E. Deniau, D. Enders / Tetrahedron Letters 43 (2002) 8055–8058
Table 1. Enehydrazides 1a–f, 2a prepared
8057
1, 2
R1
R2
R2X
(Isomer) mp (°C)
Yield (%) (E/Z)
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
OMe
H
Me
Et
n-Pr
n-Pent
Ph
MeI
EtI
Oil18
93
(E) oil (Z) 76–77
(E) oil (Z) 71–72
(E) oil (Z) 68–69
(E) oil (Z) oil
(E) oil19 (Z) 99–10020
Oil
90 (25/75)
91 (25/75)
90 (20/80)
88 (15/85)
94 (10/90)
91
n-PrI
n-BuI
n-HexI
BnBr
MeI
2a
H
References
lactams 3, 4. We anticipated that the target exocyclic
enehydrazides 1, 2 should be accessible from the parent
3-benzotriazolyl-isoindolinones 3, 4 synthesized from
the 2-bromohydrazides 5, 6 (retrosynthetic Scheme 2).
On the other hand, we decided to especially focus our
study on the synthesis of 2-dimethylamino substituted
model compounds, because this group has been recently
reported to display favourable properties towards
deprotonation15 and could act as a protecting group of
the lactam ring.14e For this purpose, the benzoic acids
7, 8 were first converted into their corresponding N,N-
dimethyl hydrazides 5, 6 via a classical Schotten–Bau-
mann reaction (Scheme 3). According to a procedure
reported by McCombie and co-workers,16 the dilithi-
ated species 9 generated by sequential treatment of
2-bromohydrazides 5, 6 with phenyllithium and n-
butyllithium17 were then quenched with dimethylfor-
mamide to afford the 3-hydroxy isoindolinones 10, 11.
In order to introduce the benzotriazolyl group into our
model compounds, the hemiaminals 10, 11 were treated
with a catalytic amount of p-toluene sulfonic acid in
the presence of benzotriazole to deliver the target 3-
substituted bicyclic lactams 3, 4 in good yields. Com-
1. (a) Uozumi, Y.; Kawasaki, N.; Mori, E.; Mori, M.;
Shibasaki, M. J. Am. Chem. Soc. 1989, 111, 3725–3727;
(b) Liebeskind, L. S.; Johnson, S. A.; McCallum, J. S.
Tetrahedron Lett. 1990, 31, 4397–4400; (c) Couture, A.;
Deniau, E.; Grandclaudon, P. Tetrahedron 1997, 53,
10313–10330; (d) Daich, A.; Marchalin, S.; Pigeon, P.;
Decroix, B. Tetrahedron Lett. 1998, 39, 9187–9190; (e)
Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56,
4777–4792.
2. (a) Kato, Y.; Ebiike, H.; Achiwa, K.; Ashizawa, N.;
Kurihara, T.; Kobayashi, F. Chem. Pharm. Bull. 1990,
38, 2060–2062; (b) Kim, J. N.; Ryu, E. K. Synth. Com-
mun. 1996, 26, 67–74; (c) Ghorab, M. M.; Nassar, O. M.;
Hassan, A. Y. Phosphorus Sulfur Silicon Relat. Elem.
1998, 134/135, 57–76; (d) Kato, Y.; Takemoto, M.;
Achiwa, K. Chem. Pharm. Bull. 1999, 47, 529–535; (e)
Cid, H. M. B.; Traenkle, C.; Baumann, K.; Pick, R.;
Mies-Klomfass, E.; Kostenis, E.; Mohr, K.; Holzgrabe,
U. J. Med. Chem. 2000, 43, 2155–2164.
3. (a) Valencia, E.; Weiss, I.; Firdous, S.; Freyer, A. J.;
Shamma, M.; Urzua, A.; Fayardo, V. Tetrahedron 1984,
40, 3957–3962; (b) Ruchirawat, S.; Lertwanawatana, W.;
Thianpatanagal, S.; Cashaw, J. L.; Davies, V. E. Tetra-
hedron Lett. 1984, 25, 3485–3488; (c) Priestap, H. A.
Phytochemistry 1985, 24, 849–852; (d) Fang, F. G.;
Fiegelson, G. B.; Danishefsky, S. J. Tetrahedron Lett.
1989, 30, 2743–2746.
4. (a) Castedo, L.; Guitian, E.; Saa, J. M.; Suau, R. Hetero-
cycles 1982, 19, 279–280; (b) Estevez, J. C.; Villaverde,
M. C.; Estevez, R. J.; Castedo, L. Tetrahedron 1995, 51,
4075–4082; (c) Couture, A.; Deniau, E.; Grandclaudon,
P.; Lebrun, S. Synlett 1997, 1475–1477; (d) Couture, A.;
Deniau, E.; Grandclaudon, P.; Hoarau, C. J. Org. Chem.
1998, 63, 3128–3132; (e) Hoarau, C.; Couture, A.; Cor-
net, H.; Deniau, E.; Grandclaudon, P. J. Org. Chem.
2001, 66, 8064–8069.
pounds 3,
4 were exposed to potassium hexa-
methyldisilazide (KHMDS, 1.1 equiv.) to induce the
formation of the benzylic a-aminocarbanions 12, which
were then allowed to react with an array of alkyl
halides to afford the alkylation products 13. Treatment
of adducts 13 with trifluoroacetic acid gave rise to the
transient iminium salts 14, which finally furnished the
bicyclic enhydrazides 1a–f, 2 after neutralisation with
potassium carbonate (Table 1).
In conclusion, we have developed a new, concise and
versatile synthesis of polysubstituted 2-dimethylamino-
3-alkyl and arylmethylene-2,3-dihydro-1H-isoindol-1-
ones from easily accessible starting materials.
Undoubtedly, this new methodology may be broadened
to the elaboration of a wide variety of N-acyl enamines.
5. (a) Ishibashi, H.; Kawanami, H.; Ikeda, M. J. Chem.
Soc., Perkin Trans. 1 1997, 817–821; (b) Couture, A.;
Deniau, E.; Grandclaudon, P.; Hoarau, C. Tetrahedron
2000, 56, 1491–1499.
6. (a) El-Maghraby, A. A.; Bedair, A. H.; Aly, F. M.;
Emam, H. A. Indian J. Chem. Sect. B 1987, 26, 979–982;
(b) Scartoni, V.; Morelli, I.; Marsili, A.; Catalano, S. J.
Chem. Soc., Perkin Trans. 1 1977, 2332–2336.
7. Vasilevskii, S. F.; Pozdnyakov, A. V.; Shvartsberg, M. S.
Izv. Akad. Nauk. SSSR, Ser. Khim. 1985, 1367–1370.
8. Rowe, F. M.; Adams, D. A. W.; Peters, A. T.; Gillam, A.
E. J. Chem. Soc. 1937, 90–109.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft (Leibniz-Preis) and the Fonds der
Chemischen Industrie. We thank Degussa AG, BASF
AG, the former Hoechst AG, and Bayer AG for the
donation of chemicals.