Organocatalytic Enantioselective Synthesis of Trifluoromethyl-Containing Tetralin Derivatives by Sequential (Hetero)Michael Reaction–Intramolecular Nitrone Cycloaddition

Article abstract of DOI:10.1002/adsc.201700975

The enantioselective synthesis of tetralin derivatives bearing a trifluoromethylated all-carbon quaternary stereocenter has been accomplished through a synthetic sequence comprising an organocatalytic β-functionalization of ortho-1-trifluoromethylvinyl-(hetero)aromatic conjugated aldehydes followed by the intramolecular nitrone 1,3-cycloaddition reaction (INCR). Both nitromethane and N-Cbz-hydroxylamine were employed as nucleophiles in the initial organocatalytic conjugate addition step, which provided the chiral information required for the subsequent diastereoselective INCR. Although diastereoselectivity was moderate, good yields and enantioselectivities were, in general, obtained. Interestingly, an inversion of the selectivity in the intramolecular cycloaddition step was observed when either nitromethane or N-Cbz-hydroxylamine was employed. This outcome was studied by means of theoretical calculations, which were in agreement with the experimental results. In addition, the ring opening of the isoxazolidine moiety furnished the corresponding fluorinated diamino alcohols in a very efficient manner. (Figure presented.).

Full text of DOI:10.1002/adsc.201700975

Title: Organocatalytic Enantioselective Synthesis of Trifluoromethyl-
Containing Tetra-lin Derivatives by Sequential (Hetero)Michael
Reaction-Intramolecular Nitrone Cycloaddition
Authors: Fernando Rabasa Alcañiz, Javier Torres Fernández, Maria
Sanchez-Rosello, Tomás Tejero, Pedro Merino, Santos
Fustero, and Carlos del Pozo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700975
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Enantioselective Synthesis of Trifluoromethyl-
Containing Tetralin Derivatives by Sequential (Hetero)Michael
Reaction-Intramolecular Nitrone Cycloaddition
Fernando Rabasa-Alcañiz,a Javier Torres,a María Sánchez-Roselló,a Tomás Tejero,b
Pedro Merino,c* Santos Fusteroa,d* and Carlos del Pozoa*
a Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
E-mail: carlos.pozo@uv.es, santos.fustero@uv.es
b
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, 50009
Zaragoza, Spain
c
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), Universidad de Zaragoza,
50009 Zaragoza, Spain
E-mail: pmerino@unizar.es
d
Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia,
Spain
Dedicated to Prof. Dr. Günter Haufe on the occasion of his retirement
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The enantioselective synthesis of tetralin Interestingly, an inversion of the selectivity in the
derivatives bearing
a
trifluoromethylated all-carbon intramolecular cycloaddition step was observed when either
quaternary stereocenter has been accomplished through a nitromethane or N-Cbz-hydroxylamine were employed.
synthetic sequence comprising an organocatalytic - This outcome was studied by means of theoretical
functionalization
of
ortho-1-trifluoromethylvinyl calculations, which were in agreement with the
(hetero)aromatic conjugated aldehydes followed by experimental results. In addition, the ring opening of the
intramolecular nitrone 1,3-cycloaddition reaction (INCR). isoxazolidine moiety rendered the corresponding
Both nitromethane and N-Cbz-hydroxylamine were fluorinated diamino alcohols in a very efficient manner.
employed as nucleophiles in the initial organocatalytic
conjugate addition step, which provided the chiral
information required for the subsequent diastereoselective
INCR. Although diastereoselectivity was moderate, good
yields and enantioselectivities were, in general, obtained.
Keywords:
fluorinated
tetralins;
organocatalysis,
quaternary stereocenter, nitro-Michael addition; aza-
Michael addition; fluorinated amino alcohols
enhance the lipophilicity and metabolic stability of
the non-fluorinated parent molecules.[4] For that
reason, the development of methodologies that enable
the synthesis of novel CF3-containing scaffolds has
attracted growing attention.[5] However, the
incorporation of fluorinated moieties in the carbon
skeleton of chiral tetralins has been scarcely explored
to date.[6]
Introduction
The tetralin or 1,2,3,4-tetrahydronaphthalene core is
present in a great variety of natural products and
drugs,[1] therefore being classified as a privileged
structural motif for the construction of drug-like
molecules.[2] Consequently, synthetic efforts to access
these valuable building blocks, especially in
enantiomerically enriched form, are always of high
interest.
On the other hand, nitrones are the most widely used
types of dipoles in 1,3-dipolar cycloadditions.[7] They
Nowadays, the introduction of fluorinated groups into are easy to prepare from readily available starting
biologically active compounds has become a powerful materials and show high stability in comparison with
strategy in order to modulate their biological other types of dipoles.[8] They react with a large
properties.[3] In particular, the occurrence of the CF3 variety of dipolarophiles, generating either isoxazole
group in pharmaceuticals is remarkable since it can or isoxazolidine scaffolds in a very simple manner.[9]
1
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
Considering the ubiquitous presence of these
heterocycles in biologically relevant compounds,
examples of its preparation by using this [3+2]
cycloaddition reaction are widespread in the
aldehydes to nitroalkenes or -unsaturated
systems.[26] For example, Zhong described this
reaction on -nitrostyrenes bearing
a suitable
dipolarophile in the ortho position for the synthesis of
highly substituted enantiomerically pure tetralins
(Scheme 1, eq. 1).[26c] To date, only one example of -
functionalization of aldehydes has been reported in
combination with an INCR, taking advantage of
iminium catalysis.[27] With these precedents, and
inspired by our interest in organofluorine chemistry,
we envisioned the possibility of employing
cinnamaldehydes, substituted at the ortho position
with a 1-trifluoromethyl alkene moiety, as starting
substrates to carry out an organocatalytic nucleophilic
conjugate addition followed by INCR. By means of
this sequence, that employs the almost unprecedented
1-trifluoromethyl alkene as dipolarophile,[28] a novel
family of fluorinated tetralins bearing an all-carbon
CF3-containing quaternary stereocenter will be
obtained (Scheme 1, eq. 2). It is worth mentioning
that the development of new synthetic strategies for
the enantioselective construction of all-carbon
quaternary chiral centers bearing a CF3 group
represents an important challenge in organic
synthesis. In fact, few examples have recently been
reported in the literature, and all of them concern
intermolecular processes.[29]
literature.[10]
Additionally,
isoxazoles
and
isoxazolidines are versatile synthetic intermediates,
easily transformed to β-amino acids, β-lactams, or β-
amino alcohols.[11] Also, other heterocyclic systems
can be accessed through different reactions, including
Mannich-type,[12] and Kinugasa[13] reactions as well as
less common transformations.[14]
The asymmetric version of this 1,3-dipolar
cycloaddition reaction of nitrones has received
significant attention as it allows the generation of
those interesting derivatives in enantiomerically
enriched manner.[15] Early examples relied on the use
of chiral starting materials, mainly based on chiral
nitrones derived from amino acids[16] and sugars.[17]
With the development of enantioselective catalysis, a
large number of reports have appeared in the literature
that take advantage of both transition metal
catalysis[18] and organocatalysis,[19] reaching a high
degree of control in the diastereo- and
enantioselectivity of the process.
Despite this exponential growth, recently highlighted
by Maruoka,[15b] the intramolecular version of those
reactions is still a big challenge[20] and, as far as we
know, no examples of enantioselective intramolecular
[3+2] cycloadditions of nitrones have been described
to date.[21] The main difficulty for achieving this
transformation is to design the correct system in
which the cycloaddition is favored once the nitrone is
generated in situ. Generation of nitrones is usually
made by either condensation or oxidation processes,[8]
which should be compatible with the presence of the
catalyst whether it is a chiral Lewis acid[22] or an
organocatalyst.[23] The electronic nature of the
reaction[24] and the spontaneous cyclization that may
take place once the nitrone is generated in the
presence of the dipolarophile (background reactivity)
pose additional inherent difficulties.
Finally, ring opening of the isoxazolidine cycle would
render valuable fluorinated 1,3-amino alcohols as
precursors of the corresponding fluorinated -amino
acids.[30]
In order to incorporate the chiral information for the
asymmetric intramolecular cycloaddition of nitrones,
a successfully employed strategy is the combination
of this process with a previous organocatalytic event.
In this manner, the enantioselectivity induced in the
organocatalytic step is transferred to the final
products in the subsequent cyclization step. In this
context, the organocatalytic -functionalization of
aldehydes is a well established methodology, using
enamine catalysis with chiral secondary amines such
as Jørgensen-Hayashi or MacMillan catalysts.[25] Most
examples that merge organocatalytic processes with
intramolecular nitrone cycloaddition reactions (INCR)
rely on this strategy, usually by means of an
enantioselective conjugated addition reaction of
Scheme 1. Synthetic strategies towards chiral tetralines.
Results and Discussion
Very recently we disclosed the utility of α-
trifluoromethyl styrenes as suitable dipolarophiles for
the intramolecular nitrone cycloaddition reaction
(INCR). In this work, we found that the CF3 acts as a
directing group in controlling the regiochemistry of
the cyclization process, affording preferential or
exclusively the corresponding fused tricyclic
2
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
cycloadducts.[28] The next step in our study was addition of nitroalkanes to enals,[32] a first attempt was
directed towards the enantioselective version of this made with nitromethane, employing diphenylprolinol
transformation. Following an analogous methodology, (I) as the catalyst in methanol at room temperature.
the preparation of the starting ortho-substituted The complete consumption of the starting aldehyde
cinnamaldehydes 3a-d and related compounds 3e,f 3a was observed after 7 days, when solvents were
was performed by means of a palladium-catalyzed removed under reduced pressure. After standard
cross-coupling reaction of 1,1,1-trifluoroacetone aqueous work-up, the crude mixture was re-dissolved
tosylhydrazone
2
with several ortho-bromo in toluene and subjected to the INCR in the presence
cinnamaldehydes or derivatives 1.[31] Under optimized of N-methylhydroxyl amine hydrochloride and
reaction conditions, good to excellent yields of sodium bicarbonate. Heating the reaction mixture
conveniently functionalized (trifluoromethyl)styrenes under microwave irradiation at 120ºC for 30 min gave
3 were obtained, as depicted in Table 1.
rise to
a
4:1 mixture of diastereomeric
Table 1. Synthesis of the starting CF3-containing ,- tetrahydronaphthalene isoxazolidines in 29% overall
unsaturated aldehydes 3
yield. Both diastereoisomers were separated by
column chromatography and the major one 5a was
obtained in 82% ee (Table 2, entry 1). When
diphenylprolinol silyl ether (II) was employed as the
chiral catalyst, the disappearance of the starting
material was observed after 16 hours at room
temperature.
methylhydroxyl amine, the INCR took place
efficiently affording again 4:1 mixture of
Upon
condensation
with
N-
Entry
Yield [%][a]
89
1
3
a
diastereoisomers in 46% yield and complete
enantioselection in favor of compound 5a (Table 2,
entry 2). Trying to improve the diastereoselectivity of
the process, lower temperatures in the organocatalytic
Michael addition step were tested. However, neither
at 0ºC nor at 10ºC the reaction progressed after 16h
(Table 2, entries 3, 4). Finally, bis(trifluoromethyl)
substituted catalyst III was also tested, resulting in
product 5a in 39% yield and 86% ee (Table 2, entry
5).
1
2
3
4
3a
1a
1b
1c
88
81
99
3b
3c
3d
1d
Table 2. Optimization of the sequence nitro-Michael
5
6
82
90
addition/INCR
3e
3f
1e
1f
[a] Isolated yields after flash column chromatography.
With the starting materials in hand, the
organocatalytic -functionalization of the aldehyde
moiety was examined next. Iminium catalysis is well
known
to
enable
the
enantioselective
functionalization at the -position of enals by means entry Catalyst T [ºC] Time
Yield
ee [%][c]
of a Michael-type nucleophilic addition. In this
[%][a],[b]
manner, we would generate suitable precursors of the
nitrone functionality, bearing a stereodefined center at
the  position, able to undergo the INCR in a
diastereoselective fashion.
1
2
3
4
5
25
25
0
10
25
7d
29
46
82
>99
-
I
II
II
II
III
16h
16h
16h
10d
[d]
-
-
[d]
-
The first Michael donor we chose was
nitromethane since its addition to cinnamaldehydes
was successfully reported by Hayashi in 2007.[32] The
enantioselective synthesis of chiral pharmaceuticals
such as baclofen or pregabalin in the cited work
illustrates how useful nitromethane is as an
aminomethylation reagent. Bearing this precedent in
mind, a slight optimization of the reaction conditions
was carried out on fluorinated cinnamaldehyde 3a as
a model substrate (Table 2). Following the conditions
previously described for the organocatalytic conjugate
39
86
[a]
Isolated yield after flash column chromatography (from
3a, without purifying intermediate 4a).
[b]
The INCR gave a 4:1 mixture of diastereoisomers, as
determined by 19F-NMR of the crude reaction mixture.
[c]
Enantiomeric excess of the major diastereoisomer
determined by HPLC on a chiral stationary phase; see
Supporting Information for details.
[d] No conversion in the organocatalytic step.
3
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
Having identified the optimal conditions for the diastereoisomer is given when purification and chiral
sequential Michael addition/condensation/INCR resolution were possible.
(Table 2, entry 2), this synthetic method was [d] The bridged regioisomer was also formed in 14% yield;
examined regarding its generality with the rest of see Supporting Information.
trifluoromethylstyrenes 3. The results obtained are
shown in Table 3.
The absolute configuration of the products was
Starting cinnamaldehydes 3a-d, with electronically inferred from X-ray analysis of an appropriate crystal
different substitution patterns on the aromatic ring, of compound 5c,[33] which displays a cis relative
afforded the corresponding enantiomerically enriched relationship of the trifluoromethyl and the nitromethyl
isoxazolidines 5a-d in good yields, moderate groups. The same stereochemistry was assumed for
diastereoselectivities
enantioselectivities
and
3,
excellent all compounds 5.
entries 1-4). A second type of organocatalytic conjugate
(Table
Additionally, other aromatic linkers between the α,β- addition we attempted for the enantioselective -
unsaturated aldehyde and the fluorinated functionalization of enals 3 was the aza-Michael
dipolarophile were compatible with the reaction reaction,[34] because of our ongoing interest in this
system, including a naphthyl and a thienyl groups field. preliminary screening of nitrogen
A
(Table 3, entries 5,6). It should be mentioned that, in nucleophiles was carried out employing 3a as a model
the case of the thienyl derivative (Table 3, entry 6), substrate. Several heterocyclic amine derivatives such
the bridged regioisomer was formed in the INCR as pyrrole, indole, phtalimide or isatin were tested
together with the fused one 5f. Structural variability unsuccessfully as no conjugate addition was observed.
could also be introduced by changing the N- Apparently, the retro-aza-Michael reaction is faster
alkylhydroxylamine employed in the cyclization step. for these systems and the steric requirements for the
Thus, the process was also performed with N- addition to an ortho-substituted cinnamaldehyde
benzylhydroxylamine to yield isoxazolidine 5g with could not be disregarded. Another commonly used
moderate
enantioselectivity in the major diastereoisomer (Table reactions
3, entry 7). In this manner,
diastereoselectivity
and
excellent nucleophile
for
is
enantioselective
aza-Michael
O-TBS-protected
N-Cbz-
a
family of hydroxylamine.[35] Unfortunately, in our reaction no
enantiomerically enriched tetraline derivatives conversion was detected again. Nevertheless, when
bearing a CF3-containing quaternary stereocenter the hydroxyl group was unprotected, i.e. when using
were efficiently synthesized.
N-Cbz-hydroxylamine,[36] the aza-Michael reaction
took place in the presence of diphenylprolinol silyl
Table 3. Scope of the sequence nitro-Michael ether (II) and yielded hemiacetal derivative 6a (Table
addition/INCR
4). Its formation in a tandem fashion seems to be the
driving force of the process. This reaction was driven
to full conversion in chloroform at room temperature.
Then, the reaction mixture was evaporated to dryness
and the crude mixture was re-dissolved in toluene for
the cyclization step. The subsequent domino
condensation with N-methylhydroxyl amine /INCR
took place under microwave irradiation at 120 ºC for
30 min, rendering a 3:1 mixture of diastereoisomers
in 42% yield overall yield. The enantiomeric excess
of the major diastereoisomer was found to be 22%
(Table 4, entry 1). It is worth mentioning that aqueous
work-up or isolation of the intermediate hemiacetal
6a did not improve the yield or the enantioselectivity
of the process.
Once identified a compatible nitrogen nucleophile
partner for the reaction with 3a, an optimization of the
reaction conditions was performed next.
In order to improve the selectivity of the sequential
protocol, lower temperatures in the organocatalytic
conjugate addition step were tested. We found that
temperature
has
a
dramatic
effect
on
enantioselectivity. While the reaction at -20 ºC did
not proceed at all (Table 4, entry 2), at 5 ºC, after the
INCR, final tetrahydronaphthalene product 7a was
obtained with 96% ee and 51% global yield (Table 4,
entry 3). On the other hand, organocatalytic reactions
with diarylprolinol derivatives as the catalysts usually
require an acidic co-catalyst such as benzoic acid.
However in our case, the incorporation of this
[a] Isolated yield after flash column chromatography.
[b] Diastereomeric ratio determined by 19F-NMR analysis of
the crude reaction mixture.
Enantiomeric excess of the major diastereoisomer
determined by HPLC methods. The ee value of the minor
[c]
4
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
additive entailed lower enantioselectivity in the Table 5. Scope of the sequence aza-Michael
formation of compound 7a (Table 4, entry 4). addition/INCR
Fluorinated Jørgensen-Hayashi catalyst III was no
effective in the aza-Michael reaction in CHCl3 at 25
ºC (Table 4, entry 5). Finally, changing the solvent to
toluene
gave
slightly
lower
yield
and
enantioselectivity (Table 4, entry 6).
Again in this sequence the INCR was completely
regioselective, although the fused regioisomer 7a was
obtained with moderate diastereoselection (3:1 dr).
Table 4. Optimization of the sequence aza-Michael
addition/INCR
Ent. Cat.
Solv.
Additive
T
Yield
ee
[ºC] [%][a],[b] [%][c]
1
II
II
II
II
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Tol.
-
-
25
-20
5
42
-
22
-
[d]
2[c]
3
4
-
51
49
96
80
-
PhCO2H
5
[d]
[a] Isolated yield after flash column chromatography.
[b] Diastereoisomeric ratio determined by 19F-NMR of the
crude mixture.
5[c] III
6
-
-
25
5
-
II
50
94
[a] Isolated yield after flash column chromatography (from
3a, without purifying intermediate 6a).
[c] Enantiomeric excess of the major diastereoisomer. The
ee value of the minor diastereoisomer is given when
purification and chiral resolution were possible.
[b] The INCR gave a 3:1 mixture of diastereoisomers, as
determined by 19F-NMR of the crude reaction mixture.
[c] Enantiomeric excess of the major diastereoisomer
determined by HPLC on a chiral stationary phase; see
Supporting Information for details.
The absolute configuration of this family of
tetralin-derived isoxazolidines 7 was determined by
X-ray diffraction of a suitable crystal of the major
diastereoisomer of compound 7b.[37] Surprisingly, the
trifluoromethyl and the hydroxycarbamate groups lay
trans to each other in this case, suggesting that
different stereoelectronic factors in the transition state
play a role in the preference of the in situ formed
nitrone for the opposed face of the dipolarophile when
compared to the nitromethane derivatives.
Computational calculations were carried out in the
hope to shed light on this interesting finding. The
cycloaddition reaction was studied at B3LYP-
D3BJ/Def2SVP level of theory to calculate
geometries and then single point calculations at
B3LYP-D3BJ/Def2TZVP/PCM=toluene level of
theory were performed (for details see Supporting
Information). E/Z isomerization of nitrones has been
considered since the difference was in the range of
20-30 kcal/mol,38 compatible with the reaction
conditions. Four approaches can be defined for each
nitrone, thus a total of eight approaches leading to
four different compounds have been studied (Scheme
2).
[d] No conversion in the organocatalytic step.
With the optimized reaction conditions in hand (Table
4, entry 3), the scope of the sequential process was
evaluated on substrates trifluoromethylstyrenes 3. The
results are summarized in Table 5.
Electron-withdrawing, electron-donating and electron
neutral substituents on the aromatic backbone of the
starting cinnamaldehydes 3a-d were compatible with
this process. The corresponding trifluoromethylated
products 7a-d were obtained in good yields but
moderate
diastereoselectivities;
whereas
enantioselectivities ranged from good to excellent
(Table 5, entries 1-4). The change in the nature of the
aromatic linker between the trifluoromethyl alkene
and the enal, i.e. when this is a naphthyl or a thienyl
moiety, resulted in a drop in chemical yield and
enantioselectivity. However, isoxazolidines 7e and 7f
were isolated practically as single diastereoisomers
(Table 5, entries 5, 6). Finally, the use of N-
benzylhydroxylamine afforded the corresponding
product 7g with comparable diastereoselectivity and
slightly lower enantioselectivity (Table 5, entry 7).
Diastereotopic faces correspond to nitrone (first) and
alkene (second). The corresponding orientation of
diastereotopic faces defines the endo/exo approach in
5
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
each case. Moreover, even though the formation of
3,4-regioisomers was not observed experimentally, it
was also computed. In the case of 3,4-regioisomers
only four approaches are possible due to steric
constraints imposed by the intramolecularity of the
reaction.
a series
(Z)-Re,Si-endo
(0.0)
(Z)-Si,Re-endo
(2.9)
b series
(Z)-Re,Si-endo
(0.7)
(Z)-Si,Re-endo
(0.0)
Figure 1. Transition structures corresponding to the most
stable (Z)-endo approaches for the a and b series. (Relative
energies are given in kcal/mol).
Although the energy difference is only 0.7 kcal/mol
being in the range of DFT error,[39] there is a clear
trend from the a to b series towards inverting the
diastereotopicity. Since the geometries of the
transition structures are relativity similar for the
different R substituents considered, there is no clear
difference between steric requirements. However,
some interactions are present in the (Z)-Re,Si-endo
approach for the b series that cannot be found in the
other models. The interaction between the N(OH)
group and a fluorine atom is weak and might
reinforce this transition structure minimizing the
difference with (Z)-Si,Re-endo. On the other hand, the
interaction between the N(OH) group and the
azomethine proton of the nitrone affects the electronic
system of the dipole. Since the reaction is a normal-
demand process in which the nitrone moiety acts as a
nucleophile, any interaction affecting such
nucleophilicity will contribute to lowering the
stability. Consequently, the (Z)-Si,Re-endo approach
in which such interaction is not present becomes the
most stable TS. These non-covalent interactions
(NCI) can be visualized through a topological NCI
analysis,[40] in which interactions are visualized as
isosurfaces. Figure 2 illustrates the presence of
interactions in the less favored (Z)-Re,Si-endo
approach which are not present in the preferred (Z)-
Si,Re-endo approach.
Scheme 2. Approaches corresponding to the intramolecular
1,3-dipolar cycloadditions (those leading to 3,4
regioisomers are not shown)
R = CH2NO2 (a series) and R = N(OH)CO2Me (b
series) were compared as substituents. A total of 24
transition structures were located. (Z)-Endo
approaches were the most stable ones in all cases. The
remaining approaches showed considerable higher
energies due to steric constraints imposed by the
intramolecularity of the process.
For R = CH2NO2 (a series) the most stable
transition structure (by 2.9 Kcal/mol) corresponds to
the (Z)-Re,Si-endo approach leading to the S,S adduct.
The lowest energy barrier corresponding to those
approaches was 12.3 kcal/mol for the a series. On the
contrary, for R = N(OH)CO2Me (b series) the most
stable transition structure (although only by 0.7
kcal/mol) corresponds to the (Z)-Si,Re-endo (energy
barrier of 18.9 kcal/mol) approach leading to R,R
adducts, in good agreement with the experimental
results (Figure 1).
6
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10.1002/adsc.201700975
Advanced Synthesis & Catalysis
O···H-C=N
interaction
quantitative yield (Scheme 3, eq. 1). The same
hydrogenation conditions were applied to compounds
7, rendering diaminoalcohols 9 bearing an amino
group directly attached to the tetralin skeleton
(Scheme 3, eq. 2). Moreover, the selective cleavage of
the N(Cbz)-OH bond in product 7c was achieved with
Mo(CO)6, leaving the N(Me)-O bond of the
isoxazolidine untouched (Scheme 3, eq, 3).
forming bonds
forming bonds
NO-H···F
interaction
(Z)-Re,Si-endo
(0.7)
(Z)-Si,Re-endo
(0.0)
Figure 2. NCI analysis for the (Z)-Re,Si-endo and (Z)-
Si,Re-endo approaches for the b series showing interactions
in the former that are not present in the latter. (green for
weak attractive interactions, blue for strong attractive
interactions and red for repulsive interactions)
A (Z)-Si,Re-endo approach in which an H-bond
interaction is present with the nitrone oxygen (Figure
3) was also calculated, being 2.8 kcal/mol less stable
than the most stable conformation of the (Z)-Si,Re-
endo approach (shown in Figure 1). Alternative routes
considering intermediate hydroxyamino anions were
also considered but higher barriers were found in all
cases (see Supporting Information).
NO-H···O-N=C
interaction
Scheme 3. Transformations on tetrahydronaphthalene
isoxazolidinones 5 and 7.
(Z)-Si,Re-endo H-bonded
forming bonds
(2.8)
Figure 3. (Z)-Si,Re-endo approach for the b series showing
H-bond interaction between the N(OH) group and the
nitrone moiety. Confirmation of interactions through NCI
analysis (right) (Relative energy is given in kcal/mol and
referred to (Z)-Si,Re-endo corresponding to the b series
shown in Figure 1).
Conclusion
In conclusion, we have developed an enantioselective
synthesis
of
two
new
families
of
a
tetrahydronaphthalene derivatives containing
trifluoromethyl all-carbon quaternary stereocenter.
Our synthetic approach to these interesting chiral
building blocks begins with an organocatalytic
conjugate addition reaction on conveniently
functionalized cinnamaldehydes and related aromatic
compounds bearing a 1-trifluoromethyl alkene group
at the ortho position. Once introduced the chirality at
the -position of the aldehyde, the in situ
condensation with an hydroxylamine followed by
intramolecular nitrone [3+2] cycloaddition gives rise
to the desired tetralin derivatives fused with an
isoxazolidine moiety, with three stereogenic centers
in good yields and excellent enantioselectivities, in
general.
In order to verify that the diastereofacial inversion
was due to the exclusive presence of the
hydroxyamino group, calculations were carried out
with R = NHCO2Me (see Supporting Information). In
this case, the same diastereoisomeric preference by a
(Z)-Re,Si-endo approach, which was found for R =
CH2NO2, was observed, confirming that the
additional OH group is responsible for the above-
mentioned interactions, explaining the diastereofacial
inversion. For comparative purposes, calculations
replacing the trifluoromethyl group by a methyl group
were also carried out (see Supporting Information).
The nitromethane-derived isoxazolidines 5c and 5d
could then be easily transformed into the
corresponding 1,3-amino alcohols by cleavage of the
O-N bond with Raney Ni under hydrogen atmosphere
in ethanol. This reaction proceeded with concomitant
reduction of the nitro group to afford
trifluoromethylated diamino alcohols 8a and 8b in
We observed that the diastereofacial selectivity in
the cycloaddition step was reversed when
nitromethane
employed as the nucleophiles in the initial
organocatalytic step. Theoretical calculations
determined that this inversion is due to unfavorable
interactions lowering the stability of the (Z)-Re,Si-
or
N-Cbz-hydroxylamine
were
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700975
Advanced Synthesis & Catalysis
endo approach in the second case (N-Cbz- separation of the minor diastereoisomer was not possible,
1
hydroxylamine as nucleophile), being the (Z)-Si,Re- the H and 19F-NMR data were extracted from the spectra
endo approach the most stable one.
of the mixture.
(3aS,5S,9bS)-3-methyl-5-(nitromethyl)-9b-
(trifluoromethyl)-1,3,3a,4,5,9b-hexahydronaphtho[2,1-
c]isoxazole (5a): Starting from 3a and N-
methylhydroxylamine hydrochloride and following the
general procedure indicated above, 5a (46% overall yield)
was obtained as a mixture of its diastereoisomers (d.r.=4/1),
which were separated by flash chromatography [n-hexane-
EtOAc (20:1)]. Major diasteroisomer (58 mg, colorless
Experimental Section
General procedure for the synthesis of fluorinated
cinnamaldehydes. A 10 mL microwave glass vial was
charged with Pd2(dba)3 (4 mol %, 0.06 mmol), Xphos (8
mol %, 0.12 mmol), Na2CO3 (2.2 equiv, 3.3 mmol) and N-
tosylhydrazone 2 (1.5 equiv, 2.25 mmol), previously
prepared from 1,1,1−trifluoroacetone (1 equiv, 22 mmol)
and N-tosylhydrazine (1 equiv, 22 mmol) by heating at
70 °C in EtOH (0.5 M) for 5 h and then filtering the
precipitate solid at room temperature as a crystalline white
solid. The solid reagents were dried together under reduced
pressure before being used. 2-Bromocinnamaldehyde 1a
(1.0 equiv, 1.5 mmol), prepared from the corresponding 2-
bromobenzaldehyde by a literature procedure,[41] was
dissolved in THF (0.3 M) and then added to the vial,
which was subsequently sealed and heated by microwave
irradiation at 100 °C for 2 h. The reaction mixture was
cooled to room temperature, opened, filtered through Celite
and concentrated under reduced pressure. The residue
obtained was purified by flash chromatography [n-hexane-
EtOAc (20:1)]. The product obtained was used
immediately in the next step.[42]
(E)-3-(2-(3,3,3-trifluoroprop-1-en-2-
yl)phenyl)acrylaldehyde (3a): Starting from 1a and
following the general procedure indicated above, 3a was
obtained as a yellow oil in 89% yield (302 mg). H NMR
(300 MHz, Chloroform-d) δ 9.69 (d, J = 7.7 Hz, 1H), 7.77-
7.72 (m, 1H), 7.61 (d, J = 15.9 Hz, 1H), 7.52 – 7.34 (m,
3H), 6.70 (dd, J = 15.9, 7.7 Hz, 1H), 6.27 (q, J = 1.4 Hz,
1H), 5.57 (q, J = 1.3 Hz, 1H). 19F NMR (282 MHz,
Chloroform-d) δ -67.35 (s, 3F).
25
1
oil): [α]D = +69.6° (c 1.0; CHCl3). H NMR (300 MHz,
Chloroform-d) δ 7.39 – 7.23 (m, 4H), 4.75 (dd, J=12.3, 5.6
Hz, 1H), 4.69 – 4.57 (m, 2H), 3.91 (d, J = 10.8 Hz, 1H),
3.84-3.75 (m, 1H), 3.40-3.25 (m, 1H), 2.83 (s, 1H), 2.19
(ddd, J = 14.0, 5.6, 5.6 Hz, 1H), 1.93 (ddd, J = 13.9, 8.6,
4.9 Hz, 1H). 13C NMR (75 MHz, Chloroform-d) δ 135.6,
131.9, 129.8, 129.0, 128.6, 128.0, 127.1 (CF3, q, J = 282.4
Hz), 79.0, 73.7, 64.6 (d, J = 2.6 Hz), 58.8 (C-CF3, q, J =
22.5 Hz), 43.7, 35.4, 27.9. 19F NMR (282 MHz,
Chloroform-d) δ -70.69 (s, 3F). HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C14H16F3N2O3 317.1108; found
317.1115. HPLC (Phenomenex Amylose 1, 90:10 hexane/
iPrOH, 1 mL/min) tR(major) = 7.60 min, tR(minor) = 12.32
1
min. Minor diasteroisomer (14 mg, colorless oil): H NMR
(300 MHz, Chloroform-d) δ 7.39 – 7.16 (m, 4H), 4.89 (dd,
J = 12.3, 10.0 Hz, 1H), 4.70 – 4.59 (m, 2H), 3.90 (dq, J =
9.1, 1.7 Hz, 1H), 3.81-3.73 (m, 1H), 3.20 (t, J = 4.9, 1H),
2.80 (s, 3H), 2.26 (dt, J = 14.8, 4.9 Hz, 1H), 1.92 (dt, J =
14.8, 4.9 Hz, 1H). 13C NMR (75 MHz, Chloroform-d) δ
135.0, 132.4, 129.8, 128.9, 128.4, 127.7, 127.1 (CF3, q, J =
282.2 Hz), 80.7, 74.1, 67.4, 58.3 (C-CF3, q, J = 24.0 Hz),
43.2, 35.4, 25.0. 19F NMR (282 MHz, Chloroform-d) δ -
71.58 (s). HPLC (Phenomenex Amylose 1, 90:10 hexane/
iPrOH, 1 mL/min) tR(major) = 6.92 min, tR(minor) = 7.33
min.
1
General procedure for the synthesis of aza-derived
isoxazolidines. To a solution of the corresponding
fluorinated cinnamaldehyde 3 (1.0 equiv, 0.5 mmol),
Jørgensen-Hayashi catalyst (20 mol%, 0.1 mmol) in
General procedure for the synthesis of nitromethane-
derived isoxazolidines. To a solution of the corresponding
fluorinated cinnamaldehyde derivative 3 (1.0 equiv, 0.5
mmol), Jørgensen-Hayashi catalyst (10 mol%, 0.05 mmol)
and benzoic acid (20 mol%, 0.10 mmol) in methanol (0.05
M), nitromethane (3.0 equiv, 1.5 mmol) was added. The
resulting mixture was stirred at room temperature for 16 h.
The reaction mixture was then quenched by addition of 20
mL of water and extracted with DCM (15 mL x 3). The
organic layer was washed with brine (15 mL x 2), dried
over anhydrous Na2SO4 and concentrated to dryness under
reduced pressure. The crude aldehyde was then used
without further purification. To a solution of the
corresponding intermediate fluorinated aldehyde in toluene
(0.1 M) in a 10 mL microwave glass vial, N-
alkylhydroxylamine hydrochloride (2.5 equiv, 1.25 mmol)
and sodium bicarbonate (2.5 equiv, 1.25 mmol) were added.
The vial was sealed and the mixture was heated by
microwave irradiation at 120 °C for 30 min. The reaction
mixture was cooled to room temperature, opened and
concentrated under reduced pressure. The residue obtained
was subjected to flash chromatography [n-hexane-EtOAc
(20:1)] to purify and/or separate the formed
chloroform
(0.05
M),
N-(benzyloxycarbonyl)
hydroxylamine (1.2 equiv, 0.6 mmol) was added at 0-5 ºC.
The resulting mixture was stirred at this temperature for 3-
5 d until disappearance of the starting material (TLC
analysis). The reaction mixture was then concentrated to
dryness under reduced pressure. The crude hemiaminal was
then used without further purification. To a solution of the
corresponding intermediate fluorinated hemiaminal in
toluene (0.1 M) in a 10 mL microwave glass vial, N-
alkylhydroxylamine hydrochloride (2.5 equiv, 1.25 mmol)
and sodium bicarbonate (2.5 equiv, 1.25 mmol) were added.
The vial was sealed and the mixture was heated by
microwave irradiation at 120 °C for 30 min. The reaction
mixture was cooled to room temperature, opened and
concentrated under reduced pressure. The residue obtained
was subjected to flash chromatography [n-hexane-EtOAc
(10:1 to 4:1)] to purify and/or separate the formed
diastereoisomeric
isoxazolidines.
When
complete
separation of the minor diastereoisomer was not possible,
1
the H and 19F-NMR data were extracted from the spectra
of the mixture.
diastereoisomeric
isoxazolidines.
When
complete
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700975
Advanced Synthesis & Catalysis
Acknowledgements
Benzyl
hydroxy((3aR,5S,9bR)-3-methyl-9b-
(trifluoromethyl)-1,3,3a,4,5,9b-hexahydronaphtho[2,1-
c]isoxazol-5-yl)carbamate (7a): Starting from 3a and N-
methylhydroxylamine hydrochloride and following the
general procedure indicated above, 7a (51% overall yield)
was obtained as a mixture of its diastereoisomers (d.r.=3/1),
which were separated by flash chromatography [n-hexane-
EtOAc (10:1 to 4:1)]. Major diasteroisomer (81 mg,
colorless oil): [α]D = -103.3° (c 1.0; CHCl3). H NMR
(300 MHz, Chloroform-d) δ 9.24 (br s, 1H), 7.60 – 7.24 (m,
9H), 5.65-5.57 (m, 1H), 5.28 (d, J = 12.3 Hz, 1H), 5.22 (d,
We gratefully thank the Spanish Ministerio de Economía y
Competitividad (CTQ-2013-43310-P to S.F. and C.P. and FEDER-
CTQ2016-76155-R to P.M. and T.T.), the Generalitat Valenciana
(GV/PrometeoII/2014/073) and the Gobierno de Aragon
(Grupos Consolidados E-10). F.R.-A. thanks the Spanish
Ministerio de Educación, Cultura y Deporte for a predoctoral
fellowship (FPU14/03520). The authors thankfully acknowledge
the resources from the supercomputers "Memento" and “Cierzo”,
technical expertise and assistance provided by BIFI-ZCAM
(Universidad de Zaragoza, Spain). Technical and human support
25
1
J = 12.3 Hz, 1H), 4.63 (d, J = 9.3 Hz, 1H), 3.92 (dq, J = 9.3, provided by SGIker (UPV/EHU, MINECO, GV/DJ, ERDF, and
ESF) is gratefully acknowledged.
1.6 Hz, 1H), 3.21 (t, J = 3.9 Hz, 1H), 2.72 (s, 3H), 2.37 (dt,
J = 15.6, 4.7 Hz, 1H), 2.27 – 2.17 (m, 1H). 13C NMR (75
MHz, Chloroform-d) δ 156.2 (C=O), 136.4, 132.9, 132.6,
129.8, 129.3, 129.1, 128.7, 128.6, 128.6, 128.4, 127.0 (CF3,
q, J = 282.4 Hz), 74.5, 67.9, 65.6, 57.5 (C-CF3, q, J = 24.5
Hz), 53.6, 42.3, 27.4. 19F NMR (282 MHz, Chloroform-d) δ
-71.41 (s, 3F). HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C21H22F3N2O4 423.1526; found 423.1534. HPLC (Chiralcel
IC, 85:15 hexane/ iPrOH, 1 mL/min) tR(major) = 8.39 min,
tR(minor) = 16.64 min. Minor diasteroisomer (27 mg,
References
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1
colorless oil): H NMR (300 MHz, Chloroform-d) δ 7.52 –
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tR(minor) = 6.68 min.
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diamino alcohols
To a solution of the corresponding isoxazolidine 5 or 7 (0.2
mmol) in dry ethanol (0.05 M), Raney ® Nickel (0.5 mL as
a slurry in water) was added and the resulting mixture was
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(trifluoromethyl)-5,6,7,8-tetrahydronaphtho[2,3-
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obtained in quantitative yield (66 mg, pale yellow oil). H
NMR (300 MHz, Chloroform-d) δ 6.92 (s, 1H), 6.74 (s,
1H), 5.92 (s, 2H), 4.19-4.09 (s, 2H), 3.30 (dd, J = 6.2, 3.8
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[M+H]+ Calcd for C19H20F3N2O4S 333.1421; found
333.1423.
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201700975
Advanced Synthesis & Catalysis
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11
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FULL PAPER
Organocatalytic Enantioselective Synthesis of CF3-
Containing Tetralin Derivatives by Sequential
(Hetero)Michael Reaction-Intramolecular Nitrone
Cycloaddition
Adv. Synth. Catal. Year, Volume, Page – Page
Fernando Rabasa-Alcañiz,a Javier Torres,a María
Sánchez-Roselló,a Tomás Tejero,b Pedro Merino,c*
Santos Fusteroa,d* and Carlos del Pozoa*
12
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