A P,N-Ligand for palladium-catalyzed ammonia arylation: Coupling of deactivated aryl chlorides, chemoselective arylations, and room temperature reactions

Article abstract of DOI:10.1002/anie.201000526

(Figure Presented) Amazing ammonia: A new air-stable P,N-ligand (Mor-DalPhos) is reported that enables the palladium-catalyzed crosscoupling of ammonia to a variety of aryl chloride and aryl tosylate substrates with high chemoselectivity and, for the first time, at room temperature (see scheme; Ad = adamantyl, Ts=para-toluenesulfonyl).

Full text of DOI:10.1002/anie.201000526

Angewandte
Chemie
DOI: 10.1002/anie.201000526
Ammonia Arylation
A P,N-Ligand for Palladium-Catalyzed Ammonia Arylation: Coupling
of Deactivated Aryl Chlorides, Chemoselective Arylations, and Room
Temperature Reactions**
Rylan J. Lundgren, Brendan D. Peters, Pamela G. Alsabeh, and Mark Stradiotto*
Ammonia is an abundant and inexpensive nitrogen source
that represents an ideal reagent for amine synthesis. Despite
its tremendous potential to provide more direct and econom-
ical routes to nitrogen-containing molecules, the use of
ammonia in transition-metal-catalyzed reactions has only
very recently begun to be realized.[1] The copper- or palla-
dium-catalyzed cross-coupling of aryl halides and amines is a
well-established and important method for the synthesis of
arylamines in both academic and industrial settings,[2] and
recent advances in catalyst design have enabled the use of
ammonia as a coupling partner to generate primary aryl-
amines.[3–7] Despite the success of these initial reports, a
number of serious limitations regarding the scope and utility
of metal-catalyzed cross-couplings of aryl halides and ammo-
nia still exist and must be addressed before this method can be
considered a viable alternative to more traditional aniline
syntheses. In the case of copper, high loadings of metal and
ligand are typically required (10–50 mol%) and less reactive
but more economically attractive aryl chlorides,[8] or more
readily accessible pseudohalides derived from phenols, are
poor reaction partners.[3] Limitations regarding the palla-
dium-catalyzed cross-coupling of ammonia[4–7] include the
coupling of electron-rich, sterically unbiased aryl chlorides as
well as the selective coupling of ammonia in the presence of
additional amine functionality (chemoselectivity).[9] In addi-
tion, currently known systems require catalyst loading of 0.5–
5 mol% of palladium as well as elevated temperatures (70–
1208C) to maintain reasonable activity for even simple aryl
chloride substrates. The slow rate of oxidative addition of
electron-rich aryl chlorides, combined with a lower tendency
for such species lacking ortho-substitution to undergo reduc-
tive elimination[10] from the requisite [LnPd(Ar)amido] spe-
cies, can provide a rationale for the difficulties posed by such
reaction partners and the elevated reaction temperatures
required for catalyst turnover. Herein, we report the prepa-
ration of a suitably designed P,N-ligand that addresses several
of the above-described challenges in ammonia cross-coupling,
including highly chemoselective transformations and the first
report of aryl chloride and aryl tosylate coupling with
ammonia at room temperature.
Recently, we initiated a research program employing P,N-
À
ligands as alternatives to more traditional archetypes in C N
coupling reactions. We envisioned that easily prepared and
tunable ligands of this type might provide a useful middle
ground in Buchwald–Hartwig aminations between strongly
chelating bisphosphanes[2a] and biarylmonophosphanes[2b]
that feature only weak secondary metal–ligand interactions.
We have found L1 (Me-DalPhos) to be a broadly useful
ligand for the palladium-catalyzed cross-coupling of aryl
chlorides and amines (including ammonia); however, mod-
estly electron-rich substrates lacking ortho-substitution gave
very poor results, requiring harsh reaction conditions and
giving undesired diarylamines as the major product.[11,12a]
Indeed, within the field of palladium-catalyzed cross-coupling
of ammonia, only the Josiphos/[Pd{P(o-tol)3}2] system devel-
oped by the Hartwig group has been reported to effect
reactions of this type (4-chlorotoluene, 55% yield; 1 mol% of
Pd at 1008C; TOF = 5.5 hÀ1).[7] With the aim of addressing
some of the outstanding issues in ammonia arylation catalysis,
a series of air-stable phenylene-bridged P,N-ligands featuring
the bulky di(1-adamantyl)phosphino (P(1-Ad)2) fragment
were synthesized (L2–L8; Scheme 1). Although attempts to
cross-couple 4-chlorotoluene under the challenging test con-
ditions (0.3 mol% of Pd, 3 equiv of NH3; 4 h) afforded poor
[*] R. J. Lundgren, B. D. Peters, P. G. Alsabeh, Prof. Dr. M. Stradiotto
Department of Chemistry
Dalhousie University, Halifax, Nova Scotia B3H 4J3 (Canada)
Fax: (+1)902-494-7190
E-mail: mark.stradiotto@dal.ca
[**] We are grateful to the NSERC of Canada and to Dalhousie University
for their support of this work.
Scheme 1. Ligand screening for the palladium-catalyzed cross-coupling
of ammonia and 4-chlorotoluene.[a] [a] Conversions and ArNH2/Ar2NH
ratio (indicated in parenthesis) determined by GC analysis. [b] 99%
conversion (15:1) after 16 hours. n.d.=not determined.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000526.
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results for most of the ligands, the variant featuring an ortho-
the coupling of these challenging substrates remained low at
1108C (0.3–0.6 mol% of Pd) and reasonable at 658C (1.5–
4 mol% of Pd). Included in the numerous examples in
Scheme 2 is the 3-fluoro-5-pyridyl-functionalized aniline 1-11,
a key intermediate in the synthesis of a potential antidepres-
sant/anxiolytic agent.[13] This ammonia cross-coupling method
(658C, 3 mol% of Pd, 87% yield) offers a viable alternative to
the reported nitro-reduction protocol mediated by a stoichio-
morpholino group (L7; Mor-DalPhos)[12a] gave exceptional
results; at 1108C, 84% conversion was achieved after 4 hours
(TOF = 70 hÀ1), with an excellent mono- to diarylation ratio
(14:1). Whereas the piperidine-derived ligand L8 performed
similarly well and exhibited only a modest decrease in
selectivity, a variant of L7 in which the P(1-Ad)2 group was
replaced by PCy2 was ineffective, only affording small
amounts of diarylated product (approx. 10%). Reactions
conducted at 658C with L7 were also successful when
1.5 mol% Pd was employed (98% at 20 h; 23:1).[12b]
[13]
metric amount of SnCl2 2-Substituted aryl chlorides were
also suitable reaction partners, as were some heteroaromatic
aryl chlorides.[14] In addition, reactions conducted at temper-
atures as low as 508C still gave excellent results (Scheme 2, 1-
10 and 1-12).
Easily prepared and inexpensive aryl tosylates are also
suitable partners for ammonia cross-coupling when employ-
ing [Pd(cinnamyl)Cl]2 and L7 (Scheme 2, 1-20–1-23);[15]
reactions were conducted under exceptionally mild condi-
tions (room temperature) with good yields for both unhin-
dered substrates and 2-substituted aryl tosylates.[16]
Having defined a catalyst system and reaction conditions
for the cross-coupling of ammonia to a deactivated, sterically
unbiased aryl chloride, we sought to explore the scope of
reactivity (Scheme 2). Aryl chloride substrates possessing
electron-donating groups at the para- or meta-positions were
easily cross-coupled at 1108C or 658C, including examples
containing N-, O-, F- or S-heteroatoms. Catalyst loadings for
À
Chemoselectivity in C N coupling reactions employing
ammonia remains a significant and unaddressed challenge.[17]
Given the apparently high affinity for ammonia when
conducting coupling reactions employing L7 with [Pd-
(cinnamyl)Cl]2, we attempted such transformations with
aminoaryl
chlorides
containing
NH functionalities
(Scheme 3). Reactions of aminoaryl chlorides featuring
secondary aryl/alkyl-, diaryl- or dialkylamines each afforded
good to excellent yields (64–98%) of the isolated ammonia-
derived arylation product. Even more impressive was the
ability of L7 and [Pd(cinnamyl)Cl]2 to selectively couple
ammonia in the presence of both primary aryl- and alkyl-
amines (Scheme 3, 2-5–2-7).[18]
Given the unique activity of L7 compared to more
established bisphosphane[4,7] or biarylphosphane[5,6] ligands
in the cross-coupling of ammonia, we attempted to gain
insight regarding the nature of the metal–ligand interactions
under conditions relevant to catalysis. Treatment of [Pd-
(cinnamyl)Cl]2 and 2 equivalents of L7 with NaOtBu in
Scheme 2. Scope of ammonia cross-coupling to aryl chlorides and
tosylates.[a] Reagents and conditions: [a] ArCl/NH3/NaOtBu=1:3–4:2,
[Pd]/L7=1:2, [ArCl]=0.10–0.05m, (2–48 h; see the Supporting Infor-
mation). Yields are of isolated material, mol% [Pd(cinnamyl)Cl]2
indicated in parentheses. A: T=1108C. B: T=658C. C: T=508C. D:
From the corresponding ArOTs at room temperature with [Pd]/
L7=1:1.5. [b] Yields were determined by GC analysis. Bn=benzyl.
Scheme 3. Chemoselective ammonia cross-coupling.[a] Reagents and
conditions: [a] AminoarylCl/NH3/NaOtBu=1:3–4:2, [Pd]/L7=1:2,
1108C, [ArCl]=0.10–0.05m. Yields are of isolated material, mol%
[Pd(cinnamyl)Cl]2 indicated in brackets. [b] Isolated as an 8:1 mixture
of mono- and diarylation product in 96% combined yield. [c] At 658C.
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chlorobenzene at room temperature resulted in the quanti-
tative formation (as evident by 31P NMR spectroscopy) of a
new species after 3 hours (Figure 1). Solution NMR spectros-
Scheme 4. Room temperature cross-coupling of aryl chlorides and
ammonia.[a] Reagents and conditions: [a] 5 mol% of C1, ArCl/NH3/
NaOtBu=1:3:2, [ArCl]=0.10–0.06m, at room temperature (1–24 h;
see the Supporting Information). Yields are of isolated material.
[b] Conversions were determined by GC analysis.
reactions. While the use of 5 mol% of C1 enabled the rapid
conversion of ortho-substituted or electron-poor aryl chlor-
ides (> 95% conversion after 1–2 h), such substrate charac-
teristics were not prerequisites for achieving high conversions
and yields at room temperature. Even though a full under-
standing of the properties of C1 that engender enhanced
reactivity under mild conditions is currently lacking,
[(L7)Pd(Ar)Cl] species, such as C1, may represent the
active catalyst in cross-coupling reactions that employ [Pd-
(cinnamyl)Cl]2/L7 precatalyst mixtures. The direct use of C1
may serve to by-pass undesirable side-reactions that may
occur during catalyst activation steps.
In conclusion, we have developed an air-stable P,N-ligand
(L7; Mor-DalPhos) that advances the scope and utility of
palladium-catalyzed ammonia cross-coupling reactions. A
variety of aryl chloride and aryl tosylate substrates can be
coupled efficiently, most notably electron-rich species lacking
ortho-substitution under a range of conditions. The unique
preference for ammonia coupling when using Pd/L7 mixtures
can be exploited in unprecedented chemoselective arylations,
and for the first time, the room temperature palladium-
catalyzed cross-coupling of ammonia has been achieved. Our
efforts to advance our understanding of the unprecedented
catalytic performance of Pd/L7, and to further utilize such
catalysts in challenging cross-coupling applications, will be the
subject of future reports.
Figure 1. Reagents and conditions: C1: Route 1: [CpPd(allyl)] and L7 in
PhCl/THF (1:1), 658C, 12 h, 93%. Route 2: [(cod)Pd(CH2TMS)2] and
L7 in PhCl, 40 min., RT, 99%. C2: [CpPd(allyl)] and L7 in 4-chloroani-
sole/THF (1:1), 12 h, 658C, 79%. C3 or C4: NH3 (3 equiv), AgOTf
(1.1 equiv), 30 min., RT (C3 90%; C4 84%). ORTEP diagrams of C1
(left) and C3 (right) shown with thermal ellipsoids at 50%; in C3 some
H atoms and OTfÀ are omitted for clarity. cod=cycloocta-l,5-diene,
Cp=cyclopentadienyl, Tf=trifluoromethanesulfonyl, THF=tetrahydro-
furan, TMS=trimethylsilyl.
copy and X-ray crystallographic studies confirmed the
identity of this species as being the square planar PdII
complex C1, in which L7 is coordinated in a k2-P,N fashion
with Cl trans to P.[19–21] Complex C1 was also prepared
successfully from alternative Pd sources in excellent yield
([CpPd(allyl)], 93%; [(cod)Pd(CH2TMS)2], 99%). The anal-
ogous 4-anisolyl derivative C2 was prepared in a similar
manner and displays solution and solid state characteristics
analogous to C1. Interestingly, no reaction was observed (as
evident by 31P NMR spectroscopy) upon exposure of C1 to
ammonia (2–10 equiv), thus suggesting that the N-donor arm
of L7 is not readily displaced from Pd during catalysis when
employing ammonia as a substrate. In an effort to examine
the reactivity of ammine ligated L7 PdII species, the cationic
ammonia adducts C3 and C4 were prepared in a high yield of
isolated product by addition of AgOTf to either C1 or C2 in
the presence of NH3 (Figure 1). Treatment of C3 with
NaN(TMS)2 at room temperature promoted the rapid reduc-
tive elimination of aniline from the unobserved intermediate
[(L7)Pd(Ph)NH2], which in turn regenerated C1 as the major
species (as evident by 31P NMR spectroscopy) in the presence
of chlorobenzene.
Received: January 29, 2010
Revised: March 23, 2010
Published online: April 30, 2010
Keywords: ammonia · arylation · homogeneous catalysis ·
.
palladium · N,P ligands
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Employing C1 as a precatalyst for ammonia arylation led
to striking results: good to excellent conversions were
observed for a number of aryl chloride substrates at room
temperature (Scheme 4).[22] These conditions are considera-
bly milder than the best conditions currently reported for such
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Communications
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À
[15] a) Room temperature C N coupling using ArOTs has been
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[11] R. J. Lundgren, A. Sappong-Kumankumah, M. Stradiotto,
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[12] a) Ligands L1 (Me-DalPhos) and L7 (Mor-DalPhos) are now
commercially available from Strem Chemicals; b) the use of
3 equivalents of NH3 gave superior results compared to 2 or
5 equivalents, and the [Pd]:L7 appeared to be less important with
minimal differences observed when varying the ratio from 1.5 to
4.
achieved recently with alternative amine coupling partners: T.
Ogata, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 13848; b) the
palladium-catalyzed amination of ArOTs substrates with ammo-
nia at 508C has been reported.[7]
[16] Electron-poor aryl tosylates led to significant amounts of the
corresponding phenol, as did aryl triflates.
[17] For selected reports on chemoselective amine cross-coupling,
see: a) X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars,
S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653; b) M. R.
Biscoe, T. E. Barder, S. L. Buchwald, Angew. Chem. 2007, 119,
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Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 2008,
130, 13552.
[18] The cross-coupling of 2-bromoaniline and ammonia has been
reported.[6]
[19] The trans disposition of P and Cl was confirmed in solution for
C1 and C3 on the basis of nOe experiments. The Supporting
Information contains experimental procedures and character-
ization data for all new compounds. CCDC 763339 (C1·CH2Cl2),
CCDC 763337 (C2·CH2Cl2), and CCDC 763338 (C3·CH2Cl2)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[20] For a recent example of a (k2-P,N)Pd species relevant to cross-
coupling catalysis, see: A. G. Sergeev, T. Schulz, C. Torborg, A.
Spannenberg, H. Neumann, M. Beller, Angew. Chem. 2009, 121,
7731; Angew. Chem. Int. Ed. 2009, 48, 7595.
[21] While Kwong and co-workers workers have developed active
P,N-ligands for palladium cross-coupling reactions, structural
studies suggest that these coordinate in a (k2-P,C)Pd manner:
a) C. M. So, Z. Zhou, C. P. Lau, F. Y. Kwong, Angew. Chem.
2008, 120, 6502; Angew. Chem. Int. Ed. 2008, 47, 6402; b) C. M.
So, C. P. Lau, F. Y. Kwong, Angew. Chem. 2008, 120, 8179;
Angew. Chem. Int. Ed. 2008, 47, 8059.
[22] To the best of our knowledge, the mildest example of palladium-
catalyzed cross-coupling of aryl chlorides with NH3 was reported
by Vo and Hartwig[7] (708C; 200 psi NH3), employing electroni-
cally activated substrates (benzoate or cyano).
[13] S. M. Bromidge et al., J. Med. Chem. 2000, 43, 1123. See the full
reference in the Supporting Information.
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