Palladium-catalyzed coupling of hydroxylamines with aryl bromides, chlorides, and iodides

Article abstract of DOI:10.1021/ol8025022

The bis-pyrazole phosphine ligand BippyPhos is effective for the palladium-catalyzed cross-coupling of hydroxylamines with aryl bromides, chlorides, and iodides. Reactions proceed smoothly at 80 °C in toluene in the presence of Cs₂CO₃

Full text of DOI:10.1021/ol8025022

ORGANIC
LETTERS
2009
Vol. 11, No. 1
233-236
Palladium-Catalyzed Coupling of
Hydroxylamines with Aryl Bromides,
Chlorides, and Iodides
Achim Porzelle,† Michael D. Woodrow,‡ and Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place,
Cardiff CF10 3AT, U.K., and ImmunoInflammation Centre of Excellence for Drug
DiscoVery, GlaxoSmithKline Medicines Research Centre, SteVenage,
Hertfordshire SG1 2NY, U.K.
tomkinsonnc@cardiff.ac.uk
Received October 29, 2008
ABSTRACT
The bis-pyrazole phosphine ligand BippyPhos is effective for the palladium-catalyzed cross-coupling of hydroxylamines with aryl bromides,
chlorides, and iodides. Reactions proceed smoothly at 80 °C in toluene in the presence of Cs2CO3 to give synthetically versatile
N-arylhydroxylamine products in good to excellent yield.
Over the past decade the palladium-catalyzed arylation of
nitrogen-containing compounds (Buchwald-Hartwig ami-
nation) has emerged as a valuable tool in synthetic chem-
istry.1 Extensive investigations have allowed for the coupling
of a number of amine nucleophiles with aryl halides to
provide a general route to a broad range of aniline derivatives
and valuable heterocyclic ring systems.2 Interestingly, despite
the biological and synthetic significance of N-aryl hydroxy-
lamines,3 only three reports of palladium-catalyzed cross-
couplings of this functionality have been disclosed.4,5 Each
of these reports is limited to the coupling of O-homoallyl
hydroxylamines in a useful tandem arylation/Heck sequence
for the preparation of isoxazolidines. This lack of investiga-
tion is surprising as N-aryl hydroxylamines are valuable
intermediates in the preparation of important nitrogen
heterocycles such as indoles,6 isoxazolidines,7 oxadiazoli-
dinones,8 and aziridines,9 among others.10 N-Aryl hydroxy-
lamines have also been studied as precursors for [3,3]-
sigmatropic rearrangements to obtain 2-aminophenols through
a formal C-H functionalization strategy.11
† Cardiff University.
‡ GlaxoSmithKline.
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Lett. 1983, 927–928. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1995, 34, 1348–1350. (c) Louie, J.; Hartwig, J. F.
Tetrahedron Lett. 1995, 36, 3609–3612.
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2002; Vol. 1, pp 1051-1096. (b) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131–209. (c) Prim, D.; Campagne, J.-M.; Joseph, D.;
Andrioletti, B. Tetrahedron 2002, 58, 2041–2075.
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10.1021/ol8025022 CCC: $40.75
Published on Web 11/26/2008
2009 American Chemical Society

As part of our ongoing research program to develop novel
hydroxylamine based reagents,12 we recently reported the
copper-catalyzed N-arylation of hydroxylamines with aryl
iodides.13 Significant limitations to this process were that
aryl bromides did not react, and ortho-substitution of the
aryl iodide was not tolerated. Another drawback was the
relatively high catalyst (up to 10%) and ligand (50 mol %)
loadings and the use of 3 equiv of aryl iodide to bring about
effective coupling. Within this Letter we describe an efficient
and versatile method for the palladium-catalyzed coupling
of hydroxylamines with aryl bromides, iodides, and chlorides
that overcomes these problems, providing a considerably
more practical and useful method for the arylation of this
important functionality.
halides overcoming problematic ꢀ-hydride elimination. It has
subsequently been shown to be a general ligand for pal-
ladium-catalyzed amination reactions. Additionally, it is also
effective for aryl ether formation and Suzuki-Miyaura
reactions.19 This current work highlights some of the unique
potential of this readily accessible ligand in palladium-
catalyzed processes.
A selection of the results using the BippyPhos ligand is
shown in Figure 2. Although not all reactions were success-
In an initial screen to establish the ability of palladium to
promote the coupling of hydroxylamines we examined the
reaction between N-Boc-O-TBDMS hydroxylamine (1) and
bromobenzene (2) in array format under a standard set of
conditions (2.5 mol % Pd; 5 mol % ligand; 2 equiv base; 60
°C; 0.25 M). Variables examined included palladium source
(Pd(OAc)2, Pd(dba)2), base (Cs2CO3, NaOtBu, K3PO4),
solvent (dioxane, DMF, PhMe, DME), and a broad range of
ligands (PCy3, PPh3, dppe, dppb, BINAP, dppf, Q-Phos,14
DavePhos,15 JohnPhos,16 TrippyPhos,17 BippyPhos17). Ad-
ditionally, we also examined the palladium precatalyst
PEPPSI within the transformation.18 Remarkably, from this
extensive reaction screen, only the Singer ligand BippyPhos
(Figure 1) provided any of the desired coupling product 3.
Figure 2. Screening results varying solvents and bases. Reaction
conditions: Pd source (2.5 mol %); BippyPhos (5 mol %); 2 (1
equiv); base (2 equiv); 60 °C; 20 h; 0.25 M concentration
hydroxylamine, PhBr (1 equiv).
ful, it is clear this ligand promotes the coupling reaction with
a range of solvents, bases, and sources of palladium. The
precise reason for all other ligands examined failing within
the reaction is unclear at present, although the observation
may explain that despite extensive reports on the Buchwald-
Hartwig amination, examples of hydroxylamine couplings
have been limited to those of homoallyl hydroxylamines.4,5
With the solvent/base combination of cesium carbonate/
toluene emerging from this initial screen as the most effective
combination, we further optimized the process with regards
temperature (80 °C), equivalents of aryl bromide (1.2 equiv),
and concentration (0.5 M with respect to hydroxylamine)
before examining the scope of the coupling procedure (Table
1).
Pleasingly, the reaction conditions developed had a broad
substrate scope in both aryl halide and hydroxylamine
coupling partners. Standard oxygen protecting groups on the
hydroxylamine were well tolerated with tert-butyl and methyl
carbamates (entries 1-6; 78-91%); however, amides were
ineffective coupling partners (entry 7). Along with aryl
bromides (entries 1-6), aryl iodides (entry 8; 90%) and aryl
Figure 1. Singer ligand BippyPhos.
BippyPhos was developed as a nonproprietary ligand
within Pfizer for the coupling of primary amines with aryl
(11) (a) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Eur. J.
Org. Chem. 2008, 5135–5143. (b) Lobo, A. M.; Prabhakar, S. Pure Appl.
Chem. 1997, 69, 547–552.
(12) (a) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones,
T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N. C. O.
Org. Lett. 2005, 7, 5729–5732. (b) Beshara, C. S.; Hall, A.; Jenkins, R. L.;
Jones, T. C.; Parry, R. T.; Thomas, S. P.; Tomkinson, N. C. O. Chem.
Commun. 2005, 1478–1480. (c) Hall, A.; Jones, K. L.; Jones, T. C.; Killeen,
N. M.; Porzig, R.; Taylor, P. H.; Yau, S. C.; Tomkinson, N. C. O. Synlett
2006, 3435–3438. (d) Hall, A.; Huguet, E. P.; Jones, K. L.; Jones, T. C.;
Killeen, N. M.; Yau, S. C.; Tomkinson, N. C. O. Synlett 2007, 293–297.
(e) Jones, T. C.; Tomkinson, N. C. O. Org. Synth. 2007, 233–241. (f) John,
O. R. S.; Killeen, N. M.; Knowles, D. A.; Yau, S. C.; Tomkinson, N. C. O.
Org. Lett. 2007, 9, 4009–4012.
(13) Jones, K. L.; Porzelle, A.; Hall, A.; Woodrow, M. D.; Tomkinson,
N. C. O. Org. Lett. 2008, 10, 797–800.
(14) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553–5566.
(15) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722–9723.
(16) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413–2416.
(18) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768–2813.
(17) (a) Singer, R. A.; Dore´, M.; Sieser, J. E.; Berliner, M. A.
Tetrahedron Lett. 2006, 47, 3727–3731. (b) Singer, R. A; Caron, S.;
McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis 2003, 1727–1731.
(19) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Process Res. DeV.
2008, 12, 480–489.
234
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Scope of Hydroxylamine Couplinga
a Standard reaction conditions: Pd(OAc)2 (2.5 mol %); BippyPhos (5 mol %); Cs2CO3 (2 equiv); 80 °C; 18 h; 0.5 M concentration of hydroxylamine;
ArBr (1.2 equiv); toluene. b Isolated yield. c Reaction performed at 100 °C.
chlorides (entry 9; 65%) were also effective within the
reaction. Aryl triflates did not couple efficiently under the
standard conditions (entry 10; <5%). Protection of the
hydroxylamine oxygen was found to be essential (entry 11),
without which starting materials were recovered from the
reaction. Functional group tolerance was also found to be
outstanding with aryl-methoxy, -alkyl, -nitro, -keto, -ester,
-halide, and -acetal being tolerated (entries 12-22; 55-91%).
Reaction of ortho-substituted partners proved difficult;
however, simply heating the reaction mixture at 100 °C
afforded the desired product in respectable yield (entry 17;
55%). With 3-bromoiodobenzene the reaction showed little
discrimination between the iodide and bromide; running the
reaction in the presence of 2 equiv of hydroxylamine
provided the bis-functionalized product (entry 21; 65%).
Overall, the broad range of couplings exemplified (Table 1)
Org. Lett., Vol. 11, No. 1, 2009
235

show this to be a robust and general coupling reaction of
hydroxylamines and aryl halides.
Scheme 1
.
Deprotection and Conversion to 1,2- and 1,4-Amino
Phenols
Finally, some potential for the hydroxylamine products
was revealed following removal of the O-TBDMS group to
give 4 (95%). Treatment of 4 with methanesulfonyl chloride
(1 equiv) gave the protected 1,2-aminophenol 5 (91%) via
O-sulfonation followed by [3,3]-sigmatropic rearrange-
ment.11a In contrast, reaction of 4 with trifluoromethane-
sulfonic anhydride (1 equiv) gave the protected 1,4-ami-
nophenol 6 (88%).20
In summary, we have described a mild and efficient
palladium-catalyzed cross-coupling of protected hydroxy-
lamines with a broad range of aryl bromides. Additionally,
aryl iodides and aryl chlorides can also be used within the
process. Key to the success of this protocol was the use of
the Singer ligand BippyPhos; use of a range of alternative
phosphine ligands failed to deliver the desired N-arylhy-
droxylamine products under the conditions examined. This
procedure provides significant advantages over alternative
methods for hydroxylamine couplings, including lower
catalyst and ligand loadings, expansion of the scope of aryl
coupling partner, improved functional group tolerance on the
hydroxylamine, and compatibility with ortho-substitution on
the aryl halide. The majority of the products described
possess standard O- and N-protecting groups, allowing full
advantage of the products to be realized.21 Current work is
focused on understanding the formation of 6 and introducing
alternative nucleophiles into this intriguing rearrangement
reaction.
Acknowledgment. The authors thank the EPSRC and
GlaxoSmithKline for financial support and the Mass Spec-
trometry Service, Swansea for high-resolution spectra.
Supporting Information Available: Analytical data,
experimental procedures, and NMR spectra for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) The precise mechanism of this reaction is unknown at present;
however, a related transformation has been described: Addition of N-phenyl
hydroxylamine to trifluoromethanesulfonic acid (solvent) gives 4-O-
trifluoromethanesulfonyl aniline (78%). See: Austin, R. P.; Ridd, J. H.
J. Chem. Soc., Perkin Trans. 2 1994, 1411–1414.
(21) For example, for the selective removal of N-Boc or O-THP groups
from protected N-aryl hydroxylamines, see ref 13.
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Org. Lett., Vol. 11, No. 1, 2009