An expeditious entry to 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO): Another highly active organocatalyst for oxidation of alcohols

Article abstract of DOI:10.1021/jo900486w

(Chemical Equation Presented) A practical, three-step synthetic route to 9-azabicyclo[3.3.1] nonane N-oxyl (ABNO, 3), an unhindered, stable class of nitroxyl radical, has been developed. ABNO exhibits a highly active nature compared with TEMPO in the catalytic oxidation of alcohols to their corresponding carbonyl compounds.

Full text of DOI:10.1021/jo900486w

3
,4
An Expeditious Entry to
-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO):
Another Highly Active Organocatalyst for
Oxidation of Alcohols
oxidations have the highest priority in the contemporary
pharmaceutical industry as efficient, mild, and environmentally
9
5
acceptable methods.
As part of our research program directed toward the develop-
ment of novel organocatalysts for advanced organic synthesis,
we recently reported that azaadamantane-type nitroxyl radicals,
namely, 2-azaadamantane N-oxyl [AZADO (2a)] and 1-Me-
AZADO (2b), are robust alternatives to TEMPO with a
markedly expanded substrate applicability (Figure 1).
Masatoshi Shibuya, Masaki Tomizawa, Yusuke Sasano, and
Yoshiharu Iwabuchi*
6
7
,8
Graduate School of Pharmaceutical Sciences, Tohoku
UniVersity, 6-3 Aobayama, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
ReceiVed March 4, 2009
FIGURE 1. Design concept of AZADO.
We confirmed with some surprise that AZADOs exhibit
extremely aggressive activities beyond our expectations and
offer more than 20-fold higher catalytic efficiency in the
oxidation of alcohols, including hindered secondary alcohols
that TEMPO completely fails to efficiently oxidize to their
7
corresponding products. A preliminary structure-activity
comparison between AZADO, 1-Me-AZADO, and 1,3-dimeth-
yl-AZADO indicated that the steric effect near the active center
exerts a critical impact on catalytic efficiency.
7
Apractical,three-stepsyntheticrouteto9-azabicyclo[3.3.1]nonane
N-oxyl (ABNO, 3), an unhindered, stable class of nitroxyl
radical, has been developed. ABNO exhibits a highly active
nature compared with TEMPO in the catalytic oxidation of
alcohols to their corresponding carbonyl compounds.
Although we have developed gram-scale routes to AZADO
(2a) and 1-Me-AZADO (2b) starting from commercially avail-
able 1,3-adamantanediol via a ten-step synthesis and a six-step
7
synthesis, respectively, we inquired into a more readily
available alternative to AZADOs for the further development
of nitroxyl radical-based methodologies in organic chemistry.
As a logical extension, we were interested in bicyclic unhindered
Since its discovery, the stable class of nitroxyl radicals, as
exemplified by TEMPO (2,2,6,6-tetramethyl piperidinyl 1-oxyl
9
,10
nitroxyl radicals,
such as 9-azabicyclo[3.3.1]nonane N-oxyl
11
11,12
(
1); Figure 1), has been inspiring chemists to explore their novel
(ABNO, 3), 8-azabicyclo[3.2.1]octane N-oxyl (ABOO, 4),
and 7-azabicyclo[2.2.1]heptene N-oxyl (ABHO, 5) (Figure
1,2
uses in a wide range of molecular sciences. The most dynamic
behavior of nitroxyl radicals, their interconversion either to
oxoammonium ions or to hydroxyl amines, is successfully
exploited as a redox catalyst applicable to several synthetic
transformations. In particular, TEMPO-catalyzed alcohol
1
2-14
2).
(
1) Likhtenshtein, G. I.; Yamauchi, J.; Nakatsuji, S.; Smirnov, A. I.; Tamura,
R. Nitroxides; Wiley-VCH, Weinheim, Germany, 2008.
2) For recent reviews, see: (a) Vogler, T.; Studer, A. Synthesis 2008, 1979–
(
1
4
2
993. (b) Galli, C.; Gentili, P.; Lanzalunga, O. Angew. Chem., Int. Ed. 2008,
7, 4790–4796. (c) Sciannamea, V.; J e´ r oˆ me, R.; Detrembleur, C. Chem. ReV.
008, 108, 1104–1126. (d) Soule, B. P.; Hyodo, F.; Matsumoto, K.; Simone,
FIGURE 2. Bicyclic nitroxyl radicals.
With accumulated knowledge indicating the stability of
N. L.; Cook, J. A.; Krishna, M. C.; Mitchell, J. B. Free Radical Biol. Med.
2
007, 42, 1632.
bridged-bicyclo N-oxyls being in the order of ABNO > ABOO
(
3) (a) Sheldon, R. A.; Arends, I. W. C. E. AdV. Synth. Catal. 2004, 346,
14-16
17
>
ABHO,
we chose ABNO as the focus of this study.
1
051–1071. (b) de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis
996, 1153–1174.
1
(4) (a) Wang, X.; Liu, R.; Jin, Y.; Liang, X. Chem.sEur. J. 2008, 14, 2679–
(5) (a) Caron, S.; Drugger, S. G.; Ruggeri, S. G.; Ragan, J. A.; Brown Ripin,
2
5
4
685. (b) Wang, N.; Liu, R.; Chen, J.; Liang, X. Chem. Commun. 2005, 5322–
324. (c) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126,
112–4113. (d) Miller, R. A.; Hoerrner, R. S. Org. Lett. 2003, 5, 285–287. (e)
D. H. Chem. ReV. 2006, 106, 2943. (b) Carey, J. S.; Laffan, D.; Thomson, C.;
Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. (c) Drugger, R. W.; Ragen,
J. A.; Brown Ripin, D. H. Org. Proc. Res. DeV. 2005, 9, 253.
(6) Moad, G.; Rizzardo, E.; Solomon, D. H. Tetrahedron Lett. 1981, 22,
1165–1168.
(7) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc.
2006, 128, 8412–8413.
(8) (a) Shibuya, M.; Sato, T.; Tomizawa, M.; Iwabuchi, Y. Chem. Commun.
2009, 1739–1741. (b) Iwabuchi, Y. J. Synth. Org. Chem. (Tokyo) 2008, 66, 1076–
1084. (c) Shibuya, M.; Tomizawa, M.; Iwabuchi, Y. Org. Lett. 2008, 10, 4715–
4718. (d) Shibuya, M.; Tomizawa, M.; Iwabuchi, Y. J. Org. Chem. 2008, 73,
4750–4752.
Bolm, C.; Magnus, A. S.; Hildebrand, J. P. Org. Lett. 2000, 2, 1173–1475. (f)
De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org.
Chem. 1997, 62, 6974–6977. (g) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre,
J. L. J. Org. Chem. 1996, 61, 7452–7454. (h) Anelli, P. L.; Banfi, S.; Montanari,
F.; Quici, S. J. Org. Chem. 1989, 54, 2970–2972. (i) Anelli, P. L.; Biffi, C.;
Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559. (j) Semmelhack, M. F.;
Schmid, C. R.; Cort e´ s, D. A.; Chou, C. S. J. Am. Chem. Soc. 1984, 106, 3374–
3
1
376. (k) Cella, J. A.; Kelley, J. A.; Kenehan, E. F. J. Org. Chem. 1975, 40,
860–1862.
1
0.1021/jo900486w CCC: $40.75  2009 American Chemical Society
J. Org. Chem. 2009, 74, 4619–4622 4619
Published on Web 05/28/2009

We herein report a scalable, three-step synthesis of ABNO and
the scope of ABNO-catalyzed alcohol oxidations.
SCHEME 1. Three-Step Preparation Method of ABNO
1
8
With our vision of evolving a protecting group-free route to
ABNO (3), we made a small modification of the historical
Robinson-Sch o¨ pf reaction and observed marked improvement
1
9-21
in the synthesis of norpseudopelletierine (7) (Scheme 1).
Thus, stirring a mixture of glutaraldehyde, acetonedicarboxylic
acid (6), and 23% ammonia-water at rt for 35 h completed
(
monitored by NMR) not only the Robinson-Sch o¨ pf annula-
19
tion, but also the subsequent decarboxylation to give, after
lyophilization, 7 as a yellow powder. Note that the “salt-free”
conditions liberated us from laborious operations to isolate polar
amine 7 from the reaction mixture. The Huang-Minlon modi-
fication of the Wolff-Kishner reduction of 7 was found to
facilitate the expedient distillation of azabicyclononane (8) from
the reaction mixture together with water. The chloroform
extracts of the distillate were dried over potassium carbonate,
concentrated, and subjected to conventional oxidation conditions
TABLE 1. Comparison of Catalytic Efficiencies of TEMPO and
1-Me-AZADO and ABNO Under Anelli’s Condition
2
2
2 4
with cat. Na WO and urea hydrogen peroxide (UHP) to furnish,
yield (%)
after silica gel chromatography, ABNO (3) in an overall yield
of 42%, thereby establishing the shortest synthesis route for
ABNO.
entry
mol %
TEMPO
1-Me-AZADO
ABNO
1
2
3
4
5
6
1
90
88
23
91
90
91
81
59
90
88
85
41
28
0.1
0.01
0.003
0.001
no catalyst
a
a
(9) Hindrance around a nitroxyl radical center was believed to be an essential
b
b
requirement for a nitroxyl radical to be stable, because simple nitroxyl radicals
with an R-hydrogen underwent rapid disproportionation to their corresponding
nitrone and hydroxyl amine.
2
(
10) Dupeyre and Rassat reported the synthesis of norpseudopelletierine
a
b
Reaction time was 30 min. Reaction time was 60 min.
N-oxyl {9-azabicyclo[3.3.1]nonane-3-one N-oxyl} as the first stable unhindered
nitroxyl radical, in which any nitrone formation would be prohibited by Bredt’s
rule. Since then, a panel of bridged-bicyclic unhindered nitroxyl radicals have
been synthesized. (a) Dupeyre, R. M.; Rassat, A. Tetrahedron Lett. 1975, 16,
TABLE 2. Comparison of Catalytic Efficiencies of TEMPO and
1-Me-AZADO and ABNO Under Margarita’s Condition
1
3
839–1840. (b) Dupeyre, R. M.; Rassat, A. J. Am. Chem. Soc. 1966, 88, 3180–
181.
(
11) Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc. 1973, 95, 6395–
6
400.
(
(
12) Aurich, H. G.; Czepluch, H. Tetrahedron Lett. 1978, 19, 1187–1190.
13) Rychnovsky and Farmer et al. demonstrated for the first time that
yield/reaction time
unhindered nitroxyl radicals indeed worked as catalysts in alcohol oxidations.
However, since their research interest was focused on the development of
enantioselective catalysts, the catalytic efficiency of the elaborated C2-symmetric
derivative of ABNO was not further examined. Graetz, B.; Rychnovsky, S.; Leu,
W.-H.; Farmer, P.; Lin, R. Tetrahedron: Asymmetry 2005, 16, 3584–3598.
entry
mol %
TEMPO
1-Me-AZADO
ABNO
1
2
10
1
95%/90 min
43%/360 min
95%/<5min
93%/40min
92%/<5 min
91%/30 min
(
14) In 2008, Onomura et al. reported the synthesis of a panel of azabicyclo
N-oxyls and preliminary results on the electrochemical oxidation of alcohols
using them as mediators to confirm their potential for the electrochemical
oxidation of hindered secondary alcohols. However, they offer few comments
on the efficiency of azabicyclo nitroxyl radicals toward oxidation of various
alcohols under chemical conditions. (a) Demizu, Y.; Shiigi, H.; Oda, T.;
Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2008, 49, 48–52. (b) Shiigi, H.;
Mori, H.; Tanaka, T.; Demizu, Y.; Onomura, O. Tetrahedron Lett. 2008, 49,
Having established a markedly improved synthesis of ABNO,
we evaluated the reactivity of ABNO by comparing it with those
of TEMPO and 1-Me-AZADO. We first examined the ap-
plicability of Anelli’s conditions using NaOCl as the bulk
4
h,i
5
247–5251.
15) Ingold et al. reported that the decomposition rate of 9-azabiclo[3.3.1]nonane
N-oxyl (ABNO) (3) was very slow, while 8-azabicylo[3.2.1]octane N-oxyl (4)
oxidant, which has acquired general popularity in TEMPO
(
7
oxidations for its practicality. Although apparently the same
1
1
results were obtained for the catalytic oxidation of 3-phenypro-
panol (9) when catalysts were loaded either in 1 or 0.1 mol %
dimerized irreversibly.
16) Rychnovsky et al. also reported that 2,5-dimethylbicyclo[2.2.1]heptane
N-oxyl (5) was too unstable to isolate.
17) Wealsosynthesized8-azabicyclo[3.2.1]octaneand7-azabicyclo[2.2.1]heptane
(
(
Table 1, entries 1 and 2, respectively), significant differences
(
and attemped their oxidation to the corresponding nitroxyl radicals. However,
we failed to isolate these nitroxyl radicals; instead, the corresponding hydroxy-
lamines were recovered.
were ascertained when the catalyst loadings were decreased to
0
1
.01 mol %: TEMPO showed a decline, whereas ABNO and
-Me-AZADO maintained their performances, demonstrating
(
18) Iwabuchi, Y.; Shibuya, M.; Tomizawa, M. U.S. 20080221331, JP
0082128532.
19) (a) Cope, A. C.; Dryden, H. L., Jr.; Howell, C. F. Organic Synthesis;
2
the reactive nature of the unhindered class of nitroxyl radicals
Table 1, entry 3). Note that 1-Me-AZADO gave apparently
(
(
Wiley: New York, 1963; Collect Vol. IV, p 816. (b) Cope, A. C.; Dryden, H. L.,
Jr.; Overberger, C. G.; D’Addieco, A. A. J. Am. Chem. Soc. 1951, 73, 3416–
better results than ABNO under conditions with a catalyst
3
418. (c) Menzies, R. C.; Robinson, R. J. Chem. Soc. 1924, 191, 2163. (d) Sch o¨ pf,
loading below 0.003 mol %, indicating the robustness of the
C.; Lehmann, G. Ann. 1935, 618, 1.
20) (a) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1992, 114, 4992–
23,24
2-azaadamantane skeleton over the 9-azabicyclo[3.3.1]nonane.
(
4
1
1
996. (b) Nelsen, S. F.; Petillo, P. A.; Rumack, D. T. J. Am. Chem. Soc. 1990,
12, 7144–7147. (c) Nelsen, S. F.; Kessel, C. R.; Brien, D. J. J. Am. Chem. Soc.
980, 102, 702–711.
We next examined Margarita’s conditions using PhI(OAc)
2
4f
as the co-oxidant, which is useful for oxidations of substrates
(
21) (a) Hamada, Y.; Okamoto, N.; Hara, O. Heterocycles 2000, 52, 929–
9
34. (b) Momose, T.; Toshima, M.; Toyooka, N.; Hirai, Y.; Eugster, C. H.
(23) We speculate that the difference came from the stability of the
oxoammonium ion generated in the catalytic cycle. For notes on the instability
of 9-oxo-9-azabicyclo[3.3.1]nonane oxoammonium ion, see ref 20c.
J. Chem. Soc., Perkin Trans. 1 1997, 1307–1313.
22) Huang-Minlon, J. Am. Chem. Soc. 1949, 71, 3301.
(
4
620 J. Org. Chem. Vol. 74, No. 12, 2009

TABLE 3. The Scope of ABNO
SCHEME 2. Comparison of the Catalytic Efficiency
similar results to 1-Me-AZADO under Anelli’s conditions
(
Method A, Table 3, entries 1-6). It is interesting to point out
that both 1-Me-AZADO and ABNO exhibited marked prefer-
ence on oxidation of primary alcohol over secondary alcohol:
in the case of oxidation of diol 19 carrying a primary and
secondary alcohol moiety employing a slight excess (125 mol
%
) NaOCl, both 1-Me-AZADO and ABNO catalyzed selective
oxidation of the primary alcohol moiety to afford aldol 20 in
6% and 72% yield, respectively (Table 3, entry 7). In the case
9
of using 300 mol % NaOCl, 1-Me-AZADO and ABNO rapidly
oxidized both the alcohol portions to give keto-aldehyde 21 in
8
7% and 82% yield, respectively (Table 3, entry 8).
Nucleic derivative 22 was also effectively oxidized under
Margarita’s conditions (Method B, Table 3, entry 9). Notably,
ABNO oxidized the congested bicyclic substrate 23 with marked
efficiency while 1-Me-AZADO completely failed to oxidize it
(
Table 3, entry 10).
During the above-mentioned experiments, we noticed some
kinetic superiority of ABNO compared with 1-Me-AZADO
Table 2, entry 2; Table 3, entries 4 and 5) that led us to conduct
a close comparison of the catalytic efficiencies of ABNO and
-Me-AZADO using a designed substrate, 24, for analysis. It
(
1
was found that ABNO completely consumed the alcohol
immediately after the addition of the bulk oxidant, while 1-Me-
AZADO took 10 min to complete the reaction (Scheme 2).
This result strongly suggests that ABNO could be advanta-
geous in the oxidation of substrates that are challenging because
of structural complexity.
In summary, we have disclosed a readily accessible, three-
step synthesis of a less-hindered persistent class of nitroxyl
radical ABNO and its scope as a highly aggressive catalyst for
the oxidation of alcohols. Although ABNO showed a slight
decline in terms of catalytic turnover compared with 1-Me-
AZADO, the kinetically more efficient ABNO may find use in
alcohol oxidations. The ready availability of ABNO will also
inspire its novel application in many branches of material
science.
a
Method A: Reactions were catalyzed by 1 mol % nitroxyl radicals
with NaOCl (150 mol %), KBr (10 mol %), nBu
NaHCO in H Cl at 0 °C for 20 min. Method B: Reactions were
catalyzed by 5 mol % nitroxyl radicals with 330 mol % of PhI(OAc) in
(0.1 M) for 14 h at rt. Isolated yield. 125 mol %of NaOCl
4
NBr (5 mol %), aq
3
2
2
2
b
c
CH
2 2
Cl
d
e
was used. 8% of 21 was also produced. 300 mol % of NaOCl was
used. Yield of 20. Reaction was catalyzed by 10 mol % of nitroxyl
racial with 200 mol % of PhI(OAc) in CH Cl (0.3 M) for 2 h at room
f
g
2
2
2
h
i
temperature. Not determined. Reaction time was 24 h.
Experimental Section
containing electron-rich moieties, such as alkenes and aromatic
rings. We confirmed a similar tendency in catalytic efficiencies:
Synthesis of 9-Aza-bicyclo[3.3.1]nonane N-Oxyl (ABNO 3).
To a solution of acetonedicarboxylic acid 6 (2.1 g, 14.4 mmol) in
7
TEMPO < ABNO ≈ 1-Me-AZADO.
We then explored the scope of ABNO chemistry, which is
summarized in Table 3. The use of 1 mol % of ABNO gives
H O (50 mL) was slowly added 23% ammonia-water (4.5 mL) at
2
0 °C. Then glutaraldehyde (1.44 g, 14.4 mmol) in water (52.5 mL)
was added over 1 h. After the solution was stirred for 35 h at rt,
2
the solvent (H O) was removed under freeze-drying condition. The
resulting yellow solid 7 was used in the next reaction without further
purification.
(
24) We have recently reported the synthesis of stable oxoammonium salts
+
-
+
-
(
1-Me-AZADO Cl and 1-Me-AZADO BF
pot oxidation of primary alcohols to carboxylic acids.
4
) and their use in the efficient one-
8a
J. Org. Chem. Vol. 74, No. 12, 2009 4621

The mixture of 7 and H
stirred at 80 °C for 2 h. To a solution of KOH (8.0 g, 144 mmol)
in triethyleneglycol (21 mL) in a two-necked round-bottomed flask
distillation apparatus, the solution of 7 and H
dropwise. After the mixture was stirred at 220 °C for 30 min, H
50 mL) was added dropwise over 2 h at 220 °C. During the
reaction, the product, amine 8, was distillated with H
2
NNH
2
·H
2
O (2.2 mL, 43.1 mmol) was
Representative Procedure for Oxidation of Alcohols under
Anelli’s Condition. To a solution of 2-phenyl-1-cyclohexanol (14)
(300 mg, 1.7 mmol), KBr (20 mg, 0.17 mmol), and TBAB (27
mg, 0.085 mmol) in CH Cl -saturated aqueous NaHCO (2:1v/v,
2
NNH
2
2
·H O was added
2
2
3
2
O
6.4 mL) was slowly added 2.5 M NaOCl (1 mL, 2.5 mmol) in
(
saturated aqueous NaHCO (2 mL) at 0 °C. After 20 min, the
3
2
O under
mixture was quenched with saturated aqueous Na SO and extracted
2
3
azeotropic condition. The resulting aqueous solution was extracted
with CHCl and dried over K CO . Evaporation of the solvent
afforded 8 as a colorless oil, which was used in the next reaction
without further purification.
To a solution of the crude 8 in MeCN (14.4 mL) was added
with CHCl . The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography [hexane-AcOEt (9:1 v/v)] to
afford 2-phenyl-1-cyclohexanone (296 mg, 1.7 mmol, 100%) as a
white solid.
3
3
2
3
Na
mixture was stirred for 30 min. After the solution was cooled to 0
C, urea hydrogen peroxide (2.7 g, 28.8 mmol) was added and the
reaction mixture was stirred at 0 °C for 1 h and at ambient
temperature for 4 h. H O was added to the reaction mixture and
the aqueous solution was extracted with CHCl . The organic layer
was dried over K CO and concentrated. The residue was purified
by silica gel column chromatography to yield ABNO (3) (0.84 g,
mmol) as a red solid. An analytical sample was prepared by
2
WO
4
2
·H O (0.95 g, 1.88 mmol) at ambient temperature and the
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (B) (No. 17390002) from
the Japan Society for the Promotion of Science, Grant-in-Aid
for Young Scientists (B) (No. 17790005), and Grant-in-Aid for
the Grobal COE Program for “International Center of Research
& Education for Molecular Complex Chemistry” from Ministry
of Education, Culture, Sports, Science, and Technology, Japan.
°
2
3
2
3
6
1
1
sublimation: phase change 50 and ca. 85 °C, mp 126-129 °C (lit-.
1
phase change 53 and ca. 70 °C, mp 129-130 °C); IR (neat, cm )
Supporting Information Available: The experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
+
1
484, 1453, 1352, 1292; EI-MS m/z 140 (M ), 81 (100%); HRMS
+
(
EI) calcd for C
8
H
14NO 140.1075 (M ), found 140.1052. Anal.
Calcd for C
8
H14NO: C 68.58; H, 10.06; N, 9.99. Found: C, 68.39;
H, 9.87; N, 9.83.
JO900486W
4
622 J. Org. Chem. Vol. 74, No. 12, 2009