Efficient and green route to γ-lactams by copper-catalysed reversed atom transfer radical cyclisation of α-polychloro-N-allylamides, using a low load of metal (0.5 mol%)

Article abstract of DOI:10.1002/adsc.201300132

The cyclisation of N-allyl-N-substituted-α-polychloroamides is efficiently obtained through a copper-catalysed activators regenerated by electron transfer-atom transfer radical cyclisation process, with a metal load of only 0.5 mol%. The redox catalyst is

Full text of DOI:10.1002/adsc.201300132

UPDATES
DOI: 10.1002/adsc.201300132
Efficient and Green Route to g-Lactams by Copper-Catalysed
Reversed Atom Transfer Radical Cyclisation of a-Polychloro-N-
allylamides, using a Low Load of Metal (0.5 mol%)
a
b
c
d
Franco Bellesia, Andrew J. Clark, Fulvia Felluga, Armando Gennaro,
d
a
a,
Abdirisak A. Isse, Fabrizio Roncaglia, and Franco Ghelfi *
Dipartimento di Scienze Chimiche e Geologiche, Universitꢀ degli Studi di Modena e Reggio Emilia, Via Campi 183,
1125 Modena, Italy
a
4
Fax : (+39)-(0)59-373-543; phone: (+39)-(0)59-205-5049; e-mail: franco.ghelfi@unimore.it
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
Dipartimento di Scienze Chimiche e Farmaceutiche, Universitꢀ degli Studi di Trieste, Via L. Giorgeri 1, 34127 Trieste,
Italy
b
c
d
Dipartimento di Scienze Chimiche, Universitꢀ degli Studi di Padova, Via Marzolo 1, 35131 Padova, Italy
Received: February 8, 2013; Revised: April 15, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300132.
Abstract: The cyclisation of N-allyl-N-substituted-
a-polychloroamides is efficiently obtained through
a copper-catalysed activators regenerated by elec-
tron transfer–atom transfer radical cyclisation pro-
cess, with a metal load of only 0.5 mol%. The redox
catalyst is introduced in its inactive form as cop-
per(II) chloride/[nitrogen ligand] complex, and con-
tinuously regenerated to the active copper(I) chlo-
ride/[nitrogen ligand] species by ascorbic acid. To
preserve the catalyst integrity, the hydrochloric
acid, released after each regeneration cycle, has
been quenched by carbonate. The choice of the sol-
vent is critical, the best performance being observed
in ethyl acetate-ethanol (3:1).
iants of the method are known (Scheme 1): (i) the in-
[
3]
termolecular ATRA, (ii) the atom transfer radical
[
4]
polymerisation (ATRP) and (iii) the atom transfer
[
5]
radical cyclisation (ATRC).
All these processes feature a common mechanism
[
3–5]
n
(Scheme 2).
First the metal complex M L , in its
m
reduced state (active form or activator), abstracts (re-
versibly) a halogen atom from the halo precursor,
generating a radical species and increasing its oxida-
n+1
tion state by one unit (M L X). The radical inter-
m
mediate then adds to the olefinic substrate yielding
a new radical. Finally, the second adduct radical is
n+1
quenched by halogen transfer from M L X (the
m
metal complex in its oxidised state or inactive form or
deactivator), regenerating the active form of the cata-
n
lyst (M L ) and affording the reaction product. The
Keywords: atom transfer radical cyclization;
ATRC; copper; cyclisation; g-lactams; radicals
m
atom transfers to and from the metal complex follow
a concerted mechanism, via an inner-sphere electron
transfer process.
Even though ATRP is the youngest among the
ATRA methods, it is certainly the most studied and
applied, allowing the controlled preparation both of
polymers with complex architectures and of hybrid
[
6]
[
7]
Introduction
The insertion of an olefinic C=C function between
the components of a CꢀX (X=Cl, Br, I) bond
through a radical chain process, named atom transfer
radical addition (ATRA) or Kharasch addition, has
become a standard technique in synthetic organic
[1]
chemistry.
Originally the ATRA was carried out with the help
of radical initiators and was limited to substrates with
[
1]
a quite weak CꢀX bond. Nowadays the scope of the
reaction has been considerably enlarged with the help
[
2]
of transition metal complexes (TMC). Three var- Scheme 1. Types of atom transfer radical reactions.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
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Franco Bellesia et al.
UPDATES
Scheme 2. Atom transfer radical addition mechanism (if a re-
ducing agent is added to the reaction mixture, as in the
ICAR or ARGET processes, catalyst regeneration occurs
via the dotted arrow, see text); in the case of ATRP the acti-
vation/deactivation/addition cycle is repeated many times re-
sulting in polymer formation.
[
4]
Scheme 3. a) Typical copper-catalysed ATRC of N-allyl-a-
polychloroamides (the cis and trans conformations around
the amide bond are highlighted in bold); b) copper-catalysed
epimerisation of the C-3 centre of g-lactams D.
materials. Redox catalysts based on copper are usu-
ally preferred and thanks to these investigations,
major achievements, regarding their structure and the
variables, which influence their activity, were accom-
[
4a,c,6a,b,8]
plished.
Many efforts have been devoted to the containment amide radical intermediate B to adopt the correct
[19a,22]
of the amount of copper required for controlling the conformation for the cyclisation (Scheme 3a).
[9]
ATRP process. This has been achieved by comple- Second, when the C-3 stereogenic centre of the
menting the catalytic system with a “reducing agent” lactam D carries a halo function, it becomes configu-
that re-establishes the catalytic cycle, regenerating the rationally unstable under the reaction conditions, and
active metal complex from the inactive oxidised form, can be epimerised by the same ATRC catalyst
[
19a,b,f,h,q,20i]
which, otherwise, because of termination reactions, (Scheme 3b).
The best stereochemical results
progressively builds up. There are three methods of are thus achievable when the thermodynamic control
choice to this end: (i) the “initiator for continuous ac- is fully operative, the preferred products being those
tivator regeneration” protocol (ICAR)-ATRP, where in which the substituents Cl and CH Cl stay on the
2
free radicals, slowly and steadily fed to the polymeris- same face of the ring.
ing mixture by decomposition of conventional radical
Recently we have proposed a “green” ARGET-
n+1
[18a]
initiators (e.g., AIBN), interact with the M L X ATRC of N-allyl-a-polychloroamides.
The process,
m
[10]
[23]
species,
(ii) the “activators regenerated by electron catalysed by CuCl/PMDETA,
worked efficiently
transfer” process (ARGET)-ATRP, which uses non- (yields 78–96%) in ethanol, using ascorbic acid (AA)
[
18a]
radical reducing reagents, such as Sn(ethyl hexan- (2.5–5 mol%) as regenerating agent (2–4 mol%);
[11]
[12]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
oate) [Sn(EH) ], ascorbic acid, aliphatic tertiary AA was also used in few copper-catalysed ARGET-
2
2
[13]
[14]
[17l,m,p]
amines,
or zerovalent metals [Cu(0) above all]
ATRA.
Previously the activator in the ATRC of unsaturat-
ATRP, where the reduction is realised through the ed amides was regenerated through an ICAR process
intake of electrons from an electrode. These tech- in CH Cl , using CuCl/TPMA (1 mol%)/AIBN
or through an ARGET process in tolu-
ion field of ATRA, but their implementation in the ene, based on Ru(II) or Os(II) (1–5 mol%)/Mg(0)
and (iii) the recently reported electrochemical (e)-
[
15]
2
2
[
16]
[18b]
niques have found some application in the compan- (10 mol%),
[
17]
[
17f–i,18]
[17f–i]
ATRC area is still in its infancy.
(3000–4000 mol%).
More recently an ARGET
One of the most popular ATRCs is the cycloiso- process exploiting the system CuSO /TPMA-KBH
4
4
[
19a]
[18c]
merisation to g-lactams of N-allyl-a-haloamides.
has been also issued.
It uses methanol as solvent,
[19]
[20]
Copper(I),
ruthenium(II)
or
sporadically and the typical load of catalyst is around 1–2.5 mol%,
[19t,21]
iron(II)
are the typical metal ions used to cata- while that of the reducing agent is 10–50 mol%. The
lyse these transformations. A number of interesting expensive nature of the Ru or Os catalysts, the exces-
natural and unnatural products, have been prepared sive load of reducing agents, the toxicity of AIBN and
[19a]
by this method,
volving ATRC,
ACHTUNGTRENNUNGe d.
and useful domino processes, in- the low concentration of substrate in the reaction
have
also
been
develop- mixture make these methods unappealing for large-
scale preparations.
[
17g,19a,k,q,u,20a,c,e]
Two pivotal aspects of the TMC-ATRC of amides
Our green ARGET alternative, however, has also
need to be highlighted. First, the presence of a sub- some disadvantages: (i) substrate solubility in ethanol
stituent R (cyclization auxiliary) on the N atom of the is not always good, (ii) metal loading is still too high
starting amide A is essential, since it allows the a- (2–4 mol%) and (iii) unsatisfactory results are
2
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Efficient and Green Route to g-Lactams by Copper-Catalysed Reversed Atom Transfer Radical Cyclisation
Table 1. Effect of solvent on the ARGET-ATRC of 1.
[a]
[
b]
[c]
[c,d]
Entry8 Solvent
Conversion
Products
[%]
[
mL]/[mmol] of 1 [%]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
AcOEt (0.5)
THF (0.5)
DME (0.5)
AN (0.5)
toluene (0.5)
DMF (0.5)
EtOH (0.5)
83
82
79
20
14
39
100
81 (59:41)
78 (59:41)
77 (59:41)
20 (53:47)
14 (58:42)
38 (55:45)
Scheme 4. Reduction of cupric cation by ascorbic acid.
[
18a]
achieved with polychloroacetamides.
Here, we now
report how these problems have been solved.
[e]
99 [93] (60:40)
[a]
All reactions were carried out under argon: substrate
8
4
mmol, CuCl/PMDETA 1 mol%, AA 2 mol%, Na CO3
Results and Discussion
2
mol%, T 358C, t 4 h.
[
b]
AcOEt (ethyl acetate), THF (tetrahydrofuran), DME
1,2-dimethoxyethane, AN (acetonitrile), DMF (N,N-di-
The system ascorbic acid/Cu(II)/Cu(I)/dehydroascor-
bic acid in water and under anaerobic conditions is
(
methylformamide, EtOH (ethanol).
GC value.
In round brackets are the cis/trans ratios (GC).
Yields determined on isolated material.
[
24]
coarsely drawn in Scheme 4. It is important to note
that the oxidation of one equivalent of AA restores
two equivalents of Cu(I), but concurrently releases
[c]
[d]
[e]
+
[24]
two equivalents of H . Unfortunately, the produc-
[
9c]
tion of acidity destabilises the catalytic complex,
[
19n,25]
undermining its activity.
For this reason a base much lower conversions than AA. The diastereomeric
(
e.g., Na CO ) has to be added to the reaction mix- ratio (cis/trans) of 1a was practically the same in all
2
3
[
18a,25]
At ure.
C
H
T
U
N
G
T
R
E
N
N
U
N
G
solvents, about 60:40. Since the cis isomer has a more
In order to identify a better solvent than ethanol interesting reactivity than its trans counterpart, being
and the most appropriate reaction conditions for the able to be smoothly dehydrohalogenated, the C-3ꢀCl
amide substrates, wherein the redox system CuCl/ and the C-4ꢀH can, in fact, easily achieve the anti-
PMDETA-AA-Na CO can work at the maximum of
its capability, we chose to study as archetypal reac-
ACHTUNGTRENNUpGN eriplanar conformation required for the elimina-
2
3
[
19a,d,f,h]
A
H
U
G
R
N
U
G
its modest prevalence makes these trans-
tion, the ATRC of the N-allyl-2,2-dichloropropan-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNGa mide 1 (Scheme 5). At first we examined the cyclo-
ACHTUNGTRENNUNG
[
27]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ol, but in AcOEt, THF and DME the cycloisomerisa- (Table 2).
tion gave also interesting results (conversions around ence of AA and carbonate to attain the best catalyst
0%). Astonishingly, the conversion was very low in performance was confirmed (Table 2, entries 1–3).
The necessity of the simultaneous pres-
8
DMF, notwithstanding the complete solubility of AA Unfortunately, the reactivity did not improve increas-
in this solvent. Considering also that at 358C the mol ing the temperature; longer reaction time was the
ꢀ
3
fraction of AA in AcOEt is 0.23·10 while in EtOH only solution to get a higher conversion. In any case
ꢀ
3 [26]
it is 3.85·10 , it is clear that the solubility of AA in the diastereomeric ratio remained stable at around
the reaction medium is not a very crucial feature in 60:40 (Table 2, entries 3–5).
the choice of the solvent. Moreover Matyjaszewski
At this point we investigated the application of tet-
observed that controlled ARGET-ATRP with AA radentate tripodal nitrogen ligands, such as
was possible only if the solubility of the reducing Me TREN and TPMA (Figure 1). Although expen-
6
agent was limited through the adoption of heteroge- sive, these ligands are widely exploited in all the
[12e]
neous conditions
the reaction mixture.
or through its slow feeding into fields of ATRA reactions, since they give rise to more
[
12f]
We also tried (unreported re- reducing and active Cu(I) complexes than PMDETA.
sults) the more lipophilic ascorbyl-6-palmitate as re- It was indeed observed that, in the same solvent,
ducing agent, but without success: it always gave there exists an excellent correlation between the E1/2
of Cu(I)X[nitrogen ligand] species and the KATRP
(
ATRP equilibrium constant), a parameter used to
[
4a,8a,f,19s,28]
rank the activity of the catalysts.
The first trial (Table 2, entries 6 and 7) with these
more active catalysts, however left us dismayed: con-
versions were quite low, much less than in the case of
PMDETA. What was happening? As the reaction
Scheme 5. Cycloisomerisation of amide 1 to g-lactam 1a.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Franco Bellesia et al.
UPDATES
[a]
Table 2. Setting of the best conditions for the ARGET-ATRC of 1 in AcOEt.
[b]
[b,c]
Entry8
Ligand
CuCl/l-AA/Na CO
T/t
[8C]/[h]
Conversion
[%]
Products
[%]
2
3
A[ mol%]
H
U
G
R
N
U
G
1
2
3
4
5
6
7
8
9
1
A
A
A
A
A
B
C
A
B
C
1/0/0
1/2/0
1/2/4
1/2/4
1/2/4
1/2/4
1/2/4
1/2/4
1/2/4
1/2/4
35/4
35/4
35/4
55/4
35/20
35/4
35/4
35/4
35/4
35/4
15
50
83
85
96
5
13
99
100
100
15 (58:42)
50 (59:41)
81 (59:41)
85 (60:40)
95 [87] (60:40)
5 (59:41)
[d]
13 (59:41)
[
[
e]
e]
[
[d]
99 [95] (83:17)
[d]
99 [95] (84:16)
e]
[d]
0
99 [94] (85:15)
[
[
[
[
[
a]
All reactions were carried out under argon: substrate 8 mmol and AcOEt 4 mL.
GC value.
In round brackets are the cis/trans ratios (GC).
Yields determined on isolated material.
b]
c]
d]
e]
Reaction performed in 4 mL of AcOEt/EtOH 3/1.
mixture did not take any hue, but instead coloured the same reducing capacity of the reactions reported
particles were observed, we concluded that the reac- in Table 2.
tivity problem had to be attributed to the insolubility
Halving the load of CuCl /PMDETA to 0.5 mol%
2
of the new copper complexes in AcOEt. We thought did not show any performance drop (Table 3, entry 3
to bypass the problem by adding EtOH as cosolvent. and Table 2, entry 8). Under these conditions, the
Unbelievably with this trivial adjustment, the reactivi- effect of the AcOEt/EtOH ratio on the reaction out-
ty of all the complexes was increased in AcOEt/ come was very interesting. In neat ethanol the effi-
EtOH 3/1. Not only did we observe total conversions ciency collapsed, but when the AcOEt/EtOH ratio
and high yields, but also the diastereomeric ratio in- was brought to 2/2 the catalyst activity was partially
creased, reaching the highest values (Table 2, en- recovered (Table 3, entries 1 and 2). In fact, while
tries 8–10).
both conversion and yield were excellent, the diaste-
These achievements opened the door to a further reomeric ratio was disappointing. A further increase
lowering of the catalyst load (Table 3). The less ex- of the AcOEt/EtOH ratio to 3/1 gave an even better
pensive ligand PMDETA was considered first.
result both in terms of conversion and yield, and cis/
Moreover, since the amount of catalyst to be used trans ratio (Table 3, entry 3). No extra improvement
began to be really small, we also decided to adopt the was noted when the AcOEt/EtOH ratio was raised
more practical reversed protocol for the ATRC (re- from 3/1 to 3.5/0.5 (Table 3, entry 4). Clearly the
versed means that the catalyst is added to the reaction redox system is the more reactive, the lower the frac-
system in its higher oxidation state), thus copper was tion of protic solvent in the solvent mixture is, and
weighed as CuCl . The percentage of AA was concur- this up to the limit of an amount of EtOH around 12–
2
rently changed (and the Na CO with it) to maintain 25%.
2
3
Confident of the good results attained, we took
a further step forward, and the catalyst load was de-
creased to 0.1 mol%, but the conversion of 1, even
with the more active complexes, was not complete
(
Table 3, entries 5–7). Believing that at such low con-
centrations the in situ formation of the complex, be-
tween CuCl and the nitrogen ligand, did not proceed
2
smoothly, we thought to employ preformed cupric
complexes in ethanol. The results were indeed better
but not as much as hoped for: only CuCl /TPMA
2
gave
a
satisfactory 96% conversion (Table 3,
entry 10), although the diastereomeric ratio still re-
mained unsatisfactory.
Efforts to improve the result by rising the tempera-
ture were in vain. Counter intuitively, the process effi-
ciency progressively declined when the temperature
Figure 1. Polydentate nitrogen ligands used in this work.
4
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Efficient and Green Route to g-Lactams by Copper-Catalysed Reversed Atom Transfer Radical Cyclisation
[a]
Table 3. Setting of the best conditions for the reversed ARGET-ATRC of 1 in AcOEt/EtOH.
[b]
[b,c]
Entry8
CuCl2
[mol%]
Ligand
[mol]
AcOEt/
EtOH
T/t
[8C]/[h]
Conversion
[%]
Products
[%]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
U
G
1
2
3
4
5
6
7
0.5
0.5
0.5
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
A (0.5)
A (0.5)
A (0.5)
A (0.5)
A (0.1)
B (0.1)
C (0.1)
A (0.1)
B (0.1)
C (0.1)
C (0.1)
C (0.1)
C (0.1)
C (0.1)
C (0.1)
0/4
2/2
3/1
3.5/0.5
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
35/8
35/8
35/8
35/8
63
60 (55:45)
[d]
100
100
100
32
48
86
47
55
96
91
98 [93][ (65:35)
d]
99 [95][ (84:16)
d]
99 [95] (84:16)
35/24
35/24
35/24
35/24
35/24
35/24
40/24
45/24
55/24
25/24
15/24
30 (57:43)
45 (57:43)
84 (60:40)
44 (58:42)
52 (58:42)
[
[
e]
e]
[
8
9
1
1
1
1
1
1
e]
e]
e]
e]
e]
e]
[d]
0
1
2
3
4
5
91 [85] (61:39)
[
[
[
[
[
89 (60:40)
88 (60:40)
80 (59:41)
91
82
100
73
[d]
98 [92] (66:34)
71 (59:41)
[
a]
All reactions were carried out under argon and with CuCl complexes: substrate 8 mmol, solvent 4 mL, AA 2.5 mol%
2
and Na CO 5.0 mol%.
GC value.
In round brackets are the cis/trans ratios (GC).
Yields determined on isolated material.
The catalyst system Cu/ligand is preformed.
2
3
[
[
[
[
b]
c]
d]
e]
[a]
Table 4. Effect of the AA and Na CO percentage on the reversed ARGET-ATRC of 1 in AcOEt/EtOH 3/1.
2
3
[b]
[c]
[c,d]
Entry
Complex
[mol%]
AA/Na CO
ACHTUNGTRNENUNG[ mol%]
w/w%
Conversion
[%]
Products
[%]
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ꢀ
ꢀ
1
1
2
3
4
5
6
CuCl A (0.5)
2.5/5.0
1.5/3.0
2.5/5.0
1.5/3.0
0/0
4.1 (0.013)
2.7 (0.009)
4.3 (1.044)
2.9 (1.040)
–
100
100
100
100
73
99 [93] (86:14)
99 [95] (85:15)
99 [93] (84:16)
99 [96] (85:15)
73 (59:41)
2
1
CuCl A (0.5)
2
CuCl /C (0.5)
CuCl /C (0.5)
CuCl/A (3)
CuCl/A (5)
2
2
0/0
5.0 (0.032)
98
98 [94] (57:43)
[
[
[
[
a]
b]
c]
d]
All reactions were carried out, under argon, with preformed complexes: substrate 8 mmol, solvent 4 mL, T 358C, t 8 h.
Catalytic system load in weight% and in parentheses its cost in E.
GC value.
In round brackets are the cis/trans ratios (GC), and in square brackets the yields determined on isolated material.
was just slightly raised (Table 3, entries 10–13). It sults that were indistinguishable from those recorded
seems that at higher temperatures the catalyst some- with the usual load of 2.5/5.0 mol% (Table 4, en-
how suffers from a premature “degradation” or tries 1–4).
a larger dissociation (more appreciable at such low
concentration levels). On the contrary the best result lysed by an amount of CuCl/PMDETA with the same
conversion 100% and yield 92%) was achieved global reducing capacity of the two previous ARGET
As a comparison, two “normal” ATRCs of 1, cata-
(
under milder conditions, at 258C (Table 3, entry 14), systems (Table 4, entries 1-4), were also carried out
but with an unacceptably low diastereomeric ratio. A (Table 4, entries 5 and 6). The results of the compari-
further decrease of the reaction temperature substan- son unambiguously indicate that the redox catalyst
tially deteriorated the performances of the process works more efficiently in the reversed ARGET-
(
Table 3, entry 15).
ATRC mode.
With the best combination between CuCl , ligand
The global catalytic system load was also expressed
2
and solvent ratio (Table 3, entry 3) in hand, we con- in [w/w %] (weight of the catalyst/weight of substrate
sidered the possibility of diminishing the load of AA/ %), an industrially more revealing parameter. The
Na CO . Indeed, working with 1.5/3.0 mol% of AA/ percentages (Table 4, column 4; values in parenthe-
2
3
Na CO gave, both with PMDETA and TPMA, re- ses) are attractive and are even lower than that for
2
3
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
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Franco Bellesia et al.
UPDATES
Scheme 6. Metal-free ATRC of 1.
a typical ATRC. Finally cost analysis shows that, effi-
ciency being equal, the redox system, based on CuCl2/
PMDETA, is to be preferred, as it is by far the cheap-
est one.
To exclude any overlapping of the copper-catalysed
cyclisation (Scheme 3a) with the hypothetical free
radical chain process, outlined in Scheme 6, we tried
to trigger the ATRC of 1 with a typical radical initia- Scheme 7. Substrates and products used to test the scope of
tor. Thus a solution of the amide 1 (8 mmol) in the method.
AcOEt/EtOH 3/1 (4 mL) was heated at 908C in the
presence of Bz O (2–4 mol%).
2
2
The absence of 1a and of any cyclisation product groups are bound to the C-3ꢀC-4 bond, the opposite
(
conversion was virtually zero) means that the phenyl is true. The weak selectivity observed for 10a, is in-
ꢀ
1
radical (BDEPhꢀCl is 95 kcalmol and k
for the ex- stead typical of substrates that carry bulky groups at
258C
ꢀ1 ꢀ1 [29]
6
traction of Cl from CCl is 6.0ꢂ10 M s ) and the C-4, which, for steric reasons, have difficulty to distin-
4
less reactive primary radical 1 (BDE stays between guish between geminal methyl and Cl substituents at
r2
ꢀ
1
ꢀ1
[19b,o]
BDEBnꢀCl 74 kcalmol and BDEMeꢀCl 83 kcalmol , C-3.
while k258C for the extraction of Cl from CCl by
The excellent outcomes with dichloroacetamide 4
4
3
ꢀ1 ꢀ1 [29]
RCH · is 7.2ꢂ10 M s ) were unable to displace and trichloroacetamide 5 deserve comment. In our
2
the a-Cl from 1. Besides, even if some initiation could previous study with CuCl/PMDETA-AA-Na CO at
2
3
occur under these conditions, the complete failure of a load ranging between 2/2.5/2.75 and 4/5/5.5 mol%,
the metal-free ATRC points to the same deduction, these compounds suffered partial hydrodehalogena-
[
18a]
i.e., the primary radical 1r2 is unable to sustain the tion and incomplete conversion, respectively.
Both
propagation step. We can thus confidently exclude phenomena have a common cause: the catalyst is too
that 1a can originate through a classic chain process, reactive and/or its concentration is too high.
during the metal-catalysed ATRC.
In the case of acetamide 4 the rotation around the
To explore the scope of the method, we prepared amide bond in the radical 4B (Scheme 3a) is not as
a variety of amides with different cyclisation auxilia- fast as in other radicals of the series. Hence the cycli-
ries, allyl moieties or groups bound to the CCl unit sation becomes relatively slow and the electrophilic
2
(
Scheme 7). Tests were carried out taking CuCl2/ N-allylcarbamoylmethyl radical B could be reduced
PMDETA as the reference redox complex, and turn- by the catalytic system. Amides, like 5, and their cycli-
ing to CuCl /TPMA, only when a highly active cata- sation products are on the other hand quite reacti-
2
[
19c]
lyst was really required. A selection of the best results ve,
obtained, under the cheapest conditions, is reported that bring about a premature catalyst depletion.
in Table 5. As reported in the ATRP field, all these side reac-
and are likely to undergo parasitic reactions
The new method appears robust and reliable, tions are second order and can be controlled through
always providing excellent yields (except with 6, see a drastic reduction of the concentration of the catalyst
[
8a,l]
below), and the highest possible diastereomeric ratios active form.
yet reported,
In our new catalytic system this condi-
[18a]
the preferred isomer being always, as tion is fully accomplished: CuCl is the starting redox
2
expected, the thermodynamic one. Generally this is component, its concentration is low (0.5 mol%) and
the cis-adduct, but in the case of 4a, where only two the AA is much less soluble in AcOEt/EtOH 3/1 than
6
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Efficient and Green Route to g-Lactams by Copper-Catalysed Reversed Atom Transfer Radical Cyclisation
[a]
Table 5. Reversed ARGET-ATRC of amides 2–12.
[c]
[d,e]
Entry
Substrate/
Method
AA/base
[mol%]
t
Conversion
[%]
Products
[%]
[
b]
A
H
U
G
R
N
U
G
[h]
1
2
3
4
5
6
7
8
9
2/I
3/I
4/II
5/I
7/I
8/I
9/I
10/I
11/II
12/II
2.5/5.0
2.5/5.0
2.5/5.0
2.5/5.0
2.5/5.0
1.5/3.0
1.5/3.0
2.5/5.0
2.5/5.0
2.5/5.0
8
8
8
8
8
8
8
8
8
8
100
100
100
100
100
100
100
100
100
100
94 (87:13)
93 (99:1)
95 (26:74)
93
96 (87:13)
94 (84:16)
96 (96:4)
95 (58:42)
96 [97
96 [82
A
T
N
T
E
N
N
ACHTUNGTRENNUNG
10
A
H
N
T
E
N
G
ACHTUNGTRENNUNG
[
a]
All reactions were carried out, under argon: substrate 8 mmol, preformed CuCl /L 0.5 mol%, AcOEt/EtOH 3/1 4 mL, T
2
3
58C, t 8 h.
[
[
[
[
b]
Method I, L=PMDETA; method II, L=TPMA.
GC value.
Yields determined on isolated material.
c]
d]
e]
1
In brackets are the cis/trans ratios (GC or H NMR).
in neat ethanol. The ensuing drop of the rate of the Table 6. E1/2 measured for CuCl complexes in different mix-
2
[a]
parasitic phenomena improved selectivity and effi- ture of AcOEt/EtOH.
ciency of 4 and 5 cycloisomerisations.
Entry Ligand
AcOEt/
EtOH
E1/2 [
E1/2
(10 d)
[V]
E1/2
(20 d)
[V]
On the contrary, ATRC of substrate 6, notwith-
standing our efforts, never gave acceptable conver-
sions. Moreover, the selectivity was always disap-
pointing. It was as if the substrate 6 and its product
b]
[b]
[b]
(1 d)
[V]
1
2
3
4
5
6
7
8
PMDETA 0/4
PMDETA 1/3
PMDETA 2/2
PMDETA 3/1
TPMA
TPMA
TPMA
TPMA
ꢀ0.082 ꢀ0.086
ꢀ0.110 ꢀ0.106
ꢀ0.130 ꢀ0.141
ꢀ0.169 ꢀ0.176
ꢀ0.226 ꢀ0.226
ꢀ0.245 ꢀ0.256
ꢀ0.283 ꢀ0.286
ꢀ0.313 ꢀ0.308
ꢀ0.078
ꢀ0.110
ꢀ0.124
ꢀ0.158
ꢀ0.228
ꢀ0.258
ꢀ0.290
ꢀ0.318
6
a were incompatible with the catalytic system.
ATRP has already come across situations of this
type.
[14d,30]
When this occurs, less active systems have
0/4
1/3
2/2
3/1
to be used. Indeed, when 6 was reacted with CuCl
[
19c]
under ligand free-like conditions,
the cyclisation
proceeded smoothly (Scheme 8), yielding a result
analogous to the one we obtained previously with the
less reducing complex CuCl/TMEDA.
[a]
[
19t]
All measurements were carried out, under argon, in the
presence of 0.1M (C H ) NBF , [CuCl ]=[ligand]=
2
5
4
4
2
Preformed cupric complexes with variable shelf life
from a few hours to 1 month) were used in our tests,
0
.01M, T 358C, potentials are referred to the ferroceni-
(
um/ferrocene.
without consequences on the reaction performances.
This well matches with the data reported in Table 6,
which show that for both complexes the shelf life has
no effect on the redox properties of the catalyst; var-
iation of E1/2 with time is in fact negligible.
[b]
In parentheses the time after which the measurement
was taken.
the metal complex (or equilibrium of electron trans-
From a thermodynamic point of view, the ATRP fer, 1/K ), electron affinity of X atom (KEA) and as-
ET
equilibrium constant (KATRP) was conveniently split sociation of the halide ion to the catalyst in its higher
[
8a,e,f,i,l]
into four elementary thermodynamic contributions oxidation state (or halidophilicity, Khalido).
(
Scheme 9): CꢀX bond homolysis (KBH), oxidation of
Since ATRP and ATRC are inherently similar pro-
cesses, considerations from the ATRP thermodynamic
model of Scheme 9 can be useful to rationalise the
solvent effect that we observed on the reaction out-
come (Table 3, entries 1–4).
Now it is well known that solvent affects at the
[
8f]
same time K , K
and Khalido,
which altogether
ET
EA
define the halogenophilicity (Khalo) of the catalyst,
i.e., the process of formation of the Cu(II)ꢀX bond
[
8a,e]
(
Scheme 9).
We attribute tentatively the observed
Scheme 8. Ligand free-like ATRC of amide 6.
dependence of reactivity on solvent composition
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

Franco Bellesia et al.
UPDATES
Conclusions
We have described a highly efficient ARGET-ATRC
for the cycloisomerisation of N-allyl-N-substituted-a-
polychloroamides to g-lactams. The catalytic system is
based on the combination of copper complexes (as
redox catalysts), ascorbic acid (as safe regenerating
agent) and Na CO (as acidity quencher). Thanks to
2
3
the individualisation of a more appropriate solvent
AcOEt/EtOH 3/1), the efficacy of this catalytic
(
system was boosted, allowing a drop of the metal load
to 0.5 mol%.
For the first time the protocol, to which we adhere,
was of the reversed type, since the catalyst was more
conveniently added to the reaction mixture as pre-
formed cupric complex (the inactive form of the
redox pair): CuCl /PMDETA or CuCl /TPMA.
Scheme 9. Factorisation of the ATRP equilibrium in 4 ele-
mentary contributions.
2
2
The new process showed to be robust and worked
reliably with all the substrates we tested, polychloro-
AHCTUNGTRENNUNGa cetamides included, allowing the highest stereoselec-
tivities compatible with the thermodynamic control.
[
8f]
(
Table 3, entries 1–4) to its strong action on Khalido
.
In fact, since halidophilicity is low in protic solvents,
The only severe exception was the N-allyl-N-
it is clear that increasing the percentage of EtOH in benzyl-2,2-dichloro-2-phenylacetamide. This arose
the solvent mixture triggers a progressive Khalido drop from the incompatibility of this highly reactive sub-
ꢀ
(
particularly marked as the halide at issue is Cl ). As strate with our catalytic system.
a consequence the ratio Khalido/KET should decrease,
Mild reaction conditions, low load of catalyst and
and with it the Khalo (side by side with KATRP) too, not- additives, handling of stable cupric complexes, use of
[
8f]
withstanding the predictable increase of KEA
.
“natural” solvents and high substrate concentrations
ꢀ
1
Interestingly, the standard potential of the (2 mmolmL of solvent) make this process really at-
ClCu(II)L/ClCu(I)L couple has shown a significant tractive for scale-up or large-scale preparations.
dependence of the solvent composition. In order to
show correctly the solvent effect on E , we used the
1/2
ferrocenium/ferrocene couple as reference system, in-
stead of the conventional aqueous saturated calomel
electrode, which would introduce an inter-solvent po-
tential that varies with the composition of the solvent.
Experimental Section
General Remarks
As can be seen in Table 6, E1/2 becomes more nega- Reagents and solvents were standard grade commercial
tive upon increasing the percentage of AcOEt (a products and used without further purification. For the cata-
lytic systems we employed: CuCl Fluka (ꢁ97%), CuCl2
moderately polar but low coordinating solvent) in the
Riedel-de Haꢃn (ꢁ97%), PMDETA Acros (+99%), TPMA
reaction mixture. The measured potentials, however,
app
Aldrich (98%), Me TREN Aldrich (ꢁ88%), AA Sigma (>
6
have to be related to the K halido/KET parameter
app
99.5%) and Na
2
CO
3
Carlo Erba (ꢁ99.5%). Silica gel for the
(
K
means apparent halidophilicity), since they
halido
[8f]
flash chromatography was the Silica Gel 60 Merck (0.040–
.063 mm). The screw-capped Schlenck tube, fitted with a ro-
also take into account the Cu(I)L halidophilicity. In
any case K halido/K
0
app
[8f]
ET
also correlates well to KATRP.
taflow valve, had a capacity of 25 mL and an external diam-
eter of 2.5 cm. An oval stirring bar (l=1 cm, d=0.5 cm) was
For similar solvent variations (e.g., from ethanol to
[
8f]
acetone or propylene carbonate) the shift of E1/2 to used. The 2,2-dichloroacyl chlorides (apart from dichloro-
app
more negative potentials raises K
/K , and with
ACHTUNGTRENNUNGa cetyl chloride and trichloroacetyl chloride, which were pur-
chased) were prepared, on our mini-pilot plant, by chlorina-
halido
ET
[
8f]
it the KATRP, notwithstanding the decrease of KEA.
tion of acyl chlorides with Cl in the presence of tetrabutyl-
Thus, as envisaged, the drop of the protic features of
the solvent mixture improves the process perfor-
mance, in terms of both conversion and selectivity
2
[31]
AHCTUNGTRENNUGNa mmonium chloride. The starting amides 1–8 and 10--12
were obtained through standard aminodechlorination of
acyl chlorides with allylic amines (all prepared by N-alkyla-
(
Table 3), because the catalyst, becoming more reduc-
[32]
tion of amines, adapting Shipmanꢄs method ). The
sulphonamide 9 was assembled by acylation of the lithium
salt of N-allylmethanesulphonamide. All the amides were
[19c]
ing, increases the reaction rate of the starting materi-
al, as well as the rate of interconversion of the two
diastereomeric products.
AHCTUNGTRENNUNG
[19a]
[
19c]
[19t]
[19c]
thoroughly purified! Products 1a,
3a,
4a,
are known com-
pounds, which were all obtained through copper-catalysed
5a,
[19t]
[19c]
[19]
[19d]
[19d]
6
a,
8a,
10a,
11a
and 12a
8
asc.wiley-vch.de
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Efficient and Green Route to g-Lactams by Copper-Catalysed Reversed Atom Transfer Radical Cyclisation
ATRC reactions. NMR spectra were recorded on a “Varian Cyclization of N-Allyl-N-phenyl-2,2-dichloropropan-
500 MHz” spectrometer. The relative configurations were
amide (7)
determined by NOESY experiments. IR and mass spectra
were recorded on a Perkin-Elmer 1600 Series FT-IR and
HP 5890 GC - HP 5989 AMS Engine, respectively. Elemen-
tal analyses were performed on the EA 1110 Carlo Erba.
Cyclic voltammetric experiments were carried out in
a three-electrode cell with a glassy carbon disc (d=3 mm,
Bioanalytical Instruments) working electrode, a Pt wire
Following the same procedure as described for 2, 7 (8 mmol,
2
.066 g) gave, after flash-chromatography on silica gel, using
a PE/Et O gradient (from 100/0 a 0/100), the lactam 7a as
2
a colourless oil; yield: 1.980 g [96%, a mixture of cis/trans
1
diastereomers (87:13, H NMR)]; anal. found: C 55.74, H
5
.07, N 5.41; C H Cl NO requires: C 55.83, H 5.08, N, 5.43;
12 13 2
ꢀ
R (70% PE/Et O) 0.60 cis-7a and 0.46 trans-7a.
counter-electrode and an AgjAgIjI reference electrode.
f
2
3
-Chloro-4-(chloromethyl)-3-methyl-1-phenylpyrrolidin-
The potential of the reference electrode was always calibrat-
ꢀ
1
1
2
-one (7a): IR (liquid film): nmax =1695 cm ; H NMR
ed at the end of the experiment versus the ferrocenium/fer-
+
(500 MHz, CDCl , cis): d=1.87 (3H, s, CH ), 2.73 (1H, m,
rocene (Fc /Fc) couple. All potentials in the paper are re-
3
3
+
H-4), 3.68 (1H, dd, J=9.5, 10.0 Hz, H-5); 3.80 (1H, dd, J=
.3, 11.3 Hz, CHCl), 3.91 (1H, dd, J=5.2, 11.3, CHCl); 4.00
1H, dd, J=7.0, 10.0 Hz, H-5), 7.21 (1H, m, ArH), 7.40
ported versus Fc /Fc.
9
(
(
Typical Procedure: Cyclization of N-Allyl-N-benzyl-
1
3
2H, m, ArH), 7.64 (2H, m, ArH); H NMR (125 MHz,
2,2-dichlorobutanamide (2)
CDCl , cis): d=25.0, 42.0, 47.1, 49.4, 69.8, 120.1, 125.4,
3
1
In an oven-dried Schlenk tube (previously rinsed with a solu-
129.0, 138.5, 169.7; H NMR (500 MHz, CDCl
, trans): d=
3
tion of NH and plenty of water in sequence) were weighed
1.73 (3H, s, CH ), 3.08 (1H, m, H-4), 3.54 (1H, dd, J=9.7,
3
3
ascorbic acid (0.2 mmol, 35.2 mg), Na CO (0.4 mmol,
11.2 Hz, CHHCl); 3.74 (1H, dd, J=4.8, 10.3 Hz, H-5), 3.84
(1H, dd, J=4.5, 11.2, CHHCl); 4.17 (1H, dd, J=7.0,
10.3 Hz, H-5), 7.21 (1H, m, ArH), 7.40 (m, 2H, ArH), 7.64
2
3
42.4 mg) and amide 2 (8 mmol, 2.290 g). After 3 cycles of
vacuum/argon (globally 10 min, approximately 8.50 min for
vacuum and 1.50 min under argon) AcOEt (3 mL) and –
when the substrate was fully solubilized – the preformed so-
1
3
(2H, m, ArH); C NMR (125 MHz, CDCl
, trans): d=21.5,
3
42.2, 47.7, 48.9, 68.7, 120.1, 125.5, 129.0, 138.5, 169.8; MS
+
+
lution of CuCl /PMDETA 0.04M in absolute ethanol (1 mL)
(ESI-ion trap): m/z=244 [M-HCl+Na] , 280 [M+Na] .
2
were added under argon. The reaction mixture was prompt-
ly immersed in a water bath at 358C and stirred (700 rpm).
After 8 h the Schlenk tube was opened (a little pressure due
Cyclization of N-Allyl-N-methylsulphonyl-3-methyl-
2,2-dichlorobutanamide (9)
to CO released during the reaction) and the reaction mix-
2
Following the same procedure as described for 2, 9 (8 mmol,
.306 g) gave, after flash-chromatography on silica gel, using
ture was diluted with water (8 mL), acidified with HCl 10%
w/v and extracted with CH Cl (3ꢂ6 mL). The combined or-
2
2
2
a PE/Et O gradient (from 100/0 a 0/100), the lactam 9a as
ganic layers were concentrated and the crude product was
purified by flash chromatography on silica gel, eluting with
2
a white solid; yield: 2.218 g [96%, a mixture of cis/trans dia-
1
stereomers (96:4, H NMR)]; anal. found: C 37.70, H 5.23,
a petroleum ether (PE bp 40–608C)/diethyl ether (Et O)
2
N 4.90, S 11.17; C H Cl NO S requires: C 37.51, H 5.25, N
gradient (from 100/0 to 0/100). This gave the 2-pyrrolidinone
9
15
2
3
4
.86, S 11.13; R (70% PE/Et O) 0.25.
2
a as a colourless oil; yield: 2.156 g [94%, an inseparable
f
2
1
3
-Chloro-4-(chloromethyl)-3-isopropyl-1-(methylsulpho-
mixture of cis/trans diastereomers (87:13, H NMR]; anal.
nyl)pyrrolidin-2-one (9a): mp 57–88C; IR (nujol): n
=
max
found: C 58.57, H 6.01, N 4.87; C H Cl NO requires: C
1
4
17
2
ꢀ
1
1
1
745 cm ; H NMR (500 MHz, CDCl , cis): d=1.11 and
5
8.75, H 5.99, N 4.89; R (70% PE/Et O) 0.65.
3
f
2
1
.19 [3H each, d, J=6.7 Hz, (CH ) CH], 2.50 [1H, septet,
1
-Benzyl-3-chloro-4-(chloromethyl)-3-ethylpyrrolidin-2-
3 2
ꢀ
1
1
J=6.7 Hz, (CH ) CH], 2.91 (1H, m, H-4), 3.29 (3H, s,
one (2a): IR (liquid film): nmax =1710 cm ; H NMR
3 2
SO CH ), 3.53 (1H, dd, J=8.7, 10.1, H-5), 3.69 (1H, dd, J=
(
500 MHz, CDCl , cis): d=1.06 (t, J=7.9 Hz, 3H, CH CH ),
2
3
3
3
2
9
4
.0, 11.2, CHHCl), 3.84 (1H, dd, J=4.1, 11.2 Hz, CHHCl),
13
2
9
.21 (2H, m, CH CH ), 2.72 (1H, m, H-4), 3.05 (1H, dd, J=
.0, 10.0 Hz, H-5), 3.39 (1H, dd, J=7.1, 10.0 Hz, H-5), 3.63
2 3
.21 (1H, dd, J=7.3, 10.1 Hz, H-5); C NMR (125 MHz,
CDCl , cis): d=17.3, 18.2, 34.7, 39.8, 40.7, 42.9, 47.4, 76.1,
(
1H, dd, J=9.7, 11.1 Hz, CHHCl), 3.79 (1H, dd, J=4.9,
3
1
1
70.1; H NMR (500 MHz, CDCl , trans): d=1.13 and 1.35
1
1
1.1 Hz, CHHCl), 4.41 and 4.49 (2H, AB system, J=
3
1
3
[
3H each, d, J=6.3 Hz, (CH ) CH], 2.25 [sept, 1H, J=
4.6 Hz, CH Ph), 7.24–7.37 (5H, m, ArH);
C NMR
3 2
2
6
2
.3 Hz, (CH ) CH], 2.93 (1H, overlapped to the signal at
3 2
.91 relative to H-4 trans, H-4), 3.53 (1H, overlapped over-
(
7
125 MHz, CDCl , cis): d=9.5, 30.6, 42.6, 43.0, 46.9, 47.6,
2.9, 127.95, 128.9, 135.45, 170.7; H NMR (500 MHz,
3
1
lapped to the signal at 3.53 relative to H-4 trans, CHHCl),
CDCl , trans): d=1.16 (t, J=7.9 Hz, 3H, CH CH ), 1.77 and
3
3
2
3
.78 (1H, dd, J=3.5, 11.5 Hz, CHHCl), 3.95 (1H, dd, J=
.0, 10.5 Hz, H-5), 4.09 (1H, dd, J=6.0, 10.5 Hz, H-5);
C NMR (trans): sample concentration too low; MS (EI,
2
.12 (1H each, m, CH CH ), 2.88 (1H, m, H-4), 3.15 (1H,
2 3
2
dd, J=4.9 and 10.4 Hz, H-5), 3.34 (1H, t, J=10.8 Hz,
CHHCl), 3.54 (1H, dd, J=6.4, 10.4 Hz, H-5), 3.68 (1H, dd,
J=4.0, 10.8 Hz, CHHCl), 4.44 and 4.59 (AB system J=
1
3
+
7
0 eV): m/z=245 [42, (Mꢀ42) ], 196 (100), 79 (18).
1
3
1
4.6 Hz, 2H, CH Ph), 7.24–7.37 (5H, m, ArH); C NMR
2
(
7
125 MHz, CDCl , trans): d=8.6, 26.6, 41.9, 47.0, 47.1, 47.65,
3
Cyclization of N-Allyl-N-benzyl-2,2-dichloro-2-
phenylacetamide (6)
2.6, 128.0, 128.9, 135.5, 170.5; MS (ESI-ion trap): m/z=286
+ +
[(M+H) ], 308 [(M+Na) ].
CuCl (50 mg, 0.5 mmol) and 2,2-dichloroamide 6 (1.672 g,
5
mmol) were weighed in a Schlenk tube fitted with a pierca-
ble septum (blocked by a screw cap) and a magnetic stirring
bar. DMF (2.5 mL) was then added under argon. The mix-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

Franco Bellesia et al.
UPDATES
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matography on silica gel, eluting with PE/Et O gradient.
2
This gave the 2-pyrrolidinone 6a as a red oil; yield: 1.486 g
red oil [89%, inseparable mixture of cis/trans diastereomers
1
2774; c) B. Lucchese, K. J. Humphreys, D.-H. Lee,
1
(
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C H Cl NO requires: C 64.68, H 5.13, N 4.19; R (70% PE/
18
17
2
f
Et O) 0.40.
2
1
-Benzyl-3-chloro-4-(chloromethyl)-3-phenylpyrrolidin-
ꢀ
1 1
2
-one (6a): IR (liquid film): nmax=1709 cm ; H NMR
(
500 MHz, CDCl , cis): d=2.98 (1H, m, H-4), 3.25 (1H, dd,
3
J=8.9, 10.1 Hz, H-5), 3.56 (1H, dd, J=6.9, 10.1 Hz, H-5),
3
.75 (2H, m, CH Cl), 4.50 and 4.72 (2H, AB system, J
2
1
4.0 Hz, CH Ph), 7.29–7.44 (8H, m, ArH), 7.54 (2H, m,
2
[
[
7] a) J.-S. Wang, K. Matyjaszewski, J. Am. Chem. Soc.
13
ArH); C NMR (125 MHz, CDCl , cis): d=41.7, 47.4, 47.7,
3
1
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4
9.1, 73.7, 127.2, 128.3, 128.65, 129.0, 135.4, 137.1, 170.6;
1
H NMR (500 MHz, CDCl , trans): d=2.78 (1H, t, J=
3
1
10.6 Hz, CHCl), 3.12–3.22 (3H, overlapped signals, H-4 and
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4
.73 (2H, AB system, J=14.0 Hz, CH Ph); 7.29–7.44 (10H,
2
13
ArH); C NMR (125 MHz, CDCl , trans): d=42.9, 47.1,
3
4
1
7.6, 50.4, 72.6, 128.1, 128.6, 128.8, 128.85, 129.05, 134.8,
35.3, 170.2; MS (EI, 70 eV): m/z=298 [40, (Mꢀ35) ], 297
+
(
(
38), 262 (7), 248 (20), 242 (9), 151 (46), 115 (47), 91
100%).
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23] In the presence of halide ions, copper complexes with
amine ligands undergo complicated speciation equili-
12
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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UPDATES
Efficient and Green Route to g-Lactams by Copper-
Catalysed Reversed Atom Transfer Radical Cyclisation of
a-Polychloro-N-allylamides, using a Low Load of Metal
13
(
0.5 mol%)
Adv. Synth. Catal. 2013, 355, 1 – 13
Franco Bellesia, Andrew J. Clark, Fulvia Felluga,
Armando Gennaro, Abdirisak A. Isse, Fabrizio Roncaglia,
Franco Ghelfi*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
13
ÞÞ
These are not the final page numbers!