Heck reaction versus free radical reaction for the synthesis of spiro[indoline-2,4′-piperidines]

Article abstract of DOI:10.1055/s-1998-1622

Spiro[indoline-2,4′-piperidines] can be prepared from 2-bromoaniline by using a Heck reaction or a free radical reaction as the key step. The radical process produces better yields of spiro[indoline-2,4′-piperidines] than the Heck process.

Full text of DOI:10.1055/s-1998-1622

March 1998
SYNLETT
251
Heck Reaction versus Free Radical Reaction for the Synthesis of Spiro[indoline-2,4'-
piperidines]
Janine Cossy*, Christophe Poitevin , Domingo Gomez Pardo
#
Laboratoire de Chimie Organique, Associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 - France
Fax: 33.1.40.79.44.25; E-mail: janine.cossy@espci.fr
Jean-Louis Peglion, Aimée Dessinges
Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes - France
#
Present address: Institut de Recherches Servier, 11 rue des Moulineaux - 92150 Suresnes - France
Received 11 November 1997
Abstract: Spiro[indoline-2,4'-piperidines] can be prepared from
2-bromoaniline by using a Heck reaction or a free radical reaction as the
key step. The radical process produces better yields of spiro[indoline-
2,4'-piperidines] than the Heck process.
Interest in spiroheterocyclic systems derives from the diverse biological
1
activities of this class of compounds . Although the synthesis of
2
3-spirooxindoles has been well studied , synthetic methods have been
less well developed for 2-spiroindolines of type A.
In this letter we would like to present the synthesis of spiro[indoline-
2,4'-piperidines] of type A from a key intermediate B according to the
following retrosynthetic scheme (Scheme 1). The key cyclization step
for obtaining spiro[indoline-2,4'-piperidines] of type A from B could be
a Heck reaction or a radical reaction.
Scheme 2
.
(ZnI , ZnCl or BF OEt ) failed to provide the desired product,
2
2
3
2
however substrate 6 could be accessed in three steps via the cyano
derivative 4. Compound 4 was obtained by treatment of 3 with TMSCN
(2 equiv. in boiling ethanol, 48 h, yield: 88%). After treatment of the
aminonitrile 4 with Dibal-H in toluene and hydrolysis (aqueous H SO ),
2
4
the aldehyde 5 was converted to the desired vinylic compound 6 by
Wittig reaction. The overall yield for the three steps was 24%. The Heck
Scheme 1
reaction was performed on compound 6 in the presence of Pd(OAc)
2
(10%), PPh (20%) and Et N (2.2 equiv.) in boiling acetonitrile for
3
3
9
48 h. The desired product 7 was isolated (64%) accompanied by 7'
(16%). These two compounds were separated by HPLC . The synthesis
Palladium salts and organometallic complexes are exceptionally
versatile catalysts for the construction of carbon-carbon bonds or
10
3
of 7 was achieved from N-Boc piperidone 2 in five steps in 12% overall
yield.
carbon-heteroatom bonds . Recently, focus has turned to the Heck
4
reaction because of its technical simplicity and tolerance of a variety of
functional groups.
5
11
The intramolecular Heck reaction has been used to build bridged
Although the generation of aryl radicals by tin hydride is less common
6
7
rings , spirocycles and tetrasubstituted carbon centers . This reaction is
regiospecific with a clear kinetic preference for 5-exo-trig cyclization
than that of alkyl radicals, these extremely reactive intermediates
provide practical routes to a variety of important target structures . To
8
12
versus 6-endo-trig cyclization. We have determined that the
construction of the [a-b] bond of compounds of type A can be achieved
by using a Heck reaction on substrate B. Our synthesis of compound A
(R = Boc) is outlined in Scheme 2.
compare the Heck methodology to the tin hydride cyclization reaction,
the acetylenic compound
8
was synthesized. Our approach to
spiro[indoline-2,4'-piperidines] using a radical reaction is outlined in
Scheme 3.
The condensation of the commercially available N-Boc protected
piperidone 2 with 2-bromoaniline 1 was achieved in boiling benzene
with azeotropic removal of water. The crude imine 3 was obtained in
90% yield. The key intermediate 6 could not be obtained in one step by
addition of vinyl organometallics to 3. Thus, addition of
vinylmagnesium bromide or vinyllithium in the presence of activators
In contrast to the addition of vinyl organometallics to 3, the addition of
lithium trimethylsilylacetylene in the presence of TMEDA (1.5 equiv.)
led to the corresponding aminoacetylenic derivative 8 in good yield
(75%). Under standard conditions (catalytic AIBN, boiling benzene),
the addition of tin hydride (2.0 equiv.) to 8 led to the desired
spiro[indoline-2,4'-piperidine] 7 via intermediate 9 according to a 5-exo-

252
LETTERS
SYNLETT
S.; Clarkson, S.; Grigg, R.; Sridharan, V. J. Chem. Soc., Chem.
Commun. 1995, 1135.
(3) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic
Press: London, 1985. Tsuji, J. Synthesis with Palladium
Compounds; Springer-Verlag: Berlin, 1980. Harrington P. J.
Transition Metals in Total Synthesis; Wiley-Interscience: New
York, 1990.
(4) Heck, R. F. Org. React. 1982, 27, 345. de Meijere, A.; Meyer, F.
E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. Negishi, E.;
Copéret, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem. Rev. 1996, 96, 365.
(5) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130. Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem.
Soc. 1990, 112, 6959. Negishi, E. I.; Zhnag, Y.; O'Connor, B.
Tetrahedron Lett. 1988, 29, 2915. Larock, R. C.; Song, H.; Baker,
B. E.; Gong, W. H. Tetrahedron Lett. 1988, 29, 2919. Neghishi, E.
I.; N'Guyen, T.; O'Connor, B. Heterocycles 1989, 28, 55.
Scheme 3
13
dig cyclization process . The intermediate 9 was transformed to the
desilylated compound 7 after purification by flash chromatography on
silica gel (80% yield from 8). We point out that when the non-silylated
compound 8’ was treated by Bu SnH, the corresponding cyclization
3
(6) Grigg, R.; Santhakumar, V.; Sridharan, V.; Stevenson, P.;
Teasdale, A.; Thornton-Pett, M.; Worakum, T. Tetrahedron 1991,
47, 9703.
product 7 was obtained with a yield of only 40%. The better yield
obtained for the transformation of 8 to 7 than for the transformation of
8’ to 7 is due to the fact that the TMS group stabilizes the radical
intermediate.
(7) Grigg, R.; Santhakumar, V.; Sridharan, V.; Thornton-Petit, M.;
Bridge, A. W. Tetrahedron 1993, 49, 5177.
(8) Grigg, R.; Stevenson, P.; Worakum, T. J. Chem. Soc., Chem.
Commun. 1984, 1073. Grigg, R.; Malone, J. F.; Mitchell, T. R. B.;
Ramassubbu, A.; Scott, R. M. J. Chem. Soc., Perkin Trans. I
1984, 1745. Grigg, R.; Stevenson, P.; Worakum, T. Tetrahedron
1988, 44, 2033. Grigg, R.; Sridharan, V.; Stevenson, P.;
Compound 7 was obtained in three steps from the N-Boc piperidone
with an overall yield of 54%, demonstrating that the process involving a
radical cyclization is more efficient than the process involving a Heck
reaction. The unprotected nitrogen in spiro[indoline-2,4'-piperidine] 7
and the exocyclic methylene group can be further modified to provide a
variety of structurally diverse analogs.
Sukirthalingam, S.; Worakum, T. Tetrahedron 1990, 46, 4003.
-1
(9) (7) C
H
N O ; M: 300 g.mol ; Rf (SiO , AcOEt/cyclohexane:
18 24
2
2
2
-1
1
15/85): 0.48. IR (nujol): 3350, 1680 (broad) cm . H NMR (300
In summary,
a
straightforward method (radical cyclization) to
MHz, CDCl ) δ: 7.35 (dd, J = 7.35 Hz, J = 1.47 Hz, 1H), 7.10
3
synthesize spiro[indoline-2,4'-piperidine] compounds has been
developed. Application of the methodology to other types of spiro
compounds is under further investigation.
(ddd, J = 7.35 Hz, J = 7.35 Hz and J = 1.47 Hz, 1H), 6.79-6.60 (m,
2H), 5.39 (s, 1H, C=CH ), 4.79 (s, 1H, C=CH ), 4.30 (s broad,
2
2
1H, NH), 4.20-4.05 (m, 2H), 2.99-2.81 (m, 2H), 1.66-1.55 (m,
13
4H), 1.44 (s, 9H, C(CH ) ). C NMR (75 MHz, CDCl ) δ: 153.7
3 3
3
(s, NCOO), 150.4 (s, C -NH), 130.0 (d), 126.7 (s), 121.1 (d),
Ar
Acknowledgment. We thank the Institut de Recherches Servier for
financial support.
118.8 (d), 110.5 (d), 99.4 (t, C=CH ), 79.5 (s, C-O), 63.3 (s, N-C),
2
40.4 (t, 2C, CH NCO), 37.9 (t, 2C, CH C), 28.3 (q, 3C, C(CH ) ).
2
2
3 3
+.
MS (EI; 70 eV) m/z: 300 (M , 57); 244 (31); 157 (61); 156 (85);
References and notes
144 (100); 143 (80); 57 (92).
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min; λ= 350 nm
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