Ortho-directed functionalization of arenes using magnesate bases

Article abstract of DOI:10.1039/c0cc01731k

Ortho-directed functionalisation of arenes using lithium alkylmagnesate bases were achieved, demonstrating the potential use of arylmagnesates as suitable arylanions, without a further transmetallation step, for challenging functionalizations such as fluorination, hydroxylation, arylation, vinylation and alkylation through epoxide ring-opening.

Full text of DOI:10.1039/c0cc01731k

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Ortho-directed functionalization of arenes using magnesate basesw
´ ´
Estelle Bellamy, Omar Bayh, Christophe Hoarau,* Francois Trecourt, Guy Queguiner and
Francis Marsais*
Received 3rd June 2010, Accepted 13th July 2010
DOI: 10.1039/c0cc01731k
Ortho-directed functionalisation of arenes using lithium alkyl-
magnesate bases were achieved, demonstrating the potential use
of arylmagnesates as suitable arylanions, without a further
transmetallation step, for challenging functionalizations
such as fluorination, hydroxylation, arylation, vinylation and
alkylation through epoxide ring-opening.
palladium-catalyzed cross-coupling processes without an additional
transmetallation step. We present here the ortho-magnesation of
aromatics using lithium tris- and (tetra)butylmagnesate bases7 and
the evaluation of the suitability of (aryl)magnesate complexes for
challenging functionalizations such as arylation, vinylation, epoxide
ring-opening, oxygenation and fluorination.
Initial investigations were focused on ortho-magnesation of
aromatics bearing electron-attractive ortho-directing groups. The
(40,40-dimethyloxazolin-2-yl)benzenes 1a–c were first treated with
Bu3MgLi (0.4 equiv.) at room temperature in THF over a 2 h
period, and the complete magnesation was further indicated by a
subsequent trapping with iodine leading to the ortho-iodo
derivatives 2a–c in fair to good yields (Table 1, entries 1–3).
Therefore, the second order Bu4MgLi2 (0.55 equiv.) was only
suitable for magnesation of both N-tert-butylbenzamide 1d–f and
N-cumylbenzamide 1g–i at room temperature and subsequent
Deprotonative metallation of aromatics has been widely used
as a powerful method for regioselective functionalization.1a,b
Ortho-lithiation using alkyllithium and lithium amide bases
has been extensively developed since lithiated species display
a high reactivity towards many electrophiles, leading to various
substitutions (e.g. halogenation, carboxylation, acylation,
hydroxymethylation, aminomethylation, sulfuration, oxygenation).
However aryllithiums can rarely be directly involved in
transition metal cross-coupling reactions and are usually
transformed in organometallic fragments suitable for standard
Negishi, Stille, Suzuki-Miyaura and Hiyama reactions.1c
Over the past decade, two main complementary alternatives
for ortho-directed functionalization of aromatics have started to
grow through the development of transition metal-catalyzed
chelated-assisted functionalization of aromatics methodologies,2
and the use of a new class of metalating agent for regio and/or
chemoselective deprotonative metallation of aromatics in smooth
reaction conditions, e.g. at room temperature (Scheme 1).
Indeed, since Eaton’s pioneering chemoselective deprotonation
of benzoate using magnesium amides (TMP2Mg; TMP =
2,2,6,6-tetramethylpiperidyl),3 various combinations of organo-
metallic compounds with alkali and/or N,N,N0,N0-tetramethylene-
diamine (TMEDA) additives including -ate complexes4
have been proposed such as R2Zn(TMP)Li.TMEDA (R =
tBu, Et, Bu),4,5a–b iBu3Al(TMP)Li,4,5c (Me3SiCH2)2Mn(TMP)-
Li.TMEDA,5d (TMP)2Zn.2MgCl2.2LiCl,5e MeCu(TMP)(CN)-
Li2,5f (TMP)3CdLi,5g Al(TMP)3ꢀ3LiCl,5h (TMP)2CuLi.5i We
recently successfully investigated the magnesation of azines
and azoles through the use of lithium tris- and tetra(alkyl)-
magnesates (Bu3MgLi and Bu4MgLi2), (alky)(amido)magnesates
(Bu2(TMP)MgLi, Bu(TMP)2MgLi) and tris- and (tetra)amido-
magnesate (TMP)3MgLi and (TMP)4MgLi2) bases,4,6 thus
demonstrating that heteroarylmagnesate complexes generated
in smooth conditions display a high nucleophilic character in
electrophilic trapping reactions and are suitable in nickel- and
Scheme 1 Directed metal-assisted C–H bond transformation
Table 1 Magnesation-iodination reactions from (oxazolinyl)benzene,
N-protected benzamides, aniline and anisolea
Base
(equiv.)
Yield %b
(%)c
Product
Entry Substrate
R
1
2
3
H
Cl
OMe 1c
1a Bu3MgLi
(0.4)
1b
2a 75 (90)
2b 68 (92)
2c 71 (93)
4
5
6
H
Cl
OMe 1f
1d Bu4MgLi2
(0.55)
1e
2d 82 (95)
2e 76 (97)
2f 84 (100)
7
8
9
H
Cl
OMe 1i
1g Bu4MgLi2
(0.55)
1h
2g 88 (98)
2h 82 (100)
2i 87 (97)
Bu4MgLi2
(1)
10
H
1k
2k 70d (73)d
´
Institut de Chimie Organique Fine associee au CNRS (UMR 6014),
11
12
H
OMe 1m
1l Bu4MgLi2
(0.3)
2l 75d
2m 91d
INSA et Universite´ de Rouen, Place Emile Blondel, BP08 76131,
Mont Saint Aignan, France. E-mail: christophe.hoarau@insa-rouen.fr,
francis.marsais@insa-rouen.fr; Fax: 0235522962; Tel: 0235522401,
0232956608
w Electronic supplementary information (ESI) available: General
information, experimental procedures and characterisation data. See
http://dx.doi.org/10.1039/c0cc01731k/
a
Conditions: substrate (1 equiv.), Bu3MgLi or Bu4MgLi2, r.t, 2 h then
b
I2, (1.1–4 equiv.), 2 h. Yield of isolated product. NMR yield of
c
d
deuteration with D2O. Reflux, 2 h.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7043–7045 7043

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Table 2 Evaluation of arylmagnesate complexes generated by deprotonation towards unusual electrophiles and in cross-coupling reactionsa
Product
Product
Product
Entry
1
Yield (%)b
Entry
11
Yield (%)b
Entry
21
Yield (%)b
3a
5a
55
5b
4d
52
8c
23
69
2
52
12
41
22
9d
3
4
4a
4b
40
53
13
14
6b
7b
42
67
23
24
3d
5d
57
51
5
6a
62
15
9b
59
25
7d
66
6
7
7a
9a
66c
43d
16
17
9c
8b
65
37
26
27
8d
9e
38
15
8
9
8a
55
18
3c
61
28
3e
50
3b
4c
42
36
19
20
5c
7c
58
67
29
30
8e
9f
42
10
n.r.
a
Conditions: preliminary ortho-magnesation step was achieved by treatment with magnesate bases under the optimized conditions depicted in Table 1
and subsequent ortho-functionalization was carried out through the following treatments: Exp. A: Methyloxirane (1.1–1.25 equiv.), 2 h, r.t.; Exp. B:
PdCl2dppf (5 mol%), iodopyridine or bromoquinoline (1.1–1.25 equiv.). Exp. C: PdCl2dppf (5 mol%), 1-methylbromoethene (1.1–1.25 equiv.). Exp. D:
b
c
d
Dry O2 bubbling, 15 min. Exp. E: NFSi (2 equiv.). Isolated yield. NMR yield. The 2-Bromo(oxazolin-2-yl)benzene was also isolated (o10%).
trapping with iodine afforded the ortho-iodo derivatives 2d–i in
high yields (entries 4–9). Interestingly, the magnesation of the
electron-rich N-pivaloylaniline 1k could also be achieved, but it
required the use of a large excess of Bu4MgLi2 (1 equiv.) along
with a 2 h refluxing period of the mixture, and the subsequent
treatment with iodine afforded the iodopivaloylaniline 2k, albeit
in a more moderate 66% yield (entry 10). Similarly, the electron-
rich anisoles 1l–m were also magnesated over a 2 h refluxing
period by treatment with Bu4MgLi2 (0.3 equiv.) and the sub-
sequent trapping with iodine thus provided the iodoanisoles 2l–m
c
7044 Chem. Commun., 2010, 46, 7043–7045
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in slightly better 75% and 91% yields. With magnesation
procedures under control, we next evaluated arylmagnesate
intermediates as arylanions for the preparation of functionalized
arenes through magnesation-trapping or cross-coupling reactions
(Table 2, experiences A–E). Lewis acid- and copper-mediated
processes are generally employed for clean epoxide ring-opening
arylithiums and Grignards reagents respectively.8 Interestingly all
magnesation-trapping sequences using 1-methyldioxirane as
electrophile from oxazolinylbenzene 1a, N-tert-butyl and cumyl-
benzamide 1d, 1g, pivaloylaniline 1k and anisole 1l led to the
isolation of the corresponding alcohols (3a–e), formed exclusively
from the selective opening at the less steric hindered site, in fair
42 to 55% yields (Table 2, entries 1,9,18,23,28). The oxidation of
monometallic aryl lithium and aryl magnesium reagents is
especially challenging, notably when using molecular oxygen.9
When the arylmagnesate intermediates generated from the ortho-
magnesation of oxazolinylbenzene 1a, N-tert-butyl 1d, pivaloyl-
aniline 1k and anisole 1l were exposed to molecular oxygen, the
phenols 8a–e were isolated in fair yields (entries 8,17,21,26,29).
Only the cumylbenzamide 1g was oxidized in a slightly moderate
23% yield (entry 21). This procedure represents one of the most
versatile routes toward functionalized phenols.10 In spite of the
latent metal-exchange reaction between the arylmagnesate and
electrophile which represents the most competitive side-reaction,
representative ortho-heteroarylations (entries 2–5,10–13, 19, 24)
of four arene-class were next successfully executed through a
magnesation-cross-coupling sequence with 2-bromo- and 3-iodo-
pyridines or 3-bromoquinoline as electrophiles affording the
corresponding arylated heterocycles 4a–d, 5a–d, 6a–b in
moderate to good yields (36–67%). The reaction failed only
when starting with the pivaloylaniline 1k, mainly due to the
excessive amount of base used for the magnesation. The ortho-
vinylation reactions (entries 6,14,20,25) with 1-methyl-
bromoethene were also achieved, providing vinylated arenes
7a–d in good yields. At the last stage of the study, the ortho-
magnesates arenes were trapped at room temperature with
N-fluorobenzenesulfonimide (NFSi) reagent which displays a
fair reactivity towards highly reactive aryllithiums.11 Except for
anisole 1l and pivalolyaniline 1k, the ortho-magnesation-NFSi
trapping sequence of arenes (entries 7, 15, 16, 22) were success-
fully realized leading to fluoroarenes 9a–d in a range of 43–69%
yields. To our knowledge we described here the first examples of
fluorination of arylate intermediates and this new procedure
gives a novel convenient synthesis of fluoroarenes.
Notes and references
1 For reviews: (a) V. Snieckus, Chem. Rev., 1990, 90, 879–933;
(b) M. Schlosser, Angew. Chem., Int. Ed., 2005, 44, 376–393;
(c) Metal-Catalyzed Cross-coupling Reactions, ed. F. Diederich
and A. de Meijere, Whiley-VCH, Weinheim, 2nd edn, 2004.
2 For recent reviews: (a) V. Ritleng, C. Sirlin and M. Pfeffer, Chem.
Rev., 2002, 102, 1731–1769; (b) F. Kakiuchi and N. Chatani, Adv.
Synth. Catal., 2003, 345, 1077–1101; (c) A. R. Dick and
M. S. Sanford, Tetrahedron, 2006, 62, 2439–2463;
(d) M. Catellani, E. Motti, N. Della Ca’ and R. Ferraccioli, Eur.
J. Org. Chem., 2007, 4153–4165; (e) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174–238; (f) L. Ackermann
and N. Chatani, Directed Metallation, in Topics in Organo-
metallic Chemistry, ed. N. Chatani, Springer-Verlag, Berlin,
2007, vol. 24; (g) F. Kakiuchi and T. Kochi, Synthesis, 2008,
3013–3039; (h) X. Chen, K. M., D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094–5115.
3 P. E. Eaton, C.-H. Lee and Y. Xiong, J. Am. Chem. Soc., 1989,
111, 8016–8018.
4 For review: R. E. Mulvey, F. Mongin, M. Uchiyama and
Y. Kondo, Angew. Chem., Int. Ed., 2007, 46, 3802–3824.
5 (a) Y. Kondo, M. Shilai, U. Uchiyama and T. Sakamoto, J. Am.
Chem. Soc., 1999, 121, 3539–3540; (b) M. Uchiyama,
Y. Kobayashi, T. Furuyama, S. Nakamura, Y. Kajihara,
T. Miyoshi, T. Sakamoto, Y. Kondo and K. Morokuma, J. Am.
Chem. Soc., 2008, 130, 472–480; (c) H. Naka, M. Uchiyama,
Y. Matsumoto, A. E. H. Wheatley, M. McPartlin, J. V. Morey
and Y. Kondo, J. Am. Chem. Soc., 2007, 129, 1921–1930;
(d) J. Garcia-Alvarez, A. R. Kennedy, J. Klett and
R. E. Mulvey, Angew. Chem., Int. Ed., 2007, 46, 1105–1108;
(e) S. H. Wunderlich and P. Knochel, Angew. Chem., Int. Ed.,
2007, 46, 7685–7688; (f) S. Usui, Y. Hashimoto, J. V. Morey,
A. E. H. Wheatley and M. Uchiyama, J. Am. Chem. Soc., 2007,
129, 15102–15103; (g) J.-M. L’Helgoual’ch, G. Bentabed-
Ababsa, F. Chevallier, M. Yonehara, M. Uchiyama,
A. Derchour and F. Mongin, Chem. Commun., 2008, 5375–5377;
(h) S. H. Wunderlich and P. Knochel, Angew. Chem., Int. Ed.,
2009, 48, 1501–1504; (i) T. T. Nguyen, F. Chevalier, V. Jouikov
and F. Mongin, Tetrahedron Lett., 2009, 50, 6787–6790.
´ ´
6 H. Hawad, O. Bayh, C. Hoarau, F. Trecourt, G. Queguiner and
F. Marsais, Tetrahedron, 2008, 64, 3236–3245.
7 Castaldi and Borsotti reported the unique use of a magnesate base
for deprotonation of (trifluoromethyl)benzenes: G. Castaldi,
G. Borsotti, Eur. Patent 491326A2, 1992 [Chem. Abstr. 1992,
117, 150667].
8 For examples of ring-opening of epoxide with organolithiums,
magnesium, copper and zincate: (a) N. G. Gaylord and
E. I. Becker, Chem. Rev., 1951, 49, 413; (b) C. Huynh,
F. Derguini-Boumechal and G. Linstrumelle, Tetrahedron Lett.,
1979, 20, 1503–1506; (c) M. J. Eis, J. E. Wrobel and B. Ganem,
J. Am. Chem. Soc., 1984, 106, 3693–3994; (d) A. Alexakis,
D. Jachiet and J. F. Normant, Tetrahedron, 1986, 42, 5607–5619;
(e) M. Uchiyama, M. Kameda, O. Mishima, N. Yokoyama,
M. Koike, Y. Kondo and T. Sakamoto, J. Am. Chem. Soc.,
1998, 120, 4934–4946; (f) B.-S. Kwon and J. Tae, Heterocycles,
2004, 62, 137–141.
In summary, we report here a highly efficient novel procedure
for the ortho-magnesation of the five main arene classes using
readily available and safe Bu3MgLi and Bu4MgLi2 magnesate
bases. The generated arylcomplexes are suitable for general access
to a wide variety of functionalized arenes, thus giving a particular
interest in this procedure by contrast to chelated-assisted direct
C–H catalytic functionalization methodologies that are focused
on one type of substitution. Notably, the lithium arylmagnesate
intermediates react in challenging electrophile-trapping as well as
in cross-coupling reactions without any further transmetallation-
assisted enhanced reactivity steps, thus allowing the introduction
of hydroxy, fluoro, hydroxyethyl, aryl and vinyl groups on the
arenes. Challenging structural determinations of generated
arylamagnesates complexes4,12 are under progress to highlight
the important variation of reactivity sometimes observed.
9 For examples of hydroxylation of organolithium and magnesium,
using molecular oxygen: (a) C. Walling and S. A. Buckler, J. Am.
Chem. Soc., 1955, 77, 6032–6033; (b) K. A. Parker and
K. A. Koziski, J. Org. Chem., 1987, 52, 674–676.
10 Kondo and Uchiyama recently claimed two examples of ortho-
directed alumination5b and cupratation5e of N,N-diisopropyl-
benzamide followed by molecular oxygen trapping employing
ZnCl2 and CuCN additives.
11 (a) V. Snieckus, F. Beaulieu, K. Mohri, W. Han, C. K. Murphy
and F. A. Davis, Tetrahedron Lett., 1994, 35, 3465–3468;
(b) F. A. Davis, W. Han and C. K. Murphy, J. Org. Chem.,
1995, 60, 4730–4737.
12 (a) K. M. Waggoner and P. P. Power, Organometallics, 1992, 11,
3209–3214; (b) R. E. Mulvey, Chem. Commun., 2001, 1049–1056
and references cited; (c) R. E. Mulvey, Organometallics, 2006, 25,
1060–1075; (d) P. C. Andrikopoulos, D. Armstrong,
A. R. Kennedy, R. E. Mulvey, C. T. O’Hara, R. B. Rowlings
and S. Weatherstone, Inorg. Chim. Acta, 2007, 360, 1370–1375.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7043–7045 7045