Palladium-catalyzed amination of aryl and heteroaryl tosylates at room temperature

Article abstract of DOI:10.1021/ja805810p

Mild palladium-catalyzed aminations of aryl tosylates and the first aminations of heteroaryl tosylates are described. In the presence of the combination of L₂Pd(0) (L = P(o-tol)₃) and the hindered Josiphos ligand CyPF-t-Bu, a variety of primary alkylamines and arylamines react with both aryl and heteroaryl tosylates at room temperature to form the corresponding secondary arylamines in high yields with complete selectivity for the monoarylamine. These reactions at room temperature occur in many cases with catalyst loadings of 0.1 mol % and 0.01 mol % in one case, constituting the most efficient aminations of aryl tosylates by nearly 2 orders of magnitude. This catalyst is made practical by the development of a convenient method to synthesize the L₂Pd(0) precursor. This complex is stable to air as a solid. In contrast to conventional relative rates for reactions of aryl sulfonates, the reactions of aryl tosylates are faster than parallel reactions of aryl triflates, and the reactions of aryl tosylates are faster than parallel or competitive reactions of aryl chlorides. Copyright

Full text of DOI:10.1021/ja805810p

Published on Web 09/24/2008
Palladium-Catalyzed Amination of Aryl and Heteroaryl Tosylates at Room
Temperature
Tokutaro Ogata and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801
Received July 24, 2008; E-mail: jhartwig@uiuc.edu
Table 1. Coupling of Aryl and Heteroaryl Tosylates with Primary
Alkylamines and Arylamines Catalyzed by Pd[P(o-tol)3]2 and
CyPF-t-Bu (1:1)a
Palladium-catalyzed aminations of aryl halides occur under mild
conditions with many catalysts,1-3 but aminations of aryl sulfonates
have been more challenging. The coupling of amines with aryl triflates
has been known for many years,1 but aryl triflates are expensive to
prepare and less stable to hydrolysis than other aryl sulfonates. Aryl
tosylates are less expensive to prepare and are stable, crystalline solids.
However, they are also less reactive. Although Suzuki and Kumada
couplings of aryl tosylates at room temperature have been reported,4,5a
only one coupling of amines with aryl tosylates at room temperature
or with low catalyst loadings has been reported.5 Moreover, the
coupling of amines with heteroaryl tosylates has not been reported,
and the couplings of primary amines with aryl tosylates are rare.
We previously reported the oxidative addition of aryl tosylates at
room temperature,5a but this fast addition did not lead to a general
coupling with amines under similar conditions. Here, we report a new
method to create a catalyst that couples aryl tosylates with primary
alkylamines, arylamines, and N-H imines with fast rates and high
turnover numbers under mild conditions. This process was achieved
by combining the hindered Josiphos ligand CyPF-t-Bu (Table 1) with
the unconventional Pd(0) precursor Pd[P(o-tol)3]2, which we show can
be made in a practical manner.
The difference between the rates of oxidative addition and the
catalytic coupling stems from the difficulty in accessing the (CyPF-
t-Bu)Pd intermediate under mild conditions. Typical catalyst precursors
include Pd(II) acetate or chloride complexes, which require reduction
to the true Pd(0) catalyst. To avoid the need for reduction to Pd(0),
Pdn(dba)m is often used, but Pd(CyPF-t-Bu)(dba) generated from CyPF-
t-Bu and Pd2(dba)3 dissociates dba particularly slowly, presumably
because the strongly donating bisphosphine leads to strong backbonding
into the electron-poor dba ligand. Thus, an alternative precatalyst was
needed to couple aryl tosylates with amines under mild conditions.
Instead of using the combination of CyPF-t-Bu and typical
catalyst precursors, we sought a practical synthesis of Pd(CyPF-
t-Bu)[P(o-tol)3] (1), which oxidatively adds aryl tosylates at room
temperature.5a Pd(0) catalyst 1 is generated in solution at room
temperature within minutes from Pd[P(o-tol)3]2 (2) and CyPF-t-
Bu (3),6 but 2 has rarely been used in catalytic chemistry because
of its lack of commercial availability and difficult synthesis.7 Thus,
we sought a more convenient method to prepare 1 independently
or a convenient method to prepare precursor 2.
a Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol ArOTs,
1.2 equiv amine and 1.4 equiv NaOt-Bu in 1 mL toluene. b Isolated yields are
an average of two runs. c At 80 °C. d Phenol was formed in 23% yield. e From
phenethylamine that is stated to be 99% ee. f Produced in 99% ee. g Run using
1.5 equiv amine. h N,N′-diphenylethylenediamine was obtained as a single
product. i Reaction conducted with 1.2 equiv K3PO4 at 100 °C. j At 110 °C.
k Run using 2.0 mol % catalyst.
Our efforts to isolate 1 in high yield were hampered by the
high solubility of this species in organic solvents. Thus, we
sought to simplify the synthesis of Pd(0) complex 2 and to use
1 generated in situ. On the basis of the most efficient synthesis
of Pd[P(t-Bu)3]2,8 we prepared 2 in 95% isolated yield from the
reaction of P(o-tol)3 and Pd(dba)2 in DMF.9 Complex 2
precipitated after 1 h at room temperature without the need for
excess P(o-tol)3. Complex 2 is stable for >1 week in air as a
solid at room temperature.10 Because CyPF-t-Bu is also stable
in air, both catalyst components can be stored outside of a
9
13848 J. AM. CHEM. SOC. 2008, 130, 13848–13849
10.1021/ja805810p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
drybox, and a solid mixture of the two materials can mimic a
single-component catalyst (vide infra).11
reactions of aryl tosylates were faster than those of aryl triflates when
conducted as separate reactions (c.f. Table 1, entry 1 vs entry 3).
Reactions of octylamine with a 1:1 ratio of these two aryl sulfonates
formed mostly phenol (14%) with only 4% yield of the coupled product
Examples of the reactions of aryl tosylates and heteroaryl tosylates
with various alkylamines are summarized in Table 1. Reactions with
0.05-1.0 mol % of the combination of 2 and 3 in toluene at room
temperature produced the corresponding monoarylamines in excellent
yields. Most reactions were complete at room temperature within 24 h.
However, similar yields could also be obtained after short (<10 min)
times at 80 °C.
Reactions of linear primary amines were fast and occurred in high
yield with 0.05-0.1 mol % catalyst (entries 1, 6, 9, and 14). The
reaction of octylamine with 2-naphthyl tosylate was particularly
efficient and occurred at 80 °C in 84% isolated yield with only 0.01
mol % of catalyst (entry 15). This turnover number of 8400 is the
highest for any type of coupling of an aryl tosylate of which we are
aware.12-14 The reactions of hindered R-branched primary amines,
such as cyclohexylamine and sec-butylamine, occurred in high yields
at room temperature with just 0.1 to 0.2 mol % of catalyst (entries
7-8, and 13). Both electron-rich and electron-poor aryl tosylates
reacted in high yield with primary amines without formation of any
diarylamine. These reactions occurred with aryl tosylates containing
ortho substituents, as well as aryl tosylates containing cyano and
carboalkoxy groups.
18
in the presence of 0.1 mol % catalyst. Reactions with Cs2CO3 did
not improve the yield from reactions of triflates. In addition, aryl
tosylates reacted faster than aryl chlorides. The reaction of 3- or
4-chlorophenyl tosylate led to coupling at the tosylate group (eq 2).
These relative rates contrast those catalyzed by complexes of dialkyl-
o-biarylphosphines,19 but parallel those catalyzed by complexes of
secondary phosphine oxides.13
In summary, we have developed a highly efficient catalyst system
for the amination of aryl tosylates at room temperature, as well as the
first examples of the Pd-catalyzed amination of heteroaryl tosylates.
The use of an unusual precatalyst now prepared in a practical fashion
enabled us to achieve this high activity.
Because this new catalyst does not require reduction to a pal-
ladium(0) species or dissociation of dba, primary arylamines also
couple with aryl tosylates at room temperature. Although these
reactions were slightly slower than those of alkylamines, reactions of
electron-rich arylamines (entries 20-21, 25, and 27), including an
ortho-substituted arylamine (entries 22 and 26), occurred in good-to-
excellent yield with complete selectivity for monoarylation. Reactions
of electron-deficient primary aryl- and heteroarylamines also occurred.
Although these reactions required higher catalyst loadings than the
reactions of electron-rich primary arylamines (entries 23-24), they
still occurred at elevated temperatures or with extended reaction times
at room temperature.
The scope of the couplings of this catalyst also includes the first
aminations of heteroaryl tosylates (entries 28-35). These reactions
occurred under the same conditions we developed for the amination
of aryl tosylates. Pyridyl and quinolyl tosylates underwent reaction
with primary alkyl- and arylamines in good-to-excellent yields. The
reactions of 2- and 3-pyridyl and 6- and 8-quinolyl tosylate also
occurred, although 0.5 and 1.0 mol % catalyst was needed in some
cases.
Acknowledgment. We thank the NIH (GM-55382) for support
of this work, Johnson-Matthey for a gift of PdCl2, and Solvias for a
gift of CyPF-t-Bu. T.O. thanks JSPS for a fellowship.
Supporting Information Available: All experimental procedures
and spectroscopic data of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Hartwig, J. F. Acc. Chem. Res. published online, Aug. 6, 2008, http://
dx.doi.org/10.1021/ar800098p. (b) Hartwig, J. F. In Modern Arene Chem-
istry; Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 107.
(c) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; pp 1051.
(d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(2) For a recent review of aminations conducted with o-biaryl dialkylphosphine
ligands, see: Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,
47, 6338.
(3) For a recent report of aminations conducted with N-heterocyclic carbenes,
see: Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan,
S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(4) (a) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058. (b) Tang,
Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron Lett. 2006, 47, 2427. (c)
Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531. (d) Limmert,
M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364. (e) Fu¨rstner,
A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856. (f) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
(5) (a) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704. For two
examples of the amination of aryl tosylates at elevated temperatures with
a related catalyst, see: (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1998, 120, 7369. For recent work on the amination of aryl mesylates,
at elevated temperatures, see: (c) So, C. M.; Zhou, Z.; Lau, C. P.; Kwong,
F. Y. Angew. Chem., Int. Ed. 2008, 47, 6402.
Consistent with the high selectivity for reactions of primary amines,
the reactions of secondary amines were slower. The reactions of aryl
tosylates with morpholine, dibutylamine, and N-methylaniline gave
no coupled products or low yield of products at 110 °C with 1 mol %
catalysts.
A comparison of these reactions to those of aryl tosylates conducted
with other precatalysts showed the value of initiating reactions with
P(o-tol)3-ligated 2. No reaction of octylamine with phenyl tosylate
catalyzed by 0.1 mol % Pd(dba)2 and 3 occurred at room temperature.
The same reaction catalyzed by 0.1 mol % of Pd(OAc)2 and 3 at room
temperature for 48 h gave the product in 6% yield, as determined by
GC, and this reaction catalyzed by 0.1 mol % PdCl2(CyPF-t-Bu)
occurred in only 65% isolated yield. Indicating the importance of
Josiphos ligand 3, the reaction of phenyl tosylate with octylamine
catalyzed by the combination of 0.1 mol % Pd(OAc)2, Pd(dba)2, or
Pd[P(o-tol)3]2 as precursor and 0.1–0.25 mol % Q-phos,15 X-phos,16,17
SIPr,3 DPPF, or BINAP as ligand gave no coupled products or very
low yield of products, even in toluene at 110 °C (see Supporting
Information for details).
Finally, a solid mixture of the two catalyst components catalyzes
the reaction with efficiency equal to that of the catalyst generated from
the two separate solids. Although expected, this procedure does allow
the use of the combination of 2 and 3 as if it were an air-stable single-
component catalyst.
A comparison of the reactions of different types of aryl sulfonates
revealed some unusual trends (Table 1, entries 1-5). Most striking,
(6) Ligand 3 is commercially available from Solvias and Strem.
(7) (a) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030. (b)
Bo¨hm, V. P. W.; Herrmann, W. A. Chem.sEur. J. 2001, 7, 4191.
(8) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(9) Complex 2 is commercially available from Johnson-Matthey and Strem
Chemicals (#46-0262).
(10) Samples left in air as a solid for one week were unchanged, as judged by
1H NMR and 31P NMR spectroscopy.
(11) Naber, J. R.; Buchwald, S. L. AdV. Synth. Catal. 2008, 350, 957.
(12) For reactions of activated aryl tosylates with 0.5 mol % palladium, see
refs 13 and 14.
(13) Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457.
(14) Zhang, L.; Meng, T.; Wu, J. J. Org. Chem. 2007, 72, 9346.
(15) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 2000,
122, 10718.
(16) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(17) Reaction with 2 mol % Pd(OAc)2 and 5 mol % X-phos at 110 °C for 18 h
occurred to 84% conversion.
(18) Åhman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(19) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11818.
JA805810P
9
J. AM. CHEM. SOC. VOL. 130, NO. 42, 2008 13849