Iron(iii)-salan complexes catalysed highly enantioselective fluorination and hydroxylation of β-keto esters and N-Boc oxindoles

Article abstract of DOI:10.1039/c4cc01631a

Chiral iron(iii)-salan complexes catalysed highly enantioselective α-fluorination and α-hydroxylation of β-keto esters and N-Boc oxindoles to give the corresponding products in high yields and good-to-excellent ee values under mild reaction conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01631a

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Iron(III)–salan complexes catalysed highly
enantioselective fluorination and hydroxylation
of b-keto esters and N-Boc oxindoles†
Xin Gu,a Yan Zhang,a Zhen-Jiang Xu*a and Chi-Ming Che*ab
Cite this: Chem. Commun., 2014,
50, 7870
Received 4th March 2014,
Accepted 27th May 2014
DOI: 10.1039/c4cc01631a
www.rsc.org/chemcomm
Chiral iron(III)–salan complexes catalysed highly enantioselective
In our endeavour to develop practical iron-catalysed organic
a-fluorination and a-hydroxylation of b-keto esters and N-Boc reactions,10 we are interested in iron complexes bearing chiral
oxindoles to give the corresponding products in high yields and tetradentate ligands that can easily be modified.11 To introduce
good-to-excellent ee values under mild reaction conditions.
new types of chiral tetradentate ligands to iron catalysis, we are
attracted to the bipyrrolidine-based salan ligands recently
Metal-catalysed C–H functionalization is a useful tool that can be reported by Kol and co-workers.12 Such salan ligands with the
used for the straightforward synthesis of organic compounds with rigid bipyrrolidine backbone have been employed to prepare
complexity.1 Over the past decades, remarkable accomplishments chiral, six-coordinate complexes of Ti,12 Zr12 and Mo13 with single
on C–H activation/functionalization catalysed by noble metal diastereomers for polymerization of 1-hexene and epoxidation of
complexes have been reported.2 Iron is an environmentally alkenes. And the chiral bipyrrolidine backbone could be synthe-
benign and the most earth abundant transition metal; iron- sized in gram scale (B55% overall yield) following the method in
catalysed C–H functionalization has been receiving a growing the literature14 and is commercially available. Herein we report
interest.3 The C–H transformations catalysed by iron com- the synthesis of a series of chiral iron complexes of bipyrrolidine-
plexes3,4 by means of oxidation,4a,d carbene4b and nitrene4e, f,h based salan ligands, and the application of these chiral iron
insertion, and coupling reactions4c,g have shown great promise complexes for enantioselective fluorination of b-keto esters and
in practical organic synthesis.
N-Boc oxindoles, and also enantioselective hydroxylation of b-keto
The asymmetric a-functionalization of carbonyl compounds5 esters, with isolated product yields of up to 99% and with an
such as b-keto esters and N-Boc oxindoles can lead to diverse enantioselectivity of up to 97% ee.
functionalized products, and various catalytic systems with high
At the outset, the iron(III) complexes of different tetradentate
or excellent enantioselectivity, including a-fluorination6 and ligands, including the cyclohexane-based salen complexes 1a–1c,15
a-hydroxylation7 using metal catalysts6a,c,d,g,h,k,l,7a–c,e or organo- the cyclohexane-based salan complex 211b and the bipyrrolidine-
catalysts,6b,e, f,i, j,7d have been developed. In this area, it is note- based salan complexes 3a–3c (Fig. 1), were prepared in moderate-
worthy that iron catalysts are less explored; only recently an to-good yields by refluxing the corresponding ligands with FeCl3
elegant iron-catalysed asymmetric a-azidation of b-keto esters in methanol (see the ESI† for details). The structure of 3c was
and oxindoles was reported by Gade and co-workers.8 Beller and determined using X-ray crystallography (Fig. 2); this complex adopts
co-workers reported the a-hydroxylation of b-keto esters with a five-coordinate geometry, which may facilitate its reaction with
H2O2 catalysed by simple iron salts such as FeCl3Á6H2O;9 the the substrates bearing two binding groups to give a cis-configured
enantioselective a-hydroxylation and a-fluorination of carbonyl six-coordinate intermediate with the dissociation of the Cl ligand.
compounds catalysed by iron complexes remain to be developed.
The catalytic fluorination reactions were initially explored using
cyclic b-keto ester 4a as the model substrate and N-fluorobenzene
sulfonamide (NFSI, 1.5 equiv.) as a fluorination reagent, in the
presence of 5 mol% of the iron complexes in dichloromethane
(DCM) with 4 Å MS at room temperature. Complexes 1a–1c gave the
a-fluorination product 5a in high yields but with low-to-moderate
ee values (entries 1–3, Table S1 in the ESI†). With Co(acac)2
(10 mol%) + Jacobson’s salen ligand (10 mol%)16 as the catalyst,
5a was obtained in only 45% yield and 38% ee (entry 4, Table S1,
ESI†). For the structurally flexible complex 2, nearly racemic 5a
a Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute
of Organic Chemistry, 354 Feng Lin Road, Shanghai, China.
E-mail: xuzhenjiang@mail.sioc.ac.cn, cmche@hku.hk; Fax: +852 2857-1586;
Tel: +852 2859-2154
b Department of Chemistry and State Key Laboratory of Synthetic Chemistry,
The University of Hong Kong, Pokfulam Road, Hong Kong, China
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization. CCDC 988873. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4cc01631a
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Table 1 Optimization of the fluorination reaction conditionsa
Entry
Ag salt
Solvent
Time (h)
Yieldb (%)
eec (%)
1
—
—
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
Toluene
THF
MeCN
MeOH
MeCN
MeCN
6
6
2.5
2.5
2.5
2
2
2.5
2
2
2
96
92
96
95
92
93
97
95
94
98
93
97
95
96
96
87
45
92
88
89
89
93
93
92
90
93
94
91
97
96
2d
3
4
5
6
AgOTf
AgPF6
AgSbF6
AgBF4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
7
8
9e
Fig. 1 Chiral iron complexes 3 prepared in this work, along with complexes
1 and 2.
10e
11e
12e
13e,f
14e,f
15e,f,g
1
2
3
5
a
Reaction conditions: substrates (0.2 mmol), 3c (5 mol%), NFSI
(0.3 mmol), 4 Å MS (80 mg) and the corresponding Ag salt (5 mol%)
were stirred in the solvent (1.5 mL) at room temperature under an Ar
b
c
atmosphere. Isolated yield. Determined by using chiral HPLC.
d
g
e
f
Without 4 Å MS. Using 0.24 mmol of NFSI. Reaction at 0 1C.
Using 2 mol% of the catalyst and 2 mol% Ag salt.
Fig. 2 X-ray crystal structure of 3c.
excellent yields (up to 99%) and ee values (up to 97%). The
size of the ester group played an important role, as larger
was produced (entry 5, Table S1, ESI†). Interestingly, complexes groups led to better enantioselectivity than the smaller ones
3a–3c resulted in significantly improved ee values (entries 6–8, (5a, 5k vs. 5h–5j). The six-membered ring b-keto ester 4l also
Table S1, ESI†), in contrast to the absence of asymmetric underwent the reaction well, affording 5l in 96% yield and
induction of the molybdenum bipyrrolidine-based salan 69% ee. Cyclic b-keto esters 4m and 4n were also suitable
catalyst for alkene epoxidation,13 and 3c gave the best result substrates for the reaction, and the products 5m and 5n were
of 96% product yield and 87% ee (entry 8, Table S1, ESI†).
obtained in high yields and ee. It is notable that the non-cyclic
With 3c as the catalyst, various common fluorination reagents b-keto esters 4o and 4p were fluorinated to afford 5o and 5p in
were screened, and NSFI gave the best results in terms of both high yields and ee. The less reactive di-ester 4q underwent the
product yield and ee value. The presence of 4 Å molecular sieves reaction to afford 5q in a good yield albeit in moderate ee.
was essential to achieve high enantioselectivity (Table 1, entries 1
3-Fluorooxindoles have broad applications in medicinal
and 2). Addition of a silver salt sufficiently accelerated the chemistry,6k and there are a few reports on metal-catalysed
reaction (Table 1, entries 3–7), and, among the several silver enantioselective fluorination of N-Boc oxindoles to give the
salts examined, AgClO4 afforded the best result of 97% product corresponding 3-fluorooxindoles.6d,g,k In our effort to expand this
yield and 93% ee (Table 1, entry 7). The acceleration by the type of reaction to iron catalysis, and after optimizing reaction
addition of silver salts can be attributed to the enhanced Lewis conditions (see Tables S2 and S3 in the ESI† for details), we
acidity of the in situ generated cationic iron complex, thereby examined the fluorination of N-Boc oxindoles 6a–6k using NFSI in
facilitating the binding of substrate 4a to the iron catalyst. Et2O at 0 1C in the presence of AgClO4 using 3c or 3d as a catalyst
Lowering the amount of NFSI from 1.5 equiv. to 1.2 equiv. gave (Table 3). The 3-methyl oxindoles 6a–6d were efficiently fluorinated
nearly the same result albeit with a little longer reaction time to give 3-fluoro oxindoles 7a–7d in 82–94% yields and 88–96% ee
(Table 1, entry 8). And the reaction was tolerant to various (Table 3, entries 1–4). N-Boc oxindoles 6e–6h with larger alkyl
common organic solvents (Table 1, entries 8–13). Lowering the substituents also underwent the reaction well, and 7e–7h were
reaction temperature to 0 1C improved the ee value slightly obtained in high yields and good-to-excellent ee, albeit with longer
(Table 1, entry 14). A loading of 2 mol% of 3c also gave reaction times (Table 3, entries 5–8). For 3-aryl oxindoles 6i–6k,
satisfactory results (Table 1, entry 15).
catalyst 3d gave better results than 3c, affording 7i–7k in high yields
With the optimized conditions and using 2 mol% of 3c, the and good ee (Table 3, entries 9–11).
fluorination of various b-keto esters 4b–4q was investigated;
The iron–salan complex 3 can also catalyse enantioselective
the corresponding products 5b–5q are depicted in Table 2. a-hydroxylation to afford a-hydroxy-b-keto esters, a type of
Incorporation of substituent(s) into the phenyl ring of 4a had biologically important molecules.7 Optimization of the reaction
little impact on the reaction, and 5b–5g were obtained in conditions was carried out using the cyclic b-keto ester 4a as
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Table 2 Enantioselective fluorination of b-keto esters catalysed by iron–
salan complex 3ca
Table 4 Enantioselective hydroxylation of b-keto esters catalysed by
iron–salan complex 3ca
a
Reaction conditions: substrates (0.2 mmol), cat. (5 mol%), oxidant
(0.24 mmol), 4 Å MS (80 mg), DCM (1.5 mL) and AgClO4 (7.5 mol%)
were stirred at À10 1C under an Ar atmosphere.
(see Table S4 in the ESI†). Complex 3c was found to be the catalyst
of choice, and the optimized reaction conditions correspond to the
use of AgClO4 as the additive, DCM as the solvent, and 2-(phenyl-
sulfonyl)-3-( p-nitrophenyl)-oxaziridine as the oxidant at a reaction
temperature of À10 1C. Under these conditions, the 3c-catalysed
reaction afforded excellent product yields of up to 97% and good ee
of up to 87% (Table 4, 8a–8f) for the b-keto ester substrates having
either an electron-donating or an electron-withdrawing group on
the phenyl ring. The b-keto esters with a simple five-membered ring
also gave good results (Table 4, 8g and 8h). The six-membered ring
cyclic b-keto ester underwent the reaction to afford the a-hydroxy
product in moderate ee (Table 4, 8i).
a
Reaction conditions: substrates (0.1 mmol), 3c (2 mol%), AgClO4
(2 mol%) 4 Å MS (40 mg) and NFSI (0.12 mmol) were stirred in MeCN
at room temperature for 10 h under an Ar atmosphere.
Table 3 Enantioselective fluorination of N-Boc oxindoles catalysed by
iron–salan complexes 3c and 3da
A plausible mechanism for the iron-catalysed a-functionalization
of b-keto esters, with a-fluorination as example, is depicted in Fig. 3,
wherein the chiral iron–salan complex acts as a Lewis acid to activate
the substrate by coordination of the two carbonyl groups to Fe(III) to
give a 6-coordinate iron species. Due to the rigid bipyrrolidine
backbone, a relatively stable ‘chiral-at-iron’ intermediate is favoured,
thus high ee is obtained when the intermediate reacts with NFSI to
afford the fluorinated product. To shed insight into the reaction
mechanism, we examined the binding interaction between the Fe
catalyst and substrate using high resolution ESI-MS. Upon addition
Entry R1/R2
Substrate Cat. Time (h) Yieldb (%) eec (%)
1
2
3
4
Me/H
Me/Me
Me/OMe
Me/F
6a
6b
6c
6d
6e
6f
6g
6h
6i
3c
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3
6
3
4
9
9
10
8
3
3
7a : 94
7b : 89
7c : 82
7d : 84
7e : 94
7f : 84
7g : 87
7h : 88
7i : 93
7j : 88
7k : 86
96
94
88
93
93
91
85
96
85
82
83
5
6
7
8
Et/H
nPr/H
iBu/H
Bn/H
9
10
11
Ph/H
p-MeC6H4/H 6j
p-FC6H4/H 6k
À
of substrate 4e to an acetonitrile solution of 3c with ClO4 as a
counter anion, a species with m/z 941.4 and an isotopic pattern that
matched the formulation of the adduct formed between the depro-
tonated form of 4e with 3c was detected (see Fig. S1 in the ESI†),
thereby lending support to the intermediate in the course of the
catalysis depicted in Fig. 3.
10
a
Reaction conditions: substrate (0.2 mmol), cat. (5 mol%), NFSI
(0.24 mmol), 4 Å MS (80 mg) and Et2O (1.5 mL) and corresponding
b
additive were stirred at 0 1C under an Ar atmosphere. Isolated yield.
c
Determined by using chiral HPLC.
In conclusion, a series of chiral iron(III)–salan complexes with a
substrate by screening oxidants and iron complexes, with the bipyrrolidine backbone have been prepared. These iron complexes
effect of additive, temperature, and solvent being considered can catalyse asymmetric a-fluorination and a-hydroxylation of
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This work was supported by grants from the Innovation and
Technology Commission (HKSAR, China) to the State Key
Laboratory of Synthetic Chemistry, the External Cooperation
Program of the Chinese Academy of Sciences (CASGJHZ200816),
NSFC (21272197 and 21102162), and the CAS-Croucher Funding
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