International Journal of Organic Chemistry, 2011, 1, 191-201
doi:10.4236/ijoc.2011.14028 Published Online December 2011 (
Copyright © 2011 SciRes. IJOC
Investigation of the Role of Electrogenerated
N-Heterocyclic Carbene in the Staudinger
Synthesis in Ionic Liquid
Marta Feroci
Department of Foundamental and Applied Sciences for Engineering (SBAI), Sapienza University of Rome, Rome, Italy
Received November 5, 2011; revised December 11, 2011; accepted December 24, 2011
Electrogenerated N-heterocyclic carbene (NHC), obtained by cathodic reduction of Bmim-BF4, behaves as
organocatalyst and base in the Staudinger synthesis from an acyl chloride and a deactivated imine in ionic
liquid to yield
-lactams. The effect of many parameters (temperature, amount of electricity, substituents,
presence of an external base) has been evaluated and a tentative mechanism for the Staudinger synthesis in a
very polar medium like the ionic liquid reported. The yields of isolated
-lactams are good, starting from
non-electrophilic imines, and predominantly trans lactams are obtained with a good diastereomeric ratio.
Keywords: Electrosynthesis, NHC, Staudinger Synthesis,
-Lactams, Organocatalyst, Ionic Liquid
1. Introduction
The use of ionic liquids (ILs) [1-3] as solvents in organic
reactions has, during the last two decades, undergone a
rapid acceleration as these salts can, in many cases, sub-
stitute the classical organic solvents (VOCs), which can
be considered air-pollutant due to their volatility. In fact,
ionic liquids have a virtually null vapour pressure and this
characteristic leads to their easy recycling.
One of the most studied and used class of ILs in or-
ganic chemistry is the imidazolium based one, due to its
air and water-stability, low cost and wide temperature
window of the liquid phase [4,5]. Nevertheless, these ILs
are not mere solvents. In fact, recently the “non inno-
cent” nature of imidazolium ILs has been described by
many authors, [6,7] as, in particular experimental condi-
tions, these cations can give rise to the formation of N-
heterocyclic carbenes (NHC). NHC can be easily pre-
pared by deprotonation of imidazolium cations [8] not
substituted in the 2-position (Scheme 1) [9-17].
N-Heterocyclic carbenes have been frequently used in
organic chemistry as ligands and, more recently, as orga-
nocatalysts [18-21] in many reactions, such as the annu-
lation of enals and sulfonylimines, [10,11] the Aza-Mo-
rita-Baylis-Hillman reaction of cyclic enones and N-to-
sylimines, [12] the benzoin condensation, [9,13] the Stet-
ter reaction, [9,13] the Mannich Reaction [15] and the
Staudinger reaction [16,17]. These stabilized singlet car-
benes behave as nucleophilic organic catalysts, due to the
presence of p-donor heteroatoms adjacent to the divalent
carbon atom [22].
ILs can be conveniently used in electrochemistry as
valid substituents of common solvent-supporting elec-
trolyte systems, as they are molten salts (and so, electro-
lytes) [23]. Electrochemistry can also be useful in the ge-
neration of NHCs from the corresponding IL. In fact, the
monoelectronic cathodic reduction of an imidazolium
cation leads to the formation of the corresponding car-
bene and molecular hydrogen (Scheme 2) [19,24-26].
Scheme 1. Chemical generation of NHCs.
Scheme 2. Electrochemical generation of NHCs.
Many reactions have been successfully catalyzed by
electrogenerated NHC, such as the Henry reaction, the
N-functionalization of benzoxazolones or oxazolidinones,
the benzoin condensation, the Stetter reaction and the cyc-
lization of linear amides to
-lactams [26,27].
-Lactams are well known molecules whose impor-
tance spreads over many fields, from industrial and che-
mical to pharmaceutical and biological [28,29]. There are
many reactions to form the azetidin-2-one ring, but pro-
bably the most important is the Staudinger synthesis. It is
described as a [2 + 2] ketene-imine cycloaddition (Sche-
me 3) [30].
Although reported for the first time in 1907, its me-
chanism is still now uncertain and object of many studies.
[31-34]. Both ketene and imine are species that can act as
either nucleophiles or electrophiles, depending on their
substituents, so the mechanism and outcome (cis or trans
-lactams) depend on the structure of the reagents. How-
ever, usually this is a reaction that needs catalysis. [35-37]
Among the catalysts, NHCs have been recently used in
the Staudinger synthesis [10,16,17,38-40] starting from
highly electrophilic imines (e.g., N-Boc, N-Ts and N-pNs
imines). These reactions are successfully carried out in
classical VOCs, using a disubstituted ketene (pre-pre-
pared) and an electrophilic imine, in the presence of an
NHC as organocatalyst.
As reported by Smith and coworkers, [17] the order of
addition of reactants is critical to the successful genear-
tion of
-lactams, the right order being ketene+NHC and
then the imine. In fact, it seems that in these conditions
(disubstituted ketene and electrophilic imine in aprotic
solvent) a NHC activation of ketene is probable, as con-
firmed by Ye and coworkers, [16] while the reaction
NHC-electrophilic imine leads to a stable adduct (in some
cases isolated). On the other hand, Wilhelm and cowork-
ers [38] add all reagents (N-pNs imine, ketene and NHC)
in toluene and obtain the desired
-lactam, proposing that
both activation of ketene and of imine are, in principle,
possible and their studies could not rule out one of them.
To the best of my knowledge, only two papers have
been published in which the Staudinger synthesis has
been carried out in ionic liquids, the first using ytter-
bium(III) triflate [41] as catalyst in N-butylpyridinium
Scheme 3. The Staudinger synthe sis.
tetrafluoroborate, while the second reports the use of an
IL-supported imine, [42] an acyl chloride and triethyl-
amine in 1-butyl-3-methylimidazolium hexafluorophos-
phate; in no case an NHC was used as an organocatalyst
in IL.
In a previous short communication, [43] our first re-
sults on a Staudinger synthesis in ionic liquids, from imi-
ne and acyl chloride, catalyzed by an electrogenerated
NHC were described. Here extension of the method and
a hypothesis of mechanism is reported. In this case, 1-
butyl-3-methylimidazolium tetrafluoroborate (Bmim-BF4)
acts both as a solvent and as a precatalyst.
2. Experimental
General 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/cm2. Electrolyses were carried out at
60˚C, under nitrogen atmosphere, using BMIM-BF4 as
anolyte and catholyte. After the consumption of the nu-
mber of Faradays per mol of imine reported in Tables 1
and 2, the current was switched off and imine (1 mmol)
was added to the catholyte under stirring; when the dis-
solution was complete, phenylacetyl chloride (1 mmol)
was added. The mixture was kept at 60˚C for 2 h. In the
cases in which triethylamine was necessary (see Tables
1 and 2), NEt3 was added to the catholyte with the imine.
The catholyte was extracted with diethyl ether, the sol-
vent was removed under vacuum and the residue was an-
alyzed by 1H-NMR and purified by flash-chromato-
graphy, affording the corresponding pure
-lactam. All
-lactams are known compounds and gave spectral data
in accordance with the ones reported in the literature.
Recycling of the catholyte: after the ethereal extraction,
the catholyte was kept under reduced pressure at 60˚C
for 1 hr to eliminate completely diethyl ether traces, then
it was reused for a new electrolysis.
Trans 1,3,4-Triphenylazetidin-2-one 2a. [44] 1H NMR
(200 MHz, CDCl3): 7.38 - 7.21 (m, 14H), 7.09 - 7.02
(m, 1H), 4.95 (d, J = 2.5 Hz, 1H), 4.27 (d, J = 2.5 Hz,
1H). 13C NMR (50 MHz, CDCl3): 165.6, 137.5, 137.4,
134.7, 129.3, 129.1, 129.0, 128.6, 127.9, 127.4, 125.9,
124.0, 117.2, 65.1, 63.7. C21H17NO: calcd. C 84.25, H
5.72, N 4.68; found C 83.84, H 6.03, N 4.52.
Trans 1-(4-Methoxyphenyl)-3,4-diphenylazetidin-2-
one 2b. [44] 1H NMR (200 MHz, CDCl3): 7.36 - 7.24
(m, 12H), 6.78 (d, J = 9.2 Hz, 2H), 4.89 (d, J = 2.2 Hz,
Copyright © 2011 SciRes. IJOC
1H), 4.24 (d, J = 2.2 Hz, 1H), 3.73 (s, 3H). 13C NMR (50
MHz, CDCl3): 164.9, 156.1, 137.6, 134.8, 131.0, 129.2,
129.0, 128.6, 127.8, 127.4, 125.9, 118.5, 114.3, 65.1,
63.8, 55.4. C22H19NO2: calcd. C 80.22, H 5.81, N 4.25;
found C 80.04, H 6.12, N 4.21.
Trans 1,4-bis(4-methoxyphenyl)-3-phenylazetidin-2-
one 2c. [44] 1H NMR (200 MHz, CDCl3): 7.36 - 7.27
(m, 9H), 6.93 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 9.2 Hz,
2H), 4.88 (d, J = 2.4 Hz, 1H), 4.25 (d, J = 2.4 Hz, 1H),
3.83 (s, 3H), 3.77 (s, 3H). 13C NMR (50 MHz, CDCl3):
165.2, 159.9, 156.1, 135.0, 131.1, 129.4, 129.0, 127.8,
127.5, 127.3, 118.6, 114.7, 114.3, 65.2, 63.6, 55.4, 55.3.
C23H21NO3: calcd. C 76.86, H 5.89, N 3.90; found C
76.67, H 6.11, N 3.77.
Trans 1-(4-methoxyphenyl)-4-(4-nitrophenyl)-3-ph-
enyl azetidin-2-one 2d. [45] 1H NMR (200 MHz, CDCl3):
8.28 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.41 -
7.24 (m, 7H), 6.84 (d, J = 9.0 Hz, 2H), 5.03 (d, J = 2.6
Hz, 1H), 4.26 (d, J = 2.6 Hz, 1H), 3.78 (s, 3H). 13C NMR
(50 MHz, CDCl3): 164.3, 156.6, 148.1, 144.9, 134.0,
133.3, 129.4, 128.6, 127.5, 126.9, 124.6, 118.5, 116.3,
65.3, 62.9, 55.5. C22H18N2O4: calcd. C 70.58, H 4.85, N
7.48; found C 70.41, H 4.93, N 7.32.
-2-one 2e. [46] 1H NMR (200 MHz, CDCl3): 7.46 -
7.43 (m, 3H), 7.35 - 7.26 (m, 4H), 6.86 - 6.82 (m, 2H),
5.48 (s, 1H), 3.78 (s, 3H). 13C NMR (50 MHz, CDCl3):
157.9, 157.3, 131.8, 129.9, 129.3, 129.2, 127.8, 119.5,
114.6, 84.2, 74.1, 55.5. C16H13Cl2NO2: calcd. C 59.65, H
4.07, N 4.35; found C 59.48, H 4.13, N 4.22.
Trans 1-benzyl-3,4-diphenylazetidin-2-one 2f. [47]
1H NMR (200 MHz, CDCl3): 7.43 - 7.20 (m, 15H),
4.99 (d, J = 14.8 Hz, 1H), 4.37 (d, J = 2.2 Hz, 1H), 4.22
(d, J = 2.2 Hz, 1H), 3.85 (d, J = 14.8 Hz, 1H). 13C NMR
(50 MHz, CDCl3): 168.3, 137.2, 135.6, 135.0, 129.1,
128.9, 128.8, 128.7, 128.6, 127.8, 127.6, 127.4, 126.5,
65.2, 63.1, 44.6. C22H19NO: calcd. C 84.31, H 6.11, N
4.47; found C 84.17, H 6.23, N 4.32.
1-benzyl-3,3-dichloro-4-phenylazetidin-2-one 2g. [46]
1H NMR (200 MHz, CDCl3): 7.47 - 7.44 (m, 3H), 7.36 -
7.33 (m, 3H), 7.28 - 7.23 (m, 2H), 7.18 - 7.13 (m, 2H),
4.98 (d, J = 14.8 Hz, 1H), 4.85 (s, 1H), 3.96 (d, J = 14.8
Hz, 1H). 13C NMR (50 MHz, CDCl3): 161.9, 133.5,
131.7, 129.9, 129.1, 128.8, 128.4, 128.1, 128.0, 84.9,
73.3, 45.0. C16H13Cl2NO: calcd. C 62.76, H 4.28, N 4.57;
found C 62.68, H 4.32, N 4.51.
Trans 3,4-diphenyl-1-p-tolylazetidin-2-one 2h. [48]
1H NMR (200 MHz, CDCl3): 7.41 - 7.36 (m, 10H),
7.28 - 7.24 (m, 2H), 7.10 - 7.06 (m, 2H), 4.94 (d, J = 2.6
Hz, 1H), 4.27 (d, J = 2.6 Hz, 1H), 2.29 (s, 3H). 13C NMR
(50 MHz, CDCl3): 165.3, 137.7, 134.9, 134.8, 133.7,
129.6, 129.3, 129.0, 128.6, 127.9, 127.5, 125.9, 117.2,
65.1, 63.7, 20.9. C22H19NO: calcd. C 84.31, H 6.11, N
4.47; found C 84.02, H 6.13, N 4.32.
Reaction of electrogenerated 1-butyl-3-methylimi-
dazol-2-ylidene with imine 1b.
Preparative electrolysis was carried out as previously
described and the current was switched off after 97 C (1
mF). Then, 1 mmol of 4-benzylidene-4-methoxyaniline 1b
was added and the catholyte was kept under stirring at
60˚C for two hours. Then the usual workup gave a crude
that was purified by crystallization from hexane. The
mother liquor gave a mixture of imine 1b and dimer 1-
-2,3-dihydro-3- methyl-1H-imidazole 5 (every attempt to
purify 5 led to its decomposition) and column chromato-
graphy of the precipitate giave N-(4-methoxy phenyl)
benzamide 3 and N-((1-butyl-1H-imidazol-2-yl) (phenyl)
methylene)-4-methoxybenzenamine 4.
N-(4-methoxyphenyl)benzamide 3. [49] 1H NMR (200
MHz, CDCl3): 7.90 - 7.85 (m, 2H), 7.8 (bs, 1H), 7.59 -
7.49 (m, 5H), 6.92 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H). 13C
NMR (50 MHz, CDCl3): 165.6, 156.6, 135.0, 131.0,
129.1, 127.4, 126.6, 122.5, 114.5, 55.7. C14H13NO2:
calcd. C 73.99, H 5.77, N 6.16; found C 73.78, H 5.85, N
N-((1-butyl-1H-imidazol-2-yl)(phenyl)met hylen e)-4-
methoxybenzenamine 4. [50] 1H NMR (200 MHz, CD-
Cl3): 7.91 - 7.87 (m, 2H), 7.69 - 7.36 (m, 7H), 7.21 -
7.17 (m, 2H), 3.67 (t, J = 7.0 Hz, 2H), 3.19 (s, 3H), 1.70 -
1.62 (m, 2H), 1.41 - 1.34 (m, 2H), .96 (t, J = 7.2 Hz, 3H).
13C NMR (50 MHz, CDCl3): 159.6, 158.9, 143.4, 139.0,
131.9, 129.1, 128.8, 127.0, 124.9, 124.6, 120.1, 60.3,
39.2, 30.0, 19.8, 13.4. C21H23N3O: calcd. C 75.65, H 6.95,
N 12.60; found C 75.33, H 7.18, N 12.32.
1-butyl-2-(1-butyl-2,3-d ihydro-3-methyl-1H-imidaz
ol-2-yl) -2,3-dihydro-3-methyl-1 H-imidazole 5 in mix-
ture with starting imine 1b. 1H NMR (200 MHz, CDCl3):
6.10 - 6.08 (m, 4H), 3.75 (d, J = 5.9 Hz, 2H), 3.51 (app.
t, J = 7.2 Hz, 4H), 3.16 (s, 3H), 1.59 - 1.52 (m, 4H), 1.32 -
1.20 (m, 4H), 0.85 (t, J = 7.2 Hz, 6H). 13C NMR (50
MHz, CDCl3): 114.3, 113.9, 111.1, 109.9, 43.2, 31.5,
30.3, 19.7, 13.6.
Reaction of electrogenerated 1-butyl-3-methy-limi-
dazol-2-ylidene with phenylacetyl chloride.
Preparative electrolysis was carried out as previously
described and the current was switched off after 97 C (1
mF). Then, 1 mmol of phenylacetyl chloride was added
and the catholyte was kept under stirring at 60˚C for two
hours. Then column chromatography of the catholyte
gave 1-(1-methyl-1H-imidazol-2-yl)-2-phenylethenol 6.
1-(1-methyl-1H-imidazol-2-y l)-2-phenylethenol 6. [51]
1H NMR (200 MHz, CDCl3): 7.41 - 7.34 (m, 5H), 7.22 -
7.21 (m, 3H), 6.73 (s, 1H), 3.89 (s, 3H). 13C NMR (50 MHz,
CDCl3): 172.1, 132.6, 130.9, 130.1, 129.5, 129.1, 127.9,
119.7, 114.6, 41.0. GC-MS (EI) m/z: M+. absent, 144 (1%),
118 (26%), 91 (100%), 77 (2%), 65 (18%), 51 (6%).
Copyright © 2011 SciRes. IJOC
Copyright © 2011 SciRes. IJOC
3. Results and Discussion
In this work, non-electrophilic imines were used as it is
reported that strongly electrophilic imines form an ad-
duct with NHC that seems to be rarely reversible [10,16]
(especially in a very polar solvent which should stabilize
the zwitterionic adduct). Moreover, having previously
proved the behaviour of this NHC as a base, [52,53] an
acyl chloride was used instead of pre-generating the cor-
responding ketene. NHC (1-butyl-3-methylimidazol-2-
ylidene) was obtaind by galvanostatic electrochemical
reduction of Bmim-BF4 (Scheme 2, R1 and R2: Me and
Bu). In Table 1, entries 1-11, the results are reported
using phenylacetyl chloride and N-benzylidene-4-meth-
oxy aniline as reagents. The best result (66% of
entry 3) was obtained using 0.5 equivalents (theoretical,
admitting a 100% current yield) of carbene, with a good
diastereomeric ratio (9/91 cis/trans ); higher or lower
amounts of carbene lead to worse results (entries 2-5; the
effect of high amounts of carbene seems not readily ex-
plainable in a ketene-imine model of reaction, in which
the base necessary to yield the ketene should be stoichi-
ometric). The nature of the counter ion of the Bmim+ ca-
tion seems to be crucial, with a noticeable decrease in the
yields of
-lactam using Bmim-PF6 or Bmim-CH3SO4
(entries 6 and 7).
As reported in the literature [17] (and also in these ex-
periments), the order of addition of the reagents seems
very important, but we found an inverted order; the best
results were obtained adding the imine to the NHC-IL
solution and, after dissolution, adding the acyl chloride.
If phenylacetyl chloride is added to NHC-IL and subse-
quently the imine (entry 8), the yield lowers to 21%,
while adding a mixture of acyl chloride-imine-IL to NHC-
IL (entry 9) only 24% yield of
-lactam is obtained. Also,
the best method to furnish energy to this reaction seems
to be heating at 60˚C (3% at room temperature, entry 11),
while using ultrasound irradiation just 35% of
was obtained (entry 10). When the best reaction condi-
tions (entry 3) were used with a less nucleophilic imine
(N-benzylideneaniline, entries 12 - 18), only 16% of the
-lactam was reached (entry 13). In this
case, the presence of an external base seems necessary
and the addition of triethylamine (1 equivalent) gave a
Table 1. NHC-catalyzed Staudinger synthesis in Bmim-BF4a.
Bmim-BF4, NEt3,
60 C, 2h
Ph Ph
1a: Ar = Ph
1b: Ar = 4-MeO-C6H4
2a: Ar = Ph
2b: Ar = 4-MeO-C6H4
Entry Ar F/molb NEt3c
-lactamd cis/transe PhCHOf amideg
1 p-MeO-C6H4 - - - - 32% 16%
2 p-MeO-C6H4 0.30 - 36% 10/90 35% 10%
3 p-MeO-C6H4 0.50 - 66% 9/91 10% 11%
4 p-MeO-C6H4 1.00 - 38% 16/84 18% 14%
5 p-MeO-C6H4 1.70 - 35% 11/89 43% 39%
6h p-MeO-C6H4 0.50 - 4% trans 21% 12%
7i p-MeO-C6H4 0.50 - 33% 13/87 8% 6%
8j p-MeO-C6H4 0.50 - 21% 7/93 63% 37%
9k p-MeO-C6H4 0.50 - 24% 6/94 12% 12%
10l p-MeO-C6H4 0.50 - 35% 11/89 21% 13%
11m p-MeO-C6H4 0.50 - 3% trans 39% 38%
12 Ph 0.15 - - - 28% 28%
13 Ph 0.50 - 16% trans 26% 18%
14 Ph - 1.0 3% trans 20% 16%
15 Ph 0.50 0.3 42% 14/86 47% 31%
16 Ph 0.50 1.0 22% trans 36% 28%
17 Ph 0.15 1.0 64% 11/89 18% 9%
18 Ph 0.15 0.5 55% 11/89 30% 11%
aA part of this table has already been reported in ref. 18. Divided cell, Pt anode and cathode, Bmim-BF4 as solvent/reagent (2 ml as catholyte and 1 ml as
anolyte), N2 atmosphere, 60˚C, galvanostatic conditions (15 mA·cm–2); at the end of the electrolysis, imine (1 mmol) and then phenylacetyl chloride (1 mmol)
were added to the catholyte. bWith respect to starting imine. cTriethylamine (1 equivalent) was added to the catholyte with imine. dIsolated yields of the mixture
of diastereoisomes. e The cis/trans ratio was determined by 1H-NMR spectroscopy of the crude mixture. fBenzaldehyde was obtained by decomposition of imine.
gAmide was obtained by reaction of phenylacetyl chloride with amine obtained by decomposition of imine. hIn Bmim-PF6. iIn Bmim-CH3SO4. jPhenylacetyl
chloride was added before the addition of imine. kPhenylacetyl chloride and imine were mixed together in a small amount of ionic liquid before their addition to
the catholyte. lUltrasound irradiation was used, instead of keeping the reaction mixture at 60˚C. m Reaction carried out at room temperature.
good yield (entry 17, 64% with a cis/trans ratio of 11/89)
only lowering the amount of carbene to 0.15 theoretical
equivalents. Again, it is diffucult to understand the dif-
ferent behaviour of NHC varying the imine in a ketene-
imine model of reaction (NHC should deprotonate the
same acyl chloride in both cases).
The presence of NHC as an organocatalyst seems ne-
cessary also using triethylamine; in fact, using solely
NEt3 in Bmim-BF4 only 3% of
-lactam was isolated
(entry 14). It has to be underlined that Bmim-BF4 be-
haves with imines not only as a solvent. In fact, when
this reaction is carried out in the absence of both NHC
and triethylamine (Table 1, entry 1), part of the starting
imine decomposes into its constituents (aldehyde and
amine) and the same behaviour is obtained in the pres-
ence of NHC and base (Table 1, all other entries), al-
though in these cases it is difficult to rule out a participa-
tion of these two reagents. To better understand this re-
action, which seems to be hardly explained with reported
models, this methodology was extended to imines of dif-
ferent nucleophilicity and to dichloroacetyl chloride us-
ing two different sets of experimental conditions (depen-
ding on the starting imine). These results are reported in
Table 2. The yields of
-lactams obtained in the absence
of triethylamine are sometimes higher than the stoi-
chiometric 50% value (Table 2, entries 3, 5, 9, 11 and
13), assuming that electrogenerated NHC acts as a base
with acyl chloride to yield the corresponding ketene; in
fact, hypothesizing a current yield of 100% in the elec-
troreduction of the Bmim+ cation, with the generation of
0.5 equivalents of carbene in a monoelectronic process
(0.5 F/mol of imine, odd entries of Table 2), the theo-
retical maximum amount of ketene (obtained by NHC-
deprotonation of the acyl chloride) is 0.5 equivalents,
corresponding to a maximum yield of 50% of
These results are therefore not in line with a ketene-
imine model of reaction. It should be considered, how-
ever, that Bmim-BF4 is not a neutral solvent for imines;
in fact (Table 1, entry 1), as previously stated, this IL is
able to decompose this molecule into its constituents,
aldehyde and amine (and the amine is isolated as amide,
after reaction with the acyl chloride). It is therefore pos-
sible that the amine, which derives from the decomposi-
tion of the imine, takes part in the Staudinger synthesis,
enhancing the yields.
Table 2. NHC-catalyzed Staudinger reac tion in Bmim-BF4a.
Bmim-BF4, NEt3,
60 C, 2h
Entry R1 R
2 R
3 R
4 F/molb NEt3c
-lactamd cis/transe
1 Ph Ph Ph H 0.50 - 2a, 16% trans
2 Ph Ph Ph H 0.15 1 eq. 2a, 64% 11/89
3 Ph 4-MeO-C6H4 Ph H 0.50 - 2b, 66% 9/91
4 Ph 4-MeO-C6H4 Ph H 0.15 1 eq. 2b, 32% trans
5 4-MeO-C6H4 4-MeO-C6H4 Ph H 0.50 - 2c, 65% 6/94
6 4-MeO-C6H4 4-MeO-C6H4 Ph H 0.15 1 eq. 2c, 22% trans
7 4-NO2-C6H4 4-MeO-C6H4 Ph H 0.50 - 2d, 23% 22/78
8 4-NO2-C6H4 4-MeO-C6H4 Ph H 0.15 1 eq. 2d, 33% trans
9 Ph 4-MeO-C6H4 Cl Cl 0.50 - 2e, 63%
10 Ph 4-MeO-C6H4 Cl Cl 0.15 1 eq. 2e, 14%
11 Ph Ph-CH2 Ph H 0.50 - 2f, 56% 21/79
12 Ph Ph-CH2 Ph H 0.15 1 eq. 2f, 22% 35/65
13 Ph Ph-CH2 Cl Cl 0.50 - 2g, 61%
14 Ph Ph-CH2 Cl Cl 0.15 1 eq. 2g, 30%
15 Ph 4-Me-C6H4 Ph H 0.50 - 2h, 9% trans
16 Ph 4-Me-C6H4 Ph H 0.15 1 eq. 2h, 68% 9/91
aDivided cell, Pt anode and cathode, Bmim-BF4 as solvent/reagent (2 ml as catholyte and 1 ml as anolyte), N2 atmosphere, 60˚C, galvanostatic conditions (15
mA·cm–2); at the end of the electrolysis, imine (1 mmol) and then acyl chloride (1 mmol) were added to the catholyte. bWith respect to starting imine.
cTriethylamine (1 equivalent) was added to the catholyte with imine. dIsolated yields of the mixture of diastereoisomes. eThe cis/trans ratio was determined by
1H-NMR spectroscopy of the crude mixture.
Copyright © 2011 SciRes. IJOC
Following this hypothesis, it is possible to correlate
the yields of
-lactams with the basicity of the amine re-
leased in the cathodic solution from the decomposition of
starting imine. Concerning this matter, Johnson [1] re-
ports that “Bases in ionic liquids appear to act in accor-
dance with their gas phase proton affinities” instead of
behaving in line with their pKbs in water. In Table 3 the
values of pKa of the conjugate ammonium ions (BH+) are
reported, in water and DMSO, along with the values of
the gas phase proton affinities of the amines (B) used in
this paper.
The three basicity scales are quite concordant. From
Table 2, it can be seen that in the cases of aniline and 4-
Me-aniline (entries 1 and 15) the yields of
-lactams are
low (16% and 9%, respectively), while adding NEt3 (en-
tries 2 and 16) these products are obtained in good yields
(64% and 68%, respectively). These last experiments
confirm that the yields of
-lactams (in all cases of this
paper) are not dependent on the imine structure, but on
the strength of the base. In the cases of 4-MeO-aniline
and benzylamine (Table 2, entries 3 and 5) the yields of
-lactams (in the absence of NEt3) are higher than stoi-
chiometric (66% and 65%, respectively), explicable only
admitting that the amine (which derives from the de-
composition of starting imine) plays a role in this reac-
tion and that in these two cases the amines have a suffi-
cient basicity to carry on the synthesis. An excess of base
leads to the decomposition of the starting material (Ta-
ble 2, entries 4 and 6, synthesis carried on in the pres-
ence of triethylamine) and to a lowering in the yields of
product (32% and 22%, respectively).
In this way, it can be therefore located a border in the
basicity value (between 215 and 217 kcal mol–1, if ex-
pressed by means of gas phase proton affinity), below
which the amine present in the reaction mixture is not
able to catalyze this Staudinger synthesis.
In order to have an insight into the mechanism of this
NHC-catalyzed Staudinger synthesis in IL, we have car-
ried out two different reactions, the first between elec-
trogenerated NHC and imine 1b and the second between
Table 3. pKa Values of ammonium ions and gas phase pro-
ton affinities of amines [54-60].
Entry Amine (B) pKa (BH+)
in H2O
pKa (BH+)
(kcal mol–1)a
1 aniline 4.58 3.82 213.39
2 4-Me-aniline 5.08 4.5 215.13
3 4-MeO-aniline 5.34 5.08 216.96
4 benzylamine 9.38 10.16 218.07
5 triethylamine 10.72 9.07 229.1
aGas phase proton affinities; the values are reported in kcal·mol–1 and not in
kJ·mol–1 to be faithful with the original literature.
NHC and phenylacetyl chloride. These experiments were
carried out to understand if electrogenerated NHC reacts
preferentially with one of the two reagents.
When NHC reacts with N-benzylidene-4-methoxyani-
line 1b, the expected product of coupling between the two
reagents (a sort of Breslow’s intermediate [61] between
NHC and imine, see Scheme 4) has not been isolated nor
evidenced. This kind of intermediate has been previously
reported by Ye and coworkers [12,16] using N-Ts imines
and it is quite stable, while using a non electrophilic im-
ine this addition has been obtained exclusively by in-
tramolecular way [62] (a molecule containing both car-
bene and imine moieties).
On the other hand, we decided to use non-electrophilic
imines just to avoid the formation of a non-reversible ad-
duct NHC-imine. From this reaction (electrogenerated NHC
and imine) three products (along with unreacted imine),
after workup and column chromatography, have been
obtained (see Figure 1). It is speculated that both prod-
ucts 3 and 4 have reference with the adduct of Scheme 4;
in fact (Scheme 5) this adduct can add a molecule of
water and, in a base-catalyzed decomposition, give rise
to the formation of amide 3. Product 4 is less easy to be
explained and it seems closely correlated to the adduct of
Scheme 4, but it has to be kept in mind that the electro-
chemical reduction of imidazolium salts leads often to
dealkylation products. [24]
Scheme 4. Addition reaction between NHC and imine 1b.
Scheme 5. Hypothesis of mechanism of formation of prod-
uct 3.
Copyright © 2011 SciRes. IJOC
Figure 1. Products of the reaction between NHC and imine 1b.
Product 5, finally, seems to derive from a dimerization
reaction during the electrochemical process. [63] It has to
be stressed that this dimerization reaction is not active
(only traces are detected) when both reagents (imine and
acyl chloride) are added to the catholyte and the Staud-
inger product is obtained.
The reaction between electrogenerated NHC and
phenylacetyl chloride gave, among many decomposition
products, compound 6 (Figure 2).
The formation of this molecule can be explained hy-
pothesizing the reaction between NHC and the acyl chlo-
ride (Scheme 6), with a successive Hofmann elimination.
Intermediates similar to I-2 have been hypothesized by
many authors, [11,15,64,65] but never isolated. It cannot
be excluded that product 6 is an artefact of the column
chromatography used trying to isolate possible addition
products. However, Townsend and coworkers [66] report
that the hydrolysis of a 2-acylated NHC leads to the for-
mation of the corresponding carboxylic acid; indeed we
evidenced the formation of phenylacetic acid in this ex-
periment, but we cannot exclude a simple hydrolysis of
acyl chloride during the workup.
Figure 2. Pr oduct of the reaction between NHC and phe ny-
lacetyl chloride.
Scheme 6. Hypothesis of mechan ism of formation of product 6.
From these results, it seems difficult to understand the
mechanism of this Staudinger synthesis. It is speculated
that that the first reaction of electrogenerated NHC is not
with acyl chloride to yield the corresponding ketene,
both because if the acyl chloride is added to the catholyte
before the imine,
-lactam can be isolated in very low
yields and because the formation and yields of
depend exclusively on the nature of amine and not on the
nature of the imine present in the reaction mixture (see
Table 2, entries 1 vs 2 and 15 vs 16), for the same acyl
chloride. It is thus probable that NHC reacts at first with
imine (giving the non stable intermediate I-1, reported
also in Scheme 4) and successively this intermediate
reacts with the acyl chloride to give intermediate I-3
(Scheme 7).
Intermediate I-3 has to be deprotonated in the 2-po-
sition (with respect to the carbonyl group) to yield the
-lactam; the “acidic” methylene should
suffer from the distal effect of the substituents on the ni-
trogen atom, [67] i.e. the lone pair of electrons of the ni-
trogen atom of intermediate I-4 can partecipate in reso-
nance with the carbonyl group: the more the lone pair is
available, the more the stabilization of the enolate anion
is effective, [68] following the trend for the gas phase
proton affinity reported in Table 3.
Many papers about the stereochemical outcome of the
Staudinger synthesis are reported, trying to indentify the
factors that influence the cis/trans selectivity. Xu and
coworkers [69] report that, being the Staudinger synthe-
sis a multi step one, involving the addition of imine and
ketene to give a linear zwitterionic intermediate (I-4, in
Scheme 7. Possible mechanism of electrogenerated NHC-ca-
talyzed Staudinger synthesis in ionic liquid.
Copyright © 2011 SciRes. IJOC
our hypothesis) and the subsequent ring closure of this
intermediate (Scheme 3), “the product ratio (cis/trans)
only depends on the rate constants of the direct ring clo-
sure (k1) and the isomerization (k2)”. In fact, the zwit-
terionic intermediate can isomerize by rotation along the
N-C bond of the imine portion of the intermediate itself.
It seems that when the ring closure of the zwitterion is
fast, a cis
-lactam is obtained, when it is slow (in com-
parison with the isomerization) a trans product is gained.
The competition between these two reactions relies on
electronic effects of the substituents on imine and ketene,
and on the steric hindrance of the same.
The solvent can play a role in this reaction; in particu-
lar, apolar solvents favour cis
-lactams, while polar
solvents favour tran s ones, probably because polar sol-
vents stabilize the zwitterionic intermediate, permitting
its isomerization. The solvent of this reaction is an ionic
liquid, highly polar, and the main product is a trans -
lactam, on line with this theory.
As regards the possibility of recycling the cathodic io-
nic liquid after the isolation of the products, the IL used
in Table 2, entry 3, was kept under vacuum (to eliminate
residual diethyl ether) and used for a new electrolysis. In
this case, however, the yield in
-lactam fell to 29%, and
only traces of product were obtained during the third
cycle. This is probaly due to a gradual degradation of the
ionic liquid during the cathodic reduction, with the for-
mation of by-products which could interfere with this
4. Conclusions
The first example of synthesis of
-lactams via Staud-
inger synthesis in ionic liquid catalyzed by an N-he-
terocyclic carbene is described. This NHC is easily ob-
tained by cathodic reduction of Bmim-BF4, under galva-
nostatic conditions, and it behaves as base and/or nucleo-
philic organocatalyst (so, under these experimental con-
ditions, IL plays the double role of solvent and precata-
lyst). Good yields of
-lactams, in predominantly trans
configuration have been obtained starting from non elec-
trophilic imines and acyl chloride and a hypothesis of
mechanism is given, not involving the formation of a ke-
5. Acknowledgements
This study was supported by MIUR and CNR (Rome).
The author thanks Mr. Marco Di Pilato for his contribu-
tion to the experimental part of this work.
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