Stereospecific asymmetric N-heterocyclic carbene (NHC)-catalyzed redox synthesis of trifluoromethyl dihydropyranones and mechanistic insights

Article abstract of DOI:10.1021/jo401433q

N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of α-aroyloxyaldehydes with β-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-β- trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.

Full text of DOI:10.1021/jo401433q

Article
pubs.acs.org/joc
Stereospecific Asymmetric N‑Heterocyclic Carbene (NHC)-Catalyzed
Redox Synthesis of Trifluoromethyl Dihydropyranones and
Mechanistic Insights
Alyn T. Davies,† James E. Taylor,† James Douglas,† Christopher J. Collett,† Louis C. Morrill,†
Charlene Fallan,† Alexandra M. Z. Slawin,† Gwydion Churchill,‡ and Andrew D. Smith*,†
†EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, United Kingdom
‡Process Research and Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA, United Kingdom
S
* Supporting Information
ABSTRACT: N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels−Alder reactions of α-aroyloxyaldehydes
with β-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl
substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee).
The process is stereospecific, with use of either (E)- or (Z)-β-trifluoromethyl enones forming syn- or anti-dihydropyranone
products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity
between chiral NHC precursor 1 and an achiral NHC precursor.
tively.9−11 In this regard, Bode and co-workers showed that
either α-chloroaldehydes or their bisulfite adducts could be
used as azolium enolate precursors in hetero-Diels−Alder
reactions with both (E)-β,γ-unsaturated α-ketoesters and (E)-
INTRODUCTION
■
The trifluoromethyl unit is widely employed within the
pharmaceutical, agrochemical, and materials industries due to
the unique physicochemical properties it can impart onto
molecules.1 In particular, heterocycles containing a stereogenic
α,β-unsaturated γ-ketoesters to form dihydropyranones with
high syn diastereoselectivity (Scheme 1).8a,b Other NHC-
trifluoromethyl group represent a major structural class of
biologically active compounds.2 The development of new
catalyzed redox [4+2] cycloadditions have been performed
using azolium enolates generated from α-chloroaldehydes,8c−e
catalytic methodologies for the asymmetric introduction of
enals,9 formyl cyclopropanes,10 and ketenes.11 In all these cases,
trifluoromethyl groups into versatile synthetic building blocks is
therefore a worthwhile goal.3 Within the field of organo-
the heterocyclic products are formed preferentially as their syn
catalysis, a number of methods have been developed for the
asymmetric introduction of fluorine atoms.4 One general
strategy for the organocatalytic construction of stereogenic
trifluoromethyl centers is asymmetric functionalization of
prochiral trifluoromethylated substrates.3a For example, con-
jugate additions of various nucleophiles into β-trifluoromethyl
enones have been catalyzed by proline derivatives,5a thiour-
eas,5b,c and Cinchona alkaloids.5d−g
N-Heterocyclic carbene (NHC)-redox catalysis is a rapidly
emerging area of organocatalysis.6,7 The addition of NHCs to
aldehydes bearing an α-reducible functional group allows access
to three distinct catalytic intermediates: acyl azoliums, azolium
enolates, and homoenolates, which can be used in a range of
further reactions. For example, azolium enolates generated
through NHC-redox catalysis undergo asymmetric hetero-
Diels−Alder reactions with unsaturated ketoesters or ketimines
to form dihydropyranones or dihydropyridinones, respec-
diastereoisomers. Interestingly, in some cases, cycloadditions of
azolium enolates generated by deprotonation of an acyl azolium
intermediate give products with preference for the anti
diastereoisomer. For example, Chi et al. found that p-
nitrophenyl esters react with (E)-α,β-unsaturated ketimines
using NHC catalysis to give anti-dihydropyridinones.12 Addi-
tionally, Rovis et al. reported that enolate equivalents generated
from aldehydes and NHCs using a stoichiometric oxidant react
with (E)-α,β-unsaturated ketimines to give anti-dihydropyr-
idinones (Scheme 1).13a However, azolium enolates formed
under identical oxidative conditions react with (E)-chalcones to
give syn-dihydropyranones.13b To date, the differing stereo-
selectivity in these processes has not been rationalized.
Received: July 10, 2013
Published: August 19, 2013
© 2013 American Chemical Society
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Scheme 1. Hetero-Diels−Alder Reactions of of Enones and α,β-Unsaturated Ketimines with Azolium Enolates
Herein we report the first example of an asymmetric NHC-
catalyzed redox [4+2] cycloaddition using β-trifluoromethyl
enones to form synthetically useful dihydropyranone products
bearing a stereogenic trifluoromethyl substituent. In particular,
the stereospecificity of this process has been demonstrated
through the use of either (E)- or (Z)-β-trifluoromethyl enones
to form either syn- or anti-dihydropyranones.14 We also detail
preliminary mechanistic insights into the reaction through
kinetic analysis and isolation of key reaction intermediates.
Table 1. Initial NHC-Catalyzed Redox [4+2] Cycloaddition
Using α-Aroyloxyaldehyde 3
RESULTS AND DISCUSSION
■
Stereospecific NHC-Catalyzed Redox Hetero-Diels−
Alder Reactions with β-Trifluoromethyl Enones. Having
previously reported that p-nitrobenzoyloxyaldehydes are bench
stable alternatives to α-haloaldehydes in NHC-catalyzed redox
esterifications,15 we evaluated their potential as azolium enolate
precursors for [4+2] cycloadditions with β-trifluoromethyl
enones. α-Aroyloxyaldehydes 2−6 are readily prepared in one
step on a gram scale from the parent aldehyde and p-
nitrobenzoic acid using the α-oxyacylation methodology
developed by Ishihara and co-workers.16,17 Initial studies
found that α-aroyloxyaldehyde 3 reacted with (E)-4,4,4-
trifluoro-1-phenylbut-2-en-1-one using 10 mol % achiral
triazolium NHC precatalyst 7 and triethylamine in THF at
room temperature to give dihydropyranone 8 predominantly as
its syn diastereoisomer but in a disappointing 17% yield (Table
1, entry 1). Pleasingly, chiral triazolium precatalyst 1 proved
significantly more reactive, giving dihydropyranone 8 in 63%
yield as its syn diastereoisomer (>95:5 dr) in >99% ee (Table 1,
entry 2). A possible explanation for the surprising difference in
reactivity between achiral NHC precatalyst 7 and chiral
precatalyst 1 was subsequently found using kinetic analysis
(vide infra).
a
1
Values for dr determined by H NMR analysis of the crude product.
b
Values for ee determined by HPLC analysis.
rich p-MeOC6H4 substituted β-trifluoromethyl enone required
24 h to reach completion, with syn-dihydropyranone 9 isolated
in 73% yield and >99% ee. The process could be applied to o-
MeOC6H4 substituted trifluoromethyl enone, although modi-
fied conditions using Cs2CO3 and heating the reaction at 40 °C
were required to give product 10 in 60% yield as a single
enantiomer. The presence of electron-withdrawing p-NO2C6H4
and p-BrC6H4 substituents significantly increased the rate of
reaction to the extent that p-NO2C6H4 β-trifluoromethyl enone
had to be added slowly via syringe pump to avoid side
reactions. The p-BrC6H4 substituted dihydropyranone 12
provided confirmation of the relative and absolute config-
uration through X-ray crystallographic analysis.18 The presence
of heteroaromatic 3-pyridyl and 2-furyl substituents was also
tolerated, giving the major syn products 13 and 14 in good
Encouraged by this initial result, the scope of the reaction
was explored using a series of aryl substituted (E)-β-
trifluoromethyl enones (Table 2). The reaction with electron-
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a,b,c
Table 2. [4+2] Cycloadditions with (E)-β-Trifluoromethyl Enones
a
b
c
Isolated yields of major diastereoisomer. Values for dr determined by 1H NMR analysis of the crude product. Values for ee determined by HPLC
d
e
analysis. Reaction using Cs2CO3 (1 equiv) at 40 °C. β-Trifluoromethyl enone added via syringe pump over 1 h.
yields (63% and 53%, respectively) and excellent ee (>99%).
However, alkyl substituted β-trifluoromethyl enones were
significantly less reactive in this process, giving reduced
conversion into the desired dihydropyranones.19 Next, the
substituent on the α-aroyloxyaldehyde was varied in reactions
with the phenyl substituted β-trifluoromethyl enone. Both
methyl and isobutyl substituted α-aroyloxyaldehydes (2 and 4)
worked well, giving the corresponding syn-dihydropyranones
(15 and 16) in high yields (69% and 70%, respectively) and
>99% ee. The reaction using α-aroyloxyaldehyde 6 gave syn-
dihydropyranone 18 with a pendant O-benzyl substituent in
81% yield as a single enantiomer. However, the reaction with α-
aroyloxyaldehyde 5 gave reduced diastereoselectivity, with
dihydropyranone 17 formed as a 89:11 syn:anti mixture. The
reaction of α-aroyloxyaldehyde 2 with p-MeOC6H4 substituted
β-trifluoromethyl enone also gave a lower dr, with product 19
obtained as a 89:11 syn:anti mixture after 40 h.
Table 3. [4+2] Cycloadditions with (Z)-β-Trifluoromethyl
Enones
a,b,c
We next probed the stereospecificity of this process using
(Z)-β-trifluoromethyl enones as substrates. In this case, the
reaction of (Z)-4,4,4-trifluoro-1-phenylbut-2-en-1-one with α-
aroyloxyaldehyde 3 using 10 mol % 1 formed anti-
dihydropyranone 20 as a single diastereoisomer, which was
isolated in 65% yield and 99% ee. This methodology was then
applied to a small number of (Z)-β-trifluoromethyl enones
(Table 3). The reaction of p-BrC6H4 substituted (Z)-β-
a
b
Isolated yields of major diastereoisomer. Values for dr determined
c
1
by H NMR analysis of the crude product. Values for ee determined
by HPLC analysis. Reaction using Et3N (1.5 equiv). Reaction at 40
°C. Reaction using 2 equiv of aldehyde.
d
e
f
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trifluoromethyl enone with α-aroyloxyaldehyde 3 was found to
be sluggish under the standard reaction conditions. However,
under modified conditions using Cs2CO3 as the base and two
equiv of α-aroyloxaldehyde 3, and performing the reaction at 40
°C, anti-dihydropyranone 21 could be isolated in 71% yield and
96% ee. These modified conditions also proved to be optimal
for the reaction with 2-furyl substituted (Z)-β-trifluoromethyl
enone, providing anti-dihydropyranone 22 in 67% yield and
95% ee. The protocol was used with α-aroyloxyaldehydes 2 and
6, forming the corresponding anti-dihydropyranones 23 and 24
in high yield (66% and 79%, respectively) and excellent ee.
The stereospecific nature of the observed reversal in
diastereoselectivity and the absolute configuration of the anti
products were confirmed through an epimerization experiment.
Treating syn-dihydropyranone 15 with triethylamine in CH2Cl2
resulted in a 58:42 syn:anti mixture after 16 h with no loss in ee
in either diastereoisomer (Scheme 2). In this case, the
between the phenyl (E)-β-trifluoromethyl enone and α-
aroyloxyaldehyde 3 was repeated on a gram scale to give syn-
dihydropyranone 8 (1.92 g) in 74% yield and >99% ee.
Treatment of syn-dihydropyranone 8 with methanol and 10
mol % 4-dimethylaminopyridine (DMAP) gave the ring-
opened ester 25 in good yield and 97% ee. Hydrogenolysis
of syn-dihydropyranone 8 with Pd/C resulted in reduction of
the alkene functionality with concomitant C−O bond cleavage
to give acid 26 as a single diastereoisomer.20 The ring opening
with methanol and the reduction could also be performed on
anti-dihydropyranone 20, obtained from the cycloaddition
using the phenyl (Z)-β-trifluoromethyl enone, to give the
diastereomeric ester 27 and acid 28.
Mechanistic Studies. The proposed catalytic cycle for
these transformations is based upon that suggested by Bode
and co-workers for related [4+2] cycloaddition reactions
(Scheme 4).9b,21 Initially, the active NHC catalyst adds to the
Scheme 2. Base Promoted Epimerization of
Dihydropyranone 15
Scheme 4. Proposed Catalytic Cycle
ab
,
a
1
Values for dr determined by H NMR analysis of the crude reaction
b
mixture. Values for ee determined by HPLC analysis.
enantiomer of anti-dihydropyranone 23 formed was opposite
to that obtained using the (Z)-β-trifluoromethyl enone. The
results are consistent with epimerization of these products
occurring at the C(3) position and the configuration of the
C(4) stereocenter being dependent upon the enone geometry.
Derivatizations. The utility of the trifluoromethyl sub-
stituted dihydropyranones was demonstrated through a series
of derivatizations to generate synthetically useful building
blocks containing a stereogenic trifluoromethyl group (Scheme
3). First, the NHC-catalyzed redox hetero-Diels−Alder reaction
a b
,
Scheme 3. Derivatization Reactions
a
b
1
Values for dr determined by H NMR analysis of the crude product. Values for ee determined by HPLC analysis.
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Figure 1. Kinetic profile using achiral NHC precatalyst 7.
α-aroyloxyaldehyde to form an adduct,22 which is deprotonated
to form the Breslow intermediate. Presumably, rapid
elimination of p-nitrobenzoate followed by deprotonation
forms an azolium enolate, which is thought to undergo an
asynchronous endo-hetero-Diels−Alder reaction with the
enone.21a
Scheme 5. Isolation of (a) Initial NHC−Aldehyde Adduct 29
a
and (b) O-Acylated Enone 30
Kinetic studies were performed to gain further insight into
the mechanism of these NHC-catalyzed cycloadditions. In
particular, we were interested in understanding why achiral
precatalyst 7 is ineffective compared with 1 and the fate of the
excess α-aroyloxyaldehyde during the reaction. To study these
observations, kinetic profiles of the reaction between α-
aroyloxyaldehyde 2 and p-MeOC6H4 substituted β-trifluor-
omethyl enone in CD2Cl2 were determined using characteristic
1
signals of each species in the H NMR spectrum relative to an
internal standard.23 With achiral salt 7 (Figure 1), the
triazolium precatalyst is quickly consumed and forms adduct
29 as a 50:50 mixture of diastereoisomers, which is consistent
with our previous mechanistic studies of the benzoin and
Stetter reactions.24 This initial adduct could be isolated and
fully characterized from a stoichiometric reaction of precatalyst
7 with aldehyde 2, with purification enriching the diaster-
eoselectivity to 83:17 (Scheme 5a). The kinetic profile shows
that aldehyde 2 is consumed at a faster rate than the enone,
with dihydropyranone 19 being formed slowly. Control
experiments showed that α-aroyloxyaldehyde 2 undergoes
reaction in the absence of the enone, with much of the
consumed aldehyde converted into propanoic acid presumably
through hydrolysis of the corresponding acyl azolium species
a
1
Conversion determined by H NMR analysis.
with precatalyst 7 also showed the buildup of another
unexpected species over time, which was identified as O-
acylated enolate 30.25 This side product could be isolated from
the stoichiometric reaction of triazolium salt 7 and α-
aroyloxyaldehyde 2 if left for extended periods of time (Scheme
5b). Additionally, O-acylated enolate 30 can be observed by 1H
NMR spectroscopy if isolated adduct 29 is re-treated with an
excess of aldehyde 2 in CD2Cl2.
1
with adventitious water. The H NMR spectra of the reaction
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Figure 2. Kinetic profile using chiral NHC precatalyst 1.
Further studies found that O-acylated enolate 30 is
completely unreactive under the reaction conditions and thus
represents a catalytic dead end.26 One possible mechanism for
the formation of 30 is through O-acylation of initial adduct 29
with an acyl azolium species, presumably formed through
equilibration with the corresponding azolium enolate, followed
by base promoted elimination of p-nitrobenzoate. The
spectroscopic observation of propanoic acid and O-acylated
enolate 30 under catalytic conditions using achiral NHC
precatalyst 7, combined with the slow rate of product
formation, account for the poor observed activity of this
catalyst.
much more reactive toward the hetero-Diels−Alder reaction
compared with achiral NHC salt 7. The rate of product
formation is also much greater than those for the unwanted side
reactions of the aldehyde with NHC 1.
Finally, the rate-determining step of the process was probed
through a 2H kinetic isotope effect (KIE). Measurement of the
initial rates of reaction with α-aroyloxyaldehyde 5 and its
deuterated analogue 5-D under the standard reaction
conditions revealed a kH/kD of 2.19 (Scheme 6).29,30 This
Scheme 6. Kinetic Isotope Effect Measurement
The kinetic experiments were then repeated using chiral
NHC salt 1 (Figure 2). The triazolium precatalyst is quickly
consumed and forms initial adduct 31 as a single
diastereoisomer.27 The β-trifluoromethyl enone and α-aroylox-
yaldehyde 2 are rapidly consumed at the start of the reaction, at
a much faster rate than the rate when the achiral catalyst 7 is
used, which also correlates with rapid formation of dihydropyr-
anone product 19. Only after 45 min does the rate of
consumption of aldehyde 2 increase beyond that of the enone.
However, in this case, the decomposition products of α-
aroyloxyaldehyde 2 could not be identified. Importantly, no
peaks corresponding to either propanoic acid or the equivalent
suggests that deprotonation of the adduct formed between
NHC 1 and the α-aroyloxyaldehyde to form the Breslow
intermediate is a kinetically significant step in these [4+2]
cycloadditions.
1
O-acylated enolate were observed in the H NMR spectra of
CONCLUSION
the reaction using chiral NHC 1, although they could still be
present in low concentrations.28 These results are consistent
with the azolium enolate formed with NHC precatalyst 1 being
■
Synthetically useful syn- and anti-dihydropyranones containing
a stereogenic trifluoromethyl substituent can be synthesized
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ethyl acetate (125 mL), and tert-butyl hydroperoxide (5.00 mL, 27.5
mmol) were reacted as described in the general procedure and purified
by column chromatography on silica (85:15 petrol:EtOAc) to give 1-
oxohexan-2-yl 4-nitrobenzoate 3 as an orange oil (4.22 g, 15.9 mmol,
64%): IR νmax (film) 2958 (CH), 1724 (CHO), 1525 (NO2), 1346
(NO2); 1H NMR (400 MHz, CDCl3) δH 0.88 (3H, t, J 7.2, CH2CH3),
1.30−1.38 (2H, m, CH2), 1.39−1.50 (2H, m, CH2), 1.80−2.03 (2H,
m, CH2), 5.22−5.27 (1H, m, CHCHO), 8.20 (2H, d, J 8.8, ArC(3)H),
8.26 (2H, d, J 8.8, ArC(2)H), 9.57 (1H, s, CHO); 13C{1H} NMR (100
MHz, CDCl3) δC 13.8 (CH2CH3), 22.4 (CH2), 27.1 (CH2), 28.3
(CH2), 79.6 (CHCHO), 123.7 (ArC(2)), 131.0 (ArC(3)), 134.6
(OCOAr), 150.8 (ArC(1)), 164.2 (ArC(4)), 197.1 (CHO); HRMS
(NSI+) m/z [M + H]+ calcd for C13H16O5N 266.1023, found
266.1020.
stereospecifically through NHC-catalyzed redox hetero-Diels−
Alder reactions of either (E)- or (Z)-β-trifluoromethyl enones
with α-aroyloxyaldehydes. Kinetic experiments revealed the
formation of O-acylated enolate species 30 when achiral
precatalyst 7 was used in these reactions, accounting for the
differences in reactivity observed compared with chiral
precatalyst 1. The measurement of a positive KIE suggests
that deprotonation of the NHC−aldehyde adduct to form the
Breslow intermediate is kinetically significant. Current research
within this laboratory is focused upon developing novel
asymmetric processes utilizing α-aroyloxyaldehydes as azolium
enolate precursors.
4-Methyl-1-oxopentan-2-yl 4-Nitrobenzoate (4). Compound (4)
was made via an alternative route. First, to a stirred solution of
isovaleraldehyde (2.79 mL, 26.0 mmol) in THF (50 mL) was added
vinyl magnesium bromide (0.7 M in THF, 40.9 mL, 28.6 mmol)
dropwise at −78 °C, and the resulting solution was stirred for 30 min.
Lithium chloride (1.32 g, 31.2 mmol) was added, followed by p-
nitrobenzoyl chloride (5.79 g, 31.2 mmol), and the reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was
quenched with water, separated with ethyl acetate, dried with sodium
sulfate, filtered, and concentrated in vacuo to give the crude product,
which was purified by column chromatography on silica (95:5
petrol:EtOAc) to give 5-methylhex-1-en-3-yl 4-nitrobenzoate as a
yellow oil (2.32 g, 8.82 mmol, 35%): 1H NMR (500 MHz, CDCl3) δH
0.90 (6H, dd, J 6.5, 4.1, CH3), 1.49 (1H, ddd, J 12.9, 7.1, 5.6,
(CH3)2CH), 1.61−1.77 (2H, m, CH2), 5.17 (1H, dt, J 10.5, 1.1,
HaHbCCH), 5.28 (1H, dt, J 17.2, 1.2, HaHbCCH), 5.52 (1H, ddd,
J 8.2, 6.8, 5.6, H2CCHCH), 5.81 (1H, ddd, J 17.2, 10.5, 6.7, H2C
CH), 8.15 (2H, d, J 8.8, ArH), 8.22 (2H, d, J 8.8, ArH).
5-Methylhex-1-en-3-yl 4-nitrobenzoate (1.00 g, 3.80 mmol) was
dissolved in CH2Cl2 (400 mL), subjected to ozonolysis, and then
quenched with dimethyl sulfide (0.558 mL, 7.60 mmol). The resulting
mixture was concentrated in vacuo to give the crude product and
purified using column chromatography on silica (80:20 petrol:EtOAc)
to give 4-methyl-1-oxopentan-2-yl 4-nitrobenzoate 4 as a pale yellow
oil (0.560 g, 2.11 mmol, 56%) with spectroscopic data in accordance
with the literature:15 1H NMR (500 MHz, CDCl3) δH 0.86−0.98 (3H,
m, CH3), 1.02 (3H, dd, J 13.3, 6.4, CH3), 1.76−1.94 (3H, m,
(CH3)2CH and CH2), 5.37 (1H, dd, J 9.2, 4.4, CHCHO), 8.27 (2H, d,
J 8.8, ArH), 8.33 (2H, d, J 8.8, ArH), 9.63 (1H, s, CHO).
1-Oxo-3-phenylpropan-2-yl 4-Nitrobenzoate (5). 3-Phenylpropio-
naldehyde (4.93 mL, 37.5 mmol), p-nitrobenzoic acid (4.18 g, 25
mmol), tetrabutylammonium iodide (1.85 g, 5.00 mmol) and
piperidine (0.25 mL, 2.50 mmol) in ethyl acetate (125 mL), and
tert-butyl hydroperoxide (5.00 mL, 27.5 mmol) were reacted as
described in the general procedure and purified by column
chromatography on silica (60:40 hexane: EtOAc) to give 1-oxo-3-
phenylpropan-2-yl 4-nitrobenzoate 5 as a pale yellow solid (3.40 g,
45%), with spectroscopic data in accordance with the literature:15 mp
85−86 °C; 1H NMR (400 MHz, CDCl3) δH 3.15 (1H, dd, J 14.5, 8.4,
PhCHaHb), 3.28 (1H, dd, J 14.5, 4.9, PhCHaHb), 5.45 (1H, dd, J 8.4,
4.9, CHCHO), 7.14−7.31 (5H, m, PhH), 8.11 (2H, d, J 8.9, ArH),
8.23 (2H, d, J 8.8, ArH), 9.61 (1H, s, CHO).
EXPERIMENTAL SECTION
■
General Information. All reactions were performed in flame-dried
glassware using anhydrous solvents. All reagents were obtained from
commercial sources and were used without further purification. Room
temperature (rt) refers to 20−25 °C, with temperatures of 0 and −78
°C obtained using ice/water and CO2(s)/acetone baths, respectively.
1H NMR spectra were acquired at 300, 400, or 500 MHz, 13C{1H}
NMR spectra were acquired at 75, 100, or 125 MHz, and 19F{1H}
NMR spectra were acquired at 282, 376, or 471 MHz. Chemical shifts
are quoted in parts per million (ppm) relative to the residual solvent
peak. Coupling constants, J, are quoted in Hertz (Hz). NMR peak
assignments were confirmed using 2D 1H correlated spectroscopy
1
(COSY), 2D H nuclear Overhauser effect spectroscopy (NOESY),
2D 1H−13C heteronuclear multiple-bond correlation spectroscopy
1
(HMBC), and 2D H−13C heteronuclear single quantum coherence
(HSQC) where necessary. Infrared spectra were recorded as thin films
using an attenuated total reflectance (ATR) accessory. Mass
spectrometry (m/z) data was acquired using electrospray ionization
(ESI), electron impact (EI), chemical ionization (CI), atmospheric
solids analysis probe (ASAP), atmospheric pressure chemical
ionization (APCI), or nanospray ionization (NSI) using a time of
flight (TOF) mass analyzer. Optical rotations were recorded with a
path length of 1 dm and concentrations, c, are quoted in g/100 mL. All
chiral high-performance liquid chromatography (HPLC) traces were
compared with an authentic racemic trace prepared using racemic 1.
General Procedure for the Synthesis of α-Aroyloxyalde-
hydes. On the basis of a literature procedure,16 tert-butyl hydro-
peroxide (5−6 M in decane) was added to a solution of the
appropriate aldehyde (1.5 equiv), p-nitrobenzoic acid (1 equiv),
tetrabutylammonium iodide (20 mol %), and piperidine (10 mol %) in
ethyl acetate (to make 0.2 M solution of acid). The resulting solution
was heated at 50 °C for 5 h before being cooled to room temperature
and quenched with Na2S2O3 and NaHCO3. The phases were
separated, the aqueous phase was extracted with ethyl acetate (×2),
and the combined organics were washed with brine before being dried
over MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography.
1-Oxopropan-2-yl 4-Nitrobenzoate (2). Propionaldehyde (2.71
mL, 37.5 mmol), p-nitrobenzoic acid (4.18 g, 25 mmol),
tetrabutylammonium iodide (1.85 g, 5.00 mmol) and piperidine
(0.25 mL, 2.50 mmol) in ethyl acetate (125 mL), and tert-butyl
hydroperoxide (5.00 mL, 27.5 mmol) were reacted as described in the
general procedure and purified by column chromatography on silica
(70:30 petrol:EtOAc) to give 1-oxopropan-2-yl 4-nitrobenzoate 2 as a
light yellow solid (4.35 g, 78%): mp 78−80 °C; IR νmax (film) 1722
1-Oxo-3-phenyl(1-2H)propan-2-yl 4-Nitrobenzoate (5-D). To a
flamed-dried two-neck round-bottomed flask fitted with a dropping
funnel under an atmosphere of N2 was added LiAlD4 (1 M in THF, 20
mL, 20 mmol) and THF (20 mL) before the solution was cooled to 0
°C. A solution of methyl 3-phenylpropanoate (2.18 g, 13.3 mmol) in
THF (18 mL) was added dropwise to the mixture via a dropping
funnel over ca. 30 min. After the reaction mixture was stirred at 0 °C
for 3 h, the reaction mixture was quenched by adding 1 M KOH (10
mL) dropwise via a dropping funnel. The resulting suspension was
stirred for 1 h before being filtered through a pad of Celite, washing
with EtOAc. The filtrate was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to give the deuterated alcohol as a
colorless oil (1.60 g, 87%) with spectroscopic data in accordance with
the literature:31 1H NMR (400 MHz, CDCl3) δH 1.35 (1H, br s, OH),
1
(CO); H NMR (500 MHz, CDCl3) δH 1.53 (3H, d, J 7.2, CH3),
5.32 (1H, q, J 7.2, CH3CH), 8.21 (2H, d, J 8.9, C(2)H), 8.26 (2H, d, J
8.9, C(3)H), 9.60 (1H, s, CHO); 13C{1H} NMR (101 MHz, CDCl3)
δC 14.2 (CH3), 75.9 (CH3CH), 123.7 (ArC(2)), 131.0 (ArC(3)),
134.5 (ArC(1)), 150.8 (CO2), 164.1 (ArC(4)), 197.2 (CHO); HRMS
(NSI+) m/z [M + H]+ calcd for C10H10O5N 224.0553, found
224.0556.
1-Oxohexan-2-yl 4-Nitrobenzoate (3). Hexanal (4.50 mL, 37.5
mmol), p-nitrobenzoic acid (4.18 g, 25 mmol), tetrabutylammonium
iodide (1.85 g, 5.00 mmol) and piperidine (0.25 mL, 2.50 mmol) in
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1.89 (2H, t, J 7.7, CH2CD2), 2.71 (2H, t, J 7.7, PhCH2), 7.17−7.23
(3H, m, ArH), 7.25−7.31 (2H, m, ArH).
7.1, 1.6, CH2), 3.51 (2H, t, J 6.1, OCH2), 4.49 (2H, s, ArCH2), 7.26−
7.38 (5H, m, ArH), 9.79 (1H, t, J 1.6, CHO).
4-(Benzyloxy)butanal (4.18 g, 23.5 mmol), p-nitrobenzoic acid
(2.62 g, 15.7 mmol), tetrabutylammonium iodide (1.16 g, 3.14 mmol)
and piperidine (155 μL, 1.57 mmol) in ethyl acetate (100 mL), and
tert-butyl hydroperoxide (3.15 mL, 17.3 mmol) were reacted as
described in the general procedure and purified by column
chromatography on silica (80:20 petrol:EtOAc) to give 4-(benzyl-
oxy)-1-oxobutan-2-yl 4-nitrobenzoate 6 as a yellow oil (4.26 g, 12.4
mmol, 79%): IR νmax (film) 2800 (CH), 1732 (CO), 1716 (C
O), 1521 (NO2), 1269 (NO2); 1H NMR (400 MHz, CDCl3) δH 2.29
(2H, q, J 5.8, CH2), 3.53−3.77 (2H, m, CH2), 4.47 (2H, d, J 1.4,
ArCH2), 5.47 (1H, t, J 5.8, CHCHO), 7.20−7.36 (5H, m, PhH),
8.12−8.16 (2H, m, ArH), 8.23−8.28 (2H, m, ArH), 9.63 (1H, s,
CHO); 13C{1H} NMR (101 MHz, CDCl3) δC 29.7 (CH2), 64.6
(OCH2), 73.2 (PhCH2), 77.0 (CHCHO), 123.6 (ArC(3)), 127.8
(PhC(4)), 127.9 (PhC(2) or PhC(3)), 128.5 (PhC(2) or PhC(3)),
131.0 (ArC(2)), 134.6 (ArC(1)), 137.6 (PhC(1)), 150.8 (ArC(4)),
164.0 (CO2Ar), 196.6 (CHO); HRMS (NSI+) m/z [M + H]+ calcd for
C18H18O6N 344.1129, found 344.1131.
General Procedure for the Synthesis of β-Trifluoromethyl
Enones. Following the procedure of Yamazaki et al.,33a n-butyl lithium
(2.5 M in hexane, 2.2 equiv) was added to a solution of
diisopropylamine (2.2 equiv) in THF (0.8 M) at −78 °C, and the
solution was stirred for 20 min. A precooled solution of 2-bromo-3,3,3-
trifluoroprop-1-ene (1.0 equiv) in THF (0.5 M) was added dropwise
at −78 °C, and the reaction mixture was stirred for 5 min before the
appropriate aldehyde (1.2 equiv) was added dropwise. The reaction
mixture was stirred for 30 min before being quenched with aqueous 1
M HCl (10 equiv). The resulting solution was extracted with ethyl
acetate (×3), and the combined organics were dried over Na2SO4,
filtered, and concentrated in vacuo to give the crude trifluoropro-
pargylic alcohol, which was used without further purification.
Deuterated alcohol (1.60 g, 11.7 mmol) was added to a two-neck
round-bottomed flask containing DMSO (7.9 mL, 35.1 mmol), Et3N
(11.4 mL, 111.2 mmol), and CH2Cl2 (100 mL), and the resulting
solution was cooled to 0 °C. Sulfur trioxide pyridine complex (5.6 g,
35.1 mmol) was added portionwise for ca. 15 min, and the solution
was stirred at 0 °C for 1 h before being warmed to rt. After the mixture
was stirred for 2 h, TLC analysis showed complete consumption of the
starting material, and the reaction mixture was quenched with
saturated aq NH4Cl (50 mL), the organic layer was separated and
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by column chromatography on
silica (90:10 petrol:EtOAc, Rf 0.38) to give a deuterated aldehyde as a
colorless oil (1.10 g, 69%) with spectroscopic data in accordance with
the literature:31 1H NMR (300 MHz, CDCl3) δH 2.79−2.84 (2H, m,
CH2COD), 2.99 (2H, br t, J 7.6, PhCH2), 7.20−7.27 (3H, m, ArH),
7.28−7.36 (2H, m, ArH).
Deuterated aldehyde (1.10 g, 8.1 mmol), p-nitrobenzoic acid (2.04
g, 12.2 mmol), tetrabutylammonium iodide (0.60 g, 1.6 mmol),
piperidine (0.08 mL, 0.08 mmol), ethyl acetate (40 mL), and tert-butyl
hydroperoxide (1.6 mL, 8.9 mmol) were reacted as described in the
general procedure and purified by column chromatography on silica
(neat CH2Cl2 to 99:1 CH2Cl2:Et2O, Rf 0.33) to give 1-oxo-3-
phenyl(1-2H)propan-2-yl 4-nitrobenzoate 5-D as a white solid (1.06 g,
43%): mp 94−95 °C; IR νmax (film) 1728 (CO), 1709 (CO),
1
1524; H NMR (400 MHz, CDCl3) δH 3.22 (1H, dd, J 14.5, 8.4,
CHaHbPh), 3.35 (1H, dd, J 14.7, 4.9, CHaHbPh), 5.52 (1H, dd, J 8.4,
4.9, CHCHaCHbPh), 7.25−7.30 (3H, m, PhH), 7.31−7.36 (2H, m,
PhH), 8.19 (2H, app dt, J 9.0, 2.0, ArH), 8.30 (2H, app dt, J 9.0, 2.1,
ArH); 13C{1H} NMR (75 MHz, CDCl3) δC 35.3, 79.8 (t, J 3.5), 123.8,
127.5, 129.0, 129.4, 131.1, 134.5, 135.1, 164.2, COD not observed;
HRMS (NSI+) m/z [M + H]+ calcd for C16H13DO5N 301.0935, found
301.0923.
Following the procedure of Yamazaki et al.,33b triethylamine (4.0
equiv) was added to a solution of the appropriate trifluoropropargylic
alcohol (1.0 equiv) in THF (0.2 M) and heated at reflux for 16 h. The
reaction mixture was cooled, quenched with 1 M HCl (5.0 equiv), and
extracted with EtOAc. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo to give the crude β-
trifluoromethyl enone, which was purified by column chromatography.
(E)-4,4,4-Trifluoro-1-phenylbut-2-en-1-one and (Z)-4,4,4-Tri-
fluoro-1-phenylbut-2-en-1-one. n-Butyl lithium (2.5 M in hexane,
25.1 mmol, 10.0 mL), diisopropylamine (3.52 mL, 25.1 mmol) in
THF (30 mL), 2-bromo-3,3,3-trifluoroprop-1-ene (1.20 mL, 11.4
mmol) in THF (20 mL), and benzaldehyde (1.39 mL, 13.7 mmol)
were reacted as described in the general procedure to give (E)-4,4,4-
trifluoro-1-phenylbut-2-yn-1-ol as an orange oil (1.97 g, 9.83 mmol,
86%) with spectroscopic data in accordance with the literature:33a 1H
NMR (400 MHz, CDCl3) δH 2.31 (1H, br s), 5.57 (1H, q, J 3.0,
ArCHOH), 7.39−7.47 (3H, m, ArH), 7.49−7.54 (2H, m, ArH);
19F{1H} NMR (471 MHz, CDCl3) δF −50.6 (CF3).
4,4,4-Trifluoro-1-phenylbut-2-yn-1-ol (3.25 g, 16.2 mmol), triethyl-
amine (9.03 mL, 64.8 mmol), and THF (85 mL) were reacted as
described in the general procedure and purified by column
chromatography (98:2 petrol: Et2O) to give (E)-4,4,4-trifluoro-1-
phenylbut-2-en-1-one as a pale yellow crystalline solid (1.21 g, 6.02
mmol, 37%) with spectroscopic data in accordance with the
literature:34a mp 27−29 °C {lit. 28 °C}; 1H NMR (500 MHz,
CDCl3) δH 6.75 (1H, dq, J 15.6, 6.6, F3CCHCH), 7.43−7.51 (3H,
m, F3CCHCH and Ar(3)H), 7.54−7.63 (1H, m, Ar(4)H), 7.89−
7.94 (2H, m, Ar(2)H); 19F NMR (282 MHz, CDCl3) δF −65.6 (dd, J
6.6, 2.0, CF3).
4-(Benzyloxy)-1-oxobutan-2-yl 4-Nitrobenzoate (6). Sodium
hydride (60% dispersion in mineral oil, 1.60 g, 39.9 mmol) was
washed with hexane and then suspended in THF (60 mL), and the
mixture was cooled to 0 °C. Butanediol (15.0 g, 166 mmol) was added
slowly via a dropping funnel, and the resulting mixture was warmed to
rt and stirred for 2 h. The mixture was cooled to 0 °C, benzyl bromide
(4.00 mL, 33.3 mmol) in THF (8 mL) was added via a dropping
funnel, and the reaction was left stirring for 16 h while warming to rt.
The reaction mixture was quenched with saturated aq NH4Cl solution
(50 mL) and extracted with ethyl acetate, the organic layer was dried
over MgSO4, filtered, and concentrated in vacuo to give the crude
product, which was purified by column chromatography on silica
(70:30 petrol:EtOAc), and pure fractions were evaporated to dryness
to give 4-(benzyloxy)butan-1-ol as a colorless oil (5.66 g, 31.4 mmol,
94%) with spectroscopic data in accordance with the literature:32 1H
NMR (400 MHz, CDCl3) δH 1.57−1.87 (4H, m, CH2 ×2), 3.52 (2H,
t, J 5.8, OCH2), 3.65 (2H, t, J 5.8, OCH2), 4.52 (2H, s, ArCH2), 7.27−
7.39 (5H, m, ArH).
Oxalyl chloride (5.31 mL, 62.8 mmol) was dissolved in CH2Cl2
(125 mL) and the solution was cooled to −78 °C. DMSO (4.91 mL,
69.1 mmol) was added dropwise via a dropping funnel, and the
reaction mixture was left to stir for 15 min. 4-(Benzyloxy)butan-1-ol
(5.66 g, 31.4 mmol) in CH2Cl2 (15 mL) was added to the mixture
dropwise via a dropping funnel, and the reaction mixture was left to
stir for 15 min. To the reaction mixture was added triethylamine (13.1
mL, 94.2 mmol) dropwise. The resulting mixture was stirred for 5 min,
and the solution was warmed to rt and stirred for 15 min. The mixture
was diluted with ethyl acetate and washed with saturated aq NH4Cl
solution and brine. The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo to give the crude product, which was
purified by column chromatography on silica (85:15 petrol:EtOAc),
and pure fractions were evaporated to dryness to give 4-(benzyloxy)-
butanal as a pale yellow oil (4.18 g, 23.5 mmol, 75%) with
spectroscopic data in accordance with the literature:32 1H NMR
(400 MHz, CDCl3) δH 1.95 (2H, tt, J 7.1, 6.1, CH2), 2.55 (2H, td, J
(Z)-4,4,4-Trifluoro-1-phenylbut-2-en-1-one was isolated as a yellow
oil (0.340 g, 1.71 mmol, 11%): IR νmax (film) 1678 (CO); 1H NMR
(300 MHz, CDCl3) δH 6.02 (1H, dq, J 12.7, 7.9, F3CCHCH), 6.80
(1H, dd, J 12.7, 0.7, F3CCHCH), 7.39−7.48 (2H, m, ArC(3)H),
7.52−7.67 (1H, m, ArC(4)H), 7.81−7.93 (2H, m, ArC(2)H); 19F
NMR (282 MHz, CDCl3) δF −61.3 (d, J 7.9, CF3); 13C{1H} NMR
(101 MHz, CDCl3) δC 121.8 (q, J 272, CF3), 123.4 (q, J 35.6,
F3CCHCH), 128.9 (ArC(3)), 129.0 (ArC(2)), 134.3 (ArC(4)),
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135.5 (ArC(1)), 136.7 (q, J 5.0, F3CCHCH), 191.9 (COAr);
HRMS (NSI+) m/z [M + NH4]+ calcd for C10H11F3ON 218.0787,
found 218.0788.
crude product, which was purified by column chromatography (80:20
petrol:EtOAc) to give 4,4,4-trifluoro-1-(4-nitrophenyl)but-2-yn-1-ol as
an orange oil (0.428 g, 1.75 mmol, 15%), with spectroscopic data in
accordance with the literature:33b 1H NMR (300 MHz, CDCl3) δH
5.64 (1H, d, J 2.9, ArCHOH), 7.64 (1H, d, J 8.2, ArC(3)H), 8.23 (1H,
d, J 8.8, ArC(4)H); 19F NMR (282 MHz, CDCl3) δF −51.4 (d, J 3.1,
CF3).
(E)-4,4,4-Trifluoro-1-(4-methoxyphenyl)but-2-en-1-one and (Z)-
4,4,4-Trifluoro-1-(4-methoxy-phenyl)but-2-en-1-one. n-Butyl lithium
(2.5 M in hexane, 25.1 mmol, 10.0 mL), diisopropylamine (3.52 mL,
25.1 mmol) in THF (30 mL), 2-bromo-3,3,3-trifluoroprop-1-ene (1.20
mL, 11.4 mmol) in THF (20 mL), and 4-methoxybenzaldehyde (1.67
mL, 13.7 mmol) were reacted as described in the general procedure to
give 4,4,4-trifluoro-1-(4-methoxyphenyl)but-2-yn-1-ol as an orange oil
(2.62 g, 11.4 mmol, quantitative) with spectroscopic data in
accordance with the literature:33b 1H NMR (400 MHz, CDCl3) δH
3.76 (3H, s, ArC(4)OCH3), 5.44 (1H, d, J 3.0, ArCHOH), 6.87 (2H,
d, J 8.0, ArC(3)H), 7.36 (2H, d, J 8.9, ArC(2)H); 19F{1H} NMR (376
MHz, CDCl3) δF −51.0 (CF3).
4,4,4-Trifluoro-1-(4-methoxyphenyl)but-2-yn-1-ol (2.62 g, 11.4
mmol), triethylamine (6.36 mL, 45.6 mmol), and THF (50 mL)
were reacted as described in the general procedure and purified by
column chromatography (98:2 petrol:EtOAc) to give (E)-4,4,4-
trifluoro-1-(4-methoxyphenyl)but-2-en-1-one as a pale yellow crystal-
line solid (0.920 g, 4.02 mmol, 35%) with spectroscopic data in
accordance with the literature:33b mp 41−43 °C {lit. 36 °C}; 1H NMR
(300 MHz, CDCl3) δH 3.90 (3H, s, ArC(4)OCH3), 6.80 (1H, dq, J
15.6, 6.7, F3CCHCH), 6.99 (2H, d, J 8.9, F3CCHCH), 7.53 (1H,
dd, J 15.5, 2.1, ArC(3)H), 7.98 (2H, d, J 9.0, ArC(2)H); 19F NMR
(376 MHz, CDCl3) δF −65.5 (dd, J 6.6, 1.9, CF3).
(Z)-4,4,4-Trifluoro-1-(4-methoxyphenyl)but-2-en-1-one was iso-
lated as a yellow oil (0.150 g, 0.655 mmol, 6%): 1H NMR (300
MHz, CDCl3) δH 3.82 (3H, s, ArC(4)OCH3), 5.97 (1H, dq, J 12.7,
7.9, F3CCHCH), 6.76 (1H, dd, J 12.7, 0.7, F3CCHCH), 6.90
(2H, d, J 9.0, ArC(2)H), 7.83 (2H, d, J 9.0, ArC(3)H); 19F{1H} NMR
(282 MHz, CDCl3) δF −61.3 (CF3).
(E)-4,4,4-Trifluoro-1-(2-methoxyphenyl)but-2-en-1-one. n-Butyl
lithium (2.5 M in hexane, 25.1 mmol, 10.0 mL), diisopropylamine
(3.52 mL, 25.1 mmol) in THF (30 mL), 2-bromo-3,3,3-trifluoroprop-
1-ene (1.20 mL, 11.4 mmol) in THF (20 mL), and 2-
methoxybenzaldehyde (1.66 mL, 13.7 mmol) were reacted as
described in the general procedure to give 4,4,4-trifluoro-1-(2-
methoxyphenyl)but-2-yn-1-ol as an orange oil (2.54 g, 11.1 mmol,
97%) with spectroscopic data in accordance with the literature:33c 1H
NMR (300 MHz, CDCl3) δH 3.92 (3H, s, ArC(2)OCH3), 5.67 (1H, q,
J 3.1, ArCHOH), 6.92−7.08 (2H, m, ArH), 7.32−7.44 (2H, m, ArH);
19F NMR (282 MHz, CDCl3) δF −50.9 (d, J 2.9, CF3).
4,4,4-Trifluoro-1-(2-methoxyphenyl)but-2-yn-1-ol (2.54 g, 11.1
mmol), triethylamine (6.19 mL, 44.4 mmol), and toluene (50 mL)
were heated at reflux in a modified version of the general procedure
and purified by column chromatography (98:2 petrol:EtOAc) to give
(E)-4,4,4-trifluoro-1-(2-methoxyphenyl)but-2-en-1-one as a yellow oil
(1.06 g, 4.59 mmol, 41%) with spectroscopic data in accordance with
the literature:35 1H NMR (400 MHz, CDCl3) δH 3.92 (3H, s,
ArC(2)CH3), 6.66 (1H, dq, J 15.6, 6.8, F3CCHCH), 7.00 (1H, dd, J
8.5, 0.9, ArC(3)H), 7.05 (1H, td, J 7.4, 1.0, ArC(5)H), 7.47 (1H, dq, J
15.7, 2.0, F3CCHCH), 7.54 (1H, ddd, J 8.4, 7.3, 1.8, ArC(4)H),
7.72 (1H, dd, J 7.5, 1.7, ArC(6)H); 19F NMR (376 MHz, CDCl3) δF
−65.4 to −65.3 (m, CF3).
(E)-4,4,4-Trifluoro-1-(4-nitrophenyl)but-2-en-1-one and (Z)-4,4,4-
Trifluoro-1-(4-nitrophenyl)-but-2-en-1-one. Following the procedure
of Yamazaki et al.,33b n-butyl lithium (2.5 M in hexane, 25.1 mmol,
10.0 mL, 2.2 equiv) was added to a solution of diisopropylamine (3.52
mL, 25.1 mmol, 2.2 equiv) in THF (30 mL) at −78 °C, and the
solution was stirred for 20 min. A precooled solution of 2-bromo-3,3,3-
trifluoroprop-1-ene (1.56 mL, 14.8 mmol, 1.3 equiv) in THF (30 mL)
was added dropwise at −78 °C, and the reaction mixture was stirred
for 5 min. A solution of tert-butyldimethylsilyl chloride (6.71 g, 44.5
mmol, 3.9 equiv) and 4-nitrobenzaldehyde (1.72 g, 11.4 mmol, 1.0
equiv) in THF (30 mL) was then added dropwise at −78 °C, and the
reaction mixture was stirred for 30 min. The reaction mixture was
quenched with aqueous 1 M HCl (100 mL), and the resulting solution
was extracted with ethyl acetate (×3). The combined organics were
dried over Na2SO4, filtered, and concentrated in vacuo to give the
4,4,4-Trifluoro-1-(4-nitrophenyl)but-2-yn-1-ol (0.428 g, 1.75
mmol), triethylamine (0.980 mL, 7.00 mmol), and THF (10 mL)
were reacted as described in the general procedure and purified by
column chromatography (95:5 petrol:EtOAc) to give (E)-4,4,4-
trifluoro-1-(4-nitrophenyl)but-2-en-1-one as a yellow crystalline solid
(0.206 g, 0.838 mmol, 48%) with spectroscopic data in accordance
with the literature:33b mp 58−60 °C {lit. 66−70 °C}; H NMR (300
1
MHz, CDCl3) δH 6.90 (1H, dq, J 15.6, 6.5, F3CCHCH), 7.52 (1H,
dq, J 15.6, 2.0, F3CCHCH), 8.14 (1H, d, J 9.0, ArC(2)H), 8.39 (1H,
d, J 9.0, ArC(3)H); 19F NMR (282 MHz, CDCl3) δF −65.8 (dd, J 6.5,
1.9, CF3).
(Z)-4,4,4-Trifluoro-1-(4-nitrophenyl)but-2-en-1-one was isolated as
an orange oil (0.144 g, 0.590 mmol, 34%) with spectroscopic data in
accordance with the literature:12 1H NMR (300 MHz, CDCl3) δH 6.20
(1H, dq, J 12.8, 7.8, F3CCHCH), 6.86 (1H, dd, J 12.7, 0.7,
F3CCHCH), 8.10 (1H, d, J 9.1, ArC(2)H), 8.37 (2H, d, J 9.0,
ArC(3)H); 19F NMR (282 MHz, CDCl3) δF −61.3 (d, J 7.9, CF3).
(E)-1-(4-Bromophenyl)-4,4,4-trifluorobut-2-en-1-one and (Z)-1-
(4-Bromophenyl)-4,4,4-trifluorobut-2-en-1-one. n-Butyl lithium (2.5
M in hexane, 37.6 mmol, 15.0 mL), diisopropylamine (5.27 mL, 37.6
mmol) in THF (45 mL), 2-bromo-3,3,3-trifluoroprop-1-ene (1.81 mL,
17.1 mmol) in THF (30 mL), and 4-bromobenzaldehyde (3.78 g, 20.5
mmol) were reacted as described in the general procedure to give
4,4,4-trifluoro-1-phenylbut-2-yn-1-ol as an orange solid (3.18 g, 11.4
mmol, quant) with spectroscopic data in accordance with the
literature:33c 1H NMR (400 MHz, CDCl3) δH 5.54 (1H, q, J 2.9,
ArCHOH), 7.67−7.71 (2H, m, ArH), 7.73−7.77 (2H, m, ArH);
19F{1H} NMR (376 MHz, CDCl3) δF −51.2 (CF3).
1-(4-Bromophenyl)-4,4,4-trifluorobut-2-yn-1-ol (4.77 g, 17.1
mmol), triethylamine (9.53 mL, 68.4 mmol), and THF (100 mL)
were reacted as described in the general procedure and purified by
column chromatography (99:1 petrol:EtOAc) to give (E)-1-(4-
bromophenyl)-4,4,4-trifluorobut-2-en-1-one as a pale yellow crystalline
solid (2.31 g, 8.26 mmol, 48%) with spectroscopic data in accordance
with the literature:33b mp 59−61 °C {lit. 51−52 °C}; H NMR (300
1
MHz, CDCl3) δH 6.83 (1H, dq, J 15.5, 6.6, F3CCHCH), 7.49 (1H,
dq, J 15.5, 2.0, F3CCHCH), 7.63−7.72 (2H, m, ArH), 7.80−7.89
(2H, m, ArH); 19F NMR (282 MHz, CDCl3) δF −65.7 (dd, J 6.6, 1.9,
CF3).
(Z)-1-(4-Bromophenyl)-4,4,4-trifluorobut-2-en-1-one was also iso-
lated as a pale orange solid (0.370 g, 1.33 mmol, 8%) with
spectroscopic data in accordance with the literature:33b mp 47−49
°C; 1H NMR (300 MHz, CDCl3) δH 6.11 (1H, dq, J 12.7, 7.9,
F3CCHCH), 6.81 (1H, dd, J 12.7, 0.7, F3CCHCH), 7.63−7.70
(2H, m, ArH), 7.74−7.84 (2H, m, ArH); 19F NMR (282 MHz,
CDCl3) δF −61.3 (d, J 7.9, CF3).
(E)-4,4,4-Trifluoro-1-(pyridin-3-yl)but-2-en-1-one. n-Butyl lithium
(2.5 M in hexane, 25.1 mmol, 10.0 mL), diisopropylamine (3.52 mL,
25.1 mmol) in THF (30 mL), 2-bromo-3,3,3-trifluoroprop-1-ene (1.20
mL, 11.4 mmol) in THF (20 mL), and nicotinaldehyde (1.29 mL, 13.7
mmol) were reacted as described in the general procedure and
quenched with saturated aq NH4Cl to give 4,4,4-trifluoro-1-(pyridin-3-
1
yl)but-2-yn-1-ol as a brown oil (1.82 g, 9.06 mmol, 79%): H NMR
(300 MHz, CDCl3) δH 5.59 (1H, q, J 2.8, ArCHOH), 7.32 (1H, ddd, J
7.9, 4.9, 0.9, ArC(5)H), 7.83 (1H, dt, J 7.9, 1.7, ArC(4)H), 8.53 (1H,
dd, J 4.9, 1.6, ArC(6)H), 8.64 (1H, d, J 1.8, ArC(2)H); 19F NMR (282
MHz, CDCl3) δF −51.2 (d, J 2.9, CF3).
4,4,4-Trifluoro-1-(pyridin-3-yl)but-2-yn-1-ol (0.428 g, 1.75 mmol),
triethylamine (0.980 mL, 7.00 mmol), and THF (10 mL) were reacted
as described in the general procedure and purified by column
chromatography (95:5 petrol:EtOAc) to give (E)-4,4,4-trifluoro-1-
(pyridin-3-yl)but-2-en-1-one as an orange crystalline solid (0.560 g,
2.78 mmol, 31%) with spectroscopic data in accordance with the
9251
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literature:34a mp 52−53 °C; H NMR (400 MHz, CDCl3) δH 6.82
131.4 (ArC(1)), 153.4 (C(6)), 168.2 (C(2)); HRMS (NSI+) m/z [M
+ H]+ calcd for C16H18F3O2 299.1253, found 299.1261.
1
(1H, dq, J 15.5, 6.5, F3CCHCH), 7.41−7.48 (2H, m, F3CCHCH
and ArC()H), 8.22 (1H, ddd, J 8.0, 2.3, 1.7, ArC()H), 8.80 (1H, dd, J
4.8, 1.7, ArC(6)H), 9.14 (1H, dd, J 2.3, 0.9, ArC(2)H); 19F NMR (376
MHz, CDCl3) δF −65.7 (dd, J 6.6, 1.9, CF3).
(3S,4S)-3-Butyl-6-(4-methoxyphenyl)-4-(trifluoromethyl)-3,4-di-
hydro-2H-pyran-2-one (9). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (80
mg, 0.300 mmol), (E)-4,4,4-trifluoro-1-(4-methoxyphenyl)but-2-en-1-
one (44 mg, 0.200 mmol), precatalyst 1 (7.4 mg, 20.0 μmol),
triethylamine (42 μL, 0.30 mmol), and THF (4 mL) were reacted as
described in the general procedure for 24 h and then purified by
column chromatography (95:5 petrol:Et2O) to give (3S,4S)-3-butyl-6-
(4-methoxyphenyl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 9
as a white crystalline solid (47.5 mg, 0.145 mmol, 73%): mp 105−107
°C; [α]2D0 +66.2 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak AD-
H 95:5 hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S)
14.2 min, tR(3R,4R) 16.5 min, >99% ee; IR νmax (solid) 2957 (CH),
(E)-4,4,4-Trifluoro-1-(furan-2-yl)but-2-en-1-one and (Z)-4,4,4-Tri-
fluoro-1-(furan-2-yl)but-2-en-1-one. n-Butyl lithium (2.5 M in
hexane, 25.1 mmol, 10.0 mL), diisopropylamine (3.52 mL, 25.1
mmol) in THF (30 mL), 2-bromo-3,3,3-trifluoroprop-1-ene (1.20 mL,
11.4 mmol) in THF (20 mL), and furfural (1.14 mL, 13.7 mmol) were
reacted as described in the general procedure to give 4,4,4-trifluoro-1-
(furan-2-yl)but-2-yn-1-ol as a yellow oil (0.930 g, 4.90 mmol, 43%)
with spectroscopic data in accordance with the literature:33b 1H NMR
(400 MHz, CDCl3) δH 5.57 (2H, q, J 2.9, ArCHOH), 6.40 (1H, dd, J
3.3, 1.9, ArC(3)H), 6.50 (1H, d, J 3.3, ArC(4)H), 7.46 (1H, dd, J 1.9,
0.8, ArC(5)H); 19F{1H} NMR (376 MHz, CDCl3) δF −51.4 (CF3).
4,4,4-Trifluoro-1-(furan-2-yl)but-2-yn-1-ol (0.930 g, 4.90 mmol),
triethylamine (2.73 mL, 19.6 mmol), and THF (30 mL) were reacted
as described in the general procedure and purified by column
chromatography (95:5 petrol:EtOAc) to give (E)-4,4,4-trifluoro-1-
(furan-2-yl)but-2-en-1-one as a pale yellow crystalline solid (0.510 g,
2.66 mmol, 54%) with spectroscopic data in accordance with the
1
1761 (CO); H NMR (500 MHz, CDCl3) δH 0.93 (3H, t, J 7.1,
CH2CH3), 1.30−1.55 (4H, m, (CH2)2), 1.68 (1H, dd, J 14.9, 6.9,
C(3)CHaHb), 2.02−2.16 (1H, m, C(3)CHaHb), 2.86 (1H, q, J 7.2,
C(3)H), 3.33 (1H, qt, J 8.7, 6.4 C(4)H), 3.83 (3H, s, ArC(4)OCH3),
5.62 (1H, d, J 6.5, C(5)H), 6.91 (2H, d, J 8.9, ArC(3)H), 7.58 (2H, d,
J 8.9, ArC(2)H); 19F NMR (282 MHz, CDCl3) δF −67.7 (d, J 8.7,
C(4)CF3); 13C{1H} NMR (126 MHz, CDCl3) δC 13.9 (CH2CH3),
22.5 (CH2), 26.1 (C(3)CH2), 29.7 (CH2), 39.3 (q, J 28.2, C(4)), 39.8
(C(3)), 55.4 (ArC(4)OCH3), 92.7 (d, J 2.6, C(5)), 114.0 (ArC(3)),
123.9 (ArC(1)), 125.9 (q, J 282, C(4)CF3), 126.5 (ArC(2)), 153.2
(C(6)), 161.0 (ArC(4)), 168.4 (C(2)); HRMS (CI+) m/z [M + H]+
calcd for C17H20F3O3 329.1365, found 329.1357.
literature:34b mp 68−70 °C {lit. 64−66 °C}; H NMR (300 MHz,
1
CDCl3) δH 6.64 (1H, dd, J 3.6, 1.7, ArC(3)H), 6.90 (1H, dq, J 15.6,
6.7, F3CCHCH), 7.39 (1H, dd, J 3.7, 0.7, ArC(4)H), 7.42 (1H, dq, J
15.7, 2.0, F3CCHCH), 7.71 (1H, dd, J 1.7, 0.7, ArC(5)H); 19F
NMR (376 MHz, CDCl3) δF −65.6 (dd, J 6.7, 2.0, CF3).
(3S,4S)-3-Butyl-6-(2-methoxyphenyl)-4-(trifluoromethyl)-3,4-di-
hydro-2H-pyran-2-one (10). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (80
mg, 0.300 mmol), (E)-4,4,4-trifluoro-1-(2-methoxyphenyl)but-2-en-1-
one (46 mg, 0.200 mmol), precatalyst 1 (7.3 mg, 20.0 μmol), cesium
carbonate (65 mg, 0.200 mmol), and THF (4 mL) were reacted as
described in the general procedure for 14 h and then purified by
column chromatography (97:3 petrol:EtOAc) to give (3S,4S)-3-butyl-
6-(2-methoxyphenyl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one
10 as a white crystalline solid (39.2 mg, 0.119 mmol, 60%): mp 46−48
°C; [α]2D0 +64.4 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak IA
98:2 hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 7.5
min, tR(3R,4R) 16.4 min, 99% ee; IR νmax (solid) 2961 (CH), 1763
(CO); 1H NMR (400 MHz, CDCl3) δH 0.94 (3H, t, J 7.1,
CH2CH3), 1.32−1.54 (4H, m, (CH2)2), 1.64−1.77 (1H, m, C(3)-
CHaHb), 2.02−2.14 (1H, m, C(3)CHaHb), 2.89 (1H, q, J 7.3, C(3)H),
3.36 (1H, qt, J 8.9, 6.4, C(4)H), 6.13 (1H, d, J 6.4, C(5)H), 6.95 (1H,
dd, J 8.3, 1.0, ArC(6)H), 7.00 (1H, td, J 7.6, 1.1, ArC(4)H), 7.35 (1H,
ddd, J 8.3, 7.4, 1.8, ArC(5)H), 7.67 (1H, dd, J 7.8, 1.8, ArC(3)H); 19F
NMR (376 MHz, CDCl3) δF −67.5 (d, J 9.2, C(4)CF3); 13C{1H}
NMR (101 MHz, CDCl3) δC 13.9 (CH2CH3), 22.5 (CH2), 25.9 (C(3)
CH2), 29.7 (CH2), 39.6 (q, J 28.0, C(4)), 39.7 (C(3)), 55.6
(ArC(4)OCH3), 99.9 (q, J 2.9, C(5)), 111.2 (ArC(6)), 120.2
(ArC(1)), 120.5 (ArC(4)), 126.0 (q, J 281.7, C(4)CF3), 128.4
(ArC(3)), 130.7 (ArC(5)), 150.0 (C(6)), 157.2 (ArC(2)), 168.5
(C(2)); HRMS (NSI+) m/z [M + H]+ calcd for C17H20F3O3 329.1359,
found 329.1359.
(3S,4S)-3-Butyl-6-(4-nitrophenyl)-4-(trifluoromethyl)-3,4-dihydro-
2H-pyran-2-one (11). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (200 mg,
0.750 mmol), precatalyst 1 (18.4 mg, 50.0 μmol), triethylamine (105
μL, 0.750 mmol), and THF (6 mL) were reacted via a modified
version of the general procedure, utilizing syringe pump addition of a
solution of (E)-4,4,4-trifluoro-1-(4-nitrophenyl)but-2-en-1-one (123
mg, 0.500 mmol) in THF (4 mL) over 1 h followed by stirring for 1 h.
The crude product was purified by column chromatography (97:3
petrol:EtOAc) to give (3S,4S)-3-butyl-6-(4-nitrophenyl)-4-(trifluoro-
methyl)-3,4-dihydro-2H-pyran-2-one 11 as a white crystalline solid
(103 mg, 0.299 mmol, 60%): mp 95−98 °C; [α]2D0 +72.5 (c 0.5,
CHCl3); chiral HPLC analysis (Chiralpak IA 95:5 hexane:IPA, flow
rate 1 mL min−1, 220 nm, 30 °C) tR(3S,4S) 25.1 min, tR(3R,4R) 32.8
min, >99% ee; IR νmax (solid) 2961 (CH), 1771 (CO), 1516
(NO2); 1H NMR (300 MHz, CDCl3) δH 0.93 (3H, t, J 7.0, CH2CH3),
1.31−1.55 (4H, m, (CH2)2), 1.65−1.81 (1H, m, C(3)CHaHb), 2.00−
2.17 (1H, m, C(3)CHaHb), 2.91 (1H, q, J 7.1, C(3)H), 3.44 (1H, qt, J
8.6, 6.4, C(4)H), 5.96 (1H, d, J 6.4, C(5)H), 7.82 (1H, d, J 9.0,
(Z)-4,4,4-Trifluoro-1-(furan-2-yl)but-2-en-1-one was isolated as a
yellow oil (0.120 g, 0.631 mmol, 13%): IR νmax (film) 1672 (CO);
1H NMR (400 MHz, CD2Cl2) δH 6.02 (1H, dq, J 12.6, 8.3, F3CCH
CH), 6.54 (1H, dd, J 3.7, 1.7, ArC(4)H), 6.82 (1H, d, J 12.6,
F3CCHCH), 7.17 (1H, dd, J 3.7, 0.8, ArC(3)H), 7.62 (1H, dd, J 1.7,
0.8, ArC(5)H); 19F NMR (376 MHz, CD2Cl2) δF −61.2 (d, J 8.2,
CF3); 13C{1H} NMR (101 MHz, CD2Cl2) δC 112.7 (ArC(4)), 119.9
(ArC(3)), 121.7 (q, J 272, CF3), 125.2 (q, J 36.1, F3CCHCH),
134.6 (q, J 5.2, F3CCHCH), 148.1 (ArC(5)), 151.7 (ArC(2)), 177.6
(ArC(2)CO); HRMS (CI+) m/z [M + H]+ calcd for C8H6F3O2
191.0320, found 191.0323.
General Procedure for NHC-Catalyzed Hetero-Diels−Alder
Reactions. The appropriate α-aroyloxyaldehyde (1.5 equiv), β-
trifluoromethyl enone (1.0 equiv), and NHC precatalyst 1 (10 mol
%) were dissolved in anhydrous THF (0.075 M) in a sealed vial
containing 4 Å molecular sieves. Triethylamine (1.5 equiv) or cesium
carbonate (1 equiv) was added as stated, and the reaction mixture was
stirred at rt until complete by TLC analysis. The mixture was diluted
with EtOAc and washed successively with 1 M HCl, saturated
NaHCO3, and brine. The organic layer was dried with MgSO4, filtered,
and concentrated in vacuo to give the crude product that was purified
by flash silica column chromatography.
(3S,4S)-3-Butyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (8). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (199 mg, 0.750
mmol), (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (100 mg, 0.500
mmol), precatalyst 1 (18.4 mg, 50.0 μmol), triethylamine (105 μL,
0.750 mmol), and THF (10 mL) were reacted as described in the
general procedure for 14 h and then purified by column
chromatography (95:5 petrol:Et2O) to give (3S,4S)-3-butyl-6-phenyl-
4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 8 as a white crystal-
line solid (93.3 mg, 0.313 mmol, 63%): mp 109−111 °C; [α]2D0 +70.8
(c 0.5, CHCl3); chiral HPLC analysis (Chiralcel OJ-H 99.8:0.2
hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 33.1 min,
tR(3R,4R) 54.2 min, >99% ee; IR νmax (solid) 2959 (CH), 1761
(CO); δH (500 MHz, CDCl3) 0.94 (3H, t, J 7.1, CH2CH3), 1.27−
1.56 (4H, m, (CH2)2), 1.64−1.79 (1H, m, C(3)CHaHb), 2.07 (1H, dd,
J 14.3, 7.5, C(3)CHaHb), 2.88 (1H, q, J 7.1, C(3)H), 3.24−3.48 (1H,
m, C(4)H), 5.76 (1H, d, J 6.3, C(5)H), 7.33−7.50 (3H, m, ArC(2)H
and ArC(4)H), 7.56−7.75 (2H, m, ArC(3)H); 19F NMR (282 MHz,
CDCl3) δF −67.5 (d, J 8.6, C(4)CF3); 13C{1H} NMR (101 MHz,
CDCl3) δC 13.8 (CH2CH3), 22.5 (CH2), 26.1 (C(3)CH2), 29.7
(CH2), 39.4 (q, J 28.3, C(4)), 39.8 (C(3)), 94.6 (C(5)), 125.0
(ArC(3)), 125.9 (q, J 282, C(4)CF3), 128.6 (ArC(2)), 130.0 (ArC(4)),
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ArC(3)H), 8.25 (1H, d, J 9.1, ArC(2)H); 19F NMR (282 MHz,
CDCl3) δF −67.2 (d, J 8.6, C(4)CF3); 13C{1H} NMR (75 MHz,
CDCl3) δC 13.8 (CH2CH3), 22.4 (CH2), 26.0 (C(3)CH2), 29.7
(CH2), 39.6 (C(3)), 39.6 (q, J 28.5, C(4)), 98.4 (C(5)), 123.9
(ArC(3)), 125.6 (d, J 282.0, C(4)CF3), 125.9 (ArC(2)), 137.2
(ArC(1)), 148.5 (ArC(4)), 151.6 (C(6)), 167.2 (C(2)); HRMS (CI+)
m/z [M + H]+ calcd for C16H17F3O4N 344.1110, found 344.1117.
(3S,4S)-6-(4-Bromophenyl)-3-butyl-4-(trifluoromethyl)-3,4-dihy-
dro-2H-pyran-2-one (12). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (200
mg, 0.750 mmol), (E)-1-(4-bromophenyl)-4,4,4-trifluorobut-2-en-1-
one (140 mg, 0.500 mmol), precatalyst 1 (13.4 mg, 50.0 μmol),
triethylamine (150 μL, 0.750 mmol), and THF (10 mL) were reacted
as described in the general procedure for 6 h and then purified by
column chromatography (98:2 petrol:EtOAc) to give (3S,4S)-6-(4-
bromophenyl)-3-butyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-
one 12 as a white crystalline solid (121 mg, 0.321 mmol, 64%): mp
126−128 °C; [α]2D0 +56.6 (c 0.5, CHCl3); chiral HPLC analysis
(Chiralpak IB 99:1 hexane:IPA, flow rate 1 mL min−1, 254 nm, 40 °C)
tR(3S,4S) 8.3 min, tR(3R,4R) 10.3 min, >99% ee; IR νmax (solid) 2961
(CH), 1769 (CO); 1H NMR (400 MHz, CDCl3) δH 0.93 (3H, t,
J 7.1, CH2CH3), 1.33−1.52 (4H, m, (CH2)2), 1.65−1.76 (1H, m,
C(3)CHaHb), 2.00−2.14 (1H, m, C(3)CHaHb), 2.87 (1H, q, J 7.2,
C(3)H), 3.27−3.43 (1H, m, C(4)H), 5.76 (1H, d, J 6.4, C(5)H),
7.48−7.56 (4H, m, ArH); 19F NMR (470 MHz, CDCl3) δF −67.0 (d, J
8.6, C(4)CF3); 13C{1H} NMR (101 MHz, CDCl3) δC 13.8
(CH2CH3), 22.5 (CH2), 26.0 (C(3)CH2), 29.7 (CH2), 39.4 (q, J
28.2, C(4)), 39.7 (C(3)), 95.1 (C(5)), 124.3 (ArC(4)), 125.7 (d, J
282, C(4)CF3), 126.6 (ArC(2) or ArC(3)), 130.3 (ArC(1)), 131.9
(ArC(2) or ArC(3)), 152.6 (C(6)), 167.8 (C(2)); HRMS (CI+) m/z
[M + H]+ calcd for C16H1679BrF3O2 377.0364, found 377.0356.
(3S,4S)-3-Butyl-6-(pyridin-3-yl)-4-(trifluoromethyl)-3,4-dihydro-
2H-pyran-2-one (13). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (200 mg,
0.750 mmol), (E)-4,4,4-trifluoro-1-(pyridin-3-yl)but-2-en-1-one (115
mg, 0.500 mmol), precatalyst 1 (18.4 mg, 50.0 μmol), triethylamine
(105 μL, 0.750 mmol), and THF (10 mL) were reacted as described in
the general procedure for 14 h and then purified by column
chromatography (85:15 petrol:EtOAc) to give (3S,4S)-3-butyl-6-
(pyridin-3-yl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 13 as
a white crystalline solid (94.9 mg, 0.317 mmol, 63%): mp 62−65 °C;
[α]2D0 +63.2 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak IA 90:10
hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 9.5 min,
tR(3R,4R) 13.9 min, >99% ee; IR νmax (solid) 2963 (CH), 1761
(CO); 1H NMR (500 MHz, CDCl3) δH 0.93 (3H, t, J 7.1,
CH2CH3), 1.29−1.53 (4H, m, (CH2)2), 1.64−1.79 (1H, m, C(3)-
CHaHb), 2.00−2.17 (1H, m, C(3)CHaHb), 2.89 (1H, q, J 7.1, C(3)H),
3.29−3.50 (1H, m, C(4)H), 5.84 (1H, d, J 6.4, C(5)H), 7.34 (1H, dd,
J 8.0, 4.8, ArC(4)H), 7.93 (1H, dt, J 8.1, 2.0, ArC(5)H), 8.55−8.70
(1H, m, ArC(6)H), 8.88 (1H, d, J 1.8, ArC(2)H); 19F NMR (376
MHz, CDCl3) δF −67.4 (d, J 7.9, C(4)CF3); 13C{1H} NMR (101
MHz, CDCl3) δC 13.8 (CH2CH3), 22.4 (CH2), 26.0 (C(3)CH2), 29.7
(CH2), 39.4 (q, J 28.4, C(4)), 39.7 (C(3)), 96.2 (d, J 2.8, C(5)), 123.4
(ArC(4)), 125.7 (q, J 282.0, C(4)CF3), 127.4 (ArC(3)), 132.5
(ArC(5)), 146.5 (ArC(2)), 150.8 (ArC(6)), 151.4 (C(6)), 167.5
(C(2)); HRMS (NSI+) m/z [M + H]+ calcd for C15H17F3NO2
300.1206, found 300.1206.
C(3)H), 3.35 (1H, qt, J 8.6, 6.4, C(4)H), 5.72 (1H, d, J 6.5, C(5)H),
6.46 (1H, dd, J 3.4, 1.8, ArC(4)H), 6.68 (1H, d, J 3.5, ArC(3)H), 7.44
(1H, dd, J 1.9, 0.9, ArC(5)H); 19F NMR (282 MHz, CDCl3) δF −67.6
(d, J 8.6, C(4)CF3); 13C{1H} NMR (75 MHz, CDCl3) δC 13.8
(CH2CH3), 22.5 (CH2), 26.2 (C(3)CH2), 29.7 (CH2), 39.2 (q, J 28.5,
C(4)), 40.1 (C(3)), 92.9 (q, J 2.9, C(5)), 109.3 (ArC(4)), 111.6
(ArC(3)), 125.8 (q, J 282, C(4)CF3), 143.9 (ArC(5)), 145.9 (ArC(1)),
146.0 (C(6)), 167.7 (C(2)); HRMS (NSI+) m/z [M + H]+ calcd for
C14H16F3O3 289.1046, found 289.1049.
(3S,4S)-3-Methyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (15). 1-Oxopropan-2-yl 4-nitrobenzoate 2 (167 mg,
0.750 mmol), (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (100 mg,
0.500 mmol), precatalyst 1 (18.4 mg, 50.0 μmol), triethylamine (105
μL, 0.750 mmol), and THF (10 mL) were reacted as described in the
general procedure for 14 h and then purified by column
chromatography (95:5 petrol: Et2O) to give (3S,4S)-3-methyl-6-
phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 15 as a white
crystalline solid (86.6 mg, 0.343 mmol, 69%): mp 90−93 °C; [α]D20
+87.4 (c 0.5, CHCl3); chiral HPLC analysis (Chiralcel OD-H 99:1
hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 24.0 min,
tR(3R,4R) 41.3 min, >99% ee; IR νmax (solid) 2961 (CH), 1769
1
(CO); H NMR (500 MHz, CDCl3) δH 1.47 (3H, dd, J 7.2, 1.8,
C(3)CH3), 3.09 (1H, p, J 7.1, C(3)H), 3.31 (1H, tdd, J 8.9, 6.5, 2.4,
C(4)H), 5.75 (1H, d, J 6.2, C(5)H), 7.38−7.44 (3H, m, ArC(2)H and
ArC(4)H), 7.62−7.69 (2H, m, ArC(3)H); 19F NMR (282 MHz,
CDCl3) δF −67.4 (dd, J 8.9, 1.9, C(4)CF3); 13C{1H} NMR (75 MHz,
CDCl3) δC 12.2 (C(3)CH3), 34.4 (C(3)), 41.0 (q, J 28.4, C(4)), 94.3
(C(5)), 125.1 (ArC(3)), 125.9 (q, J 281, C(4)CF3), 128.7 (ArC(2)),
130.0 (ArC(4)), 131.4 (ArC(1)), 153.5 (C(6)), 168.7 (C(2)); HRMS
(NSI+) m/z [M + H]+ calcd for C13H12F3O2 257.0784, found
257.0788.
(3S,4S)-3-Isobutyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (16). 4-Methyl-1-oxopentan-2-yl 4-nitrobenzoate 4 (199
mg, 0.750 mmol), (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (100 mg,
0.500 mmol), precatalyst 1 (18.4 mg, 50.0 μmol), triethylamine (105
μL, 0.750 mmol), and THF (10 mL) were reacted as described in the
general procedure for 21 h and then purified by column
chromatography (98:2 petrol:EtOAc) to give (3S,4S)-3-isobutyl-6-
phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 16 as a white
crystalline solid (104.8 mg, 0.351 mmol, 70%): mp 109−111 °C; [α]D20
+78.4 (c 0.5, CHCl3); chiral HPLC analysis (Chiralcel OJ-H 99.8:0.2
hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 24.5 min,
tR(3R,4R) 35.1 min, >99% ee; IR νmax (solid) 2957 (CH), 1765
1
(CO); H NMR (500 MHz, CDCl3) δH 0.97 (6H, dd, J 8.4, 6.6,
(CH3)2CH), 1.53−1.64 (1H, m, C(3)CHaHb), 1.81 (1H, dp, J 13.4,
6.6, CH3)2CH), 1.95 (1H, dt, J 14.5, 7.4, C(3)CHaHb), 2.98 (1H, q, J
7.2, C(3)H), 3.27−3.37 (1H, m, C(4)H), 5.77 (1H, d, J 6.4, C(5)H),
7.38−7.43 (3H, m, ArH), 7.63−7.68 (2H, m, ArH); 19F NMR (282
MHz, CDCl3) δF −67.4 (d, J 8.6, C(4)CF3); 13C{1H} (126 MHz,
CDCl3) δC 22.2 ((CH3)2CH), 22.5 (CH3)2CH), 25.4 ((CH3)2CH),
35.1 (C(3)CH2), 37.5 (C(3)), 39.5 (q, J 28.4, C(4)), 94.6 (d, J 3.1,
C(5)), 125.1 (ArC(2)), 125.8 (q, J 282, C(4)CF3), 128.6 (ArC(3)),
130.0 (ArC(4)), 131.3 (ArC(1)), 153.5 (C(6)), 168.3 (C(2)); HRMS
(NSI+) m/z [M + H]+ calcd for C16H18F3O2 299.1253, found
299.1259.
(3S,4S)-3-Butyl-6-(furan-2-yl)-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (14). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (200 mg, 0.750
mmol), (E)-4,4,4-trifluoro-1-(furan-2-yl)but-2-en-1-one (95.1 mg,
0.500 mmol), catalyst 1 (18.4 mg, 50.0 mmol), triethylamine (105
μL, 0.750 mmol), and THF (10 mL) were reacted as described in the
general procedure for 18 h and then purified by column
chromatography (97:3 petrol: Et2O) to give (3S,4S)-3-butyl-6-
(furan-2-yl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 14 as a
white crystalline solid (76.1 mg, 0.337 mmol, 53%): mp 59−60 °C;
[α]2D0 +83.4 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak AD-H
98:2 hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3S,4S) 7.4
min, tR(3R,4R) 10.4 min, >99% ee; IR νmax (solid) 2966 (CH),
(3S,4S)-3-Benzyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (17). 1-Oxo-3-phenylpropan-2-yl 4-nitrobenzoate 5 (224
mg, 0.750 mmol), (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (100 mg,
0.500 mmol), precatalyst 1 (18.4 mg, 50.0 mmol), triethylamine (105
μL, 0.750 mmol), and THF (10 mL) were reacted as described in the
general procedure for 7 h and then purified by column
chromatography (98:2 petrol: Et2O) to give (3S,4S)-3-benzyl-6-
phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 17 as a white
crystalline solid (105.7 mg, 0.316 mmol, 63%): mp 110−111 °C; [α]D20
+32.3 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak AD-H 99:1
hexane:IPA, flow rate 1 mL min−1, 254 nm, 30 °C) tR(3R,4R) 35.0
min, tR(3S,4S) 44.6 min, >99% ee; IR νmax (solid) 2963 (CH), 1769
1
1
1763 (CO); H NMR (300 MHz, CDCl3) δH 0.93 (3H, t, J 7.0,
(CO); H NMR (500 MHz, CDCl3) δH 2.99 (1H, dd, J 14.1, 9.5,
CH2CH3), 1.29−1.62 (3H, m, (CH2)2), 1.62−1.87 (1H, m, C(3)-
CHaHb), 2.07 (1H, ddt, J 5.9, 2.8, 1.5, C(3)CHaHb), 2.86 (1H, q, J 7.1,
C(3)CHaHb), 3.17−3.31 (2H, m, C(3)H and C(4)H), 3.54 (1H, dd, J
14.6, 5.7, C(3)CHaHb), 5.74 (1H, d, J 6.6, C(5)H), 7.25−7.30 (3H, m,
9253
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The Journal of Organic Chemistry
Article
C(3)CH2ArC(2)H and C(3)CH2ArC(4)H), 7.32−7.37 (2H, m,
C(3)CH2ArC(3)H), 7.40 (3H, dd, J 5.1, 1.7, C(6)ArC(2)H and
C(6)ArC(4)H), 7.64 (2H, dd, J 6.8, 3.0, C(6)ArC(3)H); 19F NMR
(282 MHz, CDCl3) δF −66.6 (d, J 8.0, C(4)CF3); 13C{1H} NMR (101
MHz, CDCl3) δC 32.0 (C(3)CH2), 38.5 (q, J 28.3, C(4)), 42.0 (C(3)),
95.0 (d, J 2.6, C(5)), 125.1 (C(6)ArC(3)), 125.9 (q, J 282, C(4)CF3),
126.9 (C(3)CH2ArC(4)), 128.7 (C(6)ArC(2)), 128.8 (C(3)-
CH2ArC(3)), 128.9 (C(3)CH2ArC(2)), 130.1 (C(6)ArC(4)), 131.2
(C(6)ArC(1)), 137.8 (C(3)CH2ArC(1)), 153.8 (C(6)), 167.8 (C(2));
HRMS (NSI+) m/z [M + NH4]+ calcd for C19H19F3O2N 350.1362,
found 350.1368.
(3S,4S)-3-(2-(Benzyloxy)ethyl)-6-phenyl-4-(trifluoromethyl)-3,4-
dihydro-2H-pyran-2-one (18). 4-(Benzyloxy)-1-oxobutan-2-yl 4-ni-
trobenzoate 6 (256 mg, 0.750 mmol), (E)-4,4,4-trifluoro-1-phenylbut-
2-en-1-one (100 mg, 0.500 mmol), precatalyst 1 (18.4 mg, 50.0
mmol), triethylamine (105 μL, 0.750 mmol), and THF (10 mL) were
reacted as described in the general procedure for 14 h and then
purified by column chromatography (97:3 petrol:EtOAc) to give
(3S,4S)-3-(2-(benzyloxy)ethyl)-6-phenyl-4-(trifluoromethyl)-3,4-dihy-
dro-2H-pyran-2-one 18 as a white crystalline solid (152.5 mg, 0.405
mmol, 81%): mp 64−66 °C; [α]2D0 +34.6 (c 0.5, CHCl3); chiral HPLC
analysis (Chiralpak AD-H 98:2 hexane:IPA, flow rate 1 mL min−1, 254
nm, 30 °C) tR(3S,4S): 15.5 min, tR(3R,4R): 24.5 min, >99% ee; IR
νmax (solid) 2880 (CH), 1765 (CO); 1H NMR (400 MHz,
CDCl3) δH 1.93−2.05 (1H, m, C(3)CHaHb), 2.36−2.47 (1H, m,
C(3)CHaHb), 3.17−3.36 (2H, m, C(3)H and C(4)H)), 3.63−3.77
(2H, m, C(3)CH2CH2), 4.51 (2H, q, J 11.8, OCH2Ar), 5.74 (1H, d, J
6.5, C(5)H), 7.27−7.38 (5H, m, ArH), 7.38−7.43 (3H, m, ArH), 7.65
(3H, ddd, J 5.2, 2.4, 1.4, ArH); 19F NMR (376 MHz, CDCl3) δF −67.4
(d, J 8.2, C(4)CF3); 13C{1H} NMR (101 MHz, CDCl3) δC 27.1 (C(3)
CH2), 35.9 (C(3)), 39.5 (q, J 28.2, C(4)), 67.0 (C(3)CH2CH2), 73.2
(OCH2Ar), 94.7 (q, J 2.6, C(5)), 125.1 (C(6)ArC(2, 3 or 4)), 125.9
(q, J 281.8, C(4)CF3), 127.8 (OCH2ArC(2, 3 or 4)), 127.8
(OCH2ArC(2, 3 or 4)), 128.5 (OCH2ArC(2, 3 or 4)), 128.6
(C(6)ArC(2, 3 or 4)), 130.0 (C(6)ArC(2, 3 or 4)), 131.4
(C(6)ArC(1)), 138.1 (OCH2ArC(1)), 153.6 (C(6)), 168.3 (C(2));
HRMS (NSI+) m/z [M + H]+ calcd for C21H20F3O3 377.1359, found
377.1360.
flow rate 1 mL min‑1, 254 nm, 30 °C) tR(3S,4S) 31.9 min, tR(3R,4R)
1
50.6 min, >99% ee; IR νmax (film) 2961 (CH), 1773 (CO); H
NMR (400 MHz, CDCl3) δH 0.84 (3H, t, J 7.2, CH2CH3), 1.20−1.47
(4H, m, (CH2)2), 1.60 (1H, dd, J 9.4, 7.5, C(3)CHaHb), 1.66−1.82
(1H, m, C(3)CHaHb), 2.87−2.97 (1H, m, C(3)H), 2.96−3.09 (1H, m,
C(4)H), 5.56 (1H, dd, J 6.4, 1.3, C(5)H), 7.31−7.37 (3H, m, ArH),
7.56−7.63 (2H, m, ArH); 19F NMR (470 MHz, CDCl3) δF −72.2 (d, J
8.8, C(4)CF3); 13C{1H} NMR (75 MHz, CDCl3) δC 14.2 (CH2CH3),
22.5 (CH2), 29.2 (CH2), 31.1 (C(3)CH2), 38.6 (C(3)), 42.2 (q, J 28.8,
C(4)), 91.3 (C(5)), 125.5 (ArC(1)), 126.1 (d, J 280, C(4)CF3), 129.1
(ArC(2)), 130.5 (ArC(4)), 131.1 (ArC(3)), 153.7 (C(6)), 168.0
(C(2)); HRMS (NSI+) m/z [M + H]+ calcd for C16H18F3O2 299.1253,
found 299.1258.
(3S,4R)-6-(4-Bromophenyl)-3-butyl-4-(trifluoromethyl)-3,4-dihy-
dro-2H-pyran-2-one (21). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (265
mg, 1.00 mmol), (Z)-1-(4-bromophenyl)-4,4,4-trifluorobut-2-en-1-one
(140 mg, 0.500 mmol), precatalyst 1 (18.4 mg, 50.0 μmol), cesium
carbonate (163 mg, 0.500 mmol), and THF (10 mL) were reacted in a
modified version of the general procedure for 14 h at 40 °C and then
purified by column chromatography (98:2 petrol:EtOAc) to give
(3S,4R)-6-(4-bromophenyl)-3-butyl-4-(trifluoromethyl)-3,4-dihydro-
2H-pyran-2-one 21 as a colorless oil (133.7 mg, 0.354 mmol, 71%):
[α]2D0 −78.6 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak IA 99:1
hexane:IPA, flow rate 1 mL min−1, 30 °C, 254 nm) tR(3R,4S) 9.9 min,
tR(3S,4R) 12.5 min, 96% ee; IR νmax (film) 2934 (CH), 1775 (C
1
O); H NMR (300 MHz, CDCl3) δH 0.91 (2H, t, J 7.1, CH2CH3),
1.28−1.49 (3H, m, (CH2)2), 1.57−1.85 (2H, m, C(3)CH2), 2.94−3.02
(1H, m, C(3)H), 3.09 (1H, qdd, J 8.6, 6.4, 1.7, C(4)H), 5.62 (1H, dd,
J 6.4, 1.3, C(5)H), 7.54 (4H, s, ArH); 19F NMR (282 MHz, CDCl3) δF
−72.6 (d, J 8.6, C(4)CF3); 13C{1H} NMR (75 MHz, CDCl3) δC 14.2
(CH2CH3), 22.5 (CH2), 29.1 (CH2), 31.1 (C(3)CH2), 38.5 (C(3)),
42.3 (q, J 29.2, C(4)), 91.8 (C(5)), 124.8 (ArC(4)), 126.0 (d, J 280,
C(4)CF3), 127.0 (ArC(2) or ArC(3)), 130.6 (ArC(1)), 132.3 (ArC(2)
or ArC(3)), 152.9 (C(6)), 167.7 (C(2)); HRMS (CI+) m/z [M + H]+
calcd for C16H1779BrF3O2 377.0364, found 377.0372.
(3S,4R)-3-Butyl-6-(furan-2-yl)-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (22). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (184 mg, 0.695
mmol), (Z)-4,4,4-trifluoro-1-(furan-2-yl)but-2-en-1-one (88.0 mg,
0.463 mmol), precatalyst 1 (17.0 mg, 46.3 μmol), cesium carbonate
(151 mg, 0.463 mmol), and THF (9 mL) were reacted in a modified
version of the general procedure for 5 h at 40 °C and then purified by
column chromatography on silica (99.5:0.5 petrol:EtOAc) to give
(3S,4R)-3-butyl-6-(furan-2-yl)-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one 22 (dr 93:7) as a colorless oil (88.9 mg, 0.308 mmol,
67%): [α]2D0 −119.2 (c 0.5, CHCl3); chiral HPLC analysis (Chiralpak
IA 99.8:0.2 hexane:IPA, flow rate 1 mL min−1, 30 °C, 220 nm)
tR(3R,4S) 10.8 min, tR(3S,4R) 13.8 min, 95% ee; IR νmax (film) 2961
(CH), 1778 (CO); 1H NMR (400 MHz, CDCl3) δH 0.83 (3H, t,
J 7.1, CH2CH3), 1.21−1.43 (4H, m, CH2 × 2), 1.51−1.65 (1H, m,
C(3)CHaHb), 1.65−1.79 (1H, m, C(3)CHaHb), 2.84−2.94 (1H, m,
C(3)H), 3.02 (1H, ddd, J 8.4, 6.6, 1.6, C(4)H), 5.51 (1H, dd, J 6.5,
1.4, C(5)H), 6.39 (1H, dd, J 3.4, 1.8, ArC(4)H), 6.63 (1H, d, J 3.4,
ArC(3)H), 7.38 (1H, dd, J 1.8, 0.8, ArC(5)H); 19F NMR (376 MHz,
CDCl3) δF −72.8 (d, J 8.6); 13C{1H} NMR (75 MHz, CDCl3) δC 13.7
(CH2CH3), 22.1 (CH2), 28.8 (CH2), 30.7 (C(3)CH2), 38.5 (C(3)),
41.6 (q, J 29.1, C(4)), 89.0 (C(5)), 109.5 (ArC(3)), 111.6 (ArC(4)),
125.7 (q, J 280.2, C(4)CF3), 144.0 (ArC(5)), 145.8 (ArC(2)), 145.9
(C(6)), 167.0 (C(2)); HRMS (NSI+) m/z [M + H]+ calcd for
C14H16F3O3 289.1046, found 289.1048.
(3S,4R)-3-Methyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (23). 1-Oxopropan-2-yl 4-nitrobenzoate 2 (223 mg, 1.00
mmol), (Z)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (100 mg, 0.500
mmol), precatalyst 1 (18.4 mg, 50.0 μmol), cesium carbonate (163
mg, 0.500 mmol), and THF (10 mL) were reacted in a modified
version of the general procedure for 10 h and then purified by column
chromatography on silica (98:2 petrol:EtOAc) to give (3S,4R)-3-
methyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 23
as a white crystalline solid (84.9 mg, 0.331 mmol, 66%): mp 71−73
°C; [α]2D0 −58.3 (c 0.4, CHCl3); chiral HPLC analysis (Chiralcel OD-
H 99:1 hexane:IPA, flow rate 1 mL min−1, 30 °C, 254 nm) tR(3R,4S)
(3S,4S)-6-(4-Methoxyphenyl)-3-methyl-4-(trifluoromethyl)-3,4-di-
hydro-2H-pyran-2-one (19). 1-Oxopropan-2-yl 4-nitrobenzoate 2
(167 mg, 0.750 mmol), (E)-4,4,4-trifluoro-1-(4-methoxyphenyl)but-
2-en-1-one (115 mg, 0.500 mmol), precatalyst 1 (18.4 mg, 50.0
mmol), triethylamine (105 μL, 0.750 mmol), and THF (10 mL) were
reacted as described in the general procedure for 40 h and then
purified by column chromatography (95:5 petrol:EtOAc) to give
(3S,4S)-6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-3,4-dihy-
dro-2H-pyran-2-one 19 as a colorless crystalline solid (106 mg, 0.369
mmol, 74%): mp 92−94 °C; [α]2D0 +78.0 (c 0.5, CHCl3); chiral HPLC
analysis (Chiralcel OD-H 95:5 hexane:IPA, flow rate 1 mL min−1, 254
nm, 30 °C) tR(3S,4S) 13.2 min, tR(3R,4R) 18.7 min, 99% ee; IR νmax
1
(solid) 2957 (CH), 1780 (CO); H NMR (300 MHz, CDCl3)
δH 1.46 (2H, dd, J 7.1, 1.9, C(3)CH3), 3.07 (1H, p, J 7.0, C(3)H), 3.27
(1H, qt, J 8.9, 6.5, C(4)H), 3.83 (3H, s, ArC(4)OCH3), 5.60 (1H, d, J
6.3, C(5)H), 6.90 (1H, d, J 9.0, ArC(3)H), 7.58 (1H, d, J 8.9, ArC(2)
H); 19F NMR (376 MHz, CDCl3) δF −67.5 (dd, J 8.8, 2.0, C(4)CF3);
13C{1H} NMR (75 MHz, CDCl3) δC 12.2 (C(3)CH3), 24.4 (C(3)),
41.0 (q, J 28.2, C(4)), 55.4 (ArC(4)OCH3), 92.3 (q, J 3.1, C(5)),
114.0 (ArC(3)), 123.9 (ArC(1)), 126.6 (ArC(2)), 129.6 (q, J 282,
C(4)CF3), 153.2 (C(6)), 161.0 (ArC(4)), 168.9 (C(2)); HRMS (CI+)
m/z [M + H]+ calcd for C14H14F3O3 287.0895, found 287.0899.
(3S,4R)-3-Butyl-6-phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-
pyran-2-one (20). 1-Oxohexan-2-yl 4-nitrobenzoate 3 (995 mg, 3.75
mmol), (Z)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (500 mg, 2.50
mmol), precatalyst 1 (92 mg, 0.25 mmol), triethylamine (0.53 mL,
3.75 mmol), and THF (50 mL) were reacted as described in the
general procedure for 14 h to give crude lactone 20 (94:6 dr). Column
chromatography on silica (95:5 petrol:Et2O) gave (3S,4R)-3-butyl-6-
phenyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyran-2-one 20 (>99:1 dr)
as a colorless oil (487 mg, 1.63 mmol, 65%): [α]2D0 −90.3 (c 0.5,
CHCl3); chiral HPLC analysis (Chiralcel OJ-H 99.8:0.2 hexane:IPA,
9254
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The Journal of Organic Chemistry
Article
12.6 min, tR(3S,4R) 16.0 min, 99% ee; IR νmax (film) 2918 (CH),
CH2), 2.54−2.74 (4H, m, C(2)H, F3CCH and CH2), 7.09−7.15 (3H,
m, ArCH), 7.19−7.24 (2H, m, ArCH); 13C{1H} NMR (125 MHz,
CDCl3) δC 13.9 (CH2CH3), 22.5 (CH2), 27.1 (CH2), 27.2 (CH2),
30.0 (CH2), 33.4 (CH2), 43.7 (C(2)), 44.2 (q, J 25.0, F3CC), 126.3
(ArC(4)), 127.7 (q, J 280, CF3), 128.4 (ArC), 128.6 (ArC), 140.8
(ArC(1)), 179.9 (C(1)); HRMS (CI+) m/z [M + H]+ calcd for
C16H22F3O2 303.1572, found 303.1576.
1
1767 (CO); H NMR (500 MHz, CDCl3) δH 1.47 (3H, d, J 7.1,
C(3)CH3), 3.01−3.13 (2H, m, C(3)H and C(4)H), 5.67 (1H, dd, J
5.2, 1.1, C(5)H), 7.38−7.45 (3H, m, ArC(3)H and ArC(4)H), 7.64−
7.70 (2H, m, ArC(2)H); 19F NMR (470 MHz, CDCl3) δF −67.8 (d, J
9.8, C(4)CF3); 13C{1H} NMR (126 MHz, CDCl3) δC 16.4 (C(3)
CH3), 33.2 (C(3)), 43.6 (q, J 28.6, C(4)), 91.6 (q, J 3.0, C(5)), 125.0
(ArC(2)), 125.7 (q, J 280, C(4)CF3), 128.7 (ArC(3)), 130.1 (ArC(4)),
131.3 (ArC(1)), 153.0 (C(6)), 168.5 (C(2)); HRMS (CI+) m/z [M +
H]+ calcd for C13H12F3O2 257.0789, found 257.0789.
(S)-Methyl 2-((R)-1,1,1-trifluoro-4-oxo-4-phenylbutan-2-yl)-
hexanoate (27). To a solution of lactone 20 (59.6 mg, 0.20 mmol)
(>99:1 dr) in MeOH (2 mL) was added DMAP (2.44 mg, 0.02
mmol), and the reaction mixture was heated at 50 °C for 1.5 h before
being concentrated in vacuo to give crude ester 27 (94:6 dr). Column
chromatography on silica (95:5 petrol:Et2O) gave (S)-methyl 2-((R)-
1,1,1-trifluoro-4-oxo-4-phenylbutan-2-yl)hexanoate 27 (98:2 dr) as a
white solid (54.0 mg, 0.164 mmol, 82%): mp 64−66 °C; [α]2D0 −2.2 (c
0.5, CHCl3); chiral HPLC analysis (Chiralpak AD-H 98:2 hexane:IPA,
flow rate 1 mL min−1, 254 nm, 30 °C) tR(2R,3S) 5.4 min, tR(2S,3R)
6.5 min, >95% ee; IR νmax (solid) 2957 (CH), 2934, 1740 (CO),
(3S,4R)-3-(2-(Benzyloxy)ethyl)-6-phenyl-4-(trifluoromethyl)-3,4-
dihydro-2H-pyran-2-one (24). 4-(Benzyloxy)-1-oxobutan-2-yl 4-ni-
trobenzoate 6 (256 mg, 0.750 mmol), (Z)-4,4,4-trifluoro-1-phenylbut-
2-en-1-one (100 mg, 0.500 mmol), precatalyst 1 (18.4 mg, 50.0
mmol), cesium carbonate (163 mg, 0.500 mmol), and THF (10 mL)
were reacted in a modified version of the general procedure for 8 h and
then purified by column chromatography on silica (95:5 petrol:E-
tOAc) to give (3S,4R)-3-(2-(benzyloxy)ethyl)-6-phenyl-4-(trifluoro-
methyl)-3,4-dihydro-2H-pyran-2-one 24 as a colorless oil (149.2 mg,
0.396 mmol, 79%): [α]2D0 −86.5 (c 0.5, CHCl3); chiral HPLC analysis
(Chiralcel OD-H 98:2 hexane:IPA, flow rate 1 mL min−1, 30 °C, 254
nm) tR(3S,4R) 20.0 min, tR(3R,4S) 24.7 min, 96% ee; IR νmax (film)
2866 (CH), 1771 (CO); 1H NMR (300 MHz, CDCl3) δH 1.95−
2.13 (2H, m, C(3)CH2), 3.17−3.36 (2H, m, C(3)H and C(4)H),
3.55−3.69 (2H, m, C(3)CH2CH2), 4.42−4.62 (2H, m, OCH2Ar),
5.57−5.70 (1H, m, C(5)H), 7.27−7.46 (8H, m, ArH), 7.60−7.74 (2H,
m, C(6)ArC(2)H); 19F NMR (376 MHz, CDCl3) δF −72.5 (d, J 8.7,
C(4)CF3); 13C{1H} NMR (101 MHz, CDCl3) δC 31.0 (C(3)CH2),
35.9 (C(3)), 41.7 (q, J 29.0, C(4)), 66.9(C(3)CH2CH2), 73.3
(OCH2Ar), 91.1 (C(5)), 125.1 (C(6)ArC(2)), 125.8 (q, J 280, C(4)
CF3), 127.8 (OCH2ArC(2)), 127.8 (OCH2ArC(4)), 128.5
(OCH2ArC(3)), 128.6 (C(6)ArC(3)), 130.1 (C(6)ArC(4)), 131.3
(C(6)ArC(1)), 137.8 (OCH2ArC(1)), 153.4 (C(6)), 167.5 (C(2));
HRMS (NSI+) m/z [M + H]+ calcd for C21H20F3O3 377.1359, found
377.1363.
1
1690 (CO); H NMR (500 MHz, CDCl3) δH 0.88 (3H, t, J 7.0,
CH2CH3), 1.24−1.34 (4H, m, CH2 × 2), 1.46−1.53 (1H, m,
C(2)CHaHb), 1.63−1.70 (1H, m, C(2)CHaHb), 2.90 (1H, dt, J 9.4,
4.7, C(2)H), 3.26−3.31 (1H, m, C(O)CHaHb), 3.55−3.61 (2H, m,
C(O)CHaHb and F3CCH), 3.73 (3H, s, OCH3), 7.52 (2H, t, J 7.7,
ArC(3)H), 7.62 (1H, t, J 7.4, ArC(4)H), 8.03−8.04 (2H, m, ArC(2)
H); 13C{1H} NMR (125 MHz, CDCl3) δC 13.9 (CH2CH3), 22.3
(CH2), 29.6 (CH2), 30.1 (CH2), 33.3 (CH2), 40.0 (q, J 26.3, F3CC),
42.7 (C(2)), 51.9 (OCH3), 127.3 (q, J 279, CF3), 128.2 (ArC), 128.8
(ArC), 133.6 (ArC(4)), 136.2 (ArC(1)), 174.3 (C(1)), 196.2
(COPh); HRMS (CI+) m/z [M + H]+ calcd for C17H22F3O3
311.1521, found 311.1524.
( )-2-(1,1,1-Trifluoro-4-phenylbutan-2-yl)hexanoic Acid (28). To
a solution of lactone ( )-20 (59.6 mg, 0.20 mmol) (>99:1 dr) in
EtOAc (5 mL) was added 10% Pd/C (21.3 mg, 0.02 mmol), and a
balloon of H2(g) was appended. The reaction mixture was stirred at rt
for 1 h before being filtered through Celite and concentrated in vacuo
to give the crude acid ( )-28 (>99:1 dr). Column chromatography on
silica (Et2O) gave 2-(1,1,1-trifluoro-4-phenylbutan-2-yl)hexanoic acid
( )-28 (>99:1 dr) as a colorless oil (50.0 mg, 0.164 mmol, 82%): IR
νmax (oil) 3500−2600 (OH), 2959 (CH), 2874, 1712 (CO);
1H NMR (500 MHz, CDCl3) δH 0.92 (3H, t, J 7.2, CH2CH3), 1.15−
1.39 (4H, m, CH2 × 2), 1.47−1.52 (1H, m, C(2)CHaHb), 1.74−1.80
(1H, m, C(2)CHaHb), 1.93−2.09 (2H, m, CH2), 2.55−2.61 (1H, m,
CH), 2.69−2.75 (2H, m, CH × 2), 2.82−2.88 (1H, m, CH), 7.21−
7.27 (3H, m, ArC(2)H and ArC(4)H), 7.34 (2H, t, J 7.5, ArC(3)H);
13C{1H} NMR (75 MHz, CDCl3) δC 13.9 (CH2CH3), 22.5 (CH2),
(S)-Methyl 2-((S)-1,1,1-trifluoro-4-oxo-4-phenylbutan-2-yl)-
hexanoate (25). To a solution of lactone 8 (59.6 mg, 0.20 mmol)
(97:3 dr) in MeOH (2 mL) was added DMAP (2.44 mg, 0.02 mmol),
and the reaction mixture was heated at 50 °C for 1.5 h before being
concentrated in vacuo to give crude ester 25 (90:10 dr). Column
chromatography on silica (97:3 petrol:Et2O) gave (S)-methyl 2-((S)-
1,1,1-trifluoro-4-oxo-4-phenylbutan-2-yl)hexanoate 25 (97:3 dr) as a
colorless oil (48.5 mg, 0.147 mmol, 73%): [α]2D0 −27.0 (c 0.5, CHCl3);
chiral HPLC analysis (Chiralcel OJ-H 95:5 hexane:IPA, flow rate 0.5
mL min−1, 211 nm, 30 °C) tR(2S,3S) 10.0 min, tR(2R,3R) 11.3 min,
97% ee; IR νmax (oil) 2957 (CH), 2934, 1740 (CO), 1690 (C
28.1 (CH2), 30.0 (CH2), 30.4 (C(2)), 33.7 (CH2), 44.2 (q, J 25.1,
F3CC), 126.4 (ArC(4)), 127.8 (q, J 280, CF3), 128.6 (ArC), 128.6
(ArC), 140.7 (ArC(1)), 179.8 (C(1)); HRMS (CI+) m/z [M + H]+
calcd for C16H22F3O2 303.1572, found 303.1576.
1
O); H NMR (400 MHz, CDCl3) δH 0.79 (3H, t, J 7.0, CH2CH3),
1.09−1.28 (4H, m, CH2 ×2), 1.39−1.47 (1H, m, C(2)CHaHb), 1.64−
1.73 (1H, m, C(2)CHaHb), 2.68 (1H, ddd, J 11.3, 4.9, 3.6, C(2)H),
3.12 (1H, dd, J 18.3, 4.6, C(O)CHaHb), 3.33 (1H, dd, J 18.3, 6.8,
C(O)CHaHb), 3.47−3.57 (1H, m, F3CCH), 3.61 (3H, s, CH3), 7.39−
7.43 (2H, m, ArC(3)H), 7.50−7.55 (1H, m, ArC(4)H), 7.88−7.91
(2H, m, ArC(2)H); 13C{1H} NMR (75 MHz, CDCl3) δC 13.9
(CH2CH3), 22.5 (CH2), 27.9 (CH2), 29.9 (CH2), 34.3 (q, J 2.0, C(O)
CH2), 40.0 (q, J 26.1, F3CC), 43.9 (q, J 1.73, C(2)), 52.1 (OCH3),
127.5 (q, J 279, CF3), 128.1 (ArC), 128.8 (ArC), 133.6 (ArC(4)),
136.3 (ArC(1)), 173.6 (C(1)), 195.7 (COPh); HRMS (CI+) m/z [M
+ H]+ calcd for C17H22F3O3 311.1521, found 311.1524.
3-(1-Hydroxy-2-(4-nitrophenoxy)propyl)-2-mesityl-6,7-dihydro-
5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (29). To a
solution of NHC precatalyst 7 (100 mg, 0.32 mmol) and aldehyde 2
(62 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added NEt3 (49 μL, 0.35
mmol). After 10 min, the solution was concentrated in vacuo and
purified by column chromatography (20:80 CH2Cl2:acetone) to give
the combined diastereoisomers of 29 (dr 83:17) as a white solid (20.0
mg, 0.04 mmol, 12%): mp 123−126 °C; IR νmax (neat) 1724 (CO),
1593 (CC), 1525 (N−O), 1348 (N−O), 1269 (C−O), 1078 (C−
−
O); m/z (NSI+) 451 ([M − BF4 ]+, 100%); HRMS (NSI+) m/z [M −
( )-2-(1,1,1-Trifluoro-4-phenylbutan-2-yl)hexanoic Acid (26). To
a solution of lactone ( )-8 (59.6 mg, 0.20 mmol) (97:3 dr) in EtOAc
(5 mL) was added 10% Pd/C (21.3 mg, 0.02 mmol), and a balloon of
H2(g) was appended. The reaction mixture was stirred at rt for 1 h
before being filtered through Celite and concentrate in vacuo to give
the crude acid ( )-26 (95:5 dr). Column chromatography on silica
(50:50 petrol:Et2O) gave 2-(1,1,1-trifluoro-4-phenylbutan-2-yl)-
hexanoic acid ( )-26 (95:5 dr) as a colorless oil (49.0 mg, 0.163
mmol, 82%): IR νmax (oil) 3500−2600 (OH), 2959 (CH), 2874,
−
BF4 ]+ calcd for C24H27N4O5 451.1976, found 451.1973.
Major: 1H NMR (500 MHz, CD2Cl2) δH 1.41−1.44 (3H, m,
CHCH3), 1.91 (3H, s, CH3), 2.11 (3H, s, CH3), 2.37 (3H, s, CH3),
2.86−2.98 (2H, m, NCH2CH2CH2), 3.22−3.28 (2H, m,
NCH2CH2CH2), 4.55−4.61 (1H, m, NCHAHBCH2CH2), 4.83−4.90
(1H, m, NCHAHBCH2CH2), 5.11−5.05 (2H, m, CH3CHC(OH)(H)),
7.02 (1H, s, MesCH), 7.11 (1H, s, MesCH), 8.05−8.06 (2H, m, 2,6-
ArH), 8.24−8.26 (2H, m, 3,5-ArH); 13C{1H} NMR (125 MHz,
CD2Cl2) δC 15.2, 17.2, 17.7, 21.3, 22.2, 27.3, 49.5, 67.9, 71.6, 123.9,
130.3, 130.6, 130.9, 131.2, 135.4, 135.5, 143.1, 151.2, 151.8, 163.5,
164.0.
1
1712 (CO); H NMR (400 MHz, CDCl3) δH 0.83 (3H, t, J 7.0,
CH2CH3), 1.14−1.34 (4H, m, CH2 × 2), 1.45−1.54 (1H, m,
C(2)CHaHb), 1.59−1.69 (1H, m, C(2)CHaHb), 1.84−1.94 (2H, m,
9255
dx.doi.org/10.1021/jo401433q | J. Org. Chem. 2013, 78, 9243−9257

The Journal of Organic Chemistry
Article
Minor: 1H NMR (500 MHz, CD2Cl2, characteristic signals) δH 2.03
(3H, s, CH3), 2.14 (3H, s, CH3), 2.33 (3H, s, CH3), 4.34−4.40 (1H,
m, NCHAHBCH2CH2), 4.83−4.90 (1H, m, NCHAHBCH2CH2), 5.11−
5.05 (2H, m, CH3CHC(OH)(H)), 6.98 (1H, s, MesCH), 7.08 (1H, s,
MesCH), 8.12−8.16 (2H, m, 2,6-ArH), 8.29−8.32 (2H, m, 3,5-ArH),
13C{1H} NMR (125 MHz, CD2Cl2, characteristic signals) δC 49.7,
10073. (c) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2012, 354,
783−789. (d) Wen, L.; Yin, L.; Shen, Q.; Lu, L. ACS Catal. 2013, 3,
502−506. (e) Kawai, H.; Sugita, Y.; Tokunaga, E.; Sato, H.; Shiro, M.;
Shibata, N. Chem. Commun. 2012, 48, 3632−3634. (f) Kawai, H.;
Okusu, S.; Tokunaga, E.; Sato, H.; Shiro, M.; Shibata, N. Angew. Chem.,
Int. Ed. 2012, 51, 4959−4962. (g) Kawai, H.; Kitayama, T.; Tokunaga,
E.; Matsumoto, T.; Sato, H.; Shiro, M.; Shibata, N. Chem. Commun.
2012, 48, 4067−4069.
(6) For reviews on NHC catalysis, see: (a) Moore, J. L.; Rovis, T.
Top. Curr. Chem. 2010, 291, 77−144. (b) Marion, N.; Diez-Gonzalez,
S.; Nolan, I. P. Angew. Chem., Int. Ed. 2007, 46, 2988−3000.
(c) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606−5655.
(7) For reviews on NHC-redox catalysis, see: (a) Vora, H. U.;
Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617−1639.
(b) Douglas, J.; Churchill, G.; Smith, A. D. Synthesis 2012, 44, 2295−
2309.
(8) (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088−15089. (b) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008,
10, 3817−3820. (c) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.;
Ryu, I. Org. Lett. 2009, 11, 3934−3937. (d) Yang, L. M.; Wang, F.;
Chua, P. J.; Lv, Y. B.; Zhong, L. J.; Zhong, G. F. Org. Lett. 2012, 14,
2894−2897. (e) Jian, T.-Y.; Sun, L.-H.; Ye, S. Chem. Commun. 2012,
48, 10907−10909.
124.2, 131.1.
(Z)-2-Mesityl-3-(1-(propionyloxy)prop-1-en-1-yl)-6,7-dihydro-5H-
[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (30). To a solution of
NHC precatalyst 7 (100 mg, 0.32 mmol) and aldehyde 2 (62 mg, 0.32
mmol) in CH2Cl2 (10 mL) was added NEt3 (88 μL, 0.64 mmol). After
16 h, the solution was concentrated in vacuo and purified by column
chromatography (50:50 CH2Cl2:acetone) to give 30 as a white solid
(37 mg, 0.18 mmol, 55%): mp 55−60 °C; IR νmax (neat) 2924, 1775
1
(CO), 1589 (CC), 1487, 1449, 1033 (CO); H NMR (500
MHz, MeOD-d4) δH 0.94 (3H, t, J 7.4, CH2CH3), 1.78 (3H, d, J 7.1,
CHCH3), 2.11 (3H, s, CH3), 2.04−2.08 (8H, m, ArCH3 and
CH2CH3), 2.38 (3H, s, ArCH3), 2.92 (2H, quintet, J 7.5,
NCH2CH2), 3.26 (2H, t, J 7.8, NCH2CH2CH2), 4.57 (2H, t, J 7.3,
NCH2), 6.55 (1H, q, J 7.1, CHCH3), 7.13 (2H, s, ArCH); 13C{1H}
NMR (125 MHz, MeOD-d4) δC 8.6, 12.7, 17.4, 21.2, 22.8, 26.7, 27.7,
50.2, 130.8, 131.2, 133.6, 134.4, 137.0, 143.6, 145.7, 164.5, 172.0; m/z
−
−
(NSI+) 340 ([M − BF4 ]+, 100%); HRMS (NSI+) m/z [M − BF4 ]+
calcd for C20H26N3O2 340.2020, found 340.2020.
(9) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418−8420. (b) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc.
Natl. Acad. Sci. U. S. A. 2010, 107, 20661−20665. (c) Fang, X.; Chen,
X.; Chi, Y. R. Org. Lett. 2011, 13, 4708−4711. (d) Fu, Z.; Sun, H.;
Chen, S.; Tiwari, B.; Li, G.; Chi, Y. R. Chem. Commun. 2013, 49, 261−
263. (e) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi, Y. R. Org. Lett. 2012,
14, 5412−5415.
ASSOCIATED CONTENT
■
S
* Supporting Information
Epimerization of syn-15, kinetic profiles, and kinetic isotope
1
effect, H and 13C{1H} NMR spectra and HPLC trances of all
dihydropyranones and derivatization products. CIF file giving
X-ray crystallographic data for syn-12. Representative spectra
from mechanistic studies. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Lv, H.; Mo, J.; Fang, X.; Chi, Y. R. Org. Lett. 2011, 13, 5366−
5369.
(11) (a) Lv, H.; Chen, X.-Y.; Sun, L.-h.; Ye, S. J. Org. Chem. 2010, 75,
6973−6976. (b) Jian, T.-Y.; Shao, P.-L.; Ye, S. Chem. Commun. 2011,
47, 2381−2383.
AUTHOR INFORMATION
Corresponding Author
*A. D. Smith. E-mail: ads10@st-andrews.ac.uk.
Notes
■
(12) Hao, L.; Du, Y.; Lv, H.; Chen, X. K.; Jiang, H. S.; Shao, Y. L.;
Chi, Y. R. Org. Lett. 2012, 14, 2154−2157.
(13) (a) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem., Int. Ed. 2012,
51, 12330−12333. (b) Mo, J.; Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R.
Org. Lett. 2013, 15, 50−53.
(14) Recently, Chi and co-workers reported NHC-catalyzed
reactions of enals with ketimines, with (E)- and (Z)-enals giving
different reaction products; see: Chen, X.; Fang, X.; Chi, Y. R. Chem.
Sci. 2013, 4, 2613−2618.
(15) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373−375.
(16) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem., Int.
Ed. 2011, 50, 5331−5334.
(17) α-Aroyloxyaldehydes are stable for a number of months when
stored in a fridge.
(18) Crystallographic data for 12 has been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 933076.
(19) For example, reaction of a pentyl substituted β-trifluoromethyl
enone with 2 gave the corresponding syn-dihydropyranone in 27%
yield.
(20) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623−1625.
(21) (a) Allen, S. E.; Mahatthananchai, J.; Bode, J. W.; Kozlowski, M.
C. J. Am. Chem. Soc. 2012, 134, 12098−12103. (b) Mahatthananchai,
J.; Bode, J. W. Chem. Sci. 2012, 3, 192−197.
(22) We have recently isolated a number of these aldehyde-NHC
adducts for related Stetter and benzoin reactions; see ref 24a.
(23) Control experiments found that reactions performed in CH2Cl2
gave comparable dr and ee to those performed in THF.
(24) (a) Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.;
O’Donoghue, A. C.; Smith, A. D. Chem. Sci. 2013, 4, 1514−1522.
(b) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A. D.;
O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421−20432.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Royal Society for a University Research
Fellowship (A.D.S.), the EPSRC (C.J.C.), the EPSRC and
AstraZeneca (Case award to J.D.), The Carnegie Trust for the
Universities of Scotland (L.C.M.), as well as European Research
Council under the European Union’s Seventh Framework
Programme (FP7/2007-2013) ERC grant agreement no.
279850 (A.T.D., C.F., and J.E.T.). We also thank the EPSRC
National Mass Spectrometry Service Centre (Swansea).
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Article
(25) α-Aroyloxyaldehyde 2 is likely to undergo other decomposition
pathways as the formation of initial adduct 29, product 19, O-acylated
enolate 30, and propanoic acid does not fully account for the rate of
decomposition observed.
(26) Chi et al. have observed deactivation of a related achiral NHC-
catalyst through a different pathway in reactions with activated esters;
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(27) Attempts to isolate adduct 31 from a stoichiometric reaction of
chiral NHC precatalyst 1 and 2 were unsuccessful due to the rapid
forward reaction.
(28) In this case, aldehyde decomposition products could not be
1
observed by H NMR spectroscopy.
(29) KIE is an average over two experiments. For full details of
kinetic experiments see the Supporting Information.
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an intramolecular Stetter reaction in which proton transfer is rate-
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