Nef-Perkow-Mumm Cascade towards Imido Phosphate Derivatives

Article abstract of DOI:10.1055/s-0036-1590856

A one-pot, four-component synthesis of imido phosphates has been achieved using a Nef-Perkow sequence followed by addition of carboxylic acid derivatives. The final imido moiety is formed via a Mumm rearrangement of an intermediate imidate.

Full text of DOI:10.1055/s-0036-1590856

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
de
A. Dos Santos et al.
Letter
Synlett
Nef–Perkow–Mumm Cascade towards Imido Phosphate Deriva-
tives
O
R3O
Aurélie Dos Santosa
Marie Cordierb
O
P
R3O
R2
N
R4COOH
base
O
R3O
P
O
R1 = CH2Cl or CHCl2
R4
R3O
Laurent El Kaïm*a
0
0
0
0
0-
0
0
1
5-
7
2
9
8-
0
1
0
Cl
R
4 = alkyl, aryl
X
O
O
X
NR2
a Laboratoire de Synthèse Organique, CNRS, Ecole
Polytechnique, ENSTA ParisTech – UMR 7652,
Université Paris-Saclay, 828 Bd des Maréchaux,
91128 Palaiseau, France
laurent.elkaim@ensta-paristech.fr
aurelie.dossantos@ensta-paristech.fr
b Laboratoire de Chimie Moléculaire, CNRS, Ecole
Polytechnique – UMR 9168, Université Paris-
Saclay, Route de Saclay, 91128 Palaiseau, France
X=H, Cl
14 examples, yields: 54 to 82%
O
1) R2NC
R2 = t-Bu, Cy...
X=H, Cl
R3 = Me, Et, i-Pr
R1
2) P(OR3)3
Cl
O
R3O
O
R3O
P
O
R2
N
P
R3O
R4COOH
O
R3O
R4
R
1 = electron-poor aryl
or COOEt
R1
R1
C
R4 = alkyl, aryl
NR2
O
O
10 examples, yields: 28 to 65%
NEF/PERKOW
MUMM REARRANGEMENT
Received: 17.05.2017
Accepted after revision: 06.07.2017
Published online: 11.08.2017
In an effort to solve this problem and extend the diversi-
ty offered by the Nef isocyanide reaction, we reported a few
years ago a Nef–Perkow sequence that afforded ketenimine
phosphates and trapped the latter in various cycloadditions
with 1,3-dipoles (Scheme 1).4 In this context, we now wish
to report a three-component, one-pot Nef–Perkow–Mumm
cascade leading to imido phosphate derivatives.
DOI: 10.1055/s-0036-1590856; Art ID: st-2017-d0375-l
Abstract A one-pot, four-component synthesis of imido phosphates
has been achieved using a Nef–Perkow sequence followed by addition
of carboxylic acid derivatives. The final imido moiety is formed via a
Mumm rearrangement of an intermediate imidate.
At the onset of this study, we envisaged the use of α-
chloroacetyl chloride as a potential probe to evaluate the ef-
ficiency of the Perkow reaction5 of α-ketoimidoyl chlorides.
Indeed after Nef reaction of α-chloroacetyl chloride, the fol-
lowing addition of trialkylphosphite might afford two re-
gioisomeric Perkow adducts according to the leaving-group
abilities of the two chlorine atoms present in the interme-
diate imidoyl chloride (Scheme 2). Thus, after solvent-free
cyclohexyl isocyanide addition to α-chloroacetyl chloride,
trimethyl phosphite was added to the resulting imidoyl
chloride obtained in quantitative yield. After a few minutes
at room temperature, the Perkow step was complete, as
monitored by 1H NMR spectroscopy, forming vinyl phos-
phate 1a in almost quantitative yield without any trace of
the regioisomeric ketenimine phosphate 1a′. After purifica-
tion by flash chromatography on silica gel, the amide 2a de-
rived from the hydrolysis of imidoyl chloride 1a was ob-
tained with an excellent 98% isolated yield (Scheme 2).
Besides the formation of a new vinyl phosphate deriva-
tive, the most interesting aspect of this transformation is
associated with the remaining imidoyl chloride function
whose potential as an electrophile is not hampered by the
competing α-carbonyl present in the Nef adduct.6 Thus sim-
ple water addition, as observed in the conversion of 1a into
2a, could be replaced by more complex nucleophilic addi-
tions as shown by the formation of the phosphorylated
tetrazole 3a obtained in 67% isolated yield on addition of
trimethylsilyl azide to 1a (Scheme 3).
Key words vinyl phosphate, keteneimine, isocyanide, Nef reaction,
Perkow reaction, Mumm rearrangement
Over the last decades, Ugi and Passerini reactions have
been largely associated with the development of the multi-
component reaction field.1 These reactions take advantage
of the low nucleophilicity of isocyanides towards carbonyl
derivatives requiring the electrophilic activation of an acid-
ic derivative such as carboxylic acid. However the more
electrophilic acyl chlorides are reactive enough to add di-
rectly to isocyanides leading to α-ketoimidoyl chlorides
without any assistance (Scheme 1). Discovered by Nef in
1892,2 this reaction has been little studied in comparison
with the more recent Ugi and Passerini reactions.3 This is
certainly associated with the lower diversity of the reaction
together with an apparent reversibility of the Nef step
when trying to trap the imidoyl chlorides with various nu-
cleophiles.
O
P(OR3)2
O
O
OPO(OR3)2
R2
O
R2NC
P(OR3)3
rt
CO2Me
N2
Cl
NR2
R1
N
R1
Cl
R1
MeO2C
R1
C
rt to 60 °C
Nef reaction
NR2
N
N
Scheme 1 Nef–Perkow sequence
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
A. Dos Santos et al.
Letter
Synlett
OPO(OMe)2
Cl
C
NCy
1a'
CyNC
O
P(OMe)3
rt, 5 min
O
rt, 5 min
Cl
Cl
Cl
NCy
Cl
neat
Nef
neat
Perkow
OPO(OMe)2
O
OPO(OMe)2
Cl
H2O
SiO2
NHCy
NCy
1a
2a 98%
Scheme 2 Nef–Perkow sequence with chloroacetyl chloride
O
O
Different benzoate salts were also evaluated as well as
benzoic acid/base combinations to allow further extension
to noncommercially available carboxylates. These trials
showed the superiority of sodium salts over potassium or
lithium salts whereas use of benzoic acid together with
Na2CO3was less efficient than using the preformed carbox-
ylate but still gave a reasonable 73% isolated yield.
A range of isocyanides, trialkyl phosphites, and carbox-
ylic acids were examined with chloroacetyl chloride in ace-
tonitrile in the presence of sodium carbonate to test the
scope of this new one-pot Nef–Perkow–Mumm cascade.
The imido vinyl phosphates 4 were isolated in moderate to
good yields as shown in Table 1.
The sequence is compatible with aliphatic (Table 1, en-
tries 7–13) and aromatic acids (Table 1, entries 1–5 and 14).
The nature of the trialkyl phosphites used seems to have lit-
tle influence on yields as shown by the close behavior of the
methyl, ethyl and isopropyl phosphites (Table 1, entries 1–
3). In the Nef step, cyclohexyl isocyanide reacts with chlo-
roacetyl chloride in five minutes at room temperature to
give the imidoyl chloride intermediate quantitatively. When
p-methoxy benzyl and homoveratryl isocyanides were
used, the reaction needs to be heated at 60 °C for one hour.
Although tert-butyl isocyanide exhibits good reactivity in
the Nef step (close to that of cyclohexyl isocyanide), the
Perkow addition is not efficient both at room or higher
temperature probably due to the steric hindrance of the
tert-butyl group together with potential conversion into a
MeO
MeO
P
P
O
O
MeO
MeO
TMSN3 (1 equiv)
N
Cl
N
t-BuOH (0.3 M)
N
NCy
1a
N
rt, 2 d
Cy
3a
Scheme 3 Nucleophilic attack on the vinyl phosphate imidoyl chloride
intermediate 1a to form the phosphorylated tetrazole 3a
In the context of this study, we decided to focus on the
addition of carboxylate salts to form imide derivatives
through a Mumm rearrangement7 of an intermediate imi-
date ester (Scheme 4). Indeed, this transformation has only
been reported once on Nef adducts and the formation of
imide derivatives could only be observed when using silver
carboxylates.8 However, when sodium benzoate was added
to 1a in dichloromethane and the mixture heated at 40 °C
for one hour we were delighted to observe the formation of
the expected imide 4a, but the major product was the am-
ide 2a. The formation of the latter could be explained by re-
sidual water in the benzoate salt or, more probably, by a
competing anhydride formation through further attack of a
second benzoate salt on the intermediate imidate before
Mumm rearrangement. Rewardingly changing the solvent
to acetonitrile allowed us to observe the exclusive forma-
tion of 4a that was obtained directly from α-chloroacetyl
chloride in an excellent 78% isolated yield (Scheme 4).
O
O
O
MeO
MeO
MeO
PhCOOM (1 equiv) or
PhCOOH/base (1 equiv)
P
P
P
O
O
O
Mumm
MeO
MeO
Cy
N
MeO
Cl
NCy
O
Ph
Ph
solvent (1.0 M)
40 °C, 1 h
NCy
O
O
O
1a
4a
1) CyNC (1 equiv)
rt, 5 min, neat
2) P(OMe)3 (1 equiv)
rt, 5 min, neat
Yield [%]
in MeCN
PhCOOK
PhCOOLi
PhCOOH/Na2CO3
PhCOOH/K2CO3
PhCOOH/Cs2CO3
with PhCOONa Yield [%]
DCM
26a
78
68
5a
MeCN
THF
toluene
13a
7a
73
60
56
O
Cl
Cl
Scheme 4 Optimization Nef–Perkow–Mumm rearrangement cascade towards imido vinyl phosphate 4a. a Amide resulting of the hydrolysis on silica
gel of the vinyl phosphate imdioyl chloride was majoritary obtained; 72% with PhCOOLi, 56% with CH2Cl2, 63% with THF and toluene.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
A. Dos Santos et al.
Letter
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Table 1 Synthesis of Imido Vinyl Phosphonate Derivatives 4
Entry
R1
R2
Cy
R3
Me
R4
Ph
Product
Yield (%)a
1
2
H
4a
4b
4c
4d
4e
4f
73 (78)
(82)
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cy
Et
Ph
3
Cy
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
(77)
(79)
(65)
(69)
4
hverb
Ph
5
p-MeOC6H3CH2
Ph
6
Cy
Ph
7
Cy
Me
4g
4h
4i
61 (75)
8
p-MeOC6H3CH2
Me
76
56
69
69
54
67
62
9
p-MeOC6H3CH2
ClCH2
CH2C(Me)
allyl
10
11
12
13
14
Cy
4j
p-MeOC6H3CH2
4k
4l
Cy
Cy
Cy
PhCHCH
PhCHC(Me)
o-IPh
4m
4n
a Yield determined for the reaction using R4CO2H together with Na2CO3. The value in parentheses for the reaction using preformed R4CO2Na.
b For R2 = hver, the starting amine used in the preparation of the isocyanide partner is homoveratrylamine.
nitrile under forcing conditions. Rewardingly, this strategy
could be extended to α-dichloroacetyl chloride leading to a
chlorovinyl phosphate. The latter was obtained as a single
stereoisomer but we could not determine its cis or trans na-
ture (Table 1, entry 6).9 The imide structure of these ad-
ducts could be further confirmed by a single-crystal X-ray
analysis of 4n.10
imine phosphate derivatives are normally obtained
(Scheme 1). The potential of these adducts has been mostly
explored in various cycloaddition and electrocyclization
processes to furnish triazoles and tetrazoles,4 indolizines,11
pyridines,12 and pyrroles.13 Compared to the previous imi-
doyl chloride 1, the ketenimine nature of the adduct might
allow a direct addition of the carboxylic acid without any
added base. After allowing cyclohexyl isocyanide to react
with p-chlorobenzoyl chloride under neat conditions at
We next envisaged extending this strategy to other acyl
chlorides. When no α-halogeno atoms are present, keten-
O
O
MeO
MeO
CyNC
P(OMe)3
(1 equiv)
rt, 5 min
neat
p-O2NC6H4COOH
(1 equiv)
40 °C, 1 h
P
P
NO2
O
O
O
O
(1 equiv)
60 °C, 2 h
neat
MeO
MeO
Cl
NCy
O
Cl
C
MeCN (1.0 M)
NCy
NCy
O
Cl
Cl
Cl
Cl
Nef
Perkow
(1 equiv)
5a 66%
Mumm
O
MeO
P
NO2
1) CyNC (1 equiv), 60 °C, 2 h, neat
2) P(OMe)3 (1 equiv), rt, 5 min, neat
3) p-O2NC6H4COOH (1 equiv), MeCN (1.0 M), 40 °C, 1 h
O
MeO
Cy
N
O
O
6a 56% (one-pot)
Cl
6a 80% (53% two steps)
Scheme 5 Nef–Perkow–Mumm rearrangement cascade towards imido phosphate 6a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
A. Dos Santos et al.
Letter
Synlett
60 °C for two hours, trimethyl phosphite was added at room
temperature leading to ketenimine 5a isolated in 66% yield
(by rapid chromatography on silica gel). When the latter
was added to p-nitrobenzoic acid under the conditions op-
timized for 4a (MeCN, 40 °C, 1 h) the new imido phosphate
6a was formed in a good 80% isolated yield. As ketenimines
are rather sensitive to hydrolysis a one-pot procedure was
preferred adding the carboxylic acid directly to the crude
ketenimine leading to a slightly better 56% yield over the
whole sequence (Scheme 5).
served for aromatic derivatives. As observed previously the
efficiency of the sequence does not show a strong depen-
dence to the nature of the trialkyl phosphites added in the
Perkow step (Table 2, entries 2 and 3).
In summary, we have further extended the synthetic
applications of the Nef–Perkow sequence. According to the
nature of the starting acyl chloride, the reaction may afford
ketenimines as well as imidoyl chlorides. We have shown
that both families of compounds may readily undergo a
Mumm rearrangement leading to complex imide deriva-
tives.15 The use of the latter in further cyclizations is under
investigation in our group.
These one-pot conditions were adopted for the prepara-
tion of various imides 6 from acyl chlorides as displayed in
Table 2.14
Acknowledgment
Table 2 Synthesis of Imido Phosphate Derivatives 6
We thank Paul Héry for his internship at ENSTA. We thank ENSTA
ParisTech for financial support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590856.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Entry R1
R2
Cy
R3
Me
R4
p-O2NC6H4
Product Yield (%)
References and Notes
1
2
p-ClC6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
56
60
57
51
44
65
28
29
30
52
0
(1) For reviews see: (a) Dömling, A. Chem. Rev. 2006, 106, 17.
(b) Dömling, A.; Wang, K.; Wang, W. Chem. Rev. 2012, 112, 3083.
(c) Multicomponent Reactions in Organic Synthesis; Zhu, J.;
Wang, Q.; Wang, M.-X., Eds.; Wiley-VCH: Weinheim, 2014.
(d) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V.
Y. Chem. Rev. 2015, 115, 2698. (e) Varadi, A.; Palmer, T. C.;
Dardashti, R. N.; Majumdar, S. Molecules 2016, 21, 19.
(f) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.;
Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295.
(2) Nef, J. U. Liebigs Ann. Chem. 1892, 270, 267.
(3) For a selection of applications, see: (a) Ugi, I.; Fetzer, U. Chem.
Ber. 1961, 94, 1116. (b) Chen, J. J.; Deshpande, S. V. Tetrahedron
Lett. 2003, 44, 8873. (c) Westling, M.; Smith, R.; Livinghouse, T.
J. Org. Chem. 1986, 51, 1159. (d) Livinghouse, T. Tetrahedron
1999, 55, 9947. (e) Tian, W. S.; Livinghouse, T. J. Chem. Soc.,
Chem. Commun. 1989, 819. (f) El Kaïm, L.; Grimaud, L.;
Wagschal, S. Synlett 2009, 1315. (g) Dos Santos, A.; El Kaïm, L.;
Grimaud, L.; Ronsseray, C. Chem. Commun. 2009, 3907.
(h) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12,
820. (i) Shaabani, A.; Mahyari, M.; Aghaei, M.; Keshipour, S.; Ng,
S. W. Synlett 2013, 24, 1968. For a review and the Nef isocyanide
reaction: (j) La Spisa, F.; Tron, G. C.; El Kaïm, L. Synthesis 2014,
46, 829.
(4) Coffinier, D.; El Kaïm, L.; Grimaud, L. Org. Lett. 2009, 8, 1825.
(5) (a) Perkow, W.; Ullerich, K.; Meyer, F. Naturwissenschaften
1952, 39, 353; Chem. Abstr. 1953, 47, 8248. For a review on the
Perkow reaction, see: (b) Lichtenthaler, F. W. Chem. Rev. 1961,
61, 607. For some recent Perkow-type reactions, see:
(c) Waszkuc, W.; Janecki, T. Org. Biomol. Chem. 2003, 1, 2966.
(d) Tarasenko, K. V.; Gerus, I. I.; Kukhar, V. P. J. Fluorine Chem.
2007, 128, 1264. (e) Paleta, O.; Pomeisl, K.; Kafka, S.; Klasek, A.;
Kubelka, V. Beilstein J. Org. Chem. 2005, 1, 17. (f) Pomeisl, K.;
Kvicala, J.; Paleta, O.; Klasek, A.; Kafka, S.; Kubelka, V.; Havlicek,
J.; Cejka, J. Tetrahedron 2007, 63, 10549.
p-FC6H4
p-FC6H4
EtO2C
Cy
Me
i-Pr
i-Pr
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3
Cy
Ph
4
hver
t-Bu
Cy
Ph
5
EtO2C
Ph
6
p-FC6H4
p-O2NC6H4
p-O2NC6H4
p-ClC6H4
p-O2NC6H4
p-O2NC6H4
p-FC6H4
EtO2C
p-ClC6H4
p-MeOC6H4
allyl
7
Cy
8
hver
Cy
9
ClCH2
ClCH2
Me
10
11
12
13
Cy
6j
–
t-Bu
Cy
CH2CH2CH
CH2CH2CH
–
0
hver
–
0
Compared to the previous Nef–Perkow–Mumm se-
quence, the scope of the carboxylic acids that may be suc-
cessfully added in the last step is slightly more limited. Aro-
matic acids (Table 2, entries 1–6) give the desired imido
phosphates 6a–f, with the highest yields observed when
the aromatic ring is substituted with electron-withdrawing
groups; whereas the addition of aliphatic acids is more
problematic as shown by the lack of product formation on
addition of acetic acid or cyclopropanecarboxylic acid (Ta-
ble 2, entries 11–13). However allyl and chloroacetic acids
(Table 2, entries 8–10) gave imido phosphates 6h–j in mod-
erate yields. The higher reactivity of α-chloroacetic acid
compared to acetic acid is consistent with the trend ob-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
A. Dos Santos et al.
Letter
Synlett
(6) Nucleophilic addition under neutral or basic conditions usually
occurs on the carbonyl group leading to simple acid derivatives
and recovery of the isocyanides: for amines, see ref. 1.
(7) Mumm, O. Ber. Dtsch. Chem. Ges. 1910, 43, 886.
(8) La Spisa, F.; Tron, G. C. Tetrahedron Lett. 2014, 55, 7060.
(9) The Perkow reaction of α-dichloroketones often gives a mixture
of isomeric cis- and trans-vinylphosphates: Borowitz, I. J.;
Firstenberg, S.; Casper, E. W. R.; Crouch, R. K. J. Org. Chem. 1971,
36, 3282.
(10) CCDC 1550094 contains the supplementary crystallographic
data for compound 4n. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
DCM, 10:90) to afford 4a as yellow oil in 73% yield (278 mg, 0.73
mmol). Rf = 0.59 (DCM/EtOAc, 5:5). H NMR (400 MHz, CDCl3):
1
δ = 7.63 (d, JHH = 8.1 Hz, 2 H), 7.52 (t, JHH = 7.3 Hz, 1 H), 7.41 (dd,
JHH = 8.1, 7.3 Hz, 2 H), 5.43 (dd, JHH,HP = 3.0, 2.0 Hz, 1 H), 5.22 (dd,
JHH,HP = 3.0, 2.0 Hz, 1 H), 4.42–4.34 (m, 1 H), 3.70 (d, JHP = 11.4 Hz,
6 H), 2.11–2.02 (m, 2 H), 1.84–1.81 (m, 4 H), 1.66–1.63 (m, 1 H),
1.39–1.18 (m, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 173.6,
166.8 (d, JCP = 8.1 Hz), 147.7 (d, JCP = 8.1 Hz), 136.7, 132.7, 129.3,
128.7, 108.4 (d, JCP = 3.7 Hz), 58.8, 55.1 (d, JCP = 6.6 Hz), 30.3,
26.2, 25.2 ppm. 31P NMR (161.9 MHz, H3PO4): δ = –4.8 ppm.
HRMS: m/z calcd for C18H24NO6P: 381.1341; found: 381.1326. IR
(neat): 3033, 2960, 2936, 2859, 1707, 1659, 1631, 1450, 1329,
1280, 1187, 1044 cm–1
.
(11) (a) Coffinier, D.; El Kaïm, L.; Grimaud, L. Synlett 2010, 2474.
(b) Yavari, I.; Naeimabadi, M.; Hosseinpour, R.; Halvagar, M. R.
Synlett 2016, 27, 2601.
(12) Coffinier, D.; El Kaïm, L.; Grimaud, L.; Ruijter, E.; Orru, R. V. A.
Tetrahedron Lett. 2011, 52, 3023.
(13) Yavari, I.; Ghanbari, E.; Hosseinpour, R. Helv. Chim. Acta 2014,
97, 1004.
(14) CCDC 1550095 contains the supplementary crystallographic
data for compound 6j. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(15) Nef–Perkow–Mumm Product 4a – Typical Procedure
Under an argon atmosphere, a mixture of chloroacetyl chloride
(80 μL, 1.0 mmol) and cyclohexyl isocyanide (124 μL, 1.0 mmol)
was stirred at rt for 5 min. Then trimethyl phosphite (118 μL,
1.0 mmol) was added, and the mixture was stirred at rt for 5
min to afford the imidoyl chloride intermediate. To a 1.0 M solu-
tion of benzoic acid (122 mg, 1.0 mmol) in MeCN were added
Na2CO3 (106 mg, 1.0 mmol) and the imidoyl chloride intermedi-
ate (formed in situ), and the mixture was stirred at 40 °C for 1 h.
The resulting mixture was dissolved in DCM and washed with
H2O. The organic layer was extracted, dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel (EtOAc/
Nef–Perkow–Mumm Product 6a – Typical Procedure
Under an argon atmosphere, a mixture of p-chlorobenzoyl chlo-
ride (128 μL, 1.0 mmol) and cyclohexyl isocyanide (124 μL, 1.0
mmol) was stirred at 60 °C for 2 h. Then trimethyl phosphite
(118 μL, 1.0 mmol) was added, and the mixture was stirred at rt
for 5 min to afford the ketenimine intermediate. To a 1.0 M solu-
tion of the keteneimine (formed in situ) in MeCN was added p-
nitrobenzoic acid (167 mg, 1.0 mmol), and the mixture was
stirred at 40 °C for 1 h. The solvent was removed under reduced
pressure, and the crude product was purified by flash chroma-
tography on silica gel (EtOAc/DCM, 5:95) to afford 6a as yellow
oil in 56% yield (292 mg, 0.56 mmol). Rf = 0.71 (DCM/EtOAc,
7:3). 1H NMR (400 MHz, CDCl3): δ = 8.26 (d, JHH = 9.1 Hz, 2 H),
7.67 (d, JHH = 9.1 Hz, 2 H), 7.38–7.33 (m, 4 H), 6.09 (d, JHP = 7.8
Hz, 1 H), 3.80 (d, JHP = 11.4 Hz, 3 H), 3.73–3.66 (m, 1 H), 3.58 (d,
JHP = 11.4 Hz, 3 H), 2.15–2.06 (m, 1 H), 2.01–1.92 (m, 1 H), 1.77–
1.72 (m, 3 H), 1.55–1.44 (m, 2 H), 1.09–1.04 (m, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 172.9, 171.6 (d, JCP = 5.1 Hz),
150.0, 140.6, 135.7, 133.1 (d, JCP = 5.9 Hz), 129.3, 129.3, 129.1,
124.0, 77.2 (d, JCP = 4.4 Hz), 60.5, 54.9 (d, JCP = 5.9 Hz), 54.5 (d,
JCP = 5.9 Hz), 30.4, 29.2, 26.2, 26.1, 24.8 ppm. 31P NMR (161.9
MHz, H3PO4): δ = 0.3 ppm. IR (neat): 2938, 2859, 1716, 1688,
1530, 1348, 1300, 1044, 909, 855 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E