Enantioselective allylation of imines catalyzed by newly developed (-)-β-pinene-based π-allylpalladium catalyst: An efficient synthesis of (R)-α-propylpiperonylamine and (R)-pipecolic acid

Article abstract of DOI:10.1039/c2ob26188j

A newly developed π-allylpalladium with a (-)-β-pinene framework and an isobutyl side chain catalyzed the enantioselective allylation of imines in good yields and enantioselectivities (20 examples, up to 98% ee). An efficient enantioselective synthesis of the (R)-α-propyl piperonylamine part of DMP 777, a human leukocyte elastase inhibitor and (R)-pipecolic acid have been achieved as a useful application of this methodology. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26188j

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PAPER
Enantioselective allylation of imines catalyzed by newly developed
(−)-β-pinene-based π-allylpalladium catalyst: an efficient synthesis of
(R)-α-propylpiperonylamine and (R)-pipecolic acid†‡
Rodney A. Fernandes* and Jothi L. Nallasivam
Received 21st June 2012, Accepted 25th July 2012
DOI: 10.1039/c2ob26188j
A newly developed π-allylpalladium with a (−)-β-pinene framework and an isobutyl side chain catalyzed
the enantioselective allylation of imines in good yields and enantioselectivities (20 examples, up to
98% ee). An efficient enantioselective synthesis of the (R)-α-propyl piperonylamine part of DMP 777,
a human leukocyte elastase inhibitor and (R)-pipecolic acid have been achieved as a useful application of
this methodology.
Amino group bonded chiral carbon centers form important
structural fragments in both natural and tailor-made biologically
active molecules where they show an immense influence in
Introduction
Methods using η3-allylpalladium complexes effect a variety of
organic transformations both stoichiometrically and catalyti-
cally.1 Although allylpalladium complexes have been known for
a number of years, the bulk of research investigating the stability
and reactivity of these complexes was principally undertaken by
Trost and Hegedus during the 1970’s. Varied π-allylpalladium
complexes have been reported by Trost et al. from a wide range
of olefins.2 While the electrophilic chemistry of these complexes
has been well explored e.g. in allylic alkylation and oxidation of
alkenes and conjugated dienes,3–8 the umpolung of π-allylpalla-
dium provided new avenues in organometallic chemistry with
new applications in catalysis. The bis(π-allylpalladium) formed
has been demonstrated to display an amphiphilic character.9
Varied synthetic applications of bis(π-allylpalladium) species
have been explored including that by Yamamoto’s group on the
first catalytic asymmetric allylation of imines.10–12 The
(−)-β-pinene based refined π-allylpalladium complex catalyzed
asymmetric allylation of imines in the presence of water and
allylstannane in good reproducibility, yields and enantioselectiv-
ity (up to 91% ee).12a Use of allylsilanes instead of stannanes
was also explored.11,12b
determining the nature and intensity of the bioactivities. As a
result, stereoselective generation of nitrogen-bonded chiral
centres is highly researched.13 The most thoroughly investigated
being addition reactions to CvN functionalities. While many
methods suffer from obvious drawbacks like the need for stoi-
chiometric or superstoichiometric quantities of the chiral source
or poor removal and recovery of the chiral auxiliaries used, cata-
lytic enantioselective addition reactions offer an attractive solu-
tion. The asymmetric allylation of imines or hydrazones
represents an important C–C bond forming reaction in organic
synthesis, providing chiral homoallylamines with two orthogonal
functional handles, an alkene and the amine group.14–17
Although several catalytic asymmetric methods have been devel-
oped, work in this area goes on unabated. The Yamamoto’s cata-
lyst based on exoethylidene β-pinene required extensive
purification based on column chromatography followed by
repeated recrystallizations to achieve a regiosiomeric purity of
400 : 1, resulting in low overall yield in catalyst preparation.12a
Noting this difficulty and that a limited number of chiral frame-
works18 have been examined we now endeavoured to further
modify β-pinene based chiral π-allylpalladium chloride com-
plexes. We report here the operational simplicity in the pre-
paration of β-pinene based chiral π-allylpalladium complexes
and also their excellent results in terms of enantioselectivity in
the allylation of imines.
Department of Chemistry, Indian Institute of Technology Bombay,
Powai, Mumbai 400 076, Maharashtra, India.
E-mail: rfernand@chem.iitb.ac.in; Fax: +91 22 25767152;
Tel: +91 22 25767174
†This paper is dedicated to Dr. Ganesh Pandey for his best wishes and
encouragement.
Results and discussion
‡Electronic supplementary information (ESI) available: Copies of
1
HPLC chromatograms of homoallylamines and H NMR and 13C NMR
We prepared several exo-alkylidenes from (+)-nopinone 2
(prepared from β-pinene 1) as shown in Scheme 1.19 The Wittig
spectra for all the compounds. CCDC 860684. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI:
10.1039/c2ob26188j
reaction of
2
with propyl, butyl, 3-methylbutyl and
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Table 1 Asymmetric allylation of imine 6a with 7 using 4a–d and
5a–da
Entry Allylpalladium chloride [mol%] Time/h % Yield % eeb
1
2
3
4
5
6
7
8
4a [5]
4b [5]
4c [5]
4d [5]
5a [5]
5b [5]
5c [5]
5d [5]
4c [1]
4c [2]
4c [10]
4c [20]
84
84
84
85
84
85
87
84
92
90
80
80
66
58
77
65
61
63
54
40
55
62
68
78
76
76
95
76
18
25
48
18
88
89
90
90
9
10
11
12
a Allylstannane (1.25 equiv). b Determined by chiral HPLC.
Scheme 1 Synthesis of β-pinene based chiral π-allylpalladium
complexes.
4c, an X-ray crystal structure was also obtained (Fig. 1).21 The
complexes exist as dimers with chloride bridges. The dimethyl
bridge on the top of the β-pinene framework would force the
ligands around palladium to be accommodated underneath. The
presence of an iBu group in the side chain will create sufficient
steric bulk to allow the approach of the imine (in the allylation
reaction) from the rear bottom side. Thus a much simpler and
overall higher yielding method enabled us to make these com-
plexes without relying on repeated recrystallizations.
We initially examined the use of complexes 4a–d and 5a–d
for asymmetric allylation of the model imine 6a following a
similar literature procedure12a using water (1 equiv) and allystan-
nane (1.25 equiv). The results are shown in Table 1. It can be
seen that the complex 4c catalyzed the reaction in the best enantio-
selectivity of 95% ee (Table 1, entry 3). The E-isomer complexes
5a–d gave poor enantioselectivities (entries 5–8). We further
investigated the catalyst loading with 1 and 2 mol% of 4c, which
resulted in a decrease in both the yields and enantioselectivities
(Table 1, entries 9 and 10). An increase in the catalyst loading to
10 or 20 mol% gave comparable results (Table 1, entries 11 and
12). The latter case resulted in better yields (entry 12, 78%).
Thus, we found 5 mol% of catalyst was the optimum require-
ment for the reaction.
We then moved our attention to screening the scope of
complex 4c in the asymmetric allylation of various imines using
allyltributyl stannane and one equivalent of water at 0 °C. The
results are presented in Table 2. Various imines 6 reacted well in
the presence of catalyst 4c giving the chiral homoallylamines in
good yields and enantioselectivities. Benzaldehyde imine 6c
delivered the homoallylamine 8c in good yield (80%) and an
enantioselectivity of 91% ee (Table 2, entry 1). Replacement of
the Bn group by PMB in the amine part yielded slightly lower
enantioselectivity (entry 2). Imines with electron-donating
groups in the para position showed a slight increase in
Fig. 1 X-ray crystal structure of 4c.
2-phenylethyl triphenylphosphonium bromide salts with tBuOK
afforded the olefin compounds 3a–d respectively as 1 : 1, Z : E
mixtures in 40–86% yields (method I). On reaction with palla-
dium(II) trifluoroacetate followed by nBu4NCl the olefins gave
the chiral π-allylpalladium complexes as mixtures of 4/5 in
55–84% yields as nearly 1.2 : 1 (Z : E) mixtures. Remarkably
when nBuLi was used as the base in the Wittig olefination
(method II, Scheme 1), the olefin compounds 3a–d were
obtained as 2–3.5 : 1, Z : E mixtures in 38–58% yields. Further
use of this olefin mixture delivered the chiral π-allylpalladium
complexes as mixtures of 4/5 (68 to 90%) now in approximately
2–3.5 : 1 (Z : E) ratio, keeping the stereochemical integrity. From
the latter reaction the mixture was separated to give the desired
Z-isomer complexes 4 in 35–45% yields and the E-isomer com-
plexes 5 in 22–31% yields by flash column chromatography fol-
lowing the method of Still et al.20 The complexes were
characterized by spectroscopic data (see ESI‡). For the complex
7790 | Org. Biomol. Chem., 2012, 10, 7789–7800
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Table 2 Catalytic asymmetric allylation of imines 6 using catalyst 4c
Entry
Imine, R
R′
Amine
Time/h
% Yield
% eea
1
2
3
4
5
6
7
8
9
6c, Ph
6d, Ph
PhCH2
p-OMe-C6H4CH2
PhCH2
p-OMe-C6H4CH2
PhCH2
p-OMe-C6H4CH2
PhCH2
8c
8d
8e
8f
8g
8h
8i
48
72
67
80
78
88
67
75
72
80
71
80
72
71
78
69
67
52
91
89
92
96
90
98
90
90
87
6e, p-Me-C6H4
6f, p-Me-C6H4
6g, p-OMe-C6H4
6h, p-OMe-C6H4
6i, o-OMe-C6H4
6j, o-OMe-C6H4
6k,
p-OMe-C6H4CH2
PhCH2
8j
8k
10
11
12
6l, 2-naphthyl
6m, 1-naphthyl
6a,
PhCH2
PhCH2
PhCH2
8l
8m
8a
90
72
84
72
78
77
96
82
95
13
6b,
p-OMe-C6H4CH2
8b
80
88
95
14
15
16
17
18
19
20
6n, 3-pyridinyl
6o, 3-pyridinyl
6p, 2-furyl
6q, 2-thienyl
6r, (E)-cinnamyl
6s, n-heptyl
PhCH2
allyl
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
8n
8o
8p
8q
8r
8s
8t
76
72
73
90
73
72
72
79
80
70
81
85
48
82
72
71
70
61
72
41
40
6t, p-NO2-C6H4
6b,
21
p-OMe-C6H4CH2
8b
88
68
93b
a Determined by chiral HPLC. b Reaction on 4 mmol of imine 6b.
enantioselectivity, 90–98% ee (Table 2, entries 3–6). A PMB
group in the amine part proved better; for example the imine 6h
gave the homoallylamine 8h in 98% ee (entry 6) against 90% ee
obtained with corresponding Bn group (entry 5). However, the
ortho-methoxy benzaldehyde imines 6i or j yielded 8i or j
respectively with lower enantioselectivity (90% ee in each case,
entries 7 and 8). N-benzylindole-3-aldehyde imine 6k reacted
well giving 8k in 87% ee (entry 9). This could be a precursor to
β-amino acid analog of tryptophan. Among the naphthaldehyde
imine regioisomers 6l and 6m (Table 2, entries 10 and 11) the
β-isomer 6l reacted well giving 8l in 96% ee (entry 10). Pipero-
nyl imines 6a and b with Bn or PMB groups furnished 8a and b
respectively each in 95% ee. The latter with the PMB group
gave a better yield (88%, entry 13). Heterocyclic imines 6n–q
reacted well to produce the corresponding homoallylamines 8n–
q in good yields of 79, 80, 70 and 81% and enantioselectivities
of 72, 71, 70, and 61% ee respectively (Table 2, entries 14–17).
The thiophene based imine 6q was sluggish in the reaction and
required a longer reaction time (entry 17). Non-aryl imines were
poorer substrates in this allylation procedure, exemplified by cin-
namyl imine 6r and n-heptyl imine 6s providing the
corresponding homoallylamines 8r and 8s in 72 and 41% ee
respectively. Imine 6t with an electron withdrawing para-nitro
group reacted well in providing 8t in 82% yield, but gave poor
enantioselectivity of 40% ee (entry 20). While most reactions
were carried on a 0.5 mmol scale, a larger batch size reaction of
4 mmol of imine 6b with 5 mol% of catalyst 4c (added in two
portions) produced the corresponding homoallylamine 8b in
68% yield and 93% ee (Table 2, entry 21). The results were
comparable to that in entry 13, Table 2, with a marginal decrease
in yield.
The reaction follows a similar mechanistic pathway as that
reported in the literature (model B, Fig. 2).12a The bis(π-allyl-
palladium) is formed initially and is the key intermediate that is
nucleophilic and transfers the allyl group to the imine, directed
by the rigid chiral pinene skeleton resulting in the observed
chiral induction. The dimethyl bridge on top of the β-pinene frame-
work forces the ligands around palladium to be accommo-
dated underneath. The presence of the isobutyl group in 4c
renders better steric crowding on the front side (model C, Fig. 2)
in comparison to the Yamamoto’s catalyst with a methyl group
(model D, Fig. 1). This forces the imine to approach from the
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Scheme 2 Synthesis of (R)-α-propylpiperonylamine 9, fragment of
DMP 777.
Fig. 2 Comparison of 4c and Yamamoto’s catalyst.
less hindered rear side (model A) resulting in the observed
higher stereoinduction. The E-complexes 5 probably suffer in
that the complexations from both the rear and front side have
almost equal probability of occurring, resulting in poor
stereoinduction.
The application of the synthetic strategy to streamline the
preparation of diverse building blocks or natural products is an
important validation of its synthetic potential and usefulness.
The intermediate homoallylamines were used in the synthesis of
useful building blocks or N-heterocyclic natural products as
shown in Schemes 2 and 3. The homoallylamine 8b obtained in
88% yield and 95% ee is a precursor for α-propylpiperonyl-
amine, an important building block of human leukocyte elastase
inhibitor L-694,458 (DMP 777).22 The catalytic hydrogenation
of 8b provided the desired amine 9 in 69% yield (Scheme 2),
[α]D25 = 11.8 (c = 1.4, CHCl3), lit.22a 10.9 (c = 1.01, CHCl3). In
another application 8h obtained in 78% yield and 98% ee was
employed in a highly enantioselective synthesis of (R)-pipecolic
acid 1223 (Scheme 3). Allylation of amine 8h gave the bis-allyl
compound (76%) which on ring closing metathesis gave 10
(76%). Subsequent hydrogenation and N-acylation afforded com-
pound 11. Finally, in situ generated RuO oxidized the aryl ring
to carboxylic acid and deacetylation completed the synthesis
of (R)-pipecolic acid 12, [α]2D5 = 26.2 (c = 0.5, H2O), lit.23b 26.7
(c = 1.0, H2O).
Scheme 3 Synthesis of (R)-pipecolic acid 12.
of the human leukocyte elastase inhibitor DMP 777, and (R)-
pipecolic acid were demonstrated as a useful application of this
methodology. Further application of this catalyst in other organic
transformations is in progress in our laboratory.
Experimental section
Solvents were dried by standard procedures. Thin-layer chromato-
graphy was performed on EM 250 Kieselgel 60 F254 silica gel
plates. The spots were visualized by staining with KMnO4,
ninhydrin or by using a UV lamp. (1S,5S)-(−)-β-Pinene, palla-
dium(II) trifluoroacetate, allyltributylstannane and nBu4NCl were
purchased from Sigma Aldrich Chemical Co. 1H-NMR and
13C-NMR were recorded on Bruker AvanceIII 400 spectrometer
and the chemical shifts are based on TMS peak at δ = 0.00 pm
for proton NMR and CDCl3 peak at δ = 77.00 ppm (t) in carbon
NMR. IR spectra were obtained on Perkin Elmer Spectrum
One FT-IR spectrometer. Optical rotations were measured with
Jasco P-2000 polarimeter using Sodium D line (589 nm). LRMS
and HRMS were recorded using Micromass: Q-Tof micro
(YA-105) spectrometer. HPLC was performed with JASCO-
Conclusions
In summary we have developed a new catalyst 4c based on a
pinene skeleton substituted with an isobutyl group which cata-
lyzed the asymmetric allylation of various imines, giving chiral
homoallylamines in good yields and enantioselectivities (up to
98% ee). The homoallylamines were transformed into useful
building blocks and N-heterocyclic compounds. Thus efficient
enantioselective syntheses of (R)-α-propylpiperonylamine, part
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(PU-2089PLUS) quaternary gradient pump with MD-2010PLUS
multiwavelength detector. Imines were prepared as reported in
the literature.24 For the π-allylpalladium chloride complexes
though solids we did not determine melting points as they
decompose on slight heating. The volatile olefin compounds
were not stable for HRMS analysis and hence LRMS were
recorded (except for olefin 3d).
2870, 1657, 1458, 1382, 1367, 1100, 910, 845, 652 cm−1
.
[α]2D5 = −11.2 (c = 1, CHCl3). H NMR (400 MHz, CDCl3):
Major diastereomer, δ = 0.71 (s, 3H), 0.87 (t, J = 7.5 Hz, 3H),
1.25 (s, 3H), 1.44 (d, J = 9.8 Hz, 1H), 1.77–1.97 (m, 3H),
2.04 (dd, J = 16.4, 8.4 Hz, 1H), 2.30–2.33 (m, 3H), 2.51–2.58
(m, 1H), 2.76 (t, J = 5.5 Hz, 1H), 5.11–5.15 (m, 1H). 13C NMR
(100 MHz, CDCl3): Major diastereomer, δ = 15.0, 19.5, 21.7,
24.0, 25.0, 26.1, 28.0, 41.0, 45.0, 52.5, 123.4, 140.3. LRMS
(ESI-TOF) calculated for C12H20 [M − H]+ m/z: 163.1, measured
163.1.
1
Synthesis of (1R,5S)-(+)-nopinone (2)
The ozonolysis of the exocyclic double bond of (1S,5S)-(−)-β-
pinene 1 by a known literature procedure25 afforded (1R,5S)-(+)-
nopinone 2 as a colorless oil in 78% yield, [α]2D5 = +39.4 (c = 1,
MeOH), lit.25 [α]2D3 = +40.52 (c = 4, MeOH).
(1R,5S)-2-Butylidene-6,6-dimethylbicyclo[3.1.1]heptane (3b)
Method II. Yield (0.245 g, 38%), Z : E = 2.5 : 1. Colorless oil;
Rf = 0.86 (petroleum ether); IR (neat): νmax = 2925, 2951, 2869,
1665, 1458, 1382, 1366, 1102, 1068, 909, 651 cm−1. [α]D25
=
General procedure for synthesis of olefins (3a–d)
1
−9.8 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): Major di-
astereomer, δ = 0.71 (s, 3H), 0.87 (t, J = 7.5 Hz, 3H), 1.21 (s,
3H), 1.30–1.38 (m, 1H), 1.44 (d, J = 9.8 Hz, 1H), 1.77–1.99 (m,
4H), 2.03 (dd, J = 14.2, 7.8 Hz, 1H), 2.26–2.34 (m, 3H),
2.51–2.60 (m, 1H), 2.77 (t, J = 5.5 Hz, 1H), 5.07–5.15 (m, 1H).
13C NMR (100 MHz, CDCl3): Major diastereomer, δ = 13.9,
19.7, 22.0, 24.0, 25.0, 26.3, 28.0, 29.0, 41.0, 45.1, 52.6, 121.5,
141.0. LRMS (ESI-TOF) calculated for C13H22 [M − H]+ m/z:
177.1, measured 177.0.
The olefin compounds were prepared from (1R,5S)-(+)-nopinone
2 by Wittig reaction using the corresponding alkyl or 2-phenyl-
ethyl triphenylphosphonium bromides and t-BuOK [method I]2c
or n-BuLi [method II] to afford olefins 3a–d.
Method I. To a stirred solution of alkyl or 2-phenylethyl tri-
phenylphosphonium bromide (10.85 mmol, 3.0 equiv) in dry
THF (25 mL) was added t-BuOK (1.22 g, 10.85 mmol, 3.0 equiv)
in portions at room temperature. After stirring for 30 min, a solu-
tion of (+)-nopinone 2 (0.5 g, 3.62 mmol) in dry THF (5 mL)
was added dropwise to the orange colored ylide solution
and stirred for 24–72 h at 80 °C. It was then cooled to
room temperature and quenched with saturated aqueous NH4Cl
solution (5 mL) and extracted with EtOAc (2 × 25 mL). The
combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The crude product was purified by
silica gel column chromatography using petroleum ether as
eluent to give the olefins 3a–d (Z : E = 1 : 1) as colorless oils in
40–86% yields.
(1R,5S)-6,6-Dimethyl-methylbutylidene)bicyclo[3.1.1]heptane
(3c)
Method II. Yield (0.382 g, 55%), Z : E = 3.5 : 1. Colorless oil;
Rf = 0.88 (petroleum ether); IR (CHCl3): νmax = 2954, 2870,
2719, 1691, 1664, 1466, 1366, 1168, 1057, 956, 801, 771,
1
708 cm−1. [α]D25 = −8.3 (c = 1, CHCl3). H NMR (400 MHz,
CDCl3): Major diastereomer, δ = 0.71 (s, 3H), 0.84 (d, J = 4.0 Hz,
3H), 0.86 (d, J = 4.1 Hz, 3H), 1.21 (s, 3H), 1.42 (d, J = 9.8 Hz,
1H), 1.45–1.67 (m, 2H), 1.75–1.84 (m, 2H), 1.90–1.97 (m, 1H),
2.08 (dd, J = 16.6, 8.4 Hz, 1H), 2.25–2.36 (m, 2H), 2.52–2.62
(m, 1H), 2.77 (t, J = 5.5 Hz, 1H), 5.11–5.15 (m, 1H). 13C NMR
(100 MHz, CDCl3): Major diastereomer, δ = 22.0, 22.3, 22.6,
24.0, 25.0, 26.1, 26.3, 29.2, 36.1, 41.0, 45.1, 52.7, 120.5, 141.5.
LRMS (ESI-TOF) calculated for C14H24 [M + H]+ m/z: 193.3,
measured 193.1.
Method II. To a stirred solution of alkyl or 2-phenylethyl tri-
phenylphosphonium bromide (10.85 mmol, 3.0 equiv) in dry
THF (25 mL) was added n-BuLi (1.6 M in hexane, 8.1 mL,
13.02 mmol, 3.6 equiv) dropwise at 0 °C. After stirring for
30 min, a solution of (+)-nopinone 2 (0.5 g, 3.62 mmol) in dry
THF (5 mL) was added dropwise to the orange colored ylide
solution and stirred for 24–72 h at 80 °C. It was then cooled to
room temperature and quenched with saturated aqueous NH4Cl
solution (5 mL) and extracted with EtOAc (2 × 25 mL). The
combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The crude product was purified by
silica gel column chromatography using petroleum ether as
eluent to afford the olefins 3a–d (Z : E = 2.0–3.5 : 1, by 1H
NMR) as colorless oils in 38–58% yields. The olefin mixture
was inseparable by column chromatography. Structural assign-
ment as Z/E was based on their conversion to the complexes 4/5
and analysis of the latter.12a
(1R,5S)-6,6-Dimethyl-2-(2-phenylethylidene)bicyclo[3.1.1]-
heptane (3d)
Method II. Yield 0.47 g, 58% (Z : E = 2 : 1). Colorless oil;
Rf = 0.69 (petroleum ether); IR (CHCl3): νmax = 3020, 2862,
1652, 1421, 1046, 927, 875, 759 cm−1. [α]D25 = −3.9 (c = 0.3,
1
CHCl3). H NMR (400 MHz, CDCl3): Major diastereomer, δ =
0.72 (s, 3H), 1.27 (s, 3H), 1.48 (d, J = 9.8 Hz, 1H), 1.81–1.91
(m, 2H), 1.96–2.02 (m, 1H), 2.12 (dd, J = 16.7, 8.4 Hz, 1H),
2.31–2.40 (m, 1H), 2.56–2.66 (m, 1H), 2.92 (t, J = 5.4 Hz, 1H),
3.25–3.29 (m, 2H), 5.28–5.34 (m, 1H), 7.14–7.29 (m, 5H).
13C NMR (100 MHz, CDCl3): Major diastereomer, δ = 21.8,
23.9, 25.0, 26.1, 26.3, 33.2, 41.0, 45.0, 52.5, 119.9, 125.6,
128.2, 128.3, 142.3, 143.2. HRMS (ESI-TOF) calcd for [C17H22
+ H]+ 227.1800, found 227.1801.
(1R,5S)-6,6-Dimethyl-2-propylidenebicylo[3.1.1]heptane (3a)
Method II. Yield (0.231 g, 39%), Z : E = 2.5 : 1. Colorless oil,
Rf = 0.88 (petroleum ether). IR (CHCl3): νmax = 2948, 2926,
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General procedure for the synthesis of π-allylpalladium
δ = 0.90 (t, J = 7.2 Hz, 3H), 0.95 (s, 3H), 1.36 (s, 3H),
1.52–1.65 (m, 4H), 1.74–1.82 (m, 2H), 2.04–2.14 (m, 1H),
2.32–2.49 (m, 1H), 2.53 (br t, J = 5.4 Hz, 1H), 2.67–2.75 (m,
1H), 3.58–3.69 (m, 1H), 3.78–3.90 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ = 13.8, 21.8, 22.2, 26.1, 30.0, 30.3, 33.8,
37.8, 40.0, 40.8, 71.6, 77.5, 135.1. HRMS (ESI-TOF) calcd for
[C26H42Pd2Cl2 − Cl]+ 601.1044, found 601.1051.
complexes (4/5)12a
To a solution of Pd(OCOCF3)2 (0.25 g, 0.752 mmol, 1.0 equiv)
in dry acetone (10 mL) at room temperature and under an argon
atmosphere was added olefin 3 (0.902 mmol, 1.2 equiv). The
mixture was stirred for 1 h (monitored by TLC). n-Bu4NCl
(0.23 g, 0.827 mmol, 1.1 equiv) in acetone (2 mL) was added
and the reaction mixture stirred for additional 1 h. The clear
brown colored solution was then filtered through a plug of celite
to remove suspended Pd-black and washed with acetone (2 ×
10 mL). The filtrate was concentrated and the residue purified by
silica gel column chromatography on 100–200 mesh silica gel
using petroleum ether–EtOAc (5 : 1) as eluent to give a mixture
of complexes 4 and 5 as yellow semi-solids in 68–90% yields.
The mixture was analyzed by 1H NMR for the 4 : 5 ratio. Further
purification by flash column chromatography on TLC mesh size
silica gel20 using petroleum ether–EtOAc (100 : 1) as eluent gave
pure E-catalysts 5 as yellow solids in 22–31% yield. Further
elution gave the Z-complexes 4 containing approximately <4%
of 5. A single slow recrystallization of this mixture using propio-
nitrile as solvent afforded pure Z-complexes 4 as yellow solids in
35–45% yield.
π-Allylpalladium chloride complex (5b)
Isolated yield of 5b, (74.4 mg, 31%). Yellow powder; Rf = 0.6
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 2995, 2929,
2871, 1646, 1464, 1369, 1333, 1264, 1101, 1004, 932, 899,
696 cm−1. [α]2D5 = +127.5 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.86 (t, J = 7.3 Hz, 3H), 0.96 (s, 3H),
1.22–1.30 (m, 2H), 1.33 (s, 3H), 1.50–1.61 (m, 2H), 1.78–1.87
(m, 2H), 2.08 (br s, 1H), 2.17 (t, J = 5.5 Hz, 1H), 2.37–2.41 (m,
1H), 2.56–2.62 (m, 1H), 4.21 (dd, J = 9.4, 5.3 Hz, 1H), 4.40 (br
d, J = 3.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 13.6,
21.8, 24.0, 26.0, 30.0, 32.9, 34.4, 38.1, 40.0, 46.6, 71.2, 77.2,
132.0. HRMS (ESI-TOF) calcd for [C26H42Pd2Cl2 − Cl]+
601.1044, found 601.1050.
π-Allylpalladium chloride complex (4c)
π-Allylpalladium chloride complex (4a)
Isolated yield of 4c, (100.2 mg, 40%). Yellow powder; Rf = 0.52
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 3020, 2962,
2828, 1646, 1366, 1046, 929, 872, 626 cm−1. [α]D25 = +5.6 (c =
Isolated yield of 4a, (103.3 mg, 45%). Yellow powder; Rf = 0.52
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 2973, 2923,
2863, 1653, 1268, 1097, 1051, 952, cm−1. [α]D25 = +59.0 (c =
1
0.82, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.86 (d, J =
1
0.4, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.97 (s, 3H),
6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.96 (s, 3H), 1.40 (s, 3H),
1.51–1.67 (m, 2H), 1.69–1.83 (m, 3H), 2.06–2.10 (m, 1H),
2.35–2.39 (m, 1H), 2.57 (br t, J = 5.4 Hz, 1H), 2.67–2.75 (m,
1H), 3.60–3.71 (m, 1H), 3.79–3.83 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ = 21.7, 21.8, 22.5, 26.1, 28.2, 29.8, 33.7,
36.6, 37.8, 39.8, 40.8, 71.2, 76.7, 135.2. HRMS (ESI-TOF)
calcd for [C28H46Pd2Cl2 − Cl]+ 629.1358, found 629.1362.
1.04 (t, J = 7.5 Hz, 3H), 1.36 (s, 3H), 1.50–1.68 (m, 2H),
1.75–1.80 (m, 2H), 2.04–2.10 (m, 1H), 2.34–2.42 (m, 1H), 2.52
(br t, J = 5.4 Hz, 1H), 2.63–2.72 (m, 1H), 3.53–3.63 (m, 1H),
3.80–3.92 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 13.3,
21.7, 21.8, 26.1, 29.9, 33.7, 37.8, 39.9, 40.6, 71.7, 79.1, 134.8.
HRMS (ESI-TOF) calcd for [C24H38Pd2Cl2 + Na]+ 631.0318,
found 631.0327.
X-Ray crystallographic data of (4c)21
π-Allylpalladium chloride complex (5a)
X-Ray diffraction data were collected on a Crystalis RED,
Oxford diffraction Ltd, using Oxford Diffraction Xcalibar-S.
Diffraction experiments employed by graphite-monochromator,
radiation type Mo K/α (λ = 0.71073 Å) and diffraction radiation
source as enhance (Mo) X-ray source and diffraction measure-
ment method was ω and φ scans, audit creation method was
SHELXL-97.
Yellow colored blocks were obtained by slowly evaporating a
propionitrile solution of 4c. A sample measuring 0.33 × 0.26 ×
0.21 mm was cut from larger plate for diffraction analysis.
Empirical formula = C28H46Pd2Cl2, Mr = 666.4304, Orthorhombic,
Plate, space group P21 21 21, a = 7.2879(10), b = 16.6931(3),
c = 21.3386(4), α = 90, β = 90, γ = 90, V = 2907(8) Å, Z = 4,
T = 150 (2) K, ρcalcd = 1.513 mg m−3, μ = 1.434 mm−1, F (000)
= 1344, θ range for data collection = 3.39–25°, total reflections
collected/unique = 21 930/5107 [R (int) = 0.0358], completeness
to θ = 25.00 (99.7%), max. and min. transmission = 0.7527 and
0.6489, refinement method = Full matrix least-squares on F2,
goodness-of-fit on F2 = 1.005, final R indices [I > 2σ(I)] = R1 =
Isolated yield of 5a, (68.8 mg, 30%). Yellow powder; Rf = 0.56
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 2995, 2931,
2871, 1605, 1459, 1369, 1331, 1264, 1100, 1011, 941, 881,
1
628 cm−1. [α]D25 = +94.1 (c = 0.4, CHCl3). H NMR (400 MHz,
CDCl3): δ = 0.97 (s, 3H), 0.98 (t, J = 7.8 Hz, 3H), 1.33 (s, 3H),
1.52–1.58 (m, 2H), 1.78–1.98 (m, 2H), 2.08–2.18 (m, 1H),
2.20–2.25 (m, 1H), 2.35–2.45 (m, 1H), 2.57–2.65 (m, 1H),
4.21–4.25 (m, 1H), 4.41 (d, J = 4.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ = 15.5, 21.7, 24.2, 26.0, 30.0, 34.2, 38.2,
40.0, 46.6, 71.4, 76.7, 131.4. HRMS (ESI-TOF) calcd for
[C24H38Pd2Cl2 + Na]+ 631.0318, found 631.0325.
π-Allylpalladium chloride complex (4b)
Isolated yield of 4b, (98.4 mg, 41%). Yellow powder; Rf = 0.56
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 3020, 2976,
2932, 2873, 1603, 1521, 1476, 1424, 1047, 929, 850, 627 cm−1
.
1
[α]2D5 = +32.3 (c = 1.4, CHCl3). H NMR (400 MHz, CDCl3):
7794 | Org. Biomol. Chem., 2012, 10, 7789–7800
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0.0255, wR2 = 0.0625, R indices (all θ) R1 = 0.0290, wR2 =
0.0632, absolute structure parameter = −0.04 (3), largest diff.
peak and hole = 0.963 and −0.372 e. Å−3, R fac = 2.38. CCDC
860684.‡
flushed with argon and stirred at 0 °C for specified time. The
reaction progress was monitored by TLC. After completion, the
turbid reaction mixture was quenched with 1 N HCl (2.5 mL)
and CH3CN (1 mL) was added and the mixture stirred at room
temperature for 10 min. The biphasic solution was extracted with
hexane (2 × 3 mL). The hexane layer was discarded, and
aqueous layer was basified with 10% aqueous NaOH (1.25 mL),
and the resulting solution was stirred for 5 min. The solution
was extracted with EtOAc (2 × 5 mL), dried over Na2SO4 and
concentrated. The crude product was purified by column chrom-
atography on 100–200 mesh silica gel using hexane–EtOAc
(5 : 1) as eluent to give the corresponding homoallylamines 8 as
colorless oils. Characterization data for known homoallylamines
were identical to literature data12a (1H NMR and 13C NMR is
only included in ESI‡ for known amines). The enantiomeric
excess was determined by converting chiral homoallylamines
into their corresponding trifluoroacetylamide form and using the
chiral columns, Chiralcel OD-H, Chiralpak IA or Chiralpak
AD-H with hexane–iPrOH as mobile phase by HPLC with UV
detection at 254 nm.
π-Allylpalladium chloride complex (5c)
Isolated yield of 5c, (70.2 mg, 28%). Yellow powder; Rf = 0.56
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 3020, 2957,
2929, 2870, 1646, 1523, 1468, 1423, 1046, 929, 877, 626 cm−1
.
[α]2D5 = +160.8 (c = 0.6, CHCl3). H NMR (400 MHz, CDCl3):
δ = 0.76 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H), 0.97 (s,
3H), 1.33 (s, 3H), 1.62–1.72 (m, 3H), 1.82–1.88 (m, 2H),
2.04–2.12 (m, 1H), 2.19 (br t, J = 5.3 Hz, 1H), 2.31–2.48 (m,
1H), 2.51–2.68 (m, 1H), 4.21 (dd, J = 10.5, 3.6 Hz, 1H), 4.37
(br d, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 21.8,
22.0, 22.6, 26.1, 29.4, 30.0, 34.7, 38.0, 39.8, 39.9, 46.7, 71.0,
77.1, 132.6. HRMS (ESI-TOF) calcd for [C28H46Pd2Cl2 − Cl]+
629.1358, found 629.1364.
1
π-Allylpalladium chloride complex (4d)
(R)-N-Benzyl-1-phenyl-3-butenylamine (8c)12a
Isolated yield of 4d, (96.7 mg, 35%). Yellow powder; Rf = 0.56
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 3019, 2931,
Yield 94.9 mg, 80%. Colorless oil; Rf = 0.7 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +51.0 (c = 0.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.75 (br s, 1H), 2.36–2.45 (m, 2H), 3.51
(d, J = 13.3 Hz, 1H), 3.67 (dd, J = 7.6, 6.8 Hz, 2H), 5.02–5.10
(m, 2H), 5.65–5.75 (m, 1H), 7.21–7.36 (m, 10H). 13C NMR
(100 MHz, CDCl3): δ = 43.0, 51.3, 61.5, 117.5, 126.7, 127.0,
127.2, 128.0, 128.2, 128.3, 135.3, 140.4, 143.6. HPLC: CHIR-
ALCEL OD-H column, hexane–iPrOH = 98 : 2, flow rate =
0.8 mL min−1, tR = 6.96 min (major), tR = 7.97 min (minor),
91% ee.
1602, 1494, 1263, 1097, 1030, 929, 875, 699, 627 cm−1. [α]D25
=
1
+36.2 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.95
(s, 3H), 1.36 (s, 3H), 1.75–1.89 (m, 2H), 2.11 (br s, 1H), 2.43
(d, J = 8.3 Hz, 1H), 2.68–2.79 (m, 2H), 2.96–3.12 (m, 2H), 3.79
(dd, J = 10.3, 4.4 Hz, 1H), 3.95–4.01 (m, 1H), 7.09–7.30 (m,
5H). 13C NMR (100 MHz, CDCl3): δ = 21.8, 26.1, 30.0, 33.8,
33.9, 38.0, 40.0, 41.0, 72.3, 75.5, 126.3, 128.1, 128.3, 129.5,
128.6, 135.3, 138.9. HRMS (ESI-TOF) calcd for [C34H42Pd2Cl2
− Cl]+ 697.1045, found 697.1035.
(R)-N-(4-Methoxybenzyl)-1-phenyl-3-butenylamine (8d)12a
π-Allylpalladium chloride complex (5d)
Yield (94.9 mg, 71%). Colorless oil; Rf = 0.32 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +49.6 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.66 (br s, 1H), 2.38–2.43 (m, 2H), 3.44
(d, J = 13.0 Hz, 1H), 3.60 (d, J = 13.0 Hz, 1H), 3.66 (dd, J =
7.5, 6.2 Hz 1H), 3.79 (s, 3H), 5.02–5.09 (m, 2H), 5.64–5.74 (m,
1H), 6.83 (ddd, J = 8.7, 2.9, 2.4 Hz, 2H), 7.15 (ddd, J = 8.6,
2.9, 2.3 Hz, 2H), 7.27–7.36 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ = 43.0, 50.7, 55.2, 61.4, 113.7, 117.5, 127.0, 127.03,
127.3, 128.3, 128.6, 129.2, 132.7, 135.4, 143.8, 158.5. HPLC:
CHIRALCEL OD-H column, hexane–iPrOH = 98 : 2, flow
rate = 1 mL min−1, tR = 7.60 min (major), tR = 8.73 min
(minor), 89% ee.
Isolated yield of 5d, (60.8 mg, 22%). Yellow powder; Rf = 0.6
(19 : 1 petroleum ether–EtOAc); IR (CHCl3): νmax = 3019, 2929,
1648, 1525, 1424, 1045, 1030, 929, 875, 620 cm−1. [α]D25
=
1
+95.0 (c = 0.2, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.98
(s, 3H), 1.58 (s, 3H), 1.77–1.97 (m, 1H), 2.18–2.26 (m, 2H),
2.41–2.48 (m, 1H), 2.60–2.72 (m, 2H), 2.95–3.10 (m, 2H), 4.36
(dd, J = 11.3, 3.6 Hz, 1H), 4.64 (br s, 1H), 7.08–7.32 (m, 5H).
13C NMR (100 MHz, CDCl3): δ = 22.0, 26.1. 30.1, 33.8, 38.1,
40.0, 41.0, 46.7, 72.2, 75.6, 126.3, 128.1, 128.3, 128.5, 128.6,
135.3, 139.4. HRMS (ESI-TOF) calcd for [C34H42Pd2Cl2 − Cl]+
697.1045, found 697.1038.
General reaction procedure for asymmetric allylation of imines 6
using catalysts (4 or 5)12a
(R)-N-Benzyl-1-(4-methylphenyl)-3-butenylamine (8e)12a
Imine 6 (0.5 mmol) was taken in a Wheaton microreactor (5 mL
capacity) and, under an argon atmosphere, dry THF (1.25 mL),
degassed water (9 μL, 0.5 mmol, 1.0 equiv) and allyltributylstan-
nane (194 μL, 0.625 mmol, 1.25 equiv) were added sequentially.
The mixture was cooled to 0 °C and the chiral π-allylpalladium
chloride complex 4 or 5 (1 to 20 mol%, see Tables 1 and 2) was
added under an argon atmosphere. The reaction mixture was
Yield (100.5 mg, 80%). Colorless oil; Rf = 0.30 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +56.2 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.79 (br s, 1H), 2.35 (s, 3H), 2.34–2.42
(m, 2H), 3.49 (d, J = 13.2 Hz, 1H), 3.60 (d, J = 13.4 Hz, 1H),
3.59–3.62 (m, 1H), 5.01–5.09 (m, 2H), 5.65–5.75 (m, 1H), 7.15
(d, J = 7.5 Hz, 2H), 7.20–7.36 (m, 7H). 13C NMR (100 MHz,
CDCl3): δ = 21.1, 43.1, 51.4, 61.2, 117.4, 126.8, 127.2, 128.1,
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128.3, 129.1, 135.6, 136.6, 140.7. HPLC: CHIRALCEL OD-H
J = 7.7, 0.7 Hz, 1H), 7.23–7.32 (m, 6H), 7.35 (dd, J = 7.5, 1.7
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 40.8, 51.5, 55.2,
56.1, 110.5, 116.8, 120.6, 126.7, 127.6, 127.9, 128.1, 128.2,
131.3, 136.1, 140.8, 157.4. HPLC: CHIRALCEL OD-H
column, hexane–iPrOH = 99 : 1, flow rate = 0.8 mL min−1, tR =
7.42 min (major), tR = 8.42 min (minor), 90% ee.
column, hexane–iPrOH = 99.5 : 0.5, flow rate = 0.7 mL min−1
tR = 7.51 min (major), tR = 8.32 min (minor), 92% ee.
,
(R)-N-(4-Methoxybenzyl)-1-(4-methylphenyl)-3-butenylamine
(8f)12a
Yield (101.3 mg, 72%). Colorless oil; Rf = 0.40 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +49.6 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.73 (br s, 1H), 2.35 (s, 3H), 2.35–2.41
(m, 2H), 3.46 (d, J = 13.0 Hz, 1H), 3.59 (d, J = 13.0 Hz, 1H),
3.61–3.77 (m, 1H), 3.79 (s, 3H), 5.01–5.08 (m, 2H), 5.64 (ddt,
J = 16.0, 9.9, 6.9 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 7.15 (d, J =
8.5 Hz, 4H), 7.23 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ = 21.0, 43.0, 50.6, 55.1, 61.1, 113.6, 117.3, 127.1,
129.0, 129.2, 132.7, 135.5, 136.4, 140.7, 158.4. HPLC: CHIR-
ALCEL OD-H column, hexane–iPrOH = 99.3 : 0.7, flow rate =
1 mL min−1, tR = 8.62 min (major), tR = 10.71 min (minor),
96% ee.
(R)-N-(4-Methoxybenzyl)-1-(2-methoxyphenyl)-3-butenylamine
(8j)
Yield (99.6 mg, 67%). Colorless oil; Rf = 0.12 (3 : 2, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3323, 3000, 2936, 2837,
1641, 1611, 1586, 1512, 1490, 1466, 1440, 1300, 1246, 1175,
1094, 1033, 910, 824, 651 cm−1. [α]D25 = +36.7 (c = 0.4,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.7 (br s, 1H),
2.35–2.42 (m, 1H), 2.47–2.54 (m, 1H), 3.46 (d, J = 12.8 Hz,
1H), 3.58 (d, J = 12.8 Hz, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 4.06
(dd, J = 7.6, 5.9 Hz, 1H), 4.98–5.10 (m, 2H), 5.60–5.80 (m,
1H), 6.81–6.89 (m, 3H), 6.95 (dt, J = 7.4, 0.9 Hz, 1H),
7.17–7.25 (m, 3H), 7.39 (dd, J = 7.5, 1.7 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ = 40.8, 50.9, 55.2, 56.0, 110.4, 113.6,
113.7, 116.7, 120.5, 127.6, 127.9, 129.3, 131.4, 133.0, 136.2,
157.4, 158.4. HRMS (ESI-TOF): calcd for [C19H23NO2 + H]+
298.1807, found 298.1800. HPLC: CHIRALCEL OD-H
column, hexane–iPrOH = 99 : 1, flow rate = 0.8 mL min−1, tR =
7.72 min (major), tR = 9.07 min (minor), 90% ee.
(R)-N-Benzyl-1-(4-methoxyphenyl)-3-butenylamine 8g12a
Yield (94.9 mg, 71%). Colorless oil; Rf = 0.28 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +57.2 (c = 0.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.79 (br s, 1H), 2.36 (ddt, J = 7.5, 6.4,
2.1 Hz, 2H), 3.49 (d, J = 13.1 Hz, 1H), 3.62 (t, J = 6.5 Hz, 1H),
3.65 (d, J = 13.1 Hz, 1H), 3.81 (s, 3H), 5.01–5.09 (m, 2H),
5.64–5.74 (m, 1H), 6.88 (d, J = 8.7, Hz, 2H), 7.20–7.32 (m,
7H). 13C NMR (100 MHz, CDCl3): δ = 43.1, 51.3, 55.2, 60.9,
113.7, 117.4, 126.8, 128.1, 128.3, 128.31, 135.6, 135.8, 140.6,
158.6. HPLC: CHIRALPAK IA column, hexane–iPrOH =
99.5 : 0.5, flow rate = 0.5 mL min−1, tR = 15.54 min (major),
tR = 18.26 min (minor), 90% ee.
(R)-N-Benzyl-1-(1-benzylindol-3-yl)but-3-en-1-amine (8k)
Yield (95.4 mg, 52%). Colorless oil; Rf = 0.24 (7 : 3, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3300, 3060, 3010, 2924,
1672, 1607, 1550, 1453, 1355, 1327, 1294, 1172, 1108, 963,
910, 668 cm−1. [α]D25 = +16.0 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.88 (br s, 1H), 2.59–2.68 (m, 2H), 3.65
(d, J = 13.2 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 4.07 (t, J =
6.7 Hz, 1H), 5.01–5.10 (m, 2H), 5.28 (s, 2H), 5.73–5.83 (m,
1H), 7.08–7.73 (m, 14H), 7.73 (d, J = 7.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ = 41.6, 50.0, 51.5, 54.3, 109.7, 117.0,
117.5, 119.0, 119.8, 121.7, 126.1, 126.7, 127.2, 127.5, 128.17,
128.2, 128.7, 136.0, 137.0, 137.6, 140.8. HRMS (ESI-TOF):
calcd for [C26H26N2 + H]+ 367.2174, found 367.2190. HPLC:
CHIRALCEL OD-H column, hexane–iPrOH = 99.5 : 0.5, flow
rate = 0.8 mL min−1, tR = 16.56 min (minor), tR = 20.61 min
(major), 87% ee.
(R)-N-(4-Methoxybenzyl)-1-(4-methoxyphenyl)-3-butenylamine
(8h)12a
Yield (116.0 mg, 78%). Colorless oil; Rf = 0.20 (3 : 2, petroleum
ether–EtOAc). [α]D25 = +52.2 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.68 (br s, 1H), 2.37–2.39 (m, 2H), 3.44
(d, J = 13.1 Hz, 1H), 3.59 (d, J = 13.0 Hz, 1H), 3.61–3.66 (m,
1H), 3.81 (s, 3H), 3.83 (s, 3H), 5.02–5.09 (m, 2H), 5.66 (ddt,
J = 16.0, 9.5, 6.4. Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.89 (d, J =
8.7 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ = 43.1, 50.6, 55.1, 55.14, 60.7,
113.6, 113.63, 117.3, 128.2, 129.2, 132.7, 135.5, 135.7, 158.4,
158.5. HPLC: CHIRALCEL OD-H column, hexane–iPrOH =
(R)-N-Benzyl-1-(2-naphthyl)-3-butenylamine (8l)12a
98 : 2, flow rate = 1 mL min−1, tR = 7.89 min (major), tR
=
Yield (103.5 mg, 72%). Colorless oil; Rf = 0.54 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +65.1 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.67 (br s, 1H), 2.48–2.53 (m, 2H), 3.54
(d, J = 13.4 Hz, 1H), 3.69 (d, J = 13.4 Hz, 1H), 3.85 (t, J =
6.2 Hz, 1H), 5.03–5.13 (m, 2H), 5.68–5.78 (m, 1H), 7.23–7.34
(m, 5H), 7.44–7.56 (m, 3H), 7.78–7.87 (m, 4H). 13C NMR
(100 MHz, CDCl3): δ = 42.8, 51.4, 61.7, 117.7, 125.3, 125.5,
125.9, 126.3, 126.9, 127.7, 127.8, 128.2, 128.24, 128.4, 132.9,
133.4, 135.2, 140.2, 140.9. HPLC: CHIRALCEL OD-H
column, hexane–iPrOH = 98 : 2, flow rate = 0.5 mL min−1, tR =
12.46 min (major), tR = 15.62 min (minor), 96% ee.
8.85 min (minor), 98% ee.
(R)-N-Benzyl-1-(2-methoxyphenyl)-3-butenylamine (8i)12a
Yield (92.2 mg, 69%). Colorless oil; Rf = 0.44 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +57.2 (c = 0.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.94 (br s, 1H), 2.43–2.60 (m, 2H), 3.56
(d, J = 13.1 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.81 (s, 3H),
4.11 (dd, J = 7.8, 5.8 Hz, 1H), 4.97–5.05 (m, 2H), 5.71 (ddt, J =
15.6, 9.5, 7.1 Hz, 1H), 6.87 (dd, J = 8.1, 0.7 Hz, 1H), 6.97 (td,
7796 | Org. Biomol. Chem., 2012, 10, 7789–7800
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(R)-N-Benzyl-1-(1-naphthyl)-3-butenylamine (8m)
138.9, 139.9, 148.5, 149.3. HRMS (ESI-TOF): calcd for
[C16H18N2 + H]+ 239.1548, found 239.1551. HPLC: CHIRAL-
CEL OD-H column, hexane–iPrOH = 90 : 10, flow rate =
1.0 mL min−1, tR = 12.50 min (major), tR = 15.12 min (minor).
72% ee.
Yield (112.1 mg, 78%). Colorless oil; Rf = 0.54 (9 : 1, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3437, 3063, 3007, 2925,
2851, 1638, 1593, 1454, 1393, 1167, 1119, 1028, 994, 917, 858,
1
666 cm−1. [α]D25 = +42.0 (c = 0.3, CHCl3). H NMR (400 MHz,
CDCl3): δ = 1.74 (br s, 1H), 2.42–2.61 (m, 1H), 2.64–2.71 (m,
1H), 3.56 (d, J = 13.2 Hz, 1H), 3.72 (d, J = 13.5 Hz, 1H), 4.57
(dd, J = 8.4, 4.8 Hz, 1H), 5.04–5.15 (m, 2H), 5.73–5.86 (m,
1H), 7.20–7.41 (m, 5H), 7.47–7.54 (m, 3H), 7.76 (t, J = 7.4 Hz,
2H), 7.85–7.91 (m, 1H), 8.08–8.21 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ = 42.1, 51.6, 57.0, 117.7, 122.9, 123.8,
125.3, 125.6, 125.7, 126.8, 127.3, 128.1, 128.3, 129.0, 131.6,
134.0, 135.5, 139.0, 140.6. HRMS (ESI-TOF): calcd for
[C21H21N + H]+ 288.1752, found 288.1750. HPLC: CHIRALCEL
(R)-N-Allyl-1-(3-pyridyl)-3-butenylamine (8o)
Yield (75.3 mg, 80%). Colorless oil; Rf = 0.24 (1 : 1, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3328, 3071, 3016, 2923,
2851, 1666, 1591, 1424, 1256, 1108, 1023, 925, 718 cm−1
.
1
[α]2D5 = +32.7 (c = 0.4, CHCl3). H NMR (400 MHz, CDCl3):
δ = 1.87 (br s, 1H), 2.36–2.55 (m, 2H), 2.99–3.14 (m, 2H), 3.74
(t, J = 6.7Hz, 1H), 5.06–5.14 (m, 4H), 5.65–5.78 (m, 1H),
5.79–5.88 (m, 1H), 7.26–7.29 (m, 1H), 7.67 (dt, J = 7.9, 1.6 Hz,
1H), 8.49–8.53 (m, 2H). 13C NMR (100 MHz, CDCl3): δ =
42.6, 49.8, 59.1, 115.9, 118.2, 123.4, 134.4, 134.6, 136.4, 138.9,
148.5, 149.3. HRMS (ESI–TOF): calcd for [C12H16N2 + H]+
189.1392, found 189.1387. HPLC: CHIRALCEL OD-H
OD-H column, hexane–iPrOH = 99 : 1, flow rate = 0.8 mL min−1
tR = 6.78 min (major), tR = 7.72 min (minor), 82% ee.
,
(R)-N-Benzyl-1-piperonyl-3-butenylamine (8a)12a
column, hexane–iPrOH = 97 : 3, flow rate = 1 mL min−1, tR
13.18 min (major), tR = 16.34 min (minor), 71% ee.
=
Yield (96.7 mg, 69%). Colorless oil; Rf = 0.72 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +59.4 (c = 0.9, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.70 (br s, 1H), 2.30–2.39 (m, 2H), 3.53
(d, J = 13.3 Hz, 1H), 3.61 (t, J = 6.5 Hz, 1H), 3.67 (d, J =
13.3 Hz, 1H), 5.02–5.09 (m, 2H), 5.63 (ddt, J = 15.6, 9.7,
6.9 Hz, 1H), 5.95 (s, 2H), 6.80 (s, 2H), 6.92 (s, 1H), 7.21–7.34
(m, 5H). 13C NMR (100 MHz, CDCl3): δ = 43.1, 51.2, 61.3,
100.8, 107.3, 107.9, 117.5, 120.6, 126.8, 128.1, 128.3, 135.3,
137.7, 140.4, 146.5, 147.8. HPLC: CHIRALCEL OD-H
column, hexane–iPrOH = 98 : 2, flow rate = 0.5 mL min−1, tR =
16.25 min (major), tR = 17.77 min (minor), 95% ee.
(R)-N-Benzyl-1-(2-furfuryl)-3-butenylamine (8p)12a
Yield (79.6 mg, 70%). Colorless oil; Rf = 0.8 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +32.8 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.64 (br s, 1H), 2.51 (t, J = 7.0, 1.1 Hz,
2H), 3.58 (d, J = 13.1 Hz, 1H), 3.75 (d, J = 13.1 Hz, 1H),
3.75–3.80 (m, 1H), 5.02–5.15 (m, 2H), 5.65–5.78 (m, 1H), 6.20
(d, J = 3.3 Hz, 1H), 6.33 (dd, J = 3.3, 1.8 Hz, 1H), 7.21–7.40
(m, 6H). 13C NMR (100 MHz, CDCl3): δ = 39.2, 51.0, 54.8,
106.7, 109.8, 117.5, 126.9, 128.2, 128.4, 134.8, 140.1, 141.6,
156.0. HPLC: CHIRALCEL AD-H column, hexane–iPrOH =
99.5 : 0.5, flow rate = 0.7 mL min−1, tR = 8.89 min (major), tR =
11.63 min (minor), 70% ee.
(R)-N-(4-Methoxybenzyl)-1-piperonyl-3-butenylamine (8b)12a
Yield (137.0 mg, 88%). Colorless oil; Rf = 0.54 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +48.0 (c = 0.6, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 1.66 (br s, 1H), 2.33–2.37 (m, 2H), 3.42
(d, J = 13.0 Hz, 1H), 3.57–3.62 (m, 2H), 3.79 (s, 3H), 5.01–5.08
(m, 2H), 5.62–5.71 (m, 1H), 5.95 (s, 2H), 6.77 (s, 2H), 6.84 (d,
J = 8.7 Hz, 2H), 6.9 (s, 1H), 7.18 (d, J = 8.6 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ = 43.1, 50.6, 55.2, 61.2, 100.8, 107.3,
107.9, 113.7, 117.5, 120.6, 129.3, 132.6, 135.4, 137.8, 146.4,
147.8, 158.5. HPLC: CHIRALCEL OD-H column, hexane–
iPrOH = 99 : 1, flow rate = 1 mL min−1, tR = 14.55 min (major),
tR = 17.0 min (minor), 95% ee.
(R)-N-Benzyl-1-(2-thienyl)-3-butenylamine (8q)12a
Yield (98.6 mg, 81%). Colorless oil; Rf = 0.6 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +18.3 (c = 0.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.29 (br s, 1H), 2.47–2.53 (m, 2H),
3.60 (d, J = 13.5 Hz, 1H), 3.79 (d, J = 13.5 Hz, 1H), 3.97 (t, J =
6.6 Hz, 1H), 5.01–5.13 (m, 2H), 5.69 (ddt, J = 15.8, 9.6, 6.5 Hz,
1H), 6.91–6.95 (m, 2H), 7.21–7.38 (m, 6H). 13C NMR
(100 MHz, CDCl3): δ = 43.4, 51.1, 57.0, 118.0, 124.1, 124.3,
126.4, 127.0, 128.3, 128.4, 134.8, 140.0, 148.7. HPLC:
CHIRALCEL AD-H column, hexane–iPrOH = 99.5 : 0.5, flow
rate = 0.8 mL min−1, tR = 9.25 min (major), tR = 11.51 min
(minor), 61% ee.
(R)-N-Benzyl-1-(3-pyridyl)-3-butenylamine (8n)
Yield (94.1 mg, 79%). Colorless oil; Rf = 0.24 (3 : 2, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3394, 3014, 2932, 1640,
1586, 1455, 1426, 1356, 1320, 1265, 1106, 1028, 923, 717,
(R,E)-N-Benzyl-1-phenylhexa-1,5-diene-3-amine (8r)12a
1
669 cm−1. [α]D25 = +32.9 (c = 0.2, CHCl3). H NMR (400 MHz,
CDCl3): δ = 1.81 (br s, 1H), 2.35–2.45 (m, 2H), 3.51 (d, J =
13.3 Hz, 1H), 3.65 (d, J = 13.3 Hz, 1H), 3.73 (t, J = 7.1 Hz,
1H), 5.05–5.11 (m, 2H), 5.63–5.74 (m, 1H), 7.22–7.34 (m, 6H),
7.73 (td, J = 8.0, 2.1 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H),
8.55 (d, J = 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ =
42.7, 51.3, 59.0, 118.2, 123.4, 126.9, 127.9, 128.3, 134.4, 134.7,
Yield (111.9 mg, 85%). Colorless oil; Rf = 0.4 (9 : 1, petroleum
ether–EtOAc). [α]D25 = +72.4 (c = 0.6, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.70 (br s, 1H), 2.27–2.39 (m, 2H), 3.29
(dt, J = 7.2, 6.5 Hz, 1H), 3.67 (d, J = 13.3 Hz, 1H), 3.86 (d, J =
13.3 Hz, 1H), 5.07–5.15 (m, 2H), 5.75–5.84 (m, 1H), 6.10 (dd,
J = 15.7, 8.2 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 7.21–7.41 (m,
This journal is © The Royal Society of Chemistry 2012
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10H). 13C NMR (100 MHz, CDCl3): δ = 40.6, 51.3, 59.5, 117.7,
126.3, 126.9, 127.4, 128.1, 128.4, 128.5, 131.3, 132.5, 135.0,
137.0, 140.4. HPLC: CHIRALCEL OD-H column, hexane–
iPrOH = 98 : 2, flow rate = 1 mL min−1, tR = 10.80 min (major),
tR = 13.19 min (minor), 72% ee.
113 mg, 2.82 mmol, 6.0 equiv) in portions at room temperature
and stirred for 20 min. Allylbromide (341.1 mg, 2.82 mmol,
6.0 equiv) was then added and the reaction mixture stirred for
6 h. It was quenched with water and extracted with EtOAc (10 ×
3 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated. The residue was purified by
silica gel column chromatography using petroleum ether–EtOAc
(19 : 1) as eluent to give the bis allyl compound 15 (120.7 mg,
76%) as a colorless oil. IR (CHCl3): νmax = 3075, 3008, 2976,
2911, 2835, 1639, 1610, 1585, 1510, 1464, 1442, 1369, 1301,
(R)-N-Benzyl-1-heptyl-3-butenylamine (8s)
Yield (58.9 mg, 48%). Colorless oil; Rf = 0.2 (3 : 1, petroleum
ether–EtOAc). IR (CHCl3): νmax = 3411, 2928, 2856, 1653,
1
1455, 1074, 759 cm−1. [α]D25 = +2.4 (c = 0.5, CHCl3). H NMR
1248, 1179, 1103, 1038, 995, 917, 831, 758, 604 cm−1. [α]D25
=
(400 MHz, CDCl3): δ = 0.87 (t, J = 7.0 Hz, 3H), 1.28–1.40 (m,
11H), 2.14–2.21 (m, 1H), 2.24–2.31 (m, 1H), 2.58–2.64 (m,
1H), 3.78 (s, 2H), 5.07–5.11 (m, 2H), 5.74–5.84 (m, 1H),
7.22–7.36 (m, 5H). 13C NMR (100 MHz, CDCl3): δ = 14.1,
22.6, 25.6, 29.5, 31.8, 33.6, 38.1, 51.0, 56.1, 117.3, 127.0,
128.3, 128.4, 135.6, 141.1. HRMS (ESI-TOF): calcd [C17H27N
+ H]+ 246.2221, found 246.2222. HPLC: CHIRALCEL AD-H
+60.8 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2.47–2.54 (m, 1H), 2.69–2.80 (m, 2H), 3.12 (d, J = 13.7 Hz,
1H), 3.18–3.25 (m, 1H), 3.69 (d, J = 13.7 Hz, 1H), 3.77–3.80
(m, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.94–5.19 (m, 4H),
5.70–5.87 (m, 2H), 6.82 (d, J = 8.7, 2H), 6.86 (d, J = 8.7 Hz,
2H), 7.15 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 9.1 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ = 36.0, 52.2, 52.7, 55.1, 55.2,
61.7, 113.2, 113.5, 115.8, 116.7, 129.7, 129.8, 131.5, 132.4,
136.7, 137.1, 158.4, 158.42. HRMS (ESI-TOF): calcd for
[C22H27NO2 + H]+ 338.2120, found 338.2130.
column, hexane–iPrOH = 99.5 : 0.5, flow rate = 1 mL min−1
tR = 6.63 min (major), tR = 7.69 min (minor), 41% ee.
,
(R)-N-Benzyl-1-(4-nitrophenyl)-3-butenylamine (8t)
(R)-1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1,2,3,6-
tetrahydropyridine (10)
Yield (115.7 mg, 82%). Colorless oil; Rf = 0.8 (9 : 1, petroleum
ether–EtOAc). [α]D = +23.5 (c = 0.3, CHCl3); IR (CHCl3)
22
νmax = 3335, 3078, 3029, 2924, 2849, 1640, 1599, 1520, 1455,
1347, 1315, 1109, 1014, 996, 920, 856, 824, 754, 700 cm−1; 1H
NMR (400 MHz, CDCl3): δ = 1.73 (br s, 1H), 2.32–2.44 (m,
2H), 3.51 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H),
3.80–3.84 (m, 1H), 5.05–5.10 (m, 2H), 5.62–5.72 (m, 1H),
7.22–7.33 (m, 5H), 7.55 (dd, J = 8.4, 1.5 Hz, 2H), 8.19 (dd, J =
8.5, 1.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 42.9, 51.6,
61.1, 118.6, 123.7, 127.1, 128.0, 128.1, 128.5, 134.2, 139.9,
147.2, 151.8. HRMS (ESI-TOF): calcd for [C17H18N2O2 + H]+
283.1447, found 283.1446. HPLC: CHIRALPAK AD-H
To a solution 15 (40 mg, 0.118 mmol) in dry degassed CH2Cl2
(30 mL) was added Grubbs-II catalyst (5 mg, 5 mol%) at room
temperature. The reaction mixture was refluxed for 4 h. It was
then cooled and filtered through a pad of celite and washed with
CH2Cl2. The filtrate was concentrated and the residue purified by
silica gel column chromatography using petroleum ether–EtOAc
(4 : 1) as eluent to give 10 (28 mg, 76%) as a pale brown oil.
IR (CHCl3): νmax = 3011, 2927, 2851, 2837, 1667, 1612, 1586,
1512, 1464, 1302, 1249, 1180, 1097, 1037, 831 cm−1. [α]D25
=
+40.8 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2.30–2.41 (m, 2H), 2.77–2.81 (m, 1H), 2.90 (d, J = 13.0 Hz,
1H), 3.1–3.21 (m, 1H), 3.50 (dd, J = 8.4, 4.9 Hz, 1H), 3.67 (d,
J = 13.0 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 5.66–5.70 (m, 1H),
5.78–5.83 (m, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.88 (d, J =
8.7 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ = 35.0, 51.6, 55.2 (2C), 58.4,
62.8, 113.5, 113.8, 124.8, 125.3, 128.9, 129.9, 131.4, 135.6,
158.5, 158.6. HRMS (ESI-TOF) calcd for [C20H23NO2 + H]+
310.1807, found 310.1804.
column, hexane–iPrOH = 99.5 : 0.5, flow rate = 0.5 mL min−1
tR = 49.0 min (major), tR = 53.6 min (minor), 40% ee.
,
(R)-α-Propylpiperonylamine (9)
To a solution of 8b (30 mg, 0.096 mmol) in ethanol (5 mL) was
added Pd/C (4 mg, 10% Pd on C). The reaction mixture was
stirred under H2 (balloon pressure) at room temperature for 14 h.
It was then filtered through a small pad of celite and washed
with CH2Cl2. The filtrate was concentrated in vacuo and the
residue was purified by column chromatography using CH2Cl2–
MeOH (4 : 1) as eluent to give 9 (12.85 mg, 69%) as a colorless
oil. [α]2D5 = +11.8 (c = 1.4, CHCl3). lit.22a [α]2D7 = +10.9 (c = 1.01,
(R)-2-(4-Methoxyphenyl)piperidine (16)
To a solution of 10 (48 mg, 0.155 mmol) in dry ethanol (10 mL)
was added Pd/C (6 mg, 10% Pd on C). The reaction mixture was
stirred under H2 (balloon pressure) at room temperature for 14 h.
It was then filtered through a small pad of celite and washed
with CH2Cl2. The filtrate was concentrated and the residue
purified by column chromatography using CH2Cl2–MeOH (4 : 1)
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 7.3 Hz,
3H), 1.18–1.39 (m, 2H), 1.50–1.81 (m, 4H), 3.81 (t, J = 6.87 Hz,
1H), 5.94 (s, 2H), 6.68–6.82 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ = 13.9, 19.6, 41.6, 55.7, 100.7, 106.5, 107.8, 119.4,
140.5, 146.2, 147.5. Other analytical data is same as in literature.22
as eluent to give 16 (18.1 mg, 61%) as a pale brown oil. [α]D25
=
+21.0 (c = 0.25, CH3OH), lit.26 −21.0 (c = 0.54, CH3OH) for
enantiomer. 1H NMR (400 MHz, CDCl3): δ = 1.45–1.89 (m,
7H), 2.77–2.80 (m, 1H), 3.11–3.20 (m, 1H), 3.61 (dd, J = 11.3,
2.5 Hz, 1H), 3.79 (s, 3H), 6.85 (d, J = 8.7 Hz, 2H), 7.33 (d, J =
8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 24.8, 24.9, 33.7,
(R)-N-Allyl-N-(4-methoxybenzyl)-1-(4-methoxyphenyl)but-3-en-
1-amine (15)
To a solution of homoallylamine 8h (140 mg, 0.47 mmol) in dry
DMF (3 mL) was added NaH (60% dispersion in mineral oil,
7798 | Org. Biomol. Chem., 2012, 10, 7789–7800
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47.1, 55.2, 61.3, 113.8, 128.1, 135.4, 158.9. Other analytical
data is the same as that reported in literature.26
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(R)-N-Trifluroacetyl-2-(4-methoxyphenyl)piperidine (11)
To a solution of 16 (16 mg, 0.084 mmol) in dry CH2Cl2 (8 mL)
was added dry Et3N (24 μL, 0.168 mmol, 2.0 equiv) at room
temperature and stirred for 10 min. Trifluoroacetic anhydride
(18 μL, 0.126 mmol, 1.5 equiv) was added at 0 °C and the
mixture stirred for 2 h at room temperature. The solvent was
removed under reduced pressure and the residue purified by
column chromatography using petroleum ether–EtOAc (9 : 1) as
eluent to give 11 (24 mg, quantitative) as colorless oil. IR
(CHCl3): νmax = 3020, 2939, 2862, 1683, 1515, 1462, 1155,
1086, 1034, 669 cm−1
.
1H NMR (400 MHz, CDCl3):
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(2 : 1 mixture of rotamers, *for the minor rotamer, the data was
compared with the phenyl analog known in the literature)23c δ =
1.54–1.74 (m, 4H + 4H*), 1.89–1.98 (m, 1H + 1H*), 2.42 (d,
J = 14.4 Hz, 1H), 2.49 (d, J = 14.4 Hz, 1H*), 2.72 (t, J = 12.3 Hz,
1H*), 3.08 (dt, J = 12.3, 2.7 Hz, 1H), 3.81 (s, 3H), 3.82 (s,
3H*), 3.81–3.84 (m, 1H), 4.39 (d, J = 13.3 Hz, 1H*), 5.23 (br s,
1H*), 5.84 (d, J = 4.6 Hz, 1H), 6.90–6.93 (m, 2H + 2H*),
7.12–7.16 (m, 2H + 2H*). 13C NMR (100 MHz, CDCl3): (*for
the minor rotamer) δ = 19.1*, 19.3, 25.5*, 26.2*, 26.9, 28.4,
29.7*, 39.6*, 42.1, 55.2*, 55.3, 114.3, 114.34*, 127.5, 127.8,
128.9*, 129.2, 158.6, 158.8*. HRMS (ESI-TOF) calcd for
[C14H16F3NO2 + H]+ 288.1211, found 288.1201.
7 J.-E. Bäckvall, Metal-catalyzed Cross Coupling Reactions, VCH,
Weinheim, 1998, p. 339.
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14 For recent reviews on allylmetal additions, see: (a) C. O. Puentes and
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(R)-Pipecolic acid (12)23
To a solution of 11 (12 mg, 0.042 mmol) in CCl4 (2 mL),
CH3CN (2 mL) and H2O (4 mL) were added sequentially NaIO4
(134.8 mg, 0.630 mmol, 15 equiv) and RuCl3·3H2O (0.6 mg,
0.0023 mmol, 5.5 mol%) under vigorous stirring. After 96 h, the
reaction mixture was diluted with CH2Cl2 (20 mL) and filtered
through a pad of celite and washed with CH2Cl2. The filtrate was
dried (Na2SO4) and concentrated. The residue was dissolved in
MeOH and K2CO3 (34 mg, 0.246 mmol) was added. The hetero-
geneous mixture was stirred for 48 h and then concentrated. The
residue was dissolved in HCl (1.2 N, 2 mL) and purified by ion
exchange chromatography (Dowex 50WX8-200, 100–200 mesh).
The HCl solution of the crude product was eluted with H2O
(10 mL), then 1.5% aq. NH4OH (10 mL), 3% aq. NH4OH
(10 mL) and finally 5% aq. NH4OH (10 mL) solution. The nin-
hydrin containing fractions were concentrated under reduced
pressure to afford 12, (R)-pipecolic acid (2.8 mg, 52%) as pale
yellow solid. M.p. 268–270 °C. [α]2D5 = +26.2 (c = 0.5, H2O),
1
lit.23b +26.7 (c = 1.0, H2O). H NMR (400 MHz, D2O): δ =
1.53–1.69 (m, 3H), 1.82–1.89 (m, 2H), 2.18 (dd, J = 9.8,
4.3 Hz, 1H), 2.95 (td, J = 12.3, 3.1 Hz, 1H), 3.40 (dd, J = 16.5,
3.5 Hz, 1H), 3.54 (dd, J = 11.4, 3.3 Hz, 1H). 13C NMR
(100 MHz, D2O): δ = 23.0, 23.3, 28.0, 45.1, 60.5, 176.1. Other
analytical data is the same as that reported in the literature.23b
Acknowledgements
We thank the Council of Scientific and Industrial Research
(CSIR) New Delhi for financial support [Grant No. 01(2267)/08/
EMR-II] and Junior Research Fellowship to J. L. Nallasivam.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7789–7800 | 7799

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16 For leading references on fluoride- or alkoxide-promoted allylation of
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22–31%, the complex 4 contained approximately <4% of 5. The latter
gets carried over during chromatographic elution along with 4. A single
slow recrystallization of this mixture using propionitrile as the solvent
afforded pure Z-complexes 4 as yellow solids in 35–45% yield.
21 Structural assignment as Z- and E-complexes is similar to that reported in
literature12a and is also supported by the X-ray structure of 4c. CCDC
860684‡ contains the supplementary crystallographic data for this paper.
All attempts to get crystalline material of the complexes 5 for X-ray
analysis failed as they were obtained as powder.
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dium) catalysis, see: R. A. Fernandes and D. A. Chaudhari, Eur. J. Org.
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19 (−)-β-Pinene is available in higher enantiomeric purity (97% ee) than
(+)-nopinone (90% ee) from Aldrich Chem. Co. Hence we used the
former to prepare the latter.
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26 R. Kammler, K. Polborn and K. Th. Wanner, Tetrahedron, 2003, 59,
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7800 | Org. Biomol. Chem., 2012, 10, 7789–7800
This journal is © The Royal Society of Chemistry 2012