Palladium-catalysed intramolecular annulation of 2-haloanilines and ketones: Enolate arylation vs. nucleophilic addition to the carbonyl group

Article abstract of DOI:10.1039/b105686g

Two alternative annulation pathways involving either the enolate arylation or the addition to the ketone carbonyl group can operate in the Pd-catalysed intramolecular coupling of 2-haloanilines and ketones.

Full text of DOI:10.1039/b105686g

View Article Online / Journal Homepage / Table of Contents for this issue
Palladium-catalysed intramolecular annulation of 2-haloanilines and
ketones: enolate arylation vs. nucleophilic addition to the carbonyl
group†
Daniel Solé,* Lluís Vallverdú, Emma Peidró and Josep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona,
Spain. E-mail: bonjoch@farmacia.far.ub.es; dsole@farmacia.far.ub.es; Fax: +34 93 402 18 96;
Tel: +34 93 402 45 40
Received (in Cambridge, UK) 28th June 2001, Accepted 6th August 2001
First published as an Advance Article on the web 3rd September 2001
Two alternative annulation pathways involving either the
enolate arylation or the addition to the ketone carbonyl
group can operate in the Pd-catalysed intramolecular
coupling of 2-haloanilines and ketones.
We examined the intramolecular coupling of these substrates
under similar conditions to those we used for the synthesis of
2,6-methano-1-benzazocines: method A, 0.2 equiv. of
Pd(PPh3)4 and 3 equiv. of KOt-Bu in THF at reflux; method B,
0.2 equiv. of PdCl2(PPh3)2 and 3 equiv. of Cs2CO3 in THF in a
sealed tube at 110 °C.3d When the above (2-haloanilino) ketones
were submitted to the cyclisation conditions of method A, no
cyclisation product was obtained, and only compounds arising
from hydrodehalogenation and degradation of the amino ketone
moiety were isolated. In contrast, we found that using method B
led to two different and competitive cyclisation pathways,6
namely enolate arylation and nucleophilic addition to the
carbonyl group, depending on the structure of the starting amino
ketone. The results are summarised in Table 1. Thus, Pd-
catalysed intramolecular coupling of g-(2-iodoanilino) ketone 1
in the presence of PdCl2(PPh3)2 and Cs2CO3 in THF at 110 °C
(entry 1) took place exclusively at the a-position to give
quinolines 6 and 7, although in low yield, together with the
hydrodehalogenation compound 8. The alcohol 7 is probably
formed by oxidation of 6 under the reaction conditions; in fact,
longer reaction times resulted in the formation of 7 as the major
cyclisation product. However, under essentially the same
reaction conditions, both b-(2-haloanilino) ketones 2a–2d, and
3a and 3b, and a-(2-haloanilino) ketones 4 and 5 afforded as the
main product compounds resulting from the addition of the
arylpalladium intermediate to the carbonyl group. It is note-
worthy that the intramolecular nucleophilic addition of ar-
ylpalladium halides to ketones is an uncommon transformation
that has not been described until very recently.7,8 After the
initial results in the aforementioned palladium-catalysed proc-
esses, we worked to optimise conditions to promote the
nucleophilic addition to the carbonyl group. Both the addition of
triethylamine and the use of toluene as the solvent, instead of
THF, increased the yield of the annulation reactions (entry 3 vs.
2, 8 vs. 7 and 12 vs. 11).9 Some additional points can be
mentioned. The use of bromide 2b, instead of iodide 2a,
decreased the yield of cyclisation and resulted mainly in the
formation of the degradation compound 10 (entry 4 vs. 3).
Interestingly, in the b-amino ketone series changing the
substituent at the nitrogen atom from alkyl to methoxycarbonyl
resulted in the formation of significant amounts of the product
from arylation of the ketone enolate (entry 6 vs. 3, 9 vs. 7, and
10 vs. 8). Finally, the Pd-catalysed cyclisation of a-(2-iodoani-
lino) ketones 4 and 5 (entries 11–14) exclusively afforded 18
and 20, respectively, from the addition to the carbonyl group, as
During the recent years there has been a growing interest in the
palladium-catalysed coupling reactions of aryl1–4 and vinyl5
halides and enolates. Perhaps the most extensive study has been
done on the palladium-catalysed intermolecular coupling of aryl
halides and ketone enolates, while, in contrast, the intra-
molecular version of the reaction has received less attention.
In this context, we have recently reported that the palladium-
catalysed intramolecular coupling of 2-haloanilines and ketone
enolates provides a useful synthetic approach to the hexahydro-
2,6-methano-1-benzazocine ring system.3d
Continuing our palladium chemistry studies we decided to
extend the carbocyclisation process to the construction of other
nitrogen heterocycles by varying the relative position of the
2-haloaniline moiety and the ketone carbonyl group. Three
types of starting ketones were studied: g-(2-iodoanilino) ketone
1, b-(2-haloanilino) ketones 2a–2d, 3a and 3b, and a-
(2-iodoanilino) ketones 4 and 5.‡
was confirmed by careful analysis of the reaction mixtures.
Nevertheless, these compounds could not be characterised due
† Dedicated with great appreciation to Professor Francisco Camps for his
contribution to organic chemistry.
1888
Chem. Commun., 2001, 1888–1889
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105686g

View Article Online
Table 1 Pd(0)-catalysed intramolecular annulation of (2-haloanilino)
ketones 1–5a
to their instability and were converted to the corresponding
indoles 19 and 21 by treatment with TFA.
In summary, we have reported that two alternative pathways
can operate in the Pd-catalysed intramolecular coupling of
2-haloanilines and ketones. At this point, it is not clear why one
reaction or the other is preferred or what the chemoselectivity
control elements are. However, the results obtained when
changing the substituent at the nitrogen atom from alkyl to
methoxycarbonyl seem to indicate that the regioselectivity of
the enolate formation10 could be the origin of the change in the
annulation pathway. Further studies to clarify this point are
underway in our laboratory.
Additive
Entry Substrate Solvent (equiv.)
Products (yield)b
1
1
THFc
—
Notes and references
‡ Satisfactory analytical (combustion and/or high resolution mass) and
spectral (1H and 13C NMR) data were obtained for all new compounds.
2
3
4
2a
2a
2b
THFc
—
1 For the Pd-catalysed intermolecular coupling of aryl halides and
enolates, see: M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 1999,
121, 1473; J. M. Fox, X. Huang, A. Chieffi and S. L. Buchwald, J. Am.
Chem. Soc., 2000, 122, 1360; D. A. Culkin and J. F. Hartwig, J. Am.
Chem. Soc., 2001, 123, 5816; and references therein.
Toluened Et3N (2)
Toluened Et3N (2)
9 (45%)
2 For the Pd-catalysed intramolecular coupling of aryl halides and
stabilized enolates, see: M. A. Ciufolini, H.-B. Qi and M. E. Browne, J.
Org. Chem., 1988, 53, 4149.
3 (a) For the Pd-catalysed intramolecular coupling of aryl halides and
ketone and aldehyde enolates, see: H. Muratake, A. Hayakawa and N.
Natsume, Tetrahedron Lett., 1997, 38, 7577; (b) H. Muratake and N.
Natsume, Tetrahedron Lett., 1997, 38, 7581; (c) H. Muratake and H.
Nakai, Tetrahedron Lett., 1999, 40, 2355; (d) D. Solé, L. Vallverdú and
J. Bonjoch, Adv. Synth. Catal., 2001, 343, 439.
4 For the Pd-catalysed intramolecular coupling of aryl halides and amide
enolates, see: K. H. Shaughnessy, B. C. Hamann and J. F. Hartwig, J.
Org. Chem., 1998, 63, 6546; R. Freund and W. W. K. R. Mederski,
Helv. Chim. Acta, 2000, 83, 1247; T. Honda, H. Namiki and F. Satoh,
Org. Lett., 2001, 3, 631; S. Lee and J. F. Hartwig, J. Org. Chem., 2001,
66, 3402.
5
6
2c
Toluened Et3N (2)
Toluened Et3N (2)
2d
5 E. Piers and J. Renaud, J. Org. Chem., 1993, 58, 11; T. Wang and J. M.
Cook, Org. Lett., 2000, 2, 2057; X. Liu, T. Wang, Q. Xu, C. Ma and J.
M. Cook, Tetrahedron Lett., 2000, 41, 6299; D. Solé, E. Peidró and J.
Bonjoch, Org. Lett., 2000, 2, 2225; A. Chieffi, K. Kamikawa, J. Ahman,
J. M. Fox and S. L. Buchwald, Org. Lett., 2001, 3, 1897.
6 Recently, a third reaction pathway, involving a palladium-catalysed
redox process to form enones from a-(2-bromobenzyl) ketones under
reaction conditions similar to those reported in this work, has been
described: K. Högenauer and J. Mulzer, Org. Lett., 2001, 3, 1495.
However, this reaction has never been observed with any of the
2-haloanilino ketones studied in this work.
7
8
3a
3a
THFc
Et3N (10)
Toluenec Et3N (10) 14 (73%, 3.5+1)
7 L. G. Quan, M. Lamrani and Y. Yamamoto, J. Am. Chem. Soc., 2000,
122, 4827.
9
3b
THFc
Et3N (10)
8 For the intramolecular addition of vinylpalladium intermediates to
ketones,8a aldehydes8b and nitriles,8c see: (a) L. G. Quan, V. Gevorgyan
and Y. Yamamoto, J. Am. Chem. Soc., 1999, 121, 3545; (b) R. C.
Larock, M. J. Doty and S. Cacchi, J. Org. Chem., 1993, 58, 4579; V.
Gevorgyan, L. G. Quan and Y. Yamamoto, Tetrahedron Lett., 1999, 40,
4089; (c) R. C. Larock, Q. Tian and A. A. Pletnev, J. Am. Chem. Soc.,
1999, 121, 3238.
9 Indole 13 (see entry 6 Table 1) arises from the oxidation, under the
reaction conditions, of the 3-acetylindoline initially formed by a-
arylation.
10
11
3b
4
Toluenec Et3N (10) 16 (45%, 2+1) 17 (31%)
THFe
Et3N (10)f
10 The effects of a- and b-heteroatom-containing groups on the re-
gioselectivity of enolate formation are well known: V. A. Martin, D. H.
Murray, N. E. Pratt, Y. Zhao and K. F. Albizati, J. Am. Chem. Soc.,
1990, 112, 6965; ; Moreover, the introduction of electron-withdrawing
groups on the nitrogen atom of amino ketones increases the tendency for
enolization toward nitrogen: M. E. Garst, J. N. Bonfiglio, D. A.
Grudoski and J. Marks, J. Org. Chem., 1980, 45, 2307.
12
13
4
5
5
Toluened Et3N (10)f 19 (83%)
THFe
Et3N (10)f
14
Toluened Et3N (10)f 21 (87%)
a
Method B: PdCl2(PPh3)2 (0.2 equiv.) and Cs2CO3 (3 equiv.) in a sealed
tube at 110 °C. b Yields refer to pure isolated products. c 48 h. d 24 h. e
65 h. After the cyclisation reaction the crude mixture was treated with
f
TFA.
Chem. Commun., 2001, 1888–1889
1889