Synthesis and structure of a novel tridentate chiral-NHC ligand precursor

Article abstract of DOI:10.1515/HC.2011.042

A novel tridentate chiral imidazolium hexafluorophosphate, a precursor for N-heterocyclic carbene (NHC) ligand, was synthesized from (S)-proline in five steps in 24 % overall yield. The compound was characterized by NMR and elemental analysis. Its molecular structure was determined by X-ray diffraction analysis. This chiral compound has two stereogenic centers which are within two chelating side chains and its specific rotation is-19.6°. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.042

Heterocycl. Commun., Vol. 17(5-6), pp. 165–167, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.042
Preliminary Communication
Synthesis and structure of a novel tridentate chiral-NHC
ligand precursor
Longguang Yang1, Changsheng Cao1,*, Rui Sun1,
Yu Peng2, Lingzhi Zhang1, Zhan Shi2,
Results and discussion
Guangsheng Pang2 and Yanhui Shi1,3,
*
To explore new efficient chiral NHC ligands for asymmet-
ric catalysis, we prepared a novel chiral imidazolium salt 5
which is a tridentate chiral-NHC ligand precursor. Compound
5 was synthesized in five steps from (S)-proline in 24% over-
all yield (Scheme 1).
1 School of Chemistry and Chemical Engineering and
Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Xuzhou Normal University, Xuzhou,
Jiangsu 221116, PR China
Compounds 1 (Kelleher et al., 2010) and 2 (Da Silva et al.,
2002) were prepared from (S)-proline according to the litera-
ture procedures. The known compound 3 (Alcon et al., 2000)
was prepared by using a modified procedure to avoid chro-
matography for purification. The NH function on (S)-proline
was first protected by tert-butoxycarbonyl (Boc) group to
give compound 1 in 85% yield. After formation of diamide
2 in 60% yield (step 2), the Boc groups were removed and
replaced by benzyl (Bn) groups to give 3 in 92% yield. It is
worth noting that in step 3, NaOH and dichloromethane were
used as base and solvent, respectively, instead of Et3N and
tetrahydrofuran (THF) used in the literature to simplify the
workup. This modification allowed the resultant product 3 to
be purified by crystallization. The amide 3 was reduced by
LiAlH4 in step 4 to give amine 4, which is a direct precursor
to the desired final product 5. Cyclization of 4 in the presence
of CH(OEt)3 and NH4PF6 in step 5 yielded 5. However, it was
surprising that an attempted reaction with NH4Cl or NH4Br
instead of NH4PF6 did not furnish the corresponding cycliza-
tion product. Compound 5 was fully characterized by NMR
and gave satisfactory elemental analysis results. Its molecu-
lar structure was determined by means of X-ray diffraction
analyses (Figure 1).
2 State Key Laboratory of Inorganic Synthesis and
Preparative Chemistry, College of Chemistry, Jilin
University, Changchun, Jilin 130012, PR China
3 State Key Laboratory of Coordination Chemistry,
Nanjing University, Nanjing, Jiangsu 210093, PR China
*Corresponding authors
e-mail: yhshi_2000@126.com; chshcao@126.com
Abstract
A novel tridentate chiral imidazolium hexafluorophosphate, a
precursor for N-heterocyclic carbene (NHC) ligand, was syn-
thesized from (S)-proline in five steps in 24% overall yield.
The compound was characterized by NMR and elemental
analysis. Its molecular structure was determined by X-ray dif-
fraction analysis. This chiral compound has two stereogenic
centers which are within two chelating side chains and its spe-
cific rotation is -19.6°.
Keywords: chiral; imidazolium salt; NHC ligand;
(S)-proline; X-ray structure.
The bond length of C1-N1 [1.275(5) Å] lies in the expected
range of C=N double bond, and the distance of C1-N2 lies in
the range of C-N single bond. The five atoms of the imidazo-
lium ring are co-planar in the first approximation. The torsion
angle of C1, N2, C3, C2 is 1.56° and the torsion angle of N1,
C2, C3, N2 is 1.96°. The molecular structure also shows that
the configuration of the two chiral carbons (C5 and C17) are
S. Compound 5 exhibits two stereogenic centers, and each of
them is within one of two chelating side chains. Its specific
rotation in dichloromethane is -19.6°.
Introduction
N,N′-Disubstituted imidazolium salts are important pre-
cursors to N-heterocyclic carbenes (NHCs) (Kuehl, 2007;
Wüertz and Glorius, 2008; Díez-González et al., 2009;
Nolan, 2011). These electron-rich ligands have been widely
employed in organometallic catalysis, such as olefin meta-
thesis (Weskamp et al., 1998; Hoveyda and Schrock, 2001;
Trnka and Grubbs, 2001), carbon-carbon and carbon-
nitrogen cross-coupling (Hillier et al., 2002), hydrogena-
tion, and hydrosilylation (Lee et al., 2001). A large number
of chiral NHC ligands for asymmetric catalysis has been
developed (Cesar et al., 2004; Snead et al., 2008). Most chi-
ral NHC ligands are monodentate and bidentate systems, and
only few are tridentate.
Experimental section
General
All reagents were commercially available and used without further
purification. The 1H NMR (400 MHz) and 13C NMR (100 MHz)
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166 L. Yang et al.
Et3N
ClCO2iBu
COOH
COOH
(Boc)2O
+
+
H2N
NH2
N
H
N
Et3N, CH2Cl2
CH2Cl2
Boc
1
85% yield
step 1
60% yield
step 2
O
O
O
O
1) CF3COOH
1) LiAlH4, THF
2) HCl
NH HN
NH HN
2) PhCH2Br, NaOH
BocN
NBoc
BnN
NBn
92% yield
step 3
80% yield
step 4
2
3
CH(OEt)3, NH4PF6
THF
NaOH
NH HN
N
N
BnN
NBn
NBn
BnN
PF6
·4HCl
64% yield
step 5
4
5
Scheme 1 Synthesis of compound 5.
spectra were recorded on a Bruker DPX 400 spectrometer in CDCl3
at room temperature. Elemental analyses were performed on a
EuroVektor Euro EA-300 elemental analyzer. Optical rotation was
measured with an Autopol IV automatic polarimeter in acetone solu-
tion. Melting points were determined on a microscope melting point
apparatus. Compounds 1 and 2 are known and their 1H NMR spectra
were essentially identical with those of authentic samples were ob-
tained by using published procedures (Da Silva et al., 2002; Kelleher
et al., 2010). Compound 3 was obtained by using the procedure given
below, which is a modification of the published method (Alcon et al.,
2000). Compound 4 was used without characterization. New com-
pound 5 was characterized by 1H NMR, 13C NMR, elemental analy-
sis, and X-ray crystallographic analysis.
layer was separated, and the aqueous phase was extracted with dichlo-
romethane (2×10 mL). The extract was washed with brine, dried over
magnesium sulfate, concentrated, and treated with petroleum ether
(5 mL). The resultant white precipitate of 3 was collected: yield 92%;
mp 98.3–99.1°C; 1H NMR: δ 1.64–1.76 (4H, m), 1.79–1.86 (2H, m),
2.13–2.23 (2H, m), 2.31–2.38 (2H, m), 3.00–3.04 (2H, m), 3.11–3.19
(4H, m), 3.30–3.37 (2H, m), 3.48 (2H, d, J=12.0 Hz), 3.77 (2H, d,
J = 12.0 Hz), 7.24–7.32 (10H, m), 7.58 (2H, br s).
1,3-Bis(((S)-1-benzylpyrrolidin-2-yl)methyl)-4,5-
dihydro-1H-imidazol-3-ium hexafluorophosphate (5)
The diamine 3 (0.44 g, 1 mmol) was added in portions over 30 min to
a rapidly stirred suspension of LiAlH4 (0.304 g, 8 mmol) in dry THF
(15 mL) at 0°C. The mixture was allowed to warm to room tempera-
ture over 30 min and then heated under reflux for 24 h. A saturated
solution of NH4Cl (0.3 mL), a 15% solution of NaOH (0.3 mL) and
a saturated solution of NH4Cl (0.6 mL) were added successively to
the above mixture at 0°C. The solid material was removed by filtra-
tion and thoroughly washed with dichloromethane. The combined
organic solutions were dried over anhydrous Na2SO4 and then con-
centrated on a rotatory evaporator to give a yellow oil. This oil was
dissolved in absolute ethanol (2 mL) and the solution was treated
with concentrated HCl (0.3 mL). After removing most of the water
and ethanol, the residue was crystallized from absolute ethanol to
give the presumed product 4 as hydroscopic white solid.
(2S,2′S)-N,N′-(Ethane-1,2-diyl)bis(1-benzylpyrrolidine-
2-carboxamide) (3)
To diamide 2 (0.454 g, 1 mmol) cooled at 0°C was added trifluoro-
acetic acid (2 mL, 26 mmol) dropwise with stirring, and the result-
ing mixture was warmed up to room temperature and stirred for
30 min. After removal of the acid, the residue was treated with dichlo-
romethane (15 mL) and aqueous NaOH (pH 12, 1 mL). Benzyl bro-
mide (0.25 mL, 2.1 mmol) was added dropwise with vigorous stirring,
and the mixture was stirred for 6 h at room temperature. The organic
To the aqueous solution of salt 4 (1.1 g, 2 mmol), a 15% solution of
NaOH was added until the pH reached 11–12. The free amine was re-
covered by extracting the aqueous solution with diethyl ether (10 mL×2),
and evaporating the solvent. The solution of the free amine in dry THF
(15 mL) was treated with triethyl orthoformate (0.6 g, 4 mmol) and
NH4PF6 (0.33 g, 2 mmol). The mixture was heated at 80°C for 2 h. After
cooling to room temperature, the solids were removed and diethyl ether
was added to the filtrate. The white precipitate of 5 was collected, washed
with diethyl ether, and dried under reduced pressure: yield 0.7 g (51%
from 3); mp 119.0–120.3°C (from THF-ether); [α]25D=-19.6° [c=1.0,
1
DCM (dichloromethane)]; H NMR: δ 1.43–1.51 (2H, m), 1.59–1.68
(2H, m), 1.70–1.79 (2H, m), 1.94–2.04 (2H, m), 2.37 (2H, m), 2.84–2.89
(2H, m), 2.97–3.02 (2H, m), 3.21–3.32 (4H, m), 3.49 (2H, d, J=12.0 Hz),
3.63–3.70 (2H, m), 3.74–3.86 (4H, m), 7.23–7.32 (10H, m), 7.78 (1H, s);
Figure 1 Molecular structure of compound 5.
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Novel tridentate chiral-NHC ligand precursor 167
13C NMR: δ 23.4 (CH2), 27.9 (CH2), 49.8 (CH2), 51.0 (CH2), 54.5
(CH2), 59.7 (CH), 61.2 (CH2), 127.2 (CH), 128.5 (CH), 128.9 (CH),
139.2 (C), 158.0 (CH). Anal. calcd for C27H37F6N4P: C, 57.64; H, 6.63;
N, 9.96. Found: C, 57.28; H, 6.32; N, 10.19%.
from L-proline. X-ray crystal structure of {[Cu(N, N′-bis[(S)-
prolyl]ethylenediamine)]ClO4}2·(MeCN)2. Inorg. Chim. Acta
2000, 306, 116–121.
Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chiral N-heterocyclic
carbenes as stereodirecting ligands in asymmetric catalysis.
Chem. Soc. Rev. 2004, 33, 619–636.
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J. D. F. Study of the protonation/deprotonation sequence of two
polyamines: bis-[(2S)-2-pyrrolidinylmethyl] ethylenediamine
and spermidine by 1H and 13C nuclear magnetic resonance.
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benes in late transition metal catalysis. Chem. Rev. 2009, 109,
3612–3676.
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X-Ray crystallographic analysis of 5
The crystal for the solid state structure of compound 5 was obtained
by slow diffusion of ether into THF solution. Preliminary examina-
tion and data collection were carried out on a Rigaku Mercury CCD
device at the window of a sealed X-ray tube with graphite-mono-
chromated Mo Kα radiation (λ=0.71073 Å). Absorption correction
was performed by the SADABS program. The structure was solved
by directed methods using the SHELXS-97 program and refined by
full-matrix least squares techniques on F2. The single-crystal of 5 is
monoclinic, space group P2(1) with a=6.0816(12) Å, b=32.899(7)
Å, c=14.360(3) Å, α=90°, β=90.56(3)°, γ=90°, Mr=2250.30,
V=2873.0(10) Å3. The formula is C108H148F24N16P4, Z=1, µ (Mo
Kα)=0.157 mm-1, -7≤h≤7, -39≤k≤39, -17≤l≤17, total number of re-
flection=9845, number of independent reflections=5254, R=0.0538,
the largest difference peak and hole of electron density are 0.178 and
-0.145 Å-3, respectively. Selected bond lengths (Å) and angles (°):
N(1)-C(1) 1.275(5), N(1)-C(2) 1.453(5), N(1)-C(4) 1.448(5), N(2)-
C(1) 1.316(5), N(2)-C(3) 1.464(5), N(2)-C(16) 1.446(6), C(2)-C(3)
1.534(6), C(4)-C(5) 1.519(5), C(16)-C(17) 1.505(6), N(1)-C(1)-
N(2) 115.6(4), C(1)-N(1)-C(4) 125.1(4), C(1)-N(1)-C(2) 109.5(3),
C(2)-N(1)-C(4) 125.4(3), C(1)-N(2)-C(16) 125.8(4), C(1)-N(2)-
C(3) 108.7(3), C(3)-N(2)-C(16) 124.9(4), N(1)-C(2)-C(3) 103.7(3),
N(2)-C(3)-C(2) 102.4(3), C(4)-C(5)-C(6) 114.1(4), C(4)-C(5)-N(3)
109.0(3), C(16)-C(17)-C(18) 115.1(4), C(16)-C(17)-N(4) 112.3(4).
CCDC-825945 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
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complex bearing an imidazol-2-ylidene ligand as alkene hydro-
genation catalyst. Organometallics 2001, 20, 1255–1258.
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Acknowledgments
Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W.
A. A. Novel class of ruthenium catalysts for olefin metathesis.
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We are grateful to the foundation of the Qing Lan Project (08QLT001
and 08QLD006) of the Jiangsu Education Committee, SRF for
ROCS, SEM, NSFC (21071121, 21172188 and 21104064), PAPD
and the State Key Laboratory of Inorganic Synthesis and Preparative
Chemistry at Jilin University (2009-06) for financial support.
References
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Received August 20, 2011; accepted October 23, 2011; previously
published online November 29, 2011
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