Reactivity of N-alkanoyloxy-2,2,6,6-tetramethylpiperidines (O-acylTEMPOs) towards hydride-transferring or metallic alkylating reagents; unprecedented stability and application to chemoselective transformations

Article abstract of DOI:10.1039/b414129f

Owing to the unprecedented stability of O-acylTEMPOs towards hydride-transferring and metallic alkylating reagents such as LiAlH₄ and RMgX, chemoselective transformation of diacid mixed alkyl/TEMP-1-yl esters, where O-acylTEMPOs remained intact, is achieved with these reagents, giving the corresponding carbinols, respectively.

Full text of DOI:10.1039/b414129f

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COMMUNICATION
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Reactivity of N-alkanoyloxy-2,2,6,6-tetramethylpiperidines
(O-acylTEMPOs) towards hydride-transferring or metallic alkylating
reagents; unprecedented stability and application to chemoselective
transformations{
Tsutomu Inokuchi,*a Hiroyuki Kawafuchib and Junzo Nokamic
Received (in Cambridge, UK) 16th September 2004, Accepted 25th October 2004
First published as an Advance Article on the web 6th December 2004
DOI: 10.1039/b414129f
corresponding aldehydes 2a–c in 83–92% yields (Scheme 1), the
reduction of these O-acylTEMPOs 1a–c with the more powerful
LAH at the same temperature resulted in a complete recovery of
the starting materials.
Owing to the unprecedented stability of O-acylTEMPOs
towards hydride-transferring and metallic alkylating reagents
such as LiAlH4 and RMgX, chemoselective transformation of
diacid mixed alkyl/TEMP-1-yl esters, where O-acylTEMPOs
remained intact, is achieved with these reagents, giving the
corresponding carbinols, respectively.
Accordingly, the reduction of 1a with LAH was examined by
increasing the temperature from 278 uC to room temperature and
it turned out that compound 1a was quite inert at less than 225 uC.
The reductions slowly proceeded at 0 uC, and substantial
conversion was only achieved by raising to room temperature
(ca. 20–30 uC) to give the corresponding carbinol 3a in 95% yield,
which was complementary to the aldehyde synthesis by DIBAL-H
reduction. A 1:1 LAH–N-methylpyrrolidine complex9 was also
effective at room temperature for the reduction of 1a, giving 3a
(80% yield). Similarly, the O-acylTEMPOs 1b and 1c were reduced
with LAH at about 0 uC, giving 2b and 2c in 40 and 69% yields,
respectively.
Although a variety of procedures have been developed for the
preparation of N-alkanoyloxy-2,2,6,6-tetramethylpiperidines
1
(O-acylTEMPOs) by nucleophilic acyl substitution of acyl halides
and acid anhydrides with TEMPO2M+ (the TEMPO anion),1
2
trapping of acyl radicals with TEMPO , and addition reaction of
?
3
TEMPO to ketenes, little is known about their properties and
?
reactivity towards nucleophiles in spite of their carboxylic acid
derivative-like structure. Only the thermal stability of
O-triphenylacetyl TEMPO4 and alkaline hydrolysis of a formyl
derivative1 were, to the best of our knowledge, reported. In our
preceding paper,5 we reported the reaction of 1 with DIBAL-H (2–
3 equiv.), giving the corresponding aldehydes, the high selectivity
of which was rationalized by stabilization of the hydride adduct by
chelation with the 2,2,6,6-tetramethylpiperidinyl function in close
resemblance to the case of the Weinreb amide.6
Other reducing reagents such as NaBH4, LiBH4, NaAlH2-
(OCH2CH2OMe)2 were of no use for the reduction of 1a at room
temperature, and the starting 1a was unchanged. Furthermore, the
reaction of 1a with PhMgBr at room temperature resulted in
recovery of the starting 1a.
We postulated that the low reactivity of 1 to an ate complex like
LAH at low temperature is ascribable to the donating nature of
the nitrogen atom of the tetramethylpiperidinyl moiety which is
linked with carboxyl oxygen.10 It is conceived that the ate complex
comprised of two different kinds of Lewis acid metals would form
specific coordination with the molecule bearing two Lewis base
sites.11 This is the case for the reaction of 1 with LAH. Thus, as
shown in Scheme 2, the aluminium of LAH may be fixed with the
nitrogen and the Li cation would be coordinated by the nearby
carbonyl oxygen to form a highly rigid chelated architecture such
as structure A.12 The fixed structure A is considered to be unable to
deliver a hydride to the carbonyl carbon if kept at low
temperature. On the other hand, the reaction of 1 with DIBAL-
H would first lead to nitrogen-coordinated structure B,13 which
Incidentally, we encountered unprecedented stability of 1
towards LiAlH4 (LAH), a highly powerful reagent towards
ordinary carboxylic acid derivatives, including Weinreb amides.
In this communication, we unveil the reactivity of 1 towards
hydride-transferring or metallic alkylating reagents and examine
chemoselective transformations,7 where an O-acylTEMPO group
is utilized as an inert function to LAH.8
We first examined the LAH reduction (2 equiv.) of aromatic 1a
(R 5 4-MeOC6H4), allylic 1b (R 5 C6H5CHLCH), and aliphatic
1c (R 5 c-C6H11) O-acylTEMPOs under varying reaction
temperatures. Although the DIBAL-H reduction (3 equiv.) of
1a–c smoothly proceeded even at –78 to –50 uC, giving the
{ Electronic supplementary information (ESI) available: Experimental
procedure and spectral data. IR, 1H and 13C NMR data. See http://
www.rsc.org/suppdata/cc/b4/b414129f/
Scheme 1
*inokuchi@cc.okayama-u.ac.jp
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Chem. Commun., 2005, 537–539 | 537

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Scheme 3
applicability of the present reaction. The reduction of 10, prepared
from 4-cyclohexene-1,2-dicarboxylic anhydride by consecutive
treatment with the TEMPO anion and MeI in THF–DMF, with
LAH at 270 to 250 uC for 5.5 h afforded the corresponding
carbinol 11 in 44% yield (65% conversion, Scheme 3). The run at
higher temperature than this led to reduction of two carbonyl
functions of 10, giving the corresponding diol. It is likely that
reduction of the mixed ester is affected with the TEMPO
substitution in the vicinity, but details are not clear at present.
In summary, the O-acylTEMPOs 1 were quite stable to hydride-
transferring or metallic alkylating reagents, in contrast to Weinreb
amide, and can be employed as an inert ester towards these
reagents in the chemoselective transformation of diacid mixed
alkyl/TEMP-1-yl esters to the corresponding carbinols. After the
nucleophilic additions, the O-acylTEMPOs were converted to the
corresponding carboxylic acids by hydrolysis.
Scheme 2
will be in equilibrium with carbonyl oxygen-coordinated structure
C, in which the two electron-donated aluminium reagents would
transfer a hydride to the carbonyl carbon even at low temperature,
leading to aldehyde.
We applied this stability of O-acylTEMPOs towards LAH or
RMgX to the chemoselective transformation of the ester function
in the presence of O-acylTEMPOs. As shown in Table 1, entry 1,
the treatment of ethyl/2,2,6,6-tetramethylpiperidine-1-yl adipate 4,
derived from adipic acid half-ester by chlorination of the
carboxylic acid followed by nucleophilic acyl substitution with
the TEMPO anion, with LAH afforded the corresponding
carbinol 7a (98% yield), the O-acylTEMPO moiety being
unaffected. Furthermore, compound 4 was selectively alkylated
at the alkyl ester site, giving the corresponding tertiary carbinols 7
(b, R 5 Ph, 83%; c, R 5 Me 54% (61% conversion); d, R 5 allyl
68%; e, PhCC, 45% (54% conversion)) on treatment with the
respective alkylmetallic reagents such as PhMgBr, MeLi,
allylMgBr and acetylenic PhCCMgBr (entries 2–5).{ A similar
trend in reactivity towards LAH and RMgX was found with
derivatives of the glutarate (5) (entries 6 and 7) and the succinate
(6) (entry 8). The carbinol 7b obtained as above was easily
converted into the corresponding carboxylic acid upon treatment
with NaOH in MeOH–H2O.
We acknowledge the financial support by the Okayama
Foundation for Science and Technology (T. I) and ‘‘SC-NMR
laboratory of Okayama University’’ for high-field NMR experi-
ments. Part of this work was supported by a Grant-in-Aid for
Scientific Research from Japan Society for the Promotion of
Science (H. K., No. 16550104). We are also grateful to Koei
?
Chemical Co., Ltd. for a research sample of TEMPO .
Tsutomu Inokuchi,*a Hiroyuki Kawafuchib and Junzo Nokamic
aDepartment of Bioscience and Biotechnology, Faculty of Engineering,
Okayama University, Tsushima-naka, Okayama, 700-8530, Japan.
E-mail: inokuchi@cc.okayama-u.ac.jp; Fax: (+81) 86 251 8021;
Tel: (+81) 86 251 8210
bDepartment of Chemical and Biochemical Engineerings, Toyama
National College of Technology, Hongo-machi, Toyama, 939-8630,
Japan. E-mail: kawafuti@toyama-nct.ac.jp
Having succeeded in the selective reduction and alkylation of
linear alkanedioic acids mixed esters 4–6, we next examined a more
congested nonlinear 1,2-diacid mixed ester in order to ascertain the
cDepartment of Applied Chemistry, Faculty of Engineering, Okayama
Table 1 Chemoselective reductions and alkylationsa
Entry
Substrate
Reagent (equiv.)/conditions
Product
R
Yieldb (%)
1
2
3
4
5
6
7
8
a
4
4
4
4
4
5
5
6
LiAlH4 (2)/230 to 235 uC, 1 h
PhMgBr (3)/0 uC to RT, 2 h
MeLi (2)/230 to 240 uC, 2 h
allylMgBr (3)/RT, 2 h
PhCCMgBr (3)/70 uC, 3.5 h
LiAlH4 (2)/250 to 220 uC, 1 h
PhMgBr (3)/0 uC to RT, 1 h
MeMgBr (4.5)/0 uC, 4 h
7a
7b
7c
7d
7e
8a
8b
9a
H
Ph
Me
allyl
PhCC
H
98 (100)
83 (100)
54 (61)
68 (100)c
45 (54)
75 (100)
62 (86)
58 (100)
Ph
Me
The reactions were carried out by using 4–6 (0.32 mmol) in THF (2 cm3) under N2. Yields are based on isolated products and the value in
b
c
the parentheses is the conversion (%) of 4–6. Diol due to double bisallylation was found in 27% yield.
538 | Chem. Commun., 2005, 537–539
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University of Science, Ridai-cho, Okayama, 700-0005, Japan.
E-mail: nogami@dac.ous.ac.jp
8 Protection of ester function to LAH: E. J. Corey and N. Raju,
Tetrahedron Lett., 1983, 24, 5571; E. J. Corey and D. J. Beames,
J. Am. Chem. Soc., 1973, 95, 5829; protection of amine to LAH:
J. E. Macor, B. L. Chenard and R. J. Post, J. Org. Chem., 1994, 59,
7496.
Notes and references
9 J. C. Fuller, E. L. Stangeland, T. C. Jackson and B. Singaram,
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{ Experimental: LiAlH4 reduction of 1a. To a solution of 1a (100 mg,
0.34 mmol) in THF (2 cm3) was added LiAlH4 (80%, 39 mg, 0.82 mmol) at
room temperature under N2 and the mixture was stirred for 1 h, quenched
with cold sat. NH4Cl, and worked up in the usual manner to give 45 mg
(95%) of 3a after column chromatography (SiO2, hexane–AcOEt 10:1 and
5:1). Grignard reaction of 4. To a solution of 4 (100 mg, 0.32 mmol) in THF
(2 cm3) was added dropwise PhMgBr (1.0 M in THF, 0.96 cm3, 0.96 mmol)
at 0 uC under N2 and the mixture was stirred at room temperature for 2 h,
quenched with cold sat. NH4Cl. Usual workup and purification by column
chromatography (SiO2, hexane–AcOEt 10:1 and 5:1) gave 112 mg (83%) of
7b (R 5 Ph).14
10 The electron density of the HOMO of O-acetylTEMPO was probed by
using PM3 semiempirical energy minimizations (MOPAC2002 in
CAChe Worksystem Pro 5.04) and the calculation showed that the
highest value was located on the nitrogen atom of the TEMPO ester.
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14 3a: IR (Neat) 3367, 3003, 2935, 2837, 1612, 1585, 1514, 1464, 1302,
1
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1248, 1174, 1111, 1034, 818, 754, 708 cm21; H NMR (400 MHz): d
2.27, (br s, 1H, OH), 3.78 (s, 3H), 4.56 (s, 2H), 6.87 (d, J 5 8.8 Hz, 2H),
7.25 (d, J 5 8.8 Hz, 2H); 13C NMR (100 MHz): d 55.2, 64.8, 113.7 (2C),
128.4 (2C), 132.9, 158.8. 7b: mp 111–112 uC; IR (KBr) 3462, 3057, 2939,
2870, 1753, 1599, 1493, 1448, 1363, 1263, 1132, 1063, 972, 937, 872, 752,
1
700 cm21; H NMR (400 MHz): d 0.94, 1.06 (s, 12H), 1.20–1.70 (m,
10H), 2.10, (br s, 1H), 2.22–2.28 (m, 4H), 7.13–7.17 (m, 2H), 7.22–7.25
(m, 4H), 7.31–7.36 (m, 4H); 13C NMR (100 MHz): d 17.1, 20.6 (2C),
23.8, 25.7, 32.0 (2C), 33.1, 39.0 (2C), 41.7, 59.9 (2C), 78.1, 125.8 (4C),
126.6 (2C), 128.0 (4C), 146.7 (2C), 172.8. HRMS (EI) calc. for
C27H37NO3: m/z 423.2773; found: 423.2766.
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