Stereospecific dearomatising cyclisation of tertiary α -amidoorganolithiums

Article abstract of DOI:10.1055/s-2003-40993

Lithiation of benzamides derived from a chiral and enantiomerically pure α-methylbenzylamine leads to diastereoselective and regioselective dearomatising cyclisations with overall conservation of the stereochemistry of the starting stereogenic centre.

Full text of DOI:10.1055/s-2003-40993

LETTER
1701
Stereospecific Dearomatising Cyclisation of Tertiary a-Amidoorganolithiums
D
earomati
o
singCyclisa
n
tion of
T
ertia
a
ry
a
-Amid
thlithiums an Clayden,* Faye E. Knowles, Christel J. Menet
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: j.p.clayden@man.ac.uk
Received 13 March 2003
O
ArCOCl, Et3N,
CH2Cl2
Abstract: Lithiation of benzamides derived from a chiral and enan-
tiomerically pure a-methylbenzylamine leads to diastereoselective
and regioselective dearomatising cyclisations with overall conser-
vation of the stereochemistry of the starting stereogenic centre.
H
Ph
N
N
R
Ph
(R)-1 or (±)-1
(R)- or (±)-2a–2l
Key words: amide;, lithiation, cyclisation, stereospecificity, dearo-
matisation
Scheme 1 Synthesis of the amides.
Table 1 Starting Benzamides
a-Heterosubstituted benzyllithiums commonly exhibit
configurational stability,1 and tertiary a-heterosubstituted
benzyllithiums are often configurationally stable on the
macroscopic (i.e. laboratory) timescale.2,3 Several exam-
ples exist of chiral benzylic esters,4 carbamates2,5,6 and
thiocarbamates7–9 which may be deprotonated to yield
enantiomerically pure organolithiums. These organo-
lithiums may go on to react stereospecifically, with either
retention or inversion or a mixture, depending on their
structure.10,11
Entry
Compound
Substituents R
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
–
4-Me
4-MeO
2-Me
2-MeO
2,4-di-MeO
3-Me
In this paper we show that the same is true for simple
chiral amides. Various N-benzoyl derivatives of a-meth-
ylbenzylamine may be deprotonated at their single stereo-
genic centre to form chiral organolithiums.12 These
organolithiums cannot be quenched with external electro-
philes because they undergo a dearomatising cyclisa-
2g
2h
2i
3-MeO
3,4-di-MeO
3,5-di-MeO
2,3-di-MeO
2,6-di-MeO
tion.13–15 We show that the overall deprotonation- 10
2j
cyclisation sequence is stereospecific,16 indicating that the
11
2k
2l
chiral organolithium is configurationally stable on the
timescale of the cyclisation.
12
The amides 2a–2l shown in Table 1 were made in both ra-
cemic and enantiomerically pure form by acylation of N-
isopropyl ( )- and (R)-a-methylbenzylamine (>99% ee) 1
Under these conditions unsubstituted benzamide 2a un-
derwent a dearomatising cyclisation13–15 to give a single
diastereoisomer of the cyclohexadiene 5 in 70% yield plus
a small amount (10%) of a mixture of other diene regio-
using
a
range of substituted benzoyl chlorides
(Scheme 1). In general these compounds had complex
NMR spectra due to interconversion of conformers about
the C–N bond. They were treated with t-BuLi in THF at
–78 °C to yield deeply coloured solutions of benzyllithi-
ums 3 which were allowed to warm to 20 °C over a period
of a few hours, generating enolates 4 (Scheme 2). In some
cases DMPU was added to facilitate the cyclisation. The
reactions were quenched with ammonium chloride and
products 5–15 were isolated as shown in Schemes 3–5
below.
O
t-BuLi, DMPU,
THF, –78 °C
O
N
Li
O
N
R
R
Ph
Ph
2
3
OLi
–78 -
+20 °C
H
NH4Cl
N
N
R
R
H
H
Ph
Ph
4
product 5–15
Synlett 2003, No. 11, Print: 02 09 2003. Web: 05 08 2003.
Art Id.1437-2096,E;2003,0,11,1701,1703,ftx,en;D06003ST.pdf.
DOI: 10.1055/s-2003-40993
Scheme 2 Lithiation and cyclisation.
© Georg Thieme Verlag Stuttgart · New York

1702
J. Clayden et al.
LETTER
isomers. Benzamides 2b and 2c, both substituted in the
para position, cyclised with similar complete diastereo-
selectivity. A single regioisomer of diene 6 was isolated;
the cyclisation product from 2c was quenched with aque-
ous acid and generated the enone 7 with no trace of other
regioisomers. To the extent of NMR detection, a single
diastereoisomer was formed in every case. Comparison of
the HPLC trace on chiral stationary phase of the products
7 derived from the racemic and the enantiomerically pure
amide 2c indicated that the deprotonation and cyclisation,
at least in this case, is fully stereospecific.17
O
O
H
H
1. t-BuLi,
THF, –78 - +20 °C
N
N
Ph
2.NH4Cl
Ph
8 60%
2d
MeO
MeO
O
O
H
H
1. t-BuLi, DMPU,
THF, –78 - +20 °C
N
N
Ph
2e
2.NH4Cl
Ph
9 74%; >99% ee
MeO
O
MeO
O
H
1. t-BuLi, DMPU,
THF, –78 - +20 °C
O
O
1. t-BuLi,
THF, –78 - +20 °C
H
N
N
N
N
N
O
MeO
Ph
2f
2.NH4Cl
H
2.NH4Cl
Ph
Ph
H
Ph
5 70%
10 52%
2a
Scheme 4 Cyclisation of ortho-substituted amides.
O
O
H
1. t-BuLi, DMPU,
THF, –78 - +20 °C
N
Ph
this effect, making this the favourable position for cycli-
sation.18 This preference in the 3,4-dimethoxy substituted
amide 2i is overridden by the unfavourability of a 1,2,3,4-
tetrasubstituted arrangement in the transition state, and 14
is the major product, though some of the regioisomer 15
is also formed. The reluctance of 2i to cyclise erodes the
ee of 14, the only cyclisation product in which we could
detect the formation of a second enantiomer from an enan-
tiomerically pure starting amide. Presumably, slow cy-
clisation onto the electron-rich ring permits partial
racemisation of the intervening organolithium.
2.NH4Cl
H
H
Ph
6 75%
2b
O
O
1. t-BuLi, DMPU,
THF, –78 - +20 °C
N
N
O
MeO
Ph
2c
2. H2O, HCl
H
Ph
7 80%, >99% ee
Scheme 3 Cyclisation of unsubstituted and para-substituted
amides.
The 3,4- and 2,3-dimethoxy amides 2j and 2k fail to cy-
With amides 2d, 2e and 2f bearing an ortho substituent,
cyclisation onto the unsubstituted carbon atom was ob-
served exclusively in each case, and again single regio-
isomers, diastereoisomers and (where measured)
enantiomers of the products 8, 9 and 10 were formed
(Scheme 4). When 2f was cyclised, the presumed initial
bis-alkoxydiene product hydrolysed during work-up to
generate the alkoxyenone 10. A single regioisomer forms,
to which we assign the regiochemistry shown on the basis
of precedent.14
clise.
Attempted
intramolecular
nucleophilic
substitution19 in 2l also failed.
Notably, in all cases where ee’s were measured, except
14, complete stereospecificity was observed, indicating
that both lithiation and cyclisation are fully stereospecific
and that the chiral lithioamide intermediate 3 is configura-
tionally stable on the timescale of its cyclisation. We have
noted previous stereospecific cyclisation reactions in
which stereochemistry was conserved in the chiral Ar-CO
axis of the amide20,21 – a form of chiral memory.22 Sym-
metry dictates that benzamides 2a–c, and precedent23–25
that benzamides 2g–i, cannot have a chiral axis, so stereo-
specificity in this current work must be ascribed simply to
the kinetic configurational stability of the organolithium
intermediate.
Benzamides with a meta substituent have the choice of cy-
clisation onto either of two unsubstituted carbon atoms
(Scheme 5). The cyclisations of 2g, 2h and 2i, along with
the results of attempted cyclisation of 2j and 2k, reveal the
factors controlling the regioselectivity of the cyclisation.
With a meta methyl substituent (2g), the cyclisation ex-
hibits no selectivity: a mixture of regioisomers 11 and 12
is formed. With a meta methoxy group (2h), cyclisation
gives a single enantiomerically pure regioisomer 13 in
which the organolithium has attacked the position ortho to
the methoxy group. A preference for cyclisation ortho,
rather than para, to a methoxy group has been noted be-
fore.15 Presumably, although p-donation deactivates the
positions ortho and para to the methoxy group, with
methoxy ortho, inductive electron withdrawal counteracts
We are currently exploring the use of this class of
stereospecific cyclisations in the introduction of quater-
nary chiral centres to a range of other ring systems.26
General procedure for the cyclisation: t-BuLi (1.3 equiv)
was added to a solution of the amide (ca. 0.50 g) in THF
(30 ml) at –78 °C with t-BuLi. The solution was allowed
to warm to room temperature over 2 h. Saturated ammo-
nium chloride solution was added and the THF was re-
moved under reduced pressure. The residue was extracted
Synlett 2003, No. 11, 1701–1703 © Thieme Stuttgart · New York

LETTER
Dearomatising Cyclisation of Tertiary a-Amidoorganolithiums
1703
O
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H
H
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N
H
Ph
14 93% ee
O
MeO
MeO
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Scheme 5 Cyclisation of meta-substituted amides
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Acknowledgement
We would like to thank the EPSRC, Aventis CropScience (Lyon)
and GlaxoSmithKline for support, and Dr Darren Mansfield and
Dr Ian Baldwin for helpful discussions.
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Synlett 2003, No. 11, 1701–1703 © Thieme Stuttgart · New York