Rhodium-catalyzed enantioselective nucleophilic fluorination: Ring opening of oxabicyclic alkenes

Article abstract of DOI:10.1002/anie.201207356

Done with 'F'lair: Enantioselective fluorination was achieved by Rh ^I-catalyzed ring opening of oxabicyclic alkenes using Et ₃Na HF. The chiral fluorinated scaffolds were obtained under mild reaction conditions in standard glass vess

Full text of DOI:10.1002/anie.201207356

Angewandte
Chemie
DOI: 10.1002/anie.201207356
Asymmetric Synthesis
Rhodium-Catalyzed Enantioselective Nucleophilic Fluorination: Ring
Opening of Oxabicyclic Alkenes**
Jiangtao Zhu, Gavin C. Tsui, and Mark Lautens*
The application of organofluorine compounds in pharma-
ceuticals, agrochemicals, high performance materials, and
medical imaging [e.g., positron emission tomography (PET)]
agents has seen an explosive increase in the past decade.[1]
Great strides have been made for developing new methods to
introduce fluorine into organic molecules, particularly in the
À
emerging area of transition-metal-catalyzed C F bond for-
mation.[2] While aryl fluoride bond formation has been
extensively studied,[3] asymmetric aliphatic C F bond forma-
À
tion remains challenging and less developed.[4] In this regard,
the majority of the reported methods relied on using electro-
philic “F+” equivalents to achieve highly enantioselective
a fluorination of carbonyl-containing compounds by employ-
ing elegantly designed chiral metal complexes, Lewis acids,
and organocatalysts.[5] However, the disadvantages of using
electrophilic fluorine sources are their high costs, limited
reactivity choices, and lower specific activity in PET applica-
tions. In contrast, the use of more abundant and inexpensive
Scheme 1. Transition-metal-catalyzed enantioselective nucleophilic
fluorinations. HFIP=1,1,1,3,3,3-hexafluoroisopropyl alcohol.
nucleophilic “FÀ” equivalents such as metal fluorides or HF-
containing reagents becomes highly desirable and provides
complementary reactivity which can lead to useful fluorinated
scaffolds which are more amenable to 18F radiolabeling.[2a]
While racemic palladium- and iridium-catalyzed nucleophilic
allylic fluorinations have been successfully developed,[6] to the
best of our knowledge, only a few examples of transition-
metal-catalyzed enantioselective nucleophilic fluorination
methods exist. Doyle and co-workers have recently devel-
oped powerful protocols of this type of fluorination.[7] For
example, asymmetric palladium-catalyzed fluorination of
cyclic and acyclic allylic halides using AgF gave chiral allylic
fluorides (Scheme 1a). A salen/cobalt catalyst with an amine
cocatalyst led to enantioselective ring opening of epoxides
using benzoyl fluoride as a latent source of fluoride and
provided chiral fluorohydrins (Scheme 1b).[8] We herein
report the first rhodium-catalyzed asymmetric ring opening
(ARO) of oxabicyclic alkenes (1) using triethylamine trihy-
drofluoride (Et3N·3HF) as the source of nucleophilic fluorine
(Scheme 1c). The chiral ring-opened products 2 contain both
allylic fluoride and fluorohydrin moieties.[9,4d]
Our group has demonstrated that rhodium-catalyzed
ARO of strained bicyclic alkenes is a highly efficient and
enantioselective process for generating a functionalized dihy-
dronaphthalene core.[10] Chiral rhodium(I) complexes cata-
lyze the ring-opening reaction of oxa- and azabicyclic alkenes
with a variety of nucleophiles such as amines and alcohols in
high yield and enantioselectivity.[11] The products are gener-
ated by an SN2’ nucleophilic displacement of the bridgehead
leaving group with inversion to give the 1,2-trans product as
a single regio- and diastereomer.[10a]
[*] Dr. J. Zhu,[+] G. C. Tsui,[+] Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
The use of a halide as the nucleophile in ARO has not
been demonstrated, and the stereochemical outcome (trans/
cis) of the halogenated ring-opened product is unknown. We
envisioned that by employing a suitable fluoride nucleophile
and a chiral rhodium(I) catalyst, the ARO of 1 could lead to
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/
[+] These authors contributed equally to this work.
À
the direct construction of an aliphatic C F bond for the rapid
[**] We gratefully thank the NSERC, Merck Frosst, and Merck for an
Industrial Research Chair. We also thank the University of Toronto
for support of our program, Dr. Alan Lough (Chemistry Department,
University of Toronto) for single-crystal X-ray structure analysis, and
Solvias AG for the generous gift of chiral ligands. J.Z. thanks SIOC
for a postdoctoral fellowship. G.C.T. thanks NSERC for a postgrad-
uate scholarship.
synthesis of the chiral fluorinated scaffolds 2.
One major challenge lies in identifying the best fluoride
source because of the dual reactivity profile of fluoride
(nucleophile versus base). It is known that the nucleophilicity
of fluoride is significantly reduced in its solvated form,
whereas desolvated fluoride can act as a strong base which
causes a competitive elimination pathway.[2a,9a] To this end, we
began by reacting oxabenzonorbornadiene (1a) with a variety
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207356.
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of fluoride sources under rhodium(I) catalysis conditions
(Table 1). A large excess of KHF2, HF-pyridine (Olahꢀs
reagent), KF, or TBAF showed no reactivity (entries 1–4).
The conditions use by Kalow and Doyle failed to give any
Table 1: Optimization of rhodium(I)-catalyzed ARO of the oxabicyclic
alkene 1a with fluoride sources.
Entry Fluoride source
(equiv)
Ligand
dppf
T
t
Yield ee
[8C] [h] [%][a] [%][b]
1[c]
KHF2 (5.0)
HF-pyridine (5.0) dppf
80
80
80
80
80
17 <5
17 <5
17 <5
17 <5
17 <5
–
–
–
–
–
2[c]
3[c,e]
4[c,e]
5[c]
KF (5.0)
dppf
dppf
dppf
TBAF[g] (5.0)
benzoylfluoride/
HFIP/Et3N (5.0)
Et3N·3HF (3.0)
Et3N·3HF (3.0)
Et3N·3HF (2.0)
Et3N·3HF (1.0)
Et3N·3HF (3.0)
Et3N·3HF (3.0)
6[c]
7[d]
8[d]
9[d]
10[c]
11
dppf
80
17 48
0.5 88
0.5 79
17 57
17 61
17 <5
–
(R,S)-ppf-PtBu2 50
(R,S)-ppf-PtBu2 50
(R,S)-ppf-PtBu2 50
(R,S)-ppf-PtBu2 RT
98
98
98
98
–
none[f]
80
[a] Yield of isolated product. [b] Enantiomeric excess (ee) was deter-
mined by HPLC analysis using a chiral stationary phase. [c] 4 mol%
[{Rh(cod)Cl}2]/8 mol% ligand. [d] 2 mol% [{Rh(cod)Cl}2]/4 mol%
ligand. [e] Reaction was run in THF/H2O (20:1 v/v) to increase solubility.
[f] Reaction was run without rhodium catalyst and ligand. [g] Tetra-n-
butylammonium fluoride (TBAF) hydrate was used. dppf=1,1’-bis(di-
phenylphosphino)ferrocene, THF=tetrahydrofuran.
Scheme 2. Scope of oxabicyclic alkenes 1 in rhodium(I)-catalyzed ARO
with Et3N·3HF. [a] Rhodium-catalyzed ARO reaction conditions: sub-
strate 1 (0.2 mmol), Et3N·3HF (3.0 equiv), [{Rh(cod)Cl}2] (4 mol%),
(R,S)-ppf-PtBu2 (8 mol%), THF (0.1m), RT or 508C, 15 min to 2 h.
[b] Two-step sequence: ARO and subsequent hydrogenation: Pd/C
(10 mol%), H2 (1 atm), EtOAc (0.1m), RT, 1 h. [c] Yield of isolated
product. [d] Determined by HPLC analysis using a chiral stationary
phase. [e] Two-step sequence: ARO and subsequent hydrogenation:
tosylhydrazine (5.0 equiv), sodium acetate (10.0 equiv), THF/H2O
(1:1), reflux, 17 h. [f] The maximum yield of this product from the ARO
reaction was 50%.
product (entry 5).[8a] Commercially available Et3N·3HF
proved to be an effective fluorinating reagent and afforded
2a in 48% yield (entry 6).[12] With the use of the chiral
Josiphos ligand (R,S)-ppf-PtBu2 at a lower catalyst loading,
we were able to isolate 2a in good yield (88%) and excellent
enantioselectivity (98% ee; entry 7). The reaction was
complete at 508C after only 30 minutes. Lower conversions
were observed when the number of equivalents of Et3N·3HF
was decreased even after a prolonged reaction time (entries 8
and 9), but the ee values remained high. The reaction was
more sluggish at room temperature and the enantioselectivity
remained the same (entry 10), and a control experiment
showed no background ring-opening reaction in the absence
of the catalyst and ligand (entry 11). We also screened other
solvents, ligands, and catalysts. Cationic [Rh(cod)2OTf]
cyclic alkenes afforded the corresponding alkenyl fluoro-
hydrin products 2b, 2c, and 2 f in good yields and excellent
enantioselectivities at 508C within 1 hour. The oxabicyclic
alkenes bearing electron-donating groups such as methylene-
dioxy and dimethoxy groups were much more reactive and
the conversion was complete at room temperature after only
15 minutes.[14] However, the ring-opened products decom-
posed to 1-naphthol by elimination on silica gel during
column chromatography or after prolonged reaction time. To
circumvent this problem, we opted to reduce the double bond
produced after ring opening by using mild hydrogenation
conditions (10 mol% Pd/C, 1 atm H2, RT, 1 h) after a rapid
aqueous work-up, thus affording the stable alkyl fluorohydrin
products 3d and 3e, which were isolable by column chroma-
tography and had excellent enantioselectivities. A similar
protocol was also applied to obtain the dibromo-substituted
3 f. By using our previously reported regiodivergent resolu-
tion of unsymmetrical oxabicyclic alkenes,[15] the pyridine-
(cod = cycloocta-1,5-diene,
Tf = trifluoromethanesulfonyl)
was shown to be equally effective (76% yield, 98% ee).[13]
All reactions were run in standard glass vessels because of the
unique properties of Et3N·3HF compared to other harsh
fluorinating reagents.[12a]
We next examined a range of oxabicyclic alkenes (1)
under the optimized reaction conditions (Scheme 2). Reac-
tions of difluoro-, dimethyl-, and dibromo-substituted oxabi-
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containing fluorohydrin product 2g was obtained in 90% ee
as one of the two possible regioisomers from a racemic
unsymmetrical substrate.[16] In contrast, both regioisomers 3h
and 3h’ can be obtained in good enantioselectivities from the
racemic unsymmetrical oxabicyclic alkene.[17] The structurally
interesting triaryl fluorohydrin product 3i was isolated with
an excellent ee value after diimide reduction. The absolute
configuration of the ring-opened product and relative trans
stereochemistry of the F and OH groups was unambiguously
established by single-crystal X-ray analysis of compound 3d
(see the Supporting Information).[18]
To demonstrate the utility of the ring-opened product, the
saturated fluorohydrin (1R,2R)-3a was prepared in an ARO/
hydrogenation sequence and subjected to further transforma-
tions (Scheme 3). The ARO reaction of 1a was run on a larger
scale (4.0 mmol) at a higher concentration (0.4m), the catalyst
loading was decreased to 0.5 mol%, and only 1.0 equivalent
(1S,2R)-5 was synthesized with complete inversion of stereo-
chemistry at the benzylic position. Subsequent reduction
(Staꢁdinger reaction) and protection yielded chiral cis-b-
fluorobenzamide (1S,2R)-6, which complements the literature
report on trans-b-fluorobenzamide.[21]
In conclusion, we have successfully developed a rho-
dium(I)-catalyzed enantioselective nucleophilic fluorination
protocol by utilizing the asymmetric ring-opening (ARO)
reaction of oxabicyclic alkenes with triethylamine trihydro-
fluoride as the nucleophile. The method is mild, safe, efficient,
and highly enantioselective. Current limitations lie in the
substrate scope as nonbenzofused substrates, bridgehead-
substituted substrates, and azabicyclic alkenes were unreac-
tive under the reaction conditions. Certain substrates gave
reduced yields because of competitive elimination which led
to 1-naphthol formation. The exact nature of the fluoride
species in the reaction mechanism is still unclear and the
formation of trans products was not intuitive. Both cis- and
trans-ring-opened products are known and harder nucleo-
philes usually lead to cis products (fluorides are classically
considered as hard nucleophiles).[22] However, the observa-
tion of trans stereochemistry of the ring-opened products
suggested that the reaction followed a similar pathway to that
of soft nucleophiles (SN2’ nucleophilic displacement)[10a] and
ruled out the likelihood of fluorometallation as a mechanistic
pathway.
Received: September 12, 2012
Published online: November 5, 2012
Keywords: asymmetric synthesis · enantioselectivity · fluorine ·
.
homogeneous catalysis · rhodium
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