Mixed Phosphite-Phosphine and Phosphinite-Phosphine Palladacyclic Complexes as Highly Active Catalysts for the Amination of Aryl Chlorides

Article abstract of DOI:10.1002/adsc.200303068

Tri-tert-butylphosphine adducts of orthopalladated phosphite and phosphinite complexes formed in situ are excellent catalysts for the Buchwald-Hartwig amination of aryl chloride substrates.

Full text of DOI:10.1002/adsc.200303068

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Mixed Phosphite-Phosphine and Phosphinite-Phosphine
Palladacyclic Complexes as Highly Active Catalysts for the
Amination of Aryl Chlorides
Robin B. Bedford*, Michael E. Blake
School of Chemistry, University of Exeter, Exeter EX4 4QD, UK
Fax: ( ‡ 44)-1392-263-434, e-mail: r.bedford@ex.ac.uk
Received: April 10, 2003; Accepted: May 19, 2003
preformed or, more typically, produced in situ from
Abstract: Tri-tert-butylphosphine adducts of ortho-
appropriate phosphines and the complexes 3 make
palladated phosphite and phosphinite complexes
excellent catalysts for both the Suzuki coupling reaction
formed in situ are excellent catalysts for the Buch-
and the Buchwald Hartwig amination of aryl chlor-
wald Hartwig amination of aryl chloride substrates.
ides.[4] Even greater activity is seen in the Suzuki
coupling of aryl chlorides with complexes of the type
Keywords: amination; aryl chlorides; metallacycles;
4, typically formed in situ from the complexes 5, in which
palladium
the ortho-metallated N-donor ligand is replaced by an
ortho-metallated phosphite or phosphinite ligand.[5] The
basis of this increase in activity has been discussed in
terms of increased catalyst longevity rather than an
The Buchwald Hartwig amination of aryl halides increase in the rate of catalysis. The complex 4a is also a
(Scheme 1) has emerged as a powerful technique for useful catalyst for the Stille coupling of aryl chlorides.[6]
the formation of N-substituted anilines.[1] A major We were interested to see whether the complexes of the
recent focus in coupling chemistry has been on the type 4 would prove to be active catalysts for the
development of catalysts that are able to activate aryl
chloride substrates since these tend to be cheaper and
more readily available than their bromide and iodide
counterparts, factors that make them particularly rele-
vant to the industrial sector. Unfortunately the com-
À
paratively high C Cl bond strength makes their activa-
tion by oxidative-addition comparatively difficult.[2]
While there are now many reports on the use of aryl
chlorides in amination reactions,[3] in most cases the
catalysts employed need to be used in relatively high
loadings (typically a few mol % Pd). Therefore the
advantages associated with the use of aryl chlorides may
be negated by the high cost of the catalyst systems and
the need to remove palladium residues from the
products down to the ppm level for use in fine chemicals
and pharmaceutical applications. Consequently there is
considerable interest in the development of catalysts
that can activate aryl chlorides at low loadings.
Our interest has been in the development and use of
palladacyclic catalysts in coupling reactions and recently
we have been particularly interested in their application
to the coupling of aryl chloride substrates. We have
shown that complexes of the type 1 and 2, either
Scheme 1. The Buchwald Hartwig amination of aryl halides.
Figure 1.
Adv. Synth. Catal. 2003, 345, 1107 1110
DOI: 10.1002/adsc.200303068
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Robin B. Bedford, Michael E. Blake
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Table 1. Amination of aryl chlorides.
amination of aryl chlorides and the preliminary results
from this investigation are presented below.
In the first instance we examined the coupling of the
deactivated (electron-rich) aryl chloride substrate 4-
chloroanisole with morpholine using a catalyst formed
in situ from complex 5a and 1 equivalent per palladium
of tricyclohexylphosphine. This catalyst did not show a
particularly high activity. Unlike in the Suzuki reaction,
where PCy3 is an excellent ligand for the coupling of aryl
chlorides, provided the correct choice of palladium
precursor is made,[4b,7] it seems, from both the data
presented here and those obtained previously using
complex 1a, that PCy3 is not a particularly useful ligand
in the amination of deactivated aryl chlorides. However,
when it is replaced by tri-tert-butylphosphine, then high
levels of activity result. The excellent maximum turn-
over number (TON, mol product/mol palladium) of 960
(entry 4) is comparable with that obtained using the
notionally related pre-catalyst system 1b.[4b] By contrast,
when this reaction is performed under identical con-
ditions with a mixture of palladium acetate (0.1 mol %
Pd) and two equivalents of P(t-Bu)3 then a conversion of
only 2% is obtained, corresponding to a TON of 20.[4b]
As with the Suzuki coupling of aryl chlorides catalysed
by PCy3 or PCy2(o-biphenyl) ligands,[4b] it can be seen
that the precise nature of the palladium source is of
enormous importance, with palladacycles acting as
highly potent precursors.
Diarylamines, alkylarylamines and dialkylamines can
all be used as substrates. As can be seen the isolated
yields of most of the coupled products are good to
excellent with a range of aryl chloride substrates, despite
the fact that the work-up was not optimised. In all cases
the H NMR of the crude mixtures showed the con-
versions to be higher than the isolated yields of pure
products, typically in the 90 100% range.
[a]
Aryl chloride (5.0 mmol), amine (6.25 mmol), NaOt-Bu
(7.0 mmol), toluene (10 mL), 1008C, 17 h.
Isolated yield, not optimised.
Conversion to coupled product, based on aryl chloride,
determined by GC (hexadecane standard).
15 mmol of HNEt2 used in a sealed tube.
1
[b]
[c]
Changing from the ortho-palladated phosphite pre-
cursor 5a to the less p-acidic phosphinite analogue 5b
leads to a reduction in activity (entries 5 and 6), in line
with the results obtained in the Suzuki coupling of aryl
chlorides with these catalysts.[5,12b]
[d]
ligand. For this reason complex 6 does not catalyse the
The active catalysts are likely to be palladium(0) coupling of this substrate.[10]
species formed from the palladacyclic precursors either
It is possible that the ortho-metallated ring in com-
thermally or by a reductive process in which the ortho- plexes of the type 5 can also be ring-opened by reductive
metallated aryl group reacts with one of the coupling elimination with an amido ligand (Scheme 3), a mech-
partners.[8,9] Hartwig has shown that the palladacyclic anism which effectively mimics the latter steps of an
catalyst 6 undergoes activation by reductive elimination amination catalytic cycle. While stoichiometric reaction
of the palladated methylene and a hydride introduced to of complex 5a with diphenylamine and NaOt-Bu in
the co-ordination sphere by b-elimination from a co- toluene at reflux temperature seems to generate palla-
ordinated diethylamido ligand (Scheme 2).[10] The dium(0) as demonstrated by the development of a black
putative catalyst is a zerovalent mono- or bis-phosphine colouration, spectroscopic characterisation of the reac-
complex. While such a mechanism may be responsible tion mixture gives, at present, equivocal results. How-
for the formation of active catalysts when 5a- and 5b-P(t- ever, a small peak in the GC/MS has a mass and
Bu)3 mixtures are used, it cannot be the only activation fragmentation pattern consistent with the formation of
pathway. This is because we observe good activity with the 2-aminated phenol 7, suggesting that, to a limited
diphenylamine, which contains no available hydrogens extent, the speculative activation pathway shown in
for b-elimination from an intermediate diphenylamide Scheme 3 may be operative. Further work to prove or
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Phosphite-Phosphine and Phosphinite-Phosphine Palladacyclic Complexes
COMMUNICATIONS
Scheme 3. A putative activation pathway for complex 5a.
Scheme 2. The activation mechanism of
a palladacyclic
catalyst via b-elimination from a co-ordinated amine.[10]
Method used for Entries 5 and 6
As above except rather than purifying the products by column
chromatography, after quenching, extraction and drying
(MgSO4) the crude reaction mixture was concentrated to
5 mL on a rotary evaporator, hexadecane (0.068 M in toluene,
1.00 mL, internal standard) was added and the conversion to
coupled product was determined by GC.
refute this putative mechanism and determine whether
any other activation processes are active is ongoing.
In conclusion, tri-tert-butylphosphine adducts of
phosphinite- and, in particular, phosphite-based palla-
dacycles show good activity as catalysts for the Buch-
wald Hartwig amination of a range of aryl chloride and
amine substrates even at loadings as low as 0.1 mol %
Pd. The very low cost of the tris(2,4-di-tert-butyl)phos-
phite ligand[11] and the facile synthesis of its palladacy-
clic complex 5a,[12] make this catalyst precursor par-
ticularly attractive for amination reactions.
Coupling of 4-Chlorotoluene with Diethylamine
(entry 10)
As for the general method, except that the reaction was
performed in a thick-walled reaction tube (~40 mL) which was
sealed with a Teflon stopcock and 15 mmol of HNEt2 were
used.
Acknowledgements
We thank the EPSRC for funding (PDRA for MEB) and
Johnson Matthey for the loan of palladium salts.
Experimental Section
General Procedure for the Amination of Aryl
Chlorides (Table 1, entries 1 4, 7 9, 11 14)
References and Notes
[1] For reviews, see: a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux,
S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805; b) J. F.
Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046; c) B. H.
Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576,
125.
In a Schlenk tube a solution of the complex 5a or b and the
appropriate trialkylphosphine in toluene (5 mL) was stirred at
room temperature for 5 min. The appropriate aryl chloride
(5.0 mmol), amine (6.25 mmol), NaOt-Bu (0.675 g, 7.0 mmol)
and more toluene (5 mL) were added and then the reaction
mixture was heated at 1008C for 17 hours. After cooling water
(50 mL) was added, the product was extracted with CH2Cl2
(4 Â 50 mL), the solution dried (MgSO4), filtered and the
solvent removed under reduced pressure. The product amines
[2] For a discussion, see: V. V. Grushin, H. Alper, Chem.
Rev. 1994, 94, 1047.
[3] For examples of aryl chloride amination reactions, see:
a) M. S. Viciu, R. M. Kissling, E. D. Stevens, S. P. Nolan,
Org. Lett. 2002, 4, 2229; b) G. Y. Li, G. Zheng, A. F.
Noonan, J. Org. Chem. 2001, 66, 8677; c) G. Y. Li,
Angew. Chem. Int. Ed. 2001, 40, 1513; d) J. P. Wolfe, H.
1
were purified by column chromatography. H and 13C NMR
spectroscopic data for the product amines are consistent with
reported data.[3f,13]
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¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Robin B. Bedford, Michael E. Blake
COMMUNICATIONS
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2000, 65, 1158; e) S. R. Stauffer, S. Lee, J. P. Stambuli,
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[11] This ligand is cheaper than triphenylphosphine. Source:
the Aldrich catalogue.
[12] a) D. A. Albisson, R. B. Bedford, S. E. Lawrence, P. N.
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