Electrogenerated NHC as an organocatalyst in the Staudinger reaction

Article abstract of DOI:10.1039/c002325f

Electrogenerated N-heterocyclic carbene can behave as an organocatalyst in the Staudinger reaction (from imine and acyl chloride) in a very polar solvent, such as an ionic liquid.

Full text of DOI:10.1039/c002325f

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Electrogenerated NHC as an organocatalyst in the Staudinger reactionw
Marta Feroci,*a Isabella Chiarotto,a Monica Orsinib and Achille Inesi*a
Received 3rd February 2010, Accepted 1st April 2010
First published as an Advance Article on the web 26th April 2010
DOI: 10.1039/c002325f
Electrogenerated N-heterocyclic carbene can behave as an
organocatalyst in the Staudinger reaction (from imine and acyl
chloride) in a very polar solvent, such as an ionic liquid.
structures. It seems that, after the attack of the imine on the
ketene and the formation of a zwitterionic intermediate, the
product cis/trans ratio depends only on the rate constants of
the direct ring closure and of the isomerization (rate constants
that, therefore, rely on the imine and ketene structures).16a
This reaction can also be catalyzed by an organocatalyst, an
NHC. In this case again, the mechanism seems to rely on the
substituents on the ketene and imine, but in order to obtain
good yields, a strongly electrophilic imine seems necessary
(N-Ts, N-Boc).7 The carbene is obtained by deprotonation of
the suitable precursor in THF or Et2O, in the presence of
the imine, and the ketene (previously prepared) is added at
the end.7
N-Heterocyclic carbenes (NHCs) have recently received much
attention as organocatalysts1 in a large variety of reactions,
such as the annulation of enals and sulfonylimines,2 the
aza-Morita–Baylis–Hillman reaction of cyclic enones and
N-tosylimines,3 the benzoin condensation,1,4 the Stetter
reaction,1,5 the Mannich reaction,6 the Staudinger reaction,7 etc.
These stabilized singlet carbenes behave, in fact, as nucleo-
philic organic catalysts, due to the presence of p-donor
heteroatoms adjacent to the divalent carbon atom.8
The most common strategy to generate NHCs is the
deprotonation of imidazolium, triazolium or thiazolium salts
(Scheme 1, chemical route). This deprotonation is carried out
by a chemical base (NEt3, t-BuOK, Cs2CO3, potassium
hexamethyldisilazane (KHMDS), etc., depending on the acidity
of the substrate) in a classical molecular solvent (THF,
toluene, Et2O, etc.).1–7
Ionic liquids (ILs) have been described as ‘‘green solvents’’
mainly due to their virtually null vapour pressure, which
allows them to be easily recycled, many times.17 Organic
reactions carried out in ILs may follow different pathways
with respect to the reactions in classical molecular solvents,
due to the ionic structures of ILs which create a very polar
environment for reagents, intermediates and products.
Only two papers (to the best of our knowledge) report the
Staudinger cycloaddition in ionic liquids.18,19
NHCs can also be generated by electrochemical reduction of
suitable imidazolium or thiazolium salts, in a one-electron
process (Scheme 1, electrochemical route).9
In previous papers about the Staudinger reaction, ILs have
been employed as precatalysts in the presence of bases in
molecular solvents,7 or as solvents in which a catalyst is used
(ytterbium(III) triflate18 or a task-specific IL19).
These electrogenerated NHCs have been successfully used
as basic catalysts in the synthesis of b-lactams via cyclization
of linear amides,9d in the Henry reaction,10 N-functionalization
of benzoxazolones or oxazolidinones,11 and as nucleophilic
catalysts in the benzoin condensation12 and in the Stetter
reaction.13
In this communication we report an easy electrochemical
methodology for the synthesis of b-lactams via the Staudinger
reaction, directly from imine and acyl chloride, in which ILs
play the dual role of solvents and precatalysts. Our preliminary
results are reported here.
The Staudinger reaction is a well-known [2 + 2] ketene–
imine cycloaddition that leads to the formation of the b-lactam
skeleton (Scheme 2).14
After the galvanostatic cathodic reduction of 1-butyl-3-
methylimidazolium tetrafluoroborate (BMIM-BF4, 0.15 to
0.50 eq. of theoretical electrogenerated carbene), the imine
was dissolved in the catholyte at 60 1C, then phenylacetyl
chloride was added. After 2 h and usual workup, the corre-
sponding b-lactam was isolated as reported in Table 1.z
As the reaction between NHCs and strongly electrophilic
imines seems to be rarely reversible,3,7a especially in a very
polar solvent which should stabilize the zwitterionic adduct,
we decided to employ less reactive imines.
The Staudinger reaction usually starts with the generation
of the ketene, generally by dehydrohalogenation of an acyl
halide or by the Wolff rearrangement of an a-diazocarbonyl
compound, and the reaction between the ‘‘in situ’’ generated
ketene and an imine in a molecular solvent.15
Although Staudinger reported this reaction for the first time
in 1907, its mechanism is still controversial, especially with
regards to the stereochemical outcome.16 In fact, the reactivity
and the stereochemistry of the products (typically cis or trans
b-lactams) depend on the substituents on the ketene and imine
a Dept. ICMA, via Castro Laurenziano 7, I-00161 Roma, Italy.
E-mail: marta.feroci@uniroma1.it, achille.inesi@uniroma1.it;
Fax: 39 0649766749; Tel: 39 0649766563
b Dept. Elettronica Applicata, via Vasca Navale 84, I-00146 Roma,
Italy
w Electronic supplementary information (ESI) available: Full experi-
mental procedures, including 1H and 13C NMR data. See DOI:
10.1039/c002325f
Scheme 1 Generation of NHCs.
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seems to act exclusively as an organocatalyst (entry 13). The
nucleophilicity of the imine nitrogen atom therefore plays a
crucial role and we think that, in this case, the mechanism of
NHC catalysis is different from the one reported in the
literature using strongly electrophilic imines. In fact,
when N-benzylidene-4-methoxyaniline is used, N-(4-methoxy-
phenyl)-2-phenylacetamide (11% in entry 3) is obtained as a
by-product, suggesting a direct attack of the imine on the
carbonyl group of the ketene as in the catalyzed version of the
Staudinger reaction.
Scheme 2 The Staudinger reaction.
a
Table 1 NHC-catalyzed Staudinger reaction in BMIM-BF4
In conclusion, we have reported the first example of the
Staudinger reaction in an IL (in the dual role of solvent and
precatalyst), catalyzed by NHC, starting from non-electrophilic
imines. We are now studying the role of this electrogenerated
carbene in the reaction mechanism and the extension of this
reaction to other substrates.
Entry Ar
F/mol NEt3 (eq)b Yield (%)c
cis/trans
We thank Marco Di Pilato for his support with the experi-
mental part of this work and Miur and CNR (Italy) for
financial support.
1
2
3
4
p-MeO-Ph
—
p-MeO-Ph 0.30
p-MeO-Ph 0.50
p-MeO-Ph 1.00
p-MeO-Ph 1.70
p-MeO-Ph 0.50
p-MeO-Ph 0.50
—
—
—
—
—
—
—
—
—
1.0
0.3
1.0
1.0
0.5
—
36
66
38
35
4
33
—
16
3
—
10/90
9/91
16/84
11/89
trans
13/87
—
trans
trans
14/86
trans
11/89
11/89
5
6d
7e
8
Notes and references
z Experimental procedure: constant current electrolyses were carried
out using a glass two-compartment home-made cell. Anolyte (ca.
0.5 ml) and catholyte (ca. 1.5 ml) were separated through a glass disk
(porosity 4). The electrode apparent surface areas were 1.0 cm2 for the
cathodic Pt spiral (99.9%) and 0.8 cm2 for the anodic Pt spiral
(99.9%). The current density was 15 mA cmꢁ2. Electrolyses were
carried out at 60 1C, under a nitrogen atmosphere, using BMIM-BF4
as anolyte and catholyte. After the consumption of the number of
Faradays per mol of imine reported in Table 1, the current was
switched off and imine (1 mmol) was added to the catholyte under
stirring; when the dissolution was complete, phenylacetyl chloride
(1 mmol) was added. The mixture was kept at 60 1C for 2 h. In the
cases in which triethylamine was necessary (see Table 1), NEt3 was
added to the catholyte with the imine. The catholyte was extracted
with diethyl ether, the solvent was removed under vacuum and the
residue was analyzed by 1H-NMR spectroscopy and purified by
flash-chromatography, affording the corresponding pure b-lactam.
All b-lactams are known compounds and gave spectral data in
accordance with those reported in the literature.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.15
0.50
—
0.50
0.50
0.15
0.15
9
10
11
12
13
14
42
22
64
55
a
Divided cell, Pt electrodes, BMIM-BF4 as anolyte and catholyte,
N2 atmosphere, 60 1C, galvanostatic conditions (15 mA cmꢁ2); at the
end of the electrolysis, imine and acyl chloride were added to
b
catholyte. Triethylamine (when necessary) added with imine.
c
Isolated yield of the mixture of diastereomers. The cis/trans ratio
was determined by 1H-NMR spectroscopy of the crude mixture.
d
e
In BMIM-PF6. In BMIM-CH3SO4.
When the imine was N-benzylidene-4-methoxyaniline, a
1 (a) A. P. Dove, R. C. Pratt, B. G. G. Lohmeijer, H. Li,
E. C. Hagberg, R. M. Waymouth and J. L. Hedrick, in
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VHC, Weinheim, 2006, p. 275; (b) V. Nair, S. Bindu and
V. Sreekumar, Angew. Chem., Int. Ed., 2004, 43, 5130.
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good yield (66%) of b-lactam was obtained with 0.5 equivalents
(theoretical) of carbene (entry 3), with a 9/91 cis/trans ratio.20
This result suggests that the NHC can behave both as an
organocatalyst and as a base (as we did not previously prepare
the ketene). Higher or lower amounts of NHC did not improve
the reaction (entries 2–5); if the reaction was carried out at rt, the
yield decreased to 3%, while if ultrasound irradiation was
used (instead of 60 1C), the yield was 35%. As reported in the
literature, the addition order of the reagents is very important
in this reaction; in fact, if the acyl chloride was added first, as
well as if imine and acyl chloride were mixed before the
addition, the b-lactam was isolated in lower yields (21% and
24% respectively). Also the anion of the IL plays a crucial role:
when CH3SO4ꢁ or PF6ꢁ were used instead of BF4ꢁ, the yields
ꢁ
decreased drastically (entries 6 and 7) (CH3SO4 seems to act
as methylating agent). The addition of a base (as reported in
the literature) does not improve the yields (32% with 1 eq. NEt3).
If N-benzylideneaniline (a less nucleophilic imine) is used, a
low yield of b-lactam is obtained (entries 8 and 9) and the
presence of a base, NEt3, seems necessary (entries 10–14); on
the other hand, the presence of NHC is essential, as NEt3
alone is not efficient (entry 10), and in this case the NHC
9 (a) L. Xiao and K. E. Johnson, J. Electrochem. Soc., 2003, 150,
E307; (b) B. Gorodetsky, T. Ramnial, N. R. Branda and J. A.
C. Clyburne, Chem. Commun., 2004, 1972; (c) J. P. Canal,
T. Ramnial, D. A. Dickie and J. A. C. Clyburne, Chem. Commun.,
2006, 1809; (d) M. Feroci, I. Chiarotto, M. Orsini, G. Sotgiu and
A. Inesi, Adv. Synth. Catal., 2008, 350, 1355.
10 M. Feroci, M. N. Elinson, L. Rossi and A. Inesi, Electrochem.
Commun., 2009, 11, 1523.
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11 (a) I. Chiarotto, M. Feroci, M. Orsini, G. Sotgiu and A. Inesi,
Tetrahedron, 2009, 65, 3704; (b) I. Chiarotto, M. M. M. Feeney,
M. Feroci and A. Inesi, Electrochim. Acta, 2009, 54, 1638.
12 M. Orsini, I. Chiarotto, M. N. Elinson, G. Sotgiu and A. Inesi,
Electrochem. Commun., 2009, 11, 1013.
Chem., 2006, 71, 6983; (c) F. P. Cossio, A. Arrieta and
M. A. Sierra, Acc. Chem. Res., 2008, 41, 925.
17 M. J. Earle and K. R. Seddon, Pure Appl. Chem., 2000, 72, 1391.
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19 X.-L. Tao, M. Lei and Y.-G. Wang, Tetrahedron Lett., 2007, 48,
5143.
20 The authors of ref. 18 report the action of IL N-butylpyridinium
tetrafluoroborate as a base in the Staudinger reaction (34% of
b-lactam in the absence of Yb(OTf)3). We are not able to exclude
such an eventuality also using BMIM-BF4 as an IL, which could
account for the non-stoichiometric amount of b-lactam (66%) with
respect to the amount of carbene (0.5 eq.). In our procedure the use
of NHC is, however, necessary (see Table 1, entry 3 vs. entry 1) to
obtain the product.
13 M. Orsini, I. Chiarotto, G. Sotgiu and A. Inesi, Electrochim. Acta,
2010, 55, 3511.
14 H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51.
15 For recent reviews on the Staudinger reaction: (a) S. France,
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2004, 37, 592; (b) A. Brandi, S. Cicchi and F. M. Cordero, Chem.
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