Amidate ligand design effects in zirconium-catalyzed enantioselective hydroamination of aminoalkenes

Article abstract of DOI:10.1016/j.jorganchem.2010.07.023

In situ generated axially chiral zirconium biphenyl amidate complexes are efficient precatalysts for the enantioselective intramolecular hydroamination of aminoalkenes, generating α-substituted pyrrolidines and piperidine with up to 74% ee. Five new chelating amide proligands and three new zirconium amidate complexes have been prepared and fully characterized in this investigation of ligand structure/catalyst function. Solid-state molecular structures of the complexes suggest that the observed moderate and highly variable enantioselectivities are a consequence of the multiple isomers accessible to this family of complexes, including a κ²-(O,O)- bonding motif. Thermal stability studies of the complexes further revealed the tendency of these complexes to undergo diastereoselective dimerization to afford homochiral dimers. These dimeric precatalysts are less efficient when used for the cyclization of aminoalkenes in comparison to their monomeric precursors. These results illustrate the variable coordination modes accessible to amidate ligands and suggest steric factors that must be considered in advanced ligand design.

Full text of DOI:10.1016/j.jorganchem.2010.07.023

Journal of Organometallic Chemistry 696 (2011) 50e60
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Amidate ligand design effects in zirconium-catalyzed enantioselective
hydroamination of aminoalkenes
*
Rashidat O. Ayinla, Travis Gibson, Laurel L. Schafer
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
In situ generated axially chiral zirconium biphenyl amidate complexes are efficient precatalysts for the
enantioselective intramolecular hydroamination of aminoalkenes, generating a-substituted pyrrolidines
Received 11 June 2010
Received in revised form
16 July 2010
Accepted 20 July 2010
Available online 29 July 2010
and piperidine with up to 74% ee. Five new chelating amide proligands and three new zirconium amidate
complexes have been prepared and fully characterized in this investigation of ligand structure/catalyst
function. Solid-state molecular structures of the complexes suggest that the observed moderate and
highly variable enantioselectivities are a consequence of the multiple isomers accessible to this family of
complexes, including a
k
2-(O,O)-bonding motif. Thermal stability studies of the complexes further
Keywords:
revealed the tendency of these complexes to undergo diastereoselective dimerization to afford homochiral
dimers. These dimeric precatalysts are less efficient when used for the cyclization of aminoalkenes in
comparison to their monomeric precursors. These results illustrate the variable coordination modes
accessible to amidate ligands and suggest steric factors that must be considered in advanced ligand
design.
Axially chiral bisamides
Zirconium amidate complexes
Enantioselective aminoalkene
hydroamination
Diastereoselective dimerization
Crown Copyright Ó 2010 Published by Elsevier B.V. All rights reserved.
1. Introduction
exploration of amidate ligated group 3 and 4 metal complexes
[7c,10] in metal-catalyzed transformations has led to the identifi-
Chiral nitrogen containing molecules are ubiquitous in naturally
occurring and biologically relevant compounds and select exam-
ples can be easily accessed in an atom efficient fashion by catalytic
NeH addition to CeC unsaturated systems (the hydroamination
reaction) [1]. Intense research into catalytic hydroamination using
metal-containing complexes from across the periodic table has
been reported over the past two decades [1e9]. Since the devel-
opment of the first metal-catalyzed asymmetric hydroamination
reaction in the early 1990s [6u,6v], much effort has been focused on
this enantioselective variant [6e9]. Many recent advances employ
rigid chiral scaffolds such as biaryl backbones in an effort to develop
a widely applicable and highly stereoselective catalyst [6e9]. This
approach controls geometric isomerization by enforcing configu-
rational stability in the resulting metal complexes and avoids the
drawbacks of the pioneering chiral ansa-metallocenes which were
shown to epimerize under the catalytic reaction conditions [6u].
Although, enantiomeric excesses of >90% have been achieved in
asymmetric hydroamination using select catalyst systems
[6h,7a,7c,7d,9b], such high enantioselectivities are substrate
dependent and no broadly applicable catalyst is yet available. Our
cation of a highly active and enantioselective zirconium pre-
catalyst, achieving ee’s of up to 93% for the hydroamination
reaction (Fig. 1, 1) [7c]. Furthermore, other reports of amidate
supported group 4 metal complexes for efficient hydroamination
catalysis have emerged [7a,7b,7d,11]. Extensive investigations of
the zirconium precatalyst made using 1 have revealed that it can
only be used for the cyclohydroamination of gem-dialkyl
substituted substrates [7c], in accord with general observations in
group 4 metal-catalyzed hydroamination [1a].
Efforts focused on expanding the substrate scope of zirconium
amidate complexes in hydroamination catalysis while maintaining
excellent enantioselectivities led to the design of the biphenyl
dicarboxamide proligand 2 (Fig. 1). This proligand was envisioned
as a more sterically encumbered alternative to the previously
reported bis(amide) 1 [7c]. The solid-state molecular structure of
the zirconium biphenyl amidate complex of proligand 1 shows
a lack of steric shielding about the O-donor atoms as the groups
attached to the carbonyl carbon are far from the metal center upon
complex formation [7c]. However, in proligand 2 the modified
substituent pattern would effectively shield the metal center upon
complexation, assuming
a similar k
4-(N,O,O,N)-bonding motif
would be adopted. Thus, proligands 1 and 2 are closely related, with
the difference being the position of the carbonyl and amine func-
tionality relative to the biphenyl framework (Fig. 1).
* Corresponding author. Tel.: þ1 604 822 9264; fax: þ1 604 822 2847.
E-mail address: schafer@chem.ubc.ca (L.L. Schafer).
0022-328X/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.07.023

R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
51
glove-box. 6,60-Dimethyl-2,20-dicarboxylic acid [12], C-(1-allylcy-
clohexyl)methylamine 4a [4t], 2,2-diphenyl-4-pentenylamine 4b
[6r], 2,2-dimethyl-4-pentenylamine 4c [4t,13], C-(1-allylcyclo-
pentyl)methylamine 4d [6j], 2-phenyl-4-pentenylamine 4e [14],
4-pentenylamine 4f [2k], 2-allyl-2-methyl-4-pentenylamine 4g
[9c], 2-methyl-2-phenyl-4-pentenylamine 4h [14], and 2,2-
dimethyl-5-hexenylamine 4i [2k], were prepared as described in
the literature. Heterocylic hydroamination products: 3-methyl-2-
azaspiro[4.5]decane 5a [9c], 2-methyl-4,4-diphenylpyrrolidine 5b
[6r], 2,4,4-trimethylpyrrolidine 5c [2k], 3-methyl-2-azaspiro[4.4]
nonane 5d [6j], N-benzoyl-2-methyl-4-phenylpyrrolidine [10o], 4-
allyl-2,4-dimethylpyrrolidine 5g [9c], and 2,5,5-trimethylpiper-
idine 5i [5e], are known compounds. All other commercially
available reagents and solvents were used as received.
R
N
H
NH
O
O
O
O
H
N
NH
R
1
2
Fig. 1. Chiral bis(amide) proligands for the preparation of zirconium precatalysts for
the asymmetric hydroamination of aminoalkenes.
2.2. Representative procedures
2.2.1. Procedure 1: Representative procedure for the synthesis of bis
(amide) proligands
2.2.1.1. Example:
Herein, we present our investigations regarding a series of
proligands of type 2 with sterically and electronically diverse
substituents on the N-functionality. These proligands (2aee) are
employed for the in situ preparation of zirconium complexes
(3aee) for the enantioselective hydroamination of aminoalkenes.
The complexes display good catalytic activities with good enan-
tioselectivities that are consistent with a recently reported related
system by Hultzsch and coworkers [11]. In an effort to understand
the trends in stereoselectivity reported here and previously
[7b,7d,11], the synthesis and full characterization of these
complexes, including solid-state molecular structures and thermal
stability investigations have been performed. Importantly, the
modified architecture of type 2 proligands promotes the formation
of alternative coordination geometries, ligand redistribution, and
unexpected complex aggregation at catalytically relevant elevated
temperatures. These findings rationalize the observed limitations
for enantioselectivities and most importantly suggest key ligand
design features that must be considered in the assembly of opti-
mized catalytic systems.
(S)-N,N0-bis(2,6-diisopropylphenyl)-6,60-dime-
thylbiphenyl-2,20-dicarboxamide 2a [15]. Thionyl chloride (2.1 mL,
29.60 mmol) was added to a solution of 6,60-dimethyl-biphenyl-
2,20-dicarboxylic acid (0.8 g, 2.96 mmol) in 10 mL of toluene. The
mixture was heated at reflux for 3 h after which the excess thionyl
chloride and toluene were removed in vacuo. The dichloride formed
was dissolved in 20 mL of chloroform, cooled to ꢁ78 ꢂC and then
added to a mixture of 2,6-diisopropylaniline (1.10 g, 1.2 mL,
6.22 mmol) and triethylamine (0.90 g, 1.2 mL, 8.88 mmol) in 20 mL
of chloroform at ꢁ78 ꢂC. The reaction mixture was allowed to warm
up to room temperature and then heated at 70 ꢂC for 16 h. The
mixture was diluted with 50 mL of chloroform and extracted with
3 M HCl (3 ꢀ 30 mL), water (1 ꢀ 30 mL), brine (1 ꢀ 30 mL) and the
organic layer was dried over anhydrous magnesium sulphate. The
solvent was removed by rotary evaporation and 50 mL of ethyl
acetate was added to the crude product. The precipitate was
collected by suction filtration and washed several times with ethyl
acetate to give the product as a white solid in 60% yield (1.05 g,
1.78 mmol). ½a 2D1
ꢃ
þ 76.0 (c 1.00, MeOH). 1H NMR (CDCl3, 300 MHz,
2. Experimental procedures
d): 0.99e1.03 (24H, 2 overlapping doublets, AreCHeCH3), 2.04 (6H,
s, Ar-CH3), 2.38e2.86 (4H, m, CHeCH3), 7.06 (4H, d, J ¼ 7.9 Hz, Ar-H),
2.1. Methods and materials
7.20 (2H, t, J ¼ 7.9 Hz, Ar-H), 7.39e7.41 (4H, m, Ar-H), 7.47e7.49 (2H,
m, Ar-H), 8.43 (2H, br s, CONH); 13C{1H} NMR (CDCl3, 100 MHz,
d):
All reactions were carried out under an atmosphere of dry
nitrogen using standard Schlenk line techniques or an MBraun
Unilab glove-box unless otherwise stated. 1H and 13C{1H} NMR
spectra were recorded on either 300 MHz, 400 MHz or 600 MHz
Bruker Avance spectrometers; chemical shifts are reported in
parts per million (ppm) relative to the residual proton in the
solvents indicated. Thin layer chromatography was performed on
silica gel (Macheney-Nagel Silica Gel 60) aluminium plates (layer
0.20 mm). Column chromatography was performed using Silicycle
silica gel 230e400 mesh. Mass spectrometry, elemental analyses
and X-ray crystallography were performed at the Department of
Chemistry, University of British Columbia. HPLC analyses were run
on an Agilent series 1100 with a UV/VIS detector using a CHIR-
ALPAK AS-H column (250 ꢀ 4.6 mm). Optical rotations were
measured on a Jasco P-1010 digital polarimeter at 589 nm. Single
crystal X-ray diffraction measurements were performed on
20.5, 24.0, 28.6, 123.6, 124.9, 128.3, 128.4, 131.0, 132.1, 136.3, 137.1,
138.1, 146.4, 170.3; MS(EI) 588 [M]þ, 412 {M
ꢁ
NH
[((CH3)2CH)2C6H3]}þ; Anal. Calcd. For C40H48N2O2: C, 81.59; H, 8.22;
N, 4.76. Found: C, 81.50; H, 8.07; N, 4.78.
2.2.1.2. (S)-N,N0-dimesityl-6,60-dimethylbiphenyl-2,20-dicarboxamide
2b. The synthetic approach to 2b is outlined in procedure 1. The
quantities of reactants utilized are: (S)-6,60-dimethylbiphenyl-2,20-
dicarboxylic acid, 1.63 g (6.03 mmol); thionyl chloride, 4.39 mL
(60.3 mmol); 2,4,6-trimethylaniline, 1.78 mL (12.7 mmol); trie-
thylamine, 2.54 mL (18.1 mmol). Purification was effected by
washing the crude solid with 50 mL of hexanes, collecting the
solid by suction filtration and further washing with 2 mL of ice
cold ethyl acetate. The yield is 1.52 g, 50% (3.01 mmol);
½
a 2D3
ꢃ
þ 138.94 (c 1.00, MeOH). 1H NMR (CDCl3, 400 MHz,
d): 1.90
(12H, s, Ar-CH3), 2.01 (6H, s, Ar-CH3), 2.19 (6H, s, Ar-CH3), 6.76 (4H,
br s, Ar-H), 7.29e7.36 (4H, m, Ar-H), 7.45 (2H, d, J ¼ 7.3, Hz, Ar-H),
a Bruker X8 APEX diffractometer using a Mo Ka radiation source
(l
¼ 0.71073 A) at 173 K. Chloroform was distilled over K2CO3;
8.65 (2H, br s, CONH); 13C{1H} NMR (CDCl3, 100 MHz,
d): 18.3, 20.6,
ꢀ
hexanes, benzene and toluene were purified over columns of
alumina. Zr(NMe2)4 was purchased from Strem and used as
received. d8-Toluene and d6-benzene were degassed by freeze-
pump-thaw process and stored over molecular sieves in the
21.0, 125.4, 128.1, 128.9, 131.4, 132.2, 135.3, 136.7, 136.8, 136.8, 137.7,
169.3; MS(EI) m/z 504 [M]þ, 370 [M ꢁ NH(CH3)3C6H2]þ; Anal.
Calcd. For C34H36N2O2 C, 80.92; H, 5.55; N, 7.19. Found: C, 80.70; H,
5.44; N, 7.51.

52
R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
2.2.1.3. (S)-6,60-dimethyl- N,N0-diphenylbiphenyl-2,20-dicarboxamide
2c. Procedure 1 was followed in the preparation of this compound.
The quantities of reactants employed are: (S)-6,60-dimethylbi-
phenyl-2,20-dicarboxylic acid, 0.60 g (2.22 mmol); thionyl chloride,
1.61 mL (22.2 mmol); aniline, 0.42 mL (4.66 mmol); triethylamine,
0.94 mL (6.66 mmol). Purification was effected by column chro-
matography using a 4:1 mixture of hexanes and ethyl acetate to
give the product as a white solid in 58% yield (0.54 g, 1.3 mmol).
128.6, 131.9, 136.6, 136.6, 137.3, 143.0, 169.7; MS(EI) m/z 476 [M]þ;
HRMS (EI) m/z calc’d for C32H32N2O2 [Mþ]: 476.24638. Found:
476.24598.
2.2.2. Procedure 2: Representative procedure for the
enantioselective hydroamination of aminoalkenes
2.2.2.1. Example 1: synthesis of 3-methyl-2-azaspiro[4.5]decane (5a) e
Table 1, entry 1. C-(1-allylcyclohexyl)methylamine (4a), 0.05
g
½
a 2D1
ꢃ
þ 82.1 (c 0.50, MeOH). 1H NMR (CDCl3, 400 MHz,
d
): 1.95 (6H,
(0.326 mmol) was added to a 0.3 mL C6D6 solution containing 0.019 g
(0.033 mmol) of proligand 2a and 0.009 g (0.033 mmol) of Zr(NMe2)4
in a 1 dram vial. The mixture was transferred into a J. Young NMR
tube after which the vial was rinsed twice with C6D6 and the rinse
added to the J. Young NMR tube for a total volume of 0.5 mL in the
NMR tube. The sealed J. Young tube was placed in an oil bath set at
110 ꢂC. After 3 h at 110 ꢂC, the reaction mixture was loaded onto
a 3 ꢀ 2.5 cm sintered glass filter filled to about 3/4 with silica gel. The
proligand was eluted with 100 mL of a 1:1 mixture of hexanes and
ethyl acetate while the product was eluted with 100 mL of an
89:10:1 mixture of dichloromethane, methanol and triethylamine
respectively. The solvent was removed under reduced pressure to
deliver the pure product in 92% yield (0.046 g, 0.300 mmol).
s, Ar-CH3), 7.05 (2H, t, J ¼ 7.2 Hz Ar-H), 7.19e7.26 (4H, m, Ar-H),
7.28e7.33 (4H, m, Ar-H), 7.45 (4H, d, J ¼ 7.2 Hz, Ar-H), 7.48e7.50
(2H, dd, J ¼ 2, 6.8 Hz, Ar-H), 8.99 (2H, br s, CONH); 13C{1H} NMR
(CDCl3, 75 MHz, d): 20.4, 120.3, 124.6, 125.0, 128.3, 129.0, 132.7,
136.6, 136.8, 137.1, 138.2, 169.2; MS(EI) m/z 420 [M]þ, 328
[M ꢁ NHPh]þ; Anal. Calcd. For C28H24N2O2: C, 79.98; H, 5.75; N,
6.66. Found: C, 79.74; H, 5.82; N, 6.70.
2.2.1.4. (S)-N,N0-diisopropyl-6,60-dimethylbiphenyl-2,20-dicarbox-
amide 2d. The titled compound was prepared according to proce-
dure 1 (heat is not required for the second step). The quantities of
reactants employed are as follows: (S)-6,60-dimethylbiphenyl-2,20-
dicarboxylic acid, 0.406 g (1.50 mmol); thionyl chloride, 1.10 mL
(15.0 mmol); isopropylamine, 0.64 mL (7.5 mmol); triethylamine,
0.63 mL (4.5 mmol). The product was obtained as a white solid in
72% yield (0.38 g, 1.1 mmol) after purification by flash column
chromatography using 1:1 hexanes to ethyl acetate mixture. The
product can also be obtained pure by recrystallization of the crude
2.2.2.2. Example 2: synthesis of 2-methyl-4,4-diphenylpyrrolidine
(5b) e Table 1, entry 6. 2,2-diphenyl-4-pentenylamine (4b), 0.100 g
(0.421 mmol) was added into a 1 dram vial containing 0.3 mL C6D6
solution of proligand 2a (0.025 g, 0.042 mmol) and 0.011 g
(0.042 mmol) of Zr(NMe2)4. The mixture was quantitatively trans-
ferred into a J. Young NMR tube by rinsing the vial twice with C6D6
for a total volume of 0.5 mL in the NMR tube. The mixture was
heated at 110 ꢂC in an oil bath for 75 min after which loaded onto
compound from ethyl acetate but in a lower yield (50%). ½a D21
þ 4.9
ꢃ
(c 1.00, MeOH). 1H NMR (CDCl3, 300 MHz,
d
): 0.76 (6H, d, J ¼ 6.6 Hz,
CHeCH3), 0.96 (6H, d, J ¼ 6.6 Hz, CHeCH3), 1.89 (6H, s, Ar-CH3),
3.87e3.94 (2H, m, CHeCH3), 6.99 (2H, br d, J ¼ 7.7 Hz, CONH),
3
a 3 ꢀ 2.5 cm sintered glass filter filled to about /4 with silica gel.
7.21e7.30 (6H, m, Ar-H); 13C{1H} NMR (CDCl3, 75 MHz,
d): 20.2,
The proligand was eluted with 100 mL of a 1:1 mixture of hexanes
and ethyl acetate while the product was eluted with 100 mL of an
89:10:1 mixture of dichloromethane, methanol and triethylamine
22.2, 22.5, 41.4, 124.5, 127.9, 131.6, 136.4, 136.5, 137.7, 169.8; MS(ESI)
352 [M]þ, 294 [M ꢁ NHCH(CH3)2]þ; Anal. Calcd. For C22H28N2O2: C,
74.97; H, 8.01; N, 7.95. Found: C, 75.12; H, 7.77; N, 7.96.
2.2.1.5. (S)-N,N0-bis(adamantyl)-6,60-dimethylbiphenyl-2,20-dicar-
boxamide 2e. The synthetic protocol for 2e is outlined in procedure
1 (heat is not required for the second step). The quantities of
reactants utilized are: (S)-6,60-dimethylbiphenyl-2,20-dicarboxylic
acid, 0.30 g (1.1 mmol); thionyl chloride, 0.81 mL (11 mmol); 1-
adamantanamine, 0.35 g (2.3 mmol); triethylamine, 0.47 mL
(3.3 mmol). The product was obtained as a white solid in 72% yield
(0.43 g, 0.80 mmol) after purification by column chromatography
Table 1
Ligand screening in enantioselective hydroamination of aminoalkenes.
using 1:1 hexanes to ethyl acetate mixture. ½a D21
ꢃ
e 20.4 (c 1.00,
CHCl3). 1H NMR (CDCl3, 300 MHz,
d): 1.59 (12H, br s, adamantyl-H),
Entry
Substrate
Product
Proligand Time (h)c Yieldd % eee
1.70-1.82 (12H, m, adamantyl-H), 1.97 (12H, br s, Ar-CH3, ada-
mantyl-H), 6.71 (2H, br s, CONH), 7.30 (4H, m, Ar-H), 7.37 (2H, m, Ar-
1a
2a
3a
4a
5a
2a
2b
2c
2d
2e
3
2
19
30
3
92
91
89
91
92
17
26
7
6
52
H); 13C{1H} NMR (CDCl3, 75 MHz,
d): 20.2, 29.8, 36.7, 41.4, 52.3,
124.7, 127.8, 131.4, 136.5, 136.9, 138.8, 169.6; MS(EI) m/z 536 [M]þ,
Anal. Calcd. For C36H44N2O2: C, 80.56; H, 8.26; N, 5.22. Found: C,
80.22; H, 8.30; N, 5.15.
6b
2a
2b
2c
2d
2e
2f
1.25
92
90
92
90
92
93
92g
19
16
22
13
28
7
7b
1
24
24
1
1
1
2.2.1.6. (S)-6,60-dimethyl-N,N0-bis((R)-1-phenylethyl)biphenyl-2,20-
dicarboxamide 2f. The synthetic approach to 2f is outlined in
procedure 1. The quantities of reactants used are: (S)-6,60-dime-
thylbiphenyl-2,20-dicarboxylic acid, 0.65 g (2.4 mmol); thionyl
chloride, 1.75 mL (24.1 mmol); (R)-1-methylbenzylamine, 0.61 g
(5.1 mmol); triethylamine, 1.0 mL (7.2 mmol). The product was
obtained as a white solid in 87% yield (1.00 g, 2.10 mmol) after
8b
9b
10b
11b
12b
2ef
27
a
[Substrate] ¼ 0.65 M.
[Substrate] ¼ 0.84 M.
b
c
recrystallization from ethyl acetate. ½a D24
ꢃ
þ 84.6 (c 1.00, MeOH). 1H
Time required to reach >96% conversion.
d
e
% Yield of isolated product.
NMR (CDCl3, 300 MHz,
d
): 1.14 (6H, d, J ¼ 7.0 Hz, CHCH3), 1.82 (6H, s,
Determined by 1H NMR or 19F NMR spectroscopy after derivatization with (S)-
Ar-CH3), 4.99e5.03 (2H, m, CHCH3), 7.16e7.29 (12H, m, Ar-H),
Mosher acid chloride.
7.31e7.36 (2H, m, Ar-H), 7.42 (2H, br d, J ¼ 8.2 Hz, Ar-H); 13C{1H}
f
5 mol% loading.
g
NMR (CDCl3, 75 MHz,
d): 20.2, 21.3, 48.7, 124.7, 126.4, 127.3, 127.9,
% Conversion estimated by 1H NMR spectroscopy.

R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
53
respectively. The solvent was removed under reduced pressure to
deliver the pure product in 92% yield (0.092 g, 0.387 mmol).
in a 20 mL scintillation vial equipped with a magnetic stir bar. After
the dissolution of the entire solid, the volatiles were removed in
vacuo to produce the complex as a white solid in 96% yield (0.257 g,
0.317 mmol). Low quality crystals suitable for X-ray were obtained
from a mixture of benzene and hexanes at ꢁ35 ꢂC. Note: Prolonged
exposure to high vacuum results in the formation of 6a; a process
that is hastened by the removal of the neutrally coordinated H
2.2.3. Procedure 3: representative procedure for the
enantioselective hydroamination of aminoalkenes in Table 2
2.2.3.1. Example: synthesis of 3-methyl-2-azaspiro[4.4]nonane (5d) e
Table 2, entry 2. An in situ precatalyst standard solution was freshly
prepared using Zr(NMe2)4, 0.199 g (0.074 mmol) and 0.040 g
(0.074 mmol) of proligand 2e in 1 mL volumetric flask. Using
a micro pipette, 0.280 mL (0.021 mmol) of the standard solution
was added to 0.058 g (0.416 mmol) of C-(1-allylcyclopentyl)
methylamine (4d) in a 1 dram vial (note: in case involving internal
standard, 0.416 mmol of 1,3,5-trimethoxybenzene was also added).
The mixture was quantitatively transferred into a J. Young NMR
tube by rinsing the vial with C6D6 for a total volume of 0.5 mL in the
NMR tube. The reaction mixture was heated at 110 ꢂC (oil bath) for
(NMe2)2. 1H NMR (CDCl3, 300 MHz,
d): 0.87 (6H, d, J ¼ 6.9 Hz, CH
(CH3)2), 0.99e1.05 (1H, m, HN(CH3)2), 1.15 (6H, d, J ¼ 6.4 Hz, CH
(CH3)2), 1.29 (6H, d, J ¼ 6.9 Hz, CH(CH3)2), 1.35 (6H, d, J ¼ 5.9 Hz, HN
(CH3)2), 1.41 (6H, d, J ¼ 6.9 Hz, CH(CH3)2), 2.21 (6H, s, Ar-CH3), 2.27
(12H, s, N(CH3)2), 2.50e2.59 (2H, m, CH(CH3)2), 3.41e3.50 (2H, m,
CH(CH3)2), 6.96e7.01 (2H, m, Ar-H), 7.04e7.09 (4H, m, Ar-H),
7.13e7.18 (4H, m, Ar-H), 7.68 (2H, br dd, J ¼ 6.9, 1.4 Hz, Ar-H) 13C{1H}
NMR (CDCl3, 75 MHz, d): 21.4, 23.2, 23.3, 23.9, 25.4, 28.3, 29.5, 38.9,
40.7, 122.4, 122.9, 123.4, 126.3, 130.6, 137.7, 138.3, 138.7, 139.7, 141.1,
146.7, 161.1; [M]þ for complex 3a was not observed in the MS(EI),
however, a signal corresponding to the [M]þ for the proligand was
noted. Anal. Calcd. For C46H65N5O2Zr: C, 68.10; H, 8.08; N, 8.63.
Found: C, 68.01; H, 7.84; N, 8.69.
5 h after which it was loaded onto a 3 ꢀ 2.5 cm sintered glass filter
3
filled to about
/
with silica gel. The proligand was eluted with
4
100 mL of a 1:1 mixture of hexanes and ethyl acetate while the
product was eluted with 100 mL of an 89:10:1 mixture of
dichloromethane, methanol and triethylamine respectively. The
solvent was removed under reduced pressure to deliver the pure
product in 87% yield (0.043 g, 0.312 mmol).
2.2.5.2. Complex 3e.NHMe2. 1H NMR (CDCl3, 300 MHz,
d): 1.69
(12H, br s, HN(CH3)2, rapid exchange between free and bound HN
(CH3)2), 1.96e2.13 (30 H, m, adamantly-H), 2.28 (6H, s, Ar-H3), 2.53
(12H, s, N(CH3)2), 7.11e7.15 (4H, m, Ar-H), 7.40e7.45 (2H, m, Ar-H);
2.2.3.2. 2,4-Dimethyl-4-phenylpyrrolidine - mixture of diastereomers
(5h and 5h0). 1H NMR (CDCl3, 600 MHz, adenotes major diaste-
reomer, bdenotes minor diastereomer, occurring in a 1.7:1 ratio as
13C{1H} NMR (CDCl3, 75 MHz,
d): 21.4, 31.0, 37.9, 39.1, 41.5, 43.5,
54.0, 125.4, 127.4, 129.4, 138.3, 138.5, 142.2, 158.6; Anal. Calcd. For
C40H54N4O2Zr: C, 67.28; H, 7.62; N, 7.85. Found: C, 67.36; H, 8.02; N,
8.00 (note: prolonged exposure to high vacuum eliminates the
neutrally coordinated H(NMe2)2). Complex 6b.
determined by integration of signals at
d
d 1.13 and 1.17 respectively,
): 1.13a (3H, d, J ¼ 6.1 Hz, CH3CH), 1.17b (3H, d, J ¼ 6.1 Hz, CH3CH),
1.29a (3H, s, CCH3,), 1.32b (3H, s, CCH3), 1.37e1.41b(1H, br dd,
CHCH2), 1.61e1.64a (1H, br dd, CHCH2), 1.90a,b (1H, br s, CH2NH),
2.04e2.07a (1H, br dd, CHCH2), 2.32e2.35b (1H, br dd, CHCH2),
2.99e3.01a,b (1H, 2 overlapping doublets, CCH2), 3.13b (1H, d,
J ¼ 10.7 Hz, CCH2), 3.21a (1H, d, J ¼ 10.7 Hz, CCH2), 3.23e3.28b (1H,
m, CH3CH), 3.41e3.46a (1H, m, CH3CH), 7.11e7.13a,b (1H, m, Ar-H),
7.19e7.21a,b (2H, m, Ar-H), 7.23e7.25a,b (2H, m, Ar-H); 13C{1H} NMR
2.2.5.3. Complex 6b. A 20 mL scintillation vial equipped with
a magnetic stir bar was charged with 0.101 g (0.200 mmol) of
(ꢄ)-2b and 5 mL of benzene, 0.053 g (0.200 mmol) of Zr(NMe2)4 in
5 mL of benzene was then added to the suspension. After the
dissolution of the entire solid, the volatiles were removed in vacuo
and the solid was recrystallized from a hot mixture of benzene and
hexanes to deliver 0.060 g (0.044 mmol) of 6b in 44% yield. 1H NMR
(CDCl3, 100 MHz, d): 22.2, 22.5, 29.5, 30.4, 48.4, 48.5, 48.7, 53.6,
54.8, 59.6, 60.7, 125.9, 126.1, 126.2, 128.4, 128.5, 149.4, 149.8; MS(EI)
m/z 175 [Mþ], 160 [(M ꢁ CH3)þ]; HRMS (EI) m/z calc’d for C12H17
N
(CDCl3, 400 MHz, d): 1.90 (12H, s, Ar-CH3), 2.09 (12H, s, Ar-CH3),
[Mþ]: 175.1361. Found: 175.1360.
2.21 (12H, s, Ar-CH3), 2.23 (12H, s, Ar-CH3), 2.59 (24H, s, N(CH3)2),
6.76 (4H, br t, J ¼ 7.7 Hz, Ar-H), 6.83 (4H, s, Ar-H), 6.97 (4H, br d,
J ¼ 7.3 Hz, Ar-H), 7.05 (4H, s, Ar-H), 7.66 (4H, br d, J ¼ 8.1 Hz, Ar-H);
2.2.4. Procedure 4: representative procedures for the determination
of enantiomeric excesses of Mosher amides by 1H and 19F NMR
spectroscopies
13C{1H} NMR (CDCl3, 150 MHz,
d): 19.5, 21.0, 21.3, 21.4, 43.2, 126.6,
128.7, 129.6, 130.5, 131.1, 132.5, 133.3, 134.0, 135.1, 142.9, 145.2,
179.2; Anal. Calcd. For C76H92N8O4Zr2: C, 66.92; H, 6.80; N, 8.21.
Found: C, 67.11; H, 7.12; N, 7.98.
(S)-Mosher acid chloride 0.009 g, (0.04 mmol) in 1 mL of
dichloromethane was added to 0.005 g (0.03 mmol) of 5a and
0.016 g (0.16 mmol) of triethylamine in 1 mL of dichloromethane.
The mixture was filtered through a 2 mL pipette filled half way with
silica gel using 5 mL of dichloromethane. The volatiles were
removed by rotary evaporation and the product was dissolved in
3. Results and discussion
3.1. Proligand synthesis and characterization
1
CDCl3 for analysis by H NMR spectroscopy at 25 ꢂC and 19F NMR
spectroscopy at 60 ꢂC.
Proligands 2aee can be synthesized in a two step procedure from
(S)-6,60-dimethylbiphenyl-2,20-dicarboxylic acid [12]. Thepreparation
of 2aee involves the in situ generation of (S)-6,60-dimethylbiphenyl-
2,20-dicarbonyl dichloride by treating (S)-6,60-dimethylbiphenyl-2,20-
dicarboxylic acid with excess thionyl chloride under reflux conditions
(Scheme 1). The dichloride is then immediately reacted with the
appropriate primary amine in the presence of an excess of triethyl-
amine (Scheme 1)toaffordthedesiredproligand.Theseproligandsare
obtained as white solids after purification, by either recrystallization
or washing with organic solvents, in isolated yields from 50 to 72%
(Scheme 1). This family of proligands has been selected to provide
varying steric and electronic effects: 2a incorporates sterically
demanding substituents [15], while the substituents in compound 2b
are the same as those of proligand 1. Proligands 2c and 2d are less
2.2.4.1. N-Benzoyl-2-methyl-4-phenylpyrrolidine [10o]. HPLC anal-
ysis (CHIRALPAK AS-H, 1% 2-propanol in hexanes, 1.00 mL/min) of
the above benzamide: tR enantiomers of major diastereomer:
35.8 min and 106.20 min, tR enantiomers of minor diastereomer:
46.6 min and 86.2 min indicated an enantiomeric excesses of 37%
and 5% respectively.
2.2.5. Procedure 5: representative procedures for the synthesis of
metal complexes
2.2.5.1. Example: complex 3a$NHMe2. A solution of 0.088
g
(0.33 mmol) of Zr(NMe2)4 in 5 mL of benzene was added to
a suspension of 0.194 g (0.329 mmol) of (ꢄ)-2a in 5 mL of benzene

54
R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
Table 2
Substrate scope investigation in enantioselective hydroamination of aminoalkenes catalyzed by in situ generated precatalyst using proligand 2e.
H
N
5 mol% Zr(NMe2)4
R
R
NH2
5 mol% 2e
n
n
R
C6D6, 110 o
C
R
n = 1, 2
Entry
1
Substratea
Product
Timeb (h)
Yield
94c
% eej
67
7
87d
2
5
57
(98c)
24e
3
4
5
96f
120f
3
5e:5e’
37/5k
1.2:1g
27h
n.d.
68i
5g:5g0
1.5:1g
73/66
H
N
H
N
92i
5h:5h0
1.7:1g
+
6
3
45/74
Ph
Ph
5h
5h'
7
48
98c
23
a
[Substrate] ¼ 0.84 M.
b
c
d
e
f
Time required to reach >96% conversion.
NMR Yield using 1,3,5-trimethoxybenzene as internal standard.
% Isolated yield.
% Combined isolated yield after derivatization with benzoyl chloride.
Reaction temperature is 145 ꢂC.
g
h
i
Determined by 1H NMR in comparison with literature assignments [7c, 10o].
% Conversion estimated by 1H NMR spectroscopy.
Combined isolated yield.
j
Determined by 1H NMR or 19F NMR spectroscopy after derivatization with (S)-Mosher acid chloride.
Determined by HPLC analyses of the benzamides. n.d. ¼ not determined.
k

R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
55
H
OH
OH
N
R
1. SOCl2, C7H8
R = 2a, 2,6-diisopropylphenyl, 60%
O
O
O
O
120 o
C
2b
2c
2d
2e
, 2,4,6-trimethylphenyl, 50%
, phenyl, 58%
2. RNH2, NEt3
R
, isopropyl, 72%
N
H
, adamantyl, 72%
2
Scheme 1.
bulky than 2a and 2b and provide a useful comparison for investi-
gating the effectof ligand steric properties on reactivityand selectivity.
Finally, proligand 2e is sterically demanding like 2a, but with an alkyl
substituent it is electronically different. The chiral bis(amides) 2aee
were dried by heating at 70 ꢂC under high vacuum for a minimum of
16 h prior to being used for the in situ formation of zirconium
complexes.
Axially chiral compounds have been known to undergo thermal
racemization [16]. Racemization of the 6,60-dimethylbiphenyl
chiral backbone under these preparative conditions has been ruled
out by synthesizing bis(amide) 2f from (S)-biphenyl and (R)-1-
methylbenzylamine (Scheme 2). If racemization is occurring under
the reaction conditions, bis(amide) 2f would be obtained as
a mixture of diastereomers. However, the 1H NMR spectrum of 2f is
consistent with the formation of only one diastereomer, suggesting
that thermal racemization of the axially chiral backbone during
dichloride synthesis does not occur [17].
bearing the 2,4,6-trimethylphenyl substituent on the N-function-
ality is the most stereoselective [11]. The effect of steric properties
on the catalytic efficiency of the in situ generated complexes is
pronounced, as a direct comparison of times required for >96%
substrate consumption shows that longer reaction times are
required when the less sterically demanding proligands 2c and 2d
are used (Table 1, entries 3 and 4). This observation would be
consistent with the formation of a mixture of complexes in situ,
including coordination isomers and/or aggregate species, that may
reduce precatalyst efficiency. Such unwanted mixtures are more
likely to form when there is inadequate steric protection about the
metal center (vide infra).
An additional comparative investigation of catalyst efficiency (as
measured by the times required for >96% substrate consumption
product formation and ee’s) with substrate 4b was undertaken.
These results using the highly reactive substrate 4b further
substantiate the designation of 2e as the most enantioselective
proligand of the series (Table 1, entries 6e10), giving an ee of 28%.
Notably, the additional stereogenic center in proligand 2f (which
has comparable steric bulk to 2d) has no positive influence on the
enantioselectivity of this precatalyst, giving 5b with an ee of only
7% (Table 1, entry 11). These preliminary screens show that the in
situ prepared catalyst system with proligand 2e, in addition to
being the most selective of this class of complexes, also results in
short reaction times for complete consumption of starting material.
This is further illustrated by using a 5 mol% loading of 2e and Zr
(NMe2)4 for the cyclization of 4b with no consequence to the ee and
little impact on reaction time (92% conversion within 1 h, Table 1,
entry 12). As a result of these catalytic screens, proligand 2e (5 mol%)
was chosen for subsequent investigations of enantioselective
hydroamination catalysis.
3.2. Hydroamination catalysis
Precatalysts 3aef are easily synthesized by a rapid protonolysis
reaction between Zr(NMe2)4 and the corresponding bis(amide)
proligand (Scheme 3) [10]. The simple and rapid formation of 3aef
via protonolysis suggests the feasibility of generating these
complexes in situ for rapid screening of catalytic activities [7b, 11].
Therefore, in situ examinations of zirconium complexes 3aee for
enantioselective hydroamination with preferred test substrate 4a
(Table 1, entries 1e5) have been undertaken. The NMR tube scale
reactions with in situ generated complexes 3a-e are accomplished
by combining equimolar quantities of Zr(NMe2)4 and the proligand
of choice in C6D6 in a 1 dram vial before the addition of substrate 4a.
The reaction mixture is then transferred to a J. Young NMR tube and
heated at 110 ꢂC. Reaction progress is monitored by 1H NMR
spectroscopy and reaction products are isolated upon completion.
The results of this catalyst screen are compiled in Table 1.
A reaction of 4a with 10 mol% each of 2a and Zr(NMe2)4 gives 5a
within 3 h with an ee of only 17% (Table 1, entry 1). Proligands 2bed
(Table 1, entries 2e4) do not fare better in this cyclization, with 5a
being produced with low enantioselectivities (6e26%) in all cases.
The sterically bulky proligand 2e gives 5a with a modest ee of 52%,
making 2e the most selective proligand for this substrate (Table 1,
entry 5). These findings are in contrast to the recently reported
analogous systems, where the least sterically demanding proligand
Similar to most group 4 metal-catalyzed aminoalkene hydro-
aminations, the presence of geminal substituents in the amino-
alkenes is crucial for the high reactivity in this system, due to
Thorpe-Ingold and reactive rotamer effects [1a]. Aminoalkenes 4c,
and 4d with gem-dialkyl substituents undergo quantitative cycli-
zationwithin a few hours to afford 5c (with 67% ee) and 5d (with 57%
ee) respectively (Table 2, entries 1 and 2). Although our previously
reported enantioselectivesystem(prepared from1)canonlybe used
with gem-disubstituted substrates [7c], here the catalyst system 3e
can be used with substrate 4e bearing only one substituent to give
two diastereomers (Table 2, entry 3). Even in the absence of
substituents (substrate 4f) the cyclohydroamination reaction
H
OH
OH
Cl
N
NH2
O
O
O
O
O
SOCl2
2f
O
C7H8
NEt3
120 oC
Cl
N
H
87% yield
Scheme 2.

56
R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
H
N
N
R = 3a, 2,6-disopropylphenyl
R
R
R
3b, 2,4,6-trimethylphenyl
3c, phenyl
Zr(NMe2)4
C6H6
O
O
O
O
Zr(NMe2)2
R
3d, isopropyl
3e
, adamantyl
N
H
N
3
2
Scheme 3.
proceeds, albeit sluggishly. The diastereomeric ratio of (entries 3, 5 &
6) show a modest selectivity for the diastereomer with the bulkier
substituent in the equatorial position of the proposed chair-like
transition state, as has been previously reported [10o]. Substrate 4h,
with Ph and Me substituents, gives diastereomeric products in
a 1.7:1 ratio with the minor diastereomer 5h’ being formed in 74% ee.
The formation of a six-membered ring proceeds more slowly than
the corresponding five-membered ring formation and with lower
stereoselectivity (entry 7). This reduced stereoselectivity is also
consistent with previous observations and is proposed to be
due to a less organized 7-membered transition state [7c].
Tobetterunderstandhowstericbulkoftheproligandaffects metal
complexation, an examination of solid-state structures, solution-
phase behaviours and thermal stabilities of complexes 3 have been
investigated. Most importantly, the full characterization of 3e,
including the solid-state molecular structure, provides information
about the coordination environmentat themetal center. Thisdetailed
investigation of metal-ligand complexation and stability provides
valuable insight for the design of advanced catalytic systems.
for 6 and 12 protons respectively. This spectral data suggests a C2
symmetric complex with hindered rotation about the CeN bond of
the aryl ring. Furthermore, the presence of a signal at d 161.1 in the
13C NMR spectrum, consistent with C]N bond character [7d, 15],
suggests an alkoxyimine bonding mode for this complex in the
solution-phase (Scheme 4).
Single crystals of the racemic complex were obtained from
a mixture of benzene and hexanes at ꢁ35 ꢂC. The solid-state
molecular structure shows the presence of a neutral dimethylamine
donor ligand, consistent with the aforementioned spectroscopic
evidence (Fig. 2). The geometry about the zirconium center is best
described as distorted trigonal bipyramidal with one of the O atoms
and the neutral amine occupying axial positions. This binding mode
is analogous to that of the recently reported tantalum complex
featuring the same ligand [15]. While this binding motif has been
previously proposed for bis(amidate) complexes of group 4 metals
[7d, 11], this is the first solid-state structural evidence of a bis(ami-
date) group 4 metal with a
k
2-O,O-binding motif. The average ZreO
ꢀ
bond lengths in complex 3a$NHMe2 (2.029 A) is much shorter than
the typical ZreO bond distance in N,O-chelating amidate complexes
ꢀ
3.3. Synthesis and characterization of zirconium bis(amidate)
complexes
(2.112e2.252 A) [7a,10n,18]. While the solid-state molecular struc-
ture is C1 symmetric, if one considers the neutral amine donor to be
labile on the NMR time-scale, this bonding motif is consistent with
the C2 symmetric structure observed in the solution-phase. We
3.3.1. Bulky zirconium bis(amidate) complexes
As mentioned earlier, zirconium complexes 3aef are accessible
by a protonolysis reaction between equimolar quantities of Zr
(NMe2)4 and the appropriate proligand in benzene. A preparative
scale reaction between Zr(NMe2)4 and racemic 2a produces the
dimethylamine adduct 3a$NHMe2 in 96% crude isolated yield after
removal of volatiles in vacuo (Scheme 4). The 1H and 13C NMR
spectra display only the signals associated with the complex;
therefore, further purification was not performed. These spectra
also indicate the coordination of one molecule of neutral dime-
thylamine to the zirconium metal, for which the resonance of the
propose that the
to relieve strain, which may occur if the
could be accessed. Unfortunately, the observed
k
2-O,O-binding mode is a consequence of the desire
k
4-bis(N,O,O,N) chelate
2-bonding
k
arrangement places the chiral biphenyl framework at a significant
distance from the reactive metal center and the alkoxyimine
bonding of the amidate group ensures that the bulky N-substituent
is also far removed from the metal center. We have verified that
there is no racemization of this chiral ligand upon metal complex
formation [19], as deliberate decomposition of the precatalyst fol-
lowed by re-isolation and characterization of proligand results in
identical values for specific rotations. This metal complex has a more
sterically accessible five-coordinate Zr metal center than our most
enantioselective system, which is isolated as a seven-coordinate Zr
complex [7c]. This suggests that increased accessibility to the reac-
tive metal center results in improved substrate scope, but that this
steric accessibility also limits the ee’s that can be obtained [11,15].
Reaction of a 1:1 M ratio of Zr(NMe2)4 and racemic proligand 2e
in benzene similarly produces the dimethylamine adduct
methyl protons on the neutral amine donor appear at d 1.35, which
is shifted 0.53 ppm upfield from the signal associated with free
dimethylamine. The protons of the isopropyl methyl groups are
inequivalent and appear as four doublets at
1.41. The corresponding methine protons for these fragments
resonate as two multiplets centered at 2.55 and 3.43. The reso-
nances for the methyl protons on the biphenyl backbone and those
d 0.89, 1.15, 1.29 and
d
on the amido ligands are singlets at
d
2.21 and 2.27, which integrate
H
N
R
N
N
R
NHMe2
O
O
O
O
Zr(NMe2)4
3a NHMe2
R =
, 2,6-diisopropylphenyl, 96%
, adamantyl, 42%
Zr(NMe2)2
3e NHMe2
C6H6
R
N
R
H
3 NHMe2
2
Scheme 4.

R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
57
Fig. 3. ORTEP representation of the solid-state molecular structure of (ꢄ)-3e$HNMe2
(ellipsoids plotted at 50% probability). All H-atoms except that attached to N5 and one
toluene solvent molecule are omitted for clarity; the H atom shown was not experi-
ꢂ
ꢀ
mentally located. Selected bond lengths (A) and angles ( ): ZreO1, 2.044 (1); ZreO2,
2.004(1); ZreN3, 2.039(2); ZreN4, 2.014(2); ZreN5, 2.428(2); C1eN1, 1.262(2);
N5eZreO2, 174.51(6); N3eZreO1, 123.77(6); O1eZreN4, 116.19(6); O2eZreN5, 98.72
(6); C6eC8eC9eC10 (biphenyl dihedral angle), 84.9(2).
Fig. 2. ORTEP representation of the solid-state molecular structure of (ꢄ)-3a$NHMe2
(ellipsoids plotted at 50% probability). All H-atoms except that attached to N5 are
ꢂ
ꢀ
omitted for clarity; the H atom is calculated. Selected bond lengths (A) and angles ( ):
ZreO1, 2.026(4); ZreO2, 2.033(4); ZreN3, 2.034(5); ZreN4, 2.018(5); ZreN5, 2.404(5),
C1eN1, 1.264(8); N5eZreO1, 171.1(2); N4eZreO1, 98.0(2); O1eZreO2, 92.2(2);
N3eZreO2, 122.8(2); C6eC8eC11eC10 (biphenyl dihedral angle), 84.6(7).
symmetric homochiral dimer (ꢄ)-6b in 44% isolated yield (Fig. 4).
Furthermore, the quantitative formation of (ꢄ)-6b can be achieved
by exposing the crude product obtained from the combination of Zr
(NMe2)4 and 2b to high vacuum for 24 h. The solid-state molecular
structure of (ꢄ)-6b reveals that the biphenyl backbone bridges
between two metal centers using one amidate to form an N,O-
chelate with one metal center and the other amidate to form
another N,O-chelate with the second metal. This results in distorted
octahedral geometry about each zirconium metal. This complex is
one of only a few examples of group 4 amidate dimers reported in
the literature [7d, 20]. In addition to being an elegant example of
the spontaneous and diastereoselective formation of a chiral,
metallacyclic coordination complex, most importantly, this is a well
characterized example of a typical yet rarely discussed aggregate
complex that can form when using amidates as ligands.
3e$NHMe2 which can be recrystallized from a mixture of hexanes
and toluene in 42% yield. The diagnostic 13C NMR spectroscopic
signal for C]N in this complex is again observed at
d 158.6. The
solid-state molecular structure of 3e$NHMe2 is isostructural with
3a$NHMe2 and is shown in Fig. 3. While the most sterically
encumbered complexes (3a and 3e) could be fully characterized in
both the solution-phase and the solid-state, the reliable formation
of a single species in solution, as observed by NMR spectroscopy, is
limited to sterically demanding proligands (2a and 2e) and more
complicated spectra, due to the formation of multiple species and/
or ligand fluxionality, are observed for the more sterically acces-
sible systems (2b, 2c, and 2d).
The 1H NMR spectrum of 6b is also highly symmetric, consistent
with the solid-state molecular structure. The spectrum also indi-
cates the formation of only one diastereomer of 6b, thus homo-
chiral dimer is formed selectively and no meso-compound is
observed. This has been verified by using enantiopure proligands
for the synthesis of dimers and the identical products are obtained,
as confirmed by NMR spectroscopy. Furthermore, this dimer is
persistent in solution, as there is no signal for an imine C in the 13C
NMR spectrum of 6b; instead, a single carbonyl resonance is
3.3.2. Dimerization of the complexes
The use of ligands with reduced steric congestion results in
different solution-phase behaviour than that observed for the
complexes discussed above. For example, an NMR tube scale
reaction of the less sterically demanding proligand 2b and Zr
(NMe2)4 was carried out to give complex 3b: initially, the 1H NMR
spectrum displays signals associated with 3b and free dimethyl-
amine, and the 13C NMR spectrum contains a diagnostic signal for
observed at
d 179.2. This chemical shift is in good agreement with
previous complexes that exhibit delocalized electron density
throughout the amidate backbone while adopting an N,O-chelating
binding mode [7c]. While a variety of other axially chiral tethered
bis(amidate) complexes have been reported for asymmetric
hydroamination with modest to good enantioselectivities, there
have been widely ranging ee’s that do not vary predictably with
substrate and/or catalyst structure [11]. This characterized dimeric
complex illustrates a significant challenge when using amidate
ligands in catalysis; optimized ligand design needs to promote the
formation of robust complexes that do not readily undergo iso-
merisation and or aggregation.
C]N at
d 161.9, as would be anticipated. A signal associated with
bound dimethylamine was not observed; however, this could be
due to exchange on the NMR time-scale with the free dimethyl-
amine liberated during the protonolysis reaction. Based upon this
solution-phase characterization data, the initial experimental
evidence suggests the major product is a complex analogous to that
observed for 3a$NHMe2 and 3e$NHMe2. However, after as little as
3 h in solutions at room temperature, new signals are observable in
the 1H and 13C NMR spectra, including singlets at
d
1.90, 2.08, and
2.56 in the 1H NMR spectrum and a new signal at
d
179.2 in the 13
C
NMR spectrum, all of which are consistent with the formation of
dimer 6b (vide infra). Indeed, recrystallization from a mixture of
benzene and hexanes at ambient temperature afforded only the D2
Complex 6b itself has been tested as a precatalyst for the
cyclization of aminoalkene 4b to pyrrolidine 5b and its efficiency as

58
R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
in C6D6 to an elevated temperature of 110 ꢂC for 5 h did not result in
any observable dimer formation. On the other hand, after 3 days at
ambient temperature a solution of 3e$NHMe2 shows the presence
of new signals consistent with dimer formation. Most importantly,
these signals are observed within 1 h at 110 ꢂC. Unfortunately,
isolation and complete characterization of “dimer 6e” was not
possible as solution-phase equilibria dominate. However, to probe
the effect of potential thermal catalyst deactivation, two concurrent
catalytic reactions were carried out using consistent concentrations
of aminoalkene 4a ([0.84 M]) and precatalyst 3e$NHMe2 ([0.42 M])
(eq (2)). In one of the reactions, the precatalyst solution was heated
to 110 ꢂC for 1 h prior to the addition of 4a, while the other had
substrate added immediately upon precatalyst preparation. While
preheating the solution to 110 ꢂC before substrate addition does not
affect the product ee’s, a decrease in catalytic activity is observed;
the preheated reaction mixture is at 68% conversion after 3 h at
110 ꢂC versus quantitative conversion for the mixture without
preheating. This behaviour mirrors that of complex 3b$NHMe2 and
6b (eq (1)), strongly suggesting that dimerization is a thermal
decomposition pathway of concern, even in the cases with the
more sterically encumbered ligand sets.
Fig. 4. ORTEP representation of the solid-state molecular structure of (ꢄ)-6b (ellip-
soids plotted at 50% probability). All hydrogen atoms and substituents on amidate
nitrogens and six benzene solvent molecules are omitted for clarity. Selected bond
lengths (A) and angles ( ): Zr1eN1, 2.263(2); Zr1eO1, 2.221(2); Zr1eN2, 2.273(3);
Zr1eO2, 2.218(2); Zr1eN6, 2.048(2); Zr2eN3, 2.263(2); Zr2eO3, 2.227(2); Zr2eN4,
2.263(2); Zr2eO4, 2.234(2); N6eZr1eO2, 150.94(7); N6eZr1eN2, 92.76(8);
O3eZr2eO4, 86.42(6); N7eZr2eO3, 154.86(7); C14eC16eC8eC6 (biphenyl dihedral
angle), 92.0(3); C30eC32eC24eC22 (biphenyl dihedral angle), 88.6(3).
(2)
ꢂ
ꢀ
4. Summary and conclusions
a catalyst has been compared to a freshly prepared sample of
3b$NHMe2 (eq (1)). In side-by-side reactions under identical
experimental conditions, precatalyst 6b requires twice the amount
of time as freshly prepared 3b$NHMe2 (2 h vs. 1 h) to reach 98%
conversion. Notably, the enantiomeric excess of 25% obtained using
6b is identical (within experimental error) to the value obtained
with the in situ generated 3b$NHMe2 (Table 1, entry 2). Based on
these results, it is possible that 6b itself behaves as a sluggish
catalyst, or perhaps more likely, based upon the observation of
identical ee’s with both precatalysts, a smaller amount of the
catalytically active species forms in situ when using 6b as a pre-
catalyst, rather than freshly prepared precatalyst 3b$NHMe2.
To summarize, we have described the use of six new catalyst
systems prepared in situ for the enantioselective hydroamination
of alkenes. While these catalyst systems display enhanced amino-
alkene substrate scope over the most enantioselective group 4
catalysts reported to date [7a,7c,7d], the activity and stereo-
selectivity of this system is observed to be very substrate depen-
dent. These observations can be attributed to the multiple
coordination modes accessible in solution, including the observed
and characterized monomeric O-bound amidate bonding mode.
Unfortunately, the O-bound bonding mode of the amidate ligand
seems to facilitate the formation of dimers. While ligand redistri-
bution in amidate complexes has been previously observed [7a,18],
clear examples of aggregation in these systems are rare [7d, 20].
The characterization data presented herein serves to provide
diagnostic signals indicative of dimerization, a potential catalyst
deactivation pathway. The multiple accessible ligand binding
modes and/or ligand redistribution/aggregation pathways are
surely contributing factors in recently reported examples in which
the absolute stereoselectivity of the catalyst system varies even
with relatively small changes in catalyst structure and/or substrate
[7a,11]. Thus, idealized catalytic systems should be resistant to such
isomerisation/dimerization pathways.
3.3.3. Stability of zirconium precatalysts
(1)
Interestingly, dimerization proceeds diastereoselectively to give
homochiral dimers in the solution-phase, and the formation of
these D2 symmetric metallacycles has been verified by X-ray crys-
tallography. As expected, as the steric bulk of the proligand is
enhanced, dimer formation is inhibited. This is critical for improved
efficiency of the catalyst system, as the elevated temperatures used
to promote catalysis also promotes deactivation of the catalytic
system via dimer formation. This results in the suggestion for
improved ligand design in amidate catalyst systems; increased
The facile formation and characterization of dimer 6b prompted
the investigation of similar dimerizations in the more sterically
demanding complexes 3a$NHMe2 and 3e$NHMe2. Prolonged
exposure of 3a$NHMe2 to high vacuum (24 h) in an attempt to
remove the neutral dimethylamine and hasten dimerization,
produces a small amount of dimer 6a (approximately 5% conver-
sion, as estimated by 1H NMR spectroscopy). Further efforts to
produce 6a by subjecting a solution of 3a (NMR tube scale reaction)

R.O. Ayinla et al. / Journal of Organometallic Chemistry 696 (2011) 50e60
59
(l) B.D. Ward, A. Maisse-Francois, P. Mountford, L.H. Gade, Chem. Commun.
(2004) 704e705;
steric bulk results in improved reactivity. This work also demon-
strates the importance of designing ligands which favor a tetra-
dentate binding mode to inhibit unwanted catalyst deactivation
routes. To this end we have recently communicated a very reactive,
achiral zirconium tethered bis(ureate) precatalyst that preferen-
tially adopts a tetradentate binding mode [10c]. On-going work in
catalyst development uses this preferred bonding motif in the
preparation of highly reactive and stereoselective hydroamination
precatalysts suitable for even the most challenging hydroamination
substrates.
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We thank Prof. Raymond Andersen of the University of British
Columbia for access to the polarimeter. Likewise, thanks are
extended to Prof. Gregory Dake and coworkers of the University
of British Columbia for access to HPLC instruments. We are
grateful to Dr. Brian Patrick and Mr. Neal Yonson of the University
of British Columbia for their help with X-ray crystallographic
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the online version at doi:10.1016/j.jorganchem.2010.07.023.
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