Ene reactions of acyl nitroso intermediates with alkenes and their halocyclization

Article abstract of DOI:10.1016/j.tetlet.2004.10.128

Highly reactive acyl nitroso intermediates were formed in situ by transition metals-catalyzed hydrogen peroxide oxidation of hydroxamic acids 1a-b and these transient species trapped with alkenes 2a-c to afford the corresponding ene products 3a-d and 4b u

Full text of DOI:10.1016/j.tetlet.2004.10.128

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9323–9326
Ene reactions of acyl nitroso intermediates with alkenes
and their halocyclization
Ahmad Fakhruddin,a Seiji Iwasa,a,* Hisao Nishiyamab and Kazuo Tsutsumia
aSchool of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
bGraduate School of Engineering, Department of Applied Chemistry, Nagoya University, Chikusa, Nagoya, Aichi 464-8603, Japan
Received 11 September 2004; revised 22 October 2004; accepted 25 October 2004
Available online 6 November 2004
Abstract—Highly reactive acyl nitroso intermediates were formed in situ by transition metals-catalyzed hydrogen peroxide oxidation
of hydroxamic acids 1a–b and these transient species trapped with alkenes 2a–c to afford the corresponding ene products 3a–d and
4b up to 91% yield, and halocyclization of 3d gave substituted oxazolidinone 5a in 77% yield.
Ó 2004 Elsevier Ltd. All rights reserved.
The ene reaction of alkenes and enophiles is one of the
useful functionalization protocol of organic molecules.
In this regard, alkenes, singlet oxygen,1 azo com-
pounds,2 carbonyl functionalities,3 and nitroso groups4
have been employed as enophiles in carbon–carbon
and carbon–heteroatom transformations with alkenes
to afford the corresponding functionalized molecules
(Scheme 1).
tion energy due to a very small HOMO–LUMO energy
gap. High reactivity leads to embarrassment in handling,
as most of nitroso compounds tend to form dimers.9 In
the case of acyl nitroso intermediates, they are generated
in situ. One drawback of the nitroso ene reaction is the
labile nature of the products. The reaction products are
themselves hydroxamic acids sensitive to the oxidizing
conditions used to form the nitrosocarbonyl com-
pounds. So, it is rather challenging to synthesize ene
products from the direct oxidation of hydroxamic
acids.10 The hydroxylamines formed tend to undergo
further transformations, and often several side products
are observed as a result of disproportionation. These in-
clude nitrones, amines, azoxy compounds, and nitrox-
ides.11 However, nitrosocarbonyl compounds may also
be generated under mild conditions by thermal dissocia-
tion of their cycloadducts with 9,10-dimethylanthracene.
The first examples of the intermolecular ene reactions of
C-nitrosocarbonyl compounds, RCONO, were observed
in this way by Kirby and co-workers10b,c and Keck
et al.5c Unfortunately, in the aforementioned methods,
the precursors are clumsy to prepare and the alkene
partner for the ene reaction must be used in large excess.
Therefore, it is very important to design an efficient
method for the in situ generation of acyl nitroso eno-
philes with the utilization of readily available starting
materials, for example, the selective oxidation of
hydroxamic acids and utilizes this for ene reactions.
Adam et al. had prominent success in this direction,
since they demonstrated that a simple one-pot proce-
dure, where acyl nitroso ene products can be achieved
in good yield under mild conditions from the oxidation
of hydroxamic acids by iodosobenzene diacetate or
Nitroso ene reactions are often used as a key step in
total syntheses of several natural products.5 Thus, alkal-
oids with active antitumor agents such as: crinane,
mesembrine, elvesine, and narciclasine are easily avail-
able from nitroso ene reactions. Moreover, allylic amines
which can be achieved from the nitroso ene products,
are versatile building blocks in organic syntheses, as
demonstrated in the preparation of carbohydrate deriva-
tives,6 a- and b-amino acids,7 and alkaloids.8
One distinguishing property of the acyl nitroso interme-
diates is high reactivity, a consequence of the low excita-
X
Y
X
Y
+
H
H
ene
enophile
Scheme 1.
Keywords: Ene reaction; Ruthenium; Iridium; Copper; Hydrogen
peroxide; Acyl nitroso; Halocyclization.
*
Corresponding author. Tel.: +81532446817; fax: +81532485833;
e-mail: iwasa@tutms.tut.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.128

9324
A. Fakhruddin et al. / Tetrahedron Letters 45 (2004) 9323–9326
cat. (2 mol%)
O
O
X
O
Y
Z
31%aq. H2O2 (1.1–1.2 equiv.)
OH
OH
X
OH
Y
+
+
R
R
N
R
N
N
Y
Z
H
X
solvent, 0 oC–r.t
1a: R = Ph
2a: X = Z = CH3, Y = H
2b: X = Ph, Y = Z = H
2c: X = Y = Z = CH3
1b: R = OtBu
A: [Ir(coe)2Cl]2
B: [Ir(cod)Cl]2
C: Ru(pybox-dh)(pydic)
D: CuI
cat.
3a-d
4b
Scheme 2.
Table 1. Catalytic hydrogen peroxide oxidation of hydroxamic acids (la and b) and their subsequent ene reactions with alkenes (2a–c)a
Entry
H.a
Alkene
Cat.
H2O2 (equiv)
Solvent
Time (h)
Product
Yield (%)c
1
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
A
B
C
C
D
D
A
B
C
C
D
A
B
C
C
C
D
D
A
B
C
D
1.1
1.1
1.1
1.1
1.2
1.2
1.1
1.1
1.1
1.1
1.2
1.2
1.1
1.1
1.1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
THF
THF
40
24
24
72
24
24
24
24
24
24
3
3a
3a
38
40
29
32
0
2
3
THF
MeOH
THF
3a
3a
4
5
3a
3a
6
MeOH
THF
THF
0
7
3b + 4b(4:1)b
76
84
50
86
83
30
31
26
12
17
78
75
73
87
56
91
8
3b + 4b(3:1)b
9
THF
3b + 4b(8:1)b
10
11
12
13
14
15
16
17
18
19
20
21
22
MeOH
THF
THF
3b + 4b(8:1)b
3b + 4b(4:1)b
48
16
48
24
48
5
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
THF
THF
MeOH
MeOH
MeOH
THF
4
THF
THF
24
8
THF
THF
24
4
a All the reactions were carried out at 0.5mmol of hydroxamic acid (H.a) and 1.5equiv of olefin with 2mol% catalyst loading and 1.0mL of solvent.
b The ratios of regioisomers were determined by 1H NMR.
c The yields are isolated products; and the yields of entries 7–11 represent the combined yields of the regioisomers.
iodosobenzene as an oxidant with 3equiv of the
O
O
alkene.12 But, this method still has some drawbacks
due to the use of a stoichiometric amount of traditional
oxidants and large excess of olefins.
OH
NIS or I2 or NBS (1.1 equiv.)
solvent, temperature
HO
O
N
N
OH
X
In this context, here, we report a simple one-pot proce-
dure for the ene reactions with alkenes, involving
Ru(II)- or Ir(I)- or Cu(I)-catalyzed oxidation of
hydroxamic acids with 31% aqueous hydrogen peroxide
(Scheme 2, Table 1) and the halocyclization of ene prod-
uct (Scheme 3, Table 2). During our ongoing research,
we have planned to apply our transition metal-catalyzed
hydrogen peroxide system13 to the ene reactions. In this
regard, aliphatic alkenes bearing allylic hydrogens were
chosen as allylic-H source and in situ generation of acyl
nitroso species as enophiles to get the products through
C–N bond formation.
5a; X=I
3d
5b; X=Br
Scheme 3.
Cu(I)-catalyst completely failed to produce any ene
product in this case (entries 5 and 6). The reactions of
Table 2. Halocyclization of ene product
Entry Halogen sourcea Solvent Temp. Time
Yield (%)b
1NIS
Et
2O
Et2O
THF
Et2O
THF
rt
40min 57
2
3
4
5
NIS
NIS
I2
0°C–rt 4h
70
77
77
46
When Ru(II)- or Ir(I)-catalyzed oxidation of hydrox-
amic acid (1a) was carried out in the presence of trisub-
stituted alkene 2a, subsequent ene product 3a was
formed in low yield (29–40%) (entries 1–4) and no regio-
isomer was detected. Surprisingly, it was noticed that the
rt
rt
rt
4h
4h
4h
NBS
a NIS: N-iodosuccinimide, NBS: N-bromosuccinimide.
b Isolated yield after silica gel column chromatography.

A. Fakhruddin et al. / Tetrahedron Letters 45 (2004) 9323–9326
9325
O
O
O
OH
HO
I2
THF
HO
O
O
N
N
N
O
I
I
I
3d
5a
Scheme 4.
the same alkene with another hydroxamic acid 1b gave
excellent results with good to moderate regioselectivity
(entries 7–11). Allylic hydrogen was abstracted from
more substituted side of the alkene and generated major
regioisomer, and the best result was found in the case of
Ru(II)-catalyst, 86% yield as well as 8:1regioselectivity
in MeOH (entry 10). Consequently, hydroxamic acid
1b responded well compared to 1a in the aforemen-
tioned ene reaction. Ru(II)- or Ir(I)-catalyzed oxidation
of hydroxamic acid (1b) showed poor yield with alkene
2b, only 12–31% yield was observed (entries 12–16),
but Cu(I)-catalyst generated good ene product 3c in
both MeOH (78%) and THF (75%) (entries 17 and
18). Good catalytic ene reactions were observed in the
case of tetrasubstituted alkene 2c and the Ir(I)- and
Cu(I)-catalyzed ene reactions produced good yields
73–91% (entries 19, 20, and 22).
General procedure is as follows (Table 1, entry 22): To a
solution of hydroxamic acid 1b (68.0mg, 0.5mmol) and
2,3-dimethyl-2-butene 2c (93lL, 0.75mmol) in THF
(1.0mL) was added a solid of CuI (2.0mg, 0.01mmol)
at 0°C and followed by addition of hydrogen peroxide
(31%, 65lL, 0.6mmoL). The resulting greenish-yellow
mixture was stirred for 4h at room temperature. The or-
ganic phase was extracted with CH2Cl2, and dried over
Na2SO4. The solvent was removed under reduced pres-
sure and the residue was purified by column chromato-
graphy on silica gel to give the ene product 3d (98.0mg)
in 91% isolated yield. 3d: pale pink liquid; Rf (hex-
ane:EtOAc = 4:1) = 0.44; IR (NaCl): 3225, 2978, 2930,
1694, 1651, 1645, 1471, 1463, 1455, 1393, 1372, 1254,
1
1158, 1111cmÀ1; H NMR (CDCl3, 300MHz): d 6.62
(s, 1H), 4.82 (br s, 1H), 4.73–4.72 (m, 1H), 1.79 (d,
J = 0.55Hz, 3H), 1.48 (br s, 15H) ppm; 13C NMR
(CDCl3, 75MHz): d 158.28, 150.58, 108.73, 82.71,
65.58, 28.35, 25.34, 19.27ppm.
Halocyclization is an interesting transformation in
organic syntheses and very recently Galeazzi et al.
demonstrated the stereoselective iodocyclization of
amides.14 This can also be employed to produce cyclic
compounds from acyclic ene products. As a test experi-
ment, we have chosen compound 3d, which was
obtained from the transition metal-catalyzed hydrogen
peroxide oxidation of hydroxamic acid 1b with alkene
2c (Scheme 3, Table 2). Both Et2O and THF are effective
as solvent for present halocyclization (Table 2, entries
1–5). In the presence of NIS or I2, iodolactonization
took place and produced 5a with 77% yield (entries 3
and 4) and when NBS is used bromolactonization
occurred and 5b was formed in 46% yield. The double
bond of vinyl group in compound 3d can originate a
cycle with the oxygen of carbonyl group and thereby
formed 3-hydroxy-5-iodomethyl-4,4,5-trimethyl oxazol-
idine-2-one, 5a and 3-hydroxy-5-bromomethyl-4,4,5-tri-
methyl oxazolidine-2-one, 5b (Scheme 4).
General procedure is as follows (Table 2, entry 3): To a
solution of ene product 3d (47.3mg, 0.22mmol) in THF
(1.5mL) was added NIS (54.0mg, 0.24mmol) at room
temperature. The resulting mixture was stirred for 4h.
Then saturated Na2S2O3 solution was added dropwise
until the iodine color disappeared. The organic phase
was extracted with CH2Cl2, and dried over Na2SO4.
The solvent was removed under reduced pressure and
the residue was purified by column chromatography
on silica gel to give the cyclic product 5a (48.6mg) in
77% isolated yield. 5a: yellow liquid; Rf (hex-
ane:EtOAc = 2:1) = 0.20; IR (NaCl): 3261, 2981, 2941,
1759, 1470, 1454, 1383, 1333, 1187, 1124, 1057,
1038cmÀ1 1H NMR (CDCl3, 300MHz): d 7.72–7.50
;
(br s, 1H), 3.49 (d, J = 10.71Hz, 1H), 3.32 (d,
J = 10.71Hz, 1H), 1.59 (s, 3H), 1.37 (d, J = 12.63Hz,
6H) ppm; 13C NMR (CDCl3, 100MHz): d 158.45,
82.77, 65.68, 21.96, 20.71, 18.48, 7.78ppm; Anal. Calcd
for C7H12NO3I: C, 29.98; H, 4.19; N, 4.51. Found: C,
29.49; H, 4.24; N, 4.91.
In conclusion, we have demonstrated a simple one-pot
method for the acyl nitroso ene reactions. Ene products
can be achieved in good yield under environmentally
friendly oxidation condition and further transformation
of the ene product leads to afford N-hydroxy halosubsti-
tuted oxazolidinone in good yield. In this reaction
although the enophile is unsymmetrical only one mode
of addition is observed, reaction always leading to the
formation of a C–N bond and generation of a N–OH
compound. Nevertheless, the nitroso ene reaction poten-
tially can be an efficient method for carbon–nitrogen
bond formation. Understanding the mechanism and
overcoming troublesome aspects of this reaction is pre-
sent interest.15
Acknowledgements
S.I. thanks the Ministry of Education, Culture, Sports,
Science and Technology for partial financial support.
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