Iron-catalysed arylation of heteroaryl halides by Grignard reagents

Article abstract of DOI:10.1016/S0040-4039(02)00568-3

Cross-coupling reaction of phenylmagnesium bromide with heteroaryl halides, in the presence of a catalytic amount of iron salts, is reported. Yields are moderate to good, and it is worth noting that this reaction has been applied to non-activate heteroaryl halides.

Full text of DOI:10.1016/S0040-4039(02)00568-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3547–3549
Iron-catalysed arylation of heteroaryl halides by Grignard
reagents
Je´roˆme Quintin, Xavier Franck, Reynald Hocquemiller and Bruno Figade`re*
Laboratoire de Pharmacognosie, associe´ au CNRS (BIOCIS), Universite´ Paris-Sud, Faculte´ de Pharmacie,
rue Jean-Baptiste Cle´ment, 92296 Chaˆtenay-Malabry, France
Accepted 20 March 2002
Abstract—Cross-coupling reaction of phenylmagnesium bromide with heteroaryl halides, in the presence of a catalytic amount of
iron salts, is reported. Yields are moderate to good, and it is worth noting that this reaction has been applied to non-activate
heteroaryl halides. © 2002 Elsevier Science Ltd. All rights reserved.
Several 2-alkyl-, 2-alkenyl-, and 2-phenylquinolines, the
chimanines have been isolated from a Bolivian plant,
Galipea longiflora,1 and have shown very promising in
vitro activity against several leishmania strains.2 Few of
them have shown in vivo, through oral administration,
leismanicide properties.3 Activity against Plasmodium
vinckei petteri was also observed for some of them.4 We
have been involved in establishing a structure–activity
relationship based on the nature of the chain branched
at the 2 position of quinoline, and recently reported the
cross-coupling reactions between multicomponent Grig-
nard reagents with N-oxycarbonylisobutyloxyquinolin-
ium chloride at low temperature to afford the desired
2-alkylquinolines in good yields.5 Next we reported the
iron-catalysed Grignard reduction-coupling reactions of
1,1-dibromo-2-(2-quinolyl)ethylene to afford 2-alkenyl
quinolines.6 To study the influence of the substitution
position on the quinoline nucleus we prepared 3-
phenylquinoline 2a in 35% yield by coupling reaction of
phenyl Grignard with 3-bromoquinoline 1a in the pres-
ence of 5% M Fe(acac)3.7 It is worth noting that this
was the first reported coupling reaction between a
heteroaryl bromide and a Grignard reagent catalysed
by an iron salt.8
non-toxic iron salts is particularly attractive in this
field. Since our first report on the preparation of 3-
phenylquinoline 2a by coupling reaction between
phenyl-Grignard and 3-bromoquinoline 1a in the pres-
ence of Fe(acac)3, in a 1:1 mixture of THF/NMP, we
have re-examined the reaction conditions in order to
improve the yield, and the results are summarised in
Table 1. We first studied the influence of the solvent on
the coupling of 2.2 equiv. of phenylmagnesium bromide
to 3-bromoquinoline 1a in the presence of 10% M
Fe(acac)3, and found that mixing more polar solvents
(entries 1–6) or less polar solvents (entries 7 and 8) into
the THF solution of 1a did not allow us to increase the
yield of 3-phenylquinoline 2a, compared to the reaction
run in THF alone (entry 9). This finding highlighted
that this coupling reaction can be performed in THF
alone (contrary to precedent reports6,8,9). Addition of
NMP or other co-solvents, did not improve the yield
but had a negative effect on the cross-coupling reaction.
Then we checked the temperature effect (entries 9–14)
and found that the best result (46%) was obtained at
−30°C in 1 h. The remaining mass balance was com-
posed of the starting material 1a (16%) and the reduced
quinoline 3a (33%) (Scheme 1). After a prolonged reac-
tion time (e.g. 3 or 20 h) the yield did not increase
significantly, and adding some more catalyst during the
reaction did not improve the result (results not shown).
Finally, the desired 3-phenylquinoline 2a was obtained
after purification by flash chromatography on silica gel
in 45% isolated yield11 after 1 h at −30°C. When
DMPU was used in equimolar quantity with 1a, the
yield was similar to the yield in THF alone (48%, entry
16, compare with entry 9). With only 1 equiv. of NMP,
the yield decreased (29%, entry 15). We then tried to
Then Fu¨rstner very recently reported the iron-catalysed
reaction of alkyl-Grignard reagents with aryl chlorides,9
and this prompted us to disclose our own results in this
area. The aryl–aryl cross-coupling reaction is an
extremely important reaction, and is usually catalysed
by palladium or nickel complexes.10 The use of cheap,
* Corresponding author. Fax: (33) (0)146835399; e-mail:
bruno.figadere@cep.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00568-3

3548
J. Quintin et al. / Tetrahedron Letters 43 (2002) 3547–3549
Table 1. Addition of 2 equiv. of PhMgBr to 3-bromoquinoline 1a to afford 3-phenylquinoline 2a
Entry
Cat. (10%)
Solvent
Additive (equiv.)
Temp. (°C)
Yielda (2a)
1a/3a
1
2
3
4
5
6
7
8
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeCl3
THF/NMP
THF/TMEDA
THF/sulfolane
THF/dioxane
THF/DMSO
THF/DMPU
Et2O
THF/toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
None
None
None
None
None
None
None
None
None
None
None
None
None
None
NMP (1)
DMPU (1)
CH3CN (1)
Bipyr (0.1)
Bipyr (0.3)
Me2S (1)
Ph3P (0.5)
MnCl2 (0.2)
ZnCl2 (0.2)
CuCN (0.2)
None
−10
−30
−30
−30
−30
−30
−30
−30
−30
−20
−10
0
35b
29
36
29
8
ND
38/25
30/24
51/15
61/20
63/24
37/8
50/15
16/33
24/26
30/23
16/30
1/38
13
8
16
46 [45]b
37
32
32
34
41
29
48
16
40
4
47
38
9
8
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Rt
−78
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
3/40
49/19
18/42
26/43
10/50
83/5
12/41
35/23
66/19
75/6
73/13
72/7
64/7
5
9
38
FeCl2
Co(acac)2
None
None
THF
25/18
a GC yields % (after 1 h) with tetradecane as internal reference.
b Isolated yield; ND: not determined.
Scheme 1.
the desired 2-phenylquinoline 2b was obtained in 65%
isolated yield.11 Again it is interesting to note that 2b
was obtained by the palladium-catalyzed cross-coupling
reaction of phenylboronic acid and 2-chloroquinoline
(reflux THF, 2 h, 67%).13 Next 2-bromopyridine 1c was
treated under the same reaction conditions, to afford
2-phenylpyridine 2c in 60% isolated yield.14 Finally,
3-methyl-2-bromopyridine 1d led, under the same reac-
tion conditions, to 3-methyl-2-phenylpyridine 2d in 66%
isolated yield.14 In this example, it is noteworthy that
ortho substitution on the aryl halide did not affect the
yield.
add some additive that could stabilise the low valent
intermediate organoiron species (entries 17–21). We
could never increase the yields but in the presence of
either 0.1 equiv. of 2,2%-bipyridine or 1 equiv. of
dimethylsulfide, 2a was obtained in similar yields to
THF alone (40 and 47% yield, respectively). Adding
some co-catalyst (such as MnCl2, ZnCl2, CuCN) did
not increase the yields but had a negative effect (entries
22–24). Surprisingly, FeCl3 and FeCl2 did not give the
desired product in reasonable yields (entries 25 and 26).
These results might be due to low solubility of these
salts in THF at −30°C. However, Co(acac)2 allowed us
to obtain 3-phenylquinoline 2a in 38% yield (entry 27).
It is worthy of note that without any catalyst, no
reaction occurred. It is interesting to note that our
coupling reaction compares favourably with the nickel-
catalysed reaction of heteroaryl-Grignard reagents with
3-bromoquinoline (reflux THF, 20 h, 44–57%).12 We
then applied this reaction to the cross-coupling of
phenylmagnesium bromide with several heteroaryl
halides (Scheme 2). When 2-chloroquinoline 1b was
treated with phenyl-Grignard in THF at −30°C for 1 h,
In conclusion we report the first aryl–aryl cross-cou-
pling reaction between phenyl-Grignard reagent and
heteroaryl halides in the presence of iron salts with
moderate to good yields. The reaction conditions are
mild (THF, −30°C), which allows one to use a large
variety of such organometallic species easily prepared
by halogen–metal exchange.15 Furthermore, the use of
cheap and friendly iron catalysts favourably competes
with nickel and palladium catalysis, and will probably

J. Quintin et al. / Tetrahedron Letters 43 (2002) 3547–3549
3549
Scheme 2.
find industrial applications. We are now applying this
procedure to the preparation of compounds of biologi-
cal interest and the results will be reported elsewhere.
54, 263–303; (b) Milstein, D.; Stille, J. K. J. Am. Chem.
Soc. 1979, 101, 4992–4998; (c) Miyaura, N.; Yanagi, T.;
Suzuki, A. Synth. Commun. 1981, 11, 513–519; (d)
Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821–1823; (e) Riguet, E.; Alami, A.; Cahiez, G.
Tetrahedron Lett. 1997, 38, 4397–4400; (f) Riguet, E.;
Alami, A.; Cahiez, G. J. Organomet. Chem. 2001, 624,
376–379; (g) Miller, J. A.; Farrell, R. P. Tetrahedron Lett.
1998, 39, 6441–6444; (h) Miller, J. A. Tetrahedron Lett.
2001, 42, 6991–6993; (i) Massicot, F.; Schneider, R.; Fort,
Y.; Illy-Cherrey, S.; Tillement, O. Tetrahedron 2001, 57,
531–536; (j) Hassan, J.; Hathroubi, C.; Gozzi, C.;
Lemaire, M. Tetrahedron 2001, 57, 7845–7855; (k) Legall,
E.; Gosmini, C.; Ne´de´lec, J. Y.; Pe´richon, J. Tetrahedron
2001, 57, 1923–1927; (l) Feuerstein, M.; Doucet, H.;
Santelli, M. Tetrahedron Lett. 2001, 42, 5659–5662; (m)
Bonnet, V.; Queguiner, G.; Knochel, P. Tetrahedron Lett.
2001, 42, 5717–5719.
Acknowledgements
We gratefully acknowledge J.-C. Jullian for NMR
experiments, Dr. M. A. Fakhfakh for preliminary stud-
ies, Dr. A Fournet for his interest in this study and Dr.
M. Alami for friendly and fruitful discussions.
References
1. Fournet, A.; Hocquemiller, R.; Roblot, F.; Cave´, A.;
Richomme, P.; Bruneton, J. J. Nat. Prod. 1993, 56,
1547–1553.
2. Fournet, A.; Barrios, A. A.; Munoz, V.; Hocquemiller,
R.; Cave´, A.; Bruneton, J. Antimicrob. Agents Chemother.
1993, 37, 859–863.
3. Fournet, A.; Ferreira, M. E.; Rojas de Arias, A.; Torres
de Ortiz, S.; Fuentes, S.; Nakayama, H.; Schivivi, A.
Antimicrob. Agents Chemother. 1996, 40, 2447–2451.
4. Gantier, J. C.; Fournet, A.; Munos, M. H.; Hoc-
quemiller, R. Planta Med. 1996, 62, 285–286.
5. Fakhfakh, M. A.; Franck, X.; Fournet, A.; Hoc-
quemiller, R.; Figade`re, B. Tetrahedron Lett. 2001, 42,
3847–3850.
6. Fakhfakh, M. A.; Franck, X.; Hocquemiller, R.;
Figade`re, B. J. Organomet. Chem. 2001, 624, 131–135.
7. (a) Fakhfakh, M. A. PhD Thesis, Universite´ Paris-Sud,
2001; (b) Fakhfakh, M. A.; Franck, X.; Fournet, A.;
Hocquemiller, R.; Figade`re, B. Synth. Commun. 2002, 32,
in press.
1
11. 3-Phenylquinoline 2a: H NMR (200 MHz, l ppm) 7.49
(m, 4H), 7.71 (m, 3H), 7.84 (d, J=8.0 Hz, 1H), 8.16 (d,
J=8.9 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.1
Hz, 1H); 13C NMR (50 MHz, l ppm) 126.49, 126.89,
127.62, 128.68, 128.89, 132.62, 133.23, 137.26, 146.84,
149.33; ESI-MS (m/z) 228 (M+Na+, 30), 206 (MH+, 100);
1
2-phenylquinoline 2b: H NMR (200 MHz, l ppm) 7.53
(m, 4H), 7.76 (m, 2H), 8.09 (d, J=8.6 Hz, 1H), 8.23 (m,
2H), 8.28 (d, J=8.6 Hz, 1H); 13C NMR (50 MHz, l
ppm) 118.60, 125.96, 126.90, 127.22, 127.31, 128.57,
129.07, 129.36, 129.47, 136.44, 139.36, 148.03, 156.93;
ESI-MS (m/z) 206 (MH+, 100).
12. Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.;
Minato, A.; Suzuki, K. Tetrahedron 1982, 38, 3347–3354.
13. Ciufolini, M. A.; Mitchell, J. W.; Roschangar, F. Tetra-
hedron Lett. 1996, 37, 8281–8284.
14. Parish, R. V.; Wright, J. P.; Pritchard, R. G. J.
Organomet. Chem. 2000, 596, 165–176.
15. (a) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel,
P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701; (b)
Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319.
8. (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199–1205;
(b) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351–360.
9. Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41,
609–612.
10. Aryl–aryl coupling: (a) Stanford, S. P. Tetrahedron 1998,