Bifunctional Thioureas with α-Trifluoromethyl or Methyl Groups: Comparison of Catalytic Performance in Michael Additions

Article abstract of DOI:10.1021/acs.joc.6b01063

Thioureas are an important scaffold in organocatalysis because of their ability to form hydrogen bonds that activate substrates and fix them in a defined position, which allows a given reaction to occur. Structures that enhance the acidity of the thiourea are usually used to increase the hydrogen-bonding properties, such as 3,5-bis(trifluoromethyl)phenyl and boronate ureas. Herein, we report the synthesis of bifunctional thioureas with a chiral moiety that include either a trifluoromethyl or methyl group. Their catalytic performance in representative Michael addition reactions was used in an effort to compare the electronic effects of the fluorination at the methyl group. The observed differences concerning yields and ee values cannot be attributed solely to the different steric environments; theoretical results indicate distinct interactions within the corresponding transition states. The calculated transition states show that the fluorinated catalysts have stronger N-H···O and C-H···F hydrogen bonds, while the nonfluorinated systems have C-H···π contacts. These results have shown that a variety of hydrogen-bonding interactions are important in determining the yield and selectivity of thiourea organocatalysis. These details can be further exploited in catalyst design.

Full text of DOI:10.1021/acs.joc.6b01063

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Article
Bifunctional thioureas with alpha-trifluoromethyl or methyl
groups: comparison of catalytic performance on Michael additions
Eddy Ivanhoe Jiménez, Wilmer Esteban Vallejo Narváez, Carlos Agustín Román-
Chavarria, Josue Vazquez-Chavez, Tomas Rocha-Rinza, and Marcos Hernández-Rodríguez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01063 • Publication Date (Web): 11 Jul 2016
Downloaded from http://pubs.acs.org on July 12, 2016
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Bifunctional thioureas with α-trifluoromethyl or methyl groups: comparison of
catalytic performance on Michael additions
Eddy I. Jiménez, Wilmer E. Vallejo Narváez, Carlos A. Román-Chavarría, Josue
Vazquez-Chavez, Tomás Rocha-Rinza, Marcos Hernández-Rodríguez*
Institute of Chemistry, National Autonomous University of Mexico
Circuito Exterior, Ciudad Universitaria, Del. Coyoacán, 04510, Mexico, Cd. Mx., Mexico
e-mail: marcoshr@unam.mx
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Abstract:
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Thioureas are an important scaffold in organocatalysis because of their ability to form
hydrogen bonds that activate substrates and fix them in a defined position, which
allows a given reaction to occur. Structures that enhance the acidity of the thiourea are
usually used to increase the hydrogen bonding properties, such as, 3,5-
bistrifluoromethylphenyl and boronate ureas. Herein, we report the synthesis of
bifunctional thioureas with a chiral moiety that includes either a trifluoromethyl or
methyl group. Their catalytic performance in representative Michael Addition reactions
was used in an effort to compare the electronic effects of the fluorination at the methyl
group. The observed differences concerning yield and ee cannot be attributed solely to
the different steric environments, theoretical results indicate distinct interactions
within the corresponding transition states. The calculated transition states show that
the fluorinated catalysts have stronger N-H···O and C-H···F hydrogen bonds, while the
non-fluorinated systems have C-H···π contacts. These results have shown that a variety
of hydrogen bonding interactions are important in determining the yield and selectivity
of thiourea organocatalysis. These details can be further exploited in catalysts design.
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Introduction
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Hydrogen bonding catalysis and chiral counterion strategy have risen recently as a
1
2
3
reliable synthetic methodology. Takemoto introduced chiral bifunctional catalysts to
activate an electrophile through hydrogen bonds (HB). They also present a tertiary
amine that deprotonates a nucleophile that is subsequently added. The Takemoto
4
catalyst (Fig. 1a), features a 3,5-bistrifluoromethylphenyl group that enhances the
acidity of the thiourea and thereby increases its hydrogen bonding properties. Boronate
ureas have a similarly enhanced HB donor capacity of the HNC(O) moiety, in this case
by means of an internal Lewis acid.5,6 Stereocontrol of the addition products can be
achieved by addition of chiral substituents to the thiourea moiety (Fig. 1b) however,
this is done at the expense of the HB activation ability. Nonetheless, if a chiral group
with electron withdrawing properties is bound to the thiourea (Fig. 1c), a good
compromise between the modulation of the steric demands and the activation by the
7
8
9
catalyst can be accomplished. On this subject, Ellman, Jacobsen, and others have used
N-sulfinyl ureas that are able to catalyze a variety of reactions. Herein we report the
synthesis and application of bifunctional thioureas with a chiral group that
incorporates a trifluoromethyl group in its structure.10 Thioureas featuring
trifluoromethyl groups have shown exceptional properties in the recognition of chiral
carboxylates with binding constants which are 10 times higher than the analogous non-
11
fluorinated compounds. The chiral moiety with –CF confers to the thioureas reported
3
in this work (1) good HB properties12 without the deactivation of the catalyst by
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intramolecular interactions13 and (2) the possibility to modulate the steric
environment. In addition, the catalysts put forward in this work are easily synthesized
and allow the incorporation of a variety of functional groups in their structure. This
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study also considers the corresponding non-fluorinated catalysts to provide insights
into the effect of the NH acidity in the yield and enantiomeric excess of the reactions
considered in this investigation.
Figure 1. Moieties used to enhance hydrogen bond donor properties or to modulate
steric effects in H-bond catalysis and counterion strategies.
Results and Discussion
The synthesis of the chiral scaffold with trifluoromethyl groups was performed
by the nucleophilic addition of the Ruppert-Prakash reagent to (S)-N-tert-
butylsulfinylimines
1a-d
affording
compounds
2a-d
with
excellent
diastereoselectivity.15 After removal of the chiral auxiliary, amines 3a-d were
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transformed to isothiocyanates 4a-d and added to both enantiomers of trans-N,N-
16
dimethyl-1,2-diaminocyclohexane to produce diastereomeric catalysts (R,S,S) 5a-d
and (R,R,R) 6a-d (Scheme 1). This same protocol led to catalysts with a methyl instead
of a trifluoromethyl group (thioureas 7a-d and 8a-d).17,18
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Scheme 1. Synthesis of the bifunctional organocatalysts considered in this work
The Michael addition of 1,3-dicarbonyl compounds to -nitrostyrene has
become an archetypical reaction to assess the performance of bifunctional catalysts. 19
We employed 2,4-pentanedione as the source of the nucleophile for this reaction. In
particular, we focused on the performance of the fluorinated and non-fluorinated
systems to compare thioureas with different HB donor properties.
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We found that systems with an -trifluoromethyl group have a strong match-
mismatch relationship (Table 1, exp. 1-8) as opposed to their non-fluorinated analogs
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Table 1, exp. 9-16). Additionally, we further studied the effect of the trifluoromethyl
group on the yield and enantioselectivity by comparison of the diastereomeric catalysts
5
b and 6b along with 7b and 8b.20
Table 1. Michael addition of 2,4-pentanedione to β-nitrostyrene with the catalysts
developed in this work.
Exp. R, X
Cat.
5a
6a
5b
6b
5c
Yield ee*
Exp. R, X
Cat.
7a
8a
7b
8b
7c
Yield
87
ee*
86
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8
Ph, F
82
96
87
94
76
87
88
90
68
-89
67
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Ph, H
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12
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15
16
68
-81
87
1-Naphth, F
9-Anthr, F
t-Bu, F
1-Naphth, H
9-Anthr, H
t-Bu, H
94
-92
46
84
-76
74
86
6c
-82
69
8c
75
-60
84
5d
6d
7d
8d
87
-94
95
-62
*
Analyzed by CSP-HPLC. Catalysts 5 and 7 afford compound (R)-9 while the enantiomer (S) is produced
with catalysts 6 and 8.
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Similar trends concerning match/mismatch relationships were found with
different nitroalkenes as reported in Table 2, i.e. fluorinated catalysts 5b and 6b have a
strong match-mismatch relationship, in contrast with catalysts 7b and 8b.
Interestingly, 6b gives yields comparable with that of Takemoto’s but its performance
is less susceptible to structural differences in the Michael acceptor. Because catalysts
6b and 8b only differ by three fluorine atoms, we expected that both systems with the
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(S,S) configuration in the diamine to be the match combination. This, however, was not
the case, catalyst 7b with the diamine having the (R,R) configuration gave better results
in this regard.
a
Table 2. Yield and ee of the Michael additions of 2,4-pentanedione to different
nitroalkenes using catalysts T, 5b, 6b, 7b and 8b.
Entry
Ar, Prod.
T
5b
6b
7b
8b
1
2
3
4
5
4-Me-C
4-OMe-C
4-Cl-C
4-NO -C
2-Br-C
6
H
4
, 10
, 11
, 12
90 (74)
74 (56)
87 (-87)
93 (76)
90 (-69)
6
H
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92 (75)
90 (69)
86 (80)
86 (86)
86 (51)
75 (56)
58 (64)
88 (49)
90 (-89)
94 (-84)
86 (-81)
92 (-84)
85 (79)
94 (76)
83 (83)
93 (76)
63 (-62)
80 (-68)
81 (-70)
92 (-68)
6
H
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2
6
H
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, 13
6
H
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, 14
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1-Naphth, 15
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72 (-60)
2-thiophene, 16
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ee shown in parenthesis, Catalysts T, 5 and 7 afford compound (R)-10-15 while with catalysts 6 and 8
the enantiomer (S) is produced. Compound 16 presents the opposite configuration by CIP rules.
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We found similar yields, selectivities and match/mismatch relationships for
other pronucleophiles addressed in this work, i.e., those leading to products 17-20
(
Table 3). We noted that the enantioselectivity of 6b was comparable to that obtained
from 7b with malonate nucleophiles.
a
Table 3. Yield and ee of the Michael addition product of a variety of nucleophiles
with trans-β-nitrostyrene using catalysts T, 5b, 6b, 7b and 8b.
NuH
Prod.
T
5b
6b
7b
8b
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2
17
83 (88)
66 (68)
69 (-87)
78 (88)
34 (-76)
18b
88 (92)
73 (64)
61 (72)
77 (25)
57 (-91)
96 (-76)
64 (90)
79 (50)
18 (-83)
59 (-80)
3
19c
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96 (88)
98 (87)
84 (-96)
94 (90)
86 (-85)
a
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ee shown in parenthesis, each diastereomeric catalyst generated a different enantiomer. 72 h reaction
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c
time, d.r. = 7:1 in all experiments.
Finally, we studied the performance of catalysts 6b and 7b in different solvents.
We observed with catalyst 6b much lower yields in ether solvents but in all cases the
reaction was stereoselective (around 90% of the major enantiomer). On the other hand,
the non-fluorinated catalyst 7b presented the opposite trend, the yield was little
affected and the stereoselectivity highly depends of the solvent used (Table 4).
Table 4. Solvent effects in the Michael addition with catalysts 6b and 7b.
Solvent
Yield (%)
eea
-92
-89
-76
-83
Yield (%)
eea
87
62
53
57
Toluene
CCl
94
87
87
55
94
93
93
82
4
DCM
MTBE
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THF
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aAnalyzed by CSP-HPLC. Catalysts 7b afford compound (R)-9 while with catalyst 6b the enantiomer (S)
is produced.
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The different behavior shown by the presented catalysts could also be attributed
to the steric difference between the methyl and trifluoromethyl groups. The van der
21
Waals radii of -CH
3
and -CF
3
are 2.0 and 2.7 Å respectively. In addition, the A value of
22
trifluoromethyl is higher than that of isopropyl and hence it has been proposed that
the -CF
3
group is of similar size23a or somewhat smaller23b than -CH(CH
3
) . We studied
2
diastereomeric catalysts 21 and 22 with isopropyl substeituents to find out if the steric
demand is the responsible factor for the difference in the obtained results. We found
that the catalysts featuring isopropyl groups have similar selectivity, but their
corresponding enantiomeric excesses (60 and 56% as shown in Scheme 2) are
considerably lower than those obtained with systems 6a and 7a (89 and 87%
respectively). We conclude that there should be other explanations for the observed
enantioselectivity. The search for a suitable interpretation of the results considered up
to this point motivated the theoretical studies presented below.
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Scheme 2. Yield and ee of the Michael addition with diastereomeric catalysts 20 and
21
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Computational analysis
We now consider the reaction mechanism of the Michael addition. Takemoto
proposed the first mechanism for this reaction, which involves the sequential activation
of the electrophile and the nucleophile.2a Afterwards, Pápai24 suggested a different
mechanism with a lower activation energy than that of Takemoto. Our results with
catalyst 6a, shown in Figure S2 of the Supporting Information (SI), are also consistent
with Pápai's mechanism. In this reaction pathway (Figure 2), the nucleophile is first
deprotonated by the tertiary amine (A), and then migrates to the cavity of the thiourea
(
B). Subsequently, the electrophile is attacked by the nucheophile·thiourea adduct,
forming the trimolecular complex (C), which is responsible for the orientation of the
new carbon-carbon bond (TS ) and the stereochemistry of the product (D).
P
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Figure 2. Bifunctional catalysts mechanism proposed by Pápai.
A model catalyst with a phenyl rather than a naphtyl group was used to reduce
the number of atoms in the system and hence the computation time of the calculations.
This is particularly reasonable inasmuch as the results obtained with catalysts
including either –C
6
H
5
or –C10
H within their structure are similar (Table 1). In this way,
7
we explored the energy profile with diastereomeric catalysts 5a and 6a along with their
non-fluorinated counterparts 7a and 8a.
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The energy profiles in Figure 3 show that the activation barrier for the
trifluoromethyl systems 6a is less than the corresponding value for 5a (4.6 and 6.7
kcal/mol respectively) in accordance to the observed rate (kobs = 0.0092 and 0.0066
respectively, see Figure S1 and Table S1 in the SI). In the non-fluorinated catalyst, the
opposite configuration of the diamine has a smaller activation barrier (4.7 kcal/mol for
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7a and 5.2 kcal/mol for 8a) also in agreement with the observed rate (kobs = 0.0331 and
0.0042 respectively). Although the theoretical calculations predict correctly the relative
reaction rate for the diastereomeric pairs 5a vs 6a and 7a vs 8a, the computations are
not fully consistent when the relative rates of all four systems are compared. This
discrepancy may be attributable to factors such as product inhibition and the
reversibility of the reaction25,26 which are not taken into account in the computational
analysis.
(
a)
b)
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Figure 3. Gibbs energy profile of the rate-limiting step in Pápai’s mechanism for the
Michael addition of 2,4-pentanedione and β-nitrostyrene with trifluoromethyl catalysts
5
a and 6a and their non-fluorinated analogs 7a and 8a. The calculations were
performed with the COSMO-(Toluene)-RIJCOSX-MP2/aug-cc-pVDZ // M06-2x/6-
31+g(d) level of theory. The structures of C, TS and D are shown in Figure 2. (a)
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P
Catalysts with the (R,R) configuration in the diamine 5a and 7a (side a), generate the
(R)-9 product while those with the (S,S) configuration 6a and 8a (side b) yield the (S)-
9
compound.
Figure 3 also shows that the fluorinated catalysts lead to different activation
energies for the formation of each enantiomer, thereby favoring the observed
enantioselectivity of the reaction. The calculated differences in activation energies are
2.0 and 3.5 kcal/mol for 5a and 6a, respectively, predicting correctly that 6a is more
enantioselective. With the non-fluorinated systems, these differences are 2.3 and 2.4
kcal/mol for 7a and 8a, respectively, which explains the lack of a strong
match/mismatch relationship in these catalysts (Tables 1-3).
Further structural analysis of the transition states revealed that:
1) Thioureas attached with a trifluoromethyl group generate a shorter HB with the
nucleophile26 as expected (Table S2 in Supporting information). These shorter and
stronger hydrogen bonds in the fluorinated systems can be responsible for the lack of
significant solvent effects on the enantioselectivity obtained with catalyst 6b. This is
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buttressed by the fact that solvent-effects are more pronounced in the ee achieved using
7b, as reported in Table 4.
2) There are other interactions that involve the arylethyl groups which are particular
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to each catalyst. The structure of the systems with an (R,R) configuration of the diamine
(5a and 7a) present the phenyl ring on the same side of the approaching -nitrostyrene
in a way that a T-shaped  contact is formed between the phenylethyl group of the
thiourea and the -C
6
H
5
part of the Ph-CH=CH-NO (Figure 4). The observed distances
2
between the centroids of the phenyl rings are 4.72 and 4.62 Å for 5a and 7a,
respectively. These values are close to the optimal distance for this interaction (5.0 Å)
computed with high level ab initio calculations.27
On the other hand, fluorinated and non-fluorinated catalysts with the (S,S)
configuration in the diamine (8a and 6a) lead to transition states with the -CH
3
and -
CF groups on the same side as the approaching nitrostyrene. Therefore, the
3
phenylethyl group in catalyst 8a is rotated to form the aforementioned interaction,
whereas the structure produced with catalyst 6a presents interactions between two
28
fluorine atoms and an ortho C-H of the nitrostyrene molecule as shown in Figure 5
and confirmed with the topological analysis of the electron density (vide infra).
After having considered the energetic and structural aspects of the transition
states of the Michael addition, we analyzed the interactions between the catalysts, the
2
9
enolate and the nitrostyrene by means of quantum chemical topology. Figure 4 shows
the molecular graph of the transition states for the Pápai’s mechanism formed with
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catalysts 5a and 7a. Both systems present bond paths between sulfur and the hydrogen
atoms of the stereogenic carbon bonded to the thiourea. These trajectories of ∇ρ(r),
suggest a moderate rigidity of the bifunctional catalysts, which facilitate the formation
of the supramolecular complex. The interactions between both the fluorinated and non-
fluorinated thioureas with the two reactants include five hydrogen bonds. Tables S3
and S5 in the Supporting Information report some selected topological properties of the
charge distribution at the corresponding bond critical points. As expected, these
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hydrogen bonds are described as closed shell interactions, reflected in the sign of the
2
Laplacian of the charge density, ∇ ρ(r) > 0, in the intermolecular region. The -CF
3
catalyst 5a has stronger NH···O hydrogen bonds (E in Table S3) and two CH··
H
interactions, while the non-fluorinated compound 7a presents three CH···
interactions. We also noted that the phenyl group in the catalyst responsible for these
CH- interactions has a less negative charge in compound 5a due to the inductive effect
of the trifluoromethyl group (Table S5). These weak interactions might explain the
better performance of 7a as compared with that of 5a. Considering the size of the
aromatic ring in the catalyst, we can assume that the 9-antracenyl is too bulky for an
optimal performance of the catalyst and the phenyl does not have a large enough
molecular area for effective π···π interactions. The naphthyl group provides a better
compromise between the establishment of efficient π···π interactions and the
avoidance of steric hindrance.
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Figure 4. Non-covalent interactions within the transition states for the Pápai's
mechanism with catalysts 5a and 7a. The complete molecular graphs of these systems
can be found in Tables S3 and S5 of the Supporting Information.
Figure 5 shows a similar topological analysis of the electron density for the
transition states with systems 6a and 8a. Once more, the fluorinated catalyst has
stronger NH··O hydrogen bonds than the non-fluorinated analog. In particular,
compound 6a forms the strongest NH
Information). Apart from these interactions, there are other hydrogen bonds between
catalysts 6a or 8a and the reactants that depend on the conformation of the –CHPhCX
1
···O interaction (see Table S4 in the Supporting
4
3
group (X = F, H). The fluorinated catalyst presents HBs between two F atoms and an
ortho hydrogen of the phenyl group of nitrostyrene whereas the non-fluorinated
system exhibits –CH···π bonds linking the two –C
6
H rings in the corresponding
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transition state. Again, the interactions between the reactants and catalyst 6a are
stronger than those found for 8a. Overall, the topological analysis of the charge
distribution indicates that the –CF group leads to a stronger association of a
3
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bifunctional thiourea with the reactants and thereby promotes the catalytic process
more efficiently, in good agreement with the larger yield and enantiomeric excess of 6a
as compared with 8a. In addition, this interactions CF···HC could explain the
ineffectiveness of systems with isopropyl 21 and 22. The i-Pr group produces no
significant attractive forces and only provides steric hindrance. In the mismatch
combination 21, the isopropyl is in the same side of the approaching nitrostyrene,
interfering in this way with the docking of this electrophile.
6a
8a
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Figure 5. Non-covalent interactions within the transition states for the Pápai's
mechanism with catalysts 6a and 8a. The complete molecular graphs of these systems
can be found in Tables S4 and S6 of the Supporting Information.
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The computational analysis indicates that the fluorinated and non-fluorinated
catalysts behave differently on account of their distinct secondary non-covalent
interactions. The trifluoromethyl group in the catalyst 6a is on the same side of the
approaching β-nitrostyrene and hence, the fluorine atoms forms CF···H-C interactions.
However, the non-fluorinated catalyst 7a has the aromatic fragment on the same side
of the approaching electrophile, which allows π-π interactions to be maximized.
Therefore, although fluorinated catalyst 6a presents the strongest NH···O HBs, non-
fluorinated system 7a exhibit a larger number of secondary non-covalent interactions
(CH·· π and CH···O), which results in the similar performance of both catalysts.
Conclusion
We found that the incorporation of chiral groups with an alpha trifluoromethyl moiety
in bifunctional thioureas has modest positive impact in the yield and selectivity of the
Michael additions considered in this work. Nevertheless, the new catalysts 6 present
stronger NH··O hydrogen bonds and CF···HC interactions with the reactants than its
methylated counterpart. The methylated systems 7, on the other hand, exhibit more
CH··π and CH···O secondary interactions, which explains the comparable yield and
selectivity. However, the chiral group presented in this work shows a good compromise
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between enhanced HB donor properties and controlled steric demands, which could be
of interest to hydrogen bonding organocatalysis.
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Experimental Section
Computational part.
The geometry of all intermediates and transition states were completely optimized
30
with the M06-2x/6-31+G(d) approximation as implemented in the Gaussian 2009
package.31 Each stationary structure was characterized as a local minimum or a saddle
point of first order by means of the computation of the corresponding harmonic
frequencies. Intrinsic reaction coordinate calculations were carried out in all cases to
verify that the localized transition state structures connect the two minima on the
potential energy hypersurface associated with reactants and products. Solvent
(
toluene) effects were considered through the COSMO model and single-point energy
calculations of all the stationary points with COSMO-(Toluene)-RIJCOSX-MP2/aug-cc-
pVDZ.32
The topological analysis of the electron density was done in accordance with the
29
33
Quantum Theory of Atoms in Molecules (QTAIM) and using the AIMAll program. In
particular, we considered the critical points of the charge distribution related with
different elements of molecular structure defined in QTAIM, especially those associated
to bonding between two atoms. The characterization of the different interactions
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between the bifunctional catalysts addressed in this study and the reactants of the
2
Michael addition was done in terms of the properties of ρ(r), including ∇ ρ(r) and
the density of the potential energy, V(r), from which hydrogen bond formation energies
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can be estimated as in reference 34.
General remarks
All starting materials were used directly as obtained commercially. THF was distilled
from sodium benzophenone ketyl. Flash column chromatography was carried out with
silica gel 60 (0.4/0.63 mm, 230-400 mesh), TLC was performed with silica gel F254
1
13
plates. Melting points are uncorrected. H and C NMR were recorded at 300 MHz and
5 MHz respectively. Chemical shifts (δ) were reported in ppm downfield from TMS
7
and coupling constants are in Hertz. Mass spectra were obtained by EI. HRMS (FAB and
DART) were measured with a quadrupole and TOF mass spectrometers, CSP-HPLC
analysis was performed using the indicated chiral column and UV detector.
2,2,2-Trifluoro-1-arylamines and precursors have been reported previously see ref 15.
General procedure for the synthesis of sulfinylimines (1a-1d)
1 Equiv. (15 mmol) of the corresponding aldehyde was dissolved in 40 mL of anhydrous
THF under nitrogen atmosphere. Then, we added 6.2 mL (30 mmol, 2 equiv.) of titanium
tetraethoxide and 1.8 g (15 mmol, 1 equiv.) of (S)-tert-butylsulfinamide and stirred at
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r.t. for 17 h. The reaction mixture was poured to 40 mL of brine with vigorous stirring
and the resulting suspension was filtered over celite. The cake was washed with EtOAc
(
20 mL X 3). The organic layer was separated and the aqueous phase was extracted with
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EtOAc (15 mL X 3). The combined organic phases were dried with Na SO and
2
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concentrated afterwards. The final product was purified by FC with hexane/EtOAc 10:0
to 8:2. The acquired NMR spectra of target compounds matched those previously
reported.
(
S)-N-benzylidene-t-butanesulfinamide, (1a).35a
2
5
Colorless liquid. 91% yield (2.86 g). Rf: 0.23 (Hexane/Ethyl acetate, 9:1). [α] +97.5 (c
D
2
5
) (Lit.35a [α] +99.7 (c 1.15, CHCl
1
1
.15, CHCl
3
3
)). H NMR (300 MHz, CDCl
3
): δ = 8.44 (s,
): δ = 162.4,
33.8, 132.1, 129.0, 128.6, 57.3, 22.3. IR (film): ṽ cm = 3355, 3065, 2961, 2926, 2870,
D
13
1H), 7.68 (m, 2H), 7.42 – 7.19 (m, 3H), 1.10 (s, 9H). C NMR (75 MHz, CDCl
3
-1
1
1606, 1573, 1479, 1451, 1363, 1314, 1216, 1173, 1118, 1085, 877, 855, 758, 735, 693.
+
MS-EI (70eV): m/z (%) = 209 (2) [M] , 153 (100), 136 (34), 126 (11), 105 (92), 77 (66),
71 (19), 57 (100), 51 (35), 4 (68), 29 (36), 18 (6).
(
S)-N-[(1-naphthyl)methylidene]-t-butanesulfinamide, (1b). 35b-c
White solid. 84% yield (3.27 g). Rf: 0.51 (Hexane/Ethyl acetate, 8:2). mp 48 – 50 °C
25
Lit.35b (R) enantiomer m. p. 52 – 54 °C). [α] +4.4 (c 1.13, CHCl
) (Lit.35c (R) enantiomer
): δ = 9.16 (s, 1H), 9.02 (d, J = 8.6 Hz,
H), 8.08-7.96 (m, 2H), 7.95-7.86 (m, 1H), 7.71 – 7.60 (m, 1H), 7.60 – 7.48 (m, 2H), 1.32
(
3
D
2
5
1
[α] -4.5 (c 1, CHCl
3
)) H NMR (300 MHz, CDCl
3
D
1
13
(
s, 9H). C NMR (75 MHz, CDCl ): δ = 162.6, 134.0, 133.4, 132.0, 131.4, 129.6, 129.0,
3
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-
1
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1
2
28.1, 126.6, 125.3, 124.5, 57.8, 22.8. IR (KBr): ṽ cm = 3061, 2995, 2966, 2917, 2862,
596, 1562, 1510, 1473, 1458, 1440, 1386, 1359, 1333, 1234, 1208, 1174, 1158, 1076,
033, 1012, 977, 798, 772, 698, 581, 549.519, 465, 440, 409. MS-EI (70eV): m/z (%) =
10
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12
13
14
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+
60 (5) [M+H] , 203 (100), 186 (12), 155 (50), 127 (23), 101 (3), 77 (4), 57 (13), 41 (2).
(
S)-N-[(9-anthracenyl)methylidene]-t-butanesulfinamide, (1c). 15b
Yellow solid. 90% yield (4.18 g). Rf: 0.33 (Hexane/Ethyl acetate, 8:2). mp 134 – 136 °C
Lit.15b (R) enantiomer m. p. 137 – 138 °C). [α] 2D 5 +76.0 (c 1, CHCl
) (Lit.15b (R)
(
3
2
5
1
enantiomer [α] -80.8 (c 1, CHCl
3
). H NMR (300 MHz, CDCl ): δ = 9.92 (s, 1H), 8.88 (d,
3
D
J = 9.0 Hz, 2H), 8.58 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.47 – 7.67 (m, 4H), 1.38 (s, 9H). 13C
NMR (75 MHz, CDCl
3
): δ = 162.0, 139.1, 132.7, 131.4, 131.3, 129.3, 128.1, 125.7, 124.6,
-1
57.7, 22.8. IR (KBr): ṽ cm = 3048, 2960, 2922, 2862, 1621, 1579, 1553, 1517, 1443,
1
360, 1250, 1173, 1076, 1022, 982, 958, 914, 788, 732, 690, 603, 575, 539, 505, 450,
+
405. MS-EI (70eV): m/z (%) = 309 (2) [M] , 253 (33), 203 (100), 178 (16), 176 (15),
1
51 (5).
S)-N-[2,2-Dimethylpropylilidene]-t-butanesulfinamide, (1d). 35d
(
2
5
Yellow oil, 94% yield (2.67 g). Rf: 0.42 (Hexane/Ethyl acetate, 9:1). [α] +117.8 (c 1.16,
D
2
5
) (Lit.35d [α] +99.7 (c 1.15, CHCl
1
CHCl
.01 (s, 9H), 0.98 (s, 9H). C NMR (75 MHz, CDCl
(film): ṽ cm-1 = 3349, 3069, 2964, 2930, 2904, 2870, 1738, 1620, 1474, 1459, 1429,
3
3
)). H NMR (300 MHz, CDCl
3
): δ = 7.74 (s, 1H),
D
13
1
3
): δ = 175.4, 56.2, 37.7, 26.5, 22.1. IR
1
364, 1262, 1186, 1162, 1118, 1086, 879, 845, 741, 709. MS-DART (positive): m/z (%)
190 (100) [M+H]+.
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General procedure for trifluoromethyl addition (2a-d)
2
0 mmol (1 equiv.) of sulfinylimine 1 and 2.15 g (4 mmol, 0.2 equiv) of TBAT
Tetrabutylammonium difluorotriphenylsilicate) were suspended in 60 mL of
anhydrous THF under nitrogen atmosphere. The reaction mixture was cooled to -50 °C
to latter add 3.6 mL (24 mmol, 1.2 equiv.) of TMSCF . The reaction mixture was stirred
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(
3
for 4 h at -50 °C and 20 h at -20 °C. The reaction was quenched with 60 mL of aqueous
ammonium chloride solution and extracted with EtOAc (50 mL X 3). The combined
organic phases were dried with Na
2
SO and then concentrated. The product was
4
purified by FC with hexane/EtOAc as eluent (proportions indicated in each compound).
The acquired NMR spectra of the compounds matched with previously reported data.15a
S)-N-[(R)-1-phenyl-2,2,2-trifluoroethyl]-t-butanesulfinamide, (2a).15a
(
Purified by FC hexane/EtOAc, 7:3. White solid. 59% yield (3.30 g). Rf: 0.52
2
5
1
(
Hexane/Ethyl acetate, 1:1) mp 95 - 97 °C. [α] = +75.2 (c 1, CHCl
). H NMR (300 MHz,
3
D
13
CDCl
MHz, CDCl
7.1, 22.5. IR (KBr): ṽ cm = 3117, 2994, 2964, 2928, 2904, 2867, 1712, 1667, 1498,
3
): δ = 7.42 (m, 5H), 5.00 – 4.70 (m, 1H), 3.68 (br, 1H), 1.25 (s, 9H). C NMR (75
3
): δ = 133.8, 129.7, 129.3, 128.1, 124.7 (q, J = 281.6 Hz), 61.5 (q, J = 30.6 Hz),
-1
5
1455, 1425, 1365, 1259, 1149, 1118, 1097, 1051, 1011, 930, 909, 849, 760, 699, 590,
+
5
55, 512, 452. MS-EI (70eV): m/z (%) = 279 (1) [M] , 223 (69), 216 (5), 176 (12), 159
(
91), 145 (22), 140 (46), 126 (5), 109 (55), 104 (28), 91 (9), 77 (24), 57 (100), 51 (12),
1 (68), 29 (34).
4
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(
S)-N-[(R)-1-(1-naphthyl)-2,2,2-trifluoroethyl]-t-butanesulfinamide, (2b).15a
Purified by FC hexane/EtOAc, 6:4. White solid. 84% yield (5.53 g). Rf: 0.48
25
1
(
Hexane/Ethyl acetate, 6:4). mp 127-131 °C. [α] = +203.0 (c 1, CHCl
3
). H NMR (300
D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl
3
): δ = 8.15 (d, J = 8.6 Hz, 1H), 7.98 – 7.85 (m, 2H), 7.71 – 7.58 (m, 2H), 7.58 –
13
7.45 (m, 2H), 5.83 – 5.61 (m, 1H), 3.78 (d, J = 5.1 Hz, 1H), 1.25 (s, 9H). C NMR (75 MHz,
CDCl ): δ = 134.1, 131.0, 130.6, 129.9, 129.3, 127.5, 126.5, 125.6, 125.3, 125.2 (q, J =
3
-1
282.0 Hz), 122.7, 57.2, 56.2 (q, J = 31.1 Hz), 22.5. IR (KBr): ṽ cm = 3216, 3051, 2965,
2904, 1596, 1510, 1458, 1395, 1366, 1328, 1301, 1244, 1176, 1112, 1053, 888, 858,
+
797, 775, 737, 698, 623, 562, 525, 442. MS-EI (70eV): m/z (%) = 330 (23) [M+H] , 273
(
(
11), 256 (41), 225 (4), 209 (100), 189 (18), 176 (15), 159 (29), 154 (26), 128 (27), 87
11), 77 (3), 57 (39), 41 (4).
(
S)-N-[(R)-1-(9-anthracenyl)-2,2,2-trifluoroethyl]-t-butanesulfinamide, (2c). 15a, 35e
Purified by FC hexane/EtOAc, 9:1 to 7:3. Yellowish solid. 69% yield (5.24 g). Rf: 0.32
25
1
(
Hexane/Ethyl acetate, 7:3). mp 153-156 °C. [α] = +182.7 (c 1, CHCl
3
). H NMR (300
): δ = 8.54 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.30 (d, J = 9.1 Hz, 1H), 8.04 (t, J =
.4 Hz, 2H), 7.68 – 7.44 (m, 4H), 6.47 (qd, J = 8.5, 3.7 Hz, 1H), 4.23 (d, J = 3.4 Hz, 1H),
D
MHz, CDCl
3
8
1
13
.29 (s, 9H). C NMR (75 MHz, CDCl ): δ = 132.0, 131.5, 131.4, 131.2, 130.4, 129.8,
3
129.7, 128.1, 127.8, 127.1, 125.9 (q, J = 283.8 Hz), 125.4, 125.0, 124.9, 124.4, 123.0, 57.2,
-1
5
1
=
6.5 (q, J = 32.4 Hz). IR (KBr): ṽ cm = 3374, 2961, 2930, 2870, 1624, 1466, 1331, 1253,
157, 1109, 1072, 930, 888, 864, 786, 729, 701, 597, 534, 458. MS-EI (70eV): m/z (%)
+
379 (5) [M] , 323 (15), 259 (100), 238 (5), 204 (14), 189 (4), 178 (43), 151 (3), 88
(
2), 57 (13), 42 (2).
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(
S)-N-[(R)-1-(tert-Butyl)-2,2,2-trifluoroethyl]-t-butanesulfinamide, (2d).15a
Purified by FC hexane/EtOAc, 7:3. White solid. 46% yield (2.39 g). Rf: 0.34
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
(
Hexane/Ethyl acetate, 7:3. TLC stain PMA). mp 97- 100 °C. [α] = +79.0 (c 1.1, CHCl
3
).
D
1H NMR (300 MHz, CDCl
CDCl
): δ = 3.44 (m, 2H), 1.25 (s, 9H), 1.12 (s, 9H). C NMR (75 MHz,
13
3
3
): δ = 125.9 (q, J = 283.7 Hz), 66.3 (q, J = 26.9 Hz), 57.1, 33.6, 27.5, 22.6. IR (KBr):
-1
ṽ cm = 3223, 2989, 2965, 2915, 2876, 1733, 1477, 1370, 1346, 1263, 1222, 1202, 1150,
1104, 1050, 941, 921, 878, 839, 704, 606, 576, 510, 465, 431. EM (IE, 70eV): m/z (%) =
+
259 (3) [M] , 203 (65), 196 (4), 188 (6), 170 (4), 156 (4), 119 (3), 105 (5), 98 (3), 87
(
7), 77 (3), 61 (10), 57 (100), 41 (94), 29 (51), 18 (5).
General procedure for amine synthesis (3a-3d).
Sulfinamide 2 (15 mmol) was suspended in 10 mL of methanol. Then, 7.5 mL (30 mmol,
2 equiv) of 4M HCl in dioxane were added. After 2 min. the suspension became a clear
solution and was stirred at room temperature 1h. It was concentrated and the residue
dissolved in 60 mL of dichloromethane. The organic layer was washed with 60 mL of
NaOH (10% aq.) and the aqueous phase was reextracted with DCM (40 mL X 2). The
combined organic layers were dried with Na
2
SO (anh.) and concentrated. The recorded
4
NMR are similar to the amine hydrochlorides.15a
(R)-1-Phenyl-2,2,2-trifluoroethylamine, (3a).
Purified by FC hexane/EtOAc, 6:4. Colorless liquid. 97% yield (2.55 g). Rf: 0.56
2
5
25
Hexane/Ethyl acetate, 6:4). [α] -12.2 (c 1, CHCl
3
) (Lit.35f [α] -17.4 (c 3.4, EtOH)). H
1
(
D
D
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NMR (300 MHz, CDCl
3
): δ = 7.51 – 7.22 (m, 5H), 4.37 (q, J = 7.5 Hz, 1H), 1.80 (br, 2H).
13C NMR (75 MHz, CDCl
3
): δ = 135.6, 129.0, 128.7, 127.9, 125.8 (q, J = 281.2 Hz), 58.0 (q,
-1
J = 29.6 Hz). IR (film): ṽ cm = 3394, 3324, 3066, 3036, 2982, 2940, 2871, 1734, 1622,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
495, 1476, 1456, 1391, 1365, 1259, 1155, 1118, 987, 890, 758, 702, 625, 585. MS-EI
+
+
(70eV): m/z (%) = 176 (100) [M+H] , 137 (39). HRMS (DART/TOF) m/z: [M+H] Calcd
for C N 176.0687; Found 176.0690.
8
H
F
9 3
(R)-1-(1-naphthyl)-2,2,2-trifluoroethylamine, (3b).
Purified by FC hexane/EtOAc, 6:4. White solid. 97% yield (3.28 g). Rf: 0.41
2
5
1
(
Hexane/Ethyl acetate, 7:3). mp 50 – 51 °C. [α] -4.8 (c 1, CHCl
3
). H NMR (300 MHz,
D
CDCl
3
): δ = 8.09 (d, J = 8.3 Hz, 1H), 7.95 – 7.81 (m, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.63 –
13
7.42 (m, 3H), 5.32 (q, J = 7.2 Hz, 1H), 1.85 (br, 2H). C NMR (75 MHz, CDCl
3
): δ = 134.0,
131.9, 131.7, 129.7, 129.2, 126.9, 126.3 (q, J = 282.3 Hz), 126.0, 125.4, 125.2, 122.9, 52.9
-1
(
q, J = 30.0 Hz). IR (KBr): ṽ cm = 3374, 3281, 3191, 3057, 2910, 1599, 1513, 1399,
1
6
369, 1339, 1258, 1184, 1152, 1115, 1030, 1003, 953, 913, 863, 799, 775, 759, 736,
+
89, 533, 456. MS-EI (70eV): m/z (%) = 225 (22) [M] , 209 (6), 189 (4), 186 (3), 156
+
(100), 129 (45), 101 (4), 78 (12), 63 (4), 51 (3). HRMS (DART/TOF) m/z: [M+H] Calcd
for C12
H
11
F N 226.0844; Found 226.0852.
3
(R)-1-(9-Anthracenyl)-2,2,2-trifluoroethylamine, (3c).
Purified by FC hexane/EtOAc, 9:1 to 7:3. Yellow solid. 80% yield (3.30 g). Rf: 0.32
2
5
1
(
Hexane/Ethyl acetate, 7:3). mp 110 – 113 °C. [α] -45.1 (c 1, CHCl
). H NMR (300
3
D
MHz, CDCl
3
): δ = 9.02 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.21 (d, J = 9.1 Hz, 1H), 8.00 (d, J =
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2
2
2
2
3
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5
5
6
1
3
8
.2 Hz, 2H), 7.68 – 7.32 (m, 4H), 6.09 (q, J = 9.1 Hz, 1H), 2.05 (br, 2H). C NMR (75 MHz,
CDCl
3
): δ = 132.6, 132.2, 131.4, 131.3, 130.6, 130.3, 129.8, 129.5, 128.9, 127.3, 126.5,
-1
1
26.0, 125.1, 124.9, 123.1, 121.34, 53.7 (q, J = 31.4 Hz). IR (KBr): ṽ cm = 3392, 3302,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
051, 1624, 1523, 1362, 1255, 1146, 1119, 1099, 1008, 930, 911, 888, 860, 838, 810,
+
727, 625, 530, 452, 375. MS-EI (70eV): m/z (%) = 275 (30) [M] , 259 (4), 139 (4), 206
+
(
100), 178 (24), 103 (20). HRMS (DART/TOF) m/z: [M+H] Calcd for C16
H
13
F N
3
276.1000; Found 276.1012.
(R)-1-(tert-butyl)-2,2,2-trifluoroethylamine hydrochloride, (3d).
The amine has a low b.p., therefore, at the end of the reaction, ether was added and then
the hydrochloride of 3d precipitates. It was filtered to obtain a white solid in a 93%
2
5
1
yield (2.67 g). [α] -1.4 (c 0.94, CH
3
OH). H NMR (300 MHz, DMSO-d
6
): δ = 9.17 (s, 3H),
): δ = 124.65 (q, J = 284.0
Hz), 58.42 (q, J = 27.7 Hz), 32.43, 26.43. IR (KBr): ṽ cm = 2938, 2853, 2029, 1593, 1527,
275, 1220, 1187, 1122, 1077, 1046, 900, 694, 583, 553, 519, 470. MS-DART (positive):
D
13
4.00 (q, J = 8.8 Hz, 1H), 1.10 (s, 9H). C NMR (75 MHz, DMSO-d
6
-1
1
m/z (%) = 156 (100) [M+H]+
General procedure for the isothiocyanate synthesis (4a-4d).
Amine 3 (5 mmol, 1 equiv.) was dissolved in 20 mL of DCM and cooled to 0 °C. We added
thiophosgene 0.42 mL (5.5 mmol, 1.1 equiv.) followed by 0.83 mL (6 mmol, 1.2 equiv.)
of triethylamine. The reaction was stirred 30 min. at 0 °C and 17h at r.t. The reaction
mixture was washed with 10 mL of NaHCO (sat. aq.), to latter be dried and
3
concentrated. The product was purified by flash chromatography with a mixture
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hexane/EtOAc 95:5 obtaining the different isothiocyanates as slightly yellow liquids.
NOTES: (1) A better yield of 3a was obtained when the order of addition was reversed
(
DCM, thiophosgene, amine and triethylamine). (2) The isothiocyanate 4d has a low
10
11
12
13
14
15
16
17
18
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
b.p., therefore, a one-pot procedure was performed to obtain catalysts 5d and 6d.
(R)-1-Phenyl-2,2,2-trifluoroethylisothiocyanate, (4a).
Purified by FC hexane/EtOAc, 95:5. Yellow liquid. 88% yield (956 mg). Rf: 0.60
25
1
(
Hexane/Ethyl acetate, 9:1). [α] -7.2 (c 2.11, CHCl
3
). H NMR (300 MHz, CDCl ): δ =
3
D
1
3
7
1
2
.46 (s, 5H), 5.19 (q, J = 6.5 Hz, 1H). C NMR (75 MHz, CDCl
3
): δ = 141.2, 130.5, 130.3,
-1
29.2, 127.9, 122.7 (q, J = 282.5 Hz), 62.4 (q, J = 33.4 Hz). IR (film): ṽ cm = 3070, 3039,
925, 2044, 1496, 1456, 1339, 1259, 1188, 1136, 871, 832, 757, 698, 632. MS-DART
+
+
(positive): m/z (%) = 218 (5) [M+H] , 150 (100). HRMS (DART/TOF) m/z: [M+H] Calcd
for C NS 218.0251; Found 218.0246.
9
H
F
7 3
(R)-1-(1-Naphthyl)-2,2,2-trifluoroethylisothiocyanate, (4b).
Purified by FC hexane/EtOAc, 95:5. Slightly yellow solid. 87% yield (1.16 g). Rf: 0.56
2
5
1
(
Hexane/Ethyl acetate, 9:1). mp 50 – 52 °C. [α] +15.4 (c 1.43, CHCl
3
). H NMR (300
D
MHz, CDCl
3
): δ = 7.96 – 7.85 (m, 3H), 7.78 (d, J = 7.2 Hz, 1H), 7.69 – 7.44 (m, 3H), 6.07
13
(q, J = 6.1 Hz, 1H). C NMR (75 MHz, CDCl
3
): δ = 141.1, 133.9, 131.0, 130.6, 129.3, 127.5,
127.0, 126.4, 126.3, 125.3, 123.2 (q, J = 283.4 Hz), 122.1, 58.5 (q, J = 33.8 Hz). IR (film):
-1
ṽ cm = 3055, 2932, 2253, 2041, 1864, 1719, 1599, 1514, 1379, 1338, 1301, 1256, 1188,
1133, 1032, 951, 916, 895, 863, 837, 797, 775, 753, 732, 694, 633. MS-DART (positive):
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