The alkylation of isatin-derived oximes: Spectroscopic and X-ray crystallographic structural characterization of oxime and nitrone products

Article abstract of DOI:10.1002/jhet.84

(Chemical Equation Presented) A series of isatin oximes was alkylated with alkyl halides and under Mitsunobu conditions to generate O-alkylated oxime ether and N-alkylated nitrone products. Alkylation of the sodium salts of oximes 5a and 5b with alkyl iod

Full text of DOI:10.1002/jhet.84

432
The Alkylation of Isatin-Derived Oximes: Spectroscopic and
X-Ray Crystallographic Structural Characterization of Oxime
and Nitrone Products
Vol 46
Ny Sin,a* Brian L. Venables,a Xiaohong Liu,b Stella Huang,b Qi Gao,b
Alicia Ng,b Richard Dalterio,b Ramkumar Rajamani,c
and Nicholas A. Meanwella
aDepartment of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway,
Wallingford, Connecticut 06492
bDepartment of Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development,
5 Research Parkway, Wallingford, Connecticut 06492
cDepartment of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5
Research Parkway, Wallingford, Connecticut 06492
*E-mail: ny.sin@bms.com
Received July 28, 2008
DOI 10.1002/jhet.84
Published online 26 May 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of isatin oximes was alkylated with alkyl halides and under Mitsunobu conditions to gener-
ate O-alkylated oxime ether and N-alkylated nitrone products. Alkylation of the sodium salts of oximes
5a and 5b with alkyl iodides produced predominantly the N-alkylated nitrones (E)-7 while alkylation of
5a and 5b with the harder electrophiles alkyl bromides and alkyl chlorides, gave mostly the O-alkylated
products, oxime ethers (E)-6. Interestingly, alkylation of oxime 5b under Mitsunobu conditions with iso-
propyl alcohol produced the N-alkylated nitrone (E)-7bd as the major product. However, alkylation of
oxime 5c, which incorporates a sterically bulky bromine substituent at the C-4 position of the isatin het-
erocycle, with 2-bromo- and 2-iodo-propane or with isopropyl alcohol under Mitsunobu conditions gave
exclusively the O-alkylated product, oxime ether (Z)-6cd. The oxime ether and nitrone products 6 and
7, respectively, were characterized by LC/MS, 1H NMR, and 13C NMR. In addition, the structures of
oxime ether (E)-6bd and nitrone (E)-7ad were determined by X-ray crystallography.
J. Heterocyclic Chem., 46, 432 (2009).
INTRODUCTION
[4]. In addition, a number of isatin and oxindole deriva-
tives demonstrate antiviral properties, exemplified by
inhibitors of poxvirus [5], ectromelia [6], rhinovirus [7],
HIV-1 [8], and the coronavirus responsible for severe
acute respiratory syndrome (SARS) [9]. Oximes have
been examined as useful pharmacophores in a range of
therapeutic agents that encompass multiple disease areas.
For example, oxime derivatives have been evaluated as
dual agonists of peroxisome proliferator-activated recep-
tors (PPARs) a and c for the treatment of type II diabe-
tes [10], vascular endothelial growth factor (VEGF)-2
kinase inhibitors as antiproliferative agents [11], N-
methyl-D-aspartate (NMDA) [12] and AMPA/kainite
[13] receptor antagonists, and c-aminobutyric acid
(GABA) uptake inhibitors as potential anticonvulsants
[14]. A particularly prominent oxime ether derivative
Oximes (1) are important synthetic intermediates in
organic synthesis that have also found application in a
medicinal chemistry setting. As a synthetically useful
functionality, oximes can be used to protect carbonyl
groups, reduced to an amine or, in the case of oximes
derived from aldehydes, undergo dehydration to a nitrile
[1]. During the course of our survey of small molecule
inhibitors of respiratory syncytial virus (RSV) fusion, we
were interested in probing the potential of isatin-derived
oximes as bioisosteres of the benzimidazol-2-one tem-
plate that has provided a series of potent antiviral agents
[2]. Isatin derivatives have found wide application as
scaffolds in medicinal chemistry, including a series of
Schiff bases and hydrazones evaluated as potential anti-
convulsants [3] and cyclin-dependent kinase-2 inhibitors
C
V
2009 HeteroCorporation

May 2009
The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic
Structural Characterization of Oxime and Nitrone Products
433
Scheme 1. Alkylation of oximes of general structure 1.
Scheme 2. Alkylation of isatin oximes.
that has been evaluated in clinical trials as an antiviral
agent for the treatment of HIV infection is SCH 351125,
an orally bioavailable CCR5 receptor antagonist [15].
To establish the potential of isatin-derived oxime
ethers as RSV fusion inhibitors, a parallel synthesis
approach was envisioned as a means of rapidly generat-
ing a series of isatin oxime ethers 6 from oximes 5 by a
simple alkylation procedure. However, it is well estab-
lished that the alkylation of oximes of general structure
1 can produce O-alkyloxime-ethers 2 and N-alkylated
nitrones 3, as shown in Scheme 1, depending upon the
site at which alkylation occurs [16,17]. The ratio of O-
to N-alkylated products can be influenced by several
factors, including the geometry of the oxime salts
derived from 1. For example, alkylation of an (E)-aldox-
ime sodium salt with alkyl halides produced mainly the
O-alkylated oximes but alkylation of the (Z)-aldoxime
sodium salt with the same series of electrophiles pro-
duced similar amounts of the N- and O-alkylated prod-
ucts [17]. Whilst there are many reports in the literature
of oxime alkylation procedures, there has not been a
systematic study of the alkylation of isatin oximes 5 and
structural characterization of the possible products, the
oxime ethers 6 and nitrones 7. The alkylation of oxime
5 is potentially a complex process since four products
can be formed: (E)- and (Z)-oximes 6 and (E)- and (Z)-
nitrones 7, and it was anticipated that product distribu-
tion would show some dependence on the reagents, the
reaction conditions, and the substitution patterns of the
aryl ring. In this article, we report the results of studies
of the alkylation of a series of isatin oximes 5 and char-
1
acterization of the products by LC/MS, H NMR, 13C
NMR and, for select examples, X-ray crystallography.
RESULTS AND DISCUSSION
The procedures for the preparation and alkylation of
isatin oximes 5 are summarized in Scheme 2. Isatin
oximes 5a-c were readily obtained from isatins 4a–c by
treatment with NH2OHꢀHCl in aqueous EtOH. Isatins 4a
and 4b were available from commercial sources and N-
methyl-4-bromo isatin (4c) was obtained by alkylation
of commercially available 4-bromoisatin with methyl
iodide in the presence of K2CO3 as the base. Alkylation
of 5a and 5b by deprotonation with NaH in DMF and
exposure to alkyl halides gave mixtures of isatin O-alky-
loxime ethers (E)-6 and nitrones (E)-7, with the distribu-
tion of the products for each reaction summarized in
Tables 1 and 2. DMF was chosen as the solvent to
Table 1
Alkylation of isatin oxime 5a with alkyl halides to give O-alkylated oxime ethers and N-alkylated nitones.
Ratio
of oxime:
nitrone (%)b
Total
yield (%)
Rxn
time (h)
No.
Oxime
Nitrone
Electrophile
R1
R2
R3
1
2
3
4
5
6
7
8
9
(E)-6aaa
(E)-6ab
(E)-6ac
(E)-6ad
(E)-6ae
(E)-6af
(E)-6ag
(E)-6ah
(E)-6ai
(E)-7aaa
(E)-7ab
(E)-7ac
(E)-7ad
(E)-7ae
(E)-7af
(E)-7ag
(E)-7ah
(E)-7ai
MeI
EtI
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
Me
Et
36:64
40:60
37:63
40:60
57:43
58:42
50:50
58:42
90:10
64c
90
91
89
97
97
94c
64
91
15
15
15
15
15
15
15
15
15
nPrI
iPrI
nPr
iPr
(CH3CH2)2CH Br
cPentyl Iodide
cHexyl Iodide
4-OMeC6H4 CH2Cl
BrCH2CO2tBu
(CH3CH2)2CH
cPen
cHex
CH2-Ph-40-OMe
CH2CO2tBu
a Letter designations: the first letter represents the substitution pattern on the isatin ring system, whereas the second letter discriminates the different
substitutions on the oxime oxygen and nitrone nitrogen.
b Ratios between isomers were determined by weights after flash column chromatography, except, entry 1 where the ratio was determined by
HPLC since the two products were not separable.
c Yields based on 10 and 34% recovered starting material for entries 1 and 7, respectively.
Journal of Heterocyclic Chemistry
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434
N. Sin, B. L. Venables, X. Liu, S. Huang, Q. Gao, A. Ng, R. Dalterio,
R. Rajamani, and N. A. Meanwell
Vol 46
Table 2
Alkylation of 5b with isopropyl halides under basic conditions and with isopropyl alcohol under Mitsunobu conditions to give O-alkylated oxime
ether (E)-6bd and N-alkylated nitone (E)-7bd.
No.
Reagent useda
Oxime (E)-6bdb (%)
Nitrone (E)-7bdb (%)
Total yield (%)
Rxn time (h)
1
2
3
4
iPrI
iPrBr
iPrCl
iPrOH
43 (48)
54 (62)
65 (70)
12 (16)
57 (52)
46 (38)
35 (30)
88 (84)
83
86
61c
84
15
15
76
18
a Alkylation of oxime 5b with alkyl halides in the presence of NaH and under Mitsunobu reaction conditions with isopropyl alcohol for entries 1–3
and entry 4, respectively.
b Isomeric product ratios were determined by weight after purification by flash column chromatography. Ratios in parentheses were determined by
integration of HPLC peaks.
c Yield based on 6% recovered starting material.
ensure high solubility of the isatin oximes 5a and 5b
and their sodium salts during the course of the reaction,
since heterogeneous reaction conditions caused by the
precipitation of oxime salts from solvents such as ace-
tone or toluene have been reported to influence the ratio
of products formed [16]. The effect of the counter ion
on product distribution was also examined, with lithium,
potassium, and tetramethylammonium salts evaluated in
addition to sodium [16]. Furthermore, the application of
the Mitsunobu reaction to this process was also studied.
Several O-alkylated isatin oxime ethers were also
obtained by combining isatins 4a–c with O-alkylated hy-
droxylamine hydrochloride salts in aqueous EtOH for
the purpose of comparison with the products obtained
from the alkylation reactions.
the effect of hard and soft electrophiles on product dis-
tribution could not be fully appreciated. In addition, the
study of aldoxime alkylation was complicated by the ge-
ometry of the aldoxime sodium salt which exerted a
profound effect on the product ratio [17]. The (E)-aldox-
ime sodium salt was found to give the oxime ether by a
preference of three to ninefold over the nitrone products,
whereas the (Z)-aldoxime sodium salt showed little pref-
erence for O- versus N-alkylation, presumably a conse-
quence of the reduced steric encumbrance around the
nitrogen atom in this conformation.
To more closely evaluate the effect of the leaving
group on the ratio of O- and N-alkylated product forma-
tion in the isatin oxime system, additional alkylation
experiments were conducted with 5b using 2-iodo-, 2-
bromo-, and 2-chloro-propane, which afforded a mixture
of O-alkyloxime ether (E)-6bd and the nitrone (E)-7bd.
In addition, since the pKa of many oximes is similar to
that of a phenol [18], alkylation of 5b with isopropyl alco-
hol under the mild conditions associated with the Mitsu-
nobu reaction was examined [19]. The results of this sur-
vey are compiled in Table 2 where the yields of products
were generally high, 83–86%, except in the case of 2-
chloropropane (Entry 3, 61% yield). The alkylation of 5b
with 2-chloropropane was a sluggish process, and the
reaction was worked up after an extended, 76 h time inter-
val. The data in Table 2 reveal a slight preference toward
the N-alkylated nitrone (E)-7bd when the soft electrophile
2-iodopropane was employed. However, the O-alkylated
product, ether (E)-6bd, predominated slightly when 2-
bromopropane was used as the electrophile, and the ratio
further amplified in the reaction of 5b with 2-chloropro-
pane. Interestingly, under Mitsunobu conditions, the
oxime 5b reacted with isopropyl alcohol to afford pre-
dominantly the N-alkylated nitrone (E)-7bd in a ratio of
88:12 over the O-alkylated oxime ether (E)-6bd (Table 2,
Entry 4). To the best of our knowledge, this experiment
represents the first example of oxime alkylation under
Mitsunobu conditions affording a nitrone product.
The results of these studies, compiled in Table 1,
reveal that the reaction yields are generally excellent,
ranging from 64 to 97% and that product distribution
between the O- and N-alkylated products is dependent
on the nature of the electrophile. When soft electro-
philes such as alkyl iodides were employed, the N-alky-
lated products, isatin nitrones (E)-7, were favored
slightly over the O-alkylated oxime ethers 6, with the
ratio ranging from just over 1:1 to 2:1 (Table 1, Entries
1–4 and 7). 2-Iodocyclopentane provided an exception,
producing a 58:42 ratio of oxime to nitrone, respectively
(Table 1, Entry 6). However, with harder electrophiles,
such as alkyl bromides (Table 1, Entries 5 and 9) and
alkyl chlorides (Table 1, Entry 8), this trend was largely
reversed with the O-alkylated products predominating,
in the range of 3:2 to 9:1.
The effect of the nature of the alkyl halide on the
ratio of O- and N-alkylated products formed in base-cat-
alyzed processes was observed earlier with both benzo-
phenone oxime [16] and aldoxime [17] systems. In those
studies, the O-alkylated products predominated by three
to ninefold, with alkyl chlorides providing the highest
preference for O-alkylation. However, the studies were
not conducted in a systematic fashion and correlation of
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May 2009
The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic
Structural Characterization of Oxime and Nitrone Products
435
Table 3
Key spectroscopic data for isatin oximes 6 and nitrones 7.
Oxime
6/Nitrone 7
1H NMR of oxime
and nitrone in CDCl3
Chemical shift differences between
oximes and nitrones
Entry
No.
Compound
No.
C4 Ar-H
(ppm)
Oxime CHn/Nitrone
CHn (ppm)
DC4 Ar-H
(ppm)
DOxime CHn/
Nitrone CHn (ppm)
1
2
3
4
5
6
7
8
9
(E)-6ab
(E)-7ab
(E)-6ac
(E)-7ac
(E)-6ad
(E)-7ad
(E)-6ae
(E)-7ae
(E)-6af
(E)-7af
(E)-6ag
(E)-7ag
(E)-6ah
(E)-7ah
(E)-6ai
(E)-7ai
(E)-6bd
(E)-7bd
7.96
8.34
7.95
8.35
7.93
8.37
7.94
8.42
7.88
8.35
7.96
8.36
7.88
8.30
8.06
8.34
8.05
8.47
4.52–4.56
4.79–4.83
4.44–4.47
4.75–4.78
4.69–4.80
6.28–6.37
4.44–4.46
6.13–6.15
5.11–5.14
6.52–6.55
4.50–4.54
5.95–6.01
5.44
ꢁ0.38
ꢁ0.27
ꢁ0.40
ꢁ0.44
ꢁ0.48
ꢁ0.47
ꢁ0.40
ꢁ0.42
ꢁ0.28
ꢁ0.42
ꢁ0.31
ꢁ1.58
ꢁ1.69
ꢁ1.41
ꢁ1.46
ꢁ0.44
ꢁ0.52
ꢁ1.52
5.88
4.93
5.45
4.78–4.87
6.30–6.39
The structures of the alkylated isatin oximes were
determined by a combination of spectroscopic methods.
The oxime ethers 6 could readily be distinguished from
the nitrones 7 by examination of the infra red spectra.
An earlier report identified unique N-O absorbances for
the nitrone and oxime between 1170–1280 and 920–
1005 cmꢁ1, respectively [16]. The IR spectrum of the
oxime ether (E)-6ad exhibits the characteristic N-O
band at 971 cmꢁ1, which is absent in the IR spectrum
of the isomeric nitrone (E)-7ad (Table 1, Entry 4). Con-
versely, a unique nitrone N-O band appeared at 1241
cmꢁ1 in the IR spectrum of nitrone (E)-7ad that is not
exhibited by the oxime ether (E)-6ad.
series of nitrones 7ab, 7ac, 7ah, and 7ai and their corre-
sponding oxime ether isomers 6ab, 6ac, 6ah, and 6ai,
compounds all prepared from primary alkyl halides, the
1H NMR chemical shifts of the methylene protons differ
by 0.27 to 0.52 ppm (Table 3, Entries 1, 2, 7, and 8).
For nitrones 7ad, 7ae, 7af, 7ag, and 7bd and oxime
ethers 6ad, 6ae, 6af, 6ag, and 6bd, derived from sec-
1
ondary alkyl halides, the differences in H NMR chemi-
cal shifts of the methine protons are more pronounced,
with a difference of 1.41 to 1.69 ppm (Table 3, Entries
3–6 and 9).
To provide further support for the structural assign-
ments, a single crystal X-ray structure was obtained for
the nitrone (E)-7ad, which indicates that this compound
possesses an (E)-geometric configuration, as depicted in
Figure 1. Attempts to recrystallize the corresponding
oxime ether (E)-6ad for X-ray crystallographic structure
determination to allow a direct comparison with (E)-7ad
were unsuccessful. However, the solid state structure
was determined for the close analogue, oxime ether (E)-
6bd in which the isatin N substituent is phenyl rather
than methyl and, as depicted in Figure 2, this compound
also possesses the (E)-geometric configuration. In the
(E)-configuration, the oxygen atoms of the oxime (E)-
6bd and nitrone (E)-7ad project away from the carbonyl
oxygen of the isatin amide moiety, presumably to opti-
mize dipole interactions and minimize the lone pair-lone
pair repulsion that would exist in the (Z)-oxime and
lone pair-negative charge repulsions that would occur in
the isomeric (Z)-nitrone (vide infra). In addition, the
1
The H NMR spectra of oxime ethers 6 and nitrones
7 are generally quite similar with the exception of the
chemical shifts for the C-4 aryl hydrogen atom and the
protons on the carbon atoms attached to the oxime oxy-
1
gen or nitrone nitrogen atoms. The H NMR chemical
shifts for the isatin C-4 aryl hydrogen, and the protons
on the carbon atom attached to the oxime oxygen and
nitrone nitrogen atoms are presented in Table 3. In the
1H NMR, the C-4 aryl hydrogen of isatin nitrones 7
consistently resonates between 0.28 and 0.48 ppm
downfield of the chemical shift of the same proton in
the corresponding isatin oxime ethers 6, attributed to a
deshielding effect induced by the nitrone moiety. Simi-
larly, the 1H NMR chemical shifts for the protons on
the carbon atom attached to the nitrone nitrogen atom in
7 resonate downfield of the protons on the carbon atom
bound to the oxygen atom in the oxime ethers 6. For the
Journal of Heterocyclic Chemistry
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436
N. Sin, B. L. Venables, X. Liu, S. Huang, Q. Gao, A. Ng, R. Dalterio,
R. Rajamani, and N. A. Meanwell
Vol 46
Figure 1. X-ray crystallographic structure of nitrone (E)-7ad.
crystallographic structures indicate that the oxygen atom
of both the oxime ether (E)-6bd and nitrone (E)-7ad are
situated within hydrogen bonding distance of the C-4-
˚
aryl hydrogen, measured at 2.527 A for (E)-6bd and
˚
2.446 A for (E)-7ad, respectively.
Figure 2. X-ray crystallographic structure of oxime ether(E)-6bd.
The X-ray crystallographic data for oxime ether (E)-
6bd and nitrone (E)-7ad indicate without ambiguity that
both are (E)-isomers. On the basis of the additional
studies and ab initio calculations described below, we
conclude that all of the oxime ethers and nitrones pre-
sented in Tables 1 and 2 most likely possess the (E)-
geometric configuration.
(E)-6bd and nitrone (E)-7bd indicated a trace of an
additional peak with a retention time close to oxime
(E)-6bd that may be the isomeric oxime, (Z)-6bd; how-
ever, this compound could not be isolated. In an attempt
to increase the production of the (Z)-oxime isomer,
direct oxime ether formation from isatin 4b was exam-
ined. Condensation of 4b with 1.2 equivalents of O-iso-
propylhydroxylamine hydrochloride in EtOH/H2O gave
a 96% yield of oxime product that was an 89:11 mixture
of (E)-6bd and (Z)-6bd as determined by HPLC (Table
4, Entry 1). Oxime ethers (E)-6bd and (Z)-6bd were
prepared in 95% yield under the same conditions but
with an equimolar quantity of pyridine included to neu-
tralize the HCl present in the reaction mixture in an
attempt to reduce interconversion between the (Z) to (E)
isomers (Table 4, Entry 2). Under these conditions, the
The (Z)-isomers of either an oxime ether or nitrone
analog were not isolated from any of the alkylation pro-
cedures, consistent with an earlier report that indicated
that the nitrone (Z)-7aa could only be produced briefly
when nitrone (E)-7aa was irradiated at a temperature
maintained between 6 and 10ꢂC [20,21]. However,
warming to room temperature resulted in isomerization
of (Z)-7aa to (E)-7aa. HPLC analysis of the products
produced in the alkylation reaction that afforded oxime
Table 4
Condensation of 4b and 4c with O-isopropyl hydroxylamine to give (E)- and (Z)-oxime ether 6.
Ratio of isomer
E:Z-oximea (%)
Total yield
(%)d
No.
(E)-Oxime
(Z)-Oxime
R1
R2
1
2
3
(E)-6bd
(E)-6bd
(E)-6cd
(Z)-6bd
(Z)-6bd
(Z)-6cd
Ph
Ph
Me
H
H
Br
89:11b
93:7b
43:57c
96
95
91
a R3 ¼ iPr for all entries.
b Ratio was determined by HPLC peak integration.
c Ratio was determined after isolation of the products by flash column chromatography.
d Total yield as a mixture.
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The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic
Structural Characterization of Oxime and Nitrone Products
437
Table 5
Ab initio calculations for nitrone and oxime ether geometric isomers.
Nitrone:D[(E)-7ad—(Z)-7ad]
(kcal/mol)
Oxime: D[(E)-6ad—(Z)-6ad]
(kcal/mol)
Oxime:D[(E)-6cd—(Z)-6cd]
(kcal/mol)
Calculation Method
B3LYP/6-31G* (solvent: H2O)
B3LYP-31G*// B3LYP-6-
31þG* (solvent: H2O)
ꢁ6.9
ꢁ6.1
ꢁ3.2
ꢁ3.5
2.1
2.3
B3LYP-31G*// B3LYP-aug-
cc- pvdz (solvent: H2O)
ꢁ5.6
ꢁ3.4
2.3
ratio of oxime ether (E)-6bd and (Z)-6bd was 93:7 by
analytical HPLC, indicating that (Z) to (E) product
isomerization was not a significant issue when the reac-
tion was conducted under slightly acidic conditions. To
further favor the formation of a (Z)-oxime isomer, a
sterically bulky bromine substituent was introduced at
the C-4 position of the isatin heterocycle. Condensation
of N-methyl-4-bromoisatin (4c) with O-isopropylhydrox-
ylamine hydrochloride in EtOH/H2O produced two
oxime ether products 6cd, which were separable by
silica gel column chromatography to give products in a
ratio of 57:43. The 1H NMR, 13C NMR and LC/MS
spectra of the two products were very similar but could
be differentiated by close inspection of the data. In the
1H NMR, the methine proton on the carbon atom
attached to the oxygen atom of the oxime ether appears
as a septet. For the minor oxime ether isomer, this
methine proton resonance is centered at 4.77 ppm,
which is slightly downfield of the methine proton for
the major oxime ether isomer, centered at 4.74 ppm.
The isatin N-Me protons resonate as singlets at 3.22
ppm for the minor isomer and 3.20 ppm for the major
isomer, whereas the signal for the two methyl protons of
the isopropyl group appear as doublets at 1.45 ppm for
the minor isomer and 1.47 ppm for the major isomer.
The minor product completely isomerized to the major
oxime ether within an hour as a solution in CDCl3 in an
NMR tube. Although the minor isomer was readily
recrystallized from a mixture of ether and hexanes at
4ꢂC, the small rod crystals that resulted failed to diffract
satisfactorily to allow a structure determination. An
attempt to prepare oxime ether (E)-6ad from the bromo
isatin oxime 6cd by subjecting each one separately to a
lithium-halogen exchange reaction followed by protona-
tion to allow correlation with (E)-6ad was unsuccessful.
In an effort to illuminate further the issue of (E) and
(Z) ratios, ab initio studies were conducted. Comparative
analysis of (E)- and (Z)-oximes 6ad and 6cd and (E)-
and (Z)-nitrones 7ad were performed through geometry
optimization and relative energy evaluation. The geome-
tries were optimized using DFT at the B3LYP/6-31G*
level of theory and basis set. The derived geometries
were then used to perform corrections using B3LYP/6-
31þG* and Dunning’s aug-cc-PVDZ basis sets [22].
Both geometry optimizations and single point energy
evaluations were performed in the presence of solvent
(water) using the PCM method available in G03 [23].
The relative energies for nitrones (E)- and (Z)-7ad, and
oximes (E)- and (Z)-6ad, and (E)- and (Z)-6cd are pre-
sented in Table 5. The conformational analysis calcula-
tion results presented in Table 5 reveal that the nitrone
7ad with the (E)-geometric configuration is stabilized by
5.9–6.9 kcal/mole when compared to its (Z)-isomer due
to an unfavorable dipole–dipole interaction between the
negatively charged oxygen of the nitrone and the
lone pair of electrons on the isatin carbonyl moiety in
the (Z)-isomer. The experimentally measured dipole
moments of a structurally similar pair of nitrone isomers
that incorporate an a-carbonyl moiety are reported to
differ by four units [21]. For example, the dipole
moments for (E)-N-(2,2,5,5-tetramethyl-4-oxodihydro-
furan-3(2H)-ylidene)methanamine oxide and its (Z)-iso-
mer were determined in dioxane to be 1.09 ꢃ 0.13 and
5.31 ꢃ 0.11, respectively [21]. The significant energy
difference between the (E)- and (Z)-nitrones 7ad is con-
sistent with earlier studies of the isomerization of
nitrone (E)-7aa to (Z)-7aa upon irradiation and explains
the difficulties encountered in isolating the nitrone (Z)-
7ad due to its facile isomerization to (E)-7ad at room
temperature [21]. For the oxime derivatives, repulsion
between the lone pairs of electrons on the oxime oxygen
atom and the isatin carbonyl moiety leads to (E)-6ad
being the more stable isomer by 3.2–3.5 kcal/mole
based on the three molecular calculation methods when
compared with (Z)-6ad. However, in oxime (Z)-6cd
where R2 ¼ Br, steric hindrance overrides the stereo
electronic effects that dominate the geometry of oxime
ether (Z)-6ad. Thus, the oxime ether (Z)-6cd is more
stable by 2.1–2.3 kcal/mole over the (E)-isomer. The
results of these calculations led us to assign the major
product as oxime ether (Z)-6cd and the minor product
as the trans-isomer, (E)-6cd (Table 4, Entry 3).
The insights associated with the effect of a Br substit-
uent at C-4 of the heterocycle on oxime geometry
prompted an examination of the effect of this substitu-
tion pattern on the outcome of oxime alkylation. Thus,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

438
N. Sin, B. L. Venables, X. Liu, S. Huang, Q. Gao, A. Ng, R. Dalterio,
R. Rajamani, and N. A. Meanwell
Vol 46
Table 6
lowed by filtration. Column chromatography was carried out
on silica gel (SiO2) according to Still’s flash chromatography
technique [24]. Melting points are uncorrected.
Alkylation of isatin oxime 5c with iso-propyl halides under basic
conditions and isopropyl alcohol under Mitsunobu conditions to give
O-alkylated (Z)-oxime ethers.
Preparative procedures.
3-(Hydroxyimino)-1-methylin-
dolin-2-one (5a). To a slurry of 1-methylisatin (4a) (5.28 g,
31.77 mmol) in EtOH (50 mL) was added a solution of
NH2OHꢀHCl (3.31 g, 47.66 mmol) in H2O (6 mL) and the
resulting brown reaction mixture stirred at rt. After 3 h, the
solvent was removed in vacuo to afford a greenish-yellow
paste that was triturated with H2O (50 mL), filtered, and
washed with H2O (50 mL). The greenish-yellow solid product
was dried in a vacuum oven overnight to give 5a (5.49 g, 98%
yield), which was used without further purification, m.p.
Entry
No.
Reagent
used
Oxime
(Z)-6cd (%)
Total
yield (%)a
Reaction
time (h)
1
2
3
iPrI
iPrBr
iPrOH
100
100
100
90
91
85
18
18
18
a Isolated yield after silica gel chromatography purification.
1
193.0–195.5ꢂC (lit. m.p. 193–197ꢂC) [25]; H NMR d 3.25 (s,
3 H), 6.83 (d, J ¼ 7.63 Hz, 1H), 7.08 (t, J ¼ 7.48 Hz, 1H),
7.40 (t, J ¼ 7.78 Hz, 1H), 8.06 (d, J ¼ 7.32 Hz, 1H), 9.57 (s,
1 H); 13C NMR d 26.2, 108.5, 115.6, 117.6, 123.3, 128.4,
132.7, 144.6, 163.8; LC-MS, MS m/z 177 (MþH).
N-methyl-4-bromoisatin oxime 5c was alkylated with
iso-propyl bromide and iso-propyl iodide under basic
conditions and also reacted with isopropyl alcohol under
Mitsunobu conditions with the result that the O-alky-
lated product (Z)-6cd was formed exclusively in high
yield in all cases. These data are presented in Table 6
and the oxime ether (Z)-6cd prepared in these reactions
was spectroscopically and chromatographically identical
to the major oxime ether product (Z)-6cd prepared by
condensing N-methyl-4-bromoisatin with O-isopropylhy-
droxylamine hydrochloride (Table 4, Entry 3). This
result presumably reflects the development of unfavora-
ble steric interactions between the nitrone N substituents
and the C-4 bromine atom in the transition state and
dominates the previously observed propensity for softer
electrophiles to react at the oxime N atom.
In summary, alkylation of the sodium salts of a series
of isatin oximes 5a and 5b with soft electrophiles such
as iodoalkanes leads to a slight preference for the N-
alkylated nitrone products, while harder electrophiles,
such as bromo- and chloro-alkanes, preferentially pro-
duce O-alkylated oxime ether products. Under Mitsu-
nobu conditions, isatin oximes 5b underwent alkylation
preferentially on nitrogen leading to a predominance of
the nitrone products. The installation of a bromine atom
at C-4 of the heteroaryl ring of oxime 5c led to the
exclusive formation of the (Z)-oxime ether, the steric
interactions provided by the bromine atom overriding
the inherent stereo electronic control exerted by the
interaction between the oxime oxygen atom and the a-
carbonyl moiety.
General alkylation procedure. To a solution of isatin
oxime 5 in DMF (0.25M) was added 1.2 equivalents of NaH
(60% dispersion in oil) followed after 10 min by 1.2 equiva-
lents of an alkyl halide. The progress of the reaction was fol-
lowed by TLC and LC/MS. When the reaction was complete,
the mixture was diluted with EtOAc and washed with dilute
aqueous HCl. The reaction of oximes 5 with 2-iodopropane and
2-bromopropane as electrophiles were typically complete after
0.5 and 2.5 h, respectively, as indicated by TLC and LC/MS.
The color of the reaction mixture changed during the course of
the reaction from an initial dark red, presumably due to the isa-
tin oxime alkoxy anion, to a brown reaction mixture after the
oxime alkoxy anion was consumed. However, both reaction
mixtures were allowed to stir at room temperature for 15 h
before work up. HPLC determination of the ratio of products
of the reaction using 2-iodopropane after 0.5 and 15 h showed
no change in the product ratio; thus, there was no interconver-
sion of products under the reaction conditions up to 15 h.
(E)-N-(1-methyl-2-oxoindolin-3-ylidene)ethanamine oxide
((E)-7ab). This compound was obtained as orange solid, m.p.
103.0–104.5ꢂC; 1H NMR d 1.52 (t, J ¼ 7.32 Hz, 3 H), 3.27
(s, 3 H), 4.81 (q, J ¼ 7.32 Hz, 2 H), 6.82 (d, J ¼ 7.63 Hz, 1
H), 7.09 (t, J ¼ 7.63 Hz, 1 H), 7.36 (t, J ¼ 7.63 Hz, 1 H),
8.33 (d, J ¼ 7.63 Hz, 1 H); 13C NMR d 13.4, 26.2, 42.5, 58.2,
107.8, 118.3, 123.2, 124.9, 131.4, 133.5, 141.1, 160.5; LC-MS,
MS m/z 205 (MþH); Anal. Calcd for C11H12N2O2: C, 64.69;
H, 5.92; N, 13.71. Found: C, 64.75; H, 5.83; N, 13.60.
(E)-3-(ethoxyimino)-1-methylindolin-2-one ((E)-6ab). This
1
compound was obtained as yellow solid, m.p. 76.0–77.0ꢂC; H
NMR d 1.44 (t, J ¼ 7.17 Hz, 3 H), 3.23 (s, 3 H), 4.54 (q, J ¼
7.12 Hz, 2 H), 6.81 (d, J ¼ 7.63 Hz, 1 H), 7.05 (t, J ¼ 7.63
Hz, 1 H), 7.37 (dt, J ¼ 7.78, 0.92 Hz, 1 H), 7.95 (d, J ¼ 7.32
Hz, 1 H); 13C NMR d 14.8, 26.1, 73.0, 108.3, 116.0, 123.0,
127.8, 132.3, 143.6, 144.5, 163.8; LC-MS, MS m/z 205
(MþH); Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N,
13.71. Found: C, 64.55; H, 5.67; N, 13.66.
(E)-N-(1-methyl-2-oxoindolin-3-ylidene)propan-1-amine ox-
ide ((E)-7ac). This compound was obtained as orange solid,
m.p. 76.5–78.0ꢂC; 1H NMR d 1.01 (t, J ¼ 7.48 Hz, 3 H),
1.95–2.03 (m, 2 H), 3.27 (s, 3 H), 4.76 (t, J ¼ 7.32 Hz, 2 H),
6.82 (d, J ¼ 7.63 Hz, 1 H), 7.09 (t, J ¼ 7.63 Hz, 1 H), 7.37
(dt, J ¼ 7.78, 1.22 Hz, 1 H), 8.35 (d, J ¼ 7.63 Hz, 1 H); 13C
NMR d 11.0, 22.0, 26.2, 64.3, 107.7, 118.2, 123.1, 124.9,
EXPERIMENTAL
1
General directions. H- and 13C NMR spectra were
obtained at 500 MHz and 126 MHz NMR, respectively. The
chemical shifts (d) are recorded in parts per million (ppm)
downfield from TMS. Unless otherwise noted, all NMR sam-
ples were prepared in CDCl3. IR spectra were recorded on Per-
kin Elmer System 2000 FT-IR. Drying of the organic layer
during work-up was carried out over anhydrous MgSO4, fol-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic
Structural Characterization of Oxime and Nitrone Products
439
131.4, 134.1, 141.0, 160.6; LC-MS, MS m/z 219 (MþH);
Anal. Calcd for C12H14N2O2: C, 66.03; H, 6.46; N, 12.83.
Found: C, 66.03; H, 6.24; N, 12.79.
116.1, 123.0, 127.6, 132.1, 143.4, 144.3, 163.9; LC-MS, MS
m/z 247 (MþH).
(E)-N-(1-methyl-2-oxoindolin-3-ylidene)cyclopentanamine
oxide ((E)-7af). This compound was obtained as orange solid,
(E)-1-methyl-3-(propoxyimino)indolin-2-one ((E)-6ac). This
1
1
m.p. 98.0–100.0ꢂC; H NMR d 1.64–1.73 (m, 2 H) 1.88–1.98
compound was obtained as yellow solid, m.p. 53.0–54.5ꢂC; H
(m, 2 H), 2.02–2.09 (m, 2 H), 2.10–2.19 (m, 2 H), 3.27 (s, 3
H), 6.45–6.53 (m, 1 H), 6.81 (d, J ¼ 7.93 Hz, 1 H), 7.08 (dt, J
¼ 7.63, 0.92 Hz, 1 H), 7.35 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 8.35
(d, J ¼ 7.63 Hz, 1 H); 13C NMR d 26.1, 26.1, 31.8, 70.7,
107.7, 118.5, 123.2, 124.8, 131.2, 133.8, 140.8, 160.7; LC-MS,
MS m/z 245 (MþH); Anal. Calcd for C14H16N2O2: C, 68.83;
H, 6.60; N, 11.46. Found: C, 68.95; H, 6.56; N, 11.44.
NMR d 1.01 (t, J ¼ 7.32 Hz, 3 H), 1.81–1.89 (m, 2 H) 3.23
(s, 3 H), 4.45 (t, J ¼ 6.56 Hz, 2 H), 6.81 (d, J ¼ 7.93 Hz, 1
H), 7.06 (t, J ¼ 7.48 Hz, 1 H), 7.38 (t, J ¼ 7.78 Hz, 1 H),
7.95 (d, J ¼ 7.63 Hz, 1 H); 13C NMR d 10.3, 22.6, 26.1, 79.0,
108.4, 116.0, 123.0, 127.7, 132.3, 143.6, 144.5, 163.8; LC-MS,
MS m/z 219 (MþH); Anal. Calcd for C12H14N2O2: C, 66.03;
H, 6.46; N, 12.83. Found: C, 65.97; H, 6.46; N, 12.74.
(E)-3-(cyclopentyloxyimino)-1-methylindolin-2-one
((E)-
(E)-3-(Isopropoxyimino)-1-methylindolin-2-one ((E)-6ad)
and (E)-N-(1-methyl-2-oxoindolin-3-ylidene)propan-2-amine
oxide ((E)-7ad). To a solution of isatin oxime 5a (1.01 g, 5.73
mmol) in DMF (23 mL, 0.25M) was added NaH (60% 0.275 g
of a dispersion in oil, 6.88 mmol) followed after 10 min by 2-
iodopropane (1.18 g, 6.88 mmol). After stirring the brown
reaction mixture at rt for 15 h, the DMF was removed in
vacuo, the residue dissolved in EtOAc (150 mL), and then
washed with 1N HCl (2 ꢄ 50 mL). The aqueous layer was
extracted with EtOAc (50 mL), and the combined organic
layers washed with brine, dried, and concentrated to afford vis-
cous brown oil. Chromatography on a column of silica gel
using a 3:1 mixture of hexane and EtOAc as eluant gave
nitrone (E)-7ad (0.675 g, 54% yield) as an orange solid fol-
lowed by oxime ether (E)-6ad (0.441 g, 45% yield) as a
viscous yellow oil which solidified upon standing at rt.
6af). This compound was obtained as yellow solid, m.p. 54.0–
55.5ꢂC; 1H NMR d 1.59–1.68 (m, 2 H), 1.70–1.81 (m, 2 H),
1.87–1.96 (m, 2 H), 1.97–2.05 (m, 2 H), 3.21 (s, 3 H), 5.06–
5.12 (m, 1 H), 6.79 (d, J ¼ 7.93 Hz, 1 H), 7.03 (dt, J ¼ 7.55,
0.76 Hz, 1 H), 7.35 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 7.88 (d, J ¼
7.32 Hz, 1 H); 13C NMR d 23.9, 25.9, 32.6, 89.2, 108.4,
116.0, 123.0, 127.5, 132.3, 143.6, 144.4, 163.8; LC-MS, MS
m/z 245 (MþH); Anal. Calcd for C14H16N2O2: C, 68.83; H,
6.60; N, 11.46. Found: C, 69.01; H, 6.52; N, 11.47.
(E)-N-(1-methyl-2-oxoindolin-3-ylidene)cyclohexanamine
oxide ((E)-7ag). This compound was obtained as orange solid,
m.p. 109.5–110.5ꢂC; 1H NMR d 1.19–1.30 (m, 1 H), 1.40–
1.54 (m, 2 H), 1.68–1.75 (m, 1 H), 1.86–1.98 (m, 6 H), 3.27
(s, 3 H), 5.94–6.02 (m, 1 H), 6.81 (d, J ¼ 7.63 Hz, 1 H), 7.08
(dt, J ¼ 7.63, 0.92 Hz, 1 H), 7.35 (dt, J ¼ 7.71, 1.37 Hz, 1
H), 8.36 (d, J ¼ 7.63 Hz, 1 H); 13C NMR d 25.1, 25.2, 26.1,
30.8, 69.6, 107.7, 118.5, 123.2, 124.8, 131.2, 133.2, 140.8,
160.6; LC-MS, MS m/z 249 (MþH); Anal. Calcd for
C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.77; H,
7.00; N, 10.82.
(E)-7ad: m.p. 113.0–114.5ꢂC; IR (neat) mmax 3055, 2982,
1701, 1610, 1551, 1466, 1241, 737 cmꢁ1 1H NMR d 1.45
;
(dd, J ¼ 6.56, 1.37 Hz, 6H), 3.27 (d, J ¼ 1.22 Hz, 3 H), 6.28–
6.37 (m, 1H), 6.82 (d, J ¼ 7.93 Hz, 1H), 7.07–7.12 (m, 1H),
8.37 (d, J ¼ 7.63 Hz, 2H); 13C NMR d 20.5, 26.2, 61.9,
107.7, 118.5, 123.2, 124.8, 131.2, 133.1, 140.9, 160.6. LC-MS,
MS m/z 219 (MþH); Anal. Calcd for C12H14N2O2: C, 66.03;
H, 6.46; N, 12.83; found: C, 66.17; H, 6.24; N, 12.69.
(E)-3-(cyclohexyloxyimino)-1-methylindolin-2-one
((E)-
6ag). This compound was obtained as yellow solid, m.p. 57.0–
60.0ꢂC; 1H NMR d 1.30–1.46 (m, 3 H), 1.53–1.59 (m, 1 H),
1.61–1.70 (m, 2 H), 1.72–1.82 (m, 2 H), 2.03–2.11 (m, 2 H),
3.23 (s, 3 H), 4.48–4.57 (m, 1 H), 6.80 (d, J ¼ 7.63 Hz, 1 H),
7.03–7.07 (m, 1 H), 7.36 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 7.95 (d,
J ¼ 7.32 Hz, 1 H); 13C NMR d 23.6, 25.6, 26.2, 31.7, 84.4,
108.3, 116.1, 123.0, 127.7, 132.2, 143.5, 144.4, 163.9; LC-MS,
MS m/z 249 (MþH); Anal. Calcd for C15H18N2O2: C, 69.74;
H, 7.02; N, 10.84. Found: C, 69.75; H, 6.96; N, 10.79.
(E)-6ad: m.p. 68.5–72.0ꢂC; IR (neat) mmax 3057, 2976,
1
1727, 1608, 1468, 1330, 971, 748 cmꢁ1; H NMR d 1.41 (dd,
J ¼ 6.41, 1.53 Hz, 6H), 3.21 (d, J ¼ 1.53 Hz, 3H), 4.69–4.80
(m, 1H), 6.79 (d, J ¼ 7.93 Hz, 1H), 7.03 (t, J ¼ 7.48 Hz, 1H),
7.32–7.38 (m, 1H), 7.93 (d, J ¼ 7.32 Hz, 1H); 13C NMR d
21.8, 26.1, 79.6, 108.3, 116.0, 122.9, 127.7, 132.2, 143.3,
144.4, 163.8; LC-MS, MS m/z 219 (MþH); Anal. Calcd for
C12H14N2O2: C, 66.03; H, 6.46; N, 12.83; found: C, 66.03; H,
6.24; N, 12.80.
(E)-N-(1-methyl-2-oxoindolin-3-ylidene)pentan-3-amine ox-
ide ((E)-7ae). This compound was obtained as orange solid,
m.p. 82.5–84.0ꢂC; 1H NMR d 0.89 (t, J ¼ 7.48 Hz, 6 H),
1.64–1.77 (m, 2 H), 1.92–2.05 (m, 2 H), 3.28 (s, 3 H), 6.06–
6.14 (m, 1 H), 6.83 (d, J ¼ 7.93 Hz, 1 H), 7.10 (dt, J ¼ 7.63,
0.92 Hz, 1 H), 7.37 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 8.42 (d, J ¼
6.71 Hz, 1 H); 13C NMR d 10.4, 26.2, 26.6, 73.0, 107.7,
118.2, 123.2, 124.9, 131.4, 135.4, 140.8, 160.8; LC-MS, MS
m/z 247 (MþH); Anal. Calcd for C14H18N2O2: C, 68.27; H,
7.36; N, 11.37. Found: C, 68.18; H, 7.13; N, 11.38.
(E)-1-(4-methoxyphenyl)-N-(1-methyl-2-oxoindolin-3-ylide-
ne)methanamine oxide ((E)-7ah). This compound was
1
obtained as orange solid, m.p. 126.0–133.0ꢂC; H NMR d 3.29
(s, 3 H), 3.78 (s, 3 H), 5.88 (s, 2 H), 6.80 (d, J ¼ 7.63 Hz, 1
H), 6.87 (d, J ¼ 8.85 Hz, 2 H), 7.06 (t, J ¼ 7.78 Hz, 1 H),
7.35 (dt, J ¼ 7.71, 1.07 Hz, 1 H), 7.55 (d, J ¼ 8.55 Hz, 2 H),
8.30 (d, J ¼ 7.63 Hz, 1 H); 13C NMR d 26.3, 55.4, 65.3,
107.8, 114.2, 118.3, 123.2, 125.0, 126.3, 131.2, 131.5, 133.4,
141.1, 160.2, 160.8; LC-MS, MS m/z 297 (MþH); Anal. Calcd
for C17H16N2O3: C, 68.90; H, 5.44; N, 9.45. Found: C, 68.69;
H, 5.42; N, 9.24.
(E)-3-(4-methoxybenzyloxyimino)-1-methylindolin-2-one
((E)-6ah). This compound was obtained as orange solid, m.p.
(E)-1-methyl-3-(pentan-3-yloxyimino)indolin-2-one ((E)-6ae).
This compound was obtained as yellow viscous oil, 1H NMR
d 0.96 (t, J ¼ 7.32 Hz, 6 H), 1.69–1.85 (m, 4 H), 3.23 (s, 3
H), 4.38–4.45 (m, 1 H), 6.81 (d, J ¼ 7.93 Hz, 1 H), 7.05 (dt, J
¼ 7.48, 0.92 Hz, 1 H), 7.36 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 7.94
(d, J ¼ 7.63 Hz, 1 H); 13C NMR d 9.6, 26.2, 89.8, 108.3,
1
96.5–101.0ꢂC; H NMR d 3.23 (s, 3 H), 3.81 (s, 3 H), 5.44 (s,
2 H), 6.80 (d, J ¼ 7.94 Hz, 1 H), 6.91 (d, J ¼ 8.55 Hz, 2 H),
7.00 (t, J ¼ 7.63 Hz, 1 H), 7.35 (dt, J ¼ 7.86, 1.07 Hz, 1 H),
7.39 (d, J ¼ 8.54 Hz, 2 H), 7.88 (d, J ¼ 7.32 Hz, 1 H); 13C
NMR d 26.2, 55.4, 79.2, 108.3, 114.1, 116.0, 123.0, 128.0,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

440
N. Sin, B. L. Venables, X. Liu, S. Huang, Q. Gao, A. Ng, R. Dalterio,
R. Rajamani, and N. A. Meanwell
Vol 46
128.5, 130.3, 132.5, 144.0, 144.6, 160.0, 163.7; LC-MS, MS
m/z 297 (MþH) ); Anal. Calcd for C17H16N2O3: C, 68.90; H,
5.44; N, 9.45. Found: C, 68.63; H, 5.31; N, 9.18.
62.2, 109.1, 118.7, 123.6, 124.9, 127.0, 128.4, 129.7, 131.2,
132.8, 134.1, 140.8, 160.0; LC-MS, MS m/z 281 (MþH);
Anal. Calcd for C17H16N2O2: C, 72.83; H, 5.75; N, 9.99.
Found: C, 72.72; H, 5.65; N, 9.92.
(E)-6bd: This compound was obtained as yellow solid, m.p.
125.5–127.0ꢂC; 1H NMR d 1.47 (d, J ¼ 6.1 Hz, 6 H), 4.78–
4.87 (m, 1 H), 6.81 (d, J ¼ 7.9 Hz, 1 H), 7.10 (t, J ¼ 7.5 Hz,
1 H), 7.30 (dt, J ¼ 7.9, 1.2 Hz, 1 H), 7.41 (d, J ¼ 7.0 Hz, 3
H), 7.52 (t, J ¼ 7.5 Hz, 2 H), 8.05 (d, J ¼ 6.4 Hz, 1 H); 13C
NMR d 21.9, 79.9, 109.7, 116.2, 123.4, 126.8, 127.9, 128.3,
129.8, 132.1, 134.0, 143.1, 144.4, 163.0; LC-MS, MS m/z 281
(MþH); Anal. Calcd for C17H16N2O2: C, 72.83; H, 5.75; N,
9.99. Found: C, 72.77; H, 5.72; N, 9.93.
(E)-3-(Isopropoxyimino)-1-phenylindolin-2-one ((E)-6bd)
and (E)-N-(2-oxo-1-phenylindolin-3-ylidene)propan-2-amine
oxide ((E)-7bd). To a solution of 5b (104 mg, 0.437 mmol),
2-propanol (67.4 lL, 0.875 mmol) and triphenylphosphine
(229 mg, 0.875 mmol) in THF (1.8 mL) maintained at 0ꢂC
was added diisopropyl azodicarboxylate (172 lL, 0.875
mmol). The resulting greenish-yellow solution was stirred at rt
for 18 h, diluted with EtOAc (25 mL) and washed with aque-
ous 10% Na2CO3. The aqueous layer was extracted with
EtOAc (25 mL), and the combined organic layers washed with
0.1N HCl (5 mL) and brine, dried and concentrated to afford a
light orange viscous oil. Chromatography on a column of silica
gel using a 4:1 mixture of hexane and EtOAc as eluant gave
nitrone (E)-7bd (91 mg, 74% yield) as an orange solid
followed by oxime ether (E)-6bd (12.3 mg, 10% yield) as a
yellow viscous oil which solidified upon standing at rt.
(E)-2-tert-butoxy-N-(1-methyl-2-oxoindolin-3-ylidene)-2-oxoe-
thanamine oxide ((E)-7ai). This compound was obtained as
orange solid, m.p. 132.0–142.0ꢂC; 1H NMR d 1.50 (s, 9 H),
3.25 (s, 3 H), 5.45 (s, 2 H), 6.83 (d, J ¼ 7.93 Hz, 1 H), 7.10
(t, J ¼ 7.63 Hz, 1 H), 7.39 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 8.34
(d, J ¼ 7.63 Hz, 1 H); 13C NMR d 26.2, 28.1, 65.4, 83.7,
107.9, 117.8, 123.3, 125.3, 132.0, 134.9, 141.6, 160.7, 164.3;
LC-MS, MS m/z 313 (MþNa); Anal. Calcd for C15H18N2O4:
C, 62.05; H, 6.24; N, 9.65. Found: C, 61.72; H, 6.50; N, 9.28.
(E)-tert-butyl-2-(1-methyl-2-oxoindolin-3-ylideneaminooxy)
acetate ((E)-6ai). This compound was obtained as yellow
1
solid, m.p. 120.5–122.0ꢂC; H NMR d 1.48 (s, 9 H), 3.22 (s, 3
H), 4.90 (s, 2 H), 6.81 (d, J ¼ 7.63 Hz, 1 H), 7.06 (dt, J ¼
7.63, 0.92 Hz, 1 H), 7.39 (dt, J ¼ 7.78, 1.22 Hz, 1 H), 8.05
(d, J ¼ 7.63 Hz, 1 H); 13C NMR d 26.2, 28.3, 73.3, 82.5,
108.5, 115.7, 123.3, 128.7, 133.0, 144.8, 145.1, 163.5, 167.7;
LC-MS, MS m/z 313 (MþNa); Anal. Calcd for C15H18N2O4:
C, 62.05; H, 6.24; N, 9.65. Found: C, 61.87; H, 6.525; N,
9.56.
(E)-3-(Isopropoxyimino)-1-methylindolin-2-one ((E)-6ad).
To a slurry of 4a (5.02 g, 6.14 mmol) in EtOH (12 mL) was
added a brown cloudy solution of 2-(ammoniooxy)propane
chloride (0.822 g, 7.37 mmol) in H2O (4 mL). The resulting
brown reaction mixture was stirred at rt for 3 h, the solvent
was removed in vacuo to leave a greenish-yellow oil which
was redissolved in EtOAc (50 mL), and washed with 1N aque-
ous HCl (2 ꢄ 10 mL). The aqueous layers were extracted with
EtOAc (50 mL), and the organic layers combined and washed
with 10% aqueous Na2CO3 (10 mL) and brine before being
dried and concentrated to afford a viscous yellow oil. 1H
NMR d 1.42 (d, J ¼ 6.10 Hz, 6H), 3.23 (s, 3H), 4.73–4.81 (m,
1H), 6.81 (d, J ¼ 7.93 Hz, 1H), 7.05 (t, J ¼ 7.63 Hz, 1H),
7.37 (t, J ¼ 7.32 Hz, 1H), 7.95 (d, J ¼ 7.63 Hz, 1H); 13C
NMR d 21.8, 26.1, 79.6, 108.3, 116.1, 122.9, 127.7, 131.7,
143.3, 144.4, 163.9; LC-MS, MS m/z 219 (MþH).
(E)-7bd: 1H NMR d 1.48 (d, J ¼ 6.4 Hz, 6 H), 6.30–6.39
(m, 1 H), 6.80 (d, J ¼ 7.9 Hz, 1 H), 7.13 (t, J ¼ 7.6 Hz, 1 H),
7.29 (dt, J ¼ 7.8, 0.9 Hz, 1 H), 7.41–7.46 (m, 3 H), 7.54 (t, J
¼ 7.5 Hz, 2 H), 8.48 (d, J ¼ 7.3 Hz, 1 H).
(E)-6bd: 1H NMR d 1.46 (d, J ¼ 6.4 Hz, 6 H), 4.78–4.87
(m, 1 H), 6.81 (d, J ¼ 7.9 Hz, 1 H), 7.10 (t, J ¼ 7.6 Hz, 1 H),
7.30 (t, J ¼ 7.8 Hz, 1 H), 7.39–7.43 (m, 3 H), 7.52 (t, J ¼ 7.5
Hz, 2 H), 8.05 (d, J ¼ 7.6 Hz, 1 H).
4-Bromo-1-methylindoline-2,3-dione (4c). K2CO3 (4.95 g,
35.84 mmol) and CH3I (10.17 g, 71.67 mmol) were added to a
solution of 4-bromoisatin (5.4 g, 23.89 mmol) in DMF (50
mL) and the mixture heated at 80ꢂC for 30 min. After cooling
to rt, the mixture was diluted with H2O (50 mL) and the pre-
cipitated red solid collected by filtration and washed with H2O
(2 ꢄ 25 mL). The product was dried in a vacuum oven to give
4c (5.20 g) as a red solid that was used further without purifi-
3-(Hydroxyimino)-1-phenylindolin-2-one (5b). 3-(Hy-drox-
yimino)-1-phenylindolin-2-one (5b) was prepared in quantita-
tive yield from 1-phenylisatin (4b) according to the procedure
described for the preparation of 5a. This compound was
obtained as orange solid, m.p. 219.0–221.0ꢂC (lit. m.p. 221ꢂC)
1
[26]; H NMR d 6.79 (d, J ¼ 7.9 Hz, 1 H), 7.14 (dt, J ¼ 7.6,
0.6 Hz, 1 H), 7.35 (dt, J ¼ 7.8, 1.2 Hz, 1 H), 7.41–7.44 (m, 2
H), 7.46 (t, J ¼ 7.6 Hz, 1 H), 7.57 (t, J ¼ 7.6 Hz, 2 H), 8.15
(d, J ¼ 7.6 Hz, 1 H); 13C NMR d 109.8, 116.2, 123.7, 127.0,
127.8, 128.7, 129.8, 132.1, 134.2, 144.0, 144.3, 164.5; Anal.
Calcd for C14H10N2O2: C, 70.58; H, 4.23; N, 11.75; found: C,
70.45; H, 4.14; N, 11.49.
1
cation, m.p.199.5–200.5ꢂC; H NMR d 3.25 (s, 3 H), 6.84 (d,
J ¼ 7.9 Hz, 1 H), 7.26 (d, J ¼ 3.4 Hz, 1 H), 7.41 (t, J ¼ 8.1
Hz, 1 H); 13C NMR d 26.4, 108.7, 116.4, 121.7, 128.6, 138.4,
153.1, 157.4, 180.7; Anal. Calcd for C9H6BrNO2: C, 45.03; H,
2.51; N, 5.83; Br, 33.28. Found: C, 44.84; H, 2.48; N, 5.83;
Br, 33.02.
(E)-3-(Isopropoxyimino)-1-phenylindolin-2-one ((E)-6bd)
and (E)-N-(2-oxo-1-phenylindolin-3-ylidene)propan-2-amine
oxide ((E)-7bd). Compounds (E)-6bd and (E)-7bd were pre-
pared from 5b in 36% and 47% yield, respectively, following
the alkylation procedure used for the preparation of (E)-6ad
and (E)-7ad.
4-Bromo-3-(hydroxyimino)-1-methylindolin-2-one
(5c).
Compound 5c was prepared from 4c using the procedure
described for the preparation of 5a with the exception that the
reaction was heated at 55ꢂC overnight. This compound was
1
obtained as orange solid, m.p. 186.0–188.5ꢂC; H NMR d 3.25
(E)-7bd: This compound was obtained as orange solid, m.p.
(s, 3 H), 6.84 (d, J ¼ 7.9 Hz, 1 H), 7.25 (d, J ¼ 7.2 Hz, 1 H),
7.41 (t, J ¼ 7.9 Hz, 1 H); 13C NMR d 26.4, 108.7, 116.4,
121.7, 128.6, 138.4, 153.1, 157.4, 180.7; Anal. Calcd for
C9H7BrN2O2: C, 42.38; H, 2.76; N, 10.98; Br, 31.32. Found:
C, 42.14; H, 2.73; N, 10.74; Br, 30.95.
1
83.0–89.0ꢂC; H NMR d 1.47 (d, J ¼ 6.4 Hz, 6 H), 6.30–6.39
(m, 1 H), 6.79 (d, J ¼ 7.9 Hz, 1 H), 7.11 (t, J ¼ 7.5 Hz, 1 H),
7.27 (t, J ¼ 7.8 Hz, 1 H), 7.42 (d, J ¼ 7.0 Hz, 3 H), 7.52 (t, J
¼ 7.5 Hz, 2 H), 8.47 (d, J ¼ 7.3 Hz, 1 H); 13C NMR d 20.5,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
The Alkylation of Isatin-Derived Oximes: Spectroscopic and X-Ray Crystallographic
Structural Characterization of Oxime and Nitrone Products
441
C W.; Li, Z.; Clarke, J.; Genovesi, E. V.; Medina, I.; Lamb, L.;
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(Z)-4-Bromo-3-(isopropoxyimino)-1-methylindolin-2-one
((Z)-6cd) and (E)-4-bromo-3-(isopropoxyimino)-1-methylindo-
lin-2-one ((E)-6cd). To a slurry of 4c (1.03 g, 4.29 mmol) in
EtOH (12 mL) was added a brown cloudy solution of 2-
(ammoniooxy)propane chloride (0.527 g, 4.72 mmol) in H2O
(4 mL). The brown mixture was stirred at 52ꢂC for 3.5 h, the
solvent removed in vacuo and the residue dissolved in EtOAc
(50 mL) and washed with H2O (50 mL). The aqueous layer
was extracted with EtOAc (50 mL), and the combined organic
layers were washed with brine, dried, and concentrated to
leave a light orange viscous oil. Chromatography on a column
of silica gel using a mixture of hexane and EtOAc (3:1 then
2:1) as eluant afforded oxime ether (Z)-6cd (0.706 g, 56%
yield) followed by oxime ether (E)-6cd (0.448 g, 35% yield)
both isolated as yellow solids.
(Z)-6cd: m.p. 67.0–68.5ꢂC; 1H NMR d 1.46 (d, J ¼ 6.41
Hz, 6H), 3.20 (s, 3H), 4.70–4.78 (m, 1H), 6.74 (d, J ¼ 7.93
Hz, 1H), 7.15 (t, J ¼ 7.93 Hz, 1H), 7.22 (d, J ¼ 8.24 Hz,
1H); 13C NMR d 21.4, 25.8, 80.1, 107.0, 116.7, 118.5, 127.6,
131.0, 141.1, 144.9, 156.6; LC-MS, MS m/z 297 (MþH);
Anal. Calcd for C12H13BrN2O2: C, 48.50; H, 4.41; N, 9.42; Br,
26.89. Found: C, 48.74; H, 4.28; N, 9.32; Br, 27.00.
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(E)-6cd: m.p. 78.0–79.5ꢂC; 1H NMR d 1.44 (d, J ¼ 6.10 Hz,
6H), 3.22 (s, 3H), 4.76–4.85 (m, 1H), 6.74 (d, J ¼ 7.93 Hz, 1H),
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C
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(Z)-6cd was also prepared exclusively by alkylation of 5c
with 2-iodopropane or 2-bromopropane under the same condi-
tions used to prepare (E)-6ad, m.p. 66.5–68.0ꢂC; 1H NMR d
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6.74 (dd, J ¼ 7.6, 0.6 Hz, 1H), 7.16 (t, J ¼ 7.9 Hz, 1H), 7.23
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(Z)-6cd was also prepared exclusively in 85% yield from 5c
and isopropyl alcohol under the Mitsunobu conditions
described for the preparation of (E)-6bd and (E)-7bd above.
This compound was obtained as yellow solid, m.p. 66.0–67.5ꢂC;
1H NMR d 1.47 (d, J ¼ 6.4 Hz, 6H), 3.21 (s, 3H), 4.70–4.79 (m,
1H), 6.75 (d, J ¼ 7.6 Hz, 1H), 7.16 (t, J ¼ 7.9 Hz, 1H), 7.24 (d,
J ¼ 8.2 Hz, 1H); LC-MS, MS m/z 297 (MþH).
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