Copper-catalyzed coupling of hydroxylamines with aryl iodides

Article abstract of DOI:10.1021/ol7029273

An efficient method for the copper-catalyzed N-arylation of hydroxylamines with aryl iodides is described. A variety of N- and O-functionalized hydroxylamines were transformed in good to excellent yield with a broad range of aryl coupling partners. Methods for the selective deprotection of either the N- or O-substituents for further functionalization are also described.

Full text of DOI:10.1021/ol7029273

ORGANIC
LETTERS
2008
Vol. 10, No. 5
797-800
Copper-Catalyzed Coupling of
Hydroxylamines with Aryl Iodides
Kerri L. Jones,† Achim Porzelle,† Adrian Hall,‡ Michael D. Woodrow,§ and
Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place, Cardiff, CF10
3AT, United Kingdom, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park,
Third AVenue, Harlow, Essex, CM19 5AW, United Kingdom, and GlaxoSmithKline
Pharmaceuticals, SteVenage, Hertfordshire, SG1 2NY, United Kingdom
tomkinsonnc@cardiff.ac.uk
Received December 4, 2007
ABSTRACT
An efficient method for the copper-catalyzed N-arylation of hydroxylamines with aryl iodides is described. A variety of N- and O-functionalized
hydroxylamines were transformed in good to excellent yield with a broad range of aryl coupling partners. Methods for the selective deprotection
of either the N- or O-substituents for further functionalization are also described.
Over the past decade the copper-catalyzed modified Ullmann
condensation of aryl halides with amines has emerged as a
powerful and robust bond construction process.1 The toler-
ance of a broad spectrum of functionality within both
coupling partners has greatly accelerated the up-take of this
chemistry worldwide such that the methodology is now an
integral part of the organic chemist’s toolbox.
acids,7 and imidazoles,8 among others, showing the outstand-
ing utility of these reactions. Despite the broad spectrum of
coupling partners that have been described, we are unaware
of any reports of the copper-catalyzed N-arylation of hy-
droxylamines even with the versatility of this functional
(3) (a) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670-674.
(b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001,
42, 4791-4793. (c) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315-4317. (d) Kelkar, A. A.; Patil, N. M.; Chaudhari, R.
V. Tetrahedron Lett. 2002, 43, 7143-7146.
With regards to the amine partner a number of methods
have been reported for the coupling of primary and secondary
amines,2 anilines,3 hydrazides,4 amides,5 carbamates,6 amino
(4) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803-
3805.
† Cardiff University.
(5) (a) Klapars, A.; Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421-7428. (c) Kang, S.-K.; Kim,
D.-H.; Pak, J.-N. Synlett 2002, 427-430.
‡ GlaxoSmithKline, Harlow.
§ GlaxoSmithKline, Stevenage.
(1) For recent reviews of copper-mediated C-N bond-forming processes
see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-
5449. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-2439. (c)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337-
2364.
(2) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581-584. (b) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742-8743.
(6) Mellesham, B.; Rajesh, B. M.; Rajmohan-Reddy, P.; Srinivas, D.;
Trehan, S. Org. Lett. 2003, 5, 963-965.
(7) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998,
120, 12459-12467.
(8) (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657-2660. (b) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006,
8, 2779-2782.
10.1021/ol7029273 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/26/2008

group in synthesis.9-11 N-Aryl hydroxylamines are valuable
in the preparation of nitrones,12 aziridines,13 electrophilic
amination reagents,14 and [3,3]-sigmatropic rearrangement
processes,15 as well as in the synthesis of indoles,16 isox-
azolidines,17 oxadiazolidinones,18 â-amino acids,19 and â-ami-
no alcohols,20 each of which have found use in the
preparation of pharmaceutical agents. As part of our ongoing
research program to develop novel hydroxylamine-based
reagents21 we were interested in differentially protected
N-aryl hydroxylamines and sought to develop methods to
obtain this class of compound. Within this letter we describe
an efficient method for the copper-catalyzed coupling of N,O-
difunctionalized hydroxylamines with aryl iodides and
methods for deprotection of the products for further synthetic
manipulation.
Table 1. Scope of the Aryl Halide Coupling Partnera
Initial investigations examined the coupling of N-Boc-O-
methyl hydroxylamine with iodobenzene. After examining
a series of copper sources, ligands, bases, solvents, and
temperatures the most efficient protocol was exploited as
shown in Table 1. The coupling reaction proceeds smoothly
in the presence of 5 mol % copper(I) iodide and 1,10-
phenanthroline (50 mol %) as the ligand, using cesium
carbonate as the base in DMF at 80 °C. The reaction was
effective for a wide variety of aryl iodides with good to
excellent yields (69-89%) and an outstanding functional
group tolerance in the substrate including aryl-nitro, -nitrile,
(9) For the copper-catalyzed O-arylation of N-hydroxyphthalimide see:
Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139-
142.
(10) For the copper-catalyzed O-arylation of oximes see: Nonappa, D.
P.; Pandurangan, K.; Maitra, U.; Wailes, S. Org. Lett. 2007, 9, 2767-
2770.
(11) For the palladium-catalyzed N-arylation of hydroxylamines see: (a)
Dongol, K. G.; Tay, B. Y. Tetrahedron Lett. 2006, 47, 927-930. (b) Peng,
J.; Lin, W.; Yuan, S.; Chen, Y. J. Org. Chem. 2007, 72, 3145-3148. (c)
Peng, J.; Jiang, D.; Lin, W.; Chen, Y. Org. Biomol. Chem. 2007, 5, 1391-
1396.
(12) (a) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8,
3351-3354. (b) Chatterjee, A.; Bhattacharya, P. K. J. Org. Chem. 2006,
71, 345-348. (c) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005,
7, 953-955.
(13) Murugan, E.; Siva, A. Synthesis 2005, 2022-2028.
(14) Srivastava, R. S.; Khan, M. A.; Nicholas, K. M. J. Am. Chem. Soc.
2005, 127, 7278-7279.
(15) Lobo, A. M.; Prabhakar, S. Pure Appl. Chem. 1997, 69, 547-552.
(16) (a) Pierre, M. HelV. Chim. Acta 1984, 67, 1647-1649. (b) Belchert,
S. Tetrahedron Lett. 1984, 25, 1547-1550.
(17) Imran, M.; Khan, S. A.; Siddiqui, N. Ind. J. Pharm. Sci. 2004, 66,
377-381.
(18) Gopalsamy, A.; Kincaid, S. L.; Ellingboe, J. W.; Groeling, T. M.;
Antrilli, T. M.; Krishnamurthy, G.; Aulaugh, A.; Friedrichs, G. S.; Crandall,
D. L. Bio. Org. Med. Chem. Lett. 2004, 14, 3477-3480.
(19) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem.
Soc. 2005, 127, 5376-5383.
a All reactions performed in duplicate at 0.5 M concentration of
hydroxylamine. b Isolated yield.
(20) Aschwanden, P.; Kværnø, L.; Geisser, R. W.; Kleinbeck, F.;
Carreira, E. M. Org. Lett. 2005, 7, 5741-5742 and references cited therein.
(21) (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, 1478-1479. (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.
-keto, -ester, and -bromide functionalities (entries 1-9). It
is also worth noting that under the conditions used within
this study aryl bromides, aryl triflates, and 2-iodotoluene
were ineffective as substrates for the coupling procedure
(entries 10-12).
After effective conditions for the coupling were developed
we examined the scope and limitations of the hydroxylamine
coupling partner with the aim of introducing N- and
798
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Scope of the Hydroxylamine Coupling Partnera
a All reactions performed in duplicate at 0.5 M concentration of hydroxylamine. b Isolated yield. c 10 mol % catalyst used.
O-substituents that could efficiently be removed to allow
further functionalization of the hydroxylamine products
(Table 2).
in no N-arylation product being isolated from the reaction
mixture (entry 18). With N-Cbz (entries 8 and 9) and O-THP
hydroxylamines (entries 15-17) 10 mol % of catalyst was
necessary to bring about efficient coupling. Despite these
limitations, the broad range of couplings exemplified (Table
2) show this to be a robust and general coupling reaction of
hydroxylamines and aryl iodides.
The conditions developed proved effective for a range of
hydroxylamine coupling partners. With regard to the nitrogen
substituent tert-butyl-, benzyl-, and methyl-carbamates all
added efficiently in good to excellent yield (52-83%) with
the oxygen substituents examined including tert-butyl, ben-
zyl, tetrahydropyranyl, and allyl, suggesting the method
should be effective for a variety of hydroxylamines. Limita-
tions revealed with the process showed that care had to be
taken with the coupling of some electron-deficient hydroxy-
lamines and/or aryl iodides. Coupling of 4-nitro iodobenzene
with N-Boc-O-allyl hydroxylamine resulted in the sole
isolated product being that of concomitant N-O bond
cleavage (75%, entry 7) and the reaction between 4-nitro
iodobenzene and N-tosyl-O-benzyl hydroxylamine resulted
When selecting our hydroxylamine coupling partners, we
elected to incorporate traditional N- and O-protecting groups
to allow subsequent unmasking of these useful functionalities
for further synthetic manipulation. A series of examples for
deprotection of both the nitrogen and oxygen groups are
outlined in Table 3. Removal of the Boc protecting group
by treatment of the N-arylhydroxylamine with trifluoroacetic
acid provided the free hydroxylamines in excellent yield
(65-98%, entries 1-3). It was also possible to efficiently
Org. Lett., Vol. 10, No. 5, 2008
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the THP protecting group could easily be removed under
mild hydrolytic conditions to give the expected products
(67-84%, entries 4-6).
Table 3. Deprotection of Coupled Products
In summary, we have described a mild and efficient
copper-catalyzed coupling of hydroxylamine derivatives
with aryl iodides. The method is tolerant of a variety of
functional groups in both the aryl and hydroxylamine
coupling partners allowing for further synthetic manipulation.
In addition, the products can be selectively N- or O-
deprotected allowing full advantage of the versatility of this
functional group to be realized. Exploitation of this work in
the preparation of arrays of drug-like molecules is currently
underway.
Acknowledgment. The authors thank the EPSRC
and GlaxoSmithKline for financial support and the
Mass Spectrometry 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.
a Isolated yield. b TFA, CH2Cl2, 0 °C, 1 h. c EtOH, PPTS, 50 °C, 2 h.
unmask the oxygen functionality while maintaining the
integrity of the sensitive hydroxylamine bond. For example,
OL7029273
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Org. Lett., Vol. 10, No. 5, 2008