Stereoselective nucleophilic fluoromethylation of aryl ketones: Dynamic kinetic resolution of chiral α-fluoro carbanions

Article abstract of DOI:10.1002/anie.201308484

Although many methods are available for the synthesis of optically enriched monofluoromethyl secondary alcohols, synthesizing optically enriched monofluoromethyl tertiary alcohols remains a challenge. An efficient and easy-to-handle nucleophilic fluoromethylation protocol was developed. The current monofluoromethylation showed much higher facial selectivity than the corresponding difluoromethylation and proceeded via a different type of transition state. Excellent stereoselective control at the fluorinated carbon chiral center was found, an effect believed to be facilitated by the dynamic kinetic resolution of the chiral α-fluoro carbanions. Fluoromethyl fix: An efficient and easy-to-handle protocol for the stereoselective synthesis of optically pure monofluoromethyl tertiary alcohols was developed, which showed higher facial selectivity than the corresponding difluoromethylation and proceeded via a different type of transition state. Stereoselective control at the fluorinated carbon chiral center is believed to be facilitated by the dynamic kinetic resolution of the chiral α-fluoro carbanions. Copyright

Full text of DOI:10.1002/anie.201308484

Angewandte
Chemie
DOI: 10.1002/anie.201308484
Fluoroalkylation
Stereoselective Nucleophilic Fluoromethylation of Aryl Ketones:
Dynamic Kinetic Resolution of Chiral a-Fluoro Carbanions**
Xiao Shen, Wenjun Miao, Chuanfa Ni, and Jinbo Hu*
Abstract: Although many methods are available for the
synthesis of optically enriched monofluoromethyl secondary
alcohols, synthesizing optically enriched monofluoromethyl
tertiary alcohols remains a challenge. An efficient and easy-to-
handle nucleophilic fluoromethylation protocol was devel-
oped. The current monofluoromethylation showed much
higher facial selectivity than the corresponding difluorometh-
ylation and proceeded via a different type of transition state.
Excellent stereoselective control at the fluorinated carbon
chiral center was found, an effect believed to be facilitated by
the dynamic kinetic resolution of the chiral a-fluoro carban-
ions.
In the past decades, several strategies have been reported
for the synthesis of optically enriched monofluoromethyl
secondary alcohols, including asymmetric reduction of mono-
[6a–c]
fluoromethyl ketones,
cally pure epoxides or enantioselective fluorination of
nucleophilic fluorination of opti-
[
6d–f]
racemic epoxides,
and enantioselective monofluorome-
[
6g]
thylation of aldehydes. However, the synthesis of optically
enriched monofluoromethyl tertiary alcohols is challenging,
and only a few reports are available.
[
6f,7]
In 1989, Bravo and
co-workers reported the addition reaction of a chiral sulfox-
ide substituted monofluoromethyl ketone with alkyl lithium
reagents, thereby affording monofluoromethyl tertiary alco-
hols with low diastereomeric ratios (up to d.r. 75:25;
[
7a]
T
he incorporation of fluorine into a bioactive molecule can
Scheme 1a). In 1995, the same group reported a stereose-
lective oxirane formation from chiral 1-fluoro-3-arylsulfinyl-
2-propanone with diazomethane, and monofluoromethyl
tertiary alcohols were obtained after the ring-opening reac-
often impart desirable chemical and biological properties
with minimal steric alterations. These properties include
stability, lipophilicity, and bioavailability, and can favorably
[1]
[7b]
affect in vivo drug transport and absorption. In this context,
monofluorinated analogues of biologically active compounds
are considered to be promising isosteres of the parent
tion (Scheme 1b). In this case, although the first step gave
the oxiranes in good d.r. (up to 94:6), the toxic, unstable, and
explosive reagent CH N was used. In 2000, Haufe and co-
2
2
[2]
molecules. In 1954, Fried and Sabo successfully synthesized
-a-fluorohydrocortisone acetate and demonstrated that it
workers reported an enantioselective nucleophilic fluorina-
tion of racemic 2-methyl-2-phenyloxirane with Jacobsenꢀs
(S,S)-(+)-(salen)chromium catalyst, but only 20% conversion
9
possessed ten to twelve times the activity of cortisone acetate
in the rat liver glycogen assay; this was one of the early
examples that showed improved bioavailability of a bioactive
[
6f]
and 6% ee were obtained (Scheme 1 c). Therefore, the
development of a new, efficient and easy-to-handle protocol
for the stereoselective synthesis of optically pure monofluo-
romethyl tertiary alcohols is highly desired.
[3]
molecule through the selective incorporation of fluorine. In
recent years, fluorine incorporation has become a routine
[
1]
strategy for drug design. Among various monofluorinated
compounds, monofluoromethylated compounds are of par-
ticular value since CH F functionality can mimic CH and
Nucleophilic fluoroalkylation with a racemic fluorinated
carbanion or carbanion equivalent has proven to be one of the
most important and efficient methods for synthesizing
2
3
[
8]
CH OH groups, which are often encountered in biologically
fluorinated organic molecules. However, the corresponding
reactions with chiral fluoroalkylation reagents designed for
the synthesis of optically pure organofluorine compounds
2
[
4]
[5]
active molecules. However, since the thalidomide tragedy,
there has been more awareness of the potential dangers of
using racemic drugs. Therefore, the development of new
methods for the synthesis of optically pure monofluoromethyl
compounds would be highly desirable for drug development.
[
*] Dr. X. Shen, W. Miao, Dr. C. Ni, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Ling-Ling Road
Shanghai, 200032 (China)
E-mail: jinbohu@sioc.ac.cn
Homepage: http://hujinbo.sioc.ac.cn/en/
[
**] Support of our work by the National Basic Research Program of
China (2012CB215500 and 2012CB821600), the National Natural
Science Foundation of China (20825209 and 21372246), the
Chinese Academy of Sciences, and the Syngenta PhD Studentship
(
to X.S.) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308484.
Scheme 1. Strategies for the synthesis of optically enriched mono-
fluoromethyl tertiary alcohols.
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775

.
Angewandte
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[
9,10]
have been much less studied.
In 2012, Sanz-Tejedor,
Table 1: Study of reaction conditions.
Ruano, and co-workers reported an asymmetric nucleophilic
monofluorobenzylation of aromatic aldehydes that resulted
[
9a]
in moderate to good diastereoselectivity.
However, the
facial selectivity and yield dramatically decreased when an
[a]
[b]
Entry 5a/2/Base Base
Solvent
THF
Yield [%]
d.r.
[
9a]
aromatic ketone was used as the substrate.
Herein, we
1
2
3
4
5
6
7
8
9
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
1.5:1:1.2
KHMDS
NaHMDS THF
LiHMDS
nBuLi
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
62
55
9
97
38
77
49
64
99:1
99:1
80:20
86:8:6
95:5
report our recent success in the synthesis of optically enriched
monofluoromethyl tertiary alcohols through a highly stereo-
selective nucleophilic fluoromethylation of aryl ketones with
THF
THF
DME
[
c]
[
d]
(
R)-PhSO(NTBS)CH F (1; NTBS = N-tert-butyldimethyl-
2
PhCH3
91:9
silyl), in which the stereoselectivity was facilitated by an
intriguing dynamic kinetic resolution of the chiral a-fluoro
carbanions (Scheme 1d).
Firstly, we developed an efficient synthesis of (R)-N-tert-
butyldimethylsilyl-S-fluoromethyl-S-phenylsulfoximine (1).
CH Cl
86:14
87:13
99:1
2
2
Et O
2
THF/HMPA 15
v/v=10:1)
(
1
11
0
1.5:1:2.5
2:1:2.5
KHMDS
KHMDS
THF
THF
77
92(85)
99:1
99:1
[
e]
(
R)-N-tosyl-S-fluoromethyl-S-phenylsulfoximine (3) was
[10b]
readily prepared according to reported procedures.
The
[
a,b] Total yield and diastereomeric ratio (d.r.) were determined by
F NMR spectroscopy, and only two diastereoisomers were observed
unless otherwise noted. [c] Three diastereoisomers were observed.
tosyl group of 3 was readily removed in aqueous H SO4
19
2
(
18.4m), thus affording (R)-S-fluoromethyl-S-phenylsulfox-
imine (4) in 97% yield. Silylation of 4 with tert-butyldimeth-
ylsilyl chloride (TBSCl) gave compound 1 in 98% yield
[d] The reaction was performed at À708C. [e] Yield in parentheses refers
to the yield of the isolated major diastereoisomer. KHMDS=potassium
bis(trimethylsilyl)amide, HMPA=hexamethylphosphoramide,
DME=1,2-dimethoxy ethane.
(
Scheme 2).
Encouraged by the above results, we further investigated
the stereoselective synthesis of optically pure monofluoro-
methyl tertiary alcohols through the chiral monofluorometh-
ylation reagent strategy. It was found that when NaHMDS
was used as the base instead of KHMDS, the yield decreased
slightly but excellent facial selectivity was still observed
(Table 1, entry 2). When the base was changed to LiHMDS,
both yield and d.r. decreased dramatically (9% yield, d.r.
80:20; Table 1, entry 3). However, when nBuLi was used as
the base, a yield of 97% was obtained with the observation of
three diastereoisomers (d.r. 86:8:6). A screening of solvents
showed that THF was the best solvent in terms of stereose-
lectivity (Table 1, entries 1, 5–8). Although the yield
decreased to 15%, the addition of HMPA did not reduce
the diastereoselectivity, a result in sharp contrast to the
influence of HMPA on the reaction of (R)-PhSO-
Scheme 2. Preparation of (R)-N-tert-butyldimethylsilyl-S-fluoromethyl-S-
phenylsulfoximine (1).
Subsequently, we investigated the addition reaction of
acetophenone 5a to monofluoromethyl sulfoximine 1 by
using similar conditions to those used for the addition of 5a to
[
10a]
difluoromethyl sulfoximine 2 (Scheme 3).
Much higher
[
10a]
Scheme 3. Different reactivities of 1 and 2 towards 5a.
(NTBS)CF H and 5a.
Further optimization of the reaction
2
conditions by changing the ratio of 5a, 2, and KHMDS
showed that when the ratio was 2:1:2.5, 6a was obtained in
92% yield with d.r. 99:1 (Table 1, entry 11).
facial selectivity was obtained for the monofluoromethylation
reaction (d.r. 99:1) than for the difluoromethylation reaction
(
d.r. 90:10), although the yield was lower for the monofluo-
With the optimized conditions, the substrate scope of the
reaction between 5 and 1 was examined (Scheme 4). Reaction
with various aryl methyl ketones gives the corresponding
enantiomerically enriched monofluoromethyl tertiary alco-
hols 6a–h in good to excellent yields (78–90%) and with
excellent facial selectivity (d.r. 97:3–99:1). The reaction
tolerates many substituents such as methyl, chloro, bromo,
iodo, and methoxy groups. A naphthyl-substituted ketone
also reacted with reagent 1 to afford the product 6i in 83%
yield, d.r. 99:1. In addition, monofluoromethylation of
a heteroaryl substituted ketone was also successful, giving
the tertiary alcohol 6j in 65% yield, d.r. 94:6. Moreover,
ketones 5k, 5l, 5m, and 5n were also suitable substrates for
the monofluoromethylation reaction, giving the products 6k
in 94% yield with d.r. 98:2, 6l in 91% yield with d.r. 96:4 , 6m
romethylation. We suppose that both the kinetically preferred
generation of the (R)-PhSO(NTBS)CF2 anion and the
subsequent nucleophilic addition of the anion to 5a over
the undesired enolization of 5a are the key factors for the
satisfactory yield of the difluoromethylation reaction. In
À
[
11]
our previous study on the synthesis of 2, it was found that
À
(R )-PhSO(NTBS)CHF possesses good thermal stability and
S
[10a,12]
was suitable for pregeneration.
pregeneration of (R )-PhSO(NTBS)CHF could improve the
yield of the monofluoromethylation reaction. When we mixed
We thus envisaged that
À
S
compound 1 with KHMDS at À788C for 30 min, then added
5
a at the same temperature and quenched the reaction 3 h
later, the yield increased to 62% without loss of facial
selectivity (Table 1, entry 1).
776
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was recovered in 100% yield without a change in d.r.
Scheme 6), thus suggesting that the addition reaction was
(
irreversible. Based on these results, we propose that complete
Scheme 6. Investigation of the stability of compound 7 in the presence
of KHMDS.
control of the stereoselectivity at the fluorinated carbon
stereogenic center results from the excellent dynamic kinetic
[14d]
resolution of the participating carbanions (Scheme 1d).
Obviously, the chiral induction from the sulfur stereogenic
center of the sulfoximine to the fluorinated carbon stereo-
genic center has a beneficial effect on the facial selectivity of
the monofluoromethylation reaction.
Scheme 4. Stereoselective monofluoromethylation of ketones and alde-
hydes with sulfoximine 1. General procedures: under N , KHMDS (1m
2
in THF, 2.5 mL, 2.5 mmol) was added to the solution of 1 (287 mg,
1
(
mmol) in THF (5 mL) at À78 8C; 30 min later, a solution of 5
2 mmol) in THF (1 mL) was added, and 3 hours later, the reaction
was quenched with 5 mL of 3m HCl (aq). The d.r. value was
Based on the fact that the addition of HMPA did not
obviously influence the diastereoselectivity of the monofluo-
romethylation of 5a with 1, we propose that the cation might
not participate in the transition state. One can envisage
several possible nonchelated transition states, such as TS-1,
TS-2, TS-3, and TS-4 shown in Scheme 7. Since the Ph···F
1
9
determined by F NMR spectroscopy before silica gel column chroma-
tography and refers to the facial selectivity unless otherwise noted.
Yield refers to the yield of the isolated major diastereoisomer. [a] The
d.r. value results from the sulfur and fluorinated carbon stereogenic
centers.
[
15]
in 89% yield with d.r. 98:2, and 6n in 88% yield with d.r. 99:1,
respectively. The reaction could also be applied to the
synthesis of enatiomerically enriched monofluoromethyl
secondary alcohols. Products 6o and 6p were obtained in
8
7% yield with d.r. 98:2, and 92% yield with d.r. 98:2,
respectively. The exclusive formation of monofluoromethyl
tertiary alcohol 6q in 96% yield with d.r. > 99:1 from
symmetrical ketone 5q shows excellent control of the
stereoselectivity at the fluorinated carbon stereogenic
center in the current monofluoromethylation reaction. The
absolute configurations of 6d and 6o were confirmed by X-
ray crystal-structure analysis (see the Supporting Informa-
Scheme 7. Proposed transition states. Repulsive interactions are indi-
cated by curved arrows.
repulsive interaction is stronger than the CH ···F interaction,
3
TS-1 is less favored than TS-4. Given that the repulsive
interaction of PhSO(NTBS)···Ph is stronger than that of
[
13]
tion), and those of the other products were assigned by
analogy.
PhSO(NTBS)···CH , TS-2 is also less favored than TS-4.
3
Finally, TS-3 is less favored than TS-4 because of the stronger
repulsive interactions of Ph···F and PhSO(NTBS)···Ph com-
pared to those of the CH ···F and PhSO(NTBS)···CH .
To probe the mechanism of the current monofluorome-
thylation reaction, we performed several experiments. Firstly,
3
3
À
a reaction of (R )-PhSO(NTBS)CHF with D O was con-
In a previous study, we found that the Mg/AcOH/AcONa
system was a good reductive desulfoximinating agent for the
S
2
ducted. Very low diastereoselectivity (d.r. 55:45) was
observed for monodeuterated product 1’ (Scheme 5), thus
indicating that carbanions in both R and S configurations at
[
10a]
synthesis of difluoromethyl alcohols.
However, the desulf-
oximination of compound 6o by using Mg/AcOH/AcONa
was found to be inefficient, giving monofluoromethyl alcohol
8a in only 37% yield (for details, see Table S-1 in the
Supporting Information). In 1988, Boys and co-workers
[
14a–c]
the fluorinated carbon were formed.
Secondly, we
examined whether the addition reaction is reversible. After
being treated with KHMDS at À788C for 3 h, compound 7
reported that the adducts of PhSO(NMe)CH Fand aldehydes
2
could be converted into monofluoroalkenes in the presence of
[
16]
Al/Hg. However, we found that monofluoromethyl alcohol
a was obtained in 91% yield with 97% ee from 6o (a
8
mixture of diastereoisomers with d.r. 99:1) without the
formation of monofluoroalkene compounds in the presence
of Al/Hg (Scheme 8). Under similar reaction conditions,
Scheme 5. Reaction of (R)-PhSO(NTBS)CH F (1) with D O.
2
2
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777

.
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selectivity of the current monofluoromethylation reaction,
a result that indicates that different transition states were
involved in the two reactions. Excellent stereoselective
control at the fluorinated carbon stereogenic center was
found, an effect believed to be facilitated by the dynamic
kinetic resolution of the chiral a-fluoro carbanions.
Received: September 29, 2013
Published online: December 4, 2013
Keywords: alcohols · chirality · fluoromethylation ·
.
Scheme 8. Synthesis of optically enriched monofluoromethyl alcohols
through reductive desulfoximination of 6. Typical procedure: under N2
atmosphere, the newly prepared Al/Hg (405 mg of Al) was added to
the solution of 6 (d.r. 99:1, 0.5 mmol) in THF/water (5 mL:5 mL) at
room temperature in several portions and stirred overnight. Substrates
stereoselective addition · sulfoximine
[
[
[
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were diastereomerically pure except for 6a. The yield refers to the
2
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optically enriched monofluoromethyl tertiary alcohols 8b–f
were obtained in good yields without loss of optical purity at
the benzylic carbon stereogenic centers.
To show the potential value of our present monofluoro-
methylation reaction in organic synthesis, the product 6n was
transformed into fluorinated analogues of the natural prod-
ucts gossonorol and boivinian B, which have interesting
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Upon treatment with
3
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2
Scheme 9. Synthesis of natural-product analogues.
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9
(
obtained in 98% ee. The NOE spectrum of the major
diastereoisomer showed that H was in the same plane as
a
H and H (see the Supporting Information).
b
c
In conclusion, an efficient and easy-to-handle protocol for
the highly stereoselective nucleophilic monofluoromethyl-
ation of ketones with large substrate scope was developed. To
our knowledge, this is the first report on the synthesis of
optically pure monofluoromethyl tertiary alcohols through
a nucleophilic fluoroalkylation strategy. The synthesis of
fluorinated analogues of the natural products gossonorol and
boivinian B demonstrated the potency of the method. The
reaction showed higher facial selectivity than the correspond-
ing difluoromethylation reaction. In contrast to the negative
effect of HMPA on the facial selectivity of the difluorometh-
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mentary crystallographic data for this paper. These data can be
Angew. Chem. Int. Ed. 2014, 53, 775 –779
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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