Zinc complexes formed by 2,2′-bipyridine and 1,10-phenanthroline moieties combined with 2-azanorbornane: Modular chiral catalysts for aldol reactions

Article abstract of DOI:10.1039/c6nj02251k

Chiral scaffolds of 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane were used for the construction of new modular catalysts containing complexing moieties pyridine, 2,2′-bipyridine and 1,10-phenanthroline appended by an imine linkage. The coordin

Full text of DOI:10.1039/c6nj02251k

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DOI: 10.1039/C6NJ02251K
Zinc Complexes Formed by 2,2’-Bipyridine and 1,10-Phenanthroline Moieties
Combined with 2-Azanorbornane: Modular Chiral Catalysts for Aldol Reaction
Elżbieta Wojaczyńska,a* Jacek Skarżewski,a Łukasz Sidorowicz,a
Robert Wieczorek,b and Jacek Wojaczyńskib
a
Departament of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology,
Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
b
Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50-383 Wrocław, Poland
*Corresponding author; phone: +0048713202410, fax +0048713202427,
e-mail: elzbieta.wojaczynska@pwr.edu.pl
1

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Abstract
Chiral scaffolds of 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane were used for
the construction of new modular catalysts containing complexing moieties of pyridine, 2,2’-
bipyridine, and 1,10-phenanthroline appended by imine linkage. Coordination abilities of the
new ligands towards Zn(II) were investigated by NMR and UV spectroscopy. Plausible
structures of the [ZnL2]2+ and [ZnLXn](2-n)+ complexes formed were established by
comparison of the experimental and DFT-calculated NMR spectra. The catalytic application
of the [ZnLXn](2-n)+-type complexes in asymmetric aldol reaction of ketones with aromatic
aldehydes produced an excess of the respective syn-aldols in up to >98% ee.
2

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Introduction
A quest for new, effective tools for asymmetric synthesis led to the concept of modular
chiral ligands and catalysts – assemblies of individual fragments performing diverse and
complementary roles.1 Each of these parts can be appropriately modified to fulfill the exact
requirements of the catalyzed reaction. In this approach one combines various functionalities,
already known for their basicity and stereodifferentiating properties, with the achiral ligands
binding metal ions serving as a Lewis acid center. Among possible elements of these modular
catalysts, N,N-bidendate ligands, with appropriately oriented nitrogen atoms that enable
formation of strong complexes are particularly promising. The versatility of aromatic
diamines: 2,2’-bipyridine, and 1,10-phenanthroline prompted various research groups to use
these motifs for the construction of chiral catalysts for stereoselective processes.2 As a recent
example, a tridendate ligand containing phenanthroline attached to an axially chiral
binaphthyl moiety was found effective in enantioselective addition of diethylzinc to aromatic
aldehydes (with up to 95% ee).3
In this contribution, we describe the use of two bicyclic chiral scaffolds: 2-
azabicyclo[2.2.1]heptane (2-azanorbornane) and 2-azabicyclo[3.2.1]octane (bridged azepane)
for the construction of bifunctional catalysts containing metal-complexing moieties of 1,10-
phenanthroline and 2,2’-bipyridine (Figure 1). We propose a simple method of module
assembling by imine linkage which introduces a favorably located additional donor atom.
Changing the ring size of the chiral scaffold, configuration of stereocenters and the
heteroaromatic amine should allow for fine tuning of the catalytic properties and optimization
of asymmetric induction.
Figure 1. Modular chiral catalysts used in this study
2-Azanorbornane bearing a stable bicyclic skeleton with an intrinsic chirality has been
recognized as a versatile scaffold for asymmetric synthesis.4 This system is readily available
3

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via the stereoselective aza-Diels-Alder reaction of chiral imines and cyclopentadiene. Its
preparation in both enantiomeric forms in a gram or even kilogram scale has been
described.5,6 Derivatives of 2-azabicyclo[2.2.1]heptane after various modifications of the
basic structure lead to a number of (N, O), (N, N), (N, P), and (N, S)-donating ligands, which
have already been applied in various enantioselective transformations.4,7 Thus, both alcohol
epimers (1 and 2), differing in the configuration on the 3-C stereocenter can be prepared from
the separated isomeric cycloadducts formed in one aza-Diels-Alder reaction. In the course of
our earlier studies, we have observed that upon attempted nucleophilic substitution of
hydroxyl group in the alcohol 2 a stereoselective ring expansion took place, yielding 2-
azabicyclo[3.2.1]octane.8 In this way, amines based on the bridged piperidine (3/4) or azepane
(5/6, Figure 2) can be prepared and applied to the construction of bifunctional catalysts
bearing a stereodifferntiating bicyclic skeleton with a tetrtiary amine function.
Figure 2. Chiral bicyclic precursors of modular ligands used in this study
Among catalytic reactions leading to the formation of new C-C bonds, the aldol reaction
plays an important role. In its asymmetric variant, two stereocenters can be generated with
high stereoselectivity.9 Nature exploits this reaction catalyzed by aldolases for biosynthesis.
While type I aldolases operate via an enamine mechanism, type II enzymes use enolate-type
activation with a metal cofactor (typically Zn2+ ion). Accordingly, both organocatalysts and
various metal complexes (in particular, Zn(II)-based catalysts) were effective in diastereo-
and enantioselective process.9,10 In this contribution, we describe our studies on the
application of zinc complexes of phenanthroline- and bipyridine-derived chiral hybrid
catalysts in the stereoselective aldol reaction.
Experimental Section
Optical rotations were measured using an Optical Activity Ltd. Model AA-5 automatic
polarimeter.; [α]D values are given in 10−1 deg cm2 g−1. IR spectra were recorded on a Perkin
1
Elmer 1600 FTIR spectrophotometer. H NMR and 13C NMR spectra were measured on a
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Bruker Avance (1H, 500 MHz) spectrometer using solvent residual peak (chloroform-d, δ(1H)
= 7.28 ppm, δ(13C) = 77.0 ppm as a reference. High resolution mass spectra were recorded
using a microTOF-Q and WATERS LCT Premier XE instruments utilizing electrospray
ionization mode. Chromatographic separations were performed on silica gel 60 (70-230 mesh).
Thin layer chromatography was carried out using silica gel 60 precoated plates. HPLC
analyses were performed on Chiracel OD-H or Chiralpak AD-H chiral columns (flow rate of
1.0 mL/min).
Preparation of compounds
Alcohols 1 and 2 were prepared according to a literature procedure.11 Their Swern
oxidation led to the corresponding aldehydes.12 Amine 3 was synthesized from aldehyde 7 in
a two-step procedure as recently described.13
Amine 4 was prepared in the analogous manner from the respective endo aldehyde
obtained from alcohol endo-2. Amines based on a bridged azepane skeleton 5, 6 were
obtained from alcohols 1 and 2, respectively, as described prevously.8
20
(1S,3S,4R,1’S)-4. Light yellow oil (0.38 g, 70%). [α]D = −23.5 (1.15, CH2Cl2). IR
1
(film): νmax/cm-1 3024, 2967, 2870, 1603, 1492, 1452, 1304, 1162, 1027, 766, 701. H NMR
(500 MHz, CDCl3) δ = 1.04-1.09 (2 H, m), 1.27-1.39 (2 H, m), 1.30 (3 H, d, J = 6.5 Hz),
1.55-1.60 (2 H, m), 1.62-1.69 (1 H, m), 1.85-1.89 (1 H, m), 2.10 (1 H, dd, J1 = 9.0 Hz, J2 =
2.5 Hz), 2.28 (1 H, d, J = 4.0 Hz), 2.58 and 2.72 (2 H, ABX, JAB = 13.0 Hz, JAX = 9.0 Hz, JBX
13
= 2.5 Hz), 2.90 (1 H, s), 3.59 (1 H, q, J = 6.5 Hz), 7.20-7.34 (5 H, m). C NMR (125 MHz,
CDCl3) δ = 22.7, 25.2, 29.1, 35.2, 40.7, 48.7, 58.9, 60.3, 70.6, 126.6, 127.4, 128.3, 146.3.
HRMS (ESI-TOF): m/z calculated for (C15H23N2)+ ([M+H]+) 231.1861; found 231.1865.
20
(1S,4R,5R,1’S)-6. Yellow oil (0.40 g, 48%). [α]D = −19.8 (0.61, CH2Cl2). IR (film):
1
νmax/cm-1 3024, 2935, 1601, 1492, 1452, 1370, 1212, 1112, 1028, 766, 701. H NMR (500
MHz, CDCl3) δ = 1.03-1.07 (1 H, m), 1.14-1.21 (1 H, m), 1.25 (3 H, d, J = 6.6 Hz), 1.30-1.36
(2 H, m), 1.63-1.79 (6 H, m), 1.90 (1 H, d, J = 11.6 Hz), 2.13-2.15 (1 H, m), 2.43 (1 H, dd, J1
= 11.6 Hz, J2 = 3.8 Hz), 2.73-2.78 (1 H, m), 2.96-2.98 (1 H, m), 3.36 (1 H, q, J = 6.6 Hz),
7.21-7.24 (1 H, m), 7.28-7.36 (4 H, m). 13C NMR (125 MHz, CDCl3) δ = 21.0, 22.1, 27.9,
33.0, 41.6, 50.6, 51.1, 57.6, 62.0, 126.7, 127.6, 128.3, 146.0. HRMS (ESI-TOF): m/z
calculated for (C15H23N2)+ ([M+H]+) 231.1861; found 231.1870.
Synthesis of imines. Amine 3 (0.12 g, 0.5 mmol) and 2-pyridinecarboxaldehyde (0.054 g,
0.5 mmol) were dissolved in 8 mL of dichloromethane and stirred overnight at room
temperature over anhydrous Na2SO4. The solution was filtered, and solvent was removed
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under reduced pressure. Washing with n-hexane/diethyl ether mixture (1:1) yielded
compound 9 as a yellow solid.
A similar procedure was applied to the synthesis of derivatives 10 and 11 using 2,2’-
bipyridyl-6-carboxaldehyde and 1,10-phenanthroline-2-carboxaldehyde, respectively. These
aldehydes were prepared from their parent compounds (2,2’-bipyridyl and 1,10-
phenanthroline) using the adopted literature procedure14 leading to primary alcohols which
were oxidized under Swern conditions. 1,10-Phenanthroline-2-carboxaldehyde was also
reacted with amines 4, 5, and 6 to yield ligands 12, 13, and 14, respectively. All imines were
found unstable on silica and attempts of chromatographic purification were unsuccessful.
20
(1S,3R,4R,1’S)-9. Yellow oil (0.16 g, 95%). [α]D = −38.4 (0.56, CH2Cl2). IR (KBr):
νmax/cm-1 3061, 3026, 2969, 2869, 1647, 1587, 1567, 1468, 1453, 1305, 1165, 774, 754, 701.
1H NMR: δH (500 MHz; CDCl3; Me4Si) 1.29-1.44 (3 H, m), 1.40 (3 H, d, 6.5 Hz), 1.61-1.68
(1 H, m), 1.83-1.89 (1 H, m), 1.99-2.04 (1 H, m), 2.30 (1 H, bd, J = 6.5 Hz), 2.32 (1 H, s),
2.54 (1 H, dd, J1 = 11.3 Hz, J2 = 2.6 Hz), 3.04 (1 H, t, J = 10.2 Hz), 3.54 (1 H, q, J = 6.5 Hz),
3.67 (1 H, s), 7.25-7.30 (2 H, m), 7.33 (t, 2H, J = 7.3 Hz), 7.41 (2 H, bd, J = 7.0 Hz), 7.67 (1
H, td, J1 = 7.8 Hz, J2 = 1.7 Hz), 7.75 (1 H, s), 7.84 (1 H, d, J = 7.9 Hz), 8.60 (1 H, ddd, J1 =
4.8 Hz, J2 = 1.7 Hz, J3 = 0.9 Hz). 13C NMR: δC (125 MHz; CDCl3; Me4Si) 22.6 (two
overlapping signals), 28.9, 35.0, 39.7, 59.0, 61.1, 66.3, 69.7, 121.3, 124.4, 127.4, 128.2, 128.4,
136.4, 145.2, 146.2, 149.3, 161.9. HRMS (ESI-TOF): m/z calculated for (C21H26N3)+
([M+H]+) 320.2127; found 320.2136.
20
(1S,3R,4R,1’S)-10. Yellow oil (0.19 g, 92%). [α]D = −30.2 (0.63, CH2Cl2). IR (KBr):
νmax/cm-1 3435, 2968, 1868, 1645, 1581, 1563, 1454, 1430, 1304, 1165, 1076, 990, 779, 701.
1H NMR: δH (500 MHz; CDCl3; Me4Si) 1.29-1.45 (3 H, m), 1.38 (3 H, d, J = 6.0 Hz), 1.58-
1.67 (1 H, m), 1.89 (1 H, d, J = 10.0 Hz), 2.02-2.06 (1 H, m), 2.31-2.33 (2 H, m), 2.63 (1 H,
dd, J1 = 11.4 Hz, J2 = 2.0 Hz), 3.07 (1 H, t, J = 10.4 Hz), 3.56 (1 H, q, J = 6.3 Hz), 3.68 (1 H,
s), 7.28-7.38 (5 H, m), 7.43 (2 H, d, J = 7.2 Hz), 7.80-7.92 (4 H, m), 8.38 (1 H, dd, J1 = 7.8
Hz, J2 = 1.0 Hz), 8.46 (1 H, dt, J1 = 8.0 Hz, J2 = 1.0 Hz), 8.69 (1 H, dd, J1 = 4.8 Hz, J2 = 1.8
Hz) ppm. 13C NMR: δC (125 MHz; CDCl3; Me4Si) 22.6 (2 signals), 29.0, 35.0, 39.7, 59.0,
61.1, 66.3, 69.7, 120.9, 121.1, 121.8, 123.8, 127.4; 128.3, 128.4, 136.9, 137.2, 146.3, 149.2,
154.4, 155.6, 155.9, 162.5. HRMS (ESI-TOF): m/z calculated for (C26H29N4)+ ([M+H]+)
397.2392; found 397.2371.
20
(1S,3R,4R,1’S)-11. Yellow solid (0.19 g, 90%). [α]D = −35.6 (0.45, CH2Cl2). Mp 82-
83 °C. UV-vis: λmax (CH2Cl2, log ε) = 233 (4.64), 277 (4.48), 309 sh, 330 (3.55), 346 (3.19).
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IR (KBr): νmax/cm-1 3420, 3028, 2967, 2868, 1709, 1644, 1554, 1491, 1450, 1304, 1164, 1081,
1026, 856, 701, 625. 1H NMR: δH (500 MHz; CDCl3; Me4Si) 1.27-1.48 (3 H, m), 1.42 (3 H, d,
J = 6.6 Hz), 1.62-1.67 (1 H, m), 1.91-1.92 (1 H, m), 2.02-2.07 (1 H, m), 2.31-2.32 (1 H, m),
2.43 (1 H, dd, J1 = 10.0 Hz, J2 = 4.0 Hz), 2.77 (1 H, ddd, J1 = 12.0 Hz, J2 = 4.0 Hz, J3 = 1.6
Hz), 3.11 (1 H, t, J = 11.0 Hz), 3.58 (1 H, q, J = 6.4 Hz), 3.69 (1 H, bs), 7.30 (1 H, t, J = 7.4
Hz), 7.35 (2 H, t, J = 7.3 Hz), 7.44 (2H, d, J = 7.2 Hz), 7.66 (1 H, dd, J1 = 8.0 Hz, J2 = 4.4
Hz), 7.78 and 7.81 (2 H, ABq, J = 8.8 Hz), 8.21 and 8.27 (2 H, ABq, J = 8.4 Hz), 8.25 (1 H, dd,
J1 = 8.0 Hz, J2 = 1.8 Hz), 8.47 (1 H, s, NH), 9.23 (1 H, dd, J1 = 4.4 Hz, J2 = 1.8 Hz). 13C
NMR: δC (125 MHz; CDCl3; Me4Si) 22.7, 22.9, 28.9, 34.9, 39.3, 59.1, 61.2, 66.0, 69.4, 120.4,
123.1, 126.4, 127.2, 127.5, 128.27, 128.30, 128.9, 129.3, 136.2, 136.4, 145.6, 146.1, 146.3,
150.6, 155.0, 163.0. HRMS (ESI-TOF): m/z calculated for (C28H28N4Na)+ ([M+Na]+)
443.2212; found 443.2213.
20
(1S,3R,4R,1’S)-12. Yellow oil (0.16 g, 71%). [α]D = +17.8 (0.62, CH2Cl2). IR (KBr):
νmax/cm-1 3435, 2965, 2868, 1644, 1618, 1491, 1451, 1304, 1161, 856, 702. 1H NMR: δH (500
MHz; CDCl3; Me4Si) 1.04-1.13 (2 H, m), 1.24-1.31 (1 H, m), 1.44 (3 H, d, J = 6.5 Hz), 1.54-
1.58 (1 H, m), 1.80-1.84 (1 H, m), 1.90-1.97 (1 H, m), 2.37 (1 H, d, J = 4.0 Hz), 2.59 (1 H, dd,
J1 = 10.0 Hz, J2 = 3.5 Hz), 2.97 (1 H, bs), 3.62 (1 H, ddd, J1 = 12.0 Hz, J2 = 10.0 Hz, J3 = 1.5
Hz), 3.67 (1 H, q, J = 6.5 Hz), 3.93 (1 H, ddd, J1 = 12.0 Hz, J2 = 3.5 Hz, J3 = 1.5 Hz), 7.22 (1
H, t, J = 7.5 Hz), 7.30 (2 H, t, J = 7.5 Hz), 7.37 (2 H, d, J = 7.4 Hz), 7.66 (1 H, dd, J1 = 8.0 Hz,
J2 = 4.3 Hz), 7.83 (2 H, s), 8.30 and 8.44 (2 H, ABq, J = 8.5 Hz), 8.27 (1 H, dd, J1 = 8.0 Hz, J2
= 2.0 Hz), 8.95 (1 H, s, NH), 9.24 (1 H, dd, J1 = 4.3 Hz, J2 = 2.0 Hz). 13C NMR: δC (125
MHz; CDCl3; Me4Si) 22.9, 25.3, 28.7, 34.9, 40.5, 59.3, 60.4, 67.8, 68.7, 120.4, 123.2, 126.5,
126.6, 127.38, 127.43, 128.3, 128.9, 129.4, 136.2, 136.6, 145.8, 146.2, 146.3, 150.7, 155.0,
163.7. HRMS (ESI-TOF): m/z calculated for (C28H29N4)+ ([M+H]+) 421.2392; found
421.2381.
20
(1S,4S,5R,1’S)-13. Yellow solid (0.14 g, 69%). [α]D = +100.0 (0.57, CH2Cl2), Mp 52-
54 °C. IR (KBr): νmax/cm-1 3443, 3059, 3026, 2932, 2863, 1711, 1641, 1491, 1451, 1370,
1
1134, 1100, 953, 857, 771, 702. H NMR: δH (500 MHz; CDCl3; Me4Si) 1.13-1.17 (1 H, m),
1.34 (3 H, d, J = 6.5 Hz), 1.58-1.63 (1 H, m), 1.76-1.82 (1 H, m), 1.90-1.96 (1 H, m), 2.25-
2.28 (1 H, m), 2.46 (1 H, d, J = 10.4 Hz), 2.72 (1 H, dd, J1 = 12.7 Hz, J2 = 4.0 Hz), 2.97 (1 H,
d, J = 12.6 Hz), 3.28 (1 H, t, J = 5.0 Hz), 3.45 (1 H, bs), 3.64 (1 H, q, J = 6.5 Hz), 7.20 (1 H, t,
J = 7.2 Hz), 7.28 (2 H, t, J = 7.4 Hz), 7.39 (2 H, d, J = 7.3 Hz), 7.67 (1 H, dd, J1 = 8.0 Hz, J2
= 4.3 Hz), 7.85 and 7.87 (2 H, ABq, J = 8.8 Hz), 8.35 and 8.61 (2 H, ABq, J = 8.3 Hz), 8.29 (1
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H, dd, J1 = 8.1 Hz, J2 = 1.7 Hz), 8.95 (1 H, s, NH), 9.25 (1 H, dd, J1 = 4.3 Hz, J2 =1.7 Hz). 13C
NMR: δC (125 MHz; CDCl3; Me4Si) 22.1, 23.2, 27.9, 32.7, 41.6, 49.7, 57.2, 62.3, 70.3, 120.8,
123.1, 126.5, 127.2; 127.5, 127.7, 128.2, 128.9, 129.3, 136.2, 136.6, 145.7, 146.2, 146.4,
150.6, 155.5, 161.2. HRMS (ESI-TOF): m/z calculated for (C28H28N4Na)+ ([M+Na]+)
443.2212; found 443.2213. 421.2146.
20
(1S,4R,5R,1’S)-14. Yellow solidifying oil (0.20 g, 95%). [α]D = +40.7 (0.36, CH2Cl2).
IR (KBr): νmax/cm-1 3430, 2930, 2860, 1641, 1617, 1554, 1490, 1451, 1370, 1113, 856, 701.
1H NMR: δH (500 MHz; CDCl3; Me4Si) 1.25-1.29 (4 H, m), 1.59-1.62 (1 H, m), 1.78-1.85 (2
H, m), 2.27-2.28 (1 H, m), 2.61 (1 H, d, J = 11.2 Hz), 2.59-2.72 (2 H, m), 3.35 (1 H, bs), 3.63-
3.68 (2 H, m), 7.20 (1 H, t, J = 7.2 Hz), 7.30 (2 H, t, J = 7.4 Hz), 7.42 (2 H, bd, J = 7.4 Hz),
7.66 (1 H, dd, J1 = 8.0 Hz, J2 = 4.3 Hz), 7.83 and 7.85 (2 H, ABq, J = 8.8 Hz), 8.35 and 8.54
(2 H, ABq, J = 8.3 Hz), 8.28 (1 H, dd, J1 = 8.0 Hz, J2 = 1.8 Hz), 8.85 (1 H, s, NH), 9.23 (1 H,
13
dd, J1 = 4.4 Hz, J2 = 1.7 Hz). C NMR: δC (125 MHz; CDCl3; Me4Si) 22.1, 23.2, 27.9, 32.7,
41.6, 49.7, 57.2, 62.3, 70.3, 120.7, 123.1, 126.5, 127.2; 127.6, 128.3, 128.6, 128.9, 129.3,
136.2, 136.5, 145.7, 146.2, 150.5, 155.3, 161.5. HRMS (ESI-TOF): m/z calculated for
(C28H28N4Na)+ ([M+Na]+) 443.2212; found 443.2216.
Typical procedure for aldol reaction15
A chiral ligand (9-14, 0.05 mmol) and 0.05 mmol of zinc(II) acetate were dissolved in 2
mL of chloroform-cyclohexanone (1:1) mixture and stirred for 10 minutes at room
temperature. The appropriate aldehyde (0.5 mmol) was then added and the resulting solution
was stirred for 6 days at room temperature. The reaction mixture was purified by column
chromatography on silica (n-hexane/ethyl acetate 3:1). Diastereomeric excess and
enantiomeric excess were determined using chiral HPLC analysis. For 2-[hydroxy-(4-
nitrophenyl)methyl]cyclohexanone product Chiralpak AD-H column was used (n-
hexane/isopropanol 90/10, 1.0 mL/min, 254 nm): tR(syn) 17.1 min, 20.4 min, tR(anti) 22.7
min, 30.8 min.
In modified variants of the procedure zinc acetate was replaced with zinc triflate; in
certain cases 0.05 mmol acetic acid was added together with zinc(II) salt. Chosen reactions
were conducted at 273 K.
Theoretical calculations
Molecular orbital studies on ligands 10, 11 and their Zn(II) complexes were performed
on the DFT level of theory using Gaussian 09 suite of programs16 with the M06 hybrid
functional17 and 6-311G(d,p) basis set. The PCM (IEFPCM) implicit model18 of methanol
environment were embodied to the DFT calculations. Proton nuclear magnetic resonance
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(NMR) shifts of investigated complexes in solvent have been computed on the basis of
density functional theory by applying the gauge-including atomic orbital method.19
Results and Discussion
Synthesis of hybrid ligands
We decided to prepare a series of new hybrid catalysts using the reaction of aldehyde
derivatives of phenanthroline, bipyridyl and pyridine with enantiopure primary amines based
on the bicyclic skeletons. Alcohol exo-(1S,3R,4R,1’S)-111 was oxidized to the aldehyde 7
under Swern conditions;12 further conversion to oxime and its reduction yielded the amine 3
in 48% overall yield (Scheme 1).13 Its ring-expanded isomer was prepared from the alcohol 1
as well. The already described8 direct nucleophilic substitution using a reaction with HN3
under Mitsunobu conditions resulted in the ring expansion and the corresponding azide
(1S,4S,5R,1’S)-8 was obtained. It was reduced to the amine 5 (81% overall yield, Scheme 1).
Similar procedures were used for preparation of amines 4 and 6 starting from alcohol endo-
(1S,3S,4R,1’S)-2 (Scheme 2). All four amines 3-6 were reacted with 1,10-phenanthroline-2-
carboxaldehyde to give isomeric imines: two 2-azanorbornyl derivatives 11, 12 and two
compounds based on the bridged azepane skeleton 13, 14 (Scheme 3). For comparison, also
2-pyridyl and 6-(2,2’-bipyridyl) derivatives (9 and 10, respectively) were prepared from
1
amine (1S,3R,4R,1’S)-3 (Scheme 3). All new hybrid ligands were fully characterized by H
NMR, 13C NMR, IR and HRMS which confirmed their identy.
Scheme 1. Synthesis of amines 3, 5.8,13
Scheme 2. Synthesis of amines 4, 6.
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Scheme 3. Synthesis of imines 9-14.
Zinc(II) coordination of hybrid ligands – spectroscopic studies
Coordination ability of the new hybrid ligands 9-11 and 14 was investigated by 1H NMR
spectroscopy. Methanol-d4 solution of zinc acetate, zinc chloride or zinc trifluoromethane-
sulfonate was added stepwise to the solution of compound 11 and the process was monitored
by 1H NMR. The representative spectra obtained during titration with Zn(OAc)2 are shown in
Figure 3. Addition of 0.1 equivalent of this salt to the solution of ligand 11 resulted in
formation of new species represented by a new set of 1H NMR resonances which were visible
together with the spectral lines of the starting compound. The formed complex predominated
after addition of 0.5 equivalent of zinc acetate (Figure 3, Trace B). An identical spectrum was
obtained when zinc chloride or zinc triflate were used as a metal source. A diverse behavior,
however, was observed upon further addition of Zn(II) salt to the obtained intermediate. In the
case of Zn(OAc)2, a stepwise disappearance of resonances of this complex was accompanied
by the building up of a new set attributed to the final form, the only one present after the
addition of 1 equivalent of Zn(II) salt. Similar changes were noted for ZnCl2 addition, though
line broadening and formation of a precipitate was observed. Interestingly, additional portions
of Zn(OTf)2 did not cause any significant alteration of the spectrum shown in Trace B of
Figure 3. These observations can be accounted for by a formation of two types of zinc
complexes during titration of 11 with zinc acetate: [ZnL2]2+, in which two ligands 11 are
coordinated to zinc(II) cation, and [ZnLXn](2-n)+ (n = 1, 2), with one ligand 11 replaced by
acetate(s) (Figure 4). The first one is formed independently on the metal source. In case of
ZnCl2 titration, the final form is presumably polymeric. Only the dimeric complex [ZnL2]2+ is
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formed when Zn(OTf)2 is used since the weakly coordinating triflate ion is not able to replace
phenanthroline derivative in the coordination sphere.
1
Figure 3. 500 MHz H NMR spectra of compound 11 (A) and its complexes formed
upon addition of 0.5 equivalent (B) and 1 equivalent (C) of zinc acetate. The most
characteristic changes of positions of resonances are indicated by straight lines. All spectra
were measured in methanol-d4 at 300 K.
(2-n)+
(X)n
N
Zn
N
N
N
n = 1 or 2
[ZnLXn](2-n)+
Figure 4. Two forms of Zn(II) complexes of ligand 11 observed during NMR
experiments
In all cases, the possible interconversion between uncoordinated ligand, [ZnL2]2+ and
[ZnLXn](2-n)+complexes was slow on the NMR scale: each form produced a separate set of
1
sharp H NMR signals and their positions remained constant in the appropriate range of zinc
salt concentrations.
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Complex containing acetate ligand(s) can be converted into [ZnL2]2+ form by addition of
compound 11 to the methanolic solution of [ZnLXn](2-n)+. Complex [ZnL2]2+ was found
insoluble in chloroform. When ligand 11 and zinc acetate were mixed in methanol in 2:1 ratio,
1
evaporated to dryness and the residue was dissolved in chloroform-d, the H NMR spectrum
showed the presence of equimolar amounts of [ZnLXn](2-n)+ and the uncomplexed ligand.
When we mixed compound 11 and zinc triflate in methanol in 1:1 ratio, the residue obtained
after solvent removal was insoluble in chloroform-d, and the 1H NMR measured in methanol-
d4 revealed the presence of [ZnL2]2+ complex, in agreement with previous observations that
for OTf− anion a monomeric complex was not formed.
Further information about the structures of the zinc(II) complexes comes from the
1
analysis of NMR chemical shifts. A complete assignment of H and 13C NMR signals was
based on correlations observed in two-dimensional spectra (1H-1H COSY, 1H-13C HMQC, 1H-
13C HMBC) and is given in Table S1 (supporting Information). The most characteristic shift
changes are shown in Figure 3 by straight lines and in Table 1. The differences of resonance
positions of complex [ZnLXn](2-n)+ and ligand 11 (Table 1, entry 4) can be attributed to the
coordination of metal ion. The data shown in Table 1 clearly demonstrate that the most
pronounced changes upon formation of Zn(II) complex are observed for phenanthroline
fragment and for protons 1” and 3” which indicates the engagement of aromatic amine and
imine nitrogen atom in binding of metal ion. In contrast, the chemical shifts of 2-
azanorbornane fragment and its 2-substituent remain practically unaffected suggesting that
tertiary amine is not involved in coordination. Two five-membered chelate rings are thus
formed, in analogy to the known complexes of phenanthroline ligands bearing appropriately
located imine, oxime or pyridine fragment.20 The coordination sphere of zinc(II) is
1
presumably filled by acetate(s), although the separate H NMR methyl signal of the
coordinated anion(s) could not be observed due to the exchange with the free CH3COO− even
1
at 200 K. A similar H NMR pattern was observed for the analogous cadmium(II) complex,
obtained by addition of 1 equivalent of Cd(II) acetate to the ethanolic solution of ligand 11
(Figure S9, Supporting Information). The differences of chemical shifts can be attributed to
the bigger size of Cd2+ ion and to the presence of ethanol.
1
In contrast, significant H NMR shift changes were observed upon formation of
[ZnL2]2+ complex. They can also be in part attributed to coordination of metal ion, but the
most pronounced changes are connected with the mutual influence of two ligand molecules.
To estimate this effect, differences of chemical shifts of [ZnL2]2+ and [ZnLXn](2-n)+ can be
calculated (Table 1, entry 5). The aromatic ring current of phenanthroline fragment causes
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upfield shifts of all protons of 2-azanorbornane part of the second coordinated ligand. In
particular, signals of 5-H protons found at 0.25 and -1.46 ppm can be regarded as a diagnostic
feature of formation of [ZnL2]2+ complex. Significant upfield shifts were also found for the
fragments directly attached to the bicyclic skeleton (1’-H, 1’-Me, 1”-H) and for the part of
phenanthroline protons while the location of the remaining protons of the aromatic amine and
3”-H in the deshielding region resulted in their downfield chemical shifts.
1
Table 1. Chosen H NMR chemical shifts of ligand 11 and its zinc
complexes (methanol-d4, 300 K; L = ligand 11, X = OAc−). Numbering
scheme for ligand 11 is shown. Entries 4 and 5 show the chemical shift
changes (see the text for details)
Entry
1
Species
1
3
4
5
1”
3”
P3 P4
P8
P9
1.38 2.71
1.71 3.11
-1.46 2.50
0.25 3.04
1.41 2.89
1.69 3.45
0.03 0.18
-0.02 0.34
-2.87 -0.39
-1.44 -0.41
Ligand 11
3.72 2.49 2.31
3.36 1.06 0.86
8.27 8.23 8.42 7.79 9.10
8.84 8.88 9.45 7.63 7.63
7.78 8.12 8.91 7.99 9.08
-0.49 -0.11 0.49 0.20 -0.02
1.06 0.76 0.54 -0.36 -1.45
2
3
4
5
[ZnL2]2+
[ZnLXn](2-n)+ 3.73 2.57 2.45
Difference
0.01 0.08 0.14
3-1
Difference
-0.37 -1.51 -1.59
2-3
Chemical shift changes caused by coordination of Zn2+ ion (for [ZnLXn](2-n)+ and
[ZnL2]2+ complexes) and aromatic ring current (for [ZnL2]2+) were also observed in 13C NMR
spectra (Supporting Information, Table S2). They confirm the participation of phenanthroline
and imine nitrogen atoms in the formation of metal complex.
Zinc acetate titration of compound 14 containing the phenanthroline fragment attached to
1
a ring-expanded skeleton resulted in similar H NMR spectral changes as for the isomeric
ligand 11. A stepwise formation of [ZnL2]2+ and [ZnLXn](2-n)+ forms was observed, and
general tendencies of chemical shift changes resembled those described above for 2-
azanorbornane derivative. Also the replacement of phenanthroline in compound 11 with 2,2’-
bipyridyl did not cause qualitative differences in the ligand coordination modes, as it can be
seen in Figure 5 showing zinc acetate titration of derivative 10. Chemical shifts of the formed
complexes are given in Tables S3 and S4 (Supporting Information) along with the differences
showing coordination-induced changes and changes caused by the ring current effect of the
neighboring aromatic moieties. These values indicate zinc chelation by the three nitrogen
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atoms of bipyridyl and the appropriately located imine and the placement of the bicyclic
fragment in the vicinity of the aromatic fragment of the second ligand in the [ZnL2]2+ complex.
1
Figure 5. 500 MHz H NMR spectra of compound 10 (A) and its complexes formed
upon addition of 0.5 equivalent (B) and 1 equivalent (C) of zinc acetate. The most
pronounced changes of positions of resonances are indicated with straight lines. All spectra
were measured in methanol-d4 at 300 K.
In contrast, a removal of one of pyridine subunits of 10 leads to a complete different
picture. Addition of zinc acetate to the methanol-d4 solution of the 2-azanorbornane-based
ligand containing 2-pyridyl substituent 9 resulted in the 1H NMR line broadening and, when a
2-fold excess of zinc salt was added to shift the equilibrium toward the formation of the
product, a set of new signals attributed to [ZnLXn](2-n)+ complex was observed (Figure 6, trace
B). Significant shift changes (in the range of 0.2-0.4 ppm) were observed for pyridine, 1” and
3” resonances suggesting that pyridine and imine nitrogen atoms are engaged in coordination
(Supporting Information, Table S5). These two donors were found insufficient for the
formation of the intermediate [ZnL2]2+-type complex observed previously for analogs 10 and
11.
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1
Figure 6. Aromatic region of 500 MHz H NMR spectra of compound 9 (A) and its
complex formed upon addition of 2 equivalents of zinc acetate (B). Both spectra were
measured in methanol-d4 at 300 K.
Formation of zinc complexes of phenanthroline derivative 11 was also followed by UV-
vis spectroscopy. Addition of zinc acetate to the methanolic solution of ligand 11 resulted in
decrease of one of the two major bands at 277 nm and build-up of a band at ca. 295 nm
accompanied with less intense maxima at ca. 340 and 357 nm (Figure 7, A). Only very subtle
differences were observed between 2:1 and 1:1 complexes: positions and intensities of all
bands are almost identical (for [ZnL2]2+complex λmax (log ε) = 230 (4.55), 296 (4.31), 327 sh,
341 (3.65), 357 (3.52), for [ZnL(OAc)n](2-n)+ form λmax (log ε) = 231 (4.54), 294 (4.32), 325
(3.71), 340 (3.68), 356 (3.62); for a better comparison, the values of log ε for the 2:1 complex
were given per 1 mole of coordinated ligand). Not surprisingly, Job’s plot (Figure 6, B)
showing the changes of absorbance at 356 nm as a function of mole fraction of zinc acetate
exhibited a maximum for 2:1 ligand to Zn2+ ratio (x(Zn(OAc)2 = 0.33). It is justified by the
fact that for this composition ligand is fully saturated with zinc and the concentration of the
coordinated phenanthroline ligand (responsible for absorption) attains a maximum value.
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Figure 7. (A) UV-vis spectra of ligand 11 and its zinc(II) complexes in methanolic
solution. (B) Job’s plot showing absorbance at 356 nm as a function of zinc acetate added to
ligand 11.
DFT calculations
Quantum mechanical calculations performed at the DFT level of theory21 allowed
comparison of possible structures and coordination modes for the obtained zinc complexes. In
addition, chemical shifts in 1H NMR spectra were calculated and compared with experimental
values as a verification of the quality of theoretical predictions.
Calculations were performed for compounds 10, 11 and their zinc complexes in
methanolic solution. Using different starting points, we found two conformations of ligands
10 and 11 differing mainly in the relative positions of the two substituents of the bicyclic
scaffold. The energy of the more compact one (Figure 8, A) appeared 3.74 kcal/mol (ligand
10) or 4.71 kcal/mol (ligand 11) higher than for the open conformation (Figure 8, B). The
1
calculated H NMR chemical shifts for the latter one were in a better agreement with
experimental values, particularly for the bicyclic fragment (Supporting Information, Tables
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S7-S17, Figures S10-S23). However, for the remaining parts of the molecule the
conformational freedom does not allow to expect a perfect fit.
Figure 8. DFT calculated structures of hybrid ligand 11. Two conformations of the
molecule are shown with their relative energies. Hydrogen atoms omitted for clarity.
For zinc complexes of 1:1 stoichiometry, the calculations were performed for two modes
of coordination. Structures in which ligand 10 or 11 coordinated metal ion using only two
nitrogen atoms of the aromatic fragment were found significantly less stable (by 15-20
kcal/mol, Suppoting Information, Table S6) than the complexes utilizing also an imine donor.
In addition, for this (3N) coordination also N-2 atom of 2-azanorbornane was located in a
binding distance (2.12 Å) from zinc(II) cation. One should notice, however, that the
competition of other possible ligands, in particular acetate anions, alcohol or water molecules
was not considered in these calculations. Our experiments indicated the (3N) coordination and
the presence of additional ligand(s) in [ZnLXn](2-n)+ complexes. Therefore, calculations were
also undertaken assuming additional coordination of one or two acetate anions. The
agreement of the obtained NMR data with the experimental chemical shifts was not
satisfactory which points for another possible structure of the 1:1 complex. One cannot
exclude, for example, the formation of polynuclear species with bridging acetate anions. We
performed several ESI MS experiments which showed either the presence of [ZnL(OAc)]+ ion
(m/z = 543.18) or [ZnL-H]+ (m/z = 483.15) which can be formed under conditions of the
experiment from any mono- and polynuclear species. So far, we were not able to further
characterize the isolated complex in the solid state (in particular, by X-ray diffraction).
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In case of complexes of 2:1 ligand to metal stoichiometry, [ZnL2]2+, DFT calculations
were performed taking into account the possible coordination by only phenanthroline or
bipyridyl fragment, leading to tetrahedral geometry (4N-type complexes) and the possible
engagement of imine nitrogen atom in the formation of zinc complexes (6N-type octahedral
structures). Again, the participation of the additional nitrogen donor in coordination resulted
in the more stable structures; the energy difference equaled 28.32 kcal/mol (for ligand 10) and
23.54 kcal/mol (ligand 11). In these structures shown in Figure 9, bicyclic fragments are
located in vicinity of aromatic fragments which should result in significant changes of
chemical shifts caused by ring current effect.
Figure 9. DFT calculated structures of 6N-coordinated [ZnL2]2+ zinc(II) complexes with
ligand 10 (A) and 11 (B). Hydrogen atoms omitted for clarity.
1
DFT calculations of H NMR chemical shifts reproduced well the experimental patterns
observed for [ZnL2]2+ complexes, including upfield shifts of 5-H in complex of 11. The
greatest deviations were observed for N-2 substituent; possibly the averaged orientation of
phenyl moiety which has a pronounced effect on the chemical shifts of 1’-H and 1’-methyl
protons differs for the calculated conformation. The representative illustration of the
similarities of calculated and measured values is presented in Figure 10. All plots and tables
showing the calculated chemical shifts are given in the Supporting Information. While in the
case of ligand 10 the differences between the calculated and experimental values are similar
regardless of the coordination number, for the ligand 11 much better correlation was found for
6N- than 4N-type coordination which is in agreement with our analysis of NMR spectra.
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10
8
y = 0.96648x + 0.11024
R = 0.99458
6
2+
4
N
N
N
N
N
N
2
Zn
N
N
0
-2
-2
0
2
4
6
8
10
Calculated 1H NMR shift
Figure 10. Comparison of experimental and DFT calculated averaged chemical 1H NMR
shift values (in ppm) of 6N-coordinated [ZnL2]2+ complex of compound 11.
The main conclusions drawn from DFT calculations are in agreement with those obtained
from NMR studies: participation of three nitrogen donors in metal ion binding which can
leave vacant coordination sites in monomeric complexes, but not for a dimeric [ZnL2]2+ form.
This implies the rational application of these complexes in asymmetric catalysis.
Stereoselective aldol reaction
Aldol reaction was chosen as a test process for checking the effect of the Zn(II) –
containing hybrid catalysts on the outcome of the catalytic process.
We decided to test the newly synthesized enantiopure hybrid catalysts in the zinc-
catalyzed aldol reaction between ketones and aromatic aldehydes. The results of structural
studies strongly suggested the use of [ZnLXn](2-n)+ complexes, where the metal coordination
sphere offers enough space for the additional coordination of reacting species. Moreover, the
reaction was performed in chloroform – a solvent in which [ZnL2]2+ complex (with the
ligands occupying 6 coordination sites) was found insoluble. Therefore, the reaction of
cyclohexanone and 4-nitrobenzaldehyde with 10 mol% of catalyst (zinc acetate and 10-14 in
1:1 molar ratio) was first tested (Table 2, entries 1-6).
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Table 2. Results of stereoselective aldol reactiona
Ligand
L*
Yield of
product
Dr
erb
Entry
1
Ar
T
Additive
syn/anti 80:20
(2R,1’R):(2S,1’S) 72:28, (2R,1’S):(2S,1’R) 46:54
syn/anti 60:40
(2R,1’R):(2S,1’S) 51:49, (2R,1’S):(2S,1’R) 53:47
syn/anti 71:29
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 298 K Zn(OAc)2
4-NO2-C6H4 273 K Zn(OAc)2
4-NO2-C6H4 273 K Zn(OAc)2
10
11
11c
12
13
14
10
11
11
11
11
11
10
11
11
11
14
11
85%
92%
16%
95%
61%
84%
50%
45%
74%
80%
70%
31%
>95%
10%
12%
17%
15%
>95%
2
3
(2R,1’R):(2S,1’S) 55:45, (2R,1’S):(2S,1’R) 53:47
syn/anti 70:30
(2R,1’R):(2S,1’S) 50:50, (2R,1’S):(2S,1’R) 48:52
syn/anti 69:31
4
5
(2R,1’R):(2S,1’S) 51:49, (2R,1’S):(2S,1’R) 47:53
syn/anti 57:43
(2R,1’R):(2S,1’S) 50:50, (2R,1’S):(2S,1’R) 50:50
syn/anti 83:17
6
7
(2R,1’R):(2S,1’S) 45:55, (2R,1’S):(2S,1’R) 52:48
syn/anti 74:26
(2R,1’R):(2S,1’S) 62:38, (2R,1’S):(2S,1’R) 55:45
syn/anti 67:33
8
Zn(OAc)2
4-NO2-C6H4 298 K
+ HOAc
9
(2R,1’R):(2S,1’S) 59:41, (2R,1’S):(2S,1’R) 46:54
syn/anti 71:29
(2R,1’R):(2S,1’S) 70:30, (2R,1’S):(2S,1’R) 50:50
syn/anti 40:60
10
11
12
13
14
15
16
17
18
4-NO2-C6H4 298 K
ZnCl2
4-NO2-C6H4 298 K Zn(OTf)2
4-NO2-C6H4 273 K Zn(OTf)2
4-NO2-C6H4 273 K Zn(OTf)2
(2R,1’R):(2S,1’S) 51:49, (2R,1’S):(2S,1’R) 70:30
syn/anti 55:45
(2R,1’R):(2S,1’S) 36:64, (2R,1’S):(2S,1’R) 44:56
syn/anti 50:50
(2R,1’R):(2S,1’S) 55:45, (2R,1’S):(2S,1’R) 35:65
syn/anti 59:41
(2R,1’R):(2S,1’S) 93:7, (2R,1’S):(2S,1’R) 74:26
syn/anti 74:26
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
273 K Zn(OAc)2
298 K Zn(OAc)2
(2R,1’R):(2S,1’S) 91:9, (2R,1’S):(2S,1’R) 53:47
Zn(OAc)2
298 K
syn/anti > 98:2
(2R,1’R):(2S,1’S) > 99:1
syn/anti 82:18
(2R,1’R):(2S,1’S) 94:6, (2R,1’S):(2S,1’R) 41:59
syn/anti 75:25
2R,1’R):(2S,1’S) 84:16, (2R,1’S):(2S,1’R) 53:47
+ HOAc
Zn(OTf)2
+ HOAc
273 K
2-NO2-C6H4 298 K Zn(OAc)2
aReaction conditions:15 1 mL of chloroform, 1 mL of cyclohexanone, 0.5 mmol of
aldehyde, 0.05 mmol of ligand, 0.05 mmol mol of zinc salt, 0.05 mmol of acetic acid (entries
b
9,16,17). Configuration assignment based on the literature data.22 c1% mol of ligand and of
zinc acetate were used.
The highest diastereomeric ratio (80:20) with 42% enantiomeric excess of the main syn
isomer accompanied by 85% overall yield were obtained for bipyridyl ligand 10. Pyridine
derivative 9 led to low diastereoselectivity (syn/anti 55:45, 65% yield) and racemic products,
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similarly to bridged azepane-based phenanthroline ligand 14. However, the use of isomer of
14, 2-azanorbornyl derivative 11, resulted in high yield but still low stereoselectivity.
Decrease of the amount of catalyst from 10% to 1% drastically lowered the reaction yield, but
slightly improved dr and ee (entry 4). The yield dropped significantly while the
diastereomeric ratio increased with the reaction temperature decrease (Table 2, entries 7-8).
Entries 9-13 show the impact of additives and metal source on the outcome of the
catalytic reaction. The addition of a Brønsted acid – acetic acid – slightly increased the
stereoselectivity of the process (entries 9, 16, and 17). It can be accounted for the protonation
of tertiary amine, thus additionally stabilizing the respective transition state by hydrogen bond.
The use of zinc triflate in place of zinc acetate with ligand 11 reversed the ratio of
diastereomers and the major anti diastereomer was obtained with 40% ee. Furthermore,
temperature lowering changed the stereochemical preference, suggesting that specific
mechanism operates for this catalyst composition.
When the reaction was performed with ligand 11 and zinc acetate replaced with cadmium
acetate, racemic products were obtained with low dr (syn/anti 52:48) in 58% yield. Copper(II)
acetate was only slightly more effective (82% yield, syn/anti 46:54, racemic products), while
for copper(II) chloride the reaction exhibited some diastereo- and enantioselectivity (syn/anti
52:48; (2R,1’R):(2S,1’S) 42:58, (2R,1’S):(2S,1’R) 56:44), albeit accompanied with lower yield
(56%).
It is well established that the outcome of the aldol reaction can strongly depend on the
solvent used.9d,22a In our hands, the results of the catalytic tests with ligand 11 and zinc acetate
in methanol were found comparable with those in chloroform (88% yield, syn/anti 55:45,
(2R,1’R):(2S,1’S) 53:47, (2R,1’S):(2S,1’R) 48:52). The reaction performed without solvent,
with the addition of 5% mol of water, resulted in reasonable yield (81%), but low
diastereoselectivity (syn/anti 56:44) and a complete loss of enantioselectivity.
When 4-chlorobenzaldehyde was used as a substrate, low reaction yields (up to 17%)
were observed. However, they were accompanied with high diastereoselectivities (up to over
98:2 dr) and enantioselectivities (82 to >98% ee for the major syn diastereomer; Table 3,
entries 14-17). Promising results were also obtained when 4-nitrobenzaldehyde was reacted
with cyclopentanone in the presence of 10 mol% of zinc acetate and 11 (syn:anti 55:45,
(2R,1’R):(2S,1’S) 70:30, (2R,1’S):(2S,1’R) 35:65, >95% yield) and in the reaction of the same
aldehyde with acetone (R:S 9:91, 58% yield).
For two ligands, 11 and 14, we tested their utility as organocatalysts in aldol reaction of
cyclohexanone and 4-nitrobenzaldehyde. In both cases similar yields (80/81%) and
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diastereomeric ratios (67:33) were noted, but only for the bridged azepane-based compound
14 nonracemic products were obtained ((2R,1’R):(2S,1’S) 55:45, (2R,1’S):(2S,1’R) 32:68).
The observed preference for the formation of syn diastereomer can be explained by the
favored formation of the Z-enolate in the transition state and placement of the aromatic
substituent of aldehyde in the less hindered region (Figure 11).23
The reversed diastereoselectivity for the catalysis with 11 and zinc triflate and its change
with temperature may result from a simultaneous operation of diverse mechanisms: the
reaction can be catalyzed by ligand itself, which may also cooperate with zinc salt present in
the solution. Though we have not observed the formation of monomeric zinc(II) complex of
ligand 11 when Zn(OTf)2 was used as a metal source, the active species may be formed under
the conditions of catalytic reaction (chloroform/cyclohexanone solution).
Figure 11. The plausible transition states for the aldol reaction catalyzed by a zinc
complex of ligand 11. Adapted from literature.23
Conclusions
New hybrid catalysts possessing a rigid chiral bicyclic skeleton with an additional
tertiary amine and 1,10-phenanthroline, 2,2’-bipyridine or pyridine moiety were obtained. The
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imine linkage provided an additional donor atom which participated in coordination. The
Zn(II) complexation studies demonstrated that two types of complexes were formed,
[ZnLXn](2-n)+ and [ZnL2]2+, and their structures were established by comparison of the
experimental and DFT calculated NMR spectra. Actually, the first complex species formed
with the chiral ligands were catalytically active in the zinc-catalyzed stereoselective aldol
reaction. The preliminary results show that the outcome of catalytic process is dependent on
the configuration of the four stereogenic centers, size of the bicyclic system as well as the
linker size. Very high diastereomeric excess and enantiomeric excess of the main syn
diastereomer were observed for the reaction of cyclohexanone and 4-chlorobenzaldehyde. The
observed direction of stereochemical induction is in agreement with the generally accepted
transition state structure for such reaction. These promising results with the known versatility
of phenanthroline, bipyridyl and pyridine derivatives substantiate a further exploration of the
possible applications of these new bifunctional, chiral ligands in asymmetric catalysis.
Supporting Information
Copies of NMR spectra, tables showing assignments of NMR signals of zinc complexes, DFT
calculated energies, comparison of DFT calculated and experimental 1H NMR chemical shifts.
Acknowledgements
Financial support from the National Science Center (grant OPUS-2013/09/B/ST5/03410) is
gratefully acknowledged.
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Table of Contents
Zinc complexes of new hybrid chiral imine ligands based on bicyclic skeleton appeared
effective modular catalysts in asymmetric aldol reaction.
26