Enantioselective NHC-Catalyzed Redox [4 + 2]-Hetero-Diels-Alder Reactions Using α,β-Unsaturated Trichloromethyl Ketones as Amide Equivalents

Article abstract of DOI:10.1021/acs.joc.5b01820

α,β-Unsaturated trichloromethyl ketones are suitable α,β-unsaturated amide and ester equivalents in N-heterocyclic carbene (NHC)-catalyzed redox hetero-Diels-Alder reactions with azolium enolates generated from α-aroyloxyaldehydes. The initially formed syn-dihydropyranone products can be isolated or can undergo ring-opening with benzylamine followed by aminolysis of the resulting CCl₃ ketone to form a range of diamides with high diastereo- and enantioselectivity (up to >95:5 dr and >99% ee).

Full text of DOI:10.1021/acs.joc.5b01820

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Article
Enantioselective NHC-Catalyzed Redox [4+2]-hetero-Diels-Alder Reactions
using alpha,beta-Unsaturated Trichloromethyl ketones as Amide Equivalents
Nassilia Attaba, James E Taylor, Alexandra M. Z. Slawin, and Andrew D. Smith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01820 • Publication Date (Web): 05 Sep 2015
Downloaded from http://pubs.acs.org on September 11, 2015
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Enantioselective NHCꢀCatalyzed Redox [4+2]ꢀheteroꢀDielsꢀ
Alder Reactions using α,βꢀUnsaturated Trichloromethyl
ketones as Amide Equivalents
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Nassilia Attaba, James E. Taylor, Alexandra M. Z. Slawin, and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews,
KY16 9ST, U.K.
Eꢀmail: ads10@stꢀandrews.ac.uk
α,βꢀUnsaturated trichloromethyl ketones are suitable α,βꢀunsaturated amide and ester
equivalents in Nꢀheterocyclic carbene (NHC)ꢀcatalyzed redox heteroꢀDielsꢀAlder reactions
with azolium enolates generated from αꢀaroyloxyaldehydes. The initially formed synꢀ
dihydropyranone products can be isolated, or can undergo ringꢀopening with benzylamine
followed by aminolysis of the resulting CCl3 ketone to form a range of diamides with high
diastereoꢀ and enantioselectivity (up to >95:5 dr and >99% ee).
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Introduction
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NꢀHeterocyclic carbenes (NHCs) are valuable Lewis base organocatalysts that can react
through a number of distinct catalytic activation modes.1 For example, azolium enolates are
versatile intermediates that react with a range of electrophiles to form a wide variety of
synthetically useful products. Azolium enolates have been accessed through reaction of
NHCs with ketenes,2 αꢀreducible aldehydes,3ꢀ7 unfunctionalized aldehydes in the presence of
an oxidant,8 and activated carboxylic acids or esters in the presence of a base.9 NHCꢀredox
catalysis proceeding through addition of an NHC to an aldehyde bearing an αꢀreducible
functional group is a particularly efficient method of forming azolium enolates.10 αꢀ
Reducible aldehydes that have been used for this purpose include αꢀchloroaldehydes,3 enals,4
αꢀaryloxyaldehydes,5 and formyl cyclopropanes6 (Scheme 1a).
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We have demonstrated that αꢀaroyloxyaldehydes are benchꢀstable azolium enolate
precursors that can be utilized in a number of asymmetric NHCꢀcatalyzed redox [4+2]ꢀ
cycloaddition reactions.7 For example, azolium enolates generated from αꢀaroyloxyaldehydes
react with substituted trifluoromethyl ketones to form dihydropyranones with high levels of
stereoselectivity (Scheme 1b).7d The NHCꢀcatalyzed redox reaction of αꢀaroyloxyaldehydes
and NꢀarylꢀN'ꢀaroyldiazenes to synthesize enantiomerically enriched αꢀamino acid derivatives
has also been explored.7c While NHCꢀcatalyzed asymmetric cycloadditions of azolium
enolates with electronꢀdeficient enones are widely reported, the use of α,βꢀunsaturated
amides and esters remains a significant challenge due to the decreased electrophilicity of
these substrates. This problem has been overcome in other Lewis basedꢀcatalyzed conjugate
additions through the use of more reactive α,βꢀunsaturated amide/ester equivalents such as Nꢀ
acylpyrroles,11 2ꢀacyl imidazoles,12 activated imides,13 αꢀketophosphonates,14,15 and
trichloromethyl
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Scheme 1. Azolium enolate precursors for [4+2] heteroꢀDielsꢀAlder reactions
a) NHC-catalyzed redox azolium enolate precursors
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9
O
O
O
R
R
H
H
R
H
H
O
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Cl
O
Ar
O
O
Ar = 4-NO2C6H4
ArO
R
H
Easily accessible
Bench stable
O
b) -Aroyloxyaldehydes in NHC-catalyzed redox [4+2] cycloadditions
O
O
R1
CF3
R
R2
22 examples
up to >95:5 dr
up to >99% ee
O
O
O
R1
CF3
R
R2
O
NHC
Base
H
O
O
O
R1
X
R
Ar
X = OR2, NHR2
unknown
Ar = 4-NO2C6H4
R1
X
ketones.16,17 However, the use of α,βꢀunsaturated amide and ester equivalents in NHCꢀ
catalyzed cycloaddition reactions remains unexplored.
Of particular relevance is the use of trichloromethyl ketones as carboxylic acid, ester and
amide equivalents in processes that use the leaving group ability of the CCl3 ketone in
haloformꢀtype reactions.18ꢀ20 α,βꢀUnsaturated trichloromethyl ketones have previously been
utilized as Michael acceptors in a small number of organocatalytic reactions.16,17 Zhao and
coꢀworkers reported the enantioselective epoxidation of α,βꢀunsaturated trichloromethyl
ketones with tertꢀbutylhydroperoxide (TBHP) catalyzed by diaryl prolinol 2.16a
Trichloromethyl ketone 3 undergoes either aminolysis or alcoholysis to provide the
corresponding amide or ester products without loss in enantioselectivity (Scheme 2a).
Various bifunctional Hꢀbonding/Lewis bases have also been used to catalyze the conjugate
addition of nucleophiles including αꢀcyano ketones,16b α,βꢀunsaturated γꢀbutyrolactones,16c
and azlactones16d into α,βꢀunsaturated trichloromethyl ketones. We have reported the
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isothioureaꢀcatalyzed
Michael
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Scheme 2. Use of α,βꢀunsaturated trichloromethyl ketones as amide and ester
equivalents
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additionꢀlactonization of substituted acetic acids and α,βꢀunsaturated trichloromethyl
ketones.17 The initially formed antiꢀdihydropyranones 8 undergo ringꢀopening followed by
alcoholysis of the CCl3 ketone with methanol to give a range of diesters 9 with high levels of
diastereoꢀ and enantioselectivity (Scheme 2b). This methodology is limited to the use of
either 2ꢀaryl or 2ꢀalkenylacetic acids and gives preferential access to the antiꢀdiastereoisomer
of the dihydropyranone intermediates.
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Herein the use of αꢀaroyloxyaldehydes as azolium enolate precursors in [4+2] heteroꢀDielsꢀ
Alder reactions with α,βꢀunsaturated trichloromethyl ketones is investigated, with the synꢀ
dihydropyranone products formed in good yields with high levels of diastereoꢀ and
enantioselectivity. Subsequent ringꢀopening followed by aminolysis of the CCl3 ketone gives
access to a wide range of diamide products without loss of enantioselectivity (Scheme 2c). In
one case, the sequential addition of two different nucleophiles led to the formation of a
differentially substituted diacid derivative. The methodology described is complementary to
the related isothioureaꢀcatalyzed process as it allows access to 3ꢀalkylꢀsubstituted
dihydropyranones and preferentially gives the synꢀdiastereoisomer of the products.
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Results and Discussion
[4+2] Cycloaddition: Optimization and Generality.
First, the NHCꢀcatalyzed redox [4+2] heteroꢀDielsꢀAlder reaction between an azolium
enolate generated from αꢀaroyloxyaldehyde 10 and α,βꢀunsaturated trichloromethyl ketone 1
was studied. αꢀAroyloxyaldehydes were prepared in oneꢀstep on a gramꢀscale from the parent
aldehyde and 4ꢀnitrobenzoic acid under oxidative conditions using a modified procedure of
that described by Ishihara and coꢀworkers.21 Trichloromethyl ketones were prepared on a
gramꢀscale using a twoꢀstep procedure first reported by Corey and coꢀworkers starting from
the corresponding α,βꢀunsaturated aldehyde and can be stored for a number of months
without decomposition.22 Initial studies found that αꢀaroyloxyaldehyde 10 reacts with
trichloromethyl ketone 1 using 10 mol% triazolium NHC precatalyst 11 and triethylamine in
THF at room temperature, giving dihydropyranone 12 in 57% yield and >95:5 dr, with the
major synꢀdiastereoisomer formed in excellent >99% ee (Table 1, entry 1).23 The reaction
proceeds in a number of different solvents, with CH2Cl2 giving dihydropyranone 12 in an
improved 67% yield without compromising the stereoselectivity (Table 1, entries 2ꢀ4).
Lowering the catalyst loading to 5 mol% gave comparable results (Table 1, entry 5), however
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further decreases in the amount of catalyst led to a significant reduction in isolated yield.
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Finally,
performing
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Table 1. Reaction optimizationa
Entry
Solvent
THF
11 (mol%)
t / h
5
drb
Yield (%)
ee (%)c
>99
1
2
10
10
10
10
5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
57
55
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67
66
84
Et2O
1.5
1.5
1
>99
3
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
>99
4
>99
5
6d
3.5
>99
5
3.5
>99
aReactions performed on 0.2 mmol scale. Determined by analysis of crude 1H NMR spectra. cDetermined by
chiral HPLC analysis. dReaction performed on a 1.2 mmol scale.
b
the reaction on a larger scale (1.2 mmol) gave synꢀdihydropyranone 12 in 84% yield as a
single diastereoisomer in >99% ee (Table 1, entry 6).
The scope and generality of this procedure was studied through variation of the substituents
on both the αꢀaroyloxyaldehyde and trichloromethyl ketone components (Table 2). A range
of αꢀaroyloxyaldehyde substituents was tolerated under the previously optimized reaction
conditions, forming functionalized synꢀdihydropyranones 12ꢀ19 with excellent levels of
diastereoꢀ and enantioselectivity. A higher catalyst loading (10 mol% 11) was required to
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form dihydropyranones 14 and 15, as lower levels of diastereoselectivity were obtained over
extended reaction times with a lower catalyst loading. For example, dihydropyranone 14 was
formed in 65:35 dr after 48 hours under the standard reaction conditions using 5 mol% 11,
with both diastereoisomers formed with high enantioselectivity (98% eesyn, >99% eeanti).
Increasing
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Table 2. Use of trichloromethyl ketones in NHCꢀredox catalyzed [4+2] heteroꢀDielsꢀ
Alder reactions
O
O
11
(5 mol%)
O
R
R
Et3N (1.5 eq)
CH2Cl2, rt
H
O
+
R1
CCl3
OCOAr
R1
CCl3
(1.5 eq)
Ar = 4-NO2C6H4
12-19
Product
Yielda (time)
drb
eec
Product
Yielda (time)
drb
eec
aIsolated yield of major synꢀdiastereoisomer. bDetermined by analysis of crude 1H NMR spectra. cDetermined
by chiral HPLC analysis. dReaction performed using 10 mol% 11. eIsolated as a mixture of diastereoisomers. fee
could not be determined by either chiral HPLC or chiral GC analysis.
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the catalyst loading to 10 mol% allowed dihydropyranone 14 to be formed in 90:10 dr, with
the major synꢀdiastereoisomer isolated in 60% yield and 99% ee. Similarly, dihydropyranone
15 was formed in 90:10 dr after 26 hours using 5 mol% 11, whereas increasing the catalyst
loading to 10 mol% allowed a single diastereoisomer to be isolated in 65% yield after 4 hours
in >99% ee. Within the trichloromethyl ketone, βꢀaryl groups containing electronꢀdonating
(4ꢀMeOC6H4) and electronꢀwithdrawing halogen (4ꢀBrC6H4) substituents were well tolerated,
forming synꢀdihydropyranones 17 and 18 as single diastereoisomers in excellent yields and
>99% ee. However, βꢀalkyl substitution was less well tolerated, forming synꢀ
dihydropyranone 19 in a low 26% yield despite using 10 mol% 11 for an extended reaction
time, although the diastereoꢀ and enantioselectivity remained high.
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To investigate the drop in diastereoselectivity observed for the reactions with some of the
αꢀaroyloxyaldehyde substituents an epimerization experiment was performed. Treating
isolated synꢀdihydropyranone 14 (90:10 dr, 99% ee) with triethylamine in CD2Cl2 at room
temperature resulted in a mixture of synꢀ14 and antiꢀ20 (67:33 dr), with both
diastereoisomers obtained in >99% ee (Scheme 3). This is consistent with a baseꢀpromoted
epimerization of the C(3) stereocenter, which accounts for the loss in diastereoselectivity in
reactions that required extended reaction times upon changing the αꢀaroyloxyaldehyde
component.
Scheme 3. Baseꢀpromoted epimerization of 14
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Trichloromethyl ketones as Ester and Amide Equivalents.
Next, the synthetic utility of the trichloromethyl substituent as an ester/amide equivalent
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was examined. It was hoped that treating the crude synꢀdihydropyranone products with an
excess of a suitable nucleophile (alcohol or amine) would lead to ringꢀopening followed by
alcoholysis/aminolysis of the CCl3 ketone. Pleasingly, adding an excess of benzylamine to
crude synꢀdihydropyranone 12 led to formation of the expected diamide 21 in excellent 85%
yield as a single diastereoisomer in >99% ee (Scheme 4a). In contrast, treating crude synꢀ
dihydropyranone 12 with DMAP (20 mol%) and an excess of methanol gave a mixture of
trichloroketoester 22 and diester 23, with both formed with high levels of
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Scheme 4. Use of trichloromethyl ketones as ester and amide equivalents
O
a)
Me
H
O
OCOAr
10 (1.5 eq)
Ar = 4-NO2C6H4
i) 11 (5 mol%)
Et3N (1.5 eq)
Me
Ph
Bn
Bn
N
H
CH2Cl2, rt
+
O
ii) BnNH2 (excess)
O
N
H
CCl3
Ph
1
21, 85%
>95:5 dr
>99% ee
b)
O
Me
H
O
O
OCOAr
10 (1.5 eq)
Ar = 4-NO2C6H4
i) 11 (5 mol%)
Et3N (1.5 eq)
Me
Ph
Me
Ph
OMe
CCl3
OMe
OMe
+
CH2Cl2, rt
+
O
ii) MeOH (excess)
DMAP (20 mol%)
O
O
CCl3
Ph
22
23
, 50%
, 20%
1
>95:5 dr
>99% ee
>95:5 dr
>99% ee
O
c)
Me
H
i) 11 (5 mol%)
Et3N (1.5 eq)
O
OCOAr
10 (1.5 eq)
Ar = 4-NO2C6H4
Me
Ph
OBn
CH2Cl2, rt
ii) BnOH (excess)
DMAP (20 mol%)
iii) BnNH2 (1.2 eq)
+
O
Bn
O
N
H
CCl3
Ph
1
24, 32%
>95:5 dr
>99% ee
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stereoselectivity (Scheme 4b).24 The observation that only partial alcoholysis of the CCl3
ketone had occurred led to the possibility of a sequential ringꢀopening and CCl3 ketone
displacement using two different nucleophiles. Firstly, benzyl alcohol and DMAP (20 mol%)
were used to ringꢀopen the initial synꢀdihydropyranone product with subsequent addition of
benzylamine (1.2 eq) leading to aminolysis of the CCl3 ketone to give γꢀester amide 24 in
32% yield and >99% ee over the three reaction steps (Scheme 4c). This reactivity is in
contrast to the use of αꢀketoꢀβ,γꢀunsaturated phosphonates as ester/amide equivalents in
related reactions where both ringꢀopening and either alcoholysis or aminolysis of the
phosphate group occurs rapidly and therefore differential substitution is not possible.14d
Moreover, dihydropyranones formed from related reactions using α,βꢀunsaturated
trifluoromethyl ketones undergo ringꢀopening with no alcoholysis / aminolysis of the
trifluoromethyl ketone observed.7d The utility of trichloromethyl ketones as amide
equivalents in this NHCꢀcatalyzed redox [4+2] cycloaddition process was
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Table 3. NHCꢀredox catalyzed [4+2] cycloaddition followed by ringꢀopening and
aminolysis
Product
Yielda (time)
drb
eec
Product
Yielda (time)
drb
eec
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aIsolated yield of major synꢀdiastereoisomer. bDetermined by analysis of crude 1H NMR spectra. cDetermined
by chiral HPLC analysis. Reaction performed using 10 mol% 11. ee could not be determined by either chiral
d
e
HPLC or chiral GC analysis.
further assessed using a range of substituted αꢀaroyloxyaldehydes and α,βꢀunsaturated
trichloromethyl ketones (Table 3). The cycloaddition reactions were performed under the
previously optimized conditions and the initially formed synꢀdihydropyranones underwent
ringꢀopening and aminolysis with benzylamine. The resulting diamide products 21, 25ꢀ33
were conveniently purified by trituration and did not require column chromatography.25
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A number of substituted αꢀaroyloxyaldehydes was successfully applied in this process,
forming diamides 21, 25ꢀ27 in high yields as single diastereoisomers and in excellent ee.
Benzyl substituted diamide 27 was formed with lower diastereoselectivity (80:20 dr), which
is consistent with baseꢀpromoted epimerization of dihydropyranone 16 under the reaction
conditions (cf. Table 2). A wide range of substituted trichloromethyl ketone derivatives was
also tolerated, including those containing electronꢀdonating aryl (4ꢀMeOC6H4), electronꢀ
withdrawing aryl (2ꢀNO2C6H4) and heteroaromatic substituents, forming functionalized
diamides 28ꢀ32 in good yields with excellent levels of stereocontrol. As observed previously,
the incorporation of a βꢀalkyl substituent led to a significantly lower yield of diamide 33. The
relative and absolute configuration of diamide 28 was confirmed by Xꢀray crystallographic
analysis,23 with the stereochemistry of all other products assigned by analogy.
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Proposed Mechanism.
The proposed catalytic cycle starts with nucleophilic addition of the free NHC into the αꢀ
aroyloxyaldehyde, with the resulting adduct 34 likely to be the resting state of the catalyst
(Scheme 5).7b,26 Deprotonation forms the Breslow intermediate, which can eliminate 4ꢀ
nitrobenzoate to form an enol that undergoes further deprotonation into the key azolium
enolate intermediate. Consistent with the work of Bode and coꢀworkers,27 the azolium enolate
is thought to undergo an asynchronous endoꢀheteroꢀDielsꢀAlder reaction with the α,βꢀ
unsaturated trichloromethyl ketone. Elimination of the catalyst generates the synꢀ
dihydropyranone product, which can undergo ringꢀopening using benzylamine or an alcohol,
with aminolysis of the resulting trichloromethyl ketone proceeding at a relatively slower rate.
Scheme 5. Proposed mechanism
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Conclusion
α,βꢀUnsaturated trichloromethyl ketones act as amide equivalents in NHCꢀcatalyzed redox
[4+2] heteroꢀDielsꢀAlder reactions with azolium enolates generated from benchꢀstable αꢀ
aroyloxyaldehydes. The initially formed synꢀdihydropyranones can be isolated in good yields
with excellent levels of diastereoꢀ and enantioselectivity. The dihydropyranone products
undergo facile ringꢀopening with benzylamine and further aminolysis of the resulting CCl3
ketone leads to the formation of diamides. A wide range of both αꢀaroyloxyaldehydes and
α,βꢀunsaturated trichloromethyl ketones can be utilized in this process, generating
functionalized diamide products in high yields with excellent levels of stereoselectivity.
Experimental Section
General: 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 °C and −10 °C
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obtained using ice/water and ice/water/salt baths, respectively. Optical rotations were
recorded with a path length of 1 dm and concentrations, c, are quoted in g/100 mL. All chiral
HPLC traces were compared with an authentic racemic trace prepared using (rac)ꢀ11. Infraꢀ
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red spectra were recorded as thin films using an ATR accessory. H NMR spectra were
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acquired at either 300, 400, 500 or 700 MHz, 13C{1H} NMR spectra were acquired at either
75, 101 or 126 MHz, and 19F{1H} NMR spectra were acquired at either 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
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confirmed using 2D H COSY, 2D H NOESY, 2D Hꢀ13C HMBC and 2D Hꢀ13C HSQC
where necessary. Mass spectrometry (m/z, HRMS) data were acquired using either
atmospheric pressure chemical ionisation (APCI) or nanospray ionisation (NSI) using a TOF
mass analyser.
NHCꢀprecatalyst 11 was synthesized on a gramꢀscale according to a literature procedure.28
Commercially available reagents were used as supplied without further purification unless
stated otherwise.
Preparation of αꢀAroyloxyaldehydes
1-Oxopropan-2-yl 4-nitrobenzoate (10). Prepared according to a previously reported
procedure as a beige solid with data in accordance with literature.7b mp 74–76 °C {lit.7b mp
1
78–80 °C}; H NMR (300 MHz, CDCl3) δH: 1.59 (3H, d, J 7.2, CH3), 5.39 (1H, q, J 7.2,
CHCH3), 8.24–8.37 (4H, m, 4ꢀNO2ArH), 9.67 (1H, s, CHO).
1-Oxo-3-phenylpropan-2-yl 4-nitrobenzoate. Prepared according to a previously reported
procedure as a beige solid with data in accordance with literature.7b mp 91–93 °C {lit.7b mp
85–86 °C}; 1H NMR (300 MHz, CDCl3) δH: 3.22 (1H, dd, J 14.5, 8.4, CHAHB), 3.35 (1H, dd,
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J 14.5, 5.0, CHAHB), 5.52 (1H, dd, J 8.3, 5.0, CHCH2), 7.27–7.38 (4H, m, ArH), 8.15–8.23
(2H, m, 4ꢀNO2ArH), 8.26–8.35 (2H, m, 4ꢀNO2ArH), 9.68 (1H, s, CHO).
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4-(1,3-Dioxoisoindolin-2-yl)-1-oxobutan-2-yl 4-nitrobenzoate. Phthalic anhydride (4.5 g,
34 mmol, 1.0 eq) and 4ꢀaminobutanꢀ1ꢀol (3.1 mL, 34 mmol, 1.0 eq) were heated in toluene
(100 mL) at reflux under DeanꢀStark conditions for 3 h. The reaction mixture was allowed to
cool to rt before being concentrated to give 2ꢀ(4ꢀhydroxybutyl)ꢀ2,3ꢀdihydroꢀ1Hꢀisoindoleꢀ
1,3ꢀdione as a pale yellow solid (7.0 g, 32 mmol, 95%), with spectroscopic data in
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accordance with the literature;29 mp 47−49 °C {lit.29mp 48−49 °C}; H NMR (500 MHz,
CDCl3) δH: 1.64 (2H, p, J 6.6, NCH2CH2), 1.80 (2H, p, J 7.3, N(CH2)2CH2), 3.71 (2H, t, J
6.4, NCH2), 3.76 (2H, t, J 7.2, N(CH2)3CH2), 7.73 (2H, dd, J 5.5, 3.0, ArH), 7.86 (2H, dd, J
5.4, 3.1, ArH).
A solution of oxalyl chloride (2.3 mL, 27 mmol, 2.0 eq) in CH2Cl2 (50 mL) was cooled to
−78 °C before a solution of DMSO (2.14 mL, 30 mmol, 2.2 eq) in CH2Cl2 (10 mL) was
added dropwise. After stirring for 15 min a solution of 2ꢀ(4ꢀhydroxybutyl)ꢀ2,3ꢀdihydroꢀ1Hꢀ
isoindoleꢀ1,3ꢀdione (3.0 g, 14 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added dropwise. The
reaction mixture was stirred for 15 min before Et3N (5.7 mL, 41 mmol, 3.0 eq) was added
dropwise. The reaction was stirred for 5 min before warming to rt and stirring for an
additional 15 min. The reaction was diluted with CH2Cl2, washed with 1
M
HCl and brine.
The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product
that was purified by flash silica column chromatography (70:30 petrol : EtOAc) to give 4ꢀ
(1,3ꢀdioxoꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ2ꢀyl)butanal as a white solid (1.7 g, 7.9 mmol, 57%),
with spectroscopic data in accordance with the literature;30 mp 66−68 °C; {lit.30 mp 72−74
1
°C}; H NMR (500 MHz, CDCl3) δH: 2.04 (2H, p, J 7.0, NCH2CH2), 2.51–2.62 (2H, m,
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N(CH2)2CH2), 3.73–3.80 (2H, m, NCH2), 7.74 (2H, dd, J 5.4, 3.1, NCOArH), 7.87 (2H, dd, J
5.5, 3.0, ArH), 9.79 (1H, t, J 1.1, CHO).
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From an adapted procedure of Ishihara et al.,21 4ꢀ(1,3ꢀdioxoꢀ2,3ꢀdihydroꢀ1Hꢀisoindolꢀ2ꢀ
yl)butanal (1.7 g, 7.9 mmol), 4ꢀnitrobenzoic acid (2.0 g, 12 mmol), n-Bu4NI (0.58 g, 1.6
mmol) and piperidine (78 ꢁL, 0.79 mmol) were dissolved in EtOAc (40 mL) and t-BuOOH
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(5−6
M
solution in decane, 1.57 mL) was added. The reaction mixture was heated at 50 °C for
5 h before being cooled to rt and quenched with Na2SO4. The phases were separated and the
aqueous extracted with EtOAc (× 2). The combined organics were washed with sat. aq.
NaHCO3 (× 2) and brine (× 2) before being dried over MgSO4, filtered and concentrated. The
crude product was purified by flash silica column chromatography (70:30 petrol : EtOAc) to
give 4ꢀ(1,3ꢀdioxoisoindolinꢀ2ꢀyl)ꢀ1ꢀoxobutanꢀ2ꢀyl 4ꢀnitrobenzoate as a pale orange solid (1.9
1
g, 4.8 mmol, 62%); mp 38−41 °C; νmax (film) 1705 (br, C=O); H NMR (300 MHz, CDCl3)
δH: 2.26–2.38 (1H, m, NCH2CHAHB), 2.40–2.51 (1H, m, NCH2CHAHB), 3.95 (2H, t, J 6.5,
NCH2), 5.35 (1H, dd, J 9.3, 3.7, CHCHO), 7.65–7.84 (4H, m, ArH), 8.19–8.26 (4H, m, 4ꢀ
NO2ArH), 9.62 (1H, s, CHO); 13C{1H} NMR (75 MHz, CDCl3) δC: 27.4 (NCH2CH2), 34.2
(NCH2), 77.4 (CHCHO), 123.5 (NCOArC(2)), 123.7 (ArC(2)), 131.1 (ArC(3)), 131.9
(NCOArC(1)), 134.1 (ArC(1)), 134.4 (NCOArC(1)), 150.9 (CO2), 164.2 (ArC(4)), 168.2
(NCOAr), 196.3 (CHO); HRMS (APCI+) C19H15N2O7 [M+H]+ found 383.0874, requires
383.0874 (+0.1 ppm).
1-(4-Methoxyphenyl)-3-oxopropan-2-yl 4-nitrobenzoate. Prepared according to
a
previously reported procedure as a viscous yellow oil with data in accordance with the
literature.7c 1H NMR (300 MHz, CDCl3) δH: 3.17 (1H, dd, J 14.6, 8.1, C(1)HAHB), 3.29 (1H,
dd, J 14.6, 5.1, C(1)HAHB), 3.78 (3H, s, ArOCH3), 5.47 (1H, dd, J 8.0, 5.0, C(2)H), 6.85 (2H,
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d, J 8.6, MeOArC(3,5)H), 7.19 (2H, d, J 8.6, MeOArC(2,6)H), 8.20 (2H, d, J 8.6, 4ꢀ
NO2ArC(2,6)H), 8.31 (2H, d, J 8.6, 4ꢀNO2ArC(3,5)H), 9.66 (1H, s, CHO).
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1-(Benzo[d][1,3]dioxol-5-yl)-3-oxopropan-2-yl 4-nitrobenzoate. Prepared according to a
previously reported procedure as a viscous orange oil with data in accordance with the
literature.7c 1H NMR (300 MHz, CDCl3) δH: 3.14 (1H, dd, J 14.6, 8.2, C(1)HAHB), 3.26 (1H,
dd, J 14.6, 5.0, C(1)HAHB), 5.46 (1H, dd, J 8.1, 5.0, C(2)H), 5.94 (2H, s, OCH2O), 6.69–6.77
(3H, m, ArCH), 8.21 (2H, d, J 8.9, 4ꢀNO2ArC(2,6)H), 8.32 (2H, d, J 8.9, 4ꢀNO2ArC(3,5)H),
9.66 (1H, s, CHO).
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1-Oxohexan-2-yl 4-nitrobenzoate. Prepared according to a previously reported procedure as
a yellow oil with data in accordance with literature.7b 1H NMR (400 MHz, CDCl3) δH: 0.95
(3H, t, J 7.2, CH3), 1.37–1.45 (2H, m, CH2), 1.45–1.54 (2H, m, CH2), 1.93 (2H, ddd, J 15.5,
14.6, 8.5, CH2), 5.31 (1H, dd, J 8.3, 4.7, CH)), 8.25–8.35 (4H, m, 4ꢀNO2ArH), 9.64 (1H, d, J
0.5, CHO).
Preparation of α,βꢀUnsaturated Trichloromethyl ketones
(E)-1,1,1-Trichloro-4-phenylbut-3-en-2-one (1). Prepared according to a previously
reported procedure as a white solid with data in accordance with literature.17 mp 57–59 °C
1
{lit.17 mp 59 °C}; H NMR (300 MHz, CDCl3) δH: 7.34 (1H, d, J 15.6, C(3)H), 7.41–7.52
(3H, m, ArH), 7.61–7.70 (2H, m, ArH), 8.01 (1H, d, J 15.6, C(4)H).
(E)-1,1,1-Trichloro-4-(4-methoxyphenyl)but-3-en-2-one. Prepared according to
a
previously reported procedure as a white solid with data in accordance with literature.17 mp
98–100 °C {lit.17 mp 98–100 °C}; 1H NMR (400 MHz, CDCl3) δH: 3.87 (3H, s, OCH3), 6.92–
6.99 (2H, m, ArH), 7.21 (1H, d, J 15.6, C(3)H), 7.58–7.65 (2H, m, ArH), 7.97 (1H, d, J 15.5,
C(4)H).
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(E)-4-(4-Bromophenyl)-1,1,1-trichlorobut-3-en-2-one. From an adapted procedure of Patil
and Singh,31 reactivated MnO2 (2.0 g, 23.mmol)32 was added portionꢀwise to a solution of
(E)ꢀ3ꢀ(4ꢀbromophenyl)propꢀ2ꢀenꢀ1ꢀol (491 mg, 2.3 mmol) and in CH2Cl2 (9.8 mL) and
stirred at rt for 3.5 h. The mixture was filtered through Celite® and concentrated to give (E)ꢀ
3ꢀ(4ꢀbromophenyl)acrylaldehyde (413 mg, 88%) as a brown solid that was used without
further purification with data in accordance with literature.33 1H NMR (300 MHz, CDCl3) δH:
6.70 (1H, dd, J 16.0, 7.6, C(2)H), 7.43–7.38 (2H, m, ArH), 7.48–7.43 (1H, m, C(3)H), 7.62–
7.54 (2H, m, ArH), 9.71 (1H, d, J 7.6, CHO).
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Following the procedure by Zhao et al.,16a (E)ꢀ3ꢀ(4ꢀbromophenyl)acrylaldehyde (387 mg,
1.83 mmol, 1.0 eq) was added to a solution of CHCl3 (293 ꢁL, 3.66 mmol, 2.0 eq) in DMF
(1.3 mL) at rt. The reaction mixture was stirred at rt for 20 min then cooled to 0 °C before a
solution of KOH (205 mg, 3.66 mmol, 2.0 eq) in EtOH (660 µL) was added dropwise. The
reaction was stirred at 0 °C for 2 h. The reaction mixture was acidified with 1
M HCl and
extracted with EtOAc (× 2). The combined organics were washed with water (× 2) and brine
(× 3) before being dried over MgSO4, filtered and concentrated to give ((E)ꢀ4ꢀ(4ꢀ
bromophenyl)ꢀ1,1,1ꢀtrichlorobutꢀ3ꢀenꢀ2ꢀol (562 mg, 93%) as a brown oil that was used
without further purification. 1H NMR (300 MHz, CDCl3) δH: 4.76 (1H, dd, J 5.9, 1.3, C(1)H),
6.37 (1H, dd, J 15.9, 5.9, C(2)H), 6.85 (1H, br d, C(3)H), 7.27–7.35 (2H, m, ArH), 7.43–7.52
(2H, m, ArH).
Following the procedure described by Evans et al.,34 ((E)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ1,1,1ꢀ
trichlorobutꢀ3ꢀenꢀ2ꢀol (562 mg, 1.70 mmol, 1.0 eq) and distilled Et3N (711 ꢁL, 5.10 mmol,
3.0 eq) were dissolved in anhydrous CH2Cl2 (13.5 mL). A solution of sulfur trioxide pyridine
complex (812 mg, 5.10 mmol, 3.0 eq) in distilled DMSO (2.7 mL) was added dropwise at 0
°C. The reaction mixture was stirred at 0 °C for 24 h before adding again sulfur trioxide
pyridine complex (812 mg, 5.10 mmol, 3.0 eq). The reaction mixture was stirred at rt for 48 h
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before being diluted in water (10 mL), extracted with Et2O (2 × 20 mL) and washed
successively with sat. aq. CuSO4 (20 mL), sat. aq. NaHCO3 (2 × 20 mL) and brine (2 × 20
mL). The organic layer was dried over MgSO4, filtered and concentrated to give (E)ꢀ4ꢀ(4ꢀ
bromophenyl)ꢀ1,1,1ꢀtrichlorobutꢀ3ꢀenꢀ2ꢀone (583 mg, quant.) as a brown solid that was used
without further purification with data in accordance with literature.16a 1H NMR (300 MHz,
CDCl3) δH: 7.32 (1H, d, J 15.7, C(2)H), 7.48–7.65 (4H, m, ArH), 7.93 (1H, d, J 15.6, C(3)H).
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(E)-1,1,1-Trichloronon-3-en-2-one. Prepared according to a previously reported procedure
as a yellow oil with data in accordance with literature.17 1H NMR (400 MHz, CDCl3) δH:
0.87–0.93 (3H, m, CH3), 1.28–1.38 (4H, m, CH2 × 2), 1.48–1.56 (2H, m, C(6)H2), 2.34 (2H,
app qd, J 7.2, 1.6, C(5)H2), 6.73 (1H, dt, J 15.3, 1.6, C(3)H), 7.34 (1H, dt, J 15.4, 7.0,
C(4)H).
(E)-1,1,1-Trichloro-4-(4-fluorophenyl)but-3-en-2-one. Prepared according to a previously
reported procedure as a white solid with data in accordance with literature.17 mp 66–64 °C
1
{lit.16a mp 60–62 °C}; H NMR (500 MHz, CDCl3) δH: 7.10–7.18 (2H, m, ArC(3,5)H), 7.26
(1H, d, J 15.6, C(3)H), 7.62–7.70 (2H, m, ArC(2,6)H), 7.97 (1H, d, J 15.6, C(4)H); 19F{1H}
NMR (471 MHz, CDCl3) δF: −106.65(ArC(4)F).
(E)-1,1,1-Trichloro-4-(2-nitrophenyl)but-3-en-2-one. Prepared according to a previously
reported procedure as a white solid with data in accordance with literature.17 mp 56–58 °C
{lit.17 mp 56–58 °C}; 1H NMR (400 MHz, CDCl3) δH: 7.24 (1H, d, J 15.5, C(3)H), 7.60–7.66
(1H, m, ArCH), 7.70–7.75 (2H, m, ArCH), 8.10–8.12 (1H, m, ArC(3)H), 8.43 (1H, d, J 15.5,
C(4)H).
(E)-1,1,1-Trichloro-4-(furan-2-yl)but-3-en-2-one. Prepared according to a previously
reported procedure as a white solid with data in accordance with literature.17 mp 40–42 °C
1
{lit.16a mp 42–44 °C}; H NMR(400 MHz, CDCl3) δH: 6.56 (1H, dd, J 3.5, 1.8, ArC(4)H),
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(1H, d, J 15.3, C(4)H).
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General Procedure for the NHCꢀcatalyzed Redox Synthesis of synꢀDihydropyranones:
The appropriate αꢀaroyloxyaldehyde (0.30 mmol, 1.5 eq), the appropriate
trichloromethylketone (0.20 mmol, 1.0 eq) and NHC precatalyst 11 (0.010 mmol, 5 mol% or
0.020 mmol, 10 mol%) were dissolved in anhydrous CH2Cl2 (2.7 mL). Et3N (0.30 mmol, 1.5
eq) was added and the reaction mixture was stirred at rt until complete by TLC analysis. The
mixture was diluted in EtOAc (10 mL) and washed with sodium bisulfite aq. 40% (10 mL)
and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to
give the crude product that was purified by flash silica column chromatography.
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(3S,4S)-3-Methyl-4-phenyl-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one
(12).
Following the general procedure, 1ꢀoxopropanꢀ2ꢀyl 4ꢀnitrobenzoate 10 (402 mg, 1.80 mmol),
(E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone 1 (300 mg, 1.20 mmol), NHC precatalyst 11 (22.1
mg, 0.060 mmol) and Et3N (251 µL, 1.80 mmol) in anhydrous CH2Cl2 (16.2 mL) at rt for 3.5
h gave a crude brown solid (˃95:5 dr) that was purified by flash silica column
chromatography (90:10 hexane : EtOAc) to give the title compound (307 mg, 84%) as a
ꢀ ꢁꢃꢄ
white solid. mp 142–145 °C; α
+237.5 (c 0.41, CH2Cl2); Chiral HPLC ADꢀH (95:5
ꢂ
hexane : IPA, flow rate 1.0 mL·minꢀ1, 220 nm, 30 °C) tR major: 5.9ꢀ min, tR minor: 7.1 min,
˃99% ee; νmax (film, cmꢀ1) 1776 (C=O), 1674 (C=C), 1601 (Ar C=C), 1493 (Ar C=C), 1454
1
(Ar C=C); H NMR (400 MHz, CDCl3) δH: 1.06 (3H, d, J 6.9, CH3), 3.08 (1H, p, J 6.9,
C(3)H), 3.75 (1H, t, J 6.8, C(4)H), 6.42 (1H, d, J 6.5, C(5)H), 7.04–7.14 (2H, m, C(4)ArCH),
7.28–7.39 (3H, m, C(4)ArCH); 13C{1H} NMR (126 MHz, CDCl3) δC: 12.1 (CH3), 38.2
(C(3)), 42.4 (C(4)), 90.1 (CCl3), 108.0 (C(5)), 128.1 (C(4)ArCH), 128.3 (C(4)ArCH), 129.2
(C(4)ArCH), 135.8 (C(4)ArC(1)), 149.5 (C(6)), 168.6 (C(2)); m/z (APCI+) 307 [(M(35Cl2,
37Cl)+H]+, 100%), 305 [(M(35Cl3)+H]+, 98%); HRMS (APCI+) C13H1235Cl3O2 [M+H]+ found
304.9903, requires 304.9897 (+1.5 ppm)
.
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(3S,4S)-3-Benzyl-4-phenyl-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one
(13).
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Following the general procedure, 1ꢀoxoꢀ3ꢀphenylpropanꢀ2ꢀyl 4ꢀnitrobenzoate (90 mg, 0.30
mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone 1 (50 mg, 0.20 mmol), NHC precatalyst
11 (3.7 mg, 0.010 mmol) and Et3N (42 µL, 0.30 mmol) in anhydrous CH2Cl2 (2.7 mL) at rt
for 4 h gave a brown oil (˃95:5 dr) that was purified by column chromatography (90:10
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60
ꢀ ꢁꢃꢄ
petrol : EtOAc) to give the title compound (62 mg, 95% pure, 81%) as a light red oil. α
ꢂ
+167.7 (c 0.43, CH2Cl2); Chiral HPLC ASꢀH (99:1 hexane : IPA, flow rate 0.5 mL·minꢀ1, 211
nm, 30 °C) tR minor: 16.6 min, tR major: 19.2 min, ˃99% ee; νmax (film, cmꢀ1) 1780 (C=O),
1
1670 (C=C), 1603 (Ar C=C), 1495 (Ar C=C), 1454 (Ar C=C); H NMR (400 MHz, CDCl3)
δH: 2.35–2.46 (1H, m, C(3)CHAHB), 3.21–3.34 (2H, m, C(3)CHAHB and C(3)H), 3.65–3.72
(1H, m, C(4)H), 6.37 (1H, d, J 6.8, C(5)H), 7.01–7.08 (2H, m, ArH), 7.11 (2H, m, ArH),
7.29–7.41 (6H, m, ArH); 13C{1H} (101 MHz, CDCl3) δC: 32.0 (CH2), 39.9 (C(4)), 44.8
(C(3)), 90.1 (CCl3), 108.6 (C(5)), 126.8 (ArCH), 128.3 (ArCH × 2), 128.4 (ArCH), 128.7
(ArCH × 2), 128.9 (ArCH × 2), 129.3 (ArCH × 2), 135.9 (C(3)ArC(1)), 137.8
(C(2)CH2ArC(1)), 149.1 (C(6)), 167.8 (C(2)); m/z (APCI+) 381 ([M(35Cl3)+H]+, 100%);
HRMS (APCI+) C19H16O235Cl3 [M+H]+ found 381.0204, requires 381.0210 (–1.7 ppm).
2-(2-((3S,4S)-2-Oxo-4-phenyl-6-(trichloromethyl)-3,4-dihydro-2H-pyran-3-yl)ethyl)iso-
indoline-1,3-dione (14). Following the general procedure 4ꢀ(1,3ꢀdioxoisoindolinꢀ2ꢀyl)ꢀ1ꢀ
oxobutanꢀ2ꢀyl 4ꢀnitrobenzoate (115 mg, 0.30 mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀ
one 1 (50 mg, 0.20 mmol), NHC precatalyst 11 (7.4 mg, 0.020 mmol, 10 mol%) and Et3N (42
µL, 0.30 mmol) in anhydrous CH2Cl2 (2.7 mL) at rt for 7 h gave a brown solid (90:10 dr) that
was purified by column chromatography (90:10 petrol : EtOAc) to give the title compound
ꢀ ꢁꢃꢄ
(55 mg, 60%) as a white solid. mp 132 °C (dec); α
+271.2 (c 0.16, CHCl3); Chiral HPLC
ꢂ
ODꢀH (97:3 hexane : IPA, flow rate 1.0 mL·minꢀ1, 211 nm, 30 °C) syn: tR minor: 34.3 min, tR
major: 42.2 min, ˃99% ee, anti: tR major: 51.3 min, tR minor: 59.2 min, ˃99% ee; νmax (film,
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cmꢀ1) 1772 and 1701 (C=O isoxindole), 1701 (C=O); H NMR (500 MHz, CDCl3) δH: 1.50–
1.60 (1H, m, C(3)CHAHB), 2.06–2.16 (1H, m, C(3)CHAHB), 2.95 (1H, q, J 7.0, C(3)H), 3.76–
3.85 (1H, m, C(3)CH2CHAHB), 3.85–3.92 (1H, m, C(3)CH2CHAHB), 4.00 (1H, t, J 7.0,
C(4)H), 6.42 (1H, d, J 6.9, C(5)H), 7.12–7.16 (2H, m, ArH), 7.29–7.38 (3H, m, ArH), 7.70–
7.75 (2H, m, C(3)(CH2)2Ar(2,5)H), 7.83–7.88 (2H, m, C(3)(CH2)2Ar(3,4)H); 13C{1H} (101
MHz, CDCl3) δC: 26.3 (CH2), 35.6(CH2), 40.7 (C(3)), 40.9 (C(4)), 90.0 (CCl3), 108.1 (C(5)),
123.4 (ArCH × 2), 128.0 (ArCH × 2), 128.5 (ArCH), 129.4 (ArCH × 2), 132.0 (NPhthArC),
134.1 (ArCH), 135.7 (NPhthArC), 149.3 (C(3)ArC(1)), 167.5 (C(2)), 168.4 (C=O × 2); m/z
(NSI+) 951 ([2M(35Cl2,37Cl)+Na]+, 100%), 949 ([2M(35Cl3)+Na]+, 85%), 486
([M(35Cl3)+Na]+, 85%); HRMS (NSI+) C22H16O4N135Cl3Na [M+Na]+ found 486.0041,
requires 486.0037 (+0.8 ppm).
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(3S,4S)-3-(4-Methoxybenzyl)-4-phenyl-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one
(15). Following the general procedure, 1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanꢀ2ꢀyl 4ꢀ
nitrobenzoate (99 mg, 0.30 mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone 1 (50 mg, 0.20
mmol), NHC precatalyst 11 (7.4 mg, 0.020 mmol) and Et3N (42 µL, 0.30 mmol) in
anhydrous CH2Cl2 (2.7 mL) at rt for 26 h gave a brown oil (˃95:5 dr) that was purified by
column chromatography (95:5 petrol : EtOAc) to give the title compound (53 mg, 65%) as a
ꢀ ꢁꢃꢄ
yellow oil. α
+300.0 (c 0.81, CHCl3); Chiral HPLC ADꢀH (99:1 hexane : IPA, flow rate
ꢂ
1.0 mL·minꢀ1, 220 nm, 30 °C) tR minor: 18.5 min, tR major: 20.7 min, ˃99% ee; νmax (film,
1
cmꢀ1) 1780 (C=O), 1612 (C=C), 1514 (Ar C=C), 1456, 1250 (Ph–O–CH3); H NMR (500
MHz, CDCl3) δH: 2.35 (1H, dd, J 14.4, 9.1, C(3)CHAHB), 3.15–3.27 (2H, m, C(3)CHAHB and
C(3)H), 3.68 (1H, t, J 6.8, C(4)H), 3.81 (3H, s, CH3O), 6.36 (1H, d, J 6.7, C(5)H), 6.85 (2H,
dd, J 9.1, 2.5, C(3)CH2ArC(3,5)H), 6.99–7.08 (4H, m, C(3)CH2ArC(2,6)H and
C(4)ArC(3,5)H), 7.31–7.39 (3H, m, C(4)ArC(2,4,6)H); 13C{1H} (126 MHz, CDCl3) δC: 31.1
(C(3)CH2), 39.9 (C(4)), 45.0 (C(3)), 55.3 (OCH3), 90.1 (CCl3), 108.6 (C(5)), 114.0
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(C(3)CH2ArC(3,5)), 128.3 (ArCH), 128.4 (ArCH), 129.2 (ArCH), 129.7(ArCH), 129.7
(ArCH), 129.9 (ArCH), 136.0 (C(4)ArC(1)), 149.1 (C(6)), 158.4 (C(3)CH2ArC(4)), 167.9
(C(2)); m/z (NSI+) 462 ([M(35Cl2, 37Cl)+MeOH+NH4]+, 51%), 460 ([M(35Cl3)+MeOH+NH4]+,
52%), 445 ([M(35Cl2, 37Cl)+MeOH+H]+, 65%), 443 ([M(35Cl3)+MeOH+H]+, 67%), 432
([M(35Cl,37Cl2)+NH4]+, 30%), 430 ([M(35Cl2,37Cl)+NH4]+, 97%), 428 ([M(35Cl3)+NH4]+,
100%), 411 ([M(35Cl2,37Cl)+H]+, 43%); HRMS (NSI+) C20H18O3Cl3 [M+H]+ found 411.0321,
requires 411.0316 (+1.2 ppm).
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(3S,4S)-(-3-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-phenyl-6-(trichloromethyl)-3,4-dihydro-
2H-pyran-2-one (16). Following the general procedure, 1ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ
oxopropanꢀ2ꢀyl 4ꢀnitrobenzoate (103 mg, 0.30 mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀphenylbutꢀ3ꢀenꢀ
2ꢀone 1 (50 mg, 0.20 mmol), NHC precatalyst 11 (3.7 mg, 0.010 mmol) and Et3N (42 µL,
0.30 mmol) in anhydrous CH2Cl2 (2.7 mL) at rt for 26 h gave a brown oil (85:15 dr) that was
purified by column chromatography (95:5 petrol : EtOAc) to give the title compound (38 mg,
ꢀ ꢁꢃꢄ
45%) as a white solid. mp 145–147 °C; α
+230.4 (c 0.51, CH2Cl2); ee could not be
ꢂ
determined by either chiral HPLC or GC; νmax (film, cmꢀ1) 1780 (C=O), 1504, 1489 and 1445
1
(Ar C=C), 1246 (CꢀO); H NMR (500 MHz, CDCl3) δH: 2.33 (1H, dd, J 14.5, 9.1,
C(3)CHAHB), 3.15 (1H, dd, J 14.5, 5.3, C(3)CHAHB), 3.18–3.22 (1H, m, C(3)H), 3.71 (1H, t,
J 6.7, C(4)H), 5.96 (2H, dd, J 4.6, 1.4, OCH2O), 6.37 (1H, d, J 6.8, C(5)H), 6.53 (1H, dd, J
7.9, 1.5, C(3)CH2ArC(6)H), 6.61 (1H, app d, J 1.6, C(3)CH2ArC(4)H), 6.75 (1H, d, J 7.9,
C(3)CH2ArC(7)H), 7.05–7.07 (2H, m, C(4)ArC(3,5)H), 7.32–7.39 (3H, m,
C(4)ArC(2,4,6)H); 13C{1H} (126 MHz, CDCl3) δC: 31.8 (C(4)CH2), 39.9 (C(4)), 45.1 (C(3)),
90.1 (CCl3), 101.0 (OCH2O), 108.4 (C(3)CH2ArC(7)), 108.6 (C(5)), 109.1 (C(3)CH2ArC(4)),
122.0 (C(3)CH2ArC(6)), 128.3 (C(4)ArCH), 128.4 (C(4)ArCH), 129.3 (C(4)ArCH), 131.4
(C(3)CH2ArC(5)), 135.9 (C(4)ArC(1)), 146.4 (C(3)CH2ArC(3a)), 147.8 (C(3)CH2ArC(7a)),
149.0 (C(6)), 167.8 (C(2)); m/z (NSI+) 481 ([M(35Cl2,37Cl)+MeOH+Na]+, 65%), 479
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([M(35Cl3)+MeOH+Na]+, 67%), 449 ([M(35Cl2, 37Cl)+Na]+, 50%), 447 ([M(35Cl3) +Na]+,
52%), 444 ([M(35Cl2,37Cl)+NH4]+, 31%), 442 ([M(35Cl3)+NH4]+, 34%), 429 ([M(35Cl,
37Cl2)+H]+, 30%), 427 ([M(35Cl2, 37Cl)+H]+, 94%), 425 [M(35Cl3)+H]+, 100%); HRMS (NSI+)
C20H16O435Cl3 [M+H]+ found 425.0107, requires 425.0109 (–0.4 ppm).
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(3S,4S)-3-Benzyl-4-(4-methoxyphenyl)-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one
(17). Following the general procedure, 1ꢀoxoꢀ3ꢀphenylpropanꢀ2ꢀyl 4ꢀnitrobenzoate (270 mg,
0.90 mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀ(4ꢀmethoxyphenyl)butꢀ3ꢀenꢀ2ꢀone (168 mg, 0.60 mmol),
NHC precatalyst 11 (11.1 mg, 0.030 mmol) and Et3N (126 µL, 0.90 mmol) in anhydrous
CH2Cl2 (8.2 mL) at rt for 3 h gave a brown oil (˃95:5 dr) that was purified by column
chromatography (90:10 petrol : EtOAc) to give the title compound (229 mg, 93%) as a white
ꢀ ꢁꢃꢄ
solide. mp 109–111 °C; α
+369.6 (c 0.575, CH2Cl2); Chiral HPLC ADꢀH (98:2 hexane :
ꢂ
IPA, flow rate 1.0 mL·minꢀ1, 220 nm, 30 °C) tR minor: 11.2 min, tR major: 12.6 min, 99% ee;
νmax (film, cmꢀ1) 1778 (C=O), 1609 (C=C), 1512 (Ar C=C), 1252 (PhꢀOꢀCH3); 1H NMR (500
MHz, CDCl3) δH: 2.41 (1H, dd, J 15.8, 10.6, C(3)CHAHB), 3.23–3.30 (2H, m, C(3)CHAHB
and C(3)H), 3.62 (1H, t, J 6.7, C(4)H), 3.82 (3H, s, CH3), 6.35 (1H, d, J 6.8, C(5)H), 6.87–
6.97 (4H, m, C(4)ArH), 7.10–7.14 (2H, m, ArH), 7.24–7.28 (1H, m, ArH), 7.30–7.35 (2H, m,
ArH); 13C{1H} (126 MHz, CDCl3) δC: 32.0 (CH2), 39.1 (C(4)), 45.0 (C(3)), 55.3 (CH3O),
90.1 (CCl3), 108.9 (C(5)), 114.6 (C(4)ArCH), 126.8 (C(3)CH2ArCH), 127.6 (C(4)ArC(1)),
128.7 (C(3)CH2ArCH), 129.0 (C(3)CH2ArCH), 129.4 (C(4)ArCH), 137.9 (C(3)CH2ArC),
148.8 (C(6)), 159.6 (C(4)ArC(4)), 168.0 (C(2)); m/z (APCI+) 411 ([M(35Cl3)+H]+, 100%),
303 ([M(35Cl3)–4ꢀOMeC6H4]+, 70%); HRMS (APCI+) C20H1735Cl3O3 [M+H]+ found
411.0313, requires 411.0316 (–0.7 ppm).
(3S,4S)-3-Benzyl-4-(4-bromophenyl)-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one (18).
Following the general procedure, 1ꢀoxoꢀ3ꢀphenylpropanꢀ2ꢀyl 4ꢀnitrobenzoate (90 mg, 0.30
mmol), (E)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ1,1,1ꢀtrichlorobutꢀ3ꢀenꢀ2ꢀone (70 mg, 0.20 mmol), NHC
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precatalyst 11 (3.7 mg, 0.010 mmol) and Et3N (42 µL, 0.30 mmol) in anhydrous CH2Cl2 (2.7
mL) at rt for 1.5 h gave a brown oil (˃95:5 dr) that was purified by column chromatography
(90:10 petrol : EtOAc) to give the title compound (60 mg, 95% pure, 55%) as a yellow oil.
9
ꢀ
ꢀ ꢁꢃꢄ
α
+71.4 (c 0.29, CH2Cl2); Chiral HPLC ODꢀH (97:3 hexane : IPA, flow rate 1.0 mL·min
ꢂ
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1, 220 nm, 30 °C) tR major: 10.3 min, tR minor: 11.7 min, ˃99% ee; νmax (film, cmꢀ1) 1780
(C=O), 1661 (C=C); 1H NMR (400 MHz, CDCl3) δH: 2.33–2.42 (1H, m, C(3)CHAHB), 3.24–
3.35 (2H, m, C(3)CHAHB and C(3)H), 3.64 (1H, t, J 6.7, C(4)H), 6.33 (1H, d, J 6.8, C(5)H),
6.86–6.93 (2H, m, C(4)ArC(2,6)H), 7.07–7.12 (2H, m, C(3)ArH), 7.27–7.36 (3H, m,
C(3)ArH), 7.46–7.52 (2H, m, C(4)ArC(3,5)H); 13C{1H}(101 MHz, CDCl3) δC: 32.0 (CH2),
39.2 (C(4)), 44.4 (C(3)), 90.2 (CCl3), 108.0 (C(5)), 123.0 (C(4)ArC(1)), 127.0
(C(3)CH2ArCH), 128.8 (C(3)CH2ArCH), 128.9 (C(3)CH2ArCH), 129.9 (C(4)ArC(2,6)),
132.4 (C(4)ArC(3,5)), 135.1 (C(4)ArC(4)), 137.8 (C(3)CH2ArC), 146.6 (C(6)), 167.7 (C(2));
m/z (APCI+) 463 ([M(35Cl,37Cl2,79Br)+H]+, 60%), 461 ([M(35Cl2,37Cl,79Br)+H]+, 100%), 458
([M(35Cl3,79Br)+H]+, 50%); HRMS (APCI+) C19H15O279Br35Cl3 [M+H]+ found 458.9312,
requires 458.9316 (–0.8 ppm).
(3S,4S)-3-Methyl-4-pentyl-6-(trichloromethyl)-3,4-dihydro-2H-pyran-2-one
(19).
Following the general procedure, 1ꢀoxopropanꢀ2ꢀyl 4ꢀnitrobenzoate 10 (67 mg, 0.30 mmol),
(E)ꢀ1,1,1ꢀtrichlorononꢀ3ꢀenꢀ2ꢀone (49 mg, 0.20 mmol), NHC precatalyst 11 (7.4 mg, 0.020
mmol) and Et3N (42 µL, 0.30 mmol) in anhydrous CH2Cl2 (2.7 mL) at rt for 22 h gave a
crude brown solid (>95:5 dr) that was purified by flash silica column chromatography (95:5
ꢀ ꢁꢃꢄ
hexane: EtOAc) to give the title compound (15 mg, >95% pure, 26%) as a yellow oil. α
ꢂ
+8.9 (c 0.44, CHCl3); Chiral GC analysis Restek RtꢀbDEXcst (length: 30 m, thickness: 0.250
mm, film thickness 0.25 ꢁm) carrier gas: He, linear velocity: 20.0 cm·sꢀ1, temperature: 160
°C tR minor: 105.3 min, tR major: 106.9 min, ˃99% ee; νmax (film, cmꢀ1) 1782 (C=O), 1668
(C=C), 1458 (Ar C=C); 1H NMR (400 MHz, CDCl3) δH: 0.88 (3H, t, J 6.9, CH3), 1.26 (3H, d,
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J 7.0, C(3)CH3), 1.27–1.40 (7H, m, C(4)CHAHB and CH3(CH2)3), 1.50–1.55 (1H, m,
C(4)CHAHB), 2.53–2.64 (1H, m, C(4)H), 2.81 (1H, p, J 7.0, C(3)H), 6.18 (1H, d, J 5.8,
C(5)H); 13C{1H} NMR (101 MHz, CDCl3) δC: 11.3 (C(3)CH3), 14.0 (CH3), 22.4 (CH3CH2),
26.0 (CH3(CH2)2CH2), 28.8 (C(4)CH2), 31.8 (CH3CH2CH2), 35.3 (C(4)), 36.9 (C(3)), 90.1
(CCl3), 109.2 (C(5)), 148.4 (C(6)), 169.9 (C(2)); m/z (APCI+) 319 ([M(35Cl2,37Cl)+H3O]+,
62%), 317 ([M(35Cl3)+H3O]+, 65%), 303 ([M(35Cl,37Cl2)+H]+, 30%), 301
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([M(35Cl2,37Cl)+H]+, 95%), 299 ([M(35Cl3)+H]+, 100%); HRMS (APCI+) C12H1735Cl3O2
+
[M+H]+ found 299.0366, requires 299.0367 (–0.3 ppm)
.
Epimerization of 14: In an NMR tube, 2ꢀ(2ꢀ((3S,4S)ꢀ2ꢀoxoꢀ4ꢀphenylꢀ6ꢀ(trichloromethyl)ꢀ
3,4ꢀdihydroꢀ2Hꢀpyranꢀ3ꢀyl)ethyl)isoindoꢀlineꢀ1,3ꢀdione 14 (13.2 mg, 0.028 mmol, 1.0 eq)
was dissolved in CD2Cl2 before Et3N (5.9 µL, 0.42 mmol, 1.5 eq) was added. The ratio
1
between the two diastereoisomers were monitored by H NMR comparing the ratio between
synꢀC(5)H (δH 6.21 (1H, d, J 3.7)) and antiꢀC(5)H (δH 6.45 (1H, d, J 6.9)). Chiral HPLC ODꢀ
H (97:3 hexane : IPA, flow rate 1.0 mL·minꢀ1, 211 nm, 30 °C) syn: tR minor: 34.3 min, tR
major: 42.2 min, ˃99% ee, anti: tR major: 51.3 min, tR minor: 59.2 min, ˃99% ee.
General Procedure for the NHCꢀcatalyzed redox [4+2]ꢀheteroꢀDielsꢀAlder reaction
followed by ringꢀopening and aminolysis: The appropriate αꢀaroyloxyaldehyde (0.30
mmol, 1.5 eq), the appropriate trichloromethyl ketone (0.20 mmol, 1.0 eq) and NHC
precatalyst 11 (0.010 mmol, 5 mol% or 0.020 mmol, 10 mol%) were dissolved in anhydrous
CH2Cl2 (2.7 mL). Et3N (0.30 mmol, 1.5 eq) was added and the reaction mixture was stirred at
rt until complete by TLC analysis. The mixture was diluted in EtOAc (10 mL) and washed
with water (10 mL × 2), sodium bisulfite aq. 40% (10 mL × 2), and brine (10 mL × 2). The
organic layer was dried over MgSO4, filtered and concentrated. The crude synꢀ
dihydropyranone was dissolved in anhydrous CH2Cl2 (6.6 mL) and benzylamine (60 mmol,
300 eq, 6.6 mL) was added. The reaction mixture was stirred at rt for 16 h before being
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diluted in EtOAc (20 ml) and washed with 1
M
HCl (20 mL × 3), sat. aq. NaHCO3 (20 mL ×
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3) and brine (20 mL × 3). The organic layer was dried over MgSO4, filtered and concentrated
to give the crude product that was triturated in Et2O then dispersed in CHCl3 and
concentrated to give the desired diamide.
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(2S,3S)-N1,N5-Dibenzyl-2-methyl-3-phenylpentanediamide (21). Following the general
procedure, 1ꢀoxopropanꢀ2ꢀyl 4ꢀnitrobenzoate 10 (67 mg, 0.30 mmol), (E)ꢀ1,1,1ꢀtrichloroꢀ4ꢀ
phenylbutꢀ3ꢀenꢀ2ꢀone 1 (50 mg, 0.20 mmol), NHC precatalyst 11 (3.7 mg, 0.010 mmol) and
Et3N (42 µL, 0.30 mmol) in anhydrous CH2Cl2 (2.7 mL) at rt for 3.5 h gave a crude orange
solid (˃95:5 dr). The crude was stirred in anhydrous CH2Cl2 (6.6 mL) with benzylamine (6.6
mL, 60 mmol) at rt for 16 h to give a crude beige solid (dr˃95:5) that was triturated in Et2O
ꢀ ꢁꢃꢄ
to give the title compound (70 mg, 85%) as a white solid. mp 172–174 °C; α –8.7 (c 0.53,
ꢂ
CHCl3); Chiral HPLC ADꢀH (90:10 hexane : IPA, flow rate 1.0 mL·minꢀ1, 211 nm, 30 °C) tR
minor: 15.3 min, tR major: 19.1 min, ˃99% ee; νmax (film, cmꢀ1) 3283 (N–H), 3258 (N–H),
1636 (C=O), 1558 (N–C=O), 1541 (N–C=O), 1495, 1454, 1435; 1H NMR (400 MHz, CDCl3)
δH: 1.20 (3H, d, J 6.9, C(2)CH3), 2.48 (1H, dd, J 13.8, 8.6, C(4)HAHB), 2.67 (1H, p, J 7.0,
C(2)H), 2.91 (1H, dd, J 13.8, 6.9, C(4)HAHB), 3.36 (1H, q, J 7.7, C(3)H), 4.14 (1H, dd, J
14.7, 5.2, N1CHAHB), 4.24 (1H, dd, J 14.9, 5.4, N5CHAHB), 4.31 (1H, dd, J 14.7, 6.1,
N1CHAHB), 4.38 (1H, dd, J 14.8, 6.1, N5CHAHB), 5.58 (1H, br t, J 5.0, N1H), 6.10 (1H, br t, J
5.0, N5H), 6.87–6.96 (3H, dd, J 6.6, 2.8, ArH), 6.97–7.02 (3H, m, ArH), 7.11–7.18 (3H, m,
ArH), 7.19–7.26 (8H, m); 13C{1H} NMR (101 MHz, CDCl3) δC: 16.0 (C(2)CH3), 40.5 (C(4)),
43.3 (NCH2), 43.4 (NCH2), 45.7 (C(2)), 46.4 (C(3)), 127.1 (ArCH), 127.27 (ArCH), 127.33
(ArCH), 127.5 (ArCH), 127.7 (ArCH), 128.3 (ArCH), 128.6 (ArCH), 137.9 (NCH2ArC(1)),
138.1 (NCH2ArC(1)), 141.3 (C(3)ArC), 171.4 (C(5)), 174.0 (C(1)); m/z (NSI+) 823
([2M+Na]+, 44%), 423 ([M+Na]+, 42%), 401 ([M+H]+, 100%); HRMS (NSI+) C26H29O2N2
[M+H]+ found 401.2221, requires 401.2224 (–0.6 ppm).
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