Consecutive iridium catalyzed C-C and C-H bond forming hydrogenations for the diastereo- and enantioselective synthesis of syn-3-fluoro-1-alcohols: C-H (2-fluoro)allylation of primary alcohols

Article abstract of DOI:10.1039/c2cc31743e

Commercially available (2-fluoro)allyl chloride serves as an efficient allyl donor in highly enantioselective iridium catalyzed carbonyl (2-fluoro)allylations from the alcohol or aldehyde oxidation level via transfer hydrogenation. Diastereoselective Crab

Full text of DOI:10.1039/c2cc31743e

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COMMUNICATION
Consecutive iridium catalyzed C–C and C–H bond forming
hydrogenations for the diastereo- and enantioselective synthesis of
syn-3-fluoro-1-alcohols: C–H (2-fluoro)allylation of primary alcoholsw
Abbas Hassan, T. Patrick Montgomery and Michael J. Krische*
Received 8th March 2012, Accepted 9th March 2012
DOI: 10.1039/c2cc31743e
Commercially available (2-fluoro)allyl chloride serves as an
efficient allyl donor in highly enantioselective iridium catalyzed
carbonyl (2-fluoro)allylations from the alcohol or aldehyde
oxidation level via transfer hydrogenation. Diastereoselective
Crabtree hydrogenation of the resulting homoallylic alcohols
provides syn-3-fluoro-1-alcohols.
Scheme 1 Synthesis of syn-3-fluoro-1-alcohols via consecutive C–C
Organofluorine compounds represent over 20% of approved
pharmaceutical agents and 30–40% of commercially available
agrochemicals.1 The importance of organofluorine compounds,
along with the fact that approximately 80% of the small molecule
drugs entering the market are estimated to contain one or more
chiral centers,2 have driven development of enantioselective
methods for the preparation of fluorinated compounds.3 Under
the conditions of C–C bond forming transfer hydrogenation,4,5
we recently reported an enantioselective iridium catalyzed
carbonyl (a-trifluoromethyl)allylation from the alcohol or
aldehyde oxidation level.5k Given the commercial availability
of (2-fluoro)allyl chloride, corresponding carbonyl (2-fluoro)-
allylations were considered. Remarkably, despite decades of work
on enantioselective carbonyl allylation,6 enantioselective carbonyl
(2-fluoro)allylations have not been reported. Here, under the
conditions of iridium catalyzed transfer hydrogenation, we
report the first enantioselective (2-fluoro)allylations, which are
achieved with equal facility from the alcohol or aldehyde
oxidation level. These adducts participate in diastereoselective
Crabtree hydrogenation,7 enabling the synthesis of syn-3-
fluoro-1-alcohols via consecutive C–C and C–H bond forming
hydrogenations (Scheme 1).
and C–H bond forming hydrogenations.
Scheme 2 More reactive chloride leaving groups compensate for
decreased stability of p-complex.
olefin substitution.8 In recently established catalytic C–C couplings
of methallyl chloride,5l it was found that use of a more reactive
leaving group in the form of chloride compensates for the shorter
lifetime associated with more highly substituted olefin-iridium
complexes. To probe the expansion of substrate scope potentially
availed by this effect, and given the aforementioned significance of
organofluorine compounds, a study on the use of (2-fluoro)allyl
chloride as an allyl donor was undertaken (Scheme 2).
Olefin coordination is a prerequisite to the ionization
of allylic leaving groups by low valent transition metals.
Consequently, in iridium catalyzed carbonyl allylations employing
allylic carboxylates, allyl donors that incorporate monosubstituted
olefins are generally required, as the stability of late transition
metal-olefin p-complex decreases with increasing degree of
Studies began with a preliminary screen of (2-fluoro)allyl
chloride and alcohol 2g using the chromatographically isolated
cyclometallated iridium p-allyl complex of 4-cyano-3-nitrobenzoic
acid and BIPHEP under conditions optimized for the reaction
of methallyl chloride.5l Although the product 4g was obtained
in good isolated yield, competing defluorination to form 5g was
observed. Attempts were made to attenuate this side reaction.
Variation of solvent, concentration and base provided no improve-
ment beyond the initially applied conditions, which involve THF
(1.0 M) and K3PO4 (100 mol%). Reaction temperature had a more
Department of Chemistry and Biochemistry, University of Texas at Austin,
Austin, TX 78712, USA. E-mail: mkrische@mail.utexas.edu;
Fax: +1 613 9418447; Tel: +1 512 2325892
w Electronic supplementary information (ESI) available: Characterization
data for all new compounds (1H NMR, 13C NMR, IR, HRMS, [a]).
Absolute stereochemical assignment of 6g by single crystal X-ray
diffraction. CCDC 867899. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2cc31743e
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4692 Chem. Commun., 2012, 48, 4692–4694
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Table 1 Enantioselective iridium catalyzed (2-fluoro)allylation from
the alcohol or aldehyde oxidation levela
Entry Product
[o] Level
Alcohol
Y [%] 4a (5a) ee [%]
76 (10)
Scheme 3 Preparation of iridium complex Ir-Cat-I.
99b
99b
98b
98b
99b
98b
98c
98c
98c
98c
95c
96c
99c
significant impact. For allylic and benzylic alcohols, which
dehydrogenate and, hence, couple at lower temperature, reactions
conducted at 40 1C were optimal in terms of maximizing product
formation and minimizing defluorination. For aliphatic alcohols,
the optimal reaction temperature was determined to be 60 1C.
To assess whether these trends in reactivity translate to
enantioselective processes, the chiral complex Ir-Cat-I (Scheme 3),
which is isolated by conventional silica gel chromatography,
was prepared and assayed in the coupling of (2-fluoro)allyl
chloride to alcohols 2a–2i. To our delight, aliphatic alcohols
2a–2c, allylic alcohols 2d–2f and benzylic alcohols 2g–2i
participate in highly enantioselective C–C coupling to furnish
the corresponding products of (2-fluoro)allylation 4a–4i. In
general, the products of (2-fluoro)allylation 4a–4i may be
separated from the defluorination products 5a–5i by silica gel
chromatography. However, to ensure an accurate evaluation of
the product distribution, 4a–4i and 5a–5i were isolated as mixtures
(Table 1). An equivalent set of adducts 4a–4i may be generated
from aldehydes 3a–3i using isopropanol as the terminal reductant
under otherwise identical conditions. Comparable isolated
yields and enantioselectivities are observed. Thus, carbonyl
(2-fluoro)allylation may be accomplished from the alcohol or
aldehyde oxidation level (Table 1).
1
Aldehyde 61 (5)
Alcohol 65 (6)
Aldehyde 55 (6)
Alcohol 89 (5)
Aldehyde 65 (6)
Alcohol 76 (4)
Aldehyde 74 (3)
Alcohol 80 (5)
2
3
4
5
6
Aldehyde 93 (4)
Alcohol
Aldehyde 74 (3)
Alcohol 86 (7)
75 (4)
With adducts 4a–4i in hand, methods for diastereoselective
hydrogenation were explored. Reduction of 4g occurs efficiently
using palladium on carbon, however, the saturated product 6g
forms as a 1 : 1 mixture of diastereomers. In contrast, using the
Crabtree catalyst,7 hydrogenation of 4g at 25 1C provides 6g as a
6 : 1 mixture of diastereomers favouring the syn-diastereomer.
Under these conditions, vinyl fluorides 4a–c and 4g were converted
to the syn-3-fluoro-1-alcohols 6a–c and 6g, respectively (Scheme 4).
In these experiments, it was found that diastereoselectivity
improved with lower temperature, lower loadings of the
Crabtree catalyst and higher dilution. Fortuitously, the syn-3-
fluoro-1-alcohol 6g is crystalline, allowing relative and absolute
stereochemical assignment via single crystal X-ray diffraction
analysisw by the anomalous dispersion method. On this basis,
the absolute stereochemistry of (2-fluoro)allylation products
4a–4i is assigned.
7
8
Aldehyde 89 (5)
Alcohol 81 (3)
99c
99c
Aldehyde 88 (5)
Alcohol 65 (5)
Aldehyde 73 (5)
99c
99c
99c
9
a
Products 4 and 5 are isolated as mixtures, but were separated for the
purpose of characterization. See Supporting Information for further
b
c
details. 60 1C. 40 1C.
In summary, using commercially available (2-fluoro)allyl
chloride, direct enantioselective iridium catalyzed C–H (2-fluoro)-
allylation of primary alcohols 2a–2i is achieved. Corresponding
aldehydes 3a–3i participate in carbonyl (2-fluoro)allylation to
furnish an identical set of adducts 4a–4i in the presence of
isopropanol under otherwise identical conditions. Diastereo-
selective Crabtree hydrogenation of the resulting vinyl fluoride
containing homoallylic alcohols 4a–c and 4g provides syn-3-fluoro-
1-alcohols 6a–c and 6g, respectively. Thus, using consecutive C–C
and C–H bond forming hydrogenations, primary alcohols are
converted to chiral fluorine containing building blocks in the
Scheme 4 Synthesis of syn-3-fluoro-1-alcohols 6a–c and 6g via Crab-
tree hydrogenation of vinyl fluorides 4a–c and 4g, respectively.
c
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absence of stoichiometric metallic reagents or stoichiometric
organic byproducts.
and M. J. Krische, Chem. Commun., 2009, 7278; (d) J. F. Bower and
M. J. Krische, Top. Organomet. Chem., 34, 107; (e) A. Hassan and
M. J. Krische, Org. Process Res. Dev., 2011, 15, 1236.
Acknowledgement is made to the Robert A. Welch Foundation
(F-0038), the NIH-NIGMS (RO1-GM069445) and the University
of Texas at Austin, Center for Green Chemistry and Catalysis
for partial support of this research. The Higher Education
Commission of Pakistan is acknowledged for graduate student
fellowship support (AH).
5 For enantioselective carbonyl allylation via iridium catalyzed C–C
bond forming transfer hydrogenation, see: (a) I. S. Kim, M.-Y. Ngai
and M. J. Krische, J. Am. Chem. Soc., 2008, 130, 6340; (b) I. S. Kim,
M.-Y. Ngai and M. J. Krische, J. Am. Chem. Soc., 2008, 130, 14891;
(c) I. S. Kim, S. B. Han and M. J. Krische, J. Am. Chem. Soc., 2009,
131, 2514; (d) S. B. Han, I. S. Kim, H. Han and M. J. Krische,
J. Am. Chem. Soc., 2009, 131, 6916; (e) Y. Lu, I. S. Kim, A. Hassan,
D. J. Del Valle and M. J. Krische, Angew. Chem., Int. Ed., 2009,
48, 5018; (f) S. B. Han, H. Han and M. J. Krische, J. Am. Chem.
Soc., 2010, 132, 1760; (g) Y. J. Zhang, J. H. Yang, S. H. Kim and
M. J. Krische, J. Am. Chem. Soc., 2010, 132, 4562; (h) S. B. Han,
X. Gao and M. J. Krische, J. Am. Chem. Soc., 2010, 132, 9153;
(i) A. Hassan, J. R. Zbieg and M. J. Krische, Angew. Chem., Int.
Ed., 2011, 50, 3493; (j) X. Gao, I. A. Townsend and M. J. Krische,
J. Org. Chem., 2011, 76, 2350; (k) X. Gao, Y. J. Zhang and
M. J. Krische, Angew. Chem., Int. Ed., 2011, 50, 4173;
(l) A. Hassan, I. A. Townsend and M. J. Krische, Chem. Commun.,
2011, 47, 10028.
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c
4694 Chem. Commun., 2012, 48, 4692–4694
This journal is The Royal Society of Chemistry 2012