Development and application of allyl, 2-sulfonylethyl and 2-thioethyl carbamate linkers for solid phase N-acyliminium ion chemistry

Article abstract of DOI:10.1039/b100998m

We have evaluated the allyl, 2-sulfonylethyl (SEC) and 2-thioethyl (TEC) carbamate linker systems for their application in solid supported N-acyliminium ion chemistry. As model reactions the syntheses of both homoallylic amines (via a three component prot

Full text of DOI:10.1039/b100998m

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Development and application of allyl, 2-sulfonylethyl and
-thioethyl carbamate linkers for solid phase N-acyliminium
ion chemistry
2
1
a
a
a
b
Jan H. van Maarseveen, Wim J. N. Meester, Johan J. N. Veerman, Chris G. Kruse,
c
a
a
Pedro H. H. Hermkens, Floris P. J. T. Rutjes* and Henk Hiemstra*
a
Laboratory of Organic Chemistry, Institute of Molecular Chemistry,
University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS, Amsterdam, The Netherlands
Solvay Pharmaceuticals Research Laboratories, PO Box 900, 1380 DA, Weesp,
The Netherlands
b
c
Lead Discovery Unit, NV Organon, PO Box 20, 5240 BH, Oss, The Netherlands
Received (in Cambridge, UK) 29th January 2001, Accepted 8th March 2001
First published as an Advance Article on the web 4th April 2001
We have evaluated the allyl, 2-sulfonylethyl (SEC) and 2-thioethyl (TEC) carbamate linker systems for their
application in solid supported N-acyliminium ion chemistry. As model reactions the syntheses of both homoallylic
amines (via a three component protocol starting from an immobilised primary carbamate) and 2-substituted
pyrrolidines (via carbamate bound 4,4-diethoxy-2-phenylbutylamine) were conducted. The required precursor
p-nitrophenyl carbonate resins were prepared in high yields from cheap starting materials. All linkers proved to
be stable under the required cationic reaction conditions. A serious drawback of the allyl carbamate linker is the
tedious work up procedure which is required for the removal of the remains of the cleavage cocktail. The SEC linker
is excellently stable to both Lewis and protic acidic conditions combined with a moderate base stability thus allowing
the use of amines as reactants or bases in subsequent reactions. Cleavage of SEC linker bound amines was easily
effected by treatment of the resins with a cocktail of 1 M NaOMe in THF–MeOH (2 : 1). The widest synthetic
scope was found with the TEC linker which combined a sufficient stability against the cationic conditions required
for N-acyliminium ion chemistry with complete stability under basic conditions. Cleavage of TEC linker bound
amines could be effected by treatment with strong acid or by oxidation of the sulfide to the sulfone (to give the
SEC linker) followed by addition of the basic cleavage cocktail.
Introduction
The unsatisfactory yields were mainly attributed to the
limited stability of the p-alkoxybenzyl carbamate linker
The majority of currently marketed drugs contain nitrogen
atoms. Synthetic methodology for functionalisation of nitrogen
atoms, such as amide formation, reductive amination or simple
alkylation, is very important and, as a result, many solid phase
synthetic approaches focus on diversification via such function-
2
towards BF ؒOEt2 leading to premature cleavage of the
3
product. The second application involved the preparation of
-substituted N-methylpyrrolidines 9 in high yields via the
immobilised 4-amino acetals 6 (L = C H ) (route B, Scheme 1).
2
2
4
Subjection of 6 to BF ؒOEt led to the cyclic N-acyliminium ion
1
3
2
alisations. We are especially interested in functionalisation of
7
which provided the adduct 8. The 2-substituted pyrrol-
2
the nitrogen atom via N-acyliminium ion chemistry, which
idine products were reductively cleaved by LiAlH treatment
4
allows the introduction of C-nucleophiles such as silyl enol
ethers and allylsilanes. The resulting CO or CC double bond,
respectively, is then amenable to additional diversification.
These reasons underline the importance of translating N-
acyliminium ion chemistry to the solid phase in order to facili-
tate its application in automated synthesis. A straightforward
solid phase approach would involve immobilising the precursor
amines as carbamate linkages, so that the activating acyl group
is part of the linker system. Liberation of the functionalised
amines should be easily accomplished by cleavage of the carb-
amate linkers. In solution phase N-acyliminium ion reactions a
range of carbamates have been successfully used for function-
alisation but most of these carbamates have drawbacks that
render them incompatible for application on the solid phase.
In two previous papers we described the first applications of
resulting in the methylated amine 9. Unfortunately, all attempts
to cleave the carbamate via hydrolytic means failed.
The aforementioned drawbacks of both the p-alkoxybenzyl
(
Wang) and ethyl carbamate linkers prompted us to search for
5
alternative carbamate linker systems.
Due to their generally high stability under various con-
ditions, carbamates which are based on the assisted cleavage
6
principle particularly drew our attention. In this paper, we
describe the synthesis of the Pd(0) labile allyl carbamate 10, the
base labile 2-alkylsulfonylethyl carbamate (SEC) 11 and the
SEC precursor 2-alkylthioethyl carbamate (TEC) 12 linkers
and their application in solid supported N-acyliminium ion
chemistry (Chart 1).
3
N-acyliminium ion chemistry on a solid support. The first
Results and discussion
4
article described a one-pot three component reaction to
Synthesis of the p-nitrophenyl carbonate based carbamate
precursor resins
prepare homoallylic amines via the corresponding cations
in moderate yields from an immobilised primary carbamate,
aromatic aldehydes and allylsilanes by using BF ؒOEt as the
Starting from Merrifield resin 14 the olefinic functionality was
3
2
Lewis acid (route A, Scheme 1).
introduced using allylmagnesium chloride according to a litera-
9
94
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b100998m

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Scheme 1
Scheme 2
Scheme 3
Allyl carbamate linker
Because the Alloc protective group is both acid and base stable,
and can be deprotected using mild and selective conditions, we
decided to develop a similar allyl carbamate linker. Although
13
several allyl ester linkers have been described only one
example of an allyl carbamate linker has been reported by
Guibé and Undén, based on an amino acid spacer moiety and
Chart 1
7
ture procedure (Scheme 2). The resulting olefin 15 was reacted
with 1,4-diacetoxybut-2-ene via a ruthenium-catalysed cross-
metathesis reaction, followed by removal of the acetate pro-
14
an allylic ether functionality (Chart 2).
8
tective group with NaOMe in THF–MeOH to provide the
immobilised allylic alcohol 16. Introduction of the carbonate
functionality was effected using the previously described
method by activation with p-nitrophenyl chloroformate to give
9
resin 17 in an overall yield of 57%.
Chart 2
Ϫ1
The actual loading of resin 17 was 0.72 mmol g , deter-
mined by elemental analysis of the nitrogen content on the
resin.
The incompatibility of the amino acid spacer with N-
acyliminium ion chemistry led us to synthesise the all carbon-
linker system 23, which was prepared in quantitative yield by
reaction of carbonate resin 17 with ammonia (Scheme 4). The
usefulness of the primary allyl carbamate 23 for N-acyliminium
ion chemistry was evaluated using the three-component
N-acyliminium ion reaction. Carbamate 23 was reacted with
benzaldehyde (20 equiv.), allyltrimethylsilane (10 equiv.) and
BF ؒOEt (1.1 equiv.) in MeCN, to provide the immobilised
10
The synthesis of the SEC linker precursor started with the
caesium carbonate-mediated coupling of 2-mercaptoethanol
with the commercially available Merrifield resin 14 to furnish
alcohol resin 18 (Scheme 3). Oxidation of the sulfide using an
excess of MCPBA, followed by reaction with p-nitrophenyl
chloroformate led to the mixed carbonate resin 20 (loading
11
9
1%). The TEC linker was prepared by activation of the
3
2
mercaptoethanol functionalised resin 18 with p-nitrophenyl
chloroformate in a yield of 99%.
homoallylic carbamate 24. Indeed, the Alloc linker was stable
under the Lewis acidic reaction conditions and no premature
12
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001
995

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ditions using an easily removable base was synthesised. This
linker system was based on the 2-(methylsulfonyl)ethoxy-
carbonyl (Msc) group, developed by Tesser and coworkers in
16
the seventies as a cheap and readily available Fmoc equivalent.
The scope of the SEC carbamate linker was determined by
the synthesis of both 1-arylhomoallylamines and 2-substituted
pyrrolidines using the same reactions as with the previously
applied p-alkoxybenzyl (Wang) and ethyl carbamate linkers as
depicted in Scheme 1.
The precursor resins 26 and 27 were prepared by treatment of
p-nitrophenyl carbonate resin 20 with ammonia or 4,4-
diethoxy-2-phenylbutylamine.
Scheme 4
Resin 26 was subjected to the three component reaction con-
15
cleavage of the product was observed during the N-acyliminium
ion reaction.
ditions with several aromatic aldehydes and BF ؒOEt , to give
3 2
the corresponding transient N-acyliminium ions which were
then trapped by allyltrimethylsilane. Cleavage was effected by
stirring in a solution of 1 M NaOMe in THF–MeOH for one
The product was cleaved from the resin using palladium
catalysis. Several nucleophiles (i.e. Et SiH, HCO H, dimedone
3
2
17
(
5,5-dimethylcyclohexane-1,3-dione), Bu SnH–AcOH and
hour. A simple partitioning between water and ethyl acetate,
followed by filtration over a solid phase extraction (SPE)
column gave the 1-arylhomoallylamines 25a–c in yields of 79%,
80% and 39%, respectively, which was generally 20% higher
than when the Wang resin was used. Only trace amounts of
1-(4-nitrophenyl)homoallylamine 25d were isolated, most
probably due to the low rate of formation of the intermediate
N-acyliminium ion.
3
piperidine) were used to trap the immobilised π-allylpalladium
species. By using Et SiH or HCO H no cleavage of the products
3
2
was observed. Dimedone only gave partial removal of the
immobilised amines, which was also found with similar solution
phase experiments (data not shown). Although Bu SnH–AcOH
3
efficiently effected the cleavage reaction, removal of the remains
of this cocktail from the highly polar product could not
be realized. The optimal cleavage conditions were 5 mol%
Pd(PPh ) and 7 equiv. of piperidine as the nucleophile in DCM
Using the SEC linker system, starting from resin 27 a number
3b
of 2-functionalised pyrrolidines were also synthesised.
A
3
4
for 30 min at room temperature. IR analysis of the resin after
cleavage and model studies in the solution phase showed that by
using these conditions the homoallylic amine 25b was liberated
quantitatively. Purification of the product by column chrom-
atography or preparative RP-HPLC was not reproducible
due to tedious removal of the remains of the cleavage cocktail
representative example is shown in Scheme 5. Subjection of
the immobilised amine 27 to the cyclisation–coupling con-
ditions provided the immobilised pyrrolidine 29, which was
cleaved quantitatively by using 1 M NaOMe in a mixture of
THF–MeOH. After workup, pyrrolidine 30b was isolated in a
yield of 81% (Scheme 5).
(
especially triphenylphosphine oxide). Although we could
obtain the products in good yields (39–85%) and purities, we
abandoned this linker system because of the laborious pro-
cedure, which cannot be used for automated parallel synthesis.
This drawback forced us to search on for yet another linker
system that is orthogonal with N-acyliminium ion chemistry.
2-Thioethyl carbamate (TEC) linker
The anticipated orthogonal chemical behavior of the SEC
linker in comparison with the TEC linker under basic condi-
tions prompted us to study the compatibility with N-
acyliminium ion chemistry. A very attractive feature of the TEC
linker system is its application as a safety-catch linker. After
performing basic reaction steps, oxidation of the sulfide to the
sulfone will generate the SEC linker to enable facile cleavage of
the product by NaOMe treatment. In addition, in reactions
prior to the cleavage, moderately acidic reagents may be used
2
-Sulfonylethyl carbamate (SEC) linker
To overcome the purification problems with the previous linker
systems, a tailor-made linker that would be stable towards
Lewis acids and would allow for cleavage under basic con-
Scheme 5
9
96
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001

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Table 1 Stability of the SEC and TEC linkers toward various acidic and basic conditions
Yield 25b (%)
from
Yield 30b (%)
from
Entry
Solvent
Reagent
Equiv.
28b
34
29
35b
1
2
3
4
5
6
7
8
9
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
SnCl4
TFA (50%)
TfOH
TsOH
DIPEA
DMAP
Piperidine (20%)
DBU
5
—
5
5
5
5
—
5
0
0
0
0
0
0
<5
57
47
0
0
0
0
0
0
0
<5
67
71
0
57
53
0
0
0
0
0
0
42
39
0
0
0
0
0
0
NaOMe (0.1 M)
—
Scheme 6
making the TEC linker even more versatile than the SEC linker
as is demonstrated in Scheme 6.
and TsOH did not effect cleavage of the product. Stirring with
DIPEA and the acylation catalyst DMAP (entries 5 and 6) did
not cause any leaching of the product either. Even prolonged
stirring with 20% of piperidine in DCM—conditions that one
commonly uses for the cleavage of Fmoc-groups operating via a
similar β-elimination mechanism—resulted in the formation of
only trace amounts of products (entry 7). These observations
clearly show the versatility of the SEC linker and set the scene
for the use of carbamates as building blocks for the intro-
duction of diversity via combinatorial chemistry. With a
stronger base like DBU extensive cleavage of the products from
the resin occurred (entry 8). Use of a tenfold lower concen-
tration of NaOMe in THF–MeOH still resulted in extensive
cleavage of the product (entry 9).
In conclusion, the SEC and TEC carbamate linker systems
proved to be well suited for N-acyliminium ion chemistry. The
SEC linker is completely stable to both Lewis and protic acidic
conditions combined with moderate base stability. The widest
synthetic scope was found with the TEC linker which combined
a sufficient stability against the cationic conditions required for
N-acyliminium ion chemistry with complete stability under
basic conditions. Cleavage of TEC linker bound amines could
be effected by oxidation of the sulfide to the sulfone (to give the
SEC linker) followed by addition of the basic cleavage cocktail
or by treatment with strong acid, albeit in lower yields.
Again, both approaches via acyclic and cyclic N-acyliminium
ions have been evaluated. Reaction of 21 with ammonia, 4,4-
diethoxybutylamine or 4,4-diethoxy-2-phenylbutylamine gave
the N-acyliminium ion precursors 32 and 33a,b, respectively.
Following the same procedures as with the SEC linker
system, treatment with BF ؒOEt2 gave the transient N-
3
acyliminium ions which were trapped with allylsilane to afford
resins 34 and 35a,b. Cleavage could now be effected via two
different procedures. Firstly, treatment with TFA–DCM (1 : 1,
v/v) directly liberated the amines 25b or 30a,b in yields of 57%,
3
3% and 42%, respectively. Alternatively, oxidation of resins
3
4 and 35a,b with 2.2 equivalents of MCPBA in DCM gave
18
the corresponding sulfone resin. Subsequent cleavage under
standard conditions provided the products 25b and 30a,b in
somewhat lower (compared to starting from sulfone resin 20),
but still good overall yields of 69%, 73% and 52%, respectively
(
4 steps).
Stability of the SEC and TEC linkers towards Lewis and protic
acidic and basic conditions
From the previous results, it was clear that the SEC and
TEC linker systems were compatible with BF ؒOEt , N,N-
3
2
diisopropylethylamine (DIPEA) and N-methylmorpholine
NMM). To further test the stability of these linker systems the
(
Experimental
resin-bound products 28b, 29 were subjected to a number of
acids and bases in different solvents. After stirring for 24 hours
at room temperature the filtrate was collected and checked (by
TLC) for the presence of products. If present, the product was
isolated to allow determination of the yield. The results are
summarized in Table 1.
General
Reagents were purchased at highest commercial quality and
used without further purification unless stated otherwise. Fluka
Merrifield resin (200–400 mesh, 1% divinylbenzene, 1.7 mmol
Ϫ1
For the SEC linker it was found that the moderately strong
Cl g ) was used. R values were obtained by using thin-layer
f
Lewis acid SnCl (entry 1) and strong protic acids TFA, TfOH
chromatography on silica gel-coated plastic sheets (Merck silica
4
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001
997

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gel 60 F245) using UV light as visualizing agent or KMnO4
solution and heat as developing agents. Chromatographic
purification refers to flash chromatography using the indicated
solvent (mixture) and ACROS silica gel (particle size 35–70
µm). Infrared spectra were recorded using a Bruker IFS 28
spectrophotometer and absorptions are reported in units of
20 h at rt. Then the reaction mixture was filtered, washed with
CH Cl , MeOH (100 ml, repeated three times), CH Cl (100 ml)
2
2
2
2
and dried in a vacuum oven (50 ЊC) to afford 10.8 g of white
Ϫ1
resin 19: νmax/cm 3442, 1280, 1107.
Resin 20
Ϫ1
cm . Infrared spectra of resins were measured in KBr using a
To a suspension of resin 19 (10.6 g, 16 mmol) in CH Cl (200
2
2
DRIFT module. Nuclear magnetic resonance (NMR) spectra
were obtained using a Bruker ARX 400 instrument (400 MHz).
Spectra are reported in units of ppm on the δ scale relative to
ml), N-methylmorpholine (4.4 ml, 40 mmol) and 4-nitrophenyl
chloroformate (8.06 g, 40 mmol) were added at 0 ЊC. The
reaction mixture was allowed to warm up to room temperature
and agitated for 18 h. Then the reaction mixture was filtered,
washed with CH Cl , MeOH (100 ml, the last two steps were
1
an internal standard of residual chloroform (7.27 ppm for H-
13
NMR and 77.0 for C-NMR). Mass spectra and accurate mass
determination data are reported as m/z (relative intensity).
Measurements were performed on a JEOL JMS SX/SX102A
four-sector mass spectrometer, coupled to a JEOL MS-MP7000
data system. Elemental analyses were performed by Dornis u.
Kolbe Mikroanalytisches Laboratorium, Mülheim a. d. Ruhr,
Germany. The solid phase reactions were either gently stirred
with a magnetic stirring bar or agitated by rotation of the
reaction vessel under an angle of 45Њ at a rotary evaporator
engine. The resins were washed according to the indicated
sequence. The resin was allowed to swell/shrink for 1 minute
before each filtration.
2
2
repeated two times), CH Cl , Et O (100 ml, the last two steps
2
2
2
were repeated two times), CH Cl (100 ml) and dried in a
2
2
Ϫ1
vacuum oven (50 ЊC) to afford 13.4 g of resin 20: νmax/cm
1
765, 1524, 1346, 1320, 1110; Elemental anal. Found: N 1.55%
Ϫ1
(
1.11 mmol g N, 91% from Merrifield resin).
Resin 21
According to the same procedure as described for 20, resin
1
8 (1.01 g, 1.61 mmol) was reacted with N-methylmorpholine
(
0.35 ml, 3.32 mmol) and 4-nitrophenyl chloroformate (649 mg,
Ϫ1
3
1
.32 mmol) to afford 1.29 g of resin 21: νmax/cm 1767, 1526,
Ϫ1
347; Elemental anal. Found: N 1.75% (1.25 mmol g N, 99%
Resin 16
from Merrifield resin).
7
Resin 15 (0.50 g, 0.84 mmol) was suspended in degassed
toluene (5.0 ml), 1,4-diacetoxybut-2-ene (578 mg, 3.36 mmol)
Resin 23
and Cl (PCy ) Ru᎐CHPh (28 mg, 0.03 mmol) were added and
2
3 2
Resin 17 (0.42 g, 0.30 mmol) was suspended in DMF (4 ml) and
the reaction mixture was stirred for 48 h under nitrogen atmos-
phere at rt. The suspension was filtered and the resin was
washed with toluene (10 ml), CH Cl (5 ml) and EtOH (5 ml,
a saturated NH –MeOH solution (1 ml) was added. After
3
stirring for 18 h at rt, the resin was filtered off, washed with
2
2
DMF (5 ml), CH Cl (5 ml), EtOH (5 ml, the last two steps were
the last two steps were repeated four times) and Et O (2 × 5 ml).
2
2
2
repeated four times) and Et O (2 × 5 ml). After drying in vacuo
After drying in vacuo (50 ЊC), the immobilised acetate (0.53 g,
2
Ϫ1
(50 ЊC) 0.40 g of resin 23 was obtained in quantitative yield:
0
.80 mmol, νmax/cm 1738) was suspended in THF (5 ml) and
Ϫ1
νmax/cm 3498, 3403, 1731; Elemental anal. Found: N 1.05%
NaOMe (0.05 ml, 0.16 mmol of a 3 M solution in MeOH) was
added. After stirring for 2 h at rt, the reaction mixture was
filtered off, washed with THF (5 ml), CH Cl (5 ml) and EtOH
Ϫ1
(
0.75 mmol g N).
2
2
1
-Phenylbut-3-enylamine, 25b (from 23)
(
5 ml, the last two steps were repeated four times) and Et O
2
(
2 × 5 ml). After drying in vacuo (50 ЊC) 0.43 g of resin 16 was
Carbamate resin 23 (100 mg, 0.07 mmol) was suspended in
Ϫ1
obtained: νmax/cm 3573, 3432.
CH Cl (1 ml). Benzaldehyde (21 µl, 0.21 mmol), allyltrimethyl-
2
2
silane (34 µl, 0.21 mmol) and BF ؒOEt (13 µl, 0.11 mmol)
were added. The reaction mixture was stirred under a nitrogen
3
2
Resin 17
atmosphere for 3 h at rt, filtered off and washed with CH Cl2
2
Immobilised alcohol 16 (1.50 g, 2.39 mmol) was suspended in
(2 ml), EtOH (2 ml, the last two steps were repeated four times)
1
5 ml CH Cl and cooled to 0 ЊC, 4-nitrophenyl chloroformate
2 2
and Et O (2 × 2 ml). After drying in vacuo (50 ЊC) resin 24 was
2
(
1.45 g, 7.17 mmol) and N-methylmorpholine (791 µl, 7.17
Ϫ1
Ϫ1
obtained: νmax/cm 3435, 1716 cm . Resin 24 was then
mmol) were added, the reaction mixture was allowed to warm
up to rt and was stirred for 18 h. The suspension was filtered,
the resin was washed with CH Cl , EtOH (15 ml, the last two
suspended in CH Cl (1 ml), piperidine (48 µl, 0.49 mmol) and
2
2
Pd(PPh ) (4 mg, 0.04 mmol) were added and the suspension
3
4
2
2
was stirred under a nitrogen atmosphere for 2 h at rt. The reac-
steps were repeated four times) and Et O (2 × 15 ml). After
2
tion mixture was filtered, the resin was washed with CH Cl2
2
drying in vacuo (50 ЊC) 1.56 g of resin 17 were obtained: νmax/
Ϫ1
(3 × 2 ml) and the collected filtrates were evaporated. The
product was purified using flash chromatography (silica,
cm 1766, 1525, 1346; Elemental anal. Found: N 1.01% (0.72
Ϫ1
mmol g N, 57% from Merrifield resin).
0
→10% MeOH in CH Cl ). Generally the product was still
2 2
contaminated with the remains of the cleavage cocktail. Typical
Resin 18
isolated yields of the pure product ranged from 39–85% (from
1
A mixture of Merrifield resin 14 (25 g, 42.5 mmol),
resin 23): R 0.20 (CH Cl –MeOH 9:1); H NMR (400 MHz,
f
2
2
2
-mercaptoethanol (25 ml, 359 mmol) and Cs CO (27.7 g, 85
CDCl ) δ 7.34–7.22 (5H, m, Ar-H), 5.81–5.70 (1H, m,
2
3
3
mmol) in dry DMF (200 ml) was agitated for 4 h at 60 ЊC and
then for 20 h at rt. The reaction mixture was filtered, washed
CH ᎐CHCH ), 5.15–5.07 (2H, m, CH ᎐CHCH ), 3.99 (1H, dd,
2 2 2 2
᎐ ᎐
J = 8.0, 5.4 Hz, NH CH), 2.51–2.33 (2H, m, CH ᎐CHCH ),
2
2
᎐
2
13
with DMF, H O (200 ml, the last two steps were repeated two
1.66 (2H, br s, NH ); C NMR (100 MHz, CDCl ) δ 148.6
2
2
3
times), CH Cl , MeOH–H O (1 : 1, 200 ml, repeated two times),
(Ar-H), 133.6 (CH ᎐CHCH ), 128.6, 127.4, 126.6 (Ar-C), 118.6
2 2
᎐
2
2
2
CH Cl , MeOH (200 ml, the last two steps were repeated two
(CH ᎐CHCH ), 55.4 (NH CH), 41.7 (CH ᎐CHCH ); νmax/
2 2 2 2 2
᎐ ᎐
Ϫ1 +
2
2
times), CH Cl (200 ml) and dried in a vacuum oven (50 ЊC) to
cm 3385, 1642; m/z (EI) 147.1037 (M . C H N requires
2
2
10 13
Ϫ1
+
afford 26.1 g of white resin 18: νmax/cm 3397.
147.1048), 147 (M , 0.3%), 106 (100), 79 (72), 77 (40), 29 (95),
1
7 (26).
Resin 19
Resin 26
To a suspension of resin 18 (10.1 g, 16.1 mmol) in CH Cl (200
2
2
ml), MCPBA (85%, 20.3 g, 100 mmol) was added in portions at
Resin 20 (6.10 g, 7.32 mmol) was suspended in DMF (50 ml)
0
ЊC. When addition was complete the mixture was agitated for
and a saturated NH –MeOH solution (10 ml) was added. After
3
9
98 J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001

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stirring for 18 h at rt, the resin was filtered off, washed with
(150 mg, 0.17 mmol) was reacted with 4-nitrobenzaldehyde
DMF (50 ml), CH Cl (50 ml), EtOH (50 ml, the last two steps
(78 mg, 0.51 mmol), allyltrimethylsilane (82 µl, 0.51 mmol) and
2
2
Ϫ1
were repeated four times) and Et O (2 × 50 ml). After drying
BF ؒOEt (32 µl, 0.26 mmol) to afford resin 28d: νmax/cm 3625,
2
3
2
Ϫ1
in vacuo (50 ЊC) 5.52 g of resin 26 were obtained: νmax/cm
3505, 1726, 1523, 1352. After cleavage a trace of 25d was
1
3
474, 3327, 1727, 1343, 1121; Elemental anal. Found: N 1.37%
obtained as a light yellow oil: R 0.17 (CH Cl –MeOH 9 : 1); H
f
2
2
Ϫ1
(
1.31 mmol g N, 92% from Merrifield resin).
NMR (400 MHz, CDCl ) δ 8.19 (2H, d, J = 8.8 Hz, Ar-H), 7.52
3
(
2H, d, J = 8.7 Hz, Ar-H), 5.75–5.67 (1H, m, CH ᎐CHCH ),
2 2
1
-(4-Methoxyphenyl)but-3-enylamine, 25a
5.30–5.06 (2H, m, CH ᎐CHCH ), 4.14 (1H, dd, J = 5.3, 7.8
2
᎐
2
Hz, NH CH), 2.48–2.32 (2H, m, CH ᎐CHCH ), 1.75 (2H,
2
2
2
Carbamate resin 26 (150 mg, 0.17 mmol) was suspended in
CH Cl (1.5 ml). p-Anisaldehyde (62 µl, 0.51 mmol), allyltri-
13
br s, NH ); C NMR (100 MHz, CDCl ) δ 151.7, 146.2
2
3
2
2
(
(
Ar-C), 134.0 (CH ᎐CHCH ), 127.2, 123.6 (Ar-C), 118.6
2 2
methylsilane (82 µl, 0.51 mmol) and BF ؒOEt (32 µl, 0.26
3
2
CH ᎐CHCH ), 54.7 (NH CH), 43.6 (CH ᎐CHCH ); νmax/
2
Ϫ1
2
2
2
2
mmol) were added. The reaction mixture was stirred under a
nitrogen atmosphere for 3 h at rt, filtered off and washed with
CH Cl (2 ml), EtOH (2 ml, the last two steps were repeated
+
cm 3356, 1598, 1520, 1345; m/z (EI) 193.0974 (M Ϫ NH .
3
C H N O requires 193.0977), 193 (19%), 176 (56), 154 (100),
10
13
2
2
2
2
1
36 (92).
four times) and Et O (2 × 2 ml). After drying in vacuo (50 ЊC)
2
Ϫ1
resin 28a was obtained: νmax/cm 3634, 3491, 1724. Resin 28a
Resin 27
was then suspended in THF (1.5 ml), NaOMe (0.75 ml of a 3 M
solution in MeOH) was added and the suspension was stirred
for 1 h at rt. The reaction mixture was filtered, the resin was
washed with CH Cl (3 × 2 ml) and the collected filtrates were
To a suspension of resin 20 (485 mg, 582 µmol) in THF (10 ml),
4,4-diethoxy-2-phenylbutylamine (414 mg, 1.75 mmol) and
DIPEA (0.31 ml, 1.78 mmol) were added and the mixture was
agitated at room temperature for 24 h. Then the reaction
mixture was filtered, washed with CH Cl , MeOH (5 ml, the last
2
2
washed with H O (2 ml), neutralized with conc. HCl and
2
extracted with EtOAc (5 × 1 ml). The collected organic phases
2
2
were dried (MgSO ) and concentrated in vacuo. The product
two steps were repeated two times), CH Cl , Et O (5 ml, the
4
2 2 2
was purified using SPE chromatography (Isolute, silica, solvent
system: 0→10% MeOH in CH Cl ) to give compound 25a
last two steps were repeated two times), CH Cl (5 ml) and dried
2 2
Ϫ1
in a vacuum oven (50 ЊC) to afford 542 mg of resin 27: νmax/cm
2
2
1
(
24 mg, 79%) as a colorless oil: R 0.13 (CH Cl –MeOH 9:1); H
3342 (br), 1724, 1324, 1118.
f
2
2
NMR (400 MHz, CDCl ) δ 7.27 (2H, d, J = 8.7 Hz, Ar-H), 6.85
3
(
2H, d, J = 8.5 Hz, Ar-H), 5.71–5.60 (1H, m, CH ᎐CHCH ),
Resin 29
2
2
5
.11–5.03 (2H, m, CH ᎐CHCH ), 4.61 (2H, br s, NH ), 3.99
2
2
2
To a suspension of resin 27 (450 mg, 482 µmol) in CH Cl (5 ml)
2
2
(
(
1H, dd, J = 14.2, 6.8 Hz, NH CH), 3.78 (3H, s, OCH ), 2.51
2
13
3
allyltrimethylsilane (0.76 ml, 4.78 mmol) and BF ؒOEt (0.18
3
2
2H, t, J = 7.0 Hz, CH ᎐CHCH ); C NMR (CDCl , 100 MHz)
2
2
3
ml, 1.42 mmol) were added at 0 ЊC. After 1 h the reaction
mixture was allowed to warm up to room temperature and
stirred for 18 h. Then the reaction mixture was filtered, washed
with CH Cl , MeOH (5 ml, the last two steps were repeated two
δ 159.2 (Ar-C), 133.6 (CH ᎐CHCH ), 127.8, 127.6 (Ar-C),
2
2
1
18.6 (CH ᎐CHCH ), 114.0, 113.7 (Ar-C), 55.1 (OCH ,
2 2 3
Ϫ1
NH CH), 42.8 (CH ᎐CHCH ); νmax/cm 3374, 1612; m/z (EI)
2
2
2
+
2
2
1
36.0757 (M Ϫ C H . C H NO requires 136.0762), 136 (66),
3 5 11 15
times), CH Cl , Et O (5 ml, the last two steps were repeated
2
2
2
3
1 (82), 17 (100).
-Phenylbut-3-enylamine, 25b
two times), CH Cl (5 ml) and dried in a vacuum oven (50 ЊC)
2
2
Ϫ1
to afford 535 mg of resin 29: νmax/cm 1708, 1324, 1118.
1
According to the same procedure as described for 25a, resin 26
150 mg, 0.17 mmol) was reacted with benzaldehyde (52 µl, 0.51
mmol), allyltrimethylsilane (82 µl, 0.51 mmol) and BF ؒOEt
2-Allyl-4-phenylpyrrolidine, 30b
(
To a suspension of resin 29 (229 mg, 218 µmol) in THF (2 ml) a
3
2
3
M solution of NaOMe in MeOH (1 ml, 3 mmol) was added
Ϫ1
(
32 µl, 0.26 mmol) to afford resin 28b: νmax/cm 3655, 3360,
and the reaction mixture was stirred for 1 h at room temper-
ature. Then the reaction mixture was filtered and washed with
CH Cl , MeOH (3 ml, the last two steps were repeated two
1
724. After subsequent cleavage and purification using SPE
chromatography compound 25b (20 mg, 80%) was obtained as
a colorless oil which was identical to the compound obtained
from the allyl carbamate resin 23.
2
2
times) and CH Cl (3 ml). The filtrate was concentrated, taken
2
2
up in 1 M NaOH (10 ml) and extracted twice with Et O (10 ml).
2
The combined ether layers were concentrated and the residue
was further purified using an SPE-column (Isolute, silica,
solvent system: CH Cl –MeOH 100 : 0→90 : 10→0 : 100),
4
-(1-Aminobut-3-enyl)benzonitrile, 25c
According to the same procedure as described for 25a, resin 26
2
2
(
150 mg, 0.17 mmol) was reacted with 4-cyanobenzaldehyde (67
to give 33 mg of 30b (81%) as a clear oil: R 0.14 (CH Cl –
f
2
2
1
mg, 0.51 mmol), allyltrimethylsilane (82 µl, 0.51 mmol) and
BF ؒOEt (32 µl, 0.26 mmol) to afford resin 28c: νmax/cm 3637,
MeOH = 9 : 1); H NMR (CDCl , 400 MHz) δ 7.18–7.32 (5H,
3
Ϫ1
m, Ph), 5.79–5.90 (1H, m, CH CH᎐CH ), 5.14 (1H, dd, J =
3
2
2
2
3
501, 2229, 1723. After subsequent cleavage and purification
1.6, 17.1 Hz, CH CH᎐CH ), 5.09 (1H, dd, J = 1.6, 10.2 Hz,
2 2
using SPE chromatography compound 25c (12 mg, 39%) was
CH CH᎐CH ), 3.44–3.51 (2H, m, NHCH CH + NHCH-
2 2 2
1
obtained as a colorless oil: R 0.24 (CH Cl –MeOH 9:1); H
(CH ) ), 3.29–3.38 (1H, m, NHCH CH), 2.93 (1H, dd,
f
2
2
2
2
2
NMR (400 MHz, CDCl ) δ 7.61 (2H, d, J = 8.3 Hz, Ar-H), 7.46
J = 9.1, 10.5 Hz, CH CH(Ph)CH ), 2.92 (1H, br s, NH), 2.30–
2 2
3
(
2H, d, J = 8.2 Hz, Ar-H), 5.76–5.65 (1H, m, CH ᎐CHCH ),
2.40 (2H, m, CH CH᎐CH ), 1.93–2.08 (2H, m, CHCH CH);
2
2
2
2
2
13
5
.13–5.01 (2H, m, CH ᎐CHCH ), 4.07 (1H, dd, J = 7.6, 5.6
C
NMR (CDCl3, 100.6 MHz)
δ
143.7 (Ph), 135.5
2
2
Hz, NH CH), 2.47–2.29 (2H, m, CH ᎐CHCH ), 1.60 (2H, br
(CH CH᎐CH ), 128.7 (Ph), 127.4 (Ph), 126.6 (Ph), 117.4
(CH CH᎐CH ), 58.7 (NHCH(CH ) ), 54.9 (NHCH CH), 44.6
2 2 2 2 2
2
2
2
2 2
13
s, NH ); C NMR (100 MHz, CDCl ) δ 143.9 (Ar-C),
2
3
1
32.2 (CH ᎐CHCH ), 127.6, 127.1 (Ar-C), 119.1, 118.5
(CH CH(Ph)CH ), 40.6 (CHCH CH), 39.3 (CH CH᎐CH );
2 2 2 2 2
Ϫ1
2
2
(
(
(
(
CN, CH ᎐CHCH ), 111.2 (Ar-C), 55.6 (NH CH), 42.1
CH ᎐CHCH ); νmax/cm 3339, 2228, 1641; m/z (EI) 156.0821
M Ϫ NH . C H N requires 156.0813), 156 (3%), 132 (24), 17
100).
νmax(film)/cm 3311 (br), 1406, 914; m/z (FAB) 188.1439
2
2
2
Ϫ1
+
+
(M + H. C H N requires 188.1439), 188 (M + H, 31%), 154
2
2
13 18
+
(100), 137 (72), 136 (71).
3
11 10
Resin 33a
1
-(4-Nitrophenyl)but-3-enylamine, 25d
According to the same procedure as described for 27, resin 21
According to the same procedure as described for 25a, resin 26
(548 mg, 685 µmol) was reacted with 4,4-diethoxybutylamine
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001
999

View Article Online
(
0.24 ml, 1.37 mmol) and DIPEA (0.24 ml, 1.37 mmol) to
105 µmol) in THF (1 ml) a 3 M solution of NaOMe in MeOH
(0.5 ml, 1.5 mmol) was added and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was
worked up as usual to give 10.2 mg of 30b (52%).
Ϫ1
afford 552 mg of resin 33a: νmax/cm 3378 (br), 1729.
Resin 33b
According to the same procedure as described for 27, resin
Acidic cleavage of 35b. Resin 35b (110 mg, 130 µmol) was
suspended in 3 ml of TFA–CH Cl (1:1, v/v) and stirred at
room temperature for 20 h. Then the reaction mixture was
2
1 (516 mg, 645 µmol) was reacted with 4,4-diethoxy-2-
2
2
phenylbutylamine (459 mg, 1.94 mmol) and DIPEA (0.34 ml,
1
Ϫ1
.95 mmol) to afford 575 mg of resin 33b: νmax/cm 3329 (br),
filtered, washed with CH Cl , MeOH (5 ml, the last two
2
2
1
726.
steps were repeated two times), CH Cl , Et O (5 ml, the last two
2
2
2
steps were repeated two times), CH Cl (5 ml) and dried in a
vacuum oven (50 ЊC). Concentration of the filtrate followed by
SPE column chromatography gave 10.2 mg of 30b (42%).
2
2
Resin 35a
According to the same procedure as described for 29, resin
3
3a (199 mg, 242 µmol) was reacted with allyltrimethylsilane
(
0.38 ml, 2.42 mmol) and BF ؒOEt (92 µl, 0.73 mmol) to afford
3
2
Acknowledgements
Ϫ1
1
85 mg of resin 35a: νmax/cm 1700.
This research has been financially supported by the Council for
Chemical Sciences (C. W.) and the Netherlands Technology
Foundation (S. T. W.) of the Netherlands Organisation for
Scientific Research (N. W. O.). Dr R. Verhage (Solvay
Pharmaceuticals) is acknowledged for carefully reading the
manuscript.
Resin 35b
According to the same procedure as described for 29, resin
3
3b (543 mg, 586 µmol) was reacted with allyltrimethylsilane
(
0.9 ml, 5.9 mmol) and BF ؒOEt (0.22 ml, 1.76 mmol) to afford
3
2
Ϫ1
1
88 mg of resin 35b: νmax/cm 1713.
Activation and basic cleavage of 35a. Resin 35a (99 mg, 129
References
µmol) was suspended in 5 ml of CH Cl and cooled to 0 ЊC.
2
2
1
(a) R. E. Dolle, J. Comb. Chem., 2000, 2, 383; (b) R. G. Franzén,
J. Comb. Chem., 2000, 2, 195; (c) R. E. Dolle and K. H. Nelson, Jr.,
J. Comb. Chem., 1999, 1, 235; (d) S. Booth, P. H. H. Hermkens, H. C.
J. Ottenheijm and D. C. Rees, Tetrahedron, 1998, 54, 15385; (e) R. C.
D. Brown, J. Chem. Soc., Perkin Trans. 1, 1998, 3293; ( f ) P. H. H.
Hermkens, H. C. J. Ottenheijm and D. C. Rees, Tetrahedron, 1997,
Then MCPBA (54 mg, 92%, 288 µmol) was added and the
reaction mixture was stirred at 0 ЊC for 2 h, filtered, washed
with CH Cl , MeOH (5 ml, the last two steps were repeated two
2
2
times), CH Cl , Et O (5 ml, the last two steps were repeated two
2
2
2
times), CH Cl (5 ml) and dried in a vacuum oven (50 ЊC) to
2
2
5
3, 5643; (g) A. Nefzi, J. M. Ostresh and R. A. Houghten, Chem.
give 103 mg of resin. To a suspension of this resin (90 mg, 113
µmol) in THF (2 ml) a 3 M solution of NaOMe in MeOH (1 ml,
mmol) was added and the reaction mixture was stirred for 1 h
Rev., 1997, 97, 449; (h) P. H. H. Hermkens, H. C. J. Ottenheijm and
D. C. Rees, Tetrahedron, 1996, 52, 4527.
(a) W. N. Speckamp and M. J. Moolenaar, Tetrahedron, 2000, 56,
3817; (b) H. Hiemstra and W. N. Speckamp, in: Comprehensive
Organic Synthesis (Vol. 2), eds., B. M. Trost and I. Fleming, Oxford,
Pergamon, 1991, p. 1047.
3
2
3
at room temperature. Then the reaction mixture was filtered
and washed with CH Cl , MeOH (3 ml, the last two steps were
2
2
repeated two times) and CH Cl (3 ml). The filtrate was concen-
2
2
(a) W. J. N. Meester, F. P. J. T. Rutjes, P. H. H. Hermkens and
H. Hiemstra, Tetrahedron Lett., 1999, 40, 1601; (b) J. J. N. Veerman,
F. P. J. T. Rutjes, J. H. van Maarseveen and H. Hiemstra, Tetrahedron
Lett., 1999, 40, 6079.
trated, taken up in 1 M NaOH (10 ml) and extracted twice with
Et O (10 ml). The combined ether layers were extracted twice
2
with 1 M HCl (10 ml) and concentrated to give 12.2 mg of
1
2
4
-allylpyrrolidine 30a (73%) as the HCl salt: H NMR (D O,
4 For a similar solution phase approach see: S. J. Veenstra and
2
00 MHz) δ 5.86–5.96 (1H, m, CH CH᎐CH ), 5.26–5.34 (2H,
P. Schmid, Tetrahedron Lett., 1997, 38, 997.
2
2
5
6
For an extensive review on linker systems see: F. Guillier, D. Orain
and M. Bradley, Chem. Rev., 2000, 100, 2091.
m, CH CH᎐CH ), 3.68–3.74 (1H, m, NHCH(CH ) ), 3.31–3.43
2
2
2 2
(
2
2H, m, NHCH CH ), 2.58–2.65 (1H, m, CH CH᎐CH ),
2
2
2
2
Several linker systems based on this principle have been reported:
.48–2.55 (1H, m, CH CH᎐CH ), 2.24–2.30 (1H, m,
2 2
(
a) M. Mutter and D. Bellof, Helv. Chim. Acta, 1984, 67, 2009;
CHCH CH ), 2.03–2.16 (2H, m, CH CH CH ), 1.72–1.82 (1H,
2
2
2
2
2
(b) Y.-Z. Liu, S.-H. Ding, J.-Y. Chu and A. M. Felix, Int. J. Pept.
Protein Res., 1990, 35, 95; (c) F. Rabanal, E. Giralt and F. Albericio,
Tetrahedron Lett., 1992, 33, 1775; (d) F. Rabanal, E. Giralt and
F. Albericio, Tetrahedron, 1995, 51, 1449; (e) R. J. Morphy,
Z. Rankovic and D. C. Rees, Tetrahedron Lett., 1996, 37, 3209; ( f )
A. R. Brown, D. C. Rees, Z. Rankovic and R. J. Morphy, J. Am.
Chem. Soc., 1997, 119, 3288; (g) X. Ouyang, R. W. Armstrong and
M. M. Murphy, J. Org. Chem., 1998, 63, 1027; (h) F. E. K. Kroll,
R. J. Morphy, D. C. Rees and D. Gani, Tetrahedron Lett., 1997, 38,
13
m, CHCH CH ); C NMR (D O, 100.6 MHz) δ 137.7
2
2
2
(
CH CH᎐CH ), 121.9 (CH CH᎐CH ), 62.8 (NHCH(CH ) ),
2 2 2 2 2 2
4
2
1
1
8.0 (NHCH CH ), 38.6 (CH CH᎐CH ), 32.1 (CHCH CH ),
2 2 2 2 2 2
Ϫ1
5.8 (CH CH CH ); νmax(KBr)/cm 2746, 1642; m/z (FAB)
2
2
2
+
+
12.1112 (M + H. C H N requires 112.1126), 112 (M + H,
7
14
00%), 107 (17), 89 (16), 77 (12), 70 (12).
8
8
573; (i) P. Heinonen and H. Lönnberg, Tetrahedron Lett., 1997, 38,
569; (j) S. B. Katti, P. K. Misra, W. Haq and K. B. Mathur, J. Chem.
Acidic cleavage of 35a. Resin 35a (198 mg, 257 µmol) was
suspended in 2 ml of TFA–CH Cl (1:1, v/v) and stirred at
2
2
Soc., Chem. Commun., 1992, 843; (k) C. García-Eccheverría,
Tetrahedron Lett., 1997, 38, 8933; (l) R. Eritja, J. Robles,
D. Fernandez-Forner, F. Albericio, E. Giralt and E. Pedroso,
Tetrahedron Lett., 1991, 32, 1511; (m) F. Albericio, E. Giralt and
R. Eritja, Tetrahedron Lett., 1991, 32, 1515; (n) M. Yamada,
T. Miyajima and H. Horikawa, Tetrahedron Lett., 1998, 39, 289; (o)
A. Barco, S. Benetti, C. De Risi, P. Marchetti, G. P. Pollini and
V. Zanirato, Tetrahedron Lett., 1998, 39, 7591; (p) W. S. Wade,
F. Yang and T. J. Sowin, J. Comb. Chem., 2000, 2, 266.
room temperature for 20 h. Then the reaction mixture was
filtered, washed with CH Cl , MeOH (5 ml, the last two steps
2
2
were repeated two times), CH Cl , Et O (5 ml, the last two steps
2
2
2
were repeated two times), CH Cl (5 ml) and dried in a vacuum
2
2
oven (50 ЊC). The filtrate was concentrated to give 19.2 mg of
0a (33%) as the TFA salt.
3
Activation and basic cleavage of 35b. Resin 35b (96 mg, 129
7
Y. Hu, J. A. Y. Porco, Jr., J. W. Labadie, O. W. Gooding and B. M.
Trost, J. Org. Chem., 1998, 63, 4518.
µmol) was suspended in 5 ml of CH Cl and cooled to 0 ЊC.
2
2
Then MCPBA (54 mg, 92%, 288 µmol) was added and the
reaction mixture was stirred at 0 ЊC for 2 h, filtered, washed
with CH Cl , MeOH (5 ml, the last two steps were repeated two
8 For similar cross-coupling reactions in solution, see: D. J. O’Leary,
H. E. Blackwell, R. E. Washenfelder and R. H. Grubbs, Tetrahedron
Lett., 1998, 39, 7427. In accordance with the findings described in
the aforementioned article, it may be assumed that the immobilised
alkene was obtained as a mixture of E–Z isomers.
9 B. A. Dressman, L. A. Spangle and S. W. Kaldor, Tetrahedron Lett.,
1996, 37, 937.
2
2
times), CH Cl , Et O (5 ml, the last two steps were repeated two
2
2
2
times), CH Cl (5 ml) and dried in a vacuum oven (50 ЊC) to
2
2
give 103 mg of resin 29. To a suspension of this resin (92 mg,
1
000 J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001

View Article Online
1
0 B. Yan, C. F. Jewell and S. W. Myers, Tetrahedron, 1998, 54,
1755.
1 The loading range was 90–100%, depending on the batch of
Merrifield resin used. This probably reflects the fluctuation in the
chlorine level of the commercially acquired resins.
Lett., 1989, 30, 2641; (b) K. Kaljuste and A. Undén, Tetrahedron
1
Lett., 1996, 37, 3031.
1
15 Currently, work is in progress to extend the scope of the three-
component N-acyliminium ion reaction to aliphatic and electron
poor aromatic aldehydes.
1
2 This linker system has also been constructed via radical
chemistry: Z. Timar and T. Gallagher, Tetrahedron Lett., 2000, 41,
16 (a) G. I. Tesser and I. C. Balvert-Geers, Int. J. Pept. Protein Res.,
1975, 7, 295; (b) G. I. Tesser, J. T. W. A. R. M. Buis, E. T. M. Wolters
and E. G. A. M. Bothé-Helmes, Tetrahedron, 1976, 32, 1069.
17 In contrast to the drawing of the residual resin after cleavage of SEC
bound products depicted in Scheme 3 in ref. 3(b), after cleavage of
the amines via an E1cb mechanism, the resulting vinyl sulfone is
immediately trapped by the methoxide nucleophiles to give resin 31.
See also the previous reference.
3
173.
3 (a) H. Kunz and B. Dombo, Angew. Chem., Int. Ed., 1988, 27, 711;
b) T. Johnson and R. C. Sheppard, J. Chem. Soc., Chem. Commun.,
991, 1653; (c) H. Kunz, Pure Appl. Chem., 1993, 65, 1223; (d) W.
1
(
1
Kosch, J. Marz and H. Kunz, React. Polym., 1994, 22, 181; (e) O.
Seitz and H. Kunz, J. Org. Chem., 1997, 62, 813; ( f ) R. C. D. Brown
and M. Fisher, Chem. Commun., 1999, 1547.
18 The oxidation was performed at 0 ЊC for a short time to prevent
epoxidation of the allylic alkene functionality.
1
4 (a) F. G. Guibé, D. Dangles, G. Balavoine and A. Loffet, Tetrahedron
J. Chem. Soc., Perkin Trans. 1, 2001, 994–1001
1001