Synthesis of Dicarbonyl Curcumin Analogues Containing the Tropane Scaffold

Article abstract of DOI:10.1002/ejoc.201900416

A general synthetic route to the unknown 1,3-dicarbonyl tropane derived curcumin analogues was developed. The method was based on the aldol condensation reaction (40–90 % yield, two steps without product isolation) and acylation of the resulting 2-benzylidenetropinones with substituted cinnamoyl cyanides (yields 41–91 %). Overall 18 new tropane derivatives featuring the characteristic curcuminoid hepta-1,6-dien-3,5-dione structure were synthesized and characterized. The range of the substituted aromatic rings in the prepared analogues included Ph, m-MeO-C₆H₄, 3,4-di-MeO-C₆H₃, 3,4,5-tri-MeO-C₆H₂, p-Br-C₆H₄, p-F-C₆H₄, p-CF₃-C₆H₄, p-NO₂-C₆H₄, 2-NO₂-4,5-di-CH₃O-C₆H₂, 2-NO₂-4,5-O-CH₂-O-C₆H₂, 3-MeO-4-[CH(CH₃)-OEt]-C₆H₃, 3-MeO-4-OH-C₆H₃, p-MeO-C₆H₄, 4,5-O-CH₂-O-C₆H₃, 3-MeO-4-MeOCOO. Two orthogonal protective groups for hydroxyl (acetal or carbonate), removable in acidic or basic conditions, were used for synthesizing curcuminoids with free phenolic groups (3-MeO-4-OH-C₆H₃).

Full text of DOI:10.1002/ejoc.201900416

A Journal of
Accepted Article
Title: Synthesis of dicarbonyl curcumin analogues containing tropane
scaffold
Authors: Karol Wołosewicz, Katarzyna Podgorska, Ewelina Rutkowska,
and Ryszard Lazny
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900416
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900416
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
Synthesis of dicarbonyl curcumin analogues containing tropane
scaffold
Karol Wolosewicz,[a] Katarzyna Podgorska,[a] Ewelina Rutkowska,[a] Ryszard Lazny*[a]
Abstract: A general synthetic route to the unknown 1,3-dicarbonyl
tropane derived curcumin analogues was developed. The method
was based on aldol condensation reaction (40-90% yield, two steps
without product isolation) and acylation of the resulting 2-
benzylidenetropinones with substituted cinnamoyl cyanides (yields
41-91%). Overall 18 new tropane derivatives feathering the
characteristic curcuminoids hepta-1,6-dien-3,5-dione structure were
synthesized and characterized. The range of the substituted
aromatic rings in the prepared analogues included Ph, m-MeO-C6H4,
3,4-di-MeO-C6H3, 3,4,5-tri-MeO-C6H2, p-Br-C6H4, p-F-C6H4, p-CF3-
C6H4, p-NO2-C6H4, 2-NO2-4,5-di- CH3O-C6H2, 2-NO2-4,5-O-CH2-O-
C6H2, 3-MeO-4-[CH(CH3)-OEt]-C6H3, 3-MeO-4-OH-C6H3, p-MeO-
C6H4, 4,5-O-CH2-O-C6H3, 3-MeO-4-MeOCOO. Two orthogonal
protective groups for hydroxyl (acetal or carbonate), removable in
acidic or basic conditions, were used for synthesizing curcuminoids
with free phenolic groups (3-MeO-4-OH-C6H3).
Numerous studies have shown that curcumin possess anti-
inflammatory,[2] antioxidant,[3] antitumor,[4] antimalarial,[5] and
many other biological activities.[6] Despite its broad spectrum of
activities and good safety profile curcumin is hard to develop as
a drug because of its poor oral bioavailability.[7] Even when
applied in huge oral doses (8 g of curcumin per day) it achieved
only average peak serum concentration of approximately 1.77
µM.[8] Major limitations for using curcumin as an active
pharmaceutical ingredient are its poor water solubility, instability
towards bases, fast metabolism and systemic elimination.[1a]
Therefore there is continued interest in the synthesis of
curcumin analogues with structures credited with biological
properties, but with improved oral bioavailability.[7] One of the
strategies to tackle this issue is the incorporation of a basic
nitrogen atom into the molecule. Introducing nitrogen into the
structure of curcumin analogues introduces a secondary binding
site (a hydrogen bond acceptor).[9] Nitrogen modified
compounds showed better free radical activity, activity against
cancer cell lines and improves solubility behavior.[10] Previously
the effect of nitrogen introduced in a form of 4-piperidone
structure to curcumin analogues was studied.[9, 11] Many of the
analogues demonstrated very good antiproliferative activities.[12]
Moreover, it was demonstrated that addition of thiols (a known
mechanism of protein binding) to α,β-unsaturated-β’-
aminoketones (enones with additional β amino nitrogen) was
significantly faster than addition to unmodified enones.[13]
Nitrogen containing derivatives including N-methyl derivatives
showed improved antiproliferative activities compared with
homocyclic congeners.[10] Moreover, fusing the diarylheptanoid
characteristic of curcumin with a structure representative of a
group of natural products such as tropanes,[14] many of which
possess biological activities,[15] could give interesting results.
Therefore we aimed at merging diarylheptanoids with tropane
core which is present in biologically active compounds like
cocaine (an inhibitor of reuptake of dopamine, noradrenaline and
serotonin)[16] or scopolamine (competitive muscarinic receptor
antagonist)[17] (Figure 2).
Introduction
Curcumin is one of three main closely related polyphenolic
natural products obtained from the rhizome of the plant Curcuma
longa (Figure 1). The other two are demethoxycurcumin ( DMC)
and bisdemethoxycurcumin (BDMC). The characteristic feature
of these compounds is the 1,3-dienone structure. Curcumin and
related compounds are credited with a wide spectrum of
biological activities.[1]
ꢀ
ꢀ
ꢁꢂꢀ
ꢃꢀ
ꢀꢁꢂ
ꢀꢃ
Curcumin
ꢀ
ꢀ
ꢀꢁꢂ
ꢀꢃ
ꢃꢀ
Demethoxycurcumin (DMC)
ꢀ
ꢀ
ꢃꢀ
ꢀꢃ
Bis-demethoxycurcumin (BDMC)
Figure 1. Structure of curcumin, demethoxycurcumin and bis-
demethoxycurcumin.
Figure 2. Structure of tropane with shown tropane numbering
and representative bioactive tropanes.
[a]
Prof. dr. Ryszard Lazny
E-mail: lazny@uwb.edu.pl
Dr. Karol Wolosewicz
Dr. Katarzyna Podgorska
Ewelina Rutkowska
Institute of Chemistry, University of Bialystok,
Ciołkowskiego 1K, 15-245 Bialystok, Poland.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
Tropane alkaloids usually have considerable water solubility,
oral bioavailability and some of them (including scopolamine and
cocaine) are able to penetrate the blood brain barrier.[16, 18]
Tropane derivatives can be synthesized by a variety of
approaches[19] including stereoselective C-C forming reactions[20]
such as acylation of tropinone enolate[21] or alkylation of
tropinone azaenolate.[22] However, to this date no synthesis of
tropane containing diarylheptanoids was published.[16, 19-20] The
only described curcumin analogues containing tropane ring are
limited to monocarbonyl derivatives and as such are lacking a
salient feature of curcuminoids.[9b, 23] The synthetic route to these
analogues was based on aldol condensation of tropinone 1 with
aromatic aldehydes (Scheme 1).[9b, 23b]
may contribute to the enhancement of stability of curcuminoids
(no alkali promoted decomposition of monoketone to ferulic acid
is possible). However, literature indicates some other products
as major curcumin metabolites in in vivo tests. The revealed
metabolites were curcumin-glucuronoside, dihydrocurcumin-
glucuronoside,
tetrahydrocurcumin
(THC)
and
tetrahydrocurcumin (THC)-glucuronoside[26] while dihydroferulic
acid together with ferulic acid were only minor biliary metabolites
during rat tests[27] The major metabolites in humans were
curcumin-glucuronoside and curcumin sulfate.[26b] The biological
properties of the bis(α,β-unsaturated)-1,3-diketo group are not
fully understood and incorporation of a heteroatom-containing
rigid ring is desirable for the structure-activity relationships
study.[4b] Moreover, the bicyclic tropane skeleton could provide
certain stabilization of the sensitive diketone by skeleton rigidity
and steric hindrance for nucleophiles (e.g. hydroxide ion)
approaching along the Burgi-Dunitz trajectory.[28] Some of the
steric shielding can be expected from both faces of the
endocyclic ketone group of the 3-tropanone: N-methyl group on
one side and the dimethylen bridge on the other side. The
exocyclic ketone group could also be slightly shielded by the
proximity of the tropane structure. Introducing amine nitrogen
provides a means of increasing water solubility by hydrogen
acceptor site and possible protonation (formation of a salt form).
Thus, a method for synthesis of dicarbonyl tropane derived
curcumin analogues is desirable. In this contribution we present
an effective synthetic approach to a series of tropane derived
curcuminoid analogues.
ꢀ
ꢄ
ꢀ
ꢄ
ꢅꢆꢇꢃꢀꢈ
ꢅꢆ
ꢅꢆ
ꢉꢄꢊꢄꢋꢀꢃꢊꢋꢌꢈꢊꢍꢎꢀꢃ
ꢁꢂ
ꢁꢂ
2a
1
ꢆꢐꢊꢑꢒꢓꢈꢊꢔꢃꢕ
ꢏꢐꢊꢅꢆꢇꢃꢀ
ꢀꢃ
ꢅꢆ
ꢅꢏꢇꢃꢀ
ꢀ
ꢄ
ꢀ
ꢄ
ꢅꢏ
ꢄꢋꢀꢃꢈꢊꢁꢂꢀꢃ
ꢅꢆ
ꢁꢂ
ꢁꢂ
2b
3
Scheme 1. Syntheses of symmetrical 2a[9b] and unsymmetrical
2b[23b] monocarbonyl derivatives of tropinone
Results and Discussion
Historically, the first synthesis of curcumin was reported in 1918
by Lampe.[29] The key step in this procedure was the reaction of
acid chloride (carbomethoxyferuloyl chloride) and ethyl
acetoacetate. Unfortunately, the product was obtained in poor
yield therefore we reject this method as the synthesis of
dicarbonyl analogues. A later approach by Pavolini[30] improved
by Pabon[31] relied on an attractive single reaction of acetyl
acetone and substituted aromatic aldehydes in the presence of
boron trioxide (B2O3), trialkyl borate and n-butylamine. Thus all
the existing schemes for the synthesis of curcumin and its diketo
analogues required a reaction of penta-2,4-dione with suitably
substituted aromatic aldehydes. Preparation of suitably
substituted β-diketone (2-acetyltropinone) substrate for these
procedures (Pavoliini, Pabon) and attempted condensations
were complicated by side reaction and were judged unsuitable.
The key substrate, 2-acetyltropinone, could be obtained in
acylation reaction with poor yield probably due to the high C-H
acidity of the electrophile (acetyl chloride and cyanide). Another
approach using the reaction of 2-cinnamoyltropinone (an
alkaloid chalcostrobamine) with the aldehyde (vanillin) was also
very low yielding and plagued by persistent impurities.
The symmetrical monocarbonyl analogues 2a (R1 = R2
=
pyridine-4-yl, pyridine-3-yl, 3,4,5-trimethoxyphenyl) have been
tested for cytotoxicity towards MBA-MB-231 breast cancer cells,
and inhibition of NF-кB transactivation in non-adherent K562
leukemia cells. One of them (2a, R1=R2= pyridine-4-yl) showed
cytotoxicity towards MBA-MB-231 breast cancer cells with EC50
value of 1.1 μM, and ability to inhibit NF-кB transactivation in
non-adherent K562 leukemia cells with IC50 value of 1.5 μM.
According to the authors this level of activity indicates the
necessity of further investigation of curcumin analogues with
heterocyclic core.[23a]
The enol form of 1,3-diketone, which is absent in known
tropinone analogues of curcumin, is reportedly responsible for
some curcumin activity. The compounds with locked diketo
moiety (hydrogen atom substituted by a fluorine atom in the
methylene position between carbonyl groups preventing
enolization) were completely inactive in the anti-androgen
activity in LNCaP and PC-3 prostate cancer cells tests in
contrast to the enolizing (i.e. non fluorinated) congeners.[24] The
presence of 1,3-diketone or rather 1,3-keto-enol moiety was also
reported beneficial for antioxidant activity. Bis(α,β-unsaturated)-
1,3-diketo compounds exhibited higher antioxidant activity than
corresponding monoketones.[25] Unfortunately, according to the
best of our knowledge, dicarbonyl (diarylheptanoid type)
analogues of curcumin containing tropane structure are
unknown.
A possible cause of lack of studies on tropinone analogues
with β-diketone moiety, besides unknown route of synthesis,
could be the hypothesis that deletion of the β-diketone moiety
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Reaction of 4a with cinnamoyl chloride and cinnamoyl cyanide
(crystallization of aldol significantly decrease the overall yields of
2-benzylidenetropinones 4a-k).
Therefore we built our strategy based on the acylation of suitably
substituted 2-benzylidenetropinones 4a-k. Reactions of
benzylidenetropinone with cinnamoyl chloride resulted in ring
opening via a retro-aza-Michael reaction (Scheme 2). We
observed that the reaction of so substituted tropane system with
acyl chloride gave cleanly, although unexpectedly, a product of
Table 1. Preparation of aldols
ꢀ
ꢄ
ꢀꢃ
ꢀ
ꢆꢐ ꢑꢒꢓꢈ ꢔꢃꢕ
ꢏꢐ ꢅꢇꢃꢀ
ꢅ
ꢄ
retro-aza-Michael reaction 5.
A related retro-aza-Michael
ꢁꢂ
ꢁꢂ
product[32] was obtained in a reaction of 2-benzylidenetropinone
with chloroformates by analogy with the ring opening of
tropinone.[33] The difficulty of the C-acylation reiterates that
tropinone enolate has to be considered as tridentate nucleophile
(has three nucleophilic sites: O, C, N). Chloroformates have
been known as the only reagents selectively attacking the N-site
leading to the opening of the five membered ring in tropinone
enolate.[33] In light of the unexpected result of the reaction with
acyl chlorides we turned our attention to acyl cyanides, which
are known C-acylating reagents.[21]
1
ꢀꢁꢂꢃꢄꢅꢆꢇ 3a-k
Entry[
R
Aldol
Yield [a]
[%]
dr [b]
exo,anti:exo,syn
a]
1
2
Ph
3a
3b
3c
3d
84
98:2
≥99:1
98:2
m-MeO-C6H4
71
62
68
3
4
3,4-di-MeO-C6H3
The model reaction, i.e. acylation of 2-benzylidenetropinone (4a)
with cinnamoyl cyanide (6a) gave the desired product 7a
validating the chosen approach (Scheme 2). To investigate the
scope of the method we decided to prepare several diversely
substituted curcumin analogues and necessary intermediates.
3,4,5-tri-MeO-C6H2
(3d)
99:1
5
6
7
8
9
p-Br-C6H4
3e
3f
73
82
82
27
69
≥99:1
≥99;1
97:3
p-F-C6H4
Substituted 2-benzylidene tropinones - the aldol reaction
In the first step of the synthesis we needed to prepare 2-
monosubstituated benzylidene tropinones. Unfortunately,
although 2-benzylidenetropinons could be obtained in a simple
p-CF3-C6H4
p-NO2-C6H4
3g
3h
3i
≥99:1
95:5
aqueous base catalyzed aldol condensation reaction[9b,
23b, 23e]
the concomitant elimination of water promoted the second aldol
reaction at α’-position giving 2,4-disubstituated tropanes. The
result was the α,α’-disubstituted tropinone 2a and a trace
amount of monobenzylidene tropinone 4a. Therefore we made
the monosubstituted aldols via a known reaction of lithium
enolates and subjected them to dehydration (elimination of
water) in a separate step. Using LDA for making the enolate
2-NO2-4,5-di-MeO-
C6H2
10
11
2-NO2-4,5-O-CH2-O-
C6H2
3j
72
75
92:8
3-MeO-4-O-[CH(CH3)-
OEt]-C6H3
3k
≥99:1
[a] Isolated yield of crystalline products except 3k (for 3k crude yield is given,
mixture of diastereomers).
under
typical
conditions[34] of
aldol
reaction
gave
monosubstituated exo,anti-aldols, which were isolated by
crystallization typically in good yields (62-84%, p-nitro derivative
27%, Table 1) and diastereoselectivities (single diasteromer by
1H-NMR). In the crude reaction mixture the minor isomer was
barely detectable by NMR (doublet of lower coupling constant
downfield of the exo,anti carbinol CH(OH) doublet). The
diastereomeric ratio is given in Table 1. For the sake of
generality we opted for the lithium enolate based procedure over
water promoted aldol reaction.[34] The water promoted aldol
reaction of tropinone,[34] although experimentally simpler could
not be used for poorly electrophilic aldehydes and often required
longer reaction times. Yields in Table 1 refer to products isolated
by crystallization with the exception of aldol 3k which was not
amenable to crystallization (the protection for hydroxyl group
resulted in a mixture of diastereomers) and was hard to isolate
in a pure form chromatographically because of its acid and base
sensitivity and propensity for retro-aldol reaction. All the
crystalline aldols were fully characterized and compared with
literature data. The aldol products isolated by crystallization had
exo,anti-configuration, which has been confirmed by comparison
of 1H-NMR signals of CH(OH) with the literature.[23b, 34] In the
synthetic sequence these aldol reaction mixtures were used in
the next step (i.e. elimination) without product isolation
[b] dr (exo,anti/exo,anti) measured by 1H NMR in crude reaction mixture. The
ratio was worsened by longer reaction time with electrophile or deferred
workup and analysis. Pure minor isomer was not isolable.
Table 2. Synthesis of 2-benzylidenetropinones
Entry
R
Product
Method
Yield[a]
[%]
1
2
Ph
4a
4b
4c
A
A
A
74
85
m-MeO-C6H4
71[b]
3
3,4-di-MeO-C6H3
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
4
3,4-di-MeO-C6H3
3,4,5-tri-MeO-C6H2
p-Br-C6H4
Curcumin analogues – acylation reaction
4c
4d
4e
4f
B
A
A
A
A
B
A
B
B
B
B
89
58
83
83
86
73
40
90
86
55
13
The planned C-acylation of tropane derived enones called for
the use of substituted cinnamoyl cyanides (vide infra). The
cyanides were prepared by reacting corresponding acyl
chlorides with dry copper(I) cyanide in acetonitrile (Table 3).[35]
5
6
7
p-F-C6H4
Table 3. Preparation of substituted cinnamoyl cyanides
8
p-CF3-C6H4
1) SOCl2, DCM
2) CuCN, MeCN
O
O
4g
4h
4i
OH
CN
R
R
9
p-NO2-C6H4
6a-f
10
11
12
13
14
2-NO2-4,5-di-MeO-C6H2
2-NO2-4,5-di-MeO-C6H2
Entry
R
Compound
Yield [%][a]
4i
1
2
3
4
5
6
H
6a
6b
6c
6d
6e
6f
89[b]
88
2-NO2-4,5-O-CH2-O-
C6H2
4j
4-MeO
3,4-diMeO
3-MeO-4-O-[CH(CH3)-
OEt]-C6H3
4k
4l
79
3,4,5-triMeO
48
[c]
3-MeO-4-OH-C6H3
3,4-O-CH2-O-
52
[a] Isolated yield of two reactions (counting on tropinone 1).
[b] about 20% of retro-aldol product was obtained.
[c] obtained as a side product during preparation of 4k.
3-MeO-4-MeOCOO
56
[a] Isolated yield.
[b] product was obtained from commercially available cinnamoyl chloride.
Substituted 2-benzylidenetropinones - dehydration of aldols
Generation of lithium enolates from enones followed by reaction
with acyl cyanides afforded in most cases products of α’-
substitution 7a-p in good isolated yields (65-91%, Table 4).
Moderate yields were noted only in reactions with nitro
substituted enones 4h-j or cyanide 6e, probably due to poor
solubility of these substrates in THF.
The dehydrations of tropinone aldols using p-toluenesulfonic
acid in toluene have been described.[23b] In our hands, the
described water elimination conditions resulted, in many cases,
in significant retroaldolization and consequently lower yields.
Gentle heating (to 60 °C) in glacial acetic acid (Method A, Table
2) turned out to be a more appealing alternative. This procedure
worked satisfactory for all aldols except the nitro-substituted
derivatives 3h, 3i, 3j and the aldol with OH protecting group 3k
because of retroaldolization and acid sensitivity respectively. In
these more difficult cases a known but longer procedure based
on acetylation of the aldol hydroxyl group followed by absorption
on silica gel was used (Method B, Table 2).[21] Changing from
the heating in acetic acid to these milder conditions allowed for
an increased yield of the enone 4i from 40% to 90% (Entry 10,
11; Table 2). Moreover, as shown in case of product 4c (Entry 3,
4; Table 2), changing of the elimination procedure minimized the
retroaldol reaction which otherwise lowered the yield by ca. 20%.
The yields of the chromatographically isolated products of the
two-stage procedure (aldol reaction followed by dehydration
without isolation of aldols) are given in Table 2. Unfortunately,
even in the mild conditions some deprotection of the hydroxyl
group in 4k occurred resulting in formation of 4l in 13% isolated
yield (Entry 14, Table 2). As can be seen from comparison of
yields of aldols and products of two combined stages, in many
cases, the isolation of aldols would be the major detrimental
factor affecting the efficacy of the procedure.
Table 4. α’-Acylation of α-benzylidenetropinones
Entry
R
R’
Product
Yield[a]
[%]
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
80
78
65
86
69
91
m-MeO-C6H4
3
4
5
6
3,4-di-MeO-C6H3
3,4,5-tri-MeO-C6H2
p-Br-C6H4
p-F-C6H4
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
7
p-CF3-C6H4
Ph
Ph
Ph
Ph
Ph
7g
7h
7i
83
42
62
41
82
74
8
p-NO2-C6H4
Moreover, the cabamate protected 7p was stable in aqueous-
ethanolic hydrogen chloride solution at rt (no decomposition was
observed after 24 hours). This, combined with base stability of
the acetal protection in 7k, shows orthogonality of the protecting
groups used (one acid labile and base stable and the other base
labile and acid stable). It is noteworthy that the new tropane
analogues exhibited reasonable stability in acidic and basic
conditions (deprotection and workup conditions).
The NMR spectra of the analogues showed dominance of the
enol form in CDCl3. The addition of methanol up to the limit of
solubility did not visibly change the tautomer equilibrium. For
simplicity, in this paper, the formulas representing compounds 7-
9 are shown as diketo forms instead of enols (vide infra).
9
2-NO2-4,5-di-MeO-C6H2
10
11
2-NO2-4,5-O-CH2-O-
C6H2
7j
3-MeO-4-O-[CH(CH3)-
OEt]-C6H3
7k
7l
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
p-MeO-
C6H4
3,4-di-
MeO-C6H3
7m
7n
7o
7p
83
88
54
68
3,4,5-tri-
MeO-C6H2
Curcumin analogues - structure and properties
3,4-O-CH2-
O-C6H3
Configuration of all 2-benzylidenetropinones obtained from aldol
dehydration was assigned as E based on H-NMR spectra (the
olefinic H singlet was observed in a range of 7.79-7.68 ppm).
The Z isomers are known to display olefinic hydrogens in a
range of 6.0-6.5 ppm.[36]
1
3-MeO-4-
MeOCOO
[a] Isolated yield.
We assumed that the configurations of the double bonds of the
crotonyl moieties were unchanged. This was confirmed by single
crystal diffraction analysis of the p-bromo derivative 7e (Figure
3). The X-ray diffraction showed that both double bonds were in
the E configuration and that the tropane ring was flattened (see
supporting information). The N-methyl group in tropane skeleton
took the axial position. Noteworthy is that the exocyclic carbonyl
was in its enol form forming a hydrogen bond to the endocyclic
carbonyl oxygen. In theory, the presence of the tertiary amine as
a hydrogen bond acceptor could provide another site for internal
H-bonding. The analysis showed that in crystal this was not the
case. Moreover the crystal structure indicated that the aromatic
ring of the p-bromobenzylidene group was off the plane of the
conjugated double bonds. This can be rationalized by the close
contact of the aromatic ring with C2 hydrogen of the tropane
skeleton and the resulting steric repulsion. The carbonyl of
endocyclic carbonyl (C3 in tropane numbering) was slightly
sterically shielded from the exo face by the N-methyl group and
from the endo face by the C6-C7 hydrogens. This combined with
the cyclic structure may increase stability of the new molecules
compared with curcumin. Coupling constants of the olefinic
protons in all the prepared analogues were in accord with the
data observed for the p-bromo derivative 7e. Therefore one can
expect that the stereochemical configuration found by X-ray for
7e is representative for all the products 7-9.
The curcumin analogue with free hydroxyl group 8 was obtained
by acidic deprotection (3% trifluoroacetic acid in
dichloromethane) of the acetal in quantitative yield (Scheme 3).
Under the acidic conditions of deprotection followed by aqueous
workup and acid-base extraction no decomposition of the
product was observed. Curcumin analogue 9, featuring the free
hydroxyl group on the opposite site of the diarylheptanoid
system, was obtained by ammonolysis of the carbonate
protecting group in 7p (Scheme 3). The deprotection reaction
gave excellent yield (96%) and no decomposition of the base-
sensitive 1,3-diketone was observed. Thus, our methodology
allowed for the preparation of products with free hydroxyl groups
located in the positions found in curcumin, at either of the aryl
rings of the analogue.
Scheme 3. Deprotection of hydroxy groups in curcumin analogues
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
and 77.0 for 13C spectra. IR spectra were recorded on Nicolet 6700
with DTGS detector; ATR (Attenuated Total Reflectance) method
was used. Melting points were measured on an EZ-Melt MPA120
apparatus. High resolution mass spectra (accurate mass analysis)
were recorded using an Agilent Accurate-Mass Q-TOF LC/MS 6530
spectrometer. All air sensitive reactions were carried out under
argon in flame dried Schlenk tubes. Tetrahydrofuran was dried by
distillation from sodium benzophenone ketyl under argon.
Dichloromethane (DCM) and diisopropylamine were distilled from
CaH2. Tropinone (from Aldrich) was dried in a desiccator over KOH
before use. The other commercially available reagents were used
without purification.
X-ray single crystal measurements
Single crystal X-ray diffraction measurement was carried out on a
Agilent Supernova diffractometer, at 100K with monochromated Cu
Kα radiation (1.54184 A). The data reduction was made by using
CrysAlisPRO software.[37a] The structures were solved by direct
methods and refined on F2 by full-matrix least-squares by using
SHELXS97 and SHELXL97.[37b] All non-hydrogen atoms were
refined as anisotropic while hydrogen atoms were placed in
calculated positions, and refined in riding mode.
General procedure 1 (for the preparation of aldols)
To a cooled to 0 °C solution of diisopropylamine (0.62 mL, 4.33
mmol) in dry tetrahydrofuran (10 mL), n-butyllithium (2.5M, 1.8 mL,
4.5 mmol) was added. The solution was stirred for 30 min, then
tropinone (1, 558 mg, 4.0 mmol) was added, and the resulting
solution was stirred at 0 °C. After 30 min the reaction mixture was
cooled to –78 ºC and aldehyde 2a-k (4.4 mmol) was added. The
reaction was stirred at −78 ºC for 5 minutes, then quenched with an
aqueous solution of NH4Cl (5 mL). After heating to room temperature
25 mL of water was added and the mixture was extracted with
dichloromethane (4 × 20 mL). The combined organic extracts were
dried with Na2SO4, filtered, and concentrated under vacuum. The
aldol product was isolated by crystallization; in the synthetic
sequence the crude product was used in the following step. The
NMR spectra of known aldols agreed with the reported data for
exo,anti isomers.
Figure 3. X-ray structure of the p-bromo derivative 7e
demonstrating enol form of the exocyclic carbonyl group and
lacking co-planarity of the extended conjugated system.
exo,anti-2-(Hydroxy(phenyl)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3a) [34]
Conclusions
Compound 3a was prepared according to the General procedure 1
from tropinone (1) and benzaldehyde. The crude product was
crystallized from toluene to give a white solid (0.824 g, 84 %). M.p.
Synthetic methods for preparing 1,3-dicarbonyl tropane derived
analogues of curcumin have been missing. We have demonstrated
that acylation of 2-benzelidenetropinones with acyl cyanides
constitutes a viable route to a new class of diversely substituted 1,3-
dicarbonyl curcumin analogues featuring tropane structure. This
approach is uncomplicated, fairly effective (yields of 2-
benzelidenetropinones from tropinone: 40-90%; acylation with
cyanides: 41-91%; additional deprotection 96-100%), and amenable
to making products with variably substituted phenyl rings, including
rings substituted with free hydroxyl groups in positions characteristic
for curcumin structure. Reagents with suitably protected phenolic
hydroxyl group can be used to make curcuminoid analogues with
free hydroxyls in the aromatic rings. The removal of orthogonal
protective groups was clean and very high yielding proving stability
of the new compounds under basic and acidic conditions. The
curcuminoid-like products showed dominance of the enole form
regardless of protic or aprotic media. The exocyclic carbonyl group
of the 1,3-dicarbonyl is the most likely enolization site as shown by
the X-ray analysis of crystalline p-bromo derivative 7e
1
117–121 ºC (decomp.); H NMR (400 MHz, CDCl3): δ = 7.66 (br s,
1H), 7.34–7.23 (m, 5H), 5.23 (d, J = 3.1 Hz, 1H), 3.60 (d, J = 7.0 Hz,
1H), 3.49 (m, 1H), 2.86 (ddd, J = 15.7, 4.7, 1.9 Hz, 1H), 2.47 (s, 3H),
2.46-2.43 (m, 1H), 2.35 (ddd, J = 15.7, 2.0, 1.9 Hz, 1H), 2.30–2.12
(m, 2H), 1.69–1.54 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 207.8,
141.7, 127.9, 127.1, 125.4, 76.5, 67.3, 64.2, 61.6, 51.4, 40. 5, 26.3,
26.1 ppm.
exo,anti-2-((3-Methoxyphenyl)(hydroxy)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3b) [34]
Compound 3b was prepared according to the General procedure 1
from tropinone (1) and 3-methoxybenzaldehyde. The crude product
was crystallized from mixed solvent (AcOEt–hexane) to give a white
1
solid (0.786 g, 71%). Mp 112-114 °C (lit.:111-113[34]); H NMR (400
MHz, CDCl3): δ = 7.61 (br s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.90-6.80
(m, 2H), 6.76 (dd, J = 8.0 Hz, 2.3 Hz, 1H), 5.18 (d, J = 3.1 Hz, 1H),
3.78 (s, 3H), 3.57 (d, J = 6.8 Hz, 1H), 3.50-3.42 (m, 1H), 2.83 (ddd, J
= 14.2 Hz, 4.6 Hz, 2.9 Hz, 1H), 2.48-2.38 (m, 1H), 2.45 (s, 3H), 2.33-
2.21 (m, 2H), 2.19-2.11 (m, 1H), 1.68-1.51 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 207.8, 159.4, 143.5, 129.0, 117.9, 112.7,
111.2, 76.4, 67.4, 64.2, 61.7, 55.0, 51.4, 40.5, 26.3, 26.2 ppm; FTIR
(ATR, ṽ): 2949, 2911, 1704, 1598, 1490, 1460, 1262, 1033, 878,
781, 702 cm−1.
exo,anti-2-((3,4-Dimethoxyphenyl)(hydroxy)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3c)
Experimental Section
Compound 3c was prepared according to the general procedure 1
from tropinone (1) and 3,4-dimethoxybenzaldehyde. The crude
product was crystallized from mixed solvent (AcOEt–hexane) to give
a white solid (0.757 g, 62%). Mp 113-116 °C; 1H NMR (400 MHz,
CDCl3): δ = 7.45 (br s, 1H), 6.86- 6.74 (m, 3H), 5.16 (d, J = 3.2 Hz,
1H), 3.85 (s, 6H), 3.54 (d, J = 6.8 Hz, 1H), 3.51-3.42 (m, 1H), 2.85
General Information.
The NMR spectra were recorded on a Bruker AVANCE II 400
1
spectrometer using 5 mm probes operating at 400 MHz for H and
100 MHz for 13C NMR spectra. The chemical shifts are reported
relative to TMS and referenced to the CDCl3 signals at δ 7.26 for 1H
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
(ddd, J = 15.7 Hz, 3.2 Hz, 1.5 Hz, 1H), 2.45 (s, 3H), 2.43-2.39 (m,
1H), 2.36-2.11 (m, 3H), 1.69-1.61 (m, 1H), 1.60-1.50 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ = 208.1, 148.4, 147.9, 134.4, 117.6,
110.6, 108.7, 76.2, 67.1, 64.4, 61.6, 55.6, 55.5, 51.2, 40.5, 26.2,
26.1 ppm; FTIR (ATR, ṽ): 2935, 2836, 1711, 1591, 1513, 1450,
1413, 1228, 1137, 1022, 959, 860, 805 cm−1; HRMS (ESI): calcd. for
C17H24NO4 [M+H]+ 306.1700; found 306.1709.
Compound 3j was prepared according to the General procedure 1
from tropinone (1) and 4-nitrobenzaldehyde. The crude product was
crystallized from AcOEt to give a white solid (0.311 g, 27%); Mp 147-
150 °C (lit. 147-150 °C[34]); H NMR (400 MHz, CDCl3): δ = 8.29 (s,
1
1H), 8.15 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 5.30 (d, J =
2.3 Hz, 1H), 3.68 (d, J = 7.1 Hz, 1H), 3.53 – 3.46 (m, 1H), 2.76 (ddd,
J = 16.0 Hz, 4.6 Hz, 1.6 Hz, 1H), 2.48 (s, 3H), 2.46-2.43 (m, 1H),
2.35–2.27 (m, 2H), 2.24–2.15 (m, 1H), 1.69-1.53 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3): δ = 207.1, 149.3, 147.0, 126.3, 123.3, 76.0,
67.5, 63.2, 61.4, 51.5, 40.5, 26.5, 26.3 ppm; FTIR (ATR, ṽ): 3120,
2951, 2881, 1702, 1598, 1507, 1447, 1341, 1205, 1102, 1066, 1036,
848, 815, 753, 701 cm−1;
exo,anti-2-(Hydroxy(3,4,5-(trimethoxyphenyl)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3d)
Compound 3d was prepared according to the General procedure 1
from tropinone (1) and 3,4,5-trimethoxybenzaldehyde. The crude
product was crystallized from mixed solvent (AcOEt–hexane) to give
1
a white solid (0.908 g, 68%). Mp: 112-114 °C; H NMR (400 MHz,
exo,anti-2-((4,5-Dimethoxy-2-nitrophenyl)(hydroxy)methyl)-8-methyl-
8-azabicyclo[3.2.1]octan-3-one (3i)
CDCl3): δ = 7.48 (s, 1H), 6.47 (s, 2H), 5.11 (d, J = 3.1 Hz, 1H),
3.81(s, 9H), 3.52 (d, J = 6.7 Hz, 1H), 3.49-3.40 (m, 1H), 2.82 (dd, J =
15.6Hz, 3.4 Hz, 1H), 2.48-2.38 (m, 1H), 2.42 (s, 3H), 2.30 (d, J =
15.6 Hz, 1H), 2.26-2.08 (m, 2H), 1.69-1.58 (m, 1H), 1.57-1.47 (m,
1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 208.1, 152.8, 137.5,
102.4, 76.5, 67.2, 64.2, 61.6, 60.7, 55.8, 51.2, 40.5, 26.2, 26.1 ppm;
FTIR (ATR, ṽ): 2941, 2834, 1716, 1590, 1506, 1456, 1416, 1230,
1127, 998, 762, 711 cm−1; HRMS (ESI): calcd. for: C18H26NO5 [M+H]+
336.1805; found: 336.1801.
Compound 3i was prepared according to the general procedure 1
from tropinone (1) and 6-nitroveratraldehyde. The crude product was
crystallized from AcOEt to give a yellow solid (0.967 g, 69%). Mp
157-159 °C; 1H NMR (400 MHz, CDCl3): δ = 8.21 (br s, 1H), 7.67 (s,
1H), 7.09 (s, 1H), 5.86 (d, J = 1.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H),
3.76 (d, J = 7.0 Hz, 1H), 3.52-3.44 (m, 1H), 2.78 (m, 1H), 2.70-2.64
(m, 1H), 2.49 (s, 3H), 2.39-2.27 (m, 2H), 2.25-2.5 (m, 2H), 1.69-1.53
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 208.1, 153.3, 147.5,
139.0, 133.6, 109.5, 107.9, 72.6, 67.6, 61.7, 61.3, 56.2, 56.2, 51.5,
40.6, 26.5, 26.4 ppm; FTIR (ATR, ṽ): 3119, 2949, 2923, 1712, 1615,
1580, 1518, 1494, 1467, 1324, 1270, 1214, 1110, 1068, 869, 796,
762, 741cm−1; HRMS (ESI): calcd. for: C17H23N2O6 [M+H]+ 351.1551;
found 351.1560.
exo,anti-2-((4-Bromophenyl)(hydroxy)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3e)
Compound 3e was prepared according to the General procedure 1
from tropinone (1) and 4-bromobenzaldehyde. The crude product
was crystallized from mixed solvent (AcOEt–hexane) to give a white
solid (0.945 g, 73%). Mp 140-144 °C (decomp.); 1H NMR (400 MHz,
CDCl3): δ = 7.89 (br s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3
Hz, 2H), 5.17 (d, J = 2.6 Hz, 1H), 3.60 (d, J = 6.9 Hz, 1H), 3.47 (m,
1H), 2.80 (ddd, J = 15.8 Hz, 3.2 Hz, 1.5 Hz, 1H), 2.46 (s, 3H), 2.4-
2.12 (m, 4H), 2.69-2.50 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ
= 207.6, 140.8, 131.1, 127.3, 121.0, 76.1, 67.5, 63.8, 61.6, 51.5,
40.6, 26.4, 26.3 ppm; FTIR (ATR, ṽ): 2962, 2806, 1706, 1486, 1448,
1396, 1205, 1072, 1007, 893, 799, 768 cm−1; HRMS (ESI): calcd.
for: C15H19BrNO2 [M+H]+ 324.0594; found 324.0587.
exo,anti-2-(Hydroxy(6-niterobenzo[d][1,3]dioxol-5-yl)methyl)-8-
methyl-8-azabicyclo[3.2.1]octan-3-one (3j)
Compound 3j was prepared according to the general procedure 1
from tropinone (1) and 6-nitropiperonal. The crude product was
crystallized from mixed solvent (AcOEt–hexane) to give a white solid
(0.963 g, 72%). Mp 106-107 °C (decomp.); 1H NMR (400 MHz,
CDCl3): δ = 8.20 (br s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 6.07 (d, J =
4.9 Hz, 2H), 5.77 (d, J = 1.5 Hz, 1H), 3.74 (d, J = 7.0 Hz, 1H), 3.49
(t, J = 5.2 Hz, 1H), 2.79 (ddd, J = 16.4 Hz, 3.1 Hz, 1.6 Hz, 1H), 2.67
(d, J = 1.1 Hz, 1H), 2.49 (s, 3H), 2.39-2.27 (m, 2H), 2.25-2.14 (m,
1H), 1.69-1.53 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 208.2,
152.2, 146.9, 140.9, 136.2, 107.4, 105.4, 102.8, 72.7, 67.5, 61.8,
61.4, 51.6, 40.6, 26.5, 26.4 ppm; FTIR (ATR, ṽ): 3102, 2912, 2872,
1706, 1617, 1511, 1320, 1262, 1203, 1121, 1068, 1037, 902, 866,
790, 762, 692 cm−1; HRMS (ESI): calcd. for: C16H19N2O6 [M+H]+
335.1238; found 335.1241.
exo,anti-2-((4-Fluorophenyl)(hydroxy)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3f) [34]
Compound 3e was prepared according to the General procedure 1
from tropinone (1) and 4-fluorobenzaldehyde. The crude product
was crystallized from mixed solvent (AcOEt–hexane) to give a white
solid (0.867 g, 82%). Mp: 102-104 °C (lit. 103-105[34]); H NMR (400
1
MHz, CDCl3): δ = 7.89 (s, 1H), 7.25-7.15 (m, 2H), 6.99 (t, J = 17.4
Hz, 8.7 Hz, 2H), 5.20 (d, J = 2.5 Hz, 1H), 3.61 (d, J = Hz, 1H), 3.52-
3.44 (m, 1H), 2.82 (ddd, J = 15.9, 4.5, 1.6 Hz, 1H), 2.46 (s, 3H),
2.41-2.46 (m, 1H), 2.35-2.11 (m, 3H), 2.70-2.60 (m, 1H), 2.58-2.50
General procedure 2 (for dehydration of aldols)
The crude aldol (3a-g) (4.0 mmol), synthesized as described in
General procedure 1, was dissolved in glacial acetic acid (6 mL) and
the resulting mixture was heated to 60 °C for 2 hours. Then the
reaction mixture was poured into ice and alkalized with 20%
aqueous K2CO3 to pH=10. The obtained mixture was extracted with
DCM (3 x 10 mL). The combined extracts were dried over Na2SO4
and concentrated under vacuum. The residue was purified by flash
column chromatography to afford the desired product 4a-g. The
yields of products 4a-g were calculated for two steps (starting from
tropinone 1)
(m, 1H); 13C NMR (100 MHz, CDCl3): δ = 207.8, 161.9 (d, JC-F
=
244.7 Hz), 137.5 (d, JC-F = 3.0 Hz), 127.0 (d, JC-F = 8.1 Hz),114.8 (d,
JC-F = 21.4 Hz), 76.1, 67.4, 64.1, 61.6, 51.5, 40.5, 26.4, 26.2 ppm;
19F NMR (376 MHz, CDCl3): δ = –115.6 ppm (s, 1F); FTIR (ATR, ṽ):
2945, 2875, 1707, 1603, 1506, 1460, 1410, 1215, 1073, 841, 767,
747 cm−1;
exo,anti-2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3g) [34]
Compound 3g was prepared according to the general procedure 1
from tropinone (1) and 4-(trifluoromethyl)benzaldehyde. The crude
product was crystallized from mixed solvent (AcOEt–hexane) to give
a white solid (1.034 g, 82%). Mp: 123-125 °C (lit. 129-132[34]); 1H
NMR (400 MHz, CDCl3): δ = 8.08 (br s, 1H), 7.56 (d, J = 8.0 Hz, 2H),
7.36 (d, J = 8.0 Hz, 2H), 5.27 (d, J = 1.51 Hz, 1H), 3.65 (d, J = 6.9
Hz, 1H), 3.55-3.42 (m, 1H), 2.80 (m, 1H), 2.48 (s, 3H), 2.46-2.41 (m,
1H), 2.37-2.25 (m, 2H), 2.24-2.12 (m, 1H), 1.72-1.50 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3): δ = 207.4, 145.8, 129.3 (q, JC-F = 42.2
Hz), 125.8, 125.0 (q, JC-F = 3.8 Hz), 124.2 (q, JC-F = 272.1 Hz), 76.2,
67.6, 63.6, 61.6, 51.5, 40.5, 26.4, 26.3 ppm; 19F NMR (376 MHz,
CDCl3): δ = –62.4 ppm (s, 3F); FTIR (ATR, ṽ): 2960, 2884, 1711,
1621, 1449, 1413, 1323, 1160, 1101, 1067, 851, 806, 751 cm−1;
General procedure 3 (for dehydration of aldol with nitro or acid
sensitive group)
To a solution of the crude aldol (3h-k) (about 4.0 mmol) in dry DCM
(20 mL) at 0 °C, was added Et3N (0.52 g, 5.14.mmols). Then acetic
anhydride (0.68 g, 6.7 mmol) was added dropwise. After competition
of reaction (monitored by TLC), silica gel (10 g) was added and the
solvents evaporated. The residue was poured on a sintered glass
funnel and washed with a mixture of MeOH:DCM (v/v, 5:95). The
filtrate was washed with 20% aqueous K2CO3, the organic layer was
dried over Na2SO4 and concentrated under vacuum (the basic
washing is necessary to purify the product from the acetic acid which
is formed in elimination process). The residue was subjected to flash
column chromatography to afford the desired product 4h-k and side
product 4i. The yields of products 4h-i were calculated for two steps
(starting from tropinone 1).
exo,anti-2-(Hydroxy(4-nitrophenyl)methyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (3h) [34]
The NMR spectra of known enones agreed with reported data for the
E isomers.
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10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
(E)-2-(4-fluorobenzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-one
(E)-2-Benzylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-one (4a) [23b]
Compound 4a was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH:DCM, 3:97) to
give a yellow oil (0.673, 74 %). 1H NMR (400 MHz, CDCl3) δ 7.50 (s,
1H), 7.42-7.28 (m, 5H), 4.29 (d, J = 6.8 Hz, 1H), 3.51 (t, J = 6.1 Hz,
1H), 2.86 (ddd, J = 18.5 Hz, 5.5 Hz, 1.4 Hz, 1H), 2.50–2.43 (m, 1H),
2.39 (s, 3H), 2.37–2.27 (m, 2H), 1.94–1.84 (m, 1H), 1.75–1.65 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 199.2, 139.6, 134.7,
133.9, 130.0, 128.6, 128.4, 60.8, 58.7, 44.6, 37.2, 30.2, 28.7 ppm.
FTIR (ATR, ṽ): 2940, 1683, 1602, 1492, 1446, 1244, 1151, 1068,
956, 758, 695 cm−1;
(4f) [23b]
Compound 4f was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 2:98) to
yield a yellow solid (0.818, 83 %). mp 59-61 °C (literature 76–
77°C[23b]); 1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1H), 7.34-7.27 (m,
2H), 7.14-7.02 (m, 2H), 4.24 (d, J = 6.9 Hz, 1H), 3.52 (t, J = 6.2 Hz,
1H), 2.86 (ddd, J = 18.6 Hz, 5.6 Hz, 1.6 Hz, 1H), 2.50-2.43 (m, 1H),
2.40 (s, 3H), 2.37-2.27 (m, 2H), 1.92-1.83 (m, 1H), 1.76-1.67 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 199.2, 162.8 (d, JC-F = 250.0
Hz), 139.5, 132.8, 132.0 (d, JC-F = 8.3 Hz), 130.9 (d, JC-F = 3.4 Hz),
115.6 (d, JC-F = 21.7 Hz), 60.8, 58.7, 44.6, 37.3, 30.2, 28.8 ppm; 19
F
NMR (376 MHz, CDCl3): δ = –111.50 ppm (s, 1F); FTIR (ATR, ṽ):
(E)-2-(3-Methoxybenzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-
one (4b) [23b]
2944, 2869, 1678, 1597, 1504, 1216, 1150, 830 cm−1.
Compound 4b was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH:DCM, 5:95) to
give a yellow oil (0.875, 85 %). 1H NMR (400 MHz, CDCl3): δ = 7.48
(s, 1H), 7.35-7.29 (m, 1H), 6.94-6.85 (m, 3H), 4.32 (d, J = 6.9 Hz,
1H), 3.83 (s, 3H), 3.53 (t, J = 6.2 Hz, 1H), 2.87 (ddd, J = 18.5 Hz, 5.6
Hz, 1.6 Hz, 1H), 2.50-2.45 (m, 1H), 2.42 (s, 3H), 2.39-2.27 (m, 2H),
1.95-1.87 (m, 1H), 1.77-1.69 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 199.2, 159.3, 139.8, 136.0, 133.9, 129.4, 122.4, 115.4,
114.2, 60.9, 58.7, 55.1, 44.5, 37.2, 30.2, 28.7 ppm; FTIR (ATR, ṽ):
2939, 2795, 1684, 1596, 1574, 1486, 1209, 1154, 1041, 966, 782,
689 cm−1.
(E)-8-methyl-2-(4-(trifluoromethyl)benzylidene)-8-
azabicyclo[3.2.1]octan-3-one (4g)
Compound 4g was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 3:97) to
1
yield a yellow solid (1.017, 86%). Mp 92-96 °C; H NMR (400 MHz,
CDCl3): δ = 7.66 (d, J = 8.1 Hz, 2H), 7.47 (s, 1H), 7.41 (d, J = 8.1
Hz, 2H), 4.21 (d, J = 7.0 Hz, 1H), 3.54 (t, J = 6.3 Hz, 1H), 2.88 (ddd,
J = 18.6 Hz, 5.5 Hz, 1.5 Hz, 1H), 2.46 (m, 1H), 2.49-2.44 (s, 3H),
2.38-2.27 (m, 2H), 1.94-1.85 (m, 1H), 1.78-1.69 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 199.2, 141.5, 138.4, 131.8, 130.4 (q, JC-
= 32.6 Hz), 130.0, 126.3 (q, JC-F = 82.2 Hz), 125.4 (q, JC-F = 3.8
F
Hz), 60.9, 58.9, 44.8, 37.3, 30, 28.7 ppm. 19F NMR (376 MHz,
CDCl3): δ = –62.8 ppm (s, 3F); FTIR (ATR, ṽ): 2961, 2800, 1689,
1614, 1575, 1468, 1323, 1259, 1166, 1101, 1062, 964, 800, 704
cm–1; HRMS (ESI): calcd. for: C16H17F3NO [M+H]+ 296.1257; found:
296.1269.
(E)-2-(3,4-dimethoxybenzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-
3-one (4c)
Compound 4c was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 5:95) to
give a yellow oil (0.816 g, 71 %) or according to the general
procedure 3 (1.022 g, 89 %). 1H NMR (400 MHz, CDCl3): δ = 7.46 (s,
1H), 6.96-6.85 (m, 3H), 4.33 (d, J = 6.8 Hz, 1H), 3.90 (s, 3H), 3.87
(s, 3H), 3.51 (t, J = 6.3 Hz, 1H), 2.85 (ddd, J = 18.6 Hz, 5.6 Hz, 1.5
Hz, 1H), 2.51-2.43 (m, 1H), 2.40 (s, 3H), 2.35-2.28 (m, 2H), 1.95-
1.86 (m, 2H), 1.75-1.67 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ
= 198.9, 149.7, 148.6, 138.0, 134.4, 127.5, 123.5, 113.3, 110.9,
61.0, 58.5, 55.8, 55.7, 44.3, 37.2, 30.3, 28.8 ppm. FTIR (ATR, ṽ):
2934, 2836, 1667, 1566, 1516, 1467, 1263, 1136, 1017, 970, 810,
712 cm−1; HRMS (ESI): calcd. for: C17H22NO3 [M+H]+ 288.1594;
found: 288.1599.
(E)-8-methyl-2-(4-nitrobenzylidene)-8-azabicyclo[3.2.1]octan-3-one
(4h) [23b]
Compound 4h was prepared according to the general procedure 3
and purified by flash column chromatography (MeOH/DCM, 2:98, or
EtOH/AcOEt, 5:95) to yield a brown solid (0.795 g, 73%). Mp 182-
1
184 °C (lit. 176-1178[23b]); H NMR (400 MHz, CDCl3): δ = 8.26 (d, J
= 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.45 (s, 1H), 4.19 (d, J = 7.1
Hz, 1H), 3.56 (t, J = 6.3 Hz, 1H), 2.89 (ddd, J = 18.6, 5.7, 1.7 Hz,
1H), 2.50-2.43 (m, 1H), 2.42 (s, 3H), 2.40-2.30 (m, 2H), 1.93-1.86
(m, 1H), 1.78–1.71 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ =
198.9, 147.4, 142.5, 141.4, 130.7, 130.5, 123.7, 60.9, 58.9, 44.9,
37.5, 29.9, 28.7 ppm. FTIR (ATR, ṽ): 3063, 2941, 1683, 1591, 1500,
1344, 1108, 1067, 850, 800, 712 cm−1.
(E)-8-methyl-2-(3,4,5-trimethoxybenzylidene)-8-
azabicyclo[3.2.1]octan-3-one (4d)
Compound 4d was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 2:98) to
give a yellow solid (0.736 g, 58%). Mp: 138-139 °C; H NMR (400
(E)-2-(4,5-dimethoxy-2-nitrobenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (4i)
1
MHz, CDCl3): δ = 7.44 (s, 1H), 6.56 (s, 2H), 4.35 (d, J = 6.9 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 6H), 3.53 (t, J = 6.3 Hz, 1H), 2.86 (ddd, J =
18.6 Hz, 5.6 Hz, 1.4 Hz, 1H), 2.53–2.44 (m, 1H), 2.42 (s, 3H), 2.33
(m, 2H), 1.99–1.86 (m, 1H), 1.78–1.67 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3): δ = 199.0, 153.0, 139.1, 138.7, 134.4, 130.2, 107.4,
61.1, 60.9, 58.5, 56.0, 44.3, 37.2, 30.3, 28.9 ppm; FTIR (ATR, ṽ):
2964, 2798, 1679, 1600, 1577, 1505, 1464, 1243, 1118, 1073, 997,
780, 726 cm−1; HRMS (ESI): calcd. for: C18H24NO4 [M+H]+ 318.1700;
found 318.1707.
Compound 4i was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 2:98) to
yield a yellow solid (0.531 g, 40%) or according to the general
procedure 3 (1.196 g, 90%). Mp 163-166 °C; 1H NMR (400 MHz,
CDCl3): δ = 7.73 (s, 1H), 7.64 (s, 1H), 6.58 (s, 1H), 3.96 (s, 3H), 3.92
(s, 3H), 3.88 (d, J = 6.2 Hz, 1H), 3.52 (s, 1H), 2.86 (dd, J = 18.4, 5.4
Hz, 1H), 2.38 (s, 3H), 2.38-2.11 (m, 3H), 1.85-1.61 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ = 199.2, 152.8, 148.7, 140.7, 139.7,
131.7, 125.5, 112.3, 108.0, 60.7, 58.6, 56.4, 56.3, 44.0, 36.3, 30.1,
28.9 ppm. FTIR (ATR, ṽ): = 2968, 2936, 1759, 1689, 1609, 1570,
1516, 1330, 1269, 1066, 876, 797, 690 cm–1. HRMS (ESI): calcd.
for: C17H21N2O5 [M+H]+ 333.1445; found: 333.1438.
(E)-2-(4-bromobenzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-one
(4e)
Compound 4e was prepared according to the general procedure 2
and purified by flash column chromatography (MeOH/DCM, 3:97) to
yield a yellow solid (0.508 g, 83%). Mp: 111-113 °C; H NMR (400
(E)-8-methyl-2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methylene)-8-
azabicyclo[3.2.1]octan-3-one (4j)
1
Compound 4j was prepared according to the general procedure 3
and purified by flash column chromatography (MeOH/DCM, 0:100 to
5:95) to yield a yellow solid (1.088 g, 86%). Mp: 146-151 °C
(decomp.); 1H NMR (400 MHz, CDCl3): δ = 7.63 (s, 1H), 7.53 (s, 1H),
6.56 (s, 1H), 6.16 (s, 2H), 3.86 (d, J = 6.4 Hz, 1H), 3.50 (t, J = 5.6
Hz, 1H), 2.84 (dd, J = 18.3, 5.4 Hz, 1H), 2.39 (s, 3H), 2.37–2.14 (m,
4H), 1.75–1.63 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 199.2,
151.7, 148.0, 142.4, 139.9, 131.1, 127.7, 109.5, 105.8, 103.3, 60.5,
58.6, 44.0, 36.2, 30.0, 28.9 ppm; FTIR (ATR, ṽ): 2951, 2930, 1683,
1597, 1510, 1480, 1333, 1271, 1241, 1073, 875, 780, 711 cm−1;
HRMS (ESI): calcd. for: C16H17N2O5 [M+H]+ 317.1132; found:
317.1128.
MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.17 (d, J =
8.4 Hz, 2H), 4.21 (d, J = 6.9 Hz, 1H), 3.52 (t, J = 6.3 Hz, 1H), 2.90–
2.81 (ddd, J = 18.6 Hz, 5.6 Hz, 1.7 Hz, 1H), 2.48–2.42 (m, 1H), 2.39
(s, 3H), 2.37–2.28 (m, 2H), 1.90–1.82 (m, 1H), 1.75–1.67 (m, 1H);
13C NMR (100 MHz, CDCl3): δ = 199.1, 140.2, 133.6, 132.5, 131.7,
131.4, 123.0, 60.9, 58.7, 44.7, 37.3, 30.1, 28.7 ppm; FTIR (ATR, ṽ):
2947, 1683, 1608, 1483, 1252, 1154, 1067, 901, 807, 650 cm−1;
HRMS (ESI): calcd. for: C15H17BrNO [M+H]+ 306.0488; found
306.0476.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
overnight. The initially formed suspension turned clear over time.
Afterwards the solvent was evaporated under vacuum the residue
was dissolved in dry DCM (40 mL) and evaporated under vacuum
again. Then copper(I) cyanide (7.834 g, 87.5 mmol, 1.5 equiv) and
dry acetonitrile (60 mL) were added under argon and the reaction
mixture was heated to reflux. After 4 hours the solvent was
evaporated under vacuum to dryness. The residue was taken up in
DCM and the suspension was filtered through a thin layer of silica
gel. The filtrate was concentrated. The crude product was dissolved
in boiling toluene and filtered hot. Product 6b crystalized from the
filtrate as a yellow solid (9.504 g, 50.8 mmol, 88%). Mp 122-124 °C
(lit. 125-126 °C[38]); 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 16.0
Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.72 (d, J
= 16.0 Hz, 1H), 3.89 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
167.1, 163.7, 154.8, 131.7, 125.5, 122.8, 114.9, 112.6, 55.5 ppm.
FTIR (ATR, ṽ): 2936, 2795, 1681, 1593, 1507, 1240, 1119, 1032 cm–
1. The NMR spectra were in agreements with those reported in the
literature.[38]
(E)-2-(4-(1-ethoxyethoxy)-3-methoxybenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (4k, two diastereoisomers )
Compound 4k was prepared according to the general procedure 3
and purified by flash column chromatography (MeOH/DCM, 3:97) to
give yellow oil (0.758 g, 55%). H NMR (400 MHz, CDCl3): δ = 7.46
(s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 5.41 (q, J =
5.2 Hz, 1H), 4.34 (d, J = 6.8 Hz, 1H), 3.85 (m, 4H), 3.62-3.49 (m,
2H), 2.93–2.79 (m, 1H), 2.53–2.43 (m, 1H), 2.41 (s, 3H), 2.36–2.28
(m, 2H), 1.97–1.85 (m, 1H), 1.77–1.66 (m, 1H), 1.52 (d, J = 5.2 Hz,
3H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
199.0, 150.3, 146.6, 138.4, 129.2, 123.2, 118.3, 114.1, 100.9, 61.9,
61.0, 58.6, 44.4, 44.3, 37.2, 30.3, 28.8, 20.2, 15.1 ppm; FTIR (ATR,
ṽ): 2936, 2795, 1681, 1593, 150, 1447, 1269, 1240, 1119, 1067,
935, 889, 709 cm−1; HRMS (ESI): calcd. for C20H28NO4 [M+H]+
346.2013; found 346.2031.
1
(E)-2-(4-hydroxy-3-methoxybenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (4l)
Compound 4l was obtained as a side product during preparation
compound 4k according to general procedure 3 and purified by flash
column chromatography (MeOH/DCM, 3:97 to 5:95) to yield a white
solid (0.163 g, 13%). Mp: 141-144 °C (decomp.). 1H NMR (400 MHz,
CDCl3): δ = 7.47 (s, 1H), 7.02 (br s, 1H), 6.91–6.81 (m, 3H), 4.36 (d,
J = 6.8 Hz, 1H), 3.83 (s, 3H), 3.54 (t, J = 6.3 Hz, 1H), 2.94–2.83 (m,
1H), 2.53–2.45 (m, 1H), 2.42 (s, 3H), 2.37–2.29 (m, 2H), 1.97–1.87
(m, 1H), 1.78–1.69 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ =
198.7, 147.1, 146.7, 137.3, 135.1, 126.7, 124.0, 114.9, 113.2, 60.9,
58.5, 55.7, 44.1, 37.0, 30.3, 28.8 ppm; FTIR (ATR, ṽ): 3066, 2936,
1674, 1568, 1513, 1447, 1281, 1207, 1122, 1067, 932, 850, 718
cm−1; HRMS (ESI): calcd. for C16H20NO3 [M+H]+ 274.1438; found
274.1433.
(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl cyanide (6c)
The compound has been listed in a patent [39]
Compound 6c was prepared according to the procedure described
for 6b from 3,4-Dimethoxycinnamic acid (12.862 g, 61.77 mmol) and
crystallized from toluene to yield a white solid (10.657g, 79%). Mp
132-134 °C; 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 16.0 Hz,
1H), 7.28 (dd, J=8.2,1.9 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.95 (d, J
= 8.2 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 167.0, 155.0, 153.6, 149.6,
125.8, 125.4, 123.0, 112.6, 111.2, 110.4, 56.1, 55.9 ppm. FTIR
(ATR, ṽ): 2951, 2843, 1647, 1589, 1508, 1221, 1141, 1015 cm−1;
(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl cyanide (6d)
The compound has been listed in a patent [39]
N-(2-((E)-benzylidene)-3-oxocyclohept-4-en-1-yl)-N-
methylcinnamamide (5)
Compound 6d was prepared according to the procedure described
for 6b from 3,4,5-Trimethoxycinnamic acid (10.261g, 43.1 mmol) and
crystallized from toluene to yield white solid (5.07g, 48%). Mp 145-
To a cooled under argon to 0 °C solution of diisporopylamine (0.32
mL, 2.2 mmol) in dry tetrahydrofuran (5 mL) was added n-
butyllithium (2.5M in hexane, 0.88 mL, 2.2 mmol). The solution was
stirred for 30 min, then a solution of enone 4 (2.0 mmol) in THF (2
mL) was added and the resulting solution was stirred at 0 °C. After
30 min the reaction mixture was cooled to –78 ºC and a solution of
cinnamoyl chloride (0.375 g, 2.25 mmol) in THF (3 mL) was added
dropwise. The reaction was stirred at −78 ºC for 30 minutes and then
quenched with 20% aqueous solution of K2CO3 (5 mL). After heating
to room temperature 20 mL of water was added and the mixture was
extracted with dichloromethane (4 × 20 mL). The combined organic
extracts were dried with Na2SO4, filtered, and concentrated in
vacuum. The crude product was predicated by flash column
chromatography (MeOH/DCM, 2:98) to yield a yellow oil (0.715 g,
99%). 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J =15.4 Hz, 1H),
7.53-7.43 (m, 3H), 7.33 (m, 8H), 6.70 (d, J =15.4 Hz, 1H), 6.23 (d,
J=11.8 Hz, 1H), 5.84 (d, J = 7.6 Hz, 0.87x1H), 5.33 (m, 0.13x 1H),
2.95 (s, 3H), 2.57-2.34 (m, 3H), 2.14-1.98 (m, 1H), 1.52-1.25 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 195.1, 166.2, 146.6, 142.75,
140.7, 140.5, 135.1, 134.6, 132.1, 129.6, 129.6, 129.0, 128.7, 128.5,
127.7, 117.3, 53.1, 32.8, 30.0, 28.5 ppm; FTIR (ATR, ṽ): 3024, 2914,
1643, 1599, 1447, 1392, 1273, 1173, 1111, 976, 856, 762, 693 cm−1;
HRMS (ESI): calcd. for C24H24NO2 [M+H]+ 358.1802; found
358.1815.
1
146 °C; H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 16.0 Hz, 1H),
6.86 (s, 2H), 6.77 (d, J = 16.0 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 6H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 167.0, 155.0, 153.5, 142.5,
127.9, 124.3, 112.5, 106.8, 60.9, 56.1 ppm.
FTIR (ATR, ṽ): 2941, 2827, 1644, 1619, 1574, 1499, 1450, 1419,
1326, 1117, 989, 833 cm−1;
(E)-3-(1,3-Benzodioxol-5-yl)prop-2-enoyl cyanide (6e)
The compound has been listed in a patent [39]
Compound 6e was prepared according to the procedure described
for 6b from trans-3,4-(Methylenedioxy)cinnamic acid (10.101g, 52.56
mmol) and crystallized from toluene to yield white solid (5.499 g,
52%). Mp 181-184 °C; 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J
=16.0Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H),
6.92 (d, J=8.0 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H), 6.10 (s, 2H) ppm;
13C NMR (100 MHz, CDCl3): δ = 167.1, 154.6, 152.3, 148.9, 127.8,
127.3, 123.3, 112.6, 109.1, 107.0, 102.2 ppm. FTIR (ATR, ṽ): 2999,
2917, 1636, 1611, 1591, 1496, 1449, 1217, 1097, 1031 cm–1;
(E)-4-(3-cyano-3-oxoprop-1-en-1-yl)-2-methoxyphenyl
carbonate (6f)
methyl
Compound 6f was prepared according to the procedure described
for 6b from trans-3-methoxy-4-methoxycarbonyloxycinnamic acid[40]
(2.051 g, 8.13 mmol) and crystallized from toluene to yield a yellow
(E)-cinnamoyl cyanide (6a)[38]
solid (1.200 g, 56%). Mp 186-188 °C; H NMR (400 MHz, CDCl3): δ
1
Compound 6a was prepared in an analogous way to compound 6b,
using cinnamoyl chloride (12.173 g, 73.1 mmol) and crystallized from
toluene to yield a white solid (10.251 g, 89%). Mp 115-117 °C (lit.
= 7.96 (d, J = 16.1 Hz, 1H), 7.26 (s, 2H), 7.20 (s, 1H), 6.81 (d, J =
16.1 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 167.1, 153.5, 153.2, 152.1, 143.9, 131.8, 125.6, 123.4,
122.8, 112.8, 112.4, 56.3, 55.7 ppm; FTIR (ATR, ṽ): 3045, 2968,
1747, 1650, 1618, 1581, 1440, 1285, 1230, 986, 933, 856, 774 cm–1;
HRMS (ESI): calcd. for: C13H12NO5 [M+H]+ 262.0710; found:
262.0698.
1
113-114 °C[38]); H NMR (400 MHz, CDCl3): δ = 8.01 (d, J=16.2 Hz,
1H), 7.69–7.61 (m, 2H), 7.59-7.47 (m, 3H), 6.87 (d, J=16.2 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 167.4, 154.9, 133.0, 132.6,
129.5, 129.4, 125.2, 112.4 ppm. The NMR spectra were in
agreements with those reported in the literature.[38]
General procedure
benzylidenetropinones 4a-k)
4
(for acylation of substituted 2-
(E)-3-(4-methoxyphenyl)prop-2-enoyl cyanide (6b) [38]
Suspension of trans-4-methoxycinnamic acid (10.274 g, 57.7 mmol)
in dry DCM (60 mL) was cooled under argon atmosphere to 0 °C,
then thionyl chloride (6.4 mL, 88.2 mmol, 1.5 eq) was added
dropwise. The resulting mixture was stirred at room temperature
To a cooled to 0 °C solution of diisporopylamine (0.32 mL, 2.2 mmol)
in dry tetrahydrofuran (5 mL) was added n-butyllithium (2.5M in
hexane, 0.88 mL, 2.2 mmol). The solution was stirred for 30 min and
then a solution of 2-benzylidenetropinone 4a-k (2.0 mmol) in THF (2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
mL) was added and the resulting mixture was stirred at 0 °C. After
30 min the reaction mixture was cooled to –78 ºC and a solution of
acyl cyanide 6a-e (2.1 mmol) in THF (3 mL) was added dropwise.
The reaction was stirred at −78 ºC for 30 minutes and then
quenched with 20% aqueous solution of K2CO3 (5 mL). After
warming up to room temperature 20 mL of water was added and the
mixture was extracted with dichloromethane (4 × 20 mL). The
combined organic extracts were dried with Na2SO4, filtered, and
concentrated under vacuum. The product was predicated by FCC.
Compound 7e was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 2:98) to
yield a yellow solid (0.601 g, 69 %). Mp 206-208 °C H NMR (400
1
MHz, CDCl3): δ = 16.56 (s, 1H), 7.78 (d, J = 15.5 Hz, 1H), 7.67 (s,
1H), 7.63-7.59 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.46-7.40 (m, 3H),
7.24 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 15.5 Hz, 1H), 4.25 (d, J = 7.3
Hz, 1H), 4.17 (d, J = 6.0 Hz, 1H), 2.59-2.42 (m, 2H), 2.34 (s, 3H),
1.94-1.86 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ= 182.8,
178.0, 141.6, 137.1, 135.2, 134.1, 132.6, 131.7, 131.3, 130.2, 128.9,
128.2, 122.9, 118.5, 111.5, 59.8, 59.1, 35.7, 32.7, 30.0 ppm;
FTIR (ATR, ṽ): 3030, 2933, 2867, 1619, 1531, 1486, 1273, 1143,
1070, 977, 923, 775, 750, 698 cm−1; HRMS (ESI): calcd. for
C24H23BrNO2 [M+H]+ 436.0907; found 436.0895.
Compound: triclinic, P-1, a= 9.2161(4), b= 10.2947(3), c=
11.2144(4) Å, α= 103.160(3), β= 108.928(4), γ=91.533(3)o
V=974.16(6) Å3, Z=2, Dcalc=1.488 g cm-1, μ=3.029 mm-1, R1=0.0343
for 3644 [ Fo > 4s(Fo)] and 0.0354 for all data, wR2=0.0939,
S=01.038.
(E)-2-benzylidene-4-cinnamoyl-8-methyl-8-azabicyclo[3.2.1]octan-3-
one (7a)
Compound 7a was prepared according to the General procedure 4
and purified by flash column chromatography (AcOEt/Hex, 50:50) to
yield a pink solid (0.572 g, 80%). Mp 191-193 °C; 1H NMR (400
MHz, CDCl3): δ = 16.63 (s, 1H), 7.78 (d, J = 15.5 Hz, 1H), 7.78 (s,
1H), 7.63–7.58 (m, 2H), 7.46-7.36 (m, 8H), 6.96 (d, J = 15.5 Hz, 1H),
4.33 (d, J = 7.4 Hz, 1H), 4.17 (d, J = 6.1 Hz, 1H), 2.59-2.42 (m, 2H),
2.35 (s, 3H), 1.96-1.87 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ
= 183.5, 177.6, 141.4, 136.4, 135.3, 134.2, 130.1, 129.9, 128.9,
128.6, 128.5, 128.2, 118.6, 111.5, 59.8, 59.2, 35.7, 32.7, 30.3 ppm;
FTIR (ATR, ṽ): 3059, 2937, 2867, 1618, 1576, 1523, 1445, 1144,
966, 922, 781, 744, 691 cm−1; HRMS (ESI): calcd. for: C24H24NO2
[M+H]+ 358.1802; found: 358.1788.
CCDC 1886747 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
(E)-2-cinnamoyl-4-(4-fluorobenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7f)
(E)-2-cinnamoyl-4-(3-methoxybenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7b)
Compound 7b was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 2:98) to
Compound 7f was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 2:98) to
1
yield a yellow solid (0.681 g, 91 %). Mp 145-148 °C; H NMR (400
MHz, CDCl3): δ= 16.58 (s, 1H), 7.77 (d, J = 15.5 Hz, 1H), 7.72 (s,
1H), 7.63-7.58 (m, 2H), 7.46-7.34 (m, 5H), 7.12 (t, J = 8.6 Hz, 2H),
6.95 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 7.3 Hz, 1H), 4.18 (d, J = 6.1
1
yield a yellow solid (0.602 g, 78 %). Mp 134-138 °C; H NMR (400
MHz, CDCl3): δ = 16.60 (s, 1H), 7.78 (d, J = 15.6 Hz, 1H), 7.75 (s,
1H), 7.63 – 7.58 (m, 2H), 7.45-7.39 (m, 3H), 7.34 (t, J = 8.4 Hz, 1H),
6.95 (m, 4H), 4.36 (d, J = 7.2 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 3.85
(s, 3H), 2.58 (d, J = 8.4 Hz, 1H), 2.49–2.42 (m, 1H), 2.36 (s, 3H),
1.95-1.87 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ= 183.3,
177.7, 159.5, 141.4, 136.6, 136.6, 135.2, 134.1, 130.1, 129.5, 128.9,
128.2, 122.4, 118.6, 115.2, 114.3, 111.5, 59.9, 59.15, 55.2, 35.7,
32.7, 30.2 ppm; FTIR (ATR, ṽ): 3055, 2935, 2880, 1617, 1578, 1536,
1459, 1245, 1170, 1036, 977, 920,782, 748, 686 cm−1; HRMS (ESI):
calcd. for: C25H26NO3 [M+H]+ 388.1907; found: 388.1897.
Hz, 1H), 2.60-2.42 (m, 2H), 2.35 (s, 3H), 1.95-1.85 (m, 2H) ppm; 13
C
NMR (100 MHz, CDCl3): δ = 183.4, 177.5, 162.7 (d, JC-F = 250.1 Hz),
141.4, 136.3, 135.1, 132.2, 131.7(d, JC-F = 8.3 Hz), 131.3 (d, JC-F
=
3.4 Hz), 130.1, 128.9, 128.2, 118.5, 115.7 (d, JC-F = 21.6 Hz), 111.4,
59.8, 59.1, 35.7, 32.7, 30.1 ppm; 19F NMR (376 MHz, CDCl3): δ =
–111.7 ppm (s, 1F); FTIR (ATR, ṽ): 3056, 2938, 2872, 1617, 1535,
1448, 1225, 1159, 1037, 969, 923, 778, 751, 694 cm−1; HRMS (ESI):
calcd. for: C24H23FNO2 [M+H]+ 376.1707; found: 376.1715.
(E)-2-cinnamoyl-8-methyl-4-(4-(trifluoromethyl)benzylidene)-8-
azabicyclo[3.2.1]octan-3-one (7g)
(E)-2-cinnamoyl-4-(3,4-dimethoxybenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7c)
Compound 7c was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 3:97) to
Compound 7g was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 1:99) to
yield a yellow solid (0.710, 83 %). Mp 197-199 °C; 1H NMR (400
MHz, CDCl3): δ= δ 16.53 (s, 1H), 7.80 (d, J = 15.5 Hz, 1H), 7.75 (s,
1H), 7.68 (d, J = 8.1 Hz, 2H), 7.64-7.58 (m, 2H), 7.50-7.38 (m, 5H),
6.95 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 7.4 Hz, 1H), 4.18 (d, J = 6.0
1
yield a yellow solid (0.543 g, 65 %). Mp 142-143 °C (decomp.); H
NMR (400 MHz, CDCl3): δ = 16.66 (s, 1H), 7.79-7-71 (m, 2H), 7.64-
7.57 (m, 2H), 7.45-7.36 (m, 3H), 7.03-6.91 (m, 4H), 4.40 (d, J = 7.1
Hz, 1H), 4.19 (d, J = 6.0 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 2.63-
2.43 (m, 2H), 2.37 (s, 3H), 1.98-1.88 (m, 2H) ppm; 13C NMR (100
MHz, CDCl3): δ= 184.13, 176.60, 149.67, 148.68, 140.98, 135.24,
134.69, 134.53, 129.99, 128.85, 128.06, 128.03, 123.36, 118.49,
113.08, 111.17, 110.98, 60.00, 58.99, 55.86, 55.72, 35.52, 32.67,
30.31 ppm; FTIR (ATR, ṽ): 2937, 2843, 1615, 1576, 1515, 1448,
1250, 1143, 1021, 968, 924, 781, 752, 692, cm−1; HRMS (ESI):
calcd. for: C26H28NO4 [M+H]+ 418.2013; found: 418.1998;.
Hz, 1H), 2.62-2.42 (m, 2H), 2.35 (s, 3H), 1.96-1.87 (m, 2H) ppm; 13
C
NMR (100 MHz, CDCl3): δ= 181.9, 178.8, 142.0, 138.8, 138.4,
135.1, 131.8, 130.6, 130.1 (q, JC-F = 32.6 Hz), 129.9, 128.9, 128.2,
125.4 (q, JC-F = 3.7 Hz), 123.1 (q, JC-F = 272.1 Hz), 118.5, 111.6,
59.8, 59.2, 35.8, 32.6, 30.0 ppm; 19F NMR (376 MHz, CDCl3): δ =
–62.7 ppm (s, 3F); FTIR (ATR, ṽ): 2935, 2868, 1613, 1536, 1449,
1408, 1321, 1164, 1106, 906, 845, 696 cm−1; HRMS (ESI): calcd.
for: C25H23F3NO2 [M+H]+ 426.1675; found: 426.1685.
(E)-2-cinnamoyl-8-methyl-4-(3,4,5-trimethoxybenzylidene)-8-
azabicyclo[3.2.1]octan-3-one (7d)
(E)-2-cinnamoyl-8-methyl-4-(4-nitrobenzylidene)-8-
azabicyclo[3.2.1]octan-3-one (7h)
Compound 7h was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 1:99) to
Compound 7d was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 1:99) to
1
1
yield a yellow solid (0.770 g, 86 %). Mp 156-159 °C; H NMR (400
yield a yellow solid (0.338 g, 42 %). Mp 195-198 °C; H NMR (400
MHz, CDCl3): δ = 16.63 (s, 1H), 7.76 (d, J = 15.5 Hz, 1H), 7.70 (s,
1H), 7.63-7.57 (m, 2H), 7.44-7.37 (m, 3H), 6.95 (d, J = 15.5 Hz, 1H),
6.63 (s, 2H), 4.39 (d, J = 7.3 Hz, 1H), 4.18 (d, J = 6.1 Hz, 1H), 3.90
(s, 3H), 3.89 (s, 6H), 2.61-2.52 (m, 1H), 2.48-2.41 (m, 1H), 2.36 (s,
3H), 1.98-1.88 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 183.4,
177.4, 153.0, 141.3, 138.7, 135.8, 135.2, 134.4, 130.6, 130.1, 128.9,
128.1, 118.5, 111.2, 107.3, 60.9, 60.1, 59.0, 56.0, 35.5, 32.7, 30.3
ppm; FTIR (ATR, ṽ): 2939, 2875, 1623, 1576, 1502, 1415, 1235,
1122, 1001, 893, 846, 695 cm−1; HRMS (ESI): calcd. for: C27H30NO5
[M+H]+ 448.2118; found: 448.2129.
MHz, CDCl3): δ= 16.47 (s, 1H), 8.27 (d, J = 8.6 Hz, 2H), 7.80 (d, J =
15.5 Hz, 1H), 7.72 (s, 1H), 7.63-1.58 (m, 2H), 7.50 (d, J = 8.6 Hz,
2H), 7.45-7.38 (m, 3H), 6.96 (d, J = 15.5 Hz, 1H), 4.19 (dd, J = 12.2,
6.7 Hz, 2H), 2.63-2.53 (m, 1H), 2.49–2.42 (m, 1H), 2.34 (s, 3H),
1.94-1.86 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ= 180.7,
179.7, 147.2, 142.4, 141.9, 139.7, 135.0, 130.5, 130.4, 130.3, 129.0,
128.3, 123.7, 118.4, 111.8, 59.9, 59.2, 35.8, 32.5, 29.8 ppm; FTIR
(ATR, ṽ): 3065, 2934, 2871, 1620, 1515, 1447, 1338, 1276, 1144,
1039, 979, 904, 850, 797, 758, 696 cm−1; HRMS (ESI): calcd. for:
C24H23N2O4 [M+H]+ 403.1652; found: 403.1665.
(E)-2-(4-bromobenzylidene)-4-cinnamoyl-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7e)
(E)-2-cinnamoyl-4-(4,5-dimethoxy-2-nitrobenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7i)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900416
European Journal of Organic Chemistry
FULL PAPER
Compound 7i was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH:DCM, 3:97) to
yield a yellow solid (0.574, 62 %). Mp 162-165 °C; 1H NMR (400
MHz, CDCl3): δ= 16.51 (s, 1H), 7.96 (s, 1H), 7.78 (d, J = 15.4 Hz,
1H), 7.76 (s, 1H), 7.59 (d, J = 4.9 Hz, 2H), 7.39 (m, 3H), 6.93 (d, J =
15.4 Hz, 1H), 6.65 (s, 1H), 4.18-4.13 (m, 1H), 4.01-3.90 (m, 1H),
3.99 (s, 3H), 3.96 (s, 3H), 2.42-2.30 (m, 2H), 2.34 (s, 3H), 1.91-1.79
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ= 181.1, 179.1, 152.7,
148.6, 141.9, 140.6, 136.4, 135.0, 131.7, 130.2, 128.9, 128.2, 125.9,
118.5, 112.5, 111.0, 108.0, 59.9, 59.2, 56.4, 56.3, 35.4, 33.1, 30.0
ppm; FTIR (ATR, ṽ): 2935, 2794, 1621, 1570, 1513, 1437, 1272,
1218, 1065, 1020, 990, 868, 749, 693 cm−1;HRMS (ESI): calcd. for:
C26H27N2O6 [M+H]+ 463.1864; found: 463.1880.
3H), 2.59-2.42 (m, 2H), 2.35 (s, 3H), 1.96-1.88 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3): 182.4, 178.6, 151.2, 149.2, 141.6, 136.4,
135.3, 133.9, 129.9, 128.5 (2xC), 128.3, 122.5, 116.4, 111.2, 111.0,
110.4, 59.8, 59.1, 56.0, 56.0, 35.6, 32.8, 30.3 ppm; FTIR (ATR, ṽ):
2933, 2840, 1620, 1578, 1513, 1440, 1281, 1024, 804, 703 cm−1;
HRMS (ESI): calcd. for: C26H28NO4 [M+H]+ 418.2013; found:
418.2024.
(E)-2-benzylidene-8-methyl-4-((E)-3-(3,4,5-
trimethoxyphenyl)acryloyl)-8-azabicyclo[3.2.1]octan-3-one (7n)
Compound 7n was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 1:99) to
1
yield a yellow solid (0.790 g, 88%). Mp 149-1150 °C; H NMR (400
MHz, CDCl3): δ= 16.67 (s, 1H), 7.78 (s, 1H), 7.69 (d, J = 15.4 Hz,
1H), 7.45-7.36 (m, 5H), 6.84-6.77 (m, 3H), 4.33 (d, J = 7.3 Hz, 1H),
4.17 (d, J = 6.1 Hz, 1H), 3.94 (s, 6H), 3.91 (s, 3H), 2.59-2.42 (m,
2H), 2.35 (s, 3H), 1.95-186 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): 183.3, 177.6, 153.5, 141.5, 140.3, 136.4, 135.2, 134.2,
130.8, 129.9, 128.6, 128.5, 117.7, 111.3, 105.5, 61.0, 59.8, 59.1,
56.3, 35.6, 32.8, 30.3 ppm. FTIR (ATR, ṽ): 2912, 2800, 1619, 1604,
1577, 1501, 1477, 1267, 1028, 869, 748 cm−1; HRMS (ESI): calcd.
for: C27H30NO5 [M+H]+ 448.2118; found: 448.2122.
(E)-2-cinnamoyl-8-methyl-4-((6-nitrobenzo[d][1,3]dioxol-5-
yl)methylene)-8-azabicyclo[3.2.1]octan-3-one (7j)
Compound 7j was prepared according to the general procedure 4
and purified by flash column chromatography (AcOEt/Hex, 50:50) to
yield a yellow solid (0.370 g, 41%). Mp 180-184 °C (decomp.); 1H
NMR (400 MHz, CDCl3): δ= 16.46 (s, 1H), 7.87 (s, 1H), 7.79 (d, J =
15.5 Hz, 1H), 7.68 (s, 1H), 7.64-7.58 (m, 2H), 7.46-7.38 (m, 3H),
6.93 (d, J = 15.5 Hz, 1H), 6.64 (s, 1H), 6.18 (s, 2H), 4.14 (d, J = 4.9
Hz, 1H), 3.89 (d, J = 6.2 Hz, 1H), 2.44-2.36 (m, 2H), 2.35 (s, 3H),
1.89-1.74 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ= 181.5,
179.2, 151.7, 147.9, 142.5, 142.0, 136.7, 135.1, 131.3, 130.3, 128.9,
128.2, 118.6, 111.1, 109.7, 105.9, 103.3, 59.7, 59.2, 35.4, 33.1, 29.9
ppm; FTIR (ATR, ṽ): 2912, 2800, 1619, 1604, 1577, 1501, 1477,
1322, 1267, 1028, 1028, 869, 748, 692 cm−1; HRMS (ESI): calcd.
for: C25H23N2O6 [M+H]+ 447.1551; found: 447.1539.
(E)-2-((E)-3-(benzo[d][1,3]dioxol-5-yl)acryloyl)-4-benzylidene-8-
methyl-8-azabicyclo[3.2.1]octan-3-one (7o)
Compound 7o was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/CM, 1:99) to
yield a pink solid (0.834 g, 54%). Mp 211-2113 °C (decomp.); 1H
NMR (400 MHz, CDCl3): δ= 16.69 (s, 1H), 7.75 (s, 1H), 7.69 (d, J =
15.4 Hz, 1H), 7.46-7.33 (m, 5H), 7.12 (s, 1H), 7.09 (d, J = 8.1 Hz,
1H), 6.85 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 15.4 Hz, 1H), 6.04 (s, 2H),
4.32 (d, J = 7.3 Hz, 1H), 4.14 (d, J = 6.1 Hz, 1H), 2.60-2.51 (m, 1H),
2.46-2.39 (m, 1H), 2.34 (s, 3H), 1.99-1.83 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): 182.4, 178.6, 149.7, 148.5, 141.3, 136.7, 135.6,
133.8, 130.1, 129.8, 128.5, 128.4, 124.5, 117.1, 111.4, 108.7, 106.7,
101.6, 60.0, 59.4, 35.7, 32.8, 30.3 ppm. FTIR (ATR, ṽ): 2938, 2873,
1602, 1499, 1487, 1439, 1234, 1147, 1038, 970, 850, 809, 753, 697
cm−1; HRMS (ESI): calcd. for: C25H24NO4 [M+H]+ 402.1700; found:
402.1688.
(E)-2-cinnamoyl-4-(4-(1-ethoxyethoxy)-3-methoxybenzylidene)-8-
methyl-8-azabicyclo[3.2.1]octan-3-one (7k)
Compound 7k was prepared according to the general procedure 4
and purified by flash column chromatography (AcOEt/Hex; from
30:70 to 40:60) to yield a yellow solid (0.784, 82%). Mp 174-176 °C;
1H NMR (400 MHz, CDCl3): δ= 16.63 (s, 1H), 7.75 (d, J = 15.5 Hz,
1H), 7.72 (s, 1H), 7.63-7.57 (m, 2H), 7.45-7.37 (m, 3H), 7.14 (d, J =
8.7 Hz, 1H), 7.00-6.90 (m, 3H), 5.44 (q, J = 5.3 Hz, 1H), 4.38 (d, J =
7.2 Hz, 1H), 4.17 (d, J = 6.1 Hz, 1H), 3.89 (s, 3H), 3.88-3.83 (m, 1H),
3.61 (dq, J = 9.2, 7.1 Hz, 1H), 2.60-2.42 (m, 2H), 2.35 (s, 3H), 1.95-
1.86 (m, 2H), 1.55 (d, J = 5.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ= 184.0, 176. 9, 150.4, 146.6 (2x, two
diastereoisomers), 141.1, 135.3, 135.2 (two diastereoisomers),
134.3, 130.0, 129.7, 128.9, 128.1, 123.1, 118.6, 118.4 (2x, two
diastereoisomers), 113.9, 111.3, 101.0 (2x, two diastereoisomers),
61.9 (2x, two diastereoisomers), 60.0, 59.1, 55.8, 35.6, 32.7, 30.3,
20.2, 15.1 ppm; FTIR (ATR, ṽ): 2934, 2794, 1618, 1575, 1509, 1446,
1246, 1117, 1034, 971, 898, 753 cm−1; HRMS (ESI): calcd. for:
C29H34NO5 [M+H]+ 476.2431; found: 476.2445.
4-[(E)-3-(4-((E)-benzylidene)-8-methyl-3-oxo-8-
azabicyclo[3.2.1]octan-2-yl)-3-oxoprop-1-en-1-yl]-2-methoxyphenyl
methyl carbonate (7p)
Compound 7p was prepared according to the general procedure 4
and purified by flash column chromatography (EtOH/DCM/AcOEt,
1
2:18:80) to yield a yellow solid (0.627 g, 68%). Mp 157-159 °C; H
NMR (400 MHz, CDCl3): δ= 16.60 (s, 1H), 7.78 (s, 1H), 7.71 (d, J =
15.5 Hz, 1H), 7.45 – 7.35 (m, 5H), 7.24 – 7.16 (m, 2H), 7.15 – 7.10
(m, 1H), 6.87 (d, J = 15.5 Hz, 1H), 4.33 (d, J = 7.3 Hz, 1H), 4.16 (d, J
= 6.1 Hz, 1H), 3.93 (s, 6H), 2.62 – 2.52 (m, 1H), 2.47 – 2.40 (m, 1H),
2.35 (s, 3H), 1.96 – 1.86 (m, 2H); 13C NMR (100 MHz, CDCl3): δ=
183.9, 176.9, 153.5, 151.4, 141.3, 140.4, 136.3, 135.1, 134.5, 129.9,
128.6, 128.5, 122.8, 120.6, 119.0, 112.1, 111.5, 59.80, 59.10, 56.04,
55.61, 35.62, 32.71, 30.21; FTIR (ATR, ṽ): 2935, 2873, 1775, 1625,
1553, 1509, 1441, 1409, 1246, 1209, 1038, 980, 921, 845 cm−1;
HRMS (ESI): calcd. for: C27H28NO6 [M+H]+ 462.5215; found:
462.5226.
(E)-2-benzylidene-4-((E)-3-(4-methoxyphenyl)acryloyl)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (7l)
Compound 7l was prepared according to the general procedure 4
and purified by flash column chromatography (AcOEt/Toluene,
30:70) to yield yellow solid (0.576 g, 74%). Mp 185-187 °C; 1H NMR
(400 MHz, CDCl3): δ = 16.74 (s, 1H), 7.75 (s, 1H), 7.75 (d, J = 15.4
Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.45-7.34 (m, 5H), 6.95 (d, J = 8.7
Hz, 2H), 6.82 (d, J = 15.4 Hz, 1H), 4.32 (d, J = 7.4 Hz, 1H), 4.15 (d,
J = 6.1 Hz, 1H), 3.87 (s, 3H), 2.59-2.41 (m, 2H), 2.34 (s, 3H), 1.96-
1.87 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): 182.1, 179.0, 161.4,
141.4, 136.4, 135.3, 133.7, 129.9 (2xC), 128.5, 128.0 (2xC), 116.2,
114.4, 111.0, 59.8, 59.2, 55.4, 35.6, 32.8, 30.2 ppm.
(E)-2-cinnamoyl-4-(4-hydroxy-3-methoxybenzylidene)-8-methyl-8-
azabicyclo[3.2.1]octan-3-one (8)
3% v/v solution of TFA in DCM (7 mL) was added to compound 7k
(0.313 g, 0.66 mmol) and stirred at room temperature. After 15
minutes 20% aqueous solution of K2CO3 was added to the reaction
to the pH = 10 followed by water (15 mL). The resulting mixture was
extracted with DCM (4x20 mL). The combined organic extracts were
dried over Na2SO4 and evaporated under vacuum. The crude
product was purified by flash column chromatography (MeOH/DCM,
5:95) to yield 8 (0.266 g, quantitatively) as an orange solid. Mp 180-
FTIR (ATR, ṽ): 2935, 2834, 1616, 1601, 1573, 1510, 1446, 1245,
1176, 1030, 972, 826, 806, 748, 692 cm−1; HRMS (ESI): calcd. for:
C25H26NO3 [M+H]+ 388.1907; found: 388.1913.
(E)-2-benzylidene-4-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-8-methyl-
8-azabicyclo[3.2.1]octan-3-one (7m)
1
Compound 7m was prepared according to the general procedure 4
and purified by flash column chromatography (MeOH/DCM, 2:98) to
yield a yellow solid (0.693, 83%). Mp 184-187 °C; 1H NMR (400
MHz, CDCl3): δ= 16.74 (s, 1H), 7.76 (s, 1H), 7.73 (d, J = 15.4 Hz,
1H), 7.46-7.36 (m, 5H), 7.22 (dd, J = 8.3, 1.7 Hz, 1H), 7.10 (d, J =
1.7 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 15.4 Hz, 1H), 4.33
(d, J = 7.3 Hz, 1H), 4.17 (d, J = 6.1 Hz, 1H), 3.97 (s, 3H), 3.95 (s,
183 °C; H NMR (400 MHz, CDCl3): δ= 16.68 (s, 1H), 7.76 (d, J =
15.8 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J = 6.6 Hz, 2H), 7.46-7.37 (m,
3H), 6.99-6.88 (m, 4H), 6.58 (br s, 1H), 4.40 (d, J = 7.1 Hz, 1H), 4.20
(d, J = 6.0 Hz, 1H), 3.90 (s, 3H), 2.62-2.43 (m, 2H), 2.37 (s, 3H),
1.98-1.87 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 184.2,
176.7, 146.8, 146.5, 141.1, 135.3, 135.0, 134.3, 130.1, 128.9, 128.1,
127.5, 124.0, 118.5, 114.8, 112.8, 111.1, 60.0, 59.1, 55.8, 35.4,
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32.7, 30.6 ppm; FTIR (ATR, ṽ): 3059, 3025, 2940, 2884, 1616, 1508,
1447, 1265, 1204, 1160, 1030, 965, 840, 748, 692 cm−1; HRMS
(ESI): calcd. for: C25H26NO4 [M+H]+ 404.1856; found: 404.1847.
Bioorg. Med. Chem. Lett. 2010, 20, 912-917; d) J. R. Dimmock, M. P.
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(2-((E)-benzylidene)-4-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)-
8-methyl-8-azabicyclo[3.2.1]octan-3-one (9)
To the cooled to 0 °C suspension of 7p (0.232 g, 0.5 mmol) in EtOH
(10 mL) was slowly added a solution of ammonia (25% solution in
water, 2 mL) in EtOH (8 mL). Reaction was stirred for 1 hour at 0 °C
and then allowed to warm up to room temperature. After completion
of the reaction (monitored by TLC) the volatiles were evaporated
under vacuum. The residue was dissolved in DCM, dried with
Na2SO4, filtered and evaporated under vacuum. The crude product
was purified by flash column chromatography (MeOH/CM, 3:97) to
yield a red solid (0.195 g, 96%). Mp 182-184 °C; 1H NMR (400 MHz,
CDCl3): δ= 16.78 (s, 1H), 7.77 (s, 1H), 7.73 (d, J = 15.4 Hz, 1H),
7.49 – 7.34 (m, 6H), 7.20 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J
= 8.1 Hz, 1H), 6.78 (d, J = 15.4 Hz, 1H), 4.35 (d, J = 7.2 Hz, 1H),
4.19 (d, J = 5.9 Hz, 1H), 3.95 (s, 3H), 2.65 – 2.56 (m, 1H), 2.56 –
2.42 (m, 1H), 2.35 (s, 3H), 1.97-1.98 (m, 2H) ppm; 13C NMR (100
MHz, CDCl3): δ= 182.1, 179.0, 148.3, 147.1, 1412.0, 136.4, 135.5,
134.0, 129.9, 128.5, 127.9, 122.8, 116.2, 115.2, 110.9, 110.5, 59.9,
59.3, 56.1, 35.5, 32.9, 30.3 ppm; FTIR (ATR, ṽ): 2947, 1617, 1593,
1508, 1426, 1270, 1210, 1028, 965, 840, 811, 747 cm−1; HRMS
(ESI): calcd. for: C25H26NO4 [M+H]+ 404.1856; found: 404.1851.
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Acknowledgements
The work was funded by the National Science Center, Poland,
grant number: 2014/15/B/ST5/04695
Keywords: acylation, aldol reaction, cyanides, curcumin
analogues, tropane derivatives
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This article is protected by copyright. All rights reserved.