Nitrile oxide 1,3-dipolar cycloaddition by dehydration of nitromethane derivatives under continuous flow conditions

Article abstract of DOI:10.1071/CH11079

Aliphatic nitrile oxides were generated in situ, by dehydration of terminal nitro compounds, and reacted with dipolarophiles using continuous flow techniques to afford substituted isoxazolines. The yields of cycloadducts were comparable with traditional f

Full text of DOI:10.1071/CH11079

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2011, 64, 1397–1401
Nitrile Oxide 1,3-Dipolar Cycloaddition by Dehydration
of Nitromethane Derivatives Under Continuous
Flow Conditions
A
A
,
A B
Malte Brasholz, Simon Saubern, and G. Paul Savage
A
CSIRO Materials Science and Engineering, Private Bag 10, Clayton South MDC,
Vic. 3169, Australia.
B
Corresponding author. Email: paul.savage@csiro.au
Aliphatic nitrile oxides were generated in situ, by dehydration of terminal nitro compounds, and reacted with
dipolarophiles using continuous flow techniques to afford substituted isoxazolines. The yields of cycloadducts were
comparable with traditional flask-based reactions but reaction times were much shorter. In-line scavenger cartridges
conveniently removed by-products and unreacted reagents to give almost pure crude products. The process was
demonstrated up to gram scale.
Manuscript received: 16 February 2011.
Manuscript accepted: 3 June 2011.
Published online: 23 August 2011.
Introduction
route is preferred for aliphatic nitrile oxides (2, R ¼ alkyl).
The 1,3-dipolar cycloaddition reaction is a convenient and ver-
satile method for constructing a wide range of five-membered
The latter process, as pioneered by Mukaiyama, involves the
dehydration of primary nitroalkanes with an aryl isocyanate in
[1,2]
heterocycles.
[21]
Nitrile oxide dipoles react with carbon dipolar-
2
to give D -isoxazolines
the presence of triethylamine.
Aliphatic nitrile oxides are
[3,4]
ophiles, recently including benzyne,
quite unstable so this method is limited to in situ transforma-
tions. For methodology development the majority of nitrile
oxide cycloaddition literature is focussed on aryl nitrile oxides
because of the operational ease in their generation, less complex
by-product mixtures, and slower dimerization compared with
aliphatic nitrile oxides.
and isoxazoles, which in turn are useful precursors to b-hydroxy
ketones, b-amino alcohols, 1,3-diols, and a range of other
[
5–8]
1
makes this reaction particularly attractive for constructing spiro
,3-disubstituted compounds.
Regiochemical predictability
[9–17]
heterocycles from exocyclic methylene compounds.
Nitrile
oxides 3 are reactive intermediates that are usually generated
in situ by one of two broad methods: formal dehydration of
aldoximes via dehydrohalogenation of hydroximoyl chlorides 1,
or dehydration of nitromethyl compounds 2, with many reagent
In recent years the laboratory innovation of continuous flow
and microreactor technology has been recognized as a competi-
tive alternative to conventional round-bottom flask proces-
[
22–27]
sing.
Several distinct advantages have been attributed to
[18]
variations to facilitate this process. Cycloaddition proceeds to
give isoxazolines4 withthe main side reaction being dimerization
to give furoxane by-products 5 (Scheme 1), which can be miti-
gated by maintaining the dipolarophile in excess or with steric
flow chemistry including improved heat transfer, rapid and
efficient mixing, safe handling of hazardous materials, and
the ability to use pre-packed, immobilized reagent cartridges.
In addition, immobilized scavenger cartridges and catch and
[28,29]
[19,20]
auxiliaries.
Generally, the dehydrohalogenation route is more conve-
nient for aryl nitrile oxides (1, R ¼ Ar) whereas the dehydration
release techniques
can be used to circumvent traditional
work-up and chromatographic purification, enabling multi-step
downstream processing. Very recently, Conti and coworkers
compared aryl nitrile oxide cycloadditions, using the dehydro-
halogenation of hydroximoyl chlorides route, under conven-
[
30]
tional conditions, microwave-assisted, and incontinuousflow.
Their analysis showed clear advantages using the flow-
based technique with an immobilized base to elicit dehydro-
N
OH
R
O
ꢀHCl
R
Cl
N
[
31–34]
ꢁ
N
ꢀ
O
4
halogenation. Our interest in continuous flow processes
1
R
prompted us to investigate whether nitrile oxide cycloadditions
via the dehydration of nitroalkanes could also be improved using
flow techniques.
3
R
R
ꢀ
H O
2
NO2
R
ꢁ
ꢀ
O
N
N
ꢂ 2
O
2
Results and Discussion
5
Hassner reported an improvement to the Mukaiyama procedure
whereby a nitroalkane is treated with di-t-butyl dicarbonate
Scheme 1.
Ó CSIRO 2011
10.1071/CH11079

1
398
M. Brasholz, S. Saubern, and G. P. Savage
NO2 (1.0 equiv.)
R1
R1
Boc O (2.2 equiv.)
2
N
O
2
O
PhCH3
R
N
R
Alkene (5.0 equiv.)
DMAP (0.1 equiv.)
1
7a R1 ꢃ Bu
7b R1 ꢃ Ph
R1
NO2
1
0 mL flow coil
PhCH3
50°C, 40 min
6
a R1 ꢃ Bu
R1
1
Fig. 1. Schematic of the flow process for nitrile oxide 1,3-dipolar
6b R ꢃ Ph
R2
1
cycloaddition by dehydration of nitromethane compounds. QP-BZA,
Ò
6c R ꢃ CO
2
Et
N
R2
O
Quadrapure benzyl amine resin.
1
1
1
1
1
1
2
8
a
R
R
R
R
R
R
ꢃ Bu, R ꢃ Ph
2
8
b
ꢃ Bu, R ꢃ CO Bu
2
O N
CO Et
2
2
2
8c
ꢃ Ph, R ꢃ OAc
2
8
d
ꢃ Ph, R ꢃ OBu
(2.5 equiv.)
2
8
e
ꢃ CO Et, R ꢃ Ph
EtOH
R2
O
2
N
2
8
f
ꢃ CO Et, R ꢃ CH Ph
2
2
Alkene (1.0 equiv.)
DABCO (0.1 equiv.)
EtOH
CO Et
2
Scheme 2.
3
1
0 mL flow coil
00°C, 250 min
Table 1. Isolated yields of cycloadducts (Scheme 2)
Fig. 2. Schematic of the flow process for base-promoted condensations of
ethyl nitroacetate with alkenes.
2
R
A
Nitro-alkane
Product
Method
Yield [ %]
B
6
a
–
–
7a
7b
8a
8b
8c
8d
8e
8f
Boc
2
O
65
(Boc O) in the presence of 0.1 equivalents of 4-dimethyl-
aminopyridine (DMAP) and a five-fold excess of a dipolaro-
C
2
6b
Boc O
2
66
66
54
60
83
73
55
6
a
Ph
2
Boc O
[
35]
phile to give the cycloadduct.
In this procedure the nitro
6a
6b
6b
CO Bu
2
Boc O
2
compound, dissolved in acetonitrile, was added in portions over
a 1 h period followed by a further 3 h reaction. Yields were
calculated by NMR against an internal standard and in two cases
isolated and purified by column chromatography. This reaction
OAc
Boc
Boc
2
O
O
OBu
Ph
2
6
6
c
c
DABCO
DABCO
2
CH Ph
Ò
was adapted for continuous flow using a Vapourtec R2þ/R4
A
Boc
2
O method is described in Fig. 1, DABCO method is described in
instrument. The reagent streams were mixed through a T-piece
and then directed through perfluoroalkoxy polymer tubing
(PFA) to a convection-heated flow coil (10 mL). Pressure within
the system was maintained using an in-line 100 psi back-
Fig. 2.
B
8
8
4:16 exo:endo
C
5:15 exo:endo.
pressure regulator and the reaction was heated at 50 8C with a
Ò
residence time of 40 min (Fig. 1). Omnifit columns packed
Ò
reactor outlet, evaporated onto neutral alumina, and then eluted
through a short plug of alumina with ethyl acetate to remove
furoxane by-products.
with Quadrapure benzyl amine resin (QP-BZA) and neutral
alumina were used for in-line scavenging of excess Boc O, any
2
furoxane dimer, and other by-products.
Recently, Machetti and coworkers demonstrated that dehy-
dration of activated primary nitro compounds to nitrile oxides
Using either the Boc O method (Fig. 1) for unactivated
2
nitroalkanes or the DABCO method (Fig. 2) for activated
nitroalkanes gave isolated yields comparable to those published
for conventional flask-based methods (Scheme 2, Table 1).
However, the in-line scavenger method, and the alumina filter
employed in the flow-based reaction, produced crude products
[
36]
could be promoted by base alone.
This reaction generally
performed best in ethanol or chloroform, using either 1,4-
diazabicyclo[2.2.2]octane (DABCO) or 1-methylimidazole as
base. The reaction requires heating at 60 8C for 40 h and the
conversion to nitrile oxides was often quite good using 0.1 to 0.2
equivalents of the base. However, the cycloaddition reaction
was very sensitive to the solvent used, and was occasionally
plagued by furoxane by-products. We speculated that a shorter
reaction time at higher temperature could be achieved under
continuous flow conditions to circumvent these issues. Hence
this reaction was also adapted to flow processing again using a
1
of at least 95 % purity by H NMR in both flow methods. The
formation of furoxane dimer that usually plagues aliphatic
nitrile oxide cycloaddition reactions was ameliorated by shorter
reactions times. Where present, this by-product was almost
entirely scavenged from the reaction stream by neutral alumina,
either in-line or following elution from the flow system. Using
flow methods the reaction times were significantly shortened
from 4 h to 40 min in the Boc O procedure, and from 40 h to
2
Ò
Vapourtec R2þ/R4 instrument. The reagent streams (ethyl
250 min in the DABCO procedure. We attribute this to the
greatly increased surface to volume ratio in a flow apparatus
compared with conventional flasks, which affords rapid heat
transfer. Hence the heating and cooling profiles of the reaction
are much quicker and this, combined with overall shorter
reaction times at elevated temperatures, diminishes the oppor-
tunity for unwanted side reactions and by-products. There were
nitroacetate and the dipolarophile with DABCO) were mixed
through a T-piece and then directed through PFA tubing to a
convection-heated flow coil set at 100 8C, with a residence time
of 250 min. The pressure within the system was maintained
using an in-line 250 psi back-pressure regulator (Fig. 2). In
the absence of Boc O, the QP-BZA resin scavenger was not
2
required so the reaction mixture was simply collected at the
also operational conveniences in that the conventional Boc O
2

Nitrile Oxide Cycloadditions in Continuous Flow
1399
procedure requires the addition of the nitroalkane in acetonitrile,
in portions, over 3 h. Under flow conditions the reactant streams
in toluene were simply pumped, each at a rate of 130 mL min ,
into a T-shaped mixing piece and through the heating coil for
3-Butyl-3a,4,7,7a-tetrahydro-4,7-methanobenzo[d]
isoxazole 7a
–
1
The reaction between nitropentane and norbornadiene gave the
product (125 mg, 65 %) as a colourless oil with an exo/endo ratio
4
0 min to give the pure products. Similarly, for the DABCO
of 84:16. Exo-isomer: d 6.21 (dd, J 3.1, 5.8Hz, 1H, ¼C-H), 5.99
H
method the reactants were heated to 60 8C for 40 h in a sealed
vessel (Schlenk) in anhydrous, ethanol-free chloroform. Under
flow conditions the two reaction streams in ethanol were simply
(
dd, J 3.3, 5.8 Hz, 1H, ¼C-H), 4.70 (td, J 1.2, 8.4 Hz, 1H, CH),
3
2
8
(
1
4
.26 (d, J 8.4 Hz, 1H, CH), 3.12 (m, 1H, CH), 2.94 (m, 1H, CH),
.29 (ddd, J 7.4, 8.4, 15.5 Hz, 1H, CH ), 2.14 (dddd, J 1.2, 5.8,
2
–
1
pumped, each at a rate of 60 mL min , into a T-shaped mixer
piece and through the heating coil for 250 min at 100 8C, to give
the product in essentially pure form. Either of these methods
could be used as key steps in an in-line, multi-component flow
.4, 15.5 Hz, 1H, CH ), 1.49–1.62 (m, 4H, 2 ꢀ CH ), 1.27–1.40
2
2
m, 2H, CH ), 0.89 (t, J 7.4 Hz, 3H, CH ). d 157.9 (C¼N),
2
3
C
39.7 (C¼C), 135.4 (C¼C), 87.5 (CH), 59.7 (CH), 49.7 (CH),
4.9 (CH), 42.9 (CH ), 28.1 (CH ), 26.3 (CH ), 22.4 (CH ), 13.2
2
2
2
2
[
37]
synthesis procedure.
Furthermore, the straightforward scal-
(
CH ). Endo-isomer: dH 6.12 (dd, J 3.1, 5.8 Hz, 1H, ¼C-H),
3
ability of flow processing allows this class of products to be
prepared in multi-gram scales. To demonstrate this, we prepared
cycloadduct 7a on a gram scale without significant modification
of the developed flow method.
6
CH), 3.66 (dd, J 4.2, 9.5 Hz, 1H, CH), 3.09 (m, 1H, CH ).
.01 (dd, J 3.0, 5.8 Hz, 1H, ¼C-H), 5.14 (dd, J 4.2, 9.5 Hz, 1H,
2
Additional signals could not be unambiguously assigned from
the mixture. dC characteristic signals: 157.6 (C¼N), 134.6
(
C¼C), 134.4 (C¼C), 85.7 (CH). Additional signals could not
Conclusion
be unambiguously assigned from the mixture. IR (film): 3060,
2
7
955, 2875, 1740, 1455, 1325, 1295, 1255, 920, 900, 860,
Flow-based reaction technology offers clear advantages in time,
convenience, automation, scaling-up opportunities, and purifi-
cation for nitrile oxide cycloaddition reactions when using
dehydration of aliphatic nitroalkanes to generate nitrile oxides
in situ. This reaction is suitable for an in-line, multi-component
flow synthesis procedure.
–
1
00 cm . m/z 214.1214. HRMS calc. for C H NONa214.1208.
1
2 17
Scaled experiment: Nitropentane (1.46 g, 12.50 mmol) and
Boc O (6.00 g, 27.50 mmol) were diluted to 25 mL volume
with toluene. Norbornadiene (5.76 g, 62.50 mmol) and DMAP
(0.23 g, 1.88 mmol) were diluted to 25 mL volume with toluene.
2
–
1
The two solutions were pumped, each at a rate of 260 mL min ,
into a T-shaped mixer piece. The resulting flow stream was
directed into a flow coil (PFA, 20 mL), and heated to 50 8C
(residence time 38.5 min). The flow stream was directed through
a back-pressure regulator (100 psi). The product solution was
collected at the reactor outlet and evaporated onto neutral
alumina. The resulting powder was charged onto a short column
of neutral alumina (activity I) and eluted with toluene. Evapo-
ration of the filtrate afforded the product (1.48 g, 62 %) as a
yellow oil.
Experimental
General
[
16]
For general details see Savage et al.
recorded at room temperature on a Bruker AV400 spectrometer
1
operating at 400 MHz for H and 100.6 MHz for C, using
NMR spectra were
13
CDCl as solvent and internal reference. Electron-impact mass
3
spectra were run on a ThermoQuest MAT95XP mass spec-
trometer using ionization energy of 70 eV. IR spectra were
recorded with neat samples, on a Thermo Scientific Nicolet
6
700 FT-IR/Smart iTR instrument. Commercial reagents were
3-Phenyl-3a,4,7,7a-tetrahydro-4,7-methanobenzo[d]
isoxazole 7b
used without further purification, and anhydrous solvents were
obtained by passing them through columns of activated alumina
(toluene) or purchased from commercial suppliers (ethanol and
ethyl acetate). Flow reactions were performed with Vapourtec
The reaction between phenylnitromethane and norbornadiene
gave the product (139 mg, 66 %) as a yellow oil with an exo/endo
Ò
ratio of 85:15. Exo-isomer: d 7.71–7.77 (m, 2H, Ph), 7.34–7.44
H
R2þ/R4 instruments (www.vapourtec.co.uk; verified June
(
m, 3H, Ph), 6.34 (dd, J 3.0, 5.8 Hz, 1H, ¼C-H), 6.08 (dd, J 3.2,
2
011), using PFA with an outer diameter of 1/16 inch and 1 mm
5
8
1
.8 Hz, 1H, ¼C-H), 4.97 (td, J 1.4, 8.2 Hz, 1H, CH), 3.78 (d, J
.2 Hz, 1H, CH), 3.27 (t, J 1.4 Hz, 1H, CH), 3.14 (br s, 1H, CH),
.73 (d, J 9.4 Hz, 1H, CH ), 1.61 (td, J 1.6, 9.4 Hz, 1H, CH ).
Ò
inner diameter. Omnifit columns (www.omnifit.com; verified
June 2011) were used for in-line purification.
2
2
d 155.7 (C¼N), 140.0 (C¼C), 135.4 (C¼C), 129.2 (ipso-Ph),
C
General Method for Boc O Dehydration Procedure
129.8 (Ph), 128.7 (Ph), 126.7 (Ph), 89.4 (CH), 57.6 (CH), 50.0
(CH), 45.1 (CH), 43.2 (CH ). Endo-isomer: d 6.17 (dd, J 3.2,
2
The appropriate nitroalkane (1.00 mmol) was diluted to 2.00 mL
volume with a stock solution of Boc O (1.20 M in toluene,
2 H
5
.8 Hz, 1H, ¼C-H), 5.92 (dd, J 3.0, 5.8 Hz, 1H, ¼C-H), 5.39 (dd,
2
J 4.4, 9.6 Hz, 1H, CH), 4.13 (dd, J 4.1, 9.6 Hz, 1H, CH), 3.36 (m,
H, CH ), 1.46 (d, J 8.9 Hz, 1H, CH ). Additional signals could
equiv. of 2.25 mmol). The alkene dipolarophile (5.00 mmol)
was diluted to 2.00 mL volume with a stock solution of DMAP
1
2
2
not be unambiguously assigned. d 156.5 (C¼N), 135.1 (C¼C),
(
0.10 M in toluene, equiv. of 0.14 mmol). The two solutions
C
–
1
134.1 (C¼C), 128.7 (Ph), 126.5 (Ph), 48.9 (CH ), 87.5 (CH),
were pumped, each at a rate of 130 mL min , into a T-shaped
mixer piece. The resulting flow stream was directed into a
flow coil (PFA, 10 mL), and heated to 50 8C (residence time
2
57.2 (CH), 47.9 (CH), 46.8 (CH). Additional signals could not
be assigned. Spectroscopic data are in agreement with those
[
38]
previously reported.
3
8.5 min). The flow stream was directed through a cartridge
Ò
(
(
Omnifit , 150 mm ꢀ 10 mm) filled with ,1.0 g QP-BZA
ꢁ1
3-Butyl-5-phenyl-4,5-dihydroisoxazole 8a
capacity 5.5 mmol g ), sand (1 cm bed height), and neutral
alumina (activity I, 3 cm bed height), and then through a back-
pressure regulator (100 psi). The product solution was collected
at the reactor outlet and evaporated to dryness to afford the crude
The reaction between nitropentane and styrene gave the product
1
(134 mg, 66 %) as a yellow oil (purity .95 % by H NMR). dH
7.25–7.37 (m, 5H, Ph), 5.52 (dd, J 8.2, 10.7 Hz, 1H, 5-H), 3.34
1
b
(dd, J 10.7, 17.0 Hz, 1H, 4-H ), 2.89 (dd, J 8.2, 17.0 Hz, 1H,
products, which were analyzed for purity by H NMR.

1
400
M. Brasholz, S. Saubern, and G. P. Savage
a
-H ), 2.36 (t, J 7.6 Hz, 2H, 1 -H), 1.50–1.60 (m, 2H, 2 -H), 1.37
0
0
4
5.74 (dd, J 8.9, 11.6 Hz, 1H, 5-H), 4.31 (q, J 7.3 Hz, 2H, O-CH ),
2
0
0
b
3.60 (dd, J 11.6, 17.8 Hz, 1H, 4-H ), 3.16 (dd, J 8.9, 17.8 Hz, 1H,
(
(
(
m, 2H, 3 -H), 0.93 (t, J 7.2 Hz, 3H, 4 -H). d 158.5 (C-3), 141.4
C
a
4-H ), 1.33 (t, J 7.3 Hz, 3H, CH ). d 160.5 (CO), 151.1 (C-3),
ipso-Ph), 128.6 (Ph), 127.9 (Ph), 125.7 (Ph), 81.2 (C-5), 45.3
0
3
C
0
0
0
C-4), 28.4 and 27.3 (C-1 and C-2 ), 22.3 (C-3 ), 13.7 (C-4 ).
139.6 (ipso-Ph), 128.8 (Ph), 128.6 (Ph), 125.8 (Ph), 84.9 (C-5),
62.0 (O-CH ), 41.4 (C-4), 14.1 (CH ). Spectroscopic data are in
[36]
agreement with those previously reported.
Spectroscopic data are in agreement with those previously
[
reported.
2
3
39]
Butyl 3-Butyl-4,5-dihydroisoxazole-5-carboxylate 8b
Ethyl 5-Benzyl-4,5-dihydroisoxazole-3-carboxylate 8f
The reaction between nitropentane and butyl acrylate gave the
product (123 mg, 54 %) as a pale yellow oil. d 4.89 (dd, J 8.0,
The reaction between ethyl nitroacetate and allylbenzene gave
the product (258 mg, 55 %) as a pale yellow oil. d 7.27–7.33
H
H
9
.9 Hz, 1H, 5-H), 4.12 (t, J 6.7 Hz, 2H, O-CH ), 3.08–3.21
2
(m, 2H, Ph), 7.18–7.26 (m, 3H, Ph), 5.03 (dddd, J 6.2, 7.0, 8.2,
0.9 Hz, 1H, 5-H), 4.31 (q, J 7.2 Hz, 2H, O-CH ), 3.16 (dd, J
2
0
(m, 2H, 4-H), 2.31 (t, J 7.5 Hz, 2H, 1 -H), 1.55–1.64 (m, 2H,
1
10.9, 17.6 Hz, 1H, 4-H ), 3.10 (dd, J 6.2, 14.0 Hz, 1H, CH Ph),
b
b
CH ), 1.45–1.54 (m, 2H, CH ), 1.26–1.38 (m, 4H, 2 ꢀ CH ),
2
2
2
2
a
2.92 (dd, J 8.2, 17.6 Hz, 1H, 4-H ), 2.87 (dd, J 7.0, 14.0 Hz, 1H,
0
1
3
1
1
.87 (t, J 7.5 Hz, 3H, CH ), 0.86 (t, J 7.5 Hz, 3H, CH ). d
3 3 C
71.0 (CO), 158.3 (C-3), 76.8 (C-5), 65.4 (O-CH ), 40.8 (C-4),
2
a
2
CH Ph), 1.33 (t, J 7.2 Hz, 3H, CH ). d 160.6 (CO), 151.4 (C-3),
3
C
0.4 (CH ), 28.2 (CH ), 26.7 (CH ), 22.0 (CH ), 18.8 (CH ),
2
2
2
2
2
136.1 (ipso-Ph), 129.4 (Ph), 128.6 (Ph), 126.9 (Ph), 84.3 (C-5),
61.9 (O-CH ), 40.7 (CH Ph), 37.9 (C-4), 14.1 (CH ). IR (film):
3.5 (CH ), 13.4 (CH ). IR (film): 2960, 2935, 2875, 1740,
3
3
2
2
3
–
465, 1280, 1200 cm . m/z 227.1522. HRMS calc. for
1
–
1
985, 1715, 1585, 1250, 1125 cm . m/z 233.1054. HRMS calc.
2
for C H NO 233.1052.
C H NO 227.1521.
1
2
21
3
1
3
15
3
3
-Phenyl-4,5-dihydroisoxazol-5-yl Acetate 8c
References
The reaction between phenylnitromethane and vinyl acetate
gave the product (124 mg, 60 %) as a pale yellow oil. dH
[1] R. Huisgen, Angew. Chem. Int. Ed. Engl. 1963, 2, 565. doi:10.1002/
ANIE.196305651
[2] A. Hassner, in Synthesis of Heterocycles via Cycloadditions 2008
7
.66–7.71 (m, 2H, Ph), 7.36–7.46 (m, 3H, Ph), 6.80 (dd, J 1.4,
b
.9 Hz, 1H, 5-H), 3.58 (dd, J 6.9, 17.8 Hz, 1H, 4-H ), 3.34 (dd,
6
J 1.4, 17.8 Hz, 1H, 4-H ), 2.04 (s, 3H, CH ). d 169.7 (CO),
(Ed. R. R. Gupta) (Springer: Berlin).
a
[
3] C. Spiteri, P. Sharma, F. Zhang, S. J. F. Macdonald, S. Keeling, J. E.
Moses, Chem. Commun. 2010, 46, 1272. doi:10.1039/B922489K
4] C. Spiteri, C. Mason, F. Zhang, D. J. Ritson, P. Sharma, S. Keeling,
J. E. Moses, Org. Biomol. Chem. 2010, 8, 2537. doi:10.1039/
B927235F
3
C
1
57.0 (C-3), 128.3 (ipso-Ph), 130.8 (Ph), 128.9 (Ph), 127.0 (Ph),
5.9 (C-5), 41.3 (C-4), 21.0 (CH ). Spectroscopic data are in
[
9
agreement with those previously reported.
3
[
40]
[
[
[
5] P. Caramella, P. Gr u¨ nanger, in 1,3-Dipolar Cycloaddition Chemistry
5
-Butoxy-3-phenyl-4,5-dihydroisoxazole 8d
1
984, Vol. 1, pp. 291–392 (Ed A. Padwa) (John Wiley & Sons:
New York, NY).
The reaction between phenylnitromethane and butyl vinyl ether
gave the product (181 mg, 83 %) as a pale yellow oil. d 7.63–
6] C. J. Easton, C. M. M. Hughes, G. P. Savage, G. W. Simpson, in
Cycloaddition Reactions of Nitrile Oxides with Alkenes 1994, Vol. 60,
pp. 261–327 (Ed. A. R. Katritzky) (Academic Press: San Diego, CA).
7] P. Grunanger, P. Vita-Finzi, Isoxazoles – Part 1. Chemistry of
Heterocyclic Compounds 1991 (Eds A. Weissberger, E. C. Taylor)
(Wiley: New York, NY).
H
7
1
9
.70 (m, 2H, Ph), 7.34–7.40 (m, 3H, Ph), 5.64 (dd, J 1.5, 6.7 Hz,
b
H, H-5), 3.84 (td, J 6.7, 9.5 Hz, 1H, O-CH ), 3.51 (td, J 6.7,
2
a
b
.5 Hz, 1H, O-CH ), 3.35 (dd, J 6.7, 17.4 Hz, 1H, 4-H ), 3.18
2
a
(dd, J 1.5, 17.4 Hz, 1H, 4-H ), 1.49–1.60 (m, 2H, CH ), 1.35 (m,
2
2
H, CH ), 0.90 (t, J 7.5 Hz, 3H, CH ). d 156.9 (C-3), 129.3
2 3 C
[8] B. M. Kelly-Basetti, I. Krodkiewska, W. H. F. Sasse, G. P. Savage,
G. W. Simpson, Tetrahedron Lett. 1995, 36, 327. doi:10.1016/0040-
4039(94)02242-4
[9] A. Singh, G. P. Roth, Org. Lett. 2011, 13, 2118. doi:10.1021/
OL200547M
10] C. K. Y. Lee, C. J. Easton, G. P. Savage, G. W. Simpson, Arkivoc 2006,
(ipso-Ph), 130.2 (Ph), 128.7 (Ph), 126.8 (Ph), 103.2 (C-5),
68.1 (O-CH ), 41.5 (C-4), 31.6 (CH ), 19.2 (CH ), 13.8 (CH ).
Spectroscopic data are in agreement with those previously
reported.
2
2
2
3
[
40]
[
3
, 175.
General Method for Base-promoted Condensations
of Ethyl Nitroacetate with Alkenes
[
11] B. M. Kelly-Basetti, M. F. Mackay, S. M. Pereira, G. P. Savage, G. W.
Simpson, Heterocycles 1994, 37, 529. doi:10.3987/COM-93-S49
[12] S. Dadiboyena, J. Xu, A. T. Hamme II, Tetrahedron Lett. 2007, 48,
Ethyl nitroacetate (550 mL, 5.00 mmol) was diluted to 2.00 mL
volume with EtOH. The alkene dipolarophile (2.00 mmol) and
DABCO (224 mg, 2.00 mmol) were diluted to 2.00 mL volume
with EtOH. The two solutions were pumped, each at a rate of
1295. doi:10.1016/J.TETLET.2006.12.005
13] S. M. Pereira, G. P. Savage, G. W. Simpson, R. J. Greenwood, M. F.
[
Mackay, Aust. J. Chem. 1993, 46, 1401. doi:10.1071/CH9931401
[14] J. Xu, A. Hamme II, Synlett 2008, 919.
15] R. Newton, G. P. Savage, Aust. J. Chem. 2008, 61, 432. doi:10.1071/
CH08111
16] N. J. Beattie, C. L. Francis, A. J. Liepa, G. P. Savage, Aust. J. Chem.
–
1
6
0 mL min , into a T-shaped mixer piece. The resulting flow
stream was directed into a flow coil (PFA, 30 mL), and heated to
00 8C (residence time 250 min). The flow stream was directed
[
[
[
1
through a back-pressure regulator (250 psi) and the reaction
mixture was collected at the reactor outlet and evaporated onto
neutral alumina (activity I). The resulting powder was charged
onto a short column of alumina and eluted with EtOAc. Evap-
oration of the filtrate afforded the product.
2
010, 63, 445. doi:10.1071/CH09479
17] G. P. Savage, Curr. Org. Chem. 2010, 14, 1478. doi:10.2174/
138527210791616812
[18] H. Feuer, K. Torssell, in Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis: Novel Strategies in Synthesis 2008 (John Wiley
and Sons: New Jersey).
[
19] G. P. Savage, G. T. Wernert, Aust. J. Chem. 2005, 58, 877. doi:10.1071/
Ethyl 5-Phenyl-4,5-dihydroisoxazole-3-carboxylate 8e
CH05189
[20] S. J. Barrow, C. J. Easton, G. P. Savage, G. W. Simpson, Tetrahedron
The reaction between ethyl nitroacetate and styrene gave the
product (320 mg, 73 %) as a yellow oil. d 7.23–7.40 (m, 5H, Ph),
H
Lett. 1997, 38, 2175. doi:10.1016/S0040-4039(97)00275-X

Nitrile Oxide Cycloadditions in Continuous Flow
1401
[
[
[
[
[
[
[
[
[
[
[
21] T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339.
doi:10.1021/JA01505A017
22] X. Y. Mak, P. Laurino, P. H. Seeberger, Beilstein J. Org. Chem. 2009,
[32] M. Brasholz, B. A. Johnson, J. M. Macdonald, A. Polyzos,
J. Tsanaktsidis, S. Saubern, A. B. Holmes, J. H. Ryan, Tetrahedron
2010, 66, 6445. doi:10.1016/J.TET.2010.04.092
[33] A. Palmieri, S. V. Ley, K. Hammond, A. Polyzos, I. R. Baxendale,
Tetrahedron Lett. 2009, 50, 3287. doi:10.1016/J.TETLET.2009.
02.059
[34] C. H. Hornung, C. Guerrero-Sanchez, M. Brasholz, S. Saubern,
J. Chiefari, G. Moad, E. Rizzardo, S. H. Thang, Org. Process Res.
Dev. 2011, 15, 593. doi:10.1021/OP1003314
[35] Y. Basel, A. Hassner, Synthesis 1997, 1997, 309. doi:10.1055/S-1997-
1181
[36] L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem. 2006, 2006,
5. doi:10.3762/BJOC.5.19
23] C. Wiles, P. Watts, Eur. J. Org. Chem. 2008, 2008, 1655. doi:10.1002/
EJOC.200701041
24] S. V. Ley, I. R. Baxendale, Chima 2008, 62, 162. doi:10.2533/
CHIMIA.2008.162
25] A. Kirschning, W. Solodenko, K. Mennecke, Chem. – Eur. J. 2006, 12,
5972. doi:10.1002/CHEM.200600236
26] I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby,
G. K. Tranmer, Chem. Commun. 2006, 2566. doi:10.1039/B600382F
27] K. J a¨ hnisch, V. Hessel, H. L o¨ we, M. Baerns, Angew. Chem. Int. Ed.
4852. doi:10.1002/EJOC.200600475
[37] D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675. doi:10.1039/
C0SC00381F
[38] G. K. Tranmer, W. Tam, Org. Lett. 2002, 4, 4101. doi:10.1021/
OL026846K
[39] L. Cecchi, F. DeSarlo, F. Machetti, Chem. 2 Eur. J. 2008, 14, 7903.
doi:10.1002/CHEM.200800554
[40] O. Moriya, H. Takenaka, M. Iyoda, Y. Urata, T. Endo, J. Chem. Soc.
2004, 43, 406. doi:10.1002/ANIE.200300577
28] A. Palmieri, S. V. Ley, A. Polyzos, M. Ladlow, I. R. Baxendale,
Beilstein J. Org. Chem. 2009, 5, 23. doi:10.3762/BJOC.5.23
29] A. Polyzos, M. O’Brien, T. P. Petersen, I. R. Baxendale, S. V. Ley,
Angew. Chem. Int. Ed. 2011, 50, 1190. doi:10.1002/ANIE.201006618
30] S. Castellano, L. Tamborini, M. Viviano, A. Pinto, G. Sbardella,
P. Conti, J. Org. Chem. 2010, 75, 7439. doi:10.1021/JO1014323
31] M. Brasholz, J. M. Macdonald, S. Saubern, J. H. Ryan, A. B. Holmes,
Chem. 2 Eur. J. 2010, 16, 11471. doi:10.1002/CHEM.201001435
Perkin Trans. 1 1994, 413. doi:10.1039/P19940000413