Synthesis and use of a phosphoramidite ligand for the copper-catalyzed enantioselective allylic substitution. Tandem allylic substitution/ring-closing metathesis

Article abstract of DOI:10.1055/s-2004-829188

A new one-pot method of reductive amination is used to prepare a chiral C2 symmetrical amine. This amine is used for the synthesis of a new chiral phosphoramidite ligand. The new ligand is, in turn, used to illustrate the enantioselective copper-catalyzed

Full text of DOI:10.1055/s-2004-829188

2586
PRACTICAL SYNTHETIC PROCEDURES
Synthesis and Use of a Phosphoramidite Ligand for the Copper-Catalyzed
Enantioselective Allylic Substitution. Tandem Allylic Substitution/Ring-
Closing Metathesis
Tandem
A
llylic Su
a
bstitution/R
r
ing-Clo
i
sing
M
n
e
tathesis e Tissot-Croset, Damien Polet, Ségolène Gille, Christine Hawner, Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet,
1211 Genève 4, Switzerland
Fax +41(22)3793215; E-mail: alexandre.alexakis@chiorg.unige.ch
PSP
Received 26 April 2004; revised 11 May 2004
No30
Abstract: A new one-pot method of reductive amination is used to prepare a chiral C2 symmetrical amine. This amine is used for the syn-
thesis of a new chiral phosphoramidite ligand. The new ligand is, in turn, used to illustrate the enantioselective copper-catalyzed allylic
substitution with Grignard reagents. When a remote double bond is located on the Grignard reagent, the newly formed alkene undergoes an
in situ ruthenium-catalyzed ring-closing metathesis to afford the cyclized product in 77% yield and 94% ee.
Key words: allylic substitution, copper catalysis, ruthenium catalysis, enantioselectivity, Grignard reagents
OMe
OMe
OMe
OMe
OMe
OMe
Ti(Oi-Pr)4
r.t.
Pd/C
+
H2N
N
N
O
Procedure 1
H
H2, 1 atm
r.t.
1
2
3 : 59% after
recrystallization
OH
OH
OMe
OMe
OMe
OMe
Cl
O
O
THF, NEt3
0 °C
PCl3
Procedure 2
+
HN
P
N
P N
4
Cl
THF, 0 °C to r.t.
OMe
OMe
3
5 : 94%
PCy3
Ru
Ph
PCy3
Cl
1.2
MgBr
Cl
7
Cl
1% CuTC, 1.1% 5
5 mol%
8
Procedure 3
CH2Cl2, –78 °C
CH2Cl2, r.t.
6
9 : 77%
ee 94%
Scheme 1
Allylic substitution is a fundamental transformation in or- allows the introduction of hard nucleophilic groups, such
ganic synthesis.1 It is even more important in the field of as alkyl groups.3
asymmetric synthesis. The reaction usually involves a
The copper-catalyzed allylic substitution has only recent-
transition metal, in catalytic amount, and a chiral ligand,
ly been studied.4 The first catalytic example reported by
most often a phosphorus-based one.2 Whereas most tran-
Bäckvall and van Koten in 19955a with 42% ee was later
sition metals (Pd, Mo, Ir, etc.) allow the efficient introduc-
improved to 64%.5b It involved an allylic substrate bear-
tion of soft nucleophiles such as malonates or amines, Cu
ing an alkyl group and a Grignard reagent. This is a unique
case where a Grignard reagent is used as primary source
of organometallics. The next report, by Knochel in 1999,6
SYNTHESIS 2004, No. 15, pp 2586–2590
x
x.
x
x
.
2
0
0
4
dealt with diorganozincs as primary organometallics
(Scheme 2). Following these pioneering reports, several
others followed, all using diorganozincs.7
Advanced online publication: 30.07.2004
DOI: 10.1055/s-2004-829188; Art ID: Z08004SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Tandem Allylic Substitution/Ring-Closing Metathesis
2587
n-BuMgI
NMe2
SCu
SCuNMe2
Bu
14% Cu-S-R*
c-Hex
OAc
Ether
0 °C
Fe
c-Hex
ee 42–64%
H2N
Fe
H2N
(Neopentyl)2Zn
Cl
1% CuBr⋅Me2S
Fe
10% H2N-R*
CF3
CF3
THF
–90 °C
ee 87–98%
Scheme 2 Enantioselective allylic substitutions by Bäckvall and Knochel
Our work focused essentially on the use of Grignard re- We report herein the detailed description of the synthesis
agents, and in 2001, we reported that EtMgBr reacts with of the 3rd generation ligand, along with one of the appli-
cinnamyl chloride, in the presence of 1% CuCN and 1% cations of this reaction: the tandem allylic substitution-
of a chiral phosphite ligand, to afford the desired product ring closing metathesis. This ligand is composed of two
with 73% ee and 94% g-selectivity.8a A second generation parts, a chiral binaphthol of S-configuration, and a chiral
phosphoramidite ligand allowed us, in 2002, to improve S,S-amine. The chiral amine is, itself prepared by a new
the ee to 86%.8b A last improvement (96% ee, 99% regio- methodology of reductive amination, where the
selectivity) was reached with our third generation ligand Ti(Oi-Pr)4 promoted formation of the imine and the Pd-
in 2004 (Scheme 3).8c
catalyzed reduction are run in a one-pot procedure, with-
out any solvent (Scheme 4).9
Et
EtMgBr
1% CuTC, 1% L*
Et
Cl
+
CH2Cl2
–78 °C
α-attack
γ-attack
OMe
O
Ph
O
O
Ph
Ph
P N
P N
O
O
O
N
O
P O
O
Me
OMe
Ph
Ph
1st generation
2
nd generation
3rd generation
Scheme 3 Enantioselective allylic substitution by Alexakis
OMe
OMe
OMe
N
OMe
OMe
OMe
Ti(Oi-Pr)4
Pd/C
+
H2N
N
O
H
r.t.
H2, 1 atm
r.t.
59% after
recrystallization
OH
OH
OMe
OMe
OMe
Cl
O
O
THF, NEt3
0 °C
PCl3
+
HN
P
N
P N
THF, 0 °C to r.t.
Cl
OMe
OMe
OMe
94%
Scheme 4 Synthesis of the 3rd generation ligand
Synthesis 2004, No. 15, 2586–2590 © Thieme Stuttgart · New York

2588
K. Tissot-Croset et al.
PRACTICAL SYNTHETIC PROCEDURES
The formation of the ketimine is usually a tedious process Other Grignard reagents react with the same efficiency.
(several days), when the dehydration is done in a Dean– Of particular interest are the reagents bearing a remote
Stark apparatus.10 The alternative procedure with TiCl4 double bond. Indeed, the resulting olefin is amenable to
and Et3N is usually preferred because it is fast and quanti- further synthetic transformations, such as a metathesis re-
tative. However, the formed Et3N·HCl has to be removed action.12 Both cross metathesis and ring-closing metathe-
by filtration before the reduction step.11 In our new proce- sis have been successfully performed without any loss of
dure Ti(Oi-Pr)4 [or Ti(OEt)4] replaces advantageously optical purity.8b From a practical point of view, it would
TiCl4 and the homogeneous liquid mixture does not im- be desirable to run both the allylic substitution and the
pede the further reduction step. In addition, the whole pro- metathesis in the same pot, provided the Ru catalyst is
cess may be run in the absence of any solvent.
compatible with the excess of Grignard reagent and the
presence of Cu salts and phosphoramidite ligand. This is
indeed the case as illustrated in Scheme 6.8c
The new phosphoramidite ligand allows the introduction
of Grignard reagents to a variety of cinnamyl-type allylic
chlorides. The electron-withdrawing or -donating nature In conclusion, we have developed a new phosphoramidite
of the groups on the aromatic ring does not influence the ligand with highly improved efficiency in the copper cat-
enantioselectivity, which remains constantly above alyzed allylic substitution, which greatly enlarge the
92%.8c On the other hand, and in contrast to most other scope of the methodology. In addition, we coupled this re-
systems, this ligand is also efficient with allylic chlorides action with the ring-closing metathesis in a one-pot prac-
bearing an alkyl group, such as cyclohexyl.8c Finally, it tical procedure. The synthesis of the chiral ligand also
should be noted that our third generation ligand is the only exploits a new method for the reductive amination.
one to also allow diethyl zinc as a source of primary orga-
nometallics (Scheme 5).8c
Et
*
EtMgBr
γ:α = 95:5 to 99:1
1% CuTC, 1% L*
R
R
Cl
ee = 92–96%
CH2Cl2, –78 °C
R = 4-Me-C6H4, 4-Cl-C6H4, 4-MeO-C6H4, 3,4-Cl2-C6H3, 4-CF3-C6H4
Et
*
EtMgBr
γ:α = 99:1
1% CuTC, 1% L*
Cl
ee = 91%
CH2Cl2, –78 °C
Et2Zn
Et
*
γ:α = 96:4
1% CuTC, 1% L*
Br
ee = 91%
THF, –40 °C
Scheme 5 Allylic substitutions with the 3rd generation ligand
OEt
1) CuTC, L*, CH2Cl2, –78 °C, 1.2 equiv EtMgBr
2) 5 mol% Grubbs 2nd generation
Cl
96% ee
O
, CH2Cl2, 40 °C
COOEt
Overall Yield = 54%
n
1) CuTC, L*, CH2Cl2, –78 °C, 1.2 equiv
MgBr
Cl
n
2) 5 mol% Grubbs 1st generation
CH2Cl2
R
R
isolated yield = 77%
R = H
Me
n = 1
ee = 94%
93%
1
2
2
79%
69%
72%
96%
H
Me
94%
Scheme 6 Tandem allylic substitution-metathesis
Synthesis 2004, No. 15, 2586–2590 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Tandem Allylic Substitution/Ring-Closing Metathesis
2589
Procedures (Scheme 1)
charged with anhyd THF (40 mL) and freshly distilled Et3N (9 mL,
64.6 mmol). The reaction mixture was cooled to 0 °C and PCl3 (0.9
mL, 10.5 mmol) was added dropwise to the solution. A flame-dried,
25 mL flask was charged with 3 (3 g, 10.5 mmol) and THF (12 mL).
This solution was added dropwise to the reaction mixture kept at
0 °C, and THF (3 mL) was used to rinse the flask containing 3. After
the addition was complete, the ice bath was removed and the mix-
ture was stirred at r.t. for 4 h. In the meantime, a flame-dried 50 mL
flask was charged with (S)-binaphthol (4; 3.02 g, 10.5 mmol) and
THF (25 mL). The resulting solution was added slowly over 2 min
to the reaction mixture containing 3 and PCl3 at 0 °C and THF (3
mL) was used to rinse the flask containing 4. The mixture was
stirred at r.t. overnight, filtered over Celite, the filter cake was
washed with Et2O and the organic phase was concentrated in vacuo.
The product was purified by column chromatography (150 g silica
gel, eluent: Et2O; Rf 0.78). The solvent was evaporated in vacuo to
afford 5.89 g of 5 as a white foam (94% yield, 95% purity according
to 31P NMR); [a]D22 +144.3 (c = 1.1, CHCl3).
1H NMR, 13C NMR and 31P NMR spectra were recorded on a Bruk-
er AC-400 (400 MHz) spectrometer. Chemical shifts are quoted in
ppm relative to tetramethylsilane (0 ppm) and referenced to the re-
sidual undeuterated solvent. Coupling constants (J) are given in
Hertz (Hz). Optical rotations were measured at 20 °C in a 10 cm cell
in the stated solvent; [a]D values are given in 10–1 deg cm2 g–1 (con-
centration c given as g/100 mL). Enantiomeric excesses were deter-
mined by chiral SFC with the stated column. Retention times (Rt)
are given in min. Flash chromatography were performed using sili-
ca gel 32–63 mm, 60 Å. PCl3 was distilled under argon at ambient
pressure and then degassed four times in vacuo at –78 °C to remove
the residual HCl. Et3N was freshly distilled on CaH2. Anhyd THF
and CH2Cl2 were distilled from sodium using benzophenone ketyl
as indicator and CaH2, respectively. Cinnamyl chloride (6) and 4-
bromobut-1-ene were commercial products and used as received.
Bis[1-(2-methoxyphenyl)ethyl]amine (3)
A 250 mL, three-necked flask equipped with a vacuum/argon stop-
cock and a magnetic stirring bar was flame-dried. A static argon at-
mosphere was maintained in the reaction vessel. The flask was
charged with (S)-1-(2-methoxyphenyl)ethylamine13 (5.0 g, 33.09
mmol) and 2-methoxyacetophenone (5.0 g, 33.3 mmol). Then
Ti(Oi-Pr) (30 mL, 101.32 mmol) was added via syringe. The reac-
tion mixture was stirred at r.t. over 20 min before adding 10% Pd/C
(180 mg, 0.17 mmol). The reaction flask was purged five times with
a light vacuum-argon sequence and five times with a light vacuum-
hydrogen sequence. The reaction mixture was stirred under one at-
mosphere (balloon) of H2 over 48 h, compensating from time to
time the consumption of H2 by refilling the balloon. The balloon of
H2 was removed, the flask was opened to air and cooled in an ice
bath, 10% aq NaOH (55 mL) was added, causing the precipitation
of titanium salts. This mixture was treated with EtOAc (50 mL), trit-
urated and decanted. The organic phase was transferred into a 250
mL Erlenmeyer flask. This sequence was repeated three times. The
combined organic phases were filtered on Celite. The Celite cake
was rinsed with EtOAc (25 mL). The resulting clear filtrate was
then dried over 60 g of anhyd Na2SO4, filtered, transferred to a 250
mL flask and concentrated on a rotary evaporator yielding 9.5–9.8
g of a mixture of 3 as a 82:18 mixture of (S,S)- and meso- isomers
as a viscous colorless oil, which gradually solidified. Under an effi-
cient hood, the solid was suspended in EtOAc (40 mL) and an aq
65% HBr (2. 5 mL) was added dropwise, causing the precipitation
of a white solid, which was directly recrystallized from a mixture of
75:27 EtOAc–EtOH (102 mL) at r.t. affording the hydrobromide
salt of 3 as colorless crystals; yield: 4.77–5.18 g (40–43%). Recrys-
tallization of the residue from the filtrate from a mixture of 75:27
EtOAc–EtOH (67 mL) gave a second crop; yield: 1.89–2.32 (16–
19%); total yield: 7.07–7.09 g (59%). The hydrobromide salt of 3
was neutralized with aq 10% NaOH and extracted with CH2Cl2. The
ratio of (S,S)-/meso-isomers >99.5:0.5 was determined by GC/MS
analysis; [a]D22 –92 (c = 0.98, CHCl3).
IR (CHCl3): 3010, 1594, 1492, 1463, 1328, 1237, 1209, 1099, 1070,
947 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.04–6.52 (m, 20 H), 4.99 (dq,
J1 = 1.24 Hz, J2 = 7.08 Hz, 2 H), 3.58 (s, 6 H), 1.55 (d, J = 7.08 Hz,
6 H).
13C NMR (100 MHz, CDCl3): d = 156.1, 149.9, 132.8, 132.5, 131.4,
130.3, 129.2, 128.3, 128.0, 127.7, 127.6, 127.4, 127.3, 125.9, 125.6,
124.7, 124.5, 124.2, 122.7, 1212.5, 119.6, 109.2, 54.6, 50.3, 50.2,
22.6, 22.5.
31P NMR (162 MHz, CDCl3): d = 152.25.
Butenyl Grignard 7
To a suspension of Mg (2.52 g, 111 mmol) in anhyd Et2O (10 mL)
under N2 at r.t. was added a single crystal of I2. A solution of 4-bro-
mobut-1-ene (10 g, 74 mmol) in anhyd Et2O (5 mL) was then added
dropwise. After completion of the addition, the reaction mixture
was stirred at r.t. for 2 h. The concentration of the Grignard reagent
was estimated to be 2.8 M by titration.14
(–)-(3S)-Phenylcyclopentene (9)15
A flame-dried 50 mL three-necked flask equipped with a magnetic
stirring bar and a thermometer was charged with copper thiophene-
2-carboxylate16 (CuTC; 0.019 mg, 0. 1 mmol) and 5 (0.066 g, 0.11
mmol) under argon. Anhyd CH2Cl2 (20 mL) was added and the mix-
ture was allowed to stir at r.t. over 20 min. To the mixture was added
cinnamyl chloride (1.52 g, 10 mmol). The mixture was stirred at r.t.
for 5 min, then kept in an EtOH bath thermostated at –80 °C until
the internal temperature reached –75 °C. In the meantime, a flame-
dried 25 mL, two-necked flask was charged with anhyd CH2Cl2 (5.7
mL) and the Grignard reagent prepared as above (4.3 mL, 12 mmol,
2.8 M in Et2O) and stirred over 2 min at r.t. under argon. The Grig-
nard solution was then added to the above mixture over exactly 4 h
with a syringe pump, maintaining the needle immersed in the reac-
tion mixture. After the completion of addition, the reaction mixture
was stirred at the same temperature during one extra hour, then the
thermostated bath was removed, allowing the reaction flask to
warm up to r.t. Grubbs 1st generation catalyst (0.5 mmoL, 0.142 g)
was added as a solid and the mixture was stirred at r.t. for 3 h. Aq 1
N HCl (20 mL) was added, the two layers were separated and the
aqueous phase was extracted with Et2O (3 × 25 mL). The combined
organic layers were washed with brine (50 mL), dried (MgSO4) and
concentrated in vacuo. Kugelrohr distillation (60 ° C/1 mm Hg) af-
forded 1.11 g of 9 (77%) with a GC-purity of 99% and an enantio-
meric excess of 94% of the S-enantiomer; [a]D22 –166.9 (c = 1.05,
CHCl3) for 94% ee. Ee was measured by chiral SFC with a chiralcel
OJ column (1% MeOH, flow rate 2 mL/min, 200 bar, 30 °C);
Rt: 3.66 (S), 4.01 (R).
IR (CHCl3): 2955, 2924, 1597, 1584, 1485, 1451, 1436, 1229, 1095,
1083, 1025 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34 (d, J = 7.04 Hz, 2 H), 7.22 (t,
J = 7.04 Hz, 2 H), 6.96 (t, J = 7.32 Hz, 2 H), 6.85 (d, J = 8.08 Hz,
2 H), 3.89 (q, J = 6.56 Hz, 2 H), 3.73 (s, 6 H), 2.12 (br, 1 H), 1.30
(d, J = 6.84 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 157.2, 133.7, 127.3, 127.1, 120.4,
110.3, 54.9, 50.1, 22.9.
O,O¢-[(S)-1,1¢-Dinaphthyl-2,2¢-diyl]-N,N¢-bis[(S,S)-1-(2-meth-
oxyphenyl)ethyl]phosphoramidite (5)
A 250 mL, two-necked flask, equipped with vacuum/argon stop-
cock and a magnetic stirring bar was flame-dried. A static argon at-
mosphere was maintained in the reaction flask. The flask was
Synthesis 2004, No. 15, 2586–2590 © Thieme Stuttgart · New York

2590
K. Tissot-Croset et al.
PRACTICAL SYNTHETIC PROCEDURES
IR (CHCl3): 3060, 3011, 2944, 2855, 1601, 1491, 1453, 1214, 1011,
914 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33–7.19 (m, 5 H), 5.96 (m, 1 H),
5.80 (m, 1 H) 3.90 (m, 1 H), 2.52–2.40 (m, 3 H), 1.74 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 146.6, 134.3, 131.9, 128.4, 127.2,
126.0, 51.3, 33.8, 32.5.
(7) (a) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.;
Hoveyda, A. H. Angew. Chem. Int. Ed. 2001, 40, 1456.
(b) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L.
Org. Lett. 2001, 3, 1169. (c) Ongeri, S.; Piarulli, U.; Roux,
M.; Monti, C.; Gennari, C. Helv. Chim. Acta 2002, 85, 3388.
(d) Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari,
C. Angew. Chem. Int. Ed. 2003, 42, 234. (e) Murphy, K. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690.
(f) Piarulli, P.; Claverie, C.; Daubos, P.; Gennari, C.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 4493.
(g) Shi, W.-J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2003, 14, 3867. (h) van Zijl, A.
W.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Adv.
Synth. Catal. 2004, 346, 413.
(8) (a) Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.;
Fournioux, X. Synlett 2001, 927. (b) Alexakis, A.; Croset,
K. Org. Lett. 2002, 4, 4147. (c) Tissot-Croset, K.; Polet, D.;
Alexakis, A. Angew. Chem. Int. Ed. 2004, 43, 2426.
(9) Alexakis, A.; Gille, S.; Prian, F.; Rosset, S.; Ditrich, K.
Tetrahedron Lett. 2004, 45, 1449.
Acknowledgment
The authors thank Stephane Rosset and Caroline Falciola for help,
the BASF company for generous gift of chiral amines, Frontier Sci-
entific Ltd for CuTC, the Swiss National Research Foundation No
20-068095.02 and COST action D24/0003/01 (OFES contract Nr.
C02.0027) for financial support.
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Synthesis 2004, No. 15, 2586–2590 © Thieme Stuttgart · New York