Room-temperature amination of deactivated aniline and aryl halide partners with carbonate base using a Pd-PEPPSI-IPentCl-o-picoline catalyst

Article abstract of DOI:10.1002/anie.201310457

Current state-of-the-art protocols for the coupling of unreactive amines (e.g., electron-poor anilines) with deactivated oxidative-addition partners (e.g., electron-rich and/or hindered aryl chlorides) involve strong heating (usually >100 °C) and/or tert-butoxide base, and even then not all couplings are successful. The aggressive base tert-butoxide reacts with and in many instances destroys the typical functional groups that are necessary for the function of most organic molecules, such as carbonyl groups, esters, nitriles, amides, alcohols, and amines. The new catalyst described herein, Pd-PEPPSI-IPent^Cl-o-picoline, is able to aminate profoundly deactivated coupling partners when using only carbonate base at room temperature. Running mild: An N-heterocyclic carbene complex of palladium (1) was systematically designed to enable the amination of strongly deactivated substrates (R¹ can be strongly electron donating, R² can be strongly electron-withdrawing) when using the most mild of bases (carbonate) at room temperature. This catalyst was used to produce elaborate, richly functionalized products for use in life-, health-, and material-science applications.

Full text of DOI:10.1002/anie.201310457

Angewandte
Chemie
DOI: 10.1002/anie.201310457
Amination
Room-Temperature Amination of Deactivated Aniline and Aryl
Halide Partners with Carbonate Base Using a Pd-PEPPSI-IPentCl-
o-Picoline Catalyst**
Matthew Pompeo, Jennifer L. Farmer, Robert D. J. Froese, and Michael G. Organ*
Abstract: Current state-of-the-art protocols for the coupling of
unreactive amines (e.g., electron-poor anilines) with deacti-
vated oxidative-addition partners (e.g., electron-rich and/or
hindered aryl chlorides) involve strong heating (usually
> 1008C) and/or tert-butoxide base, and even then not all
couplings are successful. The aggressive base tert-butoxide
reacts with and in many instances destroys the typical func-
tional groups that are necessary for the function of most
organic molecules, such as carbonyl groups, esters, nitriles,
amides, alcohols, and amines. The new catalyst described
herein, Pd-PEPPSI-IPentCl-o-picoline, is able to aminate
profoundly deactivated coupling partners when using only
carbonate base at room temperature.
electron-rich phosphanes.[1c,3] Recent efforts to increase the
bulk of both the phosphanes[4] and the NHCs[2,5] has greatly
facilitated reductive elimination (RE), both in amination and
many other cross-coupling protocols. It has been suggested
that the remaining challenges for metal-catalyzed amination
include the intervening steps of amine coordination to the
metal and deprotonation, which can often be treated together.
In this context, the nature of the amine is critical. For alkyl
amines, which are strongly basic, coordination to the electro-
philic PdII center is favorable and it is deprotonation that is
challenging owing to the pKa value (ca. 8–10) of the
corresponding metal–ammonium complex (5). Conversely,
anilines (e.g., R1 = Ar) are far less basic, which diminishes
their coordinating ability, although this is compensated for by
a reduction in the pKa value of the amine proton by several
orders of magnitude. Taken together, the difficulties in these
middle steps, and in OA in the case of some phosphane
ligands, means that amination reactions are usually heated to
very high temperatures (usually > 1008C).[6] Furthermore, to
compensate for the problems with deprotonation, the vast
majority of couplings in the literature require the use of
strong, aggressive bases such as tert-butoxide.[7] Unfortu-
nately, taken together, these forceful reaction conditions that
are currently state-of-the-art limit the use of this otherwise
useful methodology to the production of products often
devoid of more elaborate functionality.[6–8] Ideally, one single
catalyst would possess sufficient reactivity to mediate the
most challenging amination reactions at the lowest practical
temperature (RT), with the most mild of bases (e.g.,
P
alladium-catalyzed amination has been demonstrated to be
a highly valuable transformation for the preparation of
natural products and other important molecules in the
pharmaceutical, agrochemical, and materials sectors.[1] The
general amination catalytic cycle is shown in Scheme 1 and
the rate-limiting step of the process is affected by a number of
different reaction attributes. The rate of oxidative addition
(OA) is enhanced by an electron-rich metal[2] and is generally
accelerated by N-heterocyclic carbene (NHC) ligands or
carbonate), in
a reaction that is operationally simple
(merely combine the reactants and stir), and with no limit
to the functionality that can be tolerated. This challenging
goal is the focus of this report.
In 2008, we disclosed that the pyridine-enhanced precat-
alyst preparation stabilization and initiation (PEPPSI) cata-
lyst Pd-PEPPSI-IPr (8) is an effective precatalyst for the
amination of aryl chlorides and bromides with anilines and
secondary amines when using KOtBu as the base (IPr= 2,6-
diisopropylphenyl-2H-imidazol-2-ylidene).[9] In that report,
Cs2CO3 was also demonstrated to be effective when coupling
secondary amines, however only when electron-deficient aryl
halides were employed. Presumably, the electron-withdraw-
ing group was necessary to increase the acidity of the Pd–
ammonium complex (5) sufficiently for it to be deprotonated
Scheme 1. Putative amination catalytic cycle.
[*] M. Pompeo, J. L. Farmer, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
E-mail: organ@yorku.ca
Homepage: http://www.yorku.ca/organ/
Dr. R. D. J. Froese
The Dow Chemical Company
Midland, MI 48674 (USA)
À
by a base with a conjugate acid (HCO3 ) with a pKa value of
approximately 10.5. Later, a bulkier Pd-PEPPSI-IPent pre-
catalyst (11a) was shown to vastly outperform 8 in the
coupling of anilines with electronically deactivated (i.e.,
electron-rich) aryl chlorides when using Cs2CO3 as the
[**] This work was supported by NSERC (Canada) and the Ontario
Research Fund (ORF, Ontario).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310457.
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base[10] (IPent = 2,6-(3-pentyl)pentylphenyl-2H-imidazol-2-
ylidene). However, although this catalyst was effective with
a limited selection of anilines, forcing conditions (refluxing
toluene) were required.
More recently, we have demonstrated that modifying the
backbone of the NHC core can have a profound impact on
reactivity and selectivity, thereby leading to dramatic
improvements in a variety of cross-coupling reactions.[11–13]
In an attempt to improve the chronic problems associated
with amination (see above), we brought to bear what we had
learned in other applications to see if it was possible to create
a mild and general coupling procedure that would work even
with electronically deactivated coupling partners. To inves-
tigate whether a more electron-poor NHC, and thus a pre-
sumably more electrophilic Pd centre, would help to promote
both coordination and deprotonation, we began our study
with a systematic evaluation of the IPr-based NHC core (see
Table 1 and Scheme 2 for the precatalyst structures).
Scheme 2. PEPPSI precatalysts used in this amination study.
Table 1: Control amination reactions to evaluate the effect of substitu-
tions at the IPr NHC core.[a]
amination with aniline derivatives is first order with respect to
the base (carbonate) and aniline, which suggests that aniline
coordination and deprotonation are key to the overall rate
and thus the success or failure of this coupling.[10a] With Pd-
PEPPSI-IPent (11a), which features a more electron-rich Pd
center than Pd-PEPPSI-IPr (8),[12] high conversion was
observed across all three substrate pairings. Again this
would seem to indicate that electronic effects per se are
either unimportant or at least less important than steric
effects.
To further probe the above-mentioned steric/electronic
effects, we compared IPent (in 11a) and its chlorinated
analogue IPentCl (in 12a) in the coupling of deactivated
partners that proved challenging for 11a (Table 2). In every
case, 12a outperformed 11a, most strikingly with penta-
fluoroaniline to give 19, which to our knowledge represents
the first report of a successful Pd-catalysed amination
employing this profoundly deactivated aniline. Consistent
with other results from our group,[11–13] adding substituents to
the backbone of the NHC core vastly increases the reactivity
of the resultant Pd–NHC complexes.
[a] Reactions were conducted on a 0.5 mmol scale at a concentration of
1m. The precatylsts used and the associated yield are given below the
product numbers. Yields are reported for products purified by flash
chromatography and were averaged over two runs.
In this study, Pd-PEPPSI-IPr (8) showed no activity in the
reactions to give products 14 and 15. Only when the aryl
chloride OA partner was considerably activated, in which
case the reaction proceeded efficiently with all the catalysts
tested, was the product (16) produced with high yield. We
know from other cross-coupling studies that precatalyst 8
readily undergoes OA with essentially any aryl halide,[5k–n] so
the lack of reactivity with electron-neutral (simple phenyl) or
electron-rich (e.g., p-methoxyphenyl) aryl halides is not
linked to OA. From the reactivity of precatalysts 9a and 10,
which have been shown to possess a more electron-deficient
metal center,[12] there are clear signs of improved reactivity, in
particular for the synthesis of product 15. However, precata-
lyst 9b, which possesses a more electron-rich Pd center than
IPr (8),[12,14] demonstrates reactivity equal to or better than
that of 9a and 10. It would thus appear that the electronic
effects of the NHC are not solely responsible for increasing
the rate of this transformation, a result that raises the question
of whether coordination or deprotonation is more important
for the observed rate. In rate studies, we have shown that
Table 2: Comparison of Pd-PEPPSI-IPent (11a) and Pd-PEPPSI-IPentCl
(12a) for the coupling of deactivated 4-chloroanisole.[a]
[a] Reactions were conducted on a 0.5 mmol scale at a concentration of
1m. The precatylsts used and associated yields are given below the
product numbers. Yields are reported for products purified by flash
chromatography and were averaged over two runs.
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With a highly reactive catalyst in hand, we wondered
whether the relatively high temperature of 808C was required
for the coupling or whether it was necessary for precatalyst
activation. In the case of organometallic cross-coupling,
reduction of the PEPPSI precatalyst is efficient and rapid;[5]
in the case of anilines especially, the mechanism of activation
is far from clear. We have observed for sulfination that placing
bulk at the ortho position of the pyridine ring sharply
enhances activation.[11,15] Indeed when this position was
substituted with a simple methyl group (13a), precatalyst
activation occurred smoothly at room temperature, as did the
coupling, thus confirming that Pd-PEPPSI-IPentCl, once
activated, is well capable of aminating profoundly deactivated
partners with simple carbonate base at room temperature
(Table 3).
Table 3: Comparison of different pyridine IPentCl derivatives in the room-
temperature activation and coupling of 4-chloroanisole and 3,4,5-
trifluoroaniline.[a]
Entry
Precatalyst
Conversion [%][b]
1
2
3
4
5
12a
12b
13a
13b
13c
55
70
82
Scheme 3. Substrate scope of the room-temperature aryl aminations
catalyzed by Pd-PEPPSI-IPentCl-o-picoline (13a). Reactions were con-
ducted on a 0.5 mmol scale at a concentration of 1m. Yields are
reported for products purified by flash chromatography and were
averaged over two runs.
81
39[c]
[a] Reactions were conducted on a 0.5 mmol scale at a concentration of
1m. [b] Percentage conversion into product was determined by 1H NMR
spectroscopic analysis of the crude reaction mixture following filtration.
[c] 92% of precatalyst 13c was recovered after 24 h, thus suggesting that
little of the precatalyst had been activated.
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To demonstrate scope and versatility of the very mild
protocol with 13a, an impressive array of aminated products
was assembled (Scheme 3). These attractive targets of some
molecular complexity include esters (20, 22, 25, 26), borates
(21), amides (22, 25), ketones (24), and even acidic moieties
including both alcohols and amines (24, 25). Finally, hindered
substrates with ortho substituents were also coupled with
quantitative yield (26, 27).
In summary, the new NHC–Pd complex Pd-PEPPSI-
IPentCl-o-Picoline (13a) has performed very strongly relative
to other amination catalysts currently available.[16] With 13a,
it is now possible to catalyze the coupling of strongly
deactivated oxidative addition partners and amines possess-
ing a diverse array of sensitive functionality by using only the
mild base carbonate at room temperature.
Received: December 3, 2013
Revised: January 14, 2014
Published online: February 14, 2014
Keywords: amination · cross-coupling ·
.
homogeneous catalysis · palladium · PEPPSI
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