Synthesis of Chiral Nitroxides and an Unusual Racemization Reaction

Article abstract of DOI:10.1021/jo9808831

Lai's protocol for the synthesis of nitroxides has been extended to the synthesis of several new chiral piperazine and morpholine nitroxides. This strategy utilizes the Bargellini reaction as the key bond-forming step. Several optically pure nitroxides incorporating α-aromatic and α-spiro centers were prepared by this route. These chiral nitroxides will be of interest as enantioselective oxidants, as traps for prochiral radicals, and in the preparation of new materials. One of these nitroxides, compound 43, was found to racemize under mild oxidizing conditions. The mechanism for this unusual racemization reaction was investigated.

Full text of DOI:10.1021/jo9808831

J . Org. Chem. 1998, 63, 6363-6374
6363
Syn th esis of Ch ir a l Nitr oxid es a n d a n Un u su a l Ra cem iza tion
Rea ction
Scott D. Rychnovsky,* Thomas Beauchamp, Rajappa Vaidyanathan, and Tricia Kwan
Department of Chemistry, University of California, Irvine, California 92697-2025
Received May 8, 1998
Lai’s protocol for the synthesis of nitroxides has been extended to the synthesis of several new
chiral piperazine and morpholine nitroxides. This strategy utilizes the Bargellini reaction as the
key bond-forming step. Several optically pure nitroxides incorporating R-aromatic and R-spiro
centers were prepared by this route. These chiral nitroxides will be of interest as enantioselective
oxidants, as traps for prochiral radicals, and in the preparation of new materials. One of these
nitroxides, compound 43, was found to racemize under mild oxidizing conditions. The mechanism
for this unusual racemization reaction was investigated.
In tr od u ction
The recent years have witnessed an increased activity
in the area of chiral nitroxide synthesis. Nitroxides are
persistent free radicals that exhibit remarkable stability
primarily due to the absence of dimerization and dispro-
portionation. Their unique properties have sparked
considerable interest from theoretical, chemical, and
biological standpoints.1 Chiral nitroxides have been used
as catalysts in the kinetic resolution of alcohols via
enantioselective oxidation.2 They have also been em-
ployed in stereoselective coupling reactions with prochiral
radicals.3 In addition, nitroxides have found widespread
F igu r e 1. Lai’s synthesis of morpholine and morpholinone
nitroxides.
application in the development of paramagnetic chiral
liquid crystals4 and in the control of living free radical
polymerization processes.5 A recent review details the
progress made in the area of chiral nitroxide radicals.6
However, very few of the chiral nitroxides synthesized
to date possess a stereogenic center adjacent to the NO
radical moiety. We were particularly interested in syn-
thesizing six-membered ring chiral nitroxide radicals
bearing an aromatic substituent R to the nitroxyl center.7
The major difficulty in preparing such nitroxides is in
installing the two quaternary centers adjacent to the
nitrogen. Traditionally these substituents are installed
stepwise either via alkylation of nitroso compounds or
by nucleophilic addition to nitrones. Both of these reac-
tions are highly substrate dependent and are not ame-
nable to the synthesis of structurally diverse nitroxides.8
We were attracted by Lai’s protocol for the synthesis
of hindered morpholinones and piperazinones (Figure 1).9
This method involves the coupling of an amino alcohol 1
F igu r e 2. Proposed mechanism of the Bargellini reaction
between acetone and 2-amino-2-methyl-1-propanol or 1,2-
diaminopropanes.
and a ketone 2 to produce compound 3 that contains the
two quaternary centers adjacent to the amine in a single
step. Further transformation of carboxylate 3 produces
the morpholinone nitroxide 5 or morpholine nitroxide 6.
Lai prepared just a few hindered morpholines and
morpholinones by this method,9 but the general approach
appears to be versatile and would allow a rapid entry
into many different chiral nitroxides from a variety of
amino alcohols 1 and ketones 2. Our extension of the
Lai protocol to chiral nitroxide synthesis is described
below.
(1) Volodarsky, L. B.; Reznikov, V. A.; Ovcharenko, V. I. Synthetic
Chemistry of Stable Nitroxides; CRC Press: Boca Raton, FL, 1994.
(2) (a) Ma, Z.; Huang, Q.; Bobbitt, J . M. J . Org. Chem. 1993, 58,
4837-4843. (b) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J .
Org. Chem. 1996, 61, 1194-1195.
(3) Braslau, R.; Burrill, L. C., II; Mahal, L. K.; Wedeking, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 237-238.
(4) Tamura, R.; Suzuki, S.; Azuma, N.; Matsumoto, A.; Toda, F.;
Kamimura, A.; Hori, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 878-
879.
(5) Puts, R. D.; Sogah, D. Y. Macromolecules 1996, 29, 3323-3325.
(6) Naik, N.; Braslau, R. Tetrahedron 1998, 54, 667-696.
(7) Although there are several good routes for the synthesis of five-
membered ring nitroxides, very few methods exist for the synthesis of
six-membered ring chiral nitroxides. See refs 6 and 8.
(8) Einhorn, J .; Einhorn, C.; Ratajczak, F.; Durif, A.; Averbuch, M.-
T.; Pierre, J .-L. Tetrahedron Lett. 1998, 39, 2565-2568.
The generally accepted mechanism for the initial
coupling reaction is shown in Figure 2. This is an
example of the Bargellini reaction in which a ketone,
nucleophile, and chloroform react in the presence of a
S0022-3263(98)00883-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/20/1998

6364 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
Ta ble 1. Cycliza tion of Dia m in e 16 w ith Keton esa
Sch em e 1
entry
ketone
acetone
cyclohexanone
acetophenone
1-indanone
time (h)
yield (%)
1
2
3
4
5
6
24
16
16
24
48
16
76
87
0
0
16
27
p-nitroacetophenone
butanone
a
All reactions were carried out using 1.5 equiv of CHCl3, 2 equiv
of ketone, 5 equiv of NaOH (50%), catalytic NaCN, and BnEt3N+Cl-
in CH2Cl2 at 10 °C.
strong base.10 Deprotonation of chloroform by sodium
hydroxide followed by nucleophilic attack on the ketone
yields dichloro epoxide 9. The hindered N-C bond is
formed via regioselective opening of 9 by the nucleophile,
an amino alcohol9 or diamine9 in the present example.
An amino alcohol (e.g. 8, X ) O) would close to the lactone
11 (X ) O) via the acid choride 12. Subsequent hydroly-
sis of the lactone in the strongly basic reaction medium
leads to the observed product 10. A diamine (e.g. 8, X )
NR), on the other hand, cyclizes to the stable piperazi-
none 11 (X ) NR). Chiral morpholines, morpholinones,
piperazines, and piperazinones should all be accessible
on the basis of this unique reaction.
Sch em e 2
Resu lts a n d Discu ssion
Syn th esis of P ip er a zin on e a n d P ip er a zin e Ni-
tr oxid es. Synthesis of chiral piperazine and piperazi-
none nitroxides was our initial objective. With the
ultimate goal of producing optically pure nitroxides, (S)-
1-phenethylamine (14) was introduced to facilitate the
separation of diastereomers produced in the Bargellini
reaction with unsymmetric ketones. Diamine 16 was
prepared by condensation of 2-nitropropane with form-
aldehyde and 14 followed by hydrogenation in an exten-
sion of Senkus’s procedure.11 Bargellini reaction with
cyclohexanone using Lai’s conditions gave the expected
piperazinone 18 in excellent yield. Oxidation with m-
CPBA gave the stable nitroxide 19. Nitroxide 19 was
prepared in four steps and 48% overall yield from
commercially available materials.
Nitroxide 19 is chiral by virtue of the phenethylamine
center, but the stereogenic center is remote from the
nitroxide center and is unlikely to exert any interesting
effect on further chemistry. Introduction of a stereogenic
center R to the hindered amine was the next obvious step,
and this is where the limitations of the Bargellini
coupling became apparent. Table 1 shows our attempts
to couple several ketones with diamine 16. Both acetone
and cyclohexanone work well. Indanone spontaneously
polymerized upon addition of base. Acetophenone gave
essentially none of the desired product, and p-nitroac-
etophenone gave only 16% yield of the piperazinone.
Reaction with butanone afforded the cyclized product in
27% yield. The sensitivity of the reaction to variations
in the ketone structure precluded a general “combinato-
rial” synthesis of piperazinones, and so we shifted our
focus to exploring structural variations in the diamine
structure.
The diamine route was successful for the introduction
of chiral centers adjacent to the hindered amine, Scheme
2. Condensation of R-nitroethylbenzene12 20 with form-
aldehyde and 14 gave the expected adduct 21 in good
yield, as a mixture of diastereomers. Hydrogenation over
Raney Ni furnished diamine 22 as a mixture of diaster-
eomers which was used without separation. Coupling
with acetone using Lai’s conditions gave piperazinone 23
in excellent yield. The two diastereomers were easily
separated by flash chromatography, producing piperazi-
none 23 with either configuration at the C5 center. The
R-methylbenzylamine acts as an internal resolving agent
and facilitates separation of the C-5 epimers of piperazi-
none 23. Thus the chiral diamine route is effective for
the preparation of piperazines with stereogenic centers
adjacent to the hindered nitrogen.
This approach was also used to prepare optically pure
chiral nitroxide 29, Scheme 3. The 1-nitrotetralin (24)
was prepared by oxidation of the corresponding oxime13
or by displacement of the corresponding bromide with
NaNO2.12 Condensation with formaldehyde and amine
14 followed by reduction proceeded uneventfully. Bargel-
lini coupling with acetone under Lai’s conditions gave
piperazinone 26 in excellent yield as a 1.3:1 mixture of
diastereomers. Unlike in the previous example, the
diastereomeric piperazinones were not separable by flash
chromatography. LAH reduction cleanly converted 26
to the corresponding piperazine 27. The diastereomers
of 27 were not separable by chromatography, but crystal-
lization of the (+)-camphorsulfonic acid (CSA) salt was
(9) (a) Lai, J . T. J . Org. Chem. 1980, 45, 754-755. (b) Lai, J . T.
Synthesis 1981, 41-42. (c) Lai, J . T. Synthesis 1984, 122-123. (d) Lai,
J . T. Synthesis 1984, 124-125.
(10) (a) Link, G. German Patent 80,986 (J uly 14, 1894) from: Chem.
Zentr. 1895, 66 (II), 70. (b) Bargellini, G. Gazz. Chim. Ital. 1906, 36,
329-338.
(12) Kornblum, N.; Wade, P. A. J . Org. Chem. 1973, 38, 1418-
1420.
(13) Olah, G. A.; Ramaiah, P.; Lee, C.-S.; Prakash, G. K. S. Synlett
1992, 337-339.
(11) Senkus, M. J . Am. Chem. Soc. 1946, 68, 10-12.

Chiral Nitroxides
J . Org. Chem., Vol. 63, No. 18, 1998 6365
Sch em e 3
Sch em e 4
by reduction to the diol followed by dehydration-cycliza-
tion using methanesulfonic acid. Preliminary attemps
to prepare more complex morpholines by methanesulfonic
acid-mediated dehydration were not promising, so two
new routes were developed. Lactone 33 was converted
to the thionolactone 35 by treatment with Lawesson’s
reagent. Subsequent reductive desulfurization and m-
CPBA oxidation gave the morpholine nitroxide 36, but
the overall yield was disappointing. An alternative
deoxygenation began with the DIBAL-H reduction of
lactone 33 followed by conversion to the phenylthio
acetal. Lithium-ammonia reduction removed the phe-
nylthio acetal, and m-CPBA oxidation furnished the
morpholine nitroxide 36 in a good overall yield.
successful.14 Hydrogenation of diastereomerically pure
27 over Pearlman’s catalyst led to cleavage of the
phenethyl group without significant cleavage at the
tertiary benzylic amine bond. Tosylation followed by
m-CPBA oxidation gave the optically pure nitroxide in
good overall yield. The absolute configuration R to the
nitroxyl center has not been determined. The enantio-
meric excess of 29 should be >97% based on the diaster-
1
eomeric excess of 27 as determined by H NMR analy-
sis.15 Oxidation of the piperazinone 26 also led to the
chiral nitroxide 30. Thus, the chiral diamine route to
optically active nitroxides is effective where the appropri-
ate nitroalkanes are available or easily prepared.
Syn th esis of Mor p h olin e a n d Mor p h olin on e Ni-
tr oxid es. Chiral morpholine and morpholinone nitrox-
ides should also be available using the Bargellini reac-
tion. Scheme 4 outlines a route to these nitroxides from
2-methyl-2-amino-1-propanol (31). We were surprised to
find that the Bargellini coupling with acetophenone
worked very well in this case. The same reaction had
been unsuccessful with the diamine 16. The sodium salt
32 precipitated from the reaction and was isolated by
filtration. Acidification followed by heating in toluene
and neutralization with Et3N gave the lactone 33 in 57%
overall yield from the amino alcohol 31. Oxidation with
m-CPBA completed this simple and effective synthesis
of morpholinone nitroxide 34.
Another target of interest was the indane morpholine
nitroxide 43. All attempts to directly couple indanone
with commercially available amino alcohol 31 were
unsuccessful and led only to polymerization of the in-
danone.16 Synthesis of the racemic nitroxide followed our
general approach to piperazine nitroxides, Schemes 2 and
3. The 1-nitroindane17 was prepared by oxidation of the
corresponding oxime with sodium perborate.13 Base-
promoted condensation with formaldehyde and hydroge-
nation of the nitro group gave amino alcohol 39 in good
yield. Bargellini coupling with acetone gave the expected
carboxylate salt, which was acidified and dehydrated
with CSA in toluene. In cases such as this one with the
aromatic ring remote from the carbonyl, acidification of
the carboxylate salt with aqueous HCl only led to
decomposition. Dehydration of the lactone 40 was car-
ried out via the phenylthio acetal 41. In this case
acetylation of the lactol followed by TMSOTf-catalyzed
introduction of the thiophenol was more effective than
The racemic lactone 33 could be deoxygenated to
morpholine nitroxide 36. Lai had shown that simple
morpholines could be prepared from the morpholinones
(16) The trichloromethyl adduct of indanone was prepared in an
effort to avoid the use of base sensitive indanone and to bypass the
first step of the mechanism (Figure 2, intermediate 7), but on treatment
with mild base it instantly reverted to the indanone, which promptly
polymerized.
(14) The presence of the chiral phenethyl moiety allowed us to
monitor the resolution by 1H NMR analysis.
(15) When a 1: 3 mixture of diastereomers of 27 was carried through
the sequence, the resulting nitroxide 29 had an [R]D of -30.8 (c )
1.0, CHCl3), which corresponds to an ee of ca. 50% based on the optical
(17) The 1-nitroindane has also been prepared by oxidation of
1-aminoindane with CF3COCH3: (a) Yang, D.; Wong, M.-K.; Yip, Y.-
C. J . Org. Chem. 1995, 60, 3887-3889. (b) Murray, R. W.; Singh, M.;
Rath, N. Tetrahedron: Asymmetry 1996, 7, 1611-1619.
23
rotation of enantiomerically pure (+)-29.

6366 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
Sch em e 5
Sch em e 7
Sch em e 6
that both diastereomers of the acetate 44 were optically
pure. The remainder of the deoxygenation and oxidation
sequence proceeded uneventfully to give 43. We were
very surprised to find that 43 exibited a rotation of zero,
and further analysis on a chiral HPLC column showed
that it was racemic.19
The sequence from optically pure 44 to racemic 43
involved a Lewis acid promoted exchange, dissolving
metal reduction, and oxidation. Both the Lewis acid and
the reduction step might be responsible for a reversible
cleavage of the tertiary benzylic amine. Resolution of
morpholine 42 would circumvent racemization in these
steps. Resolution via the CSA salt was unsuccessful, but
treatment with (R)-(+)-(R)-methylbenzyl isocyanate gave
the diastereomeric carbamates 45 in nearly quantitative
yield, Scheme 7. The diastereomers were separated by
preparative HPLC, and the carbamate was cleaved to
give optically active morpholine 42. The optical purity
of 42 could not be directly assayed by HPLC, but it did
come from a single diastereomer of 45 and exhibited a
nonzero rotation. Once again, m-CPBA oxidation of 42
gave racemic nitroxide 43.19 These experiments demon-
strated that the racemization was taking place in the
m-CPBA oxidation rather than the previously suspected
Lewis acid treatment or dissolving metal reduction.
Small amounts of 43 were resolved by preparative
HPLC using a chiralpak-AD analytical column. Upon
further experimentation we found that the optically pure
morpholine could be oxidized to 43 without racemization
using m-CPBA under buffered, biphasic conditions. The
most expedient synthesis of optically pure 43 would
appear to be resolution of the racemate on a chiral HPLC
column or resolution of lactone 40 with (+)-CSA followed
by deoxygenation and buffered m-CPBA oxidation.20
Mech a n ism of th e Ra cem iza tion of In d a n e Ni-
tr oxid e 43. How does unbuffered m-CPBA lead to
racemization in the preparation of nitroxide 43? Nitrox-
ide 43 itself does not racemize on standing for weeks at
room temperature, either in solution or neat. Four
mechanistic possiblities for the racemization are outlined
in Figure 3. Mechanism A involves reversible opening
and closing of the protonated amine 46. In mechanism
(PhS)2-PBu3 treatment. Unlike the reduction of thio-
acetal 37, Li/NH3 reduction of 41 resulted in Birch
reduction of the aromatic ring. Overreduction was
circumvented by quenching the reaction with thioanisole.
Oxidation with m-CPBA gave the racemic nitroxide 43
in good overall yield. The synthesis of 43 demonstrates
that complex chiral morpholine nitroxides can be pre-
pared from the corresponding nitro alkanes.
P r ep a r a tion a n d Un exp ected Ra cem iza tion of a
Ch ir a l Nitr oxid e. We set out to prepare optically pure
indane nitroxide 43 but were in for a surprise. Scheme
6 illustrates the initial attempt to synthesize optically
pure 43. Lactone 40 was synthesized in 10% ee starting
from optically enriched amino alcohol 39 (10% ee).18
Resolution using (+)-CSA led to the isolation of the major
enantiomer in 79% of theory in 99% ee.22 (+)-40 was
reduced with DIBAL-H and acetylated to give a diaster-
eomeric mixture of lactol acetates. Comparison of the
HPLC trace with that of the racemic material showed
(18) The enantiomeric excess of 40 was analyzed by chiral HPLC
using
a
10
×
250 mm chiralpak-AD column eluting with 4%
i-PrOH/ hexanes at 0.5 mL/min; tR ) 17.3 min (major) and 18.8 min
(minor).
(19) The enantiomeric excess of 43 was analyzed by chiral HPLC
using a 10 × 250 mm chiralpak-AD column eluting with 2% i-PrOH/
hexanes at 0.5 mL/min; tR ) 17.1 and 18.6 min.
(20) We have not proved that the deoxygenation proceeds without
racemization.
(21) Ciganek, E.; Read, J . M.; Calabrese, J . C. J . Org. Chem. 1995,
60, 5795-5802.
(22) Lee, T. D.; Keana, J . F. W. J . Org. Chem. 1975, 40, 3145-
3147.

Chiral Nitroxides
J . Org. Chem., Vol. 63, No. 18, 1998 6367
Both of the remaining mechanistic proposals for race-
mization involve the N-oxo ammonium salt 48. When
optically pure nitroxide 43 was treated with commercial
m-CPBA without a buffer, rapid racemization ensued.
The optical purity was reduced to 35% ee in just 15 min,
and complete racemization was observed in 60 min, eq
3. Both Cella and Ganem have shown that m-CPBA is
an effective bulk oxidant for TEMPO mediated oxidations
of alcohols, where the active oxidant is an N-oxo am-
monium salt.23 Thus the most likely species involved in
the racemization is an N-oxo ammonium salt. Nitroxides
are known to reversibly disproportionate to hydroxy-
lamine salts and N-oxo ammonium salts on treatment
with acid.24 We were concerned that acid might be a
player in the racemization reaction. Optically pure
nitroxide 43 was treated separately with 3-chlorobenzoic
acid, acetic acid, and p-toluenesulfonic acid but showed
no racemization after several hours at 25 °C. In contrast,
base washed m-CPBA led to complete racemization of 43.
Thus the oxidant is necessary for the racemization but
the acid is not.
How does aqueous sodium bicarbonate prevent race-
mization (Scheme 7)? The bicarbonate or water may
simply add to the small quantities of N-oxo ammonium
ion generated, thereby preventing it from catalyzing the
racemization; vide infra. Protection of the N-oxo am-
monium ion would also explain the following observa-
tion: addition of m-CPBA and MeOD led to neither
deuterium incorporation nor racemization. The N-oxo
ammonium ion would rapidly oxidize MeOD and, thus,
have a much shorter lifetime and be protected from
racemization.
F igu r e 3. Four possible mechanisms for the racemization of
nitroxide 43.
B, racemization takes place via the hydroxylamine and
involves a reversible Cope and retro-Cope sequence.
Hydroxylamine 47 is a likely intermediate in the oxida-
tion of amine 42, and Ciganek has shown that retro-Cope
cyclizations can take place under very mild conditions.21
Mechanism C involves solvolytic opening and closing of
the N-oxo ammonium salt, an overoxidation product of
the nitroxide. Mechanism D is based on a reversible
Grob fragmentation of the same N-oxo ammonium salt
48. This set of mechanisms appeared to be the most
plausible routes for the racemization observed in the
synthesis of optically pure nitroxide 43.
To test for racemization of the morpholine salt, (+)-42
was treated with CSA for 1 h at 25 °C, eq 1. Essentially
no racemization was observed, and we conclude that
racemization of the morpholine salt under the oxidation
conditions is not feasible.
A conclusive test for the intermediacy of the N-oxo
ammonium ion in the racemization is shown in Scheme
8. Bromine is known to rapidly and quantitatively
oxidize nitroxides to N-oxo ammonium salts.25 Treat-
ment of optically pure 43 with bromine immediately gave
the bright orange N-oxo ammonium salt. Quenching this
intermediate with buffered i-PrOH after only 2 min at
25 °C returned the racemic nitroxide 43.26 This racem-
ization is much faster than with m-CPBA, which does
not give the orange color of the N-oxo ammonium ion and
presumably only produces it in low concentrations. Thus,
To test mechanism B the optically active nitroxide 43
was reduced to the hydroxylamine with phenylhydra-
zine.22 The hydroxylamine was allowed to stand for
several hours at 25 °C before reoxidation to the nitroxide
with buffered m-CPBA. No racemization was observed
under these conditions. The reaction was repeated with
acetic acid present to see if mild acid promoted racem-
ization of the hydroxylamine 47, but once again no
racemization was observed (eq 2). We concluded that the
Cope/retro-Cope sequence was not taking place and that
mechanism B could be removed from consideration.
(23) (a) Cella, J . A.; Kelley, J . A.; Kenehan, E. F. J . Org. Chem. 1975,
40, 1860-1862. (b) Ganem, B. J . Org. Chem. 1975, 40, 1998-2000.
(24) Ma, Z.; Bobbitt, J . M. J . Org. Chem. 1991, 56, 6110-6114.
(25) Bobbitt, J . M.; Flores, C. L. Heterocycles 1988, 27, 509-533.
(26) N-Oxo ammonium salt 49 oxidizes i-PrOH to acetone. The
resulting hydroxylamine is oxidized by a further 1 equiv of 49 to give
nitroxide 43.

6368 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
Sch em e 8
piperazinones may be synthesized by coupling complex
amino alcohols or diamines with sterically less demand-
ing ketones. These reactions proceed in excellent yields.
The key coupling reaction is sensitive to the structure of
the ketone component but tolerant to structural varia-
tions in the amino alcohol or diamine components.
Con clu sion s
We have adapted the Lai strategy, based on Bargellini
couplings, for the synthesis of chiral nitroxides. Chiral
piperazine, piperazinone, morpholine, and morpholinone
nitroxides can prepared by these new routes. The
Bargellini couplings are limited to a narrow range of
ketones, but structural variations can be introduced in
the amino alcohol or diamine components. A very con-
venient route to the diamine and amino alcohol precur-
sors is based on condensations of nitroalkanes. The new
chiral nitroxides available by this chemistry will be of
interest as enantioselective oxidants, as traps for prochiral
radicals, and in the preparation of new materials.
Indane nitroxide 43 is susceptible to racemization
under oxidizing conditions. This unusual epimerization
proceeds through the N-oxo ammonium salt. The facile
racemization of nitroxides upon oxidation has not been
previously reported.
electron transfer would interconvert the N-oxo am-
monium ion and nitroxide, and as a result, small amounts
of the N-oxo ammonium ion would catalyze racemization
of the nitroxide. These experiments establish the N-oxo
ammonium ion as an intermediate in the racemization
and are consistent with either mechanistic proposal C
or D.
Exp er im en ta l Section 28
5,5-Dim eth yl-2-oxo-1-[(1S)-p h en yleth yl]sp ir o[p ip er a -
zin e-3,1′-cycloh exa n e] (18). A mixture of diamine 16 (193.4
mg 1.0 mmol), cyclohexanone (0.21 mL, 2.0 mmol), chloroform
(0.12 mL, 1.5 mmol), powdered NaCN (3.1 mg, 0.06 mmol),
benzyltriethylammonium chloride (5.0 mg, 0.02 mmol), and
dichloromethane (0.5 mL) was stirred and cooled to 10 °C
under argon. An aqueous solution of 50% NaOH was added
dropwise with stirring so as to keep the temperature below
10 °C. The mixture was maintained at 10 °C overnight. The
mixture was poured into a separatory funnel, and dichlo-
romethane and water were added to dissolve the solids. The
two layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were
dried over Na2SO4, filtered, and concentrated. Purification by
flash chromatography (10% MeOH/CH2Cl2, SiO2) afforded
262.0 mg (87%) of piperazinone 18 as a white foam: IR (neat)
3313, 3030, 2932, 2857, 1627 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.34-7.22 (m, 5 H), 6.09 (q, J ) 6.9 Hz, 1 H), 2.86 (d, J )
We favor mechanism C over mechanism D largely on
the basis of circumstantial evidence. Unbuffered m-
CPBA oxidations produce 50, 51, and 29 with no appar-
ent racemization. If the Grob fragmentation were im-
portant, one might expect the N-oxo ammonium salt
from 50 and 51 to fragment more rapidly than 49 be-
cause of the more effective stabilization of the oxon-
ium ion. The N-tosyl nitroxide 29 could also participate
in a Grob fragmentation, but racemization was not
observed. In an effort to force the racemization, 29 was
treated with bromine for 2 min and then quenched as
described previously, but no racemization was observed.
Of all of the nitroxides examined, indane 43 appears
uniquely susceptible to oxidative racemization. The
unusual reactivity of 43 is best attributed to the 1-2
orders of magnitude higher rates of solvolysis for cyclo-
pentanes when compared with cyclohexanes or acyclic
systems.27
Scop e of th e Ba r gellin i Rea ction . We have ex-
plored the scope of the Bargellini reaction for the
synthesis of chiral morpholinones and piperazinones.
Only acetone and cyclohexanone could be successfully
coupled with diamine 16 in the key step. Most other
ketones, especially aryl ketones, react sluggishly, if at
all. However, reaction of amino alcohol 31 with ketones
appears more general. This is evident from the fact that
amino alcohol 31 reacts with acetophenone to furnish the
corresponding morpholinone in good yields, while di-
amine 16 does not react at all. Highly enolizable ketones
such as indanone do not react either with diamine 16 or
amino alcohol 31 but spontaneously polymerize upon
addition of base. Interesting chiral morpholinones and
(28) Gen er a l exp er im en ta l p r oced u r es: Infrared spectra were
recorded on a7 MIDAC Prospect FT-IR spectrometer. 1H NMR and
13C NMR spectra were recorded on a Nicolet Omega 500, a Nicolet
GN 500, a Nicolet QE 300, a Bruker 500, or a Bruker 300 spectrometer.
Chemical shifts of the 1H NMR and 13C NMR spectra were referenced
to residual solvent or to tetramethylsilane at 0.0 ppm. NMR data for
13C DEPT experiments are reported as quaternary (C), tertiary (CH),
secondary (CH2), and primary (CH3) carbon atoms. Combustion
analyses were performed by M-H-W Laboratories, Phoenix, AZ. Mass
spectra were determined on a AE2-MS 30, a PG 7070E-HF, a CG
Analytical 7070E, or a Fisions autospec spectrometer. Optical rotations
were measured with a J asco DIP-370 digital polarimeter. Tetrahydro-
furan, diethyl ether, and methylene chloride were dried by filtration
through alumina according to the procedure described by Grubbs
(Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518-1520). All amine bases
were distilled from calcium hydride and stored over potassium
hydroxide. Benzene and acetonitrile were distilled from calcium
hydride just prior to use. Capillary GC analysis was performed on a
Hewlett-Packard model 6890 instrument equipped with a FID detector.
Liquid chromatography was performed using forced flow (flash chro-
matography) of the indicated solvent system on E. Merck reagent silica
gel 60 (230-400 mesh). Air- and/or moisture-sensitive reactions were
carried out under N2 or Ar using oven- or flame-dried glassware and
standard syringe/septa techniques. All reagents were purchased from
Aldrich Chemical Co. or Acros and were used as received, unless
otherwise stated.
(27) Brown, H. C.; Fletcher, R. S.; J ohannesen, R. B. J . Am. Chem.
Soc. 1951, 73, 212-21.

Chiral Nitroxides
J . Org. Chem., Vol. 63, No. 18, 1998 6369
12.3 Hz, 1 H), 2.63 (d, J ) 12.3 Hz, 1 H), 1.99-1.89 (m, 2 H),
1.68-1.52 (m, 7 H), 1.45 (d, J ) 6.9 Hz, 3 H), 1.39-1.25 (m 2
H), 1.07 (s, 3 H), 0.88 (s, 3 H); 13C NMR (75 MHz, CDCl3,
DEPT) δ C, 173.9, 140.1, 57.2, 48.6; CH, 128.3, 127.5, 127.2,
49.8; CH2, 52.2, 36.6, 36.4, 31.1, 25.3, 20.9; CH3, 27.8 (overlap-
ping), 14.8. HRMS (CI, NH3): found, m/z 300.2201 (M+);
(5R)- a n d (5S)-5-p h en yl-3,3,5-tr im eth yl-1-[(1S)-p h en yl-
eth yl]p ip er a zin -2-on e (23). A mixture of diamine 22 (566.0
mg 2.23 mmol), acetone (0.35 mL, 4.45 mmol), chloroform (0.27
mL, 3.34 mmol), powdered NaCN (7.0 mg, 0.13 mmol), ben-
zyltriethylammonium chloride (10.0 mg, 0.04 mmol), and
dichloromethane (1.2 mL) was stirred and cooled to 0 °C under
argon. An aqueous solution of 50% NaOH was added dropwise
with stirring so as to keep the temperature below 10 °C. The
mixture was maintained at 10 °C overnight. The mixture was
then poured into a separatory funnel, and dichloromethane
and water were added to dissolve the solids. The two layers
were separated and the aqueous layer was extracted with CH2-
Cl2 (3×). The combined CH2Cl2 extracts were dried over Na2-
SO4, filtered, and concentrated. Crude 1H NMR indicated a
1:1 mixture of starting material and product. The crude
mixture was resubmitted to the reaction conditions and worked
up as before. Purification by flash chromatography (50%
EtOAc/hexanes, SiO2) afforded 232.0 mg of the minor diaste-
reomer and 427.9 mg of the major diastereomer, which
corresponds to an overall yield of 92%. The minor diastere-
omer was recrystallized from hexanes. Major diastereomer:
C
19H28N2O requires 300.2202.
5,5-Dim eth yl-2-oxo-1-[(1S)-p h en yleth yl]sp ir o[p ip er a -
zin e-3,1′-cycloh exa n e]-N-oxyl (19). To a solution of 18
(190.4 mg, 0.63 mmol) in CH2Cl2 (5 mL) was added m-CPBA
(330.3 mg, 1.90 mmol). The solution was stirred at room
temperature overnight. The reaction was quenched with
saturated NaHCO3, and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3×). The combined
organics were washed (water, brine), dried (Na2SO4), filtered,
and concentrated in vacuo. Flash chromatography (20%
EtOAc/hexanes, SiO2) furnished 197.4 mg (99%) of 19 as a
yellow solid: mp ) 114-116 °C; IR (neat) 2975, 2939, 2928,
2861, 1648, 1496, 1486, 1454 cm-1. HRMS (EI): found, m/z
315.2069 (M+); C19H27N2O2 requires 315.2072. Anal. Calcd
for C19H27N2O2: C, 72.35; H, 8.63; N,8.88. Found: C, 72.15;
H, 8.53; N, 8.74
[R]23 -130.5° (c, 1.14, CHCl3); IR (neat) 3318, 3086, 3060,
D
3030, 2975, 2930, 1638 cm-1
;
1H NMR (300 MHz, CDCl3) δ
(1S)-N-(2-Nit r o-2-p h en ylp r op yl)-1-p h en ylet h yla m in e
(21). A 50 mL round-bottomed flask fitted with a reflux
condenser was charged with (S)-R-methylbenzylamine (2.42
g, 0.02 mol). The flask was immersed in a water bath, the
temperature of which was maintained at 15 °C. Aqueous
formaldehyde (37%, 1.6 g, 0.02 mol) was added slowly to the
flask with constant stirring over a period of 15 min. A highly
viscous gel formed. After a further period of 5 min, 1-nitro-
1-phenylethane (3.02 g, 0.02 mol) was added all at once and
the mixture was stirred for 45 min without further cooling.
Sodium sulfate (2 g) was added to the mixture and stirring
was continued until most of the salt had dissolved. The
contents were poured into a separatory funnel and allowed to
stand for 15 days. The nonaqueous layer was separated from
the aqueous layer and chromatographed (10% EtOAc/hexanes,
SiO2) to afford 3.4 g (60%) of the product as a 1:1.5 mixture of
diastereomers that were inseparable: IR (mixture, neat) 3342,
3062, 3027, 2968, 2926, 2867, 1602, 1541 cm-1; 1H NMR (300
MHz, CDCl3) [major isomer] δ 7.45-7.26 (m, 10 H), 3.86-3.79
(m, 1 H; overlapping), 3.69 (d, J ) 13.2 Hz, 1 H), 2.82 (d, J )
13.2 Hz, 1 H), 2.02 (s, 3 H), 1.37 (d, J ) 6.6 Hz, 3 H); 1H NMR
(300 MHz, CDCl3) [minor isomer; characteristic peaks] δ 3.50
(d, J ) 12.9 Hz, 1 H), 3.05 (d, J ) 12.9 Hz, 1 H), 2.08 (s, 3 H),
1.35 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3, DEPT)
[mixture] δ C, 145.2, 145.0, 138.6, 94.0, 93.8; CH, 128.8, 128.6,
128.4, 127.0, 126.6, 126.4, 125.3, 125.1, 58.6, 58.4; CH2, 55.2,
55.1; CH3, 24.6, 24.4, 22.8, 22.5. Anal. Calcd for C17H20N2O2
[mixture]: C, 71.81; H, 7.09; N, 9.85. Found: C, 71.80; H,
6.81; N, 9.94.
7.30-7.14 (m, 10 H), 6.17 (q, J ) 6.9 Hz, 1 H), 3.23 (s, 2 H)
1.57 (d, J ) 6.9 Hz, 3 H), 1.49 (s, 3 H), 1.42 (s, 3 H), 1.23 (s, 3
H); 13C NMR (75 MHz, CDCl3, DEPT) δ C, 173.7, 145.8, 139.6,
55.6, 53.9; CH, 128.3, 127.9, 127.5, 127.3, 126.5, 125.5, 49.6;
CH2, 50.9; CH3, 30.0, 29.3, 14.8. Minor diastereomer: mp )
83-85 °C; [R]23D +14.83° (c, 2.04, MeOH); IR (neat) 3292, 2982,
2932, 1625, 1488, 1439, 1371, 1312, 1166, 869 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.45-7.20 (m, 10 H), 6.11 (q, J ) 7.2 Hz,
1 H), 3.38 (d, J ) 12.6 Hz, 1 H), 3.08 (d, J ) 12.6 Hz, 1 H),
1.49 (s, 3 H), 1.38 (d, J ) 7.2 Hz, 3 H), 1.34 (s, 3 H), 1.09 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 173.9, 146.9, 139.9, 128.4,
128.2, 127.8, 127.6, 126.9, 125.5, 55.7, 54.4, 51.1, 50.0, 30.0,
29.6, 28.5, 15.0. Anal. Calcd for C21H26N2O: C, 78.22; H, 8.13;
N, 8.69. Found: C, 78.38; H, 7.89; N, 8.51.
1-Nit r o-1-{[N-(1S)-p h e n yle t h yl]a m in om e t h yl}t e t r a -
lin . A 50 mL round-bottomed flask fitted with a reflux
condenser was charged with (S)-R-methylbenzylamine (2.1 g,
18 mmol). The flask was immersed in a water bath, the
temperature of which was maintained at 15 °C. Aqueous
formaldehyde (37%, 1.4 g, 18 mmol) was added slowly to the
flask with constant stirring over a period of 15 min. A highly
viscous gel formed. After a further period of 5 min, 1-nitrote-
tralin (3.1 g, 18 mmol) was added all at once and the mixture
was stirred for 45 min without further cooling. Sodium sulfate
(2 g) was added to the mixture, and stirring was continued
until most of the salt had dissolved. The contents were poured
into a separatory funnel and allowed to stand for 5 days. The
nonaqueous layer was separated from the aqueous layer and
chromatographed (10% EtOAc/hexanes, SiO2) to afford 4.3 g
(77%) of the product as a 1:1.3 mixture of diastereomers that
were inseparable: IR (mixture, neat) 3344, 3062, 3026, 2960,
(1S )-N -(2-Am in o -2-p h e n y lp r o p y l)-1-p h e n y le t h y l-
a m in e (22). Raney nickel (200 mg) was washed sequentially
with water (5 × 10 mL) and ethanol (5 × 10 mL). The catalyst
was then rinsed into a 125 mL pressure reaction vessel
containing nitroamine 21 (1.0 g, 3.5 mmol) in ethanol (10 mL).
The reaction vessel was pressurized to 500 psi with H2 and
stirred at 60 °C for 16 h. The reaction mixture was cooled to
room temperature, filtered through a plug of Celite, and
concentrated under reduced pressure. Purification by flash
chromatography (5% MeOH/CH2Cl2, SiO2) afforded 757.3 mg
(85%) of product as a 1:1.5 mixture of diastereomers: IR
(mixture, neat) 3365, 3311, 3083, 3060, 3026, 2967, 2925, 2895,
2872, 1603, 1538 cm-1 1H NMR (300 MHz, CDCl3) [major
;
isomer] δ 7.38-7.09 (m, 9 H), 3.82-3.73 (m, 1 H; overlapping),
3.59 (d, J ) 13.5 Hz, 1 H), 2.73 (d, J ) 13.5 Hz, 1 H), 2.95-
2.77 (m, 1 H; overlapping), 2.67-2.51 (m, 3 H; overlapping),
2.01-1.91 (m, 1 H; overlapping), 1.63 (bs, 1 H); 1.62-1.46 (m,
1 H; overlapping); 1.36 (d, J ) 6.6 Hz, 3 H); 1H NMR (300
MHz, CDCl3) [minor isomer; characteristic peaks] δ 3.43 (d, J
) 13.2 Hz, 1 H), 3.02 (d, J ) 13.2 Hz, 1 H), 1.31 (d, J ) 6.6
Hz, 3 H); 13C NMR (75 MHz, CDCl3) [mixture] δ 145.2, 145.1,
138.3, 137.9, 132.7, 132.2, 129.5, 129.4, 128.9, 128.8, 128.4,
128.3, 127.0, 126.9, 126.7, 126.5, 93.5, 92.7, 58.6, 58.5, 54.8
(overlapping), 31.5, 30.9, 29.4, 29.3, 24.7, 24.4, 19.6, 19.4.
Anal. Calcd for C19H22N2O2 [mixture]: C, 73.52; H, 7.14; N,
9.02. Found: C, 73.70; H, 7.20; N, 9.05.
2867, 2833, 1602 cm-1 1H NMR (300 MHz, CDCl3) [major
;
isomer] δ 7.53-7.19 (m, 10 H), 3.76-3.65 (m, 1 H; overlap-
ping), 2.88 (d, J ) 11.4 Hz, 1 H), 2.53 (d, J ) 11.4 Hz, 1 H),
1
1.70 (br s), 1.41 (s, 3 H), 1.26 (d, J ) 6.6 Hz, 3 H); H NMR
(300 MHz, CDCl3) [minor isomer; characteristic peaks] δ 2.77
(d, J ) 11.4 Hz, 1 H), 2.65 (d, J ) 11.4 Hz, 1 H), 1.44 (s, 3 H),
1.31 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3) [mixture]
δ 147.5, 147.4, 145.7, 128.2, 128.1, 126.6, 126.5, 126.4, 126.2,
126.1, 125.2, 59.9, 59.7, 58.4, 58.3, 55.1, 55.0, 29.2, 29.1, 24.7,
24.3. Anal. Calcd for C17H22N2 [mixture]: C, 80.27; H, 8.72;
N, 11.01. Found: C, 80.09; H, 8.52; N, 10.83.
1-Am in o-1-{[N-(1S)-p h en ylet h yl]a m in om et h yl}t et r a -
lin (25). Raney nickel (200 mg) was washed sequentially with
water (5 × 10 mL) and ethanol (5 × 10 mL). The catalyst
was then rinsed into a 125 mL pressure reaction vessel
containing the nitroamine (2.0 g, 6.8 mmol) in ethanol (20 mL).
The reaction vessel was pressurized to 500 psi with H2 and
stirred at 50 °C for 4 h. The reaction mixture was cooled to

6370 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
room temperature, filtered through a plug of Celite, and
concentrated under reduced pressure. Purification by flash
chromatography (5% MeOH/CH2Cl2, SiO2) afforded 1.4 g (77%)
of product as an inseparable mixture of diastereomers: 13C
NMR (75 MHz, CDCl3) [mixture] δ 145.6, 140.7, 137.1, 136.9,
136.8, 129.0, 128.9, 128.4, 128.2, 127.1, 126.6, 126.4, 126.2,
126.1, 126.0, 125.0, 1125.8, 60.2, 58.6, 58.5, 56.9, 54.7, 54.4,
34.9, 34.5, 29.9, 29.7, 24.4, 24.3, 19.3, 19.2. The diamine 25
was used without further characterization.
6.6 Hz, 3 H), 1.46 (m, 1 H), 1.23 (s, 3 H), 1.05 (bs, 1 H); 13C
NMR (75 MHz, CDCl3, DEPT) δ C, 145.1, 143.2, 138.0, 55.9,
50.4; CH, 128.3, 128.0 (overlapping), 127.4, 126.6, 126.2, 125.5,
64.1; CH2, 62.0, 61.6, 36.4, 29.9, 20.6; CH3, 32.3, 30.2, 20.1.
Anal. Calcd for C23H30N2: C, 82.59; H, 9.04; N, 8.37. Found:
C, 82.70; H, 9.20; N, 8.41.
(+)-6′,6′-Dim et h ylsp ir o[t et r a lin -1,2′-p ip er a zin e]. Di-
astereomerically pure piperazine 27 (187.4 mg, 0.6 mmol) was
dissolved in methanol (5 mL), and the solution was hydroge-
nated at room temperature and 50 psi in the presence of
Pearlman’s catalyst (25 mg) for 6 h. The reaction mixture was
filtered through a plug of Celite, and the filtrate was concen-
trated under reduced pressure. Purification by flash chroma-
tography (5% MeOH/CH2Cl2, SiO2) afforded 102.1 mg (79%)
of the product as a colorless oil: [R]23D +52.7° (c, 0.95, CHCl3);
3′,3′-Dim eth yl-2′-oxo-1′-[(1S)-p h en yleth yl]sp ir o[tetr a -
lin -1,5′-p ip er a zin e] (26). A mixture of diamine 25 (1.1 g 3.9
mmol), acetone (0.6 mL, 7.7 mmol), chloroform (0.46 mL, 5.8
mmol), powdered NaCN (7.0 mg, 0.13 mmol), benzyltriethy-
lammonium chloride (10.0 mg, 0.04 mmol), and dichlo-
romethane (2 mL) was stirred and cooled to 0 °C under argon.
An aqueous solution of 50% NaOH was added dropwise with
stirring so as to keep the temperature below 10 °C. The
mixture was maintained at 10 °C overnight. The mixture was
then poured into a separatory funnel, and dichloromethane
and water were added to dissolve the solids. The two layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (3×). The combined CH2Cl2 extracts were dried over Na2-
SO4, filtered, and concentrated. Crude 1H NMR indicated a
mixture of starting material and product. The crude mixture
was resubmitted to the reaction conditions and worked up as
before. Purification by flash chromatography (50% EtOAc/
hexanes, SiO2) afforded 1.3 g (96%) of the piperazinone as a
1:1.3 mixture of diastereomers: IR (mixture, neat) 3319, 3061,
IR (neat) 3050, 3012, 2929, 2865, 2837 cm-1 1H NMR (500
;
MHz, CDCl3) δ 7.81 (d, J ) 7.8 Hz, 1 H), 7.18-7.10 (m, 2 H),
7.01 (d, J ) 7.4 Hz, 1 H), 3.02 (d, J ) 12.8 Hz, 1 H), 2.84-2.63
(m, 6 H), 1.91-1.89 (m, 2 H), 1.69-1.63 (m, 3 H), 1.32 (s, 3
H), 1.08 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 140.9, 138.2,
128.7, 128.0, 126.9, 126.0, 54.7, 54.2, 52.8, 48.9, 35.5, 32.0, 29.7,
28.7, 20.4. HRMS (CI, NH3): found, m/z 230.1786 (M+);
C
15H22N2 requires 230.1783.
(+)-3′,3′-Dim eth yl-1′-[(4-m eth ylp h en yl)su lfon yl]sp ir o-
[tetr a lin -1,5′-p ip er a zin e] (28). To a solution of piperazine
obtained from the previous step (125.6 mg, 0.5 mmol) in dry
CH2Cl2 (4 mL) were added Et3N (87 µL, 0.6 mmol) and a
solution of p-toluenesulfonyl chloride (114.5 mg, 0.4 mmol) in
CH2Cl2 (1 mL). The mixture was stirred at room temperature
for 3 h. The reaction was quenched by the addition of
saturated NaHCO3 (3 mL). The layers were separated, and
the aqueous layer was extracted twice with CH2Cl2. The
combined organics were dried over Na2SO4, filtered, concen-
trated, and chromatographed (10% EtOAc/hexanes) to afford
3029, 2972, 2933, 1640 cm-1 1H NMR (300 MHz, CDCl3)
;
[major isomer] δ 7.55-7.02 (m, 9 H), 6.14 (q, J ) 6.9 Hz, 1 H),
3.05 (d, J ) 15.7 Hz, 1 H), 3.00 (d, J ) 15.6 Hz, 1 H), 2.86-
2.70 (m, 2 H), 2.19-2.13 (m, 1 H; overlapping), 1.97-1.88 (m,
1
1 H), 1.81-1.65 (m, 2 H), 1.54-1.44 (m, 10 H); H NMR (300
MHz, CDCl3) [minor isomer; characteristic peaks] δ 6.18 (q, J
) 7.1 Hz, 1 H), 3.33 (d, J ) 12.5 Hz, 1 H), 2.96 (d, J ) 12.5
Hz, 3 H); 13C NMR (75 MHz, CDCl3) [mixture] δ 173.5, 173.0,
140.8, 140.5, 139.8, 139.7, 137.5, 137.3, 128.7, 128.6, 128.4,
128.2, 127.9, 127.5, 127.2, 127.1, 126.9, 126.0, 125.9, 55.9, 55.4,
53.7, 50.9, 49.7, 49.6, 49.5, 34.2, 34.1, 32.4, 32.1, 29.9, 29.8,
29.5, 19.8, 19.1, 14.9, 14.8. HRMS (CI, i-C4H10): found, m/z
348.2189 (M +); C23H28N2O requires 348.2210.
199.8 mg (95%) of (+)-28 as a yellowish-white foam: [R]23
D
+97.3° (c, 0.89, CHCl3); IR (neat) 3332, 3062, 2961, 2927, 2865,
2256, 1598 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.66-7.60 (m,
1 H), 7.61 (d, J ) 8.1 Hz, 2 H), 7.30 (d, J ) 8.1 Hz, 2 H), 7.15-
7.03 (m, 3 H), 3.76 (d, J ) 11.4 Hz, 1 H),), 3.56 (d, J ) 11.1
Hz, 1 H), 2.85-2.74 (m, 3 H), 2.43 (s, 3 H), 2.27-2.21 (m, 2
H), 1.98-1.94 (m, 1 H), 1.86-1.63 (m, 3 H), 1.45 (s, 3 H), 1.12
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 143.3, 141.0, 138.5, 133.8,
129.6, 128.7, 128.1, 127.4, 126.9, 125.8, 56.8, 55.6, 54.8, 50.3,
35.6, 31.4, 29.7, 29.0, 21.4, 20.5. HRMS (CI, NH3): found, m/z
385.1940 (M + H+); C22H28N2O2S + H requires 385.1949.
(+)-3′,3′-Dim et h yl-1′-[4-m et h ylp h en ylsu lfon yl]sp ir o-
[tetr a lin -1,5′-p ip er a zin e]-N-oxyl [(+)-29]. To a solution of
(+)-28 (178.3 mg, 0.44 mmol) in CH2Cl2 (3 mL) was added
m-CPBA (152.5 mg, 0.88 mmol). The solution was stirred at
room temperature overnight. The reaction was quenched with
saturated NaHCO3, and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (3×). The combined
organics were washed (water, brine), dried (Na2SO4), filtered,
and concentrated in vacuo. Flash chromatography (15%
EtOAc/hexanes, SiO2) furnished 183.8 mg (100%) of (+)-29 as
3′,3′-Dim eth yl-1′-[(1S)-p h en yleth yl]sp ir o[tetr a lin -1,5′-
p ip er a zin e] (27). A 50 mL two-neck round-bottomed flask
fitted with a reflux condenser was charged with a 1.6 M
solution of LiAlH4 in THF (2.3 mL, 3.6 mmol) and cooled to 0
°C. To this was added a solution of piperazinone 26 (898 mg,
2.6 mmol) in THF (5 mL). The reaction was allowed to stir at
0 °C for 20 min and refluxed for 6 h. The reaction mixture
was cooled to 0 °C and quenched by sequential addition of H2O
(1 mL), 15% NaOH (1 mL), and H2O (3 mL). The mixture was
filtered through a plug of Celite, and the layers were sep-
arated. The aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organics were dried over Na2SO4 and
concentrated in vacuo to afford 856 mg (98%) of 27 as a
mixture of diastereomers which was used without further
purification.
a pink foam: [R]23 +64.5° (c, 0.97, CHCl3); IR (neat) 3022,
D
Resolu tion . To a solution of piperazine 27 (1.98 g, 5.7
mmol, mixture of diastereomers) in 20 mL of EtOAc was added
a solution of (R)-(-)-camphorsulfonic acid (1.51 g, 6.5 mmol)
in 5 mL of EtOAc and 1 mL of MeOH. The solution was
concentrated to ca. 5 mL under reduced pressure. A solid
crashed out. The solid was dissolved in 10 mL of EtOAc and
1 mL of MeOH. The mixture was allowed to stand at room
temperature overnight. The crystals that crashed out were
filtered out and washed with cold EtOAc. The solid was
dissolved in 5 mL of CH2Cl2 and washed with 1 N NaOH
solution (3 × 5 mL), H2O (3 × 5 mL), and brine. The organic
layer was dried over Na2SO4, filtered, and concentrated to
afford 546 mg of diastereomerically pure piperazine 27 as a
colorless oil: [R]23D -26.3° (c, 1.0, CHCl3); IR (neat) 3325, 3082,
3060, 3025, 2969, 2926, 2867, 2835, 2808, 2767, 2751, 1602
2995, 2937, 2866, 1598 cm-1. Anal. Calcd for C22H27N2O3S:
C, 66.14; H, 6.81; N,7.01. Found: C, 66.40; H, 7.00; N, 6.77.
HRMS (CI, i-C4H10): found, m/z 399.1743 (M +); C22H27N2O3S
requires 399.1742.
3,5,5-Tr im eth yl-2-oxo-3-ph en ylm or ph olin e (33). 2-Amino-
2,2-dimethylethanol (31) (1.0 g, 11.22 mmol, 1.0 equiv),
benzyltriethylammonium chloride (13 mg, 0.056 mmol, 0.005
equiv), and 2.6 mL of acetophenone (22.43 mmol, 2.0 equiv)
were dissolved in 122 mL of CH2Cl2 and cooled to 0 °C.
Powdered NaOH (2.2 g, 56.1 mmol, 5 equiv) was added in
small portions, keeping the reaction temperature below 5 °C.
After the addition, the reaction was warmed to 10 °C and
stirred at this temperature for 12 h. The resulting white
suspension was filtered using a Bu¨chner funnel, and the filter
cake was rinsed with acetone. The white powder was sus-
pended in 250 mL of MeOH and filtered, and the solvent was
removed under reduced pressure to give 2.5 g of carboxylate
salt 32. The salt was refluxed with 12 M HCl for 15 h, and
the acid was removed under reduced pressure to give a white
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 7.8 Hz, 1 H),
7.45-7.04 (m, 8 H), 3.45 (q, J ) 6.6 Hz, 1 H), 2.98-2.65 (m, 5
H), 2.12 (d, J ) 10.5 Hz, 1 H), 2.02 (d, J ) 11.4 Hz, 1 H),1.90-
1.86 (m, 1 H), 1.75-1.66 (m, 1 H), 1.53 (s, 3 H), 1.46 (d, J )

Chiral Nitroxides
J . Org. Chem., Vol. 63, No. 18, 1998 6371
solid. The solid was azeotropically dried by refluxing in 150
mL of toluene using a Dean-Stark trap. The toluene was
removed under reduced pressure and replaced with Et3N (150
mL). The suspension was sparged with argon and refluxed
for 4 h. After being cooled to room temperature, the suspen-
sion was filtered and concentrated under reduced pressure to
give the crude morpholinone (()-33. The solid was recrystal-
lized from hexane to give 1.4 g (6.35 mmol, 57%) of morpholi-
none (()-33 as a white crystalline solid: mp ) 99-100 °C; IR
(KBr) 3464, 3351, 3058, 2961, 1741, 1102 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.58 (ddd, J ) 8.0, 1.5, 1.0 Hz, 2 H), 7.36 (dddd,
J ) 8.0, 7.5, 1.5, 1.0 Hz, 2 H), 7.28 (ddd, J ) 7.5, 1.5, 1.5 Hz,
1 H), 3.78 (d, J ) 12.0 Hz, 1 H), 3.74 (d, J ) 12.0 Hz, 1 H),
1.50 (s, 3 H), 1.34 (s, 1 H), 1.30 (s, 3 H), 1.10 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 173.8, 143.1, 128.8, 127.6, 125.1, 73.4,
61.6, 51.0, 30.9, 28.6, 27.2. Anal. Calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.34; H, 7.67; N, 6.42.
3,5,5-Tr im eth yl-2-oxo-3-p h en ylm or p h olin e-N-oxyl (34).
To a 0.03 M solution of morpholone (()-33 (62 mg, 0.283 mmol,
1.0 equiv) in CH2Cl2 was added m-CPBA (97.0 mg, 0.562 mmol,
2.0 equiv). The resulting dark yellow solution was allowed to
stir at room temperature overnight. The reaction mixture was
quenched with 10% K2CO3 solution, extracted (3 × CH2Cl2),
washed (H2O, brine), dried (Na2SO4), and concentrated under
reduced pressure to give a dark yellow oil. Chromatography
(flash, SiO2, 20% EtOAc/hexanes) gave 58.6 mg (0.250 mmol,
88%) of (()-34 as a dark yellow oil: IR (neat) 3055, 2980, 1760,
cis- a n d tr a n s-3,5,5-Tr im eth yl-3-p h en yl-2-th iop h en yl-
m or p h olin e (37). To a solution of lactol obtained in the
previous step (0.20 g, 0.90 mmol, 1.0 equiv, 5.4:1 mixture of
C2 epimers) and diphenyl disulfide (0.216 g, 0.989 mmol, 1.1
equiv) in 5.0 mL of CH3CN was added Bu3P (0.266 mL, 0.989
mmol, 1.1 equiv). After being stirred at room temperature
overnight, the reaction was quenched with 1 M NaOH and
diluted with EtOAc. The layers were separated, and the
aqueous layer was extracted (3 × Et2O). The combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure to give 253 mg (0.804 mmol, 89%) of 37 in a 13:1
ratio of C2 epimers. Chromatography (flash, SiO2, 10-30%
EtOAc/hexanes) gave 17 mg (0.054 mmol, 6.0%) of the minor
diastereomer and 226 mg (0.719 mmol, 80%) of the major
diastereomer as clear, colorless oils. Major diastereomer: IR
(neat) 3307, 3059, 2963, 1583, 1479, 1284, 1061 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.67 (d, J ) 8.0 Hz, 2 H), 7.45 (d, J ) 7.5
Hz, 2 H), 7.34 (t, J ) 7.5 Hz, 2 H), 7.29 (t, J ) 7.5, 2 H), 7.23
(m, 2 H), 5.23 (s, 1 H), 3.99 (d, J ) 11.5 Hz, 1 H), 3.41 (d, J )
11.5 Hz, 1 H), 1.67 (s, 3 H), 1.54 (bs, 1 H), 1.17 (s, 3 H), 0.89
(s, 3 H); 13C NMR (125 MHz, CDCl3) δ 145. 4, 136.4, 130.7,
128.9, 127.8, 126.8, 126.7(2), 94.6, 74.5, 58.1, 49.1, 31.4, 28.9,
27.7. Anal. Calcd for C19H23NOS: C, 72.80; H, 7.40; N, 4.47.
Found: C, 72.94; H, 7.49; N, 4.38.
3,5,5-Tr im eth yl-3-p h en ylm or p h olin e via Ra n ey Nick el
Red u ction of Th ion om or p h olon e 35. Raney nickel (0.37
g, Aldrich) was washed with DI water until the pH was 7.0
and then further washed with absolute EtOH (10 × 10 mL).
The EtOH suspension was transferred to an oven dried flask.
The catalyst was placed under an argon atmosphere and
washed with anhydrous Et2O (3 × 10 mL). A solution of
thionomorpholone 35 (168 mg, 0.714 mmol) in 2 mL of Et2O
was added to the dry catalyst via cannula, and the resulting
suspension was stirred at room temperature for 1.5 h. An
additional 0.4 g of Raney nickel was added since TLC analysis
indicated incomplete reaction. After 15 min, the reaction
mixture was filtered, and the solvent was removed under
reduced pressure. Chromatography (flash, SiO2, 30% EtOAc/
hexanes) gave 70 mg (0.343 mmol, 48%) of the morpholine as
a colorless oil: Rf 0.27 (50% EtOAc/hexanes); IR (neat) 3317,
3060, 2964, 2964, 1462, 1093 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.57 (d, J ) 7.5 Hz, 2 H), 7.32 (dd, J ) 7.5, 7.0 Hz, 2 H),
7.22 (dd, J ) 7.0, 1.0 Hz, 1 H), 4.46 (d, J ) 12.0 Hz, 1 H), 3.49
(d, J ) 10.8 Hz, 1 H), 3.38 (d, J ) 12.0 Hz, 1 H), 3.27 (d, J )
10.8 Hz, 1 H), 1.40 (bs, 1 H), 1.26 (s, 3 H), 1.05 (s, 3 H), 0.66
(s, 3 H); 13C NMR (125 MHz, CDCl3) δ 147.2, 127.9, 126.2 (2),
78.0, 74.7, 53.1, 49.4, 30.4, 28.5, 26.6.
1373, 1366, 1114, 1052 cm-1 1H NMR (500 MHz, CDCl3) δ
;
very broad unresolved peaks indicative of paramagnetic radi-
cal. HRMS (EI): found, m/z 243.1125 (M+); C13H16NO3
requires 243.1130. Anal. Calcd for C13H16NO3: C, 66.65; H,
6.88; N, 5.98. Found: C, 66.55; H, 6.81; N, 5.95.
3,5,5-Trimethyl-3-phenyl-2-thionomorpholine (35). Lawes-
son’s reagent (616 mg, 1.52 mmol, 1.0 equiv) was added to
racemic morpholone 33 (336 mg, 1.52 mmol, 1.0 equiv) in 7.6
mL of toluene, and the resulting suspension was heated to
reflux. After 1 h, the reaction was cooled to room temperature.
The stir bar was removed from the flask, and 1 g of SiO2 was
added. The solvent was removed under reduced pressure, and
the SiO2 was loaded onto a flash column. Chromatography
(flash, SiO2, 0-30% EtOAc/hexanes) gave 173 mg (0.732 mmol,
48%) of 35 as a clear, colorless oil: Rf 0.50 (20% EtOAc/
hexanes); IR (neat) 3342, 3060, 2971, 1598, 1469 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.68 (dd, J ) 7.95, 1.5, Hz, 2 H),
7.23-7.36 (m, 3 H), 3.90 (d, J ) 11.1 Hz, 1 H), 3.77 (d, J )
11.1 Hz, 1 H), 1.61 (s, 3 H), 1.39 (bs, 1 H), 1.25 (s, 3 H), 1.11
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 225.1, 143.4, 129.0, 127.8,
125.8, 77.8, 67.5, 52.4, 35.5, 29.4, 27.7. HRMS (CI, NH3):
found, m/z 236.1110 (M + H+); C13H17NOS + H requires
236.1109.
3,5,5-Tr im eth yl-3-p h en ylm or p h olin e via Li/NH3 Re-
d u ction of Th ioa ceta l 37. Thioacetal 37 (197 mg, 0.626
mmol, 1.0 equiv) was dissolved in 4 mL of THF and cooled to
-78 °C. Ammonia (ca. 10 mL) was condensed into the flask,
and lithium metal (43 mg, 6.26 mmol, 10 equiv) was added to
the solution. After the reaction mixture turned blue in color,
it was allowed to proceed for an additional 2 min and quenched
via dropwise addition of MeOH. The ammonia was allowed
to evaporate, and the resulting residue was dissolved in water
and Et2O. The layers were separated, and the aqueous layer
was extracted (3 × Et2O). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
Chromatography (flash, SiO2, 30% EtOAc/hexanes) gave 104
mg (0.507 mmol, 81%) of the morpholine as a clear, colorless
oil.
2-Hyd r oxy-3,5,5-tr im eth yl-3-p h en ylm or p h olin e. Mor-
pholone (()-33 (0.50 g, 2.27 mmol, 1.0 equiv) was dissolved in
2.5 mL of Et2O and cooled to -20 °C. A 1.0 M solution of
DIBAL-H in hexane (2.72 mL, 2.72 mmol, 1.2 equiv) was added
dropwise by syringe. After 30 min, the reaction was quenched
by sequential addition of MeOH (0.7 mL) and 30% NaK
tartrate solution. The mixture was warmed to room temper-
ature, extracted (3 × EtOAc), dried (MgSO4), filtered, and
concentrated under reduced pressure to give a white solid. The
solid was recrystallized from 15:1 CH2Cl2/hexanes to give 0.453
g (2.05 mmol, 90%) of the lactol as a 5.4:1 mixture of C2
epimers: mp (5.4:1 mixture) ) 128-131 °C; IR (KBr, mixture)
3366, 2969, 1446, 1049 cm-1
;
1H NMR (500 MHz, CDCl3)
3,5,5-Tr im eth yl-3-p h en ylm or p h olin e-N-oxyl (36). To a
0.05 M solution of morpholine (46.2 mg, 0.225 mmol, 1.0 equiv)
in CH2Cl2 was added m-CPBA (77.7 mg, 0.45 mmol, 2.0 equiv)
in one portion. The resulting orange solution was allowed to
stir at room temperature for 30 min. The reaction mixture
was quenched with 10% K2CO3 solution, extracted (3 × CH2-
Cl2), washed (H2O, brine), dried (Na2SO4), filtered, and con-
centrated under reduced pressure to give a red oil. Chroma-
tography (flash, SiO2, 10% Et2O/pentane) gave 48.5 mg (0.220
mmol, 98%) of 36 as a red oil: Rf 0.24 (20% EtOAc/hexanes);
[major isomer] δ 7.62 (dd, J ) 8.1, 1.2 Hz, 2 H), 7.31 (dd, J )
7.2, 8.2 Hz, 2 H), 7.23 (dd, J ) 7.2, 1.2 Hz, 1 H); 5.29 (s, 1 H),
3.83 (d, J ) 11.1 Hz, 1 H), 3.27 (d, J ) 11.1 Hz, 1 H), 1.42 (s,
1
3 H), 1.17 (s, 3 H), 0.74 (s, 3 H); H NMR (500 MHz, CDCl3)
[minor isomer, characteristic peaks] δ 5.04 (s, 1 H), 3.81 (d, J
) 11.1 Hz, 1 H), 3.40 (d, J ) 11.1 Hz, 1 H), 1.54 (s, 3 H), 1.22
(s, 3 H), 0.89 (s, 3 H); 13C NMR [125 MHz, CDCl3, major (2,3-
trans)] δ 146.6, 127.9, 126.4, 126.2, 94.6, 71.0, 56.9, 48.8, 28.4,
27.5, 26.4; 13C NMR [125 MHz, CDCl3, minor (2,3-cis)] δ 145.5,
128.0, 126.6, 126.3, 98.2, 71.4, 57.1, 48.9, 29.6, 28.4, 28.2.
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found
(mixture): C, 70.66; H,8.62; N, 6.38.
1
IR (neat) 3060, 2974, 1356 cm-1; H NMR (300 MHz, CDCl3)
broad unresolved peaks indicative of paramagnetic radical.
HRMS (EI): found, m/z 220.1339 (M+); C15H20NO4 requires

6372 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
220.1337. Anal. Calcd for C13H18NO2: C, 70.88; H, 8.24; N,
6.36. Found: C, 70.66; H, 8.34; N, 6.31.
(20% EtOAc/hexane); mp ) 86.0-86.5 °C; HPLC (normal
phase analytical, 96% Hex/IPA, 0.5 mL/min, obs at 205, 230,
265 nm) tR ) 16.6 min, 100% purity; HPLC (chiralpak-AD,
1-(Hyd r oxym eth yl)-1-n itr oin d a n e. To a 0.4 M solution
of 1-nitroindane 38 (2.30 g, 14.1 mmol, 1.0 equiv) in THF were
added paraformaldehyde (0.85 g, 28.2 mmol, 2.0 equiv) and
0.30 mL of a 25 wt % solution of NaOMe in MeOH (5.20 mmol,
0.37 equiv). The resulting suspension was heated to reflux.
After 3 h at reflux, the solution was cooled to room tempera-
ture, poured into 1 M HCl, extracted (3 × Et2O), washed (H2O,
pH 7.0 buffer, brine), dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil. Chromatography
(MPLC, SiO2, 20% EtOAc/hexanes) gave 2.43 g (12.56 mmol,
89%) of the desired alcohol as a light yellow oil: Rf 0.17 (20%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.24-7.48 (m,
4 H), 4.53 (d, J ) 12.3 Hz, 1 H), 3.97 (d, J ) 12.3 Hz, 1 H),
3.23-3.35 (m, 1 H), 2.95-3.08 (m, 2 H), 2.5-2.61 (m, 1 H),
2.28 (bs, 1 H); 13C NMR (75 MHz, CDCl3) δ 145.0, 137.0, 130.0,
127.2, 125.4, 124.2, 105.0, 66.6, 33.6, 30.2. Anal. Calcd for
96% Hex/IPA, 0.5 mL/min, obs at 205m 239m 265 nm) tR
)
17.3, 18.8 min; 1:1 ratio at all three wavelengths; IR (neat)
3313, 2941, 1723, 1221, 1025 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.33 (d, J ) 6.0 Hz, 1 H), 7.22-7.27 (m, 3 H), 4.33 (d, J )
11.0 Hz, 1 H), 4.18 (d, J ) 11.0 Hz, 1 H), 3.0 (ddd, J ) 16.0,
9.0, 2.0 Hz, 1 H), 2.88 (ddd, J ) 15.0, 8.0, 8.0 Hz, 1 H), 2.57
(ddd, J ) 12.0, 8.0, 2.0 Hz, 1 H), 1.94 (ddd, J ) 12.0, 9.0, 8.0
Hz, 1 H), 1.54 (s, 3 H), 1.51 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 175.0, 144.5, 142.7, 128.6, 126.9, 125.0, 123.3, 73.2,
64.0, 55.4, 38.4, 31.0, 30.1, 29.2. Anal. Calcd for C14H17NO2:
C, 72.70; H, 7.41; N, 6.06. Found: C, 72.73; H, 7.30; N, 6.07.
cis- an d tr a n s-(2′S*,5′S*)-2′-acetoxy-3′,3′-dim eth ylspir o-
[in d a n -1,5′-m or p h olin e]. Morpholinone (()-40 (150 mg,
0.648 mmol, 1.0 equiv) was dissolved into 10 mL of Et2O and
cooled to 0 °C. A 0.8 M solution of DIBAL-H in hexane (1.5
mL, 1.2 mmol, 1.85 equiv) was added dropwise by syringe.
After 10 min, the reaction was quenched by sequential addition
of MeOH (1.0 mL) and 30% NaK tartrate solution. The
mixture was warmed to room temperature, extracted (3 ×
EtOAc), washed (brine), dried (MgSO4), and concentrated
under reduced pressure to give a white solid. The white solid
was dissolved in 10 mL of CH2Cl2 and treated with Et3N (0.46
mL, 3.27 mmol, 5.0 equiv), Ac2O (0.122 mL, 1.30 mmol, 2.0
equiv), and DMAP (ca. 2 mg). After being stirred for 12 h,
the reaction was quenched with saturated aqueous NaHCO3,
extracted (3 × CH2Cl2), washed (brine), dried (Na2SO4) and
concentrated under reduced pressure. Chromatography (flash,
SiO2, 20% EtOAc/hexanes) gave 70.2 mg (0.25 mmol, 39%) of
the early eluting trans acetoxy acetal as a colorless oil, 40 mg
(0.123 mmol, 18%) of the late eluting cis isomer as a white
solid, and 37.5 mg (0.117 mmol, 18%) of the bis(acetate) as a
colorless oil. When the DIBAL-H reduction was done at -78
°C, overreduction was not a problem.
Tr a n s isom er : Rf 0.16 (20% EtOAc in hexane); IR (neat)
3325, 3024, 2932, 1754 cm-1; HPLC (Alltech Econosphere 5µ,
SiO2, 96% Hex/IPA, 0.5 mL/min, obs at 234, 254, 265 nm) tR
) 10.8 min, 100%; HPLC (chiralpak-AD, 96% Hex/IPA, 0.5 mL/
min, obs at 234, 254, 265 nm) tR ) 11.9, 13.0 min; 1:1 ratio at
all three wavelengths; 1H NMR (300 MHz, CDCl3) δ 7.5 (m, 1
H), 7.20-7.23 (m, 3 H), 5.56 (s, 1 H), 3.72 (d, J ) 11.3 Hz, 1
H), 3.56 (dd, J ) 11.3, 2.2 Hz, 1 H), 2.92-2.97 (m, 1 H), 2.81-
2.89 (m, 2 H), 2.15 (s, 3 H), 1.92-1.97 (m, 1 H), 1.4 (bs, 1 H),
1.34 (s, 3 H), 1.08 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 169.8,
145.5, 142.9, 128.2, 126.7, 124.6, 123.7, 98.3, 73.9, 64.3, 52.0,
40.2, 29.9, 27.5, 22.6, 21.1. HRMS (CI): found, m/z 275.1521
(M+); C16H21NO3 requires 275.1521.
C
10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C, 61.93; H,
5.94; N, 6.83.
1-Am in o-1-(h ydr oxym eth yl)in dan e [(()-39]. Raney nickel
(0.20 g, Aldrich) was washed with DI water until the pH was
7.0 and then further washed with EtOH (10 × 15 mL). The
catalyst was then rinsed into a 125-mL pressure reaction
vessel containing the nitro alcohol (0.775 g, 4.01 mmol, 1.0
equiv) using absolute EtOH (20 mL). The reaction vessel was
pressurized to 500 psi with H2 and heated to 55 °C. After being
vigorously stirred for 12 h, the reaction mixture was cooled to
room temperature and depressurized. The mixture was
filtered through Celite and concentrated under reduced pres-
sure to give a clear syrup. Chromatography (flash, SiO2, 1%
NH4OH and 5% MeOH in CHCl3) gave a white solid which
was recrystallized from CH2Cl2 to give 0.652 g (3.93 mmol,
98%) of amine (()-39 as a white crystalline solid: mp ) 102-
103 °C; IR (neat) 3331, 3091, 2827, 1604, 1012 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.29-7.31 (m, 1 H), 7.22-7.24 (m, 3 H),
3.54 (d, J ) 11.0 Hz, 1 H), 3.51 (d, 11.0 Hz, 1 H), 2.94 (ddd, J
) 16.0, 9.0, 3.5 Hz, 1 H), 2.87 (ddd, J ) 16.0, 8.5, 8.0 Hz, 1 H),
2.38 (ddd, J ) 13.0, 8.0, 3.5 Hz, 1 H), 2.15 (bs, 3 H), 1.85 (ddd,
J ) 13.0, 9.0, 8.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 147.2,
143.1, 127.9, 126.6, 125.0, 122.9, 68.3, 65.5, 38.2, 29.3. HRMS
(CI): found, m/z 164.1072 (M+); C10H13NO requires 164.1074.
Anal. Calcd for
C10H13NO: C, 73.59; H, 8.03; N, 8.58.
Found: C, 73.77; H, 7.91; N, 8.36.
3′,3′-Dim eth yl-2′-oxosp ir o[in d a n -1,5′-m or p h olin e] [(()-
40]. Racemic amino alcohol 39 (0.213 g, 1.30 mmol, 1.0 equiv),
benzyltriethylammonium chloride (3 mg, 0.013 mmol, 0.01
equiv), and 1.0 mL of acetone (13 mmol, 10 equiv) were
dissolved in 10 mL of CH2Cl2 and cooled to 0 °C. Powdered
NaOH (0.26 g, 6.5 mmol, 5 equiv) was added in one portion,
and the reaction was maintained at a temperature between 0
and 6 °C for 6 h. After 6 h, the reaction was allowed to slowly
warm to room temperature over a 12 h period. The resulting
white suspension was filtered using a Bu¨chner funnel, and the
resulting filter cake was rinsed with CH2Cl2. The white
powder was dissolved in 50 mL of MeOH and filtered, and the
solvent was removed under reduced pressure to give 0.352 g
(quant) of the carboxylate salt: 1H NMR (500 MHz, CD3OD)
δ 7.38 (m, 1 H), 7.15 (m, 3 H), 3.47 (d, J ) 9.5 Hz, 1 H), 3.32
(m, 1 H), 3.27 (d, J ) 9.5 Hz, 1 H), 2.89-2.94 (m, 1 H), 2.78-
2.85 (m, 1 H), 2.20-2.26 (m, 1 H), 2.13-2.17 (m, 1 H), 1.26 (s,
3 H), 1.09 (s, 3 H); 13C NMR (125 MHz, CD3OD) δ 187.3, 148.9,
143.4, 128.4, 126.9, 125.3, 125.6, 71.4, 67.3, 60.2, 34.4, 31.9,
30.9, 26.0.
The crude carboxylate salt (0.352 g, 1.3 mmol) was sus-
pended in 50 mL of toluene and sparged with argon for 15
min. (+)-Camphorsulfonic acid (1.37 g, 5.89 mmol, 4.5 equiv)
was added to the suspension, and the reaction mixture was
refluxed for 10 h. The suspension was then poured into
saturated NaHCO3, extracted (3 × EtOAc), washed (brine),
dried (MgSO4), filtered, and concentrated under reduced
pressure to give a yellow oil. Chromatography (flash, SiO2,
17% EtOAc/hexanes) gave a light orange solid that was
recrystallized from hexanes to give 0.20 g (0.865 mmol, 66%)
of the desired morpholinone (()-40 as a white solid: Rf 0.18
Cis isom er : Rf 0.06 (20% EtOAc in hexane); mp ) 98-101
°C; IR (KBr) 3309, 2930, 1735, 1245, 961 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.20-7.4 (m, 4 H), 5.75 (s, 1 H), 3.66 (dd, J )
11.4, 1.95 Hz, 1 H), 3.37 (d, J ) 11.4 Hz, 1 H), 2.99 (ddd, J )
14.1, 9.3, 1.0 Hz, 1 H), 2.85-2.92 (m, 1 H), 2.78 (ddd, J ) 12.5,
7.85, 1.5 Hz, 1 H), 2.19 (s, 3 H), 2.03-2.08 (m, 1 H), 1.6 (bs, 2
H, H2O + OH), 1.41 (s, 3 H), 1.07 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 170.0, 145.7, 143.1, 128.3, 126.7, 124.8, 122.8, 93.2,
65.4, 63.3, 51.1, 39.8, 30.1, 27.6, 27.0, 21.2. HRMS (CI): found,
m/z 275.1520 (M+); C16H21NO3 requires 275.1521. Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.83;
H, 7.44; N, 5.06.
3′,3′-Dim et h yl-2′-t h iop h en ylsp ir o[in d a n -1,3′-m or p h o-
lin e] (41). To a solution of racemic trans acetoxy acetal (257
mg, 1.10 mmol, 1.0 equiv) in 20 mL of CH2Cl2 were added
TMSOTf (1.10 mL, 5.5 mmol, 5.0 equiv) and TMSSPh (2.1 mL,
11.0 mmol, 10.0 equiv). After being stirred for 3 days, the
reaction was quenched with saturated NaHCO3, extracted (3
× CH2Cl2), washed (15% NaOH, brine), dried (Na2SO4), and
concentrated under reduced pressure. Chromatography (flash,
SiO2, 7.5-20% EtOAc/hexanes) gave 25.1 mg (0.108 mmol,
10%) of starting acetal and 308 mg (0.946 mmol, 86%) of (()-
41 as an inseparable 10:1 mixture of C2′ epimers: Rf 0.35 (20%
EtOAc/hexanes); IR (neat) 3315, 2069, 2926, 1476, 1060 cm-1
;
1H NMR (500 MHz, CDCl3) [major isomer] δ 7.5 (m, 3 H),
7.19-7.30 (m, 6 H), 5.27 (s, 1 H), 4.30 (dd, J ) 11.4, 1.8 Hz, 1

Chiral Nitroxides
J . Org. Chem., Vol. 63, No. 18, 1998 6373
H), 3.35 (d, J ) 11.4 Hz, 1 H), 2.85-3.00 (m, 2 H), 2.80 (ddd,
J ) 12.4, 9.6, 2.0 Hz, 1 H), 2.05 (app q, J ) 9.7 Hz, 1 H), 1.58
(m, 4 H), 1.35 (s, 3 H); 1H NMR (500 MHz, CDCl3) [minor
isomer, characteristic peaks] δ 4.80 (s, 1 H), 3.81 (d, J ) 11.2
Hz, 1 H), 3.41 (dd, J ) 11.2, 1.9 Hz, 1 H), 1.52 (s, 3 H), 1.39 (s,
3 H); 13C NMR (125 MHz, CDCl3,) δ 146.4, 142.8, 135.5, 131.3,
128.8, 128.2, 126.7 (2), 124.5, 123.7, 92.6, 64.8, 54.1, 53.5, 41.0,
30.0, 29.9, 29.8. Anal. Calcd for C20H23NOS: C, 73.81; H, 7.12;
N, 4.30. Found: C, 74.01; H, 7.34; N, 4.27.
Salt 40‚(+)CSA was basified with saturated NaHCO3 to give
14.1 mg (87%) of morpholone (+)-40 in >99% ee as determined
by chiral HPLC (Chiralpak AD, 96% Hex/IPA, 0.5 mL/min tR
) 17.1 (100%). The proton NMR of optically enriched (+)-40
matched that of racemic 40 in all respects.
5′,5′-Dim eth yl-4′-[((R)-1-p h en yleth yl)ca r ba m oyl]sp ir o-
[in d a n -1,3′-m or p h olin e] (45). Racemic morpholine 42 (64
mg, 0.294 mmol) was dissolved in 2 mL of dry CH2Cl2, and to
this solution was added (R)-(+)-R-methylbenzyl isocyanate (46
µL, 0.324 mmol, 1.1 equiv). After stirring of the solution for
12 h at room temperature, TLC analysis indicated incomplete
reaction, so 2 mL of toluene was added and the mixture was
refluxed for 3 h. The solvent was removed under reduced
pressure, and the resulting yellow oil was purified by chro-
matography (flash, SiO2, 20% EtOAc/hexanes) to give 105 mg
(0.289 mmol, 98%) of a light yellow oil consisting of a 1:1
mixture of diastereomers. The diastereomers were separated
using a 22 mm × 25 cm Alltech Econosphere 5µ SiO2 Prep
HPLC column, eluting with 1% IPA/hexane at 11 mL/min; 3.0
mg per 25 µL injection.
Ea r ly elu tin g d ia ster eom er : Rf 0.19 (20% EtOAc/hexane),
analytical HPLC (Alltech Econosphere, 5µ SiO2, 4.6 mm × 25
cm, 98% Hex/IPA, 0.5 mL/min, obs at 254 nm) tR ) 9.2 min,
100%; 1H NMR (500 MHz, CDCl3) δ 7.36-7.38 (m, 1 H), 7.31-
7.33 (m, 2 H), 7.23-7.25 (m, 1 H), 7.14-7.21 (m, 3 H), 6.83
(dd, J ) 6.85, 1.6 Hz, 2 H), 4.68 (dddd, J ) 6.8, 6.8, 6.8, 6.8,
1 H), 4.51 (d, J ) 6.8 Hz, 1 H), 3.58 (dd, J ) 11.4, 1.5 Hz, 1
H), 3.48 (dd, J ) 11.8, 1.35 Hz, 1 H), 3.47 (d, J ) 11.4 Hz, 1
H), 3.44 (dd, 11.8, 2.50 Hz, 1 H), 2.79-2.89 (m, 2 H), 2.66 (ddd,
J ) 10.8, 6.65, 2.66 Hz, 1 H), 2.09 (dddd, J ) 12.9, 10.0, 9.7,
2.7, 1 H), 1.53 (s, 3 H), 1.50 (s, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 158.7, 145.0, 144.7, 142.0, 128.9,
128.3, 127.4, 126.7, 126.2, 125.6, 124.0, 79.8, 75.4, 68.5, 54.1,
49.7, 34.6, 29.2, 27.4, 23.2, 22.4. HRMS (CI, mixture): found,
m/z 364.2151 (M+); C23H28N2O2 requires 364.2151.
5′,5′-Dim eth ylspir o[in dan -1,3′-m or ph olin e] [(()-42]. Ra-
cemic thioacetal 41 (46.0 mg, 0.141 mmol, 1.0 equiv) was
dissolved in 5 mL of THF and cooled to -78 °C. Ammonia
(ca. 10 mL) was condensed into the flask, and lithium metal
(16 mg, 2.30 mmol, 16 equiv) was added to the solution. After
the reaction mixture turned blue in color, it was allowed to
proceed for an additional 2 min and quenched via dropwise
addition of thioanisole (ca. 0.3 mL). The ammonia was allowed
to evaporate, and the resulting residue was dissolved in water
and Et2O. The layers were separated, and the aqueous layer
was extracted (3 × Et2O). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
Chromatography (flash, SiO2, 3-25% EtOAc/hexanes) gave
26.5 mg (0.122 mmol, 87%) of 42 as a white amorphous solid:
Rf 0.12 (20% EtOAc in hexane); IR (neat) 3310, 3069, 2956,
1
1103, 1077 cm-1; H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H),
7.20 (m, 3H), 3.64 (d, J ) 10.8 Hz, 1 H), 3.58 (d, J ) 11.0 Hz,
1 H), 3.32 (dd, J ) 10.8, 0.75 Hz, 1 H), 3.15 (dd, J ) 11.0, 2.3
Hz, 1 H), 2.88 (m, 3 H), 1.90 (m, 1 H) 1.36 (m, 4 H), 1.06 (s,
1.36, 3 H); 13C NMR (125 MHz, CDCl3, DEPT) δ C 146.8, 142.9,
64.7, 49.2; CH, 127.9, 126.4, 124.5, 123.8; CH2, 77.4, 73.8, 40.2,
29.8; CH3, 28.9, 27.6. Anal. Calcd for C14H18NO2: C, 72.39;
H, 7.81; N, 6.03. Found: C, 72.12; H, 7.99; N, 6.02.
5′,5′-Dim eth ylspir o[in dan -1,3′-m or ph olin e-N-oxyl] [(()-
43]. To a solution of racemic morpholine 42 (25.1 mg, 0.108
mmol, 1.0 equiv) in CH2Cl2 was added m-CPBA (37.3 mg, 0.215
mmol, 2.0 equiv) in one portion, and the resulting solution was
allowed to stir for 6 h at room temperature. The reaction
mixture was quenched with saturated K2CO3 solution, ex-
tracted (3 × CH2Cl2), washed (15% NaOH, brine), filtered, and
concentrated under reduced pressure to give a red oil. Chro-
matography (flash, SiO2, 5-10% EtOAc/hexanes) gave 24.6 mg
(0.106 mmol, 98%) of racemic nitroxide 43 as a red oil which
solidified upon standing to give a red glass: Rf 0.22 (20%
La te elu tin g d ia ster eom er : Rf 0.19 (20% EtOAc/hexane),
analytical HPLC (Alltech Econosphere, 5µ SiO2, 4.6 mm × 25
cm, 98% Hex/IPA, 0.5 mL/min, obs at 254 nm) tR ) 10.1 min,
1
100%; H NMR (500 MHz, CDCl3) δ 7.31-7.33 (m, 3 H), 7.28
(t, J ) 3.6 Hz, 1 H), 7.23 (t, J ) 6.7 Hz, 1 H), 7.13-7.19 (m, 2
H), 6.75 (d, J ) 6.5 Hz, 2 H), 4.70 (dddd, J ) 6.8, 6.7, 6.7, 6.7,
1 H), 4.63 (d, J ) 6.8 Hz, 1 H), 3.60 (d, J ) 11.8 Hz, 1 H), 3.47
(d, J ) 11.4 Hz, 1 H), 3.38 (dd, J ) 11.8, 2.3 Hz, 1 H), 3.13
(dd, J ) 16.7, 9.9 Hz, 1 H), 2.86-3.90 (m, 1 H), 2.77-2.81 (m,
1 H), 2.35-2.42 (m, 1 H), 1.61 (s, 3 H), 1.47 (s, 3 H), 1.02 (d,
J ) 6.7 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 159.2, 145.5,
144.6, 142.3, 129.4, 128.7(2), 126.8, 126.6, 125.9, 124.4, 80.4,
76.0, 69.0, 54.5, 50.2, 34.9, 29.8, 27.7, 23.6 (2).
EtOAc in hexane); IR (neat) 2971, 1469, 1300, 1102, 1061 cm-1
;
1H NMR (300 MHz, CDCl3) broad unresolved peaks due to
existence of paramagnetic radical; HPLC (normal phase
analytical, 96% Hex/IPA, 0.5 mL/min, obs at 254 nm) tR ) 12.3
min, 100%; HPLC (chiralpak-AD, 98% Hex/IPA, 0.5 mL/min,
obs at 234, 254, 265 nm) tR ) 17.0, 18.5 min; 1:1 ratio at all
three wavelengths; HPLC (chiralpak-AD, 96% Hex/IPA, 0.5
mL/min, obs at 234, 254, 265 nm) tR ) 14.7, 15.8 min; 1:1 ratio
at all three wavelengths. HRMS (CI): found, m/z 232.1344
(-)-5′,5′-Dim eth ylsp ir o[in d a n -1,3′-m or p h olin e] [(-)-42]
via Dep r otection of Ur ea 46. To a solution of diastereo-
merically pure 46 (20 mg, 0.549 mmol, 1.0 equiv, > 95% de,
1H NMR) in 2 mL of nBuOH was added 0.20 mL of a 25 wt %
solution of NaOMe in MeOH (3.50 mmol, 6.3 equiv). The
reaction mixture was sparged with argon for 15 min and
refluxed for 8.5 h. The mixture was cooled to room temper-
ature and the solvent removed under reduced pressure (care
must be taken as the product is somewhat volatile). The
residue was diluted with H2O and CH2Cl2 and the layers
separated. The aqueous layer was extracted (3 × CH2Cl2), and
the combined organic layers were washed (brine), dried (Na2-
SO4), and concentrated under reduced pressure. Chromatog-
raphy (flash, SiO2, 20% EtOAc/hexanes) gave 11.6 mg (0.053
mmol, 97%) of (-)-42 as a white amorphous solid: Rf 0.12 (20%
(M+); C14H18NO2 requires 232.1337. Anal. Calcd for C14H18
-
NO2: C, 72.39; H, 7.81; N, 6.03. Found: C, 72.12; H, 7.99; N,
6.02.
Attem p ted Syn th esis of En a n tiom er ica lly P u r e Ni-
tr oxid e 43. (5′S)-3′,3′-Dim eth yl-2′-oxosp ir o[in d a n -1,5′-
m or p h olin e] [(+)-40] via Resolu tion w ith (+)-CSA. Mor-
pholone 40 (32.4 mg, 0.140 mmol, 10% ee, 1.0 equiv) was
dissolved in 20 mL of toluene. (+)-Camphorsulfonic acid was
added, and the solution was refluxed for 12 h. The solution
was cooled to room temperature, and the solvent was removed
under reduced pressure. The resulting white solid was
suspended in 20 mL of 3:1 pentane/EtOAc and brought to
reflux. MeOH was added dropwise to the suspension until all
of the solid dissolved. The solution was cooled to room
temperature, then to 0 °C, and finally to -32 °C. After the
solution was standing at -32 °C for 2 weeks, filtration gave
EtOAc in hexane); [R]24 ) - 69.6 ° (c ) 1.16, CH2Cl2); IR
D
(neat) 3310, 3069, 2956, 1103, 1077 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.26 (m, 1H), 7.20 (m, 3H), 3.64 (d, J ) 10.8 Hz, 1
H), 3.58 (d, J ) 11.0 Hz, 1 H), 3.32 (dd, J ) 10.8, 0.75 Hz, 1
H), 3.15 (dd, J ) 11.0, 2.3 Hz, 1 H), 2.88 (m, 3 H), 1.90 (m, 1
H) 1.36 (m, 4 H), 1.06 (s, 1.36). HRMS (CI): found, m/z
232.1344 (M+); C14H18NO2 requires 232.1337.
28 mg of crystalline white solid 40‚(+)CSA: mp 228-230 °C
1
(dec); [R]24 ) + 69.9° (c ) 1.0, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 9.75 (bs, 2 H), 7.85 (d, J ) 7.6 Hz, 1 H), 7.16-7.35
(m, 3 H), 4.80 (d, J ) 12.0 Hz, 1 H), 4.67 (d, J ) 12.0 Hz, 1 H),
3.43 (m, 1 H), 2.83-2.95 (m, 3 H), 2.22-2.48 (m, 4 H), 1.77-
1.98 (m, 10 H), 1.4 (app t, J ) 9.6 Hz, 1 H), 1.27 (app t, J )
9.6 Hz, 1 H), 0.93 (s, 3 H), 0.70 (s, 3 H),
Deprotection of the late eluting urea gave amine (+)-42 with
identical properties with the exception of rotation: [R]24
+82° (c ) 1.0, CH2Cl2).
)
D
Oxid a tion of Op tica lly En r ich ed Mor p h olin e (+)-42 to
(+)-43 u n d er Bu ffer ed Con d ition s. To a solution of mor-

6374 J . Org. Chem., Vol. 63, No. 18, 1998
Rychnovsky et al.
pholine (+)-42 (5.6 mg, 0.0258 mmol, 1.0 equiv) in 4 mL of a
1:1 mixture of saturated NaHCO3 and CH2Cl2 was added
m-CPBA (8.9 mg, 0.0516 mmol, 2.0 equiv) in one portion. The
resulting biphasic mixture was vigorously stirred at room
temperature for 1.5 h. The reaction mixture was quenched
with saturated 15% NaOH, extracted (3 × CH2Cl2), washed
(brine), filtered through cotton, and concentrated under re-
duced pressure to give 5.8 mg (0.0250 mmol, 97%) of (+)-43
as a red oil, which was pure by TLC analysis: Rf 0.22 (20%
EtOAc in hexane), HPLC (normal phase analytical, 96% Hex/
IPA, 0.5 mL/min, obs at 234, 254, and 265 nm) tR ) 12.3 min,
100%; HPLC (chiralpak-AD, 98% Hex/IPA, 0.5 mL/min, obs
at 234, 254, and 265 nm) tR ) 17.2, “18.5” min; 1:0 ratio at all
three wavelengths.
Ra cem iza tion Stu d ies. Oxid a tion of Nitr oxid e (-)-43
w ith Br om in e F ollow ed by Con com ita n t Red u ction w ith
2-P r op a n ol a n d Sa tu r a ted Na HCO3. Nitroxide (-)-43 (0.5
mg, 0.002 mmol, 1.0 equiv) was dissolved in 0.5 mL of CH2-
Cl2, and 20 µL of a 0.11 M solution of bromine (0.002 mmol,
2.0 equiv) in CH2Cl2 was added by microsyringe. The resulting
bright orange solution was stirred for 2 min and quenched with
a 1:1 mixture of IPA and saturated NaHCO3. The suspension
was diluted with 4 mL of CH2Cl2 and 4 mL of H2O. The
mixture was separated, and the aqueous phase was extracted
(3 × CH2Cl2). The combined organic layers were washed
(brine), filtered through cotton, and concentrated under re-
duced pressure to give ca. 0.5 mg (0.002 mmol, 100%) of
racemic 96 as a red oil, which was pure by TLC analysis: Rf
0.22 (20% EtOAc in hexane); HPLC (chiralpak-AD, 98% Hex/
IPA, 0.5 mL/min, obs at 234, 254, and 265 nm) tR ) 17.1, 18.6
min; 1:1 ratio at all three wavelengths.
Ack n ow led gm en t. Support has been provided the
National Science Foundation Presidential Young Inves-
tigator Program and the University of California, Irvine,
CA. S.D.R. acknowledges Zeneca Inc. for support of his
research program.
J O9808831