Gold-catalyzed synthesis of 3-pyrrolidinones and nitrones from N-sulfonyl hydroxylamines via oxygen-transfer redox and 1,3-sulfonyl migration

Article abstract of DOI:10.1002/chem.201002863

Golden touch: Gold-catalyzed reaction of N-sulfonyl hydroxylamines with terminal alkyne led to 3-pyrrolidinones by means of an oygen-transfer redox reaction. This protocol constitutes a direct method for forming α-amino carbonyl compounds. In sharp contrast, those with internal alkynes underwent 1,3-sulfonyl migration leading to 3-sulfonyl cyclic nitrones.

Full text of DOI:10.1002/chem.201002863

DOI: 10.1002/chem.201002863
Gold-Catalyzed Synthesis of 3-Pyrrolidinones and Nitrones from N-Sulfonyl
Hydroxylamines via Oxygen-Transfer Redox and 1,3-Sulfonyl Migration
Hyun-Suk Yeom, Eunsu So, and Seunghoon Shin*[a]
Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday
In order to increase the mo-
lecular complexity of simple or-
ganic substrates, atom-transfer
protocols have received intense
attention from a viewpoint of
atom- and redox-economy.[1]
For example, various hydrogen-
exchange protocols enable
a
synthetic design that bypasses
redox adjustment steps required
to generate reactive functional
À
groups for the desired C C
bond formation.[2,3] Redox reac-
tions with the cleavage of weak
À
N O bonds can also lead to an
Scheme 1. 3-Pyrrolidinones and nitrones from N-sulfonylhydroxylamines.
oxygen-atom transfer to
p
bonds, leading to diverse atom-
and redox-economical transfor-
À
the hypothesis that the N O bond cleavage step will be
rate-limiting and that an electron-withdrawing sulfonyl
group on the nitrogen atom will facilitate the overall pro-
cess.[8] During this study, we also uncovered a new method
of forming nitrones based on the alternative 5-endo-dig ni-
trogen attack, following an 1,3-sulfonyl migration (path B).[9]
We report herein a successful realization of these two con-
cepts and the details of our discovery.
mations.[4,5] Recently, we and others have reported various
electrophilic metal-catalyzed oxygen-transfer redox reac-
tions of nitrones,[6a–c] amine-N-oxides,[6d–f] oximes,[5b,6g] and
hydroxamates.[5d] Hydroxylamine derivatives are particularly
appealing for this redox application, because of its ready
availability, safety of handling, and versatile reactivity.
We projected that a formal addition of hydroxylamine de-
rivatives across alkynes would directly lead to a-amino car-
bonyl compounds that constitute an important organic
building block. Along this line, we envisioned N-sulfonylhy-
droxylamines as precursors of 3-pyrrolidinones through AuI-
catalyzed 5-exo-dig addition (path A, Scheme 1)[7] based on
With N-benzenesulfonyl homopropargylhydroxylamine
(2a), we tested various conditions for the desired oxygen-
transfer redox cyclization (Table 1). First, treatment of 2a
with [AuACHTNUGTRENNU(G PPh3)]ACHTUNGTERN[NUGN NTf2] catalysts at 608C gave extensive hy-
dration by-product 4a (20–30%). While lowering the tem-
perature or changing solvent gave no improvement, addition
of 5 ꢀ molecular sieves effectively suppressed the hydration.
Variation of ligands were then tested with the NTf2 counter-
ion (entries 1–5): N,N’-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene carbene (IPr) gave the best result and was chosen as
an optimal ligand (entry 5). Compared to the rather small
ligand effect, the counterion of a cationic Au complex had
pronounced impact on the efficiency (entries 6–9). Gratify-
[a] H.-S. Yeom, E. So, Prof. S. Shin
Department of Chemistry and
Research Institute for Natural Sciences
Hanyang University, Seoul Korea 133-791 (Korea)
Fax : (+82)2-2299-0762
E-mail: sshin@hanyang.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002863.
1764
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Chem. Eur. J. 2011, 17, 1764 – 1767

COMMUNICATION
Table 1. Optimization of conditions.
product 5j (38%), which was assigned as a nitrone based on
the spectroscopic data [Eq. (1)]. A brief optimization identi-
fied [AuACHTNUGTRENNU{G tBu2P(o-biphenyl)}]ACHTUNGTREN[NUNG NTf2] in MeOH at 608C as the
optimal condition for the nitrone formation. The possible
mechanism for its formation is given in Scheme 1 (Path B).
In the case of internal alkynes such as 2j, the nucleophilic
attack on the alkyne occurs primarily from nitrogen atom
rather than the oxygen atom giving A, and the following
1,3-N-sulfonyl migration leads to B.[9] The turnover of gold
catalyst generates the corresponding vinyl hydroxylamine,
which tautomerize into the more stable nitrone 5j.[10] Our
assignment of the nitrone structure was confirmed by react-
ing 5j with different dipolarophiles for [3+2] cycloaddition
(vide infra, Table 3).
Entry[a]
Catalyst (5 mol%)[b]
3 [%][c]
4 [%][c]
1
2
3
4
5
6
7
8
9
[Au
[Au
N
E
39
44
12
10
–
9
–
8
–
2
6
–
U
E
[Au{P
N
U
trace (71)[d]
[Au
[Au
[Au
[Au
[Au
N
G
52
trace
40
66
72
10
HOTf
no reaction
–
[a] 5 ꢀ molecular sieve was added. [b] AuI catalysts were generated in
situ by mixing of [Au(L)]Cl with AgX (1:1). [c] Crude yield based on
1H NMR spectroscopy (1,3,5-trimethoxybenzene as internal reference).
[d] Recovered starting 2a (in parenthesis).
ingly, treating 2a with [AuACHTUNGRTNEUNG(IPr)]Cl (5 mol%) and AgBF4
(5 mol%) in toluene gave desired 3a in 72% yield after 2 h
at 608C with complete suppression of hydration. Purification
of the crude mixture on a silica gel gave analytically pure 3a
as a white solid (70% yield).
À
To investigate the scope and limitation of this novel N O
redox cyclization, various N-sulfonylhydroxylamines were
subject to the optimized conditions (Table 2). Changing the
N-sulfonyl groups did not have much effect on the yield of
pyrrolidinones (entries 1–4). Various aryl and alkyl substitu-
ents at the homopropargylic position were well-tolerated,
giving reasonable yields of the corresponding pyrrolidinones
(entries 5–9).
We next investigated the scope of this novel nitrone for-
mation. As shown in Table 3, various aryl substituted al-
kynes underwent smooth reactions (entries 1–6), except the
strongly electron-withdrawing substrate 2l, which gave a
poor yield of the desired nitrone (entry 5). The current pro-
tocol could be extended to the alkyl-substituted alkynes as
well (entries 7 and 8). In these cases, much faster conversion
was observed, giving good yields of the corresponding nitro-
nes. Treating the thus obtained 5j with five equivalents of
dimethyl acetylenedicarboxylate (DMAD), ethyl propiolate,
or methyl 2-butynoate in benzene at 808C gave the respec-
tive dihydroisoxazoles 6ja–jc smoothly in excellent regio-
and diastereofacial selectivity. The sulfonyl group effectively
Table 2. Oxygen-transfer redox cyclization of terminal alkynes.
Entry[a]
Substrate
P
R
t [h]
3 [%][c]
Table 3. Nitrone formation from internal alkynes.
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Bs
H
H
H
H
1.5
1
1
1
3
4
1
1
2
70
65
67
74
57
64
58
49
58
Ms
Ts
Ns[d]
Bs
Ph
Bs
Bs
Bs
Bs
2-naphthyl
4-CH3-C6H4
4-Cl-C6H4
Me
Entry[a] Substrate R1
R2
t [h][b] 5 [%][c] 6 [%][c,d]
1
2
3
4
5
6
7
8
2j
2j
2j
2k
2l
2m
2n
2o
Ph
Ph
Ph
CO2Me 24
H
Me
CO2Me 18
81
–
–
76
39
87
88
79
89 (6ja)
83 (6jb)
60 (6jc)
86 (6ka)
83 (6la)
67ACHTUNGTRENNUNG(6ma)
25 (6na)
50 (6oa)
[a] Au catalyst was generated in situ from [AuACTHNUTRGNE(NUG IPr)]Cl (5 mol%) and
AgBF4 (5 mol%). [b] Isolated yield after chromatography. [c] p-Nitro-
benzenesulfonyl.
4-Cl-C6H4
4-NO2-C6H4 CO2Me 15[e]
1-naphthyl
Me
nBu
CO2Me 15[e]
CO2Me
CO2Me
1
1
We next investigated the reaction of internal alkyne sub-
strate 2j and surprisingly, the reaction took a completely dif-
ferent path [Eq. (1)]. Treatment of 2j under a similar condi-
[a] Au catalyst was generated in situ from [AuACTHNUGTRNENUG{tBu2PACHTUNGTREN(NGUN o-biphen)}]Cl
(5 mol%) and AgNTf2 (5 mol%). [b] The reaction time for the nitrone
formation. [c] Isolated yield after chromatography. [d] Five equivalents of
dipolarophiles; single respective diastereomers were observed. [e] At
808C.
tion ([Au
ACHTUNGTRENNUNG(IPr)]ACHTUNGTRENNUNG[NTf2] (5 mol%) in toluene with 5 ꢀ MS)
gave none of the desired pyrrolidinone 3j, but instead gave
Chem. Eur. J. 2011, 17, 1764 – 1767
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1765

S. Shin et al.
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face of nitrones. 2-Aryl-substituted nitrones 5k–m also un-
derwent smooth [3+2] cycloadditions to give good yields of
the corresponding dihydroisoxazoles 6k–m, except that the
sterically hindered 5m gave a slightly diminished yield. On
the other hand, 2-alkyl substituted nitrones 5n and 5o gave
distinctly reduced yields.
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In conclusion, we report herein a novel synthetic route to
3-pyrrolidinone derivatives by means of an intramolecular,
oxygen-atom-transfer, redox reaction of N-sulfonyl hydrox-
ylamines. Remarkably, the current procedure for the 3-pyr-
rolidinone synthesis opens new efficient entry into pharma-
ceutically useful derivatives: For example, 3-pyrrolidinones
are the precursors of 3-aminopyrrolidine,[11] 2-oxo-1,2-
dihydrobenzo[d]
[1,3]oxazine,[12] and cucurbitine
ana-
logues.[13] The current report not only demonstrates the via-
À
bility of N O bond redox chemistry of hydroxylamine, but
also provides an efficient entry into the useful 3-pyrrolidi-
none derivatives. In addition, we disclosed a new method of
forming nitrones through 1,3-sulfonyl migration from N-sul-
fonyl alkynylhydroxylamines, providing cyclic nitrones
equipped with sulfone functionality.
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Experimental Section
Representative procedure for synthesis of 3-pyrroldinone: A solution of
[AuACHTUNGTRENNUNG(IPr)]ACHTUNGTRENNUNG[BF4] (0.0111 mmol, 5 mol%) and 5 ꢀ MS (75 mg) in toluene
(2.2 mL) to a vial containing homopropargyl hydroxylamine 2a (50 mg,
0.222 mmol) and the mixture was stirred 2 h at 608C. The mixture was
quenched with three drops of triethylamine and was concentrated to dry-
ness. The residue was purified by silica gel chromatography (n-hexane/
EtOAc=4:1) to give 35.0 mg (70%) of product 3a as white solid. A simi-
lar procedure was followed for the nitrone formation except the follow-
ing ([Au
vent).
ACHTUNGTRENNUNG{tBu2PACHTUNGTRENNUNG(o-biphen)}]ACHTNUGTERN[GUNN NTf2] as catalyst precursor and MeOH as sol-
Representative procedure for a dipolar cycloaddtion between the nitrone
and the dipolarophiles: The product 5j (40 mg, 0.131 mmol) was mixed
with dimethyl acetylendicarboxylate (93 mg, 0.655 mmol) in benzene and
was heated for 24 h at 608C. After removal of solvent, the residue was
purified by silica gel chromatography (n-hexane/EtOAc=3:1) to give
52.4 mg (89%) of product 6ja as colorless oil.
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Acknowledgements
This work was supported by the National Research Foundation of Korea
(KRF-2009-000-0000-0803). H.S.Y. and E.S. thank the BK21 program for
the financial support. H.S.Y. also thanks the Seoul Science Foundation
for a fellowship.
Keywords: gold · homogeneous catalysis · hydroxylamines ·
nitrones · pyrrolidinones · redox chemistry
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Gold Catalysis
COMMUNICATION
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Received: October 5, 2010
Published online: January 5, 2011
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