Delineating ligand effects in intramolecular aryl amidation reactions: formation of a novel spiro-heterocycle by a tandem cyclisation process

Article abstract of DOI:10.1016/j.tet.2008.10.098

Ligand effects for intramolecular Pd-catalysed aryl amidation reaction were examined for the synthesis of seven-membered benzolactam rings. In an attempt to produce an eight-membered ring, tandem C-N/C-O bond forming reactions occurred to give a novel spi

Full text of DOI:10.1016/j.tet.2008.10.098

Tetrahedron 65 (2009) 525–530
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Delineating ligand effects in intramolecular aryl amidation reactions: formation
of a novel spiro-heterocycle by a tandem cyclisation process
,
Emma L. Cropper a, Aui-Ping Yuen a, Agnes Ford b, Andrew J.P. White a, King Kuok (Mimi) Hii a
*
a Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK
b AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 August 2008
Received in revised form 14 October 2008
Accepted 30 October 2008
Available online 5 November 2008
Ligand effects for intramolecular Pd-catalysed aryl amidation reaction were examined for the synthesis
of seven-membered benzolactam rings. In an attempt to produce an eight-membered ring, tandem C–N/
C–O bond forming reactions occurred to give a novel spiro-benzofuran-lactam structure.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
heterocyclic rings,4 we embarked upon a study to examine the
precise role of the phosphine ligand in these challenging C–N bond
Palladium-catalysed C–N bond forming reactions between N-
nucleophiles and aryl halides attracted a tremendous amount of
attention in the last decade, and are becoming increasingly com-
mon in industrial processes.1
formations.
2. Result and discussion
Compared to amination reactions, arylation substitution re-
actions with amides, carbamates and ureas are less common as
they are generally more challenging. The use of intramolecular Pd-
catalysed aryl amidation reaction for the formation of benzo-
lactams was first demonstrated by Buchwald et al., who showed
that while ‘generic’ monodentate phosphine ligands such as P
(o-tolyl)3 and P(2-furyl)3 are effective for the formation of five- and
six-membered heterocycles, they failed to produce larger rings.2
The synthesis of seven-membered 1-benzazepinone (1) was
Acyclic precursors were constructed using a concise three-step
procedure from commercially available reagents (Scheme 2). Tan-
dem Heck-isomerisation coupling between 2-bromoiodobenzene
and buten-3-ol or penten-4-ol delivered the corresponding
u-(2-
bromophenyl)-aldehydes 2a and 2b, respectively, in high yields.5
These were subjected to Pinnick’s oxidation to give carboxylic acids
3a and 3b, which were then coupled with benzylamine, either by
using DCC/DMAP (4a, 85%; 4b, 40%) or by the direct pyrolysis using
microwave irradiation.6 The latter method was not only cleaner and
faster, it also provided analytically pure samples in excellent yields
after a simple acid-wash (4a, 96%; 4b, 92%).
eventually accomplished by using
a sterically bulky mono-
phosphine ligand MOP (Scheme 1).3 Compared to the formation of
smaller rings, high dilution and relatively long reaction times were
required for the reaction to proceed.
Br
I
Br
OH
O
(ii)
+
(i)
Pd(OAc)2 (5 mol%)
O
n
( )-MOP (7.5 mol%)
n
Cs2CO3,
PhMe (0.06 M)
2a (n = 1, 86%)
NHBn
2
2b (n = 2, 88%)
N
Bn
Br
100 °C, 48h, 88%
O
OH
NHBn
1
(iii) or (iv)
n
n
O
O
Scheme 1. Original synthesis of 1-benzazepinone 1 by a Pd-catalysed aryl amidation
reaction.
Br
Br
3a (n = 1, 89%)
4a (n = 1)
3b (n = 2, 55%)
4b (n = 2)
As part of our ongoing effort to explore the synthetic utility of
metal-catalysed reactions for the synthesis of medium-sized
Scheme 2. Preparation of acyclic precursors. (i) Pd(OAc)2 (2 mol %), n-Bu4NCl, NaHCO3,
DMF, 65 ꢀC, 17 h. (ii) NaH2PO4, NaClO2, t-BuOH, 2-methyl-2-butene, rt. (iii) BnNH2,
DCC, DMAP, CH2Cl2, 17 h. (iv) BnNH2, mwave, 30 min.
Despite a fairly recent ligand modification study,7 the earlier
* Corresponding author. Tel.: þ44 (0) 20 7594 1142; fax: þ44 (0) 20 7594 5804.
E-mail address: mimi.hii@imperial.ac.uk (K.K. Hii).
result reported for the cyclisation of 4a to 1 (88% yield)3 remained
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.098

526
E.L. Cropper et al. / Tetrahedron 65 (2009) 525–530
unsurpassed. Given the prohibitive cost of the MOP ligand,8 we
decided to revisit the cyclisation of the amide 4a using more ac-
cessible ligands. The study was performed under previously de-
scribed conditions, and included diphosphine ligands with large
bite angles and sterically bulky monophosphines, both of which are
known to be particularly beneficial for C–N bond forming reactions
(Fig. 1, Table 1).
As expected, the reaction outcome was highly dependent upon
the structure of the ligand employed. DPPF and Xantphos, pre-
viously shown to be effective for amination and amidation re-
actions,9 furnished only very low yield of the expected product,
even after prolonged reaction times (entries 6–8). In contrast,
BINAP, with a smaller bite angle, delivered an impressive 89%
yield, although the reaction required 10 days (entry 5). This sug-
gests that the catalyst has a slow turnover, but is particularly
stable under these conditions. An attempt to facilitate the process
by microwave irradiation (100 ꢀC, 30 min)10 resulted only in cat-
alyst decomposition (Pd black) and recovery of the starting
material.
Table 1
Cyclisation of acyclic precursor 4a to 1a
Entry
Ligand
Bite angleb/ꢀ
Time/h
Yieldc/%
1
2
3
4
5
6
7
8
(ꢁ)-MOP
(ꢂ)-BINAP
(ꢂ)-BINAP
(ꢂ)-BINAP
(ꢂ)-BINAP
dppf
48
48
90
144
240
48
90
48
48
48
88d
26
56
67
89
17
18
13
11
92.7
99.1
dppf
Xantphos
JohnPhos
DavePhos
X-Phos
110.0
9
10
11
12
40
88
84
24
24
P(t-Bu)3
a
General reaction conditions: 0.06 M of 4a in toluene, 5 mol % Pd(OAc)2, 7.5 mol %
ligand, Cs2CO3 (1.4 equiv), 100 ꢀC.
b
Obtained from X-ray crystal structures of [(diphosphine)PdCl2] complexes
obtained from the Cambridge Crystallographic Database.
c
Isolated yield after column chromatography.
Ref. 3.
d
Noting that MOP and BINAP delivered essentially the same TON
but with quite different rates (entries 1 and 5), it is reasonable to
surmise that the substitution of the PPh2 donor with OMe promotes
the rate-determining step, i.e., weak coordination/hemilability of
a second donor group at the 20-position is critical. With this in
mind, other structurally-related biarylphosphines, with or without
a second coordinating group at the 20-position, were subsequently
tested: JohnPhos, DavePhos and X-Phos. The results obtained with
these ligands showed that while the presence of a 20-substituent is
beneficial (entries 9 and 10), the absence of a donor group at the 20-
substituent imparts even greater catalytic activity; demonstrated
by the result obtained with X-Phos, which delivered the same yield
as MOP in half the time (entry 11).
The result (X-Phos>MOP>BINAP) agrees with a report that the
presence of an accessible C–H at the 20-position in biarylphosphine
ligands can lead to the formation of palladacycles; this can affect
the catalytic activity in a profound way.11 Thus, we reasoned that
other sterically bulky monophosphine ligands that do not contain
such labile C–H bonds should also form active catalysts for this
reaction. Gratifyingly, the speculation appears to be correct, when
tri-tert-butylphosphine was found to deliver a comparable result to
X-Phos (entries 11 and 12).
The catalytic protocol was subsequently applied to the synthesis
of 1,5-benzodiazepin-2-one, an important core structure known for
interesting CNS biological activities12 (Scheme 3):
b-amino ester 5a
was prepared by an aza-Michael reaction between 2-bromoaniline
and ethyl acrylate. Following N-benzylation, the ester was trans-
formed into the benzylamide 6 via standard procedures. Under
previously described catalytic conditions using P(t-Bu)3 as the li-
gand (condition A), the Pd-mediated cyclisation afforded the
expected product 7 in 76% yield after column chromatography. The
result is superior to a reported synthesis of a similar structure by
copper-catalysed intramolecular N-arylation reaction (which re-
quired 60 h to achieve a moderate yield of 63%).13 As the two C–N
bond forming events occur orthogonally, this should allow for
better regiocontrol in the synthesis of unsymmetrical 1,5-di-
azepinones (with substituted aromatic rings), compared to other
methods of synthesis, e.g., ring expansion,14 or cyclisation with 1,2-
diaminobenzene.15
Br
(i)
+
CO2Et
The above study led to the identification of two ligands (X-Phos,
t-Bu3P) that are more active than MOP in the intramolecular ami-
dation reaction for the formation of seven-membered benzolactam
ring. The result clearly suggests that steric hindrance and the
(in)ability to form a palladacycle during the reaction are critical for
good catalytic activity. In contrast, the electronic effect must be
largely negligible, given the substantial difference between X-Phos
and P(t-Bu)3.
NH2
Br
Br
(iii), (iv)
O
CO2Et
(ii)
N
R
N
Bn
NHBn
5a (R = H)
5b (R = Bn)
6
Bn
N
O
Pd(OAc)2 (5 mol%)
P(t-Bu)3 (7.5 mol%)
Cs2CO3, PhMe,
100 °C, 17 h
X
PPh2
PPh2
N
Bn
7, 79%
O
Fe
Conditions A
PPh2
PPh2
PPh2
Scheme 3. Synthesis of a 1,5-diazepinone by Pd-catalysed intramolecular aryl ami-
dation. (i) Hþ, EtOH, reflux, 61%. (ii) PhCH2Br, K2CO3, CH3CN, reflux, 72%. (iii) NaOH,
MeOH, 76%. (iv) BnNH2, HOBt, DCC, 73%.
Xantphos
DPPF
X = OMe, MOP
X = PPh2, BINAP
Me2N
Given there are no known examples of eight-membered ring
formation by aryl amidation,16 it is perhaps unsurprising that the
acyclic substrate 4b defied all our efforts to produce the expected
eight-membered heterocycle. Attributing the failure to unfav-
ourable enthalpic and entropic issues associated with the confor-
mational flexibility of the acyclic chain, we investigated the
possibility of introducing steric constraints into the precursor. The
strategy has previously proven to be successful for the synthesis of
P(t-Bu)3
PCy2
i-Pr
PCy2
P(t-Bu)2
i-Pr
DavePhos
JohnPhos
X-Phos
i-Pr
Figure 1. Ligands screened for the intramolecular aryl amidation reaction of 4a.

E.L. Cropper et al. / Tetrahedron 65 (2009) 525–530
527
OH
OCONH2
OH
OH
R = OH
O
N
I
O
O
O
NH
OHC
N
FR900482
OCONH2
OMe
O
N
8
R
H2N
Me
R = H
N
NH
N
O
Mitomycin C
II
Figure 2. Core structures afforded by 1-benzazocin-5-one 8.
a novel eight-membered benzazocinone by an intramolecular Heck
arylation reaction.4a
Figure 3. Molecular structure of 12. Aromatic protons are omitted for the sake of
clarity.
For this part of the work, 1-benzazocin-5-one 8 (Fig. 2) was
chosen as our initial target, as it contains a conformationally re-
strictive sp2-hybridised carbon within the cyclising chain. The ke-
tone moiety is also synthetically useful, as it can provide access to
important core structures such as bicyclic hemiketal (I) and pyrrol-
indole (II), constituents of mitomycin C and FR900482da family of
potent cytotoxic antibodies used in the treatment of solid tumours.17
Preparation of the precursor was simply achieved by the re-
action of succinic anhydride with the Grignard reagent derived
from 2-bromobenzyl bromide. The resultant carboxylic acid 9 was
then converted to its corresponding benzylamide in good yield
(Scheme 4).
11
Cs2CO3
O
O
N
Δ
-H2O
HO
N
Bn
10
Bn
13
14
Br
Br
LPd(0)
O
O
Bn
Bn
base
N
N
O
Br Br
Br
O
(i), (ii)
66%
12
Y
O
H
Pd
L
O
base.HBr
PdLBr
15
9 (Y = OH)
10 (Y = NHBn)
Bn
(iii), 81%
Bn
Scheme 5. Formation of compounds 11 and 12.
O
Thus, the formation of 12 is attributed to a domino C–N/C–O
bond forming process, whereby the role of the Pd catalyst is to
effect a C–O aryl etheration, initiated by the oxidative addition of
keto-amide 13 to a highly active L–Pd(0) precursor. This effectively
brings the hydroxyl group within close proximity of the metal
centre, and the resultant interaction enables a lowering of pKa of
the O–H moiety, thus facilitating its deprotonation by the weak
base to furnish the palladacycle 15, which generates the spi-
rolactam 12 by reductive elimination.
Conditions A
N
N
O
O
+
O
11 10-15%
12, 49%
Scheme 4. Preparation and cyclisation of acyclic precursor 10. (i) Mg, Et2O, reflux. (ii)
succinic anhydride, THF, ꢁ78 ꢀC. (iii) BnNH2, DCC, HOBt, CH2Cl2, 23 h.
Precursor 10 was promptly subjected to the catalytic conditions
described previously (condition A), whereupon the starting mate-
rial was steadily consumed over the course of the reaction, to yield
two distinct products. Following chromatographic separation, the
mixture was found to consist of a mixture of N-benzylsuccinimide
11 (by comparison with a genuine sample) and an unknown com-
pound 12, which gave rise to the expected mass ion (m/z¼279), but
further spectroscopic analyses (infrared and 13C NMR spectra)
revealed the absence of a ketone moiety. Identity of compound 12
was eventually established by single crystal X-ray crystallography
(Fig. 3), showing the formation of a novel benzo-fused spirocyclic
Within this context, P(t-Bu)3 appeared to impart unique utility,
as other phosphines (BINAP, X-Phos, JohnPhos and MOP) were far
less effective in this reaction, furnishing <15% of 12.
3. Conclusion
Sterically bulky monophosphines X-Phos and P(t-Bu)3 have
been found to be particularly effective for the formation of 7-ben-
zolactams using Pd-catalysed aryl amidation reactions. During this
work, an unexpected tandem C–N/C–O bond forming process was
uncovered, leading to the formation of a novel spiro-benzofuran-
structure, where a benzofuran and a g-lactam are connected via
a stereogenic carbon, at the position adjacent to the heteroatom in
each ring. Extensive searches (using CCDC, CAS and Beilstein da-
tabases) showed the absence of related structures in the current
literature, thus establishing it as a novel structure motif.
The formation of the succinimide 11 prompted us to examine
the stability of the acyclic precursor. Under refluxing conditions,
a solution of 10 in toluene-d8 cyclised to form the pyrrolidinone
14 (which can be isolated), presumably the dehydrated form of
the keto-amide 13 (Scheme 5). In the presence of Cs2CO3, the
process was intercepted by an alternate elimination process to
generate 11.
g
-lactam ringda hitherto unknown structural motif.
4. Experimental section
4.1. General
Unless otherwise stated, all starting materials, reagents and
anhydrous solvents are procured commercially and used as-re-
ceived without further purification. Air-sensitive reactions were

528
E.L. Cropper et al. / Tetrahedron 65 (2009) 525–530
conducted in oven-dried glassware under a N2 atmosphere. Mi-
crowave reactions were performed using a CEM Discover Synthesis
Unit in 10 mL glass vessels.
4.1.2. Coupling of carboxylic acids 3a and 3b with benzylamine
Method A: Benzylamine (1.7 mL, 15.8 mmol, 1.1 equiv), DCC
(3.27 g, 15.8 mmol, 1.1 equiv) and DMAP (0.16 g, 1.30 mmol,
9 mol %) were added sequentially to a stirred solution of the carb-
oxylic acid (14.4 mmol, 1.0 equiv) in dry CH2Cl2 (90 mL) at 0 ꢀC.
Stirring was continued at 0 ꢀC for 1 h, before the reaction mixture
was allowed to warm up to room temperature and stirred for 16 h.
The white precipitate was removed by filtration and the filtrate was
washed with 1 M aq HCl (30 mL), brine (30 mL), dried over MgSO4
and concentrated in vacuo. The resulting pale yellow solid was
purified using column chromatography.
Method B: A microwave vessel was charged with a magnetic stir
bar, carboxylic acid (0.82 mmol, 1.0 equiv) and benzylamine
(0.13 mL, 1.23 mmol, 1.5 equiv). The contents of the reaction tube
were homogenised using a whirlimixer, before it was sealed and
irradiated at 150 ꢀC for 30 min with stirring. After cooling to room
temperature, the reaction mixture was dissolved in CH2Cl2 (10 mL)
and washed with 2 M aq HCl (5 mL), 5% aq NaHCO3 (5 mL) and
brine (5 mL). The organic layer was dried (MgSO4) and evaporated
to yield analytically pure amide.
1H and 13C NMR spectra were recorded using Bruker 400 spec-
trometers. Residual protic solvents were used as an internal stan-
dard and 13C resonances were referenced to the deuterated carbon.
Chemical shifts (d) are given in parts per million (ppm) and cou-
pling constants (J) are reported in hertz (Hz). Infrared spectra were
recorded on a Mattson Instrument Satellite FTIR spectrometer. All
liquid samples were recorded as thin films between NaCl plates,
whereas solid samples were formulated as KBr discs. Melting points
were determined using an Electrothermal Gallenkamp apparatus
and are uncorrected. Mass spectra were recorded by the Mass
Spectrometry Service at Imperial College London. Elemental anal-
yses were carried out by the Elemental Analysis Service at London
Metropolitan University.
X-ray quality crystals of compound 12 were accrued by mixed-
solvent recrystallisation, allowing crystal growth at room temper-
ature. Crystal data for 12: C18H17NO2, M¼279.33, monoclinic, P21/c
(no.14), a¼13.378(3), b¼11.1011(7), c¼9.8519(17) Å,
b
¼106.568(18)ꢀ,
V¼1402.3(4) Å3, Z¼4, Dc¼1.323 g cmꢁ3
,
m(Mo K
a
)¼0.086 mmꢁ1
,
T¼173 K, colourless needles, Oxford Diffraction Xcalibur 3 diffrac-
tometer; 4487 independent measured reflections, F2 refinement,
R1¼0.039, wR2¼0.111, 3567 independent observed absorption-
4.1.2.1. N-Benzyl-4-(2-bromo-phenyl)-butyramide (4a). Yield: 85%
(method A) or 96% (method B) as a white solid; Rf¼0.52, CH2Cl2/
MeOH (20/1); mp 110–111 ꢀC (lit.2 111–112 ꢀC); nmax (KBr)/cmꢁ1
3289 (NH), 1638 (CO); dH (360 MHz, CDCl3) 1.91–1.98 (2H, m,
ArCH2CH2), 2.21 (2H, t, J 7.6, CH2CO), 2.73 (2H, t, J 7.8, ArCH2CH2),
4.38 (2H, close AB, PhCH2), 5.63 (1H, br s, NH), 6.96–7.01 (1H, m,
ArH), 7.14–7.29 (7H, m, ArH), 7.45 (1H, d, J 8.0, ArH); dC (100.6 MHz,
CDCl3) 26.1 (1C, ArCH2CH2), 35.8 (1C, ArCH2CH2), 36.3 (1C, CH2CO),
44.1 (PhCH2), 124.8 (1C, C2), 127.9 (1C, ArC), 128.0 (1C, ArC), 128.2
(1C, C4), 128.3 (2C, ArC), 129.2 (2C, ArC), 130.9 (1C, C6), 133.2 (1C,
C3), 138.7 (1C, Cipso), 141.2 (1C, C1), 172.2 (1C, CO); m/z (EI) 333/331
(Mþ, 37/38%), 252 (47), 149 (100).
corrected reflections [jFoj>4
s
(jFoj), 2qmax¼64ꢀ], 190 parameters.
This data has been deposited at the Cambridge Crystallographic
Database (reference code: CCDC 669098).
4.1.1. Preparation of 1-benzazepinone precursors 4a and 4b
(Scheme 2)
Compounds 2a and 2b were prepared according to a reported
procedure.5
4.1.1.1. Pinnick oxidation of aldehydes. Sodium chlorite (1.70 g,
15 mmol, 3.4 equiv) was added slowly, in small portions, to a stirred
mixture of 2a (1.0 g, 4.4 mmol, 1.0 equiv), NaH2PO4 (0.60 g,
4.4 mmol, 1.0 equiv), 2-methyl-2-butene (3 mL, 28 mmol,
4.4 equiv), tert-butanol (22 mL) and H2O (7 mL). Stirring was con-
tinued for 2 h at room temperature, before the mixture was acidi-
fied by the addition of 2 M aq HCl, and diluted with CH2Cl2
(250 mL). The organic phase was separated, washed with brine
(3ꢃ50 mL) and dried (MgSO4). Finally, the solvent was evaporated,
and the residue was recrystallised from hexane.
4.1.2.2. 5-(2-Bromophenyl)-pentanoic acid benzylamine (4b). Yield:
40% (method A) or 92% (method B) as a white solid. Found: C, 62.54;
H, 5.76; N, 3.94%. Calcd for C18H20BrNO: C, 62.44; H, 5.82; N, 4.05%.
Rf¼0.46, CH2Cl2/MeOH (20/1); mp 72–73 ꢀC; nmax (KBr)/cmꢁ1 3289
(NH), 1634 (CO); dH (270 MHz, CDCl3) 1.59–1.81 (4H, m, ArCH2CH2,
CH2CH2CO), 2.26 (2H, t, J 7.2, CH2CO), 2.74 (2H, t, J 7.4, ArCH2CH2),
4.43 (2H, close AB, PhCH2), 5.72 (1H, br s, NH), 7.00–7.07 (1H, m,
ArH), 7.17–7.36 (7H, m, ArH), 7.50 (1H, d, J 8.4, ArH); dC (100.6 MHz,
CDCl3) 25.4 (1C, ArCH2CH2), 29.5 (CH2CH2CO), 35.9 (1C, ArCH2CH2),
36.5 (1C, CH2CO), 43.6 (PhCH2), 124.4 (1C, C2), 127.4 (1C, ArC), 127.5
(1C, ArC), 127.6 (1C, ArC), 127.8 (2C, ArC), 128.7 (2C, ArC), 130.4 (1C,
C6), 132.8 (1C, C3), 138.3 (1C, Cipso), 141.4 (1C, C1), 172.6 (1C, CO); m/z
(EI) 347/345 (Mþ, 14/15%), 266 (47), 149 (59), 91 (100).
4.1.1.2. 4-(2-Bromophenyl)butanoic acid (3a). Yield: 89% as a white
crystalline solid; mp 91–92 ꢀC (lit.5 88–89 ꢀC); nmax (KBr)/cmꢁ1
3033 (br s, OH), 1712 (CO); dH (360 MHz, CDCl3) 1.96–2.07 (2H, m,
ArCH2CH2), 2.45 (2H, t, J 7.4, CH2CO2H), 2.83 (2H, t, J 7.4, ArCH2),
7.06–7.11 (1H, m, ArH), 7.23–7.28 (2H, m, ArH), 7.55 (1H, d, J 8.0,
ArH),10.97 (br s, CO2H); dC (100.6 MHz, CDCl3) 24.7 (1C, ArCH2CH2),
33.3 (1C, CH2CO2H), 35.2 (1C, ArCH2), 124.4 (1C, ArC), 127.5 (1C,
ArC), 127.8 (1C, ArC), 130.5 (1C, ArC), 132.9 (1C, ArC), 140.5 (1C, ArC),
179.8 (CO2H); m/z (EI) 244/242 (Mþ, 24/25%), 184/182 (86/90), 163
(100).
4.1.3. Typical procedure for the Pd-catalysed aryl amidation
reaction (Table 1, condition A)
A dry Young’s tube was charged with Pd(OAc)2 (4.9 mg,
0.022 mmol, 5.0 mol %), 4a (143 mg, 0.43 mmol, 1.0 equiv), Cs2CO3
(196 mg, 0.60 mmol, 1.4 equiv) and the appropriate ligand
(0.032 mmol, 7.5 mol %). The reaction vessel was evacuated and
filled with N2, before the addition of dry toluene (6.5 mL, 0.06 M
wrt amide) via a syringe. Finally, the reaction vessel was sealed
with a Teflon tap and heated at 100 ꢀC in a thermostated oil bath
for the appropriate length of time, after which the reaction
mixture was filtered through Celite and purified by column
chromatography.
4.1.1.3. 5-(2-Bromophenyl)pentanoicacid(3b). Yield: 55% as a white
solid; mp 47–48 ꢀC (lit.18 40–42 ꢀC, from CCl4); nmax (KBr)/cmꢁ1
3037 (br s, OH), 1705 (CO); dH (270 MHz, CDCl3) 1.64–1.75 (4H, m,
ArCH2CH2, CH2CH2CO2H), 2.41 (2H, t, J 7.2, CH2CO2H), 2.75 (2H, t,
J 7.2, ArCH2), 7.01–7.07 (1H, m, ArH), 7.18–7.25 (2H, m, ArH), 7.51
(1H, d, J 7.8, ArH), 10.30 (br s, CO2H); dC (100.6 MHz, CDCl3) 24.3
(1C, ArCH2CH2), 29.2 (1C, CH2CH2CO2H), 33.8 (1C, ArCH2),
35.7 (1C, CH2CO2H), 124.4 (1C, ArC), 127.4 (1C, ArC), 127.6
(1C, ArC), 130.3 (1C, ArC), 132.8 (1C, ArC), 141.2 (1C, ArC),
179.7 (1C, CO2H); m/z (EI) 258/256 (Mþ, 21/22%), 171/169 (97/96),
159 (100).
4.1.3.1. 1-Benzyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (1)2. Pale
yellow oil; Rf¼0.30, hexane/EtOAc (2/1); nmax (thin film)/cmꢁ1 1660
(CO); dH (400 MHz, CDCl3) 2.14–2.16 (2H, br m, ArCH2CH2), 2.35
(2H, t, J 7.0, CH2CO), 2.51 (2H, t, J 6.8, ArCH2CH2), 5.02 (2H, br s,
PhCH2), 7.12–7.27 (9H, m, ArH); dC (100.6 MHz, CDCl3) 29.0 (1C,

E.L. Cropper et al. / Tetrahedron 65 (2009) 525–530
529
ArCH2CH2), 29.9 (1C, ArCH2CH2), 33.2 (1C, CH2CO), 51.2 (1C, PhCH2),
122.7 (1C, ArC), 126.3 (1C, ArC), 127.2 (1C, ArC), 127.4 (1C, ArC),
128.0 (2C, ArC), 128.4 (2C, ArC), 129.3 (1C, ArC), 135.8 (1C, ArC),
137.9 (1C, ArC), 142.5 (1C, ArC), 173.2 (1C, CO); m/z (EI) 251 (Mþ,
87%), 196 (43), 132 (63), 91 (100).
was warmed up to room temperature and stirred overnight. The
resultant white precipitate was removed by filtration, and the fil-
trate was washed with 1 M aq HCl (15 mL), brine (15 mL), dried
(Na2SO4) and evaporated. The residue was purified by column
chromatography, to furnish 6 as a white solid. Yield: 1.66 g, 64%.
Found: C, 65.21; H, 5.43; N, 6.60%. Calcd for C23H23BrN2O: C, 65.25;
H, 5.48; N, 6.62%. nmax (thin film)/cmꢁ1 3374 (NH); dH (400 MHz,
CDCl3) 2.55 (2H, t, J 6.5, CH2CO), 3.58 (2H, t, J 6.5, CH2CH2CO), 4.74
(1H, br s, NH), 5.97 (1H, br s, NH), 6.59–6.61 (1H, t, J 7.6, ArH), 6.68–
6.71 (1H, d, J 8.0, ArH), 7.18–7.22 (1H, m, ArH), 7.27–7.37 (7H, m,
ArH), 7.45 (1H, d, J 7.6, ArH); dC (400 MHz, CDCl3) 35.8 (1C, CH2CO),
39.983 (1C, NHCH2Ph), 43.7 (1C, CH2CH2CO), 110.2 (1C, ArC), 111.4
(1C, ArC), 118.2 (1C, ArC), 127.6 (1C, ArC), 127.8 (1C, ArC), 128.5 (2C,
ArC), 128.8 (2C, ArC), 132.6 (1C, ArC), 137.9 (1C, ArC), 144.5 (1C, ArC),
170.9 (1C, CO); m/z (CI) 335/333 (MHþ, 100%).
4.1.3.2. Ethyl 3-(2-bromophenylamino)propionate (5a). A mixture
of 2-bromoaniline (2.2 mL, 20 mmol, 1 equiv), ethyl acrylate
(2.4 mL, 22 mmol, 1.1 equiv) and concd HCl (2 mL) in ethanol
(15 mL) was heated under reflux for 48 h. The solvent was evapo-
rated and the residue was made basic by the addition of 28% aq
NH3. This was then extracted with CH2Cl2, and the combined or-
ganic fractions were washed with H2O, dried (Na2SO4) and con-
centrated. The residue was purified by column chromatography, to
give product 5a as a yellow oil. Yield: 3.3 g, 61%. Found: C, 48.56; H,
5.14; N, 5.04%. Calcd for C11H14BrNO2: C, 48.55; H, 5.19; N, 5.15%.
Rf¼0.36, petroleum ether 40–60/EtOAc (3/1); dH (400 MHz, CDCl3)
1.28 (3H, t, J 7.2, OCH2CH3), 2.65 (2H, t, J 6.5, CH2CO2Et), 3.50 (2H, q,
J 6.5, CH2CH2CO2Et), 4.17 (2H, q, J 7.2, OCH2CH3), 4.70 (1H, br s, NH),
6.58 (1H, td, J 2.0, 7.1, ArH), 6.65 (1H, dd, J 2.0, 8.0, ArH), 7.18 (1H, t,
J 7.1, ArH), 7.41 (1H, dd, J 2.0, 8.0, ArH); dC (100.6 MHz, CDCl3) 14.3
(1C, OCH2CH3), 33.9 (1C, CH2CO2Et), 39.4 (1C, CH2CH2CO2Et), 60.8
(1C, OCH2CH3), 110.1 (1C, ArC), 111.2 (1C, ArC), 118.1 (1C, ArC), 128.5
(1C, ArC), 132.6 (1C, ArC), 144.5 (1C, ArC), 172.1 (1C, CO), m/z (CI)
274/272 (MHþ, 100%).
4.1.3.5. 1,5-Dibenzyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one
(7). This was obtained from 6 (150 mg, 0.35 mmol) by employing
the catalytic procedure described before (condition A), using P(t-
Bu)3 as ligand. The heterocycle was obtained as a viscous colourless
oil. Yield: 95 mg, 79%. Found: C, 80.65; H, 6.45; N, 8.15%. Calcd for
C23H22N2O: C, 80.67; H, 6.48; N, 8.18%. Rf¼0.34, cyclohexane/EtOAc
(4/1); nmax (KBr)/cmꢁ1 1665 (CO); dH (400 MHz, CDCl3, 298 K) 2.49
(2H, br s, NCH2CH2), 3.32 (2H, br s, NCH2), 4.14 (2H, br s, CH2Ph),
5.08 (2H, br s, CH2Ph), 7.02–7.33 (14H, m, ArH); dC (100.6 MHz,
CDCl3, 298 K) 34.2 (1C, NCH2CH2), 51.3 (1C, NCH2), 56.3 (1C, CH2Ph),
57.7 (1C, CH2Ph), 120.8 (1C, ArC), 123.1 (1C, ArC), 123.3 (1C, ArC),
126.9 (1C, ArC), 127.2 (1C, ArC), 127.9 (1C, ArC), 128.3 (1C, ArC),
128.4 (1C, ArC), 137.7 (2C, ArC), 143.8 (1C, ArC), 172.4 (1C, CO); m/z
(CI) 343 (MHþ, 100%).
4.1.3.3. Ethyl 3-(N-benzyl-N-(2-bromophenyl)amino)propionate
(5b). A mixture of 5a (1.0 g, 3.67 mmol, 1 equiv), benzyl bromide
(5 equiv) and K2CO3 (1.5 g, 11.0 mmol, 3 equiv) was refluxed in
CH3CN (10 mL) for 48 h. The solvent was evaporated, and the res-
idue extracted with ether. The organic layer was washed with H2O,
dried (MgSO4), concentrated, and purified by column chromatog-
raphy to give 5b as a colourless oil. Yield: 960 mg, 72%. Found: C,
59.65; H, 5.54; N, 3.89%. Calcd for C18H20BrNO2: C, 59.68; H, 5.56; N,
3.87%. Rf¼0.48, cyclohexane/EtOAc (4/1); dH (400 MHz, CDCl3) 1.20
(3H, t, J 7.4, OCH2CH3), 2.45 (2H, t, J 6.2, CH2CO2Et), 3.38 (2H, t, J 6.2,
CH2CH2CO2Et), 4.06 (2H, q, J 7.4, OCH2CH3), 4.22 (2H, s, CH2Ph), 6.96
(1H, td, J 2.4, 6.3, ArH), 7.09 (1H, dd, J 2.0, 8.0, ArH), 7.22–7.38 (6H,
m, ArH), 7.61 (1H, dd, J 1.5, 8.0, ArH); dC (100.6 MHz, CDCl3) 14.1 (1C,
OCH2CH3), 32.4 (1C, CH2CO2Et), 47.4 (1C, CH2CH2CO2Et), 58.4 (1C,
CH2Ph), 60.4 (1C, OCH2CH3), 122.3 (1C, ArC), 124.6 (1C, ArC), 125.3
(1C, ArC), 127.2 (2C, ArC), 127.8 (2C, ArC), 128.2 (1C, ArC), 128.6 (1C,
ArC), 133.9 (1C, ArC), 137.9 (1C, ArC), 148.4 (1C, ArC), 172.3 (1C, CO);
m/z (CI) 364/362 (MHþ, 100%).
4.1.3.6. 5-(2-Bromophenyl)-4-oxo-pentanoic acid (9). A three-necked
round-bottomed flask equipped with a reflux condenser and drop-
ping funnel was charged with dried Mg turnings (1.0 g, 41.1 mmol,
1.5 equiv), which were activated by stirring overnight under a dry N2
atmosphere. 2-Bromobenzyl bromide (10.3 g, 41.1 mmol, 1.5 equiv)
was added dropwise as a solution in anhydrous Et2O (90 mL) over 1 h,
during which a gentle reflux was established and maintained. Fol-
lowing the addition, the reaction mixture was heated at reflux for 3 h
then allowed to cool to ambient temperature. In a separate flask,
a solution of succinic anhydride (2.74 g, 27 mmol, 1.0 equiv) was dis-
solved in anhydrous THF (160 mL) and cooled to ꢁ78 ꢀC, before the
addition of the Grignard reagent slowly via cannula. The reaction
mixture was stirred at ꢁ78 ꢀC for 3.5 h, then quenched by the addition
of H2O (30 mL) and 2 M aq HCl (70 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc. Finally, the com-
bined organic layers were dried (MgSO4) and concentrated in vacuo to
give a yellow solid, which was then subjected to column chroma-
tography to give 9 as a white solid. Yield: 4.9 g, 66%. Found: C, 48.66;
H, 4.06%. Calcd for C11H11BrO3: C, 48.74; H, 4.09%. Rf¼0.23, CH2Cl2/
EtOAc (4/1); mp 88–89 ꢀC; nmax (KBr)/cmꢁ1 2854 (OH),1713 (CO),1693
(CO2H); dH (270 MHz, CDCl3) 2.68 (2H, t, J 6.0, CH2CO2H), 2.83 (2H, t,
J 6.0, CH2CH2CO2H), 3.93 (2H, s, ArCH2), 7.17 (1H, t, J 8.0, ArH), 7.24–
7.33 (2H, m, ArH), 7.59 (1H, dd, J 1.0, 8.0, ArH); dC (100.6 MHz, CDCl3)
27.7 (1C, CH2CO2H), 36.7 (1C, CH2CH2CO2H), 49.9 (1C, ArCH2), 125.0
(1C, ArC), 127.7 (1C, ArC), 129.0 (1C, ArC), 131.8 (1C, ArC), 132.9 (1C,
ArC),134.4 (1C, ArC),177.9 (1C, CO2H), 205.0 (1C, CO); m/z (CI) 290/288
([MþNH4]þ, 97/100).
4.1.3.4. 3-(N-Benzyl-N-(2-bromophenyl)amino)-N-benzyl-propan-
amide (6). The ester 5b was hydrolysed by refluxing in methanol
(20 mL) with NaOH (5 equiv) for 12 h. After cooling to ambient
temperature, methanol was evaporated and the residue was acid-
ified by the addition of 1 M aq HCl, before it was extracted with
Et2O, washed (H2O), dried (MgSO4) and evaporated to yield the
carboxylic acid as a colourless oil (76%). It was used directly in the
next step without further purification. Rf¼0.45, EtOAc/petroleum
ether (1/1); dH (400 MHz, CDCl3) 2.49 (2H, t, J 6.4, CH2CO2H), 3.35
(2H, t, J 6.5, CH2CH2CO2H), 4.22 (2H, s, CH2Ph), 7.00–7.08 (2H, m,
ArH), 7.25–7.34 (6H, m, ArH), 7.65 (1H, dd, J 1.5, 8.0, ArH); dC
(100.6 MHz, CDCl3) 31.8 (1C, CH2CO2H), 46.8 (1C, CH2CH2CO2H),
59.0 (1C, CH2Ph), 122.2 (1C, ArC), 124.5 (1C, ArC), 126.1 (1C, ArC),
127.6 (1C, ArC), 128.0 (2C, ArC), 128.3 (2C, ArC), 129.0 (1C, ArC),
134.2 (1C, ArC), 136.8 (1C, ArC), 147.2 (1C, ArC), 176.8 (1C, CO); m/z
(CI) 336/334 (MHþ, 100%).
4.1.3.7. 5-(2-Bromophenyl)-4-oxo-pentanoic acid benzylamide (10). A
solution of 9 (2.0 g, 6.92 mmol, 1.0 equiv) and 1-hydroxybenzo-
triazole monohydrate (1.14 g, 6.92 mmol, 1.0 equiv) in dry CH2Cl2
(35 mL) was cooled to 0 ꢀC. Benzylamine (7.61 mmol, 1.1 equiv) and
DCC (1.43 g, 6.92 mmol, 1.0 equiv) were added sequentially as so-
lutions in CH2Cl2 (10 mL). The reaction mixture was stirred at 0 ꢀC
for 2 h, then warmed to room temperature and stirred for a further
The carboxylic acid (2.05 g, 6.12 mmol, 1 equiv) was dissolved in
dry CH2Cl2 (30 mL) and cooled to 0 ꢀC, whereupon benzylamine
(0.67 mL, 6.12 mmol, 1 equiv), 1-hydroxybenzotriazole mono-
hydrate (0.83 g, 6.12 mmol, 1 equiv), and DCC (1.26 g, 6.12 mmol,
1 equiv) were added sequentially. After 1 h, the reaction mixture

530
E.L. Cropper et al. / Tetrahedron 65 (2009) 525–530
23 h. The white precipitate was removed by filtration and the fil-
trate washed with 2 M aq HCl (20 mL), brine (20 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography, furnishing 10 as a white solid. Yield: 2.0 g,
81%. Found: C, 59.96; H, 4.95; N, 3.90%. Calcd for C18H18NO2Br: C,
60.01; H, 5.04; N, 3.89%. Rf¼0.39, CH2Cl2/EtOAc (4/1); mp 126–
127 ꢀC; nmax (KBr)/cmꢁ1 3301 (NH), 1714 (CO), 1640 (NCO); dH
(270 MHz, CDCl3) 2.47 (2H, t, J 6.4, CH2CONH), 2.90 (2H, t, J 6.4,
CH2CH2CONH), 3.90 (2H, s, ArCH2), 4.41 (2H, close AB, PhCH2), 5.96
(1H, br s, NH), 7.11–7.35 (8H, m, ArH), 7.56 (1H, dd, J 1.0, 8.0, ArH); dC
(100.6 MHz, CDCl3) 29.9 (1C, CH2CONH), 37.7 (1C, CH2CH2CONH),
43.6 (1C, PhCH2), 50.0 (1C, ArCH2), 124.9 (1C, ArC), 127.4 (1C, ArC),
127.6 (1C, ArC), 127.7 (2C, ArC), 128.6 (2C, ArC), 128.9 (1C, ArC), 131.8
(1C, ArC), 132.8 (1C, ArC), 134.5 (1C, ArC), 138.2 (1C, ArC), 171.6 (1C,
NCO), 206.2 (1C, CO); m/z (EI) 359/361 (Mþ, 50/47%), 252/254
(29/30), 190 (50), 91 (100).
td, J 2.0, 7.8, CH2), 4.87 (2H, s, PhCH2), 5.97 (1H, s, CH]C), 7.03 (1H,
td, J 2.0, 7.2, ArH), 7.23–7.37 (7H, m, ArH), 7.56 (1H, d, J 7.2, ArH); dC
(100.6 MHz, CDCl3) 23.3 (1C, CH2), 29.0 (1C, CH2), 44.2 (1C, PhCH2),
103.6 (1C, CH]C), 124.5 (1C, C2), 127.1 (1C, ArC), 127.3 (1C, ArC),
127.6 (3C, ArC), 128.6 (1C, ArC), 128.7 (2C, ArC), 132.9 (1C, ArC),
135.8 (1C, ArC), 136.2 (1C, ArC), 142.8 (1C, Cipso), 175.6 (1C, CO); m/z
(EI) 343/341 (24/25%), 91 (100).
Acknowledgements
We thank AstraZeneca and EPSRC for the award of a doctoral
training grant (GR/P01816/01) and Johnson Matthey plc for the loan
of Pd salts. K.K.H. acknowledges the support of the National
University of Singapore (NUS) during her appointment there as
a Visiting Associate Professor, which enabled her to prepare this
manuscript.
4.1.3.8. Spiro[benzofuran-2,50-(1-benzylpyrrolidin-2-one)]
(12). A
Young’s tube was charged with 10 (200 mg, 0.56 mmol, 1.0 equiv),
Cs2CO3 (253 mg, 0.78 mmol, 1.4 equiv) and Pd(OAc)2 (6 mg,
0.026 mmol, 5 mol %). To this was added P(t-Bu)3 (10 wt % in hex-
ane, 0.11 mL, 10 mol %) and anhydrous toluene (9.25 mL, 0.06 M wrt
substrate). The tube was sealed with a PTFE tap and stirred at room
temperature for 10 min, followed by heating at 100 ꢀC for 16 h.
After this time, the reaction mixture was cooled, filtered through
a short plug of Celite and concentrated in vacuo. The crude mixture
was purified by column chromatography, to give 12 as a colourless
oil, which solidified on standing to give a white solid. Yield: 76 mg,
49%. Rf¼0.31, CH2Cl2/EtOAc (7/1, visualised using a vanillin dip); mp
110–110 ꢀC; nmax (KBr)/cmꢁ1 1709 (CO); dH (400 MHz, CDCl3) 2.21–
2.35 (1H, m, CH2), 2.50–2.63 (2H, m, CH2), 2.70–2.83 (1H, m, CH2),
3.18 (2H, close AB, ArCH2), 4.01 (1H, d, J 15.6, PhCH2), 4.69 (1H, d,
J 15.6, PhCH2), 6.66 (1H, d, J 8.2, ArH), 6.88 (1H, t, J 7.7, ArH), 7.05–
7.31 (7H, m, ArH); dC (100.6 MHz, CDCl3) 28.9 (1C, CH2), 33.9 (1C,
CH2), 38.7 (1C, CH2), 43.1 (1C, PhCH2), 104.1 (1C, OCN), 109.0 (1C,
ArC), 120.9 (1C, ArC), 124.5 (1C, ArC), 127.2 (1C, C1), 127.4 (2C, ArC),
127.8 (1C, ArC),128.3 (2C, ArC),128.5 (1C, ArC), 137.8 (1C, ArC), 158.1
(1C, ArC), 175.5 (1C, CO); m/z (EI) 279 (Mþ, 91%), 188 (87), 91 (100),
55 (67); HRMS (EI) 279.1262, C18H17NO2 requires 279.1259.
References and notes
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Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348,
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1735; (b) Qadir, M.; Cobb, J.; White, A. J. P.; Sheldrake, P. W.; Whittall, N.; Hii,
K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70, 1545–1551; (c)
Qadir, M.; Cobb, J.; White, A. J. P.; Sheldrake, P. W.; Whittall, N.; Hii, K. K.;
Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70, 1552–1557; (d) Qadir, M.;
Priestley, R. E.; Rising, T. D. W. F.; Gelbrich, T.; Coles, S. J.; Hursthouse, M. B.;
Sheldrake, P. W.; Whittall, N.; Hii, K. K. Tetrahedron Lett. 2003, 44, 3675–3678.
5. Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 447–455.
6. Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155–2162.
7. Kitamura, Y.; Hashimoto, A.; Yoshikawa, S.; Odaira, J.; Furuta, T.; Kan, T.; Tanaka,
K. Synlett 2006, 115–117.
8. Optically pure MOP costs £58.80/50 mg (Sigma–Aldrich Catalogue 2008). rac-
MOP is not commercially available.
9. For example, see: (a) Messaoudi, S.; Audisio, D.; Brion, J. D.; Alami, M. Tetra-
hedron 2007, 63, 10202–10210; (b) Lebedev, A. Y.; Khartulyari, A. S.; Vosko-
boynikov, A. Z. J. Org. Chem. 2005, 70, 596–602; (c) Yin, J. J.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 6043–6048.
10. Microwave irradiation was employed for the synthesis of oxindoles by Pd-
catalysed amidation reactions: Poondra, R. R.; Turner, N. J. Org. Lett. 2005, 87,
863–866.
4.1.3.9. 1-Benzyl-5-(2-bromo-benzyl)-5-hydroxy-pyrrolidin-2-one (13). A
clean sample could not be isolated, but its presence in the reaction
mixture can be detected by 1H NMR and by LC–MS: dH (400 MHz,
CDCl3) 1.73–1.80 (1H, m, CH2), 2.28–2.61 (3H, m, CH2), 3.01 (1H, d,
J 14.0, ArCH2), 3.36 (1H, d, J 14.0, ArCH2), 4.53 (1H, d, J 15.2, PhCH2),
4.73 (1H, d, J 15.2, PhCH2); m/z (ESI) 362/360 ([MþH]þ, 96/100%).
11. Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 925–928.
12. For example, see: (a) Chimirri, A.; Gitto, R.; Grasso, S.; Monforte, A. M.; Romeo,
G.; Zappala, M. Heterocycles 1993, 36, 601–637.
13. Yang, T.; Lin, C. X.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett. 2005, 7, 4781–4784.
14. Tapia, R. A.; Centella, C. Synth. Commun. 2004, 34, 2757–2765.
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1225–1227.
16. One example of an intramolecular aryl amination can be found, where a highly
substituted 8-membered heterocycle was prepared by Pd catalysis: Neogi, A.;
Majhi, T. P.; Mukhopadhyay, R.; Chattopadhyay, P. J. Org. Chem. 2006, 71, 3291–
3294.
17. (a) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477–2495; (b) Uchida,
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4.1.3.10. 1-Benzyl-5-[1-(2-bromo-phenyl)-methylidene]-pyrrolidin-2-
one (14). Isolated as a white solid. Found: C, 63.32; H, 4.59; N,
4.01%. Calcd for C20H22INO: C, 63.17; H, 4.71; N, 4.09%. Rf¼0.52,
hexane/EtOAc (1/2); mp 105–106 ꢀC; nmax (KBr)/cmꢁ1 1702 (CO),
1638 (C]C); dH (400 MHz, CDCl3) 2.68 (2H, t, J 7.8, CH2), 2.95 (2H,
18. Woolford, R. G.; Lin, W. S. Can. J. Chem. 1966, 44, 2783–2791.