Copper-catalyzed aerobic oxidation of hydroxamic acids leads to a mild and versatile acylnitroso ene reaction

Article abstract of DOI:10.1021/ja204603u

A mild formation of transient acylnitroso intermediates using a copper chloride catalyst and 1 atm of air as the terminal oxidant is described. The mild reaction conditions enable the inter- and intramolecular acylnitroso ene reaction with a wide range of functionalized alkene partners, as well as the first asymmetric variant. Notably, this transformation provides a practical and operationally simple method for effecting allylic amidation using an environmentally benign oxidant and a readily abundant transition metal.

Full text of DOI:10.1021/ja204603u

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pubs.acs.org/JACS
Copper-Catalyzed Aerobic Oxidation of Hydroxamic Acids Leads to a
Mild and Versatile Acylnitroso Ene Reaction
Charles P. Frazier, Jarred R. Engelking, and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
Table 1. Screening Reaction Conditionsa
ABSTRACT: A mild formation of transient acylnitroso
intermediates using a copper chloride catalyst and 1 atm of
air as the terminal oxidant is described. The mild reaction
conditions enable the inter- and intramolecular acylnitroso
ene reaction with a wide range of functionalized alkene
partners, as well as the first asymmetric variant. Notably, this
transformation provides a practical and operationally simple
method for effecting allylic amidation using an environmen-
tally benign oxidant and a readily abundant transition metal.
entry
catalyst
additive
oxidant
time
3 h
% yieldb
1
FeCl3
RuCl3
NiCl2
CuCl2
CuCl
CuCl2
CuCl
CuCl
CuCl
CuCl
À
Et3N
HOOH
HOOH
HOOH
HOOH
HOOH
air
25
53
0
2
3c
6 h
À
6 h
4
À
20 min
30 min
144 h
29 h
6 h
79
78
68
87
93
94
0
5
À
cylnitroso intermediates are exceptionally reactive electro-
philes with a rich history in the hetero-DielsÀAlder reaction.1
Several variants of the acylnitroso DielsÀAlder reaction have been
developed, and since the pioneering report by Kirby in 1973, it
has found widespread application in the synthesis of natural
products.2 In contrast, the acylnitroso ene reaction,3 which can
be used for the direct allylic amination of olefins, is vastly under-
developed despite the synthetic utility of allylic amines for the
construction of R- and β-amino acids, alkaloids, and carbohy-
drate derivatives.4
6
À
A
7
À
air
8
pyridine
DTBMPd
pyridine
air
9
10c
air
29 h
À
48 h
a All reactions were performed with reagent-grade THF containing
250 ppm BHT inhibitor. The following amounts of reagents were used
according to Table 1: 5 mol % catalyst, 120 mol % peroxide, 1.25 mol %
pyridine, and 1.25 mol % DTBMP. b Isolated yields. c Starting material
recovered. d DTBMP = 2,6-di-tert-butyl-4-methylpyridine.
The most common method to conduct an acylnitroso ene
reaction was independently developed by Keck5 and Kirby.6
Their elegant two-step transfer protocol generates acylnitroso
intermediates by a thermo retro-cleavage of the corresponding
DielsÀAlder adducts. While Keck’s and Kirby’s two-step process
allowed for the preliminary development of the acylnitroso ene
reaction, it also revealed the main challenge. Due to their high
reactivity, acylnitroso intermediates can only be generated in situ
and thus are conveniently obtained from the oxidation of hydrox-
amic acid derivatives using periodate salts.3 However, this in situ
oxidation protocol commonly used in the DielsÀAlder reaction
is not compatible with the acylnitroso ene reaction because the
initially formed hydroxylamine ene product is susceptible toward
subsequent decomposition reactions such as oxidation, dispro-
portionation, and elimination.3a
Notably absent from current acylnitroso ene methods are
examples with functionalized alkene partners and the develop-
ment of an asymmetric manifold. In addition, excess olefin is
often required to obtain high yields of the ene product. A possible
reason for the slow advance of acylnitroso ene reactions has been
an inability to identify a general and practical oxidant.7 In this
Communication, we describe our initial efforts in this area using
copper(I) chloride catalyst and air as the terminal oxidant for the
in situ oxidation of N-hydroxycarbamates.8 This new process
provides straightforward access to a range of functionalized allylic
hydroxycarbamates via the inter- and intramolecular acylnitroso
ene reaction and enables the first intermolecular asymmetric
acylnitroso ene reaction.
The recent work of Iwasa, Whiting, and others led us to
initially focus on oxidation methods that relied on transition
metals and stoichiometric peroxides as the terminal oxidant.7b,9
A preliminary screen revealed copper salts in combination with
hydrogen peroxide were optimal for the intramolecular ene
reaction of N-hydroxycarbamate 1 (Table 1, entries 1À5). Treat-
ment of 1 with 5 mol % copper(II) chloride and hydrogen
peroxide gave the intramolecular ene product in up to 79% yield
(entry 4). Unfortunately, obtaining consistent isolated yields
proved problematic due to the rate of product decomposition
under the reaction conditions.10 Consequently, an alternative,
milder method to oxidize the hydroxamic acids was sought.
After extensive screening, we discovered that 1 atm of air and
5 mol % copper catalyst at room temperature provided a mild
oxidation system (Table 1, entries 6 and 7).11 Importantly,
these conditions suppress the rate of ene product decomposition.10
Received: May 19, 2011
Published: June 16, 2011
r
2011 American Chemical Society
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Table 2. Substrate Scope Studies for the Intramolecular Ene
Reactiona
Table 3. Substrate Scope Studies for the Intermolecular Ene
Reactiona
AMSb
12
13
14
15
5 equiv w
90%
57%
87%
80%
83%
76%
83%
81%
1.1 equiv w
a Reactions were performed with reagent-grade THF containing
a All reactions were performed with reagent-grade THF containing 250
ppm BHT inhibitor. b Product 6 resulted from the reaction of trans-2-
hexenyl hydroxycarbamate. c The yield is a combined yield of both olefin
isomers. d Starting material decomposed.
250 ppm BHT inhibitor. b AMS = R-methylstyrene.
(entries 1À9). The best results were generated from substrates
with electron-rich olefins, which is consistent with other ene
processes.3 The reaction can also tolerate alkenes that are deacti-
vated by electron-withdrawing substituents, as well as an alkene
bearing a free hydroxyl group (entries 6À8). Geranyl acetate was
used to further probe the reactivity of electronically differentiated
alkenes (entry 9). The major product arose from reaction at the
6,7-double bond, since the allylic acetate electronically deactivates
the 2,3-double bond (9:1 mixture was obtained). Similar to ArNO
enophiles, the acylnitroso abstracts a hydrogen atom from the
geminal alkyl group on the more substituted side of the alkene
(entries 5À9).3 In addition, 1-methyl-1-cyclohexene revealed the
preference for acylnitroso enophiles to approach the alkene with a
skew geometry. Hydrogen atom abstraction predominately oc-
curred from the twix position (twix:twin ratio 6:1, entry 5),15
consistent with typical ene reaction patterns.3
We next turned our attention to bimolecular reactions with
tiglic acid derivatives because they provide rapid access to R,
β-disubstituted amino acids. Direct methods to access this
important structural motif are limited.16 Nitroso reactions with
tiglic acid derivatives, electron-deficient ene substrates, are often
low yielding, especially with acylnitroso enophiles.7a Therefore,
we were thrilled when we discovered that use of 1.2 equiv of
methyl tiglate resulted in a 73% yield of the desired ene product
(entry 10). The unprotected amide and acid derivates also
afforded product in 72% and 37%, respectively (entry 11 and 12).
The benzamide analogue underwent clean reaction; however, it
cyclized in situ to form R-methylene isoxazolidinone (entry 13).
Inspired by these results we set out to control the absolute
stereochemistry of the newly formed carbonÀnitrogen bond by
employing a chiral auxiliary on the tiglic acid derivative. Guided
by Adam’s work, we prepared the tiglic-acid with Oppolzer’s
derived sultam (19) and subjected it to our optimized reaction
conditions (eq 1).17
Furthermore, air is the ideal oxidant because it is readily available,
inexpensive and the byproducts are environmentally benign.12
Addition of catalytic pyridine ensured cleaner and more efficient
reactions (entry 8). No rate enhancement was observed when
2,6-di-tert-butyl-4-methylpyridine was used, which suggests the
role of pyridine is not simply as a base (entry 9). In addition, no
reaction was observed under anaerobic conditions (entry 10).
With the optimized reaction conditions (5 mol % copper(I)
chloride, 1.25 mol % pyridine, reagent grade THF, air, rt), we
investigated the scope of the intramolecular acylnitroso ene
reaction (Table 2). The allylic and homoallylic nitrosoformate
esters both cyclize by a Type I mechanism, according to Oppolzer
and Snieckus’s classification,13 to construct the 2-oxazolidinone
and 1,3-oxazin-2-one scaffold (2, 5À7). Olefin geometry plays an
important role and currently the intramolecular reaction does not
accommodate substrates bearing a Z-alkene (8).
Having established a mild, single-pot method for the intra-
molecular acylnitroso ene reaction, we evaluated the bimolecular
reaction which provides a simple method for effecting allylic
amidation. Our investigations focused on N-hydroxycarbamates
bearing protecting groups that were easy to prepare, commonly
used in synthesis and could be orthogonally deprotected. Hydro-
xylamines protected with Boc, Cbz, Fmoc and Troc groups all
participated in the intermolecular ene reaction in greater than
80% yield (Table 3). Significantly, with the exception of tert-
butyl-N-hydroxycarbamate, comparable yields were also ob-
tained with only 1.1 equivalents of R-methylstyrene. Based on
reaction trends, vide infra, we currently believe the copperÀair
catalyst system is oxidizing the N-hydroxycarbamate and gen-
erating a transient acylnitroso intermediate. However, the nature
of the copper-oxidant species and the oxidation mechanism
require further studies. Under the aerobic oxidation conditions
tetrahydrofuran can form peroxides, however, alternative sol-
vents like 2-methyltetrahydrofuran (2-MeTHF) can be used to
reduce the risk of peroxide formation.14
To our gratification, the R-methylene isoxazolidinone (20) was
produced in situ as predominately a single enantiomer (98.5:1.5 er)
and Oppolzer’s chiral auxiliary could be quantitatively recovered
from the reaction. This represents the first example of an asym-
metric intermolecular acylnitroso ene reaction.18,19
Single-crystal X-ray analysis was used to establish the S-
configuration of the newly formed stereocenter in ene product 20
(Scheme 1).20 To explain the observed selectivity we postulate a
We chose to investigate the scope of the intermolecular ene
reaction with 1.2 equiv of the alkene partner and the carbobenzy-
loxy (Cbz)-protected hydroxylamine (16) (Table4). The reaction
tolerated a series of alkene reaction partners and furnished allylic
N-hydroxycarbamate derivates in moderate to excellent yields
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Journal of the American Chemical Society
COMMUNICATION
Table 4. Substrate Scope Studies for the Intermolecular Ene
Reactiona
Scheme 1. Asymmetric Acylnitroso Ene Reaction and
Proposed Stereochemical Model
favored because the sulfonyl oxygen atoms shield the Re-face.
Since both enantiomers of the camphorsultam chiral auxiliary are
commercially available, both stereoisomers of the ene product
are available.
Preliminary studies demonstrate R-methylene isoxazolidi-
none compounds have similar biological activity as R-methyli-
dene-γ-lactones and are potent against mouse L-1210 as well
as human HL-60 and NALM-6 leukemia cell lines.22 The
precise mechanism of activity is currently unknown, but these
compounds are believed to react as Michael-type acceptors
with bionucleophiles. Despite their potential as possible novel
therapeutics, access to R-methylene isoxazolidinone compounds
is virtually unknown,17,22 especially in an asymmetric sense.
Moreover, isoxazolidinones represent well-established building
blocks that can serve as synthons for R,β-disubstituted amino
acids.16
In conclusion, we have developed mild reaction conditions for
the in situ formation of transient acylnitroso compounds. The
new strategy is operationally simple and provides a practical
solution for the acylnitroso ene reaction and should allow for
future advances in the field of acylnitroso chemistry. Reactions
are performed with reagent grade THF, employ 1 atm of air as the
terminal oxidant and the only byproduct is water. In addition, the
mild reaction conditions enabled the development of the first
asymmetric acylnitroso ene reaction using a traceless chiral
auxiliary. Further investigations are underway to clarify the
mechanism of this transformation and to explore the scope of
acylnitroso chemistry.
a Reactions were performed with reagent-grade THF containing
250 ppm BHT inhibitor. b Isolated yields. c The yield is a combined
yield of both olefin isomers. d A third product resulting from reaction at
the lone position was also isolated in 5%; see Supporting Information for
details. e The yield is a combined yield of both regioisomers.
reactive conformation of 19a based on literature precedent.17,21
The favored conformation features an anti-orientation between
the carbonyl group and the sulfonyl functionality and an s-trans
conformation of the carbonyl group and the double bond. A
skewed approach of the enophile from the less hindered Si-face is
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental de-
b
tails and spectral data for all compounds described. This material
is available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
(15) (a) Adam, W.; Bottke, N.; Krebs, O. J. Am. Chem. Soc. 2000,
122, 6791. (b) Quadrelli, P.; Romano, S.; Piccanello, A.; Caramella, P.
J. Org. Chem. 2009, 74, 2301.
Corresponding Author
javier@chem.ucsb.edu
(16) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991 and references
therein.
(17) Adam, W.; Degen, H.-G.; Krebs, O.; Saha-M€oller, C. R. J. Am.
Chem. Soc. 2002, 124, 12938.
’ ACKNOWLEDGMENT
(18) Optically active allylic amines are valuable precursors to a
variety of nitrogen-containing molecules, and the enantioselective
nitroso ene reaction offers a direct route to these compounds. However,
only limited examples of asymmetric nitroso ene reactions have been
reported. For a diastereoselective intramolecular example with an
acylnitroso compound, see: (a) Matsumura, Y.; Aoyagi, S.; Kibayashi,
C. Org. Lett. 2003, 5, 3249–3252. For examples using preformed stable
nitroso compounds and a chiral auxiliary for stereocontrol, see:
(b) Braun, H.; Felber, H.; Krefle, G.; Ritter, A.; Schmidtchen, F. P.;
Schneider, A. Tetrahedron 1991, 47, 3313 and ref 18 therein. For a
recent catalytic asymmetric example using iminonitroso compouds, see:
(c) Yang, B.; Miller, M. J. Tetrahedron Lett. 2010, 51, 328.
(19) For a related catalytic asymmetric intramolecular acylnitroso
DielsÀAlder reaction using a metal-catalyzed oxidation, see: (a) Chow,
C. P.; Shea, K. J. J. Am. Chem. Soc. 2005, 127, 3678. (b) Flower, K. R.;
Lightfoot, A. P.; Wan, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1
2002, 2058.
(20) CCDC 824260 contains the supplementary crystallographic
data for compound (S)-20. The data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(21) Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G.
Tetrahedron Lett. 1988, 29, 3559.
(22) (a) Janecki, T.; Wasek, T.; Ruzalski, M.; Krajewska, U.;
Studzian, K.; Janecka, A. Bioorg. Med. Chem. Lett. 2006, 16, 1430. (b)
Rozalski, M.; Krajewska, U.; Panczyk, M.; Mirowski, M.; Rozalska, B.;
Wasek, T.; Janecki, T. Eur. J. Med. Chem. 2007, 42, 248.
Financial support from UCSB and Eli Lilly is gratefully
acknowledged. We thank Prof. Zakarian for helpful discussions
and Dr. Guang Wu (UCSB) for X-ray analysis.
’ REFERENCES
(1) For select reviews on acylnitroso DielsÀAlder reactions, see:
(a) Streith, J.; Defoin, A. Synthesis 1994, 1107. (b) Kibayashi, C.; Aoyagi,
S. Synlett 1995, 1995, 873. (c) Vogt, P. F.; Miller, M. J. Tetrahedron 1998,
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2031. (e) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50,
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(2) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun.
1973, 704.
(3) For recent reviews on nitroso ene reactions, see: (a) Adam, W.;
Krebs, O. Chem. Rev. 2003, 103, 4131 and references therein. (b) Iwasa,
S.; Fakhruddin, A.; Nishiyama, H. Mini-Rev. Org. Chem. 2005, 2, 157.
(4) For a review on allylic amination, see: Johannsen, M.; Jorgensen,
K. A. Chem. Rev. 1998, 98, 1689 and references therein.
(5) Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron 1981, 37, 4007.
(6) Kirby, G. W.; McGuigan, H.; McLean, D. J. Chem. Soc., Perkin
Trans. 1 1985, 1961.
(7) Moderate success has been achieved in the single-pot acylnitroso
ene reaction for unfunctionalized alkenes by the oxidation of hydroxamic
acids, see: (a) Adam, W.; Bottke, N.; Krebs, O.; Saha-M€oller, C. R. Eur.
J. Org. Chem. 1999, 1963. (b) Fakhruddin, A.; Iwasa, S.; Nishiyama, H.;
Tsutsumi, K. Tetrahedron Lett. 2004, 45, 9323. (c) Kalita, B.; Nicholas,
K. M. Tetrahedron Lett. 2005, 46, 1451. Alternative methods to access
acylnitroso compounds for the ene reaction have also been employed,
see: (d) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1998,
39, 3233. (e) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett.
1999, 40, 797.
(8) While this manuscript was in review, a similar copper-catalyzed
aerobic oxidation was reported and developed for the acylnitroso
DielsÀAlder reaction: Chaiyaveij, D.; Cleary, L.; Batsanov, A.; Marder,
T. B.; Shea, K. J.; Whiting, A. Org. Lett. 2011 , DOI: 10.1021/ol201188d.
(9) For select examples of acylnitroso DielsÀAlder reactions cata-
lyzed by a transition metal and stochiometric hydrogen peroxide, see:
(a) Iwasa, S.; Tajima, K.; Tsushima, S.; Nishiyama, H. Tetrahedron Lett.
2001, 42, 5897. (b) Flower, K. R.; Lightfoot, A. P.; Wan, H.; Whiting, A.
Chem. Commun. 2001, 1812. (c) Adamo, M. F. A.; Bruschi, S. J. Org.
Chem. 2007, 72, 2666.
(10) Ene product decomposition was observed within 30 min when
2 was resubjected to the reaction conditions found in entries 4 and 5.
The rate of product decomposition was slighly slower when copper(I)
chloride was used. Only slight product decomposition was observed for
entry 8, even after 24 h. Overall, the degree of product decomposition
varied depending on the nature of the substrate when stoichiometric
peroxide was used as the terminal oxidant.
(11) For select reviews on copper-oxo species, see: (a) Mirica, L. M.;
Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013. (b) Lewis,
E. A.; Tolman, W. B. Chem. Rev. 2004, 104, 1047.
(12) For select reviews on metal-catalyzed reactions with molecular
oxygen as the terminal oxidant, see: (a) Stahl, S. S. Angew. Chem., Int. Ed.
2004, 43, 3400. (b) Gligorich, K. M.; Sigman, M. S. Chem. Commun.
2009, 3854.
(13) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. 1978, 17, 476.
(14) 13 was produced in 75% yield in 2-MeTHF. The reaction to
form product 13 can also be conducted in methanol (68%), ethyl acetate
(77%), and toluene (77%). Further studies with these more environ-
mentally friendly solvents are currently under investigtion.
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