Palladium-catalyzed multiple aryl animations of polybromobenzenes

Article abstract of DOI:10.1055/s-1998-1692

Morpholinobenzenes with up to four N-morpholino groups have been synthesized efficiently from the corresponding bromobenzenes via palladium catalyzed multiple aryl amination reactions. Surprisingly, hexabromobenzene (1) yielded selectively 1,2,4,5-(N,N,N,N)-tetra-(23) and 1,3,5-(N,N,N)-trimorpholinobenzene (14).

Full text of DOI:10.1055/s-1998-1692

504
LETTERS
SYNLETT
Palladium-Catalyzed Multiple Aryl Aminations of Polybromobenzenes
Bernhard Witulski, Stefan Senft, Andreas Thum
Fachbereich Chemie, Universität Kaiserslautern, Erwin Schrödinger Straße, D-67663 Kaiserslautern, Germany
Fax: +49 (0)631 205 3921; Bernhard@chemie.uni-kl.de
Received 2 February 1998
Abstract: Morpholinobenzenes with up to four N-morpholino groups
have been synthesized efficiently from the corresponding
bromobenzenes via palladium catalyzed multiple aryl amination
reactions. Surprisingly, hexabromobenzene (1) yielded selectively
1,2,4,5-(N,N,N,N)-tetra-(23) and 1,3,5-(N,N,N)-trimorpholinobenzene
(14).
dibromobenzene ( ), as well as with 1,3,5-tri- ( ), 1,2,4-tri- ( ) and
11 13 15
1,2,3-tribromobenzene ( ) are summarized in Table 1: With the
17
exception of the 1,4-dibromobenzene-( ) case - where significant higher
9
yields of the double aminated product were obtained with P(o-tolyl)
10
3
as ligand - catalysts based on the bidentate ligands BINAP, or DPPF
turned out to be consistently more efficient. Particularly, the bidentate
ligands BINAP and DPPF were essential for aryl aminations at two
11
adjacent positions (see entries 3 and 5, Table 1). Major by-products,
Benzenes having two and more amino substituents have received
considerable interest due to their strong electron donor character, their
that were formed via a β-hydride elimination from reactive palladium-
amido intermediates yielding the hydrogenolysis of the aryl bromide,
1
easy oxidation to the mono-, di-, or even higher cations, and their
were either N-morpholinobenzene ( ) in the case of twofold aryl
8
capability to form crystalline charge transfer complexes and radical salts
aminations, or 1,3-(N,N)-bismorpholinobenzene ( ) in the case of
7
13
2
with suitable electron acceptor molecules. Whereas 1,3,5-N,N,N-
and , respectively. The coupling of with three adjacent positions
15
could not be achieved under the conditions employed. Interestingly,
1,2,3-tribromobenzene yielded selectively 1,3-(N,N)-
could not be found in the
2
(dialkyl)-substituted aminobenzenes have served as model systems for
3
the understanding of the electrophilic aromatic substitution,
( )
17
aminobenzenes with C or higher symmetry have gained interest in the
3
bismorpholinobenzene ( ). Its isomer
7
12
quest for the benzene dication and for organic ferromagnetic
reaction mixture.
4
compounds. However, the access to oligoaminobenzenes is often
limited by multistep syntheses, forcing reaction conditions, and/or the
1-5
scope of the available methods.
A direct approach to this class of electron-rich aminobenzenes can be
imagined in the palladium mediated multiple coupling of primary or
secondary amines to readily available polybromobenzenes. Inter- and
intramolecular palladium catalyzed aryl aminations of numerous
bromobenzenes with primary and secondary amines have been studied
6
by the groups of Buchwald and Hartwig in detail. However, the
7
efficiency of multiple aryl aminations, which would transform more or
less electron-poor benzenes into extremely electron-rich ones, and the
compatibility of the palladium mediated catalytic cycle with such easily
oxidizable aminobenzenes have not been investigated yet.
From the background of already achieved palladium catalyzed sixfold
8
9
alkynylations and alkenylations of hexabromobenzene (1) yielding 3
and the sterically encumbered benzene 4, respectively, we investigated
the palladium catalyzed multiple amination reactions of morpholine (2)
with various polybromobenzenes, asking whether the sixfold coupling
of 2 with 1 could lead to the hexaaminated product 5 (Scheme 1).
The difference in reactivity between multifold couplings in 1,4- and 1,3-
position seemed to be due to the enhanced electron donating effect of a
para amino substituent causing an increase in the rates of β-hydride
eliminations, and such electronic effects appear to be less favorable for
catalyst systems based on bidentate ligands. This result was underlined
by the reactions of N-phenylpiperazidine
(
)
with tris(4-
19
12
11
bromophenyl)amine (
18
)
and (Scheme 2). Once more P(o-tolyl)
13
was the more efficient ligand for coupling reactions resulting in
products having a 1,4-bis-aminobenzene moiety. Whereas product
3
20
was isolated in 60% yield with P(o-tolyl) as ligand, complex mixtures
of aryl amination and reduction products were obtained with BINAP as
ligand. In contrast the latter gave best results for the threefold coupling
3
Scheme 1
Products, yields, and reaction conditions of the two- and threefold
of
with
. The efficiency of this protocol leading to
(98%
21
19
13
13
coupling reactions of
with 1,3-di- ( ), 1,4-di- ( ) and 1,2-
6 9
yield) might have potential for the synthesis of higher generation
2

May 1998
SYNLETT
505
dendrimers; dendrimers that should have very interesting redox and
electron transfer properties.
observed selectivity in the palladium catalyzed aryl amination reactions
with , and (see Table 1 and Scheme 4).
4, 12
,
,
13 15 17
1
A
fourfold coupling reaction could be achieved with 1,2,4,5-
tetrabromobenzene (22) and 2 and with either Pd (dba) /BINAP, or
2
3
Pd(DPPF)Cl /DPPF as catalyst providing 1,2,4,5-(N,N,N,N)-tetra-
2
14
morpholinobenzene (23) in 72% and 43% yield, respectively. The
1,2,4-tris-isomer 16 was the major by-product (Scheme 3).
Acknowledgment: We would like to thank Prof. Dr. M. Regitz for his
generous support. Financial support of the ‘Fonds der Chemischen
Industrie’ is acknowledged.
References and Notes
The palladium catalyzed aryl amination of hexabromobenzene ( ) with
1
did not give the exhaustively aminated product . Surprisingly,
1,2,4,5-(N,N,N,N)-tetra-( ) and 1,3,5-(N,N,N)-trimorpholinobenzene
23
) were isolated instead in 37% and 36% yield, respectively (Scheme
14
2
5
(1) Wolff, J. J.; Zietsch, A.; Irngartinger, H.; Oeser, T. Angew. Chem.
1997, 109, 637; Angew. Chem. Int. Ed. Engl. 1997, 36, 621.
Effenberger, F.; Mündel, G. Chem. Ber. 1992, 125, 247. Upsani,
R. B.; Chiang, L. Y.; Goshorn, D. P.; Tindall, P. Mol. Cryst. Liq.
Cryst. 1990, 190, 35. Dietrich, M.; Heinze, J. J. Am. Chem. Soc.
1990, 112, 5142. Chance, J. M.; Kahr, B.; Buda, A. B.; Toscano,
J. P.; Mislow, K. J. Org. Chem. 1988, 53, 3226. Elbl, K.; Krieger,
C.; Staab, H. A. Angew. Chem. 1986, 98, 1024; Angew. Chem. Int.
Ed. Engl. 1986, 25, 1023.
(
4). The pronounced selectivity observed in this case and in aryl
aminations with 1,2,3-tribromobenzene indicates that three
( )
13
adjacent amino groups cannot be introduced into an aromatic ring via
the palladium catalyzed multiple arylamination reaction, at least under
the conditions employed here. In addition the β-hydride elimination
‘side-reaction’ yielding a hydrogenolysis of the aryl bromide seems to
be more facile between two amino substituents, and that should be
mainly attributed to steric effects. This result is illustrated by the

506
LETTERS
SYNLETT
1
13
(2) Keller, H. J.; Niebl, R.; Renner, G.; von der Ruhr, D.; Kilic, A. K.;
(11) All new compounds were characterized by IR, MS, H- and
NMR, elemental analysis and/or HRMS.
C
Schweitzer, D. Z. Naturforsch. 1989, 44b, 327.
(12) For recent investigations to utilize 18 in the synthesis of discrete
molecular weight dendrimers via the aryl amination protocol see:
Louie, J.; Hartwig, J. F.; Fry, A. J. J. Am. Chem. Soc. 1997, 119,
11695.
(3) Effenberger, F. Acc. Chem. Res. 1989, 22, 27.
(4) Stickley, K. R.; Blackstock, S. C. J. Am. Chem. Soc. 1994, 116,
11576. Krusic, P. J.; Wasserman, E. J. Am. Chem. Soc. 1991, 113,
2322. Miller, J. S.; Dixon, D. A.; Calabrese, J. C.; Vazquez, C.;
Krusic, P. J.; Ward, M. D.; Wasserman, E.; Harlow, R. L. J. Am.
Chem. Soc. 1990, 112, 381. Thomaides, J.; Maslak, P.; Breslow,
R. J. Am. Chem. Soc. 1988, 110, 3970.
(13) Spectroscopic data of : colorless solid; m.p. 169-171 °C; R =
21
f
1
0.24 (Alox/N-TLC, hexanes/ethyl acetate = 9 : 1 (v/v)); H NMR
(400 MHz, CDCl ) δ = 7.29 (dd, J = 7.3 Hz, J = 8.1 Hz, 2H), 6.97
3
(d, J = 8.1 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.20 (s, 1H), 3.30 (s,
13
(5) Effenberger, F.; Prossel, G.; Auer, E.; Fischer, P. Chem. Ber.
1970, 103, 1456. Effenberger, F.; Auer, E.; Fischer, P. Chem. Ber.
1970, 103, 1440. Effenberger, F.; Niess, R. Chem. Ber. 1968, 101,
3787. Biemans, H. A. M.; Zhang, C.; Smith, P.; Kooijman, H.;
Smeets, W. J. J.; Spek, A. L.; Meijer, E. W. J. Org. Chem. 1996,
61, 9012. Wolff, J. J.; Limbach, H.-H. Liebigs Ann. Chem. 1991,
691. Praefcke, K.; Kohne, B.; Korinth, F.; Psaras, P.; Nasielski, J.;
Verhoeven, C.; Nasielski-Hinkens, R. Liebigs Ann. Chem. 1989,
617.
8H). C NMR (100 MHz, CDCl ) δ = 153.1 (s), 151.2 (s), 129.1
3
(d), 116.2 (d), 119.9 (d), 98.5 (d), 49.9 (t), 49.4 (t); IR (KBr) ν =
-1
3058 cm ; 3035, 2956, 2820, 1590, 1499, 1448, 1382, 1335,
1310, 1271, 1234, 1205, 1152, MS (EI, 70 eV) m/z (%): 558 (28,
+
M ), 426 (81), 266 (14), 120 (25), 44 (100); C
H N : calc.: C
36 42 6
77.38, H 7.58, N 15.04; found C 76.91, H 7.44; N 14.69. EI-
HRMS: calc. for C N 558.3471; found 558.3486.
H
36 42
6
(14) Typical procedure: In a Schlenk tube with screw cap were
introduced under argon 1,2,4,5-tetrabromobenzene (22) (276 mg,
0.70 mmol), morpholine (2) (292 mg, 3.36 mmol), sodium tert-
butoxide (376 mg, 3.92 mmol), Pd (dba) (19 mg, 0.02 mmol),
(6) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451. Hartwig, J. F. Synlett 1997, 329. Marcoux, J. F.;
Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1568.
Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217. Guram, S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem. 1995, 107, 1456; Angew. Chem. Int. Ed. Engl. 1995, 34,
1348.
2
3
BINAP (39 mg, 0.06 mmol), and toluene (5 ml). The sealed tube
was kept at 100 °C for 2 d. The reaction mixture was diluted with
brine and extracted with CH Cl . After evaporation of the
2
2
solvents the organic residues were extracted with diethyl ether
dissolving compound 16 only. Column chromatography of the
residue (SiO ; CH Cl /hexanes/ethyl ether = 8 : 2 : 2 (v/v/v)) gave
2
2
2
analytically pure 23 (210 mg, 0.50 mmol, 72%). Compound 16
(7) For Pd-catalyzed polycondensations between 1,3-bisanilines and
6 see: Kanbara, T.; Izumi, K.; Nakadani, Y.; Narise, T.;
Hasegawa, K. Chem. Lett. 1997, 1185.
was obtained after chromatography of the ether extracts (SiO ,
2
hexanes/diethyl ether = 3 : 7 (v/v) yielding analytically pure 16
(50 mg, 0.15 mmol, 21%).
: colorless plates (CHCl /pentane); m.p. >300 °C; R = 0.3
23
(8) Diercks, R.; Armstrong, J. C.; Boese, R.; Vollhardt, K. P. C.
Angew. Chem. 1986, 98, 270; Angew. Chem. Int. Ed. Engl. 1986,
25, 268. Boese, R.; Green, J. R.; Mittendorf, J.; Mohler, D. L.;
Vollhardt, K. P. C. Angew. Chem. 1992, 104, 1643; Angew. Chem.
Int. Ed. Engl. 1992, 31, 1643.
3
f
1
(SiO -TLC, CH Cl /hexanes/diethylether = 8 : 2 : 2 (v/v/v)); H
2
2
2
NMR (200 MHz, CDCl ) δ = 6.53 (s, 2H), 3.80 (‘t’, J ~ 4.5 Hz, 16
3
13
H), 3.15 (‘t’, J ~ 4.5 Hz, 16 H); C NMR (100 MHz, CDCl ) δ =
139.6 (s), 109.3 (d), 67.6 (t), 50.3 (t); IR (KBr) ν = 2965 cm ;
3
-1
2794, 1514, 1438, 1258, 1209, 1113, 972, 934, 915; MS (EI, 70
eV) m/z (%): 419 (25); 418 (100, M ), 360 (2), 302 (2), 243 (4);
(9) Rinz, P.; Lansky, A.; Haumann, T.; Boese, R.; Noltemeyer, M.;
Knieriem, B.; de Meijere, A. Angew. Chem. 1997, 109, 1343;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1289.
+
C
H N O : calc.: C 63.13, H 8.19, N 13.39; found: C 62.73, H
22 34 4 4
7.99, N 13.19.
: colorless plates (CH Cl /hexanes), m.p. 125-126 °C; R : 0.3
10
(10) Synthesis of 1,2,3-tri-bromobenzene 17: Tietze, L. F.; Eicher, Th.
Reaktionen und Synthesen Thieme: Stuttgart, 1991, p. 501. The
morpholinobenzenes 7, 10, 12, 14, and 16 have been previously
synthesized by non-catalytic methods: 7 and 12: Kawaguchi, M.;
Ohashi, J. Synthesis 1985, 701. 10: Axe, W. N.; Freeman, C. J.
Am. Chem. Soc. 1934, 56, 478. 14: Effenberger, F.; Niess, R.
Angew. Chem. 1967, 79, 1100; Angew. Chem. Int. Ed. Engl. 1967,
6, 1067. 16: Baroni, S.; Rivera, E.; Stradi, R.; Sacarello, M. L.
Tetrahedron Lett. 1980, 21, 889.
16
(SiO -TLC, hexanes/ethyl acetate = 3 : 7 (v/v)); H NMR (200
2
2
f
1
2
MHz, CDCl ) δ = 6.83-6.9 (m, 1 H), 6.52-6.57 (m, 2 H), 3.79-3.87
3
13
(m, 12 H); C NMR (200 MHz, CDCl ) δ = 147.7 (s), 145.4 (s),
3
138.1 (s), 119.0 (d), 109.8 (d), 107.7 (d), 67.6 (t), 66.9 (t), 50.5 (t),
-1
50.2 (t), 50.1 (t); IR (KBr) ν = 2957 cm , 2850, 1602, 1506, 1448,
+
1253, 1117; MS (70 eV) m/z (%): 333 (85, M ), 249 (13), 248
(100), 190 (30), 132 (37); C
H N O calc.: C 64.84, H 8.16, N
18 27 3 3
12.60; found: C 64.79, H 8.11, N 12.77.