Dearopmatizing Anionic Cyclization of Substituted N-Cumyl-N-benzylbenzamides on Treatment with LDA: Synthesis of Partially Saturated Substituted Isoindolones

Full text of DOI:10.1021/ol006786n

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4229-4232
Dearomatizing Anionic Cyclization of
Substituted N-Cumyl-N-benzyl-
benzamides on Treatment with LDA:
Synthesis of Partially Saturated
Substituted Isoindolones
,†
Jonathan Clayden,* Christel J. Menet,† and Darren J. Mansfield‡
Department of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K., and AVentis CropScience SA, Centre de Recherche de La
Dargoire, 14-20 rue Pierre Baizet - BP 9163, 69263 Lyon Cedex 09, France
j.p.clayden@man.ac.uk
Received October 27, 2000
ABSTRACT
On treatment with LDA, substituted N-benzylbenzamides (including those bearing electron-withdrawing, electron-donating, or conjugating
groups) become lithiated and cyclize to give, after aqueous quench, a range of partially saturated isoindolones as single regio- and stereoisomers.
In general, the isoindolones resist rearomatization. Reaction of N-cumyl-N-benzylbenzamides leads to cyclized products which may be deprotected
to give N-unsubstituted isoindolones.
LDA can deprotonate tertiary amides and is known to effect
ortholithiation,1 lateral lithiation,2 or lithiation R to nitrogen3
according to the amide’s substitution pattern. For cases in
which the Complex-Induced Proximity Effect4 (which gov-
erns the regioselectivity in kinetic-controlled lithiation) and
thermodynamic stability are opposed, LDA favors formation
of the most thermodynamically stable organolithium.5 R-Lithi-
ation can be forced by blocking all alternative positions for
deprotonation,6 but the R position is also the preferred site
of lithiation of simple N-benzyl amides.7
product of the deprotonation is unstable at temperatures
approaching 0 °C and undergoes a remarkable dearomatizing
cyclization reaction. We have previously reported a similar
cyclization of simple benzamides8 and of 1-naphthamides,9
and we used the t-BuLi/HMPA-initiated cyclization of
p-methoxybenzamide 1b in a synthesis of (()-kainic acid.10
However, the conditions we now report are much milder and
more versatile, avoiding the highly basic, toxic, and nucleo-
philic reagents t-BuLi and HMPA. We also now establish
that the reaction tolerates a variety of substitution patterns.
In this paper, we confirm that LDA successfully depro-
tonates simple N-benzylbenzamides, but we report that the
N-Benzylbenzamides are readily lithiated by t-BuLi R to
nitrogen at -78 °C, and we had already noted that HMPA
† University of Manchester.
‡ Aventis CropScience SA.
(7) Fraser, R. R.; Boussard, G.; Potescu, I. D.; Whiting, J. J.; Wigfield,
(1) Snieckus, V. Chem. ReV. 1990, 90, 879.
(2) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(3) Beak, P.; Reitz, D. B. Chem. ReV. 1978, 78, 275.
(4) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(5) Court, J. J.; Hlasta, D. J. Tetrahedron Lett. 1996, 37, 1335.
(6) See, for example: Schlecker, R.; Seebach, D.; Lubosch, W. HelV.
Chim. Acta 1978, 61, 512.
Y. Y. Can. J. Chem. 1973, 51, 1109.
(8) Ahmed, A.; Clayden, J.; Yasin, S. A. J. Chem. Soc., Chem. Commun.
1999, 231.
(9) Ahmed, A.; Clayden, J.; Rowley, M. J. Chem. Soc., Chem. Commun.
1998, 297.
(10) Clayden, J.; Tchabanenko, K. J. Chem. Soc., Chem. Commun. 2000,
317.
10.1021/ol006786n CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/29/2000

was essential for good yields in the cyclization reaction
between -78 and -40 °C.8 However, we found that by
lithiating the benzamide 1a at -78 °C and then raising the
temperature to 0 °C, it was possible to obtain the acid-
sensitive cyclized dienyl ether 4a even without HMPA
(Scheme 1, Method A). Mild acid hydrolysis returned the
Table 1. Dearomatizing Anionic Cyclizations of
N,N-Dialkylbenzamides
Scheme 1. Dearomatizing Anionic Cyclizationa
a Reagents: (i) t-BuLi, -78 °C, THF; (ii) LDA, 0 °C, THF; (iii)
-78 to 0 °C, 120 min; (iv) 0 to 20 °C, 90 min; (v) NH4Cl, H2O;
(vi) HCl, H2O. Method A ) (i), (iii), (v), (vi). Method B ) (ii),
(iv), (v), (vi).
more readily handled enone 5a as a single diastereoisomer.11
Simplifying this procedure, we carried out the lithiation of
1a at 0 °C with LDA and simply allowed the mixture to
warm to 20 °C over 1.5 h (Method B). The enone 5a was
obtained (after an acidic workup) in 73% yield. In both cases,
R-lithiation to give 2a appears to be followed by attack of
the organolithium on the aromatic ring, forming an extended
enolate 3a which is protonated on workup.12
The reaction is tolerant of other N-substituents in place
of the tert-butyl group (Table 1). Yields of the enones 5b-e
were acceptable from the N-cumyl-N-benzyl amide 1b, the
N,N-dibenzyl amide 1c and its p-methoxy analogue 1d (in
which only the unsubstituted benzyl group cyclizes),13 and
the N-benzyl-N-prenyl amide 1e. Bulky (tert-butyl or cumyl)
nitrogen substituents appear to be necessary for fully
diastereoselective formation of the cyclized products 5,14 and
out of tert-butyl and cumyl, the latter is preferable because
it can be removed by acid-catalyzed elimination (see
below).15 We found the tert-butyl group to be much harder
to remove from the cyclized products.
by mechanisms involving nucleophilic attack at their car-
bonyl groups.16
Next, we assessed the scope for modification of the
benzamide ring. N-Benzylcumylamine 8 was acylated with
a range of acid chlorides in parallel using a Carousel Reaction
Station (Radleys), giving the amides 9 shown in Table 2.
The amides were then treated with LDA in THF at 0 °C,
allowed to warm to room temperature over a period of 1.5
h, and quenched with ammonium chloride or ammonium
chloride and dilute hydrochloric acid (Scheme 2) The results
are shown in Table 2.
The cyclization tolerates electron-withdrawing and electron-
donating groups; importantly, the use of LDA allows the
cyclization of compounds containing functionality with
reactivity toward t-BuLi such as cyano and bromo groups
(9h-j). Excellent yields are obtained with the 1- and
2-naphthamide derivatives 9b,c: 2-naphthamides fail to
The N-allyl and N-Boc amides underwent quite different
rearrangement reactions to give ketones 6 and 7, respectively,
(15) We introduced the cumyl group as an alkyllithium-stable, acid-labile
protecting group for our synthesis of (()-kainic acid (ref 10). Snieckus has
independently reported the use of the cumyl group in ortholithiation
reactions: see Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999,
1, 1183.
(11) Relative stereochemistry was assigned by analogy with previous
work (refs 8-10), in which structures were determined using a combination
of NMR, synthetic, and X-ray crystallographic studies.
(12) The detailed mechanism of the attack on the ring is under
investigation but may be regarded as a six-electron electrocyclic ring closure.
(13) The selectivity presumably arises from destabilisation by the p-OMe
group of the alternative benzylic organolithium.
(16) The formation of compounds related to 7 by acyl transfer from N
to C is known (see Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998,
39, 5537), but the origin of benzyl phenyl ketone 6 is less obvious. We
assume 6 arises by elimination of benzyllithium after lithiation of the allyl
group, followed by attack of BnLi inter- or intramolecularly on the amide
carbonyl group. We have observed the occasional formation of 6 in
lithiations of other N-benzylbenzamides bearing two N-substituents prone
to metalation (ref 17).
(14) The minor diastereoisomer is tentatively assigned the trans ring
3
junction from the fact that each pair of 5 and epi-5 have similar JHH
coupling constants between H-3 and H-3a. Unfortunately, the H-3a to H-7a
coupling is not resolved.
4230
Org. Lett., Vol. 2, No. 26, 2000

Scheme 2. Dearomatizing Anionic Cyclization of Substituted
Table 2. Dearomatizing Anionic Cyclizations of Substituted
N-Cumyl-N-benzylbenzamides
Benzamidesa
a Reagents: (i) ArCOCl, Et3N, CH2Cl2, 20 °C, 16 h; (ii) LDA,
THF, 0-25 °C, 90 min; NH4Cl, H2O; (HCl, H2O).
cyclize in good yield with t-BuLi because of a competing
addition of t-BuLi to the 1-position.17 Substrates which failed
to cyclize included those bearing methoxy substituents at
the 3-position, 9f-g. Compounds bearing other 3-substituents
(9c and 9i) cyclized to give single regioisomers, with the
formation of 10c presumably being under electronic control
and the formation of 10i being under steric control.
Most cyclization products were surprisingly resistant to
aromatization in air, although we were unable to prevent
significant rearomatization of the product 10j from cyano-
substituted 9j to give 11. The aromatization appears to be
an oxidation of the enolate intermediate analogous to 3;
oxidation byproducts were occasionally observed in other
cyclizations if the enolate was not quenched within 2 h.
Removal of the cumyl group from the partially saturated
isoindolones 10 was achieved with strong acid (Scheme
3).10,15 The amides 10b, 10c, and 10e were heated with
Scheme 3. Removal of the Cumyl Groupa
a Reagent: (i) CF3CO2H, CH2Cl2, ∆, 3 h.
trifluoroacetic acid for 3 h to give the secondary amides 12b,
12c, and 12e18 in good to excellent yield. The simple route
9 f 10 f 12 constitutes a new and efficient route to a range
of functionalized, substituted, and partially saturated iso-
indolones.
(17) Ahmed, A.; Clayden, J. Unpublished results
(18) The regiochemistry of 10e and 12e has not been firmly established.
We have tentatively assigned the 5-oxo-7-methoxy (rather than the
1
5-methoxy-7-oxo) structure to 10e and 12e on the basis that the H NMR
signals for H-4 and H-3a are almost identical in chemical shift and coupling
pattern with those of 5b.
(19) Dixon, J. A.; Fishman, D. H.; Dudinyak, R. S. Tetrahedron Lett.
1964, 613.
Org. Lett., Vol. 2, No. 26, 2000
4231

Dearomatizing nucleophilic addition to naphthalene rings
is well-known, both for naphthalene itself19 and for naph-
thalenes substituted by electron-withdrawing groups.20 Com-
pounds in the naphthyloxazoline series have been extensively
employed as starting materials for the synthesis of a range
of carbocyclic synthetic targets,21 and our discovery of the
dearomatizing cyclization of lithiated amides was based upon
an observation in the naphthamide series.9,22 Dearomatizing
nucleophilic addition to benzene rings has also been known
for some time23 but usually requires activation by metals or
by substituents which are themselves susceptible to nucleo-
philic attack, limiting the versatility of the method. Nonethe-
less, the synthesis of carbocyclic and heterocyclic rings by
the dearomatization of aromatic precursors allows the re-
giocontrol available with aromatic compounds to be exploited
in the synthesis of saturated and partially saturated targets.24
Stereocontrolled dearomatization is all the more powerful,
and the reaction we report here adds to the number of
methods are available for the stereoselective conversion of
benzenoid25 and heterocyclic26 aromatic compounds to
versatile, partially saturated, synthetic intermediates.
(20) Plunian, B.; Mortier, J.; Vaultier, M.; Toupet, L. J. Org. Chem.
1996, 61, 5206. Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990,
31, 1739. Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D.
J. Am. Chem. Soc. 1988, 110, 4611. Meyers, A. I.; Brown, J. D.; Laucher,
D. Tetrahedron Lett. 1987, 28, 5283. Shindo, M.; Koga, K.; Asano, Y.;
Tomioka, K. Tetrahedron 1999, 55, 4955. Shindo, M.; Koga, K.; Tomioka,
K. J. Org. Chem. 1998, 63, 9351. Clayden, J.; Frampton, C. S.; McCarthy,
C.; Westlund, N. Tetrahedron 1999, 55, 14161.
(21) Shimano, M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 6437.
Shimano, M.; Meyers, A. I. J. Org. Chem. 1996, 61, 5714. Shimano, M.;
Matsuo, A. Tetrahedron 1998, 54, 4787. James, B.; Meyers, A. I.
Tetrahedron Lett. 1998, 39, 5301. Kolotuchin, S. V.; Meyers, A. I. J. Org.
Chem. 2000, 65, 3018.
Acknowledgment. We are grateful to the EPSRC for a
grant.
(22) Ahmed, A.; Clayden, J.; Rowley, M. Tetrahedron Lett. 1998, 39,
6103. Ahmed, A.; Clayden, J.; Rowley, M. Synlett 1999, 1954. Bragg, R.
A.; Clayden, J. Tetrahedron Lett. 1999, 40, 8323. Bragg, R. A.; Clayden,
J. Tetrahedron Lett. 1999, 40, 8327.
Supporting Information Available: Experimental details
and characterization data for 5a-e, 10a-e, 10h-j, 11, 12b,
12c, and 12e. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993. Saito,
S.; Shimada, K.; Yamamoto, H.; Mart´ınez de Marigorta, E.; Fleming, I. J.
Chem. Soc., Chem. Commun. 1997, 1299. Winemiller, M. D.; Harman, W.
D. J. Org. Chem. 2000, 65, 1249. Hunter, R.; Richards, P. Tetrahedron
Lett. 2000, 41, 3755. Ku¨ndig, E. P.; Ripa, A.; Bernardinelli, G. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1071. Padwa, A.; Filipkowski, M. A.; Kline,
D. N.; Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1993, 58, 2061. Pearson,
A. J.; Gontcharov, A. V.; Zhu, P. Y. Tetrahedron 1997, 53, 3849. Brown,
D. W.; Lindquist, M.; Mahon, M. F.; Malm, B.; Nilsson, G. N.; Ninan, A.;
Sainsbury, M.; Westerlund, C. J. Chem. Soc., Perkin Trans. 1 1997, 2337.
Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 9091.
Saito, S.; Sone, T.; Shimada, K.; Yamamoto, H. Synlett 1999, 81.
OL006786N
(24) Bach, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 729.
(25) Schultz, A. G. J. Chem. Soc., Chem. Commun. 1999, 1263.
(26) Donohoe, T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry
1996, 7, 317.
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