Chiral N-1-adamantyl-N-trans-cinnamylaniline type ligands: Synthesis and application to palladium-catalyzed asymmetric allylic alkylation of indoles

Article abstract of DOI:10.1039/c6ob01354f

Such chiral phosphine-internal olefin hybrid type ligands as N-1-adamantyl-N-cinnamylaniline derivatives 1 with C(aryl)-N(amine) bond axial chirality were synthesized and utilized for the palladium-catalyzed asymmetric allylic alkylation of indoles to aff

Full text of DOI:10.1039/c6ob01354f

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Chiral N-1-adamantyl-N-trans-cinnamylaniline
type ligands: synthesis and application to
palladium-catalyzed asymmetric allylic alkylation
of indoles†
Cite this: DOI: 10.1039/c6ob01354f
Takashi Mino,*a,b Kenji Nishikawa,a Moeko Asano,a Yamato Shima,a
Toshibumi Ebisawa,a Yasushi Yoshidaa,b and Masami Sakamotoa,b
Received 23rd June 2016,
Accepted 7th July 2016
Such chiral phosphine–internal olefin hybrid type ligands as N-1-adamantyl-N-cinnamylaniline derivatives 1
with C(aryl)–N(amine) bond axial chirality were synthesized and utilized for the palladium-catalyzed asym-
metric allylic alkylation of indoles to afford the desired products in high enantioselectivities (up to 98% ee).
DOI: 10.1039/c6ob01354f
www.rsc.org/obc
chiral phosphine–internal olefin hybrid type ligands14,15 with
the C(aryl)–N(amine) bond axial chirality of aniline derivatives.
Introduction
Indole moieties are the most widely distributed heterocyclic Although Du previously reported a chiral phosphine–internal
compounds in nature, especially chiral indoles and their olefin hybrid type ligand such as an N-cinnamyl type ligand
derivatives, which are widely present in various biologically L5, it was ineffective for palladium-catalyzed asymmetric
and medicinally important compounds.1 Recently the syn- allylic alkylation.5 Here, we report the synthesis and the
thesis of optically active indoles by the palladium-catalyzed optical resolution of N-1-adamantyl-N-cinnamylaniline deriva-
asymmetric allylic alkylation of indoles with 1,3-diphenyl-2- tives 1 with C(aryl)–N(amine) bond axial chirality (Fig. 1), the
propenyl acetate has been reported. Chan and Hoshi reported
chiral ferrocenyl P/S ligands2 and P/S-type sulfur-MOP ligands3
for this reaction. Du reported a chiral phosphine–terminal
olefin hybrid type4 and phosphorus amidite–terminal olefin
hybrid type5 ligands with a binaphthyl framework. Recently
similar reactions have also been reported, including the syn-
thesis of indolenines from 3-substituted indoles using a palla-
dium/chiral phosphorus amidite–olefin type ligand system,6
the N-allylic alkylation of indoles using a palladium/sulfoxide–
phosphine ligand system,7 and the iridium-catalyzed intra-
molecular allylic alkylation of indoles.8
On the other hand, we reported the synthesis of P/N-type
ligands with C(aryl)–N(amine) bond axial chirality, such as
chiral N-aryl indoline-type aminophosphine L1,9 chiral N-aryl
indole-type aminophosphine L2,10 and acyclic chiral amino-
phosphines L3 11 and L4.12 We also reported that aminophos-
phine L2 was an effective ligand for the palladium-catalyzed
asymmetric allylic alkylation of indoles.13 We are interested in
aDepartment of Applied Chemistry and Biotechnology, Graduate School of
Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
E-mail: tmino@faculty.chiba-u.jp
bMolecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
†Electronic supplementary information (ESI) available. CCDC 1486809–1486811.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ob01354f
Fig. 1 Chiral ligands L1–L5 and 1.
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investigation of a rotation barrier for C–N bond axial stability,
and an application to chiral phosphine–internal olefin hybrid
type ligands for the palladium-catalyzed asymmetric allylic
alkylation of indoles.
Results and discussion
Racemic aminophosphines ( )-1 were easily prepared in two
steps from N-1-adamantylaminophosphine oxides 2.11 The
N-alkylation of 2a with cinnamyl bromide occurred in the pres-
ence of K2CO3. This aminophosphine oxide 3a was converted
into the desired racemic aminophosphine ( )-1a using
trichlorosilane–triethylamine in good yield (Scheme 1).
Racemic aminophosphines ( )-1b and ( )-1c were also easily
prepared from 2b and 2c in the same manner.
Scheme 2 Preparation of racemic aminophosphine ( )-5.
We also prepared a similar compound to aminophosphine
1c, aminophosphine 5, which does not have an internal olefin,
in the same manner as the preparation of ( )-1 from phos-
phine oxide 2c with 1-iodo-3-phenylpropane instead of cinna-
myl bromide (Scheme 2).
To investigate whether C(aryl)–N(amine) bond axial chirality
exists in aminophosphines 1 and 5, we analytically separated
these isomers using HPLC with a chiral stationary phase
column and obtained nearly resolved UV plots for aminophos-
phines ( )-1 and ( )-5 and a pair of clear positive (+) and nega-
tive (−) CD trace signals of a HPLC run.
Although at this stage we could not obtain enantiopure
aminophosphine 1a by optical resolution using a chiral
palladium resolving agent9a,12 and a semi-preparative chiral
HPLC method, we successfully obtained the optical resolution
of ( )-1b, ( )-1c, and ( )-5 using a semi-preparative chiral HPLC
(Scheme 3). The optical purities of each of the enantiomers
exceeded 99% ee from the chiral HPLC analyses.
Scheme 3 Optical resolution of ( )-1b, 1c and 5 by chiral HPLC.
The determination of the absolute configurations was made
by a single-crystal X-ray analysis of (aS)-(+)-1b, (aR)-(−)-1c, and
(aR)-(−)-5 (Fig. 2–4).16
We also determined the barriers to the racemization of
aminophosphines 1b, 1c, and 5 in dodecane for the stability of
the C–N bond axial chirality (Tables S1–S3 and Fig. S1–S3, see
the ESI†). A small portion of the solution of optically active
aminophosphine 1b, 1c, or 5 in dodecane was removed at
regular intervals and subsequently analyzed for enantiomeric
excess by chiral HPLC analysis. We repeated the experiment at
four temperatures and determined the rate constants (krac) of
1b, 1c, and 5 at each temperature. For example, the rotational
barrier (ΔG‡rac) of 1b was found to be 34.0 kcal mol−1 in
dodecane at 25 °C based on the Arrhenius and Eyring
equations.10 This result corresponds to a half-life of approxi-
mately 1.4 × 104 years in dodecane at 25 °C (Table 1).
Finally, we investigated the ability of chiral aminophos-
phines 1b, 1c, and 5 as ligands for the palladium-catalyzed
asymmetric allylic alkylation of indole derivatives. The reaction
of indoles with 1,3-diphenyl-2-propenyl acetate was performed
in the presence of 3 mol% of [Pd(η3-C3H5)Cl]2 and 6 mol% of
Scheme 1 Preparation of racemic aminophosphines ( )-1.
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Fig. 4 X-ray structure of (aR)-(−)-5. Ellipsoids are shown at the 50%
probability level.
Fig. 2 X-ray structure of (aS)-(+)-1b. Ellipsoids are shown at the 50%
probability level.
Table 1 Racemization parameters of 1b, 1c and 5
Thermodynamic
parameters at 25 °C
1b
1c
5
Half-life (year)
1.4 × 104
7.64 × 10−13
30.3
−12.5
34.0
5.1 × 101
2.15 × 10−10
26.9
−12.5
30.6
7.3 × 109
1.50 × 10−18
38.0
−12.5
41.8
Krac
ΔH (kcal mol−1
)
ΔS (cal mol−1 K−1
ΔG (kcal mol−1
)
)
6a in 78% yield with good enantioselectivity (80% ee) (entry 1).
We tested (aR)-(−)-1c and (aR)-(−)-5 in this reaction and found
that the former was an effective ligand with high enantio-
selectivity (96% ee) (entry 2). On the other hand, the reaction
using similar aminophosphines without internal olefin such
as (aR)-(−)-5 gave an opposite enantiomer of 6a with low
enantioselectivity (entry 3). We found that the absolute con-
figuration and enantioselectivity of the product were controlled
by the existence of a carbon–carbon double bond at the cinna-
myl moiety in the ligand. We next investigated the effects of
various solvents (entries 2, and 4–8). Using THF, ethyl acetate,
and toluene as solvents, the enantioselectivity decreased to
around 90% ee. When the reaction was carried out in dichloro-
methane and benzotrifluoride, the enantioselectivity also
slightly decreased. We next changed the base for the reaction
in acetonitrile (entries 2, 9, and 10). Using Na2CO3 as a base,
product 6a was obtained with a similar level of enantio-
selectivity (entry 9). But the yield of 6a decreased to 53%. With
Fig. 3 X-ray structure of (aR)-(−)-1c (the other molecule is omitted for
clarity). Ellipsoids are shown at the 50% probability level.
ligand (Pd/ligand = 1/1) as a model reaction (Table 2). The KOAc, the enantioselectivity decreased (entry 10). We investi-
reaction using (aR)-(−)-1b and 2 equiv. of K2CO3 as a base in gated the effects of reaction temperature (entries 2, 11, and
acetonitrile at 40 °C for 18 h gave the corresponding product 12). For the reaction at room temperature and 50 °C, product
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Table 2 Optimization of palladium-catalyzed asymmetric allylic alkylation of indoles
Entry
Ligand
Solv.
Base
Temp.
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
(aR)-(−)-1b
(aR)-(−)-1c
(aR)-(−)-5
MeCN
MeCN
MeCN
THF
EtOAc
PhMe
DCM
PhCF3
MeCN
MeCN
MeCN
MeCN
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KOAc
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
r.t.
78
69
89
63
62
57
76
63
53
71
70
69
80
96
−12
88
91
89
94
93
96
79
95
96
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
(aR)-(−)-1c
9
10
11
12
K2CO3
K2CO3
50 °C
a Isolated yield. b Determined by HPLC analysis using a chiral column.
6a was obtained with similar levels of enantioselectivity and (entry 4), with 1,3-diphenyl-2-propenyl acetate gave the corres-
yield. ponding products in good to high enantioselectivities with
With the optimized conditions in hand (Table 2, entry 2), good yields (entries 2–8). On the other hand, the reaction
we examined the scope and limitation of the palladium-cata- using 7-bromoindole did not give any product (entry 9). When
lyzed asymmetric allylic alkylation of various indoles with we used 5-bromoindole and 4-bromoindole, the reaction gave
allylic esters using the chiral phosphine–internal olefin hybrid products 6i and 6j with high enantioselectivities (entries 10
type ligand (aR)-(−)-1c in MeCN at 40 °C (Table 3). The reac- and 11). The reaction with 4-methylindole and 2-phenylindole
tions of 6-substituted indoles, except for 6-benzyloxyindole also led to good enantioselectivities (entries 12 and 13). On
Table 3 Palladium-catalyzed asymmetric allylic alkylation of indoles using (aR)-(−)-1c
Entry
R
X
Ar
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
H
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OPiv
OAc
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClC6H4
69 (6a)
72 (6b)
62 (6c)
70 (6d)
62 (6e)
68 (6f)
69 (6g)
63 (6h)
N.R.
67 (6i)
61 (6j)
60 (6k)
74 (6l)
N.R.
96
94
83
57
95
95
96
91
—
95
98
86
95
—
97
97
6-Me
6-OMe
6-OBn
6-NO2
6-F
6-Cl
6-Br
7-Br
5-Br
4-Br
4-Me
2-Ph
N-Me
H
9
10
11
12
13
14
15
16
82 (6a)
82 (6m)
H
a Isolated yield. b Determined by HPLC analysis using a chiral column.
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the other hand, the reaction using N-methylindole failed to
proceed (entry 14). Finally, we tested the reaction of indoles
Conclusions
with 1,3-diphenyl-2-propenyl pivalate and 1,3-di-(4-chloro- In conclusion, we found that the palladium-catalyzed asym-
phenyl)-2-propenyl acetate. These reactions also gave the metric allylic alkylation of indoles with 1,3-diphenyl-2-prope-
corresponding products with high enantioselectivities nyl acetate using N-1-adamantyl-N-cinnamylaniline derivative
(97% ee) (entries 15 and 16). The absolute configurations of 1c with C(aryl)–N(amine) bond axial chirality as a ligand in
products 6 were assigned by comparing the optical rotation MeCN gave the desired products 6 in good yields with moder-
with the reported data13 or tentatively assigned by analogy.
We suggest the plausible asymmetric induction process of
the palladium-catalyzed asymmetric allylic alkylation of indole
derivatives with 1,3-diphenyl-2-propenyl acetate using the
chiral ligand (aR)-(−)-1c as shown in Fig. 5. There are two can-
didates, W-type intermediate A and M-type intermediate B,
which are the possible structures formed from the chiral
ligand (aR)-(−)-1c. Intermediate B is unstable because of the
steric hindrance between the phenyl rings of the allylic sub-
strate and the ligand’s cinnamyl moiety. Therefore, the reac-
tion probably proceeds through the intermediate A rather than
B. The nucleophilic attack of indole potassium salt (Nu−)
occurs predominantly at the allyl terminus from the trans to
the phosphine atom and gives the intermediate C. As a result,
(R)-products 6 were obtained in this reaction using the chiral
ligand (aR)-(−)-1c.
ate to high enantioselectivities (up to 98% ee).
Experimental section
Preparation of aminophosphine oxide 3a
To a solution of phosphine oxide 2a (1.373 g, 3.0 mmol) in
MeCN (5.0 mL) were added K2CO3 (0.829 g, 6.0 mmol) and cin-
namyl bromide (1.419 g, 7.2 mmol) in MeCN (10.0 mL) at
room temperature. The reaction mixture was stirred for 38 h at
80 °C. The reaction mixture was filtered and evaporated under
reduced pressure. The residue was purified by silica gel
chromatography (hexane : EtOAc = 2 : 1).
N-[2′-(Diphenylphosphinyl)-6′-methoxylphenyl]-N-cinnamyl-
adamantanamine (3a). 87% yield (1.503 g, 2.6 mmol) as a
white solid; m.p. 138–139 °C; 1H NMR (300 MHz, CDCl3):
δ 7.80–7.69 (m, 4H), 7.45–7.39 (m, 6H), 7.28–7.23 (m, 2H),
7.18–7.02 (m, 5H), 6.63 (ddd, J = 14.2, 6.9 and 2.2 Hz, 1H), 6.09
(d, J = 15.9 Hz, 1H), 4.85 (ddd, J = 15.9, 9.5 and 4.1 Hz, 1H),
4.20 (dd, J = 15.3 and 9.5, 1H), 3.84 (s, 3H), 3.17 (ddd, J = 7.6,
3.9 and 2.2 Hz, 1H), 2.05–1.82 (m, 9H), 1.54–1.45 (m, 6H);
13C NMR (75 MHz, CDCl3): δ 160.6 (d, JCP = 11.6 Hz), 144.4 (d,
JCP = 4.8 Hz), 137.9, 136.1 (d, JCP = 27.1 Hz), 135.0 (d, JCP = 32.1
Hz), 134.2 (d, JCP = 44.4 Hz), 132.7, 132.3 (d, JCP = 8.8 Hz),
130.95 (d, JCP = 3.0 Hz), 130.87 (d, JCP = 3.2 Hz), 130.8 (d, JCP
=
9.8 Hz), 128.3 (d, JCP = 12.7 Hz), 128.2, 128.1 (d, JCP = 13.8 Hz),
127.5, 126.5, 126.3 (d, JCP = 13.1 Hz), 126.1, 125.9 (d, JCP
=
15.7 Hz), 115.2, 57.5, 55.0, 52.6, 41.0, 36.7, 30.5; 31P NMR
(121 MHz, CDCl3): δ 26.6; HRMS (ESI-orbitrap) calcd for
C38H41O2NP [M + H]+ 574.2869, found 574.2859.
Preparation of aminophosphine oxide 3b
To a solution of phosphine oxide 2b (0.441 g, 1.0 mmol) in
MeCN (5.0 mL) were added K2CO3 (0.691 g, 5.0 mmol) and cin-
namyl bromide (0.394 g, 2.0 mmol) in MeCN (6.0 mL) at room
temperature. The reaction mixture was stirred for 22 h at
60 °C. The reaction mixture was filtered and evaporated under
reduced pressure. The residue was purified by silica gel chro-
matography (hexane : EtOAc = 5 : 1).
N-[2′-(Diphenylphosphinyl)-6′-methylphenyl]-N-cinnamyl-
adamantanamine (3b). Quantitative yield (0.580 g, 1.0 mmol)
as a yellow solid; m.p. 107–108 °C; 1H NMR (300 MHz, CDCl3):
δ 7.75–7.68 (m, 2H), 7.62–7.57 (m, 2H), 7.56–7.23 (m, 9H),
7.19–7.11 (m, 3H), 7.03–6.89 (m, 2H), 6.13 (d, J = 15.9 Hz, 1H),
5.18 (ddd, J = 15.9, 8.5 and 4.9 Hz, 1H), 4.35–4.24 (m, 1H), 3.53
(ddd, J = 15.0, 4.7 and 1.7 Hz, 1H), 2.52 (s, 3H), 1.97–1.89 (m,
9H), 1.47 (br-s, 6H); 13C NMR (75 MHz, CDCl3): δ 153.5 (d,
JCP = 3.9 Hz), 141.9 (d, JCP = 8.0 Hz), 137.7, 136.9, 135.8 (d,
JCP = 2.6 Hz), 135.5 (d, JCP = 16.3 Hz), 134.1 (d, JCP = 19.2 Hz),
Fig. 5 Plausible asymmetric induction process of palladium-catalyzed
asymmetric allylic alkylation using chiral ligand (aR)-(−)-1c.
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133.4 (d, JCP = 14.0 Hz), 132.4 × 2, 132.3 (d, JCP = 2.9 Hz), 131.1, (d, JCP = 3.2 Hz), 36.7, 30.3; 31P NMR (121 MHz, CDCl3): δ −15.2;
22.5, 131.0 (d, JCP = 3.0 Hz), 130.9 (d, JCP = 2.1 Hz), 128.3 (d, HRMS (ESI-orbitrap) calcd for C38H41ONP [M + H]+ 558.2920,
JCP = 12.0 Hz), 128.2, 128.05, 127.98, 126.6, 126.4, 126.2, 124.5 found 558.2914; HPLC (Daicel CHIRALPAK® IA, 0.46 × 25 cm ×
(d, JCP = 14.9 Hz), 57.8, 52.6, 41.5, 36.5, 30.4; 31P NMR 2 + Daicel CHIRALPAK® IA-3, 0.46 × 25 cm, UV 254 nm,
(121 MHz, CDCl3): δ 28.8; HRMS (ESI-orbitrap) calcd for hexane : 2-propanol = 99.5 : 0.1, mL min−1) tR = 65.5 min (CD:
C38H41ONP [M + H]+ 558.2920, found 558.2907.
λext (Δε) 254 (−)), tR = 67.8 min (CD: λext (Δε) 254 (+)).
Preparation of aminophosphine oxide 3c
Preparation of aminophosphine ( )-1b
To a solution of phosphine oxide 2c (0.448 g, 1.0 mmol) in To a mixture of phosphine oxide 3b (0.837 g, 1.50 mmol) and
MeCN (5.0 mL) were added K2CO3 (0.689 g, 5.0 mmol) and cin- triethylamine (3.6 mL, 36 mmol) in m-xylene (35 mL) was
namyl bromide (0.393 g, 2.0 mmol) in MeCN (5.0 mL) at room added trichlorosilane (2.52 mL, 18 mmol) at 0 °C under an Ar
temperature. The reaction mixture was stirred for 88 h at atmosphere. The reaction mixture was stirred at 120 °C for
60 °C. The reaction mixture was filtered and evaporated under 30 h. After being cooled to room temperature, the mixture was
reduced pressure. The residue was purified by silica gel diluted with CHCl3 and quenched with 2 M aqueous NaOH
chromatography (hexane : CHCl3 : EtOAc = 5 : 1 : 1).
solution. The organic layer was washed with brine, dried over
N-[2′-(Diphenylphosphinyl)-6′-naphthalenyl]-N-cinnamyl- MgSO4, and concentrated under reduced pressure. The residue
adamantanamine (3c). 96% yield (0.569 g, 0.96 mmol) as a was purified by silica gel chromatography (hexane : EtOAc =
yellow solid; m.p. 196–197 °C; 1H NMR (300 MHz, CDCl3): 40 : 1).
δ 8.54–8.51 (m, 1H), 7.83–7.72 (m, 3H), 7.57–7.45 (m, 8H),
N-[2′-(Diphenylphosphino)-6′-naphthalenyl]-N-cinnamyl-
7.37–7.26 (m, 3H), 7.22–7.06 (m, 6H), 6.12 (d, J = 16.0 Hz, 1H), adamantanamine (( )-1b). 65% yield (0.532 g, 0.98 mmol) as a
5.71 (ddd, J = 15.8, 7.6 and 5.7 Hz, 1H), 4.59 (dd, J = 15.2 and yellow solid; m.p. 137–138 °C; 1H NMR (300 MHz, CDCl3):
7.1 Hz, 1H), 4.00 (ddd, J = 15.2, 5.7 and 1.5 Hz, 1H), 2.05–1.92 δ 7.32–7.10 (m, 16H), 6.99 (t, J = 7.5 Hz, 1H), 6.90–6.67 (m,
(m, 9H), 1.44 (br-s, 6H); 13C NMR (75 MHz, CDCl3): δ 154.3 (d, 1H), 6.05–6.04 (m, 2H), 4.16–4.10 (m, 1H), 3.91–3.85 (m, 1H),
JCP = 3.2 Hz), 137.7, 137.3 (d, JCP = 9.5 Hz), 136.6 (d, JCP = 42.6 2.44 (s, 3H), 1.99–1.83 (m, 9H), 1.53–1.39 (m, 6H); 13C NMR
Hz), 135.9 (d, JCP = 55.3 Hz), 134.8 (d, JCP = 96.1 Hz), 132.4, (75 MHz, CDCl3): δ 152.4 (d, JCP = 26.0 Hz), 141.4 (d, JCP = 6.6
131.9 (d, JCP = 62.1 Hz), 131.3 (d, JCP = 9.4 Hz), 131.16 (d, JCP
=
Hz), 140.9 (d, JCP = 3.9 Hz), 139.9 (d, JCP = 15.2 Hz), 139.0 (d,
2.9 Hz), 131.14, 130.6 (d, JCP = 73.3 Hz), 130.1, 129.9, 128.5, JCP = 15.8 Hz), 137.6, 134.1, 133.9 (d, JCP = 19.9 Hz), 133.2 (d,
128.4, 128.24, 128.21, 128.1, 128.0, 127.5, 126.6, 126.2, 125.8, JCP = 19.3 Hz), 132.1, 131.5, 129.0, 128.34 (d, JCP = 6.5 Hz),
125.1 (d, JCP = 13.6 Hz), 57.9, 53.2, 41.4, 36.4, 30.2 (d, JCP = 12.9 128.25, 128.19 (d, JCP = 6.1 Hz), 128.1, 127.8, 126.7, 126.2,
Hz); 31P NMR (121 MHz, CDCl3): δ 28.8; HRMS (ESI-orbitrap) 125.5, 56.3, 51.1 (d, JCP = 8.3 Hz), 42.1 (d, JCP = 5.0 Hz), 36.5,
calcd for C41H41ONP [M + H]+ 594.2920, found 594.2897.
30.2, 21.8 (d, JCP = 1.9 Hz); 31P NMR (121 MHz, CDCl3):
δ −13.6; HRMS (ESI-orbitrap) calcd for C38H41NP [M + H]+
542.2971, found 542.2955; HPLC (Daicel CHIRALCEL® OD,
Preparation of aminophosphine ( )-1a
To a mixture of phosphine oxide 3a (1.722 g, 3.0 mmol) and 0.46 × 25 cm + CHIRALCEL® OD-H, 0.46 × 25 cm, UV 220 nm,
triethylamine (2.5 mL, 18 mmol) in m-xylene (18 mL) was hexane = 100, 0.4 mL min−1) tR = 57.8 min (CD: λext (Δε)
added trichlorosilane (1.8 mL, 18 mmol) at 0 °C under an Ar 254 (−)), tR = 78.4 min (CD: λext (Δε) 254 (+)).
atmosphere. The reaction mixture was stirred at 120 °C for
Preparation of aminophosphine ( )-1c
43 h. After being cooled to room temperature, the mixture was
diluted with CHCl3 and quenched with 2 M aqueous NaOH To a mixture of phosphine oxide 3c (0.297 g, 0.50 mmol) and
solution. The organic layer was washed with brine, dried over triethylamine (0.42 mL, 3.0 mmol) in m-xylene (3.0 mL) was
MgSO4, and concentrated under reduced pressure. The white added trichlorosilane (0.30 mL, 3.0 mmol) at 0 °C under an Ar
solid precipitated and was collected by filtration, washed with atmosphere. The reaction mixture was stirred at 120 °C for
CHCl3, and dried in vacuo.
48 h. After being cooled to room temperature, the mixture was
N-[2′-(Diphenylphosphino)-6′-methoxyphenyl]-N-cinnamyl- diluted with CHCl3 and quenched with 2 M aqueous NaOH
adamantanamine (( )-1a). 57% yield (0.984 g, 1.76 mmol) as solution. The organic layer was washed with brine, dried over
a white solid; m.p. 206–207 °C; 1H NMR (300 MHz, CDCl3): MgSO4, and concentrated under reduced pressure. The residue
δ 7.31–7.30 (m, 5H), 7.22–7.13 (m, 8H), 7.10–7.01 (m, 3H), 6.82 was purified by silica gel chromatography (hexane : EtOAc =
(d, J = 7.0 Hz, 1H), 6.52–6.48 (m, 1H), 6.04 (d, J = 15.9, 1H), 40 : 1).
5.84 (dt, J = 13.8 and 6.9 Hz, 1H), 3.94 (dd, J = 15.0 and 7.2 Hz,
N-[2′-(Diphenylphosphino)-6′-naphthalenyl]-N-cinnamylada-
1H), 3.80 (s, 3H), 3.60 (dd, J = 14.0 and 6.3 Hz, 1H), 1.93 (br-s, mantanamine (( )-1c). 62% yield (0.179 g, 0.31 mmol) as a
6H), 1.81 (br-d, J = 10.1 Hz, 3H), 1.54–1.43 (m, 6H); 13C NMR yellow solid; m.p. 140–141 °C; 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3): δ 159.5 (d, JCP = 4.3 Hz), 143.2 (d, JCP
=
δ 8.47 (d, J = 8.3 Hz, 1H), 7.78–7.75 (m, 1H), 7.58–7.32 (m, 8H),
2.2 Hz), 142.0 (d, JCP = 24.1 Hz), 139.5 (d, JCP = 14.9 Hz), 139.2 7.21–7.09 (m, 9H), 7.02–7.00 (m, 2H), 6.24 (dt, J = 10.1 and
(d, JCP = 16.3 Hz), 137.8, 134.2 × 2 (d, JCP = 20.5 Hz), 133.6 (d, 6.7 Hz, 1H), 6.03 (d, J = 15.9 Hz, 1H), 4.40 (ddd, J = 15.3, 6.8
JCP = 20.3 Hz), 132.4, 128.5, 128.3, 128.23, 128.16 × 2, 128.1, and 0.8 Hz, 1H), 4.17 (ddd, J = 15.2, 6.5 and 1.1 Hz, 1H),
127.9, 126.5, 126.4, 126.3, 126.1, 111.6, 56.5, 54.9, 50.3, 41.6 2.05–1.94 (m, 9H), 1.45 (dd, J = 29.7 and 12.2 Hz, 6H);
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13C NMR (75 MHz, CDCl3): δ 152.3 (d, JCP = 26.9 Hz), 139.8 (d, 2.33–2.23 (m, 2H), 2.02–1.87 (m, 9H), 1.57–1.38 (m, 8H); 13C
JCP = 15.5 Hz), 138.8 (d, JCP = 16.0 Hz), 137.48 (d, JCP = 5.0 Hz), NMR (100 MHz, CDCl3): δ 152.4 (d, JCP = 27.2 Hz), 142.4, 139.5
137.42, 136.6 (d, JCP = 5.4 Hz), 135.1, 133.8 (d, JCP = 19.3 Hz), (d, JCP = 15.5 Hz), 139.1 (d, JCP = 15.5 Hz), 137.4 (d, JCP = 5.7
133.0 (d, JCP = 19.2 Hz), 132.1 (d, JCP = 2.1 Hz), 131.6 (d, JCP
=
Hz), 136.8 (d, JCP = 11.0 Hz), 135.0, 133.4 (d, JCP = 18.8 Hz),
1.1 Hz), 129.2, 128.4 (d, JCP = 6.4 Hz), 128.22, 128.17, 128.1, 133.1 (d, JCP = 19.3 Hz), 132.5 (d, JCP = 2.1 Hz), 128.4 (d, JCP
=
128.0, 127.7, 127.1 (d, JCP = 1.8 Hz), 126.6, 126.4, 126.2, 126.0, 4.3 Hz), 128.3 (d, JCP = 5.7 Hz), 128.26 × 2, 128.04, 128.00,
125.5, 56.8, 52.0 (d, JCP = 8.6 Hz), 42.1 (d, JCP = 4.8 Hz), 36.4, 127.98, 127.8, 127.5 (d, JCP = 2.2 Hz), 126.5, 125.8, 125.44,
30.1; 31P NMR (121 MHz, CDCl3): δ −14.9; HRMS (ESI-orbitrap) 125.36, 56.5, 49.4 (d, JCP = 12.4 Hz), 42.1 (d, JCP = 5.2 Hz), 36.5,
calcd for C41H41NP [M + H]+ 578.2971, found 578.2971; HPLC 33.9, 32.7, 30.1; 31P NMR (121 MHz, CDCl3): δ −15.1; HRMS
(Daicel CHIRALCEL® OD-H, 0.46 × 25 cm, UV 254 nm, hexane (ESI-orbitrap) calcd for C41H43NP [M + H]+ 580.3128, found
= 100, 0.7 mL min−1) tR = 38.6 min (CD: λext (Δε) 254 (+)), tR
65.3 min (CD: λext (Δε) 254 (−)).
=
580.3110; HPLC (Daicel CHIRALCEL® OD-H, 0.46 × 25 cm, UV
254 nm, hexane = 100, 0.3 mL min−1) tR = 15.4 min (CD: λext
(Δε) 240 (+)), tR = 16.5 min (CD: λext (Δε) 240 (−)).
Preparation of aminophosphine oxide 4
Optical resolution of ( )-1b
To a mixture of phosphine oxide 4 (0.956 g, 2.0 mmol) and
K2CO3 (3.767 g, 20 mmol) was added 1-iodo-3-phenylpropane HPLC resolution of ( )-1b (30.9 mg, 0.057 mmol) dissolved in
(9.85 g, 40 mmol) in MeCN (10 mL) at room temperature. The hexane (3.5 mL) was carried out by successive injections of
reaction mixture was stirred for 72 h at 60 °C. The reaction 1 mL on a CHIRALCEL® OD-H (1.0 × 25 cm) + CHIRALCEL®
mixture was filtered and evaporated under reduced pressure. OD (1.0 × 25 cm). A hexane was used as the eluent working at a
The residue was purified by silica gel chromatography flow rate of 1.2 mL min−1 and with UV monitoring at 220 nm.
(hexane : CHCl3 : EtOAc = 5 : 1 : 1). Enantiomerically pure (S)-(+)-1b and (R)-(−)-1b were, respec-
N-[2′-(Diphenylphosphinyl)-6′-naphthalenyl]-N-3-phenyl- tively, obtained by evaporation of fractions.
propaneadamantanamine (4). 28% yield (0.336 g, 0.56 mmol)
(aS)-(+)-1b. 42% yield (13.0 mg, 0.024 mmol) as a white
1
as a brown solid; m.p. 90–92 °C; H NMR (300 MHz, CDCl3): solid, >99% ee; [α]2D0 = +13.5 (c 0.52, CHCl3); 1H NMR
δ 8.50–8.49 (m, 1H), 7.80–7.77 (m, 1H), 7.70–7.63 (m, 2H), (300 MHz, CDCl3): δ 7.32–7.10 (m, 16H), 6.98 (t, J = 7.5 Hz,
7.55–7.42 (m, 9H), 7.38–7.32 (m, 2H), 7.19–7.06 (m, 4H), 6.93 1H), 6.91–6.86 (m, 1H), 6.06–6.04 (m, 2H), 4.17–4.09 (m, 1H),
(d, J = 6.8 Hz, 2H), 3.76–3.66 (m, 1H), 3.45 (ddd, J = 13.4 and 3.91–3.85 (m, 1H), 2.44 (s, 3H), 2.00–1.84 (m, 9H), 1.59–1.39
11.9 and 5.0 Hz, 1H), 2.25 (t, J = 8.1 Hz, 2H), 1.90 (br-s, 9H), (m, 6H); 13C NMR (75 MHz, CDCl3): δ 152.4 (d, JCP = 26.0 Hz),
1.68–1.58 (m, 2H), 1.48–1.24 (m, 6H); 13C NMR (100 MHz, 141.4 (d, JCP = 6.5 Hz), 140.9 (d, JCP = 3.9 Hz), 139.9 (d, JCP
CDCl3): δ 153.8 (d, JCP = 3.1 Hz), 142.6, 138.4 (d, JCP = 10.0 Hz), 15.0 Hz), 139.0 (d, JCP = 15.8 Hz), 137.6, 134.2, 133.9 (d, JCP
=
=
136.1 (d, JCP = 14.3 Hz), 135.8 (d, JCP = 33.1 Hz), 135.1, 134.6, 19.9 Hz), 133.2 (d, JCP = 19.5 Hz), 132.1, 131.5, 129.1, 128.37 (d,
132.2 (d, JCP = 9.1 Hz), 131.7 (d, JCP = 9.3 Hz), 131.2 (dd, JCP JCP = 6.2 Hz), 128.25, 128.19 (d, JCP = 5.9 Hz), 128.1, 127.8,
2.6 and 5.4 Hz), 130.5 (d, JCP = 42.0 Hz), 129.9 (d, JCP = 46.3 126.7, 126.2, 125.5, 56.3, 51.1 (d, JCP = 8.6 Hz), 42.1 (d, JCP
Hz), 128.34 (d, JCP = 6.7 Hz), 128.31 × 2, 128.24 (d, JCP
5.0 Hz), 36.5, 30.2, 21.8 (d, JCP = 1.7 Hz); 31P NMR (121 MHz,
=
=
=
6.7 Hz), 128.0 × 2, 127.8, 127.6, 125.7, 125.3, 124.5, 124.4, 57.4, CDCl3): δ −14.3; HRMS (ESI-orbitrap) calcd for C38H41NP [M +
49.4, 41.5, 36.4, 34.0, 33.0, 30.2; 31P NMR (121 MHz, CDCl3): H]+ 542.2971, found 542.2961; HPLC (Daicel CHIRALCEL®
δ 29.9; HRMS (ESI-orbitrap) calcd for C41H43ONP [M + H]+ OD, 0.46 × 5 cm + CHIRALCEL® OD-H, 0.46 × 25 cm, UV
596.3077, found 596.3057.
220 nm, hexane = 100, 0.4 mL min−1) tR = 56.9 min (CD: λext
(Δε) 254 (−)) (major), tR = 77.4 min (CD: λext (Δε) 254 (+))
(minor).
Preparation of aminophosphine ( )-5
To a mixture of phosphine oxide 4 (0.477 g, 0.80 mmol) and
triethylamine (2.2 mL, 16 mmol) in m-xylene (16.0 mL) was
X-ray diffraction analysis data of (aS)-(+)-1b
added trichlorosilane (1.6 mL, 16 mmol) at 0 °C under an Ar Colorless prismatic crystals from hexane, orthorhombic space
atmosphere. The reaction mixture was stirred at 120 °C for group P212121, a = 10.51380(10) Å, b = 14.5405(2) Å, c =
96 h. After being cooled to room temperature, the mixture was 19.6851(3) Å, α = 90.000(0)°, β = 90.000(0)°, γ = 90.000(0)°, V =
diluted with Et2O and quenched with 2 M aqueous NaOH solu- 3009.38(7) Å3, Z = 4, ρ = 1.196 g cm−3, μ (CuKα) = 0.996 mm−1
.
tion. The organic layer was washed with brine, dried over Absolute structure parameter: 0.0(0). The structure was solved
MgSO4, and concentrated under reduced pressure. The residue by the direct methods of full-matrix least-squares, where the
was purified by silica gel chromatography (hexane : EtOAc = final R and wR were 0.0338 and 0.0942 for 15 331 reflections.
100 : 1).
(aR)-(−)-1b. 41% yield (13.0 mg, 0.024 mmol) as a white
N-[2′-(Diphenylphosphino)-6′-naphthalenyl]-N-3-phenyl- solid, >99% ee; [α]2D0 = −15.7 (c 0.51, CHCl3); 1H NMR
propaneadamantanamine (( )-5). 43% yield (0.199 g, (300 MHz, CDCl3): δ 7.32–7.10 (m, 16H), 6.99 (t, J = 7.4 Hz,
0.34 mmol) as a white solid; m.p. 132–134 °C; 1H NMR 1H), 6.91–6.86 (m, 1H), 6.06–6.04 (m, 2H), 4.17–4.09 (m, 1H),
(300 MHz, CDCl3): δ 8.52–8.49 (m, 1H), 7.77–7.74 (m, 1H), 7.57 3.91–3.85 (m, 1H), 2.44 (s, 3H), 2.00–1.84 (m, 9H), 1.57–1.39
(d, J = 8.6 Hz, 1H), 7.48–7.44 (m, 2H), 7.34–7.06 (m, 14H), 6.89 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 152.4 (d, JCP = 26.0 Hz),
(d, J = 6.8 Hz, 2H), 3.72–3.61 (m, 1H), 3.52–3.42 (m, 1H), 141.4 (d, JCP = 6.6 Hz), 140.9 (d, JCP = 3.9 Hz), 139.9 (d, JCP
=
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15.0 Hz), 139.0 (d, JCP = 15.9 Hz), 137.6, 134.2, 133.9 (d, JCP
=
578.2971; HPLC (Daicel CHIRALCEL® OD-H, 0.46 × 25 cm, UV
19.8 Hz), 133.2 (d, JCP = 19.5 Hz), 132.1, 131.5, 129.1, 128.34 (d, 254 nm, hexane = 100, 0.7 mL min−1) tR = 44.1 min (CD:
JCP = 6.2 Hz), 128.26, 128.19 (d, JCP = 6.1 Hz), 128.1, 127.8, λext (Δε) 254 (+)) (minor), tR = 68.8 min (CD: λext (Δε) 254 (−))
126.7, 126.2, 125.5, 56.3, 51.1 (d, JCP = 8.3 Hz), 42.1 (d, JCP = 4.9 (major).
Hz), 36.5, 30.2, 21.8 (d, JCP = 1.8 Hz); 31P NMR (121 MHz,
CDCl3): δ −14.3; HRMS (ESI-orbitrap) calcd for C38H41NP [M +
X-ray diffraction analysis data of (aR)-(−)-1c
H]+ 542.2971, found 542.2958; HPLC (Daicel CHIRALCEL® Colorless prismatic crystals from hexane, orthorhombic space
OD, 0.46 × 25 cm + CHIRALCEL® OD-H, 0.46 × 25 cm, UV group P212121, a = 10.61960(10) Å, b = 22.1572(2) Å, c =
220 nm, hexane = 100, 0.4 mL min−1) tR = 58.9 min (CD: 26.8016(3) Å, α = 90.000(0)°, β = 90.000(0)°, γ = 90.000(0)°, V =
λext (Δε) 254 (−)) (minor), tR = 77.2 min (CD: λext (Δε) 254 (+)) 6306.43(11) Å3, Z = 8, ρ = 1.217 g cm−3, μ (CuKα) =
(major).
0.985 mm−1. Absolute structure parameter: 0.0(0). The struc-
ture was solved by the direct methods of full-matrix least-
squares, where the final R and wR were 0.0393 and 0.1051 for
Optical resolution of ( )-1c
HPLC resolution of ( )-1c (41.3 mg, 0.072 mmol) dissolved in 11 015 reflections.
hexane (10 mL) was carried out by successive injections of
1 mL on a CHIRALCEL® OD (1.0 × 25 cm). A hexane was used
Optical resolution of ( )-5
as the eluent working at a flow rate of 0.5 mL min−1 and with HPLC resolution of ( )-5 (40.4 mg, 0.0570 mmol) dissolved in
UV monitoring at 220 nm. Enantiomerically pure (S)-(+)-1c and hexane (8 mL) was carried out by successive injections of 1 mL
(R)-(−)-1c were, respectively, obtained by evaporation of on a CHIRALCEL® OD-H (1.0 × 25 cm) + CHIRALCEL® OD
fractions.
(1.0 × 25 cm). A hexane : EtOH = 1600 : 1 was used as the
(aS)-(+)-1c. 41% yield (17.0 mg, 0.029 mmol) as a yellow eluent working at a flow rate of 1.0 mL min−1 and with UV
solid, >99% ee; [α]2D0 = +85.4 (c 0.50, CHCl3); m.p. 140–141 °C; monitoring at 220 nm. Enantiomerically pure (S)-(+)-5 and
1H NMR (300 MHz, CDCl3): δ = 8.47 (d, J = 8.3 Hz, 1H), (R)-(−)-5 were, respectively, obtained by evaporation of fractions.
7.78–7.75 (m, 1H), 7.58–7.32 (m, 8H), 7.21–7.09 (m, 9H),
(aS)-(+)-5. 39% yield (16.0 mg, 0.028 mmol) as a yellow solid,
7.02–7.00 (m, 2H), 6.24 (dt, J = 10.3 and 6.6 Hz, 1H), 6.03 (d, >99% ee; [α]2D0 = +95.2 (c 0.50, CHCl3); 1H NMR (300 MHz,
J = 15.8 Hz, 1H), 4.40 (ddd, J = 15.2, 6.9 and 0.9 Hz, 1H), 4.17 CDCl3): δ 8.51–8.49 (m, 1H), 7.77–7.74 (m, 1H), 7.57 (d, J =
(ddd, J = 15.2, 6.3 and 0.9 Hz, 1H), 2.05–1.94 (m, 9H), 1.45 (dd, 8.5 Hz, 1H), 7.48–7.43 (m, 2H), 7.32–7.05 (m, 14H), 6.90–6.87
J = 29.7 and 12.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 152.3 (m, 2H), 3.69–3.62 (m, 1H), 3.52–3.44 (m, 1H), 2.33–2.23 (m,
(d, JCP = 26.9 Hz), 139.9 (d, JCP = 15.5 Hz), 138.8 (d, JCP = 16.0 2H), 2.02–1.87 (m, 9H), 1.55–1.39 (m, 8H); 13C NMR (75 MHz,
Hz), 137.48 (d, JCP = 5.0 Hz), 137.42, 136.6 (d, JCP = 5.4 Hz), CDCl3): δ 152.6 (d, JCP = 2.1 Hz), 142.4, 139.4 (d, JCP = 14.5 Hz),
135.1, 133.8 (d, JCP = 19.5 Hz), 133.0 (d, JCP = 18.9 Hz), 132.1 139.1 (d, JCP = 16.0 Hz), 137.4 (d, JCP = 5.9 Hz), 136.7 (d, JCP
=
(d, JCP = 1.8 Hz), 131.6 (d, JCP = 1.1 Hz), 129.2, 128.4 (d, JCP
6.2 Hz), 128.22, 128.17, 128.1, 128.0, 127.7, 127.1 (d, JCP
2.2 Hz), 126.6, 126.4, 126.1 × 2, 126.0, 125.5, 56.7, 52.0 (d, JCP
=
=
=
11.3 Hz), 135.0, 133.4 (d, JCP = 18.9 Hz), 133.1 (d, JCP = 19.3
Hz), 132.5 (d, JCP = 1.8 Hz), 128.4 (d, JCP = 4.0 Hz), 128.3 (d,
JCP = 4.3 Hz), 128.25 × 2, 128.04, 128.00, 127.98, 127.7, 127.4
8.4 Hz), 42.1 (d, JCP = 4.8 Hz), 36.4, 30.1; 31P NMR (121 MHz, (d, JCP = 1.5 Hz), 126.5, 125.8, 125.44, 125.35, 56.5, 49.4 (d,
CDCl3): δ −14.9; HRMS (ESI-orbitrap) calcd for C41H41NP JCP = 13.4 Hz), 42.1 (d, JCP = 5.4 Hz), 36.5, 33.9, 32.7, 30.1;
[M
+
H]+ 578.2971, found 578.2971; HPLC (Daicel 31P NMR (121 MHz, CDCl3): δ −15.0; HRMS (ESI-orbitrap)
CHIRALCEL® OD-H, 0.46 × 25 cm, UV 254 nm, hexane = 100, calcd for C41H43NP [M + H]+ 580.3128, found 580.3114; HPLC
0.7 mL min−1) tR = 32.7 min (CD: λext (Δε) 254 (+)) (major), tR = (Daicel CHIRALCEL® OD-H, 0.46 × 25 cm, UV 254 nm, hexane
52.7 min (CD: λext (Δε) 254 (−)) (minor).
(aR)-(−)-1c. 38% yield (16.0 mg, 0.028 mmol) as a yellow (major), tR = 20.3 min (CD: λext (Δε) 240 (−)) (minor).
solid, >99% ee; [α]D20 = −92.2 (c 0.50, CHCl3); 1H NMR
= 100, 0.3 mL min−1) tR = 17.2 min (CD: λext (Δε) 240 (+))
(aR)-(−)-5. 40% yield (16.0 mg, 0.028 mmol) as a white solid,
(300 MHz, CDCl3): δ 8.47 (d, J = 8.3 Hz, 1H), 7.78–7.75 (m, 1H), >99% ee; [α]2D0 = −94.7 (c 0.50, CHCl3); H NMR (300 MHz,
7.58–7.32 (m, 8H), 7.21–7.09 (m, 9H), 7.02–7.00 (m, 2H), 6.24 CDCl3): δ 8.52–8.49 (m, 1H), 7.77–7.73 (m, 1H), 7.58–7.55 (m,
(dt, J = 6.6 and 13.4 Hz, 1H), 6.03 (d, J = 15.8 Hz, 1H), 4.40 1H), 7.50–7.45 (m, 2H), 7.32–7.08 (m, 14H), 6.90–6.87 (m, 2H),
(ddd, J = 15.2, 6.9 and 0.2 Hz, 1H), 4.17 (ddd, J = 15.3, 6.5 and 3.74–3.61 (m, 1H), 3.52–3.42 (m, 1H), 2.38–2.18 (m, 2H),
0.9 Hz, 1H), 2.05–1.94 (m, 9H), 1.45 (dd, J = 29.6 and 12.0 Hz, 2.02–1.87 (m, 9H), 1.55–1.39 (m, 8H); 13C NMR (75 MHz,
6H); 13C NMR (75 MHz, CDCl3): δ 152.3 (d, JCP = 27.1 Hz), CDCl3): δ 152.4 (d, JCP = 27.1 Hz), 142.4, 139.5 (d, JCP = 15.5
139.8 (d, JCP = 15.5 Hz), 138.8 (d, JCP = 16.0 Hz), 137.48 (d, JCP
5.0 Hz), 137.42, 136.6 (d, JCP = 5.4 Hz), 135.1, 133.8 (d, JCP
=
=
Hz), 139.1 (d, JCP = 15.8 Hz), 137.4 (d, JCP = 5.7 Hz), 136.7 (d,
JCP = 10.9 Hz), 135.0, 133.4 (d, JCP = 19.4 Hz), 133.1 (d, JCP
=
19.5 Hz), 133.0 (d, JCP = 18.9 Hz), 132.1 (d, JCP = 1.9 Hz), 131.6 19.3 Hz), 132.5 (d, JCP = 2.3 Hz), 128.4 (d, JCP = 4.0 Hz), 128.3
(d, JCP = 1.5 Hz), 129.2, 128.4 (d, JCP = 6.2 Hz), 128.22, 128.16, (d, JCP = 4.4 Hz), 128.25 × 2, 128.04, 127.99, 127.98, 127.7,
128.1, 128.0, 127.7, 127.1 (d, JCP = 1.7 Hz), 126.6, 126.4, 126.1 × 127.4 (d, JCP = 1.7 Hz), 126.5, 125.8, 125.43, 125.35, 56.5, 49.4
2, 126.0, 125.5, 56.7, 52.0 (d, JCP = 7.9 Hz), 42.0 (d, JCP
=
(d, JCP = 12.4 Hz), 42.1 (d, JCP = 5.5 Hz), 36.5, 33.9, 32.7, 30.1;
4.8 Hz), 36.4, 30.1; 31P NMR (121 MHz, CDCl3): δ −14.9; HRMS 31P NMR (121 MHz, CDCl3): δ −15.0; HRMS (ESI-orbitrap)
(ESI-orbitrap) calcd for C41H41NP [M + H]+ 578.2971, found calcd for C41H43NP [M + H]+ 580.3128, found 580.3114; HPLC
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(Daicel CHIRALCEL® OD-H, 0.46 × 25 cm, UV 254 nm, hexane (M+, 100); HPLC (Daicel CHIRALPAK® IB, 0.46 × 25 cm, UV
= 100, 0.3 mL min−1) tR = 17.1 min (CD: λext (Δε) 240 (+)) 254 nm, hexane : ethanol = 99 : 1, 0.5 mL min−1) tR = 61.3 min
(minor), tR = 18.8 min (CD: λext (Δε) 240 (−)) (major).
(major), tR = 65.6 min (minor).
(R)-(−)-6-Methoxy-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole
X-ray diffraction analysis data of (aR)-(−)-5
(6c)13 (Table 3, entry 3). 62% yield (41.8 mg, 0.123 mmol) as a
Colorless prismatic crystals from hexane, orthorhombic space white solid, 83% ee; [α]D20
= −42.9 (c 0.50, CHCl3);
group P212121, a = 10.5997(3) Å, b = 14.5202(4) Å, c = 21.0270(6) m.p. 148–150 °C; 1H NMR (300 MHz, CDCl3): δ 7.86 (br-s, 1H),
Å, α = 90.000(0)°, β = 90.000(0)°, γ = 90.000(0)°, V = 3236.26(16) 7.37–7.20 (m, 11H), 6.83–6.66 (m, 4H), 6.43 (d, J = 15.9 Hz,
Å3, Z = 4, ρ = 1.190 g cm−3, μ (CuKα) = 0.960 mm−1. Absolute 1H), 5.06 (d, J = 7.4 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz,
structure parameter: 0.0(0). The structure was solved by the CDCl3): δ 156.5, 143.4, 137.5, 137.4, 132.5, 130.5, 128.44 × 2,
direct methods of full-matrix least-squares, where the final 128.38, 127.1, 126.34, 126.28, 121.4, 121.2, 120.5, 118.6, 109.3,
R and wR were 0.0382 and 0.1041 for 28 871 reflections.
94.6, 55.6, 46.3; EI-MS m/z (rel. intensity) 339 (M+, 100); HPLC
(Daicel CHIRALPAK® IB, 0.46 × 25 cm, UV 254 nm, hexane :
Elucidation of the thermal racemization of optically active 1b,
1c and 5
ethanol = 99 : 1, 0.9 mL min−1) tR = 76.2 min (major), tR
=
82.9 min (minor).
A small amount of optically active (aS)- or (aR)-1b, 1c, and 5
(R)-(−)-6-Benzyloxy-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole
was dissolved in dodecane at room temperature. The solution (6d)13 (Table 3, entry 4). 70% yield (57.9 mg, 0.139 mmol) as a
was kept at a constant temperature in a thermostat oil bath, a yellow solid, 57% ee; [α]D20
= −36.5 (c 0.50, CHCl3);
small portion removed every passage of time, and the tran- m.p. 133–135 °C; 1H NMR (300 MHz, CDCl3): δ 7.84 (br-s, 1H),
sitions of enantiomeric excess were measured by chiral HPLC 7.45–7.19 (m, 16H), 6.89 (d, J = 2.1 Hz, 1H), 6.79–6.75 (m, 2H),
analysis.
6.70 (dd, J = 15.6 and 7.4 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H),
5.07–5.05 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 155.6, 143.3,
137.5, 137.4, 137.3, 132.5, 130.5, 128.5, 128.44 × 2, 128.38,
127.8, 127.4, 127.1, 126.4, 126.3, 121.49, 121.45, 120.5, 118.7,
General procedure for the palladium-catalyzed asymmetric
allylic alkylation of indoles using (aR)-(−)-1c
To a mixture of indoles or substituted indoles (0.2 mmol), 1,3- 110.0, 96.0, 70.5, 46.2; EI-MS m/z (rel. intensity) 415 (M+, 59);
diaryl-2-propenyl acetate (0.24 mmol), (aR)-(−)-1c (7.0 mg, HPLC (Daicel CHIRALPAK® IA-3, 0.46 × 25 cm, UV 254 nm,
12 μmol), [Pd(η3-C3H5)Cl]2 (2.2 mg, 6 μmol), and K2CO3 hexane : ethanol = 99 : 1, 0.7 mL min−1) tR = 131.9 min (minor),
(55.7 mg, 0.4 mol) was added MeCN (0.2 mL) at room tempera- tR = 146.1 min (major).
ture under an Ar atmosphere. After stirring for 18 h at 40 °C,
(R)-(−)-6-Nitro-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole
the mixture was quenched with water and diluted with diethyl (6e) (Table 3, entry 5). 62% yield (43.8 mg, 0.124 mmol) as a
ether. The organic layer was washed with water and brine, and yellow solid, 95% ee; [α]D20
= −48.8 (c 0.50, CHCl3);
dried over MgSO4. The filtrate was concentrated with a rotary m.p. 79–81 °C; 1H NMR (300 MHz, CDCl3): δ 8.58 (br-s, 1H),
evaporator and the residue was purified by column chromato- 8.34 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.8 and 2.0 Hz, 1H),
graphy (elution with n-hexane/EtOAc/Et3N = 40/2/1).
(R)-(−)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-1H-indole
7.45–7.21 (m, 12H), 6.69 (dd, J = 15.8 and 7.3 Hz, 1H), 6.42 (d,
(6a)13 J = 15.9 Hz, 1H), 5.13 (d, J = 7.3 Hz, 1H); 13C NMR (75 MHz,
(Table 2, entry 2). 69% yield (43.0 mg, 0.140 mmol) as a yellow CDCl3): δ 143.3, 142.5, 137.0, 135.1, 131.44, 131.39, 131.2,
solid, 96% ee; [α]2D0 = −41.5 (c 0.50, CHCl3); m.p. 109–111 °C; 128.65, 128.56, 128.5, 128.3, 127.4, 126.8, 126.3, 119.83,
1H NMR (300 MHz, CDCl3): δ 7.98 (br-s, 1H), 7.44–7.15 (m, 119.79, 115.0, 108.1, 45.9; EI-MS m/z (rel. intensity) 354 (M+,
13H), 7.05–7.00 (m, 1H), 6.90 (d, J = 1.77 Hz, 1H), 6.73 (dd, J = 100); HRMS (ESI-orbitrap) calcd for C23H18O2N2Na [M + Na]+
15.8 and 7.3 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 5.12 (d, J = 7.3 377.1260, found 377.1261; HPLC (Daicel CHIRALPAK® IA-3,
Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 143.3, 137.5, 136.6, 0.46 × 25 cm, UV 254 nm, hexane : ethanol = 98 : 2, 0.5 mL
132.5, 130.5, 128.5 × 2, 128.4, 127.1, 126.8, 126.4, 126.3, 122.6, min−1) tR = 113.7 min (minor), tR = 122.7 min (major).
122.1, 119.9, 119.4, 118.7, 111.1, 46.2; EI-MS m/z (rel. intensity)
(R)-(−)-6-Fluoro-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole
309 (M+, 100). HPLC (Daicel CHIRALPAK® IB, 0.46 × 25 cm, (6f)13 (Table 3, entry 6). 68% yield (44.6 mg, 0.136 mmol) as a
UV 254 nm, hexane : ethanol = 99 : 1, 0.7 mL min−1) tR
54.1 min (major), tR = 59.7 min (minor).
=
yellow solid, 95% ee; [α]D20
m.p. 47–49 °C; 1H NMR (300 MHz, CDCl3): δ 7.98 (br-s, 1H),
= −33.8 (c 0.50, CHCl3);
(R)-(−)-6-Methyl-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole 7.38–7.18 (m, 11H), 7.03 (dd, J = 9.6 and 2.2 Hz, 1H), 6.88 (dd,
(6b)13 (Table 3, entry 2). 72% yield (46.2 mg, 0.143 mmol) as a J = 1.6 and 1.0 Hz, 1H), 6.81–6.67 (m, 2H), 6.42 (d, J = 15.8 Hz,
yellow solid, 94% ee; [α]D20
=
−40.4 (c 0.52, CHCl3); 1H), 5.08 (d, J = 7.3 Hz, 1H); 13C NMR (75 MHz, CDCl3):
m.p. 138–140 °C; 1H NMR (300 MHz, CDCl3): δ 7.85 (br-s, 1H), δ 160.0 (d, JC–F = 237.7 Hz), 143.1, 137.3, 136.6 (d, JC–F = 12.4
7.38–7.14 (m, 12H), 6.85 (dd, J = 8.1 and 1.2 Hz, 1H), 6.82 (dd, Hz), 132.2, 130.7, 128.50, 128.46, 128.4, 127.2, 126.5, 126.3,
J = 2.7 and 0.5 Hz, 1H), 6.72 (dd, J = 15.8 and 7.3 Hz, 1H), 6.43 123.4, 122.9 (d, JC–F = 3.3 Hz), 120.6 (d, JC–F = 10.1 Hz), 118.8,
(d, J = 15.9, 1H), 5.09 (d, J = 7.3 Hz, 1H), 2.43 (s, 3H); 13C NMR 108.2 (d, JC–F = 24.3 Hz), 97.4 (d, JC–F = 26.0 Hz), 46.1; EI-MS
(75 MHz, CDCl3): δ 143.4, 137.5, 137.1, 132.6, 131.9, 130.4, m/z (rel. intensity) 327 (M+, 100); HPLC (Daicel CHIRALPAK®
128.45, 128.44, 128.37, 127.1, 126.3 × 2, 124.7, 122.0, 121.2, IA, 0.46 × 25 cm, UV 254 nm, hexane : ethanol = 99 : 1, 0.5 mL
119.5, 118.5, 111.0, 46.2, 21.7; EI-MS m/z (rel. intensity) 323 min−1) tR = 79.6 min (minor), tR = 85.9 min (major).
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(R)-(−)-6-Chloro-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole 7.3 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 5.28 (d, J = 7.2 Hz, 1H);
(6g)13 (Table 3, entry 7). 69% yield (46.8 mg, 0.136 mmol) as a 13C NMR (75 MHz, CDCl3): δ 143.4, 137.5, 136.2, 135.6, 132.9,
yellow solid, 96% ee; [α]D20
= −43.9 (c 0.50, CHCl3); 132.2, 131.0, 128.8, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9,
m.p. 106–108 °C; 1H NMR (300 MHz, CDCl3): δ 7.98 (br-s, 1H), 127.1, 126.3, 126.1, 122.1, 121.2, 119.7, 113.8, 110.9, 45.1;
7.38–7.20 (m, 12H), 6.98 (dd, J = 8.4 and 1.8 Hz, 1H), 6.90 (dd, EI-MS m/z (rel. intensity) 385 (M+, 87); HPLC (Daicel CHIRAL-
J = 2.4 and 1.0 Hz, 1H), 6.69 (dd, J = 15.9 and 7.3 Hz, 1H), 6.41 PAK® IB, 0.46 × 25 cm, UV 254 nm, hexane : ethanol = 99 : 1,
(d, J = 15.9 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H); 13C NMR (75 MHz, 0.9 mL min−1) tR = 17.6 min (minor), tR = 19.4 min (major).
CDCl3): δ 143.0, 137.3, 137.0, 132.1, 130.8, 128.49, 128.48,
(R)-(−)-3-[(E)-1,3-Diphenyl-2-propen-1-yl]-1H-indole
(6a)13
128.4, 128.0, 127.3, 126.5, 126.3, 125.4, 123.2, 120.8, 120.2, (Table 3, entry 15). 82% yield (50.1 mg, 0.161 mmol) as a
118.9, 111.0, 46.1; EI-MS m/z (rel. intensity) 343 (M+, 100); brown solid, 97% ee; [α]2D0
= −32.9 (c 0.60, CH2Cl2);
HPLC (Daicel CHIRALPAK® IA-3, 0.46 × 25 cm, UV 254 nm, m.p. 60–62 °C; 1H NMR (300 MHz, CDCl3): δ 8.02 (br-s, 1H),
hexane : ethanol = 99 : 1, 0.5 mL min−1) tR = 75.9 min (minor), 7.15–7.44 (m, 13H), 7.00–7.05 (m, 1H), 6.92 (d, J = 1.6 Hz, 1H),
tR = 82.5 min (major).
6.73 (dd, J = 15.9 and 7.4 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H),
(R)-(−)-6-Bromo-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole 5.12 (d, J = 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 143.3,
(6h)13 (Table 3, entry 8). 63% yield (48.9 mg, 0.126 mmol) as a 137.4, 136.6, 132.5, 130.5, 128.5 × 2, 128.4, 127.1, 126.8, 126.4,
white solid, 91% ee; [α]D20
= −38.2 (c 0.50, CHCl3); 126.3, 122.6, 122.1, 119.9, 119.4, 118.6, 111.1, 46.2; EI-MS m/z
m.p. 136–138 °C; 1H NMR (300 MHz, CDCl3): δ 8.00 (br-s, 1H), (rel. intensity) 309 (M+, 100). HPLC (Daicel CHIRALPAK® IB,
7.51 (d, J = 1.4 Hz, 1H), 7.37–7.20 (m, 11H), 7.11 (dd, J = 8.5 0.46 × 25 cm, UV 254 nm, hexane : ethanol = 99 : 1, 0.7 mL
and 1.7 Hz, 1H), 6.90–6.89 (m, 1H), 6.68 (dd, J = 15.9 and 7.3 min−1) tR = 63.5 min (major), tR = 70.8 min (minor).
Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H); 13C
(R)-(−)-3-[(E)-1,3-Di-(4-chlorophenyl)-2-propen-1-yl]-1H-indole
NMR (75 MHz, CDCl3): δ 143.0, 137.4, 137.3, 132.0, 130.8, (6m) (Table 3, entry 16). 82% yield (61.8 mg, 0.163 mmol) as a
128.49, 128.48, 128.4, 127.3, 126.5, 126.3, 125.7, 123.2, 122.7, brown solid, 97% ee; [α]2D0 = −46.1 (c 0.52, CH2Cl2) (lit.
121.1, 118.9, 115.7, 114.0, 46.0; EI-MS m/z (rel. intensity) 387 [α]2D0 +21.1 (c 0.55, CH2Cl2) (for 80% ee (S)));4 m.p. 121–123 °C;
(M+, 77); HPLC (Daicel CHIRALPAK® IA-3, 0.46 × 25 cm, UV 1H NMR (300 MHz, CDCl3): δ 8.06 (br-s, 1H), 7.17–7.40 (m,
254 nm, hexane : 2-propanol = 98 : 2, 0.7 mL min−1) tR
53.5 min (minor), tR = 59.6 min (major).
=
11H), 7.01–7.06 (m, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.66 (dd, J =
15.9 and 7.2 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 5.09 (d, J =
(R)-(−)-4-Bromo-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 141.5, 136.6, 135.7,
(6j) (Table 3, entry 11). 62% yield (47.8 mg, 0.123 mmol) as a 132.9, 132.6, 132.2, 129.8, 129.7, 128.62, 128.56, 127.5, 126.5,
brown solid, 98% ee; [α]D20
= −53.7 (c 0.50, CHCl3); 122.6, 122.3, 119.64, 119.58, 117.9, 111.2, 45.5; EI-MS m/z (rel.
m.p. 58–60 °C; 1H NMR (300 MHz, CDCl3): δ 8.12 (br-s, 1H), intensity) 377 (M+, 100); HRMS (APCI-orbitrap) calcd for
7.35–7.18 (m, 12H), 7.02–6.92 (m, 2H), 6.73 (dd, J = 15.6 and C23H17Cl2N [M]+ 377.0733, found 377.0725; HPLC (Daicel
6.5 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 5.90 (d, J = 6.4 Hz, 1H); CHIRALPAK® IB, 0.46 × 25 cm, UV 254 nm, hexane : ethanol =
13C NMR (75 MHz, CDCl3): δ 143.9, 137.8, 137.6, 133.8, 130.7, 98 : 2, 0.7 mL min−1) tR = 45.8 min (major), tR = 60.6 min (minor).
129.0, 128.4, 128.2, 127.0, 126.3, 126.2, 124.89, 124.86, 124.4,
123.0, 119.2, 114.4, 110.5, 44.7; EI-MS m/z (rel. intensity) 387
(M+, 93); HRMS (ESI-orbitrap) calcd for C23H18BrNNa [M + Na]+
410.0515, found 410.0508; HPLC (Daicel CHIRALPAK® IA-3,
Acknowledgements
0.46 × 25 cm, UV 254 nm, hexane : ethanol = 99 : 1, 0.3 mL This work was supported by a Grant-in-Aid for Scientific
min−1) tR = 118.8 min (minor), tR = 127.3 min (major).
Research (C) (No. 26410109) from Japan Society for the Pro-
(R)-(−)-4-Methyl-3-[(E)-1,3-diphenyl-2-propen-1-yl]-1H-indole motion of Science (JSPS) and the COE Program in Chiba
(6k)13 (Table 3, entry 12). 60% yield (38.7 mg, 0.120 mmol) as University.
a
white solid, 86% ee; [α]D20
= −65.2 (c 0.50, CHCl3);
m.p. 170–172 °C; 1H NMR (300 MHz, CDCl3): δ 8.01 (br-s, 1H),
7.36–7.19 (m, 11H), 7.06 (t, J = 7.6 Hz, 1H), 6.85–6.70 (m, 3H),
6.23 (d, J = 15.9 Hz, 1H), 5.45 (d, J = 6.4 Hz, 1H), 2.52 (s, 3H);
13C NMR (75 MHz, CDCl3): δ 144.0, 137.5, 137.0, 133.9, 131.1,
130.7, 128.9, 128.5, 128.3, 127.1, 126.3 × 2, 125.6, 123.5, 122.2,
121.3, 119.0, 109.0, 46.5, 20.4; EI-MS m/z (rel. intensity) 323
(M+, 100); HPLC (Daicel CHIRALPAK® IA-3, 0.46 × 25 cm, UV
254 nm, hexane : ethanol = 99 : 1, 0.3 mL min−1) tR = 28.3 min
(minor), tR = 39.5 min (major).
Notes and references
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Org. Biomol. Chem.
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16 CCDC 1486809 ((aS)-(+)-1b), 1486810 ((aR)-(−)-1c), and
1486811 ((aR)-(−)-5) contain the supplementary crystallo-
graphic data for this paper.
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