Nucleophilic substitution reactions of N-alkoxyimidoyl fluorides by carbon nucleophiles

Article abstract of DOI:10.1139/V07-097

Nucleophilic substitutions of N-alkoxybenzoimidoyl fluorides [p-ClArC(F)=NOR; R = CH₃, i-Pr] by enolate-type ions have been performed to produce compounds that can exist in two tautomeric forms: the imine form{p-ClArC(Y)=NOR [Y = CH(CN)₂

Full text of DOI:10.1139/V07-097

913
Nucleophilic substitution reactions of
N-alkoxyimidoyl fluorides by carbon nucleophiles
Debra D. Dolliver, David B. Delatte, Derek B. Linder, James E. Johnson,
Diana C. Canesco, and Jeffrey E. Rowe
Abstract: Nucleophilic substitutions of N-alkoxybenzoimidoyl fluorides [p-ClArC(F)=NOR; R = CH3, i-Pr] by enolate-
type ions have been performed to produce compounds that can exist in two tautomeric forms: the imine form{p-
ClArC(Y)=NOR [Y = CH(CN)2, CH(CN)(CO2Et), CH(CO2Et)2]}or the enamine form {p-ClArC(NHOR)=C(R1)(R2)
[R1, R2 = CN, CO2Et]}. These compounds display varying ratios of imine–enamine tautomerizm in chloroform: the
diester compound exists almost solely in the imine form, the dicyano compound exists solely in the enamine form, and
the cyano-ester compound exists in both tautomeric forms. Comparison of the imine–enamine equilibrium in chloro-
form of the cyano-ester compound to an analogue where the p-ClAr group has been replaced by a methyl group re-
veals that the aromatic ring has a significant effect on the imine–enamine distribution. The former exists in both the
imine and enamine form, while the latter exists solely in the enamine form. Complete NMR characterization data for
the enamine form of CH3C(NHOCH3)=C(CN)(CO2Et) is also reported. The acidity of p-ClArC(NHOR)=C(CN)2 is
demonstrated by a high degree of dissociation of the enamine proton in DMSO. Substitution reactions of p-
ClArC(F)=NOi-Pr by Grignard reagents (PhMgBr, CH3MgBr, and PhCCMgBr) have also been performed to produce
single geometric isomers of p-ClArC(Ph)=NOi-Pr, p-ClArC(CCPh)=NOi-Pr, and p-ClArC(CH3)=NOi-Pr. A modified
synthesis of N-alkoxyimidoyl fluorides, which prevents a competing reaction of the product with the solvent, is re-
ported.
Key words: N-alkoxyimidoyl fluoride, enolate ion substitution, Grignard substitution, imine–enamine tautomerizm,
carbon acid.
Résumé : On a effectué des réactions de substitutions nucléophiles de fluorures de N-alkoxybenzoimidoyle [p-
ClArC(F)=NOR; R = CH3, i-Pr] par des ions de type énolate pour obtenir des composés qui existent sous deux formes
tautomères: la forme imine {p-ClArC(Y)=NOR [Y = CH(CN)2, CH(CN)(CO2Et), CH(CO2Et)2]} ou la forme énamine
{p-ClArC(NHOR)=C(R1)(R2) [R1 = R2 = CN, CO2Et]. Dans le chloroforme, ces composés présentent des rapports di-
vers de tautomérie imine–énamine; le composé dicyano existe uniquement sous la forme énamine alors que le composé
cyano-ester existe sous les deux formes tautomères. Une comparaison de l’équilibre imine–énamine dans le chloro-
forme du composé cyano-ester avec celui observé avec un analogue dans lequel le groupe p-ClAr a été remplacé par
un groupe méthyle révèle que le noyau aromatique joue un rôle important sur la distribution imine–énamine. Le pre-
mier existe dans les deux formes imine et énamine alors que le deuxième n’existe que sous la forme énamine. On rap-
porte aussi les données RMN pour une caractérisation complète de la forme CH3C(NHOCH3)=C(CN)(CO2Et). L’acidité
du composé p-ClArC(NHOR)=C(CN)2 est démontrée par le degré élevé de dissociation du proton énamine dans le
DMSO. On a aussi réalisé des réactions de substitutions en solution du p-ClArC(F)=NOiPr par des réactifs de Grignard
(PhMgBr, CH3MgBr et PhCCMgBr) qui ont conduit aux isomères géométriques uniques p-ClArC(Ph)=NOiPr, p-
ClArC(CCPh)=NOiPr et p-ClArC(CH3)=NOiPr. On a aussi mis au point une synthèse modifiée des fluorures de N-al-
koxyimidoyles qui élimine une réaction compétitive avec le solvant.
Mots-clés : fluorure de N-alkoxyimidoyle, substitution par un ion énolate, substitution de Grignard, tautomérie
imine–énamine, carbone acide.
[Traduit par la Rédaction] Dolliver et al. 922
Received 24 April 2007. Accepted 06 July 2007. Published on the NRC Research Press Web site at canjchem.nrc.ca on
7 September 2007.
D.D. Dolliver,1 D.B. Delatte, and D.B. Linder. Department of Chemistry and Physics, Southeastern Louisiana University, SLU
10878, Hammond, LA 70402, USA.
J.E. Johnson and D.C. Canseco. Department of Chemistry and Physics, Texas Woman’s University, Denton, TX 76204–5859,
USA.
J.E. Rowe. School of Chemistry, La Trobe University, Victoria 3086, Australia.
1Corresponding author (e-mail: ddolliver@selu.edu).
Can. J. Chem. 85: 913–922 (2007)
doi:10.1139/V07-097
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914
Can. J. Chem. Vol. 85, 2007
Fig. 1. (Z)-N-alkoxyimines.
Introduction
X
OR
Nucleophilic addition–elimination reactions at the C=O
bond of acid halides are commonplace in synthetic schemes.
This type of reaction has also been studied in imidoyl
halides (1), hydrazonyl halides (2), and N-alkoxyimidoyl
halides (3). These latter reactions, however, have been lim-
ited because of the diminished electrophilicity of the azo-
methine carbon in these compounds and the lability of the
N–O bond. In addition, there are synthetic challenges posed
because of the existence of possible E–Z isomeric mixtures
around the C=N bond (4). To enhance the electrophilicity of
the C=N bond of N-alkoxyimine compounds, Lewis acids
have sometimes been included in the reaction medium (5).
N-Alkoxyimidoyl chloride (2) and bromide (3) compounds
(Fig. 1) are known to undergo nucleophilic substitution reac-
tions with nucleophiles, such as amines, amide ions, and
alkoxide ions, but these types of substitution reactions are
relatively sluggish and are viewed as having limited syn-
thetic utility (3). It has been found, however, that N-
alkoxyimidoyl fluorides (1) are much more electrophilic
than their bromo- or chloro-analogues (2 or 3) and will un-
dergo nucleophilic attack by methoxide ion at an accelerated
rate (3a). The tetrahedral intermediate formed from the
nucleophilic attack of methoxide then rapidly loses the fluo-
ride ion to reform the C=N bond faster than it undergoes ro-
tation to another conformer. Therefore, the stereochemistry
of the product from this reaction is retained exclusively
when starting from the Z isomer and is predominately re-
tained when starting from the E-isomer. This is due to the
fact that the tetrahedral intermediate first formed by
methoxide attack in the case of the Z isomer (A in
Scheme 1) already has a pair of electrons anti-periplanar to
the fluoride leaving group. In the E-isomer case, the first-
formed intermediate (B) must undergo rotation to align lone
pair electrons in an anti-periplanar configuration. The rota-
tional barrier 1 is lower than rotational barrier 2, and con-
former B therefore predominately rotates over the lower
rotational energy barrier to a conformation that leads to re-
tained stereochemistry (3a). Owing to the enhanced
electrophilicity of (Z)-N-alkoxyimidoyl fluoride compounds,
their ability to undergo a methoxide substitution at a much
faster rate, and the retention of stereochemistry demon-
strated in the product, it was felt that they might be good
candidates for synthetically useful routes to specific geomet-
ric isomers of oxime ethers.
C
N
Z
1a: X = F, Z = Cl, R = CH3
1b: X = F, Z = Cl, R = i-Pr
1c: X = F, Z = H, R = CH3
2: X = Cl
3: X = Br
4: X = OR
gle geometric isomer (5, 6b). This paper discusses a tech-
nique by which a specific geometric stereoisomer of an
oxime ether may be prepared even when there is little differ-
ence in the thermodynamic stability of the two geometric
isomers. This can be accomplished by nucleophilic substitu-
tion of an N-alkoxyimidoyl fluoride by a Grignard reagent.
In addition, the nucleophilic substitution reaction of N-
alkoxyimidoyl fluorides by enolate-type anions will be dis-
cussed. The compounds produced by this technique are in-
teresting in that they display varying degrees of imine–
enamine tautomerizm.
Results and discussion
Enolate-type ion substitution of N-alkoxyimidoyl
fluorides
The substitution of the fluorine in (Z)-N-alkoxy-4-
chlorobenzenecarboximidoyl fluoride (1a and 1b) with dif-
ferent enolate-type ions to produce 5 was achieved in moder-
ate yields (Scheme 2). The target molecules of this study are
interesting in that they contain three electron-withdrawing
groups attached to a single carbon (R1, R2, and the oxime
ether moiety). Related molecules have been previously syn-
thesized by methods similar to those discussed in this paper
with comparable yields. Methanetricarboxylic esters have
been made by acylating malonates with various acid chlo-
rides with yields that vary from 30% to 90% (9). In addition,
trifluoromethyl imidoyl chlorides have been acylated with
lithium enolates (1a, 1b).
The methine carbon attached to the three electronegative
groups in these molecules is felt to have a fairly acidic pro-
ton and would exhibit a pKa range similar to that of related
compounds. By making comparisons to similar compounds,
one may begin to predict pKa ranges for 5a–5d (Table 1).
The acidities of 5c and 5d were qualitatively demonstrated
by low integration for this proton’s signal when these com-
pounds were dissolved in d6-DMSO. This indicates that
these compounds are partially ionized in the case of 5d and
extensively ionized in the case of 5c and would suggest that
5c and 5d have pKa’s around –1.5 (pKa of protonated
DMSO) (12).
This paper discusses the nucleophilic substitution of N-
alkoxyimidoyl fluoride compounds (1a and 1b) by enolate-
type anions and Grignard reagents.
The N-alkoxyimine or oxime ether moiety has become
important in pharmaceutical compounds and as a starting
material for the synthesis of asymmetric amines, which are
also widely incorporated in pharmaceuticals and agrochemicals
(4–6). It has been found that the geometric stereochemistry
around the C=N bond (E vs. Z) has a direct effect on the
stereochemical purity of an asymmetric amine derived from
an oxime ether (5, 7). Many methods for the synthesis of ox-
imes and oxime ethers produce either a mixture of geometric
isomers or allow only the preparation predominantly of the
thermodynamically more stable isomer (5, 8). Oftentimes,
subsequent separations must be performed to prepare a sin-
In similar compounds, which contain a carbon attached to
three electron withdrawing groups, keto–enol and imine–
enamine tautomerizm is seen (1a, 1b, 13). One would also
expect the compounds described in this paper to display
© 2007 NRC Canada

Dolliver et al.
915
Scheme 1. Tetrahedral intermediates formed by methoxide attack on N-alkoxyimidoyl fluorides.
OR
OR
CH O
3
OR
F
CH O
3
F
-
-
-F
OCH
3
C
N
N
C
N
Ar
Ar
1Z
Ar
retained
stereochemistry
A
OR
F
OR
rotational
barrier 1
Ar
F
OCH
Ar
3
-
OCH
3
C
N
N
N
Ar
OR
1E
F
OCH
3
-
B
C
-F
rotational
barrier 2
CH O
3
OR
N
C
N
CH O
3
F
Ar
OR
-
-F
Ar
A
OR
CH O
3
C
N
Ar
of compound 5a in CDCl3 showed primarily one species in
solution. No appreciable signal in the region expected for an
enamine (N–H) proton was seen. There was an indication of
a methine proton at δ 5.17, which integrated for one proton.
In addition, a DEPT experiment in CDCl3 indicated the pres-
ence of a C–H bond for the signal at δ 51.73. From these ex-
periments, it appears that compound 5a exists in the imine
tautomeric form in chloroform solution.
Scheme 2. Enolate-type ion substitution on 1a.
R1
R2
OR
F
R1
∆
DMSO
OR
H
C
C
N
+
F
H
C
R2
C
N
+
Cl
Cl
5
1a or 1b
Compound
R1
CO2Et
CO2Et
CN
R2
CO2Et
CN
R
% Yield
41%
1H NMR of compounds 5c and 5d also show these mole-
cules to exist in predominantly one tautomeric form in chlo-
roform solution; however, they appear to be in the enamine
form rather than the imine form. There is no discernable res-
onance in the region expected for the methine proton of the
imine tautomer. Compound 5c was so sparingly soluble in
CDCl31 that 13C NMR could not be effectively run. Addi-
tional H NMR and 13C NMR studies on these compounds
5a
5b
5c
5d
CH3
CH3
CH3
i-Pr
56%
CN
46%
CN
CN
62%
some degree of tautomerizm. Figure 2 displays the theoreti-
cally possible tautomeric forms for 5a, 5b and 5c, and 5d. In
addition, the imine tautomers of 5a–5d could theoretically
exist in either the E or Z isomeric form around the C=N
bond.
1
were therefore run in d6-DMSO. H NMR of compound 5c
in d6-DMSO revealed no appreciable signal for this acidic
1
proton (either in the enamine or imine tautomeric form). H
NMR of compound 5d in d6-DMSO revealed a signal for the
N–H proton of the enamine form (δ 12.09), but it only inte-
grated for 0.7 protons. The absence of this proton signal for
To determine the tautomeric form(s) of each compound,
1
NMR experiments were performed. H NMR and 13C NMR
© 2007 NRC Canada

916
Can. J. Chem. Vol. 85, 2007
Table 1. Comparison of the predited pKa values for 5a, 5b, 5c, and 5d to known pKa values for related compounds.
R1
R1
H+
R2
C
+
R2
C
H
R3
R3
Entry Compd.
R1
CN
CN
CO2R
R2
H
CN
R3
H
H
CO2R
pKa
~ 25
11.2
~7.8
~7.8
ref
10
10
1
2
3
4
CO2R
11
this work
5a
5b
CO2Et CO2Et
C(p-ClAr)=NOCH3
C(p-ClAr)=NOCH3
C(p-ClAr)=NOR
predicted
< 7.8 and > pKa for 5c this work
predicted
< pKa for 5b and >-2.8 this work
predicted
5
6
CO2Et
CN
CN
CN
5c &
5d
7
8
CN
CN
CN
CN
CO2CH3
CN
-2.8
-5, -5.13
10
10
5c and the low integration value for this proton in 5d could
be due to ionization to some degree of this fairly acidic pro-
ton. Protonated DMSO has a pKa value of –1.5 (12). It is es-
timated by comparison with similar compounds that
compound 5c would have a pKa approaching that of methyl-
2,2-dicyanoacetate (Table 1, entry 7), which is –2.8. If this
is the case, this low or negligible integration value for the
N–H proton may actually represent a partial loss of this pro-
ton to the solvent. Since 5d was more soluble in chloroform,
it was possible to run the 13C NMR on this compound. The
13C NMR of 5d showed two signals for the cyano carbons.
This observation is consistent with the compound being in
the enamine tautomer rather than the imine form. If 5d ex-
isted in the imine form, the two cyano carbons signals would
have to be explained by the presence of Z and E isomers.
This explanation is not plausible, since the 13C NMR spec-
trum of 5d shows only two signals for the isopropyl carbons.
1H NMR of compound 5b in CDCl3 reveals a mixture of
the two tautomeric forms. 13C NMR of 5b in CDCl3 reveals
21 distinct signals, while there are only 11 unique carbons in
the molecule. Every non-aromatic carbon appears as two sig-
nals, and all of the aromatic carbons are also doubled up ex-
cept for one quaternary carbon that could not be located.
This too suggests that two distinct tautomeric species are
present in solution. All the NMR studies suggest that mole-
cule 5b exists in two predominant tautomeric forms in chlo-
roform solution, and one is the imine form. While the
enamine N–H proton resonance for 5c in chloroform is at δ
8.15, and the proton of interest in compound 5b has a reso-
nance of δ 11.69, it is not reasonable to rule out the enamine
tautomeric form for 5b because of the rather large difference
in the chemical shift. It should be recognized that there are
enhanced intramolecular H-bonding capabilities through a
six-membered ring system in the enamine tautomer of 5b
compared with that of the enamine tautomer of 5c, which
could account for large differences in the chemical shift of
an N–H proton in these species.
To help solve this problem, X-ray crystallography was
performed on a single crystal of 5b. This showed that 5b ex-
isted in the enamine form in the solid state. This crystal
structure shows the intramolecular H-bonding seen in other
similar enamine compounds capable of forming a six-
membered cyclic N–H···O=C interaction (14).
Interestingly, a similar compound (6) has been previously
made by reacting ethyl-α-cyano-β-methoxycrotonate with
methoxylamine (15) (Scheme 3). Only the chemical shift of
the N–H proton of 6 was reported (11.64 ppm in CDCl3) in
this work. As compound 6 was reported to only exist in the
enamine tautomer in CDCl3 solution, and as the initial report
on the synthesis of this compound only supplied limited
1
NMR data, 6 was synthesized in our lab, and its H NMR
1
and 13C NMR data were recorded. Both the H NMR and
13C NMR spectra of 6 showed no evidence of the imine tau-
tomer in solution. Therefore, it appears that the aromatic
ring in 5b has a significant effect on the imine–enamine
equilibrium. While both tautomers of 5b have resonance
with the aromatic ring and are thereby stabilized by this res-
onance effect, the relative stabilizing effect must be more
significant in the imine tautomer.
1
Comparisons with H NMR resonances of other known
enamine N–H protons were also made. It appears that the
N–H chemical shift for compounds capable of a six-
membered cyclic intramolecular H-bond can be found from
δ 9.18–15.90 in CDCl3 (13a, 13f) and δ 9.3–11.99 in d6-
DMSO (13c). All of the compounds used for comparison
display intramolecular H-bonding through a six-membered
cyclic structure. The N–H chemical shift for 5b, which can
form the six-member cyclic intramolecularly H-bonded
© 2007 NRC Canada

Dolliver et al.
917
Fig. 2. Possible tautomeric forms of 5a, 5b, 5c, and 5d.
EtO
EtO
O
N
C
C
C
O
H
C
EtO2C
C
H
EtO2C
p-ClAr
C
N
OCH3
OCH3
p-ClAr
5a
5a
imine tautomer
enamine tautomer
EtO
EtO
C
O
C
O
H
NC
C
C
H
NC
p-ClAr
N
C
C
N
OCH3
p-ClAr
OCH3
5b
5b
enamine tautomer
imine tautomer
N
N
C
H
C
N
H
C
C
C
N
C
OR
C
N
N
C
p-ClAr
OR
p-ClAr
5c & 5d
enamine tautomer
5c & 5d
imine tautomer
six-membered ring, but are still suggestive of a highly
deshielded proton, which would be expected for a proton in
the enamine form.
Scheme 3. Synthesis of a similar enamine compound (15).
EtO
EtO
O
C
O
C
NH2OCH3
NC
C
Grignard reagent substitution of (Z)-N-isopropoxy-4-
NC
C
H
chlorobenzenecarboximidoyl fluoride
N
C
OCH3
C
Nucleophilic substitution of hydroximates [RC(OR·)=NOR·,
4] by Grignard reagents have previously been reported (16).
This same type of reaction was initially attempted with 1a;
however, it was found that a competing nucleophilic attack
of the Grignard reagent on the O-methyl group appeared to
account for about 50% of the reaction process. Therefore,
the alkyl group attached to oxygen was changed to an
isopropyl group to slow down the SN2 attack at this site. In
previous work (17), hydroximoyl fluorides were prepared by
heating a hydroximoyl bromide with potassium fluoride in
CH3
OCH3
CH3
6
structure is δ 11.69 in CDCl3. This value falls in the middle
of those found for the comparison structures. For 5c and 5d,
the N–H chemical shifts were found to be δ 8.15 and 8.56,
respectively, in CDCl3 and δ 12.09 for 5d in d6-DMSO.
These values fall outside the ranges seen for the structures
capable of the intramolecular hydrogen bonding through a
© 2007 NRC Canada

918
Can. J. Chem. Vol. 85, 2007
Scheme 4. Route to nucleophilic substitution of 1b by a Grignard reagent.
O
Br
C
N
7
Cl
NaF
sulfolane
O
N
F
O
R
Et2O
C
+ RMgX
C
N
Cl
Cl
8
1b
8a: R = CH3, yield = 45%
b: R = Ph, yield = 77%
c: R = C CPh, yield = 81%
DMSO. Under these reaction conditions a methyl O-
methylbenzothiohydroximate was also formed by reaction of
the hydroximoyl fluoride with DMSO. In the present work,
(Z)-N-isopropoxybenzenecarboximidoyl bromide (7) was re-
acted with sodium fluoride in sulfolane to make (Z)-N-
isopropoxybenzenecarboximidoyl fluoride (1b). This new
synthetic procedure prevents subsequent reaction of the
hydroximoyl fluoride with the solvent. Grignard reagents
were then reacted with 1b to make 8a–8c with the yields in-
dicated in Scheme 4.
By NMR and GC–MS, these reactions yield only one geo-
metric stereoisomer of the product (8a–8c). Substitution of
(Z)-N-methoxybenzenecarboximidoyl fluoride (1a and 1c)
by methoxide is known to also yield only one isomer: the
product isomer with retained stereochemistry around the
C=N bond. This reaction is believed to go through an addi-
tion–elimination step in which the nucleophilic attack by
methoxide is rate-limiting. The stereochemistry is main-
tained in this process, despite the formation of a single bond
between carbon and nitrogen in the intermediate. This has
been found to be due to high barriers to rotation around the
C–N bond of the intermediate compared with the barrier for
elimination of the fluoride ion from the intermediate (3a).
With this in mind, it is likely that the isomer produced by
nucleophilic substitution of the fluoride of 1b by a Grignard
reagent is also the one with retained stereochemistry.
OCH3 carbon of each isomer at 61.89 and 61.86 ppm. Be-
cause of the poor resolution of these two isomers by
300 MHz NMR, it was difficult to determine the absolute
percentages of each isomer. Additionally, these isomers
were inseparable by TLC on silica or by GC–MS and there-
fore would present a considerable challenge for isolation of
a single geometric isomer. The reaction to produce the O-
methyloxime of 4-nitrobenzophenone by the same method
also yielded two geometric isomers. These isomers were al-
1
most resolvable by 300 MHz H NMR with OCH3 chemical
shifts of 4.04 and 4.00 ppm in a 62%:38% ratio by integra-
tion. These isomers were also almost resolvable by GC–MS
and yielded approximately the same ratio composition with
the first eluted isomer comprising 61%–62% of the mixture.
Again, these two isomers did not separate well on TLC and
would prove difficult to isolate from each other, thereby
demonstrating the potential utility of the substitution of an
N-methoxyimidoyl fluoride by a Grignard reagent.
Conclusions
N-alkoxyimidoyl fluorides have undergone nucleophilic
substitution reactions with enolate-type anions and with
Grignard reagents. The products of the enolate-type anion
substitutions are compounds that contain a single methine
carbon that bears three electron withdrawing groups. The
proton on this carbon is therefore believed to be fairly
acidic, and these compounds display varying degrees of
imine–enamine tautomerizm and ionization in chloroform
and DMSO. The products derived from the nucleophilic sub-
stitution of N-alkoxyimidoyl fluorides by Grignard reagents
result in a single geometric configuration about the C=N
bond. Comparison studies using common methods to synthe-
size similar oxime ethers demonstrate that the other methods
To demonstrate the difficulty in preparing a single geo-
metric isomer of an oxime ether where the substituents on
carbon are similar, the O-methyloxime of 4-chlorobenzo-
phenone and 4-nitrobenzophenone were prepared by a
commonly used method (5c, 18). The reaction of 4-chloro-
benzophenone with methoxylamine hydrochloride in
pyridine yielded both the E and Z isomers, which were only
discernable by 13C NMR spectra with the two signals for the
© 2007 NRC Canada

Dolliver et al.
919
would result in mixtures of both geometric isomers, which
would prove difficult to separate.
cooled to room temperature, acidified with concentrated
HCl, and placed in a continuous liquid–liquid extractor with
chloroform for 24 h. The chloroform was then removed by
rotary evaporation to yield a dark brown liquid. Purification
was performed on silica gel, 200–300 mesh, with an eluent
progressively changing from 3:7 CHCl3:hexane to 1:1
CHCl3:hexane. This yielded very light yellow crystals
(1.82 g). These crystals were recrystallized in 2:1 hexane:
chloroform to yield whitish crystals (1.41 g, 56%). IR
Experimental section
General procedure
All chemicals used in this research were reagent-grade ex-
1
cept as noted. The H NMR and 13C NMR spectra were per-
formed on either a Varian Mercury 300 MHz spectrometer
or a Bruker AC 300 MHz NMR spectrometer using either
CDCl3 or d6-DMSO. Melting points were determined on a
Thomas–Hoover capillary melting-point apparatus and are
uncorrected. IR spectra were either determined from Nujol
mulls between sodium chloride plates for solids or neat on
sodium chloride plates for liquids on a Nicolet Magna IR
560 spectrometer or a PerkinElmer 16 PC FTIR over the fre-
quency range of 4000–600 cm–1. Elemental analyses of the
new compounds were performed at Midwest Microlab, Indi-
anapolis, Inc. Exact masses were obtained by the Central
Science Laboratory at the University of Tasmania.
1
(nujol): 3198, 2203, 1666, 1547, 1461, 1375 cm–1. H NMR
(300 MHz, CDCl3) δ: 11.69 (s, 0.6 H, NH), 7.60–7.38 (m, 4
H, ArH), 5.32 (s, 0.2 H, CH), 4.26 (q, 2H, J = 6.9 Hz,
OCH2), 4.09 (s, 0.7 H, OCH3), 3.56 (s, 2.3 H, OCH3), 1.41–
1.23 (m, 3H, CH2CH3). 13C NMR (75.5 MHz, CDCl3) δ:
167.64 (C=O), 167.16 (C=O), 162.54 [C=C(CN)(CO2Et)],
145.00 (C=N), 137.09 (Ar C), 136.18 (Ar C), 130.76 (Ar C),
129.74 (Ar CH), 128.85 (Ar CH), 128.70 (Ar CH), 127.59
(Ar CH), 117.16 (CN), 112.87 (CN), 71.50 [C=C(CN)(CO2Et)],
64.84 (OCH3), 63.44 (OCH2), 63.03 (OCH3), 61.18 (OCH2),
35.68 (CH), 14.28 (CH2CH3), 13.81 (CH2CH3).2 A DEPT
experiment showed only C–H attachments belonging to the
aromatic ring except for a single C–H bond belonging to the
resonance at δ 35.69, indicative of the imine tautomer. Anal.
calcd. For C13H13N2O3Cl: C, 55.62; H, 4.67; N, 9.98; Cl,
12.63. Found: C, 55.67; H, 4.70; N, 9.94; Cl, 12.66.
Preparation of diethyl 2-[2-aza-1-(4-chlorophenyl)-2-
methoxyvinyl]propane-1,3-dioate (5a)
Lithium diisopropylamide (2.0 mol/L in heptane,
ethylbenzene, and tetrahydrofuran) (6.3 mL, 0.013 mol) was
added dropwise with stirring to diethylmalonate (2.67 g,
0.017 mol) under nitrogen purge. (Z)-O-Methyl-4-chloro-
benzohydroximoyl fluoride (1a) (1.50 g, 0.0080 mol) in
dimethyl sulfoxide (10 mL) was added dropwise to the flask.
The reaction mixture was heated under nitrogen at 115 °C
for 27 h. The reaction mixture was cooled to room tempera-
ture, acidified with concentrated HCl, and placed in a con-
tinuous liquid–liquid extractor with chloroform for 50 h. The
chloroform was then removed by rotary evaporation to yield
a dark brown liquid. Purification was performed on silica
gel, 200–300 mesh, with an eluent progressively changing
from 1:10 CHCl3:hexane to 7:3 CHCl3:hexane. This yielded
a very light yellow viscous oil (1.07 g, 41%). IR (neat);
Preparation of [2-aza-1-(4-chlorophenyl)-2-
methoxyvinyl]methane-1,1-dicarbonitrile (5c)
A sodium ethoxide solution was prepared by dissolving
sodium metal (1.63 g, 0.071 mol) in absolute ethanol
(30 mL). Malononitrile (5.02 g, 0.076 mol) was placed in
the sodium ethoxide solution. The mixture was stirred for
approximately five minutes, and a visible solid formed in the
flask. The remaining ethanol was removed under a vacuum
with heating for 1 h. (Z)-O-Methyl-4-chlorobenzohydroxi-
moyl fluoride (1a) (3.25 g, 0.017 mol) and the freshly pre-
pared sodium salt of malononitrile (4.55 g, 0.052 mol) were
placed in a 25 mL round-bottomed flask. The flask was
sealed and heated to 90 °C with periodic venting at the be-
ginning of the reaction. At 3.5 h, another portion of the dry
sodium salt of malononitrile (1.52 g, 0.017 mol) was added.
The reaction mixture was then heated at 90 °C for an addi-
tional 50 h. The reaction mixture was then cooled to room
temperature, placed in 100 mL of ice-cold water, and acidi-
fied with concentrated HCl. The reaction mixture was placed
in a liquid–liquid continuous extractor with chloroform for
72 h. The chloroform was then removed by rotary evapora-
tion. The crude yield was 3.54 g of light brownish-yellow
solid. This solid was recrystallized in 2:1 hexane:chloroform
to yield a slightly yellow powder (1.88 g, 46%). IR (nujol)
1
2986, 2933, 1754, 1739, 1600, 1489, 1370, 1152 cm–1. H
NMR (300 MHz, CDCl3) δ: 7.55 (d, 2H, J = 9.0 Hz, ArH),
7.33 (d, 2H, J = 9.0 Hz, ArH), 5.17 (s, 1H, CH), 4.16 (q,
4H, J = 7.2 Hz, OCH2), 4.01 (s, 3H, OCH3), 1.15 (t, 6H, J =
7.2 Hz, OCH2CH3). 13C NMR (75.5 MHz, CDCl3) δ: 165.96
(C=O), 149.32 (C=N), 135.16 (Ar C), 132.51 (Ar C), 129.53
(Ar CH), 128.32 (Ar CH), 62.49 (OCH3), 61.96 (OCH2),
51.73 (CH), 13.82 (CH2CH3). Anal. calcd. For C15H18NO5Cl:
C, 54.97; H, 5.54; N, 4.27; Cl, 10.82. Found: C, 54.74; H,
5.59; N, 4.19; Cl, 10.73.
Preparation of ethyl 4-aza-3-(4-chlorophenyl)-2-cyano-4-
methoxybut-3-enoate (5b)2
1
2217, 2200, 1458, 1377 cm–1. H NMR (300 MHz, CDCl3)
Lithium diisopropylamide (2.0 mol/L in heptane, ethyl-
benzene, and tetrahydrofuran) (17.5 mL, 0.035 mol) was
added dropwise with stirring to ethylcyanoacetate (8.02 g,
0.071 mol) under nitrogen purge. (Z)-O-Methyl-4-
chlorobenzohydroximoyl fluoride (1a) (1.68 g, 0.0090 mol)
in dimethyl sulfoxide (5 mL) and hexane (3 mL) was added
dropwise to the flask. The reaction mixture was heated un-
der nitrogen at 80 °C for 3 h. The reaction mixture was
δ: 8.15 (br s, 0.8 H, NH), 7.51–7.41 (m, 4H, ArH), 3.89 (s,
1
3H, OCH3). H NMR (300 MHz, d6-DMSO) δ: 7.63 (s, 4H,
ArH), 3.84 (s, 3H, OCH3). 13C NMR (75.5 MHz, d6-DMSO)
δ: 162.23 (C–N), 136.63 (Ar C), 130.59 (Ar CH), 128.67
(Ar CH), 127.60 (Ar C), 116.16 (CN), 64.17 (OCH3), 46.69
[C(CN)2]. A DEPT experiment performed on 5c revealed no
C–H attachments other than those seen in the aromatic sys-
tem. Anal. calcd. for C11H8N3OCl: C, 56.55; H, 3.45; N,
2 This 13C NMR is corrected from a previous erroneous report in ref. 14 where an additional resonance frequency of δ 43.93 is reported.
© 2007 NRC Canada

920
Can. J. Chem. Vol. 85, 2007
17.98; Cl, 15.27. Found: C, 56.56; H, 3.27; N, 17.90; Cl,
15.07.
136.26 (Ar C). GC–MS: m/z 277 (18%), 275 (M, 13), 235
(11), 233 (9), 198 (4), 196 (14), 156 (32), 154 (100), 139
(11), 137 (35), 125 (11), 123 (20), 113 (9), 111 (29), 102
(23), 75 (18). Anal. calcd. For C10H11BrClNO: C, 43.43; H,
4.01; Br, 28.89; Cl, 12.82; N, 5.06. Found: C, 43.22; H,
4.02; Br, 28.51; Cl, 12.66, N, 4.96.
Preparation of [2-aza-1-(4-chlorophenyl)-2-
isopropoxyvinyl]methane-1,1-dicarbonitrile (5d)
Malononitrile (1.69 g) was added to a solution of sodium
methoxide prepared from 0.545 g (0.0237 mol) of sodium in
absolute ethanol (20 mL). After evaporation of the ethanol, a
portion of the solid sodium salt of malononitrile (1.5 g,
0.023) was added to O-isopropyl-4-chlorobenzohydroximoyl
fluoride (1.2 g, 0.0056 mol) in a sealed flask. The flask was
heated to 90 °C in a sand bath with periodic venting. After
three hours, the remaining portion of the sodium salt was
added to the flask, and the reaction was heated for 50 h at
90 °C. The resulting dark solid was extracted with chloro-
form (3 × 100 mL). Evaporation of the chloroform gave
1.36 g of a yellowish solid. One recrystallization from 2:1
hexane–chloroform gave a light yellow solid (0.85 g, 62%).
Several additional recrystallizations from hexane–chloro-
form gave a light yellow powder 138–139 °C (dec). IR
(nujol): 3190, 2217, 2198,1581, 1541 cm–1. 1H NMR
(300 MHz, CHCl3) δ: 1.33 (6H, d, J = 6 Hz, (CH3)2), 4.27
(1H, m, CH), 7.40 (2H, d, J = 9 Hz, ArH), 7.48 (2H, d, J =
8.4 Hz, ArH), 8.56 (1H, s, NH). 13C NMR (75.5 MHz,
CDCl3) δ: 19.72 [CH(CH3)2], 52.02 [C(CN)2], 80.35
[CH(CH3)2], 114.36 (CN), 116.07 (CN), 117.58 (ArC)
127.27 (ArC), 129.65 (ArCH), 129.93 (ArCH), 139.06
(=CNH). 1H NMR (300 MHz, d6-DMSO) δ: 1.30 [6H, d, J =
6 Hz, (CH3)2)], 4.30 (1H, septet, J = 6 Hz, CH), 7.40 (4H, s,
ArH), 12.09 (0.7H, broad s, NH). 13C NMR (75.5 MHz, d6-
DMSO) δ: 19.57 [CH(CH3)2], 47.11 [C(CN)2], 78.70
[CH(CH3)2], 128.25 (Ar C), 128.93 (ArCH), 130.94 (ArCH)
136.72 (ArC), 163.20 [C=C(CN)2]. (Found: M+C, 261.06685.
C13H12ClN3O requires M+C, 261.06688).
Preparation of (Z)-O-isopropyl-4-chlorobenzo-
hydroximoyl fluoride (1b)
(Z)-O-Isopropylbenzohydroximoyl bromide (7) (6.723 g,
0.0243 mol), potassium fluoride (Aldrich, spray-dried, 99%)
(10.405 g, 0.179 mol) in 108 mL of sulfolane was placed in
a 250 mL round-bottomed flask fitted with a thermometer, a
CaCl2 drying tube, and a nitrogren gas inlet. The resulting
solution was heated to 146 °C with stirring for 10 days. The
reaction mixture was cooled to room temperature. Water
(100 mL) was poured into the cooled reaction mixture, and
the mixture was continuously extracted with heptane for
4 days. Heptane extract was washed with water (2 × 50 mL),
and the heptane extract was dried with anhyd. magnesium
sulfate. Heptane was removed by rotary evaporation. This
yielded a yellowish liquid (4.938 g). The compound was pu-
rified by vacuum distillation to yield a clear, colorless liquid
(3.362 g, 64%). IR (neat): 2978, 2933, 1646, 1601, 1494,
1
1321, 993 cm–1. H NMR (300 MHz) δ: 1.34 (d, JHH
=
6.4 Hz, 6H, CH3), 4.39 (m, JHH = 6.3, 1H, OCH), 7.40 (d,
JHH = 8.6 Hz, 2H, ArH), 7.70 (d, JHH = 8.6 Hz, 2H, ArH).
13C (75 MHz) δ: 21.38 (CH3), 77.32 (d, JCONCF = 1.8, CH),
125.59 (d, JCCF = 31.9 Hz, Ar C), 126.90 (d, JCCCF = 5.0 Hz,
Ar CH), 128.80 (d, JCCCCF = 1.8 Hz, Ar CH), 136.76 (Ar C–
Cl), 151.00 (d, JCF = 320.0 Hz, C=N). GC–MS: m/z 217
(9%), 215 (M, 26), 175 (31), 173 (100), 158 (5), 156 (13),
111 (30), 107 (32), 75 (22). (Found: M+C, 215.05072.
C10H11ClFNO requires M+C, 215.05132).
Preparation of ethyl α-cyano-β-methoxyaminocrotonate
Preparation of the (E)-isomer of O-isopropyloxime of 4-
chloroacetophenone (7a)
(6)
The procedure for the synthesis of this compound is as
1
that described by Baba et al. (15). H NMR (300 MHz) δ
Preparation of Grignard reagent
1.28 (t, JHH = 7.11 Hz, 3H, CH3), 2.33 (s, 3H, C=CCH3),
3.77 (s, 3H, OCH3), 4.17 (q, JHH = 7.11 Hz, 2H, OCH2),
11.60 (s, 1H, N–H). 13C NMR (75 MHz) δ: 14.14 (CH3),
15.28 (CH3), 60.50 (CH2), 64.73 (OCH3), 68.95
[C=C(CN)(CO2Et)], 117.72 (CN), 166.88 [C=C(CN)(CO2Et)],
167.75 (C=O).
Magnesium metal (1.372 g, 0.0564 mol) was placed in a
dry 25 mL round-bottomed flask fitted with a dry Claisen
adaptor, a dry dropping funnel, a dry water-cooled condenser
with a dry nitrogen inlet and a CaCl2 drying tube-protected
outlet. Methyl iodide (4 mL, 0.0640 mol) in 6 mL of anhyd.
ether was added dropwise to form Grignard reagent. This re-
sulted in approximately 6 mL of an approximately 10 mol/L
methylmagnesium iodide solution.
Preparation of (Z)-O-isopropyl-4-chlorobenzohydroximoyl
bromide (7)
Reaction of 4-chloro-O-methylbenzohydroximoyl fluoride
with methylmagnesium iodide
The procedure for the synthesis of this compound is as
that described by Johnson et al. (3b) in their synthesis of
(Z)-O-methyl-4-nitrobenzohydroximoyl
bromide.
This
4-Chloro-O-methylbenzohydroximoyl fluoride (0.635 g,
0.00294 mol) in 7 mL of anhyd. ether was added dropwise
to approximately 6 mL of ~10 mol/L methylmagnesium io-
dide in diethyl ether solution. This mixture was refluxed for
4 h. The reaction was then poured onto approximately 40 g
of dry ice. The resulting residue was washed with hexane
(approximately 300 mL). The hexane was evaporated under
reduced pressure. This yielded a light yellow oil (0.280 g,
45%). This was distilled under vacuum with short path dis-
tillation apparatus to yield microanalytically pure sample of
a colorless oil (0.200 g, 32.1%). IR (neat): 2975, 2930,
yielded yellow semi-solid material, which was
a
recrystallized in methanol. The first recrystallization yielded
light tan crystals (16.177 g, 73%). A second recrystallization
in methanol yielded white crystals (12.210 g, 55%), mp
37.0–37.5 °C. Rf (hexane, alumina): 0.88. IR: 1592, 1583,
1465, 1092, 996 cm–1. 1H NMR (300 MHz) δ: 1.39 (d,
JHH = 6.4 Hz, 6H, CH3), 4.61 (m, JHH = 6.2, 1H, OCH), 7.36
(d, JHH = 8.6 Hz, 2H, ArH), 7.79 (d, JHH = 8.6 Hz, 2H,
ArH). 13C (75 MHz) δ: 21.64 (CH3), 77.77 (CH), 127.92
(C=N), 128.45 (Ar CH), 129.30 (Ar CH), 132.82 (Ar C),
© 2007 NRC Canada

Dolliver et al.
921
1
1609, 1490, 1369, 1004. H NMR (300 MHz) δ: 1.32 (d,
JHH = 6.2 Hz, 6H, C(CH3)2), 2.21 (s, 3H, CH3), 4.46 (m,
JHH = 6.2 Hz, 1H, CH), 7.33 (d, JHH = 8.6 Hz, 2 H, ArH),
7.61 (d, JHH = 8.6 Hz, 2H, ArH). 13C (75 MHz) δ: 12.53
(CH3), 21.84 (CH3), 75.74 (CH), 127.13 (Ar CH), 128.41
(Ar CH), 134.59 (Ar C), 135.47 (Ar C), 152.37 (C=N). GC–
MS: m/z 213 (21%), 211 (M, 64), 171 (32), 169 (100), 154
(22), 152 (51), 137 (29), 130 (17), 128 (56), 113 (28), 111
(77), 103 (42), 77 (31), 75 (65). Anal. calcd. for
C11H14ClNO: C, 62.41; H, 6.67; Cl, 16.75; N, 6.62. Found:
C, 62.47; H, 6.89; Cl, 16.73, N, 6.56.
(Ar C), 132.01 (Ar CH), 132.50 (Ar C), 135.16 (Ar C),
137.90 (C=N). GC–MS: m/z 299 (16%), 297 (M, 45), 257
(3), 255 (9), 227 (17), 225 (48), 189 (57), 105 (100), 77
(11), 75 (23). (Found: M+C, 297.09206. C18H16ClNO re-
quires M+C, 297.09204).
Acknowledgements
Acknowledgment is made to the American Chemical So-
ciety Petroleum Research Fund Grant (PRF #44412-GB1),
Southeastern Louisiana University’s Faculty Development
Grant, Southeastern Louisiana University’s OSCAR/STAR
Grant, the Minority Biomedical Research Support Program
of the National Institutes of Health (NIH-MBRS Grant R25-
GM55380), The Robert A. Welch Foundation (Grant No. M-
0200), and the Texas Woman’s University Research En-
hancement Program for support of this work.
Preparation of the (E)-isomer of O-isopropyloxime of 4-
chlorobenzophenone (7b)
(Z)-O-Isopropyl-4-chlorobenzohydroximoyl fluoride (1b)
(0.308g, 0.00143 mol) was placed in a dry 25 mL round-
bottomed flask fitted for distillation under nitrogen purge.
Phenylmagnesium bromide (4.7 mL of 1.0 mol/L in THF,
0.00470 mol) was added to the flask, and the mixture was
heated to distill off 2.2 mL of THF. Reaction was then
heated at reflux for 17 h. Mixture was then cooled to room
temperature and quenched in 25 mL of ice-cold water. This
was extracted with ether (5 × 50 mL). The ether layer was
dried with magnesium sulfate and ether removed by rotary
evaporation. This yielded 0.471 g of medium yellow colored
oil. This material was purified by column chromatography
(silica 63–200 and hexanes) to yield a colorless viscous oil
(0.299g, 77%). IR (neat): 3082, 3058, 3029, 2975, 2932,
References
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1
1577, 1488, 1444, 1369, 1324, 1121, 1092, 971. H NMR
(300 MHz) δ: 1.27 (d, JHH = 6.2 Hz, 6H, C(CH3)2), 4.48 (m,
JHH = 6.2 Hz, 1H, CH), 7.25–7.43 (m, 9 H, ArH). 13C
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128.51 (Ar CH), 128.93 (Ar CH), 129.31 (Ar CH), 129.69
(Ar CH), 133.20 (Ar C), 135.08 (Ar C), 135.79 (Ar C),
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(11), 111 (26), 77 (42), 75 (31). (Found: M+C, 273.09238.
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Preparation of the (Z)-isomer of the O-isopropyloxime
of 1-(4-chlorophenyl)-3-phenyl-prop-2-yn-1-one (7c)
(Z)-O-Isopropyl-4-chlorobenzohydroximoyl fluoride (1b)
(0.240g, 0.00111 mol) was placed in a dry 25 mL round-
bottomed flask fitted for distillation under nitrogen purge.
Phenylmagnesium bromide (3.7 mL of 1.0 mol/L in THF,
0.00370 mol) was added to the flask, and the mixture was
heated to distill off 1.5 mL of THF. Reaction was then
heated at reflux for 48 h. Mixture was then cooled to room
temperature and quenched in 30 mL of ice-cold satd. ammo-
nium chloride solution. This was extracted with ether (4 ×
50 mL). The ether layer was dried with magnesium sulfate
and ether removed by rotary evaporation. This yielded
0.778 g of reddish-amber colored liquid. This material was
purified by column chromatography (silica 63–200 and hex-
anes) to yield a colorless viscous oil (0.268g, 81%). IR
(neat): 3056, 2976, 2929, 2202, 1598, 1488, 1328, 1120,
1094, 1052, 983. H NMR (300 MHz) δ: 1.37 (d, JHH
6.3 Hz, 6H, C(CH3)2), 4.55 (m, JHH = 6.2 Hz, 1H, CH),
7.29–7.85 (m, 9 H, ArH). 13C (75 MHz) δ: 21.66 (CH3),
77.31 (CH), 79.50 (CC), 100.90 (CC), 121.83 (Ar C),
127.50 (Ar CH), 128.35 (Ar CH), 128.44 (Ar CH), 129.37
1
=
© 2007 NRC Canada

922
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© 2007 NRC Canada