reactive intermediates, can be used in the copper-catalyzed
cross-coupling reaction with arylmagnesium reagents. Be-
cause we have recently reported several methods for prepar-
ing polyfunctionalized aryl and heteroarylmagnesium spe-
cies,7 this approach would allow the preparation of highly
functionalized diarylmethanes of type 2.
Scheme 2. Substituted Indole Derivatives 2m-2r
Thus, we have found that polyfunctionalized arylmagne-
sium reagents of type 3, which were easily prepared via a
halogen-magnesium exchange or by direct insertion, smoothly
react with benzylic phosphates of type 4 in the presence of
a Cu(I) catalyst, leading to highly functionalized diaryl-
methanes 2 in good to excellent yields. Triethyl phosphite,
which is stabilizing the intermediate arylcopper reagent, and
tetrabutylammonium iodide proved to be essential additives.
The reaction is very fast, and full conversion is observed
after 1 h at 60 °C. The scope of this new cross-coupling
reaction is summarized in Table 1.
Both electron-poor arylmagnesium reagents, bearing an
ester or nitrile function 3a, 3c, 3d, or 3e, and an electron-
rich arylmagnesium reagent, bearing a methoxy group 3b,
undergo the reaction with functionalized benzylic phosphates
in good to excellent yields. The benzyl phosphates may bear
a bromide 4c, a methyl group 4b, or a methoxy group in
ortho (4d) or para (4e) position. Cross-coupling between
these reagents leads to the desired diarylmethanes 2a-2g in
high yields up to 88% (entries 1-7).
Also, heterocyclic phosphates such as the furan derivative
4f or the thiophene derivatives 4g and 4h are excellent
electrophiles in this reaction, yielding 3-substituted func-
tionalized furans 2h-2j (entries 8-10) and 2- or 3-substi-
tuted functionalized thiophenes 2k and 2l (entries 11 and
12) in yields up to 88%.
Scheme 3. Synthesis of Trimethoprim 1
Furthermore, using this copper-catalyzed cross-coupling
reaction, a broad variety of functionalized indole derivatives
can be prepared (Scheme 2).
Thus, the readily available magnesiated indoles 3g and 3f
can be coupled with benzylic phosphates bearing an ester
group 4i or a bromide 4j leading to the desired products 2m-
2o in 70-85% yield, as shown in Scheme 2.
Moreover, two heterocyclic moieties can be linked to-
gether. Thus, various magnesiated functionalized indoles 3f-
3h were treated with furan 4f or thiophene 4h leading to the
heterocyclic derivatives 2p-2r in 82-92% yield.
To demonstrate the synthetic potential of this reaction, we
have developed a synthetic route, to synthesize Trimethoprim
1 in four steps (Scheme 3). The treatment of 5-bromo-2,4-
di-tert-butoxypyrimidine (5) with iPrMgCl‚LiCl (0 °C, 4 h)
provides the intermediate magnesium reagent in >95%
yield.8 Its cross-coupling with diethyl 3,4,5-trimethoxybenzyl
phosphate (6) (60 °C, 1 h) led to 2,4-di-tert-butoxy-5-(3,4,5-
trimethoxybenzyl)-pyrimidine (7) in 81% yield.
trimethoxybenzyl)-pyrimidine (8) by using POCl3 in 75%
yield over two steps.9 The nucleophilic substitution of the
chlorines by two amino functions was performed by heating
The pyrimidine derivative 7 was deprotected using con-
centrated HCl in methanol giving the corresponding uracil
derivative, which was converted to the 2,4-dichloro-5-(3,4,5-
(6) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron 1994, 50,
6017.
(7) (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) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333.
(8) For the preparation of 5, see: Peters, D.; Ho¨rnfeldt, A. B.; Gronowitz,
S. J. Heterocycl. Chem. 1990, 27, 2165. For the Br-Mg exchange on
pyrimidines, see: Boudet, N.; Knochel, P. Org. Lett. 2006, 8, in press.
(5) (a) Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945. (b) Kuwano,
R.; Yokogi, M. Chem. Commun. 2005, 5899. (c) McLaughlin, M. Org. Lett.
2005, 7, 4875. (d) Flaherty, A.; Trunkfield, A.; Barton, W. Org. Lett. 2005,
7, 4975. (e) Nobre, S. M.; Monteiro, A. L. Tetrahedron Lett. 2004, 45,
8225.
Org. Lett., Vol. 8, No. 18, 2006
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