Synthesis of Quinolines and 2H-Dihydropyrroles by Nucleophilic Substitution at the Nitrogen Atom of Oxime Derivatives

Article abstract of DOI:10.1055/s-2003-42439

Isomerization of oxime derivatives was researched in detail to find out the methods for the syn-anti isomerization of O-substituted oximes. Based on these findings were developed simple methods for the preparation of aza-heterocycles from both stereoisomers of oximes. Quinolines were synthesized from β-aryl ketone oximes by treatment with trifluoroacetic anhydride and 4-chloranil. γ,δ-Unsaturated O-methoxyacetyloximes were transformed to 2H-dihydropyrroles by reaction with methoxy-acetic acid.

Full text of DOI:10.1055/s-2003-42439

FEATURE ARTICLE
2415
Synthesis of Quinolines and 2H-Dihydropyrroles by Nucleophilic Substitution
at the Nitrogen Atom of Oxime Derivatives
T
ransformationof Oxi
i
t
aza-H
e
s
terocyclesuru Kitamura, Masayuki Yoshida, Takashi Kikuchi, Koichi Narasaka*
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58006891.; E-mail: narasaka@chem.s.u-tokyo.ac.jp.
Received 2 June 2003
Abstract: Isomerization of oxime derivatives was researched in de-
tail to find out the methods for the syn-anti isomerization of O-sub-
stituted oximes. Based on these findings were developed simple
methods for the preparation of aza-heterocycles from both stereo-
isomers of oximes. Quinolines were synthesized from -aryl ketone
oximes by treatment with trifluoroacetic anhydride and 4-chloranil.
, -Unsaturated O-methoxyacetyloximes were transformed to 2H-
dihydropyrroles by reaction with methoxy-acetic acid.
Equation 3
Key words: nucleophilic substitution, oxime derivatives, quino-
lines, tetrahydroquinolines, 2H-dihydropyrroles
It was considered that both oximes stereoisomers can be
employed for the cyclization if the syn-anti isomerization
of oxime derivatives occurs under the cyclization condi-
tions. Actually, quinoline derivative 4 was obtained in
high yield from a 1:1 mixture of the syn- and anti- -aryl
ketone oximes 3 by treatment with tetrabutylammonium
perrhenate and trifluoromethanesulfonic acid,1 because
the oxime itself was easily isomerized under acidic condi-
tions (Equations 2 and 3).7,8 Although both stereoisomers
of oximes could be employed in this rhenium-catalyzed
cyclization, it is desirable to carry out the transformation
by employing common reagents under milder reaction
conditions.
To carry out a substitution at the sp2 nitrogen of the oxime,
it is necessary to convert the hydroxy group into an appro-
priate leaving group. As mentioned, isomerization of
oxime itself readily proceeds under acidic conditions,
whereas O-substituted oxime hardly isomerizes under
mild conditions.7–11 For example, 4-phenylbutan-2-one
oxime (5) isomerized by the treatment with trifluo-
romethanesulfonic acid, while the O-methyloxime 6 un-
derwent very little isomerization under the same
conditions (Scheme 1).
We have been engaged in the synthesis of aza-heterocy-
cles from oxime derivatives based on the substitution at
the sp2 nitrogen of oximes.1–3 That is, intramolecular nu-
cleophilic moieties such as active methine and aryl groups
attack the oxime nitrogen to give cyclization products as
shown in Equations 1,3 2, and 31 and these reactions were
revealed to proceed via SN2-type mechanism.1–4 Due to
the stereospecificity of SN2-type reaction, only the anti-
isomer5 of O-mesyloxime 1 was converted to imine 2
while the syn-isomer 1 was recovered under the same re-
action conditions.3 This stereospecificity, however, caus-
es a serious drawback in applying this reaction to organic
synthesis, because it is quite hard to prepare oxime deriv-
atives in a stereoselective manner.6
Equation 1
Equation 2
Scheme 1
O-Methyloxime 6 was found to isomerize by the com-
bined use of trifluoromethanesulfonic acid and a nucleo-
phile such as methanol-d4. As no substitution product
SYNTHESIS 2003, No. 15, pp 2415–2426
Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42439; Art ID: M02703SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3

2416
M. Kitamura et al.
FEATURE ARTICLE
such as O-(methyl-d3)oxime was obtained, isomerization
of O-methyloxime 6 occurred by protonation onto the
oxime nitrogen and the successive addition-elimination of
methanol (Equation 4).9c
O-Acyloximes were isomerized by the action of carboxy-
lic acid however this occurred slowly. The treatment of O-
acetyloxime anti-7 with benzoic acid caused the isomer-
ization at 80 °C in toluene, and the isomer ratio attained at
equilibrium after 6 hours was 3:1 (anti/syn). Probably, this
isomerization proceeds by addition-elimination of benzo-
ic acid to the imino group (Equation 5).
Equation 4
Biographical Sketches
Mitsuru Kitamura was born ance of Prof. K. Suzuki, he thetic Organic Chemical So-
in Takamatsu, Japan, in was appointed as a research ciety (2001). His research
1971 and received his BSc associate in Prof. Narasa- interests are the synthesis of
in 1994 and MSc in 1996 ka’s group at The University nitrogen heterocycles and
from Keio University. After of Tokyo. He received The the total synthesis of natural
receiving his PhD in 1999 Inoue Research Award for products.
from Tokyo Institute of Young Scientists (2000) and
Technology under the guid- a Toray Award of the Syn-
Masayuki Yoshida was born University of Tokyo, where K. Narasaka. He currently
in Nagoya, Japan in 1975. he received his BSc in 1998 works at the Research Insti-
He studied chemistry at De- and PhD in 2003 under the tute of Sankyo Co., Ltd.
partment of Chemistry, The under the guidance of Prof.
Takashi Kikuchi was born Tokyo and received his BSc under the guidance of Prof.
in Kumagaya, Japan in in 2002. He is currently K. Narasaka.
1980. He was trained as a studying as a graduate stu-
chemist at The University of dent at the same university
Koichi Narasaka was born a lecturer. His postdoctoral (France, 2001), Merck
in Miyagi, Japan, in 1944 work was with Prof. E. J. Schuchardt-Lectureship
and received his BSc in Corey at Harvard University (Germany, 2002), IAP Lec-
1967 from Tokyo Institute from 1975 to 1976. He was tureship (Columbia Univer-
of Technology. He received appointed to the position of sity,
USA,
2002),
his PhD in 1972 under the associate professor in 1978, Boehringer-Ingelheim Lec-
guidance of Prof. T. Mu- and has been a professor ture Award (University of
kaiyama. He became a re- since 1987. He received The Toronto, Canada, 2003).
search associate of the same Chemical Society of Japan His research interests are in
group in 1972, and then in Award for Young Chemists the area of development of
1975, moved with Prof. Mu- (1979), The Chemical Soci- new methods of organic
kaiyama to The University ety of Japan Award (2000), synthesis.
of Tokyo, where he became Louis
Pasteur
Medal
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

FEATURE ARTICLE
Transformation of Oximes to aza-Heterocycles
2417
Equation 5
Furthermore, O-acyloxime 8 having a more labile acyl
group such as trifluoroacetyl group, isomerized by treat-
ment with trifluoroacetic acid at room temperature to at-
tain at equilibrium, giving an anti/syn mixture of 3:1
(Equation 6). The isomerization of this labile O-acyl- Scheme 2 (CF3CO)2O-mediated cyclization of anti-9a
oxime is supposed to proceed not only by the above men-
tioned addition-elimination mechanism but also by the
the treatment of 9a with a mixture of trifluoroacetic anhy-
dride and 4-chloranil, resulted in smooth cyclization of
anti-9a, affording 11a in the same yield. The use of other
oxidants, such as 2,3-dichloro-5,6-dicyano-p-benzo-
quinone, 4-methylmorpholine N-oxide, MnO2, gave the
desired quinoline 11a in poor to moderate yields.
following pathways. As another observation, the treat-
ment of acetone O-chlorodifluoroacetyloxime with tri-
fluoroacetic acid resulted in the generation of a mixture of
acetone O-trifluoroacetyl- and O-chlorodifluoroacetyl-
oximes. This scrambling of the acyl groups indicated that
the isomerisation may also occur by SN2 substitution at
the oxime nitrogen with acids and/or acyl exchange,
through the formation of a mixed anhydride and the free
oxime.
Equation 6
Scheme 3
Based on these findings on the isomerization, we consid-
ered that treatment of a syn- and anti-mixture of -aryl
oxime with trifluoroacetic anhydride would generate the
O-trifluoroacetyloxime,1 in which the anti-isomer would
cyclize to quinoline through activation by O-protonation
of the acyl group. The remaining syn-isomer would be
isomerized to the anti-isomer by the trifluoroacetic acid
generated.
A plausible mechanism for this cyclization is shown in
Scheme 4. After trifluoroacetylation of the oxime 9a, nu-
cleophilic attack by the aryl moiety occurs onto the oxime
nitrogen to form azaspirotrienes. Then successive cyclo-
hexadienone-phenol-type rearrangement13 and oxidation
of the generated 3,4-dihydroquinoline 10 with 4-chloranil
yielded 11a.
To examine the above hypothesis, 4-(4-methoxyphenyl)
butan-2-one (E)-oxime (anti-9a), was treated with 3
equivalents of trifluoroacetic anhydride at room tempera-
ture (Scheme 2). The cyclization occurred as expected to
give quinoline 11a and 1,2,3,4-tetrahydroquinoline 12 in
26% and 10% yields, respectively, as the disproportionat-
ed products of the preliminary formed dihydroquinoline
10.12 By the analysis of the 1H and 13C NMR spectra of the
crude reaction mixture, 3,4-dihydroquinoline 10 was
found to be formed in 94% yield, whereas the isolated
yield of 11a and 12 was low. To obtain quinoline 11a in
good yield as a sole product, the conversion of 3,4-dihy-
droquinoline 10 into quinoline 11a by oxidation was ex-
amined.1
In fact, oxidation of the crude reaction mixture with 4-
chloranil gave quinoline 11a in 86% yield with a trace
amount of spiro compound 13 (Scheme 3). Furthermore,
Scheme 4 Plausible mechanism of formation of quinoline 11a
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

2418
M. Kitamura et al.
FEATURE ARTICLE
As explained above, anti-oxime anti-9a could be convert-
ed to quinoline 11a by the simple treatment with trifluoro-
acetic anhydride and 4-chloranil at room temperature.
Then, we examined the influence of the stereochemistry
of oximes on the cyclization. Because it was hard to iso-
late the syn-isomer of 9a in a pure form, we studied the cy-
clization of both the stereoisomers of m-methoxyphenylethyl
ketone oxime 9b (Scheme 5). From the anti-9b, 6-meth-
oxy-2-methylquinoline (11a) and 8-methoxy-2-meth-
ylquinoline (11b), which correspond to para- and ortho-
cyclization products, were obtained in 83% and 5%
yields, respectively. Even from the syn-9b, quinolines 11a
and 11b were also formed in 81% and 9% yield, respec-
tively. Thus the cyclization proceeds irrespective of the
stereochemistry of oximes, due to the isomerization of the
oxime 9b and the intermediate O-trifluoroacetyloxime,
under the reaction conditions.
Equation 8
Equation 9
the previous rhenium-trifluoromethanesulfonic acid
method.1b
Since it became apparent that both anti- and even syn-
oximes could be transformed to quinolines by this simple
procedure, the cyclization of several -aryl ketone oximes
was examined as shown in Table 1. p-Methyl and non-
substituted phenethyl ketone oximes anti-9e and 5 were
converted to the corresponding quinolines 11e and 11f in
refluxing 1,2-dichloro-ethane in 76% and 72% yields, re-
spectively (entries 1 and 2). Though the reaction of
oximes having acetamido and N,N-dimethylamino groups
on the -phenyl group, did not give fruitful results, benzy-
loxycarbonyl(methyl)amino derivative 9g was trans-
formed to the desired quinoline 11g in 72% yield (entry
3). The introduction of bromo substituent to methoxyphe-
nyl group led to a slowing down of the cyclization, but the
quinoline 11h was obtained in good yield (82%, entry 4).
Scheme 5 Influence of syn/anti-stereochemistry
Then secondary oxime 9c was prepared to confirm the
generality for the cyclization of sterically unfavorable
syn-isomers. This oxime exist almost exclusively in the
syn-form at equilibrium, due to steric repulsion. Though
the cyclization of syn-9c required refluxing in dichlo-
romethane, quinoline 11c was obtained in 77% yield
(Equation 6). And it is noteworthy that no Beckmann re-
arrangement product was detected, although the second-
ary alkyl ketone oxime readily undergoes the
rearrangement.
Table 1 Synthesis of Various Qunolines 11 from -Aryl Ketone
Oximes
Entry R1
R2
anti:syn Substrate Time
Yield
(%)
(h)
1a
Me
H
H
>99:<1 9e
24
24
24
48
77 (11e)
72 (11f)
72 (11g)
82 (11h)
2b,c
3d
H
>99:<1
3:2
5
CBzMeN
MeO
H
9g
9h
4e
Br
9:1
a Compound 14 (Figure 1) was obtained in 7%.
Equation 7
b 1,2-Dichloroethane was used as solvent at refluxing temperature.
c Beckmann rearrangement product 15 was obtained in 10% yield.
d Compound 13 was obtained in 5% yield.
The oxime of -keto ester 9d14 was also successfully
transformed to quinoline 11d at 40 °C in 82% yield
(Equations 8 and 9), which was obtained in poor yield in
e Compound 16 was obtained in 4% yield.
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

FEATURE ARTICLE
Transformation of Oximes to aza-Heterocycles
2419
Figure 1
Equation 11
Thus, the cyclization of -aryl ketone oximes proceeded
successfully, whereas aldoxime 17 did not cyclize but
gave nitrile 18 by Beckmann fragmentation
(Equation 10).15
, -Unsaturated ketone O-methoxyacetyl oxime 22a was
treated with methoxyacetic acid in refluxing 1,2-dichloro-
ethane to form the imine.16 The expected dihydropyrrole
23a having 2-methoxyacetoxymethyl group was obtained
in 22% yield with 2-methyldihydropyrrol 24, which was
formed by a radical process17 (Table 3, entry 1). In a polar
solvent like nitromethane at 70 °C, the reaction proceeded
smoothly by treatment with 10 equivalents of methoxy-
acetic acid, and the addition of 4 Å molecular sieves in-
creased the yield of 23a up to 83% (entries 2–4).
Equation 10
Table 3 Synthesis of dihydropyrrole 23a from oxime 22a
As described above, -aryl ketone oximes are transformed
to quinolines by reaction with trifluoroacetic anhydride
and 4-chloranil via the intermediate, 3,4-dihydroquino-
lines. Accordingly, it was expected that 1,2,3,4-tetrahyd-
roquinolines would be formed by the reduction of the
intermediate. In fact, treatment of -aryl ketone oximes 9a
and 9b with trifluoroacetic anhydride followed by the re-
duction with sodium cyanoborohydride in methanol af-
forded 1,2,3,4-tetrahydroquinoline 12 in 85% and 73%
yield, respectively (Table 2).
Entry Solvent
Temp
Additive Time Yield23aYield24
(h)
12
2
(%)
22
45
55
(%)
11
7
1
2
3
4
ClCH2CH2Cl reflux
–
Table 2 Synthesis of Tetrahydroqunoline 12 from -Aryl Oximes
CH3NO2
CH3NO2
CH3NO2
reflux
reflux
70 °C
–
MS 4 Å
2
7
MS 4 Å 24
83
5
Entry
Oxime 9
anti-9a
anti-9b
Time (h)a
Yield (%)
Because the cyclization proceeded via an SN2-type ionic
process, a chlorine atom could be introduced instead of
the acyloxy group by performing the reaction under mod-
ified conditions with CsCl and trifluoroacetic acid
(Equation 12).
1
17
24
85
73
2
a 1st step.
In the above quinoline synthesis, aryl groups play the role
as intramolecular nucleophiles for the cyclization. A sim-
ilar intramolecular substitution was attempted by intro-
ducing an olefinic moiety as a nucleophile instead of an
aryl group. , -Unsaturated ketone oxime 19 was treated
similarly with trifluoroacetic anhydride, we expected the
formation of cyclic imine 20 and/or 21 (Equation 11). We,
however, could not observe the formation of cyclic imine
20, which was found to react with trifluoroacetic anhy-
dride and decompose. Because the use of acid anhydride
has to be avoided for the preparation of cyclic imines, we
tried the cyclization starting from O-acyloximes of , -
unsaturated ketones.
Equation 12
The transformation proceeded with wide generality as
shown in Table 4. Various , -unsaturated O-methoxy-
acetyloximes 22 having a variety of olefinic moieties, ter-
minal mono- and di- -substituted, mono- and di- -
substituted, and terminal vinyl, were successfully con-
verted to the corresponding dihydropyrroles 23 in good
yields.
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

2420
M. Kitamura et al.
FEATURE ARTICLE
ridine (4.42 g, 54.0 mmol) were added, and the mixture was stirred
for 12 h at r.t. After removal of the solvent in vacuo, water was add-
ed, and organic materials were extracted with EtOAc. The com-
bined organic extracts were washed with brine and dried over
MgSO4. The solvent was removed under reduced pressure, and the
obtained solid was recrystallized from hexane–Et2O to afford 4-
phenylbutan-2-one (E)-oxime (2.46 g, 15.1 mmol) in 56% yield;
colorless crystals; mp 86 °C.
Table 4 Synthesis of Various Dihydropyrroles 23 from Oximes 22
IR (KBr): 3220, 1681, 1602, 1452, 1361, 950, 746, 698 cm–1.
1H NMR: = 1.91 (3 H, s), 2.51 (2 H, t, J = 8.2 Hz), 2.83 (2 H, t,
J = 8.2 Hz), 7.18–7.30 (5 H, m), 8.81 (1 H, br s).
13C NMR: = 13.8, 32.6, 37.7, 126.1, 128.3, 128.4, 141.0, 157.9.
Run R1
R2
H
R3
H
R4
H
Substrate Yield/%
1
2
3
4
PhCH2CH2
22a
22b
22c
22d
22e
83 (23a)
59 (23b)
72 (23c)a
72 (23d)b
88 (23e)
Anal. Calcd for C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C,
73.80; H, 8.11; N, 8.60.
PhCH2CH2
PhCH2CH2
Me
Me
H
H
H
Me
Ph
Me
H
4-Phenylbutan-2-one (Z)-Oxime (syn-5)
Colorless oil.
H
H
IR (ZnSe): 3215, 2864, 1662, 1603, 1495, 1454, 1377, 1038, 950,
746, 696 cm–1.
5c,d PhCH2CH2
H
Me
1H NMR: = 1.82 (3 H, s), 2.66–2.69 (2 H, m), 2.82–2.86 (2 H, m),
7.18–7.30 (5 H, m), 9.30 (1 H, br s).
13C NMR: = 20.2, 30.7, 31.4, 126.1, 128.3, 128.4, 141.2, 158.3.
a Diastereomer mixture (3:2).
b Single diastereomer.
c The reaction was carried out for 12 h.
d 2-isopropenyl-5-phenylethyl-3,4-Dihydro-2H-pyrrole (26) was
formed in 5% yield.
4-Phenylbutan-2-one (E)-O-Methyloxime (anti-6)
To a solution of 4-phenylbutan-2-one (1.48 g, 10.0 mmol) in MeOH
(20 mL), O-methylhydroxylamine hydrochloride (1.60 g, 20.0
mmol) and pyridine (1.58 g, 20.0 mmol) was added, and the mixture
was stirred for 12 h at r.t. After removal of the solvent in vacuo, wa-
ter was added, and organic materials were extracted with EtOAc.
The combined organic extracts were washed with brine and dried
over MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica gel
(hexane–EtOAc) to afford 4-phenylbutan-2-one (E)-O-methy-
loxime (0.76 g, 4.3 mmol) as less polar compounds than (Z)-oxime
in 43% yield; colorless oil.
In conclusion, convenient methods for the transforma-
tions of phenylethyl ketone oximes to quinolines and , -
unsaturated ketone O-methoxyacetyl oximes to dihydro-
pyrroles have been developed based on the intramolecular
SN2-type reaction. In these reactions, both stereoisomers
of oximes can be employed for the preparation of these
aza-heterocycles.
IR (ZnSe): 2937, 1637, 1603, 1454, 1367, 1052, 746, 698 cm–1.
1H NMR: = 1.85 (3 H, s), 2.47 (2 H, t, J = 8.0 Hz), 2.82 (2 H, t,
J = 8.0 Hz), 3.83 (3 H, s), 7.19–7.20 (3 H, m), 7.27–7.28 (2 H, m).
13C NMR: = 14.1, 32.9, 37.7, 61.1, 126.0, 128.3, 128.4, 141.1,
156.8.
1
IR spectra were recorded on Horiba FT-300S. H NMR spectra
were recorded with a Bruker Avance 500 (500 MHz) and a Bruker
DRX 500 (500 MHz) spectrometer. 13C NMR spectra were recorded
with a Bruker Avance 500 (125 MHz) and a Bruker DRX 500 (125
MHz) spectrometer. Chemical shift values were given in ppm rela-
tive to tetramethylsilane for H NMR and CDCl3 for 13C NMR.
1
Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C,
74.50; H, 8.58; N, 7.70.
High resolution mass spectra were taken with a JEOL JMS-700M
spectrometer. Melting points (mp) were uncorrected. Silica Gel 60
N (spherical, neutral) (Kanto Chemical) was used for column chro-
matography, and Wakogel® B-5F (Wako Pure Chemical Industries)
was used for preparative thin-layer chromatography. All the sol-
vents were stored over MS 4 Å after purification. Dichloromethane
and 1,2-dichloroethane were distilled from phosphorous pentoxide
and calcium hydride, successively. Toluene was dried over calcium
chloride and distilled after decantation. Nitromethane was distilled
from calcium chloride. Methanol-d4 (Aldrich) and chloroform-d
(Nippon Sanso) were used as received. Trifluoroacetic anhydride,
trifluoroacetic acid, and trifluoromethanesulfonic acid were dis-
tilled from phosphorous pentoxide before use. Benzoic acid (Tokyo
Chemical Industry) was used as received. Methoxyacetic acid was
distilled from calcium chloride. Triethylamine was distilled from
calcium hydride before use. 4-Chloranil was recrystallized from dry
toluene. Configurations of oximes (syn or anti) were determined by
the 13C NMR.18
4-Phenylbutan-2-one (Z)-O-Methyloxime (syn-6)
Colorless oil.
IR (ZnSe): 3336, 2937, 1768, 1602, 1454, 1377, 1058, 891, 746,
698 cm–1.
1H NMR: = 1.80 (3 H, s), 2.60 (2 H, t, J = 8.0 Hz), 2.79 (2 H, t,
J = 8.0 Hz), 3.81 (3 H, s), 7.19–7.21 (3 H, m), 7.27–7.30 (2 H, m).
13C NMR: = 20.2, 31.2, 31.6, 61.1, 126.0, 128.2, 128.4, 141.1,
157.5.
4-Phenylbutan-2-one (E)-O-Acetyloxime (anti-7)
To a solution of 4-phenylbutan-2-one (E)-oxime (1.63 g, 10.0
mmol) in CH2Cl2 (50 mL), Et3N (3.22 g, 30.0 mmol) and Ac2O
(2.17 g, 20.0 mmol) was added, and the mixture was stirred for 12
h at r.t. The reaction was quenched with sat. aq NaHCO3, and organ-
ic materials were extracted with EtOAc. The combined organic ex-
tracts were washed with brine and dried over MgSO4. The solvent
was removed under reduced pressure, and the residue was purified
by column chromatography on silica gel (hexane–EtOAc) to afford
4-Phenylbutan-2-one (E)-Oxime (anti-5)1b
To a solution of 4-phenylbutan-2-one (4.05 g, 27.0 mmol) in MeOH
(30 mL), hydroxylamine hydrochloride (3.80 g, 54.0 mmol) and py-
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

FEATURE ARTICLE
Transformation of Oximes to aza-Heterocycles
2421
4-phenylbutan-2-one (E)-O-acetyloxime (anti-7) (1.75 g, 8.53
mmol) in 85% yield; colorless oil.
IR (ZnSe): 3028, 1763, 1641, 1365, 1200, 912, 727, 698 cm–1.
1H NMR: = 1.99 (3 H, s), 2.21 (3 H, s), 2.63 (2 H, t, J = 8.1 Hz),
2.89 (2 H, t, J = 8.1 Hz), 7.21–7.30 (5 H, m).
(27 mL) was added, and the mixture was stirred for 1 d. After addi-
tion of water, organic materials were extracted with EtOAc. The
combined organic extracts were washed with brine and dried over
Na2SO4. The solvent was removed by evaporation, and the residue
was recrystallized from EtOH to afford 4-(3-methoxyphenyl)butan-
2-one (E)-oxime (9b) (2.60 g, 13.5 mmol) in 44% yield.
13C NMR: = 15.6, 19.5, 32.4, 37.4, 126.2, 128.1, 128.4, 140.2,
165.5, 166.7.
4-(4-Methoxyphenyl)butan-2-one (E)-Oxime (anti-9a)1b
Colorless crystals; mp 77 °C.
IR (KBr): 3240, 1678, 1610, 1512, 1242 cm–1.
Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C,
70.44; H, 7.59; N, 6.82.
1H NMR: = 1.91 (3 H, s), 2.47 (2 H, t, J = 8.5 Hz), 2.78 (2 H, t,
J = 8.5 Hz), 3.78 (3 H, s), 6.83 (2 H, d, J = 8.6 Hz), 7.11 (2 H, d,
J = 8.6 Hz), 8.72 (1 H, br s).
13C NMR: = 13.7, 31.7, 38.0, 55.2, 113.8, 129.2, 133.1, 157.9,
158.0.
4-Phenylbutan-2-one (Z)-O-Acetyloxime (syn-7)
Colorless oil.
IR (ZnSe): 3026, 1755, 1365, 1201, 914, 746, 698 cm–1.
1H NMR: = 1.98 (3 H, s), 2.11 (3 H, s), 2.71 (2 H, t, J = 7.6 Hz),
2.85 (2 H, t, J = 7.6 Hz), 7.18–7.32 (5 H, m).
4-(3-Methoxyphenyl)butan-2-one (E)-oxime (anti-9b)1b
Colorless crystals; mp 59 °C.
IR (KBr): 3240, 1603, 1493, 1259, 1169, 1039, 764, 700 cm–1.
13C NMR: = 19.5, 20.4, 31.8, 32.5, 126.4, 128.1, 128.3, 128.5,
140.0, 166.1.
1H NMR: = 1.92 (3 H, s), 2.51 (2 H, t, J = 8.1 Hz), 2.81 (2 H, t,
J = 8.1 Hz), 3.79 (3 H, s), 6.74–6.79 (3 H, m), 7.19–7.22 (1 H, m),
8.33 (1 H, br s).
13C NMR: = 13.7, 32.6, 37.6, 55.1, 111.4, 114.0, 120.6, 129.4,
142.7, 158.0, 159.6.
Isomerization of Oximes 5–7 (Scheme 1 or Equations 4, 5)
4-Phenylbutan-2-one (E)-oxime (5); Typical Procedure
To a solution of 4-phenylbutan-2-one (E)-oxime (15.3 mg, 0.104
mmol) in CH2Cl2 (0.75 mL), trifluoromethanesulfonic acid (31.2
mg, 0.208 mmol) was added at r.t., and the reaction was followed
by 1H NMR. After the reaction mixture was stirred for 2 h, the reac-
tion was quenched with sat. aq Na2CO3. Organic materials were ex-
tracted with EtOAc, and the combined organic extracts were dried
over MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by preparative thin-layer chromatography
(hexane–EtOAc, 3:1) to afford 4-phenylbutan-2-one oxime
(E/Z = 2:1) (14.7 mg, 0.101 mmol) in 97% yield.
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C,
68.49; H, 8.02; N, 7.04.
4-(3-Methoxyphenyl)butan-2-one (Z)-Oxime (syn-9b)
Colorless oil.
IR (ZnSe): 3217, 1660, 1601, 1583, 1489, 1257, 1151, 1038, 775,
692 cm–1.
1H NMR: = 1.92 (3 H, s), 2.50 (2 H, t, J = 8.1 Hz), 2.82 (2 H, t,
J = 8.1 Hz), 3.79 (3 H, s), 6.74–6.83 (3 H, m), 7.19–7.22 (1 H, m),
9.37 (1 H, br s).
13C NMR: = 20.2, 30.5, 31.4, 55.1, 111.4, 113.9, 120.6, 129.4,
142.8, 158.2, 159.6.
Isomerization of 4-Phenylbutan-2-one (E)-O-Trifluoroacetyl-
oxime (Equation 6)
To a solution of 4-phenylbutan-2-one (E)-oxime (11.8 mg, 0.0723
mmol) in CDCl3 (0.75 mL), Et3N (31 L, 0.22 mmol) and trifluoro-
acetic anhydride (31 L, 0.22 mmol) were added successively at r.t.,
and the mixture was left to stand for 30 min to generate 4-phenyl-
butan-2-one (E)-O-trifluoroacetyloxime in situ. Then trifluoroace-
tic acid (23 L, 0.30 mmol) was added to the mixture, the progress
of the reaction was followed 1H NMR.
1-(4-Methoxyphenyl)-4-methylpentan-3-one (E)-Oxime (syn-
9c)
Colorless crystals; mp 71–72 °C.
4-(3-Methoxyphenyl)butan-2-one (E)-oxime (9b); Typical Pro-
cedure
IR (KBr): 3248, 2964, 1612, 1510, 1244, 1176, 1036, 939, 806
cm–1.
1H NMR: = 1.08 (6 H, d, J = 6.9 Hz), 2.41 (1 H, septet, J = 6.9
Hz), 2.55 (2 H, t, J = 8.2 Hz), 2.83 (2 H, t, J = 8.2 Hz), 3.79 (3 H,
s), 6.84 (2 H, d, J = 8.7 Hz), 7.16 (2 H, d, J = 8.7 Hz), 8.14 (1 H, br
s).
To a solution of 3-methoxybenzaldehyde (6.80 g, 49.4 mmol) in ac-
etone (38 mL) was added 1 M aq NaOH (100 mL) dropwise over 30
min, and the mixture was stirred for 1 h. After neutralization with 6
M aq HCl, acetone was removed by evaporation. The remaining
aqueous layer was extracted with EtOAc, and the combined organic
extracts were washed with brine and dried over Na2SO4. The sol-
vent was removed under reduced pressure, and the residue was pu-
rified by column chromatography on silica gel (hexane–EtOAc) to
afford 4-(3-methoxyphenyl)-3-buten-2-one (7.22 g, 41.0 mmol) in
82% yield.
13C NMR: = 19.8, 29.3, 31.0, 33.9, 55.2, 113.8, 129.2, 134.0,
157.9, 165.0.
Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C,
70.37; H, 8.69; N, 6.11.
A suspension of 4-(3-methoxyphenyl)-3-buten-2-one (7.22 g, 41.0
mmol), 5% Pd/C (732 mg) and HOAc (ca 80 mg) in EtOH (40 mL)
was stirred under H2 atmosphere for 1 d. After purging the H2 with
argon, the reaction mixture was filtered through a celite pad. The
solvent was removed under reduced pressure, the residue was puri-
fied by column chromatography on silica gel (hexane–EtOAc) to
give 4-(3-methoxyphenyl)butan-2-one (5.36 g, 30.1 mmol) in 73%
yield.
Ethyl 2-Hydroxyimino-4-(4-methoxyphenyl)butyrate (9d)
Colorless crystals; mp 91–92 °C.
IR (ZnSe): 3228, 1724, 1610, 1512, 1441, 1246, 1194, 1007, 827,
766 cm–1.
1H NMR: = 1.31 (3 H, t, J = 7.1 Hz), 2.79 (2 H, t, J = 7.9 Hz), 2.89
(2 H, t, J = 7.9 Hz), 3.79 (3 H, s), 4.26 (2 H, q, J = 7.1 Hz), 6.84 (2
H, d, J = 11.5 Hz), 7.16 (2 H, d, J = 11.5 Hz), 9.54 (1 H, br s).
13C NMR: = 14.1, 27.0, 30.9, 55.2, 61.8, 113.8, 129.3, 132.9,
152.5, 158.0, 163.3.
To a solution of 4-(3-methoxyphenyl)butan-2-one (5.42 g, 30.4
mmol) in EtOH (57 mL), a solution of hydroxylamine hydrochlo-
ride (4.22 g, 60.7 mmol) and pyridine (4.96 g, 62.7 mmol) in EtOH
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

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M. Kitamura et al.
FEATURE ARTICLE
Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C,
62.23; H, 6.77; N, 5.51.
stirred for 1 h. The mixture was extracted with CH2Cl2, and the
combined organic extracts were washed with brine and dried over
Na2SO4. Na2SO4 was filtered off, and the solvent was removed un-
der reduced pressure. The residue was purified by preparative thin-
layer chromatography (silica gel, hexane–EtOAc, 1:1) to afford 6-
methoxy-2-methylquinoline 11a (73.4 mg, 42.4 mmol) in 86%
yield.
4-(4-Methyphenyl)butan-2-one (E)-Oxime (anti-9e)
Colorless crystals; mp 90–92 °C.
IR (ZnSe): 3228, 2925, 1676, 1512, 1367, 1211, 951, 862, 810, 754,
644 cm–1.
1H NMR: = 1.91 (3 H, s), 2.31 (3 H, s), 2.48 (2 H, t, J = 8.2 Hz),
2.79 (2 H, t, J = 8.2 Hz), 7.07–7.09 (4 H, m), 8.05 (1 H, br s).
6-Methoxy-2-methylquinoline (11a)1b
Colorless crystal; mp 65 °C.
13C NMR: = 13.7, 21.0, 32.2, 37.9, 128.1, 129.1, 135.6, 138.0,
158.0.
IR (KBr): 2964, 1624, 1603, 1498, 1238, 1113, 1030, 879 cm–1.
1H NMR: = 2.69 (3 H, s), 3.88 (3 H, s), 7.00 (1 H, d, J = 2.8 Hz),
7.20 (1 H, d, J = 8.4 Hz), 7.32 (1 H, dd, J = 2.8, 9.2 Hz), 7.90 (1 H,
d, J = 8.4 Hz), 7.91 (1 H, d, J = 9.2 Hz).
Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C,
74.57; H, 8.63; N, 7.81.
13C NMR: = 24.9, 55.3, 105.1, 121.7, 122.1, 127.2, 129.9, 134.9,
143.7, 156.2, 157.0.
Benzyl N-[4-(3-Hydroxyiminobutyl)phenyl]-N-methylcarbam-
ate (9g)
Colorless crystal; mp 63–65 °C; E/Z = 2:1.
IR (ZnSe): 3365, 2920, 1699, 1684, 1689, 1514, 1346, 1149 cm–1.
8-Methoxy-2-methylquinoline (11b)1b
Colorless crystal; mp 117–119 °C.
1H NMR: = 1.81 (1 H, s), 1.91 (2 H, s), 2.50 (1.3 H, t, J = 8.4 Hz),
2.66 (0.7 H, t, J = 8.4 Hz), 2.81 (2 H, t, J = 8.4 Hz), 3.30 (3 H, s),
5.15 (2 H, s), 7.16–7.29 (9 H, m), 8.86 (1 H, br s).
13C NMR: = 13.7, 20.3, 30.5, 30.9, 32.0, 37.5, 37.8, 67.2, 125.7,
127.6, 127.8, 128.3, 128.7, 128.8, 136.6, 139.0, 139.1, 141.2, 155.5,
157.6, 158.1.
IR (KBr): 2960, 1603, 1263, 1111, 1074 cm–1.
1H NMR: = 2.80 (3 H, s), 4.08 (3 H, s), 7.04 (1, dd, J = 1.4, 7.5
Hz), 7.32 (1 H, d, J = 8.5 Hz), 7.35 (1 H, dd, J = 1.4, 7.8 Hz), 7.40
(1 H, dd, J = 7.5, 7.8 Hz), 8.02 (1 H, J = 8.5 Hz).
13C NMR: = 25.7, 56.0, 107.6, 119.4, 122.6, 125.7, 127.5, 136.1,
139.7, 154.8, 158.1.
Anal. Calcd for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58. Found: C,
70.12; H, 6.93; N, 8.47.
2-Isopropyl-6-methoxyquinoline (11c)
Colorless oil.
4-(3-Bromo-4-methoxyphenyl)butan-2-one Oxime (9h)
IR (KBr): 2962, 1624, 1601, 1500, 1464, 1379, 1163, 1031, 933
cm–1.
1H NMR: = 1.38 (6 H, d, J = 6.9 Hz), 3.88 (3 H, s), 3.22 (1 H, sep-
tet, J = 6.9 Hz), 7.01 (1 H, d, J = 2.9 Hz), 7.25 (1 H, d, J = 8.5 Hz),
7.33 (1 H, dd, J = 2.9, 9.2 Hz), 7.95 (1 H, d, J = 9.2 Hz), 7.95 (1 H,
J = 8.5 Hz).
Colorless crystal; mp 76–84 °C; E/Z = 9:1.
IR (ZnSe): 3224, 3116, 2943, 1604, 1495, 1281, 1254, 1053, 806,
725 cm–1.
1H NMR: = 1.82 (0.3 H, s), 1.91 (2.7 H, s), 2.47 (1.8 H, t, J = 8.1
Hz), 2.62 (0.2 H, t, J = 8. 1 Hz), 2.76 (2 H, t, J = 8.1 Hz), 3.86 (3 H,
s), 6.81 (1 H, d, J = 8.4 Hz), 7.08 (0.9 H, dd, J = 2.2, 8.4 Hz), 7.09
(0.1 H, dd, J = 2.2, 8.4 Hz), 7.38 (0.9 H, d, J = 2.2 Hz), 7.42 (0.1 H,
d, J = 2.2 Hz), 8.91 (1 H, br s).
13C NMR: = 22.5, 36.9, 55.3, 105.0, 119.2, 121.6, 127.6, 130.3,
135.1, 143.6, 157.0, 165.0.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.52; H, 7.46; N, 6.87.
13C NMR: = 13.8, 20.3, 30.3, 30.7, 31.3, 37.7, 56.2, 111.5, 111.9,
128.2, 133.0, 134.6, 154.2, 157.6.
Anal. Calcd for C11H14BrNO2: C, 48.55; H, 5.19; N, 5.15. Found: C,
48.72; H, 5.28; N, 4.88.
Ethyl 6-Methoxyquinoline-2-carboxylate (11d)
Colorless crystals; mp 127–128 °C.
IR (ZnSe): 2983, 2217, 1724, 1620, 1385, 1274, 1225, 1159, 1105,
1018, 831, 723 cm–1.
1H NMR: = 1.46 (3 H, t, J = 7.2 Hz), 3.94 (3 H, s), 4.52 (2 H, q,
J = 7.2 Hz), 7.08 (1 H, d, J = 2.8 Hz), 7.40 (1 H, dd, J = 2.8, 9.3 Hz),
8.12 (1 H, d, J = 9.9 Hz), 8.14 (1 H, d, J = 9.9 Hz), 8.19 (1 H, d,
J = 9.3 Hz).
3-(4-Methoxyphenyl)propanal Oxime (17)
Colorless crystal; mp 108 °C; E/Z = 1:1.
IR(KBr): 3174, 3080, 2839, 1610, 1514, 1437, 1244, 1032, 833, 815
cm–1.
1H NMR: = 2.49 (1 H, dt, J = 4.8, 7.7 Hz), 2.68 (1 H, dt, J = 4.8,
7.7 Hz), 2.76 (2 H, t, J = 7.7 Hz), 3.79 (3 H, s), 6.74 (0.5 H, t, J = 4.8
Hz), 6.84 (2 H, d, J = 8.6 Hz), 7.12 (2 H, d, J = 8.6 Hz), 7.45 (0.5
H, t, J = 4.8 Hz), 7.86 (0.5 H, br s), 8.32 (0.5 H, br s).
13C NMR: = 14.4, 55.6, 62.0, 104.6, 121.5, 123.4, 130.8, 132.3,
135.6, 143.8, 145.8, 159.4, 165.6.
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C,
67.67; H, 5.77; N, 5.92.
13C NMR: = 26.6, 31.1, 31.4, 31.9, 55.2, 113.9, 129.2, 129.3,
132.6, 132.7, 151.5, 151.9, 158.0.
2,6-Dimethylquinoline (11e)19
Colorless crystals; mp 57–58 °C.
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
67.28; H, 7.41; N, 7.65.
IR (KBr): 3388, 2951, 1601, 1496, 1309, 1222, 1119, 831 cm–1.
Cyclization of anti-9a;Typical Procedure
To a solution of 4-(4-methoxyphenyl)butan-2-one (E)-oxime (anti-
9a) (96.3 mg, 0.498 mmol) in CH2Cl2 (4 mL), trifluoroacetic anhy-
dride (317 mg, 1.51 mmol) in CH2Cl2 (3 mL) was added dropwise
over 3 min at r.t. 4-Chloranil (135 mg, 0.550 mmol) was added im-
mediately to the mixture, which was stirred for 21 h. 1 M aq NaOH
(? mL) was added to the reaction mixture, and the mixture was
1H NMR: = 2.52 (3 H, s), 2.73 (3 H, s), 7.25 (1 H, d, J = 8.4 Hz),
7.51 (1 H, dd, J = 1.7, 8.6 Hz), 7.53 (1 H, d, J = 1.7 Hz), 7.91 (1 H,
d, J = 8.6 Hz), 7.96 (1 H, d, J = 8.4 Hz).
13C NMR: = 21.4, 25.3, 121.9, 126.4, 126.5, 128.3, 131.6, 135.4,
135.5, 146.4, 158.0.
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

FEATURE ARTICLE
Transformation of Oximes to aza-Heterocycles
2423
2-Methylquinoline (11f)1b
Colorless oil.
IR (ZnSe): 3055, 1623, 1601, 1506, 1423 cm–1.
1H NMR: = 3.01 (3 H, s), 7.25 (1 H, d, J = 8.4 Hz), 7.45 (1 H, dd,
J = 6.9, 8.2 Hz), 7.65 (1 H, dd, J = 6.9, 8.4 Hz), 7.74 (1 H, d, J = 8.2
Hz), 8.00 (1 H, d, J = 8.4 Hz), 8.01 (1 H, d, J = 8.4 Hz).
1H NMR: = 2.74 (3 H, s), 4.05 (3 H, s), 7.35 (1 H, d, J = 8.7 Hz),
7.48 (1 H, d, J = 9.2 Hz), 8.01 (1 H, d, J = 9.2 Hz), 8.41 (1 H, d,
J = 8.7 Hz).
13C NMR: = 24.9, 57.1, 107.5, 116.4, 123.4, 126.9, 129.4, 134.7,
143.9, 153.4, 157.4.
HRMS (FAB+): m/z calcd for C11H11BrNO, (M + H)+, 252.0024;
found, 252.0040.
13C NMR: = 25.4, 122.0, 125.6, 126.4, 127.4, 128.6, 129.4, 136.1,
147.9, 159.0.
3-(4-Methoxyphenyl)propanenitrile (18)21
Colorless oil.
Benzyl N-Methyl-N-(2-methylquinolin-6-yl)carbamate (11g)
Yellow oil.
IR (ZnSe): 2935, 2245, 1610, 1510, 1244, 1178, 1030, 833 cm–1.
IR (ZnSe): 3032, 1699, 1623, 1601, 1496, 1321, 1143, 1005, 835,
748, 696 cm–1.
1H NMR: = 2.57 (2 H, t, J = 7.3 Hz), 2.89 (2 H, t, J = 7.3 Hz), 3.79
(3 H, s), 6.87 (2 H, d, J = 8.7 Hz),7.15 (2 H, d, J = 8.7 Hz).
1H NMR: = 2.74 (3 H, s), 3.42 (3 H, s), 5.19 (2 H, s), 7.26–7.31 (6
H, m), 7.61 (2 H, m), 7.97–7.99 (2 H, m).
13C NMR: = 25.3, 37.8, 67.4, 122.4, 122.7, 126.4, 127.7, 127.9,
128.1, 128.4, 129.2, 135.8, 136.4, 140.4, 146.0, 155.4, 159.0.
HRMS (FAB+): m/z calcd for C19H19N2O2: (M + H)+, 307.1447;
found, 307.1466.
13C NMR: = 19.6, 30.7, 55.2, 114.2, 119.2, 129.3, 130.1, 158.7.
6-Methoxy-2-methyl-3,4-Dihydroquinoline (10)22
1H NMR: = 2.50 (3H, s), 2.86-2.94 (4H, m), 3.75 (3H, s), 6.68
(1H, d, J = 2.5 Hz), 6.74 (1H, dd, J = 2.5, 8.6 Hz), 7.38 (1H, d,
J = 8.6 Hz); 13C NMR 21.2, 23.8, 29.3, 55.6, 113.1, 114.4, 122.9,
126.0, 127.8, 161.3, 180.2.
6-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (12)23
7-Bromo-6-methoxy-2-methylquinoline (11h)
Colorless crystals; mp 84–85 °C.
IR (ZnSe): 2935, 1597, 1471, 1344, 1238, 1134, 1039, 847 cm–1.
1H NMR: = 2.70 (3 H, s), 4.00 (3 H, s), 7.05 (1 H, s), 7.26 (1 H, d,
J = 8.4 Hz), 7.92 (1 H, d, J = 8.4 Hz), 8.26 (1 H, s).
13C NMR: = 25.1, 56.4, 105.5, 116.8, 122.5, 126.4, 133.2, 134.8,
143.8, 153.3, 157.4.
To a solution of 4-(4-methoxyphenyl)butan-2-one (E)-oxime (9a)
(103 mg, 0.533 mmol) in CH2Cl2 (2 mL), trifluoroacetic anhydride
(336 mg, 1.56 mmol) in CH2Cl2 (2 mL) was added dropwise over 3
min at r.t. After the mixture was stirred for 14 h, NaBH3CN (178
mg, 2.83 mmol) in MeOH (2 mL) was added to the mixture. The
mixture was stirred for 1 h, and the reaction was quenched with 1 M
aq NaOH. Then, organic materials were extracted with CH2Cl2, and
the combined extracts were washed with brine, and dried over
MgSO4. After the solvent was removed under reduced pressure, the
residue was purified by preparative thin-layer chromatography (sil-
ica gel) to afford 6-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline
12 (79.6 mg, 0.450 mmol) in 85% yield.
Anal. Calcd for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,
52.35; H, 4.06; N, 5.34.
2-Methyl-1-azaspiro[4.5]deca-1,6,9-trien-8-one (13)1b
Colorless oil.
Colorless crystals; mp 65 °C.
IR (KBr): 2960, 1504, 1441, 1240, 1153, 1041, 808 cm–1.
IR (ZnSe): 2944, 1664, 1624, 914, 858, 744 cm–1.
1H NMR: = 2.06 (2 H, t, J = 8.0 Hz), 2.13 (3 H, s), 2.81 (2 H, t,
J = 8.0 Hz), 6.23 (2 H, d, J = 10.0 Hz), 6.62 (2 H, d, J = 10.0 Hz).
1H NMR: = 1.20 (3 H, d, J = 6.3 Hz), 1.57 (1 H, m), 1.91 (1 H, m),
2.70 (1 H, m), 2.84 (1 H, m), 3.33 (1 H, m), 3.72 (3 H, s), 6.44 (1 H,
d, J = 8.4 Hz), 6.57 (1 H, d, J = 2.9 Hz), 6.59 (1 H, dd, J = 2.9, 8.4
Hz).
13C NMR: = 22.5, 26.9, 30.3, 47.5, 55.8, 112.8, 114.6, 115.3,
122.5, 138.9, 151.8.
13C NMR: = 20.0, 33.9, 40.1, 74.8, 127.9, 150.4, 179.4, 182.9.
4-(4-Hydroxymethylphenyl)butan-2-one (14)
Colorless oil.
IR (KBr): 3340, 2924, 1705, 1508, 1362, 1161, 1012 cm–1.
1H NMR: = 2.14 (3 H, s), 2.75 (2 H, t, J = 7.3 Hz), 2.89 (2 H, t,
J = 7.3 Hz), 4.65 (2 H, s), 7.19 (2 H, d, J = 6.9 Hz), 7.28 (2 H, d,
J = 6.9 Hz).
13C NMR: = 29.4, 30.0, 45.1, 65.1, 127.3, 128.5, 138.7, 140.5,
207.9.
HRMS (FAB+): m/z calcd for C11H15O2 (M + H)+, 179.1072; found,
179.1102.
, -Unsaturated Ketone O-Methoxyacetyloximes 22; Typical
Procedure
To a solution of 3-phenylpropionic acid (25.0 g, 166.5 mmol) in
CH2Cl2 (50 mL), oxalyl chloride (21.16 g, 166.7 mmol) was added,
and the mixture was stirred for 5 h. CH2Cl2 was removed under re-
duced pressure to afford 3-phenylpropionyl chloride in quantitative
yield.
The crude acid chloride (9.3 g, 55 mmol) and Et3N (15.1 mL, 110
mmol) was added to a solution of N,O-dimethylhydroxylamine hy-
drochloride (5.3 g, 55 mmol) in CH2Cl2 (100 mL), and the mixture
was stirred overnight. After the reaction was quenched with water,
organic materials were extracted with EtOAc, and the combined or-
ganic extracts were dried over MgSO4. Solvents were removed in
vacuo, and the residue was purified by column chromatography on
silica gel (hexane–EtOAc) to give N-methoxy-N-methyl-3-phenyl-
propionamide (7.7 g, 55 mmol) in 79% yield.
N-Phenethylacetamide (15)20
Colorless oil.
1H NMR: = 1.91 (3 H, s), 2.78 (2 H, t, J = 7.0 Hz), 3.50 (2 H, t,
J = 7.0 Hz), 5.44 (1 H, br s), 7.17–7.31 (5 H, m).
5-Bromo-6-methoxy-2-methylquinoline (16)
Yellow oil.
IR (ZnSe): 2935, 2842, 1612, 1597, 1493, 1340, 1265, 1128, 1066,
813 cm–1.
To a suspension of Mg (0.73 g, 30 mmol) in THF (10 mL), a small
amount of I2 was added, and then 1-bromo-3-butene (3.67 g, 27
mmol) was added dropwise. The reaction mixture was refluxed for
1.5 h, and then cooled to 0 °C. N-Methoxy-N-methyl-3-phenylpro-
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

2424
M. Kitamura et al.
FEATURE ARTICLE
pionamide (3.79 g, 20.9 mmol) in THF (10 mL) was added to the
reaction mixture, which was refluxed for 30 min. After adding 2 M
aq HCl to the reaction mixture, organic materials were extracted
with Et2O. The combined organic extracts were washed with sat. aq
NaHCO3 and brine, successively, and dried over MgSO4. After re-
moval of Et2O under reduced pressure, the residue was purified by
column chromatography on silica gel (hexane–EtOAc) to give1-
phenyl-7-hepten-3-one (2.98 g, 15.5 mmol) in 76% yield.
(1 H, s), 4.18 (1 H, s), 5.31–5.42 (1 H, m), 5.43–5.54 (1 H, m), 7.17–
7.22 (3 H, m), 7.26–7.31 (2 H, m).
13C NMR: = 17.8, 28.8, 29.1, 29.7, 31.5, 32.0, 32.2, 34.2, 36.0,
59.5, 69.1, 69.2, 126.3, 126.4, 126.5, 126.7, 128.2, 128.3, 128.5,
128.6, 128.8, 129.1, 140.2, 140.5, 168.5, 168.7, 169.1, 169.1.
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.83; H, 8.31; N, 4.91.
To a solution of 1-phenyl-7-hepten-3-one (4.3 g, 23 mmol) in
MeOH (46 mL), hydroxylamine hydrochloride (8.0 g, 0.12 mol)
and pyridine (10 mL, 0.12 mol) was added, and the mixture was
stirred overnight. The reaction was quenched with water, and organ-
ic materials were extracted with EtOAc. The combined organic ex-
tracts were dried over MgSO4. The solvent was removed under
reduced pressure to give crude product 1-phenyl-7-heptene-3-one
oxime (4.6 g, 23 mmol).
(5E)-6-Phenylhex-5-en-2-one (E)-O-Methoxyacetyloxime (22d)
Colorless oil.
IR (ZnSe): 2925, 1770, 1647, 1448, 1369, 1163, 1117, 935, 744,
694 cm–1.
1H NMR: = 2.00 (3 H, s), 2.48–2.53 (4 H, m), 3.47 (3 H, s), 4.18
(2 H, s), 6.15–6.20 (1 H, m), 6.41–6.44 (1 H, m), 7.18–7.33 (5 H,
m).
13C NMR: = 15.5, 29.5, 35.4, 59.4, 69.1, 126.0, 127.2, 128.1,
128.5, 131.2, 137.2, 166.4, 168.5.
To a solution of the crude product (298 mg, 1.47 mmol) in CH2Cl2
(8 mL), Et3N (602 L, 4.40 mmol) and methoxyacetyl chloride (319
mg, 2.94 mmol) was added successively at 0 °C, and the mixture
was stirred overnight. The reaction was quenched with sat. aq
Na2CO3, and organic materials were extracted with CH2Cl2. The
combined organic extracts were dried over NaSO4. After removal of
the solvent under reduced pressure, the residue was purified by
chromatography on silica gel (hexane–EtOAc) to afford 1-phenyl-
7-heptene-3-one O-methoxyacetyloxime (22a) (E/Z = 1:1) (315
mg, 1.14 mmol) in 78% yield (2 steps).
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.67; H, 7.47; N, 5.24.
1-Phenyl-7-methyloct-6-en-3-one O-Methoxyacetyloxime (22e)
Colorless oil; E/Z = 1:1.
IR (ZnSe): 2925, 1770, 1450, 1111, 933, 746, 700 cm–1.
1H NMR: = 1.60 (3 H, s), 1.69 (3 H, s), 2.19–2.32 (3 H, m), 2.41–
2.44 (1 H, m), 2.63–2.71 (2 H, m), 2.83 (1 H, t, J = 8.0 Hz), 2.91 (1
H, t, J = 8.0 Hz), 3.48 (1.5 H, s), 3.49 (1.5 H, s), 4.14 (1 H, s), 4.18
(1 H, s), 5.06–5.09 (1 H, m), 7.17–7.22 (3 H, m), 7.26–7.31 (2 H,
m).
13C NMR 17.6, 17.7, 24.5, 24.7, 25.6, 25.6, 29.8, 31.5, 32.1, 32.3,
34.5, 36.2, 59.5, 69.2, 69.2, 122.1, 122.3, 126.3, 126.5, 128.2,
128.3, 128.5, 128.6, 133.1, 133.6, 140.2, 140.6, 168.6, 168.6, 169.3,
169.4.
1-Phenylhept-6-en-3-one O-Methoxyacetyloxime (22a)
Colorless oil; E/Z = 1:1.
IR (ZnSe): 2929, 1770, 1637, 1454, 1373, 1113, 1012, 993, 933,
924, 748, 700 cm–1.
1H NMR: = 2.25–2.39 (3 H, m), 2.49–2.52 (1 H, m), 2.64–2.70 (2
H, m), 2.82–2.85 (1 H, m), 2.89–2.93 (1 H, m), 3.48 (1.5 H, s), 3.48
(1.5 H, s), 4.14 (1 H, s), 4.17 (1 H, s), 5.00–5.07 (2 H, m), 5.73 (1
H, m), 7.18–7.23 (3 H, m), 7.28–7.32 (2 H, m).
13C NMR: = 29.0, 29.8, 30.0, 31.4, 31.9, 32.1, 33.7, 35.9, 59.4,
59.4, 69.1, 69.1, 115.7, 116.0, 126.3, 126.5, 136.2, 136.5, 140.1,
140.4, 168.4, 168.7, 168.8, 168.8.
Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C,
71.49; H, 8.57; N, 4.59.
2H-Dihydropyrroles; Typical Procedure
Under an argon atmosphere, to a solution of 1-phenyl-6-hepten-3-
one O-methoxyacetyloxime (22a) (67.5 mg, 0.245 mmol) in ni-
tromethane (4 mL), MS 4 Å (270 mg) and methoxyacetic acid (221
mg, 2.45 mmol) was added, and the mixture was stirred at 70 °C for
24 h. The reaction was quenched with sat. aq Na2CO3, and organic
materials were extracted with EtOAc. The combined organic ex-
tracts were dried over NaSO4. The solvents were removed under re-
duced pressure, and the residue was purified by preparative TLC
(silica gel, hexane–EtOAc, 1:2) to afford 2-(methoxyacetoxy)meth-
yl-5-phenyl-3,4-dihydro-2H-pyrrole 23a (56.0 mg, 0.204 mmol) in
83% yield.
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C,
69.69; H, 7.82; N, 4.97.
6-Methyl-1-phenylhept-6-en-3-one O-Methoxyacetyloxime
(22b)
Colorless oil; E/Z = 1:1.
IR (ZnSe): 2931, 2343, 1772, 1647, 1456, 1169, 1114, 935, 746,
700 cm–1.
1H NMR: = 1.74 (3 H, d, J = 9.1 Hz), 2.19–2.28 (2 H, m), 2.40–
2.43 (1 H, m), 2.53–2.56 (1 H, m), 2.64–2.71 (2 H, m), 2.83–2.86 (1
H, m), 2.89–2.93 (1 H, m), 3.48 (1.5 H, s), 3.49 (1.5 H, s), 4.14 (1
H, s), 4.18 (1 H, s), 4.69 (1 H, s), 4.76 (1 H, d, J = 9.1 Hz), 7.18–
7.24 (3 H, m), 7.29–7.32 (2 H, m).
13C NMR: = 22.2, 22.3, 28.1, 31.4, 32.0, 32.2, 32.7, 33.6, 33.8,
35.9, 59.5, 69.1, 69.2, 110.9, 111.1, 126.3, 126.5, 128.2, 128.3,
128.5, 128.6, 140.1, 140.5, 143.7, 144.0, 168.5, 168.7, 169.2.
2-(Methoxyacetoxy)methyl-5-phenylethyl-3,4-dihydro-2H-pyr-
role (23a)
[5-(2-phenylethyl)-3,4-dihydro-2H-pyrrol-2-yl]methyl meth-
oxyacetate
Colorless oil.
IR (ZnSe): 2927, 1751, 1734, 1641, 1456, 1192, 1126, 752, 702
cm–1.
1H NMR: = 1.54–1.62 (1 H, m), 2.01–2.08 (1 H, m), 2.43–2.58 (2
H, m), 2.66–2.69 (2 H, m), 2.87–2.98 (2 H, m), 3.45 (3 H, s), 4.05
(2 H, s), 4.19–4.32 (3 H, m), 7.20–7.30 (5 H, m).
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.46; H, 8.17; N, 4.65.
(6E)-1-Phenyloct-6-en-3-one O-methoxyacetyloxime (22c)
Colorless oil; E/Z = 1:1.
13C NMR: = 25.2, 32.5, 35.1, 37.6, 59.1, 67.2, 69.5, 70.6, 125.9,
128.1, 128.3, 141.0, 170.2, 179.1.
HRMS (FAB+): m/z calcd for C16H22NO3 (M + H)+, 276.1600;
IR (ZnSe): 2931, 1772, 1637, 1603, 1452, 1117, 748, 700 cm–1.
1H NMR: = 1.60-1.65 (3 H, m), 2.17–2.29 (2 H, m), 2.32–2.35 (1
H, m), 2.43–2.50 (1 H, m), 2.60–2.71 (2 H, m), 2.84 (1 H, t, J = 7.5
Hz), 2.90 (1 H, t, J = 7.5 Hz), 3.48 (1.5 H, s), 3.49 (1.5 H, s), 4.14
found, 276.1624,
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

FEATURE ARTICLE
Transformation of Oximes to aza-Heterocycles
2425
2-(Methoxyacetoxy)methyl-2-methyl-5-phenylethyl-3,4-dihy-
IR (neat): 2960, 1643, 1603, 1496, 1454, 906, 750, 700 cm–1.
dro-2H-pyrrole (23b)
Colorless oil.
1H NMR: = 1.24–1.25 (3 H, m), 1.30–1.39 (1 H, m), 2.02–2.09 (1
H, m), 2.40–2.44 (1 H, m), 2.47–2.54 (1 H, m), 2.60–2.64 (2 H, m),
2.91–2.95 (2 H, m), 4.01–4.07 (1 H, m), 7.15–7.20 (3 H, m), 7.24–
7.28 (2 H, m).
IR (ZnSe): 2929, 1753, 1734, 1645, 1454, 1192, 1126, 750, 700
cm–1.
1H NMR: = 1.24 (3 H, s), 1.58–1.64 (1 H, m), 1.83–1.87 (1 H, m),
2.54 (2 H, t, J = 7.9 Hz), 2.63–2.66 (2 H, m), 2.91 (2 H, t, J = 7.9
Hz), 3.42 (3 H, s), 4.00 (2 H, s), 4.09–4.16 (2 H, m), 7.18–7.22 (3
H, m), 7.27–7.30 (2 H, m).
13C NMR: = 22.0, 30.6, 32.7, 35.3, 37.7, 67.7, 125.9, 128.2, 128.3,
141.4, 176.1.
2-Chloromethyl-5-phenylethyl-3,4-dihydro-2H-pyrrole (25)
Colorless oil.
13C NMR: = 24.2, 31.8, 32.7, 35.2, 38.0, 59.3, 69.6, 70.8, 74.7,
126.1, 128.2, 128.4, 141.0, 170.2, 177.1.
HRMS (FAB+): m/z calcd for C17H24NO3 (M + H)+, 290.1756;
IR (ZnSe): 2951, 1641, 1602, 1495, 1454, 1427, 1290, 748, 700
cm–1.
1H NMR: = 1.75–1.77 (1 H, m), 2.06–2.08 (1 H, m), 2.47–2.51 (1
H, m), 2.55–2.62 (1 H, m), 2.65–2.70 (2 H, m), 2.92–2.98 (2 H, m),
3.63–3.67 (1 H, m), 3.74–3.78 (1 H, m), 4.33–4.36 (1 H, m), 7.18–
7.22 (3 H, m), 7.26–7.30 (2 H, m).
found, 290.1759.
2-(1-Methoxyacetoxy)ethyl-5-phenylethyl-3,4-dihydro-2H-pyr-
role (23c)
Colorless oil; (dr 3:2).
13C NMR: = 26.0, 32.6, 35.2, 38.1, 48.6, 72.9, 126.0, 128.2, 128.4,
141,1, 179.5.
HRMS (FAB+): m/z calcd for C13H17ClN (M + H)+, 222.1050;
IR (ZnSe): 2933, 1749, 1731, 1645, 1454, 1192, 1124, 752, 700
cm–1.
1H NMR: = 1.27–1.28 (3 H, m), 1.53–1.60 (0.4 H, m), 1.61–1.69
(0.6 H, m), 1.92–2.01 (1 H, m), 2.40–2.56 (2 H, m), 2.61–2.71 (2 H,
m), 2.86–2.96 (2 H, m), 3.42 (1.8 H, s), 3.45 (1.2 H, s), 3.97–4.01
(2 H, m), 4.09–4.16 (1 H, m), 5.08–5.16 (1 H, m), 7.18–7.22 (3 H,
m), 7.27–7.30 (2 H, m).
13C NMR: = 16.6, 16.9, 24.2, 24.6, 32.5, 32.7, 35.3, 35.4, 37.5,
37.8, 59.2, 59.3, 69.9, 73.5, 73.5, 75.3, 75.9, 126.0, 126.0, 128.2,
128.2, 128.4, 128.4, 141.1, 141.3, 169.7, 169.9, 178.8, 179.0.
found, 222.1049.
2-Isopropenyl-5-phenylethyl-3,4-dihydro-2H-pyrrole (26)
Colorless oil.
IR (KBr): 2915, 1720, 1496, 1454, 894, 750, 700 cm–1.
1H NMR: = 1.59–1.64 (1 H, m), 1.67 (3 H, s), 2.08–2.10 (1 H, m),
2.40–2.47 (1 H, m), 2.50–2.56 (1 H, m), 2.69 (2 H, t, J = 8.1 Hz),
2.92–3.02 (2 H, m), 4.48 (1 H, t, J = 7.2 Hz), 4.76 (1 H, s), 4.82 (1
H, s), 7.17–7.29 (5H, m).
HRMS (FAB+): m/z calcd for C17H24NO3 (M + H)+, 290.1756;
found, 290.1740.
13C NMR: = 19.3 28.2, 32.7, 35.3, 37.8, 77.1, 109.9, 126.0, 128.4,
141.4, 146.8, 177.5.
HRMS (FAB+): m/z calcd for C15H20N (M + H)+, 214.1596; found,
2-(1-Methoxyacetoxy-1-methyl)ethyl-5-phenylethyl-3,4-dihyro-
2H-pyrrole (23e)
Colorless oil.
214.1619.
IR (ZnSe): 2933, 1745, 1726, 1645, 1452, 1369, 1298, 1196,
1120m, 741, 700 cm–1.
1H NMR: = 1.40 (3 H, s), 1.60 (3 H, s), 1.65–1.72 (1 H, m), 1.88–
1.95 (1 H, m), 2.38–2.54 (2 H, m), 2.63–2.73 (2 H, m), 2.87–2.97 (2
H, m), 3.42 (3 H, s), 3.89 (2 H, s), 4.31–4.34 (1 H, m), 7.18–7.22 (3
H, m), 7.26–7.29 (2 H, m).
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Rese-
arch on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic
Molecules’ and a Grant-in-Aid for The 21st Century COE Program
for Frontiers in Fundamental Chemistry from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
13C NMR: = 22.0, 23.7, 23.8, 32.6, 35.2, 37.8, 59.1, 79.8, 85.2,
126.0, 128.3, 128.4, 141.2, 169.5, 178.4, 178.4.
HRMS (FAB+): m/z calcd for C18H26NO3 (M + H)+, 304.1913;
found, 304.1905
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IR (ZnSe): 2947, 1749, 1647, 1456, 1379, 1186, 1124, 962, 701
cm–1.
1H NMR: = 1.47–1.54 (1 H, m), 1.72–1.83 (1 H, m), 2.01 (3 H, s),
2.23–2.48 (2 H, m), 3.43 (3 H, s), 4.04 (1 H, d, J = 16.4 Hz), 4.17 (1
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2-Methyl-5-phenylethyl-3,4-dihydro-2H-pyrrole (24)24
Yellow oil.
Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York

2426
M. Kitamura et al.
FEATURE ARTICLE
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Synthesis 2003, No. 15, 2415–2426 © Thieme Stuttgart · New York