2j, 57%
2k, 63%
2l, 34%
Scheme 2 Conversion of -diazo--oxophosphonates 5 into phos-
phonamides 220
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
A. Inyutina et al.
Letter
Synlett
TLC analysis, and the respective (E)-configured piperamides
1a–f were isolated chromatographically in good yields
(Scheme 3). The (E)-configuration of the double bond in
these products was confirmed by single-crystal X-ray crys-
tallographic structure of compound 1a (see the Supporting
Information).
O
CH3
DBU, LiCl
(EtO)2(O)P
N
H
THF, r.t., 2 h
O
CH3
N
H
O
2i
7, 76%
Scheme 5 Preparation of 2-quinolone 7
H
R4
R1 R2
N
R1 R2
N
O
nates with trapping of the ketene intermediate in situ with
various amines. The resulting phosphonamides can be puri-
fied chromatographically and used in the HWE reaction or
the latter can be performed, with comparable yields, in
one-pot format, without the isolation of the phos-
phonamide reagent.
R4
R3
(EtO)2(O)P
R3
NaH
THF, r.t.
1–3 h
O
O
2a–c,j–k
1a–f
O
O
O
NHPh
NHPh
NHPh
CH3
CH3
CH3
F
Cl
F3C
1a, 74%
1b, 68%
1c, 72%
Br
O
Funding Information
O
O
O
O
N
N
N
H
This research was supported by the Russian Foundation for Basic Re-
H
H
CH3
CH3
S
CH3
F
search (project grant 19-33-60010).
R
u
si
a
n
F
o
u
n
d
ati
o
n
for
B
asi
c
R
esearc
h
(19-33-6
0
0
1
0)
1d, 73%
1e, 81%
1f, 65%
Scheme 3 HWE olefination with selected phosphonamides 2
Acknowledgment
We thank the Research Center for Magnetic Resonance and the Center
for Chemical Analysis and Materials Research of Saint Petersburg
State University Research Park for obtaining the analytical data.
At this point we wondered whether the generation of
phosphonamides 2 and their use for HWE olefination could
be coupled in a one-pot sequence. To this end, we tested the
preparation of acrylamide 1a (combined yield 47% over two
steps) in one-pot format by preparing phosphonamide 2a
from the Ohira–Bestmann reagent (5a) and performing the
subsequent olefination of 4-chlorobenzaldehyde in the
same toluene solution.21 To our delight, the yield of com-
pound 1a obtained after chromatographic purification
(45%) was comparable to that calculated over two steps
(Scheme 4).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707200. Included are experimental
details and copies of the 1H, 13C and 31P NMR spectra.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
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L.; Molamström, J.; Turkina, M. V.; D’Arcy, P.; Walters, M. A.;
Sunnerhagen, M.; Linder, S. Sci. Rep. 2019, 9841.
1) PhNH2, toluene
MW, 140 °C, 1 h
O
O
(EtO)2(O)P
NHPh
CH3
2) 4-ClC6H4CHO
NaH (1.5 equiv)
r.t., 18 h
CH3
N2
5a
Cl
1a, 45%
Scheme 4 One-pot preparation of compound 1a from the Ohira–Best-
mann reagent (5a)
Finally, we noted that compound 2i was set for intramo-
lecular HWE olefination involving the nearby acetyl
group.22 Indeed, treatment of this compound with DBU in
THF in the presence of lithium chloride22–23 gave hitherto
unreported 2-quinolone 7 in very good yield (Scheme 5).
In summary, we have developed a new synthetic ap-
proach to -carbamoyl phosphonates, which are useful re-
agents for the Horner–Wadsworth–Emmons olefination of
aldehydes en route to medicinally relevant polysubstituted
acrylamides. The methodology relies on the microwave-
promoted Wolff rearrangement of -acyl--diazophospho-
(6) Gan, F.-F.; Kaminska, K. K.; Yang, H.; Liew, C.-Y.; Leow, P.-C.; So,
C.-L.; Tu, L. N. L.; Roy, A.; Yap, C.-W.; Kang, T.-S.; Chui, W.-K.;
Chew, E.-H. Antioxid. Redox Signaling 2013, 19, 1149.
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I.; Žalubovskis, R.; Senćanski, M.; Glišić, S.; Sharoyko, V.;
Tennikova, T.; Dar’in, D.; Pešić, M.; Krasavin, M. Eur. J. Med.
Chem. 2019, 181, 111580. (b) Jovanović, M.; Zhukovsky, D.;
Podolski-Renić, A.; Žalubovskis, R.; Dar’in, D.; Sharoyko, V.;
Tennikova, T.; Pešić, M.; Krasavin, M. Eur. J. Med. Chem. 2020,
191, 112119.
(8) Kato, M. J.; Furlan, M. Pure Appl. Chem. 2007, 79, 529.
(9) McGrath, N. A.; Raines, R. T. Acc. Chem. Res. 2011, 44, 752.
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(10) (a) Albrecht, A.; Koszuk, J. F.; Modranka, J.; Rozalski, M.;
Krajewska, U.; Janecka, A.; Studzian, K.; Janecki, T. Bioorg. Med.
Chem. 2008, 16, 4872. (b) Blaszczyk, E.; Krawczyk, H.; Janecki, T.
Synlett 2004, 2685.
(11) Kim, S.; Lim, C.; Lee, S.; Lee, S.; Cho, H.; Lee, J.-Y.; Shim, D. S.;
Park, H. D.; Kim, S. ACS Comb. Sci. 2013, 15, 208.
3 H, OCH2CH3). 13C NMR (101 MHz, CDCl3):  = 167.11 (d, J =
3.1 Hz), 132.30 (d, J = 9.6 Hz), 129.46 (d, J = 6.0 Hz), 128.58 (d,
J = 2.9 Hz), 127.64 (d, J = 3.5 Hz), 63.41 (d, J = 6.5 Hz), 62.51 (d,
J = 7.2 Hz), 50.57 (d, J = 143.8 Hz), 48.68, 46.28, 28.92, 27.40,
26.82, 26.43, 16.41 (d, J = 6.1 Hz), 16.26 (d, J = 6.3 Hz). 31P NMR
(162 MHz, CDCl3):  = 20.32. HRMS-ESI: m/z [M + Na] calcd for
(12) Hernández-Fernández, E.; Fernández-Zertuche, M.; García-Bar-
radas, O.; Muñoz-Muñiz, O.; Ordóñez, M. Synlett 2006, 440.
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2019, 4721.
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42, 8455. (b) Kim, S.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs,
P. L. J. Am. Chem. Soc. 1999, 121, 2056.
(16) (a) Chen, Y. P.; Chantegrel, B.; Deshayes, C. Heterocycles 1995,
41, 175. (b) Zhang, W.; Romo, D. J. Org. Chem. 2007, 72, 8939.
(17) (a) Patil, B. S.; Vasanthakumar, G.-R.; Babu, V. V. S. Lett. Pept. Sci.
2002, 9, 232. (b) Presset, M.; Coquerel, Y.; Rodrigez, J. J. Org.
Chem. 2009, 74, 415. (c) Sudrik, S. G.; Chavan, S. P.;
Chandrakumar, K. R. S.; Pal, S.; Date, S. K.; Chavan, S. P.; Sonawe,
H. R. J. Org. Chem. 2002, 67, 1574.
C18H28NNaO4P: 376.1648; found: 376.1645.
Compound 2i: Yield: 261 mg (66%); yellowish solid; mp 118.9–
120.6 °C. 1H NMR (400 MHz, CDCl3):  = 11.87 (s, 1 H, NH), 8.78
(dd, J = 8.4, 1.2 Hz, 1 H), 7.92 (dd, J = 8.0, 1.6 Hz, 1 H), 7.57 (ddd,
J = 8.7, 7.2, 1.6 Hz, 1 H), 7.15 (ddd, J = 8.2, 7.3, 1.2 Hz, 1 H), 4.29–
4.09 (m, 4 H, OCH2CH3), 2.77 (dd, J = 20.5, 9.7 Hz, 1 H, CH), 2.69
(s, 3 H, CH3), 2.29–2.17 (m, 2 H), 1.87–1.74 (m, 2 H), 1.74–1.61
(m, 2 H), 1.40–1.26 (m, 8 H), 1.26–1.13 (m, 3 H). 13C NMR (101
MHz, CDCl3):  = 202.4, 167.7 (d, J = 4.1 Hz), 140.6, 135.1, 131.6,
122.6, 122.0, 120.9, 62.5 (d, J = 7.1 Hz), 62.3 (d, J = 6.6 Hz), 56.6
(d, J = 130.9 Hz), 37.6 (d, J = 3.8 Hz), 31.9 (d, J = 3.3 Hz), 31.8 (d,
J = 7.9 Hz), 30.89, 28.5, 26.0, 25.9, 16.38, 16.33. 31P NMR (162
MHz, CDCl3):  = 23.22. HRMS-ESI: m/z [M + H] calcd for
C
20H30NNaO5P: 396.1934; found: 396.1936.
Compound 2j: Yield: 181 mg (58%); white solid; mp 97.4–
1
(18) Dar’in, D.; Kantin, G.; Krasavin, M. Chem. Commun. 2019, 55,
5239.
99.1 °C. H NMR (400 MHz, CDCl3):  = 8.81 (s, 1 H, NH), 7.60–
7.54 (m, 2 H), 7.33–7.28 (m, 2 H), 7.13–7.06 (m, 1 H), 4.27–4.20
(m, 2 H, OCH2CH3), 4.16 (m, 2 H, OCH2CH3), 2.19 (dd, J = 21.6,
10.5 Hz, 1 H, CH), 1.44–1.25 (m, 7 H, OCH2CH3, CH2CHCH2),
0.82–0.67 (m, 2 H, CH2CHCH2), 0.55–0.40 (m, 2 H, CH2CHCH2).
13C NMR (101 MHz, CDCl3):  = 165.9, 138.0, 128.9, 124.2, 119.8,
63.4 (d, J = 6.8 Hz), 62.8 (d, J = 7.0 Hz), 52.20 (d, J = 130.1 Hz),
16.51 (d, J = 5.8 Hz), 16.40 (d, J = 6.0 Hz), 9.4 (d, J = 4.6 Hz), 4.42,
4.27. 31P NMR (162 MHz, CDCl3):  = 25.01. HRMS-ESI: m/z [M +
Na] calcd for C15H22NNaO4P: 334.1179; found: 334.1181.
(21) One-Pot Procedure for the Preparation of 1a from 5a: -Keto-
phosphonate 5a (1.2 mmol) and aniline (1 mmol) were dis-
solved in toluene and placed in a 5 mL microwave vial. The solu-
tion was irradiated at 140 °C for 1 h. Upon cooling to r.t., NaH
(1.5 mmol, 60% suspension in mineral oil) was added portion-
wise. After the evolution of hydrogen gas stopped, 4-chloro-
benzaldehyde (1 mmol) was added. The reaction mixture was
stirred at r.t. overnight and washed with ice-cold water (10 mL).
The aqueous phase was back-extracted with Et2O (2 × 10 mL)
and the combined organics was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The residue was subjected
to flash column chromatography.
(19) Synthesis of 2a–l; General Procedure: Diazo ketophosphonate
5 (1.2 mmol) and amine (1 mmol) were dissolved in anhydrous
toluene (2 mL) and placed in a 5 mL microwave vial. The solu-
tion was then irradiated at 140 °C for 1 h. The resulting mixture
was concentrated in vacuo and subjected to flash column chro-
matography on SiO2 (n-hexane/acetone, gradient from 85:15 to
60:40) to afford phosphonamide 2.
(20) Characterization data of selected compounds:
Compound 2d: Yield: 168 mg (54%); light-brown solid; mp
1
39.0–40.3 °C. H NMR (400 MHz, CDCl3):  = 8.27 (d, J = 8.2 Hz,
1 H), 7.24–7.15 (m, 2 H), 7.08–6.99 (m, 1 H), 4.63–4.52 (m, 1 H,
NCH2CH2), 4.25–4.12 (m, 4 H, OCH2CH3), 4.11–4.00 (m, 1 H,
NCH2CH2), 3.37–3.14 (m, 3 H, NCH2CH2, CH), 1.53 (dd, J = 18.1,
6.9 Hz, 3 H, CH3), 1.36 (t, J = 6.2 Hz, 3 H, OCH2CH3), 1.32 (t, J =
6.1 Hz, 3 H, OCH2CH3). 13C NMR (101 MHz, CDCl3):  = 167.0 (d,
J = 4.2 Hz), 142.9, 131.7, 127.4, 124.5, 123.9, 117.5, 63.1 (d, J =
6.6 Hz), 62.5 (d, J = 6.9 Hz), 48.6, 39.3 (d, J = 132.7 Hz), 27.9, 16.5
(d, J = 2.4 Hz), 16.4 (d, J = 2.5 Hz), 12.5 (d, J = 6.9 Hz). 31P NMR
(162 MHz, CDCl3):  = 24.17. HRMS-ESI: m/z [M + Na] calcd for
C15H22NNaO4P: 312.1359; found: 312.1359.
Compound 2g: Yield: 170 mg (48%); yellow oil. 1H NMR (400
MHz, CDCl3):  = 7.53–7.45 (m, 2 H), 7.38–7.26 (m, 3 H), 4.48 (d,
J = 22.8 Hz, 1 H, CH), 4.31–4.19 (m, 2 H, OCH2CH3), 4.1–3.94 (m,
2 H, OCH2CH3), 3.62–3.31 (m, 4 H, NCH2), 1.81–1.42 (m, 7 H),
1.39–1.25 (m, 4 H, OCH2CH3, NCH2CH2CH2), 1.20 (t, J = 7.1 Hz,
(22) Peters, J.-U.; Capuano, T.; Weber, S.; Kritter, S.; Saegesser, M.
Tetrahedron Lett. 2008, 49, 4029.
(23) Zhao, S.; He, Y.-H.; Wu, D.; Guan, Z. J. Fluorine Chem. 2010, 131,
597.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D