Solid-phase synthesis of hydroxypiperazine derivatives using phenethylamine linker by oxidation-Cope elimination

Article abstract of DOI:10.1016/j.tet.2005.07.061

A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation-Cope elimination of polymer-bound phenethylamine linker with m-CPBA. The key intermediate of phenethylamine N-oxide resins was separable on solid-phase for subsequent β-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and yields without any significant contamination at 90°C for 2 h. The utility of the methodology for solid-phase synthesis of general hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins and were characterized by LC/MS, ¹H NMR, and ¹³C NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2005.07.061

Tetrahedron 61 (2005) 9305–9311
Solid-phase synthesis of hydroxypiperazine derivatives using
phenethylamine linker by oxidation–Cope elimination
Jin-soo Seo,a,b Hye-won Kim,a,c Cheol Min Yoon,b Deok Chan Hac and Young-Dae Gonga,
*
aMedicinal Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung-gu, Daejeon 305-600, South Korea
bGraduate School of Biotechnology, Korea University, Sungbuk-gu, Seoul 136-701, South Korea
cDepartment of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, South Korea
Received 23 June 2005; revised 15 July 2005; accepted 19 July 2005
Available online 8 August 2005
Abstract—A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation–Cope
elimination of polymer-bound phenethylamine linker with m-CPBA. The key intermediate of phenethylamine N-oxide resins was separable
on solid-phase for subsequent b-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and
yields without any significant contamination at 90 8C for 2 h. The utility of the methodology for solid-phase synthesis of general
hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates
by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins
1
and were characterized by LC/MS, H NMR, and 13C NMR spectroscopy.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of hydroxylamines on REM resin was accom-
plished through premature elimination reaction during the
oxidation procedure with meta-chloroperbenzoic acid (m-
CPBA) to generate N-oxide intermediate at room tempera-
ture. As the results of in situ b-elimination of N-oxide
intermediate, were contaminated with meta-chlorobenzoic
acid (m-CBA) and excess m-CPBA. Consequently further
purification steps such as extraction and column chroma-
tography were needed to obtain pure hydroxylamines after
cleavage from the REM resins. To solve this problem,
therefore, we tried to find more stable linker for the solid-
phase synthesis of hydroxylamine derivatives under m-
CPBA oxidation condition at room temperature because we
needed to develop a facile and rapid solid-phase approach
for construction of drug-like hydroxypiperazine derivatives
as a part of our research on drug discovery program.7
Solid-phase synthesis has emerged as a powerful technique
in generating combinatorial libraries of small organic
molecules useful for drug discovery.1 Hydroxylamines
provide scaffold, on which pharmacophore can be arranged
to yield potent and selective drugs.2 Therefore, many
hydroxylamine derivatives have been reported, since a
variety of hydroxylamine derivatives possess drug-like
characteristics and exhibit biological activities similar to
their corresponding amines as a bioisostere.3 Especially,
hydroxypiperazine, a kind of hydroxylamine, showed good
antimicrobial activity.4 However, hydroxylamine deriva-
tives have scarcely been reported in the research field of
drug-like library construction by solid-phase synthesis, as
compared with their tertiary amine analogues.5 As only
example, Kurth reported about solid-phase synthesis of
hydroxylamines using REM (polymer-bound benzyl aryl-
ate) resin by b-elimination strategy, which is a good
example of traceless linker.6 The b-elimination strategy as a
traceless cleavage method is very useful for construction of
tertiary amine libraries and N,N-disubstituted hydroxyl-
amines derivatives using REM resin. However, the
Herein, we would like to report a solid-phase synthesis of
hydroxypiperazine derivatives using phenethylamine linker.
The polymer bound phenethylamine N-oxide, produced by
oxidation reaction with m-CPBA on the phenethylamine
resin, served as key intermediate. And further b-elimination
reaction on this phenethylamine N-oxide resin under
thermal condition, generated the desired various hydroxy-
piperazine derivatives with high purities. And we also
attempted to develop the methodology of solid-phase
synthesis of general hydroxylamine derivatives using the
same linker.
Keywords: Solid-phase; Hydroxypiperazine; Phenethylamine linker;
Oxidation–Cope.
Corresponding author. Tel.: C82 42 860 7149; fax: C82 42 861 1291;
e-mail: ydgong@krict.re.kr
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.061

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J. Seo et al. / Tetrahedron 61 (2005) 9305–9311
Our initial studies were concentrated to the design of
thermally more stable linker than REM resin under
m-CPBA oxidation condition. To this end, we decided to
examine N-oxide formation from polymer bound phenethyl-
amine under the same condition in hope that Cope
elimination reaction would not occur at room temperature
but take place at a higher temperature. The pKa value of
b-proton in REM resin 2 is about 25. On the other hand, the
value of phenethylamine resin 1 is about 40, much higher
than that of REM resin as shown in Figure 1.8 That is to say,
the phenethylamine N-oxide linker was expected to need
much higher energy for b-elimination reaction, compared
with REM resin. Fortunately we confirmed that the results
of the experiment coincided with our expectation.
tetrabromide to give phenethylbromide resin, the formation,
of which was confirmed by the disappearance of the
hydroxyl group stretching frequency at 3350 cmK1
(Fig. 2, A and B). The phenethylbromide resin 5 was
transformed to the polymer bound piperazine 6 by a
nucleophilic substitution reaction with piperazine in the
presence of triethylamine as a base in N,N-dimethylforma-
mide (DMF) at 50 8C. To perform further derivatization on
the piperazine resin 6, we examined the reaction with
various electrophiles, such as acid halides and sulfonyl
halides, to introduce amide and sulfonamide functional
groups on the nitrogen atom (Na) of piperazine resin 6. The
completion of the reaction was confirmed by a negative
chloranil test9 with the substituted (Na) phenethylpiperazine
resins 7. And we could successfully obtain the desired
various phenethylpiperazine N-oxide resins 8 from the
substituted (Na) phenethylpiperazine resins 7 by oxidation
reaction with m-CPBA at room temperature. Finally, to
confirm formation of the final products 9, we performed the
b-elimination reaction of the polymer bound N-oxide resins
8 in toluene at 90 8C for 2 h, and we could obtain the desired
various hydroxypiperazine derivatives in high purities and
yields without any significant impurities from the key
intermediate N-oxide resins 8. The key intermediates, the
phenethylpiperazine N-oxide resins 8, were prepared in a
six-step procedure starting from the Merrifield resin 3, as
shown in Scheme 1. As listed in Table 1, variously
substituted (Na) hydroxypiperazine derivatives were suc-
cessfully synthesized in high six-step overall yields from
Merrifield resin 3 with high purities by oxidation–Cope
elimination of the phenethylpiperazine N-oxide resin 8.
The progress of these reactions could be monitored by
ATR-FTIR spectroscopy on single beads (Fig. 2, C–E).
Figure 1. Comparision of stability toward b-elimination reaction.
As the first step, we selected Merrifield resin 3 as a polymer
support for the preparation of phenethylamine, since the
chloride group in the Merrifield resin 3 is suitable for the
introduction of 4-hydroxyphenethyl alcohol through ether
formation under the condition of sodium methoxide in
N,N-dimethylacetamide (DMA) at 50 8C. The hydroxyl
group of phenethyl alcohol resin 4 was changed to bro-
mide in the presence of triphenylphosphine in carbon
Further, we attempted to develop the methodology for solid-
phase synthesis of general hydroxylamine derivatives using
the same linker. The phenethylbromide resin 5 was
transformed to the polymer bound secondary amines 11
by a nucelophilic substitution reaction with various primary
aliphatic and aromatic amines in the presence of triethyl-
amine as base in DMF at 50 8C. The secondary phenethyl-
amine resins 11 were changed to the polymer bound tertiary
amines 12 by reductive alkylation with various aldehyde
and boran–pyridine complex. The completion of this step
was also checked by a negative chloranil test. With the
tertiary phenethylamine resins 12, we examined the
oxidation reaction with m-CPBA to obtain the desired
phenethylamine N-oxide resins 13. And we could success-
fully obtain the desired phenethylamine N-oxide resins 13 as
the key intermediate. Finally, to confirm formation of the
final products 14, we carried out thermal reaction with the
polymer bound N-oxide resins 13 for b-elimination reaction
in toluene at 90 8C for 2 h, as shown in Scheme 2. By using
this sequence of reactions, we could obtain the desired
hydroxylamine derivatives 14 in relatively good six-step
overall yields and purities from Merrifield resin 3. However,
the yields of most of the desired hydroxylamine derivatives
14 by this multistep synthetic method on solid phase were
lower than those of hydroxypiperazines 9. The reason was
assumed that substituted hydroxyamines 14 were partly
oxidized to the corresponding nitrone compounds 15
under the standard condition. In fact, we could identify
Figure 2. ATR-FTIR spectra on single bead of resin 4 (A), 5 (B), 6 (C), 7c
(D) and 7h (E).

J. Seo et al. / Tetrahedron 61 (2005) 9305–9311
9307
Scheme 1. Reagents and conditions: (a) 4-hydroxyphenethyl alcohol, NaOMe, DMA, 50 8C, 18 h; (b) CBr4, PPh3, CH2Cl2, rt, 12 h; (c) piperazine, TEA, DMF,
50 8C, 18 h; (d) acid halide or sulfonyl halide, TEA, DMF, rt, 18 h; (e) m-CPBA, CH2Cl2, rt, 2 h; (f) toluene, 90 8C, 2 h.
Table 1
Product
X
R1
Puritya
(%)
Yieldb
(%)
Product
X
R1
Purity
(%)
Yield
(%)
9a
9b
–SO2–
–SO2–
4-MeO-Ph
4-NO2-Ph
99
94
50
57
9g
9h
–CO–
–CO–
4-MeO-Ph
4-NO2-Ph
98
99
39
49
9c
–SO2–
4-Cl-Ph
97
45
9i
–CO–
97
24
9d
9e
–SO2–
–SO2–
2,4,6-Triisopropyl-Ph
1-Naphthalene
95
96
33
57
9j
9k
–CO–
–CO–
Cyclohexane
1-Naphthalene
97
99
55
29
9f
–SO2–
4-tert-Bu-Ph
93
55
9l
–CO–
97
24
a Calculated from integrated peak areas recorded by LC/MS of the crude products.
b Six-step overall yields from Merrifield resin 3 (loading capacity of the resin 3 in 1.6 mmol/g).
the nitrones 15 by LC/MS spectroscopy of the crude
products (Table 2).
hydroxypiperazines 9 and hydroxylamines 14 by using
phenethylamine N-oxide resins 8, 13 as the key inter-
mediate. The key intermediates of N-oxide resins 8, 13 were
separable on solid phase for subsequent b-elimination
In summary, we succeeded in the solid-phase synthesis of
Scheme 2. Reagents and conditions: (a) amine, TEA, 50 8C, 18 h; (b) aldehyde, boran–pyridine complex, DMF/EtOH (4:1), rt, 3 days; (c) m-CPBA, CH2Cl2, rt,
2 h; (d) toluene, 90 8C, 2 h.

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J. Seo et al. / Tetrahedron 61 (2005) 9305–9311
Table 2
Product
R2
R3
Purity
(%)
Yield
(%)a
Product
R2
R3
Purity (%)
Yield
(%)
14a
14b
14c
14d
14ed
Bn
Bn
Bn
Bn
Bn
Ph
82b
81
49
82
68
93c
97
96
92
—
40
38
17
35
22
14f
14g
14h
14i
Ph
92
95
97
88
93
—
33
34
23
24
20
4-F-Ph
4-F-Ph
86
88
74
55
4-NO2-Ph
4-tBu-Ph
Isopropyl
4-MeO-Ph
4-tBu-Ph
Isopropyl
14jd
a Six-step overall yields from Merrifield resin 3 after purification (loading capacity of the resin 3 in 1.6 mmol/g).
b Calculated from integrated peak areas recorded by LC/MS of the isolated products.
c Calculated from integrated peak areas recorded by LC/MS of the crude products.
d Compounds. 14e and 14j compounds could be not isolated from mixture of the hydroxylamine and nitrone.
reaction, from which the desired hydroxypiperazine and
hydroxylamine products 9, 14 could be obtained without
any significant contamination at 90 8C. Especially, the
hydroxypiperazine derivatives could be obtained in high
six-step overall yields with high purities from Merrifield
resin 3 without any purification step after the thermal
cleavage step. With the high yields and purities, this method
is the versatile approach to develop combinatorial libraries
of hydroxypiperazine and hydroxylamine derivatives useful
for the synthesis of biologically interesting compounds,
which is a subject for our current research.
alcohol resin 4 was filtered and washed with DMF (2!
100 mL), DCM (2!100 mL) and MeOH (2!100 mL), and
dried under high vacuum.
2.3. Procedure for the synthesis of the phenethylbromide
resin 5
To a suspension of phenethyl alcohol resin 4 (5 g, 8.0 mmol)
in dry DCM (dichloromethane: 60 mL) was added
triphenylphosphine (10.49 g, 40 mmol), followed by slow
addition of carbon tetrabromide (13.27 g, 40 mmol) in dry
DCM at 0 8C. The suspension was shaken for 12 h at room
temperature under Ar gas. The phenethylbromide resin 5
was filtered and washed with DMF (2!100 mL), DCM
(2!100 mL) and MeOH (2!100 mL), and dried under
high vacuum.
2. Experimental
2.1. Materials and methods
The polystyrene Merrifield resin (1.6 mmol/g, 1% cross-
linking, 100–200 mesh) was obtained from NovaBiochem.
Solvents were purchased from Merck and were anhydrous
and HPLC grade. Reactions, filtrations, and washings were
carried out on a MiniBlock (Bohdan). Solvent evaporation
was performed on a GeneVac Atlas HT-4 centrifugal
evaporator. Crude products were purified by parallel
chromatography using QuadFlash silica-cartridges (Biotage
Catalog no. QK0-1107-1504L). All of the intermediate
resins were monitored by ATR-FTIR (SensIR Technology).
The structures of final products were confirmed by 1H NMR
and 13C NMR (Bruker AMX-500 FT NMR), and LC/MS
spectroscopy. LC/MS data were recorded on a Waters ZQ
electrospray mass spectrometer (EI) equipped with PDA
(200–600 nm) detection using XTerraMS column (C18,
5 mM, 4.6!100 mm) from Waters (UK). Typical gradient
were5–95% MeCN/H2O containing 0.1% trifluoroacetic acid.
2.4. Procedure for the synthesis of the polymer-bound
piperazine resin 6
The phenethylbromide resin 5 (2.0 g, 3.2 mmol) was
suspended in dry DMF (30 mL), and piperazine (1.4 g,
16.0 mmol) and TEA (2.23 mL, 16.0 mmol) were succes-
sively added. The mixture was shaken for 18 h at 50 8C. The
polymer-bound piperazine resin 6 was filtered and washed
with DMF (2!100 mL), DCM (2!100 mL) and MeOH
(2!100 mL), and dried under high vacuum.
2.5. Procedure for the synthesis of the resin 7a
The polymer-bound piperazine resin 6 (100 mg, 0.16 mmol)
was swollen in DMF (4 mL) and TEA (0.07 mL,
0.45 mmol) followed by addition of 4-methoxybenzene-
sulfonyl chloride (92 mg, 0.45 mmol). After the reaction
was shaken for 18 h at room temperature, the sulfonyl
piperazine resin 7a was filtered and washed with DMF
(2!20 mL), DCM (2!20 mL) and MeOH (2!20 mL)
and dried under high vacuum.
2.2. Procedure for the synthesis of the phenethyl alcohol
resin 4
Sodium methoxide (1.30 g, 24.0 mmol) was added to a
solution of 4-hydroxyphenethyl alcohol (3.32 g, 24.0 mmol)
in cold DMA (80 mL) at 0 8C. The solution was stirred at
room temperature for 2 h and Merrifield resin 3 (5 g,
8.0 mmol, loading 1.6 mmol/g: chloromethylated 1%
vinylbenzene–styrene copolymer) was added. The resulting
suspension was stirred for 18 h at 50 8C. The phenethyl
2.6. Representative procedure for the oxidation and
Cope elimination steps 9a
To the pre-swollen sulfonyl piperazine resin 7a (100 mg,
0.16 mmol) in DCM (4 mL) was added m-CPBA (158 mg,
0.64 mmol, w70%) at 0 8C. The resin was agitated for 2 h at

J. Seo et al. / Tetrahedron 61 (2005) 9305–9311
9309
room temperature and washed with 3% TEA/DMF (3!
20 mL), DMF (3!20 mL), MeOH (3!20 mL), and then
DCM (20 mL). After drying under high vacuum for 30 min,
the resin 8a was heated in 4 mL of toluene at 90 8C for the
Cope elimination during 2 h. The resin was filtered off and
washed with toluene (2!3 mL) and DCM (2!3 mL). The
combined filtrate was concentrated under high vacuum and
afforded the desired sulfonylpiperazine derivatives with
high purities.
2H, JZ7.2 Hz), 6.92 (d, 2H, JZ7.2 Hz), 3.84 (s, 3H), 3.22
(br, 4H), 2.67 (br, 2H); 13C NMR (125 MHz, CDCl3) d
170.36, 160.97, 129.15, 113.81, 57.50, 55.38; LC/MS (ESI)
m/z 237 [MCH]C; HRMS (ES): [M]C calcd for
C12H16N2O3, 236.1161; found, 236.1163.
2.6.8. (4-Hydroxypiperazin-1-yl)-(4-nitrophenyl)metha-
1
none 9h. H NMR (500 MHz, CDCl3) d 8.29 (d, 2H, JZ
8.0 Hz), 7.58 (d, 2H, JZ8.0 Hz), 3.29 (br, 2H), 3.14 (br,
4H), 2.63 (br, 2H); LC/MS (ESI) m/z 252 [MCH]C; HRMS
(ES): [M]C calcd for C11H13N3O4, 251.0906; found,
251.0906.
2.6.1. 4-(4-Methoxybenzenesulfonyl)piperazin-1-ol 9a.
1H NMR (500 MHz, CDCl3) d 7.68 (d, 2H, JZ7.0 Hz),
7.00 (d, 2H, JZ7.0 Hz), 3.88 (s, 3H), 3.53 (m, 2H), 3.16 (m,
2H), 2.48–2.42 (m, 1H), 1.80 (br s, 2H), 1.70 (br s, 3H), 1.51
(m, 2H), 1.25 (m, 3H); 13C NMR (125 MHz, CDCl3) d
163.23, 129.86, 127.14, 114.35, 56.36, 55.65, 44.09; LC/MS
(ESI) m/z 273 [MCH]C; HRMS (ES): [M]C calcd for
C11H16N2O4S, 272.0831; found, 272.0828.
2.6.9. Benzo[1,3]dioxol-5-yl-(4-hydroxypiperazin-1-yl)
methanone 9i. H NMR (500 MHz, CDCl3) d 6.92 (dd,
1
1H, JZ7.9, 1.6 Hz), 6.90 (d, 1H, JZ1.6 Hz), 6.83 (d, 1H,
JZ7.9 Hz), 6.00 (s, 2H), 4.41–4.10 (m, 1H), 3.21 (m, 5H),
2.66 (m, 3H); 13C NMR (125 MHz, CDCl3) d 139.71,
134.30, 129.53, 129.10, 56.21, 43.83; LC/MS (ESI) m/z 251
[MCH]C; HRMS (ES): [M]C calcd for C12H14N2O4,
250.0954; found, 250.0956.
The following compounds were synthesized using the above
protocol.
2.6.2. 4-(4-Nitrobenzenesulfonyl)piperazin-1-ol 9b. 1H
NMR (500 MHz, CDCl3) d 8.40 (d, 2H, JZ8.6 Hz), 7.96 (d,
2H, JZ8.6 Hz), 3.57 (br, 2H), 3.21 (br, 2H), 2.85 (br, 4H);
LC/MS (ESI) m/z 288 [MCH]C; HRMS (ES): [M]C calcd
for C10H13N3O5S, 287.0576; found, 287.0579.
2.6.10. Cyclohexyl-(4-hydroxypiperazin-1-yl)methanone
9j. H NMR (500 MHz, CDCl3) d 4.45 (m, 1H), 3.86 (m,
1
1H), 3.29–3.21 (m, 3H), 2.93 (t, 1H, JZ10.9 Hz), 2.60 (m,
2H), 2.48–2.42 (m, 1H), 1.80 (br s, 2H), 1.70 (br s, 3H), 1.51
(m, 2H), 1.25 (m, 3H); LC/MS (ESI) m/z 213 [MCH]C;
HRMS (ES): [M]C calcd for C11H20N2O2, 212.2887; found,
212.2886.
1
2.6.3. 4-(4-Chlorobenzenesulfonyl)piperazin-1-ol 9c. H
NMR (500 MHz, CDCl3) d 7.69 (d, 2H, JZ8.5 Hz), 7.52 (d,
2H, JZ8.5 Hz), 3.52 (m, 2H), 3.18 (m, 2H), 2.84 (t, 2H, JZ
8.9 Hz), 2.73 (m, 2H); 13C NMR (125 MHz, CDCl3) d
139.71, 134.30, 129.53, 129.10, 56.21, 43.83; LC/MS
(ESI) m/z 277 [MCH]C; HRMS (ES): [M]C calcd for
C10H13ClN2O3S, 276.0335; found, 276.0339.
2.6.11. (4-Hydroxypiperazin-1-yl)naphthalen-1-yl-
methanone 9k. H NMR (500 MHz, CDCl3) d 7.90–7.87
(m, 3H), 7.56–7.38 (m, 4H), 3.40 (br, 4H), 2.98 (br, 2H),
2.82 (br, 2H); LC/MS (ESI) m/z 257 [MCH]C; HRMS
(ES): [M]C calcd for C15H16N2O2, 256.1212; found,
256.1215.
1
2.6.4. 4-(2,4,6-Triisopropylbenzenesulfonyl)piperazin-1-
ol 9d. 1H NMR (500 MHz, CDCl3) d 4.14 (m, 1H), 3.52 (m,
2H), 3.22 (m, 2H), 3.06 (t, 2H, JZ10.8 Hz), 2.90 (m, 1H),
2.72 (t, 2H, JZ10.1 Hz), 1.26 (s, 9H), 1.25 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 153.54, 151.89, 129.33, 124.00,
56.63, 42.58, 34.19, 29.34, 24.87, 23.54; LC/MS (ESI) m/z
369 [MCH]C; HRMS (ES): [M]C calcd for C19H32N2O3S,
368.2134; found, 368.2135.
2.6.12. (4-Hydroxypiperazin-1-yl)-(4-phenoxyphenyl)
methanone 9l. H NMR (500 MHz, CDCl3) d 7.41–7.36
1
(m, 4H), 7.17 (m, 1H), 7.05 (d, 2H, JZ7.7 Hz), 7.00 (d, 2H,
JZ8.6 Hz), 4.48–4.37 (m, 1H), 3.91–3.84 (m, 1H), 3.22 (m,
5H), 2.67 (m, 2H); LC/MS (ESI) m/z 299 [MCH]C; HRMS
(ES): [M]C calcd for C17H18N2O3, 298.1317; found,
298.1317.
2.6.5. 4-(Naphthalene-1-sulfonyl)piperazin-1-ol 9e. 1H
NMR (500 MHz, CDCl3) d 8.33 (s, 1H), 7.99–7.92 (m,
3H), 7.75–7.63 (m, 3H), 3.61 (br, 2H), 2.16 (br, 2H), 2.80
(br, 4H); 13C NMR (125 MHz, CDCl3) d 134.99, 132.82,
132.22, 129.39, 129.25, 129.12, 129.00, 127.97, 127.70,
122.84, 56.35, 44.06, 29.71; LC/MS (ESI) m/z 293 [MC
H]C; HRMS (ES): [M]C calcd for C14H16N2O3S, 292.0882;
found, 292.0883.
2.7. Procedure for the synthesis of polymer-bound
secondary amine resins 11a
The phenethylbromide resin 5 (2 g, 3.2 mmol) was
suspended in dry DMF (30 mL), and benzyl amine
(1.75 mL, 16.0 mmol) and triethyl amine (2.23 mL,
16.0 mmol) were successively added. The mixture was
shaken for 18 h at 50 8C. Secondary amine resin 11a was
filtered and washed with DMF (2!100 mL), DCM (2!
100 mL) and MeOH (2!100 mL), and dried under high
vacuum.
2.6.6. 4-(4-tert-Butylbenzenesulfonyl)piperazin-1-ol 9f.
1H NMR (500 MHz, CDCl3) d 7.68 (d, 2H, JZ8.4 Hz),
7.54 (d, 2H, JZ8.4 Hz), 3.56 (br, 2H), 3.18 (br, 2H), 2.82
(br, 2H), 2.71 (br, 2H), 1.33 (s, 9H); LC/MS (ESI) m/z 299
[MCH]C; HRMS (ES): [M]C calcd for C11H22N2O3S,
298.4011; found, 298.4014.
2.8. Procedure for the reductive alkylation of polymer-
bound secondary amine resin 12a
Secondary amine resin 11a (100 mg, 0.16 mmol)
was swollen in DMF/EtOH (4:1, 4 mL) and followed by
addition of benzaldehyde (0.13 mL, 1.28 mmol) and
2.6.7. (4-Hydroxypiperazin-1-yl)-(4-methoxyphenyl)
methanone 9g. H NMR (500 MHz, CDCl3) d 7.37 (d,
1

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J. Seo et al. / Tetrahedron 61 (2005) 9305–9311
borane–pyridine complex (0.13 mL, 1.28 mmol). After the
reaction was shaken for three days at room temperature, the
tertiary amine resin 12a was filtered and washed with DMF
(2!20 mL), DCM (2!20 mL) and MeOH (2!20 mL) and
dried under high vacuum.
5H), 6.87 (d, 1H, JZ0.9 Hz), 6.79 (dd, 1H, JZ7.9, 0.9 Hz),
6.76 (d, 1H, JZ7.9 Hz), 5.93 (s, 2H), 3.83 (s, 2H), 3.76 (s,
2H); LC/MS (ESI) m/z 258 [MCH]C; HRMS (ES): [M]C
calcd for C15H15NO3, 257.1052; found, 257.1050.
2.9.7. N-Benzo[1,3]dioxol-5-ylmethyl-N-(4-fluorobenzyl)
hydroxylamine 14g. H NMR (500 MHz, CDCl3) d 7.32–
1
2.9. Procedure for the oxidation and Cope elimination
steps 14a
7.29 (m, 2H), 7.01 (t, 2H, JZ8.6 Hz), 6.85 (s, 1H), 6.78 (d,
1H, JZ7.8 Hz), 6.75 (d, 1H, JZ7.8 Hz), 5.93 (s, 2H), 3.77
(s, 2H), 3.74 (s, 2H); LC/MS (ESI) m/z 276 [MCH]C;
HRMS (ES): [M]C calcd for C15H14FNO3, 275.0958;
found, 275.0961.
To pre-swollen tertiary amine resin 12a (100 mg,
0.16 mmol) in DCM (4 mL) was added the m-CPBA
(158 mg, 0.64 mmol, w70%) at 0 8C. The resin was agitated
for 3 h at room temperature and washed with 3%
TEA(triethylamine)/DMF (3!20 mL), DMF (3!20 mL),
MeOH (3!20 mL), and then DCM (20 mL). After drying
under high vacuum for 30 min, the resin 13a was heated in
4 mL of toluene at 90 8C for the Cope elimination during
2 h. The resin was filtered off and washed with toluene
(2!3 mL) and DCM (2!3 mL).
2.9.8. N-Benzo[1,3]dioxol-5-ylmethyl-N-(4-methoxyben-
zyl)hydroxylamine 14h. H NMR (500 MHz, CDCl3) d
1
7.28–7.25 (m, 2H), 6.87–6.86 (m, 3H), 6.78–6.75 (m, 2H),
5.92 (d, 2H, JZ7.8 Hz), 3.79–3.78 (m, 5H), 3.75 (s, 2H);
LC/MS (ESI) m/z 288 [MCH]C; HRMS (ES): [M]C calcd
for C11H16N2O4S, 287.1158; found, 287.1159.
The combined filtrate was evaporated and purified by silica
gel column chromatography.
2.9.9. N-Benzo[1,3]dioxol-5-ylmethyl-N-(4-tert-butyl-
benzyl)hydroxylamine 14i. H NMR (500 MHz, CDCl3)
1
2.9.1. N,N-Dibenzylhydroxylamine 14a. 1H NMR
(500 MHz, CDCl3) d 7.36–7.26 (m, 10H), 3.81 (s, 4H);
13C NMR (125 MHz, CDCl3) d 137.48, 129.52, 128.34,
127.42, 64.04; LC/MS (ESI) m/z 214 [MCH]C; HRMS
(ES): [M]C calcd for C14H15NO, 213.1154; found,
213.1155.
d 7.34 (d, 2H, JZ8.2 Hz), 7.27 (d, 2H, JZ8.2 Hz), 6.87 (d,
1H, JZ0.8 Hz), 6.78 (dd, 1H, JZ7.9, 0.8 Hz), 6.75 (d, 2H,
JZ7.9 Hz), 5.93 (s, 2H), 3.79 (s, 2H), 3.73 (s, 2H), 1.30 (s,
9H); LC/MS (ESI) m/z 314 [MCH]C; HRMS (ES): [M]C
calcd for C19H23NO3, 313.1678; found 313.1676.
2.9.10. N-Benzo[1,3]dioxol-5-ylmethyl-N-isopropyl-
hydroxylamine 14j. H NMR (500 MHz, CDCl3) d 6.87
1
The following compounds were synthesized using the above
protocol.
(d, 1H, JZ1.1 Hz), 6.79 (dd, 1H, JZ7.9, 1.1 Hz), 6.76 (d,
1H, JZ7.9 Hz), 5.94 (s, 2H), 3.71 (s, 2H), 2.48 (d, 2H, JZ
6.9 Hz), 1.96–1.89 (m, 1H), 0.94 (s, 3H), 0.92 (s, 3H); LC/
MS (ESI) m/z 224 [MCH]C; HRMS (ES): [M]C calcd for
C12H17NO3, 223.1208; found, 223.1207.
2.9.2. N-Benzyl-N-(4-fluorobenzyl)hydroxylamine 14b.
1H NMR (500 MHz, CDCl3) d 7.34–7.29 (m, 7H), 7.01
(t, 2H, JZ8.7 Hz), 3.82 (s, 2H), 3.79 (s, 2H); LC/MS (ESI)
m/z 232 [MCH]C; HRMS (ES): [M]C calcd for
C14H14FNO, 231.1059; found, 231.1062.
Acknowledgements
2.9.3. N-Benzyl-N-(4-nitrobenzyl)hydroxylamine 14c. 1H
NMR (500 MHz, CDCl3) d 8.19 (d, 2H, JZ8.5 Hz), 7.55 (d,
2H, JZ8.5 Hz), 7.39–7.33 (m, 5H), 3.98 (s, 4H); LC/MS
(ESI) m/z 259 [MCH]C; HRMS (ES): [M]C calcd for
C14H14N2O3, 258.1004; found, 258.1003.
We are grateful to the Center for Biological Modulators and
the Ministry of Commerce Industry and Energy of Korea for
financial support of this research.
2.9.4. N-Benzyl-N-(4-tert-butylbenzyl)hydroxylamine
1
14d. H NMR (500 MHz, CDCl3) d 7.35–7.32 (m, 6H),
7.27–7.25 (m, 3H), 3.79 (s, 2H), 1.29 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 150.33, 137.56, 134.38, 129.48,
129.26, 128.31, 127.37, 125.25, 64.00, 63.67, 34.50,
31.37; LC/MS (ESI) m/z 270 [MCH]C; HRMS (ES):
[M]C calcd for C18H23NO, 269.1780; found, 269.1781.
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