SPANamine derivatives in the catalytic asymmetric α-fluorination of β-keto esters

Article abstract of DOI:10.1016/j.tetasy.2011.08.023

The use of C₂-symmetric enantiopure nitrogen ligands in the asymmetric catalytic α-fluorination of β-ketoesters is described. SPANamine 1 in the presence of nickel salts gives up to 63% ee in the fluorination of tert-butyl 2-oxocyclopentanecarb

Full text of DOI:10.1016/j.tetasy.2011.08.023

Tetrahedron: Asymmetry 22 (2011) 1490–1498
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
SPANamine derivatives in the catalytic asymmetric
a-fluorination
of b-keto esters
Olivier Jacquet a,b, Nicolas D. Clément b, Zoraida Freixa b,c, Aurora Ruiz a, Carmen Claver a,
Piet W.N.M. van Leeuwen b,
⇑
a Departament de Química Física i Química Inorgànica, Universitat Rovira i Virgili, c/Marcel.li Domingo s/n, 43007 Tarragona, Spain
b Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
c Departamento de Quimica Aplicada, Facultad de Ciencias Quimicas, Universidad del País Vasco UPV-EHU, Apdo. 1072, 20080 San Sebastian, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2011
Accepted 30 August 2011
Available online 28 September 2011
The use of C2-symmetric enantiopure nitrogen ligands in the asymmetric catalytic
a-fluorination of b-
ketoesters is described. SPANamine 1 in the presence of nickel salts gives up to 63% ee in the fluorination
of tert-butyl 2-oxocyclopentanecarboxylate with N-fluorosuccinimide (NFSI). The same enantioselectivity
is obtained when SPANamine 1 is used as an organocatalyst, although the reaction is much slower.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
As the starting point of our studies, we set out to use our new
enantiopure nitrogen ligands in the nickel-catalyzed asymmetric
Direct asymmetric fluorination has recently become an impor-
tant tool in organic chemistry. It is one of the most useful methods
to obtain access to quaternary chiral centers bearing a fluorine
atom. The general methods that lead to these molecules involve
the use of a chiral fluorine donor, the application of a chiral organ-
ocatalyst, or the use of a chiral ligand coordinated to a metal.1 The
a-fluorination of b-ketoesters, beginning with the commonly used
racemic substrate 2.2b,3b–d,g,i,6
2. Results and discussion
2.1. Nickel catalysts
asymmetric
a-fluorination of b-ketoesters is particularly interest-
ing in view of the possibility of further derivatization of the chiral
product. Nitrogen based molecules proved suitable compounds to
The first experiments were aimed at establishing the influence
of the solvent on the catalytic performance of a mixture of nickel
chloride, as metallic salt, and SPANamine 1 as the chiral ligand
(Table 1).
convert b-ketoesters into their
a-fluorinated products, either as
organocatalysts2 or chiral ligands.3
Recently our group described the synthesis of a new family of
chiral, C2-symmetric diamines,4 SPANamines, and the first applica-
tion of one of them in the palladium catalyzed asymmetric resolu-
tion of phenylethanol by an oxidation reaction. Previously these
enantiopure ligands were obtained through derivatization of race-
mic SPANdiamine rac-1 or SPANdialdehyde, respectively, with (ꢀ)-
(1R,2S,5R)-menthyl chloroformate and (ꢀ)-cis-myrtanylamine and
separation of the enantiopure diastereoisomers. The enantiopure
SPAN derivatives used in our work were obtained by direct separa-
tion of the enantiomers of 1 and SPANdialdehyde with a semi-pre-
parative HPLC column (vide infra Section 4). We now also report
the synthesis of the chiral SPANbisoxazoline 10,5 and the applica-
tion of these SPAN derivatives as chiral ligands in the asymmetric
The results show that the use of a coordinating solvent (THF,
DMF, MeCN) gives a high conversion into the fluorinated product
but no enantioselectivity was achieved. Dichloromethane was re-
vealed to be the best solvent, giving both high conversion and good
enantioselectivity.
Subsequently several nickel precursors were tested in the pres-
ence of (ꢀ)-1 and the results are gathered in Table 2. Note that the
commonly used nickel perchlorate3a,d,e,i,7 was not tested here be-
cause of its potentially dangerous handling.
With each nickel precursor the conversion was over 80% and the
best enantioselectivities were obtained with the nickel halide salts.
These dissolved only partially in dichloromethane at room temper-
ature and thus an excess of free ligand 1 is probably present in
solution. The soluble nickel sources, such as Ni(acac)2, Ni(oct)2ꢁx-
H2O, and Ni(cod)2 gave a faster reaction, but lower ee’s.
Surprisingly, the reaction carried out without a nickel salt pro-
vided almost the same enantiomeric excess as the one with nickel
chloride, but with a much lower conversion. A preliminary expla-
nation might be that non-ligated nickel causes a fast catalytic
a-fluorination of b-ketoesters.
⇑
Corresponding author.
E-mail addresses: pvanleeuwen@iciq.es, oliv_jacquet@yahoo.fr (P.W.N.M. van
Leeuwen).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.023

O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
1491
Table 1
Table 2
Influence of the solvent
Influence of the nickel precursor
O
O
O
O
O
O
O
NiCl2 (10 mol%)
(-)-1 (11 mol%)
O
F
F
Ni precursor (10 mol%)
(-)-1 (11 mol%)
OtBu
OtBu
OtBu
+
NFSI
OtBu
NFSI
+
Solvent, rt, 3h
CH2Cl2, rt, 3h
3
2
3
2
Solvent
Conv.a (%)
eeb (%)
Ni precursor
Conv.a (%)
eeb (%)
CH2Cl2
THF
DMF
MeCN
Toluene
87
100
92
100
70
63
3
0
0
43
NiCl2
87
91
82
87
97
63
55
42
53
6
61
18
10
61
NiCl2,DME
Ni(OAc)2ꢁ4H2O
NiSO4, 6H2O
Ni(acac)2
NiF2
a
93
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
b
Ni(oct)2ꢁxH2O
100
100
48
Ni(cod)2
None
a
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
fluorination giving racemic product, and that 1 acts independently
as an organocatalyst giving enantioselectivity. Alternatively, the
two entities might act together, nickel activating the substrate
and the organocatalyst delivering chirality. In part the system
may work via the route planned, namely with a chiral nickel com-
plex as the catalyst.
The reaction was also tested with an equimolar amount of an
aqueous solution of potassium carbonate but the conversion and
enantioselectivity were very low (15%, racemic), proving that 1
does not act as a chiral phase transfer agent.
Table 3 shows the results obtained in a screen of diamines and
diimines in the presence and absence of NiCl2. Several SPANamine
derivatives and commercially available ligands were tested. The
best result for nickel chloride was obtained with bisoxazoline 15
with full conversion after three hours and an enantiomeric excess
of 65%. In comparison with SPANamine 1 the enantiomeric excess
is similar, although the conversion with 1 is slightly lower. Apart
from the dibenzyl derivatives SPAN 6 and 7 that provided a signif-
icant ee (41% and 53%, respectively), the other SPAN derivatives
only led to a racemic product. Ligands 8, 9, and 10 have an Nꢁ ꢁ ꢁN
distance different from that of 1, while ligands 4 and 5 exert a ste-
ric hindrance that is larger than that of 1.
b
slower than that with the two other fluorine donors and the
enantioselectivity was lower than that of the reaction with NFSI.
In the case of NFPY (N-fluoropyridinium trifluoromethanesulfo-
nate) the activity obtained was the same as with NFSI, but the fluo-
rinated product obtained was racemic.
The catalyzed asymmetric fluorination using SPANamine 1 was
also tested using other substrates, 20–24, under both metal-cata-
lyzed and organocatalyzed conditions (Scheme 1). For 20, the cat-
alytic results are similar to those obtained for substrate 2, although
slightly lower ee’s were obtained. This effect had already been re-
ported in the literature; when changing a tert-butyl group for an
ethyl group in the a-fluorination of 2-oxocyclopentanecarboxylate
derivatives the ee dropped.3f For the ethyl and tert-butyl-2-oxocyc-
lopentanecarboxylate-1-oxo-2,3-dihydro-1H-indene-2-carboxyl-
ates 21 and 22 fluorination only occurs in the presence of nickel
chloride. Moreover, the enantioselectivities are lower than the
ones obtained with substrates 2 and 20.
Finally, ethyl a-cyano-a-phenylacetate 23 and the unsymmetri-
SPANamine derivative 6, SPANimine 7, and H8-binaphthyl-
amine 14 show the same behavior as 1, in that the enantioselectiv-
ities are almost the same in the reactions with or without nickel.
The results obtained with protonated SPANamine 17 and 18
demonstrate the importance of the NH2 unit both for the activity
and the enantioselectivity (Table 4).
cal malonate 24 could not be converted into the expected fluori-
nated products by either method, and only the starting material
was recovered.
2.3. Mechanistic studies
In conclusion, in the SPANamine/Ni catalytic systems, nickel
only seems to activate the substrate but it does not appear neces-
sary to induce enantioselectivity. In the case of bisoxazoline 15,
however, a chiral nickel complex must be involved, because com-
pound 15 does not induce chirality when used as an
organocatalyst.
Three potential mechanisms for obtaining enantioselectivity in
the organocatalyzed reaction with 1 are presented in Scheme 2.
A first explanation for the enantioselectivity obtained with SPAN-
amine 1 could be the formation of a chiral enamine via a reaction
of the SPANamine and the ketone (Scheme 2). This mechanism was
proposed for proline or pyrrolidine derivatives as organocatalysts.8
Another possibility might be that first the fluorination of amine
takes place, resulting in an intermediate that can act as a chiral
fluorine donor (Scheme 2), similar to the examples involving alka-
loids.9 Finally, a hydrogen-bond interaction could occur between
the enolic form of the substrate and SPANamine, leading to a chiral
intermediate (Scheme 2).
In order to obtain more insight into the possible mechanism of
this reaction several NMR experiments were performed in deuter-
ated chloroform at room temperature (note that the results are
comparable with those obtained with dichloromethane). First, a
1H NMR experiment of a 1:1 mixture of substrate/SPANamine did
not show any formation of enamine or enolate. If there would be
any interaction between the substrate and 1, we expected to see
a change in the chemical shift of the protons of the amine and/or
2.2. Organocatalysts
In view of these results, we continued our study using the un-
ique property of 1 to act as an organocatalyst, and further investi-
gated the influence of the reaction conditions on the asymmetric
organocatalyzed reaction on substrate 2 (Table 5).
Similar to the results given in Table 1, dichoromethane is the
best solvent for the organocatalyzed reaction. The reaction is faster
in a protic solvent such as ethanol but the enantioselectivity is
lower.
The results displayed in Table 6, reveal a dramatic effect of the
fluorinating agent both on the activity and on the enantioselectiv-
ity of the reaction. When Selectfluor was used the fluorination was

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O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
Table 3
Ligand screeninga
O
O
O
O
O
O
O
O
NH2
H2N
N
N
NH
HN
NH
Ph
HN
Ph
Ph
Ph
(-)-1
(-)-4
(-)-5
(-)-6
O
O
O
N
O
O
O
O
O
N
N
N
N
N
O
O
HN
NH
Ph
Ph
Ph
Ph
Ph
Ph
R
R
(-)-7
(-)-8
(-)-9
(-)-10a,b: R=Ph
(-)-11a,b: R=iPr
H
H
N
NH2
NH2
N
H
O
O
O
O
NH2
NH2
N
N
N
N
Ph
Ph
tBu
tBu
H
(-)-13
(R,R)-12
(S,S)-16
(S,S)-15
(R)-14
Ligand
Conv. (%) (without NiCl2)b
ee (%) (without NiCl2)c
1
4
5
87 (81)
44 (9)
85
63 (62)
0 (0)
0
6
7
8
9
85 (55)
81 (53)
87 (13)
85
41 (40)
60 (53)
0 (0)
0
10
12
13
14
15
16
81 (10)
69 (61)
52
100 (91)
100 (58)
90
5 (0)
0 (2)
0
18 (17)
65 (0)
58
a
b
c
Reaction conditions: NFSI (1.1 equiv), NiCl2 (10 mol %), ligand (11 mol %), dichloromethane, rt, 3 h. In parentheses data without NiCl2.
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
a disappearance of the acidic proton of the substrate; however, in
this case both reagents remained unchanged. It seems there is no
interaction between 1 and 2 unless for some reason it cannot be
detected by NMR.
1, 5, 6, 7, and 14 were employed a similar deep green coloration
appeared during the catalytic reactions.
A possible explanation of these observations (coloration and
broad peaks) could be the oxidation of amine by NFSI, leading to
small amounts of radical (cation) species. However, this partial oxi-
dation of SPANamine may not be relevant for the fluorination reac-
tion. Next, EPR experiments were performed on several mixtures of
1, NFSI, and 2 but no conclusive results occurred. In the presence of
nickel chloride an enolate complex forms, but surprisingly for
amines the chiral induction is the same for the nickel/amine cata-
lyzed reactions and the organocatalyzed reactions. The NMR exper-
iments did not lead to any conclusion concerning the mechanism
and does not favor any of the previously proposed pathways. Thus,
there still remains at least two possible mechanisms for SPAN-
amine derivatives or bis-oxazolines such as 15. When other
In Scheme 3 are presented the 1H NMR spectrum of 1 and the 1H
and 19F NMR spectra of NFSI. Then we mixed a 1/2 ratio of these
compounds and recorded several 1H and 19F NMR spectra of the
mixture after 2, 4, and 8 h. The 19F NMR spectrum showed no fluo-
rinated compound other than NFSI; we followed the conversion of
the catalytic reaction by 19F NMR which showed both the gradual
consumption of NFSI and the formation of the fluorinated b-keto-
ester (vide infra in Section 4). In the 1H NMR spectra (Scheme 3)
the signals of 1 with 2 equiv of NFSI added became broad, indicat-
ing that paramagnetic species may be involved, and simulta-
neously a green color was observed. Interestingly though, when

O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
1493
Table 4
Use of protonated SPANamine
O
O
O
O
(-)-1 (10 mol%)
F
NFSI (1.1eq)
OtBu
OtBu
DCM,15h, rt
2
3
O
O
O O
H2N
H3N
NH3
BF4
NH3
BF4
BF4
17
18
Ligand
Conv.a (%)
eeb (%)
17
18
78
30
10
5
a
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
b
Table 5
Table 6
Influence of the solvent in organocatalysis
Influence of the fluorine donor
O
O
O
O
(-)-1 (10 mol%)
NFSI (1.1eq)
(-)-1 (10 mol%)
fluorine donor (1.1eq)
F
O
O
O
O
F
OtBu
OtBu
OtBu
OtBu
solvent,15h, rt
DCM,15h, rt
3
2
3
2
Conv.a (%)
eeb (%)
Solvent
Conv.a (%)
eeb (%)
Fluorine donor
CH2Cl2
THF
Et2O
Toluene
MeCN
DMF
81
22
44
59
23
62
7
24
39
10
4
NFSI
Selectfluor
NFPY
81
35
82
62
37
2
a
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
b
11
EtOH
Acetone
100
42
30
22
a
4. Experimental
4.1. General
Determined by GC analysis.
Determined by chiral GC analysis with a b-Dex column.
b
Unless otherwise specified, materials were obtained from com-
mercial suppliers and were used without further purification. All
reactions requiring anhydrous conditions were conducted in
oven-dried glassware in a dry argon atmosphere. All solvents were
dried using a Solvent Purification System (SPS) or using standard
procedures. 1H and 13C NMR spectra were recorded in CDCl3 on a
Bruker Avance 400 Ultrashield NMR spectrometer (400 MHz for
1H and 100 MHz for 13C). Chemical Shifts (d) for 1H and 13C were
referred to internal solvent references. Optical rotations were mea-
sured on a Jasco P-1030 polarimeter. HPLC analysis was performed
on a Water apparatus, using a Daicel Chiralpak IC and IA column,
250 mm length, 4.6 mm diameter (10 mm for semi-preparative),
metallic salts were employed such as copper triflate or zinc acetate
only racemic products were obtained, and thus, whatever the
mechanism is, it cannot be generalized.
3. Conclusion
In conclusion, enantiopure SPANamine derivatives are active
organocatalysts for the asymmetric
a-fluorination of b-ketoesters
and their behavior is different from those described previously.
When using unreactive substrates, the use of nickel salts increases
the reactivity without loss of enantioselectivity, except with oxaz-
oline-based ligands. Moreover, these compounds are not air sensi-
tive and most are not water sensitive. We are currently working on
the synthesis of new SPAN-N derivatives in order to increase the
enantioselectivities and to apply them in the fluorination of other
substrates, as organocatalysts and as a chiral ligand on a transition
metal.
5
lm particle size. GC analyses were performed on a GC-FID
equipped with HP-5 (5% phenyl methyl siloxane;
a
30 m ꢂ 320 m ꢂ 0.25) capillary column or Daicel b-Dex 120 m.
Substrates 2,10 21,11 22,12 23,13 and 2414 were prepared by previ-
ously reported methods. NMR and chiral GC or HPLC data of fluo-
rinated products data were identical to the reported ones.3b,d,j,9c

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O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
O
O
O
O
O
O
O
O
OtBu
OEt
OtBu
OEt
2
20
21
22
A: conv: 87%, ee: 63%
B: conv: 81%, ee: 62%
A: conv: 100%, ee: 27%
B: conv <5%
A: conv: 66%, ee: 51%
B: conv: 96%, ee: 43%
A: conv: 100%, ee: 9%
B: conv <5%
O
O
NC
CO2Et
MeO
OtBu
Ph
23
Bn
24
A: no conversion
A: no conversion
B: no conversion
B: no conversion
A: NiCl2 (10 mol%), (-)-1 (12 mol%), NFSI (1.1eq), CH2Cl2, rt, 3h
B: (-)-1 (10 mol%), NFSI (1.1eq), CH2Cl2, rt, 15h
Scheme 1.
4.1.1. Synthesis of SPANoxazolines (‘SPANbox’) 10a,b, 11a,b
KOH
2.2eq nBuLi
O
O
O
O
O
O
THF/MeOH
3eq ClCO2Et
65 °C
overnight
then HCl
CO2Et
CO2Et
CO2H
CO2H
Br
Br
THF, -78 to RT
3h
( )-26
( )-25
( )-27
DMAP (5%mol)
Et3N, MsCl
1) SOCl2, 2h, 60 °C
O
N
O
N
O
O
O
O
N
O
N
2) Et3N, 2-phenylglycinol
or valinol, DCM,o vernight, RT
DCM,15h, RT
then separation with a chiral
semi-preparative HPLC column
O
R
HN
NH
O
O
O
O
R
R
R
R
R
OH
HO
(-)-10a (R=Ph)
and (-)-11a (R=iPr)
(-)-10b (R=Ph)
and (-)-11b (R=iPr)
enantiopure 28a,b (R=Ph)
and 29a,b (R=iPr)
4.1.1.1. Compound 26. 8,80-Dibromo-4,4,40,40,6,60-hexamethyl-
2,20-spirobi[chroman] 25 (2 g, 4.05 mmol) was dissolved in 60 mL
of dry THF and cooled to ꢀ78 °C. Then nBuLi 1.6 M in hexane
(7.59 mL, 12.14 mmol) was added dropwise. After stirring 30 min
at this temperature ethyl chloroformate (1.16 mL, 12.14 mmol)
was syringed in the flask and the resulting mixture was stirred
overnight while warming slowly to room temperature. Water
and ethyl acetate were added and the aqueous layer was washed
twice with ethyl acetate. The organic layers were mixed, dried over
MgSO4, and the solvent removed under vacuum. The residue was
purified by flash chromatography over silica gel (hex 95/5 AcOEt
then gradient) in order to render the pure product as a white solid
(1.1 g, 57%yield). 1H NMR: 1.03 (6H, t, J = 6.94 Hz); 1.35 (6H, s);
1.60 (6H, s); 2.11 (2H, d, J = 14.3 Hz); 2.22 (2H, d, J = 14.3 Hz);
2.28 (6H, s); 3.97 (4H, 2 dq, J = 7.05 and 10.58 Hz); 7.18 (2H, d,
J = 2.05 Hz); 7.22 (2H, d, J = 2.05 Hz). 13C NMR: 13.9; 20.6; 30.9;
31.6; 32.5; 47.3; 60.5; 98.7; 122; 128.3 ; 129.9 ; 130.1; 133.5;
147.2; 166.9. IR (cmꢀ1): 2955; 1728; 1710; 1449; 1194; 1100.
HRMS (IE, m/z): experimental: 503.2389 (M+Na), calculated:
503.2410. Enantiomers were resolved on a IA column: 254 nm,
heptane/isopropanol 95/5, 1 ml/min. (ꢀ)-enantiomer: 4.25 min,
½
a 2D4
ꢃ
¼ ꢀ49 (c 0.1198, CH2Cl2); (+)-enantiomer: 6.05 min.
4.1.1.2. Compound 27. Diethyl 4,4,40,40,6,60-hexamethyl-2,20-spi-
robi[chroman]-8,80-dicarboxylate 26 (1.1 g, 2.29 mmol) was dis-
solved in 20 mL of THF, then 20 mL of methanol was added
followed by an aqueous solution of KOH (2 g of KOH in 10 mL of
water, 35.6 mmol). The mixture was stirred 18 h at 65 °C. Then

O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
1495
O
H
O
O
O
O
O
H
O
N
NH2
N
H2N
(PhSO2)2N
H2N
H
F
H
O
H
"F
CO2tBu
"
CO2tBu
CO2tBu
"F
"
chiral enamine intermediate
A
chiral fluorine donor
hydrogen bond
C
B
Scheme 2.
most of the THF and methanol were removed under vacuum with a
rotavapor, the flask was put in an ice bath and concentrated hydro-
gen chloride was slowly added until acidic pH (<3). The diacid pre-
cipitated and was filtered off and washed with water. After being
dried under vacuum the diacid was obtained as a white solid
(965 mg, 99% yield). IR (cmꢀ1): 2958; 2616; 1696; 1445; 1224;
1165; 875. HRMS (IE, m/z): experimental: 447.1789 (M+Na), calcu-
lated: 447.1784.
4.1.1.3. Compounds 28a and 28b. In a first step SPANdiacid 27
(300 mg, 0.707 mmol) was placed in a Schlenk tube with 3 equiv
of triethylamine (296
l
l, 2.121 mmol) and 8 mL of thionyl chloride.
16 15 14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
-1 -2
ppm
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm
SPANamine 1
NFSI
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
19
NFSI (F)
Scheme 3. 1H and 19F NMR study (in CDCl3) of a 1/2 mixture of 1/NFSI.

1496
O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
20
0
-20
-40
-60
-80
-100 -120 -140 -160 -180 -200
ppm
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
SPANamine + NFSI (2h)
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
SPANamine + NFSI (4h)
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
ppm
SPANamine + NFSI (8h)
Scheme 3 (continued)
The resulting dark mixture was stirred for 3 h at 60 °C, then the
volatiles were removed under vacuum. The crude diacyl chloride
was dissolved in 7 mL of DCM, then 3 equiv of triethylamine
(296 ll, 2.121 mmol) and 3 equiv of (S)-(+)-phenylglycinol
(291 mg, 2.121 mmol) (previously dissolved in 1 mL of DCM) were
15 h at rt. Then water was added, the aqueous layer was washed
twice with DCM, the organic layers were mixed, dried over MgSO4,
and the volatiles were removed under reduced pressure. The crude
product was pure by NMR and used without further purification
for next step. 1H NMR (400 MHz, CDCl3): 1.32 (6H, s); 1.34 (6H,
s); 1.36 (12H, s); 2.08 (2H, d, J = 14.3 Hz); 2.17 (2H, d,
successively added.. The resulting brown solution was stirred for

O. Jacquet et al. / Tetrahedron: Asymmetry 22 (2011) 1490–1498
1497
J = 14.3 Hz); 2.23 (2H, d, J = 14.3 Hz); 2.24 (2H, d, J = 14.3 Hz); 2.33
(6H, s); 2.35 (6H, s); 3.48 (4H, m); 3.62 (4H, m); 4.87 (2H, ddd,
J = 2.3, 3.9 and 6.2 Hz); 5.07 (2H, ddd, J = 3.2, 3.8 and 7 Hz); 6.89
(2H, d, J = 2 Hz); 6.91 (2H, d, J = 1.4 Hz); 7.04 (2H, d, J =
2 Hz); 7.06 (2H, d, J = 2.4 Hz); 7.19 (12H, m); 7.28 (2H, d,
J = 2 Hz); 7.65 (2H, d, J = 2 Hz); 7.77 (2H, d, J = 7 Hz); 7.81 (2H, d,
J = 1.9 Hz); 7.95 (2H, d, J = 6.9 Hz).
4.1.1.6. Compounds 11a and 11b. At first, N8,N80-bis((S)-1-
hydroxy-3-methylbutan-2-yl)-4,4,40,40,6,60-hexamethyl-2,20-spiro-
bi[chroman]-8,80-dicarboxamide is dissolved in 8 mL of dry
dichloromethane, to this are successively added N,N-dimethyl-
aminopyridine (4.32 mg, 0.035 mmol) and triethylamine
(0.592 mL, 4.242 mmol). The mixture is then cooled to 0 °C
and methanesulfonyl chloride (0.164 mL, 2.121 mmol) is added.
It is stirred overnight letting it slowly warm up to room tem-
perature. Water is added and the aqueous layer is washed twice
with dichloromethane. The organic layers are mixed, dried over
MgSO4, and the solvents are removed under vacuum. The crude
NMR shows a small amount of unreacted substrate. Diastereoi-
somers are resolved on a Chiralpak IC column: 254 nm, hexane/
isopropanol/diethylamine 90/10/0.1, 1 ml/min. Compound 11a is
obtained as a clear paste (80 mg, yield: 41%) and 11b is ob-
tained as a viscous solid (125 mg, yield: 63%). Overall yield:
52% starting from the diacid.
4.1.1.4. Compounds 10a and 10b. The latter was dissolved in
8 mL of dry dichloromethane, then N,N-dimethylaminopyridine,
(3.6 mg, 0.029 mmol) and triethylamine (0.411 mL, 2.95 mmol)
were added successively. The mixture was then cooled to 0 °C
and methanesulfonyl chloride (0.114 mL, 1.47 mmol) was added.
The mixture was stirred overnight while warming to room
temperature.
Water was added and the aqueous layer was washed twice with
dichloromethane. The organic layers were mixed, dried over
MgSO4, and the solvents were removed under vacuum. The crude
NMR showed a small amount of unreacted substrate. Diastereoiso-
mers were resolved on a Chiralpak IC column: 254 nm, hexane/iso-
propanol/diethylamine 60/40/0.1, 1 mL/min.
Compound 11a: 1H NMR: 0.75 (6H, d, J = 6.7 Hz); 0.85 (6H, d,
J = 6.7 Hz); 1.31 (6H, s); 1.56 (6H, s); 1.62 (2H, m); 2.11 (2H, d,
J = 14.2 Hz); 2.22 (2H, d, J = 14.2 Hz); 2.26 (6H, s); 3.7 (4H, m);
3.93 (2H, dd, J = 7.1 and 8.5 Hz); 7.15 (2H, d, J = 2.2 Hz); 7.21 (2H,
d, J = 2.2 Hz).13CNMR: 18.1; 18.9; 20.6; 31; 31.4; 32.4; 32.5; 47.8;
69.6; 72.1; 99.1; 118.2; 128.8; 129.2; 130.1; 133.7; 147.5;
163.1.IR (cmꢀ1): 2957; 1649; 1459; 1359; 1192; 981; 891.HRMS
(IE, m/z): experimental: 559.3525 (M+H), calculated: 559.3536.
The pure product is obtained as a pale yellow solid (140 mg, 50%
yield).
Compound 10a: 1H NMR: 1.34 (6H, s); 1.62 (6H, s); 2.13 (2H, d,
J = 14.26 Hz); 2.23 (2H, d, J = 14.26 Hz); 2.28 (6H, s); 3.83 (2H, t, J =
8.59 Hz); 4.36 (2H, dd, J = 8.36 and 10.30 Hz); 5.08 (2H, dd, J = 8.36
and 10.30 Hz); 7.10 (2H, d, J = 1.46 Hz); 7.12 (2H, d, J = 1.46 Hz);
7.26 (10H, m).13C NMR: 20.6; 25.4; 30.9; 31.7; 33.1; 47.1; 69.6;
74.5; 98.5; 117.9; 126.8; 127.3; 128.5; 129.2; 129.5; 130.1;
133.5; 142.5; 147.4; 164.7.IR (cmꢀ1): 2959; 1644; 1630; 1451;
1163; 886. HRMS (IE, m/z): experimental: 627.3198 (M+H), calcu-
½
a 2D4
ꢃ
¼ ꢀ16 (c 0.1048, CH2Cl2).
Compound 11b: 1H NMR: 0.73 (6H, d, J = 6.7 Hz); 0.85 (6H, d,
J = 6.7 Hz); 1.31 (6H, s); 1.60 (6H, s); 1.62 (2H, m); 2.08 (2H, d,
J = 14.2 Hz); 2.16 (2H, d, J = 14.2 Hz); 2.24 (6H, s); 3.74 (4H, m);
3.94 (2H, dd, J = 6.7 and 8.4 Hz); 7.09 (2H, d, J = 2.2 Hz); 7.13 (2H,
d, J = 2.2 Hz).13CNMR: 18.0; 19.0; 20.6; 30.7; 31.9; 32.4; 33.2;
46.8; 69.7; 72.2; 98.1; 118.5; 128.9; 129.1; 130.1; 133.1; 146.8;
163.0. IR (cmꢀ1): 2955; 1641; 1449; 1318; 1163; 1001; 888. HRMS
(IE, m/z): experimental: 559.3549 (M+H), calculated: 559.3536.
lated: 627.3223. ½a D24
¼ ꢀ20 (c 0.11, CH2Cl2)
ꢃ
Compound 10b: 1H NMR: 1.33 (6H, s); 1.51 (6H, s); 2.15
(2H, d, J = 14.23 Hz); 2.26 (2H, d, J = 14.23 Hz); 2.30 (6H, s);
3.81 (2H, t, J = 8.31 Hz); 4.28 (2H, dd, J = 8.35 and 10.41 Hz);
5.07 (2H, dd, J = 8.36 and 10.40 Hz); 7.11 (2H, d, J = 2.06 Hz);
7.13 (2H, d, J = 2.06 Hz); 7.26 (10H, m).13C NMR: 20.6; 31.1;
31.2, 32.2; 48.0; 69.6; 74.3; 99.5; 117.8; 126.8, 127.2; 128.4;
129.3; 129.4; 130.2; 134.0; 142.7; 148.0; 164.5. IR (cmꢀ1):
2960; 1642; 1604; 1452; 1261; 999; 698. HRMS (IE, m/z):
½
a 2D4
ꢃ
¼ ꢀ31 (c 0.1012, CH2Cl2).
Procedure A with substrate 2: NiCl2 (2.6 mg, 0.02 mmol) and
(ꢀ)-1 (8 mg, 0.022 mmol) were placed in a Schlenk tube and
1.5 mL of dry DCM was added. The resulting mixture was stirred
for 1 h at rt. Then the substrate, 2 (37 mg, 0.2 mmol) previously
dissolved in 1.5 ml of dry DCM was added , followed by NFSI
(69 mg, 0.22 mmol) in one portion. After 3 h of stirring at rt the
crude mixture was filtered over a pad of silica gel and DCM re-
moved under reduced pressure. The conversion and enantioselec-
tivity were determined by GC analysis.
experimental: 627.3215 (M+H), calculated: 627.3223.
ꢀ61 (c 0.1034, CH2Cl2).
½
a 2D4
ꢃ
¼
4.1.1.5. Compounds 29a and 29b. In the first step SPANdiacid 27
(300 mg, 0.707 mmol) was placed in a Schlenk tube with 3 equiv of
triethylamine (296 ll, 2.121 mmol) and 8 mL of thionyl chloride.
The resulting dark mixture was stirred for 3 h at 60 °C, then the
volatiles were removed under vacuum. The crude diacyl chloride
was dissolved in 7 mL of DCM, then 3 equiv of triethylamine
Procedure B with substrate 2: To SPAN amine (ꢀ)-1 (7.3 mg,
0.02 mmol) dissolved in 1.5 mL of dry DCM in a Schlenk tube,
were successively added substrate 2 (37 mg, 0.2 mmol), previ-
ously dissolved in 1.5 mL of dry DCM, and NFSI (69 mg,
0.22 mmol) in one portion. After 18 h of stirring at rt the crude
mixture was filtered over a pad of silica gel and DCM was re-
moved under reduced pressure. The conversion and enantiose-
lectivity were determined by GC analysis. The NMR spectra of
isolated fluorinated products were similar to previously re-
ported compounds.
(296
l
l, 2.121 mmol) and 3 equiv of
L-valinol (219 mg,
2.121 mmol) (previously dissolved in 1 mL of DCM) were succes-
sively added. The resulting brown solution was stirred for 15 h at
rt. Then water was added, the aqueous layer was washed twice
with DCM, the organic layers were mixed, dried over MgSO4 and
the volatiles were removed under reduced pressure. The crude
product was pure by NMR and is used without further purification
for the next step.1H NMR: 0.75 (6H, t, J = 6.5 Hz); 0.82 (6H, t,
J = 6.9 Hz); 1.41 (12H, s); 1.45 (6H, s); 1.47 (6H, s); 1.6 (4H, m);
2.19 (2H, d, J = 14.4 Hz); 2.30 (2H, d, J = 14.3 Hz); 2.35 (6H, s);
2.36 (6H, s); 2.37 (2H, d, J = 14.4 Hz); 2.38 (2H, d, J = 14.3 Hz);
2.89 (2H, m); 3.11 (2H, m); 3.25 (2H, dd, J = 6.7 and 11 Hz); 3.47
(2H, m); 3.51 (2H, m); 3.66 (2H, m); 7.24 (2H, d, J = 1.9 Hz); 7.26
(2H, d, J = 1.9 Hz); 7.37 (4H, m); 7.66 (2H, d, J = 1.9 Hz); 7.72 (2H,
d, J = 1.9 Hz).
19F NMR (in CDCl3) profile of SPANamine 1 catalyzed fluorina-
tion of substrate 2:
Acknowledgments
This work was supported by grants from the Spanish govern-
ment MICINN: a ‘Ramon y Cajal’ contract (ZF), financial support
for projects CTQ2005-03416, CTQ2008-00683, Consolider Ingenio
2010 (Grant No. CSD2006_0003). We acknowledge the European
Union for a Marie Curie Chair of Excellence Grant (PWNMvL)
(MEXC-CT-2005-0023600).

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20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
pp m
After 30min
After 2h
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
-200
ppm
After 6h
After 12h
2004, JP 2004010555.; (d) Toullec, P.; Bonaccorsi, C.; Mezzetti, A.; Togni, A.
Proc. Nat. Am. Sci. 2004, 101, 5810; (e) Hamashima, Y.; Suzuki, T.; Takano, H.;
Shimura, Y.; Tsuchiya, Y.; Moriya, K.-I.; Goto, T.; Sodeoka, M. Tetrahedron 2006,
62, 7168; (f) Suzuki, S.; Furuno, H.; Yokohama, Y.; Inanaza, J. Tetrahedron:
Asymmetry 2006, 17, 504; (g) Lee, N. R.; Kim, S. M.; Kim, D. Y. Bull. Kor. Chem.
Soc. 2009, 30, 829; (h) Chambers, R. D.; Nakano, T.; Okazoe, T.; Sandford, G. J.
Fluorine Chem. 2009, 130, 792.
References
1. For review see: (a) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005,
475; (b) Oestreich, M. Angew. Chem., Int. Ed. 2005, 44, 2324; (c) Prakash, G. K. S.;
Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172; (d) Bobbio, C.; Gouverneur, V.
Org. Biomol. Chem. 2006, 4, 2065; (e) Shibata, N.; Ishimaru, T.; Nakamura, S.;
Toru, T. J. Fluorine Chem. 2007, 128, 469; (f) Brunet, V. A.; O’Hagan, D. Angew.
Chem., Int. Ed. 2008, 47, 1179; (g) Ma, J.-A.; Cahard, D. Chem. Rev 2008, 108, 1;
(h) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005; (i) Cahard,
D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev. 2010, 558; (j)
Valero, G.; Companyó, X.; Rios, R. Chem. Eur. J. 2011, 17, 2018.
7. (a) Ishimaru, T.; Shibata, N.; Reddy, D. S.; Horikawa, T.; Nakamura, S.; Toru, T.
Beilstein. J. Org. Chem. 2008, 4, 16; (b) Reddy, D. S.; Shibata, N.; Horikawa, T.;
Suzuki, S.; Nakamura, S.; Toru, T.; Motoo, S. Chem. Asian J. 2009, 4, 1411.
8. (a) Enders, D.; Hüttl, M. R. M. Synlett 2005, 991; (b) Steiner, D. D.; Mase, N.;
Barbas, C. F. Angew. Chem., Int. Ed. 2005, 44, 3706; (c) Marigo, M.; Fielenbach,
D.; Braunton, A.; Kjœrsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44,
3703; (d) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Kjœrsgaard, A.; Jørgensen,
K. A. Chem. Eur. J. 2006, 6039; (e) Beeson, T.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 8826; (f) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 15051.
9. (a) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728; (b)
Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001; (c)
Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K. L. J. Org. Chem. 2003, 68, 2494; (d)
Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. Synlett 2004, 2509; (e) Wang,
M.; Wang, B. M.; Shi, L.; Tu, Y. Q.; Fan, C.-A.; Wang, S. H.; Hu, X. D.; Zhang, S. Y.
Chem. Commun. 2005, 44, 5580; (f) Fukuzumi, T.; Shibata, N.; Sugiura, M.;
Nakamura, S.; Toru, T. J. Fluorine Chem. 2006, 127, 548; (g) Ramirez, J.; Huber, D.
P.; Togni, A. Synlett 2007, 1143; (h) Ishimaru, T.; Shibata, N.; Horikawa, T.;
Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47,
4157.
2. (a) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (b) Wang, X.; Lan, Q.; Shirakawa,
S.; Maruoka, K. Chem. Commun. 2010, 46, 321.
3. (a) Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703; (b)
Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007; (c) Ma, J.-A.;
Cahard, D. J. Fluorine Chem. 2004, 125, 1357; (d) Shibata, N.; Kohno, J.; Takai, K.;
Ishimaru, T.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2005,
44, 4204; (e) Shibatomi, K.; Tsuzuki, Y.; Nakata, S.-I.; Sumikawa, Y.; Iwasa, S.
Synlett 2007, 551; (f) Shibata, N.; Yasui, H.; Nakamura, S.; Toru, T. Synlett 2007,
1153; (g) Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. Organometallics 2007,
26, 5902; (h) Shibatomi, K.; Jpn Kokai Tokkyo Koho 2008, 1pp, JP 2006-
19502220060718.; (i) Shibatomi, K.; Tsuzuki, Y.; Iwasa, S. Chem. Lett. 2008, 37,
1098; (j) Frings, M.; Bolm, C. Eur. J. Org. Chem. 2009, 24, 4085; (k) Assalit, A.;
Billard, T.; Chambert, S.; Langlois, B. R.; Queneau, Y.; Coe, D. Tetrahedron:
Asymmetry 2009, 20, 593; (l) Kang, S. H.; Kim, D. Y. Adv. Synth. Catal. 2010, 352,
2783.
4. Sala, X.; García Suárez, E. J.; Freixa, Z.; Benet-Bulchholz, J.; Van Leeuwen, P. W.
N. M. Eur. J. Org. Chem. 2008, 6197.
10. Bunnage, M. E.; Davies, S. G.; Parkin, R. M.; Roberts, P. M.; Smith, A. D.; Withey,
J. M. Org. Biomol. Chem. 2004, 2, 3337.
5. While this manuscript was in preparation a publication appeared in which a
SPANbox was reported and successfully applied in asymmetric oxygenation: Li,
J.; Chen, G.; Wang, Z.; Zhang, R.; Zhang, X.; Ding, K. Chem. Sci. 2011, 2, 1141.
6. (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc.
2002, 124, 1453; (b) Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org.
Lett. 2003, 5, 3225; (c) Sodeoka, M.; Hamashima, Y.; Jpn Kokai Tokkyo Koho
11. Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076.
12. Brown, D. S.; Marples, B. A.; Smith, P.; Walton, L. Tetrahedron 1995, 51, 5587.
13. Moss, T. A.; Alba, A.; Hepworth, D.; Dixon, D. J. Chem. Commun. 2008, 2474.
14. Khumtaveeporn, K.; Ullmann, A.; Matsumoto, K.; Davis, B. G.; Jones, J. B.
Tetrahedron: Asymmetry 2001, 12, 249.