First cross-coupling reactions of arylmagnesates: A convenient access to heteroarylquinolines

Article abstract of DOI:10.1016/S0040-4039(03)00786-X

2-, 3- and 4-Bromoquinolines were converted to the corresponding lithium tri(quinolyl)magnesates at -10°C on treatment with Bu₃MgLi in THF. The resulting organomagnesium derivatives were involved in catalyzed cross-coupling reactions with heteroaryl bromides and chlorides to afford functionalized quinolines.

Full text of DOI:10.1016/S0040-4039(03)00786-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3877–3880
First cross-coupling reactions of arylmagnesates: a convenient
access to heteroarylquinolines
Sylvain Dumouchel, Florence Mongin,* Franc¸ois Tre´court and Guy Que´guiner
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
76131 Mont-Saint-Aignan Ce´dex, France
Received 17 December 2002; accepted 8 February 2003
Abstract—2-, 3- and 4-Bromoquinolines were converted to the corresponding lithium tri(quinolyl)magnesates at −10°C on
treatment with Bu3MgLi in THF. The resulting organomagnesium derivatives were involved in catalyzed cross-coupling reactions
with heteroaryl bromides and chlorides to afford functionalized quinolines. © 2003 Elsevier Science Ltd. All rights reserved.
We describe the first cross-couplings with lithium
triarylmagnesates.
The first experiments were conducted on lithium tri(3-
quinolyl)magnesate (1a), prepared by treating 3-bromo-
quinoline (1) with lithium tributylmagnesate in THF at
−10°C.10 Under palladium catalysis, reactions between
arylmagnesium halides and aryl chlorides, bromides, or
iodides are possible at rt.6f,i,l,m,11 Nickel, which is harder
than palladium, was most often chosen for
chlorides6d,h,l and fluorides,12 which are harder than
bromides and iodides. Indeed, attempts to realize the
subsequent cross-coupling reactions of 1a in a ‘one-pot’
procedure with heteroaromatic bromides under nickel
catalysis were unsuccessful. So we turned our attention
to palladium catalysis. The reaction could be achieved
when catalytic amounts of bis(dibenzylideneace-
tone)palladium(0) (Pd(dba)2) and 1,1%-bis(diphenylphos-
phino)ferrocene (dppf) were used.6i,l,m,13 The low to
medium yields observed are based on 3-bromoquinoline
(1). The first step proceeds in 85–90% yield, as demon-
strated by quenching the intermediate 1a with benzalde-
hyde, the remaining 10–15% being essentially butylated
products formed through addition of the residual butyl-
magnesium species to the quinoline ring.10 The coupling
step results of the successive reactions of the lithium
tri(3-quinolyl)magnesate, the bi(3-quinolyl)magnesium,
and the 3-quinolylmagnesium bromide with the bromo
substrate. It appears that less than 10% of 3,3%-biquino-
line could be detected, the main by-product being quin-
oline, obtained in 15 to 50% yield depending on the
reactivity of the bromide involved. The best results
were observed with p-deficient substrates such as bro-
mopyridines and bromoquinolines, for which the oxida-
tive addition step is easier (Table 1, entries 1–5), while
lower yields were obtained with less activated bromo-
thiophenes (Table 1, entries 6 and 7). Moreover, the
Interest in azine and diazine natural products either for
pharmaceuticals or as building blocks for various appli-
cations within materials science and supramolecular
chemistry has led to extensive efforts devoted to a
variety of synthetic methodologies.1 In these series, the
development of transition metal-catalyzed cross-cou-
plings, such as Negishi,2,3 Suzuki,2,4 Stille2,4d,f,5 and
Kharasch2,6 reactions, is of crucial importance.
An organomagnesate (R3MgLi) was first published in
1951.7 However, while the structure of such complexes
has long been investigated,8 their synthetic applications
remained unexplored until very recently.9 In 2001, the
first halogen–magnesium exchanges via organomagne-
sates were published by Oshima in the benzene, pyri-
dine and thiophene series.9i,l The method has since been
extended to the mono-exchange of dibromobenzenes
and dibromoheteroarenes (pyridine and thiophene
series) by Iida and Mase using lithium tributyl-
magnesate.9m
We have been interested in the bromine–magnesium
exchange of 2-, 3- and 4-bromoquinolines using lithium
tributylmagnesate.10 Herein, we describe the behavior
of the lithium tri(quinolyl)magnesates thus prepared in
the catalyzed cross-coupling reactions with heteroaro-
matic bromides and chlorides.
Keywords: cross-coupling; ate complexes; magnesium; quinoline.
* Corresponding author. Tel.: +33 (0) 2 35 52 29 00; fax: +33 (0) 2 35
52 29 62; e-mail: florence.mongin@insa-rouen.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00786-X

3878
S. Dumouchel et al. / Tetrahedron Letters 44 (2003) 3877–3880
Table 1. Cross-coupling reactions of 1a with bromides
Scheme 2.
Table 2. Cross-coupling reactions of 1a with chlorides
yields depend on the position of the bromine atom on
the ring, better results being noted with 2-bromo sub-
strates (Scheme 1, Table 1).
synthesis through bromine-magnesium exchange, but
also to a lower reactivity, when compared to magne-
sates 1a and 4a (Scheme 3, Table 3).
We then investigated the reaction with chlorides. In this
case, we have shown that it is advantageous to use
bis(acetylacetonate)nickel(II) (Ni(acac)2) instead of
Pd(dba)2; 1,3-bis(diphenylphosphino)propane (dppp)
was found to be the best ligand.6a–i,l,m The reaction of
1a with heteroaromatic chlorides was carried out in
THF, in a ‘one-pot’ procedure at rt. It generally pro-
ceeds in modest yields, depending on the substrate used
(better yields with diazines, for which the oxidative
addition step is easier), but also on the position of the
chlorine atom on the ring (Scheme 2, Table 2).
In conclusion, 2-, 3- and 4-substituted quinolines could
be synthesized from the corresponding bromo deriva-
tives in a ‘one-pot’ procedure through bromine-magne-
sium exchange reaction and subsequent cross-coupling
with heteroaryl halides. Even if the yields are not high,
To evaluate the scope of this reaction, it was applied to
the lithium tri(quinolyl)magnesates 3a and 4a, respec-
tively, derived from 2- and 4-bromoquinolines (3 and
4).16 It appears that the yields obtained from magnesate
3a are lower:10 this may be attributed to its incomplete
Scheme 3.
Scheme 1.

S. Dumouchel et al. / Tetrahedron Letters 44 (2003) 3877–3880
3879
Table 3. Cross-coupling reactions of 3a and 4a with bromides
our method is interesting since it avoids a preliminary
synthesis of the organometallic substrate, usually at low
temperatures via its corresponding lithio derivative.
2892–2897; (e) Hargreaves, S. L.; Pilkington, B. L.; Rus-
sel, S. E.; Worthington, P. A. Tetrahedron Lett. 2000, 41,
1653–1656; (f) Loren, J. C.; Siegel, J. S. Angew. Chem.,
Int. Ed. 2001, 40, 754–757; (g) Karig, G.; Spencer, J. A.;
Gallagher, T. Org. Lett. 2001, 3, 835–838; (h) Karig, G.;
Thasana, N.; Gallagher, T. Synlett 2002, 808–810.
4. (a) Ishikura, M.; Kamada, M.; Terashima, M. Synthesis
1984, 936–938; (b) Ishikura, M.; Oda, I.; Terashima, M.
Heterocycles 1985, 23, 2375–2386; (c) Deshayes, K.;
Broene, R. D.; Chao, I.; Knobler, C. B.; Diederich, F. J.
Org. Chem. 1991, 56, 6787–6795; (d) Godard, A.; Turck,
A.; Ple´, N.; Marsais, F.; Que´guiner, G. Trends Hetero-
cycl. Chem. 1993, 3, 19–29; (e) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457–2483; (f) Godard, A.; Marsais,
F.; Ple´, N.; Tre´court, F.; Turck, A.; Que´guiner, G. Hete-
rocycles 1995, 40, 1055–1091; (g) Fernando, S. R. L.;
Maharoof, U. S. M.; Deshayes, K. D.; Kinstle, T. H.;
Ogawa, M. Y. J. Am. Chem. Soc. 1996, 118, 5783–5790;
(h) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168;
(i) Schomaker, J. M.; Thomas, T. J. J. Org. Chem. 2001,
66, 7125–7128; (j) Bouillon, A.; Lancelot, J.-C.; Collot,
V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 2885–
2890; (k) Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy,
P. R.; Rault, S. Tetrahedron 2002, 58, 3323–3328; (l)
Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2002, 58, 4369–4373.
5. (a) Stille, J. K. Angew. Chem. 1986, 98, 504–519; (b)
Schubert, U. S.; Eschbaumer, C.; Heller, M. Org. Lett.
2000, 2, 3373–3376; (c) Fallahpour, R.-A. Synthesis 2000,
1138–1142; (d) Kimber, M.; Anderberg, P. I.; Harding,
M. M. Tetrahedron 2000, 56, 3575–3581; (e) Fallahpour,
R.-A.; Neuburger, N. Eur. J. Org. Chem. 2001, 1853–
1856; (f) Mathieu, J.; Gros, P.; Fort, Y. Tetrahedron Lett.
2001, 42, 1879–1881.
6. (a) Pridgen, L. N. J. Heterocycl. Chem. 1975, 12, 443–
444; (b) Takei, H.; Miura, M.; Sugimura, H.; Okamura,
H. Chem. Lett. 1979, 1447–1450; (c) Tamao, K.;
Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.;
Cross-coupling typical procedure: BuLi (1.6 M in hex-
anes, 1.3 mmol) was added to a solution of BuMgCl
(2.0 M in diethyl ether, 0.65 mmol) in THF (4 mL) at
−10°C. After stirring for 1 h at −10°C, 3-bromoquino-
line (1, 0.23 mL, 1.7 mmol) was introduced at −30°C.
After 2.5 h at −10°C, 2-bromopyridine (0.16 mL, 1.7
mmol) in THF (3 mL), Pd(dba)2 (48 mg, 85 mmol) and
dppf (47 mg, 85 mmol) were added and the mixture was
stirred for 18 h at rt. Addition of water saturated with
NH4Cl (0.5 mL), dilution with CH2Cl2 (50 mL), drying
over MgSO4 and column chromatography using
CH2Cl2/Et2O (80:20) as an eluent afforded compound
2a (56% yield).
References
1. (a) Katritzky, A. R.; Rees, C. W. Comprehensive Hetero-
cyclic Chemistry; Boulton, A. J.; McKillop, A., Eds.,
Pergamon Press, 1984; Vol. 2; (b) Que´guiner, G.; Mar-
sais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem.
1991, 52, 187–304; (c) Mongin, F.; Que´guiner, G. Tetra-
hedron 2001, 57, 4059–4090; (d) Turck, A.; Ple´, N.;
Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489–
4505.
2. Stanforth, S. P. Tetrahedron 1998, 54, 263–303 and refer-
ences cited therein.
3. (a) Negishi, E.; King, A. O.; Okukado, N. J. J. Org.
Chem. 1977, 42, 1821–1823; (b) Sakamoto, T.; Kondo,
Y.; Murata, N.; Yamanaka, H. Tetrahedron 1993, 49,
9713–9720; (c) Tre´court, F.; Gervais, B.; Mallet, M.;
Que´guiner, G. J. Org. Chem. 1996, 61, 1673–1676; (d)
Tre´court, F.; Gervais, B.; Mongin, O.; Le Gal, C.;
Mongin, F.; Que´guiner, G. J. Org. Chem. 1998, 63,

3880
S. Dumouchel et al. / Tetrahedron Letters 44 (2003) 3877–3880
Suzuki, K. Tetrahedron 1982, 38, 3347–3354; (d) Sen-
(l) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 2001, 66, 4333–4339; (m) Iida, T.; Wada,
T.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42,
4841–4844; (n) Inoue, A.; Kondo, J.; Shinokubo, H.;
Oshima, K. Chem. Eur. J. 2002, 8, 1730–1740.
gupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.;
Snieckus, V. J. Org. Chem. 1992, 57, 4066–4068; (e)
Albers, W. M.; Canters, G. W.; Reedijk, J. Tetrahedron
1995, 51, 3895–3904; (f) Meth-Cohn, O.; Jiang, H. J.
Chem. Soc., Perkin Trans. 1 1998, 3737–3745; (g) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; (h)
Bo¨hm, V. P. W.; Weskamp, T.; Gsto¨ttmayr, C. W. K.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2000, 39,
1602–1604; (i) Bonnet, V.; Mongin, F.; Tre´court, F.;
Que´guiner, G.; Knochel, P. Tetrahedron Lett. 2001, 42,
5717–5719; (j) Fu¨rstner, A.; Leitner, A. Angew. Chem.,
Int. Ed. 2002, 41, 609–612; (k) Fu¨rstner, A.; Leitner, A.;
Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856–13863; (l) Bonnet, V.; Mongin, F.; Tre´court, F.;
Breton, G.; Marsais, F.; Knochel, P.; Que´guiner, G.
Synlett 2002, 1008–1010; (m) Bonnet, V.; Mongin, F.;
Tre´court, F.; Que´guiner, G.; Knochel, P. Tetrahedron
2002, 58, 4429–4438; (n) Quintin, J.; Franck, X.; Hoc-
quemiller, R.; Figade`re, B. Tetrahedron Lett. 2002, 43,
3547–3549.
10. Dumouchel, S.; Mongin, F.; Tre´court, F.; Que´guiner, G.
Tetrahedron Lett. 2003, 44, 2033–2035.
11. (a) Sekiya, A.; Ishikawa, N. J. Organomet. Chem. 1976,
118, 349–354; (b) Widdowson, D. A.; Zhang, Y. Z.
Tetrahedron 1986, 42, 2111–2116; (c) Huang, J.; Nolan, S.
P. J. Am. Chem. Soc. 1999, 121, 9889–9890.
12. (a) Kiso, Y.; Tamao, K.; Kumada, M. J. Organomet.
Chem. 1973, 50, C12–C14; (b) Cahiez, G.; Lepifre, F.;
Ramiandrasoa, P. Synthesis 1999, 2138–2144; (c) Bo¨hm,
V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp, T.; Herr-
mann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387–
3389; (d) Mongin, F.; Mojovic, L.; Guillamet, B.; Tre´-
court, F.; Que´guiner, G. J. Org. Chem. 2002, 67,
8991–8994.
13. Concerning the use of this catalyst, see: (a) Hayashi, T.;
Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158–163; (b)
Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576,
254–278; (c) Sato, F.; Urabe, H.; Okamoto, S. Chem.
Rev. 2000, 100, 2835–2886.
7. Wittig, G.; Meyer, F. J.; Lange, G. Liebigs Ann. Chem.
1951, 571, 167–201.
8. (a) Seitz, L. M.; Brown, T. L. J. Am. Chem. Soc. 1966,
88, 4140–4147; (b) Coates, G. E.; Heslop, J. A. J. Chem.
Soc. (A) 1968, 514–518; (c) Thoennes, D.; Weiss, E.
Chem. Ber. 1978, 111, 3726–3731; (d) Greiser, T.; Kopf,
J.; Thoennes, D.; Weiss, E. Chem. Ber. 1981, 114, 209–
213; (e) Mulvey, R. E. Chem. Commun. 2001, 1049–1056.
9. (a) Ashby, E. C.; Chao, L.-C.; Laemmle, J. J. Org. Chem.
1974, 39, 3258–3263; (b) Kamienski, C. W.; Gastonia, N.
C.; Eastham, J. F. US Patent 3,847,883, 1974; Chem.
Abstr. 1975, 82, 58590; (c) Richey, H. G., Jr.; Farkas, J.,
Jr. Tetrahedron Lett. 1985, 26, 275–278; (d) Richey, H.
G., Jr.; Farkas, J., Jr. Organometallics 1990, 9, 1778–
1784; (e) Castaldi, G.; Borsotti, G. Eur. Pat. Appl. EP
491,326, 1992; Chem. Abstr. 1992, 117, 150667; (f)
Yasuda, M.; Ide, M.; Matsumoto, Y.; Nakata, M. Syn-
lett 1997, 899–902; (g) Yasuda, M.; Ide, M.; Matsumoto,
Y.; Nakata, M. Bull. Chem. Soc. Jpn. 1998, 71, 1417–
1429; (h) Ide, M.; Yasuda, M.; Nakata, M. Synlett 1998,
936–938; (i) Kitagawa, K.; Inoue, A.; Shinokubo, H.;
Oshima, K. Angew. Chem., Int. Ed. 2000, 39, 2481–2483;
(j) Iida, T.; Wada, T.; Mase, T. Japan Application No. JP
2000-024613 20000202, 2000; Chem. Abstr. 2001, 135,
152370; (k) Kondo, J.; Inoue, A.; Shinokubo, H.;
Oshima, K. Angew. Chem., Int. Ed. 2001, 40, 2085–2087;
1
14. Compound 2c: H NMR (CDCl3): 9.34 (d, 1H, J=2.2),
8.68 (d, 1H, J=8.3), 8.58 (d, 1H, J=2.2), 8.03 (d, 1H,
J=8.3), 7.79 (m, 2H), 7.75 (m, 2H), 7.46 (m, 1H). Com-
1
pound 2h: H NMR (CDCl3): 9.85 (d, 1H, J=1.0), 9.12
(d, 1H, J=1.0), 8.78 (d, 2H, J=1.5), 8.09 (d, 1H, J=8.0),
7.88 (d, 1H, J=7.0), 7.69 (m, 1H), 7.50 (m, 1H), 7.18 (m,
1H). Compound 2i: 1H NMR (CDCl3): 9.51 (d, 1H,
J=2.5), 9.14 (d, 1H, J=1.5), 8.73 (d, 1H, J=2.0), 8.66
(d, 1H, J=1.5), 8.55 (d, 1H, J=2.5), 8.10 (d, 1H, J=8.0),
7.89 (d, 1H, J=8.3), 7.75 (m, 1H), 7.55 (m, 1H). Com-
1
pound 6a: H NMR (CDCl3): 8.92 (d, 1H, J=4.3), 8.74
(d, 1H, J=4.5), 8.11 (d, 1H, J=8.5), 8.05 (d, 1H, J=8.5),
7.79 (t, 1H, J=7.6), 7.66 (t, 1H, J=7.2), 7.4 (m, 4H).
1
Compound 6b: H NMR (CDCl3): 8.93 (d, 1H, J=4.4),
8.82 (d, 1H, J=2.1), 8.12 (d, 1H, J=8.3), 8.02 (d, 1H,
J=7.8), 7.95 (dd, 1H, J=8.3, 2.4), 7.68 (m, 1H), 7.5 (m,
2H), 7.42 (d, 1H, J=4.4).
15. Fort, Y.; Becker, S.; Caube`re, P. Tetrahedron 1994, 50,
11893–11902.
16. Prepared using a published procedure: Grundmann, G.
Chem. Ber. 1948, 81, 7.
17. The physical and spectral data are analogous to those
obtained for a commercial sample.