Palladium-catalyzed cross-coupling reaction of secondary benzylic bromides with grignard reagents

Article abstract of DOI:10.1021/ol902335c

"Chemical Equation Presented" A mild palladium-catalyzed Kumada-Corriu reaction of secondary benzylic bromides with aryl and alkenyl Grignard reagents has been developed. In the presence of the Xantphos ligand, the undesired β-elimination pathway Is minimized, affording the corresponding cross-coupling products In acceptable to good yields. The reaction proceeds with inversion of the configuration.

Full text of DOI:10.1021/ol902335c

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5514-5517
Palladium-Catalyzed Cross-Coupling
Reaction of Secondary Benzylic
Bromides with Grignard Reagents
Ana Lo´pez-Pe´rez, Javier Adrio,* and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
jaVier.adrio@uam.es; juancarlos.carretero@uam.es
Received October 9, 2009
ABSTRACT
A mild palladium-catalyzed Kumada-Corriu reaction of secondary benzylic bromides with aryl and alkenyl Grignard reagents has been developed.
In the presence of the Xantphos ligand, the undesired ꢀ-elimination pathway is minimized, affording the corresponding cross-coupling products
in acceptable to good yields. The reaction proceeds with inversion of the configuration.
Metal-catalyzed cross-coupling reactions are undoubtedly one
of the most powerful tools for C-C bond formation1 and
have produced a deep impact in retrosynthesis2 and industrial
synthesis.3 Although initially focused on aryl and alkenyl
electrophiles, the huge progress achieved over the last three
decades has allowed the development of very efficient
procedures for the cross-coupling reactions between sp-, sp2-,
and sp3-hybridized carbon atoms, including Csp3 electro-
philes, mainly primary alkyl halides and sulfonates.4 In this
context, the secondary alkyl halides are more challenging
coupling partners due to the extra steric hindrance and
electron richness of these substrates. In the last five years
great effort has been devoted to this field, and several
efficient metal-catalyzed protocols for the coupling of
secondary alkyl halides have been reported,5 especially using
nickel, iron, and cobalt catalysts, including a handful of
outstanding catalytic asymmetric procedures.6 On the other
hand, efficient protocols for the complementary cross-
(1) (a) Topics in Organometallic Chemistry: Palladium in Organic
Synthesis; Tsuji, J., Ed.; Springer: New York, 2005. (b) Metal-catalyzed
Cross-coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004. (c) Beller, M., Bolm, C., Eds., Transition Metals
for Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004. (d) Buchwald,
S. L. Acc. Chem. Res. 2008, 41, 1439 (especial issue on metal-catalyzed
cross-coupling reactions)
(5) For a comprehensive recent review on cross-coupling reactions of
secondary alkyl electrophiles, see: (a) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656 (and references cited therein). For selected
recent examples on metal-catalyzed coupling reactions of secondary alkyl
electrophiles with Grignard reagents, see: Ni catalysts. (b) Vechorking, O.;
Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756. Fe catalysts: (c)
Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (d) Cahiez,
G.; Duplais, C.; Moyeux, A. Org. Lett. 2007, 9, 3253. (e) Cahiez, G.; Habiak,
V.; Duplais, C.; Moyeux, A. Angew. Chem., Int. Ed. 2007, 46, 4364. (f)
Gue´rinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2007, 46,
6521. Co catalysts: (g) Cahiez, G.; Caboche, C.; Duplais, C.; Moyeux, A.
Org. Lett. 2009, 11, 277. (h) Someya, H.; Ohmiya, H.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2007, 9, 1565. Zn catalysts: (i) Studte, C.; Breit, B.
Angew. Chem., Int. Ed. 2008, 47, 5451. Ag catalysts: (j) Someya, H.;
Yorimitsu, H.; Oshima, K. Tetrahedron Lett. 2009, 50, 3270. (k) Someya,
H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 969. V: (l)
Yasuda, S.; Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81,
287.
(2) For reviews on applications in natural product synthesis, see: (a)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442. (b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4544.
(3) Beller, M.; Zapf, A.; Magerlein, W. Chem. Eng. Technol. 2001, 24,
575.
(4) For recent reviews, see: (a) Liegault, B.; Renaud, J.-L.; Bruneau, C.
Chem. Soc. ReV. 2008, 37, 290. (b) Frisch, A. C.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 674. (c) Fu¨rstner, A.; Mart´ın, R. Chem. Lett. 2005, 34,
624. (d) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525.
(e) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
10.1021/ol902335c CCC: $40.75
Published on Web 11/02/2009
 2009 American Chemical Society

coupling reaction of secondary alkyl organometallics with
Csp2 electrophiles have also been reported.7
competitive ꢀ-hydride elimination pathway (Table 1). After
some experimentation, we found that bidentate ligands with
a large bite angle such as dppf (96°) and, especially,
Xantphos13 (111°) turned out to be excellent ligands for the
cross-coupling reaction, driving the reaction to complete
conversion after 7 h at room temperature, styrene not being
detected in the reaction mixture (entries 1 and 2). Interest-
ingly, a similar result was obtained using 3 mol % of the
Pd(CH3CN)2Cl2/Xantphos catalyst system (entry 3). Never-
theless, no reaction was observed when the catalyst loading
was reduced to 1 mol % (entry 4). From a practical point of
view, it is interesting to note that both catalyst components
are air stable and commercially available.
However, a survey of the literature reveals that examples
of palladium-catalyzed cross-coupling reactions of secondary
alkyl halides are scarce.8 A pioneering work by Sustmann
and co-workers described the Pd(0)-catalyzed Stille coupling
reaction of 1-bromoethylbenzene bromide with tetramethyl
and tetraethyl tin.8a Twenty years later, Glorius and co-
workers reported the Sonogashira coupling of secondary alkyl
bromides catalyzed by CuI and an N-heterocyclic carbene
palladium complex.8b Recently, Asensio′s group demon-
strated that secondary bromo sulfoxides are effective sub-
strates in the Suzuki reaction with aryl boronic acids,8c and
Lautens’ group reported the Catellani intramolecular reaction
of secondary alkyl iodides.8d,e Interestingly, unlike the Ni-,
Fe-, and Co-catalyzed processes, in which there is ample
evidence of the participation of radical mechanisms, it has
been established that at least some Pd(0)-catalyzed reactions
occur by SN2-type oxidative addition to the alkyl halide.9
This different mechanistic behavior can have important
stereochemical consequences, especially from enantioen-
riched secondary alkyl halides. Herein, we report our initial
results on the Pd-catalyzed Kumada-Corriu cross-coupling
reaction of racemic and enantioenriched secondary benzylic
bromides with vinyl and aryl Grignard reagents.10
Table 1. Screening of Ligands for the Kumada-Corriu
Cross-Coupling Reaction
entry
X
liganda
dppf
Xantphos
Xantphos
Xantphos
time (h)
yield (%)b
1
2
3
4
10
10
3
7
7
14
14
86
97
98
--c
We chose as a model reaction the coupling of 1-bromo-
ethylbenzene11 with vinyl magnesium bromide. Preliminary
experiments were performed in THF using 10 mol % of
Pd(CH3CN)2Cl2 as catalyst and a variety of ligands12 in an
attempt to find a catalytic system capable of minimizing the
1
a See Supporting Information for results with other ligands. b Isolated
yield after column chromatography. c No reaction was observed.
(6) For a review, see: (a) Glorius, F. Angew. Chem., Int. Ed. 2008, 47,
8347. For a very recent example, see: (b) Lundin, P. M.; Esquivias, J.; Fu,
G. C. Angew. Chem., Int. Ed. 2009, 48, 154.
Encouraged by these initial findings, we next examined
the scope of this protocol with regard to the Grignard reagent
(Table 2). Under the standard optimized reaction conditions,
the cross-coupling reaction of 1-bromoethylbenzene with
phenyl magnesium bromide and a variety of substituted aryl
Grignard reagents proceeded in good to excellent yields
regardless of the electronic nature of the substituents14
(entries 1-5). A heteroaryl Grignard reagent, such as
2-thienyl, is also a suitable nucleophile for this reaction (entry
6). However, a lower yield was obtained with 2-naphthyl
magnesium bromide (57% yield, entry 7), and no coupling
reaction was observed with the bulkier o-tolyl Grignard
reagent (entry 8) showing that this cross-coupling reaction
(7) For selected recent references, see: (a) Han, C.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 7532. (b) Imao, K.; Glasspoole, B- W.;
Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (c)
Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257. (d) van den Hoogenband, A.; Lange, J. H. M.;
Terpstra, J. W.; Koch, M.; Visser, G. M.; Visser, M.; Korstanje, T. J.;
Jastrzebski, J. T. B. H. Tetrahedron Lett. 2008, 49, 4122. (e) Luo, X.; Zhang,
H.; Duan, H.; Liu, Q.; Shu, L.; Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571.
(8) (a) Sustmann, R.; Lau, J.; Zipp, M. Tetrahedron Lett. 1986, 27, 5207.
(b) Altenhoff, G.; Wu¨rtz, S.; Glorius, F. Tetrahedron Lett. 2006, 47, 2925.
(c) Rodr´ıguez, N.; Ram´ırez de Arellano, C.; Asensio, G.; Medio-Simo´n,
M. Chem.sEur. J. 2007, 13, 4223. (d) Rudolph, A.; Rackelmann, N.;
Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485. (e) See also: Catellani,
M.; Motti, E.; Minari, M. Chem. Commun. 2000, 157. For Pd-catalyzed
carbonylation reactions of secondary alkyl electrophiles, see: (f) Urata, H.;
Maekawa, H.; Takahashi, S.; Fuchikami, T. J. Org. Chem. 1991, 56, 4320.
(g) Imbeaux, M.; Mestdagh, H.; Moughamir, K.; Roland, C. J. Chem. Soc.,
Chem. Commun. 1992, 1678. (h) For an isolated example of a Pd-catalyzed
cross-coupling with trialkynylindium reagents, see ref 11b.
(13) The great bite angle and flexibility of Xantphos have been invoked
as key elements in other Pd-catalyzed processes. For a review, see: (a)
Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem.
ReV. 2000, 100, 2741. For recent examples, see (b) Martinelli, J. R.; Watson,
D. A.; Freckmann, D. M. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem.
2008, 73, 7102. (c) Dongol, K. G.; Koh, H.; Sau, M.; Chai, C. L. L. AdV.
Synth. Catal. 2007, 349, 1015.
(9) (a) Hills, I. D.; Netherton, M. R.; Fu, C. G. Angew. Chem., Int. Ed.
2003, 42, 5749. (b) For recently reported radical-mediated Kumada cross-
couplings with aryl bromides, see: Manolikakes, G.; Knochel, P. Angew.
Chem., Int. Ed. 2009, 48, 205.
(10) In 1986 the (dppf)Pd(0)-catalyzed cross-coupling reaction of a
secondary alkyl iodide with Grignard reagents was reported: (a) Castle,
P. L.; Widdowson, D. A. Tetrahedron Lett. 1986, 27, 6013. Later, these
results were re-examined, disclosing that the reaction leads to reduction or
ꢀ-elimination products rather than the coupling products: (b) Yuan, K.; Scott,
W. J. Tetrahedron Lett. 1989, 30, 4779.
(14) Typical procedure for the Kumada-Corriu cross-coupling: To
a solution of the Xantphos ligand (4.6 mg, 0.008 mmol) and Pd(CH3CN)2Cl2
(2.0 mg, 0.008 mmol) in THF (1.0 mL), under nitrogen atmosphere, was
added 1-bromoethylbenzene (35 mL, 0.26 mmol). The resulting solution
was cooled to 0 °C, and the Grignard reagent (1.0 M in THF, 0.33 mL,
0.33 mmol) was added dropwise. The mixture was stirred overnight (10-14
h) at room temperature and filtered through a plug of Celite with the aid of
CH2Cl2 (5.0 mL). The solvent was removed under reduced pressure, and
the residue was purified by silica gel flash chromatography. We also
confirmed that the reaction can be performed at a higher scale: in a 500 mg
scale reaction (2.6 mmol of the benzylic bromide) the reaction illustrated
in entry 2 (Table 2) was accomplished in 93% yield.
(11) Examples of cross-coupling reaction of secondary benzylic elec-
trophiles are scarce, see: (a) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 10482. (b) Caeiro, J.; Pe´rez Sestelo, J.; Sarandeses, L. A. Chem.sEur.
J. 2008, 14, 74.
(12) Either no reaction or major formation of styrene was observed in
the presence of ligands such as PPh3, PCy3, Binap, DTBM-Segphos, or
Josiphos (see Supporting Information for ligand screening details).
Org. Lett., Vol. 11, No. 23, 2009
5515

is very sensitive to steric effects. Disappointingly, the
coupling reaction also did not occur with an alkyl Grignard
reagent such as MeMgBr (entry 9).
Table 3. Pd-Catalyzed Kumada-Corriu Reaction of Secondary
Benzylic Bromides
Table 2. Pd-Catalyzed Kumada-Corriu Reaction of
1-Bromoethylbenzene with Aryl Grignard Reagents14
entry
R
yieldb
1
2
3
4
5
6
7
8
9
Ph
96
95
98
94
70
95
57b
0c
(p-F)C6H4
(p-OMe)C6H4
(p-Ph)C6H4
(m-OMe)C6H4
2-thienyl
2-naphthyl
(o-Me)C6H4
Me
0c
a Isolated yield after column chromatography. b A 40% yield of styrene
was also isolated. c A similar outcome was obtained using CH3CN as solvent.
We next extended the scope of this reaction to other
secondary benzyl-type electrophiles15 (Table 3). The reaction
of 1-bromoindene with vinyl magnesium bromide under the
standard conditions afforded the coupling product in low
yield (entry 1). Pleasingly, a very efficient coupling reaction
occurred when acetonitrile was used as solvent instead of
THF16 (entry 1 vs 2). 4-Bromochromene was also a suitable
substrate, albeit the isolated yields in the coupling products
were moderate due to the competitive ꢀ-elimination pathway
(entries 4 and 5). The coupling reaction proceeded in nearly
quantitative yield from bromodiphenylmethane, allowing the
straightforward construction of triarylmethanes (entry 6).
Interestingly, this procedure tolerates the presence of an ester
moiety at the electrophile (entries 8-10). Unfortunately,
neither the cyclohexyl bromide nor the cyclohexyl iodide
coupled with vinyl magnesium bromide (entry 11).
a Isolated yield after column chromatography. b THF was used as solvent.
c The ꢀ-elimination product was also isolated as a minor product (see
Supporting Information for details).
type,8d and Heck-type reactions20a of enantiopure secondary
halides.
Scheme 1
Finally, we studied the stereochemical course of the
reaction from a nonracemic secondary bromide (Scheme 1).
The Pd-catalyzed reactions of (S)-1-bromoethylbenzene
(85-86% ee)17 with p-methoxy and p-fluorophenyl magne-
sium bromide provided the coupling products with nearly
full inversion of the configuration18,19 (84%-85% ee). This
stereochemical outcome is in full agreement with the
previously reported Pd-catalyzed Suzuki-type,8c,20b Catellani-
In summary, we have developed a procedure for the Pd-
catalyzed cross-coupling reaction of secondary benzylic
bromides with aryl and vinyl Grignard reagents. This protocol
strongly relies on the use of the Xantphos ligand to minimize
(15) The primary benzyl bromides are also suitable substrates for
this Kumada-Corriu coupling reaction (see Supporting Information for
details).
(16) Low yields were also obtained in other solvents, such as DMA,
DMF, NMP, or toluene.
(17) (S)-1-Bromoethylbenzene was prepared in 85-86% ee by bromi-
nation of (R)-1-phenyl-1-ethanol (94% ee) with POBr3 using DMAP as
base. See also: Dauben, H. J.; McCoy, L. L. J. Am. Chem. Soc. 1959, 81,
5404.
(19) In contrast, it has been reported that the Fe-catalyzed reaction of
enantiopure secondary halides with Grignard reagents leads to racemic
coupling products: Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686. For the Zn-catalyzed enantiospecific reaction
of R-hydroxy ester triflates, see ref 5i.
(20) (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(b) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910.
(18) Compound (R)-1 had been previously described, which allowed
us to confirm the inversion of configuration: Fessard, T. C.; Andrews, S. P.;
Motoyoshi, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 9331
.
5516
Org. Lett., Vol. 11, No. 23, 2009

the ꢀ-hydride elimination pathway. In addition, we have
shown that the reaction proceeds with inversion of the
configuration. Further investigations into this and related
methods, as well as mechanistic studies, are ongoing.
PPQ-4454). A.L. thanks the Comunidad Autónoma de Madrid
for a predoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the Spanish
Ministerio de Ciencia e Innovación (grants CTQ2006-01121
and CTQ2009-07791) and UAM-Consejer´ıa de Educacio´n de
la Comunidad Auto´noma de Madrid (project CCG08-UAM/
OL902335C
Org. Lett., Vol. 11, No. 23, 2009
5517