Sterically encumbered chiral amino alcohols for titanium-catalyzed asymmetric intramolecular hydroamination of aminoallenes

Article abstract of DOI:10.1016/j.tetasy.2009.04.013

A variety of sterically encumbered amino alcohol ligands were prepared in a two-step modular synthesis. The titanium complexes of these ligands were prepared in situ and used as catalysts for hydroamination. The intramolecular hydroamination of 6-methyl-h

Full text of DOI:10.1016/j.tetasy.2009.04.013

Tetrahedron: Asymmetry 20 (2009) 1279–1285
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Sterically encumbered chiral amino alcohols for titanium-catalyzed
asymmetric intramolecular hydroamination of aminoallenes
Amanda J. Hickman , Lauren D. Hughs , Casey M. Jones , Hanhan Li , Joanne E. Redford,
*
Samuel J. Sobelman, J. Andrew Kouzelos, Adam. R. Johnson
Department of Chemistry, Harvey Mudd College, 301 Platt Blvd., Claremont, CA 91711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of sterically encumbered amino alcohol ligands were prepared in a two-step modular synthesis.
The titanium complexes of these ligands were prepared in situ and used as catalysts for hydroamination.
The intramolecular hydroamination of 6-methyl-hepta-4,5-dienylamine at 135 °C with 5 mol % catalyst
gave exclusively 2-(2-methyl-propenyl)-pyrrolidine with enantiomeric excesses up to 16%.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 March 2009
Accepted 21 April 2009
Available online 15 May 2009
1. Introduction
product mixtures, and has therefore been less studied. Amidate
complexes of titanium do catalyze the intermolecular reaction
The hydroamination reaction, which is the addition of an N–H
bond across an unsaturated C–C bond, has been the subject of
ever-increasing scrutiny due to its highly atom-economical forma-
tion of nitrogen-containing compounds of potential utility for
industrial and pharmaceutical applications. The reaction is gener-
ally thermoneutral or slightly exothermic, but the reaction requires
a catalyst due to the large electronic repulsion between the nitro-
gen and the unsaturated group.1 Both inter- and intramolecular
variations of the reaction have been reported for the hydroamina-
tion of olefins, alkynes, and allenes, and the field has been exten-
sively reviewed.1–7
regioselectively for both aryl and alkylamines.40 More interesting,
from a product standpoint, is the intramolecular reaction, as the
products are highly valuable nitrogen-containing heterocycles
with a pendant vinyl group for further substitution (Scheme 1, 3a
and 3b). The intramolecular cyclization by silver, mercury, palla-
dium,41–44 titanium,45,46 and lanthanides is also known.39,47,48
R
H
NH2
b
a
N
N
R'
R'
R
Catalysts for the reaction range from alkali metal bases,8–11
early12–16 and late17,18 transition metal complexes, gold,19–25 and
lanthanide6,26,27 complexes, but there has been a recent significant
focus on the early metal catalysts due to their relatively lower air-
and moisture sensitivity compared to lanthanide organometallics.
Titanium, zirconium, and yttrium bisamide derivatives catalyze
the intramolecular cyclization of aminoalkynes to give the imine
product.28,29 Neutral group IV amide,30 amidate,31 pyrrolyl,32 and
cyclopentadienyl complexes33,34 are effective catalysts for the
intramolecular hydroamination of unactivated olefins, as are cat-
ionic zirconocene and titanocene complexes.35 Often, the sub-
strates for the olefin cyclizations require gem dialkyl substitution
that encourages preorganization via either a compression of the
bond angle (the Thorpe–Ingold effect)36 or raising the energy of
the ground state (the ‘reactive rotamer’ effect).37
·
R'
R
2a
, R = R' = CH3
1a
, R = R' = CH3
3a
, R = R' = CH3
3b
2b
1b
, R = CH3, R' = H
, R = CH3, R' = H
, R = CH3, R' = H
Scheme 1.
The mechanism for the intramolecular hydroamination has
been the subject of careful investigation. Lanthanide metal and cat-
ionic group IV metal catalysts react first to form a neutral or cat-
ionic amido complex which undergoes a 1,2-insertion reaction on
the unsaturated carbon–carbon bond to form a metal alkyl com-
plex.39,47,48 The addition of a second equivalent of amine substrate
leads to protonolysis of the alkyl and regeneration of the amido
complex. In a closely related mechanism, neutral early metal com-
plexes initially react with a substrate to form an imido complex
(Scheme 2). A subsequent [2+2] cycloaddition with the unsatu-
rated bond results in an azametallocycle that can be removed by
protonation by the next equivalent of incoming amine.45,46 Com-
putational studies have helped to confirm and elaborate upon the
The hydroamination of allenes is thermodynamically more
favorable than that of alkenes,38,39 but leads to more complex
* Corresponding author.
E-mail address: Adam_Johnson@hmc.edu (A. R. Johnson).
These authors contributed equally to the preparation of this manuscript.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.013

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A. J. Hickman et al. / Tetrahedron: Asymmetry 20 (2009) 1279–1285
X2Ti
N
+ H2NR
- 2 HNMe2
X2Ti(NMe2)2
X2Ti
R'
N
·
R'
HN
NHR
X2Ti
H2NR
N
R'
R'
Scheme 2.
1)
2)
O
O
O
H2N
NH
O
NH
OH
L-H2VPM
Scheme 3. Reagents and conditions: (1) NaHCO3/acetone/NaBH(OAc)3 and (2) MeMgBr.
basic mechanistic picture described here for aminoallene
substrates.49,50
clized product with enantioselectivies as high as 80%ee.71 Progress
on the asymmetric cyclization of aminoallenes has focused on the
use of gold complexes with bulky chiral phosphine complexes,
resulting in high enantioselectivities (70–90%ee).72–74 In a related
reaction, when starting with chiral allenes, catalysis with gold ha-
lides can yield products that retain their configuration.75,76
The first reported asymmetric intramolecular hydroamination
of an allene by a titanium catalyst was reported by our group in
2004 using chiral titanium complexes with amino alcohol-derived
ligands.77 Herein, we report the results of the hydroamination
using improved ‘second generation’ catalysts. We sought to im-
prove our initial results through rational modification of our cata-
lysts. Our ‘first generation’ catalysts were amino alcohols with
primary alcohols and varied steric protection at nitrogen and the
carbon alpha to the nitrogen. Due to the modular nature of the li-
gand design, it was straightforward to prepare new tertiary alcohol
derivatives with altered steric environments at the carbon alpha to
the oxygen (Fig. 1).
As the cyclization of aminoalkene or -allene substrates results
in the formation of a chiral nitrogen heterocycle, there has been
much effort in further development of the asymmetric reaction.
The first example of asymmetric hydroamination was reported
for the cyclization of aminoolefins using a chiral lanthanide cata-
lyst,51 with enantioselectivities of up to 74%ee. Chiral lanthanocene
catalysts can undergo epimerization under catalytic hydroamina-
tion conditions (presence of amine),52 although high enantioselec-
tivities can still be observed with equilibrium epimer ratios of
95:5.53,54 Still, it is important to develop improved chiral ligands
that are resistant to this process. The asymmetric intramolecular
hydroamination of alkenes using lanthanide catalysts has been fur-
ther optimized to give very high enantioselectivities ranging from
70% to 90%ee.55,56 Ligands giving high enantioselectivities include
those that are binaphthyl based,57–60 or polydentate amide
based.61,62
More recently, a variety of cyclopentadienyl and imido com-
plexes of the early metals have been examined for asymmetric
reactions. For the intramolecular reaction of aminoalkenes, group
IV alkyl complexes with chelating bis-amidate ligands catalyze
the enantioselective hydroamination/cyclization with enantiose-
lectivities above 90%ee.63,64 The corresponding zirconium amide
complexes also catalyze the cyclization if the substrate has gem-di-
methyl substitution. Chiral binaphtholate-derived yttrium com-
plexes catalyze the asymmetric hydroamination of aminoalkenes
with enantioselectivities up to 89%ee.65–67 Chiral polydentate
N,O-ligands on zirconium result in the cyclization of aminoalkenes
with enantioselectivities of up to 82%ee.68 Related chemistry using
yttrium results in cyclizations with enantioselectivities in the 20–
40%ee range.69 Chiral yttrium amide complexes were used to
investigate the cyclization of a variety of substrates, all with 2,2-
dialkyl substitution; enantioselectivities were as high as 68%ee.70
Group IV complexes with a variety of chiral bidentate ligands cat-
alyze the hydroamination of aminaoalkenes enantioselectively.
Zirconium diphosphinic amides were found to be the best cata-
lysts, and the optimized reaction conditions gave yields of the cy-
2. Results and discussion
2.1. 1. Synthesis of ligands
The ligands used in this study (Fig. 1) were prepared in a two-
step procedure from the methyl esters of the respective amino
acids such as valine (V) and phenylalanine (P). The ligands were
prepared with substitution at the amino nitrogen with isopropyl
(P), cyclohexyl, (C) or adamantyl (A) groups, and at the position
a
to the alcohol with methyl (M), butyl (B), or phenyl (P) groups.
The synthesis and nomenclature is illustrated for -H2VPM (Valin-
L
ol-N-Propyl-diMethyl, Scheme 3). First, the N-isopropyl group was
added to the amino nitrogen (the free base is generated in situ by
the addition of sodium bicarbonate) of valine methyl ester by
reductive amination of the corresponding ketone, acetone in this
case, with NaBH(OAc)3 to give the intermediate.78,79 Second, the
ester was alkylated to the tertiary alcohol with methyl magnesium
bromide to generate the desired ligand. A total of 17 new ligands
were prepared for this study; the primary alcohol derivatives

A. J. Hickman et al. / Tetrahedron: Asymmetry 20 (2009) 1279–1285
1281
R'
R'
R'
R'
R
NH
OH
R NH
OH
L
-H2VPH(M, B, P), R = iPr, R' = H (Me, nBu, Ph)
L
-H2PPH(M, B, P), R = iPr, R' = H (Me, nBu, Ph)
L
L-H2VCH(M, B, P), R = c-C6H11, R' = H (Me, nBu, Ph)
-H2VAH (M, B, P ), R = 2-Ad, R ' = H (M e, nBu, Ph)
-H2PCH(M, B, P), R = c-C6H11, R' = H (Me, n Bu, Ph)
L
-H2PAH(M, B, P), R = 2-Ad, R' = H (Me, nBu, Ph)
L
Figure 1. Ligands used in this study (iPr = CCH(CH3)2, 2-Ad = 2-adamantyl; the ligands are named as illustrated for l-H2VPM (Valinol-N-Propyl-diMethyl).
(VPH, VCH, VAH, PPH, PCH, and PAH) were reported previously.77,80
Although it was possible to prepare the phenyl derivatives for most
of the ligands, it is still not possible to prepare the VPP ligand. N-
Isopropyl-valine methyl ester did not react cleanly with either
commercial PhMgBr or PhLi, or with freshly prepared PhMgBr;
the same batches of alkylating agent did react cleanly with other
starting materials to generate the phenyl derivatives of those li-
gands. All reactions that failed proceeded to give multiple products
that could not be conclusively identified by NMR or IR spectros-
copy. The reason for the failed synthesis of this ligand is unknown.
As reported previously for the first generation ligands of valine
and phenylalanine,77 no evidence was observed for the racemiza-
tion of the ligands during their synthesis. The addition of one
and two equivalents of (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol
to the appropriate valine- and phenylalanine-derived ligands re-
sulted in the shifting of the ligand hydrogen signals due to the for-
mation of transient diastereomeric complexes, but no splitting of
the resonances into two sets of peaks was observed, indicating that
the ligands were enantiomerically pure.
Livinghouse and Lee reported the use of the chiral resolving
agent (R)-(O)-acetylmandelic acid for the determination of the
enantiomeric excess of hydroamination products by NMR spec-
troscopy.66 The product amine and the benzene-d6 were separated
from the catalyst solution by vacuum transfer, and 1 equiv of (R)-
(O)-acetylmandelic acid was added. The NMR spectrum revealed
a distinct diastereomeric splitting of the doublet for the pyrrolidine
product at 5.3 ppm with a baseline resolution. Integration of the
peaks allowed for the determination of the percent of each stereo-
isomer, although the absolute stereochemistry of the isomers re-
mains to be determined. All ligands show modest but
reproducible enantioselectivities of up to 16% (Table 1). In several
cases, enantiomeric excesses were determined by preparing benz-
amide derivatives of the catalysis products and then separating
them on a chiral GC column (Chiraldex b-DM) as described previ-
ously;77 enantioselectivity was found to be the same by both meth-
ods within error ( 2%).
The enantioselectivity of the hydroamination reaction broadly
correlates with the sterics of the ligand, with the phenylalanine-
derived ligands showing higher enantioselectivities than the va-
line-derived ligands. However, the desired increase in selectivity
due to increased substitution at the alkoxy carbon was not realized
(compare first generation ligands, entries 1, 5, 9, 13, 17, and 21
with the other entries in the table). The valine-derived ligands
generally show very low enantioselectivity, with the best ligand
being VAB (entry 11, 10%ee). The phenylalanine-derived ligands
behaved more consistently; increased steric bulk at the alkoxy
2.2. Catalytic intramolecular hydroamination with titanium
complexes of amino alcohols
We reported the first titanium-catalyzed asymmetric intramo-
lecular hydroamination of aminoallene substrates in 2004.77 When
hepta-4,5-dienylamine 1b (Scheme 1) was used as the substrate,
all three possible products (Z- and E-5-exo pyrrolidine 3b and
tetrahydropyridine 2b) were observed by 1H NMR spectroscopy.
On the other hand, when 6-methyl-hepta-4,5-dienylamine 1a
was used as the substrate, only the pyrrolidine product 3a was ob-
served. To simplify the analysis, catalytic hydroamination of only
substrate 1a was carried out with the new catalysts. The allene
substrate was prepared as previously described from 2-methyl-3-
butyne-2-ol.46,77,81
The catalytic cyclization of substrate 1a with the various tita-
nium catalysts was carried out in benzene-d6 in high-pressure
NMR tubes. Titanium precatalyst complexes were prepared
in situ by mixing stock solutions of the desired ligand (ca.
0.06 M) with stock solutions of Ti(NMe2)4 (ca. 0.09 M) in ben-
zene-d6. Although we have been unable to isolate these precata-
lysts in pure form due to their high solubility and oily nature,
we believe them to have a dimeric structure similar to those pre-
viously reported complexes based on their similar NMR spec-
tra.80,82 The catalytic reaction was initiated by adding a stock
solution of the appropriate aminoallene (ca. 1.5 M). Catalysis by
particulate matter from the molecular sieves used to dry the li-
gand solutions was ruled out by a control experiment.77 This reac-
tion can be carried out at either 135 °C or 110 °C, but is
significantly slower at 110 °C (presumably due to the steric bulk
of the allene); all catalyses were therefore carried out at the high-
er temperature. The amino alcohol-based catalysts are again sig-
nificantly faster than Ti(NMe2)4 as reported previously; the
reaction was determined to have reached completion by 1H
NMR spectroscopy after approximately 18 h. All reactions exclu-
sively formed the 5-exo pyrrolidine 3a quantitatively by NMR
spectroscopy.
Table 1
Hydroamination of 6-methyl-hepta-4,5-dienylamine at 135 °C with in situ catalysts
(5 mol % catalyst)
Entry
L
eea (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
VPH
VPM
VPB
VPP
VCH
VCM
VCB
VCP
VAH
VAM
VAB
VAP
PPH
PPM
PPB
4b
À2c
5
—
4b
À1c
1
5
5b
2
10
0
2b
À4c
3
PPP
16
6b
À1c
À5c
16
15b
À2c
1
PCH
PCM
PCB
PCP
PAH
PAM
PAB
PAP
7
a
By chiral shift NMR spectroscopy using (R)-(O)-acetylmandelic acid.66
Data from Ref. 77.
Enantiomer with opposite configuration favored.
b
c

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A. J. Hickman et al. / Tetrahedron: Asymmetry 20 (2009) 1279–1285
carbon increased the enantioselectivity (entries 16 and 20, 16%ee).
However, increasing the steric bulk of the best ligand from our
prior study (entry 21) resulted in a loss of selectivity (entries 22–
24).
68.2, 48.5, 29.2, 28.3, 25.5, 24.5, 23.1, 17.9, 14.6. HRMS (EI+) calcd
for C10H22NO (MH+ÀH2): 172.1701, found: 172.1693; Calcd for
C10H24NO (MH+): 174.1852, found: 174.1859. [
EtOAc).
a]D = 24.3 (c 5.49,
4.3. L-N-Isopropyl-dibutyl valinol (L-H2VPB)
3. Conclusions
L
-H2VPB was prepared according to typical procedure 1 starting
L
We have prepared a series of chiral amino alcohol ligands via a
modular 2-step synthesis. The steric environment of the ligands
was changed in a rational fashion using methyl, butyl, and phenyl
substitution at the alkoxy carbon. The titanium complexes of the
amino alcohol ligands catalyze the intramolecular hydroamination
of 6-methyl-hepta-4,5-dienylamine, forming exclusively the pyr-
rolidine product. The pyrrolidines are formed with low enantiose-
lectivity, up to 16% ee, but no obvious trends between the steric
environment provided by the ligand and the enantioselectivity
were observed.
from
-N-isopropyl-valine methyl ester (1.245 g, 7.18 mmol)77 to
give a yellow oil (1.7474 g, 6.8 mmol, 94% yield). The oil was puri-
fied by vacuum distillation. Bp 120–122 °C, <1 mmHg. 1H NMR
(400 MHz, CDCl3): d = 0.85–0.95 (m, 8H), 1.1–1.2 (m, 8H), 1.3–1.5
(m, 14H), 1.9 (dsept, J1 = 2.4 Hz, J2 = 7.6 Hz, 1H), 2.5 (d, J = 2.4 Hz,
1H), 2.9 (sept, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d = 14.6, 18.11, 23.3, 23.93, 24.15, 24.58, 25.23, 26.12, 26.17,
28.54, 35.92, 37.07, 48.96, 64.39, 74.48 (one carbon not observed).
Anal. Calcd for C16H35NO: C, 74.64; H, 13.7; N, 5.44. Found: C,
74.32; H, 13.61; N, 5.44. HRMS (EI+) calcd for C16H36NO(MH+):
258.2797, found: 258.2790. [
a
]
D = +17.8 (c 2.485, EtOAc).
4. Experimental
4.1. General
4.4.
L
-N-Cyclohexyl-dimethyl valinol ( -H2VCM)
L
L
-H2VCM was prepared according to typical procedure 1 starting
L
All reagents were obtained from commercial suppliers and puri-
fied by standard methods83 or used as received. Solvents were
purified by distillation from sodium/benzophenone or by passage
through a column of activated alumina (Innovative Technology
PS-400-5-MD) and stored under nitrogen. All air and/or moisture
sensitive compounds were manipulated under an atmosphere of
nitrogen using standard Schlenk techniques, or in a glove box
(MBraun UNIlab). Microanalyses were performed by Columbia
Analytical Services (Tucson, AZ). Mass spectra were obtained at
the Mass Spectrometry Facility, California Institute of Technology.
All NMR spectra were recorded at ambient temperature on a Brü-
ker Avance 400 spectrometer. Chemical shifts (d) are given in ppm
relative to TMS and were determined by reference to the residual
1H and 13C solvent resonances. Melting points were taken on a
Meltemp melting apparatus and are uncorrected. Polarimetry
was carried out using a JASCO P1010 instrument. Ligand precursors
were prepared as previously described.77,80 6-Methyl-hepta-4,5-
dienylamine 1c was prepared by slight modification of the pub-
lished procedures,46,81 and was dried (CaH2) and stored over 4 Å
sieves.47,48
from
-N-cyclohexyl-valine methyl ester (1.4150 g, 6.63 mmol)77 to
give an impure yellow oil (1.5129 g, 7.1 mmol, 107% yield). The oil
was purified by flash chromatography (8% ethyl acetate, 0.5% tri-
ethylamine, hexane). 1H NMR (400 MHz, CDCl3): d = 0.9255 (d,
3H, J = 6.8), 1.011 (s, 3H), 1.060 (d, 3H, J = 7.2) 1.202 (s, 3H),
1.559–1.920 (br m, 11H), 2.363 (d, 1H, J = 2.8), 2.551 (m, 1H). 13C
NMR (400 MHz, CDCl3): d = 71.41, 68.10, 57.05, 35.29, 34.45,
29.42, 28.60, 26.66, 25.85, 25.56, 25.28, 24.83, 18.28. Anal. Calcd
for C13H27NO: C, 73.18; H, 12.56; N, 6.56. Found: C, 72.83; H,
12.78; N, 6.55. HRMS(EI):calcd for C13H28NO: 214.2171, found:
214.2178. [
a
]D = +28.6 (c 2.885, EtOAc).
4.5.
L
-N-Cyclohexyl-dibutyl valinol ( -H2VCB)
L
L-H2VCB was prepared according to typical procedure 1 starting
from
L
-N-cyclohexyl-valine methyl ester (2.7038 g, 12.6 mmol)77
to give an impure yellow oil (2.8638 g, 9.6 mmol, 80.2% yield).
The product was purified via flash column chromatography (5%
EtOAc, 0.1% Et3N, hexanes). 1H NMR (400 MHz, CDCl3): d = 0.809
(d, 1H, J = 6.8 Hz), 0.926 (td, J1 = 1.4 Hz, J2 = 5.6 Hz, 4H), 0.979 (d,
2H, J = 6.8), 1.061 (d, 2H, J = 7.2 Hz) 1.27–1.98 (br m, 25H), 2.555
(m, 2H), 3.128 (d, J = 5.2 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d = 74.575, 64.155, 57.317, 37.127, 35.821, 35.050, 34.325,
28.511, 26.456, 26.162, 26.125, 25.719, 25.236, 25.068, 24.123,
23.907, 18.149, 14.563 (one carbon not observed). Anal. Calcd for
C19H39NO: C, 76.70; H, 13.21; N, 4.71. Found: C, 76.20; H, 13.34;
N, 3.74. HRMS (EI+) calcd for C19H40NO (MH+): 298.3110, found:
4.2. Typical procedure 1 for synthesis of new amino alcohol
ligands:
L-N-isopropyl-dimethyl valinol (L-H2VPM)
L
-N-Isopropyl-valine methyl ester (2.8338 g, 16.36 mmol)77 was
dissolved in dry THF (100 mL) in a 500 mL round-bottomed flask
under an atmosphere of nitrogen. The reaction vessel was cooled
to À78 °C and 1.4 M solution of methyl magnesium bromide in
THF (46.73 mL, 65.42 mmol) was added dropwise via syringe.
The solution was allowed to warm to room temperature and was
stirred overnight. The reaction mixture was quenched by the slow
addition of saturated ammonium chloride solution (30 mL) and
water (30 mL). The solution was separated, and the aqueous layer
washed with ether. The organic layers were combined, washed
with saturated sodium chloride solution, and dried over magne-
sium sulfate. The solvents were removed by rotary evaporation
to give a yellow oil (2.4368 g, 14.06 mmol, 86% yield). The oil
was purified by flash chromatography (10% ethyl acetate, 0.5% tri-
ethylamine, hexane). Bp 63 °C, <1 mmHg. 1H NMR (400 MHz,
CDCl3): d = 0.94 (d, 3H, J = 6.8 Hz), 1.02 (s, 3H), 1.04 (d, 3H,
8.4 Hz), 1.08 (d, 3H, 6.3 Hz), 1.10 (d, 3H, 5.6 Hz), 1.22 (s, 3H),
1.84 (d of sept, 1H, J1 = 6.8 Hz, J2 = 2.4 Hz), 2.34 (d, 1H, J = 2.4 Hz),
2.97 (sept, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 71.1,
298.3115. [
a
]D = +19.3 (c 1.985, EtOAc).
4.6.
L
-N-Cyclohexyl-diphenyl valinol (L-H2VCP)
L-H2VCP was prepared according to typical procedure 1 starting
from
L
-N-cyclohexyl-valine methyl ester (1.415 g, 6.64 mmol)77 to
give a light yellow solid (2.0583 g, 6.10 mmol, 92% yield). The solid
was recrystallized from boiling ethanol. Mp 141–143 °C. 1H NMR
(400 MHz, CDCl3): d = 0.6 (d, J = 6.8 Hz, 3H), 0.83–0.86 (m, 4H),
1.0 (d, 6.8 Hz, 3H), 1.5–1.8 (m, 6H), 2.1 (sept, 1H), 3.6 (d,
J = 2.0 Hz, 1H), 7.15–7.18 (m, 2H), 7.26–7.30 (m, 4H), 7.5 (m, 2H),
7.6 (m, 2H). 13C NMR (100 MHz, CDCl3): d = 16.3, 23.5, 25.7, 25.8,
26.4, 28.9, 35.2, 34.4, 35.2, 55.4, 65.2, 78.4, 126.5, 127.5, 128.2,
128.3, 146.2, 149.5 (two additional aromatic carbons appear to
overlay at 126.5 ppm). Anal. Calcd for C23H31NO: C, 81.85; H,
9.26; N, 4.15. Found: C, 81.83; H, 9.09; N, 4.34. HRMS (EI+) calcd

A. J. Hickman et al. / Tetrahedron: Asymmetry 20 (2009) 1279–1285
1283
for C23H32NO: 338.2484, found: 338.2499. [
CH2Cl2).
a]D = À42.3 (c 2.23,
C
14H24NO: 222.1858, found: 222.1853.
[a
]D = À20.9 (c 5.705,
EtOAc).
4.7.
L
-N-Adamantyl-dimethyl valinol (
L
-H2VAM)
4.11. L-N-Isopropyl-dibutyl phenylalanol (L-H2PPB)
L-H2VAM was prepared according to typical procedure 1 start-
L-H2PPB was prepared according to typical procedure 1 starting
ing from
L
-N-adamantyl-valine methyl ester (1.7266 g,
from -N-isopropyl-phenylalanine methyl ester (1.69 g,
L
6.565 mmol)77 to give a yellow oil (1.0613 g, 3.998 mmol, 60.9%).
This was then purified with flash column chromatography (5%
EtOAc, 0.5% Et3N, hexanes). The final product was a colorless oil.
1H NMR (400 MHz, CDCl3): d = 2.869 (br s, 1H), 2.358 (d, 1H,
J = 2.4 Hz), 2.055–1.537(m, 15H) 1.220 (s, 3H), 1.079 (d, 3H,
J = 7.2 Hz), 1.063 (s, 3H), 0.953 (d, 3H, J = 7.2 Hz). 13C NMR
(400 MHz, CDCl3): d =71.271, 69.089, 61.755, 38.190, 37.847,
37.158, 34.204, 31.477, 31.361, 31.284, 28.711, 27.985, 27.651,
25.172, 24.365, 17.49 (one carbon not observed). Anal. Calcd for
C17H31NO: C, 76.92; H, 11.77; N, 5.28. Found: C, 77.04; H, 11.92;
7.63 mmol)77 to give a yellow oil (2.16 g, 7.07 mmol, 93%). The
oil can be purified by vacuum distillation under an atmosphere
of nitrogen. Bp 110–118 °C, <1 mmHg. 1H NMR (400 MHz, CDCl3):
d = 0.68 (d, J = 6.0 Hz, 3H), 0.83 (d, J = 6.00 Hz, 3H), 0.92–0.94 (m,
6H), 1.4–1.6 (m, 12H), 2.1 (sept, J = 6.0 Hz, 1H), 2.3 (dd,
J1 = 10.4 Hz, J2 = 13.6 Hz, 1H), 2.8 (dd, J1 = 3.6 Hz, J2 = 10.4 Hz, 1H),
3.0 (dd, J1 = 3.6 Hz, J2 = 13.6 Hz, 1H), 7.2 (m, 5H). 13C NMR
(100 MHz, CDCl3): d = 14.6, 14.6, 23.5, 23.9, 24.1, 25.9, 26.0, 36.2,
36.7, 39.3, 48.6, 63.4, 73.7, 126.7, 128.8, 129.5, 140.7 (one aliphatic
carbon not observed). Anal. Calcd for C20H35NO: C, 78.63; H, 11.55;
N, 4.58. Found: C, 78.28; H, 11.61; N, 4.42. HRMS (FAB):calcd for
N, 5.18. [
a]
D = +26.05 (c 4.78, EtOAc).
C20H36NO: 306.2797, found: 306.2798. [
a]
D = +1.1 (c 5.49, EtOAc).
4.8.
L
-N-Adamantyl-dibutyl valinol (L-H2VAB)
4.12. -N-Isopropyl-diphenyl phenylalanol (
L
L
-H2PPP)
L
-H2VAB was prepared according to typical procedure 1 starting
L
from
-N-adamantyl-valine methyl ester (1.3583 g, 5.118 mmol)77
L-H2PPP was prepared according to typical procedure 1 starting
to give a yellow oil (1.5847 g, 4.533 mmol, 88.6%). This was then
purified with flash column chromatography (3% EtOAc, 0.5% Et3N,
hexane). 1H NMR (400 MHz, CDCl3): d = 0.85–0.94 (m, 12H),
1.052 (d, J = 7.2 Hz, 3H), 1.2–2.2 (m, 24H) 2.503 (d, 1H,
J = 2.4 Hz), 2.806 (br s, 1H). 13C NMR (400 MHz, CDCl3): d = 75.10,
66.20, 62.75, 60.98, 38.79, 38.40, 37.84, 37.28, 36.09, 34.60,
32.32, 32.07, 31.86, 28.56, 28.18, 26.42, 26.37, 25.44, 24.36,
24.13, 21.65, 18.16, 14.78. Anal. Calcd for C23H43NO: C, 79.02; H,
12.40; N, 4.01. Found: C, 78.71; H, 12.17; N, 4.02. HRMS(EI): calcd
from -N-isopropyl-phenylalanine methyl ester (1.28 g,
L
5.79 mmol) to give a yellow solid (2.02 g, 5.87 mmol, 101%). The
solid was recrystallized from boiling hexane. Mp 110–113 °C. 1H
NMR (400 MHz, CDCl3): d = 0.402 (d, J = 6.0 Hz, 3H), 0.623 (d,
J = 6.4 Hz, 3H), 1.847 (sept, J = 6.0 Hz, 1H), 2.188 (dd, J1 = 14.0 Hz,
J2 = 10.4 Hz, 1H), 2.954 (dd, J1 = 2.4 Hz, J2 = 14.0 Hz, 1H), 3.905
(dd, J1 = 2.8 Hz, J2 = 10.8 Hz, 1H), 7.2–7.4 (m, 11H), 7.6–7.7 (m,
4H). 13C NMR (100 MHz, CDCl3): d = 22.6, 24.4, 38.8, 47.6, 64.0,
78.2, 126.4, 126.5, 126.8, 126.9, 127.0, 128.5, 128.6, 129.0, 129.7,
140.1, 145.8, 148.2. Anal. Calcd for C24H27NO: C, 83.44; H, 7.88;
N, 4.05. Found: C, 83.25; H, 8.03; N, 4.07. HRMS (EI+) calcd for
for C23H44NO: 350.3423, found: 350.3428. [a]D = +22.2 (c 3.745,
EtOAc).
C24H28NO: 346.2171, found: 346.2154. [a]D = +3.6 (c 5.00, EtOAc).
4.9. L-N-Adamantyl-diphenyl valinol (L-H2VAP)
4.13. -N-Cyclohexyl-dimethyl phenylalanol (L-H2PCM)
L
l-H2VAP was prepared according to typical procedure 1 starting
L
from
-N-adamantyl-valine methyl ester (1.74 g, 6.56 mmol)77 to
L-H2PCM was prepared according to typical procedure 1 starting
give an impure yellow solid (2.6657 g, 6.85 mmol, 104% yield).
The solid was recrystallized from boiling hexane. Mp 177–182 °C.
1H NMR (400 MHz, CDCl3): d = 0.68 (d, J = 6.8 Hz, 3H), 1.04 (d,
J = 6.8 Hz, 3H), 1.1–1.9 (14H), 2.1 (m, 2H), 3.6 (d, J = 1.6 Hz, 1H),
7.16–7.17 (m, 2H), 7.25–7.30 (m, 4H), 7.56 (d, 2H), 7.66 (d, 2H).
13C NMR (100 MHz, CDCl3): d = 16.5, 23.7, 27.8, 29.1, 31.8, 31.8,
32.0, 33.8, 38.1, 38.1, 38.2, 60.5, 67.1, 78.6, 126.5, 126.5, 126.7,
128.2, 128.3, 146.3, 149.5. (two carbon signals not observed). Anal.
Calcd for C27H35NO: C, 83.24; H, 9.06; N, 3.60. Found: C, 83.03; H,
9.85; N, 3.65. HRMS (EI+) calcd for C27H36NO: 390.2797, found:
from -N-cyclohexyl-phenylalanine methyl ester (1.90 g,
L
7.29 mmol)77 to give an impure yellow oil. The oil could be purified
by vacuum distillation (0.8178 g, 3.13 mmol, 43%). Bp 121–127 °C,
<1 mmHg. 1H NMR (400 MHz, CDCl3): d = 0.4–1.1 (m, 5H), 1.12 (s,
3H), 1.24 (s, 3H), 1.4–1.8 (m, 6H), 2.38 (dd, J1 = 9.9 Hz,
J2 = 13.7 Hz, 1H), 2.66 (dd, J1 = 4.0 Hz, J2 9.9 Hz, 1H), 3.00 (dd,
J1 = 4.0 Hz, J2 = 13.7 Hz, 1H), 7.2 (m, 5H). 13C NMR (100 MHz,
CDCl3): d = 24.5, 25.0, 25.4, 26.3, 27.6, 34.4, 34.5, 39.7, 56.4, 66.4,
71.1, 126.7, 128.8, 129.5, 140.4. Anal. Calcd for C17H27NO: C,
78.11; H, 10.41; N, 5.36. Found: C, 77.94; H, 10.28; N, 5.26.
HRMS(EI):calcd for C17H28NO: 262.2171, found: 262.2170.
390.2792. [
a]
D = À34.3 (c 2.21, CH2Cl2).
[a
]D = À8.6 (c 5.945, EtOAc).
4.10. -N-Isopropyl-dimethyl phenylalanol (L-H2PPM)
L
4.14. -N-Cyclohexyl-dibutyl phenylalanol (L-H2PCB)
L
L-H2PPM was prepared according to typical procedure 1 starting
from -N-isopropyl-phenylalanine methyl ester (1.78 g,
L
L-H2PCB was prepared according to typical procedure 1 starting
8.06 mmol)77 to give an impure yellow oil in greater than quanti-
tative yield. The oil could be purified by vacuum distillation
(0.7624 g, 3.44 mmol, 43%). Bp 97–98 °C, <1 mmHg. 1H NMR
(400 MHz, CDCl3): d = 0.71 (d, J = 6.0 Hz, 3H), 0.84 (d, J = 6.0 Hz,
3H), 1.1 (s, 3H), 1.2 (s, 3H), 2.18 (sept, J = 6.0 Hz, 1H), 2.4 (dd,
J1 = 9 Hz, J2 = 15 Hz, 1H), 2.6 (dd, J1 = 4.5 Hz, J2 = 10 Hz, 1H), 3.0
(dd, J1 = 4.5 Hz, J2 = 14 Hz, 1H), 7.2 (m, 5H). 13C NMR (100 MHz,
CDCl3): d = 23.5, 24.0, 24.5, 27.5, 39.8, 48.2, 66.6, 71.0, 126.7,
128.9, 129.4, 140.5. Anal. Calcd for C14H23NO: C, 75.97; H, 10.47;
N, 6.33. Found: C, 75.39; H, 10.33; N, 6.10. HRMS(FAB):calcd for
from -N-cyclohexyl-phenylalanine methyl ester (1.50 g,
L
5.75 mmol)77 to give a yellow oil (1.96 g, 5.67 mmol, 99%). The
oil was purified by vacuum distillation. Bp 148–152 °C, <1 mmHg.
1H NMR (400 MHz, CDCl3): d = 0.75–1.0 (m, 9H), 1.3–1.6 (m, 19H),
1.8 (br m, 1H), 2.36 (dd, J1 = 10.4 Hz, J2 = 13.6 Hz, 1H), 2.82 (dd,
J1 = 3.6 Hz, J2 = 10.4 Hz, 1H), 2.97 (dd, J1 = 13.6 Hz, J2 = 3.6 Hz, 1H),
7.2 (m, 5H). 13C NMR (100 MHz, CDCl3): d = 14.6, 22.7, 23.9, 24.1,
25.0, 25.5, 25.9, 26.3, 34.3, 34.4, 36.2, 36.7, 37.8, 39.2, 56.8, 63.3,
73.8, 126.7, 128.9, 129.5, 140.6. Anal. Calcd for C23H39NO: C,
79.94; H, 11.38; N, 4.05. Found: C, 79.30; H, 11.12; N, 3.68. HRMS

1284
A. J. Hickman et al. / Tetrahedron: Asymmetry 20 (2009) 1279–1285
(EI+) calcd for C23H40NO: 346.3110, found: 346.3120. [
5.205, EtOAc).
a
]D = +9.4 (c
C
31H35NO: C, 85.08; H, 8.06; N, 3.20. Found: C, 84.90; H, 8.13; N,
3.21. HRMS (EI+) calcd for C31H36NO: 438.2797, found: 438.2815.
D = +4.1 (c 4.90, EtOAc).
[a]
4.15. L-N-Cyclohexyl-diphenyl phenylalanol (L-H2PCP)
4.19. Typical procedure 2 for catalytic hydroamination
L-H2PCP was prepared according to typical procedure 1 starting
from -N-cyclohexyl-phenylalanine methyl ester (1.74 g,
L
Hydroamination was carried out with 5% catalyst loading. Solu-
tions of ligands (ꢀ0.050 M) and aminoallene (ꢀ1.6 M) in C6D6 were
dried over molecular sieves overnight and stored at À35 °C when
not in use. Solutions of titanium tetrakisdimethylamide (ꢀ1.2 M)
in C6D6 were also prepared. In the glove box, the titanium tetrakis-
6.64 mmol)77 to give a yellow solid (2.43 g, 6.32 mmol, 95%). The
solid was recrystallized from boiling ethanol. Mp 100–102 °C. 1H
NMR (400 MHz, CDCl3): d = 0.6–0.9 (m, 4H), 1.2–1.4 (m, 7H), 2.20
(dd, J1 = 10.3 Hz, J2 = 14.4 Hz, 1H), 2.95 (dd, J1 = 2.8 Hz,
J2 = 14.0 Hz, 1H), 3.98 (dd, J1 = 2.8 Hz, J2 = 10.8 Hz, 1H), 7.3 (m,
11H), 7.6 (m, 4H). 13C NMR (100 MHz, CDCl3): d = 25.3, 25.5, 26.2,
33.3, 35.0, 38.6, 55.0, 63.5, 78.1, 126.4, 126.5, 126.8, 126.9, 126.9,
128.4, 128.6, 129.0, 129.6, 140.2, 145.8, 148.2. Anal. Calcd for
C27H31NO: C, 84.11; H, 8.18; N, 3.63. Found: C, 83.80; H, 8.24; N,
3.65. HRMS (EI+): calcd for C27H32NO: 386.2484, found:
dimethylamide solution (70
l
L, 6.0 Â 10À3 mmol) ligand (120
lL,
6.0 Â 10-3 mmol), and deuterated benzene (110
lL) were com-
bined in a J. Young NMR tube, and an NMR spectrum was acquired,
showing the formation of dimethylamine as the ligand displaces
two of the dimethylamide ligands. Next, aminoallene solution
(100 lL, 0.120 mmol) was added, and the tube was placed into a
386.2494. [
a
]
D = +5.6 (c 2.885, EtOAc).
heated oil bath. The progress of the reaction was monitored peri-
odically by NMR spectroscopy. After completion of the reaction,
the volatiles from the reaction were vacuum transferred to a new
4.16. -N-Adamantyl-dimethyl phenylalanol (L-H2PAM)
L
tube containing (R)-(O)-acetylmandelic acid (14.6 mg, 75 lmol).
L
-H2PAM was prepared according to typical procedure 1 starting
An NMR spectrum revealed diastereomeric splitting of the doublet
at 5.3 ppm with baseline separation. The two doublets were inte-
grated, the percent of each isomer was calculated, and the enantio-
meric excess was determined.
from -N-adamantyl-phenylalanine methyl ester (0.542 g,
L
1.73 mmol)77 to give an impure yellow oil (0.336 g, 1.07 mmol,
62%). The oil was purified by column chromatography (15% EtOAc,
hexanes). Mp 100–102 °C. 1H NMR (400 MHz, CDCl3): d =1.161 (s,
3H), 1.236 (s, 3H), 1.3–1.8 (m, 12H), 1.8–1.9 (br m, 2H), 2.165 (br
s, 1H), 2.440 (dd, J1 = 13.7 Hz, J2 = 9.6 Hz, 1H), 2.655 (dd,
J1 = 9.6 Hz, J2 = 4.0 Hz, 1H), 3.012 (dd, J1 = 4.0 Hz, J2 = 13.7 Hz, 1H),
7.2–7.3 (m, 5H). 13C NMR (100 MHz, CDCl3): d = 14.5, 23.1, 24.6,
27.7, 27.9, 31.6, 32.0, 32.1, 37.4, 38.2, 39.8, 61.5, 67.9, 71.4, 77.4,
126.7, 128.8, 129.4, 140.5. Anal. Calcd for C21H31NO: C, 80.46; H,
Acknowledgments
The authors gratefully acknowledge the financial support of the
Harvey Mudd College Research Fund, the Donors of the American
Chemical Society Petroleum Research Fund, and the National Sci-
ence Foundation (REU-CHE-0648597 and RUI-CHE-0615724). We
thank Dianna C. McAnnally-Linz and Ryan J. Pakula for their syn-
thetic efforts. This work is dedicated to MGW.
9.97; N, 4.47. Found: C, 80.09; H, 9.92; N, 4.46. [
2.435, EtOAc).
a]D = +0.2 (c
4.17.
L
-N-Adamantyl-dibutyl phenylalanol (
L-H2PAB)
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