Copper-catalyzed aerobic oxidation of N-substituted hydroxylamines: Efficient and practical access to nitroso compounds

Article abstract of DOI:10.1021/ol301414k

A general and efficient aerobic oxidation of N-substituted hydroxylamines is described. The mild reaction conditions employed provide a catalytic and sustainable alternative to stoichiometric oxidation methods to gain access to a range of nitroso compound

Full text of DOI:10.1021/ol301414k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Copper-Catalyzed Aerobic Oxidation of
N-Substituted Hydroxylamines: Efficient
and Practical Access to Nitroso Compounds
Charles P. Frazier, Alejandro Bugarin, Jarred R. Engelking, and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106, United States
javier@chem.ucsb.edu
Received May 22, 2012
ABSTRACT
A general and efficient aerobic oxidation of N-substituted hydroxylamines is described. The mild reaction conditions employed provide a catalytic
and sustainable alternative to stoichiometric oxidation methods to gain access to a range of nitroso compounds, such as acylnitroso,
nitrosoformate, nitrosoformamide, iminonitroso, arylnitroso, and P-nitrosophosphine oxide derivatives in excellent yield.
Aerobic oxidations have recently emerged as a promising
new area capable of replacing hazardous classical oxidation
protocols.1 From an economical and environmental view-
point, molecular oxygen represents the ideal oxidant due to its
low cost and lack of toxic byproduct.2 Aerobic oxidation
methodology has largely focused on the oxidation
of alcohol-based systems, despite the important role
oxidation chemistry plays in other functional group
transformations.3ꢀ5 For example, the analogous aero-
bic oxidation of hydroxylamines to nitroso compounds
has remained underdeveloped, despite its potential
synthetic utility and environmetal impact.
(1) For select review, see: (a) Dugger, R. W.; Ragan, J. A.; Ripin,
D. H. B. Org. Process Res. Dev. 2005, 9, 253. (b) Caron, S.; Dugger, R. W.;
Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943.
(2) For select reviews on recent advances in aerobic oxidation, see: (a)
Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50,
11062. (b) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (c) Shi,
Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381.
(3) For select examples using copper catalysts, see: (a) Marko, I. E.;
Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science 1996, 274,
2044. (b) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-Regnaut, I.;
Gautier, A.; Brown, S. M.; Urch, C. J. J. Org. Chem. 1999, 64, 2433.
(4) For select examples using palladium catalysts, see: (a) Stahl, S. S.
Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Gligorich, K. M.; Sigman,
M. S. Chem. Commun. 2009, 3854.
Hydroxylamines not only represent an important structural
motif prevalent in natural products and biologically active
molecules but also serve as a precursor to nitroso compounds.
During the past four decades, nitroso compounds have been
utilized as synthetically useful intermediates for organic
synthesis.6 In spite of the significant achievements, most
methods used for the preparation of nitroso compounds still
rely on the use of stoichiometric oxidants, which impose
constraints on nitroso chemistry, such as functional group
(5) For select examples using ruthenium catalysts, see: (a) Marko,
I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-Regnaut, I.; Urch, C. J.;
Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661. (b) Yamaguchi, K.;
Mizuno, N. Angew. Chem., Int. Ed. 2002, 41, 4538. (c) Zhan, B.-Z.;
White, M. A.; Sham, T.-K.; Pincock, J. A.; Doucet, R. J.; Rao, K. V. R.;
Robertson, K. N.; Cameron, T. S. J. Am. Chem. Soc. 2003, 125, 2195. (d)
Mori, S.; Takubo, M.; Makida, K.; Yanase, T.; Aoyagi, S.; Maegawa,
T.; Monguchi, Y.; Sajiki, H. Chem. Commun. 2009, 5159.
(6) For select reviews on the use of nitroso compounds in synthesis,
see: (a) Streith, J.; Defoin, A. Synthesis 1994, 1107. (b) Kibayashi, C.;
Aoyagi, S. Synlett 1995, 873. (c) Vogt, P. F.; Miller, M. J. Tetrahedron
1998, 54, 1317. (d) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131.
(e) Iwasa, S.; Fakhruddin, A.; Nishiyama, H. Mini-Rev. Org. Chem.2005, 2,
157. (f) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006, 2031.
(g) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50, 5630.
r
10.1021/ol301414k
XXXX American Chemical Society

Scheme 1. Aerobic Oxidation of Substituted Hydroxylamines
Scheme 2. Aerobic Oxidation of N-Substituted Hydroxylamines
compatibility, new reaction development, and removal of a
potentially toxic oxidation byproduct.7,8
During our study of the nitroso ene reaction, we discov-
ered an efficient, mild, and environmentally benign in situ
process for the oxidation of N-hydroxycarbamates to nitro-
soformate esters (Scheme 1).9 This system, based on a Cu(I)-
catalyzed aerobic oxidation, enabled the development of
a practical and general acylnitroso ene reaction. Simulta-
neously, Shea, Whiting and co-workers independently
reported a similar Cu(II)-catalyzed aerobic oxidation pro-
tocol.10 Their process provides straightforward access to
carbobenzyloxy(Cbz)-protected oxazines via a nitroso het-
ero-DielsꢀAlder (HDA) reaction. At present, aerobic oxi-
dation protocols are limited to the formation of nitro-
soformate derivatives (2), with the exception of two intra-
molecular reactions.11 Given the importance of nitroso
chemistry and the myriad of N-substituted nitroso com-
pounds used in synthesis, such as acylnitroso 3, nitrosofor-
mamide 4, iminonitroso 5, P-nitroso phosphine oxide 6,
P-nitroso phosphate 7, and arylnitroso 8 derivatives, the
development of a general aerobic oxidation of N-substituted
hydroxylamines is still desired.6 Herein, we describe a Cu(I)-
catalyzed oxidation of these major classes of substituted
hydroxylamines at rt using air as the terminal oxidant
(Scheme 1). The process provides a general, cata-
lytic, and sustainable alternative to stoichiometric oxidation
methods to gain access to a range of nitroso compounds.
Due to the instability and transient nature of nitroso
compounds 2ꢀ7, we elected to use the nitroso HDA
reaction to investigate the generality of our catalytic aerobic
a Reactions conducted at 50 °C. bNppoc = 20-nitrophenylpropyloxy-
carbonyl.
oxidation protocol. It is well-known that nitroso com-
pounds that are directly connected to an electron-with-
drawing group (2ꢀ7) undergo rapid [4 þ 2] cycloaddition
reactions with conjugated dienes.6 Furthermore, the HDA
reaction is a valuable transformation that plays a central
role in the synthesis of natural products and biologically
active molecules. These advantageous properties were key
factors in our selection of the nitroso HDA reaction as a
platform to test our new oxidation methodology.
Our investigations began with our previously developed
oxidation conditions (5 mol % CuCl, 1.25 mol % pyridine,
reagent grade THF, and 1 atm air). Under these conditions,
reactions with acyl-substituted hydroxylamines required
long reaction times and proved impractical. However, it
was found that the aerobic oxidation protocol was more
efficient and tolerant of a variety of N-substituted hydro-
xylamines when the catalyst loading was increased to
20 mol % CuCl and 5 mol % pyridine (Scheme 2). Generally,
compounds containing a more electron-withdrawing group
on the nitrogen substituent reacted slower. Within the acyl-
substituted series, N-hydroxyacetamide and N,2-dihy-
droxybenzamide afforded the lowest yields (58% and
73% respectively) and required heating to 50 °C to help
facilitate the reaction. Under these conditions, decom-
position of the acylnitroso species became competitive
with the HDA reaction, which resulted in the lower
yields.
(7) For select examples, see: (a) Kirby, G. W.; Mackinnon, J. W. M.;
Sharma, R. P. Tetrahedron Lett. 1977, 18, 215. (b) Keck, G. E.; Webb, R. R.;
Yates, J. B. Tetrahedron 1981, 37, 4007. (c) Adam, W.; Bottke, N.; Krebs, O.;
€
Saha-Moller,C.R.Eur. J. Org. Chem. 1999,1999, 1963. (d) Gowenlock, B. G.;
Richter-Addo, G. B. Chem. Rev. 2004,104, 3315. For an asymmetric example,
see: (e) Yamamoto, Y; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128.
(8) More recently, some progress has been made in metal-catalyzed
oxidations with stoichiometric peroxides, see: (a) Flower, K. R.; Lightfoot,
A. P.; Wan, H.; Whiting, A. Chem. Commun. 2001, 1812. (b) Iwasa, S.;
Tajima, K.; Tsushima, S.; Nishiyama, H. Tetrahedron Lett. 2001, 42, 5897.
(c) Adamo, M. F. A.; Bruschi, S. J. Org. Chem. 2007, 72, 2666 and
references therein.
(9) Frazier, C. P.; Engelking, J. R.; Read de Alaniz, J. J. Am. Chem.
Soc. 2011, 133, 10430.
(10) Chaiyaveij, D.; Cleary, L.; Batsanov, A. S.; Marder, T. B.; Shea,
K. J.; Whiting, A. Org. Lett. 2011, 13, 3442.
(11) Shea, Whiting and co-workers examined the intramolecular trapping
of an acyl-substituted hydroxylamine and an acyl-substituted hydrazide.
B
Org. Lett., Vol. XX, No. XX, XXXX

Hydroxylamines bearing orthogonal formate-based
protecting groups, such as Cbz, Boc, Troc, Fmoc, and
Nppoc, all participated in the acylnitroso HDA reaction
in greater than 87% yield (16ꢀ20). Other Cbz-derived
N-hydroxycarbamates bearing p-substituted functional
groups proceeded under the reaction conditions with no
complications. Nitrosoformamide compounds 25ꢀ28 re-
acted analogously and universally afforded products in
high yield. Importantly, this includes the formation of
hydroxyurea cycloaddition adduct 25 that previously re-
sulted in low isolated yield when stoichiometric periodate
oxidation was used.12 Finally, the mild oxidation protocol
can be performedsuccessfully in a number ofreagent grade
solvents, such as 2-MeTHF, MeOH, EtOH, i-PrOH, EtOAc,
and toluene (see Supporting Information for more details).
We next explored the capacity of these conditions to
catalyze the aerobic oxidation of other known classes of
N-substituted hydroxylamines (Scheme 3). Although less
studied, HDA reaction with P-nitrosophoshine oxide and
nitrosoamidine allows for the direct installation of phos-
phinamide and guanidine functional groups, which are
prevalent in asymmetric catalysts and biologically active
molecules.13 In addition, King and co-workers have shown
that N-phosphinoylnitroso compounds hydrolyze to lib-
erate nitroxyl (HNO), the biologically important reduced
form of nitric oxide.14 Therefore, we were encouraged to
observe that N-hydroxyphosphinamide and N-hydroxy-
phosphoramidate could be oxidized and readily trapped
with 1,3-cyclohexadiene in excellent to moderate yield, 32
and 33. Phosphorus migration is a known problem with
N-hydroxyphosphoramidates and may contribute to the
reduced yield of 33.14b The oxidation protocol also worked
with N,N0-bis-Boc-N00-hydroxylguanidine.13c
Arylnitroso compounds are benchtop stable and con-
sequently much less reactive in the hetero-DielsꢀAlder
reaction in comparison to acylnitroso compounds.6g In
general, a considerable drop in yield is observed for these
reactions. In addition, in situ oxidation of the arylhydroxy-
lamine is usually avoided because it is difficult to prevent
overoxidation and formation of a coupling byproduct,
such as azoxybenzene.15 Initially, subjection of phenylhy-
droxylamine to the optimized reaction conditions resulted
in the exclusive formation of azoxybenzene. To circumvent
this undesired side reaction, we added the arylhydroxyla-
mine via syringe pump over the course of 2 h. Utilizing this
protocol, the azoxybenzene formation could be minimized
and the nitroso HDA adducts 35 and 36 were isolated in high
yield (84% and 81%). This approach represents a viable
solution to the arylnitroso DielsꢀAlder cycloaddition.
HDA trapping of transient nitroso species is not limited to
the use of 1,3-cyclohexadiene; other more elaborate and less
Scheme 3. Aerobic Oxidation of N-Substituted Hydroxylamines
a Synthesis of 33 commenced from diethyl (trimethylsilyl)oxy-
phosphoramidate, see Supporting Information. bThe arylhydroxyla-
mines were added over 2 h via syringe pump.
reactive dienes can also be used (Table 1). Good functional
group compatibility was observed (entries 1ꢀ7). For example,
nitroso DielsꢀAlder adducts of ergosterol 46 and ergosteryl
acetate 47 were isolated and produced in good yield and
excellent regioselectivity (16:1 and 35:1 respectively).16 Deri-
vatives of these and other diene-containing natural products
have been studied for their biological activity.17
Shea and Whiting showed that by using their mild oxida-
tion protocol they could accurately determine the product
distribution for dienes that are capable of undergoing both
DielsꢀAlder cycloaddition and ene reactions.10 As expected,
we observed similar results with 2,3-dimethylbuta-1,3-diene
(DMB) 50 and 2-methyl-buta-1,3-diene 52 (entries 6ꢀ7). The
combined yields were high, and the DielsꢀAlder adducts
could be isolated in 71% and 43% yield, respectively. 2-Sub-
stituted 1,3-dienes often provide the oxazine with moderate
selectivity; we observed a 2:1 ratio of regioisomeric Dielsꢀ
Alder adducts 53 and 54 when isoprene was used.
We were curious about the origin of the competing ene
reaction when DMB and isoprene were used. It is generally
believed that the HDA reaction is more rapid if the free
nitroso compound is present. A number of studies have
indicated the involvement of a metal-bound nitroso com-
plex when the ene adduct is observed as a major product
in the presence of a DielsꢀAlder trapping agent.18 These
control experiments are typically conducted with DMB as
the DielsꢀAlder trapping agent. However, it is well-known
that DMB exists as a mixture of s-trans and s-cis
conformers.19 We hypothesized that the formation of
the ene product could be a reflection of the diene
(16) (a) Kirby, G. W.; Mackinnon, J. W. M. J. Chem. Soc., Perkin
Trans. 1 1985, 887. (b) Yang, B.; Miller, P. A.; Mollmann, U.; Miller,
M. J. Org. Lett. 2009, 11, 2828.
(17) Krchnak, V.; Zajicek, J.; Miller, P. A.; Miller, M. J. J. Org.
Chem. 2011, 76, 10249.
(18) (a) Srivastava, R. S.; Nicholas, K. M. Chem. Commun. 1996,
2335. (b) Ho, C.-M.; Lau, T.-C. New J. Chem. 2000, 24, 859. (c)
Srivastava, R. S.; Khan, M. A.; Nicholas, K. M. J. Am. Chem. Soc.
2005, 127, 7278 and references therein.
(19) Squillacote, M. E.; Semple, T. C.; Mui, P. W. J. Am. Chem. Soc.
1985, 107, 6842.
(12) Xu, Y.; Alavanja, M.-M.; Johnson, V. L.; Yasaki, G.; King, S. B.
Tetrahedron Lett. 2000, 41, 4265.
(13) (a) Gamble, M. P.; Smith, A. R. C.; Wills, M. J. Org. Chem.
1998, 63, 6068. (b) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617.
(c) Miller, C. A.; Batey, R. A. Org. Lett. 2004, 6, 699.
(14) (a) Ware, R. W.; King, S. B. J. Am. Chem. Soc. 1999, 121, 6769.
(b) Ware, R. W.; King, S. B. J. Org. Chem. 2000, 65, 8725. (c) Ware,
R. W.; Day, C. S.; King, S. B. J. Org. Chem. 2002, 67, 6174.
(15) Møller, E. R.; Jørgensen, K. A. J. Org. Chem. 1996, 61, 5770.
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C

dienes locked in the required and reactive s-cis confor-
mation were found to out-compete the intramolecular
ene reaction (eq 1). No product derived from the
intramolecular ene reaction was observed. In contrast,
in the presence of DMB the predominant product
resulted from an intramolecular ene reaction (72%).
The overall ratio of products for this transformation
was 14:3:1 (intramolecular ene (72%)/nitroso HDA
cycloaddition (16%)/intermolecular ene with 50 (6%)).
These results reveal that DMB is less reactive in the
acylnitroso HDA cycloaddition than cylopentadiene
and 1,3-cyclohexadiene.20 They also suggest that the
use of less reactive dienes could result in the ene reaction
proceeding in preference to the DielsꢀAlder cycloaddi-
tion. The involvement of a metal-bound acylnitroso
complex cannot be ruled out at this time.
Table 1. Hetero-DielsꢀAlder Reaction with Various Dienes
Finally, we wanted to investigate a diastereoselective
nitroso HDA reaction. While there are a number of elegant
methods for performing asymmetric nitroso HDA reac-
tions, the most common method for inducing chirality
utilizes a chiral auxiliary on the acylnitroso dienophile. We
chose to investigate the asymmetric HDA reaction using
Oppolzer’s camphorsultam derivative 60. As shown in eq 2
exposure of 60 to the optimized reaction conditions pro-
duced 61 as a single diastereomer in 99% yield.
In conclusion, we have developed a highly general cop-
per-catalyzed aerobic oxidation of N-substituted hydroxy-
lamines for the in situ formation of nitroso compounds.
These transient nitroso compounds were efficiently trapped
using an HDA reaction, and a variety of N-substituted
oxazines were formed in high to moderate yields. Impor-
tantly, this oxidation protocol is operationally simple, using
reagent grade solvents, 1 atm of air, and only a slight excess
of diene. Further investigations are underwayto explorethe
scope of aerobic oxidations and nitroso chemistry.
a Isolated as a nonseparable mixture of regioisomers (16:1). b Isolated as
a nonseparable mixture of regioisomers (35:1). c 17% of the acylnitroso ene
product was isolated. d 36% of the acylnitroso ene product was isolated.
conformation/reactivity and not the involvement of a
metal-bound acylnitroso complex.
Acknowledgment. This work was supported by UCSB.
Additional support was kindly provided by Eli Lilly (New
Faculty Award to J.R.A.) and the Hellman Family Foun-
dation. We thank Prof. Dr. Andy Whiting (Durham
University) for helpful discussions.
In order to further evaluate the rate difference, a competi-
tion experiment between an intermolecular HDA cycloaddi-
tion and an intramolecular ene reaction was designed using
prenyl alcohol derived N-hydroxycarbamate 55. Cyclic
Supporting Information Available. Detailed experimen-
tal procedures, characterization data, and copies of
1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) To our knowledge, the reactivity of different dienes with acylni-
troso compounds have not been measured. For related studies using
different dienes with cycloalkenones, see: (a) Dols, P. PM. A.; Klunder,
A. J. H.; Zwanenburg, B. Tetrahedron 1994, 50, 8515. (b) Paton, R. S.;
Kim, S.; Ross, A. G.; Danishefsky, S. J.; Houk, K. N. Angew. Chem. Int.,
Ed. 2011, 50, 10366 and references therein.
The authors declare no competing financial interest.
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