4-Isocyano-2,2,6,6-tetramethylpiperidin-1-oxyl: A valuable precursor for the synthesis of new nitroxides

Article abstract of DOI:10.1021/ol036298q

To enrich the limited set of isonitriles typically employed, 4-isocyano-2,2,6,6-teramethylpiperidin-1-oxyl (1) is proposed as an isonitrile bearing a nitroxyl moiety, Isocyanide 1 was used in some reactions characteristic of isonitriles. Isoselenocyanate, amides (products of Passerini and Ugi reactions), and tetrazole derivative were obtained. The EPR spectra of the urea derivative 5b and a product of an Ugi reaction 7 (both dinitroxides) were analyzed.

Full text of DOI:10.1021/ol036298q

ORGANIC
LETTERS
2
004
Vol. 6, No. 5
95-697
4
1
-Isocyano-2,2,6,6-tetramethylpiperidin-
-oxyl: A Valuable Precursor for the
Synthesis of New Nitroxides
6
,†
‡
†
Jerzy Zakrzewski,* Julia Jezierska, and Jarosław Hupko
Institute of Industrial Organic Chemistry, 6 Annopol, 03-236 Warsaw, Poland, and
Faculty of Chemistry, UniVersity of Wrocław, 14 Joliot-Curie Street,
50-383 Wrocław, Poland
zakrzewski@ipo.waw.pl
Received November 25, 2003
ABSTRACT
To enrich the limited set of isonitriles typically employed, 4-isocyano-2,2,6,6-teramethylpiperidin-1-oxyl (1) is proposed as an isonitrile bearing
a nitroxyl moiety. Isocyanide 1 was used in some reactions characteristic of isonitriles. Isoselenocyanate, amides (products of Passerini and
Ugi reactions), and tetrazole derivative were obtained. The EPR spectra of the urea derivative 5b and a product of an Ugi reaction 7 (both
dinitroxides) were analyzed.
Recently, we described an efficient synthesis of an isonitrile
bearing a nitroxyl moiety: 4-isocyano-2,2,6,6-tetramethyl-
Scheme 1. Synthesis of
4-Isocyano-2,2,6,6-tetramethylpiperidin-1-oxyl (1)
1
piperidin-1-oxyl (1). Formylation of 4-amino-2,2,6,6-tetra-
methylpiperidin-1-oxyl (2) with ethyl formate, followed by
dehydration of 4-formamido-2,2,6,6-tetramethylpiperidin-1-
oxyl (3) with phosgene, resulted in the formation of 1 in
84% yield. The Hofmann carbylamine reaction of 2 with
chloroform under PTC conditions gave 1, but with a yield
of only 16% (Scheme 1).1
The importance of isonitriles has increased in the past few
years due to their application in such multicomponent
to aryl, benzyl, cyclohexyl, and tert-butyl isocyanides.
4-Isocyano-2,2,6,6-tetramethylpiperidin-1-oxyl (1) increases
2-4
reactions (MCRs) as the Passerini and Ugi reactions. They
are in turn ideal tools for creating combinatorial libraries.
Isonitriles are also used as versatile building blocks for the
the range of available isonitriles and furthermore allows
insertion of a spin-labeled fragment into MCR products. This
enables the study of the structures of product libraries created
5
synthesis of heterocyclic systems. Typical isonitriles com-
monly used in the above reactions have been limited mainly
(3) (a) Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.;
Koh, H. Y.; Kim, Y. Org. Lett. 2001, 3 (26), 4149-4152. (b) Gedey, Y.;
v.d. Eycken, J.; F u¨ l o¨ p, F. Org. Lett. 2002, 4 (11), 1967-1969. (c) Nixey,
T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002, 43 (9), 1637-1639.
(d) Tempest, P.; Vu, Ma; Thomas, S.; Zheng, Hua; Kelly, M. G.; Hulme,
C. Tetrahedron Lett. 2001, 42, 4959-4962. (e) Marcaccini, S.; Pepino, R.;
Polo, C.; Pozo, M. C. Synthesis 2001 (1), 85-88. (f) Marcaccini, S.; Pepino,
R.; Pozo, M. C. Tetrahedron Lett. 2001, 42, 2727-2728.
†
Institute of Industrial Organic Chemistry.
University of Wrocław.
‡
(
1) Zakrzewski, J.; Hupko, J. Org. Prep. Proc. Int. 2003, 35 (4), 387-
90 and references therein.
2) (a) Xia, Q.; Ganem, B. Org. Lett. 2002, 4 (9), 1631-1634. (b) Jenner,
G. Tetrahedron Lett. 2002, 43 (7), 1235-1238.
3
(
1
0.1021/ol036298q CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/12/2004

in MCR reactions and/or hetrocycles built from isonitriles
by the spin-labeling technique.
The carbenoid character attributed to the isonitrile group
or 2 as amines. The resulting urea derivatives 5a and 5b,
respectively, were isolated, 5b being a dinitroxide.
The reaction of isocyanide 1 and cyclohexanone with
acidic components, water or acetic acid, leads to products
of a Passerini reaction 6a or 6b, respectively, whereas acetic
acid together with the amine 2 results in the product of an
Ugi reaction 7. When 2,2,6,6-tetramethyl-4-piperidinon-1-
oxyl was used as the ketone component instead of cyclo-
hexanone, both Passerini and Ugi reactions failed, probably
due to the instability of 2,2,6,6-tetramethyl-4-piperidinon-
1-oxyl. Both 2,6-dimethyl-6-nitrosohept-2-en-4-one10 and
phorone (2,6-dimethylhepta-2,5-dien-4-one) were recognized
as products. Additionally, slow hydrolysis of 1 to 3 was also
observed.
+
-
[
R-N ≡C T R-NdC:] may potentially be incompatible
with the unpaired electron of the nitroxyl moiety. The ability
of isonitriles bearing a nitroxyl moiety to react in a
characteristic manner, is not apparent. Hence, in this work
we wish to present the application of 4-isocyano-2,2,6,6-
tetramethylpiperidin-1-oxyl 1 in some typical reactions of
isonitriles.
Products. The reactions of isocyanide 1 are shown in
Scheme 2.
The ability of isocyanide 1 to insert into the N-H bond
Scheme 2. Reactions of 1
1
1
in the presence of cuprous chloride was demonstrated for
piperidine as a typical amine. As a result, the compound 8
was obtained.
12
The reaction of 1 with hydrazoic acid caused 1,3-dipolar
cycloaddition leading to the tetrazole derivative 9. This
demonstrates the ability of 1 to undergo a cyclization.
Procedures for the synthesis of 4-9 are available in the
Supporting Information. Yields, melting points, and R
f
data
of 4-9 are presented in Table 1.
Table 1. Yields, Melting Points, and R Data for 4-9
f
product
yield (%)
mp (°C)
Rfb
4
38
54
16
86
85
49
57
33
156-158
85-87
118-120a
139-142
119-122
oil
0.75
0.32
0.18
0.21
0.28
0.20
5
5
6
6
7
8
9
a
b
a
b
89-92
157-159
0.35b
The reaction of isocyanide 1 with selenium yielded
0.23
isoselenocyanate 4, an example of a nitroxide containing a
selenium atom.6
a Melting point literature data for 5b: 116-118 °C (EtOAc/pentane),13
15 b
1
45 °C (benzene),14 198-199 °C (hexane).
benzene/methanol 9:1.
On silica (8 on alumina),
Isonitriles cannot be oxidized directly by oxygen unless
7
in the presence of a catalyst. To obtain the corresponding
isocyanate, isocyanide 1 was oxidized with several oxidizing
8
systems. The use of DMSO/p-CH
3
C
6
H
4
SO
3
H and DMSO/
EPR Spectra of Dinitroxides 5b and 7. The EPR spectra
for both 5b and 7 (Figure 1) exhibit the biradical nature of
9
Br
m-CPBA (m-ClC
corresponding isocyanate, which was trapped with piperidine
2
as oxidizers was unsuccessful. The oxidation with
1
6-19
H
6 4
CO H) resulted in the formation of the
3
the compounds.
The presence of five or more lines in
the EPR spectrum results from the hyperfine interaction
(
4) (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard,
(10) Zakrzewski, J. J. Prakt. Chem. 1985, 327 (6), 1011-1014.
(11) Saegusa, T.; Ito, T.; Kobayashi, S.; Hirota, K.; Yoshioka, H.
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Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43
(
6), 943-946. (c) Mandair, G. S.; Light, M.; Russel, A.; Hursthouse, M.;
Bradley, M. Tetrahedron Lett. 2002, 43 (23), 4267-4269.
5) (a) Kobayashi, K.; Nakahashi, R.; Takanohashi, A.; Kitamura, T.;
(12) Zimmerman, D. M.; Olofson, R. A. Tetrahedron Lett. 1969, (58),
5081-5084.
(
(13) Anzai, K.; Hunt, J. B.; Zon, G.; Egan, W. J. Org. Chem. 1982, 47,
4281-4285.
Morikawa, O.; Konishi, H. Chem. Lett. 2002, (6), 624-625. (b) Tsunenishi,
Y.; Ishida, H.; Itoh, K.; Ohno, M. Synlett 2000, (9), 1318-1320. (c)
Moderhack, D.; Daoud, A.; Ernst, L.; Jones, P. G. J. Prakt. Chem. 2000,
(14) Ohnishi, S.; Cyr, T. J. R.; Fukushima, H. Bull. Chem. Soc. Jpn.
1970, 43, 673-676.
3
42 (7), 707-710.
6) Blum, T.; Ermert, J.; Coenen, H. H. Appl. Radiat. Isot. 2002, 57 (1),
1-56.
7) Otsuka, S.; Nakamura, A.; Tatsuno, Y. J. Chem. Soc., Chem.
Commun. 1967, 836.
(15) Rozantsev, E. G.; Golubev, V. A.; Neiman, M. B.; Kokhanov, Yu.
V. IzV. Akad. Nauk SSSR, S. Kh. 1965, (3), 572-573; Chem. Abstr. 1966,
63, 574b-c).
(
5
(
(16) Rozantsev, E. G. SVobodnyje Iminoksylnyje Radikaly; Khimija:
Moskva, 1970 (in Russian); pp 122-139 (especially 125-130, 137); English
translation: Rozantsev, E. G. Free Nitroxyl Radicals; Plenum Press: New
York, 1970.
(
8) Martin, D.; Weise, A. Angew. Chem. 1967, 79, 145.
(
9) (a) Johnson, H. W.; Daughhetee, P. H. J. Org. Chem. 1964, 29, 246-
2
1
47. (b) Johnson, H. W.; Krutzsch, H. J. Org. Chem. 1967, 32, 1939-
(17) Buczaczenko, A. L.; Wasserman, A. M. Stabilnyje Radikaly;
Khimija: Moskva, 1973 (in Russian); pp 223-254.
941.
696
Org. Lett., Vol. 6, No. 5, 2004

approximately a half of the a
intensity ratio between the spectral lines is close to 1:1:1:
:1. Assuming a static mechanism of exchange interaction
N
determined for 5b. The
1
between unpaired electrons of the radical, the spectrum of 7
in toluene quite closely resembles the spectrum calculated
1
7,19
theoretically, for J/a
N
∼ 10.
In toluene solution the
molecular structure of 7 may be treated as basic since it is
weakly affected by the nonpolar solvent. However, the
dissolution of biradical 7 in the polar solvent, DMSO,
substantially changes the spectral properties leading to the
three EPR lines separated by 1.58 mT. This fact, together
with a strong static exchange between unpaired electrons of
7
(consistent with J/a
N
∼ 10 for toluene solution), indicates
the presence of a dynamic exchange between the radical
conformers. A stabilization of different radical conformations
by solvents seems to be more probable for 7, due to its
unsymmetrical structure, than for 5b. The exchange between
the conformations modulates the isotropic hyperfine interac-
tion with nitroxide nitrogen nuclei, and the spectral lines
located between the basic triplet are broadened according to
the mechanism postulated for other biradicals. This mech-
anism for 7 in toluene leads to the smallest change of the
spectral lines, in dichloromethane to the characteristic line
broadening, and finally in DMSO, due to the slowest
exchange between the molecular conformations, to the
appearance of a three line spectrum. It has been shown
17
Figure 1. EPR spectra of biradicals 5b and 7 in different solvents
at room temperature.
N
(measured by a parameter) between nitroxide nitrogen
nuclei and biradical unpaired electrons efficiently coupled
by the exchange interaction. The exchange interaction
1
9
theoretically that the spectra change from the 1:2:3:2:1
quintet (for the highest speed of exchange between the
conformers) to the 1:1:1 triplet (for the lowest speed) in the
(
measured by J integral) leads to the triplet (S ) 1) and
singlet (S ) 0) states for the case when J/a > 0.
N
case when J ) 33a
the spectra observed by us for 7 correspond to J/a
smaller than 33 and greater than 1. The spectral analysis
reveals only a small change of giso parameter value upon
the solvent. In toluene, dichloromethane and DMSO solutions
N
which supports our supposition that
value
For 7, the spectra recorded in toluene, dichloromethane,
and DMSO significantly differ from each other. A similar
dependence of the spectral feature on the solvent was
N
•
16
•
•
•
described for 2,2′-di(R )biphenyl and for R-R (R )
2
,2,6,6-tetramethyl-4-piperidyl-1-oxyl).17 The spectra of 7,
g
2
iso ) 2.00619, 2.00608, 2.00606 for 5b and 2.00619,
.00608, 2.00604 for 7, respectively.
however, differ substantially from those observed by us in
this work and those previously observed for biradical 5b in
the same solvents.1
In conclusion, 4-isocyano-2,2,6,6-teramethylpiperidin-1-
4,18,20
oxyl (1) was successfully used as an isonitrile bearing a
nitroxyl moiety in some typical reactions of isonitriles. The
expected compounds were obtained: isoselenocyanate, amides
The EPR spectra of biradical 5b exhibit seven lines due
to the “triplet” -“triplet” (T) resonances and two much lower
intensity lines due to the “singlet” -“triplet” (S) resonances.
(products of Passerini and Ugi reactions), and tetrazole
The hyperfine coupling constants a
resonances for the hypothetical case when J/a
weakly dependent on the solvent polarity. The value of a
N
(measured between T
derivative. The yields varied from medium to good. Signifi-
cantly, the application of 1 in MCR reactions would allow
the design of combinatorial libraries which may contain a
nitroxide fragment useful for spin-label measurements.
N
≈ 0) are
N
changes from 1.53 mT in toluene to 1.57 in dichloromethane
and 1.58 in DMSO and is in agreement with the results
20
Acknowledgment. We thank the Polish State Committee
for Scientific Research (429 E-142/S/2002-1) for financial
support. We wish to thank Mrs. Anna Kiełczewska, Mrs.
Hanna Konopka, and Mrs. Małgorzata Grela for MS, IR,
and HRMS analyses, respectively. Special thanks go to Mr.
Mark Lewis, Dr. Ashley Keating, and Dr. Leszek Konopski.
reported in. The spectral feature is similar to that observed
1
7
previously for 5b which was assigned to J/a
N
∼ 1.1.
The EPR spectra of 7 shown in Figure 1 are strongly
dependent on the solvent. The spectrum of 7 in toluene
consists of five lines separated by 0.77 mT which is
(
18) Luckhurst, G. R. In Spin Labeling, Theory and Application; Berliner
L. J., Ed.; Academic Press: New York, 1976; pp 133-181.
19) Parmon, V. N.; Kokorin, A. I.; Zhidomirov, G. M. Zh. Str. Khim.
977, 18, 132-177.
20) Metzner, E. K.; Libertini, L. J.; Calvin, M. J. Am. Chem. Soc. 1974,
6, 6515-6516.
Supporting Information Available: Experimental Sec-
tion. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
1
(
9
OL036298Q
Org. Lett., Vol. 6, No. 5, 2004
697