Diastereoselective protonation of extended pyrrol-3-en-2-one enolates: An attempted 'de-epimerisation'

Article abstract of DOI:10.1016/j.tetasy.2005.05.042

The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolactam) was deuterated at the 5-position with very high diastereoselectivity if the nitrogen atom carries an α-methyl-p- methoxybenzyl group. A similar diastereoselective protonation was observed in a pyrrol-3-en-2-one formed by dearomatising cyclisation of a pyrrole. Protonation of an N-α-methyl-p-methoxybenzyl dihydroisoindolone lacked stereoselectivity.

Full text of DOI:10.1016/j.tetasy.2005.05.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2235–2241
Diastereoselective protonation of extended pyrrol-3-en-2-one
enolates: an attempted ‘de-epimerisation’
Jonathan Clayden,a,* Rachel Turnbulla and Ivan Pintob
aDepartment of Chemistry, Manchester University, Oxford Road, Manchester M13 9PL, UK
bGlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK
Received 11 April 2005; accepted 25 May 2005
Abstract—The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolactam) was deuterated at the 5-position with
very high diastereoselectivity if the nitrogen atom carries an a-methyl-p-methoxybenzyl group. A similar diastereoselective proton-
ation was observed in a pyrrol-3-en-2-one formed by dearomatising cyclisation of a pyrrole. Protonation of an N-a-methyl-p-meth-
oxybenzyl dihydroisoindolone lacked stereoselectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
OLi
N
O
OMe
LDA
N
N-Benzyl-N-a-methylbenzyl amides and carbamates can
be deprotonated diastereoselectively: the stereochemis-
try of the resulting benzylic organolithium can be used
as a means of making, diastereoselectively, some meso
amines.1 Recent work in connection with a dearomatis-
ing cyclisation reaction2,3 suggests that an a-methyl-p-
methoxybenzyl substituent4 is able to govern the facial
selectivity of reprotonation. Pyrrol-3-en-2-one 5 is
formed from 1 as a single diastereoisomer5 on treatment
with base, a result which can be explained only if ex-
tended butenolactam enolate 4, formed by fragmenta-
tion of the dearomatising anionic cyclisation product
2, is reprotonated diastereoselectively (Scheme 1).2
Recent developments in enantioselective protonation6
have demonstrated its potential in asymmetric synthesis
by Ôde-racemisingÕ a chiral starting material: we hoped
that this comparable diastereoselective protonation
could be developed into means of Ôde-epimerisingÕ a mix-
ture of diastereoisomers, imposing uniform stereochem-
istry at the site of protonation and hence, after
deprotection of the nitrogen atom, allowing an enantio-
selective synthesis of pyrrol-3-en-2-ones.7 Many com-
pounds in this class are biologically active.8
Ph
N
DEB
THF
0 oC
H
Ph
N
1
2
DEB
OMe
O
N
LiN
DEB
Ph
3
OMe
O
OLi
NH4Cl
N
N
HN
DEB
HN
DEB
Ph
Ph
4
5
OMe
OMe
DEB = COCEt3
Scheme 1. Cyclisation, ring opening and reprotonation of pyrrole.
2. Results and discussion
We started by stripping away the complexities of bute-
nolactam 3 to reveal the simple parent structure 8. But-
enolactam 8 was made by allylation of acrylamide 6
followed by ring closing metathesis9 with the Ôfirst-gener-
ationÕ ruthenium based catalyst of Grubbs. Formation
of the extended enolate and alkylation with methyl
iodide led to a-methylated lactam 9 (Scheme 2). With
*
Corresponding author. Tel.: +44 161 275 4614; fax: +44 161 275
4939; e-mail: j.p.clayden@man.ac.uk
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.042

2236
J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
O
O
O
O
NaH,
DMF
Xylene, 48h
reflux
N
N
H
N
N
Br
OMe
OMe
OMe
6
7 48%
13b
2.5:1
OMe
OMe
15
60%, 2:1
O
O
Grubbs'
catalyst
1. LDA
2. MeI
O
1. NaH,
N
N
THF, 0 ˚C
CH2Cl2
D
N
8 85%
9 60%
OMe
2. CD3OD
OMe
16
99%, 2.5:1
O
N
Scheme 4. A 5-substituted pyrrol-3-en-2-one by [3,3]-sigmatropic
rearrangement, and its deuteration.
10
OMe
15 (Scheme 4). 5-Allylbutenolactam 15 was successfully
formed from 13b on heating to refluxin xylene for 48 h,
but with poor diastereoselectivity, presumably due to
stereospecific transformation of the 2.5:1 mixture of
a-allylated diastereoisomers. Deprotonation with sodium
hydride (deprotonation with LDA failed) gave an
enolate, which was however unfortunately deuterated
a-, rather than c-, to the carbonyl group, and with
modest diastereoselectivity, to yield 16. Steric hindrance
from the allyl group presumably diverts deuteration to
the a-position, in contrast with protonation of 4, while
the increased distance from the stereocontrolling influ-
ence of the a-methyl-p-methoxybenzyl group results in
modest diastereoselectivity.
Scheme 2. Synthesis and alkylation of a simple chiral butenolactam.
excess LDA, however, 10 was formed as a by-product.
With 3 equiv LDA, 10 was formed in 66% yield.
Lactam 9 was converted to the extended lithium enolate
(lithioxypyrrole) 11 by thorough degassing and treat-
ment with LDA in THF. Deuteration of the enolate
gave, as hoped, a single diastereoisomer (by NMR) of
the deuterated lactam 12,10 suggesting that diastereo-
selective protonation may be a general feature of these
chiral enolates (Scheme 3). Unless the reaction was
degassed, the major product was a mixture of hydroxyl-
ated lactams 14.11
A further structural modification was therefore made.
Chiral 3-substituted dihydroisoindolones are important
building blocks for several classes of alkaloid natural
products,13 and can be seen simply as benzo-fused ana-
logues of 8. Chiral dihydroisoindolones 17 have been
made enantioselectively,14 but we attempted the applica-
tion of the diastereoselective deuteration reaction to
their synthesis by Ôde-epimerisationÕ of an initial mixture
of diastereoisomers formed without selectivity, by
deprotonation and reprotonation (Scheme 5).
O
OLi
LDA,
THF,
0 °C
D2O
N
N
9
11
E+
D
12
OMe
OMe
OMe
O2
85%, >99:1 but
stereochemistry
unknown
O
O
E
N
N
OH
13a (E = Et; 58 %, 2:1)
OMe
13b (E = Allyl; 58 %, 2.5:1)
13c (E = Bn; 71 %, 3:1)
14
O
O
1. base
2. H+
76%, 1:1
N
X*
N X*
Scheme 3. Diastereoselectivity in deuteration, alkylation and oxida-
tion of the chiral lactam 9.
?
R
R
17
Scheme 5. Proposed Ôde-epimerisationÕ of a dihydroisoindolinone.
The diastereoselectivity of this protonation is in accor-
dance with the diastereoselective protonation of enolate
4, and gave us confidence that it may be possible
similarly to reprotonate a range of pyrrol-3-en-2-ones
diastereoselectively. However, the synthesis of pyrrol-
3-en-2-ones bearing a substituent at the 5-position,
required for the diastereoselective formation of a stereo-
genic centre, turns out to be complicated by the fact that
alkylation, unlike deuteration, takes place invariably at
the a-position of enolate 11 and its congeners, leading
to mixtures of diastereoisomers of lactams 13 (Scheme
3).12
Condensation of chiral amine 19 with N,N-diethyl-
2-formylbenzamide 1815 gave imine 20, which on
treatment with phenyllithium, afforded the dihydroiso-
indolones16 anti-21 and syn-21 in a ratio of 1:1.5
(Scheme 6). The stereochemistry of syn-21 was con-
firmed by an X-ray crystal structure determination
(Fig. 1). However, treatment of either syn-21 or a mix-
ture of anti- and syn-21 with NaH followed by aqueous
quench returned only the same 1:1.5 mixture of diastereo-
isomers formed by the addition of PhLi to the imine.
Presumably, this ratio represents the diastereoselectivity
of reprotonation in this system: further reactions with
dihydroisoindolinones were not pursued.
We therefore turned to a [3,3]-sigmatropic rearrange-
ment of 13b as a means to make 5-substituted lactam

J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
2237
chloride disks. Absorption maxima (mmax) are quoted in
wavenumbers (cmꢀ1).
O
N
CHO
1H and 13C NMR spectra were recorded on a Varian
Inova 300 Spectrometer operating at ambient probe
temperature using an internal deuterium lock
Et2N
O
18
N
MeOH
OH
+
OMe
1
(300 MHz for H NMR and 75 MHz for 13C NMR).
20 100%
Chemical shifts are reported in parts per million (d) at
lower frequencies relative to tetramethylsilane (TMS).
They are reported as; position, multiplicity, coupling
constant (Hz) and assignment. Standard abbreviations
are used throughout (s–singlet, d–doublet, dd–doublet
of doublets, t–triplet, q–quartet, m–multiplet and
br–broad).
H2N
PhLI, THF, -78 oC
O
19
O
+
N
N
Ph
anti-21 20%
Ph
syn-21 30%
OMe
OMe
Mass spectra, including chemical ionisation (CI) and
electron impact (EI), were recorded on a Micromass
VG Trio 2000 quadrupole mass spectrometer. Accurate
mass measurements were recorded on a Kratos Con-
cept-1S mass spectrometer and are correct to 0.001.
Scheme 6. Formation of a chiral dihydroisoindolinone.
The solvents used were either distilled over appropriate
drying agents, or of analytical grade. Petrol refers to
the fraction of light petroleum ether boiling between 40
and 60 ꢁC. All other commercially available reagents
were purified as necessary following standard proce-
dures.
Flash chromatography17 was performed using Apollo
silica gel (40–63 lm). Analytical thin layer chromatogra-
phy (TLC) was carried out using ALUGRAMꢂ SIL G/
UV254 plates with visualisation using either UV light or
alkaline potassium permanganate.
4.1. Method A: Amide formation
Figure 1. X-ray crystal structure of syn-21.
Triethylamine (6.0 mmol, 2.0 equiv), amine (6.1 mmol,
2.2 equiv) and DMAP (0.3 mmol, 0.1 equiv) in CH2Cl2
(10 mL) were stirred at 0 ꢁC under a nitrogen atmo-
sphere for 15 min. A solution of the acryloyl chloride
(3.0 mmol, 1.0 equiv) in CH2Cl2 (2 mL) was added
dropwise at 0 ꢁC over 10 min and the solution stirred
at room temperature for 14 h. HCl (2 M) was added
and the layers separated. The organic layer was washed
with 2 M HCl and water, dried over MgSO4 and concen-
trated under reduced pressure to yield the crude
product.
3. Conclusion
In conclusion, it is possible to protonate or deuterate
pyrrol-3-en-2-ones, such as 3 and 9, with remarkably
high diastereoselectivity. However changing the struc-
ture of the pyrrol-3-en-2-ones by the introduction of a
5-substituent or by ring fusion leads to a change in the
regioselectivity of protonation and/or loss of diastereo-
selectivity, preventing the development of a synthetically
useful Ôde-epimerisationÕ procedure for such 5-substi-
tuted pyrrol-3-en-2-ones.
4.2. Method B: Allylation
The amide (1.9 mmol, 1.0 equiv) in DMF (2 mL) was
added dropwise to a suspension of sodium hydride
(2.9 mmol, 1.5 equiv of a 60% suspension in oil) in
DMF (2 mL) at 0 ꢁC under a nitrogen atmosphere.
The solution was stirred at room temperature for
30 min and a solution of the appropriate allyl bromide
(2.4 mmol, 1.2 equiv) in DMF (2 mL) added dropwise
at 0 ꢁC. The solution was stirred at room temperature
for 1 h and quenched by the addition of water. The mix-
ture was extracted with EtOAc and the combined
organic fractions washed with water, dried over MgSO4
and concentrated under reduced pressure to yield the
crude product.
4. Experimental
Melting points (mp) were measured using a Gallenkamp
melting point apparatus and are uncorrected. Optical
rotations were measured with a Perkin–Elmer 241 polar-
imeter using a cell with a path length of 0.25 dm. Con-
centrations (c) are given in grams per 100 mL.
Infra-red spectra were recorded on a Perkin–Elmer 1710
Fourier transform spectrometer (225–4400 cmꢀ1). The
samples were prepared as evaporated films on sodium

2238
J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
4.3. Method C: Deprotonation and enolate quench
pressure. Purification by flash column chromatography
(SiO2; 1:1 petrol–EtOAc) afforded the title compound
22
D
n-Butyllithium (0.69 mmol, 1.0 equiv of a 2.4 M solution
in hexane) was added dropwise to a solution of diiso-
propylamine (0.69 mmol, 1.0 equiv) in THF (2.5 mL)
at 0 ꢁC under a nitrogen atmosphere. The LDA solution
was stirred at 0 ꢁC for 20 min and a solution of the 1,5-
dihydropyrrol-2-one (0.69 mmol, 1.0 equiv) in THF
(2.5 mL) added dropwise. The solution was degassed
and stirred at 0 ꢁC for 3 h and then quenched by the
addition of the electrophile (1.4 mmol, 2.0 equiv). The
mixture was allowed to warm to room temperature for
30 min and water added. The mixture was extracted
with EtOAc and the combined organic layers washed
with water, dried over MgSO4 and concentrated under
reduced pressure to yield the crude product.
(0.11 g, 85%) as a yellow oil: ½aŠ ¼ ꢀ122.0 (c 0.15,
CHCl3); Rf (5:1 petrol–EtOAc) 0.20; mmax (CHCl3)/
cmꢀ1 2934 (CH), 1687 (C@O); dH (300 MHz, CDCl3)
7.25 (2H, d, J 8.5, ArH), 7.02 (1H, dd, J 6.0 and 1.5,
CH2CHCH), 6.85 (2H, d, J 8.5, ArH), 6.18 (1H, dd, J
6.0 and 1.5, CH2CHCH), 5.55 (1H, q, J 7.0, CHCH3),
3.80 (3H, s, OCH3), 3.58–4.0 (2H, dd, J 18.5 and 1.5,
NCH2), 1.60 (3H, d, J 7.5, CHCH3); dC (75 MHz,
CDCl3) 171.2, 159.1, 143.0, 133.3, 128.4, 128.2, 114.2,
55.5, 48.8, 48.6, 18.4; m/z (CI) 218 (100%, M+H+). Found:
M+, 217.1102. C13H15NO2 requires 217.1103.
4.7. 1-[1-(4-Methoxyphenyl)ethyl]-3-methyl-1,5-dihydro-
pyrrol-2-one 9
4.4. N-[1-(4-Methoxyphenyl)ethyl]acrylamide 6
1-[1-(4-Methoxyphenyl)ethyl]-1,5-dihydropyrrol-2-one 8
(0.15 g, 0.7 mmol, 1.0 equiv) and iodomethane (0.10
mL, 1.4 mmol, 2.0 equiv) were treated according to
Method C. Purification by flash column chromatogra-
(S)-(ꢀ)-1-(4-Methoxyphenyl)ethylamine (10.0 g, 66.2
mmol, 2.2 equiv) was treated according to Method A
to afford the title compound (6.06 g, 98%) as needles:
phy (SiO2; 15:1 petrol–EtOAc) afforded the title com-
22
22
D
mp 107.5 ꢁC; ½aŠ ¼ ꢀ159.7 (c 0.12, CHCl3); Rf (5:1 pet-
pound (0.09 g, 60%) as a yellow oil: ½aŠ ¼ ꢀ124.2
D
rol–EtOAc) 0.35; mmax (CHCl3)/cmꢀ1 3270 (NH), 2971
(CH), 1657 (C@O); dH (300 MHz, CDCl3) 7.23 (2H, d,
J 8.5, ArH), 6.83 (2H, d, J 8.5, ArH), 6.24 (1H, dd, J
17.5 and 1.5, CHAHBCH), 6.10 (2H, m, J 10.0, NH
and CH2CH), 5.60 (1H, dd, J 10.0 and 1.5, CHAHBCH),
5.15 (1H, q, J 7.0, CHCH3), 3.78 (3H, s, OCH3), 1.50
(3H, d, J 7.0, CHCH3); dC (75 MHz, CDCl3) 164.5,
158.7, 135.2, 130.9, 127.4, 126.4, 113.9, 109.9, 55.3,
48.2, 21.5; m/z (CI) 206 (100%, M+H+). Found: M+,
205.1104. C12H15NO2 requires 205.1103.
(c 0.15, CHCl3); Rf (1:1 petrol–EtOAc) 0.60; mmax
(CHCl3)/cmꢀ1 2972 (CH), 1658 (C@O); dH (300 MHz,
CDCl3) 7.25 (2H, d, J 8.5, ArH), 6.90 (2H, d, J 8.5,
ArH), 6.62 (1H, d, J 1.0, NCH2CH), 5.55 (1H, q, J
7.0, CHCH3), 3.82 (3H, s, OCH3), 3.75 (1H, dd, 18.5
and 1.5, NCHAHBCH), 3.45 (1H, dd, J 18.5 and 1.5,
NCHAHBCH), 1.95 (3H, s, CH3), 1.60 (3H, d, J 7.0,
CHCH3); dC (75 MHz, CDCl3) 171.8, 159.1, 135.8,
135.4, 133.6, 129.2, 128.4, 114.1, 55.5, 49.1, 46.6, 18.1,
11.6; m/z (CI) 232 (100%, M+H+). Found: M+,
231.1266. C14H17NO2 requires 231.1259.
4.5. N-Allyl-N-[1-(4-methoxyphenyl)ethyl]acrylamide 7
4.8. 1-[1-(4-Methoxyphenyl)ethyl]-3,3-dimethyl-1,3-di-
hydropyrrol-2-one 10
N-[1-(4-Methoxyphenyl)ethyl]acrylamide
6
(0.25 g,
1.22 mmol, 1.0 equiv) was treated according to Method
B. Purification by flash column chromatography (SiO2;
15:1 petrol–EtOAc) afforded the title compound
n-Butyllithium (1.04 mL of a 2.0 M solution in hexane,
2.1 mmol, 3.0 equiv) was added dropwise to a solution
of diisopropylamine (0.29 mL, 2.1 mmol, 3.0 equiv) in
THF (2.5 mL) at 0 ꢁC, under a nitrogen atmosphere.
The LDA solution was stirred at 0 ꢁC for 20 min and
a solution of 1-[1-(4-methoxyphenyl)ethyl]-1,5-dihydro-
pyrrol-2-one 9 (0.15 g, 0.69 mmol, 1.0 equiv) in THF
(2.5 mL) added dropwise. The solution was stirred at
0 ꢁC for 3 h and quenched by the addition of iodome-
thane (0.26 mL, 4.14 mmol, 6.0 equiv). The mixture
was warmed to room temperature for 30 min and water
(5 mL) added. The mixture was extracted with EtOAc
(4 · 5 mL) and the combined organic layers washed with
water (10 mL), dried over MgSO4 and concentrated un-
der reduced pressure. Purification by flash column chro-
22
(0.142 g, 48%) as a clear oil: ½aŠ ¼ ꢀ86.0 (c 0.02,
D
CHCl3); Rf (5:1 petrol–EtOAc) 0.35; mmax (CHCl3)/
cmꢀ1 2971 (CH), 1676 (C@O); dH (300 MHz, DMSO,
100 ꢁC) 7.22 (2H, d, J 8.5, ArH), 6.90 (2H, d, J 8.5,
ArH), 6.65 (1H, dd, J 16.5 and 10.5, CHCH2), 6.18
(1H, dd, J 16.5 and 2.5, CHCHAHB), 5.60–5.70 (3H,
m, CHCH3 and CH2CHCH2), 5.0 (2H, m, CHCHAHB
and CH2CHCH2), 3.75 (3H, s, OCH3), 3.60–4.0 (2H,
m, CH2CHCH2), 1.48 (3H, d, J 7.0, CHCH3); dC
(75 MHz, CDCl3) 158.5, 136.1, 133.0, 129.4, 128.6,
128.2, 115.9, 113.7, 55.1, 50.3, 44.8, 38.7, 16.9; m/z
(CI) 246 (100%, M+H+). Found: M+, 245.1420.
C15H19NO2 requires 245.1416.
matography (SiO2; 5:1 petrol–EtOAc) afforded the title
22
D
4.6. 1-[1-(4-Methoxyphenyl)ethyl]-1,5-dihydropyrrol-2-
one 8
compound (0.11 g, 66%) as a yellow oil: ½aŠ ¼ ꢀ126.4
(c 0.15, CHCl3); Rf (5:1 petrol–EtOAc) 0.25; mmax
(CHCl3)/cmꢀ1 2967 (CH), 1695 (C@O); dH (300 MHz,
CDCl3) 7.18 (2H, d, J 8.5, ArH), 6.85 (2H, d, J 8.5,
ArH), 6.26 (1H, d, J 5.5, NCHCH), 5.35 (1H, q, J 7.0,
CHCH3), 5.30 (1H, d, J 5.5, NCHCH), 3.80 (3H, s,
OCH3), 1.55 (3H, d, J 7.0, CHCH3), 1.20 (3H, s,
CH3), 1.17 (3H, s, CH3); dC (75 MHz, CDCl3) 182.3,
159.1, 133.3, 129.0, 128.7, 127.9, 126.8, 117.9, 114.2,
GrubbsÕ catalyst9 (0.05 g, 0.061 mmol, 0.1 equiv) was
added portion wise to a solution of N-allyl-N-[1-(4-
methoxyphenyl)ethyl]acrylamide 7 (0.15 g, 0.61 mmol,
1.0 equiv) in CH2Cl2 (20 mL) at room temperature
under a nitrogen atmosphere. The solution was heated
under refluxfor 12 h and concentrated under reduced

J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
2239
55.5, 48.7, 46.9, 26.1, 23.4, 18.9; m/z (CI) 246 (100%,
M+H+). Found: M+, 245.1412. C15H19NO2 requires
245.1416.
CH2CHCH2), 3.80 (3H, s, OCH3), 2.35–2.36 (2H,
m, CH2CHCH2), 1.58 (3H, d, J 7.0, CHCH3), 1.20
(3H, s, CH3); dC (75 MHz, CDCl3) 181.2, 159.2, 133.7,
133.1, 128.5, 128.4, 127.7, 121.7, 115.4, 55.5, 50.8,
48.7, 41.7, 21.8, 19.1, 18.9; m/z (CI) 272 (100%,
M+H+). Found: M+, 271.1560. C17H21NO2 requires
271.1572.
4.9. 1-[1-(4-Methoxyphenyl)ethyl]-3-methyl-5-deutero-
1,5-dihydropyrrol-2-one 12
1-[1-(4-Methoxyphenyl)ethyl]- 3-methyl-1,5-dihydropyr-
rol-2-one 11 (0.15 g, 0.65 mmol, 1.0 equiv) and deute-
rium oxide (0.5 mL) were treated according to Method
C. Purification by flash column chromatography (SiO2;
4.12. 3-Benzyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-
1,3-dihydropyrrol-2-one 13c
10:1 petrol–EtOAc) afforded the title compound (0.11 g,
1-[1-(4-Methoxyphenyl)-ethyl]-3-methyl-1,5-dihydropyr-
rol-2-one 11 (0.10 g, 0.43 mmol, 1.0 equiv) and benzyl
bromide (0.06 mL, 0.52 mmol, 1.2 equiv) were treated
according to Method C. Purification by flash column
chromatography (SiO2; 25:1 petrol–EtOAc) afforded
the title compound (0.098 g, 71%) as a yellow oil in a 3:1
ratio of diastereoisomers: Rf (1:1 petrol–EtOAc) 0.85;
mmax (CHCl3)/cmꢀ1 2968 (CH), 1688 (C@O); dH (300
MHz, CDCl3) 7.10–7.30 (7H, m, ArH), 6.82 (2H, d, J
8.5, ArH), 6.65 (1H, d, J 5.0, NCHCHmajor), 6.55 (1H,
22
85%) as a colourless oil: ½aŠ ¼ ꢀ95.1 (c 0.10, CHCl3);
D
Rf (3:1 petrol–EtOAc) 0.65; mmax (CHCl3)/cmꢀ1 2973
(CH), 1668 (C@O); dH (300 MHz, CDCl3) 7.25 (2H, d,
J 8.5, ArH), 6.90 (2H, d, J 8.5, ArH), 6.65 (1H, d, J
2.0, NCDCH), 5.55 (1H, q, J 7.0, CHCH3), 3.80 (3H,
s, OCH3), 3.65 (1H, d, J 8.5, NCDCH), 1.95 (3H, s,
CH3), 1.60 (3H, d, J 7.0, CHCH3); dC (75 MHz, CDCl3)
171.9, 159.2, 136.1, 135.5, 135.4, 133.7, 128.5, 114.2,
55.6, 49.2, 46.2 (t), 18.2, 11.7; m/z (CI) 233 (100%,
M+H+). Found: M+, 232.1314. C14H16NO2D requires
232.1317.
d, J 5.0, NCHCHminor), 6.05 (1H, d, J 5.0, NCHCHmajor
)
6.0 (1H, d, J 5.0, NCHCHminor), 5.25 (1H, q, J 7.0,
CHCH3), 3.80 (3H, s, OCH3), 3.02 (1H, dd, J 13.0 and
3.5, CHAHBPh), 2.78 (1H, d, J 13.0 and 4.0, CHAHBPh),
1.25 (3H, s, CH3), 1.15 (3H, d, J 7.0, CHCH3); dC
(75 MHz, CDCl3) 181.0, 159.2, 137.4, 133.2, 130.5,
130.4, 128.2, 128.1, 128.0, 127.8, 127.6, 126.8, 115.3,
114.3, 114.1, 55.6, 52.6, 52.5, 48.6, 48.5, 43.9, 43.6, 23.2,
22.3, 19.2, 18.5; m/z (CI) 322 (100%, M+H+). Found:
M+, 321.1722. C21H23NO2 requires 321.1723.
4.10. 3-Ethyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-1,3-
dihydropyrrol-2-one 13a
1-[1-(4-Methoxyphenyl)ethyl]- 3-methyl-1,5-dihydropyr-
rol-2-one 11 (0.10 g, 0.43 mmol, 1.0 equiv) and iodoe-
thane (0.05 mL, 0.52 mmol, 1.2 equiv) were treated
according to Method C. Purification by flash column
chromatography (SiO2; 50:1 petrol–EtOAc) afforded
the title compound (0.065 g, 58%) as a yellow oil in a
2:1 ratio of diastereoisomers: Rf (5:1 petrol–EtOAc)
0.35; mmax (CHCl3)/cmꢀ1 2935 (CH), 1660 (C@O); dH
(300 MHz, CDCl3) 7.25 (2H, d, J 8.5, ArH), 6.92 (2H,
d, J 8.5, ArH), 6.35 (1H, d, J 5.0, NCHCH), 5.45 (1H,
q, J 7.0, CHCH3), 5.28 (1H, d, J 5.0, NCHCH), 3.85
(3H, s, OCH3), 1.75 (2H, q, J 7.5, CH2CH3), 1.62 (3H,
d, J 7.0, CHCH3), 1.25 (3H, s, CH3), 0.82 (3H, t,
J 7.5, CH2CH3), 0.75 (3H, t, J 7.5, CH2CH3); dC
(75 MHz, CDCl3) 181.9, 159.3, 133.4, 129.2, 128.9,
128.3, 128.2, 127.8, 115.8, 114.6, 114.3, 114.2, 55.6,
51.7, 48.9, 48.8, 31.6, 30.4, 22.6, 22.4, 19.2, 19.1, 9.5,
9.3; m/z (CI) 260 (100%, M+H+). Found: M+,
259.1563. C16H21NO2 requires 259.1567.
4.13. 5-Hydroxy-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-
1,5-dihydropyrrol-2-one 14
1-[1-(4-Methoxyphenyl)- ethyl]-3-methyl-1,5-dihydro-
pyrrol-2-one 11 (0.10 g, 0.43 mmol, 1.0 equiv) was trea-
ted according to Method C with saturated aqueous
ammonium chloride quench. Purification by flash col-
umn chromatography (SiO2; 25:1 petrol–EtOAc) affor-
ded the title compound (0.08 g, 76%) as a yellow oil in
a 1:1 ratio of diastereoisomers: Rf (1:1 petrol–EtOAc)
0.65; mmax (CHCl3)/cmꢀ1 3376 (OH), 2935 (CH), 1678
(C@O); dH (300 MHz, CDCl3) 7.40 (2H, d, J 8.5,
ArHA), 7.32 (2H, d, J 8.5, ArHB), 6.90 (2H, d, J 8.5,
ArHA), 6.85 (2H, d, J 8.5, ArHB), 6.48 (1H, t, J 2.0,
CHC(H)OHA), 6.40 (1H, t, J 2.0, CHC(H)OHB), 5.48
(1H, d, J 9.0, CHC(H)OHA), 5.40 (1H, q, J 7.0,
CHCH3A), 5.22 (1H, q, J 7.0, CHCH3B), 5.04 (1H, d,
J 9.0, CHC(H)OHB), 3.78 (6H, s, 2 · OCH3A+B), 1.88
(6H, s, 2 · CH3A+B), 1.74 (3H, d, J 7.0, CHCH3A),
1.68 (3H, d, J 7.0, CHCH3B); dC (75 MHz, CDCl3)
170.6, 170.5, 159.3, 159.2, 138.5, 138.2, 137.7, 137.2,
134.7, 133.2, 129.2, 128.8, 114.5, 114.2, 81.6, 81.2,
55.7, 50.4, 50.3, 19.3, 18.4, 11.3, 11.2, 0.4; m/z (CI) 248
(100%, M+H+). Found: M+, 247.1201. C14H17NO3 re-
quires 247.1203.
4.11. 3-Allyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-1,3-
dihydropyrrol-2-one 13b
1-[1-(4-Methoxyphenyl)-ethyl]-3-methyl-1,5-dihydro-
pyrrol-2-one 11 (0.15 g, 0.65 mmol, 1.0 equiv) and allyl
bromide (0.08 mL, 0.97 mmol, 1.5 equiv) were treated
according to Method C. Purification by flash column
chromatography (SiO2; 30:1 petrol–EtOAc) afforded
the title compound (0.065 g, 58%) as a colourless oil in
a
2.5:1 ratio: Rf (5:1 petrol–EtOAc) 0.65; mmax
(CHCl3)/cmꢀ1 2968 (CH), 1698 (C@O); dH (300 MHz,
CDCl3) 7.22 (2H, d, J 7.0, ArH), 6.90 (2H, d,
J 7.0, ArH), 6.30 (1H, d, J 4.97, NCHCH), 5.65–5.66
(1H, m, CH2CHCH2), 5.40 (1H, q, J 7.02, CHCH3),
5.28 (1H, d, J 5.0, NCHCH), 5.03–5.05 (2H, m,
4.14. 5-Allyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-1,5-
dihydropyrrol-2-one 15
3-Allyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-1,3-dihy-
dropyrrol-2-one 13b (0.11 g, 0.41 mmol, 1.0 equiv) in

2240
J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
xylene (7 mL) was heated under reflux for 48 h and the
mixture concentrated under reduced pressure. Purifica-
tion by flash column chromatography (SiO2; 25:1
petrol–EtOAc) afforded the title compound (0.06 g,
(1H, m, ArH), 7.26–7.42 (5H, m, ArH), 6.88 (2H, d, J
6.5, ArH), 4.49 (1H, q, J 6.5, CHCH3), 3.82 (3H, s,
OCH3), 3.60 (2H, q, J 7.0, CH2CH3), 3.08 (2H, q, J
7.0, CH2CH3), 1.56 (3H, d, J 6.5, CHCH3), 1.26 (3H,
t, J 7.0, CH2CH3), 0.98 (3H, t, J 7.0, CH2CH3); dC
(75 MHz, CDCl3) 170.0, 158.7, 156.8, 138.1, 137.2,
132.8, 130.5, 129.0, 127.9, 126.9, 126.3, 114.0, 69.4,
55.5, 43.3, 39.3, 24.8, 14.1, 13.2; m/z (CI) 339 (100%,
M+H+). Found: M+, 338.1994. C21H26N2O2 requires
338.1994.
60%) as a colourless oil in a 2:1 mixture of diastereoiso-
22
mers: ½aŠ ¼ ꢀ113.7 (c 0.15, CHCl3); Rf (10:1 petrol–
D
EtOAc) 0.35; mmax (CHCl3)/cmꢀ1 2924 (CH), 1680
(C@O); dH (300 MHz, CDCl3) 7.30 (2H, d, J 8.5,
ArH), 6.90 (2H, d, J 8.5, ArH), 6.55 (1H, t, J 2.0,
CHCHCH2), 5.53–5.55 (1H, m, CH2CHCH2), 5.45–
5.46 (2H, m, CH2CHCH2), 5.06–5.08 (2H, m,
CH2CHCH2), 5.02 (1H, d, J 2.0, CHCHCH2), 3.80
(3H, s, OCH3), 1.94 (3H, s, CH3), 1.70 (3H, d, J 7.0,
CHCH3); dC (75 MHz, CDCl3) 172.6, 159.0, 140.4,
134.9, 132.9, 132.8, 128.6, 118.6, 118.5, 113.9, 59.6,
55.5, 50.7, 36.8, 18.8, 11.5; m/z (CI) 272 (100%,
M+H+). Found: M+, 271.1567. C17H21NO2 requires
271.1572.
4.17. 2-[1-(4-Methoxyphenyl)ethyl]-3-phenyl-2,3-dihyd-
roisoindol-1-one syn-21
Phenyllithium (0.82 mL of a 2.0 M solution in dibutyl
ether, 1.62 mmol, 1.2 equiv) was added dropwise to a
solution of N,N-diethyl-2-{[1-(4-methoxyphenyl)ethyl-
imino]methyl}benzamide 20 (0.46 g, 1.35 mmol, 1.0
equiv) in THF (15 mL) at ꢀ78 ꢁC under a nitrogen
atmosphere. The solution was stirred at ꢀ78 ꢁC for
3 h, quenched by the addition of saturated aqueous
ammonium chloride solution (5 mL) and allowed to
warm to room temperature over 12 h. Water (5 mL)
was added and the mixture extracted with EtOAc
(4 · 10 mL). Combined organics were washed with
water (10 mL), dried over MgSO4 and concentrated
under reduced pressure. Purification by flash column
chromatography (SiO2; 50:1 petrol–EtOAc) afforded
4.15. 5-Allyl-5-deutero-1-[1-(4-methoxyphenyl)ethyl]-
3-methyl-1,5-dihydropyrrolo-2-one 16
5-Allyl-1-[1-(4-methoxyphenyl)ethyl]-3-methyl-1,5-dihy-
dropyrrol-2-one 15 (0.13 g, 0.48 mmol, 1.0 equiv) in
THF (5 mL) was added dropwise to a suspension of so-
dium hydride (0.04 g, 0.72 mmol, 1.5 equiv) in THF
(5 mL) at 0 ꢁC under a nitrogen atmosphere. The suspen-
sion was stirred at 0 ꢁC for 3 h after which CD3OD
(1 mL) was added dropwise. The mixture was allowed
to warm to room temperature and then extracted with
EtOAc (4 · 5 mL). The combined organic phases were
washed with water, dried over MgSO4 and concentrated
under reduced pressure. Purification by flash column
chromatography (SiO2; 1:1 petrol–EtOAc) afforded the
title compound (0.13 g, 99%) as a colourless oil in a
2.5:1 ratio of diastereoisomers: Rf (1:1 petrol–EtOAc)
0.65; mmax (CHCl3)/cmꢀ1 2926 (CH), 1684 (C@O); dH
(300 MHz, CDCl3) 7.25 (2H, d, J 8.5, ArH), 7.05 (1H,
d, J 1.5, CH), 6.90 (2H, d, J 8.5, ArH), 5.57–5.59 (1H,
m, CH2CHCH2), 5.39–5.41 (2H, m, CH2CHCH2),
5.09–5.10 (2H, m, CH2CHCH2), 4.82 (1H, q, J 7.0,
CHCH3), 3.80 (3H, s, OCH3), 1.94 (3H, s, CH3), 1.70
(3H, d, J 7.0, CHCH3); dC (75 MHz, CDCl3) 169.4,
161.2, 134.8, 132.0, 128.5, 128.1, 115.9, 113.4, 113.1,
105.2, 59.8, 48.5, 39.7, 36.4, 21.3, 19.7; m/z (CI) 273
(100%, MꢀH+). Found: M+, 272.1638. C17H20NO2D re-
quires 272.1635.
the title compound (0.080 g, 30%) as
a yellow
22
oil: ½aŠ ¼ ꢀ193.3 (c 0.10, CHCl3); Rf (10:1 petrol–
D
EtOAc) 0.65; mmax (CHCl3)/cmꢀ1 2924 (CH), 1687
(C@O); dH (300 MHz, CDCl3) 7.88 (1H, dd, J 5.5
and 2.5, ArH), 7.40–7.45 (2H, m, ArH), 7.18–7.22
(5H, m, ArH), 7.04 (1H, d, J 6.0, ArH), 6.98 (2H, d,
J 6.0, ArH), 6.68 (2H, d, J 8.5, ArH), 5.45 (1H, s,
CHPh), 5.05 (1H, q, J 7.5, CHCH3), 3.72 (3H, s,
OCH3), 1.85 (3H, d, J 7.5, CHCH3); dC (75 MHz,
CDCl3) 169.5, 158.9, 146.9, 138.0, 134.3, 132.5, 132.1,
129.1, 128.9, 128.6, 128.1, 123.8, 123.3, 113.9, 65.1,
55.6, 52.7, 30.1, 19.0, 0.4; m/z (CI) 344 (100%,
M+H+). Found: M+, 343.1567. C23H21NO2 requires
343.1572.
Also obtained was 2-[1-(4-methoxyphenyl)ethyl]-3-phen-
yl-2,3-dihydroisoindol-1-one anti-21 (0.070 g, 20%) as
22
a yellow oil: ½aŠ ¼ þ171.9 (c 0.08, CHCl3); Rf (10:1
D
petrol–EtOAc) 0.65; mmax (CHCl3)/cmꢀ1 2932 (CH),
1686 (C@O); dH (300 MHz, CDCl3) 7.90 (1H, dd, J
6.5 and 1.5, ArH), 7.38–7.44 (3H, m, ArH), 7.28–7.30
(2H, m, ArH), 7.12 (2H, d, J 8.5, ArH), 7.0 (2H, dd, J
7.5 and 1.5, ArH), 6.95 (1H, d, J 7.5, ArH), 6.85 (2H,
d, J 8.5, ArH), 5.75 (1H, q, J 7.5, CHCH3), 5.05 (1H,
s, CHPh), 3.85 (3H, s, OCH3), 1.20 (3H, d, J 7.5,
CHCH3); dC (75 MHz, CDCl3) 168.2, 158.2, 146.4,
138.1, 131.7, 131.0, 129.5, 128.2, 127.9, 127.7, 127.4,
127.3, 122.8, 122.2, 112.9, 62.4, 54.5, 49.6, 17.3, 0.5; m/z
(CI) 344 (100%, M+H+). Found: M+, 343.1566.
C23H21NO2 requires 343.1572.
4.16. N,N-Diethyl-2-{[1-(4-methoxyphenyl)ethylimino]-
methyl}benzamide 20
A mixture of N,N-diethyl-2-formylbenzamide 18 (0.50 g,
2.4 mmol, 1.0 equiv) and (S)-1-(4-methoxyphenyl)ethyl-
amine (0.36 g, 2.4 mmol, 1.0 equiv) in methanol (15 mL)
was stirred at room temperature, under a nitrogen atmo-
˚
sphere, over 4 A sieves for 12 h. The sieves were re-
moved by filtration and washed with EtOAc (10 mL).
Combined organics were dried over MgSO4 and concen-
trated under reduced pressure to afford the title com-
22
pound (0.83 g, 100%) as a clear oil: ½aŠ ¼ þ236.0 (c
The data for the X-ray crystal structure of syn-21
have been deposited with the Cambridge X-ray
crystallographic database, deposition number CCDC
268131.
D
0.12, CHCl3); Rf (1:1 petrol–EtOAc) 0.55; mmax
(CHCl3)/cmꢀ1 2971 (CH), 1667 (C@O), 1632 (C@N);
dH (300 MHz, CDCl3) 8.40 (1H, s, HC@N), 8.05–8.06

J. Clayden et al. / Tetrahedron: Asymmetry 16 (2005) 2235–2241
2241
7. For asymmetric syntheses of related compounds, see (a)
Huang, P.-Q.; Deng, J. Synlett 2004, 247; (b) Huang,
P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5, 4341; (c)
Acknowledgements
We are grateful to both the EPSRC and to Glaxo-
SmithKline for a CASE award to R. Turnbull and to
R. Copley of GlaxoSmithKline for assistance with the
X-ray crystal structure of syn-21.
´
Planas, L.; Perard-Viret, J.; Royer, J.; Selkti, M.; Thomas,
A. Synlett 2002, 1629; (d) Dudot, B.; Chiaroni, A.; Royer,
J. Tetrahedron Lett. 2000, 41, 6355.
8. Royles, B. J. L. Chem. Rev. 1995, 95, 1981.
9. (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18, and references cited therein; Ma, S.; Ni, B. Org. Lett.
2002, 4, 639.
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10. High stereoselectivity is indicated by the disappearance
from the H NMR of only one of the two diastereotopic
protons at the 5-position.
11. Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059.
12. For a related reaction, see: Ahmed, A.; Clayden, J.; Yasin,
S. A. Chem. Commun. 1999, 231, and references cited
therein. Reaction at the c-position in an extended aldol
reaction of an extended enol silane has been reported (See
Ref. 7d), but we were unable to repeat these reactions with
the lactam 9.
13. (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M.
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1
1. Bragg, R. A.; Clayden, J.; Menet, C. J. Tetrahedron Lett.
2002, 43, 1955.
2. Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6,
609.
3. See also (a) Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto,
I. Chem. Commun. 2004, 2430; (b) Clayden, J.; Kenwor-
thy, M. N. Synthesis 2004, 1721; (c) Clayden, J. Total
Synthesis of Kainoids by Dearomatizing Anionic Cyclisa-
tion In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Academic Press, 2004; Vol. 4, pp 72–
96; (d) Clayden, J. Organolithiums: Selectivity for Synthe-
sis; Pergamon: Oxford, 2002, pp 327–329; For a recent
application of dearomatising cyclisation in synthesis, see
(e) Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am.
Chem. Soc. 2005, 127, 2412.
4. We used this variant of the a-methylbenzyl group in the
expectation that the p-methoxy group would offer oppor-
tunities for oxidative cleavage in addition to the more
common reductive methods. See: Clayden, J.; Knowles, F.
E.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3397, for an
example.
5. We have been unable to confirm unequivocally the
stereochemistry of this compound, and we arbitrarily
assign the stereochemistry shown.
6. (a) Eames, J. Tetrahedron: Asymmetry 2001, 12, 1; (b)
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2567.
17. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.