Conjugate Addition of 3-Buytn-2-one to Anilines in Ethanol: Alkene Geometric Insights through in Situ FTIR Monitoring

Article abstract of DOI:10.1021/acs.joc.6b01110

A convenient, mild and effective conjugate addition of 3-butyn-2-one to a variety of anilines in ethanol is reported. The reaction was monitored and characterized through in situ FTIR, and the dynamics of the facile E/Z alkene geometry interconversion of the resultant aniline-derived enaminones was explored through NMR, FTIR and X-ray crystallography. A straightforward purification protocol that employs direct Kugelrohr distillation was identified, and the method was further extended to other amines and ynones, allowing rapid access to these interesting compounds.

Full text of DOI:10.1021/acs.joc.6b01110

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Article
Conjugate addition of 3-buytn-2-one to anilines in ethanol:
alkene geometric insights through in situ FTIR monitoring
David R. Chisholm, Roy Valentine, Ehmke Pohl, and Andrew Whiting
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01110 • Publication Date (Web): 28 Jul 2016
Downloaded from http://pubs.acs.org on July 29, 2016
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Conjugate addition of 3-buytn-2-one to anilines in ethanol: alkene
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geometric insights through in situ FTIR monitoring
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David R. Chisholma, Roy Valentineb, Ehmke Pohlac and Andrew Whitinga*
a
Centre for Sustainable Chemical Processes, Department of Chemistry, Durham
University, South Road, Durham, UK
Eꢀmail: andy.whiting@durham.ac.uk; Fax: +44 (0)191 384 4737;
Tel: +44 (0)191 334 2081
b
High Force Research Limited, Bowburn North Industrial Estate, Bowburn,
Durham, DH6 5PF, UK
c
Biophysical Sciences Institute, Durham University, South Road, Durham, DH1
3LE, UK
Table of contents
Abstract
A convenient, mild and effective conjugate addition of 3ꢀbutynꢀ2ꢀone to a variety of
anilines in ethanol is reported. The reaction was monitored and characterized through
in situ FTIR, and the dynamics of the facile E/Z alkene geometry interconversion of
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the resultant anilineꢀderived enaminones was explored through NMR, FTIR and Xꢀ
ray crystallography. A straightforward purification protocol that employs direct
Kugelrohr distillation was identified and the method was further extended to other
amines and ynones, allowing rapid access to these interesting compounds.
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Introduction
One of the most widely studied methods for forming CꢀN bonds is the azaꢀMichael
addition.1 This has classically involved the addition of aliphatic amines to α, βꢀ
unsaturated carbonyl compounds, but has been expanded to suit a plethora of
acceptors and donors.1 Due to the reduced nucleophilicity of aromatic amines,
methods for conjugate additions to these compounds are less varied, and are often
limited to reactive acceptors such as methyl vinyl ketone.2ꢀ4 Activation using Lewis
acids,5 or high pressures,6 are examples of the conditions required for conjugate
addition to other acceptors. Clearly, more varied and practical methods are required
for these important reactions.
During attempts to assemble enamine functionalities, we noticed that aniline 1a
underwent an efficient conjugate addition to 3ꢀbutynꢀ2ꢀone 2a in EtOH at RT without
any activation (Scheme 1). Enaminone 3a was easily isolated in an excellent yield by
Kugelrohr distillation, with high selectivity for the Zꢀisomer, according to NMR. Such
a reaction has been reported in water,7 and a variety of methods have been developed
to synthesize similar compounds,8 including the use of palladium catalysts,9 and
silica.10 In comparison, our protocol was more convenient and effective, and did not
require any specialized reagents or catalysts. Accordingly we decided to further
investigate the applicability of this convenient method towards anilines and other
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amines of varied nucleophilicity, and to explore the structural characteristics of the
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resultant enaminones using in situ FTIR spectroscopy.
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Scheme 1: Facile conjugate addition of aniline 1a to 3ꢀbuytnꢀ2ꢀone 2a to give the corresponding
enaminone 3a.
Results and Discussion
Previous FTIR studies showed that enaminones exhibit a carbonyl stretch at lower
wavenumber than typical ketones due to conjugation with the amine group.11 We
therefore anticipated that we could use in situ FTIR spectroscopy (ReactIRTM),12 to
explore and follow the conjugate addition reaction in detail by tracking the loss of the
ynone carbonyl stretch of 2a and the rise of the enaminone carbonyl stretch.
Table 1. Comparison of the reaction solvent in the conjugate addition of aniline 1a to 3ꢀbutynꢀ2ꢀone 2a
to give enaminone 3a.a
Reaction solvent
Monitoring period
Approx. conversion to 3aa/%
Toluene
DCM
THF
EtOH
H2O
16 h
16 h
6 h
27
22
trace
100
67
1 h
16 hb
24 h
DMSO
57
Aniline 1a (0.0910 mL, 1.0 mmol) was stirred with 3ꢀbutynꢀ2ꢀone 2a (0.0782 mL, 1.0 mmol) in the
reaction solvent (4 mL). The disappearance of the ynone carbonyl stretch (around 1680ꢀ1690 cmꢀ1) and
appearance of the enaminone carbonyl stretch (around 1640ꢀ1660 cmꢀ1) was monitored until no further
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change was detected. The solution was then diluted with EtOAc, washed with H2O and brine, dried
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1
a
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(MgSO4), evaporated and then analyzed by H NMR. Estimated via analysis of the crude H NMR
spectra in chloroformꢀd1 by comparing the relative integrals of the starting 1a and enaminone 3a. bFTIR
monitoring in this case was unreliable due to rapid precipitation of 3a.
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The effect of the solvent on the reaction between aniline, 1a and 3ꢀbutynꢀ2ꢀone, 2a
was first assessed, with monitoring by in situ FTIR. In all solvents, a clear carbonyl
stretch was detected at around 1680ꢀ1690 cmꢀ1 upon addition of 2a. When 1a was
added, in the case of EtOH a rapid decline of the 2a carbonyl stretch was detected,
and was accompanied by the concomitant appearance of the 3a enaminone carbonyl
stretch at around 1640 cmꢀ1. In the nonpolar toluene, a similar spectral effect was
observed, although the reaction was found to be significantly slower, and indeed was
far from completion after 16 hours according to 1H NMR. A comparably slow rate
was observed in DCM. The more polar THF showed no obvious reaction by in situ
FTIR and only trace amounts of 3a were evident by 1H NMR. Only the reactions with
the more polar solvents H2O and DMSO exhibited reasonable conversions to 3a
,
although still at a significantly slower rate than the reaction in EtOH. Clearly, at room
temperature, EtOH exhibited a substantial rate enhancement compared to the solvents.
With the ideal solvent identified, the reaction was conducted using a variety of
anilines, with monitoring by in situ FTIR. Close monitoring of the reaction between
aniline 1a and 2a indicated a rapid reaction, with only around 20 minutes required to
effect complete conversion to enaminone 3a (Table 2), which allowed straightforward
isolation of 3a in a 92% yield via Kugelrohr distillation.
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Table 2. Addition of anilines 1a-m to 3ꢀbutynꢀ2ꢀone 2a to give enaminones 3a-m.
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Aniline
Approx.
timea
Enaminone Alkene
geometryb
Yield/%
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Aniline, 1a
20 mins
20 mins
20 mins
40 mins
20 mins
20 mins
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
E
92
93
87
94
86d
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33e
72e
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93
3a
3b
3c
3d
3e
3f
3g
3h
3i
2ꢀMethylaniline, 1b
4ꢀMethylaniline, 1c
3,5ꢀDimethylaniline, 1d
4ꢀHydroxyaniline, 1e
4ꢀMethoxyaniline, 1f
Ethyl 4ꢀaminobenzoate, 1g 24 hc
4ꢀChloroaniline, 1h
4ꢀBromoaniline, 1i
4ꢀNitroaniline, 1j
4ꢀIodoaniline, 1k
4ꢀIodoꢀ2ꢀmethylaniline, 1l 5 h
NꢀMethylaniline, 1m
6 h
3.5 h
>5 daysc
5 h
3j
3k
3l
20 mins
3m
aEstimated using FTIR. Assessed by H NMR in chloroformꢀd1. cEstimated using TLC. dIsolated by
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chromatography. eIsolated by recrystallization.
Both mildly, and strongly activated anilines (1bꢀf) reacted with 2a at similar rates
compared to 1a, and the resulting enaminones 3b-f were isolated in excellent yields
by Kugelrohr distillation, which proved to be a quick, easy and highly effective
purification method. Reactions of 2a with electron deficient anilines were much
slower. For example, 4ꢀchloroaniline and 4ꢀbromoaniline (1h-i) reacted to give
enaminones 3h-i in 6 and 3.5 hours respectively, but with similarly high yields to the
activated anilines. Accurate FTIR monitoring of the reaction between 2a and ethyl 4ꢀ
aminobenzoate 1g was difficult due to the overlap of the carbonyl stretch of 2a with
the ester carbonyl stretch of 1g. TLC indicated conversion to 3g after 24 hours.
Addition of 2a to 4ꢀnitroaniline 1j was found to be remarkably slow, and
precipitation of the product 3j also caused unreliable FTIR monitoring. After 5 days,
3j was isolated in a 33% yield by recrystallization. This reduced rate is likely caused
by the deactivating nitroꢀgroup, though the difference in reactivity to the other
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anilines is striking. 4ꢀIodoaniline and 4ꢀiodoꢀ2ꢀmethylaniline 1k-l, were converted to
the corresponding enaminones 3k-l in good yields over 5 hours.
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Figure 1. The in situ FTIR spectra of the reaction between 1f and 2a at selected time points (time
proceeds from blue to red). The decline of the carbonyl stretch of 2a (1693 cmꢀ1) and the consequent
rise of the carbonyl stretch of 3f (1640 cmꢀ1) is shown as the reaction proceeded. The carbonyl stretch
of 2a fell to 50% intensity after approximately 2 minutes. A subtle shoulder is evident at 1669 cmꢀ1 that
corresponds to the Eꢀisomer of 3f.
Figure 1 shows the FTIR spectra of the reaction between 1f and 2a at select time
points. After addition of 2a (t = 0:00), the carbonyl stretch of 2a (1693 cmꢀ1) was
visible. When 1f was added, a rapid appearance of the 3f carbonyl stretch (1640 cmꢀ1)
was observed. This was accompanied by the decline of the carbonyl stretch of 2a
.
Clearly the majority of product 3f was formed after only around 3 minutes, and the
reaction rate decreased as the concentration of the reactants declined. At t = 21:16, the
carbonyl stretch of 2a was no longer evident, and the carbonyl stretch of 3f remained
constant indicating that the reaction was complete.
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The spectra in Figure 1 show that the ketone of 3f in EtOH exhibited a peak at
1640 cmꢀ1, but a subtle shoulder at 1669 cmꢀ1 was also evident. The E-isomers of
similar enaminones are known to exhibit lower intensity carbonyl stretches at higher
wavenumbers compared to the Zꢀisomers, due to the lack of intramolecular hydrogen
bonding.11,13 This shoulder therefore clearly indicated that both the Z- (1640 cmꢀ1) and
Eꢀisomers (1669 cmꢀ1) were formed during the reaction. Analysis of the full spectra
showed that there were no obvious intermediate species, i.e. infrared bands that rose
and fell, even when the spectral update frequency was increased to one per second.
Um et al. suggested that the corresponding reaction in water was catalyzed by
protonation of the ketone of 2a.7 A substantial rate and yield increase was observed in
EtOH for the reaction of 1a and 2a compared to water, and the other solvents in Table
1, but the pKa of the alcoholic proton of EtOH is unlikely to be low enough for the
reaction to proceed via acid catalysis. Therefore, although a shortꢀlived, catalytic
intermediate such as that suggested for the reaction in water cannot be ruled out, the
FTIR monitoring experiments support a direct azaꢀconjugate addition mechanism in
EtOH, perhaps assisted via hydrogen bonding.
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Z
E
N
H
O
N
H
O
11.58 ppm
7.13 ppm
Scheme 2. Configurational and conformational equilibrium between Z,s-cisꢀ (left) and Eꢀisomers
1
(shown in the s-trans conformation, right) of 3a as determined by H NMR in chloroformꢀd1. The
intramolecular hydrogen bond evident in the Zꢀisomeric form is shown as a dashed red line.
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Analysis of the 1H NMR spectra of the enaminones in chloroformꢀd1 (Scheme 2)
highlighted a variety of structural features. Firstly, the NꢀH proton of 3a was
identified as a low field broad doublet at 11.58 ppm, thus indicating that this proton
forms a strong hydrogen bond.14 Furthermore, the proton of the alkene in the αꢀketo
position presents as a doublet at 5.30 ppm with a 7.7 Hz coupling, indicating the
presence of a Zꢀalkene. Both these features indicate the adoption of a Z,s-cis geometry
of the alkene configuration and NꢀC=C single bond conformation, which would be
maintained by the presence of an intramolecular hydrogen bond between the NꢀH
proton and the carbonyl oxygen.13ꢀ16 A small amount (3%) of the Eꢀisomer was also
present, as indicated by a 13.1 Hz coupling of the corresponding αꢀketoꢀcarbon proton.
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Figure 2. Ballꢀandꢀstick representation of the Xꢀray structure of 3g, highlighting the Zꢀalkene
configuration, s-cis CꢀN bond conformation and intramolecular hydrogen bond (red, dotted line).
Figure produced using Olex2.17
To confirm the assignment of the Zꢀisomer, enaminones 3g (Figure 2) and 3l were
crystallized and their structures solved by single crystal Xꢀray diffraction. Both
structures showed that in the solid state, the Zꢀconfiguration is stabilized by a medium
length hydrogen bond (3g, OꢀꢀH distance = 1.99 Å, NꢀHꢀꢀO angle = 132.9o)
consistent with typical values.18,19 Comparison of the N7ꢀC8 bond (1.35 Å) with the
C8ꢀC9 double bond (1.36 Å) shows that this NꢀC bond is slightly shorter than the
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alkene. This is consistent with this formal single bond possessing a significant degree
of imine character.
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Interestingly, when the 1H NMR spectrum of 3a was recorded in chloroformꢀd1
immediately after SiO2 chromatography, the compound had isomerized to a 1:1
mixture of the Z- and Eꢀisomers. The broad signal for the NꢀH proton of the Eꢀisomer
was evident at much higher field (7.13 ppm) compared to the Zꢀisomer, indicating
that this proton was not significantly hydrogen bonded.14,21 Furthermore, when the 1H
NMR spectrum of a second fraction of 3a was recorded one hour after
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chromatography, the Z/E-ratio had returned to 97:3, where it remained indefinitely in
chloroformꢀd1. This observation provided clear evidence that enaminones 3a-3l exist
in configurational equilibria that favor the Zꢀisomer, and that the observed Z/E-ratio is
not governed by the initial conjugate addition reaction.11,15 Passing the products
through SiO2 likely causes protonation of 3a, presumably via the ketone oxygen,
which disrupts the internal hydrogen bond required for stabilization of the Z-isomer
and thus results in the temporary adoption of the sterically, and electronically favored
Eꢀisomer. However, the thermodynamic stabilization gained from formation of the
intramolecular hydrogen bond shifts the equilibrium towards the Zꢀisomer over time.
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Figure 3. The 1H NMR spectrum of 3a in chloroformꢀd1 monitored over 48 hours after a D2O shake
experiment. The αꢀcarbonyl proton of the Z- and Eꢀisomers are shown. Immediately after agitation with
D2O the Eꢀisomer predominates (2 mins), but over time is found to preferentially isomerize to the
thermodynamically favored Zꢀisomer.
This intriguing equilibrium was further probed by a D2O exchange experiment. When
the 1H NMR spectrum of 3a in chloroformꢀd1 was recorded immediately after
agitation with D2O (Figure 3), 3a was shown to exist in a 7:93 ratio of the Z- and Eꢀ
forms, respectively. After 30 minutes, and then after 2 hours, the equilibrium still
favored the Eꢀform (14:86 and 24:76, respectively), but after 6 hours, the equilibrium
shifted towards the Zꢀform (76:24). The equilibrium relaxed over 48 hours to a 97:3
ratio as shown by 1H NMR. These results indicated that 3a converts to the Eꢀ
configuration during deuterium exchange, but that the NꢀDꢀꢀO deuterium bond
interaction in deuterated 3a is equally as thermodynamically favored as the NꢀHꢀꢀO
interaction.
In light of the fascinating isomerization behavior observed in chloroformꢀd1, the
effect of the solvent upon the position of the Z/E equilibrium of 3a was examined in
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acetoneꢀd6, methanolꢀd4, DMSOꢀd6, tolueneꢀd8 and MeCNꢀd3 (Figure 4). The 1H
NMR spectra were recorded as quickly as possible after preparation of the samples.
After 5 minutes the E-isomer was the predominant form in all solvents. After 15
minutes, the equilibrium was found to significantly shift towards the Z-isomer in
acetoneꢀd6, tolueneꢀd8 and MeCNꢀd3, but exhibited a 1:1 ratio in methanolꢀd4, and
favored the E-form in DMSOꢀd6. When these equilibria were followed over 6 days,
the Z-form was favored in the nonpolar aprotic solvent, tolueneꢀd8 (Z:E, 97:3), and
polar aprotic solvents; acetoneꢀd6 (84:16) and MeCNꢀd3 (86:14). In polar protic
methanolꢀd4 the equilibrium was maintained at a 1:1 ratio of the Z- and Eꢀisomers,
and in the dipolar aprotic DMSOꢀd6 the Eꢀform predominated (30:70).14,20,21
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Figure 4. Relative percentage of the Zꢀisomer of 3a over time in different deuterated solvents.
Percentages were determined from 1H NMR by comparing the integrals of the αꢀketo proton of the Z-
and Eꢀisomers.
The fascinating effect of hydrogen bonding is highlighted in Figure 4.20,21 After 5
minutes; the Eꢀform is favored in all solvents except for chloroformꢀd1, presumably
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due to kinetically controlled hydrogen bond formation with the solvent via the ketone
oxygen. However, as the system equilibrates, the thermodynamic benefit of the
intramolecular hydrogen bond prevails over a reduction in steric hindrance in tolueneꢀ
d8, acetoneꢀd6 and MeCNꢀd3.14 In methanolꢀd4 and DMSOꢀd6 , disruption of the
intramolecular hydrogen bond by the solvent results in a significant equilibrium
proportion of the Eꢀform. In DMSOꢀd6 in particular, the Eꢀform of 3a exhibited a
lower field NꢀH proton (9.65 ppm) than in all other solvents; a characteristic that
tallies with the low Z-isomer proportion in DMSOꢀd6, and indicates significant
hydrogen bonding to the solvent.16,21
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The equilibrium proportion of the E configuration in acetoneꢀd6 and MeCNꢀd3 is
around four times greater than that observed in chloroformꢀd1 and tolueneꢀd8. Given
the even higher E proportions observed in methanolꢀd4 and DMSOꢀd6, we can infer
that the position of the configurational equilibrium in the enaminone products 3a-l
can essentially be related to the hydrogen bond accepting ability of the solvent.
Indeed, Figure 4 suggests that the solvents fall into three classes, i.e. weak hydrogen
bond acceptors (chloroformꢀd1 and tolueneꢀd8), medium hydrogen bond acceptors
(acetoneꢀd6 and MeCNꢀd3) and strong hydrogen bond acceptors (methanolꢀd4 and
DMSOꢀd6).22,23
The reaction with 2a was performed using Nꢀmethylaniline, 1m to eliminate
the intramolecular hydrogen bond and assess the resulting configurational and
conformational effects. The reaction proceeded with equal efficacy to the activated
anilines, and FTIR monitoring showed that the carbonyl stretch of enaminone 3m
presented at a higher wavenumber than the other enaminones in EtOH (1658 cmꢀ1,
compared to around 1640 cmꢀ1).13 After isolation in a 93% yield, 1H NMR analysis in
chloroformꢀd1 showed that 3m exclusively existed in an E configuration. While the
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addition of the methyl group likely induces a greater steric barrier to the adoption of
the Zꢀconfiguration, it is clear that the removal of the ability to hydrogen bond also
has a profound effect on the alkene geometry of 3m. NOESY NMR experiments
indicated that, on the NMR timescale, neither the E,s-cis nor E,s-trans forms are
favored (according to NOE interactions between the ketone methyl and the alkene
protons), presumably due to facile rotation of the alkenyl ketone unit around the CꢀN
bond.14
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Differentiation between Z,s-trans and Z,s-cis forms of enaminones via FTIR is
straightforward, whereas conformational assignment of the E-isomers has typically
been more difficult due to the very subtle differences between the corresponding IR
spectra.22 We therefore cannot unequivocally assign the conformation (or suggest that
one predominates at all) of the Eꢀisomer of 3m, and by extension, enaminones 3a-l 22
.
Higher wavenumber carbonyl stretches in solid state FTIR, and lower λmax
values have been observed for Eꢀenaminones compared to the corresponding Zꢀ
systems.16,23,24 Indeed, the carbonyl stretch of 3m was also identified at a higher
wavenumber (1662 cmꢀ1), and of lower intensity when the solid state FTIR spectrum
was compared to those of the other enaminones, 3a-l (1627ꢀ1660 cmꢀ1). Furthermore,
The ketone stretches of all the enaminones are also very sharp in the solid state FTIR
spectra, with no obvious shoulders in the case of 3a-l (unlike Figure 1). These
findings indicate that enaminones 3a-l exist exclusively in the Zꢀconfiguration in the
solid state.21 UVꢀVis analysis also showed that 3a in chloroform exhibited a
significantly longer wavelength, lower intensity absorbance band (343 nm) compared
to 3m (316 nm).16
These analyses further supported the notion that the subtle shoulder at 1669
cmꢀ1 in Figure 1 originates from the Eꢀisomer of 3f.22 The consistent 1:1 ratio of the
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Z/Eꢀisomers of 3a exhibited in methanolꢀd4 over 6 days shows that isomerization is
likely to be very rapid in alcohols. Therefore, upon formation in the reaction, the
enaminones are instantly converted to a 1:1 ratio of Z/Eꢀisomers.
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Figure 5. In situ FTIR monitoring of the 1620ꢀ1690 cmꢀ1 region of 3a in chloroformꢀd1 immediately
after isolation. The relaxation of the Z/E equilibrium was followed by monitoring the intensity of the
carbonyl stretches of the E- and Zꢀisomers over time (time proceeds from blue to red). Initially a small
amount of the Eꢀisomer (1672 cmꢀ1) is present, but this converts to the Zꢀisomer (1644 cmꢀ1) over 1
hour.22
To confirm this hypothesis, we utilized in situ FTIR monitoring to observe the
isomerization equilibrium as it relaxes after isolation of 3a (Figure 5). A chloroformꢀ
d1 solution prepared immediately after Kugelrohr distillation of 3a was monitored by
FTIR. Initially, two wellꢀseparated bands corresponding to the E- (1672 cmꢀ1) and Z-
carbonyl (1644 cmꢀ1) stretches were evident.22 Over time, the Eꢀstretch quickly
diminished and was accompanied by the growth of the Zꢀstretch. After 1 hour, the Zꢀ
stretch was the major constituent, and remained so indefinitely. This experiment
confirmed that the E- and Zꢀisomers exhibit distinct carbonyl stretches in solution
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state FTIR. Indeed, when enaminones 3a-l are returned, upon isolation, to EtOH, a
low intensity band at around 1670 cmꢀ1 is observed via FTIR monitoring.11,25 When
performing the same analysis in DMSO, a higher intensity band at 1670 cmꢀ1 is
observed, which correlates with the greater proportion of the E-isomer observed in 1H
NMR in DMSOꢀd6 (Figure 4).
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In an attempt to understand the mechanism of this facile isomerization process,
we prepared separate solutions of 3a with a conjugate addition acceptor (methyl vinyl
ketone), and with a conjugate addition donor (4ꢀmethoxyaniline, 1f), in a range of
deuterated solvents. If the isomerization proceeded via rapid elimination, rotation and
readdition of the enone unit, one would expect to observe additional conjugate
addition products. However, 1H NMR monitoring of these solutions over one week
indicated that there was no perturbation of the Z/E equilibrium and no additional
conjugate addition products. Therefore, given the significant degree of imine
character evident in the Xꢀray crystal structures of 3g and 3l, we can suggest that the
enaminone alkene configurations interconvert through a simple rotational process.15,23
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Table 3. Addition of amines 1n-w to ynones 2a-c to give enaminones 3n-w.
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Amine
R2
Approx.
timea
Enaminone Alkene
geometryb
Yield/%
4ꢀMethoxybenzylamine, 1n
1ꢀAminoꢀ3,3ꢀdiethoxypropane, 1o
Diisopropylamine, 1p
2,2,6,6ꢀTetramethylpiperidine, 1q
2ꢀAminoꢀ6ꢀmethylpyridine, 1r
4ꢀAminoquinaldine, 1s
2ꢀAminopyrimidine, 1t
Morpholine, 1u
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Me, 2a
Ph, 2b
Ph, 2b
OMe, 2c
10 mins
12 mins
10 mins
6 h
>48 h
>48 h
ꢀ
6 mins
30 minsc
35 h
Z
Z
E
E
Z
Z
-
93
99
98
95
3n
3o
3p
3q
3r
3s
(<30)d
(<15)d
0
3t
Z
Z
E
86
88
82
3u
3v
3w
Aniline, 1a
Aniline, 1a
c
aEstimated using FTIR. bAssessed by 1H NMR in chloroformꢀd1. Precipitated after 5 mins.dNot
isolated. Enaminones 3n-q and 3u-w were all isolated via Kugelrohr distillation. Yields in parentheses
were estimated from crude 1H NMR analysis.
With the conformational preferences of enaminones 3a-l understood, we
assessed the utility of the method towards amines and ynones of varied structure
(Table 3). As expected, in situ FTIR indicated that unhindered primary alkylamines,
1n and 1o, reacted even faster with 2a than the activated anilines due to their
increased nucleophilicity.3,4,7 Even the hindered diisopropylamine 1p reacted at a
similar rate, presumably due to the strongly electron donating alkyl groups. However,
further increasing steric hindrance (2,2,6,6ꢀtetramethylpiperidine 1q) caused a
significant reduction in rate, though the reaction still provided enaminone 3q in a
convenient timeframe (6 hours). The alkylamineꢀderived enaminones were all easily
isolated in excellent yields via Kugelrohr distillation.
Heteroaromatic amines exhibited a significant decrease in reactivity, due to
their reduced nucleophilicity. In-situ FTIR analysis of the reactions between 1r-t and
2a was much more complex than the other amines, and the solutions swiftly turned a
very dark red color. Indeed, all three reactions returned viscous black tars. In contrast
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to the exceptionally clean crude reaction mixtures of the other amines, crude 1H NMR
and GCMS analysis of the heteroaromatic amine reactions indicated mainly unreacted
amines, an array of unidentified side products and low conversion to the desired
enaminone (3r and 3s). Due to these very complex mixtures, we were unable to
isolate enaminones 3r-s chromatographically. Enaminone 3t was not observed in the
case of the reaction between 2ꢀaminopyrimidine 1t and 2a and mainly unreacted
starting material was evident.
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The reaction was conducted with 1ꢀphenylꢀ2ꢀpropynꢀ1ꢀone 2b and methyl
propiolate 2c in order to assess the effect of the ynone acceptor.7 Morpholine 1u and
aniline 1a reacted with 2b at similar rates to the reactions of nucleophilic amines with
2a due to the similar electrophilicity of the ynone. However, reaction of 1a with the
less electrophilic 2c exhibited a significant reduction in rate.37 Enaminones 3u-w were
all also isolated in good yields using the Kugelrohr distillation protocol.
Indeed, the rapid reaction time and straightforward purification of most of the
enaminones reported herein indicate that this conjugate addition methodology would
be ideal for quick generation or diversification of compound libraries for drug
screening.
Conclusion
In conclusion, a mild, effective and practical protocol for the synthesis of a range of
enaminones has been demonstrated. In situ FTIR highlighted the facile E/Zꢀ
isomerization of the enaminone products during the reaction. Further analytical work
explored this isomerization equilibrium, and confirmed the preferential adoption of a
Zꢀconfiguration in the solid state and in solvents with poor hydrogen bonding ability;
a characteristic that has occasionally been mistakenly attributed to stereoselective
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reaction conditions in the past. Given the high degree of imine character exhibited in
the crystal structures of 3g and 3l, it can be suggested that the enaminone alkene
configurations interconvert through a simple rotational process. The straightforward
method and Kugelrohr purification protocol enables rapid access to these interesting
compounds.
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Experimental Section
Typical laboratory grade ethanol was used for all reactions. Reagents were purified
via Kugelrohr distillation under vacuum, if required. Vacuum distillation/sublimation
was performed using a Kugelrohr operating at a pressure of around 0.5ꢀ2.0 Torr.
NMR peaks are reported as singlet (s), doublet (d), triplet (t), quartet (q), broad (br),
combinations thereof, or as a multiplet (m) with reference to the CHCl3 peak (1H =
7.26 ppm, 13C = 77.23 ppm). ESꢀMS was performed using a TQD mass spectrometer
with a UPLC, and accurate mass measurements were obtained using a QtoF mass
spectrometer with a UPLC. Solid state FTIR spectra were recorded using an FTꢀIR
spectrometer. Melting points were uncorrected. All in situ FTIR spectroscopy
experiments were carried out using an in situ FTIR spectrometer with MCT detector,
sampling at 2000ꢀ650 cmꢀ1. The 1H NMR spectra of the Z enaminones exhibit small
amounts (0ꢀ3%) of the corresponding E isomer due to the observed isomerization
equilibrium.
Example synthetic procedure: An amine (1.0 mmol) was added to a solution of 3ꢀ
butynꢀ2ꢀone, 2a (0.078 mL, 1.0 mmol) in EtOH (4 mL) and the resulting solution was
stirred at RT until in situ FTIR analysis, or TLC, indicated that the reaction was
complete. The solution was then diluted with EtOAc, washed with H2O and brine,
dried (MgSO4), evaporated and then directly distilled under vacuum using a
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Kugelrohr apparatus, recrystallized or purified by SiO2 chromatography to give the
enaminone product.
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The reactions were monitored by in situ FTIR spectroscopy according to the
following: (a) EtOH was added to a reaction flask with the FTIR probe inserted. The
infrared spectrum of EtOH was then recorded and subtracted from the signal; (b)
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Acceptor
was added, and both the reduction of the carbonyl stretch of
rise of the lower wavenumber carbonyl stretch of the resulting enaminone
examined over time (all reaction progress plots shown in the ESI). The reaction was
adjudged to be complete when the carbonyl stretch of was no longer evident, and
the carbonyl stretch of enaminone was stable over time. Intensity measurements in
reactions plots and spectra were multiplied by a factor of 10 to aid comprehension.
2
was then added and the ynone carbonyl stretch was identified; (c) Amine
and the consequent
was
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(3Z)-4-(Phenylamino)but-3-en-2-one, 3a: Aniline (0.0910 mL, 1.0 mmol) and 3ꢀ
butynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL) (completion
indicated after 20 mins) to give compound 3a as a white solid (0.149 g, 92%) after
purification by Kugelrohr distillation under vacuum (100ꢀ120 oC): m.p. = 95ꢀ96 oC;
1H NMR (600 MHz, CDCl3) δ 2.16 (s, 3H), 5.30 (d, J = 7.7 Hz, 1H), 7.00ꢀ7.07 (m,
3H), 7.22 (dd, J = 12.3, 7.7 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 11.58 (br d, J = 13.2 Hz,
1H); 13C NMR (151 MHz, CDCl3) δ 29.8, 97.6, 116.3, 123.6, 129.9, 140.6, 143.2,
199.1; IR (neat) ν
max/cmꢀ1 3236m, 3057w, 3036w, 2998w, 1660m, 1600m, 1545s,
1471s, 1260s, 961s; MS (ES): m/z = 162.1 [M+H]+; HRMS (ES) calcd. for C10H12NO
[M+H]+: 162.0919, found: 162.0923; Found: C, 74.43; H, 6.85; N, 8.70. Calc. for
C10H11NO: C, 74.51; H, 6.88; N, 8.69%.26
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(3
Z)-4-[(2-Methylphenyl)amino]but-3-en-2-one, 3b: 2ꢀMethylaniline (0.107 mL,
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6
7
8
1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 20 mins) to give compound 3b as an offꢀwhite solid
(0.160 g, 93%) after purification by Kugelrohr distillation under vacuum (120ꢀ130
oC): m.p. = 34ꢀ36 oC; 1H NMR (600 MHz, CDCl3) δ 2.18 (s, 3H), 2.36 (s, 3H), 5.35
(d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.17ꢀ7.22 (m,
2H), 7.31 (dd, J = 12.1, 7.6 Hz, 1H), 11.82 (br d, J = 10.5 Hz, 1H); 13C NMR (151
MHz, CDCl3) δ 17.8, 29.7, 97.8, 113.7, 123.4, 126.3, 127.3, 131.3, 139.1, 143.6,
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199.0; IR (neat) ν
max/cmꢀ1 3200w, 3059w, 2984w, 2910w, 1635m, 1585m, 1563s,
1465s, 1274s, 743s; MS (ES): m/z = 176.1 [M+H]+; HRMS (ES) calcd. for C11H14NO
[M+H]+: 176.1075, found: 176.1076; Found: C, 75.27; H, 7.46; N, 7.94. Calc. for
C11H13NO: C, 75.40; H, 7.48; N, 7.99%.
(3Z)-4-[(4-Methylphenyl)amino]but-3-en-2-one, 3c: 4ꢀMethylaniline (0.107 g, 1.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 20 mins) to give compound 3c as an offꢀwhite solid (0.153
g, 87%) after purification by Kugelrohr distillation under vacuum (100ꢀ120 oC): m.p.
= 109ꢀ110 oC; 1H NMR (700 MHz; CDCl3) δ 2.15 (s, 3H), 2.30 (s, 3H), 5.27 (d, J =
7.7 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.19 (dd, J = 12.4, 7.7
Hz, 1H), 11.57 (br d, J = 9.1 Hz, 1H); 13C NMR (176 MHz; CDCl3) δ 20.9, 29.7,
97.1, 116.4, 130.4, 133.3, 138.2, 143.7, 198.8; IR (neat) ν
max/cmꢀ1 3182m, 3033w,
2977w, 2858w, 1634m, 1609m, 1564s, 1475s, 1282s, 812s; MS (ES): m/z = 176.1
[M+H]+; HRMS (ES) calcd. for C11H14NO [M+H]+: 176.1075, found: 176.1085;
Found: C, 75.39; H, 7.46; N, 8.04. Calc. for C11H13NO: C, 75.40; H, 7.48; N,
7.99%.27
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(3
Z)-4-[(3,5-Dimethylphenyl)amino]but-3-en-2-one, 3d: 3,5ꢀDimethylaniline
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(0.125 mL, 1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in
EtOH (4 mL) (completion indicated after 40 mins) to give compound 3d as a clear
light yellow oil (0.178 g, 94%) after purification by Kugelrohr distillation under
vacuum (120ꢀ140 oC): 1H NMR (700 MHz, CDCl3) δ 2.14 (s, 3H), 2.29 (s, 6H), 5.26
(d, J = 7.7 Hz, 1H), 6.65 (s, 2H), 6.69 (s, 1H), 7.21 (dd, J = 12.4, 7.7 Hz, 1H), 11.50
(br d, J = 10.4 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ 21.5, 29.7, 97.2, 114.1, 125.4,
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139.6, 140.5, 143.4, 198.8; IR (neat) ν
max/cmꢀ1 3259w, 3027w, 2918w, 2861w, 1637s,
1571s, 1476m, 1278s, 1171s, 955m, 831m; MS (ES): m/z = 190.1 [M+H]+; HRMS
(ES) calcd. for C12H16NO [M+H]+: 190.1232, found: 190.1237; Found: C, 75.55; H,
8.04; N, 6.99. Calc. for C12H15NO: C, 76.16; H, 7.99; N, 7.40%.
(3Z)-4-[(4-Hydroxyphenyl)amino]but-3-en-2-one, 3e: 4ꢀAminophenol (0.546 g, 5.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.391 mL, 5.0 mmol) were stirred in EtOH (10 mL)
(completion indicated after 20 mins) to give compound 3e as a yellow solid (0.760 g,
86%) after purification by SiO2 column chromatography (Et2O, with 1% Et3N as
eluent): m.p. = 138ꢀ140 oC; 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 5.25 (d, J =
7.6 Hz, 1H), 5.61 (br s, 1H), 6.79ꢀ6.87 (m, 2H), 6.87ꢀ6.95 (m, 2H), 7.09ꢀ7.17 (dd, J =
12.4, 7.6 Hz, 1H), 11.60 (br d, J = 12.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 29.5,
96.7, 116.7, 118.2, 134.1, 144.7, 152.6, 198.8; IR (neat) ν
max/cmꢀ1 3100br, 3080w,
3032w, 2956w, 2813w, 1635m, 1554m, 1489s, 1263s, 1205s, 830s, 747s; MS (ES):
m/z = 178.1 [M+H]+; HRMS (ES) calcd. for C10H12NO2 [M+H]+: 178.0868, found:
178.0873; Found: C, 67.37; H, 6.23; N, 7.79. Calc. for C10H11NO2: C, 67.78; H, 6.26;
N, 7.90%. Note: 3e exhibited low solubility in CDCl3. 3e was also highly susceptible
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to degradation when heated. Mild heating with a heat gun, or in a Kugelrohr caused a
rapid colour change to dark red/brown.28
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1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 20 mins) to give compound 3f as a white solid (0.168 g,
88%) after purification by Kugelrohr distillation under vacuum (100ꢀ120 oC): m.p. =
62ꢀ64 oC; 1H NMR (600 MHz, CDCl3) δ 2.13 (s, 3H), 3.77 (s, 3H), 5.24 (d, J = 7.6
Hz, 1H), 6.83ꢀ6.88 (m, 2H), 6.94ꢀ7.00 (m, 2H), 7.12 (dd, J = 12.4, 7.6 Hz, 1H), 11.60
(br d, J = 11.4 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 29.6, 55.7, 96.7, 115.1, 117.9,
134.2, 144.3, 156.3, 198.5; IR (neat) ν
max/cmꢀ1 3228w, 3004w, 2956w, 2914w,
2836w, 1634s, 1595m, 1565s, 1477s, 1352m, 1291m, 1201s, 823s; MS (ES): m/z =
192.1 [M+H]+; HRMS (ES) calcd. for C11H14NO2 [M+H]+: 192.1031, found:
192.1025; Found: C, 69.07; H, 6.85; N, 7.31. Calc. for C11H13NO2: C, 69.09; H, 6.85;
N, 7.32%.29
4-[(1Z)-3-Oxobut-1-en-1-yl]aminobenzoate, 3g: Ethyl 4ꢀaminobenzoate (0.165 g,
1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 24 h) to give compound 3g as a white solid (0.199 g, 85%)
after purification by Kugelrohr distillation under vacuum (140ꢀ160 oC): m.p. = 75ꢀ76
oC; 1H NMR (700 MHz, CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 2.18 (s, 3H), 4.35 (q, J =
7.1 Hz, 2H), 5.38 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.24 (dd, J = 12.1, 7.9
Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 11.63 (br d, J = 11.8 Hz, 1H); 13C NMR (176 MHz,
CDCl3) δ 14.6, 30.0, 61.0, 99.3, 115.2, 125.1, 131.7, 141.7, 144.4, 166.2, 199.8; IR
(neat)
ν
max/cmꢀ1 3246w, 3036w, 2989w, 2964w, 1703s, 1646m, 1598m, 1558m,
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1475m, 1259s, 746s; MS (ES): m/z = 234.1 [M+H]+; HRMS (ES) calcd. for
C13H16NO3 [M+H]+: 234.1130, found: 234.1129; Found: C, 66.98; H, 6.50; N, 6.00.
Calc. for C13H15NO3: C, 66.94; H, 6.48; N, 6.00%. Note: Overlapping ketone
stretches from the starting aniline and enaminone 3g meant that assessing completion
by in situ FTIR monitoring was difficult. TLC analysis indicated completion after 24
hours.30
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(3Z)-4-[(4-Chlorophenyl)amino]but-3-en-2-one, 3h: 4ꢀChloroaniline (0.128 g, 1.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 6 h) to give compound 3h as a white solid (0.18 g, 92%)
after purification by Kugelrohr distillation under vacuum (120ꢀ140 oC): m.p. = 111ꢀ
113 oC; 1H NMR (600 MHz, CDCl3) δ 2.15 (s, 3H), 5.31 (d, J = 7.8 Hz, 1H), 6.92ꢀ
6.97 (m, 2H), 7.14 (dd, J = 12.2, 7.8 Hz, 1H), 7.24ꢀ7.29 (m, 2H), 11.57 (br d, J = 9.3
Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 29.8, 98.2, 117.4, 128.5, 129.9, 139.3, 142.8,
199.4; IR (neat) ν
max/cmꢀ1 3175w, 3093w, 3002w, 2960w, 1643s, 1594s, 1569s,
1472s, 1291s, 1220s, 1090m, 818s; MS (ES): m/z = 196.0 [M+H]+; HRMS (ES)
calcd. for C10H11NOCl [M+H]+: 196.0529, found: 196.0521; Found: C, 61.51; H,
5.17; N, 7.14. Calc. for C10H10NOCl: C, 61.39; H, 5.15; N, 7.16%.31
(3Z)-4-[(4-Bromophenyl)amino]but-3-en-2-one, 3i: 4ꢀBromoaniline (0.172 g, 1.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 3.5 h) to give compound 3i as a yellow solid (0.21 g,
88%) after purification by Kugelrohr distillation under vacuum (115ꢀ140 oC): m.p. =
121ꢀ124 oC; 1H NMR (700 MHz, CDCl3) δ 2.16 (s, 3H), 5.32 (d, J = 7.8 Hz, 1H),
6.87ꢀ6.92 (m, 2H), 7.14 (dd, J = 12.2, 7.8 Hz, 1H), 7.38ꢀ7.43 (m, 2H), 11.56 (br d, J =
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12.1 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ 29.9, 98.3, 115.9, 117.7, 132.8, 139.7,
142.6, 199.4; IR (neat) ν
max/cmꢀ1 3177w, 3073w, 2994w, 2908w, 1634m, 1591s,
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1566s, 1471s, 1289m, 1180m, 814s, 752s; MS (ES): m/z = 240.0 [M+H]+; HRMS
(ES) calcd. for C10H11NOBr [M+H]+: 240.0024, found: 240.0039; Found: C, 50.09;
H, 4.19; N, 5.81. Calc. for C10H10NOBr: C, 50.02; H, 4.20; N, 5.83%.
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(3Z)-4-[(4-Nitrophenyl)amino]but-3-en-2-one, 3j: 4ꢀNitroaniline (0.691 g, 5.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.39 mL, 5.0 mmol) were stirred in EtOH (10 mL) for 5
days to give compound 3j as a yellow/orange solid (0.34 g, 33%) after
recrystallization from EtOH: m.p. = 178ꢀ180 oC; 1H NMR (700 MHz, CDCl3) δ 2.21
(s, 3H), 5.48 (d, J = 8.0 Hz, 1H), 7.04ꢀ7.09 (m, 2H), 7.22 (dd, J = 11.8, 8.0 Hz, 1H),
8.18ꢀ8.23 (m, 2H), 11.73 (br d, J = 11.9 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ
30.3, 101.0, 115.2, 126.2, 140.6, 142.9, 146.1, 200.4; IR (neat) ν
max/cmꢀ1 3201w,
3094w, 3003w, 1647m, 1575s, 1496s, 1473s, 1377m, 1325s, 1274s, 838s; MS (ES):
m/z = 207.0 [M+H]+; HRMS (ES) calcd. for C10H11N2O3 [M+H]+: 207.0770, found:
207.0772; Found: C, 57.80; H, 4.82; N, 13.50. Calc. for C10H10N2O3: C, 58.25; H,
4.89; N, 13.59%. Note: Precipitation of 3j caused unreliable in situ FTIR monitoring.
The reaction was therefore halted after 5 days according to TLC analysis.14a
(3Z)-4-[(4-Iodophenyl)amino]but-3-en-2-one, 3k: 4ꢀIodoaniline (1.10 g, 5.0 mmol)
and 3ꢀbutynꢀ2ꢀone (0.39 mL, 5.0 mmol) were stirred in EtOH (10 mL) (completion
indicated after 5 h) to give compound 3k as a beige solid (1.04 g, 72%) after
recrystallization from EtOH: m.p. = 128ꢀ130 oC; 1H NMR (700 MHz, CDCl3) δ 2.15
(s, 3H), 5.32 (d, J = 7.8 Hz, 1H), 6.76ꢀ6.81 (m, 2H), 7.14 (dd, J = 12.2, 7.8 Hz, 1H),
7.56ꢀ7.61 (m, 2H), 11.54 (br d, J = 11.8 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ
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29.9, 86.0, 98.4, 118.1, 138.7, 140.4, 142.4, 199.4; IR (neat) ν
max/cmꢀ1 3174w, 3075w,
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2990w, 2915w, 1633m, 1588s, 1561s, 1465s, 1366m, 1280m, 1120w, 812s; MS (ES):
m/z = 288.0 [M+H]+; HRMS (ES) calcd. for C10H11INO [M+H]+: 287.9885, found:
287.9892. Note: 3k was susceptible to degradation when heated above 120 oC in a
Kugelrohr under vacuum. Precipitation of 3k caused unreliable in situ FTIR
monitoring.
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(3Z)-4-[(4-Iodo-2-methylphenyl)amino]but-3-en-2-one, 3l: 4ꢀIodoꢀ2ꢀmethylaniline
(1.17 g, 5.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.39 mL, 5.0 mmol) were stirred in EtOH (10
mL) (completion indicated after 5 h) to give compound 3l as a beige solid (1.28 g,
85%) after recrystallization from EtOH: m.p. = 106ꢀ107 oC; 1H NMR (700 MHz,
CDCl3) δ 2.18 (s, 3H), 2.30 (s, 3H), 5.38 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H),
7.23 (dd, J = 11.9, 7.7 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H), 11.75 (br d, J =
11.3 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ 17.4, 29.8, 86.1, 98.6, 115.3, 128.6,
136.1, 139.0, 139.8, 142.7, 199.4; IR (neat) ν
max/cmꢀ1 3331m, 3030w, 3010w, 2964w,
1630m, 1577m, 1393m, 1255s, 760s, 669m; MS (ES): m/z = 302.0 [M+H]+; HRMS
(ES) calcd. for C11H13INO [M+H]+: 302.0042, found: 302.0052; Found: C, 43.95; H,
3.96; N, 4.65. Calc. for C11H12INO: C, 43.88; H, 4.02; N, 4.65%. Note: 3l was
susceptible to degradation when heated above 120 oC in a Kugelrohr. Precipitation of
3l caused unreliable in situ FTIR monitoring.
(3E)-4-[Methyl(phenyl)amino]but-3-en-2-one, 3m: NꢀMethylaniline (0.107 mL, 1.0
mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 20 mins) to give compound 3m as a yellow oil (0.164 g,
93%) after purification by Kugelrohr distillation (125ꢀ145 oC) under vacuum: 1H
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NMR (700 MHz, CDCl3) δ 2.18 (s, 3H), 3.27 (s, 3H), 5.41 (d, J = 13.1 Hz, 1H), 7.12ꢀ
7.18 (m, 3H), 7.33ꢀ7.39 (m, 2H), 7.89 (d, J = 13.1 Hz, 1H); 13C NMR (176 MHz,
CDCl3) δ 28.4, 37.1, 102.0, 120.5, 124.9, 129.7, 146.7, 148.6, 196.4; IR (neat)
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max/cmꢀ1 3061w, 2909w, 2828w, 1662m, 1612m, 1583s, 1544s, 1494s, 1427m,
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1251s, 950s, 756s; MS (ES): m/z = 176.1 [M+H]+; HRMS (ES) calcd. for C11H14NO
[M+H]+: 176.1078, found: 176.1075.32
(3Z)-4-{[(2-Methoxyphenyl)methyl]amino}but-3-en-2-one, 3n: 2ꢀ
Methoxybenzylamine (0.131 mL, 1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0
mmol) were stirred in EtOH (4 mL) (completion indicated after 10 mins) to give
compound 3n as a light yellow oil (0.190 g, 93%) after purification by Kugelrohr
distillation under vacuum (180ꢀ190 oC): 1H NMR (700 MHz; CDCl3) δ 2.04 (s, 3H),
3.86 (s, 3H), 4.33 (d, J = 6.3 Hz, 2H), 4.99 (d, J = 7.4 Hz, 1H), 6.72 (dd, J = 12.8, 7.4
Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.92 (td, J = 7.4, 1.1Hz, 1H), 7.17 (d, J = 7.4 Hz,
1H), 7.27 (td, J = 8.1, 1.7 Hz, 1H), 10.06 (br s, 1H); 13C NMR (176 MHz; CDCl3) δ
29.2, 48.8, 55.5, 94.0, 110.6, 120.8, 126.6, 128.7, 129.3, 152.8, 157.4, 197.5; IR
(neat) ν
max/cmꢀ1 3261br, 3042w, 2939w, 2838w, 1637m, 1601m, 1557m, 1489m,
1354m, 1240s; MS(ES): m/z = 206.4 [M+H]+; HRMS (ES) calcd. for C12H16NO2
[M+H]+: 206.1181, found 206.1187.
(3Z)-4-[(3,3-Diethoxypropyl)amino]but-3-en-2-one, 3o: 1ꢀAminoꢀ3,3ꢀ
diethoxypropane (0.162 mL, 1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol)
were stirred in EtOH (4 mL) (completion indicated after 12 mins) to give compound
3o as a yellow oil (0.213 g, 99%) after purification by Kugelrohr distillation under
vacuum (155ꢀ160 oC): 1H NMR (700 MHz; CDCl3) δ 1.19 (t, J = 7.1 Hz, 6H), 1.84
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(td, J = 6.8, 5.6 Hz, 2H), 2.02 (s, 3H), 3.26 (q, J = 6.6 Hz, 2H), 3.46ꢀ3.50 (m, 2H),
3.61ꢀ3.65 (m, 2H), 4.53 (t, J = 5.6 Hz, 1H), 4.95 (d, J = 7.3 Hz, 1H), 6.60 (dd, J =
12.8, 7.3 Hz, 1H), 9.75 (br s, 1H); 13C NMR (176 MHz; CDCl3) δ 15.5, 29.1, 35.1,
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45.2, 61.9, 93.9, 100.8, 152.6, 197.5; ν
max/cmꢀ1 3267br, 2975w, 2930w, 2886w,
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1639m, 1557m, 1486m, 1373w, 1254m, 1122s; MS(ES): m/z = 216.5 [M+H]+;
HRMS (ES) calcd. for C11H22NO3 [M+H]+: 216.1600, found 216.1606.
(3E)-4-[Bis(propan-2-yl)amino]but-3-en-2-one, 3p: Diisopropylamine (0.140 mL,
1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 10 mins) to give compound 3p as a yellow oil (0.166 g,
98%) after purification by Kugelrohr distillation under vacuum (120ꢀ125 oC): 1H
NMR (400 MHz, CDCl3) δ 1.20 (d, J = 6.8 Hz, 12H), 2.07 (s, 3H), 3.56 (br, 1H), 3.81
(br, 1H), 5.20 (d, J = 12.9 Hz, 1H), 7.61 (br, 1H); 13C NMR (101 MHz, CDCl3) δ
19.8, 23.7, 29.1, 48.1, 49.0, 95.7, 147.4, 195.2; IR (neat) ν
max/cmꢀ1 2975w, 2934w,
2879w, 1649m, 1597m, 1545m, 1456m, 1297s; MS (ES): m/z = 170.1 [M+H]+;
HRMS (ES) calcd. for C10H20NO [M+H]+: 170.1545, found 170.1543.33
(3E)-4-(2,2,6,6-Tetramethylpiperidin-1-yl)but-3-en-2-one, 3q: 2,2,6,6ꢀ
Tetramethylpiperidine (0.169 mL, 1.0 mmol) and 3ꢀbutynꢀ2ꢀone (0.0782 mL, 1.0
mmol) were stirred in EtOH (4 mL) (completion indicated after 6 h) to give
compound 3q as a colourless crystalline solid (0.197 g, 95%) after purification by
Kugelrohr distillation under vacuum (145ꢀ155 oC): m.p. = 92ꢀ94 oC; 1H NMR (600
MHz; CDCl3) δ 1.38 (s, 12H), 1.58ꢀ1.66 (m, 6H), 2.10 (s, 3H), 5.42 (d, J = 13.8 Hz,
1H), 7.79 (br d, J = 13.6 Hz, 1H); 13C NMR (151 MHz; CDCl3) δ 16.4, 29.3, 41.1,
58.0, 102.8, 148.3, 195.4; IR (neat) ν
max/cmꢀ1 2971w, 2939w, 2863w, 1653m, 1534m,
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1465m, 1344s, 1245s, 1163s; MS (ES): m/z = 210.5 [M+H]+; HRMS (ES) calcd. for
C13H24NO [M+H]+: 210.1858, found 210.1859; Found: C, 74.58; H, 10.99; N, 6.64.
Calc. for C13H23NO: C, 74.59; H, 11.08; N, 6.69%. Note: 13C NMR signal for the
ketone methyl group was not observed.
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1-Phenylprop-2-yn-1-one, 2b: Ethynyl magnesium bromide (0.5 M in THF, 36 mL,
18.0 mmol) was added dropwise under Ar to a solution of benzaldehyde (1.53 mL,
15.0 mmol) in anhydrous THF (10 mL) at ꢀ78 oC. The resultant solution was allowed
to warm to RT and stirred for 2.5 h. The solution was quenched with sat. NH4Cl,
diluted with DCM, and the organics washed with H2O, dried (MgSO4) and evaporated
to give a crude yellow oil. This was purified by SiO2 chromatography (DCM:hexane,
4:1 as eluent) to give 1ꢀphenylpropꢀ2ꢀynꢀ1ꢀol as a yellow oil (1.79 g, 90%). 1ꢀ
Phenylpropꢀ2ꢀynꢀ1ꢀol (1.79 g, 13.5 mmol) was then dissolved in acetone (10 mL),
and a solution of CrO3 (0.9 g, 9.00 mmol) in a mixture of H2O (7 mL) and conc.
H2SO4 (3 mL) was added dropwise over 20 mins at 0 oC. The resultant suspension
was stirred at 0 oC for 5 h, before being diluted with H2O and extracted with CHCl3
(3x). The organics were washed with H2O, dried (MgSO4), and evaporated to give a
crude yellow solid. This was distilled under vacuum using a Kugelrohr (105ꢀ115 oC)
to give 1ꢀphenylpropꢀ2ꢀynꢀ1ꢀone, 2b, as a white solid (1.18 g, 67%): m.p. = 41ꢀ44 oC;
1H NMR (700 MHz, CDCl3) δ 3.46 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.59 (t, J = 7.4
Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H); 13C NMR (176 MHz, CDCl3) δ 80.4, 81.1, 128.8,
129.8, 134.6, 136.2, 177.5; IR (neat) ν
max/cmꢀ1 3232s, 3099w, 3067w, 2091s, 1637s,
1595m, 1580m, 1452m, 1247s, 692s; MS (EI): m/z = 130.1 [M]+.34,35
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)-3-(Morpholin-4-yl)-1-phenylprop-2-en-1-one, 3u: Morpholine (0.0874 mL,
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1.0 mmol) and 1ꢀphenylpropꢀ2ꢀynꢀ1ꢀone (0.13 g, 1.0 mmol) were stirred in EtOH (4
mL) (completion indicated after 6 mins) to give compound 3u as a yellow oil (0.187
g, 86%) after purification by Kugelrohr distillation under vacuum (210ꢀ220 oC): 1H
NMR (700 MHz; CDCl3) δ 3.38 (t, J = 4.9 Hz, 4H), 3.73ꢀ3.76 (m, 4H), 5.87 (d, J =
12.6 Hz, 1H), 7.38ꢀ7.42 (m, 2H), 7.43ꢀ7.47 (m, 1H), 7.72 (d, J = 12.6 Hz, 1H), 7.85ꢀ
7.88 (m, 2H); 13C NMR (176 MHz; CDCl3) δ 66.5, 92.7, 127.7, 128.4, 131.4, 140.4,
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152.9, 189.4; IR (neat) ν
max/cmꢀ1 3005w, 2965w, 2908w, 2854w, 1636m, 1580m,
1531s, 1439m, 1203s; MS (ES): m/z = 218.8 [M+H]+; HRMS (ES) calcd. for
C13H16NO2 [M+H]+: 218.1181, found 218.1187.36
(2Z)-1-Phenyl-3-(phenylamino)prop-2-en-1-one, 3v: Aniline (0.0910 mL, 1.0
mmol) and 1ꢀphenylpropꢀ2ꢀynꢀ1ꢀone (0.13 g, 1.0 mmol) were stirred in EtOH (4 mL)
(completion indicated after 30 mins) to give compound 3v as a yellow crystalline
solid (0.196 g, 88%) after purification by Kugelrohr distillation under vacuum (205ꢀ
215 oC): m.p. = 128ꢀ130 oC; 1H NMR (600 MHz; CDCl3) δ 6.03 (d, J = 7.8 Hz, 1H),
7.06ꢀ7.14 (m, 3H), 7.32ꢀ7.38 (m, 2H), 7.43ꢀ7.49 (m, 2H), 7.47ꢀ7.56 (m, 2H), 7.92ꢀ
7.98 (m, 2H), 12.16 (d, J = 12.7 Hz, 1H); 13C NMR (151 MHz; CDCl3) δ 93.9, 116.5,
123.9, 127.5, 128.6, 129.9, 131.8, 139.4, 140.4, 145.1, 191.2; IR (neat) ν
max/cmꢀ1
3260br, 3058w, 3033w, 1623m, 1593m, 1549m, 1508m, 1451m, 1238s, 741s; MS
(ES): m/z = 224.4 [M+H]+; HRMS (ES) calcd. for C15H14NO [M+H]+: 224.1075,
found 224.1072.37
Methyl (2Z)-3-(phenylamino)prop-2-enoate, 3w: Aniline (0.0910 mL, 1.0 mmol)
and methyl propiolate (0.0890 mL, 1.0 mmol) were stirred in EtOH (4 mL)
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