The synthesis of functionalised β- and γ-lactams by cyclisation of enamides using copper(I) or ruthenium(II)

Article abstract of DOI:10.1016/S0040-4039(01)00320-3

Cyclisation of a variety of halo-enamides with copper(I) or ruthenium(II) complexes has been investigated. The regioselectivity of the radical cyclisation, which can proceed via either a 4-exo or 5-endo pathway, to form β- or γ-lactam products respectively, is determined by the nature of the metal oxidant and the reaction conditions. Thus, whereas copper(I)/bipyridine reactions give predominantly γ-lactams, the use of copper(I)/TMEDA or dichlorotris(triphenylphosphine)ruthenium(II) affords mainly β-lactams.

Full text of DOI:10.1016/S0040-4039(01)00320-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2901–2905
The synthesis of functionalised b- and g-lactams by cyclisation of
enamides using copper(I) or ruthenium(II)
Justin S. Bryans,a Nicola E. A. Chessum,b Andrew F. Parsonsb,* and Franco Ghelfic
aPfizer Global Research and Development, Forvie Site, Robinson Way, Cambridge CB2 2QB, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
cDipartimento di Chimica, Universita` degli Studi di Modena e Reggio Emilia, Via Campi 183, I-41100 Modena, Italy
Received 25 January 2001; accepted 21 February 2001
Abstract—Cyclisation of a variety of halo-enamides with copper(I) or ruthenium(II) complexes has been investigated. The
regioselectivity of the radical cyclisation, which can proceed via either a 4-exo or 5-endo pathway, to form b- or g-lactam products
respectively, is determined by the nature of the metal oxidant and the reaction conditions. Thus, whereas copper(I)/bipyridine
reactions give predominantly g-lactams, the use of copper(I)/TMEDA or dichlorotris(triphenylphosphine)ruthenium(II) affords
mainly b-lactams. © 2001 Elsevier Science Ltd. All rights reserved.
Radical cyclisation of unsaturated organohalides to
form N-heterocycles has attracted considerable syn-
thetic interest in recent years.1 A wide variety of five-
and six-membered rings in particular, can be prepared
under mild reaction conditions using a variety of cycli-
sation methods. For example, g-lactams can be pre-
pared from tributyltin hydride-mediated cyclisation of
N-allyl or N-vinyl (enamide) halo-amides, by 5-exo2 or
5-endo3 pathways, respectively (Scheme 1). The 5-endo-
trig cyclisation of halo-enamides is intriguing because
the initial carbamoylmethyl radical 1 prefers to form
g-lactam 2 rather than undergo the more favourable
4-exo-trig cyclisation leading to b-lactam 3. Indeed, the
4-exo-trig reaction is generally only observed when
bulky radical-stabilising (e.g. R=aromatic) groups are
introduced on the b-position of the enamide double
bond. These R groups can stabilise b-lactam radical 2
(by electronic effects) and also hinder attack at the
b-position of carbamoylmethyl radical 1 (by steric
effects).4 The R1 substituents are also important and,
for example, the introduction of radical stabilising
groups at this position favours the formation of g-lac-
tam radical 2.5 These results have been explained on the
basis of a reversible cyclisation mechanism; the 4-exo
cyclisation produces the kinetically favoured b-lactam
while the 5-endo cyclisation produces the thermody-
namically more stable g-lactam.5
As part of a programme to develop alternative radical
reagents to tributyltin hydride, we recently reported the
cyclisation of enamides using copper(I) chloride/
bipyridine or dichlorotris(triphenylphosphine)ruthen-
ium(II).6,7 Hence, cyclisation of chloro-enamides such
as 4 was observed to give dienes in excellent yield by a
5-endo radical cyclisation (Scheme 2). No b-lactams
were isolated from these reactions, which were pro-
R
R1
R1
O
R
R
R
β
R1
R
4-exo
5-endo
R
α
N
N
P
O
N
O
P
P
kinetic product
thermodynamic product
1
3
2
Scheme 1.
Keywords: copper and compounds; lactams; radicals and radical reactions; ruthenium and compounds.
* Corresponding author. Tel.: +44-1904-432608; fax: +44-1904-432516; e-mail: afp2@york.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00320-3

2902
J. S. Bryans et al. / Tetrahedron Letters 42 (2001) 2901–2905
R1
R1
X
R
R
Cl
Cl
Cl3C
O
Cl
CuCl
N
O
bipyridine
94%
N
N
N
O
O
Bn
Bn
Bn
Bn
R = R = CH3
R = R = (CH2)5
6
4
5
Scheme 2.
posed to involve deprotonation of an intermediate N-
acyliminium ion of type 5. With a view to increasing
the generality and flexibility of this cyclisation method,
as well as probing the mechanism of these types of
reaction, we now report the novel cyclisation of enam-
ides of type 6 using copper(I) or ruthenium(II) com-
plexes. These enamides possess some important
structural features. To encourage 4-exo cyclisation they
contain two b-substituents and to prevent deprotona-
tion of an intermediate N-acyliminium ion they have no
a-substituent.8
product, although the ratio of 9:8 did vary from 9.6 to
2.6:1. Purification of the crude product using column
chromatography (on silica) resulted in the hydrolysis of
a-chloro-g-lactam 9 to give a-hydroxy-g-lactam 10,
while reaction with methanol gave a-methoxy-g-lactam
11. Hence when 7 was reacted with copper(I) chloride/
bipyridine (0.5 equiv./0.5 equiv.) and the crude product
stirred with methanol (for 24 h at rt), column chro-
matography afforded 8, 10 and 11 in 9, 43 and 43%
yields, respectively. It should be noted that 11 is con-
verted to 10 on column chromatography. This was
indicated by the 1H NMR spectrum of the crude
product, which showed a 6.7:1 ratio of 11:10 prior to
chromatography.
Our preliminary work focused on the cyclisation of
trichloro-enamide 7 [prepared by N-acylation of the
imine derived from benzylamine and isobutyraldehyde]
using copper(I) chloride/bipyridine in boiling toluene
(Scheme 3).9 After heating overnight and (acidic)
Interestingly, when trichloro-enamide 7 was reacted
with copper(I) chloride/bipyridine (0.5 equiv./0.5
equiv.) or copper(I) chloride/TMEDA (0.5 equiv./0.5
equiv.) in boiling acetonitrile, only b-lactam 8 was
formed in 85–86% yield (Scheme 4). The crude 1H
NMR spectra showed no evidence for the formation of
g-lactam 9. It should be noted, however, that an
1
workup, the H NMR spectrum of the crude reaction
mixture showed the complete disappearance of starting
material and the clean formation of b-lactam 8 and
g-lactam 9. This reaction was carried out a number of
times and on each occasion g-lactam 9 was the major
Cl
Cl
OH
N
CuCl (0.5 equiv.),
O
Cl
Cl
Cl
O
bipyridine (0.5 equiv.),
toluene, heat
Cl
Bn
10
43%
Cl
Cl3C
O
+
Cl
N
N
N
then MeOH and
Cl
O
Cl
O
Bn
9%
Bn
Bn
column chromatography
9
7
8
OMe
N
Bn
11
43%
Scheme 3.
Cl
Cl
CuCl (0.5 equiv.),
acetonitrile, heat
H
Cl
Cl
Cl
Cl3C
O
N
N
N
TMEDA (0.5 equiv.) or
bipyridine (0.5 equiv.)
O
O
Bn
Bn
Bn
85-86%
12
8
7
Scheme 4.

J. S. Bryans et al. / Tetrahedron Letters 42 (2001) 2901–2905
2903
increase in the number of equivalents of the copper(I)
chloride/TMEDA complex did result in the formation
of an alternative product. Hence when 7 was heated
with 1 equivalent of copper(I) chloride and 2 equiva-
lents of TMEDA in acetonitrile, b-lactam 8 together
with dichloro-b-lactam 12 were formed in 60 and 31%
yields, respectively.
because of steric interaction between the (bulky)
bromine substituents and a terminal methyl substituent,
which lowers the rate of 5-endo cyclisation.10
The effect of introducing a cyclohexyl group at the
terminus of the alkene double bond (in place of the
dimethyl substituents) was also investigated (Scheme 6).
Thus, heating trichloride 16 with copper(I) chloride/
bipyridine (0.5 equiv./0.5 equiv.) in toluene for 12 h
afforded predominantly g-lactam 18 (in an excellent
81% yield) after column chromatography. As for
trichloride 7, the use of copper(I) chloride/bipyridine in
toluene therefore leads to a predominance of the ther-
modynamically more stable g-lactam.
The change in the regioselectivity of the cyclisation can
be rationalised by a reversible mechanism8 in which the
b-lactam is the kinetic product and the g-lactam is the
thermodynamic product (Scheme 1). Hence, 4-exo
cyclisation of radical 1, to give 3, is expected to be
faster than 5-endo cyclisation leading to 2. The cop-
per(I) complexes are soluble in acetonitrile and so the
formation of a tertiary radical of type 3 is expected to
be followed by rapid oxidation to form the b-lactam
product. However, the copper(I) chloride/bipyridine
complex is much less soluble in toluene. As a conse-
quence, the rate of oxidation of 3 is expected to be
slower and so equilibration to the more stable radical 2
can take place prior to oxidation leading to a predomi-
nance of the g-lactam product. Further evidence for
this mechanism came from reacting 7 with only 0.1
(rather than 0.5) equivalents of copper(I) chloride/
bipyridine in boiling toluene. Lowering the copper(I)
concentration was expected to facilitate radical equili-
bration leading to the predominant formation of the
thermodynamically favoured (g-lactam) products.
Indeed, after heating for 22 h, only g-lactams 9 and 10
were formed in 59 and 9% yields, together with unre-
acted starting material (18%), as determined from the
1H NMR spectrum.
For comparison, the cyclisation of halo-enamides 7,
19 and 20 with dichlorotris(triphenylphosphine)-
ruthenium(II) was also carried out (Scheme 7). For
each of these reactions, the main (or exclusive) product
was a b-lactam. For example, cyclisation of trichloro-
enamide 7 gave a combined 48% yield of b-lactams 8
and 21 and only a 17% yield of g-lactam 10. When
using bromides 19 and 20, excellent yields of unsatu-
rated b-lactams 23 and 25 were isolated, presumably
resulting from bromine atom transfer followed by elim-
ination of hydrogen bromide. This can be compared to
the corresponding copper(I) chloride/bipyridine medi-
ated cyclisation of 19, which gave b-lactam 23 in 36%
yield and g-lactam 24 in 26% yield. The predominance
of b-lactams over g-lactams using the ruthenium(II)
complex can be rationalised in a similar way to the
copper(I)/acetonitrile reactions. Hence, the ruthenium-
(II) complex is soluble in boiling toluene and so the
intermediate b-lactam radical (of type 3) is expected to
be rapidly oxidised.
Steric effects also influence the regioselectivity as illus-
trated by the cyclisation of tribromide 13 (Scheme 5).
After heating 13 with copper(I) chloride/bipyridine (0.5
equiv./0.5 equiv.) for 2 h in toluene, b-lactam 14 and
g-lactam 15 were isolated in 48 and 43%, respectively,
after column chromatography. The introduction of
bromine rather than chlorine substituents (at the site of
radical generation) therefore leads to an increase in the
amount of b-lactam product. This is presumably
This work has shown that halo-enamides of type 6 can
undergo both 4-exo and 5-endo radical cyclisations to
form a variety of highly substituted b- and g-lactams
using copper(I) or ruthenium(II). The use of copper(I)
or ruthenium(II) has a number of advantages over
related cyclisation methods including nickel/acetic acid8
or tributyltin hydride.4,5 This includes mild reaction
Br
Br
Br
O
Br
Br
Br3C
O
CuCl, bipyridine
toluene, heat
+
OH
43%
N
N
N
O
Bn
48%
Bn
13
Bn
14
15
Scheme 5.
Cl
Cl
O
CuCl, bipyridine,
Cl
Cl
Cl3C
toluene, heat
Cl
+
OH
81%
N
N
N
O
then chromatography
O
Bn
Bn
16
11%
Bn
17
18
Scheme 6.

2904
J. S. Bryans et al. / Tetrahedron Letters 42 (2001) 2901–2905
Cl
Cl
OH
Cl
O
RuCl2(PPh3)3
(0.5 equiv.)
Cl
Cl
Cl
Cl
Cl3C
O
+
+
+
OH
17%
N
N
N
N
toluene, heat
(2.5 h)
O
O
Bn
Bn
45%
3%
Bn
Bn
8
21
10
7
Br
H
RuCl2(PPh3)3
(0.5 equiv.)
OH
N
N
N
O
N
O
O
toluene, heat
(6.5 h)
O
84%
9%
Bn
Bn
Bn
Bn
24
19
23
22
Br
RuCl2(PPh3)3
(0.5 equiv.)
toluene, heat
(19.5 h)
N
N
O
74%
O
Bn
Bn
20
25
Scheme 7.
conditions, efficient conversions, simple purification of
products and the ability to easily change the regioselec-
tivity of the cyclisation by varying the reaction solvent
and the nature of the redox catalyst. Thus, although we
found that 7 could be efficiently cyclised to N-benzyl-b-
isopropyl-b-lactam (18%) and N-benzyl-b,b-dimethyl-g-
lactam (58%) using tributyltin hydride (1.1 equivalent
added over 1 h followed by immediate addition of 2.2
further equivalents), this required high dilution condi-
tions and rigorous purification to remove the tin
residues. The use of copper(I) or ruthenium(II) also
produces highly functionalised lactams bearing halogen
or alkene functional groups. The formation of highly
substituted/sterically congested g-lactams is particularly
noteworthy and these types of compounds could act as
precursors to, for example, N-acyliminium ions.11 Fur-
ther studies directed towards the application of this
methodology in amino acid synthesis are currently
underway.
Syst. 1997, 1, 355–400.
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We thank Parke-Davis/Pfizer (Cambridge) and the
BBSRC for funding.
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.