Aromatic aminations by heterogeneous Ni0/C catalysis

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4492::AID-ANIE4492>3.0.CO;2-8

Cost counts! And green chemistry is "in". Thus, for Pd⁰- or Ni⁰-catalyzed aminations of aryl halides, which are usually conducted under homogeneous conditions, a new methodology is disclosed which allows for amination reactions on less costly aryl chlorides mediated by an especially inexpensive heterogeneous catalyst, nickel-on-charcoal (Ni/C,see scheme; DPPF 00= 1,1′-bis(diphenylphosphanyl)ferrocene).

Full text of DOI:10.1002/1521-3773(20001215)39:24<4492::AID-ANIE4492>3.0.CO;2-8

COMMUNICATIONS
Aromatic Aminations by Heterogeneous Ni0/C
Catalysis**
Bruce H. Lipshutz* and Hiroshi Ueda
Dedicated to Professor Harry H. Wasserman
on the occasion of his 80th birthday
Replacement of a leaving group on an aryl ring by nitrogen
has been the focus of much research of late.[1] Most successful
have been methods which rely on Pd0 catalysis,[2] where a
variety of primary and secondary amines can replace a
bromide, iodide, or pseudo halide, including in some cases
chlorides,[3] to afford the corresponding aniline compounds.
Other approaches, which invoke Ni0 catalysis[4] or titanium ±
nitrogen fixation,[5] are uniformly conducted under homoge-
neous conditions.[6] Given the importance of aryl amines in a
variety of contexts ?e.g., pharmaceuticals), a potentially
scaleable heterogeneous[7] process which utilizes inexpensive
precursor chlorides and nickel rather than palladium may
provide a welcomed complement to existing protocols. Here-
in, we describe our initial work leading to an expedient
method for effecting aminations of aryl chlorides using the
heterogeneous catalyst[8] nickel-on-charcoal [Ni/C; Eq. ?1)].
Scheme 1. Ligands shown to be unsuitable for displacement by amine.
In our previous work carbon ± carbon bond-forming reac-
tions mediated by Ni/C ?e.g., Negishi,[9a] Kumada,[9b] and
Suzuki[9c] couplings) were usually best achieved in the
presence of four equivalents of Ph3P, relative to the percent
loading of Ni?NO3)2 onto charcoal ?ca. 5 ± 10%). In the
presence of Ph3P, nBuLi ?two equivalents relative to nickel)
was introduced presumably generating the phosphane-ligated
active Ni0/C. However, this combination was not applicable to
displacements by an amine ?i.e., conversions were low or no
reaction occurred), nor were alternatives based on a screening
of several other phosphane ligands ?Scheme 1). Eventually it
was observed that not only did 1,1'-bis?diphenylphosphanyl)-
ferrocene ?DPPF) lead to high yields of aminated aryl-ring
products, but only one half of an equivalent ?relative to
nickel) of this bidentate ligand was necessary. In most cases,
5 mole% Ni/C was sufficient, which translated into the use of
only 2.5% DPPF. While other ratios of Ni/C:DPPF could be
employed ?Figure 1), the 2:1 relationship was the best
compromise. Either dioxane or toluene at reflux[10] appears
to be suitable as solvent, whereas THF ?with a lower boiling
point) led to limited levels of educt consumption. Curiously,
the base LiOtBu consistently gave statistically significant
Figure 1. Reactivity of various %ratios of Ni/C:DPPF in aromatic
amination reactions. y?%) ˆ %Conversion.
greater rates of coupling and ultimately higher isolated yields
than either the sodium[2a] or potassium analogues ?Schemes 2
and 3). Other bases ?e.g., Cs2CO3) were ineffective. The
Scheme 2. Base: LiOtBu ?93% conversion); NaOtBu ?84% conversion);
KOtBu ?0% conversion).
Scheme 3. Base: LiOtBu ?100% conversion); NaOtBu ?19% conversion);
KOtBu ?18% conversion).
[*] Prof. B. H. Lipshutz, H. Ueda
Department of Chemistry
monodentate ligand 1,[11] examined in place of DPPF,[12] was
ineffective at the 2.5% or 10% level versus substrate ?3% and
24% conversion, respectively).
With LiOtBu ?1.2 equiv)[13] and the amine
?2 equiv) in the presence of Ni/C, various aryl
chlorides could be smoothly converted to their
aniline derivatives ?Table 1). The aryl chlorides
University of California
Santa Barbara, CA 93106 ?USA)
Fax : ?‡1)805-893-8265
E-mail: lipshutz@chem.ucsb.edu
[**] We thank the NIH ?GM 40 287) for supporting our programs, and the
Sumitomo Chemical Co. Ltd. for a research assistantship awarded to
H.U.
4492
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4492 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 24

COMMUNICATIONS
Table 1. Ni/C-catalyzed aminations of aryl chlorides.
Entry
Halide
Amine
Product[a]
Ni/DPPF loading [mol%]
Solvent[b]
Time [h]
Yield [%][c]
5/10
5/2.5
5/2.5
dioxane
dioxane
toluene
5
4.5
2.5
91
87
88
1
2
10/20
dioxane
6
78
92
3
4
5/2.5
5/2.5
toluene9
toluene
77
3.5
5
6
10/20
5/10
dioxane
dioxane
4791
20
93
90
7
8
10/20
5/5
dioxane
toluene
24
52
70
76
9
5/2.5
toluene
46
10
11
5/2.5
5/5
toluene
toluene
16
15
87
69
[a] Fully characterized by IR, NMR, and MS data. [b] Oil bath temperature was maintained at 1308C. [c] Isolated, chromatographically pure material.
Bn ˆ benzyl, Hex ˆ hexyl.
[1] a) J. F. Hartwig, Angew. Chem. 1998, 110, 2154 ± 2177; Angew. Chem.
which reacted favorably range from the electron-poor to the
electron-rich, and include a test case for steric effects of ortho
substitution ?entry 9). Several anilines could be used as
Int. Ed. 1998, 37, 2046 ± 2067; b) C. G. Frost, P. Mendonca, J. Chem.
Soc. Perkin Trans. 1 1998, 2615 ± 2623; c) A. J. Belfield, G. R. Brown,
A. J. Foubister, Tetrahedron 1999, 55, 11399 ± 11428; d) P. Y. S. Lam,
nucleophiles, including an ortho-methylated example ?en-
try 2). Pyrrolidyl ?entry 10), morpholinyl ?entries 1, 5 and 8),
and a piperidinyl system ?entry 4) all participated, as did
primary ?entries 9 and 11) and secondary amines ?e.g.,
dibenzylamine, entry 3). No aryl amination reactions were
noted with hexamethyldisilazane, imidazole, 13-aza-
[15]crown-5,[14] and the sta base.[15]
In summary, a novel method for effecting aromatic
aminations using aryl chlorides under heterogeneous condi-
tions[16] is presented. Reliance on the combination of a NiII
salt[17] supported on activated charcoal may be viewed as an
experimentally appealing and economical alternative to
existing protocols, in particular to those which utilize Pd0
S. Deudon, K. M. Averill, R. Li, M. Y. He, P. De Shong, C. G. Clark, J.
Am. Chem. Soc. 2000, 122, 7600 ± 7601.
[2] a) J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144 ± 1157;
b) J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy, L. M.
Alcazar-Roman, J. Org. Chem. 1999, 64, 5575 ± 5580; c) I. P. Belet-
skaya, A. G. Bessmertnykh, R. Guilard, Synlett 1999, 1459 ± 1461;
d) M. C. Harris, O. Geis, S. L. Buchwald, J. Org. Chem. 1999, 64,
6019 ± 6022; e) Y. D. Ward, V. Farina, Tetrahedron Lett. 1996, 37,
6993 ± 6996; f) C. A. Willoughby, K. T. Chapman, Tetrahedron Lett.
1996, 37, 7181 ± 7184. See also L. M. Alcazar-Roman, J. F. Hartwig,
A. L. Rheingold, L. M. Liable-Sands, I. A. Guzei, J. Am. Chem. Soc.
2000, 122, 4618 ± 4630.
[3] a) S. R. Stauffer, S. Lee, J. P. Stambuli, S. I. Hauck, J. F. Hartwig, Org.
Lett. 2000, 2, 1423 ± 1426; b) J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin,
S. L. Buchwald, J. Org. Chem. 2000, 65, 1158 ± 1174; c) X. Bei, A. S.
Guram, H. W. Turner, W. H. Weinberg, Tetrahedron Lett. 1999, 40,
1237± 1240; d) J. Huang, G. Grasa, S. P. Nolan, Org. Lett. 1999, 1,
1307± 1309; e) M. Beller, T. H. Riermeier, C.-P. Reisinger, W. A.
under homogeneous conditions.
Received: August 9, 2000
Revised: September 29, 2000 [Z15609]
Angew. Chem. Int. Ed. 2000, 39, No. 24
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4493 $ 17.50+.50/0
4493

COMMUNICATIONS
Herrmann, Tetrahedron Lett. 1997, 38, 2073 ± 2074; f) N. P. Reddy, M.
Tanaka, Tetrahedron Lett. 1997, 38, 4807± 4810.
Application of a Spin-Labeled Spin-Trap to the
Detection of Nitric Oxide 'NO)**
[4] a) C. Desmarets, R. Schneider, Y. Fort, Tetrahedron Lett. 2000, 41,
2875 ± 2879; b) E. Brenner, R. Schneider, Y. Fort, Tetrahedron Lett.
2000, 41, 2881 ± 2884; c) J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc.
1997, 119, 6054 ± 6058; d) R. Cramer, D. R. Coulson, J. Org. Chem.
1975, 40, 2267± 2273.
[5] K. Hori, M. Mori, J. Am. Chem. Soc. 1998, 120, 7651 ± 7652.
[6] For aromatic aminations a) in the absence of solvent, see: L. Schio, G.
Lemoine, M. Klich, Synlett 1999, 1559 ± 1562; b) under high pressure,
see: H. Kotski, H. Sakai, T. Shinohara, Synlett 2000, 116 ± 118; c) by
nucleophilic substitution, see: A. J. Belfield, G. R. Brown, A. J.
Foubister, P. D. Ratcliffe, Tetrahedron 1999, 55, 13285 ± 13300.
[7] G. V. Smith, F. Notheisz in Heterogeneous Catalysis in Organic
Chemistry, Academic Press, San Diego, 1999.
[8] a) J. S. Bradley, B. Tesche, W. Busser, M. Maase, M. T. Reetz, J. Am.
Chem. Soc. 2000, 122, 4631 ± 4636; b) M. T. Reetz, E. Westermann,
Angew. Chem. 2000, 112, 170 ± 173; Angew. Chem. Int. Ed. 2000, 39,
165 ± 168; c) M. T. Reetz, R. Breinbauer, P. Wedemann, P. Binger,
Tetrahedron 1998, 54, 1233 ± 1240.
[9] a) B. H. Lipshutz, P. A. Blomgren, J. Am. Chem. Soc. 1999, 121, 5819 ±
5820; b) B. H. Lipshutz, T. Tomioka, P. A. Blomgren, J. Sclafani,
Inorg. Chim. Acta 1999, 296, 164 ± 169; c) B. H. Lipshutz, J. A.
Sclafani, P. A. Blomgren, Tetrahedron 2000, 56, 2139 ± 2144.
[10] It was important to maintain a strong reflux, which was accomplished
by setting the oil bath temperature to 1308C.
Â
Lucien Marx and Andre Rassat*
When a dilute monoradical reacts to give diamagnetic
products, its EPR signal decays without major changes, while
when a diradical is transformed into a monoradical, a new
EPR spectrum is generally observed. In the case of a diradical
with strong dipolar interaction,[1] the single broad line is
replaced by three narrow lines, and there is a very large
increase of the monoradical signal. A narrow-line monorad-
ical in very low concentration and a broad-line diradical in
much higher concentration display peaks of similar height,[2]
as shown in Figure 1 where the EPR spectra of synthetic
mixtures of tempone ?2,2,6,6-tetramethyl-4-oxo-1-oxypiperi-
dine ?radical); line width DH ˆ 0.18 mT) and of diradical 1[3]
?DH ˆ 4.2 mT) are presented: even when the monoradical
constitutes only 0.1% of the total paramagnetic species, its
signal can be detected.
[11] D. Guillaneux, H. B. Kagan, J. Org. Chem. 1995, 60, 2502 ± 2505.
[12] A similar observation has been made in the case of 2,2'-bis?diphenyl-
phosphanyl)-1,1'-binaphthyl ?BINAP) and its monodentate ana-
logue.[2a] By contrast, in refluxing dioxane ?5% Ni/C, LiOtBu, 18 h),
use of 2.5% DPPF led to 95% conversion.
[13] M. Prashad, B. Hu, Y. Lu, R. Draper, D. Har, O. Repic, T. J. Blacklock,
J. Org. Chem. 2000, 65, 2612 ± 2614.
[14] B. Witulski, Synlett 1999, 1223 ± 1226.
[15] S. Djuric, J. Venit, P. Magnus, Tetrahedron Lett. 1981, 22, 1787 ± 1790.
Commercially available from Gelest.
[16] Representative procedure for the amination of aryl chlorides ?Table 1,
entry 1): NiII/C ?50.5 mg, 0.038 mmol, 0.74 mmolgÀ1), DPPF ?10.7mg,
0.019 mmol), and lithium tert-butoxide ?74.3 mg, 0.90 mmol) were
added to a flame-dried 5 mL round-bottomed flask under a blanket of
argon at room temperature. Dry toluene ?0.5 mL) was added by
syringe and the slurry allowed to stir for 90 min. n-Butyllithium
?31 mL, 2.42m in hexanes, 0.075 mmol) was added dropwise with
swirling. After 30 min, 4-chlorobenzonitrile ?104.2 mg, 0.75 mmol),
which was dissolved in dry toluene ?0.5 mL), and morpholine ?132 mL,
1.50 mmol) were added, followed by heating to reflux for 2.5 h ?the oil
bath temperature was set to 1308C). After cooling to room temper-
ature, the crude reaction mixture was then filtered through a glass
filter and the filter cake further washed with methanol and dichloro-
methane. The filtrate was collected, solvents were removed on a
rotary evaporator and the crude product was then purified by flash
chromatography with cyclohexane/EtOH ?7/3) to give 123.8 mg
?0.66 mmol; 88%) N-?4-cyanophenyl)-morpholine as a pale yellow
solid.[4c]
Figure 1. EPR spectra of ethanol solutions of synthetic mixtures contain-
ing ?from top to bottom) 0, 0.1, 0.5, and 1 mole% of tempone relative to
10À3 m diradical 1.
This suggests a new use of diradicals as spin-labeled spin-
traps. These reagents would combine a stable radical ?RT),
designed to trap selectively the radical to be detected and to
yield diamagnetic products, and another radical ?RL), un-
reactive during this reaction, at a distance such that the
diradical EPR spectrum would be a single line.[4] In this way,
as RT reacts, the signal of the RL moiety would be detected at
the very beginning of the reaction, with both the concen-
tration of spin trap and of spin adduct being monitored on the
same spectrum. Furthermore, the rate of the trapping reaction
?usually bimolecular) could easily be increased by increasing
the biradical concentration.
[17] The extent of nickel bleed from the charcoal was quantitatively
assessed to be 2.3 ± 2.9% of the 5% Ni/C ?i.e., 0.15% relative to
substrate) using inductively coupled plasma ?ICP) atomic emission
spectrometry. For an overview of this technique, see: Inductively
Coupled Plasma Mass Spectrometry ?Ed.: A. Montaser), Wiley-VCH,
New York, 1998.
[*] Prof. A. Rassat, Dr. L. Marx
Â
UMR CNRS 8640, Departement de Chimie
Â
Ecole Normale Superieure
24 rue Lhomond, 75231 Paris CEDEX 05 ?France)
Fax : ?‡33)144323325
E-mail: andre.rassat@ens.fr
[**] This work was supported by the French Ministry of Education ?ENS),
the French Ministry of Defense, and CNRS.
4494
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4494 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 24