Novel exploration of the SNAr reaction

Article abstract of DOI:10.1055/s-1998-1762

Propargylic, allylic and benzylic alcohols prove to be fairly successful as activated nucleophiles, under mild conditions for the S_NAr reaction.

Full text of DOI:10.1055/s-1998-1762

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Novel Exploration of the S Ar Reaction
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Stéphane Raeppel, Franck Raeppel and Jean Suffert*
Laboratoire de Pharmacochimie de la Communication Cellulaire, Faculté de Pharmacie - ERS 655 du CNRS, 74, route du Rhin - BP 24 - F-67401
Illkirch Cedex - France
Fax (33) 3 88 67 47 94 ; E-mail jeansu@pharma.u-strasbg.fr
Received 14 April 1998
Abstract : Propargylic, allylic and benzylic alcohols prove to be fairly
benzaldehyde derivatives (entry 10) have to be discarded in this type of
reaction, since only dehydrated or oxidized products are formed
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successful as activated nucleophiles, under mild conditions for the S Ar
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reaction.
leading mainly to degradation. Interestingly, 2-fluorobenzonitrile (entry
14) when submitted to the same reaction condition at 60°C, gave a 98%
yield of the corresponding propargylic ether.
1
The aromatic nucleophilic substitution reaction has not been often used
in the past for the synthesis of complex molecules because of the drastic
2
reaction conditions needed for this transformation. Recently, Zhu et al.
In conclusion, we have shown a new application of the S Ar reaction.
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have successfully employed this method to build several macrocycles
occurring in natural products via an intramolecular biaryl or aryl-alkyl
ether bond formation, under mild conditions. Thereafter, several other
groups have employed this new synthetic strategy to elaborate different
Extension of this methodology for the synthesis of more complex
molecules in the field of the enediyne prodrugs is currently under
investigation in our laboratory and will be reported in due course.
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target molecules.
References and Notes
In the course of the synthesis of polyunsaturated macrocyclic
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(1) Crampton, M. R. Organic Reaction Mechanisms 1986, A. C.
Knipe, W. E. Watts, Eds., 1988, John Wiley & Sons, New York,
247-262.
compounds in our laboratories, we have recently been interested in the
use of the S Ar reaction in order to introduce a propargylic moiety on a
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polysubstituted aromatic ring, either by an inter- or by an intramolecular
process. The reaction was then extended to the introduction of allylic
(2) a) Beugelmans, R.; Singh, G. P.; Zhu, J. Tetrahedron Lett.
1993
,
5
alcohols as well as benzylic alcohols. Up to now, the only nucleophiles
34, 7741-7744; b) Zhu, J. Synlett 1997, 133-144; c) Laïb, T.; Zhu,
J. Tetrahedron Lett. 1998, 39, 283-286; d) Bigot, A.; Zhu, J.
which have been used in S Ar, are phenoxides, amines, alkoxides,
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fluoride ions, thiols and activated carbanions. To our knowledge,
,
Tetrahedron Lett. 1998 39, 551-554.
5a
aromatic nucleophilic reactions, using propargylic, allylic
or
(3) a) Rao, A. V. R.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994,
35, 8465-8468; b) Burgess, K.; Lim, D.; Martinez, C. I. Angew.
Chem. Int. Ed. Engl. 1996, 35, 1077-1078; c) Evans, D. A.;
Watson, P. Tetrahedron Lett. 1996, 37, 3251-3254; d) Boger, D.
L.; Zhou, J.; Borzilleri, R. M.; Nukui, S.; Castle, S. L. J. Org.
Chem. 1997, 62, 2054-2069; e) Roussi, G.; González Zamora, E.;
Carbonnelle, A.-C.; Beugelmans, R. Tetrahedron Lett. 1997, 38,
4401-4404.
5a,g
benzylic
alcohols have not been reported in the literature yet. We
present in this communication the results of a study towards this goal.
Most substrates and nucleophiles used in these experiments are
commercially available or already described in the literature. Each
substrate bears at least one nitro function as an activating group, which
2
may be of use for subsequent transformations (e.g. into NH , Cl, OH,
2
H) and one fluoro leaving group. Both of them have been selected
2,3
because the yields are generally better for this type of reaction
(4) a) Eckhardt, M.; Brückner, R; Suffert, J. Tetrahedron Lett. 1995,
36, 5167-5170; b) Brickmann, K.; Hambloch, F.; Suffert, J.;
Brückner, R. Liebigs Ann. 1996, 457-471; c) Suffert, J.; Abraham,
E.; Raeppel, S.; Brückner, R. Liebigs Ann. 1996, 447-456;
d) Suffert, J.; Toussaint, D. Tetrahedron Lett. 1997, 38, 5507-
5510; e) Raeppel, S.; Toussaint, D.; Suffert, J. Synlett 1998,
accepted.
(Scheme 1).
Scheme 1
(5) a) Whalley, W.B. J. Chem. Soc. 1950, 2241-2243; b) Beck, J. R. J.
Org. Chem. 1972, 37, 3224-3226; c) Maehr, H.; Blount, J. F.;
Leach, M.; Stempel, A. Helv. Chim. Acta 1974, 57, 936-940;
d) Kornblum, N.; Cheng, L.; Kerber, R. C.; Kestner, M. M.;
Newton, B. N.; Pinnick, H. W.; Smith, R. G.; Wade, P. A. J. Org.
Chem. 1976, 41, 1560-1564; e) Pilichowski, J. F.; Gramain J. C.
Synthetic Commun. 1984, 14, 1247-1255; f) Idoux, J. P.;
Madenwald, M. L.; Garcia, B. S.; Chu, D.-L. J. Org. Chem. 1985,
50, 1876-1878; g) Loupy, A.; Philippon, N.; Pigeon, P.; Sansoulet,
J.; Galons, H. Synthetic Commun. 1990, 20, 2855-2864; h) Vlasov,
V. M. J. Fluorine Chem. 1993, 61, 193-216.
In a first set of experiments, we tested the addition of different activated
nucleophiles to 2-fluoro-nitrobenzene as a model substrate (Table 1). It
is interesting to note that the relative reactivity of activated primary
alcohols toward 2-fluoro-nitrobenzene decreases in the order
propargylic > allylic > benzylic. Surprisingly, secondary and homo-
propargylic alcohols still react, but require higher reaction temperature
to proceed. The use of silylated alkynes (entry 2) is not compatible with
the reaction conditions because of the release of fluoride ions.
In a second set of experiments, we studied the influence of the leaving
group position on the aromatic core with respect to the activator, in the
presence of electron-donating or electron-withdrawing substituents on
the aromatic ring (Table 2). 2-Fluoro- or 4-fluoro-nitrobenzene
derivatives substituted by one or more electron-withdrawing groups
reacted easily with the nucleophile (entries 1, 3 to 6). On the other hand,
no reaction occurred either with 3-fluoro-nitrobenzene, or when an
(6) Method A : substrate (1.0 equiv.) in DMF, addition of nucleophile
(1.5 equiv.) and anhydrous K CO (3.0 equiv.).
2
3
Method B : substrate (1.0 equiv.) in DMF, addition of nucleophile
(3.0 equiv.) and anhydrous K CO (5.0 equiv.).
2
3
Method C : substrate (1.0 equiv.) in DMF, addition of nucleophile
(1.5 equiv.) and TBAF 1M solution in THF (1.0 equiv.).
electron-donating group (e.g. OH, NH ) is present on the aromatic ring
2
(entries 12, 13). Secondary benzylic alcohol (entry 11), and
All reactions were run in dry DMF at the concentration of 0.2-0.4

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M under argon at the indicated temperature and time.
in this work have been isolated in pure form and characterized by
H and C NMR, and IR.
1
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The reaction mixture was diluted with Et O, washed with water
2
and brine, dried (Na SO ), concentrated, and the crude was
2
4
(7) Bigot, A.; Beugelmans, R.; Zhu, J. Tetrahedron 1997, 53, 10753-
purified by flash chromatography. All new compounds described
10764.