4674
P. Le Maux et al. / Tetrahedron 72 (2016) 4671e4675
contrast to our previous studies however,28 no [CuL*] species was
detected. To complement this point, an experiment using para-
cresol as substrate and a ratio Cu:L¼1:2 was realized to check
a possible involvement of such species. After one hour, the yield
was only 22% (ee¼87%) whereas a yield of 77% (ee¼90%) was ob-
tained with a ratio Cu:L¼1:1 (line 4, Table 2). Thus an inhibition of
the catalytic reaction is observed in presence of 2 equiv of L.
Therefore a ratio Cu:L¼1:1 was chosen in the following scheme
(Silica gel 60 with fluorescent indicator UV254). Compounds were
visualized with UV light at 254 nm. Column chromatographies
were carried out using silica gel from Merck (0.063e0.200 mm).
1
13
3
H NMR and C NMR in CDCl were recorded using Bruker
(Advance 400dpx spectrometer) at 400 MHz and 125 MHz, re-
spectively. High resolution mass spectra were recorded on
a Thermo-Fisher Q-Exactive (Q-Tof 2) spectrometer in ESI positive
mode at the CRMPO at Rennes. All catalytic reactions were con-
trolled on a Varian CP-3380 GC system that was equipped with
a CP-Chirasil-Dex Column (25 m, 0.25 mm I.D.) The chiral HPLC
analyses were performed at the Plateforme de chromatographie
chirale at Aix-Marseille Universit eꢀ on an Agilent 1260 Infinity unit
(pump G1311B, autosampler G1329B, DAD G1315D), with Igloo-Cil
ovens, monitored by SRA Instruments Seleccol software (Version
1.2.3.0), Agilent OpenLAB CDS Chemstation LC and CE Drivers
(A.02.08SP1) and Agilent OpenLAB Intelligent reporting
(A.01.06.111). Chiroptical detection was used with Jasco OR-1590
and CD-2095, polarimetric and circular dichroism detectors. The
sign given by the on-line circular dichroïsm at 254 nm is the sign
of the compound in the solvent used for the chromatographic
separation. The sign given by the on-line polarimeter is the sign
of the compound in the solvent used for the chromatographic
separation. The analytical column (250x4.6 mm) used is Lux-
Cellulose-3 from Phenomenex (Le Pecq, France), cellulose tris-
(4-methylbenzoate) coated on silica. Heptane and i-PrOH, HPLC
(
vide infra).
In the copper-catalyzed insertion reaction, the carbene pathway
is predominant and the Cu complex generally acts as a carbene-
transfer. For Cu(II)-system, however, the work of Salomon and
3
4
Kochi shows that it is very difficult to identify the oxidation state
of the active Cu used as catalyst. One example with copper(II)/
18
bisazaferrocene was previously reported by Fu but without de-
tailed mechanistic studies. A possible reduction of the Cu(II)-
catalyst to Cu(I) by the diazoester was also suggested during the
3
4
35
course of the reaction by Kochi and Fraile. Concerning the Cu
oxidation state in our experiments, we check by proton NMR the
addition of diazo derivatives onto Cu(I)L* and Cu(II)L* species (ratio
Cu:L¼1/1). It was not clear that Cu(II) is reduced in the NMR tube.
Thus we do not have direct evidence of the reduction of Cu(II)
during the course of the catalytic reaction and consequently, this
aspect will not further developed.
It is generally accepted that insertions into XeH bond bearing
lone-pair electrons on the X atom most likely proceed by a stepwise
ylide mechanism.36 As it has already been seen in the NeH in-
sertion, the possible mechanism involves the formation of an
electron-deficient carbene and its insertion into the NeH bond via
grade, were degassed and filtered on a 0.45 mm Millipore mem-
brane before use. The optical rotations were recorded on a Perki-
nElmer model 341 polarimeter. The bis(oxazoline) ligands L* was
2
6,38
synthetized as previously described in the literature.
The alkyl
3
6
a copper-associated ylide intermediate. Although we have not yet
conducted detailed mechanistic studies, we can suggest in the OeH
insertion reaction that a copper-associated ylide is formed by attack
of the lone-pair electrons of the phenol O atom onto the electron-
deficient copper carbene and then simultaneous proton transfer
and dissociation of the chiral copper-catalyst to yield the insertion
product. Because the chiral catalyst is involved during the process,
chiral induction can be expected and so high enantioselectivities
obtained.
a
-diazopropionate were prepared according to procedures de-
2
3,32
scribed in the literature.
4.2. General procedure for asymmetric OeH insertion
reaction
Cu(II)(OTf)
2
or Cu(I)(OTf) (5
m
mol), ligand L* (6
Cl
m
mol) and
ꢀ
NaBARF (6 mol) were mixed in CH
m
2
2
(1 ml) for 30 mn at 20 C in
ꢁ
the presence of 100 mg molecular sieves (4 A), then alcohol
3
. Conclusion
(500
m
mol) and ethyl
a
-diazopropionate (100
m
mol) were sequen-
ꢀ
tially introduced and the reaction mixture stirred for 1 h at 20 C.
The insertion yield was determined by GC analysis on the crude
reaction mixture. After purification by flash chromatography on
silica gel (ethyl acetate/hexane¼0.1/9.9), the enantiomeric excess of
the insertion product was determined by chiral GC equipped with
a CP-Chirasil-Dex CB Column.
In summary, we have developed a new Cu(I) or Cu(II)-
bicyclobisoxazoline-catalyst system for the asymmetric insertion
of -diazocarbonyl compounds into the OeH bond of different aryl
and alkyl alcohols under mild conditions. Good yields and high
enantioselectivities of up to 94% ee can be obtained when the
catalyst is associated with NaBARF in the presence of molecular
a
ꢁ
sieves (4 A). A comparative study between Cu(I) and Cu(II)-catalysts
activity in the OeH insertion reaction shows that the efficiency of
these catalysts is very close. Accordingly, it seems reasonable to
think that the same active species is implicated in the reaction. A
stepwise insertion mechanism involving simultaneous proton
transfer and catalyst dissociation as major pathway has been pro-
4.3. Analytical data for OeH insertion products
4.3.1. (S)-(ꢁ)-Ethyl 2-phenoxypropionate 3a. Yield: 62%; 1H NMR
(CDCl
3
):
d
¼1.27 (t, 3H), 1.64 (d, 3H), 4.24 (q, 2H), 4.77 (q, 1H), 6.90
13
(d, 2H), 6.99 (t, 1H), 7.29 (t, 2H); C NMR (CDCl
3
): 14.12, 18.57,
2
0
posed. Possible application of these new chiral ligands using iron or
61.26, 72.63, 115.12, 121.55, 129.52, 157.61, 172.27; [
a
]
D
¼ꢁ41.3 (c
ruthenium complexes2
2,37
for the insertion reaction into OeH bond
0.8, CHCl
); ee¼90% (GC conditions: CP-Chirasil-Dex column,
3
ꢀ
ꢀ
ꢁ1
ꢀ
can be expected in the near future.
100 C (1 min), 2.5 C min 100e180 C, t
R
¼12.04 min for minor
isomer, t
R
¼12.22 min for major isomer). HRESIMS (m/z) calcd for
þ
4
4
. Experimental
C H
11 14
O
3
Na: 217.08406 [MþNa] , found: 217.0842.
.1. General
4.3.2. (ꢁ)-Ethyl 2-(o-tolyloxy)propionate 3b. Yield: 49%; 1H NMR
(
CDCl
3
):
d
¼1.27 (t, 3H),1.66 (d, 3H), 2.31 (s, 3H), 4.23 (q, 2H), 4.76 (q,
13
All reactions were performed under argon. Solvents were
1H), 6.71 (d, 1H), 6.90 (t, 1H), 7.12 (t, 1H), 7.17 (d, 1H); C NMR
(CDCl ): 14.12, 16.29, 18.68, 61.15, 72.97, 112.02, 121.25, 126.62,
127.54, 130.97, 155.95, 172.42; [
(GC conditions: CP-Chirasil-Dex column, 100
2.5 C min
distilled from an appropriate drying agent prior to use: CH
2
Cl
2
3
2
0
from CaH . Commercially available reagents were used without
2
a]
D
¼ꢁ25.1 (c 0.8, CHCl
3
); ee¼88%
ꢀ
further purification unless otherwise stated. All reactions were
monitored by TLC with Merck precoated aluminum foil sheets
C
(1 min),
ꢀ
ꢁ1
ꢀ
100e180 C, t
R
¼13.61 min for minor isomer,