Asymmetric 1,2-Perfluoroalkyl Migration: Easy Access to Enantioenriched α-Hydroxy-α-perfluoroalkyl Esters

Article abstract of DOI:10.1021/jacs.5b01517

This study has led to the development of a novel, highly efficient, 1,2-perfluoro-alkyl/-aryl migration process in reactions of hydrate of 1-perfluoro-alkyl/-aryl-1,2-diketones with alcohols, which are promoted by a Zn(II)/bisoxazoline and form α-perfluoro-alkyl/-aryl-substituted α-hydroxy esters. With (-)-8-phenylmenthol as the alcohol, the corresponding menthol esters are generated in high yields with excellent levels of diastereoselectivity. The mechanistic studies show that the benzilic ester-type rearrangement reaction takes place via an unusual 1,2-migration of electron-deficient trifluoromethyl group rather than the phenyl group. The overall process serves as a novel, efficient, and simple approach for the synthesis of highly enantioenriched, biologically relevant α-hydroxy-α-perfluoroalkyl carboxylic acid derivatives.

Full text of DOI:10.1021/jacs.5b01517

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Communication
Asymmetric 1,2-Trifluoromethyl Migration: Easy Access to
1-Hydroxyl-1-trifluoromethyl Carboxylic Acid Derivatives
Pan Wang, Liang-Wen Feng, Lijia Wang, Jun-Fang Li, Saihu Liao, and Yong Tang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 25 Mar 2015
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Asymmetric 1,2-Perfluoroalkyl Migration: Easy Access to Enantio-
enriched α-Hydroxy-α-perfluoroalkyl Esters
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Pan Wang, Liang-Wen Feng, Lijia Wang, Jun-Fang Li, Saihu Liao and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Scienc-
es, 345 Lingling Lu, Shanghai 200032, China
Supporting Information Placeholder
Recently, we found that hydrate of 1-trifluoromethyl-1,2-
ABSTRACT: This study has led to the development of a
novel, highly efficient, 1,2-perfluoro-alkyl/-aryl migration
diketones5 could undergo facile, Lewis acid promoted, ben-
zilic ester type rearrangement reactions involving CF3-
migration under mild conditions. The results stimulated an
effort aimed at the development of a new method for the
synthesis of optically active α-perfluoro-alkyl and-aryl α-
hydroxy esters. In this communication, we report the prelim-
inary results (Scheme 1).
process in reactions of hydrate of 1-perfluoro-alkyl/–aryl-1,2-
diketones with alcohols, which are promoted by
a
Zn(II)/bisoxazoline and form α-perfluoro-alkyl/–aryl-
substituted α-hydroxy esters. With (-)-8-phenylmenthol as
the alcohol, the corresponding menthol esters are generated
in high yields with excellent levels of diastereoselectivity.
The mechanistic studies show that the benzilic ester type
rearrangement reaction takes place via an unusual 1,2-
migration of electron-deficient trifluoromethyl group rather
than the phenyl group. The overall process serves as a novel,
efficient and simple approach for the synthesis of highly en-
Scheme 1. Asymmetric 1,2-Rf Migration
antio-enriched,
biologically
relevant
α-hydroxy-α-
perfluoroalkyl carboxylic acid derivatives.
Benzilic acid (ester) rearrangement (BAR) reactions of α-
diketones are atom-economic and efficient processes that are
widely employed for the synthesis of tertiary α-hydroxy acids
and esters.6 We envisioned that, if successful, a rearrange-
ment protocol of this type could be applied to 1,2-diketones 1
as part of a new strategy for the preparation of α-
trifluoromethyl tertiary α-hydroxy acids. To test the validity
of this proposal, we conducted a study using the hydrate of 1-
phenyl-2-trifluoromethyl-1,2-diketone (1a) as a model sub-
strate. In contrast to nucleophilic trifluoromethylation reac-
tions that do not occur in solvents containing acidic pro-
tons,3a the trifluoromethyl migration reaction of 1a in the
presence of 50 equivalents of methanol was observed to take
α-Hydroxy-α-trifluoromethyl carboxylic acid derivatives
have received increasing attention in recent years owing to
their unique pharmaceutical and agrochemical properties. To
date, over 2800 bioactive compounds containing this struc-
tural unit have been prepared as part of drug development
studies and have been the subjects of 330 patents (docu-
mented by Reaxys1).2,3 In the past decades, an increased effort
has been given to the development of concise synthesis of
multi-functionalized
derivatives
of
α-hydroxy-α-
trifluoromethyl carboxylic acids.4 For example, Jørgensen et
al recently described a strategy for facile preparation of these
substances which employs Cu(II)/bisoxazoline catalyzed
Friedel-Crafts reactions of electron rich aromatic compounds
with trifluoropyruvates. This process produces α-hydroxy-α-
trifluoromethyl phenylacetic esters in high yields with excel-
lent levels of enantioselectivity.4a,4b In addition, a method
employing asymmetric nucleophilic trifluromethylation of α-
ketoesters has been shown to provide direct access to enan-
tiomerically enriched α-hydroxy-α-trifluoromethyl carbox-
ylates. However, the highest level of enantiomeric control
was 60% ee, observed by Mukaiyama et al using a cinchoni-
dine derived quaternary ammonium phenoxide to catalyze
the nucleophilic trifluromethylation reaction of tert-butyl 2-
oxo-2-phenylacetate.4h,4i Thus, enantiocontrol of reactions
that generate these targets remains as a major hurdle.
o
place efficiently at 80 C by employing 10 mol% Cu(II)/L4a
(Scheme 1) as a catalyst.7 Significantly, the product of this
reaction, methyl α-trifluoromethyl-α-phenyl-α-hydroxy ace-
tate (3a), was isolated in near quantitative yield.8 An asym-
metric version of this process using Cu(II) complexes was
explored with chiral bisoxazoline (BOX) and trisoxazoline
(TOX) ligands, which are efficient in asymmectric intramo-
lecular Cannizzaro reaction.9 However, trials on stereochem-
ical control of this process by these chiral Lewis acid catalysts
failed.10
Because of its potential utility in organic synthesis, we
tried an alternative approach to this goal involving the use of
chiral alcohols as nucleophiles. This strategy was explored in
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studies of reactions of 1a with various chiral alcohols and
(entry 15) or when 20 mol% of triflic acid was employed as
the catalyst (entry 16).
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4
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6
7
8
Cu(II) complexes in DCE as the solvent. As shown in Table 1,
reactions of 1a with (S)-α-phenylethanol 2a, chiral amino
alcohol 2b and (-)-menthol 2c in the presence of Cu(II)/L4a
took place efficiently but the diastereomeric ratios (dr) were
only ca. 50/50 (entries 1-3, Table 1). However, reaction of 1a
with (-)-8-phenylmenthol (2d) to form the corresponding
ester was modestly high yielding (57%) and it occurred with
a much higher level of diastereoselectivity (94/6 dr, entry 4).
Moreover, the process was found to be more efficient when
Zn(II) rather than Cu(II) based catalysts were employed, and
toluene rather than DCE was used as solvent (entries 5 and
6). An examination of the effects of ligands showed that
changing from bis-oxazoline L4a to bis-thiazoline L4b led to
both a lower yield and dr (entry 7). Furthermore, no im-
provements in yield and stereoselectivity were engendered
by using other ligands (L4c-h, entries 8-13). In contrast, the
process took place in only 9% yield when 10 mol% of
Zn(OTf)2 was utilized in the absence of any ligand (entry 14)
and no reaction occurred in the absence of Zn(II)/L catalysts
The substrate scope of the process was investigated next
under the optimized conditions. As shown in Table 2, the
new 1,2-CF3 migration process took place smoothly with a
variety of 1-aryl-2-trifluoromethyl-1,2-diketones including
those that contain both electron-rich and electron-poor phe-
nyl ring substituents (entries 1-20, Table 2). Various func-
tional groups such as OMe, F, Cl, Br, I and CF3 in substrates
1a-1s were well tolerated in reactions that form the corre-
sponding α-hydroxy esters 3a-3s in high to excellent yields
with excellent levels of diastereoselectivity. Compared with
para- and meta-phenyl substituted substrates, those pos-
sessing ortho-substituents reacted to give products in slightly
lower yields and degrees of stereoselectivity (entries 2 and 17).
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Table 2. Reaction Scope.a
Table 1. Reaction Optimization.a
entry
1
2
3
4
5
6
7
8
1
R
R’
product time (h) yield(%) b dr c
1a Ph
1b 2-FC6H4
1c 3-FC6H4
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
48
168
47
37
33
86
68
87
87
39
13
89
60
95
99
94
94
94
90
86
91
95
86
90
84
94
95
62
89
92
90
72
77
95
86
96/4
92/8
96/4
96/4
97/3
96/4
97/3
96/4
96/4
96/4
97/3
95/5
95/5
96/4
97/3
97/3
91/9
96/4
96/4
95/5
93/7
92/8
95/5
97/3
1d 3-ClC6H4
1e 3-CF3C6H4
1f 3-MeOC6H4
1g 4-FC6H4
1h 4-ClC6H4
1i 4-BrC6H4
1j 4-IC6H4
1k 4-CF3C6H4
1l 4-MeOC6H4
1m 4-MeC6H4
1n 4-PhC6H4
1o 3,4-F2C6H3
1p 3-4-Cl2C6H3
1q 2,4-Cl2C6H3
1r 3,4-(MeO)2C6H3
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24
a
110
137
89
33
33
112
110
48
86
6
4
40
96
1s 3,4-(OCH2O)C6H3 CF3
1t 2-naphthyl
1u CH2CH2C6H5
1v CH2CH2C6H4CH3 CF3
1w Ph
1x Ph
3s
3t
3u
3v
CF3
CF3
CF2CF3 3w
C6F5 3x
Lewis
acid
entry
L
solvent
ROH time (h) yield (%) b dr c
1
2
3
4
5
6
7
8
Cu(OTf)2 L4a DCE
Cu(OTf)2 L4a DCE
Cu(OTf)2 L4a DCE
Cu(OTf)2 L4a DCE
Zn(OTf)2 L4a DCE
Zn(OTf)2 L4a toluene 2d
Zn(OTf)2 L4b toluene 2d
Zn(OTf)2 L4c toluene 2d
Zn(OTf)2 L4d toluene 2d
Zn(OTf)2 L4e toluene 2d
Zn(OTf)2 L4f toluene 2d
Zn(OTf)2 L4g toluene 2d
Zn(OTf)2 L4h toluene 2d
2a
2b
2c
2d
2d
12
42
18
99
99 d
80
57
50/50
55/45
55/45
94/6
95/5
96/4
94/6
89/11
96/4
92/8
95/5
96/4
96/4
95/5
-
Reaction conditions: Zn(OTf)2 (0.03 mmol), L4a (0.036 mmol), 1
b
(0.3 mmol), and 2d (0.6 mmol) in 6.0 mL of toluene, N2. Isolated
yield. The diastereomeric ratio (dr) was determined by using 19F
c
41
NMR spectroscopic analysis of the crude reaction mixture.
60
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48
61
89
85
91
44
49
32
76
61
9
Notably, the rates of reactions of 1-phenyl-2-
trifluoromethyl-1,2-diketones
containing
electron-
withdrawing phenyl ring substituents are higher than those
of analogues with electron-donating phenyl substituents.
This observation suggests that the migrating trifluoromethyl
group in the reaction has nucleophilic character. Importantly,
1-alkyl-2-trifluoromethyl-1,2-diketones 1u and 1v also served
as acceptable substrates for this rearrangement reaction,
giving the corresponding products 3u and 3v in high yields
and high diastereoselectivities (entries 21 and 22). Further-
more, not only trifluoromethyl diketones but also the pen-
tafluoroethyl analogue 1w reacted smoothly to give the mi-
gration product 3w in 95% yield and a 95/5 diastereomeric
ratio (entry 23). Likewise, the pentafluorophenyl-diketone 1x
was a suitable substrate for this process, which produced the
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12
13
14
15
16 e
Zn(OTf)2
-
-
-
-
-
toluene 2d
toluene 2d
toluene 2d
N.R.
N.R.
-
a Reaction conditions: Zn(OTf)2 (0.02 mmol), L (0.024 mmol), 1a (0.2
c
mmol), and 2 (0.4 mmol) in 2.0 mL of solvent, N2.b Isolated yield.
The diastereomeric ratio (d.r.) was determined by using 19F NMR
spectroscopic analysis of the crude reaction mixture. d Conversion of
1a, determined by using both H and 19F NMR spectroscopic analysis
1
of the crude reaction mixture. e 20 mol% of TfOH was used.
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corresponding hydroxy ester 3x in a high yield and diastere-
ver products detected.10 These results clearly demonstrate
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oselectivity (entry 24). The stereochemical outcome of the
reaction of 1x is highly significant because the similar steric
sizes of the α-phenyl and α-pentafluorophenyl groups makes
it difficult to conceive of other methods to prepare substanc-
es like 3x with high levels of diastereoselectivity.
that the reaction takes place exclusively through a unique
pathway14 in which the trifluoromethyl group migrates to the
neighboring carbonyl center.
Further insight into the mechanism for this process came
from the results of a preliminary kinetic experiment in which
19F NMR spectroscopy was used to monitor changes in con-
centrations of the diketone reactant A (Figure 1), hemiacetal
intermediate C and product D.10 By viewing the plot of con-
centrations versus time displayed in Figure 1, it can be seen
that in the initial phase of this reaction, intermediate C
formed rapidly and then in a second stage it disappeared
with simultaneous formation of product D. This result shows
clearly that the first step of the process, interconverting A
and C, is reversible and that the CF3-migration step is rate-
determining (i. e., k-1 > k2, k1 ≫ k2).10
The practical utility of the current reaction is demonstrat-
ed by its application to gram scale synthesis of (R)-Mosher’s
acid. As the results summarized in Scheme 2, ester 3a could
be readily transformed to highly enantio-enriched (93% ee)
(R)-α-methoxy-α-trifluoromethyl-phenyl acetic acid13, known
as (R)-Mosher’s acid, used as a chiral resolution reagent11 and
a key intermediate in the synthesis of hundreds of bioactive
substances.3,4,12 In addition, (-)-8-phenylmenthol could be
readily recovered in 95% yield following the saponification
step.
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Scheme 2. Gram-scale Synthesis of (R)-Mosher’s acid.
Two possible mechanistic pathways exist for this Lewis ac-
id promoted reaction.6c, 6d Specifically, this benzylic acid re-
arrangement process can occur by routes involving migration
of either an aryl or trifluromethyl group following addition of
the alcohol to one of the two carbonyl centers in the
diketone (Scheme 3, eq 1). An isotope labeling experiment
was performed,10 using 1-13C-1-phenyl-2-trifluoromethyl-1,2-
diketone, to distinguish between the two mechanistic routes.
The results (Scheme 3, eq 2) show that the 13C labelled car-
bon remains connected to the phenyl group in the 2-13C-2-
hydroxy-2-trifluoromethyl-2-phenylacetate ester (3a’) formed
under the optimal conditions. In addition, a crossover exper-
iment was also carried out under the same conditions by
employing the mixture of substrates 1j and 1w, which result-
ed in the corresponding mixture of 3j and 3w without crosso
Figure 1. Monitoring reaction progress using 19F NMR spectroscopy.
Plot of the concentrations of substrate A, intermediate C and prod-
uct D function of reaction time using PhCF3 as a 19F NMR integra-
tion standard. Starting conditions: [A] (0.1 M), [B] (1 M), Zn(OTf)2
(10 mol%), L4a (12 mol%) in toluene-d8, 80 °C.
In summary, a highly stereoselective Lewis acid catalyzed
1,2-perfluoroalkyl and perfluoroaryl migration reaction of 1,2-
diketones was developed. The process serves as the basis for
an efficient and simple method to prepare enantio-enriched
α-perfluoroalkyl and α-perfluoroaryl substituted α-hydroxy
carboxylic acid derivatives, overcoming the limitations of the
synthetic methods reported.3 13C labeling study confirmed
that an intramolecular trifluoromethyl migration is involved
in this reaction. Importantly, as far as we are aware, this is
the first example of an asymmetric intramolecular migration
of a trifluoromethyl group, as well as pentafluoroethyl and
pentafluorophenyl groups. The newly developed method has
a number of advantages, including high yield, mild reaction
conditions, simple recovery and reuse of the chiral auxiliary,
ready scaling up and excellent diastereoselectivity. In partic-
ular, the broad substrate scope and fluorine-containing mi-
gration groups make this reaction useful for the synthesis of
biologically active substances in medicinal chemistry studies.
Scheme 3. Isotope Labeling Study of the Rearrange-
ment Reaction.
ASSOCIATED CONTENT
Supporting Information
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(j) Liu, Y.-L.; Liao, F.-M.; Niu, Y.-F.; Zhao, X.-L.; Zhou, J. Org.
Chem. Front. 2014, 1, 742.
Experimental procedures, characterizations and analytical
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data of products, and data of NMR and HPLC. This material
is available free of charge via the Internet at
http://pubs.acs.org.
(6) (a) Liebig, J. Ann. Pharm. 1838, 25, 1; (b) Doering, W. V. E.;
Urban, R. S. J. Am. Chem. Soc. 1956, 78, 5938; (c) Selman, S.;
Eastham, J. F. Quat. Rev. 1960, 14, 221; (d) Bryon, G. G. in
Comprehensive Organic Synthesis, Vol.3 (Eds: Trost, B. M.;
Fleming, I.), PERGAMON PRESS, New York, 1991, 821; (e) March,
J., in Advanced Organic Chemistry, 4th ed., JOHN WILEY &
SONS, INC., New York, 1992, 1080; (f) Burke, A. J.; Marques, C. S.,
Mini. Rev. Org. Chem. 2007, 4, 310; (g) Li, J. J., in Name Reactions
for Homologations: Part II, JOHN WILEY & SONS, INC.,
Hoboken, 2009, 395.
Corresponding Author
tangy@sioc.ac.cn
Notes
The authors declare no competing financial interest.
9
ACKNOWLEDGMENT
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(7) For selected examples of using L4a as ligand: (a) Yasuhara, S.;
Sasa, M.; Kusakabe, T.; Takayama, H.; Kimura, M.; Mochida, T.;
Kato, K. Angew. Chem., Int. Ed. 2011, 50, 3912; (b) Zhou, J.-L.;
Liang, Y.; Deng, C.; Zhou, H.; Wang, Z.; Sun, X.-L.; Zheng, J.-C.;
Yu, Z.-X.; Tang, Y. Angew. Chem., Int. Ed. 2011, 50, 7874; (c)
Karyakarte, S. D.; Smith, T. P.; Chemler, S. R. J. Org. Chem. 2012,
77, 7755; (d) Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R. J.
Am. Chem. Soc. 2012, 134, 12149; (e) Qu, J.-P.; Liang, Y.; Xu, H.;
Sun, X.-L.; Yu, Z.-X.; Tang, Y. Chem. - Eur. J. 2012, 18, 2196; (f)
Del Bel, M.; Rovira, A.; Guerrero, C. A. J. Am. Chem. Soc. 2013,
135, 12188; (h) Liao, S. H.; Sun, X. L.; Tang, Y., Acc. Chem. Res.
2014, 47, 2260.
The authors express their appreciation for financial support
from the National Natural Sciences Foundation of China (No.
21121062, 21432011, and 21272250) and the Chinese Academy of
Sciences. We also thank Professor Martin Klußmann (Max-
Planck-Institut für Kohlenforschung) and Professor Zhong-
Han Hu (Jilin University) for valuable discussions and sug-
gestions about the kinetic studies.
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