Synthesis of N-alkyl-N′-aryl or Alkenylpiperazines: A Copper-Catalyzed C–N Cross-Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

Article abstract of DOI:10.1002/hlca.201700082

Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward, direct arylation and alkenylation of 1,4-diaza-bicyclo[2.2.2]octane would obviate the inefficiencies associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or alkenyl triflates, and 1,4-diaza-bicyclo[2.2.2]octane for the synthesis of N-alkyl-N′-aryl or alkenylpiperazines. The optimum conditions are developed using CuCl, t-BuOLi in NMP. Alkenyl triflates requires N,N′-dimethylethylenediamine and higher temperature to afford the desired cross-coupled product. Substrates bearing electron-deficient and electron-rich groups were successfully coupled under the optimum reaction conditions.

Full text of DOI:10.1002/hlca.201700082

Article Type: Full Paper
Synthesis of N-alkyl-N′-aryl or Alkenylpiperazines: A Copper-catalyzed C-
N Cross-coupling in the Presence of Aryl and Alkenyl Triflates and
DABCO
by Majid Ghazanfarpour-Darjani*, Forugh Barat-Seftejani, Mehdi Khalaj, Seyed Mahmoud
Mousavi-Safavi
Young researchers and elite club, Islamic Azad University, Buin Zahra Branch, Qazvin, Iran
E-mail: m.ghazanfarpour@modares.ac.ir
Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the
selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward,
direct arylation and alkenylation of 1,4-diaza-bicyclo[2.2.2]octane would obviate the inefficiencies
associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or
alkenyl triflates, and 1,4-diaza-bicyclo[2.2.2]octane for the synthesis of N-alkyl-N′-aryl or
alkenylpiperazines. The optimum conditions are developed using CuCl, t-BuOLi in NMP. Alkenyl
triflates requires N, N′-dimethyl ethylenediamine and higher temperature to afford the desired
cross-coupled product. Substrates bearing electron-deficient and electron-rich groups were
successfully coupled under the optimum reaction conditions.
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doi: 10.1002/hlca.201700082
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Keywords
C-N bond formation
DABCO
Copper catalysis
N-Alkyl-N′-arylpiperazines
Aryl triflate
Alkenyl triflate
Introduction. - The ability to selectively form carbon-nitrogen bond between different fragments has
been crucial to the development of synthetic organic chemistry.1-3 Over the past decades, the selective
coupling of nucleophilic nitrogen with aryl sources using transition metal catalysts has almost replaced
classical methods of aryl-nitrogen bond formations.4-10 The piperazine scaffold is a common motif in
pharmaceuticals and bioactive natural products.11-12 Several piperazine-containing drugs are within the
top 100 best-selling pharmaceutical products. The high value of the piperazine motif is reflected in the
myriad strategies for its construction, the majority of which involve stepwise synthesis.13-17 These
studies are very well recapitulated in a review written by Dai.18 Since the pioneering work of Ross,19
the ring-opening of DABCO prompted by nucleophilic attack on the corresponding bicyclic quaternary
ammonium salts have been well developed over the past decades.20-26 The literature on ring-opening
reactions of quinuclidine derivatives has been reviewed up to the year 1984.27 Wang and co-workers
have documented an efficient N-arylation/dealkylation of electron deficient heteroaryl chlorides and
DABCO under microwave irradiation.28 Peters reported the ring opening of N-benzylquinuclidinium
bromide using a range of nucleophiles.29 While the importance of such reports cannot be overstated,
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these transformations are limited to form N-alkyl and/or N-arylpiperazines bearing strong electronic
directing groups. It is worth mentioning that a decent range of the piperazine-containing small-
molecule drugs have aryl- or heteroaryl substitution on either both nitrogen atoms or on a single
nitrogen atom. The lack of efficient synthetic methods, particularly those that provide high selectivity
for N-arylation of piperazines with unactivated aryl halides and use readily available starting materials,
represents one of the hurdles in unleashing the full therapeutic potential of piperazines. Moreover, a
facile catalytic N-arylation and N-alkenylation of DABCO with unactivated aryl haildes and alkenyl
halides is still a challenge. Recently, Yavari and co-workers have developed a concise procedure for
the synthesis of N-alkyl-N′-arylpiperazines from readily available DABCO, unactivatied aryl halides,
and alkyl halides.30 The ring-opening cross-coupling strategy gave N-alkyl-N′-arylpiperazines in high
yields. This method is appealing because N-arylpiperazines could be achieved selectively from readily
available DABCO and common aryl halides. Successful catalytic formation of N-aryl and N-
heteroarylpiperazines using aryl and heteroaryl halides could find broad utility owing to the presence
in a wide range of drugs skeletons. The problem addressed above encouraged us to examine the
efficiency of aryl and alkenyl halides or triflates in a reaction involving quaternary ammonium salt of
DABCO to form diverse N-aryl and N-alkenyl arylpiperazines.
In continuation of our reports in catalysis,31-32 we describe the direct conversion of DABCO to N-
alkyl-N′-arylpiperazines and N-alkyl-N′-alkenylpiperazines by the reaction with aryl or alkenyl triflates
and alkyl halides catalytic in copper.
Results and Discussion. - To test our hypothesis and identify systems capable of mediating this highly
desirable process, we chose as a model reaction the cross-coupling of DABCO (1), benzyl chloride
(2a), and phenyl trifluoromethanesulfonate (3a) using copper(I) iodide and t-BuOK. Stirring in
DMSO at 70 °C for 14 h, gave N-alkyl-N′-arylpiperazine 4a only in 15% yield. To develop the
reaction conditions, we began by screening the reaction conditions and optimizing with respect to
catalyst, solvent, and base. No the desired reaction took place in the absence of a copper source even
at higher temperatures (not shown in Table 1). The reaction proceeded in high yield using CuOTf and
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CuCl (Table 1, entries 1 and 2). Other copper(I) salts also mediated the reaction however, the yield
were unsatisfactory (Table 1, entries 3-6). Coper(II) salts were not suitable in this transformation
(Table 1, entries 7-9). The choice of base source was found to influence the reaction outcome in
appreciable manner: only a bulky base with lithium as the counter-cation afforded the product in high
yield, indicating that strong proton abstracting character of the t.BuO and strong Lewis acid property
of Li is crucial (Table 1, entries 2 and 3). Yavari has reported that the addition of lithium iodide
increased the efficiency of aryl triflates in C-N cross-coupling reaction.33 We believe that lithium
cation participates in addition oxidation step of aryl triflate to copper salt by coordination to triflate
group and hereby facilitates the reaction progress. When the reaction was conducted with t-BuOK at
elevated temperature the desired product obtained in comparatively good yield (Table 1, entry 22).
With t-BuOCs as the base source, phenyl trifluoromethanesulfonate (3a) was recovered in 90% yield
and no product arising from the cross-coupling reaction is detected using GC analysis (Table 1, entry
1
10). H-NMR analysis indicated that trans-stilbene was formed as the side product in 53% yield. It
could be deduced that strongly basic t-BuOCs let to formation of stilbenes via deprotonation at the
benzylic position. Moreover, the counter-cation might participate in the reaction progress beyond the
acting as the Lewis acid.1 The reaction is completely selective for cross-coupling reaction and no
compounds arising from the attack on benzyne motif are detected by crude GC-MS analysis.
Moreover, almost no desired reaction took place in the presence of other common inorganic bases at
70 °C (Table 1, entries 10-14). Finally, a solvent screen showed that NMP was superior to other
solvents (Table 1, entries 2 and 3). The reaction proceeded in moderate yield in dimethyl acetamide
(DMA) (Table 1, entry 17). Toluene and 1,4-dioxane failed to increase the yield of the desired product
(Table 1, entries 19-20). Reaction conducted in ethylene glycol formed only a low yield of the desired
product (Table 1, entry 21).
1
We are grateful to a Referee of this paper for his suggestion about the formation of stilbene as the side product in the presence of
t.BuOCs.
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A wide variety of aryl triflates were reacted under the conditions for entry 2 of Table 1.
Phenyl and 2-naphtyl triflates (3a and 3b) were readily transformed to the desired products (Table 2,
entries 1 and 2). Electron-rich aryl triflates were less reactive. The use of twice the amounts of the
catalyst and 1.5 mmol of DABCO was required to convert t-butyl-, methyl, and methoxy-substituted
triflates to the corresponding products within acceptable reaction times (Table 2, entries 3-6). Aryl
triflates having an electron-withdrawing group such as acetyl, cyano, and nitro reacted in high yields
(Table 2, entries 7-8 and 11-13). Heteroaryl triflates also afforded the products in good yields (Table
2, entries 9 and 10). Notably, the tolerance for the heteroaromatic ring offers an opportunity for
expedient synthesis of heteroarylpiperazine-containing drugs likes Buspirone, Gepirone, Ipsapirone,
Tandospirone, and Zalospirone.
This transformation was further generalized, allowing the coupling of a range of alkenyl
iodides and triflates in moderate to good yields (Table 3). The use of N, N′-dimethyl ethylenediamine
as ligand was required to furnish the transformation in good yields within acceptable reaction periods.
Alkenyl iodides were reacted more effectively than those of alkenyl triflates. It should be noted that
the reaction proceeded almost in stereoselective manner as the Z-isomer gives the Z-alkenylated
product in high yield (Table 3, entry 2) and the E-isomers give the E-alkenylated products in high
yields (Table 3, entries 3 and 5).
The coupling of other alkyl chlorides was also examined with the same catalyst system (Table
4). The amination of n-butyl and n-hexyl chlorides (2b and 2c) was found to proceed with acceptable
yields (Table 4, entries 1 and 2). Allyl chloride (2d) afforded the corresponding alkylated product in
good yield (Table 4, entry 3). Steric hindrance of the substrates adversely affected the reaction
progress, as 1-chloro-2-methylpropane (2e) and 2-chloropropane (2f) gave the desired products in
moderate yields (Table 4, entries 5 and 6). It is important to stop the reaction at the time indicated;
extended heating resulted in decomposition of the products probably due to the Hofmann type
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elimination. Reaction conducted with 1,2-dichloroethane resulted in formation of a complicated
reaction mixture (not shown in Table 4).
To show the advantages and disadvantages of the proposed method we provide a comparison with
the pervious reported methods. In 2007, Wolfe and co-workers reported a 2,6-disubstituted N-alkyl-
N′-arylpiperazines synthesis via a palladium-catalyzed carboamination reaction.34 Generally the
products were formed in good yields and a variety of aryl halides can be used to introduce structural
diversity. The reaction proceeds through 4-5 synthetic steps which require the isolation of the
intermediates. Farfán reported a multi-step route for the synthesis of N-alkyl-N′-arylpiperazines using
ethyl oxalyl chloride and o-aminophenol as the starting materials, which are further treated with
norephedrine and reduced with BH3 to give N-alkyl-N′-arylpiperazines.35 Although this transformation
provided high yields and excellent diastereoselectivity, this route is limited to terminal olefins and
uses costly reagents and catalyst systems. Watanabe and co-workers published a pioneering
ruthenium-catalyzed reaction to convert 1,5-diols and primary amines into N-alkyl-N′-
arylpiperazines.36 As opposed to the carboamination approach, this process uses inexpensive and
readily available alcohols and only a catalytic amount of ruthenium catalyst. In 2015, Xie and co-
workers reported a novel method for the synthesis of N-alkyl-N′-alkenylpiperazines in a reaction
involving DABCO, electron-deficient acetylenes, and aryl acids.37 This N-alkenylation reaction
utilized highly activated acetylenic esters as the alkenyl source which limits the reaction scope. The
study indicates that catalytic N-arylation and alkenylation of DABCO with aryl and alkenyl halides or
triflates is almost a more effective procedure with respect to reaction scope, time, cost, and yield
than those methods previously reported. Moreover, the method offers an opportunity for the
synthesis of a wide range of N-aryl and –heteroaryl piperazine-containing drugs in a single step from
the readily available reactants without the isolation of the intermediates. While, the present method
is limited to the production of piperazines which have substitutions on both nitrogen atoms and
suffers from the low atom economy.
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The reaction conducted with 5 (isolated salt) and 3a in optimum reaction conditions described in
Table 1, formed 4a in 81% yield. It could be deduced that the reaction starts with the formation of 5,
followed by coordination of the ionic adduct to the copper slat to give 6. It is interesting for us to note
that no product arising from the ring opening of DABCO formed when DABCO®-CuCl complex (0.5
mmol) was warmed up to 110 ˚C in the presence of LiCl (0.5 mmol) in NMP.
Aryl triflate 3 could be oxidatively added to the Cu(I)-complex 6 to form a Cu(III)-intermediate 7.
Reductive elimination of intermediate 7 could produce the arylammonium species 8 and releases the
Cu(I) species. The intermediate is further converted to 9 through the ring-opening prompted by
nucleophilic attack of chloride ion, which finally give the desired aminated product 4 by reacting with
t-BuOLi in a Hofmann type elimination reaction. The latter elimination is further supported by the
fact that when the reaction was conducted with benzyl iodide instead of benzyl chloride, iodoethene
is detected by crude GC-MS analysis. Note that no the desired product formation occurred when
benzyl triflate was employed as the alkyl source. This result proposed that the reaction proceeds
through the nucleophilic attack of halide ion on the corresponding bicyclic quaternary ammonium
salt.
In conclusion, we have attempted to demonstrate the importance of the reaction parameters for
enabling unique reactivity and selectivity in C-N bond formation. Methods for selective synthesis of
N-alkyl-N′-aryl or alkenylpiperazines represent an important class of C–N bond formation, and the
reactions described above highlight the utility of such methods in the synthesis of a wide range of
piperazines-containing drugs. These reactions achieve good conversions and acceptable product
yields, and the catalyst tolerates useful substrate functional groups. Further studies are being
conducted to develop the reaction scope with poorer leaving groups like −OTs and−OPO(OPh)2.
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Experimental Part
Alkyl chlorides, DABCO, solvents, bases, and catalyst were obtained from Merck and were used
without further purification. Aryl and alkenyl triflates were obtained from Hangzhou Yuhao Chemical
Technology Co., Ltd. Melting points were measured with Electrothermal-9100 apparatus. IR Spectra
1
were recorded with Shimadzu IR-460 spectrometer. H and 13C-NMR spectra were recorded with
Bruker DRX-500 AVANCE instrument; in CDCl3 at 500.1 and 125.7 MHz, respectively; in ppm. Mass
spectra were recorded with EI-MS (70 eV): Finnigan-MAT-8430 mass spectrometer. Elemental
analyses (C, H, N) were performed with a Heraeus CHN-O-Rapid analyzer. The results agreed
favorably with the calculated values. Column chromatography was performed using silica gel 60
(particle size 63–200 µm) (Merck, item number 7734-3). TLC was performed using silica gel 60
(Merck, item number 116835). Known compounds (4a, 4c, 4d, and 4e) gave satisfactory 1H-NMR and
13C-NMR data and were consistent with that reported in the literature.
Compounds 4: General Procedure. A mixture of DABCO (1.2-1.5 mmol, see Table 2 and 3) and alkyl
chloride (1.0 mmol) was stirred for 15 min in neat reaction condition. Then, aryl or alkenyl triflate
(1.0 mmol), CuCl (0.05-0.1 mmol, see Table 2 and 3), t-BuOLi (1.5 mmol), and NMP (3 mL, see Table 2
°
and 3) were added and the mixture was stirred for 14-18 h at 70-90 C. After completion of the
reaction, it was diluted by EtOAc (5 mL) and a saturated NH4Cl solution (5 mL). The mixture was
stirred for additional 30 min and two layers were separated. The aqueous layer was then extracted
with EtOAc (3 ×8 mL). The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexane:EtOAc
4:1) to give the desired product.
1-Benzyl-4-(2-naphthyl)piperazine (4b)
Pale yellow oil; yield: 0.26 g (85%). IR (KBr) (νmax, cm-1): 2961, 1631, 1511, 1328, 1189.
3
3
1H NMR(500 MHz, CDCl3): δH= 2.76 (4 H, t, J = 6.9 Hz, 2 CH2), 3.30 (4 H, t, J = 6.9
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Hz, 2 CH2), 3.60 (2 H, s, CH2N), 7.04 (1 H, s, CH), 7.20 (2 H, t, 3J = 6.5 Hz, 2 CH), 7.33
(1 H, t, 3J = 6.5 Hz, CH), 7.36 (1 H, d, 3J = 6.6 Hz, CH), 7.41 (2 H, d, 3J = 6.6 Hz, 2 CH),
7.45 (2 H, t, 3J = 6.9 Hz, 2 CH), 7.71 (3 H, d, 3J = 8.7 Hz, 3 CH). 13C NMR (125.7 MHz,
CDCl3): δC = 49.0 (2 CH2), 54.5 (2 CH2), 61.9 (CH2N), 108.1 (CH), 118.1 (CH), 124.3
(CH), 127.0 (CH), 128.1 (CH), 128.4 (CH), 129.0 (CH), 129.3 (2 CH), 129.4 (C), 129.6
(CH), 130.9 (2 CH), 134.6 (C), 137.9 (C), 149.2 (C). MS: m/z (%) = 302 (M+, 1), 287 (15),
146 (24), 91 (100), 56 (45). Anal. Calcd for C21H22N2 (302.42): C, 83.40; H, 7.33; N,
9.26%; Found: C, 83.60; H, 7.48; N, 9.48%.
1-benzyl-4-(4-(tert-butyl)phenyl)piperazine (4f)
Pale yellow oil; yield: 0.24 g (79%). IR (KBr) (νmax, cm-1): 2934, 1604, 1510, 1348, 1142.
3
1H NMR(500 MHz, CDCl3) δH = 1.46 (9 H, s, 3 Me), 2.71 (4 H, t, J = 6.1 Hz, 2 CH2),
3
3
3.34 (4 H, t, J = 6.1 Hz, 2 CH2), 3.76 (2 H, s, CH2N), 6.71 (2 H, d, J = 7.8 Hz, 2 CH),
3
7.01 (2 H, d, J = 7.8 Hz, 2 CH), 7.27-7.36 (5 H, m, 5 CH). 13C NMR (125.7 MHz,
CDCl3): δC = 33.2 (3 Me), 36.8 (C), 49.1 (2 CH2), 54.8 (2 CH2), 67.3 (CH2N), 114.3 (2
CH), 128.3 (2 CH), 128.9 (CH), 129.3 (2 CH), 129.7 (2 CH), 137.1 (C), 141.3 (C), 148.9
(C). MS: m/z (%) = 308 (M+, 3), 251 (45), 133 (34), 91 (100), 77 (26), 57 (83). Anal.
Calcd for C21H28N2 (308.47): C, 81.77; H, 9.15; N, 9.08%; Found C, 82.04; H, 9.42; N,
9.15%.
1-(4-(4-benzylpiperazin-1-yl)phenyl)ethan-1-one (4g).
Pale yellow oil; yield: 0.27 g (91%). IR (KBr) (νmax, cm-1): 2932, 2832, 1718, 1579, 1464,
1
3
1248. H NMR(500 MHz, CDCl3): δH = 2.58 (3 H, s, Me), 2.69 (4 H, t, J = 5.5 Hz, 2
3
3
CH2), 3.29 (4 H, t, J = 5.5 Hz, 2 CH2), 3.79 (2 H, s, CH2N), 7.03 (2 H, d, J = 7.2 Hz, 2
3
13
CH), 7.26-7.34 (5 H, m, 5 CH), 7.86 (2 H, t, J = 7.2 Hz, 2 CH). C NMR (125.7 MHz,
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CDCl3): δC = 28.1 (Me), 51.0 (2 CH2), 59.7 (2 CH2), 67.9 (CH2N), 126.4 (2 CH), 127.6
(CH), 128.9 (2 CH), 129.2 (2 CH), 130.3 (2 CH), 132.3 (C), 136.8 (C), 139.2 (C), 198.5
(C). MS: m/z (%) = 294 (M+, 11), 175 (31), 119 (56), 91 (100), 56 (16). Anal. Calcd for
C19H22N2O (294.40): C, 77.52; H, 7.53; N, 9.52%; Found: C, 77.91; H, 7.68; N, 9.47%..
4-(4-butylpiperazin-1-yl)benzonitrile (4h)
Colorless solid, mp: 108-111 ˚C; Yield: 0.21 g (88%). IR (KBr) (νmax, cm-1): 2944, 2236,
1603, 1496, 1217. 1H NMR(500 MHz, CDCl3): δH = 0.97 (3 H, t, 3J = 7.3 Hz, CH3), 1.30-
3
3
1.44 (4 H, m, 2 CH2), 2.79 (4 H, t, J = 6.1 Hz, 2 CH2), 3.17 (4 H, t, J = 6.1 Hz, 2 CH2),
3
3
3
3.35 (2 H, t, J = 7.5 Hz, CH2N), 6.98 (2 H, d, J = 8.3 Hz, 2 CH), 7.41 (2 H, d, J = 8.3
Hz, 2 CH). 13C NMR (125.7 MHz, CDCl3): δC = 15.3 (CH3), 23.4 (CH2), 29.8 (CH2), 50.1
(2 CH2), 55.2 (2 CH2), 57.1 (CH2N), 105.5 (C), 116.3 (2 CH), 117.1 (CN), 132.8 (2 CH),
154.3 (C). MS: m/z (%) = 243 (M+, 75), 217 (100), 141 (56), 102 (15), 77 (22), 57 (11).
Anal.Calcd for C15H21N3 (243.35): C, 74.03; H, 8.70; N, 17.27%; Found: C, 74.39; H,
8.98; N, 17.11%.
1-butyl-4-(pyridin-2-yl)piperazine (4i)
Yellow oil; yield: 0.20 g (91%). IR (KBr) (νmax, cm-1): 3041, 2969, 16280, 1325, 1110. 1H
NMR(500 MHz, CDCl3): δH = 0.91 (3 H, t, 3J = 7.3 Hz, CH3), 1.32-1.47 (4 H, m, 2 CH2),
3
3
3
2.83 (4 H, t, J = 5.2 Hz, 2 CH2), 3.36 (4 H, t, J = 5.2 Hz, 2 CH2), 3.79 (2 H, t, J = 7.1
Hz, CH2N), 6.76-6.81 (2 H, m, 2 CH), 7.67 (1 H, t, 3J = 7.9 Hz, CH), 8.13 (1 H, t, 3J = 7.3
Hz, CH). 13C NMR (125.7 MHz, CDCl3): δC = 13.7 (CH3), 24.1 (CH2), 29.2 (CH2), 48.6 (2
CH2), 52.3 (2 CH2), 55.5 (CH2N), 107.3 (CH), 118.2 (CH), 139.1 (CH), 149.2 (CH), 162.3
(C). MS: m/z(%) = 219 (M+, 15), 162 (13), 141 (54), 85 (34), 78 (100), 58 (13). Anal.
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Calcd for C13H21N3 (219.33): C, 71.19; H, 9.65; N, 19.16%; Found C, 71.35; H, 9.98; N,
19.13%.
6-(4-butylpiperazin-1-yl)quinoline (4j)
1
Yellow oil; yield: 0.23 g (84%). IR (KBr) (νmax, cm-1): 2961, 1631, 1511, 1328, 1189. H
NMR(500 MHz, CDCl3): δH= 0.96 (3 H, t, 3J = 7.3 Hz, CH3), 1.34-1.45 (4 H, m, 2 CH2),
3
3
3
2.88 (4 H, t, J = 5.3 Hz, 2 CH2), 3.25 (4 H, t, J = 5.3 Hz, 2 CH2), 3.46 (2 H, t, J = 7.1
3
3
Hz, CH2N), 6.79 (1 H, s, CH), 7.28 (1 H, t, J = 6.5 Hz, CH), 7.65 (1 H, d, J = 6.8 Hz,
3
13
CH), 8.36-846 (2 H, m, 2 CH), 8.78 (1 H, d, J = 6.6 Hz, CH). C NMR (125.7 MHz,
CDCl3): δC = 15.1 (CH3), 22.1 (CH2), 31.3 (CH2), 51.6 (2 CH2), 54.5 (2 CH2), 57.1
(CH2N), 121.1 (CH), 122.2 (CH), 124.3 (CH), 128.2 (CH), 133.1 (C), 136.1 (CH), 143.7
(C), 147.9 (2 CH), 151.4 (C). MS: m/z (%) = 269 (M+, 13), 212 (18), 141 (22), 128 (100),
56 (38). Anal. Calcd for C17H23N3 (269.39): C, 75.80; H, 8.61; N, 15.60%; Found: C,
75.97; H, 8.79; N, 15.73%.
1-benzyl-4-(4-nitrophenyl)piperazine (4k)
Yellow solid, mp: 151-153 ˚C; yield: 0.28 g (93%). IR (KBr) (νmax, cm-1): 2944, 1595,
1
3
1536, 1351, 1237. H NMR (500 MHz, CDCl3): δH = 2.68 (4 H, t, J = 5.5 Hz, 2 CH2),
3
3
3.45 (4 H, t, J = 5.5 Hz, 2 CH2), 3.78 (2 H, s, CH2N), 7.11 (2 H, t, J = 7.3 Hz, 2 CH),
7.27-7.34 (5 H, m, 5 CH), 8.21 (2 H, t, 3J = 7.3 Hz, 2 CH). 13C NMR (125.7 MHz, CDCl3):
δC = 54.9 (2 CH2), 59.3 (2 CH2), 65.1 (CH2N), 115.1 (2 CH), 126.3 (2 CH), 127.1 (CH),
129.1 (2 CH), 129.8 (2 CH), 136.1 (C), 139.2 (C), 157.3 (C). MS: m/z (%) = 297 (M+, 13),
119 (58), 104 (35), 91 (100), 77 (27), 56 (66). Anal. Calcd for C17H19N3O2 (297.36): C,
68.67; H, 6.44; N, 14.13%; Found: C, C, 68.93; H, 6.56; N, 14.24%.
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1-butyl-4-(4-nitrophenyl)piperazine (4l)
Yellow solid, mp: 98-101 ˚C; yield: 0.24 g (91%). IR (KBr) (νmax, cm-1): 3041, 2965,
1539, 1368, 1207. 1H NMR (500 MHz, CDCl3): δH = 0.87 (3 H, t, 3J = 7.0 Hz, CH3), 1.33-
3
3
1.45 (4 H, m, 2 CH2), 2.83 (2 H, t, J = 6.8 Hz, CH2N), 3.11 (4 H, t, J = 5.9 Hz, CH2),
3.52 (4 H, t, 3J = 5.9 Hz, 2 CH2), 7.13 (2 H, t, 3J = 6.7 Hz, 2 CH), 8.16 (2 H, t, 3J = 6.7 Hz,
13
2 CH). C NMR (125.7 MHz, CDCl3): δC = 14.1 (CH3), 26.2 (CH2), 31.3 (CH2), 51.7 (2
CH2), 56.1 (CH2N), 59.3 (2 CH2), 116.3 (2 CH), 127.5 (2 CH), 138.5 (C), 156.9 (C). MS:
m/z (%) = 263 (M+, 8), 206 (21), 141 (35), 122 (100), 77 (16), 56 (67). Anal. Calcd for
C14H21N3O2 (263.34): C, 63.85; H, 8.04; N, 15.96%; Found: C, C, 64.23; H, 8.36; N,
15.87%.
1-hexyl-4-(4-nitrophenyl)piperazine (4m)
Yellow solid, mp: 105-108 ˚C; yield: 0.27 g (93%). IR (KBr) (νmax, cm-1): 3047, 2948,
1553, 1348, 1235. 1H NMR(500 MHz, CDCl3): δH = 0.91 (3 H, t, 3J = 6.7 Hz, CH3), 1.30-
3
3
1.49 (8 H, m, 4 CH2), 2.78 (2 H, t, J = 6.3 Hz, CH2N), 3.11 (4 H, t, J = 6.8 Hz, CH2),
3
3
3
3.49 (4 H, t, J = 5.0 Hz, 2 CH2), 7.11 (2 H, d, J = 7.0 Hz, 2 CH), 8.13 (2 H, t, J = 7.0
Hz, 2 CH). 13C NMR (125.7 MHz, CDCl3): δC = 13.1 (CH3), 21.5 (CH2), 27.8 (CH2), 28.3
(CH2), 32.5 (CH2), 50.3 (2 CH2), 51.4 (CH2N), 57.2 (2 CH2), 115.8 (2 CH), 126.3 (2 CH),
138.1 (C), 156.5 (C). MS: m/z (%) = 291 (M+, 36), 206 (27), 169 (100), 122 (34), 56 (13).
Anal.Calcd for C16H25N3O2 (291.40): C, 65.95; H, 8.65; N, 14.42%; Found: C, 66.23; H,
8.97; N, 14.58%
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1-benzyl-4-(4-(tert-butyl)cyclohex-1-en-1-yl)piperazine (4n)
1
Pale yellow oil, yield: 0.25 g (80%).IR (KBr) (νmax, cm-1): 2937, 1600, 1501, 1237. H
NMR(500 MHz, CDCl3): δH = 0.93 (9 H, s, 3 CH3), 1.39-2.27 (9 H, m, 9 CH), 2.78 (4 H, t,
3J = 5.3 Hz, 2 CH2), 3.13 (4 H, t, 3J = 5.3 Hz, 2 CH2), 3.67 (2 H, s, CH2N), 4.58 (1 H, t, 3J
= 6.2 Hz, CH), 7.23-7.29 (5 H, m, 5 CH). 13C NMR (125.7 MHz, CDCl3): δC = 22.3 (CH2),
24.1 (CH2), 25.8 (CH2), 29.3 (3 CH3), 34.9 (C), 47.1 (CH), 49.9 (2 CH2), 54.8 (2 CH2),
64.2 (CH2N), 101.3 (CH), 127.6 (2 CH), 127.9 (CH), 129.1 (2 CH), 137.2 (C), 146.9 (C).
MS: m/z (%) = 312 (M+, 23), 225 (13), 137 (59), 91 (100), 77 (56), 57 (89). Anal. Calcd
for C21H32N2 (312.50): C, 80.71; H, 10.32; N, 8.96%; Found: C, 80.98; H, 10.67; N,
9.13%.
1-benzyl-4-(3-phenylprop-1-en-1-yl)piperazine (4o).
Pale yellow oil; yield: 0.25 g (86%). IR (KBr) (νmax, cm-1): 3049, 2941, 1655, 1581, 1237.
3
1H NMR (500 MHz, CDCl3): δH = 2.69 (4 H, t, J = 6.2 Hz, 2 CH2), 3.28 (2 H, s, CH2),
3.45 (4 H, t, 3J = 6.2 Hz, 2 CH2), 3.68 (2 H, s, CH2N), 5.11 (1 H, m, CH), 5.87 (1 H, d, 3J
13
= 11.8 Hz, CH), 7.20-7.31 (10 H, m, 10 CH). C NMR (125.7 MHz, CDCl3): δC = 37.1
(CH2), 49.1 (2 CH2), 55.6 (2 CH2), 66.3 (CH2N), 104.5 (CH), 126.1 (CH), 126.5 (CH),
127.4 (2 CH), 128.4 (2 CH), 129.3 (2 CH), 129.9 (2 CH), 137.8 (C), 139.2 (CH), 141.0
(C). MS: m/z (%) = 292 (M+, 11), 201 (13), 175 (35), 117 (39), 91 (100), 77 (61). Anal.
Calcd for C20H24N2 (292.43): C, 82.15; H, 8.27; N, 9.58%; Found: C, C, 82.43; H, 8.51; N,
9.70%.
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1-benzyl-4-(2-cyclohexylvinyl)piperazine (4p).
1
Pale yellow oil; yield: 0.22 g (78%). IR (KBr) (νmax, cm-1): 2961, 1585, 1511, 1226. H
NMR(500 MHz, CDCl3): δH = 1.32-1.68 (10 H, m, 10 CH), 2.57 (1 H, m, CH), 2.79 (4 H,
3
3
t, J = 5.7 Hz, 2 CH2), 3.41 (4 H, t, J = 5.7 Hz, 2 CH2), 3.76 (2 H, s, CH2N), 4.81 (1 H,
3
3
13
dd, J = 11.1 Hz, CH), 5.88 (1 H, d, J = 11.1 Hz, CH), 7.23-7.28 (5 H, m, 5 CH). C
NMR (125.7 MHz, CDCl3): δC = 27.1 (2 CH2), 28.3 (CH2), 36.4 (2 CH2), 38.2 (CH), 51.4
(2 CH2), 57.2 (2 CH2), 65.3 (CH2N), 105.2 (CH), 127.2 (CH), 128.3 (2 CH), 128.9 (2 CH),
138.1 (C), 142.5 (C). MS: m/z (%) = 284 (M+, 15), 175 (18), 109 (68), 91 (100), 83 (79),
77 (46), 56 (42). Anal. Calcd for C19H28N2 (284.45): C, 80.23; H, 9.92; N, 9.85%; Found:
C, 80.46; H, 10.19; N, 9.79%.
1-benzyl-4-(1-phenylvinyl)piperazine (4q).
Pale yellow oil; yield: 0.25 g (89%). IR (KBr) (νmax, cm-1): 3027, 2940, 1631, 1509, 1221.
3
1H NMR(500 MHz, CDCl3): δH = 2.61 (4 H, t, 3J = 5.9 Hz, 2 CH2), 3.48 (4 H, t, J = 5.9
Hz, 2 CH2), 3.62 (2 H, s, CH2N), 4.11 (1 H, d, 2J = 3.9 Hz, CH), 4.53 (1 H, d, 2J = 3.9 Hz,
3
CH), 7.24-7.30 (5 H, m, 5 CH), 7.67-7.71 (3 H, m, 3 CH), 7.79 (2 H, d, J = 7.6 Hz, 2
CH). 13C NMR (125.7 MHz, CDCl3): δC = 51.8 (2 CH2), 57.1 (2 CH2), 65.8 (CH2N), 103.1
(CH2), 126.4 (CH), 127.2 (CH), 127.9 (2 CH), 128.5 (2 CH), 128.9 (2 CH), 129.7 (2 CH),
136.1 (C), 139.2 (C), 161.2 (C). MS: m/z (%) = 278 (M+, 15), 187 (58), 175 (27), 103 (16),
91 (100), 77 (63), 56 (49). Anal. Calcd for C19H22N2 (278.40): C, 81.97; H, 7.97; N,
10.06%; Found C, 82.24; H, 8.32; N, 10.15%.
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1-benzyl-4-(non-1-en-1-yl)piperazine (4r)
Pale yellow oil; yield: 0.25 g (83%). IR (KBr) (νmax, cm-1): 3018, 2972, 1610, 1519, 1217.
3
1H NMR(500 MHz, CDCl3): δH = 0.91 (3 H, t, J = 6.7 Hz, CH3), 1.28-1.37 (10 H, m, 5
CH2), 2.28-2.32 (2 H, m, CH2), 2.69 (4 H, t, 3J = 6.1 Hz, 2 CH2), 3.41 (4 H, t, 3J = 6.1 Hz,
3
2 CH2), 3.55 (2 H, s, CH2N), 4.61-4.65 (1 H, m, CH), 5.91 (1 H, d, J = 10.9 Hz, CH),
13
7.24-7.30 (5 H, m, 5 CH). C NMR (125.7 MHz, CDCl3): δC = 14.6 (CH3), 25.1 (CH2),
26.3 (CH2), 28.2 (CH2), 29.5 (CH2), 29.9 (CH2), 33.1 (CH2), 48.9 (2 CH2), 571 (2 CH2),
67.1 (CH2N), 106.4 (CH), 125.6 (CH), 127.6 (2 CH), 128.9 (2 CH), 136.1 (C), 139.8 (C).
MS: m/z (%) = 300 (M+, 15), 175 (29), 125 (11), 91 (100), 77 (69), 56 (48). Anal. Calcd
for C20H32N3 (300.49): C, 79.94; H, 10.73; N, 9.32%; Found: C, 80.26; H, 10.98; N,
9.28%.
1-benzyl-4-(3-styrylcyclopent-1-en-1-yl)piperazine (4s)
Pale yellow oil; yield: 0.33 g (88%). IR (KBr) (νmax, cm-1): 3047, 2975, 1648, 1530, 1216.
3
1H NMR(500 MHz, CDCl3): δH = 1.87-2.28 (4 H, m, 4 CH), 2.61 (4 H, t, J = 6.4 Hz, 2
CH2), 3.51 (4 H, t, 3J = 6.4 Hz, 2 CH2), 3.58 (1 H, t, 3J = 7.1 Hz, CH), 3.67 (2 H, s, CH2N),
3
3
4.61 (1 H, d, J = 7.1 Hz, CH), 6.11 (1 H, m, CH), 6.49 (1 H, d, J = 6.7 Hz, CH), 7.25-
7.36 (6 H, m, 6 CH), 7.41 (2 H, t, 3J = 6.9 Hz, 2 CH), 7.64 (2 H, d, 3J = 6.9 Hz, 2 CH). 13C
NMR (125.7 MHz, CDCl3): δC = 28.1 (CH2), 35.1 (CH2), 38.3 (CH), 49.9 (2 CH2), 53.7 (2
CH2), 65.4 (CH2N), 100.1 (CH), 117.9 (CH), 125.2 (CH), 126.2 (CH), 127.6 (2 CH), 128.1
(2 CH), 128.6 (CH), 129.6 (2 CH), 131.3 (CH), 135.5 (C), 139.2 (C), 153.1 (C). MS: m/z
(%) = 344 (M+, 11), 241 (13), 175 (35), 169 (26), 91 (100), 77 (68). Anal. Calcd for
C24H28N2 (344.50): C, 83.68; H, 8.19; N, 8.13%; Found: C, 83.91; H, 8.27; N, 8.31%.
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1-benzyl-4-(non-4-en-4-yl)piperazine (4t)
Pale yellow oil; yield: 0.23 g (78%). IR (KBr) (νmax, cm-1): 3023, 2965, 1658, 1519, 1237.
1H NMR(500 MHz, CDCl3): δH = 0.91-0.95 (6 H, m, 2 CH3), 1.30-1.37 (6 H, m, 3 CH2),
3
3
2.24-2.32 (4 H, m, 2 CH2), 2.51 (4 H, t, J = 6.1 Hz, 2 CH2), 3.41 (4 H, t, J = 6.1 Hz, 2
3
13
CH2), 3.67 (2 H, s, CH2), 4.48 (1 H, t, J = 6.8 Hz, CH), 7.23-7.30 (5 H, m, 5 CH). C
NMR (125.7 MHz, CDCl3): δC = 13.7 (CH3), 14.1 (CH3), 23.9 (CH2), 26.1 (CH2), 27.8
(CH2), 33.1 (CH2), 35.9 (CH2), 51.3 (2 CH2), 57.8 (2 CH2), 65.1 (CH2N), 103.0 (CH),
126.1 (CH), 127.1 (2 CH), 129.2 (2 CH), 139.2 (C), 155.1 (C). MS: m/z (%) = 300 (M+,
11), 209 (41), 175 (39), 125 (18), 91 (100), 77 (58). Anal.Calcd for C20H32N2 (300.49): C,
79.94; H, 10.73; N, 9.32%; Found: C, 80.34; H, 10.96; N, 9.48%.
1-butyl-4-(1-phenylvinyl)piperazine (4u)
Colorless oil; yield: 0.19 g (78%). IR (KBr) (νmax, cm-1): 3061, 2967, 1645, 1321, 1267. 1H
NMR(500 MHz, CDCl3): δH = 0.82 (3 H, t, 3J = 6.4 Hz, CH3), 1.37-1.49 (4 H, m, 2 CH2),
3
3
3
2.71 (4 H, t, J = 6.1 Hz, 2 CH2), 3.12 (2 H, t, J = 5.9 Hz, CH2N), 3.64 (4 H, t, J = 6.1
Hz, 2 CH2), 3.81 (1 H, d, 2J = 4.2 Hz, CH), 4.73 (1 H, d, 2J = 4.2 Hz, CH), 7.42 (2 H, t, 3J
3
3
13
= 6.2 Hz, 2 CH), 7.58 (1 H, t, J = 6.2 Hz, 2 CH), 7.84 (2 H, d, J = 6.7 Hz, 2 CH). C
NMR (125.7 MHz, CDCl3): δC = 15.1 (CH3), 25.2 (CH2), 35.1 (CH2), 51.4 (2 CH2), 59.1
(2 CH2), 60.2 (CH2N), 106.3 (CH2), 126.7 (CH), 127.5 (2 CH), 128.2 (2 CH), 136.4 (C),
163.2 (C). MS: m/z (%) = 244 (M+, 8), 187 (31), 141 (15), 112 (40), 102 (67), 77 (100), 57
(48). Anal. Calcd for C19H24N2 (244.38): C, 78.64; H, 9.90; N, 11.46%; Found C, 78.87;
H, 10.12; N, 11.61%.
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1-hexyl-4-(1-phenylvinyl)piperazine (4v)
Colorless oil; yield: 0.21 g (76%). IR (KBr) (νmax, cm-1): 3058, 2978, 1647, 1541, 1342,
1226. 1H NMR(500 MHz, CDCl3): δH = 0.83 (3 H, t, 3J = 6.2 Hz, CH3), 1.36-1.56 (8 H, m,
4 CH2), 2.70 (4 H, t, 3J = 6.1 Hz, 2 CH2), 3.25 (2 H, t, 3J = 5.6 Hz, CH2), 3.67 (4 H, t, 3J =
6.1 Hz, 2 CH2), 3.87 (1 H, d, 2J = 4.0 Hz, CH), 4.68 (1 H, d, 2J = 4.0 Hz, CH), 7.38 (2 H, t,
3
3J = 6.4 Hz, 2 CH), 7.65 (1 H, t, J = 6.4 Hz, 2 CH), 7.81 (2 H, d, 3J = 6.4 Hz, 2 CH). 13C
NMR (125.7 MHz, CDCl3): δC = 13.8 (CH3), 25.9 (CH2), 32.3 (CH2), 36.1 (CH2), 38.5
(CH2), 52.2 (2 CH2), 57.9 (2 CH2), 63.1 (CH2N), 106.3 (CH2), 126.9 (CH), 127.8 (2 CH),
128.9 (2 CH), 136.7 (C), 161.9 (C). MS: m/z (%) = 272 (M+, 18), 187 (36), 169 (22), 112
(68), 85 (41), 77 (100), 56 (48). Anal. Calcd for C18H28N2 (272.44): C, 79.36; H, 10.36; N,
10.28%; Found C, 79.58; H, 10.58; N, 10.39%.
1-allyl-4-(1-phenylvinyl)piperazine (4w)
Colorless oil; yield: 0.19 g (84%). IR (KBr) (νmax, cm-1): 3089, 2971, 1656, 1637, 1543,
1328, 1241. 1H NMR(500 MHz, CDCl3): δH = 2.69 (4 H, t, 3J = 5.6 Hz, 2 CH2), 3.18 (2 H,
td, 3J = 5.8 Hz, 3J = 1.8 Hz, CH2N), 3.62 (4 H, t, 3J = 5.6 Hz, 2 CH2), 4.15 (1 H, d, 2J = 3.9
2
Hz, CH), 4.67 (1 H, d, J = 3.9 Hz, CH), 5.24-5.26 (2 H, m, 2 CH), 6.04 (1 H, m, CH),
3
7.44-7.51 (3 H, m, 3 CH), 7.82 (2 H, d, J = 6.4 Hz, 2 CH). 13C NMR (125.7 MHz,
CDCl3): δC = 50.2 (2 CH2), 60.2 (2 CH2), 62.1 (CH2N), 105.5 (CH2), 119.1 (CH2), 126.8
(CH), 128.4 (2 CH), 128.9 (2 CH), 135.8 (CH), 137.1 (C), 160.6 (C). MS: m/z (%) = 228
(M+, 3), 187 (39), 124 (43), 102 (68), 77 (100), 56 (48), 41 (61). Anal. Calcd for C15H20N2
(228.34): C, 78.90; H, 8.83; N, 12.27%; Found C, 79.14; H, 8.97; N, 12.46%.
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1-isobutyl-4-(1-phenylvinyl)piperazine (4x)
Colorless oil; yield: 0.15 g (61%). IR (KBr) (νmax, cm-1): 3037, 2968, 1651, 1327, 1251. 1H
3
NMR(500 MHz, CDCl3): δH = 0.96 (6 H, d, J = 5.5 Hz, 2 CH3), 1.89 (1 H, m, CH), 2.48
(2 H, s, CH2N), 2.73 (4 H, t, 3J = 5.7 Hz, 2 CH2), 3.61 (4 H, t, 3J = 5.7 Hz, 2 CH2), 4.16 (1
2
2
H, d, J = 3.6 Hz, CH), 4.68 (1 H, d, J = 3.6 Hz, CH), 7.48-7.55 (3 H, m, 3 CH), 7.81 (2
3
13
H, d, J = 6.6 Hz, 2 CH). C NMR (125.7 MHz, CDCl3): δC = 21.1 (2 CH3), 30.1 (CH),
53.1 (2 CH2), 60.5 (2 CH2), 73.1 (CH2N), 106.9 (CH2), 126.1 (CH), 127.9 (2 CH), 128.5 (2
CH), 136.5 (C), 161.0 (C). MS: m/z (%) = 244 (M+, 4), 187 (41), 141 (30), 112 (58), 102
(79), 77 (100), 57 (83). Anal. Calcd for C16H24N2 (244.38): C, 78.64; H, 9.90; N, 11.46%;
Found C, 78.89; H, 10.24; N, 11.72%.
1-isopropyl-4-(1-phenylvinyl)piperazine (4y)
Colorless oil; yield: 0.11 g (46%). IR (KBr) (νmax, cm-1): 3045, 2961, 1646, 1521, 1341,
1221. 1H NMR(500 MHz, CDCl3): δH = 1.13 (6 H, d, 3J = 5.2 Hz, 2 CH3), 2.68 (4 H, t, 3J
= 5.9 Hz, 2 CH2), 3.11 (1 H, q, 3J = 5.2 Hz, CH2N), 3.51 (4 H, t, 3J = 5.9 Hz, 2 CH2), 4.11
2
2
3
(1 H, d, J = 3.9 Hz, CH), 4.71 (1 H, d, J = 3.9 Hz, CH), 7.51 (1 H, t, J = 6.1 Hz, CH),
7.60 (2 H, t, 3J = 6.5 Hz, 2 CH), 7.85 (2 H, d, 3J = 6.7 Hz, 2 CH). 13C NMR (125.7 MHz,
CDCl3): δC = 21.8 (2 CH3), 54.8 (2 CH2), 57.1 (2 CH2), 69.4 (CHN), 105.1 (CH2), 126.5
(CH), 128.2 (2 CH), 128.9 (2 CH), 136.1 (C), 160.3 (C). MS: m/z (%) = 230 (M+, 2), 187
(42), 152 (36), 102 (67), 77 (100), 56 (49). Anal. Calcd for C15H22N2 (230.36): C, 78.21;
H, 9.63; N, 12.16%; Found C, 78.47; H, 9.85; N, 12.23%.
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Table 1
Table 1. Optimization of reaction conditionsa
Entry Catalyst
Solvent
Base
Yield (%)
86
80
traces
35
29
48
16
traces
traces
1
2
3
4
5
6
7
8
9
Cu(OTf)
CuCl
CuBr
CuBr.Me2S NMP
CuI
Cu2O
CuF2
CuBr2
Cu(BF4)2
NMP
NMP
NMP
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
NMP
NMP
NMP
NMP
NMP
10
11
12
13
14
15
16
17
18
19
20
21
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
NMP
NMP
NMP
NMP
NMP
DMF
DMSO
DMA
HMPA
toluene
dioxane
Ethylene
glycol
NMP
t-BuOCs
t-BuOK
Li2CO3
K3PO4
traces
21
-
-
-
23
29
53
traces
16
-
EtOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
29
22
CuCl
t-BuOK
78b
a Reaction conditions: DABCO (1.2 mmol), benzyl chloride (1.0 mmol), phenyl
trifluoromethanesulfonate (1.0 mmol), base (1.5 mmol), copper salt (0.05 mmol), solvent (3 mL),
70 ˚C, 14 h.
b Reaction mixture was stirred at 110 ˚C.
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Table 2
Table 2. Synthesis of unsymmetrical piperazines using aryl triflatesa
Entry
1
R
Ar
Product
4a
Yield (%)
86
2
3
Bn
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
3a
3b
3c
3d
3e
3f
2
Bn
2-naphthyl
4-MeC6H4
3-MeC6H4
3-MeOC6H4
4-t.BuC6H4
4-Acetylphenyl
4-CNC6H4
2-Pyridyl
6-quinolyl
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
85
4b
4c
3
Bn
80b
82b
73b
79b
91
4
Bn
4d
4e
5
Bn
6
Bn
4f
7
Bn
3g
3h
3i
4g
8
Bu
88
4h
4i
9
Bu
91
10
11
12
13
Bu
84
3j
4j
Bn
93
3k
3k
3k
4k
4l
n-Bu
n-Hexyl
91
93
4m
aFor all entries except stated otherwise: 1 (1.2 mmol), 2 (1.0 mmol), 3 (1.0 mmol), t-BuOLi (1.5
mmol), CuCl (0.05 mmol), NMP (3.0 mL), 70 ˚C, 14 h.
bReactions were conducted with 1.5 mmol of 1 using 0.1 mmol of CuCl.
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Table 3. Synthesis of unsymmetrical piperazines using alkenyl iodide and triflatea
Entry
1
5
Product
Yield (%)
X = I
Yield (%)
X = OTf
4n
80
73
5a
2
3
4o
4p
86
71(3/97)b
(7/93)b
5b
78
65(99/1)b
(95/5)b
5c
4
5
4q
4r
89
83
85
5d
69(96/4)b
(92/8)b
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5e
6
7
4s
4t
88
78
73
63
5f
5g
aFor all entries: 1 (1.2 mmol), 2a (1.0 mmol), 5 (1.0 mmol), t-BuOLi (1.5 mmol), CuCl (0.10
mmol), N, N′-dimethyl ethylenediamine (0.10 mmol), NMP (3.0 mL), 90 ˚C, 18 h.
bThe digit in parentheses described the E/Z ratio.
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Table 4
Table 4. Synthesis of unsymmetrical piperazines using different alkyl chloride and 5da
Entry
2
R2
Product
4u
Yield (%)
78
1
2
3
4
5
2b
2c
2d
2e
2f
n-Bu
n-Hexyl
4v
76
Allyl
4w
84
2-Methylpropane
4x
61
i.Pr
4y
46
aFor all entries: 1 (1.2 mmol), 2 (1.0 mmol), 5d (1.0 mmol), t-BuOLi (1.5 mmol), CuCl (0.10
mmol), N, N′-dimethyl ethylenediamine (0.10 mmol), NMP (3.0 mL), 90 ˚C, 22 h.
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Scheme 1
Cl
R
N
+
Bn-Cl
N
DABCO
2a
1
5
Cl
TfO
Ar
N
N Bn
Cl
Ar N
N Bn
TfO
CuX
9
8
t.BuOLi
Cl
N
Li
Bn
TfO
N
Cu(I)
Cl
N Bn
Cl
N
(III)Cu
Ar
6
N
Bn
7
Ar
N
Ar-OTf
4
3
Scheme 1. Proposed mechanism for the formation of unsymmetrical piperazines
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