Chiral amino diol derivatives as new modular organocatalysts for the enantioselective α-chlorination of cyclic β-keto esters

Article abstract of DOI:10.1002/adsc.201000594

Highly modular chiral amino diol derivatives have been used as organocatalysts in the enantioselective α-chlorination of cyclic β-keto esters. Optimization of the catalyst structure and the reaction conditions has allowed the synthesis of optically active α-chlorinated products with high enantioselectivities (up to 96% ee) using inexpensive commercially available N-chlorosuccinimide (NCS) as the chlorine source under mild conditions. Copyright

Full text of DOI:10.1002/adsc.201000594

FULL PAPERS
DOI: 10.1002/adsc.201000594
Chiral Amino Diol Derivatives as New Modular Organocatalysts
for the Enantioselective a-Chlorination of Cyclic b-Keto Esters
Pablo Etayo,a,b Ramꢀn Badorrey,a Marꢁa D. Dꢁaz-de-Villegas,a,*
and Josꢂ A. Gꢃlveza,*
a
Departamento de Quꢁmica Orgꢃnica, Instituto de Ciencia de Materiales de Aragꢀn, Instituto Universitario de Catꢃlisis
Homogꢂnea, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Fax : (+34)-976-761-202; phone: (+34)-976-762-274; e-mail: loladiaz@unizar.es or jagl@unizar.es
Present address: Institute of Chemical Research of Catalonia (ICIQ), Avgda. Paꢄsos Catalans 16, 43007 Tarragona, Spain
b
Received: July 26, 2010; Revised: October 18, 2010; Published online: December 7, 2010
Abstract: Highly modular chiral amino diol deriva- cially available N-chlorosuccinimide (NCS) as the
tives have been used as organocatalysts in the enan- chlorine source under mild conditions.
tioselective a-chlorination of cyclic b-keto esters.
Optimization of the catalyst structure and the reac-
tion conditions has allowed the synthesis of optically Keywords: amines; asymmetric catalysis; chlorina-
active a-chlorinated products with high enantioselec- tion; enantioselectivity; b-keto esters; organocataly-
tivities (up to 96% ee) using inexpensive commer- sis
Introduction
polyhalogenated quinolinone as the halogen source.
Under these conditions the reactivity significantly de-
The importance of a-halocarbonyl compounds as syn- creased and the presence of an inorganic base was
thetically useful intermediates for a range of differ- necessary to reach moderate to good yields. Very re-
ently functionalized valuable building blocks in organ- cently Feng et al.[15] described the use of a series of
ic synthesis and precursors of biologically active chiral N,N’-dioxides as organocatalysts in the enantio-
drugs[1] has led to increased interest in the develop- selective a-chlorination of b-keto esters using easily
ment of stereocontrolled syntheses of these com- available N-chlorosuccinimide (NCS) as the chlorine
pounds.[2] Among the existing approaches, the catalyt- source. The use of low temperature with an optimized
ic enantioselective halogenation of carbonyl com- organocatalyst gave good yields and high levels of
pounds provides a reliable and efficient procedure to enantioselectivity but only in the a-chlorination of 1-
generate the stereogenic carbon attached to the halo- oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylates.
gen atom[3] and considerable effort has recently been
As a part of a research program related to the de-
devoted to the development of sustainable enantiose- velopment of new organocatalysts we assessed the use
lective routes based on the use of chiral organocata- of chiral amino diol derivatives in the enantioselective
lysts.[4–7]
a-chlorination of a series of cyclic b-keto esters.
Several metal-mediated approaches for the enantio-
selective a-chlorination of b-keto esters have been re-
ported using chiral Ti(TADDOLato) complexes,[8] bis- Results and Discussion
ACHTUNGTRENNUNG
oxazoline-copper complexes,[9] bisoxazoline-nickel
complexes,[10] sulfoximine-copper complexes,[11] oxazo- The general structure of chiral amino diol derivatives
line-Schiff base-copper complexes,[12] or Jacobsenꢅs C used as organocatalysts in this work is illustrated in
salen-cobalt complexes.[13] However, the organocata- Figure 1.
lytic enantioselective a-chlorination of b-keto esters
remains relatively unexplored.
This kind of chiral acyclic secondary amine is easily
accessible in enantiomerically pure form by diastereo-
In 2005 Melchiorre et al.[14] described the first orga- selective addition of organometallic reagents to
nocatalytic enantioselective a-chlorination of b-keto imines derived from conveniently protected d-glycer-
esters using O-benzoylquinine as the organocatalyst. aldehyde according to our previously optimized meth-
Good levels of enantioinduction (80–96% ee) were odology.[16] The main advantage of these chiral orga-
obtained on working at low temperature and using a nocatalysts is the ease of tuning by simply selecting
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Figure 2. Structure of chiral amino diol derivative C3’.
Figure 1. Chiral amino diol derivatives C used as organoca-
talysts in the enantioselective a-chlorination of b-keto
esters.
The influence of the nature of the substituent R2 on
the nitrogen was investigated next (Scheme 2). It was
observed that N-benzylamines C3 and C8 gave higher
the organometallic reagent, the amine and the ketal enantioselectivities than N-phenylamine C9, N-allyl-
moiety. As a consequence, three points for structural
diversity (R1, R2 and R3, respectively) can be varied.
To identify the best organocatalyst structure race-
mic ethyl-2-oxocyclopentane carboxylate 1a was
chosen as the model substrate and an initial survey of
the behaviour of chiral amino diol derivatives in the
enantioselective a-chlorination was carried out with
compounds C1–C7, which have an anti relative config-
uration. Chlorination of 1a with NCS (2) (1.2 equiv.)
in the presence of the enantiopure amino diol deriva-
tive (10 mol%) using toluene as solvent was investi-
gated first (Scheme 1). We were pleased to find that
a-chlorination of 1a proceeded smoothly and, after
stirring overnight at room temperature, conversion
into ethyl 1-chloro-2-oxocyclopentane carboxylate 3a
was complete, except when C4 was used as the orga-
Scheme 2. Enantioselective a-chlorination of 1a with chiral
nocatalyst (Scheme 1). The enantioselectivity – deter- amino diol derivatives C8–C12 as organocatalysts.
mined by GC using a Chiraldexꢇ G-TA column – was
low and depended on the substituent R1 on the hydro-
carbon skeleton. Vinyl-substituted catalysts (C3, C4)
led to better ee values that the alkyl (C1, C2), aryl version was not complete with N-phenyl- and N-allyl-
(C5, C6) or benzyl (C7) substituted counterparts. amines. Comparison of catalysts C3 and C12 shows
ACHTUNGTRENaNUNG mine C10 or N-homoallylamine C11. Moreover, con-
A change in the stereochemistry of the organocata- that the introduction of an additional phenyl substitu-
lyst was detrimental and the use of compound C3’ ent at the benzylic position had a detrimental effect
(Figure 2) with a syn relative configuration, as the or- on both conversion and enantioselectivity.
ganocatalyst gave compound 3a with a disappointing
3% ee.
The data shown in Scheme 3 enable a comparison
of the catalytic properties of chiral amino diol deriva-
tives as a function of substituent R3. Organocatalysts
C13–C23 afforded ethyl 1-chloro-2-oxocyclopentane
carboxylate 3a with total conversion after stirring
overnight at room temperature. The nature of the
substituent linked to the carbon in the ketal moiety
played an essential role in determining the enantiose-
lectivity. Diphenylmethylene ketal C15 gave higher
enantioselectivity than isopropylidene ketal C3, cyclo-
hexylidene ketal C13 or dibenzylmethylene ketal C14.
The presence of substituents on the aromatic rings
modulates to some extent the enantioselectivity levels
of the a-chlorination reaction and enantiomeric ex-
cesses varying from 42 to 70% were observed on
using organocatalysts C16–C21. Constraining the aro-
matic ring orientations near to coplanarity by includ-
ing the two benzene rings in a rigid polycyclic system
(C22, C23) did not improve the results.
Scheme 1. Enantioselective a-chlorination of 1a with chiral
amino diol derivatives C1–C7 as organocatalysts.
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Chiral Amino Diol Derivatives as New Modular Organocatalysts
Figure 3. Chlorinating agents (1.2 equiv.) tested in the enan-
tioselective a-chlorination of 1a using chiral amino diol de-
rivative C15 (10 mol%) as the organocatalyst.
of ionic pairs. As a result, the effect of the solvent
was investigated next (Table 1).
Full conversion of the starting material was ob-
served in the enantioselective a-chlorination of 1a
using chiral amino diol derivative C15 irrespective of
the solvent. On using aromatic solvents the enantiose-
lectivity was in the range 45–71% ee and this in-
creased as the solvent polarity decreased. This trend
was similar with non-aromatic solvents and the best
result was obtained when the reaction was performed
Scheme 3. Enantioselective a-chlorination of 1a with chiral
amino diol derivatives C13–C23 as organocatalysts.
Of the catalysts C1–C23, (S)-N-benzyl-1-[(S)-2,2-di- in cyclohexane (ee 78%, Table 1, entry 15).
phenyl-1,3-dioxolan-4-yl]-2-propen-1-amine C15 was At this point fine-tuning of the structure of the
the most efficient with respect to both conversion and amino diol derivatives was carried out by altering the
enantioselectivity. Chlorination of 1a with NCS (2,
1.2 equiv.) in the presence of 10 mol% of the chiral
amine C15 and using toluene as solvent took place
Table 1. Effect of the solvent in the enantioselective a-
with full conversion of the starting material after stir- chlorination of 1a using chiral amino diol derivative C15 as
the organocatalyst.[a]
ring overnight at room temperature. The reaction
cleanly afforded the enantioenriched a-chloro b-keto
ester 3a with 71% ee as the only product.
Entry
Solvent
ee[b] [%]
In an effort to improve the results several variables
in the reaction conditions were modified. A brief
screening of the chlorine donors revealed that NCS
(2) was the best choice (Figure 3). The use of com-
mercially available reagents 4, 7 and 8, which have ni-
trogen-chlorine bonds, afforded compound 3 with full
conversion but had a detrimental effect on the enan-
tioselectivity, mainly when 1,3-dichloro-5,5-dimethyl-
hydantoin (7) and 1,3,5-trichloroisocyanuric acid (8)
were employed as chlorinating agents. On using halo-
gen donor 5,7,7-trichloro-7H-quinolin-8-one (5) with
carbon-chlorine bonds or trifluoromethanesulfonyl
chloride (6) with a sulfur-chlorine bond both the con-
version and enantiomeric excess were substantially di-
minished.
1
2
3
4
5
6
7
8
toluene
benzene
xylenes
chlorobenzene
anisole
71
67
71
54
56
45
12
29
42
44
60
70
71
67
78
74
PhCF3
perfluorodecalin
1,4-dioxane
EtOAc
1,2-dichloroethane
tert-butyl methyl ether
CCl4
n-hexane
isooctane
cyclohexane
cyclopentane
9
10
11
12
13
14
15
16
[a]
The reaction medium can strongly influence a cata-
lytic process by altering important parameters such as
solubility, solvation of reactive species or stabilization
Reaction conditions: catalyst (10 mol%), NCS (2;
1.2 equiv.), room temperature, overnight.
[b]
Determined by GC using a Chiraldexꢇ G-TA column.
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electronic properties of the N-benzyl substituents. For
this purpouse compounds C24–C35 were used in the
enantioselective a-chlorination of 1a with NCS at
room temperature using cyclohexane as solvent. With
these chiral amino diol derivatives (10 mol%) as orga-
nocatalysts full conversion of the starting material
was achieved in all cases after stirring overnight and
the a-chlorinated b-keto ester 3a was obtained cleanly
as the only reaction product in variable enantiomeric
excesses (Scheme 4). The results obtained on using
Figure 4. 5-Membered ring cyclic b-keto esters tested in the
enantioselective a-chlorination using chiral amino diol de-
rivative C31 as the organocatalyst.
Table 2. Enantioselective a-chlorination of b-keto esters
1a–g using chiral amino diol derivative C31 as the organoca-
talyst.[a]
Entry Substrate Temp. [8C] Conv.[b] (Yield [%]) ee[c] [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
1f
1f
1g
1g
r.t.
0
r.t.
0
r.t.
0
r.t.
0
r.t.
0
r.t.
0
0
r.t.
0
>98
84
83
85
83
91
93
91
87
89
92
84
68
90
87
92
>98 (78)[e]
>98
>98 (74)[e]
>98
>98 (77)[e]
>98 (80)[e]
94
9
>98
>98 (89)
>98
>98
>98 (98)
>98
10
11
12
13[d]
14
15
Scheme 4. Enantioselective a-chlorination of 1a with chiral
amino diol derivatives C24–C35 as organocatalysts.
>98 (96)
[a]
Reaction conditions: catalyst (C31; 10 mol%), NCS (2;
1.2 equiv.), cyclohexane for reactions at room tempera-
ture or methylcyclohexane for reactions at 08C, over-
night.
the organocatalyst with substituents in the para-posi-
tion of the aromatic ring show that better enantiose-
lectivities are achieved with electron-withdrawing
groups (organocatalysts C26 and C27) than with elec-
tron-donating groups (organocatalysts C24 and C25).
The presence of one or more electron-withdrawing
groups on the ring was beneficial and depended on
the size and relative disposition of substituents. Only
organocatalysts C29 and C34, with electron-donating
groups in both ortho-positions, led to severe deterio-
ration of the enantioselectivity. Other derivatives led
[b]
[c]
1
Determined by H NMR of the crude reaction mixture.
Determined by GC using a Chiraldexꢇ G-TA column
[1a–1e] or HPLC using a Chiralpakꢇ IB column [1f–1g].
Solvent: toluene.
[d]
[e]
The lower isolated yield is due to the volatility of the
product.
to the a-chlorination of 1a with enantioselectivity ucts with total conversion and very good enantioselec-
levels even better than those obtained previously. tivity (84–91% ee) regardless of the nature of the sub-
Among the screened amino diol derivatives C31 stituent attached to the ester group. Carboxylates
proved to be the most efficient organocatalyst as the with sterically more bulky isopropyl (1c and 1g) or
enantioselectivity increased up to 84% ee.
tert-butyl ester groups (1d) gave higher enantioselec-
To further explore the substrate scope we elected tivities (Table 2, entries 5, 7 and 14). The effect of
to examine the organocatalyzed a-chlorination of rac- lowering the reaction temperature was investigated
emic 5-membered cyclic b-keto esters 1b–1g next. For this study a change of solvent was required
(Figure 4) with NCS. The results are collected in in order to avoid freezing at low temperature (cyclo-
Table 2.
hexane mp: 6.58C) and methylcyclohexane (mp:
Enantioselective a-chlorination of b-keto esters 1a– À126.38C) was the solvent of choice. In some cases
1g using C31 as the chiral organocatalyst was investi- enantioselectivities were slightly improved on de-
gated first. After stirring overnight at room tempera- creasing the reaction temperature from room temper-
ture the reaction gave the expected chlorinated prod- ature to 08C and enantiomeric excesses of up to 93%
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Chiral Amino Diol Derivatives as New Modular Organocatalysts
were achieved at 08C. Surprisingly, the use of methyl ing the temperature from room temperature to 08C in
ester 1f as the substrate led to a decrease in the enan- all cases led to an improvement in enantioselectivity,
tiomeric excess of the a-chlorination at 08C to 68% although the reactivity was slightly reduced and
(Table 2, entry 12). The origin of the diminished enan- longer reaction times were required to reach high
tioselectivity in this reaction is not clear but we were conversions. Very high enantioselectivity levels (83–
gratified to discover that the enantiomeric excess 96% ee) were achieved regardless of the alkyl sub-
could be improved to 90% by switching the solvent stituent tethered to the ester group and in this case
from methylcyclohexane to toluene (Table 2, the influence of the steric bulk was almost negligible.
entry 13).
Furthermore, the influence of a decrease in the or-
To extend the substrate scope of the reaction race- ganocatalyst/substrate ratio on the efficiency of the
mic 6-membered ring cyclic b-keto esters 1h–1n were chlorination reaction of a set of substrates (1a, 1i, and
used as substrates (Figure 5, Table 3).
1k) was assessed. Enantioselective a-chlorination of
Although six-membered ring esters were less reac- selected b-keto esters was carried out with NCS (2)
tive than five-membered ring esters in most cases, a- (1.2 equiv.) at 08C for 24 h in the presence of 2 mol%
chlorination proceeded with high conversion levels of amino diol derivative C35 and the results were
after stirring overnight at room temperature. Lower- compared with those obtained under the same reac-
tion conditions using 10 mol% of organocatalyst. As
shown in Scheme 5 a reduction of the organocatalyst
loading to 2 mol% led to conversions of ca. 80% with
only a moderate decrease in the enantiomeric excess,
which represents a very interesting result from a syn-
thetic point of view.
Chiral amino diol derivative C31 was obtained by
an extension of our previously described methodology
by diastereoselective addition of organometallic re-
agents to imines derived from conveniently protected
d-glyceraldehyde.[16] As shown in Scheme 6, d-manni-
Figure 5. 6-Membered ring cyclic b-keto esters tested in the
tol-derived chiral diol 9, obtained from d-mannitol ac-
cording to the literature procedure,[17] was cleaved
with lead tetraacetate and the resulting aldehyde was
immediately treated with 3-fluoro-4-(trifluoromethyl)-
benzylamine to afford the corresponding imine, which
was used in the next step without isolation. Addition
of vinylmagnesium bromide to BF3·OEt2 precomplexd
enantioselective a-chlorination using chiral amino diol de-
rivative C31 as the organocatalyst.
Table 3. Enantioselective a-chlorination of b-keto esters
1h–1n using chiral amino diol derivative derivative C31 as
the organocatalyst.[a]
Entry Substrate Temp. Time [h] Conv.[b]
ee[c]
[8C]
(Yield [%])
[%]
1
2
4
5
7
8
10
11
13
14
16
17
1h
1h
1i
1i
1j
r.t.
0
r.t.
0
r.t.
0
r.t.
0
overnight 93
24
84
90
87
90
83
90
90
94
92
94
89
96
88 (71)[d]
overnight 95
24
88 (77)[d]
overnight 94
1j
24
91 (78)[d]
1k
1k
1l
1l
1m
1n
overnight >98
24
93 (92)
r.t.
0
0
overnight 93
24
24
24
94 (92)
91 (90)
>98 (100)
0
[a]
Reaction conditions: catalyst (10 mol%), NCS (2;
1.2 equiv.), cyclohexane for reactions at room tempera-
ture or methylcyclohexane for reactions at 08C.
[b]
[c]
1
Determined by H NMR of the crude reaction mixture.
Determined by GC using a Chiraldexꢇ G-TA column
[1h–1j] or by HPLC using a Chiralpakꢇ IB column [1k],
Chiralpakꢇ IA column [1l], Chiralcelꢇ OD-H column
[1m], and Chiralpakꢇ AD-H column [1n].
Scheme 5. Influence of the organocatalyst loading on the
enantioselective a-chlorination of cyclic b-keto esters 1a, 1i
and 1k.
[d]
The lower isolated yield is due to the volatility of the
product.
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Pablo Etayo et al.
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ative 11, which is easily obtained on a multigram-
scale from d-mannitol according to the literature pro-
cedure[18] (Scheme 7). Compound 11 was cleaved with
sodium metaperiodate and the resulting aldehyde was
immediately treated with 3-fluoro-4-(trifluoromethyl)-
benzylamine to afford the corresponding imine, which
was used in the next step without isolation. Addition
of vinylmagnesium bromide to imine 12 at À208C af-
forded the corresponding amino diol as a 91/9 anti/syn
diastereomeric mixture from which the major diaste-
reoisomer 13 (anti configuration) was isolated in 54%
yield by column chromatography. Subsequent cleav-
age of the ketal moiety followed by camphorsulfonic
acid-promoted ketalization with benzophenone di-
methyl ketal in refluxing acetonitrile afforded com-
pound C31 in 81% yield for the two steps. In this way,
enantiomerically pure amino diol derivative C31 was
obtained in 44% overall yield starting from selectively
protected d-mannitol 11.
Scheme 6. Synthesis of organocatalyst C31 by diastereoselec-
tive addition of vinylmagnesium bromide to imine 10b de-
rived from protected d-glyceraldehyde.
imine 10b at À208C afforded the corresponding Conclusions
amino diol derivative as a 60/40 anti/syn diastereo-
meric mixture from which the major diastereoisomer In conclusion, members of a new family of highly
C31 (anti configuration) was isolated by column chro- modular chiral amino diol derivatives have been eval-
matography in 31% yield from conveniently protected uated as chiral organocatalysts in the enantioselective
d-mannitol 9.
a-chlorination of cyclic b-keto esters. The use of the
To improve the synthesis of compound C31 an al- appropriate organocatalyst cleanly gave optically
ternative route was developed using d-mannitol deriv- active a-chlorinated b-keto esters in excellent conver-
sions and with high enantioselectivities (up to 96%
ee) using inexpensive commercially available NCS as
the chlorine source under mild reaction conditions.
The particular features of these compounds mean that
a large number of novel, simple organocatalysts can
be easily prepared from natural and renewable sour-
ces. These organocatalysts could potentially be tuned
for use in different asymmetric transformations.
Experimental Section
General Methods
Melting points were determined in open capillaries using a
Gallenkamp capillary melting point apparatus and are not
corrected. FT-IR spectra of oils were recorded as thin films
on NaCl plates and FT-IR spectra of solids were recorded as
KBr pellets, using a Thermo Nicolet Avatar 360 FT-IR spec-
trometer; nmax values expressed in cmÀ1 are given for the
main absorption bands. Optical rotations were measured on
a Jasco 1020 polarimeter at l=589 nm and 258C in a cell
with 10 cm path length, [a]D values are given in 10À1
deg·cmgÀ1 and concentrations are given in g/100 mL. NMR
spectra were acquired on Bruker AV-400 instrument operat-
ing at 400 MHz for 1H NMR, 100 MHz for 13C NMR and
376 MHz or 282 MHz for 19F NMR using a 5 mm probe. The
chemical shifts (d) are reported in parts per million and
Scheme 7. Improved synthetic route to organocatalyst C31.
were referenced to the residual solvent peak. Coupling con-
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Chiral Amino Diol Derivatives as New Modular Organocatalysts
stants (J) are quoted in Hertz. The following abbreviations
are used: d, doublet; m, multiplet; bs, broad singlet; dd,
doublet of doublets; bd, broad doublet; dq, doublet of quar-
tets; ddd, doublet of doublet of doublets; qd, quartet of dou-
blets; bdd, broad doublet of doublets; qdd, quartet of dou-
blet of doublets; sept, septuplet. High resolution mass spec-
tra were recorded using a Bruker Daltonics MicroToF-Q
electrospray instrument from methanolic solutions using the
positive electrospray ionization mode (ESI+). Microanalyses
were performed using a Perkin–Elmer 2400 CHNS elemen-
tal analyser. Column chromatography was performed using
silica gel (60 ꢈ, 35–70 mm). Gas chromatography analyses
benzylamine (3.57 mg, 18.5 mmol) were added successively.
The reaction mixture was stirred for 5 h at room tempera-
ture filtered and evaporated and the remainder was dis-
solved in dry diethyl ether (80 mL) and cooled to at À208C.
Then a 1.0M solution of vinylmagnesium bromide in THF
(16.7 mL, 16.7 mmol) was added under argon at À208C and
the reaction mixture was stirred overnight at the same tem-
perature. The stirred reaction mixture was quenched with
saturated aqueous NH4Cl (20 mL) at 08C. Then water
(20 mL) and diethyl ether (35 mL) were added and the
emulsion was filtered through a pad of Celiteꢇ. The filtered
material was decanted and aqueous phase was extracted
with diethyl ether (2ꢉ35 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrat-
ed to give the corresponding amino diol derivative as a 91/9
anti/syn mixture of diastereoisomers. Purification of the
crude product by silica gel column chromatography eluting
with diethyl ether/hexanes (1:2) afforded diastereomerically
pure compound 13 with the anti configuration; yield: 3.58 g
(54%); colourless oil; [a]2D5: +16.6 (c 1.00, CHCl3). IR
were performed using
a Varian CP-3800 instrument
equipped with a flame ionization detector using an Astec
Chiraldexꢇ G-TA 30 mꢉ0.25 mm capillary column. HPLC
chromatography analyses were performed using a Waters
600-E HPLC instrument equipped with a Waters 991 photo-
diode array detector or a Waters 600 HPLC system equiped
with a 2996 photodiode array detector using Daicel Chiral-
pakꢇ IA, IB, or AD-H column, or Daicel Chiralcelꢇ OD-H
column, 25ꢉ0.46 cm.
(neat): n=3327, 1630, 1586, 1511, 1176 cmÀ1
;
1H NMR
(400 MHz, CDCl3) d=1.35 (s, 3H), 1.41 (s, 3H), 1,66 (bs,
1H), 3.16 (dd, J=9.4 Hz, J=4.5 Hz, 1H), 3.70 (d, J=
14.6 Hz, 1H), 3.89 (d, J=14.6 Hz, 1H), 3.90 (dd, J=8.1 Hz,
J=6.6 Hz, 1H), 4.00 (dd, J=8.1 Hz, J=6.6 Hz, 1H), 4.17
(ddd, J=6.6 Hz, J=6.6 Hz, J=4.5 Hz, 1H), 5.20 (dd, J=
17.1 Hz, J=1.2 Hz, 1H), 5.30 (dd, J=10.3 Hz, J=1.2 Hz,
1H), 5.64 (ddd, J=17.1 Hz, J=10.3 Hz, J=8.4 Hz, 1H),
7.15–7.25 (m, 2H), 7.52 (dd, J=7.8 Hz, J=7.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=25.0, 26.3, 49.8 (d, J=
1.5 Hz), 62.0, 65.8, 78.1, 109.2, 116.1 (d, J=20.7 Hz), 116.7
(qd, J=32.8 Hz, J=12.5 Hz), 119.0, 122.7 (qd, J=271.9 Hz,
J=1.1 Hz), 123.2 (d, J=3.5 Hz), 126.9 (qd, J=4.5 Hz, J=
1.9 Hz), 135.8, 148.1 (dc, J=7.4 Hz, J=1.1 Hz), 160.3 (dc,
J=255.6 Hz, J=2.3 Hz); 19F{1H} NMR (282 MHz, CDCl3):
d=À61.2 (d, J=12.4 Hz, 3F), À114.9 (q, J=12.4 Hz, 1F);
HR-MS (ESI+): m/z=334.1437, calcd. for C16H20F4NO2
[M+H]+: 334.1425.
Materials
All reagents for reactions were of analytical grade and were
used as obtained from commercial sources. Solvents used as
mobile phases in HPLC analyses were of chromoscan grade.
All manipulations with air-sensitive reagents were carried
out under a dry argon atmosphere using standard Schlenk
techniques and anhydrous solvents. Whenever possible the
reactions were monitored by thin layer chromatography
(TLC). TLC was performed on precoated silica gel polyester
plates and products were visualized using UV light (254 nm)
or ninhydrin, or phosphomolybdic acid visualizing agents
followed by heating. (1S,2S)-1,2-Bis[(R)-2,2-diphenyl-1,3-di-
oxolan-4-yl]ethane-1,2-diol[17] (9), (1S,2S)-1,2-bis[(R)-2,2-di-
methyl-1,3-dioxolan-4-yl]ethane-1,2-diol[18] (11), and 5,7,7-
trichloro-7H-quinolin-8-one[7] (5) were prepared following
the literature procedures. Commercially available b-keto
esters 1a, 1b, 1h, 1i were used as obtained from commercial
sources. b-Keto esters 1c,[19] 1d,[20] 1e,[19] 1f,[21] 1g,[22] 1j,[23]
and 1k,[24] were prepared according to reported procedures.
b-Keto ester 1l was prepared by analogy to the preparation
of 1g and b-keto esters 1m and 1n were prepared by analogy
to the preparation of 1k.
AHCTUNGTREG(NNUN 2S,3S)-3-[3-Fluoro-4-(trifluoromethyl)benzylamino]-
pent-4-ene-1,2-diol (14)
To a solution of compound 13 (1.0 g, 3.0 mmol) in THF
(8 mL) 2N HCl (8 mL) was added and the resulting solution
was stirred for 1 h at 458C. The solvent was evaporated
under reduced pressure and the remainder was extracted
with dichloromethane (3ꢉ10 mL). The aqueous phase was
neutralized by the addition of 10% NaOH aqueous solution
and extracted with dichloromethane (3ꢉ15 mL). The com-
bined organic layers were dried over anhydrous MgSO4, fil-
tered and evaporated under vacuum to afford of diol 14 as a
yellowish solid; yield: 829 mg (94%); mp 65–678C; [a]2D5:
+11.2 (c 1.00, CHCl3). IR (neat): n=3456, 3301, 3113, 1630,
(S)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-N-[3-
fluoro-4-(trifluoromethyl)benzyl]prop-2-en-1-amine
(13)
To a mixture of (1S,2S)-1,2-bis[(R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]ethane-1,2-diol (11) (2.62 g, 10.0 mmol), saturated
aqueous NaHCO3 (2.0 mL) and dichloromethane (25 mL) at
08C solid sodium metaperiodate (4.28 g, 20.0 mmol) was
added in small portions with vigorous stirring and the result-
ing suspension was stirred for 45 min at room temperature.
The reaction mixture was filtered and the residue evaporat-
ed under vacuum to give (R)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde which was immediately dissolved in dry dieth-
yl ether (35 mL) and used in the next step without purifica-
tion. To this solution stirred at room temperature anhydrous
MgSO4 (3.34 g, 27.8 mmol) and 3-fluoro-4-(trifluoromethyl)-
1
1588, 1512, 1136 cmÀ1; H NMR (400 MHz, CDCl3); d=2.00
(sa, 3H), 3.25 (dd, J=8.6 Hz, J=4.4 Hz, 1H), 3.58–3.75 (m,
4H), 3.91 (d, J=14.0 Hz, 1H), 5.24 (dd, J=17.2 Hz, J=
1.2 Hz, 1H), 5.34 (dd, J=10.0 Hz, J=1.2 Hz, 1H), 5.72
(ddd, J=17.2 Hz, J=10.0 Hz, J=8.6 Hz, 1H), 7.10–7.20 (m,
2H), 7.53 (dd, J=7.6 Hz, J=7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=49.9, 63.7, 64.3, 73.0, 116.2 (d, J=
20.6 Hz), 116.9 (qd, J=32.9 Hz, J=12.6 Hz), 119.4, 122.6
(qd, J=271.9 Hz, J=1.1 Hz), 123.5 (d, J=3.5 Hz), 127.1 (qd,
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Pablo Etayo et al.
FULL PAPERS
J=4.5 Hz, J=1.8 Hz), 135.8, 147.1 (dq, J=7.3 Hz, J=
1.1 Hz), 159.8 (dq, J=255.9 Hz, J=2.2 Hz); 19F NMR
(376 MHz, CDCl3): d=À61.2 (d, J=12.4 Hz, 3F), (À114.5)–
(À114.7) (m, 1F); HR-MS (ESI+): m/z=294.1115, calcd.
for C13H16F4NO2 [M+H]+ : 294.1112.
J=8.1 Hz, 1H), 7.00–7.09 (m, 2H), 7.19–7.36 (m, 6H), 7.41–
7.57 (m, 5H); 13C NMR (100 MHz, CDCl3): d=49.8 (d, J=
0.9 Hz), 62.1, 66.1, 78.8, 109.9, 116.0 (d, J=20.7 Hz), 116.6
(qd, J=32.8, J=12.6 Hz), 119.0, 122.7 (qd, J=271.8, J=
0.8 Hz), 123.2 (d, J=3.4 Hz), 125.9, 126.2, 129.9 (qd, J=4.4,
J=1.6 Hz), 128.1, 128.1, 128.2, 128.2, 135.8, 141.9, 142.1,
147.9 (d, J=7.4 Hz), 159.89 (dq, J=255.7, J=1.6 Hz);
19F NMR (376 MHz, CDCl3): d=À114.8 (qdd, J=12.4, J=
12.3, J=7.5 Hz, 1F), À61.0 (d, J=12.4 Hz, 3F); HR-MS
(ESI+): m/z=458.1755, calcd. for C26H24F4NO2 [M+H]+:
458.1738.
(S)-1-[(S)-2,2-Diphenyl-1,3-dioxolan-4-yl]-N-[3-
fluoro-4-(trifluoromethyl)benzyl]-2-propen-1-amine
(C31)
Method A: To a solution of (1S,2S)-1,2-bis[(R)-2,2-diphenyl-
1,3-dioxolan-4-yl]ethane-1,2-diol (9) (510 mg, 2.0 mmol) in
toluene (20 mL) at room temperature lead tetraacetate
(887 mg, 2.0 mmol) was added and the resulting suspension
was stirred for 40 min at room temperature. The reaction
mixture was filtered and the residue washed with diethyl
ether (30 mL). The filtrate was washed with saturated aque-
ous NaHCO3 (3ꢉ30 mL) and the combined organic layers
were dried over anhydrous MgSO4, filtered and concentrat-
ed to give (R)-2,2-diphenyl-1,3-dioxolane-4-carbaldehyde
which was immediately dissolved in dry diethyl ether
(20 mL) and used in the next step without purification. To
this solution stirred at room temperature anhydrous MgSO4
(361 mg, 3.0 mmol) and 3-fluoro-4-(trifluoromethyl)benzyl-
General Procedure for Optimization of
Organocatalytic Asymmetric a-Chlorination of b-
Keto Esters
To a solution of the corresponding chiral amino diol deriva-
tive C (0.0135 mmol) in the appropriate solvent (1 mL) the
corresponding b-keto ester (0.135 mmol) was added and the
mixture was stirred for 10 min at room temperature. Then
NCS (22 mg, 0.162 mmol) was added at the required temper-
ature, the mixture was diluted with additional solvent
(1 mL) and stirring was continued for the indicated time.
The crude reaction mixture was filtered though a silica gel
pad using diethyl ether/hexanes (1:5) as eluent. After evapo-
ration of the solvent under vacuum the conversion was de-
termined by 1H NMR and enantiomeric excess was deter-
mined by GC or HPLC analysis using chiral stationary
phases.
ACHTUNGTRENNUNGamine (386 mg, 2.0 mmol) were added successively. The re-
action mixture was stirred for 2 h at room temperature, fil-
tered and evaporated and the remainder was dissolved in
dry diethyl ether (20 mL) and cooled to at À208C. To this
solution BF3·OEt2 (0.25 mL, 2.0 mmol) was added dropwise
and stirring was continued for 10 min at the same tempera-
ture. Then a 1.0M solution of vinylmagnesium bromide in
THF (4.0 mL, 4.0 mmol) was added under argon at À208C
and the reaction mixture was stirred for 12 h at the same
temperature. The stirred reaction mixture was treated with
saturated aqueous NH4Cl (20 mL) at 08C and extracted
with diethyl ether (3ꢉ30 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrat-
ed to give the corresponding amino diol derivative as a 60/
40 anti/syn mixture of diastereoisomers. Purification of the
crude product by silica gel column chromatography eluting
with diethyl ether/hexanes (1:2) afforded diastereomerically
pure compound C31 with anti configuration; yield: 283 mg
(31%).
General Procedure for the Organocatalytic
Asymmetric a-Chlorination of b-Keto Esters
To a solution of chiral amino diol derivative C31 (30.9 mg,
0.0675 mmol) in the appropriate solvent (10 mL) the corre-
sponding b-keto ester (0.675 mmol) was added and the mix-
ture was stirred for 10 min at room temperature. Then NCS
(108 mg, 0.81 mmol) was added at the required temperature
and stirring was continued for the indicated time. The crude
reaction mixture was added to a silica gel column and
eluted using dichloromethane/hexanes (1:1 or 2:1) as eluent
depending on the product polarity. After evaporation of the
solvent under vacuum the enantiomeric excess of the corre-
sponding isolated a-chloro-b-keto ester was determined by
GC or HPLC analysis using chiral stationary phases.
Ethyl 1-chloro-2-oxocyclopentanecarboxylate (3a): Col-
ourless oil, known compound.[9] GC conditions: Chiraldexꢇ
G-TA; T1 =508C, t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =
15 min, v2 =108CminÀ1, T3 =508C, t3 =1 min; tR =20.1
[minor], tR =22.8 [major].
Method B: To a solution of compound 14 (300 mg,
1.02 mmol) in dry acetonitrile (8 mL) camphorsulfonic acid
(261 mg, 1.12 mmol) and benzophenone dimethyl ketal
(467 mg, 2.05 mmol) were added and the solution was re-
fluxed for 3 h. Saturated aqueous NaHCO3 was added until
the pH was basic and the solution was extracted with diethyl
ether (3ꢉ20 mL) and the combined organic layers were
dried over anhydrous MgSO4, filtered and evaporated under
vacuum. Purification of the crude product by silica gel
column chromatography eluting with 1) diethyl ether/hex-
anes (1:7) and 2) diethyl ether/hexanes 1:3 afforded diaste-
reomerically pure compound C31; yield: 401 mg (86%); col-
ourless oil; [a]2D5: +42.7 (c 0.99, CHCl3). IR (neat): n=3324,
Methyl 1-chloro-2-oxocyclopentanecarboxylate (3b): Col-
ourless oil, known compound.[11] GC conditions: Chiraldexꢇ
G-TA; T1 =508C, t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =
15 min, v2 =108CminÀ1, T3 =508C, t3 =1 min; tR =19.3
[minor], tR =22.3 [major].
Isopropyl 1-chloro-2-oxocyclopentanecarboxylate (3c):
Colourless oil. GC conditions: Chiraldexꢇ G-TA; T1 =508C,
t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =10 min, v2 =
108CminÀ1, T3 =508C, t3 =1 min; tR =19.0 [minor], tR =19.8
1
1630, 1208, 1176 cmÀ1; H NMR (400 MHz, CDCl3): d=1.79
(bs, 1H), 3.25 (dd, J=8.1, J=4.3 Hz, 1H), 3.62 (d, J=
14.5 Hz, 1H), 3.82 (d, J=14.5 Hz, 1H), 3.95 (dd, J=8.0, J=
7.3 Hz, 1H), 4.12 (dd, J=8.0, J=6.1 Hz, 1H), 4.23 (ddd, J=
7.3, J=6.1, J=4.3 Hz, 1H), 5.20 (bd, J=17.2 Hz, 1H), 5.25
(bdd, J=10.3, J=1.1 Hz, 1H), 5.61 (ddd, J=17.2, J=10.3,
1
[major]. H NMR (400 MHz, CDCl3): d=1.27 (d, J=6.4 Hz,
3H), 1.28 (d, J=6.4 Hz, 3H), 2.04–2.20 (m, 2H), 2.34–2.43
(m, 2H), 2.50–2.60 (m, 1H), 2.73 (ddd, J=14.4 Hz, J=
3336
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ꢆ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3329 – 3338

Chiral Amino Diol Derivatives as New Modular Organocatalysts
9.2 Hz, J=8.0 Hz, 1H), 5.10 (sept, J=6.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=19.1, 21.4, 21.6, 35.4, 38.3,
69.8, 71.1, 166.7, 206.2.
tert-Butyl 1-chloro-2-oxocyclopentanecarboxylate (3d):
Yellowish solid, known compound.[12] GC conditions: Chiral-
dexꢇ G-TA; T1 =508C, t1 =1 min, v1 =88CminÀ1, T2 =
1358C, t2 =25 min, v2 =108CminÀ1, T3 =508C, t3 =1 min;
tR =23.4 [major], tR =23.7 [minor].
2H), 3.16–3.24 (m, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 7.12 (dd,
J=8.4 Hz, J=2.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.54 (d,
J=2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=24.8, 35.3,
53.8, 55.5, 70.7, 110.5, 123.1, 130.0, 130.3, 135.2, 158.7, 168.0,
187.5.
Methyl
2-chloro-7-bromo-1-oxo-1,2,3,4-tetrahydronaph-
thalene-2-carboxylate (3n): White solid, HPLC conditions:
Daicel Chiralpakꢇ AD-H; hexane/IPA (98/2), 1.0 mLminÀ1,
254 nm; tR =12.2 [major], tR =13.0 [minor]. 1H NMR
(400 MHz, CDCl3): d=2.50–2.55 (m, 1H), 2.93–3.09 (m,
2H), 3.17–3.25 (m, 1H), 3.85 (s, 3H), 7.17 (d, J=8.4 Hz,
1H), 7.64 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 8.19 (bs, 1H),
13C NMR (100 MHz, CDCl3): d=25.1, 29.7, 34.8, 53.9, 70.2,
121.2, 130.5, 131.0, 131.5, 137.2, 141.2, 167.6, 186.3.
Benzyl
1-chloro-2-oxocyclopentanecarboxylate
(3e):
HPLC conditions: Daicel Chiralpakꢇ IB; hexane/IPA (99.2/
0.8), 1.0 mLminÀ1, 220 nm); tR =16.3 [minor], tR =17.1
1
[major]. H NMR (400 MHz, CDCl3): d=1.96–2.13 (m, 2H),
2.26–2.35 (m, 2H), 2.44–2.53 (m, 1H), 2.67 (ddd, J=
14.4 Hz, J=9.6 Hz, J=7.2 Hz, 1H), 5.16 (d, J=12.2 Hz,
1H), 5.20 (d, J=12.2 Hz, 1H), 7.25–7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3): d=19.1, 35.3, 38.3, 66.2, 68.5, 128.0,
128.5, 128.6, 134.7, 167.1, 205.9.
Methyl 2-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxyl-
ate (3f): Pale yellow solid, known compound.[12] HPLC con-
ditions: Daicel Chiralpakꢇ IB; hexane/IPA (97/3),
1.0 mLminÀ1, 245 nm); tR =9.8 [major], tR =11.0 [minor].
Isopropyl 2-chloro-1-oxo-2,3-dihydro-1H-indene-2-carbox-
ylate (3g): Colourless oil, known compound.[12] HPLC condi-
tions: Daicel Chiralpakꢇ IB; hexane/IPA (99/1),
0.8 mLminÀ1, 245 nm); tR =10.4 [major], tR =11.3 [minor].
Methyl 1-chloro-2-oxocyclohexanecarboxylate (3h): Col-
ourless oil, GC conditions: Chiraldexꢇ G-TA; T1 =508C,
t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =15 min, v2 =
108CminÀ1, T3 =508C, t3 =1 min; tR =22.0 [minor], tR =25.3
Acknowledgements
The financial support of the Spanish Ministry of Science and
Innovation and European Regional Development Fund
(CTQ2008-00187/BQU) and the Government of Aragꢀn
(GA E-71) is acknowledged.
References
[1] a) H. House, Modern Synthetic Reactions, 2nd edn.,
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[2] C. Czekelius, C. C. Tzschucke, Synthesis 2010, 543–566.
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[major]. H NMR (400 MHz, CDCl3): d=1.65–1.78 (m, 1H),
1.85–2.00 (m, 3H), 2.14 (ddd, J=14.0 Hz, J=8.0 Hz, J=
3.2 Hz, 1H), 2.41 (ddd, J=13.7 Hz, J=6.6 Hz, J=6.6 Hz,
1H), 2.73–2.89 (m, 2H), 3.82 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=21.9, 26.6, 38.6, 39.5, 53.6, 73.3, 166.7, 199.6.
Ethyl 1-chloro-2-oxocyclohexanecarboxylate (3i): Colour-
less oil, known compound.[6] GC conditions: Chiraldexꢇ G-
TA ; T1 =508C, t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =
15 min, v2 =108CminÀ1, T3 =508C, t3 =1 min; tR =22.4
[minor], tR =26.0 [major].
Isopropyl 1-chloro-2-oxocyclohexanecarboxylate (3j): Col-
ourless oil, GC conditions: Chiraldexꢇ G-TA; T1 =508C,
t1 =1 min, v1 =88CminÀ1, T2 =1508C, t2 =15 min, v2 =
108CminÀ1, T3 =508C, t3 =1 min; tR =21.0 [minor], tR =23.9
1
[major]. H NMR (400 MHz, CDCl3): d=1.28 (d, J=6.4 Hz,
6H), 1.68–1.77 (m, 1H), 1.78–2.00 (m, 3H), 2.05–2.13 (m,
1H), 2.42 (ddd, J=14.0 Hz, J=9.2 Hz, J=5.2 Hz, 1H),
2.76–2.86 (m, 2H), 5.11 (sept, J=6.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=21.3, 21,4, 22,3, 26.7, 39.0, 39.7, 70.0,
73.7, 166.6, 199.6.
Methyl
2-chloro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (3k): Pale yellow oil, known compound.[12]
HPLC conditions: Daicel Chiralpakꢇ IB; hexane/IPA (98/2),
1.0 mLminÀ1, 245 nm; tR =10.7 [mayor], tR =12.3 [minor].
Isopropyl 2-chloro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (3l): Colourless oil, known compound.[12] HPLC
conditions: Daicel Chiralpakꢇ IA; hexane/IPA (99/1),
0.8 mLminÀ1, 245 nm; tR =11.3 [minor], tR =12.5 [major].
Methyl 2-chloro-7-methoxy-1-oxo-1,2,3,4-tetrahydronaph-
thalene-2-carboxylate (3m): White solid. HPLC conditions:
Daicel Chiralcelꢇ OD-H; hexane/IPA (98/2), 1.0 mLminÀ1,
254 nm; tR =19.9 [major], tR =21.8 [minor]. 1H NMR
(400 MHz, CDCl3): d=2.48–2.54 (m, 1H), 2.91–3.00 (m,
[4] For recent reviews on organocatalysis in enantioselec-
tive halogenation reactions see: a) G. Guillena, D. J.
Ramꢀn, Tetrahedron: Asymmetry 2006, 17, 1465–1492;
b) M. Marigo, K. A. Jørgensen, Chem. Commun. 2006,
2001–2011; c) P. M. Pihko, Angew. Chem. 2006, 118,
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d) M. Ueda, T. Kano, K. Maruoka, Org. Biomol. Chem.
2009, 7, 2005–2012.
[5] For organocatalytic a-chlorination of ketones see: M.
Marigo, S. Bachmann, N. Halland, A. Braunton, K. A.
Adv. Synth. Catal. 2010, 352, 3329 – 3338
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asc.wiley-vch.de
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FULL PAPERS
Jørgensen Angew. Chem. 2004, 116, 5623–5626;
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[14] G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Mel-
chiorre, L. Sambri Angew. Chem. 2005, 117, 6375–
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rigendum: Angew. Chem. 2006, 118, 348; Angew.
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[15] Y. Cai, W. Wang, K. Shen, J. Wang, X. Hu, L. Lin, X.
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