Convenient preparation of (E)-3-arylidene-4-diazopyrrolidine-2,5-diones in array format

Article abstract of DOI:10.1016/j.mencom.2021.01.010

A practically convenient synthesis of (E)-3-arylidene-4-diazopyrrolidine-2,5-diones from N-substituted maleimides via the Wittig reaction and the Regitz diazo transfer has been developed. In all 26 cases studied, only one chromatographic purification was required with no need for aqueous workup, which makes this protocol amenable to producing the emerging class of diazo compounds in parallel format.

Full text of DOI:10.1016/j.mencom.2021.01.010

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 36–38
Convenient preparation
of (E)-3-arylidene-4-diazopyrrolidine-2,5-diones in array format
Evgeny G. Chupakhin,a,b Grigory P. Kantin,a Dmitry V. Dar’in*a and Mikhail Krasavin*a,b
a Institute of Chemistry, St. Petersburg State University, 199034 St. Petersburg, Russian Federation.
E-mail: m.krasavin@spbu.ru; d.dariin@spbu.ru
b Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russian Federation
DOI: 10.1016/j.mencom.2021.01.010
A practically convenient synthesis of (E)-3-arylidene-4-
diazopyrrolidine-2,5-diones from N-substituted maleimides
via the Wittig reaction and the Regitz diazo transfer has been
developed. In all 26 cases studied, only one chromatographic
purification was required with no need for aqueous workup,
which makes this protocol amenable to producing the
emerging class of diazo compounds in parallel format.
Ar
O
Ar
N2
4-O2NC6H4SO2N3
ArCHO, PPh3
O
O
DBU, CH2Cl2
20 °C, 1–2 h
O
O
MeOH, 20 °C
4–16 h
N
R
N
N
O
R
R
64–94%
26 examples
30–98%
Keywords: privileged structures, maleimides, Wittig reaction, Michael acceptors, diazo transfer, diazo compounds, parallel synthesis.
Besides their notoriety as potential sources of false-positives in
biological assays,1 the so-called Michael acceptors (electron-
deficient olefins capable of undergoing 1,4-conjugate nucleo-
philic addition) have found significant utility in medicinal
chemistry. Michael addition of cysteine residues has been
successfully exploited in the design of targeted covalent
inhibitors.2 Many natural products endowed with anticancer
activity possess Michael acceptor motifs3 which are essential
pharmacophoric elements of these compounds.4
Recently, 3-arylidene pyrrolidine-2,5-diones 1 have drawn our
attention as a potential source of tunable-reactivity Michael
acceptors. Not only have such compounds displayed various
biological activity documented in the literature (such as antiviral,5
anticancer6 and vasorelaxant7), they have been recently termed
‘exocyclic methylidene maleimides’ and employed in the study
on bioconjugation to cysteines.8 Moreover, the unsubstituted
methylene group in 1 has recently been shown to be sufficiently
acidic to allow for direct Regitz diazo transfer as demonstrated by
Bhat and co-workers who prepared several 3-arylidene-4-
diazopyrrolidine-2,5-diones 2 and used them in [2+1] cyclo-
addition with aldehydes.9 Our own expertise in diazo chemistry
inspired us to consider diazo succinimides 2 as promising templates
for introducing various new elements of diversity at position 4 of
3-arylidene pyrrolidine-2,5-diones 1 (Figure 1). In particular, we
have been able to involve them in Rhii-catalyzed X–H insertion
reactions with alcohols, thiols and carboxylic acids.10 This even
more encouraged us to cover as large chemical space of 3-arylidene-
4-diazopyrrolidine-2,5-diones 2 as possible, preferably in parallel
format. Synthetic procedure reported by Bhat and co-workers9 was
not amenable to array synthesis as it involved an aqueous extractive
workup operation. Hence, we aimed to develop such a synthesis of
compounds 2 which would exclude aqueous workup and thus
allow for the preparation of these compounds in fairly large cohorts
in parallel. Herein, we report a successful realization of this goal.
(E)-Configured 3-arylidene pyrrolidine-2,5-diones 1a–z were
prepared in parallel from N-aryl maleimides using a reported
approach based on the conjugate addition of triphenylphosphine
and the subsequent Wittig reaction of the resulting phosphonium
ylide with aromatic aldehydes (Scheme 1).11 However, unlike
noted recently, the reaction was remarkably efficient, clean and
high-yielding at room temperature in methanol.† Crystalline
3-arylidene succinimides 1a–z thus obtained did not require further
purification and were directly used in the diazo transfer step.
As to the latter, we considered the relatively high lipophilicity
of substrates 1a–z (for instance, LogP value for 1t was
calculated12 as 2.64) and deemed them unsuitable substrates for
the recently developed ‘sulfonyl-azide-free’ (SAFE) diazo
transfer protocol in aqueous medium.13 Moreover, the SAFE
protocol would not allow avoiding the extractive workup
operation which was our initial goal. Hence, the diazo transfer
step was conducted using 4-nitrophenylsulfonyl azide and DBU
in dichloromethane for all substrates.‡ Considering that both
†
General procedure for the preparation of compounds 1a–z via the
Wittig reaction. To a solution of N-substituted maleimide (10 mmol) in
methanol (50 ml), triphenylphosphine (11 mmol) was added, and the
mixture was stirred for 20 min followed by the addition of an aromatic
aldehyde (10.5 mmol). In several minutes, precipitation was observed,
and the mixture was stirred at ambient temperature for 4–16 h. Upon
cooling in ice bath, the thick precipitate was filtered off, washed with
methanol (20 ml) and air-dried to afford benzylidene succinimides 1a–z.
direct
diazo
transfer
O
O
Ar
Ar
‡
General procedure for the preparation of compounds 2a–z via the
N
R
N
R
Regitz diazo transfer. To a stirred solution/suspension of imide 1
(2 mmol) in CH2Cl2 (15 ml), 4-O2NC6H4SO2N3 (479 mg, 2.1 mmol) and
DBU (313 μl, 2.1 mmol) were added, and the mixture was stirred at
ambient temperature for 1–2 h (TLC control). The resulting mixture was
loaded on a silica gel column eluted with CH2Cl2 to afford pure diazo
compounds 2a–z.
N2
O
O
2
1
Figure 1 Compounds 1 and 2 explored as templates for a new medicinally
important Michael acceptor design.
© 2021 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2021, 31, 36–38
R2
R2
N2
O
i
ii
O
O
O
O
N
N
R1
1a–z
N
R1
O
R1
2a–z
Yield (%)
Yield (%)
R1
2
R1 R2
2
R2
1
1
4-MeOC6H4 4-F3CC6H4
4-Me2NC6H4 84
a
b
c
d
e
f
g
h
i
74
93
89
84
93
85
94
87
86
72
84
64
69
81
92
87
83
98
91
95
59
89
84
94
54
88
n
o
p
q
r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92
96
88
84
89
87
84
81
76
77
75
33
30
Ph
Ph
Bn
3,4,5-(MeO)3C6H2
4-MeO2CC6H4
Ph
4-MeOC6H4
3-MeC6H4
2-MeOC6H4
4-MeC6H4
2-MeC6H4
Ph
4-FC6H4
3-FC6H4
4-ClC6H4
4-F3CC6H4
4-O2NC6H4
3-O2NC6H4
85
82
78
87
80
82
86
81
90
81
90
93
Ph
2-FC6H4
*
4-MeC6H4
piperonyl
4-FC6H4
4-ClC6H4
4-MeC6H4
Bn
Ph
s
t
O
O
3,4-(MeO)2C6H3
Ph
3,4-(MeO)2C6H3
CH=CHPh-(E)
4-ClC6H4
u
v
w
x
y
z
(piperonyl)
j
k
l
4-FC6H4
4-O2NC6H4
m
4-MeOC6H4 2-thienyl
Scheme 1 Reagents and conditions: i, R2CHO, PPh3, MeOH, 20 °C, 4–16 h; ii, 4-O2NC6H4SO2N3, DBU, CH2Cl2, 20 °C, 1–2 h.
DBU and 4-nitrobenzenesulfonamide (the secondary reaction
product) were significantly more polar compared to compounds
2a–z, the latter were easily purified chromatographically by
loading the reaction mixture directly on a silica gel column.
Thus, the aqueous workup step was avoided altogether, which
facilitated performing the 26 reactions as well as the purification
of the resulting yellow to orange crystalline products 2a–z in
parallel format (see Scheme 1).
ꢀaꢁ
ꢀbꢁ
Several observations could be made regarding the scope of
the syntheses of compounds 1a–z and their transformations
into diazo counterparts 2a–z. Firstly, the yields and product
purities were uniformly high in the first step (the Wittig
reaction) for all substituent combinations on the succinimide
core (the crude products obtained in these reactions were
sufficiently pure to be directly used in the next step). The same
could be noted for the second (the Regitz diazo transfer) step,
except for the markedly lower yields obtained with substrates
containing nitrobenzylidene moiety (cf. 2l, 2y–z). While the
reasons for this remain unclear, one could speculate that the
nitrobenzylidene group could over-stabilize the enolate
intermediate formed before the diazo transfer event and thus
lower the effectiveness of the latter.
Figure 2 Single-crystal X-ray crystallographic structure of compounds
(a) 2f and (b) 2j.
was possibly changed in the diazo transfer step. However, as
shown for two representative products (2f and 2j)§ for which
we managed to obtain a single-crystal X-ray diffraction
structure, the double bond in question retained its (E)-
configuration with respect to the imide carbonyl group
(Figure 2).
While the (E)-configuration of the Wittig products 1a–z
In summary, we have described a practically convenient
synthesis of the recently reported 3-arylidene-4-
diazopyrrolidine-2,5-diones. The 26 representative examples
were produced in generally high yields over two steps, the
Wittig reaction of a succinimide phosphonium ylide generated
in situ, and the Regitz diazo transfer reaction using
4-O2NC6H4SO2N3 and DBU. In all cases, only one
chromatographic purification was employed with no need for
aqueous workup. This makes this method amenable to
producing compounds of such chemotype in parallel format.
With the new, broad arsenal of these reactants in hand, we will
proceed studying their transformations in the classical reactions
of diazo compounds.
had been established previously,11 we were curious to see if it
§
Crystal data for 2f. C18H13N3O2 (M = 303.32), monoclinic, space
group P21, a = 9.34450(10), b = 13.38360(10) and c = 23.8971(2) Å,
b = 99.4670(10)°, V = 2947.94(5) Å3, Z = 2, T = 100.0(10) K,
μ = 0.747 mm–1, dcalc = 1.367 g cm–3, 60289 reflections measured, 12289
independent reflections (Rint = 0.0347, Rs = 0.0269) which were used in
all calculations. The final R1 was 0.0446 [I > 2s(I)] and wR2 was 0.1259
(all data).
Crystal data for 2j. C20H15N3O2 (M = 329.35), triclinic, space group
–
P1, a = 6.21290(10), b = 9.2395(2) and c = 14.5466(3) Å, a = 79.089(2)°,
b = 85.627(2)°, g = 76.324(2)°, V = 796.26(3) Å3, Z = 2, T = 100.0(10) K,
μ = 0.737 mm–1, dcalc = 1.374 g cm–3, 8190 reflections measured, 3031
independent reflections (Rint = 0.0298, Rs = 0.0309) which were used in
all calculations. The final R1 was 0.0525 [I > 2s(I)] and wR2 was 0.1583
(all data).
CCDC 2014276 and 1999007 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.
This research was supported by the Russian Science
Foundation (project grant no. 20-13-00024). We thank the
Research Center for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research and the Center for
X-ray Diffraction Methods of Saint Petersburg State University
Research Park for obtaining the analytical data.
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Mendeleev Commun., 2021, 31, 36–38
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