A simple method of synthesis of (±)-2,3-diarylpiperazines and a novel method of resolution of (±)-2,3-diphenylpiperazine

Article abstract of DOI:10.1021/jo060083n

Intramolecular reductive coupling of diimines in the presence of Zn/Ti(OⁱPr)₂Cl₂ gives the corresponding (±)-2,3-diarylpiperazines in 73-83% yields with dl/meso ratio >99%: <1%. The (±)-2,3-diphenylpiperazine obtained in t

Full text of DOI:10.1021/jo060083n

SCHEME 1. Synthesis (()-2,3-Diarylpiperazines 1
A Simple Method of Synthesis of
(()-2,3-Diarylpiperazines and a Novel Method of
Resolution of (()-2,3-Diphenylpiperazine
Pothiappan Vairaprakash and Mariappan Periasamy*
School of Chemistry, UniVersity of Hyderabad,
desirable. Though, the 2,5-disubstituted piperazines can be
synthesized via the reduction of the corresponding diketopip-
erazines,4 it is much more difficult to access the 2,3-disubstituted
piperazines, which have been predicted to have interesting
biological activity.1f,2 Generally, intermolecular reductive dimer-
ization of imines are carried out using Mn0,5 Mg0,6 alkali metal,6
photolysis,7 other metal reductants,8-15 electrochemistry,16 and
low-valent titanium reagents.17 However, very few methods give
dl products in good yields.5,16 Herein, we report a diastereose-
lective synthesis of (()-trans-2,3-disubstituted piperazines 1
using the Ti(OiPr)2Cl2/Zn reagent system and resolution of (()-
2,3-diphenylpiperazine 1a using L-(+)-tartaric acid following
a novel method of enhancement of enantiomeric purity of
partially resolved samples to obtain samples of >99% ee via
preparation of hydrogen-bonded salt aggregates using oxalic
acid.
Central UniVersity P.O., Hyderabad 500 046, India
mpsc@uohyd.ernet.in
ReceiVed January 16, 2006
We have observed that the diastereomerically pure (()-2,3-
diarylpiperazines 1 are readily prepared in 73-83% yields by
intramolecular reductive coupling of diimines in the presence
of Zn/Ti(OiPr)2Cl2 (Scheme 1).
We have initially carried out the reductive coupling using
reagent systems such as Zn/TiCl4 17 and iPrMgBr/TiCl4. In these
cases, the piperazine derivatives were obtained in 45-60% yield
(Table 1, entries 2, 4, and 6). The yield was lower using the
TiCl3 prepared in the reaction of the TiCl4/Et3N reagent system,
since the imine was cleaved to some extent into aldehyde under
Intramolecular reductive coupling of diimines in the presence
of Zn/Ti(OiPr)2Cl2 gives the corresponding (()-2,3-dia-
rylpiperazines in 73-83% yields with dl/meso ratio >99%:
<1%. The (()-2,3-diphenylpiperazine obtained in this way
was readily resolved partially using L-(+)-tartaric acid, and
the enantiomeric purity was enhanced to >99% ee via
preparation of hydrogen-bonded salt aggregates using oxalic
acid.
(4) Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909-4913.
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Smith, J. G.; Veach, C. D. Can. J. Org. Chem. 1966, 44, 2497-2502. (c)
Eisch, J. J.; Kaska, D. D.; Peterson, C. J. J. Am. Chem. Soc. 1966, 88,
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Piperazine moieties are found in a large number of biologi-
cally active compounds.1 A recent molecular docking study of
estrogenically active compounds with 1,2-diarylethane and 1,2-
diarylethene pharmacophores reveals that the 2,3-diarylpipera-
zines are potentially active estrogen receptor modulators.2 In
addition, the piperazine derivatives were also used as chiral
ligands in asymmetric catalysis.3 Hence, a method of preparation
of enantiomerically pure 2,3-diarylpiperazine derivatives is
(1) For examples, see: (a) Tagat, J. R.; Steensma, R. W.; McCombie,
S. W.; Nazareno, D. V.; Lin, S.; Neustadt, B. R.; Cox. K.; Xu, S.; Wojcik,
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B. J. Med. Chem. 1996, 39, 4689-4691. (e) Corey, E. J.; Gin, D. Y.; Kania,
R. S. J. Am. Chem. Soc. 1996, 118, 9202-9203. (f) Giardina´, D.; Gulini,
U.; Massi, M.; Piloni, M. G.; Pompei, P.; Rafaiani, G.; Melchiorre, C. J.
Med. Chem. 1993, 36, 690-698. (g) Giardina´, D.; Brasili, L.; Gregori, M.;
Massi, M.; Picchio, M. T.; Quaglia, W.; Melchiorre, C. J. Med. Chem. 1989,
32, 50-55. (h) Witiak, D. T.; Trivedi, B. K. J. Med. Chem. 1981, 24, 1329-
1332. (i) Manoury, P. M.; Dumas, A. P.; Najer, H. J. Med. Chem. 1979,
22, 554-559.
(9) Pb/Al: Tanaka, H.; Dhimane, H.; Fujita, H.; Ikemoto, Y.; Torii, S.
Tetrahedron Lett. 1988, 29, 3811-3814.
(10) Mn: Rieke, R. D.; Kim, S. J. Org. Chem. 1998, 63, 5235-5239.
(11) Yb: Takaki, K.; Tsubaki, Y.; Tanaka, S.; Beppu, F.; Fujiwara, Y.
Chem. Lett. 1990, 203-204.
(12) In: Kalyanam, N.; Rao, G. V. Tetrahedron Lett. 1993, 34, 1647-
1648.
(13) Ti: Talukdar, S.; Banerji, A. J. Org. Chem. 1998, 63, 3468-3470.
(14) V: Hatano, B.; Ogawa, A.; Hirao, T. J. Org. Chem. 1998, 63, 9421-
9424.
(15) Zr: Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan,
J. C. J. Am. Chem. Soc. 1989, 111, 4486-4494.
(16) Siu, T.; Li, W.; Yudin, A. K. J. Comb. Chem. 2001, 3, 554-558.
(17) (a) Smith, J. G.; Boettger, T. J. Synth. Commun. 1981, 11, 61-64.
(b) Alexakis, A.; Aujard, I.; Kanger, T.; Mangeney, P. Org. Synth. 1999,
76, 23. (c) Tsukinoki, T.; Nagashima, S.; Mitoma, Y.; Tashiro, M. Green
Chem. 2000, 2, 117-119. (d) Periasamy, M.; Srinivas, G.; Karunakar, G.
V.; Bharathi, P. Tetrahedron Lett. 1999, 40, 7577. (e) Talukdar, S.; Banerji,
S. J. Org. Chem. 1998, 63, 3468. (f) Periasamy, M.; Srinivas, G.; Suresh,
S. Tetrahedron Lett. 2001, 42, 7123.
(2) Kekenes-Huskey, P. M.; Muegge, I.; Rauch, M.; Gustd, R.; Knapp,
E. W. Bioorg. Med. Chem. 2004, 12, 6527-6537.
(3) Shono, T.; Kise, N.; Shirakawa, E.; Matsumoto, H.; Okazaki, E. J.
Org. Chem. 1991, 56, 3063-3067.
10.1021/jo060083n CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/04/2006
3636
J. Org. Chem. 2006, 71, 3636-3638

TABLE 1. Intramolecular Reductive Coupling of Diimines with
Zn/TiCl2X2
SCHEME 2. Resolution of (()-2,3-Diphenylpiperazine 1a
TABLE 3. Purification of Nonracemic 2,3-Diphenylpiperazine 1a
Using Oxalic Acida
piperazine 1a obtained from
precipitate
fraction
filtrate
fraction
substrate
% eeb/(mmol)/
config
oxalic
acid
(mmol)
% eeb/
yieldc
(%)
% eeb/
config
yieldc
(%)
entry
config
a The products were identified using physical constants and spectroscopic
1
2
3
4
5
6
39 (2.00) (S,S)
45 (2.00) (S,S)
73 (2.00) (S,S)
53 (5.00) (S,S)
84 (0.75) (S,S)
48 (2.00) (R,R)
0.60
0.75
1.30
1.00
0.55
0.80
71 (S,S)
73 (S,S)
99 (S,S)
84 (S,S)
99 (S,S)
77 (R,R)
30
51
62
21
67
36
22 (S,S)
18 (S,S)
21 (S,S)
28 (S,S)
20 (S,S)
19 (R,R)
65
37
33
77
28
60
1
data (IR, H and 13C NMR, and mass spectral data) and comparison with
reported data.3
TABLE 2. Resolution of (()-2,3-Diphenylpiperazine 1a Using
Chiral L-(+)-Tartaric Acid
a All of the reactions were carried out using nonracemic piperazine 1a
piperazine 1a obtained from
and oxalic acid in THF. b All ee values reported here are based on HPLC
precipitate
fraction
filtrate
fraction
analysis and the maximum [R]25 ) -104.6 (c 1.0, CHCl3) for (S,S)-1a.
D
c The yields are of the isolated products.
solvent
(mL)a
L-(+)-tartaric % eeb/ yieldc % eeb/ yieldc
entry
acid (mmol)
config
(%)
config
(%)
The configuration of the enantiomer (-)-1a was assigned as
(S,S) by single-crystal X-ray analysis of the corresponding
tartrate salt 3a,19 and the enantiomeric ratio was determined by
HPLC analysis.
1
2
3
4
5
6
7
8
THF (50)
5
5
2.5
5
5
5
16 (S,S)
20 (S,S)
20 (S,S)
31 (S,S)
48 (S,S)
15 (S,S)
45 (S,S)
61 (S,S)
56
62
38
38
42
43
32
33
8 (R,R)
25 (R,R)
12 (R,R)
16 (R,R)
22 (R,R)
12 (R,R)
27 (R,R)
15 (R,R)
39
38
52
54
57
51
67
63
THF (100)
THF (100)
THF (250)
THF (500)
acetone (50)
CH2Cl2 (200)
CH2Cl2 (250)
We have also examined the effect of amount of THF and the
amount of resolving agent on the resolution process (Table 2).
Reasonable results were realized when the (()-2,3-diphenylpip-
erazine 1a and L-(+)-tartaric acid were used in a 1:0.5 molar
ratio (Table 2, entries 1, 2, 4-7). Use of 1a and L-(+)-tartaric
acid in a 1:0.25 molar ratio gave samples with only 20% ee in
the precipitate fraction and samples with 12% ee in the filtrate
fraction (Table 2, entry 3). Results are better when 50 mL of
THF was used per 1 mmol of amine (Table 2, entry 5). There
was no appreciable change in ee when acetone was used as
solvent instead of THF (Table 2, entries 1 and 6). When the
(()-2,3-diphenylpiperazine 1a and L-(+)-tartaric acid were used
in a 1:1 molar ratio in THF, precipitation occurred but there
was no resolution. However, appreciable resolution was realized
by using the (()-2,3-diphenylpiperazine 1a and L-(+)-tartaric
acid in a 1:1 mole ratio in CH2Cl2 (Table 2, entry 8).
Recently, a simple method of purification of certain nonra-
cemic samples of amino alcohols via preparation of the
corresponding hydrogen-bonded aggregates using achiral di-
carboxylic acids was developed in this laboratory.20 We have
followed this methodology to enhance the optical purity of the
partially resolved piperazine 1a. Enantiomerically enriched
samples with 99% ee can be readily obtained following this
method (Table 3).
5
10
a All experiments were carried out using 10 mmol of (()-2,3-diphe-
nylpiperazine 1a. b All ee values reported here are based on HPLC analysis
and the maximum [R]25D ) -104.6 (c 1.0, CHCl3) for (S,S)-1a. c The yields
are of the isolated products.
the reaction conditions. The Ti(OiPr)2Cl2/Zn system gave better
yields (Table 1, entries 1, 3, 5, 7, and 8). Optimum yields were
obtained by using 5 equiv of zinc powder, and yields were low
when 2 equiv of zinc powder was used.
The configuration of the product was confirmed to be trans
by single-crystal X-ray analysis of the trifluoroacetamide
derivative 2a of the product (()-1a,18 and the dl/meso ratio was
determined to be >99:<1 by HPLC analysis.
Resolution methods are widely used, especially when both
the isomers are required. Surprisingly, methods were not
reported for the resolution of (()-2,3-diarylpiperazines 1. We
have examined the resolution of the (()-2,3-diphenylpiperazine
1a. We have carried out the resolution of (()-2,3-diphenylpip-
erazine 1a in various solvents using L-(+)-tartaric acid (Table
2). Partial resolution could be easily realized under these
conditions, and the partially resolved 1a could be readily
enriched to obtain samples of >99% ee by repeating the
operation (Table 2 and Scheme 2).
(19) Crystal Data. For compound 3a: molecular formula C20H28N2O8,
MW ) 424.44, orthorhombic, space group P2(1)2(1)2, a ) 9.2088(10) Å,
b ) 35.387(4) Å, c ) 6.2519(7) Å, V ) 2037.3(4) Å3, Z ) 4, Fc ) 1.384
mg M-3, µ ) 0.107 mm-1, T ) 273(2) K. Of the 23736 reflections collected,
4860 were unique (Rint ) 0.0451). Refinement on all data converged at R1
) 0.0483, wR2 ) 0.1071.
(18) Crystal Data. For compound 2a: molecular formula C20H16F6N2O2,
MW ) 430.35, monoclinic, space group P2(1)/c, a ) 22.3786(10) Å, b )
16.5405(7) Å, c ) 11.1443(5) Å, â ) 103.3050(10)°, V ) 4014.4(3) Å3,
Z ) 8, Fc ) 1.424 mg M-3, µ ) 0.130 mm-1, T ) 273(2) K. Of the 45980
reflections collected, 9632 were unique (Rint ) 0.0378). Refinement on all
data converged at R1 ) 0.0799, wR2 ) 0.2291.
(20) Periasamy, M.; Sivakumar, S.; Reddy, M. N.; Padmaja, M. Org.
Lett. 2004, 6, 265-268.
J. Org. Chem, Vol. 71, No. 9, 2006 3637

(()-2,3-diphenylpiperazine 1a (2.40 g, 10.0 mmol) were taken in
CH2Cl2 (250 mL), and the contents were stirred at 25 °C for 6 h
and filtered. The precipitate was suspended in a mixture of CH2-
Cl2 and aq Na2CO3 (2 M) and stirred until dissolution occurred.
The organic extracts were washed with brine, dried (MgSO4), and
evaporated to obtain the (S,S)-1a enantiomer (61% ee, 33% yield).
The filtrate was treated as outlined above to obtain 1a enriched in
the (R,R)-enantiomer (15% ee, 63% yield).
In conclusion, the simple, convenient method of synthesis
of (()-2,3-diarylpiperazines by the intramolecular reductive
coupling of diimines in the presence of Zn/Ti(OiPr)2Cl2 and the
partial resolution of the (()-2,3-diphenylpiperazine 1a using
L-(+)-tartaric acid and enhancement of the enantiomeric purity
using oxalic acid have good synthetic potential, in view of the
potential biological activity predicted for 2,3-disubstituted
piperazines.2
Resolution of Nonracemic 2,3-Diphenylpiperazine 1a Using
L-(+)-Tartaric Acid. To a solution of nonracemic 2,3-diphenylpip-
erazine (S,S)-1a (61% ee, 0.60 g, 2.5 mmol) in CH2Cl2 (60 mL)
was added L-(+)-tartaric acid (0.38 g, 2.5 mmol), and the contents
were stirred at room temperature for 12 h and filtered. The
precipitate was suspended in a mixture of CH2Cl2 and aq Na2CO3
(2 M) and stirred until dissolution occurred. The organic extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness to obtain the (S,S)-1a isomer (>99% ee, 35% yield). The
filtrate was concentrated, and the residue was treated as outlined
above to obtain 1a enriched in the (S,S)-enantiomer (38% ee, 61%
yield).
Enrichment of Enantiomeric Purity of Nonracemic 2,3-
Diphenylpiperazine 1a Using Oxalic Acid. To a solution of
nonracemic 2,3-diphenylpiperazine (S,S)-1a (73.0% ee, 2.0 mmol)
in THF (30 mL) was added oxalic acid (0.165 g, 1.30 mmol), and
the contents were stirred at room temperature for 2 h and filtered.
The precipitate was suspended in a mixture of CH2Cl2 and aq Na2-
CO3 (2 M) and stirred until dissolution occurred. The organic
extracts were washed with brine, dried over MgSO4, and evaporated
to dryness to obtain the (S,S)-1a isomer (>99% ee, 62% yield).
The filtrate was concentrated, and the residue was treated as outlined
above to obtain 1a enriched in the (S,S)-enantiomer (21% ee, 33%
yield).
Experimental Section
Representative Procedure for the Intramolecular Coupling
of Diimines Using Zn and Ti(OiPr)2Cl2. In a 100 mL, two-necked
round-bottom (RB) flask, containing a magnetic stirring bar
equipped with a dropping funnel and an air condenser protected
by mercury trap, were placed CH2Cl2 (40 mL), TiCl4 (1.043 g, 5.5
mmol), and Ti(OiPr)4 (1.563 g, 5.5 mmol) under nitrogen, and the
mixture was stirred for 10-15 min. To this was added activated
zinc powder (1.634 g, 25.0 mmol) in three portions, and the stirring
was continued for another 1 h. Then, diimine (5.0 mmol) dissolved
in CH2Cl2 (10 mL) was added in drops through a dropping funnel
at 0 °C. After the addition was completed, the reaction mixture
was stirred at 25 °C for 5-6 h. The reaction mixture was poured
into saturated aqueous K2CO3 solution at 0 °C and filtered. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 20 mL). The combined organic extract was
washed with water and brine solution and dried using anhydrous
K2CO3. The solvent was evaporated, and the product was purified
by column chromatography (Basic alumina, hexane/CHCl3 ) 9/1
and then CHCl3).
Spectral data for products 1a-e:
1a: yield 83% (0.99 g); mp 94-96 °C (lit.3 mp 96-98 °C); IR
(KBr) 3318, 3280, 3030, 2949, 2820, 1603, 1491 cm-1; H NMR
1
(400 MHz, CDCl3) δ 2.00 (br s, 2 H, NH), 3.15 (s, 4 H), 3.72 (s,
2 H), 7.07-7.12 (m, 10 H); 13C NMR (50 MHz, CDCl3) δ 47.0,
68.1, 127.3, 127.8, 128.0, 141.2; MS (EI) m/z ) 238 [M+].
1b: yield 73% (1.08 g); mp 106-108 °C; IR (KBr) 3314, 3032,
3006, 2955, 1605, 1585 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.96
(br s, 2 H, NH), 3.10 (s, 4 H), 3.56 (s, 6 H), 4.30 (s, 2 H), 6.61 (d,
2 H, J ) 8.8 Hz), 6.76 (t, 2 H, J ) 6.8 Hz), 7.04 (t, 2 H, J ) 6.8
Hz), 7.28 (d, 2 H, J ) 8.8 Hz); 13C NMR (50 MHz, CDCl3) δ
46.9, 55.1, 59.9, 110.2, 120.1, 127.9, 128.9, 129.2, 157.0; MS (EI)
m/z ) 298 [M+].
HPLC Analysis of the Trifluoroacetamide Derivatives of 2,3-
Diarylpiperazines. The diamine (1a-e) (0.5 mmol) in CH2Cl2 (ca.
25 mL) was stirred overnight with excess trifluoroacetic anhydride
(TFAA). The solution was concentrated under reduced pressure to
remove the solvent, and excess TFAA and the residue were
recrystallized from hexane/CH2Cl2 (99:1) mixture. The trifluoro-
acetamide derivatives were dissolved in 2-propanol (∼10 mg/mL),
and HPLC analyses were performed using a Chiralcel OD-H column
supplied by Daicel Chemical Industries, Ltd., with an isochratic
method using hexane/2-propanol (98:2) with a flow rate 0.5 mL/
min. Retention times for the trifluoroacetamide derivatives (2a) of
2,3-diphenylpiperazine are 10.5 min for the (R,R) and 12.3 min
for the (S,S).
1c: yield 75% (1.12 g); mp 96-98 °C (lit.3 mp 100-101 °C);
IR (KBr) 3271, 3040, 3003, 2957, 1612, 1584 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.27 (br s, 2 H, NH), 3.10 (s, 4 H), 3.63 (s, 2 H),
3.70 (s, 6 H), 6.65 (d, 4 H, J ) 8.0 Hz), 7.00 (d, 4 H, J ) 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ 47.0, 55.1, 67.4, 113.2, 129.0, 133.6,
158.6; MS (EI) m/z ) 298 [M+].
Acknowledgment. P.V. is thankful to the CSIR for the
research fellowship. We are thankful to the ILS-UOH-MOU
for a research grant. UGC support under the “University with
Potential for Excellence (UPE)” and “Centre for Advance Study
(CAS-SAP)” programs is gratefully acknowledged. We are
thankful to the DST for the 400 MHz NMR spectrometer and
National XRD-CCD facilities in the School of Chemistry,
University of Hyderabad.
1d: yield 80% (1.23 g); mp 119-120 °C; IR (KBr) 3317, 3047,
3003, 2947, 2893, 1593, 1485 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.91 (br s, 2 H, NH), 3.11 (s, 4 H), 3.60 (s, 2 H), 6.99 (d, 4 H,
J ) 8.4 Hz), 7.10 (d, 4 H, J ) 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 46.9, 67.7, 128.1, 129.3, 133.0, 139.7; MS (EI) m/z )
306 [M+].
1e: yield 76% (1.01 g); mp 128-130 °C (lit.3 mp 122-125 °C);
IR (KBr) 3321, 3024, 2953, 2814, 1658, 1512 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.88 (br s, 2 H, NH), 2.23 (s, 6 H), 3.13 (s, 4 H),
3.68 (s, 2 H), 6.93 (d, 4 H, J ) 7.6 Hz), 6.98 (d, 4 H, J ) 7.6 Hz);
13C NMR (100 MHz, CDCl3) δ 21.1, 47.3, 67.8, 128.0, 128.5, 136.6,
138.7; MS (EI) m/z ) 266 [M+].
Supporting Information Available: 13C NMR spectra of
compounds 1a-e. Crystallographic diagrams and CIF for com-
pounds 2a and 3a. This material is available free of charge via the
Internet at http://pubs.acs.org.
Resolution of (()-2,3-Diphenylpiperazine 1a Using L-(+)-
Tartaric Acid. The L-(+)-tartaric acid (1.50 g, 10.0 mmol) and
JO060083N
3638 J. Org. Chem., Vol. 71, No. 9, 2006