An efficient and versatile one-pot Beckmann rearrangement of ketoximes using mesitylenesulfonyl chloride

Article abstract of DOI:10.1055/s-2008-1042948

A variety of oxime mesitylenesulfonates, generated in situ from their heterocyclic, carbocyclic, and acyclic ketoximes in the presence of lithium hydroxide in tetrahydrofuran, efficiently rearrange into their corresponding lactams and amides. The stereochemistry of diazepan-5-one lactams resulting from the rearrangement of heterocyclic ketoximes (piperidin-4-one oximes), has been deduced based on one- and two-dimensional NMR analyses. The seven-membered heterocyclic ring of the product lactams adopts chair conformations with equatorial configurations of all the alkyl and aryl substituents except one of the methyl groups at C-3 on a 3,3-disubstituted product, which possess an axial configuration. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042948

PAPER
1351
An Efficient and Versatile One-Pot Beckmann Rearrangement of Ketoximes
Using Mesitylenesulfonyl Chloride
O
ne-Pot Beckma
h
e
K
e
toximes Usi
n
ngMesityle
n
a
esulfonyl
C
n
hloride Ramalingan, Yong-Tae Park*
Department of Chemistry, Kyungpook National University, Taegu 702-701, Korea
Fax +82(53)9506330; E-mail: ytpark@knu.ac.kr
Received 6 December 2007; revised 15 January 2008
Me
Me
O
O
Abstract: A variety of oxime mesitylenesulfonates, generated in
situ from their heterocyclic, carbocyclic, and acyclic ketoximes in
the presence of lithium hydroxide in tetrahydrofuran, efficiently
rearrange into their corresponding lactams and amides. The stereo-
chemistry of diazepan-5-one lactams resulting from the rearrange-
ment of heterocyclic ketoximes (piperidin-4-one oximes), has been
deduced based on one- and two-dimensional NMR analyses. The
seven-membered heterocyclic ring of the product lactams adopts
chair conformations with equatorial configurations of all the alkyl
and aryl substituents except one of the methyl groups at C-3 on a
3,3-disubstituted product, which possess an axial configuration.
HO
R2
R4
N
NH
Cl
R1
R3
R2
R4
R1
R3
S
Me
O
N
N
Me
LiOH
THF, 60 °C
Me
1a–f
2a–f
Scheme 1 Synthesis of diazepan-5-one lactams 2a–f from piperi-
din-4-one oximes 1a–f
Key words: piperidin-4-one oximes, ketoximes, mesitylenesulfo-
nyl chloride, Beckmann rearrangement, diazepan-5-ones, lactams,
amides
When mesitylenesulfonyl chloride was added to a stirring
THF solution of the E-isomer of oxime 1a (OH anti to C-
3),10,11,12 in the presence of lithium hydroxide at ambient
temperature, and the mixture was further stirred at the
Beckmann rearrangement has become a powerful tool in same temperature for one hour then at 60 °C for 10 hours,
the syntheses of amides and lactams from their corre- diazepan-5-one lactam 2a was formed in 75% yield
sponding oximes since its discovery in 1886.1 This rear- (Scheme 1; R1 = Me, R2 = R3 = R4 = H). Thus, insertion
rangement usually takes place in strongly acidic and of an NH group into the bond between the imino carbon
dehydrating media such as sulfuric acid at high reaction and the a-carbon bearing the methyl group, occurred dur-
temperature. To avoid these requisite harsh conditions, ing the rearrangement.
several methodologies in liquid-phase,2–4 in supercritical
The structure of the diazepanone lactam 2a was unequiv-
water,5 in ionic liquids,6 and in the vapor-phase7 have
ocally established on the basis of IR, NMR, GC/MS, and
been developed. Of the liquid-phase rearrangements, the
elemental analysis. Representative 1H NMR (A) and 13C
NMR (B) spectra, including the specific assignments of
the lactam 2a are shown in Figure 1.
use of rhodium complex2 and cyanuric chloride,3 are ele-
gant and recent approaches. We recently reported another,
milder methodology for the rearrangement of ketoximes
1
In the H NMR spectrum, the observed vicinal coupling
into amides/lactams using mercury chloride in aceto-
constants for the hydrogens on C-7 (d, 11.0 Hz) and C-2
nitrile.8 Since some 1,4-diazepanone cores exhibit diverse
(d, 8.5 Hz), vicinal and geminal coupling constants for
biological activities,9 we have directed our recent research
one of the hydrogens on C-6 (dd, 10.9 Hz and 14.6 Hz, re-
towards the syntheses of 1,4-diazepanones as biological
spectively) and a geminal coupling constant for the sec-
agents. Thus, the methodologies using the rhodium com-
ond C-6 hydrogen (d, 14.6 Hz), imply that the seven-
membered heterocyclic ring adopts a chair conformation
with equatorial orientations of both the phenyl groups on
C-7 and C-2, and the methyl group on C-3.13 In other
words, the plausible conformation of the seven-membered
heterocyclic ring is a chair in which the hydrogens on C-
7, C-3 and C-2 occupy axial positions. Of the hydrogens
on C-6, the proton resonating as a doublet (d = 2.49 ppm)
with geminal coupling takes an equatorial orientation,
while the second, which exhibits a doublet of doublet
(d = 3.29 ppm) takes an axial orientation. The axial orien-
tation of the hydrogens on C-7, C-3, C-2, and one of the
two hydrogens on C-6, has further been confirmed by
NOESY experiments. In addition, the absence of any cou-
pling for the axial hydrogen on C-7 with the equatorial hy-
plex and cyanuric chloride2,3 were applied to the piperi-
din-4-one oxime 1a in order to form the diazepanone
lactam 2a. These methods, however, resulted only in ex-
clusive recovery of the starting oxime, despite the report-
ed high efficiency on other systems. Application of the
mercury-catalysis method to the piperidin-4-one oxime
1a also failed to provide the lactam 2a. During further ef-
forts at converting 1a, we found a mild and efficient ‘one-
pot’ rearrangement method using lithium hydroxide and
mesitylenesulfonyl chloride in tetrahydrofuran (THF).
Several other ketoximes were also examined in order to
generalize the new method.
SYNTHESIS 2008, No. 9, pp 1351–1358
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1042948; Art ID: F22407SS
© Georg Thieme Verlag Stuttgart · New York

1352
C. Ramalingan, Y.-T. Park
PAPER
Figure 1 400 MHz 1H NMR (A) and 13C NMR (B) spectra of 2a in CDCl3
drogen on C-6 suggests a dihedral angle of ~90°.13 The gens on C-7 and C-2 are axial but that one of them is not
relative stereochemistry of 2a is thus 2RS, 3SR, and 7SR. exactly antiperiplanar to the lone-pair electrons on N-1.
In the 13C NMR spectrum, the deshielded absorption of C- The effect of various bases/reagents on the rearrangement
2 (Dd = ~11.4 ppm) compared to that of C-7 is due to the of 1a has also been examined. The use of tosyl chloride or
combined effect of the equatorial methyl group at C-3 and
the NH group beta to C-2, while the deshielded absorption
Table 1 Effect of Solvents on the Yield of the Beckmann Rear-
rangement of Oxime 1a
of C-3 (Dd = ~6.9 ppm) compared to that of C-6 is largely
due to the a-effects of both the equatorial methyl group at
C-3 and the NH group.
Entry
Solvent
THF
Temp (°C) Time (h) Yield (%)
The assignment for the carbons C-2, C-3, C-6 and C-7 of
the seven-membered heterocyclic ring of 2a was further
accomplished by their one-bond hetero-correlation (1H–
13C COSY/HETCOR) with the associated hydrogens. The
deshielding absorption of the methyl carbon on N-1, com-
pared to the methyl carbon on C-3 is obviously due to the
presence of the electronegative nitrogen and equatorial
phenyl groups on both the carbons beta to the methyl
group.
1
2
3
4
5
6
7
8
9
10
60
11.5
11.5
11.5
11.5
11.5
11.5
11.5
11.5
11.5
11.5
75
69
57
54
52
48
45
31
30
6
MeCN
DCE
60
60
DMF
60
toluene
acetone
n-hexane
DMA
60
reflux
60
Furthermore, it is known from IR that the Bohlmann
bands arise due to the interaction of the lone-pair electrons
of nitrogen in its axial orientation with at least two anti-
periplanar a-hydrogens.14 Hence, in the IR spectrum of
2a, the weak Bohlmann bands observed in the region be-
tween 2800 and 2700 cm–1 indicate that both the hydro-
60
1,4-dioxane
DMSO
60
60
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

PAPER
One-Pot Beckmann Rearrangement of Ketoximes Using Mesitylenesulfonyl Chloride
1353
Table 2 The Yields of Diazepan-5-one Lactams 2a–f from Piperidin-4-one Oximes 1a–f
Entry
Oxime
Time (h)
11.5
Lactam
Yield (%)
O
HO
N
NH
NH
NH
NH
NH
NH
Me
Me
1
75
70
N
N
Me
Me
1a E-isomer
2a
O
HO
N
Me
Me
Me
Me
2
3
4
5
11.5
13.0
13.0
13.0
N
N
Me
Me
1b
2b
2c
2d
2e
2f
O
HO
N
Me
76
63
59
Me
N
N
Me
Me
1c E-isomer
O
HO
N
Me
Me
Me
Me
N
N
Me
Me
1d E-isomer
O
HO
N
Me
Me
Me
Me
N
N
Me
Me
1e E-isomer
O
HO
N
6
9.5
83
N
N
Me
Me
1f
benzenesulfonyl chloride in place of mesitylenesulfonyl THF; the use of a basic solvent, pyridine without lithium
chloride reduced the yield of lactam formation (50 and hydroxide provided the lactam 2a in only 6% yield.
35%, respectively). Probably, the greater bulk of the mes-
itylenesulfonate of the reactant oxime has a higher pro-
The effect of various solvents on the rearrangement of 1a
in the presence of lithium hydroxide was examined.
pensity for leaving than tosylate and benzenesulfonate,
Among solvents such as THF, acetonitrile, 1,2-dichloro-
and thus produces the lactam in better yield. Common
ethane (DCE), N,N-dimethylformamide (DMF), toluene,
acetone, n-hexane, dimethylacetamide (DMA), 1,4-diox-
ane, and dimethylsulfoxide (DMSO), THF proved to be
bases such as potassium hydroxide and sodium hydroxide
in place of lithium hydroxide afforded the lactam 2a in
lower yield (45 and 60%, respectively). The superiority of
the most preferable (Table 1). Thus, the above reaction
lithium hydroxide over sodium hydroxide and potassium
conditions with mesitylenesulfonyl chloride and LiOH in
hydroxide is presumably due to its facile solubility in
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

1354
C. Ramalingan, Y.-T. Park
PAPER
OH
OH
Table 3 Synthesis of Amides 4a–i from Acyclic Ketoximes 3a–i
MSC, LiOH
O
N
N
THF, 60 °C, 6 h
NH
Entry Oxime
Time Amide
(h)
Yield
(%)
5
6 (10%)
OH
O
N
N
H
N
MSC, LiOH
NH
1
7.0
98
98
THF, 60 °C, 8 h
O
O
7a
8a (97%)
4a
3a
O
OH
Me
H
N
OH
Me
Me
MSC, LiOH
N
NH
2
7.0
THF, 60 °C, 8 h
Me
Me
Me
Me
4b
Me
3b E-isomer
Me
OH
E-isomer
Br
Br
N
H
N
7b
8b (86%)
3
4
8.5
83
92
Me
O
OH
MSC, LiOH
O
N
4c
3c E-isomer
NH
THF, 60 °C, 8 h
OH
Me
N
9
10 (53%)
H
N
Me
Scheme 2 Synthesis of lactams from five-, six- and seven-
membered carbocyclic ketoximes
8.5
O
Br
Br
4d
3d E/Z-isomer
(9.7:0.3)
OH
Similarly, a series of piperidin-4-one oximes (1b–f) was
smoothly transformed into their corresponding diaz-
epanone lactams (2b–f) in good yields (Table 2). The
NMR analyses confirmed that the diazepanone lactams
2b–f adopt chair conformations akin to 2a with the equa-
torial dispositions of all the alkyl and aryl substituents ex-
cept for 2e, in which one of the methyl groups on C-3
occupies the axial position (see the experimental section
for complete characterization). The effects of substituents
alpha to the oximino carbon of piperidin-4-one oxime on
the rearrangement were pronounced. For example, piperi-
din-4-one oximes with bulky groups such as isopropyl and
gem-dimethyl groups at the 3-position of the piperidine
ring provided the corresponding lactams in lower yields
(63% and 59% respectively; entries 4 and 5), while pipe-
ridin-4-one oxime without any substituent at the 3-posi-
tion of the piperidine ring afforded the corresponding
lactam in higher yield (83%; entry 6). Furthermore, the
more substituted, electron-rich carbon exclusively migrat-
ed; an observation that is consistent with the migration to
an electron-deficient species in analogy to the classical
Beckmann rearrangement.
Cl
Cl
N
H
N
Me
5
6
14.0
85
89
Me
O
4e
3e E-isomer
Me
OH
Me
O
O
N
H
N
Me
12.0
Me
O
3f E-isomer
4f
OH
Me
O
N
Me
H
O
N
Me
Me
7
7.5
85
O
3g E/Z-isomer
4g
(9.8:0.2)
OH
Me
H
N
N
Me
8
9
10.0
98
76
O
O
O
Me
Me
The compatibility of this method with various types of
oximes, such as acyclic ketoximes and carbocyclic ket-
oximes, which include five-, six- and seven-membered
rings, has been investigated under the optimal conditions
(Scheme 2 and Table 3). All the unsymmetrical ket-
oximes used in this investigation possess E-geometric
configuration except 3d and 3g, which possessed mainly
E-isomers with a small amount of their Z-isomers (3% and
2%, respectively) as minor components. Acyclic ket-
oximes without substituents on the aryl moieties cleanly
underwent the Beckmann rearrangement with yields of
4h
3h E-isomer
OH
I
I
N
H
N
Me
Me
10.0
O
4i
3i E-isomer
THF proved optimal for the conversion of piperidin-4-one
oxime 1a into its corresponding lactam 2a.
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

PAPER
One-Pot Beckmann Rearrangement of Ketoximes Using Mesitylenesulfonyl Chloride
1355
Li +
O–
R
Me
Me
O
N
Me
O
Me
Cl
R
S
R1
O
OH
N
Me
N
S
O
+ H2O
+ LiCl
+ LiOH
R1
Me
O
R1
R
O– Li +
11
N
13
R1
O
Me
R
S
12
O-
O
HO–
Me
R1
Me
14
R
N
R
O
R
NH
R1
N
+
HO
R1
17
16
15
Scheme 3 Mechanism for the Beckmann rearrangement
~98% (entries 1 and 2). However, acyclic ketoximes with A general schematic representation for a plausible mech-
ortho substituents on the aryl moieties provided the anism of Beckmann rearrangement is depicted in
amides in yields of around 10–22% lower than that of the Scheme 3.
unsubstituted analogue (entries 3, 5, 6 and 9). Among the
The intermediate, E-(2RS,3SR,6SR)-1,3-dimethyl-2,6-
para-substituted aryl oximes, the one with an electron-
diphenylpiperidin-4-one oxime mesitylenesulfonate (13a)
withdrawing group afforded the amide in a yield 6% low-
was isolated at lower temperature (2 °C) because of its in-
er than that of the unsubstituted counterpart (entry 4),
stability at the optimized reaction temperature (see the ex-
whereas the oxime with an electron-donating group gave
1
perimental section for the detailed procedure). In the H
the amide in a yield akin to that of the unsubstituted aryl
NMR spectrum of this intermediate, the signal for the
oxime (entry 8). In the case of unsymmetrical acyclic ket-
equatorial proton on C-5 was observed at an unusual
oximes, exclusive migrations of electron-rich phenyl
downfield region compared to the protons on C-2 and C-
groups over alkyl groups occurred (Table 3).
6, as in the case of its corresponding oxime 1a, due to the
Although the conversions of cyclohexanone oxime (7a), 1,3-spatial proximity effect. This would imply that 13a
2-tert-butylcyclohexanone oxime (7b), and cyclohep- also possess E (anti) geometric configuration akin to that
tanone oxime (9) furnished their corresponding lactams in of its corresponding oxime 1a. The presence of one of the
good to excellent yields under the optimal conditions, the intermediates in the reaction, (2RS,3SR,6SR)-1,3-dimeth-
conversion of cyclopentanone oxime (5) into its corre- yl-2,6-diphenylpiperidin-4-one
oxime
mesitylene-
sponding lactam was not as efficient (Scheme 2). For this sulfonate, with E-geometry, supports the proposed
rearrangement, neither changing to solvents such as DMF mechanism.
or acetonitrile nor changing the LiOH concentration gave
In conclusion, the synthesis of diazepan-5-ones from their
significantly improved yields. Other reactions of the
corresponding piperidin-4-one oximes through in situ
strained cyclopentanone oxime 5 probably competed with
generation of oxime mesitylenesulfonates has efficiently
been accomplished. The one- and two-dimensional NMR
the rearrangement since, although the rearrangement yield
was low, the reactant disappeared completely. The recent
analyses show that the conformation of all the diazepan-
liquid-phase methodologies that have been developed,
5-ones 2a–f is chair, in which all the alkyl and aryl substit-
uents occupy equatorial positions, except diazepanone 2e,
in which one of the methyl groups at C-3 occupies the ax-
such as the use of rhodium complex2 and cyanuric chlo-
ride,3a,b were examined for the rearrangement of cyclo-
pentanone oxime, however, neither approaches provided
ial position. This method has led to the syntheses of vari-
the corresponding lactam. The use of an equimolar
ous amides and lactams from both acyclic and cyclic
amount of cyanuric chloride in DMF (cyanuric chloride–
oximes, reflecting its versatility.
DMF complex)3a afforded only trace amounts of the pipe-
ridin-2-one lactam (<5% yield). Tamura et al.15 achieved
All reagents were purchased as reagent grade and were used without
further purification. All solvents were distilled prior to use. Thin-
layer chromatography (TLC) was performed on Silica gel 60 F
plates eluted with the solvents indicated. Flash column chromatog-
the synthesis of piperidin-2-one lactam (6) in good yield
(81%) directly from cyclopentanone via its oxime mesity-
lenesulfonate by condensing o-mesitylenesulfonyl hy-
droxylamine with cyclopentanone, followed by
Beckmann rearrangement. In the case of the unsymmetri-
cal cyclic system 7b, the bulky and electron-rich group
exclusively migrated to the nitrogen terminus of the
oxime.
raphy was performed on Silica gel 230–400 mesh slurry packed in
glass columns with the eluent systems indicated. All the reported
melting points were measured in open capillaries and are uncorrect-
1
ed. H NMR spectra were acquired at 400 MHz or 300 MHz, and
13C NMR spectra were acquired at 100 MHz and 75 MHz using
CDCl3 or DMSO-d6 as solvents (25 °C), on Bruker Avance 400 and
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

1356
C. Ramalingan, Y.-T. Park
PAPER
Varian 300 instruments. GC-MS were performed on an HP6890 and
Agilent 5973N MSD instrument. IR spectra were recorded on a
Mattson Galaxy 7020A FTIR spectrometer. Elemental analyses
were obtained using a FISONE EA1106 instrument.
(2RS,3SR,7SR)-3-Ethyl-1-methyl-2,7-diphenyl[1,4]diazepan-5-
one (2c, Table 2, Entry 3)
Mp 183–184 °C.
IR (KBr): 3203, 3082, 3030, 2982, 2795, 2787, 1664, 1492, 1453,
1427, 1365, 1303, 1173, 1117, 1027 cm–1.
Rearrangement of Ketoximes into Lactams/Amides; General
Procedure
1H NMR (400 MHz, CDCl3): d = 7.41–7.24 (m, 10 H, ArH), 6.24
[br d, 1 H, N(4)H], 3.73–3.68 (m, 1 H, H-3ax), 3.65 (d, J = 11.0 Hz,
1 H, H-7ax), 3.24 (d, J = 6.5 Hz, 1 H, H-2ax), 3.28 (dd, J = 10.9, 14.7
Hz, 1 H, H-6ax), 2.46 (d, J = 14.6 Hz, 1 H, H-6eq), 1.77 [s, 3 H,
C(1)CH3], 1.07–0.96 (m, 2 H, CH2CH3), 0.80 (t, J = 7.3 Hz, 3 H,
CH2CH3).
13C NMR (100 MHz, CDCl3): d = 175.3 (C-5), 146.4, 142.9 (2 ×
Cipso), 128.8, 128.6, 128.0, 127.5, 127.1, 126.4 (6 × Ar), 76.6 (C-2),
66.5 (C-7), 58.1 (C-3), 45.2 (C-6), 44.4 [C(1)CH3], 26.4 (CH2CH3),
10.5 (CH2CH3).
To a solution of oxime (1.5 mmol) in THF (4 mL) in a two-necked
flask equipped with reflux condenser and addition funnel under ni-
trogen atmosphere, was added LiOH (1.8 mmol). After being stirred
for 30 min at r.t., a solution of mesitylenesulfonyl chloride (1.5
mmol) in THF (4 mL) was added and stirring was continued for 1 h
at ambient temperature followed by 60 °C until the reaction was
complete (monitored by TLC). The reaction was allowed to cool
and quenched by addition of H2O (10 mL). The solvents were re-
moved under reduced pressure and then H2O (15 mL) and Et2O (15
mL) were added. The organic phase was separated and the aqueous
phase was extracted with Et2O (2 × 15 mL). The combined organic
phases were washed with brine (2 × 10 mL), dried over Na2SO4 and
filtered. The crude product obtained after evaporation of the filtrate
was purified by flash column chromatography (CH2Cl2–MeOH,
100:2) to provide the lactam/amide.
GC-MS: m/z (%) = 308 [M+], 293, 279, 251, 222, 208, 190, 160,
131, 120 (100), 104, 91, 77, 68, 58, 42, 30.
Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C,
77.78; H, 8.02; N, 9.16.
(2RS,3SR,7SR)-3-Isopropyl-1-methyl-2,7-diphenyl[1,4]diaz-
epan-5-one (2d, Table 2, Entry 4)
Mp 178–179 °C.
(2RS,3SR,7SR)-1,3-Dimethyl-2,7-diphenyl[1,4]diazepan-5-one
(2a, Table 2, Entry 1)
Mp 190–191 °C.
IR (KBr): 3222, 3086, 3029, 2969, 2884, 2798, 2782, 1670, 1490,
1454, 1418, 1360, 1297, 1262, 1132, 1076, 1013 cm–1.
IR (KBr): 3203, 3083, 3027, 2976, 2910, 2844, 2810, 2793, 2779,
1672, 1601, 1492, 1442, 1421, 1356, 1327, 1275, 1227, 1173, 1138,
1116, 1083 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.61–7.23 (m, 10 H, ArH), 6.07
[br s, 1 H, N(4)H], 3.95–3.90 (m, 1 H, H-3ax), 3.65 (d, J = 11.0 Hz,
1 H, H-7ax), 3.29 (dd, J = 10.9, 14.6 Hz, 1 H, H-6ax), 3.20 (d, J = 8.5
Hz, 1 H, H-2ax), 2.49 (d, J = 14.6 Hz, 1 H, H-6eq), 1.79 [s, 3 H,
N(1)CH3], 0.75 [d, J = 6.8 Hz, 3 H, C(3)CH3].
1H NMR (400 MHz, CDCl3): d = 7.41–7.26 (m, 10 H, ArH), 5.76
[br d, 1 H, N(4)H], 3.78–3.74 (m, 1 H, H-3ax), 3.66 (d, J = 10.5 Hz,
1 H, H-7ax), 3.36 (d, J = 9.0 Hz, 1 H, H-2ax), 3.27 (dd, J = 11.1, 18.4
Hz, 1 H, H-6ax), 2.49 (d, J = 18.6 Hz, 1 H, H-6eq), 1.77 [s, 3 H,
C(1)CH3], 1.39–1.32 [m, 1 H, CH(CH3)2], 0.86 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 0.80 (d, J = 6.5 Hz, 3 H, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 175.3 (C-5), 146.4, 142.7
(2 × Cipso), 128.8, 128.6, 128.0, 127.5, 127.1, 126.4 (6 × Ar), 74.6
(C-2), 66.4 (C-7), 60.9 (C-3), 45.2 (C-6), 44.3 [C(1)CH3], 28.8
[CH(CH3)2], 21.2, 14.2 [2 × CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 174.9 (C-5), 146.3, 143.1 (2 ×
Cipso), 128.8, 128.6, 127.8, 127.5, 127.1, 126.4 (Ar), 77.6 (C-2),
66.2 (C-7), 52.1 (C-3), 45.2 (C-6), 44.4 [C(1)CH3], 21.0 [C(3)CH3].
GC-MS: m/z (%) = 322 [M+], 307, 279, 261, 251, 231, 222, 208,
GC-MS: m/z (%) = 294 [M+], 281, 222, 207, 191, 176, 165, 146,
194, 175, 160, 146, 131, 120 (100), 104, 91, 77, 65, 55, 42, 30.
131, 120 (100), 104, 91, 77, 65, 56, 44, 32.
Anal. Calcd for C21H26N2O: C, 78.22; H, 8.14; N, 8.69. Found: C,
78.02; H, 8.28; N, 8.78.
Anal. Calcd for C19H22N2O: C, 77.51; H, 7.53; N, 9.52. Found: C,
77.28; H, 7.84; N, 9.52.
(2RS,7SR)-1,3,3-Trimethyl-2,7-diphenyl[1,4]diazepan-5-one
(2e, Table 2, Entry 5)
Mp 198–199 °C.
(2RS,3SR,6RS,7SR)-1,3,6-Trimethyl-2,7-diphenyl[1,4]diaz-
epan-5-one (2b, Table 2, Entry 2)
Mp 197–198 °C.
IR (KBr): 3207, 3082, 3028, 2982, 2883, 2798, 2780, 1675, 1490,
1418, 1327, 1302, 1223, 1114, 1027 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44–7.22 (m, 10 H, ArH), 6.18
[br s, 1 H, N(4)H], 3.56 (d, J = 12.0 Hz, 1 H, H-7ax), 3.40 (s, 1 H, H-
2ax), 3.39–3.32 (m, 1 H, H-6ax), 2.53–2.45 (m, 1 H, H-6eq), 1.75 [s,
3 H, C(1)CH3], 1.74 [s, 3 H, C(3)CH3(ax)], 0.88 [s, 3 H, C(3)CH3(eq)].
13C NMR (100 MHz, CDCl3): d = 174.4 (C-5), 146.6, 142.3
(2 × Cipso), 128.8, 128.7, 128.2, 127.4, 127.1, 126.4 (6 × Ar), 80.8
(C-2), 67.8 (C-7), 54.5 (C-3), 45.8 (C-6), 45.7 [C(1)CH3], 32.9
[C(3)CH3(ax)], 22.6 [C(3)CH3(eq)].
IR (KBr): 3223, 3094, 3023, 2997, 2985, 2937, 2916, 2851, 2792,
2784, 1673, 1453, 1409, 1381, 1355, 1318, 1293, 1180, 1111, 1085,
1067 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.20 (m, 10 H, ArH), 5.84
[br d, 1 H, N(4)H], 4.10–3.98 (m, 1 H, H-3ax), 3.40 (d, J = 9.6 Hz,
1 H, H-7ax), 3.35–3.28 (m, 1 H, H-6ax), 3.22 (d, J = 9.0 Hz, 1 H, H-
2ax), 1.80 [s, 3 H, N(1)CH3], 0.77 [d, J = 6.6 Hz, 3 H, C(3)CH3],
0.64 [d, J = 6.6 Hz, 3 H, C(6)CH3].
13C NMR (75 MHz, CDCl3): d = 177.3 (C-5), 143.9, 143.4 (2 ×
Cipso), 128.5, 128.3, 128.1, 127.8, 127.4, 127.1 (6 × Ar), 77.6 (C-2),
71.5 (C-7), 51.0 (C-3), 44.8 [C(1)CH3], 41.6 (C-6), 20.7 [C(3)CH3],
15.4 [C(6)CH3].
GC-MS: m/z (%) = 308 [M+], 294, 275, 265, 251, 235, 222, 208,
194, 174, 165, 152, 141, 131, 120, 106 (100), 91, 77, 68, 58, 42, 30.
GC-MS: m/z (%) = 308 [M+], 291, 279, 265, 250, 236, 220, 208,
194, 186, 175, 165, 153, 145, 134, 120 (100), 112, 103, 91, 77, 65,
51.
Anal. Calcd for C20H24N2O: C, 77.88; H, 7.86; N, 9.09. Found: C,
77.69; H, 8.00; N, 9.13.
(2RS,7SR)-1-Methyl-2,7-diphenyl[1,4]diazepan-5-one (2f, Ta-
ble 2, Entry 6)
Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C,
77.78; H, 8.04; N, 9.17.
Mp 163–164 °C.
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

PAPER
One-Pot Beckmann Rearrangement of Ketoximes Using Mesitylenesulfonyl Chloride
1357
IR (KBr): 3230, 3086, 3032, 2846, 2796, 2788, 1705, 1490, 1453,
1422, 1354, 1330, 1261, 1141, 1114, 1075 cm–1.
7-tert-Butylazepan-2-one (8b, Scheme 2)22
1H NMR (400 MHz, CDCl3): d = 5.68 (br s, 1 H), 3.03 (dd, J = 9.5,
6.0 Hz, 1 H), 2.52 (dt, J = 2.2, 12.8 Hz, 1 H), 2.45–2.40 (m, 1 H),
2.04–2.00 (m, 1 H), 1.97–1.92 (m, 1 H), 1.90–1.85 (m, 1 H), 1.60–
1.45 (m, 2 H), 1.27–1.18 (m, 1 H), 0.96 (s, 9 H).
1H NMR (400 MHz, CDCl3): d = 7.44–7.23 (m, 10 H, ArH), 6.34
[br s, 1 H, N(4)H], 3.74–3.70 (m, 1 H, H-3ax), 3.60 (d, J = 10.8 Hz,
1 H, H-7ax), 3.46 (d, J = 9.0 Hz, 1 H, H-2ax), 3.27 (dd, J = 10.8, 14.5
Hz, 1 H, H-6ax), 3.12–3.06 (m, 1 H, H-3eq), 2.51 (d, J = 14.6 Hz,
1 H, H-6eq), 1.82 [s, 3 H, C(1)CH3].
13C NMR (100 MHz, CDCl3): d = 175.8 (C-5), 145.8, 143.2 (2 ×
Cipso), 128.9, 128.8, 127.6, 127.2, 126.8, 126.6 (6 × Ar), 72.4 (C-2),
66.1 (C-7), 49.2 (C-3), 45.3 (C-6), 43.8 [C(1)CH3].
Azocan-2-one (10, Scheme 2)21
1H NMR (400 MHz, CDCl3): d = 7.28 (br s, 1 H), 3.36–3.34 (m,
2 H), 2.44 (t, J = 6.5 Hz, 2 H), 1.93–1.86 (m, 2 H), 1.82–1.79 (m,
2 H), 1.63–1.58 (m, 2 H), 1.55–1.49 (m, 2 H).
GC-MS: m/z (%) = 280 [M+], 252, 222, 207, 177, 162, 133, 120
(100), 104, 91, 77, 65, 44, 32.
E-(2RS,3SR,6SR)-1,3-Dimethyl-2,6-diphenylpiperidin-4-one
Oxime Mesitylenesulfonate (13a)
To a stirred mixture of piperidin-4-one oxime 1a (440 mg, 1.50
mmol) and LiOH (72 mg, 3.00 mmol) in THF (6 mL) cooled to
about –35 °C for 30 min, was added a solution of mesitylenesulfo-
nyl chloride (492 mg, 2.25 mmol) in THF (6 mL). The solution was
stirred at –35 °C for 1 h and then at ~2 °C for 6 h. The mixture was
allowed to reach r.t. and then poured into ice-cold water. After stir-
ring the mixture for a few minutes, a white solid was produced.
Crystallization (MeOH) yielded pure 13a.
Anal. Calcd for C18H20N2O: C, 77.11; H, 7.29; N, 9.99. Found: C,
76.90; H, 7.43; N, 9.92.
N-Phenylbenzamide (4a, Table 3, Entry 1)16
1H NMR (400 MHz, CDCl3): d = 7.91 (br s, 1 H), 7.85–7.83 (m,
2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.54–7.49 (m, 1 H), 7.46–7.43 (m,
2 H), 7.36–7.32 (m, 2 H), 7.14–7.11 (m, 1 H).
N-Phenylacetamide (4b, Table 3, Entry 2)3b
1H NMR (400 MHz, CDCl3): d = 8.44 (br s, 1 H), 7.50 (d, J = 8.5
Hz, 2 H), 7.25 (t, J = 7.8 Hz, 2 H), 7.05 (t, J = 7.2 Hz, 1 H), 2.09 (s,
3 H).
Yield: 680 mg (95%); mp 149–150 °C.
1H NMR (400 MHz, CDCl3): d = 7.43–7.28 (m, 10 H, ArH), 7.00
(s, 2 H, ArH), 3.47 (t, J = 12.6 Hz, 1 H, H-5eq), 3.20 (d, J = 8.0 Hz,
1 H, H-6ax), 2.86–2.83 (m, 1 H, H-2ax), 2.71 (s, 1 H, H-3ax), 2.67 (s,
6 H, 2 × o-CH3), 2.34 (s, 3 H, p-CH3), 2.30 (s, 1 H, H-5ax), 1.70 [s,
3 H, C(1)CH3], 0.69 [d, J = 6.0 Hz, 3 H, C(3)CH3].
13C NMR (100 MHz, CDCl3): d = 167.8 (C-4), 143.7, 142.3, 141.1,
140.1, 139.2, 137.5, 131.9, 131.3, 131.1, 129.2, 129.0, 128.4, 128.1,
127.8, 127.5 (Ar), 69.6 (C-2), 68.4 (C-6), 44.1 (C-3), 41.6
[C(1)CH3], 36.6 (C-5), 23.3 (2 × o-CH3), 21.5 (p-CH3), 12.5
[C(3)CH3].
N-(2-Bromophenyl)acetamide (4c, Table 3, Entry 3)17
1H NMR (400 MHz, CDCl3): d = 8.31 (d, J = 8.5 Hz, 1 H), 7.68 (br
s, 1 H), 7.54 (dd, J = 8.0, 1.5 Hz, 1 H), 7.31 (dt, J = 1.3, 8.0 Hz,
1 H), 6.99 (t, J = 7.3 Hz, 1 H), 2.25 (s, 3 H).
N-(4-Bromophenyl)acetamide (4d, Table 3, Entry 4)18
1H NMR (400 MHz, DMSO-d6): d = 10.04 (br s, 1 H), 7.55 (d,
J = 8.5 Hz, 2 H), 7.46 (d, J = 9.0 Hz, 2 H), 2.03 (s, 3 H).
GC-MS: m/z (%) = 357 [M+ – mesityl], 341 [sulfoxy oxime], 275
(100) [iminopiperidine], 184 [M+ – mesitylsulfonyl], 325, 311, 261,
234, 217, 199, 185, 171, 156, 142, 129, 115, 91, 77, 63, 42.
N-(2-Chlorophenyl)acetamide (4e, Table 3, Entry 5)19
1H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 8.0 Hz, 1 H), 7.65 (br
s, 1 H), 7.35 (dd, J = 8.0, 1.5 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.03 (t,
J = 7.3 Hz, 1 H), 2.23 (s, 3 H).
Anal. Calcd for C28H32N2O3S: C, 70.56; H, 6.77; N, 5.88. Found: C,
70.65; H, 6.70; N, 5.93.
N-(2-Methoxyphenyl)acetamide (4f, Table 3, Entry 6)3b
1H NMR (400 MHz, CDCl3): d = 8.36 (dd, J = 1.8, 7.8 Hz, 1 H),
7.77 (br s, 1 H), 7.08–6.93 (m, 2 H), 6.87 (dd, J = 1.8, 8.1 Hz, 1 H),
3.87 (s, 3 H), 2.21 (s, 3 H).
Acknowledgment
Financial support from Korea Research Foundation (KRF-2006-
005-J02401) is gratefully acknowledged.
N-(3-Methoxyphenyl)acetamide (4g, Table 3, Entry 7)3b
1H NMR (400 MHz, CDCl3): d = 7.75 (br s, 1 H), 7.29–7.17 (m,
2 H), 6.94 (d, J = 8.1 Hz, 1 H), 6.63 (dd, J = 2.1, 8.0 Hz, 1 H), 3.80
(s, 3 H), 2.17 (s, 3 H).
References
(1) (a) Gawley, R. E. Org. React. 1988, 35, 1. (b) Donaruma,
L. G.; Heldt, W. Z. Org. React. 1960, 11, 1.
(2) Arisawa, M.; Yamaguchi, M. Org. Lett. 2001, 3, 311.
(3) (a) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org.
Chem. 2002, 67, 6272. (b) Furuya, Y.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 11240.
(4) (a) Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett.
2002, 43, 2455. (b) Dongare, M. K.; Bhagwat, V. V.;
Ramana, C. V.; Gurjar, M. K. Tetrahedron Lett. 2004, 45,
4759. (c) Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.;
Suo, L. Tetrahedron Lett. 2004, 45, 3369. (d) Li, D.;Shi, F.;
Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671.
(e) Kusama, H.; Yamashita, Y.; Narasaka, K. Bull. Chem.
Soc. Jpn. 1995, 68, 373. (f) Narasaka, K.; Kitamura, M. Eur.
J. Org. Chem. 2005, 4505; and references cited therein.
N-(4-Methoxyphenyl)acetamide (4h, Table 3, Entry 8)3b
1H NMR (400 MHz, CDCl3): d = 7.38 (d, J = 9.0 Hz, 2 H), 7.06 (br
s, 1 H), 6.84 (d, J = 9.0 Hz, 2 H), 3.80 (s, 3 H), 2.15 (s, 3 H).
N-(2-Iodophenyl)acetamide (4i, Table 3, Entry 9)20
1H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.0 Hz, 1 H), 7.78 (d,
J = 8.0 Hz, 1 H), 7.46 (br s, 1 H), 7.34 (dt, J = 1.0, 7.8 Hz, 1 H),
6.85 (t, J = 7.5 Hz, 1 H), 2.24 (s, 3 H).
Piperidin-2-one (6, Scheme 2)21
1H NMR (400 MHz, CDCl3): d = 7.44 (br s, 1 H), 3.34–3.29 (m,
2 H), 2.36–2.32 (m, 2 H), 2.00–1.54 (m, 4 H).
Azepan-2-one (8a, Scheme 2)21
1H NMR (400 MHz, CDCl3): d = 7.46 (br s, 1 H), 3.21–3.16 (m,
2 H), 2.45–2.40 (m, 2 H), 1.75–1.71 (m, 2 H), 1.68–1.62 (m, 4 H).
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York

1358
C. Ramalingan, Y.-T. Park
PAPER
(5) (a) Ikushima, Y.; Hatakeda, K.; Sato, O.; Yokoyama, T.;
Arai, M. Angew. Chem. Int. Ed. 1999, 38, 2910.
proximity effect between the equatorial proton on C-5 and
the oxygen of the oxime (Refer to references 10 and 12 for
more details).
(b) Ikushima, Y.; Hatakeda, K.; Sato, M.; Sato, O.; Arai, M.
Chem. Commun. 2002, 19, 2208. (c) Boero, M.; Ikeshoji,
T.; Liew, C. C.; Terakura, K.; Parrinello, M. J. Am. Chem.
Soc. 2004, 126, 6280.
(12) Cope, A. C.; Cotter, R. J.; Roller, G. G. J. Am. Chem. Soc.
1955, 77, 3590.
(13) (a) Abraham, R. J.; Fisher, J.; Loftus, P. Introduction to
NMR Spectroscopy; John Wiley: New York, 1988, 45.
(b) Cooper, J. W. Spectroscopic Techniques for Organic
Chemists; John Wiley: New York, 1980, 45.
(14) (a) Katritzky, A. R. Advances in Heterocyclic Chemistry,
Vol. 36; Academic Press: New York, 1984, 42. (b) Trager,
W. F.; Lee, C. M.; Beckett, A. H. Tetrahedron 1967, 23,
365. (c) Wiewiorowski, M.; Skolik, J.; Krueger, P. J.
Tetrahedron 1968, 24, 5439.
(15) Tamura, Y.; Fujiwara, H.; Sumoto, K.; Ikeda, M.; Kita, Y.
Synthesis 1973, 215.
(16) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607.
(6) (a) Guo, S.; Deng, Y. Catal. Commun. 2005, 6, 225.
(b) Guo, S.; Du, Z.; Zhang, S.; Li, D.; Li, Z.; Deng, Y. Green
Chem. 2006, 8, 296.
(7) (a) Forni, L.; Fornasari, G.; Giordano, G.; Lucarelli, C.;
Katovic, A.; Trifiro, F.; Perri, C.; Nagy, J. B. Phys. Chem.
Chem. Phys. 2004, 6, 1842. (b) Ghiaci, M.; Abbaspur, A.;
Kalbasi, R. Appl. Catal., A 2005, 287, 83.
(8) Ramalingan, C.; Park, Y.-T. J. Org. Chem. 2007, 72, 4536.
(9) (a) Kelly, T. A.; McNeil, D. W.; Rose, J. M.; David, E.; Shih,
C. K.; Grob, P. M. J. Med. Chem. 1997, 40, 2430.
(b) Tucker, H.; Le Count, D. J. Comprehensive Heterocyclic
Chemistry II, Vol. 9; Newkome, G. R., Ed.; Elsevier:
Oxford, 1996, 151 and 1039. (c) Thurston, D. E. Molecular
Aspects of Anticancer Drug-DNA Interactions; The
Macmillan Press Ltd.: London, 1993, 54. (d) Thurston, D.
E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(17) Young, C. G.; Pauline, R.; Jenny, J.; Christian, M.; Carsten,
B. Org. Lett. 2004, 6, 3293.
(18) Chretien, J. M.; Zammattio, F.; Le Grognec, E.; Paris, M.;
Cahingt, B.; Montavon, G.; Quintard, J. P. J. Org. Chem.
2005, 70, 2870.
(10) Ramalingan, C.; Park, Y.-T.; Kabilan, S. Eur. J. Med. Chem.
2006, 41, 683; and references cited therein.
(19) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi,
Z. J. Am. Chem. Soc. 2006, 128, 7416.
(11) The E-oxime 1a adopts classical chair-conformation with
equatorial orientations of the phenyl groups on C-2 and C-6,
and the methyl group on C-3. Key evidence for the
orientation of the hydroxyl group of the oxime being anti (E)
to C-3 is the unusual downfield absorption of the equatorial
proton on C-5 compared to the absorptions of the protons on
C-2 and C-6 in the 1H NMR spectrum, due to the 1,3-spatial
(20) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
1998, 63, 7652.
(21) 1H NMR spectra were compared to those obtained from
corresponding authentic samples.
(22) Matallana, A.; Kruger, A. W.; Kingsbury, C. A. J. Org.
Chem. 1994, 59, 3020.
Synthesis 2008, No. 9, 1351–1358 © Thieme Stuttgart · New York