6
C.C. Ence et al. / Tetrahedron xxx (xxxx) xxx
values matched reported values [47]. Ligand 11 was synthesized
according to the general procedure from (R)-(þ)-2,20-bis(diphe-
nylphosphinoamino)-1,10-binapthyl (1 g, 1.5 mmol) n-BuLi (2.5 M in
was placed in dry flask and dissolved in 10 mL dry CH2Cl2. N,N-
Diisopropylethylenediamine (0.366 mL, 2.1 mmol, 1.5 eq.) was
added and the reaction was cooled to 0 ꢁC. Methanesulfonyl chlo-
ride was added (0.326 mL, 4.2 mmol, 3 eq.) and reaction was stirred
overnight. Reaction was then diluted with 10 mL CH2Cl2 and
washed with 5 mL aqueous, saturated sodium bicarbonate. The
organic layer was dried over sodium sulfate and concentrated.
Purification on silica gel with 90% DCM, 9% MeOH, and 1% water
afforded the desired chloride product. Rf ¼ 0.39. The product was
then dissolved in CH2Cl2 and washed with sodium bicarbonate to
obtain the free base and then the organic layer was dried over so-
dium sulfate and the solvent removed. The product was azeotroped
with benzene three times to remove residual water and collected as
a yellow solid (0.187 g, 48%). IR (film): v ¼ 3305, 3029, 2908, 2848,
2773, 2436, 1451, 1356, 968; 1H NMR (500 MHz, CDCl3):
hexanes, 1.2 mL, 3 mmol,
2 eq.) and titanium tetrachloride
(0.164 mL, 1.5 mmol, 1 eq) to give a dark solid (0.97 g, 84%). Product
was isolated as a 10:1 mixture of starting material and product. X-
ray quality single crystals were grown via slow vapor deposition
with benzene/hexanes. 1H NMR (500 MHz, CDCl3):
(d, 2H), 6.55 (t, 4H), 6.83 (q, 4H), 6.97 (t, 4H), 7.18e7.28 (m, 2H), 7.31
d
(ppm) ¼ 6.42
(d, 2H), 7.42 (t, 2H), 7.54 (d, 4H), 7.63 (t, 2H), 7.82 (d, 2H), 8.07 (q,
4H); 31P NMR (500 MHz, CDCl3):
d
(ppm) ¼ ꢀ12.53 (s, 2P); 13C NMR
(500 MHz, CDCl3):
d
(ppm) ¼ 119.3, 125.0, 125.5, 126.4, 127.8, 128.0,
128.1, 128.3, 128.5, 128.7, 128.9, 129.6, 131.1, 131.2, 132.1, 133.5,136.2.
4.2.5. bis((1R,2R)-(ꢀ)-1,2-Diaminocyclohexane(di(o-tolyl)
d
(ppm) ¼ 1.44 (m, 1H), 1.68 (m, 9H), 1.77 (m, 6H), 2.1 (m, 6H), 2.67
(m, 2H), 4.04 (d, 2H), 5.64 (m, 1H), 5.76 (m, 1H); 13C NMR (500 MHz,
CDCl3):
phenylphsophanyl)amino)titanium (IV)dichloride (18)
(1R,2R)-(ꢀ)-1,2-Diaminocyclohexane (80 mg, 0.7 mmol) was
dissolved in 6 mL dry toluene. Chlorodi(o-tolyl)phosphine (348 mg,
1.4 mmol, 2 eq.), distilled triethylamine (141.4 mg, 1.4 mmol, 2 eq.),
and one crystal of DMAP were added. The reaction was stirred
overnight. The mixture was then filtered and concentrated. 20 mL
dry diethyl ether was added and the reaction was cooled to ꢀ78 ꢁC.
n-BuLi (2.5 M in hexanes, 0.56 mL, 1.4 mmol, 2 eq.) was added
dropwise, the reaction was stirred for 3 h at room temperature, and
then distilled TiCl4 (0.072 mL, 0.7 mmol, 1 eq.) was added dropwise
at ꢀ78 ꢁC. The reaction was allowed to warm to room temperature
and then moved to a glovebox where it was stirred overnight. The
ether was evaporated and then toluene added and the solids were
filtered off. The filtrate was concentrated to give a dark solid (70 mg,
29% yield), which was used directly in the enantioselective allylic
d
(ppm) ¼ 26.7, 29.5, 29.7, 31.9, 36.5, 40.1, 41.8, 45.4, 69.9,
126.2, 135.7. HRMS (ESI): C17H28ClN (M þ H) calculated 282.1983,
found 282.1982.
4.9.2. N-((E)-6-chlorohex-4-en-1-yl)adamantan-1-amine (20)
N-((E)-6-chlorohex-4-en-1-yl)adamantan-1-amine was pre-
pared with the same procedure as substrate 12 with 6-((ada-
mantan-2-yl)amino)hex-2-en-1-ol
(1.24 g,
5 mmol),
N,N-
Diisopropylethylenediamine (1.3 mL, 7.5 mmol, 1.5 eq.), meth-
anesulfonyl chloride (1.17 mL,15 mmol, 3 eq.) in 13 mL DCM. A silica
gel column was run with 9% MeOH and 1% water in DCM (Rf ¼ 0.33).
Product was washed with sodium bicarbonate to give free base and
then dried over sodium sulfate to give a yellow solid (1.02 g, 76%) IR
(film): v ¼ 966, 1024, 1227, 1363, 1653, 1700, 2480, 2907, 3744; 1H
amination. 1H NMR (500 MHz, CDCl3):
d
(ppm) ¼ 1.32 (d, 2H), 1.52
NMR (500 MHz, CDCl3, TMS as internal standard):
d
(ppm) ¼ 1.56
(d, 2H), 1.77 (d, 2H), 2.22 (d, 2H), 2.52 (s, 3H), 2.57 (s, 3H), 4.40 (d,
(m, 3H), 1.72 (m, 6H), 2.08 (m, 4H), 2.18 (m, 6H), 2,89 (m, 2H), 4.02
2H), 7.12 (t, 4H), 7.21 (m, 4H), 7.32 (m, 4H), 7.47 (m, 4H); 31P NMR
(d, 2H), 5.71 (m, 2H), 8.96 (s, 2H); 13C NMR (500 MHz, CDCl3, TMS as
(500 MHz, CDCl3):
d
(ppm) ¼ ꢀ18.2; 13C NMR (500 MHz, CDCl3):
internal standard):
d
(ppm) ¼ 20.9, 28.7, 29.5, 30.2, 36.4, 39.7, 41.4,
d
(ppm) ¼ 24.9, 29.7, 33.0, 125.6, 125.7, 130.2, 130.7, 131.0, 132.4,
65.1, 124.7, 170.9. HRMS (ESI): C17H28ClN (M þ H) calculated
134.0.
268.1827, found 268.1827.
4.2.6. bis(((R)-(þ)-1,10-Bi(napthylamine)di(o-tolyl)-
5. Enantioselective catalysis
phenylphosphanyl)amino)titanium(IV)dichloride (19)
(R)-(þ)-1,10-Binaphthyl-2,20-diamine (199 mg, 0.7 mmol) was
dissolved in 6 mL dry toluene. Chlorodi(o-tolyl)phosphine (348 mg,
1.4 mmol, 2 eq.), distilled triethylamine (141.4 mg, 1.4 mmol, 2 eq.),
and one crystal of DMAP were added. The reaction was stirred at
40 ꢁC overnight. The reaction was filtered and concentrated and a
short column was run in 100% toluene (Rf ¼ 0.95). Product was
concentrated and 20 mL dry diethyl ether was added. The reaction
was cooled to ꢀ78 ꢁC and n-BuLi (2.5 M in hexanes, 0.56 mL,
1.4 mmol, 2 eq.) was added dropwise. The reaction was stirred for
3 h at room temperature and then distilled TiCl4 (0.072 mL,
0.7 mmol, 1 eq.) was added dropwise at ꢀ78 ꢁC. The mixture was
allowed to warm to room temperature and then moved to glovebox
where it was stirred overnight. The ether was evaporated and then
toluene added and the solids filtered off. The filtrate was concen-
trated to give a dark solid, which was used in the enantioselective
allylic amination without further purification. Product was isolated
as a 4:1 mixture with starting material. 1H NMR (500 MHz, CDCl3):
General Procedure: In glove box, (2-methylallyl)palladium(II)
chloride dimer (0.4 mg, 0.0011 mmol, 0.025 eq.) and silver triflate
(0.6 mg, 0.00225 mmol, 0.05 eq.) were diluted with 0.1 mL CH2Cl2
and then stirred for 10 min. In a separate vial, the respective chiral
titanium phosphonamide ligand or other chiral ligand
(0.00225 mmol, 0.05 eq.) was dissolved in 0.1 mL CH2Cl2 and then
added slowly to the palladium solution and stirred 20 min. Chloride
12 or 20 (12.5 mg, 0.045 mmol, 1 eq.) was then added and trie-
thylamine (0.006 mL, 0.045 mmol, 1 eq.), diluted in 0.1 mL CH2Cl2,
was added. The reaction was stirred until completion (10e15 min)
and then taken out of box. Product was purified on a short column
of neutralized aluminum oxide using 9% MeOH and 1% water in
CH2Cl2 as eluent. Rf ¼ 0.9. Fractions containing product were
collected and washed with sodium bicarbonate to obtain free base.
Product was dried using sodium sulfate and then solvent was
removed to obtain the pure product. Yields obtained are shown in
Table 1, Table 2, and Fig. 6.
d
(ppm) ¼ 2.57 (12H, s), 6.44 (2H, d), 6.51 (2H, m), 6.61 (2H, m), 6.80
(2H, m), 7.06 (2H, m), 7.44 (8H, m), 7.50 (4H, m), 7.56 (d, 4H); 31P
5.1. 1-(1-adamantyl)-2-vinylpiperidine (13)
NMR (500 MHz, CDCl3):
d
(ppm) ¼ ꢀ23.9.
Product matched previously reported spectra [23]. IR (film):
v ¼ 3060, 2931, 2907, 2845, 2680, 1441, 1220, 1113; 1H NMR
4.9. Substrate synthesis
(500 MHz, CDCl3):
d
(ppm) ¼ 1.59 (m, 9H), 1.71 (m, 3H), 1.79 (m,
4.9.1. N-((E)-7-chlorohept-5-en-1-yl)adamantan-1-amine (12)
(E)-7-((adamantan-1-yl)amino)hex-2-en-1-ol (0.37 g, 1.4 mmol)
4H), 2.03, (m, 2H), 2.66 (t, 1H), 2.88 (d, 1H), 3.85 (m, 1H), 5.05 (m,
1H), 6.5 (m, 1H); 13C NMR (500 MHz, CDCl3):
d
(ppm) ¼ 20.5, 27.3,
Please cite this article as: C.C. Ence et al., Synthesis of chiral titanium-containing phosphinoamide ligands for enantioselective heterobimetallic