Preparation of polyfunctional amines by the addition of functionalized organomagnesium reagents to nitrosoarenes

Article abstract of DOI:10.1055/s-2003-38738

The addition of functionalized arylmagnesium reagents to nitrosoarenes at -20°C in THF furnishes after a reductive work-up polyfunctional diarylamines in 43-74% yield.

Full text of DOI:10.1055/s-2003-38738

LETTER
885
Preparation of Polyfunctional Amines by the Addition of Functionalized
Organomagnesium Reagents to Nitrosoarenes
P
reparation of
e
P
olyfuncti
l
onal
A
m
i
ines x Kopp, Ioannis Sapountzis, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax +49(89)21807680; E-mail: knoch@cup.uni-muenchen.de
Received 19 March 2003
allowing the direct addition of various arylmagnesium
compounds 1 to various nitrosoarenes 4 leading after re-
ductive workup to the polyfunctional diarylamines 3a–k
(Scheme 2 and Table 1).
Abstract: The addition of functionalized arylmagnesium reagents
to nitrosoarenes at –20 °C in THF furnishes after a reductive work-
up polyfunctional diarylamines in 43–74% yield.
Key words: diarylamines, nitrosoarenes, organomagnesium re-
agents, arylation of amines, amination reaction
The reaction mixture of PhMgCl (1a; 1.2 equiv) with ni-
trosobenzene (4a; 1 equiv) in THF at –20 °C was stirred
for 1 h and treated with FeCl2/NaBH4 at 25 °C for 2 h af-
fording diphenylamine (3a) in 68% yield (entry 1 of
Table 1). Several functionalized arylmagnesium com-
pounds (1b–f) bearing either electron-withdrawing or
electron-donating groups add to nitrosobenzene 4a in sat-
isfactory yields (entries 2–6). Functionalized or substitut-
ed nitrosobenzenes like 4b–c undergo the addition
reaction furnishing the polyfunctional diarylamines 3g–k
in 42–74% yield (entries 7–11). This new procedure al-
lows the preparation of polyfunctional diarylamines 3
bearing various functional groups with an optimum atom
economy, since only 1.2 equivalents of the Grignard re-
agent are used compared to 2.3 equivalents, which are
required in the reaction with nitroarenes.
The amination of aryl halides is an important reaction.1
Recently, several Pd(0)2 and Cu(I)3 catalyzed reactions
between aromatic halides and various amines have been
reported.4 We found that this synthetic transformation can
also be realized by reacting various polyfunctional aryl-
magnesium species 1 with nitroarenes 2 leading after a re-
ductive workup procedure to polyfunctional amines of
type 3 (Scheme 1).5 This reaction requires two equiva-
lents of the arylmagnesium reagent 1 since a first equiva-
lent is wasted for the generation of the reactive
nitrosoarene 4, which reacts in a second step with
Ar1MgX 1 providing the magnesiated hydroxylamine 5.6
After reduction with FeCl2/NaBH4 the amines 3 are pro-
duced in good yields. Since a wide range of polyfunction-
al arylmagnesium reagents 17 can be used for this
amination, the waste of one equivalent of Ar1MgX (con-
verted to Ar1OH) is disturbing. This could now be avoided
by using directly the nitrosoarene8 4 for the amination
reaction. Herein, we wish to report an efficient method
O
H
N
1.) THF, –20 °C, 1 h
Ar2
N
+
Ar1MgX
Ar2
Ar1
2.) FeCl2 / NaBH4,
r.t., 2 h
4
1a–g (1.2 equiv)
3a–k: 42–74 %
Scheme 2
1.) Ar1MgX (1; 2 equiv),
In summary, we have developed a new synthesis of poly-
functional diarylamines by the addition of arylmagnesium
halides to nitrosoarenes. The study of the extension of
this reaction is currently underway in our laboratories.
H
–20 °C, 2 h
N
Ar2 NO2
Ar2
Ar1
2.) FeCl2, NaBH4
2
3: 63–94 %
Ar1MgX
FeCl2 / NaBH4
1
Ar1OMgX
Preparation of 4-Iodophenyl-phenylamine (3d); Typical Proce-
dure
O
OMgX
Ar1
A dry, argon-flushed Schlenk-flask equipped with a septum and a
magnetic stirring bar was charged with 1,4-diiodobenzene (791 mg,
2.40 mmol, 1.2 equiv) in anhydrous THF (8 mL) and cooled to
–20 °C. i-PrMgCl (3.30 mL, 2.64 mmol, 1.3 equiv; 0.8 M in THF)
was added dropwise via a cannula. The resulting mixture was stirred
0.5 h at –20 °C. When the iodine-magnesium-exchange was com-
plete (as indicated by GC-MS-analysis of a reaction aliquot), ni-
trosobenzene (4a; 214 mg, 2.00 mmol) was added neat as one
portion and the mixture was stirred for another 1.5 h at –20 °C. After
quenching the reaction mixture by addition of ethanol (1 mL), it was
allowed to warm up to room temperature. Iron(II)chloride (507 mg,
4.00 mmol, 2.0 equiv) and sodium borohydride (76 mg, 2.00 mmol,
1.0 equiv) were added. The reaction mixture was stirred for 2 h at
Ar2
N
Ar2
N
Ar1MgX
4
5
1
Scheme 1
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0885,0887,ftx,en;G03203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

886
F. Kopp et al.
LETTER
room temperature and poured into brine (30 mL). The aqueous layer
was extracted with diethyl ether (3 × 30 mL), the combined or-
ganic extracts were washed with brine (50 mL) and dried (Na2SO4).
The solvent was removed in vacuo and the crude product was puri-
fied by flash chromatography (silica gel, pentane/CH2Cl2, 7:1).
After chromatographical purification, the product was dried in
high vacuum, dissolved again in ether and filtered over cotton
wool. Removal of solvent afforded the product (3d) as pale yellow,
crystalline solid (419 mg, 1.42 mmol, 71% yield).9
Table 1 Polyfunctional Diarylamines of Type 3 Obtained by the Reaction of Arylnitroso Compounds 4 with Functionalized Arylmagnesium
Reagents 1
Entry
1
Ar2NO 4
Ar1MgX 1
Diarylamines 3
Yield (%)a
68
PhNO
4a
PhMgCl
1a
H
N
3a
2
PhNO
4a
p-EtO2C-C6H4-MgCl
1b
73
H
N
EtO2C
3b
3
4
5
6
7
PhNO
4a
p-MeO-C6H4-MgBr
1c
50
71
43
58
42
H
N
MeO
3c
PhNO
4a
p-I-C6H4-MgCl
1d
H
N
I
3d
PhNO
4a
p-Br-C6H4-MgCl
1e
H
N
Br
3e
PhNO
4a
m-CN-C6H4-MgCl
1f
H
N
NC
3f
o-Me-C6H4-NO
p-COOEt-C6H4-MgCl
4b
1b
H
N
EtO2C
3g
8
p- Me2N-C6H4NO
4c
PhMgCl
1a
73
H
N
NMe2
3h
Synlett 2003, No. 6, 885–887 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparation of Polyfunctional Amines
887
Table 1 Polyfunctional Diarylamines of Type 3 Obtained by the Reaction of Arylnitroso Compounds 4 with Functionalized Arylmagnesium
Reagents 1 (continued)
Entry
9
Ar2NO 4
Ar1MgX 1
Diarylamines 3
Yield (%)a
72
p-Me2N-C6H4-NO
4c
p-EtO2C-C6H4-MgCl
1b
H
N
EtO2C
NMe2
3i
H
N
10
11
p-Me2N-C6H4-NO
4c
p-MeO-C6H4-MgBr
1c
74
60
MeO
NMe2
3j
p-Me2N-C6H4-NO
o-Me2N-C6H4-MgCl
NMe2
4c
1g
H
N
NMe2
3k
(6) (a) Köbrich, G.; Buck, P. Chem. Ber. 1970, 103, 1412.
(b) Yost, Y.; Gutmann, H. R.; Muscoplat, C. C. J. Chem.
Soc. C 1971, 2119.
(7) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.;
Vu, V. A.; Knochel, P. Synthesis 2002, 265. (b) Rottländer,
M.; Boymond, L.; Bérillon, L.; Leprêtre, A.; Varchi, G.;
Avolio, S.; Laaziri, H.; Quéguiner, G.; Ricci, A.; Cahiez, G.;
Knochel, P. Chem.–Eur. J. 2000, 6, 767.
(8) Recently, the utility of addition reactions of silyl enol ethers
to N=O-bonds has been demonstrated: (a) Momoyama, N.;
Yamamoto, H. Angew. Chem. Int. Ed. 2002, 41, 2986.
(b) Momoyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.
(9) Analytical data of 3d:
Acknowledgment
We thank the Aventis Pharma (Frankfurt a. M.) for a fellowship to
I. S. We thank the Fonds der Chemischen Industrie for the generous
support of research. We also thank the BASF AG, Degussa AG,
Chemetall GmbH and Bayer AG for generous gifts of chemicals.
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Mp: 103–104 °C; 1H NMR (300 MHz, CDCl3): δ [ppm] =
5.59 (br s, 1 H, NH), 6.73–6.76 (d, 3J = 8.48 Hz, 2 H,
CHarom.), 6.87–6.99 (m, 3 H, CHarom.), 7.18–7.23 (m, 2 H,
CHarom.), 7.42–7.45 (d, 3J = 8.48 Hz, 2 H, CHarom.); 13C NMR
(75 MHz, CDCl3): δ [ppm] = 82.07, 118.53, 119.25, 121.80,
129.42, 138.06, 142.16, 143.13; IR (KBr): [cm–1] = 3399 (s),
3054 (w), 3028 (w), 1932 (w), 1603 (s), 1581(vs), 1503(vs),
1482(vs), 1441 (m), 1387 (m), 1338 (w), 1315(vs), 1282
(m), 1238 (m), 1175 (m), 1154 (w), 1106 (w), 1078 (w),
1058 (w), 1027 (w), 1000 (w), 932 (w), 873 (w), 836 (m),
826 (m), 806 (m), 749 (s), 702 (m), 691 (s), 670 (w), 650 (w),
626 (w), 588 (w), 502 (m), 488 (w); MS (EI): m/z (I): 295
(100, M+), 167 (31), 139 (2), 84 (8), 77 (2); HRMS: calcd:
294.9858; found: 294.9856; C12H10IN: calcd: C: 48.84; H:
3.42; N: 4.75; I: 43.00; found: C: 48.93; H: 3.40; N: 4.74; I:
42.99.
(4) For nickel-catalyzed aminations: (a) Lipshutz, B. H.; Ueda,
H. Angew. Chem. Int. Ed. 2000, 39, 4492. (b) Desmarets,
C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001, 42, 247.
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Synlett 2003, No. 6, 885–887 ISSN 0936-5214 © Thieme Stuttgart · New York