Reactivity of TEMPO anion as a nucleophile and its applications for selective transformations of haloalkanes or acyl halides to aldehydes

Article abstract of DOI:10.1016/j.tet.2004.09.067

Sodium 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO^-Na ⁺), generated by reduction of TEMPO·with sodium naphthalenide in THF, reacted with alkyl halides or acyl halides to produce O-alkylated or acylated TEMPOs, which were in turn oxidized with mCPBA or reduced with DIBAL-H to afford the corresponding aldehydes, thus accomplishing a new protocol for the halides-carbonyls conversion. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.09.067

Tetrahedron 60 (2004) 11969–11975
Reactivity of TEMPO anion as a nucleophile and its applications
for selective transformations of haloalkanes or acyl halides
to aldehydes
a,* b
Tsutomu Inokuchi and Hiroyuki Kawafuchi
a
Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Tsushima-naka, Okayama 700-8530, Japan
Department of Chemical and Biochemical Engineerings, Toyama National College of Technology, Hongo-machi, Toyama 939-8630, Japan
b
Received 21 June 2004; accepted 13 September 2004
Available online 28 October 2004
K
C
Abstract—Sodium 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO Na ), generated by reduction of TEMPO$ with sodium naphthalenide
in THF, reacted with alkyl halides or acyl halides to produce O-alkylated or acylated TEMPOs, which were in turn oxidized with mCPBA or
reduced with DIBAL-H to afford the corresponding aldehydes, thus accomplishing a new protocol for the halides-carbonyls conversion.
q 2004 Elsevier Ltd. All rights reserved.
5
a,12,13
1. Introduction
aldehydes.
On the other hand, 2,2,6,6-tetramethyl-
piperidine-N-oxide (the TEMPO anion), a reduced form of
TEMPO$, is also useful species to produce O-alkyl
TEMPOs. However, the TEMPO anion was usually
generated in aqueous media by treatment with sodium or
calcium ascrobates followed by deprotonation of the
resulting 1-hydroxyTEMP (TEMPOH) with NaH in
Selective oxidation of the benzylic and allylic positions of
arenes and alkenes to the corresponding carbonyl
compounds is an important task especially in the synthesis
1
of bioactive and medicinally significant compounds.
Radical halogenation at the benzylic and allylic positions,
followed by the oxidation of the resulting halides 1 is one of
the most practical methods leading to the desired carbonyl
compounds 3. However, the most conventional method of
1
4,6b
THF
and the reactivity of the TEMPO anion as a
6
c
nucleophile has not been well explored. We, therefore,
utilized a direct method to generate this anionic species by
reduction of TEMPO$ with sodium naphthalenide in THF,
which is featured by the repeated use of naphthalene, and
applied it to the nucleophilic substitution of a variety of
alkyl halides 1 including benzylic and allylic halides.
Subsequently, oxidation of the resulting O-alkylated
2
this conversion, relied on acyloxylation followed by
successive hydrolysis and oxidation of the hydroxy
3
group, is a time-consuming procedure. We, therefore,
developed an efficient method for the conversion of 1 to 3 by
way of the intermediate 2, by utilizing the 2,2,6,6-
tetramethylpiperidine-N-oxy (TEMPO)-substituted carbon
0
TEMPOs 2 and 2 to the corresponding carbonyl
0
4
,5
of 2 as a latent carbonyl function (Scheme 1).
compounds 3 and 3 was examined.
Furthermore, we found that the reduction of O-acylated
TEMPOs with DIBAL-H produced primarily the
corresponding aldehydes 3.
A variety of methods for the preparation of TEMPO-based
molecules have thus far been investigated by trapping the
carbon centered radical with 2,2,6,6-tetramethylpiperidine-
6
–11
N-oxyl radical (abbreviated as TEMPO$) and by the
reaction of its N-oxoammonium salts with ketones and
Keywords: TEMPO and compounds; Oxidation; Reduction; mCPBA;
DIBAL-H; Aldehyde.
*
Corresponding author. Tel.: C81 86 251 8210; fax: C81 86 251 8021;
e-mail: inokuchi@cc.okayama-u.ac.jp
Scheme 1. Benzylic and allylic C–X bond oxidation via substitution with
the TEMPO anion.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.067

11970
T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
2
. Result and discussion
Although reduction of TEMPO$ to the TEMPO anion with
sodium metal or lithium naphthalenide in DME was
6
c
reported by Whitesides et al., we devised a catalytic
procedure with respect to naphthalene (2–10 mol%) by
stirring with a stoichiometric amount of sodium as a real
reducing reagent in THF, during which the red brown color
of TEMPO$ faded as it was converted to the TEMPO anion.
The resulting TEMPO anion-containing solution was used
Scheme 2. Hydrolysis of a-TEMPO substituted acetals 2.
The reactivity of the TEMPO anion toward different
electrophiles such as acyl halides or acid anhydrides 5
and others was also examined. The O-acyl TEMPOs 6
were easily produced (75–88%) by nucleophilic acyl
for the S 2 reactions of a variety of primary and secondary
N
halides 1, giving the corresponding O-alkyl TEMPOs 2.
1
5
As shown in Table 1, primary alkyl halides 1 reacted with
the TEMPO anion to give the corresponding alkoxyamines
2 in good to excellent yields (runs 1–7). The lower reactivity
of 2-halo acetals 1b,c, presumably due to some steric
hindrance, was improved by adding dimethylpropyleneurea
substitution of 5. The reaction of the TEMPO anion
with phenylthiomethyl chloride 7 led quantitatively to
bis(phenylthio)methane 8 instead of the expected O-
phenylthiomethylTEMPO, which is in sharp contrast to
1
6
substitution of 7 with sodium alkoxide (Scheme 3).
(DMPU) or 1,3-dimethyl-2-imidazolidinone (DMI) as a co-
solvent (runs 2 and 3). Similar additive effect was also
attained with HMPA. O-Alkylation with primary benzylic
(
runs 4 and 5) and allylic halide (runs 6 and 7) proceeded
smoothly. On the other hand, secondary halides were less
reactive and moderate yield was obtained with benzylic
halide (run 8).
Our attempts at the substitution reaction of 2-halo ketones
and esters such as bromoacetophenone and bromoacetate
with the TEMPO anion were unsuccessful. However, a
synthetically equivalent and/or useful class of aldehyde 4b
and ketone 4c was obtained in 70–75% yields by hydrolysis
of the acetals 2b and 2c, prepared by the present method
Scheme 3. Reactions of the TEMPO anion with acyl halides or acid
anhydrides 5 and PhSCH Cl (7).
(
Scheme 2).
2
Table 1. O-Alkylations of 2,2,6,6-tetramethylpiperidine-N-oxide anion
a
b
Entry
1
1
Temp/time
Product, 2
Yield/% (method)
a, XZBr
Reflux/18 h
92 (A)
c
2
b, XZBr
rt/17 h, 70 8C/65 h
43 (B)
d
3
4
c, XZBr
d, XZBr
Reflux/110 h
67 (B)
99 (A)
d
rt/0.5 h
d
5
e, XZBr
rt/10 h
99 (A)
6
7
f, XZCl
g, XZCl
Reflux/20 h
Reflux/24 h
89 (A)
76 (B)
8
h, XZBr
Reflux/89 h
45 (A)
a
The reactions were carried out in THF under Ar.
b
c
d
Yields are based on isolated products and calculated based on (A) the halides or (B) TEMPO$.
Carried out in the presence of DMPU.
Carried out in the presence of 1,3-dimethyl-2-imidazolidinone (DMI).

T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
11971
As shown in Table 2, selected O-benzyl- and O-allyl-
TEMPOs 2 were transformed to carbonyl compounds 3. We
examined a variety of oxidizing reagents such as Mn(OAc) ,
3
4
Cu(OAc) , tert-BuOOH for this purpose, but it turned out
b
2
that m-chloroperbenzoic acid (mCPBA) was highly efficient
to complete quickly the reaction at 0–5 8C and the
corresponding 3, conjugated with arenes and CZC double
5
a
bond, were obtained in excellent yields (runs 1–3). In the
mCPBA oxidation, 1-hydroxyTEMP (TEMPOH) along
with a small amount of TEMPO$ was produced as the one
1
7
of fragments from 2.
Furthermore, in addition to the case of a simple alkanal 3a
from 2a (run 4), this reaction was successfully applied to
Scheme 4. Allylic oxidation via halogenation and substitution with the
TEMPO anion followed by mCPBA oxidation. a: (1) Electrolysis, K2e,
1
8
the synthesis of diverse carbonyl compounds including
-acetoxyketone 10 (run 5), acetal of 1,2-dione 12 (run 6),
CH
2 2 2 2
Cl —aq. NaCl/1 N HCl (81%), (2) DHP, pTsOH, CH Cl (81%), b:
K
Nal, acetone, heated (74%), c: TEMPO Na , THF, reflux, 20 h (45%)
C
2
1
9
(
(
2 2 2 2 2
YZCH CH(Me)CH CH OTHP), E:ZZca. 2:1, d: mCPBA, CH Cl
78%).
and 4-oxo-2-enoate 14 (run 7) from the corresponding
precursors 9, 11, and 13, derived from 2-TEMPO-
substituted undecanal as a common starting material.
1
2
Alternatively, the conversion of O-acylated TEMPOs 6 to
the corresponding aldehydes 3 was examined by a hydride
The allylic oxidation of the prenyl derivative 15 was
examined by employing the present protocol (Scheme 4).
21
reduction. Thus, the treatment of 6f (RZPhCHZCH) with
2
0
DIBAL-H (3 equiv) at K78 to K50 8C for 75 min afforded
cleanly the corresponding aldehyde 3f (91% yield) (run 3), the
overreduction to carbinol was negligibly small, while ethyl
trans-cinnamate, an analogue of 6f, produced the corres-
Thus, the electrochemical ene-type chlorination of 15 and
the subsequent protection of the hydroxy group as a THP
ether, giving 16, was followed by the Cl/I exchange reaction
with NaI to afford the allylic iodide 17 (E:ZZca. 2:1). The
SN2 reaction of 17 with the TEMPO anion afforded 18 in
22
ponding primary alcohol under the same conditions.
Examples of the selective reduction of 6 to aldehydes,
including aldol derivative (run 5), are shown in Table 3.
45% yield. The enal 19 was obtained by oxidation with
mCPBA as a ca. 2:1 E/Z mixture in 78% yield, which, on
standing in CDCl , converged to E-isomer.
3
Table 3. Reduction of O-acylated 2,2,6,6-tetramethylpiperidinyl-1-oxyls
with DIBAL-H to aldehydes
a
Table 2. Oxidations of (2,2,6,6-tetramethylpiperidinyl-1-oxy)alkanes to
aldehydes and ketones
a
b
Entry
1
Substrates
Products
Yield/%
95
b
Entry
1
Substrates
Products
Yield/%
6
a
i
3a
(Me)
2d
99
c
72
2
3
2
CH–CHO
3
3
d
e
6
3i
2
3
4
2e
2f
86
86
91
92
6f
3f
Ar–CHO
d
4
3
3
f
2a
88
90
6
j
3j
a
d,e
5
f
c
5
94
9
10
12
14
2
0
21
c
6
96
89
a
Carried out by using excess DIBAL-H (2–3 equv.) in toluene at K78w
K50 8C for 30 min to 1 h.
Yields are based on isolated products.
Yield calculated by comparing with an internal standard (PhCHZCHCHO,
added after the reaction) due to volatility of the product.
11
b
c
c
7
d
e
13
6 4
ArZ4-MeOC H .
The substrate anti-20 was prepared by the aldol reaction of 6 (RZEt)
and 4-MeOC H CHO with LDA (ca. 7:1 ds. mixture) followed by
protection of the anti-adduct, purified by recrystallization, as a THP
either.
Overreduction to the carbinol (4%) was found.
a
Carried out by using slightly excess mCPBA in CH
–5 8C for 30 min.
2
Cl
2
with cooling at
6
4
0
b
c
Yields are based on isolated products.
RZn-C
f
9
H
19
.

11972
T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
1
3
brs at 1.26), 3.71 (t, JZ6.6 Hz, 2H); C NMR (75.5 MHz)
d 14.1, 17.2, 20.1 (2C), 22.7, 26.5, 28.7, 29.4, 29.6, 29.7
(2C), 29.8, 31.9, 33.0 (2C), 39.6 (2C), 59.5 (2C), 76.8.
HRMS (EI) calcd for C H NO 311.3188, found 311.3205.
2
0 41
Similarly, the compound 2c was prepared as follows.
A solution of the TEMPO anion, prepared from TEMPO$
Scheme 5. A proposed mechanism for reduction of O-acyl TEMPOs 6 with
DIBAL-H.
(
(
2.59 g, 16.6 mmol), C H (240 mg, 1.87 mmol), and Na
10 8
420 mg, 18.3 mmol) in THF (20 mL), was added to a
Accordingly, it is conceived that the DIBAL-H reduction of
6 proceeds through the chelated intermediate A with close
resemblance with the case of N-methoxy-N-methylamdies
solution of BrCH C(OMe) CH (1c, 3.5 g, 19.2 mmol) in
3
2
2
THF (10 mL) and DMI (3.6 mL) at 0 8C. The mixture was
gradually raised to room temperature and then heated at
reflux for 110 h, during which solids precipitated. Usual
workup and the removal of volatile materials including the
unreacted TEMPO$ (1.65 g) by distillation of the crude
product at 62 8C (1.5 Torr, bath temperature 90 8C), which
2
3
developed by Weinreb et al., which explain the lack of
over-reduction (Scheme 5).
3. Conclusion
was followed by column chromatography (SiO , hexane and
2
hexane-AcOEt 10:1) of the residual oil to give the TEMPO
substituted acetal 2c (2.9 g, 67% yield based on the starting
TEMPO$): IR (neat) 2933, 2829, 1469, 1454, 1375, 1360,
The TEMPO-attached carbon was shown to be a synthon of
carbonyl group. Haloalkanes were efficiently converted to
aldehyde via O-alkylated TEMPOs by oxidation with
mCPBA (up to 98% yields for two steps). The O-acyl
TEMPOs were selectively reduced to the aldehydes even
with excess DIBAL-H owing to chelating ability of
tetramethylpiperidine group for stabilization of the
hydride-adduct intermediate.
K1 1
261, 1242, 1178, 1132, 1090, 958, 849, 800, 702 cm ; H
1
NMR (300 MHz) d 1.13, 1.19 (s, 12H), 1.41(s, 3H), 1.42–
13
.59 (m, 6H), 3.23 (s, 6H), 3.77 (s, 2H); C NMR
1
(
(
75.5 MHz) d 16.9, 20.0, 20.3, 32.9 (2C), 39.7 (2C), 48.1
2C), 59.8 (2C), 77.4, 100.0. HRMS (EI) calcd for
C H NO 259.2147, found 259.2169.
3
1
4
29
4
2
7
1
.2.2. Compound 2b. Bp 78–82 8C (0.1 Torr); IR (neat)
831, 1469, 1359, 1245, 1135, 1081, 970, 923, 856, 786,
4
. Experimental
K1 1
13 cm ; H NMR (300 MHz) d 1.10, 1.17 (s, 12H), 1.25–
4
.1. General
.55 (m, 6H), 3.39 (s, 6H), 3.84 (d, JZ5.2 Hz, 2H), 4.49
1
3
(
t, JZ5.2 Hz, 1H); C NMR (75.5 MHz) d 16.6, 19.5 (2C),
2.4 (2C), 39.1 (2C), 53.3 (2C), 59.3 (2C), 76.7, 101.9.
HRMS (EI) calcd for C H NO 245.1991, found
IR spectra were obtained with a Horiba, Model FT-210, or a
JASCO, Model FT/IR-230, fourier transform infrared
spectrometer instrument, and only major absorptions are
cited. H and C NMR spectra were recorded on JEOL
JNM-AL400 and Varian Mercury-300 instruments with
CDCl as a solvent unless otherwise indicated.
3
1
3
27
3
2
45.1959.
1
13
4.2.3. Compound 2d. Mp 82.5–83.5 8C; IR (KBr) 3003,
2976, 2927, 2868, 1477, 1360, 1263, 1186, 1132, 1039, 933,
3
K1
29, 775, 750, 706 cm ; H NMR (400 MHz) d 1.04, 1.08
1
8
(s, 12H), 1.20–1.59 (m, 6H), 4.72 (s, 2H), 7.19–7.65 (m,
4
.2. General procedure for preparation of O-alkyl
TEMPOs 2
1
3
9H); C NMR (100 MHz) d 17.5, 20.7 (2C), 33.2 (2C), 40.1
2C), 60.2 (2C), 77.5, 127.1, 127.3, 127.4, 128.1 (2C),
(
In a 50 mL one-necked flask were placed C H (221 mg,
0 8
129.1, 129.4 (2C), 129.9, 135.8, 141.2, 141.8. HRMS (EI)
calcd for C H NO 323.2249, found 323.2277.
1
1
(
2
.72 mmol), TEMPO$ (2.7 g, 17.3 mmol), and THF
15 mL). To this solution was added Na metal (477 mg,
0.7 mmol) and the mixture was stirred at room temperature
2
2 29
4.2.4. Compound 2e. Mp 88–89 8C; IR (KBr) 3003, 2974,
2931, 2889, 1485, 1469, 1448, 1373, 1360, 1261, 1182,
C
K$
until Na dissolved and blue-black color of Na [C H ]
1
0 8
K1
1
; H NMR
persisted. To a solution of n-C H Br (1a, 3.66 g,
23
1132, 1030, 991, 862, 823, 764, 702 cm
(400 MHz) d 1.25, 1.37 (s, 12H), 1.20–1.70 (m, 6H), 4.95
1
1
1
5.5 mmol) in THF (5 mL), placed in a 100 mL one-necked
1
3
flask, was transferred by double-ended needle the above
TEMPO anion with cooling at 0–4 8C. The mixture was
allowed to warm gradually to room temperature and to
(s, 2H), 7.37–7.47 (m, 9H); C NMR (100 MHz) d 17.2,
20.4 (2C), 33.2 (2C), 39.8 (2C), 60.0 (2C), 78.4, 126.8 (2C),
126.9 (2C), 127.0, 127.7 (2C), 128.5 (2C), 137.1, 140.1,
140.8. HRMS (EI) calcd for C H NO 323.2249, found
5
0 8C, stirred for 2 h, and then heated at reflux for 18 h. The
reaction was quenched with cold aqueous NaHCO and
2
2 29
3
323.2216.
products were extracted with AcOEt. Extracts were washed
with brine, dried (MgSO ), and concentrated. The products
were purified by distillation and the fraction of boiling range
137–138 8C (0.15 Torr, bath temperature 150–155 8C) was
collected; 4.47 g (92% yield).
4
4.2.5. Compound 18 (E/Z mixture). IR (Neat) 2929, 1454,
1373, 1358, 1261, 1201, 1184, 1134, 1078, 1030, 991, 908,
870, 814, 735 cm ; H NMR (400 MHz) d 0.87, 0.90 (d,
JZ6.8 Hz, 3H), 1.09, 1.15, 1.19 (s, 12H), 1.65, 1.79 (s, 3H),
K1
1
1
.25–2.12 (m, 19H), 3.33–3.52 (m, 2H), 3.70–3.90 (m, 2H),
4
1
.2.1. Compound 2a. IR (neat) 1467, 1373, 1263, 1133,
047, 759, 711 cm ; H NMR (300 MHz) d 0.88 (complex
4.11, 4.25 (s, 2H), 4.56, 4.81 (s, 1H, OCH), 5.25, 5.37 (t, JZ
6.8 Hz, 1H); C NMR (100 MHz) d 14.3, 17.0, 19.5, 20.0
and 20.1 (2C), 24.8, 25.3, 29.5, 30.6 (2C), 32.8 and 32.9,
K1 1
13
t, JZ6.9 Hz, 3H), 1.09, 1.14 (s, 12H), 1.23–1.56 (m, 24H,

T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
11973
1
3
3
6
1
3
6.4 and 36.5, 37.2 and 37.3, 39.5 (2C), 59.5 (2C), 62.0,
5.6 and 65.7, 75.1, 82.3, 98.4 and 98.6, 128.3, 131.4 and
31.5. HRMS (EI) calcd for C H NO 395.3399, found
C NMR (100 MHz) d 9.3, 19.4 and 19.5, 19.6 and 19.8,
25.6, 26.6, 29.8, 30.8, 35.5 and 35.7, 36.5, 62.4, 65.5 and
65.6, 98.7 and 99.0, 139.0, 154.7, 194.9
2
4
45
4
95.3310.
4.4. Hydrolysis of 2c to 4c
4.3. General procedure for oxidation of O-alkyl
TEMPOs 2 to aldehydes and ketones 3
To a solution of 2c (3.96 g, 15.3 mmol) in THF (80 mL) was
added at 0–4 8C cold 1N HCl (15 mL). The mixture was
allowed to warm to room temperature and stirred for 5 h.
To a solution of the O-alkyl TEMPO 2a (RZC H ,
1
0 21
3
11 mg, 1.0 mmol) in CH Cl (5 mL) was added portion-
The reaction was quenched with aqueous NaHCO and
3
2
2
wise mCPBA (70–75% assay, 296 mg, 1.2 equivalent) over
0 min at 0–4 8C. The reaction was exothermic and the
products were extracted with AcOEt. Usual workup
followed by purification on column chromatography
(SiO , hexane-AcOEt 10:1 and 7:1) gave 2.44 g (75%) of
1
temperature was kept under 8 8C. The mixture was stirred at
the same temperature for 30 min, and the reaction was
quenched with cold aqueous Na S O , and the products
2
the TEMPO-substituted acetone 4c: IR (neat) 1720, 1359,
K1
1
1234, 1133, 1081, 995, 923, 702 cm
(300 MHz) d 1.13, 1.15 (s, 12H), 1.30–1.60 (m, 6H), 2.21
;
H NMR
2
2 3
were extracted with CH Cl (first) and AcOEt (second).
2
2
1
3
(s, 3H), 4.38 (s, 2H); C NMR (75.5 MHz) d 16.8, 19.9
Extracts were washed with aqueous NaHCO3 and with
brine, dried (MgSO ), and concentrated. The crude products
(2C), 27.0, 32.7 (2C), 39.4 (2C), 59.8 (2C), 83.1, 206.6.
4
were purified by column chromatography (SiO , hexane-
2
AcOEt, 7:1, 5:1, 3:1, 2:1, then 1:1) to give 150 mg (88%) of
the aldehyde 3a (RZC H , R Z0.52, hexane-AcOEt 7:1),
4.4.1. Compound 4b. Yield 70%; IR (neat) 2976, 2933,
1736, 1469, 1375, 1362, 1263, 1246, 1134, 1080, 912,
1
0
21
f
K1
735 cm ; H NMR (400 MHz) d 1.12 (s, 12H), 1.20–1.67
1
1
0 mg of TEMPO$, and 101 mg (64%) of a mixture of
1
(m, 6H), 4.41 (s, 2H), 9.73 (s, 1H); C NMR (100 MHz) d
3
TEMPO$ and the N-hydroxypiperidine (R Z0.12, hexane-
f
AcOEt 7:1).
17.1, 20.2 (2C), 32.9 (2C), 39.7 (2C), 60.2 (2C), 83.6, 200.6.
4
2
8
.3.1. 2-Phenylbenzaldehyde 3d. IR (neat) 3062, 2848,
754, 2252, 1655, 1597, 1473, 1394, 1254, 1196, 1009, 910,
4.5. Preparation of O-acyl TEMPOs 6
K1
27, 733, 704, 646 cm ; H NMR (400 MHz) d 7.35–8.04
1
To a cooled (0–4 8C) solution of p-anisoyl chloride 5j
(RZ4-MeOC H , 3.5 g, 20.5 mmol) in THF (10 mL) was
added dropwise a chilled solution of the TEMPO anion,
1
3
(
m, 9H, Ph), 9.97 (s, 1H, CHO); C NMR (100 MHz) d
6
4
1
1
27.4, 127.6, 128.0, 128.3 (2C), 129.9 (2C), 130.6, 133.4,
33.5, 137.5, 145.8, 192.2.
prepared from TEMPO$ (3.12 g, 20 mmol), C H (150 mg,
0 8
1
1.17 mmol), and Na metal (506 mg, 22 mmol). The mixture
4
2
.3.2. 4-Phenylbenzaldehyde 3e. IR (neat) 3059, 3032,
827, 2735, 2252, 1699, 1604, 1566, 1487, 1450, 1412, 1385,
was allowed to warm to room temperature and stirred for
4 h. The reaction was quenched with cold aqueous NaHCO3
and products were extracted with AcOEt, worked up in a
usual manner, and purified by distillation; fraction of
147–152 8C (0.03 Torr) was collected: 5.12 g (88% based
on TEMPO$).
K1
1
308, 1215, 1171, 1007, 910, 839, 762, 731, 696 cm
H NMR (400 MHz) d 7.35–7.96 (m, 9H, Ph), 10.04 (s, 1H,
;
1
1
CHO); C NMR (100 MHz) d 127.1 (2C), 127.4 (2C), 128.2,
3
1
28.5 (2C), 130.0 (2C), 134.9, 139.4, 146.9, 191.5.
4
(
1
.3.3. 1-Acetoxy-2-undecanone 10. Mp 51.5–52.5 8C; IR
KBr) 1862, 1724, 1467, 1409, 1378, 1232, 1130, 1079,
4.5.1. Compound 6j. Mp 89–91 8C (from hexane-AcOEt);
IR (KBr) 1747, 1604, 1510, 1459, 1442, 1317, 1249, 1160,
K1 1
037, 985, 873, 838, 717 cm ; H NMR (300 MHz) d 0.87
K1 1
1130, 1072, 1024, 912, 846, 765, 692, 607 cm ; H NMR
(300 MHz) d 1.10, 1.26 (s, 12H), 1.42–1.48 (m, 1H), 1.54–
1.84 (m, 5H), 3.87 (s, 3H), 6.94 (d, JZ9.1 Hz, 2H), 8.03 (d,
(
complex t, JZ6.2 Hz, 3H), 1.26 (brs, 12H), 1.60 (m, 2H),
1
3
2
.17 (s, 3H), 2.40 (t, JZ7.4 Hz, 2H), 4.65 (s, 2H); C NMR
1
3
(
2
75.5 MHz) d 14.1, 20.5, 22.6, 23.3, 29.1, 29.2, 29.28,
9.33, 31.8, 38.8, 67.9, 170.2, 204.0 HRMS (EI) calcd for
C H O 228.1725, found 228.1772.
JZ9.1 Hz, 2H); C NMR (75.5 MHz) d 16.9, 20.7 (2C),
31.8 (2C), 38.9 (2C), 55.3, 60.2 (2C), 113.6 (2C), 121.8,
131.3 (2C), 163.2, 166.0. HRMS (EI) calcd for C H NO
3
1
3
24
3
17 25
291.1834, found 291.1849.
4
1
7
6
.3.4. Ethyl 4-oxotridec-2-enoate 14. IR (neat) 1727, 1689,
635, 1465, 1367, 1301, 1182, 1095, 1031, 981, 867,
23 cm ; H NMR (300 MHz) d 0.88 (complex t, JZ
.9 Hz, 3H), 1.27 (brs, 12H), 1.32 (t, JZ7.1 Hz, 3H), 1.64
4.5.2. Compound 6a. Yield 85%; IR (neat) 2927, 2854,
1770, 1466, 1377, 1363, 1265, 1246, 1209, 1182, 1134,
K1
1
K1
1
1101, 1045, 935, 721 cm ; H NMR (400 MHz) d 0.85
(complex t, JZ6.8 Hz, 3H), 1.02, 1.12 (s, 12H), 1.20–1.73
(
m, 2H), 2.63 (t, JZ7.4 Hz, 2H), 4.27 (q, JZ7.1 Hz, 2H),
1
3
13
6 C
NMR (300 MHz) d 12.1, 12.2, 20.6, 21.7, 27.1, 27.2, 27.3,
.67 (d, JZ15.9 Hz, 1H), 7.07 (d, JZ15.9 Hz, 1H);
(m, 22H), 2.31 (t, JZ7.6 Hz, 2H); C NMR (100 MHz) d
14.2, 17.1, 20.6 (2C), 22.8, 25.4, 29.3, 29.4, 29.5 (2C), 29.6,
2
7.4, 29.8, 39.5, 59.4, 128.6, 137.3, 163.5, 197.8.
32.0 (2C), 33.1 (2C), 39.0 (2C), 59.9 (2C), 173.0. HRMS
(EI) calcd for C H NO 325.2981, found 325.2986.
20 39 2
4
1
1
.3.5. Enal 19 (E-isomer). IR (neat) 2943, 2871, 1685,
645, 1454, 1381, 1354, 1265, 1201, 1184, 1136, 1120,
4.5.3. Compound 6f. Yield 75%; mp 104–105 8C; IR (KBr)
3066, 1739, 1575, 1450, 1307, 1203, 1124, 1042, 1012, 973,
923, 864, 804, 767, 715, 675 cm ; H NMR (300 MHz) d
1.10, 1.22 (s, 12H), 1.40–1.48 (m, 1H), 1.53–1.80 (m, 5H),
6.49 (d, JZ16.0 Hz, 1H), 7.37–7.42 (m, 3H), 7.55–7.59 (m,
K1
076, 1034, 910, 868, 812, 733 cm ; H NMR (400 MHz)
1
K1
1
d 0.92 (d, JZ6.4 Hz, 3H), 1.73 (s, 3H), 1.25–1.82(m, 11H),
2
4
.25–2.40 (m, 2H), 3.33–3.50 (m, 2H), 3.70–3.85 (m, 2H),
.50–4.55 (m, 1H), 6.45 (t, JZ7.2 Hz, 1H), 9.35 (s, 1H);

11974
T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
1
3
2
1
1
H), 7.76 (d, JZ16.0 Hz, 1H); C NMR (75.5 MHz) d
3. Saunders, J. Top Drugs: Top Synthetic Routes; Oxford
University Press: Oxford, 2000; Chapter 2.
6.8, 20.4 (2C), 31.8 (2C), 38.8 (2C), 60.0 (2C), 116.5,
27.9 (2C), 128.7 (2C), 130.1, 134.3, 144.9, 167.0. HRMS
EI) calcd for C H NO 287.1885, found 287.1924.
18 25 2
4. (a) Semmelhack, M. F.; Schmid, C. R.; Cort e´ s, D. A.
Tetrahedron Lett. 1986, 27, 1119–1122. (b) Rossi, I.;
Venturini, A.; Zedda, A. J. Am. Chem. Soc. 1999, 121,
(
7
914–7917.
4
6
.6. General procedure for reduction of O-acyl TEMPOs
to aldehydes 3
5
. (a) Hunter, D. H.; Barton, D. H. R.; Motherwell, W. J.
Tetrahedron Lett. 1984, 25, 603–606. (b) Skene, W. G.;
Connolly, T. J.; Scaiano, J. C. Tetrahedron Lett. 1999, 40,
To a cooled (K78 8C) solution of 6f (RZPhCHZCH,
23 mg, 2.5 mmol) in toluene (10 mL) was added dropwise
DIBAL-H (1.0 N in toluene, 7.9 mL, 3.1 equivalents) over
7
297–7302.
7
6
. Use of Grignard reagents or organolithium reagents: (a)
Sholle, V. D.; Golubev, V. A.; Rozantsev, E. G. Dokl. Akad.
Nauk SSSR 1971, 200, 137. Chem. Abstr. 1972, 76, 25049e.
5 min. The mixture was stirred at K78 to K50 8C for
75 min and excess DIBAL-H was decomposed with AcOEt
(
b) Hawker, C. J.; Barclay, G. G.; Orellana, A.; Dao, J.;
Devonport, W. Macromolecules 1996, 29, 5245–5254.
c) Whitesides, G. M.; Newirth, T. L. J. Org. Chem. 1975,
0, 3448–3450.
and the reaction was quenched with aqueous NaHCO3
1.0 mL). The mixture was diluted with AcOEt, treated with
a Celite, and filtered from a short Celite pad. The filtrate was
(
(
4
washed with cold 2N HCl, brine, dried (MgSO ), and
4
1
concentrated. The crude products were analyzed by H
7
. Oxidation of enolates; use of Cu(II): (a) Braslau, R.; Burrill,
L. C. II; Siano, M.; Naik, N.; Howden, R. K.; Mahal
Macromolecules 1997, 30, 6445–6450. (b) Wetter, C.; Jantos,
C.; Woithe, K.; Studer, A. Org. Lett. 2003, 5, 2899–2902. Use
of ferroceniu salt: (c) Jahn, U.; Hartmann, P.; Dix, I.; Jones,
P. G. Eur. J. Org. Chem. 2001, 3333–3335.
NMR (300 MHz) to ensure the amount of aldehyde over
carbinol and purified by column chromatography (SiO2,
hexane-AcOEt, 10:1, 7:1, 5:1, 3:1, 2:1, then 1:1) to give
3
08 mg (91%) of 3f (R Z0.36, hexane-AcOEt 5:1),
f
identical in all respects with that obtained above. The
structures of the aldehydes 3a, 3i, 3f, and 3j in Table 3 were
confirmed by comparison of their spectral data with those of
authentic samples.
3
8. Use of radical initiators; Bu SnH: (a) Boger, D. L.; McKie,
J. A. J. Org. Chem. 1995, 60, 1271–1275. Cu(II)(cat.)/Cu(0):
(b) Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor,
S. G.; Metzner, Z. Macromolecules 1998, 31, 5955–5957.
B-Alkylcatecholborane: (c) Ollivier, C.; Chuard, R.; Renaud,
P. Synlett 1999, 807–809.
4
1
.6.1. Aldol 21. IR (neat) 2715, 1727, 1612, 1586, 1513,
303, 1251, 1116, 1035, 1022, 968, 906, 869, 817 cm
K1
;
1
9
2
. Irradiation with radical initiators; use of Mn (CO)10: Gilbert,
H NMR (300 MHz) d 0.85 (d, JZ6.9 Hz, 3H), 1.35–
B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A. F.;
Whittaker, D. T. E. Tetrahedron Lett. 1999, 40, 6095–6098.
1
3
.85 (m, 6H), 2.70–2.85 (m, 1H), 3.15–3.80 (m, 2H),
.809 and 3.813 (s, 3H), 4.40 and 4.80 (m, 1H), 4.64
Use of [Cp(CO)
Refs. 6b,7a.
2 2 2 2
Fe] , (PhS) , (tert-BuO) and others, see
(
(
(
d, JZ8.5 Hz) and 4.78 (d, JZ9.6 Hz, 1H), 6.85–6.90
m, 2H), 7.21–7.28 (m, 2H), 9.82 (d, JZ2.5 Hz) and 9.90
d, JZ3.3 Hz, 1H). HRMS (EI) calcd for C H O
6 22 4
1
1
0. Irradiation of [(alkylcarbonyloxy)iodo]benzene: Togo, H.;
Aoki, M.; Kuramochi, T.; Yokoyama, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 2417–2427.
1
2
78.1518, found 278.1484.
1. Addition to ketene: Allen, A. D.; Cheng, B.; Fenwick, M. H.;
Huang, W.-w.; Missiha, S.; Tahmassebi, D.; Tidwell, T. Org.
Lett. 1999, 1, 693–696.
Acknowledgements
1
2. Inokuchi, T.; Nakagawa, K.; Torii, S. Tetrahedron Lett. 1995,
This work was financially supported by the Okayama
Foundation for Science and Technology. We thank
3
6, 3223–3226.
3. (a) Ren, T.; Liu, Y.-C.; Guo, Q.-X. Bull. Chem. Soc. Jpn 1996,
9, 603–606.(b) Church, K. M.; Holloway, L.; Matley, R.;
1
‘
SC-NMR laboratory of Okayama University’ for high-
6
field NMR experiments and are indebted to Professor J.
Nokami, Okayama University of Science, for HRMS
analyses. We are grateful to Koei Chemical Co., Ltd,
Mitsui Chemicals, Inc., and Kuraray Co., Ltd for research
samples of TEMPO$, DMI, and citronellol, respectively.
Brower, R. J. Abstracts of Papers, 224th ACS National
Meeting, Boston, MA, August 18–22, 2002; MEDI-378. AN
2
002; 618229. (c) Sch a¨ mann, M.; Sch a¨ fer, H. J. Synlett 2004,
1601–1603.
1
1
4. (a) Anderson, J. E.; Casarini, D.; Corrie, J. E. T.; Lunazzi, L.
J. Chem. Soc., Perkin Trans. 2 1993, 1299–1304. (b) Studer,
A. Angew. Chem., Int. Ed. Engl. 2000, 39, 1108–1111.
(c) Henry-Riyad, H.; Tidwell, T. T. J. Phys. Org. Chem.
2003, 16, 559–563.
References and notes
5. Braslau, R.; Anderson, M. O.; Rivera, F.; Jimenez, A.;
Haddad, T.; Axon, J. Tetrahedron 2002, 58, 5513–5523.
1
. Page, P. C. B.; McCarthy, T. J. In Comprehensive Organic
Synthesis, Vol. 7; Pergamon: New York, 1991; pp 83–117.
. (a) Hudlicky, M. Oxidation in Organic Chemistry In ACS
Monograph 186; American Chemical Society: Washington,
DC, 1990; pp 109–114. (b) Kilenyi, S. N. In Comprehensive
Organic Synthesis, Vol. 7; Pergamon: New York, 1991;
pp 653–670. Recent examples on C—halogen oxidation:
16. (a) Kruse, B.; Br u¨ ckner, R. Chem. Ber. 1989, 122, 2023–2025.
(b) Kersey, I. D.; Fishwick, C. W. G.; Findlay, J. B. C.; Ward,
P. Tetrahedron 1995, 51, 6819–6834.
2
17. The liberated TEMPOH can be recovered and reused.
18. The 2-TEMPO-substituted undecanal was prepared by the
reaction of undecanol with the TEMPO$/RuCl
(PPh
system in toluene. This compound was converted to 9 by
treatment with NaBH (94% yield) followed with Ac O (95%
) /O
2
3 3 2
1
2
(c) Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6, 103–106
and references cited therein.
4
2

T. Inokuchi, H. Kawafuchi / Tetrahedron 60 (2004) 11969–11975
11975
yield), to 11 with CH(OMe) /pTsOH in MeOH (82% yield),
3
20. Uneyama, K.; Hasegawa, N.; Kawafuchi, H.; Torii, S. Bull.
Chem. Soc. Jpn 1983, 56, 1214–1218.
2 2 2
and to 13 with (i-PrO) P(O)CH CO Et/NaH (97% yield).
2
1. Johnstone, R. A. W. In Comprehensive Organic Synthesis,
Vol. 8; Pergamon: New York, 1991; pp 259–81.
2
2
2. Winterfeldt, E. Synthesis 1975, 617–630.
3. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
1
9. The same compound 14 was produced on standing 13 under
very weak acidic conditions (in CDCl ) at room temperature
3
815–3818.
3
5
for a long period.