Heterocyclization by catalytic carbonickelation of alkynes: A domino sequence involving vinylnickels

Article abstract of DOI:10.1039/b902095k

Reaction of Ni(0) in the presence of iodoarylethers 1 leads, after syn intramolecular carbonickelation of the triple bond, to nucleophilic vinylnickels which can be trapped, in a tandem process, by various electrophiles introduced at the onset of the reac

Full text of DOI:10.1039/b902095k

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Heterocyclization by catalytic carbonickelation of alkynes: a domino
sequence involving vinylnickelsw
´
Muriel Durandetti,* Lucie Hardou, Marie Clement and Jacques Maddaluno*
Received (in Cambridge, UK) 2nd February 2009, Accepted 10th June 2009
First published as an Advance Article on the web 6th July 2009
DOI: 10.1039/b902095k
Reaction of Ni(0) in the presence of iodoarylethers 1 leads, after
syn intramolecular carbonickelation of the triple bond, to
nucleophilic vinylnickels which can be trapped, in a tandem
process, by various electrophiles introduced at the onset of the
reaction.
Scheme 1 Access to dihydrobenzofurans 2a–c and chromane 2d by
carbonickelation of alkynes 1a–d.
Carbometallations are a source of new and useful ways to create
carbon–carbon bonds.1 Alkynes are particularly attractive
substrates for these reactions since they afford reactive vinyl-
metals that can be further exploited.2 Zinc, lithium, magnesium,
indium, titanium and of course palladium are the metals of
choice in this case, sometimes in the presence of another metal.3
Hence, catalytic amounts of nickel proved very useful to
improve the regio- and stereoselectivities of the addition of
other organometallics across the triple bond.4 An inter-
molecular sequence catalyzed by the nickel itself was recently
brought to the fore by Cheng et al., who showed that arylnickels
add efficiently to triple bonds,5,6 leading for instance to
functionalized (iso)quinolines.7 We report here our results
about a tandem sequence relying on: (i) an intramolecular
carbonickelation of alkynes leading to nucleophilic vinylnickels;
(ii) the intermolecular trapping of these intermediates by
various electrophiles. This nickel-catalyzed reaction, which does
not require the preparation of any other organometallic
reagent, provides a convenient and mild method for a one-pot
synthesis of substituted benzofurans and chromanes.
temperature. The expected 5-exo-dig cyclization product 2a
(Scheme 1) was quantitatively obtained after 30 minutes as a
1
single isomer. The H NMR spectrum of the crude product
recorded in CDCl3 or C6D6 showed that this isomer is not that
obtained by carbolithiation.9 A NOESY experiment confirmed
that 2a was recovered as the Z isomer exclusively, following a
syn addition of the arylnickel intermediate on the triple bond.
Attempts to purify 2a by chromatography on silica gel
(eluant = pentane–diethyl ether, 95 : 5) led to only 53% of
2a plus 29% of elimination product 3 (Fig. 1, Z/E = 63 : 37)
formed on silica.15
In the same reaction conditions, ethers 1b and c afford the
corresponding dihydrobenzofurans 2b and
c in 65%
(Z/E = 100 : 0) and 54% (Z/E = 83 : 17) yield, respectively.
Note that a partial aromatization of 2b to give benzofuran 4b
was observed upon flash chromatography on silica gel. This
result is worth underlining since 1b did not undergo cyclization
in the original carbolithiation conditions.8a
Lithium was unable to perform 6-exo-dig cyclizations. In
contrast, nickel, alike palladium,8b,10a,c mediates this ring
closing: treating homopropargyl ether 1d in the above conditions
led to chromane 2d in 62% yield (100% E, Scheme 1).
It was checked that nickel (and not manganese) is the active
metal in this sequence by performing the reaction on 1c using
We described recently an efficient carbolithiation transforming
aryl propargyl ethers into 3-vinyl-benzofurans, furopyridines
and indoles.8 The scope of this reaction is however limited to
propargylic acetals.9 To further widen this process, we had to
resort to the more tolerant palladium.8b,10 The ability of nickel
derivatives to promote both the catalysis of coupling reactions11
and the reductive coupling of alkynes and aldehydes,12 enals
and enones13 prompted us to examine the carbonickelation of
a set of aryl propargyl ethers. As shown below, these reactivities
could be combined in a new cascade process.
We first exposed iodoaryl 1a8a to our recent bench-friendly
technique to generate Ni(0) in situ by chemical reduction of
stable Ni(II) complexes with Mn(0).14 Following a protocol
optimized for arylnickel synthesis, we treated 1a in DMF with
1 equiv. of Ni(II) in the presence of manganese metal at room
´
´ ´
Laboratoire des Fonctions Azotees & Oxygenees Complexes de
l’IRCOF, CNRS UMR 6014 & FR 3038, Universite´ de Rouen et
INSA de Rouen, 76821 Mont St Aignan Cedex, France.
E-mail: muriel.durandetti@univ-rouen.fr, jmaddalu@crihan.fr;
Fax: +33 235 522 971; Tel: +33 235 522 437, +33 235 522 446
w Electronic supplementary information (ESI) available: Experimental
procedure and compound characterization data. See DOI:
10.1039/b902095k
Fig. 1 Products of the intramolecular carbonickelation of 1a–d.
Chem. Commun., 2009, 4753–4755 | 4753
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Table 1 Domino cyclization–condensation of iodoaryls 1a–d in the
presence of benzaldehyde
Entry Aryl Conditions
Product Yielda (%)
1
2
3
4
5
1b
1b
1a
1d
1c
1 equiv. Ni(II), rt, 5 min
10 mol% Ni(II), 50 1C, 2 h
10 mol% Ni(II), 50 1C, 2 h
10 mol% Ni(II), 50 1C, 4 h
10 mol% Ni(II), 50 1C, 23 h
6b
6b
6a
6d
—
88
91
48 (94)
59
0
a
Yield after flash chromatography (GC yield in parentheses).
Scheme 2 Evolution of the vinylnickel resulting from the intra-
molecular carbonickelation of 1b.
only Mn. After 3 days, B90% starting material was observed
by GC, together with B10% reduction product ArH. This
result implies that the insertion of manganese metal into the
carbon–iodine bond does not take place in these conditions.
In addition, when the reaction is performed in the presence
of anhydride or acyl chloride, no ketones were observed,
in disagreement with the formation of organomanganous
compounds.16
When working with iodoaryls 1b–d, significant amounts of
dimer of type 5 slowly accumulate in the medium (20% for 1b),
to the detriment of product 2b. This suggested that the putative
Scheme 4 Proposed mechanism for the cyclization–hydroxyalkylation
process of 1b in the presence of benzaldehyde.
alcohol, providing benzofuran 7a as a single E isomer in 65%.
Treating substrate 1d in similar Barbier’s conditions showed
that the domino process applied to a 6-exo-dig cyclization
(Table 1, entry 4). Alcohol 6d Z was isolated in 59% yield,
while an acidic dehydration afforded directly 2H-chromene 7d,
as a sole E isomer, in 65% yield. This reaction could not be
extended to substrate 1c, only 10% of benzofuranylidene 2c
being obtained in this case. Even after 23 h at 50 1C, no
alkylated product was found (Table 1, entry 5).
vinylnickel intermediate underwent
equilibration (Scheme 2).17
a slow Schlenk-type
This observation prompted us to take advantage of the
vinylic intermediate by trapping it in situ, in a domino process,
with electrophiles introduced at the onset of the reaction
(Barbier’s conditions). In a comparable experiment, Hodgson
and Wells used a terminal alkyne and a bimetallic Cr–Ni
system (Nozaki–Hiyama–Kishi conditions).3a These authors
observed the expected heterocyclization but the vinylic
intermediate revealed inert toward benzaldehyde.
The scope of this sequence toward electrophiles was next
evaluated with aryl iodides 1b and 1d. The products are
described in Fig. 1 and details are given in Table 2. Apart
from methyl methacrylate (Table 2, entry 7), the catalytic
sequence is reasonably efficient for a fair range of electro-
philes, going from alkanals to activated electrophiles such as
benzyl chloride, allyl acetate or a-chloroesters.11a,d It applies
equally well to dihydrobenzofurans (Table 2, entries 1–7) and
Aryl iodide 1b and benzaldehyde were first considered in a
Ni(II) stoichiometric process (Scheme
3 and Table 1).
Compounds 6b–14 are displayed in Fig. 1
The benzofuranylidene 6b, resulting from a cyclization–
hydroxyalkylation process, was recovered in good yield and
as a single E isomer (Table 1, entry 1). Actually, the nickel
alkoxide is likely to transmetalate with the Mn(II) generated
during the original redox process;14 we thus considered a
catalytic version using only 10 mol% NiBr2bipy (Scheme 4).
In these catalytic conditions the rate of the sequence de-
creased significantly; however, prolonging the reaction time
for 2 h at 50 1C restored the original yields (Table 1, entry 2).
The same conditions applied to functionalized substrate 1a
(Table 1, entry 3). In this case, the poorly stable product 6a (Z)
was obtained in 94% yield (GC, 48% after flash chromato-
graphy). Note that an acidic work-up (HCl 1 N) triggered the
hydrolysis of the acetal and the dehydration of the benzylic
Table 2 Cyclization of iodoaryl 1b and d in the presence of 10 mol%
Ni(II) and direct trapping by various electrophiles
Entry Electrophile
ArI Product Yielda (%) E/Zb
1
2
3
4
5
6
7
8
9
10
Nonanalc
1b 8b
1b 9b
1b 10b
1b 11
47 (84)
60 (70)
69 (81)e
42 (70)
54 (80)
28 (65)
25 (40)
56
100 : 0
85 : 15
100 : 0
100 : 0
100 : 0
85 : 15
58 : 42
0 : 100
30 : 70
15 : 85
Benzyl chlorided
Allyl acetatec
Methyl chloroacetatec
Methyl chloro-2-propionatec 1b 12
Ethyl acrylatef
Methyl methacrylatef
Nonanalc
1b 13
1b 14
1d 8d
1d 9d
1d 10d
Benzyl chlorided
Allyl acetatec
64
71e
a
After flash chromatography (NMR or GC yields in parentheses).
c
b
d
As determined by GC and NOESY. 1.3 equiv., 50 1C. 1.8 equiv.,
e
50 1C. Total yield calculated for 10 + (E,E) conjugated diene
(from 70 : 30 to 85 : 15). 4.0 equiv., 80 1C, 40% Ni(II).
f
Scheme 3 Tandem intramolecular carbonickelation of 1b.
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to chromanes (Table 2, entries 8–10), but the former are
poorly stable on silica gel, explaining the differences between
NMR or GC yields (70–80%) and isolated yields (Table 2).
The syn addition products are always the major isomers
after one hour. Note that (i) the allylation of 1 is followed by a
partial migration of the lateral double bond, affording a
conjugated diene, inseparable from 10 (Table 2, entries 3
and 10); (ii) benzyl chloride leads to a mixture of E and Z
isomers (Table 2, entries 2 and 9), probably due to the
isomerization of the intermediate vinylnickel before reaction;18
(iii) the sequence is efficient with sensitive electrophiles such as
a-chloroesters (Table 2, entries 4 and 5), a problem not tackled
by palladium chemistry. In contrast, the results could not be
extended to acetic anhydride or pivaloyl chloride; only 2b, 4b
and dimer 5 were recovered in these cases. A series of
unsaturated esters was also considered to assess the ability
of vinylnickels to promote conjugate additions. Increasing the
temperature and the concentration of the electrophile was
required to obtain reasonable results. The data in Table 2
suggest that the reaction is slow but affords the expected
1,4-addition products 13 and 14 (Table 2, entries 6 and 7).
The latter is obtained as a E–Z mixture, the sluggishness of the
reaction probably allowing isomerization of the vinylnickel.
Finally, b-substituted ethyl crotonate did not react under these
conditions.
Y. Sato, J. Am. Chem. Soc., 1999, 121, 4712–4713. Copper:
(d) J.-L. Moreau and M. Gaudemar, J. Organomet. Chem., 1976,
108, 159–164. Manganese: (e) J. Tang, K. Okada, H. Shinokubo
and K. Oshima, Tetrahedron, 1997, 53, 5061–5072. Iron: ref. 2d.
Indium: (f) R. Yanada, S. Obika, Y. Kobayashi, T. Inokuma,
M. Oyama, K. Yanada and Y. Takemoto, Adv. Synth. Catal.,
2005, 347, 1632–1642; (g) K. Endo, T. Hatakeyama, M. Nakamura
and E. Nakamura, J. Am. Chem. Soc., 2007, 129, 5264–5271.
4 (a) I. N. Houpis and J. Lee, Tetrahedron, 2000, 56, 817–846;
(b) S.-i. Ikeda, in Modern Organonickel Chemistry, ed.
Y. Tamaru, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
Germany, 2005, pp. 102–136.
5 D. K. Rayabarapu and C. H. Cheng, Chem. Commun., 2002,
942–943.
6 D. K. Rayabarapu, C. H. Yang and C. H. Cheng, J. Org. Chem.,
2003, 68, 6726–6731.
7 (a) R. P. Korivi and C. H. Cheng, Org. Lett., 2005, 7, 5179–5182;
(b) R. P. Korivi and C. H. Cheng, J. Org. Chem., 2006, 71,
7079–7082.
8 (a) F. Le Strat and J. Maddaluno, Org. Lett., 2002, 4, 2791–2793;
(b) F. Le Strat, D. C. Harrowven and J. Maddaluno, J. Org.
Chem., 2005, 70, 489–498.
9 The carbolithitation of 1a takes place in an anti fashion:
(a) C. Fressigne
J. Maddaluno, Angew. Chem., Int. Ed., 2008, 47, 891–893;
(b) C. Fressigne A.-L. Girard, M. Durandetti and
´
,
A.-L. Girard, M. Durandetti and
´
,
J. Maddaluno, Chem.–Eur. J., 2008, 14, 5159–5167.
10 Among recent examples of heterocyclization by intramolecular
catalytic carbopalladation of alkynes, see: (a) O. Barberan,
M. Alami and J.-D. Brion, Tetrahedron Lett., 2001, 42, 2657–2659;
(b) D. Bouyssi and G. Balme, Synlett, 2001, 1191–1193; (c) H. Zhang
and R. C. Larock, J. Org. Chem., 2003, 68, 5132–5138;
(d) R. Yanada, S. Obika, T. Inokuma, K. Yanada, M. Yamashita,
S. Ohta and Y. Takemoto, J. Org. Chem., 2005, 70, 6972–6975.
In conclusion, these results suggest that the vinylnickels
resulting from the intramolecular carbonickelation of alkynes
are nucleophilic entities, able to react with unusual electro-
philes such as a-chloroesters, or to condensate with aldehydes
in the absence of chromium salts (required in the NHK
reaction19). Nickel can thus be considered as an appropriate
metal to perform domino heterocyclization–coupling sequences.
Extension of this work to the (asymmetric) synthesis of other
heterocycles such as 3-substituted indoles and carbocycles will
be disclosed in a forthcoming full paper.
11 (a) M. Durandetti, J.-Y. Nedelec and J. Perichon, J. Org. Chem.,
´ ´ ´
1996, 61, 1748–1755; (b) E. Negishi and F. Liu, in Cross Coupling
Reactions, ed. P. J. Stang and F. Diederich, VCH, Weinheim, 1998,
ch. 1, pp. 1–47; (c) B. H. Lipshut and P. A. Blomgren, J. Am.
Chem. Soc., 1999, 121, 5819–5820; (d) M. Durandetti and
J. Perichon, Synthesis, 2004, 3079–3083; (e) C. Fischer and
´
G. C. Fu, J. Am. Chem. Soc., 2005, 127, 4594–4595.
12 For leading references, see: (a) E. Oblinger and J. Montgomery,
J. Am. Chem. Soc., 1997, 119, 9065–9066; (b) K. M. Miller,
W.-S. Huang and T. F. Jamison, J. Am. Chem. Soc., 2003, 125,
3442–3443.
We acknowledge the Region Haute-Normandie for a PhD
´
fellowship to LH. MC joined this project as a Master student
of the ESCOM (Cergy-Pontoise). We thank Prof. Serge R. Piettre
(Rouen) for helpful discussions.
13 (a) A. Herath, B. B. Thompson and J. Montgomery, J. Am. Chem.
Soc., 2007, 129, 8712–8713; (b) A. Herath, W. Li and
J. Montgomery, J. Am. Chem. Soc., 2008, 130, 469–471.
14 M. Durandetti, C. Gosmini and J. Perichon, Tetrahedron, 2007, 63,
´
1146–1153. The usual chemical routes to the arylnickel compounds
require the delicate preparation of Ni(0) complexes such as
Ni(cod)2.
Notes and references
1 (a) I. Marek, N. Chinkov and D. Banon-Tenne, in Metal-catalyzed
cross-coupling reactions, ed. F. Diederich and A. de Meijere,
Wiley-VCH, Stuttgart, 2004, ch. 7, pp. 395–478; (b) A.-M. L.
Hogan and D. F. O’Shea, Chem. Commun., 2008, 3839–3851.
2 For reviews: (a) J.-F. Normant and A. Alexakis, Synthesis, 1981,
841–870; (b) I. Marek, Chem. Rev., 2000, 100, 2887–2990. For
recent examples: (c) Y. Liu, Z. Zhong, K. Nakajima and
T. Takahashi, J. Org. Chem., 2002, 67, 7451–7456; (d) D. Zhang
and J. M. Ready, J. Am. Chem. Soc., 2006, 128, 15050–15051.
3 Nickel: (a) D. M. Hodgson and C. Wells, Tetrahedron Lett., 1994,
15 The crude NMR spectrum shows only 2a (see ESIw).
16 G. Friour, A. Alexakis, G. Cahiez and J. Normant, Tetrahedron,
1984, 40, 683–693.
17 (a) K. W. R. De Franc¸ a, M. Navarro, E. Leonel, M. Durandetti
´
and J.-Y. Nedelec, J. Org. Chem., 2002, 67, 1838–1842;
´
´
(b) A. Jutand, Chem. Rev., 2008, 108, 2300–2347.
18 (a) J. M. Huggins and R. G. Bergman, J. Am. Chem. Soc., 1981,
103, 3002–3011; (b) R. S. E. Conn, M. Karras and B. B. Snider, Isr.
J. Chem., 1984, 24, 108–112.
19 For a review see: L. A. Wessjohan and G. Scheid, Synthesis, 1999,
1–36.
35, 1601–1604; (b) T. Studemann and P. Knochel, Angew. Chem.,
¨
Int. Ed. Engl., 1997, 36, 93–95; (c) S.-i. Ikeda, D.-M. Cui and
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