.
Angewandte
Communications
entry 7).[15] The addition of lithium chloride proved detri-
mental to the reaction (Table 1, entry 8).[16]
the conjugated p systems into proximal position to the C Cl
bond.
À
A slightly elevated reaction temperature (308C) and slow
addition of the Grignard species were highly beneficial, the
latter preventing catalyst aggregation (Table 1, entries 9–
11).[17] The selectivity of the reaction was significantly
increased by the use of 1 mol% of [Fe(acac)3] (Table 1,
entry 12). A 10-fold increase in the reaction scale afforded 2
in 82% yield of isolated product (Table 1, entry 13). The
addition of ethyl benzoate resulted in slightly lower selectivity
(Table 1, entry 14),[7e] while ketones were not tolerated.
Table 2 shows the influence of the stereoelectronic
properties and positions of various substituents on the
reactivity of chloroarenes under modified standard conditions
(rapid addition of PhMgBr). The arylation of activated
chloroarenes (4-benzoate, 2-pyridyl) was already reported
by Fꢀrstner et al. (Table 2, entries 1 and 2).[7e] Without
electronegative or with electron-donating substituents, no
conversion was observed (Table 2, entries 4–6). Alkenyl
groups had a slightly deactivating effect because of their
electron-rich p systems, yet we postulate an olefin coordina-
tion to the catalyst followed by haptotropic[18] migration along
Unlike 2-chlorostyrene, the 3- and 4-chloro isomers
À
showed no selective activation of the C Cl bonds (Table 2,
entries 7–9). This effect is attributed to a strong coordination
of the distal vinyl groups which inhibits haptotropic migra-
tion. On the other hand, the (slight) steric hindrance of ortho-
chlorostyrene (1) favors a migration of the iron species. a-
Methyl substitution of the ortho-vinyl group effects a twisting
of the olefin and aryl planes, thus breaking the conjugated
À
system and prohibiting C Cl activation (Table 2, entry 10).
Our hypothesis of an essential coordination and migration
along the conjugated p systems is also manifested in the
reactivity of substituted 4-chlorostyrenes. The installation of
an a-methyl- or a b-phenyl group in combination with low
steric hindrance and retention of planarity led to clean
À
arylation of the distal C Cl bond (Table 2, entries 13 and 14).
This comparative study shows that, besides electron-with-
drawing moieties (as in 2-chloropyridine and ethyl-4-chlor-
obenzoate),[7e] olefins with proper substitution and position-
ing facilitate the activation of aryl chlorides. Phenylations of
2-chlorostyrene, 1-chloro-4-isopropenylbenzene, and 4-chlor-
ostilbene each proceeded with product selectivities greater
than 90% (Table 2, entries 7, 13, and 14). This new mode of
activation has then been exploited for the synthesis of diverse
hetero-biaryl compounds (Tables 3 and 4).
Table 2: Influence of substituents on reactivity of aryl chlorides.
The aryl Grignard reagents were prepared from aryl
bromides and magnesium ribbons in THF at room temper-
ature.[19] The cross-coupling reactions were conducted under
argon at 308C, with the Grignard species (0.5m in THF) being
slowly added over a period of 20 min. Fluoro-substituted
arylmagnesium bromides gave better yields upon rapid
addition (Table 3, entries 5–7, 11, 14, 16, and 18). Such less
basic Grignard reagents showed low propensity to undergo
homo-biaryl coupling and reductive catalyst deactivation/
aggregation.[17] The reaction conditions tolerate amine-,
ether-, fluoro-, chloro-, acetal-, and alkene functions. Both
aryl components can bear electron-withdrawing or electron-
donating substituents. Aryl Grignard reagents with ortho-
substituents afforded low yields (< 35%), with major for-
mation of the homo-biaryl compound.
Aryl chlorides with para- and meta-alkenyl substituents
exhibited similar reactivities under identical conditions
(Table 4), however, substrates that carry isopropenyl sub-
stituents were subject to slow deprotonation at the allylic
methyl group.[20] Cross-coupling of the resultant anionic
chlorostyrenes did not occur under the reaction conditions.
Slow addition of the arylmagnesium bromide solution over
40 minutes resulted in suppression of deprotonation and a
selective cross-coupling reaction (Table 4, entries 1–3 and 7–
9). Strongly basic Grignard reagents (Table 4, entries 5 and 6),
an excess of ArMgBr (Table 4, entries 4 and 6) or their rapid
addition (< 1 min, Table 4, entry 10) led to nonproductive
deprotonation and recovery of the aryl chloride (> 50%)
after aqueous work-up. 2-Chloronaphthalene showed only
minimal reactivity (Table 4, entry 11).
Entry
1[b]
Aryl chloride
2-pyridyl
Biaryl
Yield [%][a]
73
2[b]
4-MeCO2CC6H4
28
3[c]
4[c]
5[c]
6[c]
R’=F
H
OMe
Me
0
1
0
0
7
8
9
2-vinylphenyl
3-vinylphenyl
4-vinylphenyl
56 (61)
1 (16)
3 (20)
10
2-iso-propenylphenyl
12 (13)
11[d]
12[c]
2-allylphenyl
0 (30)
0
2-cyclopropylphenyl
13
14
4-iso-propenylphenyl
4-b-styrylphenyl
48 (49)
46 (51)
For the first time, iron-catalyzed hetero-biaryl coupling
reactions of deactivated aryl chlorides with aromatic
Grignard reagents have been realized in good yields under
[a] Yields determined by GC analysis, conversion of aryl chloride in
brackets. [b] Ref. [7e]. [c]<8% conversion. [d] Isomerization to 1-chloro-
2-propenylbenzene (20%).
1358
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1357 –1361