Preparation of β- and γ-lactams via ring closures of unsaturated carbamoyl radicals derived from 1-carbamoyl-1-methylcyclohexa-2,5-dienes

Article abstract of DOI:10.1039/b313932h

l-Carbamoyl-1-methylcyclohexa-2,5-dienes produced the corresponding delocalised 1-carbamoyl-1-methylcyclohexa-2,5-dienyl radicals on treatment with radical initiators. At temperatures above ca. 300 K dissociation to produce toluene and aminoacyl (carbamoy

Full text of DOI:10.1039/b313932h

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Preparation of ꢀ- and ꢁ-lactams via ring closures of unsaturated
carbamoyl radicals derived from 1-carbamoyl-1-methylcyclohexa-
2,5-dienes
A. Franco Bella, Leon V. Jackson and John C. Walton*
University of St. Andrews, School of Chemistry, St. Andrews, Fife, UK KY16 9ST.
E-mail: jcw@st-and.ac.uk; Fax: 01334 463808; Tel: 01334 463864
Received 4th November 2003, Accepted 2nd December 2003
First published as an Advance Article on the web 14th January 2004
1-Carbamoyl-1-methylcyclohexa-2,5-dienes produced the corresponding delocalised 1-carbamoyl-1-methyl-
cyclohexa-2,5-dienyl radicals on treatment with radical initiators. At temperatures above ca. 300 K dissociation to
produce toluene and aminoacyl (carbamoyl) radicals took place. The alternative dissociation of the 1-carbamoyl-1-
methylcyclohexa-2,5-dienyl radicals to release methyl radicals and an aromatic amide did not compete. Aminoacyl
radicals with allyl, butenyl or similar side chains underwent cyclisations. Moderate yields of N-benzyl-azetidin-2-ones
and N-benzyl-pyrrolidin-2-ones were isolated for a range of substituents. The main by-products were N-benzyl-
N-alkenylformamides. Ring closure did not take place to a significant extent for precursors with alk-2-ynyl or
2-cyanoalkyl side chains. An improved yield of 1,3-dibenzylazetidin-2-one was obtained by use of lauroyl peroxide
as initiator and by inclusion of methyl thioglycolate as polarity reversal catalyst.
Introduction
The β- and γ-lactam structural units occur in many biologically
active molecules.1 Synthetic routes to β-lactams include Ugi
reactions,2 Paterno–Büchi type [2ϩ2] cycloadditions of ketenes
and imines3 and numerous base promoted condensations of
imines and oxime ethers with a variety of enolate types.4 In
addition, reactions of the dianion derived from trisylhydrazone
with aldehydes yield β-lactams,5 as do rhodium catalysed
intramolecular C–H insertion reactions of diazoamides.6 Vari-
Scheme 1 Aminoacyl radical generation from N-benzyl-N-alkenyl-
ous other methods are also available.7 Most of these synthetic
(1-methyl)cyclohexa-2,5-diene-1-carboxamides.
routes employ powerful bases (or other stringent conditions)
that necessitate tedious protection/deprotection strategies.
Free-radical based synthetic methods usually involve neutral
conditions and, because these reactive species seldom attack
functional groups, this permits key steps to proceed without the
need for protection. Recently, several free-radical mediated
syntheses of β- and γ-lactams have been reported. For
example, organotin hydride promoted cyclisations of unsatur-
ated β-chloroamides yielded lactam rings and were employed
in syntheses of PS-5 and thienamycin.8 Modest yields of
β-lactams were also obtained from 4-exo-cyclisations of
carbamoylcobalt salophens.9 To date, radical methods for
lactams have suffered either from poor yields or have employed
toxic organotin reagents.
described here was summarised in a preliminary communi-
cation.14
Results and discussion
The 1-methyl substituted compounds 1 were chosen because
methyl is the least stabilised of the simple alkyl radicals. It
follows that the unwanted β-scission of the intermediate cyclo-
hexadienyl radicals 2, to produce methyl radicals and aromatic
amides 4, should be markedly disfavoured. 1-Methylcyclohexa-
2,5-diene-1-carbonyl chloride (6) is readily available from the
corresponding acid prepared by Birch reduction/methylation
of benzoic acid.10,15 Preliminary experiments with amides
derived from primary amines were less successful and therefore
N-benzyl protected-amides 1 were utilised in most subsequent
experiments. Secondary amines 5, with unsaturation at the 2- or
3-positions of side chains R, were obtained either by boro-
hydride reduction of alkenylimines or by treatment of benzyl-
amine with an appropriate alkenyl, alkynyl or cyanoalkyl
halide. The CHD-amides (1) were obtained in satisfactory
yields on addition of 6 to DCM solutions of individual amines
containing Et3N and a catalytic amount of DMAP (Scheme 2).
Scheme 3 shows the anticipated course of the reaction. The
unsaturated aminoacyl radical 8, released from the initial
cyclohexadienyl radical 7, should either abstract a bisallylic
hydrogen from more 1 to produce formamide 10, or cyclise to
give the corresponding azetidin-2-one, or pyrrolidine-2-one, 11.
The formation of pyrrolidinones was tested by examining the
thermally induced decomposition of the but-3-enyl amide 1e
with dibenzoyl peroxide.
1-Alkyl-cyclohexa-2,5-diene-1-carboxylic acids,10 esters of
1-methylcyclohexa-2,5-diene-1-carboxylic acid,11 and of
1-phenylcyclohexa-2,5-diene-1-carboxylic acid,12 as well as
silylated cyclohexadienes,13 have been successfully used as
precursors in ring-forming free-radical processes. The main
drawback to their use was unwanted competition from an
alternative dissociation of the intermediate 1-methyl-1-carb-
oxalatocyclohexadienyl radicals that released methyl radicals
and benzoate esters.
These findings suggested, however, that analogous amides 1
could function as precursors of aminoacyl radicals 3 (Scheme 1)
and that suitably functionalised examples could ring close to
afford lactams as the main products. Synthetic routes to a
representative series of 1-carbamoyl-1-methylcyclohexa-2,5-
dienes (CHD-amides, 1) are described in this paper, together
with an investigation of aminoacyl (carbamoyl) radical gener-
ation and subsequent cyclisation reactions. Part of the work
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
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Table 1 Preparation of pyrrolidinones from induced decompositions of N-substituted-N-benzyl-(1-methyl)cyclohexa-2,5-diene-1-carboxamidesa
CHD-amide
Conditions
Lactam 11 % (unreacted 1 %)
Formamide 10 %
1e
(BzO)2, PhH, reflux, 24 h
11e 53
10e 37f
10e 22b
10e 13b
1e
1e
DTBPOO,d PhH, reflux
DTBP, UV, 60 ЊC, 4 h
11e 21b (57)b
11e 43b (44)b
1f
(BzO)2, PhH, reflux, 24 h
11f 17 de 60%e
11f 21c de 69%
10f trace
10f 8b
1f
DTBP, UV, 60 ЊC, 7 h.
a Yields are for isolated products except those markedb,c
.
b Obtained by GC. c Obtained by NMR. d Di-t-butylperoxy oxalate. e 4 : 1 mixture of trans-
and cis-diastereoisomers. f 1.1 : 1 mixture of rotamers.
in a disappointing 17% yield. The chromatograms of the prod-
uct mixture were comparatively clean, except for debris from
the dibenzoyl peroxide. The low yield was partly due to losses
sustained during purification and separation from these by-
products. A similar yield was obtained in the UV/DTBP
initiated reaction (Table 1), the problem here being unreacted
starting amide. Interestingly, the GC-MS chromatograms
showed minor amounts of two additional products having
molecular ions and fragmentation patterns consistent with
structures 12 (4%) and 13 (6%).
Scheme 2 Reagents and conditions: (i) Et3N, cat. DMAP, DCM reflux.
The 3-methylenepyrrolidinone 12f was probably formed by
disproportionation of the intermediate 9f with other radicals in
the system. Likewise, the 3-ethyl-derivative 13 probably resulted
from combination of 9f with methyl radicals derived from
β-scission of the initiator-derived t-butoxyl radicals. The pres-
ence of these radical–radical products suggested that chain
propagation by H-atom abstraction from the starting amides
was inefficient.
The use of cyclohexadienyl-amides 1 for the preparation of
β-lactams was next investigated. The induced decomposition
of 1b was carried out thermally with dibenzoyl peroxide as
initiator in refluxing benzene. The products were shown to be
1-benzyl-3-ethylazetidin-2-one (11b) accompanied by a signifi-
cant amount of N-benzyl-N-but-2-enylformamide (10b) as a
1.3 : 1 mixture of trans- and cis-isomers. Considering that this
ring closure is of the unfavourable 4-exo-variety, the yield of
β-lactam (Table 2) was encouraging. Thermally initiated reac-
tions of the cyanomethyl derivative 1c gave solely the uncyclised
formamide product of type 10. In the photochemically initiated
reactions with DTBP, amide conversions of only 60–70% could
be achieved. The only products isolated from the thermally
induced reaction of the propynylamide 1d were the formamide
isomers 10d. However, the GC-MS chromatogram showed a
small amount of a second product having the correct molecular
mass for the product of 4-exo-dig cyclisation. The MS of this
component showed the characteristic cross-ring fragmentation
of a 4-membered ring and hence it was probably N-benzyl-3-
methyleneazetidin-2-one (11d), although this was not con-
firmed by isolation and NMR spectral characterisation. In
these reactions of 1c and 1d the cyclised species contain exo-
cyclic double bonds, as well as 4-membered rings, so it was not
at all surprising that ring closure of the aminoacyl radicals was
too slow to compete effectively with hydrogen abstraction.
Scheme
3
Induced decomposition of cyclohexa-2,5-diene-1-carb-
oxamides.
On refluxing 1e and dibenzoyl peroxide in benzene for 24 h,
the 3-methyl-N-benzylpyrrolidin-2-one 11e was isolated in 53%
yield along with a significant amount of the corresponding
formamide 10e as a mixture of trans- and cis-isomers (Table 1).
Thermally induced decomposition of 1e using di-t-butyl per-
oxyoxalate (DTBPOO) as initiator gave the same products but
in reduced yields because much of the starting amide remained
unreacted (Table 1). The reaction was also carried out using
photolysis of di-t-butyl peroxide (DTBP) as the initiation
mode. The yield of pyrrolidinone 11e obtained was 43% on a
conversion of 56%. Amide 1f contained bis-methyl substitution
of the butenyl chain and it was hoped that ring closure of the
carbamoyl radical derived from this compound would be more
efficient because of a Thorpe–Ingold effect. Thermally initiated
decomposition of 1f led to the isolation of the tetramethyl-
pyrrolidinone 11f as a mixture of diastereoisomers (60–70% de)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
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Table 2 Preparation of azetidinones from induced decompositions of N-substituted-N-benzyl-(1-methyl)cyclohexa-2,5-diene-1-carboxamidesa
CHD-amide
Conditions
Lactam 11 % (unreacted 1 %)
Formamide 10 % (isomer ratio)
1b
(BzO)2, PhH, reflux, 24 h
11b 34
10b 31 (1.3 : 1)
10b 38b
1b
1c
DTBP, UV, rt, 2 h
11b 42b
(BzO)2, PhH, reflux, 24 h
11c 0
10c 57 (3.8 : 1)
10d 64 (1.4 : 1)
1d
1g
(BzO)2, PhH, reflux, 24 h
(BzO)2, PhH, reflux, 48 h
11d 7b (29)b
11g 12b (64)
11g ca. 12b
11g 15b (16)
13g 5b
10g 5
1g
1g
DTBP/PhH, 70 ЊC, hν, 8 h
10g ca. 5b
10g 10b
DTBPOOd, PhH, reflux, 24 h
1g
1g
DTBPOOd, PhH, RSHe, reflux, 12 h
11g 24c
14g 65b
10g 11c
DTBPOOd, PhH, cat. RSHe, reflux, 12 h
11g 38c
13g 28c
1g
Lauroyl, PhH, RSHe, reflux
11g 66b (10)
14g 24b
a Yields are for isolated products except those markedb,c
thioglycolate.
.
b Obtained by GC. c Obtained by NMR. d Di-t-butylperoxy oxalate. e RSH = Methyl
The cinnamyl-substituted amide 1g was chosen for more
detailed study because the Ph substituent was expected to
confer resonance stabilisation on the cyclised radical 9g and
hence to expedite the 4-exo-cyclisation step. However, as an
additional consequence of this resonance stabilisation of 9g it
was anticipated that the H-atom abstraction step would be dis-
favoured. The thermal and photochemical reactions initiated
with dibenzoyl peroxide, DTBPOO and DTBP gave the corre-
sponding azetidin-2-one 11g but the yields were low (Table 2).
We reasoned that addition of a good H-atom donor would
enable the ring closed benzyl type radical 9g to be trapped more
easily. Accordingly, we carried out a reaction initiated with
DTBPOO but including 1.2 mol eq. of methyl thioglycolate
(RSH). The yield of 1,3-dibenzylazetidinone 11g did signifi-
cantly increase under these conditions (24%, Table 2), but a
new product, {1-benzyl-2-[benzyl(formyl)amino]ethyl}sulfanyl
acetate (14g) was a major by-product. It is probable that 14g
was formed by radical addition of the thioglycolate to the first
formed formamide 10g (Scheme 4).
yield of 11g. The azetidinylbenzyl radical 9g will be resonance
stabilised and nucleophilic. Hence a polar effect should favour
H-abstraction from the electronegative RSH. The electrophilic
ؒ
thiyl radical (RS ) generated in this way will, in turn, H-abstract
more readily from the cyclohexadienyl site of 1g, thus regener-
ating RSH and continuing the chain. In the lauroyl peroxide
initiated reactions, products derived from the initiator included
undecane and docosane. These compounds significantly
increased the viscosity of the reaction medium thus slowing
radical–radical reactions which are normally diffusion con-
trolled. This may account for the suppression of termination
products 12g and 13g with this initiator.
Under certain experimental conditions, ring expansion of
β-oxocycloalkyl radicals might take place via azabicyclo[n.1.0]-
alkyloxyl radicals 15 (Scheme 5).17 However, no five-membered
ring containing pyrrolidinones were observed from reactions of
1b–d. It is likely that higher reaction temperatures would be
required for this alternative to become viable.
Scheme 5 Potential ring enlargement of β-oxoazetidinylmethyl and
related radicals.
Scheme 4 Formation of thiol adduct 14g.
When a catalytic amount of RSH was employed, formation
of 14g was suppressed, and the β-lactam (11g) yield increased
(Table 2), but radical–radical reactions again became important
leading to formation of 13g.
Use of lauroyl peroxide as initiator, in concert with 1 eq. of
RSH, led to a greatly improved β-lactam yield (66%, Table 2).
Some thiol adduct 14g was still produced, but the termination
product 13g was undetectable under these conditions. It is likely
that polarity reversal catalysis16 played a part in enhancing the
Conclusions
The results show that induced decompositions of cyclohexa-
dienyl amides of type 1 readily afford aminoacyl (carbamoyl)
radicals. No products from the undesired methyl radical release
process i.e. aromatic amides 4 (Scheme 1) were detected for
any of the precursors studied. Thus, the dissociations of the
delocalised amide radicals 2 are clean and are more efficient
than for the analogous 1-alkylcyclohexa-2,5-diene-1-carboxylic
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
423

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acids or the analogous esters. In several cases, the cyclo-
hexadienyl radicals 2, and released aminoacyl radicals 3, were
observed by EPR spectroscopy. These observations supported
the proposed mechanism and enabled kinetic data for dissoci-
ation of 2 to be obtained in certain cases.18 It is probable that
the comparatively efficient extrusion of aminoacyl radicals
from 2 is because they are somewhat more thermodynamically
stabilised (by the amide FG) than the alkyl or alkoxycarbonyl
radicals released in the cases of the acids and esters respectively.
The only previous reports of cyclisations of aminoacyl
radicals are those of Pattenden from his work with cobalt
salophens.9 We found that 5-exo-trig-ring closures took place
efficiently, without complications from ring expansion via aza-
bicyclo[n.2.0]alkyloxyl radicals. As expected, 4-exo-trig-cyclis-
ations were more difficult and the isolated yield of the β-lactam
11b was modest.
One reason for the modest yields was the comparatively slow
donation of hydrogen by the cyclohexadienyl amides during
chain propagation. Chain propagation was consequently not
very efficient and comparatively large quantities of dibenzoyl
peroxide initiator had to be added to maintain the reactions.
Yields were reduced because of having to remove initiator
debris from the products. Although cleaner systems were
achieved with DTBPOO initiator, and in photochemical sys-
tems with DTBP, reactions were difficult to drive to completion
under these conditions. Inclusion of methyl thioglycolate in the
reaction medium led to increased β-lactam yields, probably
because polarity reversal catalysis resulted from favourable
polar effects on the H-atom abstractions.
(δH = δC = 0) as reference. Coupling constants are expressed in
Hz. Ether refers to diethyl ether. Light petroleum refers to the
fraction boiling in the range 40–60 ЊC. EI mass spectra were
obtained with 70 eV electron impact ionisation and CI spectra
with isobutane as the target gas on a VG Autospec spectro-
meter. GC-MS analyses were run on a Finnigan Incos 50 quad-
rupole instrument, and/or on the VG Autospec, coupled to a
Hewlett Packard HP 5890 chromatograph fitted with a 25 m
HP 17 capillary column (50% phenyl methyl silicone). For
the calculation of yields from GC data, the detector response
was calibrated with known amounts of authentic materials
(or close analogues). Chromatographic purifications were
carried out using either Sorbsil C60 40/60A or BDH 40–63 µm
silica gel eluting with the given solvent mixture. Ammonia
was obtained from BOC and used directly from the cylinder;
drying and distillation had no perceptible effect on the
yields. N-Benzyl-N-but-2-enylidineamine,9 N-benzyl-N-but-
2-enylamine,9 benzylaminoacetonitrile,19 prop-2-ynylbenzyl-
amine,20 1-methylcyclohexa-2,5-diene-1-carbonyl chloride (6),10
2,2-dimethylbut-3-enoic acid,21 3,3-dimethylpent-4-en-2-one,22
N-benzyl-3-phenylprop-2-enylamine23 and but-3-enylbenzyl-
amine24 were prepared according to literature procedures.
N-Benzyl-N-but-2-enyl-(1-methyl)cyclohexa-2,5-diene-1-
carboxamide (1b). (General procedure for cyclohexadienyl
amides)
1-Methylcyclohexa-2,5-diene-1-carbonyl chloride 6 (2.0 g, 13
mmol) was dissolved in dry dichloromethane (10 cm3) and
added dropwise to a mixture of N-benzyl-N-but-2-enylamine
(1.6 g, 10 mmol), triethylamine (1.0 g, 10 mmol) and a catalytic
amount of DMAP in dry dichloromethane (20 cm3). The
resultant mixture was refluxed for 5 h before washing with H2O
(2 × 100 cm3) and drying (MgSO4). The solvent was evaporated
to give the product as a brown oil, which was purified by
column chromatography, eluting with 2% ethyl acetate in light
petroleum, in order to furnish 1b (2.02 g, 72%) as a pale yellow
oil; δH 1.38 (3 H, s, CH3), 1.68 (3 H, br s, CH3), 2.67 (2 H, m,
allylic-H), 3.70–3.97 (2 H, m, CH2), 4.48–4.72 (2 H, m,
Ar–CH2), 5.25–5.48 (2 H, m, 2 × CH), 5.70–5.81 (4 H, br s,
4 × CH), 7.08–7.34 (5 H, m, Ar H); δC 17.7 (CH3), 25.8 (CH2),
28.8 (CH3), 45.0 (C), 47.7 (CH2), 48.6 (CH2), 122.9, 125.7,
126.9, 127.3, 127.4, 127.8, 128.4, 128.6, 129.4, 130.0, 130.6
Significant yields of formamides accompanied all the cyclis-
ations. A possible cause of this appeared to be a non-radical
electrocyclic elimination. The lowest energy conformation of 1
is probably 16a with the Me group pseudo-axial. However,
there will be a minor population of conformer 16b with the
amide group pseudo-axial. Direct electrocyclic elimination of
formamide, as shown, can be envisaged from this structure
(Scheme 6).
(11 × CH), 138.0 (C), 173.5 (C᎐O); HRMS m/z found Mϩ
᎐
281.1776, C19H23NO requires 281.1780.
Thermally initiated reaction of N-benzyl-N-but-2-enyl-
(1-methyl)-cyclohexa-2,5-diene-1-carboxamide (1b)
Amide 1b (0.5 g, 1.8 mmol) was dissolved in benzene (10 cm3)
and heated to reflux before dibenzoyl peroxide (0.5 g) was
added portion wise over a period of 24 h. After complete addi-
tion, the solvent was evaporated before dissolving the impure
product in ether (50 cm3), washing with NaOH (2 × 50 cm3),
HCl (2 × 50 cm3) and water (2 × 50 cm3) and drying (MgSO4).
The solvent was evaporated under reduced pressure to yield a
brown oil (0.42 g), which was purified by column chromato-
graphy, eluting with 5% ethyl acetate in light petroleum. A
sample of the purified product was analysed by GC-MS; peak
no. 902, β-lactam 11b m/z (relative intensity) 189 (Mϩ, 6), 160
(3), 133 (38), 119 (3), 105 (50), 91 (100), 77 (16), 65 (37), 55 (22),
41 (46), 39 (43), 27 (33); peak no. 908, cis- or trans-N-benzyl-N-
but-2-enylformamide 10b (31% combined cis ϩ trans), 189 (Mϩ,
7), 160 (1), 148 (2), 134 (36), 115 (2), 106 (34), 98 (30), 91 (100),
79 (39), 77 (17), 70 (33), 65 (49), 55 (27), 39 (46), 28 (95); peak
no. 914, cis- or trans-N-benzyl-N-but-2-enylformamide 10b 189
(Mϩ, 20), 160 (6), 134 (21), 118 (13), 106 (28), 98 (28), 91 (100),
79 (25), 77 (19), 70 (18), 65 (44), 55 (26), 39 (56), 28 (77), 18
(100). The N-benzyl-3-ethylazetidin-2-one 11b was finally iso-
lated as a colourless oil (34%) by preparative TLC, eluting with
2% ethyl acetate in pentane; δH 0.98 (3 H, t, J 6.0, CH3), 1.51–
Scheme
6
Possible electrocyclic elimination of formamide from
cyclohexadienyl amides.
When a solution of 1b in benzene (no initiator) was heated at
60 ЊC and photolysed with UV light for 4 h, GC-MS analysis
showed only unreacted amide. Similarly, a solution of 1f in
CDCl3 was heated continuously at 82 ЊC in a sealed tube. How-
1
ever, monitoring by H NMR showed no reaction after 23 h.
Production of formamide by the electrocyclic process of
Scheme 6 can therefore be ruled out and its formation must be
attributed to H-abstraction (Scheme 3). Overall, the induced
carbamoyl-cyclohexadiene decompositions represent com-
paratively ‘clean’ tin-free radical routes that are applicable for
the preparation of a range of lactams from secondary amine
starting materials.
Experimental
1H NMR spectra were recorded at 300 MHz and 13C NMR
spectra at 75 MHz, in CDCl3 solution with tetramethylsilane
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
424

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1
1.90 (2 H, m, CH2), 2.84 (1 H, m, CH), 3.12–3.20 (1 H, m, CH),
3.20–3.25 (1 H, m, CH), 4.38 (2 H, AB, Ar–CH2), 7.19–7.41
(5 H, m, ArH); δC 11.2 (CH3), 21.9 (CH2), 44.5 (CH2), 45.8
(Ar–CH2), 51.3 (CH), 127.8, 128.1, 128.8 (5 × CH), 135.8 (C),
oil (0.38 g), which was analysed, by H NMR and GC-MS;
peak no. 104, toluene, peak no. 687, benzoic acid (from initi-
ator); peak no. 768, biphenyl (from initiator); peak nos. 882
and 890 (essentially identical MS) cis- and trans-N-benzyl-N-
cyanomethylformamide, 10c; m/z (%) 174 (Mϩ, 16), 134 (71),
106 (83), 91 (100), 79 (97), 65 (76), 51 (61), 39 (81), 28 (92), 18
(13); peak no. 913, phenyl benzoate (from initiator); peak no.
1097, unreacted 1c. The product was purified by column
chromatography, eluting with 10% ethyl acetate in light petrol-
eum, to give N-benzyl-N-cyanomethylformamide 10c as a mix-
ture of the two isomers (3.8 : 1) (0.19 g, 57%) major isomer
(79 rel.%) δH 4.12 (2 H, s, CH2), 4.55 (2 H, s, Ar–CH2), 7.24–
170.6 (C᎐O); HRMS m/z found Mϩ 189.1149, C12H15NO
᎐
requires 189.1154. The mixture of cis- and trans-10b (31%,
major : minor = 1.25 : 1) was also isolated as a colourless oil;
δH (major isomer shifts first) 1.68, 1.72 (2 × 3 H, d, J 6.0, CH3),
3.67, 3.80 (2 × 2 H, d, J 6.0 CH2), 4.37, 4.52 (2 × 2 H, s, CH2)
5.24–5.71 (2 × 2 H, br m, CH), 7.18–7.42 (2 × 5 H, m, Ar H),
8.21, 8.30 (2 × 1 H, s, HC᎐O); δ 17.7, 30.3 (CH3), 43.3, 44.8
᎐
C
(CH2), 48.6, 50.3 (CH2), 124.6, 125.6, 127.4, 127.6, 128.0, 128.3,
128.5, 128.9, 129.5 (CH), 136.0, 136.4 (C), 162.5, 162.6 (C᎐O).
7.49 (5 H, m, Ar H), 8.31 (1 H, s, HC᎐O); δ 29.4 (CH ), 51.1
᎐
C 2
᎐
In a control experiment 1b (0.1 g) in benzene (2 cm3) was
heated at 60 ЊC in a quartz tube and photolysed with UV light
from a 400 W Hg lamp for 4 h. At the end of this period GC-
MS analysis showed only unchanged 1b.
(CH2), 114.3 (CN), 127.9, 128.9, 129.3 (3 × CH), 133.5 (C),
162.0 (C᎐O); minor isomer (21 rel.%) δ 4.02 (2 H, s, CH ), 4.68
᎐
H
2
(2 H, s, CH ), 7.24–7.49 (5 H, m, ArH), 8.23 (1 H, s, HC᎐O),
᎐
2
δC 35.0 (CH2), 45.8 (CH2), 114.3 (CN), 128.5, 128.7, 129.1
(3 × CH), 134.0 (C), 161.6 (C᎐O). HRMS m/z found Mϩ
᎐
Photochemically initiated reaction of 1b
174.0786, C10H10N2O requires 174.0793.
Amide 1b (0.2 g, 0.7 mmol) was dissolved in DTBP (250 µl) and
added to a quartz tube (od 0.4 cm). The tube was capped and
irradiated with light from a 400 W medium pressure Hg lamp
for 2 h. Analysis of the reaction mixture by GC-MS indicated
that all of the cyclohexadienyl amide had been consumed, lead-
ing to identical peaks in the GC-MS to those observed with the
thermally initiated radical reaction. GC yield measurements,
using a formamide standard, confirmed that the β-lactam 11b
was formed in 42% and the two formamide isomers 10b in a
combined yield of 38%.
Photochemically initiated reaction of 1c
Amide 1c (0.2 g, 0.75 mmol) was dissolved in DTBP (250 µl) in
a quartz tube and irradiated at ambient temperature with light
from a 400 W high pressure Hg lamp for 2 h. Analysis of the
reaction mixture by GC-MS confirmed the presence of both
isomers of N-benzyl-N-cyanomethylformamide (10c) (together
with unreacted 1c) in an approximate ratio of 2 : 1. The only
detectable impurities were those derived from the photolytic
breakdown of DTBP.
N-Benzyl-1-methylcyclohexa-2,5-diene-1-carboxamide (1a)
N-Benzyl-N-prop-2-ynyl-(1-methyl)cyclohexa-2,5-diene-1-
carboxamide (1d)
The general method described for 1b was employed with benzyl-
amine (0.77 g, 7.2 mmol) and 6. The crude product was purified
by crystallisation with pentane/ethyl acetate yielding 1a as a
white crystalline solid (1.4 g, 97%); mp 79–80 ЊC; δH 1.4 (3H, s,
CH3), 2.7 (2H, s, bisallylic H), 4.42 (2H, m, PhN–CH2), 5.7–6.0
Prepared from 6 and prop-2-ynylbenzylamine (3.19 g, 22 mmol)
by the method described for 1b. The solvent was evaporated to
give the product as a brown oil, which was purified by column
chromatography, eluting with 10% ethyl acetate in hexane, in
order to furnish 1d (3.09 g, 53%) as a pale yellow oil; δH 1.41
(3 H, s, CH3), 2.24 (1 H, s, CH), 2.73 (2 H, br s, allylic-H), 4.16
(2 H, s, CH2), 4.80 (2 H, s, Ar–CH2), 5.82 (4 H, m, 4 × CH),
7.18–7.42 (5 H, m, Ar H); δC 21.9 (CH3), 32.1 (CH2), 33.2
(CH2), 45.2 (C), 55.1 (CH2), 72.8 (C), 80.9 (CH), 126.8, 127.2,
127.8, 128.2, 128.7, 129.0, 129.5, 130.1, 130.6 (9 × CH), 139.2
(4H, br m, ᎐CH), 6.0–6.2 (1H, br s, NH), 7.1–7.4 (5H, m, ArH);
᎐
δC 25.4 (CH3), 25.9 (CH2), 43.6 (C), 45.0 (CH2), 127.3 (CH),
128.6 (CH), 130 (CH), 138.5 (C), 174.6 (C᎐O); found: C, 78.81;
᎐
H, 7.49; N, 6.09. Calc. for C15H17NO: C, 79.26; H, 7.54; N,
6.16%; m/z (relative intensity), 227 (Mϩ, 5), 212 (5), 134 (5), 94
(5), 91 (100), 77 (50), 65 (38), 51 (18), 39 (24).
(C), 172.2 (C᎐O); m/z (relative intensity), 174 (3), 172 (6), 134
᎐
N-Benzyl-N-cyanomethyl-(1-methyl)cyclohexa-2,5-diene-1-
carboxamide (1c)
(3), 105 (5), 93 (26), 91 (100), 77 (27), 65 (20), 51 (11), 39 (23),
28 (8), 18 (29); HRMS m/z found Mϩ 265.1465, C18H19NO
requires 265.1467.
Prepared from 6 and benzylaminoacetonitrile (2.28 g, 16 mmol)
as for 1b. The solvent was evaporated to give the product as a
brown oil, which was purified by column chromatography, elut-
ing with 5% ethyl acetate in hexane, in order to furnish the title
compound 1c (2.54 g, 60%) as a pale yellow oil; δH 1.26 (3 H, s,
CH3), 2.63 (2 H, s, allylic-H), 3.99 (2 H, s, CH2), 4.64 (2 H, s,
Ar–CH2), 5.83 (4 H, m, 4 × CH), 7.18–7.39 (5 H, m, Ar H);
δC 22.1 (CH3), 33.4 (CH2), 34.7 (CH2), 46.1 (C), 54.6 (CH2),
114.4 (CN), 127.3, 127.5, 127.8, 128.3, 128.6, 129.2, 129.7,
Thermally initiated reaction of N-benzyl-N-prop-2-ynyl-
(1-methyl)cyclohexa-2,5-diene-1-carboxamide (1d)
Amide 1d (0.5 g, 1.9 mmol) was dissolved in benzene (10 cm3)
and heated to reflux before dibenzoyl peroxide (0.5 g) was
added portion wise over a period of 24 h. After complete addi-
tion, the solvent was evaporated before dissolving the impure
product in ether (50 cm3), washing with NaOH (50 cm3), HCl
(50 cm3) and water (2 × 50 cm3) and drying (MgSO4). The
solvent was evaporated under reduced pressure to yield a
brown oil (0.47 g). GC-MS; peak no. 190, toluene; peak no. 692,
benzoic acid (from initiator); peak no. 772, biphenyl (from
initiator); peak no. 843, N-benzyl-N-prop-2-ynylformamide
(10d) (62%, both isomers); m/z (relative intensity) 173 (Mϩ, 6),
144 (2), 134 (65), 128 (12), 115 (9), 106 (42), 91 (64), 79 (58), 65
(50), 51 (35), 39 (100), 28 (88); peak no. 867, probably N-benzyl-
3-methyleneazetidin-2-one (11d) (7%); m/z (relative intensity)
173 (Mϩ, 11) 172 (18), 144 (7), 133 (22), 105 (45), 104 (33), 91
(100), 77 (26), 65 (42), 51 (48), 39 (89); peak no. 915, phenyl
benzoate (from initiator); peak no. 1086, unreacted 1d (31%).
The crude product was purified by column chromatography,
eluting with 10% ethyl acetate in light petroleum, to give 10d
130.1, 130.4 (9 × CH), 137.2 (C), 170.2 (C᎐O); m/z (relative
᎐
intensity), 266 (Mϩ, 1), 251 (1), 175 (2), 173 (2), 93 (74), 91
(100), 77 (53), 65 (37), 51 (32), 39 (36); HRMS, m/z found Mϩ
266.1416, C17H18N2O requires 266.1419.
Thermally initiated reaction of N-benzyl-N-cyanomethyl-
(1-methyl)cyclohexa-2,5-diene-1-carboxamide (1c)
Amide 1c (0.5 g, 1.9 mmol) was dissolved in benzene (10 cm3)
and heated to reflux before dibenzoyl peroxide (0.5 g) was
added portion wise over a period of 24 h. After complete addi-
tion, the solvent was evaporated before dissolving the impure
product in ether (50 cm3), washing with NaOH (50 cm3), HCl
(50 cm3) and water (2 × 50 cm3) and drying (MgSO4). The
solvent was evaporated under reduced pressure to yield a brown
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
425

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(64%, mixture of isomers, 1.4 : 1) as a colourless oil; major
major isomer δH 2.18–2.35 (2 H, m, CH2), 3.14–3.27 (2H, m,
isomer, δH 2.26 (1 H, t, J 3.0, CH), 4.07 (2 H, d, J 3.0, CH2), 4.55
CH ), 4.46 (2 H, s, Ar–CH ), 4.9–5.19 (2 H, m, ᎐CH ), 5.59–
᎐
2 2 2
(2 H, s, Ar–CH ), 7.23–7.42 (5 H, m, Ar H), 8.30 (1 H, s, HC᎐
5.85 (1 H, m, ᎐CH), 7.18–7.41 (5 H, m, Ar H), 8.25 (1 H, s, HC᎐
O); δC 32.6 (CH ), 45.4 (CH ), 51.5 (Ar–CH ), 118.1 (᎐CH ),
᎐
2 2 2 2
᎐
᎐ ᎐
2
᎐
᎐
O); δ 30.6 (CH ), 50.3 (CH ), 72.4 (C᎐), 77.2 (C᎐), 127.8, 128.6,
᎐
᎐
C
2
2
129.0 (3 × CH), 135.0 (C), 161.98 (C᎐O); minor isomer δH 2.40
127.9, 128.2, 128.7 (5 × CH), 134.0 (CH), 136.4 (C), 162.8 (HC᎐
᎐
᎐
(1 H, t, J 3.0, CH), 3.87 (2 H, d, J 3.0, CH2), 4.66 (2 H, s, CH2),
O); minor isomer δH 2.18–2.35 (2 H, m, CH2), 3.14–3.27 (2H, m,
7.2–7.4 (5 H, m, ArH), 8.25 (1 H, s, HC᎐O); δ 36.2 (CH ), 45.0
CH ), 4.58 (2 H, s, Ar–CH ), 4.9–5.19 (2 H, m, ᎐CH ), 5.59–
᎐
2 2 2
᎐
C
2
᎐
᎐
(CH ), 73.8 (HC᎐), 77.0 (C᎐), 128.3, 128.8, 129.0 (3 × CH),
5.85 (1 H, m, ᎐CH), 7.18–7.41 (5 H, m, ArH), 8.30 (1 H, s, HC᎐
᎐
᎐
᎐ ᎐
2
135.4 (C), 162.04 (C᎐O), HRMS m/z found Mϩ 173.0838,
O); δC 32.6 (CH ), 45.4 (CH ), 51.5 (Ar–CH ), 122.8 (᎐CH ),
᎐
2 2 2 2
᎐
C11H11NO requires 173.0841.
127.2, 127.5, 128.3 (5 × CH), 134.0 (CH), 135.8 (C), 162.9 (HC᎐
᎐
O) HRMS m/z found Mϩ 189.1149, C12H15NO requires
189.1154. The experiment was repeated using DTBPOO (1.9
mmol) as the thermally activated radical initiator. GC analysis
indicated 10e (21%), 11e (22%) and unreacted 1e (57%).
Photochemically initiated reaction of 1d
Amide 1d (0.5 g, 1.9 mmol) was dissolved in benzene (2 cm3),
which contained DTBP (1.10 g, 7.5 mmol). The resultant
solution was placed in a quartz tube, heated to 60 ЊC using a
quartz paraffin oil bath and the sample irradiated with light
from a 400 W high pressure Hg lamp over a 3 h period. Analysis
of the reaction mixture by GC-MS confirmed the formation
of both formamide 10d plus minor amounts of N-benzyl-
3-methyleneazetidin-2-one (11d) and unreacted amide 1d.
The only detectable impurities were those derived from the
photolytic breakdown of DTBP.
Photochemically initiated reaction of 1e
Amide 1e (0.5 g, 1.8 mmol) was dissolved in benzene (2 cm3),
which contained DTBP (1.3 g, 9 mmol). The resultant solution
was placed in a quartz tube, heated to 60 ЊC using a quartz
paraffin oil bath and the sample was irradiated with light from a
400 W medium pressure Hg lamp over a 4 h period. Analysis of
the reaction mixture by GC-MS confirmed the presence of both
1-benzyl-3-methylpyrrolidin-2-one (11e) and the N-benzyl-N-
but-3-enylformamide (10e) in an approximate ratio of 2 : 1. The
only detectable impurities were those derived from the photo-
lytic breakdown of DTBP, with no evidence for the competitive
release of methyl radicals to form N-benzyl-N-but-3-enyl-
benzamide.
N-Benzyl-N-but-3-enyl-(1-methyl)cyclohexa-2,5-diene-1-
carboxamide (1e)
Prepared from 6 (2.0 g, 14.5 mmol) and but-3-enylbenzylamine
(2.24 g, 14.0 mmol) as described for 1b. The solvent was evap-
orated to give a brown oil, which was purified by column
chromatography, eluting with 10% ethyl acetate in hexane, in
order to furnish 1e (2.44 g, 60%) as a pale yellow oil; δH 1.37 (3
H, s, CH3), 2.27 (2 H, m, CH2), 2.69 (2 H, br s, allylic-H), 3.21–
3.50 (2 H, m, CH2), 4.67 (2 H, s, Ar–CH2), 4.99 (2 H, d,
J 7, CH2), 5.59–5.84 (5 H, m, 5 × CH), 7.10–7.46 (5 H, m, Ar
H); δC 25.7 (CH2), 28.8 (CH3), 31.3 (CH2), 32.8 (CH2), 44.9 (C),
51.0 (CH2), 116.3 (CH2), 126.8, 127.2, 128.3, 128.6, 130.3
N-Benzyl-3,3-dimethylpent-4-enylamine
Sodium borohydride (0.2 g, 5.3 mmol) was added portion wise
over a period of 10 min to a stirred and cooled (0 ЊC) solution
of the imine (2.56 g, 12.7 mmol) in dry methanol (40 cm3) under
an atmosphere of nitrogen. The solution was allowed to warm
to ambient temperature and then stirred for 20 h, during which
time the yellow colour of the solution faded. The solution was
cooled (0 ЊC) before concentrated HCl was added dropwise
until the mixture attained pH 1. The resulting suspension was
evaporated under reduced pressure to leave a white solid. The
residue was dissolved in water (50 cm3) and the resulting aque-
ous solution was washed with ether (2 × 100 cm3). The remain-
ing aqueous solution was brought to pH 10 by careful addition
of potassium hydroxide pellets, and the liberated amine was
extracted into ether (3 × 100 cm3). The combined organic
phases were dried (MgSO4) and then evaporated to dryness to
leave a pale yellow oil. The product was purified by distillation
to yield the title amine (1.63 g, 63%) as a colourless liquid;
(9 × CH), 135.4 (CH), 137.7 (C), 173.6 (C᎐O); m/z (relative
᎐
intensity), 281 (Mϩ 1), 240 (1), 190 (2), 188 (19), 174 (1), 160 (1),
148 (3), 93 (21), 91 (100), 77 (19), 65 (20), 51 (4), 39 (11), 28 (4),
18 (3); HRMS m/z found Mϩ 281.1784, C19H23NO requires
281.1780.
Thermally initiated reaction of N-benzyl-N-but-3-enyl-
(1-methyl)cyclohexa-2,5-diene-1-carboxamide (1e)
Amide 1e (0.5 g, 1.8 mmol) was dissolved in benzene (10 cm3)
and heated to reflux before dibenzoyl peroxide (0.5 g) was
added portion wise over a period of 24 h. After complete addi-
tion, the solvent was evaporated before dissolving the mixture
in ether (50 cm3), washing with NaOH (50 cm3), HCl (50 cm3)
and water (2 × 50 cm3) and drying (MgSO4). The solvent was
evaporated under reduced pressure to yield a brown oil (0.56 g).
GC-MS; toluene, plus benzoic acid and biphenyl (from initi-
ator); peak no. 895, N-benzyl-N-but-3-enylformamide (isomers
unresolved) (10e), m/z (relative intensity) 189 (Mϩ, 2), 148 (16),
134 (2), 130 (2), 119 (2), 106 (2), 98 (2), 91 (100), 77 (4), 65 (20),
51 (6), 39 (21), 28 (13), 18 (10); peak no. 915, 1-benzyl-3-
methylpyrrolidin-2-one (11e), 189 (Mϩ, 69), 174 (10), 160 (12),
146 (5), 132 (13), 118 (10), 106 (23), 98 (25), 91 (100), 77 (10), 65
(32), 55 (19), 51 (12), 39 (35), 28 (23), 18 (9); peak no. 1118,
unreacted 1e. The product was purified by column chromato-
graphy, eluting with 10% ethyl acetate in light petroleum, and
by preparative TLC to give the γ-lactam, 11e (53%) as a colour-
less oil; δH 1.24 (3 H, d, J 7, CH3), 1.63 (1 H, dq, J 7, 9 CH),
2.18–2.28 (1 H, m, CH), 2.55 (1 H, sextet, J 7, CH), 3.19 (2 H,
m, CH2), 4.47 (2 H, AB, Ar–CH2), 7.21–7.37 (5 H, m, Ar H);
δC 16.4 (CH3), 27.1 (CH2), 36.8 (CH), 44.6 (CH2), 46.8 (CH2),
δH 0.9–1.0 (9H, 3 × CH3), 2.3 (1H, q, CH, 3J = 6.3), 3.7 (2H, AB
2
system, Ar–CH , J = 13.5), 5.0 (2H, m, ᎐CH ), 5.7 (1H, m,
᎐
2
2
᎐CH), 7.2–7.3 (5H, m, ArH). δ 14.5 (CH3), 21.9 (CH3), 24.4
᎐
C
(CH ), 40.9 (C), 52.2 (CH ), 59.8 (CH), 112.0 (᎐CH ), 126.7,
᎐
3
2
2
128.1, 128.2 (5 × ArCH), 140.9 (C), 146.8 (᎐CH); HRMS
᎐
m/z found (M ϩ 1)ϩ 204.1745, C14H22N requires 204.1752.
N-Benzyl-1-methyl-N-(1,2,2-trimethylbut-3-enyl)cyclohexa-2,5-
diene-1-carboxamide (1f)
Prepared from N-benzyl-3,3-dimethylpent-4-enylamine (1.63 g,
8.0 mol), and 6 as described for 1b. The amide was obtained as
a pale yellow oil (1.91 g, 74%). δH 1.00 (3H, s, CH3), 1.10 (3H, s,
CH3), 1.13 (3H, d, CH3), 1.30 (3H, s, CH3), 2.43–2.87 (2H, br
m, allylic-CH2), 4.14 and 4.73 (2H, AB, Ph–CH2), 4.46 (1H, q,
J 6.8, CH), 4.99–5.05 and 5.80–6.05 (7H, m, ᎐CH), 7.05–7.37
᎐
(5H, m, ArH); δC 15.1 (CH3), 23.5 (CH3), 25.8 (CH3), 28.0
(CH3), 29.7 (CH2), 41.5 (C), 45.7 (C), 47.1 (CH2), 59.3 (CH),
112.7 (᎐CH ), 122.3 (᎐CH), 122.4 (᎐CH), 126.1, 126.4, 129.1
᎐
᎐
᎐
2
127.3, 127.9, 128.5 (5 × CH), 136.7 (C), 177.4 (C᎐O); HRMS
(5 × CH), 130.8 (᎐CH), 132.4 (᎐CH), 139.7 (C), 145.3 (᎐CH),
᎐
᎐ ᎐ ᎐
m/z found Mϩ 189.1158, C12H15NO requires 189.1154. The pair
of formamides 10e was isolated as a colourless oil (37%, 1.1 : 1);
174.4 (C᎐O); HRMS m/z found Mϩ ϩ 1 324.2339, C22H30NO
᎐
requires 324.2327.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
426

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Thermally initiated reaction of N-benzyl-1-methyl-N-(1,2,2-
trimethylbut-3-enyl)cyclohexa-2,5-diene-1-carboxamide (1f)
dibenzylazetidin-2-one, (11g) m/z (%) 251 (Mϩ, 8), 160 (11), 118
(100), 117 (57), 115 (23), 91 (54), 65 (13), peak 648 N-benzyl-N-
(3-phenylallyl)formamide (10g) m/z (%) 251 (Mϩ, 24), 160 (54),
115 (100), 91 (67), 65 (13).
Amide 1f (0.15 g, 0.46 mmol) was dissolved in benzene (5 cm3)
and heated to reflux before dibenzoyl peroxide (0.12 g, 0.50
mmol) was added portion wise over a period of 24 h. After
complete addition, the solvent was evaporated, the impure
product was dissolved in ether (30 cm3), washed with NaOH
(30 cm3), HCl (30 cm3) and water (2 × 50 cm3) and dried
(MgSO4). The solvent was evaporated to yield a brown oil 0.028
g (26%), which was analysed by GC-MS; peak nos. 583 and 590
(identical MS), cis- and trans-1-benzyl-3,4,4,5-tetramethyl-2-
pyrrolidinone, (11f ), 231 (Mϩ, 59), 216 (42), 161 (6), 140 (9),
134 (17), 106 (10), 91 (100), 83 (11), 70 (10), 65 (9), 55 (14); peak
no. 717, unreacted 1f; by-products from dibenzoyl peroxide
were also observed. The product was purified by column
chromatography, eluting with 10% ethyl acetate in hexane, to
give γ-lactam 11f as a mixture of two diastereoisomers (4 : 1)
(0.018 g, 17%). Major isomer (60% de) δH 0.80 (3H, s, CH3),
Dibenzoyl peroxide mediated thermolysis of 1g
Dibenzoyl peroxide (0.3 g, 1.2 mmol) was dissolved in benzene
(2 cm3) and added dropwise over a period of 24 h, by using a
syringe pump, to a refluxing benzene solution (7 cm3) contain-
ing amide 1g (0.3 g, 0.9 mmol). After complete addition, the
mixture was left to reflux for 24 h. The solvent was evaporated
before dissolving the impure product in ether (50 cm3), washing
with NaOH (2 × 50 cm3), HCl (2 × 50 cm3) and water (2 ×
50 cm3) and drying (MgSO4). The solvent was evaporated under
reduced pressure to yield a brown oil (0.25 g); GC-MS peak no.
330, biphenyl (from initiator); peak no 438 phenyl benzoate;
(from initiator); peak no 569, N-benzylbenzamide, peak no.
618, 1,3-dibenzylazetidin-2-one 11g (12%), m/z (relative inten-
sity) 251 (Mϩ, 7) 160 (9), 118 (100), 117 (82), 105 (5), 91 (55), 77
(7), 65 (15), peak no.648 N-benzyl-(3-phenyl-2-propenyl)form-
amide 10g (5%), m/z (relative intensity) 251 (Mϩ, 20), 160 (55),
134 (8), 115 (100), 105 (10), 91 (65), 77 (9), 65 (12); peak no.
772, unreacted amide 1g (64%).
3
0.98 (3H, s, CH3), 1.02 (3H, d, CH3, J 6.8), 1.07 (3H, d, CH,
3J 7.7), 2.29 (1H, q, CH, 3J 7.2), 2.98 (1H, q, CH, 3J 6.8), 3.87
(1H, d, Ar–CH2, 2J 14.9), 5.02 (1H, d, Ph–CH2, 2J 14.9), 7.22–
7.31 (5H, m, ArH); major isomer δC 9.1 (CH3), 13.1 (CH3), 22.8
(2 × CH3), 38.9 (C), 44.3 (CH), 45.4 (CH2), 60.8 (CH), 127.4,
128.3, 128.5 (5 × ArH), 136.9 (C), 176.1 (C᎐O). Minor isomer
᎐
DTBP mediated photolysis 1g
δH 0.74 (3H, s, CH3), 0.95 (3H, s, CH3), 1.03 (3H, d, CH3,
3
3
3J 6.8), 1.11 (3H, d, CH, J = 7.2), 2.17 (1H, q, CH, J = 7.2),
Amide 1g (0.2 g, 0.6 mmol) was dissolved in benzene (2 cm3),
which contained DTBP (0.5 g, 3.42 mmol). The resultant solu-
tion was placed in a quartz tube, heated to 70 ЊC using a quartz
paraffin oil bath, and the sample was irradiated with light from
a 400 W medium pressure Hg lamp over an 8 h period. Analysis
of the reaction mixture by GC-MS indicated that photolytic
radical fragmentation of amide 1g led to identical peaks in the
GC-MS to those observed with the thermally initiated radical
reaction (except for initiator-derived products). GC measure-
ments using N,N-dimethylbenzamide as a standard, demon-
strated that the β-lactam 11g and formamide 10g were formed
in a similar percentage to that obtained from thermal
decomposition.
3.14 (1H, q, CH, 3J = 6.8), 4.00 (1H, d, Ph–CH, 2J = 14.9), 4.94
(1H, d, Ph–CH, J = 14.9), 7.22–7.31 (5H, m, ArH); minor
2
isomer δC 12.6 (CH3), 16.3 (CH3), 22.5 (2 × CH3), 39.0 (C), 43.9
(CH), 48.2 (CH2), 60.9 (CH), 127.2, 128.1, 128.2 (5 × ArH),
137.3 (C), 169.1 (C᎐O).
᎐
Photochemically initiated reaction of 1f
Amide 1f (0.03 g) was dissolved in DTBP (200 µl) and placed in
a quartz tube. The tube was capped and irradiated at ambient
temperature with light from a 400 W medium pressure Hg lamp
for 7 h. Analysis of the reaction mixture by GC-MS confirmed
the presence of cis- and trans-1-benzyl-3,4,4,5-tetramethyl-2-
pyrrolidinone isomers (11f ) (ratio 1 : 5.4, de 69%) together with
unreacted 1f and by-products derived from the photolytic
breakdown of DTBP. Benzyl-(1,2,2-trimethyl-3-butenyl)form-
amide (10f ) was formed in only a trace, but 1-benzyl-4,4,5-tri-
methyl-3-methylenepyrrolidin-2-one (12f ) m/z (%) 229 (Mϩ,
54), 228 (54), 214 (13), 196 (31), 131 (37), 119 (54), 105 (35), 91
(100), 77 (22) and 1-benzyl-3-ethyl-4,4,5-trimethylpyrrolidin-2-
one (13f ) m/z (%) 245 (Mϩ, 19), 231 (16), 178 (15), 162 (29), 134
(26), 105 (30), 91 (100), 57 (15) were observed as minor
components.
DTBPOO mediated thermolysis of 1g
Amide 1g (0.2 g, 0.6 mmol) was dissolved in benzene (10 cm3)
and heated to reflux before DTBPOO (0.25 g, 1 mmol) was
added, by syringe pump, over a period of 8 h. After complete
addition, the solvent was evaporated before dissolving the mix-
ture in ether (30 cm3); a residue separated from the organic layer
which was filtered off. The solvent was evaporated under
reduced pressure to yield a yellow oil (0.25 g). GC-MS, peak
14.8 min, biphenyl (from initiator); peak 23.9 min, 1,3-di-
benzylazetidin-2-one (11g), (15.4%); peak 24.7 min, N-benzyl-
(3-phenyl-2-propenyl)formamide (10g), (10.1%), (unresolved
isomers); peak 25.5 min, 1-benzyl-3-(1-phenylethyl)-2-azeti-
dinone (13g) (4.5%), m/z (relative intensity), 265 (Mϩ, 5), 237
(8), 207 (15), 174 (58), 105 (63), 91 (100), 77 (43), 65 (10),
28 (100), 18(32), peak 29.1 min, unreacted amide 1g (15.7%).
The product was purified by column chromatography, eluting
with 20% ethyl acetate in hexane to give the β-lactam, 11g;
δH 2.87–2.90 and 3.17 (2H, m, 3J = 2.4, Jgem = 5.3, CH2), 2.91–
3.13 (2H, ddd, 2J = 14.5, 3J = 4.8 and 8.2, AB system, Ar–CH2),
3.51 (1H, m CH), 4.17–4.47 (2H, dd, J = 15.4, AB system,
Ar–NCH2), 7.18–7.40 (10H, m, ArH), δC 34.2 (Ar–CH2),
43.9 (CH), 45.7 (Ar–CH2), 50.7 (CH2), 126.6, 127.6, 127.9,
128.6, 128.7, 129.1 (10 × CH), 135.5 (C), 138.0 (C), 169.7
(C᎐O); IR (ν cmϪ1) 1740; HRMS (FAB) m/z found Mϩ ϩ 1
N-Benzyl-1-methyl-N-3-phenyl-2-propenylcyclohexa-2,5-diene-
1-carboxamide (1g)
Prepared from N-benzyl-3-phenyl-2-propenylamine (1.5 g, 6.7
mmol), and 6 according to the general procedure. Amide 1g was
obtained as a colourless oil (1.5 g, 65%); IR (nujol) cmϪ1: 1712
(C᎐O, stretch), 1586 (C᎐C), 1270 (C᎐C), δ 1.40 (3H, s, CH3),
᎐
᎐
᎐
H
2.43–2.86 (2H, m, bisallylic-CH2), 4.00–4.17 (2H, m, N–CH2),
4.60–4.72 (2H, m, Ar–CH ), 5.66–6.32 (6H, m, ᎐CH), 7.18–7.34
᎐
2
(10H, m, ArH); δC 25.8 (CH2), 28.8 (CH3), 45.1 (C), 48.1, 48.4
(N–CH ), 48.8, 52.8 (CH ), 123.1 (2 ᎐CH), 126.3, 127.0, 127.2,
᎐
2
2
128.4, 128.5 (10 × ArH), 127.6 (᎐CH), 130.4 (2 × ᎐CH), 132.7
᎐
᎐
(᎐CH), 136.6 (C), 137.8 (C), 173.7 (C᎐O); HRMS m/z found
᎐
᎐
Mϩϩ1 344.2022, C30H26NO requires 344.2014.
᎐
max
Thermally initiated reaction of 1g
252.1390, C17H18NO: requires 252.1388. The mixture of cis-
and trans-N-benzyl-(3-phenyl-2-propenyl)formamides (10g)
(major : minor = 1.4 : 1); δH (major isomer shifts first), 3.89, 4.01
(2 × 2 H, d, J = 6.8 CH2), 4.41, 4.57 (2 × 2 H, s, CH2), 5.98–6.50
(2 × 2 H, br m, CH), 7.12–7.45 (2 × 10 H, m, Ar H), 8.30, 8.36
Amide 1g (0.15 g) was dissolved in benzene (5 cm3) and heated
to reflux before dibenzoyl peroxide (0.12 g, 0.50 mmol) was
added portion wise over a period of 24 h. After complete addi-
tion, the solvent was evaporated and the products were exam-
ined by GC-MS. Peak 569 N-benzylbenzamide, peak 618 1,3-
(2 × 1 H, s, HC᎐O).
᎐
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
427

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3 G. Cainelli, M. Panunzio, D. Giacomini, G. Martelli and G. Spunta,
J. Am. Chem. Soc., 1988, 110, 6879; E. E. Colvin, D. McGarry and
M. J. Nugent, Tetrahedron, 1988, 44, 4157; L. S. Hegedus and
S. D’Andrea, J. Org. Chem., 1988, 53, 3113; D. A. Evans, J. V. Nelson
and T. R Taber, Top. Stereochem., 1982, 13, 1.
4 F. H. Van der Steen, J. T. B. H. Jastrzebski and G. van Koten,
Tetrahedron Lett., 1988, 29, 2467; N. Yamasaki, M. Murakami and
T. Mukaiyama, Chem. Lett., 1986, 1013; G. Iwasaki and
M. Shibasaki, Tetrahedron Lett., 1987, 28, 3257; K. Ikeda,
Y. Yoshinaga, K. Achiwa and M. Sekiya, Chem. Lett., 1984, 369.
5 R. M. Adlington, A. G. M. Barrett, P. Quate and A. Walker,
J. Chem. Soc., Chem. Commun., 1981, 404.
6 R. Southgate and R. J. Ponsford, J. Chem. Soc., Chem. Commun.,
1979, 846; M. P. Doyle, M. S. Shanklin, S.-M. Oon, H. Q. Pho,
F. R. van der Heide and W. R. Veal, J. Org. Chem., 1988, 53,
3386.
7 M. C. Sleeman, C. H. MacKinnon, K. S. Hewitson and C. J.
Schofield, Bioorg. Med. Chem. Lett., 2002, 12, 597; B. A. Frieman,
C. W. Bock and K. L. Bhat, Heterocycles, 2001, 55, 2099–2108;
M. R. Linder, W. U. Frey and J. Podlech, J. Chem. Soc., Perkin
Trans. 1, 2001, 2566; U. Nubbemeyer, Top. Curr. Chem., 2001, 216,
125.
8 H. Ishibashi, C. Kameoka, H. Iriyama, K. Kodama, T. Sato and
M. Ikeda, J. Org. Chem., 1995, 60, 1276; H. Ishibashi, C. Kameoka,
K. Kodama, T. Sato and M. Ikeda, Tetrahedron, 1996, 52, 489.
9 G. B. Gill, G. Pattenden and S. J. Reynolds, J. Chem. Soc., Perkin
Trans. 1, 1994, 369; G. Pattenden and S. J. Reynolds, J. Chem. Soc.,
Perkin Trans. 1, 1994, 379.
10 G. Binmore, J. C. Walton and L. Cardellini, J. Chem. Soc., Chem.
Commun., 1995, 27; G. Binmore, L. Cardellini and J. C. Walton,
J. Chem. Soc., Perkin Trans. 2, 1997, 757.
11 P. A. Baguley, G. Binmore, A. Milne and J. C. Walton, J. Chem. Soc.,
Chem. Commun., 1996, 2199; P. A. Baguley and J. C. Walton,
J. Chem. Soc., Perkin Trans. 1, 1998, 2073.
12 P. A. Baguley, L. V. Jackson and J. C. Walton, J. Chem. Soc., Perkin
Trans. 1, 2002, 304.
13 A. Studer and S. Amrein, Angew. Chem., Int. Ed., 2000, 39, 3080;
S. Amrein, A. Timmermann and A. Studer, Org. Lett., 2001, 3, 2357;
A. Studer, S. Amrein, F. Schleth, T. Schulte and J. C. Walton, J. Am.
Chem. Soc., 2003, 125, 5726.
14 L. V. Jackson and J. C. Walton, Chem. Commun., 2000, 2327.
15 H. V. Bekkum, C. B. V. D. Bosch, G. V. Minnen-Pathius, J. C. Mos
and A. M. V. Wijk, Recl. Trav. Chim. Pays-bas, 1971, 90, 137.
16 B. P. Roberts, Chem. Soc. Rev., 1999, 28, 25; H.-S. Dang, M. R. J.
Elsegood, K.-M. Kim and B. P. Roberts, J. Chem. Soc., Perkin Trans.
1, 1999, 2061; A. J. Fielding and B. P. Roberts, Tetrahedron Lett.,
2001, 42, 4061.
17 See: C. Chatgilialoglu, D. Crich, M. Komatsu and J. Ryu, Chem.
Rev., 1999, 99, 1991 for a discussion.
18 A. F. Bella, L. V. Jackson and J. C. Walton, J. Chem. Soc.,
Perkin Trans. 2, 2002, 8139.
19 H. Ishibashi, Y. Fuke, T. Yamashita and M. Ikeda, Tetrahedron:
Asymmetry, 1996, 7, 2531.
Thermolysis of 1g with DTBPOO and thiol
DTBPOO (0.1 g, 0.43 mmol) was dissolved in benzene (1.5 cm3)
and added portion wise, over 12 h, to a refluxing benzene
solution containing amide 1g (0.1 g, 0.3 mmol) and methyl
thioglycolate (0.032 g, 0.3 mmol). After complete addition the
solution was refluxed for 24 h, the solvent evaporated at
reduced pressure leaving a crude product which was dissolved
in DCM (20 cm3) and treated with a warm 6 M solution of
KOH (50 cm3). The aqueous phase was extracted with DCM
(3 × 25 cm3) and the combined organic layer evaporated at
reduced pressure to leave a yellow product. GC-MS, peak 23.9
min 1,3-dibenzylazetidin-2-one (11g) (24%), peak 28.6 min cis
and trans-methyl({1-benzyl-2-[benzyl(formyl)amino]ethyl}sul-
fanyl) acetate (14g) (65%), m/z (relative intensity) 357 (Mϩ, 2)
284 (22), 252 (40), 222 (25), 177 (10), 160 (8), 149 (28), 116 (20),
91 (100), 77 (5), 65 (12), peak 29.1 min, unreacted amide. When
only a catalytic amount of thiol was used the yield of β-lactam
increased to 38%, sulfanylformamide 14g was not detected,
only 11% of formamide 10g together with 28% of azetidin-2-
one 13g was formed under these conditions.
Thermolysis of 1g with lauroyl peroxide and thiol
Amide 1g (0.1 g, 0.3 mmol) was dissolved in benzene (7 cm3)
and heated to reflux before lauroyl peroxide (total 0.18 g, 0.45
mmol) in benzene (3 cm3) was added in portions (0.35 cm3 of
soln.) over a period of 8 h. Following the first addition, the
solution was refluxed for 5 min and then methyl thioglycolate
(0.032 g, 0.3 mmol) was added. After complete addition, the
solvent was evaporated to yield a yellow crude product. GC-
MS, peak 3.6 min, methyl thioglycolate, peak 10.3 min, unde-
cane (from initiator), peak 16.1 min, disulfide (dimer of thiol),
peak 17.1 min, lauric acid (from initiator) peak. 23.5 min,
docosane (from initiator), peak 23.9 min, 1,3-dibenzyl azetidin-
2-one (11g) (66%); peak 25.7 min, undecyl laurate (from
initiator), peak 28.6 min cis- and trans-methyl({1-benzyl-2-
[benzyl(formyl) amino]ethyl}sulfanyl) acetate (14g) (24%), peak
29.1 min unreacted amide 1g (10%).
Acknowledgements
We thank the EPSRC for financial support of this research
(Grant GR/N38763) and the Royal Society of Chemistry for a
travel grant.
20 R. Boese, A. P. Van Sickle and K. P. C. Vollhardt, Synthesis, 1994,
12, 1374.
21 M. A. Schexnayder and P. S. Engel, J. Am. Chem. Soc., 1975, 97,
4825.
References and notes
1 C. E. Newall and P. D. Hallam in Comprehensive Medicinal
Chemistry, Vol. 2, ed. P. G. Sammes, Pergamon, 1990, pp. 609; P. H.
Bentley and R. Southgate, eds. Recent Advances in the Chemistry of
β-Lactam Antibiotics, RSC Special Publ. No. 70, London, 1989.
2 I. Ugi and C. Steinbrückner, Chem. Ber., 1961, 96, 2802; I. Ugi,
Angew. Chem., Int. Ed. Engl., 1982, 21, 810; H. P. Isenring and
W. Hofheinz, Tetrahedron, 1983, 39, 2591.
22 P. S. Engel and M. A. Schexnayder, J. Am. Chem. Soc., 1975, 97,
145.
23 R. Melvin and R. D. W. Eurby, J. Chem. Res. (M), 1987, 554.
24 K. M. J. Brands, A. A. P. Meekel and U. K. Pandit, Tetrahedron,
1991, 47, 2005.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 2 1 – 4 2 8
428