Surface-Mediated Reactions. 9. Selective Oxidation of Primary and Secondary Amines to Hydroxylamines

Article abstract of DOI:10.1021/jo0002083

OXONE over silica gel or, in some cases, alumina has been found to oxidize the primary and secondary amines 3 selectively to the corresponding hydroxylamines 4, in either the presence or absence of a solvent. Treatment of Boc-protected L-lysine (6) under the latter conditions afforded hydroxylamine 7 in excellent yield. The trialkylamine 1a and pyridine (1b), in which selectivity is not an issue, were readily oxidized to the corresponding oxides 2 by OXONE over silica gel or alumina, as well as by (CH₃)₃COOH over silica gel. Solvent-free oxidation assisted by microwave irradiation was more forcing, while still affording the hydroxylamines 4 selectively, and is the synthetic method of choice. The mechanistic aspects of these reactions are discussed.

Full text of DOI:10.1021/jo0002083

J . Org. Chem. 2000, 65, 5937-5941
5937
Su r fa ce-Med ia ted Rea ction s. 9. Selective Oxid a tion of P r im a r y
a n d Secon d a r y Am in es to Hyd r oxyla m in es1
J ohn D. Fields and Paul J . Kropp*
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290
kropp@unc.edu
Received February 14, 2000
OXONE over silica gel or, in some cases, alumina has been found to oxidize the primary and
secondary amines 3 selectively to the corresponding hydroxylamines 4, in either the presence or
absence of a solvent. Treatment of Boc-protected L-lysine (6) under the latter conditions afforded
hydroxylamine 7 in excellent yield. The trialkylamine 1a and pyridine (1b), in which selectivity is
not an issue, were readily oxidized to the corresponding oxides 2 by OXONE over silica gel or
alumina, as well as by (CH3)3COOH over silica gel. Solvent-free oxidation assisted by microwave
irradiation was more forcing, while still affording the hydroxylamines 4 selectively, and is the
synthetic method of choice. The mechanistic aspects of these reactions are discussed.
Sch em e 1
Oxidation of an amine initially affords the correspond-
ing amine oxide (Scheme 1). For a tertiary amine the
oxide is the final product. However, oxides derived from
primary and secondary amines (R ) H) rearrange to the
corresponding hydroxylamines. Still possessing a pair of
n electrons, hydroxylamines are vulnerable to further
oxidation, affording a secondary product that varies
depending on the structure of the amine.2
Ta ble 1. Oxid a tion of Am in es 1a
Hydroxylamines are useful synthetic intermediates
and also exhibit a wide range of pharmacological and
physiological activities.3 However, their direct prepara-
tion by oxidation of the corresponding amines is compli-
cated by the ease of overoxidation to secondary products,
especially for primary systems.4 We reported recently the
selective oxidation of sulfides to sulfoxides with (CH3)3-
COOH and OXONE5 mediated by the surfaces of silica
gel and alumina.1 We report here an extension of those
studies to the selective oxidation of primary and second-
ary amines to hydroxylamines, as well as tertiary amines
to their oxides.
yield, %
amine
oxidant
adsorbent
SiO2
1
2
1a
1a
1a
1a
1a
1a
1a
1a
(CH3)3COOH
(CH3)3COOH
(CH3)3COOH
(CH3)3COOH
(CH3)3COOH
OXONE
OXONE
OXONE
OXONE
(CH3)3COOH
(CH3)3COOH
(CH3)3COOH
OXONE
98
2
3
15
76
97
30
65
3
95
6
9
10
21
2
93
94
85
12
trd
63
35
96
3
85
64
89
61
SiO2b
SiO2(OSiMe3)c
Al2O3
Resu lts
Our studies began with the tertiary amine 1a . As seen
in Table 1, amine 1a readily underwent oxidation to
SiO2
SiO2(OSiMe3)c
Al2O3
1a
1be
1be
1be
1be
1be
(1) Part 8: Kropp, P. J .; Breton, G. W.; Fields, J . D.; Tung, J . C.;
Loomis, B. R. J . Am. Chem. Soc. 2000, 122, 4280-4285.
SiO2
Al2O3
SiO2
(2) For reviews of the oxidation of amines, see: (a) Challis, B. C.;
Butler, A. R. In The Chemistry of the Amino Group; Patai, S., Ed.;
Wiley and Sons: London, 1968; pp 320-338. (b) Rosenblatt, D. H.;
Burrows, E. P. In Supplement F: The Chemistry of Amino, Nitroso,
and Nitro Compounds and Their Derivatives, Patai, S.; Ed.; Wiley and
Sons: Chichester, 1982; Part 2, pp 1085-1149. (c) Gilchrist, T. L. In
Comprehensive Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 7, pp 735-752.
OXONE
Al2O3
a
Conducted for 1 h at 80 °C according to the standard procedure
b
with solvent as described in the Experimental Section. Run with
silica gel that had been previously used and recycled five times.
c Partially silylated as described previously.1 Trace. e Conducted
d
(3) See, for example, Murray, R. W.; Singh, M. Synth. Commun.
1989, 19, 3509-3522.
for 5 h; pyridine (1b) and oxide 2b were isolated by washing the
adsorbent with (C2H5)2O followed by CH3OH.
(4) Primary and secondary amines have been selectively oxidized
to the corresponding hydroxylamines with dimethyldioxirane; see (a)
ref 3. (b) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J . J . Org.
Chem. 1990, 55, 1981-1983. However, the reagent must first be
prepared (from OXONE!). Moreover, several primary and secondary
amines gave only overoxidation products even with this reagent.
(5) OXONE is a product of the Du Pont Company consisting of a
2:1:1 mixture of the active ingredient KOSO2OOH, along with KHSO4
and K2SO4, respectively.
amine oxide 2a on treatment with (CH3)3COOH/silica gel
or with OXONE/alumina at 80 °C.6 No significant oxida-
tion occurred under similar conditions in the absence of
silica gel or alumina. With (CH3)3COOH, silica gel
showed no loss of activity when previously used and
10.1021/jo0002083 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

5938 J . Org. Chem., Vol. 65, No. 19, 2000
Fields and Kropp
Ta ble 2. Oxid a tion of Am in es 3 w ith OXONEa
Ta ble 3. Oxid a tion of Am in es 3 w ith (CH3)3COOHa
yield, %
yield, %
amine
equivb
adsorbent
time, h
3
4
5
amine
adsorbent
time, h
3
4
5
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
1.5
3.0
1.5
1.5
1.5
1.5
1.5
1.5
3.0
1.5
SiO2
SiO2
Al2O3
SiO2
Al2O3
SiO2
Al2O3
SiO2
SiO2
Al2O3
8
24
8
24
24
8
trc
98
95
81
100
98
84
50
95
97
95
3a
3a
3b
3c
3c
3d
SiO2
Al2O3
SiO2
SiO2
Al2O3
SiO2
8
8
24
6
12
4
41
76
97
48
70
32
43
12
16
trc
trc
13
27
9
50
10
21
18
trc
6
17
10
33
5
6
a
Conducted according to the standard procedure with solvent.
0.5
12
2
trc
Ta ble 4. Solven t-F r ee Oxid a tion of Am in e 1a w ith
OXONE/Alu m in a a
trc
a
Conducted at 80 °C according to the standard procedure with
yield, %
solvent. [KOSO2OOH]/[3]. c Trace.
b
treatment
1a
2a
recycled five times. Pyridine (1b) afforded oxide 2b in
good yield with (CH3)3COOH/silica gel or OXONE/silica
gel. The surface-mediated approach obviates the need to
thermally dissociate the acetic acid complex encountered
in the standard preparation of pyridine N-oxide (2b)
using CH3CO3H.7
80 °C, 1 h
µwave, 40 s
8
1
92
94
a
Conducted according to the standard solvent-free procedure
described in the Experimental Section.
Ta ble 5. Solven t-F r ee Oxid a tion of Am in es 3 w ith
OXONEa
With a standard procedure in hand, attention was
turned to the secondary and primary amines 3. As seen
in Table 2, the secondary amines 3a ,b and primary
amines 3c,d were readily and selectively converted to the
corresponding hydroxylamines 4 on treatment with OX-
ONE/silica gel at 80 °C. Indeed, amines 3a and 3d
yield, %
amine
adsorbent
time, s
3
4
5
3a
3b
3c
3d
3d
SiO2
SiO2
SiO2
SiO2
Al2O3
40
60
60
40
40
trb
5
8
5
6
97
93
89
92
90
3
3
trb
a
Conducted with microwave irradiation according to the stan-
b
dard solvent-free procedure. Trace.
Solven t-F r ee Oxid a tion s. It has become increasingly
apparent that the use of a solvent in many surface-
mediated reactions is unnecessary.9 Thus simple mixing
of a solid mixture of alumina, tertiary amine 1a , and
OXONE at 80 °C afforded oxide 2a at a rate comparable
to that observed in the presence of solvent (Table 4).10
Reaction time was dramatically shortened to 40 s with
microwave irradiation. Similar treatment of the second-
ary and primary amines 3a ,c,d afforded the correspond-
ing hydroxylamines 4 in yields comparable with those
obtained at 80 °C in the presence of solvent (Table 5).
The Boc derivative of L-lysine (6) similarly afforded the
ꢀ-hydroxylamine 7 in 93% yield, which was readily
converted to the free amino acid 8. Thus solvent-free
resisted oxidation beyond the hydroxylamine stage even
on treatment with double the amount of oxidant. OX-
ONE/alumina was about equally effective with the
secondary amines 3a ,b and the substituted primary
amine 3d but afforded substantial overoxidation of the
unsubstituted primary amine 3c to the oxime 5c. Much
less selectivity and slower rates of oxidation were ob-
served with (CH3)3COOH over either adsorbent (Table
3). The highly substituted secondary amine 3b was
unreactive toward this oxidant.8 Thus, under these
conditions OXONE/silica gel is the reagent of choice for
selective oxidation of primary and secondary alkylamines.
oxidation is more forcing without affording significant
overoxidation.
Discu ssion
Thus OXONE/silica gel and, in some cases, OXONE/
alumina readily oxidize primary and secondary alky-
lamines to the corresponding hydroxylamines with high
(6) To provide qualitative rate data, oxidations were terminated
prior to total conversion. For preparative purposes, complete oxidation
can be effected by using longer reaction times or employing a small
excess of oxidant.
(7) Mosher, H. S.; Turner, L.; Carlsmith, A. Organic Syntheses; Wiley
& Sons: New York, 1963; Collect. Vol. 4, 828-830.
(8) However, amine 3b did afford hydroxylamine 4b on treatment
with 3-C6H4CO3H in solution, as described in the Experimental Section.
We are indebted to D. A. Rasheed for this result.
(9) See, for example, ref 1, as well as references therein.
(10) As we recently noted,1 the traditional evaporative deposition
of the reagent on the substrate is not required.

Surface-Mediated Reactions
Sch em e 2
J . Org. Chem., Vol. 65, No. 19, 2000 5939
Sch em e 3
selectivity, permitting their facile synthesis by direct
oxidation of the amine in either the presence of absence
of a solvent. The selectivity apparently arises, as de-
scribed below, from the strong adsorption of hydroxyl-
amines to the surface, protecting them from further
oxidation. The trialkylamine 1a and pyridine (1b), in
which selectivity is not an issue, were effectively oxidized
under these conditions, as well as by (CH3)3COOH/silica
gel, which was ineffective for the primary and secondary
amines 3.
The differences in behavior between the two oxidants
OXONE and (CH3)3COOH can be understood in terms
of their individual mechanisms, which are presumably
analogous with those recently delineated for the oxidation
of sulfides.1 The surface of silica gel consists of two types
of silanol groups: isolated (9) and associated (10).11 The
Ta ble 6. Ad sor p tion of Am in es a n d Oxid a tion P r od u ctsa
substrate
adsorbent
SiO2
SiO2(OSiMe3)
Al2O3
SiO2
SiO2(OSiMe3)
SiO2
SiO2
SiO2
Al2O3
SiO2
adsorbed, %
1a
1a
1a
2a
2a
3a
3b
3c
3c
3d
3d
4d
4d
100
64
8
100
43
95
100
90
54
92
45
Al2O3
SiO2
SiO2(OSiMe3)
100
84
a
Conducted at 80 °C as described in the Experimental Section.
Sch em e 4
latter are more acidic than their isolated counterparts
and react preferentially with hexamethyldisilazane,12
affording a convenient method for probing their involve-
ment in surface-mediated reactivity. (CH3)3COOH ad-
sorbs predominantly at the isolated sites where it can
enter into reciprocal hydrogen bonding, in which both the
silanol group and the hydroperoxide each serve as a
hydrogen bond donor and acceptor (Scheme 2) without
disrupting existing hydrogen bonding as would be re-
quired at the associated sites.1 The resulting complex is
poised for nucleophilic attack by the amine, resulting in
a pair of proton shifts and the transfer of an oxygen atom
to the amine. As expected for a process centered at the
isolated sites, selective silylation of the associated sites
had no significant effect on the rate of oxidation of amine
1a (Table 1).
Once formed, the amine oxides 2 from the tertiary
amine 1a and pyridine (1b) should be preferentially
adsorbed at the more acidic associated sites, where they
would not interfere with the adsorption of (CH3)3COOH.
By contrast, the hydroxylamines 4 from the primary and
secondary amines 3 should be preferentially adsorbed at
the isolated sites, where they can enter into reciprocal
hydrogen bonding (Scheme 3A) in analogy with (CH3)3-
COOH. Indeed, adsorption of hydroxylamine 4d to silica
gel was only slightly affected by partial silylation (Table
6). Thus in oxidation of primary and secondary amines
with (CH3)3COOH the hydroxylamine product, once
formed, should compete with remaining (CH3)3COOH for
adsorption to the isolated sites, slowing the rate of
oxidation and rendering less of the oxidant activated for
reaction. At the same time, this competition for the
isolated sites decreases the amount of hydroxylamine
that is bound and thus protected from further oxidation,
thereby decreasing selectivity. Thus (CH3)3COOH/silica
gel is effective for oxidizing tertiary amines and pyridines
to their oxides, but not the selective conversion of primary
and secondary amines to hydroxylamines.13
Unlike (CH3)3COOH, OXONE binds preferentially to
the associated sites of silica gel (Scheme 4).1 There it
must thus compete with the starting amine, as well as
with amine oxides emanating from tertiary amines and
pyridines (Scheme 3B,C) but not with hydroxylamines
formed from primary and secondary amines, which are
adsorbed preferentially at the associated sites (Scheme
3A) and thereby rendered unavailable for further oxida-
tion. Thus OXONE/silica gel is excellent for selectively
oxidizing primary and secondary amines to hydroxy-
lamines. OXONE/alumina generally exhibited similar
behavior.14
In contrast with the activation of (CH3)3COOH through
reciprocal hydrogen bonding to the isolated sites of silica
gel, mediation of the oxidant OXONE by silica gel
(11) For descriptions of current models for the surfaces of alumina
and silica gel, see: (a) Kno¨zinger, H. In The Hydrogen Bond. III.
Dynamics, Thermodynamics and Special Systems; Schuster, P., Zundel,
G., Sandorfy, C., Eds.; North-Holland: Amsterdam, 1976; Chapter 27.
(b) Dufour, P.; Houtman, C.; Santini, C. C.; Ne´dez, C.; Basset, J . M.;
Hsu, L. Y.; Shore, S. G. J . Am. Chem. Soc. 1992, 114, 4248-4257.
(12) Sindorf, D. W.; Maciel, G. E. J . Phys. Chem. 1982, 86, 5208-
5219.
(13) As observed previously with sulfides,1 (CH3)3COOH/alumina is
generally a poor oxidant, presumably because (CH3)3COOH is depro-
tonated by the basic support.
(14) An exception is the oxidation of pyridine (1b), which is partially
bound irreversibly to Al+ sites on the alumina surface. See: Kno¨zinger,
H. Adv. Catal. 1976, 25, 184-271.

5940 J . Org. Chem., Vol. 65, No. 19, 2000
Fields and Kropp
OXONE. This slurry was brought to reflux and stirred at 80
°C for the specified amount of time. After cooling to 25 °C, the
slurry was transferred to a 200-mL round-bottomed flask and
stirred overnight at 25 °C with 100 mL of CH3OH. The
adsorbent was then removed by vacuum filtration and washed
with an additional 50 mL of CH3OH. After filtration the
solvents were removed under vacuum and the residue chro-
matographed on a silica gel or alumina column by elution with
diethyl ether and CH3OH.
involves its dispersal on the surface through adsorption
to the associated silanol sites, thereby facilitating nu-
cleophilic attack by the amine on the bound reagent
(Scheme 4).1 The more highly nucleophilic tertiary amine
1a underwent oxidation faster than the secondary and
primary analogues 3a and 3c (Tables 1 and 2). The more
highly substituted R,R-dimethylamine 3d also underwent
oxidation faster than its unsubstituted analogue 3c,
presumably because of increased nucleophilicity due to
a larger inductive effect.
Microwave-assisted oxidation with OXONE over silica
gel or alumina under solvent-free conditions effected
selective oxidation of each of the primary and secondary
amines 3, as well as the tertiary amine 1a , in high yield
and short reaction time and is thus the synthetic method
of choice.
N,N-Dim eth yloctyla m in e N-oxid e (2a ). According to the
preparative-scale procedure, 0.472 g (3.0 mmol) of amine 1a
was treated with 0.270 g (3.0 mmol) of (CH3)3COOH and 7.5
g of silica gel for 4 h. Separation of the residue on
a
chromatographic silica gel column afforded 0.468 g (90% yield)
1
of N-oxide 2a as a colorless solid: H NMR (CDCl3) δ 0.88 (t,
3 H, J ) 6.8 Hz), 1.31 (m, 10 H) 1.88 (m, 2 H) 3.23 (m, 8 H);
13C NMR (CDCl3) δ 13.95, 22.40, 23.76, 26.49, 28.88, 29.10,
31.51, 58.50, 71.64; lit.18 no spectral data.
P yr id in e N-Oxid e (2b). According to the preparative-scale
procedure, 0.237 g (3.0 mmol) of pyridine (1b) was treated with
0.270 g (3.0 mmol) of (CH3)3COOH and 7.5 g of silica gel for
24 h. Separation of the residue on a chromatographic silica
gel column afforded 0.214 g (75% yield) of oxide 2b as a
colorless solid: 1H NMR (CDCl3) δ 7.27 (m, 3 H), 8.22 (m, 2
H); 13C NMR (CDCl3) δ 125.30, 126.93, 137.88; lit.19 1H NMR
(CDCl3) δ 7.33 (m, 3 H), 8.25 (m, 2 H);13C NMR (CDCl3) δ
125.59, 126.79, 138.86.
N,N-Dibu tylh yd r oxyla m in e (4a ). According to the pre-
parative-scale procedure, 0.387 g (3.0 mmol) of amine 3a was
treated with 1.39 g (2.25 mmol) of OXONE and 7.5 g of silica
gel for 24 h. Separation of the residue on a chromatographic
alumina column afforded 0.414 g (95% yield) of hydroxylamine
4a as a clear, yellow liquid: 1H NMR (CDCl3) δ 0.87 (t, 6 H, J
) 7.3 Hz), 1.38 (m, 4 H), 1.72 (m, 4 H), 2.97 (m, 4 H);13C NMR
(CDCl3) δ 13.30, 19.60, 27.55, 47.74; lit.20 1H NMR (CDCl3) δ
0.93 (t, 6 H, J ) 6 Hz), 1.48 (m, 8 H), 2.69 (t, 4 H, J ) 8 Hz).
2,2,6,6-Tetr a m eth ylp ip er id in -1-ol (4b). Treatment of
0.424 g (3.0 mmol) of amine 3b with 0.812 g (4.0 mmol) of 55%
3-ClC6H4CO3H in 15 mL of refluxing C6H6 for 24 h afforded
0.425 g (99% yield) of hydroxylamine 4b upon separation of
the residue on a chromatographic alumina column as a clear,
yellow liquid having spectral properties consistent with those
of material obtained by solvent-free oxidation (Table 5): IR
(neat) 3445, 2974, 2938, 1714, 1466, 1360, 1242, 1130, 976,
733 cm-1; 1H NMR (CDCl3) δ 1.45 (s, 12 H), 1.55 (s, 6 H), 4.08
(s, 1 H); lit.21 1H NMR (CDCl3) δ 1.22 (s, 12 H), 1.56 (s, 6 H),
4.03 (s, 1 H).
N-(1-Octyl)h yd r oxyla m in e (4c). According to the pre-
parative-scale procedure, 0.388 g (3.0 mmol) of amine 3c was
treated with 1.39 g (2.25 mmol) of OXONE and 7.5 g of silica
gel for 24 h. Separation of the residue on a chromatographic
silica gel column afforded 0.331 g (76% yield) of hydroxylamine
4c as a colorless solid: IR (KBr) 3264, 3160, 2922, 2853, 1508,
1468, 1381, 1152, 1061, 892, 721, 548 cm-1; 1H NMR (CDCl3)
δ 0.88 (t, 3 H, J ) 6.6 Hz), 1.32 (m, 12 H), 1.65 (m, 2 H), 2.94
(t, 2 H, J ) 7.2 Hz);13C NMR (CDCl3) δ 14.06, 22.62, 26.96,
27.13, 29.19, 29.48, 31.79, 53.93; lit.22 no spectral data.
This material was spectrally consistent with a specimen
prepared independently by a modification of the general
procedure23 To a solution of 0.423 g (3.0 mmol) of oxime 5c in
100 mL of CH3OH was added 2 mL of a 1.0 M solution of
NaBH3CN in tetrahydrofuran, along with a trace of methyl
orange to give a yellow solution. A 1.0 M solution of HCl in
diethyl ether was added via syringe to achieve pH 3 (indicated
We continue to study the unique and powerful syn-
thetic utility of surface-mediated reactions, as well as the
mechanisms involved.
Exp er im en ta l Section
Sta n d a r d P r oced u r e w ith Solven t. Into a 25-mL round-
bottomed flask was weighed 2.5 g of Merck 10181 silica gel or
Fisher A540 alumina that had been equilibrated with the
atmosphere at 120 °C for at least 48 h. The flask was
stoppered, and the contents were allowed to cool to 25 °C. For
oxidations with OXONE, 0.5 mL of water was added, and the
adsorbent was tumbled on a rotary evaporator at atmospheric
pressure until uniformly free-flowing.16 A solution of 1.0 mmol
each of amine and diphenylmethane, as an internal standard,
in 5 mL of C6H6 was added to the flask with stirring followed
by 137 µL (1.0 mmol) of 70% aqueous (CH3)3COOH or 462 mg
of OXONE (1.5 mmol of KOSO2OOH). The slurry was brought
to reflux and stirred at 80 °C for the specified amount of time.
After cooling to 25 °C, the slurry was transferred to a 200 mL
round-bottomed flask, diluted with 100 mL of CH3OH, and
stirred overnight at 25 °C. The adsorbent was then removed
by vacuum filtration and washed with an additional 50 mL of
CH3OH. The combined filtrates were concentrated under
reduced pressure, and the residue was analyzed by column
1
chromatography or by H NMR analysis.
Sta n d a r d Solven t-F r ee P r oced u r e. A 2.5-g portion of the
adsorbent was prepared as described above. The amine was
added without solvent and the resulting mixture tumbled until
uniformly free-flowing. The oxidant was then added and the
mixture again tumbled. After being heated for the specified
period of time,17 the mixture was allowed to cool to 25 °C and
was stirred overnight with 100 mL of CH3OH. The adsorbent
was collected by vacuum filtration and washed with an
additional 50 mL of CH3OH, and the combined filtrates were
concentrated under reduced pressure. The residue was weighed
1
and analyzed by H NMR spectroscopy.
P r ep a r a tive-Sca le P r oced u r e. Into a 100-mL round-
bottomed flask was weighed the indicated amount of Merck
10181 chromatographic silica gel or Fisher A540 alumina,
which had been equilibrated to the atmosphere at 120 °C for
at least 48 h. The flask was stoppered, and the contents were
allowed to cool to 25 °C. A solution of 15 mL of C6H6 and the
indicated amount of substrate was added to the flask, followed
by the indicated amount of 70% aqueous (CH3)3COOH or
(15) The more forcing effect of solvent-free conditions is apparently
not due to the involvement of higher bulk temperatures under
microwave irradiation since the temperature of the reaction mixture
did not exceed 52 °C. Moreover, the survival of the Boc protecting group
of the L-lysine derivative 6 under these conditions indicates that the
maximum localized temperature was no higher than 150 °C, as the
group cleaves just above that temperature: Rawal, V. H.; Cava, M. P.
Tetrahedron Lett. 1985, 26, 6141-6142.
(18) Lawson, K. D. J . Phys. Chem. 1965, 69, 3204-3205.
(19) Murray, R. W.; Singh, M.; J eyaraman, R. J . Am. Chem. Soc.
1992, 114, 1346-1351.
(20) Wawzonek, S.; Kempf, J . V. Org. Prep. Proced. Int. 1972, 4,
135-151. See also, Yaouanc, J . J .; Masse, G.; Sturtz, G. Synthesis 1985,
807-810.
(21) Bordwell, F. G.; Liu, W.-Z. J . Am. Chem. 1996, 118, 10819-
10823.
(22) Doleschall, G. Tetrahedron Lett. 1987, 28, 2993-2994.
(23) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-2904.
(16) The need for this step varied from batch to batch of OXONE.
(17) Microwave heating was conducted with a commercial 500-W
Little Litton oven.

Surface-Mediated Reactions
J . Org. Chem., Vol. 65, No. 19, 2000 5941
by red color). The solvents were removed under aspirator
vacuum, and the resulting yellow residue was dissolved in 20
mL of H2O, adjusted to pH 9 with 6 N NaOH, extracted with
3 × 50 mL of CHCl3, and backwashed with 50 mL of H2O.
The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated to afford a pale yellow solid,
which on recrystallization from hexanes afforded colorless
flakes: mp 70-71 °C; lit.24 mp 73.5 °C.
6 H), 2.01 (s, 2 H); lit.28 1H NMR (CCl4) δ 0.82 (s, 9 H), 1.04 (s,
6 H), 2.34 (s, 2 H).
Oxid a tion of N1-(ter t-Bu toxyca r bon yl)-L-lysin e (6). A
solution of 256 mg (1.0 mmol) of amino acid 6 in 0.5 mL of
water was adsorbed on silica gel and treated with OXONE for
60 s under microwave heating according to the standard
solvent-free procedure. Isolation in the usual way afforded 249
mg (92% yield) of N1-(tert-butyoxycarbonyl)-N6-hydroxy-L-
lysine (7), which was dissolved in 100 mL of CH3OH along
with 342 mg (3.0 mmol) of CF3COOH. After being stirred at
25 °C for 3 h, the solution was concentrated under reduced
pressure to give N6-hydroxy-L-lysine (8) as a colorless solid,
which was recrystallized from aqueous CH3CH2OH to afford
colorless rods: mp 218-220 °C (dec); 1H NMR (D2O) δ 3.89 (t,
1 H, J ) 6.2 Hz), 3.02 (t, 2 H, J ) 7.5 Hz), 1.92 (m, 2 H), 1.73
(m, 2 H), 1.51 (m, 2 H); lit.29 mp 223-225 °C (dec); lit.30 1H
NMR (D2O) δ 3.35 (t, 1 H, J ) 5.7 Hz), 2.86 (t, 2 H, J ) 7.3
Hz), 1.46 (m, 2 H), 1.35 (m, 2 H), 1.06 (m, 2 H).
Octa n a l Oxim e (5c). According to the preparative-scale
procedure, 0.388 g (3.0 mmol) of amine 3c was treated with
0.541 g (6.0 mmol) of (CH3)3COOH and 7.5 g of alumina for
48 h. Separation of the residue on a chromatographic silica
gel column afforded 0.232 g (54% yield) of oxime 5c as a
colorless solid: IR (CCl4) 3603, 3271, 3104, 2934, 2859, 1549,
1
1466, 1254, 905, 781 cm-1; H NMR (CDCl3) δ 0.85 (t, 3 H, J
) 6.6 Hz), 1.38 (m, 10 H), 2.26 (dt, 2 H, J ) 7.4, 5.6) 6.70 (t,
1 H); lit.25 3280, 2960, 2920, 2860, 1670, 1470, 1380, 1350, 900
cm-1; lit.26 1H NMR (CDCl3) δ 1.20-1.80 (m, 12 H), 2.10-2.60
(m, 3 H), 6.68-6.99 (t, 1 H), 9.01-9.47 (s, 1 H).
Ad sor p tion Stu d ies. Into a 25-mL round-bottomed flask
was weighed 2.5 g of Merck 10181 chromatographic silica gel
or Fisher A540 chromatographic alumina that had been
equilibrated to the atmosphere at 120 °C for at least 48 h. The
flask was stoppered, and the contents were allowed to cool to
25 °C. A solution of 1.0 mmol each of substrate and a known
amount of diphenylmethane, as an internal standard, in 5 mL
of C6H6 was added to the flask with stirring. After 5 min 137
µL (1.0 mmol) of 70% aqueous (CH3)3COOH (with amine 1a )
or 462 mg of OXONE (with other amines) was added. The
slurry was heated at reflux for 5 min, after which a 250-µL
aliquot of the supernatant liquid was removed, evaporated to
This material was spectrally consistent with a specimen
prepared independently. To a solution of 25 g (360 mmol) of
hydroxylamine hydrochloride in 150 mL of water was added
10 g (78 mmol) of 1-octanal, 100 mL of 10% NaOH, and 250
mL of CH3CH2OH. The resulting solution was heated on a
steam bath for 2 h, allowed to cool, and allowed to stand
overnight. The resulting colorless crystals were dried for 2 h
under vacuum: mp 57-59 °C; lit.26 mp 59-60 °C.
N-(1,1,3,3-Tetr a m eth ylbu tyl)h yd r oxyla m in e (4d ). Ac-
cording to the preparative-scale procedure, 0.388 g (3.0 mmol)
of amine 3d was treated with 1.39 g (2.25 mmol) of OXONE
and 7.5 g of silica gel for 24 h. Separation of the residue on a
chromatographic alumina column afforded 0.363 g (83% yield)
of hydroxylamine 4d as a colorless, amorphous solid: mp 228-
231 °C; 1H NMR (CDCl3) δ 1.02 (s, 9 H), 1.48 (s, 6 H), 1.72 (s,
2 H), 3.72 (s, 1 H), 7.5 (br s, 1 H); 13C NMR (CDCl3) δ 26.84,
1
dryness, and analyzed by H NMR spectroscopy.
Ack n ow led gm en ts. Generous financial support by
the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, and by the
National Science Foundation Science and Technology
Center for Environmentally Responsible Solvents and
Processes is gratefully acknowledged, along with techni-
cal assistance by W. T. Pickard.
1
31.13, 50.01, 52.05, 56.98; lit.27 H NMR (CDCl3) δ 1.00 (s, 9
H), 1.17 (s, 6 H), 1.48 (s, 2 H), 5.52 (s, 1 H).
2,2,4-Tr im eth yl-4-n itr osop en ta n e (5d ). According to the
preparative-scale procedure, 0.388 g (3.0 mmol) of amine 3d
was treated with 0.541 g (6.0 mmol) of (CH3)3COOH and 7.5
g of silica gel for 48 h. Separation of the residue on a
chromatographic alumina column afforded hydroxylamine 4d
as a colorless solid: 1H NMR (CDCl3) δ 0.942 (s, 9 H), 1.62 (s,
J O0002083
(24) Feuer, H.; Vincent, B. F., J r.; Bartlett, R. S. J . Org. Chem. 1965,
30, 2877-2880.
(25) Bakke, J . Acta Chem. Scand. 1971, 25, 859-865.
(26) Sosnovsky, G.; Krogh, J . A. Synthesis 1978, 703-705.
(27) Stowell, J . C.; Lau, C. M. J . Org. Chem. 1986, 51, 3355-3357.
(28) Stowell, J . C. J . Org. Chem. 1971, 36, 3055-3056.
(29) Isowa, Y.; Ohmori, M. Bull. Chem. Soc. J pn. 1974, 47, 2672-
2675.
(30) Genet, J . P.; Thorimbert, S.; Mallart, S.; Kardos, N. Synthesis
1993, 321-324.