Chemistry of polyhalogenated nitrobutadienes, part 7: A novel synthetic access to chlorinated nitrile oxides

Article abstract of DOI:10.1055/s-0029-1216906

Reaction of gem-dichloronitroalkenes with base leads to the formation of chlorinated nitrile oxides, probably via a cyclic intermediate. The 1,3-dipoles can be trapped with alkenes to give dihydroisoxazoles with a chlorinated side chain in 3-position. Thi

Full text of DOI:10.1055/s-0029-1216906

PAPER
2719
Chemistry of Polyhalogenated Nitrobutadienes, Part 7: A Novel Synthetic
Access to Chlorinated Nitrile Oxides
C
hlorinatedNit
v
rile
O
xides a Nutz, Viktor A. Zapol’skii, Dieter E. Kaufmann*
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722834; E-mail: dieter.kaufmann@tu-clausthal.de
Received 14 August 2008; revised 6 May 2009
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday
thus forming a cyclic nitrone 8. Upon addition of HCl –
extruded before – and a subsequent cycloreversion two in-
termediates are formed: isocyanate 9 and nitroso com-
pound 10. Subsequent coupling of 10 with the second
equivalent of aniline 4 leads to the Z-isomer of allylidene
arylhydrazines 5 (Scheme 2) after an additional isomer-
ization step.
Abstract: Reaction of gem-dichloronitroalkenes with base leads to
the formation of chlorinated nitrile oxides, probably via a cyclic in-
termediate. The 1,3-dipoles can be trapped with alkenes to give di-
hydroisoxazoles with a chlorinated side chain in 3-position. This
novel synthetic method is fairly general.
Key words: nitro compounds, halides, nitrile oxides, heterocycles,
isoxazoles, 1,3-dipolar cycloaddition, nitrones
H
C6H4 EWG
O
N
Cl
C6H4 EWG
N
Cl
Due to its stepped reactivity, 2-nitroperchlorobuta-1,3-di-
ene (1) has proved a valuable synthetic building block for
heterocycles via SNVin reactions.1–4 Substitution with two
equivalents of primary N-nucleophiles such as aniline and
its electron-rich derivatives 2 (ERG = electron-releasing
group) leads to the formation of ketene aminals 3, proba-
bly via the corresponding amidines.5 On the contrary, dur-
4
Cl
Cl
1
Cl
Cl
N
– HCl
NO2
OH
Cl
Cl
7
6
N
EWG C6H4
Cl
Cl
ing reaction with electron deficient anilines
4
HCl
O
Cl
Cl
4
5
N
(EWG = electron-withdrawing group) such as 4-nitro-
aniline a different reaction channel is opened instead after
the first N-substitution, leading to allylidene arylhydra-
zines 5 (Scheme 1).6
N
– 9
– HCl
– H2O
O
O–
Cl
10
Cl
Cl
8
9 =
OCN C6H4 EWG
Cl
Cl
Cl
HN C6H4 ERG
HN C6H4 ERG
Scheme 2
(2)
H2N C6H4 ERG
O2N
Parallel to the HCl addition, direct cycloreversion of the
proposed heterocycle 8 could also simultaneously lead to
two reactive molecules: isocyanate 9 and a chlorinated ni-
trile oxide 11. Trapping of 11 with an alkene in a 1,3-di-
polar cycloaddition should then result in the formation of
a dihydroisoxazole such as 13 (Scheme 3).7–9 The second
reaction option for 11 is the addition of hydrochloric acid
to form hydroximoyl chloride 14 as a reactive intermedi-
ate, which tautomerizes easily to the nitroso compound
10. This reaction path of nitrile oxides was already report-
ed by Ponzio et al.10 To test this hypothesis,
1.5 equivalents of norbornene (12) were added to the re-
action mixture of 1 and 4-nitroaniline (1.8 equiv) in anhyd
THF. Indeed, the expected dihydroisoxazole 13 could be
obtained in low yield (6%), a proof for the intermediate
formation of the nitrile oxide 11.
Cl
Cl
Cl
Cl
Cl
3
O2N
Cl
Cl
Cl
H2N C6H4 EWG (4)
1
N
HN C6H4 EWG
Cl
5
Scheme 1
The assumed mechanism of this unexpected reaction of 1
can be rationalized by a competitive situation: after mono-
substitution by 4 giving 6 and subsequent tautomerization
to the imide chloride 7, an intramolecular nitronic acid ox-
ygen is now apparently more nucleophilic than the amino
group of a second molecule of the deactivated aniline 4,
Both, nitrile oxides as well as their cycloadducts are valu-
able building blocks in organic synthesis.8,11–13 A number
of synthetic methods for nitrile oxides are known, for ex-
ample, the dehydrohalogenation of hydroxamic acid chlo-
rides.14 Primary nitroalkanes serve as starting materials in
SYNTHESIS 2009, No. 16, pp 2719–2724
Advanced online publication: 14.07.2009
DOI: 10.1055/s-0029-1216906; Art ID: T13908SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2720
E. Nutz et al.
PAPER
feasible to use a monophasic system by changing the sol-
vent to diglyme; the same yield of 13 was obtained.
N
O
Cl
12
The proposed mechanism of this reaction is given in
Scheme 4. A SNVin reaction of 1 with a hydroxide anion
leads in the first step to the formation of an enol 16, fol-
lowed by two tautomerization reactions so that both, a ni-
tronic acid and an acid chloride are formed. Subsequently,
the nitronate attacks the acid chloride intramolecularly to
form an oxazetinone-N-oxide 18 under loss of HCl. This
very strained molecule undergoes cycloreversion to form
nitrile oxide 11 and carbon dioxide (Scheme 4).
Cl
Cl
Cl
Cl
N
O
8
13
Cl
– 9
Cl
Cl
N OH
HCl
11
10
Cl
Cl
14
12 =
9 = OCN–C6H4–EWG
Scheme 3
Cl
OH
Cl
O
OH–
– Cl–
the Mukaiyama reaction,15 and furoxanes in cyclorever-
sion reactions.16 Less general synthetic methods are, for
example, the addition of nitric acid to alkynes in the pres-
ence of a gold catalyst,17 or the photolysis of 1,2-diaryl-
substituted nitroethylenes.18
Cl
Cl
Cl
Cl
O
1
NO2
N
OH
Cl
Cl
16
17
The regioselectivity of 1,3-dipolar cycloaddition reac-
tions with nitrile oxides has been investigated, both by ex-
periment and calculation.7,19–22 Because of steric reasons
the 5-isomer is usually the favored product. Using b-cy-
clodextrin as a molecular scaffold it is feasible though to
reverse the usual regioselectivity.19 In the case of dihy-
droisoxazoles 28, 29, 31, 33, and 34 we observed forma-
tion of the 5-isomer, exclusively. NMR analysis of 30 also
showed traces of the 4-isomer (4%, GC-MS).
O
O
Cl
Cl
N
N
O
O–
– HCl
– CO2
Cl
Cl
Cl
Cl
18
11
Scheme 4
Variation of the alkene cyclophiles 12 and 25–27 led to a
number of unknown dihydroisoxazoles 13, 28–30 with a
synthetically interesting trichlorovinyl moiety in 3-posi-
tion. Modification of the gem-dichloronitroalkenes 1 to
19–21 proved as well feasible. Therefore, this reaction can
also be applied to more complex structures. Even another
nitro group in the side chain such as in 2023 was tolerated.
Only the bicyclic starting material 2124 did not react, pos-
sibly due to sterical hindrance at the exo-gem-dichloroni-
trovinyl group. The introduced dipolarophiles cover an
important spectrum of structurally different alkenes; their
cycloadducts are all of synthetic interest (Scheme 5,
Table 1).
Cycloaddition reactions of nitrile oxides to norbornene
derivatives proceed diastereoselectively.21,22 In the case of
the dihydroisoxazoles 13 and 15 (vide infra) attack of the
exo-face was observed and the structure proved by 2-di-
mensional NMR techniques and NOE experiments. The
H,H-COSY spectrum shows the W-coupling between
10b-H and 2-H and 6-H. The NOE-experiment shows the
endo-endo coupling between 2-H and 9endo-H as well as in
the case of 6-H and 8endo-H. The expected missing of the
coupling between 2-H and 9exo-H as well as between 6-H
and 8exo-H presents additional proof of the exo-configura-
tion (Figure 1).
10b
10a
N
O
R3
9exo
9endo
8exo
2endo
6endo
Cl
O
8endo
N
O2N
R1
Cl
Cl
R3
R2
base
R1
N O
15
R1
– COCl2
R2
Figure 1 Structure of 15 showing the exo and endo hydrogens
1, 19–21
11, 22–24
12, 25–27
13,15, 28–34
Scheme 5
Up to now, a-halovinylic nitrile oxides are unknown.
Therefore, we first tried to optimize the reaction condi-
tions in the case of 1 to obtain the 3-trichlorovinyldihy- It is remarkable that only dihydroisoxazoles 31 and 33 are
droisoxazoles as the main products. Starting from 1 known so far.25 This important class of heterocycles can
without any amine, but using solid sodium hydroxide in- be easily converted into isoxazoles, which also show syn-
stead as base to trap HCl immediately after its formation, thetic potential due to their weak nitrogen–oxygen bond.8
and performing the reaction in toluene in the presence of Additionally, these five-membered heterocycles are often
a phase-transfer catalyst, the desired dihydroisoxazole 13 structural units in biologically active compounds, for ex-
was isolated in a maximum yield of 63%. It also proved ample, the antitumor antibiotic Acivicin (AT-125) or the
cholinergic channel activator ABT 418.8,26
Synthesis 2009, No. 16, 2719–2724 © Thieme Stuttgart · New York

PAPER
Chlorinated Nitrile Oxides
2721
All synthesized dihydroisoxazoles 13, 15, and 28–34 car- tion products dihydroisoxazoles starting from structurally
ry functional side chains, which can be easily used to con- different types of gem-dichloronitroalkenes and structur-
struct more complex molecules. The proposed method is ally different dipolarophiles. Most of the synthesized
a fairly general way to obtain dihydroisoxazoles with a nitrile oxides as well as the corresponding dihydroisox-
chlorinated substituent in 3-position. Side chains in 4- and azoles were unknown, and due to their interesting substi-
5-positions are also tolerated.
tution pattern are valuable building blocks for even
complex molecules.
In conclusion, we have found a new, unusual one-pot way
to generate chlorinated nitrile oxides and their cycloaddi-
Table 1 Preparation of Dihydroisoxazoles
Chloronitroalkene
Nitrile oxide
Alkene
Product
N
O
Cl
O2N
Cl
Cl
Cl
N
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
12
13
63%a
1
11
O
Cl
O2N
Cl
Cl
N
Cl
Cl
N
O
Cl
Cl
Cl
Cl
Cl
Cl
1
11
25
26
28
53%a
O
N
Cl
O2N
Cl
Cl
Cl
N
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
29
29%a
1
11
O
N
O
Cl
Cl
O2N
Cl
Cl
N
O
Cl
OBu
Cl
OBu
Cl
Cl
O
Cl
Cl
Cl
30
43%a
27
12
1
11
N
O
O2N
Cl
Cl
N
N
O
O
Cl
Cl
Cl
22
15
32%,a 22%b
19
O
N
O2N
Cl
Cl
Cl
Cl
Cl
22
19
31
22%,a 31%b
25
26
O
N
O2N
Cl
Cl
Cl
N O
Cl
Cl
22
32
10%,a 22%b
19
N
O
O
O2N
Cl
Cl
OBu
Cl
Cl
N O
OBu
Cl
O
22
33
25%,a 23%b
19
27
Synthesis 2009, No. 16, 2719–2724 © Thieme Stuttgart · New York

2722
E. Nutz et al.
PAPER
Table 1 Preparation of Dihydroisoxazoles (continued)
Chloronitroalkene
Nitrile oxide
Alkene
Product
O
O
N
O2N
Cl
Cl
H
Cl
N O
OBu
OBu
O2N
Cl
O
O2N
Cl
O2N
27
34
29%a
23
20
O
OBu
O
N
Cl
O2N
Cl
O
OBu
N
Cl
O2N
Cl
Cl
O
27
O2N
O2N
21
24
35
0%a
a Aqueous workup.
b Direct chromatographic workup.
Workup Procedure b: The reaction mixture was placed on top of a
silica gel column (50 g) and after absorption eluted with PE (300
mL, to remove the toluene), PE–EtOAc (10:1, 600 mL), and PE–
EtOAc (2:1, 440 mL). The product fraction was identified by GC-
MS analysis.
All chemicals were obtained from commercial suppliers and used
without further purification. 1H and 1H decoupled 13C NMR spectra
were measured on a Bruker Avance 400 (400 MHz) or Bruker DPX
200 (200 MHz) spectrometer. NMR spectra were referenced to the
residual solvent peak of CDCl3, d = 7.26 (1H) and d = 77.0 (13C).
Multiplicities of 13C NMR signals were detected by the DEPT-135
method: + for CH or CH3, – for CH2, and o for C. IR spectral data
were obtained on a Bruker Vector 22 FT-IR spectrometer. Mass
spectra (GC-MS) were recorded on a Varian Saturn 2100T spec-
trometer, usually in direct mode with electron impact (70 eV). In the
case of chlorinated compounds, all peak values of molecular ions as
well as fragments m/z refer to the isotope 35Cl. High-resolution ESI
mass spectra were measured with a Bruker APEX IV 7 Tesla FT ion
cyclotron resonance mass spectrometer. TLC was performed on
Merck TLC plates (aluminum-backed) silica gel 60 F 254. Flash
chromatography was carried out on silica gel 60 (Merck).
5-Trichlorovinyl-3-oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene (13)
Reaction of 1 and 12 for 3 d, following the general reaction proce-
dure I or II, workup procedure a; yield: 334 mg (63%); yellow oil.
IR (film): 2965, 2877, 1576, 1527, 1474, 1456, 1317, 1257, 1205,
1129, 1025, 976, 950, 923, 911, 846, 817, 752, 721 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.09–1.15 (m, 1 H, 9-Hendo),
1.22–1.27 (m, 2 H, 8-Hendo, 10-Hb), 1.47–1.53 (m, 1 H, 10-Ha),
1.53–1.60 (m, 2 H, 8-Hexo, 9-Hexo), 2.43 (d, J = 1.6 Hz, 1 H, 7-H),
2.60, (d, J = 2.3 Hz, 1 H, 1-H), 3.44 (d, J = 8.6 Hz, 1 H, 6-Hendo),
4.63 (d, J = 8.6 Hz, 1 H, 2-Hendo).
13C NMR (100 MHz, CDCl3): d = 22.6 (–, C-9), 26.9 (–,C-8), 32.3
(–, C-10), 39.2 (+, C-7), 42.8 (+, C-1), 57.8 (+, C-6), 89.2 (+, C-2),
120.7 (o, CCl), 124.0 (o, =CCl2), 153.4 (o, C-5).
The chloronitroalkenes trichloronitroethene (19),27 2-nitroperchlo-
robuta-1,3-diene (1),28 and 1,1,4-trichloro-2,4-dinitrobuta-1,3-di-
ene (20)23 were prepared by nitration of the corresponding
precursors. Petroleum ether (PE) used refers to the fraction boiling
at 60–70 °C.
GC-MS (EI): m/z (%) = 265 (M+, 73), 197 (38), 171 (M+ – nor-
bornene, 20), 129 (trichlorovinyl+, 11), 91 (24), 67 (100), 53 (22),
48 (12).
Dihydroisoxazoles 13, 15, 28–34
General Procedure I: The alkene (20 mmol) was added to a solution
of the chloronitroalkene (2 mmol) in anhyd toluene (15 mL). Sub-
sequently, 18-crown-6 (66 mg, 0.25 mmol), activated molecular
sieves 4 Å (250 mg), and finally powdered NaOH (3.3 mol equiv)
were added to the reaction mixture, which was stirred at 60 °C until
TLC showed the absence of starting material.
HRMS (ESI): m/z calcd for C10H11Cl3NO [M+ + H]: 265.9901;
found: 265.9903; m/z calcd for C10H10Cl3NO + Na [M+ + Na]:
287.9720; found: 287.9722.
Anal. Calcd for C10H10Cl3NO (266.55): C, 45.06; H, 3.78; N, 5.25;
Cl, 39.90. Found: C, 45.04; H, 3.82; N, 5.07; Cl, 40.59.
General Procedure II: The alkene (20 mmol) was added to a solu-
tion of the chloronitroalkene (2 mmol) in anhyd diglyme (15 mL).
Subsequently, activated molecular sieves 4 Å (250 mg) and pow-
dered NaOH (3.3 mol equiv) were added to the reaction mixture,
which was stirred at 60 °C until TLC showed the absence of starting
material.
5-Phenyl-3-(trichlorovinyl)-4,5-dihydroisoxazole (28)
Reaction of 1 and 25 for 2 d, following the general reaction proce-
dure I or II, workup procedure a; yield: 288 mg (53%); yellow vis-
cous oil.
IR (film): 3063, 3029, 2926, 2853, 1953, 1881, 1723, 1680, 1601,
1576, 1536, 1494, 1454, 1433, 1365, 1319, 1289, 1230, 1206, 1181,
1157, 1078, 1028, 973, 924, 884, 843, 757, 700, 604 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.32 (dd, J = 8.6, 17.2 Hz, 1 H,
4-H1), 3.77 (dd, J = 11.2, 17.2 Hz, 1 H, 4-H2), 5.76 (dd, J = 8.6,
11.2 Hz, 1 H, 5-H), 7.32–7.41 (m, 5 H, C6H5).
Workup Procedure a: After cooling to r.t., the mixture was poured
into sat. aq NH4Cl (50 mL) at 0 °C. The resulting mixture was ex-
tracted with EtOAc (3 × 50 mL). The combined organic extracts
were washed with brine (70 mL), dried (Na2SO4), and purified by
flash chromatography (60 g SiO2, PE–EtOAc, 10:1).
Synthesis 2009, No. 16, 2719–2724 © Thieme Stuttgart · New York

PAPER
Chlorinated Nitrile Oxides
2723
13C NMR (100 MHz, CDCl3): d = 44.5 (–, C-4), 84.4 (+, C-5),
121.3 (o, CCl), 124.7 (o, =CCl2), 125.8 (+, 2 C, Ph-C2, Ph-C6),
128.6 (+, Ph-C4), 128.9 (+, 2 C, Ph-C3, Ph-C5), 139.6 (o, Ph-C1),
152.5 (o, C-3).
2.59 (d, J = 3.9 Hz, 1 H, 1-H), 3.12 (d, J = 8.2 Hz, 1 H, 6-Hendo),
4.64 (d, J = 8.2 Hz, 1 H, 2-Hendo).
13C NMR (100 MHz, CDCl3): d = 22.4 (–, C-9), 26.6 (–, C-8), 32.2
(–, C-10), 38.3 (+, C-7), 43.0 (+, C-1), 59.4 (+, C-6), 88.7 (+, C-2),
150.2 (o, C-5).
GC-EIMS: m/z = 171 (M+, 41), 118 (11), 104 (13), 91 (15), 77 (22),
67 (100), 51 (13).
GC-EIMS: m/z (%) = 275 (M+, 62), 209 (45), 162 (26), 104 (sty-
rene+, 100), 91 (12), 63 (9).
HRMS (ESI): m/z calcd for C11H9Cl3NO [M+ + H]: 275.9744;
found: 275.9746; [M+ + Na]: 297.9564; found: 297.9565.
HRMS (ESI): m/z calcd for C8H11ClNO[M+ + H]: 172.0524; found:
172.0524; C8H10ClNO + Na [M+ + Na]: 194.0343; found 194.0344.
3-(Trichlorovinyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isox-
azole (29)
Reaction of 1 and 26 for 3 d, following the general reaction proce-
dure I, workup procedure a; yield: 139 mg, (29%); yellow waxy sol-
id.
3-Chloro-5-phenyl-4,5-dihydroisoxazole (31)25
Reaction of 19 (10 mmol) and 25 for 27 h, following the general re-
action procedure I, workup procedure a: yield: 22%; b: yield:
556 mg (31%); yellow oil.
IR (film): 2952, 2867, 2495, 1834, 1739, 1594, 1578, 1530, 1465,
1446, 1314, 1279, 1248, 1230, 1191, 1166, 1130, 1084, 1038, 1016,
998, 975, 952, 917, 900, 853, 825, 804, 770, 743, 652 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.42–1.61 (m, 1 H, cyclopentane-
H) 1.63–1.96 (m, 4 H, cyclopentane-H), 2.11–2.21 (m, 1 H, cyclo-
pentane-H), 3.97–4.06 (m, 1 H, 6a-H), 5.18–5.25 (m, 1 H, 3a-H).
13C NMR (50 MHz, CDCl3): d = 23.2 (–, C-5), 31.2 (–, C-4), 35.6
(–, C-6), 53.1 (+, C-3a), 88.9 (+, C-6a), 120.8 (o, CCl), 124.3 (o,
=CCl2), 154.6 (o, C-3).
IR (film): 3065, 3033, 2928, 2738, 2217, 1958, 1886, 1783, 1701,
1634, 1587, 1552, 1520, 1494, 1456, 1366, 1343 1291, 1204, 1155,
1126, 1078, 1028, 1001, 967, 902, 839, 757, 699 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.17 (dd, J = 9.1, 17.2 Hz, 1 H,
4-H1), 3.57 (dd, J = 10.9, 17.2 Hz, 1 H, 4-H2), 5.75 (dd, J = 9.1,
10.9 Hz, 1 H, 5-H), 7.36–7.40 (m, 5 H, C6H5).
13C NMR (50 MHz, CDCl3): d = 46.2 (–, C-4), 83.8 (+, C-5), 125.9
(+, 2 C, Ph-C2, Ph-C6), 128.7 (+, Ph-C4), 128.9 (+, 2 C, Ph-C3, Ph-
C5), 139.2 (o, Ph-C1), 148.4 (o, C-3).
GC-MS (EI): m/z (%) = 239 (M+, 100), 171 (M+ – C5H8, 22), 137
(10), 102 (10).
GC-MS: m/z (%) = 182 (M+ + H, 100), 115 (23), 105 (38).
HRMS (ESI): m/z calcd for C9H9ClNO [M+ + H]: 182.0367; found:
182.0367; C9H8ClNO + Na [M+ + Na]: 204.0187; found:
1204.0187.
HRMS (ESI): m/z calcd for C8H9Cl3NO[M+ + H]: 239.9744; found:
239.9745; C8H8Cl3NO + Na [M+ + Na]: 261.9564; found: 261.9565.
Butyl 3-(Trichlorovinyl)-4,5-dihydroisoxazole-5-carboxylate
(30)
Reaction of 1 and 27 for 1 d, following the general reaction proce-
dure I, workup procedure a; yield: 259 mg (43%); yellow oil; con-
tains 4% of the 4-isomer (GC-MS).
3-Chloro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole (32)
Reaction of 19 (10 mmol) and 26 for 1 d, following the general re-
action procedure I, workup procedure a: yield: 10%; b: yield:
320 mg (22%); yellow oil.
IR (film): 3147, 2963, 2873, 2491, 2229, 1809, 1632, 1584, 1511,
1462, 1450, 1434, 1330, 1286, 1249, 1200, 1165, 1137, 1122, 1076,
1032, 1008, 954, 913, 867, 823 800 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.39–1.52 (m, 1 H, cyclopentane-
H), 1.56–1.83 (m, 3 H, cyclopentane-H), 2.00–2.17 (m, 2 H, cyclo-
pentane-H), 3.61–3.71 (m, 1 H, 3a-H), 5.18–5.24 (m, 1 H, 6a-H).
13C NMR (50 MHz, CDCl3): d = 22.9 (–, 1 C, C-5), 30.2 (–, 1 C, C-
4), 36.1 (–, 1 C, C-6), 55.0 (+, 1 C, C-3a), 88.2 (+, 1 C, C-6a), 150.8
(o, 1 C, C-3).
IR (film): 3443, 2961, 2935, 2874, 1735, 1577, 1541, 1465, 1395,
1322, 1205, 1167, 1119, 1064, 1020, 973, 940, 891, 851, 755 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 3 H, 4butyl
H3), 1.38 (tq, J = 7.2, 7.4 Hz, 2 H, 3butyl-H2), 1.66 (tt, J = 6.7,
7.4 Hz, 2 H, 2butyl-H2), 3.62 (d, J = 10.3 Hz, 1 H, 4-H), 3.63 (d,
J = 8.3 Hz, 1 H, 4-H), 4.22 (t, J = 6.7 Hz, 2 H, 1butyl-H2), 5.18 (dd,
J = 8.3, 10.3 Hz, 1 H, 5-H).
13C NMR (50 MHz, CDCl3): d = 13.6 (+, C-4butyl), 18.9 (–, C-3butyl),
30.4 (–, C-2butyl), 40.2 (–, C-4), 66.0 (–, C-1butyl), 79.5 (+, C-5),
120.4 (o, CCl), 125.6 (o, =CCl2), 152.5 (o, C-3), 169.1 (o, Ccarboxyl).
-
GC-EIMS: m/z (%) = 146 (M+ + H, 100).
HRMS (ESI): m/z calcd for C6H9ClNO [M+ + H]: 146.0367; found:
GC-EIMS: m/z (%) = 300 (M+ + H, 100), 282 (19), 254 (9), 198 (5),
170 (M+ – trichlorovinyl, 6), 135 (19), 101 (4).
146.0368.
HRMS (ESI): m/z calcd for C10H13Cl3NO [M+ + H]: 299.9956;
found: 299.9956; C10H12Cl3NO + Na [M+ + Na]: 321.9775; found:
321.9775.
Butyl 3-Chloro-4,5-dihydroisoxazole-5-carboxylate (33)
Reaction of 19 (10 mmol) and 27 for 1 d, following the general re-
action procedure I, workup procedure a: yield: 25%; b: yield:
473 mg (23%); yellow oil.
5-Chloro-3-oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene (15)
Reaction of 19 (10 mmol) and 12 for 2 d, following the general re-
action procedure I, workup procedure a; yield: 32%; b: yield:
385 mg (22%); yellow oil; mixture of exo- and endo-isomers
(0.93:0.07).
IR (film): 2962, 2875, 1742, 1592, 1561, 1466, 1433, 1396, 1352,
1296, 1207, 1158, 1129, 1062, 1021, 934, 894, 861, 754 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7.3 Hz, 3 H, 4butyl
-
H3), 1.37 (tq, J = 7.3, 7.4 Hz, 2 H, 3butyl-H2), 1.65 (tt, J = 6.7,
7.4 Hz, 2 H, 2butyl-H2), 3.43 (d, J = 9.3 Hz, 2 H, 4-H2), 4.20 (t,
J = 6.7 Hz, 2 H, 1butyl-H2), 5.14 (t, J = 9.3 Hz, 1 H, 5-H).
13C NMR (100 MHz, CDCl3): d = 13.5 (+, C-4butyl), 18.9 (–, C-
3butyl), 30.3 (–, C-2butyl), 41.7 (–, C-4), 66.1 (–, C-1butyl), 78.9 (+, C-
5), 148.6 (o, C-3), 168.8 (o, Ccarboxyl).
IR (film): 3143, 2967, 2878, 2481, 2228, 1723 1623, 1582, 1545,
1475, 1456, 1355, 1319, 1300, 1276, 1220, 1193, 1162, 1132, 1046,
1003, 991, 950, 927, 919, 896, 849, 826, 812, 791, 762, 689, 667,
617 cm–1.
exo-15
GC-EIMS: m/z (%) = 205 (M+ + H, 96), 159 (26), 150 (28), 104
(100), 57 (44).
1H NMR (400 MHz, CDCl3): d = 1.06–1.13 (m, 1 H, 9-Hendo),
1.15–1.33 (m, 2 H, 8-Hendo, 10-Hb), 1.50–1.55 (m, 1 H, 10-Ha),
1.56–1.63 (m, 2 H, 8-Hexo, 9-Hexo), 2.53 (d, J = 3.1 Hz, 1 H, 7-H),
Synthesis 2009, No. 16, 2719–2724 © Thieme Stuttgart · New York

2724
E. Nutz et al.
PAPER
HRMS (EI): m/z calcd for C8H12ClNO3 + Na [M+ + Na]: 228.0398;
found: 228.0399.
(9) Caldirola, P.; Ciancaglione, M.; De Amici, M.; De Micheli,
C. Tetrahedron Lett. 1986, 27, 4647.
(10) (a) Ponzio, G. Gazz. Chim. Ital. 1936, 66, 115. (b) Ponzio,
G. Gazz. Chim. Ital. 1941, 71, 693.
(11) Torssel, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: Weinheim, 1988.
(12) (a) Jäger, V.; Colinas, P. A. In The Chemistry of
Heterocyclic Compounds, Vol. 59; Padwa, A.; Pearson, W.
H., Eds.; Wiley: New York, 2002, 361. (b) Kislyi, V. P.;
Laikhter, A. L.; Ugrak, B. I.; Semenov, V. V. Russ. Chem.
Bull. 1994, 43, 98. (c) Barrett, D.; Bentley, P. D.; Perrior, T.
R. Synth. Commun. 1996, 26, 3401.
Butyl 3-[(Z)-2-Chloro-2-nitrovinyl]-4,5-dihydroisoxazole-5-
carboxylate (34)
Reaction of 20 (1 mmol) and 27 for 20 h, following the general re-
action procedure I, workup procedure a; yield: 79 mg (29%); yellow
oil.
IR (film): 3063, 2963, 2875, 1743, 1651, 1621, 1552, 1465, 1435,
1317, 1287, 1234, 1208, 1062, 1020, 941, 843, 729, 693 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.1 Hz, 3 H, 4butyl
-
H3), 1.40 (tq, J = 7.1, 7.5 Hz, 2 H, 3butyl-H2), 1.68 (tt, J = 6.8,
7.5 Hz, 2 H, 2butyl-H2), 3.67 (dd, J = 0.8, 11.3 Hz, 1 H, 4-H), 3.70
(dd, J = 0.8, 7.8 Hz, 1 H, 4-H), 4.23 (t, J = 6.8 Hz, 2 H, 1butyl-H2),
5.26 (dd, J = 7.8, 11.3 Hz, 1 H, 5-H), 8.21 (s, 1 H, 1¢-H).
13C NMR (100 MHz, CDCl3): d = 13.6 (+, C-4butyl), 19.0 (–, C-
3butyl), 30.4 (–, C-2butyl), 37.5 (–, C-4), 66.3 (–, C-1butyl), 80.4 (+, C-
5), 121.5 (+, C-1¢), 152.4 (o, C-3), 168.8 (o, Ccarboxyl). CClNO2 was
undetectable due to its high NOE effect.
GC-EIMS: m/z (%) = 277 (M+ + H, 29), 221 (100), 175 (42), 148
(34), 129 (33), 101 (46), 66 (35), 57 (56), 41 (73).
HRMS (ESI): m/z calcd for C10H13ClN2O5 + Na [M+ + Na]:
299.0406; found: 299.0405.
(13) (a) Kanemasa, S. In Science of Synthesis, Vol. 19;
Murahashi, S.-I., Ed.; Thieme: Stuttgart, 2004, 17.
(b) Belen’kii, L. I. Nitrile Oxides, In Nitrile Oxides, Nitrones
and Nitronates in Organic Synthesis, 2nd ed.; Feuer, H., Ed.;
Wiley: Hoboken, 2008, 1.
(14) Huisgen, R.; Mack, W.; Anneser, E. Angew. Chem. 1961, 73,
656.
(15) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
(16) Curran, D. P.; Fenck, C. J. J. Am. Chem. Soc. 1985, 107,
6023.
(17) Gasparrini, F.; Giovannoli, M.; Misiti, D.; Natile, G.;
Palmieri, G.; Maresca, L. J. Am. Chem. Soc. 1993, 115,
4401.
(18) Grant, R. D.; Pinhey, J. T. Aust. J. Chem. 1984, 37, 1231.
(19) (a) Barr, L.; Lincoln, S. F.; Easton, C. J. Chem. Eur. J. 2006,
12, 8571. (b) Meyer, A. G.; Easton, C. J.; Lincoln, S. F.;
Simpson, G. W. J. Org. Chem. 1998, 63, 9069.
(20) (a) Kanemasa, S.; Okuda, K.; Yamamoto, H.; Kaga, S.
Tetrahedron Lett. 1997, 38, 4095. (b) Alguacil, R.; Fariña,
F.; Martín, M. V. Tetrahedron 1996, 52, 3457.
(21) Bagatti, M.; Rastelli, A.; Burdisso, M.; Gandolfi, R. J. Phys.
Org. Chem. 1992, 5, 819.
(22) Namboothiri, I. N. N.; Rastogi, N.; Ganguly, B.; Mobin, S.
M.; Cojocaru, M. Tetrahedron 2004, 60, 1453.
(23) Preparation: Zapol’skii, V. A.; Potkin, V. I.; Kaberdin, R. V.
Russ. J. Org. Chem. 1994, 30, 1435.
Acknowledgment
We thank Dr. H. Frauendorf, University of Göttingen, for high re-
solution mass spectra and M. Spillner, Clausthal University of
Technology, for technical assistance.
References
(1) Kaberdin, R. V.; Potkin, V. I.; Zapol’skii, V. A. Russ. Chem.
Rev. 1997, 10, 827.
(2) Zapol’skii, V. A.; Namyslo, J. C.; Adam, A. E. W.;
Kaufmann, D. E. Heterocycles 2004, 63, 1281.
(3) Zapol’skii, V. A.; Namyslo, J. C.; Gjikaj, M.; Kaufmann, D.
E. Synlett 2007, 1507.
(24) Preparation: Zapol’skii, V. A.; Namyslo, J. C.;
Blaschkowski, B.; Kaufmann, D. E. Synlett 2006, 3464.
(25) Halling, K.; Thomsen, I.; Torssell, K. B. G. Liebigs Ann.
Chem. 1989, 985.
(4) Vashkevich, E. V.; Potkin, V. I.; Kozlov, N. G. Russ. J. Org.
Chem. 2005, 41, 739.
(5) Ol’dekop, Y. S.; Kaberdin, R. V.; Potkin, V. I.; Shingel, I. A.
J. Org. Chem. USSR (Engl. Transl.) 1979, 15, 39.
(6) Zapol’skii, V. A.; Nutz, E.; Namyslo, J. C.; Adam, A. E. W.;
Kaufmann, D. E. Synthesis 2006, 2927.
(7) Litvinovskaya, R. P.; Khripach, V. A. Russ. Chem. Rev.
2001, 70, 405.
(26) Stevens, R. V.; Polniaszek, R. P. Tetrahedron 1983, 39, 743.
(27) Preparation: Meyer, C. h. r.; Zapol’skii, V. A.; Adam, A. E.
W.; Kaufmann, D. E. Synthesis 2008, 2575.
(28) Preparation:Ol’dekop, Y. A.; Kaberdin, R. V. J. Org. Chem.
USSR (Engl. Transl.) 1976, 12, 1986.
(8) Melo, T. Curr. Org. Chem. 2005, 9, 925.
Synthesis 2009, No. 16, 2719–2724 © Thieme Stuttgart · New York