Asymmetric hydroamination catalyzed by in situ generated chiral amidate and ureate complexes of zirconium - Probing the role of the tether in ligand design

Article abstract of DOI:10.1139/v11-091

Simple chiral proligands have been synthesized from inexpensive chiral starting materials. These amidate and ureate ligands support zirconium complexes that successfully catalyze intramolecular hydroamination with up to 26% ee. Several elements necessary for successful ligand design are highlighted and discussed. In particular, the strict control of metal geometry through multidentate tethered ligands is determined to be an essential aspect of future ligand development.

Full text of DOI:10.1139/v11-091

1222
Asymmetric hydroamination catalyzed by in situ
generated chiral amidate and ureate complexes of
zirconium — Probing the role of the tether in
ligand design
Philippa R. Payne, Jason A. Bexrud, David C. Leitch, and Laurel L. Schafer
Abstract: Simple chiral proligands have been synthesized from inexpensive chiral starting materials. These amidate and ure-
ate ligands support zirconium complexes that successfully catalyze intramolecular hydroamination with up to 26% ee. Sev-
eral elements necessary for successful ligand design are highlighted and discussed. In particular, the strict control of metal
geometry through multidentate tethered ligands is determined to be an essential aspect of future ligand development.
Key words: ureate, amidate, hydroamination, zirconium, enantioselective.
Résumé : On a réalisé la synthèse de proligands chiraux simples à partir de produits de départ chiraux peu coûteux. Ces li-
gands amidates et uréates supportent des complexes du zirconium qui peut catalyseur avec succès des hydroaminations intra-
moléculaires avec des excès d’énantiomère allant jusqu’à 26 %. On met en évidence et on discute de plusieurs éléments
nécessaires au bon développement d’un ligand. En particulier, on a déterminé qu’un aspect essentiel du développement du
futur ligand est le contrôle strict de la géométrie du métal par le biais de ligands multidentates bien fixés,
Mots‐clés : uréate, amidate, hydroamination, zirconium, énantiosélective.
[Traduit par la Rédaction]
ocyclic products.10 The development of a chiral ligand
Introduction
system that imparts both the high activity and selectivity of
the ureates and instills high enantioselectivity is of the utmost
importance for the efficient synthesis of chiral amines. Thus,
the synthesis of alternate urea proligands provides valuable
understanding regarding the role of the urea functionality
and the tether in the unprecedented reactivity accessed by
such ureate zirconium complexes.
Many chiral catalysts have been explored recently for
asymmetric hydroamination2b,5a,9d,11 and group 4 transition-
metal systems have been shown to be particularly effi-
cient.12,9a–9c However, excellent enantioselectivities (>90%)
have only been reported for a select number of catalyst–
substrate combinations, in particular those that make use of
axially chiral biphenyl/binaphthyl tethered ligands.7c,13 While
these contributions illustrate the potential power of such
transformations, they are only a first step toward realizing
the goal of a broadly applicable asymmetric alkene hydro-
amination catalyst. In an effort to better understand the limi-
tations of such catalysts, we present here our recent
investigations of simple untethered, chiral amide and urea
proligands that can be rapidly assembled from inexpensive,
enantiopure, and commercially available starting materials to
generate bis(amidate or ureate)bis(amido) zirconium com-
plexes (eq. [1]).
Hydroamination, the addition of an N–H bond across unsa-
turated C–C bonds, has shown great promise for the efficient
synthesis of amines.1 Numerous systems exist for this highly
desirable transformation, encompassing alkali and alkaline
earth metal,2 actinide3 and lanthanide,1c,2b early1d,2b,4 and
late5 transition-metal complexes, and main group metal sys-
tems.6 In particular, group 4 catalysts are attractive because
of their low toxicity, low cost, and improved stability over
lanthanide complexes1d while exhibiting excellent reactivity
comparable to late transition metals. N,O-Chelating amida-
te,4a,7 pyridonate,8 and ureate4b ligands for group 4 transition
metals have been investigated by our group and others9 for
hydroamination. The proligand that induces the most promis-
ing scope of reactivity for both inter- and intra-molecular hy-
droamination is a tethered urea proligand for an easily
synthesized zirconium complex (Fig. 1).4b This ureate preca-
talyst is the most generally useful group 4 metal complex re-
ported to date, promoting reactions with both primary and
secondary amine substrates, exhibiting vastly expanded sub-
strate scope and functional group tolerance, as well as
excellent chemoselectivity for hydroamination. The chemose-
lectivity is of particular interest, as other group 4 systems can
be plagued with unwanted hydroaminoalkylation side reac-
tions to give amine-substituted carbocycles rather than heter-
Received 18 March 2011. Accepted 31 May 2011. Published at www.nrcresearchpress.com/cjc on 13 September 2011.
P.R. Payne, J.A. Bexrud, D.C. Leitch, and L.L. Schafer. Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, BC V6T 1Z1 Canada.
Corresponding author: Laurel L. Schafer (schafer@chem.ubc.ca).
Can. J. Chem. 89: 1222–1229 (2011)
doi:10.1139/V11-091
Published by NRC Research Press

Payne et al.
1223
Fig. 1. Tethered bis(ureate) zirconium precatalyst for hydroamina-
tion.
five steps from L-valine (Scheme 1).21 A solid-state molecu-
lar structure was obtained (see Supplementary data).
Simple chiral amide proligands can also be synthesized in
minimal steps from any chiral ketone starting material22 via
reductive amination and subsequent derivatization with ben-
zoyl chloride (eq. [2]). This modular synthetic route, like the
route employed to synthesize the urea proligands, is attractive
as a wide variety of proligands can be synthesized in a few
steps from inexpensive starting materials. For the purpose of
this investigation, (–)-menthone was chosen to synthesize
chiral amide proligands.
iPr2N
NMe2
O
N
N
Zr NMe2
O
HNMe2
iPr2N
½1ꢀ
½2ꢀ
Other untethered chiral ligands have been successful as al-
ternatives for bidentate ligands in asymmetric transforma-
tions; in particular, chiral monodentate phosphoramidite
ligands have proven to be remarkably effective.14 This versa-
tile class of untethered ligands has exhibited excellent levels
of stereocontrol for a variety of asymmetric transformations
including allylic substitutions, hydrovinylations, cycloaddi-
tions, and hydrogenation of a wide variety of substrates.14b
The parent ligand (MonoPhos) is used industrially as a ligand
in the rhodium-catalyzed hydrogenation of a cinnamic acid
for the production of the renin inhibitor aliskiren.15
Here we report the facile synthesis of new chiral urea and
amide proligands from commercially available and inexpen-
sive chiral amino acids and amines. This study compares
and contrasts the reactivity and selectivity of amidate versus
ureate, cyclic versus acyclic, and tethered versus untethered
ligands, and explores the use of untethered chiral ligands for
affecting enantioselectivity. Through the characterization of
the resultant coordination complexes in these systems we can
identify critical features required for improved reactivity and
selectivity.
Interestingly, upon isolation it was determined that the re-
action produces a mixture of compounds (1R,2R,5R)-HL2
and (1R,2S,5R)-HL3 (eq. [2]). As determined by X-ray crys-
tallography (see Supplementary data), the stereochemistry of
these compounds is identical in the 5-position of the cyclo-
hexyl ring as well as the stereogenic centre adjacent to nitro-
gen. However, epimerization occurred over the course of the
reaction resulting in differing stereochemistry at the isopropyl
position. The oxime formed in the initial step of the reaction
may tautomerize to allow the observed epimerization at the
2-position. Compounds HL2 and HL3 can be separated by
selective recrystallization.
These proligands are representative examples of a large
class of readily accessed auxiliary ligands. The synthetic
routes employed are modular and use inexpensive enantio-
pure starting materials such as amino acids or chiral ketones.
Notably, the urea proligands employed here are cyclic and of
a defined conformation, whereas the amide proligands have
two possible conformations accessible (Fig. 2), which may
impact metal chelation modes.4a
Results and discussion
Cyclic ureas, efficiently synthesized from the chiral pool of
natural amino acid starting materials, are an attractive modu-
lar class of proligands for the generation of group 4 asym-
metric hydroamination precatalysts. While cyclic ureas have
been investigated for their medicinal properties,16 examined
for potential application as Lewis basic organocatalysts,17
used as chiral auxiliaries for asymmetric syntheses,18 and uti-
lized as substrates for intermolecular hydroamination,19 these
compounds represent a new proligand motif for coordination
of early transition metals. Zirconium alkyl and amido com-
plexes supported by related achiral imidazolone ligands have
recently been reported and have been shown to be effective
catalysts for intramolecular hydroamination.20
Using urea and amide proligands, a series of zirconium
complexes can be easily synthesized by a simple protonolysis
route from Zr(NMe2)4 (eq. [1]). Synthesis of the bis(ureate)
bis(amido) zirconium complex 1 results in crude material
having elemental analysis data consistent with the target com-
1
plex. However, the complicated H and 13C NMR spectra for
this compound suggest that multiple species are present in
the solution phase. Synthesis of complex 2 using the amide
proligand HL2 proceeds in an analogous manner to generate
an amorphous material having elemental analysis data consis-
tent with that of the target complex. NMR spectral data are
also notably complicated, presumably because of the pres-
ence of multiple isomers in solution. No free ligand remains
in either case, as is evident by loss of the diagnostic amide
The synthesis of proligand HL1 proceeds in a straightfor-
ward manner, and produces HL1 as a crystalline solid in
Published by NRC Research Press

1224
Can. J. Chem. Vol. 89, 2011
Scheme 1. Modular route for synthesis of urea proligand HL1.
occurring under catalytic conditions to generate Zr(NMe2)4
in solution, which could also act as a catalyst for the transfor-
mation resulting in the substrate scope limitations and poor
enantioselectivities observed. Ligand redistribution and dis-
proportionation has been observed previously with group 4
amidate systems9b and has been postulated to occur during
the attempted synthesis of zirconium alkyl complexes sup-
ported by acyclic untethered ureate ligands.24
CyNH2,
HOBt,
DCC
O
O
O
Boc2O,
NEt3
iPr
iPr
iPr
Cy
HO
HO
N
1:1
dioxane:
H2O
DIPEA,
CH2Cl2
H
NH2
NHBoc
NHBoc
94% yield
74% yield
TFA,
CH2Cl2
O
iPr
Tr iphos-
gene
Indeed, in the only example of crystalline material obtained
from a solution of complex 1, an unexpected ligand stoichi-
ometry (three ligands for two metal centres) is observed in
the isolated product (Fig. 3). This suggests that ligand redis-
tribution is a complicating factor under catalytic conditions
and provides a rationale for both the poor ees and limited sub-
strate scope observed. These crystals were obtained in very
low yield over the course of a few weeks from a saturated
pentane solution of the crude material cooled to –30 °C.
The isolated bimetallic complex has three bridging ureate
ligands; the steric bulk of the ligand perhaps being insuffi-
cient to support monomeric species of the highly electro-
philic metal centres. The dimeric nature of this species is not
without precedent as the related zirconium imidazolone com-
plexes reported20 also assume dimeric solid-state structures
with bridging imidazolone ligands. The isolated chiral com-
pound is C1 symmetric with pseudo-octahedral geometry
about each zirconium atom. Selected bond lengths and angles
for complex 4 (Fig. 3) are summarized in Table 3 and crys-
tallographic parameters are summarized in Table 4. The C–
N2,N4,N6 (1.317–1.325 Å) and C–O (1.271–1.290 Å) bond
lengths of the metal-bound ureate fragments are consistent
with moderate delocalization within the ureate backbone.
The respective C–N bonds to the tertiary amine (N1,N3,N5,
1.361–1.368 Å) are slightly longer than those of the bonding
moiety; however, these and the sum of 353° for the subtend-
ing angles are indicative of sp2 hybridization and limited
lone-pair donation to the p system. Interestingly, the Zr–N
bonds to the ureate ligands (2.2372(9) and 2.2459(9) Å) are
slightly shorter than those of the tethered ureate complex
(2.279(1) Å),4b the exception being the Zr–N6 bond, which
is presumably lengthened because of the presence of the
strongly donating trans-dimethylamido ligand. Comparable
bis(amidate)bis(amido) Zr–N(amidate) bonds are significantly
longer (~2.32 Å).25,12d The Zr–O bond lengths in complex 4,
excluding those related to O1 (which is bridging two metal
centres), are significantly shorter (by >0.1 Å), than those of
related bis(amidate)bis(amido)12e,25 and bis(ureate)bis(amido)4b
zirconium complexes. Zr–NMe2 (2.035–2.130 Å) bond lengths
in complex 4 are slightly longer on average than Zr=N bonds
reported in the literature (<2.043 Å).25 Related tethered12d and
untethered25 bis(amidate)bis(amido) zirconium complexes have
Zr–N(amido) bond lengths of 2.065–2.069 Å and 2.043(3) Å,
respectively. The tethered bis(ureate)bis(amido)4b zirconium
complex has Zr–NMe2 bond lengths of 2.0292(2) Å.
Cy
LiAlH4
Cy
THF, ?
Cy
N
iPr
NH2
iPr
NH2
N
O
N
H
NH
CH2Cl2
H
84 %yield
46% yield overall
88% yield
90% y ield
L1
H
Fig. 2. Flexible cisoid and transoid configurations of amide versus
rigid cyclic urea proligand.
R
O
NH
R
O
R
O
N
or
NH
HN
?
?R
R?
R
N–H signal at 7.18 ppm (HL1) and 6.15 ppm (HL2). Un-
fortunately, the product mixtures are resistant to recrystalliza-
tion and high yielding crystalline material could not be
obtained.
Although rigorous characterization of the resultant coordi-
nation complexes could not be achieved, the in situ prepared
complexes are suitable for screening for hydroamination reac-
tivity. Thus, the abilities of L1–L3 ligated complexes to me-
diate enantioselective hydroamination were investigated for
the cyclization of 2,2-diphenyl-1-amino-4-pentene, a standard
test substrate (Table 1). The use of cyclic ureate L1 in iso-
lated complex 1 (Table 1, entry 1) and the in situ procedure
(entry 2) generates the heterocyclic product in good yield
with low enantioselectivity. The complex with amidate proli-
gand L2 was also tested and improved enantioselectivity is
observed (entry 3). Lowering the reaction temperature does
not improve the enantioselectivity (entry 4). The zirconium
precatalyst with ligand L3 showed comparable reactivity to
complex 2, but was unsuccessful in mediating enantioselec-
tivity (entry 5). These results show that strict control of the
geometry about the metal centre is required to control enan-
tioselectivity for this reaction.
One of the exceptional elements of the tethered urea zirco-
nium catalyst (Fig. 1), is the broadened substrate scope it dis-
plays compared with other existing group
4 catalyst
systems.4b To discern if this improved scope of reactivity
can be attributed to the urea functionality or to the tether, re-
activity with a broader range of substrates was investigated
using in situ prepared complex 1 (Table 2).4b The substrate
scope using complexes prepared with proligand HL1 is very
limited; the reaction progresses in good yield to generate 5-
and 6-membered heterocycles (Table 2, entries 1–5), however,
no conversion to product is observed with secondary amines,
internal olefins, and substrates without gem-disubstituents.
This limited reactivity profile is reminiscent of substrate
scope limitations previously reported for Zr(NMe2)4 as a pre-
catalyst for the intramolecular hydroamination of amino-
alkenes.23 We suggest that ligand redistribution could be
Summary and conclusions
Easily prepared chiral ureate and amidate ligands can be
efficiently assembled from inexpensive chiral ketones or
amino acids. The in situ prepared complexes using untethered
urea and amide proligands result in modestly enantioselective
Published by NRC Research Press

Payne et al.
1225
Table 1. Enantioselectivity hydroamination studies with chiral urea and
amide proligands.
Ph
Ph
Ph Ph
10 mol% catalyst
?
NH2
d8-toluene
N
H
Entry
Catalyst
L1c
Conditions
Yield (%)a
92
>98
>98
91
ee (%)b
11
12
26
23
1
2
3
4
5
12 h, 100 °C
4 h, 100 °C
5 h, 110 °C
48 h, 65 °C
48 h, 65 °C
L1d
L2
L2
L3d
94
<5
a1H NMR yield determined using 1,3,5-trimethoxybenzene as a standard.
1
bee based on H NMR spectroscopy of derivatized product with (+)-(S)-a-meth-
oxy-a-trifluoromethylphenylacetyl chloride.
cReaction time was not optimized; 5 mol% complex used.
dCatalyst prepared in situ using 10 mol% Zr(NMe2)4 and 20 mol% proligand.
Table 2. Reactivity studies using proligand HL1 for intramolecular hydroamination with alkenes.
R2
R2
20 mol% HL1
10 mol% Zr(NMe2)4
R2 R2
?
H
N
R1
N
R1
( )n
d8-toluene
Entry
1b
Substrate
Product
Conditions
15 h, 100 °C
Isolated yield (%), ee (%)a
>98, 12c
2
4 h, 100 °C
92, 11
3
4
8 h, 100 °C
89, <5
71, ndd
18 h, 100 °C
5
24 h, 145 °C
>95, ndc
1
aee based on H NMR spectroscopy of derivatized product with (+)-(S)-a-methoxy-a-trifluoromethylphenylacetyl chlor-
ide.
b5 mol% complex 2.
1
cNMR yield determined by H NMR using 1,3,5-trimethoxybenzene as internal standard owing to product volatility.
dDerivitized with p-tolylsulfonyl chloride to aid in isolation.
cyclohydroamination reactions with reactivity reminiscent of
Zr(NMe2)4, suggesting that ligand redistribution may be oc-
curring. Despite the moderate reactivity and poor selectivity
observed, these results provide important insights for ad-
vanced ligand design; improvements in the state of the art for
these catalyst systems must take advantage of the enhanced
stability and reactivity trends of tethered amidate and ureate
ligands. The role of the tether is not restricted to control of
geometry at the metal centre but also dramatically improves
stability by reducing the propensity for ligand redistribution.
The incorporation of these design principles in a catalyst
system that demonstrates the unparalleled reactivity imparted
by previously reported tethered proligands4b with chirality in-
tegrated from inexpensive starting materials such as chiral ke-
tones or amino acids is presently under investigation and
results will be reported in due course.
Published by NRC Research Press

1226
Can. J. Chem. Vol. 89, 2011
Fig. 3. ORTEP representation of the solid-state molecular structure
of 4 (ellipsoids plotted at 50% probability; methyl groups of
dimethylamido ligands (N7–11) and cyclohexyl groups attached to
N1, N3, and N5 of the ureate ligands have been removed for
clarity).
Materials and methods
Reaction materials and instrumentation
All reactions were preformed in oven-dried glassware
under inert atmosphere conditions of dry nitrogen unless
noted otherwise, using Schlenk line or glovebox techniques.
Catalytic reactions were performed in Teflon-sealed J. Young
tubes (5 mm). Toluene, pentanes, and hexanes, which were
used as reaction solvents for catalyst preparation and recrys-
tallization, were purified by passage over an activated alumi-
num oxide column and degassed prior to use.
Dichloromethane was distilled from CaH2 and degassed. d8-
Toluene was degassed and dried over activated 4 Å molecular
sieves overnight before use. Reagents for substrate and proli-
gand synthesis were purchased from commercial suppliers and
used without further purification. Zr(NMe2)4 was purchased
from Strem and used as received. 1,3,5-Trimethoxybenzene,
used as an internal standard, was purchased from Sigma-
Aldrich and purified by sublimation under reduced pressure.
Flash chromatography was performed using SilicaFlash F60
1
silica gel (230–400 mesh). H and 13C NMR spectra were re-
corded on either a Bruker 300 MHz, 400 MHz Advance, or
600 MHz spectrometer at ambient temperature unless noted
otherwise. Chemical shifts are reported in parts per million
(ppm) relative to the corresponding residual solvent signal:
chloroform 1H 7.26 ppm, 13C 77.0 ppm; benzene 1H
1
7.16 ppm, 13C 128.39 ppm; and toluene H 2.09 ppm. Multi-
plicities are listed as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and the coupling constants are given
in Hz. Single crystal X-ray structure determinations and mass
spectral and elemental analyses determinations were per-
formed at the Department of Chemistry, University of British
Columbia, Vancouver, British Columbia.
Synthesis of proligands HL1–HL3
Table 3. Relevant bond lengths (Å) and angles (°) for
complex 2.
(S)-1-Cyclohexyl-4-isopropylimidazolidin-2-one HL1
The precursor (S)-2-amino-N-cyclohexyl-3-methylbutan-
amide was prepared by the procedure described in the litera-
ture26 from L-valine with cyclohexylamine substituted for
tert-butyl amine and purified by recrystallization from ethyl
acetate prior to N-Boc deprotection, which proceeded
cleanly. (S)-N1-Cyclohexyl-3-methylbutane-1,2-diamine was
prepared through reduction with LiAlH4 as described in the
literature.27 (S)-N1-Cyclohexyl-3-methylbutane-1,2-diamine
(2.62 g, 14.176 mmol) was dissolved in dry CH2Cl2 and the
solution was cooled to 0 °C prior to addition of triphosgene
(1.472 g, 4.962 mmol) in one portion. Pyridine (2.28 mL,
28.352 mmol) was added and the solution warmed to room
temperature with stirring. After 3 h the solution was diluted
with 1 mol/L HCl and the organic layer was collected. The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and
the organic layers were combined, dried over MgSO4, fil-
tered, and concentrated. Pure (S)-1-cyclohexyl-4-isopropyl-
imidazolidin-2-one was obtained as colourless needles in
84% yield by recrystallization from a minimal amount of
CH2Cl2. 1H (C6D6, 600 MHz) d: 0.69 (2H, d, J =
6.78 Hz, –CH3), 0.84–0.90 (4H, m, –CH3, CH2 of Cy),
1.04–1.19 (4H, m, CH2 of Cy), 1.38–1.44 (2H, m, –CH
(CH3)2, CH2 of Cy), 1.54–1.68 (4H, m, CH2 of Cy), 2.68
(1H, t, J = 7.68 Hz, –N(Cy)CH2CH–), 2.96 (1H, t, J = 8.58 Hz,
Bond lengths (Å)
Bond angles (°)
Sum about N1
Sum about N3
Sum about N5
C1–N2
1.323(1)
348.7
354.3
355.6
C13–N4
C25–N6
C1–N1
1.325(1)
1.317(1)
1.361(1)
1.368(1)
1.290(1)
1.271(1)
1.282(1)
1.362(1)
2.2459(9)
2.2372(9)
2.073(1)
2.035(1)
2.4420(8)
2.1386(8)
2.3353(9)
2.073(1)
2.077(1)
2.130(1)
2.3286(8)
2.1745(8)
C25–N5
C1–O1
C13–O2
C25–O3
C13–N3
Zr1–N2
Zr1–N4
Zr1–N7
Zr1–N8
Zr1–O1
Zr1–O3
Zr2–N6
Zr2–N9
Zr2–N10
Zr2–N11
Zr2–O1
Zr2–O2
Published by NRC Research Press

Payne et al.
1227
Table 4. Crystallographic parameters for complex 4.
Parameter
Empirical formula
fw
Complex 4
C46H93N11O3Zr2
1030.75
Colour, habit
Crystal dimensions (mm)
Crystal system
Space group
Z
Yellow, prism
0.4×0.3×0.2
Orthorhombic
P212121
4
a (Å)
12.493(1)
b (Å)
20.562(2)
c (Å)
20.876(2)
a (°)
90
b (°)
90
g (°)
90
Collection ranges
Temperature (K)
Volume (Å3)
h = –17→17, k = –29→29, l = –29→29
100
5362(1)
Dcalcd (Mg m–3)
1.277
Radiation
Mo Ka, l = 0.71073 Å
Absorption coeff. (m) (mm–1)
Absorption correction
F(000)
0.44
Multiscan
2200
qmin to qmax (°)
1.9–30.1
Measured reflections
Independent reflections
Data/restraints/parameters
Maximum shift/error
Goodness-of-fit on F2
Final R indices (I > 2s(I))
R indices (all data)
Absolute structure parameter
Extinction coefficient
Largest diff. peak and hole (e Å–3)
231 343
15 815 (Rint = 0.025)
15 815/0/576
0.003
1.087
R1 = 0.017,wR2 = 0.045
R1 = 0.0183, wR2 = 0.0451
0.000(11)
N/A
0.447 and –0.249
–N(Cy)CH2CH–), 3.03 (1H, q, J = 7.42 Hz, –NHCH–), 3.95
(1H, t, J = 11.3 Hz, CH of Cy), 7.18 (1H, s, –NH). 13C
(C6D6, 150 MHz) d: 18.4 (CH3), 18.9 (CH3), 26.2 (CH2),
26.3 (CH2), 26.3 (CH2), 30.4 (CH2), 31.3 (CH2), 34.0 (CH),
44.8 (CH2), 51.3 (CH), 56.8 (CH), 162.7 (C). HRMS calcd
for C12H22N2O: 210.1733; found: 210.1732.
cooled to 0 °C prior to addition of benzoyl chloride
(2.60 mL, 22.6 mmol) and NEt3 (8.0 mL, 57 mmol). After
stirring for 20 h, the solution was diluted with CH2Cl2
(240 mL), washed successively with 1 mol/L HCl (3 ×
50 mL), 1 mol/L NaOH (3 × 50 mL), water (50 mL), and
brine (50 mL). The organic phase was then dried over
MgSO4, filtered, and concentrated. Column chromatography
(18:1:1 hexanes–CH2Cl2–MeOH) afforded ~2 g of a mixture
of crude HL2 and HL3 in a ratio of approximately 3:1 in fa-
vor of HL2. Repeated recrystallization from Et2O afforded
HL2 as a pure compound and crystals suitable for X-ray
crystallography. Repeated recrystallization from hexanes/
CH2Cl2 (~4:1) of the residue afforded HL3 as a pure com-
pound and crystals suitable for X-ray crystallography.
N-((1R,2R,5R)-2-Isopropyl-5-methylcyclohexyl)-benzamide
HL2 and N-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-
benzamide HL3
NH2OH·HCl (2.11 g, 30.4 mmol), pyridine (2.50 mL,
30.9 mmol), and (–)-menthone (3.50 mL, 20.3 mmol) were
dissolved in EtOH (30 mL) and the mixture was heated at re-
flux for 40 h. The crude reaction mixture was concentrated,
dissolved in Et2O (300 mL), washed successively with water
(3 × 50 mL) and brine (50 mL), dried over Na2SO4, filtered,
and concentrated. The crude oxime mixture was dissolved in
THF (100 mL) and cooled to 0 °C prior to portionwise addi-
tion of LiAlH4 (1.3 g, 34.3 mmol). The reaction mixture was
heated at reflux for 40 h. After cooling the solution was
quenched with sequential addition of water (1.5 mL), aque-
ous 1 mol/L NaOH (1.5 mL), Et2O (100 mL), and water
(4.5 mL). After stirring for 0.5 h, the mixture was filtered
and the filtrate was dried over MgSO4. Following concentra-
tion, dry CH2Cl2 (60 mL) was then added and the flask was
(N-((1R,2R,5R)-2-Isopropyl-5-methylcyclohexyl)-
benzamide) HL2
1H NMR (CDCl3, 400 MHz) d: 0.90–1.00 (9H, m), 1.20–
1.32 (1H, m), 1.53–1.72 (7H, m), 1.78–1.86 (1H, m), 4.32–
4.38 (1H, m, –CH(NHBz)–), 6.17–6.18 (1H, br d, –NHBz),
7.39–7.49 (3H, m, Ar-H), 7.72–7.77 (2H, m, Ar-H). 13C
NMR (CDCl3, 100 MHz) d: 21.7 (CH3), 21.7 (CH3), 22.3
(CH3), 24.0 (CH2), 27.6 (CH), 29.3 (CH), 30.4 (CH2), 36.6
(CH2), 44.3 (CH), 49.7 (CH), 126.7 (CH), 128.6 (CH),
131.2 (CH), 135.2 (C), 166.3 (C). MS (EI) m/z: 259 (M+).
Published by NRC Research Press

1228
Can. J. Chem. Vol. 89, 2011
Chem. 2005, 690 (20), 4441. doi:10.1016/j.jorganchem.2004.
11.058; (b) Hultzsch, K. C. Org. Biomol. Chem. 2005, 3 (10),
1819. doi:10.1039/b418521h; (c) Arrowsmith, M.; Crimmin,
M. R.; Barrett, A. G. M.; Hill, M. S.; Kociok-Köhn, G.;
Procopiou, P. A. Organometallics 2011, 30 (6), 1493. doi:10.
1021/om101063m.
Anal. calcd for C19H25NO: C 78.72, H 9.71, N 5.40; found:
C 79.10, H 9.76, N 5.42.
(N-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)-benzamide)
HL3
1H NMR (CDCl3, 400 MHz) d: 0.83–0. 39 (9H, m), 1.16–
1.19 (2H, m), 1.45–1.60 (1H, m), 1.67–1.76 (2H, m), 1.94–
2.01 (1H, m), 2.05–2.11 (1H, m), 3.95–4.04 (1H, m, –CH
(NHBz)–), 5.82–5.85 (1H, br d, –NHBz), 7.40–7.50 (3H, m,
Ar-H), 7.74–7.76 (2H, m, Ar-H). 13C (CDCl3, 100 MHz) d:
16.3 (CH3), 21.2 (CH3), 22.2 (CH3), 24.0 (CH2), 27.1 (CH),
31.9 (CH), 34.6 (CH2), 43.2 (CH2), 48.4 (CH), 50.4 (CH),
126.8 (CH), 128.5 (CH), 131.2 (CH), 135.2 (C), 166.7 (C).
MS (EI) m/z: 259 (M+). Anal. calcd for C19H25NO: C 78.72,
H 9.71, N 5.40; found: C 78.64, H 10.00, N 5.62.
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Procedure for in situ hydroamination
Proligand HL1 (15.8 mg, 0.075 mmol) and Zr(NMe2)4
were weighed into a small vial. d8-Toluene (0.47 mL) and
1,3,5-trimethoxybenzene (0.03 mL of a 1.25 mol/L solution
in d8-toluene) were added and the solution shaken gently.28
The hydroamination substrate was then added (0.375 mmol)
and the solution transferred to a J. Young NMR tube. The
solution was then heated at reaction temperature and reaction
1
progress was monitored by H NMR spectroscopy.
Supplementary data
Supplementary data are available for this article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/v11-091. CCDC 829545–829548 contain the X-ray
data in CIF format for this manuscript. These data can be ob-
tained, free of charge, via http://www.ccdc.cam.ac.uk/cgi-bin/
catreq.cgi (Or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1Ez, UK; fax +44
1223 336033; or deposit @ccdc.cam.ac.uk).
(8) Bexrud, J. A.; Schafer, L. L. Dalton Trans. 2010, 39 (2), 361.
doi:10.1039/b913393c.
(9) (a) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P.
Organometallics 2007, 26 (7), 1729. doi:10.1021/om061087l;
(b) Zi, G.; Zhang, F.; Xiang, L.; Chen, Y.; Fang, W.; Song, H.
Dalton Trans. 2010, 39 (17), 4048. doi:10.1039/b923457h; (c)
Zi, G.; Liu, X.; Xiang, L.; Song, H. Organometallics 2009, 28
(4), 1127. doi:10.1021/om801061v; (d) Reznichenko, A. L.;
Hultzsch, K. C. Organometallics 2010, 29 (1), 24. doi:10.
1021/om9008907.
(10) (a) Roesky, P. W. Angew. Chem. Int. Ed. 2009, 48 (27), 4892.
doi:10.1002/anie.200900735; (b) Bexrud, J. A.; Eisenberger,
P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. J. Am. Chem. Soc.
2009, 131 (6), 2116. doi:10.1021/ja808862w; (c) Kubiak, R.;
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Acknowledgements
The authors gratefully acknowledge Boehringer Ingelheim
(Canada) Ltd. and the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) for supporting this work.
P.R.P. thanks NSERC for an Alexander Graham Bell Canada
Graduate Scholarship (CGS D). J.A.B. thanks NSERC for a
Postgraduate Scholarship (PGS D) award. D.C.L. thanks
NSERC for a CGS D scholarship. The authors thank N. Yonson,
Dr. B. Patrick, and Dr. N.C. Payne for help with the X-ray
crystallography studies.
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