Iron-catalyzed chemoselective ortho arylation of aryl imines by directed C-H bond activation

Full text of DOI:10.1002/anie.200900454

Angewandte
Chemie
DOI: 10.1002/anie.200900454
Cross-Coupling
Iron-Catalyzed Chemoselective ortho Arylation of Aryl Imines by
À
Directed C H Bond Activation**
Naohiko Yoshikai, Arimasa Matsumoto, Jakob Norinder, and Eiichi Nakamura*
Iron is cheap, ubiquitous, nontoxic, and ideal for catalysis;[1]
however, the true interest of chemists resides in the unique d-
orbital properties of iron that may give rise to unique catalytic
activities.[2] Having an interest in the latter subject as well as in
the former,[3] we reported on asymmetric carbometalation[4]
bromine or triflate substitution under palladium catalysis.
Control experiments indicated that 1,2-dichloroisobutane
(DCIB) is essential to achieve the observed preference for
À
the C H bond activation in the iron catalysis.
Screening of the substrate and the catalytic system
(Table 1) indicated that a combination of 10 mol% of [Fe-
(acac)3] (acac = acetylacetonate) and 4,4’-di-tert-butyl-2,2’-
bipyridine (dtbpy) used together with the mild oxidant,
DCIB (2 equiv), and a Ph2Zn reagent [prepared from 6 equiv
of phenylmagnesium bromide and 3 equiv of ZnCl2·TMEDA
À
and on C H bond activation reactions of pyridine deriva-
tives.[5] We report herein an iron-catalyzed coupling of an
aromatic imine and a diarylzinc reagent which results in the
À
direct displacement of the ortho-C H bond of the imine by
the aryl group of the zinc reagent, providing a convenient
method for the synthesis of ortho-substituted aromatic
ketones. A unique feature of this reaction is that the
substitution of the ortho-hydrogen atom occurs preferentially
to that of the electrofugal leaving groups on the same aryl
ring. This feature is illustrated in Scheme 1, wherein the
reaction of an imine and a Ph2Zn reagent results in a
hydrogen atom substitution under iron catalysis, and in
(TMEDA = N,N,N’,N’-tetramethylethylenediamine)]
con-
verts effectively an acetophenone-derived imine (e.g.,
4-methoxy-N-(1-phenylethylidene)aniline) into the corre-
sponding ortho-phenylated product. The stoichiometry of
the reaction is such that one equivalent of the Ph2Zn reagent
serves to remove the ortho-hydrogen atom, another equiv-
alent to introduce the product, and a small amount to
generate a low-valent reactive iron catalyst.[5] A PhZnBr
reagent was found to be entirely unreactive. A phenylation
reaction did not take place when [Fe(acac)3] was replaced by
[Mn(acac)3], [Co(acac)2], or [Ni(acac)2].[6] The reaction was
complete in about 20 hours at 08C; elevated temperatures
tend to destroy the catalytic activity.
As shown in Table 1, entry 1, virtually no reaction took
place in the absence of any aromatic diamine ligand. 1,10-
Phenanthroline (phen, 10 mol%), which served as the best
additive in our previous study,[5] was found to be unsatis-
factory, and 2,2’-bipyridine (bpy) was found to not be very
Table 1: Screening the conditions for the iron-catalyzed reaction of aryl
imines with a diphenylzinc reagent.[a]
Entry
R
Ligand
Conversion [%][b]
Scheme 1. Iron- or palladium-catalyzed reaction of a halogen (pseudo-
halogen)-bearing aryl imine and a diphenylzinc reagent. Tf=trifluor-
omethanesulfonyl, THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
1
2
3
4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
4-MeC6H4
4-CF3C6H4
2-MeC6H4
none
phen
bpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
2
86
54
100 (91)[c]
52
5[d]
6
[*] Dr. N. Yoshikai, A. Matsumoto, Dr. J. Norinder, Prof. Dr. E. Nakamura
Department of Chemistry, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5800-6889
100
100
94
7
8
9
74
E-mail: nakamura@chem.s.u-tokyo.ac.jp
[**] We thank MEXT (Japan) for financial support (Grant-in-Aid for
Scientific Research, no.18105004 for E.N. and no.20038014 for
N.Y.) and the Global COE program for Chemistry Innovation.
[a] The reaction was carried out on a 0.4 mmol scale. [b] The conversion
was determined by GC analysis, employing n-tridecane as an internal
standard. [c] The yield of the isolated product of the corresponding
ketone after hydrolysis is shown in parentheses. [d] Used 1,2-dichloro-
ethane instead of 1,2-dichloroisobutane.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900454.
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2925

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Table 2: Iron-catalyzed direct phenylation of aryl imine derivatives with a
effective (Table 1, entries 2 and 3). After screening a variety
diphenylzinc reagent.[a]
of bidentate aromatic amines, we found that using dtbpy leads
quantitatively to desired product (Table 1, entry 4). After
in situ hydrolysis of the product, the corresponding ortho-
phenylated ketone was obtained in 91% yield upon isolation.
The use of 1,2-dichloroethane in place of DCIB resulted in
much lower conversion (Table 1, entry 5).
Entry
Substrate
Product
t
Yield
[h] [%][b]
1
2
1a
1b
2a
2b
20
20
91
99
We found that an imine group was the best directing group
À
in this C H bond activation, and chose, for the subsequent
studies, the (4-methoxyphenyl)imines 1 because of the ease of
their preparation and handling. Acetophenone itself, the
corresponding methoxime, and N,N-dimethylhydrazone were
found to be entirely unreactive. We examined imines derived
from aniline, 4-methyl-, 4-methoxy-, 4-trifluoromethyl-,
2-methyl-, and 2-methoxyanilines, all of which gave good to
excellent yields after a 20 hour reaction time at 08C (Table 1,
entries 6–9 and see the Supporting Information). The
4-trifluoromethylphenylimine and the 2-methylphenylimine
reacted at a slightly slower rate than the others, which implies
that coordination at the imine nitrogen atom is involved in the
reaction, but is not the step that greatly affects the reaction
rate.
Table 2 summarizes the substrate scope of the iron-
catalyzed, imine-directed arylation reaction. Imines derived
from acetophenone (1a), propiophenone (1b), and tetralone
(1c) gave the desired monophenylated products 2a–2c in
yields ranging from 91% to 99% (Table 2, entries 1–3). A
2-thienyl imine derivative 1d also smoothly underwent
phenylation at the 3-position to give a product 2d in 96%
yield (Table 2, entry 4). The reaction of the aldehyde-derived
imine 1e afforded a mixture of a diphenylated product 3e
(58% yield) and a monophenylated product 2e (6% yield).
We consider that this mixture results from the higher
conformational flexibility of the aldehyde-derived imine
than that of the ketone-derived imines.
The present reaction shows a good tolerance for halide
and pseudohalide groups, which is particularly notable in view
of the similarity of the reaction conditions to those of iron-
catalyzed cross-coupling of aryl halides and pseudohalides
(Table 2, entries 6–12).[1,7] Chloro- and bromoaryl compounds
1 f–1i reacted more slowly than the parent substrate 1a, but
still gave phenylated products 2 f–2i in yields of 83% to 92%
after 48–72 hours (Table 2, entries 6–9). The chlorine atoms of
1 f and 1g were entirely retained, and the bromine atoms of
1h and 1i were reductively removed only to a small extent
(3% yield).
3
4
1c
1d
2c
20
20
93
96
2d
2e
(R=H) 48
3e
(R=Ph)
6
58
5[c]
1e
1 f
1g
1h
1i
48
6
2 f
2g
2h
2i
72
92
87
83
88
7
72
48
72
8[d]
9
10[d]
11[e,f]
12[e]
13
1j
2j
3
9
14
89
1k
1l
2k
2l
(20) (89)
9
20
9
89
94
90
57
1m
1n
1o
2m
2n
2o
14[e]
15
72
Notably, the reaction of the bromide substrate 1h in the
absence of DCIB resulted in a mixture of compounds formed
[a] Unless otherwise noted, the reaction was carried out on a 0.4 mmol
scale under the reaction conditions indicated in Scheme 1. [b] Yields of
isolated products. [c] Used Fe(acac)3/dtbpy (15 mol%), PhMgBr
(12 equiv), ZnCl2·TMEDA (6 equiv), and of 1,2-dichloroisobutane
(4 equiv). [d] Obtained as a mixture containing a dehalogenated product;
yield was determined by 1H NMR analysis. [e] Used ZnCl2·TMEDA
(2.5 equiv) and PhMgBr (5 equiv). [f] Data for a 1.5 g scale reaction are
shown in parentheses (see the Experimental Section).
À
from the C H bond activation, the reductive removal of the
À
bromide, and the cross-coupling at the C Br group (see the
Supporting Information). The phenylation of meta-chloro and
meta-bromo substrates 1g and 1i took place exclusively at the
less hindered side of the two ortho positions. Reductive
removal of the iodine atom in the aryl iodide substrate 1j was
predominant, but the reaction still afforded a reasonable
amount of the desired phenylated product 2j (Table 2,
entry 10). The ortho-halogenated imines resulted in the
complete loss of the halogen atom and gave only an ortho-
phenylated product, either because of direct halogen sub-
stitution or of dehalogenation and subsequent phenylation
(see the Supporting Information).
The reaction also tolerates the presence of triflate and
tosylate groups (Table 2, entries 11 and 12). The sulfonate
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Table 3: Iron-catalyzed direct arylation of aryl imine 1k with a diarylzinc
reagent.[a]
compounds 1k and 1l reacted much faster than the parent
substrate 1a, and complete conversion of the starting material
was achieved by using
a near stoichiometric amount
(2.5 equiv) of the diphenylzinc reagent for a shorter reaction
time (9 h).[8]
Overall, the rate of the present reaction was found to
show a rather peculiar substituent dependence. Whereas the
para-methoxy compound 1m reacted at essentially the same
rate as that of the parent compound 1a (Table 2, entry 13), the
para-trifluoromethyl compound 1n was much more reactive
(Table 2, entry 14; 90% yield with 2.5 equiv of the diphenyl-
zinc reagent within 9 h). In contrast, the reaction of the para-
cyano compound 1o was much more sluggish, and gave the
product 2o in 57% yield after 72 hours (Table 2, entry 15).
The order of reactivity of the substituted acetophenone-
derived imines can be qualitatively summarized as 4-CF3,
OTf, OTs > H (parent), 4-OMe > 4-X, 2-X (X = Br, Cl) >
Entry
1
R
Product
t [h] Yield [%][b]
Ph
2k
9
89
88
2
3
4
5
6
4-MeOC6H4
4-tBuC6H4
4-ClC6H4
2-MeC6H4
Me
2p 20
2q 20
2r 72
2s 72
2t 72
À
4-CN, suggesting that the C H bond activation reaction is
86
52
0
influenced by both the inductive and resonance effects of the
substituent.[9]
The scope of the diaryl reagents was studied for the
reaction of the triflate substrate 1k (Table 3). 4-Methoxyphe-
nylzinc and 4-tert-butylphenylzinc reagents smoothly partici-
pated in the reaction, and afforded the corresponding
arylation products 2p and 2q in 88% and 86% yields,
respectively (Table 3, entries 2 and 3). In contrast, the
reaction of the 4-chlorophenylzinc reagent was much more
sluggish (Table 3, entry 4). A 2-tolylzinc reagent did not give
the arylation products at all, perhaps because of the steric
effect (Table 3, entry 5). A Me2Zn reagent prepared from
MeMgBr gave the expected methylation product 2t, albeit in
a low yield (Table 3, entry 6).[10,11]
18
The compatibility of the present catalysis with aryl–X
(halogen or pseudohalogen) bonds allows us to carry out
[a] Unless otherwise noted, the reaction was carried out on a 0.4 mmol
scale under the reaction conditions indicated in the equation. [b] Yields
of isolated products.
À
regioselective, sequential functionalization of aromatic C H
À
and C X bonds. For example, the bromo biaryl 2h, obtained
by the iron catalysis, was quantitatively converted into a
terphenyl derivative by palladium-catalyzed Suzuki–Miyaura
coupling with 4-methoxyphenylboronic acid [Eq. (1)].
pounds.[14] The reaction exhibits some unusual characteristics
which are difficult to understand at this time, and will be an
interesting subject of mechanistic studies in the future.
Experimental Section
Iron-catalyzed phenylation of the imine 1k: ZnCl2·TMEDA (2.53 g,
10.0 mmol) was placed in a Schlenk tube, cooled to 08C, and then a
THF solution of phenylmagnesium bromide (17.2 mL, 1.16m,
20.0 mmol) was added dropwise to the reaction mixture. After
stirring the mixture for 1 h, the imine 1k (1.49 g, 4.0 mmol), THF
(20 mL), 1,2-dichloroisobutane (0.92 mL, 8.0 mmol), and a 0.1m
solution of Fe(acac)3 and 4,4’-di-tert-butyl-2,2’-bipyridine in THF
(4.0 mL, 0.4 mmol) were sequentially introduced. The reaction
mixture was stirred at 08C for 20 h and then quenched by the
addition of 3 n HCl (40 mL). The resulting mixture was stirred for 3 h
at room temperature and extracted with ethyl acetate (20 mL ꢀ 3).
The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography (eluent: n-hexane/EtOAc 19:1) to give the ketone
2k as a colorless oil (1.23 g, 89% yield).
In summary, we have developed an iron-catalyzed imine-
À
À
directed conversion of an ortho C H bond into a C C bond.
The reaction takes place under mild conditions (08C in THF)
and tolerates the presence of reactive functional groups such
as aryl bromides, chlorides, and sulfonates. The reaction
À
provides not only an interesting new example of C H bond
Received: January 23, 2009
Published online: March 17, 2009
activation,[12,13] but also a new synthesis for biaryl com-
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À
Angew. Chem. Int. Ed. 2005, 44, 1654 – 1658; c) A. Fꢁrstner, A.
Leitner, M. Mꢃndez, H. Krause, J. Am. Chem. Soc. 2002, 124,
13856 – 13863.
Keywords: arylation · C H activation · cross-coupling ·
homogeneous catalysis · iron
.
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GC analysis when 3 equivalents of the diphenyl reagent was
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[9] One of the reviewers suggested that the low reactivity of 1o
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