New chiral titanium complexes for enantioselective reductive cyclizations of diimines to trans-2,3-diarylpiperazines

Article abstract of DOI:10.1016/j.tetlet.2007.12.038

Enantioselective intramolecular reductive coupling of diimines by chiral titanium complexes, prepared using a titanium(IV) reagent and hemisalen ligands derived from chiral β-amino alcohols, gives trans-2,3-diarylpiperazines in up to 97% ee.

Full text of DOI:10.1016/j.tetlet.2007.12.038

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1233–1236
New chiral titanium complexes for enantioselective reductive
cyclizations of diimines to trans-2,3-diarylpiperazines
Pothiappan Vairaprakash, Mariappan Periasamy *
School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 046, India
Received 28 October 2007; revised 29 November 2007; accepted 6 December 2007
Available online 14 December 2007
Abstract
Enantioselective intramolecular reductive coupling of diimines by chiral titanium complexes, prepared using a titanium(IV) reagent
and hemisalen ligands derived from chiral b-amino alcohols, gives trans-2,3-diarylpiperazines in up to 97% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Enantioselective reductive coupling; Diimine; Hemisalen ligand; 2,3-Diarylpiperazines
Though enantioselective pinacol couplings of aromatic
aldehydes using chiral titanium and chromium complexes1
are widely reported, very few reports are available for the
enantioselective reductive coupling of chiral imines.2
Recently, we reported intramolecular reductive coupling
of diimines in the presence of the Ti(OiPr)2Cl2/Zn reagent
system to afford ( )-trans-2,3-diarylpiperazines.3 Herein,
we report the enantioselective intramolecular reductive
coupling of diimines derived from ethylenediamine leading
to enantiomerically pure 2,3-diarylpiperazines 2 using
various chiral titanium complexes consisting of a chiral
diamide, a chiral diol or a chiral b-amino alcohol.
Initially, we examined the enantioselective reductive
coupling of N,N0-dibenzylidene-1,2-ethanediamine 1a using
different chiral ligands (Scheme 1, Fig. 1). The results are
summarized in Table 1.
In the case of diamide R,R-3a, only racemic 2,3-diphenyl-
piperazine 2a was obtained when the TiCl4/iPrMgBr
reagent system was used (Table 1, entry 1). Lowering the
temperature to ꢀ40 °C did not result in any enantioselec-
tivity; instead the yield of the product decreased (Table 1,
entry 2). A slight enhancement in the enantioselectivity
was achieved using the Ti(OiPr)2Cl2/Zn reagent system
Ph
Ph
Ph
Ph
ligand (3a-3d)
Lewis acid
N
N
HN
NH
reductant
1a
2a
Scheme 1. Reductive coupling of diimine 1a in the presence of chiral
ligands 3a–d.
H3C
CH3
H
OH
CH3
NHTs
NHTs
OH
OH
OH
R,R-3a
1
R,2
R,3
S,5
R-3c
R
-3b
Ph Ph
Ph
Ph
R'
O
O
OH
OH
R
R
R
R
-4a R = H, R' = Ph
N
OH
-4b R = tBu, R' = Ph
-4c R = H, R' = PhCH2
-4d R = tBu, R' = PhCH2
R
OH
Ph Ph
R,R-3d
R
Fig. 1. Chiral ligands examined for reductive coupling of diimine.
(Table 1, entry 3). Although 2,3-diphenylpiperazine was
obtained in higher yields in the presence of chiral R-
BINOL 3b, the enantioselectivity was poor (Table 1, entries
*
Corresponding author. Tel.: +91 40 2313 4814; fax: +91 40 2301 2460.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.038

1234
P. Vairaprakash, M. Periasamy / Tetrahedron Letters 49 (2008) 1233–1236
Table 1
Ar
Ar
Reductive coupling of diimine 1a in the presence of chiral ligands 3a–da
Ar
Ar
[Ti*]/Zn
N
N
HN
NH
Entry
Ligand
Lewis acid
T (°C) Yieldb (%) ee/confc (%)
1d
2d
3d
4
5
6
7e
8e
9
R,R-3a
R,R-3a
R,R-3a
R-3b
R-3b
R-3b
3c
TiCl4
TiCl4
25
ꢀ40
25
60
40
75
65
60
82
75
70
40
—
—
12 (S,S)
—
5 (R,R)
—
—
10 (R,R)
10 (S,S)
2
1
Ar = Ph, 4-MeO-C6H4
Ti(OiPr)2Cl2
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)2Cl2
TiCl4
Scheme 3. Reductive coupling of diimines 1 using chiral titanium complex
7 [Ti*]/Zn.
25
ꢀ70
25
25
Table 2
3c
R,R-3d
TiCl4
TiCl4
ꢀ70
Asymmetric synthesis of 2,3-diarylpiperazine 2 using a catalytic amount of
chiral titanium complexes 7b and 7da
25
a
Unless noted otherwise, all the reactions were carried out with
1.0 mmol of diimine 1a, 2.5 mmol of chiral ligands 3a, b and d, 2.2 mmol
of Lewis acid and 5 mmol of Zn dust in CH2Cl2.
Entry Chiral titanium
complex
Ar
Yieldb
(%)
ee/confc
(%)
b
Yield of isolated product after flash column chromatography on silica.
All ee values reported here are based on HPLC analysis on a Chiralcel
1
2
R-7b
R-7b
Ph
77
60
15 (R,R)
18 (R,R)
c
4-MeO–
C6H4
Ph
4-MeO–
C6H4
OD-H column.
d
i
THF was used as a solvent and PrMgBr was used as a reductant.
4.0 mmol of diimine 1a, 11.0 mmol of chiral ligand 3c, 10.0 mmol of
3
4
S-7d
S-7d
54
48
15 (S,S)
28 (S,S)d
e
TiCl4 and 25 mmol of Zn were used.
a
Unless noted otherwise, all the reactions were carried out with
2.5 mmol of diimine 1, 0.5 mmol of chiral titanium complex 7 (prepared
in situ), 10.0 mmol of Zn dust in CH2Cl2 (20 mL), CH3CN (5 mL) and
TMSCl (5.0 mmol) at 25 °C.
4–6). The use of pinanediol 3c and (R,R)-trans-a,a0-
(2,2-dimethyl-1,3-dioxalane-4,5-diyl)bis(diphenylmethanol)
TADDOL 3d gave enantioselectivity of only up to 10%
(Table 1, entries 7–9).
Previously, the chiral titanium complex 7d prepared
from tridentate hemisalen ligand 4d was used in the enan-
tioselective pinacol coupling of aldehydes.1d,4 We have pre-
pared the chiral titanium complexes 7a–d in situ (Scheme 2)
and used them for the reductive coupling of diimines 1.5
When the titanium complexes 7b and 7d were used in cat-
alytic amounts (10 mol %), products 2 were obtained in
moderate to good yields but the enantioselectivities
obtained were poor (Scheme 3, Table 2).
b
Yield of isolated product after flash column chromatography on silica.
c
All ee values reported here are based on HPLC analysis on a Chiralcel
OD-H column.6
d
Absolute configuration was assigned as (S,S) by single crystal X-ray
analysis of the corresponding (S)-camphorsulfonate salt.7
Table 3
Asymmetric synthesis of 2,3-diarylpiperazines 2 using a stoichiometric
amount of chiral titanium complexes 7a
Entry Chiral Ti
complex
Ar
T
Yieldb
(%)
ee/confc
(%)
(°C)
1
2
3
4
5
6
R-7a
R-7b
S-7c
S-7c
S-7d
S-7d
Ph
Ph
Ph
Ph
Ph
4-MeO–
C6H4
25
25
25
45
72
55
40
75
55
60 (R,R)
76 (R,R)
50 (S,S)
55 (S,S)
88 (S,S)
97 (S,S)d
When a stoichiometric amount of complex 7a was used,
moderate enantioselectivity was achieved (Table 3, entry
1). Encouraged by this result, we carried out the reductive
coupling under different conditions and also with chiral
ꢀ10
25
25
a
Unless noted otherwise, all the reactions were carried out with
0.5 mmol of diimine 1, 1.25 mmol of chiral titanium complexes 7a–d
(prepared in situ), and 2.5 mmol of Zn dust in CH2Cl2 (10 mL), CH3CN
(5 mL).
O
R
OH
i) SOCl2,
CH3OH
b
R'
CO2H
NH2
R'
Ph
Ph
Yield of isolated product after flash column chromatography on silica.
c
R
All ee values reported here are based on HPLC analysis.6
d
H2N
OH
ii) PhMgBr
Absolute configuration was assigned (S,S) by single crystal X-ray
analysis of the corresponding (S)-camphorsulfonate salt.7
5
R-6a: R' = Ph
CH2Cl2
S-6b: R' = PhCH2
4 Å M.S.
titanium complexes containing different substitution
patterns 7b–d (Table 3). We observed that the presence of
a bulky group such as the tert-butyl group on the phenyl
ring had a significant role in enhancing the enantioselecti-
vity as well as the yield. The chiral titanium complexes 7b
and 7d gave the 2,3-diphenylpiperazine product 2a in good
ee (Table 3, entries 2 and 5). Decreasing the reaction
temperature (ꢀ10 °C) did not lead to any improvement in
enantioselectivity (Table 3, entry 4). By using the chiral
Ph
Ph
R'
R'
Ph
Ph
N
OH
Cl
N
O
O
Ti Cl
O
i) Ti(OiPr)4, THF
R
OH
R
ii) TMSCl
R
R
7
4
Scheme 2. Synthesis of chiral titanium complexes 7a–d.

P. Vairaprakash, M. Periasamy / Tetrahedron Letters 49 (2008) 1233–1236
1235
Fig. 2. ORTEP diagram of the (S)-camphorsulfonate salt 8 (thermal ellipsoids are drawn at 20% probability).
2. (a) Mercer, G. J.; Sigman, M. S. Org. Lett. 2003, 5, 1591–1594; (b)
Periasamy, M.; Srinivas, G.; Suresh, S. Tetrahedron Lett. 2001, 42,
7123–7125; (c) Hesemann, P.; Moreau, J. J. E.; Soto, T. Synth.
Commun. 2003, 33, 183–189; (d) Annunziata, R.; Benaglia, M.;
Caporale, M.; Raimondi, L. Tetrahedron: Asymmetry 2002, 13, 2727–
2734; (e) Kise, N.; Oike, H.; Okazaki, E.; Yoshimoto, M.; Shono, T.
J. Org. Chem. 1995, 60, 3980–3992.
titanium complex 7d, 2,3-bis(4-methoxyphenyl)piperazine
2b was obtained with very good enantioselectivity, up to
97% ee (Table 3, entry 6). The absolute configurations of
the newly formed chiral centres in 2b were assigned (S,S)
by single crystal X-ray analysis of the corresponding (S)-
camphorsulfonate salt 8 (Fig. 2).7
3. Vairaprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71, 3636–3638.
4. (a) Liu, L.; Kang, Y.-F.; Wang, R.; Zhou, Y.-F.; Chen, C.; Nia, M.;
Gong, M.-Z. Tetrahedron: Asymmetry 2004, 15, 3757–3761; (b) Deng,
L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–4323.
5. Representative procedure for the enantioselective intramolecular reduc-
tive coupling of diimines 1 using chiral titanium complexes 7a–d and Zn:
In a 25 mL two necked flask equipped with a dropping funnel and an
air condenser protected by a mercury trap, were placed CH2Cl2
(5 mL), 2-hydroxy-3,5-di(tert-butyl)benzaldehyde (340 mg, 1.1 mmol),
(R)-2-amino-1,1,2-triphenylethanol (R)-6a (320 mg, 1.1 mmol) and
It has been reported that ligand 4 forms hexacoordinated
complex 7b, which is monomeric in nature.1d Presumably,
complexes 7a, 7c and 7d could also form hexacoordinate
complexes that are monomeric in nature.
In summary, we have developed new chiral titanium
reagents for the enantioselective intramolecular reductive
cyclizations of diimines yielding chiral 2,3-diarylpipera-
zines with good enantioselectivity. In view of the potential
applications of the chiral piperazine products in asymmet-
ric catalysis,8 organocatalysis9 and also the biological activ-
ity reported for molecules containing this skeleton,10 the
synthetic method reported here has potential for further
exploitation.
˚
4 A molecular sieves (1.0 g) under nitrogen and the reaction stirred for
6–8 h. To this, Ti(OiPr)4 (284 mg, 1.0 mmol) and THF (1 mL) were
added and stirring was continued for another 1 h. The chiral titanium
complex 7b was formed by the addition of TMSCl (220 mg, 2.0 mmol)
in CH3CN (5 mL), followed by stirring for 15 min. To this, activated
zinc powder (325 mg, 5.0 mmol) was added and stirring was continued
for another 1 h after which the reaction was cooled to the appropriate
temperature. Then, diimine (0.5 mmol) dissolved in CH3CN (5 mL)
was added dropwise. After the addition was complete, the reaction
mixture was stirred at the same temperature for 24 h. The reaction
mixture was poured into saturated aqueous K2CO3 solution at 0 °C
and then 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 and then dried over
anhydrous K2CO3. The solvent was evaporated and the product was
purified by flash column chromatography (silica gel, CHCl3 and then
CHCl3/CH3OH = 9:1). The ee of the product was obtained from
HPLC analysis using a Chiralcel OD-H column. Physical and spectral
data for products 2a and 2b: Compound 2a: mp: 88–90 °C; FTIR
(KBr) mmax (cmꢀ1): 3318, 3280, 3030, 2949, 2820, 1603, 1491; 1H NMR
(400 MHz, CDC13, d ppm) 2.00 (br s, 2H, NH), 3.15 (s, 4H), 3.72 (s,
2H), 7.07–7.12 (m, 10H); 13C NMR (50 MHz, CDC13) d 47.0, 68.1,
127.3, 127.8, 128.0, 141.2. Compound 2b: mp: 90–92 °C; FTIR (KBr)
Acknowledgements
P.V. is thankful to the CSIR and NATCO for a 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)’ programmes is gratefully acknowl-
edged. We are thankful to the DST for a 400 MHz NMR
spectrometer and National XRD-CCD facilities in the
School of Chemistry, University of Hyderabad. The award
of the JC Bose Fellowship grant to M.P. is gratefully
acknowledged.
mmax (cmꢀ1): 3271, 3040, 3003, 2957, 1612, 1584 cmꢀ1 1H NMR
;
References and notes
(400 MHz, CDCl3, d ppm) 2.27 (br s, 2H, NH), 3.10 (s, 4H), 3.63 (s,
2H), 3.70 (s, 6H), 6.65 (d, 4H, J = 8.0 Hz), 7.00 (d, 4H, J = 8.0 Hz);
13C NMR (100 MHz, CDC13) d 47.0, 55.1, 67.4, 113.2, 129.0, 133.6,
158.6.
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overnight with excess trifluoroacetic anhydride (TFAA). The solution
was concentrated under reduced pressure to remove the solvent and

1236
P. Vairaprakash, M. Periasamy / Tetrahedron Letters 49 (2008) 1233–1236
excess TFAA and the residue was purified by flash column chromato-
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˚
˚
˚
P2(1), a = 6.7095(10) A, b = 17.741(3) A, c = 16.365(3) A, b =
99.641(2)°, V = 1920.5(5) A , Z = 2, qc = 1.319 mg mꢀ3
,
l =
3
˚
0.198 mmꢀ1, T = 298(2) K. Of the 13,082 reflections collected, 6705
were unique (Rint = 0.0317). Refinement on all data converged at
R1 = 0.0781, wR2 = 0.2063 (CCDC Deposition Number: CCDC
664992).
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