Catalytic enantioselective protonation of enol trifluoroacetates by means of hydrogenocarbonates and cinchona alkaloids

Article abstract of DOI:10.1021/jo201146b

Herein is disclosed an efficient catalytic enantioselective protonation of enol acetates by means of a readily implementable transition-metal-free chemical process. By making use of simple hygrogenocarbonates as the proton source and hydroquinine anthraquinone-1,4-diyl diether as the chiral proton shuttle, a series of cyclic enol trifluoroacetates are protonated under mild conditions to yield the corresponding ketones in up to 93% ee.

Full text of DOI:10.1021/jo201146b

NOTE
pubs.acs.org/joc
Catalytic Enantioselective Protonation of Enol Trifluoroacetates by
Means of Hydrogenocarbonates and Cinchona Alkaloids
Aurꢀelie Claraz, Jꢀer^ome Leroy, Sylvain Oudeyer,* and Vincent Levacher*
Chimie Organique Bio-organique Rꢀeactivitꢀe et Analyse, CNRS UMR 6014 & FR 3038, Universitꢀe et Institut National des Sciences
Appliquꢀees (INSA) de Rouen, Rue Tesniꢁere, 76130 Mont-Saint-Aignan, France
S Supporting Information
b
ABSTRACT: Herein is disclosed an efficient catalytic enantioselective
protonation of enol acetates by means of a readily implementable
transition-metal-free chemical process. By making use of simple hygro-
genocarbonates as the proton source and hydroquinine anthraquinone-
1,4-diyl diether as the chiral proton shuttle, a series of cyclic enol
trifluoroacetates are protonated under mild conditions to yield the
corresponding ketones in up to 93% ee.
nantioselective protonation (EP) of prostereogenic enol de-
E
rivatives has become a method of choice for the preparation
of enantioenriched R-substituted carbonyl compounds.1 Ever
since the first reports by Duhamel and Plaquevent in the late
1970s,2,3 great advances have been accomplished making EP an
attractive and useful tool in asymmetric synthesis.
In particular, much effort has been devoted to developing
efficient catalytic processes with metal enolates derived from
ketones4À6 and amides7 as well as with a large variety of latent
enolates, including mainly silyl enolates,8À17 ketenes,18À24 ke-
tene disilyl acetals,25 malonate derivatives,26,27 and unsaturated
carbonyl compounds.28 Somewhat surprisingly, enol esters re-
main one of the last important classes of latent enolates almost
unexplored in catalytic EP,29 although asymmetric biocatalytic
protonation has already been successfully reported by means of
esterases.30 As an extension of our efforts directed toward the
development of new catalytic EP strategies, we report herein an
efficient nonenzymatic catalytic EP of enol esters under mild and
transition-metal-free conditions. Our approach is based on the
simple use of hydrogenocarbonates not only providing the
protonating agent but also serving as a nucleophilic activator to
release the transient enolate (Figure 1b). A chiral Brønsted base
is expected to act as a chiral proton shuttle to ensure the asymmetric
proton transfer. One can draw some parallels between this
approach and enzymatic hydrolysis of enol esters illustrated in
Figure 1a.
To probe the feasibility of this biomimetic approach, we first
investigated the reactivity of various enol esters 1aaÀ1ac derived
from 2-methyltetralone in the presence of 1.2 equiv of KHCO3
and 10 mol % hydroquinine anthraquinone-1,4-diyl diether
[(DHQ)2AQN], a readily commercially available ligand com-
monly used in Sharpless’s enantioselective dihydroxylation
reactions.31 Although enol acetate 1aa was recovered quantita-
tively under these initial conditions (Table 1, entry 1), enol
trichloroacetate 1ab afforded the desired tetralone 2a in 54%
yield and 28% ee (Table 1, entry 2). The use of the more reactive
Figure 1. (a) Biocatalytic hydrolysis of enol esters by esterases.
(b) Proposed biomimetic approach using MHCO3 as both the nucleo-
philic activator and proton source combined with a chiral Brønsted base.
enol trifluoroacetate 1ac eventually resulted in a substantial
increase in both the yield and the enantioselectivity, providing
2a in 80% yield and 43% ee within 5 h (Table 1, entry 3).
Encouraged by these initial results, we then examined the
impact of the most relevant reaction parameters during protona-
tion of enol trifluoroacetate 1ac (Table 2). Attempts to use
nonpolar solvents such as toluene or dichloromethane afforded
lower enantioselectivities compared to those initially obtained
in acetonitrile (Table 2, entries 1À3). Although the more polar
N-methylpyrrolidone (NMP) did not exhibit better results
(Table 2, entry 4), we were delighted to find that the reaction
performed in DMF and DMSO proceeded with significantly
higher enantioselectivities of 77% and 86%, respectively (Table 2,
entries 5 and 6).
The reaction temperature was also found to have a significant
effect on the stereoinduction. Whereas a noticeable drop in
enantioselectivity was recorded when the reaction temperature
Received: June 9, 2011
Published: June 16, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201146b J. Org. Chem. 2011, 76, 6457–6463
|

The Journal of Organic Chemistry
NOTE
Table 1. Evaluation of Various Enol Esters 1aaÀaca
Table 2. Optimization of Reaction Parameters during EP of
Enol Trifluoroacetate 1aca
entry
R
enol ester 1a
time (h)
yieldb (%)
eed (%)
1
2
3
Me
1aa
1ab
1ac
72
72
5
0
54c
85
CCl3
CF3
28 (S)
43 (S)
a Reactions performed with 1.0 equiv of enol esters 1aaÀac (1 mmol),
1.2 equiv of KHCO3, and 0.1 equiv of (DHQ)2AQN in acetonitrile.
b Isolated yields. c Protonation of enol trichloroacetate 1ab gave rise to
the desired tetralone 2a along with 2-chloro-2-methyltetralone in
30% yield. d Determined by chiral HPLC analysis. The absolute config-
uration was determined by comparison with literature data.
was increased from 20 to 30 °C (Table 2, entry 6), against all
odds, a deleterious impact on the level of stereoinduction was
also observed when the reaction was conducted at 0 °C (Table 2,
entry 5). Consequently, stringent control of the temperature was
essential to achieve optimal enantioselectivity.32 We next studied
the efficiency of this EP process with regard to the catalytic
amount of the Brønsted base. The reaction conducted in the
presence of 20 mol % (DHQ)2AQN did not lead to any further
increase in the enantioselectivity (Table 2, entry 7), whereas a
slight erosion of the level of stereoinduction was observed by
using 5 mol % (DHQ)2AQN (Table 2, entry 8). While changing
the protonating agent from KHCO3 to NaHCO3 did not alter
the performance of the process (Table 2, entries 6 and 9), the use
of CsHCO3 resulted in a somewhat lower enantioselectivity
(Table 2, entry 10). From the outset of this investigation, we
focused our attention on (DHQ)2AQN mainly owing to its good
performance previously reported during catalytic EP of silyl
enolates.14 Surprisingly, when we screened other cinchona
alkaloids, including biscinchona alkaloids such as hydroquinine
2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2PYR, 3e] and
hydroquinine 1,4-phthalazinediyl diether [(DHQ)2PHAL, 3d],
structurally close to (DHQ)2AQN (3f), tetralone 2a was ob-
tained as a racemic mixture in all cases (Table 2, entries 11À14).
Among all other chiral Brønsted bases tested, only Fu’s DMAP
3a furnished a modest 18% ee (Table 2, entry 15). On the basis of
these screening results, (DHQ)2AQN turned out to be the sole
candidate capable of acting as an effective chiral proton shuttle in
this enantioselective process.
The scope of the reaction was then explored under the pre-
viously optimized reaction conditions with various enol trifluoro-
acetates 1acÀo in the tetralone, indanone, and chromanone
series (Table 3). Generally speaking, one can notice that, in all
cases, ketones 2aÀo were isolated in high yields and enantios-
electivities ranging from fair to excellent. With the exception of
enol trifluoroacetate 1k affording tetralone 2k in 55% ee
(Table 3, entry 11), the highest levels of selectivity were obtained
in the tetralone series, reaching 93% ee with enol trifluoroacetate
1f (Table 3, entries 1À10). In the chromanone and indanone
series, while the level of stereoinduction was found to be some-
what lower, it still remained acceptable, giving rise to the
corresponding ketones 2lÀo in enantioselectivities ranging from
69% to 80% ee (Table 3, entries 12À15).
entry
solvent
chiral base
MHCO3
yield b (%)
ee c (%)
1
2
MeCN
toluene
DCM
3f
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
NaHCO3
CsHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
85
90
88
95
84
96
94
88
88
88
81
83
87
92
98
43
3f
29
3
3f
24
4
NMP
3f
45
77 (40)d
86 (78)e
5
DMF
3f
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3f
7
3ff
3fg
3f
85
81
85
70
0
8
9
10
11
12
13
14
15
3f
3b
3c
3d
3e
3a
0
0
0
18
a Reactions were conducted on a 0.5 mmol scale at 18À20 °C unless
otherwise stated. b Isolated yields. Determined by chiral HPLC. The
c
absolute configuration was assigned as S in all cases by comparison with
literature data. d Reaction performed at 0 °C. Reaction performed at
e
30 °C. f A 20 mol % concentration was used. g A 5 mol % concentration
was used.
Although the mechanism of asymmetric induction is not fully
understood at present, some experimental observations that we
have made helped to shed some light on the broad outline of this
EP process (Scheme 1). First and foremost, it is worth noting
that comparable protonation rates could be observed without
any addition of (DHQ)2AQN. This raises the question of how
good levels of enantioselectivity can be reached with catalytic use
of (DHQ)2AQN, whereas no acceleration effect induced by this
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The Journal of Organic Chemistry
NOTE
Table 3. Substrate Scope of the Reactiona
Scheme 1. Plausible Reaction Pathway for the EP of Enol
Trifluoroacetates 1 with KHCO3 in the Presence of
(DHQ)2AQN (3f)
entry
X
R2
R1
1
yieldb (%)
eec (%)
1
2
(CH2)2
H
H
H
H
Me
Et
1ac
1b
1c
1d
1e
1f
85
95
99
80
99
98
88
78
89
95
83
83
75
84
91
86 (S)
81 (S)
3
Bn
F
86 (R)
85 (S)
4
5
5-OMe
5-OMe
5-OMe
6-OMe
6-OMe
6-OMe
7-OMe
H
Me
Bn
o-tol
Me
Bn
allyl
Bn
Me
Bn
Me
Et
89 (nd)
93 (nd)
83 (nd)
72 (nd)
82 (nd)
76 (nd)
55 (nd)
73 (nd)
80 (nd)
69 (S)
6
7
1g
1h
1i
8
9
10
11
12
13
14
15
1j
catalytic EP process. Further studies to gain insight into the
mechanism of this enantioselective process and to explain the
exceptional performances of (DHQ)2AQN are under way in our
laboratory.
1k
1l
OCH2
CH2
H
1m
1n
1o
H
H
73 (S)
a Reactions carried out with 1.0 equiv of enol esters 1 (0.5 mmol),
’ EXPERIMENTAL SECTION
1.2 equiv of KHCO3, and 0.1 equiv of (DHQ)2AQN in DMSO (1 mL)
c
at 18À20 °C. b Isolated yields. Determined by chiral HPLC analysis.
General Experimental Information. CH2Cl2, CH3CN, DMF,
DMSO, and toluene were distilled from CaH2. THF and Et2O were
distilled from Na/benzophenone. All reagents were used as received
from commercial sources unless otherwise indicated. The following
compounds were prepared according to published procedures: 1aa,35
1ab,36 1ac,29 2a,b,c,e,f,n,o,14 2d,m,15 and 2h,i,j,k.17 All these compounds
gave satisfactory 1H and 13C NMR analyses. The potassium enolate of
2-methyl-1-tetralone (2a) was prepared from 1-acetoxy-2-methyltetral-
1-ene (1aa) according to the literature procedure.34 The NMR spectra
were recorded at 300 MHz (1H), 75 MHz (13C), and 282 MHz (19F)
using CDCl3 as the solvent and the residual solvent (δ 7.26, 1H ; δ 77.16,
13C) as the internal standard unless otherwise indicated. Melting points
are uncorrected, and analytical thin layer chromatography (TLC) was
performed on a precoated silica on aluminum and visualized by UV fluores-
cence quenching, vanillin, KMnO4, or PMA staining. Flash chromatog-
raphy was performed with silica gel (70À230 μm) unless otherwise
indicated. HPLC analyses were performed on chiral columns (4.6 mm Â
25 cm) with heptane/2-propanol solvent mixtures and visualization at
254 nm (UV detector) unless otherwise stated. Gas chromatography
was performed on a 30 m  0.25 mm  25 μm column. All experiments
were conducted under a nitrogen atmosphere in oven-dried glassware
with magnetic stirring using standard Schlenk techniques.
Enol Acetate 1aa. 2a (5 mmol, 750 μL) and acetic anhydride (50 mmol,
4.2 mL) were dissolved in CCl4 (3.3 mL) at 0 °C. Some drops of
concentrated HClO4 were added, and the stirred mixture was allowed to
warm to rt. After 1.5 h, the mixture was diluted in precooled saturated
aqueous NaHCO3 solution (10 mL) and extracted with Et2O(3 Â 10 mL).
The combined organic phases were washed with water and dried over
MgSO4 and the solvents removed in vacuum. The residue was purified by
flash chromatography on silica gel (petroleum ether/AcOEt, 95/5) to
afford 1aa as a colorless solid (0.780 g, 77%). Mp: 50À51 °C. 1H NMR
(300 MHz, CDCl3): δ 1.84 (s, 3H), 2.37 (s, 3H), 2.46 (t, 2H, J = 8.0 Hz),
2.93 (t, 2H, J = 8.1 Hz), 7.09À7.11 (m, 1H), 7.12À7.21 (m, 3H). 13C
NMR (75 MHz, CDCl3):δ 16.7, 20.3, 27.3, 28.7, 120.0, 123.9, 126.2, 126.8,
127.2, 130.9, 135.1, 140.0, 168.6. IR (KBr, cmÀ1): 779, 1206, 1748,
1673, 2937.
The absolute configuration was assigned from literature data.
chiral Brønsted base has been highlighted. This is likely made
possible thanks to the poor solubility of hydrogenocarbonates in
most organic solvents, allowing the process to take place under
heterogeneous liquidÀsolid reaction conditions.33 One can
assume that the first step involves the reaction between KHCO3
and the enol trifluoroacetate 1 to afford the tetrahedral intermediate
A. This is supported by the fact that any interaction between
either (DHQ)2AQN and KHCO3 or (DHQ)2AQN and enol
trifluoroacetate 1a could be detected from 1H NMR experiments
conducted in DMSO-d6, suggesting that (DHQ)2AQN is pre-
sumably not involved at an early stage of the reaction pathway.
On the other hand, a control experiment revealed that the
protonation of a preformed potassium enolate, B, prepared from
enol acetate 1aa in DMSO, with a full equivalent of ammonium
trifluoroacetate salt 3f CF3COOH or 3f 2CF3COOH afforded
3
3
2a as a racemic mixture in both cases.34 This result seems to rule
out any mechanism involving late protonation of the free enolate
B by the mono- or diprotonated (DHQ)2AQN salts (Scheme 1,
route 1). In light of these initial data, we currently favor an
alternative mechanism wherein the putative tetrahedral inter-
mediate A would protonate (DHQ)2AQN while triggering a
concerted decarboxylationÀprotonation sequence to give the
enantioenriched ketone 2 together with the regeneration of the
chiral inducer 3f (Scheme 1, route 2).
In conclusion, we have developed an efficient catalytic EP
process of a new class of latent enolates, i.e., enol trifluoroace-
tates. Good to high enantioselectivities and excellent yields were
obtained under mild and straightforward reaction conditions
from a large range of cyclic enol trifluoroacetates. This work
represents a significant contribution in this field by expanding
the panel of valuable latent enolates successfully subjected to a
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NOTE
Enol Trichloroacetetate 1ab. 2a (5 mmol, 750 μL) in trichloroacetic
anhydride (27 mmol, 5 mL) was treated with p-toluenesulfonic acid
(2.9 mmol, 0.5 g). The reaction mixture was heated for 6 h at
130À135 °C until no 2a remained (TLC control). The reaction mixture
was cooled to room temperature and poured into a saturated cold
NaHCO3 solution (10 mL). The reaction mixture was stirred until the
evolution of CO2 release, extracted with Et2O (3 Â 15 mL), dried over
MgSO4, and concentrated. The residue was purified by flash chromato-
graphy on silica gel (petroleum ether/Et2O, 96/4) to afford 1ab (1.2 g,
80%) as a glassy solid. 1H NMR (300 MHz, CDCl3): δ 1.85 (s, 3H), 2.47
(t, 2H, J = 7.8 Hz), 2.9 (t, 2H, J = 7.8 Hz), 7.18 (m, 4H). 13C NMR
(75 MHz, CDCl3): δ 16.6, 27.4, 29.1, 99.9, 119.8, 125.5, 126.7, 127.6,
127.7, 129.8, 135.3, 140.5, 159.9. IR (KBr, cmÀ1): 634, 672, 725, 756, 794,
1063, 1126, 1156, 1604, 1675, 1906, 1942, 2835, 2893, 2927, 3025, 3074.
HRMS (EI, m/z): calcd for C13H11Cl3O2, 303.9825; found, 303.9820.
General Procedures for Synthesis of Enol Trifluoroacetates
1acÀo. Procedure I. A solution of racemic ketones 2aÀm (5 mmol) in
dichloromethane (7.5 mL) was added at 0 °C and under an inert
atmosphere to a solution of 2,6-di-tert-butyl-4-methylpyridine (5 mmol)
and trifluoroacetyl triflate (10 mmol) in dichloromethane (7.5 mL). After
being stirred for 16 h at the same temperature, the mixture was con-
centrated in vacuum and the residue was diluted with Et2O. The resulting
precipitate was filtered, and the filtrate was washed with brine and dried
over MgSO4. The solvent was removed under vacuum to afford enol
trifluoroacetates 1acÀm, which could be used in enantioselective pro-
tonation reaction without further purification.
Procedure II. A solution of racemic ketones 2n,o (1.5 mmol) and tri-
fluororacetic anhydride (40 mmol, 6 mL) was refluxed until complete
consumption of the starting material (monitored by GC). The volatile
compounds were removed under vacuum to afford enol trifluoroacetates
1n,o, which could be used in enantioselective protonation reaction
without further purification.
2-Methyl-1-(trifluoroacetoxy)tetral-1-ene (1ac). This compound was
preparedaccording to procedureIfrom2a(801 mg, 5 mmol) asadarkred
oil (1.18 g, 92% yield). 1H NMR (300 MHz, CDCl3): δ 1.81 (s, 3H), 2.46
(t, 2H, J = 7.8 Hz), 2.90 (t, 2H, J = 7.8 Hz), 6.98À7.14 (m, 1H),
7.13À7.26 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 16.7, 27.3, 29.0,
114.9 (q, J = 284 Hz), 119.7, 125.5, 126.8, 127.7, 127.8, 129.3, 135.3,
139.5, 155.4 (q, J = 42 Hz). 19F NMR (282 MHz, CDCl3): δ À74.50. IR
(KBr, cmÀ1): 748, 765, 1136, 1170, 1225, 1276, 1681, 1799, 2936. HRMS
(EI, m/z): calcd for C13H11F3O2, 256.0711; found, 256.0714.
(m, 2H), 3.09 (td, 2H, J = 8.1 Hz, J = 2.4 Hz), 7.05À7.08 (m, 1H),
7.14À7.23 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 24.3 (d, J = 3.4 Hz),
27.6 (d, J = 6.8), 114.8 (q, J = 284 Hz), 120.3 (d, J = 6.8 Hz), 126.3 (d,
J = 12.8 Hz), 127.2, 127.9, 128.1 (d, J = 2.3 Hz), 128.3, 132.4, 151.6 (d,
J = 273 Hz), 155.6 (q, J = 44 Hz). 19F NMR (282 MHz, CDCl3): δ
À74.26, À115.3. IR (KBr, cmÀ1): 750, 1169, 1229, 1707, 1806, 2952,
3074. HRMS (EI, m/z): calcd for C12H8F4O2, 260.0460; found, 260.0479.
5-Methoxy-2-methyl-1-(trifluoroacetoxy)tetral-1-ene (1e). This com-
pound was prepared according to procedure I from 2e (951 mg, 5 mmol)
1
as a red oil (1.16 g, 81% yield). H NMR (300 MHz, CDCl3): δ 1.80
(s, 3H), 2.44 (t, 2H, J = 8.4 Hz), 2.90 (t, 2H, J = 8.4 Hz), 3.84 (s, 3H), 6.66
(d, 1H, J = 7.8 Hz), 6.81 (d, 1H, J = 8.4 Hz), 7.13À7.19 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ 16.6, 19.7, 28.5, 55.6, 110.4, 112.5, 114.9
(q, J = 284 Hz), 123.1, 125.6, 127.2, 130.4, 139.4, 155.5 (q, J = 42 Hz),
156.3. 19F NMR (282 MHz, CDCl3): δ À74.52. IR (KBr, cmÀ1): 740,
1054, 1140, 1175, 1225, 1265, 1682, 1798, 2921, 3048. HRMS (CI+, m/z):
calcd for C14H14F3O2 [M + H]+, 287.0895; found, 287.0911.
2-Benzyl-5-methoxy-1-(trifluoroacetoxy)tetral-1-ene (1f). This com-
pound was prepared according to procedure I from 2f (1.33 g, 5 mmol) as
a red oil (1.79 g, 99% yield). 1H NMR (300 MHz, CDCl3): δ 2.29 (t, 2H,
J =8.4 Hz), 2.82(t, 2H, J =8.4 Hz), 3.48(s, 2H), 3.78 (s, 3H), 6.69 (d, 1H,
J = 7.8 Hz), 7.01 (d, 1H, J = 8.4 Hz), 7.13À7.31 (m, 6H). 13C NMR
(75 MHz, CDCl3): δ 19.8, 26.2, 36.5, 55.6, 110.8, 113.0, 114.9 (q,
J = 284 Hz), 123.6, 126.8, 127.3, 128.1, 128.8 (2C), 129.0 (2C), 130.2,
137.8, 140.1, 155.9 (q, J = 43 Hz), 156.7. 19F NMR (282 MHz, CDCl3):
δ À74.33. IR (KBr, cmÀ1): 700, 718, 744, 770, 788, 1046, 1115, 1136,
1169, 1225, 1263, 1582, 1601, 1681, 1798, 2838, 2935, 3028. HRMS (CI+,
m/z): calcd for C20H18F3O3 [M + H]+, 363.1208; found, 363.1205.
5-Methoxy-2-(2-methylbenzyl)-1-(trifluoroacetoxy)tetral-1-ene (1g).
This compound was prepared according to procedure I from 2g (1.40 g,
1
5 mmol) as a glassy solid (1.77 g, 94% yield). H NMR (300 MHz,
CDCl3): δ 2.26 (t, 2H, J = 8.1 Hz), 2.31 (s, 3H), 2.85 (t, 2H, J = 8.4 Hz),
3.52(s, 2H),3.84(s, 3H), 6.72(d, 1H, J=7.8 Hz), 6.84 (d, 1H, J=8.1Hz),
7.15À7.23 (m, 5H). 13CNMR (75MHz, CDCl3): δ19.6, 19.8, 26.0, 34.0,
55.6, 110.8, 112.9, 115.1 (q, J = 284 Hz), 123.5, 126.2, 126.9, 127.2, 127.5,
129.6, 130.2, 130.4, 135.7, 136.9, 140.0, 155.9 (q, J= 42 Hz), 156,5. 19FNMR
(282 MHz, CDCl3): δ À74.37. IR (KBr, cmÀ1): 723, 743, 760, 781, 1041,
1141, 1170, 1224, 1579, 1682, 1796, 2840, 2895, 2934, 3011, 3079. HRMS
(CI+, m/z): calcd for C21H20F3O3 [M + H]+, 377.1364; found, 377.1354.
6-Methoxy-2-methyl-1-(trifluoroacetoxy)tetral-1-ene (1h). This com-
pound was prepared according to procedure I from 2h (951 mg, 5 mmol)
as a glassy solid (1.39 g, 97% yield). 1H NMR (300 MHz, CDCl3): δ 1.79
(s, 3H), 2.43 (t, 2H, J = 8.4 Hz), 2.87 (t, 2H, J = 8.1 Hz), 3.79 (s, 3H),
6.70À6.73 (m, 2H), 6.92À6.95 (m, 1H). 13C NMR (75 MHz, CDCl3): δ
16.4, 27.3, 28.9, 55.3, 111.1, 114.1, 114.9 (q, J = 284 Hz), 120.9, 122.3,
122.4, 137.2, 139.3, 155.4 (q, J = 43 Hz), 159.3. 19F NMR (282 MHz,
CDCl3): δ À74.53. IR (KBr, cmÀ1): 770, 1037, 1137, 1226, 1256, 1606,
1681, 1798, 2935. HRMS (CI+, m/z): calcd for C14H14F3O3 [M + H]+,
287.0895; found, 287.0897.
2-Benzyl-6-methoxy-1-(trifluoroacetoxy)tetral-1-ene (1i). This com-
pound was prepared according to procedure I from 2i (1.33 g, 5 mmol) as
a brown oil (1.76 g, 97% yield). 1H NMR (300 MHz, CDCl3): δ 2.37
(t, 2H, J = 8.1 Hz), 2.86 (t, 2H, J = 8.1 Hz), 3.54 (s, 2H), 3.84 (s, 3H), 6.79
(d, 2H, J = 7.8 Hz), 7.034 (d, 1H, J = 8.1 Hz), 7.28À7.40 (m, 5H). 13C
NMR (75 MHz, CDCl3): δ 26.5, 28.0, 36.3, 55.3, 111.3, 114.2, 114.9 (q,
J = 284 Hz), 121.5, 122.0, 125.1, 126.7, 128.7 (2C), 128.9 (2C), 137.6,
138.0, 140.0, 156.9 (q, J = 43 Hz), 159.6. 19F NMR (282 MHz, CDCl3):
δ À74.32. IR (KBr, cmÀ1): 705, 752, 1141, 1177, 1220, 1255, 1602, 1673,
1794, 2838, 2940, 3028, 3066. HRMS (CI+, m/z): calcd for C20H18F3O3
[M + H]+, 363.1208; found, 363.1210.
2-Ethyl-1-(trifluoroacetoxy)tetral-1-ene (1b). This compound was
prepared according to procedure I from 2b (871 mg, 5 mmol) as an
orange oil (1.26 g, 93% yield). 1H NMR (300 MHz, CDCl3): δ 1.08 (t,
3H, J = 7.5 Hz), 2.18 (q, 2H, J = 7.5 Hz), 2.46 (t, 2H, J = 7.8 Hz), 2.90 (t,
2H, J = 7.8 Hz), 6.98À6.99 (m, 1H), 7.15À7.21 (m, 3H). 13C NMR (75
MHz, CDCl3): δ 11.9, 23.9, 26.59, 27.8, 115.2 (q, J = 284 Hz), 120.1,
127.0, 127.9, 128.1, 129.6, 131.2, 135.7, 139.0, 156.0 (q, J = 43 Hz). 19F
NMR (282 MHz, CDCl3): δ À74.49. IR (KBr, cmÀ1): 748, 1135, 1168,
1225, 1668, 1799, 2881, 2940, 2974. HRMS (EI, m/z): calcd for
C14H13F3O2, 270.0868; found, 270.0872.
2-Benzyl-1-(trifluoroacetoxy)tetral-1-ene (1c). This compound was
prepared according to procedure I from 2c (1.18 g, 5 mmol) as an orange
1
oil (1.58 g, 95% yield). H NMR (300 MHz, CDCl3): δ 2.34 (t, 2H,
J = 8.1 Hz), 2.86 (t, 2H, J = 8.1 Hz), 3.51 (s, 2H), 7.03À7.06 (m, 1H),
7.13À7.34 (m, 8H). 13C NMR (75 MHz, CDCl3): δ 26.6, 27.5, 36.5,
111.2 (q, J = 284 Hz), 120.2, 126.8, 126.9, 127.8, 128.2, 128.2, 128.8
(2C), 129.0 (2C), 129.1, 135.7, 137.8, 140.2, 155.9 (q, J = 43 Hz). 19F
NMR (282 MHz, CDCl3): δ À74.34. IR (KBr, cmÀ1): 702, 748, 766,
1133, 1170, 1226, 1668, 1799, 2935, 3028, 3064. HRMS (EI, m/z): calcd
for C19H15F3O2, 332.1024; found, 332.1023.
2-Allyl-6-methoxy-1-(trifluoroacetoxy)tetral-1-ene (1j). This com-
pound was prepared according to procedure I from 2j (1.08 g, 5 mmol)
as a brown oil (1.48 g, 95% yield). 1H NMR (300 MHz, CDCl3): δ 2.44
(t, 2H, J = 8.1 Hz), 2.88 (t, 4H, J = 8.4 Hz), 3.82 (s, 3H), 5.10À5.20
2-Fluoro-1-(trifluoroacetoxy)tetral-1-ene (1d). This compound was
prepared according to procedure I from 2d (821 mg, 5 mmol) as a brown
1
oil (1.08 g, 83% yield). H NMR (300 MHz, CDCl3): δ 2.73À2.80
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The Journal of Organic Chemistry
NOTE
(m, 2H), 5.71À5.89 (m, 1H), 6.72À6.75 (m, 2H), 6.94À6.96 (m, 1H).
13C NMR (75 MHz, CDCl3): δ 26.7, 28.0, 34.9, 55.4, 111.3, 113.0, 114.9
(q, J = 284 Hz), 117.2, 121.4, 122.3, 124.1, 133.7, 137.6, 149.9, 155.7
(q, J = 42 Hz), 155.6. 19F NMR (282 MHz, CDCl3): δ À74.51. IR
(KBr, cmÀ1): 768, 1134, 1168, 1126, 1255, 1602, 1638, 1674, 1799,
2838, 2937, 3079. HRMS (CIÀ, m/z): calcd for C16H15F3O3, 312.0973;
found, 312.0952.
2-Benzyl-7-methoxy-1-(trifluoroacetoxy)tetral-1-ene (1k). This com-
pound was prepared according to procedure I from 2k (1.33 g, 5 mmol) as
a brown oil (1.58 g, 87% yield). 1H NMR (300 MHz, CDCl3): δ 2.33
(t, 2H, J = 8.1 Hz), 2.78 (t, 4H, J = 8.1 Hz), 3.52 (s, 2H), 3.80 (s, 3H), 6.63
(d, 1H, J = 2.7 Hz), 6.74À6.77 (m, 1H), 7.05À7.20 (m, 1H), 7.20À7.35
(m, 5H). 13C NMR (75 MHz, CDCl3): δ 26.7, 27.1, 36.6, 55.4, 106.7,
113.0, 115.1 (q, J = 287 Hz), 126.8, 127.8, 128.6, 128.8, 128.9 (2C), 129.0
(2C), 130.2, 137.8, 140.0, 155.8 (q, J = 42 Hz), 158.7. 19F NMR (282
MHz, CDCl3): δ À74.36. IR (KBr, cmÀ1): 702, 755, 1038, 1135, 1171,
1223, 1609, 1790, 1681, 2936. HRMS (CI+, m/z): calcd for C20H18F3O3
[M + H]+, 363.1208; found, 363.1221.
washed with brine (3 Â 10 mL), dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (petroleum ether/AcOEt,
95/5, as eluent) to afford the pure ketones 2aÀo, which were analyzed by
HPLC using a chiral column. A control experiment indicated that no
racemization was observed when 2a was stirred in DMSO for 1.5 h in the
presence of potassium trifluoroacetate (1 equiv).
2-Methyltetralone (2a). Enantioenriched 2a (68 mg, 85% yield) was
prepared according to the general procedure from 1ac (128 mg,
0.5 mmol) in 86% ee. HPLC: OD-H, heptane/2-propanol, 99.6/0.4,
flow rate 0.5 mL/min, 20 °C, retention time of both enantiomers, 7.52 min
(minor), 8.29 min (major, S enantiomer). The absolute configuration
was assigned by comparison with literature data.27
2-Ethyltetralone (2b). Enantioenriched 2b (83 mg, 95% yield) was
prepared according to the general procedure from 1b (135 mg, 0.5 mmol)
in 81% ee. HPLC: AD-H, heptane/2-propanol, 99.96/0.04, flow rate
1.2 mL/min, 20 °C, retention time of both enantiomers, 14.41 min
(major, S enantiomer), 16.54 min (minor). The absolute configuration
was assigned by comparison with literature data.11
2-Benzyltetralone (2c). Enantioenriched 2c (117 mg, 99% yield) was
prepared according to the general procedure from 1c (166 mg, 0.5 mmol)
in86% ee. HPLC: OJ-H, heptane/2-propanol, 90/10, flow rate 1 mL/min,
20 °C, retention time of both enantiomers, 9.48 min (major, R en-
antiomer), 11.65 min (minor). The absolute configuration was assignedby
comparison with literature data.37
2-Fluorotetralone (2d). Enantioenriched 2d (66 mg, 80% yield) was
prepared according to the general procedure from 1d (130 mg, 0.5 mmol)
in 85% ee. HPLC: Daicel Chiralcel OJ-H, heptane/2-propanol, 95/5,
flow rate 1 mL/min, 20 °C, retention time of both enantiomers, 13.65 min
(major, S enantiomer), 15.04 min (minor). The absolute configuration
was assigned by comparison with literature data.15
5-Methoxy-2-methyltetralone (2e). Enantioenriched 2e (94 mg, 99%
yield) was prepared according to the general procedure from 1e (143 mg,
0.5 mmol) in 89% ee. HPLC: AD-H, heptane/2-propanol, 99.8/0.2, flow
rate 1 mL/min, 20 °C, retention time of both enantiomers, 13.57 min
(major), 17.66 min (minor).
2-Benzyl-5-methoxytetralone (2f). Enantioenriched 2f (130 mg, 98%
yield) was prepared according to the general procedure from 1f (181 mg,
0.5 mmol) in 93% ee. HPLC: OB, heptane/2-propanol, 99/1, flow rate
1 mL/min, 20 °C, retention time of both enantiomers, 15.80 min (major),
28.34 min (minor).
5-Methoxy-2-(2-methylbenzyl)tetralone (2g). Enantioenriched 2g
(123 mg, 88% yield) was prepared according to the general procedure
from 1g (188 mg, 0.5 mmol) as a pale yellow solid in 83% ee. Mp:
69À70 °C. 1H NMR (300 MHz, CDCl3): δ 1.76À1.85 (m, 1H),
2.09À2.18 (m, 1H), 2.34 (s, 3H), 2.5À2.74 (m, 3H), 3.08 (dt, 1H,
J = 18.0 Hz, J = 4.5 Hz), 3.58 (dd, 1H, J = 3.9 Hz, J = 14.1 Hz), 3.86 (s,
3H), 7.02 (d, J = 8.1 Hz), 7.15 (s, 4H), 7.29 (t, 1H, J = 8.1 Hz), 6.9 (d,
1H, J = 7.8 Hz). 13C NMR (75 MHz, CDCl3): δ 19.9, 22.5, 27.4, 33.2,
48.0, 56.0, 114.4, 119.4, 125.1, 126.6, 127.2, 130.4, 130.8, 133.3, 133.9,
135.8, 138.67, 157.1, 200.2. IR (KBr, cmÀ1): 750, 764, 795, 1195, 1224,
1260, 1539, 1599, 2833, 2851, 2915, 2950, 3004, 3064. HRMS (CI+, m/
z): calcd for C19H21O2 (M + H)+, 281.1541; found, 281.1547. HPLC:
OD-H, heptane/2-propanol, 99/1, flow rate 0.8 mL/min, 20 °C, reten-
tion time of both enantiomers, 14.11 min (minor), 14.99 min (major).
6-Methoxy-2-methyltetralone (2h). Enantioenriched 2h (74 mg,
78% yield) was prepared according to the general procedure from 1h
(143 mg, 0.5 mmol) in 72% ee. HPLC: OB, heptane/2-propanol, 99.8/
0.2, flow rate 0.8 mL/min, 20 °C, retention time of both enantiomers,
41.99 min (major), 55.19 min (minor).
3-Methyl-4-(trifluoroacetoxy)-(2H)-chromene (1l). This compound
was prepared according to procedure I from 2l (811 mg, 5 mmol) as an
orange oil (1.02 g, 83% yield). 1H NMR (300 MHz, CDCl3): δ 1.69 (s,
3H), 4.86 (s, 2H), 6.82À6.84 (m, 1H), 6.90À6.91 (m, 2H), 7.12À7.20
(m, 1H). 13C NMR (75 MHz, CDCl3): δ 12.6, 69.4, 114.8 (q, J = 284
Hz), 116.1, 117.8, 119.0, 120.2, 121.6, 130.0, 136.6, 154.0, 155.0 (q,
J = 43 Hz). 19F NMR (282 MHz, CDCl3): δ À74.37. IR (KBr, cmÀ1):
759, 1037, 1148, 1609, 1636, 2925, 3383. HRMS (EI, m/z): calcd for
C12H9F3O3, 258.0504; found, 258.0489.
3-Benzyl-4-(trifluoroacetoxy)-(2H)-chromene (1m). This compound
was prepared according to procedure I from 2m (1.19 g, 5 mmol) as a
yellow oil (1.54 g, 92% yield). 1H NMR (300 MHz, CDCl3): δ 3.44, (s,
2H), 4.74 (s, 2H), 6.81À6.84 (m, 1H), 6.92À6.96 (m, 2H), 7.15À7.34
(m, 6H). 13C NMR (75 MHz, CDCl3): δ 33.5, 67.9, 114.7 (q, J = 284
Hz), 116.3, 117.8, 120.7, 121.4, 121.8, 127.3, 128.8 (2C), 129.1 (2C),
130.4, 135.9, 137.4, 154.2, 155.4 (q, J = 44 Hz). 19F NMR (282 MHz,
CDCl3): δ À74.20. IR (KBr, cmÀ1): 700, 757, 1032, 1133, 1170, 1224,
1606, 1636, 1687, 1802, 2920, 3030, 3068. HRMS (CIÀ, m/z): calcd for
C18H13F3O3, 334.08178; found, 334.0810.
2-Methyl-3-(trifluoroacetoxy)indan-1-ene (1n). This compound was
prepared according to procedure II from 2n (219 mg, 1.5 mmol) as an
orange oil (301 mg, 83% yield). 1H NMR (300 MHz, CDCl3): δ 2.03 (s,
3H), 3.40 (s, 2H), 7.09 (d, 1H, J = 7.2 Hz), 7.20À7.32 (m, 2H), 7.40
(d, 1H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 12.3, 39.4, 114.8 (q,
J = 284 Hz), 117.0, 124.1, 125.5, 126.7, 130.0, 138.0, 139.9, 142.8, 155.0
(q, J = 43 Hz). 19F NMR (282 MHz, CDCl3): δ À74.31. IR (KBr, cmÀ1):
714, 754, 1140, 1231, 1355, 1735, 1802, 2920. HRMS (CI+, m/z): calcd
for C12H10F3O2, [M + H]+ 243.0633; found, 243.0630.
2-Ethyl-3-(trifluoroacetoxy)indan-1-ene (1o). This compound was
prepared according to procedure II from 2o (240 mg, 1.5 mmol) as a
brown oil (327 mg, 85% yield). 1H NMR (300 MHz, CDCl3): δ 1.21
(t, 3H, J = 7.5 Hz), 2.45 (q, 2H, J = 7.5 Hz), 3.42 (s, 2H), 7.11 (d, 1H,
J = 7.2 Hz), 7.21À7.34 (m, 2H), 7.43 (d, 1H, J = 7.2 Hz). 13C NMR (75
MHz, CDCl3): δ 13.1, 20.1, 36.9, 114.8 (q, J = 284 Hz), 117.1, 124.3,
125.6, 126.8, 135.7, 138.0, 140.0, 141.9, 155.2 (q, J = 43 Hz). 19F NMR
(282 MHz, CDCl3): δ À74.32. IR (KBr, cmÀ1): 753, 1140, 1170, 1229,
1354, 1802, 2974. HRMS (CI+, m/z): calcd for C13H12F3O2, [M + H]+
257.0789; found, 257.0793.
General Procedure for Catalytic Enantioselective Proton-
ation of Enol Trifluoroacetates 1acÀo. Freshly distilled DMSO
(1 mL) was added to (DHQ)2AQN (0.05 mmol, 43 mg) and dry
potassium hydrogenocarbonate (0.6 mmol, 60 mg). After stabilization of
the temperature to 18À20 °C and complete solubilization of (DHQ)2-
AQN, enol trifluoroacetates 1acÀo(0.5 mmol) were added to the mixture.
The reaction was stirred at 18À20 °C until complete disappearance of
1acÀo(monitored by GC). The solution was diluted with AcOEt (10 mL),
2-Benzyl-6-methoxytetralone (2i). Enantioenriched 2i (119 mg, 89%
yield) was prepared according to the general procedure from 1i (181 mg,
0.5 mmol) in 82% ee. HPLC: OJ-H, heptane/2-propanol, 90/10, flow
rate 1 mL/min, 20 °C, retention time of both enantiomers, 14.95 min
(major), 19.22 min (minor).
6461
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The Journal of Organic Chemistry
NOTE
2-Allyl-6-methoxytetralone (2j). Enantioenriched 2j (103 mg, 95%
yield) was prepared according to the general procedure from 1j (156 mg,
0.5 mmol) in 76% ee. HPLC: AD-H, heptane/2-propanol, 99.8/0.2, flow
rate 1 mL/min, 20 °C, retention time of both enantiomers, 42.68 min
(major), 54.56 min (minor).
chromatograms for enantioenriched ketones 2aÀo. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
2-Benzyl-7-methoxytetralone (2k). Enantioenriched 2k (132 mg, 99%
yield) was prepared according to the general procedure from 1k (181 mg,
0.5 mmol) in55% ee. HPLC: OJ-H, heptane/2-propanol, 90/10, flow rate
1 mL/min, 20 °C, retention time of both enantiomers, 14.21 min (major),
16.32 min (minor).
Corresponding Author
*E-mail: vincent.levacher@insa-rouen.fr; sylvain.oudeyer@
insa-rouen.fr . Phone: +33(0)235522485. Fax: +33(0)235522962.
2-Methylchromanone (2l). Enantioenriched 2l (67 mg, 83% yield)
was prepared according to the general procedure from 1l (123 mg,
0.5 mmol) as a pale yellow oil in 73% ee. 1H NMR (300 MHz, CDCl3):
δ 1.20 (d, 2H, J = 7.2 Hz), 2.78À2.91 (m, 1H), 4.13 (t, 1H, J = 11.1),
4.46À4.51 (m, 1H), 6.92À7.02 (m, 2H), 7.41À7.47 (m, 1H), 7.89 (d, 1H,
J = 1.5 Hz). 13C NMR (75 MHz, CDCl3): δ 10.8, 40.8, 72.3, 117.8,
120.6, 121.4, 127.4, 135.8, 161.8, 194.9. IR (KBr, cmÀ1): 756, 1297,
1694, 2876, 2973. HRMS (EI, m/z): calcd for C10H10O2, 162.0681;
found, 162.0681. HPLC: OJ-H, heptane/2-propanol, 99.6/0.4, flow rate
1 mL/min, 20°C, retention timeofbothenantiomers, 14.90 min (minor),
16.72 min (major).
2-Benzylchromanone (2m). Enantioenriched 2m (95 mg, 80% yield)
was prepared according to the general procedure from 1m (167 mg,
0.5 mmol) in 75% ee. HPLC: OD-H, heptane/2-propanol, 99.2/0.8,
flow rate 1 mL/min, 20 °C, retention time of both enantiomers, 18.38 min
(minor), 20.48 min (major).
’ ACKNOWLEDGMENT
This work was supported by the CNRS, Universitꢀe et INSA de
Rouen, andRꢀegion Haute-Normandie. A.C. thanksthe CRUNCH
network for a grant.
’ REFERENCES
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Angew. Chem., Int. Ed. Engl. 1996, 35, 2566. (b) Eames, J.; Weerasooriya,
N. Tetrahedron: Asymmetry 2001, 12, 1. (c) Duhamel, L.; Duhamel, P.;
Plaquevent, J. C. Tetrahedron: Asymmetry 2004, 15, 3653. (d) Mohr,
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(8) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am.
Chem. Soc. 1996, 118, 12854.
2-Methylindanone (2n). Enantioenriched 2n (61 mg, 84% yield)
was prepared according to the general procedure from 1n (121 mg,
0.5 mmol) in 69% ee. HPLC: OJ-H, heptane/2-propanol, 99.6/0.4, flow
rate 1 mL/min, 20 °C, retention time of both enantiomers, 15.58 min
(major, S enantiomer), 18.62 min (minor). The absolute configuration
was assigned by comparison with literature data.27
2-Ethylindanone (2o). Enantioenriched 2o (73 mg, 91% yield) was
prepared according to the general procedure from 1o (128 mg, 0.5 mmol) in
73% ee. HPLC: OJ-H, heptane/2-propanol, 99.6/0.4, flow rate 1 mL/min,
20 °C, retention time of enantiomers, 10.51 min (major, S enantiomer),
12.80 min (minor). The absolute configuration was determined by analogy
with that of 2n.
(9) Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
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Protonation of the Potassium Enolate of 2-Methyltetra-
lone by (DHQ)2AQN CF3COOH or (DHQ)2AQN 2CF3COOH.
3
3
A solution of (DHQ)2AQN CF3COOH or (DHQ)2AQN 2CF3COOH
3
3
was previously prepared by addition of 0.5 mmol of CF3COOH (37 μL)
or 1 mmol of CF3COOH (74 μL), respectively, to a solution of
(DHQ)2AQN (0.5 mmol, 429 mg) in DMSO (1.2 mL) under an inert
atmosphere and was stirred for 3 h.
A solution of 1aa (0.5 mmol, 100 mg) in DMSO at room temperature
(0.6 mL) was added to a mixture of t-BuOK (56 mg, 0.5 mmol) in
DMSO (0.2 mL). After 30 min (red solution) and control of the
disappearance of the starting material (monitored by GC), the solution
of (DHQ)2AQN CF3COOH or (DHQ)2AQN 2CF3COOH (0.5 mmol)
(18) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999,
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3
3
in DMSO at room temperature (1.2 mL) was added to the previous
stirred solution. After 1 h, the solution was diluted with AcOEt (20 mL)
and washed with water (20 mL), and the aqueous layer was extracted
with AcOEt (2 Â 20 mL). The combined organic layers were washed
with brine (3 Â 50 mL) and dried over MgSO4. The solvent was removed
under vacuum, and the residue was purified by flash chromatography
(petroleum ether/AcOEt, 95/5), affording the pure 2-methyltetralone
(63 mg, 79%) as a racemic mixture according to chiral HPLC analysis.
(19) Blake, A. J.; Friend, C. L.; Outram, R. J.; Simpkins, N. S.;
Whitehead, A. J. Tetrahedron Lett. 2001, 42, 2877.
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(26) Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.; Rouden, J.
Eur. J. Org. Chem. 2008, 5493 and references therein.
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Chem. Soc. 2006, 128, 11348.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra for
b
all new compounds and control experiments and HPLC
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The Journal of Organic Chemistry
NOTE
(28) For selected examples of conjugated addition/protonation
sequences, see: (a) Pracejus, H.; Wilcke, F. W.; Hanemann, K. J. Prakt.
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