Modular multidentate phosphine ligands: Application to palladium-catalyzed allylic alkylations

Article abstract of DOI:10.1039/b513906f

Multidentate phosphines were readily obtained by reaction of chiral multidentate amines, prepared via ring opening of (S)-N-tosyl-2- isopropylaziridine with ammonia, primary, and secondary amines, with achiral phosphorus containing building blocks. The phosphines were used in palladium-catalyzed alkylation of rac-3-cyclohexenyl and cyclopentenyl carbonates. The enantioselectivity and reactivity were largely dependent on the structure of the amine core of the ligands. Up to 88% ee was observed in reactions with the six-membered substrate. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b513906f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Modular multidentate phosphine ligands: application to
palladium-catalyzed allylic alkylations
Yuxin Pei, Emilie Brule´ and Christina Moberg*
Received 30th September 2005, Accepted 5th December 2005
First published as an Advance Article on the web 4th January 2006
DOI: 10.1039/b513906f
Multidentate phosphines were readily obtained by reaction of chiral multidentate amines, prepared via
ring opening of (S)-N-tosyl-2-isopropylaziridine with ammonia, primary, and secondary amines, with
achiral phosphorus containing building blocks. The phosphines were used in palladium-catalyzed
alkylation of rac-3-cyclohexenyl and cyclopentenyl carbonates. The enantioselectivity and reactivity
were largely dependent on the structure of the amine core of the ligands. Up to 88% ee was observed in
reactions with the six-membered substrate.
Introduction
Results and discussion
The design and synthesis of new chiral ligands are urged by the
demand for reactive and selective asymmetric metal catalysts.1
Ligands which can be prepared from cheap and easily available
starting materials in few synthetic steps, and which are designed
to allow for facile structural variations, are particularly useful since
efficient transfer of chirality in catalytic reactions usually requires
optimization of the ligand structure for each particular reaction
and each substrate.
Ligand design and preparation
To achieve the desired structural variation, we used am-
monia (1), butylamine (2), 1,2-diaminoethane (3), (R,R)-1,2-
diaminocyclohexane (4), (S,S)-1,2-diaminocyclohexane (ent-4),
and tris(2-aminoethyl)amine (TREN, 5) as nucleophiles for the
ring opening of a chiral aziridine. An activated aziridine is
required for the reactions to proceed readily. (S)-N-Tosyl-2-
isopropylaziridine (6) was selected since the activating group can
be easily removed subsequent to the ring opening.
We have recently developed a modular approach for the
preparation of multidentate nitrogen ligands.2 The synthesis
is based on the nucleophilic ring opening of activated chiral
aziridines, obtained from easily available amino acids, by amines.
By employing ammonia, primary and secondary monoamines
and diamines as nucleophiles, chiral ligand backbones with easily
variable structures are obtained. Thus, C3-symmetric3 amines can
be prepared from ammonia,4,5 whereas compounds with C2 and
C1 symmetry are obtained from primary and secondary amines,
respectively.6 The multidentate product amines can be employed
directly as chiral nitrogen ligands7 or the amino groups can serve
as attachment points for suitable achiral or chiral donor functions,
thus providing access to various types of multidentate ligands.
We were particularly interested in studying whether chiral
information may be delivered from the chiral core to achiral
catalytically active sites on the periphery of the ligand and
whether the structure of the amine containing core and the size
of the chiral pockets would influence the enantioselectivity in
catalytic reactions. If that would be the case, facile structural
variations would permit tuning of the catalytic properties. We
present here the preparation of polydentate chiral amines and their
functionalization with achiral phosphorus containing building
blocks to provide polydentate phosphine ligands. The new ligands
were applied in palladium-catalyzed asymmetric allylic alkylations
of rac-methyl 3-cyclohexenyl and rac-ethyl 3-cyclopentenyl car-
bonate.
We have previously shown that ammonia and butylamine react
with three and two equivalents, respectively, of the aziridine to
afford 7 and 9, which after deprotection using HBr and phenol,
gave 8 and 10 (Scheme 1). Diamine 3 reacted smoothly with four
equivalents of the aziridine, providing 11 and, after deprotection,
12. In contrast, the more sterically hindered chiral amines 4 and
ent-4 reacted with only two molecules of the aziridine to yield
secondary amines 13 and 15, in analogy to what we have previosuly
observed in the ring opening of N-triflic aziridine.2 Although
the yields in these reactions were somewhat lower than those in
reactions with other amines, deprotection occurred smoothly to
provide 14 and 16 in acceptable overall yields. Finally, we were
pleased to discover that reaction of TREN provided a high yield
of hexasubstituted product 17 and, after removal of the tosyl
group, 18.
As a phosphorus containing achiral moiety, 2-(diphenyl-
phosphino)benzoic acid (19a) was used and attached to the
primary amino groups, via amide formation links, as previ-
ously achieved for the preparation of 20 and 21 from 8 and
10, respectively.8 The amines prepared were thus reacted with
19a using either DCC–DMAP or EDC·HCl–HOBt, affording
Department of Chemistry, Organic Chemistry, Royal Institute of Technology,
SE 100 44, Stockholm, Sweden. E-mail: kimo@kth.se; Fax: +46 8 791 2333;
Tel: +46 8 790 9036
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Scheme 1 Reagents and conditions: (a) (i) amine, MeOH, microwaves 160 ◦C; (ii) HBr (48% aq.), PhOH, reflux; (b) (i) amine, MeOH, 0–55 ◦C;
(ii) HBr (48% aq.), PhOH, reflux.
phosphines 20–25, with structures analogous to that of the
Trost ligand 28.9 We anticipated that the properties of the
ligand might be influenced by the nature of the linker. In
order to explore this possibility, C3-symmetric imine 26 and
amine 27, with a larger degree of freedom, were also prepared.
For the condensation between the chiral TREN derivative 8
and 2-(diphenylphosphino)benzaldehyde (19b), several different
reaction conditions were attempted. In acetonitrile at room
temperature, only 50% conversion was achieved after 48 h, as
determined by 31P NMR spectroscopy, and at reflux temperature
the ligand underwent degradation. However, in CH2Cl2–CH3OH
(1 : 3)10 the aldehyde was totally consumed after 72 h at room
temperature, and the desired ligand 26 was isolated as a yellow
solid.
latter ligand, the nature of the counter ion of the nucleophile
and the solvent was shown to be of significant importance due
to a memory effect.13 Reactions run in methylene chloride using
the tetrahexylammonium salt of the malonate exhibited the
highest enantioselectivity. These conditions were therefore used
in reactions employing 20–27 as ligands. The amount of ligand
used was adjusted to maintain a phosphorus–palladium ratio
of 3 : 1 in all reactions.14
Use of a catalyst (2.5 mol%, i.e. 5% Pd) containing C3-symmetric
ligand 20 in the alkylation of 29 resulted in full conversion to
product 31 with high enantioselectivity (85% ee) within less than
50 min at room temperature (entry 1, Table 1). A lower reaction
temperature did not provide any advantage (entry 2). A catalyst
containing ligand 21 exhibited somewhat lower reactivity and
selectivity (entry 3). Ligand 22 was also slightly less selective than
20, and the selectivity decreased with the temperature (entries 4–
6). In analogy to what was observed with ligand 28, reactions
in THF in place of methylene chloride (entry 7) and without
addition of tetrahexylammonium bromide (entry 8) resulted in
lower enantioselectivity. The ligands obtained from chiral 1,2-
diaminocyclohexanes and containing secondary amine functions,
23 and 24, resulted in catalysts with poor reactivity (entries 9
and 10). In contrast to these ligands, C3-symmetric ligand 25
resulted in rapid formation of highly enantioenriched product
(entry 11). Ligands 26 and 27, having the amide group replaced
by an imino or amino function, provided inferior results (entries
12–15). Under the conditions we used for ligands 20–27, Trost’s
ligand 28 gave the product with 93% ee at room temperature, which
is somewhat higher then that observed with the most selective
ligand 20 at the same temperature (85%). The reactivity of 28 was
however somewhat lower than that of, e.g., 25, which afforded full
conversion after 10 min at room temperature.
Finally, the imine functions in 26 were reduced by sodium
borohydride11 to yield phosphine amine ligand 27 in 70%.
Catalytic reactions
Having access to phosphine ligands 20–27, we decided to study
the influence of the chiral core on the reactivity and selectivity in
catalytic reactions. Palladium-catalyzed asymmetric allylic alkyla-
tion of rac-methyl 3-cyclohexenyl and rac-ethyl 3-cyclopentenyl
carbonate with malonate was selected as a suitable reaction
(Scheme 2), providing the opportunity to compare the behavior
of the new ligands with that of Trost’s ligand 28.12 With the
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Conclusions
We have demonstrated that chiral multidentate phosphines are
readily obtained by a modular ligand synthesis. Ring opening
of a chiral activated aziridine with ammonia, primary amines,
diamines, or triamines was used as a key step to provide mul-
tidentate amines, which were substituted with achiral phosphine
building blocks via amide or imine formation. Since a large variety
of amines can be used in the aziridine ring opening, extensive
variation of the ligand structures is possible. In palladium-
catalyzed asymmetric allylic alkylations it was demonstrated that
the structure of the chiral nucleus has a profound influence on the
catalytic properties of metal complexes of the ligands.
Scheme 2 Allylic alkylation of cyclohexenyl and cyclopentenyl carbonate.
Alkylation of cyclopentenyl carbonate (30) with tetrahexy-
lammonium malonate occurred with the same high rate as the
alkylation of the six-membered carbonate, but with considerably
lower enantioselectivity, the highest ee, 53%, being observed using
ligand 25 (entries 17–19).
The influence of the amount of catalyst was then investigated.
It was found that decreasing the amount of catalyst led to slightly
improved results, although somewhat longer reaction times were
required (Table 2). Thus, up to 88% ee and full conversion
were observed for ligand 20 when merely 1.25 mol% palladium
(0.63 mol% of the dimer) was used (entry 10).
Experimental
All reactions were run under an atmosphere of dry nitro-
gen unless otherwise indicated. Anhydrous solvents were trans-
ferred using oven-dried syringes. Glassware was oven- or flame-
dried. Triethylamine was distilled from CaH2. Dichloromethane,
diethyl ether, THF, and DMF were taken from Meyer’s
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Table 1 Allylic alkylation of methyl 3-cyclohexenyl carbonate and ethyl 3-cyclopentenyl carbonate with sodium dimethyl malonatea
Entry
1
Ligand
Substrate
Solvent
DCM
Temp (◦C)
rt
Time
Conversion (%)b
ee (%)c
20
29
20 min
50 min
1 h
10 min
40 min
1 h
96
100
99
58
83
93
97
100
59
100
53
85 (S)
85 (S)
85 (S)
79 (S)
76 (S)
76 (S)
75 (S)
81 (S)
76 (S)
71 (S)
62 (S)
36 (S)
37 (S)
30 (S)
—
31 (R)
72 (S)
5 (S)
16 (S)
5 (R)
5 (R)
2
3
20
21
29
29
DCM
DCM
−3
rt
2 h
4
5
22
22
29
29
DCM
DCM
rt
−3
10 min
30 min
70 min
100 min
15 min
15 min
1 h
6
22
22
22
29
29
29
DCM
THF
THF
−20 to −8
7
rt
rt
100
71
100
5
8d
9
10
23
24
25
26
26
27
27
28
29
29
29
29
29
29
29
29
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
rt
rt
rt
70 h
43 h
52
11
12
13
14
15
16
10 min
30 min
30 min
30 min
6 h
20 min
60 min
30 min
20 min
10 min
100
100
43
100
14
85
95
100
100
100
−3
rt
−78
rt
93 (R)
93 (R)
31 (S)
18 (S)
53 (S)
17
18
19
20
22
25
30
30
30
DCM
DCM
DCM
rt
rt
rt
a NaH: 0.5 mmol, DMM: 0.6 mmol, THAB: 0.52 mmol, (C3H5PdCl)2: 4.2 lmol (2.5 mol%), ligand: 12.5 (21, 23, 24); 8.3 (20, 26, 27); 6.3 (22); 4.2 (25)
lmol, carbonate: 0.165 mmol, solvent: 3 mL. b Determined by GC-MS. c Determined by HPLC (30) or the combination of optical rotation data15 and 1H
NMR chiral shift experiments (31).13 d No THAB added.
Table 2 The influence of the amount of ligands and palladium to allylic alkylation of methyl 2-cyclohexenyl carbonate with sodium dimethyl malonatea
Conversion (%)c
ee (%)d
b
Entry
Ligand
(C3H5PdCl)2 (mol%)
Time (min)
1
2
22
22
2.5
1.25
10
10
30
30
60
10
10
40
10
40
20
30
60
40
70
100
96
100
91
100
100
84
100
76
100
96
96
100
95
100
81 (S)
85 (S)
84 (S)
84 (S)
83 (S)
72 (S)
77 (S)
75 (S)
75 (S)
74 (S)
85 (S)
87 (S)
86 (S)
88 (S)
88 (S)
3
22
0.63
5
5
25
25
2.5
1.25
7
25
0.63
8
9
20
20
2.5
1.25
10
20
0.63
a NaH: 0.5 mmol, DMM: 0.6 mmol, THAB: 0.52 mmol, carbonate: 0.165 mmol, DCM: 3 mL, rt. b Pd : P ratio 1 : 3. c Determined by GC-MS. d Determined
by HPLC.
Solvent Dispensing System. Sodium hydride was washed
with pentane and dried in vacuo. Tetrahexylammonium bro-
mide (THAB) was washed with diethyl ether and dried
in vacuo. Methanol and all the other reagents were used as received.
1H and 13C spectra were recorded on a Bruker Advance 400
instrument or a Bruker DMX 500 instrument in CDCl3, using the
residual signals from CHCl3 (1H: d 7.25 ppm; 13C: d 77.0 ppm)
as internal standard. 31P NMR spectra were recorded on a
Bruker DMX 500 instrument in CDCl3 using H3PO4 as external
standard. Optical rotations were recorded with a Perkin-Elmer
343 polarimeter at the sodium D line at ambient temperature.
Flash chromatography was carried out using SDS silica gel 60
(40–63 lm). Melting points were measured in open capillary
tubes using an electrothermal instrument and were uncorrected.
HRMS was carried out by Instrumentstationen, Kemicentrum,
Lund University, Sweden.
Compounds 21,8 6,2 29,16 and 3016 were synthesized via pub-
lished procedures. Aldehyde 19b was prepared in a two-step reac-
tion from 2-bromoiodobenzene, which was reacted with isopropy-
lmagnesium bromide17 to promote an aryl exchange, followed by
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introduction of the phosphine using chlorodiphenylphosphine,
to form 2-(diphenylphosphino)bromobenzene18 in 60% yield. o-
Lithiation and reaction with DMF afforded 19b.19
chromatography (silica gel, hexane–EtOAc 4 : 1 to hexane–EtOAc
3 : 1 + 0.25% Et3N and 0.25% MeOH) gave 22 as a white foam
(547 mg, 56%): Rf (hexane–EtOAc 3 : 1 + 6% Et3N and 6% MeOH)
0.73; [a]2D5 −67.4 (c 0.26 in CHCl3); mp 115–116 ◦C; dH (400 MHz,
CDCl3) 0.72 (12 H, d, J 6.8), 0.77 (12 H, d, J 6.8), 1.81 (4 H, octet,
J 6.8), 2.39 (2 H, dd, J 12.5 and 3.9), 2.49–2.61 (2 H, m), 2.64–2.76
(2 H, m), 2.85 (4 H, app t, J 11.8), 4.02–4.15 (4 H, m), 6.38 (4 H, t,
J 7.43), 6.55 (4 H, d, J 8.8), 6.77 (4 H, dd, J 6.9 and 3.9), 6.94 (4 H,
t, J 7.2), 6.99 (8 H, t, J 6.9), 7.09 (8 H, t, J 6.8), 7.12–7.27 (28 H,
m); dC (125 MHz, CDCl3) 18.4, 19.3, 30.8, 48.2, 51.6, 55.4, 127.2,
127.3, 128.15–128.25 (multiple signals), 129.4, 133.4, 133.6, 134.0,
134.1, 136.9 (d, J 21.7), 138.3 (d, J 10.5), 138.6 (d, J 14.2), 141.3
(d, J 24.7), 169.0; dP (202 MHz, CDCl3) −8.34 (s); HRMS (FAB+)
calcd for C98H104N6O4P4 [M + H] 1553.7148. Found: 1553.7151.
Compound 9
Compound 9 was prepared following our previous procedure2
using n-butylamine (1.34 mL, 13.6 mmol) and aziridine 6 (6.6 g,
27.4 mmol) in MeOH (18 mL), giving compound 9 as a white
powder (7.02 g, 85%): Rf (hexane–EtOAc 7 : 3) 0.7; [a]2D5 +29.5
(c 1.09 in CHCl3); mp 116–117 ◦C; dH (400 MHz, CDCl3) 0.75
(6 H, d, J 7.0), 0.77 (6 H, d, J 7.0), 0.86 (3 H, t, J 7.2), 1.01–1.31
(4 H, m), 1.93 (2 H, dhept, J 7.0 and 4.0), 2.12–2.23 (1 H, m), 2.24–
2.34 (1 H, m), 2.31 (2 H, dd, J 13.1 and 5.5), 2.38 (2 H, dd, J 13.1
and 8.8), 2.41 (6 H, s), 3.26–3.39 (2 H, m), 5.21 (2 H, br s), 7.27 (4 H,
d, J 8.2), 7.79 (4 H, d, J 8.2); dC (125 MHz, CDCl3) 14.0, 17.7,
20.5, 21.5, 27.1, 29.7, 53.0, 53.7, 56.0, 127.0, 129.5, 138.6, 143.0.
Compound 13
Compound 13 was synthesized in a similar way disclosed
previously2 using (1R,2R)-diaminocyclohexane (4, 173 mg,
1.52 mmol), aziridine 6 (731 mg, 3.05 mmol), and MeOH (2.0 mL).
The mixture was exposed to microwave at 160 ◦C for 75 min. The
solvent was removed and the brown solid obtained was purified
by chromatography (hexane–EtOAc 3 : 1 + 0–1% Et3N and 0–3%
MeOH) to give the product as a yellow foam (578 mg, 63%): Rf
(hexane–EtOAc 3 : 1 + 1% Et3N and 3% MeOH) 0.13; [a]2D5 −51.6
Compound 10
Compound 10 was prepared in the same way as described
previously5 from 9 (6.82 g, 12.36 mmol), phenol (7.51 g,
79.79 mmol), and HBr (48% aq., 104.5 mL), giving the product
(2.49 g, 83%) as a light brown oil: [a]2D5 +106.5 (c 0.76 in CHCl3);
dH (400 MHz, CDCl3) 0.894 (3 H, t, J 7.3), 0.896 (6 H, d, J 6.8),
0.91 (6 H, d, J 6.8), 1.16–1.45 (4 H, m), 1.50 (2 H, octet, J 6.8),
1.82 (4 H, br s), 2.17–2.27 (1 H, m), 2.22 (2 H, dd, J 12.6 and 10.3),
2.30 (2 H, dd, J 12.6 and 3.0), 2.45–2.54 (1 H, m), 2.60–2.68 (2 H,
m); dC (100 MHz, CDCl3) 14.0, 18.7, 18.9, 20.6, 28.0, 31.0, 54.3,
54.6, 56.5.
◦
(c 0. 69 in CHCl3); mp 139–140 C; dH (400 MHz, CDCl3) 0.67
(6 H, d, J 6.8), 0.70 (6 H, d, J 6.8), 1.04–1.23 (4 H, m), 1.65 (2 H,
octet, J 6.8), 1.54–1.74 (4 H, m), 1.88 (2 H, d, J 12.6), 2.17–2.27
(2 H, m), 2.40 (6 H, s), 2.57 (2 H, dd, J 11.8 and 7.1), 2.77 (2 H,
dd, J 11.8 and 3.4), 3.12–3.19 (2 H, m), 6.14 (2 H, br s), 7.26
(4 H, d, J 8.3), 7.78 (4 H, d, J 8.3); dC (125 MHz, CDCl3) 18.9,
19.0, 21.5, 25.1, 30.3, 31.8, 47.0, 60.15, 60.22, 126.9, 129.4, 139.0,
142.8.
Compound 11
Compound 11 was prepared analogously to 13 using di-
aminoethane (3, 30 mg, 0.5 mmol), 6 (718 mg, 3 mmol), and
MeOH (2 mL). The precipitate formed was filtered off and rinsed
with MeOH three times to give 11 as a white powder (359 mg,
71%): [a]2D5 +36.6 (c 0.66 in CHCl3); mp 190–191 ◦C; dH (400 MHz,
CDCl3) 0.70 (12 H, d, J 6.9), 0.74 (12 H, d, J 6.9), 1.80 (4 H, dhept,
J 6.9 and 4.0), 2.32–2.50 (10 H, m), 2.38 (12 H, s), 2.74–2.86 (2 H,
m), 3.29–3.39 (4 H, m), 5.67 (4 H, d, J 6.3), 7.25 (8 H, d, J 8.3),
7.80 (8 H, d, J 8.3); dC (100 MHz, CDCl3) 17.5, 18.0, 21.5, 30.0,
45.8, 51.9, 53.6, 56.5, 126.9, 129.4, 139.1, 142.8.
Compound 14
Compound 14 was prepared in the same way described previously5
from 13 (1.40 g, 2.36 mmol), phenol (1.42 g, 15.1 mmol), and HBr
(48% aq., 19.8 mL) giving the product (549 mg, 82%) as a pink
thick oil: [a]2D5 −48.4 (c 0.79 in CHCl3); dH (400 MHz, CDCl3) 0.88
(6 H, d, J 6.8), 0.90 (6 H, d, J 6.8), 0.93–1.08 (2 H, m), 1.53–1.78
(4 H, m), 1.60 (2 H, dhept, J 6.8 and 5.5), 2.00–2.14 (4 H, m), 2.17
(2 H, dd, J 11.2 and 9.1), 2.46–2.54 (2 H, m), 2.85 (2 H, dd, J 11.2
and 3.5); dC (100 MHz, CDCl3) 17.8, 19.5, 25.1, 32.1, 32.3, 51.8,
57.5, 62.7.
Compound 12
Compound 12 was prepared as described previously5 from 11
(1.01 g, 1.0 mmol), phenol (1.21 g, 12.8 mmol), and HBr (48% aq.,
17 mL), giving the product (343 mg, 86%) as a colorless oil: [a]D25
+172.4 (c 0.52 in CHCl3); dH (400 MHz, CDCl3) 0.89 (12 H, d,
J 6.8), 0.90 (12 H, d, J 6.8), 1.48 (4 H, octet, J 6.8), 1.5 (8 H,
br s), 2.21 (2 H, dd, J 12.3 and 10.7), 2.33 (2 H, dd, J 12.3 and
2.3), 2.37–2.45 (2 H, m), 2.58–2.70 (6 H, m); dC (100 MHz, CDCl3)
18.2, 19.3, 32.2, 52.8, 53.7, 60.0.
Compound 23
Ligand 23 was synthesized using
a modified literature
procedure.20 2-(Diphenylphosphino)benzoic acid (19a, 1.05 g,
3.33 mmol), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hy-
drochloride (EDC·HCl) (638 mg, 3.33 mmol), and 1-
hydroxylbenzotriazole hydrate (HOBt) (450 mg, 3.33 mmol) were
stirred in DMF (46 mL) for 30 min at rt. 14 (473 mg, 1.66 mmol)
was added, and the reaction mixture stirred for 24 h. 1 N HCl
(92 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 90 mL). The combined organic phases were washed
with brine (3 × 90 mL). The solvent was removed in vacuo and the
crude product was purified by chromatography (silica gel, hexane–
EtOAc 3 : 1, + 1–3% Et3N and 2–3% MeOH) to give the 23 as a
Compound 22
Ligand 22 was synthesized analogously to 23 using 2-
(diphenylphosphino)benzoic acid (19a, 772 mg, 2.52 mmol),
EDC·HCl (483 mg, 2.52 mmol,), HOBt (341 mg, 2.52 mmol),
12 (253 mg, 0.63 mmol), and DMF (11.2 mL). Purification by
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white foam (808 mg, 56%): Rf (hexane–EtOAc 3 : 1 + 6% Et3N and
6% MeOH) 0.43; [a]D25 −81.4 (c 0.56 in CHCl3); mp 88–90 ◦C; dH
(400 MHz, CDCl3) 0.77 (6 H, d, J 6.8), 0.81 (6 H, d, J 6.8), 0.83–
0.94 (2 H, m), 1.16 (2 H, app t, J 10.2), 1.46 (2 H, br s), 1.58–1.71
(2 H, m), 1.76 (2 H, octet, J 6.8), 1.91–2.06 (4 H, m), 2.50 (2 H, dd,
J 12.3 and 5.0), 2.67 (2 H, dd, J 12.3 and 4.7), 3.79–3.89 (2 H, m),
6.15 (2 H, d, J 8.8), 6.94 (2 H, dd, J 7.1 and 3.8), 7.18–7.37 (24 H,
m), 7.58 (2 H, dd, J 6.8 and 3.5); dC (125 MHz, CDCl3) 18.4,
19.5, 25.0, 29.2, 31.8, 47.5, 55.2, 62.0, 127.7, 127.8, 128.5, 128.59,
128.60, 128.7, 128.8, 128.9, 130.0, 133.6, 133.7, 133.8, 133.9, 134.3,
135.2 (d, J 20.2), 137.1 (d, J 11.2), 137.4 (d, J 12.0), 142.4 (d,
J 27.7), 168.8; dP (202 MHz, CDCl3) −10.4 (s); HRMS (FAB+)
calcd for C54H62N4O2P2 [M + H] 861.4426. Found: 861.4412.
(2 H, m); dC (125 MHz, CDCl3) 17.8, 19.4, 24.9, 29.4, 31.4, 47.5,
54.8, 61.2, 127.82, 127.86, 128.50, 128.55, 128.60, 128.65, 128.73,
128.81, 130.0, 133.70, 133.74, 133.86, 133.89, 134.32, 135.5 (d,
J 21.1), 137.2 (d, J 11.5), 137.4 (d, J 11.5), 143.4 (d, 25.9), 168.9;
dP (202 MHz, CDCl3) −9.98 (s).
Compound 17
Compound 17 was prepared analogously to 13 using TREN (5,
48.3 mg, 0.33 mmol), 6 (718 mg, 3 mmol), and MeOH (2 mL). The
crude product was purified by chromatography (silica gel, hexane–
EtOAc 4 : 1 to hexane–EtOAc 3 : 1 + 3–6% Et3N and 3–6% MeOH)
to give 17 as a white foam (370 mg, 95%): Rf (hexane–EtOAc 3 : 1 +
6% Et3N and 6% MeOH) 0.10; [a]2D5 +34.5 (c 1.49 in CHCl3); mp
85–87 ◦C; dH (400 MHz, CDCl3) 0.71 (18 H, d, J 6.9), 0.74 (18 H,
d, J 6.9), 1.85 (6 H, dhept, J 6.9 and 3.7), 2.33 (6 H, dd, J 13.5
and 4.1), 2.37 (18 H, s), 2.40–2.47 (3 H, m), 2.44 (6 H, dd, J 13.5
and 10.2), 2.47–2.57 (6 H, m), 2.72–2.86 (3 H, m), 3.29–3.40 (6 H,
m), 5.81 (6 H, br s), 7.23 (12 H, d, J 8.2), 7.77 (12 H, d, J 8.2);
dC (125 MHz, CDCl3) 17.2, 18.1, 21.5, 30.0, 51.5, 51.7, 53.2, 56.1,
127.0, 129.4, 139.0, 142.7.
Compound 15
Compound 15 was prepared analogously to 13 using (1S,2S)-
diaminocyclohexane (ent-4, 173 mg, 1.52 mmol), compound 6
(731 mg, 3.05 mmol), and MeOH (2.0 mL). The brown solid
obtained was purified by chromatography (silica gel, hexane–
EtOAc 3 : 1 + 1% Et3N and 2% MeOH) to give the product
as a white-yellowish foam (519 mg, 58%): Rf (hexane–EtOAc 3 :
1 + 6% Et3N and 6% MeOH) 0.38; [a]2D5 +4.5 (c 0.67 in CHCl3);
mp 45–46 ◦C; dH (400 MHz, CDCl3) 0.64 (6 H, d, J 6.7), 0.75
(6 H, d, J 6.7), 0.93–1.07 (2 H, m), 1.14–1.23 (2 H, m), 1.56–1.81
(4 H, m), 1.72 (2 H, octet, J 6.7), 1.98 (2 H, d, J 13.1), 2.13–2.22
(2 H, m), 2.40 (6 H, s), 2.59 (2 H, dd, J 12.1 and 3.5), 2.87 (2 H,
dd, J 12.1 and 5.0), 3.01–3.11 (2 H, m), 6.12 (2 H, br s), 7.26
(4 H, d, J 8.3), 7.80 (4 H, d, J 8.3); dC (125 MHz, CDCl3) 18.9,
19.4, 21.5, 25.2, 29.8, 31.8, 47.1, 60.0, 61.0, 126.9, 129.5, 138.6,
142.9.
Compound 18
Compound 18 was prepared in the same way described previously5
using compound 17 (1.84 g, 1.16 mmol), phenol (2.11 g,
22.4 mmol), and HBr (48% aq., 30 mL), giving the product
(663 mg, 87%) as a whitish semisolid: [a]2D5 +155.0 (0.40 in MeOH);
dH (400 MHz, CDCl3) 0.89 (18 H, d, J 6.8), 0.90 (18 H, d, J 6.8),
1.48 (6 H, octet, J 6.8), 1.5 (12 H, br s), 2.20 (6 H, dd, J 12.5 and
10.3), 2.35 (6 H, dd, J 12.5 and 2.8), 2.29–2.41 (3 H, m), 2.47–2.59
(6 H, m), 2.59–2.68 (9 H, m); dC (100 MHz, CDCl3) 18.3, 19.4,
32.2, 53.1, 53.4, 53.8, 60.2.
Compound 16
Compound 16 was prepared in the same way described previously6
using compound 15 (1.29 g, 2.17 mmol), phenol (1.32 g,
14.0 mmol), and HBr (48% aq., 18.4 mL), giving the product
(560 mg, 91%) as a clear light yellow oil: [a]2D5 +115. 9 (c 0.73 in
CHCl3); dH (400 MHz, CDCl3) 0.88 (6 H, d, J 6.8), 0.90 (6 H, d,
J 6.8), 0.92–1.04 (2 H, m), 1.16–1.25 (2 H, m), 1.39 (6 H, br s), 1.57
(2 H, dhept, J 6.8 and 5.0), 1.64–1.76 (2 H, m), 2.01–2.15 (4 H,
m), 2.46 (2 H, dd, J 12.1 and 9.8), 2.55 (2 H, dd, J 12.1 and 3.5),
2.52–2.60 (2 H, m); dC (100 MHz, CDCl3) 17.6, 19.5, 25.1, 31.8,
32.1, 50.9, 56.4, 61.2.
Compound 25
Ligand 25 was synthesized analogously to 23 using 2-
(diphenylphosphino)benzoic acid (19a, 184 mg, 0.6 mmol),
EDC·HCl (115 mg, 0.6 mmol,), HOBt (81 mg, 0.6 mmol), 18
(66 mg, 0.1 mmol), and 2.8 mL DMF. The purification by
chromatography (silica gel, hexane–EtOAc 3 : 1 + 0.5% Et3N and
0.5% MeOH) gave 25 as a white foam (56 mg, 24%): Rf (hexane–
EtOAc 3 : 1 + 6% Et3N and 6% MeOH) 0.71; [a]2D5 −190.5 (0.23 in
◦
CH2Cl2); mp 127.3–129.5 C; dH (400 MHz, CDCl3) 0.67 (18 H,
d, J 6.8), 0.71 (18 H, d, J 6.8), 1.50–1.63 (6 H, m), 2.02–2.14 (3 H,
m), 2.27 (6 H, dd, J 12.5 and 3.4), 2.37–2.49 (3 H, m), 2.58–2.70
(6 H, m), 2.82 (6 H, app t, J 11.7), 3.92–4.04 (6 H, m), 6.29 (6 H, t,
J 7.4), 6.75 (6 H, dd, J 7.3 and 4.0), 6.89 (12 H, t, J 7.2), 6.98 (12 H,
t, J 7.7), 7.05 (12 H, t, J 7.2), 7.13–7.29 (42 H, m); dC (100 MHz,
CDCl3) 18.9, 19.2, 30.2, 51.9, 52.7, 53.3, 56.1, 127.42, 127.45,
128.0, 128.1, 128.23–128.32 (multiple signals), 129.1, 133.6, 133.8,
133.9, 134.1, 134.3, 136.9 (d, J 22.4), 138.2 (app t, J 14.2 and 12.7),
141.3 (d, J 22.4), 169.0; dP (202 MHz, CDCl3) −8.0 (s); HRMS
(FAB+) calcd for C150H162N10O6P6 [M + H] 2386.1183. Found:
2386.1196.
Compound 24
Ligand 24 was synthesized analogously to 23 using 2-
(diphenylphosphino)benzoic acid (19a, 472 mg, 1.54 mmol),
EDC·HCl (295 mg, 1.54 mmol,), HOBt (208 mg, 1.54 mmol),
16 (218 mg, 0.77 mmol), and 19 mL DMF. Purified by chromatog-
raphy (silica gel, hexane–EtOAc 3 : 1 + 1–6% Et3N and 2–6%
MeOH) to give 24 as a white foam (309 mg, 47%): Rf (hexane–
EtOAc 3 : 1 + 6% Et3N and 6% MeOH) 0.24; [a]2D5 −6.8 (c 0.30
in CHCl3); mp 81–82 ◦C; dH (400 MHz, CDCl3) 0.69 (6 H, d,
J 6.8), 0.78 (6 H, d, J 6.8), 0.80–0.91 (2 H, m), 1.18 (2 H, app t,
J 10.2), 1.52–1.81 (4 H, m), 1.75 (2 H, octet, J 6.8), 1.99 (2 H,
d, J 12.8), 2.08–2.18 (2 H, m), 2.43 (2 H, dd, J 12.4 and 5.0),
2.30 (2 H, dd, J 12.4 and 6.7), 3.84–3.95 (2 H, m), 6.11 (2 H,
d, J 8.8), 6.89–6.97 (2 H, m), 7.15–7.37 (24 H, m), 7.53–7.61
Compound 26
Under nitrogen atmosphere,
8 (0.5 mmol, 0.136 g) and
diphenylphosphine benzaldehyde 19b (1.55 mmol, 0.5 g) were
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dissolved in a solution of anhydrous CH2Cl2–CH3OH (1 : 3)
(100 mL). The homogeneous solution was stirred at room
temperature for 72 h. The solvents were then evaporated under
vacuum until a yellow precipitate appeared. This was filtered,
washed with cold methanol to yield 26 (60%) as a yellow solid:
[a]2D5 −44.5 (c 0.49 in CHCl3); dH (400 MHz, CDCl3) 0.54 (9 H,
d, J 6.8), 0.62 (9 H, d, J 6.8), 1.57–1.71 (3 H, m), 2.28 (3 H, dd,
J 13.5 and 7.4), 2.42 (3 H, dd, J 13.5 and 4.5), 2.88–2.99 (3 H, m),
6.80–6.88 (3 H, m), 7.17–7.31 (36 H, m), 7.42–7.47 (3 H, m), 8.51
(3 H, d, J 4.3); dC (100 MHz, CDCl3) 17.7, 20.1, 30.6, 59.2, 75.2,
128.3–128.5 (multiple signals), 129.11, 129.14, 129.4, 133.5, 133.8,
133.99, 134.04,134.2, 137.1 (d, J 21.7), 137.6 (d, J 9.8), 137.8 (d,
J 11.9), 139.8 (d, J 17.2), 158.7 (d, J 14.9); dP (202 MHz, CDCl3)
−11.0.
dropwise to generate a solution of tetrahexylammonium dimethyl
malonate. The catalytic solution was added to it at once. The
reaction was monitored by GC-MS. The enantiomeric excess was
determined by HPLC (31: 0.25% iPrOH in hexane, 0.5 mL min−1,
Chiralcel OD–H, wavelength: 220 nm, tR = 28.3 min, tS
=
29.8 min, rt).
The same procedure was used for ethyl 3-cyclopentenyl carbon-
ate (30) except the enantiomeric excess was determined by the
1
combination of optical rotation data15 and H NMR chiral shift
study (32).13
Acknowledgements
The project was financed by EU grant HPRN-CT-2001-00187 and
by the Swedish Research Council.
(S,S,S)-Tris[2-(2ꢀ-diphenylphosphinobenzamino)-3-
methylbutyl]amine (27)
References
1 (a) Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley, New York,
2000; (b) Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999.
2 F. Lake and C. Moberg, Eur. J. Org. Chem., 2002, 3179–3188.
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5 Y. Pei, K. Brade, E. Brule´, L. Hagberg, F. Lake and C. Moberg,
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9 B. M. Trost, D. L. Van Vranken and C. Bingel, J. Am. Chem. Soc., 1992,
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10 B. Crociani, S. Antonaroli, V. Beghetto, U. Matteoli and A. Scrivanti,
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13 B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1996, 118, 235–
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NaBH4 (3.3 mmol, 0.125 g) was added in two portions to
phosphine imine ligand 26 (1 mmol, 1.09 g) in anhydrous CH2Cl2–
CH3OH (1 : 2) (20 mL). After stirring overnight at room tem-
perature, diethyl ether (20 mL) and saturated aqueous NaHCO3
were added. The aqueous phase was extracted with diethyl ether.
The combined organic phases were dried over MgSO4 and the
solvents were evaporated. A pale yellow solid corresponding to the
amine ligand was obtained in 70%: [a]2D5 +5.4 (c 0.26 in CHCl3); dH
(400 MHz, CDCl3) 0.65 (9 H, d, J 6.9), 0.71 (9 H, d, J 6.9), 1.67
(3 H, s br), 1.7–1.87 (3 H, m), 2.16 (3 H, dd, J 12.8 and 5.0), 2.25
(3 H, dd, J 12.8 and 7.8), 2.38–2.47 (3 H, m), 3.86 (6 H, s), 6.74–
6.81 (3 H, m), 6.98–7.11 (6 H, m), 7.13–7.30 (3 H, m), 7.40–7.45
(30 H, m); dC (100 MHz, CDCl3) 17.6, 17.8, 28.1, 50.2, 50.5,
56.2, 60.0, 126.7, 128.4–128.5 (multiple signals), 128.76, 128.81,
128.9, 133.2, 133.7, 133.8, 133.92, 133.98, 135.1 (d, J 13.6), 137.0
(d, J 11.2), 137.2 (d, J 11.2), 145.6 (d, J 23.2); dP (202 MHz,
CDCl3) −14.8.
14 The ligand coordinates in different modes: G. C. Lloyd-Jones, S. C.
Stephen, I. J. S. Fairlamb, A. Martorell, B. Dominguez, P. M. Tomlin,
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15 P. Sennhenn, B. Gabler and G. Helmchen, Tetrahedron Lett., 1994, 35,
8595–8598.
16 J.-P. Genet, S. Juge, S. Achi, S. Mallart, J. Ruiz Montes and G. Levif,
Tetrahedron, 1988, 44, 5263–5275.
17 L. Berillon, PhD thesis, Munich, 2004.
Typical procedure for catalytic asymmetric allylic alkylation
Allylic alkylation followed Trost’s procedure12 with a slight
modification. DCM (0.5 mL) was added to a flask charged with
allylic palladium chloride dimer (4.2 lmol, 1.5 mg) and ligand
22 (6.3 lmol, 9.6 mg). The mixture was stirred for 5 min at rt
before methyl 3-cyclohexenyl carbonate (29, 0.165 mmol, 26 mg)
was added; 2.5 mL DCM was added to another flask charged
with sodium hydride (0.5 mmol, 12 mg) and THAB (0.52 mmol,
225 mg). Then dimethyl malonate (0.6 mmol, 81 mg) was added
18 K. Tappe, PhD thesis, Munich, 2004.
19 M. Lotz, PhD thesis, Munich, 2004.
20 L. F. Tietze, J. K. Lohmann and C. Stadler, SYNLETT, 2004, 1113–
1116.
550 | Org. Biomol. Chem., 2006, 4, 544–550
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©