Methods for the Synthesis of Piperazine Derivatives Containing a Chiral Bi-2-naphthyl Moiety

Article abstract of DOI:10.1055/s-0037-1610731

Piperazine derivatives containing 1,1′-bi-2-naphthyl moiety were synthesized starting from 2,2′-dimethoxy-1,1′-bi-naphthalene via acylation using ethyl chlorooxoacetate and subsequent condensation with 1,2-diamines followed by reduction of the corresponding dihydro-2-piperazinone intermediate using the NaBH ₄ /I ₂ reagent system. The corresponding chiral piperazine derivatives containing bi-2-napthyl moiety was synthesized by asymmetric reduction of ethyl dimethoxy-bi-2-naphthyloxoacetate by chiral oxazoborolidine catalyst prepared in situ using S -diphenylprolinol (S -DPP), B(OCH ₃) ₃ and H ₃ B·THF. The resulting diols were mesylated and cyclized using 1,2-diamines to obtain the corresponding chiral piperazine derivatives.

Full text of DOI:10.1055/s-0037-1610731

SYNTHESIS
0
0
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9
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7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
M. Periasamy et al.
Paper
Synthesis
Methods for the Synthesis of Piperazine Derivatives Containing a
Chiral Bi-2-naphthyl Moiety
Mariappan Periasamy*
H
N
H
N
H
N
Boda Venkanna
Miriyala Nagaraju
Lakavathu Mohan
O
O
H2N
NH2
H3B·THF
H3B·THF
CH3OH
reflux, 3 h
N
Ar
N
H
Ar
N
H
Ar
reflux 78 °C, 12 h
reflux 78 °C, 24 h
up to 90%
75–80%
70–75%
O
School of Chemistry, University of Hyderabad,
Central University P. O, Hyderabad 500046, India
mpsc@uohyd.ac.in
O
Ar
OCH3
OCH3
Ar =
O
Ph
Ph
OH
(R)
(R)-1
NH
H
N
H2N
NH2
OH
OH
B(OCH3)3
30 mol%
OMs
Ar
Et3N/MsCl
CH2Cl2, 24 h
MsO
Ar
CH2Cl2
–20 °C
N
Ar
·
3
ring formation
H
(aR,S)
(aR,R) 90%
75%, de >95%
Received: 29.05.2019
Accepted after revision: 09.09.2019
Published online: 01.10.2019
In recent years, methods were reported for the synthe-
sis of several 2,3-diarylpiperazine derivatives (Scheme 1).5,6
The trans-2,3-diphenylpiperazine derivatives were readily
accessed via a diastereoselective coupling method using
Ti(III) prepared in situ followed by resolution using optical-
ly active tartaric acid.5a Methods were also reported for the
synthesis of meso- 2,3-diphenylpiperazine derivatives.7 Al-
so, the chiral camphorylpiperazine derivatives were pre-
pared by condensation of ethylenediamine with optically
active camphorquinone.8 A similar condensation process
with 1,2 diaminocyclohexane was also reported.9
Herein, we report methods for synthesis of piperazine
derivatives containing chiral bi-2-napthyl moiety. Initially,
the product (R)-3 was prepared in 80% yield by Friedel–
Crafts acylation using bi-2-naphthyl derivative (R)-1, ethyl
chlorooxoacetate (2; 1.2 equiv), and anhydrous AlCl3
(Scheme 2). Subsequent condensation of this keto ester
(R)-3 with ethylenediamine (4) in anhydrous methanol
gave the product (R)-5 in 90% yield. We have observed that
similar condensation reactions of (R)-3 with 1,2-diamino-
benzene (6) and (2R,3R)-1,2-diaminocyclohexane (8) under
reflux conditions furnished cyclic products (R)-7 and (R)-9
in 90% and 88% yield, respectively.
DOI: 10.1055/s-0037-1610731; Art ID: ss-2019-z0241-op
Abstract Piperazine derivatives containing 1,1′-bi-2-naphthyl moiety
were synthesized starting from 2,2′-dimethoxy-1,1′-bi-naphthalene via
acylation using ethyl chlorooxoacetate and subsequent condensation
with 1,2-diamines followed by reduction of the corresponding dihydro-
2-piperazinone intermediate using the NaBH4/I2 reagent system. The
corresponding chiral piperazine derivatives containing bi-2-napthyl
moiety was synthesized by asymmetric reduction of ethyl dimethoxy-
bi-2-naphthyloxoacetate by chiral oxazoborolidine catalyst prepared in
situ using S-diphenylprolinol (S-DPP), B(OCH3)3 and H3B·THF. The re-
sulting diols were mesylated and cyclized using 1,2-diamines to obtain
the corresponding chiral piperazine derivatives.
Key words piperazine, 1,2-diamines, bi-2-naphthyl, ethyl chlorooxo-
acetate
N-Heterocycles are widely present in biologically active
molecules. Recently, methods for the synthesis of a variety
of chiral N-heterocycles have been reviewed.1 Among the
N-heterocycles, the piperazine derivatives are widely pres-
ent in life saving drug molecules.2 Recent reports show that
piperazine derivatives are the most commonly used N-hetero-
cycles in pharmaceuticals.3 Presumably, piperazine moi-
eties enhance the hydrophilic surface area, have additional
hydrogen bond accepting and donating nature due to piper-
azine nitrogen atoms, which improve water solubility, oral
bioavailability, absorption in intestine, and smooth excre-
tion properties.4a,b Accordingly, efficient synthetic methods
with high regio-, stereo-, and enantioselectivity to access
piperazine derivatives will be of interest to synthetic and
medicinal chemists.
The mechanism and intermediates shown in Scheme 3
may be considered to rationalize these condensation and
cyclization processes. Initial reaction of the more reactive
keto group with the ethylenediamine (4) followed by for-
mation of ketimine and reaction of the amino group with
the ester moiety would give the cyclic product (R)-5. Simi-
lar reactions in the case of the diamines 6 and 8 would give
the corresponding condensation products (R)-7 and (R)-9,
respectively.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

B
M. Periasamy et al.
Paper
Synthesis
We then carried out the reduction of the compound (R)-
5 using H3B·THF prepared in situ with the NaBH4 and I2
reagent combination.10 We observed that the reaction at
reflux conditions for 12 hours gave the product 3-[2,2′-di-
methoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-one [(R)-15]
in 78% yield and further reduction using the NaBH4/I2 re-
agent system under reflux conditions for 24 hours gave the
corresponding piperazine product R-16 in 73% yield
(Scheme 4). Unfortunately, the highly sterically hindered
(4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-
4a,5,6,7,8,8a-hydroquinoxalin-2(1H)-one [(R)-7] failed to
undergo reduction under the same conditions. However,
the (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-
4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one [(R)-9] gave
the corresponding reduction products (4aR,8aR)-3-[2,2′-di-
methoxy-(1,1′-binaphthalen)-6-yl]-octahydroquinoxalin-
2(1H)-one [(R)-17] and (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-
binaphthalen)-6-yl]decahydroquinoxaline [(R)-18] in 73%
and 72% yield, respectively, under the same conditions. Un-
fortunately, there was no selectivity at the newly formed
Previous work:
Zn(0) (5.0 equiv)
H
N
H
N
Ar
Ar
Ar
Ar
TiCl2(OiPr)2 (2.2 equiv)
L-(+)-tartaric acid
partial resolution
oxalic acid
N
Ar
Ar
CH2Cl2, 0–25 °C, 6 h
Ref. 5,6
N
enhancement of
enantiomeric purity
N
H
N
H
(
)-2,3-diarylpiparazine
99% ee
H
H
N
NaBH4, AcOH
THF
N
Ph
Ph
Ph
Ph
+
0–25 °C, 12 h
N
H
N
H
O
H2N
N
N
Ph
Ph
EtOH
80 °C, 2 h
Ref. 7
2:1, 78%
Ph
+
Ph
H
H
H2N
O
N
Ph
Ph
N
Ph
NaBH4, CH3OH
0–25 °C, 12 h
82%
+
N
H
Ph
N
H
86%
trace
NH2
H
N
O
NH2
R
NaBH4, CH3OH
0–25 °C
N
PTSA, toluene
reflux, 2 h
S
N
N
H
O
90% yield
D-(–)-camphorquinone
Ref. 8
O
H2N
H
1. H3B·THF
70 °C, 24–36 h
N
N
iPrOH
rt, 24–36 h
Ref. 9
OHC
OEt
H2N
2. KOH(s) (20 mol%)
100 °C, 24 h
O
N
H
N
H
89% y
96% y
Present Work:
OCH3
OCH3
H
N
H
N
O
NH2
NH2
N
(R)-1
O
NaBH4 (2 equiv)
I2 (1 equiv)
THF
N
H
CH3OH
O
OCH3
OCH3
Cl
AlCl3 (1.5 equiv)
CH2Cl2
OCH3
OCH3
reflux, 70 °C
3 h
O
H3B·THF
78 °C, 24 h
(1.2 equiv), rt
O
O
90%
73%
O
H
N
OCH3
OCH3
OH
Ph
Ph
N
N
H
1. Et3N, MsCl
–20 °C, 2 h
H
OH
OH
OCH3
OCH3
B(OCH3)3
(30 mol%)
90%
OCH3
OCH3
2.
NH2
NH2
CH2Cl2
0–25 °C, 24 h
H3B·THF
(3 equiv)
90%, >95% dr
75%
Scheme 1 Synthesis of piperazine derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

C
M. Periasamy et al.
Paper
Synthesis
H
N
O
N
NH2
NH2
OCH3
OCH3
CH3OH
4
reflux, 70 °C, 3 h
(R)-5, 90%
O
H
N
NH2
NH2
O
O
O
Cl
O
O
N
O
6
CH3OH
OCH3
OCH3
OCH3
OCH3
2
(1.2 equiv)
OCH3
OCH3
reflux, 70 °C, 3 h
AlCl3 (1.5 eq)
CH2Cl2
r.t.
(R)-1
(R)-3, 80%
H
N
(R)-7, 90%
O
NH2
NH2
N
CH3OH
8
OCH3
OCH3
reflux, 70 °C, 3 h
(aR,R,R)-9, 88%
Scheme 2 Protocol for the synthesis of bi-2-naphthyl derivative (R)-3 and its conversion into piperazenone derivatives (R)-5, (R)-7, (aR,R,R)-9
stereogenic centers in the corresponding piperazine prod-
ucts (R)-15 and (R)-17. The absence of stereoselectivity in
the reduction of piperazenones may be due to remoteness
of the atropochiral stereogenic bi-2-naphthyl system.
Next, we turned our attention towards a new protocol
involving asymmetric reduction of the carbonyl group in
the bi-2-naphthyl derivative (R)-3 involving the CBS-cata-
lyzed process. There have been several reports on the asym-
metric reduction of prochiral ketone to corresponding chi-
ral alcohol with 95% ee using (S)-DPP and H3B-Lewis base
complexes.11 In recent years, several borane reagent sys-
tems in combination with I2, benzyl chloride, and (S)-di-
phenylprolinol [(S-DPP) 19] were used in chiral reduction of
aryl alkyl ketones to obtain the corresponding secondary
alcohol with R-configuration with >95% ee.12 Also, aryl alkyl
ketones containing a chiral biaryl moiety were reduced to
NH2
NH2
O
O
O
H2N
O
O
H2N
O
O
N
H
N
H
O–
OH
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
(R)-3
(R)-10
(R)-11
– H2O
H
H
N
H
N
H
O
O
N
N
O
O–
H2N
O
O
H
O
N
N
N
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
C2H5OH
– C2H5OH
(R)-5
(R)-14
(R)-13
(R)-12
Scheme 3 Tentative mechanism for the condensation of compound (R)-3 with ethylenediamine (4)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

D
M. Periasamy et al.
Paper
Synthesis
H
N
H
N
H
N
O
O
N
H
N
N
H
NaBH4 (2 equiv)
I2 (1 equiv)
THF
NaBH4 (2 equiv)
I2 (1 equiv)
THF
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H3B·THF
78 °C, 12 h
H3B·THF
78 °C, 24 h
(R)-15, 78%
(R)-5
(R)-16, 73%
H
N
H
H
N
N
O
O
N
H
N
N
H
NaBH4 (2 equiv)
I2 (1 equiv)
NaBH4 (2 equiv)
I2 (1 equiv)
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
THF
THF
H3B·THF
H3B·THF
78 °C, 24 h
78 °C, 12 h
(aR,R,R)-9
(aR,R,R)-18, 72%
(aR,R,R)-17, 76%
Scheme 4 Reduction of 3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-one derivatives using NaBH4/I2 reagent system
the corresponding secondary alcohols with >95% ee with
the S-DPP/B(OCH3)3/H3B·THF with R-configuration at the
new stereogenic center.13a,b Previously, we have also ob-
served that asymmetric reduction of several 6-acyl deriva-
tives prepared using 2,2′-dimethoxy-1,1′-binaphthalene
(R)-1 with the S-DPP/B(OCH3)3/H3B·THF reagent combina-
tion gave the corresponding alcohols with R-configuration
with >95% ee.13c Accordingly, we have carried out the asym-
metric reduction of the 2-[2,2′-dimethoxy-(1,1′-binaphtha-
len)-6-yl]-2-oxoacetate with S-DPP (30 mol%) and B(OCH3)3
using H3B·THF (2 M, 3 equiv) at 0 °C to obtain the corre-
sponding 1,2-diol product (aR,R)-20 in 90% yield and with
>95% dr. In this reaction, alignment of smaller R group with
phenyl group in the oxazaborolidine intermediate over the
larger bi-2-naphthyl group is expected to result in highly
specific transfer of chirality while hydride is transferred to
afford the chiral 1,2-diol 20 (Scheme 5).11
Subsequently, we have carried out the preparation of
the dimesylate 21 and its reaction with the diamines 4 and
8 (Scheme 6). Whereas, the (2S)-2-[2,2′-dimethoxy-(1,1′-
binaphthalen)-6-yl]piperazine [(aR,S)-22] was obtained in
76% yield, the (2R,4aS,8aR)-2-[2,2′-dimethoxy-(1,1′-
binaphthalen)-6-yl]decahydroquinoxalin [(R)-23] was ob-
tained in 75% yield. In this reaction, the compounds (R)-22
and (R)-23 were obtained in diastereomerically pure forms
and other diastereomer was not detected by 1H and 13C
NMR spectral data.
A tentative SN2 type mechanism may be considered for
these transformations as outlined in Scheme 7. Accordingly,
the stereochemistry of the new stereogenic centers added
in the products 22 and 23 are assigned the S-configuration.
In summary, convenient methods have been developed
for the synthesis of piperazine derivatives containing the
bi-2-naphthyl moiety. Since these procedures utilize readily
accessible reagent systems, the methods described here
open new prospects for the synthesis and study of chiral
piperazine derivatives.
Ph
Ph
OH
O
OH
NH
19
O
B(OCH3)3
OH
O
OCH3
OCH3
(30 mol%)
OCH3
OCH3
Melting points are uncorrected and were determined using a Super fit
capillary point apparatus. IR (KBr) spectra were recorded on JASCO
FT-IR spectrophotometer model 5300 and the neat IR spectra were
recorded on SHIMADZU FT-IR spectrophotometer model 8300 with
polystyrene as reference. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on Bruker Avance-400 spectrometer in CDCl3
as solvent and TMS as reference ( = 0). The chemical shifts are ex-
pressed in  downfield from the signal of internal TMS. Elemental
analyses were carried out using a PerkinElmer elemental analyzer
model-240C and Thermo Finnegan analyzer series Flash EA 1112.
Mass spectral analyses were carried out on VG 7070H mass spec-
trometer using EI technique at 70 eV. Optical rotations were mea-
sured with an AUTOPOL-II automatic polarimeter (readability
± 0.01°). Analytical TLC chromatographic tests were carried out on
glass plates (3 × 10 cm) coated with 250 m Acme’s silica gel-G and
H3B·THF
(3 equiv)
(aR,R)-20
90%, >95% dr
(R)-3
R
Ph
H
O
Ph
Ar
H
B
O
MeO
N
B
H
H
Intermediate
Scheme 5 Asymmetric reduction of bi-2-naphthylmethoxy-6-oxoace-
tate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

E
M. Periasamy et al.
Paper
Synthesis
H
N
NH2
N
H
NH2
4
OCH3
OCH3
CH2Cl2, 0–25 °C
24 h
OH
OMs
(aR,S)-22 76%
OH
OMs
OCH3
OCH3
Et3N/MsCl
OCH3
OCH3
H
N
–20 °C to 25 °C,
3 h
NH2
N
H
(aR,R)-20
(aR,R)-21
NH2
OCH3
8
OCH3
CH2Cl2, 0–25 °C
24 h
(aR,R,R,S)-23 75%
Scheme 6 Condensation of 1,2-diamines 4 and 8 with the dimesylate 21
Ms
H
N
Ms
H
H
OMs
NH2
NH2
MsO
N
S
S
MsO
NH2
R
N
N
H
NH2
OCH3
OCH3
Ms
H
H
OCH3
OCH3
OCH3
OCH3
SN2
OCH3
OCH3
2 MsOH
(aR,S)-22
(R)-21
(R)-24
(R)-25
Scheme 7 Tentative mechanism for the condensation of ethylenediamine 4 with the dimesylate (aR,R)-21
GF-254 containing 13% CaSO4. The spots were visualized by short ex-
posure to I2 vapor or UV light. Column chromatography was carried
out using Acme silica gel (100–200 mesh) or neutral alumina. All an-
hydrous solvents and reagents (liquids) used were distilled from ap-
propriate drying agents.
IR (KBr): 3055, 2937, 2839, 1732, 1676, 1614, 1508, 1479, 1265, 1222,
1045, 910, 808, 740 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.61 (s, 1 H), 8.60–8.14 (d, J = 4.0 Hz, 1
H), 8.12–8.02 (d, J = 8.0 Hz, 1 H), 8.0–7.90 (d, J = 4.0 Hz, 1 H), 7.88–
7.78 (d, J = 94.4 Hz, 1 H), 7.78–7.76 (d, J = 8.0 Hz, 1 H), 7.76–7.76 (d, J =
8.3 Hz, 1 H), 7.55–7.53 (d, J = 8.6 Hz, 1 H), 7.48–7.45 (d, J = 8.4 Hz, 1
H), 7.34–7.23 (m, 2 H), 7.06–7.06 (d, J = 8.0 Hz, 1 H), 4.51–4.41 (q, J =
4.0 Hz, 2 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 1.52–1.43 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 186.4, 164.5, 158.3, 155.1, 137.5,
134.3, 133.9, 132.2, 130.1, 129.3, 128.3, 127.9, 127.8, 126.8, 126.4,
124.8, 124.5, 123.8, 119.9, 118.2, 114.7, 113.9, 62.4, 56.4, 56.2, 14.2.
As a routine practice, all organic extracts were washed with brine
(brine), dried over anhyd Na2SO4, and concentrated on Heidolph-rota-
ry evaporator. All yields reported are of isolated materials judged ho-
mogeneous by TLC, IR spectroscopy, and NMR spectrometry. CH2Cl2
and CHCl3 were distilled over CaH2 and dried over molecular sieves.
(S)-DPP was supplied by Gerchem Labs, India and (S)-proline was sup-
plied by Lancaster Synthesis Ltd., UK.
MS (EI): m/z = 415 (M + 1)+.
Anal. Calcd for C26H22O5: C, 75.35; H, 5.35; O, 19.30. Found: C, 75.25;
H, 5.20; O, 19.28.
Ethyl 2-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-2-oxoacetate
[(R)-3]
To a mixture of 2,2′-dimethoxy-1,1′-binaphthalene [(R)-1; 314 mg, 1
mmol] and anhyd AlCl3 (200 mg, 1.5 mmol) was added ethyl chloro-
oxoacetate (2; 164 mg, 1.2 mmol) in CH2Cl2 (10 mL) at rt and the reac-
tion mixture was stirred for 3 h. Then, the mixture was poured into
ice-cold H2O, and CH2Cl2 (10 mL) was added. The organic layer was ex-
tracted with CH2Cl2 (2 × 10 mL) and the combined organic layers were
washed with brine (10 mL) and dried (anhyd Na2SO4). The solvent
was removed and the residue was subjected to column chromatogra-
phy (silica gel, hexane–EtOAc 80:20); yield: 0.332 g (80%); white sol-
id; mp 92–94 °C; []D25 +6.15 (c 0.052, CHCl3).
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-5,6-dihydropiperzin-
2(1H)-ones (R)-5
and (R)-7; General Procedure
To a stirred solution of (R)-3 (414 mg, 1 mmol) in CH3OH (10 mL) was
added the respective 1,2-diamine 4 or 6 (1 mmol) and the contents
were refluxed at 70 °C for 3 h. The mixture was brought to 25 °C and
the solid precipitate was collected by suction filtration. The precipi-
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F
M. Periasamy et al.
Paper
Synthesis
tate was washed thoroughly with sat. aq NH4Cl (15 mL), H2O (2 × 10
mL), and brine (10 mL). The products (R)-5 and (R)-7 were dried un-
der vacuum.
1H NMR (400 MHz, CDCl3):  = 8.61–8.60 (d, J = 8.2 Hz, 1 H), 8.11–8.08
(d, J = Hz, 1 H), 7.91–7.82 (m, J = 9.1 Hz, 3 H), 7.43–7.29 (m, J = 9.1 Hz,
4 H), 7.25–7.20 (m, J = 9.0 Hz, 1 H), 7.04–7.02 (d, J = 8.0 Hz, 1 H), 5.03
(br s, 1 H), 3.79 (s, 3 H), 3.10–3.09 (d, J = 8.8 Hz, 2 H), 2.40 (d, J = 8.8
Hz, 1 H), 1.88–1.77 (m, 2 H), 1.74–1.70 (m, 1 H), 1.48–1.28 (m, 6 H).
13C NMR (100 MHz, CDCl3):  = 160.8, 158.6, 156.9, 151.5, 135.1,
133.8, 129.7, 128.6, 126.7, 124.8, 117, 115, 113.9, 62.7, 60.4, 56.4,
53.9, 31.8, 30.8, 25.1, 23.7.
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-5,6-dihydropiperzin-
2(1H)-one [(R)-5]
Yield: 0.370 g (90%); yellow solid; mp 238–240 °C.
IR (KBr): 3270, 3042, 2928, 1682, 1630, 1598, 1460, 1342, 1084, 906,
MS (EI): m/z = 465 (M + 1)+.
802 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.61–8.60 (t, J = 8.4 Hz, 1 H), 8.07–8.04
(d, J = 8.2 Hz, 1 H), 7.99–7.97 (d, J = 8.1 Hz, 2 H), 7.87–7.85 (d, J = 6.8
Hz, 1 H), 7.75–7.72 (d, J = 8.5Hz, 1 H), 7.47–7.44 (m, 2 H), 7.43–7.29
(m, 1 H), 7.22–7.20 (t, J = 6.9 Hz, 2 H), 7.18–7.10 (m, 2 H), 7.09–6.23
(m, 2 H), 3.97–3.97 (m, 2 H), 3.85 (br s, 3 H), 3.75 (br s, 3 H), 3.54–3.52
(m, 2 H).
Anal. Calcd for C30H28N2O3: C, 77.56; H, 6.08; N, 6.03; O, 10.33. Found:
C, 77.47; H, 6.05; N, 6.01; O, 10.21.
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-ones (R)-
15 and (R)-17; General Procedure
NaBH4 (76 mg, 2 mmol) was suspended in anhyd THF (10 mL) under
an inert atmosphere in a two-necked septum capped round-bot-
tomed flask. I2 (127 mg, 1 mmol) dissolved in anhyd THF (5 mL) was
taken in an liquid additional funnel and was added dropwise slowly at
0 °C during 1 h to prepare the H3B·THF complex. Then, the compound
(R)-5 or (R)-9 (1 mmol) dissolved in anhyd THF was added dropwise
slowly. The mixture was stirred at 0 °C for 1 h and brought to rt and
refluxed for 12 h. The contents were brought to rt and carefully
quenched by the dropwise addition of 3 N aq HCl (2 mL) and extract-
ed with EtOAc (2 × 5 mL). The combined organic layers were washed
with aq NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL) and dried (an-
hyd Na2SO4). After removal of the solvent, the product was purified by
column chromatography (silica gel 100–200 mesh, hexane–EtOAc
20:80).
13C NMR (100 MHz, CDCl3):  = 161.9, 158, 156.1, 154.9, 135.1, 133.9,
132, 130, 129.4, 127.9, 126, 125, 123.5, 119.5, 114.5, 56.8, 56.6, 48.2,
39.0.
MS (EI): m/z = 412 (M + 1)+.
Anal. Calcd for C26H22N2O3: C, 76.08; H, 5.40; N, 6.82; O, 11.69. Found:
C, 76.02; H, 5.28; N, 6.81; O, 11.53.
3-[2,3-Dimethoxy-(1,1′-binaphthlen)-6-yl]quinoxalin-2(1H)-one
[(R)-7]
Yield: 0.412 g (90%); brown solid; mp 258–260 °C.
IR (KBr): 3272, 3057, 2935, 1680, 1628, 1598, 1467, 1340, 1084, 1068,
908, 810 cm–1
.
1H NMR (400 MHz, CDCl3):  = 12.60–12.52 (br s, 1 H), 9.19–9.19 (d,
J = 8.16 Hz, 1 H), 9.18–9.18 (d, J = 16 Hz, 1 H), 8.70–8.70 (d, J = 16.1 Hz,
1 H), 8.40–8.24 (t, J = 8.0 Hz, 1 H), 8.42–8.11 (t, J = 12.0 Hz, 1 H), 7.82–
7.80 (t, J = 4.0 Hz, 1 H), 7.98 (m, 2 H), 7.69–7.65 (m, 2 H), 7.52–7.50 (t,
J = 12.0 Hz, 1 H), 7.73–7.30 (m, 2 H), 7.08–7.00 (m, 1 H), 6.39–6.37 (t,
J = 12.0 Hz, 1 H), 4.48–4.67 (m, 1 H), 3.99–3.82 (q, J = 4.6 Hz, 1 H), 3.30
(br s, 6 H).
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-one [(R)-
15]
25
Yield: 0.320 g (78%); yellow solid; mp 237–239 °C; []D –72.0 (c
0.030, CHCl3).
IR (KBr): 3233, 3049, 2932, 1686, 1620, 1589, 1332, 1261, 1080, 910,
816 cm–1
.
13C NMR (100 MHz, CDCl3):  = 186.9, 164.6, 158.5, 156.4, 155.2, 154,
153, 137, 135.4, 134.4, 132.3, 131.1, 130.5, 129.1, 128.3, 127.2, 124.2,
123.8, 118.5, 117.7, 115.5, 114.7, 56.7.
1H NMR (400 MHz, CDCl3):  = 7.88–7.84 (m, 1 H), 7.83–7.77 (m, 3 H),
7.43–7.37 (m, 2 H), 7.34–7.30 (m, 2 H), 7.24–7.20 (m, 1 H), 7.18–7.01
(m, 1 H), 6.99–6.91 (m, 1 H), 4.96–4.63 (m, 2 H), 3.78 (s, 3 H), 3.7 (s, 3
H), 2.72 (br s, 1 H), 1.63 (br s, 2 H).
MS (EI): m/z = 459 (M + 1)+.
13C NMR (100 MHz, CDCl3):  = 167.8, 155.8, 154.9, 133.9, 133.8, 130,
129.9, 129.2, 128.6, 128.1, 126.5, 126.3, 125.9, 125.7, 125, 123.7,
119.3, 119.1, 118.9, 114.8, 114.3, 67.7, 67.5, 57, 56.8, 56.6, 44.7, 44.3,
37.6, 29.7.
Anal. Calcd for C30H22N2O3: C, 78.59; H, 4.84; N, 6.11; O, 10.47. Found:
C, 78.47; H, 4.79; N, 6.09; O, 10.20.
(4aR,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-
4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one [(R)-9]
LCMS: m/z = 413 (M + 1)+.
To a stirred solution of (R)-3 (414 mg, 1 mmol) in anhyd CH3OH (10
mL) was added (R,R)-cyclohexyldiamine (8; 114 mg, 1 mmol) at rt and
the reaction mixture was refluxed at 70 °C for 3 h. CH3OH was re-
moved under rotor evaporator. To the residue was added sat. aq NH4Cl
(5 mL). The contents were extracted with EtOAc (2 × 10 mL) and the
combined organic layers were washed with brine (10 mL) and dried
(anhyd Na2SO4). After removal of the solvent, the residue was subject-
ed to column chromatography (silica gel, hexane–EtOAc 20:80); yield:
0.400 g (88%); brown gum.
Anal. Calcd for C26H24N2O3:C, 76.08; H, 5.40; N, 6.82; O, 11.69. Found:
C, 76.02; H, 5.39; N, 6.81; O, 11.63.
(4aR,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]octahydro-
quinoxalin-2(1H)-one [(R)-17]
Yield: 0.350 g (76%); brown gum; []D25 –420.1 (c 0.212, CHCl3).
IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342,
1267, 1091, 1066, 908, 810 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.92–7.90 (d, J = 8.6 Hz, 2 H), 7.87–7.75
(m, 4 H), 7.38–7.31 (m, 2 H), 7.29–7.23 (m, 1 H), 7.21–7.20 (m, 9 H),
7.19–7.12 (m, 2 H), 6.90–6.87 (m, 2 H), 4.63 (s, 1 H), 4.16–4.123 (m, 3
H), 3.95 (s, 3 H), 3.7 (s, 3 H), 2.92 (m, 2 H), 2.50 (m, 2 H), 1.67–1.6 5
(m, 8 H).
IR (Neat): 3272, 3057, 2935, 1680, 1628, 1598, 1467, 1340, 1268,
1084, 1068, 908, 810 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

G
M. Periasamy et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 171, 156, 151.6, 135.1, 133.9, 133.7,
130.6, 129.5, 129.2, 128.3, 128, 127.4, 126.2, 25.5, 124.8, 123, 118,
116.5, 115.3, 114.1, 64.7, 58.4, 58.4, 58, 56.6, 30.8, 30.3, 29.7, 29.3,
24.5 23.7.
MS (EI): m/z = 453 (M + 1)+.
Anal. Calcd for C30H32N2O2: C, 79.61; H, 7.09; N, 6.19; O, 7.07. Found:
C, 79.41; H, 7.09; N, 6.13; O, 7.05.
MS (EI): m/z = 467 (M + 1)+.
Chiral (R)-1-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]ethane-1,2-
diol [(R)-20]
Anal. Calcd for C30H30N2O3: C, 77.23; H, 6.48; N, 6.00; O, 10.26. Found:
C, 77.22; H, 6.37; N, 5.57; O, 10.20.
NaBH4 (76 mg, 2 mmol) was suspened in anhyd THF (10 mL) under N2
atmosphere in a two-necked septum capped round-bottome flask. I2
(127 mg, 1 mmol) dissolved in anhyd THF (5 mL) was taken in liquid
additional funnel and was added dropwise slowly at 0 °C during 1 h to
prepare the H3B·THF complex. To this, a solution of (S)-DPP (19; 76
mg, 0.3 mmol) and B(OCH3)3 (31 mg, 0.3 mmol) in anhyd THF (5 mL)
was added and the contents were stirred for 20 min. Then, the com-
pound (R)-3 (414 mg, 1 mmol) dissolved in anhyd THF (5 mL) was
added slowly during 1 h at 10 °C and the contents were further stirred
at rt for 1 h. The mixture was carefully quenched with 1 N aq HCl (2
mL) and extracted with Et2O (2 × 5 mL). The combined organic ex-
tracts were washed with brine (5 mL) and dried (anhyd Na2SO4). The
solvent was removed under reduced pressure and the product was
purified by column chromatography (silica gel, 100–200 mesh, hex-
ane–EtOAc 20:80); yield: 0.330 g (90%); white solid; mp 112–114 °C;
[]D25 +28.4 (c 0.100, CHCl3);.
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzines (R)-16 and
(R)-18; General Procedure
NaBH4 (76 mg, 2 mmol) was suspended in anhyd THF (10 mL) under
N2 atmosphere in a two-necked septum capped round-bottomed
flask. I2 (1 mmol) dissolved in anhyd THF (5 mL) was taken in liquid
additional funnel and was added dropwise slowly at 0 °C during 1 h to
prepare the H3B·THF complex. Then, the compound (R)-15 or (R)-17
(1 mmol) dissolved in anhyd THF was added dropwise slowly. The
mixture was stirred at 0 °C for 1 h and brought to rt and refluxed for
24 h. The mixture was brought to rt and carefully quenched by slowly
adding with 3 N aq HCl (2 mL). The contents were extracted with
EtOAc (2 × 5 mL). The combined organic layers were washed with aq
NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL) and dried (anhyd
Na2SO4). After removal of the solvent, the product was purified by col-
umn chromatography (silica gel 100–200 mesh, hexane–EtOAc
20:80).
IR (KBr): 3402, 2935, 2837, 1622, 1593, 1506, 1462, 1263, 1064, 895,
808 cm–1
.
1H NMR (400 MHz, CHCl3):  = 7.99–7.97 (d, J = 8.0 Hz, 1 H), 7.89–7.87
(d, J = 8.1 Hz, 2 H), 7.45–7.49 (d, J = 7.8 Hz, 2 H), 7.20–7.18 (d, J = 8.0
Hz, 2 H), 6.97–6.95 (d, J = 4.4 Hz, 2 H), 4.80–4.77 (t, J = 12.0 Hz, 2 H),
3.79–3.76 (s, 8 H), 2.57 (br s, 1 H), 2.09 (br s, 1 H).
3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzine [(R)-16]
25
Yield: 0.290 g (73%); yellow solid; mp 248–250 °C; []D –40.0 (c
0.140, CHCl3).
13C NMR (100 MHz, CDCl3):  = 157.3, 155.1, 154.9, 135.5, 133.9,
133.7, 129.5, 129.2, 128.9, 128, 126.4, 125.6, 125.2, 124.7, 123.6,
119.4, 114.5, 114.1, 74.6, 67.8, 56.8.
IR (KBr): 3320, 3042, 3010, 2952, 2898, 1590, 1332, 1268, 1042, 889,
802 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.88–7.87 (d, J = 8.3 Hz, 2 H), 7.85–7.84
(d, J = 8.8 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.33–7.31 (m, 1 H), 7.29–7.20
(m, 2 H), 7.29–7.07 (m, 2 H), 6.90–6.88 (m, 1 H), 4.67 (s, 1 H), 3.75 (s,
3 H), 3.74 (s, 3 H), 3.50–3.40 (m, 1 H), 3.33–3.30 (m, 1 H), 3.130–3.110
(m, 1 H), 3.09–3.00 (m, 1 H).
MS (EI): m/z = 375 (M + 1)+.
Anal. Calcd for C24H22O4: C, 76.99; H, 5.92; O, 17.09. Found: C, 76.02;
H, 5.62; O, 16.86.
13C NMR (100 MHz, CDCl3):  = 155.2, 155, 134.8, 134.1, 133.7, 129.6,
129.5, 129.2, 129.1, 128, 127.8, 127.6, 127.0, 126.9, 126.4, 125.8,
125.3, 123.6, 119.5, 114.3, 114.2, 63.8, 63.6, 56.7, 42.9, 41, 40.8.
(2S)-2-(2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl)piperazines (R)-
22 and (R)-23; General Procedure
To a stirred solution of the compound (R)-20 (374 mg, 1 mmol, 99%
ee) and Et3N (252 mg, 2.2 mmol) in CH2Cl2 (5 mL) was added MsCl
(2.2 mmol) at –20 °C. The reaction mixture was stirred for 2 h at –20
°C and then quenched with sat. aq NH4Cl (2 mL). The contents were
brought to 25 °C. The organic layer was washed with H2O (5 mL), sat.
aq NaHCO3 (2 mL), and brine (5 mL). The organic extract was dried
(anhyd Na2SO4) and concentrated under reduced pressure to approxi-
mately 3 mL. This crude dimesylate (R)-21 was added to ethylenedi-
amine 4 or 8 (0.5 mL) at 0 °C and stirred at rt for 24 h. The excess
amine was removed under reduced pressure. The residue was dis-
solved in Et2O (5 mL) and washed successively with sat. aq NaHCO3 (2
mL), H2O (5 mL), and brine (5 mL). The organic extract was dried (an-
hyd Na2SO4) and concentrated. The crude product was purified by col-
umn chromatography (silica gel 100–200 mesh, EtOAc 95:5).
MS (EI): m/z = 399 (M + 1)+.
Anal. Calcd for C26H26N2O2: C, 78.36; H, 6.58; O, 8.03; S, 7.03. Found:
C, 78.22; H, 6.51; O, 8.01; S, 7.05.
(4aS,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]decahydro-
quinoxalin [(R)-18]
Yield: 0.320 g (72%); brown gum; []D25 –782.8 (c 0.211, CHCl3).
IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342,
1267, 1091, 1066, 908, 810 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.03–8.01 (m, 1 H), 7.99–7.90 (d, J = 8.1
Hz, 1 H), 7.88–7.83 (m, 2 H), 7.76–7.75 (d, J = 6.8 Hz, 1 H), 7.47–7.45
(d, J =8.2 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.38–7.31 (m, 1 H), 7.29–7.21
(m, 1 H), 7.19–7.10 (m, 1 H), 7.09–7.02 (m, 1 H), 3.92 (br s, 1 H), 3.78
(s, 4 H), 3.52–3.43 (m, 1 H), 3.25–3.24 (m, 1 H), 2.39–3.33 (m, 2 H),
2.16–2.15 (s, 1 H), 1.95–1.63 (m, 3 H), 1.30–1.25 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 155.0, 151.7, 135.6, 133.7, 129.2,
128.3, 127.1, 125.5, 124.3, 122.0, 118.0, 117.0, 114.0, 113.1, 60.8, 60.6,
58.8, 55.8, 51.7, 48.7, 30.8, 30.49, 24.3, 24.09.
(2S)-2-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperazine [(R)-
22]
25
Yield: 0.310 g (76%); yellow solid; mp 251–253 °C; []D –43.4 (c
0.140, CHCl3).
IR (KBr): 3320, 3031, 3012, 2952, 2898, 1596, 1328, 1268, 1062, 889,
810 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

H
M. Periasamy et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.88–7.87 (d, J = 8.3 Hz, 2 H), 7.85–7.84
(d, J = 8.8 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.33–7.31 (m, 1 H), 7.29–7.20
(m, 2 H), 7.29–7.07 (m, 2 H), 6.90–6.88 (m, 1 H), 4.67 (s, 1 H), 3.75 (s,
3 H), 3.74 (s, 3 H), 3.50–3.40 (m, 1 H), 3.33–3.30 (m, 1 H), 3.13–3.11
(m, 1 H), 3.09–3.0 (m, 1 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610731.
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13C NMR (100 MHz, CDCl3):  = 155.2, 155, 134.8, 134.1, 133.7, 129.6,
129.5, 129.2, 129.1, 128, 127.8, 127.6, 127.0, 126.9, 126.4, 125.8,
125.3, 123.6, 119.5, 114.3, 114.2, 63.8, 63.6, 56.7, 42.9, 41, 40.8.
References
(1) Vol, C. V. T.; Bode, T. W. J. Org. Chem. 2014, 79, 2809.
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(3) Vitarin, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
MS (EI): m/z = 399 (M + 1)+.
Anal. Calcd for C26H26N2O2: C, 78.36; H, 6.58; O, 8.03; S, 7.03. Found:
C, 78.20; H, 6.47; O, 8.01; S, 7.05.
(4) (a) Walker, M. A. Expert Opin. Drug Discovery 2014, 9, 1421.
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(5) (a) Viraprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71, 3636.
(b) Viraprakash, P.; Periasamy, M. J. Chem. Sci. 2008, 120, 175.
(c) Viraprakash, P.; Periasamy, M. Tetrahedron Lett. 2008, 49,
1233.
(2S,4aR,8aR)-2-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]decahy-
droquinoxalin [(R)-23]
Yield: 0.330 g (75%); brown gum; []D25 –823.05 (c 0.210, CHCl3).
IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342,
1267, 1091, 1066, 908, 810 cm–1
.
(6) (a) Periasamy, M.; Sanjeevkumar, N.; Dalai, M.; Gurubrahmam,
R.; Reddy, P. O. Org. Lett. 2012, 14, 2932. (b) Periasamy, M.;
Reddy, P. O.; Edukondalu, A.; Dalai, M.; Alakanda, L. M.;
Udaykumar, B. Eur. J. Org. Chem. 2014, 6067.
(7) Periasamy, M.; Edukondalu, A.; Ramesh, E. ChemistrySelect
2017, 2, 7615.
1H NMR (400 MHz, CDCl3):  = 8.03–8.01 (m, 1 H), 7.99–7.90 (d, J = 8.1
Hz, 1 H), 7.88–7.83 (m, 2 H), 7.76–7.75 (d, J = 6.8 Hz, 1 H), 7.47–7.45
(d, J = 8.2 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.38–7.31 (m, 1 H), 7.29–7.21
(m, 1 H), 7.19–7.10 (m, 1 H), 7.09–7.02 (m, 1 H), 3.92 (br s, 1 H), 3.78
(s, 4 H), 3.52–3.43 (m, 1 H), 3.25–3.24 (m, 1 H), 2.39–3.33 (m, 2 H),
2.16–2.15 (s, 1 H), 1.95–1.63 (m, 3 H), 1.30–1.25 (m, 3 H).
13C NMR (100 MHz, CDCl3 and CD3OD):  = 155.0, 151.7, 135.6, 133.7,
129.2, 128.3, 127.1, 125.0, 124.0, 122.0, 118.0, 117.0, 114.0, 113.1,
60.89, 60.6, 58.8, 55.89, 51.7, 30.8, 30.49, 24.3, 24.0.
(8) Periasamy, M.; Sanjeevkumar, N.; Reddy, P. O. Synthesis 2012,
44, 3185.
(9) Elsevier, C. J.; Vermeer, P. J. J. Org. Chem. 1989, 54, 3726.
(10) (a) Narayana, C.; Periasamy, M. J. Organomet. Chem. 1987, 323,
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5964. (c) Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahe-
dron 1992, 48, 462. (d) Periasamy, M.; Muthukumaragopal, G.
P.; Sanjeevakumar, N. Tetrahedron Lett. 2007, 48, 6966.
(11) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; GuzmanPerez, A.; Lazerwith, S. E.
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MS (EI): m/z = 453 (M + 1)+.
Anal. Calcd for C30H32N2O2: C, 79.61; H, 7.09; N, 6.19; O, 7.07. Found:
C, 79.37; H, 7.01; N, 6.11; O, 7.05.
Funding Information
(12) (a) Periasamy, M.; Seenivasaperumal, M.; Dharma Rao, V. Syn-
thesis 2003, 2507. (b) Periasamy, M.; Gurubrahamam, R.;
Muthukumargopal, G. P. Synthesis 2009, 1739. (c) Anwar, S.;
Periasamy, M. Tetrahedron: Asymmetry 2006, 17, 3244.
(13) (a) Delogu, G.; Fabbri, D.; de Candia, C.; Patti, A.; Pedotti, S.
Tetrahedron: Asymmetry 2002, 13, 891. (b) Delogu, G.; Dettori,
M. A.; Patti, A.; Pedotti, S. A.; Casalone, G. Tetrahedron: Asymme-
try 2003, 14, 2467. (c) Nagaraju, M. Ph. D. Thesis; University of
Hyderabad: Hyderabad, 2012.
We are thankful to the DST-SERB, New Delhi for support (SB/S5/GC-
01/2014) to M. P. and for the DST support to the school of chemistry
under the FIST and IRPHA programs. Support of the CSIR-HRDG (No:
02/0176/14/EMR-II) to M. P. and support of the UGC under UPE and
CAS programs are also thankfully acknowledged.
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Acknowledgment
B.V. is thankful to the CSIR (New Delhi) and DST-SERB for research fel-
lowships.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H