Asymmetric nucleophilic monofluorobenzylation of carbonyl compounds: Synthesis of enantiopure vic-fluorohydrins and α-fluorobenzylketones

Article abstract of DOI:10.1002/chem.201103919

Asymmetric nucleophilic monofluoroalkylation of a broad range of aldehydes with an α-fluoro-γ-sulfinylbenzyl carbanion takes place with complete control of the facial selectivity at the carbanion and good to high anti-diastereoselectivity to give easily s

Full text of DOI:10.1002/chem.201103919

DOI: 10.1002/chem.201103919
Asymmetric Nucleophilic Monofluorobenzylation of Carbonyl Compounds:
Synthesis of Enantiopure vic-Fluorohydrins and a-Fluorobenzylketones
Yolanda Arroyo,[a] M. Ascensiꢀn Sanz-Tejedor,*[a] Alejandro Parra,[b] and
Josꢁ Luis Garcꢂa Ruano*[b]
Abstract: Asymmetric nucleophilic
monofluoroalkylation of a broad range
of aldehydes with an a-fluoro-g-sulfi-
nylbenzyl carbanion takes place with
complete control of the facial selectivi-
ty at the carbanion and good to high
anti-diastereoselectivity to give easily
separable mixtures of two optically
pure 1,2-fluorohydrin derivatives (up
to 24:1 anti/syn). Separation and re-
moval of the p-tolylsulfinyl group with
tBuLi provides enantiomerically pure
anti-1,2-disubstituted-1,2-fluorohydrins,
whereas a-fluorobenzylketones can be
obtained by desulfinylation of the mix-
ture followed by pyridinium chloro-
chromate oxidation (one-pot process).
Keywords: asymmetric synthesis ·
fluorine · fluorohydrins · fluoro-
AHCTUNGTREGkNNUN etones · sulfoxides
Introduction
cant thermal stability and they are effective nucleophilic
monofluoromethylating reagents of wide scope. Neverthe-
less, this strategy places the fluorine atom in the primary po-
sition after the removal of the sulfonyl group(s), therefore,
does not allow introduction of the fluorine atom on a stereo-
genic center. To overcome this limitation, we recently devel-
oped 1-(fluoromethyl)-2-((S)-p-tolylsulfinyl)benzene ((S)-1)
as a chiral monofluorinated reagent. The reactions of (S)-
1 with N-sulfinyl aldimines were completely stereoselective
and yielded enantiomerically pure b-fluorinated b-phenyl-
Fluorine-containing organic compounds occupy a significant
place in pharmaceutical, agrochemical, and materials scien-
ces because of the ability of the fluorine atom to modulate
molecular properties, such as metabolic stability or binding
affinity.[1] Particularly, monofluorinated analogues of biologi-
cally active compounds are of great importance with regards
to isostere-based drug design.[2] Electrophilic fluorination
and nucleophilic monofluoroalkylation reactions of carbonyl
compounds are two straightforward operations for the con-
struction of monofluorinated compounds and their asym-
metric versions are particularly useful. The former allows to
access to a-fluorocarbonyl compounds and allylic fluorides
in high enantiomeric excess (ee).[3] On the other hand, nu-
cleophilic fluorination strategies for the synthesis of mono-
fluoroalkyl derivatives have only recently emerged, with im-
portant contributions from the groups of Prakash and
Olah,[4] Hu,[5] and Shibata and Toru.[6] They proved that flu-
oromethylcarbanions with removable electron-withdrawing
group(s)—usually a sulfonyl functionality—possess signifi-
AHCTUNGTRENNUNG
ethylamines[7] (Scheme 1). These results encouraged us to
Scheme 1. Reactions of prochiral fluoride synthon [Li]-(S)-1 with
N-sulfinylimines and carbonyl compounds.
study the monofluoroalkylation of carbonyl compounds with
the carbanion of (S)-1 as an easy route to 1,2-fluorohydrins
in which both the fluorine and hydroxyl groups are attached
to a chiral center (Scheme 1).
[a] Prof. Dr. Y. Arroyo, Prof. Dr. M. A. Sanz-Tejedor
Organic Chemistry Department
Escuela de Ingenierꢀas Industriales
Universidad de Valladolid
Paseo del Cauce, 59
1,2-Fluorohydrins are versatile building blocks and key in-
termediates for the synthesis of monofluorinated analogues
of many bioactive compounds[8] and they find application as
derivatizing agents for the determination of enantiomeric
composition by 19F NMR spectroscopy.[9] Additionally, im-
portant new materials, such as liquid crystals, contain this
functional group relationship.[10] Despite this great interest,
there is no simple and direct method to obtain optically
active 1,2-fluorohydrins and their synthesis is even more
challenging when the fluorine atom occupies a benzylic posi-
47011 Valladolid (Spain)
Fax : (+34)983423310
E-mail: atejedor@eii.uva.es
[b] Dr. A. Parra, Prof. Dr. J. L. Garcꢀa Ruano
Organic Chemistry Department (C-I)
Universidad Autꢁnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914973966
E-mail: joseluis.garcia.ruano@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103919.
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FULL PAPER
Table 1. Monofluorobenzylation of carbonyl compounds 2a–s with (S)-
1 by a single asymmetric-induction procedure.[a]
tion. The most often applied approach for preparation of
1,2-fluorohydrins is the ring opening of enantiopure epox-
ides with nucleophilic fluorine reagents.[11] However, the
synthetic usefulness of this strategy is mainly restricted by
the incomplete regio- and stereoselectivity of the process.
Desymmetrization of meso epoxides has also been stud-
ied;[12] only recently, high enantiodifferentiation (up to
95% ee) was achieved in the fluoride ring-opening of epox-
ides by using a chiral amine and chiral Lewis acid as cooper-
ative catalysts.[13] Alternatively, a-fluoroaldols have been
prepared by asymmetric aldol reaction either with fluoroke-
tene silyl acetal as a donor with Masamunesꢃs catalyst[14] or
from fluoroacetone in the presence of a variety of organoca-
talysts.[15] High enantioselectivities were usually achieved
but with low diastereo and/or regioselectivity. Finally, 1,2-
fluorohydrins have been prepared through deracemization
by classical or enzymatic processes,[16] and through catalytic
transfer hydrogenation of a-fluoroketones by dynamic ki-
netic resolution (DKR).[17] In any case, all of the reported
methods for the preparation of stereodefined 1,2-fluorohy-
drins in enantiopure form present severe limitations, so ad-
ditional synthetic efforts in this field are necessary. Herein,
we present our results for the asymmetric monofluoroalkyla-
tion of a broad range of carbonyl compounds with the a-
fluoro-g-sulfinylbenzyl carbanion derived from (S)-1, which
allows the synthesis of vic-fluorohydrins with two adjacent
stereogenic centers.
Entry Carbonyl
compound
R1
R2
d.r. (anti-3/ Yield of
syn-4)[b]
anti-3[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
C6H5
4-Me C6H4
4-MeO C6H4
3-MeO C6H4
3,4,5-tri-MeO C6H2 96:4
2-naphthyl
1-naphthyl
2-Me C6H4
2-MeO C6H4
92:8
91:9
92:8
93:7
80
79
79
81
79
78
78
66
63
69
62
59
63
69
70
91
89
50
75
À
À
À
À
93[d]:7
92:8
À
80:20
81:19
86:14[e]
84:16[f]
75:25
76:24
80:20[d]
À
À
3-Cl C6H4
À
4-Cl C6H4
n-butyl
iPr
tBu
trans PhCH=CH
Ph
86:14
[g]
–
–
[g]
CH3 CH3
CH3 4-OMe C6H4
CH3 tBu
À
70:30
89:11
2s
[a] All reactions were performed on a 0.5 mmol scale. [b] Diastereomeric
ratio (d.r.) determined by 1H NMR spectroscopy on the crude reaction
mixture. [c] Yield of isolated product. [d] ORTEP representations of anti-
3 f and syn-4n can be found in the Supporting Information. [e] A 84:14:2
mixture of three fluorohydrins was observed. [f] A 81:15:4 mixture of
three fluorohydrins was observed. [g] Single enantiomer.
Results and Discussion
Compound (S)-1 is readily available from 2-bromobenzylic
alcohol in a three-step sequence (sulfinylation, tosylation,
and fluorination with CsF) in high yield by our previously
reported procedure.[7] The aldehydes and ketones used in
this study were commercially available. We studied the reac-
tion of (S)-1 with aldehydes 2a–o. We found that optimal re-
action conditions involved quick addition of the electrophile
to the carbanion (generated by treatment with lithium diiso-
propylamine (LDA)) at À788C. In all cases, the reactions
were complete in less than one minute. As summarized in
Table 1, this process generally provided a mixture of only
two fluorhydrins, anti-3 and syn-4, that differ in the configu-
ration at the hydroxylic carbon atom. The major isomer had
the anti configuration. In all cases, both diastereoisomers
were readily separated by column chromatography. The re-
action of benzaldehyde (2a) evolved with high anti-diaste-
reoselectivity to afford a 92:8 mixture of anti-3a/syn-4a. The
major isomer anti-3a was isolated in 80% yield (Table 1,
entry 1).
actions of sterically demanding naphthyl aldehydes 2 f and
2g also proceeded with high anti diastereoselectivity (86 and
84% de, respectively; Table 1, entries 6 and 7). Aldehydes
2h–i, with a substituent at the ortho position, provided
lower diastereoselectivity than those with the same substitu-
ent at the para or meta position (Table 1, entries 8 and 9
versus 2 and 3). Aldehydes 2j and 2k, which contain the
weakly electron-withdrawing group chlorine at the meta or
para position, respectively, also evolved with good anti dia-
stereoselectivity, although a small amount of a third diaste-
1
reoisomer was also detected in the H NMR spectrum of the
reaction mixture (Table 1, entries 10 and 11). Unfortunately,
reactions with arylaldehydes that contained electron-with-
drawing groups p-CF3 or p-CN were less successful and mix-
tures of four fluorohydrins were formed with low diastereo-
selectivity (36:26:20:18 and 36:31:24:9, respectively). The
method was also found to be successful for aliphatic alde-
hydes 2l–n, to furnish anti fluorohydrins 3l–n as the major
isomers with moderate diastereoselectivity. The anti/syn
ratio ranged from 3:1 to 4:1; the stereoselectivity slightly in-
creased with the size of the R group (Table 1, entries 12–
14). Conjugate aldehyde 2o was also compatible with the re-
action conditions and afforded 1,2-addition products anti-3o
and syn-4o in a 6:1 ratio (Table 1, entry 15). It is remarkable
that despite the moderate stereoselectivity observed in these
Reactions carried out with arylaldehydes 2b–e, with elec-
tron-donating groups at the para and/or meta positions,
showed similar behavior. Anti/syn ratios ranged from 10:1 to
24:1 (Table 1, entries 2–5). A slight improvement of the anti
selectivity was observed when the aromatic ring was activat-
ed by several electron-donating groups, as in the case of 2e
(diastereomeric excess (de)=92%, Table 1, entry 5). The re-
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M. A. Sanz-Tejedor, J. L. Garcꢀa Ruano et al.
latter reactions, the isolated yield of the major anti-3 iso-
mers is typically higher than 60%.
To broaden the scope of this strategy, we also studied the
behavior of (S)-1 with ketones to afford a,a-dibranched-b-
fluoroalcohols. The exclusive formation of fluorohydrins 3p
and 3q in high yield from symmetrical ketones 2p and 2q,
respectively, was observed (ee>98%; Table 1, entries 16 and
17). Furthermore, the method was found to be applicable to
nonsymmetrical ketones 2r and 2s, although only 2s gave
high anti diastereoselectivity (Table 1, entries 18 and 19).
The full scope of the reaction of (S)-1 with ketones is cur-
rently being investigated.
Taking into account that all of the reactions of electro-
philes with g-sulfinylbenzyl carbanions studied so far
evolved with a complete control of the stereoselectivity at
the benzylic position,[18] we first assumed that compounds
anti-3 and syn-4 were epimers at the hydroxylic carbon
atom, C1. To confirm this assumption, the independent oxi-
dation of pure compounds anti-3h and syn-4h with pyridini-
um chlorochromate (PCC) was performed. Both reactions
afforded the same a-fluoroketone, 5h (Scheme 2), indicative
that the epimers only differ in the configuration at C1. Simi-
lar conclusions could be established for anti-3n and syn-4n,
which were both oxidized with PCC into 5n.
Scheme 3. Desulfinylation of 1,2-fluorohydrins anti-3 with tBuLi.
esters, which allowed us to conclude that the desulfinylation
process proceeded without epimerization at the chiral
carbon atoms.[19]
Chiral, nonracemic a-fluoroketones are valuable building
blocks for the construction of active compounds[1,2] and, in
recent years, they have become promising reagents for the
asymmetric epoxidation of alkenes.[20] Most strategies to pre-
pare simple a-fluoroketones are based on enolate or enam-
ine methodologies, but only a few examples yield high ee
values.[3] Thus, high diastereoselectivity has been achieved
starting from chiral a-silylketones[21] but harsh conditions
are required to remove the (S)-1-amino-2-(methoxymethyl)-
pyrrolidine (SAMP) hydrazone auxiliary used in the prepa-
ration of the silylketone. Alternatively, an oxazolidinone
was used as a chiral auxiliary to direct the addition of a fluo-
rine atom in the preparation of a-fluoroketones via Weinreb
N-methoxy-N-methyl amides.[22] Enantioselective fluorina-
tion by transition-metal catalysis or organocatalysis has
been widely used but this approach is limited to the fluori-
nation of b-ketoesters and, only very recently, a highly enan-
tioselective a-fluorination of cyclic ketones by enamine or-
ganocatalysis has been reported.[23]
Scheme 2. PCC oxidations of anti- and syn-1,2-fluorohydrins 3 and 4.
The results presented in Schemes 2 and 3 suggest that any
product mixture obtained from the reaction of (S)-1 with al-
dehydes 2 could be desulfinylated and subsequently oxidized
into a-fluorobenzylketones. Given that the conditions of the
PCC oxidation are not overly favorable for epimerization of
the fluorinated carbon atom, we thought this procedure
could provide enantiomerically pure a-fluoroketones. To
confirm this assumption, we prepared compounds 7a and 7e
by reaction of (S)-1 with aldehydes 2a and 2e, respectively,
further treatment of the resulting fluorohydrins with tBuLi,
and finally oxidation with PCC (Scheme 4). We also checked
that the conditions of these reactions were efficient when
they were applied to the crude mixture of the reaction of
(S)-1 with 2, which allowed the direct synthesis of de-
These results prove that the remote sulfinyl group on the
nucleophile completely controls the configuration at the a-
fluorobenzylic carbon atom through a 1,4-asymmetric-induc-
tion process.
Configurational assignment of compounds 3 and 4 was
tentatively made from the NMR spectroscopic data (signifi-
cant differences between the diastereoisomers) and later un-
equivocally confirmed by X-ray analysis of anti-3 f and syn-
4n (see the Supporting Information). The fact that all of the
reactions evolved similarly, with complete control of the
configuration at the a-fluorobenzylic carbon atom and good
to high anti/syn diastereoselectivity, suggests that the abso-
lute configuration is (1R,2S) for fluorohydrins anti-3a–o,
anti-3r, and anti-3s and (2S) for 3p and 3q. Likewise, the
minor isomers syn-4a–o, syn-4r, and syn-4s should exhibit
a (1S,2S) configuration.
Compounds 3 could be easily transformed into 1,2-fluoro-
hydrins
6
by C-desulfinylation with tBuLi at À788C
(Scheme 3). We checked the efficiency of this procedure in
the cases of 3a, 3e, and 3n–p. The corresponding 1,2-fluoro-
hydrins 6 were obtained in good yields as pure compounds.
The ee values of anti-6a and anti-6e were established as
Scheme 4. One-pot conversion of (S)-1 and aldehyde 2a or 2e into desul-
finylated a-fluoroketones 7a and 7e.
1
higher than 98% from a H NMR study of their Mosherꢃs
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Synthesis of Enantiopure Fluorohydrins
FULL PAPER
A
Acknowledgements
nor the sulfinyl derivatives 6 were isolated). Under the con-
ditions of the one-pot process, a-fluoroketones 7a and 7e
were isolated in good yield (54 and 63%, respectively) and
complete control of the configuration at the fluorinated
chiral carbon atom was achieved (ee>98%; see the Sup-
porting Information).
Financial support of this work by the Spanish Government (CTQ2009-
12168) is gratefully acknowledged.
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À
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and 4.
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À
atom (C F). Nevertheless, the formation of mixtures of epi-
mers at the hydroxylic carbon atom in these reactions indi-
cates that the approach of the a-fluoro-g-sulfinylbenzyl
carbanion to the electrophile can take place at either of its
two diastereotopic faces, with the antiperiplanar arrange-
À
ment of the C F and C=O bonds maintained to minimize
their dipolar repulsion. Stronger steric interactions in the
approach that yields syn-4 ((Ar/R)gauche
the observed anti stereoselectivity.
+ACTHNGUTERN(NUG R/F)gauche) justifies
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We have described the first asymmetric monofluoroalkyla-
tion of a broad range of aldehydes with the a-fluoro-g-sulfi-
nylbenzyl carbanion derived from (S)-1 to generate anti-1,2-
fluorohydrins with two contiguous stereogenic centers in
high isolated yields. The sulfinyl group exerts complete con-
trol of the facial selectivity at the benzylic carbon atom. The
observed anti diastereoselectivity ranges from 3:1 to 24:1,
dependent on the starting aldehyde (higher ratios are ob-
served in the presence of larger substituents). Furthermore,
this protocol also provides a-fluorobenzyl ketones in a one-
pot fluorobenzylation/desulfinylation/PCC oxidation se-
quence.
Chem. Eur. J. 2012, 18, 5314 – 5318
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Received: December 14, 2011
Published online: March 19, 2012
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