Trifluoromethide as a strong base: [CF3-] mediates dichloromethylation of nitrones by proton abstraction from the solvent

Article abstract of DOI:10.1021/jo402028r

An unprecedented reactivity of CF₃-TMS has been revealed, which exploits the basic character of the generated [CF₃^-] capable of delivering dichloromethide from dichloromethane with subsequent transfer to nitrones under smooth conditions. The proton-abstraction pathway was demonstrated through isotopic labeling experiments in CD₂Cl₂. The same reaction was achieved in acetonitrile with the introduction of a cyanomethyl group onto the nitrones.

Full text of DOI:10.1021/jo402028r

Article
pubs.acs.org/joc
−
Trifluoromethide as a Strong Base: [CF3 ] Mediates
Dichloromethylation of Nitrones by Proton Abstraction from the
Solvent
Jean-Bernard Behr,* Dani Chavaria, and Richard Plantier-Royon*
Universite
́
de Reims Champagne-Ardenne, Institut de Chimie Molec
́
ulaire de Reims (ICMR), CNRS UMR 7312, UFR Sciences
Exactes et Naturelles, 51687 Reims Cedex 2, France
S
* Supporting Information
ABSTRACT: An unprecedented reactivity of CF3-TMS has been
−
revealed, which exploits the basic character of the generated [CF3 ]
capable of delivering dichloromethide from dichloromethane with
subsequent transfer to nitrones under smooth conditions. The
proton-abstraction pathway was demonstrated through isotopic
labeling experiments in CD2Cl2. The same reaction was achieved in
acetonitrile with the introduction of a cyanomethyl group onto the
nitrones.
INTRODUCTION
■
Fluoroform (HCF3) is a very weak acid (pKa 25−28 in water),
the utility of which has been extremely scarce in organic
synthesis, until recently.1 In contrast to the other haloforms,
deprotonation of trifluoromethane to generate the trifluor-
−
omethide [CF3 ], a reactive form of HCF3, is challenging due
to the high instability of this electron-rich anion and its
instantaneous collapse in solution, even at very low temper-
ature.2 The stabilization of [CF3 ] has been achieved by
−
coordination to a metal such as Ag, Cu, Sn, Hg, and Zn (mainly
covalent organometallics) or to Si, giving rise to convenient
trifluoromethyl transfer reagents.3 (Trifluoromethyl)-
trimethylsilane (CF3-TMS), often referred to as the Rup-
pert−Prakash reagent,4 is the gold-standard source of
trifluoromethide, the utility of which has been demonstrated
during the two last decades for the trifluoromethylation of C
O-,5 CN-,6 sulfur-,7 or Si-containing8 electrophiles. The
−
Figure 1. Two possible pathways for collapsing of [CF3 ].
panes and gem-difluorocyclopropenes from alkenes and alkynes,
respectively,12 the development of the proton abstraction
pathway is still pending. We present here a first synthetic
application of CF3-TMS/F− as a strong base, capable of
−
delivering [CHCl2 ] in situ after proton abstraction from
−
generation of [CF3 ] from CF3-TMS is usually performed in
dichloromethane. In the presence of a nitrone the correspond-
ing 2-(dichloromethyl) hydroxylamine is obtained in fairly
good yield.
THF and requires activation by a fluoride salt or, alternately, by
other nucleophilic species such as amine N-oxides.9 The high
efficiency of (trifluoromethyl)trimethylsilane for transferring
the CF3 moiety, even at room temperature, was attributed to
the tendency of silicon to increase its coordination sphere,
accepting supplementary electron-rich substituents, which
allows the transfer in a nearly intramolecular fashion, limiting
decomposition. Other trifluoromethylating reagents have been
developed recently, but the enhanced reactivity of CF3-TMS
make it indispensable in many cases.10,11 In the absence of a
suitable electrophile, two pathways prevail for the decom-
RESULTS AND DISCUSSION
■
Only a few reports have given observations on the basicity of
[CF3 ]. Experimental evidence of this character is scarce and
results from unwanted and low-yielding side reactions. For
instance, deprotonation of an aromatic ring to a benzyne
intermediate by [CF3 ] was postulated to account for the
formation of several isomers (<14%) during aromatic
nucleophilic substitution.13 In another report, the use of CF3-
TMS/F− in acetonitrile was found to generate [CH2CN−],
which could in turn react with benzophenone to give the
−
−
−
position of the kinetically unstable [CF3 ]: either α-
elimination, which generates difluorocarbene and a fluoride
anion, or proton abstraction from the solvent to afford HCF3
(Figure 1). Whereas the production of difluorocarbene from
the CF3-TMS/F− system has been recently highlighted by a
first application toward the synthesis of gem-difluorocyclopro-
Received: September 12, 2013
© XXXX American Chemical Society
A
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Article
corresponding adduct in 12% yield.14 However, the F− anion
itself was previously known to give [CH2CN−],15 so that the
exact reactive base in this reaction remains elusive. At the same
To our delight, after a standard workup (addition of water,
extraction with Et2O), purification of the crude product
afforded the expected dichloromethyl hydroxylamine as the
O-trimethylsilyl derivative 2a in 67% yield. No product
−
time, the formation of [CHCl2 ] and its addition to
−
resulting from the nucleophilic addition of [CF3 ] to the
electrophiles is a very difficult task. The generation of the
dichloromethide ion was described by reaction of methylene
chloride with butyllithium or (tetramethylpiperidine)lithium at
very low temperature (−100 °C).16 In this work, we explored
the tendency for the trifluoromethyl anion, generated from
CF3-TMS/F−, to abstract proton from dichloromethane with
concomitant transfer of the so-formed dichloromethide to a
nitrone. We chose a nitrone as the electrophilic partner to limit
nitrone was detected. Modification of the reaction conditions
was attempted to determine the requirements of the trans-
formation in terms of equivalents of reagents, temperature, and
fluoride sources. Thus, control experiments in the absence of
either CF3-TMS or TMAF (Table 1, entries 2 and 3) showed
no transformation of the starting nitrone, precluding a possible
participation of fluoride to the initial acid−base reaction as was
observed with CH3CN.15,17 An autocatalytic process, the
nitrone itself playing eventually the role of the promoter in
the same manner as for amine N-oxides, also had to be ruled
out.
Reducing the amount of TMAF to 1 or 0.3 equiv while
keeping an excess of (trifluoromethyl)trimethylsilane (3 equiv)
showed that subequimolar quantities of fluoride are insufficient
for complete conversion, whereas 1 equiv afforded 2a in 69%
yield (Table 1, entries 4 and 5). This is surprising, since TMAF
is sparsely soluble in CH2Cl2 and the reaction is clearly
heterogeneous.18 However, with larger amounts of activator the
availability of fluoride ion might increase by a significant
increase in the surface area, which could explain the higher
activity. At the same time, experiments with various amounts of
CF3-TMS (entries 6−8) showed that 2 equiv was required to
consume all the nitrone, only 70% conversion occurring with
equimolar quantities. Although the reactions were carried out
under strictly anhydrous conditions, partial consumption of
reactant by residual water could explain this observation.
Finally, the optimal conditions combined 1 equiv of TMAF and
2.5 equiv of CF3-TMS, affording 2a in 71% yield. Interestingly,
O-desilylation could be performed in situ at −50 °C by addition
of equimolar TBAF, which resulted in deprotected dichlor-
omethylhydroxylamine (2b) in 58% yield after purification
(entry 9).
−
the competitive nucleophilic addition of [CF3 ], the trifluor-
omethylation of nitrones being usually not as efficient as that of
aldehydes or ketones, for instance.
In a first assay (Table 1, entry 1), 5,5-dimethylpyrroline N-
oxide 1 was dissolved in dichloromethane and stirred at −50 °C
with an excess of (trifluoromethyl)trimethylsilane (3 equiv) and
tetramethylammonium fluoride (TMAF) as the promoter (2
equiv). TLC monitoring revealed a rapid disappearance of the
starting nitrone within a few minutes accompanied by cessation
of gas release and darkening of the reaction mixture.
Table 1. Optimization of the Reaction Conditions for the
Dichloromethylation of Nitrone 1
amt of
CF3-TMS
(equiv)
product;
yield
F source (amt
(equiv))
conversion
a
bc
,
entry
T (°C)
(%)
(%)
1
2
3
4
5
6
7
8
9
TMAF (2 equiv)
3
3
−50
−50
−50
−50
−50
−50
−50
−50
−50
100
0
2a; 67
TMAF (1 equiv)
TMAF (1 equiv)
TMAF (0.3 equiv)
TMAF (1 equiv)
TMAF (1 equiv)
TMAF (1 equiv)
0
3
100
30
2a; 69
Other commercial sources of fluoride were then tested.
Surprisingly, TBAF (THF solution) and TBAT, which both are
soluble in dichloromethane, gave less favorable outcomes with
only 41% and 36% conversions, respectively. When the reaction
was repeated with variable amounts of TBAF/TBAT (entries
10−14), almost complete transformation of the nitrone was
observed only with 1.3 equiv of fluoride as a mixture of TBAT
and TBAF and a large excess of CF3-TMS (6 equiv) yielding
63% of deprotected 2b. We also studied the possibility of
performing the reaction at higher temperature, using the best
conditions stated above to access either 2a or 2b. A significant
reduction in yield was observed at −20, 0, and 20 °C mainly
due to the formation of side products, as characterized by the
dark brown reaction mixtures. Nevertheless, the targeted
dichloromethyl N-hydroxylamine was obtained in 32−48%
yield, even at temperatures assumed to be incompatible with
3
2.5
2
100
100
70
2a; 71
2a; 44
1
TMAF (1 equiv)
then TBAF
(1 equiv)
2.5
100
2b; 58
10
11
12
13
14
TBAF (2 equiv)
TBAT (2 equiv)
TBAT (1 equiv)
TBAT (0.3 equiv)
3
3
6
6
6
−50
−50
−50
−50
−50
41
36
49
35
96
TBAT (0.3 equiv)
+ TBAF
(1 equiv)
2b; 63
15
16
17
TMAF (1 equiv)
TMAF (1 equiv)
TMAF (1 equiv)
2.5
2.5
2.5
−20
0
95
94
66
2a; 48
2a; 38
−
−
room
temp
the presence of either [CF3 ] or [CHCl2 ]. The rapidity of the
reaction cascade could explain this surprising result.
18
19
TBAT (0.3 equiv)
+ TBAF
6
6
0
90
90
2b; 41
2b; 32
To gain further insight into the reaction mechanism, the
dichloromethylation of nitrone 1 was performed in CD2Cl2 and
(1 equiv)
1
was followed by H and 19F NMR. Remarkably, monitoring
TBAT (0.3 equiv)
+ TBAF
(1 equiv)
room
temp
showed complete disappearance of the nitrone 1 over 5 min
with concomitant formation of deuterium-labeled adduct 3a
and DCF3 as the only reaction products (Scheme 1).
Formation of DCF3 was easily evidenced by 19F NMR (δ
−79 ppm, t, JFD = 12.1 Hz; see the Supporting Information).
a
b
Based on recovered nitrone 1. After purification by silica gel
c
chromatography (when conversion >90%). Desilylation of 2a slightly
occurred on silica gel.
B
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methyl hydroxylamines 4−6 and 7a after O-desilylation with
TBAF (Chart 1), in 36−82% overall yields.
Scheme 1. Labelling Experiments in CD2Cl2
Chart 1. Structures of the Prepared α-Dichloromethyl
Hydroxylamines
Desilylation with TBAF afforded deuterated hydroxylamine 3b.
2
The presence of the H atom in the final structure of 3b was
apparent from the respective NMR spectra of 2b/3b with a net
disappearance of the signal of CHCl2 in 3b and a simplification
of the splitting pattern of the neighboring 2-H (Figure 2). In
Interestingly, the addition proved highly stereoselective with
a chiral carbohydrate-derived nitrone, affording the 2S
diastereoisomer 7a in 68% yield after purification. The
configuration at C-2 in 7a was unambiguously assigned after
NOE experiments, revealing interactions between −CHCl2 and
H-3 and between H-2 and H-5, assessing a relative cis position
of each set of protons. The same selectivity was previously
observed for nucleophilic addition of other reagents to the
same nitrone.20 This reaction seems particularly interesting,
allowing access to an unprecedented series of imino sugars
featuring a reactive function at the pseudoanomeric position,
which might react with the nucleophilic residues of the catalytic
site of glycosidases and glycosyltransferases. It is worth noting
that the reaction of nitrone 8, the precursor of 7, under
analogous experimental conditions but using THF in place of
CH2Cl2 gave the desired trifluoromethyl adduct.20a To compare
1
Figure 2. Partial H NMR spectra (250 MHz, CDCl3, 298 K) of
compounds 2b (a) and 3b (b) isolated after reaction in CH2Cl2 and
CD2Cl2, respectively.
the same way, mass spectroscopy analysis proved unambigu-
ously the labeling with deuterium, resulting in a mass increase
of 1 Da (m/z 198.0443 and 199.0511 for 2b and 3b,
respectively). Since CD2Cl2 is the only source of deuterium
in the system, this observation evidenced the role of
trifluoromethide as a strong base responsible for proton
abstraction from the solvent and subsequent transfer of a
dichloromethyl group to the nitrone. The competing collapse
of trifluoromethide into the corresponding carbene could
explain also the low conversion observed when equimolar
amounts of CF3-TMS were used (Table 1, entry 8).
Nevertheless, when the reaction was performed in the presence
of phenylacetylene, no difluorocarbene addition product was
formed, suggesting that this intermediate is present only in low
−
the efficiency of [CF3 ] to act as either a nucleophile or a base
in our system, 8 was treated with CF3-TMS/TBAT in THF in
the presence of only 6 mol equiv of dichloromethane.
Surprisingly, only the dichloromethylhydroxylamine was
formed during the reaction, strengthening the prevalence of
the kinetically favored acid−base pathway over nucleophilic
−
addition of [CF3 ].
The replacement of CF3-TMS by other alkyltrimethylsilanes
R-TMS (where R is allyl, benzyl, ethynyl, or ethyl acetate) as
putative generators of a strong base failed. Indeed, when the
mannose-derived nitrone 8 was reacted with these silyl
reagents, no formation of the targeted dichloromethyl
hydroxylamine 7a was observed (Scheme 2). When the
reaction was carried out at −50 °C, the starting nitrone was
recovered unaffected. However, except for allyltrimethylsilane,
new compounds 7b−d were obtained in 20−41% yield when
the reaction was conducted at 0 °C, which resulted from direct
nucleophilic addition of the R group to the nitrone. As for 7a, a
single stereoisomer was obtained after addition of the R
substituent exclusively from the less hindered side.
Next, we wished to explore the capability of the CF3-TMS/
F− system to abstract protons from other solvents to generate
alternative nucleophiles. We used nitrone 9 as the electrophilic
trap for this series of experiments, since 9 gave the best results
among the tested nitrones during dichloromethylation. The
procedure stated above (Table 1, entry 6) was applied
successively to CH2Br2, CH2I2, CHCl3, phenylacetylene,
butyronitrile, and acetonitrile, adapting the temperature of the
amounts.12 At this stage, the true nature of [CF3 ] as either a
free base in solution or a complex with hypervalent silicon
species is not clear cut.
Another mechanistic possibility could be the transient
formation of TMS-CHCl2, this intermediate being the true
source of [CHCl2 ]. Nevertheless, when commercial TMS-
CHCl2 was reacted with TMAF in CD2Cl2 at −50 °C, no
reaction occurred, suggesting that such a mechanistic pathway
is unlikely. Finally, the formation of the dichloromethyl
hydroxylamine could also result from the addition of a
chlorocarbene (formed in situ by reaction of methylene
chloride with the base and concomitant release of Cl−) to
the nitrone, affording an aziridinium ion, which would
subsequently react with the released chloride.19
The general applicability of this new reaction was challenged
using other nitrone substrates. Following the optimized
protocol, several aliphatic and aromatic nitrones were
successfully transformed into the corresponding α-dichloro-
−
−
C
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a
Scheme 2.
EXPERIMENTAL SECTION
■
General Information. Nitrone 1 was purchased from commercial
sources. The other nitrones were prepared according to previously
reported procedures.21 Dichloromethane was purified by simple
distillation before use. All reactions were performed under argon.
Silica gel F254 (0.2 mm) was used for TLC plates, detection being
carried out by spraying with an alcoholic solution of phosphomolybdic
acid, followed by heating. Flash column chromatography was
performed over silica gel M 9385 (40−63 μm) Kieselgel 60. NMR
spectra were recorded at 250 MHz for H, 62.5 MHz for 13C or 500
1
MHz for 1H, 125 MHz for 13C. Chemical shifts are expressed in parts
per million (ppm) and were calibrated to the residual solvent peak.
Coupling constants are in Hz, and splitting pattern abbreviations are as
follows: br, broad; s, singlet; d, doublet; t, triplet; m, multiplet. Optical
rotations were determined at 20 °C in the specified solvents. High
resolution mass spectra (HRMS) were performed on a Q-TOF
instrument (ESI).
General Procedure for Dichloromethylation of Nitrones. To
a solution of the nitrone (0.1 mmol) in CH2Cl2 (0.5 mL) at −50 °C
were added successively TMAF (9.3 mg, 0.1 mmol) and CF3-TMS (38
μL, 0.25 mmol). The heterogeneous mixture was left to react for 30
min at −50 °C. At this stage, variations of the protocol permitted
isolation of either the N-OTMS protected hydroxylamine or the N-
OH analogue. To obtain the protected form, after addition of water
(0.5 mL), the reaction was warmed to room temperature and extracted
with supplementary CH2Cl2/water. The organic phase was dried for a
short 5 min period with MgSO4 and purified using a 3−5 cm height
column chromatograph (Et2O/petroleum ether, 5/95, v/v). To isolate
the deprotected N-OH product, TBAF (100 μL of a 1 M solution, 0.1
mmol) was added at −50 °C and the reaction mixture was stirred for a
supplementary 30 min period. Water was then added, and the mixture
was warmed to room temperature and extracted with supplementary
CH2Cl2/water. The organic phase was dried (MgSO4), concentrated,
and purified by silica gel chromatography (Et2O/petroleum ether, 2/8,
v/v).
a
Conditions: (i) TMAF (1 equiv), TMS-R (3 equiv), CH2Cl2, −50
°C; (ii) TBAT (0.3 equiv), TMS-R (6 equiv), CH2Cl2, 0 °C, then
TBAF (1 equiv).
reaction to the melting point of each solvent, to avoid freezing
(Scheme 3). Only the reaction in acetonitrile afforded the
a
Scheme 3.
2-(Dichloromethyl)-5,5-dimethyl-1-((trimethylsilyl)oxy)pyrrolidine
(2a): colorless oil, 18 mg (71%); Rf = 0.72 (Et2O/petroleum ether, 1/
1
9, v/v); H NMR (CDCl3) 0.20 (9H, s), 1.09 (3H, s), 1.12 (3H, s),
1.58−1.60 (2H, m), 1.83−2.05 (2H, m), 3.49 (1H, ddd, J = 2.3, 6.5,
9.2 Hz), 5.80 (1H, d, J = 2.3 Hz); 13C NMR (CDCl3) 0.8, 18.4, 19.7,
29.6, 34.4, 65.5, 72.5, 74.9; HRMS (ESI) calcd for C10H22NOCl2Si [M
+ H] 270.0848, found 270.0859.
2-(Dichloromethyl)-5,5-dimethyl-1-hydroxypyrrolidine (2b):
a
Conditions: (i) TMAF (1 equiv), TMS-CF3 (2.5 equiv), CH3CN,
white solid, 11.5 mg (58%); Rf = 0.25 (Et2O/petroleum ether, 1/9,
−40 °C to room temperature; (ii) TBAF (1 equiv).
1
v/v); H NMR (CDCl3) 1.10 (3H, s), 1.23 (3H, s), 1.53−1.70 (2H,
m), 1.75−1.82 (1H, m), 1.89−2.11 (1H, m), 3.49 (1H, ddd, J = 3.5,
5.6, 9.6 Hz), 4.72 (1H, br s), 5.81 (1H, d, J = 3.5 Hz); 13C NMR
(CDCl3) 18.2, 20.7, 26.9, 34.4, 65.0, 71.1, 75.3; HRMS (ESI) calcd for
C7H14NOCl2 [M + H] 198.0452, found 198.0443.
d-2-(Dichloromethyl)-5,5-dimethyl-1-((trimethylsilyl)oxy)-
pyrrolidine (3a): colorless oil, 15 mg (56%); Rf = 0.72 (Et2O/
petroleum ether, 1/9, v/v); 1H NMR (CDCl3) 0.20 (9H, s), 1.09 (3H,
s), 1.12 (3H, s), 1.61 (2H, dd, J = 6.3, 9.2 Hz), 1.83−2.05 (2H, m),
3.49 (1H, dd, J = 6.7, 9.3 Hz); 13C NMR (CDCl3) 0.9, 18.5, 19.8, 29.7,
34.5, 65.7, 72.6; HRMS (ESI) calcd for C10H212HNOCl2Si [M + H]
271.0911, found 271.0916.
d-2-(Dichloromethyl)-5,5-dimethyl-1-hydroxypyrrolidine (3b):
white solid, 9 mg (47%); Rf = 0.25 (Et2O/petroleum ether, 1/9, v/
v); 1H NMR (CDCl3) 1.10 (3H, s), 1.23 (3H, s), 1.53−1.70 (2H, m),
1.75−1.82 (1H, m), 1.89−2.11 (1H, m), 3.49 (1H, dd, J = 5.6, 9.7
Hz), 4.60 (1H, br s); 13C NMR (CDCl3) 18.3, 20.9, 26.8, 34.5, 65.2,
71.1; HRMS (ESI) calcd for C7H132HNOCl2 [M + H] 199.0515,
found 199.0511.
expected addition product 10, the starting nitrone 9 being
recovered unreacted in all other attempts. Compounds 11 and
7e were obtained in the same manner, illustrating the generality
of the reaction with acetonitrile also.
CONCLUSION
■
In summary, we have reported a new reactivity of the Ruppert−
Prakash reagent. In the presence of TMAF and CH2Cl2 or
CH3CN as the solvent, CF3-TMS generates the strong base
−
[CF3 ], which abstracts proton from the solvent. The new
nucleophilic species thus formed can be trapped by nitrones to
yield 2-(dichloromethyl) or 2-(cyanomethyl) hydroxylamines
under smooth conditions. The course of the reaction was
analyzed through isotopic labeling experiments with CD2Cl2.
Different reaction parameters were studied, such as the
temperature, the source of fluoride, the nature of the solvent,
and the use of other commercial trimethylsilanes. The reaction
was observed exclusively with CF3-TMS, and better results
were obtained at low temperature using TMAF as the
promoter. To the best of our knowledge, this is the first
N-Benzyl-α-(dichloromethylbenzyl)hydroxylamine (4): colorless
1
oil, 24 mg (82%); Rf = 0.24 (Et2O/petroleum ether, 1/9, v/v); H
NMR (CDCl3) 3.20 (1H, d, J = 13.6 Hz), 3.79 (1H, d, J = 13.6 Hz),
4.13 (1H, d, J = 5.4 Hz), 5.03 (1H, br s), 6.46 (1H, d, J = 5.4 Hz),
7.27−7.50 (10H, m); 13C NMR (CDCl3) 62.0, 73.1, 77.0, 127.5,
128.1, 128.4, 129.0, 129.2, 130.5, 133.8, 137.1; HRMS (ESI) calcd for
C15H15NOCl2Na [M + Na] 318.0428, found 318.0428.
−
application of [CF3 ] as a base in synthetic chemistry.
D
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N-Methyl-(1′-dichloromethyl)heptylhydroxylamine (5): yellow oil,
General Procedure for Cyanomethylation of Nitrones. To a
solution of the nitrone (0.1 mmol) in CH3CN (0.5 mL) at −40 °C
were added successively TMAF (9.3 mg, 0.1 mmol) and CF3-TMS (38
μL, 0.25 mmol). In some cases, additional CF3-TMS (38 μL) was
added to improve the conversion. The mixture was left to react for 30
min at −40 °C and then warmed to room temperature. After 30 min at
room temperature, TBAF (100 μL of a 1 M solution in THF) was
added and the mixture was stirred for an additional hour at room
temperature. Water was added, and the mixture was extracted with
CH2Cl2. The organic phase was dried (MgSO4), concentrated, and
purified by silica gel chromatography.
1
8 mg (36%); Rf = 0.62 (Et2O:petroleum ether, 35:65, v/v); H NMR
(CDCl3) 0.78−0.87 (3H, t), 1.25−1.60 (9H, m), 1.75−1.83 (1H, m),
2.75 (3H, s), 2.95 (1H, m), 6.12 (1H, br s), 6.25 (1H, d, J = 2.9 Hz);
13C NMR (CDCl3) 14.1, 22.6, 26.5, 28.1, 29.4, 31.6, 44.8, 73.8, 74.5;
HRMS (ESI) calcd for C9H20NOCl2 [M + H] 228.0922, found
228.0918.
1-(Dichloromethyl)-N-hydroxy-1,2,3,4-tetrahydroisoquinoline
(6): white solid, 11 mg (48%); Rf = 0.24 (Et2O/petroleum ether, 2/8,
1
v/v); H NMR (CDCl3) 2.70−2.81 (1H, m), 2.90−3.16 (2H, m),
3.42−3.55 (1H, m), 4.60 (1H, d, J = 1.9 Hz), 5.24 (1H, br s), 6.20
(1H, d, J = 1.9 Hz), 7.04−7.22 (3H, m), 7.45−7.50 (1H, m); 13C
NMR (CDCl3) 28.1, 53.8, 74.6, 75.0, 126.3, 127.3, 127.8, 128.3, 131.6,
135.8; HRMS (ESI) calcd for C10H12NOCl2 [M + H] 232.0296, found
232.0292.
N-Benzyl-α-((cyanomethyl)benzyl)hydroxylamine (10): yellow oil,
15 mg (60%); Rf = 0.28 (Et2O/petroleum ether, 35/65, v/v); 1H
NMR (CDCl3) 2.95 (1H, dd, J = 7.0, 16.5 Hz), 3.05 (1H, dd, J = 5.4,
16.5 Hz), 3.53 (1H, d, J = 13.4 Hz), 3.78 (1H, d, J = 13.4 Hz), 4.01
(1H, dd, J = 5.4, 7.0 Hz), 5.24 (1H, br s), 7.25−7.50 (10H, m); 13C
NMR (CDCl3) 23.8, 61.8, 67.5, 122.4, 127.5−129.2 (Ar-C); HRMS
(ESI) calcd for C16H17N2O [M + H] 253.1341, found 253.1347.
2-(Cyanomethyl)-1-hydroxy-5,5-dimethylpyrrolidine (11): color-
(2S,3R,4S,5S)-3,4-Dihydroxy-5-((1′R)-1′,2′-dihydroxyethyl)-
3,4:1′,2′-di-O-isopropylidene-2-(dichloromethyl)pyrrolidine (7a):
white solid, 10 mg (starting from 11 mg of nitrone 8, 68%); Rf =
20
0.34 (EtOAc/petroleum ether, 2/8, v/v); [α]D = −69.0° (c 0.5,
1
1
less oil, 5 mg (33%); Rf = 0.40 (Et2O/petroleum ether, 6/4, v/v); H
CHCl3); H NMR (CDCl3) 1.26 (3H, s), 1.27 (3H, s), 1.48 (3H, s),
NMR (CDCl3) 1.03 (3H, s), 1.21 (3H, s), 1.38−1.71 (3H, m), 1.90−
2.05 (1H, m), 2.59 (2H, d, J = 5.4 Hz), 3.25 (1H, m), 4.70 (1H, br s);
13C NMR (CDCl3) 18.4, 22.9, 23.7, 27.1, 34.0, 59.8, 63.6, 118.5;
HRMS (ESI) calcd for C8H15N2O [M + H] 155.1184, found
155.1191.
(2R,3R,4S,5S)-3,4-Dihydroxy-5-((1′R)-1′,2′-dihydroxyethyl)-
3,4:1′,2′-di-O-isopropylidene-2-cyanomethylpyrrolidine (7e): white
solid, 15 mg (starting from 19 mg of nitrone 8, 68%); Rf = 0.45 (Et2O/
petroleum ether, 7/3, v/v); [α]D20 = −30.4° (c 0.5, CHCl3); 1H NMR
(CDCl3) 1.29 (3H, s), 1.36 (3H, s), 1.50 (3H, s), 1.51 (3H, s), 2.70
(1H, dd, J = 4.2, 17.0 Hz), 2.81 (1H, dd, J = 4.8, 17.0 Hz), 3.05−3.17
(2H, m), 3.96 (1H, dd, J = 4.8, 9.0 Hz), 4.10 (1H, dd, J = 6.7, 9.0 Hz),
4.23−4.39 (3H, m), 5.72 (1H, br s); 13C NMR (CDCl3) 19.5, 25.2,
25.3, 26.6, 27.2, 66.3, 68.2, 74.4, 76.5, 77.3, 78.5, 110.3, 114.5, 117.3;
HRMS (ESI) calcd for C14H22N2O5Na [M + Na] 321.1426, found
321.1436.
1.50 (3H, s), 3.05 (1H, t, J = 6.1 Hz), 3.54 (1H, dd, J = 2.7, 3.9 Hz),
3.93 (1H, dd, J = 4.8, 8.8 Hz), 4.03 (1H, dd, J = 6.3, 8.8 Hz), 4.18−
4.26 (2H, m), 4.62 (1H, dd, J = 3.9, 6.9 Hz), 5.51 (1H, br s), 5.87 (1H,
d, J = 2.7 Hz); 13C NMR (CDCl3) 25.3, 25.4, 26.5, 27.4, 66.2, 71.1,
74.4, 76.6, 76.8, 77.3, 78.3, 110.3, 114.2; HRMS (ESI) calcd for
C13H21NO5Cl2Na [M + Na] 364.0694, found 364.0693.
Reaction of Nitrone 8 with Other Alkyltrimethylsilanes. To a
solution of nitrone 8 (13 mg, 0.05 mmol) in CH2Cl2 at 0 °C was
added successively TBAT (7 mg, 0.013 mmol) and 6 equiv of
RSi(CH3)3 (R = allyl, benzyl, ethynyl, CH2CO2Et). The reaction
mixture was stirred at 0 °C for 30 min, and TBAF (100 μL of a 1 M
solution in THF) was added. After 30 min, water was added and the
mixture was extracted with CH2Cl2. The organic phase was dried
(MgSO4), concentrated, and purified by silica gel chromatography
using Et2O/petroleum ether (5/5, v/v) as the eluent.
(2R,3R,4S,5S)-3,4-Dihydroxy-5-((1′R)-1′,2′-dihydroxyethyl)-
3,4:1′,2′-di-O-isopropylidene-2-benzylpyrrolidine (7b): white solid, 7
mg (starting from 13 mg of nitrone 8, 41%); Rf = 0.38 (Et2O/
petroleum ether, 5/5, v/v); 1H NMR (CDCl3) 1.16 (3H, s), 1.29 (3H,
s), 1.40 (3H, s), 1.41 (3H, s), 2.97 (1H, dd, J = 6.7 14.2 Hz), 3.02−
3.07 (2H, m), 3.29 (1H, dt, J = 5.4, 6.5 Hz), 3.91 (1H, dd, J = 5.4, 8.7
Hz), 4.06 (1H, dd, J = 5.4, 7.1 Hz), 4.14 (1H, dd, J = 5.4, 7.1 Hz), 4.18
(1H, dd, J = 5.6, 7.1 Hz), 4.28 (1H, dt,, J = 5.5, 6.5 Hz), 5.20 (1H, br
s), 7.17−7.31 (5H, m); 13C NMR (CDCl3) 25.4, 25.5, 26.6, 27.1, 37.4,
66.4, 73.3, 74.4, 77.1, 77.6, 79.9, 110.0, 113.8, 126.3, 128.4, 129.7,
138.3; HRMS (ESI) calcd for C19H28NO5 [M + H] 350.1967, found
350.1976.
(2R,3R,4S,5S)-3,4-Dihydroxy-5-((1′R)-1′,2′-dihydroxyethyl)-
3,4:1′,2′-di-O-isopropylidene-2-ethynylpyrrolidine (7c): yellow oil, 8
mg (starting from 20 mg of nitrone 8, 38%); Rf = 0.25 (Et2O/
petroleum ether, 5/5, v/v); 1H NMR (CDCl3) 1.30 (3H, s), 1.37 (3H,
s), 1.49 (3H, s), 1.54 (3H, s), 2.41 (1H, d, J = 2.0 Hz), 3.11 (1H, dd, J
= 5.3, 5.9 Hz), 3.73 (1H, dd, J = 2.0, 6.4 Hz), 3.93 (1H, dd, J = 5.2, 8.7
Hz), 4.09 (1H, dd, J = 6.6, 8.7 Hz), 4.33 (1H, dd, J = 5.9, 7.0 Hz), 4.37
(1H, m), 4.51 (1H, dd, J = 6.4, 7.0 Hz), 5.49 (1H, br s); 13C NMR
(CDCl3) 25.3, 25.3, 26.6, 27.3, 64.9, 66.3, 73.2, 74.1, 76.1, 77.8, 81.1,
81.2, 110.2, 114.6; HRMS (ESI) calcd for C14H21NO5Na [M + Na]
306.1317, found 306.1308.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra of compounds 2−7a−
e, 10, and 11 and NMR monitoring of the reaction in CD2Cl2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail for J.-B.B.: jb.behr@univ-reims.fr.
*E-mail for R.P.-R.: richard.plantier-royon@univ-reims.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Charles Portella, who
made significant contributions to the fields of fluorine and
silicon chemistry, on the occasion of his retirement. We warmly
thank Dr. Murielle Muzard and Dr. Dominique Harakat for
their help in some aspects of this project. Financial support by
Ministry of Higher Education and Research (MESR), CNRS,
and EU-programme FEDER to the PlAneT CPER project is
gratefully acknowledged.
(2R,3R,4S,5S)-3,4-Dihydroxy-5-((1′R)-1′,2′-dihydroxyethyl)-
3,4:1′,2′-di-O-isopropylidene-2-(carboxyethyl)methylpyrrolidine
(7d): colorless oil, 3 mg (starting from 11 mg of nitrone 8, 20%); Rf =
1
0.56 (Et2O/petroleum ether, 7/3, v/v); H NMR (CDCl3) 1.26 (3H,
t, J = 7.1 Hz), 1.36 (3H, s), 1.29 (3H, s), 1.48 (3H, s), 1.53 (3H, s),
2.58 (1H, dd, J = 2.9, 14.7 Hz), 2.62 (1H, dd, J = 3.4, 14.7 Hz), 3.08
(1H, t, J = 5.6 Hz), 3.37 (1H, q, J = 5.9 Hz), 3.93 (1H, dd, J = 5.3, 8.7
Hz), 4.08 (1H, dd, J = 6.6, 8.7 Hz), 4.12−4.20 (2H, m), 4.25 (1H, dd,
J = 5.4, 7.0 Hz), 4.28−4.33 (1H, m), 4.35 (1H, dd, J = 6.0, 7.0 Hz),
5.30 (1H, br s); 13C NMR (CDCl3) 14.3, 25.4, 25.4, 26.6, 27.4, 36.8,
60.7, 66.4, 69.7, 74.3, 76.7, 77.6, 80.1, 110.1, 114.0, 171.6; HRMS
(ESI) calcd for C16H27NO7Na [M + Na] 368.1685, found 368.1682.
REFERENCES
■
(1) (a) Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A.
Science 2012, 338, 1324. (b) Langlois, B. R.; Billard, T.; Roussel, S. J.
Fluorine Chem. 2005, 126, 173.
E
dx.doi.org/10.1021/jo402028r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(b) Joubert, J.; Roussel, S.; Christophe, C.; Billard, T.; Langlois, B. R.;
Vidal, T. Angew. Chem., Int. Ed. 2003, 42, 3133.
(21) (a) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8,
3351. (b) Murahashi, S.-H.; Mitsui, H.; Shiota, T.; Tsuda, T.;
Watanabe, S. J. Org. Chem. 1990, 55, 1736. (c) Colacino, E.; Nun, P.;
Colacino, F. M.; Martinez, J.; Lamaty, F. Tetrahedron 2008, 64, 5569.
(3) (a) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.; Hu, J. J. Am.
́
Chem. Soc. 2013, 135, 2955. (b) Folleas, B.; Marek, I.; Normant, J.-F.;
Saint-Jalmes, L. Tetrahedron 2000, 56, 275. (c) Burton, D. J.; Lu, L. In
Organofluorine Chemistry, Techniques and Synthons; Chambers, R. D.,
Ed.; Springer: Berlin, 1997; pp 46−89. (d) Burton, D. J.; Yang, Z. Y.
Tetrahedron 1992, 48, 189.
(4) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393. (b) Ruppert, I.; Schlich, K.; Volbach, W.
Tetrahedron Lett. 1984, 25, 2195.
(5) For reviews, see: (a) Prakash, G. K. S.; Mandal, M. J. Fluorine
Chem. 2001, 112, 123. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron
2000, 56, 7613.
(6) (a) Dilman, A.; Levin, V. V. Eur. J. Org. Chem. 2011, 831.
(b) Shevchenko, N. E.; Vlasov, K.; Nenajdenko, V. G.; Roschenthaler,
̈
G.-V. Tetrahedron 2011, 67, 69. (c) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Eur. J. Org.
Chem. 2008, 5226. (d) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A.
J. Org. Chem. 2007, 72, 8604.
(7) (a) Radix-Large, S.; Billard, T.; Langlois, B. R. J. Fluorine Chem.
2003, 124, 147. (b) Billard, T.; Langlois, B. R. Tetrahedron Lett. 1996,
37, 6865.
(8) (a) Berber, H.; Brigaud, T.; Lefebvre, O.; Plantier-Royon, R.;
Portella, C. Chem. Eur. J. 2001, 7, 903. (b) For a review, see: Portella,
C.; Brigaud, T.; Lefebvre, O.; Plantier-Royon, R. J. Fluorine Chem.
2000, 101, 193.
(9) Prakash, G. K. S.; Panja, C.; Vaghoo, H.; Surampudi, V.;
Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J. Org.
Chem. 2006, 71, 6806.
(10) For nucleophilic trifluoromethylation reactions with HCF3 as
the donor, see ref 1 and: (a) van der Born, D.; Herscheid, J. D. M.;
Orru, R. V. A.; Vugts, D. J. Chem. Commun. 2013, 49, 4018. (b) Large,
S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848.
(11) For nucleophilic trifluoromethylation reactions with trifluor-
oacetaldehyde and analogues, see: (a) Prakash, G. K. S.; Zhan, Z.;
Wang, F.; Munoz, S.; Olah, G. A. J. Org. Chem. 2013, 78, 3300.
(b) Riofski, M. V.; Hart, A. D.; Colby, D. A. Org. Lett. 2013, 15, 208.
(c) Langlois, B. R.; Billard, T. Synthesis 2003, 185. (d) Billard, T.;
Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001, 1467. (e) Billard, T.;
Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101. (f) Jablonski, L.;
Joubert, J.; Billard, T.; Langlois, B. R. Synlett 2002, 230.
(12) Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.;
Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed.
2011, 50, 7153.
(13) Adams, D. J.; Clark, J. H.; Hansen, L. B.; Sanders, V. C.;
Tavener, S. J. J. Chem. Soc., Perkin Trans. 1 1998, 3081.
(14) Adams, D. J.; Clark, J. H.; Hansen, L. B.; Sanders, V. C.;
Tavener, S. J. J. Fluorine Chem. 1998, 92, 123.
(15) Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng, J.-a.
J. Am. Chem. Soc. 1990, 112, 7619.
(16) (a) Boxer, M. B.; Yamamoto, H. Org. Lett. 2008, 10, 453.
(b) Brown, H. C.; Naik, R. G.; Bakshi, R. K.; Pyun, C.; Singaram, B. J.
Org. Chem. 1985, 50, 5586.
(17) TMAF was shown to react slowly with CH2Cl2 affording
substitution products; see: Christe, K. O.; Wilson, W. W. J. Fluorine
Chem. 1990, 47, 117.
(18) A reaction between TMAF and CF3-TMS occurs in acetonitrile
or THF to form soluble intermediates; see ref 14 and: Maggiarosa, N.;
Tyrra, W.; Naumann, D.; Kirij, N. V.; Yagupolskii, Y. L. Angew. Chem.,
Int. Ed. 1999, 38, 2252.
(19) We thank the reviewers for their valuable comments and
suggestions concerning alternative mechanistic pathways.
(20) (a) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem. 2013,
2692. (b) Fu, Y.; Liu, Y.; Chen, Y.; Hugel, H. M.; Wang, M.; Huang,
̈
D.; Hu, Y. Org. Biomol. Chem. 2012, 10, 7669. (c) Kaliappan, K. P.;
Das, P.; Chavan, S. T.; Sabharwal, S. G. J. Org. Chem. 2009, 74, 6266.
F
dx.doi.org/10.1021/jo402028r | J. Org. Chem. XXXX, XXX, XXX−XXX