Stereochemical studies of chiral acyclic nitroxides coupling with a prochiral radical

Article abstract of DOI:10.1081/SCC-120039497

A series of acyclic chiral nitroxides bearing a hydrogen atom on the carbon adjacent to the nitroxide nitrogen was investigated for stereoselectivity in a coupling reaction with the prochiral radical 1-phenethyl. In one case, an x-ray structure of the maj

Full text of DOI:10.1081/SCC-120039497

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Stereochemical Studies of
Chiral Acyclic Nitroxides
Coupling with a Prochiral
Radical
Rebecca Braslau a , Vladimir Chaplinski a , Aaron
Nilsen a & Navamoney Arulsamy b
a Department of Chemistry and Biochemistry ,
University of California , Santa Cruz, California,
95064, USA
b Department of Chemistry , University of
Wyoming , Laramie, Wyoming, USA
Published online: 10 Jan 2011.
To cite this article: Rebecca Braslau , Vladimir Chaplinski , Aaron Nilsen &
Navamoney Arulsamy (2004) Stereochemical Studies of Chiral Acyclic Nitroxides
Coupling with a Prochiral Radical, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:13, 2433-2442,
DOI: 10.1081/SCC-120039497
To link to this article: http://dx.doi.org/10.1081/SCC-120039497
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2433–2442, 2004
Stereochemical Studies of Chiral
Acyclic Nitroxides Coupling
with a Prochiral Radical
1
1
Rebecca Braslau,1, Vladimir Chaplinski, Aaron Nilsen,
*
and Navamoney Arulsamy2
1Department of Chemistry and Biochemistry, University of California,
Santa Cruz, California, USA
2Department of Chemistry, University of Wyoming,
Laramie, Wyoming, USA
ABSTRACT
A series of acyclic chiral nitroxides bearing a hydrogen atom on the
carbon adjacent to the nitroxide nitrogen was investigated for stereoselec-
tivity in a coupling reaction with the prochiral radical 1-phenethyl. In one
case, an x-ray structure of the major diastereomer was obtained, which
corroborates a model for predicting the stereoselectivity.
Key Words: Diastereoselectivity; Prochiral radical; Nitroxide;
N-Alkoxyamine.
*
Correspondence: Rebecca Braslau, Department of Chemistry and Biochemistry,
University of California, Santa Cruz, CA 95064, USA; E-mail: braslau@chemistry.
ucsc.edu.
2433
DOI: 10.1081/SCC-120039497
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2434
Braslau et al.
INTRODUCTION
The ability to control stereochemistry in systems involving acyclic radicals
has been demonstrated for substrates which favor a preferred conformation. A
number of systems have been investigated invoking predictive models involving
A-strain or Felkin-Ahn type selectivity.[1] We have previously investigated the
ability of chiral nitroxides to distinguish between the enantiotopic faces of
prochiral carbon radicals in a radical–radical coupling reaction.[2]
The 1-phenethyl radical has been chosen for most of our studies as it contains
three distinctly different substituents: a small hydrogen atom, a moderate sized
methyl group, and a planar phenyl ring. In addition, this radical is planar due to
benzylic delocalization of the unpaired electron into the aromatic ring. Acyclic nitr-
oxides with no preferred conformation such as camphor-derived 1[2a] gave poor
selectivity, whereas experiments with conformationally rigid cyclic nitroxides
gave mixed results. For cyclic nitroxides in which the two faces of the three-
electron N–O p bond are diastereotopic, multiple competing transition states led
to selectivities varying from very poor to good. For example, camphoxyl nitroxi-
de[2b] 2 gave poor selectivity, whereas the steroidal doxyl nitroxide[2a] 3 gave
good selectivity. More consistent control was achieved using the C-2 symmetric
cyclic nitroxide[2c] 4, in which the two faces of the three-electron N–O nitroxide
pbondareidentical, thusrestrictingthenumberofpossibletransitionstates(Fig. 1).
Most acyclic nitroxides bearing a hydrogen atom on the carbon adjacent
to the nitroxide nitrogen are unstable; they undergo disproportionation to form
nitrone and hydroxylamine. However Iwamura and Inamoto,[3] and later
Reznikov and Volodarsky[4] introduced a family of alpha-hydrogen nitroxides
5 that are stable and readily isolable under normal laboratory conditions. Both
ESR and x-ray evidence indicate that these nitroxides adopt a conformation in
which the alpha-hydrogen lies just slightly out of the nodal plane of the three-
electron N–O p bond.[5] It has been suggested that when the surrounding sub-
stituents are sterically bulky, there is restricted rotation around the C–N bond
at room temperature, preventing disproportionation by minimizing overlap
between the C–H bond and the N–O p bond.[6] At higher temperature,
these nitroxides do undergo disproportionation (Fig. 2).
Figure 1. Chiral nitroxides coupled to prochiral radicals.

Chiral Acyclic Nitroxides Coupling with Prochiral Radical
2435
Figure 2. Alpha-hydrogen nitroxides: conformation postulated for disproportionation.
This family of alpha-hydrogen nitroxides has proven to be highly effec-
tive in controlling both molecular weight and polydispersity in nitroxide-
mediated polymerizations.[7] Because these acyclic nitroxides adopt a well-
defined conformation, and as they contain a stereogenic carbon immediately
adjacent to the nitroxide functionality, we undertook an investigation of the
stereoselectivity in the coupling with the prochiral 1-phenethyl radical.
RESULTS AND DISCUSSION
The series of chiral, racemic acyclic nitroxides 5a–h were prepared as
described previously (Sch. 1).[7a] The prochiral secondary benzylic radical
was formed by nucleophilic displacement of 1-phenethyl bromide with neat
fuming hydrazine under sonnication, followed by brief aqueous work-up
Scheme 1. Generation and trapping of prochiral 1-phenethyl radical by acyclic chiral
nitroxides.

2436
Braslau et al.
and isolation of the benzylic hydrazine, and then immediate addition to a mix-
ture of the nitroxide and lead oxide in toluene. The N-alkoxyamine products 6
were isolated by column chromatography, and the diastereomeric ratios deter-
mined by 1H-NMR. Care was taken in collecting fractions from the chromato-
graphic purification to ensure that all of the N-alkoxyamine product was
collected, so that the ratio of diastereomers was not inadvertently altered.
The results are shown in Table 1. Experiments carried out at 2788C and
quenched at low temperature gave low yields. Subsequent multi-temperature
ESR experiments with TEMPO[2c] revealed that no carbon radical is generated
at 2788C to 2388C, and that at 08C, about half of the nitroxide is consumed
every 30 min. Thus, it is likely that the small amount of N-alkoxyamine pro-
duct 6 formed in the “2788C” experiments was probably formed during the
quenching process at a higher temperature.
The ratios of diastereomers in the products 6a–h were disappointingly
low. However, it is clear that both steric and electronic factors are contributors
to the selectivity. Although these acyclic nitroxides are expected to adopt a
predictable conformation at the low temperatures of these coupling reactions,
Table 1. Stereoselectivity in the coupling of prochiral 1-phenethyl radical with
acyclic chiral nitroxides.
Yield
(%)
6
R
Y
Temperature
dra
a
a
b
c
i-Pr
Ph
73
17b
58
59
19
88
2788C to rt
2788C for 2 hr
08C to rt
1.3 : 1
1.4 : 1
1.1 : 1
1.3 : 1
1.9 : 1
1.8 : 1
i-Pr
t-Bu
4-F3C-C6H4
Ph
2788C to 08C
2788C for 2 hr
2788C for 5 min,
then rt for 12 hr
2788C to 08C
2788C for 5 min,
then rt for 12 hr
2788C to 08C
08C to rt
c
d
t-Bu
t-Bu
4-F3C-C6H4
d
e
20
55
1.6 : 1
1.2 : 1c
4-Me2N-C6H4
e
f
18d
25
42
42
66
1.3 : 1c
1.7 : 1
1.6 : 1
1.6 : 1
1.0 : 1
i-Pr
t-Bu
2,4,6-Me3-C6H3
P(O)(OEt)2
g
g
h
2788C to rt
08C to rt
i-Pr
Ph
08C to rt
1
aEvaluated by H-NMR integration.
b80% of the reduced nitroxide (the hydroxyl amine) was recovered.
cProduct unstable: dr is approximate (see Experimental).
d82% of the nitroxide was recovered.

Chiral Acyclic Nitroxides Coupling with Prochiral Radical
2437
there are a minimum of four different transition states leading to two diaster-
eomeric products. Each diastereotopic face of the N–O p bond should react
preferentially with one of the two enantiotopic faces of the prochiral benzylic
radical. If approach of the prochiral radical is not exclusively from one face of
the N–O p bond, the overall selectivity may be diminished.
In order to determine which diastereomer was the major coupling product,
the diastereomeric mixture of N-alkoxyamine 6a was subjected to chromato-
graphy. Although the two diastereomers could not be completely separated,
1
enrichment of the major species was achieved, and confirmed by H-NMR.
This enriched sample was then allowed to crystallize in the freezer from
1
concentrated hexanes, and separated from the mother liquors. H-NMR of
the mother liquors now showed an enrichment in the minor diastereomer,
providing evidence that indeed the major diastereomer was that obtained in
crystalline form. X-ray crystallography (the x-ray structure of a similar
N-alkoxyamine produced by a different manner has been published; see
Ref.[8]) revealed the major product to be the R,S and S,R racemates, which
pair in the unit cell (Fig. 3)
Figure 3. X-ray structure of the major diastereomer of N-alkoxyamine 6a: R,S and
S,R racemic pair.

2438
Braslau et al.
The x-ray structure is in agreement with our prediction using the simple
transition state depicted in Fig. 4. Nitroxide 5a is expected to sit approximately
in the conformation shown in Fig. 4. Making the assumption that the prochiral
radical will react from the less sterically hindered bottom face of the N–O
p bond (A value for iPr is 2.15, A value for Ph is 3.0), approach of the prochiral
radical along the trajectory and orientation depicted will result in formation of
the R,S diastereomer. Approach from the top face of the N–O bond would give
different selectivity, which could enhance or erode that from the bottom face.
It is noteworthy that the two diastereomers of 6a and 6g have been
examined experimentally by Fisher, and were found to dissociate upon heating
at essentially the same rate, whereas the diastereomeric products of 5g coupled
.
with 2-methyl propionate radical (MeHC CO2Me) dissociate with rates that
differ by a factor of approximately three.[9] In nitroxide-mediated polymeri-
zation reactions, the N-alkoxyamine initiator is used as a mixture of diastereo-
mers. These polymerizations are typically carried out around 1258C. At this
temperature, no stereoselectivity is expected in the recombination reaction
between the growing polymer chain radical and the nitroxide.
CONCLUSION
In summary, despite the restricted conformation of these acyclic nitrox-
ides, stereoselectivity in coupling with a prochiral radical is low, probably
due to different inherent selectivity of the two diastereotopic nitroxide faces.
These results confirm that the use of C-2 symmetric chiral nitroxides, in
which the nitroxide faces are identical, are a better choice for these stereoche-
mical studies. The x-ray structure establishes the major diastereomer of 6a as
the R,S and S,R racemate, in agreement with the predicted transition state
model.
Figure 4. Proposed approach leading to the major diastereomer in the stereoselective
coupling of nitroxide 5a and the prochiral 1-phenethyl radical.

Chiral Acyclic Nitroxides Coupling with Prochiral Radical
EXPERIMENTAL
2439
General Procedure for Coupling of Nitroxide 5 with
1-Phenethyl Radical to form N-Alkoxyamines 6
The coupling of nitroxide 5a to prepare 2,2,5-trimethyl-3-(1-phenyl-
ethoxy)-4-phenyl-3-azahexane 6a is representative: a two-phase mixture of
(1-bromoethyl)benzene (111 mg, 0.60 mmol) and fuming hydrazine (0.192 cm3,
6.0 mmol) was sonicated for 30 min under nitrogen until a single cloudy
phase was observed. The mixture was diluted with 10 cm3 diethyl ether and
the organic and hydrazine layers were separated. The hydrazine layer was
washed with 5 cm3 of diethyl ether. The organic phases were combined and
washed with 5 cm3 of 10% aqueous potassium hydroxide followed by 5 cm3
of brine, dried over magnesium sulfate, and filtered. Volatiles were removed
in vacuo to give a slightly yellow oil, which was diluted with toluene (0.5 cm3)
and cooled to 2788C. In a separate flask, lead dioxide (215 mg, 0.90 mmol),
2,2,5-trimethyl-4-phenyl-3-azahexane 3-nitroxide 5a (66.1 mg, 0.30 mmol)
and toluene (0.5 cm3) were sonicated under nitrogen for 5 min and then cooled
to 2788C. The benzylic hydrazine solution was added by cannula and the
residues were washed in with an additional 0.5 cm3 of toluene. The reaction
was allowed to warm to room temperature, diluted with 10 cm3 of diethyl
ether, filtered through Celite, and washed with 15 cm3 of diethyl ether. Vola-
tiles were removed in vacuo to give a colorless oil. Purification by flash
column chromatography (10 mm column, 100: 1 hexane : ethyl acetate) afforded
71.0 mg of pure coupling product 6a as a colorless oil (73% yield). The coupling
product was determined to be a 1: 1.3 mixture of the diastereomers as indicated
by integration of the methyl hydrogens at d 0.54 and 0.22ppm.
TLC: 100 : 1 hexane : ethyl acetate, molybdenum stain, Rf ¼ 0.48; IR
(CDCl3) 2956, 1492, 1452, 1382, 1207, 1061cm21 1H-NMR (250MHz,
;
CDCl3, both diastereomers) d 7.5–7.1 (m, 20H), 4.90 (q þ q, 2H, J ¼ 6.5 Hz,
both diastereomers), 3.41 (d, 1H, J ¼ 10.8Hz, major diastereomer), 3.29
(d, 1H, J ¼ 10.8Hz, minor diastereomer), 2.35 (two m, 2H, both diastereo-
mers), 1.62 (d, 3H, J ¼ 6.8 Hz, major diastereomer), 1.54 (d, 3H, J ¼ 7.0 Hz,
minor diastereomer), 1.31 (d, 3H, J ¼ 6.3 Hz, major diastereomer), 1.04
(s, 9H, minor diastereomer), 0.92 (d, 3H, minor diastereomer), 0.77 (s, 9H,
major diastereomer), 0.54 (d, 3H, J ¼ 6.5 Hz, major diastereomer), 0.22
(d, 3H, J ¼ 6.5 Hz, minor diastereomer); 13C-NMR (APT) (63 MHz, CDCl3,
both diastereomers) d 145.87 (s), 145.08 (s), 142.56 (s), 142.35 (s), 131.03
(d), 128.15 (d), 127.46 (d), 127.37 (d), 127.28 (d), 127.09 (d), 126.70 (d),
126.43 (d), 126.25 (d), 83.58 (d), 82.91 (d), 72.30 (d), 72.21 (d), 60.59 (s),
60.45 (s), 32.12 (d), 31.69 (d), 28.48 (q), 28.3 (q), 24.81 (q), 23.26 (q), 23.23
(q), 22.05 (q), 21.26 (q), 21.14 (q). MS (FAB) m/z 326 ([M þ 1]þ, 3), 221

2440
Braslau et al.
(11), 178 (31), 148 (15), 133 (75), 122 (21), 106 (17), 105 ([C8Hg]þ, 100);
HRMS exact mass calcd for [M þ 1]þ C22H32NO 326.2484, found 326.2485.
Further chromatographic separation gave a sample enriched in the major
diastereomer, which was recrystallized after standing in the freezer from cold
hexanes to provide crystals, which were submitted for x-ray analysis.a
1H-NMR of the mother liquor showed enhancement of the minor diastereomer.
The spectral data for compounds 6b, 6c, 6d, 6g, 6h have been published.[7a]
Data for 2,2,5,5-tetramethyl-4-(4-dimethylaminophenyl)-3-azahexane
3-nitroxide 5e. The nitroxide was prepared from N-tert-butyl-a-tert-butylnitrone
(314 mg, 2.00 mmol), 4-bromo-N,N-dimethylaniline (800 mg, 4.00 mmol) and
magnesium turnings (106 mg, 4.40 mmol) following the general procedure
described previously[7a] to give 334 mg of the title compound as a bright
red solid (55% yield). TLC: 16 : 1 hexane : ethyl acetate, molybdenum stain,
Rf ¼ 0.35; mp 1008C; IR (CDCl3) 2959, 1612, 1520, 1362, 1190, 1163,
1064 cm21; ESR (CH2Cl2) doubled triplet, an ¼ 15.462 G, ah ¼ 2.785 G; MS
(FAB) m/z 278 ([M þ 2]þ, 68), 221 ([M 2 C4H9]þ, 64), 190 ([M 2 C4H9–
NO]þ, 100); HRMS exact mass calcd for [M þ 1]þ C17H30N2O 278.2359,
found 278.2358; 1H-NMR (250 MHz, CDCl3) gave a broad, amorphous spec-
trum. Addition of phenyl hydrazine provided the following spectrum of the
corresponding hydroxylamine: d 3.55 (s, 1H), 2.91 (s, 6H), 0.96 (s, 18H).
Data for 2,2,5,5-tetramethyl-3-(1-phenylethoxy)-4-(4-dimethylamino-
phenyl)-3-azahexane 6e. The N-alkoxyamine 6e was obtained after purifi-
cation by flash chromatography in 18% yield, with all of the remaining
82% of red nitroxide recovered from the column. The product 6e was a
1 : 1.3 mixture of diastereomers as indicated by integration of the methyl
hydrogens at d 2.94 and 2.86 ppm. Upon standing in CDCl3, hydrolysis took
place to form 2,2-dimethyl-1-(4-dimethylamino)phenyl-1-propanol and
N-(1-phenylethoxy)-t-butylamine, with one diastereomer decomposing faster
than the other. TLC: hexane : ethyl acetate 16 : 1, molybdenum stain,
Rf ¼ 0.26; 1H-NMR (250 MHz, CDCl3, both diastereomers) d 7.5–7.0
(m, 14H), 6.65 (d, 2H, J ¼ 8.5 Hz, major diastereomer), 6.47 (d, 2H,
J ¼ 8.3 Hz, minor diastereomer), 5.22 (q, 1H, J ¼ 6.8Hz, minor diastereomer),
5.08 (q, 1H, J ¼ 6.8 Hz, major diastereomer), 3.76 (s, 1H, minor diastereomer),
3.67 (s, 1H, major diastereomer), 2.94 (s, 6H, major diastereomer), 2.86
(s, 6H, minor diastereomer), 1.65 (d, 3H, J ¼ 6.8 Hz, major diastereomer),
aThe crystallographic data for 6a has been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication no. CCDC 205620. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).

Chiral Acyclic Nitroxides Coupling with Prochiral Radical
2441
1.61 (d, 3H, J ¼ 6.8 Hz, minor diastereomer), 1.10 (s, 9H, minor diastereo-
mer), 1.06 (s, 9H, major diastereomer), 0.92 (s, 9H, minor diastereomer),
0.71 (s, 9H, major diastereomer); 13C-NMR (63 MHz, CDCl3, both diastereo-
mers) d 148.8, 148.7, 144.3, 133.5, 128.6, 128.1, 127.9, 127.4, 127.3, 126.9,
126.5, 111.0, 110.8, 82.3, 73.5, 73.4, 61.4, 61.1, 40.6, 40.5, 35.9, 35.7, 29.4,
29.3, 28.93, 28.87, 24.0, 22.8 ppm.
Data for 2,2,5-trimethyl-4-(2,4,6-trimethylphenyl)-3-azahexane
3-nitroxide 5f. Nitroxide 5f was prepared following the general procedure
described previously[7a] as 597 mg of a slightly impure yellow oil
(11% yield). TLC: 16 : 1 hexane : ethyl acetate, molybdenum stain,
1
Rf ¼ 0.29; IR (CDCl3) 2962, 1720, 1466, 1290, 1129, 1074 cm21; H-NMR
(250 MHz, CDCl3) addition of phenyl hydrazine provided the corresponding
hydroxylamine: d 2.29 (s, 9H), 1.19 (s, 9H).
Data for 2,2,5-trimethyl-3-(1-phenylethoxy)-4-(2,4,6-trimethylphenyl)-
3-azahexane 6f. The title compound was obtained as 101 mg of pure colorless
oil (25% yield), as a 1.7 : 1 mixture of diastereomers as indicated by inte-
gration of the methyl hydrogens at d 2.29 and 2.22 ppm. TLC: pure hexanes,
molybdenum stain, Rf ¼ 0.30; IR (CDCl3) 2970, 1602, 1452, 1360, 1208,
1065 cm21 1H-NMR (250 MHz, CDCl3, both diastereomers) d 7.4–7.1
;
(m, 20H), 6.89 (s, 1H), 6.78 (s, 1H), 6.72 (s, 2H), 4.75 (m, 2H, both diastereo-
mers), 3.45 (d, 1H), 3.25 (d, 1H), 2.29 (s, 9H, major diastereomer), 2.22 (s, 9H,
minor diastereomer), 1.53 (d, 3H, J ¼ 6.8 Hz, major diastereomer), 1.48
(d, 3H, J ¼ 6.5 Hz, minor diastereomer), 1.15 (s, 9H, minor diastereomer),
1.08 (d, 3H, J ¼ 6.8 Hz), 0.90 (s, 9H, major diastereomer), 0.80 (m, 6H),
0.49 (d, 3H, J ¼ 6.3 Hz, major diastereomer); 13C-NMR (APT) (63 MHz,
CDC13, both diastereomers) d 145.1 (s), 144.9 (s), 142.9 (s), 137.4 (s),
137.2 (s), 128.1 (d), 128.0 (d), 127.8 (d), 127.2 (d), 126.9 (d), 126.8 (d),
125.2 (d), 124.9 (d), 82.7 (d), 81.7 (d), 66.2 (d), 65.8 (d), 35.4 (d), 34.4 (d),
27.5 (q), 23.6 (q), 21.7 (q), 21.6 (q), 21.4 (q), 20.6 (q), 20.2 (q).
ACKNOWLEDGMENTS
Financial support from the National Science Foundation (CHE 9527647
and CHE 0078852) is gratefully acknowledged.
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Received in the USA March 3, 2004