2-[1-(Dimethylamino)ethyl]ferrocenylphosphinic acid as an organocatalyst of Michael and Friedel—Crafts reactions

Article abstract of DOI:10.1007/s11172-021-3233-0

Racemic 2-[1-(dimethylamino)ethyl]ferrocenylphosphinic acid was tested as an organocatalyst in the Michael and Friedel—Crafts reactions. The use of this zwitterion provides 78% conversion in the Michael reaction between cyclohexanone and β-nitrostyrene, a

Full text of DOI:10.1007/s11172-021-3233-0

Russian Chemical Bulletin, International Edition, Vol. 70, No. 7, pp. 1415—1417, July, 2021
1415
Brief Communications
2-[1-(Dimethylamino)ethyl]ferrocenylphosphinic acid as an organocatalyst
of Michael and Friedel—Crafts reactions*
R. P. Shekurov, L. H. Gilmanova, А. А. Zagidullin, and V. А. Miluykov
Arbuzov Institute of Organic and Physical Chemistry,
Federal Research Center ″Kazan Scientific Center of the Russian Academy of Sciences″,
8 ul. Arbuzova, 420088 Kazan, Russian Federation.
E-mail: shekurovruslan@gmail.com
Racemic 2-[1-(dimethylamino)ethyl]ferrocenylphosphinic acid was tested as an organo-
catalyst in the Michael and Friedel—Crafts reactions. The use of this zwitterion provides 78%
conversion in the Michael reaction between cyclohexanone and β-nitrostyrene, and 84% con-
version in the Friedel—Crafts reaction between β-nitrostyrene and indole.
Key words: organocatalysis, ferrocenylphosphinic acid, Ugi’s amine, Michael reaction,
Friedel—Crafts reaction.
Asymmetric organocatalysis is a useful strategy for
obtaining various chiral compounds. Of special interest
are the addition reactions between nucleophiles and
electron-deficient alkenes (Michael and Friedel—Crafts
reactions), being among the most effective methods for
the formation of the carbon—carbon and carbon—hetero-
atom bonds.1,2 The Michael and related Friedel—Crafts
reactions with activated arenes in the presence of chiral
organocatalysts significantly enhanced the potential of
enantioselective synthesis of analogs of natural and bio-
logically active compounds.3 This resulted in improved
yields and/or enantiomeric excess of the products, and
also opened access to compounds that could not be ob-
tained by metal complex catalysis.
In recent years, a considerable interest of researchers
has been drawn to zwitterions as to bifunctional organo-
catalysts for various practically relevant reactions.4—7
Zwitterions are electroneutral molecules containing both
negatively and positively charged moieties, where these
ion pairs can function synergistically thus activating sub-
strates. To move these studies forward and to develop new
catalysts for organic reactions, it was of interest to study
the catalytic activity of racemic 2-[1-(dimethylamino)-
ethyl]ferrocenylphosphinic acid (1)8 based on the Ugi´s
amine as a novel chemotype of zwitterionic organocatalysts
with an element of axial chirality. Note that chiral ferro-
cenes relate to the so-called "privileged" universal ligands
* Based on the materials of the report at the II Scientific
Conference "Dynamic Processes in the Chemistry of Organo-
element Compounds", dedicated to the 75th anniversary of
the Arbuzov Institute of Organic and Physical Chemistry of
Kazan Scientific Center of the Russian Academy of Sciences
(November 11—13, 2020, Kazan, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1415—1417, July, 2021.
1066-5285/21/7007-1415 © 2021 Springer Science+Business Media LLC

Shekurov et al.
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Russ. Chem. Bull., Int. Ed., Vol. 70, No. 7, July, 2021
used in the design of chiral catalysts for asymmetric ca-
talysis.9,10
in isopropyl alcohol at 75 °C in the absence of acid addi-
tives (run 5).
The indole derivatives can act as nucleophiles in the
reactions with α-nitroalkenes. Catalysts for these reactions
are chiral thioureas16,17 and phosphates18, activating the
nitroalkene by hydrogen bonding. To test organocatalyst 1,
the Friedel—Crafts reaction of indole with β-nitrostyrene 2
was chosen (Scheme 2, Table 2).
Results and Discussion
The addition of С-nucleophiles (carbonyl compounds,
derivatives of malonic or acetoacetic acids, etc.) to
α-nitroalkenes is widely used in the syn-
thesis of chiral nitro compounds11—13
and several other useful chiral carbo-
and heterocyclic compounds.14,15 To
test organocatalyst 1, the catalytic
Michael reaction of cyclohexanone
and β-nitrostyrene 2 was chosen
(Scheme 1, Table 1).
Scheme 2
Scheme 1
Reaction conditions: catalyst 1 (15 mol.%), solvent.
The reactions were carried out in isopropyl alcohol.
The best results (84% conversion) were achieved in the
course of heating at 75 °C for 48 h in the presence of
15 mol.% of organocatalyst 1 and 15 mol.% of diethyl-
amine additive (run 6). Probably, upon the addition of
organic bases, zwitterion 1 releases a hydrogen ion into
the solution, thereby accelerating the acid-catalyzed reac-
tion between indole and β-nitrostyrene.
To conclude, racemic 2-[1-(dimethylamino)ethyl]-
ferrocenylphosphinic acid (1), which is the first represen-
tative of the novel class of axially chiral zwitterionic or-
ganocatalysts, has been tested as an organocatalyst in
Michael and Friedel—Crafts reactions. Its use ensures the
organocatalytic Michael reaction between cyclohexanone
and β-nitrostyrene 2 to proceed with 78% conversion. The
use of compound 1 in the Friedel—Crafts reaction between
indole and β-nitrostyrene 2 leads to the formation of the
corresponding product 4 of the catalytic reaction with 84%
conversion.
Reaction conditions: catalyst 1 (15 mol.%), solvent.
It was found that the highest yields were achieved when
carrying out the reaction in alcohols (EtOH and PriOH),
while the reaction in THF, chloroform, and DMF failed.
The use of organic acid (HCO2H, AcOH, PhCO2H) ad-
ditives only decreases the conversion of the starting com-
pounds (runs 6—8). Probably, with an organic acid added,
zwitterion 1 picks up a proton, thereby decreasing
its basicity and catalytic activity. The best combina-
tion of the conversion value (78%) and the ratio of dia-
stereomers, 86:14, was obtained in the course of heating
Table 1. Optimization of conditionsa for a model reaction be-
tween cyclohexanone and β-nitrostyrene 2
Table 2. Optimization of conditionsa for a model reaction between
indole and β-nitrostyrene 2
Run
Acid
(mol.%)
T/°C
τ/h
C (%)b
d.r.c
(syn-/anti-)
1
2
3
4
5
6
7
8
—
60
60
50
60
75
75
75
75
48
48
72
72
72
72
72
72
45
54
52
64
78
34
48
49
85 : 15
88 : 12
90 : 10
84 : 16
86 : 14
85 : 15
83 : 17
89 : 11
Run
Base (mol.%)
τ/h
C (%)b
—
—
—
—
1
2
3
4
5
6
7
—
48
48
48
48
72
48
48
59
—
62
72
57
84
61
Na2CO3 (15)
Et2NH (30)
Et2NH (45)
Et3N (15)
HCOOH (15)
MeCOOH (15)
PhCOOH (15)
Et2NH (15)
PhNH2 (15)
a Reaction conditions: cyclohexanone (0.25 mmol), 2 (0.25 mmol),
catalyst 1 (15 mol.%), solvent PriOH (2 mL).
b Conversion by GC-MS.
a Reaction conditions: indole (0.25 mmol), 2 (0.25 mmol),
catalyst 1 (15 mol.%), solvent PriOH (2 mL), 75 °C.
b Conversion by GC-MS.
с Diastereomeric ratio by 1H NMR.

Ferrocene-based organocatalyst
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 7, July, 2021
1417
Experimental
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The study was financially supported by the Russian
Science Foundation (Project No. 19-73-00297).
The authors are grateful to the Assigned Spectral-
Analytical Center FRC ″Kazan Scientific Center of the
Russian Academy of Sciences″ for technical assistance in
research.
This paper does not contain descriptions of studies on
animals or humans.
Received January 22, 2021;
in revised form February 4, 2021;
accepted February 8, 2021
The authors declare no competing interests.