Angewandte
Chemie
[a]
Table 1: Synthesis of 3-substitutedindoles.
yield. Control experiments confirmed the importance of the
ligand and the catalytic nature of the reaction.
The yield of 3 was improved from 59 to 85% by starting
the reaction at room temperature,heating to 140 8C over
about 0.5 h,and then heating at 140 8C for 2 h. When
[Pd2dba3] was replaced with Pd(OAc)2,the yield decreased
to 45%,whereas [Pd(dppf)Cl ]–CH2Cl2 did not promote the
2
desired reaction at all. The Heck reaction did not proceed
with K3PO4 as the base,and the yield decreased to 60% with
Cs2CO3.
85%
71%[b]
67%[b]
72%
65%
On the basis of well-known intramolecular Heck
approaches to indoles and related compounds[11–13,22] and the
use of allylamine as an ammonia equivalent in aryl amination
reactions,[23] it seemed plausible that the synthesis of 3
proceeds through an initial aryl amination. Indeed,the
isolation of the aniline 2 indicated that a clean stepwise
reaction takes place (Scheme 2). In accordance with this
observation,all substrates that could react to give regioiso-
meric products were transformed only into the isomer that
results from aryl amination at the position with the iodide
substituent.
75%
73%
63%
64%
64%
71%
60%
56%
61%[c]
59%[d]
[a] Reactions were performedon a 1.5-mmol scale in dry toluene (4 mL)
in closedvials. [b] [Pd 2dba3]: 2.5 mol%; dppf: 10 mol%. [c] 2,3-Dichloro-
pyridine was used as the substrate. (No product was observed in the
absence of the catalyst). [d] (E)-3-Phenylallylammonium chloride was
usedas the allylic substrate in the presence of 3.5 equivalents of
NaOtBu.
(76% yield) from 2-bromoiodobenzene by treatment with
allylamine in the presence of [Pd2dba3] (1.25 mol%) in
p-xylene at reflux for 5 h.
It was possible to functionalize 3 through in situ
N arylation by adding either an aryl iodide or an aryl bromide
after the completion of the first two steps (Scheme 3).[25] One
Scheme 2. The isolation of 2 suggests a stepwise reaction. The aniline
2 was obtainedin 91% yieldwhen the reaction was stoppedafter 0.5 h
(when the temperature reached140 8C), whereas scatole (3) was
obtainedin 85% yieldafter 2 h at 140 8C.
The reaction proceeded well when electron-withdrawing
or electron-donating groups were present on the aromatic
ring of the substrate,and substitution ortho to the iodine or
bromine substituent was possible (Table 1). The 3-substituted
indoles were formed in yields ranging from 56 to 85%,which
correspond to yields of 75–92% per bond formed. The scope
of the reaction could be extended to the synthesis of an
azaindole when 2,3-dichloropyridine was used.[24] No aza-
indole was formed from other dihalogenated pyridines. The
reaction was also applicable to simple functionalized allylic
amines,as exemplified by the formation of 3-benzylindole in
good yield. The desired product was not formed from the
nonaflate derived from 2-bromophenol,and the use of 2-
iodobromobenzenes with an additional bromine substituent
led to complex product mixtures. Attempts to prepare chain-
elongated,functionalized indoles were largely unsuccess-
ful.[24]
Although the regiochemistry of the reaction was con-
trolled by the selective amination of the aryl iodide, 3 could
also be prepared from 2-bromochlorobenzene (in 66% yield),
2-chloroiodobenzene (47%),21-,dichlorobenzene (43%),
1,2-dibromobenzene (70%), and 1,2-diiodobenzene (15%).
Thus,the preparation of functionalized products is limited by
the accessibility of the corresponding 1,2-dihalo arenes. The
reaction could be scaled up to produce 3 in a quantity of 10 g
Scheme 3. In situ N arylation.
À
À
C C and two C N bonds were formed in this way in
approximately 60% yield per step. For comparison, 3 can be
coupled to 4-bromofluorobenzene in 62% yield under con-
ditions described by Hartwig and co-workers ([Pd2dba3]
(1.25 mol%),dppf (5 mol%),140 8C).[26]
In summary,we have developed a novel approach to
indoles on the basis of sequential aryl amination and Heck
cyclization reactions in a one-flask operation with a single
catalyst.
Experimental Section
General procedure: [Pd2dba3] (1.25 mol%),dppf (5 mol%),NaO-
(tBu) (3.75 mmol),the aryl halide (1.5 mmol),toluene (4 mL),and
allylamine (1.5 mmol) were placed in a 7-mL screw-cap vial. The
Angew. Chem. Int. Ed. 2008, 47, 888 –890
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