Asymmetric hydroamination of aminoallenes catalyzed by titanium and tantalum complexes of chiral sulfonamide alcohol ligands

Article abstract of DOI:10.1016/j.jorganchem.2010.08.001

A series of bidentate sulfonamide alcohol ligands with varying steric and electronic properties was synthesized. The titanium and tantalum complexes of these ligands, prepared in situ from either Ti(NMe₂)₄ or Ta(NMe₂)

Full text of DOI:10.1016/j.jorganchem.2010.08.001

Journal of Organometallic Chemistry 696 (2011) 81e86
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Asymmetric hydroamination of aminoallenes catalyzed by titanium and tantalum
complexes of chiral sulfonamide alcohol ligands
*
Katherine E. Near, Brette M. Chapin, Diana C. McAnnally-Linz, Adam R. Johnson
Harvey Mudd College, 301 Platt Blvd., Claremont, CA 91711, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of bidentate sulfonamide alcohol ligands with varying steric and electronic properties was
synthesized. The titanium and tantalum complexes of these ligands, prepared in situ from either Ti(NMe2)4
or Ta(NMe2)5, were used as catalysts for the asymmetric hydroamination of 6-methyl-hepta-4,5-dienyl-
Received 18 June 2010
Received in revised form
31 July 2010
Accepted 2 August 2010
Available online 10 August 2010
amine, giving exclusively the a-vinylpyrrolidine product. The titanium derived catalysts gave products with
low stereoselectivity, up to 11%ee favoring (þ)-2-(2-methyl-propenyl)-pyrrolidine, while the tantalum
derived catalysts gave products with higher and opposite stereoselectivity, up to 34%ee favoring (ꢀ)-2-
(2-methyl-propenyl)-pyrrolidine.
Keywords:
Asymmetric hydroamination
Sulfonamide
Ó 2010 Elsevier B.V. All rights reserved.
Amino alcohol
Titanium
Tantalum
1. Introduction
aminoalkene) substrates results in the formation of a chiral
nitrogen heterocycle, there has been much effort to develop the
The hydroamination reaction, the addition of an NeH bond
across an unsaturated CeC bond, is a highly atom economical
method for synthesizing nitrogen-containing compounds with
potential utility for industrial and pharmaceutical applications. The
reaction is generally thermoneutral or slightly exothermic, but the
reaction requires a catalyst due to the large electronic repulsion
between the nitrogen and the unsaturated group [1]. Both inter-
and intramolecular variations of the reaction have been reported
for the hydroamination of olefins, alkynes and allenes, and the field
has been extensively reviewed [1e11].
The hydroamination of allenes is thermodynamically more
favorable than that of alkenes [12,13], and the intramolecular
reaction with 4,5-dienylamines (Scheme 1, 1) can give nitrogen-
containing heterocycles with a pendant vinyl group for further
substitution (2). There are regiochemical considerations; the cor-
responding addition to the external double bond yields achiral
tetrahydropyridine products (3). The intramolecular hydro-
amination/cyclization of aminoallenes by silver, mercury, palla-
dium [14e17], titanium [18,19], and lanthanides [13,20,21] is well
known. As the cyclization of these aminoallene (and related
asymmetric reaction.
The first asymmetric intramolecular hydroamination of an
aminoallene (1a and 1b) by a titanium catalyst was reported by our
group in 2004 using chiral titanium complexes with aminoalcohol
ligands [22]. Ti(NMe2)4 reacts with the aminoalcohol to form
a dimeric complex with bridging oxygens [22,23] that can enter the
catalytic cycle proposed by Bergman [12] by generating an imido
complex derived from the incoming substrate (Scheme 2). The
imido can react by a [2 þ 2] cycloaddition to form the corre-
sponding azametallacyclobutane, and protonolysis by incoming
substrate regenerates the catalytically active imido. The resulting
pyrrolidines were obtained in quantitative yield for 2a and with
greater than 4:1 regioselectivity favoring 2b over 3b, but the
enantioselectivity of the reaction was low (up to 16%ee) for both
substrates. Using a rational steric tuning approach, bulkier alkyl
groups were added to the ligands, but these new catalysts did not
result in an improved enantioselectivity [24]. Recent advances for
the asymmetric cyclization of aminoallenes have been seen by
others with gold complexes of bulky chiral phosphine complexes,
often resulting in high enantioselectivities (70e90%ee) [25e27].
One of the first examples of intramolecular hydroamination of
aminoallenes using an early transition metal catalyst was reported
by Bergman using a racemic titanium sulfonamide complex derived
from trans-1,2-diaminocyclohexane (Scheme 3) [18,19]. The parent
* Corresponding author. Tel./fax: þ1 909 607 8450.
E-mail address: adam_johnson@hmc.edu (A.R. Johnson).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.08.001

82
K.E. Near et al. / Journal of Organometallic Chemistry 696 (2011) 81e86
Scheme 3. Catalytic hydroamination with titanium amides; 4a, R ¼ CH3, 4b, R ¼ Ts.
structure of our catalyst; the aminoalcohol complexes we have
prepared previously are dimeric in nature with bridging oxygens
[23,38], and a number of complexes of bidentate sulfonamide
alcohols have been prepared that have an identical core structure
[39e41]. Chiral sulfonamide complexes of titanium have been used
in other asymmetric catalytic reactions, especially for the asym-
metric alkylation of aldehydes. Their use in this reaction was first
reported in 1989 [42], was later examined extensively by Walsh
[43e45], and further research continues [46e48]. Only recently
have sulfonamide complexes been used for the catalytic hydro-
amination of aminoalkenes, though in most cases titanium and
zirconium sulfonamide complexes are poor catalysts for the reac-
tion with low or no turnover and reduced enantioselectivity
compared to structurally related ligands [49e52].
Scheme 1.
complex, Ti(NMe2)4, was a competent catalyst for the intra-
molecular hydroamination/cyclization of 4,5-dieneylamine (1c) to
give the cyclized product (3c) with only 41% conversion in 26 h at
25 ꢁC. The bis-N-Me complex 4a gave only 18% conversion in 24 h at
25 ꢁC. However, the corresponding bis-N-tosyl complex 4b gave
100% conversion in 5 h at 25 ꢁC. The improved conversion to
product was attributed to the electron withdrawing properties of
the sulfonamide ligand and not the chelating nature of the ligand
due to the similarity between Ti(NMe2)4 and catalyst 4a.
These results are consistent with the work of Schafer, who has
studied electronically differentiated amidate ligands (Scheme 4).
Amidate complexes of titanium catalyze the anti-Markovnikov
addition of aliphatic amines to alkynes [28]. A later study reported
a small series of amidates with tunable steric and electronic
properties, and their use in intra- and intermolecular hydro-
amination of alkynes. The perfluorophenyl derivative 5c was
significantly more reactive than the phenyl (5b) or isopropyl (5a)
derivatives for the hydroamination/cyclization of aminoalkyne
substrates [29]; the enhanced catalytic activity was attributed to
the more Lewis acidic metal center resulting from the more elec-
tron withdrawing ligands. The increased reactivity of fluorinated
amidates resulted in a reduced Markovnikov/anti-Markovnikov
selectivity in the intermolecular hydroamination of alkynes with
anilines [30]. A later report established a similar trend with pyr-
imidinoxide ligands: an increase in reactivity (and a concomitant
decrease in selectivity) with the increase in electrophilicity at the
metal center [31]. Schafer [32e36] and others [37] have continued
to study early metal complexes of amidate ligands for the asym-
metric hydroamination of aminoalkenes and aminoalkynes.
2. Experimental
2.1. General
All reagents were obtained from commercial suppliers and were
purified by standard methods [53] or used as received. (S)-3-
Amino-2-methyl-4-phenyl-2-butanol was prepared according to
literature procedures [54,55]. 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). 1H and 13
C
NMR spectra were recorded at ambient temperature on a Brüker
Avance 400 spectrometer. Polarimetry was carried out using
a JASCO P1010 instrument. GC analysis was carried out using
a Hewlett Packard 5890 Series II Gas Chromatograph. Mass spectra
were obtained at the Mass Spectrometry Laboratory, California
Institute of Technology, Pasadena, CA. Elemental analyses were
performed by Columbia Analytical Services, Tucson, AZ.
Based on the prior work by Bergman and Schafer using more
electron withdrawing ligands that result in a more Lewis acidic
metal center, we sought to improve our bidentate aminoalcohol
ligands in a similar fashion by including an electron withdrawing
sulfonamide group. We hypothesized that adding electron with-
drawing groups to our aminoalcohol ligands would enhance the
Lewis acidity of the metal center and increase their reactivity at
reduced temperatures. Transition state theory suggests that
lowering the temperature of the reaction should improve
the enantioselectivity in the formation of pyrrolidine product 2a.
The addition of the sulfonamide should not significantly impact the
2.2. Procedure 1, synthesis of sulfonamide 6a
(S)-(ꢀ)-2-Amino-3-phenyl-1-propanol (1.52 g, 10.1 mmol), NEt3
(3.00 mL, 21.5 mmol), and a small amount of DMAP were combined
in CH2Cl2 (100 mL) and cooled to ꢀ78 ꢁC. p-Tosyl chloride (1.96 g,
10.3 mmol) in CH2Cl2 (20 mL) was added dropwise to the cooled,
magnetically stirred reaction solution. After the addition was
complete, the reaction solution was allowed to stir at 23 ꢁC for 24 h
under an atmosphere of nitrogen. The reaction was quenched by
addition of 5% NaHCO3 (10 mL) and 1.0 M HCl (20 mL). The resul-
tant two phases were separated and the aqueous layer was
extracted two times with CH2Cl2 (15 mL). The combined organic
extracts were washed three times with brine (20 mL), dried over
Scheme 4. Catalytic hydroamination with titanium amidates; 5a, R ¼ iPr, 5b, R ¼ Ph,
5c, R ¼ C6F5.
Scheme 2.

K.E. Near et al. / Journal of Organometallic Chemistry 696 (2011) 81e86
83
anhydrous MgSO4, and the solvent was removed in vacuo to yield
a white solid (2.26 g, 7.41 mmol, 73.4%). The product can be purified
by recrystallization from 6:1 hexanes/CH2Cl2.
5.52 mmol). The resulting crude solid was purified by flash column
chromatography (40% EtOAc/60% hexanes) and recrystallized from
6:1 hexanes/CH2Cl2 to yield a white solid (0.784 g, 2.35 mmol,
44.0%).
M.p. 60e62 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 7.61 (d, J ¼ 6.5 Hz,
2H, eSO2(C6H2H2)), 7.20 (m, 5H, Ar), 7.00 (d, J ¼ 5.6 Hz,
2H, eSO2(C6H2H2)), 3.65 (m, 1H, eCHHOH), 3.55 (m, 1H,
eCHHOH), 3.46 (m, 1H, eCH), 2.80 (dd, J1 ¼13.8 Hz, J2 ¼ 7.1 Hz,
1H, eCHHAr), 2.71 (dd, J1 ¼13.8 Hz, J2 ¼ 7.2 Hz, 1H, eCHHAr), 2.43
M.p. 130e132 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 7.35
(d, J ¼ 8.3 Hz, 2H, eSO2(C6H2H2)), 7.08 (m, 5H, Ar), 6.93
(d, J ¼ 6.7 Hz, 2H, eSO2(C6H2H2)), 4.54 (d, J ¼ 7.9 Hz, 1H, eNH), 3.46
(m, 1H, eCH), 3.01 (dd, J1 ¼14.2 Hz, J2 ¼ 4.2 Hz, 1H, eCHHAr), 2.55
(s, 1H, eOH), 2.43 (dd, J1 ¼14.2, J2 ¼ 9.6 Hz, 1H, eCHHAr), 2.40 (s,
3H, eArCH3), 1.28 (s, 3H, eCH3), 1.26 (s, 3H, eCH3). 13C NMR
(s, 3H, eArCH3). 13C NMR (100 MHz, CDCl3):
d
¼ 143.6, 137.1, 137.0,
129.9, 129.4, 128.9, 127.3, 126.9, 64.2, 56.9, 38.0, 21.8.
23.6
[
a]
¼ ꢀ37.8ꢁ (c ¼ 0.0520 g/mL, EtOAc). Anal. Calcd for
(100 MHz, CDCl3):
126.6, 72.9, 64.6, 37.8, 27.9, 25.7, 21.6. [
mL, EtOAc). Anal. Calcd for C18H23O3NS: C, 64.84; H, 6.95; N, 4.20.
Found: C, 63.85; H, 6.85; N, 4.24. HRMS (FABþ) Calcd for
C18H24O3NS (MHþ): 334.1477, found: 334.1485.
d
¼ 143.0, 137.6, 137.1, 129.6, 129.2, 128.7, 127.0,
D
24.5
C16H19NO3S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.70; H, 6.08; N,
4.74. HRMS (ESþ) Calcd for C16H20NO3S (MHþ): 306.1164, found:
306.1158.
a]
¼ ꢀ60.4ꢁ (c ¼ 0.036 g/
D
2.3. Synthesis of sulfonamide 6b
2.6. Synthesis of methylated sulfonamide 6e
Ligand 6b was prepared according to procedure 1 starting from
(S)-(ꢀ)-2-amino-3-phenyl-1-propanol (2.09 g, 13.8 mmol), NEt3
(4.30 mL, 30.9 mmol), DMAP and 4-(trifluoromethyl)benzene
sulfonyl chloride (3.43 g, 14.0 mmol). The resulting crude solid was
purified by flash column chromatography (30% EtOAc/70% hexanes)
and then recrystallized from 6:1 hexanes/CH2Cl2 to yield a white
solid (2.86 g, 7.95 mmol, 57.6%).
Ligand 6e was prepared according to procedure 1 starting from
(S)-3-amino-2-methyl-4-phenyl-2-butanol (0.716 g, 3.99 mmol),
NEt3 (1.14 mL, 8.18 mmol), DMAP and 4-(trifluoromethyl)benzene
sulfonyl chloride (0.921 g, 4.10 mmol). The resulting crude solid
was purified by flash column chromatography (35% EtOAc/65%
hexanes) and recrystallized from 6:1 hexanes/CH2Cl2 to yield
a white solid (0.395 g, 1.02 mmol, 25.6%).
M.p. 137e139 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 7.71 (d,
J ¼ 8.3 Hz, 2H, eSO2(C6H2H2)), 7.61 (d, J ¼ 8.5 Hz, 2H,
eSO2(C6H2H2)), 7.15 (m, 3H, Ar), 6.96 (d, J ¼ 9.1 Hz, 2H, Ar), 4.99
(d, J ¼ 7.3 Hz, 1H, eNH), 3.74 (m, 1H, eCHHOH), 3.68 (m, 1H,
eCHHOH), 3.51 (m, 1H, eCH), 2.87 (dd, J1 ¼13.9 Hz, J2 ¼ 5.8, 1H,
eCHHAr), 2.69 (dd, J1 ¼13.9 Hz, J2 ¼ 8.7, 1H, eCHHAr), 2.18 (t,
M.p. 122e124 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 7.47
(s, 4H, eSO2(C6H4)), 7.07 (t, J ¼ 7.2 Hz, 1H, Ar), 7.00 (t, J ¼ 7.5 Hz, 2H,
Ar), 6.88 (d, J ¼ 7.1 Hz, 2H, Ar), 4.73 (d, J ¼ 8.5 Hz, 1H, eNH), 3.55 (m,
1H, eCH), 3.05 (dd, J1 ¼14.2 Hz, J2 ¼ 3.3 Hz, 1H, eCHHAr), 2.41 (dd,
J1 ¼14.2, J2 ¼ 8.2 Hz, 1H, eCHHAr), 2.28 (s, 1H, eOH), 1.40 (s, 3H,
J ¼ 5.4 Hz, 1H, eOH). 13C NMR (100 MHz, CDCl3):
d
¼ 143.7, 137.0,
eCH3), 1.38 (s, 3H, eCH3). 13C NMR (100 MHz, CDCl3):
d
¼ 144.4,
2
2
134.7 (q, JCF ¼ 33.0 Hz), 129.3, 129.1, 127.7, 127.3, 126.5 (q,
137.9, 133.8 (q, JCF ¼ 33.3 Hz), 129.5, 128.9, 127.3, 127.2, 126.3 (m),
23.5
3JCF ¼ 3.7 Hz), 123.6 (q, 1JCF ¼ 272.7 Hz), 65.2, 57.7, 38.3.
123.7 (q, 1JCF ¼ 272.5 Hz), 73.3, 65.8, 37.6, 28.4, 26.5. [
a
]
¼ ꢀ66.8ꢁ
D
24.1
[
a]
¼ ꢀ44.4ꢁ (c ¼ 0.051 g/mL, EtOAc). Anal. Calcd for
(c ¼ 0.030 g/mL, EtOAc). Anal. Calcd for C18H20NSO3F3: C, 55.80; H,
5.20; N, 3.62. Found: C, 55.43; H, 5.04; N, 3.70. HRMS (FABþ) Calcd
for C18H21NSO3F3 (MHþ): 388.1194, found: 388.1177.
D
C16H16F3O3NS: C, 53.48; H, 4.49; N, 3.90. Found: C, 53.47; H, 4.31; N,
3.90. HRMS (FABþ) Calcd for C16H17F3O3NS (MHþ): 360.0881,
found: 360.0879.
2.7. Synthesis of methylated sulfonamide 6f
2.4. Synthesis of sulfonamide 6c
Ligand 6f was prepared according to procedure 1 starting from
(S)-3-amino-2-methyl-4-phenyl-2-butanol (0.696 g, 3.88 mmol),
NEt3 (1.20 mL, 11.9 mmol), DMAP and 3,5-bis-(trifluoromethyl)
benzenesulfonyl chloride (1.16 g, 3.70 mmol). The resulting crude
solid was purified by flash column chromatography (20% EtOAc/
80% hexanes) and recrystallized from 6:1 hexanes/CH2Cl2 to yield
a white solid (0.346 g, 0.777 mmol, 21.0%).
Ligand 6c was prepared according to procedure 1 starting from
(S)-(ꢀ)-2-amino-3-phenyl-1-propanol (0.755 g, 5.00 mmol), NEt3
(1.50 mL, 10.8 mmol), DMAP and 3,5-bis-(trifluoromethyl)benzene
sulfonyl chloride (1.61 g, 5.15 mmol). The resulting crude solid was
purified by flash column chromatography (30% EtOAc/70% hexanes)
and recrystallized from 6:1 hexanes/CH2Cl2 to yield a white solid
(1.00 g, 2.34 mmol, 46.8%).
M.p. 213e216 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 7.86
M.p. 124e125 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼ 8.07 (s, 2H,
(s, 2H, eSO2(C6H2H)), 7.85 (s, 1H, eSO2(C6H2H)), 6.89 (m, Ar), 4.94
(d, J ¼ 9.1 Hz, 1H, eNH), 3.62 (m, 1H, eCH), 3.06 (dd, J1 ¼14.1 Hz,
J2 ¼ 3.2 Hz, 1H, eCHHAr), 2.46 (dd, J1 ¼14.1, J2 ¼ 4.4 Hz, 1H,
eCHHAr), 1.96 (s, 1H, eOH), 1.46 (s, 3H, eCH3), 1.42 (s, 3H, eCH3).
eSO2(C6H2H)), 7.97 (s, 1H, eSO2(C6H2H)), 7.08 (m, 3H, Ar), 6.94 (m,
2H, Ar), 4.92 (d, J ¼ 7.3 Hz, 1H, eNH), 3.80 (m, 1H, eCHHOH), 3.72
(m, 1H, eCHHOH), 3.61 (m, 1H, eCH), 2.91 (dd, J1 ¼14.0 Hz,
J2 ¼ 5.5 Hz, 1H, eCHHAr), 2.69 (dd, J1 ¼14.0 Hz, J2 ¼ 9.1 Hz, 1H,
13C NMR (100 MHz, CDCl3):
d
¼ 144.1, 137.6, 132.7 (q, 2JCF ¼ 34.1 Hz),
1
eCHHAr), 1.92 (t, J ¼ 5.3 Hz, 1H, eOH). 13C NMR (100 MHz, CDCl3):
129.3, 128.8, 127.2, 127.1 (m), 126.0 (m), 122.8 (q, JCF ¼ 273.4 Hz),
2
23.8
d
¼ 143.3, 136.7, 133.1 (q, JCF ¼ 34.3 Hz), 129.2, 129.0, 127.5, 127.4
73.3, 65.9, 37.1, 28.7, 26.9. [
a]
¼ ꢀ54.5ꢁ (c ¼ 0.026 g/mL, EtOAc).
D
1
(m), 126.4 (m), 125.5 (q, JCF ¼ 273.4 Hz), 65.4, 58.1, 38.3.
Anal. Calcd for C19H19NSO3F6: C, 50.11; H, 4.21; N, 3.08. Found: C,
50.03; H, 3.52; N, 3.07. HRMS (FABþ) Calcd for C19H20NO3F6S
(MHþ): 456.1068, found: 456.1060.
24.5
[
a
]
¼ ꢀ40.7ꢁ (c ¼ 0.038 g/mL, EtOAc). Anal. Calcd for
D
C17H15NSO3F6: C, 47.78; H, 3.54; N, 3.28. Found: C, 47.43; H, 3.27; N,
3.27. HRMS (FABþ) Calcd for C17H16NSO3F6 (MHþ): 428.0755,
found: 428.0770.
2.8. Procedure 2, hydroamination with Ti(NMe2)4
2.5. Synthesis of methylated sulfonamide 6d
Sulfonamide ligand (75
m
L
of
L of a 0.0375 M solution in C6D6,
mol), 6-methyl-hepta-4,5-dienylamine (50 L of a 1.5 M
mol, 20 equiv), and C6D6 (175 L) were
combined in a J. Young NMR tube in the glovebox to make a 5 mol%
a 0.05 M solution in C6D6,
3.75
3.75
m
m
mol), Ti(NMe2)4 (100 m
Ligand 6d was prepared according to procedure 1 starting from
(S)-3-amino-2-methyl-4-phenyl-2-butanol (0.957 g, 5.34 mmol),
NEt3 (1.75 mL, 12.6 mmol), DMAP and p-tosyl chloride (1.05 g,
m
solution in C6D6, 75
m
m

84
K.E. Near et al. / Journal of Organometallic Chemistry 696 (2011) 81e86
Scheme 5. Reagents and conditions, Et3N, DMAP, CH2Cl2.
catalyst solution (400
m
L total volume). The tube was heated in an
2.11. Polarimetry of (ꢀ)-2-(2-methyl-propenyl)-pyrrolidine
oil bath (either 135 ꢁC or 125 ꢁC) and monitored using 1H NMR
spectroscopy until the reaction stopped progressing. The reactions
were quenched with isopropanol (1 mL) and diluted with diethyl
The product of a hydroamination catalyzed by Ta(NMe2)5 and
sulfonamide 6e was quenched with isopropanol (100 mL) and
ether (3 mL). Benzoyl chloride (9
m
L, 77
m
mol) and NEt3 (21
m
L,
diluted to a total volume of 2 mL with benzene. The polarimeter
150 mol) were added. The reaction solution was allowed to stir for
m
reading (
a
) was ꢀ0.068ꢁ. Thus, the enantiomer with the longer
at least 2 h. Water (1 mL) was added to the reaction mixture, and
the layers were separated. The organic layer was washed with
saturated aqueous NaCl (1 mL) and dried over MgSO4. The crude
benzamide was injected on a GC capillary column (Chiraldex B-DM,
retention time on the GC is the (ꢀ) enantiomer and the enantiomer
with the shorter retention time is the (þ) enantiomer. When
considering the enantioselectivity of the reaction (26%ee),
[a
]D ¼ ꢀ55ꢁ (c ¼ 4.70$10ꢀ3 g/mL, benzene).
30 m ꢂ 0.25
m
m, 40 ꢁC, 8 min, 1 ꢁC/min to 180 ꢁC, 180 ꢁC 15 min).
The two enantiomers were separated with retention times of 135
and 136 min.
3. Results and discussion
3.1. Synthesis and purification of sulfonamides
2.9. Procedure 3, hydroamination with Ta(NMe2)5
A family of six sulfonamide alcohol ligands was prepared by
a similar method to that reported by Gagné (Scheme 5) [39]. The
ligands differ in their degree of fluorination of the sulfonamide in
order to alter the electronic profile of the ligand, and contain either
primary or tertiary alcohol groups in order to present different steric
profiles to the metal center. The synthesis of sulfonamide alcohols
Sulfonamide ligand (75
m
L
of
L of a 0.0375 M solution in C6D6,
mol), 6-methyl-hepta-4,5-dienylamine (50 L of a 1.5 M
mol, 20 equiv), and C6D6 (175 L) were
combined in a J. Young NMR tube in the glovebox to make a 5 mol%
a 0.05 M solution in C6D6,
3.75
3.75
m
m
mol), Ta(NMe2)5 (100 m
m
solution in C6D6, 75
m
m
6ae6c started with (S)-(ꢀ)-2-amino-3-phenyl-1-propanol (
L-phe-
catalyst solution (400
m
L total volume). The tube was heated in an
nylalanol), while the synthesis of the methylated sulfonamide alco-
hols 6de6f started with (S)-3-Amino-2-methyl-4-phenyl-2-butanol.
Addition of sulfonyl chloride, either p-toluenesulfonyl chloride,
oil bath (either 135 ꢁC or 125 ꢁC), monitored using 1H NMR spec-
troscopy, and analyzed as in Procedure 2.
p-(trifluoromethyl)benzenesulfonyl
chloride
or
3,5-bis-(tri-
fluoromethyl)benzenesulfonyl chloride, in the presence of triethyl-
amine and a catalytic amount of DMAP resulted in the formation of
the desired ligands in good yield. Purification by recrystallization or
column chromatography resulted in white solid materials in all six
cases.
2.10. Variations of hydroamination procedures 2 and 3
Some sulfonamides did not completely dissolve in benzene at
0.05 M concentrations. When this occurred, more C6D6 was added
to make
a 0.025 M solution in C6D6, 3.75
(100 L of a 0.0375 M solution in C6D6, 3.75
4,5-dienylamine (50 L of a 1.5 M solution in C6D6, 75
20 equiv), and C6D6 (100 L) were combined in a J. Young NMR tube
in the glovebox. The combined volume of the reaction solution
(400 L) is the same as the combined volume of the reaction
solution containing the 0.05 M ligand.
Some reactions with titanium were unsuccessful with 5 mol%
catalyst loading, so the reactions were performed using 10 mol%
a
0.025 M solution. Sulfonamide ligand (150
mol), Ti(NMe2)4 or Ta(NMe2)5
mol), 6-methyl-hepta-
mol,
mL of
m
3.2. Catalytic hydroamination
m
m
m
m
The synthesis of metal complexes of the sulfonamide ligands
was carried out in situ. A solution of ligand in C6D6 was mixed with
a solution of either Ti(NMe2)4 or Ta(NMe2)5 in a J. Young NMR tube
as described previously [22,24]. Attempts to obtain X-ray quality
crystals of these ligands on titanium or tantalum have been
unsuccessful to date. Based on the similarity of the NMR spectra,
solubility behavior, and reactivity between the new sulfonamide
alcohol complexes and our previous structurally characterized
aminoalcohol complexes [23,38], we believe them to be dimeric in
solution and in the solid state as in Scheme 2. This structural type is
well-precedented for titanium complexes of sulfonamide alcohols
[39e41].
Catalysis was initiated by adding a solution of 6-methyl-hepta-
4,5-dienylamine (1a) in C6D6 (ca. 20 equiv). The resulting solution
was heated at either 135 ꢁC or 125 ꢁC and periodically monitored by
1H NMR spectroscopy. Most of the reactions reached completion to
the pyrrolidine 2a within 18e24 h, though some reactions were
significantly slower. In some cases, where reactivity was especially
m
m
catalyst loading. Sulfonamide ligand (150
C6D6, 7.5 mol), Ti(NMe2)4 (200 L of a 0.0375 M solution in C6D6,
7.5 mol), and 6-methyl-hepta-4,5-dienylamine (50 L of a 1.5 M
solution in C6D6, 75 mol, 10 equiv) were combined in a J. Young
NMR tube in the glovebox. For the more dilute ligand solutions,
sulfonamide ligand (300 L of a 0.025 M solution in C6D6, 7.5 mol),
Ti(NMe2)4 (200 L of a 0.0375 M solution in C6D6, 7.5 mol), and 6-
methyl-hepta-4,5-dienylamine (50 L of a 1.5 M solution in C6D6,
75 mol, 10 equiv) were combined in a J. Young NMR tube in the
mL of a 0.05 M solution in
m
m
m
m
m
m
m
m
m
m
m
glovebox. The combined volume (550
solutions.
mL) is larger than other

K.E. Near et al. / Journal of Organometallic Chemistry 696 (2011) 81e86
85
Table 1
titanium, favoring the formation of the (ꢀ)-enantiomer. The
methylated ligands (6de6f) gave high conversions to product in
a reasonable time (15e19 h at either 125 or 135 ꢁC, entries 10e12),
with only a marginal loss of stereoselectivity relative to the non-
methylated ligands at 125 ꢁC.
Hydroamination of 6-methyl-hepta-4,5-dienylamine with in situ sulfonamide
catalysts.
Entry Catalyst (M) 135 ꢁC
125 ꢁ
C
ee (%)a Conv. (%)b Time (h) ee (%)a Conv. (%)b Time (h)
The titanium complexes of the sulfonamide ligands proceeded
with high regioselectivity but with lower conversions to product
than in our previous results with aminoalcohols. These results can
be rationalized if the sulfonamide ligands do not provide a more
Lewis acidic metal center as postulated. A number of similar
dimeric titanium sulfonamide complexes display ligation by one of
the sulfonyl oxygens to the metal center in the solid state [40,
61e65]. Electron donation to the metal center by a sulfonyl
oxygen would result in an increase in electron density at the metal
center, and therefore a reduced Lewis acidity and reactivity. The
only catalysts that gave reasonable conversion and enantiose-
lectivity are the methylated ligands on tantalum (entries 10e12);
we are currently investigating the catalytic activity of other
tantalum complexes in order to determine any trends with the
tantalum catalysts.
1
2
3
4
5
6
7
8
6a (Ti)
6b (Ti)
6c (Ti)
6d (Ti)
6e (Ti)
6f (Ti)
6a (Ta)
6b (Ta)
6c (Ta)
6d (Ta)
6e (Ta)
6f (Ta)
3
4c
7
65
73
85
95
61
80
60
32
34
40
18
15
18
40
37
124
69
69
18
18
19
11c
9c
0
38
61
29
33
55
45
20
85
100
88
51
51
49
40
49
6
4
7c
8c
2
5
27
21d
5d
17d
15d
26d
7d
24d
28d
34d
24d
20d
23d
132
115
71
17
15
9
10
11
12
100
100
100
100
100
15
a
Determined by GC using Chiraldex B-DM (ꢃ5%).
b
c
Determined by 1H NMR spectroscopy.
Reactions performed with 10 mol% catalyst instead of 5 mol%.
The (ꢀ)-enantiomer was favored.
d
low, a 10% catalyst loading was used rather than the 5% catalyst
loading for other samples. Regioselectivity was excellent in all
cases; there was no formation of tetrahydropyridine 3a.
When the reactions reached completion (or did not progress
further), the reaction was quenched with isopropanol and the
resulting pyrrolidine (2a) was converted to the benzamide deriv-
ative. This compound was injected onto a GCeMS instrument and
the enantioselectivity (%ee) was determined by integrating the area
under the peaks corresponding to the two enantiomers. Results of
the catalytic study are presented in Table 1.
Hydroamination using ligand 6e on tantalum (entry 11) gave the
highest stereoselectivity at 135 ꢁC, as verified by several replicate
runs, and went to completion in a reasonable time period, so one
trial of the reaction was quenched in order to determine the
absolute configuration of the pyrrolidine product. The observed
4. Conclusions
A series of sulfonamide ligands with varied steric and electronic
profiles was prepared, and the catalytic hydroamination of ami-
noallenes using their titanium and tantalum complexes was
investigated. The titanium catalysts favored the formation of the
(þ)-enantiomer of 2-(2-methyl-propenyl)-pyrrolidine while the
tantalum catalysts favored the formation of the (ꢀ)-enantiomer.
The catalytic reactions with tantalum complexes were generally
more stereoselective than those with titanium complexes. The
expected trends relating more electron withdrawing ligands with
higher reactivity, and lower temperatures with higher stereo-
selectivity were not observed. The sulfonamides may be less elec-
tron withdrawing than anticipated due to the electron donation to
the metal center by the sulfonyl oxygen. For the tantalum
complexes, a slight increase in stereoselectivity was observed at
lower temperatures. There is no correlation between electron
withdrawing nature of the ligand and reactivity of the resulting
complexes, but the ligands with tertiary alcohols are more reactive
than those with primary alcohols.
a
was ꢀ0.068ꢁ, which, when factoring in the enantioselectivity of
26%ee, corresponds to [
fore assign the enantiomer with the longer retention time as the
(ꢀ)-enantiomer.
a
]
of ꢀ55ꢁ for the pyrrolidine. We there-
D
The conversion to product using titanium catalysts (entries 1e6)
is rather low in some cases. At 135 ꢁC, all reactions reached at least
60% conversion within 40 h, but the reactions typically reached
70e90% conversion within 18 h. However, the enantioselectivities
we observed with the titanium sulfonamide complexes are below
7% in all cases, favoring the formation of the (þ)-enantiomer. These
results are not substantially different from related phenylalanine-
derived catalysts with alkylamine substituents we have reported
[22,24].
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
Science Foundation (REU-CHE-0648597 and RUI-CHE-0615724).
The corresponding reactions carried out at 125 ꢁC were more
sluggish, reaching low levels of conversion even after more than
40 h in most cases. In some cases, the enantioselectivies were
marginally higher at the lower temperature (entries 1 and 2), but in
general the difference in stereoselectivity at the lower temperature
does not exceed experimental error. The titanium catalyzed reac-
tions again favored the (þ)-enantiomer.
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