General and efficient α-oxygenation of carbonyl compounds by TEMPO induced by single-electron-transfer oxidation of their enolates

Job/Unit: O20736

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FULL PAPER

DOI: 10.1002/ejoc.201200736

General and Efficient α-Oxygenation of Carbonyl Compounds by TEMPO

Induced by Single-Electron-Transfer Oxidation of Their Enolates

[a]

[b]

[a]

[c]

ˇ

Emanuela Dinca, Philip Hartmann, Jakub Smrcek, Ina Dix, Peter G. Jones, and

Ullrich Jahn*^[b]

Keywords: Oxidation / Radicals / Electron transfer / Carbonyl compounds / Enolates

A generally applicable method for the synthesis of protected

α-oxygenated carbonyl compounds is reported. It is based on

the single-electron-transfer oxidation of easily generated

enolates to the corresponding α-carbonyl radicals. Coupling

with the stable free radical TEMPO provides α-(piperidin-

yloxy) ketones, esters, amides, acids or nitriles in moderate-

to-excellent yields. Enolate aggregates influence the out-

come of the oxygenation reactions significantly. Competitive

reactions have been analyzed and conditions for their minim-

ization are presented. Chemoselective reduction of the prod-

ucts led to either N–O bond cleavage to α-hydroxy carbonyl

compounds or reduction of the carbonyl functionality to

monoprotected 1,2-diols or O-protected amino alcohols.

Introduction

Polyfunctional oxygen-containing compounds are very

important in all areas of chemistry and biology. Accord-

ingly, there is a high demand for methods for their selective

synthesis. An important subclass is formed by α-oxygenated

carbonyl compounds, which are a common motif in biolo-

gically active natural products or pharmaceuticals I–III

(Figure 1).^[1]

A number of methods, such as glycolate enolate alkyl-

ations,^[2]epoxidations,^[3]dihydroxylations^[4]or aminohy-

droxylations,^[5]are available for the synthesis of these com-

pounds. Recently, organocatalytic oxygenation reactions

with nitrosobenzene,^[6]TEMPO (1),^[7]peroxides^[8]or oxy-

gen^[9]have been developed. These methods are, however, Figure 1. Natural products and drugs displaying α-oxy carbonyl

motifs.

mostly limited to aldehydes as substrates. The most com-

monly applied strategy for synthesizing α-hydroxy carbonyl

compounds is enolate oxygenation^[10]using reagents such and percarbonates, however, these have not generally been

as MoOPH or MoOPD, N-sulfonyloxaziridines^[10c]or per- used.^[10]For β-dicarbonyl compounds^[11a]or oxindoles,^[11b]

oxides. For further selective manipulation, protection of the molecular oxygen can also be used as an oxygenating rea-

generated hydroxy function is often necessary. Some rea- gent.

gents for the introduction of protected oxygen functions are

Our interest in protected α-oxy carbonyl compounds was

also available. Most notable are bis(trimethylsilyl) peroxide sparked through the development of radical cyclization re-

actions in the absence of tin using enolates as precursors

and tandem reactions that combine anionic and radical re-

[a] Institut für Organische Chemie, Technische Universität

Braunschweig,

actions.^[12]Because it is an excellent free-radical trap,

TEMPO (1)^[13]has been used to test the efficiency of oxi-

dative electron transfer with a range of oxidants. These

studies revealed ferrocenium hexafluorophosphate (2) to be

the oxidant of choice. At the same time, it became apparent

that the combination TEMPO/ferrocenium hexafluoro-

phosphate is useful for the preparation of α-oxygenated es-

ters (Scheme 1, EWG = CO₂R).^[14]In parallel, Braslau et

al. reported the oxygenation of ethyl propionate enolate in-

Hagenring 30, 38106 Braunschweig, Germany

[b] Institute of Organic Chemistry and Biochemistry, Academy of

Sciences of the Czech Republic,

Flemingovo námeˇsti 2, 16610 Prague 6, Czech Republic

E-mail: jahn@uochb.cas.cz

Homepage: http://ww w .uochb.cz/web/structure/616.html

[c] Institut für Anorganische und Analytische Chemie, Technische

Universität Braunschweig,

Hagenring 30, 38106 Braunschweig, Germany

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200736.

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E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

FULL PAPER

duced by the CuCl₂/TEMPO combination, the aim being tions to minimize the concentration of α-ester radicals. An

to obtain new initiator units for nitroxide-mediated living- increase in the concentration of the reactants (entry 2) and

radical polymerization reactions.^[15](Tetramethylpiperidin- more significantly an increase in the concentration of

yloxy)malonate was synthesized by the same method and TEMPO (entry 3) had only a small effect.^[19]This was very

applied in radical addition reactions by Studer and co- unexpected because Fischer and co-workers have deter-

workers.^[16]Renaud and Studer and co-workers reported re- mined the rate constant for the coupling of α-ester radicals

cently the α-oxygenation of enol borinates by using 1,^[17a]to TEMPO (1) to range from 6.3ϫ10⁸to

whereas Hayashi et al. oxygenated silyl enol ethers by using 2.3ϫ10⁹m^–1s^–1.^[20]Thus, the applied conditions should not

nitroxyl radicals.^[17b]Moreover, Schämann and Schäfer lead to 5a in significant yields, but furnish radical cross-

used the TEMPO-derived N-oxoiminium salt to oxygenate coupling product 4a selectively.

enolates of β-dicarbonyl compounds and cyclohexanone.^[18]

Table 1. Oxygenation of ethyl heptanoate (3a) by TEMPO (1)/

ferrocenium hexafluorophosphate (2).

Scheme 1. α-Oxygenation of carbonyl compounds.

We present herein a general and considerably improved

method for the high-yielding preparation of α-(tetrameth-

ylpiperidin-1-yloxy) carbonyl compounds B via the enolates

of the major classes of carbonyl compounds

A

(Scheme 1).^[14]We present insights into the chemo- and dia-

stereoselectivity of the oxygenation reaction together with

studies to elucidate the mechanism of the process. We have

also studied the reductive removal of the piperidinyl pro-

tecting group in the presence of the carbonyl group to ac-

cess free α-hydroxy carbonyl compounds C and the compat-

ibility of the tetramethylpiperidinyloxy group with hydride

reduction of the carbonyl groups.

Entry Equiv. Additive Conc.

Yield^[a][%]

[m] 4a^[b]meso-5a^[b]d,l-5a^[b]6a^[b]7a^[c]

1

(equiv.)

1^[d]

2^[d]

3

1.5

2.5

1.5

–

0.075 42

0.2 45

0.075 44

22

15

25

–

20

16

20

25

3

4

trace

11

9

6

4

HMPA 0.075 67

trace trace

(6)^[e]

5

1.1

LiCl (5)

0.1 92

3

–

Results

[a] Isolated yield unless noted otherwise. [b] Yield based on starting

material, configuration assigned according to ref.^[21][c] Inseparable

diastereomeric mixture. [d] 1.3 equiv. LDA, THF, –78 °C, 30 min,

Initially, the reaction conditions were optimized with

non-volatile ethyl heptanoate (3a). Thus, 3a was deproton-

ated to the enolate, which was followed by the addition of then addition of 1, followed by portionwise addition of 2 until con-

sumption ceased. [e] 6 equiv. based on 3a.

TEMPO (1). Ferrocenium hexafluorophosphate (2) was

subsequently added in small portions until it was no longer

consumed, which can be easily monitored by the change in

color from orange to blue (Table 1). α-Oxygenated ester 4a

HMPA as an additive increased the yield of 4a, but did

was isolated in moderate yield. Several other products, not prevent the formation of dimers 5a (entry 4). More sur-

namely dimerization products 5a, β-keto ester 6a and tri- prisingly, only the d,l diastereomer was formed in this ex-

merization products 7a, were also found (Table 1, entry 1). periment. Significantly, the addition of 4–6 equiv. of anhy-

Thus, the overall mass balance of products 4a–7a based on drous LiCl under otherwise identical conditions led to a

3a was good. The formation of undesired Claisen condensa- dramatic increase in the yield of 4a to 92% and an almost

tion product 6a was minimized by adding a THF solution complete suppression of the formation of dimers 5a (en-

of 3a dropwise to LDA, and performing the deprotonation try 5).^[22]

of 3a for less than 20 min at –78 °C suppressed the forma-

Prompted by these results, the reactions of a number of

tion of 7a. The selection of the base was important. esters 3b–l were investigated to define the scope of the

LiHMDS afforded comparable or somewhat lower overall method and to discover the factors influencing the course

yields of 4a, whereas neither NaHMDS nor KHMDS were of the reactions (Table 2).

effective. The formation of substantial amounts of dimers

The size of the ester group, as in tert-butyl heptanoate

5a was unexpected because a high concentration of 1 was (3b), had only a marginal effect on the efficiency of the

present from the beginning and 2 was added in small por- oxygenation reaction compared with 3a (Table 2, entries 1–

2

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α-Oxygenation of Carbonyl Compounds

Table 2. Oxygenation of esters 3 with 1 and 2.

Entry

3

R¹

R²

R³

R⁴

Additive

(equiv.)

Yield^[a][%]

5^[b](meso/d,l)

4

Others

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

b

tBu

nBu

Et

H

Me

–

53

72

86

87

76

75

42

72

89

28 (5.2:1)

19 (1:1)

–

3b 7

–

HMPA (6)

LiCl (6)

b

–

c

Et

4 (1:0)

trace

–

23 (2.3:1)

20 (1:2.3)

trace

6 (1:1)

7 (1:1)

–

d

prenyl^[c]

H

e

–CH₂–

LiCl (6)

f

Et

Me

Et

iPr

–

6f 10, 7f 14

f

HMPA (6)

LiCl (6)

6f 3

–

f

g

Ph

–

94

93

56

g^[d]

h

–(CH₂)₂–

Et

Me

i

Me

OH

H

91^[e,f]

89^[g,f]

90^[i,f]

73^[j,f]

94^[l,f]

77^[n,f]

95

HMPA (6)

trace

j^[h]

k^[k]

k^[m]

l

–

Et

Me

HMPA (6)

–

LiCl (4.7)

–

Me

CO₂Me

Me

l

Me

H

HMPA (6)

92

[a] Isolated yield unless noted otherwise. [b] Yield based on starting material, configuration assigned according to ref.^[21][c] Prenyl =

(H₃C)₂C=CHCH₂–. [d] Reaction on a 50 mmol scale. [e] 2:1 syn/anti mixture. [f] Assignment of configuration after deprotection (see

below). [g] 1.75:1 syn/anti mixture. [h] 2.5 equiv. LDA, deprotonation for 30 min. [i] 1:2.85 syn/anti. [j] 1:3.3 syn/anti. [k] 2.5 equiv. LDA,

deprotonation for 1 h at –78 to –50 °C. [l] 1:2 syn/anti. [m] 2.3 equiv. LDA, deprotonation for 30 min. [n] 1:1.4 syn/anti.

3, cf. Table 1). Esters with linear chains, such as 3c,d, and termediate alkoxyl radicals were detected. It should be

esters branched in remote positions, such as 3f, afforded noted that the hydroxy groups in 3j,k have to be unprotec-

the oxygenated products 4c,d,f in good-to-excellent yields ted because OH-protected derivatives underwent elimi-

provided that the oxygenation reaction was performed in nation to the corresponding α,β-unsaturated esters on de-

the presence of LiCl (entries 4, 5 and 9). A potential 5-exo protonation (not shown). The oxidant ferrocenium hexaflu-

cyclization did not compete with the oxygenation of 3d (en- orophosphate (2) is recyclable. The reduced ferrocene was

try 5). Butyrolactone 3e also gave a good yield of the oxy- recovered from the oxygenation reactions as the most apo-

genated compound with 6 equiv. of LiCl (entry 6). The α- lar component by column chromatography. Alternatively, it

or β-branched esters 3g–l provided the TEMPO adducts can be removed by sublimation from the reaction mixture

4g–l in good-to-excellent yields even in the absence of LiCl of non-volatile apolar products. Ferrocene was routinely

(entries 10–20). The reaction was scaled up to 50 mmol with collected, recrystallized and reoxidized to 2 by simply stir-

3g giving essentially the same yield of 4g as on the small ring it in concentrated sulfuric acid followed by precipi-

scale (entries 10 vs. 11). The 2-cyclopropylacetate 3h pro- tation with aqueous KPF₆solution.^[12c]

vided the ring-closed product exclusively (entry 12).

The oxidative enolate oxygenation by 1 and 2 is also ap-

Esters with a chiral center at the β position, such as 3i– plicable to other carboxylic acid derivatives such as nitriles

k, were oxygenated in good yields, however, the diastereo- 8a–e and tertiary amides 8f–g (Table 3). Phenylacetonitrile

selectivity remained moderate. Although 3i predominantly (8a) afforded 93% of 9a; a somewhat lower yield was ob-

provided the syn diastereomer (entries 13 and 14), hydroxy tained in the presence of LiCl (Table 3, entries 1 and 2).

esters 3j and 3k gave the anti isomer as the major dia- Aliphatic linear and branched nitriles 8b,d provided the ad-

stereomer (entries 15–18). The configurations of the major ducts 9b and 9d in very good yields (entries 3, 4 and 6).

isomers were assigned after reductive cleavage of the tet- Similarly to the corresponding ester, cyclopropylacetonitrile

ramethylpiperidinyl unit by comparison with the known 2- (8c) afforded ring-closed product 9c exclusively in 80%

hydroxy esters (see below). It is remarkable that the oxi- yield (entry 5). An unprotected alcohol function is tolerated

dation of the intermediate dianions of 3j,k was very chemo- because 3-hydroxy-3-methylbutyronitrile (8e) gave the oxy-

selective towards the enolate. No products derived from in- genated derivative 9e in high yield (entry 7).

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FULL PAPER

Table 3. Oxygenation of nitriles and acyclic tertiary amides 8a–i.

LiHMDS^[23]followed by oxygenation provided lactam 9k

as the sole product in 70% yield as a 1:1.2 diastereomeric

mixture at the newly formed stereocenter with complete re-

tention of the configuration at C-2. The enantiomeric pu-

rity of the diastereomers of 9k was confirmed by HPLC

using a DAICEL-OD column. However, an excess of base

must be avoided because the use of 1.3 equiv. of LiHMDS

led to epimerization and a decrease in the enantiomeric ex-

cess of the diastereomers to 78 and 81%, respectively.

The relative configuration of the minor diastereomer

(2S,4R)-9k was proved by X-ray crystallography (Fig-

ure 2).^[24]The trans orientation of the substituents is clearly

established. The relative configuration of (2S,4S)-9k was

confirmed by NOE measurements.

Entry

8

EWG

R¹

R²

Additive Yield of

(equiv.)

9 [%]

1

2

3

4

5

6

7

8

9

a

b

c

CϵN

Ph

C₆H₁₃

c-C₃H₅

CH₃

H

CH₃

H

CH₃

H

–

93

73

78

92

80

76

99

94

LiCl (4.7)

–

LiCl (4.7)

–

d

e^[a]CϵN

C(OH)(CH₃)₂

C₃H₇

C₄H₉

CH₃

(CH₂)₂CONMe₂

LiCl (6)

–

LiCl (6)

–

f

g

h

CONEt₂

CONBn₂

CONMe₂

74

10

13^[b]

28^[d]

11 i^[c]CONMe₂

LiCl (6)

[a] Deprotonation with 2.3 equiv. LDA at –78 to –50 °C for 35 min.

[b] A very polar material containing an isobutyramide unit, the

structure of which could not be determined, was the major product.

[c] Deprotonation with 2.3 equiv. LDA. [d] Twofold oxygenation

giving a 4:1 mixture of d,l/meso-diastereomers.

The acyclic N,N-disubstituted amides 8f,g were oxygen-

ated in good yields (entries 8 and 9). The α-branched N,N-

dimethylamide 8h, in contrast, provided 9h in only low yield

(entry 10). Dioxygenation succeeded with 8i to give a 4:1

d,l/meso diastereomeric mixture of 9i in moderate yield (en-

try 11). The configuration was assigned on the basis of the

NMR spectroscopic data.

N-Methylpyrrolidone 8j gave the oxygenated lactam 9j in

yields of 50 and 57% in the absence and presence of LiCl,

respectively (Scheme 2). (S)-N-Boc-pyroglutamate 8k was

also tested to check the compatibility with a potentially la-

bile stereocenter.^[23]Deprotonation with 1.05 equiv. of

Figure 2. X-ray crystallographic view of (2S,4R)-9k.

The performance of the enediolate 10^–derived from

heptanoic acid (10) was also tested (Scheme 3). In line with

literature precedent, two-fold deprotonation was more ef-

ficiently accomplished by using lithium diethylamide in

THF instead of LDA.^[25]SET oxidation/oxygenation gave

moderate yields of the α-oxygenated acid 11. In addition to

Scheme 2. Oxygenation of lactams 8j,k by 1 and 2.

Scheme 3. Oxygenation of heptanoic enediolate 10^–.

4

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α-Oxygenation of Carbonyl Compounds

substantial amounts of recovered 10, the dimerization and the major products were the dimers 16h,i in yields of 59

disproportionation products 12 and 13 were also isolated. and 55%, respectively, which were formed moreover with

Addition of LiCl increased the yield of 11 to 51%, however, excellent d,l/meso diastereoselectivities of 10.5:1 and 45:1

the formation of 12 and 13 could not be further suppressed. (entries 12 and 15). Such a high selectivity has never before

Aliphatic acyclic and cyclic ketones 14a–d afforded good- been detected in an oxidative dimerization reaction of un-

to-excellent yields of oxygenated derivatives 15a–d (Table 4, hindered substrates.^[27]Addition of HMPA, or better, anhy-

entries 1–6). Addition of LiCl improved the yield of 15a drous LiCl increased the yield of the oxygenation product

only slightly (entry 2). In contrast, cyclopentanone in the 15h, and the yield and d,l/meso diastereoselectivity of 16h

absence of LiCl gave reproducibly low yields of 15e (en- decreased correspondingly (entries 13 and 14). The effect of

try 7). This was compounded by decomposition during LiCl was similar to that observed in the reactions of un-

workup, as evidenced by the change in color observed on branched esters (see above). In contrast, the oxygenation of

concentration of the reaction mixture. Addition of LiCl and isobutyrophenone (14j) provided a poor yield of 15j (en-

careful workup improved the yield to 84% (entry 8). A try 17) even though a stoichiometric amount of oxidant 2

good yield was obtained in the oxygenation of camphor, was consumed as fast as in the other experiments, which

but no diastereoselectivity was observed (entries 9 and 10). suggests that at least the enolate oxidation reaction oc-

This is in contrast to polar oxygenation reactions of 14f in curred as desired. These results imply differences in the oxy-

which good-to-high diastereoselectivities for either the exo genation of aliphatic and aromatic ketones.

or endo isomer were often found.^[26]Cyclohexenone (14g),

In contrast to ketones 14a–j, unsymmetrical aliphatic

as an α,β-unsaturated ketone, afforded the oxygenated com- methyl ketones 14k–m gave only low yields of the desired

pound 15g, however, the use of lithium chloride was man- oxygenated compounds 15k–m (Table 5). Surprisingly,

datory to achieve a reasonable yield (entry 11).

products 17 resulting from an aldol addition of the initially

Aromatic ketones displayed more complex behavior in formed products 15k–m with 14k–m were the major prod-

the oxygenation reactions (entries 12–17). Propio- and ucts (entries 2, 3, 5 and 6). Addition of anhydrous LiCl

butyrophenone 14h,i gave excellent combined yields of radi- proved to be beneficial to prevent undesired dimerization

cal-derived products 15h,i and 16h,i after deprotonation to compounds 16 and 18, which competed to some extent

with LDA in the absence of additives, but only moderate (entries 4, 6 vs. 3, 5). It had, however, no significant effect

yields of 30 and 38% of 15h,i, respectively. Unexpectedly, on the ratio of 15 and 17 (entries 1, 2, 4 and 6). The regiose-

Table 4. Oxygenation of ketones 14a–j.^[a]

Entry

14

R¹

R²

R³

Additive

(equiv.)

Yield^[a][%]

16 (meso/d,l)^[c]

15 (dr)

1

2

3

4

5

6

7

8

9

10

11^[f]

12

13

14

15

16

17

a

b

c

d

e

f

Et

tBu

Me

H

–

78

90

94

85

77

87

32

–

LiCl (6)

–

–(CH₂)₄–

–

LiCl (4.7)

–

LiCl (6)

–

LiCl (4.7)

LiCl (5)

–

HMPA (6)

LiCl (4.7)

–

9 (2.5:1)

–(CH₂)₄–

–(CH₂)₅–

–(CH₂)₃–

–

84

–

2 (exo,exo)^[e]

–

(R)-camphor

–(CH₂)₂CH=CH–

85 (1:1.1)^[d]

f

95 (1.1:1)^[d]

g

h

i

j

H

Me

56

30

52

78

38

–

Ph

Me

Et

Me

59 (1:10.5)

47 (1:6)

21 (1:5)

55 (1:45)

30 (0:1)

–

LiCl (4.7)

–

70

18^[g]

[a] Deprotonation with 1.3 equiv. LDA at –78 °C for 20 min. [b] Isolated yields. [c] Yield, based on starting ketone. [d] exo/endo ratio. [e]

Configuration assigned according to ref.^[28][f] Only 0.9 equiv. of 1 was used. [g] 62% of 14j recovered.

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Table 5. Oxygenation of methyl ketones 14k–m.

Entry

14

R¹

R²

Additive

(equiv.)

Yield [%]

15+15Ј

17+17Ј

16+18

19

(15/15Ј)^[a]

(16/18)

1^[b]

2^[c]

3^[c]

4^[c]

5^[f]

6^[g]

k

l

C₅H₁₁

H

LiCl (6)

–

LiCl (6)

–

37 (8.8:1)

29 (12:1)

16 (1.9:1)

43 (7.4:1)

4 (1:0)

24+trace

30+trace

26+0

trace

–

14 (1.3:1)

–

42 (1:1)

trace

14

–

9

–

prenyl^[d]

l

19+0^[e]

50+0

m

c-C₃H₅

LiCl (6)

23 (1:0)

68+0

–

[a] Ratio determined by ¹H NMR spectroscopy. [b] Deprotonation for 30 min. [c] Deprotonation for 5 min. [d] Prenyl = (H₃C)₂-

C=CHCH₂–. [e] With traces of an unknown isomer. [f] Deprotonation for 20 min. [g] Deprotonation for 10 min.

lectivity of the deprotonation/oxygenation is generally good

because compounds 15Ј and 17Ј were formed to only a

minor extent, if at all (entries 1, 2 and 4–6).

The unexpected formation of dimers and even more of

ring-closed cyclopropane derivatives 4h and 9c (Table 2, en-

try 12; Table 3, entry 5) cast doubt on the involvement of a

radical coupling reaction with 1. Therefore the significantly

more sensitive 2-phenylcyclopropane probes 22 and 23 were

used in the oxygenation reactions (Scheme 4).^[29]They were

synthesized in a straightforward manner by a Simmons–

Smith cyclopropanation of cinnamic alcohol (20),^[30]fol-

lowed by the bromination of 21.^[31]Kolbe nitrile synthesis

furnished 22,^[32]which was transformed by hydrolysis and

alkylation into (2-phenylcyclopropyl)acetate 23 in good

overall yield. The oxygenation of 23 indeed exclusively pro-

vided ring-opened products 24 and 25. TEMPO-coupling

product 24 formed initially, and apparently exclusively, but

transformed under ambient conditions into ethyl 5-phenyl- Scheme 4. Synthesis of probe 23 and its oxygenation by 1 and 2.

6

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α-Oxygenation of Carbonyl Compounds

2,4-pentadienoate (25), as indicated by the conversion of an ramethylpiperidinyloxy)propiophenone (15h) was an excep-

NMR sample containing a 5:1 mixture of 24/25 into a 1:1.4 tion. Its reduction under identical conditions did not give

mixture of 24/25 at room temperature over 80 h. Under the corresponding adduct 28h, but afforded propiophenone

identical conditions nitrile 22 gave a complex mixture in 14h in quantitative yield (not shown). Thus, the method

which no cyclopropane resonances were detected.

may not be suited to reductive N–O bond cleavage with

aromatic ketones, which have a significantly lower re-

duction potential than other carbonyl compounds.^[36]The

initial electron transfer in 15h occurs not to the N–O bond,

but to the ketone leading to a ketyl radical anion, which

undergoes a facile β-fragmentation of 1 with the re-forma-

tion of 14h.

Recently, an oxidative deprotection of N-alkoxy-2,2,6,6-

tetramethylpiperidines leading to aldehydes or ketones was

reported.^[37]Although this method is indeed generally ap-

plicable to alkyl or allyl derivatives,^[12d,12f]it gave a complex

mixture when applied to 15c or 15d.

Reductive Cleavage of the Alkoxyamine Function to α-

Hydroxy Carbonyl Compounds

Selected α-aminoxy carbonyl compounds 4, 9 and 15 fur-

nished α-hydroxy carbonyl compounds 26–28, mostly in

good yields, on treatment with excess zinc powder in acetic

acid at 50 °C for 30–60 min (Table 6, entries 1–8, 10, 11 and

13–16).^[33,34]The deprotection can be performed in the pres-

ence (Method 1) or absence (Method 2) of water, the latter

being especially advantageous if hydrophilic products are

formed. The workup procedure was also crucial. Initially,

The chemoselective reduction of the carbonyl groups in

simple filtration through silica gel was used to remove ex- carboxylic acid derivatives 4 and 9 was accomplished by the

cess zinc and all salts (Conditions A–C and E). Different use of hydride reagents. The oxygenated esters 4c and 4g

conditions were subsequently applied to obtain optimal re- were reduced chemoselectively at the ester function by lith-

sults for hydrophobic (Conditions A, B and E), hydrophilic ium aluminium hydride, providing monoprotected 1,2-diols

(Condition D) and volatile (Conditions B and C) products. 29c and 29g in high yields (Scheme 5). No N–O bond cleav-

The diastereomeric ratios of the hydroxy compounds age was observed. Compound 29c is interesting in its own

26i–k and 28f did not differ significantly in comparison right because it can be used as an initiator in nitroxide-

with those of the starting materials 4i–k and 14f (entries 5– mediated living radical polymerization.^[38]Butyrolactone 4e

8 and 16). The relative configurations of the hydroxy esters can be reduced similarly to the monoprotected triol 29e.

26i–k^[35]and ketone 28f^[26]were assigned by comparison of The O-protected cyanohydrins 9a,b underwent selective re-

their NMR spectra with those of authentic material. α-(Tet- duction of the nitrile function, similarly affording O-pro-

Table 6. Reductive N–O bond cleavage for the synthesis of α-hydroxy carbonyl compounds 26–28.

Entry

4,9,15

EWG

R¹

R²

R³

Method/condition

Product [%]

1

2

3

4

5

6

7

8

9

10

11

12^[f]

13

14

15

16

4a

4b

CO₂Et

CO₂tBu

C₄H₉

H

Me

H

1/A

2/B

2/A

1/C

1/A

26a 86

26b 94

4e

–CO₂CH₂–

26e 63

4g

4i

4j

CO₂Et

CO₂Me

CO₂Et

CO₂Me

CN

CONEt₂

COtBu

Ph

26g 85

Et

Me

CO₂Me

Me

C₆H₁₃

Et

Me

OH

H

26i 84^[a]

26j 84^[b]

26k 80^[c]

26k 62^[d]

26l 52^[e]

27b 94

1/A

4k

4l

2/D

1/C

1/A

2/B

1/C

1/B

9b

9f

27f 83

9f

27f 44

15b

15c

15d

15f^[g]

H

28b 71

–CO(CH₂)₃–

–CO(CH₂)₄–

(R)-camphor-3-yl

28c 90

28d 77

1/A, 1/E

28f 71, 28f 87

[a] syn/anti ratio of 1.75:1 as in the starting material 4i. [b] syn/anti ratio of 1:11.5 as in the starting material 4j. [c] Starting with a anti/syn

ratios of 1:1 gave a 1.2:1 mixture of (2S,3R)/(2S,3S)-26k, whereas a 1:4.5 mixture provided a 1:5 ratio of (2S,3R)/(2S,3S)-26k. [d] Starting

with an anti/syn ratio of 8:1 gave an 8:1 mixture of (2S,3R)/(2S,3S)-26k. [e] Yield losses are attributable to the volatility of the product.

[f] Only 20 equiv. of zinc dust were used with a reaction time of 9 h. [g] Both diastereomers of 15f gave the same results. No epimerization

was observed.

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tected amino alcohols 30a,b in good-to-excellent yields. The dride donor. These results will be the subject of a subse-

reactivity and diastereoselectivity of ketones 15 in reduction quent publication.

reactions vary widely and are dependent on the selected hy-

Discussion

The oxygenation method presented here has a broad

scope: it is applicable to most classes of acidic carbonyl

compounds. Nonetheless, some features, which seem to be

general, need further comment. The reactions proceed by

an initial deprotonation of the carbonyl compounds to the

corresponding enolates 31, which are known to be aggre-

gated in solution (Scheme 6). Typically dimers or tetramers

are formed, but other aggregates have also been found.^[39]

SET oxidation of these enolates 31 by ferrocenium hexa-

fluorophosphate (2) produces α-carbonyl radicals 32, which

are oxygenated by 1 to give compounds 4, 9, 11 or 15

(Path A). An alternative initial oxidation of 1 by 2 to

oxoiminium ion 33 can be discarded because 33 is not

formed from 1 and 2 in the absence of substrate under iden-

tical conditions.^[12e]The competing formation of dimers 5,

12 or 16 from unhindered esters, carboxylic acids and aryl

ketones (Path B) is very surprising given that 2 is added in

very small portions to the reaction mixture, which guaran-

tees that TEMPO (1) is always present in a large excess with

respect to radicals 32. Accordingly, on the basis of the

known rate constants for radical coupling reactions with 1,

this should lead to the selective formation of cross-coupling

Scheme 5. Hydride reduction of selected adducts 4 and 9 derived

from carboxylic acid derivatives.

products.^[20,40]The formation of 5, 12 and 16 indicates in-

Scheme 6. Mechanistic rationalization of product formation in oxygenation reactions (nitriles have been omitted for clarity, but the

rationalization also applies to them).

8

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α-Oxygenation of Carbonyl Compounds

stead that the radicals generated under the reaction condi- be assumed that the chelated alkoxide enolate is oxidized to

tions are not free but at least partially retained in the aggre- a radical in which the chelate remains intact after oxidation.

gates 34. For unhindered linear ester and aryl ketone enol- Coupling with 1 occurs preferentially at the less hindered

ates, these aggregate-bound radicals 34 not only react with face through transition state B to form the anti dia-

1, but add competitively to another enolate unit in the ag- stereomers, similarly to the highly diastereoselective Frater–

gregate, leading to the dimers via transition states such as Seebach alkylation.^[43]

35. This also explains why an increase in the concentration

Another yield-limiting factor was found for methyl

of TEMPO does not prevent dimerization to 5 or 16. ketones 14k–m (Scheme 6). The oxygenated derivatives

Branched esters, nitriles, amides and aliphatic ketones are 15k–m are initially formed in a reliable manner after re-

apparently less well preorganized for such intramolecular gioselective kinetic deprotonation at the methyl group and

addition reactions, and thus dimerization cannot compete oxidation of a part of 31k–m by the slow addition of 2.

with coupling to 1.

However, the aldol addition of unoxidized enolate 31 to

Although no hard structural evidence is available, it is 15k–m competes effectively with further oxidation (Path D).

likely that excess lithium chloride modifies the enolate ag- Because base-mediated aldol additions are known to be

gregates significantly by destroying homoaggregates and fast^[44]for enolates unsubstituted at the α position, and be-

forming mixed enolate–LiCl aggregates 36 (Path C). These cause also the electrophilicity of the carbonyl function is

are easily oxidized by 2 to radicals 37, which couple more increased in 15k–m, this reaction path dominates. It may be

selectively with 1 to provide oxygenated compounds 4, 9, that the initially formed oxygenated compounds 15 remain

11 or 15 in high yield.

bound in aggregates, such as 38, thus facilitating the access

Note that the radicals 32 or 34 derived from cycloprop- to compounds 17 via Zimmerman–Traxler transition states

ylacetate 4h, which has a ring-opening rate constant of 39A or 39B. However, lithium chloride exerts only a limited

2ϫ10⁸s^–1as a free radical,^[41]remain closed to an appreci- influence on the reaction course, and thus intermolecular

able extent on coupling with TEMPO at –78 °C. This indi- reaction pathways may also operate.

cates on the one hand that the rate constant for the cross-

α-(Tetramethylpiperidinyloxy) carbonyl compounds 4, 9

coupling with 1 should not deviate significantly from that and 15 are valuable building blocks in organic synthesis.

determined for the coupling of free α-ester radicals with 1 They can be further manipulated chemoselectively both at

(see above).^[20]On the other hand, it might be that the ring the TEMPoxy group and at the carbonyl group. Com-

opening of an aggregate-bound radical is retarded to some pounds having a benzylic tetramethylpiperidinyloxy unit

extent. The more sensitive 2-phenylcyclopropylcarbinyl rad- may be especially valuable as initiators in nitroxide-medi-

ical derived from 23 leads in contrast to complete ring ated living-radical-polymerization reactions.^[13a,45]The

opening after oxidation. The different behaviors of 4h and products 9a–e are interesting in their own right because

23 demonstrate clearly that a radical coupling mechanism they represent a new class of O-protected cyanohydrins that

operates and that the coupling of potentially aggregate- may prove useful as substrates in umpolung or C₁chain-

bound radicals with TEMPO (1) remains facile.

shortening reactions.

The ease of cross-coupling of radicals derived from esters

3i–k, ethyl pyroglutamate 8k or camphor 14f with 1 also

provides a rationale for the generally low-to-moderate dia-

stereoselectivities. Whereas the polar oxygenation or alkyl-

ation reactions of these substrates, which occur with good-

to-high diastereoselectivity, are rather slow, the radical cou-

pling with 1 proceeds faster by several orders of magnitude

Conclusions

A generally applicable methodology for the synthesis of

and consequently through much earlier transition states in α-oxygenated carbonyl compounds has been developed that

which subtle steric effects apparently do not play such a displays a wide scope and good chemoselectivity. The SET

significant role. The preferred syn selectivity for the forma- oxidation of the enolate generated by a simple deproton-

tion of 4i can be explained by transition state A, in which ation of the starting carbonyl compound proceeds reliably

the best σ donor is oriented coplanar with respect to the α- for all compounds by using ferrocenium hexafluorophos-

carbonyl radical and the attack of 1 proceeds antiperiplanar phate (2). The intramolecular addition of aggregate-bound

to it (Figure 3).^[42]In the oxygenation of 3j and 3k it can radicals to enolate units competes efficiently in unhindered

substrates leading to the competitive formation of dimeriza-

tion products. This limitation is overcome by the addition

of lithium chloride leading to mixed aggregates. Their oxi-

dation and coupling with TEMPO (1) furnishes oxygenated

carbonyl compounds in high yields. The tetramethylpiperid-

inyl group can be removed chemoselectively for most sub-

strates except for those having a reduction potential lower

than that of the N–O bond. These insights bear many impli-

cations for the design of new oxidative reaction sequences.

Research along these lines is underway in these laboratories.

Figure 3. Preferred transition states for the radical coupling of 3i

and 3j,k.

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FULL PAPER

For compounds 3j,k and 8e, the deprotonation was performed with

4–4.6 mmol of LDA (for exact amounts see Table 2 and Table 3).

The mixture was stirred at –78 °C for 5–30 min (see Tables 1–5).

Dry HMPA (2.09 mL, 12 mmol) was added through a syringe.

Experimental Section

General: All reactions were conducted in flame- or oven-dried

glassware under nitrogen. THF and CH₂Cl₂were dried following

standard methods under argon. TLC plates POLYGRAM SIL G/

UV₂₅₄(Macherey–Nagel) were used for monitoring the reactions.

Flash column chromatographic separations were performed on sil-

ica gel 60 (Fluka, 230–400 mesh). IR spectra were recorded with a

Bruker ALPHA FT-IR spectrometer as neat samples using an ATR

device. Solid samples were analyzed as a KBr tablet with a Nicolet

320 FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded,

unless otherwise noted, in CDCl₃with Bruker Avance 500 and 400

TEMPO (1; 343 mg, 2.2 mmol) was added in one portion at –78 °C

and the mixture was stirred until it dissolved (ca. 5 min). For 8i,

4.2 mmol of TEMPO was used. Ferrocenium hexafluorophosphate

(2) was added in small portions at –78 °C as it was consumed (the

blue color of the oxidant disappears when added to the enolate

solution). Addition was continued until the reaction mixture re-

mained dark blue (0.993–1.32 g, 3.0–3.7 mmol; for 8i a minimum

of 4 mmol of 2 was added). Stirring was continued at –78 °C for

15 min to 1 h and the reaction was monitored by TLC [ferrocene

R_f= 0.9 (hexane/EtOAc, 10:1) and TEMPO R_f= 0.4 (hexane/

EtOAc, 10:1)]. The reaction was quenched with 3–10 drops of

water, diluted with diethyl ether (20 mL), warmed to room tem-

perature and filtered through a pad of silica gel, which was washed

with diethyl ether. The solvent was evaporated in vacuo, the in-

homogeneous mixture was pre-adsorbed on silica gel, added to a

filled column and purified by flash chromatography.

1

spectrometers at 500.0 and 400.1 MHz for H NMR or 125.7 and

100.6 MHz for ¹³C NMR, or with a Bruker AC-200 spectrometer

1

at 200.1 MHz for H NMR and 50.1 MHz for ¹³C NMR, respec-

tively. Connectivities were determined by ¹H–¹H COSY experi-

ments. Relative configurations were determined by NOE or

NOESY experiments. ¹³C NMR assignments were obtained from

DEPT and HSQC experiments. EI mass spectra were recorded with

a Waters GCT Premier spectrometer at 70 eV. ESI mass spectra

were recorded with a Thermo Fisher Scientific LCQ Fleet spec-

trometer, sample concentration approx. 1 μg/mL, spray voltage

positive mode: 3.3 kV. HRMS spectra were measured with a Waters

Q-Tof micro spectrometer at a resolution of 100000. Combustion

analyses were performed at the microanalytical laboratories of

Technische Universität Braunschweig and IOCB AS CR Prague.

Ethyl 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)heptanoate (4a): Iso-

lated by flash chromatography (hexane/EtOAc, 60:1, from the be-

ginning of TEMPO elution 20:1). For yields and ratios, see Table 1.

The dimer 5a,^[14]if formed, was repurified after sublimation of

TEMPO (hexane/EtOAc, 40:1). Colorless oil. IR (film): ν = 2957,

˜

2934, 2872, 1749, 1739, 1467, 1376, 1362, 1261, 1178, 1133,

1042 cm^–1. ¹H NMR (200 MHz): δ = 0.80 (t, J = 6.1 Hz, 3 H,

CH₃CH₂CH₂), 0.97 (s, 3 H, NCCH₃), 1.04 (s, 6 H, NCCH₃), 1.11

(s, 3 H, NCCH₃), 1.17 (m, 2 H, NCCH₂CH₂CH₂CN), 1.21 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.22 (m, 6 H, H₃CCH₂CH₂CH₂), 1.37

(m, 4 H, NCCH₂CH₂CH₂CN), 1.74 (m, 2 H, CH₂CHON), 4.10 (q,

J = 7.1 Hz, 2 H, OCH₂), 4.13 (pseudo-t, J = 7.1 Hz, 1 H,

CHON) ppm. ¹³C NMR (50 MHz): δ = 13.9 (q, CH₂CH₂CH₃),

14.1 (q, OCH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 20.1 (q,

NCCH₃), 22.4 (t, CH₂CH₂CH₃), 24.1 (t, CH₂CH₂CH₂CH₃), 31.6

(t, CH₂CH₂CH₃), 32.0 (t, CH₂CHON), 33.0 (q, NCCH₃), 33.5 (q,

NCCH₃), 40.2 (t, NCCH₂CH₂CH₂CN), 59.3 (s, NCCH₃), 60.1 (s,

NCCH₃), 62.1 (t, OCH₂), 85.7 (d, CHON), 173.6 (s, CO₂) ppm.

MS (+CI): m/z (%) = 314 (100) [M + H]⁺, 313 (6) [M]⁺, 156 (65)

[TEMPO]⁺. C₁₈H₃₅NO₃(313.48): calcd. C 68.96, H 11.25, N 4.47;

found C 68.57, H 11.21, N 4.22.

(2-Phenylcyclopropyl)acetic acid was prepared according to the lit-

erature.^[32]The analytical data are in agreement with those pub-

lished previously. The following compounds had been prepared

previously by using different methods: 4g,^[46]15c,^[7a,18a]15e,^[17a]

15h,^[17a]16m,^[47]19k,^[48]23,^[49]26a,^[50]26i,^[35a]26j,^[35b–35d]26l,^[51]

27b,^[52]28b,^[53]28d,^[54]28f^[26]and 29g.^[55]Their analytical data are

in agreement with those published. Compounds 13, 25, 26e, 26g,

26k and 28c are commercially available. The analytical data of the

prepared compounds are in agreement with those of authentic sam-

ples.

General Procedure for the Synthesis of α-(2,2,6,6-Tetramethylpiper-

idin-1-yloxy) Carbonyl Compounds 4, 9 and 15

General: nBuLi (1.625 mL, 2.6 mmol, 1.6 m solution in hexane) was

added dropwise through a syringe to a solution of dry iPr₂NH

(0.367 mL, 2.6 mmol) in dry THF (19 mL, 0.1 m) at –78 °C. After

stirring at –78 °C for 0.5 h, the substrate 3, 8 or 14 (2.0 mmol)

dissolved in THF (1 mL) was added dropwise at –78 °C. For com-

pounds 3j,k and 8e,i, the deprotonation was performed with 4–

4.6 mmol of LDA (for exact amounts see Table 2 and Table 3). The

mixture was stirred at –78 °C for 5–30 min (see Tables 1–5).

tert-Butyl 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)heptanoate (4b):

Isolation by flash chromatography (hexane/EtOAc, 80:1, from the

beginning of TEMPO elution 20:1); yield 584 mg (86%) as a color-

less oil. R = 0.5 (hexane/EtOAc, 5:1). IR (film): ν = 2930, 1742,

˜

f

1457, 1365, 1258, 1211, 1151, 1132, 1041, 991, 975, 958, 917, 845,

1

796, 750 cm^–1. H NMR (400 MHz): δ = 0.84 (t, J = 6.7 Hz, 3 H,

With LiCl: Anhydrous LiCl (399.5 or 510 mg, 9.4 or 12 mmol) was

flame-dried under high vacuum in a Schlenk flask five times for

around 2 min. Dry THF (19 mL, 0.1 m solution) followed by dry

iPr₂NH (0.367 mL, 2.6 mmol) were added. nBuLi (1.625 mL,

2.6 mmol, 1.6 m solution in hexane) was added dropwise through a

syringe at –78 °C. After stirring at –78 °C for 0.5 h, the substrate

3, 8 or 14 (2.0 mmol) dissolved in THF (1 mL) was added dropwise

at –78 °C. For compounds 3j,k and 8e,i the deprotonation was per-

formed with 4–4.6 mmol of LDA (for exact amounts see Table 2

and Table 3). The mixture was stirred at –78 °C for 5–30 min (see

Tables 1–5).

CH₂CH₃), 1.07 (s, 6 H, NCCH₃), 1.09 (s, 3 H, NCCH₃), 1.12 (s, 3

H, NCCH₃), 1.15–1.33 (m,

7

H, H₃CCH₂CH₂CH₂,

NCCH₂CH₂CH₂CN), 1.36–1.45 (m, 5 H, NCCH₂CH₂CH₂CN),

1.42 [s, 9 H, C(CH₃)₃], 1.76 (m, 2 H, CH₂CHON), 4.07 (t, J =

6.7 Hz, 1 H, CHON) ppm. ¹³C NMR (101 MHz): δ = 14.2 (q,

CH₂CH₃), 17.4 (t, NCCH₂CH₂CH₂CN), 20.4 (q, NCCH₃), 22.7 (t,

CH₂CH₃), 24.3 (t, CH₂CH₂CH₂CH₃), 28.3 [q, C(CH₃)₃], 31.9 (t,

CH₂CH₂CH₃), 32.7 (t, CH₂CHON), 33.7 (q, NCCH₃), 33.9 (q,

NCCH₃), 40.6 (t, NCCH₂CH₂CH₂CN), 59.7 (s, NCCH₃), 60.1 (s,

NCCH₃), 80.9 [s, OC(CH₃)₃], 86.2 (d, CHON), 173.2 (s, CO₂) ppm.

MS (+ESI): m/z (%) = 342 (100) [M + H]⁺, 286 (70) [M –

With HMPA: nBuLi (1.625 mL, 2.6 mmol, 1.6 m solution in hex-

ane) was added dropwise through a syringe to a solution of dry

iPr₂NH (0.367 mL, 2.6 mmol) in dry THF (19 mL, 0.1 m) at

–78 °C. After stirring at –78 °C for 0.5 h, the substrate 3, 8 or 14

(2.0 mmol) dissolved in THF (1 mL) was added dropwise at –78 °C.

+

CH₂=C(CH₃)₂]⁺. HRMS: calcd. for C₂₀H₄₀NO₃342.3003; found

342.3004.

Ethyl

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)pentanoate

(4c):

Flash chromatography (hexane/EtOAc, 80:1, gradient to 10:1) gave

10

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α-Oxygenation of Carbonyl Compounds

ferrocene followed by 496 mg (87%) of 4c and 21 mg (4%) of dimer

dimer 5f^[14]was repurified after TEMPO sublimation (hexane/

5c as pale-yellow oils. R = 0.5 (hexane/EtOAc, 10:1). IR (film): ν

EtOAc, 40:1). Colorless oil. IR (film): ν = 2977, 2960, 2938, 2921,

˜

f

= 2964, 2935, 2874, 1748, 1467, 1376, 1362, 1261, 1245, 1181, 1133,

2872, 1736, 1467, 1377, 1191, 1143, 1134, 1032, 790 cm^–1. ¹H NMR

1031 cm^–1. ¹H NMR (400 MHz): δ = 0.85 (t, J = 7.3 Hz, 3 H,

(200 MHz): δ = 0.84 (d, J = 6.4 Hz, 3 H, CHCH₃), 0.85 (d, J =

CH₂CH₂CH₃), 0.96 (s, 3 H, NCCH₃), 1.04 (s, 3 H, NCCH₃), 1.05 6.5 Hz, 3 H, CHCH₃), 0.96 (s, 3 H, NCCH₃), 1.00–1.57 [m, 7 H,

(s, 3 H, NCCH₃), 1.11 (s, 3 H, NCCH₃), 1.14–1.29 (m, 2 H,

CH₂CH₂CH₃), 1.21 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.31–1.57 (m,

NCCH₂CH₂CH₂CN, (H₃C)₂CH], 1.02 (s, 3 H, NCCH₃), 1.04 (s, 3

H, NCCH₃), 1.12 (s, 3 H, NCCH₃), 1.21 (t, J = 7.1 Hz, 3 H,

6 H, NCCH₂CH₂CH₂CN), 1.73 (m, 2 H, CHCH₂), 4.09 (q, J = OCH₂CH₃), 1.66 (AAЈBX, J = 12.9, 10.9, 9.7, 4.6, 4.2 Hz, 2 H,

7.1 Hz, 2 H, OCH₂), 4.14 (dd, J = 7.4, 6.8 Hz, 1 H, CHON) ppm.

CH₂CHON), 4.09 (q, J = 7.1 Hz, 2 H, OCH₂), 4.16 (dd, J = 10.9,

¹³C NMR (100 MHz): δ = 14.0 (q, CH₂CH₂CH₃), 14.2 (q,

4.6 Hz, 1 H, CHON) ppm. ¹³C NMR (50 MHz): δ = 14.1 (q,

OCH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 17.9 (t, CH₂CH₂CH₃), OCH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 19.9 (q, NCCH₃), 20.2

20.0 (q, NCCH₃), 20.2 (q, NCCH₃), 33.0 (q, NCCH₃), 33.5 (q, (q, NCCH₃), 21.6 (q, CHCH₃), 23.8 (q, CHCH₃), 24.5 [d,

NCCH₃), 34.2 (t, CH₂CH₂CH₃), 40.2 (t, NCCH₂CH₂CH₂CN), CH(CH₃)₂], 33.0 (q, NCCH₃), 33.5 (q, NCCH₃), 40.1 (t,

40.3 (t, NCCH₂CH₂CH₂CN), 59.3 (s, NCCH₃), 60.1 (t, CH₂O),

85.5 (d, CHON), 173.6 (s, CO₂) ppm. MS (+CI): m/z (%) = 286

(100) [M + H]⁺, 164 (12), 142 (22) [TMPH₂]⁺, 126 (13), 116 (12).

C₁₆H₃₁NO₃(269.43): calcd. C 67.33, H 10.95, N 4.91; found C

67.24, H 11.06, N 5.06.

NCCH₂CH₂CH₂CN), 40.2 (t, NCCH₂CH₂CH₂CN), 41.1 (t,

CH₂CHON), 59.1 (s, NCCH₃), 60.1 (s, NCCH₃), 60.3 (t, OCH₂),

84.8 (d, CHON), 173.7 (s, CO₂) ppm. MS (EI): m/z (%) = 299 (2)

[M]⁺, 284 (3), 256 (2), 241 (4), 156 (100) [TEMPO]⁺, 140 (18), 123

(15), 97 (7), 83 (9), 69 (10). C₁₇H₃₃NO₃(299.45): calcd. C 68.18, H

11.08, N 4.67; found C 68.12, H 11.14, N 4.41.

Prenyl 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)propionate (4d):

Flash chromatography (hexane/EtOAc, 80:1, gradient to 10:1) gave

ferrocene followed by 451 mg (76%) of 4d as a pale-yellow oil. R_f

Methyl 2-Cyclopropyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)acet-

ate (4h): Isolation by flash chromatography (hexane/EtOAc, 50:1,

from the end of ferrocene elution 20:1); yield 304 mg (56%) as a

= 0.7 (hexane/EtOAc, 10:1). IR (film): ν = 2974, 2932, 1747, 1449,

˜

1376, 1361, 1260, 1179, 1129, 1075, 1029, 946, 790, 722, 682 cm^–1.

colorless oil. R = 0.75 (hexane/EtOAc, 5:1). IR (film): ν = 2931,

˜

f

¹H NMR (400 MHz): δ = 0.98 (s, 3 H, NCCH₃), 1.06 (s, 6 H,

1741, 1457, 1362, 1263, 1195, 1151, 1134, 1044, 1024, 991, 975,

789 cm^–1. ¹H NMR (400 MHz):

δ = 0.32–0.46 (m, 1 H,

NCCH₃), 1.12 (s,

3 H, NCCH₃), 1.22–1.30 (m, 1 H,

CH₂CH₂CH), 0.46–0.60 (m, 2 H, CH₂CH₂CH), 0.65–0.80 (m, 1 H,

CH₂CH₂CH), 1.03 (s, 3 H, NCCH₃), 1.10 (s, 3 H, NCCH₃), 1.14

(s, 3 H, NCCH₃), 1.10–1.20 (m, 1 H, CHCHON), 1.24–1.33 (m, 4

NCCH₂CH₂CH₂CN), 1.34 (d, J = 6.9 Hz, 3 H, CH₃CHON), 1.35–

1.54 (m, 5 H, NCCH₂CH₂CH₂CN), 1.65 (s, 3 H, cis-CH₃C=CH),

1.70 (s, 3 H, trans-CH₃C=CH), 4.26 (q, J = 6.8 Hz, 1 H, CHON),

H, NCCH₃, NCCH₂CH₂CH₂CN), 1.37–1.60 (m,

5

H,

4.54 (d,

J

=

7.2 Hz,

2

H, =CHCH₂O), 5.31 (m,

1 H,

=CHCH₂O) ppm. ¹³C NMR (101 MHz):

δ

=

17.0 (t,

NCCH₂CH₂CH₂CN), 3.73 (s, 3 H, OCH₃), 3.82 (d, J = 9.0 Hz, 1

H, CHON) ppm. ¹³C NMR (101 MHz): δ = 1.4 (t, CH₂CH₂CH),

6.9 (t, CH₂CH₂CH), 13.9 (d, CH₂CH₂CH), 17.4 (t,

NCCH₂CH₂CH₂CN), 20.3 (q, NCCH₃), 20.5 (q, NCCH₃), 33.2 (q,

NCCH₃), 34.1 (q, NCCH₃), 40.5 (t, NCCH₂CH₂CH₂CN), 51.4 (q,

OCH₃), 59.9 (s, NCCH₃), 60.6 (s, NCCH₃), 89.0 (d, CHON), 172.9

(s, CO₂) ppm. MS (+ESI): m/z (%) = 292 (100) [M + Na]⁺, 180

(70) [TEMPOH + Na]⁺. HRMS: calcd. for C₁₅H₂₇NO₃Na⁺

292.1883; found 292.1883.

NCCH₂CH₂CH₂CN), 17.9 (q, cis-CH₃C=CH), 18.1 (q,

CH₃CHON), 19.9 (q, NCCH₃), 20.1 (q, NCCH₃), 25.6 (q, trans-

CH₃C=CH), 32.9 (q, NCCH₃), 33.5 (q, NCCH₃), 40.0 (t,

NCCH₂CH₂CH₂CN), 40.2 (t, NCCH₂CH₂CH₂CN), 59.3 (s,

NCCH₃), 59.8 (s, NCCH₃), 61.1 (t, =CHCH₂O), 81.7 (d, CHON),

118.3 (d, CH₃C=CH), 139.0 (s, CH₃C=CH), 174.0 (s, CO₂) ppm.

MS (+CI): m/z (%) = 298 (100) [M + H]⁺, 156 (19) [TEMPO]⁺.

C₁₇H₃₁NO₃(297.42): calcd. C 68.65, H 10.51, N 4.71; found C

68.52, H 10.52, N 4.47.

Methyl anti/syn-3-Methyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-

valerate (4i): Isolation by flash chromatography (hexane/EtOAc,

60:1, from the beginning of TEMPO elution 20:1). For yields and

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)butyrolactone (4e): Isola-

tion by flash chromatography (hexane/EtOAc, 50:1, from the begin-

ning of TEMPO elution 20:1); yield 362 mg (75%) as a colorless

ratios, see Table 2. Colorless oil. IR (film): ν = 2968, 2935, 2877,

˜

1752, 1739, 1465, 1376, 1362, 1260, 1195, 1135, 1052 cm^–1. MS

(+CI): m/z (%) = 286 (100) [M + H]⁺, 285 (3) [M]⁺, 270 (3), 156

(36) [TEMPO]⁺, 142 (3), 123 (2). C₁₆H₃₁NO₃(285.42): calcd. C

67.33, H 10.95, N 4.91; found C 67.59, H 11.07, N 4.74. syn-4i: ¹H

NMR (400 MHz): δ = 0.89 (t, J = 6.9 Hz, 3 H, CHCH₂CH₃), 0.90

(d, J = 6.6 Hz, 3 H, CHCH₃), 0.99 (s, 3 H, NCCH₃), 1.01 (m, 1

H, CHCH₂CH₃), 1.07 (s, 3 H, NCCH₃), 1.11 (s, 3 H, NCCH₃),

1.16 (s, 3 H, NCCH₃), 1.20–1.55 (m, 6 H, NCCH₂CH₂CH₂CN),

1.62 (m, 1 H, CHCH₂CH₃), 2.00 (m, 1 H, CHCH₂CH₃), 3.64 (s,

3 H, OCH₃), 4.14 (d, J = 6.0 Hz, 1 H, CHON) ppm. ¹³C NMR

(100 MHz): δ = 11.9 (q, CHCH₂CH₃), 15.5 (q, CHCH₃), 17.1 (t,

NCCH₂CH₂CH₂CN), 20.3 (br. q, NCCH₃), 23.8 (t, CHCH₂CH₃),

33.0 (q, NCCH₃), 33.9 (q, NCCH₃), 37.4 (d, CHCHON), 40.4 (t,

NCCH₂CH₂CH₂CN), 50.8 (q, OCH₃), 59.7 (s, NCCH₃), 60.2 (s,

oil. R = 0.3 (hexane/EtOAc, 5:1). M.p. 21–22 °C. IR (film): ν =

˜

f

2932, 1786, 1472, 1375, 1261, 1217, 1159, 1113, 1022, 995, 951,

711 cm^–1. ¹H NMR (400 MHz): δ = 1.10 (s, 3 H, NCCH₃), 1.16

(s, 3 H, NCCH₃), 1.23 (s, 3 H, NCCH₃), 1.32 (s, 4 H, NCCH₃,

NCCH₂CH₂CH₂CN), 1.38–1.66 (m, 5 H, NCCH₂CH₂CH₂CN),

2.29 (m, 1 H, CH₂CHON), 2.65 (m, 1 H, CH₂CHON), 4.05 (ddd,

J = 5.7, 9.2, 10.8 Hz, 1 H, OCH₂), 4.32 (td, J = 1.7, 8.9 Hz, 1 H,

OCH₂), 4.70 (dd, J = 8.0, 10.9 Hz, 1 H, CHON) ppm. ¹³C NMR

(101 MHz): δ = 17.2 (t, NCCH₂CH₂CH₂CN), 20.3 (q, NCCH₃),

20.5 (q, NCCH₃), 31.8 (t, CH₂CHON), 32.6 (q, NCCH₃), 34.4 (q,

NCCH₃), 40.4 (t, NCCH₂CH₂CH₂CN), 59.7 (s, NCCH₃), 61.3 (s,

NCCH₃), 64.2 (t, OCH₂), 80.5 (d, CHON), 174.4 (s, CO₂) ppm.

MS (+ESI): m/z (%) = 264 (20) [M + Na]⁺, 242 (100) [M + H]⁺.

+

HRMS: calcd. for C₁₃H₂₄NO₃242.1749; found 242.1751; calcd.

1

NCCH₃), 88.7 (d, CHON), 172.7 (s, CO₂) ppm. anti-4i: H NMR

for C₁₃H₂₃NO₃Na⁺264.1570, found 264.1570. C₁₃H₂₃NO₃

(241.33): calcd. C 64.70, H 9.61, N 5.80; found C 64.35, H 10.02,

N 5.88.

(400 MHz): δ = 0.87 (t, J = 6.8 Hz, 3 H, CHCH₂CH₃), 0.92 (d, J

= 6.7 Hz, 3 H, CHCH₃), 0.99 (s, 3 H, NCCH₃), 1.03 (m, 1 H,

CHCH₂CH₃), 1.07 (s, 3 H, NCCH₃), 1.11 (s, 3 H, NCCH₃), 1.16

(s, 3 H, NCCH₃), 1.20–1.55 (m, 6 H, NCCH₂CH₂CH₂CN), 1.35

(m, 1 H, CHCH₂CH₃), 2.04 (m, 1 H, CHCH₂CH₃), 3.64 (s, 3 H,

OCH₃), 4.22 (d, J = 6.0 Hz, 1 H, CHON) ppm. ¹³C NMR

Ethyl 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)isocaproate (4f): Iso-

lation by flash column chromatography (hexane/EtOAc, 60:1, from

the beginning of TEMPO elution 20:1). For yields, see Table 2. The

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

11

Job/Unit: O20736

/KAP1

Date: 26-07-12 15:48:49

Pages: 23

E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

FULL PAPER

(100 MHz): δ = 11.8 (q, CHCH₂CH₃), 13.7 (q, CHCH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 20.3 (br. q, NCCH₃), 20.6 (br. q, NCCH₃),

NCCH₂CH₂CH₂CN), 20.3 (br. q, NCCH₃), 25.9 (t, CHCH₂CH₃), 33.2 (br. q, NCCH₃), 34.1 (br. q, NCCH₃), 40.4 (t,

33.0 (q, NCCH₃), 33.9 (q, NCCH₃), 37.6 (d, CHCHON), 40.3 (t, NCCH₂CH₂CH₂CN), 52.0 (q, OCH₃), 52.8 (q, OCH₃), 60.0 (s,

NCCH₂CH₂CH₂CN), 50.7 (q, OCH₃), 59.6 (s, NCCH₃), 60.1 (s, NCCH₃), 60.9 (s, NCCH₃), 71.0 (d, CHOH), 86.0 (d, CHON),

NCCH₃), 87.6 (d, CHON), 172.5 (s, CO₂) ppm.

169.9 (s, NOCHCO₂), 172.4 (s, HOCHCO₂) ppm.

Ethyl anti/syn-3-Hydroxy-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-

butyrate (4j): Isolation by flash chromatography (hexane/EtOAc,

20:1, from the beginning of TEMPO elution 10:1, then 7:1 for

product elution) as a partly separable anti,syn diastereomeric mix-

ture. For yields and diastereomeric ratios, see Table 2. Colorless

oils. MS (+CI): m/z (%) = 288 (100) [M + H]⁺, 287 (2) [M]⁺, 272

(3), 156 (12) [TEMPO]⁺, 140 (2). C₁₅H₂₉NO₄(287.40): calcd. C

62.69, H 10.17, N 4.87; found C 62.61, H 10.63, N 4.61. syn-4j: IR

Methyl 2-Methyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)butyrate

(4l): Isolation by flash chromatography (hexane/EtOAc, 60:1, from

the beginning of TEMPO elution 20:1). For yields, see Table 2. Col-

orless crystals. M.p. 53–54.5 °C. IR (film): ν = 2974, 2936, 2880,

˜

1

1738, 1462, 1374, 1236, 1153, 1133, 1052, 975, 926 cm^–1. H NMR

(200 MHz): δ = 0.78 (t, J = 7.6 Hz, 3 H, CCH₂CH₃), 0.84 (s, 3 H,

NCCH₃), 1.04 (s, 3 H, NCCH₃), 1.09 (s, 3 H, NCCH₃), 1.12 (s, 3

H, NCCH₃), 1.22–1.55 (m, 6 H, NCCH₂CH₂CH₂CN), 1.43 (s, 3

H, OCCH₃), 1.77 (AAЈX₃, J = 13.4, 7.6, 7.4 Hz, 2 H, CCH₂CH₃),

3.67 (s, 3 H, OCH₃) ppm. ¹³C NMR (50 MHz): δ = 8.9 (q,

CCH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 18.9 (q, OCCH₃), 20.3

(q, NCCH₃), 20.7 (q, NCCH₃), 32.8 (q, NCCH₃), 33.9 (q,

NCCH₃), 34.0 (t, CCH₂CH₃), 40.4 (t, NCCH₂), 40.8 (t, NCCH₂),

51.4 (q, OCH₃), 59.5 (s, NCCH₃), 59.6 (s, NCCH₃), 84.7 (s, CON),

175.4 (s, CO₂) ppm. MS (EI): m/z (%) = 271 (0.5) [M]⁺, 256 (1.5),

156 (100) [TEMPO]⁺, 142 (30), 123 (28), 114 (8), 84 (10), 83 (19),

69 (40), 55 (35). C₁₅H₂₉NO₃(271.40): calcd. C 66.38, H 10.77, N

5.16; found C 66.05, H 11.05, N 5.01.

(film): ν = 3457, 2973, 2934, 2874, 1744, 1466, 1376, 1260, 1184,

˜

1134, 1046, 958 cm^–1. ¹H NMR (400 MHz): δ = 1.09 (d, J = 6.2 Hz,

3 H, CHCH₃), 1.12 (s, 9 H, NCCH₃), 1.26 (t, J = 7.1 Hz, 3 H,

OCH₂CH₃), 1.29 (s,

3

H, NCCH₃), 1.45 (m,

6

H,

NCCH₂CH₂CH₂CN), 4.15 (q, J = 7.1 Hz, 2 H, OCH₂), 4.21 (m, 1

H, CHOH; on irradiation of δ = 1.09 ppm simplification to d, J =

8.2 Hz), 4.26 (d, J = 8.2 Hz, 1 H, CHON), 4.45 (br. s, 1 H,

OH) ppm. ¹³C NMR (100 MHz): δ = 14.0 (q, OCH₂CH₃), 17.0 (t,

NCCH₂CH₂CH₂CN), 18.2 (q, CHCH₃), 20.2 (br. q, NCCH₃), 33.6

(br. q, NCCH₃), 40.3 (t, NCCH₂CH₂CH₂CN), 60.1 (br. s,

NCCH₃), 60.7 (t, CH₂O), 68.5 (s, OCHCH₃), 87.2 (d, CHON),

Diethyl meso- and

D,L-Octane-4,5-dicarboxylates (5c): Flash

170.3 (s, CO ) ppm. anti-4j: IR (film): ν = 3473, 2977, 2935, 2873,

˜

2

1743, 1467, 1377, 1260, 1183, 1134, 1048, 958 cm^–1. ¹H NMR

(400 MHz): δ = 1.02 (s, 3 H, NCCH₃), 1.11 (s, 3 H, NCCH₃), 1.12

(s, 3 H, NCCH₃), 1.15 (d, J = 6.6 Hz, 3 H, CHCH₃), 1.18 (s, 3

H, NCCH₃), 1.27 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.47 (m, 6 H,

NCCH₂CH₂CH₂CN), 2.47 (d, J = 4.4 Hz, 1 H, OH), 4.17 (d, J =

3.9 Hz, 1 H, CHON), 4.19 (dq, J = 7.1, 1.7 Hz, 2 H, OCH₂), 4.32

(m, 1 H, CHOH; on irradiation of δ = 2.47 simplification to dq, J

= 6.6, 3.9 Hz) ppm. ¹³C NMR (50 MHz): δ = 14.1 (q, OCH₂CH₃),

17.0 (t, NCCH₂CH₂CH₂CN), 19.0 (q, CHCH₃), 20.2 (br. q,

NCCH₃), 33.0 (q, NCCH₃), 33.8 (q, NCCH₃), 40.3 (t,

NCCH₂CH₂CH₂CN), 60.1 (br. s, NCCH₃), 60.4 (t, CH₂O), 67.6

(d, HOCHCH₃), 88.1 (d, CHON), 170.9 (s, CO₂) ppm.

chromatography (hexane/EtOAc, 80:1, gradient to 30:1) gave meso-

and d,l-5c as a colorless oil. meso-5c: R_f= 0.35 (hexane/EtOAc,

1

15:1). IR (film): ν = 2962, 1733, 1255, 1174, 1156 cm^–1. H NMR

˜

(400 MHz): δ = 0.84 (t, J = 7.1 Hz, 6 H, CH₂CH₂CH₃), 1.16–1.33

(m, 6 H, CH₂CH₂CH₃), 1.23 (t, J = 7.1 Hz, 6 H, OCH₂CH₃), 1.56

(m, 2 H, CH₂CH₂CH₃), 2.58 (m, 2 H, CHCO₂), 4.12 (q, J = 7.1 Hz,

4

H, OCH₂) ppm. ¹³C NMR (100 MHz):

δ = 13.8 (q,

CH₂CH₂CH₃), 14.2 (q, OCH₂CH₃), 20.5 (t, CH₂CH₂CH₃), 32.9 (t,

CH₂CH₂CH₃), 48.2 (d, CHCO₂), 60.2 (t, OCH₂), 174.3 (s,

CO₂) ppm. MS (EI): m/z (%) = 258 (1) [M]⁺, 213 (66) [M – OEt]⁺,

185 (39) [M – OEt – CO]⁺, 130 (70), 129 (100) [M/2]⁺, 101 (92), 69

(24), 55 (32). d,l-5c: R_f= 0.27 (hexane/EtOAc, 15:1). ¹H NMR

(400 MHz): δ = 0.87 (t, J = 7.1 Hz, 6 H, CH₂CH₂CH₃), 1.15–1.35

(m, 6 H, CH₂CH₂CH₃), 1.21 (t, J = 7.1 Hz, 6 H, OCH₂CH₃), 1.53

(m, 2 H, CH₂CH₂CH₃), 2.62 (m, 2 H, CHCO₂), 4.08 (dq, J = 1.2,

7.1 Hz, 4 H, OCH₂) ppm. ¹³C NMR (100 MHz): δ = 14.0 (q,

CH₂CH₂CH₃), 14.2 (q, OCH₂CH₃), 20.1 (t, CH₂CH₂CH₃), 31.3 (t,

CH₂CH₂CH₃), 46.5 (d, CHCO₂), 60.3 (t, OCH₂), 174.7 (s,

CO₂) ppm. MS (EI): m/z (%) = 258 (0.1) [M]⁺, 213 (31) [M –

OEt]⁺, 185 (12) [M – OEt – CO]⁺, 130 (55), 129 (77) [M/2]⁺, 101

(100), 69 (40), 55 (32), 41 (47).

Dimethyl (2S,3S)- and (2S,3R)-2-Hydroxy-3-(2,2,6,6-tetramethyl-

piperidin-1-yloxy)succinates (4k): Isolation by flash chromatog-

raphy (hexane/EtOAc, 20:1 gradient to 1:1). For yields and ratios,

see Table 2. Colorless oils. IR (film): ν = 3496, 2934, 1744, 1437,

˜

1363, 1260, 1206, 1133, 1108, 1076, 915, 794 cm^–1. MS (+ESI): m/z

(%) = 340 (100) [M + Na]⁺, 184 (15) [M + Na – TEMPO]⁺. HRMS:

+

calcd. for C₁₅H₂₈NO₆318.1911; found 318.1909; calcd. for

C₁₅H₂₇NO₆Na⁺340.1731; found 340.1731. C₁₅H₂₇NO₆(317.38):

calcd. C 56.77, H 8.57, N 4.41; found C 56.98, H 8.71, N 4.22.

(2S,3S)-4k: R_f= 0.2 (hexane/EtOAc, 10:1). [α]²_D⁰= –1.4 (c = 0.941,

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)-2-phenylacetonitrile (9a):

CH₂Cl₂). ¹H NMR (400 MHz): δ = 1.07 (br. s, 3 H, NCCH₃), 1.10 Flash chromatography (hexane/EtOAc, 80:1, gradient to 50:1) gave

(br. s, 6 H, NCCH₃), 1.24 (br. s, 3 H, NCCH₃), 1.24–1.35 (m, 1

ferrocene followed by 9a. Yellow oily solid that turned dark yellow

H, NCCH₂CH₂CH₂CN), 1.38–1.62 (m, 5 H, NCCH₂CH₂CH₂CN), or orange over a few hours at room temperature; unstable to light

3.71 (s, 3 H, OCH₃), 3.77 (s, 3 H, OCH₃), 4.36 (s, 1 H, OH), 4.62 and heat. For yields, see Table 3. R_f= 0.5 (hexane/EtOAc, 10:1).

(s, 2 H, CHCH) ppm. ¹³C NMR (101 MHz): δ = 17.0 (t, IR (film): ν = 3070, 2971, 2942, 2874, 2214, 1687, 1602, 1583, 1548,

˜

NCCH₂CH₂CH₂CN), 20.2 (br. q, NCCH₃), 33.2 (br. q, NCCH₃), 1451, 1382, 1315, 1271, 1175, 1120, 1070, 1025, 935, 793, 710 cm^–1.

40.3 (t, NCCH₂CH₂CH₂CN), 52.0 (q, OCH₃), 52.7 (q, OCH₃), 60.8

(br. s, NCCH₃), 60.9 (br. s, NCCH₃), 71.5 (d, CHOH), 83.6 (d,

CHON), 170.3 (s, NOCHCO₂), 172.0 (s, HOCHCO₂) ppm.

(2S,3R)-4k: R_f= 0.1 (hexane/EtOAc, 10:1). [α]²_D⁰= +2.1 (c = 0.963,

¹H NMR (200 MHz): δ = 0.94 (s, 3 H, NCCH₃), 1.02 (s, 3 H,

NCCH₃), 1.11 (s,

3 H, NCCH₃), 1.21–1.59 (m, 6 H,

NCCH₂CH₂CH₂CN), 1.41 (s, 3 H, NCCH₃), 5.50 (s, 1 H, CHON),

7.29–7.44 (m, 5 H, Ph) ppm. ¹³C NMR (50 MHz): δ = 17.0 (t,

CH₂Cl₂). ¹H NMR (400 MHz): δ = 1.04 (br. s, 3 H, NCCH₃), 1.10 NCCH₂CH₂CH₂CN), 20.4 (q, NCCH₃), 20.5 (q, NCCH₃), 33.8 (q,

(br. s, 3 H, NCCH₃), 1.17 (br. s, 6 H, NCCH₃), 1.24–1.36 (m, 1

H, NCCH₂CH₂CH₂CN), 1.38–1.48 (m, 4 H, NCCH₂CH₂CH₂CN), NCCH₃), 60.9 (s, NCCH₃), 76.7 (d, CHON), 118.9 (s, CN), 127.2

1.47–1.58 (m, 1 H, NCCH₂CH₂CH₂CN), 3.10 (d, J = 5.4 Hz, 1 H, (d, Ph), 128.9 (d, Ph), 129.4 (d, Ph), 134.9 (s, Ph) ppm. MS (+ESI):

OH), 3.71 (s, 3 H, OCH₃), 3.79 (s, 3 H, OCH₃), 4.75–4.85 (m, 2 H, m/z (%) = 295 (100) [M + Na]⁺, 273 (40) [M + H]⁺, 179 (41)

CHCH) ppm. ¹³C NMR (101 MHz): 17.0 (t, [TEMPO + Na]⁺, 158 (21) [TEMPOH₂]⁺, 142 (3) [TMPH₂]⁺.

NCCH₃), 34.6 (q, NCCH₃), 40.0 (t, NCCH₂CH₂CH₂CN), 60.3 (s,

δ

=

12

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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20736

/KAP1

Date: 26-07-12 15:48:49

Pages: 23

α-Oxygenation of Carbonyl Compounds

C₁₇H₂₄N₂O (272.39): calcd. C 74.96, H 8.88, N 10.28; found C

75.16, H 8.88, N 10.21.

[s, 6 H, HOC(CH₃)₂], 1.16–1.60 (m, 6 H, NCCH₂CH₂CH₂CN),

2.25 (br. s, 1 H, OH), 4.59 (s, 1 H, CHON) ppm. ¹³C NMR

(50 MHz): δ = 16.1 (t, NCCH₂CH₂CH₂CN), 19.9 (q, NCCH₃),

24.8 [q, (CH₃)₂COH], 24.9 [q, (CH₃)₂COH], 33.0 (q, NCCH₃), 33.3

( q , N C C H ₃) , 3 9 . 2 ( t , N C C H ₂C H ₂C H ₂C N ) , 3 9 . 5 ( t ,

NCCH₂CH₂CH₂CN), 59.6 (s, NCCH₃), 71.6 [s, (CH₃)₂COH], 80.0

(d, CHON), 117.7 (s, CN) ppm. MS (ESI): m/z (%) = 531 (37) [2M

+ Na]⁺, 277 (100) [M + Na]⁺, 179 (43) [TEMPO + Na]⁺.

C₁₄H₂₆N₂O₂(254.37): calcd. C 66.10, H 10.30, N 11.01; found C

65.99, H 10.33, N 11.15.

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)capronitrile (9b): Flash

chromatography (hexane/EtOAc, 100:1, gradient to 2:1) gave ferro-

cene followed by a mixture of ferrocene and 9b, which was further

purified. For yields, see Table 3. Pale-yellow oil. R_f= 0.64 (hexane/

EtOAc, 10:1). IR (film): ν = 2933, 2238, 1467, 1363, 1133 cm^–1. ¹H

˜

NMR (400 MHz): δ = 0.86 (t, J = 6.8 Hz, 3 H, CH₂CH₃), 1.05 (s,

3 H, NCCH₃), 1.07 (s, 3 H, NCCH₃), 1.13 (s, 3 H, NCCH₃), 1.27

(m, 7 H, NCCH₂CH₂CH₂CN, CH₂CH₂CH₂CH₃), 1.30 (s, 3 H,

NCCH₃), 1.43–1.50 (m,

7 H, CH₂CH₂CHON, NCCH₂CH₂-

N,N-Diethyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)pentanamide

(9f): Flash chromatography (hexane/EtOAc, 20:1, gradient to 2:1)

gave ferrocene followed by 9f; yield 589 mg (94%) as a pale-yellow

CH₂CN), 1.82 (m, 2 H, CH₂CHON), 4.56 (dd, J = 7.9, 5.9 Hz, 1

H, CHON) ppm. ¹³C NMR (100 MHz): δ = 13.4 (q, CH₂CH₃),

16.4 (t, NCCH₂CH₂), 19.6 (br. q, NCCH₃), 19.8 (br. q, NCCH₃),

21.9 (t), 24.2 (t, CH₂CH₂CHON), 28.3 (t), 30.9 (t), 32.3 (t,

CH₂CHON), 33.1 (br. q, NCCH₃), 33.2 (br. q, NCCH₃), 39.3 (t,

NCCH₂CH₂CH₂CN), 39.4 (t, NCCH₂CH₂CH₂CN), 59.2 (s,

NCCH₃), 60.2 (s, NCCH₃), 73.7 (d, CHON), 119.2 (s, CϵN) ppm.

MS (EI): m/z (%) = 280 (0.1) [M]⁺, 265 (2), 156 (100) [TEMPO]⁺,

123 (26), 69 (29), 55 (22), 41 (27). C₁₇H₃₂N₂O (280.4): calcd. C

72.79, H 11.51, N 10.00; found C 72.46, H 11.63, N 10.40.

oil. R = 0.66 (hexane/EtOAc, 2:1). IR (film): ν = 2964, 2933, 2874,

˜

f

1652, 1463, 1455, 1432, 1377, 1362, 1259, 1133, 1123, 1023 cm^–1.

¹H NMR (400 MHz): δ = 0.88 (t, J = 7.3 Hz, 3 H, CH₂CH₂CH₃),

0.98 (s, 3 H, NCCH₃), 1.02 (s, 3 H, NCCH₃), 1.06 (t, J = 7.1 Hz,

3 H, NCH₂CH₃), 1.09 (s, 3 H, NCCH₃), 1.16 (s, 3 H, NCCH₃),

1.17 (t, J = 7.1 Hz, 3 H, NCH₂CH₃), 1.19 (m, 2 H, CH₂CH₂CH₃),

1.13–1.49 (m, 6 H, NCCH₂CH₂CH₂CN), 1.67–1.85 (m, 2 H,

CHCH₂), 3.26 (m, 2 H, NCH₂), 3.35 (dq, J = 13.7, 6.9 Hz, 1 H,

NCH₂), 3.81 (dq, J = 14.6, 7.3 Hz, 1 H, NCH₂), 4.41 (dd, J =

10.0, 4.7 Hz, 1 H, CHON) ppm. ¹³C NMR (100 MHz): δ = 12.4

(q, CH₂CH₂CH₃), 14.3 (q, NCH₂CH₃), 14.6 (q, NCH₂CH₃), 17.0

(t, NCCH₂CH₂CH₂CN), 18.6 (t, CH₃CH₂CH₂), 19.9 (q, NCCH₃),

20.2 (q, NCCH₃), 32.9 (q, NCCH₃), 33.3 (q, NCCH₃), 34.4 (t,

CH₂CHON), 40.2 (t, NCCH₂CH₂CH₂CN), 40.3 (t, CH₂N), 40.4

(t, NCCH₂CH₂CH₂CN), 41.5 (t, CH₂N), 59.0 (s, NCCH₃), 60.4 (s,

NCCH₃), 81.4 (d, CHON), 172.3 (s, CO) ppm. MS (+CI): m/z (%)

= 313 (100) [M + H]⁺, 189 (6), 158 (17) [TEMPOH₂]⁺, 142 (38)

[TMPH₂]⁺, 126 (18), 116 (9). C₁₈H₃₆N₂O₂(312.49): calcd. C 69.18,

H 11.61, N 8.96; found C 69.44, H 11.80, N 9.17.

2-Cyclopropyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)acetonitrile

(9c): Isolation by flash chromatography (hexane/EtOAc, 50:1 with

1 vol.-% NEt₃), from the end of ferrocene elution 20:1 with 1 vol.-

% NEt₃; yield 380 mg (80%) as a pale-orange oil. R_f= 0.5 (hexane/

EtOAc, 10:1). IR (film): ν = 2933, 1469, 1377, 1363, 1260, 1243,

˜

1209, 1183, 1133, 1029, 989, 957, 931, 906, 892, 874, 783, 700 cm^–1.

¹H NMR (400 MHz): δ = 0.50–0.61 (m, 2 H, CH₂CH₂CH), 0.62–

0.72 (m, 2 H, CH₂CH₂CH), 1.09 (s, 3 H, NCCH₃), 1.12 (s, 3 H,

NCCH₃), 1.17 (s, 3 H, NCCH₃), 1.26–1.36 (m, 5 H, NCCH₃,

CH₂CH₂CH, NCCH₂CH₂CH₂CN), 1.39–1.58 (m, 5 H,

NCCH₂CH₂CH₂CN), 4.44 (d, J = 6.8 Hz, 1 H, CHON) ppm. ¹³C

NMR (101 MHz): δ = 2.2 (t, CH₂CH₂CH), 4.3 (t, CH₂CH₂CH),

13.2 (d, CH₂CH₂CH), 17.1 (t, NCCH₂CH₂CH₂CN), 20.4 (q,

NCCH₃), 20.5 (q, NCCH₃), 33.8 (q, NCCH₃), 34.0 (q, NCCH₃),

40.0 (t, NCCH₂CH₂CH₂CN), 40.1 (t, NCCH₂CH₂CH₂CN), 60.1

(s, NCCH₃), 61.0 (s, NCCH₃), 78.0 (d, CHON), 118.4 (s, CN) ppm.

MS (+ESI): m/z (%) = 259 (65) [M + Na]⁺, 237 (100) [M + H]⁺,

179 (70) [TEMPO + Na]⁺. HRMS: calcd. for C₁₄H₂₅NO⁺

237.1961; found 237.1961.

N,N-Dibenzyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)hexanamide

(9g): Flash chromatography (hexane/EtOAc, 80:1, gradient to 5:1)

gave ferrocene followed by 9g; yield 667 mg (74%) as a pale-yellow

solid. M.p. 49–52 °C. R = 0.42 (hexane/EtOAc, 10:1). IR (film): ν

˜

f

= 2928, 2871, 1651, 1495, 1453, 1426, 1376, 1361, 1241, 1203, 1182,

1132, 1079, 1028, 1008, 988, 974, 956, 916, 732, 698 cm^–1. ¹H NMR

(400 MHz): δ = 0.87 (t, J = 6.9 Hz, 3 H, CH₃CH₂), 0.91 (s, 3 H,

NCCH₃), 1.05 (s, 3 H, NCCH₃), 1.09 (s, 6 H, NCCH₃), 1.13–1.30

(m, 5 H, CH₃CH₂CH₂, NCCH₂CH₂CH₂CN), 1.32–1.51 (m, 5 H,

NCCH₂CH₂CH₂CN), 1.88 (m, 2 H, CH₂CHO), 4.49 (d, J =

14.1 Hz, 1 H, CH₂N), 4.59 (m, 3 H, CH₂N, CHON), 4.96 (d, J =

17.0 Hz, 1 H, CH₂N), 7.29 (m, 10 H, Ph) ppm. ¹³C NMR

(100 MHz): δ = 13.2 (q, CH₃CH₂), 16.3 (t, NCCH₂CH₂CH₂CN),

19.3 (q, NCCH₃), 19.6 (q, NCCH₃), 22.1 (t, CH₃CH₂), 26.8 (t,

CH₂CH₂CHO), 31.2 (t, CH₂CHO), 32.4 (q, NCCH₃), 32.8 (q,

NCCH₃), 39.6 (t, NCCH₂CH₂CH₂CN), 47.6 (t, NCH₂), 48.6 (t,

NCH₂), 58.7 (s, NCCH₃), 59.5 (s, NCCH₃), 81.4 (d, CHON), 126.1

(d, Ph), 126.64 (d, Ph), 126.65 (d, Ph), 127.5 (d, Ph), 127.9 (d, Ph),

128.8 (d, Ph), 136.0 (s, Ph), 136.1 (s, Ph), 172.4 (s, CO) ppm. MS

(+ESI): m/z (%) = 451 (100) [M + H]⁺, 317 (5). HRMS: calcd.

2-Methyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)propionitrile (9d):

Flash chromatography (hexane/EtOAc, 50:1, gradient to 10:1) and

crystallization from CHCl₃gave 341 mg (76%) of 9d as a colorless

solid. M.p. 83 °C. R = 0.53 (hexane/EtOAc, 10:1). IR (KBr): ν

˜

f

= 2925, 2230, 1471, 1381, 1209, 1149, 1134, 913 cm^–1. ¹H NMR

(400 MHz): δ = 1.20 (s, 6 H, NCCH₃), 1.31 (s, 6 H, NCCH₃), 1.59

(m, 6 H, NCCH₂CH₂CH₂CN), 1.77 [s, 6 H, NOC(CH₃)₂] ppm. ¹³

C

NMR (100 MHz): δ = 15.8 (t, NCCH₂CH₂CH₂CN), 19.4 (q,

NCCH₃), 26.2 (q, NOCCH₃), 33.0 (br. q, NCCH₃), 39.3 (t,

NCCH₂CH₂CH₂CN), 58.8 (s, NCCH₃), 73.6 (s, CON), 121.6 (s,

CϵN) ppm. MS (EI): m/z (%) = 224 (55) [M]⁺, 155 (55), 137 (23),

121 (26), 96 (29), 91 (100), 65 (22), 41 (49). C₁₃H₂₄N₂O (224.34):

calcd. C 69.60, H 10.78, N 12.49; found C 69.51, H 11.01, N 12.37.

+

for C₂₉H₄₃N₂O₂451.3325; found 451.3319. C₂₉H₄₂N₂O₂(450.66):

calcd. C 77.29, H 9.39, N 6.22; found C 77.33, H 9.48, N 6.00.

3-Hydroxy-3-methyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-

butyronitrile (9e): Deprotonation with 2.3 equiv. LDA at –78 to

N,N-Dimethyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)isobutyr-

–50 °C for 35 min. Flash chromatography (hexane/EtOAc, 20:1, amide (9h): Flash chromatography (hexane/EtOAc, 40:1, gradient

gradient to 2:1) gave ferrocene followed by 9e; yield 530 mg (99%)

as a white solid. M.p. 22–23 °C. R_f= 0.34 (hexane/EtOAc, 5:1). IR

to 2:1) afforded ferrocene followed by residual TEMPO and 9h;

yield 70 mg (13%) as a pale-yellow oil. R_f= 0.59 (hexane/EtOAc,

(film): ν = 3431, 3338, 3011, 2976, 2938, 2871, 2250, 1465, 1382,

2:1). IR (film): ν = 2974, 2934, 2932, 1643, 1472, 1382, 1362, 1260,

˜

1363, 1259, 1235, 1182, 1133, 1070, 1003, 953, 913, 895, 808, 1184, 1182, 1145, 1119, 923, 827 cm^–1. ¹H NMR (400 MHz): δ =

708 cm^–1. ¹H NMR (200 MHz): δ = 1.11 (s, 3 H, NCCH₃), 1.17 (s,

1.04 (s, 6 H, NCCH₃), 1.10 (s, 6 H, NCCH₃), 1.13–1.55 (m, 6 H,

3 H, NCCH₃), 1.24 (s, 3 H, NCCH₃), 1.34 (s, 3 H, NCCH₃), 1.41 NCCH₂CH₂CH₂CN), 1.52 [s, 6 H, (CH₃)₂CON], 2.94 [s, 3 H,

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

13

Job/Unit: O20736

/KAP1

Date: 26-07-12 15:48:49

Pages: 23

E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

FULL PAPER

N(CH₃)₂], 3.39 [s, 3 H, N(CH₃)₂] ppm. ¹³C NMR (100 MHz): δ =

17.1 (t, NCCH₂CH₂CH₂CN), 21.5 (q, NCCH₃), 25.5 [q, was added to a solution of (S)-8k (257 mg, 1 mmol) in dry THF

(CH₃)₂CON], 33.3 (q, NCCH₃), 37.2 [q, N(CH₃)₂], 38.2 [q, (10 mL) at –78 °C. After stirring for 0.5 h, 1 (172 mg, 1.1 mmol)

(9k): A solution of LiHMDS (1.05 mL, 1.05 mmol, 1.0 m in THF)

N(CH₃)₂], 40.3 (t, NCCH₂CH₂CH₂CN), 59.4 (s, NCCH₃), 83.5 [s, was added to the reaction mixture. Stirring was continued for 5 min

(CH₃)₂CON], 174.8 (s, CO) ppm. MS (+ESI): m/z (%) = 833 (93) until it dissolved. Ferrocenium hexafluorophosphate (2) was added

[3M + Na]⁺, 563 (83) [2M + Na]⁺, 412 (27) [M + TMPH₂]⁺, 271 in portions at –78 °C until the solution remained dark blue for

(100) [M + H]⁺. C₁₅H₃₀N₂O₂(270.41): calcd. C 66.62, H 11.18, N

10.36; found C 66.58, H 10.78, N 9.56.

at least 5 min. Workup was performed according to the general

procedure (see above). Flash chromatography (hexane/ethyl acetate,

40:1, gradient to 1:1) afforded, starting from a polarity of 10:1,

110 mg of (2S,4R)-9k, followed by 80 mg of a mixture of (2S,4R)-

9k and (2S,4S)-9k, and finally 100 mg of (2S,4S)-9k, all as colorless

solids; yield 290 mg (70%) of (2S,4R)-9k/(2S,4S)-9k (1:1.2). HPLC

investigations on a DAICEL-OD chiral column showed

that (2S,4R)-9k and (2S,4S)-9k were enantiomerically pure.

2,4-Bis(2,2,6,6-tetramethylpiperidin-1-yloxy)-N,N,NЈNЈ-tetra-

methylglutardiamide (9i): Flash chromatography (hexane/EtOAc,

30:1, gradient to 1:2) afforded ferrocene, followed by residual

TEMPO and finally 9i. Yield (using 2.0 equiv. TEMPO, 4.7 equiv.

LiCl): 230 mg (23%, d,l/meso 4:1); yield (using 2.1 equiv. TEMPO,

6 equiv. LiCl): 280 mg (28%, d,l/meso 4:1) as a colorless solid. M.p.

C

₂₁H₃₆N₂O₆(412.52): calcd. C 61.14, H 8.80, N 6.79; found C

21–22 °C. R = 0.20 (hexane/EtOAc, 2:1). IR (film): ν = 2932, 2873,

˜

f

60.92, H 8.90, N 6.54. (2S,4R)-9k: [α]²_D⁰= +4.5 (c = 0.353, CHCl₃).

1644, 1499, 1466, 1398, 1377, 1361, 1334, 1261, 1132, 1106, 1017,

982, 956, 910, 877, 793, 708, 656 cm^–1. MS (+ESI): m/z (%) = 1015

(10) [2M + Na]⁺, 519 (100) [M + Na]⁺, 223 (23). C₂₇H₅₂N₄O₄

(496.73): calcd. C 65.29, H 10.55, N 11.28; found C 65.19, H 10.66,

(2S,4S)-9k: [α]²_D⁰= –24.4 (c = 0.468, CHCl₃). (2S,4R)-9k: M.p. 119–

121 °C. R = 0.45 (hexane/EtOAc, 5:1). IR (KBr): ν = 2933, 1792,

˜

f

1749, 1320, 1200 cm^–1. H NMR (400 MHz): δ = 1.04 (br. s, 3 H,

1

NCCH₃), 1.08 (br. s, 3 H, NCCH₃), 1.22 (br. s, 3 H, NCCH₃), 1.25

( t , J = 7 . 1 H z , 3 H , O C H ₂C H ₃) , 1 . 2 7 ( m , 2 H ,

NCCH₂CH₂CH₂CN), 1.32 (br. s, 3 H, NCCH₃), 1.43 (m, 4 H,

NCCH₂CH₂CH₂CN), 1.47 [s, 9 H, OC(CH₃)₃], 2.22 (ddd, J = 12.8,

11.4, 9.9 Hz, 1 H, CH₂CHON), 2.56 (dd, J = 12.8, 8.2 Hz, 1 H,

CH₂CHON), 4.18 (q, J = 7.1 Hz, 2 H, OCH₂), 4.48 (d, J = 9.3 Hz,

1 H, CHN), 4.69 (dd, J = 11.4, 8.2 Hz, 1 H, CHON) ppm. ¹³C

N M R ( 1 0 0 M H z ) : δ = 1 4 . 1 ( q , O C H ₂C H ₃) , 1 7 . 1 ( t ,

NCCH₂CH₂CH₂CN), 20.1 (br. q, NCCH₃), 20.3 (br. q, NCCH₃),

27.9 [q, OC(CH₃)₃], 31.7 (t, CH₂CHON), 32.2 (br. q, NCCH₃),

34.3 (br. q, NCCH₃), 40.2 (br. t, NCCH₂CH₂CH₂CN), 40.4 (br. t,

NCCH₂CH₂CH₂CN), 54.7 (d, CHN), 59.2 (br. s, NCCH₃), 61.4

(br. s, NCCH₃), 61.8 (t, OCH₂), 81.5 (d, CHON), 83.8 [s, OC-

(CH₃)₃], 149.7 (s, NCO₂), 170.2 (s, CO), 170.9 (s, CO) ppm. MS

(EI): m/z (%) = 412 (0.4) [M]⁺, 397 (2), 156 (15) [TEMPO]⁺, 142

(13), 126 (100) [M – TEMPO – OtBu – CO – Et]⁺, 108 (8), 98 (8),

84 (4), 70 (24), 69 (22), 58 (32), 44 (32), 41 (23). HRMS: calcd.

N 10.81. d,l-9i: H NMR (400 MHz): δ = 0.97 (s, 6 H, NCCH₃),

1.04 (s, 6 H, NCCH₃), 1.09 (s, 6 H, NCCH₃), 1.20 (s, 6 H, NCCH₃),

1.21–1.54 (m, 12 H, NCCH₂CH₂CH₂CN), 2.22 (dt, J = 13.6,

3.4 Hz, 1 H, CHCH₂CH), 2.68 (dt, J = 13.6, 9.5 Hz, 1 H,

C

H

C

H

C

H

)

,

2

.

8

4

[

s

,

6

H ,

2

N(CH₃)₂], 3.21 [s, 6 H, N(CH₃)₂], 4.72 (dd, J = 9.5, 3.4 Hz, 2 H,

C H C H ₂C H ) p p m . ^{1 3}C N M R ( 1 0 0 M H z ) : δ = 1 7 . 1 ( t ,

NCCH₂CH₂CH₂CN), 20.1 (q, NCCH₃), 20.3 (q, NCCH₃), 32.6 (q,

NCCH₃), 33.3 (q, NCCH₃), 33.7 (t, CHCH₂CH), 35.7 [q,

N(CH₃)₂], 37.4 [q, N(CH₃)₂], 40.2 (t, NCCH₂CH₂CH₂CN), 40.5 (t,

NCCH₂CH₂CH₂CN), 59.3 (s, NCCH₃), 60.4 (s, NCCH₃), 79.3 (d,

CHON), 171.9 (s, CO) ppm. meso-9i: ¹H NMR (400 MHz): δ =

0.94 (s, 6 H, NCCH₃), 1.04 (s, 6 H, NCCH₃), 1.09 (s, 6 H, NCCH₃),

1.19 (s, 6 H, NCCH₃), 1.21–1.54 (m, 12 H, NCCH₂CH₂CH₂CN),

2.43 (dd, J = 9.1, 6.4 Hz, 2 H, CHCH₂CH), 2.88 [s, 6 H,

N(CH₃)₂], 3.19 [s, 6 H, N(CH₃)₂], 4.32 (dd, J = 9.0, 6.5 Hz, 2 H,

C H C H ₂C H ) p p m . ^{1 3}C N M R ( 1 0 0 M H z ) : δ = 1 7 . 1 ( t ,

NCCH₂CH₂CH₂CN), 19.9 (q, NCCH₃), 20.3 (q, NCCH₃), 32.3 (q,

NCCH₃), 33.1 (q, NCCH₃), 34.1 (t, CHCH₂CH), 35.8 [q,

N(CH₃)₂], 37.4 [q, N(CH₃)₂], 40.2 (t, NCCH₂CH₂CH₂CN), 40.5 (t,

NCCH₂CH₂CH₂CN), 59.2 (s, NCCH₃), 60.4 (s, NCCH₃), 79.1 (d,

CHON), 172.0 (s, CO) ppm.

+

for C₂₁H₃₆N₂O₆412.2573; found 412.2578. (2S,4S)-9k: M.p. 93–

94 °C. R = 0.3 (hexane/EtOAc, 5:1). IR (KBr): ν = 2935, 1776,

˜

f

1744, 1721, 1383, 1314, 1253, 1145 cm^–1. H NMR (400 MHz): δ

1

= 1.04 (br. s, 3 H, NCCH₃), 1.09 (br. s, 3 H, NCCH₃), 1.18 (br. s,

3 H, NCCH₃), 1.25 (m, 2 H, NCCH₂CH₂CH₂CN), 1.26 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.29 (br. s, 3 H, NCCH₃), 1.43 (m, 4 H,

NCCH₂CH₂CH₂CN), 1.47 [s, 9 H, OC(CH₃)₃], 1.97 (dt, J = 12.5,

9.1 Hz, 1 H, CH₂CHON), 2.73 (dt, J = 12.5, 7.6 Hz, 1 H,

CH₂CHON), 4.17 (dq, J = 10.8, 7.1 Hz, 1 H, OCH₂), 4.20 (dq, J

= 10.6, 7.1 Hz, 1 H, OCH₂), 4.23 (dd, J = 8.7, 7.3 Hz, 1 H, CHN),

4.55 (dd, J = 9.4, 8.1 Hz, 1 H, CHON) ppm. ¹³C NMR (100 MHz):

δ = 13.9 (q, OCH₂CH₃), 16.9 (t, NCCH₂CH₂CH₂CN), 20.0 (br. q,

NCCH₃), 27.7 [q, OC(CH₃)₃], 31.2 (t, CH₂CHON), 32.3 (br. q,

NCCH₃), 34.2 (br. q, NCCH₃), 40.1 (br. t, NCCH₂CH₂CH₂CN),

40.2 (br. t, NCCH₂CH₂CH₂CN), 54.8 (d, CHN), 59.3 (br. s,

NCCH₃), 61.0 (br. s, NCCH₃), 61.5 (t, OCH₂), 81.9 (d, CHON),

83.7 [s, OC(CH₃)₃], 149.4 (s, NCO₂), 169.7 (s, CO), 170.3 (s,

CO) ppm. MS (EI): m/z (%) = 412 (4) [M]⁺, 397 (6), 297 (12), 270

(6), 229 (4), 173 (4), 156 (100) [TEMPO]⁺, 123 (7), 108 (5), 84 (11),

1-Methyl-3-(2,2,6,6-tetramethylpiperidin-1-yloxy)pyrrolidin-2-one

(9j): Flash chromatography (hexane/EtOAc, 15:1, gradient to 1:1)

gave 290 mg (57%) of 9j as a colorless solid. M.p. 89 °C. R_f= 0.23

(hexane/EtOAc, 2:1). IR (KBr): ν = 2931, 1702, 1693, 1401, 1302,

˜

1075, 970 cm^–1. ¹H NMR (400 MHz): δ = 1.06 (br. s, 3 H, NCCH₃),

1.13 (br. s, 3 H, NCCH₃), 1.20 (br. s, 3 H, NCCH₃), 1.28 (m, 1

H, NCCH₂CH₂CH₂CN), 1.38 (br. s, 3 H, NCCH₃), 1.43 (m, 4 H,

NCCH₂CH₂CH₂CN), 1.53 (m, 1 H, NCCH₂CH₂CH₂CN), 2.01

(dq, J = 12.3, 9.3 Hz, 1 H, CH₂CHON), 2.46 (dddd, J = 12.2, 8.0,

6.6, 1.6 Hz, 1 H, CH₂CHON), 2.81 (s, 3 H, NCH₃), 3.10 (dt, J =

9.5, 6.5 Hz, 1 H, CH₂N), 3.20 (dt, J = 9.4, 1.6 Hz, 1 H, CH₂N),

4.54 (dd, J = 9.1, 8.5 Hz, 1 H, CHON) ppm. ¹³C NMR (100 MHz):

δ = 17.0 (t, NCCH₂CH₂CH₂CN), 20.0 (br. q, NCCH₃), 20.2 (br.

q, NCCH₃), 28.8 (t, CH₂CHON), 29.9 (q, NCH₃), 32.3 (br. q,

NCCH₃), 34.3 (br. q, NCCH₃), 40.3 (t, NCCH₂CH₂CH₂CN), 44.7

(t, CH₂N), 58.9 (br. s, NCCH₃), 61.0 (br. s, NCCH₃), 82.8 (d,

CHON), 172.0 (s, C=O) ppm. MS (EI): m/z (%) = 254 (7) [M]⁺,

239 (15) [M – CH₃]⁺, 156 (100) [TEMPO]⁺, 123 (24), 69 (24), 55

(26), 41 (30). C₁₄H₂₆N₂O₂(254.4): calcd. C 66.11, H 10.30, N 11.01;

found C 66.18, H 10.50, N 10.98.

+

69 (11), 41 (16). HRMS: calcd. for C₂₁H₃₆N₂O₆412.2573; found

412.2575.

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)heptanoic Acid (11): A solu-

tion of nBuLi (2.75 mL, 4.4 mmol, 1.6 m in hexane) was added at

–78 °C to a solution of anhydrous LiCl (400 mg, 9.4 mmol) and

dry diethylamine (0.455 mL, 321 mg, 4.4 mmol) in dry THF

Ethyl (2S,4R)- and (2S,4S)-1-(tert-Butyloxycarbonyl)-5-oxo-4- (20 mL). The reaction mixture was stirred at –78 °C for 10 min and

(2,2,6,6-tetramethylpiperidin-1-yloxy)pyrrolidine-2-carboxylates at 0 °C for 20 min. The acid 10 (0.284 mL, 2 mmol) was added

14

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α-Oxygenation of Carbonyl Compounds

through a syringe at –78 °C. After stirring at the same temperature

for 10 min and at 0 °C for 1 h, the reaction was cooled to –78 °C

and TEMPO (1; 374 mg, 2.4 mmol) was added. Stirring was con-

tinued for 5 min and ferrocenium hexafluorophosphate (2; 0.99 g,

3 mmol) was added in portions at –78 °C over 10 min until a blue

color persisted in the mixture. The reaction mixture was stirred at

–78 °C for 10 min and quenched with water (30 mL). The organic

layer was extracted twice with water. The combined aqueous layers

were acidified with conc. HCl (3.5 mL) and extracted with diethyl

ether. The combined ethereal layers were washed with water and

brine, dried with Na₂SO₄and the solvent was removed in vacuo.

Flash chromatography (hexane/EtOAc, 10:1, gradient to 2:1; 11

eluted at a polarity 2:1) afforded ferrocene followed by residual 10,

80 mg of a mixture of 10 and 13, and 360 mg of a mixture of 11 and

12. Yield based on the NMR spectra: 57 mg (22%) of recovered 10,

23 mg (9%) of 13, 291 mg (51%) of 11 and 36 mg (14%) of 12.

Further purification of the product allowed the analytical charac-

Na + H]⁺, 704 (8), 660 (8), 615 (8), 505 (25) [2M + Na]⁺, 443 (7),

270 (6), 264 (68) [M + Na]⁺, 242 (7), 186 (29), 142 (100)

[TMPH₂]⁺, 126 (26). HRMS: calcd. for C₁₄H₂₈NO₂242.2115;

+

found 242.2114. C₁₄H₂₇NO₂(241.20): calcd. C 69.66, H 11.27, N

5.80; found C 69.55, H 11.47, N 5.90.

2,2-Dimethyl-4-(2,2,6,6-tetramethylpiperidin-1-yloxy)pentan-3-one

(15b): Flash chromatography (hexane/EtOAc, 100:1, gradient to

20:1) afforded ferrocene followed by 15b and residual 14b; yield

506 mg (94%) as a pale-yellow oil. R_f= 0.54 (hexane/EtOAc, 10:1).

IR (film): ν = 2971, 2933, 2872, 1718, 1477, 1363, 1133, 1047, 983,

˜

938 cm^–1. ¹H NMR (400 MHz): δ = 0.97 (br. s, 3 H, NCCH₃), 1.12

(br. s, 6 H, NCCH₃), 1.18 [s, 9 H, C(CH₃)₃], 1.19 (br. s, 3 H,

NCCH₃), 1.25–1.62 (m, 6 H, NCCH₂CH₂CH₂CN), 1.30 (d, J =

6.7 Hz, 3 H, CHCH₃), 4.81 (q, J = 6.8 Hz, 1 H, CHON) ppm.

¹³C NMR (100 MHz): δ = 17.1 (t, NCCH₂CH₂CH₂CN), 18.4 (q,

CHCH₃), 20.3 (q, NCCH₃), 26.8 [q, C(CH₃)₃], 33.9 (q, NCCH₃),

40.3 (t, NCCH₂CH₂CH₂CN), 43.3 [s, OCC(CH₃)₃], 59.7 (s,

NCCH₃), 80.2 (d, CHON), 216.3 (s, CO) ppm. MS (+CI): m/z (%)

terization. R = 0.35 (hexane/EtOAc, 2:1). IR (film): ν = 3350–2450

˜

f

(br. w), 2930, 2870, 1718, 1464, 1376, 1362, 1239, 1211, 1180, 1132,

1039, 957, 793, 712 cm^–1. ¹H NMR (400 MHz): δ = 0.84 (t, J =

7.0 Hz, 3 H, CH₂CH₂CH₃), 1.19 (s, 3 H, NCCH₃), 1.21 (s, 3 H,

NCCH₃), 1.24 (s, 3 H, NCCH₃), 1.28 (m, 4 H, CH₃CH₂CH₂), 1.29

(s, 3 H, NCCH₃), 1.44 (m, 3 H, CHCH₂CH₂, NCCH₂CH₂-

CH₂CN), 1.61 (m, 5 H, NCCH₂CH₂CH₂CN), 1.74 (m, 1 H,

CHCH₂), 2.03 (m, 1 H, CHCH₂), 4.37 (dd, J = 8.5, 4.0 Hz, 1 H,

CHON), 14.58 (br. s, 1 H, COOH) ppm. ¹³C NMR (100 MHz): δ

= 13.7 (q, CH₂CH₃), 16.1 (t, NCCH₂CH₂CH₂CN), 20.7 (q,

NCCH₃), 22.1 (t, CH₂CH₃), 25.0 (t, CHCH₂CH₂), 30.0 (q,

NCCH₃), 30.9 (q, NCCH₃), 31.2 (t, CH₃CH₂CH₂), 31.6 (t,

C H C H ₂) , 3 8 . 9 ( t , N C C H ₂C H ₂C H ₂C N ) , 3 9 . 0 ( t ,

NCCH₂CH₂CH₂CN), 62.4 (s, NCCH₃), 62.7 (s, NCCH₃), 80.0 (d,

CHON), 174.0 (s, COOH) ppm. MS (+CI): m/z (%) = 286 (23) [M

+ H]⁺, 158 (9) [TEMPOH₂]⁺, 142 (100) [TMPH₂]⁺, 126 (10), 111

(11), 98 (9), 75 (9), 69 (20), 61 (28). HRMS (+ESI): calcd. for

+

= 270 (100) [M + H]⁺. HRMS (ESI): calcd. for C₁₆H₃₂NO₂

270.2427; found 270.2428; calcd. for C₁₆H₃₁NO₂Na⁺292.2247,

found 292.2248. C₁₆H₃₁NO₂(269.42): calcd. C 71.33, H 11.60, N

5.20; found C 71.61, H 11.77, N 5.46.

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)cycloheptanone (15d): Flash

chromatography (hexane/EtOAc, 80:1, gradient to 10:1) gave ferro-

cene followed by 15d; yield 467 mg (87%) as a colorless solid. M.p.

23–24 °C. R = 0.48 (hexane/EtOAc, 10:1). IR (film): ν = 2999,

˜

f

2970, 2929, 2869, 2679, 1705, 1452, 1411, 1376, 1359, 1262, 1241,

1208, 1184, 1134, 1101, 1083, 1048, 1018, 990, 957, 932, 854, 831,

790 cm^–1. ¹H NMR (400 MHz): δ = 0.98 (s, 3 H, NCCH₃), 1.15 (s,

9 H , N C CH ₃) , 1 . 22 –1 . 5 3 ( m, 8 H , CH₂CH₂CH₂C=O,

CH₂CH₂CHO, NCCH₂CH₂CH₂CN), 1.63–1.81 (m, 4 H,

CH₂CH₂CH₂CH₂CHON), 1.96 (m, 2 H, CH₂CH₂C=O,

CH₂CHON), 2.34 (ddd, J = 15.0, 9.2, 5.2 Hz, 1 H, CH₂C=O), 2.79

(ddt, J = 15.1, 6.0, 1.3 Hz, 1 H, CH₂C=O), 4.31 (dd, J = 8.1,

3.2 Hz, 1 H, CHON) ppm. ¹³C NMR (100 MHz): δ = 17.0 (t,

NCCH₂CH₂CH₂CN), 20.3 (q, NCCH₃), 23.4 (t, CH₂CH₂C=O),

24.5 (t, CH₂CH₂CHON), 28.3 (t, CH₂CH₂CH₂C=O), 30.4 (t,

CH₂CHON), 33.7 (q, NCCH₃), 40.1 (t, NCCH₂CH₂CH₂CN), 41.4

(t, CH₂C=O), 59.5 (s, NCCH₃), 92.4 (d, CHON), 213.8 (s,

C=O) ppm. MS (+CI): m/z (%) = 268 (100) [M + H]⁺, 156 (5)

[TEMPO]⁺, 142 (3) [TMPH₂]⁺. HRMS (ESI): calcd. for

C

₁₆H₃₁NO₃Na⁺308.2202; found 308.2199. C₁₆H₃₁NO₃(285.42):

calcd. C 67.33, H 10.95, N 4.91; found C 67.04, H 11.10, N 4.90.

1

meso/

D

,

L

-Dodecane-6,7-dicarboxylic Acids (12): meso-12: H NMR

(200 MHz): δ = 0.89 (m, 6 H, CH₂CH₃), 1.28–1.62 (m, 16 H,

CH₂CH₂CH₂CH₂CH₃), 2.66 (m, 2 H, CHCOOH), 11.92 (br. s, 2

H, COOH) ppm. ¹³C NMR (50 MHz): δ = 14.1 (q, CH₂CH₃), 22.1

(t, CH₃CH₂), 27.0 (t, CH₂), 30.6 (t, CH₂), 31.5 (t, CHCH₂), 48.0

(d, CHCOOH), 178.1 (s, COOH) ppm. d,l-12: Detectable reso-

+

1

C₁₉H₂₉NO₂267.2192; found 267.2192. C₁₆H₂₉NO₂(267.41):

nances: H NMR (200 MHz): δ = 0.89 (m, 6 H, CH₂CH₃), 1.28–

calcd. C 71.86, H 10.93, N 5.24; found C 71.61, H 11.16, N 5.46.

1.62 (m, 16 H, CH₂CH₂CH₂CH₂CH₃), 2.71 (m, 2 H, CHCOOH),

11.92 (br. s, 2 H, COOH) ppm. ¹³C NMR (50 MHz): δ = 22.4 (t,

CH₃CH₂), 26.3 (t, CH₂), 28.7 (t, CH₂), 31.6 (t, CHCH₂), 46.0 (d,

CHCOOH), 180.7 (s, COOH) ppm.

(R)-2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)camphor (15f): Flash

chromatography (hexane/EtOAc, 100:1, gradient to 5:1) afforded

ferrocene followed by a mixture of endo-15f, exo-15f and sometimes

exo,exo-dimer 16f^[27]as colorless solids. For yields and ratios, see

Table 4. The following analyses were performed on the dia-

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)pentan-3-one (15a): Flash

chromatography (hexane/EtOAc, 40:1, gradient to 2:1) gave ferro-

cene followed by 15a; yield 435 mg (90%) as a pale-yellow oil. R_fstereomeric mixture prior to further separation. IR (KBr): ν =

˜

= 0.40 (hexane/EtOAc, 5:1). IR (film): ν = 2975, 2933, 2874, 1717,

3010, 2991, 2965, 2939, 2890, 2871, 2848, 1750, 1470, 1453, 1391,

1375, 1360, 1259, 1181, 1131, 1063, 1010, 994, 958, 945, 840 cm^–1.

MS (+EI): m/z (%) = 307 (48) [M]⁺, 292 (42) [M – CH₃]⁺, 156

˜

1456, 1375, 1361, 1260, 1242, 1209, 1184, 1133, 1093, 1045, 1018,

1

992, 958, 926, 881, 789, 713 cm^–1. H NMR (400 MHz): δ = 0.92

(br. s, 3 H, NCCH₃), 0.99 (t, J = 7.3 Hz, 3 H, CH₃CH₂CO), 1.04 (100) [TEMPO]⁺, 142 (14) [TMPH₂]⁺, 123 (53) [M – TEMPO –

(br. s, 3 H, NCCH₃), 1.09 (br. s, 6 H, NCCH₃), 1.18–1.52 (m, 6 H, CH₂=CH₂]⁺, 81 (14) [M – TEMPO – CH₂=CH₂–C(CH₃)₂]⁺, 69

NCCH₂CH₂CH₂CN), 1.25 (d, J = 7.0 Hz, 3 H, CH₃CHCO), 2.48 (11), 55 (19), 41 (18). C₁₉H₃₃NO₂(307.47): calcd. C 74.22, H 10.82,

(dq, J = 18.5, 7.2 Hz, 1 H, OCCH₂CH₃), 2.65 (dq, J = 18.5, 7.3 Hz,

1 H, OCCH₂CH₃), 4.22 (q, J = 7.0 Hz, 1 H, CHON) ppm. ¹³C

N M R ( 1 0 0 M H z ) : δ = 7 . 1 ( q , C H ₂C H ₃) , 1 7 . 0 ( t ,

N 4.56; found C 74.15, H 10.90, N 4.33. (R)-2-exo-15f: R_f= 0.43

(hexane/EtOAc, 10:1). ¹H NMR (400 MHz): δ = 0.86 (s, 3 H,

CH₂CCH₃), 0.88 (s, 3 H, CHCCH₃), 0.95 (s, 3 H, CHCCH₃), 1.06

NCCH₂CH₂CH₂CN), 18.0 (q, CHCH₃), 20.2 (q, NCCH₃), 31.3 (t, (br. s, 3 H, NCCH₃), 1.16 (br. s, 6 H, NCCH₃), 1.23–1.42 (m, 6

CH₃CH₂CO), 33.7 (q, NCCH₃), 34.2 (q, NCCH₃), 40.2 (t, H, NCCH₂CH₂CH₂CN, CCH₂CH₂CH, NCCH₃), 1.42 (br. s, 4 H,

NCCH₂CH₂CH₂CN), 59.4 (s, NCCH₃), 59.9 (s, NCCH₃), 87.1 (d, N C C H ₂C H ₂C H ₂C N ) , 1 . 5 2 ( m , 2 H , C H ₂C C = O ,

CHON), 213.4 (s, CO) ppm. MS (+ESI): m/z (%) = 748 (6) [3M +

NCCH₂CH₂CH₂CN), 1.90 (m, 1 H, CH₂CH₂CH), 2.43 (d, J =

Eur. J. Org. Chem. 0000, 0–0

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E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

4.9 Hz, 1 H, CHCHON), 4.02 (s, 1 H, CHON) ppm. ¹³C NMR NCCH₃), 1.30 (s, 3 H, NCCH₃), 2.02 (m, 2 H, CH₂CHON), 4.86

FULL PAPER

(100 MHz): δ = 9.1 (q, CH₃CC=O), 17.1 (t, NCCH₂CH₂CH₂CN),

(dd, J = 8.4, 5.4 Hz, 1 H, CHCH₂), 7.50 (m, 3 H, m,p-Ph), 8.10

19.8 (q, CHCCH₃), 20.2 (q, NCCH₃), 20.8 (q, CHCCH₃), 25.0 (t, (dd, J = 8.3, 1.7 Hz, 2 H, o-Ph) ppm. ¹³C NMR (50 MHz): δ = 9.1

CH₂CHCH), 28.8 (t, CH₂CH₂CH), 32.1 (q, NCCH₃), 35.0 (q, (q, CH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 20.2 (q, NCCH₃), 25.8

NCCH₃), 40.4 (NCCH₂CH₂CH₂CN), 46.2 [s, CHC(CH₃)₂], 48.3 (t, CH₂CH₃), 33.6 (q, NCCH₃), 33.8 (q, NCCH₃), 40.3 (t,

(d, CHCHON), 56.8 (s, CH₃CCO), 59.5 (s, NCCH₃), 61.5 (s,

NCCH₃), 90.7 (d, CHON), 217.5 (C=O) ppm. (R)-2-endo-15f: M.p.

25–26 °C. R_f= 0.51 (hexane/EtOAc, 10:1). ¹H NMR (400 MHz): δ

= 0.81 (s, 3 H, CHCCH₃), 0.85 (s, 3 H, CH₂CCH₃), 0.93 (s, 3 H,

CHCCH₃), 1.06 (br. s, 3 H, NCCH₃), 1.09 (br. s, 3 H, NCCH₃),

NCCH₂CH₂CH₂CN), 59.7 (s, NCCH₃), 90.8 (d, CHON), 128.4 (d,

Ph), 129.1 (d, Ph), 132.8 (d, Ph), 136.0 (s, Ph), 201.2 (s, CO) ppm.

MS (+CI): m/z (%) = 304 (100) [M + H]⁺, 157 (9) [TEMPO +

H]⁺, 156 (62) [TEMPO]⁺, 142 (7) [TMPH₂]⁺, 105 (12) [PhC=O]⁺.

HRMS (ESI): calcd. for C₁₉H₂₉NO₂Na⁺326.2096; found 326.2090.

1.17 (br. s, 3 H, NCCH₃), 1.20–1.59 (m, 10 H, NCCH₂CH₂CH₂CN, C₁₉H₂₉NO₂(303.44): calcd. C 75.21, H 9.63, N 4.62; found C

CCH₂CH₂CH, NCCH₃), 1.64 (m, 2 H, CCH₂CH₂CH), 1.87 (m, 1 75.27, H 9.77, N 4.67.

H, CCH₂CH₂CH), 2.37 (t, J = 4.3 Hz, 1 H, CHCHON), 4.46 (dd,

D,L- and meso-2,3-Diethyl-1,4-diphenyl-1,4-butanedione (16i): d,l-

J = 4.7, 1.1 Hz, 1 H, CHON) ppm. ¹³C NMR (100 MHz): δ = 9.5

(q, CH₃CC=O), 17.0 (t, NCCH₂CH₂CH₂CN), 18.85 (t,

CH₂CH₂CH), 18.86 (q, CHCCH₃), 19.8 (q, CHCCH₃), 20.0 (q,

NCCH₃), 20.1 (q, NCCH₃), 32.1 (t, CCH₂CH₂), 32.1 (q, NCCH₃),

34.2 (q, NCCH₃), 40.5 (t, NCCH₂CH₂CH₂CN), 42.1 [s, CHC-

(CH₃)₂], 48.4 (d, CHCHON), 58.4 (s, CH₃CCO), 59.0 (s, NCCH₃),

62.0 (s, NCCH₃), 88.5 (d, CHON), 216.7 (s, C=O) ppm.

1

16i: R_f= 0.5 (hexane/EtOAc, 5:1). H NMR (400 MHz): δ = 0.81

(t, J = 7.5 Hz, 6 H, CH₂CH₃), 1.69–1.88 (m, 4 H, CH₂CH₃), 4.07

(m, 2 H, CHCH₂), 7.36–7.54 (m, 6 H, Ph), 7.97 (m, 4 H, Ph) ppm.

¹³C NMR (100 MHz): δ = 10.1 (q, CH₃), 21.9 (t, CH₂CH₃), 46.5

(d, CH), 128.2 (d, Ph), 128.3 (d, Ph), 132.6 (d, Ph), 137.4 (s, Ph),

203.9 (s, CO) ppm. MS (+ESI): m/z (%) = 611 (3) [3M + Na]⁺, 317

+

(100) [M + Na]⁺, 295 (13) [M + H]⁺. HRMS: calcd. for C₂₀H₂₃O₂

6-(2,2,6,6-Tetramethylpiperidin-1-yloxy)-2-cyclohexenone (15g): Iso-

lation by flash chromatography (hexane/EtOAc, 50:1, gradient to

295.1698; found 295.1693; calcd. for C₂₀H₂₂O₂Na⁺317.1517; found

317.1512. C₂₀H₂₂O₂(294.39): calcd. C 81.60, H 7.53; found C

1:1). Remaining TEMPO was removed by sublimation at 40 °C; 81.42, H 7.50. meso-16i: Detectable resonances: R_f= 0.57 (hexane/

yield 256 mg (56%) as a pale-yellow oil. R_f= 0.4 (hexane/EtOAc,

EtOAc, 5:1). ¹H NMR (400 MHz): δ = 0.69 (t, J = 7.4 Hz, 6 H,

CH₂CH₃), 1.69–1.88 (m, 4 H, CH₂CH₃), 3.94 (m, 2 H, CHCH₂),

7.36–7.54 (m, 6 H, Ph), 8.07 (m, 4 H, Ph) ppm. ¹³C NMR

5:1). IR (film): ν = 2928, 1687, 1470, 1436, 1376, 1361, 1259, 1242,

˜

1209, 1133, 1087, 1048, 959, 926, 833, 755, 706 cm^–1. ¹H NMR

(400 MHz): δ = 1.01 (br. s, 3 H, NCCH₃), 1.09 (br. s, 3 H, NCCH₃), (100 MHz): δ = 11.5 (q, CH₃), 25.2 (t, CH₂CH₃), 48.8 (d, CH),

1.14 (s, 6 H, NCCH₃), 1.23–1.32 (m, 1 H, NCCH₂CH₂CH₂CN), 128.6 (d, Ph), 138.3 (s, Ph), 203.9 (s, CO) ppm. MS (EI): m/z (%)

1.34–1.66 (m, 5 H, NCCH₂CH₂CH₂CN), 2.07–2.21 (m, 1 H, = 294 (2) [M]⁺, 276 (10), 261 (3), 189 (3) [M – PhCO]⁺, 161 (6),

CH₂CHON), 2.21–2.40 (m, 2 H, CH₂CH₂CHON), 2.46–2.64 (m, 148 (25), 105 (100) [PhCO]⁺, 77 (45) [Ph]⁺, 51 (7). HRMS: calcd.

+

1 H, CH₂CH₂CHON), 4.23 (dd, J = 3.5, 8.2 Hz, 1 H, CHON), for C₂₀H₂₂O₂294.1620; found 295.1616.

5.94 (d, J = 10.0 Hz, 1 H, CH=CHCO), 6.84 (dt, J = 3.6, 10.1 Hz,

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)isobutyrophenone (15j):

Flash chromatography (hexane/EtOAc, 80:1, gradient to 20:1) af-

1 H, CH=CHCO) ppm. ¹³C NMR (100 MHz): δ = 17.3 (t,

NCCH₂CH₂CH₂CN), 20.4 (q, NCCH₃), 24.3 (t, CH₂CH₂CHON),

forded a mixture of ferrocene, 15j and isobutyrophenone 14j, fol-

29.8 (t, CH₂CHON), 33.7 (q, NCCH₃), 34.2 (q, NCCH₃), 40.3 (t,

lowed by an inseparable mixture of 15j, 14j and 1 with R_f= 0.3

NCCH₂CH₂CH₂CN), 60.3 (s, NCCH₃), 84.1 (d, CHON), 129.0 (d,

(hexane/EtOAc, 10:1). For yields and ratios, see Table 4. Pale-yel-

CHCO), 149.0 (d, CHCHCO), 198.1 (s, CO) ppm. MS (+ESI): m/z

low oil. R_f= 0.54 (hexane/EtOAc, 10:1). ¹H NMR (400 MHz): δ =

(%) = 274 (79) [M + Na]⁺, 252 (68) [M + H]⁺. HRMS: calcd. for

0.988 (s, 6 H, NCCH₃), 0.990 (s, 6 H, NCCH₃), 1.25–1.59 (m, 6 H,

+

C₁₅H₂₆NO₂252.1958; found 252.1958.

NCCH₂CH₂CH₂CN), 1.62 [s, 6 H, NOC(CH₃)₂], 7.41–7.56 (m, 3

D,L- and meso-2,3-Dimethyl-1,4-diphenyl-1,4-butanedione (16h): d,l-

H, m,p-Ph), 8.30 (d, J = 7.1 Hz, 2 H, o-Ph) ppm. ¹³C NMR

(100 MHz): δ = 16.7 (t, NCCH₂CH₂CH₂CN), 20.8 (q, NCCH₃),

16h: M.p. 84 °C. R = 0.4 (hexane/EtOAc, 5:1). IR (KBr): ν = 2971,

˜

f

1677, 1446, 1208, 966, 703 cm^–1. ¹H NMR (400 MHz): δ = 1.19 2 5 . 4 [ q , N O C ( C H ₃

(m, 6 H, CHCH₃), 3.89 (m, 2 H, CHCH₃), 7.16–7.48 (m, 6 H, Ph),

7.93 (m, 4 H, Ph) ppm. ¹³C NMR (100 MHz): δ = 15.5 (q, CH₃), Ph), 130.6 (d, Ph), 131.9 (d, Ph), 134.7 (s, Ph), 201.8 (s, C=O) ppm.

)

₂] , 3 3 . 1 ( q , N C C H ₃) , 4 0 . 1 ( t ,

NCCH₂CH₂CH₂CN), 59.1 (s, NCCH₃), 86.9 (s, CON), 127.6 (d,

43.6 (d, CH), 128.4 (d, Ph), 128.6 (d, Ph), 132.9 (d, Ph), 136.1 (s,

Ph), 204.2 (s, CO) ppm. meso-16h: R_f= 0.5 (hexane/EtOAc, 5:1).

MS (+ESI; mixture of 15j/14j 3.3:1): m/z (%) = 629 (34) [2M +

Na]⁺, 482 (26), 473 (26), 326 (100) [M + Na]⁺, 284 (57), 179 (44)

¹H NMR (400 MHz): δ = 1.08 (m, 6 H, CHCH₃), 3.98 (m, 2 H, [TEMPO + Na]⁺, 158 (39) [TEMPOH₂]⁺, 142 (19) [TMPH + H]⁺.

CHCH₃), 7.38–7.58 (m, 6 H, Ph), 7.99 (m, 4 H, Ph) ppm. ¹³C NMR

(100 MHz): δ = 17.4 (q, CH₃), 43.3 (d, CH), 128.4 (d, Ph), 128.8

(d, Ph), 133.3 (d, Ph), 136.8 (s, Ph), 203.7 (s, CO) ppm. MS (EI):

m/z (%) = 266 (18) [M]⁺, 105 (100) [PhCO]⁺, 77 (26). HRMS: calcd.

for C₁₈H₁₈O₂⁺266.1307; found 266.1308. C₁₈H₁₈O₂(266.33): calcd.

C 81.17, H 6.81; found C 80.89, H 6.90.

HRMS: calcd. for C₁₉H₂₉NO₂Na⁺326.2096; found 326.2094.

1-(2,2,6,6-Tetramethylpiperidin-1-yloxy)octan-2-one (15k): Flash

chromatography (hexane/EtOAc, 80:1, gradient to 5:1) gave ferro-

cene followed by a mixture of 15k and 15Јk, a mixture of 15k and

traces 18k, aldol/TEMPO trapping product 17k, and finally a mix-

ture of 17k and 19k. The yield was determined from the NMR

spectra. The products were further purified. For yields and ratios,

see Table 5. Pale-yellow oils. R_f= 0.47 (hexane/EtOAc, 10:1). IR

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)butyrophenone (15i): Flash

chromatography (hexane/EtOAc, 80:1, gradient to 5:1) afforded

ferrocene followed by 15i and d,l/meso dimers of 16i. For yields

and ratios, see Table 4. Colorless solid. M.p. 63–65 °C. R_f= 0.50

(film): ν = 2929, 2870, 1718, 1466, 1376, 1360, 1262, 1244, 1209,

˜

1184, 1132, 1074, 993, 972, 957, 926, 791, 722, 705 cm^–1. ¹H NMR

(400 MHz): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH₂CH₃), 1.13 (s, 6 H,

N C C H ₃) , 1 . 1 6 ( s, 6 H , N C C H ₃) , 1 . 2 2 – 1 . 3 5 ( m , 7 H ,

NCCH₂CH₂CH₂CN, CH₂CH₂CH₂CH₃), 1.47 (m, 4 H,

(hexane/EtOAc, 10:1). IR (film): ν = 2971, 2933, 2875, 1679, 1597,

˜

1448, 1375, 1361, 1265, 1241, 1213, 1182, 1133, 1045, 1015, 988,

1

962, 914, 850, 794, 777, 698 cm^–1. H NMR (200 MHz): δ = 0.79

(t, J = 7.5 Hz, 3 H, CH₂CH₃), 0.87 (s, 3 H, NCCH₃), 1.05 (s, 3 H, N C C H ₂C H ₂C H ₂C N ) , 1 . 5 8 ( m , 3 H , C H ₂C H ₂C O ,

NCCH₃), 1.15–1.49 (m, 6 H, NCCH₂CH₂CH₂CN), 1.20 (s, 3 H, NCCH₂CH₂CH₂CN), 2.51 (t, J = 7.4 Hz, 2 H, CH₂CO), 4.39 (s, 2

16

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α-Oxygenation of Carbonyl Compounds

H, CH₂ON) ppm. ¹³C NMR (100 MHz): δ = 13.9 (q, CH₂CH₃), (t, =CHCH₂), 25.6 [q, (E) =CCH₃], 36.0 (t, OCCH₂CH₂CO), 42.8

16.9 (t, NCCH₂CH₂CH₂CN), 20.0 (q, NCCH₃), 22.4 (t, CH₂CH₃), (=CHCH₂CH₂), 122.7 (d, =CH), 132.6 (s, =C), 209.3 (s, CO) ppm.

2 3 . 1 ( t , C H ₂C H ₂C = O ) , 2 8 . 8 ( t , C H ₂C H ₂C H ₃o r MS (EI): m/z (%) = 250 (30) [M]⁺, 232 (8), 207 (6), 166 (16), 163

CH₂CH₂CH₂CH₃), 31.5 (t, CH₂CH₂CH₃or CH₂CH₂CH₂CH₃), (21), 139 (37), 125 (68) [M/2]⁺, 124 (39), 109 (93), 69 (100), 55

32.7 (q, NCCH₃), 39.5 (t, NCCH₂CH₂CH₂CN), 39.6 (t, (19), 43 (40), 41 (63). HRMS: calcd. for C₁₆H₂₆O₂⁺250.1933; found

CH₂CH₂CO), 59.9 (s, NCCH₃), 83.0 (t, CH₂ON), 208.7 (s, 250.1924.

CO) ppm. MS (+ESI): m/z (%) = 589 (10) [2M + Na]⁺, 306 (100)

6-Hydroxy-2,12-dimethyl-6-(2,2,6,6-tetramethylpiperidin-1-yloxy-

methyl)trideca-2,11-dien-8-one (17l): R_f= 0.42 (hexane/EtOAc,

[M + Na]⁺, 179 (3) [TEMPO + Na]⁺. C₁₇H₃₃NO₂(283.45): calcd.

C 72.03, H 11.73, N 4.94; found C 71.92, H 11.74, N 5.07.

10:1). IR (film): ν = 3491, 2970, 2928, 1704, 1449, 1406, 1376, 1359,

˜

7-Hydroxy-7-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)penta-

1262, 1243, 1184, 1132, 1077, 1051, 991, 957, 925, 835, 814,

705 cm^–1. ¹H NMR (400 MHz): δ = 1.09 (br. s, 6 H, NCCH₃),

1.14 (s, 3 H, NCCH₃), 1.15 (s, 3 H, NCCH₃), 1.22–1.52 (m, 6 H,

decan-9-one (17k): R = 0.37 (hexane/EtOAc, 10:1). IR (film): ν =

˜

f

3498, 2928, 2871, 2858, 1702, 1467, 1407, 1374, 1360, 1262, 1244,

1133, 1059, 1046, 993, 956, 925, 820, 725 cm^{–1 1}H NMR NCCH₂CH₂CH₂CN), 1.56 (m, 2 H, CH₂CH₂COH), 1.61 (s, 6 H,

.

(400 MHz): δ = 0.87 (t, J = 6.7 Hz, 3 H, CH₂CH₃), 0.88 (t, J = 2 =CCH₃), 1.67 (s, 6 H, 2 =CCH₃), 2.07 (m, 2 H, CH₂CH₂COH),

6.8 Hz, 3 H, CH₂CH₃), 1.09 (s, 6 H, NCCH₃), 1.12 (s, 3 H, 2.26 (m, 2 H, O=CCH₂CH₂CH=), 2.48 (m, 2 H, CH₂CH₂C=O),

NCCH₃), 1 . 1 4 (s, 3 H , N CCH₃), 1. 28–1.70 (m, 24 H, 2.67 (AB system, J = 16.9 Hz, 2 H, O=CCH₂COH), 3.75 (AB sys-

NCCH₂CH₂CH₂CN, CH₃CH₂CH₂CH₂CH₂CH₂COH, tem, J = 8.9 Hz, 2 H, CH₂ON), 5.07 (m, 2 H, CH=) ppm. ¹³C

CH₃CH₂CH₂CH₂CH₂CH₂CO), 2.47 (dt, J = 1.7, 7.4 Hz, 2 H,

CH₂CH₂C=O), 2.55 (A part of AB system, J = 16.9 Hz, 1 H,

NMR (100 MHz): δ = 16.6 (t, NCCH₂CH₂CH₂CN), 17.2 (q,

=CCH₃), 17.3 (q, =CCH₃), 19.9 (q, NCCH₃), 21.5 (t,

COCH₂COH), 2.75 (B part of AB system, J = 16.8 Hz, 1 H, CH₂CH₂COH), 21.7 (t, CH₂CH₂C=O), 25.2 (q, =CCH₃), 25.3 (q,

COCH₂COH), 3.74 (AB system, J = 8.8 Hz, 2 H, CH₂ON) ppm. =CCH₃), 32.6 (q, NCCH₃), 32.7 (q, NCCH₃), 37.8 (t,

¹³C NMR (100 MHz): δ = 13.89 (q, CH₂CH₃), 13.94 (q, CH₂CH₃),

CH₂CH₂COH), 39.4 (t, NCCH₂CH₂CH₂CN), 44.1 (t,

16.9 (t, NCCH₂CH₂CH₂CN), 20.2 (q, NCCH₃), 22.4 (t, CH₃CH₂), CH₂CH₂C=O), 47.0 (t, OCCH₂COH), 59.6 (s, NCCH₃), 72.9 (s,

22.5 (t, CH₃CH₂), 23.1 (t, CH₂), 23.2 (t, CH₂), 28.7 (t, CH₂), 29.7 COH), 80.8 (t, CH₂ON), 122.1 (d, CH=C), 123.9 (d, CH=C), 131.2

(t, CH₂), 31.5 (t, CH₂), 31.7 (t, CH₂), 33.0 (q, NCCH₃), 38.4 (t,

(s, CH=C), 132.4 (s, CH=C), 211.9 (s, CO) ppm. MS (+ESI): m/z

CH₂), 39.7 (t, NCCH₂CH₂CH₂CN), 44.5 (t, CH₂CH₂C=O), 47.3 (%) = 707 (16), 585 (30), 563 (19), 430 (100) [M + Na]⁺, 408 [M +

(t, OCCH₂COH), 59.9 (s, NCCH₃), 73.4 (s, COH), 81.2 (t, H]⁺, 304 (20) [(CH₃)₂C=CHCH₂CH₂COCH₂OTMP + Na]⁺, 301

+

CH₂ON), 212.7 (s, CO) ppm. MS (+ESI): m/z (%) = 434 (100) [M

(44). HRMS: calcd. for C₂₅H₄₆NO₃408.3478; found 408.3472.

C₂₅H₄₅NO₃(407.63): calcd. C 73.66, H 11.13, N 3.44; found C

+ Na]⁺, 412 (57) [M + H]⁺, 301 (5), 277 (6), 241 (9) [M –

+

C₆H₁₃CO – C₄H₉]⁺. HRMS: calcd. for C₂₅H₅₀NO₃412.3791; 73.71, H 11.46, N 3.49.

found 412.3785. C₂₅H₄₉NO₃(411.66): calcd. C 72.94, H 12.00, N

Cyclopropyl (2,2,6,6-Tetramethylpiperidin-1-yloxy)methyl Ketone

(15m): Flash chromatography (hexane/ethyl acetate, 80:1, gradient

6-Methyl-1-(2,2,6,6-tetramethylpiperidin-1-yloxy)-5-hepten-2-one to 5:1) afforded ferrocene followed by 15m, aldol addition/TEMPO

3.40; found C 73.05, H 11.92, N 3.18.

(15l): Flash chromatography (hexane/EtOAc, 80:1, gradient to 5:1)

afforded ferrocene followed by an inseparable mixture of 15l and

15Јl, 18l containing small amounts of an unknown dimer contain-

ing the tetramethylpiperidinyloxy unit, aldol/TEMPO trapping

product 17l, 16l and 19l. For structure elucidation and analysis, a

second and third purification was performed. For yields and ratios,

see Table 5. Pale-yellow oils. The following analyses were per-

trapping product 17m and an inseparable mixture of dimers 16m

and 18m in a 1:1 ratio. For yields and ratios, see Table 5. Pale-

yellow oils. R = 0.48 (hexane/EtOAc, 10:1). IR (film): ν = 3012,

˜

f

2978, 2935, 2915, 2877, 2849, 1708, 1471, 1448, 1392, 1374, 1360,

1340, 1264, 1188, 1132, 1050, 1017, 995, 955, 928, 907, 858, 820,

774, 716 cm^{– 1}¹H NMR (200 MHz): δ = 0.93 (m, 2 H,

.

CH₂CHCO), 1.09 (m, 2 H, CH₂CHCO), 1.17 (s, 12 H, NCCH₃),

1.25–1.63 (m, 6 H, NCCH₂CH₂CH₂CN), 2.30 (m, 1 H,

CH₂CHCO), 4.51 (s, 2 H, CH₂ON) ppm. ¹³C NMR (50 MHz): δ

= 11.2 (t, CHCH₂), 17.0 (d, CHCO), 17.2 (t, NCCH₂CH₂CH₂CN),

formed with the regioisomeric mixture of 15l and 15Јl: IR (film): ν

˜

= 2972, 2929, 2873, 1718, 1467, 1447, 1376, 1359, 1262, 1244, 1209,

1185, 1133, 1071, 991, 972, 957, 925, 792, 733, 706 cm^–1. MS

(+ESI): m/z (%) = 585 (13) [2M + Na]⁺, 304 (100) [M + Na]⁺, 179 20.2 (q, NCCH₃), 32.8 (q, NCCH₃), 39.6 (t, NCCH₂CH₂CH₂CN),

(11) [TEMPO + Na]⁺. C₁₇H₃₁NO₂(281.43): calcd. C 72.55, H 60.0 (s, NCCH₃), 83.4 (t, CH₂ON), 208.6 (s, CO) ppm. MS (+ESI):

11.10, N 4.98; found C 72.56, H 11.25, N 5.22. 15l: R_f= 0.56

m/z (%) = 501 (39) [2M + Na]⁺, 262 (100) [M + Na]⁺, 179 (4)

(hexane/EtOAc, 10:1). ¹H NMR (400 MHz): δ = 1.13 (s, 6 H, [TEMPO + Na]⁺. C₁₄H₂₅NO₂(239.35): calcd. C 70.25, H 10.53, N

N C C H ₃) , 1 . 1 6 ( s, 6 H , N C C H ₃) , 1 . 2 6 – 1 . 5 6 ( m , 6 H , 5.85; found C 70.29, H 10.66, N 5.83.

NCCH₂CH₂CH₂CN), 1.62 (s, 3 H, =CCH₃), 1.67 (d, J = 1.1 Hz,

1,3-Dicyclopropyl-3-hydroxy-4-(2,2,6,6-tetramethylpiperidin-1-

yloxy)butan-1-one (17m): R_f= 0.34 (hexane/EtOAc, 10:1). IR

3 H, =CCH₃), 2.28 (q, J = 7.3 Hz, 2 H, =CHCH₂), 2.53 (t, J =

7.4 Hz, 2 H, OCCH₂CH₂), 4.38 (s, 2 H, CH₂ON), 5.09 (tq, J =

(film): ν = 2975, 2933, 2875, 1717, 1455, 1376, 1361, 1260, 1242,

˜

7.2, 1.4 Hz, 1 H, =CH) ppm. ¹³C NMR (100 MHz): δ = 16.9 (t,

NCCH₂CH₂CH₂CN), 17.6 [q, (Z) =CCH₃], 20.1 (q, NCCH₃), 21.9

(t, =CHCH₂), 25.6 [q, (E) =CCH₃], 32.8 (q, NCCH₃), 39.5 (t,

NCCH₂CH₂CH₂CN), 39.6 (t, CH₂CO), 60.0 (s, NCCH₃), 83.1 (t,

CH₂ON), 122.7 (d, CH=C), 132.6 (s, CH=C), 208.4 (s, CO) ppm.

1184, 1133, 1091, 1018, 992, 959, 927, 882, 790, 713 cm^–1. ¹H NMR

(400 MHz): δ = 0.34 (m, 2 H, CH₂CH₂CHCOH), 0.50 (m, 2 H,

CH₂CH₂CHCOH), 0.95 (m, 2 H, CH₂CH₂CHC=O), 1.02–1.16 (m,

3 H, CH₂CHCOH, CH₂CH₂CHC=O), 1.12 (br. s, 9 H, NCCH₃),

1.19 (br. s, 3 H, NCCH₃), 1.22–1.62 (m, 6 H, NCCH₂CH₂CH₂CN),

2.03 (tt, J = 4.5, 7.8 Hz, 1 H, CH₂CHC=O), 2.81 (A part of AB

2,13-Dimethyltetradeca-2,12-diene-6,9-dione (16l): R_f= 0.44 (hex-

ane/EtOAc, 5:1). IR (film): ν = 2916, 1713, 1377, 1081 cm^–1. ¹H system, J = 16.3 Hz, 1 H, COCH₂COH), 3.03 (B part of AB sys-

˜

NMR (400 MHz): δ = 1.63 (s, 6 H, =CCH₃), 1.70 (s, 6 H, =CCH₃),

2.27 (q, J = 7.3 Hz, 4 H, =CHCH₂), 2.51 (t, J = 7.4 Hz, 4 H,

=CHCH₂CH₂), 2.70 (s, 4 H, OCCH₂CH₂CO), 5.07 (m, 2 H,

=CH) ppm. ¹³C NMR (100 MHz): δ = 17.6 [q, (Z) = CCH₃], 22.4

tem, J = 16.3 Hz, 1 H, COCH₂COH), 3.76 (AB system, J = 8.3 Hz,

2 H, CH₂ON), 4.00 (br. s, 1 H, OH) ppm. ¹³C NMR (100 MHz):

δ = –0.2 (t, CH₂CHCOH), 0.2 (t, CH₂CHCOH), 11.4 (t,

CH₂CHC=O), 11.9 (t, CH₂CHC=O), 16.9 (t, NCCH₂CH₂-

Eur. J. Org. Chem. 0000, 0–0

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E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

FULL PAPER

CH₂CN), 18.0 (d, CH₂CHCOH), 20.2 (q, NCCH₃), 22.1 (d, OCH₂CH₃), 125.8 (d, p-Ph), 126.2 (d, o-Ph), 128.4 (d, m-Ph), 142.7

CH₂CHC=O), 32.8 (q, NCCH₃), 32.9 (q, NCCH₃), 39.7 (t, (s, i-Ph), 172.8 (s, CO₂) ppm. MS (+ESI): m/z (%) = 227 (100) [M

NCCH₂CH₂CH₂CN), 49.1 (t, HOCCH₂C=O), 59.9 (s, NCCH₃), + Na]⁺, 205 (25) [M + H]⁺, 159 (8) [M – OEt]⁺. HRMS: calcd. for

70.8 (s, COH), 81.9 (t, CH₂ON), 213.2 (s, CO) ppm. MS (+ESI):

m/z (%) = 669 (10) [2M + Na]⁺, 583 (28), 346 (100) [M + Na]⁺, 271

(4). C₁₉H₃₃NO₃(323.47): calcd. C 70.55, H 10.28, N 4.33; found C

70.60, H 10.33, N 4.48.

C₁₃H₁₆O₂Na⁺227.1043; found 227.1042.

Ethyl (E)-5-Phenyl-5-(2,2,6,6-tetramethylpiperidin-1-yloxy)pent-2-

enoate (24) and Ethyl (2E,4E)-5-Phenylpenta-2,4-dienoate (25):

nBuLi (0.41 mL, 0.65 mmol, 1.6 m in hexane) was added dropwise

to a solution of iPr₂NH (85 μL, 0.65 mmol) in dry THF (4 mL) at

–78 °C under argon. After 20 min, 23 (102 μL, 0.5 mmol) was

added. The reaction mixture was stirred for 15 min at –78 °C and

1 (86 mg, 0.55 mmol) was then added in one portion. Subsequently

small portions of ferrocenium hexafluorophosphate (2) were added

at –78 °C until the color of the mixture remained green-blue

(220 mg, 0.66 mmol). The reaction mixture was stirred for 60 min,

quenched with a few drops of water and warmed to room tempera-

ture. The solution was diluted with diethyl ether and filtered

through a plug of silica gel. The solvent was evaporated, the in-

homogeneous residue was pre-adsorbed onto silica gel and purified

by column chromatography (hexane/EtOAc, 50:1, gradient to 1:1)

to give 48 mg (47%) of 25 followed by 30 mg (17%) of 24. Dienoate

25 is commercially available and the analytical data correspond to

the authentic material. 24: R_f= 0.3 (hexane/EtOAc, 5:1). IR (film):

2-(2-Phenylcyclopropyl)acetonitrile (22): Triphenylphosphane

(3.55 g, 13.7 mmol) was added in portions to a solution of 21

(1.37 g, 9.3 mmol) and CBr₄(3.78 g, 11.4 mmol) in dry CH₂Cl₂

(45 mL) at 0 °C over 1 h. After an additional 20 min, the mixture

was poured into pentane. The precipitate was filtered off and the

filtrate was evaporated in vacuo. The precipitation procedure was

repeated several times until no further precipitate was observed.

The mass of the crude bromide was 2.2 g. This material was dis-

solved in dry DMSO (20 mL) and added dropwise to a mixture of

NaCN (453 mg, 9.3 mmol) in DMSO (20 mL). The reaction mix-

ture was stirred at 120 °C until full conversion was indicated by

TLC (ca. 20 h). The reaction mixture was cooled and partitioned

between diethyl ether and water. The organic layer was collected,

washed with water and brine, dried with MgSO₄and the solvents

evaporated. The product was isolated by flash chromatography

(hexane/EtOAc, 20:1, gradient to 1:1); yield 629 mg (43%) as a

ν = 2928, 2362, 1733, 1714, 1626, 1497, 1458, 1366, 1259, 1239,

˜

1178, 1134, 1031, 1001, 973, 958, 792, 754, 713, 697 cm^–1. ¹H NMR

(400 MHz): δ = 0.62 (s, 3 H, NCCH₃), 1.02 (s, 3 H, NCCH₃), 1.17

(s, 3 H, NCCH₃) 1.24 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.31 (s, 3

H, NCCH₃), 1.34–1.65 (m, 6 H, NCCH₂CH₂CH₂CN), 2.63–2.83

(m, 1 H, CH₂CHON), 2.96–3.07 (m, 1 H, CH₂CHON), 4.12 (q, J

= 7.1 Hz, 2 H, OCH₂CH₃), 4.76 (dd, J = 4.2, 9.0 Hz, 1 H, CHON),

5.70 (d, J = 15.7 Hz, 1 H, =CHCO₂), 6.75 (m, 1 H, CH=CHCO₂),

7.23–7.28 (m, 3 H, p,m-Ph), 7.28–7.33 (m, 2 H, o-Ph) ppm. ¹³C

NMR (101 MHz): δ = 13.4 (q, OCH₂CH₃), 16.4 (t, NCCH₂CH₂-

CH₂CN), 19.5 (q, NCCH₃), 33.2 (q, NCCH₃), 33.7 (q, NCCH₃),

38.4 (t, CH₂CHON), 39.6 (t, NCCH₂CH₂CH₂CN), 59.0 (s,

NCCH₃), 59.1 (s, NCCH₃), 59.3 (t, OCH₂CH₃), 84.9 (d, CHON),

122.5 (d, =CHCO₂), 127.1 (d, p-Ph), 127.2 (d, o-Ph), 127.7 (d, m-

Ph), 141.5 (s, i-Ph), 144.2 (d, CH=CHCO₂), 165.5 (s, CO₂) ppm.

MS (+ESI): m/z (%) = 719 (75) [2M + H]⁺, 360 (100) [M + H]⁺,

158 (35) [M – TEMPO – OEt or TMPOH₂]⁺. HRMS: calcd. for

pale-orange oil. R = 0.3 (hexane/EtOAc, 5:1). IR (film): ν = 3028,

˜

f

2249, 1604, 1498, 1462, 1445, 1420, 1084, 1031, 963, 911, 755, 742,

1

696 cm^–1. H NMR (400 MHz): δ = 1.03 (dt, J = 5.6, 9.1 Hz, 1 H,

CHCH₂CH), 1.11 (dt, J = 5.6, 8.4 Hz, 1 H, CHCH₂CH), 1.31–1.40

(m, 1 H, NCCH₂CH), 1.88–1.96 (m, 1 H, PhCH), 2.53 (dd, J =

6.2, 17.3 Hz, 1 H, CH₂CN), 2.60 (dd, J = 6.1, 17.3 Hz, 1 H,

CH₂CN), 7.07 (m, 2 H, o-Ph), 7.18 (m, 1 H, p-Ph), 7.27 (m, 2 H,

m-Ph) ppm. ¹³C NMR (101 MHz): δ = 15.0 (t, CHCH₂CH), 17.7

(d, NCCH₂CH), 21.6 (t, NCCH₂), 23.0 (d, PhCH), 118.4 (s, CN)

126.2 (d, o-Ph), 126.3 (d, p-Ph), 128.7 (d, m-Ph), 141.2 (s, i-

Ph) ppm. MS (EI): m/z (%) = 157 (23) [M]⁺, 130 (25) [M –

HCN]⁺, 117 (100) [M – CH₂CN]⁺, 91 (25) [Bn]⁺. HRMS: calcd.

for C₁₁H₁₁N⁺157.0891; found 157.0895.

Ethyl 2-(2-Phenylcyclopropyl)acetate (23): A solution of 22

(315 mg, 2 mmol) and NaOH (160 mg, 4 mmol) in water (1.5 mL)

was heated under reflux for 10 h. A 20% HCl solution (8 mL) was

added after cooling to room temperature. The aqueous layer was

extracted with diethyl ether (3ϫ5 mL). The organic layer was dried

with MgSO₄and the solvent evaporated. A solution of 2-(2-phenyl-

cyclopropyl)acetic acid (336 mg, 1.9 mmol) in dry DMF (5 mL)

was added dropwise to a mixture of NaH (100 mg, 2.5 mmol, 60%

in mineral oil) in dry DMF (5 mL) at 0 °C. The mixture was then

stirred for 15 min and EtI (0.4 mL, 5.0 mmol) was added. The reac-

tion mixture was warmed to room temperature and stirred for 15 h.

It was diluted with water and extracted with diethyl ether

(2ϫ50 mL) and ethyl acetate (2ϫ50 mL). The combined organic

fractions were dried with MgSO₄and the solvents evaporated. The

residual oil was purified by flash chromatography (hexane/EtOAc,

10:1 with 1 vol.-% NEt₃); yield 322 mg (78% over the two steps) as

+

C₂₂H₃₄NO₃360.2533; found 360.2534.

α-Hydroxy Carbonyl Compounds 26–28

Method 1: Substrates 4, 9 or 15 (1 mmol) were heated with zinc

dust (2.65 g, 40 mmol) and AcOH (6 mL, 105 mmol) in THF

(2 mL) and H₂O (2 mL) at 50 °C until the reaction was complete

(0.5–2 h). The reaction mixture was diluted with diethyl ether.

Workup and isolation was performed under the conditions de-

scribed below (see also Table 6).

Method 2: Substrates 4b,e,k or 15b (1 mmol) were heated with zinc

dust (2.65 g, 40 mmol) and AcOH (6 mL, 105 mmol) in THF

(2 mL) at 50 °C until the reaction was complete (0.5–2 h). The reac-

tion mixture was diluted with diethyl ether. Workup and isolation

was performed under the conditions described below (see also

Table 6).

a colorless oil. R = 0.6 (hexane/EtOAc, 5:1). IR (film): ν = 2980,

˜

f

2930, 1732, 1708, 1626, 1605, 1497, 1463, 1447, 1367, 1298, 1257,

1238, 1176, 1131, 1030, 1001, 960, 917, 877, 834, 755, 697 cm^–1. ¹H

NMR (400 MHz): δ = 0.86 (dt, J = 5.3, 8.7 Hz, 1 H, CHCH₂CH),

1.00 (dt, J = 5.2, 8.5 Hz, 1 H, CHCH₂CH), 1.25 (t, J = 7.1 Hz, 3

H, OCH₂CH₃), 1.33–1.42 (m, 1 H, PhCHCH), 1.76 (m, 1 H,

PhCH), 2.34 (dd, J = 7.1, 15.7 Hz, 1 H, CH₂CO₂), 2.42 (dd, J =

7.0, 15.7 Hz, 1 H, CH₂CO₂), 4.15 (q, J = 7.1 Hz, 2 H, OCH₂), 7.09

(m, 2 H, o-Ph), 7.13 (m, 1 H, p-Ph), 7.24 (m, 2 H, m-Ph) ppm. ¹³C

Workup Conditions A: For non-volatile compounds: The reaction

mixture was filtered through a plug of silica gel. The solvent was

evaporated and the product was purified by flash chromatography.

If the purified product still contained small amounts of acetic acid,

it was dried under high vacuum using a cooling trap.

Workup Conditions B: For volatile and non-volatile compounds:

NMR (101 MHz): δ = 14.4 (q, OCH₂CH₃), 15.4 (t, CHCH₂CH), The reaction mixture was diluted with diethyl ether and filtered

18.7 (d, PhCHCH), 23.1 (d, PhCH), 39.2 (t, CH₂CO₂), 60.6 (t, through a pad of a mixture of silica and solid K₂CO₃. The solvent

18

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α-Oxygenation of Carbonyl Compounds

was carefully evaporated and the product was purified by flash

chromatography.

vent was evaporated in vacuo and the pale-yellow oil was purified

by flash chromatography (hexane/EtOAc, 10:1) to give 29c,g as col-

orless oils.

Workup Conditions C: For volatile products: The reaction mixture

was filtered through a plug of silica gel. The filtrate was neutralized

carefully with solid K₂CO₃at 0 °C. The organic layer was decanted

and the solid AcOK was washed well with diethyl ether. The com-

bined organic layers were dried with Na₂SO₄. The solvent was care-

fully evaporated and the product was purified by flash chromatog-

raphy.

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)-1-pentanol (29c): Yield

116 mg (90%). R_f= 0.18 (hexane/EtOAc, 10:1); R_f= 0.5 (hexane/

EtOAc, 5:1). IR (film): ν = 3430, 3305, 2956, 2932, 2872, 1455,

˜

1380, 1363, 1254, 1243, 1212, 1182, 1131, 1078, 1048, 1020, 992,

1

976, 958, 922, 724, 653 cm^–1. H NMR (400 MHz): δ = 0.86 (t, J

= 7.1 Hz, 3 H, CH₂CH₃), 1.03 (s, 3 H, CH₃CN), 1.10 (s, 3 H,

CH₃CN), 1.16 (m, 1 H, NCCH₂CH₂CH₂CN), 1.25 (s, 6 H,

NCCH₃), 1.27–1.56 [m, 9 H, NCCH₂CH₂CH₂CN, CH(CH₂)₂CH₃],

3.50 (br. d, J = 11.8 Hz, 1 H, CHCH₂OH), 3.89 (dd, J = 11.4,

9.7 Hz, 1 H, CHCH₂OH), 4.20 (dddd, J = 11.8, 9.4, 4.8, 2.0 Hz, 1

H, CHON), 5.90 (s, 1 H, OH) ppm. ¹³C NMR (100 MHz): δ = 14.2

(q, CH₂CH₃), 17.1 (t, NCCH₂CH₂CH₂CN), 19.1 (t, CH₂CH₃),

20.3 (q, NCCH₃), 20.4 (q, NCCH₃), 32.3 (q, NCCH₃), 33.3 (t,

CH₂CH₂CH₃), 34.6 (q, NCCH₃), 39.8 (t, NCCH₂CH₂CH₂CN),

40.3 (t, NCCH₂CH₂CH₂CN), 59.7 (s, NCCH₃), 61.4 (s, NCCH₃),

68.6 (t, CHCH₂OH), 79.8 (d, CH₂CHCH₂OH) ppm. MS (+ESI):

Workup Conditions D: For water-soluble, non-volatile products:

The reaction mixture was filtered through a paper filter and the

solvents evaporated. The crude product was purified by flash

chromatography.

Workup Conditions E: For water-insoluble non-volatile products:

The reaction mixture was filtered through a plug of silica gel. To

remove the acetic acid more easily, water (ca. 15 mL) was added to

the filtrate and the layers were separated. The aqueous layer was

extracted with diethyl ether, the organic layers were washed with

water, the solvent was removed and the crude product was purified

by flash chromatography.

+

m/z (%) = 244 (100) [M]⁺. HRMS: calcd. for C₁₄H₃₀NO₂

244.2277; found 244.2271. C₁₄H₂₉NO₂(243.39): calcd. C 69.09, H

12.01, N 5.75; found C 69.11, H 12.12, N 5.93.

tert-Butyl 2-Hydroxyheptanoate (26b): Isolated by method 2/condi-

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)butane-1,4-diol (29e): A

solution of LiAlH₄(100 μL, 0.2 mmol, 2 m in THF) was added to

dry THF (0.5 mL) at –78 °C. A solution of 4e (49 mg, 0.2 mmol)

in dry THF (1 mL) was added dropwise. The reaction mixture was

slowly warmed to room temperature and stirred until full conver-

sion was observed. The reaction was quenched by the addition of

a few drops of water at 0 °C. The mixture was diluted with diethyl

ether, filtered through a pad of silica gel, extracted with EtOAc and

the solvents evaporated. Flash chromatography (hexane/EtOAc,

2:1) gave 42 mg (86%) of 29e as a colorless oil. R_f= 0.3 (hexane/

tions B, flash chromatography (pentane/Et₂O, 5:1); yield 190 mg

(94%) as a colorless oil. R = 0.3 (hexane/EtOAc, 5:1). IR (film): ν

˜

f

= 3515, 2956, 2930, 2861, 1722, 1459, 1394, 1369, 1255, 1160, 1133,

1085, 1040, 948, 847, 748, 728 cm^–1. ¹H NMR (400 MHz): δ = 0.85

( t , J = 6 . 8 H z , 3 H , C H ₂C H ₃) , 1 . 1 5 – 1 . 3 8 ( m , 6 H ,

CH₃CH₂CH₂CH₂), 1.42 [s, 9 H, C(CH₃)₃], 1.50–1.61 (m, 1 H,

CH₂CHOH), 1.64–1.74 (m, 1 H, CH₂CHOH), 2.83 (d, J = 5.5 Hz,

1 H, OH), 4.00 (ddd, J = 4.5, 5.6, 7.0 Hz, 1 H, CHOH) ppm. ¹³C

NMR (101 MHz): δ = 14.1 (q, CH₂CH₃), 22.7 (t, CH₂CH₃), 24.5

(t, CH₂CH₂CHOH), 28.2 [q, C(CH₃)₃], 31.8 (t, CH₃CH₂CH₂), 34.6

(t, CH₂CHOH), 70.8 (d, CHOH), 82.4 [s, C(CH₃)₃], 174.9 (s,

CO₂) ppm. MS (+ESI): m/z (%) = 446 (20), 427 (45) [2M + Na]⁺,

409 (20) [2M – H₂O + Na]⁺, 225 (100) [M + Na]⁺, 169 (23) [M +

Na – CH₂=C(CH₃)₂]⁺. HRMS: calcd. for C₁₁H₂₂O₃Na⁺225.1461;

found 225.1460.

EtOAc, 1:1). IR (film): ν = 3325, 2929, 1455, 1364, 1257, 1182,

˜

1

1131, 1063, 988, 974, 917, 801, 725 cm^–1. H NMR (400 MHz): δ

= 1.09 (s, 3 H, NCCH₃), 1.15 (s, 3 H, NCCH₃), 1.32 (s, 3 H,

N C C H ₃) , 1 . 3 3 ( s, 3 H , N C C H ₃) , 1 . 3 4 – 1 . 3 9 ( m , 1 H ,

NCCH₂CH₂CH₂CN), 1.42–1.60 (m, 6 H, NCCH₂CH₂CH₂CN,

CH₂CH₂CHON), 1.62–1.74 (dddd, J = 5.2, 7.1, 9.0, 14.4 Hz, 1 H,

CH₂CH₂CHON), 2.47 (br. s, 1 H, OH), 3.54 (dd, J = 2.0, 12.1 Hz,

1 H, HOCH₂CHON), 3.68–3.84 (m, 2 H, HOCH₂CH₂), 4.00 (dd,

J = 9.6, 12.1 Hz, 1 H, HOCH₂CHON), 4.43–4.53 (m, 1 H,

CHON), 5.57 (br. s, 1 H, OH) ppm. ¹³C NMR (101 MHz): δ =

17.4 (t, NCCH₂CH₂CH₂CN), 20.9 (q, NCCH₃), 32.7 (q, NCCH₃),

34.1 (t, HOCH₂CH₂), 34.8 (q, NCCH₃), 40.2 (t, NCCH₂CH₂-

CH₂CN), 40.6 (t, NCCH₂CH₂CH₂CN), 60.4 (s, NCCH₃), 61.0 (t,

HOCH₂CH₂), 61.8 (s, NCCH₃), 68.5 (t, HOCH₂CHON), 80.9 (d,

CHON) ppm. MS (+ESI): m/z (%) = 246 (100) [M + H]⁺. HRMS:

N,N-Diethyl-2-hydroxypentanamide (27f): Isolated by method 1/

conditions A, flash chromatography (hexane/EtOAc, 5:1, gradient

to 1:1); yield 144 mg (83%) as a pale-yellow oil. R_f= 0.29 (hexane/

EtOAc, 2:1). IR (film): ν = 3418, 2962, 2936, 2874, 1636, 1464,

˜

1399, 1382, 1363, 1309, 1281, 1220, 1122, 1101, 1071 cm^{–1 1}H

.

NMR (200 MHz): δ = 0.91 (t, J = 6.9 Hz, 3 H, CH₂CH₂CH₃), 1.10

(t, J = 7.1 Hz, 3 H, NCH₂CH₃), 1.18 (t, J = 7.2 Hz, 3 H,

NCH₂CH₃), 1.35–1.58 (m, 4 H, CHCH₂CH₂CH₃), 3.14–3.38 (m, 3

H, NCH₂), 3.53 (sext., J = 6.7 Hz, 1 H, NCH₂), 4.27 (dd, J = 6.9,

3.3 Hz, 1 H, CHOH), 5.24 (br. s, 1 H, OH) ppm. ¹³C NMR

(50 MHz): δ = 12.7 (q, CH₂CH₂CH₃), 13.8 (q, NCH₂CH₃), 14.0

(q, NCH₂CH₃), 18.2 (t, CH₂CH₂CH₃), 37.5 (t, CHCH₂), 40.2 (t,

CH₂N), 40.9 (t, CH₂N), 67.7 (d, CHOH), 173.8 (s, CO) ppm. MS

(EI): m/z (%) = 173 (1.2) [M]⁺, 131 (32) [M – C₃H₆]⁺, 130 (20) [M –

C₃H₇]⁺, 101 (30) [M – C₃H₇– C₂H₅]⁺, 100 (85) [Et₂NC=O]⁺, 86

(47) [M – C₃H₇– C₂H₅– CH₃]⁺, 72 (100) [NEt₂and M – NEt₂–

Et]⁺, 58 (27) [M – C₃H₇– NEt₂]⁺, 44 (24). C₉H₁₉NO₂(173.25):

calcd. C 62.39, H 11.05, N 8.08; found C 62.28, H 11.38, N 7.87.

+

calcd. for C₁₃H₂₈NO₃246.2064; found 249.2063.

Reduction of the Nitrile Function in 9a,b to Amino Alkoxyamines

30a,b: A solution of 9a,b (1 mmol) dissolved in dry diethyl ether

(1 mL) was added to a suspension of LiAlH₄(76 mg, 2 mmol) in

dry diethyl ether (2 mL) at room temperature. After 1.5 h the reac-

tion was quenched with water (0.3 mL), diluted with diethyl ether

(10 mL) and stirred for a further 10 min. The reaction mixture was

decanted from the soft white solid. The solid residue was washed

three times with diethyl ether. The combined ethereal layers were

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy) Alcohols 29c,g: LiAlH₄washed twice with saturated NaHCO₃solution and extracted three

(25 mg, 0.66 mmol) was added at 0 °C in one portion to a solution

of 4c,g (0.63 mmol) in dry THF (3 mL). After the vigorous reaction

had ceased, the reaction mixture was stirred for 60 min (complete

times with 2 n HCl solution (10 mL). The combined aqueous layers

were washed once with diethyl ether, made basic with 2 n NaOH

solution (40 mL) and extracted three times with diethyl ether

by TLC). The mixture was hydrolyzed with five drops of water, (10 mL). The combined ethereal layers were washed twice with

stirred for 15 min, diluted with diethyl ether (15 mL) and filtered

through a pad of silica gel to remove inorganic material. The sol-

water, twice with brine, dried with Na₂SO₄, evaporated and dried

in vacuo to give the pure products 30a,b.

Eur. J. Org. Chem. 0000, 0–0

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E. Dinca, P. Hartmann, J. Smrcˇek, I. Dix, P. G. Jones, U. Jahn

FULL PAPER

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2-Phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-1-ethylamine

(30a): Yield 204 mg (74%) as a pale-yellow oil. R_f= base line (hex-

ane/EtOAc, 5:1). IR (film): ν = 3380, 3001, 2970, 2929, 2870, 1600,

˜

1452, 1376, 1360, 1258, 1241, 1132, 1015, 987, 956, 922, 878, 847,

796, 759, 700 cm^–^{1 1}H NMR (200 MHz): δ = 0.71 (s, 3 H,

.

NCCH₃), 1.06–1.47 (m, 17 H, NCCH₃, NCCH₂CH₂CH₂CN,

NH₂), 3.11 (d, J = 5.5 Hz, 2 H, CH₂NH₂), 4.69 (t, J = 5.4 Hz, 1

H, CHON), 7.19–7.40 (m, 5 H, Ph) ppm. ¹³C NMR (50 MHz): δ

= 17.1 (t, NCCH₂CH₂CH₂CN), 20.4 (q, NCCH₃), 33.9 (q,

NCCH₃), 40.4 (t, NCCH₂CH₂CH₂CN), 46.6 (t, CH₂NH₂), 59.8 (s,

NCCH₃), 87.9 (d, CHON), 127.2 (d, Ph), 127.4 (d, Ph), 128.0 (d,

Ph), 141.8 (s, Ph) ppm. MS (+ESI): m/z (%) = 299 (18) [M +

Na]⁺, 277 (100) [M + H]⁺. C₁₇H₃₆N₂O (276.42): calcd. C 73.87, H

10.21, N 10.13; found C 73.90, H 10.27, N 10.36.

[5]

[6]

2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)-1-octylamine (30b): Yield

260 mg (91%) as a pale-yellow oil. R_f= base line (hexane/EtOAc,

5:1). IR (film): ν = 3380, 2926, 2857, 1577, 1464, 1376, 1360, 1297,

˜

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1258, 1241, 1208, 1182, 1132, 958, 926, 815, 786, 717 cm^–1. ¹H

NMR (200 MHz): δ = 0.89 (t, J = 6.5 Hz, 3 H, CH₂CH₃), 1.13

(s, 6 H, NCCH₃), 1.13–1.46 [m, 17 H, NCCH₂CH₂CH₂CN, NH₂,

CH₃(CH₂)₄, CH₂CHON], 1.29 (s, 3 H, NCCH₃), 1.46 (s, 3 H,

NCCH₃), 1.70 (m, 1 H, CH₂CHON), 2.82 (m, 2 H, CH₂NH₂), 3.76

(m, 1 H, CHON) ppm. ¹³C NMR (50 MHz): δ = 14.0 (q, CH₂CH₃),

17.2 (t, NCCH₂CH₂CH₂CN), 20.4 (q, NCCH₃), 22.6 (t, CH₃CH₂),

26.0 (t, CH₂), 29.6 (t, CH₂), 31.1 (t, CH₂), 31.8 (t, CH₂), 34.3 (q,

NCCH₃), 40.3 (t, NCCH₂CH₂CH₂CN), 44.8 (t, CH₂NH₂), 59.8 (s,

NCCH₃), 83.2 (d, CHON) ppm. MS (+ESI): m/z (%) = 285 (100)

[M + H]⁺. C₁₇H₃₆N₂O (284.48): calcd. C 71.77, H 12.76, N 9.85;

found C 72.07, H 12.93, N 10.25.

Supporting Information (see footnote on the first page of this arti-

cle): Experimental procedures, analytical data, results of NOE ex-

periments and NMR spectra.

[8]

Acknowledgments

[9]

We gratefully acknowledge generous funding by the Deutsche For-

schungsgemeinschaft (DFG) (Ja896/1-1, Ja896/3-1), the Fonds der

Chemischen Industrie, and the Institute of Organic Chemistry and

Biochemistry of the Academy of Sciences of the Czech Republic

(RVO:61388963). E. D. thanks the Friedrich-Ebert-Stiftung for a

doctoral fellowship.

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Published Online: ᭿

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Pages: 23

α-Oxygenation of Carbonyl Compounds

Enolate Oxygenation

ˇ

E. Dinca, P. Hartmann, J. Smrcek, I. Dix,

P. G. Jones, U. Jahn* ...................... 1–23

General and Efficient α-Oxygenation of

Carbonyl Compounds by TEMPO In-

duced by Single-Electron-Transfer Oxi-

dation of Their Enolates

The oxygenation of enolates proves to be

the most general and effective methodology

for the synthesis of O-protected α-oxy carb-

onyl compounds and nitriles A. The scope

and limitations of the electron-transfer-

induced radical coupling reaction with

TEMPO are presented. The reaction path-

ways are outlined. Methods for the depro-

tection to α-hydroxy carbonyl compounds

B are provided and discussed.

Keywords: Oxidation / Radicals / Electron

transfer / Carbonyl compounds / Enolates

Eur. J. Org. Chem. 0000, 0–0

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23

Article Doi

General and efficient α-oxygenation of carbonyl compounds by TEMPO induced by single-electron-transfer oxidation of their enolates

DOI: 10.1002/ejoc.201200736

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Authors:

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Full text of DOI:10.1002/ejoc.201200736

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