Enantioselective synthesis of 1-vinyltetrahydroisoquinolines through palladium-catalysed intramolecular allylic amidation with chiral PhthalaPhos ligands

Article abstract of DOI:10.1016/j.tetasy.2014.04.018

The PhthalaPhos ligands, chiral BINOL monophosphites endowed with a phthalamide group, have been screened in the synthesis of 1- vinyltetrahydroisoquinolines by intramolecular palladium-catalysed asymmetric allylic amidation (AAA) of achiral tosylamidocarbonates. Identification of the best ligand followed by optimisation of the reaction conditions allowed the desired product to be obtained with up to 83% ee. Remarkably, the reaction is stereoconvergent, affording the same enantiomer of the desired product regardless of the geometry of the allylic carbonate's double bond, which allows, in principle, the use of E/Z mixtures.

Full text of DOI:10.1016/j.tetasy.2014.04.018

Tetrahedron: Asymmetry 25 (2014) 844–850
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of 1-vinyltetrahydroisoquinolines
through palladium-catalysed intramolecular allylic amidation
with chiral PhthalaPhos ligands
a
Luca Pignataro a,b, , Enrico Marelli , Cesare Gennari a,b, Raffaella Ferraccioli b,
⇑
⇑
a Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19-20133 Milano, Italy
b CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via C. Golgi, 19-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The PhthalaPhos ligands, chiral BINOL monophosphites endowed with a phthalamide group, have been
screened in the synthesis of 1-vinyltetrahydroisoquinolines by intramolecular palladium-catalysed
asymmetric allylic amidation (AAA) of achiral tosylamidocarbonates. Identification of the best ligand fol-
lowed by optimisation of the reaction conditions allowed the desired product to be obtained with up to
83% ee. Remarkably, the reaction is stereoconvergent, affording the same enantiomer of the desired prod-
uct regardless of the geometry of the allylic carbonate’s double bond, which allows, in principle, the use
of E/Z mixtures.
Received 3 April 2014
Accepted 29 April 2014
Available online 2 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
MeO
MeO
MeO
MeO
R
*
Pd, L*
OR'
NHR
N
Chiral 1-vinyltetrahydroisoquinolines are important synthetic
targets, that are the key-precursors of the tetrahydroisoquinoline
core of several pharmacologically active molecules (i.e.,
Schulzeines A–C, Almorexant).1 Efficient synthetic alternatives to
traditional routes (i.e., enantioselective Pictet–Spengler and Bisch-
ler–Napieralski reaction)1 are based on asymmetric intramolecular
allylic amidations (AAA) using a metal catalyst such as iridium2 or
palladium.3 In particular, the palladium-catalysed asymmetric
substitution of allylic alcohol derivatives with an amine, amide
or carbamate has become a powerful tool for the construction of
nitrogen heterocycles.4
Two research groups have applied this methodology to synthe-
sise 1-vinyltetrahydroisoquinolines (Fig. 1): Katsuki et al. reported
that palladium complexes generated from chiral 2-(phosphinophe-
nyl)pyridines as P,N-ligands promote the cyclisation of achiral
cis-allylic acetates (Fig. 1A) leading to the product with good enan-
tiomeric excess (88%), albeit at a very slow rate (12 day reaction
time required for synthetically useful conversion).3a Improved
reaction rates (10 h for full conversion) and enantioselectivities
(up to 96% ee) were achieved by Ojima et al. when they used
A. Katsuki et al.: R = COCF3
R' = COCH3, COt-Bu
R = COCF3, Ts
B. Ojima et al.:
R' = COOCH3, COOPh, COOt-Bu
Figure 1. Previously reported syntheses of 1-vinyltetrahydroisoquinolines by Pd-
catalysed intramolecular allylation.3a,b
cis-allylic carbonates as substrates and chiral biphenol-based
monophosphoramidites as ligands (Fig. 1B).3b
The same authors also published the catalytic applications of
structurally related chiral monodentate phosphites,5,6 but no
results in intramolecular allylic substitutions were reported with
these ligands. To the best of our knowledge, the only examples of
asymmetric CAN bond forming allylic substitutions promoted by
monophosphite Pd-complexes have been reported by Lyubimov,
Gavrilov, Tsarev et al., who described the intermolecular AAA of
1,3-diphenyl-3-acetoxyprop-1-ene with nitrogen nucleophiles
(up to 74% ee)7a–d and the desymmetrisation of a meso-1,3-diol
biscarbamate (up to 67% ee).7e
⇑
Corresponding authors. Tel.: +39 02 503 14090; fax: +39 02 503 14072 (L.P.);
Our research group has recently developed a new class of chiral
BINOL-derived monophosphites, named PhthalaPhos (Fig. 2),8
which possess a phthalamide functional group capable of supra-
tel.: +39 02 503 14141; fax: +39 02 503 14139 (R.F.).
E-mail addresses: luca.pignataro@unimi.it (L. Pignataro), raffaella.ferraccioli@
istm.cnr.it (R. Ferraccioli).
http://dx.doi.org/10.1016/j.tetasy.2014.04.018
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
B. substrate orientation effect in enantioselective hydrogenation
845
A. sites of diversity
ancillary amide group
NHAc
R2
R1
O
O
, [Rh], H2
Me
N
R'
N
H
O
O
H
H
NHAc
R2
L*
P
R
O
NH
Rh
O
R1
O
R1
linker
ArHN
H
O
*
O
N
O
P
R2
H
O
R
BINOL
substitution
size and geometry
of the linker
Figure 2. (A) Modular structure of PhthalaPhos ligands; (B) proposed substrate orientation effect in Rh-catalysed hydrogenation (see Ref. 8b).
molecular hydrogen bonding interactions.9 The PhthalaPhos ligand
CF3
library has been screened in the rhodium-catalysed hydrogenation
of olefins, and has shown excellent levels of enantioselectivity with
several dehydroamino ester and enamide substrates. Mechanistic,
spectroscopic and computational studies strongly suggest that
the phthalamide moiety exerts a substrate orientation effect in
the hydrogenation catalytic cycle (Fig. 2B),8b which explains their
superior enantioselectivity compared to structurally related phos-
phites devoid of hydrogen bonding groups.
CF3
N
NH2
O
CF3
a)
b)
CF3
c)
O
N
H
F3C
CF3
COOH
O
3
4
CF3
CF3
Air-stable and easy to prepare (see below), the PhthalaPhos
ligands possess a modular structure featuring the following sites
of diversity (Fig. 2A): (i) the linker between the phosphite and
the phthalamide moieties; (ii) the substitution on the binaphtholic
portion; and (iii) the ancillary amide, namely the amide group
which is not connected to the phosphite moiety.
O
O
d)
N
CF3
N
H
CF3
OH
H
O
H
H
P
O
N
N
O
O
O
5
L4
Herein we report the use of the PhthalaPhos ligands in the syn-
thesis of 1-vinyltetrahydroisoquinolines P1 and P2 (Fig. 3) by pal-
ladium-catalysed intramolecular amidation of allylic carbonates 1
and 2, as a benchmark reaction to evaluate the catalytic potential
of ligands in the enantioselective synthesis of heterocycles.
Scheme 1. Synthesis of ligand L4. Reagents and conditions: (a) Phthalic anhydride,
CHCl3, reflux, 98%; (b) (CF3CO)2O, TEA, THF, 0 °C to rt, 99%; (c) 3-aminophenol, THF,
rt, quantitative; (d) (S)-BINOL-PCl, TEA, THF, rt, 68%.
in situ from 2.5 mol % of [Pd2(dba)3ꢀCHCl3] (5 mol % of Pd) and
10.5 mol % of the selected ligand in DCM at 25 °C. The reaction con-
ditions and results are shown in Table 1.
2. Results and discussion
2.1. Ligand synthesis
The size and geometry of the linker between the phosphite
moiety and the diamide group turned out to strongly affect the cat-
alytic properties. Phosphites L1, L2 and L4, with a meta-substituted
phenol linker, gave full conversion and moderate enantioselectivi-
ty (entries 3, 4 and 6), while ligand L10, featuring a para-
substituted phenol linker, gave incomplete conversion and lower
stereocontrol (entry 12). Benzyl phosphites L5-7, L8-9 and
L11-15 led to full conversion in most cases (entries 7–9, 10–11
and 14–15), but with very low or no enantioselectivity. Finally,
no reaction occurred in the presence of naphthyl phosphite ligands
L16-17 or with ligand L18, featuring an aliphatic linker (entries
18–20).
The ancillary amide (i.e., not bearing the phosphite group)
strongly affects the catalytic behaviour, as can be observed by com-
paring the results obtained with ligands L1, L3 and L4, which only
differ in this structural element: an aromatic ancillary amide is
necessary in order to achieve full conversion (entries 3 and 6),
while only trace amounts of the desired product were formed with
L3, possessing a n-butyl amide group (entry 5). The more acidic
The PhthalaPhos ligands can be synthesised via a straightfor-
ward four-step protocol,8 which is exemplified by the preparation
of ligand L4 (Scheme 1).10
2.2. PhthalaPhos ligand library screening
The PhthalaPhos library was initially screened in the cyclisation
of the trans-allylic carbonate (E)-1a (Fig. 3)3b in order to select the
most promising ligand, to be used for further optimisation of the
reaction conditions. In each experiment, substrate (E)-1a was trea-
ted with a catalytic amount of the palladium complex generated
H
MeO
MeO
MeO
MeO
N
R
Pd, L*
N
OR'
R
*
3,5-bis(trifluoromethyl)phenyl group of L4 gave
a
better
R = Ts
R = COCF3
2:
P1: R = Ts
P2: R = COCF3
enantioselectivity than the 4-butylphenyl amide of L1 (entry 6 vs
entry 3). No reaction took place when (E)-1a was treated with
[Pd2(dba)3ꢀCHCl3] in the absence of any ligand (entry 21).
1a:
R' = COOMe
R' = COOMe
1b: R' = COOt-Bu
It is noteworthy that palladium complexes of ligands L1, L2 and
L4 gave enantiomeric excesses which exceeded those obtained in
Figure 3. Synthesis of 1-vinyltetrahydroisoquinolines using PhthalaPhos ligand
palladium complexes.

846
L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
Table 1
Results of the screening of PhthalaPhos ligand library in the Pd-catalysed allylic amidation of (E)-1a
H
N
MeO
MeO
MeO
MeO
[Pd2(dba)3·CHCl3] (2.5 mol%)
ligand (10.5 mol%)
O
O
O
O
Ts
O
N
S
=
OMe
Ts
DCM(C0, sub.= 13.9 mM)
25 °C, 16 h
*
O
1a
P1
Entry Ligand
Conv.
(%)a
ee (%),b abs.
conf.c
Entry Ligand
Conv.a
(%)
eeb (%), abs.
conf.c
n-Bu
O
N
H
H
O
O
N
S
O
P
O
O
S
O
P
O
1
6
100
12, (R)
12
L10
90
8, (S)
n-Bu
O
N
O
O
H
O
O
P
S
S
O
P
H
O
N
n
O
13
14
15
L11 (n = 0)
L12 (n = 1)
L13 (n = 2)
19
100
100
0
5, (R)
4, (R)
2
7
17
0
n-Bu
n-Bu
O
O
N
N
H
H
H
H
N
N
n
n
O
O
O
S
O
O
P
O
O
P
S
O
3
4
L1 (n = 0)
L2 (n = 2)
100
100
30, (R)
37, (R)
16
17
L14 (n = 1)
L15 (n = 2)
20
<5
n. d.
n. d.
n-Bu
O
O
N
H
N
H
H
N
O
O
H
S
N
O
P
O
O
O
O
S
P
O
5
L3
<5
n. d.
18
L16
<5
n. d.
CF3
n-Bu
O
O
N
N
CF3
H
H
H
O
O
O
O
H
N
O
P
S
S
N
O
P
O
O
6
L4
100
43, (R)
19
L17
<5
n. d.
n-Bu
n-Bu
O
O
N
N
H
H
O
O
H
H
O
O
N
O
P
S
N
O
P
S
n
O
O
7
8
9
L5 (n = 0)
L6 (n = 1)
L7 (n = 2)
100
100
100
0
0
5, (R)
20
L18
<5
n. d.

L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
847
Table 1 (continued)
Entry Ligand
Conv.
(%)a
ee (%),b abs.
conf.c
Entry Ligand
Conv.a
(%)
eeb (%), abs.
conf.c
CF3
O
N
H
CF3
O
O
H
N
O
P
S
n
O
10
11
L8 (n = 0)
L9 (n = 1)
100
100
12, (R)
0
21
None
0
—
a
b
c
Conversion determined by 1H NMR analysis of the crude reaction mixture.
Determined by HPLC analysis (column: Chiralpak AD-H; eluent: 8:2 hexane/i-PrOH) of the product purified by flash chromatography.
Assigned by comparison of the sign of the specific rotation with the literature data (see Ref. 3b).
the presence of reference (S)-BINOL-phosphites 6 and 7, which lack
the phthalamide fragment (entries 3, 4, 6 vs entries 1, 2). These
results suggest that the diamide moiety plays an important role
in determining the stereochemical course of the reaction. It is
likely that, analogously to what we observed for rhodium-cata-
lysed hydrogenations,8b the PhthalaPhos ligands’ amide groups
take part in guiding the approach of the substrate towards the
metal through the formation of a hydrogen bonding interaction.
These ligand–substrate secondary interactions9 have already been
suggested for palladium-catalysed allylations carried out in the
presence of bidentate ligands possessing polar groups (such as
Trost’s11 and Hayashi’s-Ito’s9,12 ligands).
hypothesised occurrence of ligand–substrate hydrogen bonding
interactions. Remarkably, reversed stereodiscrimination was
observed in acetonitrile and isopropanol (entries 11–12). Accord-
ingly, further optimisation of the reaction parameters was carried
out in toluene, which is less toxic than benzene and more volatile
than m-xylene and chlorobenzene.
Results summarised in Table 3 indicate that a palladium-
to-ligand ratio of 1/2 provides the best combination of activity
and stereoselectivity (entry 3 vs entries 1–2). When the catalyst
loading was reduced to 2.5 mol %, conversion turned out to be
incomplete and the ee dropped to 50% (entry 4). Moreover, the
use of a
p–allylpalladium chloride dimer as the palladium source
gave very low conversion and ee (entry 5). Finally, we observed
that the enantioselectivity increased up to 73% when the reaction
was carried out at 0 °C for 16 h (entry 6). Lowering the temperature
to ꢁ10 °C made the reaction slower and less enantioselective
(entry 7).
2.3. Reaction condition optimisation
Optimisation of the intramolecular palladium-catalysed AAA of
(E)-1a in the presence of the best performing ligand L4 began with
solvent screening. Results reported in Table 2 show that aromatic
solvents are best suited for this reaction. In particular, using tolu-
ene, benzene, m-xylene and chlorobenzene led to significantly
improved ee values (entries 3–6) compared to DCM or 1,2-dichlo-
roethane (entries 1–2). On the other hand, aliphatic hydrocarbons,
such as hexane and cyclohexane, gave modest conversion and poor
enantioselectivity (entries 8–9). The use of coordinating solvents
(entries 10–12) resulted in high or complete substrate conversion
but reduced enantioselectivity, which is consistent with the
2.4. Impact of the substrate structure on the enantioselectivity
With the optimised reaction conditions established, we reacted
the allylic carbonates (Z)-1a, (Z)-2a and (E)-1b (Fig. 3) to study the
effect of their structural features on the reaction (Table 4).
We observed that the olefin geometry did not affect the sense of
enantiocontrol: (E)- and (Z)-isomers of 1a both led to the (R)-enan-
tiomer of P1, although in the latter case the reaction was slower
Table 2
Solvent effect on the intramolecular amidation of (E)-1a catalysed by the L4–Pd complex
H
MeO
MeO
N
[Pd2(dba)3·CHCl3] (2.5 mol%)
L4
Ts
O
(10.5 mol%)
N
OMe
MeO
Ts
solvent (C0,sub. = 13.9 mM),
25 °C, 16 h
MeO
*
O
1a
(E)-
Solvent
P1
b
Entry
Conversiona (%)
ee (%), abs. conf.
1
2
3
4
5
6
7
8
DCM
100
100
100
100
100
100
100
28
43, (R)
30, (R)
63, (R)
64, (R)
62, (R)
64, (R)
50, (R)
28, (R)
26, (R)
7, (R)
1,2-DCE
Toluene
Benzene
Chlorobenzene
m-Xylene
Anisole
Hexane
Cyclohexane
THF
9
41
10
11
12
100
100
95
i-PrOH
CH3CN
19, (S)
23, (S)
a
Conversion determined by 1H NMR analysis of the crude reaction mixture.
See the footnotes of Table 1.
b

848
L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
Table 3
Effect of Pd/L4 ratio, catalyst loading, Pd source and temperature in the AAA of (E)-1a in toluene
H
MeO
MeO
MeO
N
Ts
O
[Pd] / L4
N
OMe
Ts
toluene (C0,sub. = 13.9 mM),
MeO
16 h
O
1a
(E)-
P1
Entry
Pd catalyst (mol %)
Pd/L
T (°C)
Conv.a (%)
eeb (%)
1c
2
3
4
5
[Pd2(dba)3]ꢀCHCl3 (2.5)
[Pd2(dba)3]ꢀCHCl3 (2.5)
[Pd2(dba)3]ꢀCHCl3 (2.5)
[Pd2(dba)3]ꢀCHCl3 (1.25)
[Pd(allyl)Cl]2 (2.5)
1/2
1/1
1/3
1/2
1/2
1/2
1/2
25
25
25
25
25
0
ꢁ10
100
100
85
90
53
63
59
59
50
50
73
61
6
[Pd2(dba)3]ꢀCHCl3 (2.5)
100
75
7d
[Pd2(dba)3]ꢀCHCl3 (2.5)
a
b
c
Conversion determined by 1H NMR analysis of the crude reaction mixture.
(R)-Configuration (determined as shown in Table 1) in all cases.
No effect on conversion and ee was observed using a substrate concentration of 6.95 mm and 27.8 mm, respectively.
Reaction time = 48 h.
d
Table 4
Cyclisation of structurally modified substrates
H
N
MeO
MeO
MeO
[Pd2(dba)3·CHCl3] (2.5 mol%)
R
O
L4 (10.5 mol%)
OR'
N
R
toluene (C0,sub. = 13.9 mM)
MeO
O
R = Ts
R = COCF3
P1: R = Ts
P2: R = COCF3
1a: R' = COOMe
1b: R' = COOt-Bu
2: R' = COOMe
Entry
Substrate
T (°C)
t (h)
Conv.a (%)
ee (%), abs. conf.
Yieldb (%)
1
2
3
4
(E)-1a
(Z)-1a
(Z)-2
0
0
25
0
16
104
20
100
100
100d
100
73, (R)c
62, (R)c
9,e (R)f
83, (R)c
82
85
59
81
(E)-1b
44
a
b
c
d
e
f
Conversion determined by 1H NMR analysis of the crude reaction mixture.
Isolated yields.
See the footnotes of Table 1.
30% conversion after 104 h at 0 °C.
Determined by HPLC analysis (column: Chiralpak OJ-H; eluent: 9:1 hexane/i-PrOH) of the product purified by flash chromatography.
Assigned by comparison of the HPLC elution order with the literature data (see Ref. 2).
(entry 2 vs entry 1). The cis-isomer (Z)-1a gave the product in high
yield and with slightly lower enantiopurity (62% ee) than the trans
counterpart (73% ee). Since the reaction is stereoconvergent, sub-
strates with low E/Z purity can in principle be employed without
a significant erosion of the ee. On the contrary, Ojima reported that
the reaction of the same substrates, in the presence of chiral mono-
phosphoramidite ligands, is stereodivergent: (E)-1a affords (R)-P1
with 71% ee, while (Z)-1a gives the opposite enantiomer (S)-P1
with 74% ee.3b
3. Conclusion
In conclusion, we have shown that PhthalaPhos ligands8 can be
successfully employed in palladium-catalysed transformations:
the screening of the library allowed the identification of an effi-
cient ligand L4 for the synthesis of N-tosyl-1-vinyltetrahydroiso-
quinoline P1 by palladium-catalysed intramolecular asymmetric
allylic amidation (AAA). For the first time, monophosphite ligands
could be used for carrying out this transformation with full conver-
sion and good enantioselectivity (up to 83% ee). The diamide func-
tionality of the PhthalaPhos ligands plays a key role in determining
their activity and stereoselectivity in this reaction, and it is likely
involved in substrate orientation effects. We are currently explor-
ing new applications of PhthalaPhos ligands in other palladium-
catalysed enantioselective transformations.
The nature of the nucleophile greatly influences the reaction
selectivity, as observed when switching from (Z)-1a to (Z)-2, con-
taining the trifluoroacetyl group as
a nitrogen substituent
(Fig. 3): the latter underwent full conversion at 25 °C, and the
desired tetrahydroisoquinoline (R)-P2 was isolated in good yield
but dramatically lower ee (entry 3 vs entry 2). By contrast, Ojima
reported that the same substrate led to (S)-P2 with 79% ee with
monophosphoramidite ligands.3b
The size of the leaving group also has an impact on the stereo-
chemical outcome of the reaction: allylic t-Bu-carbonate (E)-1b
gave (R)-P1 with higher ee (83%) compared to the corresponding
Me-carbonate (E)-1a (entry 4 vs entry 1). Until now, this is the best
result obtained in the synthesis of chiral N-Ts substituted
tetrahydroisoquinolines.
4. Experimental
4.1. General
All reactions were carried out in flame-dried glassware with
magnetic stirring under a nitrogen atmosphere, unless otherwise
stated. Solvents for reactions were distilled over the following

L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
849
drying agents and transferred under nitrogen: THF (Na), Et3N
(CaH2). Dry Et2O and DCM (over molecular sieves in bottles with
crown cap) were stored under nitrogen. Reactions were monitored
by analytical thin-layer chromatography (TLC) using silica gel 60
F254 pre-coated glass plates (0.25 mm thickness). Visualisation
was accomplished by irradiation with a UV lamp and/or staining
with a ceric ammonium molybdate solution. Flash column chro-
matography was performed using silica gel (60 Å, particle size
(282 MHz, CD3OD): d = ꢁ65.0 (s); IR (KBr):
m
= 3270.7, 1644.0,
1416.5, 1382.7, 1277.6, 1129.1, 886.1 cmꢁ1; HRMS (ESIꢁ): m/z
467.08378 [MꢁH]ꢁ (calcd for C22H13N2O3F6: 467.08359).
4.2.2. N1-(3,5-Bis(trifluoromethyl)phenyl)-N2-(3-((11bS)-dinap-
htho [2,1-d:10,20-f][1,3,2]dioxaphosphepin-4-yloxy)phenyl)phth-
alamide L4
(S)-BINOL-PCl (96.4 mg, 0.274 mmol, 1 equiv) was added to a
stirred 0.1 M solution of alcohol 5 (128.3 mg, 0.274 mmol, 1 equiv)
and Et3N (0.115 mL, 83.2 mg, 0.822 mmol, 3 equiv) in THF. The
obtained mixture was stirred overnight and then filtered through
a pad of Celite (rinsing with THF). The solvent was evaporated
under reduced pressure and the crude product was purified by trit-
uration with 4:1 Et2O/DCM, which gave a white solid. Yield:
40–64 lm) as stationary phase, following the procedure by Still
and co-workers.13 Proton NMR spectra were recorded on a spec-
trometer operating at 400.13 MHz. Proton chemical shifts are
reported in ppm (d) with the solvent reference relative to tetra-
methylsilane (TMS) employed as the internal standard (CDCl3
d = 7.26 ppm; CD2Cl2, d = 5.32 ppm; [D]6acetone, d = 2.05 ppm;
CD3OD, d = 3.33 ppm). The following abbreviations are used to
describe spin multiplicity: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad signal, dd = doublet–doublet,
td = triplet–doublet. 13C NMR spectra were recorded on a 400 MHz
spectrometer operating at 100.56 MHz, with complete proton
decoupling. Carbon chemical shifts are reported in ppm (d) relative
to TMS with the respective solvent resonance as the internal stan-
dard (CDCl3, d = 77.23 ppm; CD2Cl2, d = 54.00 ppm; [D]6acetone,
d = 206.26 ppm and 29.84 ppm; CD3OD, d = 49.05 ppm). 31P NMR
spectra were recorded on a 400 MHz spectrometer operating at
162 MHz, with complete proton decoupling. 31P NMR chemical
shifts are reported in ppm (d) relative to external 85% H3PO4 at
0 ppm (positive values downfield). 19F NMR were recorded on a
300 MHz spectrometer operating at 282 MHz. 19F NMR chemical
shifts are reported in ppm (d) relative to external CFCl3 at 0 ppm
(positive values downfield). The coupling constant values are given
in Hz. Infrared spectra were recorded on a standard FT/IR spec-
trometer. Optical rotation values were measured on an automatic
polarimeter with a 1 dm cell at the sodium D line (k = 589 nm).
High resolution mass spectra (HRMS) were performed on a Fourier
Transform Ion Cyclotron Resonance (FT-ICR) Mass Spectrometer
APEX II and Xmass software (Bruker Daltonics)—4.7 T Magnet
(Magnex) equipped with ESI source, available at CIGA (Centro
Interdipartimentale Grandi Apparecchiature) c/o Università degli
Studi di Milano.
146.1 mg (68%). Mp = 167–168 °C; [a]
20 = +43.3 (c 0.96, acetone);
D
1H NMR (400 MHz, [D]6acetone): d = 10.27 (s, 1H), 9.85 (s, 1H), 8.46
(s, 2H), 8.18 (d, 3J(H,H) = 8.8 Hz, 1H), 8.09 (d, 3J(H,H) = 8.2 Hz, 1H),
8.03 (d, 3J(H,H) = 8.8 Hz, 1H), 8.01 (d, 3J(H,H) = 8.2 Hz, 1H), 7.89 (s,
1H), 7.81–7.74 (m, 2H), 7.70 (s, 1H), 7.67 (d, 3J(H,H) = 8.8 Hz, 1H),
7.62–7.48 (m, 6H), 7.39–7.32 (m, 5H), 7.00 (dd, 3J(H,H) = 8.1 Hz,
4J(H,H) = 2.0 Hz, 1H); 13C NMR (100 MHz, [D]6acetone): d = 168.5,
167.6, 152.6, 148.5, 147.8, 142.2, 141.8, 137.4, 137.1, 133.6,
133.3, 132.8, 132.6 (q, 2J(C,F) = 33.0 Hz), 131.8, 131.4, 131.2,
131.0, 131.0, 129.6, 129.4, 128.9, 127.5, 127.4, 127.4, 127.3,
126.4, 126.1, 125.1, 124.4 (q, 2J(C,F) = 272.2 Hz), 123.5, 122.7,
122.5, 120.4, 117.4, 116.7, 116.6, 116.5, 112.8; 31P NMR
(162 MHz, [D]6acetone): d = 144.6 (s); 19F NMR (282 MHz, [D]6ace-
tone): d = ꢁ64.0 (s); IR (KBr):
m = 3248.5, 3057.1, 1648.8, 1585.7,
1472.4, 1438.5, 1382.7, 1277.6, 1133.9, 948.8 cmꢁ1; HRMS (ESI+):
m/z 805.12915 [M+Na]+ (calcd for C42H25N2O5F6PNa: 805.12975).
4.3. Allylic amination cyclisation experiments
4.3.1. General procedure for the ligand screening in the allylation
of substrate (E)-1a (Table 1)
In each vessel of a carousel multireactor at 25 °C, [Pd2(dba)3-
ꢀCHCl3] was added as a 2.781 mM DCM stock solution (0.2 mL,
0.556
(2.336
mixture was stirred for 10 min and then a 0.222 M DCM solution
of substrate (E)-1a (0.1 mL, 22.2 mol, 1 equiv) was added. The
lmol, 0.025 equiv), followed by the selected ligand
lmol, 0.105 equiv) and by 1.3 mL of DCM. The resulting
The synthesis and characterisation of ligands L1-3/L5-18 have
been reported elsewhere.8 Ligands 6 and 7 are known com-
pounds,14 that we prepared according to a published procedure.15
Chlorophosphite (S)-BINOL-PCl was prepared from (S)-BINOL on a
gram scale according to a literature procedure.16 Substrates (Z)-
1a, (E)-1a, (E)-1b and (Z)-2a were prepared following published
procedures.3b,c
l
reaction mixture was stirred overnight (conversion was monitored
by TLC with 7:3 hexane/AcOEt eluent), then the solvent was
quickly evaporated. The conversion was determined by proton
NMR analysis of the residue.17 Reaction product P13b was purified
by flash chromatography (eluent: DCM), and then analysed by chi-
ral HPLC for determining the enantiomeric excess (column: Daicel
Chiralpak AD-H; eluent: 8:2 hexane/i-PrOH; flow: 0.8 mL/min;
k = 210 nm; tR = 23.5 min [(S)-enantiomer] and 33.4 min [(R)-enan-
tiomer]18). Rf 0.29 (DCM). 1H NMR of product P13b (400 MHz, CD2-
Cl2): d = 7.64 (d, 3J(H,H) = 7.5 Hz, 2H), 7.22 (d, 3J(H,H) = 7.5 Hz, 2H),
6.53 (s, 1H), 6.47 (s, 1H), 5.89 (ddd, 3J(H,H) = 17.0, 10.2, 5.8 Hz, 1H),
5.40 (d, 3J(H,H) = 5.8 Hz, 1H), 5.15 (d, 3J(H,H) = 10.2 Hz, 1H), 5.05
(d, 3J(H,H) = 17.0 Hz, 1H), 3.83 (dd, 3J(H,H) = 13.7, 6.0 Hz, 1H),
3.77 (s, 3H), 3.75 (s, 3H), 3.30 (m, 1H), 2.64 (m, 1H), 2.50 (m,
1H), 2.37 (s, 3H).
4.2. Synthesis of ligand L4
4.2.1. N1-(3,5-Bis(trifluoromethyl)phenyl)-N2-(3-hydroxyphenyl)
phthalamide 5
Phthalisoimide 48 (184.2 mg, 0.513 mmol, 1 equiv) was added
to
a
stirred 0.11 M solution of 3-aminophenol (67.2 mg,
0.6154 mmol, 1.2 equiv) in THF. The mixture was stirred overnight
at rt. The mixture was diluted with AcOEt (triple volume with
respect to THF) and washed three times with 1 M HCl. The organic
phase was dried over Na2SO4 and evaporated. Purification by flash
chromatography (9:1 and then 8:2 DCM/AcOEt) afforded the prod-
uct as a white solid. Yield: 240 mg (quantitative). mp = 134–
135 °C; 1H NMR (400 MHz, CD3OD): d = 8.32 (s, 2H), 7.77 (m, 2H),
7.68 (s, 1H), 7.67 (m, 2H), 7.27 (t, 4J(H,H) = 1.6 Hz, 1H), 7.14 (t,
3J(H,H) = 8.1 Hz, 1H), 7.04 (d, 3J(H,H) = 8.1 Hz, 1H), 6.59 (dd,
3J(H,H) = 8.1 Hz, 4J(H,H) = 1.6 Hz, 1H); 13C NMR (100 MHz, CD3OD):
d = 170.1, 169.4, 158.9, 142.1, 140.8, 137.6, 137.0, 133.2 (q,
2J(C,F) = 33.3 Hz), 131.8, 131.6, 130.5, 129.1, 129.1, 124.7 (q,
2J(C,F) = 272.0 Hz), 121.1, 117.9, 113.2, 112.8, 109.1; 19F NMR
4.3.2. General procedure for the next catalytic tests (Tables 2–4)
In each vessel of a carousel multireactor at 25 °C, [Pd2(dba)3-
ꢀCHCl3] was added as a 2.781 mM DCM stock solution (0.2 mL,
0.556 lmol, 0.025 equiv). Next, DCM was evaporated off under
high vacuum and then the residue was re-dissolved in the selected
solvent (0.5 mL). Ligand L4 (1.8 mg, 2.336 mol, 0.105 equiv) was
l
added, followed by 1 mL of the selected solvent. The resulting mix-
ture was stirred for 10 min and then the temperature was set to
the selected value (if different from 25 °C). A 0.222 M DCM solution

850
L. Pignataro et al. / Tetrahedron: Asymmetry 25 (2014) 844–850
4. Reviews: (a) Tsuji, J. Palladium Reagents and Catalysis, Innovations in Organic
of substrate (0.1 mL, 22.2 lmol, 1 equiv) was then added. The reac-
Synthesis; Wiley: New York, 1995; (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 395; (c) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345; (d)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2943; (e) Trost, B. M.;
Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747–760; (f) Lu, Z.; Ma, S.
Angew. Chem., Int. Ed. 2008, 47, 258–297; (g) Trost, B. M.; Zhang, T.; Sieber, J. D.
Chem. Sci. 2010, 1, 427–440.
tion mixture was stirred overnight (conversion was monitored by
TLC with 7:3 hexane/AcOEt eluent), then the solvent was quickly
evaporated. The residue was dissolved in CD2Cl217 and the conver-
sion was determined by proton NMR. For product P1, the purifica-
tion and determination of the ee were carried out as described
above. Product P22,3b was purified by flash chromatography (elu-
ent: 3:1 hexane/AcOEt), and then analysed by chiral HPLC for
determining the enantiomeric excess (column: Daicel Chiralcel
OJ-H; eluent: 9:1 hexane/i-PrOH; flow: 0.7 mL/min; k = 210 nm;
tR = 19.5 min [S enantiomer] and 24.5 min [R enantiomer]19). Rf of
P2 0.25 (3:1 hexane/AcOEt). 1H NMR of product P2 (400 MHz,
CD2Cl2): mixture of rotamers A and B (6:4). d = 6.69 (s, 1H, rotamer
B), 6.67 (s, 1H, rotamer A), 6.65 (s, 1H, rotamer A), 6.61 (s, 1H,
rotamer B), 6.07–5.94 (m, 2H), 5.47–5.32 (m, 1H, overlapped with
the solvent peak), 5.20–5.06 (m, 1H), 4.48 (m, 1H, rotamer B), 4.02
(m, 1H, rotamer A), 3.84 (s, 3H), 3.83 (s, 3H, rotamer B), 3.82
(s, 3H, rotamer A), 3.58 (m, 1H, rotamer A), 3.29 (m, 1H, rotamer B),
2.99 (m, 1H), 2.78 (m, 1H).
5. (a) Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831–3834; (b) Chapsal, B.
D.; Hua, Z.; Ojima, I. Tetrahedron: Asymmetry 2006, 17, 642–657.
6. For a recent review on phosphite-containing ligands and their applications in
asymmetric synthesis, see: van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver, C.;
Pàmies, O.; Diéguez, M. Chem. Rev. 2011, 111, 2077–2118.
7. (a) Gavrilov, K. N.; Lyubimov, S. E.; Petrovskii, P. V.; Zheglov, S. V.; Safronov, A.;
Skazov, R. S.; Davankov, V. A. Tetrahedron 2005, 61, 10514–10520; (b) Tsarev, V.
N.; Lyubimov, S. E.; Shiryaev, A. A.; Zheglov, S. V.; Bondarev, O. G.; Davankov, V.
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E. B.; Davankov, V. A. J. Mol. Catal. A: Chem. 2005, 231, 255–260; (d) Gavrilov, K.
N.; Lyubimov, S. E.; Zheglov, S. V.; Benetsky, E. B.; Petrovskii, P. V.; Rastorguev,
E. A.; Grishina, T. B.; Davankov, V. A. Adv. Synth. Catal. 2007, 349, 1085–1094;
(e) Gavrilov, K. N.; Zheglov, S. V.; Gavrilova, M. N.; Novikov, I. M.; Maksimova,
M. G.; Groshkin, N. N.; Rastorguev, E. A.; Davankov, V. A. Tetrahedron 2012, 68,
1581–1589.
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1400.
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Acknowledgments
We thank the European Commission [EID-ITN Network ‘REDUC-
TO’, contract n. PITN-GA-2012-316371] and Consiglio Nazionale
delle Ricerche (CNR) for financial support. L.P. thanks the Diparti-
mento di Chimica, Università di Milano, for financial support
(Piano di sviluppo dell’Ateneo—anno 2014—Linea B.1—grants for
young researchers).
10. Preparation and characterisation of all the remaining ligands discussed in this
paper (L1-3, L5-18) have been reported elsewhere (see Ref. 8).
11. Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P.-O.; Sale, D. A.; Schramm, Y. J.
Am. Chem. Soc. 2009, 131, 9945–9957.
12. (a) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am.
Chem. Soc. 1989, 111, 6301–6311; (b) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito,
Y. Tetrahedron Lett. 1990, 31, 1743–1746.
13. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
14. For 6, see: Albrow, V. E.; Blake, A. J.; Fryatt, R.; Wilson, C.; Woodward, S. Eur. J.
Org. Chem. 2006, 2549–2557; For 7, see: Scholz, U.; Vogtl, E.; Gerlach, A.;
Habfeld, J. Patent Application DE-A 10240803.3, 2002.
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19. Assigned by comparison of HPLC elution order with the literature data (see Ref. 2).