Organocatalytic Domino Michael-heterocyclization reaction of α,β-Unsaturated aldehydes and α-cyano ketones: Synthesis of enantioenriched 4,5,6-trisubstituted 3,4-dihydropyranones

Article abstract of DOI:10.1002/ejoc.201402982

α,β-Unsaturated aldehydes with aliphatic, electron-poor aromatic, or electron-withdrawing substituents at the β position easily react with different ketones leading to enantioenriched hemiacetals, which were further oxidized to give 4,5,6-trisubstituted-3,4-dihydropyranones in good yields and with excellent enantioselectivities. The behavior of the ketones is dependent on the α substituent of the carbonyl group, and a fine-tuning of the pK_a values is necessary to obtain good results.

Full text of DOI:10.1002/ejoc.201402982

FULL PAPER
DOI: 10.1002/ejoc.201402982
Organocatalytic Domino Michael–Heterocyclization Reaction of α,β-
Unsaturated Aldehydes and α-Cyano Ketones: Synthesis of Enantioenriched
4,5,6-Trisubstituted 3,4-Dihydropyranones
James O. Guevara-Pulido,[a] José M. Andrés,[a] and Rafael Pedrosa*[a]
Keywords: Asymmetric synthesis / Domino reactions / Cyclization / Michael addition / Oxygen heterocycles
α,β-Unsaturated aldehydes with aliphatic, electron-poor aro-
matic, or electron-withdrawing substituents at the β position
easily react with different ketones leading to enantio-
enriched hemiacetals, which were further oxidized to give
4,5,6-trisubstituted-3,4-dihydropyranones in good yields and
with excellent enantioselectivities. The behavior of the
ketones is dependent on the α substituent of the carbonyl
group, and a fine-tuning of the pKa values is necessary to
obtain good results.
electron-withdrawing groups as nucleophiles, because the
addition product would equilibrate with the enol under the
reaction conditions.
Introduction
The organocatalytic enantioselective synthesis of pyran
derivatives has recently received a lot of attention as a result
of the biological interest of these compounds, their natural
occurrence, and their value as intermediates in organic syn-
thesis.[1] Two different approaches have been developed for
the organocatalytic synthesis of this class of heterocycles:
inverse-electron-demand Diels–Alder reactions,[2] and
domino Michael-addition–heterocyclization processes.[3]
Combinations of activated ketones, such as β,γ-unsatu-
rated-α-keto esters[4] or α,β-unsaturated ketones with ad-
ditional electron-withdrawing substituents at the α posi-
tion,[5] have been used as acceptors together with aldehydes
or ketones as donors in these transformations. In similar
approaches, α,β-unsaturated aldehydes have been used as
acceptors together with highly acidic β-functionalized
ketones[6] as donors; functionalized nitroalkenes[7] or nitro-
alkanes,[8] and carbonyl compounds have also been used in
these reactions.
Given the interest in enantioenriched polysubstituted
3,4-dihydropyranones, we envisaged that they could be ob-
tained by oxidation of the corresponding hemiacetals,
which could be easily prepared by an organocatalytic tan-
dem Michael–heterocyclization process. To achieve such a
one-pot tandem reaction, the adduct formed in the initial
Michael reaction must be able to form an enol, which
would promote the hemiacetalization process. We focused
our attention on the use of α-functionalized ketones with
Results and Discussion
We decided to study the scope of the domino Michael-
addition–hemiacetalization of α,β-unsaturated aldehydes
with different substitution patterns on the double bond (i.e.,
2a–2k) with functionalized ketones with only one reactive
position (i.e., 1a–1c), or with two methylene positions with
different pKa values (i.e., 1d–1g). The reaction of α-cyano-
acetophenone (1a) with cinnamaldehyde (2a) was selected
as a model reaction to establish the ideal reaction condi-
tions. Initially, we tested bifunctional organocatalyst (S)-1-
(pyrrolidin-2-ylmethyl)pyrrolidine (A)[9] in the presence of
p-nitrobenzoic acid (PNBA) as co-catalyst. This catalyst
would be able to activate the electrophile by formation of
an iminium ion with the secondary amine, and to activate
the nucleophile by deprotonation promoted by the tertiary
amine component, but the Knoevenagel condensation com-
pound (i.e., 3aa) was the only isolated product (Scheme 1).
In contrast, reactions catalyzed by monofunctional O-tri-
methylsilyl diphenylprolinol (B) and PNBA gave the Knoe-
venagel product together with an equimolar mixture of epi-
meric hemiacetals 4aa, which were transformed into 3,4-
dihydropyranone 5aa by oxidation with PCC (pyridinium
chlorochromate; Scheme 1).
After extensive work looking for the best reaction condi-
tions, the results summarized in Table 1 show that, at room
temperature, the best enantioselectivity was obtained in
dichloromethane as solvent (compare Table 1, entries 1–4),
and that at 0 °C the formation of condensation product 3aa
was not observed, and the enantiomeric excess (ee) of 5aa
increased to 78% (Table 1, entry 5). The yield and the ee
[a] Instituto CINQUIMA (Centro de Innovación en Química y
Materiales Avanzados) and Departamento de Química
Orgánica, Facultad de Ciencias, Universidad de Valladolid,
Paseo de Belén 7, 47011 Valladolid, Spain
E-mail: pedrosa@qo.uva.es
http://sintesisasimetrica.blogs.uva.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402982.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Organocatalytic Domino Michael–Heterocyclization
Scheme 1. Screening of conditions for the reaction of cinnamaldehyde and α-cyano acetophenone. TMS = trimethylsilyl.
increased to 75 and 92%, respectively, when the reaction at the β position. In all these reactions, 3,4-dihydropyr-
was carried out at –18 °C, although this was at the expense anones 5aa–5af were obtained as single products in good
of increasing the reaction time to 11 h (Table 1, entry 6). yields and with excellent enantioselectivities (Table 2, en-
The intermediate Michael adducts were not detected in any tries 1–7). Surprisingly, electron-rich p-methoxycinnamal-
reaction.
dehyde (2g) and heteroaromatic aldehyde 2h reacted very
quickly, but led to Knoevenagel condensation products 3ag
and 3ah, respectively (Table 2, entries 8 and 9), as insepa-
rable mixtures of diastereoisomers.[10] α,β-Disubstituted al-
dehydes 2i–2k did not react with cyano ketone 1a under the
described conditions, and they were recovered unchanged
after 240 h (Table 2, entries 16–18).
The lack of reactivity of α-substituted aldehydes in
Michael additions promoted by prolinol derivatives has
been observed previously.[6b,11] However, α-branched acro-
leins participate in different organocatalytic transforma-
tions promoted by chiral primary amines or prolinol deriva-
tives with acidic or basic additives as co-catalysts.[12] This
fact has been attributed to the low stability of the α-substi-
tuted iminium intermediate due to steric hindrance. It has
been reported that cinnamaldehyde (2a) easily forms the im-
inium triflate by reaction with catalyst B and aqueous
TfOH after 1 h in diethyl ether.[13] In our case, 2-methyl
cinnamaldehyde (2i) was recovered unchanged after 96 h at
room temp. under the same conditions. This observation
confirms that under the studied reaction conditions, the
first Michael addition does not occur as a result of the in-
ability of the α-substituted enals to form the activated imin-
ium intermediate.
Table 1. Reaction of cyanoketone 1a and cinnamaldehyde (2a) cata-
lyzed by B under different conditions, and subsequent oxidation.
Entry Solvent T [°C] Time [h][a] Products (yield [%])[b] ee [%][c]
1
2
3
4
5
6
Et2O
Toluene r.t.
MeOH r.t.
CH2Cl2 r.t.
CH2Cl2
CH2Cl2 –18
r.t.
4 + 3
4 + 3
2 + 3
3 + 3
7 + 3
11 + 3
3aa (45) 5aa (55)
3aa (60) 5aa (40)
3aa (50) 5aa (50)
3aa (50) 5aa (50)
5aa (65)[d]
46
50
54
64
78
92
0
5aa (75)[d]
[a] The first time refers to the coupling reaction, and the second
one to the oxidation reaction. [b] Ratio determined by 1H NMR
spectroscopic analysis of the reaction mixture. [c] Data refer to
product 5aa, and were determined by chiral HPLC. [d] Yields refer
to pure and isolated compounds.
Having established the best reaction conditions, we went
on to study the scope of the catalytic enantioselective ad-
dition-cyclization reaction using α,β-unsaturated aldehydes
with different substituents (Scheme 2). To this end, cyano-
ketone 1a was treated with aldehydes 2b–2k in CH2Cl2 at
–18 °C in the presence of diphenyl prolinol derivative B
(20 mol-%) and PNBA (20 mol-%), followed by oxidation
with PCC of the reaction mixture. The results are collected
in Table 2, entries 3–9. The reaction worked very well for
The influence of the structure of the donor was studied
aldehydes with alkyl groups (2b–2d), an electron-with- for the reaction of E-2-pentenal (2c) as acceptor with dif-
drawing group (2e), or an electron-poor aryl substituent (2f) ferent activated ketones 1b–1g (Table 2, entries 10–15). In
Scheme 2. Scope of the organocatalytic reactions of ketones 1a–1g with aldehydes 2b–2k, and subsequent oxidation.
Eur. J. Org. Chem. 2014, 8072–8076
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J. O. Guevara-Pulido, J. M. Andrés, R. Pedrosa
FULL PAPER
Table 2. Reaction of different aldehydes and ketones catalyzed by or 4ec, which may be converted into lactones 5dc or 5ec by
B.[a]
oxidation with PCC.
Entry Ketone Aldehyde Time [h][b] Products (yield [%])[c] ee[d]
Guided by these results, we decided to extend the reac-
tion to multifunctional α-cyano ketones 1f and 1g in an
attempt to prepare 3,4-dihydropyranones with additional
functional groups at C-6. Unfortunately, α-cyano diketone
1f and α-cyano keto ester 1g, for which the differences are
smaller (3–4 units) between the pKa values of the hydrogens
at the two α positions of the carbonyl groups, behave dif-
ferently from 1d–1e. 4-Benzoyl-3-oxobutyronitrile (1f) re-
acted very quickly to give phenol derivative 6fc as a single
regioisomer in moderate yield (Table 2, entry 14). This com-
pound was probably formed in a Knoevenagel–cyclization–
aromatization sequence.[16] Finally, ethyl 4-cyano-3-oxo
butyrate (1g) easily reacted with 2c but led to a very com-
plex mixture of products (Table 2, entry 19).
The described organocatalytic domino approach consists
of an initial Michael addition of the enol derived from the
activated ketone to the unsaturated aldehyde, activated as
an iminium ion, followed by enolization of the adducts and
subsequent heterocyclization to give the final hemiacetal.
The proposed mechanism is summarized in Scheme 3. The
activation of the enal and the addition of the nucleophile
follow the general path previously described.[17] This means
that the stereochemistry of the final product is dictated by
the β-attack of the nucleophile from the less hindered Re
face in the iminium ion, leading to intermediate 7. Because
the Michael adducts have been never observed, we propose
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2a
2a
2b
2c
2d
2e
2f
2g
2h
2c
2c
2c
2c
2c
2c
2i
11 + 3
12 + 3
12 + 3
12 + 3
12 + 3
4 + 3
7 + 3
1
1.5
6
144
13 + 3
14 + 3
4
4
240
5aa (75)
5aa (72)
5ab (67)
5ac (70)
5ad (65)
5ae (70)
5af (63)
3ag (70)
3ah (65)
3bc (85)
nr
5dc (65)
5ec (73)
6fc (60)
–
nr
nr
92
94
88
90
92
96
Ͼ99[f]
–
–
–
–
92
94
–
–
–
2[e]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1g
1a
1a
1a
1g
2j
2k
2c
240
240
12
–
–
–
nr
complex mixture
[a] The reactions were carried out in CH2Cl2 at –18 °C with catalyst
(20 mol-%) and p-NBA (20 mol-%), followed by oxidation of the
reaction mixture with PCC in CH2Cl2. [b] The first time refers to
the coupling reaction, and the second one to the oxidation reaction.
[c] Yields refer to pure and isolated compounds, nr = no reaction.
[d] Determined by chiral HPLC. [e] The reaction was scaled up to
3 mmol. [f] Ͼ99 means that only one enantiomer was detected by
HPLC.
these reactions, the results were highly dependent on the a rapid enolization of 7 to intermediate 8, which cyclizes to
nature of the substituent at the carbonyl group and on the 4 by a fast hemiacetalization.[6d,6f] Oxidation of hemiacetal
acidity of the methylene group. For instance, whereas α- 4 with PCC yields the final enantioenriched trisubstituted
cyano acetophenone 1a yielded 3,4-dihydropyranone 5ac in 3,4-dihydropyranone (i.e., 5). Hemiacetal 4 could also be
high yield and with excellent enantioselectivity (Table 2, en- formed by hydrolysis of N,O-acetal intermediate 9 resulting
try 4), trifluoromethylated analog 1c did not react, and it from the cyclization of 8,[18] but we were unable to isolate
was recovered unchanged after 144 h under the described
conditions (Table 2, entry 11). The much more acidic α-
nitro acetophenone[14] 1b led to Knoevenagel condensation
product 3bc as an inseparable mixture of Z and E diastereo-
isomers (Table 2, entry 10). In an attempt to minimize the
formation of Knoevenagel products, the reactions of 1a
with 2g and 2h and of 1b with 2g were carried out at –35 °C,
but the starting materials were recovered unchanged after
100 h.
The reactions of 2c with ketones 1d–1g, which may be
deprotonated in two different α positions, are much more
interesting. The final products are dependent on the differ-
ence in acidities of the methylene groups α to the carbonyl
group. Thus, the reactions of 3-oxo-pentanenitrile (1d), with
a difference of Ͼ10 pKa units between the hydrogens at C-
2 and C-4, or 3-oxo-4-phenyl butyronitrile (1e), with a dif-
ference of 7 pKa units,[15] with 2c were not only enantio-
selective, but also regioselective, leading to 5dc and 5ec,
respectively, in good yields and with excellent enantio-
selectivity (Table 2, entries 12 and 13). This indicates that,
as expected, the nucleophile is formed at the more acidic
position to give a single enol, which reacts with the acti-
vated enal to give the Michael adducts. These then cyclize
to give an equimolar mixture of epimeric hemiacetals 4dc of hemiacetals.
Scheme 3. Proposed mechanism for the organocatalytic formation
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Eur. J. Org. Chem. 2014, 8072–8076

Organocatalytic Domino Michael–Heterocyclization
(m, 10 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 35.6, 40.4, 91.5,
or detect that intermediate when 1a and 2a were treated
with 1 equiv. catalyst.[19]
117.5, 126.9, 128.0, 128.7, 128.9, 129.7, 132.1, 138.0, 162.2,
164.2 ppm. IR: ν = 2920, 2847, 2214, 1768, 1119 cm–1. HPLC (Chi-
˜
ralpak AD-H; hexane/iPrOH, 90:10; 1.0 mL/min): tR = 19.5 min
(major); tR = 18.0 min (minor). HRMS: calcd. for C18H14NO2 [M
+ H] 276.1019; found 276.1023.
Conclusions
In summary, we have developed a prolinol-ether-cata-
lyzed enantioselective domino Michael-addition–hetero-
cyclization process that yields enantioenriched hemiacetals,
which were then oxidized to give valuable trisubstituted 3,4-
dihydropyranones with a stereogenic center at C-5, in high
yields and with excellent enantioselectivities. In these reac-
tions, α,β-unsaturated aldehydes with aliphatic, electron-de-
ficient aromatic, or electron-withdrawing groups at the β
position can be used as electrophiles. Different ketones can
also be used as nucleophiles, but a fine-tuning of the pKa
values of the hydrogen atoms at the α position is necessary.
Cyanoketones worked well, but much more acidic nitro-
ketones yielded the Knoevenagel product. We have also
shown that the reactions of ketones with two different
methylene positions were regioselective when the difference
in the pKa values of the hydrogens at the two α positions
was Ͼ5 units.
(4R)-4-Methyl-2-oxo-6-phenyl-3,4-dihydro-2H-pyran-5-carbonitrile
(5ab): Colorless oil. [α]2D0 = +24.2 (c = 1.5, CHCl3, 86% ee). 1H
NMR (400 MHz, CDCl3): δ = 1.38 (d, J = 7.0 Hz, 3 H), 2.59 (dd,
J = 15.8, 7.3 Hz, 1 H), 2.89 (dd, J = 15.8, 6.0 Hz, 1 H), 3.06–2.93
(m, 1 H), 7.57–7.40 (m, 3 H), 8.00–7.72 (m, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 19.1, 29.2, 35.3, 93.4, 117.3, 127.9, 128.8,
130.3, 130.5, 131.8, 161.4, 165.0 ppm. IR: ν = 2972, 2930, 2209,
˜
1789, 1353, 1124 cm–1. HPLC (Chiralpak AD-H; hexane/iPrOH,
90:10; 1.0 mL/min): tR = 13.3 min (major); tR = 12.5 min (minor).
HRMS: calcd. for C13H12NO2 [M + H] 214.0862; found 214.0869.
(4R)-4-Ethyl-2-oxo-6-phenyl-3,4-dihydro-2H-pyran-5-carbonitrile
(5ac): Colorless oil. [α]2D0 = +19.2 (c = 2, CHCl3, 90% ee). 1H NMR
(400 MHz, CDCl3): δ = 1.07 (t, J = 7.4 Hz, 3 H), 1.73–1.50 (m, 1
H), 1.85 (ddd, J = 13.6, 7.4, 5.9 Hz, 1 H), 2.71 (dd, J = 15.2, 4.6 Hz,
1 H), 2.86–2.73 (m, 1 H), 2.87 (dd, J = 15.2, 6.2 Hz, 1 H), 8.00–
7.17 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 10.7, 26.7,
32.6, 35.7, 92.2, 117.8, 127.9, 128.8, 129.1, 130.3, 130.5, 131.8,
161.7, 165.2 ppm. IR: ν = 2967, 2925, 2209, 1789, 1358, 1124 cm–1.
˜
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1.0 mL/min): tR
=
11.4 min (major); tR = 10.7 min (minor). HRMS: calcd. for
C14H14NO2 [M + H] 228.1019; found 228.1022.
Experimental Section
(4R)-2-Oxo-6-phenyl-4-propyl-3,4-dihydro-2H-pyran-5-carbonitrile
(5ad): Colorless oil. [α]2D0 = +36.7 (c = 1, CHCl3, 94% ee). 1H NMR
(400 MHz, CDCl3): δ = 0.99 (t, J = 7.2 Hz, 3 H), 1.66–1.29 (m, 3
H), 1.83–1.67 (m, 1 H), 2.70 (dd, J = 17.9, 7.0 Hz, 1 H), 2.98–2.76
(m, 2 H), 7.98–7.34 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 13.9, 19.6, 33.1, 34.2, 35.7, 92.5, 117.8, 127.9, 128.8, 129.1,
General Remarks: Specific rotations were measured using a 5 mL
cell with a 1 dm path length, and a sodium lamp, and concentra-
tions are given in g/100 mL. Melting points were measured using
open capillary tubes. Flash chromatography was carried out using
silica gel (230–240 mesh). Yields refer to pure isolated substances.
TLC analysis was carried out on glass-backed plates coated with
silica gel 60 and an F254 indicator, and plates were visualized by
staining with phosphomolybdic acid solution. Chiral HPLC analy-
sis was performed using different Daicel Chiralcel Columns. UV
detection was monitored at 220 nm or at 254 nm. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded in
CDCl3. 1H chemical shifts are reported in ppm from tetramethylsil-
ane. 13C chemical shifts are reported in ppm from tetramethylsil-
ane, and are referenced to the carbon resonance of the solvent.
Data are reported as follows: chemical shift, multiplicity (s = sing-
let, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),
coupling constants in Hertz, and integration.
130.3, 130.5, 131.8, 161.6, 165.2 ppm. IR: ν = 2962. 2930, 2214,
˜
1789, 1124 cm–1. HPLC (Chiralcel OD; hexane/iPrOH, 90:10;
1.0 mL/min): tR = 16.122 min (major); tR = 14.821 min (minor).
HRMS: calcd. for C15H16NO2 [M + H] 242.1175; found 242.1178.
Ethyl (4R)-5-Cyano-2-oxo-6-phenyl-3,4-dihydro-2H-pyran-4-carb-
oxylate (5ae): Colorless oil. [α]2D0 = +15.8 (c = 1.4, CHCl3, 96% ee).
1H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H), 2.88
(dd, J = 16.4, 6.9 Hz, 1 H), 3.19 (dd, J = 16.4, 3.0 Hz, 1 H), 3.70
(dd, J = 6.9, 3.0 Hz, 1 H), 4.29 (dq, J = 7.1, 1.0 Hz, 2 H), 7.50 (dt, J
= 8.6, 7.2 Hz, 3 H), 7.97–7.83 (m, 2 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.2, 29.8, 29.9, 40.0, 62.9, 85.8, 117.0, 128.1, 128.6,
128.9, 129.8, 132.4, 162.9, 163.6, 169.2 ppm. IR: ν = 2988, 2936,
˜
2214, 1773, 1721, 1368 cm–1. HPLC (Chiralpak AD-H; hexane/iP-
rOH, 90:10; 1.0 mL/min): tR = 21.7 min (major); tR = 20.6 min
(minor). HRMS: calcd. for C18H14N2O4 [M + H] 272.0917; found:
272.0918.
Organic compounds were used as received. Solvents were dried, if
needed, and stored over microwave-activated 4 Å molecular sieves.
General Procedure: A solution of the ketone (0.24 mmol), the corre-
sponding aldehyde (0.29 mmol, 1.2 equiv.), and the catalyst
(0.048 mmol, 0.2 equiv.) in CH2Cl2 (4 mL) was cooled to –18 °C,
and stirred for the time given in Table 2. Once the ketone has been
consumed (TLC), solid pyridinium chlorochromate (0.72 mmol,
3 equiv.) and 4 Å mol. sieves (500 mg) were added. The reaction
mixture was allowed to reach room temp. and stirred for 3 h. The
reaction mixture was filtered through a pad of Celite, the solvent
was evaporated under vacuum, and the products were purified by
flash chromatography on silica gel (hexane/ethyl acetate, 8:1) to
give the desired lactone.
(S)-4-(2-Nitrophenyl)-2-oxo-6-phenyl-3,4-dihydro-2H-pyran-5-
carbonitrile (5af): Colorless oil. [α]2D0 = +72 (c = 2.5, CHCl3 99.5%
1
ee). H NMR (500 MHz, CDCl3): δ = 3.14 (dd, J = 16.4, 4.5 Hz,
1 H), 3.32 (dd, J = 16.4, 7.7 Hz, 1 H), 4.88 (dd, J = 7.7, 4.5 Hz, 1
H), 8.20–7.33 (m, 9 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
35.3, 36.5, 89.9, 117.0, 126.4, 128.1, 128.7, 129.0, 129.7, 130.0,
132.5, 132.7, 134.6, 148.8, 163.4, 163.80 ppm. IR: ν = 2925, 2858,
˜
2214, 1789, 1519, 1347 cm–1. HPLC (Chiralpak AD-H; hexane/iP-
rOH, 80:20; 1.0 mL/min): tR = 18.9 min (major); tR = 20.3 min
(minor). HRMS: calcd. for C18H13N2O4 [M + H] 321.0869; found:
321.0870.
(S)-2-Oxo-4,6-diphenyl-3,4-dihydro-2H-pyran-5-carbonitrile (5aa):
Colorless oil. [α]2D0 = +34.5 (c = 2, CHCl3, 93% ee). 1H NMR
(500 MHz, CDCl3): δ = 3.02 (dd, J = 16.1, 4.8 Hz, 1 H), 3.16 (dd,
J = 16.1, 7.2 Hz, 1 H), 4.11 (dd, J = 7.2, 4.8 Hz, 1 H), 8.43–6.72
(4R)-4,6-Diethyl-2-oxo-3,4-dihydro-2H-pyran-5-carbonitrile (5dc):
Colorless oil. [α]2D0 = +19.7 (c = 1, CHCl3 92% ee). 1H NMR
Eur. J. Org. Chem. 2014, 8072–8076
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J. O. Guevara-Pulido, J. M. Andrés, R. Pedrosa
FULL PAPER
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(500 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H), 1.21 (t, J =
7.5 Hz, 3 H), 1.51 (dt, J = 14.5, 7.4 Hz, 1 H), 1.72 (ddd, J = 13.3,
7.4, 5.7 Hz, 1 H), 2.65–2.51 (m, 4 H), 2.74 (dd, J = 15.3, 6.0 Hz, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 10.3, 11.2, 26.3, 26.6,
32.6, 33.8, 92.0, 116.6, 165.3, 167.7 ppm. IR: ν = 2967, 2936, 2214,
˜
1789, 1649, 1129 cm–1. HPLC (Chiralpak AD-H; hexane/iPrOH,
97:3; 0.7 mL/min): tR = 13.5 min (major); tR = 12.8 min (minor).
HRMS: calcd. for C10H14NO2 [M + H] 180.1019; found: 180.1022.
(4R)-6-Benzyl-4-ethyl-2-oxo-3,4-dihydro-2H-pyran-5-carbonitrile
(5ec): Colorless oil. [α]2D0 = +8.8 (c = 0.5, CHCl3 94% ee). 1H NMR
(500 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H), 1.62–1.40 (m, 1
H), 1.74 (ddd, J = 13.5, 7.2, 6.0 Hz, 1 H), 2.54 (dd, J = 15.3, 5.0 Hz,
1 H), 2.79–2.59 (m, 2 H), 3.81 (q, J = 14.5 Hz, 2 H), 7.33 (s, 5 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 10.4, 26.6, 32.5, 34.0, 39.0,
93.2, 116.8, 127.6, 128.8, 128.9, 134.6, 164.9, 165.0 ppm. HPLC
(Chiralpak AD-H; hexane/iPrOH, 97:3; 0.7 mL/min): tR = 18.2 min
(major); tR = 19.0 min (minor). HRMS: calcd. for C15H15NO2 [M
+ Na] 240.1238; found: 240.1240.
Supporting Information (see footnote on the first page of this arti-
1
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Acknowledgments
The authors thank the Spanish DGICYT (Project CTQ 2011-
28487) and JC y L (Project VA064U13) for financial support.
J. O. G.-P. also thanks the University of Valladolid for a pre-doc-
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Published Online: November 17, 2014
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