Synthesis and crystal structure of the chiral β-amino alcohol (S)-α,α-diphenyl-2-pyrrolidine methanol

Article abstract of DOI:10.3184/030823410X12868999388477

Optically pure (S)-α,α-diphenyl-2-pyrrolidine methanol was prepared from L-proline via protection of the amino group, reaction with the Grignard reagents and deprotection of the amino-protected groups in 54.4% yield. The synthetic conditions to prepare (S)-α,α-diphenyl-2- pyrrolidinemethanol were optimised. Single crystal X-ray diffraction analysis revealed that the molecular structure of the compound was enantiomerically pure. The crystals are orthorhombic, space group P2(1)2(1)2(1), with unit cell parameters a = 8.9000(18) A, b = 9.2405(18) A, c = 16.671(3) A, V = 1371.1(5) A³, D_x = 1.227 g cm ^-3, Z =4, T = 113(2)K, F(000) = 628, R¹ = 0.0335 and wR² = 0.0707. The absolute structure parameter was -1.6(17).

Full text of DOI:10.3184/030823410X12868999388477

610 RESEARCH PAPER
NOVEMBER, 610–612
JOURNAL OF CHEMICAL RESEARCH 2010
Synthesis and crystal structure of the chiral β-amino alcohol
(S)-α,α-diphenyl-2-pyrrolidine methanol
Yu-Mei Zhang*, Peng Liu and Hong-Li Zhang
College of Sciences, Hebei University of Science &Technology, Shijiazhuang, 050018, P. R. China
Optically pure (S)-α,α-diphenyl-2-pyrrolidine methanol was prepared from L-proline via protection of the amino
group, reaction with the Grignard reagents and deprotection of the amino-protected groups in 54.4% yield. The syn-
thetic conditions to prepare (S)-α,α-diphenyl-2-pyrrolidinemethanol were optimised. Single crystal X-ray diffraction
analysis revealed that the molecular structure of the compound was enantiomerically pure. The crystals are ortho-
rhombic, space group P2(1)2(1)2(1), with unit cell parameters a = 8.9000(18) Å, b = 9.2405(18) Å, c = 16.671(3) Å, V =
1371.1(5) Å3, Dx = 1.227 g cm−3, Z =4, T = 113(2)K, F(000) = 628, R1 = 0.0335 and wR2 = 0.0707. The absolute structure
parameter was –1.6(17).
Keywords: (S)-α,α–diphenyl-2-pyrrolidine methanol, crystal structure, chirality
Table 1 Crystallographic data and structure refinement
Many optically active β-amino alcohols and other amino acid
derivatives are important chiral reagents and are important
precursors of chiral catalysts.1,2 They have been widely used in
many asymmetric catalysis reaction, for example, asymmetric
reduction of ketones,3,4 addition reactions of diethyl zinc to
aldehydes,5 and Diels-Alder reactions.6 (S)-α,α–diphenyl-2-
pyrrolidine methanol 4 is a very important chiral β-amino
alcohol catalyst precursor.7 To the best of our knowledge, the
crystal structure of the title compound has not been reported.
summary
CCDC deposit no.
741092
Empirical formula
Formula weight
Temperature(K)
Wavelength (Mo Ka) (A °)
Crystal system
C17H19NO’
253.33
113(2)
0.71073
Orthorhombic
P2(1)2(1)2(1)
Space group
Unit cell dimensions
a (Å)
8.9000(18)
b (Å)
9.2405(18)
c (Å)
16.671(3)
Volume(Å 3)
1371.1(5)
Z
4
Crystal size
0.16 x 0.12 x 0.06
1.227
Calculated density (Mg m−3)
Absorption coefficient (mm)
F(000)
0.076
544
Reflections collected/unique
Completeness to theta = 24.98
Data/restraints/parameters
Limiting indices
9219/2405 [R(int) = 0.0334]
99.5 %
2405/1/178
–9<=h<=10, –10<=k<=10,
–18<=l<=19
Goodness of fit on F2
1.054
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0405, wR2 = 0.1010
R1 = 0.0436, wR2 = 0.1040
–1.6(17)
Absolute structure parameter
Largest diff. peak and hole (e A-3) 0.371 and –0.252
We present here the crystal structure of (S)-α,α–diphenyl-
2-pyrrolidine methanol 4 and its preparation, which may give
a better understanding of the mechanism of the catalytic
reactions.
Fig. 1 ORTEP drawing of the structure of 6, n-pentane as well
as H atoms have been omitted for clarity except the H atoms on
the OH. Thermal ellipsoids are drawn at 50% probability level.
Scheme 1 Preparation of (S)- α, α -diphenyl-2-pyrrolidine methanol 4.
* Correspondent. E-mail: zhangym.jy@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2010 611
Fig. 2 Three-dimensional molecular-packing diagram of the title compound.
Results and discussion
molecular hydrogen bond O1–H1…N1 in unit cell [H1…
N1=2.25Å, O1–H1…N1 =116.3°] (Table 3).
Optically pure (S)-α, α-diphenyl-2-pyrrolidinemethanol was
prepared from L-proline in three steps involving protection of
the amino protection, reaction with the Grignard reagents and
deprotection of the amino-protected groups.
N-Ethoxy carbonyl was chosen as a protecting group as it is
introduced under mild alkaline conditions (K2CO3/MeOH).
Although the total yield was slightly lower than other methods,
the easy access to raw materials, easy operation and simple
processing, made this synthetic method more suitable for
large-scale production.
Experimental
All reactions were carried out under argon and monitored by TLC.
THF was dried using Na under reflux. Melting points (uncorrected)
were measured with a XT4 melting point apparatus. 1H spectra were
recorded on a Varian Mercury plus 300 MHz using CDCl3 as solvent
unless otherwise noted and TMS as the internal standard. All chemical
shifts were reported in parts per million (ppm), Optical rotations were
measured on a WZZ-3 polarimeter. The title compound was prepared
according to Scheme 1.
Synthesis of S-(–)-N-ethoxycarbonyl proline methyl ester (2):8
K2CO3 (2.8 g, 40 mmol) was added into a solution of L –proline 1
(2.3 g, 20 mmol) in CH3OH (30 mL) in an ice bath. The heteroge-
neous mixture was stirred, and ethyl chloroformate (4.4 g, 40 mmol)
was slowly added at 0°C. The reaction mixture was warmed to room
temperature and stirred overnight. The methanol was removed under
reduced pressure and 20 mL water was added, the mixture was
extracted with CH2Cl2 (3 × 30 mL) and the combined organic phases
were washed with brine, dried (anhydrous MgSO4) and evaporated
Crystal structure
Single crystal X-ray diffraction analysis reveals that the molec-
ular structure of compound 4 confirms the formulation of the
compound (shown in Fig. 1). This compound is enantiomeri-
cally pure and crystallised in the noncentrosymmetric P212121
space group (Table 1).
It can be seen from Figs 1 and 2, that in order to relieve
strain, the four carbon atoms of the pyrrolidine ring nearly
exists in a plane, as shown by the torsion angle of C(1)–C(2)–
C(3)–C(4) is –7.3(3)° (Table 2), while its nitrogen atom is out-
side the plane. The ring exists as an envelope conformation.
The N atom is located near the OH side. This facilitates the
coordination atoms in complex formation. There are intra-
Table 3 Hydrogen-bonding geometry [Å, deg] for 4
D–H...A
d(D–H)
0.82
d(H...A) d(D...A) <(DHA)
2.25 2.719(2) 116.3
O(1)–H(1C)...N(1)
Table 2 Selected bond lengths (Å) and angles (deg) for 4
Bond
Distance
Bond angle
deg
O(1)–C(5)
N(1)–C(1)
N(1)–C(4)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(5)–C(12)
C(6)–C(11)
C(6)–C(7)
C(7)–C(8)
C(8)–C(9)
1.430(2)
1.465(3)
1.473(2)
1.491(4)
1.515(3)
1.541(3)
1.550(3)
1.523(3)
1.543(3)
1.382(3)
1.394(3)
1.386(3)
1.381(3)
C(1)–N(1)–C(4)
106.85(17)
103.73(19)
106.4(2)
N(1)–C(1)–C(2)
C(1)–C(2)–C(3)
N(1)–C(4)–C(3)
103.50(15)
108.20(15)
113.09(15)
105.60(18)
–15.3(2)
N(1)–C(4)–C(5)
C(3)–C(4)–C(5)
C(2)–C(3)–C(4)
C(2)–C(3)–C(4)–N(1)
N(1)–C(1)–C(2)–C(3)
C(4)–N(1)–C(1)–C(2)
C(1)–C(2)–C(3)–C(4)
C(1)–N(1)–C(4)–C(3)
N(1)–C(4)–C(5)–O(1)
27.4(3)
–38.4(2)
–7.3(3)
33.34(19)
–52.69(18)

612 JOURNAL OF CHEMICAL RESEARCH 2010
to give a brown oil. The crude product was purified by column chro-
matography (flash silica gel, eluent: EtOAc/n-hexane 1:4) to give
a colourless liquid 2. (3.5 g, 87.1%)[α]20D = –69.2° (c = 1.2, CHCl3).
and cooled. A white solid was obtained and filtered to afford 4 (7.7 g,
85.0%), m.p. 74–76 °C, [α]25D = –57.1° (c = 1.11, CHCl3 ), (lit.10 m.p.
1
74.0–74.8 °C, [α]25 = –68° (c = 3, CH3OH ) ), H NMR(300MHz,
D
1
IR (cm−1): 1710–1740 cm−1; H NMR (300 MHz, CDCl3, ppm): δ
CDCl3, ppm): δ 1.51–1.75 (m, 4H, CH2CH2 ), 2.92–3.23 (m, 4H, OH,
NH, NCH2 ), 4.23–4.28 (m, 1H, NCH ), 7.13- 7.60 (m, 10H, ArH).
IR(cm−1): 3344, 2957, 1490, 1393, 751, 706 cm−1. Calcd for C17H19NO,
80.60; H, 7.56; N, 5.53. Anal. Found: C, 80.74; H, 7.63; N, 5.63%.
CIMS(m/z): 253(M+).
Crystallographic data for the structure reported in this paper
have been deposited with the Cambridge Crystallographic
Data Center as supplementary publications (no. CCDC-
251130). Copies of available materials can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retreiving.ht mL (or
from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK, fax: +44-1223-336033; or
deposit@ccdc.cam.ac.
1.18–1.23 (t, J = 6.8 Hz, 3H, CH3), 1.83–2.26 (m, 4H, CH2CH2),
3.35–3.58 (m, 2H, NCH2), 3.71 (s, 3H, OCH3), 4.03–4.21 (q, 2H,
OCH2), 4.24–4.38 (m, 1H, NCH ). CIMS(m/z): 201(M+).
(S)-N-ethoxycarbony - α, α -diphenyl-2-pyrrolidinemethanol (3):8,9
Bromobenzene (10.0 g, 63.5 mmol) in THF (30 mL) was added por-
tion-wise into a suspension of magnesium filings (1.5 g, 63.5 mmol)
and a little iodine in THF (30 mL) at 0°C. The heterogeneous mixture
was stirred for 0.5 h, and a solution of 2 4.0 g (20.0 mmo l) in THF
(30 mL) was added. The mixture was stirred at 0°C for 4 h. Saturated
ammonium chloride solution was added and the solution was filtered
through Celite. The residue was extracted with CHCl3(3 × 30 mL ),
the combined organic phase was washed with water, dried (anhydrous
MgSO4) and evaporated to give a yellow liquid 3, The yellow liquid
was dissolved in hot petroleum ether and cooled. A white solid was
obtained which was filtered and recrystallised from anhydrous ethanol
Received 27 June 2010; accepted 4 September 2010
Paper 1000225 doi: 10.3184/030823410X12868999388477
Published online: 24 November 2010
to afford 3 (4.9 g, 73.5%) as a white crystalline solid. m.p. 111–
1
113 °C, [α]25 = + 56.8° (c = 4.11, CH3OH). H NMR (300MHz,
D
CDCl3, ppm): δ 1.23–1.26 (t, J = 7.2 Hz,3H, CH3 ), 1.45–2.16 (m, 4H,
CH2CH2), 3.01 (m, 2H, NCH2), 3.38–3.46 (m, 1H), 4. 05–4.19 (q, J =
4.5 Hz, 2H, OCH2), 4.93 (m, 1H, NCH), 7.26–7.40 (m, 10H, ArH). IR
(cm−1): 3375, 1680 cm−1. Calcd for C20H23NO3: 73.82; H, 7.12; N,
4.30. Anal. Found: C, 73.66; H, 7.18; N, 4.28%. CIMS(m/z):
325(M+).
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