Synthesis of N-arylhydroxylamines by Pd-catalyzed coupling

Article abstract of DOI:10.1016/j.tetlet.2010.12.034

Pd-catalyzed coupling of aryl halides with TeocNHOTBS, followed by treatment of the products with TBAF, provides effective access to a wide range of N-arylhydroxylamines by a route that produces stable doubly-protected intermediates and allows the protective groups to be removed under mild conditions that do not cause extensive degradation of the final product.

Full text of DOI:10.1016/j.tetlet.2010.12.034

Tetrahedron Letters 52 (2011) 2221–2223
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of N-arylhydroxylamines by Pd-catalyzed coupling
⇑
Daniel Beaudoin , James D. Wuest
Département de Chimie, Université de Montréal, Montréal, Québec, Canada H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 15 December 2010
Pd-catalyzed coupling of aryl halides with TeocNHOTBS, followed by treatment of the products with
TBAF, provides effective access to a wide range of N-arylhydroxylamines by a route that produces stable
doubly-protected intermediates and allows the protective groups to be removed under mild conditions
that do not cause extensive degradation of the final product.
Ó 2011 Published by Elsevier Ltd.
X
N-Arylhydroxylamines and their derivatives are widely used as
intermediates in synthesis,1,2 and they show significant biological
activity.2–5 In particular, they have been used to inhibit enzymes
and release NO,3 and their formation as metabolites appears to
be responsible for the toxicity, mutagenicity, and carcinogenicity
of diverse arylamines and nitroarenes.4,5 N-Arylhydroxylamines
form a class of inherently unstable compounds, and they readily
degrade by acid-induced Bamberger rearrangement, dispropor-
tionation, and other processes.6–9 The toxic, mutagenic, and carcin-
ogenic effects of N-arylhydroxylamines can be attributed to
subsequent reactions of electrophilic species generated by their
degradation.8
Ph
Ph
(t-Bu)2P
Ph
N
N
X
X
N
N
2
X
1a (X = NHOH)
1b (X = NO2)
1c (X = Br)
1d (X = N(Teoc)OTBS)
To be able to exploit the useful properties of N-arylhydroxylam-
ines, chemists have worked for many decades to develop effective
ways to make them.7,10–12 However, the intrinsically high reactiv-
ity of these compounds continues to make their synthesis very
challenging, especially when they must be isolated and purified be-
fore use in subsequent steps. The classic way to make N-arylhydr-
oxylamines, discovered more than a century ago by Bamberger,7
involves reducing the corresponding nitroarenes using metals un-
der acidic conditions. Despite later refinements,12 however, precise
control of the conditions is needed to prevent over-reduction or
decomposition of the desired product, and full purification is often
difficult. Indeed, the standard preparation of N-arylhydroxylam-
ines by reducing nitroarenes with zinc in the presence of ammo-
nium chloride has been described as ‘frustratingly erratic, and
may be entirely unsatisfactory in some cases’.13 As a consequence,
modified reductive methods for transforming nitroarenes into N-
arylhydroxylamines continue to be published frequently,2 demon-
strating a need for further improvement.
various established conditions. All attempts led to complex mix-
tures containing the products of over- and under-reduction, and
we were unable to obtain target 1a in pure form. We therefore
turned to newer methods based on metal-catalyzed coupling,14,15
and the procedure of Tomkinson and co-workers appeared to be
particularly attractive.14 In this approach, aryl halides undergo effi-
cient Pd-catalyzed coupling with doubly N- and O-protected deriv-
atives of hydroxylamine in the presence of the ligand Bippyphos
(2).16 A single example of O-deprotection by removal of a t-butyl-
dimethylsilyl (TBS) group was reported to give an N-arylhydroxyl-
amine N-protected with
a t-butyloxycarbonyl (Boc) group;
however, in no case was complete N- and O-deprotection effected
to provide an isolated N-arylhydroxylamine. In our attempts to
carry out further N-deprotection, we found that N-arylhydroxyl-
amines degrade rapidly under the acidic conditions used for re-
moval of Boc groups, and we could not obtain material of
acceptable purity.
To solve the problem of making N-arylhydroxylamines, we
developed a modified coupling procedure using a derivative of
hydroxylamine protected with TBS and [2-(trimethylsilyl)eth-
oxy]carbonyl (Teoc) groups.17 TeocNHOTBS (3) was synthesized
in 75% overall yield by the route summarized in Scheme 1, which
is based in part on a published method for making 2-(trimethyl-
In the course of work related to the construction of predictably
ordered molecular solids, we tried to prepare N-arylhydroxy-
lamine 1a by reducing tetrakis(4-nitrophenyl)methane (1b) under
⇑
Corresponding author.
E-mail address: james.d.wuest@umontreal.ca (J.D. Wuest).
Fellow of the Natural Sciences and Engineering Research Council of Canada.
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.12.034

2222
D. Beaudoin, J. D. Wuest / Tetrahedron Letters 52 (2011) 2221–2223
O
Acknowledgments
N
N
1)
N
N
We are grateful to the Natural Sciences and Engineering Re-
H
N
search Council of Canada, the Ministère de l’Éducation du Québec,
the Canada Foundation for Innovation, the Canada Research Chairs
Program, and the Université de Montréal for financial support.
OH
O
Me3Si
Me3Si
OR
O
2) NH2OH
R = H
TBSCl/Et3N
Supplementary data
3 (R = TBS)
Supplementary data (characterizations of all new compounds)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.12.034.
Scheme 1.
TeocNHOTBS ( 3; 1.1 eq)
Pd2dba3 (2.5 mol% Pd)
Bippyphos (2; 5.0 mol%)
Cs2CO3 (2.0 eq)
References and notes
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TBAF (4.0 eq)
THF/40 °C/90 min
Teoc
Ar
X
Ar
N
Ar NHOH
OTBS
PhMe/80 °C/16 h
5a-g
4a-h
Scheme 2.
Table 1
Pd-catalyzed coupling of aryl halides with TeocNHOTBS (3) and subsequent depro-
tection to give N-arylhydroxylamines
Entry
Ar-X
Ar-N(Teoc)OTBS (% yield)
Ar-NHOH (% yield)
1
2
3
4
5
6
7
8
9
C6H5Br
C6H5I
4a (96)
4a (81)
4b (95)
4c (84)
4d (90)
4e (96)
4f (79)
4g (73)
4h (<5)
5a (85)
—
4-MeC6H4Br
4-ClC6H4Br
3-CNC6H4Br
4-CO2EtC6H4Br
4-NO2C6H4I
3,5-Me2C6H3I
2-MeC6H4I
5b (83)
5c (88)
5d (92)
5e (95)
5f (79)
5g (42)
—
silyl)ethyl carbamate.18 The conditions used by Tomkinson and co-
workers to couple aryl halides with BocNHOTBS gave only modest
yields when applied to analog 3, but we found that the combina-
tion of Bippyphos (2) with dibenzylideneacetone (dba) complex
Pd2dba3 was generally very effective (Scheme 2, Table 1).19 Aryl
bromides were found to give higher yields than iodides. Hindered
substrates coupled poorly and gave only traces of product, even at
elevated temperatures (entry 9). In the cases studied, coupled
products could be deprotected efficiently with tetrabutylammo-
nium fluoride (TBAF) in THF to give the desired N-arylhydroxylam-
ines in pure form.20,21 No examples with highly electron-donating
substituents such as methoxy were examined because N-arylhydr-
oxylamines of this type are known to be particularly prone to deg-
radation.22 The relatively low overall yield in Entry 8 presumably
reflects the inherent instability of N-arylhydroxylamines with elec-
tron-donating groups; nevertheless, our methodology is effective
even in this demanding example.
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Part 1; Rappoport, Z., Liebman, J. F., Eds.; John Wiley & Sons: Chichester, 2009;
pp. 117–162.
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New York, 1993; Collect. Vol. 8, pp. 16–19; Kamm, O. In Organic Syntheses;
Wiley: New York, 1941; Collect. Vol. 1, pp. 435–437; Marvel, C. S.; Kamm, O. J.
Am. Chem. Soc. 1919, 41, 276–282.
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2008, 10, 797–800; Peng, J.; Lin, W.; Yuan, S.; Chen, Y. J. Org. Chem. 2007, 72,
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489.
These results gave us confidence that our modified method
could be used to make more complex N-arylhydroxylamines such
as compound 1a.23 Indeed, coupling of tetrabromide 1c24 under
the standard conditions of Scheme 2 gave a 62% yield of protected
derivative 1d, which was then converted by the action of TBAF into
target 1a in 77% yield. This demonstrates that our methodology
provides effective access to a wide range of N-arylhydroxylamines
by a route that offers two key advantages: (1) It produces stable
doubly-protected intermediates that can be purified easily and
(2) it allows the protective groups to be removed under mild con-
ditions that do not cause extensive degradation of the final
product.
17. Carpino, L. A.; Tsao, J.-H.; Ringsdorf, H.; Fell, E.; Hettrich, G. Chem. Commun.
1978, 358–359.

D. Beaudoin, J. D. Wuest / Tetrahedron Letters 52 (2011) 2221–2223
2223
18. Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 3667–3670.
19. General procedure for the formation of doubly-protected N-
extracts were dried over Na2SO4, and the volatiles were removed by
evaporation under vacuum. The residue was purified by column
chromatography (MeOH/CH2Cl2). CAUTION: N-Arylhydroxylamines are
inherently unstable compounds and present a risk of explosions.21
21. Rondestvedt, C. S., Jr.; Johnson, T. A. Synthesis 1977, 851–852.
arylhydroxylamines: A solution of Ar-X (2.0 mmol), TeocNHOTBS (3; 640 mg,
2.2 mmol), Bippyphos (2; 51 mg, 0.10 mmol), and Pd2dba3 (23 mg,
0.025 mmol) in toluene (8 mL) was treated with Cs2CO3 (1.3 g, 4.0 mmol). N2
was bubbled through the mixture for 30 min, and then the mixture was heated
and stirred at 80 °C for 16 h under N2. The resulting mixture was purified
directly by column chromatography (EtOAc/hexanes).
22. For example, see: Fountain, K. R.; Hutchinson, L. K.; Mulhearn, D. C.; Xu, Y. B. J.
Org. Chem. 1993, 58, 7883–7890.
23. For two previous publications that report complex N-arylhydroxylamines but
do not describe their purification and characterization, see: Jain, V. K.;
Mandalia, H. C.; Suresh, E. J. Incl. Phenom. Macrocycl. Chem. 2008, 62, 167–
178; Jayswal, K. P.; Patela, J. R. Acta Chim. Slov. 2008, 55, 502–507.
24. Rathore, R.; Burns, C. L.; Guzei, I. A. J. Org. Chem. 2004, 69, 1524–1530; Grimm,
M.; Kirste, B.; Kurreck, H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1097–1098.
20. General procedure for the formation of unprotected N-arylhydroxylamines: To
a solution of Ar-N(Teoc)OTBS (1 mmol) in THF (6 mL) was added a solution of
TBAF in THF (4 mL, 1 M, 4 mmol), and the resulting mixture was stirred at 40 °C
for 90 min under N2. The mixture was then treated with aqueous phosphate
buffer (10 mL, 0.1 M, pH 7). The desired product was extracted with EtOAc, the