Iridium-catalyzed regio- and enantioselective allylic alkylation of fluorobis(phenylsulfonyl)methane

Article abstract of DOI:10.1039/b914315g

Highly regio- and enantioselective allylic alkylation of fluorobis(phenylsulfonyl)methane (FBSM) has been realized by [Ir(COD)Cl] ₂/phosphoramidite, affording enantiopure fluorobis(phenylsulfonyl) methylated compounds bearing a terminal alkene,

Full text of DOI:10.1039/b914315g

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Iridium-catalyzed regio- and enantioselective allylic alkylation
of fluorobis(phenylsulfonyl)methanew
Wen-Bo Liu,a Sheng-Cai Zheng,b Hu He,a Xiao-Ming Zhao,*b Li-Xin Daia and Shu-Li You*a
Received (in Cambridge, UK) 16th July 2009, Accepted 2nd September 2009
First published as an Advance Article on the web 15th September 2009
DOI: 10.1039/b914315g
Highly regio- and enantioselective allylic alkylation of fluorobis-
(phenylsulfonyl)methane (FBSM) has been realized by
[Ir(COD)Cl]2/phosphoramidite, affording enantiopure fluorobis-
(phenylsulfonyl)methylated compounds bearing a terminal alkene,
which could be converted to monofluoro-methylated ibuprofen in
just two steps without loss of the optical purity (95% ee).
of 1a and 1.1 equivalents of Cs2CO3, reaction of FBSM (3a)
with allylic carbonate 2a in DCM for 12 h gave a mixture of
4aa and 5aa in 92% yield with high levels of both branch-
selectivity (88/12) and enantioselectivity of 4aa (93% ee)
(entry 1, Table 1). Encouraged by these results, various bases
were examined. As listed in Table 1, several inorganic bases
such as K3PO4, NaH and KOAc, all led to good branch-
selectivity and enantioselectivity, except for Li2CO3
(entries 2–5, Table 1). In addition, the reaction proceeded
smoothly with organic bases such as urotropine, DABCO,
BSA, quinine, though not DBU (entries 6–10, Table 1). To our
great delight, the use of excess Cs2CO3 (2.2 equiv.) increased
greatly the regioselectivity, branched product 4aa was formed
exclusively with excellent enantioselectivity (94% ee) (entry 11,
Table 1). After testing different solvents such as CDCl3, THF,
ether, toluene and CH3CN, DCM was found to be the optimal
solvent (entries 11–17, Table 1).
Fluoroorganic compounds have exhibited unique physical,
chemical and biological properties.1 As a consequence, the
development of efficient methodology for the synthesis of
organofluorine compounds has attracted considerable attention
in organic synthesis, pharmaceutical chemistry and material
sciences.1,2 Various fluorination reactions have been
documented,3,4 and among these, fluoroalkylation reactions
represent a straightforward and powerful method to construct
fluorine-containing molecules. Their asymmetric versions are
particularly attractive and useful in medicinal chemistry.3,4 In
this context, compounds with a monofluoromethyl unit are of
great importance with regards to isostere-based drug design.5
Notably, with the significant pioneering studies by Shibata
and Toru,6 Hu,7 Prakash and Olah,8 monofluoro-bisphenyl-
sulfonylmethane (FBSM) has been demonstrated successfully
as a synthetic equivalent of CH2F. Particularly, palladium-
catalyzed asymmetric allylic alkylation of FBSM with
symmetrical allylic substrates was realized, providing the
access to monofluorinated ibuprofen.6a,9 In connection with
our research interest in iridium-catalyzed allylic alkylation
reactions,10,11 we envisioned iridium complexes could be
utilized for allylic alkylation of FBSM with 1,3-unsymmetrical
allylic substrates to afford the enantiopure fluorobis(phenyl-
sulfonyl)methylated compounds bearing a terminal alkene,
which would enable the subsequent transformation more atom
economical and efficient. Here, we report the highly regio- and
enantioselective iridium-catalyzed allylic alkylation of fluoro-
bis(phenylsulfonyl)methane and the synthesis of monofluorinated
ibuprofen and naproxen as a demonstration of the utility of
the current methodology.
Under the conditions listed in entry 11, Table 1, different
chiral ligands were evaluated, and the results are summarized
in Table 2. Phosphoramidite ligands 1b and 1c, varying the
substituents on the amine moiety, afforded the products in
slightly lower yields but with excellent ees (entries 1–3,
Table 2). Unfortunately, ligands 1d and 1f were not effective
for the reaction (entries 4 and 6, Table 2). The reaction with
1e, a diastereoisomer of 1a, led to the product in a lower yield
with decreased selectivity, indicating the match of chiralities in
(S,S,Sa)-1a (entry 5, Table 2). Interestingly, Phox ligand 1g
could also give 4aa in moderate yield with 82% ee (entry 7,
Table 2).
Under the optimized reaction conditions [2 mol% of
[Ir(COD)Cl]2, 4 mol% of 1a, 250 mol% of Cs2CO3, DCM at rt],
the generality of Ir-catalyzed allylic alkylation of fluorobis-
(phenylsulfonyl)methane was examined. As summarized in
Table 3, aryl allylic carbonates 2b–f with electron-donating
groups such as p-OMe, m-OMe, p-Me and p-iBu on the phenyl
ring all gave excellent yields with 91–95% ee (entries 2, 3, 5
and 6, Table 3). The ortho-methoxy phenyl substrate 2d can
also be tolerated but with moderate enantioselectivity
(4ad, 86% yield, 70% ee, entry 4, Table 3). The unfavorable
ortho substituent effect is in agreement with the previous
At the outset, we utilized
a well-developed iridium
catalytic system including [Ir(COD)Cl]2 and 1a as the catalyst
(Fig. 1). In the presence of 2 mol% of [Ir(COD)Cl]2, 4 mol%
a State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China.
E-mail: slyou@mail.sioc.ac.cn; Fax: (+86) 21-54925087
b Department of Chemistry, Tongji University, 1239 Siping Lu,
Shanghai 200092, China. E-mail: xmzhao08@mail.tongji.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds, CIF file of (S)-4ah.
CCDC 730835. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b914315g
Fig. 1 Chiral ligands 1a–g.
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Table
1
Optimizing reaction conditions for Ir-catalyzed allylic
Table 3 The substrate scopea
alkylation of FBSMa
Entry
R
t/h 4 (%)
4/5b
eec (%)
1d
2
3
4
C6H5
10 4aa, 89 (79) 499/1 94 (499)
Entry Baseb
Solvent t/h Yield (%) 4aa/5aac eed (%)
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-iBuC6H4
3-ClC6H4
4-BrC6H4
4-CF3C6H4
12 4ab, 95
10 4ac, 91
24 4ad, 86
10 4ae, 94
10 4af, 96
48 4ag, 41
99/1
95/5
499/1 70
97/3
97/3
499/1 94
95
91
1
2
3
4
Cs2CO3
Li2CO3
K3PO4
NaH
DCM
DCM
DCM
DCM
DCM
12 92
72 Trace
17 77
40 28
36 44
72 30
48 57
48 Trace
18 91
24 93
10 89
16 56
10 87
24 18
22 22e
88/12
—
93
—
93
93
90
91
92
—
94
90
94
95
90
89
—
—
—
5
6
94
95
85/15
87/13
85/15
84/16
93/7
7e
8d
9
5
KOAc
17 4ah, 66 (54) 499/1 92 (499)
6
Urotropine DCM
40 4ai, 60
499/1 91
499/1 93
499/1 96
7
8
9
DABCO
DBU
BSA
DCM
DCM
DCM
DCM
DCM
DCE
10
11
12
13
14f
6-MeO-2-naphthyl 15 4aj, 94
—
2-Thienyl
(E)-1-Propenyl
Me
14 4ak, 28
82/18
88/12
499/1
499/1
499/1
95/5
499/1
499/1
—
5
8
4al, 52
4am, 92
84/16
87/13
75
89
10
11
12
13
14
15
16
17
Quinine
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
C6H5
13 4ba, 42
499/1 90
CDCl3
THF
Et2O
a
Reaction conditions: 2 mol% of [Ir(COD)Cl]2, 4 mol% of (S,S,Sa)-
1a, 250 mol% of Cs2CO3, 110 mol% of 2 and 100 mol% 3 (0.1M) in
DCM at rt. Determined by 1H NMR of the crude reaction mixture.
b
Toluene 24 14e
c
d
The ee of 4 was determined by chiral HPLC analysis. Values in
MeCN
72 NRf
e
parenthesis were those obtained after recrystallization. Under
f
reflux. HCF(SO2-1-naphthyl)2 was used.
a
Reaction conditions: 2 mol% of [Ir(COD)Cl]2, 4 mol% of (S,S,Sa)-
b
1a, 110 mol% of 2a and 3a (0.1 M) at rt. 110 mol% for entries 1–10;
220 mol% for entries 11–17. Determined by 1H NMR of the crude
c
d
reaction mixture. Determined by chiral HPLC analysis (Chiralcel
by recrystallization. An X-ray crystallographic analysis
(see ESIw) of enantiopure 4ah disclosed the absolute configuration
as S (Fig. 2). The stereochemistry of the current reaction with
(S,S,Sa)-1a parallels that of our previous studies.10a,c
e
OD-H column). NMR yield. NR = no reaction.
f
Table 2 Screening the chiral ligandsa
To test the practicality of the current methodology, a gram
scale reaction was carried out for allylic carbonate 2f. To our
delight, the reaction proceeded smoothly and 4af was obtained
in 97% yield and 94% ee (Scheme 1). To explore the synthetic
utility of the products obtained here, the sulfonyl groups of 4af
were removed by treatment with activated magnesium in
methanol, and subsequent oxidation with RuCl3 led to 6af.12
Both enantiomers of 4af were converted to the mono-
fluorinated ibuprofen in high yields without loss of the optical
purity.13 The highly shortened synthetic route (two vs. four steps)
is likely due to that the desulfonyl conditions, Mg/MeOH,
could be tolerated by the isolated terminal alkene in product 4,
but not the conjugated double bond.6a Notably, the
RuCl3 oxidation is not suitable for the synthesis of mono-
fluorinated naproxen, which was successfully synthesized by
dihydroxylation, oxidation with sodium periodate, and then
Pinnick oxidation14 (Scheme 2).
Entry
Ligand
t/h
Yield (%)
4aa/5aa
ee (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
10
22
12
48
48
48
16
72
89
61
76
NR
42
NR
48
499/1
499/1
499/1
—
89/11
—
94
92
95
—
65
—
82
—
1g
1h
499/1
—
NR
a
Reaction conditions: as listed in entry 11, Table 1.
iridium-catalyzed asymmetric allylic substitution reactions.10b,c
Allylic carbonates 2g–i bearing electron-withdrawing groups
(m-Cl, p-Br and p-CF3) were tolerated well to furnish the
fluorobis(phenylsulfonyl)methylated products in moderate
yields with high regio- and enantioselectivities (entries 7–9,
Table 3).
The reaction of 6-methoxynaphthyl allylic carbonate with
3a underwent well to afford 4aj in 94% yield with 93% ee
(entry 10, Table 3). Reaction of 2-thienyl substituted allylic
carbonate 2k led to 4ak in a lower yield mainly due to the
decomposition of the substrate under the reaction conditions
(entry 11, Table 3). Aliphatic allylic carbonates 2l and 2m were
both suitable substrates (entries 12 and 13, Table 3). Notably,
when the steric bulky nucleophile HCF(SO2-1-naphthyl)2 (3b)
was used, 4ba was smoothly obtained in moderate yield with
excellent selectivity (entry 14, Table 3).
To determine the absolute configuration of the product, the
enantiopure bromo-containing compound 4ah was obtained
Fig. 2 X-Ray structure of (S)-4ah (thermal ellipsoids are set at 30%
probability).
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In summary, we found that [Ir(COD)Cl]2/phosphoramidite
1a is an efficient catalytic system for highly regio- and enantio-
selective allylic alkylation of fluorobis(phenylsulfonyl)methane.
The monofluoromethylated products could be transformed to
the fluorobis(phenylsulfonyl)methylated ibuprofen family in a
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nucleophiles, see: (a) M. Nakamura, A. Hajra, K. Endo and
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We gratefully acknowledge the NSFC (20872159, 20821002
and 20942003), National Basic Research Program of China
(973 Program 2009CB825300), and Innovative Program of
Shanghai Education Committee (09ZZ36) for generous financial
support.
´
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This journal is The Royal Society of Chemistry 2009
6606 | Chem. Commun., 2009, 6604–6606