Convenient Procedures for the Asymmetric Reduction of 1,4-Diphenylbutane-1, 4-dione and Synthesis of 2,5-Diphenylpyrrolidine Derivatives

Article abstract of DOI:10.1055/s-2003-42447

Asymmetric reduction of 1,4-diphenylbutane-1,4-dione (1) was carried out using the reducing agents NaBH₄, BH₃·THF, and PhNEt₂·BH₃ in combination with the chiral reagents (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol (4) or (S)-proline (5), in the presence of TMSCl or B(OMe)₃ under various conditions to obtain the corresponding 1,4-diol 2 in 52% to 97% ee. The chiral 1,4-diol 2 was converted to various C₂-symmetric (2S,5S)-2,5-diphenylpyrrolidine derivatives 3a-e (45 to 75% yield) via the corresponding dimesylate prepared using MsCl and Et₃N.

Full text of DOI:10.1055/s-2003-42447

PAPER
2507
Convenient Procedures for the Asymmetric Reduction of 1,4-Diphenylbutane-
1,4-dione and Synthesis of 2,5-Diphenylpyrrolidine Derivatives
A
symmetric Reduction
a
of 1, 4-Dip
r
henylbu
i
tane-1,4
a
-dione ppan Periasamy,* Muthu Seenivasaperumal, Vutukuri Dharma Rao
School of chemistry, University of Hyderabad, Hyderabad 500 046, India
Fax +91(40)23012460; E-mail: mpsc@uohyd.ernet.in
Received 21 July 2003; revised 18 August 2003
reduction. For example, an extremely effective ox-
azaborolidine catalyst can be easily and rapidly prepared
in situ from the amino alcohol 4 and trimethyl borate (1 h
at r.t.).9 Also, it has been reported10 that (S)-proline (5)
Abstract: Asymmetric reduction of 1,4-diphenylbutane-1,4-dione
(1) was carried out using the reducing agents NaBH4, BH3·THF, and
Ph Et2·
in combination with the chiral reagents (S)-(–)- , -
3
diphenyl-2-pyrrolidinemethanol (4) or (S)-proline (5), in the pres-
ence of TMSCl or B(OMe)3 under various conditions to obtain the (Figure 1) and BH3·THF reagent combination was effec-
corresponding 1,4-diol 2 in 52% to 97% ee. The chiral 1,4-diol 2
was converted to various C2-symmetric (2S,5S)-2,5-diphenyl-
pyrrolidine derivatives 3a–e (45 to 75% yield) via the correspond-
simplified, convenient procedures for the asymmetric re-
ing dimesylate prepared using MsCl and Et3N.
tive in enantioselective reduction of acetophenone at 110
°C in 10 minutes. Accordingly, it is desirable to develop
duction of the 1,4-diphenylbutane-1,4-dione (1). We wish
to report here the results of detailed studies on the prepa-
ration and use of the chiral 1,4-diol 2 for the synthesis of
Key words: asymmetric reduction, chiral 1,4-diols, chiral pyrroli-
dine derivatives, 1,4-dione
several chiral 2,5-diphenylpyrrolidine derivatives.
Asymmetric synthesis is one of the major expanding areas
of research in organic chemistry. The use of C2-symmetric
chiral auxiliaries has gained considerable importance in
current asymmetric syntheses.1 Among the various chiral
auxiliaries, the 2,5-disubstituted pyrrolidine system is an
important class of reagents. The trans-2,5-dimethyl-
Figure 1 Structures of chiral alcohols 4 and 5
pyrrolidine was first developed as a useful chiral auxiliary
for enantioselective alkylation of enamines derived from
it.2–4 In this case, the recovery and recycling of chiral aux-
The required diphenylbutane-1,4-dione (1) is easily pre-
iliary are somewhat difficult. Therefore, several groups
pursued the synthesis of the corresponding diphenyl ano-
logue, a nonvolatile, stable, crystalline compound. The
preparation of this system involves the enantioselective
reduction of 1,4-diphenylbutane-1,4-dione (1) and cycli-
sation of the resultant diol derivative 2 (Scheme 1).
pared by following an established protocol via the
Friedel–Craft acylation of benzene with fumaryl chloride
and subsequent reduction with SnCl2/HCl.11,12
The borane reagents like BH3·SMe2, BH3·THF, diborane,
and catecholborane suffer from drawbacks such as ther-
mal decomposition, low concentration, noxious odor or
expense. Accordingly, we have examined the asymmetric
reduction of 1,4-dione 1 using borane reagents generated
in situ using NaBH4 and amine-boranes in combination
with (S)-(–)- , -diphenyl-2-pyrrolidinemethanol (4) and
(S)-proline (5). The results are summarised in Tables 1
and 2. When (S)-(–)- , -diphenyl-2-pyrrolidinemethanol
(4) (10 mol%) was used in combination with NaBH4/
Me3SiCl reagent, the 1,4-diol 2 was obtained in 70%
yield, with dl/meso ratio 75:25 and in 52% ee (Table 1,
entry 1). The results were better when B(OMe)3 was used
in combination with NaBH4/Me3SiCl, BH3·THF and
PhNEt2·BH3 as hydride sources, (Table 1, entries 2, 3 and
4) (Scheme 2).
OH
O
Asymmetric
Reduction
Ph
OH
Ph
Ph
Ph
Ph
N
R
3
Ph
O
1
2
Scheme 1 Synthesis of 2,5-Diphenyl pyrrolidine derivatives
The asymmetric reduction of the diferrocenyl-1,4-dike-
tone to obtain the corresponding diol samples of >98% ee
has been reported5 using the CBS oxazaborolidine cata-
lyst, which requires considerable care for preparation to
achieve good selectivities.6 In these reductions, the borane
reagents such as BH3·THF, and BH3·SMe2, have been
used. In recent years, several simplified procedures have
appeared7,8 for the oxazaborolidine catalysed asymmetric
The chiral (S)-(–)- , -diphenyl-2-pyrrolidinemethanol
(4) was prepared from (S)-proline (5) in several steps.14
Although good enantioselectivities (Table 1) were
achieved using this reagent, we have examined the devel-
opment of a practical method for the reduction using (S)-
proline (5) itself. Buono et al.10 have reported that (S)-pro-
line (5) gives good results in the asymmetric reduction of
SYNTHESIS 2003, No. 16, pp 2507–2510
x
x.
x
x
.
2
0
0
3
Advanced online publication: 21.10.2003
DOI: 10.1055/s-2003-42447; Art ID: Z10103SS
© Georg Thieme Verlag Stuttgart · New York

2508
M. Periasamy et al.
PAPER
Table 2 Asymmetric Reduction of 1,4-Dione 1 to 1,4-Diol 2 Using
(S)-Proline (5)
Entry Borane Reagent
Yield
(%)a
dl/meso
ee
Ratiob
(%)c
1d,e
2d,f
3f,h
4f,h
NaBH4
60
60
60
75
22:78
62:38
76:24
73:27
64 (1S,4S)
81 (1R,4R)
53 (1R,4R)
85 (1R,4R)
BH3·THFg
BH3·THFi
PhNEt2·BH3
Scheme 2 Asymmetric reduction using (S)-(–)- , -diphenyl-2-pyr-
rolidinemethanol (4) in combination with borane reagent and
B(OMe)3 (dl/meso = 75:25 to 93:7; 52–97% ee, 70–85% yield)
a Yields are of 1,4-diol 2 isolated by column chromatography on silica
gel using hexane–EtOAc as eluent.
b The dl/meso ratios were calculated from 13C NMR data.
cAll ee values reported here are based on maximum [ ]D21 –58.5 (c =
1.01, CHCl3, >98% ee) for (1S,4S)-(–)-213 and the % of ee was calcu-
lated based on amount of dl (i.e. R,R- and S,S-isomers) present in the
mixture.
Table 1 Asymmetric Reduction of 1,4-Dione 1 to 1,4-Diol 2 Using
(S)-(–)- , -Diphenyl-2-pyrrolidinemethanol (4)
Entrya Borane Reagent
Yield
(%)b
dl/meso
ee
ratioc
(%)d
d 100 mol% of 5 was used.
1e
2
NaBH4/TMSCl
NaBH4/TMSCl
BH3·THF
70
70
85
70
75:25
93:7
52 (1R,4R)
93 (1R,4R)
97 (1R,4R)
97 (1R,4R)
e 2.5 mmol of the 1,4-dione 1 was used.
f 2 mmol of the 1,4-dione 1 was used.
g (S)-Proline (5) was added to BH3·THF prepared in situ using NaBH4/
I2.
3
88:12
90:10
h 20 mol% of 5 was used.
i BH3·THF prepared in situ using NaBH4/I2 was added to (S)-proline
(5).
4
Ph Et2·
3
a All the reactions were carried out using 10 mol% of catalyst 4 and 5
mmol of 1,4-dione 1.
b Yields are of 1,4-diol 2 isolated by column chromatography on silica
gel using hexane–EtOAc as eluent.
In conclusion, the enantioselective reduction of 1,4-
diphenylbutane-1,4-dione (1) to the corresponding 1,4-
diol 2 is conveniently carried out using (S)-(–)- , -diphe-
nyl-2-pyrrolidinemethanol (4) and (S)-proline (5) and
easy to handle borane reagents. The convenient synthetic
procedures described here for the preparation of the chiral
2,5-diphenylpyrrolidine system 3 should facilitate the
syntheses and application of these derivatives.
c The dl/meso ratios were calculated from 13C NMR data.
dAll ee values reported here are based on maximum [ ]D21 –58.5 (c =
1.01, CHCl3, >98% ee) for (1S,4S)-(–)-213 and the % of ee was calcu-
lated based on amount of dl (i.e. R,R- and S,S-isomers) present in the
mixture.
e Reaction was performed without using B(OMe)3.
acetophenone at refluxing conditions. Accordingly, we
have examined the asymmetric reduction of the 1,4-dione
1 using (S)-proline 5 along with various hydride sources.
The results are summarised in Table 2.
Reduction of 1,4-Diphenylbutane-1,4-dione (1) Using BH3·THF
Complex/(S)-(–)- , -Diphenyl-2-pyrrolidinemethanol (4)/
B(OMe)3 (10 mol%) Reagent Combination (Entry 3, Table 1)
NaBH4 (0.76 g, 20 mmol) was suspended in anhyd THF (40 mL)
under N2. The reaction mixture was cooled to 0 °C and a solution of
I2 (2.1 g, 8.3 mmol) in THF (25 mL) was added dropwise during 2.5
h at 0 °C using a pressure equalizing dropping funnel. A solution of
4 (0.8 mmol) and B(OMe)3 (1 mmol) in THF (10 ml) was added and
the mixture was stirred for 10 min. To this mixture, was added slow-
ly 1,2-dibenzoylethane (1 g, 4.6 mmol) dissolved in THF (15 mL)
with a pressure equalizing dropping funnel during 1 h at 10 °C and
the mixture was further stirred at 25 °C for 1 h. The mixture was hy-
drolysed using 2 N HCl (15 mL) and the organic layer was separat-
ed. The aquous layer was extracted with Et2O. The combined
organic extracts were washed with brine (10 mL) and dried
(MgSO4). After evaporation, the crude product was purified on a sil-
ica gel column using hexane–EtOAc (80:20) as eluent to obtain the
Unfortunately, the 1,4-diol 2 was obtained only with low-
er selectivities using (S)-proline (5). However, the mix-
ture of nonracemic and meso diastereomers of 2 has been
readily purified to obtain the samples of >95 ee using (S)-
proline (5) and B(OH)3.15 The resultant 1,4-diol 2 (>95%
ee) was readily cyclised using primary amines to obtain
the corresponding 2,5-diphenylpyrrolidine derivatives
3a–e via the dimesylate 6 (Scheme 3).
(+)-1,4-diol 2 in 97% ee; yield: 1.02 g (85%); mp 63–65 °C; dl/
21
meso ratio = 88:12; [ ]D21 +49.8 (c = 0.542, CHCl3) {Lit.13 [ ]D
58.5 (c = 1.01, CHCl3, >98% ee) for (1S,2S)-(–)-2}.
–
1H NMR (200 MHz, CDCl3): = 1.2–1.9 (m, 4 H), 2.8 (s, 2 H), 4.6–
4.7 (m, 2 H), 7.2–7.4 (m, 10 H).
13C NMR (50 MHz, CDCl3): = 35.1 (meso), 36.0 (dl), 73.9 (meso),
74.4 (dl), 126.0, 127.4, 128.4, 144.8.
Scheme 3 Synthesis of (2S,5S)-N-alkyl and N-aryldiphenylpyrroli-
dine derivatives
Synthesis 2003, No. 16, 2507–2510 © Thieme Stuttgart · New York

PAPER
Asymmetric Reduction of 1,4-Diphenylbutane-1,4-dione
2509
Reduction of 1,4-Diphenylbutane-1,4-dione (1) with NaBH4/(S)-
Proline (5) Complex (Entry 1, Table 2)
uct was purified on a silica gel column using hexane as eluent; yield:
0.234 g (75%); [ ]D21 –126 (c = 0.435, CHCl3).
NaBH4 (0.19 g, 5 mmol) and (S)-proline (5; 0.58 g, 5 mmol) were
taken in THF (10 mL) and stirred for 2 h at r.t. 1,2-Dibenzoylethane
(0.59 g, 2.5 mmol) in THF (10 mL) was added to this suspension of
sodium L-prolinate borane complex and the mixture was stirred at
40 °C for 4 d. The excess reagent was decomposed with H2O and
the mixture was concentrated under reduced pressure and extracted
with Et2O. The organic extracts were washed with 10% HCl (10
mL), aq sat. NaHCO3 solution (10 mL), brine (10 mL), and dried
(MgSO4). The solvent was evaporated and the crude product was
purified on a silica gel column using hexane–EtOAc (80:20) as elu-
ent to obtain the (–)-1,4-diol (–)-2 in 64% ee, yield: 0.36 g (60%);
IR (neat): 3061, 1602 cm–1.
1H NMR (200 MHz, CDCl3): = 1.98–2.2 (m, 2 H), 2.4–2.8 (m, 2
H), 3.15 (d, J = 14 Hz, 1 H), 3.65 (d, J = 14 Hz, 1 H), 4.28 (m, 2 H),
7.1–7.3 (m, 15 H).
13C NMR (50 MHz, CDCl3): = 33.4, 51.1, 65.5, 126.4, 127.0,
128.0, 128.2, 128.3, 128.4, 140.2, 144.1.
Anal. Calcd for C23H23N: C, 88.25; H, 7.40; N, 4.47. Found: C,
88.50; H, 7.65; N, 4.65.
(2S,5S)-N-Phenyl-2,5-diphenylpyrrolidine (3b)
Yield: 0.134 g (45%); mp 190–1 94 °C; [ ]D –31 (c = 0.236,
CHCl3).
dl/meso ratio = 22:78; [ ]D21 –8.0 (c = 0.25, CHCl3) {Lit.13 [ ]D
21
21
–58.5 (c = 1.01, CHCl3),, >98% ee for (1S,4S)-(–)-2}.
1H NMR (200 MHz, CDCl3): = 1.7–2.0 (m, 4 H), 2.4 (s, 2 H), 4.6–
4.8 (m, 2 H), 7.2–7.4 (m, 10 H).
13C NMR (50 MHz, CDCl3): = 35.0 (meso), 36.0 (dl), 74.1 (meso),
74.5 (dl), 125.9, 127.4, 128.4, 144.6.
IR (KBr): 3020, 2935, 1597, 1502, 1359, 748, 698 cm–1.
1H NMR (200 MHz, CDCl3): = 1.7–1.9 (m, 2 H), 2.5–2.7 (m, 2
H), 5.2–5.4 (m, 2 H), 6.4–6.7 (m, 3 H) 7.0–7.6 (m, 12 H).
13C NMR (50 MHz, CDCl3): = 32.5, 63.3, 114.0, 115.7, 126.2,
126.7, 128.6, 128.8, 144.0, 145.1.
MS (EI): m/z = 299 (M+).
Reduction of 1,4-Diphenylbutane-1,4-dione (1) using (S)-Pro-
line (5) (20 mol%) and N,N-Diethylaniline·BH3 Complex (Entry
4, Table 2)
To a stirred suspension of (S)-proline (5; 0.095 g, 0.83 mmol) in tol-
uene (7 mL) was added a 1 M toluene solution of N,N-diethyla-
niline·BH3 (0.83 mL, 0.83 mmol) at 25 °C. After stirring for a
further 10 min, the reaction mixture was heated to reflux (110 °C).
1,2-Dibenzoylethane (0.476 g, 2 mmol) in THF (10 mL) was added,
followed by dropwise addition of a 1 M toluene solution of N,N-di-
ethylaniline·BH3 (4 mL, 4 mmol) over 15 min. The mixture was fur-
ther stirred for 0.5 h. After cooling to 25 °C, Et2O (20 mL) was
added. After work-up and purification, the (+)-1,4-diol (+)-2 was
obtained in 85% ee; yield: 0.36 g (75%); dl/meso ratio = 73:27,
(2S,5S)-N-(2-Methoxyphenyl)-2,5-diphenylpyrrolidine (3c)
Yield: 0.148 (45%); [ ]D21 –15 (c = 0.100, CHCl3).
IR (KBr): 3052, 2965, 1596, 740, 700 cm–1.
1H NMR (200 MHz, CDCl3): = 1.9–2.1 (m, 2 H), 2.3–2.5 (m, 2
H), 3.4 (s, 3 H), 4.8–4.9 (t, 2 H, J = ? Hz), 6.6–6.9 (m, 4 H), 7.2–7.6
(m,10 H).
13C NMR (50 MHz, CDCl3): = 34.5, 55.2, 67.8, 112.6, 120.8,
121.8, 122.0, 126.1, 126.5, 128.0, 139.0, 146.2, 153.1.
MS (EI): m/z = 329 (M+).
21
21
[ ]D +36.2 (c = 0.276, CHCl3) {Lit.13 [ ]D –58.5 (c = 1.01,
CHCl3), >98% ee for (1S,2S)-(–)-2}.
1H NMR (200 MHz, CDCl3): = 1.3–1.9 (m, 4 H), 2.6 (s, 2 H), 4.6–
4.8 (m, 2 H), 7.2–7.4 (m, 10 H).
13C NMR (50 MHz, CDCl3): = 35.0 (meso), 35.9 (dl), 74.0 (meso),
74.4 (dl), 126.0, 127.4, 128.4, 144.7.
(2S,5S)-N-(2-Hydroxyethyl)-2,5-diphenylpyrrolidine (3d)
Yield: 0.186 g (70%); [ ]D21 –123 (c = 0.155, CHCl3).
IR (neat): 3375, 1602 cm–1.
1H NMR (200 MHz, CDCl3): = 1.8–2.1 (m, 2 H), 2.3–2.8 (m, 5
H), 3.0–3.3 (m, 1 H), 3.35–3.6 (m, 1 H), 4.2–4.5 (m, 2 H), 7.1–7.6
(m, 10 H).
13C NMR (50 MHz, CDCl3): = 33.5, 49.1, 59.4, 66.5, 127.2, 127.7,
128.6, 144.1.
(1R,4R)-1,4-Bis(methanesulfonyloxy)-1,4-diphenylbutane (6)13
To methanesulfonyl chloride (0.4 mL, 5.3 mmol) in CH2Cl2 (20
mL) at –20 °C was added a solution of (1R,4R)-1,4-diphenylbutane-
1,4-diol (2; 0.5 g, 2.06 mmol, 96% ee) and Et3N (0.87 mL, 6.2
mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred for 1.45
h at –20 °C and then quenched with aq sat. NH4Cl (2 mL). It was
brought to 25 °C and concentrated to approximately 17 mL. The so-
lution was then diluted with EtOAc (80 mL) and washed succes-
sively with a mixture of H2O–brine–aq sat. Na2CO3 (1:2:1, 2 × 20
mL), and aq sat. NaHCO3 (2 × 20 mL). The organic layer was dried
(MgSO4), filtered through Celite and concentrated to approximately
8 mL. The solution was then cooled to 0 °C. The crude dimesylate
was precipitated out by dropwise addition of hexane (80 mL). The
resulting solid was filtered, dried and immediately used for the next
reaction without further purification.
Anal. Calcd for C18H21NO: C, 80.97; H, 7.92; N, 5.24. Found: C,
81.35; H, 7.98; N, 5.50.
(2S,5S)-N-Butyl-2,5-diphenylpyrrolidine (3e)
Yield: 0.153 g (55%); [ ]D21 –90 (c = 0.140, CHCl3).
IR (neat): 3063, 2959, 1602 cm–1.
1H NMR (200 MHz, CDCl3): = 0.5–0.71 (t, 3 H), 0.8–1.2 (m, 4
H), 1.7–2.0 (m, 2 H), 2.1–2.3 (m, 2 H), 2.4–2.6 (t, 2 H, J = ? Hz),
3.7–3.9 (t, 2 H, J = ? Hz), 7.2–7.6 (m, 10 H)
13C NMR (50 MHz, CDCl3): = 13.7, 20.5, 29.3, 34.9, 53.0, 69.4,
126.6, 127.2, 128.2, 146.2
MS (EI): m/z = 279 (M+).
N-Substituted 2,5-Diphenylpyrrolidines; (2S,5S)-N-Benzyl-2,5-
diphenylpyrrolidine (3a);Typical Procedure
Benzylamine (21 mL, 196 mmol) was added at 0 °C to (1R, 4R)-1,4-
bis(methanesulfonyloxy)-1,4-diphenylbutane (6; 0.32 g, 1 mmol)
and the mixture was stirred at 0 °C for 14 h. After warming to 25 °C,
the excess benzylamine was evaporated and the residue was dis-
solved in Et2O (25 mL). The contents were successively washed
with aq sat. NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), and
concentrated to afford the crude product as a gum. The crude prod-
Acknowledgement
We are thankful to the CSIR and DST (New Delhi) for financial
support. Support of the UGC (New Delhi) under ‘University of Po-
tential for Excellence’ programme is gratefully acknowledged.
Synthesis 2003, No. 16, 2507–2510 © Thieme Stuttgart · New York

2510
M. Periasamy et al.
PAPER
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Synthesis 2003, No. 16, 2507–2510 © Thieme Stuttgart · New York