A green way to γ-lactams through a copper catalyzed ARGET-ATRC in ethanol and in the presence of ascorbic acid

Article abstract of DOI:10.1016/j.tet.2010.11.025

A 'green' ARGET-ATRC, for the CuCl[PMDETA] catalysed cyclo-isomerization of N-allyl-α-polychloroamides to γ-lactams is described. The process works efficiently (yields 78-96%), uses a bio-solvent, as ethanol, and exploits the reducing feature of ascorbic acid to limit, at a low level (2-4%), the amount of catalyst. To preserve the efficacy of the catalytic cycle, addition of Na₂CO₃ is essential, which quenches the HCl released during the CuCl[PMDETA] regeneration step. Profitable features of the process are: mild reaction temperatures (25-37 °C), relatively short reaction times (usually 5 h) and low solvent volumes (2 mmol of substrate/mL of ethanol). The method, upon stoichiometric adjustment, was also used for the synthesis of α,β-unsaturated-γ-lactams from N-(2-chloroallyl)-α- polychloroamides, via a tandem process involving an ATRC and a reductive [1,2]-elimination. Copyright

Full text of DOI:10.1016/j.tet.2010.11.025

Tetrahedron 67 (2011) 408e416
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A green way to
g
-lactams through a copper catalyzed ARGET-ATRC in ethanol
and in the presence of ascorbic acid
,
a
Roberto Casolari a, Fulvia Felluga b, Vincenzo Frenna c, Franco Ghelfi a , Ugo M. Pagnoni ,
*
Andrew F. Parsons d, Domenico Spinelli e
a
ꢀ
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, via Campi 183, I-41125 Modena, Italy
b
ꢀ
Dipartimento di Scienze Chimiche, Universita degli Studi di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy
c
ꢀ
ꢀ
Dipartimento di Chimica Organica ‘E.Paterno’, Universita degli Studi di Palermo, Viale delle ScienzedParco d’Orleans II, I-90128 Palermo, Italy
d Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
e Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum, Via Selmi 2, I-40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A ‘green’ ARGET-ATRC, for the CuCl[PMDETA] catalysed cyclo-isomerization of N-allyl-a-polychloroamides
Received 1 October 2010
Accepted 4 November 2010
Available online 11 November 2010
to g-lactams is described. The process works efficiently (yields 78e96%), uses a bio-solvent, as ethanol, and
exploits the reducing feature of ascorbic acid to limit, at a low level (2e4%), the amount of catalyst. To
preserve the efficacy of the catalytic cycle, addition of Na2CO3 is essential, which quenches the HCl released
during the CuCl[PMDETA] regeneration step. Profitable features of the process are: mild reaction tem-
peratures (25e37 ꢀC), relatively short reaction times (usually 5 h) and low solvent volumes (2 mmol of
substrate/mL of ethanol). The method, upon stoichiometric adjustment, was also used for the synthesis of
Keywords:
Halocompounds
ATRC
a,
b
-unsaturated-
g
-lactams from N-(2-chloroallyl)-
a
-polychloroamides, via a tandem process involving an
g-Lactams
ATRC and a reductive [1,2]-elimination.
CuCl
Ascorbic acid
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
generating a radical species and thereby increasing the oxidation
state of the metal by one (Mnþ1LmX). The radical intermediate, in
the next step, adds to the olefinic substrate yielding a new radical.
Finally, the adduct radical is quenched by halogen transfer from
The addition of C-radicals, obtained by CeX bond homolysis, to
the olefinic C]C double bond has nowadays become a standard
technique in synthetic organic chemistry.1 Two common strategies
that can be adopted to accomplish this goal are: (1) the method of
Giese, where metal hydrides (generally tin hydrides) are used2 and
(2) the atom transfer radical addition (ATRA).3 The second alter-
native is not only safer (as toxic tin compounds are excluded), but it
is synthetically more appealing, since the reaction products recover
the versatile halogen functionality that is present in the starting
material.4
M
nþ1LmX (the metal complex in its oxidized state), regenerating
the active form of the catalyst (MnLm) and affording the reaction
product. The atom transfers to and from the metal complex follow
a concerted mechanism, via an inner-sphere electron transfer
process.7,8
From the seminal studies of Kharash,5 where the ATRA was
carried out with the help of peroxide initiators, the technique has
substantially improved with the introduction of transition metal
complexes, which behave as ‘single electron transfer’ redox cata-
lysts.6 The recognized mechanism for the transition metal cata-
lyzed ATRA (TMC-ATRA) consists of three elementary steps
(Scheme 1).7 First the metal complex MnLm, in its reduced state,
abstracts (reversibly) a halogen atom from the halo-precursor,
Scheme 1. Atom transfer radical addition mechanism.
The effectiveness and high selectivity of the TMC-ATRA is due to
the capability of the system to maintain the radical species at a low
concentration, guaranteeing that undesired radical side reactions
* Corresponding author. Tel.: þ39 059 2055049; fax: þ39 059 373543; e-mail
address: franco.ghelfi@unimore.it (F. Ghelfi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.025

R. Casolari et al. / Tetrahedron 67 (2011) 408e416
409
are minimal. Three variations of the method are known (Scheme 2):
(1) the inter-molecular ATRA,9 (2) the atom transfer radical poly-
merization (ATRP)10 and (3) the atom transfer radical cyclization
(ATRC).11
Scheme 3. Methods for the regeneration of the active form of the catalyst.
Scheme 2. Basic types of atom transfer radical reactions.
ATRC can be considered, on the contrary, occasional.7 The only
examples, reported thus far, involve, for the ARGET-ATRA, the
employment of Mg0, as reducing reagent, with a Ru(II)12a,13a,17 or Os
(II)17c catalyst, and for the ICAR-ATRA, the use of the radical initi-
ators AIBN or 2,20-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-
70) with Cu(I) or Ru(II) redox complexes.18 Moving on to ATRC, the
picture is even more sparse and we retrieved only five examples
from the literature; four concerned the ARGET method,12a,b,13a,17c
with Ru(II) or Os(II)/Mg0 systems, and only one the ICAR ap-
proach, with CuCl complexes/AIBN.19
In the ATRA the halo-reagent (R-X) is usually employed in excess
in comparison with the radicophilic partner (C]C), to ensure
a complete conversion of the alkene and, at the same time, help to
control the parasitic oligomerization process. The opposite is true
for the ATRP. Here, on the contrary, the alkene is present in very
large excess, the target being now the generation of a polymeric
material. An even different situation is encountered for the ATRC,
where the radical precursor and radicophilic components are
tethered. Notwithstanding the similar reaction mechanisms, these
differences mean that the experimental conditions cannot simply
be translated among the three ATRA types, but instead require
them to be adjusted. For example, it can be inferred from the lit-
erature that the amount of the same redox catalyst has to be sub-
stantially increased (with respect to the halo-precursor) moving
from ATRA to ATRC,12a,b from ATRC to ATRP12cee and from ATRA to
ATRP;12feh a few exceptions are reported, though.13
g
-Lactams are central structures in organic chemistry20 either
for their biological properties21a,b or as intermediates in syn-
thesis.21cee,22gei Their assembly through a copper catalyzed ATRC
(Scheme 4) of N-allyl-
a-polichloroamides A has become nowadays
one of the most valuable methods of preparation.11,22
Although ATRP is the youngest among the ATRA methods, being
discovered independently by Matyjaszewski14a and Sawamoto,14b
only 15 years ago, it is by far the most studied and applied ATRA
method, since it allows the preparation of polymers with well de-
fined compositions, architectures and functionality.10 This is the
result of the controlled nature of this process, which is an example
of ‘living polymerization’.
The most significant advances, regarding the structure of the
redox catalysts and of the variables, which influence their activity,
are essentially due to researchers operating in the field of ATRP.10
Recently, many efforts have been devoted to the development of
‘green’ methods, mainly targeted to the containment of the amount
of catalyst required for controlling the polymerization.10cee The
addition of a reducing agent to these systems appeared the most
effective solution. The catalytic cycle continues in the presence of
a reducing agent as this reduces the metal complex in its oxidized
state, which, otherwise, progressively builds up, because of ‘para-
sitical’ side reactions: radical-radical couplings or radical re-
ductions. Regeneration of the catalyst can be achieved in two ways
(Scheme 3).10cee In one case, known as ‘initiator for continuous
activator regeneration’ (ICAR)-ATRP, free radicals are slowly and
steadily fed to the polymerizing mixture by the decomposition of
conventional radical initiators, e.g., azoisobutyronitrile (AIBN).
These interact with the Mnþ1LmX, which is accumulating, and re-
duce it into the active form MnLm.15 In the other case, more com-
mon and named ‘activators regenerated by electron transfer’
(ARGET)-ATRP, non-radical reducing reagent are used,10cee typi-
cally Sn(ethylhexanoate)2 [Sn(EH)2],16aef although ascorbic
acid16g,h or aliphatic tertiary amines have found some use.16i,j
Although these techniques have been fully incorporated into the
ATRP dominion, their adoption in the companion fields of ATRA or
Scheme 4. Copper catalyzed ATRC of N-allyl-a-polychloroamides to g-lactams (in bold
are highlighted the cis and trans conformation around the amide bond).
Main features of the process are: (i) the mild reaction condi-
tions, (ii) easy execution and work-up, (iii) high yields, (iv) use of
a catalytic amount of copper and, last but not least, (vi) the
preservation of all the starting CeCl functionalities in the het-
erocyclic skeleton. Notwithstanding ruthenium(II) complexes
have found some use in the TMC-ATRC, cuprous halide complexes
with polydentate nitrogen ligands are by far the preferred cata-
lysts,7,11,22a because they are both cheap and easy to prepare.
Moreover they are versatile since the redox features can be simply
adjusted by changing the ligand.12e,23 When using particularly
reactive amides or a nucleophilic solvent, like DMF, the ligand can
be left out.22a
Two pivotal points of the TMC-ATRC of amides D are of note.
First, the presence of a substituent R (cyclization auxiliary) on the N
atom of the amide A is an essential structural requisite, since it
allows B to adopt the correct conformation for the cyclization
(Scheme 4).22,24 Second, the C-3 stereogenic center of D is config-
urationally unstable under the reaction conditions, and is epi-
merized by the same ATRC catalyst (Scheme 5).22b,c,25

410
R. Casolari et al. / Tetrahedron 67 (2011) 408e416
active12e,23 and as a tripodal ligand is cheap and commercially
available.
The reaction conditions of the green ARGET-ATRC with the
catalytic system CuCl[PMDETA]/AA/Na2CO3 were tested using
N-allyl-N-benzyl-2,2-dichloropropanamide (Scheme 7), and
1
Table 1 shows the most significant results we obtained.
Scheme 5. Epimerization of the C-3 center of g-lactams D.
Currently no real ‘environmental friendly’ ATRC procedures are
available for the preparation of -lactams. The use of unsafe sol-
g
vents, such as acetonitrile, CH2Cl2, sym-dichloroethane and toluene
pose environmental concerns particularly on scale-up. Neither the
Scheme 7. ARGET-ATRC of the N-allyl-2,2-dichloroamide 1.
published ARGET12a,b,13a or ICAR19 ATRC of N-allyl-
a-halogen-
oamides can be regarded as a viable solution, although the catalyst
amount was substantially reduced. Fatal flaws are: (i) the use of
expensive catalysts [CuCle(Me6-tren), CuCleTPA or RuCl2Cp$
(PPh3)] at a relatively high level (1e5 mol %), (ii) the utilization of
CH2Cl2 or toluene, as solvents, (iii) the low concentration of sub-
strate in the reaction mixture (0.15 M) and (iv) the high percentage
of the reducing additives, which increase from 5 mol % for AIBN
(toxic) to even 3000e4000 mol % for Mg0.
We thus resolved to develop a greener and sustainable TMC-ATRC
procedure to obtain g-lactams. In this articlewe show that this canbe
successfully accomplished with a copper catalysed ARGET-ATRC,
using ascorbic acid (AA) as reducing agent, in ethanol. The method
Table 1
ARGET-ATRC of 1a
No.
1
CuCl/Lb
(mol %)
AA/Na2CO3
(mol %)
T (ꢀC)
t (h)
Convc
(%)
1ac,d
(%)
(mmol)
1
2
3
4
5
6
7
4
4
4
4
4
8
8
4/4
4/4
5/5.5
0/0
0/0
rt
rt
31
rt
rt
2
2
6
2
2.5
7
6
100
35
100
57
35
98
95 (81/19)
31 (53/47)
89 (78/22)
54 (52/48)
29 (52/48)
94 (59/41)
50 (57/43)
14/14.7
4/4
5/0
4e/4
2/2
5/5.5
2.5/2.75
2.5/2.75
rt
31
2/4f
53
can bealsoused for thesynthesis of
a,b-unsaturated4-chloromethyl-
a
g-lactams from N-(2-chloroallyl)-a-polichloroamides.
All reactions were carried out in absolute EtOH (2 mL), under argon.
L¼PMDETA.
b
c
d
e
f
Yields and conversions are determined on isolated material.
In round brackets, cis/trans ratios (by 1H-NMR spectroscopy) are quoted.
Cu0 powder replaces CuCl.
2. Results and discussion
The ARGET technique is a good starting point for the de-
velopment of an environmentally friendly ATRC process, especially
if coupled with a safe reductant like AA. Since we are working with
redox catalysts based on Cu(I) complexes, we must take into ac-
count that in the oxidation of AA with cupric ions, 2 equiv of Cu(II)
are expended and 2 equiv of Hþ concurrently released (Scheme
6).26 Unfortunately the occurrence of acidity in the system de-
stabilizes the catalytic complex,15b prejudicing its activity and, as
a consequence, the running of the catalytic cycle.22g,27 We suc-
ceeded to overcome the drawback, complementing the reaction
mixture with an inorganic carbonate.27 As one molecule of AA re-
generates two cupric complexes, it is clear that the carbonate to add
has to be at least equimolecular with AA.
L¼TMEDA.
In the presence of AA and Na2CO3, respectively, at 2.5e5 mol %
and 2.75e5.5 mol %, the ATRC proceeded smoothly with the cu-
prous complex at 2e4 mol % (Table 1, No.1 and 6). The new catalytic
system is so active that conversion of 1 was completed in only
2e7 h at room temperature, while with a standard redox catalyst in
acetonitrile the same substrate required 20 h ca.22i,j Furthermore,
the reaction was carried using a high concentration of substrate
(2e4 mmol of substrate/mL of ethanol). On replacing PMDETA with
N,N,N0,N0-tetramethylethylendiammine (TMEDA), another com-
mercially available and cheap ligand we have widely used, however
resulted in an unsatisfactory performance (Table 1, No. 7).
The role played by the couple AA/Na2CO3 is crucial. Indeed,
when excluding the reductant and base in the reaction mixture, the
efficiency of CuCl[PMDETA] was impaired (Table 1, No. 2), and only
on trebling of the mol % of the redox complex, it was possible to
arrive at a total conversion of 1 (Table 1, No. 3).
As expected, the use of ascorbic acid alone was unable to ensure
an effective ATRC (Table 1, No. 4). Its acidity and the Hþ released,
during the reduction of Cu(II) to Cu(I) (Scheme 6), affect the sta-
bility of the complex, interfering with the interaction between the
basic nitrogen ligand and the metal cation.27 The addition of
Na2CO3 is thus required for safeguarding the integrity of the
catalyst.
Since it is known that cuprous salts or complexes can be prone,
mostly in protic solvents, to disproportionation29 (Scheme 8), the
mechanism of the ATRC may not involve the generation of the in-
termediate N-allylcarbamoylmethyl radical from amide 1, through
Scheme 6. Oxidation of ascorbic acid by cupric ions.
The work of Shalmashi, who studied the AA solubility in
a number of solvents at different temperatures,28 helped us to
identify the appropriate reaction solvent. Because the activity of
a reducing reagent is more effective in a homogeneous phase,
water, methanol and ethanol appeared the most suitable solvents,
however water cannot solubilise the substrate and methanol is
toxic. The remaining option was thus ethanol, but luckily this is
a safe and biodegradable solvent that can be produced by fer-
mentation from renewable natural resources.
direct abstraction of an a-Cl by the cuprous complex (Scheme 4).
Instead, as Percec proposed for the single electron transfer-living
radical polymerization (SET-LRP),29 the homolytic cleavage of the
carbon halogen bond might entail a SET process, carried out by Cu0
(Scheme 9).
As for the redox catalyst, CuCl-N,N,N0,N00,N00-pentam-
ethyldiethylentriamine (PMDETA) was preferred, being fairly

R. Casolari et al. / Tetrahedron 67 (2011) 408e416
411
Table 2
ARGET-ATRC of amides 1e11a
No. Sub.
(mmol) (%)
1 (4) 4/4/5/5.5
CuCl/Lb/AA/Na2CO3 t (h) Convc Productsc,d
(%)
(%)
1
1
6
5
7
5
4
20
4
4
4
100
99
1a [91 (81/19)]
1a [96 (61/39)]
Scheme 8. Disproportionation/comproportionation equilibrium.
2
1 (8)
2 (4)
2 (8)
3 (4)
4 (4)
5 (4)
6 (4)
7 (4)
7 (8)
8 (4)
9 (4)
10 (4)
10 (4)
11 (4)
2/2/2.5/2.75
4/4/5/5.5
3
100
100
100
100
100
100
100
100
100
89
2a [88 (23/77)], 12e [6]
2a [87 (25/75)], 12e [6]
3a [89 (21/79)], 13e [4]
4a [91 (25/75)], 14e [8]
5a [92 (69/31)]
6a [92 (72/28)]g
7a [87 (82/18)]
7a [88 (82/18)]
8a [94 (89/11)]h
9a [83]
4
5
2/2/2.5/2.75
4/4/5/5.5
6
4/4/5/5.5
4/4/5/5.5
4/4/5/5.5
7f
8
9
4/4/5/5.5
10
11
12
13i
14i
15
2/2/2.5/2.75
4/4/5/5.5
4/4/5/5.5
4/4/5/5.5
7.6/7.6/9.5/10.5
4/4/5/5.5
5
5
5
81
10a [63]
4
4
100
89
10a [83]
11a [78]
a
All reactions were carried out in absolute EtOH (2 mL) at 37 ꢀC, under Argon.
L¼PMDETA.
b
c
Yields and conversions are determined on isolated material.
In round brackets are the cis/trans ratios, from 1H NMR excepting 3a (GC value).
N,N-Diallyl-2-chloroacetamide (12), tert-butyl 2-(N-allyl-2-chloroacetamido)-
d
e
Scheme 9. SET mechanism for the copper(I) catalysed ATRC of a generic N-allyl-
chloroamide A.
a-
acetate (13), N-allyl-N-benzyl-2-chloroacetamide (14).
f
T¼55 ꢀC.
g
Cis and trans isomers are mixtures of two diastereomers in the ratios 74/26 and
Even though we did not observe the formation of copper powder
inside the reaction mixture, this cannot exclude disproportionation
and the Persec’s mechanism, since the nascent Cu0 might be rapidly
oxidized by the substrate. As a consequence a test, wherein CuCl was
replaced by an equivalent amount of Cu0 powder, was conceived
68/32, respectively (GC values).
h
Cis and trans isomers are mixtures of two diastereomers in the ratios 92/8 and
90/10, respectively (GC values).
i
EtOH (4 mL).
(Table 1, No. 5). Under these conditions, formation of the g-lactam 1a
was accompanied by a significant amount of 1-benzyl-4-(chlor-
omethyl)-3-methylpyrrolidin-2-one, a side-product arising from
the hydro-de-chlorination of 1a (the ratio of 1a/side-product was 1/
5, whereas in the transformations catalyzed by CuCl it was 1/49).
This evidence is not supportive of the SET mechanism, although it is
not totally convincing. More convincingly, the hypothetical alter-
native mechanism pathway, depicted in Scheme 9, was rejected,
when a blank test (no added substrate) in ethanol was compared to
another test reaction in water. Under these conditions, if dis-
mutation were active, Cu0 has to build up in the reaction mixture, as
no oxidizing reagent (in our case, the amide 1) is present. Only in
water did we observe the formation of copper metal (virtually im-
mediately), whereas in ethanol, even after 48 h, no change was
detected. Clearly under our reaction conditions, the cuprous com-
plex CuCl[PMDETA] is quite stable and unable to dismutate.
Cl
Cl
Cl
Cl
Cl
Cl
O
N
O
O
4a
N
N
2a
3a
Bn
All
COOt-But
Cl
Cl
Cl
Cl
Cl
N
Cl
N
Cl
Cl
5a
O
N
O
O
O
N
Bn
8a
7a
6a
All
Bn
Ph
Cl Cl
Cl
Cl
Cl
H
Cl Cl
Cl Cl
Ph
H
H
O
O
N
Bn
N
Bn
O
11a
N
Bn
9a
H
10a
The method was than extended to a number of N-allyl-
dichloroacetamides 2e4, N-allyl-2,2-dichloroamides 5e8 and
N-allyl-trichloroacetamides 9e11 (Fig. 1). The results are summar-
ised in Table 2. In all reactions we recovered the expected g-lactams
(Fig. 2), generally in good yields (78e96%).
Fig. 2.
g-Lactam products from the ARGET-ATRC of amides 2e11.
Quite surprisingly, the lower product yields (63e83%) were
derived from tricloroacetamides 9e11 (Table 2, No. 12, 13 and 15),
which otherwise gave higher yields (90e100%) in standard ATRC
conditions.4a Moreover the conversions were incomplete
(80e90%), indicating that these molecules were the less reactive.
This is surprising since the trichloroacetamides are typically
amongst the most reactive substrates.22a It is likely that the partial
conversion is a consequence of an early degradation of the catalyst.
Evidence for this hypothesis was the complete reaction of 10, when
the amounts of each constituent of the catalytic system were
doubled (Table 2, No. 14).
Despite the mild reaction conditions, even the less reactive 2,2-
dichloroacetamides 2e422a were completely converted into cyclic
products, which emphasizes the high reactivity of the new catalytic
system. The expected
g-lactams 2ae4a were recovered in high
yield, but along with some
a-chloroacetamides (4e8%) (12e14).
These adducts originated evidently from the hydro-de-halogena-
tion of the starting materials 2e4. It means that the equilibrium
between the cis and trans rotamers of the intermediate radical B
Fig. 1. Amides precursors for the ARGET-ATRC.

412
R. Casolari et al. / Tetrahedron 67 (2011) 408e416
was not fast enough (Scheme 4). As a result the cyclization is rel-
atively slow and so the electrophilic N-allylcarbamoylmethyl B has
time to be reduced by the catalytic system.
CO2
Na2CO3
Cl
N
Cl
Cl
Bn Cl
N
Cl Cl
The diastereoselectivity of
g-lactams 1ae8a is in line with that
CuCl
HCl
NaCl + H2O
O
O
reported in the literature, for the most effective catalytic system-
s.4a,22a Besides, when using a chiral cyclization auxiliary, like the
(R)-1-phenyl-1-ethyl group, a negligible chiral induction at posi-
tions C-3 and C-4 was found in 5a, which is similar to that observed
for the same transformation catalyzed by CuCl[TMEDA]2 in
acetonitrile.22j
OH
OH
O
k
ATRC
15a
O
15
Bn
O
O
CuCl
HO
OH
kRE
k
k
RE > ATRC
HO
O
CuCl2
Cl
O
Some years ago we were interested in the ATRC of 15. The re-
action, promoted by either CuCl[TMEDA]2 or CuCl[bipyridine]2,
HO
O
N
Bn
15b
ascorbic acid
gave the g
-lactam 15a in low yields (Scheme 10).22h The discour-
aging outcome was a direct consequence of the modest conversion,
which we ascribed to the instability of 15a; indeed, 15a was able to
Scheme 12. Mechanism of the sequential ATRC/[1,2]-RE using CuCl[PMDETA]/AA/
Na2CO3.
block the ATRC of N-allyl-
a
-polychloroamides, otherwise capable of
reacting.
With great satisfaction we verified that our hypothesis was
correct. After a series of tests, the optimal 15/AA/Na2CO3 ratio was
determined as 4/4.1/4.2 (Table 3, No. 1). To allow an easy stirring of
the reaction mixture, the amount of ethanol was increased to 5 mL/
4 mmol of substrate. Glucose was also tried as reductant,33 but this
proved unsuccessful. In addition, reaction temperatures above
60e70 ꢀC have to be carefully avoided, since, otherwise, a third
reaction, the ethoxy-de-halogenation of the allylic chlorine, is
Cl
Cl
Bn Cl
Cl Cl
Cl
CuCl(TMEDA)2
N
O
N
Bn
AN, 25 °C,
20 h
O
15a
15
(conv. 20%, yield 9%)
appended to the [1,2]-RE. The formation of trichloro g-lactam 15a
was always detected, even at short reaction times, in minimal
Scheme 10. ATRC of the N-benzyl-2,2-dichloro-N-(2-chloroallyl)propanamide 15.
amounts (<2%), indicating that the RE step is faster than ATRC.
As aforementioned, the redox catalyst can epimerize the C-3
stereogenic center of
generation of a 3-pyrrolidin-2-onyl radical E (Scheme 6). Naga-
a-chloro g-lactam D through the reversible
Table 3
ATRC-ER of amides 16e20a
shima studied the activation of this peculiar a-Cl function and ap-
No.
Substrate
T (ꢀC)
t (h)
Conv.b (%)
bb (%)
cb (%)
plied it in intra-12d,25a,30a and inter-molecular25a,30b ATRA.
We deemed that radical generation at C-3 might explain the
poor efficacy of the redox complex in the cyclo-isomerization of 15.
1
2
3
4
5
6
15
16
17
18
19
20
25
25
25
25
25
25
4
4
4
4
4
4
100
90
100
100
100
57
83
73
dc
59
27
d
8
11
d
d
d
10
The intermediate 3-pyrrolidin-2-onyl radical has a
which should be liable to elimination, furnishing the
unsaturated -lactam 15b (Scheme 11). A radical mechanism, with
loss of a Cl atom (
-fragmentation),31 or a stepwise ionic path, with
b-Cl-function,
a,b-
g
a
All reactions were carried out in absolute EtOH (5 mL), substrate (4 mmol), CuCl-
PMDETA (5 mol %), AA (4.1 mmol), and Na2CO3 (4.2 mmol), under Argon.
b
release of a chloride anion, after reduction of the radical center to
give a carbanion, can be assumed.32 Whatever happens, the elim-
ination consumes 2 equiv of cuprous complex, leading a breakdown
of the catalytic cycle.
b
Yields and conversions are determined on isolated material.
N-Benzyl-2-chloro-N-(2-chloroallyl)acetamide
c
(22)
was
quantitatively
obtained.
A dimeric species, 15c, was also isolated, albeit in low yield (8%).
This is derived from a formal reductive homo-coupling of 15b, by
linking the two allylic carbons Cexo (Scheme 13), a further reaction
most likely mediated by the cuprous complex. Clearly, the
remaining allylic CeCl function is still fairly reactive.
Scheme 13. Reductive homo-coupling of 15b.
Scheme 11. cyclo-Isomerization of 15 to 15a followed by the elimination.
To study the extension of the tandem ATRC-RE, a range of N-(2-
Since formation of 15b is expected to follow a two-step process,
wherein the initial ATRC, and the subsequent reductive [1,2]-elimi-
nation (RE) are mediated by the same redox complex, we surmised
that, simply by adjusting the amounts of AA and Na2CO3, the new
method could promote the efficient transformation of 15 into 15b
(Scheme 12). As far we are aware only two other examples of tandem
ATRC-RE are known, but both involve [1,3]-eliminations.13a,32
chloroallyl)-
prepared.
a-polychloroamides (Fig. 3, substrates 16e20) was
Table 3 summarises the results we obtained, while Fig 4 shows the
structures of the products isolated. Disappointingly, the method was
lacking in general applicability. Indeed, we did never observe
a selectivity better than the one registered for 15. On the contrary it just
seems that each of the amides 16e20 exhibits a peculiar behaviour.

R. Casolari et al. / Tetrahedron 67 (2011) 408e416
413
3. Conclusions
This work has shown that a ‘green’ ARGET-ATRC, for the
CuCl-PMDETA catalysed cyclo-isomerization of N-allyl- -poly-
chloroamides into -lactams, proceeds efficiently (yields between 78
a
g
and 96%). The catalytic system works in ethanol, a safe solvent ob-
tainable from renewable bio-resources, and exploits the reducing
features of ascorbic acid to limit the amount of the redox complex to
only 2e4 mol %. To preserve the efficacy of the catalytic cycle, it is
essential that Na2CO3 is added. It neutralises the HCl released during
the regeneration of the active cuprous form of the redox catalyst.
Other advantages of the method are: mild reaction temperatures
(25e37 ꢀC), relatively short reaction times (usually 5 h) and low sol-
vent volumes (2 mmol of substrate/mL of ethanol). These features
altogether make the reaction attractive for an eventual scale-up.
The method does have some limitations, when using the N-allyl-
2,2-dichloroamides and the N-allyl-trichloroacetamides. In the first
case some reduction of the starting amides was noted and, in the
other case, conversions were incomplete, unless to increase the
amount of CuCl[PMDETA]/AA/Na2CO3. We have also ascertained
that, under our conditions, the reaction proceeds with a typical
inner-sphere mechanism, propelled by CuCl, whereas the hypo-
thetical SET mechanism, based on Cu0, cannot be operative.
The method, upon stoichiometric adjustment of the reagents,
Fig. 3. Precursor amides for the tandem ATRC-RE.
Fig. 4. Products from the tandem ATRC-RE of amides 16e20.
Even though the a,b-unsaturated g-lactam 16b (Table 3, No. 2)
was attained in a good yield (73%) from 16, the conversion was
partial (90%), despite attempts at optimization. Moreover the dimer
by-product 16c, secured in 11% yield, was unexpectedly derived
from a connection between Cexo and Cendo carbons of the two allylic
precursors.
From 17, instead, we quantitatively recovered the N-benzyl-2-
chloro-N-(2-chloroallyl)acetamide 22 (Scheme 14) (Table 3, No. 3).
The result indicates that the intermediate a-amide radical, derived
from chlorine abstraction from 17, has no tendency to cyclise, un-
like the dichloroacetamides 2e4. Instead, even on increasing the
reaction temperature to 70 ꢀC, it is gradually reduced to 22 (Scheme
14). Perhaps this may be explained by formation of an inter-mo-
looked also suitable for the synthesis of
a
,b
-unsaturated 4-chlor-
omethyl- -lactams from N-(2-chloroallyl)-
g
a-polychloroamides, via
a tandem process involving an ATRC and a reductive [1,2]-elimi-
nation. Unfortunately, this second application is not general. In fact,
each of the experienced amides (16e20) investigated exhibited
a peculiar behaviour, although satisfactory results were achieved
with substrates 15 and 16. Product 18b, even if isolated in only 59%
yield, is quite appealing as it carries both a vinylic and an allylic
chloro function. Finally, the isolation of dimeric products, in these
reactions, means that the allylic chlorine atom of the
a,b-un-
saturated 4-chloromethyl-
4. Experimental part
4.1. General
g-lactams is somewhat reactive.
lecular hydrogen bond between the a-H (of the amide moiety), and
the vinylic chlorine (in the allylic moiety), which forces the amide
17, and the intermediate carbamoylmethyl radical 21, to adopt
a conformation unsuitable for the cyclization.
Reagents and solvents were standard grade commercial prod-
ucts, purchased from Aldrich, Acros, Fluka or RdH, and used with-
out further purification. The silica gel used for flash
chromatography was Silica Gel 60 Merck (0.040e0.063 mm). The
starting amides 1e11 and 15e20 were obtained through amino-de-
chlorination of acyl chlorides with allyl amines (all prepared by
N-alkylation of amines, adapting the Shipman’s method)34 fol-
lowing typical procedures.4a,14 The 2,2-dichloropropanoyl and
2,2-dichlorobutanoyl chlorides were, respectively, prepared from
2,2-dichloropropanoic and 2,2-dichlorobutanoic acids35 by halo-
de-hydroxylation with (COCl)2, following the literature.22 Products
2a,22a 4a,22a 5a,22h 6a,4a 7a,22a 8a,4a 9a,4a 10a4a and 11a4a are known
compounds. NMR spectra were recorded on a ‘Bruker DPX 200’ and
a ‘Varian 500 MHz’ spectrometer. The relative configuration of 3a
was determined by NOESY experiments. IR and MS spectra were
recorded, respectively, on a ‘Perkin Elmer 1600 Series FT-IR’ and ‘HP
5890 GCeHP 5989 AMS Engine’. Only for 15b was the MS spectra
obtained on an ‘LCeMS(n) Ion Trap 6310A Agilent Technologies’.
Elemental analysis was performed on the ‘EA 1110 Carlo Erba’.
Scheme 14. Hydro-de-halogenation of the amide 17.
Substrates 18 and 19 (Table 3, No. 4 and 5) afforded the expected
unsaturated
g-lactams: 19b in poor yields (27%) and 18b with
a fairly better outcome (59%). Both transformations were not clean
and it was impossible for us to isolate any dimer. Finally, the only
important product isolated from the reaction with the tetra-
chloroamide 20, although in a small amount (10%), was 20c (Table
3, No. 6). The molecule is a symmetric dimer, where the hetero-
cyclic rings are joined by a vinylene bridge, likely arising from the
presumed ATRC intermediate 20b through a tandem reductive
homo-coupling/[1,2]-RE process (Scheme 15).
4.2. Typical procedure for the cyclization of amides 1e11:
reaction of tert-butyl 2-(N-allyl-2,2-dichloroacetamido)
acetate (3)
CuCl (0.16 mmol,16 mg), ascorbic acid (0.2 mmol, 35 mg), Na2CO3
(0.22 mmol, 23 mg) and amide 3 (4 mmol, 1.129 g) were weighed in
Scheme 15. Transformation of the amide 20 into the dimer 20c.

414
R. Casolari et al. / Tetrahedron 67 (2011) 408e416
a Schlenk tube fitted with a pierceable septum (blocked by a screw
cap) and a magnetic stirring bar. Absolute ethanol (2 mL) was then
added under argon. The reaction mixture (only in this case) was
heated to a moderate extent until all the substrate was dissolved.
CDCl3) 1.76 (4H, s, CH2CH2), 2.43 (6H, s, CH3), 3.58 (4H, s, 2ꢁC(5)H2),
4.58 (4H, s, 2ꢁNeCH2), 7.11e7.39 (10H, m, 2ꢁPh); dC (50.32 MHz,
CDCl3) 8.8, 26.3, 46.1, 51.8, 127.5, 127.9, 128.7, 129.8, 137.3, 147.7,
172.1; m/z (ESI-Ion Trap) 423.2 [4 (MþNa)þ], 401.2 [100% (MþH)þ].
Afterwards PMDETA (0.16 mmol, 36 mL) was injected through the
septum with a microsyringe and the Schlenk tube promptly im-
mersed in a water bath at 37 ꢀC. The reaction mixture was stirred for
5 h and then diluted with water (8 mL), acidified with HCl 10% w/v
and extracted with ethyl acetate (3ꢁ6 mL). The combined organic
layers were concentrated and the crude product was purified by
flash chromatography on silica gel, eluting with a petroleum ether
(PE: bp 40e60 ꢀC)/diethyl ether (Et2O) gradient (from 100/0 to 0/
100). This gave the 2-pyrrolidinone 3a (1.005 g, colourless oil, 89%),
as an inseparable mixtureof cis/trans diastereomers(21/79,1HNMR)
[found: C, 47.0; H, 6.2; N, 5.1. C11H17Cl2NO3 requires 46.82; H, 6.07; N,
4.96] and 13 (0.040 g, colourless oil, 4%).
4.4. Reaction of 2,2-dichloro-N-(2-chloroallyl)-N-
propylpropanamide (16)
Following the procedure, used for 15, 16 (4 mmol, 1.034 g) gave,
after flash-chromatography of the crude product on silica gel, using
a PE/Et2O gradient (from 100/0 to 0/100), the a,b-unsaturated-g-
lactam 16b (0.548 g, 73%), as a slightly brown oil [found: C, 57.4; H,
7.5; N, 7.4. C9H14ClNO requires C, 57.60; H, 7.52; N, 7.46], Rf (50% PE/
Et2O) 0.096, and the dimer 16c (0.070 g 11%), as a colourless oil
[found: C, 71.2; H, 9.3; N, 9.1. C18H28N2O2 requires C, 71.02; H, 9.27;
N, 9.20], Rf (Et2O) 0.075.
4.2.1. tert-Butyl 2-[3-chloro-4-(chloromethyl)-2-oxopyrrolidin-1-yl]
4.4.1. 1-Propyl-4-(chloromethyl)-3-methyl-1H-pyrrol-2(5H)-one
acetate (3a). nmax (liquid film) 1740 and 1717 cmꢂ1
;
dH cis
(16b). nmax (liquid film) 1681 cmꢂ1
; dH (200 MHz, CDCl3) 0.89 (3H,
(500 MHz, CDCl3) 1.47 (9H, s, CMe3), 2.99 (1H, m, H-4), 3.44 (1H, dd,
J 9.7, 7.9, H-5), 3.61 (1H, dd, J 9.7, 7.0, H-5), 3.82 (2H, m, CH2Cl), 3.96
and 4.03 (2H, J 17.5, pseudoq AB, CH2CO), 4.49 (1H, d, J 6.4, CHCl); dH
trans 1.47 (9H, s, CMe3), 2.91 (1H, m, H-4), 3.64 (1H, dd, J 9.6, 7.9, H-
5), 3.47 (1H, dd, J 9.6, 7.0, H-5), 3.76 (2H, ddd, J 11.5, 6.6, 4.8, CH2Cl),
3.87 (1H, d, J 17.5, part A of an AB, CHCO), 4.14 (1H, d, J 17.5, part B of
an AB, CHCO), 4.38 (1H, d, J 7.8, H-3); dC cis (125.68 MHz, CDCl3)
27.8, 40.6, 41.8, 44.7, 48.8, 56.7, 82.6, 166.6, 168.9; dC trans 27.8, 43.1,
44.9, 47.9, 55.9, 82.6, 166.6, 168.9; m/z (EI, 70 eV) 225 [12 (Mꢂ56)þ],
208 (12), 190 (5), 181 (18), 180 (43), 146 (55), 57 (100%).
t, J 6.9, CH2CH3), 1.58 (2H, sext, J 6.9, CH2CH3), 1.85 (3H, s, CH3), 3.38
(2H, t, J 6.9, NeCH2), 3.93 (2H, s, C5H2), 4.32 (2H, s, CH2eCl); dC
(50.32 MHz, CDCl3) 9.0, 11.2, 21.8, 37.6, 44.0, 51.5, 133.1, 143.2, 171.2;
m/z (EI, 70 eV) 187 (38, Mþ), 158 (100), 152 (47%).
4.4.2. 3-Methyl-4-((3-methyl-4-methylene-2-oxo-1-propylpyrroli-
din-3-yl)methyl)-1-propyl-1H-pyrrol-2(5H)-one (16c). nmax (liquid
film) 1682, 1654 cmꢂ1
;
dH (500 MHz, CDCl3) 0.87 and 0.88 (6H, 2ꢁt,
2ꢁCH3CH2), 1.32 (3H, s, CH3eC), 1.52 (4H, m, 2ꢁCH3CH2), 1.78 (3H,
s, CH3C]C), 2.63 and 2.76 (2H, J 13.6, app. q AB, exocyclic tethering
CH2), 3.26 (2H, t, NeCH2), 3.32 (2H, m, NeCH2), 3.59 and 3.60 (2H,
AB, J 16.2, app. q NeCH2eC]C), 3.74 (1H, td, J 2.0, 14.3, part A of an
ABXX0, NeCHHeC]CH2) 3.91 (1H, td, J 2.3, 14.3 Hz, part B of an
ABXX0, NeCHHeC]CH2), 5.14 (2H, ddd, J 2.0, 2.5, 4.2, part X and X0,
CH2]C); dC (125.68 MHz, CDCl3) 9.5, 11.1, 11.2, 20.3, 21.8, 25.5, 37.2,
43.6, 43.8, 48.9, 50.6, 53.7, 108.8, 131.8, 145.0, 146.1, 172.0, 176.5; m/z
(EI, 70 eV) 275 [1, (Mꢂ29)þ], 152 (100%).
4.2.2. tert-Butyl 2-(N-allyl-2-chloroacetamido)acetate (13). m/z (EI,
70 eV) 191 [23 (Mꢂ56)þ], 174 (11), 146 (60), 114 (22), 70 (92), 57
(100), 41 (52%). This MS spectrum is identical to the one of an
original sample of 13, prepared by reaction of 2-chloropropionyl
chloride with tert-butyl 2-(allylamino)acetate.
4.3. Reaction of N-benzyl-2,2-dichloro-N-(2-chloroallyl)
propanamide (15)
4.5. Reaction of N-benzyl-2,2,2-trichloro-N-(2-chloroallyl)
acetamide (18)
CuCl (0.2 mmol, 0.020 g), ascorbic acid (4.1 mmol, 0.722 g),
Na2CO3 (4.2 mmol, 0.445 g) and amide 15 (4 mmol, 1.227 g) were
weighed in a Schlenk tube fitted with a pierceable septum (blocked
by a screw cap) and a magnetic stirring bar. Absolute ethanol (5 mL)
was then added under argon and the Schlenk tube immersed in
Following the procedure, used for 15, 18 (4 mmol, 1.308 g) gave,
after flash-chromatography of the crude product on silica gel, using
a PE/Et2O gradient (from 100/0 to 0/100), 1-benzyl-4-(chlor-
omethyl)-3-chloro-1H-pyrrol-2(5H)-one (18b) (0.604 g, 59%), as
a slightly brown solid [found: C, 56.1; H, 4.3; N, 5.5. C12H11Cl2NO
requires C, 56.27; H, 4.33; N, 5.47], Rf (50% PE/Et2O) 0.18; mp
a water bath at 25 ꢀC. After 100, PMDETA (0.2 mmol, 41
mL) was
injected through the septum with a microsyringe. The reaction
mixture was stirred for 4 h and then diluted with ethyl acetate
(50 mL), acidified with HCl 10% w/v and washed with water
(3ꢁ20 mL). The organic layer was concentrated and the crude
product was purified by flash chromatography on silica gel, eluting
with a gradient fromPE/Et2O (100/0) to Et2O/MeOH (95/5). This gave
96e98 ꢀC; nmax (KBr) 1708 cmꢂ1
; dH (200 MHz, CDCl3) 3.94 (2H, s,
C2H5), 4.37 (2H, s, CH2Cl), 4.65 (2H, s, NeCH2), 7.15e7.43 (5H, m,
Ph); dC (50.32 MHz, CDCl3) 36.66, 47.12, 50.41, 127.08, 128.00,
128.20, 128.94, 136.15, 143.94, 165.00; m/z (EI, 70 eV) 255 (20, Mþ),
220 (100), 91 (88).
the
a,b-unsatured-g-lactam 15b (0.782 g, 83%), as a white solid
[found: C, 66.5; H, 6.1; N, 6.0. C13H14ClNO requires C, 66.24; H, 5.99;
N, 5.94], Rf (50% PE/Et2O) 0.075, and the dimer 15c (0.063 g 8%), as
a slightly brownish solid [found: C, 77.8; H, 7.1; N, 7.0. C26H28N2O2
requires C, 77.97; H, 7.05; N, 6.99], Rf (95% Et2O/MeOH) 0.27.
4.6. Reaction of N-benzyl-2,2-dichloro-N-(2-chloroallyl)-2-
phenyl-acetamide (19)
Following the procedure, used for 15, 19 (4 mmol, 1.475 g) gave,
after flash-chromatography of the crude product on silica gel, using
a PE/Et2O gradient (from 100/0 to 30/70), 1-benzyl-4-(chlor-
omethyl)-3-phenyl-1H-pyrrol-2(5H)-one (19b) (0.322 g, 27%), as
a yellow oil [found: C, 72.7; H, 5.5; N, 4.8. C18H16ClNO requires C,
72.60; H, 5.42; N, 4.70], Rf (70% PE/Et2O) 0.092; nmax (KBr)
4.3.1. 1-Benzyl-4-(chloromethyl)-3-methyl-1H-pyrrol-2(5H)-one
(15b). Mp 91e93 ꢀC; nmax (KBr) 1718 cmꢂ1
; dH (200 MHz, CDCl3)
1.92 (3H, s, CH3), 3.85 (2H, s, C(5)H2), 4.30 (2H, s, CH2Cl), 4.63 (2H, s,
NeCH2), 7.18e7.40 (5H, m, Ph); dC (50.32 MHz, CDCl3) 9.1, 38.9, 47.7,
51.8, 124.7, 125.3, 125.8, 133.8, 138.6, 144.7, 171.1; m/z (EI, 70 eV) 235
(25, Mþ), 200 (100), 91 (73%).
1684 cmꢂ1
; dH (200 MHz, CDCl3) 4.03 (2H, s, C(5)H2), 4.44 (2H, s,
CH2Cl), 4.72 (2H, s, NeCH2), 7.20e7.60 (10H, m, Ar); dC (50.32 MHz,
CDCl3) 38.63, 46.53, 50.97, 127.73, 128.26, 128.56, 128.72, 129.16,
130.38, 135.61, 136.98, 128.83, 144.99, 169.87; m/z (EI, 70 eV) 297
(24, Mþ), 262 (51), 248 (10), 91 (100).
4.3.2. 4,40-(Ethane-1,2-diyl)bis[1-benzyl-3-methyl-1H-pyrrol-2(5H)-
one] (15c). Mp 117e120 ꢀC; nmax (KBr) 1672 cmꢂ1
; dH (200 MHz,

R. Casolari et al. / Tetrahedron 67 (2011) 408e416
415
13. (a) Thommes, K.; Kiefer, G.; Scopelliti, R.; Severin, K. Angew. Chem., Int. Ed. 2009,
4.7. Reaction of 2,2-dichloro-N-(2,3-dichloroallyl)-N-
propylpropanamide (20)
ꢁ
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Following the procedure, used for 15, 20 (4 mmol, 1.172 g) gave,
after flash-chromatography of the crude product on silica gel,
using a gradient from PE/Et2O (100/0) to Et2O/MeOH (95/5), (E)-
4,40-(ethene-1,2-diyl)bis(3-methyl-1-propyl-1H-pyrrol-2(5H)-one)
(20c) (0.121 g, 10%), as yellowish solid [Found: C, 71.8; H, 8.7; N, 9.3.
C18H26N2O2 requires C, 71.49; H, 8.67; N, 9.26], Rf (95% Et2O/MeOH)
0.22; mp 169e171 ꢀC; nmax (KBr) 1680 cmꢂ1
; dH (200 MHz, CDCl3)
0.91 (6H, t, J 6.8, 2ꢁCH2CH3), 1.62 (4H, sext, J 6.8, 2ꢁCH2CH3), 1.95
(6H, s, 2ꢁCH3), 3.44 (4H, t, J 6.8, 2ꢁNeCH2), 4.06 (4H, s, 2ꢁC5H2),
6.68 (2H, s, 2ꢁ ]CH); dC (50.32 MHz, CDCl3) 9.41, 11.26, 21.80,
44.06, 50.15, 122.17, 133.39, 142.96, 171.79; m/z (EI, 70 eV) 302 (51,
Mþ), 273 (100).
ꢁ
ꢁ
17. (a) Fernandez-Zumel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierz-
~
chala, K.; Severin, K. Chem.dEur. J. 2009, 15, 11601e11607; (b) Munoz-Molina, J.
Acknowledgements
ꢁ
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M.; Belderraõn, T. R.; Perez, P. J. Adv. Synth. Catal. 2008, 350, 2365e2372;
ꢁ
ꢁ
(c) Fernandez-Zumel, M. A.; Kiefer, G.; Thommes, K.; Scoppelliti, R.; Severin, K.
ꢀ
We thank the Ministero dell’Istruzione, dell’Universita e della
Eur. J. Org. Chem. 2010, 3596e3601.
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