Diastereoselective ritter-like reaction on cyclic trifluoromethylated N,O-acetals derived from L-tartaric acid

Article abstract of DOI:10.1021/acs.joc.7b01814

Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic α-trifluoromethylated N-acyliminium ions were successfully generated from fluorinated O-acetyl-N,O-acetal L-tartaric acid derivatives. The addition of nitriles on these intermediates occurred with high to excellent syn diastereoselectivity and led, in most cases, to oxazolines and amides as single diastereomers. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives, bearing the fluorinated substituent on a tetrasubstituted carbon.

Full text of DOI:10.1021/acs.joc.7b01814

Article
pubs.acs.org/joc
Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated
N,O‑Acetals Derived from L‑Tartaric Acid
Abdelkhalek Ben Jamaa and Fabienne Grellepois*
́ ́
Universite de Reims Champagne-Ardenne, Institut de Chimie Moleculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et
Naturelles, BP 1039, 51687 Reims Cedex 2, France
S
* Supporting Information
ABSTRACT: Despite the presence of the highly electron-withdrawing
fluorinated substituent, cyclic α-trifluoromethylated N-acyliminium
ions were successfully generated from fluorinated O-acetyl-N,O-acetal
L-tartaric acid derivatives. The addition of nitriles on these
intermediates occurred with high to excellent syn diastereoselectivity
and led, in most cases, to oxazolines and amides as single
diastereomers. The diastereoselectivity of the addition and the nature
of the reaction product depend on the substituents on the hydroxyl
groups of the tartaric acid scaffold. This methodology gave access to
enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one
derivatives, bearing the fluorinated substituent on a tetrasubstituted
carbon.
they have to be generated in situ from a more stable precursor,
INTRODUCTION
■
usually an N,O-acetal.14 However, the trifluoromethyl group
not only strongly stabilizes N,O-acetal functions, and thus
renders the formation of the α-trifluoromethyl N-acyliminium
ions difficult, but also greatly destabilizes and hinders these
ions. A few studies dealing with the addition of nucleophiles on
these peculiar species have been reported.11,12a,b,15 To date,
only two studies leading to the functionalization of 5-
(trifluoromethyl)-pyrrolidin-2-one derivatives have been de-
scribed, and none are asymmetric.11,12a,b Fused nitrogen
heterocycles carrying the fluorinated group on the bridgehead
position were obtained by an intramolecular Friedel−Craft
reaction on 5-silyloxy- or 5-hydroxy-5-(trifluoromethyl)-pyrro-
lidin-2-ones using an excess of a relatively strong Brønsted
acid.12a,b The creation of a C−O bond was performed by the
addition of methanol in the presence of hydrochloric acid on a
α-trifluoromethylated N,F-acetal lactam derivative, because the
corresponding N,O-acetal resisted most deoxygenation proce-
dures except for deoxyfluorination.11 The creation of a
tetrasubstituted stereogenic carbon bearing a sterically demand-
ing trifluoromethyl substituent by the addition of a nucleophile
on a α-trifluoromethylated N-acyliminium ion is still challeng-
ing.
Five-membered aza-heterocycles are one of the privileged
fragments of synthetic and natural biologically active sub-
stances.1 Of these, 2-pyrrolidone structural motifs exhibit a high
potential as a precursor of other N-heterocycles, such as
pyrrolidines2 and cyclic amidines,3 and as a core of small
molecules with multiple biological interests.4 By way of an
example, inter alia, 2-pyrrolidone derivatives have been
described as γ-lactam analogues of prostaglandins by being a
potent and selective EP4 receptor agonist and exhibiting a good
pharmacological profile.5
Many pharmaceuticals and agrochemicals include a fluorine
atom or a fluorine-containing group6 as the introduction of this
family of substituents may have a range of beneficial effects on
the biological and physicochemical properties of bioactive
molecules.7 For example, the substitution of one or more
hydrogen atoms by fluorine close to an amine function not only
decreases its basicity but also enhances its metabolic stability.8
Among all the fluorinated substituents, the trifluoromethyl
group is one of the most important.9
5-(Trifluoromethyl)-pyrrolidin-2-ones, for which the fluori-
nated substituent is borne by a tetrasubstituted carbon, have
been reported as conformationally restricted amino acids,10
thrombin inhibitors,11 and natural product analogues.12 This
family of synthons has been mainly prepared by the
construction of the γ-lactam ring.10,12c,13 A more challenging
pathway, scarcely explored, is the elaboration of the
tetrasubstituted carbon bearing the trifluoromethyl group by
the addition of a nucleophile on a cyclic α-trifluoromethylated
N-acyliminium ion.11,12a,b
A few years ago, we reported the diastereoselective synthesis
of aziridines, morpholines, and oxazepanes bearing a trifluor-
omethyl group on a tetrasubstituted carbon starting from L-
tartaric acid following a strategy based on the ring construction
of these aza-heterocycles.16 We now report a practical way to
prepare some original, highly functionalized derivatives of 2-
N-Acyliminium ions have been widely used in organic
Received: July 20, 2017
synthesis.14 Due to their highly reactive nature as electrophiles,
© XXXX American Chemical Society
A
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trifluoromethylpyrrolidinones using a strategy based on the
creation of the tetrasubstituted carbon bearing the fluorinated
substituent. For this purpose, we have studied the addition of
various nitriles17 on cyclic α-trifluoromethyl N-acyliminium
ions derived from L-tartaric acid, which were generated in situ
under an acidic treatment of the corresponding α-trifluor-
omethyl N,O-acetals. During this work, we have highlighted the
influence of the protecting groups of the tartaric acid scaffold
alcohols both on the nature of the reaction product and on the
diastereoselectivity of the reaction.
that the best yield for the nucleophilic trifluoromethylation of
tartrimide 1a, O- and N-protected with a benzyl group, was
obtained using 2.04 equiv of CF3SiMe3 and 0.048 equiv of
tetramethylammonium fluoride (TMAF·4H2O) in THF (Table
1, entry 1). The in situ hydrolysis of the formed silylether led to
N,O-acetal 2a as an 86:14 mixture of two diastereomers, which
were isolated in 80% yield. Both diastereomers of 2a can be
easily separated by chromatography on silica gel. Due to N-
para-methoxybenzyl-O,O′-dibenzyltartrimide (1b) being in-
soluble in THF, these conditions were not suitable for the
preparation of the corresponding N,O-acetal 2b. However, a
smooth trifluoromethylation of tartrimide 1b took place upon
treatment with 4 equiv of CF3SiMe3 and 0.2 equiv of K2CO3 in
DMF (Table 1, entry 2).16a,22 After treatment of the reaction
mixture, desilylation was best achieved using fluoride instead of
water, and N,O-acetal 2b was isolated in 63% yield as a 71:29
mixture of two diastereomers. Both experimental conditions
were applied to N-benzyl-O,O′-dimethyl tartrimide 1c.
Nucleophilic trifluoromethylation in the presence of TMAF·
4H2O followed by the hydrolysis step led to N,O-acetal 2c as a
84:16 mixture of two diastereomers, albeit in a moderate yield
(39%) due to the formation of a considerable amount of a
trifluoromethylated byproduct whose structure could not be
elucidated (Table 1, entry 3). Using CF3SiMe3 and K2CO3 in
DMF substantially improved the yield of N,O-acetal 2c, which
was directly isolated in 77% yield after the trifluoromethylation
step but with a slightly lower diastereoselectivity (75:25)
(Table 1, entry 4). These latter conditions were successfully
applied to N-benzyl-tartrimide 1d containing free alcohol
functions (Table 1, entry 5). The desired N,O-acetal 2d was
obtained with a very good yield (90%) and a good
diastereoselectivity (89:11). Disappointingly, none of the
experimental conditions permitted the nucleophilic trifluor-
omethylation of tartrimide 1e whose hydroxyl groups were
protected as acetyl groups (Table 1, entry 6).
RESULTS AND DISCUSSION
■
The requisite tartrimides 1a−e were prepared by a one-pot
activation−condensation−ring-closure sequence applied to the
suitable O,O′-diprotected L-tartaric acid derivatives or directly
to L-tartaric acid.18,19
The nucleophilic trifluoromethylation of various cyclic imides
has been reported using trifluoromethyltrimethylsilane in the
presence of an activating agent as a trifluoromethide equivalent.
Although most studies were performed under conventional
conditions, with a fluoride anion as the initiator in THF,11,12b,20
the use of tri-tert-butylphosphine in DMF also enabled this
reaction.21 Our results concerning the nucleophilic trifluor-
omethylation of tartrimides 1a−e are summarized in Table 1.
After screening of a wide variety of fluoride anions, we found
Table 1. Synthesis of α-Trifluoromethylated N,O-Acetals
2a−d
Since the configuration of the leaving group can have a
strong impact on the generation of the iminium ion,23 the
absolute configuration of the created trifluoromethylated
stereocenter has been determined for the two diastereomers.
The X-ray crystallography of the major diastereomer of 2a24
revealed that a cis-relationship between the CF3 group and the
neighboring benzyloxy group exists and that the absolute
configuration of the new quaternary stereocenter is R (Table
1). To rationalize the stereochemical outcome of the reaction,
we propose that the attack of the rather bulky CF3 nucleophile
on the carbonyl group of the imide occurred on the face where
steric repulsion with the benzyloxy group is minimized
a
b
c
entry tartrimide conditions
N,O-acetal dr (trans/cis) yield (%)
according to the Burgi−Dunitz trajectory,25 affording the
d
̈
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
A
2a
2b
2c
2c
2d
86:14
71:29
84:16
75:25
89:11
80
63
39
77
90
trans-isomer as the major diastereomer (Scheme 1).
B
We first attempted to generate the α-trifluoromethylated N-
acyliminium ions directly from the trifluoromethylated N,O-
acetals 2a and 2d. N,O-Acetals 2a and 2d were treated with 3
equiv of BF3·Et2O in acetonitrile, standard conditions reported
for the reaction of the nitrile with N-acyliminium ions derived
from (4S)-4,5-dihydroxypyrrolidin-2-one17a (Table 2). No
reaction occurred at room temperature (Table 2, entries 1
and 2). The reaction was then conducted at reflux of the nitrile.
Starting from O,O′-benzyl-N,O-acetal 2a, only the fully O-
debenzylated oxazoline derivative 3 was formed and was
isolated in 77% yield (Table 2, entry 3). This oxazoline 3 can be
obtained in a similar yield (77%) directly from N,O-acetal 2d
bearing two nonprotected hydroxyl groups (Table 2, entry 4).
A
B
B
e
A or B
a
Reaction conditions A: CF3TMS (2.04 equiv), TMAF·4H2O (0.048
equiv), THF, −20 °C then H2O, rt. Reaction conditions B: CF3TMS
(3.9−4 equiv), K2CO3 (0.2 equiv), DMF, rt then TBAF (0.5−1
b
equiv), THF/H2O (3:1), rt. Diastereomeric ratios were determined
c
by 19F NMR of the crude mixture. Unless noticed, the diastereomers
d
were not separated. Both diastereomers were separated by
chromatography on silica gel (yield major diastereomer trans-2a,
68%; yield minor diastereomer cis-2a, 12%). No reaction observed
regardless of the experimental conditions.
e
B
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Scheme 1. Proposed Transition State for the Nucleophilic
Trifluoromethylation of Tartrimides
Table 3. Synthesis of α-Trifluoromethylated O-Acetyl-N,O-
acetals 4a−d
a
entry
N,O-acetal
dr (trans/cis)
O-acetyl-N,O-acetal
yield (%)
1
2
3
4
5
6
trans-2a
cis-2a
2a
100:0
0:100
86:14
71:29
75:25
89:11
trans-4a
cis-4a
4a
99
93
92
83
91
95
2b
4b
Table 2. Reaction of N,O-Acetals 2a and 2d with Acetonitrile
in the Presence of BF3·Et2O
a
2c
4c
2d
4d
a
Diastereomeric ratios of starting materials 2a−d and products 4a−d
were determined by 19F NMR.
Table 4. Optimization of the Ritter-like Reaction Conditions
a
on N,O-Acetals trans-4a and cis-4a
entry
N,O-acetal
T (°C)
time (h)
yield (%)
1
2
3
4
2a
2d
2a
2d
rt
7.5
18
5
b
rt
b
reflux
reflux
75
77
2
a
b
b
Reaction conditions: BF3·Et2O (3 equiv) in MeCN. No reaction.
entry
N,O-acetal
MeCN
T (°C)
time (h)
yield (%)
97
1
2
3
4
5
trans-4a
trans-4a
trans-4a
trans-4a
cis-4a
solvent
solvent
10 equiv
10 equiv
solvent
rt
24
1.5
30
8
In order to use a milder reaction temperature to generate the
c
reflux
rt
80
N-acyliminium ions, O-acetyl-N,O-acetals 4, analogues of N,O-
acetals 2 containing a better leaving group, were thus prepared
and evaluated as precursors.
d
65
e
reflux
rt
71
f
26
39
Treatment of each diastereomer of N,O-acetal 2a and the
mixture of diastereomers of 2a−c with 1.7 equiv of acetic
anhydride, 1.5 equiv of pyridine, and 0.1 equiv of DMAP in
dichloromethane led to the corresponding O-acetyl-N,O-acetals
trans-4a, cis-4a, and 4a−c with very good yields ranging from
83% to 99% (Table 3, entries 1−5). The reaction of 2d, in
which alcohol functions are not protected, was performed using
a bigger excess of acetic anhydride (5 equiv) and pyridine (4.51
equiv) in the presence of DMAP (0.3 equiv) in order to esterify
the three hydroxyl groups (Table 3, entry 6). Thus, the
corresponding peracetyl-N,O-acetal 4d was isolated in 95%
yield. Using this procedure circumvented the absence of the
reaction of O,O′-acyltartrimide 1e under the nucleophilic
trifluoromethylation conditions (Table 1, entry 6)
The experimental conditions for the addition of acetonitrile
were optimized on the major diastereomer trans-4a and 3 equiv
of BF3·Et2O and were utilized in all cases (Table 4, entries 1−
4). Using acetonitrile as the solvent at rt, O-benzyl oxazoline 5a
was smoothly formed (24 h of reaction) and was then isolated
with an excellent yield of 97% (Table 4, entry 1). It is
noteworthy that this Ritter-like reaction product 5a can also be
obtained in only 90 min at reflux of acetonitrile but in a slightly
lower yield (80%) due to the formation of a small amount of
amide 6a (Table 4, entry 2). Amide 6a results from the ring
opening of oxazoline 5a with water (see Table 8 for the
structure). The reaction could also be performed with only 10
equiv of acetonitrile in dichloromethane as the solvent (Table
a
Reaction conditions: BF3·Et2O (3 equiv) in MeCN or BF3·Et2O (3
b
equiv), MeCN (10 equiv) in CH2Cl2. trans-4a: From the major
diastereomer of 2a, the absolute configuration of the stereocenter
bearing the CF3 group is R. cis-4a: From the minor diastereomer of 2a,
the absolute configuration of the stereocenter bearing the CF3 group is
c
S. Ratio oxazoline 5a/amide 6a 85:15 determined by the 19F NMR
spectra of the crude reaction mixture. 12% of amide 6a was also
d
isolated. 90% conversion. 6% of cis-4a and 18% of 2a (dr trans/cis
96:4) were also detected by 19F NMR of the crude reaction mixture.
e
97% conversion. 5% of cis-4a and 17% of 2a (dr trans/cis 99:1) were
f
also detected by 19F NMR of the crude reaction mixture. 42%
conversion determined by 19F NMR.
4, entries 3 and 4). At rt, the reaction was not complete (90%
conversion after 30 h of stirring), and oxazoline 5a was isolated
in only 65% yield due to the concomitant formation of a non-
negligible amount of N,O-acetals cis-4a and 2a (6% and 18%
conversion detected, respectively, in the 19F NMR of the crude
reaction mixture) (Table 4, entry 3). At reflux of dichloro-
methane, the reaction was faster (97% conversion after 8 h of
stirring), and the yield of oxazoline 5a was slightly improved to
71%. However, similar amounts of N,O-acetals cis-4a and 2a
were also formed (5% and 17% detected, respectively, in the
19F NMR of the crude reaction mixture) (Table 4, entry 4).
The formation of cis-2a, trans-2a, and cis-4a during the course
of the reaction can be rationalized by the competitive
nucleophilic attack of H2O and AcOBF3 on the intermediate
C
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N-acyliminium ion. It is noteworthy that, when using O-acetyl-
N,O-acetal 4a as the starting material, no traces of debenzylated
oxazoline 3 were detected in the 19F NMR spectra of the crude
reaction mixture regardless of the reaction conditions. Better
conversions in oxazoline 5a have been obtained using
acetonitrile as the solvent (Table 4, entries 1 and 2) instead
of only 10 equiv in dichloromethane (Table 4, entries 3 and 4),
but these latter conditions will be particularly advantageous for
nitriles that cannot be used as a solvent. The best experimental
conditions (acetonitrile as the solvent, at rt) were then applied
to N,O-acetal cis-4a, the minor diastereomer (Table 4, entry 5).
Only 42% conversion of cis-4a in oxazoline 5a after 18 h of
stirring was detected by 19F NMR, and oxazoline 5a was thus
isolated in 39% yield. The slowness of this reaction on cis-4a
might be attributed to the more difficult generation of the
intermediate N-acyliminium ion from the minor cis-4a
diastereomer in comparison with that of the major trans-4a
for conformational reasons.23 The structure of 5a was
confirmed by 2D NOESY and 19F,1H HOESY (heteronuclear
NOESY) experiments (Figure 1).
Table 5. Ritter-Type Reaction on Benzyl-Protected N,O-
Acetals 4a and 4b
a
a
Reaction conditions for 5a−e,g: BF3·Et2O (3 equiv) in R2CN, rt, 21−
48 h. Reaction conditions for 5f: BnCN (10 equiv), BF3·Et2O (3.05
equiv) in CH2Cl2, rt, 48 h.
Figure 1. NOE connectivities on oxazoline 5a.
Table 6. Addition of Acetonitrile on O,O′-Methyl-Protected
a
Even if the Ritter-type reaction was sluggish with the minor
diastereomer of N,O-acetal 4a, the addition of various nitriles in
the presence of 3 equiv of BF3·Et2O was carried out on a
mixture of diastereomers of O,O′-benzyl-N,O-acetals 4a and 4b
at room temperature (Table 5). Optimized conditions, with
nitrile as the solvent, were used except for nitrile having a high
boiling point, for which only 10 equiv was used in
dichloromethane to facilitate the purification of the oxazoline.
The addition of various aliphatic nitriles led to the
corresponding oxazolines 5a−d, which were isolated in good
to very good yields (ranging from 70% to 83%). However, due
to the steric hindrance around the electrophilic carbon of the
iminium ion function caused by the trifluoromethyl substituent,
the addition of sterically hindered iso-propyl cyanide or tert-
butyl cyanide was slower than the addition of acetonitrile (41−
48 h instead of 28−31 h). A similar long reaction time (40 h)
was necessary to complete the addition of phenyl cyanide on
N,O-acetal 4a. After purification, oxazoline 5e was isolated in
83% yield. The reaction with benzyl cyanide was performed in
dichloromethane and gave, after 48 h at room temperature, the
corresponding oxazoline 5f in a slightly lower yield (63%). The
addition of allyl cyanide resulted in oxazoline 5g, in which the
double bond CC migrated to be conjugated with the double
CN bond. Oxazoline 5g was isolated in 89% yield after 21 h
of reaction.
N,O-Acetal 4c
yield (%)
b
entry
T (°C)
time (h)
ratio (5h/cis-7a)
5h
cis-7a
c
1
2
3
rt
23
55:45
63:37
87:13
29
46
68
19
21
13
50
6
reflux
1.5
a
b
Reaction conditions: BF3·Et2O (3 equiv) in MeCN. Ratios
determined by 19F NMR of the crude reaction mixture. A single
c
diastereomer was detected for each compound, 5h and cis-7a. 73%
conversion determined by 19F NMR of the crude reaction mixture.
The influence of α-trifluoromethylated N,O-acetals bearing
other hydroxyl protecting groups on the course of the reaction
was then evaluated.
The reaction of O,O′-methyl-N,O-acetal 4c with acetonitrile
in the presence of 3 equiv of BF3·Et2O was first examined
(Table 6). The reaction was not complete after 23 h at room
temperature (73% conversion) (Table 6, entry 1). Oxazoline
5h, for which the formation implied a challenging demethyla-
tion step during the reaction, was the major compound. As this
demethylation step is not favored, O,O′-methyl amide cis-7a
was also isolated. It is interesting to note that, although the
diastereoselectivity of the addition of nucleophiles to the N-
acyliminium ions generated in situ from cyclic imides derived
from tartaric acid or malic acid is typically modest,14c amide 7a
was formed as a single diastereomer. The cis-relationship
between the amide group and the adjacent oxygenated
D
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substituent of 7a24 was determined from its X-ray structural
analysis. Conducting the reaction at higher temperatures
allowed a full conversion of the starting N,O-acetal 4c,
increased the intramolecular cyclization rate leading to
oxazoline 5h, and thus decreased the formation of amide cis-
7a (until a 87:13 ratio at reflux of acetonitrile) (Table 6, entries
2 and 3). At reflux of acetonitrile, oxazoline 5h and amide cis-7a
were isolated in 68% and 13% yields, respectively (Table 6,
entry 3).
Table 7. Addition of Acetonitrile on O,O′-Acetyl-Protected
a
N,O-Acetal 4d
The excellent cis diastereoselectivity for the formation of
oxazolines 5a−h and of amide 7a can be rationalized on the
basis of the mechanism suggested by Pyne17a for the addition of
nitriles on N-acyliminium ions derived from (4S)-4,5-
dihydroxypyrrolidone and (4S)-4-(benzyloxy)-5-hydroxypyrro-
lidone (Scheme 2). The attack of nitriles on N-acyliminium ion
yield (%)
Scheme 2. Proposed Mechanism for the Formation of
Oxazolines 5a−h and Amide cis-7a from N,O-Acetals 4a−c
b
entry
T (°C)
time (h)
dr 7b (cis/trans)
cis-7b
trans-7b
c
d
d
1
2
3
rt
46
89:11
86:14
85:15
31
31
50
30
6
73
10
13
reflux
63
a
b
Reaction conditions: BF3·Et2O (3 equiv) in MeCN. Diastereomeric
ratios of amides 7b determined by 19F NMR of the crude reaction
c
mixture. 45% conversion determined by 19F NMR of the crude
d
reaction mixture. Diastereomers not separated.
Scheme 3. Proposed Mechanism for the syn Selectivity of the
Addition of Acetonitrile on O,O′-Acetyl N-Acyliminium Ion
Derived from N,O-Acetal 4d
cis/trans diastereomers) was the only product formed. The cis-
relationship between the amide group and the adjacent
oxygenated substituent of the major diastereomer of 7b24 was
determined from its X-ray structural analysis. At 50 °C, acetal
4d was fully converted into O,O′-acetyl amides 7b, which were
formed in an 86:14 mixture of diastereomers and isolated in
73% and 10% yields, respectively (Table 7, entry 2). Similar
results were obtained at reflux of acetonitrile (Table 7, entry 3).
Due to the oxygen atom of the neighboring acetoxy group
being less nucleophilic than that of the one of the benzyloxy or
methoxy groups, no traces of oxazoline were formed, even at
reflux.
The formation of a 85:15 to 89:11 mixture of cis- and trans-
amide 7b should reflect the prevalent syn addition of nitrile on
the N-acyliminium ion generated from O,O′-acetyl-N,O-acetal
4d. Since the neighboring group participation of the 4-O-acetyl
group in the stereocontrol of the reaction should favor the anti
addition of the nucleophile,14d,27 it would appear that the 3-O-
A giving the cis- and trans-nitrilium ion B might be reversible,
and due to its cis stereochemistry, the cis-nitrilium ion B more
readily cyclizes to the oxazoline cationic intermediate C.26
Debenzylation or demethylation gives the oxazolines 5a−h.
Due to demethylation being less favorable than debenzylation,
and amide 7a being only obtained as its cis isomer, we propose
that cis-7a stems from the concomitant hydrolysis of the
methoxy cyclic intermediate C, not from the hydrolysis of
nitrilium ion B.
O,O′-Acetyl-N,O-acetal 4d was treated under the same
experimental conditions (Table 7). At room temperature,
only a low conversion of the starting N,O-acetal 4d was
observed (45%, Table 7, entry 1). Amide 7b (89:11 mixture of
E
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acetyl group provided the anchimeric assistance, leading to the
preferential formation of the cis-isomer28 (Scheme 3).
Scheme 4. Hydrolysis of Oxazoline 5a into Corresponding
Hydroxylamine 8
Acid hydrolysis of oxazolines 5a−f,h with HCl in methanol at
room temperature led to the corresponding cis-hydroxyamides
6a−g, in which one alcohol function has been selectively
deprotected (Table 8). With most of the substituents on the
Table 8. Hydrolysis of Oxazolines 5a−f,h into
Corresponding Hydroxylamides 6a−g
Table 9. Reaction Sequence “Addition of Nitrile−Acid
ab
,
Hydrolysis” on N,O-Acetals 4a and 2d
oxazoline ring (methyl, iso-propyl, or benzyl), this reaction was
complete in a short reaction time (4 h or less), and amides 6a−
c,f,g were isolated with a yield ranging from 80% to 94%.
However, the efficiency of the reaction seems to depend on the
bulkiness of this substituent. With tert-butyl and phenyl groups,
the reactions were not complete even after long reaction times
(55% and 75% conversion after 46−48 h at room temperature),
and the corresponding amides 6d and 6e were thus isolated in
only 43% and 69% yields, respectively.
a
Reaction conditions for 6a and 6f: RCN (solvent), BF3·Et2O (3
equiv), rt then HCl (6 N aq), MeOH, rt. Reaction conditions for 8:
MeCN (solvent), BF3·Et2O (3 equiv), rt then HCl (6 N aq), MeOH,
60 °C. Reaction conditions for 6h−i: RCN (10 equiv), BF3·Et2O (3
equiv), CH2Cl2, rt then HCl (6 N aq), MeOH, rt. Reaction conditions
for 6j: MeCN (solvent), BF3·Et2O (3 equiv), reflux then HCl (6 N
b
aq), MeOH, rt. The yield for the whole sequence with purification of
the intermediate oxazoline is indicated between brackets.
The retention of the cis-relationship between the hydroxyl
group and the exo amide function was confirmed by 2D
NOESY and 19F,1H HOESY (heteronuclear NOESY) experi-
ments on compound 6a (Figure 2).
room temperature followed, after work up, by the hydrolysis
under acidic conditions (HCl 6 N aq in methanol) led to
hydroxyamide 6a or hydroxylamine 8 depending on the
temperature of the deprotection reaction. These two-step
sequences get similar yields to the ones obtained when
oxazoline 5a was purified (64% and 54% instead of 70% and
52%, respectively). This process was particularly convenient for
performing the reaction with a nitrile that has a high boiling
point, for which purification of the intermediate oxazoline can
be difficult. In this case, the Ritter-like reaction step is
performed with 10 equiv of a suitable nitrile in dichloro-
methane as the solvent, and after hydrolysis, the hydroxyamides
6f,h,i, variously substituted on the amide alkyl chain, were
obtained in moderate to good yields (from 31% to 58%). These
yields reflect the partial conversion observed for one or both
steps of the reaction sequence. The yield of 6f was identical to
that of the global one obtained when oxazoline 5f was isolated.
This approach was also applied directly to N,O-acetal 2d. In
this latter case, the Ritter-like reaction step was performed at
Figure 2. NOE connectivities on hydroxyamide 6a.
Full deprotection of oxazoline 5a with HCl in methanol at 60
°C gave, after 29 h of reaction, the conformationally stable cis-
hydroxyamine 8 in 68% yield (Scheme 4).
Finally, we have shown that the Ritter-like reaction and the
hydrolysis step can also be carried out without purification of
the intermediate oxazoline (Table 9). Treatment of N,O-acetal
4a with acetonitrile in the presence of 3 equiv of BF3·Et2O at
F
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H NMR (500 MHz, CDCl3) δ 4.41 (s, 2H), 4.66 (d, J = 14.0 Hz,
reflux of acetonitrile, and hydroxyamide 6j was isolated, after
1H), 4.69 (d, J = 14.0 Hz, 1H), 4.78 (d, J = 11.5 Hz, 2H), 5.02 (d, J =
11.5 Hz, 2H), 7.31−7.41 (m, 15H); 13C NMR (125.8 MHz, CDCl3) δ
42.4, 73.6, 78.9, 128.30, 128.36, 128.37, 128.8, 129.0, 135.1, 136.6,
172.5; HRMS (ESI+) m/z calcd for C25H23NNaO4 [M + Na]+
424.1525, found 424.1522.
the acid hydrolysis reaction, in 70% yield.
CONCLUSION
■
Although the electron-withdrawing trifluoromethyl group has
not only rendered the formation of adjacent N-acyliminium
ions difficult by strongly stabilizing the N,O-acetal precursor
but also destabilized and hindered these ions, rendering the
reactions with nucleophiles arduous, α-trifluoromethylated
iminium ions have been successfully generated by the treatment
of O-acetyl-N,O-acetals derived from L-tartaric acid with BF3·
Et2O. Using nitriles as nucleophiles afforded the corresponding
3a-(trifluoromethyl)-pyrrolo[2,3-d]-oxazolone and 2-acyl-2-tri-
fluoromethylpyrrolidone derivatives. Hydroxyl groups and
ether substituents directed the Ritter-like reaction mostly or
exclusively toward the formation of oxazoline derivatives, while
esters led to an amide function, which was obtained with high
syn diastereoselectivity. A small library of original, highly
functionalized 5-(trifluoromethyl)-pyrrolidin-2-ones bearing
the fluorinated substituent on a tetrasubstituted carbon was
thereby obtained.
(3R,4R)-3,4-Bis(benzyloxy)-1-(4-methoxybenzyl)pyrrolidine-2,5-
dione (1b). According to a general procedure, O,O′-benzyl L-tartaric
acid25 (7.1 g, 21.5 mmol) reacted with acetyl chloride (15 mL, 210.2
mmol, 9.8 equiv). Then the formed anhydride reacted with p-
methoxybenzylamine (3.4 mL, 26.0 mmol, 1.21 equiv) in CH2Cl2 (23
mL), and finally the obtained amido acid reacted with acetyl chloride
(20 mL, 280.2 mmol, 13 equiv). Purification by recrystallization in
EtOAc afforded the known tartrimide 1b18,25 (7.04 g, 76%) as a beige
solid: mp 132 °C; [α]D20 +203 (c 0.80, CH2Cl2); IR (KBr) νmax 699,
1
746, 1105, 1251, 1342, 1606, 1722, 2062, 2610, 2886, 3427 cm−1; H
NMR (250 MHz, CDCl3) δ 3.78 (s, 3H), 4.38 (s, 2H), 4.60 (s, 2H),
4.75 (d, J = 11.5 Hz, 2H), 5.00 (d, J = 11.5 Hz, 2H), 6.84 (d, J = 8.5
Hz, 2H), 7.32 (m, 12H); 13C NMR (62.9 MHz, CDCl3) δ 41.9, 55.4,
73.6, 79.0, 114.2, 127.4, 128.4, 128.6, 130.9, 136.6, 159.6, 172.5;
HRMS (ESI+) m/z calcd for C26H25NNaO5 [M + Na]+ 454.1630,
found 454.1614.
(3R,4R)-1-Benzyl-3,4-dimethoxypyrrolidine-2,5-dione (1c). Ac-
cording to a general procedure, O,O′-methyl L-tartaric acid30 (3.32
g, 18.6 mmol) reacted with acetyl chloride (22 mL, 308.3 mmol, 16.5
equiv). Then the formed anhydride reacted with benzylamine (2.2 mL,
20.1 mmol, 1.08 equiv) in CH2Cl2 (25 mL), and finally the obtained
amino acid reacted with acetyl chloride (22 mL, 308.3 mmol, 16.5
equiv). Purification by chromatography on silica gel (PE/EtOAC 4:1)
afforded tartrimide 1c (2.19 g, 47%) as a white solid: mp 126 °C; [α]D20
+190 (c 1.01, CHCl3); IR (KBr) νmax 703, 961, 1074, 1118, 1152,
1340, 1431, 1716, 2834, 2951, 2987, 3486 cm−1; 1H NMR (250 MHz,
EXPERIMENTAL SECTION
■
THF, CH2Cl2, and MeCN were dried using a Pure Solv solvent drying
system over aluminum oxide under an argon atmosphere. DMF (extra
dry, water <0.005%) was purchased from Acros Organics. CF3SiMe3
was distilled under Ar prior to use. Thin-layer chromatography using
precoated aluminum backed plates (Merck Kieselgel 60F254) was
visualized by UV light and by phosphomolybdic acid. Silica gel 40−63
μm (Macherey−Nagel GmbH & Co KG) was used for flash
chromatography. NMR spectra were recorded in CDCl3 with 250,
500, or 600 MHz spectrometers. Chemicals shifts (δ) were reported in
CDCl3) δ 3.68 (s, 6H), 4.12 (s, 2H), 4.63 (s, 2H), 7.30 (m, 5H); 13
C
NMR (62.9 MHz, CDCl3) δ 42.3, 59.8, 81.4, 128.3, 128.8, 129.0,
135.1, 172.2; HRMS (ESI+) m/z calcd for C13H15NNaO4 [M + Na]+
272.0899, found 272.0893.
1
ppm relative to TMS for H and 13C NMR spectra and to CFCl3 for
19F NMR spectra. In the 13C NMR data (J-MOD), reported signal
(3R,4R)-1-Benzyl-2,5-dioxopyrrolidine-3,4-diyl Diacetate (1e). A
solution of L-tartaric acid (15 g, 100 mmol) in acetyl chloride (73 mL,
1023 mmol, 10.2 equiv) was heated at reflux under Ar for 24 h. After
cooling to room temperature, the reaction mixture was concentrated
under reduced pressure, and the solid residue was dissolved in
anhydrous THF (120 mL). Benzylamine (12 mL, 109.9 mmol, 1.1
equiv) was added dropwise at 0 °C. After 15 min of stirring at 0 °C
and 3 h at reflux, the reaction mixture was cooled to room temperature
and concentrated under reduced pressure. A solution of the residue in
acetyl chloride (70 mL, 981 mmol, 9.8 equiv) was heated at reflux for 5
h, then cooled to room temperature, and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate and washed with a
saturated aqueous solution of NaHCO3. The aqueous layer was
extracted with ethyl acetate. The organic layer was washed with brine
and an aq solution of 10% (v/v) HCl , dried (MgSO4), filtered, and
concentrated under reduced pressure to give the known tartrimide
1e31 (25.2 g, 82%) as a white solid: mp 121 °C; [α]2D0 +113 (c 1.01,
CH2Cl2); IR (KBr) νmax 705, 1023, 1072, 1174, 1224, 1354, 1439,
1720, 3007, 3492 cm−1; 1H NMR (250 MHz, CDCl3) δ 2.17 (s, 6H),
4.67 (d, J = 14.0 Hz, 1H), 4.76 (d, J = 14.0 Hz, 1H), 5.53 (s, 2H),
7.30−7.38 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 20.4, 43.2, 72.8,
128.4, 128.9, 134.6, 169.2, 169.9; HRMS (ESI+) m/z calcd for
C15H15NNaO6 [M + Na]+ 328.0797, found 328.0798.
(3R,4R)-1-Benzyl-3,4-dihydroxypyrrolidine-2,5-dione (1d). A sol-
ution of tartrimide 1e (20 g, 65.5 mmol) and acetyl chloride (14 mL,
196 mmol, 3 equiv) was stirred for 15 min at 0 °C and 24 h at rt and
was then concentrated under reduced pressure to give the known
tartrimide 1d32 (14.4 g, 99%) as a yellowish solid: mp 201 °C; [α]2D0
+135 (c 2.00, MeOH); IR (KBr) νmax 693, 1007, 1162, 1348, 1711,
2922, 3287 cm−1; 1H NMR (250 MHz, CD3OD) δ 4.27 (s, 2H), 4.39
(d, J = 15.0 Hz, 1H), 4.46 (d, J = 15.0 Hz, 1H), 6.18 (br s, 2H), 7.14
(m, 5H); 13C NMR (62.9 MHz, CD3OD) δ 50.7, 84.0, 137.0, 138.1,
145.5, 184.1; HRMS (ESI+): m/z calcd for C11H11NNaO4 [M + Na]+
244.0586, found 244.0583.
multiplicities were related to the C−F coupling. The following
abbreviations were used to indicate the multiplicities: s (singlet), br s
(broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
hept (heptuplet), m (multiplet). COSY, HSQC, and HMBC 2D NMR
experiments were used to confirm the NMR peak assignments for
compounds 2−8. Diastereomeric ratios (dr) were determined by 19F
NMR. HRMS were recorded on an ESI-Q-TOF mass spectrometer
using an electrospray source in positive mode. Melting points (mp)
were determined on a Tottoli apparatus and were uncorrected. Optical
rotations were measured at room temperature (ca. 20 °C).
General Procedure for Preparation of Tartrimides 1a−c by a
One-Pot Activation−Condensation−Ring-Closure Sequence.18
A solution of O,O′-protected L-tartaric acid in acetyl chloride (8.4−
16.5 equiv) was heated at reflux under Ar for 4 h. After cooling to
room temperature, the reaction mixture was concentrated under
reduced pressure, and the solid anhydride was dissolved in
dichloromethane. The amine (1.08−1.21 equiv) was added dropwise
at 0 °C. After 15 min of stirring at 0 °C and 5 h at reflux, the reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. A solution of amido acid in acetyl chloride (8.4−
16.5 equiv) was heated at reflux for 6 h, then cooled to room
temperature, and concentrated under reduced pressure. Purification of
the residue afforded tartrimide 1.
(3R,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidine-2,5-dione (1a).
According to a general procedure, a solution of O,O′-benzyl L-tartaric
acid25 (13.7 g, 41.5 mmol) reacted with acetyl chloride (25 mL, 350.3
mmol, 8.4 equiv). Then the formed anhydride reacted with
benzylamine (5.5 mL, 50.3 mmol, 1.2 equiv) in CH2Cl2 (23 mL),
and finally the obtained amido acid reacted with acetyl chloride (25
mL, 350.3 mmol, 8.4 equiv). Purification by chromatography on silica
gel (PE/EtOAC 8:1) afforded the known tartrimide 1a29 (12.9 g,
78%) as a white solid: mp 90 °C; [α]2D0 +152 (c 1.00, CHCl3); IR
(KBr) νmax 698, 1022, 1080, 1102, 1337, 1709, 1786, 2863, 3030 cm−1;
G
DOI: 10.1021/acs.joc.7b01814
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The Journal of Organic Chemistry
Article
2
General Procedure for the Preparation of N,O-Acetals 2a−d
by Nucleophilic Trifluoromethylation of Tartrimides 1a−d.
General Procedure A. To a solution of tartrimide 1 in THF were
slowly added, at −20 °C under Ar, TMAF·4H2O (0.048 equiv) and
CF3TMS (2.04 equiv). The reaction was stirred at this temperature
until the full conversion of the starting tartrimide (reaction monitored
by TLC and 19F NMR). Water was added, and the reaction was stirred
at room temperature. After the complete conversion of the silyl ether
intermediate (reaction monitored by TLC and 19F NMR), the reaction
was extracted three times with Et2O. The combined organic layers
were washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel afforded N,O-acetals 2.
General Procedure B. To a solution of tartrimide 1 and K2CO3 (0.1
equiv) in DMF was slowly added, at 0 °C under Ar, CF3TMS (2
equiv). After 20 min of stirring at 0 °C and 2 h at room temperature,
supplementary amounts of K2CO3 (0.1 equiv) and CF3TMS (2 equiv)
were added. After the complete conversion of the starting tartrimide
(reaction monitored by TLC and 19F NMR), the reaction was
quenched with water and extracted three times with EtOAc. The
combined organic layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was then dissolved
in a mixture of THF/H2O (3:1), and a solution of tetra-n-
butylammonium fluoride (1 M in THF, 0.1 equiv) was added at
room temperature. After the complete conversion of the silyl ether
intermediate (reaction monitored by TLC and 19F NMR), the reaction
was quenched with water and extracted three times with EtOAc. The
combined organic layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Purification of the residue by
chromatography on silica gel afforded N,O-acetals 2.
88.5 (CHCCF3), 88.6 (q, JCF = 30.5 Hz, CCF3), 124.9 (q,
2JCF = 288.0 Hz, CF3), 128.1 (CHar), 128.6 (CHar), 128.9 (CHar),
129.1 (CHar), 129.2 (CHar), 129.3 (CHar), 129.4 (CHar), 138.4
(CIVar, NBn), 138.6 (CIVar, CF3CCHOBn), 138.8
(CIVar, OCCHOBn), 172.3 (CO); HRMS (ESI+) m/z
calcd for C26H24F3NNaO4 [M + Na]+ 494.1555, found 494.1548. An
analytical sample of trans-2a was crystallized from Et2O/PE.
(3R,4R)-3,4-Bis(benzyloxy)-5-hydroxy-1-(4-methoxybenzyl)-5-
(trifluoromethyl)pyrrolidin-2-one (2b). According to General Proce-
dure B, a mixture of tartrimide 1b (1.5 g, 3.47 mmol), K2CO3 (98 mg,
0.71 mmol, 0.2 equiv), and CF3TMS (2 mL, 13.53 mmol, 3.9 equiv) in
DMF (28 mL) was stirred for 21 h. After treatment, a solution of the
residue and TBAF (1.75 mL, 1.75 mmol, 0.5 equiv) in a mixture of
THF/H2O (40 mL) was stirred for 1 h. Purification of the residue (dr
= 71:29) on silica gel (PE/EtOAc 4:1) afforded N,O-acetal 2b (1.1 g,
63%, dr = 71:29) as a yellow oil: IR (film) νmax 699, 754, 1029, 1111,
1193, 1250, 1353, 1454, 1514, 1613, 1699, 2935, 3032, 3273 cm−1; 19
NMR (CDCl3, 235.5 MHz) δ −76.9 (s, 3F, CF3, major), −79.4 (s, 3F,
CF3, minor); H NMR (CDCl3, 500 MHz) δ 3.73 (s, 3H, OCH3,
F
1
major), 3.76 (s, 3H, OCH3, minor), 3.89 (br s, 1H, OH, major), 4.06
3
(d, J = 5.0 Hz, 1H, CHCO, minor), 4.16 (m, 1H, CHC
2
CF3, major), 4.17 (m, 1H, CHCCF3, minor), 4.22 (d, J = 15.5
3
Hz, 1H, NCHaHb, major), 4.31 (d, J = 8.0 Hz, 1H, CHCO,
2
major), 4.38 (br s, 1H, OH, minor), 4.46 (d, J = 15.0 Hz, 1H, N
2
CHaHb, minor), 4.56 (d, J = 15.0 Hz, 1H, NCHaHb, minor), 4.63
(d, 2J = 11.5 Hz, 1H, CHaHbOCHCCF3, major), 4.65 (d, 2J
2
= 11.5 Hz, 1H, CHaHbOCHCCF3, minor), 4.73 (d, J =
2
11.5 Hz, 1H, CHaHbOCHCO, major), 4.74 (d, J = 11.5
Hz, 1H, CHaHbOCHCO, minor), 4.76 (d, 2J = 15.5 Hz, 1H,
2
NCHaHb, major), 4.79 (d, J = 11.5 Hz, 1H, CHaHbOCH
CCF3, minor), 4.81 (d, 2J = 11.5 Hz, 1H, CHaHbOCHC
(3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-hydroxy-5-(trifluoro-
methyl)pyrrolidin-2-one (2a). According to General Procedure A, a
solution of tartrimide 1a (4.8 g, 12.0 mmol), TMAF·4H2O (95 mg,
0.58 mmol, 0.048 equiv), and CF3TMS (3.6 mL, 24.5 mmol, 2.04
equiv) in THF (115 mL) was stirred for 1.5 h and was then
hydrolyzed with H2O (100 mL) for 21 h. Purification of the residue
(dr = 86:14) on silica gel (CH2Cl2/Et2O 10:0 to 19:1) afforded the
minor diastereomer cis-2a (650 mg, 12%) followed by the major
diastereomer trans-2a (3.86 g, 68%). cis-2a: pale yellow solid; mp 73
°C; [α]2D0 +79 (c 1.01, CHCl3); IR (KBr) νmax 701, 948, 1031, 1112,
1180, 1321, 1454, 1735, 2951, 3033, 3357 cm−1; 19F NMR (CDCl3,
235.5 MHz) δ −80.6 (s, 3F, CF3); 19F NMR (CD3OD, 235.5 MHz) δ
−80.6 (s, 3F, CF3); 1H NMR (CD3OD, 500 MHz) δ 4.19 (d, 3J = 5.0
Hz, 1H, CHCCF3), 4.29 (d, 3J = 5.0 Hz, 1H, CHCO), 4.48
(d, 2J = 15.5 Hz, 1H, NCHaHb), 4.60 (d, 2J = 12.0 Hz, 1H,
CHaHbOCHCCF3), 4.63 (d, 2J = 15.5 Hz, 1H, N
CHaHb), 4.74 (d, 2J = 12.0 Hz, 1H, CHaHbOCHCO), 4.76
2
CF3, major), 5.01 (d, J = 11.5 Hz, 1H, CHaHbOCHCO,
minor), 5.04 (d, 2J = 11.5 Hz, 1H, CHaHbOCHCO, major),
6.78 (m, 2H, 2 CHar, major), 6.81 (m, 2H, 2 CHar, minor), 7.22−7.38
(m, 12H, 12 CHar, major and minor); 13C NMR (CDCl3, 125.7
MHz) δ 43.1 (NCH2, major), 44.1 (NCH2, minor), 55.3 (OCH3,
minor), 55.4 (OCH3, major), 73.0 (CH2OCHCO, minor),
73.6 (CH2OCHCO, major), 73.9 (CH2OCHC
CF3, major), 74.0 (CH2OCHCCF3, minor), 77.2 (CH
CCF3, minor), 78.1 (CHCCO, minor), 78.4 (CHC
CO, major), 85.9 (q, 2JCF = 33.0 Hz, CCF3, minor), 87.1 (CH
2
CCF3, major), 88.0 (q, JCF = 31.0 Hz, CCF3, major), 113.8
1
(CHar, minor), 114.2 (CHar, major), 122.9 (q, JCF = 288.5 Hz, CF3,
minor), 123.3 (q, 1JCF = 286.0 Hz, CF3, major), 128.0 (CHar, major),
128.1 (CHar, minor), 128.2 (CHar, major), 128.4 (CHar, minor),
128.48 (CHar, minor), 128.53 (CHar, major), 128.6 (CHar, major),
128.7 (CHar, minor), 128.83 (CHar, major), 128.86 (CHar, minor),
129.4 (CIVar, NCH2Ph, major), 129.7 (CHar, major), 129.9
(CHar, minor), 135.7 (CIVar, CF3CCHOBn, minor),
137.00 (CIVar, OCCHOBn, minor), 137.04 (CIVar, CF3
CCHOBn, major), 137.4 (CIVar, OCCHOBn,
major), 159.00 (CIVar, CH3OPh, major), 159.03 (CIVar, CH3
OPh, minor), 170.6 (CO, major), 171.8 (CO, minor); HRMS
(ESI+) m/z calcd for C27H26F3NNaO5 [M + Na]+ 524.1661, found
524.1656.
2
(d, J = 12.0 Hz, 1H, CHaHbOCHCCF3), 4.86 (br s, 1H,
2
OH), 4.92 (d, J = 12.0 Hz, 1H, CHaHbOCHCO), 7.20−
7.37 (m, 15H, 15 CHar (aromatic)); 13C NMR (CD3OD, 125.7 MHz)
δ 44.9 (NCH2), 73.8 (CH2OCHCO), 74.3 (CH2O
CHCCF3), 79.0 (CHCCF3), 80.2 (CHCO), 88.3 (q,
2
1JCF = 32.5 Hz, CCF3), 124.4 (q, JCF = 286.0 Hz, CF3), 128.1
(CHar), 128.7 (CHar), 129.07 (CHar), 129.15 (CHar), 129.18
(CHar), 129.4 (CHar), 137.9 (CIVar, NBn), 138.3 (CIVar, CF3
CCHOBn), 138.6 (CIVar, OCCHOBn), 173.8
(CO); HRMS (ESI+) m/z calcd for C26H24F3NNaO4 [M + Na]+
494.1555, found 494.1556. trans-2a: white solid; mp 104 °C; [α]2D0 +80
(c 1.00, CHCl3); IR (KBr) νmax 694, 738, 1025, 1062, 1163, 1197,
1256, 1358, 1451, 1498, 1690, 3031, 3184 cm−1; 19F NMR (CDCl3,
235.5 MHz) δ −78.6 (s, 3F, CF3); 19F NMR (CD3OD, 235.5 MHz) δ
−74.6 (s, 3F, CF3); 1H NMR (CD3OD, 500 MHz) δ 4.29 (d, 3J = 8.0
Hz, 1H, CHCCF3), 4.40 (d, 3J = 8.0 Hz, 1H, CHCO), 4.52
(3R,4R)-1-Benzyl-5-hydroxy-3,4-dimethoxy-5-(trifluoromethyl)-
pyrrolidin-2-one (2c). According to General Procedure B, a mixture of
tartrimide 1c (1.2 g, 4.81 mmol), K2CO3 (135 mg, 0.98 mmol, 0.2
equiv), and CF3TMS (2.86 mL, 19.34 mmol, 4 equiv) in DMF (25
mL) was stirred for 7.5 h. After treatment, N,O-acetal 2c (dr = 75:25)
was directly purified on silica gel (PE/EtOAc 3:1) to afford N,O-acetal
2c (1.18 g, 77%, dr = 75:25) as a yellow oil: IR (film) νmax 699, 757,
1075, 1199, 1265, 1350, 1449, 1709, 2841, 2941, 3004, 3280 cm−1; 19
F
2
2
(d, J = 15.5 Hz, 1H, NCHaHb), 4.61 (d, J = 15.5 Hz, 1H, N
NMR (CDCl3, 235.5 MHz) δ −77.4 (s, 3F, CF3, major), −79.7 (s, 3F,
CF3, minor); 1H NMR (CDCl3, 600 MHz) δ 3.53 (s, 3H, CH3O
CHCCF3, major), 3.60 (s, 3H, CH3OCHCO, major),
3.61 (s, 3H, CH3OCHCCF3, minor), 3.64 (s, 3H, CH3
OCHCO, minor), 3.84 (d, 3J = 5.0 Hz, 1H, CHCO,
minor), 3.88 (d, 3J = 5.0 Hz, 1H, CHCCF3, minor), 3.93 (d, 3J =
2
CHaHb), 4.70 (d, J = 11.5 Hz, 1H, CHaHbOCHCCF3),
2
2
4.75 (d, J = 11.5 Hz, 1H, CHaHbOCHCO), 4.93 (d, J =
11.5 Hz, 1H, CHaHbOCHCCF3), 4.97 (d, 2J = 11.5 Hz, 1H,
CHaHbOCHCO), 7.20−7.36 (m, 15H, 15 CHar); 13C
NMR (CD3OD, 125.7 MHz) δ 44.0 (NCH2), 74.2 (CH2O
CHCO), 75.0 (CH2OCHCCF3), 79.5 (CHCO),
3
8.0 Hz, 1H, CHCCF3, major), 4.01 (d, J = 8.0 Hz, 1H, CH
H
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CO, major), 4.32 (d, 2J = 15.5 Hz, 1H, NCHaHb, major), 4.36 (br
methane was stirred at rt under Ar. After the complete conversion of
the starting N,O-acetal (reaction monitored by TLC and 19F NMR),
the reaction was quenched with an aqueous solution of hydrochloric
acid (10%) and extracted twice with CH2Cl2. The combined organic
layers were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was then purified by
chromatography on silica gel (PE/EtOAc).
2
s, 1H, OH, minor), 4.52 (d, J = 15.5 Hz, 1H, NCHaHb, minor),
4.59 (d, 2J = 15.5 Hz, 1H, NCHaHb, minor), 4.70 (d, J = 15.5 Hz,
2
1H, NCHaHb, major), 4.80 (br s, 1H, OH, major), 7.20−7.29 (m,
5H, 5 CHar, major and minor); 13C NMR (CDCl3, 151 MHz) δ 43.4
(NCH2, major), 44.6 (NCH2, minor), 59.3 (CH3OCH
CO, minor), 59.64 (CH3OCHCCF3, minor), 59.7
(CH3OCHCO, major), 60.2 (CH3OCHCCF3,
major), 79.1 (CHCCF3, minor), 80.3 (CHCO, major), 80.8
(CHCO, minor), 85.7 (q, 2JCF = 33.5 Hz, CCF3, minor), 87.8
(2R,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl Acetate (trans-4a). According to a general procedure,
a solution of N,O-acetal trans-2a (1.50 g, 3.18 mmol), pyridine (387
μL, 4.80 mmol, 1.5 equiv), acetic anhydride (510 μL, 5.40 mmol, 1.7
equiv), and DMAP (40 mg, 0.33 mmol, 0.1 equiv) in CH2Cl2 (23 mL)
was stirred for 1.5 h. Purification on silica gel (PE/EtOAc 4:1)
afforded O-acetyl-N,O-acetal trans-4a (1.63 g, 99%) as a colorless oil:
[α]2D0 +33 (c 1.00, CHCl3); IR (film) νmax 699, 1038, 1118, 1206, 1363,
1425, 1741, 2874, 2929, 3032, 3065 cm−1; 19F NMR (CDCl3, 235.5
2
(q, JCF = 31.0 Hz, CCF3, major), 89.7 (CHCCF3, major),
122.7 (q, 1JCF = 286.0 Hz, CF3, minor), 123.2 (q, 1JCF = 288.5 Hz, CF3,
major), 127.6 (CHar, major), 127.8 (CHar, major), 128.2 (CHar,
minor), 128.4 (CHar, minor), 128.7 (CHar, major), 136.2 (CIVar,
minor), 137.0 (CIVar, major), 170.6 (CO, major), 171.7 (CO,
minor); HRMS (ESI+) m/z calcd for C14H16F3NNaO4 [M + Na]+
342.0929, found 342.0921.
1
MHz) δ −75.5 (s, 3F, CF3); H NMR (CDCl3, 600 MHz) δ 1.74 (s,
2
3
3H, CH3), 4.39 (d, J = 15.5 Hz, 1H, NCHaHb), 4.40 (d, J = 7.0
(3R,4R)-1-Benzyl-3,4,5-trihydroxy-5-(trifluoromethyl)pyrrolidin-2-
one (2d). According to General Procedure B, a mixture of tartrimide
1d (2 g, 9.04 mmol), K2CO3 (252 mg, 1.82 mmol, 0.2 equiv), and
CF3TMS (5.40 mL, 36.53 mmol, 4 equiv) in DMF (50 mL) was
stirred for 5 h. After treatment, a solution of the residue and TBAF (9
mL, 9 mmol, 1 equiv) in a mixture of THF/H2O (40 mL) was stirred
for 2 h. Purification of the residue (dr = 89:11) on silica gel (PE/
EtOAc 3:1) afforded N,O-acetal 2d (2.37 g, 90%, dr = 89:11) as a
beige solid: IR (KBr) νmax 698, 959, 1114, 1191, 1354, 1415, 1704,
2925, 3339 cm−1; 19F NMR (CD3OD, 235.5 MHz) δ −78.0 (s, 3F,
CF3, major), −80.6 (s, 3F, CF3, minor); 1H NMR (CD3OD, 500
MHz), major isomer, δ 4.18 (m, 1H, CHCCF3), 4.29 (d, 3J = 8.5
Hz, 1H, CHCO), 4.60 (d, 2J = 11.5 Hz, 1H, CHaHbOCH
2
2
CCF3), 4.63 (d, J = 15.5 Hz, 1H, NCHaHb), 4.69 (d, J = 11.5
2
Hz, 1H, CHaHbOCHCCF3), 4.81 (d, J = 11.5 Hz, 1H,
CHaHbOCHCO), 5.05 (d, 2J = 11.5 Hz, 1H, CHaHbO
3
CHCO), 5.22 (d, J = 7.0 Hz, 1H, CHCCF3), 7.25−7.39
(m, 15H, 15 CHar); 13C NMR (CDCl3, 151 MHz) δ 21.4 (CH3), 44.5
(NCH2), 72.8 (CH2OCHCO), 74.2 (CH2OCH
2
CCF3), 78.9 (CHCO), 80.6 (CHCCF3), 92.1 (q, JCF
=
2
32.0 Hz, CCF3), 122.1 (q, JCF = 288.0 Hz, CF3), 127.7 (CHar),
128.0 (CHar), 128.2 (CHar), 128.3 (CHar), 128.50 (CHar), 128.54
(CHar), 128.55 (CHar), 128.6 (CHar), 135.5 (CIVar, NBn), 136.8
(CIVar, CF3CCHOBn), 137.8 (CIVar, OCCHO
Bn), 168.2 (CH3CO), 171.6 (CO); HRMS (ESI+) m/z calcd
for C28H26F3NNaO5 [M + Na]+ 536.1661, found 536.1669.
2
Hz, 1H, CHCO), 4.49 (d, J = 15.5 Hz, 1H, NCHaHb), 4.55
2
(d, J = 15.5 Hz, 1H, NCHaHb), 7.19−7.22 (m, 1H, CHar), 7.25−
7.30 (m, 4H, 4 CHar); 13C NMR (CD3OD, 125.7 MHz), major
(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl Acetate (cis-4a). According to a general procedure, a
solution of N,O-acetal cis-2a (725 mg, 1.54 mmol), pyridine (188 μL,
2.32 mmol, 1.52 equiv), acetic anhydride (249 μL, 2.63 mmol, 1.7
equiv), and DMAP (19 mg, 0.16 mmol, 0.1 equiv) in CH2Cl2 (15 mL)
was stirred for 3 h. Purification by chromatography (PE/EtOAc 4:1)
afforded O-acetyl-N,O-acetal cis-4a (732 mg, 93%) as a colorless oil:
[α]2D0 +43 (c 0.41, CHCl3); IR (film) νmax 700, 744, 1026, 1137, 1194,
1312, 1353, 1455, 1737, 1770, 2944, 3033, 3064 cm−1; 19F NMR
(CD3OD, 235.5 MHz) δ −75.6 (s, 3F, CF3); 1H NMR (CD3OD, 500
isomer, δ 44.2 (NCH2), 74.1 (CHCO), 83.4 (CHCCF3),
2
1
88.5 (q, JCF = 30.0 Hz, CCF3), 125.0 (q, JCF = 288.0 Hz, CF3),
128.0 (CHar), 128.6 (CHar), 129.2 (CHar), 138.6 (CIVar), 174.1
(CO); HRMS (ESI+) m/z calcd for C12H12F3NNaO4 [M + Na]+
314.0616, found 314.0612.
General Procedure for the Preparation of Oxazoline 3 from
N,O-Acetals 2a and 2d. A solution of α-trifluoromethylated N,O-
acetals 2a and 2d and BF3·Et2O (3 equiv) in acetonitrile was heated at
reflux under Ar. The reaction mixture was cooled to rt, quenched with
a saturated aqueous solution of NaHCO3, and extracted three times
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was then purified by chromatography on silica gel.
2
MHz) δ 1.61 (s, 3H, CH3), 4.27 (d, J = 15.5 Hz, 1H, NCHaHb),
3
3
4.34 (d, J = 5.0 Hz, 1H, CHCCF3), 4.48 (d, J = 5.0 Hz, 1H,
2
CHCO), 4.53 (d, J = 11.5 Hz, 1H, CHaHbOCHC
2
CF32), 4.60 (d, J = 11.5 Hz, 1H, CHaHbOCHCCF3), 4.79
(3aR,6R,6aS)-4-Benzyl-6-hydroxy-2-methyl-3a-(trifluoromethyl)-
6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (3). From 2a,
according to a general procedure, a solution of N,O-acetal 2a (80
mg, 0.17 mmol) and BF3·OEt2 (65 μL, 0.53 mmol, 3 equiv) in
acetonitrile (5 mL) was stirred for 5 h at reflux. Purification on silica
gel (PE/EtOAc 7:1) afforded oxazoline 3 (40 mg, 75%) as a white
solid. From 2d, according to a general procedure, a solution of N,O-
acetal 2d (80 mg, 0.27 mmol) and BF3·OEt2 (101 μL, 0.82 mmol, 3
equiv) in acetonitrile (5 mL) was stirred for 2 h at reflux. Purification
on silica gel (PE/EtOAc 7:1) afforded oxazoline 3 (66 mg, 77%) as a
white solid. Oxazoline 3: mp 114 °C; [α]2D0 +6 (c 0.50, CHCl3); IR
(KBr) νmax 735, 969, 1014, 1127, 1174, 1202, 1337, 1658, 1710, 3390
2
(d, J = 11.5 Hz, 1H, CHaHbOCHCO), 4.89 (d, J = 15.5
Hz, 1H, NCHaHb), 5.04 (d, 2J = 11.5 Hz, 1H, CHaHbOCH
CO), 7.19−7.21 (m, 2H, 2 CHar), 7.26−7.39 (m, 13H, 13 CHar);
13C NMR (CD3OD, 125.7 MHz) δ 20.9 (CH3), 45.1 (NCH2), 73.9
(CH2OCO), 74.2 (CH2OCHCCF3), 79.4 (CH
2
CCF3), 80.7 (CHCO), 91.6 (q, JCF = 32.5 Hz, CCF3),
123.5 (q, 1JCF = 285.5 Hz, CF3), 128.8 (CHar), 128.9 (CHar), 129.08
(CHar), 129.12 (CHar), 129.4 (CHar), 129.5 (CHar), 129.6 (CHar),
129.9 (CHar), 136.8 (CIVar, NBn), 138.2 (CIVar, CF3CCH
OBn), 138.6 (CIVar, OCCHOBn), 170.6 (CH3CO),
174.9 (CO); HRMS (ESI+) m/z calcd for C28H26F3NNaO5 [M +
Na]+ 536.1661, found 536.1658.
1
cm−1; 19F NMR (CD3OD, 235.5 MHz) δ −78.9 (s, 3F, CF3); H
NMR (CD3OD, 500 MHz) δ 2.09 (s, 3H, CH3), 4.39 (d, 3J = 1.5 Hz,
1H, CHCO), 4.49 (d, 2J = 16.0 Hz, 1H, NCHaHb), 4.72 (d, 2J
= 16.0 Hz, 1H, NCHaHb), 4.95 (d, 3J = 1.5 Hz, 1H, CHCCF3),
7.23−7.31 (m, 5H, 5 CHar); 13C NMR (CD3OD, 125.7 MHz) δ 14.0
(CH3), 46.6 (NCH2), 74.0 (CHCO), 85.9 (CHCCF3),
(3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl Acetate (4a). According to a general procedure, a
mixture of N,O-acetal 2a (1.51 g, 3.20 mmol, dr = 86:14), pyridine
(390 μL, 4.83 mmol, 1.5 equiv), acetic anhydride (515 μL, 5.45 mmol,
1.7 equiv), and DMAP (39 mg, 0.32 mmol, 0.1 equiv) in CH2Cl2 (25
mL) was stirred for 5.5 h. Purification on silica gel (PE/EtOAc 7:1)
afforded O-acetyl-N,O-acetal 4a (1.52 g, 92%, dr = 86:14) as a
colorless oil: HRMS (ESI+) m/z calcd for C28H26F3NNaO5 [M + Na]+
536.1661, found 536.1670.
2
1
93.3 (q, JCF = 33.0 Hz, CCF3), 124.3 (q, JCF = 283.0 Hz, CF3),
128.3 (CHar), 128.6 (CHar), 129.2 (CHar), 137.6 (CIVar, NBn),
174.4 (CN), 174.9 (CO); HRMS (ESI+) m/z calcd for
C14H13F3N2NaO3 [M + Na]+ 337.0776, found 337.0768.
General Procedure for the Preparation of O-Acetyl-N,O-
acetals 4a−d from 2a−d. A solution of α-trifluoromethylated N,O-
acetals 2a−d, pyridine, acetic anhydride, and DMAP in dichloro-
(3R,4R)-3,4-Bis(benzyloxy)-1-(4-methoxybenzyl)-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl Acetate (4b). According to a general
procedure, a solution of N,O-acetal 2b (1.08 g, 2.15 mmol, dr =
I
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
71:29), pyridine (260 μL, 3.22 mmol, 1.5 equiv), acetic anhydride
(345 μL, 3.65 mmol, 1.7 equiv), and DMAP (27 mg, 0.22 mmol, 0.1
equiv) in CH2Cl2 (18 mL) was stirred for 19 h. Purification on silica
gel (PE/EtOAc 6:1) afforded O-acetyl-N,O-acetal 4b (972 mg, 83%, dr
= 71:29) as a yellow oil: IR (film) νmax 699, 741, 1032, 1112, 1205,
1317, 1514, 1612, 1736, 1767, 2939, 3032, 3415 cm−1; 19F NMR
(CDCl3, 235.5 MHz) δ −75.4 (s, 3F, CF3, major), −78.0 (s, 3F, CF3,
minor), 60.3 (CH3OCHCCF3, major), 80.6 (CHC
CF3, minor), 80.8 (CHCO, major), 82.0 (CHCO, minor),
2
83.7 (CHCCF3, major), 90.1 (q, JCF = 32.5 Hz, CCF3,
2
1
minor), 92.2 (q, JCF = 32.0 Hz, CCF3, major), 122.1 (q, JCF
=
1
288.0 Hz, CF3, major), 122.2 (q, JCF = 286.0 Hz, CF3, minor), 127.7
(CHar, major), 127.9 (CHar, minor), 128.47 (CHar, minor), 128.52
(CHar, major), 128.54 (CHar, major), 129.3 (CHar, minor), 135.3
(CIVar, minor), 135.5 (CIVar, major), 168.37 (CH3CO, major),
168.38 (CH3CO, minor), 171.2 (CO, major), 172.7 (CO,
minor); HRMS (ESI+) m/z calcd for C16H18F3NNaO5[M + Na]+
384.1035, found 384.1024.
1
minor); H NMR (CDCl3, 500 MHz) δ 1.59 (s, 3H, CH3, minor),
1.78 (s, 3H, CH3, major), 3.783 (s, 3H, OCH3, major), 3.786 (s, 3H,
2
OCH3, minor), 4.12 (d, J = 15.0 Hz, 1H, NCHaHb, minor), 4.29
(d, 3J = 5.5 Hz, 1H, CHCCF3, minor), 4.34 (d, 2J = 15.0 Hz, 1H,
3
NCHaHb, major), 4.39 (d, J = 7.0 Hz, 1H, CHCO, major),
(3R,4R)-1-Benzyl-5-oxo-2-(trifluoromethyl)pyrrolidine-2,3,4-triyl
Triacetate (4d). According to a general procedure, a solution of N,O-
acetal 2d (500 mg, 1.72 mmol, dr = 89:11), pyridine (625 μL, 7.75
mmol, 4.51 equiv), acetic anhydride (810 μL, 8.57 mmol, 5 equiv), and
DMAP (62 mg, 0.51 mmol, 0.3 equiv) in CH2Cl2 (10 mL) was stirred
for 4 h. Purification on silica gel (PE/EtOAc 4:1) afforded O-acetyl-
N,O-acetal 4d (680 mg, 95%, dr = 89:11) as a pale yellow oil: IR (film)
νmax 702, 754, 975, 1039, 1227, 1369, 1434, 1760, 2945, 3029, 3497
cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −75.9 (s, 3F, CF3, major),
3
2
4.55 (d, J = 5.5 Hz, 1H, CHCO, minor), 4.56 (d, J = 11.5 Hz,
2
1H, CHaHbOCHCCF3, minor), 4.59 (d, J = 15.0 Hz, 1H,
2
NCHaHb, major), 4.61 (d, J = 11.5 Hz, 1H, CHaHbOCH
2
CCF3, major), 4.62 (d, J = 11.5 Hz, 1H, CHaHbOCHC
CF3, minor), 4.70 (d, 2J = 11.5 Hz, 1H, CHaHbOCHCCF3,
major), 4.78 (d, 2J = 11.5 Hz, 1H, CHaHbOCHCO, minor),
4.82 (d, 2J = 12.0 Hz, 1H, CHaHbOCHCO, major), 4.99 (d,
2J = 15.0 Hz, 1H, NCHaHb, minor), 5.06 (d, J = 12.0 Hz, 1H,
2
1
CHaHbOCHCO, major), 5.18 (d, 2J = 11.5 Hz, 1H,
−78.7 (s, 3F, CF3, minor); H NMR (CDCl3, 500 MHz) δ 1.54 (s,
3
3H, CH3, minor), 1.81 (s, 3H, CH3, major), 2.07 (s, 3H, CH3, minor),
2.13 (s, 3H, CH3, major), 2.16 (s, 3H, CH3, minor), 2.19 (s, 3H, CH3,
CHaHbOCHCO, minor), 5.22 (d, J = 7.0 Hz 1H, CH
CCF3, major), 6.83 (m, 2H, 2 CHar, major and minor), 7.20−7.40
(m, 12H, 12 CHar, major and minor); 13C NMR (CDCl3, 125.7
MHz) δ 21.0 (CH3, minor), 21.5 (CH3, major), 43.6 (NCH2,
minor), 44.0 (NCH2, major), 55.3 (O−CH3, major), 55.4 (O−CH3,
minor), 72.7 (CH2OCHCO, major), 73.2 (CH2O
CHCO, minor), 73.3 (CH2OCHCCF3, minor), 74.2
(CH2OCHCCF3, major), 78.3 (CHCCF3, minor),
78.9 (CHCCO, major), 79.8 (CHCCO, minor), 80.6
2
2
major), 4.15 (d, J = 15.0 Hz, 1H, NCHaHb, minor), 4.41 (d, J =
2
15.5 Hz, 1H, NCHaHb, major), 4.75 (d, J = 15.5 Hz, 1H, N
2
CHaHb, major), 5.15 (d, J = 15.0 Hz, 1H, NCHa3Hb, minor), 5.71
3
(d, J = 6.0 Hz, 1H, CHCO, minor), 5.77 (d, J = 6.0 Hz, 1H,
CHCCF3, minor), 5.78 (d, 3J = 7.0 Hz, 1H, CHCO, major),
6.41 (d, 3J = 6.0 Hz, 1H, CHCCF3, major), 7.25−7.32 (m, 5H, 5
CHar, major and minor); 13C NMR (CDCl3, 125.7 MHz) δ 20.5
(CH3, major), 20.6 (CH3, minor), 20.7 (CH3, major), 21.1 (CH3,
major), 44.6 (NCH2, minor), 45.9 (NCH2, major), 69.5 (CH
CCF3, minor), 71.2 (CHCO, major), 72.6 (CHCCF3,
2
(CHCCF3, major), 90.4 (q, JCF = 32.5 Hz, CCF3, minor),
2
1
92.1 (q, JCF = 32.0 Hz, CCF3, major), 112.1 (q, JCF = 288.1 Hz,
1
CF3, major), 112.3 (q, JCF = 286.0 Hz, CF3, minor), 113.8 (CHar,
2
minor), 113.9 (CHar, major), 127.60 (CIVar, NCH2Ph, major),
127.66 (CIVar, NCH2Ph, minor), 127.7 (CHar, minor), 128.0
(CHar, major), 128.06 (CHar, minor), 128.13 (CHar, major), 128.15
(CHar, major), 128.3 (CHar, minor), 128.46 (CHar, minor), 128.48
(CHar, minor), 128.5 (CHar, major), 128.6 (CHar, major), 130.0
(CHar, major), 130.6 (CHar, minor), 136.8 (CIVar, CF3CCH
OBn, major), 137.0 (CIVar, CF3CCHOBn, minor), 137.4
(CIVar, OCCHOBn, minor), 137.5 (CIVar, OCCH
OBn, major), 159.1 (CIVar, CH3OAr, major), 159.3 (CIVar,
CH3OAr, minor), 168.2 (CH3CO, major), 168.5 (CH3
CO, minor), 171.6 (CO, major), 173.0 (CO, minor); HRMS
(ESI+) m/z calcd for C29H28F3NNaO6 [M + Na]+ 566.1766, found
566.1765.
major), 73.7 (CHCO, minor), 91.0 (q, JCF = 32.0 Hz, CCF3,
major), 121.9 (q, 1JCF = 286.5 Hz, CF3, minor), 123.9 (q, 1JCF = 288.0
Hz, CF3, major), 128.0 (CHar, major), 128.2 (CHar, minor), 128.63
(CHar, major), 128.66 (CHar, minor), 128.9 (CHar, major), 129.4
(CHar, minor), 134.8 (CIVar, minor), 135.0 (CIVar, major), 168.1
(CO, major), 168.2 (OCO, minor), 168.5 (OCO,
major), 168.6 (OCO, minor), 169.3 (CO, minor), 169.8
(OCO, major), 169.9 (OCO, major), 170.0 (OCO,
minor); HRMS (ESI+) m/z calcd for C18H18F3NNaO7 [M + Na]+
440.0933, found 440.0925.
General Procedures for the Addition of Nitriles on O-Acetyl-
N,O-acetals 4a−d. General Procedure C (with Nitrile as a Solvent).
To a solution of O-acetyl-N,O-acetals 4a−d in nitrile was slowly added,
at rt under Ar, BF3·OEt2 (3 equiv). After stirring of the reaction
mixture at room temperature (with acetals 4a and 4b) or at reflux
(with acetals 4c and 4d) (reaction monitored by TLC and 19F NMR),
the reaction was quenched with a saturated aqueous solution of
NaHCO3 and extracted three times with EtOAc. The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was then purified
by chromatography on silica gel (PE/EtOAc).
General Procedure D (using 10 Equiv of Nitrile in Dichloro-
methane). To a solution of O-acetyl-N,O-acetal 4a and nitrile (10
equiv) in dichloromethane was slowly added, at rt under Ar, BF3·OEt2
(3 equiv). After stirring at room temperature (reaction monitored by
TLC and 19F NMR), the reaction was quenched with a saturated
aqueous solution of NaHCO3 and extracted three times with EtOAc.
The combined organic layers were washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The residue was then
purified by chromatography on silica gel (PE/EtOAc).
(3R,4R)-1-Benzyl-3,4-dimethoxy-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl acetate (4c). According to a general procedure, a
solution of N,O-acetal 2c (1.17 g, 3.67 mmol, dr = 74:26), pyridine
(445 μL, 5.51 mmol, 1.5 equiv), acetic anhydride (590 μL, 6.24 mmol,
1.7 equiv), and DMAP (45 mg, 0.37 mmol, 0.1 equiv) in CH2Cl2 (18
mL) was stirred for 4 h. Purification on silica gel (PE/EtOAc 5:1)
afforded O-acetyl-N,O-acetal 4c (1.20 g, 91%, dr = 75:25) as a
colorless oil: IR (neat) νmax 700, 1014, 1037, 1125, 1180, 1315, 1736,
1767, 2840, 2940 cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −75.8 (s,
1
3F, CF3, major), −78.1 (s, 3F, CF3, minor); H NMR (CDCl3, 500
MHz) δ 1.56 (s, 3H, CH3CO, minor), 1.82 (s, 3H, CH3CO,
major), 3.49 (s, 3H, CH3OCHCCF3, minor), 3.53 (s, 3H,
CH3OCHCCF3, major), 3.70 (s, 3H, CH3OCH
CO, major), 3.73 (s, 3H, CH3OCHCO, minor), 3.97 (d,
3
3J = 5.0 Hz, 1H, CHCCF3, minor), 4.10 (d, J = 7.0 Hz, 1H,
2
CHCO, major), 4.12 (d, J = 15.0 Hz, 1H, NCHaHb, minor),
3
2
4.26 (d, J = 5.0 Hz, 1H, CHCO, minor), 4.38 (d, J = 15.5 Hz,
1H, NCHaHb, major), 4.64 (d, 2J = 15.5 Hz, 1H, NCHaHb,
major), 4.95 (d, 3J = 7.0 Hz, 1H, CHCCF3, major), 5.02 (d, 2J =
15.0 Hz, 1H, NCHaHb, minor), 7.23−7.30 (m, 5H, 5 CHar, major
and minor); 13C NMR (CDCl3, 125.7 MHz) δ 20.7 (CH3CO,
minor), 21.5 (CH3CO, major), 44.1 (NCH2, minor), 44.4
(NCH2, major), 59.2 (CH3OCHCO, major), 59.3
(CH3OCHCO, minor), 59.6 (CH3OCHCCF3,
(3aR,6R,6aS)-4-Benzyl-6-(benzyloxy)-2-methyl-3a-(trifluorometh-
yl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5a). Accord-
ing to General Procedure C, a solution of N,O-acetal 4a (100 mg, 0.19
mmol) and BF3·OEt2 (72 μL, 0.59 mmol, 3 equiv) in acetonitrile (4
mL) was stirred for 31 h at rt. Purification on silica gel (PE/EtOAc
3:1) afforded oxazoline 5a (60 mg, 76%) as a colorless oil: [α]2D0 +50
(c 0.40, CHCl3); IR (film) νmax 704, 738, 978, 1027, 1113, 1195, 1268,
J
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1338, 1402, 1659, 1721, 2927, 3060, 3329 cm−1; 19F NMR (CDCl3,
7.21−7.42 (m, 10H, 10 CHar); 13C NMR (CDCl3, 125.7 MHz) δ 27.4
(CH3), 33.8 (CIV), 45.7 (NCH2), 72.9 (OCH2), 78.0 (CHC
O), 82.2 (CHCCF3), 92.6 (q, 2JCF = 33.0 Hz, CCF3), 123.1 (q,
1JCF = 283.5 Hz, CF3), 127.5 (CHar), 128.31 (CHar), 128.32 (CHar),
128.7 (CHar), 136.5 (CIVar, NBn), 136.7 (CIVar, OBn), 170.9
(CO), 180.5 (CN); HRMS (ESI+) m/z calcd for
C24H25F3N2NaO3 [M + Na]+ 469.1715, found 469.1714.
1
235.5 MHz) δ −77.2 (s, 3F, CF3); H NMR (CDCl3, 600 MHz) δ
2.07 (s, 3H, CH3), 4.19 (d, 3J = 1.5 Hz, 1H, CHCO), 4.56 (d, 2J
= 15.5 Hz, 1H, NCHaHb), 4.78 (d, 2J = 15.5 Hz, 1H, NCHaHb),
2
3
4.91 (d, J = 12.0 Hz, 1H, OCHaHb), 4.92 (d, J = 1.5 Hz, 1H,
2
CHCCF3), 5.03 (d, J = 12.0 Hz, 1H, OCHaHb), 7.26−7.45
(m, 10H, 10 CHar); 13C NMR (CDCl3, 151 MHz) δ 14.3 (CH3), 45.7
(NCH2), 72.9 (OCH2), 77.6 (CHCO), 82.4 (CHC
(3aR,6R,6aS)-4-Benzyl-6-(benzyloxy)-2-phenyl-3a-(trifluorometh-
yl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5e). Accord-
ing to General Procedure C, a solution of N,O-acetal 4a (200 mg, 0.39
mmol) and BF3·OEt2 (150 μL, 1.22 mmol, 3.1 equiv) in benzonitrile
(5 mL) was stirred for 40 h at rt. Purification on silica gel (PE/EtOAc
10:1) afforded oxazoline 5e (150 mg, 83%) as a colorless oil: [α]2D0 +72
(c 0.51, CHCl3); IR (film) νmax 701, 735, 1027, 1121, 1197, 1349,
1452, 1496, 1581, 1640, 1724, 2926, 3033, 3065 cm−1; 19F NMR
2
1
CF3), 92.4 (q, JCF = 33.0 Hz, CCF3), 122.8 (q, JCF = 283.5 Hz,
CF3), 127.5 (CHar), 127.9 (CHar), 128.30 (CHar), 128.36 (CHar),
128.39 (CHar), 128.7 (CHar), 136.1 (CIVar, NBn), 136.6 (CIVar,
OBn), 171.1 (CN), 171.8 (CO); HRMS (ESI+): m/z calcd for
C21H19F3N2NaO3 [M + Na]+ 427.1245, found 427.1241.
(3aR,6R,6aS)-6-(Benzyloxy)-4-(4-methoxybenzyl)-2-methyl-3a-
(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one
(5b). According to General Procedure C, a solution of N,O-acetal 4b
(250 mg, 0.46 mmol) and BF3·OEt2 (170 μL, 1.38 mmol, 3 equiv) in
acetonitrile (6 mL) was stirred for 28 h at rt. Purification on silica gel
(PE/EtOAc 2:1) afforded oxazoline 5b (140 mg, 70%) as a yellow oil:
[α]2D0 +35 (c 0.50, CHCl3); IR (film) νmax 702, 978, 1029, 1111, 1176,
1247, 1303, 1338, 1400, 1513, 1695, 1722, 2935, 3418 cm−1; 19F NMR
1
(CDCl3, 235.5 MHz) δ −76.8 (s, 3F, CF3); H NMR (CDCl3, 600
MHz) δ 4.27 (d, 3J = 1.5 Hz, 1H, CHCO), 4.71 (d, 2J = 15.5 Hz,
1H, NCHaHb), 4.73 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.92 (d, 2J =
2
12.0 Hz, 1H, OCHaHb), 5.05 (d, J = 12.0 Hz, 1H, OCHaHb),
3
5.07 (d, J = 1.5 Hz, 1H, CHCCF3), 7.21−7.45 (m, 12H, 12
CHar), 7.56 (t, 3J = 7.5 Hz, 1H, 1 CHar), 7.87 (m, 2H, 2 CHar); 13
C
1
(CDCl3, 235.5 MHz) δ −77.2 (s, 3F, CF3); H NMR (CDCl3, 500
NMR (CDCl3, 151 MHz) δ 45.8 (NCH2), 73.0 (OCH2), 77.8
3
2
MHz) δ 2.04 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.13 (d, J = 1.0
(CHCO), 82.5 (CHCCF3), 92.7 (q, JCF = 33.0 Hz, C
2
1
Hz, 1H, CHCO), 4.47 (d, J = 15.0 Hz, 1H, NCHaHb), 4.67
CF3), 123.1 (q, JCF = 283.5 Hz, CF3), 125.4 (CIVar, NCPh),
(d, 2J = 15.0 Hz, 1H, NCHaHb), 4.86 (s, 1H, CHCCF3), 4.87
127.5 (CHar), 128.2 (CHar), 128.36 (CHar), 128.38 (CHar), 128.4
(CHar), 128.72 (CHar), 128.73 (CHar), 129.3 (CHar), 133.4
(CHar), 136.3 (CIVar, NBn), 136.7 (CIVar, OBn), 169.2 (C
N), 170.9 (CO); HRMS (ESI+) m/z calcd for C26H21F3N2NaO3 [M
+ Na]+ 489.1402, found 489.1408.
2
2
(d, J = 12.0 Hz, 1H, OCHaHb), 4.99 (d, J = 12.0 Hz, 1H, O
CHaHb), 6.83 (m, 2H, 2 CHar), 7.27 (m, 2H, 2 CHar), 7.31−7.42 (m,
5H, 5 CHar); 13C NMR (CDCl3, 125.7 MHz) δ 14.3 (CH3), 45.3
(NCH2), 55.3 (OCH3), 72.9 (OCH2), 77.6 (CHCO),
2
82.5 (CHCCF3), 92.4 (q, JCF = 33.0 Hz, CCF3), 113.7
(3aR,6R,6aS)-2,4-Dibenzyl-6-(benzyloxy)-3a-(trifluoromethyl)-
6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5f). According to
General Procedure D, a solution of N,O-acetal 4a (150 mg, 0.29
mmol), benzyl cyanide (340 μL, 2.95 mmol, 10 equiv), and BF3·OEt2
(108 μL, 0.88 mmol, 3.05 equiv) in CH2Cl2 (3 mL) was stirred for 48
h at rt. Purification on silica gel (PE/EtOAc 7:1) afforded oxazoline 5f
(88 mg, 63%) as a pale yellow oil: [α]2D0 +14 (c 0.50, CHCl3); IR
(film) νmax 700, 980, 1026, 1110, 1175, 1337, 1398, 1455, 1497, 1653,
1724, 2928, 3033, 3064 cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −77.1
(CHar), 122.9 (q, 1JCF = 283.5 Hz, CF3), 128.3 (CHar), 128.32 (CIVar,
NCH2Ph), 128.4 (CHar), 128.7 (CHar), 129.6 (CHar), 136.6
(CIVar, OBn), 159.0 (CIVar, CH3OPh), 170.9 (CO), 171.7
(CN); HRMS (ESI+) m/z calcd for C22H21F3N2NaO4 [M + Na]+
457.1351, found 457.1342.
(3aR,6R,6aS)-4-Benzyl-6-(benzyloxy)-2-isopropyl-3a-(trifluoro-
methyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5c). Ac-
cording to General Procedure C, a solution of N,O-acetal 4a (250 mg,
0.49 mmol) and BF3·OEt2 (180 μL, 1.46 mmol, 3 equiv) in
isobutyronitrile (4 mL) was stirred for 48 h at rt. Purification on
silica gel (PE/EtOAc 9:1) afforded oxazoline 5c (175 mg, 83%) as a
colorless oil: [α]2D0 +18 (c 0.50, CHCl3); IR (film) νmax 700, 979, 1028,
1189, 1330, 1400, 1650, 1723, 2879, 2979, 3033, 3426 cm−1; 19F NMR
1
2
(s, 3F, CF3); H NMR (CDCl3, 600 MHz) δ 3.62 (d, J = 15.0 Hz,
2
1H, NCCHaHb), 3.66 (d, J = 15.0 Hz, 1H, NCCHaHb),
4.07 (d, 3J = 1.5 Hz, 1H, CHCO), 4.62 (d, 2J = 15.5 Hz, 1H, N
CHaHb), 4.70 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.83 (d, 2J = 12.0 Hz,
1H, OCHaHb), 4.90 (d, 3J = 1.5 Hz, 1H, CHCCF3), 4.96 (d, 2J
= 12.0 Hz, 1H, OCHaHb), 7.15 (m, 2H, 2 CHar), 7.27−7.37 (m,
13H, 13 CHar); 13C NMR (CDCl3, 151 MHz) δ 34.8 (CH2CN),
45.8 (NCH2), 72.9 (OCH2), 77.6 (CHCO), 82.6 (CH
1
(CDCl3, 235.5 MHz) δ −77.2 (s, 3F, CF3); H NMR (CDCl3, 500
3
3
MHz) δ 1.11 (d, J = 7.0 Hz, 3H, CH3), 1.13 (d, J = 7.0 Hz, 3H,
3
3
CH3), 2.56 (hept, J = 7.0 Hz, 1H, CH(CH3)2), 4.13 (d, J = 1.5 Hz,
1H, CHCO), 4.46 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.67 (d, 2J
= 15.5 Hz, 1H, NCHaHb), 4.87 (d, 3J = 1.5 Hz, 1H, CHCCF3),
2
1
CCF3), 92.4 (q, JCF = 33.0 Hz, CCF3), 122.9 (q, JCF = 283.5
Hz, CF3), 127.6 (CHar), 127.7 (CHar), 128.1 (CHar), 128.3 (CHar),
128.35 (CHar), 128.4 (CHar), 128.7 (CHar), 128.9 (CHar), 129.0
(CHar), 133.1 (CIVar, NCBn), 136.1 (CIVar, NBn), 136.5
(CIVar, OBn), 170.9 (CO), 172.8 (CN); HRMS (ESI+) m/z
calcd for C27H23F3N2NaO3 [M + Na]+ 503.1558, found 503.1550.
(3aR,6R,6aS)-4-Benzyl-6-(benzyloxy)-2-((E)-prop-1-en-1-yl)-3a-
(trifluoromethyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one
(5g). According to General Procedure C, a solution of N,O-acetal 4a
(205 mg, 0.40 mmol) and BF3·OEt2 (149 μL, 1.20 mmol, 3 equiv) in
allyl cyanide (3 mL) was stirred for 21 h at rt. Purification of the
residue by chromatography (PE/EtOAc 6:1) afforded oxazoline 5g
(152 mg, 89%) as a colorless oil: [α]2D0 +22 (c 0.50, CHCl3); IR (film)
νmax 701, 736, 973, 1031, 1113, 1191, 1351, 1398, 1605, 1670, 1722,
2923, 3034, 3422 cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −77.1 (s,
2
2
4.88 (d, J = 12.0 Hz, 1H, OCHaHb), 5.00 (d, J = 12.0 Hz, 1H,
OCHaHb), 7.23−7.35 (m, 6H, 6 CHar), 7.37−7.43 (m, 4H, 4
CHar); 13C NMR (CDCl3, 125.7 MHz) δ 19.2 (CH3), 19.3 (CH3),
28.5 (CH(CH3)2), 45.7 (NCH2), 72.9 (OCH2), 77.8 (CHC
O), 82.1 (CHCCF3), 92.4 (q, 2JCF = 33.0 Hz, CCF3), 123.0 (q,
1JCF = 283.5 Hz, CF3), 127.5 (CHar), 128.2 (CHar), 128.3 (CHar),
128.33 (CHar), 128.7 (CHar), 136.4 (CIVar, NBn), 136.7 (CIVar
OBn), 170.9 (CO), 178.5 (CN); HRMS (ESI+) m/z calcd for
C23H23F3N2NaO3 [M + Na]+ 455.1558, found 455.1552.
(3aR,6R,6aS)-4-Benzyl-6-(benzyloxy)-2-(tert-butyl)-3a-(trifluoro-
methyl)-6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5d). Ac-
cording to General Procedure C, a solution of N,O-acetal 4a (300 mg,
0.58 mmol) and BF3·OEt2 (216 μL, 1.75 mmol, 3 equiv) in
trimethylacetonitrile (4 mL) was stirred for 41 h at rt. Purification
on silica gel (PE/EtOAc 10:1) afforded oxazoline 5d (199 mg, 76%) as
a yellow oil: [α]2D0 +2 (c 0.50, CHCl3); IR (film) νmax 699, 980, 1028,
1
3
4
3F, CF3); H NMR (CDCl3, 500 MHz) δ 1.92 (dd, J = 7.0 Hz, J =
2
1.5 Hz, 3H, CH3), 4.18 (s, 1H, CHCO), 4.55 (d, J = 15.5 Hz,
1H, NCHaHb), 4.75 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.89 (d, 2J =
1106, 1197, 1338, 1400, 1643, 1723, 2875, 2976, 3034, 3423 cm−1; 19
F
12.0 Hz, 1H, OCHaHb), 4.91 (s, 1H, CHCCF3), 5.02 (d, 2J =
1
3
4
NMR (CDCl3, 235.5 MHz) δ −77.2 (s, 3F, CF3); H NMR (CDCl3,
500 MHz) δ 1.11 (s, 9H, 3 CH3), 4.10 (d, 3J = 1.5 Hz, 1H, CHC
O), 4.61 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.71 (d, 2J = 15.5 Hz, 1H,
12.0 Hz, 1H, OCHaHb), 5.95 (dq, J = 16.0 Hz, J = 1.5 Hz, 1H,
3
3
CHCHCH3), 6.81 (dq, J = 16.0 Hz, J = 7.0 Hz, 1H, CH
CHCH3), 7.24−7.35 (m, 6H, 6 CHar), 7.40 (m, 4H, 4 CHar); 13C
NMR (CDCl3, 125.7 MHz) δ 18.8 (CH3), 45.8 (NCH2), 72.9
=
3
2
NCHaHb), 4.85 (d, J = 1.5 Hz, 1H, CHCCF3), 4.87 (d, J =
2
12.0 Hz, 1H, OCHaHb), 5.00 (d, J = 12.0 Hz, 1H, OCHaHb),
(OCH2), 77.8 (CHCO), 81.9 (CHCCF3), 92.3 (q, 2JCF
K
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
33.0 Hz, CCF3), 117.4 (CHCHCH3), 123.0 (q, JCF = 283.5
Hz, CF3), 127.4 (CHar), 128.0 (CHar), 128.31 (CHar), 128.34
(CHar), 128.4 (CHar), 128.7 (CHar), 136.2 (CIVar, NBn), 136.7
(CIVar, OBn), 145.3 (CHCH3), 168.3 (CN), 171.1 (CO);
HRMS (ESI+) m/z calcd for C23H21F3N2NaO3 [M + Na]+ 453.1402,
found 453.1408.
3H, CH3(CO)NH), 2.06 (s, 3H, CH3(CO)OCH
CCF3), 2.15 (s, 3H, CH3(CO)OCHCO), 4.23 (d,
2J = 15.5 Hz, 1H, NCHaHb), 4.90 (d, 2J = 15.5 Hz, 1H, N
CHaHb), 5.75 (d, 3J = 6.0 Hz, 1H, CHCCF3), 5.82 (s, 1H, NH),
3
5.85 (d, J = 6.0 Hz, 1H, CHCO), 7.26−7.31 (m, 5H, 5 CHar);
13C NMR (CDCl3, 125.7 MHz) δ 20.6 (CH3(CO)OCH
CCF3), 20.7 (CH3(CO)OCHCO), 23.1
(CH3(CO)NH), 44.6 (NCH2), 70.0 (CHCCF3),
(3aR,6R,6aR)-4-Benzyl-6-methoxy-2-methyl-3a-(trifluoromethyl)-
6,6a-dihydro-3aH-pyrrolo[2,3-d]oxazol-5(4H)-one (5h) and
(2R,3S,4R)-N-1-Benzyl-3,4-dimethoxy-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl)acetamide (cis-7a). According to General Procedure
C, a solution of N,O-acetal 4c (160 mg, 0.44 mmol) and BF3·OEt2
(165 μL, 1.34 mmol, 3 equiv) in acetonitrile (4 mL) was stirred for 1.5
h at reflux. Purification of the residue (5h/cis-7a 87:13) on silica gel
(PE/EtOAc 4:1 to 3:2) afforded oxazoline 5h (98 mg, 68%) followed
by amide cis-7a (21 mg, 13%). Oxazoline 5h: white solid; mp 66 °C;
[α]2D0 +5 (c 0.41, CHCl3); IR (neat) νmax 696, 709, 727, 963, 1016,
1171, 1192, 1314, 1651, 1724, 2925 cm−1; 19F NMR (CDCl3, 235.5
2
74.2 (CHCO), 75.6 (q, JCF = 30.5 Hz, CCF3), 123.2 (q,
1JCF = 289.0 Hz, CF3), 127.9 (CHar), 128.5 (CHar), 128.6 (CHar),
135.5 (CIVar, NBn), 169.1 (OCCHCCF3), 169.4 (C
O), 170.1 (OCOCHCO), 170.5 (OCNH); HRMS
(ESI+) m/z calcd for C18H19F3N2NaO6 [M + Na]+ 439.1093, found
439.1097. An analytical sample of cis-7b was crystallized from hexane/
CH2Cl2.
General Procedures for the Synthesis of Amides 6a−j and
Amine 8. General Procedure E (Acid Hydrolysis of Oxazolines 5a−
f,h). A solution of oxazolines 5a−f,h in MeOH and 6 N aqueous HCl
(1:1 mixture) was stirred at room temperature (synthesis of amides 6)
or at 60 °C (synthesis of amine 8). After completion of the reaction
(reaction monitored by TLC and 19F NMR), the mixture was
neutralized with solid NaHCO3 and extracted five times with EtOAc.
The combined organic layers were washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The residue was then
purified by chromatography on silica gel (PE/EtOAc).
General Procedure F (Reaction Sequence “Addition of Nitrile−
Acid Hydrolysis“ on N,O-Acetal 4a or 2d). To a solution of α-
trifluoromethylated N,O-acetal 4a or 2d in nitrile or a solution of α-
trifluoromethylated O-acetyl-N,O-acetal 4a and nitrile (10 equiv) in
dichloromethane was slowly added, at rt under Ar, BF3·OEt2 (3 equiv).
After stirring at room temperature (with 4a) or at reflux (with 2d)
(reaction monitored by TLC and 19F NMR), the reaction was
quenched with a saturated aqueous solution of NaHCO3 and extracted
three times with EtOAc. The combined organic layers were washed
with brine, dried (MgSO4), and concentrated under reduced pressure.
The resulting residue was then dissolved in MeOH and 6 N aq HCl
(1:1 mixture) at room temperature (reaction monitored by TLC and
19F NMR). The reaction mixture was neutralized with solid NaHCO3
1
MHz) δ −77.3 (s, 3F, CF3); H NMR (CDCl3, 500 MHz) δ 2.06 (s,
3
3H, NCCH3), 3.66 (s, 3H, OCH3), 3.98 (d, J = 1.0 Hz, 1H,
2
2
CHCO), 4.50 (d, J = 15.5 Hz, 1H, NCHaHb), 4.75 (d, J =
3
15.5 Hz, 1H, NCHaHb), 4.84 (d, J = 1.0 Hz, 1H, CHCCF3),
7.22−7.31 (m, 5H, 5 CHar); 13C NMR (CDCl3, 125.7 MHz) δ 14.3
(NCCH3), 45.7 (NCH22), 59.2 (CH3), 80.6 (CHCO),
81.9 (CHCCF3), 92.4 (q, JCF = 33.0 Hz, CCF3), 122.8 (q,
1JCF = 283.5 Hz, CF3), 127.5 (CHar), 127.9 (CHar), 128.4 (CHar),
136.0 (CIVar, NBn), 170.8 (CO), 171.8 (CN); HRMS (ESI+)
m/z calcd for C15H15F3N2NaO3 [M + Na]+ 351.0932, found 351.0925.
Amide cis-7a: pale yellow solid; mp 148 °C; [α]2D0 +44 (c 0.41,
CHCl3); IR (neat) νmax 696, 720, 1085, 1115, 1155, 1179, 1263, 1307,
1696, 2923, 3051, 3210 cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −77.5
(s, 3F, CF3); 1H NMR (CDCl3, 600 MHz) δ 1.66 (s, 3H, H3CC
O), 3.47 (s, 3H, H3COCHCCF3), 3.74 (s, H3CO
CHCO), 3.93 (d, 3J = 6.0 Hz, 1H, CHCCF3), 4.23 (d, 2J =
3
15.5 Hz, 1H, NCHaHb), 4.40 (d, J = 6.0 Hz, 1H, CHCO),
4.76 (d, 2J = 15.5 Hz, 1H, NCHaHb), 5.77 (s, 1H, NH), 7.21−7.27
(m, 5H, 5 CHar); 13C NMR (CDCl3, 151 MHz) δ 23.5 (H3CC
O), 44.3 (NCH2), 59.22 (H3COCHCCF3), 59.23
2
(H3COCHCO), 76.1 (q, JCF = 30.0 Hz, CCF3), 80.9
1
(CHCCF3), 82.2 (CHCO), 123.5 (q, JCF = 287.0 Hz,
and extracted five times with EtOAc. The combined organic layers
were washed with brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was then purified by chromatography
on silica gel (PE/EtOAc).
CF3), 127.5 (CHar), 128.4 (CHar), 128.5 (CHar), 136.1 (CIVar, N
Bn), 170.7 (H3CCO), 172.9 (CO); HRMS (ESI+) m/z calcd
for C16H19F3N2NaO4 [M + Na]+ 383.1195, found 383.1189. An
analytical sample of cis-7a was crystallized from CHCl3/pentane.
(3S,4R)-2-Acetamido-1-benzyl-5-oxo-2-(trifluoromethyl)-
pyrrolidine-3,4-diyl Diacetate (7b). According to General Procedure
C, a solution of N,O-acetal 4d (130 mg, 0.31 mmol) and BF3·OEt2
(115 μL, 0.93 mmol, 3 equiv) in acetonitrile (5 mL) was stirred for 6 h
at reflux. Purification of the residue (dr = 15:85) on silica gel (PE/
EtOAc 1:1) afforded amide trans-7b (8 mg, 6%) followed by amide cis-
7b (82 mg, 63%). Amide trans-7b: white solid; mp 196 °C; [α]2D0 −4 (c
0.50, CH2Cl2); IR (KBr) νmax 702, 1070, 1184, 1231, 1370, 1554,
1716, 1761, 2939, 3045, 3214, 3283 cm−1; 19F NMR (CDCl3, 235.5
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)acetamide (6a). From 5a, according
to General Procedure E, a solution of oxazoline 5a (70 mg, 0.38
mmol) in MeOH and 6 N aq HCl (8 mL) was stirred for 40 min at rt.
Purification on silica gel (PE/EtOAc 1:1) afforded hydroxylamide 6a
(68 mg, 93%) as a white solid. From 4a, according to General
Procedure F, a solution of N,O-acetal 4a (2.5 g, 4.87 mmol) and BF3·
OEt2 (1.80 μL, 14.58 mmol, 3 equiv) in acetonitrile (40 mL) was
stirred for 28 h at rt. A solution of the resulting residue in MeOH and
6 N aq HCl (12 mL) was stirred for 1 h at rt. Purification on silica gel
(PE/EtOAc 1:1) afforded hydroxylamide 6a (1.40 g, 68%) as a white
solid. Hydroxylamide 6a: mp 141 °C; [α]2D0 +17 (c 0.50, CH2Cl2); IR
(KBr) νmax 702, 751, 1016, 1118, 1168, 1297, 1573, 1681, 1714, 2930,
3094, 3290 cm−1; 19F NMR (CDCl3 neutralized on basic Al2O3, 235.5
1
MHz) δ −75.0 (s, 3F, CF3); H NMR (CDCl3, 500 MHz) δ 1.87 (s,
3H, CH3(CO)NH), 2.11 (s, 3H, CH3(CO)OCH
CO), 2.18 (s, 3H, CH3(CO)OCHCCF3), 4.48 (d,
2J = 15.5 Hz, 1H, NCHaHb), 4.51 (d, 2J = 15.5 Hz, 1H, N
3
CHaHb), 5.82 (d, J = 7.5 Hz, 1H, CHCO), 6.08 (s, 1H, NH),
1
6.55 (d, 3J = 7.5 Hz, 1H, CHCCF3), 7.23−7.30 (m, 5H, 5 CHar);
13C NMR (CDCl3, 125.7 MHz) δ 20.6 (CH3(CO)OCH
CCF3), 20.8 (CH3(CO)OCHCO), 23.7
(CH3(CO)NH), 44.7 (NCH2), 70.8 (CHCO), 73.0
MHz) δ −77.4 (s, 3F, CF3); H NMR (CDCl3 neutralized on basic
3
Al2O3, 600 MHz) δ 1.40 (s, 3H, CH3), 2.99 (d, J = 11.0 Hz, 1H,
OH), 3.97 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.46 (dd, 3J = 11.0 Hz,
3J = 6.0 Hz, 1H, CHCCF3), 4.64 (d, 3J = 6.0 Hz, 1H, CHC
O), 4.92 (d, 2J = 12.0 Hz, 1H, OCHaHb), 5.11 (d, 2J = 12.0 Hz, 1H,
2
1
(CHCCF3), 76.5 (q, JCF = 29.5 Hz, CCF3), 122.9 (q, JCF
=
2
OCHaHb), 5.22 (d, J = 15.5 Hz, 1H, NCHaHb), 5.80 (s, 1H,
289.0 Hz, CF3), 127.7 (CHar), 128.1 (CHar), 128.6 (CHar), 135.6
(CIVar, NBn), 168.1 (CO), 170.10 (OCOCHCO),
170.12 (OCCHCCF3), 170.8 (OCNH); HRMS
(ESI+) m/z calcd for C18H19F3N2NaO6 [M + Na]+ 439.1093, found
439.1099. Amide cis-7b: white solid; mp 199 °C; [α]2D0 +33 (c 0.51,
CH2Cl2); IR (KBr) νmax 707, 1020, 1089, 1183, 1234, 1303, 1370,
1414, 1548, 1709, 1759, 3056, 3309 cm−1; 19F NMR (CDCl3, 235.5
NH), 7.25−7.32 (m, 6H, 6 CHar), 7.36 (t, 3J = 7.5 Hz, 2H, 2 CHar),
3
7.45 (d, J = 7.5 Hz, 2H, 2 CHar); 13C NMR (CDCl3 neutralized on
basic Al2O3, 151 MHz) δ 23.1 (CH3), 44.1 (NCH2), 73.2 (O
2
CH2), 74.6 (CHCCF3), 76.7 (q, JCF = 29.5 Hz, CCF3), 80.7
1
(CHCO), 123.8 (q, JCF = 283.5 Hz, CCF3), 128.0 (CHar),
128.1 (CHar), 128.2 (CHar), 128.4 (CHar), 128.6 (CHar), 129.0
1
MHz) δ −77.8 (s, 3F, CF3); H NMR (CDCl3, 500 MHz) δ 1.64 (s,
(CHar), 136.3 (CIVar, NBn), 137.5 (CIVar, OBn), 171.8 (CO),
L
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
172.9 (NHCO); HRMS (ESI+) m/z calcd for C21H21F3N2NaO4
136.4 (CIVar, NBn), 137.7 (CIVar, OBn), 172.0 (CO), 180.7
(NHCO); HRMS (ESI+) m/z calcd for C24H27F3N2NaO4 [M +
Na]+ 487.1821, found 487.1817.
[M + Na]+ 445,1351, found 445.1351.
N-((2R,3S,4R)-4-(Benzyloxy)-3-hydroxy-1-(4-methoxybenzyl)-5-
oxo-2-(trifluoromethyl)pyrrolidin-2-yl)acetamide (6b). According to
General Procedure E, a solution of oxazoline 5b (110 mg, 0.25 mmol)
in MeOH and 6 N aq HCl (10 mL) was stirred for 3.5 h at rt.
Purification on silica gel (PE/EtOAc 1:2) afforded hydroxylamide 6b
(92 mg, 80%) as a white solid: mp 168 °C; [α]2D0 +8 (c 0.50, CH2Cl2);
IR (KBr) νmax 1025, 1109, 1177, 1253, 1301, 1514, 1675, 1711, 3102,
3234, 3297 cm−1; 19F NMR (CDCl3 neutralized on basic Al2O3, 235.5
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)benzamide (6e). According to Gen-
eral Procedure E, a solution of oxazoline 5e (168 mg, 0.36 mmol) in
MeOH and 6 N aq HCl (12 mL) was stirred for 46 h at rt. Purification
on silica gel (PE/EtOAc 3:1) afforded hydroxylamide 6e (120 mg,
69%) as a white solid: mp 74 °C; [α]2D0 +72 (c 0.40, CH2Cl2); IR
(KBr) νmax 701, 1000, 1113, 1178, 1279, 1532, 1713, 2930, 3064, 3387
cm−1; 19F NMR (CDCl3 neutralized on basic Al2O3, 235.5 MHz) δ
−77.4 (s, 3F, CF3); 1H NMR (CDCl3 neutralized on basic Al2O3, 600
1
MHz) δ −77.5 (s, 3F, CF3); H NMR (CDCl3 neutralized on basic
3
Al2O3, 500 MHz) δ 1.47 (s, 3H, CH3), 2.94 (d, J = 11.0 Hz, 1H,
OH), 3.76 (s, 3H, OCH3), 3.92 (d, 2J = 15.5 Hz, 1H, NCHaHb),
3
2
MHz) δ 3.10 (d, J = 10.5 Hz, 1H, OH), 4.07 (d, J = 15.5 Hz, 1H,
NCHaHb), 4.58 (dd, 3J = 10.5 Hz, 3J = 6.0 Hz, 1H, CHCCF3),
4.81 (d, 3J = 6.0 Hz, 1H, CHCO), 4.96 (d, 2J = 11.5 Hz, 1H, O
4.44 (dd, 3J = 11.0 Hz, 3J = 6.0 Hz, 1H, CHCCF3), 4.62 (d, 3J =
2
6.0 Hz, 1H, CHCO), 4.91 (d, J = 11.5 Hz, 1H, OCHaHb),
2
2
2
2
5.10 (d, J = 11.5 Hz, 1H, OCHaHb), 5.16 (d, J = 15.5 Hz, 1H,
NCHaHb), 5.79 (s, 1H, NH), 6.83 (m, 2H, 2 CHar), 7.18 (m, 2H, 2
CHar), 7.30 (m, 1H, CHar), 7.37 (m, 2H, 2 CHar), 7.44 (m, 2H, 2
CHar); 13C NMR (CDCl3 neutralized on basic Al2O3, 125.7 MHz) δ
23.3 (CH3), 43.5 (NCH2), 55.5 (OCH3), 73.2 (OCH2), 74.6
(CHCCF3), 76.7 (q, 2JCF = 29.5 Hz, CCF3), 80.7 (CHC
CHaHb), 5.17 (d, J = 11.5 Hz, 1H, OCHaHb), 5.19 (d, J = 15.5
3
Hz, 1H, NCHaHb), 6.35 (s, 1H, NH), 6.91 (t, J = 7.5 Hz, 1H,
3
3
CHar), 7.05 (t, J = 7.5 Hz, 2H, 2 CHar), 7.21 (t, J = 7.5 Hz, 3H, 3
CHar), 7.29 (m, 5H, 5 CHar), 7.38 (t, 3J = 7.5 Hz, 2H, 2 CHar), 7.48
(m, 3H, 3 CHar); 13C NMR (CDCl3 neutralized on basic Al2O3, 151
MHz) δ 44.3 (NCH2), 73.4 (OCH2), 74.8 (CHCCF3), 77.2
1
2
1
O), 114.3 (CHar), 123.8 (q, JCF = 287.5 Hz, CF3), 128.1 (CHar),
(q, JCF = 29.0 Hz, CCF3), 80.9 (CHCO), 123.9 (q, JCF
=
128.2 (CHar), 128.4 (CIVar, NCH2Ph), 128.6 (CHar), 129.7
(CHar), 137.5 (CIVar, OBn), 159.3 (CIVar, CH3OPh), 171.7
(CO), 172.7 (NHCO); HRMS (ESI+) m/z calcd for
C22H23F3N2NaO5 [M + Na]+ 475.1457, found 475.1465.
287.5 Hz, CF3), 127.0 (CHar), 127.7 (CHar), 128.0 (CHar), 128.1
(CHar), 128.2 (CHar), 128.58 (CHar), 128.61 (CHar), 128.8
(CHar), 131.8 (CIVar, NHCOPh), 132.9 (CHar), 135.9 (CIVar,
NBn), 137.6 (CIVar, OBn), 168.8 (NHCO), 172.0 (CO);
HRMS (ESI+) m/z calcd for C26H23F3N2NaO4 [M + Na]+ 507.1508,
found 507.1516.
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)isobutyramide (6c). According to
General Procedure E, a solution of oxazoline 5c (125 mg, 0.29
mmol) in MeOH and 6 N aq HCl (10 mL) was stirred for 4 h at rt.
Purification on silica gel (PE/EtOAc 3:1) afforded hydroxylamide 6c
(111 mg, 85%) as a white solid: mp 127 °C; [α]2D0 +25 (c 0.50,
CH2Cl2); IR (KBr) νmax 700, 1109, 1182, 1230, 1295, 1551, 1667,
1707, 2975, 3067, 3282 cm−1; 19F NMR (CDCl3 neutralized on basic
Al2O3, 235.5 MHz) δ −77.6 (s, 3F, CF3); 1H NMR (CDCl3
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)-2-phenylacetamide (6f). From 5f,
according to General Procedure E, a solution of oxazoline 5f (90 mg,
0.19 mmol) in MeOH and 6 N aq HCl (8 mL) was stirred for 4 h at rt.
Purification on silica gel (PE/EtOAc 2:1) afforded hydroxylamide 6f
(88 mg, 94%) as a white solid. From 4a, according to General
Procedure F, a solution of N,O-acetal 4a (250 mg, 0.486 mmol),
benzyl cyanide (560 μL, 4.85 mmol, 10 equiv), and BF3·OEt2 (180 μL,
1.46 mmol, 3 equiv) in dichloromethane (40 mL) was stirred for 48 h
at rt. A solution of the resulting residue in MeOH and 6 N aq HCl (12
mL) was stirred for 2 h at rt. Purification on silica gel (PE/EtOAc 3:1)
afforded hydroxylamide 6f (140 mg, 58%) as a white solid.
Hydroxylamide 6f: mp 98 °C; [α]2D0 +8 (c 0.50, CH2Cl2); IR (KBr)
νmax 699, 1079, 1112, 1177, 1299, 1549, 1707, 2928, 3034, 3064, 3300,
3403 cm−1; 19F NMR (CDCl3 neutralized on basic Al2O3, 235.5 MHz)
3
neutralized on basic Al2O3, 500 MHz) δ 0.80 (d, J = 7.0 Hz, 3H,
3
3
CH3), 0.93 (d, J = 7.0 Hz, 3H, CH3), 1.86 (hept, J = 7.0 Hz, 1H,
3
2
CH(CH3)2), 2.97 (d, J = 10.5 Hz, 1H, OH), 4.08 (d, J = 15.5 Hz,
1H, NCHaHb), 4.49 (dd, J = 10.5 Hz, 3J = 6.0 Hz, 1H, CHC
3
3
2
CF3), 4.68 (d, J = 6.0 Hz, 1H, CHCO), 4.90 (d, J = 11.5 Hz,
1H, OCHaHb), 5.03 (d, 2J = 15.5 Hz, 1H, NCHaHb), 5.14 (d, 2J =
11.5 Hz, 1H, OCHaHb), 5.84 (s, 1H, NH), 7.24−7.31 (m, 6H, 6
CHar), 7.36 (t, 3J = 7.5 Hz, 2H, 2 CHar), 7.45 (m, 2H, 2 CHar); 13
C
1
NMR (CDCl3 neutralized on basic Al2O3, 125.7 MHz) δ 18.5 (CH3),
19.5 (CH3), 35.5 (CH(CH3)2), 44.2 (NCH2), 73.4 (OCH2),
74.6 (CHCCF3), 76.6 (q, 2JCF = 29.5 Hz, CCF3), 81.0 (CH
CO), 123.8 (q, 1JCF = 287.5 Hz, CF3), 127.9 (CHar), 128.0 (CHar),
128.15 (CHar), 128.2 (CHar), 128.6 (CHar), 128.8 (CHar), 136.3
(CIVar, NBn), 136.7 (CIVar, OBn), 172.0 (CO), 179.2 (NH
CO); HRMS (ESI+) m/z calcd for C23H25F3N2NaO4 [M + Na]+
473.1664, found 473.1655.
δ −77.9 (s, 3F, CF3); H NMR (CDCl3 neutralized on basic Al2O3,
3
2
600 MHz) δ 2.87 (d, J = 10.5 Hz, 1H, OH), 2.96 (d, J = 16.5 Hz,
2
1H, CHaHbCO), 3.06 (d, J = 16.5 Hz, 1H, CHaHbCO),
4.00 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.47 (dd, 3J = 10.5 Hz, 3J = 6.0
Hz, 1H, CHCCF3), 4.71 (d, 3J = 6.0 Hz, 1H, CHCO), 4.92
2
2
(d, J = 11.5 Hz, 1H, OCHaHb), 5.09 (d, J = 15.5 Hz, 1H, N
2
CHaHb), 5.15 (d, J = 11.5 Hz, 1H, OCHaHb), 5.82 (s, 1H, NH),
3
4
6.93 (dd, J = 7.5 Hz, J = 2.0 Hz, 2H, 2 CHar), 7.26−7.42 (m, 11H,
11 CHar), 7.47 (d, J = 7.0 Hz, 2H, 2 CHar); 13C NMR (CDCl3
3
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)pivalamide (6d). According to Gen-
eral Procedure E, a solution of oxazoline 5d (160 mg, 0.36 mmol) in
MeOH and 6 N aq HCl (12 mL) was stirred for 48 h at rt. Purification
on silica gel (PE/EtOAc 4:1) afforded hydroxylamide 6d (71 mg,
43%) as a colorless oil: [α]2D0 +2 (c 0.50, CH2Cl2); IR (film) νmax 701,
739, 1113, 1168, 1301, 1404, 1453, 1521, 1710, 2967, 3034, 3451
cm−1; 19F NMR (CDCl3 neutralized on basic Al2O3, 235.5 MHz) δ
−77.6 (s, 3F, CF3); 1H NMR (CDCl3 neutralized on basic Al2O3, 600
neutralized on basic Al2O3, 151 MHz) δ 43.1 (CH2CONH), 44.1
2
(NCH2), 73.3 (OCH2), 74.5 (CHCCF3), 76.6 (q, JCF
=
1
29.5 Hz, CCF3), 80.8 (CHCO), 123.6 (q, JCF = 287.5 Hz,
CF3), 128.0 (CHar), 128.05 (CHar), 128.07 (CHar), 128.2 (CHar),
128.3 (CHar), 128.6 (CHar), 128.9 (CHar), 129.3 (CHar), 129.4
(CHar), 132.8 (CIVar, OCBn), 136.3 (CIVar, NBn), 137.5
(CIVar, OBn), 171.9 (NHCO), 173.3 (CO); HRMS (ESI+)
m/z calcd for C27H25F3N2NaO4 [M + Na]+ 521.1664, found 521.1671.
N-((2R,3S,4R)-1-Benzyl-3-hydroxy-4-methoxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)acetamide (6g). According to Gen-
eral Procedure E, a solution of oxazoline 5h (83 mg, 0.25 mmol) in
MeOH and 6 N aq HCl (8 mL) was stirred for 1 h at rt. Purification
on silica gel (PE/EtOAc 1:2) afforded hydroxylamide 6g (80 mg,
92%) as a white solid: mp 181 °C; [α]2D0 +91 (c 0.50, EtOAc); IR
(neat) νmax 604, 663, 721, 971, 1117, 1129, 1169, 1274, 1403, 1678,
1697, 3326 cm−1; 19F NMR (CD3COCD3, 235.5 MHz) δ −74.2 (s,
3F, CF3); 1H NMR (CD3COCD3, 600 MHz) δ 1.82 (s, 3H, OC
CH3), 3.65 (s, 3H, OCH3), 4.27 (d, 3J = 6.0 Hz, 1H, CHCO),
3
MHz) δ 0.92 (s, 9H, C(CH3)3), 2.89 (t, J = 11.0 Hz, 1H, OH), 4.11
(d, 2J = 15.5 Hz, 1H, NCHaHb), 4.52 (dd, 3J = 10.0 Hz, 3J = 6.0 Hz,
3
1H, CHCCF3), 4.72 (d, J = 6.0 Hz, 1H, CHCO), 4.93 (d,
2J = 11.5 Hz, 1H, OCHaHb), 5.05 (d, 2J = 15.5 Hz, 1H, N
2
CHaHb), 5.20 (d, J = 11.5 Hz, 1H, OCHaHb), 6.01 (s, 1H, NH),
7.26−7.46 (m, 10H, 10 CHar); 13C NMR (CDCl3 neutralized on basic
Al2O3, 151 MHz) δ 27.0 (CH3), 39.6 (C(CH3)3), 44.1 (NCH2),
2
73.4 (OCH2), 74.7 (CHCCF3), 76.5 (q, JCF = 29.0 Hz, C
1
CF3), 81.1 (CHCO), 123.9 (q, JCF = 283.5 Hz, CF3), 127.9
(CHar), 128.0 (CHar), 128.2 (CHar), 128.6 (CHar), 128.8 (CHar),
M
DOI: 10.1021/acs.joc.7b01814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
3
2
4.36 (dd, J = 7.5 Hz, J = 6.0 Hz, 1H, CHCCF3), 4.41 (d, J =
reflux. A solution of the resulting residue in MeOH and 6 N aq HCl
(12 mL) was stirred for 4 h at rt. Purification on silica gel (EtOAc
100%) afforded hydroxylamide 6j (200 mg, 70%) as a white solid: mp
165 °C; [α]2D0 +58 (c 0.50, MeOH); IR (KBr) νmax 1105, 1184, 1296,
1413, 1575, 1674, 1710, 2398, 3089, 3225, 3279, 3399 cm−1; 19F NMR
(CD3OD, 235.5 MHz) δ −78.6 (s, 3F, CF3); 1H NMR (CD3OD, 600
MHz) δ 1.74 (s, 3H, CH3), 4.28 (d, 3J = 6.5 Hz, 1H, CHCCF3),
2
16.0 Hz, 1H, NCHaHb), 4.47 (d, J = 16.0 Hz, 1H, NCHaHb),
3
3
5.09 (d, J = 7.5 Hz, 1H, OH), 7.23 (m, 1H, CHar), 7.28 (d, J = 7.5
Hz, 4H, 4 CHar), 7.86 (s, 1H, NH); 13C NMR (CD3COCD3, 151
MHz) δ 23.3 (OCCH3), 44.8 (NCH2), 59.0 (OCH3), 74.1
(CHCCF3), 77.6 (q, 2JCF = 29.0 Hz, CCF3), 84.3 (CHC
1
O), 124.8 (q, JCF = 283.5 Hz, CF3), 127.9 (CHar), 128.89 (CHar),
2
3
4.32 (d, J = 15.5 Hz, 1H, NCHaHb), 4.55 (d, J = 6.5 Hz, 1H,
CHCO), 4.62 (d, 2J = 15.5 Hz, 1H, NCHaHb), 7.21−7.27 (m,
5H, 5 CHar); 13C NMR (CD3OD, 151 MHz) δ 22.9 (CH3), 45.5
128.91 (CHar), 138.0 (CIVar, NBn), 172.1 (OCCH3), 173.9
(CO); HRMS (ESI+) m/z calcd for C15H17F3N2NaO4 [M + Na]+
369.1038, found 369.1041.
(NCH2), 75.6 (CHCCF3), 76.4 (CHCO), 78.1 (q, 2JCF
=
Methyl 3-(((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)amino)-3-oxopropanoate (6h). Ac-
cording to General Procedure F, a solution of N,O-acetal 4a (250 mg,
0.49 mmol), methyl cyanoacetate (430 μL, 4.87 mmol, 10 equiv), and
BF3·OEt2 (180 μL, 1.46 mmol, 3 equiv) in CH2Cl2 (4 mL) was stirred
for 28 h at rt. A solution of the resulting residue in MeOH and 6 N aq
HCl (12 mL) was stirred for 1 h at rt. Purification on silica gel (PE/
EtOAc 2:1) afforded hydroxylamide 6h (125 mg, 54%) as a colorless
oil: [α]2D0 +24 (c 0.50, CH2Cl2); IR (film) νmax 701, 1019, 1081, 1113,
1
29.0 Hz, CCF3), 125.0 (q, JCF = 286.0 Hz, CF3), 128.3 (CHar),
129.1 (CHar), 129.4 (CHar), 137.5 (CIVar, NBn), 174.3 (NH
CO), 176.8 (CO); HRMS (ESI+) m/z calcd for
C14H15F3N2NaO4 [M + Na]+ 355.0882, found 355.0878.
(3R,4S,5R)-5-Amino-1-benzyl-3-(benzyloxy)-4-hydroxy-5-
(trifluoromethyl)pyrrolidin-2-one (8). From 5a, according to General
Procedure E, a solution of oxazoline 5a (100 mg, 0.25 mmol) in
MeOH and 6 N aq HCl (10 mL) was stirred for 29 h at 60 °C.
Purification on silica gel (PE/EtOAc 2:1) afforded hydroxylamine 8
(64 mg, 68%) as a colorless oil. From 4a, according to General
Procedure F, a solution of N,O-acetal 4a (200 mg, 0.39 mmol) and
BF3·OEt2 (145 μL, 1.17 mmol, 3 equiv) in MeCN (4 mL) was stirred
for 48 h at rt. A solution of the resulting residue in MeOH and 6 N aq
HCl (12 mL) was stirred for 48 h at 60 °C. Purification on silica gel
(PE/EtOAc 2:1) afforded hydroxylamine 8 (80 mg, 54%) as a
colorless oil. Hydroxylamine 8: [α]2D0 +12 (c 0.41, CH2Cl2); IR (KBr)
νmax 701, 746, 1110, 1165, 1264, 1415, 1609, 1700, 2931, 3033, 3402
cm−1; 19F NMR (CDCl3, 235.5 MHz) δ −78.4 (s, 3F, CF3); 1H NMR
(CDCl3, 500 MHz) δ 1.85 (br s, 2H, NH2), 3.62 (br s, 1H, OH), 4.13
1171, 1271, 1353, 1407, 1442, 1556, 1720, 2953, 3066, 3310 cm−1; 19
F
NMR (CDCl3 neutralized on basic Al2O3, 235.5 MHz) δ −77.7 (s, 3F,
CF32); 1H NMR (CDCl3 neutralized on basic Al2O3, 500 MHz) δ 2.37
3
(d, J = 19.5 Hz, 1H, OCCHaHb), 2.85 (d, J = 10.5 Hz, 1H,
OH), 2.89 (d, 2J = 19.5 Hz, 1H, OCCHaHb), 3.68 (s, 3H, CH3),
3.96 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.48 (dd, 3J = 10.5 Hz, 3J = 6.0
Hz, 1H, CHCCF3), 4.64 (d, 3J = 6.0 Hz, 1H, CHCO), 4.92
2
2
(d, J = 11.5 Hz, 1H, OCHaHb), 5.12 (d, J = 11.5 Hz, 1H, O
CHaHb), 5.26 (d, 2J = 15.5 Hz, 1H, NCHaHb), 7.23−7.31 (m, 6H, 6
CHar), 7.36 (m, 2H, 2 CHar), 7.45 (m, 2H, 2 CHar), 8.64 (s, 1H,
NH); 13C NMR (CDCl3 neutralized on basic Al2O3, 125.7 MHz) δ
38.9 (OCCH2), 44.1 (NCH2), 52.9 (OCH3), 73.3 (O
2
3
(d, J = 15.5 Hz, 1H, NCHaHb), 4.18 (d, J = 7.0 Hz, 1H, CH
3
2
2
CO), 4.33 (d, J = 7.0 Hz, 1H, CHCCF3), 4.84 (d, J = 12.0
Hz, 1H, OCHaHb), 5.01 (d, 2J = 15.5 Hz, 1H, NCHaHb), 5.07 (d,
2J = 12.0 Hz, 1H, OCHaHb), 7.26−7.34 (m, 8H, 8 CHar), 7.41 (m,
2H, 2 CHar); 13C NMR (CDCl3, 125.7 MHz) δ 44.2 (NCH2), 72.4
(CHCCF3), 73.1 (OCH2), 75.2 (q, 2JCF = 30.0 Hz, CCF3),
CH2), 74.4 (CHCCF3), 76.4 (q, JCF = 29.5 Hz, CCF3), 80.8
(CHCO), 123.8 (q, 1JCF = 287.5 Hz, CF3), 127.7 (CHar), 128.1
(CHar), 128.2 (CHar), 128.57 (CHar), 128.59 (CHar), 128.8
(CHar), 136.1 (CIVar, NBn), 137.5 (CIVar, OBn), 167.2
(HNCO), 170.1 (OCO), 171.7 (CO); HRMS (ESI+)
m/z calcd for C23H23F3N2NaO6 [M + Na]+ 503.1406, found 503.1408.
N-((2R,3S,4R)-1-Benzyl-4-(benzyloxy)-3-hydroxy-5-oxo-2-
(trifluoromethyl)pyrrolidin-2-yl)cinnamamide (6i). According to
General Procedure F, a solution of N,O-acetal 4a (250 mg, 0.49
mmol), cinnamonitrile (610 μL, 4.86 mmol, 10 equiv), and BF3·OEt2
(180 μL, 1.46 mmol, 3 equiv) in CH2Cl2 (4 mL) was stirred for 48 h
at rt. A solution of the resulting residue in MeOH and 6 N aq HCl (12
mL) was stirred for 30 h at rt. Purification on silica gel (PE/EtOAc
3:1) afforded hydroxylamide 6i (78 mg, 31%) as a colorless oil; [α]D20
+70 (c 0.50, CH2Cl2); IR (film) νmax 699, 976, 1110, 1169, 1216, 1349,
1
79.1 (CHCO), 124.2 (q, JCF = 287.0 Hz, CF3), 128.0 (CHar),
128.1 (CHar), 128.22 (CHar), 128.23 (CHar), 128.6 (CHar), 128.8
(CHar), 136.6 (CIVar, NBn), 137.3 (CIVar, OBn), 171.4 (CO);
HRMS (ESI+) m/z calcd for C19H19F3N2NaO3 [M + Na]+ 403.1245,
found 403.1247.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01814.
■
S
1549, 1627, 1710, 2929, 3063, 3302 cm−1
;
19F NMR (CDCl3
1
X-ray structural data for trans-2a, cis-7a, and cis-7b (CIF)
Copies of all 1D NMR spectra for compounds 1−8
(PDF)
neutralized on basic Al2O3, 235.5 MHz) δ −77.4 (s, 3F, CF3); H
3
NMR (CDCl3 neutralized on basic Al2O3, 600 MHz) δ 3.22 (d, J =
11.0 Hz, 1H, OH), 4.05 (d, 2J = 15.5 Hz, 1H, NCHaHb), 4.54 (dd, 3J =
3
3
11.0 Hz, J = 6.0 Hz, 1H, CHCCF3), 4.76 (d, J = 6.0 Hz, 1H,
2
2
CHCO), 4.96 (d, J = 11.5 Hz, 1H, OCHaHb), 5.15 (d, J =
11.5 Hz, 1H, OCHaHb), 5.19 (d, 2J = 15.5 Hz, 1H, NCHaHb), 5.77
(d, 3J = 15.5 Hz, 1H, OCCHCH), 5.83 (s, 1H, NH), 7.05 (t, 3J
AUTHOR INFORMATION
Corresponding Author
*E-mail: fabienne.grellepois@univ-reims.fr.
■
3
3
= 7.5 Hz, 1H, CHar), 7.19 (t, J = 7.5 Hz, 2H, 2 CHar), 7.26 (d, J =
7.5 Hz, 1H, CHar), 7.29−7.40 (m, 9H, 9 CHar), 7.33 (d, 3J = 15.5 Hz,
1H, OCCHCH), 7.46 (d, 3J = 7.5 Hz, 2H, 2 CHar); 13C NMR
(CDCl3 neutralized on basic Al2O3, 151 MHz) δ 44.3 (NCH2), 73.3
(OCH2), 74.9 (CHCCF3), 77.2 (q, 2JCF = 29.5 Hz, CCF3),
ORCID
Fabienne Grellepois: 0000-0002-0992-722X
Notes
The authors declare no competing financial interest.
1
80.9 (CHCO), 117.9 (CHCHPh), 123.8 (q, JCF = 287.5
Hz, CF3), 127.7 (CHar), 128.1 (CHar), 128.2 (CHar), 128.25
(CHar), 128.28 (CHar), 128.6 (CHar), 128.9 (CHar), 129.1 (CHar),
130.7 (CHar), 133.8 (CIVar, HCCHPh), 136.1 (CIVar, NBn),
137.5 (CIVar, OBn), 144.2 (CHCHPh), 167.8 (NHCO),
172.0 (CO); HRMS (ESI+) m/z calcd for C28H25F3N2NaO4 [M +
Na]+ 533.1664, found 533.1670.
ACKNOWLEDGMENTS
We gratefully acknowledge the “reg
for financial support and the CNRS, the Conseil Reg
■
́
ion Champagne-Ardenne”
ional de
́
Champagne-Ardenne, and the EU-program FEDER for the
facilities of the analytical platform (PlAneT CPER project). We
thank A. Martinez (NMR analyses including NOE measure-
ments), S. Lanthony (chiral HPLC analyses and HRMS), Dr. S.
Chevreux (X-ray crystallographic structure determination), Dr.
N-((2R,3S,4R)-1-Benzyl-3,4-dihydroxy-5-oxo-2-(trifluoromethyl)-
pyrrolidin-2-yl)acetamide (6j). According to General Procedure F, a
solution of N,O-acetal 2d (250 mg, 0.86 mmol) and BF3·OEt2 (317
μL, 2.57 mmol, 3 equiv) in acetonitrile (6 mL) was stirred for 2.5 h at
N
DOI: 10.1021/acs.joc.7b01814
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The Journal of Organic Chemistry
Article
(11) Hoffmann-Roder, A.; Schweizer, E.; Egger, J.; Seiler, P.; Obst-
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ChemMedChem 2006, 1, 1205−1215.
̈
D. Harakat (HRMS), A. Robert (NMR analyses), and A. Vallee
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also thank the French Fluorine Network (GIS CNRS).
́
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