Nickel catalyzed cross-coupling of modified alkyl and alkenyl Grignard reagents with aryl- and heteroaryl nitriles: Activation of the C-CN bond

Article abstract of DOI:10.1016/S0040-4039(03)00075-3

The nickel catalyzed cross-coupling of alkyl and alkenyl Grignard reagents with aryl nitrile derivatives affords good yields of the corresponding aryl alkanes or aryl alkenes via activation of the C-CN bond. To prevent direct addition of the nucleophile to the nitrile group, the reactivity of the Grignard reagent was modulated by reaction with either LiOt-Bu or PhSLi prior to cross-coupling. The optimum catalyst was determined to be NiCl₂(PMe₃)₂, which is a convenient air stable commercially available complex.

Full text of DOI:10.1016/S0040-4039(03)00075-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1907–1910
Nickel catalyzed cross-coupling of modified alkyl and alkenyl
Grignard reagents with aryl- and heteroaryl nitriles: activation of
the CꢀCN bond
Joseph A. Miller and John W. Dankwardt*
DSM Pharmaceuticals, 5900 NW Greenville Blvd, Greenville, NC 27834, USA
Received 19 November 2002; revised 3 January 2003; accepted 7 January 2003
Abstract—The nickel catalyzed cross-coupling of alkyl and alkenyl Grignard reagents with aryl nitrile derivatives affords good
yields of the corresponding aryl alkanes or aryl alkenes via activation of the CꢀCN bond. To prevent direct addition of the
nucleophile to the nitrile group, the reactivity of the Grignard reagent was modulated by reaction with either LiOt-Bu or PhSLi
prior to cross-coupling. The optimum catalyst was determined to be NiCl (PMe ) , which is a convenient air stable commercially
2
3 2
available complex. © 2003 Published by Elsevier Science Ltd.
Transition-metal (usually as Pd(0) or Ni(0) complexes)
coupling reactions have taken a prominent role in the
formation of CꢀC bonds. The cross-coupling of
organozinc, organoborane, organomagnesium, and
organostanannes with aryl or alkenyl halides are all
this Ni-catalyzed coupling reaction to allow use of alkyl
and alkenyl Grignard reagents (RMgX/t-BuOLi or
PhSLi).
A survey of catalysts indicated that NiCl (PMe ) was
2
3 2
1
standard procedures in modern organic synthesis. In
generally superior to other Ni or Pd based catalyst
5,6
most cases the corresponding organohalide derivatives
are utilized as the coupling partner. Recently, efforts
have been made to expand the scope of the reaction
and substrates which were previously deemed unreac-
tive (e.g. aryl fluorides, carbamates, thioethers) have
now been found to be suitable in transition-metal cross-
systems. It is interesting to note that palladium cata-
lyst precursors (Pd(dba) , PMe ) could participate in
2
3
the cross-coupling of the nitrile substrates, however, the
yields were too low for the reaction to have any syn-
thetic value. For example, under the Pd(0) conditions
described above, the reaction of 4-methoxybenzonitrile
and 1-propenyl magnesium tert-butoxide provided a
small amount (8/1 mixture of 1a and 3a) of the cross-
coupling product 3a.
2
coupling procedures. Interestingly, the activation of
the CꢀCN bond of benzonitriles using nickel catalysis
3
has been previously described. However, until our
recent disclosure, this CꢀC bond cleavage reaction had
not been exploited in a synthetically useful fashion. We
reported last year that the NiCl (PMe ) mediated
The synthetic scope of the cross-coupling of various
benzonitriles with modified Grignard reagents is illus-
trated in Table 1 and Scheme 1. As can be seen from
the list of results the coupling procedure can be applied
to benzonitrile derivatives with both electron donating
substituents (entries 1–5) in the para position as well as
electron withdrawing functionality (entry 13). In gen-
eral, the alkenyl Grignard reagent 2a (E/Z mixture)
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3 2
CꢀCN bond activation of benzonitriles could be par-
layed into a useful preparation of unsymmetrical
4
biaryls. For example, the coupling of benzonitrile with
p-tolMgCl/t-BuOLi in the presence of this nickel cata-
lyst provides an 88% yield of the desired coupling
product Ph-tol. The Grignard reagents were typically
modified by the addition of either t-BuOLi or PhSLi to
reduce the amount of nucleophilic addition to the
nitrile group during the cross-coupling event. The pur-
pose of this Letter is to expand the synthetic scope of
*
0
Corresponding author. Tel.: 252-707-3144; fax: 252-707-2568;
e-mail: john.dankwardt@dsm.com
Scheme 1. Nickel(0) promoted cross-coupling of alkyl- and
alkenylmagnesium reagents and benzonitriles (see Table 1).
040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(03)00075-3

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J. A. Miller, J. W. Dankwardt / Tetrahedron Letters 44 (2003) 1907–1910
d,e
Table 1. NiCl (PMe ) catalyzed cross-coupling of ArCN with organomagnesium reagents
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J. A. Miller, J. W. Dankwardt / Tetrahedron Letters 44 (2003) 1907–1910
1909
Table 1. (Continued)
provides styrene adducts (3a, d, h, j, m–o) as a mixture
of E and Z isomers. Kumada has demonstrated that the
coupling of stereodefined Grignard reagents under
Ni(0)-catalysis produces a mixture of (E) and (Z) alke-
nes via isomerization of the nickel coordinated alkenyl
In summary, the nickel catalyzed cross-coupling of aryl
nitriles and Grignard reagents provides an efficient
method for the preparation of styrene and alkyl arene
derivatives via activation of the CꢀCN bond by Ni
catalysis. We are continuing to pursue other related
transformations of this novel chemistry in our
laboratories.
7
magnesium reagent. More sterically demanding
organomagnesium reagents such as (2b) are also com-
patible to the Ni catalyzed cross-coupling methodology
affording synthetically useful yields of the desired sty-
rene compounds (3b,e, and l). The cyclopropyl Grig-
nard reagent couples efficiently, however, the yield of
the reaction is superior if the thiophenoxide derivative
Acknowledgements
(
3
2d) is used as the cross-coupling partner (compound
c, entries 3 and 4). In addition, heterocyclic nitrile
compounds such as 2-thiophene carbonitrile 1f and
-furan carbonitrile 1g are also effective substrates in
The authors would like to thank Professor B. M. Trost
(Stanford University) for helpful discussions concerning
this work.
2
this nickel catalyzed carbon–carbon bond forming pro-
cedure (entries 15 and 16). This Ni(0)-catalyzed method
is ideal for the construction of alkylarenes via the
coupling of benzonitriles with modified alkyl Grignard
reagents. Thus, the coupling of either MeMgOt-Bu or
n-BuMgOt-Bu with p-methylbenzonitrile 1d provides
the desired arene compounds p-xylene and n-butyl-
toluene in 66% and 43% yield respectively (entries 7 and
References
1. For general references, see: (a) Negishi, E.-i.; Liu, F. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp. 1–48;
(b) Farina, V. In Comprehensive Organometallic Chemistry
II; Abel, E. W.; Stone, F. G. A.; Wilkinson, G.; Hegedus,
L. S., Eds.; Pergamon: Oxford, 1995; Vol. 3.4, pp. 161–
8).

1
910
2
J. A. Miller, J. W. Dankwardt / Tetrahedron Letters 44 (2003) 1907–1910
40. (c) For a review on nickel catalyzed cross-coupling of
methylbiphenyl) failed to provide any of the desired
Grignard reagents and aryl halides, see: Kumada, M. Pure
Appl. Chem. 1980, 52, 669.
styrene adduct 3a resulting in complete recovery of the
benzonitrile starting material (1a). Pd(t-Bu P)2 was also
3
2
. (a) For an example of CꢀF bond activation of aryl
fluorides, see: Bohm, V. P. W.; Gstottmayer, C. W. K.;
Weskamp, T.; Herrmann, W. A. Angew. Chem., Int. Ed.
Engl. 2001, 40, 3387; (b) For an example using a carba-
mate leaving group, see: Sengupta, S.; Leite, M.; Rasland,
D. S.; Quesnelle, C.; Snieckus, V. J. Org. Chem. 1992, 57,
found to be ineffective as a catalyst in this cross-coupling
reaction. A combination of 5 mol% Pd(OAc) and 2-(dicy-
2
clohexylphosphino)-2%-methylbiphenyl (7.5 mol%) afforded
small amounts of the desired styrene compound with the
starting benzonitrile as the major component (1/9.8 3a/1a
by GC).
4
066; (c) For an example using a thioalkyl leaving group,
7
. Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.;
Fujioka, A.; Kodama, S.-i.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958.
. Representative procedure: (1-cyclopropyl-4-methoxyben-
zene 3c, entry 4). A solution of lithium thiophenoxide in
THF (4.0 mL, 4.0 mmol, Aldrich) was treated at 0°C with
cyclopropyl magnesium bromide (7.5 mL, 3.75 mmol,
Aldrich) and the resulting solution was initially warmed to
room temperature (for 30 min) and then heated at 60°C
for 1 h. The solution of 2d was cooled to room tempera-
ture and added to a solution of 4-methoxybenzonitrile 1a
see: Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.;
Wenkert, E. Tetrahedron Lett. 1982, 23, 4629.
3. (a) Morvillo, A.; Turco, A. J. Organomet. Chem. 1981,
8
2
08, 103; (b) Abla, M.; Yamamoto, T. J. Organomet.
Chem. 1997, 532, 267; (c) Garcia, J. J.; Brunkan, N. M.;
Jones, W. D. J. Am. Chem. Soc. 2002, 124, 9547.
. Miller, J. A. Tetrahedron Lett. 2001, 42, 6991.
4
5
. NiCl (PMe ) is now commercially available from Aldrich
2
3 2
(catalog number 56,767-1).
6. It was determined that 5 mol% Ni(acac) /2PMe was an
2
3
equally effective catalyst system in these cross-coupling
reactions. Phosphine ligands with larger cone angles were
found to be less effective. For example, NiCl (PEt ) will
(
249 mg, 1.875 mmol), NiCl (PMe ) (29 mg, 0.103 mmol)
2 3 2
and tridecane (196 mg, 1.07 mmol) in THF (2 mL). The
reaction was heated to 60°C for 15 h. An aliquot was
withdrawn and quenched with 1 M solution of sodium
citrate. GC analysis indicated the formation of 3c (1.21
mmol, 64%) and the cyclopropyl(4-methoxyphenyl)-
methanone (0.21 mmol).
2
3 2
indeed activate the CꢀCN bond; however, the scope of the
reaction with this catalyst is not general and the yields
are inferior versus NiCl (PMe ) . The application of
2
3 2
Ni(acac) /1,3-bis(2,4,6-trimethylphenyl)imidazolium chlo-
2
ride or the Buchwald ligand (2-(dicyclohexylphosphino)-2%-