Angewandte
Chemie
functional-grouptolerance and site selectivity. They are
therefore likely to find broad utility in synthesis. Ester and
acetylated hydroxy groups are not usually tolerated by DoM
methods (Table 3, entries 6 and 7). In DoM reactions, halides
at ortho and para positions either affect the site selectivity
(not the case in Table 3, entries 8–13) or react with the
metalation reagent, which may be an alkyl lithium reagent
(see, in contrast, Table 3, entry 14). The aryl halide products
of the present ortho-iodination reaction, with F, Cl, Br, and I
at various positions, can undergo further sequential coupling
reactions owing to the different reactivities of the different
halide substituents towards Pd0.[17] The previously described
use of NIS as the iodination reagent[6a,c] led to low conversion
and a poor yield of the product (Table 3, entry 1).
significant improvement in monoselectivity was observed
upon varying the catalyst in this way. However, we were
pleased to find that tetraalkyl ammonium salts not only
À
promote the C H insertion in the absence of another base,
but also drastically improve the monoselectivity (Table 4,
entries 1–4).[18–20] A significant improvement in monoselec-
tivity in favor of the less-hindered ortho position was also
observed with substrates 22, 24, and 25. The lower mono-
selectivity with substrates 13 and 23 is most likely a result of
noncatalyzed electrophilic iodination of the electron-rich
arenes. The proposed catalytic cycle in Scheme 2 shows the
Unfortunately, monoselectivity was not observed, even if
the reaction was stopped at an early stage (Table 4, entries
1–3). This problem is commonly encountered in PdII/PdIV
Table 4: Monoselective iodination of meta-substituted benzoic acids.[a]
Entry
Substrate
Product
Mono/Di[b] Yield
[%][c]
1[d]
2[e]
3[f]
4[g]
2:1
3:5
2:1
25
30
20
75
15:1
Scheme 2. Monoselective ortho iodination assisted by tetraalkyl ammo-
5[h]
6[h]
7[i]
5:1
16:1
5:1
63
62
65
74
72
nium cations.
role of the tetraalkyl ammonium salt. The formation of an ion
pair is crucial for the reaction,[18–20] although it is not clear at
II
À
this stage whether the Pd center initiates the C H cleavage
by coordinating with the lone pair of the carbonyl group or
simply by displacing the ammonium cation to form a Pd
carboxylate. Both pathways would lead to the formation of
the same intermediate B.
The next challenge was to developthe reaction further to
proceed with monoselectivity in the absence of meta sub-
stitution. The difficulty of this problem is evident from the
8[h]
9[h]
14:1
16:1
[a] Reaction conditions: Pd(OAc)2 (5 mol%), IOAc (2 equiv), DCE, 808C,
2 h. [b] Ratio of the monoiodinated to the diiodinated product. [c] Yield
of the isolated product. [d] The reaction was carried out with 1 equivalent
of IOAc in DMF. [e] DMF was used as the solvent. [f] The reaction was
carried out with NaOAc (1 equiv). [g] The reaction was carried out with
Bu4NI (1 equiv). [h] The reaction was carried out with IOAc (4 equiv) and
Bu4NI (1.5 equiv) for 6 h. [i] The reaction was carried out with Bu4NI
(1 equiv) at 608C for 12 h. DCE=1,2-dichloroethane.
À
previously reported ortho C H functionalization of benzoic
acids.[10,14d] Poor monoselectivity was observed when substrate
4 was subjected to our newly developed iodination protocol
(the ratio of diiodinated and monoiodinated products is
typically 2:1) and the product was either not formed or
obtained in low yield.
Extensive screening of tetraalkyl ammonium salts led us
to find that the use of tetrabutylammonium bromide
(1.5 equiv) gives the brominated product with greatly
improved monoselectivity (Table 5, entry 3). The reaction of
IOAc with Bu4NBr should form the known brominating
reagent IBr,[21] which could brominate the aryl palladium
intermediate to give the brominated product and PdI2. We
have shown previously that PdI2 is converted into Pd(OAc)2
by IOAc to regenerate the catalyst. The improved mono-
selectivity observed in the presence of ammonium cations can
catalysis, as the product remains coordinated to PdII, and
further reaction occurs before the products are exchanged for
external substrates. Moderate monoselectivity was made
possible previously through the use of biphenyl systems.[6c]
In an attempt to make the current ortho-iodination
reaction monoselective, we tested various PdII sources, such
as Pd(tfa)2 (tfa = trifluoroacetate), Pd(Piv)2 (Piv = pivolate),
and Pd(OTf)2 (OTf = para-toluenesulfonate), with the meta-
substituted carboxylic acid 11 as the substrate. A number of
sterically hindered and electron-deficient ligands were also
screened as additives. (Strong donating ligands were not
be attributed to the following factors: First, bromination
II
À
deactivates the aryl ring. Second, Pd I species are formed
II
À
À
chosen, as they retard C H insertion.) Despite the fact that
instead of Pd OAc species (Scheme 2) following bromina-
II
À
the two ortho positions in 11 are sterically distinct, no
tion with IBr. The Pd I species are less reactive or
Angew. Chem. Int. Ed. 2008, 47, 5215 –5219
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5217