Direct preparation of new organozinc reagents, aminophenylzinc iodides, and their applications

Article abstract of DOI:10.1016/j.tetlet.2015.01.053

New organozinc reagents, 4-aminophenyl zinc iodide (A) and 3-aminophenyl zinc iodide (B), have been generated easily and effectively by the direct insertion of active zinc to iodoanilines which possess acidic protons. The subsequent coupling reactions of the organozincs with various acid chlorides turned out to be an efficient tool for the preparation of aminophenyl ketones.

Full text of DOI:10.1016/j.tetlet.2015.01.053

Tetrahedron Letters 56 (2015) 1004–1006
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct preparation of new organozinc reagents, aminophenylzinc
iodides, and their applications
⇑
Hye-Soo Jung, Seung-Hoi Kim
Department of Chemistry, Dankook University, 119 Dandaero, Cheonan 330-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
New organozinc reagents, 4-aminophenyl zinc iodide (A) and 3-aminophenyl zinc iodide (B), have been
generated easily and effectively by the direct insertion of active zinc to iodoanilines which possess acidic
protons. The subsequent coupling reactions of the organozincs with various acid chlorides turned out to
be an efficient tool for the preparation of aminophenyl ketones.
Received 11 November 2014
Revised 30 December 2014
Accepted 7 January 2015
Available online 14 January 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Active zinc
Direct insertion
Aminophenylzinc
Cross-coupling
Aminophenyl ketone
The aromatic amine subunit has frequently appeared as a key
building block in a wide range of areas in synthetic chemistry such
as fine chemicals, pharmaceuticals, and agrochemicals. This unique
functionality has also been found in naturally occurring bioactive
derivatives.1 In the field of synthetic chemistry, in general, this
subunit has been utilized in transition metal-catalyzed carbon–
carbon bond forming reactions. When the aromatic amine is used
in a cross-coupling reaction, it is most commonly employed in hal-
ogenated forms, while playing the role of either coupling partners
or organometallic species. However, one of the drawbacks of this
approach is the acidic character of the amine compounds, which
causes significant limitations of the use of these derivatives. To
overcome such limits, masking the acidity of amine could be a pos-
sible solution.2 In this case, an additional procedure, involving pro-
tection/deprotection steps, is required for a positive result. An
alternative is to use a synthetic equivalent such as a nitro group.
Recent examples reported by Lipshutz and Kazemi, respectively,
showed the chemoselective reduction of nitro aromatic com-
pounds to the corresponding amino aromatic products.3
examples have been reported concerning the preparation and
application of aromatic organometallic reagents bearing directly
attached amino groups.9 As expected, aminophenylboronic acids
are commercially available, and utilized in transition metal-cata-
lyzed coupling reactions.10
Considering the promising results from the previous work on
boronic acid, it was anticipated that the direct preparation of amin-
ophenylzinc reagents would be readily obtainable. The fundamen-
tals of our strategy were based upon the high reactivity of active
zinc.
Toward this aim, an initial attempt was made starting with
commercially available iodoanilines and active zinc prepared by
the literature procedure.11 To our delight, treatment of iodoani-
lines with active zinc afforded the corresponding aminophenylzinc
iodides (A and B) described in Scheme 1. The oxidative addition of
active zinc to the carbon–iodine bond of 4-iodoaniline was com-
pleted at room temperature in 24 h, affording the corresponding
organozinc reagent (A). Here, we report the easy preparation of
Despite the limitations, several worthy examples of the utiliza-
tion of haloaromatic amines in cross-coupling reactions have been
reported. In the majority of such works, halogenated aromatic
amine has been employed as a coupling partner in transition
metal-mediated coupling reactions such as the Suzuki,4 Negishi,5
Heck,6 Stille,7 and Hiyama8 reactions. In contrast, very few
O
I
ZnI
2.0 eq Zn*
acid
R, (Het)Ar
H2N
H2N
4-NH2
H2N
chloride
THF/rt/24 h
1.0 eq
A
(
)
B
( )
3-NH2
Scheme 1. Preparation of aminophenylzinc iodides and coupling reactions.
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
http://dx.doi.org/10.1016/j.tetlet.2015.01.053
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

H.-S. Jung, S.-H. Kim / Tetrahedron Letters 56 (2015) 1004–1006
1005
aminophenylzinc iodides and the subsequent coupling reaction
with carbonyl derivatives.12
corresponding (4-aminophenyl)(4-bromophenyl)methanone (1a)
was obtained in 70% isolated yield (entry 1, Table 1). Coupling
reactions of A with other acid chlorides containing an electron-
donating group (OCH3 and t-Bu) and a halogen (F, Cl, and Br) were
also performed, successfully giving rise to the ketones (1b–1e) in
moderate to good yields (entries 2–5, Table 1). Heteroaromatic acid
chlorides were also demonstrated to be suitable coupling partners
for the preparation of diaryl ketones under the same conditions. A
good result (1f, 73% yield) was obtained from the coupling reaction
with 2-furancarbonyl chloride (entry 6, Table 1). It is of interest
that the reaction conditions used for the aforementioned coupling
reactions also worked well for the coupling reaction with nicoti-
noyl chlorides. As shown in Table 1, coupling products (1g and
1h) were successfully achieved from the coupling reactions
with 6-chloropyridinecarbonyl chloride and 2-chloropyridine-
3-carbonyl chloride (entries 7 and 8, Table 1), respectively. Further
applications were explored by employing alkyl acid chlorides. Cyc-
lic alkyl carbonyl chlorides also worked well with A, furnishing
aminophenyl alkyl ketones (1i, 1j, and 1k) in moderate to good
yields (entries 9–11, Table 1).
Following the observations from the application of
4-aminophenylzinc iodide (A), 3-aminophenylzinc iodide (B) then
was treated with a variety of electrophiles in the same manner as
that employed in the case of A. The results are summarized in
Table 2. To our great delight, the coupling reactions with carbonyl
compounds proceeded smoothly under the mild conditions, afford-
ing the desired ketones (2a–2k) in similar yields to those obtained
in the case of A.
Next, we turned our attention to expansion of the applicability
of the new organozinc reagents. This was achieved by the reaction
of A and B with the more challenging carbonyl derivatives,
4-morpholinecarbonyl chloride and diethylcarbamoyl chloride. As
Prior to general application of the new organozincs (A and B) to
the cross-coupling reactions, the reagents were treated with iodine
to confirm the formation of organozinc reagents. The results
showed the reformation of 4-iodoaniline and 3-iodoaniline at over
95% in both cases, as determined by GC–MS. Therefore, it could be
concluded that the corresponding aminophenylzinc iodides were
successfully prepared under the reaction conditions used in this
study.
In order to investigate the reactivity of the new organozinc
reagent (A), it was coupled with a wide range of acid chlorides
under the typical copper-catalyzed cross-coupling reaction condi-
tions. 4-Bromobenzoyl chloride was first reacted with A in the
presence of 10 mol % CuI/20 mol % LiCl at 0 °C. As expected, the
Table 1
Coupling of A with acid chlorides
ZnI
10 % CuI
acid
ketones
1a 1k
~
+
chlorides
20 % LiCl
H2N
THF/0 oC/1 h
A (1.2 eq)
1.0 eq
Entry
1
Acid chloride
COCl
Ketone
Yielda (%)
70
O
1a
1b
1c
Br
H2N
H2N
H2N
H2N
Br
COCl
O
2
3
71
72
F
F
COCl
O
MeO
Table 2
OMe
Coupling of B with acid chlorides
COCl
COCl
O
H2N
ZnI
10 % CuI
acid
ketones
+
chloride
20 % LiCl
4
1d
70
0 oC/3 h/THF
2a - 2k
1.0 eq
B (1.2 eq)
Cl
O
O
O
O
Entry
Product
Yielda (%)
Cl
5
1e
1f
83
73
61
48
50
60
81
1
2
X = 4-Br
4-F
2a
2b
86
70
H2N
H2N
H2N
H2N
H2N
H2N
H2N
O
COCl
O
O
H2N
3
4-OMe
2c
78
6
X
4
5
4-tBu
3-Cl
2d
2e
80
87
COCl
7
1g
1h
1i
Cl
N
O
O
N
N
Cl
H2N
H2N
O
6
7
2f
95
85
COCl
8
N
Cl
Cl
2g
COCl
O
O
O
N
N
Cl
9
O
H2N
H2N
8
9
2h
2i
70
93
COCl
Cl
O
10
11
1j
n = 0
COCl
10
11
1
3
2j
71
94
1k
n
2k
a
a
Isolated yield (based on acid chloride).
Isolated yield (based on acid chloride).

1006
H.-S. Jung, S.-H. Kim / Tetrahedron Letters 56 (2015) 1004–1006
Table 3
Preparation of amides
A (1.2 eq)
10 % CuI
20 % LiCl
0
acid
chloride
(1.0 eq)
amides
or
+
3a - 3d
B (1.2 eq)
oC/1 h/THF
Entry
ArZnX
Acid chloridea
Product
Yieldb (%)
O
O
1
2
A
B
I
I
X = 4-NH2
3-NH2
3a
3b
41
31
N
X
X
O
3
4
A
B
II
II
X = 4-NH2
3-NH2
3c
3d
58
35
H3C
N
CH3
a
I: 4-morpholinecarbonyl chloride, II: dimethylcarbamoyl chloride.
Isolated yield (based on acid chloride).
b
7. For a selected examples: see; Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507.
8. For a selected examples: see; Nakamura, H.; Aizawa, M.; Takeuchi, D.; Murai,
A.; Shimoura, O. Tetrahedron Lett. 2000, 41, 2185.
9. (a) Fillon, H.; Gosmini, C.; Périchon, J. J. Am. Chem. Soc. 2003, 125, 3867; (b)
Gosmini, C.; Rollin, Y.; Nedelec, J. Y.; Perichon, J. J. Org. Chem. 2000, 65, 6024; (c)
Le Gall, E.; Gosmini, C.; Nedelec, J. Y.; Perichon, J. Tetrahedron 1923, 2001, 57;
(d) Perichon, J.; Gosmini, C.; Fillon, H. Rhodia Chim. Fr. 2003, 26
is shown in Table 2, the coupling reaction was carried out success-
fully under the same conditions as used above, affording the
expected amides (3a–3d) in moderate yields (Table 3).
In conclusion, we have demonstrated an efficient synthetic
route toward the preparation of aminophenyl aryl ketones. It was
completed by the combination of aminophenylzinc iodide synthe-
sis and its subsequent coupling reaction with a range of carbonyl
derivatives under mild conditions. Further studies to elucidate this
synthetic protocol are currently underway in our laboratory.
10. (a) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173; (b)
Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911.
11. Rieke, R. D.; Hanson, M. V.; Brown, J. D. J. Org. Chem. 1996, 61, 2726.
12. Representative procedure: (a) Preparation of 4-aminophenylzinc iodide (A); In
an oven-dried 250 mL round-bottomed flask equipped with a stir bar was
added 6.54 g of active zinc (Zn⁄, 100.0 mmol) in 100 mL of THF. The flask was
then cooled down to 0 °C using an ice-bath. Next, 4-iodoaniline (10.9 g,
50.0 mmol) solution dissolved in 40.0 mL of THF was cannulated into the flask
at 0 °C. The resulting mixture was allowed to warm up to room temperature
and stirred at ambient temperature for 24 h. The whole mixture was settled
down and then the supernatant was used for the subsequent coupling
reactions. (b) Cross-coupling reaction of A; Into a 25 mL round-bottomed
flask was placed 4-aminophenylzinc iodide (4.0 mL, 0.25 M in THF, 1.0 mmol)
under argon atmosphere, then the flask was cooled down to 0 °C using an ice-
bath. Next, 4-methoxybenzoyl chloride (0.13 g, 0.8 mmol) was added, then
stirred at 0 °C for 30 min., quenched with saturated NH4Cl solution, then
extracted with ethyl acetate (3 Â 10 mL). It was washed with saturated
NaHCO3, 8% NH4OH solutions and brine, then dried over anhydrous MgSO4.
Purification by recrystallization (hexanes/ethyl ether) afforded 0.13 g of (4-
aminophenyl)(4-methoxyphenyl)methanone (1c) in 72% isolated yield as an
off-white solid (mp 160–161 °C); 1H NMR (CDCl3/DMSO-d6, 500 MHz) d = 9.69
(s, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
6.95 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H); 13C NMR (CDCl3/DMSO-d6, 125 MHz)
d = 206.7, 165.6, 162.0, 139.1, 137.2, 128.5, 123.6, 120.6, 113.3, 55.3; IR (KBr):
~
References and notes
1. Kumar, J. S.; Ho, M. M.; Toyokuni, T. Tetrahedron Lett. 2001, 42, 5601.
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2014, 16, 6160.
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Hosseini, S. Tetrahedron Lett. 2014, 55, 338.
4. For selected examples: see; (a) Liu, B.; Moffet, K. K.; Joseph, R. W.; Dorsey, B. D.
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Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002, 67, 7541.
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Schade, M. A.; Metzger, A.; Knochel, P. J. Org. Chem. 2008, 73, 8422; (c) Stanetty,
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m
= 3337, 3052, 2959, 1655, 1590, 1438 cmÀ1. MS (70 eV, EI): m/z (%) = 227 (M+,
50), 135 (100), 92 (19), 77 (19).
6. For a selected examples: see; Dong, Y.; Busacca, C. A. J. Org. Chem. 1997, 62,
6464.