Stereoselective ZrCl4-Catalyzed Mannich-type Reaction of β-Keto Esters with Chiral Trifluoromethyl Aldimines

Article abstract of DOI:10.1021/acs.joc.5b01379

A method for the synthesis of fluorinated β′-amino β-dicarbonyl compounds using a Zr-catalyzed Mannich-type reaction has been developed, starting from N-protected trifluoromethyl aldimines and cyclic or acyclic β-keto esters bearing different ester residues. The in situ generated metallic complex reacted with optically pure trifluoromethyl aldimine derived from (R)-α-methylbenzylamine, giving a highly diastereoselective asymmetric Mannich-type addition with formation of a chiral quaternary center. The absolute configuration at the new chiral centers was assigned through two-dimensional nuclear Overhauser effect spectroscopic analysis coupled with computational studies.

Full text of DOI:10.1021/acs.joc.5b01379

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Stereoselective ZrCl ꢀCatalyzed Mannichꢀtype
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Reaction of βꢀKeto Esters with Chiral
Trifluoromethyl Aldimines
Luca Parise, Lucio Pellacani, Fabio Sciubba, Laura Trulli, and Stefania Fioravanti*
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, Iꢀ
00185 Roma, Italy
ABSTRACT. A method for the synthesis of fluorinated β'ꢀamino βꢀdicarbonyl compounds using
a Zrꢀcatalyzed Mannichꢀtype reaction has been developed, starting from Nꢀprotected
trifluoromethyl aldimines and cyclic or acyclic βꢀketo esters bearing different ester residues. The
in situ generated metallic complex reacted with optically pure trifluoromethyl aldimine derived
from (R)ꢀαꢀmethylbenzylamine giving a highly diastereoselective asymmetric Mannichꢀtype
addition with formation of a chiral quaternary center. The absolute configuration at the new
chiral centers was assigned through 2D NOESY analysis coupled with computational studies.
INTRODUCTION
The carbon−carbon bond forming reactions are among the most important organic reactions and
1
widely studied for synthetic purposes. Among these reactions, the Mannich reaction is one of
the most powerful methodologies. Imines can be used as preformed starting materials in addition
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reactions with appropriate carbon nucleophiles, giving direct access to nitrogen functionalized
compounds. In this field, αꢀtrifluoromethyl amines were obtained by Mannich reactions of
2
trifluoromethyl aldimines and suitable nucleophiles, such as malonates and ester enolates,
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1
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0
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acetone, and aldehydes.
5
Many catalysts have been explored in order to maximize the stereoselectivity of the reaction,
but it is always important to develop new inexpensive and highly efficient catalytic methods for
this reaction, possibly focusing on the synthetic procedures befitting the green and sustainable
6
chemistry criteria. Recently we reported the nonꢀtoxic, inexpensive, and stable ZrCl as an ideal
4
catalyst to promote addition reactions between trifluoromethyl aldimines and nitro alkanes,
7
giving new fluorinated βꢀnitro amines. The reported methodology can be considered a green
procedure, not only because an ecoꢀfriendly catalyst was used, but also because the oneꢀpot key
step takes place under solventꢀfree conditions. In addition, working with optically pure
fluorinated imines, the formation of a chiral metal complex key intermediate allowed us to
8
control the stereoselective reaction outcome.
Continuing our studies, herein we report a direct ZrCl ꢀcatalyzed Mannichꢀtype reaction of
4
suitable trifluoromethyl aldimines with diethyl malonate and with βꢀketo esters. While malonate
did not give relevant results, starting from chiral Nꢀprotected trifluoromethyl aldimines we were
able to obtain a highly diastereoselective direct addition when the reactions were performed on
βꢀketo esters, leading to nitrogen fluorinated dicarbonyl compounds. The usefulness of these
selective catalytic Mannichꢀtype reactions was enhanced by a diastereoselective decarboxylation
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reaction of the newly obtained βꢀketo esters. In fact, it is wellꢀknown that the direct addition
reaction of enolizable ketones to imines suffers from low yields and/or low selectivity.
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Furthermore, the use of silyl enol ethers as ketone surrogates may result in higher yields, but
1
0
diastereoselectivities remain low.
RESULTS AND DISCUSSION
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A first reaction was performed in equimolar ratio between trifluoromethyl aldimines 1a,b and
diethyl malonate 2.
Table 1. Reaction Condition Optimization of Diethyl Malonate 2
a
entry
1
Pg
catalyst
CuCl2
molar (%)
25
time (min) temp (°C)
yield (%)
5
25
0
50
35
40
2
25
30
60
30
30
30
10
30
30
30
30
30
30
30
3
25
−20
25
25
25
25
25
25
25
25
25
25
25
4
Bn
50
−
5
AlCl3
ZrCl4
CuCl2
25
−
6
10
−
7
10
75
−
8
50
9
25
−
10
11
10
−
PMP
50
−
1
1
1
2
3
4
AlCl3
ZrCl4
25
−
10
−
10
79
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2
2
2
2
2
2
2
2
2
3
3
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3
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3
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3
4
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5
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5
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5
5
6
a
After flash chromatography on silica gel (eluent hexane/ethyl acetate = 8:2).
As reported in Table 1, while no reaction was observed starting from either 1a or 1b (entries 4ꢀ6
and 11ꢀ13) in the presence of AlCl , the use of ZrCl (entries 7 and 14) as catalyst gave
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4
0
1
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9
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9
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1
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9
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compounds 3a,b in higher yields and shorter times than when the reactions were performed with
CuCl (entries 1ꢀ3 and 8ꢀ10).
2
Thus, once optimized the reaction conditions, a direct diastereoselective ZrCl ꢀcatalyzed
4
1
1
Mannichꢀtype reaction was attempted starting from optically pure trifluoromethyl aldimine 1c,
but no induction was observed (Scheme 1).
Scheme 1. ZrCl ꢀCatalyzed MannichꢀType Reaction with Optically Pure 1c
4
Therefore, we turned our attention towards the reactivity of βꢀketo esters. To optimize the
reaction conditions for direct catalytic Mannichꢀtype additions of βꢀketo esters to trifluoromethyl
aldimines, imine 1a and ethyl acetoacetate (6) in equimolar ratio were considered as opportune
starting materials and reacted under different catalytic conditions (Table 2).
Table 2. Reaction Condition Optimization of βꢀKeto Ester 6.
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temp
(°C)
a
entry
catalyst
molar (%)
solvent
time
yield (%)
1
2
3
4
−
−
−
2 d
4 h
4 h
1 d
25
25
25
0
−
−
−
−
−
−
−
Et N
3
100
100
THF
THF
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KF
cinchonidine 10
CH Cl2
2
5
6
7
8
9
10
30
−
24 h
2 h
25
25
25
25
25
−
Lꢀproline
10
10
10
DMSO
NMP
THF
24 h
3 h
c
<5
c
2 d
<5
1
1
1
0
1
2
10
10
25
25
25
25
25
25
10
10
10
10
25
−
1 d
25
25
25
0
−
b
c
NMP
−
3 d
<5
5 min
30 min
1 h
50
35
40
40
36
30
75
35
30
−
13
14
15
16
CuCl2
AlCl3
−
−
−20
−
15 min 25
25 min
−
0
1
1
1
2
2
7
8
9
0
1
1
−
45 min −20
−
10 min 25
−
1 h
3 h
6 h
6 h
0
ZrCl4
−
−20
−70
−70
−
1
−
−
a
b
After flash chromatography on silica gel (eluent hexane/ethyl acetate = 8:2). (S)ꢀ
c
19
α,αꢀdiphenylprolinol. Conversion determined by F NMR.
Considering that the reaction performed without catalyst did not give the expected product (entry
1), different catalysts were chosen to test the imine reactivity, from the most common organic or
inorganic bases (entries 2 and 3) or cinchonidine,
L
ꢀproline or its derivative (entries 4ꢀ11). As
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1
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2
2
2
2
2
2
2
2
3
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5
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5
5
5
6
reported in Table 2, only when using
L
ꢀproline (entries 8 and 9) or (S)ꢀα,αꢀdiphenylprolinol
(entry 11) in the presence of a suitable solvent it has been possible to observe the formation of
the expected Mannich adducts, but only in trace amounts (<5%) by NMR.
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
0
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0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Then, we considered CuCl as catalyst (entries 12ꢀ14), widely used to promote different addition
2
1
1
7,8,12
reactions, AlCl (entries 15ꢀ17), and ZrCl ,
(entries 18ꢀ22) as easily disposable, ecoꢀ
3
4
1
3
friendly, and efficient Lewis acid. Finally, the reactions performed under solventꢀfree
conditions gave the expected product, the best conditions being those reported in entry 18. In all
cases, 7/7'a were obtained in an equimolar ratio, even by changing the reaction temperature
(entries 19ꢀ20).
Under the best conditions, the ZrCl ꢀcatalyzed Mannichꢀtype reactions were performed starting
4
from different βꢀketo esters and using Nꢀprotected trifluoromethyl aldimines 1a,b, as opportune
substrates. The results are reported in Table 3.
Table 3. Solventꢀfree ZrCl ꢀCatalyzed MannichꢀType Reaction of Different βꢀKeto Esters
4
a
b
entry
Pg
Bn
βꢀketo ester
product
11a/11'a
12a/12'a
13a
time (min) major/minor
yield (%)
c
1
2
3
4
5
8
30
10
10
30
10
10
7:3
7:3
9:1
7:3
7:3
65
75
78
68
73
85
c
9
10
8
c
c
11b/11'b
12b/12'b
13b
PMP
9
6
10
9.9:0.1
a
19
b
Determined by F NMR spectra performed on the crude mixtures. After flash
c
chromatography on silica gel. The ratio did not change by working at lower temperatures.
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In all cases the reactions occurred with success in a short time, affording the Mannich adducts in
good yields and very high stereoselectivity, especially when sixꢀmembered cyclic βꢀketo esters
were used (entries 3 and 6). A catalytic pathway can be proposed (Figure 1).
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O
H
*
O
N
*
Pg
Cl
Cl
Cl
Cl
Zr
+
O
CF3
O
O
Cl
Cl Zr Cl
Cl
O
6
O
O
Cl Cl
Zr
O
O
I
Cl
H
N
Cl
O
Pg
II O
CF3
F3C
N
Pg
Cl
Cl
O
Cl Zr
Cl
-
O
H
F3C
N
O
Pg
Figure 1. Proposed pathway for ZrCl ꢀcatalyzed Mannichꢀtype addition of 6
4
Zr(IV) coordinates both βꢀdicarbonyl oxygen atoms (I) so determining an increase of acidity of
methylene protons, which can be then deprotonated by trifluoromethyl aldimine. Finally, an
intermolecular nucleophilic attack to form II brings to the formation of the expected fluorinated
β'ꢀamino βꢀdicarbonyl compounds and restores the catalytic cycle.
Then, considering the hypothesized reaction outcome, we thought to perform the Mannichꢀtype
reaction starting from the optically pure trifluoromethyl aldimine 1c, hoping that the presence of
a chiral resident center on the electrophilic imine could lead to a diastereoselective addition
reaction without the need of a chiral ligand addition (Table 4).
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1
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2
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2
2
2
2
2
2
2
3
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3
3
4
4
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4
4
4
4
4
4
4
5
5
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5
5
5
5
5
5
5
6
Table 4. ZrCl ꢀCatalyzed MannichꢀType Reaction with Optically Pure 1c
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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9
0
1
2
3
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5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
a
a
b
entry βꢀketo ester
time (min) product
majorꢀ16,17
dr
major/minor
5:5
yield (%)
1
2
3
4
5
6
30
10
10
20
30
30
5:5
72
68
78
78
65
64
minorꢀ16',17'
8
18
≥ 9.9
≥ 9.9
≥ 9.9
5:5
9.9:0.1
9.9:0.1
9.9:0.1
5:5
9
19
10
14
15
20
majorꢀ21,22
minorꢀ21',22'
14
6
23
≥ 9.9
9.9:0.1
a
19
b
Determined by F NMR spectra performed on the crude mixtures. After flash
chromatography on silica gel.
As reported in Table 4, the stereoselective control failed in the absence of a steric hindrance on
the methylene active group of βꢀketo compounds (entries 1 and 5). Moreover, under our reported
reaction conditions, changing the ester residue did not influence the reaction stereochemistry,
1
5
unlike in the literature. In fact, in tertꢀbutyl ester 14 (entry 5), dr and major/minor ratio did not
change compared with methyl ester 6 (entry 1). Instead, very high dr values and major/minor
ratios were obtained starting from methyl substituted or cyclic methylene active compounds 8ꢀ10
and 15 (entries 2ꢀ4, 6), in all cases forming only one of the four possible diastereomers, a
quaternary chiral center being selectivity formed.
To determine the absolute configuration of the new chiral centers, as well as the anti or syn
configuration of the major or minor obtained diastereomers, the diastereoselective
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decarboxylation of compound 23 was performed (Scheme 2), following the procedure reported
1
5
in the literature.
Scheme 2. Decarboxylation Reaction of 23
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
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60
1
5
Considering that the equally high selectivity has been retained during the decarboxylation step
5
and following the already reported methodology, 2D NOESY analysis on 24 coupled with
computational studies (see Supporting Information) permitted to assign the (R,R,R) absolute
configuration to the obtained synꢀisomer 24. As a consequence, the (R,R,S) absolute
configuration can be assigned to the starting β'ꢀamino βꢀketo ester antiꢀisomer 23. Thanks to the
ability of Zr to coordinate both oxygen atoms, thus forming an octahedralꢀlike intermediate, in
which the enolate is constrained in a planar geometric disposition, the nucleophilic attack takes
place only on the sterically less hindered prochiral Re face of optically pure aldimine 1c (Figure
2).
Figure 2. Model for the preferred faceꢀselective addition reaction
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5
5
5
5
5
6
Considering the stereochemical results reported in Table 3, a steric hindrance on the E double
bond of zirconium complex III was required to obtain complete stereoselective control (Scheme
3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Stereoselective Synthesis of β'ꢀAmino βꢀKeto Ester 18
In fact, starting from unsubstituted acyclic βꢀketo esters 6 or 15 low dr values and no syn/anti
selectivity was observed.
To confirm the relevance of Zr on the highly stereoselective reaction outcome, a Mannichꢀtype
addition reaction was performed between trifluoromethyl aldimine 1c and βꢀketo ester 8 by using
AlCl as catalyst (Scheme 4).
3
Scheme 4. AlCl ꢀCatalyzed MannichꢀType Reaction
3
In this case, all the four possible diastereomers were obtained in equimolar ratios, the Al
coordinating only the carbonyl oxygen (IV) and giving, as a consequence, the acyclic anionic
intermediate V (Figure 3).
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Figure 3. Proposed pathway for AlCl ꢀcatalyzed Mannichꢀtype addition of 8
3
Finally, the solvent effect on the reaction diastereoselectivity was investigated. Thus, the ZrCl4ꢀ
catalyzed Mannichꢀtype reaction of 8 with chiral aldimine 1c was performed by using some
different organic solvents (DMSO, THF, CHCl , and PhCH ).
3
3
Working in DMSO the reaction did not take place, probably because ZrCl is coordinated to the
4
solvent and no longer available to promote the catalytic cycle. In fact, the use of less polar THF
or CHCl gave, as expected, only the diastereomerically pure 18, although in yields lower than
3
those obtained in reactions performed under solventꢀfree conditions (32 and 43%, respectively).
Finally, performing the reaction in almost non polar toluene, the Mannich addition takes place in
satisfactory yields (68%), but surprisingly all the four possible diastereomers antiꢀ18,25 and synꢀ
18',25' are formed in equimolar ratios.
CONCLUSION
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
In conclusion, a new direct diastereoselective Mannich reaction of βꢀketo esters with
trifluoromethyl Nꢀprotected aldimines has been developed. The ester residue did not affect the
reaction outcome: in fact no difference in reactivity was found by changing the ester moiety. On
the contrary, very important seems the presence of an alkyl substituent on the methylene active
group of βꢀketo esters and the use of Zr as coordinating metal to control the reaction
stereoselectivity.
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Furthermore, the use of common and inexpensive chiral (R)ꢀαꢀmethylbenzylamine, easily
removable by hydrogenolysis after Mannichꢀtype addition, to synthesize the optically pure
aldimine permits to obtain a complete stereoselective induction without the need for other added
organocatalysts. Thus, working under solventꢀfree conditions and even at room temperature the
only antiꢀisomer Mannich adducts, bearing a quaternary chiral center, were obtained as pure
diastereomers.
EXPERIMENTAL SECTION
General. IR spectra were recorded on a FT/IR spectrophotometer in CHCl as the solvent and
3
ꢀ1
1
13
19
reported in cm . H, C, and F NMR spectra NMR spectra were recorded by a 300 or a 400
MHz instrument and reported in δ units. CDCl was used as the solvent and CHCl (δ = 7.26
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3
1
13
19
ppm for H NMR), CDCl (δ = 77.0 ppm for C NMR) and C F (δ = −164.9 for F NMR) were
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6 6
used as internal standard. The NOESY experiments were performed by a 400 MHz instrument
using CDCl as the solvent and CHCl as the internal standard and used to assist in structure
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17
elucidation. ESI MS analyses were performed using a quadrupoleꢀtime of flight (QꢀTOF) mass
spectrometer equipped with an ESI source and a syringe pump. The experiments were conducted
in the positive ion mode. Optical rotation was determined at 25 °C at a wavelength of 589 nm,
using a quartz cell of 1 cm length. Imines 1aꢀc were prepared by reaction of
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trifluoroacetaldehyde ethyl hemiacetal and an opportune primary amine, following the reported
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procedure. Diethyl malonate (2), βꢀketo esters 6, 8ꢀ10, and 14, ZrCl , and trimethylsilyl
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trifluoromethanesulfonate (TMSOTf) are commercially available and used as received. βꢀKeto
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ester 15 was prepared following the reported procedure.
ZrCl ꢀCatalyzed MannichꢀType Reactions. General Procedure.
4
To a mixture of trifluoromethyl aldimines 1aꢀc (1 mmol) and diethyl malonate (2) or βꢀketo
esters 6, 8ꢀ10, and 14 (1 mmol), ZrCl (10 mol %) was added. The reactions were performed
4
under solventꢀfree conditions and stirred at room temperature for 10ꢀ30 min. After H O addition,
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the crude mixtures were extracted with Et O. The collected organic layers were dried on
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anhydrous Na SO , the solvent evaporated in vacuo and the residues purified by flash
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chromatography on silica gel (eluent hexane/ethyl acetate = 8:2).
Diethyl 2ꢀ[1ꢀ(benzylamino)ꢀ2,2,2ꢀtrifluoroethyl]malonate (3a). Yellow oil (299 mg, 80%). IR:
ꢀ1
ꢀ1 1
1
748 cm , 1760 cm . H NMR (CDCl ): δ 1.22–1.33 (m, 6H), 2.40 (br, 1H), 3.71 (d, J = 6.0 Hz,
3
19
1H), 3.86–4.07 (m, 3H), 4.15–4.29 (m, 4H), 7.21–7.31 (m, 5H). F NMR (CDCl ): δ –72.23 (d,
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1
3
J = 7.2 Hz). C NMR (CDCl ): δ 13.8, 13.9, 52.0, 52.3, 58.7 (q, J = 28.4 Hz), 61.8, 62.1, 125.8
3
(
q, J = 286.3 Hz), 127.2, 128.1 (2C), 128.2 (2C), 139.2, 166.5, 166.6. HRꢀMS (ESI QꢀTOF)
+
(m/z) [M + H] calcd for C H F NO 348.1423, found 348.1424.
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Diethyl 2ꢀ[2,2,2ꢀtrifluoroꢀ1ꢀ(4ꢀmethoxyphenylamino)ethyl]malonate (3b). Brown oil (287
ꢀ1
ꢀ1 1
mg, 79%). IR: 1750 cm , 1758 cm . H NMR (CDCl ): δ 1.15 (t, J = 7.1 Hz, 3H), 1.28 (t, J =
3
7.1 Hz, 3H), 3.74 (s, 3H), 3.82 (d, J = 3.5 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.1 Hz,
19
13
2
H), 4.61–4.76 (m, 2H), 6.69–6.79 (m, 4H). F NMR (CDCl ): δ –74.10 (d, J = 7.2 Hz). C
3
NMR (CDCl ): δ 13.8, 13.9, 50.7, 55.6, 57.3 (q, J = 30.2 Hz), 62.1, 62.5, 114.7 (2C), 115.7 (2C),
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+
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25.1 (q, J = 284.7 Hz), 139.8, 153.3, 166.0, 167.0. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd
for C H F NO 364.1372, found 364.1375.
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Diethyl 2ꢀ[2,2,2ꢀtrifluoroꢀ1ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}ethyl]malonate (4,5c). Colorless (263
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ꢀ1
ꢀ1 1
mg, 73%). IR: 1743 cm , 1751 cm . H NMR (CDCl ): δ 1.28–1.35 (m, 18H), 2.73 (br, 2H),
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1
9
3.64 (d, J = 5.1 Hz, 1H), 3.71 (d, J = 5.1 Hz, 1H), 3.93–4.31 (m, 12H), 7.24–7.34 (m, 10H). F
13
NMR (CDCl ): δ –73.39 (d, J = 7.4 Hz), –70.66 (d, J = 7.0 Hz). C NMR (CDCl ): δ 13.8, 13.9
3
3
(
2C), 14.0, 23.6, 25.1, 51.3, 51.7, 55.4, 55.7, 56.4 (q, J = 28.0 Hz), 56.5 (q, J = 28.8 Hz), 61.7,
61.8, 62.0, 62.2, 125.5 (q, J = 284.3 Hz), 126.0 (q, J = 288.4 Hz), 126.8 (2C), 127.1 (2C), 127.2,
1
27.3, 128.3 (2C), 128.4 (2C), 143.7, 144.7, 166.4, 166.8 (2C), 166.9. HRꢀMS (ESI QꢀTOF)
+
(m/z) [M + H] calcd for C H F NO 362.1579, found 362.1582.
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Methyl 2ꢀacetylꢀ3ꢀ(benzylamino)ꢀ4,4,4ꢀtrifluorobutanoate (7,7'a). Yellow oil (227 mg, 75%).
ꢀ1
ꢀ1 1
IR: 1740 cm , 1715 cm . H NMR (CDCl ): δ 1.84 (br, 1H), 2.01 (br, 1H), 2.20 (s, 3H), 2.24 (s,
3
3
H), 3.73 (s, 3H), 3.75 (s, 3H), 3.78 (d, J = 2.1 Hz, 1H), 3.79 (d, J = 3.7 Hz, 1H), 3.82–3.86 (m,
1
9
2
H), 3.92–4.05 (m, 4H), 7.23–7.34 (m, 10H). F NMR (CDCl ): δ –72.03 (d, J = 7.2 Hz) –71.91
3
13
(
d, J = 7.1 Hz). C NMR (CDCl ): δ 29.1, 29.8, 52.3 (2C), 52.7, 52.9, 58.0 (q, J = 28.6 Hz),
3
58.6, 58.9 (q, J = 28.1 Hz), 59.4, 127.3, 127.4, 127.5 (q, J = 282.5 Hz, 2C), 128.3 (4C), 128.4
+
(
4C), 138.8, 139.1, 167.2, 167.5, 198.8, 199.8. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for
C H F NO 304.1161, found 304.1165.
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17
3
3
Ethyl 2ꢀacetylꢀ3ꢀ(benzylamino)ꢀ4,4,4ꢀtrifluoroꢀ2ꢀmethylbutanoate (11,11'a). Red oil (215
ꢀ1
ꢀ1 1
mg, 65%). IR: 1743 cm , 1720 cm . H NMR (CDCl ): δ 1.21–1.28 (m, 6H), 1.40 (s, 3H, minor
3
syn isomer), 1.48 (s, 3H, major anti isomer), 1.83 (br, 2H), 2.18 (s, 6H), 3.79–3.85 (m, 2H),
1
9
4
.07–4.30 (m, 7H), 4.38 (q, J = 7.3 Hz, 1H), 7.26–7.34 (m, 10H). F NMR (CDCl ): δ –65.60
3
13
(
d, J = 7.6 Hz, minor syn isomer), –65.39 (d, J = 7.0 Hz, major anti isomer). C NMR (CDCl ):
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δ 13.4, 13.8, 13.9, 15.5, 25.8, 26.3, 52.7, 53.1, 61.9, 62.1, 62.2 (q, J = 26.6 Hz), 62.3, 62.6 (q, J =
26.7 Hz), 63.2, 126.0 (q, J = 288.6 Hz), 126.2 (q, J = 288.2 Hz), 127.3, 127.5, 128.0 (2C), 128.2
(2C), 128.3 (2C), 128.4 (2C), 138.8, 139.3, 169.4, 169.5, 200.7, 202.2. HRꢀMS (ESI QꢀTOF)
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+
(
m/z) [M + H] calcd for C H F NO 332.1474, found 332.1470.
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Ethyl 2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ3ꢀ(4ꢀmethoxyphenylamino)ꢀ2ꢀmethylbutanoate (11,11'b). Red
ꢀ1
ꢀ1 1
oil (236 mg, 68%). IR: 1750 cm , 1729 cm . H NMR (CDCl ): δ 1.16 (t, J = 7.1 Hz, 3H, major
3
anti isomer), 1.25 (t, J = 7.0 Hz, 3H, minor syn isomer), 1.54 (s, 3H, syn isomer), 1.56 (s, 3H,
major anti isomer), 2.19 (s, 6H), 3.73 (s, 6H), 4.02–4.27 (m, 6H), 4.76–4.87 (m, 1H, major anti
19
isomer), 4.92–5.03 (m, 1H, minor syn isomer), 6.67–6.78 (m, 8H). F NMR (CDCl ): δ –67. (d,
3
1
3
J = 7.4 Hz, minor syn isomer), –67.63 (d, J = 8.0 Hz, major anti isomer). C NMR (CDCl ): δ
3
13.7, 13.8, 15.1, 16.4, 26.2, 26.5, 55.5 (2C), 58.7 (q, J = 28.4 Hz), 59.8 (q, J = 28.2 Hz), 61.3
(
(
(
2C), 62.0, 62.3, 114.7 (2C), 114.8 (2C), 115.2 (2C), 115.5 (2C), 125.3 (q, J = 286.9 Hz), 125.4
q, J = 286.5 Hz), 139.3, 139.6, 153.2, 153.4, 169.5, 169.6, 201.8, 202.0. HRꢀMS (ESI QꢀTOF)
+
m/z) [M + H] calcd for C H F NO 348.1423, found 348.1425.
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21
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Ethyl 1ꢀ[1ꢀ(benzylamino)ꢀ2,2,2ꢀtrifluoroethyl]ꢀ2ꢀoxocyclopentanecarboxylate (12,12'a). Red
ꢀ1
ꢀ1 1
oil (257 mg, 75%). IR: 1758cm 1725 cm . H NMR (CDCl ): δ 1.21–1.31 (m, 6H), 1.59 (br,
,
3
2
H), 1.98–2.05 (m, 6H), 2.17–2.76 (m, 6H), 3.78–4.09 (m, 4H), 4.12–4.41 (m, 6H), 7.24–7.34
1
9
(
m, 10H). F NMR (CDCl ): δ –65.25 (d, J = 8.4 Hz, minor syn isomer), –65.50 (d, J = 8.4 Hz,
3
13
major anti isomer). C NMR (CDCl ): δ 13.8, 13.9, 19.5, 20.2, 27.0, 27.1, 37.2, 38.5, 52.7, 54.2,
3
6
2.0, 62.2 (q, J = 26.5 Hz, 2C), 62.2, 63.1, 64.5, 125.9 (q, J = 287.6 Hz, 2C), 127.3, 127.4, 128.0
+
(
4C), 128.3 (4C), 139.0, 139.3, 166.7, 166.8, 210.1, 210.4. HRꢀMS (ESI QꢀTOF) (m/z) [M + H]
calcd for C H F NO 344.1474, found 344.1471.
1
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Ethyl
2ꢀoxoꢀ1ꢀ[2,2,2ꢀtrifluoroꢀ1ꢀ(4ꢀmethoxyphenylamino)ethyl]cyclopentanecarboxylate
ꢀ1
ꢀ1 1
(12,12'b). Brown oil (262 mg, 73%). IR: 1762 cm , 1759 cm . H NMR (CDCl ): δ 1.04 (t, J =
3
7
2
.1 Hz, 3H, major anti isomer), 1.23 (t, J = 7.1 Hz, 3H, minor syn isomer), 1.93–2.47 (m, 10H),
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.54–2.83 (m, 2H), 3.54 (br, 1H), 3.74 (s, 6H), 3.85 (br, 1H), 3.90–4.04 (m, 2H), 4.10–4.25 (m,
1
9
2H), 4.82–4.96 (m, 2H), 6.69–6.78 (m, 8H). F NMR (CDCl ): δ –69.89 (d, J = 7.2 Hz, minor
3
1
3
syn isomer), –68.37 (d, J = 7.0 Hz, major anti isomer). C NMR (CDCl ): δ 13.7, 13.9, 19.5,
3
20.0, 27.2, 28.2, 37.1, 38.3, 55.6 (2C), 59.7 (q, J = 28.1 Hz), 61.0 (q, J = 27.7 Hz), 62.0, 62.3,
62.5, 63.9, 114.7 (4C), 115.7 (2C), 116.4 (2C), 125.1 (q, J = 285.9 Hz), 125.6 (q, J = 286.6 Hz),
+
139.5, 139.9, 153.5, 153.8, 166.4, 167.2, 209.4, 210.7. HRꢀMS (ESI QꢀTOF) (m/z) [M + H]
calcd for C H F NO 360.1423, found 360.1427.
17 21
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Ethyl 1ꢀ[1ꢀ(benzylamino)ꢀ2,2,2ꢀtrifluoroethyl]ꢀ2ꢀoxocyclohexanecarboxylate (13a). White oil
ꢀ1
ꢀ1 1
(278 mg, 78%). IR: 1743 cm , 1729 cm . H NMR (CDCl ): δ 1.21 (t, J = 7.1 Hz, 3H), 1.64–
3
1
9
1.94 (m, 6H), 2.36–2.52 (m, 3H), 3.73–4.10 (m, 2H), 4.13–4.28 (m, 3H), 7.22–7.33 (m, 5H). F
1
3
NMR (CDCl ): δ –63.79 (d, J = 7.8 Hz). C NMR (CDCl ): δ 13.8, 21.9, 25.9, 30.9, 40.7, 52.8,
3
3
61.6 (q, J = 27.4 Hz), 61.9, 64.3, 126.0 (q, J = 288.7 Hz), 127.3, 128.1 (2C), 128.3 (2C), 139.1,
+
168.5, 203.8. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO 358.1630, found
1
8
23
3
3
358.1635.
Ethyl
2ꢀoxoꢀ1ꢀ[2,2,2ꢀtrifluoroꢀ1ꢀ(4ꢀmethoxyphenylamino)ethyl]cyclohexanecarboxylate
ꢀ1
ꢀ1 1
(13b). White oil (317 mg, 85%). IR: 1745 cm , 1728 cm . H NMR (CDCl ): δ 1.11 (t, J = 7.1
3
Hz, 3H), 1.63–2.03 (m, 6H), 2.42–2.54 (m, 3H), 3.73 (s, 3H), 3.97 (q, J = 7.2 Hz, 1H), 4.08 (q, J
1
9
=
7.1 Hz, 1H), 4.83–4.91 (m, 1H), 6.66–6.76 (m, 4H). F NMR (CDCl ): δ –67.03 (d, J = 7.5
3
1
3
Hz). C NMR (CDCl ): δ 13.7, 22.0, 26.2, 31.4, 40.8, 55.7, 58.9 (q, J = 29.1 Hz), 62.2, 63.8,
3
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14.8 (2C), 115.3 (2C), 125.1 (q, J = 286.2 Hz), 139.8, 153.3, 168.3, 203.9. HRꢀMS (ESI Qꢀ
+
TOF) (m/z) [M + H] calcd for C H F NO 374.1579, found 374.1571.
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Methyl 2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ3ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}butanoate (antiꢀ16,17/synꢀ
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ꢀ1
ꢀ1 1
1
6',17'). Yellow oil (228 mg, 72%). IR: 1739 cm , 1725 cm . H NMR (CDCl ): δ 1.29–1.34
3
(m, 12H), 1.67 (br, 1H), 2.05 (s, 3H), 2.12 (s, 3H), 2.21 (br, 1H), 2.29 (s, 3H), 2.32 (s, 3H), 2.50
19
(
br, 1H), 3.65–3.81 (m, 20H), 3.98–4.09 (m, 5H), 7.23–7.36 (m, 20H). F NMR (CDCl ): δ –
3
1
3
7
3.16 (d, J = 7.6 Hz), –72.63 (d, J = 6.9 Hz), –70.52 (d, J = 6.9 Hz), –70.07 (d, J = 7.9 Hz). C
NMR (CDCl ): δ 22.7, 23.1, 24.7, 24.8, 28.7, 29.3, 29.9, 30.9, 52.5, 52.7 (2C), 52.9, 55.3, 55.4,
3
5
5.6 (q, J = 26.3 Hz), 55.7 (2C), 55.7 (q, J = 27.8 Hz), 56.6 (q, J = 28.3 Hz), 56.7 (q, J = 27.7
Hz), 57.6, 58.2, 59.0, 59.1, 125.6 (q, J = 277.4 Hz), 126.0 (q, J = 288.1 Hz), 126.6 (2C), 126.7
(2C), 127.1 (q, J = 284.4 Hz), 127.2 (q, J = 280.4 Hz), 127.3 (2C), 127.4 (4C), 127.6 (2C), 128.3
(
2C), 128.4 (4C), 128.5 (2C), 143.1, 143.2, 144.7, 144.8, 167.3, 167.5, 167.7, 167.8, 199.0,
+
1
99.1, 200.4 (2C). HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO 318.1317, found
15 19
3
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318.1312.
Ethyl
(2S,3R)ꢀ2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ2ꢀmethylꢀ3ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}butanoate
ꢀ1
(18). Light yellow oil (234 mg, 68%). [α] = +86.0 (c = 1 g/100 mL, CHCl ). IR: 1742 cm ,
D
3
ꢀ1 1
1
726 cm . H NMR (CDCl ): δ 1.28–1.31 (m, 6H), 1.46 (s, 3H), 1.97 (br, 1H), 2.22 (s, 3H), 4.04
3
(
q, J = 6.2 Hz, 1H), 4.18 (q, J = 7.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 1H), 4.36 (q, J = 8.1 Hz, 1H),
1
9
13
7.22−7.32 (m, 5H). F NMR (CDCl ): δ –64.99 (d, J = 8.5 Hz). C NMR (CDCl ): δ 13.9, 15.3,
3
3
2
1
3
1.6, 26.6, 55.5, 59.1 (q, J = 26.7 Hz), 62.1, 63.2, 126.0 (q, J = 288.4 Hz), 126.5 (2C), 127.4,
+
28.5 (2C), 145.5, 169.4, 202.2. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO
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46.1630, found 346.1633.
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Ethyl
(1S)ꢀ2ꢀoxoꢀ1ꢀ[(1R)ꢀ2,2,2ꢀtrifluoroꢀ1ꢀ{[(R)ꢀ1ꢀ
phenylethyl]amino}ethyl]cyclopentanecarboxylate (19). Light yellow oil (278 mg, 78%). [α]D
ꢀ1
ꢀ
1
1
=
+54.0 (c = 1 g/100 mL, CHCl ). IR: 1731 cm , 1718 cm . H NMR (CDCl ): δ 1.23–1.28 (m,
3 3
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6H), 1.60 (br, 1H), 1.85–1.96 (m, 3H), 2.12–2.23 (m, 1H), 2.19–2.28 (m, 1H), 2.59–2.63 (m,
1H), 3.96 (q, J = 6.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 1H), 4.21 (q, J = 7.1 Hz, 1H), 4.29 (q, J = 7.3
1
9
13
Hz, 1H), 7.16−7.29 (m, 5H). F NMR (CDCl ): δ –64.99 (d, J = 8.5 Hz). C NMR (CDCl ): δ
3
3
14.0, 19.6, 21.6, 27.2, 37.2, 55.3, 59.2 (q, J = 26.3 Hz), 62.3, 64.5, 126.5 (2C), 126.9 (q, J =
+
288.4 Hz), 127.5, 128.6 (2C), 146.4, 166.8, 210.0. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd
for C H F NO 358.1630, found 358.1636.
1
8
23
3
3
Ethyl
(1S)ꢀ2ꢀoxoꢀ1ꢀ[(1R)ꢀ2,2,2ꢀtrifluoroꢀ1ꢀ{[(R)ꢀ1ꢀ
phenylethyl]amino}ethyl]cyclohexanecarboxylate (20). Colorless oil (289 mg, 78%). [α] =
D
ꢀ1
ꢀ1 1
+79.0 (c = 1 g/100 mL, CHCl ). IR: 1740 cm , 1715 cm . H NMR (CDCl ): δ 1.26–1.33 (m,
3
3
6
7
7
H), 1.57–1.67 (m, 3H), 1.84–1.99 (m, 4H), 2.37–2.41 (m, 1H), 2.52–2.63 (m, 1H), 4.02 (q, J =
.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.2 Hz, 1H), 4.31 (q, J = 7.2 Hz, 1H),
19
13
.23−7.31 (m, 5H). F NMR (CDCl ): δ –64.99 (d, J = 8.5 Hz). C NMR (CDCl ): δ 13.9, 21.5,
3
3
22.1, 25.7, 30.3, 40.9, 55.2, 58.2 (q, J = 26.6 Hz), 62.0, 64.3, 126.2 (q, J = 287.8 Hz), 126.5
+
(2C), 127.4, 128.5 (2C), 145.5, 168.4, 203.7. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for
C H F NO 372.1787, found 372.1785.
19
25
3
3
tert-Butyl 2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ3ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}butanoate (antiꢀ21,22/synꢀ
ꢀ1
ꢀ1 1
21',22'). Colorless oil (233 mg, 65%). IR: 1737 cm , 1712 cm . H NMR (CDCl ): δ 1.48–1.58
3
(m, 52H), 2.04 (s, 3H), 2.07 (s, 3H), 2.29–2.30 (m,6H), 3.50– 3.73 (m, 6H), 3.99–4.08 (m, 6H),
1
9
7.26−7.36 (m, 20H). F NMR (CDCl ): δ –70.08 (d, J = 8.6 Hz), –70.50 (d, J = 7.7 Hz), –72.21
3
13
(d, J = 8.5 Hz), –72.83 (d, J = 7.5 Hz). C NMR (CDCl ): δ 22.6, 23.3, 24.9, 25.5, 27.6 (2C),
3
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7.8 (12C), 28.3 (2C), 54.6, 55.3, 55.4, 55.6, 56.1 (q, J = 28.0 Hz), 56.3 (q, J = 27.5 Hz), 56.4
(
q, J = 30.0 Hz), 56.5 (q, J = 28.0 Hz), 59.2, 59.7, 59.9, 60.5, 82.8, 82.9, 83.0, 83.1, 125.7 (q, J
278.8 Hz), 125.8 (q, J = 279.8 Hz), 125.9 (q, J = 285.5 Hz), 126.1 (q, J = 288.5 Hz), 126.7
2C), 126.9 (2C), 127.0 (2C), 127.3 (2C), 127.4, 127.5, 127.6 (2C), 128.4 (4C), 128.5 (2C),
=
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(
128.7 (2C), 143.0, 143.4, 143.8, 144.8, 165.9, 166.1, 166.7, 166.8, 199.7, 199.8, 200.5, 200.8.
+
HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO 360.1787, found 360.1789.
18
25
3
3
tertꢀButyl (2S,3R)ꢀ2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ2ꢀmethylꢀ3ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}butanoate
ꢀ1
(23). Yellow oil (238 mg, 64%). [α] = +123.0 (c = 1 g/100 mL, CHCl ). IR: 1752 cm , 1719
D
3
ꢀ1
1
cm . H NMR (CDCl ): δ 1.25 (d, J = 6.4 Hz, 3H) 1.34 (s, 3H), 1.40 (s, 9H), 1.95 (br, 1H), 2.15
3
1
9
(
s, 3H), 3.98 (q, J = 6.4 Hz, 1H), 4.15−4.24 (m, 1H), 7.14−7.26 (m, 5H). F NMR (CDCl ): δ –
3
1
3
64.3 (d, J = 6.3 Hz). C NMR (CDCl ): δ 15.8, 21.4, 26.5, 27.7 (3C), 55.3, 59.5 (q, J = 26.5
3
Hz), 63.6, 82.7, 126.1 (q, J = 288.9 Hz), 126.4 (2C), 127.2, 128.4 (2C), 146.5, 168.4, 202.6. HRꢀ
+
MS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO 374.1943 found 374.1941.
19 27
3
3
(3R,4R)ꢀ5,5,5ꢀtrifluoroꢀ3ꢀmethylꢀ4ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}pentanꢀ2ꢀone (24). Yellow oil
ꢀ1
1
(
75 mg, 43%). [α] = +72.0 (c = 1 g/100 mL, CHCl ). IR: 1715 cm . H NMR (CDCl ): δ 1.19
D 3 3
(d, J = 7.1 Hz, 3H), 1.26 (d J = 6.4 Hz, 3H), 1.51 (br, 1H), 2.15 (s, 3H), 2.76–2.83 (m, 1H),
1
9
3
.60–3.67 (m, 1H), 3.91 (q, J = 6.4 Hz, 1H), 7.20−7.29 (m, 5H). F NMR (CDCl ): δ –72.35 (d,
3
1
3
J = 8.9 Hz). C NMR (CDCl ): δ 11.1, 23.3, 28.6, 46.4, 55.6, 56.4 (q, J = 27.0 Hz), 126.8 (2C),
3
+
127.4, 127.7 (q, J = 245.8 Hz), 128.5 (2C), 144.7, 208.8. HRꢀMS (ESI QꢀTOF) (m/z) [M + H]
calcd for C H F NO 274.1419, found 274.1421.
1
4
19 3
AlCl ꢀCatalyzed Mannichꢀtype reactions of βꢀketo ester 8 with aldimine 1c.
3
To a mixture of trifluoromethyl aldimines 1c (1 mmol) and βꢀketo esters 8 (1 mmol), AlCl (10
3
mol %) was added. The reaction was performed under solventꢀfree conditions and stirred at room
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temperature for 30 min. After H O addition, the crude mixtures were extracted with Et O. The
2
2
collected organic layers were dried on anhydrous Na SO , the solvent evaporated in vacuo and
2
4
the residues purified by flash chromatography on silica gel (eluent hexane/ethyl acetate = 8:2).
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Ethyl
2ꢀacetylꢀ4,4,4ꢀtrifluoroꢀ2ꢀmethylꢀ3ꢀ{[(R)ꢀ1ꢀphenylethyl]amino}butanoate
(antiꢀ
ꢀ
ꢀ1 1
1
1
3
8,25/synꢀ18',25'). Yellow oil (169 mg, 49%). IR: 1751 cm 1, 1715 cm ; H NMR (CDCl ): δ
3
.12−1.41 (m, 36H), 1.46−1.58 (br, 4H), 1.81 (s, 3H), 2.04 (s, 3H), 2.22 (s, 3H), 2.32 (s, 3H),
19
.89–4.39 (m, 16H), 7.22−7.35 (m, 20H). F NMR (CDCl ): δ –63.29 (d, J = 7.0 Hz), –63.54 (d,
3
1
3
J = 6.7 Hz), –64.99 (d, J = 8.3 Hz), –65.22 (d, J = 6.8 Hz). C NMR (CDCl ): δ 13.6, 13.7, 13.8,
3
13.9, 14.2, 15.2, 16.5 (2C), 21.3 (2C), 21.6 (2C), 24.3, 24.8, 26.1, 26.4, 53.1, 55.3, 55.5, 55.8,
59.0 (q, J = 27.3 Hz), 59.1 (q, J = 26.6 Hz), 60.0 (q, J = 26.6 Hz), 60.8 (q, J = 26.3 Hz), 61.9,
62.0, 62.2 (2C), 62.6 (3C), 63.2, 125.8 (q, J = 280.8 Hz ), 125.9 (q, J = 267.5 Hz ), 125.9 (q, J =
288.1 Hz ), 126.4 (2C), 127.0 (2C), 127.4 (4C), 127.7 (2C), 128.0 (2C), 128.3 (2C), 128.4 (2C),
128.6 (4C), 127.7 (q, J = 245.8 Hz), 142.8, 143.4, 145.2, 145.5, 169.4 (2C), 169.8, 169.9, 201.2,
+
201.3, 202.4, 202.6. HRꢀMS (ESI QꢀTOF) (m/z) [M + H] calcd for C H F NO 346.1630
17
23
3
3
found 346.1623.
ASSOCIATED CONTENT
Supporting Information
1
13
19
Complete characterization data ( H, C and F NMR data) for all new compounds,
computational details, 2D NMR spectra, and optimized geometries to determine the absolute
configuration of the new chiral centers. The Supporting Information is available free of charge
via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*
eꢀmail: stefania.fioravanti@uniroma1.it
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ACKNOWLEDGEMENTS
th
Dedicated to Prof. Paolo Antonio Tardella on the occasion of his 80 birthday. We thank the Università degli Studi
di Roma “La Sapienza” and the Dipartimento di Chimica of the same university for financial support, and Prof.
Ruggero Caminiti (Dipartimento di Chimica of the same university) for providing free computing time on NARTEN
Cluster HPC Facility.
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