Copper(II)-catalyzed room temperature aerobic oxidation of hydroxamic acids and hydrazides to acyl-nitroso and Azo intermediates, and their Diels-Alder trapping

Article abstract of DOI:10.1021/ol201188d

CuCl₂, in the presence of a 2-ethyl-2-oxazoline ligand, is an effective catalyst for the room temperature, aerobic oxidation of hydroxamic acids and hydrazides, to acyl-nitroso and azo dienophiles respectively, which are efficiently trapped in

Full text of DOI:10.1021/ol201188d

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3442–3445
Copper(II)-Catalyzed Room Temperature
Aerobic Oxidation of Hydroxamic Acids
and Hydrazides to Acyl-Nitroso and Azo
Intermediates, and Their DielsꢀAlder
Trapping
Duangduan Chaiyaveij,† Leah Cleary,‡ Andrei S. Batsanov,† Todd B. Marder,*,†
Kenneth J. Shea,*,‡ and Andrew Whiting*,†
Centre for Sustainable Chemical Processes, Department of Chemistry, Durham
Univertsity, Science Laboratories, South Road, Durham, DH1 3LE, U.K., and
Department of Chemistry, University of California, Irvine, California 92697-2025,
United States
todd.marder@durham.ac.uk; kjshea@uci.edu; andy.whiting@durham.ac.uk
Received May 4, 2011
ABSTRACT
CuCl2, in the presence of a 2-ethyl-2-oxazoline ligand, is an effective catalyst for the room temperature, aerobic oxidation of hydroxamic acids and
hydrazides, to acyl-nitroso and azo dienophiles respectively, which are efficiently trapped in situ via both inter- and intramolecular hetero-
DielsꢀAlder reactions with dienes. Both inter- and intramolecular variants of the DielsꢀAlder reaction are suitable under the reaction conditions
using a variety of solvents. Under the same conditions, an acyl hydrazide was also oxidized to give an acyl-azo dienophile which was trapped
intramolecularly by a diene.
Nitroso dienophiles are known to undergo [4 þ 2]
cycloaddition reactions with conjugated dienes1 to provide
heteroatom DielsꢀAlder adducts. These cycloadducts are
valuablesyntheticintermediates for naturalproduct synth-
esis and have been used to synthesize novel oxazine
derivatives, possessing new biological properties.2,3 How-
ever, electron-rich nitroso compounds are not particularly
reactive. They readily dimerize1 and are known to form
unreactive complexes with Lewis acids.5 Far more useful
for the DielsꢀAlder reaction are nitroso species bearing
electron-withdrawing groups.2e,f In particular, the highly
reactive, unstable acyl-nitroso compounds have found the
greatest utility.4
The formation of acyl-nitroso dienophiles is generally
carried out in situ in the presence of the diene to trap the
unstable species.6 The oxidation of hydroxamic acids has
been achieved using periodates, DMSO-based oxidants,
and lead(IV) reagents.7 Recent advances involve more
atom-economic and less toxic, metal-catalyzed oxidations
involving peroxides.8 Peroxides, however, are still not ideal
reagents because yields are substrate, oxidant, and catalyst
dependent.8d There is a need, therefore, to develop new,
clean, green, mild, and general in situ hydroxamic acid
oxidation reactions. Herein, we report such a process using
catalytic Cu(II) in air.
† Durham Univertsity.
‡ University of California.
(1) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1.
(2) (a) Wichterle, O. Collect. Czech. Chem. Commun. 1947, 12, 292.
(b) Arbuzov, Y. A. Dokl. Akad. Nauk S.S.S.R. 1948, 60, 993. (c)
Hammer, J.; Ahmad, A.; Holliday, R. E. J. Org. Chem. 1963, 28,
3034. (d) Kresze, G.; Firl, J.; Zimmerr, H.; Wollnik, U. Tetrahedron
1964, 20, 1605. (e) Yamamoto, H.; Momiyama, N. Chem. Commun.
2005, 3514. (f) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006,
2031. (g) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50, 2.
Following mechanistic studies on the oxidation of
hydroxamic acids catalyzed by various metals, and the
r
10.1021/ol201188d
Published on Web 06/06/2011
2011 American Chemical Society

in situ formation of Cu(II)-based catalyst systems in the
presence of aryl-nitroso species,9 we began to explore the
potential for developing a hydroxamic acid oxidation
procedure which did not involve peroxides or other strong
oxidants. Indeed, from the point of view of developing an
environmetally benign oxidation process, an aerobic oxi-
dation was highly attractive. Among potential oxidative
systems that could be employed for such a process, we
examined various palladium(II) systems with ligands that
included thioureas, oxazolines, and phosphines, together
with co-oxidants such as copper(II) salts because related
systems have been employed for other oxidative transforma-
tions.10 These were screened for the in situ oxidation of the
Z-protectedhydroxamic acid1 toderivethecorresponding
acyl-nitroso species 2. Formation of intermediate acyl-
nitroso compound 2 was initially followed by trapping
with cyclohexaadiene 3b to give cycloadduct 4b to screen
potential catalytic systems. Preliminary results were en-
couraging; however, more detailed studies revealed that
the palladium(II) salts were not involved, and indeed, it
was in fact the copper(II) salt alone which was acting as a
catalytic oxidant in air, i.e. as outlined in eq 1 (Table 1).
Examination of different copper(II) salts (i.e., CuCl2,
CuBr2, CuI2) and loadings, with different ligands (includng
tetramethylthiourea, 2-ethyl-2-oxazoline and mixed ligand
systems10), showed that CuCl2 (10 mol %), in the presence
of 2-ethyl-2-oxazoline (20 mol %), in air at RT in various
solvents (vide infra) including CHCl3 (eq 1) gave essentially
quantitative conversion of hydroxamic acid 1 to the cy-
cloadduct 4b, which was isolated in 86% yield after
recrystallization. Cycloadduct 4b gave single crystals sui-
table for X-ray structure analysis (see Supporting Infor-
mation (SI)).
Further studies with a variety of dienes (Table 1) re-
vealed that the Cu(II)-catalyzed, room temperature aero-
bic oxidation reaction was indeed a general and useful
process in the solvent CHCl3. Although reaction times
vary from 3 (Table 1, entry 2) to 24 h (Table 1, entries 3 and
5ꢀ7), the isolated yields were universally high, represent-
ing a substantial improvement upon our previous pre-
ferred oxidation systems.8b,d For example, the formation
of the DMA adduct is readily achieved in 24 h in 86% yield
after recrystallization (Table 1, entry 6), contrasting with a
previous best reaction yield of 36% in 96 h using a
ruthenium-salen þ TBHP oxidation system.8b Crystals of
cycloadduct 4f suitable for single-crystal X-ray diffraction
were grown (see SI). Cycloadduct 4g was also isolated in a
substantially improved yield of 74%, compared with 16%
using an iron catalyst.8d For dienes which are capable of
undergoing both DielsꢀAlder addition and ene-reactions,
the overall yields were also high and we were able to
ascertain accurately the ratio of cycloaddtion to ene pro-
duct. Thus, in the case of 2,3-dimethylbuta-1,3-diene 3c,
reaction with acyl-nitroso species 2 resulted in a 75%
combined yield of an inseparable mixture of products 4c
and 5c in a ratio of 3:1. (Table 1, entry 3). Similarly, when
isoprene 3ewas employed (Table 1, entry 5), the 9:1 ratio of
DielsꢀAlder to ene products obtained was reasonable,
with a 2:1 ratio of regioisomeric DielsꢀAlder adducts 4e
and 4e0 being produced. This shows that the slightly more
electron-rich end of the diene prefers to react at the nitroso
nitrogen atom rather than at oxygen.
Despite the success of the reactions shown in Table 1,
development of a more environmentally benign oxidation
process led to an examination of different solvent systems
for the reaction. Thus, a solvent screen was performed with
2,3-dimethylbutadiene 3c employed as the trapping diene
(Table 2). The effects of solvent upon the rate, yield, and
ratio of competing nitroso-DielsꢀAlder cycloaddition and
ene reactions were studied.14
The reaction was carried out in a range of solvents
(Table 2), with universally high yields being obtained (80
to 89%). All of the reactions carried out in CHCl3 were
then repeated in the preferable, inexpensive solvent
MeOH, as the reaction proceeded at the highest rate in
this solvent (Table 2, entry 1). Significant effects on both
the rate of reaction and the product distribution as a
function of solvent polarity were observed. For example,
the reaction shown in eq 2 was approximately 70 times
(3) (a) Yang, B.; Zhu, Z. C.; Goodson, H. V.; Miller, M. J. Bioorg.
Med. Chem. Lett. 2010, 20, 3831. (b) Yang, B.; Miller, P. A.; Mollmann,
U.; Miller, M. J. Org. Lett. 2009, 11, 2828. (c) Li, F. Z.; Yang, B. Y.;
Miller, M. J.; Zajicek, J.; Noll, B. C.; Mollmann, U.; Dahse, H.-M.;
Miller, P. Org. Lett. 2007, 9, 2923. (d) Krchnak, V.; Waring, K. R.; Noll,
B. C.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J. Org. Chem. 2008,
73, 4559. (e) Ruan, B. F.; Pong, K.; Jow, F.; Bowlby, M.; Crozier, R. A.;
Liu, D.; Liang, S.; Chen, Y.; Mercado, M. L.; Feng, X. D.; Bennett, F.;
Schack, D. V.; McDonald, L.; Zaleska, M. M.; Wood, A.; Reinhart,
P. H.; Magolda, R. L.; Skotnicki, J.; Pangalos, M. N.; Koehn, F. E.;
Carter, G. T.; Abou-Gharbia, M.; Graziani, E. I. Proc. Natl. Acad. Sci.
U.S.A. 2008, 105, 33. (f) Kirby, G. W.; Mackinnon, J. W. M. J. Chem.
Soc., Perkin Trans. 1 1985, 887. (g) Kirby, G. W.; Mackinnon, J. W. M.
J. Chem. Soc., Chem. Commun. 1977, 1, 23. (h) Kirby, G. W.; Bentley,
K. W.; Horsewood, P.; Singh, S. J. Chem. Soc., Perkin Trans. 1 1979,
3064. (i) Kirby, G. W.; Sweeny, J. G. Chem. Commun. 1973, 704.
(4) (a) Sklarz, B.; Al-Sayyab, A. F. J. Chem. Soc. 1964, 1318. (b)
Rowe, J. E.; Ward, A. D. Aust. J. Chem. 1968, 21, 2761. (c) Lerch, U.;
Moffat, J. G. J. Org. Chem. 1971, 36, 3391.
(5) Lightfoot, A. P.; Pritchard, R. G.; Wan, H.; Warren, J. E.;
Whiting, A. Chem. Commun. 2002, 2072.
(6) (a) Kirby, G. W.; Mackinnon, J. W. M.; Sharma, R. P. Tetra-
hedron Lett. 1977, 18, 215. (b) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc.,
Chem. Commun. 1973, 704.
(7) (a) Dao, L. H.; Dusk, J. M.; Mackay, D.; Watson, K. N. Can. J.
Chem. 1979, 57, 1712. (b) N. E. Jenkins, N. E.; Ware, R. W., Jr.;
Atkinson, R. N.; King, S. B. Synth. Commun. 2000, 30, 947.
(8) (a) Flower, K. R.; Lightfoot, A. P.; Wan, H.; Whiting, A. Chem.
Commun. 2001, 1812. (b) Flower, K. R.; Lightfoot, A. P.; Wan, H.;
Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 2058. (c) Iwasa, S.;
Tajima, K.; Tsushima, S.; Nishiyama, H. Tetrahedron Lett. 2001, 42,
5897. (d) Howard, J. A. K.; Ilyashenko, G.; Sparks, H.; Whiting, A.
Dalton Trans. 2007, 2108. (e) Adamo, M. F. A.; Bruschi, S. J. Org. Chem.
2007, 72, 2666.
(9) Howard, J. A. K.; Ilyashenko, G.; Sparkes, H. A.; Whiting, A.;
Wright, A. R. Adv. Synth. Catal. 2008, 350, 869.
(11) Kirby, G. W.; McGuigan, H.; Machinnon, J. W. M.; McLean,
D.; Sharma, R. P. J. Chem. Soc., Perkin Trans. 1 1985, 1437.
(12) Defoin, A.; Joubert, M.; Heuchel, J.-M.; Strehler, C.; Streith, J.
Synthesis 2000, 12, 1719.
(13) Tolman, V.; Hanus, J.; Sedmera, P. Collect. Czech. Chem.
Commun. 1999, 64, 696.
(10) (a) Liang, B.; Liu, J.; Gao, Y.-X.; Wongkhan, K.; Shu, D.-X.;
Lan, Y.; Li, A.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.; Chen,
J.-H.; Yang, Z. Organometallics 2007, 26, 4756. (b) Gao, Y.-X.; Chang,
L.; Shi, H.; Liang, B.; Wongkhan, K.; Chaiyaveij, D.; Batsanov, A. S.;
Marder, T. B.; Li, C.-C.; Yang, Z.; Huang, Y. Adv. Synth. Catal. 2010,
352, 1955.
(14) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131.
Org. Lett., Vol. 13, No. 13, 2011
3443

Table 1. Products and Isolated Yields for the in Situ Z-Nitroso Dienophile Generation and DielsꢀAlder Trapping
a Typical procedure: MeOH (5 mL), diene (0.75 mmol), CuCl2 (0.06 mmol), 2-ethyl-2-oxazoline (0.12 mmol), N-(benzyloxycarbonyl)hydroxylamine
(0.63 mmol), stirred at rt in air. At completion, the solvent evaporated and the product was purified by silica gel chromatography. Isolated yields quoted
after purification (see Supporting Information). b See ref 11. c See ref 12. d See ref 13. e Isolated with 10% benzyl methyl carbonate derived from 1 by
methanolysis.
slower in acetronitrile (Table 2, entry 3) than in MeOH
(Table 2, entry 1), yet the ratio of DielsꢀAlder adduct 4c to
ene adduct 5c increased from 5:1 in MeOH to 25:1 in
MeCN. The origin of this effect is unclear, as is the increased
4c:5c ratio observed in MTBE, iPrOH, 2-MeTHF, and
toluene (Table 2, entries 2, 6ꢀ8).
variant of the decomposition of 2 has been used deliber-
ately to generate HNO.15
Having developed an efficient aerobic oxidation of
hydroxamic acid 1 with subsequent intermolecular trap-
ping with different dienes (Table 1), this method was
applied to intramolecular analogues, as outlined in eq 3.
To our gratification, in situ oxidations of hydroxamic
acids 6a and 6b both proceeded smoothly. The intramole-
cular diene efficiently intercepted the intermediate acyl-
nitroso species to provide bridged bicyclic cycloadducts 7a
and 7b, respectively, in high yields (eq 3).
As shown in Table 1, isolated yields of cycloadducts 3
when the reactions were carried out in MeOH were even
greater than when run in CHCl3. The reactions were gen-
erally either moderately or considerably faster, reinforcing
the general utility of MeOH as the solvent. Interestingly,
the DMA adduct 4f (Table 1, entry 6) was isolated with a
small amount (10%) benzyl methyl carbonate. Hydroxa-
mic acid 1 is stable in MeOH, suggesting that intermediate
2 is indeed unstable, as discussed elsewhere,4 and is a
source of HNO in hydroxylic solvents. An intramolecular
The success of the intramolecular nitroso DielsꢀAlder
reactions also led us to examine the corresponding
(15) Zeng, B. B.; Huang, J.; Wright, M. W.; King, S. B. Biorg. Med.
Chem. Lett. 2004, 14, 5565.
3444
Org. Lett., Vol. 13, No. 13, 2011

application for in situ acyl-nitroso and azo formation.
These reactive intermediates are readily trapped under
the reaction conditions, both inter- and intramolecularly,
to provide the corresponding cycloadducts in good yields.
In addition, we observed interesting solvent effects on the
rate as well as the regio- and chemoselectivity of the reac-
tion. The same conditions alsoprovide acyl-azoderivatives
in situ via the oxidation of acyl-hydrazide compounds.
Table 2. Solvent Effects for the RT Oxidation of 1 and Trapping
with 3c
entry
solvent
MeOH
time (h) ratio 4c:5c yield (%)a
1
2
3
4
5
6
7
8
9
10
2
20
144
7
5:1
15:1
25:1
4:1
85
85
80
83
81
89
88
82
82
75
MTBE
MeCN
EtOH
EtOAc
7
4:1
iPrOH
48
20
4
13:1
12:1
12:1
5:1
2-MeTHF
toluene
MeOH/toluene, 1:4
CHCl3
3
3
7:1
a Isolated yields after purification (see Supporting Information).
Acknowledgment. D.C. thanks the Royal Thai Govern-
ment for a postgraduate scholarship. T.B.M. thanks the
Royal Society for a Wolfson Research Merit Award and
an International Joint Project Grant, EPSRC for an Over-
seas Research Travel Grant, and the Royal Society of
Chemistry for a Journals Grant for International Authors.
We thank Dr. Y. Xiang Gao and Prof. Z. Yang
(Laboratory of Chemical Genomics, Shenzhen Graduate
School of Peking University, Shenzhen, China; Key La-
boratory of Bioorganic Chemistry; Molecular Engineering
of Ministry of Education and Beijing National Laboratory
for Molecular Science, College of Chemistry, Peking Uni-
versity, Beijing, China) for thiourea ligands.
acyl-hydrazide system 8 (eq 4). Exposure to the aerobic
oxidation conditions again caused efficient oxidation,
followed by trapping of the azo dienophile by the diene,
providing acyl-azo cycloadduct 9 in 94% yield. Therefore,
this novel oxidation system is also useful for the in situ
formation of highly reactive acyl-azo compounds.16
In summary, we have developed a particularly efficient,
mild, and more environmentally benign in situ process for
the oxidation of hydroxamic acids to acyl-nitroso deriva-
tivesbasedon Cu(II) catalysis. Althoughaerobicoxidation
probably involving Cu(II) catalysis has been used for
oxidative processes previously,17 this is the first such
(16) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80,
595. (b) Molina, L.; Chow, C. P.; Shea, K. J. J. Org. Chem. 2007, 72,
6816.
Supporting Information Available. Experimental de-
tails and characterization data for new compounds; X-ray
crystallographic data for 4b and 4f in CIF format
(CCDC-820904 and 820905, respectively). This material
is available free of charge via the Internet at http://pubs.
acs.org.
(17) (a) Lina, L.; Juanjuana, M; Liuyana, J.; Yunyanga, W. J. Mol.
ꢀ
Catal. A: Chem. 2008, 291, 1. (b) Marko, I. E.; Giles, P. R.; Tsukazaki,
ꢀ
M; Gautier, A.; Dumeunier, R.; Doda, K.; Philippart, F.; Chelle-
Regnault, I.; Mutonkole, I.-L.; Brown, S. M.; Urch, C. J. Angew. Chem.,
Int. Ed. 2004, 43, 1588.
Org. Lett., Vol. 13, No. 13, 2011
3445