One-step cyclization: Synthesis of N -heteroalkyl-N′-tosylpiperazines

Article abstract of DOI:10.1021/jo3012896

Piperazine derivatives are important intermediates in organic synthesis and useful building blocks in pharmaceutical and fine chemical industries. Currently available synthetic routes for these heterocyclic compounds have limited scope owing to the harsh reaction conditions, low yields, and multistep process. Herein, we reported a practical method for synthesis of alkyl-, alcohol-, amine-, and ester-extended tosylpiperazines under mild conditions with moderate to high yields. This protocol exhibits potential applicability in the synthesis of pharmaceuticals and natural products because of the operational simplicity and the conveniently available reactants. On the basis of the experimental and theoretical results, a plausible mechanism of aliphatic nucleophilic substitution (S_N) in the cyclization has been postulated and evidence for the formation of a six-membered ring has also been confirmed by means of density functional theory (DFT) calculations.

Full text of DOI:10.1021/jo3012896

Article
pubs.acs.org/joc
One-Step Cyclization: Synthesis of N‑Heteroalkyl‑N′‑tosylpiperazines
Jianying Huang,*,† Weiyuan Xu,† Hujun Xie,† and Shijun Li*,‡
†College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, P. R. China
‡College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, P. R. China
S
* Supporting Information
ABSTRACT: Piperazine derivatives are important intermediates in
organic synthesis and useful building blocks in pharmaceutical and fine
chemical industries. Currently available synthetic routes for these
heterocyclic compounds have limited scope owing to the harsh reaction
conditions, low yields, and multistep process. Herein, we reported a
practical method for synthesis of alkyl-, alcohol-, amine-, and ester-
extended tosylpiperazines under mild conditions with moderate to high
yields. This protocol exhibits potential applicability in the synthesis of
pharmaceuticals and natural products because of the operational
simplicity and the conveniently available reactants. On the basis of the
experimental and theoretical results, a plausible mechanism of aliphatic
nucleophilic substitution (SN) in the cyclization has been postulated and
evidence for the formation of a six-membered ring has also been
confirmed by means of density functional theory (DFT) calculations.
necessary to use a preferable catalyst containing a Group VB
metal oxide, a Group VB metal phosphate, or mixtures thereof.9
Another reported strategy to synthesize asymmetric piperazine
derivatives is selective monoprotection of one nitrogen atom
with tert-butoxycarbonyl (Boc) in acidic medium, followed by
substitution of another unprotected nitrogen and then
deprotection to provide the desired products.15,16 However,
this kind of method involves regioselective substitution and
deprotection, which usually leads to low yields and is time-
consuming because of side reactions during the protection and
deprotection of the Boc group, which is not very stable under
basic conditions at high temperature. Therefore, because of the
limitations of the known methods for diversely substituted
piperazines, practical one-step cyclization routes to synthesize
N-heteroalkyl-N′-tosylpiperazines are of particular interest. This
kind of tosyl-substituted compound, as well as other
sulfonamide piperazine compounds, has exibited potential as
an antimalarial drug.17
INTRODUCTION
■
The piperazine scaffold not only is a very useful building block
in coordination polymers and fine industrial chemicals,1,2 but it
is also an important pharmacophore found in a large number of
biologically active compounds.3−8 Amine- and alcohol-extended
piperazines have considerably extensive applications in the
preparation of hardeners of epoxy resins, corrosion inhibitors,
insecticides, accelerators for rubber, urethane catalysts, and
antioxidants.9,10 1-(2-Aminoethyl)piperazine is used as inter-
media of nonviral gene delivery vectors.4 Recently, piperazine
derivatives have even been developed as CO2 capturing
materials.11
The synthesis of simple 1,4-disubstituted piperazines has
received considerable attention, but only a comparatively small
number of 1,4-disubstituted piperazines have been prepared by
one-step cyclization. In the past decades, amine-extended
piperazines were formed as a byproduct of the reaction with
ethylene dichloride and ammonia or amines to prepare higher
amines in the presence of acid catalysts. This reaction was
usually performed at a very high temperature, 300 °C or even
higher, and the products were difficult to purify.12 Another
adaptation of the ring closure treatment by hydrochlorides of
diethanolamine and aniline in stoichiometric quantities
involved heating at about 240 °C for a period of 8 h to
provide N-monophenylpiperazine.13,14 Although these methods
are one-step cyclizations, their versatility is restricted mainly
because of the harsh conditions, including the usage of forced
catalysts, high temperatures, and extended reaction times.
A common process for preparing alcohol- and amine-
extended piperazines is the coupling of an aliphatic alcohol
with an amine reactant, wherein the aliphatic alcohol and/or
reactant amine contains a piperazine moiety. Furthermore, it is
In continuation of our work on the synthesis of 1-methyl-4-
tosylpiperazine from N,N′-dimethylethylenediamine and
tosylbis(2-(tosyloxy)ethyl)amine (Scheme 1),18 we promote
the method for using differently substituted amines, even
Scheme 1. Previously Reported Synthesis of 1-Methyl-4-
tosylpiperazine
Received: June 26, 2012
Published: July 31, 2012
© 2012 American Chemical Society
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polyamines and amino acid esters, as substrates to synthesize a
series of piperazine derivatives. The mechanism of six-
membered ring formation is postulated based on the reaction
products and detailed computational information.
site that couples with tosylbis(2-(tosyloxy)ethyl)amine to
predominantly yield tertiary amine-extended piperazines.
To expand the scope of the substrates, hydroxyl-derived
amines were also applied as precursors to couple with
tosylbis(2-(tosyloxy)ethyl)amine to furnish two different
alcohol-extended piperazines, with yields of 67% and 72%,
respectively (entries 9 and 10, Table 1). Importantly, although
there are two functional groups (NH2 and OH) on the
structures, only the reactive amine group reacted in this
synthetic system, which is the main reason why only one
product was observed compared with the substrates containing
two active primary amines (entries 9 and 10 vs entries 2−5,
Table 1). Kaushik and co-workers have reported an imidazole-
catalyzed protocol for monoacylation of 2-(4-tosylpiperazin-1-
yl)ethanol in 92% yield.19 However, the starting material 2-
(piperazin-1-yl)ethanol in that reaction is difficult to synthesize
whereas, with the present method, 2-(4-tosylpiperazin-1-
yl)ethanol 10 was easily obtained by one-step cyclization
from two conveniently available reactants, tosylbis(2-
(tosyloxy)ethyl)amine and 2-aminoethanol. It was also
observed that secondary amine groups in the substrates did
not react with tosylbis(2-(tosyloxy)ethyl)amine when primary
amine existed (entries 3 and 9, Table 1).
RESULTS AND DISCUSSION
■
In our studies, tosylbis(2-(tosyloxy)ethyl)amine is chosen as
one of starting materials, which can be easily tosylated from
cheap chemical diethanolamine. Initially, different diamines
possessing two active primary amine groups were used as
substrates, coupling with tosylbis(2-(tosyloxy)ethyl)amine in
refluxing acetonitrile with potassium carbonate as the base
under nitrogen atmosphere, to afford two substituted products,
amine-extended piperazines and ditosylpiperazine derivatives
(entries 2−5, Table 1). The selectivity for these two kinds of
products can be modified by using an optional excess of
reactants. Yields of over 90% were achieved when asymmetri-
cally substituted diamines having one active primary amine and
one tertiary amine were used (entries 6−8, Table 1). These
asymmetrically substituted diamines only have one SN reaction
Table 1. Synthesis of Amine- and Alcohol-Extended
Piperazine Derivatives
This protocol was further investigated for aromatic amine,
which reacted with tosyl-protected diethanolamine to yield N-
arylpiperazines. But the cyclization of aniline furnished N-
phenylpiperazine only in a yield of 15% (entry 6, Table 2), and
Table 2. Synthesis of N-Alkyl-N′-tosylpiperazines and N-
Aryl-N′-tosylpiperazines
no corresponding product was detected for 4-bromobenzen-
amine. Pleasingly, 1-benzyl-4-tosylpiperazine was obtained
under the same reaction conditions in moderate yield (entry
3, Table 2). Previous researchers have reported the synthesis of
1-benzyl-4-tosylpiperazine by one-pot sulfonamidation from 1-
benzylpiperazine.20 Nevertheless, this compound was obtained
via several steps that included protection and deprotection.
Similarly, when other alkylamines were applied as starting
materials, corresponding N-alkylpiperazines were afforded in
high yields (entries 1 and 2, Table 2).
Subsequently, to further explore the efficiency and scope of
this approach, amino acid esters were utilized. It was found that
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this general one-step cyclization approach was also applicable
for the synthesis of tosylpiperazine acid esters, which were
achieved in moderate to high yields (entries 4 and 5, Table 2).
All of these results indicated that the present protocol is
effective for one-step cyclization of N-heteroalkyl-N′-tosylpi-
perazines.
To illuminate this interesting reaction, we postulate that
there are several substep aliphatic nucleophilic substitutions
(SN) in the cyclization reaction (Scheme 2). After one of the
Scheme 2
Figure 1. The optimized transition state (TS1) for nucleophilic attack
in the formation of a six-membered ring compound.
respectively. The C−N and N−O bond lengths in TS2 are
computed to be 2.104 and 2.037 Å, respectively (Figure 2). On
amino nitrogen atoms attacks tosylbis(2-(tosyloxy)ethyl)amine
to form intermediate a, the identical nitrogen atom attacks
another carbon, connected to a OTs group, through an
intramolecular SN reaction to give the six-membered ring
quaternary ammonium transition compound b. When R1 is
methyl or another alkyl group, another nitrogen atom attacks
the carbon atom alpha to the quaternary ammonium to give
compound c. However, when R1 is hydrogen, quaternary
ammonium transition compound b converts to amine-extended
piperazine e. Subsequently, an intermolecular SN reaction
occurs on the nitrogen atom of another terminal amine in
compound e to give compound f in the case of R2 = H.
Evidence for the formation of the six-membered ring was also
confirmed on the basis of density functional theory (DFT)
calculations (considering N,N′-dimethylethane-1,2-diamine as
the model substrate).
Figure 2. The optimized transition state (TS2) for the nucleophilic
attack reaction in the formation of the multiring compound.
As shown in Table 3, the reaction can proceed via two
alternative pathways. One involves the formation of a six-
the basis of the present calculations, in contrast to the
formation of a multiring compound, the reaction involving the
generation of the six-membered ring compound is kinetically
more favored. This agrees well with our experimental results
that we only obtain the six-membered ring compound during
the reaction process.
Table 3. The Relative Energy (RE in kcal/mol) of
Nucleophilic Attack Reaction Obtained from the B3LYP/6-
31++G(d,p) Method in the Gas Phase and Surrounding
Acetonitrile
Six-Membered Ring
CONCLUSION
R1
TS1
P1
■
a
We developed a general and practical one-step protocol for
selectively synthesizing alkyl-substituted tosylpiperazines and
amine/alcohol-extended tosylpiperazines under mild reaction
conditions with moderate to high yields, utilizing different
commercially available amines and tosylbis(2-(tosyloxy)ethyl)-
amine, which can be easily tosylated from diethanolamine.
More advantageously, this method avoided the problem of
protection and deprotection for the synthesis of asymmetric
piperazine derivatives and exhibited attractive applicability in
the synthesis of pharmaceuticals and natural products. Based on
the results of experiments and theoretical calculations, a
plausible mechanism of aliphatic nucleophilic substitution
(SN) in the cyclization was postulated. The favorable formation
of the six-membered ring was also confirmed by means of
density functional theory (DFT) calculations.
0.00 (0.00)
25.41 (16.86)
Multiring
−14.78 (−17.56)
R2
TS2
P2
0.00 (0.00)
29.60 (20.17)
−15.33 (−21.4)
a
Values in parentheses are obtained from surrounding acetonitrile.
membered ring compound, and the predicted activation
energies (TS1) are about 25.41 and 16.86 kcal/mol in the gas
phase and surrounding acetonitrile, respectively. As Figure 1
depicts, the C−N and N−O bond lengths in TS1 are calculated
to be 2.096 and 2.009 Å, respectively. The other pathway is
related to the formation of a multiring compound. As Table 3
shows, the activation energies (TS2) are equal to 29.60 and
20.17 kcal/mol in the gas phase and surrounding acetonitrile,
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2.50 (m, 4 H), 2.49−2.47 (m, 5 H), 2.43 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ 143.5, 132.4, 129.5, 127.7, 57.2, 52.3, 51.7, 46.1, 46.0,
41.1, 21.6. LRMS (ESI): m/z = 327 ([M + H]+). HRMS (ESI): calcd
for C15H27N4O2S ([M + H]+): 327.1855; found: 327.1856.
EXPERIMENTAL SECTION
■
General Methods. Chemicals were commercial reagent grade and
used as received without further purification unless otherwise stated.
The NMR spectra were recorded in CDCl3 as the internal standards
for 1H NMR (400 MHz) and 13C NMR (100 MHz) at room
temperature. Chemical shifts (δ) are given in ppm and are referenced
to residual solvent peaks. Electrospray ionization mass spectra (ESI-
MS) and high-resolution mass spectra (HRMS) were recorded using
ESI-mode. Melting points were recorded using an electrothermal
capillary melting point apparatus and are uncorrected. Thin-layer
chromatography (TLC) was performed on silica gel detected with UV
light (254 nm) or visualized by spraying with phosphomolybdic acid
and heating at 200 °C. Silica gel (H, 300−400 mesh) was used for
flash chromatography.
Synthesis of Tosylbis(2-(tosyloxy)ethyl)amine. Diethanolamine
(27.5 g, 0.262 mol) was dissolved in distilled CH2Cl2 (500 mL) in a
three-necked flask. The solution was cooled to 0 °C under a stream of
anhydrous N2, and Et3N (122 mL, 88.6 g, 0.880 mol) was added. With
the temperature maintained at 0 °C, solid TsCl (157 g, 0.823 mol) was
added in portions to the vigorously stirred reaction mixture over 5 h.
The reaction mixture was then stirred at r.t. overnight. The Et3N·HCl
that had formed was removed by filtration, and the resulting pale
yellow filtrate was washed with 1 M aq HCl (3 × 100 mL), followed
by H2O (5 × 200 mL) and sat. aq NaHCO3 (5 × 200 mL). The
organic layer was dried with anhydrous Na2SO4. The solvent was
removed by rotary evaporation, and the residue was recrystallized
(EtOH), which gave a white product (120 g, 80%): mp 98−99 °C
(lit.19 97−99 °C).
Bis(2−4-tosypiperazin-1-yl)ethyl)amine (3b). 3b was obtained
as a white solid in 18% yield (0.81 g): mp 50.3−51.2 °C. IR (KBr,
cm−1): 3429, 3133, 2924, 2853, 1629, 1455, 1400, 1164, 951, 731. 1H
NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.0 Hz, 4 H), 7.30 (d, J = 8.0
Hz, 4 H), 2.96 (br, 8 H), 2.67 (t, J = 6.4 Hz, 4 H), 2.48−2.45 (m, 12
H), 2.43 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ 143.6, 132.2,
129.5, 127.6, 56.6, 52.2, 46.0, 21.6. LRMS (ESI): m/z = 550.0 ([M +
H]+). HRMS (ESI): calcd for C26H40N5O4S2 ([M + H]+): 550.2522;
found: 550.2536.
3-(4-Tosylpiperazin-1-yl)propan-1-amine (4a). 4a was ob-
tained as a yellow oil in 72% yield (2.14 g). IR (KBr, cm−1): 2966,
1
2810, 1598, 1455, 1351, 1166, 949, 813, 732. H NMR (400 MHz,
CDCl3): δ 7.60 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 3.00
(br, 4 H), 2.69 (t, J = 6.8 Hz, 2 H), 2.52−2.49 (m, 4 H), 2.42 (s, 3 H),
2.38 (t, J = 6.8 Hz, 2 H), 1.61−1.54 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ 143.4, 129.4, 127.6, 94.2, 55.8, 52.2, 46.0, 40.4, 29.9, 21.5.
LRMS (ESI): m/z = 298 ([M + H]+).
General Procedure for the Synthesis of N-Heteroalkyl-N′-
tosylpiperazine. Tosylbis(2-(tosyloxy)ethyl)amine (5.83 g, 10.0
mmol), K2CO3 (8.00 g, 58.0 mmol), amine (10.0 mmol), and
anhydrous MeCN (50 mL) were added to a round-bottom flask. The
mixture was heated to reflux under an N2 atmosphere for 12 h. The
mixture was cooled to r.t. and filtered. The filtrate was concentrated,
and the residue was purified by flash chromatography (SiO2, CH2Cl2−
MeOH−Et3N as eluent) to give N-heteroalkyl-N′-tosylpiperazine (see
Table 1, Table 2, and Supporting Information).
1-Tosyl-4-(3-(4-tosylpiperazin-1-yl)propyl)piperazine (4b).
4b was obtained as a white solid in 16% yield (0.83 g): mp 169.1−
169.7 °C. IR (KBr, cm−1): 3410, 3101, 3062, 2954, 2812, 1597, 1454,
1348, 1169, 1163, 1092, 947, 822, 732. 1H NMR (400 MHz, CDCl3):
δ 7.59 (d, J = 8.0 Hz, 4 H), 7.28 (d, J = 8.0 Hz, 4 H), 2.97 (br, 8 H),
2.47−2.44 (m, 8 H), 2.42 (s, 6 H), 2.28 (t, J = 7.2 Hz, 4 H), 1.62 (s, 2
H). 13C NMR (100 MHz, CDCl3): δ 143.4, 131.9, 129.3, 127.6, 55.8,
52.1, 45.9, 24.1, 21.5. LRMS (ESI): m/z = 521 ([M + H]+). HRMS
(ESI): calcd for C25H37N4O4S2 ([M + H]+): 521.2256; found:
521.2227.
1-(2′-Aminoethyl)-4-tosylpiperazine (2a). 2a was obtained as a
pale-yellow liquid in 70% yield (1.98 g). IR (KBr, cm−1): 3356, 2948,
2816, 1596, 1454, 1349, 1164, 950, 733. 1H NMR (400 MHz, CDCl3):
δ 7.61 (d, J = 6.4 Hz, 2 H), 7.31 (d, J = 6.4 Hz, 2 H), 3.00 (br, 4 H),
2.72 (t, J = 6.0 Hz, 2 H), 2.51 (br, 4 H), 2.43−2.42 (m, 5 H), 2.13 (s, 2
H). 13C NMR (100 MHz, CDCl3): δ 143.4, 132.1, 129.4, 127.6, 60.0,
52.2, 46.0, 38.4, 21.5. LRMS (ESI): m/z = 284 ([M + H]+). HRMS
(ESI): calcd for C13H22N3O2S ([M + H]+); 284.1433; found:
284.1423.
2-(2-(4-Tosylpiperazin-1-yl)ethoxy)ethanamine (5a). 5a was
obtained as a light yellow liquid in 71% yield (2.32 g). IR (KBr, cm−1):
1
3375, 3134, 2921, 2856, 1597, 1456, 1348, 1167, 953, 734. H NMR
(400 MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2
H), 3.51 (t, J = 5.6 Hz, 2 H),3.44 (t, J = 5.2 Hz, 2 H), 3.01 (br, 4 H),
2.84 (t, J = 5.6 Hz, 2 H), 2.58−2.55 (m, 6 H), 2.42 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ 143.7, 129.4, 127.7, 94.2, 72.3, 68.3, 57.4, 52.5,
45.9, 41.2, 21.6. LRMS (ESI): m/z = 328 ([M + H]+). HRMS (ESI):
calcd for C15H26N3O3S ([M + H]+): 328.1695; found: 328.1688.
1-Tosyl-4-(2-(4-tosylpiperazin-1-yl)ethyl)piperazine (2b). 2b
was obtained as a white solid in 20% yield (1.01 g): mp 253.3−253.6
°C. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 4 H), 7.28 (d,
J = 8.0 Hz, 4 H), 2.96 (br, 8 H), 2.51−2.49 (m, 8 H), 2.41 (s, 10 H).
13C NMR (100 MHz, CDCl3): δ 143.5, 132.0, 129.5, 127.7, 55.3, 52.6,
46.0, 21.6. LRMS (ESI): m/z = 507 ([M + H]+).
1-(2-(2-(4-Tosylpiperazin-1-yl)ethoxy)ethyl)-4-tosylpipera-
zine (5b). 5b was obtained as a white solid in 20% yield (1.10 g): mp
140.2−141.2 °C. IR (KBr, cm−1): 3130, 2933, 2808, 1597, 1451, 1388,
1343, 1163, 1109, 950, 732. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J
= 8.4 Hz, 4 H), 7.30 (d, J = 8.4 Hz, 4 H), 3.45 (t, J = 6.0 Hz, 4 H),
2.98 (br, 8 H), 2.55−2.50 (m, 12 H), 2.42 (s, 6 H). 13C NMR (100
MHz, CDCl3): δ 143.5, 131.9, 129.4, 127.7, 68.5, 57.1, 52.6, 45.9, 21.6.
LRMS (ESI): m/z = 551 ([M + H]+). HRMS (ESI): calcd for
C26H39N4O5S2 ([M + H]+): 551.2362; found: 551.2367.
N1-(2-(4-Tosylpiperazin-1-yl)ethyl)ethane-1,2-diamine (3a).
3a was obtained as a light yellow oil in 72% yield (2.34 g). IR (KBr,
1
cm−1): 3429, 3138, 2853, 1629, 1400, 1163, 952, 731. H NMR (400
MHz, CDCl3): δ 7.61 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H),
3.01 (br, 4 H), 2.77 (t, J = 6.0 Hz, 2 H), 2.67−2.63 (m, 4 H), 2.53−
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Butyl-4-tosylpiperazine (11). 11 was obtained as a white solid in
71% yield (2.10 g): mp 79−80 °C. IR (KBr, cm−1): 3050, 2925, 2850,
1
2809, 2746, 1596, 1447, 1352, 1174, 941, 810, 729. H NMR (400
N,N-Dimethyl-3-(4-tosylpiperazin-1-yl)propan-1-amine (6). 6
was obtained as a yellow solid in 92% yield (2.99 g): mp 66−68 °C. IR
MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H),
3.00 (bt, 4 H), 2.50 (t, J = 4.8 Hz, 4 H), 2.42 (s, 3 H), 2.30 (t, J = 7.6
Hz, 2 H), 1.43−1.35 (m, 2 H), 1.31−1.22 (m, 2 H), 0.87 (t, J = 7.2
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ 143.2, 132.2, 129.3, 127.6,
57.8, 52.2, 46.0, 28.8, 21.4, 20.4, 13.7. LRMS (ESI): m/z = 297 ([M +
H]+).
1
(KBr, cm−1): 2948, 2816, 1596, 1454, 1349, 1164, 950, 815, 733. H
NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0
Hz, 2 H), 3.00 (br, 4 H), 2.52−2.49 (m, 4 H), 2.42 (s, 3 H), 2.35 (t, J
= 7.6 Hz, 2 H), 2.23 (t, J = 7.6 Hz, 2 H), 2.18 (s, 6 H), 1.62−1.55 (m,
2 H). 13C NMR (100 MHz, CDCl3): δ 143.4, 132.0, 129.4, 127.7, 57.6,
56.1, 52.2, 46.0, 45.4, 29.7, 25.1. LRMS (ESI): m/z = 326 ([M + H]+).
HRMS (ESI): calcd for C16H28N3O2S ([M + H]+): 326.1902; found:
326.1885.
1-Cyclohexyl-4-tosylpiperazine (12). 12 was obtained as a white
solid in 83% yield (2.67 g): mp 113−116 °C. IR (KBr, cm−1): 3050,
2925, 2850, 2809, 2746, 1596, 1447, 1352, 1174, 1060, 941, 810, 729.
1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2 H), 7.29 (d, J =
8.0 Hz, 2 H), 2.98 (br, 4 H), 2.63 (t, J = 4.8 Hz, 4 H), 2.41 (s, 3 H),
2.25−2.19 (m, 1 H), 1.78−1.74 (m, 4 H), 1.62−1.59 (m, 1 H),1.25−
1.03 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ 143.2, 132.1, 129.3,
127.6, 63.2, 48.1, 46.5, 28.9, 26.2, 25.8, 21.5. LRMS (ESI): m/z = 323
([M + H]+).
N,N-Diethyl-3-(4-tosylpiperazin-1-yl)propan-1-amine (7). 7
was obtained as a light yellow oil in 90% yield (3.18 g). IR (KBr,
1
cm−1): 2966, 2810, 1598, 1455, 1351, 1166, 949, 813, 732. H NMR
(400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2
H), 3.00 (br, 4 H), 2.52−2.44 (m, 8 H), 2.42 (s, 3 H), 2.39−2.31 (m,
4 H), 1.60−1.53 (m, 2 H), 0.98 (t, J = 7.0 Hz, 6 H). 13C NMR (100
MHz, CDCl3): δ 143.3, 132.0, 129.3, 127.6, 56.3, 52.2, 50.6, 46.8, 46.0,
24.5, 21.5, 11.7. LRMS (ESI): m/z = 354 ([M + H]+). HRMS (ESI):
calcd for C18H32N3O2S ([M + H]+): 354.2215; found: 354.2211.
1-Benzyl-4-tosylpiperazine (13). 13 was obtained as a light
yellow solid in 59% yield (1.95 g): mp 119−120 °C. IR (KBr, cm−1):
3113, 3024, 2938, 2907, 2848, 2821, 1592, 1449, 1396, 1341, 1162,
1
938, 814, 741. H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz, 2
H), 7.30−7.20 (m, 7 H), 3.46 (s, 2 H), 3.00 (br, 4 H), 2.50 (t, J = 4.8
Hz, 4 H), 2.41 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 143.4,
137.3,132.3, 129.5, 128.9, 128.1, 127.7, 127.1, 62.6, 52.1, 46.1, 21.6.
LRMS (ESI): m/z = 331 ([M + H]+).
N,N,2,2-Tetramethyl-3-(4-tosylpiperazin-1-yl)propan-1-
amine (8). 8 was obtained as a light yellow solid in 95% yield (3.35
g): mp 84−86 °C. IR (KBr, cm−1): 2948, 2816, 1596, 1454, 1349,
1164, 950, 733. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2
H), 7.31 (d, J = 8.0 Hz, 2 H), 2.96 (br, 4 H), 2.59−2.57 (m, 4 H), 2.44
(s, 3 H), 2.21 (s, 6 H), 2.14 (s, 2 H), 2.01 (s, 2 H), 0.78 (s, 6 H). 13C
NMR (100 MHz, CDCl3): δ 143.2, 132.5, 129.4, 127.6, 68.8, 66.3,
54.7, 48.8, 46.4, 38.1, 24.4, 21.6. LRMS (ESI): m/z = 354 ([M + H]+).
HRMS (ESI): calcd for C18H32N3O2S [M+ + H]: 354.2215; found:
354.2207.
Ethyl 3-(4-Tosylpiperazin-1-yl)propanoate (14). 14 was
obtained as a white solid in 61% yield (2.07 g): mp 82−83 °C. IR
(KBr, cm−1): 2966, 2910, 2819, 1722, 1596, 1459, 1393, 1347, 1159,
1
936, 813, 737. H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.0 Hz, 2
H), 7.30 (d, J = 8.0 Hz, 2 H), 4.08 (q, J = 6.8 Hz, 2 H), 2.99 (br, 4 H),
2.67 (t, J = 6.8 Hz, 2 H), 2.53 (t, J = 4.8 Hz, 4 H), 2.42 (s, 3 H), 2.41−
2.39 (m, 2 H), 1.21 (t, J = 6.8 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ 171.8, 155.6, 143.4, 129.4, 127.6, 60.4, 53.1, 51.9, 45.9, 32.3,
21.5, 14.2. LRMS (ESI): m/z = 341 ([M + H]+).
2-(2-(4-Tosylpiperazin-1-yl)ethylamino)ethanol (9). 9 was
obtained as a yellow solid in 67% yield (2.19 g): mp 67−68 °C. IR
(KBr, cm−1): 3158, 2922, 2845, 1596, 1454, 1341, 1163, 1058, 946,
1
812, 731. H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.4 Hz, 2 H),
7.30 (d, J = 8.4 Hz, 2 H), 3.57 (t, J = 4.8 Hz, 2 H), 3.00 (br, 4 H),
2.73−2.66 (m, 4 H), 2.53−2.46 (m, 6 H), 2.43 (s, 3 H), 2.22 (br, 2
H). 13C NMR (100 MHz, CDCl3): δ 143.6, 129.5, 127.7, 94.3, 60.8,
57.2, 52.3, 50.9, 46.0, 45.6, 21.5. LRMS (ESI): m/z = 328.0 ([M +
H]+). HRMS (ESI): calcd for C15H26N3O3S ([M + H]+): 328.1695;
found: 328.1687.
Ethyl 3-Phenyl-2-(4-tosylpiperazin-1-yl)propanoate (15). 15
was obtained as a white solid in 75% yield (3.12 g): mp 126−128 °C.
IR (KBr, cm−1): 3029, 2977, 2899, 2838, 1726, 1450, 1398, 1331,
1249, 1161, 946, 738. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0
Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.23−7.14 (m, 3 H), 7.12−7.09
(m, 2 H), 4.07−4.00 (m, 2 H), 3.88 (q, J = 5.2 Hz, 1 H), 3.04−2.98
(m, 5 H), 2.86−2.76 (m, 3 H), 2.72−2.66 (m, 2 H), 2.43 (s, 3 H), 1.12
(t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ 170.4, 155.6,
143.4, 137.4, 129.4, 128.9, 128.2, 127.7, 126.3, 69.2, 60.4, 48.9, 46.4,
35.6, 21.6, 14.4. LRMS (ESI): m/z = 417 ([M + H]+), 439 ([M +
Na]+). HRMS (ESI): calcd for C22H29N2O4S ([M + H]+): 417.1848;
found: 417.1827.
2-(4-Tosylpiperazin-1-yl)ethanol (10). 10 was obtained as a
white solid in 72% yield (2.05 g): mp 131−132 °C. IR (KBr, cm−1):
1
3411, 2912, 2809, 2766, 1451, 1338, 1163, 1092, 1055, 949, 738. H
NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 3.56 (t, J = 5.6 Hz, 2 H), 3.01 (br, 4 H), 2.59−2.57 (m, 4
H), 3.53 (t, J = 5.6 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ 143.5, 132.2, 129.5, 127.6, 58.9, 57.8, 52.0, 46.1, 21.6.
LRMS (ESI): m/z = 285 ([M + H]+).
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dx.doi.org/10.1021/jo3012896 | J. Org. Chem. 2012, 77, 7506−7511

The Journal of Organic Chemistry
Article
1-Phenyl-4-tosylpiperazine (16). 16 was obtained as a white
solid in 15% yield (0.23 g). 1H NMR (400 MHz, CDCl3): δ = 7.66 (d,
J = 8.8 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.25−7.21 (m, 2 H), 6.89−
6.84 (m, 3 H), 3.23 (t, J = 4.4 Hz, 4 H), 3.14 (t, J = 4.4 Hz, 4 H), 2.43
(s, 3 H). LRMS (ESI): m/z = 317 ([M + H]+).
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Computational Methods. In the present studies, all geometries of
reaction species were calculated by means of B3LYP/6-31++G(d,p)
method,21−23 and frequency calculations were also employed to
confirm the structures as minimum points in energy and achieve the
relevant zero point energy (ZPE) in the gaseous phase. For each
transition state, intrinsic reaction coordinate (IRC) calculations were
performed to guarantee its correct connection to the designated local
minima. Solvation energies were added as single-point calculations
using the conductor-like solvation model CPCM24,25 at the B3LYP/6-
31++G (d, p) level based on the gas-phase structures. In this model, a
cavity around the system is surrounded by a polarizable dielectric
continuum. In addition, a dielectric constant of 36.64 is used to model
the surrounding acetonitrile.
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(18) Huang, J. Y.; Zhou, Z. Y.; Chan, T. H. Synthesis 2009, 2341−
2344, 3941−3942.
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4232−4235.
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Amini, Z.; Behrouz., M. Synthesis 2009, 3983−3988.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(24) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995−2001.
(25) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem.
2003, 24, 669−681.
Computational detail and copies of spectra for the products 2−
16. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: 86 571 8807 1024 7590. E-mail: huangjy@mail.zjgsu.edu.
cn(J.H.); l_shijun@hznu.edu.cn (S.L.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21102129, 21072039), Technology
Planning Project of Zhejiang Province of China
(2011C12031), Public Welfare Technology and Application
Program of Zhejiang Province of China (2010C31042), Natural
Science Foundation of Zhejiang Province of China
(Y3110204), and Opening Foundation of Zhejiang Provincial
Top Key Discipline of New Materials and Process Engineering.
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