Magnesiation of electron-rich aryl bromides and their use in nickel-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ol070841b

Electron-rich aryl bromides are rapidly converted to the corresponding lithium triarylmagnesiates with (n-Bu)₃MgLi, which undergo efficient nickel-catalyzed Kumada-Corriu cross-coupling reactions with a variety of aryl and alkenyl bromides, chlorides, tosylates, and triflates.

Full text of DOI:10.1021/ol070841b

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2239-2242
Magnesiation of Electron-Rich Aryl
Bromides and Their Use in
Nickel-Catalyzed Cross-Coupling
Reactions
Stephen Y. W. Lau,*,† Greg Hughes,† Paul D. O’Shea,† and Ian W. Davies‡
Department of Process Research, Merck Frosst Centre for Therapeutic Research,
16711 Trans Canada Highway, Kirkland, QC, Canada H9H 3L1, and
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
stephen_lau@merck.com
Received April 10, 2007
ABSTRACT
Electron-rich aryl bromides are rapidly converted to the corresponding lithium triarylmagnesiates with (n-Bu)3MgLi, which undergo efficient
nickel-catalyzed Kumada Corriu cross-coupling reactions with a variety of aryl and alkenyl bromides, chlorides, tosylates, and triflates.
−
The Kumada-Corriu cross-coupling reaction between Grig-
nard reagents and alkenyl or aryl halides in the presence of
nickel-phosphine catalysts is a simple, yet powerful method
of direct cross-coupling.1 While other cross-coupling reac-
tions catalyzed mainly by palladium have become increas-
ingly popular, nickel is much less expensive than palladium2
and the nickel-catalyzed Kumada-Corriu coupling is still
an effective reaction for substrates whose functional groups
are compatible with Grignard reagents. With the ever-
increasing diversity of natural products and active pharma-
ceutical ingredients, there is a demand for access to a variety
of non-commercially available Grignard reagents, which may
be synthesized via direct magnesium insertion or through
halogen-magnesium exchange reactions between alkyl
Grignards and aryl and alkenyl halides. However, a major
drawback is that such reactions on electron-rich aryl halides
are not trivial and indeed can be quite challenging on some
substrates. In some instances, lithium-halogen exchange can
also be used to activate the carbon-halogen bond. However,
we have found that the corresponding organolithium species
are often thermally unstable, requiring the use of cryogenic
conditions which can become problematic during scale-up.
Recently, we wanted to investigate the use of electron-
rich aryl bromide 1 in Kumada-Corriu couplings by making
the corresponding organomagnesium reagent. However,
direct Mg insertion attempts or halogen-magnesium ex-
change with i-PrMgCl3 or i-PrMgCl‚LiCl4 failed in our
hands. Magnesiation5 with (s-Bu)2Mg‚LiCl6 proceeded but
required long reaction times (12 h) to obtain complete
(3) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302. (b) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V.
A.; Knochel, P. Synthesis 2002, 565.
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Research Laboratories.
(1) (a) Tamao, K.; Sumitani, M.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun.
1972, 144. (c) For a recent retrospective, see: Tamao, K. J. Organomet.
Chem. 2002, 653, 23.
(2) For example, 98% NiCl2 is ca. $69/mol ($133/250 g) while 99%
PdCl2 is ca. $6800/mol ($5780/150 g). Prices listed are in Canadian dollars.
Source: www.sigmaaldrich.com.
(4) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(5) First magnesiate synthesis: Wittig, G.; Meyer, F. J.; Lange, G. Liebigs
Ann. Chem. 1951, 571, 167. Representative structural studies: (a) Seitz, L.
M.; Brown, T. L. J. Am. Chem. Soc. 1966, 88, 4140. (b) Coates, G. E.;
Heslop, J. A. J. Chem. Soc. A 1968, 514. (c) Squiller, E. P.; Whittle, R. R.;
Richey, H. G., Jr. J. Am. Chem. Soc. 1985, 107, 432. (d) Wagonner, K.
M.; Power, P. P. Organometallics 1992, 11, 3209.
10.1021/ol070841b CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/05/2007

magnesiation. Thus, we decided to turn our attention to the
use of the lithium trialkylmagnesiate reagent (n-Bu)3MgLi.7
Use of 0.4 equiv of (n-Bu)3MgLi (1.2 equiv of Bu-) at 0 °C
led to rapid and efficient bromine-magnesium exchange8
to afford the lithium triarylmagnesiate 2 as evidenced by the
disappearance of 1 via LC or GC-MS, whereupon a 1 M
HCl quench gave the protonated species 3 (Scheme 1).9
5 as an electron-rich aryl bromide model system to compare
standard methods of organomagnesium formation with
magnesiation with (n-Bu)3MgLi. As shown in Table 1,
Table 1. Metalation of 4-Bromoanisole
Scheme 1. Magnesiation with (n-Bu)3MgLi
entry
conditions
time
conversion
1
2
3
4
5
Mg, I2 (cat.), THF, reflux
i-PrMgCl, THF, 0 °C to rt
i-PrMgCl‚LiCl, THF, 0 °C to rt 48 h
(s-Bu)2Mg‚LiCl, THF, rt
(n-Bu)3MgLi, THF, 0 °C
24-48 h
48 h
100%
NR
NR
100%
100%
8 h
<5 min
magnesiation with (n-Bu)3MgLi resulted in vastly superior
reaction times compared to direct Mg insertion or magne-
siation with (s-Bu)2Mg‚LiCl. Magnesium exchange reactions
with i-PrMgCl or i-PrMgCl‚LiCl did not proceed in our
hands.
With an efficient means of obtaining electron-rich lithium
triarylmagnesiates, we then went on to investigate the scope
of Ni-catalyzed Kumada-Corriu couplings of lithium tri-
arylmagnesiates. A variety of Ni catalysts were evaluated,
the results of which are summarized in Table 2. When no
The palladium-catalyzed cross-coupling of lithium triaryl-
magnesiates with aryl bromides has been reported9l by
Mongin and co-workers, for example, between the lithium
triarylmagnesiate derived from 3-bromoquinoline and 2-bro-
mopyridine, using 5 mol % of Pd(dba)2 and dppf to give the
cross-coupled biaryl in 56% yield. It was reported that nickel-
catalyzed cross-couplings were unsuccessful with aryl bro-
mides and only gave low yields with aryl chlorides. However,
in our hands, when a solution of lithium tri-3-quinolylmag-
nesiate was added to a degassed THF solution containing
2-bromopyridine and 1 mol % of NiCl2‚dppp, the reaction
proceeded to give the desired biaryl system in 63% yield.
Similarly, when the lithium triarylmagnesiate 2 was added
to bromobenzene in degassed THF in the presence of 1 mol
% of NiCl2‚dppp, we observed rapid conversion to the
desired cross-coupled product 4 in good yield (Scheme 2).
Table 2. Catalyst Study Results
Scheme 2. Ni-Catalyzed Cross-Coupling
entry
catalyst
none
NiCl2‚(PPh3)2
NiCl2‚dppe
NiCl2‚dppp
NiI2‚dppp
NiCl2‚(PCy3)2
NiCl2‚dppp
Pd(PPh3)4
PdCl2‚dppb
PdCl2‚dppf
Co(acac)2
yield of 7
yield of 8
1
2
3
4
5
6
7a
8
9
10
11
NR
30%
50%
93%
39%
72%
82%
3%
10%
20%
NR
20%
12%
5%
13%
18%
15%
ND
4%
6%
-
a Grignard reagent 4-methoxymagnesium bromide used.
To explore the potential of the magnesiation/Ni-cata-
lyzed coupling procedure further, we used 4-bromoanisole
catalyst was employed, no reaction was observed and no
scrambling between 6 and bromobenzene occurred as
(6) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 159.
2240
Org. Lett., Vol. 9, No. 11, 2007

Table 3. 4-Bromoanisole Lithium Magnesiate Nickel-Catalyzed Cross-Coupling Results
determined by LC or GC-MS. With nickel-phosphine
catalysts, the reactivity followed the generally observed order
NiCl2‚dppp > NiCl2‚dppe > NiCl2(PPh3)2 as reported by
Kumada.1a Homocoupling of the magnesiate 6 forming 8 was
always observed in small amounts as a byproduct, as
explained by the catalytic cycle proposed by Kumada.1a
While the amount of 8 generated seemed to increase as the
cross-coupling activity of the catalyst decreased, more
importantly, the amount of 8 generated from coupling the
lithium triarylmagnesiate with use of NiCl2‚dppp was three
times less than the amount generated by using the corre-
sponding Grignard reagent (Table 2, entry 4 versus entry
7). Finally, as a further comparison, when Pd catalysts were
employed, isolated yields were low (Table 2, entries 8-10),
and no reaction was observed with Co(acac)2 (Table 2, entry
11).10
product, aryl and alkenyl chlorides gave yields that were
lower than those of the corresponding bromides (Table 3,
entries 1 and 7 versus entries 2 and 8), while phenyl tosy-
late (Table 3, entry 3) only gave 13% isolated yield. Less
than 10% of homocoupled product 8 was observed in all
cases.
Finally, a variety of aryl bromides, both electron-rich and
electron-poor, were subjected to the magnesiation and cross-
coupling reaction conditions. Results are summarized in
Table 4. Magnesiation and cross-coupling occurs quite
readily to give good yields of the desired coupled products.
In all cases, less than 10% of the homocoupled Ar-Ar was
formed with the exception of the electron-poor aryl bromide
1-bromo-4-(trifluoromethyl)benzene (Table 4, entry 8). While
magnesiation was still rapid, approximately 20% homo-
coupled product was obtained. However, this is likely a
consequence of the reactivity of electron-poor organomag-
nesium compounds and not the lithium magnesiate species
itself.11
With the optimal Ni catalyst, NiCl2‚dppp, in hand, a variety
of aryl and alkenyl bromides, chlorides, tosylates, and tri-
flates were coupled with the lithium magnesiate of 4-bro-
moanisole, the results of which are summarized in Table 3.
While all proceeded to give the desired cross-coupled
In summary, we have demonstrated that electron-rich aryl
bromides can undergo facile and efficient magnesiation with
Table 4. Lithium Magnesiate Nickel-Catalyzed Cross-Coupling Results
a As an inseparable 4:1 mixture of product:4,4′-bis(trifluoromethyl)biphenyl.
Org. Lett., Vol. 9, No. 11, 2007
2241

(n-Bu)3MgLi more rapidly than with previously reported
halogen-magnesium exchange reactions. The resulting
lithium triarylmagnesiates can undergo Kumada-Corriu
nickel-catalyzed cross-couplings with a variety of aryl and
alkenyl bromides, chlorides, or sulfonate esters in good
yields, building on the arsenal of cross-coupling methods
available.
(7) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001,
42, 4841.
(8) (a) Kitigawa, K.; Inoue, A.; Shinokobu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2000, 39, 2481. (b) Inoue, A.; Kitagawa, K.; Shinokobu,
H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
Acknowledgment. We thank Mr. Danny Gauvreau,
Process Research, Merck Frosst Centre for Therapeutic
Research, for providing bromide 1 and Dr. Wayne Mullett,
Process Research, Merck Frosst Centre for Therapeutic
Research, and Dr. Tom Novak, Process Research, Merck
Research Labs, for analytical support.
(9) For applications of trialkylmagnesiates, see also: (a) Dolman, S. J.;
Gosselin, F.; O’Shea, P. D.; Davies, I. W. Tetrahedron 2006, 62, 5092. (b)
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Supporting Information Available: General procedure
and spectral data for compounds 3, 4, 7, and 8 and all entries
in Tables 3 and 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL070841B
(10) For, cobalt-catalyzed cross-coupling reactions with Grignard,
reagents, see: (a) Kuno, A.; Saino, N.; Kamachi, T.; Okamoto, S.
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(11) The coupling of 4-(trifluoromethyl)phenylmagnesium bromide with
bromobenzene gave similar results (68% yield, 3:1 product:Grignard
homocoupling) as entry 8 of Table 4. As expected, the Grignard reagent
gave more homocoupled product than the lithium triarylmagnesiate.
2242
Org. Lett., Vol. 9, No. 11, 2007