to the steric congestion caused by the neighboring quaternary
carbon center, which interferes the SN2 reaction by an iodide
ion (entry 3).13 An acyclic secondary alkyl tosylate reacted
efficiently to afford the desired product in good yield (entry
4). Five- and seven-membered cyclic seconday alkyl tosylates
showed high reactivity (entries 5 and 7), while the reaction
of a six-membered cyclic alkyl tosylate gave a poor result
due to the sluggish substitution and relatively fast ꢀ-hydrogen
elimination (entry 6).14 Interestingly, a bulky 2-adamantyl
tosylate, which possesses no ꢀ-hydrogen available for
elimination, afforded the coupling product in 57% yield
(entry 8). The oxygen functionality at the ꢀ-position of the
tosylate group slightly affected the reactivity to afford a
mixture of the cross-coupling product and the rearranged
product, (1-methoxypropyl)benzene, in 87% and 9% yield,
respectively (entry 9). Ester functionality was tolerated under
the reaction conditions (entry 10). Furthermore, an alkyl 1,3-
bistosylate was successfully converted to the diarylated
compound by using 2.4 equivalents of phenylzinc reagents
(entry 11).
transmetalation from magnesium to zinc and the subse-
quent treatment with Me3SiCH2MgCl. The cross-coupling
reactions of heteroarylzinc reagents, such as 2- or 3-thie-
nylzinc reagents, afford the products in 72% yields (entries
1 and 2). The reactions of the p- or m-cyanophenylzinc
reagents with 1 gave the coupling products in excellent
yield, while the reaction of the o-cyanophenylzinc reagent
gave the product in 60% yield despite the use of 3.0 equiv
of the arylzinc reagent and 5 mol % of FeCl3. The arylzinc
reagents possessing a p-methoxycarbonyl group reac-
ted with primary and secondary alkyl halides to afford
the products in 75 and 71% yield, respectively (entries 6
and 7).
The stereochemical environment of the leaving groups
impacted the product distribution in the cross-coupling of
substituted cyclohexyl tosylates: When trans isomer 6 was
reacted with a diarylzinc reagent, the coupling product 8 was
obtained in 60% yield along with the formation of olefin 9
in 40% yield (eq 1).16 On the other hand, cis isomer 7 gave
no coupling product and resulted in the quantitative formation
of 9 (eq 2). Due to the antiperiplanar alignment of the leaving
group and the ꢀ protons imposed by the bulky cyclohexyl
substituent at the 4-position, E2 elimination of cis isomer 7
is significantly more rapid than SN2 substitution by an iodide
ion. In the case of the trans isomer 6, SN2 substitution is
faster than ꢀ-elimination to afford the iodohexane, which
undergoes a rapid iron-catalyzed cross-coupling reaction with
arylzinc reagent via a radical mechanism.17 The in situ
generated iodide also possesses a ꢀ-hydrogen in the anti-
periplanar relationship, and an elimination reaction from the
iodide competes to give the elimination product 9 in 40%.
These experiments demonstrate that the present cross-
The results of cross-couplings of alkyl tosylates with
functionalized arylzinc reagents are summarized in Table 3.
Table 3. Cross-Coupling Reactions of Alkyl Tosylates with
Functionalized Arylzinc Reagentsa
(8) Selected papers: (a) Tamura, M.; Kochi, J. J. Am. Chem. Soc. 1971,
93, 1487–1489. (b) Molander, G. A.; Rahn, B. J.; Shubert, D. C.; Bonde,
S. E. Tetrahedron Lett. 1983, 24, 5449–5452. (c) Cahiez, G.; Marquais, S.
Pure Appl. Chem. 1996, 68, 53–60. (d) Cahiez, G.; Avedissian, H. Synthesis
1998, 1199–1205. (e) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett
2001, 1901–1904. (f) Fu¨rstner, A.; Leitner, A.; Méndez, M.; Krause, H.
J. Am. Chem. Soc. 2002, 124, 13856–13863. (g) Norinder, J.; Matsumoto,
A.; Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858–5859.
(h) Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew. Chem.,
Int. Ed. 2009, 48, 2925–2928.
(9) Anhydrous FeCl3 (>99.99%, Aldrich, Inc.) was used as a precatalyst
throughout the present study. The iron salt has been reported rather free
from the contamination of a trace amount of copper, see: Buchwald, S. L.;
Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586–5587.
(10) The similar effect of magnesium salts in organozinc coupling have
been reported, see ref 2g.
(11) (a) Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem.
Soc. 1996, 118, 10906–10907. (b) Berger, S.; Langer, F.; Lutz, C.; Knochel,
P.; Mobley, T. A.; Reddy, C. K. Angew. Chem., Int. Ed. 1997, 36, 1496–
1498.
a The reactions were carried out according to procedure C shown in
Scheme 1 (X ) I). For the details, see the Supporting Information. b Isolated
yield. c 3.0 equiv of TMEDA and 3 mol % of FeCl3 were used. d 3.0 equiv
of the arylzinc reagent and TMEDA and 5 mol % of FeCl3 were used.
(12) Place, P.; Roumestant, M.-L.; Gore, J. Bull. Soc. Chim. Fr. 1976,
169–176.
(13) Charton, M. J. Am. Chem. Soc. 1975, 97, 3694–3697.
(14) It is known that nucleophilic substitution of cyclohexyl tosylate is
generally slow and is often accompanied with elimination reaction; see:
(a) Lambert, J. B.; Putz, G. J.; Mixan, C. E. J. Am. Chem. Soc. 1972, 94,
5132–5133. (b) Nordlander, J. E.; McCrary, T. J., Jr. J. Am. Chem. Soc.
1972, 94, 5133–5135, and references cited therein.
The functionalized arylzinc reagents were prepared ac-
cording to the method reported by Knochel via a
halogen-magnesium exchange reaction of aryl bromides
or aryl iodides with i-PrMgCl·LiCl.15 Competitive cross-
coupling between the arylzinc reagents and the isopropyl
halide (i-PrX) formed during the halogen-magnesium
exchange reaction (ArX + i-PrMgCl·LiCl f ArMgCl·LiCl
+ i-PrX) could be avoided by thorough evaporation after
(15) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–
3336.
(16) The substitution reaction procceded in a non-stereospecific manner
to afford a 61:39 mixture of the diastereomers, representing the characteristic
reactivity profile of iron-catalyzed haloalkane cross-coupling reaction (cf.
ref 7a,e).
(17) Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima,
H. J. Am. Chem. Soc. 2009, 131, 6078–6079.
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Org. Lett., Vol. 11, No. 19, 2009