Tandem iminium/copper catalysis: Highly enantioselective synthesis of α,β-disubstituted aldehydes

Article abstract of DOI:10.1002/ejoc.201300333

With the goal of synthesizing biologically and synthetically valuable products under environmentally benign and economic conditions, an asymmetric organocatalytic reaction was combined with a copper catalytic reaction. This iminium/copper catalysis allowed highly optically active α,β- disubstituted aldehydes to be synthesized with good yields in one-pot fashion. The β-substitution took place through iminium-catalyzed Michael addition of nitromethane or diethyl malonate to the α,β-unsaturated aldehydes, followed by copper-assisted addition of TEMPO (2,2,6,6-tetramethylpiperidin-1- yloxyl) at the aldehyde α-position. An iminium/copper-catalyzed tandem addition product was converted into a 3,4,5-trisubstituted piperidine for X-ray crystallographic analysis. Copyright

Full text of DOI:10.1002/ejoc.201300333

Job/Unit: O30333
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FULL PAPER
Asymmetric Catalysis
The combination of a chiral amine catalyst
and a copper complex allows the synthesis
of α,β-disubstituted aldehydes from un-
saturated aldehydes with good yields and
excellent stereoselectivity.
J.-H. Kim, E.-J. Park, H.-J. Lee,
X.-H. Ho, H.-S. Yoon, P. Kim, H. Yun,
H.-Y. Jang* ...................................... 1–9
Tandem Iminium/Copper Catalysis: Highly
Enantioselective Synthesis of α,β-Disubsti-
tuted Aldehydes
Keywords: Synthetic methods / Asymmetric
catalysis / Copper / Michael addition /
Aldehydes
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DOI: 10.1002/ejoc.201300333
Tandem Iminium/Copper Catalysis: Highly Enantioselective Synthesis of α,β-
Disubstituted Aldehydes
Ju-Hye Kim,[a] Eun-Jin Park,[a] Hwa-Jung Lee,[a] Xuan-Huong Ho,[a] Hyo-Sang Yoon,[a]
Pilsoo Kim,[a] Hoseop Yun,[a] and Hye-Young Jang*[a,b]
Keywords: Synthetic methods / Asymmetric catalysis / Copper / Michael addition / Aldehydes
With the goal of synthesizing biologically and synthetically
lyzed Michael addition of nitromethane or diethyl malonate
valuable products under environmentally benign and econ- to the α,β-unsaturated aldehydes, followed by copper-as-
omic conditions, an asymmetric organocatalytic reaction was
combined with a copper catalytic reaction. This iminium/cop-
per catalysis allowed highly optically active α,β-disubstituted
aldehydes to be synthesized with good yields in one-pot
fashion. The β-substitution took place through iminium-cata-
sisted addition of TEMPO (2,2,6,6-tetramethylpiperidin-1-
yloxyl) at the aldehyde α-position. An iminium/copper-cata-
lyzed tandem addition product was converted into a 3,4,5-
trisubstituted piperidine for X-ray crystallographic analysis.
tions[10] or metal-catalyzed reactions[11] have both been re-
ported, but the combination of these reactions in a one-
pot process has not been reported so far. Optically active
nitroaldehydes have potential for use in the syntheses of
biologically important γ-aminocarbonyl, aminoalkane, and
2-pyrrolidone derivatives.[12,13] Abundant examples of
asymmetric organocatalytic reactions for highly stereoselec-
tive substitution of nitroaldehydes have consequently been
reported.[9,14] Iminium-catalyzed nitroalkane addition to
α,β-unsaturated aldehydes affords β-substituted nitroalde-
hydes, whereas enamine-catalyzed aldehyde addition to
nitroolefins gives α,β-disubstituted nitroaldehydes, both with
high stereoselectivities. In terms of diversity-oriented syn-
thesis, investigation into catalytic reactions for installation
of various functional groups at different positions in alde-
hydes might contribute to the building of libraries of op-
tically active nitroaldehyde collections for further applica-
tion in the pharmaceutical and fine chemical industries. Al-
though enamine-catalyzed aldehyde addition to nitroolefins
sets two stereogenic centers with high enantio- and dia-
stereoselectivities, the functional groups introduced onto
the aldehydes in such cases are alkyl or aromatic groups. In
this study, through the employment of iminium catalysis
and copper-catalyzed TEMPO addition, syntheses of
α-oxyaminated, β-aryl- or β-alkyl-substituted nitroalde-
hydes with excellent enantio- and diastereoselectivities have
been demonstrated.
Introduction
Multicatalytic reactions involving transition-metal com-
plexes and organocatalysts have emerged as powerful tools
for highly stereoselective step-economic multibond forma-
tion.[1,2] With the aim of developing highly stereoselective
multiple-bond-forming catalytic reactions for synthesizing
pharmaceutically and synthetically valuable compounds, we
recently reported asymmetric syntheses of α,β-disubstituted
aldehydes by means either of tandem iminium/rutheni-
um(II)-catalyzed photoreactions[3] or of iminium/copper-
catalyzed reactions.[4] Although catalytic reaction condi-
tions for forming each single bond were reported, optimiza-
tion for a multistep one-pot process is still challenging.[5–7]
Judicious choices of organocatalysts, additives, and solvents
are prerequisite for high yields and stereoselectivities of the
tandem multicatalytic reactions.
In the context of expanding the scope of α,β-substitution
of aldehydes under multicatalytic conditions, installation of
a nitroalkyl substituent at the β-position of the aldehyde
by asymmetric iminium catalysis together with addition of
TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxyl) at the α-
position through a copper-catalyzed reaction was consid-
ered. Michael addition of nitromethane to α,β-unsaturated
aldehydes by enantioselective iminium catalysis[5,6,8,9] and
α-oxyamination of saturated aldehydes through photoreac-
[a] Division of Energy Systems Research, Ajou University,
Suwon 443-749, Korea
To allow further investigation of multiple-catalytic tan-
dem additions of nucleophiles and TEMPO to α,β-unsatu-
rated aldehydes, previously reported multiple-catalytic tan-
dem additions of diethyl malonate and TEMPO to α,β-un-
saturated aldehydes under copper-catalyzed conditions were
revisited.[4] Iminium/copper-based multiple-bond-forming
Fax: +82-31-219-1615
E-mail: hyjang2@ajou.ac.kr
Homepage: http://ajou.ac.kr/~hyjang2
[b] Korea Carbon Capture & Sequestration R&D Center,
Deajeon 305-343, Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300333.
2
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Iminium/Cu Catalysis
catalysis affords a wide range of α,β-disubstituted aldehydes formation.[5–7] The highest yield of 1b was obtained with
in one-pot fashion with good yields and high enantio- CHCl3 (Entry 4). In DMF, CH3CN, and CH2Cl2 the ad-
selectivities. Depending on the nucleophiles, different reac- dition of nitromethane to 1a was not efficient, showing
tion conditions are required, as discussed in this report.
lower yields. CuBr2 and Cu(OTf)2 as copper sources pro-
vided product 1b in diminished yields (Entries 6 and 7).
Copper oxide (Cu2O and CuO) did not promote this trans-
formation (Entries 8 and 9). In addition to copper com-
plexes, an iron(III) complex that promoted the addition of
TEMPO to enamine species was used,[11] but formation of
Results and Discussion
To implement tandem nitromethane/TEMPO addition to 1b was not observed (Entry 10). For promotion of nitro-
aldehydes, (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrol- methane addition, adamantanecarboxylic acid and LiOAc
idine (A, Table 1) and metal complexes (copper and iron base additives were also tested (in addition to benzoic acid),
complexes) were used. Chiral pyrrolidine A forms a chiral and afforded 1b in 65% (adamantanecarboxylic acid) and
iminium intermediate for nitromethane addition, and the 45% (LiOAc) yields (Entries 11 and 12). Compound 1b was
1
resulting enamine intermediates produced by nitromethane observed as a single diastereomer by H NMR (Ͼ95% de).
addition to the iminium system react with an ionic electro- The relative stereochemistry was assigned on the basis of
philic metal-TEMPO complex.[11,15] The role of each cata- previous organocatalyzed nitromethane additions to α,β-
lyst is considered in the context of previously reported tan- unsaturated aldehydes and TEMPO additions to hydrocin-
dem oxidation/malonate addition/oxyamination sequences namaldehyde.[3,4,9–11]
with allylic alcohols in the presence of copper complexes
In view of the results of the solvent and metal screening
and chiral organocatalysts.[4] To optimize the stereoselective of tandem nitromethane/TEMPO addition, previously re-
tandem α,β-functionalization of aldehydes, different sol- ported enantioselective tandem allylic alcohol oxidations
vents, copper species, additives, and organocatalysts were and malonate/TEMPO additions to aldehydes in the pres-
tested.
ence of CuCl and catalyst A were re-examined. In the pre-
viously developed three-step, one-pot reactions, the use of
DMF as a solvent and a CuCl·TEMPO complex was re-
quired for complete oxidation of the allylic alcohols, to gen-
erate α,β-unsaturated aldehydes. The employment of an
α,β-unsaturated aldehyde as the starting material allowed
the in situ oxidation of an allylic alcohol to be omitted. A
wide range of metal species (mostly copper complexes) and
solvents were therefore applied to tandem additions of di-
ethyl malonate and TEMPO to α,β-unsaturated aldehyde
1a (Table 2). A variety of different solvents (DMF, CH3CN,
CH2Cl2, CHCl3, and toluene) were tested; the best yield
(80%) was obtained with CH3CN (Entries 1–5).
Table 1. Optimization of tandem nitromethane/TEMPO addition
to 1a.
Copper and iron complexes were then tested. CuBr2, Cu-
(OTf)2, and CuCl showed good catalytic activities for this
transformation (Entries 6–10). As well as adamantane-
carboxylic acid, benzoic acid and LiOAc were also used,
providing 1c in 55% and 50% yields, respectively (En-
tries 11 and 12).
The reactivities of chiral organocatalysts were next com-
pared (Table 3). For nitromethane/TEMPO addition, CuCl
in CHCl3 was used (Table 1, Entry 4). The pyrrolidine-type
catalysts A and B catalyzed the reaction to afford the de-
sired tandem product 1b, whereas the imidazolidinone-type
catalysts C and D did not. Similarly, for the formation of
1c, catalysts A and B showed good activities, but catalysts
C and D provided only malonate addition products. The
optimized conditions from Table 2 were used to form 1c.
The substituent on catalyst B is smaller than that on A, and
this reduces the enantiopurities of 1b and 1c.
A solution of cinnamaldehyde (1a, Table 1), nitrometh-
Next, a range of α,β-unsaturated aldehydes were sub-
ane (3 equiv.), and TEMPO (2 equiv.) was treated with jected to tandem Michael/TEMPO addition. As listed in
CuCl (10 mol-%) and catalyst A (20 mol-%) under aerobic Table 4, nitromethane and diethyl malonate were used as
conditions in the solvent indicated (Entries 1–5). Benzoic the nucleophiles for the Michael addition. Tandem nitro-
acid (10 mol-%) was added to accelerate the iminium salt methane/TEMPO addition to α,β-unsaturated aldehydes
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Table 2. Optimization of tandem malonate/TEMPO addition to 1a. yields but high stereoselectivities. The cyclopropyl-substi-
tuted aldehyde 7a also participated in this reaction, afford-
ing 7b in 64% yield but with slightly decreased diastereo-
(78% de) and enantioselectivity (94% ee).
Table 4. Substrate scope.
Table 3. Optimization of organocatalysts.
mainly favored the conditions involving CuCl, organocata-
lyst A, and benzoic acid as additive in CHCl3. Cinnamal-
dehyde (1a) and its phenyl-substituted derivatives 2a and 3a
were transformed into α,β-substituted nitroaldehydes 1b,
2b, and 3b in good yields and with excellent stereoselectivi-
ties. The α,β-unsaturated aldehydes containing naphthalene
(compound 4a), nitro-substituted phenyl (compound 5a),
and thiophene groups (compound 6a) showed slightly lower
4
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Iminium/Cu Catalysis
In the case of tandem malonate/TEMPO addition, a
mixture of Cu(OTf)2 (or CuCl), catalyst A, and the ada-
mantanecarboxylic acid additive in CH3CN was employed.
As in the addition of nitromethane, cinnamaldehyde (1a)
and its phenyl-substituted derivatives 2a and 3a participated
in tandem malonate/TEMPO addition to afford 1c–3c with
good yields and excellent stereoselectivities. The naphthyl-
substituted aldehyde 4c showed slightly reduced yields
(57%) but high diastereo- and enantioselectivities. The
nitro-substituted cinnamaldehyde 5c and thiophene-substi-
tuted aldehyde 6c gave the highest yields and good stereo-
selectivities. The cyclopropyl-substituted compound 7c was
tested with both CuCl and Cu(OTf)2; a higher yield and
selectivity (44% yield and 96% ee) were obtained with CuCl
than with Cu(OTf)2 (40% yield and 93% ee).
The tandem addition products can be converted into het-
erocyclic compounds with potential pharmaceutical and
biological activities.[16] As an example, the bromo-substi-
tuted compound 8c was synthesized under the copper/or-
Figure 1. The molecular structure of 8d.
ganocatalytic conditions, with subsequent reductive amin- compound 8d suitable for X-ray crystallography (Figure 1)
ation/cyclization providing 3,4,5-trisubstituted piperidine was obtained from a solvent mixture of dichloromethane
derivative 8d in 66% yield (Scheme 1). A single crystal of and hexane (evaporation at –20 °C) . The X-ray crystallo-
Scheme 1. Synthesis of 3,4,5-trisubstituted piperidine 8d from 8a.
Scheme 2. Proposed catalytic cycle.
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(104 mg, 60%). 1H NMR (CDCl3, 400 MHz): δ = 1.12–1.55 (m, 18
H), 4.09 (m, 1 H), 4.43 (m, 1 H), 4.74 (m, 1 H), 4.94 (m, 1 H), 7.19
(d, J = 8 Hz, 2 H), 7.29 (m, 4 H), 9.75 (d, J = 0.8 Hz, 1 H) ppm.
13C NMR (CDCl3, 100 Hz): δ = 14.4, 17.2, 20.9, 22.9, 31.8, 34.3,
40.1, 40.3, 45.0, 60.3, 61.8, 76.6, 87.5, 128.3, 128.4, 128.7, 129.0,
graphic data for 8d also confirmed the relative and absolute
stereochemistry of 8c.
A proposed catalytic cycle for tandem nucleophilic nitro-
methane and malonate/TEMPO addition is given in
Scheme 2. It begins with formation of iminium salt I from
cinnamaldehyde and an organocatalyst. The subsequent ad-
dition of a nucleophile to the β-position of iminium I pro-
vides enamine intermediate II, which undergoes either hy-
drolysis or copper-TEMPO addition. In the presence of
TEMPO and the copper complex, intermediate II reacts
with the copper-TEMPO complex to afford an α,β-disubsti-
tuted aldehyde. The structure and reactivity of the copper-
TEMPO complex was proposed in investigations of CuCl2/
TEMPO-catalyzed alcohol oxidations and CuCl2-catalyzed
α-oxyamination of aldehydes.[11c,17] Copper(I) complexes
that were either added at the beginning of the reaction or
generated during the reaction underwent oxidation in the
presence of TEMPO or oxygen, forming active copper(II)-
TEMPO complexes.
134.2, 201.2 ppm. IR (neat): ν = 2974, 2932, 1730, 1556, 1455,
˜
1377, 1257, 1047, 700 cm–1. HRMS calcd. for C19H28N2O4
[M + H]+ 349.2127; found 349.2127. HPLC Chiracel AD-H 99:1
(hexane/iPrOH), 210 nm, 0.5 mLmin–1, retention time 22.7 min
(minor) and 24.5 min (major).
4-Nitro-3-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)butan-1-ol
(1d): The representative experimental procedure for the catalytic
reaction and hydrogenation was applied to compound 1a (67 mg,
1
0.5 mmol) to yield product 1d (110 mg, 63%). H NMR (CDCl3,
400 MHz): δ = 1.12–1.60 (m, 18 H), 3.40 (d, J = 10.8 Hz, 1 H),
3.53 (m, 1 H), 3.98 (t, J = 11.0 Hz, 1 H), 4.54 (t, J = 9.4 Hz, 1 H),
4.63 (m, 1 H), 4.97 (m, 1 H), 5.97 (s, 1 H), 7.18 (d, J = 7.6 Hz, 1
H), 7.30 (m, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 17.3, 21.1,
21.1, 32.6, 34.9, 40.1, 40.6, 46.3, 60.5, 62.3, 66.7, 77.7, 82.2, 127.9,
128.2, 129.1, 136.7 ppm. IR (neat): ν = 2930, 1555, 1454, 1379,
˜
1256, 1053, 701 cm–1. HRMS calcd. for C19H30N2O4 [M + H]+
351.2284; found 351.2284. HPLC Chiracel OD-H 90:10 (hexane/
iPrOH), 210 nm, 0.5 mLmin–1, retention time 20.6 min (minor)
and 26.4 min (major).
Conclusions
4-Nitro-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-3-p-tolylbutanal
(2b): The representative experimental procedure was applied to
compound 2a (73 mg, 0.5 mmol) for 4 h to yield product 2b
(110 mg, 61%). 1H NMR (CDCl3, 400 MHz): δ = 1.12–1.55 (m, 18
H), 2.30 (s, 1 H), 4.05 (m, 1 H), 4.40 (m, 1 H), 4.70 (m, 1 H), 4.92
(m, 1 H), 7.09 (m, 4 H), 9.71 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR
(CDCl3, 100 Hz): δ = 17.0, 20.6, 20.7, 21.2, 34.1, 34.2, 39.9, 40.2,
44.5, 60.1, 61.6, 87.4, 128.0, 129.6, 130.8, 138.0, 200.8 ppm. IR
A tandem protocol based on iminium and copper cataly-
sis produced highly optically active α,β-disubstituted alde-
hydes. A wide range of α-oxyaminated and β-alkylated alde-
hydes were synthesized under the optimized conditions for
each β-alkylating agent. Depending on the nucleophile for
β-alkylation, different copper sources, solvents, and addi-
tives were employed; in terms of chiral amine catalysts, cat-
alyst A mainly gave good conversions and stereoselectivi-
ties. One of α,β-disubstituted aldehydes was cyclized to pro-
(neat): ν = 2974, 2930, 1730, 1556, 1465, 1377, 1257, 1241,
˜
733 cm–1. HRMS calcd. for C20H30N2O4 [M + H]+ 363.2284; found
vide the 3,4,5-trisubstituted piperidine; this demonstrates 363.2284. HPLC Chiracel OD-H 99:1 (hexane/iPrOH), 254 nm,
0.5 mL min–1, retention time 20.8 min (major) and 23.5 min
(minor).
potential applications of this method for the synthesis of
biologically useful building block. Overall, this tandem
transformation might offer environmentally benign and
step-economic processes for the syntheses of pharmaceuti-
cally, biologically, and synthetically useful aldehydes.
3-(4-Methoxyphenyl)-4-nitro-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)butanal (3b): The representative experimental procedure was
applied to compound 3a (81 mg, 0.5 mmol) for 3.5 h to yield prod-
uct 3b (113 mg, 60%). 1H NMR (CDCl3, 400 MHz): δ = 1.13–1.55
(m, 18 H), 3.77 (s, 1 H), 4.02 (m, 1 H), 4.39 (m, 1 H), 4.69 (m, 1
H), 4.92 (m, 1 H), 6.83 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2
H), 9.71 (d, J = 4.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ
= 17.2, 20.7, 20.8, 34.2, 34.3, 40.1, 40.3, 44.3, 55.3, 60.2, 61.7, 76.8,
77.0, 77.2, 77.5, 87.5, 114.4, 125.9, 129.4, 159.4, 201.0 ppm. IR
(neat): ν˜ = 2935, 1730, 1515, 1378, 1254, 1035, 736 cm–1. HRMS
calcd. for C20H30N2O5 [M + H]+ 379.2233; found 379.2233. HPLC
Chiracel AD-H 95:5 (hexane/iPrOH), 254 nm, 0.5 mLmin–1, reten-
tion time 15.7 min (minor) and 18.1 min (major).
Experimental Section
General Procedure for the Tandem Nitromethane/TEMPO Addition:
A mixture of aldehyde (0.5 mmol), CuCl (10 mol-%), TEMPO
(2 equiv.),
(S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(10 mol-%), benzoic acid (10 mol-%), and nitromethane (3 equiv.)
in CHCl3 (0.4 m) was stirred under oxygen (1 atm). The solvent was
removed with a rotary evaporator to produce a residue, which was
purified by column chromatography on silica gel with elution with
hexane and ether. To confirm the enantioselectivity and yield of
1b, the compound was exposed to reduction conditions. Reduction
conditions: the aldehyde (1 equiv.) was treated with an anhydrous
THF solution containing NaBH4 (4 equiv.) at 0 °C for 50 min, and
the reaction mixture was then stirred for 12 h at room temperature,
to afford the alcohol 1d. The diastereopurity of each compound
was measured by 1H NMR and the enantiopurity was measured
by HPLC analysis.
3-(Naphthalen-2-yl)-4-nitro-2-(2,2,6,6-tetramethylpiperidin-1-yl-
oxy)butanal (4b): The representative experimental procedure was
applied to compound 3a (91 mg, 0.5 mmol) for 3 h to yield product
1
4b (88 mg, 44%). H NMR (CDCl3, 400 MHz): δ = 1.12–1.53 (m,
18 H), 4.26 (m, 1 H), 4.53 (m, 1 H), 4.84 (m, 1 H), 5.02 (m, 1 H),
7.31 (d, J = 8.4 Hz, 1 H), 7.45 (m, 2 H), 7.65 (s, 1 H), 7.79 (m, 3
H), 9.79 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ
= 17.0, 20.6, 20.7, 34.1, 39.9, 40.2, 45.0, 60.1, 61.6, 74.5, 87.3,
125.3, 126.2, 126.3, 127.4, 127.6, 127.6, 128.6, 128.8, 131.5, 132.8,
4-Nitro-3-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)butanal 133.0, 201.0 ppm. IR (neat): ν = 2974, 2931, 1730, 1555, 1467,
˜
(1b): The representative experimental procedure was applied to
compound 1a (66 mg, 0.5 mmol) for 4 h to yield product 1b
1376, 1241, 1131, 735 cm–1. HRMS calcd. for C23H30N2O4
[M + H]+ 399.2284; found 399.2284. HPLC Chiracel AD-H 95:5
6
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Iminium/Cu Catalysis
(hexane/iPrOH), 254 nm, 0.5 mLmin–1, retention time 21.6 min
(hexane/iPrOH), 210 nm, 0.5 mL min–1, retention time 12.9 min
(major) and 27.4 min(minor).
(minor) and 16.7 min (major).
4-Nitro-3-(4-nitrophenyl)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
butanal (5b): The representative experimental procedure was ap-
plied to compound 5a (88 mg, 0.5 mmol) for 7 h to yield product
5b (106 mg, 54%). 1H NMR (CDCl3, 400 MHz): δ = 1.10–1.50 (m,
18 H), 4.23 (d, J = 7.5 Hz, 1 H), 4.49 (s, 1 H), 4.83 (m, 1 H), 4.96
(m, 1 H), 7.44 (d, J = 8.5 Hz, 2 H), 8.21 (d, J = 8.5 Hz, 2 H), 9.91
(d, J = 2.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 16.8,
17.0, 20.6, 20.7, 27.5, 29.6, 33.9, 34.1, 39.9, 40.2, 44.4, 60.5, 61.8,
Diethyl 2-[3-Oxo-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-1-p-tol-
ylpropyl]malonate (2c): The representative experimental procedure
was applied to compound 2a (37 mg, 0.25 mmol) for 24 h to yield
1
product 2c (85 mg, 74%). H NMR (CDCl3, 400 MHz): δ = 0.93–
0.98 (m, 6 H), 1.06 (s, 3 H), 1.19–1.29 (m, 12 H), 1.40–1.41 (m, 3
H), 2.28 (s, 3 H), 3.85–3.93 (m, 2 H), 3.95–3.97 (m, 2 H), 4.20–4.25
(m, 2 H), 4.44–4.47 (m, 1 H), 7.04–7.09 (m, 4 H), 9.65 (d, J =
5.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 13.9, 14.2, 17.2,
20.8, 21.3, 29.9, 34.2, 34.3, 40.2, 40.4, 46.0, 54 0, 60.1, 61.4, 61.9,
87.8, 128.9, 129.1, 132.3, 37.2, 167.1, 167.7, 203.7 ppm. IR (neat):
86.7, 124.1, 129.5, 142.3, 147.8, 201.3 ppm. IR (neat): ν = 2925,
˜
2853, 1729, 1524, 1469, 1376, 1374, 1258, 720 cm–1. HRMS calcd.
for C19H27N3O6 [M + H]+ 394.1978; found 394.1978. HPLC Chira-
cel AS-H 80:20 (hexane/iPrOH), 254 nm, 0.5 mLmin–1, retention
time 26.1 min (minor) and 32.3 min (major).
ν = 786, 1028, 1180, 1368, 1465, 1735, 2935 cm–1. HRMS calcd.
˜
for C26H39NO6 [M + H]+ 462.2856; found 462.2856. HPLC Chira-
cel AD-H 95:5 (hexane/iPrOH), 210 nm, 0.5 mLmin–1, retention
time 13.8 min (minor) and 17.7 min (major).
4-Nitro-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-3-(thiophen-2-yl)-
butanal (6b): The representative experimental procedure was ap-
plied to compound 6a (69 mg, 0.5 mmol) for 9 h to yield product
Diethyl 2-[1-(4-Methoxyphenyl)-3-oxo-2-(2,2,6,6-tetramethylpiper-
idin-1-yloxy)propyl]malonate (3c): The representative experimental
procedure was applied to compound 3a (41 mg, 0.25 mmol) for
18 h to yield product 3c (92 mg, 77 %). 1H NMR (CDCl3,
400 MHz): δ = 0.94–0.99 (m, 6 H), 1.06 (s, 3 H), 1.19–1.28 (m, 12
H), 1.40 (m, 3 H), 3.76 (s, 3 H), 3.88–3.92 (m, 4 H), 4.20–4.25 (m,
2 H), 4.44–4.46 (m, 1 H), 6.79 (d, J = 8.8 Hz, 2 H), 7.13 (d, J =
8.8 Hz, 2 H), 9.65 (d, J = 5.2 Hz, 1 H) ppm. 13C NMR (CDCl3,
100 Hz): δ = 13.9, 14.2, 17.2, 20.7, 34.2, 34.3, 40.2, 40.4, 45.6, 54.1,
55.3, 61.5, 61.9, 87.7, 113.6, 127.3, 130.3, 158.8, 167.2, 167.7,
1
6b (82 mg, 46%). H NMR (CDCl3, 400 MHz): δ = 1.11–1.51 (m,
18 H), 4.43 (m, 2 H), 4.71 (m, 1 H), 4.89 (m, 1 H), 6.89 (d, J =
2.8 Hz, 1 H), 6.94 (t, J = 4.4 Hz, 1 H), 7.25 (m, 1 H), 9.79 (d, J =
3.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 17.2, 20.8, 20.9,
29.9, 34.3, 40.2, 40.4, 60.5, 61.7, 77.0, 87.4, 125.9, 126.7, 127.1,
201.4 ppm. IR (neat): ν = 2929, 1730, 1557, 1436, 1377, 1257,
˜
1132 cm–1. HRMS calcd. for C17H26N2O4S [M + H]+ 355.1692;
found 355.1692. HPLC Chiracel OD-H 90:10 (hexane/iPrOH),
254 nm, 0.5 mL min–1, retention time 16.6 min (minor) and
20.2 min (major).
203.7 ppm. IR (neat): ν = 2935, 1734, 1515, 1374, 1253, 1182, 1033,
˜
832 cm–1. HRMS calcd. for C26H39NO7 [M + H]+ 478.2805; found
478.2805. HPLC Chiracel AD-H 95:5 (hexane/iPrOH), 210 nm,
0.5 mL min–1, retention time 20.7 min (minor) and 31.9 min
(major).
3-Cyclopropyl-4-nitro-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
butanal (7b): The representative experimental procedure was ap-
plied to compound 7a (48 mg, 0.5 mmol) for 4 h to yield product
7b (100 mg, 64%). 1H NMR (CDCl3, 400 MHz): δ = 0.26 (s, 2 H),
0.58 (d, J = 7.6 Hz, 2 H), 0.76 (t, J = 3.6 Hz, 1 H), 1.11–1.55 (m,
18 H), 2.05 (m, 1 H), 4.33 (s, 1 H), 4.55 (m, 1 H), 4.64 (m, 1 H),
9.93 (t, J = 2.2 Hz, 1 H), 10.22 (s, 1 H) ppm. 13C NMR (CDCl3,
100 Hz): δ = 3.5, 4.3, 4.6, 4.8, 9.2, 10.2, 16.6, 20.0, 20.1, 33.6, 34.0,
39.5, 39.8, 44.0, 46.3, 59.6, 61.1, 76.3, 76.5, 86.1, 86.6, 201.5,
Diethyl 2-[1-(Naphthalen-2-yl)-3-oxo-2-(2,2,6,6-tetramethylpiper-
idin-1-yloxy)propyl]malonate (4c): The representative experimental
procedure was applied to compound 4a (45 mg, 0.25 mmol) for
48 h to yield product 4c (72 mg, 57 %). 1H NMR (CDCl3,
400 MHz): δ = 1.33 (m, 4 H), 1.15–1.25 (m, 11 H), 0.98 (s, 3 H),
0.86 (s, 3 H), 0.75 (t, J = 7.2 Hz, 3 H), 3.74 (m, 2 H), 4.05 (d, J =
10.8 Hz, 1 H), 4.15 (m, 3 H), 4.49 (m, 1 H), 7.30 (d, J = 8 Hz, 1
H), 7.36 (m, 2 H), 7.58 (s, 1 H), 7.69 (m, 3 H), 9.64 (d, J = 4.8 Hz,
1 H), 9.71 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz):
δ = 13.9, 14.3, 17.3, 20.9, 30.0, 34.3, 34.4, 40.3, 40.5, 46.6, 53.9,
60.2, 61.6, 62.0, 87.7, 126.0, 126.1, 127.3, 127.6, 127.8, 127.9, 128.3,
204.0 ppm. IR (neat): ν = 2940, 1725, 1551, 1433, 1376, 1256, 1132,
˜
745 cm–1. HRMS calcd. for C16H28N2O4 [M + H]+ 313.2127; found
313.2127. HPLC: Chiracel OD-H 99:1 (hexane/iPrOH), 254 nm,
0.5 mL min–1, retention time 13.9, 15.1 min (minor) and 15.7,
18.8 min(major).
General Procedure for the Tandem Diethyl Malonate/TEMPO Ad-
dition: A mixture of aldehyde (0.25 mmol), diethyl malonate
(3 equiv.), TEMPO (2 equiv.), adamantanecarboxylic acid (10 mol-
%), and (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(20 mol-%) in CH3CN (0.4 m) was stirred. The solvent was removed
with a rotary evaporator to produce a residue, which was purified
by column chromatography on a silica gel with elution with hexane
and ether.
132.7, 133.0, 133.3, 167.2, 167.7, 204.0 ppm. IR (neat): ν = 2978,
˜
2933, 1732, 1733, 1259, 1185, 751 cm–1. HRMS calcd. for
C29H39NO6 [M + H]+ 498.2856; found 489.2852. HPLC Chiracel
AD-H 95:5 (hexane/iPrOH), 210 nm, 0.5 mLmin–1, retention time
18.2 min (minor) and 28.0 min (major).
Diethyl 2-[1-(4-Nitrophenyl)-3-oxo-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)propyl]malonate (5c): The representative experimental pro-
cedure was applied to compound 5a (44 mg, 0.25 mmol) for 72 h
Diethyl 2-[3-Oxo-1-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-
propyl]malonate (1c): The representative experimental procedure
1
to yield product 5c (113 mg, 91%). H NMR (CDCl3, 400 MHz):
was applied to compound 1a (33 mg, 0.25 mmol) for 20 h to yield
δ = 0.99 (m, 10 H), 1.25 (m, 11 H), 1.37 (m, 4 H), 3.91 (m, 2 H),
1
product 1c (95 mg, 80%). H NMR (CDCl3, 400 MHz): δ = 0.90– 4.01 (m, 1 H), 4.12 (m, 1 H), 4.21 (m, 2 H), 4.53 (m, 1 H), 7.42 (d,
0.96 (m, 6 H), 1.06 (s, 3 H), 1.20–1.22 (m, 6 H), 1.28 (m, 5 H), 1.40 J = 0.02 Hz, 2 H), 8.14 (d, J = 8.8 Hz, 2 H), 9.73 (d, J = 4.4 Hz,
(m, 4 H), 3.84–3.91 (m, 1 H), 4.00 (m, 2 H), 4.22 (m, 2 H), 4.46– 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 14.0, 14.2, 17.2, 21.0,
4.49 (m, 1 H), 7.20–7.28 (m, 5 H), 9.68 (d, J = 4.8 Hz, 1 H) ppm.
34.2, 34.3, 40.3, 40.5, 46.3, 53.0, 60.4, 61.7, 61.9, 62.3, 86.7, 123.4,
13C NMR (CDCl3, 100 Hz): δ = 13.9, 14.3, 17.2, 20.7, 34.2, 34.3, 130.3, 143.8, 147.2, 147.2, 166.7, 167.2, 203.6 ppm. IR (neat): ν =
˜
40.3, 40.4, 46.5, 53.8, 60.1, 61.5, 62.0, 87.6, 127.7, 128.2, 129.3,
2979, 2934, 1733, 1524, 1466, 1348, 1259, 1181, 856 cm–1. HRMS
135.5, 167.1, 167.7, 204.0 ppm. IR (neat): ν = 2936, 1735, 1455, calcd. for C25H36N2O8 [M + H]+ 493.2550; found 493.2550. HPLC
˜
1375, 1259, 1181, 1029, 702 cm–1. HRMS calcd. for C25H37NO6
[M + H]+ 448.2699; found 448.2699. HPLC Chiracel AD-H 95:5
Chiracel AD-H 85:15 (hexane/iPrOH), 210 nm, 0.5 mLmin–1, re-
tention time 22.3 min (minor) and 36.6 min (major).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30333
/KAP1
Date: 25-05-13 11:17:51
Pages: 9
H.-Y. Jang et al.
FULL PAPER
Diethyl 2-[3-Oxo-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-1- Supporting Information (see footnote on the first page of this arti-
(thiophen-2-yl)propyl]malonate (6c): The representative experimen-
tal procedure was applied to compound 6a (35 mg, 0.25 mmol) for
48 h to yield product 6c (113 mg, 99 %). 1H NMR (CDCl3,
400 MHz): δ = 1.08 (10 H), 1.21 (s, 4 H), 1.29 (m, 8 H), 1.42 (m,
5 H), 4.01 (m, 3 H), 4.22 (m, 2 H), 4.32 (m, 1 H), 4.49 (t, J =
5.6 Hz, 1 H), 6.86 (m, 1 H), 6.90 (m, 1 H), 7.18 (d, J = 4.8 Hz, 1
H), 9.70 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ
= 203.4, 167.3, 166.9, 137.4, 126.8, 126.4, 125.1, 86.9, 62.0, 61.7,
61.3, 60.2, 54.3, 41.4, 40.4, 40.2, 34.3, 20.8, 17.2, 14.2, 13.9 ppm.
cle): Copies of 1H NMR, 13C NMR, and HPLC spectra for 1b–7b,
1c–8c, and 8d.
Acknowledgments
This study was supported by the Korea Research Foundation (No.
2009-0094046) and by a Korea CCS R&D Center (KCRC) grant
(No.2012-0008935) funded by the Korea Government (Ministry of
Education, Science and Technology).
IR (neat): ν = 2979, 2934, 1734, 1635, 1366, 1259, 1183, 701 cm–1.
˜
HRMS calcd. for C23H35NO6S [M + H]+ 454.2263; found
454.2263. HPLC Chiracel AD-H 93:7 (hexane/EtOH), 210 nm,
0.5 mL min–1, retention time 10.6 min (minor) and 14.4 min
(major).
[1] For selected review articles of tandem organocatalytic reac-
tions, see: a) H.-C. Guo, J.-A. Ma, Angew. Chem. 2006, 118,
362; Angew. Chem. Int. Ed. 2006, 45, 354–366; b) D. Enders,
C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119, 1590;
Angew. Chem. Int. Ed. 2007, 46, 1570–1581; c) Z. Shao, H.
Zhang, Chem. Soc. Rev. 2009, 38, 2745–2755; d) J. Zhou, Chem.
Asian J. 2010, 5, 422–434; e) C. Zhong, X. Shi, Eur. J. Org.
Chem. 2010, 2999–3025; f) N. T. Patil, V. S. Shinde, B. Gajula,
Org. Biomol. Chem. 2012, 10, 211–224.
[2] For selected recent articles of tandem organocatalytic reactions
with transition-metal complexes, see: a) S. L. Poe, M. Kobasˇ-
lija, D. T. McQuade, J. Am. Chem. Soc. 2006, 128, 15586–
15587; b) S. L. Poe, M. Kobasˇlija, D. T. McQuade, J. Am.
Chem. Soc. 2007, 129, 9216–9221; c) B. Simmons, A. M. Walji,
D. W. C. MacMillan, Angew. Chem. 2009, 121, 4413; Angew.
Chem. Int. Ed. 2009, 48, 4349–4353; d) S. Chercheja, S. K. Na-
dakudity, P. Eilbracht, Adv. Synth. Catal. 2010, 352, 637–643;
e) A. Quintard, A. Alexakis, Adv. Synth. Catal. 2010, 352,
1856–1860; f) S. Lin, G.-L. Zhao, L. Deiana, J. Sun, Q. Zhang,
H. Leijonmarck, A. Córdova, Chem. Eur. J. 2010, 16, 13930–
13934; g) A. Quintard, A. Alexakis, C. Mazet, Angew. Chem.
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h) M. Rueping, H. Sundén, L. Hubener, E. Sugiono, Chem.
Commun. 2012, 48, 2201–2203.
Diethyl 2-[1-Cyclopropyl-3-oxo-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)propyl]malonate (7c): The representative experimental pro-
cedure was applied to compound 7a (24 mg, 0.25 mmol) for 24 h
1
to yield product 7c (45 mg, 44%). H NMR (CDCl3, 400 MHz): δ
= 0.22 (m, 2 H), 0.48 (m, 2 H), 0.92 (m, 1 H), 1.11 (d, J = 8.4 Hz,
7 H), 1.18 (d, J = 8 Hz, 6 H), 1.26 (m, 6 H), 1.42 (m, 6 H), 1.95
(m, 1 H), 3.77 (d, J = 7.2 Hz, 1 H), 4.20 (m, 4 H), 4.39 (m, 1 H),
9.85 (m, 1 H) ppm. 13C NMR (CDCl3, 100 Hz): δ = 203.4, 168.8,
168.4, 88.7, 61.8, 61.6, 60.2, 53.3, 45.3, 40.6, 40.3, 34.9, 34.3, 20.9,
7.5, 14.5, 10.9, 5.6, 5.2 ppm. IR (neat): ν = 2935, 1732, 1466, 1372,
˜
1146 cm–1. HRMS calcd. for C22H37NO6 [M + H]+ 412.2699;
found 412.2699. HPLC Chiracel AS-H 99:1 (hexane/EtOH),
210 nm, 0.5 mL min–1, retention time 10.2 min (major) and
11.9 min (minor).
Diethyl 2-[1-(4-Bromophenyl)-3-oxo-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)propyl]malonate (8c): The representative experimental pro-
cedure was applied to compound 8a (53 mg, 0.25 mmol) for 48 h
1
to yield product 8c (73 mg, 55%). H NMR (CDCl3, 400 MHz): δ
[3] H.-S. Yoon, X.-H. Ho, J. Jang, H.-J. Lee, S.-J. Kim, H.-Y. Jang,
Org. Lett. 2012, 14, 3272–3275.
[4] X.-H. Ho, H.-J. Oh, H.-Y. Jang, Eur. J. Org. Chem. 2012, 5655–
5659.
= 0.96–1.00 (m, 6 H), 1.06 (s, 3 H), 1.19–1.22 (m, 6 H), 1.25–1.28
(m, 5 H), 1.41 (m, 4 H), 3.90–3.93 (m, 2 H), 3.97 (d, J = 2.8 Hz, 2
H), 4.19–4.25 (m, 2 H), 4.46 (m, 1 H), 7.09 (d, J = 8.4 Hz, 2 H),
7.38 (d, J = 8.4 Hz, 2 H), 9.68 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 100 Hz): δ = 13.9, 14.2, 17.2, 20.7, 34.2, 34.3, 40.2, 40.4,
45.9, 53.4, 60.2, 61.6, 62.0, 87.1, 121.7, 130.9, 131.3, 134.8, 166.9,
[5] For books on aminocatalysis, see: a) A. Berkessel, H. Gröger,
Asymmetric Organocatalysis, Wiley-VCH, Weinheim, Ger-
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Reactions and Experimental Procedures, Wiley-VCH,
Weinheim, Germany, 2007; c) D. W. C. MacMillan, G. Lelais
New Frontiers in Asymmetric Catalysis (Eds.: K. Mikami, M.
Lautens), John Wiley & Sons, Hoboken, USA, 2007.
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Commun. 2006, 819–824; c) C. Palomo, A. Mielgo, Angew.
Chem. 2006, 118, 8042; Angew. Chem. Int. Ed. 2006, 45, 7876–
7880; d) M. J. Gaunt, C. C. C. Johansson, A. McNally, N. T.
Vo, Drug Discovery Today 2007, 12, 8–27; e) A. Erkkilä, I. Ma-
jander, P. M. Pihko, Chem. Rev. 2007, 107, 5416–5470; f) Y.
Zhang, W. Wang, Catal. Sci. Technol. 2012, 2, 42–53.
[7] For selected articles relating to malonate addition to α,β-unsat-
urated carbonyl compounds with the aid of iminium catalysis,
see: a) M. Yamaguchi, T. Shiraishi, M. Hirama, Angew. Chem.
1993, 105, 1243; Angew. Chem. Int. Ed. Engl. 1993, 32, 1176–
1178; b) M. Yamaguchi, T. Shiraishi, M. Hirama, J. Org. Chem.
1996, 61, 3520–3530; c) N. Holland, P. S. Aburel, K. A.
Jørgensen, Angew. Chem. 2003, 115, 685; Angew. Chem. Int.
Ed. 2003, 42, 661–665; d) K. R. Knudsen, C. E. T. Mitchell,
S. V. Ley, Chem. Commun. 2006, 66–68; e) S. Brandau, A.
Landa, J. Franzén, M. Marigo, K. A. Jørgensen, Angew. Chem.
2006, 118, 4411; Angew. Chem. Int. Ed. 2006, 45, 4305–4309;
f) Y. Wang, L. Pengfei, X. Liang, J. Ye, Adv. Synth. Catal. 2008,
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tin, Eur. J. Org. Chem. 2009, 5134–5137; h) X. Companyó, M.
167.4, 203.7 ppm. IR (neat): ν = 3054, 2986, 1422, 1265, 747 cm–1.
˜
HRMS calcd. for C25H36BrNO6 [M + H]+ 526.1802; found
526.1802. HPLC Chiracel AD-H 95:5 (hexane/iPrOH), 210 nm,
0.5 mL min–1, retention time 18.6 min (minor) and 29.0 min
(major).
Ethyl 1-Benzyl-4-(4-bromophenyl)-2-oxo-5-(2,2,6,6-tetramethyl-
piperidin-1-yloxy)piperidine-3-carboxylate (8d): The mixture of 8c
(55 mg, 0.104 mmol), sodium cyanoborohydride (0.135 mmol),
benzylamine (0.156 mmol), and acetic acid (2–3 drops) in dioxane
(5 mL) was stirred at 40 °C for 18 h to yield 8d (39.3 mg, 66%). 1H
NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 8.5 Hz, 2 H), 7.32 (m,
5 H), 7.20 (d, J = 8.5 Hz, 2 H), 5.40 (d, J = 14.5 Hz, 1 H), 4.32 (s,
1 H), 4.21 (d, J = 12.0 Hz, 1 H), 4.11 (m, 2 H), 3.87 (dd, J = 14.0,
1.0 Hz, 1 H), 3.77 (d, J = 14.0 Hz, 1 H), 3.57 (dd, J = 12.5, 2.0 Hz,
1 H), 3.27 (dd, J = 13.5, 3.5 Hz, 1 H), 1.22–1.49 (m, 6 H), 1.13 (t,
J = J = 7.0 Hz, 3 H), 1.07 (s, 3 H), 0.95 (s, 3 H), 0.78 (s, 3 H), 0.64
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 169.9, 166.0,
137.2, 136.2, 131.3, 130.3, 128.7, 128.5, 127.6, 121.2, 76.0, 61.3,
59.7, 50.3, 49.4, 48.9, 45.4, 40.6, 40.4, 34.1, 32.5, 21.1, 20.6, 16.9,
14.0 ppm. HRMS calcd. for C30H39N2O4 [M + H]+ 573.2156;
found 573.2175. IR (neat): ν = 2930, 1737, 1649, 1490, 1368, 1241,
˜
1152, 1075, 1010 cm–1.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30333
/KAP1
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Pages: 9
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Received: March 6, 2013
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