Soluble polymer-supported flow synthesis: A green process for the preparation of heterocycles

Article abstract of DOI:10.1002/ejoc.201101726

PEG-supported aqueous flow synthesis coupled with ultrafiltration as the separation technique has been investigated for the first time. This strategy was applied to the preparation of new 3,4-dihydropyrimidin-2(1H)-ones, tetrazoles and tetrahydro-1,3-oxaz

Full text of DOI:10.1002/ejoc.201101726

FULL PAPER
DOI: 10.1002/ejoc.201101726
Soluble Polymer-Supported Flow Synthesis: A Green Process for the
Preparation of Heterocycles
Nicolò Prosa,[a] Raphaël Turgis,[a] Riccardo Piccardi,[a] and Marie-Christine Scherrmann*[a]
Keywords: Flow chemistry / Green chemistry / Ultrafiltration / Synthetic methods / Heterocycles
PEG-supported aqueous flow synthesis coupled with ultrafil-
tration as the separation technique has been investigated for
the first time. This strategy was applied to the preparation of
nally, various new tetrahydro-1,3-oxazines were prepared by
four-step synthesis, that is, Baylis–Hillman reaction,
Michael addition of amines, cyclization with formaldehyde
a
new 3,4-dihydropyrimidin-2(1H)-ones, tetrazoles and tetra- and hydrolysis of the linkage to PEG. The use of water during
hydro-1,3-oxazines from the same PEG-linked aldehyde as
case studies. Dihydropyrimidinones were prepared by a cop-
per(II)-catalysed Biginelli reaction whereas a new tetrazole-
containing compound was obtained by Baylis–Hillman reac-
tion followed by reduction and 1,3-dipolar cycloaddition. Fi-
the synthesis and most of the purification steps, as well as
the benefits of the flow process in terms of improved safety
and heat transfer agree with the principles of green chemis-
try.
from byproducts and reagents of low molecular weight.[12]
In these syntheses, organic solvents were used during the
transformations and/or the separation steps. On the other
hand, a sustainable methodology should not only improve
the chemistry, but also the process by improving its effi-
ciency, energy consumption and safety. In this context, con-
tinuous flow micro- or mesofluidic systems represent a
good alternative to conventional reaction vessels as their
dimensions, typically in the order of less than 1 mm with a
high surface area to volume ratio, allow improved control
of mass and heat transfer whereas the inherently low reac-
tion volume increases safety making them valuable tools for
green chemistry.[13] This technique has been applied to the
synthesis of various products,[14] in particular, heterocy-
cles.[14i,14j] Many flow processes are based on the use of
polymer-supported reagents, catalysts and/or solid-phase
scavengers to facilitate the treatment of reaction mix-
tures,[14f,14g] but, to the best of our knowledge, reactions of
supported substrates under flow conditions have never been
explored. With the aim of developing an environmentally
benign and efficient process, we have investigated PEG-sup-
ported aqueous flow reactions coupled with ultrafiltration
as the separation technique for the synthesis of various
heterocycles starting from the same PEG-bound aldehyde
(Scheme 1). The synthesis of 3,4-dihydropyrimidin-2(1H)-
ones (DHPMs) by a one-step three-component reaction
was chosen as proof of concept of the methodology. The
process was then applied to the preparation, in a three-step
procedure, of a new tetrazole-containing compound. Fi-
nally, various new tetrahydro-1,3-oxazines have been pre-
pared in four steps from the same PEG-linked aldehyde.
Introduction
The development of more sustainable methodologies in
synthesis is a challenge for chemists.[1] In particular, efforts
have been made to replace volatile organic solvents with
alternative media such as water,[2] supercritical fluids,[3]
ionic liquids[4] and, more recently, polyethylene glycols
(PEGs)[5] or solventless conditions.[6] Water is a cheap and
non-toxic solvent that can be used and stored in large
amounts without any associated hazard and its treatment
as waste is nowadays an accomplished technology.[7] In
many cases, the advantages of using greener media for reac-
tions are counterbalanced by the use of organic solvents
during the work-up procedures. Polymer-supported reac-
tions offer the advantage of easy isolation of products by
simple filtration, in the case of solid-phase chemistry, or
by extraction and precipitation when soluble supports are
used.[8] Soluble supports, like PEGs, also offer the possibil-
ity of exploiting ultrafiltration techniques to separate mole-
cules on the basis of their molecular weight. Low-molecu-
lar-weight molecules pass through the semi-permeable
membrane whereas high-molecular-weight species are re-
tained by the membrane with a defined range of pore sizes.
This technology has been used in biochemistry but also in
synthesis for homogeneous catalyst recycling[9] or to sepa-
rate PEG-bound polypeptides[10] and oligosaccharides[11]
[a] Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR
CNRS 8182, Université Paris-Sud,
Bâtiment 410, 91400 Orsay, France
E-mail: marie-christine.scherrmann@u-psud.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101726.
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Soluble Polymer-Supported Flow Synthesis
The purity of 1a and 1b was established by 1H NMR and
MS analyses.[16] In particular, the MALDI-TOF MS spec-
tra showed the characteristic Gaussian-type distribution of
isotopic cluster ions with a spacing of m/z = 44.[17]
One-Step Synthesis and Purification of
Heterocycles
We first envisaged the synthesis of 3,4-dihydropyrimidin-
2(1H)-ones (DHPMs) through the Biginelli reaction.[18]
This multicomponent reaction, involving a β-dicarbonylic
compound, an aldehyde and a urea (or thiourea), has been
extensively studied. Some of the large number of reports
on the Biginelli reaction described the search for greener
conditions, including the use of water[19] or PEGs[20] as sol-
vents as well as solvent-free conditions using various cata-
lysts with or without microwave activation.[21] Solid- and
solution-phase strategies have also been described[22] and,
in particular, the use of PEG as a support was explored by
Xia and Wang.[22a,22b] They described a reaction carried out
in CH3CN or under solvent-free conditions using micro-
Scheme 1. General strategy for the synthesis of various heterocycles
from the same PEG-linked aldehyde.
Results and Discussion
PEG-Bound Aldehyde
The linkage of 4-carboxybenzaldehyde to PEG4000 was wave activation, however, organic solvents were still used
previously performed in CH2Cl2 (8 mL/g of PEG) at room for the separations. First, we performed the reaction in
temperature for 24 h in the presence of a stoichiometric batch by using 1a and pentane-2,4-dione in water as the
amount of dicyclohexylcarbodiimide (DCC) and a catalytic solvent. Various catalysts known to be efficient for this kind
amount of DMAP.[15] We found that the esterification of of transformation in water were tested, including cerium-
PEG2000 and PEG4000 took place at 70 °C (melted PEG) (III) chloride,[23] ammonium carbonate[24] and Brønsted
in the presence of diisopropylcarbodiimide (DIC) without acids.[25] Unfortunately, we never observed a conversion
additional solvent whereas the use of DCC as coupling higher than 35% (1H NMR). It is known that metal triflim-
agent was unsuccessful, presumably because DCC is poorly ides such as Ni(NTf2)2, Cu(NTf2)2 and Yb(NTf2)3 in the
soluble in melted PEG (Scheme 2). The conversion was presence of HCl catalyse the Biginelli reaction in water
complete after 3.5 h as judged by H NMR analysis. In- more efficiently than the corresponding metal triflates.[26]
1
stead of the classical work-up, that is, precipitation of the By using Cu(NTf2)2·HCl, we observed (NMR and MS) that
PEG derivatives from the CH2Cl2 solution by addition of aldehyde 1a was efficiently converted into dihydropyrimid-
iPrOH (40 mL/g) and subsequent washing of the solid with inone 2 (Scheme 3). Having obtained this good result, we
Et2O (≈40 mL/g), we applied the aqueous ultrafiltration decided to investigate the use of commercially available and
technique. Hence, after the addition of water, filtration of inexpensive copper(II) salts such as CuCO3 and CuCl2 as
insoluble material and ultrafiltration by forcing the aqueous catalysts. We observed that both were efficient in the aque-
solution through a regenerated cellulose membrane with a ous Biginelli reaction when associated with HCl.
molecular-size cut-off of 1000, PEG-bound aldehydes 1a
and 1b were recovered in 65 and 75% yields, respectively.
By using this procedure, only 12 mL of water per gram of
PEG was used instead of 88 mL of organic solvents such as
CH2Cl2 (harmful and suspected human carcinogen), iPrOH
(flammable) and Et2O, which is hazardous in terms of
flammability, low flash point and explosion risk because of
peroxide contamination.
a batch reaction.
Scheme 3. Aqueous Biginelli reaction of PEG-linked aldehydes in
The reaction was then tested under flow conditions by
using a commercially available platform, the Vapourtec
R2+/R4 combination.[27] Optimization of the reaction pa-
rameters, that is, flow-rate, temperature and concentration
of aldehyde 1a as well as the amount of the diketone and
urea led us to the best conditions (Table 1). We observed
that byproducts were formed at a temperature of 70 °C and
above (Table 1, entries 1 and 2). Complete conversion was
Scheme 2. Solvent-free preparation of PEG-linked aldehydes.
obtained at 60 °C by using 4 equiv. of urea and diketone at
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N. Prosa, R. Turgis, R. Piccardi, M.-C. Scherrmann
FULL PAPER
a flow rate of 0.06 mL/min at a concentration of 1a of
Although we chose to use the PEG as a support to carry
0.06 mol/L (Table 1, entry 4). This concentration could be out the reactions in water, for the sake of comparison we
increased to 0.095 mol/L (maximum concentration that also realized the Biginelli reaction between aldehyde 1a,
gives a reasonable viscosity for pumping) without affecting pentane-2,4-dione and urea in organic solvents. Because the
the conversion. The flow rate could be increased to PEG-supported Biginelli synthesis of DHPM has already
0.08 mL/min only if 6 equiv. of urea and diketone were em- been reported in CH3CN,[22a,22b] we carried out the reaction
ployed (Table 1, entry 8). Finally, we selected conditions in this solvent (8.5 mL/g of 1a) under the same conditions
using the least amount of excess reagents (Table 1, entry 6). as used in the batch reaction performed in water (see
These involved the premixing of the PEG-bound aldehyde above). Hence, after 14 h at room temp., the CuCl2·HCl-
1a (0.095 m in water) and pentane-2,4-dione (4 equiv.) and catalysed reaction was treated by removing the solvent un-
the pumping of this mixture (stream A, 0.03 mL/min), der reduced pressure, dissolving the residue in CH2Cl2
which was then mixed through a T-piece with a premixed (8 mL/g) and washing the organic phase with water (8 mL/
aqueous solution of urea (4 equiv.), CuCl2 (10%) and HCl g). After concentration of the organic phase to one third of
(12.5%; stream B, 0.03 mL/min). The mixture was heated to its volume, the product was precipitated by the addition of
60 °C through a convection flow coil (CFC, 10 mL internal Et2O (nine volumes of CH2Cl2) and washed several times
1
volume, 1 mm i.d.) to give a residence time of 167 min. On with Et2O (30 mL/g). H NMR analysis of the precipitate
exiting the CFC the flow stream was directly collected over indicated an incomplete conversion and the presence of un-
185 min (11.1 mL) in a stirred 50 mL ultrafiltration cell identified PEG-linked compounds (Table 2, entry 3). Be-
(SUFC) equipped with a regenerated cellulose membrane cause the flow conditions could not be tested with CH3CN
(molecular-size cut-off of 1000) filled with water (30 mL; because of the poor solubility of urea in this solvent
Scheme 4). Ultrafiltration was carried out by applying a (0.070 m at 25 °C),[28] the reaction was carried out in DMF,
pressure of 3.5 bar and the flow from the reactor was col- a solvent previously used to perform this multicomponent
lected in a second ultrafiltration cell. Concentration of the transformation under continuous flow conditions.[29] The
retentate afforded 2a in 72% yield (calculated from the col- reaction was also carried out in batch, as described above.
lected volume and the flow rate, see the Exptl. Sect.). In both cases (batch at room temp. or flow at 60 °C, under
PEG4000-linked aldehyde 1b was also treated in flow condi- the same conditions as used for the aqueous reaction), we
tions with pentanedione and urea in the presence of the also obtained poor conversions and unidentified PEG-
same catalyst. Because the aqueous solution of 1b was quite linked compounds (Table 2, entries 4 and 5). Thus, under
viscous, a more diluted solution (0.061 m) containing pen- conditions identical to those optimized for water, the Bigi-
tanedione (6 equiv.) was mixed with the solution of urea nelli reaction in organic solvents led to inferior results in
(6 equiv.) and catalyst (CuCl2·HCl). A complete conversion terms of yield. Although we cannot exclude that further
was obtained at 60 °C with a 200 min residence time.
PEG4000-linked DHMP 2b was purified by ultrafiltration to
give 79% yield.
Table 2. Comparison of the Biginelli reaction in water and in or-
ganic solvents.
Solvent (volume
[mL/g])[a]
Solvent(s)
treatment
[mL/g][a]
1a[b] 2a[b] Unidentified PEG-
[%]
[%]
linked com-
Table 1. Optimization of the Biginelli reaction under flow condi-
tions.
pounds[b] [%]
1
2
3
H2O[c] (8.5)
H2O (85)
H2O (85)
H2O (8)
CH2Cl2 (8)
Et2O (64)
H2O (8)
CH2Cl2 (8)
Et2O (64)
H2O (8)
CH2Cl2 (8)
Et2O (64)
0
0
5
100
100
30
0
0
65
[1a]
Urea
[mol/L] [equiv.]
Pentanedione Flow rate
T
Conv.
[%][a]
H2O[d] (8.5)
CH3CN[c] (8.5)
[equiv.]
[mL/min] [°C]
1
2
3
4
5
6
7
8
0.045
0.045
0.045
0.060
0.095
0.095
0.095
0.095
4
4
4
4
4
4
4
6
4
4
4
4
4
4
4
6
0.1
80
70
60
60
60
60
40
60
59[b]
70[b]
70
100
95
100
98
100
0.08
0.08
0.06
0.08
0.06
0.06
0.08
4
5
DMF[c] (8.5)
DMF[d] (8.5)
50
40
5
45
40
20
1
[a] The conversion was determined by H NMR spectroscopy. [b]
Unidentified byproducts were observed.
[a] Volume of solvent per g of the starting PEG-linked aldehyde
1a. [b] Determined by H NMR analysis. [c] Batch. [d] Flow.
1
Scheme 4. CuCl2·HCl-catalysed aqueous Biginelli reaction under flow conditions.
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Soluble Polymer-Supported Flow Synthesis
optimization could give results similar to those obtained in presence of acrylonitrile, to maintain an elevated concentra-
aqueous medium, the use of water as solvent gave quantita- tion of the substrate we decided to start with two storage
tive yields of product under very mild and safe conditions. solutions (A and B), both containing 1a (Scheme 6).
Note also that similar volumes of solvents were required for
both treatments, that is, ultrafiltration or extraction/precipi-
tation (Table 2).
DHMP 3 was released from the PEG support by basic
hydrolysis (1 m aqueous NaOH) of the ester linkage
(Scheme 5). Acidification of the reaction mixture gave solid
6 contaminated by less than 5% of PEG (1H NMR). Most
of the remaining PEG could be removed by ultrafiltration
of an aqueous basic (pH 8) solution. Indeed, upon acidifi-
cation of the filtrate, compound 3 was isolated by filtration
(purity Ͼ98%, NMR) in 60% yield from 1a and 70% from
1b. We also checked (NMR) that released PEG was pure
enough to be reused. In fact, when the recovered PEG was
reused to prepare 1a or 1b, similar yields and purities were
obtained.
Scheme 6. Aqueous Baylis–Hillman reaction of PEG2000-linked al-
dehyde under flow conditions.
The initial concentration of 1a in these solutions, the
quantity of DABCO and acrylonitrile, as well as the resi-
dence time and the temperature of the CFC, were optimized
(Table 3). First, the experiments were performed by setting
the concentrations of 1a in solutions A and B at 0.08 m with
0.25 equiv. of DABCO and 3 equiv. of acrylonitrile. At a
total flow rate of 0.2 mL/min and 65 °C, a 47% conversion
was observed (Table 1, entry 1). No significant improve-
ment was found by increasing the concentration of 1a
(Table 3, entry 2) whereas a higher temperature (100 °C)
gave rise to the formation of byproducts and hydrolysis of
the ester linkage (Table 3, entry 3). To facilitate the pump-
ing of the PEG-supported substrate solution by lowering its
viscosity, the concentration of 1a in the solution containing
acrylonitrile (solution B) was increased, maintaining the fi-
nal concentration in the reaction cell. Under these experi-
mental conditions, a repeatable constant flow rate of
0.3 mL/min could be tested and we observed that an in-
crease in flow rate and quantity of DABCO resulted in an
enhancement of the conversion up to 80% (Table 3, en-
try 4), although hydrolysis of the ester linkage still occurred
(≈30%). This side-reaction could be limited to 10% by low-
ering the temperature (Table 3, entries 5–8). Optimal condi-
tions allowing a complete conversion of 1a were found
(Table 3, entry 7) and applied to the preparation of 12 g of
4 (84% yield), purified by ultrafiltration of the resulting
aqueous solution.[34]
Scheme 5. Hydrolysis of the PEG linkage.
These experiments showed that water is the solvent of
choice for the PEG-supported reactions and that purifica-
tion by ultrafiltration would avoid the use of potentially
dangerous and/or toxic solvents. The slightly lower isolated
yields obtained by ultrafiltration using the smaller PEG as
the support were compensated by the higher loading ca-
pacity of PEG2000 (1 mmol/g) compared with that of
PEG4000 (0.5 mmol/g). Furthermore, the higher viscosity of
PEG4000 derivatives could be problematic during the pump-
ing operation; therefore we decided to test the process for
the multistep synthesis of heterocycles (Scheme 1) using
PEG2000 as the support.
Multistep Syntheses and Purification of
Heterocycles
Table 3. Optimization of the Baylis–Hillman reaction under flow
conditions.
Due to presence of various functional groups, Baylis–
Hillman adducts can be used for the synthesis of a broad
range of compounds.[30] Although numerous cases of the
Baylis–Hillman reaction in the presence of water have been
reported,[31] few examples of the reaction in water as solvent
have been described.[32] Quite recently, Acke and Stevens
reported on the study of this reaction in water/dioxane un-
der continuous flow conditions.[33] They found, in particu-
lar, that the reaction was faster under flow conditions than
under batch conditions and that the stopped-flow technique
as well as a high concentration of the reagents were re-
quired to achieve complete conversion.
[1a] [mol/L],
[1a] DABCO Acryloni- Flow
T
Conv.
sol. A
[mol/ [equiv.]
trile
rate
[mL/
min]
[°C] [%][a]
L],
[equiv.]
sol. B
1
2
3
4
5
6
7
8
0.08
0.21
0.08
0.21
0.085
0.13
0.25
0.25
0.25
0.5
0.5
0.5
3
3
3
3
3
4
5
5
0.2
0.2
0.2
0.3
0.3
0.3
0.3
0.4
65
65
47
50
0.085
0.043
0.043
0.032
0.032
0.032
100 50[b]
100 80[b]
0.13
80
60
90[c]
98[c]
0.097
0.097
0.097
0.5
0.5
60 100[c]
60
98[c]
The reaction between 1a and acrylonitrile was carried
out in the presence of DABCO. Because the viscosity of
1
[a] The conversion was determined by H NMR spectroscopy. [b]
Unidentified byproducts and ca. 30% hydrolysis were observed. [c]
the PEG-bound aldehyde aqueous solution decreased in the Ͻ10% hydrolysis was observed.
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In the next step, the double bond of the PEG-supported necessary to obtain compound 7. As our equipment does
Baylis–Hillman adduct 4 was reduced. The reaction, carried not function at temperatures above 150 °C, we optimized
out in batch by using H2 and 10% Pd/C as catalyst, was the flow conditions (Table 5) and were able to obtain com-
complete after 2 h at room temp. To perform the reduction plete conversion by using 2.5 equiv. of ZnBr2 at 150 °C with
under flow conditions, we investigated the use of Pd En- a residence time of 166 min. The crude aqueous reaction
CatTM as catalyst and ammonium formate as hydrogen medium containing compound 7, PEG and excess reactants
source. Hence, an aqueous solution of 4 and ammonium in this case too was submitted to ultrafiltration. This treat-
formate was passed through an Omnifit cartridge contain- ment allowed recovery of the PEG and, at the same time, a
ing the catalyst (Scheme 7). The optimal flow rate and tem- solution containing 7 that could be isolated almost pure
perature, determined to be 0.111 mL/min and 50 °C, led to upon extraction with ethyl acetate after acidification (60%
5 as a 60:40 diastereoisomeric mixture (1H NMR) in a resi- yield).
dence time of 3 min.[34] PEG-linked compound 5 was sepa-
Table 5. Optimization of the tetrazole synthesis under flow condi-
tions.
rated from the ammonium formate by ultrafiltration and
isolated in 90% yield.
ZnBr2 [equiv.]
Flow rate [mL/min]
Conv. [%][a]
1
2
3
4
5
1.5
1.5
1.5
2.5
2.5
0.166
0.111
0.08
0.08
0.06
50
70
80
83
100
Scheme 7. Reduction of PEG-linked Baylis–Hillman adduct in flow
condition.
1
[a] Conversions determined by H NMR spectroscopy.
PEG-linked nitrile 5 was then treated with sodium azide
to prepare the 1H-tetrazole derivative 7. This reaction is
generally carried out in DMF in the presence of ammonium
salts[35] but also in water with zinc salt as promoter as dem-
onstrated by Sharpless and co-workers.[36] Hence, we inves-
tigated the use of ammonium chloride and ZnBr2 as pro-
moters and water and DMF as solvents at various tempera-
tures (Table 4). PEG-linked tetrazole 6 was obtained in
DMF at 140 °C in the presence of NH4Cl (12 equiv.) in 12 h
(Table 4, entry 1) whereas the reaction was effective at
170 °C in water in the presence of ZnBr2 (1.5 equiv.) also in
12 h. Concomitant hydrolysis of the ester linkage afforded
the 1H-tetrazole derivative 7 (Table 4, entry 6).
Then we envisaged using the same process to prepare
new tetrahydro-1,3-oxazines from PEG-linked aldehyde 1a
through a four-step synthesis, that is, Baylis–Hillman reac-
tion, Michael addition of a range of amines, cyclization
with formaldehyde and hydrolysis of the linkage to PEG.
Various catalysts are known to be efficient in the aqueous
aza-Michael addition reaction[38] but the reaction is also
known to proceed without any catalyst.[39] Hence, aqueous
solutions of amines 8a–e were added to the PEG-linked
Baylis–Hillman adduct 5 without additives. Complete con-
versions were observed in a residence time of 30 min at
30 °C with benzylamine, butylamine and allylamine, and at
45 °C in a residence time of 45 min with propargylamine
and 2-aminopyridine. The β-aminopropionitriles 9a–e were
obtained as approximately 70:30 diastereoisomeric mixtures
(1H NMR[40]). The aqueous solutions obtained under flow
conditions were directly pumped and mixed through a T-
piece with a formaldehyde aqueous solution (Scheme 8) to
form the tetrahydro-1,3-isoxazine 10a–e, which was purified
by ultrafiltration (Table 6).[41]
Table 4. Optimisation of tetrazole formation in batch.
Solvent
T [°C] Promoter Conv. [%][a] Hydrolysis [%][a]
1
2
3
4
5
6
H2O
DMF
H2O
H2O
H2O
H2O
140
140
75
100
140
170
NH4Cl
NH4Cl
ZnBr2
ZnBr2
ZnBr2
ZnBr2
0
100
0
15
40
100
0
0
15
26
100
100
1
[a] Determined by H NMR analysis.
The advantage of using the microreactor approach in
such an energy-demanding transformation has recently
been demonstrated.[37] Kappe and co-workers obtained
good results by using NMP/H2O/AcOH as solvent under
high-temperature conditions[37a] (220 °C, 34 bar back-pres-
sure regulator), whereas Palde and Jamison described a
non-catalysed flow process in NMP/H2O at 190 °C (17 bar
back-pressure regulator).[37b] Our preliminary tests under
Scheme 8. Two-step preparation of tetrahydro-1,3-isoxazine under
batch conditions showed that a temperature of 170 °C was flow conditions.
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Soluble Polymer-Supported Flow Synthesis
Table 6. Optimization of preparation of tetrahydro-1,3-isoxazine in formed in organic solvents. Of course, the wastewater must
flow condition.
be treated like all chemical waste, but various methodolo-
gies, including membrane techniques[7a–7d] and microchan-
nel reactors,[42] have been proven to be effective for remov-
ing hazardous pollutants.
RNH2
[equiv.]
T [°C][a] Residence HCHO
Prod-
uct
Yield
[%][b]
time [min][a] [equiv.]
1
2
3
4
5
8a (1.3)
8b (1.3)
8c (1.5)
8d (4)
30
30
30
45
45
30
30
30
45
45
3
3
3
4
4
10a
10b
10c
10d
10e
80
76
64
75
85
Experimental Section
8e (3)
General: 1H and 13C NMR spectra were recorded at room tempera-
ture with Bruker spectrometers (250, 300 or 360 MHz). Chemical
shifts are reported in parts per million (ppm) relative to Me4Si for
1H NMR spectroscopy. Signals were assigned on the basis of the
results of 1H–1H COSY and gradient-HMQC experiments.
MALDI-TOF MS spectra were performed at the Service de Spec-
trométrie de Masse IMAGIF/ICSN, CNRS (Gif-sur-Yvette,
France) with a Perseptive Voyager DE STR MALDI-TOF mass
spectrometer (Perseptive Biosystems) by using 2,5-dihydroxy-
benzoic acid as the matrix. The spectra of the compounds were
compared with commercial PEG2000 [calcd. for C94H190NaO48 [M
+ Na]+ (n = 46) 2110.23; found 2110.31 (batch A); calcd. for
C86H174NaO44 [M + Na]+ (n = 42) 1935.13; found 1935.15 (batch
B)] or commercial PEG4000 [calcd. for C190H382NaO96 [M + Na]+
(n = 94) 4223.49; found 4223.53]. HRMS were recorded in positive
mode with a Microtof-QII spectrometer (Bruker) using electro-
spray ionization. The yields of the continuous flow process were
calculated from the collected volume and the flow rate.
[a] For both steps. [b] Products purified by ultrafiltration through
a regenerated cellulose membrane (molecular size cut-off of 1,000)
at a pressure of 3.5 bar.
Finally, the tetrahydro-1,3-isoxazines 11a–e were released
from the PEG by treatment with sodium methoxide to ob-
tain the corresponding methyl ester derivatives. The dia-
stereoisomers were separated by flash chromatography, the
only non-aqueous separation of the sequence, and charac-
terized by NMR analysis.
General Procedure for Ultrafiltration: Ultrafiltration of the aqueous
solutions was performed in an Amicon 8050 or 8200 stirred cell
fitted with Amicon Ultracell PL Membrane Disk with a molecular
weight cut-off of 1000 under a pressure of 3.8 bar. The ultrafiltra-
tion retentate was concentrated under reduced pressure to afford
the product.
In all cases, the cis-disubstituted compound was obtained
as the major compound (cis/trans ca. 2:1). The relationship
between the substituents at C-5 and C-6 was established by
PEG-Bound Aldehyde 1a: A mixture of PEG2000 (10.0 g, 4.8 mmol),
4-formylbenzoic acid (5.8 g, 38.4 mmol) and N,NЈ-diisopropyl-
carbodiimide (8.6 mL, 55.2 mmol) was heated at 70 °C for 3.5 h
and cooled to room temp. The product was diluted with water
(40 mL), filtered through a PVDF membrane (47 mm, 0.45 μm)
and subjected to ultrafiltration. After the first ultrafiltration, the
retentate (10 mL) was diluted with water (40 mL) and the solution
was subjected to ultrafiltration again. The operation was repeated
once to afford 7.3 g of 1a as a white powder (65%). 1H NMR
(250 MHz, CDCl3): δ = 3.45–3.90 (m, ca. 180 H, PEG backbone),
4.53 (t, J = 5.0 Hz, 4 H, PEG-CH2OCO), 7.98 (d, J = 8.0 Hz, 4 H,
4-H), 8.24 (d, J = 8.0 Hz, 4 H, 3-H), 10.13 (s, 2 H, CHO) ppm.
1
examining the H NMR coupling pattern of the isoxazine
protons. Irrespective of the substituent on the nitrogen
atom, the heterocycles adopt a chair conformation in which
the phenyl moiety is in an equatorial position, as shown by
the NOE observed between 2-H and 4-H and 6-H as well
as a W coupling constant between 2-H and 4-H [J2eq,4eq
=
1.5 or 2.0 Hz] for compounds 11a–e. The cis relative orien-
tation at C-5 and C-6 was deduced from the small (2.5 or
3.0 Hz) coupling constant between 6ax-H and 5-H, whereas
a large coupling constant was observed (10.0 or 11.0 Hz) in
the trans compounds.
13C NMR (75 MHz, CDCl3):
(CH2CH2OCO), 70.0 (PEG), 128.9 (C-4), 129.7 (C-3), 134.5 (C-2),
δ = 64.1 (CH2OCO), 68.5
138.6 (C-5), 164.9 (COO-PEG), 191.1 (CHO) ppm. IR (KBr): ν =
˜
1112 (C–O), 1650 (C=C Ar), 1698 (C=O), 2628 (CO–H) 1967 (Ar),
2880 (C–H) cm–1. MS (MALDI-TOF): calcd. for C110H198NaO52
[M + Na]+ (n = 46) 2374.27; found 2374.39.
Conclusions
PEG-Bound Aldehyde 1b: PEG4000 (8.0 g, 1.9 mmol) was treated
with 4-formylbenzoic acid (2.3 g, 15.3 mmol) and N,NЈ-diisoprop-
ylcarbodiimide (3.6 mL, 23 mmol) as described for the preparation
of 1a to afford, after ultrafiltration, 6.4 g of 1b as a white powder
(75%). 1H NMR (300 MHz, CDCl3): δ = 3.45–3.88 (m, 380 H,
PEG backbone), 4.53 (t, J = 5.0 Hz, 4 H, PEG-CH2OCO), 7.97 (d,
J = 8.0 Hz, 4 H, 4-H), 8.23 (d, J = 8.0 Hz, 4 H, 3-H) 10.12 (s, 2
We have shown that a PEG-supported multistep synthe-
sis could be achieved in aqueous media under continuous
flow conditions. PEG2000 offers a good compromise be-
tween charge capacity and recovery rate by ultrafiltration.
The coupling of flow synthesis in water with ultrafiltration
reduces the use of organic solvents in both the synthetic
and purification steps, and allows safer working conditions.
We also demonstrated in the study of the Biginelli reaction
that the volume of wastewater generated by this process is
H, CHO) ppm. 13C NMR (90.56 MHz, CDCl3):
δ = 64.5
(CH2OCO), 68.8 (CH2CH2OCO), 70.4 (PEG), 129.3 (C-4), 130.1
(C-3), 134.8 (C-2), 139.1 (C-5), 165.2 (C-1), 191.5 (CHO) ppm. IR
similar to that produced in the synthesis and work-up per- (KBr): ν = 1112 (C–O), 1650 (C=C Ar), 1698 (C=O), 2628 (CO–
˜
Eur. J. Org. Chem. 2012, 2188–2200
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2193

N. Prosa, R. Turgis, R. Piccardi, M.-C. Scherrmann
FULL PAPER
H) 1967 (Ar), 2880 (C–H) cm–1. MS (MALDI-TOF): calcd. for
backbone), 4.37 (t, J = 4.0 Hz, 4 H, CH2OCO), 5.32 (d, J = 3.0 Hz,
2 H, 4-H), 7.38 (d, J = 8.0 Hz, 4 H, 3Ј-H, 5Ј-H), 7.91 (d, J =
8.0 Hz, 6 H, 2Ј-H, 6Ј-H, 1-H), 9.25 (s, 2 H, 3-H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 19.32 (CH3), 30.21 (CH3CO), 54.68 (C-
4), 63.72 (CH2OCO), 68.71 (CH2CH2OCO), 70.1 (PEG), 110.27
(C-5), 126.2 (C-2Ј, C-6Ј), 129.31 (C-1Ј), 129.9 (C-3Ј, C-5Ј), 146.34
(C-6), 147.68 (C-4Ј), 152.68 (C-2), 165.56 (COO), 194.24
(CH3CO) ppm. MS (MALDI-TOF): calcd. for C218H406N4NaO102
[M + Na]+ (n = 94) 4735.66; found 4735.43.
C206H390NaO100 [M + Na]+ (n = 94) 4487.53; found 4487.52.
PEG-Bound DHPM 2a, Batch Procedure: An aqueous 1 m solution
of HCl (30 μL) was added to a solution of 1a (588 mg, 0.25 mmol),
pentane-2,4-dione (200 μL, 2 mmol), urea (120 mg, 2 mmol) and
CuCl2·2H2O (4.3 mg, 0.025 mmol) in water (5 mL). The reaction
mixture was then stirred at room temperature overnight, diluted
with water (20 mL) and subjected to ultrafiltration. The retentate
(10 mL) was diluted with water (15 mL) and the solution was sub-
jected to ultrafiltration again. The operation was repeated to afford
2a as a white powder (465 mg, 72%).
5-Acetyl-4-(4-carboxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-
one (3): A solution of 2a (570 mg) or 2b (1.04 g) in 1 m NaOH
(5 mL) was stirred at room temperature for 24 h. A 0.5 m HCl solu-
tion was added until pH 2, the resulting suspension was stirred for
1 h at 0 °C and the precipitate was filtered. The solid (contaminated
by ca. 5% PEG) was suspended in water (40 mL), the pH was ad-
justed to 8 with 1 m NaOH and the resulting solution was subjected
to ultrafiltration. The filtrate was concentrated to 10 mL, 0.5 m
HCl was then added until pH 2 and the resulting suspension was
stirred for 1 h at 0 °C. The precipitate was filtered and washed with
water (20 mL) to afford 3 contaminated by less than 2% PEG
Flow Procedure: An aqueous solution of 1a (0.095 m, 8.4 mL) con-
taining pentane-2,4-dione (660 μL, 6.4 mmol; stream A) and an
aqueous solution of urea (0.76 m, 8.4 mL) containing CuCl2·2H2O
(27 mg, 0.16 mmol) and aqueous HCl (1 m, 0.2 mL; stream B) were
filtered with a PTFE syringe filter (13 mm, 20 μm). Streams were
mixed together at the same flow rate (0.03 mL/min) in a T-mixer
at room temperature and the resulting stream (0.06 mL/min) was
passed through the Vapourtec R4® reactor (10 mL heated volume,
167 min residence time) at 60 °C. Two 8 bar back-pressure regula-
tors were employed. The leading (ca. 1.0 mL) and trailing ends of
the plug were rejected to ensure that only the steady-state reaction
mixture was purified. The aqueous solution was collected for
185 min (11.1 mL) in an Amicon 8050 stirred cell containing water
(40 mL) and subjected to ultrafiltration. The retentate (10 mL) was
diluted with water (35 mL) and the solution was again subjected to
ultrafiltration. The operation was repeated to afford 2a as a white
1
(72 mg, 60% from 2a, 84 mg, 70% from 2b). H NMR (360 MHz,
DMSO): δ = 2.12 (s, 3 H, CH3), 2.29 (s, 3 H, CH3CO), 5.30 (d, J
= 3.0 Hz, 1 H, 4-H) 7.29 (d, J = 8.0 Hz, 2 H, 3Ј-H, 5Ј-H), 7.85 (m,
3 H, 2Ј-H, 6Ј-H, NH), 9.18 (s, 1 H, NH) ppm. 13C NMR
(75.47 MHz, DMSO): δ = 194.61 (COCH3), 168.19 (COOH),
152.54 (C-2), 148.81 (C-4Ј), 148.01 (C-6), 133.39 (C-1Ј), 129.95 (C-
2Ј, C-6Ј), 126.63 (C-3Ј, C-5Ј), 109.99 (C-5), 54.08 (C-4), 30.86
(CH3CO), 19.43 (CH3) ppm. HRMS (ESI-TOF): calcd. for
C14H13N2O4 [M – H]– 273.0875; found 273.0883.
1
powder (990 mg, 72%). H NMR (250 MHz, MeOD): δ = 2.23 (s,
4.8 H, 12-H), 2.41 (s, 4.6 H, 14-H), 3.48–3.95 (m, 200 H, PEG
backbone), 4.47 (t, J = 4.0 Hz, 4 H, CH2OCO), 5.52 (s, 1.6 H, 6-
H), 7.47 (d, J = 8 Hz, 3.2 H, 4-H), 8.04 (d, J = 8 Hz, 3.3 H, 3-
H) ppm. 13C NMR (75.47 MHz, DMSO): δ = 19.2 (C-12), 30.6 (C-
14), 53.7 (C-6), 64.2 (CH2OCO), 68.6 (CH2CH2OCO), 70.0 (PEG),
109.6 (C-11), 126.9 (C-4), 128.9 (C-5), 129.5 (C-3), 148.8 (C-10),
149.7 (C-2), 152.2 (C-8), 165.6 (C-1), 194.2 (C-13) ppm. IR (KBr):
PEG-Bound BH Adduct 4: An aqueous solution (stream A, 55 mL)
of 1a (12.5 g, 5.33 mmol) and acrylonitrile (4.6 mL, 70 mmol), and
an aqueous solution (55 mL; stream B) of 1a (4.1 g, 1.76 mmol)
and DABCO (795 mg, 7.1 mmol) were filtered through a PTFE
syringe filter (25 mm, 20 μm) before flow processing. Streams were
mixed together at the same flow rate (0.150 mL/min) in a T-mixer
at room temperature and the resulting stream (0.300 mL/min) was
passed through the Vapourtec R4® reactor (10 mL heated volume,
33 min residence time) at 60 °C. Two 8 bar back-pressure regulators
were employed. The leading sample (ca. 6.6 mL) was rejected, and
the aqueous solution was collected for 150 min (45 mL) in an Am-
icon 8200 stirred cell containing water (150 mL) and subjected to
ultrafiltration and the output of the reactor was collected for
150 min (45 mL) in a second Amicon 8200 stirred cell also contain-
ing water (150 mL). The retentate (40 mL) was diluted with water
(150 mL) and the solution was again subjected to ultrafiltration.
The operation was repeated. The ultrafiltration retentates were con-
centrated under reduced pressure to afford 12 g (84%) of 4. 1H
NMR (360 MHz, CDCl3): δ = 3.40–3.71 (m, 180 H, PEG back-
bone), 4.48 (t, J = 4.5 Hz, 4 H, CH2OCO), 5.40 (s, 2 H, 6-H), 6.04
(s, 2 H, 8a-H), 6.15 (s, 2 H, 8b-H), 7.50 (d, J3-4 = 8.0 Hz, 4 H, 4-
H), 8.07 (d, 4 H, 3-H) ppm. 13C NMR (90.56 MHz, CDCl3): δ =
64.2 (CH2OCO), 69.2 (CH2CH2OCO), 70.6 (PEG), 73.2 (C-6),
117.0 (C-9), 126.6 (C-4), 126.7 (C-8), 129.9 (C-7), 130.1 (C-3), 130.1
ν = 1107 (C–O), 1654 (C=C Ar), 1717 (C=O), 1967 (Ar), 2879
˜
(C–H), 3567 (N–H) cm–1. MS (MALDI-TOF): calcd. for
C122H214N4NaO54 [M + Na]+ (n = 46) 2622.40; found 2622.41.
PEG-Bound DHPM 2b, Batch Procedure: PEG-bound aldehyde 1b
(1.12 g, 0.25 mmol) was treated with pentane-2,4-dione (200 μL,
2 mmol), urea (120 mg, 2 mmol), CuCl2·2H2O (4.3 mg,
0.025 mmol) and 1 m aqueous HCl (30 μL) as described for the
preparation of 2a to afford, after ultrafiltration, 2b as a white solid
(946 mg, 87%).
Flow Procedure: An aqueous solution of 1b (0.061 m, 4.1 mL) con-
taining pentane-2,4-dione (310 μL, 3 mmol; stream A) and an
aqueous solution of urea (0.73 m, 4.1 mL) containing CuCl2·2H2O
(8.5 mg, 0.05 mmol) and 1 m aqueous HCl (65 μL; stream B) were
filtered through a PTFE syringe filter (13 mm, 20 μm). Streams
were mixed together at the same flow rate (0.025 mL/min) in a T-
mixer at room temperature and the resulting stream (0.05 mL/min)
was passed through the Vapourtec R4® reactor (10 mL heated vol-
ume, 200 min residence time) at 60 °C. Two 8 bar back-pressure
regulators were employed. The leading (ca. 1.0 mL) and trailing
ends of the plug were rejected to ensure that only the steady-state
reaction mixture was purified. The aqueous solution was collected
for 100 min (5 mL) in an Amicon 8050 stirred cell containing water
(20 mL) and subjected to ultrafiltration. The retentate (10 mL) was
diluted with water (15 mL) and the solution was subjected to ultra-
filtration again. The operation was repeated to afford 2b as a white
(C-5), 145.2 (C-2), 166.1 (C-1) ppm. IR (KBr): ν = 1108 (C–O),
˜
1637 (C=C Ar), 1717 (C=O), 1968 (Ar), 2224 (CN), 2874 (C–H),
3433
(O–H) cm–1.
MS
(MALDI-TOF):
calcd.
for
C116H204N2NaO52 [M + Na]+ (n = 46) 2480.22; found 2480.30.
Compound 5, Batch Procedure: Pd/C (10%, 22 mg, 0.021 mmol)
was added to a solution of 4 (250 mg, 0.105 mmol) in water
(2.5 mL). The reaction mixture was stirred at 25 °C under H2 for
2 h, diluted with water (30 mL), filtered through a short pad of
1
powder (567 mg, 79%). H NMR (300 MHz, DMSO): δ = 2.13 (s,
6 H, CH3), 2.29 (s, 6 H, CH3CO), 3.41–3.73 (m, ca. 380 H, PEG Celite and subjected to ultrafiltration. The retentate (10 mL) was
2194
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2188–2200

Soluble Polymer-Supported Flow Synthesis
diluted with water (25 mL) and the solution was subjected to ultra-
filtration again. The operation was repeated to afford 5 (225 mg,
90%) as a solid.
through a PTFE syringe filter (25 mm, 20 μm) before flow pro-
cessing. A stream (0.06 mL/min) was passed through the Vapourtec
R4® reactor (10 mL heated volume, 166 min residence time) at
150 °C. Two 8 bar back-pressure regulators were employed. The
leading sample (ca. 0.5 mL) of the plug was rejected and the solu-
tion was then collected for 108 min (6.5 mL) in an Amicon 8050
stirred cell containing water (25 mL) and subjected to ultrafiltra-
tion. The retentate (10 mL) was diluted with water (25 mL) and the
solution was subjected to ultrafiltration again. The operation was
repeated and the ultrafiltration filtrate (71.5 mL) was treated as
described before to give compound 7 contaminated by around 2%
Flow Procedure: An aqueous solution of 4 (0.041 m, 10 mL) and
ammonium formate (1.4 g, 22.6 mmol) was filtered through a
PTFE syringe filter (25 mm, 20 μm) before flow processing. A col-
umn reactor (6.6 mm id) was charged with Pd EnCat (490 mg). A
stream (0.111 mL/min) was passed through the column reactor
(3 min residence time) at 50 °C. Two 8 bar back-pressure regulators
were employed. The leading (ca. 0.5 mL) and trailing ends of the
plug were rejected so that only the steady-state reaction product
was used for establishing product yield and purity. The product
was collected for 80 min (8.9 mL) in an Amicon 8050 stirred cell
containing water (25 mL) and subjected to ultrafiltration. The re-
tentate (10 mL) was diluted with water (25 mL) and the solution
was subjected to ultrafiltration again. The operation was repeated
1
PEG (95 mg, 56%). H NMR (360 MHz, MeOD): δ = 1.30 (d, J8-
= 7.5 Hz, 1.3 H, 8-H minor), 1.36 (d, J8-7 = 7.5 Hz, 1.7 H, 8-H
7
major), 3.52–3.63 (m, 1 H, 7-H), 4.88 (d, J6-7 = 7.0 Hz, 0.4 H, 6-
H minor), 5.03 (d, J6-7 = 5.5 Hz, 0.6 H, 6-H major), 7.33 (d, J4–3
= 8.5 Hz, 1.2 H, 4-H major), 7.38 (d, J4–3 = 8.5 Hz, 0.8 H, 4-H
minor), 7.94 (d, 1.2 H, 3-H major), 7.97 (d, 0.8 H, 3-H minor) ppm.
13C NMR (90.56 MHz, CDCl3): δ = 13.7 (C-8 major), 16.5 (C-8
minor), 38.9 (C-7 major), 39.3 (C-7 minor), 76.2 (C-6 major), 76.9
(C-6 minor), 127.5 (C-4 major), 127.7 (C-4 minor), 130.7 (C-3
major), 130.9 (C-3 minor), 131.2 (C-5 major), 131.5 (C-5 minor),
148.7 (C-2 major), 149.2 (C-2 minor), 159.2 (C-9 minor), 159.5 (C-
1
to afford 5 (802 mg, 90%). H NMR (250 MHz, CDCl3): δ = 1.28
(d, J8-7 = 7.5 Hz, 6 H, 8-H), 2.95 (dq, J7-6 = 5.5 Hz), 3.54–3.91 (m,
230 H, PEG backbone), 4.49 (t, J = 4.5 Hz, 4 H, CH2OCO), 4.80
(d, 0.8 H, 6-H minor), 4.88 (d, 1 H, 6-H major), 7.46 (d, J3-4
=
8.5 Hz, 1.5 H, 4-H minor), 7.48 (d, J3-4 = 8.5 Hz, 2.5 H, 4-H
major), 8.07 (d, 4 H, 3-H) ppm. 13C NMR (90.56 MHz, CDCl3): δ
= 13.4 (C-8 minor), 14.5 (C-8 major), 33.9 (C-7 major), 34.4 (C-7
minor), 61.6 (CH2OH), 64.2 (CH2OCO), 69.1 (CH2CH2OCO), 70.6
(PEG), 72.5 (C-6 major), 73.5 (C-6 minor), 120.7 (C-9 minor),
120.9 (C-9 major), 126.4 (C-4 minor), 128.5 (C-4 major), 129.7 (C-
3 major), 129.8 (C-3 minor), 130.1 (C-5), 145.7 (C-2 major), 146.0
9 major), 169.7 (C-1) ppm. IR (KBr): ν = 1611 (C=C Ar), 1685
˜
(C=O), 1943 (Ar), 2924 (C–H), 3446 (N–H, O–H) cm–1. HRMS
(ESI): calcd. for [C11H11N4O3 – H]– 247.0837; found 247.0855.
PEG-Bound Tetrahydro-1,3-oxazines 10a–e: An aqueous solution
of 4 (0.1 m, 7.9 mL) was mixed with an aqueous solution of amine
8 (7.9 mL; 0.26 m 8a or 8b, 0.3 m 8c, 0.8 m 8d or 0.6 m for 8e) at
the same flow rate (0.167 mL/min for 8a, 8b or 8c or 0.111 mL/min
for 8d or 8e) in a T-mixer at room temperature and the resulting
stream (0.333 or 0.222 mL/min) was passed through the Vapourtec
R4® reactor (10 mL heated volume, 30 or 45 min residence time,
(C-2 minor), 166.1 (C-1) ppm. IR (KBr): ν = 1108 (C–O), 1637
˜
(C=C Ar), 1717 (C=O), 1967 (Ar), 2241 (CN), 2872 (C–H), 3466
(O–H) cm–1. MS (MALDI-TOF): calcd. for C116H208N2O52Na [M
+ Na]+ (n = 46) 2484.37; found 2484.31.
Compound 6: NaN3 (624 mg, 9.6 mmol) and NH4Cl (513 mg,
9.6 mmol) were added to a solution of 5 (1 g, 0.4 mmol) in DMF respectively) at 45 °C. Two 8 bar back-pressure regulators were em-
(10 mL). The reaction mixture was stirred at 140 °C in a screw- ployed. The leading sample (ca. 0.4 mL) of the plug was rejected
locked tube overnight, diluted with H2O and extracted with
CH2Cl2. The organic layer was dried with Na2SO4, filtered, and
concentrated to around 2 mL under reduced pressure. Et2O (ca.
20 mL) was added, under vigorous stirring, at 0 °C to precipitate
the solid, which was filtered, washed with Et2O (ca. 40 mL) and
dried under vacuum to give 727 mg of 6 (72%). 1H NMR
(250 MHz, CDCl3): δ = 1.21 (d, J8-7 = 7.5 Hz, 1.7 H, 8-H major),
1.25 (d, J8-7 = 7.5 Hz, 1.4 H, 8-H minor), 3.31–3.91 (m, 237 H,
PEG, 7-H), 4.44 (t, J = 4.0 Hz, CH2OCO), 4.81 (d, J6-7 = 7.0 Hz,
0.7 H, 6-H minor), 5.20 (m, 6-H major), 7.41 (d, J4-3 = 8.0 Hz, 2.5
and 15.4 mL of the aqueous solutions of 9a–e were collected (for
analytical purposes, some experiments were carried out in which
solutions of 9a–e were subjected to ultrafiltration, see below) and
mixed with aqueous formaldehyde (15.4 mL; 0.3 m for 9a–c, 0.4 m
for 9d–e) in a T-mixer at room temperature at the same flow rate
(0.167 mL/min for 9a–c or 0.111 mL/min for 9d and 9e) The re-
sulting stream (0.333 or 0.222 mL/min) was passed through the Va-
pourtec R4® reactor (10 mL heated volume) at 30 °C. Two 8 bar
back-pressure regulators were employed. The leading sample (ca.
1.8 mL) of the plug was rejected and the aqueous solution (29 mL)
H, 4-H), 7.94 (d, 2.6 H, 3-H) ppm. 13C NMR (62.90 MHz, CDCl3): was collected in an Amicon 8050 stirred cell containing water
δ = 12.3 (C-8 major), 16.3 (C-8 minor), 37.4 (C-7 major), 38.0 (C- (20 mL) and subjected to ultrafiltration. The retentate (10 mL) was
7 minor), 61.6 (PEG-CH2OH), 64.15 (CH2OCO), 70.6 (PEG), 73.7 diluted with water (40 mL) and the solution was subjected to ultra-
(C-6), 126.2 (C-4 major), 126.8 (C-4 minor), 129.1 (C-3 minor), filtration again. The operation was repeated. The ultrafiltration re-
129.6 (C-3 major), 129.8 (C-5), 147.3 (C-2), 159.4 (C-9), 166.4 (C- tentate was concentrated under reduced pressure to afford com-
1) ppm.
pounds 10a–e.
9a: 1H NMR (360 MHz, CDCl3): δ = 2.85–2.92 (m, 2 H, 7-H), 2.95
4-[1-Hydroxy-2-(1H-tetrazol-5-yl)propyl]benzoic Acid (7), Batch
Procedure: NaN3 (312 mg, 4.8 mmol) and ZnBr2 (135 mg,
0.6 mmol) were added to a solution of 5 (500 mg, 0.2 mmol) in
water (3 mL). The reaction mixture was stirred at 170 °C in a
screw-locked tube for 12 h, diluted with water (10 mL), filtered
through a short pad of Celite and subjected to ultrafiltration twice
(Amicon 8050 stirred cell). The ultrafiltration filtrate (40 mL) was
concentrated (5 mL) and acidified to pH 2 with 1 m HCl and ex-
tracted with AcOEt (3ϫ 5 mL). The organic layer was dried with
Na2SO4, filtered and concentrated to afford compound 7 (62 mg,
62%).
(dd, J9b-7 = 4.5, J9a-9b = 12.5 Hz, 2 H, 9b-H), 3.13 (dd, J9a-7
=
4.5 Hz, 2 H, 9a-H), 3.35–3.77 (m, 240 H, PEG backbone), 3.77 (d,
J10a-10b = 13.0 Hz, 10a-H), 3.84 (d, 2 H, 10b-H), 4.40 (t, J = 4.5 Hz,
4 H, CH2OCO), 5.00–5.02 (m, 1.5 H, 6-H), 7.16–7.32 (m, 10 H,
11-H, 12-H, 13-H, 14-H), 7.37 (d, J4-3 = 8.5 Hz, 1.3 H, 4-H minor),
7.42 (d, J4-3 = 8.5 Hz, 2.3 H, 4-H major), 7.96 (d, 3-H minor), 7.98
(d, 4 H, 3-H major) ppm. 13C NMR (90.56 MHz, CDCl3): δ = 39.1
(C-7 minor), 40.5 (C-7 major), 48.2 (C-9 minor), 49.2 (C-9 major),
53.7 (C-10 minor), 53.8 (C-10 major), 61.8 (CH2OH), 64.3
(CH2OCO), 69.3 (CH2CH2OCO), 70.7 (PEG), 73.7 (C-6 major),
74.4 (C-6 minor), 118.3 (C-8 major), 118.9 (C-8 minor), 126.0 (C-
Flow Procedure: An aqueous solution of 5 (0.0529 m, 7 mL), NaN3
(577 mg, 8.88 mmol) and ZnBr2 (417, mg, 1.85 mmol) was filtered 4 major), 126.4 (C-4 minor), 127.7 (C-14), 128.3 (C-13 major),
Eur. J. Org. Chem. 2012, 2188–2200
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2195

N. Prosa, R. Turgis, R. Piccardi, M.-C. Scherrmann
FULL PAPER
128.4 (C-13 minor), 128.6 (C-12 minor), 128.8 (C-12 major), 130.0
= 4.0 Hz, 1.5 H, 9b-H major), 3.19 (m, 1 H, 9a-H minor, 9b-H
7
(C-3), 130.2 (C-5), 138.5 (C-11 minor), 138.6 (C-11 major), 145.8 minor), 3.30 (dd, J9a-7 = 5.5 Hz, 1.5 H, 9a-H major), 3.44–3.94 (m,
(C-2), 166.2 (C-1) ppm. IR (KBr): ν = 1108 (C–O), 1653 (C=C Ar),
224 H, PEG backbone), 3.99 (d, J10a-10b = 15.5 Hz, 10a-H), 4.04
(d, 2 H, 10b-H), 4.45 (t, J = 4.5 Hz, 4 H, CH2OCO), 5.21–5.23 (m,
1.5 H, 6-H), 7.22–7.30 (m, 4 H, 12-H, 14-H), 7.50 (d, J4-3 = 8.0 Hz,
1 H, 4-H minor), 7.52 (d, J4-3 = 8.0 Hz, 3 H, 4-H major), 7.65
(ddd, J12-13 = 7.5, J13-14 = 7.5, J13-15 = 1.5 Hz, 2 H, 13-H), 8.09 (d,
4 H, 3-H), 8.57–8.60 (m, 2 H, 15-H) ppm. 13C NMR (90.56 MHz,
CDCl3): δ = 39.7 (C-7 minor), 40.5 (C-7 major), 47.9 (C-9 minor),
48.9 (C-9 major), 53.7 (C-10 minor), 54.2 (C-10 major), 61.5
(CH2OH), 64.0 (CH2OCO), 69.1 (CH2CH2OCO), 70.7 (PEG), 72.5
(C-6 major), 73.1 (C-6 minor), 118.4 (C-8 major), 119.1 (C-8
minor), 122.2 (C-12, C-14), 125.9 (C-4 major), 126.3 (C-4 minor),
129.8 (C-3, C-5), 136.7 (C-13), 146.0 (C-2), 149.0 (C-15 minor),
˜
1717 (C=O), 1968 (Ar), 2240 (CN), 2873 (C–H), 3434 (O–H) cm–1.
MS (MALDI-TOF): calcd. for C130H223N4O52 [M + H]+ (n = 46)
2672.48; found 2672.47.
1
9b: H NMR (360 MHz, CDCl3): δ = 0.96 (t, J13-12 = 7.5 Hz, 6 H,
13-H), 1.34–1.46 (m, 4 H, 12-H), 1.49–1.56 (m, 4 H, 11-H), 2.66–
2.73 (m, 2.5 H, 10-H major), 2.77–2.84 (m, 1.5 H, 10-H minor),
2.88–2.93 (m, 0.6 H, 7-H minor), 2.99–3.02 (m, 1.4 H, 7-H major),
3.04–3.09 (m, 2 H, 9b major, 9b minor), 3.16 (dd, J9a-9b = 12.5,
J9a-7 = 8.0 Hz, 0.7 H, 9a-H minor), 3.33 (dd, J9a-9b = 12.5, J9a-7
=
4.5 Hz, 1.4 H, 9a-H major), 3.44–3.86 (m, 249 H, PEG backbone),
4.49 (t, J = 4.5 Hz, 4 H, CH2OCO), 5.14–5.16 (m, 1.8 H, 6-H),
7.52 (d, J4-3 = 8.5 Hz, 1.5 H, 4-H minor), 7.55 (d, J4-3 = 8.5 Hz,
2.5 H, 4-H major), 8.09 (d, 4 H, 3-H) ppm. 13C NMR (62.90 MHz,
CDCl3): δ = 13.7 (C-13), 20.1 (C-12), 31.7 (C-11 major), 31.9 (C-
11 minor), 38.5 (C-7 minor), 39.9 (C-7 major), 49.1 (C-10), 49.3
(C-9 major), 49.7 (C-9 minor), 61.4 (CH2OH), 64.0 (CH2OCO),
69.0 (CH2CH2OCO), 70.4 (PEG), 73.5 (C-6 major), 74.3 (C-6
minor), 118.1 (C-8 major), 118.7 (C-8 minor), 125.8 (C-4 major),
126.2 (C-4 minor), 129.7 (C-3), 129.9 (C-5), 145.8 (C-2 major),
149.2 (C-15 major), 146.0 (C-11), 166.0 (C-1) ppm. IR (KBr): ν =
˜
1113 (C–O), 1613 (C=C Ar), 1715 (C=O), 1965 (Ar), 2241 (CN),
2883 (C–H), 3500 (O–H) cm–1. MS (MALDI-TOF): calcd. for
C120H205N6O48 [M + H]+ (n = 42) 2498.37; found 2498.32.
1
10a: Yield 80%. H NMR (360 MHz, CDCl3): δ = 2.83 (m, 1.5 H,
5eq-H major), 2.95 (ddd, J5ax-4ax = 11.0, J5ax-6ax = 11.0, J5ax-4eq
5.0 Hz, 0.5 H, 5ax-H minor), 3.16 (dd, J4ax-4eq = 13.5, J4ax-5eq
=
=
3.0 Hz, 1.5 H, 4ax-H major), 3.25–3.91 (m, 270 H, PEG backbone,
4eq-H minor, 4ax-H minor, 4eq-H major, 1Јa-H minor), 4.03 (d,
J1Јa-1Јb = 13.5 Hz, 0.5 H, 1Јb-H minor), 4.04 (d, J1Јa-1Јb = 13.5 Hz,
1.5 H, 1Јa-H major), 4.18 (d, 1.5 H, 1Јb-H major), 4.38 (d, J2ax-2eq
= 10.0 Hz, 1.5 H, 2ax-H major), 4.45 (t, J = 4.5 Hz, 4 H, CH2OCO),
4.51 (d, J2ax-2eq = 10.5 Hz, 0.5 H, 2ax-H minor), 4.60 (d, 0.5 H, 2eq-
H minor), 4.64 (d, 0.5 H, 6ax-H minor), 4.73 (d, J6ax-5eq = 2.5 Hz,
1.5 H, 6ax-H major), 4.79 (dd, J2eq-4eq(W) = 1.5 Hz, 1.5 H, 2eq-H
major), 7.23–7.40 (m, 10 H, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H), 7.49 (d,
J2ЈЈ-3ЈЈ = 8.0 Hz, 3 H, 2ЈЈ-H major), 7.52 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 1 H,
2ЈЈ-H minor), 8.08 (d, 4 H, 3ЈЈ-H minor, 3ЈЈ-H major) ppm. 13C
NMR (75.47 MHz, CDCl3): δ = 30.2 (C-5 minor), 32.0 (C-5
major), 51.1 (C-4 major), 51.8 (C-4 minor), 55.5 (C-1Ј minor), 56.5
(C-1Ј major), 61.7 (CH2OH), 64.3 (CH2OCO), 69.3
(CH2CH2OCO), 70.6 (PEG), 78.2 (C-6 major), 80.2 (C-6 minor),
84.0 (C-2 minor), 85.1 (C-2 major), 117.8 (CN minor), 119,1 (CN
major), 125.6 (C-2ЈЈ major), 126.5 (C-5Ј major), 127.8 (C-5Ј
minor), 128.6 (C-4Ј major), 128.7 (C-4Ј minor), 128.9 (C-3ЈЈ
major), 130.2 (C-3ЈЈ minor), 130.2 (C-1ЈЈ), 137.1 (C-2Ј minor),
137.5 (C-2Ј major), 143.1 (C-4ЈЈ minor), 143.3 (C-4ЈЈ major), 166.1
145.9 (C-2 minor), 165.9 (C-1) ppm. IR (KBr): ν = 1094 (C–O),
˜
1611 (C=C Ar), 1716 (C=O), 1957 (Ar), 2242 (CN), 2868 (C–H),
3253 (O–H) cm–1. MS (MALDI-TOF): calcd. for C116H221N4O48
[M + H]+ (n = 42) 2428.41; found 2428.37.
1
9c: H NMR (360 MHz, CDCl3): δ = 2.91–3.09 (m, 4 H, 7-H, 9a-
H), 3.23 (dd, J9b-9a = 12.5, J9b-7 = 4.5 Hz, 2 H, 9b-H), 3.30 (dd,
J10a-10b = 14.0, J10a-11 = 6.5 Hz, 2 H, 10a-H), 3.38 (dd, J10b-11
=
6.5 Hz, 2 H, 10b-H), 3.42–3.85 (m, 235 H, PEG backbone), 4.45
(t, J = 4.5 Hz, 4 H, CH2OCO), 5.08–5.12 (m, 1.7 H, 6-H), 5.14–
5.24 (m, 4 H, 12-H), 5.80–5.91 (m, 2 H, 11-H), 7.49 (d, J4-3
=
8.5 Hz, 1 H, 4-H minor), 7.51 (d, J4-3 = 8.5 Hz, 3 H, 4-H major),
8.06 (d, 3-H) ppm. 13C NMR (62.90 MHz, CDCl3): δ = 39.0 (C-7
minor), 40.3 (C-7 major), 48.0 (C-9 minor), 48.8 (C-9 major), 51.7
(C-10 minor), 51.9 (C-10 major), 61.5 (CH2OH), 64.2 (CH2OCO),
69.1 (CH2CH2OCO), 70.5 (PEG), 72.5 (C-6 major), 73.3 (C-6
minor), 117.3 (C-12), 118.3 (C-8 major), 118.8 (C-8 minor), 125.9
(C-4 major), 126.3 (C-4 minor), 129.8 (C-3, C-5), 135.3 (C-11),
145.9 (C-2), 166.1 (C-1) ppm. IR (KBr): ν = 1109 (C–O), 1647–
˜
1654 (C=C Ar), 1718 (C=O), 1957 (Ar), 2242 (CN), 2877 (C–H),
3447 (O–H) cm–1. MS (MALDI-TOF): calcd. for C114H203N4O48
[M + H]+ (n = 42) 2396.35; found 2396.34.
(COO minor), 166.2 (COO major) ppm. IR (KBr): ν = 1112 (C–
˜
O), 1647 (C=C Ar), 1718 (C=O), 1968 (Ar), 2240 (CN), 2882 (C–
H) cm–1.
1
9d: H NMR (360 MHz, CDCl3): δ = 2.31 (t, J12-10 = 2.0 Hz, 0.5
1
10b: Yield 76%. H NMR (300 MHz, CDCl3): δ = 0.88 (t, J4Ј-3Ј
=
H, 12-H minor), 2.32 (t, J12-10 = 2 Hz, 1.1 H, 12-H major), 3.00–
3.06 (m, 1.6 H, 7-H), 3.08 (dd, J9a-9b = 12.0, J9a-7 = 4.5 Hz, 1.6 H,
9a-H), 3.37 (dd, J9b-7 = 4.5 Hz, 1.6 H, 9b-H), 3.44–3.86 (m, 249 H,
PEG backbone, 10-H), 4.49 (t, J = 4.5 Hz, 4 H, CH2OCO), 5.13–
5.16 (m, 1.6 H, 6-H), 7.53 (d, J4-3 = 8.0 Hz, 1.3 H, 4-H minor),
7.55 (d, J4-3 = 8.0 Hz, 2.4 H, 4-H major), 8.10 (d, 4 H, 3-H) ppm.
13C NMR (75.47 MHz, CDCl3): δ = 37.9 (C-10 minor), 38.1 (C-10
major), 39.4 (C-7 minor), 40.5 (C-7 major), 47.3 (C-9 minor), 48.2
(C-9 major), 61.6 (CH2OH), 64.2 (CH2OCO), 69.2
(CH2CH2OCO), 70.6 (PEG), 72.5 (C-12), 72.8 (C-6 major), 73.4
(C-6 minor), 80.7 (C-11), 118.3 (C-8 major), 118.9 (C-8 minor),
126.0 (C-4 major), 126.4 (C-4 minor), 129.9 (C-3), 130.2 (C-5),
7.0 Hz), 1.29–1.39 (m, 4 H, 3Ј-H), 1.40–1.51 (m, 4 H, 2Ј-H), 2.79
(m, 2 H, 5-H), 2.82–2.94 (m, 4 H, 1Ј-H), 3.12 (dd, J4ax-4eq = 13.5,
J4ax-5eq = 3.5 Hz, 1.4 H, 4ax-H major), 3.22–3.85 (m, 256 H, PEG
backbone, 4eq-H minor, 4ax-H minor, 4eq-H major), 4.26 (d,
J2ax-2eq = 9.5 Hz, 1.3 H, 2ax-H major), 4.42 (t, J = 4.5 Hz, 4 H,
CH2OCO), 4.53 (d, J2ax-2eq = 10.5 Hz, 0.6 H, 2ax-H minor), 4.62
(d, 0.6 H, 2eq-H minor), 4.66 (d, J6ax-5eq = 2.0 Hz, 1.3 H, 6ax-H
major), 4.75 (d, 1.3 H, 2eq-H major), 7.43 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 3 H,
2ЈЈ-H major), 7.46 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 1 H, 2ЈЈ-H minor), 8.04 (d,
4 H, 3ЈЈ-H minor, 3ЈЈ-H major) ppm. 13C NMR (62.90 MHz,
CDCl3): δ = 13.9 (C-4Ј), 20.2 (C-3Ј), 30.1 (C-2Ј), 33.0 (C-5), 50.7
(C-4 minor), 51.9 (C-4 major), 52.0 (C-1Ј major), 52.6 (C-1Ј
minor), 61.7 (CH2OH), 64.2 (CH2OCO), 69.2 (CH2CH2OCO), 70.6
(PEG), 78.1 (C-6 major), 80.1 (C-6 minor), 84.1 (C-2 minor), 85.0
(C-2 major), 117.8 (CN minor), 118.9 (CN major), 125.5 (C-2ЈЈ
major), 126.4 (C-2ЈЈ minor), 130.0 (C-3ЈЈ), 130.1 (C-1ЈЈ major),
130.7 (C-1ЈЈ minor), 143.2 (C-4ЈЈ minor), 143.4 (C-4ЈЈ major), 166.0
145.9 (C-2), 166.1 (C-1) ppm. IR (KBr): ν = 1111 (C–O), 1638
˜
(C=C Ar), 1716 (C=O), 1952 (Ar), 2242 (CN), 2880 (C–H), 3449
(OH,
CϵC–H) cm–1.
MS
(MALDI-TOF):
calcd.
for
C114H199N4O48 [M + H]+ (n = 42) 2392.35; found 2392.28.
9e: 1H NMR (360 MHz, CDCl3): δ = 2.89–2.94 (m, 0.5 H, 7-H
minor), 2.99–3.03 (m, 1.5, 7-H major), 3.16 (dd, J9a-9b = 12.5, J9b-
(COO minor), 166.1 (COO major) ppm. IR (KBr): ν = 1114 (C–
˜
2196
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2188–2200

Soluble Polymer-Supported Flow Synthesis
O), 1653 (C=C Ar), 1718 (C=O), 1967 (Ar), 2240 (CN), 2885 (C–
H) cm–1.
= 8.5 Hz, 3 H, 2ЈЈ-H major), 7.52 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 1 H, 2ЈЈ-H
minor), 7.52 (d, J3Ј-4Ј = 7.5 Hz, 1.5 H, 3Ј-H major), 7.67–7.72 (m,
2 H, 4Ј-H major, 4Ј-H minor), 8.09 (d, 1 H, 3ЈЈ-H minor), 8.10 (d,
1
10c: Yield 64%. H NMR (300 MHz, CDCl3): δ = 2.84 (m, 1.2 H,
3
H, 3ЈЈ-H major), 8.57–8.59 (m, 2 H, 6Ј-H minor, 6Ј-H
5eq-H major), 2.91 (ddd, J5ax-4ax = 10.0, J5ax-6ax = 10.0, J5ax-4eq
3.5 Hz, 0.8 H, 5ax-H minor), 3.19 (dd, J4ax-4eq = 13.5, J4ax-5eq
=
=
major) ppm. 13C NMR (90.56 MHz, CDCl3): δ = 29.8 (C-5 minor),
31.1 (C-5 major), 51.6 (C-4 minor), 51.7 (C-4 major), 57.0 (C-1Ј
minor), 57.8 (C-1Ј major), 61.3 (CH2OH), 64.0 (CH2OCO), 68.9
(CH2CH2OCO), 70.3 (PEG), 77.7 (C-6 major), 79.8 (C-6 minor),
84.3 (C-2 minor), 84.9 (C-2 major), 117.4 (CN minor), 118.7 (CN
major), 122.3 (C-5Ј major), 122.5 (C-5Ј minor), 122.8 (C-3Ј minor),
122.9 (C-3Ј major), 125.4 (C-2ЈЈ major), 126.3 (C-2ЈЈ minor), 129.8
(C-3ЈЈ major), 129.9 (C-3ЈЈ minor), 129.9 (C-1ЈЈ major), 130.5 (C-
1ЈЈ minor), 136.6 (C-4Ј major), 136.7 (C-4Ј minor), 142.8 (C-4ЈЈ
minor), 143.0 (C-4ЈЈ major), 149.3 (C-6Ј), 157.3 (C-2Ј), 165.7
3.5 Hz, 1.5 H, 4ax-H major), 3.35–3.89 (m, 256 H, PEG backbone,
4eq-H minor, 4ax-H minor, 4eq-H major, 1Ј-H), 4.36 (d, J2ax-2eq
=
10.0 Hz, 1.3 H, 2ax-H major), 4.48 (t, J = 4.5 Hz, 4 H, CH2OCO),
4.60 (d, J2ax-2eq = 9.5 Hz, 0.7 H, 2ax-H minor), 4.69 (dd, J2eq-4eq(W)
= 1.5 Hz, 0.7 H, 2eq-H minor), 4.73 (d, J6ax-5eq = 2.5 Hz, 1.3 H,
6ax-H major), 4.82 (dd, J2eq-4eq(W) = 1.5 Hz, 1.3 H, 2eq-H major),
5.25 (dd, J3Јe-2Ј = 9.5, J3Јe-3Јz = 1.0 Hz, 2 H, 3Јe-H), 5.35 (dd,
J3Јz-2Ј = 15 Hz, 2 H, 3Јz-H), 5.77–5.90 (m, 2 H, 2Ј-H), 7.49 (d,
J2ЈЈ-3ЈЈ = 8.0 Hz, 2.5 H, 2ЈЈ-H major), 7.52 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 1.5
(COO) ppm. IR (KBr): ν = 1108 (C–O), 1653 (C=C Ar), 1717
˜
H, 2ЈЈ-H minor), 8.09 (d, 4 H, 3ЈЈ-H minor, 3ЈЈ-H major) ppm. 13
C
(C=O), 2240 (CN), 2876 (C–H) cm–1.
NMR (62.90 MHz, CDCl3): δ = 30.2 (C-5 minor), 32.9 (C-5
major), 51.3 (C-4 major), 51.8 (C-4 minor), 54.4 (C-1Ј minor), 55.4
(C-1Ј major), 61.7 (CH2OH), 64.3 (CH2OCO), 69.2
(CH2CH2OCO), 70.6 (PEG), 78.1 (C-6 major), 80.0 (C-6 minor),
83.9 (C-2 minor), 84.7 (C-2 major), 118.8 (CN), 119.0 (C-3Ј), 125.6
(C-2ЈЈ major), 126.5 (C-2ЈЈ minor), 130.1 (C-3ЈЈ), 130.2 (C-1ЈЈ),
134.5 (C-2), 143.1 (C-4ЈЈ minor), 143.3 (C-4ЈЈ major), 166.1
General Procedure for the Synthesis of Tetrahydro-1,3-oxazines 11a–
e: Compound 10 (0.68 mmol) was added to a 0.1 m solution of
MeONa in MeOH (2 mL). The reaction mixture was stirred at
room temperature for 3 h and a 0.1 m solution of CH3COOH in
MeOH (2 mL) was added and the mixture was stirred at room tem-
perature for 10 min. Et2O (25 mL) was added, under vigorous stir-
ring, at room temperature to precipitate the PEG, which was fil-
tered and washed with Et2O. The solution was concentrated under
reduced pressure and the residue was purified by flash chromatog-
raphy.
(COO) ppm. IR (KBr): ν = 1113 (C–O), 1614 (C=C Ar), 1718
˜
(C=O), 1969 (Ar), 2233 (CN), 2881 (C–H) cm–1.
1
10d: Yield 75%. H NMR (360 MHz, CDCl3): δ = 2.35 (t, J3Ј-1Ј
=
2.5 Hz, 1 H, 3Ј-H major), 2.39 (t, J3Ј-1Ј = 2.5 Hz, 0.5 H, 3Ј-H
minor), 2.95 (m, 1.3 H, 5eq-H major), 3.04 (ddd, J5ax-4ax = 11.5,
J5ax-6ax = 10.5, J5ax-4eq = 4.5 Hz, 0.7 H, 5ax-H minor), 3.31 (dd,
J4ax-4eq = 13.0, J4ax-5eq = 3.5 Hz, 1.6 H, 4ax-H major), 3.37–3.88
(m, 261 H, PEG backbone, 4eq-H minor, 4ax-H minor, 4eq-H major,
1Ј-H), 4.40 (d, J2ax-2eq = 10.0 Hz, 1.3 H, 2ax-H major), 4.49 (t, J =
4.5 Hz, 4 H, CH2OCO), 4.53 (d, J2ax-2eq = 10.5 Hz, 0.7 H, 2ax-H
minor), 4.61 (d, 0.5 H, 6ax-H minor), 4.71 (d, J6ax-5eq = 2.5 Hz, 1.3
H, 6ax-H major), 4.77 (dd, J2eq-4eq(W) = 2.0 Hz, 0.6 H, 2eq-H
minor), 4.87 (dd, J2eq-4eq(W) = 1.5 Hz, 1.3 H, 2eq-H major), 7.50 (d,
J2ЈЈ-3ЈЈ = 8.5 Hz, 2.5 H, 2ЈЈ-H major), 7.53 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 1.5
3-Benzyl-5-cyano-6-(4-methoxycarbonylphenyl)-tetrahydro-2H-1,3-
oxazine (11a): Flash chromatography of the residue (AcOEt/petro-
leum ether, 2:8) afforded first cis-11a (160 mg, 35%) as a white
solid (m.p. 144–147 °C). 1H NMR (360 MHz, CDCl3): δ = 2.84 (m,
1 H, 5-H), 3.21 (dd, J4ax-4eq = 12, J4ax-5eq = 3.0 Hz, 1 H, 4ax-H),
3.52 (dm, 1 H, 4eq-H), 3.94 (s, 3 H, CH3), 4.10 (d, J1Јa-1Јb = 13.0 Hz,
1 H, 1Јa-H), 4.23 (d, 1 H, 1Јb-H), 4.43 (d, J2ax-2eq = 9.0 Hz, 1 H,
2ax-H), 4.75 (d, J6ax-5eq = 2.5 Hz, 1 H, 6ax-H), 4.84 (dd, J2eq-4eq(W)
= 1.5 Hz, 1 H, 2eq-H), 7.29–7.45 (m, 5 H, ArЈ), 7.54 (d, J2ЈЈ-3ЈЈ
=
8.5 Hz, 2 H, 2ЈЈ-H), 8.12 (d, 2 H, 3ЈЈ-H) ppm. 13C NMR
(62.90 MHz, CDCl3): δ = 32.9 (C-5), 51.1 (C-4), 52.1 (CH3), 56.4
(C-1Ј), 78.2 (C-6), 85.1 (C-2), 119.0 (CN), 125.5 (C-2ЈЈ), 127.5 (C-
5Ј), 128.5 (C-4Ј), 128.8 (C-3Ј), 130.0 (C-3ЈЈ), 130.3 (C-1ЈЈ), 137.5
H, 2ЈЈ-H minor), 8.11 (d, 4 H, 3ЈЈ-H minor, 3ЈЈ-H major) ppm. 13
C
NMR (90.56 MHz, CDCl3): δ = 30.6 (C-5 minor), 33.5 (C-5
major), 40.9 (C-1Ј minor), 41.8 (C-1Ј major), 51.1 (C-4 major),
51.4 (C-4 minor), 61.6 (CH2OH), 64.2 (CH2OCO), 69.1
(CH2CH2OCO), 70.5 (PEG), 73.9 (C-3Ј major), 74.0 (C-3Ј minor),
77.7 (C-2Ј), 78.0 (C-6 major), 79.8 (C-6 minor), 83.7 (C-2 minor),
84.2 (C-2 major), 117.3 (CN minor), 118.5 (CN major), 125.5 (C-
2ЈЈ major), 126.4 (C-2ЈЈ minor), 129.9 (C-3ЈЈ major), 130.0 (C-3ЈЈ
minor), 130.2 (C-1ЈЈ), 142.7 (C-4ЈЈ minor), 142.8 (C-4ЈЈ major),
(C-2Ј), 143.1 (C-4ЈЈ), 166.7 (COOMe) ppm. IR (KBr): ν = 1614
˜
(C=C Ar), 1719 (C=O), 2076 (Ar), 2234 (CN), 2864 (C–H) cm–1.
HRMS (ESI): calcd. for [C20H20N2O3 + Na]+ 359.1372; found
359.1352.
1
Eluted second was trans-11a (119 mg, 26%) as a colourless oil. H
NMR (250 MHz, CDCl3): δ = 2.97 (ddd, J5ax-4ax = 11.0, J5ax-6ax
=
165.9 (COO) ppm. IR (KBr): ν = 1108 (C–O), 1613 (C=C Ar),
˜
11.0, J5ax-4eq = 5.5 Hz, 1 H, 5ax-H), 3.31 (dd, J4ax-4eq = 14.0 Hz, 1
H, 4ax-H), 3.41 (ddd, J4eq-2eq = 1.5 Hz, 1 H, 4eq-H), 3.90 (d,
J1Јa-1Јb = 13.5 Hz, 1 H, 1Јa-H), 3.92 (s, 3 H, CH3), 4.04 (d, 1 H,
1Јb-H), 4.52 (d, J2ax-2eq = 10.5 Hz, 1 H, 2ax-H), 4.61 (d, 1 H, 6ax-
H), 4.66 (dd, 1 H, 2eq-H), 7.27–7.39 (m, 5 H, ArЈ), 7.53 (d, J2ЈЈ-3ЈЈ
= 8.5 Hz, 2 H, 2ЈЈ-H), 8.08 (d, 2 H, 3ЈЈ-H) ppm. 13C NMR
(90.56 MHz, CDCl3): δ = 30.3 (C-5), 52.1 (C-4), 52.4 (CH3), 55.7
(C-1Ј), 80.4 (C-6), 84.3 (C-2), 117.9 (CN), 126.7 (C-2ЈЈ), 128.0 (C-
5Ј), 128.9 (C-4Ј), 129.0 (C-3Ј), 130.3 (C-3ЈЈ), 131.0 (C-1ЈЈ), 137.3
1719 (C=O), 1957 (Ar), 2242 (CN), 2870 (C–H), 3511 (CϵC–
H) cm–1.
1
10e: Yield 85%. H NMR (360 MHz, CDCl3): δ = 2.90 (m, 1.5 H,
5eq-H major), 3.07 (ddd, J5ax-4ax = 10.0, J5ax-6ax = 10.0, J5ax-4eq
5.5 Hz, 0.5 H, 5ax-H minor), 3.27 (dd, J4ax-4eq = 13.5, J4ax-5eq
=
=
3.5 Hz, 1.5 H, 4ax-H major), 3.37–3.44 (m, 2 H, 4ax-H minor, 4eq-
H minor), 3.49 (dm, 1.5 H, 4eq-H major), 3.53–3.87 (m, 237 H,
PEG backbone), 4.08 (d, J1Јa-1Јb = 14.0 Hz, 0.5 H, 1Јa-H minor),
4.19 (d, 0.5 H, 1Јb-H minor), 4.20 (d, J1Јa-1Јb = 14.0 Hz, 1.5 H, 1Јa-
H major), 4.26 (d, 1.5 H, 1Јb-H major), 4.43 (d, J2ax-2eq = 9.5 Hz,
1.5 H, 2ax-H major), 4.45 (t, J = 4.5 Hz, 4 H, CH2OCO), 4.60 (d,
J2ax-2eq = 10.5 Hz, 0.5 H, 2ax-H minor), 4.62 (d, 0.5 H, 6ax-H
(C-2Ј), 143.2 (C-4ЈЈ), 166.7 (COOMe) ppm. IR (KBr): ν = 1614
˜
(C=C Ar), 1719 (C=O), 2076 (Ar), 2234 (CN), 2864 (C–H) cm–1.
HRMS (ESI): calcd. for [C20H20N2O3 + H]+ 337.1547; found
337.1541.
minor), 4.71 (dd, J2eq-4eq(W) = 1.0 Hz, 0.5 H, 2eq-H minor), 4.74 (d, 3-Butyl-5-cyano-6-(4-methoxycarbonylphenyl)tetrahydro-2H-1,3-ox-
J6ax-5eq = 3.0 Hz, 1.5 H, 6ax-H major), 4.86 (dd, J2eq-4eq(W) azine (11b): Flash chromatography of the residue (Et2O/petroleum
=
1.5 Hz, 1.5 H, 2eq-H major), 7.18–7.23 (m, 2 H, 5Ј-H major, 5Ј-H ether, 2:3 then 7:3) afforded first cis-11b (162 mg, 39%) as a white
1
minor), 7.40 (d, J3Ј-4Ј = 8.0 Hz, 0.5 H, 3Ј-H minor), 7.50 (d, J2ЈЈ-3ЈЈ solid (m.p. 105–107 °C). H NMR (250 MHz, CDCl3): δ = 0.94 (t,
Eur. J. Org. Chem. 2012, 2188–2200
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2197

N. Prosa, R. Turgis, R. Piccardi, M.-C. Scherrmann
J4Ј-3Ј = 7.0 Hz, 3 H, 4Ј-H), 1.34–1.45 (m, 2 H, 3Ј-H), 1.46–1.58 (m, petroleum ether, 7:3) afforded first cis-11d (143 mg, 37%) as a white
FULL PAPER
1
2 H, 2Ј-H), 2.83 (m, 1 H, 5-H), 2.86–3.02 (m, 2 H, 1Ј-H), 3.18 (dd,
J4ax-4eq = 13.0, J4ax-5eq = 3.5 Hz, 1 H, 4ax-H), 3.53 (dm, 1 H, 4eq- J3Ј-1Ј = 2.5 Hz, 1 H, 3Ј-H) 2.91 (m, 1 H, 5-H), 3.26 (dd, J4ax-4eq
H), 3.92 (s, 3 H, CH3), 4.31 (d, J2ax-2eq = 10.0 Hz, 1 H, 2ax-H), 4.71 13.0, J4ax-5eq = 3.5 Hz, 1 H, 4ax-H), 3.49 (dm, 1 H, 4eq-H), 3.71
(d, J6ax-5eq = 3.0 Hz, 1 H, 6ax-H), 4.82 (dd, J2eq-4eq(W) = 1.5 Hz, 1 (dd, J1Јa-1Јb = 13.5 Hz, 1 H, 1Јa-H), 3.80 (dd, 1 H, 1Јb-H), 3.89 (s,
H, 2eq-H), 7.50 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 2 H, 2ЈЈ-H), 8.09 (d, 2 H, 3ЈЈ- 3 H, CH3), 4.35 (d, J2ax-2eq = 9.5 Hz, 1 H, 2ax-H), 4.66 (d, J6ax-5eq
H) ppm. 13C NMR (62.90 MHz, CDCl3): δ = 13.9 (C-4Ј), 20.2 (C- = 2.5 Hz, 1 H, 6ax-H), 4.83 (dd, J2eq-4eq(W) = 1.5 Hz, 1 H, 2eq-H),
solid (m.p. 138–140 °C). H NMR (360 MHz, CDCl3): δ = 2.31 (t,
=
3Ј), 30.1 (C-2Ј), 33.1 (C-5), 52.0 (C-4, C-1Ј, CH3), 78.2 (C-6), 85.0
(C-2), 118.8 (CN), 125.5 (C-2ЈЈ), 129.9 (C-3ЈЈ), 130.2 (C-1ЈЈ), 143.2
7.46 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 2 H, 2ЈЈ-H), 8.05 (d, 2 H, 3ЈЈ-H) ppm. 13
C
NMR (62.90 MHz, CDCl3): δ = 33.8 (C-5), 42.1 (C-1Ј), 51.4 (C-
4), 52.3 (CH3), 73.9 (C-3Ј), 77.9 (C-6), 78.2 (C-2Ј), 84.5 (C-2), 118.7
(C-4ЈЈ), 166.7 (COOMe) ppm. IR (KBr): ν = 1613 (C=C Ar), 1716
˜
(C=O), 1967 (Ar), 2244 (CN), 2868 (C–H) cm–1. HRMS (ESI): (CN), 125.7 (C-2ЈЈ), 130.1 (C-3ЈЈ), 130.5 (C-1ЈЈ), 142.9 (C-4ЈЈ),
calcd. for [C17H22N2O3 + H]+ 303.1709; found 303.1703.
166.7 (COOMe) ppm. IR (KBr): ν = 1613 (C=C Ar), 1710 (C=O),
˜
1949 (Ar), 2240 (CN), 2836 (C–H), 3408 (CϵC–H) cm–1. HRMS
1
Eluted second was trans-11b (63 mg, 15%) as a colourless oil. H
NMR (360 MHz, CDCl3): δ = 0.97 (t, J4Ј-3Ј = 7.5 Hz, 3 H, 4Ј-H),
1.34–1.44 (m, 2 H, 3Ј-H), 1.48–1.56 (m, 2 H, 2Ј-H), 2.67–2.74 (m,
(ESI): calcd. for [C16H16N2O3 + Na]+ 307.1053; found = 307.1053.
1
Eluted second was trans-11d (77 mg, 20%) as a colourless oil. H
1 H, 1Јa-H), 2.87–2.97 (m, 2 H, 5-H, 1Јb-H), 3.33 (dd, J4ax-4eq
=
NMR (360 MHz, CDCl3): δ = 2.39 (t, J3Ј-1Ј = 2.5 Hz, 1 H, 3Ј-H),
3.02 (ddd, J5ax-4ax = 11.5, J5ax-6ax = 10.0, J5ax-4eq = 4.5 Hz, 1 H,
13.5, J4ax-5 = 11.5 Hz, 1 H, 4ax-H), 3.47 (ddd, J4eq-5 = 4.0,
J4eq-2eq(W) = 1.5 Hz, 1 H, 4eq-H), 3.94 (s, 3 H, CH3), 4.48 (d,
J2ax-2eq = 10.5 Hz, 1 H, 2ax-H), 4.60 (d, J6ax-5 = 10.0 Hz, 1 H, 6ax-
H), 4.69 (dd, 1 H, 2eq-H), 7.53 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 2 H, 2ЈЈ-H),
8.09 (d, 2 H, 3ЈЈ-H) ppm. 13C NMR (90.56 MHz, CDCl3): δ = 14.1
(C-4Ј), 20.4 (C-3Ј), 30.3 (C-2Ј, C-5), 50.9 (C-1Ј), 52.4 (CH3), 52.8
(C-4), 80.3 (C-6), 84.3 (C-2), 118.0 (CN), 126.7 (C-2ЈЈ), 130.2 (C-
3ЈЈ), 130.9 (C-1ЈЈ), 143.3 (C-4ЈЈ), 166.8 (COOMe) ppm. IR (KBr):
5
ax-H), 3.34 (dd, J4ax-4eq = 13.5 Hz, 1 H, 4ax-H), 3.64 (ddd,
J4eq-2eq(W) = 2.0 Hz, 1 H, 4eq-H), 3.65 (dd, J1Јa-1Јb = 17.0 Hz, 1 H,
1Јa-H), 3.70 (dd, 1 H, 1Јb-H), 3.94 (s, 3 H, CH3), 4.50 (d, J2ax-2eq
= 10.5 Hz, 1 H, 2ax-H), 4.57 (d, 1 H, 6ax-H), 4.74 (dd, 1 H, 2eq-H),
7.50 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 2 H, 2ЈЈ-H), 8.06 (d, 2 H, 3ЈЈ-H) ppm. 13
C
NMR (62.90 MHz, CDCl3): δ = 30.9 (C-5), 41.3 (C-1Ј), 51.7 (C-
4), 52.4 (CH3), 74.1 (C-3Ј), 79.1 (C-2Ј), 80.2 (C-6), 84.0 (C-2), 117.6
(CN), 126.7 (C-2ЈЈ), 130.2 (C-3ЈЈ), 131.0 (C-1ЈЈ), 142.8 (C-4ЈЈ),
ν = 1613 (C=C Ar), 1716 (C=O), 1967 (Ar), 2244 (CN), 2868 (C–
˜
H) cm–1. HRMS (ESI): calcd. for [C17H22N2O3 + H]+ 303.1703;
found 303.1697.
166.7 (COOMe) ppm. IR (KBr): ν = 1613 (C=C Ar), 1710 (C=O),
˜
1949 (Ar), 2240 (CN), 2836 (C–H), 3408 (CϵC–H) cm–1. HRMS
(ESI): calcd. for [C16H16N2O3 + Na]+ 307.1053; found 307.1048.
3-Allyl-5-cyano-6-(4-methoxycarbonylphenyl)tetrahydro-2H-1,3-
oxazine (11c): Flash chromatography of the residue (Et2O/petro-
leum ether, 3:7 then 7:3) afforded first cis-11c (171 mg, 44%) as a
white solid (m.p. 121–123 °C). 1H NMR (360 MHz, CDCl3): δ =
2.84 (m, 1 H, 5-H), 3.21 (dd, J4ax-4eq = 14.0, J4ax-5eq = 3.5 Hz, 1 H,
5-Cyano-6-(4-methoxycarbonylphenyl)-3-(2-pyridylmethyl)tetrahydro-
2H-1,3-oxazine (11e): Flash chromatography of the residue
(AcOEt) afforded first cis-11e (183 mg, 40%) as a white solid (m.p.
149–151 °C). 1H NMR (360 MHz, CDCl3): δ = 2.86 (m, 1 H, 5-
H), 3.24 (dd, J4ax-4eq = 13.5, J4ax-5eq = 3.5 Hz, 1 H, 4ax-H), 3.48
(dm, 1 H, 4eq-H), 3.89 (s, 3 H, CH3), 4.18 (d, J1Јa-1Јb = 14.5 Hz, 1
H, 1Јa-H), 4.24 (d, 1 H, 1Јb-H), 4.41 (d, J2ax-2eq = 10.0 Hz, 1 H,
2ax-H), 4.72 (d, J6ax-5eq = 2.5 Hz, 1 H, 6ax-H), 4.81 (dd, J2eq-4eq(W)
= 1.5 Hz, 1 H, 2eq-H), 7.18 (dd, J5Ј-4Ј = 7.5, J5Ј-6Ј = 5.0 Hz, 1 H,
5Ј-H), 7.49 (d, J2ЈЈ-3ЈЈ = 8.5 Hz, 2 H, 2ЈЈ-H), 7.52 (d, J3Ј-4Ј = 7.5 Hz,
1 H, 3Ј-H), 7.68 (ddd, J4Ј-6Ј = 1.5 Hz, 1 H, 4Ј-H), 8.07 (d, 2 H, 3ЈЈ-
H), 8.57 (dd, 1 H, 6Ј-H) ppm. 13C NMR (90.56 MHz, CDCl3): δ =
33.6 (C-5), 52.1 (C-4), 52.3 (CH3), 58.2 (C-1Ј), 78.3 (C-6), 85.3 (C-
2), 119.0 (CN), 122.7 (C-5Ј), 123.4 (C-3Ј), 125.7 (C-2ЈЈ), 130.2 (C-
3ЈЈ), 130.5 (C-1ЈЈ), 137.0 (C-4Ј), 143.2 (C-4ЈЈ), 149.8 (C-6Ј), 157.6
4ax-H), 3.58 (dm, 1 H, 4eq-H), 3.61 (dd, J1Јa-1Јb = 13.5, J1Јa-2Ј
=
6.5 Hz, 1 H, 1Јa-H), 3.65 (dd, J1Јb-2Ј = 6.5 Hz, 1 H, 1Јb-H), 3.94 (s,
3 H, CH3), 4.37 (d, J2ax-2eq = 10.0 Hz, 1 H, 2ax-H), 4.73 (d, J6ax-5eq
= 3.0 Hz, 1 H, 6ax-H), 4.84 (dd, J2eq-4eq(W) = 2.0 Hz, 1 H, 2eq-H),
5.25 (dd, J3Јe-2Ј = 10.5, J3Јe-3Јz = 1.0 Hz, 1 H, 3Јe-H), 5.36 (dd,
J3Јz-2Ј = 17.0 Hz, 1 H, 3Јz-H), 5.85 (dddd, 1 H, 2Ј-H), 7.51 (d,
J2ЈЈ-3ЈЈ = 8.0 Hz, 2 H, 2ЈЈ-H), 8.10 (d, 2 H, 3ЈЈ-H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 33.1 (C-5), 51.5 (C-4), 52.3 (CH3), 55.6
(C-1Ј), 78.4 (C-6), 84.9 (C-2), 119.0 (C-3Ј), 119.1 (CN), 125.7 (C-
2ЈЈ), 130.2 (C-3ЈЈ), 130.5 (C-1ЈЈ), 134.6 (C-2Ј), 143.3 (C-4ЈЈ), 166.9
(COOMe) ppm. IR (KBr): ν = 1645 (C=C Ar), 1715 (C=O), 1955
˜
(Ar), 2236 (CN), 2852 (C–H) cm–1. HRMS (ESI): calcd. for
[C16H18N2O3 + H]+ 287.1396; found 287.1389.
(C-2Ј), 166.8 (COOMe) ppm. IR (KBr): ν = 1614 (C=C Ar), 1720
˜
(C=O), 1936 (Ar), 2236 (CN), 2884 (C–H) cm–1. HRMS (ESI):
calcd. for [C19H20N3O3 + H]+ 338.1499; found 338.1495.
1
Eluted second was trans-11c (85 mg, 22%) as a colourless oil. H
NMR (360 MHz, CDCl3): δ = 2.93 (ddd, J5ax-4ax = 11.5, J5ax-6ax
=
1
10.0, J5ax-4eq = 4.0 Hz, 1 H, 5ax-H), 3.32 (dd, J4ax-4eq = 13.5 Hz, 1
H, 4ax-H), 3.41 (dd, J1Јa-1Јb = 13.5, J1Јa-2Ј = 6.5 Hz, 1 H, 1Јa-H),
Eluted second was trans-11e (92 mg, 20%) as a colourless oil. H
NMR (360 MHz, CDCl3): δ = 3.05 (ddd, J5ax-4ax = 10.0, J5ax-6ax
=
3.50 (ddd, J4eq-2eq(W) = 1.5 Hz, 1 H, 4eq-H), 3.53 (dd, J1Јb-2Ј
=
10.0, J5ax-4eq = 5.5 Hz, 1 H, 5ax-H), 3.34–3.44 (m, 2 H, 4ax-H, 4eq-
H), 3.91 (s, 3 H, CH3), 4.08 (d, J1Јa-1Јb = 14.0 Hz, 1 H, 1Јa-H), 4.19
(d, 1 H, 1Јb-H), 4.60 (d, J2ax-2eq = 10.5 Hz, 1 H, 2ax-H), 4.62 (d, 1
H, 6ax-H), 4.71 (dd, J2eq-4eq(W) = 1 Hz, 1 H, 2eq-H), 7.21 (dd, J5Ј-4Ј
= 8.0, J5Ј-6Ј = 5.5 Hz, 1 H, 5Ј-H), 7.40 (d, J3Ј-4Ј = 7.5 Hz, 1 H, 3Ј-
H), 7.52 (d, J2ЈЈ-3ЈЈ = 8.0 Hz, 2 H, 2ЈЈ-H), 7.69 (ddd, J4Ј-6Ј = 1.5 Hz,
1 H, 4Ј-H), 8.07 (d, 2 H, 3ЈЈ-H), 8.57 (dd, 1 H, 6Ј-H) ppm. 13C
NMR (90.56 MHz, CDCl3): δ = 30.2 (C-5), 52.0 (C-4), 52.4 (CH3),
57.5 (C-1Ј), 80.3 (C-6), 84.7 (C-2), 117.8 (CN), 122.9 (C-5Ј), 123.1
(C-3Ј), 126.7 (C-2ЈЈ), 130.2 (C-3ЈЈ), 130.9 (C-1ЈЈ), 137.1 (C-4Ј),
143.1 (C-4ЈЈ), 149.8 (C-6Ј), 157.6 (C-2Ј), 166.8 (COOMe) ppm. IR
6.5 Hz, 1 H, 1Јb-H), 3.95 (s, 3 H, CH3), 4.51 (d, J2ax-2eq = 10.5 Hz,
1 H, 2ax-H), 4.62 (d, 1 H, 6ax-H), 4.71 (dd, 1 H, 2eq-H), 5.27 (dd,
J3Јe-2Ј = 10.0, J3Јe-3Јz = 1.0 Hz, 1 H, 3Јe-H), 5.32 (dd, J3Јz-2Ј
17.0 Hz, 1 H, 3Јz-H), 5.85 (dddd, 1 H, 2Ј-H), 7.54 (d, J2ЈЈ-3ЈЈ
=
=
8.5 Hz, 2 H, 2ЈЈ-H), 8.10 (d, 2 H, 3ЈЈ-H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 30.3 (C-5), 51.9 (C-4), 52.4 (CH3), 54.5
(C-1Ј), 80.2 (C-6), 84.0 (C-2), 117.9 (CN), 119.1 (C-3Ј), 126.7 (C-
2ЈЈ), 130.2 (C-3ЈЈ), 130.9 (C-1ЈЈ), 134.5 (C-2Ј), 143.2 (C-4ЈЈ), 166.9
(COOMe) ppm. IR (KBr): ν = 1645 (C=C Ar), 1715 (C=O), 1955
˜
(Ar), 2236 (CN), 2852 (C–H) cm–1. HRMS (ESI): calcd. for
[C16H18N2O3 + H]+ 287.1390; found 287.1392.
(KBr): ν = 1614 (C=C Ar), 1720 (C=O), 1936 (Ar), 2236 (CN),
˜
5-Cyano-6-(4-methoxycarbonylphenyl)-3-propargyltetrahydro-2H-
1,3-oxazine (11d): Flash chromatography of the residue (AcOEt/
2884 (C–H) cm–1. HRMS (ESI): calcd. for [C19H20N3O3 + H]+
338.1499; found 338.1498.
2198
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2188–2200

Soluble Polymer-Supported Flow Synthesis
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Supporting Information (see footnote on the first page of this arti-
cle): Analytical data of by-products obtained during PEG esterifi-
cation, 1H NMR, 13C NMR and MALDI-TOF mass spectra of
the prepared compounds.
Acknowledgments
We thank the Ministère de l’Enseignement Supérieur et de la
Recherche, the Centre National de la Recherche Scientifique
(CNRS), and the Université Paris-Sud for financial support.
[15]
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X.-F. Lin, J. Zhang, S.-L. Cui, Y.-G. Wang, Synthesis 2003, 10,
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Received: November 30, 2011
Published Online: February 22, 2012
2200
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