Pyrrolidinone-fused cyclohexenones by regioselective dearomatising anionic cyclisation of 2-, 3- or 4-methoxybenzamides

Article abstract of DOI:10.1055/s-2001-10772

On treatment with t-BuLi in the presence of HMPA, 2-, 3- or 4-methoxybenzamides (o-, m- or p-anisamides) bearing N-benzyl substituents cyclise with dearomatisation to give methyl dienyl ethers which hydrolyse to give single stereo- and regioisomers of pyr

Full text of DOI:10.1055/s-2001-10772

302
LETTER
Pyrrolidinone-fused Cyclohexenones by Regioselective Dearomatising Anionic
Cyclisation of 2-, 3- or 4-Methoxybenzamides
Jonathan Clayden,a* Kirill Tchabanenko,a Samreen A. Yasin,a Michael D. Turnbullb
aDepartment of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
bZeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire, RG42 6EY, UK
E-mail: j.p.clayden@man.ac.uk
Received 14 December 2000
O
O
Me
H
Abstract: On treatment with t-BuLi in the presence of HMPA, 2-,
3- or 4-methoxybenzamides (o-, m- or p-anisamides) bearing N-
benzyl substituents cyclise with dearomatisation to give methyl di-
enyl ethers which hydrolyse to give single stereo- and regioisomers
of pyrrolidine-fused cyclohexenones. The bicyclic enones are ver-
satile synthetic intermediates which undergo transformations such
as stereoselective reduction and conjugate addition, regioselective
Baeyer-Villiger oxidation, bromination and hydrogenation.
Me
+
N
R
N R
H
Ph
Ph
5aα (R = Bn) 40%
5bα (R = t-Bu) 35%
5aγ (R = Bn) 33%
5bγ (R = t-Bu) 36%
(ii)
OLi
N
(i)
Key words: amide, cyclisation, lithiation, enone, regioselectivity
1a or 1b
R
H
4
Ph
The lithiation to nitrogen of aromatic amides bearing
benzylic substituents has been known for many years,
with Fraser1 and Durst2 reporting the -lithiation by LDA
of N-benzylamides 1a, 2 and 3. In 1999, we reported3 that
the organolithiums derived from simple N-benzyl benz-
amides 1a and 1b are unstable at 78 °C in the presence
of HMPA: they undergo a cyclisation reaction with loss of
aromaticity in the benzamide ring, leading to pyrrolidine-
fused cyclohexadienes 5 and 6 (Scheme 1). The interme-
diate in the cyclisation reactions is an extended enolate 4,
which unfortunately does not react regioselectively with
electrophiles - a serious limitation to the synthetic appli-
cation of the dearomatising reaction.
(iii)
O
O
H
H
+
N
R
N
R
H
Ph
Ph
6aα (R = Bn) 68%
6bα (R = t-Bu) 75%
6aγ (R = Bn) 21%
6bγ (R = t-Bu) 5%
Scheme 1 Lithiation and Dearomatisation of N-Benzyl Amides; (i)
t-BuLi, THF, HMPA, 78 °C; (ii) MeI; (iii) NH4Cl, H2O
by ortholithiation5 and benzylation of the secondary ben-
zamide 10 (Scheme 2). They were each treated under our
standard conditions3 for dearomatising cyclisation (Meth-
od A: t-BuLi, THF, HMPA, 78 °C, or, for 8 and 11, 40
°C) and the reactions were quenched with aqueous ammo-
nium chloride (Scheme 3).
O
R
R
N
N
Ph
Ph
O
1a, R = Bn
1b, R = t-Bu
2, R = Ph
3, R = allyl
The o-anisamide 7 was the only amide to cyclise with a
lack of stereoselectivity, giving 76% of the cyclised prod-
uct 12 as a mixture of stereoisomers,6 which were separa-
ble by flash chromatography on silica, though slightly
unstable. Each of exo- and endo-12 was obtained as a sin-
gle regioisomer only. The m-anisamide 8, which in prin-
ciple could cyclise onto either the 2- or the 6-position of
the ring, similarly gave only a single regioisomer 14, but
the cyclisation required temperatures of 40 °C to return
good yields of 14. The p-anisamides 9a, 9b and 11 cyc-
lised stereoselectively, but sometimes gave mixtures of
regioisomers arising from - or -attack on the enolate in-
termediate. 16a and 16b were typically obtained as single
regioisomers;7 19 and 19 were obtained in a 5:1 ratio;
and 18 and 18 (produced by alkylating the intermediate
enolate with MeI) were obtained in a 1:2 ratio.
In this Letter, we now report that benzamides 7-9 and 11
bearing methoxy groups also cyclise with dearomatisa-
tion, but that the regioselectivity of the electrophilic
quench step is immaterial to the formation of single final
product because hydrolysis of a mixture of first-formed
dienyl ethers usually generates a single regioisomer of a
cyclohexenone. The cyclohexenone products are versatile
synthetic intermediates which undergo stereoselective
functionalisation.4
The four anisamides (methoxybenzamides) 7, 8, 9a and
9b were made by acylation of N-benzyl-t-butyl amine or
N-p-methoxybenzyl-t-butyl amine. Amide 11 was made
Synlett 2001, No. 2, 302–304 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pyrrolidinone-fused Cyclohexenones by Dearomatising Anionic Cyclisation
303
O
MeO
O
MeO
O
O
O
O
H
H
N
N
N
N
N
Ph
Ph
MeO
Ar
9a (Ar = Ph)
H
H
Ph
Ph
7
8
OMe
(i)
(A) or (B)
α,β-13 20%c; 25%b,d
exo-12 56%a
9b (Ar = p-OMeC6H4)
7
HCl,
H2O
MeO
O
O
COCl
O
H
H
H
7 85%; 8 96%; 9a100%; 9b 100%
MeO
N
N
Ph
(ii)
H
Ph
β,γ-13 19%c; 32%b,d
endo-12 20%a
O
Me
O
(iii), (iv)
N
H
N
O
H
O
H
MeO
MeO
Ph
HCl,
H2O
(A)
N
N
10
11
8
H
H
Ph
Ph
15 70%c
Scheme 2 Anisamides as starting materials. (i) BnNHt-Bu for 9a
or p-MeOC6H4CH2NHt-Bu (made quantitatively from t-BuNH2 and
p-methoxybenzyl chloride) for 9b, NaOH, H2O, CH2Cl2, 24 h: 85%
7, 96% 8, 100%, 9a; 100%, 9b; (ii) t-BuNH2, CH2Cl2, NaOH, H2O:
100%; (iii) 1. n-BuLi, THF, 0 °C, 30 min; 2. t-BuLi, 78 °C, 1 h;
3. MeI: 63%; (iv) 1. NaH, DMF, 2. BnBr: 72%.
OMe
O
14 71%a; 0%b
O
H
O
H
9a (A) or (B)
HCl,
H2O
N
N
or
9b
MeO
O
H
H
Ar
Ar
17a (Ar = Ph) 71%c, 73%a,d
16a (Ar = Ph) 59-75%a,e
16b (Ar = p-MeOC6H4) 100%a, 0%b,f
The dearomatised products exo-12, 14, 16a, 16b and 19
were hydrolysed by treatment with dilute hydrochloric ac-
id, yielding the enones 13 (39%), 15 (70%) and 17a (71%)
17b (100%) and 20 (80%). Except in one case that of 13
single regioisomers of enones were obtained even from
regioisomeric mixtures of intermediates, solving the prob-
lem of lack of regioselectivity in the cyclisation step. Cu-
17b (Ar = p-MeOC6H4) 100%a,d
O
O
Me
Me
(A)
9a
N
+
N
[MeI
MeO
MeO
quench]
H
H
Ph
Ph
18α 23%a
18γ 47%a
riously, enone 13 was obtained as a mixture of
- and
Me
O
-unsaturated regioisomers. The hydrolysis product
H
from endo-12 was not isolated.
N
Since our original publication on the cyclisation,3 we have
found that LDA also promotes the cyclisation of N-benzyl
amides, provided the lithiated intermediate is warmed to 0
°C or above, avoiding the need for the use of toxic HM-
PA.8 The three amides 7, 8 and 9b were therefore addi-
tionally treated with LDA at 0 °C and allowed to warm to
room temperature (Method B). Method B improved the
yields of the enones 13, but failed to yield cyclisation
products with the less reactive amide 8. Treatment with
LDA caused decomposition of 9b to the secondary amide
10.
Me
O
H
H
MeO
H
Ph
(A)
HCl,
H2O
19α 67%a,g
N
11
Me
O
O
Ph
20 80%a,d
N
MeO
H
Ph
19γ 13%a,g
Scheme 3 Dearomatising Anionic Cyclisation of N-Benzylanis-
amides. (A) 1. t-BuLi, THF, HMPA, 78 °C ( 40 °C for 8 and 11),
2. NH4Cl, H2O or 2. MeI (leading to 18); (B) 1. LDA, THF, 0-20 °C,
2. NH4Cl, H2O. aUsing method A; bUsing method B; cYield from iso-
d
O
lated cyclised intermediate enol ether; Yield over two steps (one
e
f
pot) from uncyclised amide; 0-12% 16a also obtained; The only
product isolated from reaction of 9b with LDA was 10; g19 and 19
formed in 5:1 ratio but not isolated.
N
MeO
H
Ph
16aγ
tive cyclisation (onto the 6-position of lithiated 8) would
produce a less sterically hindered product: presumably the
MeO group directs attack into the 2-position by some
form of coordination in the transition state of the cyclisa-
tion. A similar Li-OMe coordination may be the cause of
the loss of stereoselectivity in the cyclisation of 7.
The stereo- and regiochemistry of enone 15 was proved
by X-ray crystal structure, shown in the Figure. We have
found the preferred ring-junction stereochemistry to be cis
in all dearomatising cyclisation reactions of benzamides.
The regiochemistry of 15 is interesting since the alterna-
Synlett 2001, No. 2, 302–304 ISSN 0936-5214 © Thieme Stuttgart · New York

304
J. Clayden et al.
LETTER
Typical Procedure
A solution of tert-butyllithium (1.3 equiv. of a 1.7 M solution in
pentane) was added dropwise to a stirred solution of the amide 9a
(785 mg; 2.64 mmol) and HMPA [TOXIC] (2.75 mL; 15.8 mmol;
6 equiv.) in THF (20 mL) at 78 ºC under nitrogen. After 16 h at
78 °C, dilute HCl (10 mL) was added, and the mixture was
allowed to warm to room temperature and stirred for 1 h. The layers
were separated, and the aqueous phase was extracted three times
with ether. The combined extracts were washed with sodium bi-
carbonate solution, water and brine, and dried (MgSO4). Evapora-
tion under reduced pressure gave a crude product which was
purified by flash chromatography to yield the enone 17a (546 mg,
73%).
Acknowledgement
We are grateful to the EPSRC for a studentship (to SAY), to the Le-
verhulme Trust (KT) and Zeneca Agrochemicals (SAY) for sup-
port, and to Dr Madeleine Helliwell for determining the X-ray
crystal stucture of 15.
Figure X-ray crystal structure of 15
References and Notes
The enone products have great potential for further appli-
cations in synthesis, and we have already demonstrated
the use of a compound related to 17a as an intermediate in
the synthesis of (±)-kainic acid.4 Scheme 4 illustrates
some of the simple transformations which enones 17a and
17b readily undergo. Bromination of 17a followed by
elimination gave the bromide 21. Reduction of the enone
(1) Fraser, R. R.; Boussard, G.; Potescu, I. D.; Whiting, J. J.;
Wigfield, Y. Y. Can. J. Chem. 1973, 51, 1109.
(2) Durst, T.; van der Elzen, R.; LeBelle, M. J. J. Am. Chem. Soc.
1972, 94, 9261.
(3) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999,
231.
(4) Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317.
(5) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.
(6) The stereochemistry of the major product exo-12 and all other
cyclisation products was assigned by noting the similarity of
the coupling constants of the protons around the pyrrolidinone
ring to those of compounds of known stereochemistry (see ref.
3, 4). Our assignment of the stereochemistry of endo-12 is
more tentative, and is based on the fact that the coupling
3JNCHCH (6.5 Hz) is very different from the same coupling (0
Hz) in exo-12, while the ring junction couplings 3JCHCHC=O are
similar in the two diastereoisomers (9 Hz and 13 Hz).
(7) The occasional formation of up to 12% of regioisomer 16a
seemed to depend capriciously on the fine details of the work-
up, and in most cases only 16a was isolated from this reaction.
(8) Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. in press.
(9) (a) Luche, J. L. J. Am. Chem. Soc., 1978, 100, 2226;
(b) Luche, J. L.; Hahn, L. R.; Crabbe, P. J. Chem. Soc., Chem.
Comm., 1978, 601; (c) Gemal, A. L.; Luche, J. L. J. Am.
Chem. Soc., 1981, 103, 5454.
9
in the presence of CeCl3 gave a single diastereoisomer of
the allylic alcohol 22, while hydrogenation of 17b gave
23. Addition of lithium dimethylcuprate to 17b in the
presence of Me3SiCl gave a silyl enol ether which hydro-
lysed to a single diastereoisomer of the ketone 24,4 while
Baeyer-Villiger oxidation of the enone10 17b gave the ver-
satile enol lactone 25.
O
O
H
H
Br
(i)
(ii)
N
N
17a
O
HO
H
21
H
H
Ph
Ph
O
22
Me
O
H
H
(10) Mendelovici, M.; Glotter, E. J. Chem. Soc., Perkin Trans. 1
1992, 1735.
(iii)
(iv)
N
N
17b
O
O
(v)
H
H
23
24
Article Identifier:
1437-2096,E;2001,0,02,0302,0304,ftx,en;L20300ST.pdf
O
H
H
O
N
OMe
OMe
O
25
OMe
Scheme 4 Transformations of a pyrrolidine-fused enone. (i) Br2,
Et3N, 50%; (ii) NaBH4, CeCl3, 67%; (iii) H2, Pd/C (12 mol%), 86%;
(iv) 1. Me2CuLi, Me3SiCl; 2. HCl, H2O, 90%; (v) m-CPBA,
CF3CO2H, CH2Cl2, 55%.
Synlett 2001, No. 2, 302–304 ISSN 0936-5214 © Thieme Stuttgart · New York