Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b02564

By using cheap and innocuous reagents, such as NaClO₂, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp³)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

Full text of DOI:10.1021/acs.joc.8b02564

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Article
Selective, Catalytic and Dual C(sp3)-H Oxidation of Piperazines
and Morpholines Under Transition Metal-Free Conditions
Delfino Chamorro-Arenas, Urbano Osorio-Nieto, Leticia
Quintero, Luís Hernández-García, and Fernando Sartillo-Piscil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02564 • Publication Date (Web): 15 Nov 2018
Downloaded from http://pubs.acs.org on November 15, 2018
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Selective, Catalytic and Dual C(sp3)−H Oxidation of
Piperazines and Morpholines Under Transition Metal-
Free Conditions
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Delfino Chamorro-Arenas,† Urbano Osorio-Nieto,† Leticia Quintero,† Luís Hernández-García,‡ and
Fernando Sartillo-Piscil.†*
†Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de
Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México.
‡Centro de Investigación e Innovación Tecnológica, Instituto Tecnológico de Nuevo León, Av. De la
Alianza #507, PIIT. Carretera Monterrey-Aeropuerto Km.10, Apodaca NL. 66628, México
† D. C. A. and U. O. N., contributed equally to this work
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*To whom correspondence should be addressed (fernando.sartillo@correo.buap.mx). Telephone:+52
222 2955500 ext. 7391. Fax number: + 52 222 2454972
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
KEYWORDS C−H Oxidation, diketopiperazines, TEMPO, NaClO2, NaOCl, environmentally friendly
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Abstract: By using cheap and innocuous reagents, such as NaClO2, NaOCl and catalytic amounts of
TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)−H
oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-
MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides
significant advantages over the traditional N-monoacylation/intramolecular C−N cyclization procedure.
Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared
from morpholine derivatives, which would enable further functionalization at the C-2 position of the
morpholine skeleton.
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INTRODUCTION
Diketopiperazines (DKPs), in the three isomeric forms (2,3-DKP, 2,5-DKP and 2,6-DKP), belong to a
privileged class of organic compounds, which due to their structural resemblance to peptides, have
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attracted interest of chemists focused in drug discovery.1 A numerous of naturally occurring bioactive
products are DKP derivatives,2 and another vast number of synthetic DKPs have been prepared for the
purpose to mimic the conformational and biological properties of peptides.3 On the other hand, although
3-morpholinones (3-MPs) are not common in nature,4 they are frequently prepared in the laboratory as
key precursors for pharmaceutical drugs.5 A representative example of each KDPs and 3-MP is
showcased in Figure 1. Orychophragine A is a 2,3-DKP derivative recently isolated from
Orychophragmus violaceus which exhibited remarkable cytotoxicity against three cell lines.6
Brevianamide F is a biosynthetic precursor of biologically active metabolites produced by the fungi A.
fumigates and Asperguillus sp.7 An inhibitor of the virus of influenza (virus A) is the 2,6-DKP
derivative Flutimide.8 On the other hand, an important 3-MP derivative is the 4-(4-aminophenyl)-3-
morpholinone,9 a key intermediate for the synthesis of rivaroxaban.10
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Figure 1. Isomeric DKPs and biologically important DKPs
In spite of the high importance of these organic compounds, there is, in fact, only one synthetic
strategy for accessing to all of them.1 For instance, the general strategy for preparing 2,3-DKPs includes
the classical N-monoacylation followed by intramolecular amidation sequence process (eq 1, Scheme
1),1,11 in which long and tedious activation processes of the carbonyl group are often required.12
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Furthermore, an apparent solution to this synthesis problem might be the direct functionalization of
preexisting heterocycle13 via a direct C−H oxidation of piperazines to 2,3-DKPs or morpholines to 3-
MPs. Unfortunately, the latter strategy does not provide consistent results when transition metals are
employed (eq 2, Scheme 1).14 Consequently, the current investigation offers a novel protocol for the
direct functionalization of piperazines and morpholines to 2,3-diketopiperazines and 3-morpholinones,
respectively, under transition-metal-free conditions, and using environmentally friendly reagents (eq 3,
Scheme 1).
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Scheme 1. Synthesis strategies to 2,3-diketopiperidines
RESULTS AND DISCUSSION
This novel dual C−H oxidation reaction of piperazines to 2,3-DKPs was inspired by a previous
chemical reaction mechanism, in which piperidines and pirrolidines were directly transformed into their
respective 3-alkoxyamino lactams via a selective and tandem C−H oxidation at the alpha and beta
positions (eq 4, Scheme 2).15
Scheme 2. Mechanistic proposal for the selective and dual C−H oxidation of cyclic amines to 3-
alkoxyamine lactams (eq 4). TEMPO-catalyzed mechanistic proposal for accessing to 2,3-DKP from
piperazines (eq 5)
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According to the proposed reaction mechanism, TEMPO oxammonium cation (1), which is generated
in situ by oxidation of TEMPO radical (2) with NaClO2 and NaOCl, enables selective alpha C−H
activation of cyclic amines to iminium cation (3) plus TEMPOH (4), and the latter is re-oxidized to
oxammonium cation 1. Then, intermediate 3 is spontaneously transformed into enamine 5. Nucleophilic
attack of 5 to 1 engenders intermediate 6,16 which after oxidation with chlorite anion, produces the 3-
alkoxyamine lactam (eq 4, Scheme 2). Assuming that TEMPO oxammonium cation 1 is regenerated
during the reaction course, then we anticipated that substituted piperazine could follow similar
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sequential reaction course as for the cyclic amines (7 → 8 → 9), albeit due to the presence of the second
nitrogen atom at the C4 position, TEMPOH (4) would be expelled and incorporated into the catalytic
cycle; finally, the formed diiminnium cation 10 would be oxidized to 2,3-DKP. Thus, a successful
execution of this mechanistic proposal may open access to the development of a novel TEMPO-
catalyzed dual C−H oxidation reaction of piperazines to 2,3-diketopiparazines in a very low economic
and ecological cost (eq 5, Scheme 2).
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Benzyl piperazine 11 was selected as a suitable substrate for testing the mechanistic proposal
showcased in Scheme 2 (eq 2). Initial reaction conditions were taken from the original dual C−H
oxidation reaction protocol,15 in which TEMPO (1.5 equiv), NaClO2 (3.0 equiv) NaOCl (1.5 equiv) and
NaH2PO4 (10 equiv) were used, and after 2 h of reaction at room temperature in CH3CN, piperazine 11
was transformed into 2,3-DKP 12 in 80% yield (Table 1, entry 1). Despite the dramatic decreasing of the
amount of TEMPO from 3 equivalents to catalytic amount (0.1 equiv), and keeping the same quantities
of the other reagents, the chemical yield of 12 was not affected (entry 2). Having promptly achieved this
novel catalytic dual C−H oxidation mediated by TEMPO, further screening condition were explored
with the intention to optimize other chemical reagents. When amounts of NaOCl and NaH2PO4 were
reduced to more than fifty percent, the reaction gave a better chemical yield (entry 3). However,
reducing only the amount of NaOCl to 0.1 equiv, chemical yield of 12 dropped to traces (entry 4).
Similar behavior was observed when NaClO2 was also reduced to less than 3 equivalents (entry 5). On
the other hand, starting material 11 remained unchanged when buffer (NaH2PO4) was not employed
(entry 6). The use of greener solvents such as MeOH (entry 7) or acetone (entry 8) did not provided the
desired results, and further oxidized compounds like benzoic acid was obtained. And by reducing the
amount of TEMPO to 5% mol, the chemical yield dropped to 65% (entry 9). Similar results were
observed by reducing equivalents of TEMPO and co-oxidizing reagent NaOCl (entries 10 and 11). It is
important to note that in the absence of TEMPO the benzylic C-H oxidation is a competitive reaction.15
Therefore, this screening studies established that using only 10% mol of TEMPO, 3 equivalents of
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NaClO2 and NaH2PO4, and 0.7 equiv of NaOCl at 0 °C in acetonitrile as solvent, piperazine 11 can be
transformed to diketopiperazine 12 in 95% yield (Table 1).
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Table 1.a,b Screening conditions for TEMPO-catalyzed selective dual C−H oxidation of piperazine 11 to
2,3-diketopiparezine 12
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Entry
NaClO2
NaH2PO4
TEMPO
NaOCl
Solvent
Time
Isolated yield
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0.7
0.1
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0.7
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
Acetone
MeCN
MeCN
MeCN
2 h
2 h
80%
88%
95%
traces
45%
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0.1
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0.1
0.1
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0.05
0.03
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3
1 h
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10 h
10 h
24 h
1 h
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1.5 h
2 h
45%
65%c
50%c
48%
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11
2 h
2 h
aStarting material remained unchanged. Starting material is transformed into unwanted byproducts. Benzoic acid is
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c
formed.
With optimized reaction conditions in hands, the scope of this novel catalytic reaction was evaluated.
A series of symmetrical and non-symmetrical N-piperazines (13a-q) were selected with the idea of not
only to prepare synthetic relevant precursors but also synthetic models that may provide mechanistic
findings for this novel catalytic chemical reaction. Yields up to or more than 90% were obtained (Table
2, 13a-13p). Because the N-ethyl-2,3-DKP molecular fragment is present in various pharmaceutical
antibiotics such as piperacillin,17 piperazines (13a-c, 13e and 13f) were prepared and tested for the
catalytic dual oxidation giving good to high yields of 2,3-DKP (14a-c, 14e and 14f). By taking
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advantage of this novel reaction, 1-benzyl-4-ethyl-2,3-DKP 14b was obtained from its piperazine
derivative 13b in high yield, which after oxidative debenzylation with ceric ammonium nitrate (CAN),
the relevant pharmacological intermediate ethyl-2,3-DKP was obtained.18
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Table 2.a,b TEMPO-catalyzed selective dual C−H oxidation of piperazines to 2,3-diketopiparezines
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Because the presence of either indole moiety or phenyl group in 2,3-DKPs potentializes their
biologically activity,19 the respective piperazines 13c-d and 13i-k were prepared and subjected to
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catalytic dual oxidation to obtain DKPs 14c, 14d, 14i, 14j and 14k, respectively, in good to high yields.
Similar results were observed with N-Alkyl and N-allyl-piperazines (13g, 13h, 13m and 13n); however,
when N-allyltetrahydroquinoxaline 13o was tested, quinoxaline 14o was obtained instead the expected
N-allyl-2,3-DKP (not shown). It seems that the formation of the pyrazine ring is favored by
aromatization via deallylation reaction.20 For mechanistic purposes, optically pure piperazine 13p was
prepared. It is well-known that benzylic C−H bonds are weaker than most of alkylic C−H bonds, then
benzylic C−H oxidation of piperazines, e. g., 11 in eq 6 to iminium A, could be a more favored process
than the direct C−H oxidation of an endocyclic hydrogen to B; therefore, the likely formation of B from
A was a chemical process that needed to be revised (Scheme 3, eqs 6 and 7).21
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Scheme 3. Stereochemical proof for selective C−H oxidation of piperazines
Thus, erosion of the optical purity in the chiral piperazine 13p after reduction of 14p would provide
experimental evidence for the selective C−H oxidation of piperazines. Optically pure piperazine 13p
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was oxidized to chiral 2,3-DKP 14p followed by reduction with LiAlH4 to return to 13p. Analysis of the
optical rotation of the reduction product, which was identical to the initial piperazine 13p, revealed a
complete preservation of the optical purity (Scheme 3, eq 7). Additionally, N-boc-benzyl piperazine 13q
was prepared to gain further insights on the reaction mechanism (eq 8, Scheme 2). We hypothesized the
following: if one nitrogen atom compromises its lone pair toward a carbonyl group (red atom), the first
C−H oxidation would be highly selective upon the side where the nitrogen atom maintains the basic
character (blue atom), and the catalytic cycle might be either interrupted or delayed preventing thus the
dual oxidation. Accordingly, piperazine 13q was tested under the same reaction conditions as for the
other piperazines, and three oxidized compounds were obtained (14q, 14r and 14s). As expected, the
first C−H oxidation occurred away from the amide nitrogen atom forming intermediate C, which
produces 14q after being attacked by ClO2 anion.22 Intermediate E is generated via a selective
electrophilic attack of oxammonium cation 1 to intermediate D, which the latter is either oxidized to 14r
or transformed into intermediate F via TEMPOH elimination followed by chlorite anion attack to form
13s (eq 8, Scheme 3). While the formation of 14q can be explained in terms of an interrupted catalytic
process, the formation of 14s in low yield evidences the inefficient capacity of the amide nitrogen atom
for restoring the catalytic TEMPO cycle by expelling the TEMPOH group.
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With this mechanistic information in mind, which suggests that the C−H oxidation reaction of
piperazines can be modulated by the electronic nature of the nitrogen atom; we thought that a more
electronegative atom such as the oxygen atom could delay or interrupt the dual C−H oxidation reaction.
Consequently, it was envisioned the possibility of transforming morpholines 15 into 3-morpholinones
16 under this novel environmentally friendly reaction conditions.23 Consequently, benzyl, alkyl and
phenyl morpholines underwent the expected C−H oxidation reaction alpha to the nitrogen atom giving
3-morpholinones in good to high yields (16a, 16c, 16d and 16g); moderated or low yield when the
aromatic ring in the benzyl group is found either activated (16b) or when the alkyl groups are
susceptible to bond cleavage (16e). Interestingly, the free hydroxyl group in 16e resulted to be
unreactive under this reaction conditions, indicating that the amine group is more reactive with the
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oxammonium cation 1 than the hydroxyl group.15 Unfortunately, 3-morpholine derived from indole
(15f) was not transformed to the respective 3-morpholinone16f in acceptable yield (Table 3).
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The isolation, in traces, of byproducts 16h and 16i from N-benzyl morpholine (15a) suggests that
morpholines can be selectively transformed into 2-alkoxyamino-3-morpholinones under non-catalytic
TEMPO conditions. To proof this, N-benzyl morpholine 15a was subjected to dual non-catalytic
conditions (1.5 equivalents of TEMPO), and 2-aminoalkoxy-3-morpholinone 16i was obtained in 75%
yield (Scheme 4).
Scheme 4. Synthesis of 2-alkoxyamino-3-morpholinone 16j from benzyl morpholine 15a
CONCLUSIONS
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We have developed, in an unprecedented tandem-catalytic fashion and using environmentally friendly
reagents, a new chemical reaction that allows the direct access to 2,3-diketopiperazines and 3-
morpholinones from piperazines and morpholines, respectively. This novel methodology is highly
competitive in efficiency and efficacy with the traditional N-monoacylation/intramolecular C−N
cyclization procedure. Additionally, it was showed that under non-catalytic TEMPO conditions,
morpholines can be transformed into 2-aminoalkoxy-3-morpholinones, which in turn, may offer a new
way for functionalization of morpholinones. Thus, a new case of direct functionalization of preexisting
heterocycle at low-economic and ecological cost was successfully achieved. Further application of this
methodology to the synthesis of biologically relevant products is underway and will be reported soon.
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EXPERIMENTAL SECTION
General considerations
C−H Oxidation reactions were carried out under air atmosphere at 0 °C, and the solvents used were non-
anhydrous. Reactions sensitive to air or moisture were carried out under argon atmosphere in dry and
freshly distilled solvents under anhydrous conditions. Reactions were monitored by thin layer
chromatography (TLC), which were monitored by ultraviolet (UV). Purifications of products were
performed by column chromatography using silica gel (230-400 mesh). NMR spectra were obtained in a
1
500 MHz spectrometer (500 MHz for H and 125 MHz for 13C{1H}). All samples were analyzed in
CDCl3 with TMS as internal reference using a relative scale in parts per millon (ppm) for the chemical
shift (δ), Hz for coupling constants (J) and are calibrated using residual solvents signals (1H NMR:
CHCl3 = 7.26 ppm; 13C{1H}: CHCl3 = 77.16 ppm). Splitting patterns are designated as follow: s,
singlet; d, doublet; q, quartet; m, multiplet; dd, doublet doublet; br, broad; and their combinations.
Optical rotation of the compounds was measured on a polarimeter on the D-line of sodium (589 nm) and
expressed in degrees. The measurements were performed at a temperature of 20 °C and the
concentration of the sample was expressed in g/100 mL. High resolution mass spectra (HRMS) were
acquired in electron-impact (EI), electrospray ionization (ESI) mode using a TOF mass analyzer or in
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fast-atom-bombardment (FAB) mode using a QMS mass analyzer. Melting points were determined
with a fusiometer and are not corrected.
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Preparation of piperazine derivatives
1,4-Dibenzylpiperazine (11)24
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To a suspension of piperazine (1.00 g, 11.61 mmol) and K2CO3 (4.01 g,
29.02 mmol) in CH3CN (28 mL) was added dropwise benzyl bromide (3.04
mL, 25.54 mmol). The reaction mixture was stirred at room temperature for 2 h. Then, the reaction
mixture was cooled to room temperature and the resulting solids were filtered and washed with EtOAc
(3 x 15 mL). The organic portion was concentrated under reduced pressure and the residue was purified
by flash chromatography on silica gel (Hexane/EtOAc, 3:1) to give 2.79 g (90%) of 11 as a white solid.
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Mp = 88-90 °C. H NMR (500 MHz, CDCl3) δ 2.51 (br, 8H), 3.53 (s, 4H), 7.30 (m, 10H). C{1H}
NMR (125 MHz, CDCl3) δ 53.0, 63.1, 127.2, 128.3, 129.4, 138.9.
1-Benzyl-4-ethylpiperazine (13a)25
To a suspension of 1-ethylpiperazine (0.56 mL, 4.38 mmol) and K2CO3 (0.79 g,
5.69 mmol) in CH3CN (10 mL) was added dropwise benzyl bromide (0.57 mL,
4.81 mmol). The resulting reaction mixture was stirred at room temperature for 2.5 h. Then, the reaction
mixture was cooled to room temperature and the resulting solids were filtered and washed with EtOAc
(3 x 10 mL). The organic portion was concentrated under reduced pressure and the residue was purified
by flash chromatography on silica gel (Hexane/EtOAc/MeOH, 1:2:0.5) to give 0.74 g (83%) of 13a as a
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yellow oil. H NMR (500 MHz, CDCl3) δ 1.08 (t, J = 7.0 Hz, 3H), 2.41 (q, J = 7.0 Hz, 2H), 2.49 (br,
8H), 3.51 (s, 2H), 7.28 (m, 5H). 13C{1H} NMR (125 MHz, CDCl3) δ 12.1, 52.4, 52.9, 53.1, 63.2, 127.1,
128.2, 129.3, 138.1.
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1-(p-Methoxybenzyl)-4-ethylpiperazine (13b)26
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A mixture of 1-ethylpiperazine (1.27 mL, 10.00 mmol) and Na2CO3 (1.58 g,
15.00 mmol) in CH3CN (20 mL) was added p-methoxybenzyl chloride
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(1.40 mL, 10.00 mmol). The reaction mixture was heated at reflux for 5 h. Then, the reaction mixture
was cooled at room temperature and the resulting solids were filtered and washed with EtOAc (3 x 15
mL). The organic portion was concentrated under reduced pressure and the residue was purified by flash
chromatography on silica gel (Hexane/EtOAc, 1:1) to give 1.58 g (68%) of 13b as a yellow oil. 1H NMR
(500 MHz, CDCl3) δ 1.07 (t, J = 7.5 Hz, 3H), 2.40 (q, J = 7.5 Hz, 2H), 2.48 (br, 8H), 3.45 (s, 2H), 3.79
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(s, 3H), 6.84 (m, 2H), 7.22 (m, 2H). C{1H} NMR (125 MHz, CDCl3) δ 12.1, 52.4, 52.8, 53.0, 55.3,
62.5, 113.6, 130.1, 130.5, 158.7.
tert-Butyl 3-(2-(4-ethylpiperazin-1-yl)ethyl)-1H-indole-1-carboxylate (13c)
To a suspension of N-Boc-2-bromoethylindole (0.40 g, 1.23 mmol) and K2CO3
(0.25 g, 1.84 mmol) in CH3CN (12 mL) was added 1-ethylpiperazine (0.18 mL,
1.47 mmol). The resulting reaction mixture was heated at reflux for 2 h. After
this time, the mixture was cooled to room temperature and the resulting solids were filtered and washed
with EtOAc (3 x 10 mL). The organic portion was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95:05) to give 0.41 g (93%) of 13c
as a brown oil. 1H NMR (500 MHz, CDCl3) δ 1.12 (t, J = 7.0 Hz, 3H), 1.67 (s, 9H), 2.47 (q, J = 7.0 Hz,
2H), 2.61 (br, 8H), 2.73 (t, J = 8.0 Hz, 2H), 2.90 (app t, J = 8.0 Hz, 2H), 7.24 (ddd, J = 8.0, 8.0, 1.0 Hz,
1H), 7.31 (ddd, J = 8.5, 7.5, 1.5 Hz, 1H), 7.41 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 8.11 (br, 1H). 13C{1H}
NMR (125 MHz, CDCl3) δ 12.0, 22.7, 28.4, 52.5, 52.9, 53.2, 58.3, 83.5, 115.4, 119.0, 119.0, 122.5,
122.8, 124.4, 130.7, 135.5, 149.9. HRMS (ESI-TOF): calcd. for C21H32N3O2 [M + H]+ 358.2494; found
358.2487.
di-tert-Butyl 3,3'-(piperazine-1,4-diylbis(ethane-2,1-diyl))bis(1H-indole-1-carboxylate) (13d)
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A suspension of piperazine (0.10 g, 1.16 mmol), N-Boc-2-
bromoethylindole (0.82 g, 2.55 mmol) and K2CO3 (0.48 g, 3.48 mmol)
in CH3CN (10 mL) was heated at reflux for 6 h. After this time, the
mixture was cooled at room temperature and the resulting solids were
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filtered and washed with EtOAc (3 x 10 mL). The organic portion was concentrated under reduced
pressure and the residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 1:5) to give
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0.54 g (81%) of 13d as a cream solid. Mp = 131-133 °C. H NMR (500 MHz, CDCl3) δ 1.67 (s, 18H),
2.68 (br, 8H), 2.74 (t, J = 7.5 Hz, 4H), 2.92 (t, J = 7.5 Hz, 4H), 7.24 (ddd, J = 8.0, 8.0, 1.0 Hz, 2H), 7.31
(ddd, J = 8.5, 7.5, 1.5 Hz, 2H), 7.43 (s, 2H), 7.54 (d, J = 8.0 Hz, 2H), 8.12 (br, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 22.8, 28.4, 53.4, 58.4, 83.5, 115.4, 119.0, 119.0, 122.5, 122.8, 124.4, 130.8, 135.5,
149.9. HRMS (FAB-QMS): calcd. for C34H45N4O4 [M + H]+ 573.3441; found 573.3436.
Ethyl 2-(4-ethylpiperazin-1-yl)acetate (13e)
To a suspension of 1-ethylpiperazine (0.83 mL, 6.58 mmol) and K2CO3 (1.07 g,
7.78 mmol) in CH3CN (12 mL) was added ethyl bromoacetate (0.66 mL, 5.98
mmol). The resulting reaction mixture was stirred at room temperature for 12 h. Then, the formed solids
were filtered and washed with EtOAc (3 x 10 mL). The organic portion was concentrated under reduced
pressure and the residue was purified by flash chromatography on silica gel (EtOAc/ MeOH, 4:1) to give
1.11 g (93%) of 13e as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 1.09 (t, J = 7.0 Hz, 3H), 1.28 (t, J =
13
7.0 Hz, 3H), 2.43 (q, J = 7.0 Hz, 2H), 2.58 (br, 8H), 3.21 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H). C{1H}
NMR (125 MHz, CDCl3) δ 12.1, 14.3, 52.3, 52.6, 53.2, 59.7, 60.7, 170.4. HRMS (FAB-QMS): calcd.
for C10H21N2O2 [M + H]+ 201.1603; found 201.1612.
2-(4-Ethylpiperazin-1-yl)ethan-1-ol (13f)
To a suspension of 1-ethylpiperazine (0.88 mL, 7.00 mmol) and K2CO3 (1.25 g,
9.10 mmol) in CH3CN (10 mL) was added 2-bromoethanol (0.54 mL, 7.69
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mmol). The resulting reaction mixture was stirred at room temperature overnight. Then, the formed
solids were filtered and washed with EtOAc (3 x 10 mL). The organic portion was concentrated under
reduced pressure and the residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH,
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8:1) to give 0.86 g (78%) of 13f as a colorless oil. H NMR (500 MHz, CDCl3) δ 1.10 (t, J = 7.0 Hz,
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3H), 2.43 (q, J = 7.0 Hz, 2H), 2.56 (m, 10H), 2.94 (br, 1H), 3.63 (t, J = 5.5 Hz, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 12.0, 52.4, 52.8, 52.8, 57.8, 59.4. HRMS (ESI-TOF): calcd. for C8H19N2O1 [M + H]+
159.1497; found 159.1496.
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1-Benzyl-4-isobutylpiperazine (13g)27
To a suspension of piperazine (0.20 g, 2.30 mmol) and Na2CO3 (0.40 g, 3.80
mmol) in CH3CN (15 mL) was added iso-butyl bromide (0.2 mL, 1.92 mmol).
The resulting reaction mixture was heated at reflux for 4 h. Then, the reaction mixture was cooled at
room temperature and benzyl bromide (0.23 mL, 1.93 mmol) was added. The reaction mixture was
stirred overnight at room temperature. Then, the resulting solids were filtered and washed with EtOAc
(3 x 15 mL). The organic portion was concentrated under reduced pressure and the residue was purified
by flash chromatography on silica gel (Hexane/EtOAc, 5:1) to give 0.16 g (30%) of 13g as a colorless
oil. 1H NMR (500 MHz, CDCl3) δ 0.88 (d, J = 6.5 Hz, 6H), 1.76 (m, 1H), 2.07 (d, J = 6.0 Hz, 2H), 2.47
(m, 8H), 3.50 (s, 2H), 7.23 (m, 1H), 7.30 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3) δ 21.1, 25.4, 53.2,
53.3, 53.6, 63.3, 127.0, 128.3, 129.4, 138.3.
1,4-bis(sec-Butyl)piperazine (13h)28
To a suspension of piperazine (0.18 g, 2.00 mmol) and K2CO3 (0.70, 5.00 mmol) in
CH3CN (10 mL) was added sec-butyl bromide (0.49 mL, 4.40 mmol). The resulting
reaction mixture was heated at reflux for 8h. Then, the resulting solids were filtered
and washed with EtOAc (3 x 10 mL). The organic portion was concentrated under reduced pressure and
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the residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1) to give 0.26 g
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(65%) of 13h as a yellow oil. H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.5 Hz, 6H), 1.02 (d, J = 7.0
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Hz, 6H), 1.28 (m, 2H), 1.62 (m, 2H), 2.43 (m, 2H), 2.58 (m, 8H). C{1H} NMR (125 MHz, CDCl3) δ
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11.3, 14.0, 25.9, 48.5, 60.7.
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1-Benzyl-4-phenylpiperazine (13i)29
To a suspension of 1-phenylpiperazine (0.81 g, 5.00 mmol), Na2CO3 (0.79 g,
7.50 mmol) in CH3CN (15 mL) was added benzyl bromide (0.71 mL, 6.00
mmol). The mixture was stirred at room temperature overnight. Then, the
resulting solids were filtered and washed with EtOAc (3 x 15 mL). The organic portion was
concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel
(Hexane/EtOAc, 5:1) to give 1.06 g (84 %) of 13i as a white solid. Mp = 47-49 °C. 1H NMR (500 MHz,
CDCl3) δ 2.61 (app t, J = 5.0 Hz, 4H), 3.20 (app t, J = 5.0 Hz, 4H), 3.57 (s, 2H), 6.84 (app tt, J = 7.5, 1.0
Hz, 1H), 6.92 (m, 2H), 7.26 (m, 3H), 7.34 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3) δ 49.2, 53.2,
63.2, 116.1, 119.7, 127.2, 128.4, 129.2, 129.3, 138.0, 151.5.
rac–trans-2-(4-Phenylpiperazin-1-yl)cyclohexanol (13j)30
To a solution of cyclohexene oxide (0.62 mL, 6.11 mmol) in H20 (2.5 mL) was
added dropwise 1-phenylpiperazine (1.12 mL, 7.33 mmol). The resulting
reaction mixture was stirred at room temperature overnight. The reaction mixture
was extracted with CH2Cl2 (5 x 8 mL). The combined organic layers were dried with Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel
1
(EtOAc/MeOH, 1:0.3) to give 1.73 g (98%) of 13j as a white solid. Mp = 132-134 °C. H NMR (500
MHz, CDCl3) δ 1.24 (m, 4H), 1.73 (m, 1H), 1.80 (m, 1H), 1.86 (m, 1H), 2.15 (m, 1H), 2.29 (ddd, J =
11.5, 9.5, 3.0 Hz, 1H), 2.59 (ddd, J = 11.5, 7.5, 3.5 Hz, 2H), 2.90 (ddd, J = 11.5, 8.0, 3.5 Hz, 2H), 3.20
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(m, 4H), 3.42 (ddd, J = 14.5, 10.0, 4.5 Hz, 1H), 4.02 (br, 1H), 6.87 (t, J = 7.25 Hz, 1H), 6.94 (d, J = 8.0
Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 22.3, 24.1, 25.6, 33.2, 48.3, 49.9,
68.7, 70.2, 116.3, 120.0, 129.2, 151.4.
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Ethyl 2-(4-phenylpiperazin-1-yl)acetate (13k)31
A suspension of K2CO3 (0.45 g, 3.23 mmol) in CH3CN (7 mL) was added 1-
phenylpiperazine (0.33 mL, 2.16 mmol) and ethyl bromoacetate (0.26 mL, 2.37
mmol). The resulting reaction mixture stirred at room temperatura overnight.
Then, the formed solids were filtered and washed with EtOAc (3 x 10 mL). The organic portion was
concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel
(Hexane/EtOAc, 3:1) to give 0.40 g (75%) of 13k as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 1.29 (t,
J = 7.0 Hz, 3H), 2.75 (t, J = 5.0 Hz, 3H), 3.26 (t, J = 5.0 Hz, 3H), 3.28 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H),
6.87 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 7.27 (dd, J = 8.5, 7.0 Hz, 2H). C{1H} NMR (125
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MHz, CDCl3) δ 14.3, 49.0, 53.1, 59.6, 60.8, 116.2, 119.9, 129.2, 151.2, 170.3. HRMS (ESI-TOF): calcd.
for C14H21N2O2 [M + H]+ 249.1603; found 249.1598.
Dimethyl 2,2'-(piperazine-1,4-diyl)diacetate (13l)
To a suspension of piperazine (0.42 g, 5.01 mmol), Na2CO3 (1.32 g, 12.51
mmol) in CH3CN (15 mL) was added methyl bromoacetate (1.04 mL,
11.03 mmol). The reaction mixture was stirred at room temperature overnight. Then, the resulting solids
were filtered and washed with EtOAc (3 x 15 mL). The organic portion was concentrated under reduced
pressure and the residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 1:1) to give
0.69 g (60%) of 13l as white solid. Mp = 59-61 °C. 1H NMR (500 MHz, CDCl3) δ 2.66 (br, 8H), 3.24 (s,
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4H), 3.73 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 51.9, 52.9, 54.4, 170.8. HRMS (FAB-QMS):
calcd. for C10H19N2O4 [M + H]+ 231.1345; found 231.1341.
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1,4-bis(3-Methylbut-2-en-1-yl)piperazine (13m)
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To a suspension of piperazine (0.3 g, 3.48 mmol) and NaH (0.27 g, 6.96
mmol, 60% dispersion in mineral oil) in THF (3 mL) at 0°C was added
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dropwise 3,3-dimethylallyl bromide (0.89 mL, 7.66 mmol). After 10 min,
the reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was cooled to
room temperature, and H2O (3 mL) was added. The reaction mixture was extracted with EtOAc (5 x 5
mL). The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 1:2) to give 0.66 g
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(86%) of 13m as yellow oil. H NMR (500 MHz, CDCl3) δ 1.63 (s, 6H), 1.72 (s, 6H), 2.43 (br, 8H),
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2.96 (d, J = 7.5 Hz, 4H), 5.25 (app t, J = 7.5 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 18.1, 26.0,
53.1, 56.0, 120.8, 135.5. HRMS (EI-TOF): calcd. for C14H26N2 [M]+ 222.2096; found 222.2099.
1,4-bis(2-Methylallyl)piperazine (13n)
To a suspension of piperazine (0.5 g, 5.80 mmol) and NaH (0.46 g, 11.61 mmol,
60% dispersion in mineral oil) in THF (5 mL) at 0°C was added dropwise 3-
bromo-2-methylpropene (0.89 mL, 7.66 mmol). After 10 min, the reaction mixture was stirred at room
temperature overnight. Then, the mixture was cooled to room temperature, and H2O (3 mL) was added.
The mixture was extracted with EtOAc (5 x 8 mL). The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on
silica gel (Hexane/EtOAc, 5:1) to give 0.88 g (78%) of 13n as yellow oil. 1H NMR (500 MHz, CDCl3) δ
1.74 (s, 6H), 2.40 (br, 8H), 2.87 (s, 4H), 4.83 (s, 2H), 4.86 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
21.1, 53.3, 65.5, 113.0, 142.8. HRMS (EI-TOF): calcd. for C12H22N2 [M]+ 194.1783; found 194.1789.
1,4-bis(3,3-Dimethylallyl)-1,2,3,4-tetrahydroquinoxaline (13o)
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To a solution of phenylenediamine (0.50 g, 4.60 mmol) in THF (5 mL) was
added glyoxal (0.63 mL, 40% sol. in water, 5.50 mmol). The resulting
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removed under reduced pressure. The crude product was used in the next reaction without further
purification. To a solution of the crude product in THF (5 mL) at 0 °C was treated with LiAlH4 (0.51 g,
13.50 mmol). The resulting reaction mixture was stirred overnight at room temperature. A brine solution
was added, and the solution was extracted with CH2Cl2 (5 x 5 mL). The combined organic phases were
dried with Na2SO4 and the solvent was removed under reduced pressure to obtain 0.57 g (93%) of
thetrahydroquinoxaline which was used without purification to the next reaction. To a mixture of CaCO3
(0.28 g, 2.80 mmol) and tetrahydroquinoxaline (0.17 g, 1.40 mmol) in CH3CN (3 mL) was added
dropwise 3,3-dimethylallyl bromide (0.34 mL, 2.80 mmol) at room temperature. The mixture reaction
was stirred for 4 h at room temperature until total consumption of starting material. The solvent was
removed under reduced pressure and the solids were washed with CH2Cl2 (3 x 5 ml). The organic
portion was dried with Na2SO4 and the solvent was removed under reduced pressure. The residue was
purified by flash chromatography on silica gel (Hexane/EtOAc, 9:1) to give 0.63 g (55 %) of 13o as a
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brown oil. H NMR (500 MHz, CDCl3) δ 1.71 (d, J = 7.5 Hz, 12H), 3.30 (s, 4H), 3.80 (d, J = 6.0 Hz,
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4H), 5.26 (m, 2H), 6.56 (m, 2H), 6.63 (m, 2H). C{1H} NMR (125 MHz, CDCl3) δ 18.1, 25.8, 47.1,
49.1, 111.5, 117.9, 120.5, 135.5, 135.9. HRMS (FAB-QMS): calcd. for C18H27N2 [M + H]+ 271.2174;
found 271.2179.
1,4-bis((S)-1-Phenylethyl)piperazine (13p)32
To a mixture of 1,4-bis((S)-1-phenylethyl))piperazin-2,5-dione33 (0.63 g, 1.95 mmol)
and LiAlH4 (0.22 g, 5.85 mmol) at 0 °C, was added dropwise THF (6 mL). After 15
minutes, the reaction was stirred at room temperature for 1 h. Then, the mixture was
cooled to 0 °C and H2O was added dropwise until the formation of solids, which were washed with
EtOAc (5 × 5 mL). The organic phase was dried with Na2SO4 and the solvent was removed under
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reduced pressure. The residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 3:1)
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to give 0.43 g (74 %) of 13p as a white solid. Mp = 43-45 °C.
= –29.0 (c = 1.0, CHCl3),
= –
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38.6 (c = 2.5, MeOH). Lit.32 = –34.2 (c = 2.54, MeOH). 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J
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= 7.0 Hz, 6H), 2.39 (br, 8H), 3.32 (q, J = 7.0 Hz, 2H), 7.23 (m, 10H). 13C{1H} NMR (125 MHz, CDCl3)
δ 20.0, 50.9, 65.1, 126.9, 127.8, 128.3, 143.8. HRMS (FAB-QMS): calcd. for C20H27N2 [M + H]+
295.2174; found 295.2180.
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tert-Butyl 4-phenylpiperazine-1-carboxylate (13q)34
To a solution of di-tert-butyl dicarbonate (1.22 g, 5.59 mmol) and DMAP
(0.11 g, 0.86 mmol) in CH2Cl2 (14 mL) were added drowise 1-
phenylpiperazine (0.66 mL, 4.13 mmol) and Et3N (0.64 mL, 4.30 mmol). The
resulting reaction mixture was stirred for 2 h. After this time, H2O (10 mL) was added. The mixture was
extracted with CH2Cl2 (5 x 15 mL). The combined organic layers were dried with Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel
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(Hexane/EtOAc, 18:1) to give 1.11 g (98%) of 13q as a white solid. Mp = 69-71 °C. H NMR (500
MHz, CDCl3) δ 1.49 (s, 9H), 3.13 (t, J = 5.0 Hz, 4H), 3.58 (t, J = 5.0 Hz, 4H), 6.90 (t, J = 7.5 Hz, 1H),
6.94 (d, J = 7.5 Hz, 2H), 7.28 (td, J = 7.0, 2.0 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 28.6, 43.1,
44.2, 49.6, 80.0, 116.8, 120.4, 129.3, 151.4, 154.9.
4-Benzylmorpholine (15a)35
To a suspension of morpholine (1.51 mL, 17.22 mmol) and K2CO3 (3.09 g, 22.38
mmol) in CH3CN (20 mL) was added dropwise benzyl bromide (2.25 mL, 18.94
mmol). The mixture was stirred at room temperature for 2 h. Then, the resulting solids were filtered and
washed with EtOAc (3 x 20 mL). The organic portion was concentrated under reduced pressure and the
residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 6:1) to give 2.87 g (94%) of
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15a as a pale-yellow oil. 1H NMR (500 MHz, CDCl3) δ 2.42 (t, J = 4.5 Hz, 4H), 3.47 (s, 2H), 3.68 (t, J
= 4.5 Hz, 4H), 7.27 (m, 5H). 13C{1H} NMR (125 MHz, CDCl3) δ 53.7, 63.6, 67.1, 127.3, 128.4, 129.4,
137.7.
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4-(p-Methoxybenzyl)morpholine (15b)35
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To a stirring mixture of morpholine (0.50 mL, 5.74 mmol) and NaH (0.17 g,
7.08 mmol, 60% dispersion in mineral oil) in THF (4 mL) was added dropwise
to a solution of p-methoxybenzyl chloride (0.99 g, 6.32 mmol) in THF (6 mL). To mixture reaction was
heated to reflux for 6 h. Then, the mixture was cooled at room temperature, and H2O (3 mL) was added.
The mixture was extracted with EtOAc (5 x 8 mL). The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on
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silica gel (Hexane/EtOAc, 1:1) to give 1.13 g (98%) of 15b as a colorless oil. H NMR (500 MHz,
CDCl3) δ 2.41 (br, 4H), 3.42 (s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.78 (s, 3H), 6.84 (d, J = 8.5 Hz, 2H), 7.22
(d, J = 8.0 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 53.5, 55.2, 62.8, 67.0, 113.6, 129.7, 130.4,
13
158.8.
4-(p-Nitrobenzyl)morpholine (15c)35
To a suspension of 1-(iodomethyl)-4-nitrobenzene (1.20 g, 4.56 mmol) and
K2CO3 (0.82 g, 5.96 mmol) in CH3CN (20 mL) was added dropwise
morpholine (0.40 mL, 4.59 mmol). The reaction mixture was stirred at room temperature for 2 h. Then,
the resulting solids were filtered and washed with EtOAc (3 x 20 mL). The organic portion was
concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel
(Hexane/EtOAc, 5:1) to give 0.99 (98%) of 15c as a yellow solid. Mp = 75-77 °C. 1H NMR (500 MHz,
CDCl3) δ 2.47 (br, 4H), 3.60 (s, 2H), 3.73 (t, J = 4.5 Hz, 4H), 7.54 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 9.0
Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 53.7, 62.6, 67.0, 123.7, 129.6, 146.0, 147.2.
4-(Cyclohexylmethyl)morpholine (15d)36
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The Journal of Organic Chemistry
To a suspension of morpholine (1.00 mL, 11.48 mmol) and K2CO3 (1.90 g, 13.77
mmol) in CH3CN (15 mL) was added dropwise (bromomethyl)cyclohexane (1.76
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mL, 12.62 mmol). The reaction mixture was stirred at room temperature for 6 h. Then, the formed solids
were filtered and washed with EtOAc (3 x 15 mL). The organic portion was concentrated under reduced
pressure and the residue was purified by flash chromatography on silica gel (Hexane/EtOAc, 4:1) to give
1.34 g (62%) of 15d as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.87 (m, 2H), 1.19 (m, 3H), 1.48
(m, 1H), 1.69 (m, 3H), 1.77 (m, 2H), 2.11 (d, J = 7.0 Hz, 2H), 2.38 (br, 4H), 3.70 (t, J = 5.0 Hz, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 26.2, 26.9, 32.0, 34.7, 54.3, 66.2, 67.1.
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2-Morpholinoethan-1-ol (15e)
To a suspension of morpholine (0.50 mL, 5.73 mmol) and K2CO3 (1.03 g, 7.45
mmol) in CH3CN (10 mL) was added 2-bromoethanol (0.48 mL, 6.88 mmol). The
resulting reaction mixture was stirred at room temperature for 18 h. Then, the formed solids were
filtered and washed with EtOAc (3 x 10 mL). The organic portion was concentrated under reduced
pressure and the residue was purified by flash chromatography on silica gel (EtOAc/MeOH, 4:1) to give
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0.56 g (75%) of 15e as a pale red oil. H NMR (500 MHz, CDCl3) δ 2.52 (br, 4H), 2.55 (t, J = 5.5 Hz,
2H), 2.99 (br, 1H), 3.64 (t, J = 5.5 Hz, 2H), 3.78 (t, J = 5.0 Hz, 4H). 13C{1H} NMR (125 MHz, CDCl3)
δ 53.4, 57.6, 60.0, 70.0. HRMS (FAB-QMS): calcd. for C6H14N1O2 [M + H]+ 132.1025; found
132.1033.
tert-Butyl 3-(2-morpholinoethyl)-1H-indole-1-carboxylate (15f)
To a suspension of N-Boc-2-bromoethylindole (0.40 g, 1.23 mmol) and K2CO3
(0.22 g, 1.59 mmol) in CH3CN (12 mL) was added morpholine (0.12 mL, 1.46
mmol). The reaction mixture was heated at reflux for 6 h. Then, the mixture was
cooled to room temperature and the resulting solids were filtered and washed with EtOAc (3 x 10 mL).
The organic portion was concentrated under reduced pressure and the residue was purified by flash
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chromatography on silica gel (Hexane/EtOAc, 1:1) to give 0.39 g (94%) of 15f as a yellow oil. 1H NMR
(500 MHz, CDCl3) δ 1.67 (s, 9H), 2.57 (br, 4H), 2.70 (app t, J = 8.5 Hz, 2H), 2.90 (t, J = 8.5 Hz, 2H),
3.77 (t, J = 4.5 Hz, 4H), 7.24 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.32 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.43
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(s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 8.12 (br, 1H). C{1H} NMR (125 MHz, CDCl3) δ 22.5, 28.4, 53.8,
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58.7, 67.1, 83.6, 115.4, 118.8, 119.0, 122.5, 122.8, 124.5, 130.7, 135.5, 149.9. HRMS (FAB-QMS):
calcd. for C19H27N2O3 [M + H]+ 331.2022; found 331.1997.
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General procedure for the selective and catalytic C-H oxidation
To a stirring mixture of NaH2PO4 (0.9 mmol) and TEMPO (0.03 mmol) in CH3CN (4 mL) at 0 °C, was
added a solution of piperazine or morpholine derivates (0.3 mmol) in CH3CN (1 mL), and after stirring
for 5 minutes, NaClO2 (0.9 mmol) and NaOCl (0.7 mL of an aqueous solution of 3%) were added.
When the reaction mixture turned from red to purple color the reaction is going well. The reaction
course was monitored by TLC until the starting material is consumed. Then, a saturated solution of
NaOH was added dropwise until the purple color disappeared. The phases were separated by funnel, the
organic phase was washed with brine (2 x 3 mL) and the aqueous phase was extracted with EtOAc (3 x
3 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude was purified by flash chromatography on silica gel with mixtures of
Hexane/EtOAc as mobile phase. It is important to note that in some cases is necessary to add 2-methyl-
2-butene as a HOCl scavenger (see Table 2).
1,4-Dibenzylpiperazine-2,3-dione (12)37
Eluent: hexane/EtOAc, 1:3. Isolated 0.5 g (95%) of 12 as a white solid. Mp
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= 199-201 °C. H NMR (500 MHz, CDCl3) δ 3.34 (s, 4H), 4.67 (s, 4H),
7.31 (m, 10H). 13C{1H} NMR (125 MHz, CDCl3) δ 43.4, 50.6, 128.1,
128.4, 128.9, 135.4, 157.4.
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The Journal of Organic Chemistry
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1-Benzyl-4-ethylpiperazine-2,3-dione (14a)
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Eluent: CH2Cl2/EtOAc, 1:1. Isolated 0.10 g (90%) of 14a as a white solid. Mp =
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117-119 °C. H NMR (500 MHz, CDCl3) δ 1.18 (t, J = 7.0 Hz, 3H), 3.42 (m,
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2H), 3.47 (m, 2H), 3.53 (q, J = 7.0 Hz, 2H), 4.68 (s, 2H), 7.32 (m, 5H). 13C{1H}
NMR (125 MHz, CDCl3) δ 12.3, 42.4, 43.6, 43.9, 50.6, 128.2, 128.5, 129.0, 135.6, 157.0, 157.7. HRMS
(ESI-TOF): calcd. for C13H17N2O2 [M + H]+ 233.1290; found 233.1293.
1-(p-Methoxybenzyl)-4-ethylpiperazine-2,3-dione (14b)
Eluent: hexane/EtOAc, 1:4. Isolated 0.18 g (70%) of 14b as a colorless
solid. Mp = 133-135 °C. 1H NMR (500 MHz, CDCl3) δ 1.17 (t, J = 7.0 Hz,
3H), 3.39 (m, 2H), 3.43 (m, 2H), 3.52 (q, J = 7.0 Hz, 2H), 3.80 (s, 3H), 4.61
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(s, 2H), 6.86 (br, J = 8.5 Hz, 2H), 7.22 (br, J = 8.5 Hz, 2H). C{1H} NMR (125 MHz, CDCl3) δ 12.2,
42.3, 43.1, 43.7, 49.8, 55.2, 114.1, 127.5, 129.8, 157.0, 157.4, 159.3. HRMS (FAB-QMS): calcd. for
C14H19N2O3 [M + H]+ 263.1395; found 263.1397.
tert-Butyl 3-(2-(4-ethyl-2,3-dioxopiperazin-1-yl)ethyl)-1H-indole-1-carboxylate (14c)
Eluent: CH2Cl2/MeOH, 97:03. Isolated 0.075 g (70%) of 14c as a cream solid.
Mp = 163-165 °C. 1H NMR (500 MHz, CDCl3) δ 1.15 (t, J = 7.0 Hz, 3H), 1.67
(s, 9H), 3.04 (t, J = 7.5 Hz, 2H), 3.30 (m, 2H), 3.35 (m, 2H), 3.49 (q, J = 7.0
Hz, 2H), 3.77 (t, J = 7.5 Hz, 2H), 7.25 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.33 (ddd, J = 8.5, 7.5, 1.5 Hz,
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1H), 7.44 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 8.15 (br, 1H). C{1H} NMR (125 MHz, CDCl3) δ 12.3,
23.2, 28.3, 42.4, 43.8, 45.8, 48.6, 83.9, 115.4, 117.3, 119.0, 122.8, 123.4, 124.7, 130.2, 135.6, 149.7,
157.0, 157.6. HRMS (ESI-TOF): calcd. for C21H28N3O4 [M + H]+ 386.2079; found 386.2068.
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di-tert-Butyl 3,3'-((2,3-dioxopiperazine-1,4-diyl)bis(ethane-2,1-diyl))bis(1H-indole-1-carboxylate)
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Eluent: hexane/EtOAc, 3:5. Isolated 0.10 g (65%) of 14d as a colorless
oil. 1H NMR (500 MHz, CDCl3) δ 1.66 (s, 18H), 3.00 (t, J = 7.5 Hz, 4H),
3.16 (s, 4H), 3.73 (app t, J = 7.5 Hz, 4H), 7.23 (ddd, J = 8.0, 8.0, 1.0 Hz,
2H), 7.32 (ddd, J = 8.5, 8.5, 1.5 Hz, 2H), 7.42 (s, 2H), 7.57 (d, J = 8.0 Hz,
2H), 8.12 (br, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 23.2, 28.3, 45.6, 48.5, 83.9, 115.5, 117.3, 119.0,
122.8, 123.4, 124.8, 130.3, 135.6, 149.7, 157.4. HRMS (FAB-QMS): calcd. for C34H41N4O6 [M + H]+
601.3021; found 601.3003.
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Ethyl 2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetate (14e)
Eluent: CH2Cl2/EtOAc, 1:2. Isolated 0.11 g (68%) of 14e as a white solid. Mp =
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66-68 °C. H NMR (500 MHz, CDCl3) δ 1.21 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0
Hz, 3H), 3.56 (q, J = 7.0 Hz, 2H), 3.62 (m, 2H), 3.66 (m, 2H), 4.21 (q, J = 7.0 Hz,
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2H), 4.26 (s, 2H). C{1H} NMR (125 MHz, CDCl3) δ 12.3, 14.2, 42.4, 43.9, 45.6, 48.4, 61.8, 156.5,
157.9, 168.2. HRMS (FAB-QMS): calcd. for C10H17N2O4 [M + H]+ 229.1188; found 229.1165.
1-Ethyl-4-(2-hydroxyethyl)piperazine-2,3-dione (14f)
Eluent: CH2Cl2/MeOH, 93:07. Isolated 0.14 g (59%) of 14f as a white solid. Mp
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= 117-119 °C. H NMR (500 MHz, CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 2.39 (br,
1H), 3.52 (q, J = 7.0 Hz, 2H), 3.57 (app dd, J = 6.0, 4.0 Hz, 2H), 3.60 (t, J = 5.5
Hz, 2H), 3.73 (app dd, J = 6.0, 4.0 Hz, 2H), 3.83 (t, J = 5.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3)
δ 12.3, 42.4, 44.0, 46.2, 50.6, 60.2, 157.3, 158.2. HRMS (FAB-QMS): calcd. for C8H15N2O3 [M + H]+
187.1083; found 187.1086.
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1-Benzyl-4-isobutylpiperazine-2,3-dione (14g)
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Eluent: hexane/EtOAc, 2:1. Isolated 0.044 g (67%) of 14g as a colorless solid.
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Mp = 140-142 °C. H NMR (500 MHz, CDCl3) δ 0.92 (d, J = 6.5 Hz, 6H),
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1.97 (m, 1H), 3.94 (d, J = 7.5 Hz, 2H), 3.41 (m, 2H), 3.44 (m, 2H), 4.69 (s, 2H), 7.30 (m, 5H). 13C{1H}
NMR (125 MHz, CDCl3) δ 20.1, 26.8, 43.5, 45.2, 50.6, 55.0, 128.2, 128.5, 129.0, 135.6, 157.5, 157.7.
HRMS (FAB-QMS): calcd. for C15H21N2O2 [M + H]+ 261.1603; found 261.1602.
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1,4-bis(sec-Butyl)piperazine-2,3-dione (14h)
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Eluent: EtOAc. Isolated (61%) of 14h as a colorless solid. Mp = 183-186 °C. H
NMR (500 MHz, CDCl3) δ 0.90 (t, J = 7.5 Hz, 6H), 1.15 (ddd, J = 7.0, 2.5, 1.0 Hz,
6H), 1.50 (m, 4H), 3.33 (m, 4H), 4.62 (st, J = 7.0 Hz, 2H). 13C{1H} NMR (125 MHz,
CDCl3) δ 11.1, 17.7, 26.4, 38.5, 50.7, 157.8. HRMS (FAB-QMS) calcd. for C12H23N2O2 [M + H]+
227.1760; found 227.1758.
4-Benzyl-1-phenylpiperazine-2,3-dione (14i)37
Eluent: hexane/EtOAc, 1:2. Isolated 0.063 g (75%) of 14i as a white solid.
Mp = 131-133 °C. 1H NMR (500 MHz, CDCl3) δ 3.57 (ddd, J = 7.5, 5.5, 4.0
Hz, 2H), 3.89 (ddd, J = 7.5, 6.0, 4.0 Hz, 2H), 4.75 (s, 2H), 7.27 (m, 1H), 7.36
(m, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 43.8, 47.7, 50.8, 124.6, 127.3, 128.3, 128.6, 129.1, 129.3,
135.5, 140.8, 156.7, 157.7.
rac–trans-1-(2-Hydroxycyclohexyl)-4-phenylpiperazine-2,3-dione (14j)
Eluent: hexane/EtOAc/MeOH, 3:2:0.5. Isolated 0.29 g (87%) of 14j as a white
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solid. Mp = 245-247 °C. H NMR (500 MHz, CDCl3) δ 1.25 (m, 2H), 1.44 (m,
3H), 1.81 (m, 2H), 2.15 (m, 1H), 2.80 (br, 1H), 3.56 (br, 1H), 3.61 (ddd, J =
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11.5, 8.0, 3.5 Hz, 1H), 3.73 (ddd, J = 11.0, 7.0, 3.5 Hz, 1H), 3.90 (ddd, J = 11.0, 7.5, 3.5 Hz, 1H), 4.07
(ddd, J = 11.5, 7.5, 3.5 Hz, 1H), 4.24 (td, J = 10.5, 4.0 Hz, 1H), 7.33 (m, 5H). 13C{1H} NMR (125 MHz,
CDCl3) δ 24.7, 24.9, 28.7, 35.1, 40.3, 48.0, 60.7, 70.3, 124.7, 127.2, 129.3, 141.0, 157.2, 158.8. HRMS
(ESI-TOF): calcd. for C16H21N2O3 [M + H]+ 289.1552; found 289.1547.
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Ethyl 2-(2,3-dioxo-4-phenylpiperazin-1-yl)acetate (14k)
Eluent: hexane/EtOAc, 2:3. Isolated 0.085 g (55%) of 14k as a colorless oil. 1H
NMR (500 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 3H), 3.79 (m, 2H), 4.04 (m, 2H),
4.24 (q, J = 7.0 Hz, 2H), 4.32 (s, 2H), 7.30 (m, 2H), 7.35 (m, 2H), 7.42 (m, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 14.3, 45.9, 47.8, 45.6, 61.9, 124.6, 127.4, 129.4, 140.8, 156.3,
158.0, 168.2. HRMS (ESI-TOF): calcd. for C14H17N2O4 [M + H]+ 277.1188; found 277.1178.
Dimethyl 2,2'-(2,3-dioxopiperazine-1,4-diyl)diacetate (14l)
Eluent: EtOAc. Isolated 0.054 g (70%) of 14l as a colorless crystal. Mp = 112-
114 °C. 1H NMR (500 MHz, CDCl3) δ 3.72 (s, 4H), 3.76 (s, 6H), 4.28 (s, 4H).
13C{1H} NMR (125 MHz, CDCl3) δ 45.6, 48.3, 52.6, 157.2, 168.5. HRMS
(FAB-QMS): calcd. for C10H15N2O6 [M + H]+ 259.0930; found 259.0924.
1,4-bis(3-Methylbut-2-en-1-yl)piperazine-2,3-dione (14m)
Eluent: hexane/EtOAc, 1:4. Isolated 0.053 g (71%) of 14m as a colorless oil.
1H NMR (500 MHz, CDCl3) δ 1.71 (s, 6H), 1.75 (s, 6H), 3.44 (s, 4H), 4.08
(d, J = 3.0 Hz, 4H), 5.15 (t, J = 3.0 Hz, 2H). 13C{1H} NMR (125 MHz,
CDCl3) δ 17.9, 25.7, 43.1, 44.3, 117.5, 138.6, 157.2. HRMS (FAB-QMS): calcd. for C14H23N2O2 [M +
H]+ 251.1756; found 251.1751.
1,4-bis(2-Methylallyl)piperazine-2,3-dione (14n)
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The Journal of Organic Chemistry
Eluent: hexane/EtOAc/MeOH, 2:4:1. Isolated 0.046 g (68%) of 14n as a
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colorless solid. Mp = 111-113 °C. H NMR (500 MHz, CDCl3) δ 1.72 (s, 6H),
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3.43 (s, 4H), 4.07 (s, 4H), 4.88 (s, 2H), 4.97 (s, 2H). C{1H} NMR (125 MHz,
CDCl3) δ 15.4, 39.2, 51.4, 127.5, 128.1, 128.9, 139.1, 157.4. HRMS (FAB-QMS): calcd. for
C12H19N2O2 [M + H]+ 223.1446; found 223.1440.
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1,4-bis((S)-1-Phenylethyl)piperazine-2,3-dione (14p)
Eluent: hexane/EtOAc, 1:2. Isolated 0.063 g (58%) of 14p as a white solid. Mp =
252-255 °C.
= –136.2 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) δ 1.50 (d,
J = 7.0 Hz, 6H), 2.89 (m, 2H), 3.13 (m, 2H), 6.00 (q, J = 7.0 Hz, 2H), 7.32 (m, 10H).
13C{1H} NMR (125 MHz, CDCl3) δ 15.2, 39.0, 51.2, 127.3, 127.9, 128.7, 138.9, 157.3. HRMS (EI-
TOF): calcd. for C20H22N2O2 [M]+ 322.1681; found 322.1689.
tert-Butyl 3-oxo-4-phenylpiperazine-1-carboxylate (14q)
Eluent: hexane/EtOAc, 3:1. Isolated 0.047 g (27%) of 14q as a cream solid.
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Mp = 155-157 °C. H NMR (500 MHz, CDCl3) δ 1.50 (s, 9H), 3.74 (m, 2H),
3.78 (m, 2H), 4.26 (s, 2H), 7.29 (m, 3H), 7.41 (m, 2H). C{1H} NMR (125
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MHz, CDCl3) δ 28.4, 40.5, 48.4, 49.8, 81.0, 125.7, 127.3, 129.4, 141.8, 153.9,
165.8. HRMS (FAB-QMS): calcd. for C15H21N2O3 [M + H]+ 277.1552; found 277.1549.
tert-Butyl 3-oxo-4-phenyl-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)piperazine-1-carboxylate (14r)
Eluent: hexane/EtOAc, 9:1. Isolated 0.010 g (4%) of 14r as a cream solid. Mp =
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146-148 °C. NMR data is reported as a mixture of E/Z rotamers. H NMR (500
MHz, CDCl3) δ 1.11 (m), 1.46 (m), 1.55 (s), 3.60 (m), 3.68 (m), 3.75 (m), 4.21
(m), 4.27 (m), 6.14 (s), 6.19 (s), 7.26 (m), 7.34 (m), 7.41 (m). 13C{1H} NMR
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