An Improved Synthesis of O-Benzoyl Protected Hydroxamates

Article abstract of DOI:10.1021/jo971126q

Several primary amines (R-NH₂) were converted to their corresponding O-benzoyl protected hydroxamates under biphasic conditions. The intermediate (benzoyloxy)amines (R-NHOCOPh) were generated using benzoyl peroxide dissolved in CH₂Cl₂ and an aqueous carbonate buffer (pH 10.5) at room temperature. Subsequent acylation with R'COCl gave the protected hydroxamates (R'CONROCOPh) in good overall yields (56-89%).

Full text of DOI:10.1021/jo971126q

8104
J . Org. Chem. 1997, 62, 8104-8108
An Im p r oved Syn th esis of O-Ben zoyl P r otected Hyd r oxa m a tes
Queenie Xianghong Wang, J ennifer King, and Otto Phanstiel IV*
Department of Chemistry, University of Central Florida, Orlando, Florida 32816
Received J une 20, 1997X
Several primary amines (R-NH2) were converted to their corresponding O-benzoyl protected
hydroxamates under biphasic conditions. The intermediate (benzoyloxy)amines (R-NHOCOPh) were
generated using benzoyl peroxide dissolved in CH2Cl2 and an aqueous carbonate buffer (pH 10.5)
at room temperature. Subsequent acylation with R′COCl gave the protected hydroxamates
(R′CONROCOPh) in good overall yields (56-89%).
In tr od u ction
Iron is essential for life. To access this important
micronutrient, microorganisms synthesize low molecular
weight, virtually ferric ion specific ligands (i.e., sidero-
phores) from amino acid sources such as L-ornithine and
L-lysine.1 Decarboxylation of these amino acids provides
a source of the diamines: putrescine and cadaverine,
respectively. In Streptomyces pilosus bacteria these
diamines are oxidized, acylated, and coupled together to
generate a variety of ligands containing hydroxamic acid
[R′-C(O)N(OH)R] linkages. The best known of these
ligands is deferrioxamine B (1, DFO),2 an efficient iron
chelating agent, which has an iron binding constant
near 1030 M-1 3
In general, bacteria and other microor-
.
ganisms use siderophores to bind exogenous iron(III) and
to incorporate it into their cells. Three of these sidero-
phores2,4-7 are shown in Figure 1.
Interestingly, the ligand used by S. pilosus to access
iron from its environment has found clinical use in the
treatment of iron-overloaded humans.8 In humans, iron
is usually stored by the protein ferritin. The ability of
DFO to compete for ferric ion in vivo and to convert it
into a form excretable in the bile and urine enables the
clearance of iron from mammals. In fact, 1 as its
methanesulfonate salt (Novartis tradename: Desferal)
has been used clinically in the treatment of iron poisoning
for over 35 years.9 However, the triweekly regimen of
intravenous DFO infusions raises issues of patient
compliance. Therefore, research has focused on the
development of orally active iron chelators.10
F igu r e 1. Deferrioxamine B (1), Acinetoferrin (2), and Nan-
nochelin A (3).
allow for the transformation of a primary amine into a
hydroxamic acid. As a result, the oxidation and N-
acylation of primary amines (A) to their corresponding
O-benzoyl protected hydroxamates (C) is a useful syn-
thetic transformation for which few reliable methods
exist (Scheme 1).
To evaluate different iron binding ligands, medicinal
chemists have desired new synthetic methods to access
complex hydroxamic acids. To this end, organic chemists
have struggled to provide selective reagents, which would
In 1983, Ganem and Biloski demonstrated the conver-
sion of secondary amines to (benzoyloxy)amines using
benzoyl peroxide (BPO) as the oxidant.11
In 1990,
Milewska and Chimiak illustrated the oxidation of the
free Nδ-amine of NR-(benzyloxycarbonyl)-L-ornithine tert-
butyl ester with BPO to the corresponding Nδ-(benzoy-
loxy)amine, followed by Nδ-acetylation with acetyl chlo-
ride.12 This useful two-step transformation was employed
in the synthesis of a novel siderophore, nannochelin A
(2), albeit in 25% yield.6
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Neilands, J . B. Annu. Rev. Biochem. 1981, 50, 715.
(2) Bergeron, R. J .; McManis J . S. CRC Handbook of Microbial Iron
Chelates; CRC Press: Boca Raton, FL, 1991; pp 271-304.
(3) Anderegg, G.; L’Eplattenier, F.; Schwarzenbach, G. Helv. Chim.
Acta 1963, 46, 1409.
(4) Okujo, N.; Sakakibara, Y.; Yoshida, T.; Yamamoto, S. Biometals
1994, 7, 170-176.
(5) Bergeron, R. J .; McManis, J . S.; Phanstiel IV, O.; Vinson, J . R.
T. J . Org. Chem. 1995, 60, 109-114.
Our focus was to evaluate a variety of reaction param-
eters to increase the yield and selectivity of the benzoyl
peroxide mediated process. Optimization of this process
is important as the intermediate (benzoyloxy)amines offer
one entry to R,â-unsaturated hydroxamic acid architec-
(6) Bergeron, R. J .; Phanstiel IV, O. J . Org. Chem. 1992, 57, 7140-
7143.
(7) Kunze, B.; Trowitzsch-Kienast, W.; Hofle, G.; Reichenbach, H.
J . Antibiot. 1992, 45, 147-150.
(8) Aksoy, M.; Birdwood, G. F. B. Hypertransfusion and Iron
Chelation in Thalassemia; Hans Huber Publishers: Berne, 1985; p
80.
(9) Warne, P., Ed. Ciba Geigy J . 1991, 4, 32-35.
(10) Singh, S. Chem. Ind. (London) 1994, 452-455.
(11) Biloski, A. J .; Ganem, B. Synthesis 1983, 537.
(12) Milewska, M. J .; Chimiak, A. Synthesis 1990, 233-234.
S0022-3263(97)01126-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis of O-Benzoyl Protected Hydroxamates
J . Org. Chem., Vol. 62, No. 23, 1997 8105
Sch em e 1. Oxid a tion , Acyla tion , a n d
Dep r otection Step s for Con ver sion of a P r im a r y
Am in e to a Hyd r oxa m ic Acid
F igu r e 2. Yield of 4 at various pH.
Ta ble 1. Yield s of 4 a n d 5 a t Va r iou s p H
pH
4 (%)
5 (%)
4/5
8
8.5
9.5
10
10.5
11
27
46
48
55
59
48
46
38
21
17
16
15
14
19
22
23
1.3
2.7
3
3.7
4.2
2.5
2.1
1.7
Sch em e 2. Oxid a tion of P h en eth yla m in e w ith
BP O
11.5
12
outcome of this reaction. Using an aqueous carbonate
buffer/CH2Cl2 mixture sharply increased the yield of
the N-oxidized product 4 at the expense of the amide 5
(see Scheme 2). Encouraged by these results, we em-
barked on a detailed study of the benzoyl peroxide-
mediated oxidation of phenethylamine using biphasic
conditions.
Reverse-phase HPLC was used to quantify the yields
of the desired product 4 and the byproduct 5. The
analysis was based on the respective molar absorptivity
ratios of 4 and 5 versus a diphenylmethane standard.
Diphenylmethane was chosen as the internal standard
as it was stable to the oxidation conditions.
Since our process was biphasic, we were interested in
finding the optimal pH of the aqueous phase to obtain
the maximum yield of the N-oxidation product. Different
pH buffer solutions were prepared by combining 0.75 M
NaHCO3 and 1.5 M NaOH solutions at certain ratios. To
neutralize the benzoic acid as it formed, at least 0.5 mL
of buffer solution per 0.1 mmol phenethylamine was
needed to maintain the pH throughout the entire reaction
time. The pH experiments were conducted at room
temperature with 1 equiv of BPO (0.4 mmol), 1 equiv of
phenethylamine (0.4 mmol), 3 mL of methylene chloride,
and 3 mL of aqueous buffer solution. The data from the
pH study are listed in Table 1. The pH/yield profile for
the oxidation of phenethylamine (see Figure 2) suggested
that a pH of 10.5 was optimal for this reaction.
Using a pH 10.5 buffer, we varied the molar ratios of
phenethylamine and BPO in order to observe their
respective concentration effects. Reactions were con-
ducted at room temperature with 1 equiv of phenethy-
lamine (0.4 mmol), 3 mL of methylene chloride, 3 mL of
pH 10.5 aqueous buffer solution, and varying concentra-
tions of BPO. This concentration study (see Table 2)
indicated that 2 equivalents of BPO and 1 equiv of
phenethylamine provided good yields of 4.
tures as found in the siderophores 2 and 3. The unsatur-
ated hydroxamic acids are not readily accessible via the
commonly used O-benzyl protected hydroxamates. Depro-
tection of an O-benzyl protected R,â-unsaturated hydrox-
amate via hydrogenation would compromise the ap-
pended double bond. In short, progress in this area
would allow for rapid access to new iron binding ligands
for further clinical evaluation.
Resu lts a n d Discu ssion
The early studies by Milewski used benzoyl peroxide
as the oxidant and identified two competing pathways:
N-oxidation and N-acylation.12 Our first attempt was to
apply their method to a primary amine model system (i.e.,
phenethylamine). Phenethylamine contains an appended
aromatic ring system, which is easily monitored by UV
detection. Unfortunately, in our hands their procedure
(CH2Cl2 and solid Na2CO3) gave low yields of the desired
(benzoyloxy)amine and instead gave mostly the benza-
mide byproduct (i.e. structures 4 and 5 in Scheme 2,
respectively).
To date, the highest yields of 4 were obtained with
equal volumes of a pH 10.5 carbonate buffer solution and
0.1 M phenethylamine in CH2Cl2 using 2 equiv of benzoyl
peroxide (vs the amine) at room temperature.
The (benzoyloxy)amine 4 could be separated from the
benzamide 5 by column chromatography or the mixture
Using a more biomimetic approach,13 we discovered
that the presence of water significantly altered the
(13) Thariath, A. M.; Valvan, M. A.; Viswanatha, T. The Develop-
ment of Iron Chelators for Clinical Use; Bergeron, R. J ., Brittenhaum,
G. M., Eds.; 1994; Chapter 9, pp 169-186.

8106 J . Org. Chem., Vol. 62, No. 23, 1997
Wang et al.
Ta ble 2. Yield s of 4 a n d 5 w ith Va r iou s Equ iva len ts of
BP O
mmol) in 3 mL of pH 10.5 aqueous buffer solution at room
temperature. The disappearance of the starting material was
monitored by TLC (2% NH3/MeOH, Rf ) 0.39). After the
reaction was complete, the water layer was extracted twice
with 10 mL of CH2Cl2. The organic layers were combined and
concentrated to give the crude product.
Ch r om a togr a p h ic P r oced u r e. Instrument: UV spec-
troscopy revealed that both 4 and 5 absorbed strongly near
224 nm. Therefore, the wavelength of 224 nm was selected
for UV detection. Analyses were carried out by using a Gilson
HPLC system equipped with a reversed-phase C-18 column
and a UV detector measuring absorbency at 224 nm. Crude
reaction mixtures were eluted using 70% acetonitrile/water
with a flow rate of 1 mL/min. The retention times for 5, 4,
BPO, and diphenylmethane were 3.91, 6.98, 8.86, and 11.22
min, respectively.
Ca libr a tion : N-(Benzoyloxy)phenethylamine (26 mg, 0.108
mmol), N-(2-phenylethyl)benzamide (12.5 mg, 0.056 mmol),
and diphenylmethane (0.0715 g, 0.43 mmol) were combined
and dissolved in 25 mL of 70% acetonitrile/water. An aliquot
of this solution was injected into the HPLC and gave the molar
absorptivity ratios of 4 versus diphenylmethane (2.39) and 5
versus diphenylmethane (2.83), respectively.
Deter m in a tion of th e Yield s of P r od u ct 4 a n d Byp r od -
u ct 5. The crude product of the model study was dissolved in
10 mL of 100% acetonitrile. The crude product solution (1 mL)
was added to 5 mL of a 70% acetonitrile/water solution. An
aliquot of this solution was injected into the HPLC to give the
corresponding absorbency expressed in area %. The yields
were calculated using the above calibration data and the moles
of standard added (i.e., 0.4 mmol).
BPO:amine
4 (%)
5 (%)
4/5
1
2
3
4
59
60
41
14
14
11
22
39
4.2
5.4
1.9
0.4
simply acetylated (with CH3COCl) in the same pot to give
the corresponding O-benzoyl protected hydroxamate 6
and recovered 5, which were readily separated by column
chromatography (see Experimental Section).
To evaluate the scope of this new procedure, a variety
of primary amines (R-NH2) were oxidized to their corre-
sponding (benzoyloxy)amines. Each intermediate B was
subsequently acylated to the respective O-benzoylhy-
droxamate C (see Scheme 1). The results are sum-
marized in Table 3.
In general, the product yield for the one-pot-two-step
process increased as the steric bulk of the R-group
increased. The reaction time of the acylation step (i.e.
B to C in Scheme 1) was also dependent on the steric
bulk of the R group. In particular, acylation became
quite slow with the hindered (benzoyloxy)amine precur-
sor to 12.
The mild conditions of this “one-pot” synthesis (room
temperature, pH 10.5) make it ideally suited for convert-
ing a primary amine to the corresponding O-benzoyl
protected hydroxamate. In general, O-benzoyl groups
can be deprotected with 10% NH3/CH3OH at -23 °C to
give high yields of the corresponding hydroxamic acids.6
While the benzoyl peroxide oxidant has been used
previously, our biphasic method is novel. Our discovery
is significant as it allows facile entry to R,â-unsaturated
hydroxamic acids via masked systems such as 8. This
technology should be of immense value to medicinal
chemists interested in synthesizing functionalized hy-
droxamic acids for iron chelation therapy and metalloen-
zyme inhibition.14,15
Gen er a l P r oced u r e for th e Sequ en tia l Oxid a tion a n d
Acyla tion of a P r im a r y Am in e. A solution of BPO (1.92 g,
8 mmol) in 40 mL of CH2Cl2 was added quickly to a mixture
of the amine (4 mmol) in 40 mL of pH 10.5 buffer solution at
room temperature. In general, TLC (2% NH3/MeOH) was used
to monitor the consumption of the starting material.
A
solution of the acid chloride (4 mmol) in 5 mL of CH2Cl2 was
added to the reaction mixture after all the starting amine was
consumed. After the acylation reaction was complete, the
water layer was extracted twice with 20 mL of CH2Cl2. The
organic layers were combined, dried over anhydrous Na2SO4,
filtered, and concentrated to give the crude product. The
product mixture was subjected to flash column chromatogra-
phy, eluting with 20% ethyl acetate/hexane to isolate the
masked O-benzoyl hydroxamate. The yields are listed in Table
3.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Reagents were purchased from
the ACROS Chemical Company. All commercially available
amines were distilled prior to use. 1H NMR spectra were
recorded at 200 MHz on Varian XL-200 spectrometer. Dif-
ferent pH buffer solutions were prepared by combining 0.75
M NaHCO3 and 1.5 M NaOH solutions at certain ratios.
Gen er a l P r oced u r e for th e Oxid a tion of P h en eth y-
la m in e a t Va r iou s p H. A solution of BPO (0.096 g, 0.4 mmol)
in 3 mL of CH2Cl2 was added quickly to a mixture of
phenethylamine (0.048 g, 0.4 mmol) and diphenylmethane
(0.067 g, 0.4 mmol) in 3 mL of an aqueous buffer solution (pH
) 8, 8.5, 9.5, 10, 10.5, 11, 11.5, and 12, respectively) at room
temperature. The disappearance of the starting material was
monitored by TLC (2% NH3/MeOH, Rf ) 0.39). After the
reaction was complete, the water layer was extracted twice
with 10 mL of CH2Cl2. The organic layers were combined and
concentrated to give the crude product.
N-(Ben zoyloxy)-2-p h en eth yla m in e (4) a n d N-(2-P h e-
n yleth yl)ben zam ide (5). Oxidation of phenethylamine (0.484
g, 4 mmol) was carried out as described in the general
procedure. Column chromatography (20% EtOAc/hexane)
gave 4 (0.70 g, 73%) and the N-(2-phenylethyl)benzamide (5)
(0.09 g, 10%), respectively. 4: Rf ) 0.47 in 20% ethyl acetate/
hexane; 1H NMR (CDCl3): δ 8.01 (d, 2H, aromatic H), 7.35 (m,
8H, aromatic H), 3.45 (t, 2H, CH2N), 2.98 (t, 2H, CH2); high-
resolution mass spectrum (FAB): theory for (C15H15N1O2) M
+ 1 ) 242.1209, found M + 1 ) 242.1204. Anal. Calcd for
C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 75.04; H,
1
6.45; N, 5.86. 5: Rf ) 0.25 in 20% ethyl acetate/hexane; H
NMR (CDCl3): δ 7.65 (d, 2H, aromatic H), 7.20 (m, 8H,
aromatic H), 3.6 (q, 2H, CH2), 2.82 (t, 2H, CH2).
N-(Ben zoyloxy)-N-(2-p h en yleth yl)a ceta m id e (6). The
oxidation and acylation of phenethylamine (0.484 g, 4 mmol)
were carried out as described in the general procedure to give
0.813 g of the protected hydroxamate 6 (72%). 6: Rf ) 0.20
in 20% ethyl acetate/hexane; 1H NMR (CDCl3): δ 8.01 (d, 2H,
aromatic H), 7.67 (m, 1H, aromatic H), 7.51 (m, 2H, aromatic
H), 7.25 (m, 5H, aromatic H), 4.07 (t, 2H, CH2N), 2.99 (t, 2H,
CH2), 2.00 (s, 3H, CH3). Anal. Calcd for C17H17NO3: C, 72.07;
H, 6.05; N, 4.94. Found: C, 71.80; H, 6.09; N, 4.94.
Gen er a l P r oced u r e for th e Oxid a tion of P h en eth y-
la m in e by Usin g Va r iou s Equ iva len ts of Ben zoyl P er -
oxid e. A solution of BPO (1, 2, 3, 4 equiv, respectively) in 3
mL of CH2Cl2 was added quickly to a mixture of phenethy-
lamine (0.048 g, 0.4 mmol) and diphenylmethane (0.067 g, 0.4
(14) Summers, J . B.; Gunn, B. P.; Mazdiyasni, H.; Goetze, A. M.;
Young, P. R.; Bouska, J . B.; Dyer, R. D.; Brooks, D. W.; Carter, G. W.;
Martin, J . G., Stewart, A. O. J . Med. Chem. 1988, 31, 3-5.
(15) Wright, S. W.; Harris, R. R.; Kerr, J . S.; Green, A. M.; Pinto,
D. J .; Bruin, E. M.; Collins, R. J .; Dorow, R. L.; Mantegna, L. R.; Sherk,
S. R.; Covington, M. B.; Nurnberg, S. A.; Welch, P. K.; Nelson, M. J .;
Magolda, R. L. J . Med. Chem. 1992, 35, 4061-4068.
N-(Ben zoyloxy)-N-h exyla ceta m id e (7). The oxidation
and acylation of hexylamine (0.404 g, 4 mmol) were carried
out as described in the general procedure to give 0.74 g of the
desired product 7 (70%). 7: Rf ) 0.19 in 20% ethyl acetate/
hexane; 1H NMR (CDCl3): δ 8.05 (d, 2H, aromatic H), 7.59
(m, 3H, aromatic H), 3.81 (t, 2H, CH2N), 2.05 (s, 3H, CH3),

Synthesis of O-Benzoyl Protected Hydroxamates
J . Org. Chem., Vol. 62, No. 23, 1997 8107
Ta ble 3. Con ver sion of P r im a r y Am in es to O-ben zoyl P r otected Hyd r oxa m a tes
1.65 (m, 2H, CH2), 1.31 (m, 6H, CH2), 0.89 (t, 3H, CH3). Anal.
Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.52; H, 8.03; N, 5.36.
mL). The organic layers were combined, dried over anhydrous
Na2SO4, filtered, and concentrated to give the crude product.
The crude hydroxamate was subjected to flash column chro-
matography and eluted with 30% ethyl acetate/hexane to give
8 (8.58 g: 68%) as a colorless oil. 8: Rf ) 0.33 in 30% ethyl
acetate/hexane; 1H NMR (CDCl3): δ 8.12 (d, 2H, aromatic),
7.71 (t, 1H, aromatic H), 7.54 (t, 2H, aromatic H), 7.03 (dt,
1H, olefinic), 6.05 (d, 1H, olefinic), 5.20 (broad, 1H, NH), 3.92
(t, 2H, CH2NO), 3.24 (q, 2H, CH2), 2.15 (q, 2H, CH2CdC), 1.82
(m, 2H, CH2), 1.64 (m, 2H, CH2), 1.53-1.15 (m, 13H, tert-butyl
and 2 CH2), 0.83 (t, 3H, CH3); Anal. Calcd for C23H34N2O5:
C, 66.01; H, 8.19; N, 6.69. Found: C, 65.83; H, 8.17; N, 6.61.
N-(Ben zoyloxy)-N-ben zyla ceta m id e (9). Oxidation and
acylation of benzylamine (0.429 g, 4 mmol) were carried out
as described in the general procedure to give 0.605 g of the
desired product 9 (56%). 9: Rf ) 0.20 in 20% ethyl acetate/
hexane; 1H NMR (CDCl3): δ 7.97 (d, 2H, aromatic H), 7.64
(m, 1H, aromatic H), 7.46 (m, 3H, aromatic H), 7.34 (m, 4H,
aromatic H), 4.99 (s, 2H, CH2), 2.11 (s, 3H, CH3). Anal. Calcd
for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.11;
H, 5.59; N, 5.14.
N-(3-(ter t-Bu t oxyca r b on yla m in o)p r op yl)-N-(b en zoy-
loxy)-2-(E)-octen a m id e 8. A solution of BPO (14.52 g, 60
mmol) and CH2Cl2 (225 mL) was added dropwise at room
temperature to a vigorously stirred mixture of N1-BOC-
propanediamine (5.22 g, 30 mmol) and 300 mL of a carbonate
buffer solution (at pH ) 10.5). The buffer solution was
prepared by combining 222 mL of 0.75 N aqueous NaHCO3
and 78 mL of 1.5 N aqueous NaOH. The starting material
was consumed after 4 h as shown by TLC (4% NH3/MeOH).
Note: Column chromatography (40% ethyl acetate/hexane) can
be used to separate the (benzoyloxy)amine intermediate (BOC-
NHCH2CH2CH2NHOCOPh) 13 and the benzamide (BOC-
NHCH2CH2CH2NHCOPh) 14 (e.g. Rf ) 0.43 and 0.29, respec-
tively). [The characterization of 13 is included for completeness.
13: 1H NMR (CDCl3): δ 8.03 (d, 2H, aromatic H), 7.52 (m,
3H, aromatic H), 6.80 (broad m, 1H, NH), 4.81 (broad m, 1H,
NH), 3.22 (m, 4H, CH2), 1.82 (m, 2H, CH2), 1.41 (s, 9H, tert-
butyl); high-resolution mass spectrum (FAB): theory for
(C15H23N2O4) M + 1 ) 295.1658, found M + 1 ) 295.1645]. A
solution of trans-2-octenoyl chloride (4.81 g, 30 mmol) in 30
mL of CH2Cl2 was added dropwise to the mixture of 13 and
14 over 15 min. The disappearance of 13 was monitored by
TLC (40% ethyl acetate/hexane). After the acylation was
complete, the organic layer was separated, and the remaining
water layer was washed twice with additional CH2Cl2 (100
N-(Ben zoyloxy)-N-(1-m eth ylh eptyl)acetam ide (10). Oxi-
dation and acylation of 1-methylheptylamine (0.517 g, 4 mmol)
were carried out as described in the general procedure to give
0.99 g of the desired product 10 (85%). 10: Rf ) 0.20 in 20%
ethyl acetate/hexane; 1H NMR (CDCl3): δ 8.11 (d, 2H, aromatic
H), 7.61 (m, 3H, aromatic H), 4.75 (broad s, 1H, CH), 2.06 (s,
3H, CH3), 1.35 (m, 13H, CH2 and CH3), 0.90 (t, 3H, CH3). Anal.

8108 J . Org. Chem., Vol. 62, No. 23, 1997
Wang et al.
Calcd for C17H25NO3: C, 70.07; H, 8.64; N, 4.81. Found: C,
70.17; H, 8.66; N, 4.82.
N -(Be n zoyloxy)-N -(1,1,3,3-t e t r a m e t h ylb u t yl)a ce t a -
m id e (12). Oxidation and acylation of tert-octylamine (0.517
g, 4 mmol) were carried out as described in the general
procedure to give 1.04 g of the desired product 12 (89%). 12:
N-(Ben zoyloxy)-N-cycloh exyla ceta m id e (11). Oxida-
tion and acylation of cyclohexylamine (0.397 g, 4 mmol) were
carried out as described in the general procedure to give 0.93
g of the desired product 11 (89%). 11: Rf ) 0.19 in 20% ethyl
acetate/hexane; 1H NMR (CDCl3): δ 8.10 (d, 2H, aromatic H),
7.60 (m, 3H, aromatic H), 4.50 (broad s, 1H, CH), 2.69 and
2.47 (dt, 2H, CH2), 2.15-1.00 (m, 11H, CH2 and CH3). Anal.
Calcd for C15H19NO3: C, 68.90; H, 7.33; N, 5.36. Found: C,
69.02; H, 7.29; N, 5.42.
1
Rf ) 0.20 in 19% ethyl acetate/hexane; H NMR (CDCl3): δ
8.11 (d, 2H, aromatic H), 7.60 (m, 3H, aromatic H), 2.00 (s,
3H, CH3), 1.69 (s, 5H, CH2 and CH3), 1.35 (m, 3H, CH3), 1.09
(t, 9H, CH3). Anal. Calcd for C17H25NO3: C, 70.07; H, 8.64;
N, 4.81. Found: C, 69.97; H, 8.68; N, 4.75.
J O971126Q