Synthesis of chiral 2,3-disubstituted 1,4-diazabicyclo[2.2.2]octane derivatives

Article abstract of DOI:10.1021/jo502688b

Racemic 2,3-diaryl-1,4-diazabicyclo[2.2.2]octane (DABCO) derivatives are synthesized from the readily accessible piperazines in 50-64% yield by cyclization using ethylene bromide, triethylamine, and KI at 80 °C. The enantiomerically enriched 2,3-diphenylpiperazine and the 2,3-bis(1-naphthyl)piperazine derivatives are prepared by a resolution method using commercially available optically active acids, yielding the corresponding DABCO derivatives in 51-64% yield with up to 99% ee. This mild cyclization can also be applied to enantiopure camphanyldiamine derivatives, and the products are obtained in 72-86% yields.

Full text of DOI:10.1021/jo502688b

Note
pubs.acs.org/joc
Synthesis of Chiral 2,3-Disubstituted 1,4-Diazabicyclo[2.2.2]octane
Derivatives
Mariappan Periasamy,* Athukuri Edukondalu, and Polimera Obula Reddy
School of Chemistry, University of Hyderabad Central University, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: Racemic 2,3-diaryl-1,4-diazabicyclo[2.2.2]octane (DABCO) deriva-
tives are synthesized from the readily accessible piperazines in 50−64% yield by
cyclization using ethylene bromide, triethylamine, and KI at 80 °C. The
enantiomerically enriched 2,3-diphenylpiperazine and the 2,3-bis(1-naphthyl)-
piperazine derivatives are prepared by a resolution method using commercially
available optically active acids, yielding the corresponding DABCO derivatives in
51−64% yield with up to 99% ee. This mild cyclization can also be applied to
enantiopure camphanyldiamine derivatives, and the products are obtained in 72−
86% yields.
Scheme 1
1,4-Diazabicyclo[2.2.2]octane (DABCO) is a cagelike unique
structure with two nucleophilic and strongly basic nitrogens at
the bridgehead positions. The DABCO skeleton has proven to
have applications in the synthesis of multifunctional molecules,1
and DABCO is widely used as a base catalyst in organic
reactions.2 Also, optically active DABCO derivatives have been
employed as ligands and catalysts in asymmetric reactions.3 For
example, recently, an asymmetric electrophilic fluorocyclization
method using optically active DABCO-based N-F reagents was
reported.4 Previously, the DABCO derivatives were prepared
by cyclization of substituted stilbene diamines,4−6 ethylene
diamine,7 and piperzines.3,8−11 However, it was reported that
the cyclization of meso 2,3-diphenylpiperazine using ethylene
bromide and triethylamine gave the corresponding DABCO
derivative in only 14% yield, and the reaction failed to give the
cyclized DABCO product using the (R,R)-2,3-diphenylpiper-
azine.11 Recently, methods for accessing enantiopure Troger
base, a compound with bridgehead nitrogens, were reported by
this laboratory.12 Also, methods based on resolution and
asymmetric synthesis of trans-2,3-diarylpiperazine derivatives
have been reported.13,14 Accordingly, we undertook studies
aimed at the synthesis of enantiopure DABCO derivatives via
development of a simple general method of cyclization of the
corresponding piperazine derivatives. Herein, the results are
described.
a
Table 1. Optimization of the Reaction Condition
b
entry
base
solvent
Br(CH2)2Br (equiv)
yield (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
NaH
−
8 mL
26
CH3CN
1
1
1
1
2
4
6
trace
trace
22
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et3N
28
Et3N
39
Et3N
64
Et3N
65
a
The reactions were conducted with ( )-2,3-diphenylpiperazine 2a (5
mmol), KI (20 mol %), and base (10 mmol) at 80 °C for 14 h.
b
Isolated yield of 3a.
cyclo[2.2.2]octane 3a in 26% yield in the presence of K2CO3
(Table 1, entry 1). Whereas the reaction using ethylene
bromide (1 equiv) in CH3CN and THF solvents gave the
( )-2,3-diphenyl-1,4-diazabicyclo[2.2.2]octane 3a product in
only trace amounts using K2CO3 as a base (Table 1, entries 2
and 3). Fortunately, the reaction of piperazine ( )-2a with 2
and 4 equiv of ethylene bromide using triethylamine gave
( )-2,3-Diphenylpiperazine 2a can be readily accessed via a
method using Ti(IV) reagent developed in this laboratory.13a
Initially, we have examined the reaction of this readily
accessible ( )-2,3-diphenylpiperazine 2a using ethylene bro-
mide in the presence of 20 mol % KI and different bases and
solvents at 80 °C (Scheme 1 and Table 1).
We have observed that racemic piperazine 2a reacts with neat
ethylene bromide to afford ( )-2,3-diphenyl-1,4-diazabi-
Received: November 26, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502688b
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The Journal of Organic Chemistry
Note
Table 2. Synthesis of ( )-2,3-Diarylpiperazine Derivatives 2 and Reaction with Ethylene Bromide
a
b
The reactions were conducted using ( )-2,3-diarylpiperazine derivatives (5 mmol), KI (20 mol %), and Et3N (10 mmol) at 80 °C for 14 h. The
yields are for isolated products.
Scheme 2
product ( )-3a in 39 and 64% yields, respectively (Table 1,
entries 6 and 7). The product 3a was characterized by X-ray
single-crystal structural analysis.15 We have also examined the
reaction using 6 equiv of ethylene bromide, but there was no
significant change in the yields of product ( )-3a (Table 1,
entry 8).
To further examine the scope of this reaction, we have
synthesized several diastereomerically pure ( )-2,3-diarylpiper-
azines 2b−f in 72−80% yields by the reductive coupling of
diimines 1 using the Zn/Ti(OiPr)2Cl2 reagent system.13a
Racemic piperazine derivatives 2b−f were then reacted with
ethylene bromide and triethylamine in the presence of KI under
the optimized experimental conditions (Table 1, entry 7). The
results are summarized in Table 2. The reaction of ( )-2,3-
bis(1-naphthyl)piperazine 2b gave the corresponding ( )-2,3-
bis(1-naphthyl)-1,4-diazabicyclo[2.2.2]octane 3b in 52% yield
(Table 2, entry 1). The ortho methyl- and ortho chloro-
substituted ( )-2,3-diphenylpiperazine derivatives 2c and 2e
afforded the ( )-2,3-di-o-tolyl-1,4-diazabicyclo[2.2.2]octane 3c
and ( )-2,3-bis(2-chlorophenyl)-1,4-diazabicyclo[2.2.2]octane
3e in 59 and 55% yield, respectively (Table 2, entries 2 and 4).
Also, para methyl- and para chloro-substituted ( )-2,3-
B
DOI: 10.1021/jo502688b
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The Journal of Organic Chemistry
Note
diphenyl-1,4-diazabicyclo[2.2.2]octane 3d and 3f were obtained
in 50 and 53% yield, respectively (Table 2, entries 3 and 5).
Enantiomerically enriched 2,3-diphenylpiperazine compound
2a was previously synthesized by resolution methods using L-
(+)-tartaric acid and 1S-(+)-10-camphorsufonic acid (CSA)
developed in this laboratory.13a,b We have found that these
resolution methods using L-(+)-tartaric acid or (+)-CSA are not
effective in the case of racemic 2,3-bis(1-naphthyl)piperazine
2b. Fortunately, the resolution of racemic 2,3-bis(1-naphthyl)-
piperazine 2b using the (−)-dibenzoyl-L-tartaric acid 4 in
acetone solvent was successful, and (+)-2b compound was
obtained in 28% yield with 98% ee (Scheme 2).12a,b
applicable for the synthesis of several such aryl-substituted
enantiomerically pure 2,3-diaryl DABCO derivatives.
The chiral camphanyl piperazine (+)-7 and the analogous
chiral diamine (+)-8 are also readily accessible following a
method reported by this laboratory.16 Accordingly, it was also
of interest to us to examine the efficacy of the method of
cyclization developed for the reaction of 2,3-diarylpiperazines
for cyclizations using the camphanyl piperazine (+)-7 and the
analogous diamine (+)-8. Indeed, the camphanyl piperazine
(+)-7 reacts with ethylene bromide in the presence of
triethylamine to give the enantiopure DABCO derivative
(−)-9 in 86% yield. Similarly, the camphanyl diazepine (+)-8
was readily converted to the corresponding enantiopure
diazepine derivative (−)-10 in 72% yield (Scheme 4).
In summary, we have devised a simple, convenient method
for the synthesis of racemic and enantiomerically enriched 2,3-
diaryl-1,4-diazabicyclo[2.2.2]octane derivatives from the corre-
sponding piperazines using ethylene bromide for cyclization.
The cyclization method is also useful for accessing the
camphanyl DABCO 9 and camphanyl diazepine 10 derivatives
via reaction of the corresponding bicyclic camphanyldiamine
derivatives 7 and 8. Because the starting 2,3-diarylpiperazines
and the camphanyldiamines can be readily accessed from
simple starting materials and reagents, the synthetic methods
described here have good potential for applications in organic
synthesis.
The (S,S)-isomer of 2,3-bis(1-naphthyl)piperazine 2b was
obtained in 98% ee from the precipitate fraction, while the
(R,R)-isomer of 2,3-bis(1-naphthyl)piperazine 2b was obtained
in 50% ee from the filtrate fraction. The (R,R)-isomer was easily
enriched up to 99% ee by repeating the experiment using the
(+)-dibenzoyl-D-tartaric acid 4.
Diastereomeric complex 5a [(+)-2b·(−)-4)]15 was crystal-
lized to obtain crystals suitable for single-crystal X-ray analysis.
The configuration of enantiomer (+)-2b was assigned as (S,S)
relative to the chiral acid (R,R)-(−)-4 used, and the
enantiomeric ratio was determined by HPLC analysis.
We have also examined the cyclization reactions using the
enantiomerically enriched piperazines 2a and 2b following the
same reaction conditions followed for entry 7 of Table 1
(Scheme 3). The (R,R) and (S,S) enantiomers of 2,3-diphenyl-
EXPERIMENTAL SECTION
■
Scheme 3
General Procedure for the Preparation of 2,3-Diaryl-1,4-
diazabicyclo[2.2.2]octane Derivatives (3a−f). To a reaction flask
cooled under N2 were added 2,3-diarylpiperazine 2a−f (5 mmol) and
KI (0.166 g, 20 mol %) in acetonitrile (40 mL). Then triethylamine
(1.01 g, 1.3 mL, 10 mmol) and ethylene bromide (3.76 g, 1.7 mL, 20
mmol) were added at 25 °C, and the reaction mixture was refluxed for
14 h. It was then cooled to 25 °C; the solvent was removed and the
reaction quenched with a 2 M NaOH solution. The aqueous layer was
extracted with CH2Cl2 (2 × 15 mL), and the combined organic extract
was successively washed with water and brine and dried over
anhydrous Na2SO4. After removal of the solvent, the residue was
subjected to chromatography on silica gel using 2−5% methanol in
ethyl acetate to elute the desired 2,3-diaryl-1,4-diazabicyclo[2.2.2]-
octane 3a−f derivatives.
2,3-Diphenyl-1,4-diazabicyclo[2.2.2]octane 3a. Yield: 0.85 g
(64%). Pale yellow solid. Mp: 73−75 °C (lit.4a mp 74−76 °C). IR
(KBr): 3090, 3052, 3024, 2926, 2854, 1495, 1441, 1369, 1326, 1238,
1189, 1090, 1046, 980, 920, 816, 750, 701 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.48−7.46 (m, 4H), 7.38−7.34 (m, 4H), 7.30−7.27 (m,
2H), 4.17 (s, 2H), 3.03−2.98 (m, 4H), 2.83−2.75 (m, 2H), 2.65−2.58
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 141.2, 128.4, 127.7, 127.1,
62.4, 49.5, 41.1. HRMS (ESI-TOF): [M + H]+ calcd for C18H20N2 m/
z 265.1705, found m/z 265.1706.
2,3-Bis(1-naphthyl)-1,4-diazabicyclo[2.2.2]octane 3b. Yield: 0.95
g (52%). Pale yellow solid. Mp: 165−167 °C. IR (KBr): 3084, 3035,
2964, 2931, 2909, 2849, 1594, 1501, 1457, 1095, 1041, 827, 778 cm−1.
1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 8.40 Hz, 2H), 7.87 (d, J =
1,4-diazabicyclo[2.2.2]octane 3a were obtained in 64 and 63%
yield and 97.5 and 98% ee, respectively. Also, the reaction of
(R,R) and (S,S) enantiomers of the 2,3-bis(1-naphthyl)-
piperazine 2b furnished corresponding DABCO derivatives
3b in 51 and 52% yield with up to 99% ee. Product (S,S)-
(+)-3b was also characterized by single-crystal X-ray structural
analysis.15
The enantioselective 2,3-diarylpiperazines can be also
accessed following asymmetric coupling of the corresponding
diimines using a chiral Ti(IV) complex followed by enhance-
ment of enantiomeric purity via preparation of homochiral or
heterochiral aggregates using carboxylic acids like oxalic or
fumaric acids reported from this laboratory.13c Accordingly, the
synthetic method developed here (Scheme 3) to access
enantiopure DABCO derivatives 3a and 3b should be widely
7.92 Hz, 2H), 7.75 (d, J = 8.08 Hz, 2H), 7.67 (t, J = 7.2 Hz, 2H),
7.55−7.51 (m, 2H), 7.47 (d, J = 7.0 Hz, 2H), 7.30−7.28 (m, 2H), 5.35
(s, 2H), 3.53−3.50 (m, 2H), 3.08−2.91 (m, 4H), 2.73−2.68 (m, 2H).
13C NMR (100 MHz, CDCl3): δ 134.5, 134.1, 133.3, 128.9, 128.7,
126.6, 125.7, 124.7, 124.6, 123.2, 55.6, 49.2, 41.3. HRMS (ESI-TOF):
[M + H]+ calcd for C26H24N2 m/z 365.2018, found m/z 365.2017.
2,3-Di-o-tolyl-1,4-diazabicyclo[2.2.2]octane 3c. Yield: 0.86 g
(59%). Yellow liquid. IR (neat): 3013, 2958, 2936, 2920, 2860,
1
1490, 1463, 1375, 1260, 1068, 1035, 980, 816, 745 cm−1. H NMR
(400 MHz, CDCl3): δ 7.36−7.34 (m, 2H), 7.24−7.23 (m, 2H), 7.18−
7.13 (m, 4H), 4.60 (s, 2H), 3.26−3.18 (m, 4H), 2.97−2.83 (m, 4H),
C
DOI: 10.1021/jo502688b
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The Journal of Organic Chemistry
Note
Scheme 4
2.57 (s, 6H), 2.57−2.50 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
139.2, 137.0, 131.4, 127.4, 125.4, 125.1, 56.1, 49.7, 40.6, 20.0. HRMS
(ESI-TOF): [M + H]+ calcd for C20H24N2 m/z 293.2018, found m/z
293.2017.
122.5, 60.3, 47.6. HRMS (ESI-TOF): [M + H]+ calcd for C24H22N2
m/z 339.1862, found m/z 339.1862.
2,3-Di-o-tolylpiperazine 2c. Yield: 1.0 g (75%). Yellow solid. Mp:
116−118 °C. IR (KBr): 3271, 3150, 3063, 3019, 2926, 2843, 1583,
1484, 1457, 1315, 1117, 909, 756 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.67 (d, J = 6.96 Hz, 2H), 7.13−7.09 (m, 2H), 7.04−7.00 (m, 2H),
6.85 (d, J = 7.44 Hz, 2H), 4.19 (s, 2H), 3.14 (s, 4H), 1.91 (s, 2H), 1.87
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 138.5, 136.2, 129.9, 127.9,
127.2, 125.6, 61.6, 46.3, 19.3. HRMS (ESI-TOF): [M + H]+ calcd for
C18H22N2 m/z 267.1862, found m/z 267.1863.
2,3-Di-p-tolyl-1,4-diazabicyclo[2.2.2]octane 3d. Yield: 0.73 g
(50%). Yellow liquid. IR (neat): 3024, 2958, 2926, 2871, 1512,
1
1457, 1375, 1079, 1052, 1024, 860, 805, 756 cm−1. H NMR (400
MHz, CDCl3): δ 7.36 (d, J = 7.36 Hz, 4H), 7.17 (d, J = 7.48 Hz, 4H),
4.12 (s, 2H), 3.01−2.97 (m, 4H), 2.83−2.75 (m, 2H), 2.64−2.57 (m,
2H), 2.36 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 138.1, 136.7,
129.1, 127.7, 62.2, 49.5, 41.0, 21.0. HRMS (ESI-TOF): [M + H]+
calcd for C20H24N2 m/z 293.2018, found m/z 293.2022.
2,3-Bis(2-chlorophenyl)piperazine 2e. Yield: 1.2 g (73%). Yellow
solid. Mp: 94−96 °C. IR (KBr): 3287, 3227, 3063, 2926, 2849, 1581,
1
1479, 1441, 1358, 1320, 1112, 1041, 865, 821, 756 cm−1. H NMR
2,3-Bis(2-chlorophenyl)-1,4-diazabicyclo[2.2.2]octane 3e. Yield:
0.91 g (55%). Pale yellow solid. Mp: 182−184 °C. IR (KBr): 3068,
(400 MHz, CDCl3): δ 7.61 (s, 2H), 7.15−7.09 (m, 4H), 7.04−7.00
(m, 2H), 4.51 (s, 2H), 3.14−3.08 (m, 4H), 2.05 (s, 2H). 13C NMR
(100 MHz, CDCl3): δ 137.9, 133.5, 129.8, 129.1, 128.5, 126.7, 61.2,
47.2. HRMS (ESI-TOF): [M + H]+ calcd for C16H16Cl2N2 m/z
307.077, found m/z 307.0772.
1
2947, 2920, 2865, 1463, 1441, 1205, 1123, 1073, 1035, 750 cm−1. H
NMR (400 MHz, CDCl3): δ 7.51−7.45 (m, 4H), 7.26−7.19 (m, 4H),
4.88 (s, 2H), 3.37−3.31 (m, 2H), 2.99−2.83 (m, 4H), 2.67−2.60 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 136.9, 135.9, 130.7, 128.9,
127.0, 126.5, 56.1, 49.6, 40.4. HRMS (ESI-TOF): [M + H]+ calcd for
C18H18N2Cl2 m/z 333.0926, found m/z 333.0920.
General Procedure for the Preparation of Camphanyldi-
amine Derivatives 9 and 10. To a reaction flask cooled under N2
were added camphanylamines 7 and 8 (5 mmol) and KI (0.166 g, 20
mol %) in acetonitrile (40 mL). Then triethylamine (1.01 g, 1.3 mL,
10 mmol) and ethylene bromide (3.76 g, 1.7 mL, 20 mmol) were
added at 25 °C, and the reaction mixture was refluxed for 14 h. It was
then cooled to 25 °C; the solvent was removed and the reaction
quenched with a 2 M NaOH solution. The aqueous layer was
extracted with CH2Cl2 (2 × 15 mL), and the combined organic
extracts were successively washed with water and brine and dried over
anhydrous Na2SO4. After removal of the solvent, the residue was
subjected to chromatography on silica gel using 40% ethyl acetate in
hexane to elute desired compounds 9 and 10.
2,3-Bis(4-chlorophenyl)-1,4-diazabicyclo[2.2.2]octane 3f. Yield:
0.88 g (53%). Yellow liquid. IR (neat): 3052, 2958, 2926, 2865,
1490, 1457, 1397, 1369, 1315, 1265, 1084, 1052, 1008, 904, 849, 800
1
cm−1. H NMR (400 MHz, CDCl3): δ 7.38−7.30 (m, 8H), 4.02 (s,
2H), 2.98−2.94 (m, 4H), 2.72−2.58 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 139.4, 133.1, 129.0, 128.6, 61.9, 49.3, 41.0. HRMS (ESI-
TOF): [M + H]+ calcd for C20H24N2 m/z 333.0926, found m/z
333.0924.
General Procedure for the Preparation of ( )-2,3-Diary-
lpiperazine Derivatives (2a−f) Using Zn and Ti(OiPr)2Cl2.13a To
a reaction flask cooled under N2 were added TiCl4 (1.04 g, 0.6 mL, 5.5
mmol) and Ti(OiPr)4 (1.56 g, 1.62 mL, 5.5 mmol) in CH2Cl2 (40
mL). After the mixture had been stirred for 10−15 min, activated zinc
powder (1.65 g, 25 mmol) was added in three portions and continued
for an additional 1 h. The diimine (5 mmol) dissolved in CH2Cl2 (10
mL) was added dropwise through a dropping funnel at 0 °C for 20
min. Then the reaction mixture was stirred at 25 °C for 5−6 h. The
reaction was quenched with a 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 successively washed with water and brine and dried over
anhydrous K2CO3. After removal of the solvent, the residue was
subjected to chromatography on silica gel using 5−10% methanol in
ethyl acetate to elute the desired ( )-2,3-diarylpiperazine 2a−f
derivatives.
(5R,8S)-5,9,9-Trimethyloctahydro-1,4-ethano-5,8-methanoqui-
noxaline 9. Yield: 0.946 g (86%). White solid. Mp: 120−122 °C.
25
[α]D −22.3 (c 0.57, CHCl3). IR (KBr): 3065, 2961, 2893, 2698,
1651, 1560, 1483, 1452, 1415, 1396, 1284, 1153, 1111, 1074, 1051,
1
902, 661, 613 cm−1. H NMR (400 MHz, CDCl3): δ 3.82−3.78 (m,
1H), 3.40−3.35 (m, 2H), 3.21−3.14 (m, 2H), 3.12−3.04 (m, 2H),
2.70 (s, 1H), 2.61 (d, J = 8.0 Hz, 1H), 2.42−2.35 (m, 1H), 2.05 (d, J =
4.0 Hz, 1H), 1.84−1.78 (m, 1H), 1.66−1.59 (m, 1H), 1.48 (s, 3H),
1.25 (s, 4H), 1.12−1.05 (m, 1H), 0.86 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 68.6, 64.0, 55.3, 49.0, 47.5, 46.4, 45.4, 39.7, 35.1, 27.9, 26.1,
21.8, 21.3, 12.3. HRMS (ESI-TOF): [M + H]+ calcd for C14H24N2 m/
z 221.2018, found m/z 221.2021.
(6R,9S)-6,10,10-Trimethyloctahydro-2H-1,5-ethano-6,9-
methanobenzo[b][1,4]diazepine 10. Yield: 0.846 g 72%. White solid.
25
Mp: 126−128 °C. [α]D −32.2 (c 0.36, CHCl3). IR (KBr): 2951,
2,3-Bis(1-naphthyl)piperazine 2b. Yield: 1.21 g (72%). Yellow
solid. Mp: 106−108 °C (lit.17 mp 100−101 °C). IR (KBr): 3326,
3276, 3057, 2953, 2909, 2849, 1600, 1506, 1402, 1326, 1117, 1084,
2824, 1730, 1668, 1604, 1454, 1386, 1309, 1257, 1213, 1174, 1130,
1111, 1010, 935, 896 cm−1. 1H NMR (400 MHz, CDCl3): δ 3.41−3.33
(m, 2H), 3.26−3.20 (m, 1H), 3.13−3.06 (m, 1H), 3.02−2.95 (m, 2H),
2.56 (s, 2H), 2.37−2.32 (m, 2H), 1.90 (d, J = 4.76 Hz, 1H), 1.70−1.67
(m, 2H), 1.51−1.47 (m, 2H), 1.10 (s, 4H), 1.04−0.97 (m, 1H), 0.86
(s, 3H), 0.72 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 74.6, 74.3,
1
958, 778, 717 cm−1. H NMR (400 MHz, CDCl3): δ 7.96−7.26 (m,
14H), 5.01 (s, 2H), 3.34−3.24 (m, 4H), 2.33 (s, 2H). 13C NMR (100
MHz, CDCl3): δ 137.1, 133.5, 131.4, 128.5, 127.7, 125.5, 125.1, 124.9,
D
DOI: 10.1021/jo502688b
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The Journal of Organic Chemistry
Note
58.3, 57.1, 50.7, 49.0, 47.8, 46.7, 36.4, 32.2, 28.6, 27.2, 21.7, 20.5, 13.1.
HRMS (ESI-TOF): [M + H]+ calcd for C15H26N2 m/z 235.2175,
found m/z 235.2174.
ACKNOWLEDGMENTS
■
We are thankful to the DST (New Delhi, India) for a J. C. Bose
National Fellowship grant to M.P. and also for the FIST and
IRPHA programs. Support of the UGC under UPE and CAS
programs is also gratefully acknowledged. E.A. and P.O.R. are
thankful to the CSIR (New Delhi) for a research fellowship.
Resolution of 2,3-Bis(1-naphthyl)piperazine 2b Using
(−)-Dibenzoyl-L-tartaric acid 4. The (−)-dibenzoyl-L-tartaric acid
4 (10.75 g, 30 mmol) and ( )-2,3-bis(1-naphthyl)piperazine 2b (3.4
g, 10 mmol) were taken in acetone (150 mL), and the contents were
stirred at 25 °C for 6 h and filtered. The precipitate was suspended in a
mixture of CH2Cl2 and a 2 M Na2CO3 solution and stirred until
dissolution occurred. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic
extract was washed with brine and dried over anhydrous K2CO3, and
the solvent was evaporated to obtain the enriched (S,S)-2b enantiomer
REFERENCES
■
(1) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1983, 22,
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25
(0.95 g, 28% yield, 98% ee). [α]D = +260.8 (c 1.08, CHCl3). The
filtrate was concentrated, and the residue was treated as outlined above
to produce the (R,R)-2b enantiomer (2.13 g, 63% yield, 50% ee). The
(R,R)-2b enantiomer with 50% ee was further enriched by repeating
the experiment using the (+)-dibenzoyl-D-tartaric acid 4 to produce
25
the sample of 99% ee (1.31 g, 39% yield). [α]D = −261.9 (c 1.0,
CHCl3). The enatiomeric purity was estimated by chiral HPLC
analysis on a chiralcel OJ-H column: 97:3 hexanes/2-propanol, flow
rate of 1.5 mL/min, 254 nm, retention times of 14.4 min (R,R) and
21.4 min (S,S).
The enantiomerically enriched compounds 3a and 3b were
prepared from samples of 2a and 2b, respectively, using ethylene
bromide according to the following general procedure.
A sample of (R,R)-2a with 98% ee13b was utilized for the
25
preparation of (R,R)-3a. Yield: 0.85 g (64%). 97.5% ee. [α]D
=
−93.3 (c 0.5, MeOH) [lit.4a [α]D = −93.9 (c 0.5, MeOH)].
22
A sample of (S,S)-2a with 99% ee13a was utilized for the preparation
of (S,S)-3a. Yield: 0.83 g (63%). 98% ee. [α]D = +93.4 (c 0.5,
25
MeOH) [lit.6 [α]D = +93.1 (c 4.34, MeOH)].
25
HPLC analyses were conducted using a chiral column: chiralcel
OD-H, 99:1 hexanes/i-PrOH, flow rate of 1.0 mL/min, 254 nm,
retention times of 7.8 min (R,R) and 10.5 min (S,S).
A sample of (S,S)-2b with 98% ee was utilized for the preparation of
(S,S)-3b. Yield: 0.95 g (52%). 98% ee. [α]D25 = +373.4 (c 0.7, CHCl3).
A sample of (R,R)-2b with 98% ee was utilized for the preparation
25
of (R,R)-3b. Yield: 0.93 g (51%). 99% ee. [α]D = −374.9 (c 0.7,
(8) Soai, K.; Oshio, A.; Yoneyama, H. Tetrahedron: Asymmetry 1992,
3, 359.
(9) Fuji, K.; Tanaka, K.; Takasu, K.; Taga, T. Tetrahedron: Asymmetry
1996, 7, 1749.
(10) Qiu, L.-H.; Shen, Z.-X.; Chen, W.-H.; Zhang, Y.; Zhang, Y.-W.
Chin. J. Chem. 2003, 21, 1098.
CHCl3).
HPLC analyses were conducted using a chiral chiralcel OD-H
column [99.5:0.5 hexanes/i-PrOH, flow rate of 1.5 mL/min, 254 nm,
retention times of 24.6 min (S,S) and 35.1 min (R,R)] and also using a
chiral chiralcel cellulose-1 column [95:5 hexanes/i-PrOH, flow rate of
0.5 mL/min, 220 nm, retention times of 21.8 min (S,S) and 25.5 min
(R,R)]. The enatiomeric purities of samples (S,S)-3b and (R,R)-3b
were determined on the basis of HPLC analyses using a chiralcel
cellulose-1 column that gave better resolution.
X-ray Crystallography. X-ray reflections were collected on a
CCD X-ray diffractometer equipped with a Cu Kα X-radiation (λ =
1.54184 Å) source and Mo Kα X-radiation (λ = 0.71073 Å) at 298 K.
CCDC-1027412 (for 3a), CCDC-1027414 (for 5a), and CCDC-
1027413 (for 3b) contain the crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(11) Gouverneur, V.; Sandford, G. PCT. Int. Appl. WO 2014068341
A2, 2014; Chem. Abstr. 2014, 160, 708517.
(12) (a) Satishkumar, S.; Periasamy, M. Tetrahedron: Asymmetry
2006, 17, 1116. (b) Satishkumar, S.; Periasamy, M. Tetrahedron:
Asymmetry 2009, 20, 2257. (c) Periasamy, M.; Suresh, S.; Satishkumar,
S. Tetrahedron: Asymmetry 2012, 23, 108.
(13) (a) Vairaprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71,
3636. (b) Vairaprakash, P.; Periasamy, M. J. Chem. Sci. 2008, 120, 175.
(c) Vairaprakash, P.; Periasamy, M. Tetrahedron Lett. 2008, 49, 1233.
(14) (a) Periasamy, M.; Sanjeevakumar, N.; Dalai, M.;
Gurubrahamam, R.; Reddy, P. O. Org. Lett. 2012, 14, 2932.
(b) Periasamy, M.; Reddy, P. O.; Edukondalu, A.; Dalai, M.;
Alakonda, L. M.; Udaykumar, B. Eur. J. Org. Chem. 2014, 6067.
(15) See the Supporting Information for crystal data.
ASSOCIATED CONTENT
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S
* Supporting Information
(16) Periasamy, M.; Sanjeevakumar, N.; Reddy, P. O. Synthesis 2012,
44, 3185.
(17) Shono, T.; Kise, N.; Shirakawa, E.; Matsumoto, H.; Okazaki, E.
J. Org. Chem. 1991, 56, 3063.
Copies of the 1H and 13C NMR spectra of the products, HPLC
analysis profiles, and X-ray crystallographic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mpsc@uohyd.ernet.in.
■
Notes
The authors declare no competing financial interest.
E
DOI: 10.1021/jo502688b
J. Org. Chem. XXXX, XXX, XXX−XXX