Catalytic One-Pot Diastereoselective Michael-Initiated Ring-Closure of Methyl Ketones with 3-Bromochromones: Synthesis of Cyclopropa[b]chromanones

Article abstract of DOI:10.1002/ejoc.201600413

A one-pot diastereoselective base-catalyzed Michael-initiated ring-closure (MIRC) of activated methyl ketones with 3-bromochromones to give cyclopropa[b]chromanones is described. Three asymmetric centres are generated in the new cyclopropa[b]chromanone skeleton. Stereochemistry studies based on NMR spectroscopy and single-crystal X-ray diffraction analysis revealed the trans configuration of the cyclopropane ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as was further confirmed by chiral HPLC. The use of acetone in our reaction produced a 1-acetyl-substituted cyclopropa[b]chromanone that can undergo a subsequent MIRC reaction with a second molecule of 3-bromochromone to give the first described 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers as a meso form.

Full text of DOI:10.1002/ejoc.201600413

DOI: 10.1002/ejoc.201600413
Full Paper
Cyclopropa[b]chromanones
Catalytic One-Pot Diastereoselective Michael-Initiated Ring-
Closure of Methyl Ketones with 3-Bromochromones: Synthesis
of Cyclopropa[b]chromanones
Joana L. C. Sousa,[a] Oualid Talhi*[a,b] Ricardo F. Mendes,[c] Filipe A. Almeida Paz,[c]
Khaldoun Bachari,[b] and Artur M. S. Silva*[a]
Abstract: A one-pot diastereoselective base-catalyzed Michael- ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as
initiated ring-closure (MIRC) of activated methyl ketones with was further confirmed by chiral HPLC. The use of acetone in
3-bromochromones to give cyclopropa[b]chromanones is de- our reaction produced a 1-acetyl-substituted cyclopropa[b]-
scribed. Three asymmetric centres are generated in the new chromanone that can undergo a subsequent MIRC reaction
cyclopropa[b]chromanone skeleton. Stereochemistry studies with a second molecule of 3-bromochromone to give the first
based on NMR spectroscopy and single-crystal X-ray diffraction described 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers
analysis revealed the trans configuration of the cyclopropane as a meso form.
Introduction
thesis of 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-
ones and their optimization as new PLK4 inhibitors. The study
revealed that a structural insertion of a cyclopropane ring sig-
nificantly improved the physicochemical, ADME (absorption,
distribution, metabolism, and excretion), and pharmacokinetic
properties of the resulting molecules compared to their alkene-
linked congeners.[5]
Cyclopropane is the smallest cycloalkane ring system. It is wide-
spread in nature, and can be found in a variety of natural prod-
ucts including fatty acids I, monoterpenes II, diterpenes III,
sugar-containing compounds IV, and steroids V (Figure 1),
among others.[1,2] It is considered to be an essential pharmaco-
phore, and is found as a substructure of several approved drugs,
including efavirenz (VI; anti-HIV agent), saxagliptin (VII; antidia-
betic), and ciprofloxacin (VIII; antibiotic) (Figure 1), and in many
other synthetic pharmaceuticals.[3] Stereochemical investiga-
tions have largely underlined the importance of chirality in cy-
clopropane-based scaffolds and its influence on the physiologi-
cal and pharmacological properties of compounds containing
this substructure, especially on their interactions with chiral bio-
receptors.[3] Cyclopropane-containing compounds are biologi-
cally relevant and interesting pharmacological agents that are
commonly used as antitumor agents,[4,5] antiviral com-
pounds,[6,7] selective serotonin 2C agonists,[8] and peptidomi-
metics.[9] A recent paper by Sampson et al. described the syn-
[a] QOPNA, Department of Chemistry, University of Aveiro,
3810-193 Aveiro, Portugal
E-mail: artur.silva@ua.pt
oualid.talhi@ua.pt
https://sites.google.com/site/artursilvaua/
[b] Centre de Recherche Scientifique et Technique en Analyses Physico-
Chimiques CRAPC,
BP384, Bou-Ismail 42004, Tipaza, Algeria
E-mail: bachari2000@yahoo.fr
https://www.crapc.dz
[c] CICECO – Aveiro Institute of Materials, Department of Chemistry, University
of Aveiro,
Figure 1. Examples of natural products and pharmaceuticals containing a
cyclopropane motif.
3810-193 Aveiro, Portugal
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600413.
Beyond the possible biological applications, cyclopropanes
are important intermediates in synthetic organic chemistry, as
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Scheme 1. Retrosynthetic analysis of cyclopropa[b]chromanones 3 and of the meso form of dimers 6a and 6b.
they undergo useful ring-opening reactions.[10] Their prepara- first described 1,1′-carbonylbis(cyclopropa[b]chromanone) di-
tion remains, though, a critical issue, and the established syn- mers 6. These dimers exist in the meso form as a result of the
thetic methods have several limitations. There are various well- clear bilateral symmetry of their structures (Scheme 1). The syn-
known methods for the synthesis of cyclopropane-based com- thesized products could be valuable compounds in their own
pounds.[3] The Simmons–Smith reaction, for example, is a classi- right, with potential biologically applications. Alternatively, they
cal method involving the cyclopropanation of an alkene with a could be used as versatile building blocks for further ring trans-
zinc carbenoid.[11–13] The transition-metal-catalyzed decomposi- formations. They are donor–acceptor cyclopropanes (DACs),
tion of diazoalkanes is an alternative method that can give bet- which have been used for the construction of essential struc-
ter cyclopropanation reactions with olefins.[14–16] Conversely, tural motifs.[26] For instance, they have been often used in the
the so-called Michael-initiated ring-closure (MIRC) reaction is total synthesis of biologically active natural products.[27]
the most commonly used procedure for the preparation of cy-
clopropanes.[17–20] This procedure involves a conjugate addition
to an electrophilic alkene and a subsequent intramolecular cy-
clopropane ring closure. Some of the reported methods are
Results and Discussion
Syntheses
multicomponent and/or multistep procedures that require prior
synthesis of commercially unavailable reagents or complex cat-
alysts. Hence, interest in the development of one-pot economi-
cal MIRC pathways to construct the cyclopropane skeleton has
recently increased.[17]
In this context, 3-halochromones are desirable, cheap, and
versatile starting materials that have been widely used in the
synthesis of a variety of polycyclic molecules.[21] For example,
3-bromochromones were recently used by our research group
to prepare highly functionalized polysubstituted furans[22] and
polyhydroxylated xanthones,[23] both of which are important
classes of naturally occurring oxygen-containing heterocycles
with proven biological properties.
Cyclopropa[b]chromanone 3a was prepared by allowing 3-bro-
mochromone (1a) to react in refluxing acetone (2a; used as
reagent and solvent), using a catalytic amount of the organic
base pyrrolidine.[22,28] The reaction was monitored by TLC for
72 h. During this time, we observed a gradual production of
the desired 1-acetylcyclopropa[b]chromanone (3a), which was
ultimately isolated in a modest yield (25 %), together with unre-
acted starting material 1a and two minor products. These were
1
identified by H NMR spectroscopic analysis to be 3-(2-oxopro-
pyl)-4H-chromen-4-one (4; 11 % yield; probably resulting from
cyclopropane ring-opening) and 4H-chromen-4-one (5; 11 %
yield; formed by dehalogenation of starting material 1a)
(Scheme 2 and Table 1, Entry 1).
In this manuscript, we report a one-pot Michael-initiated
With the aim of improving the reaction yield and avoiding
ring-closure of activated methyl ketones 2 with 3-bromo- the formation of by-products, we tested an alternative synthetic
chromones 1 under alkali-catalyzed or organic-base-catalyzed approach using sodium hydroxide solution (60 % aq.). Addition
conditions to generate a new series of cyclopropa[b]chromano- of a few drops of this base to a solution of 1a in a 1:1 mixture
nes 3 containing acetyl, benzoyl, or cinnamoyl functional of acetone 2a/THF at reflux allowed the isolation of the desired
groups (Scheme 1). Thus, a chromanone[24,25] and a cyclopro- compound (i.e., 3a) as the sole product, in a higher yield (47 %),
pane, both of which show excellent biological properties, are after 48 h (Table 1, Entry 2). A similar alkali-catalyzed reaction
combined in the same molecule. The resulting cyclo- was carried out at room temperature, and after only a few
propa[b]chromanone 3 contains three asymmetric centres, and hours, TLC monitoring revealed the production of 3a (24 %
it is prepared with high diastereoselectivity, as revealed by NMR yield) and two minor compounds. These were found to be dia-
spectroscopy and single-crystal X-ray diffraction analysis. The stereomers of 1,1′-carbonylbis{1a,7a-dihydrocyclopropa[b]-
cyclopropane ring was found to have a trans configuration. We chromen-7(1H)-one} (6a) (9 % yield, 1:1 diastereomeric mix-
also demonstrate that the obtained 1-acetyl-substituted cyclo- ture), and were characterized by 1H NMR spectroscopy and
propa[b]chromanone structures can also be considered as acti- high-resolution mass spectrometry (HRMS) (Table 1, Entry 3).
vated methyl ketones to carry out a further MIRC coupling with A similar result was observed when the same alkali-catalyzed
a second molecule of 3-bromochromone 1 to give rise to the conditions were used with 3-bromo-7-methoxychromone (1b).
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Scheme 2. Synthesis of cyclopropa[b]chromanones 3a–3l and 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers 6a–6c.
Table 1. Optimization of the reaction conditions for the preparation of cyclopropa[b]chromanones 3.
Entry
Methyl ketone
Base
Solvent
t [h]
T [°C]
Product (yield [%])
3
4
5
6
7
1
2
3
4
5
6
7
2a
2a
2a
3a
2c
2c
2g
pyrrolidine[a]
NaOH (60 %)[a]
NaOH (60 %)[a]
NaOH (60 %)[a]
NaOH (60 %)[a]
NaOH (60 %)[b]
NaOH (60 %)[a]
acetone
acetone/THF (1:1)
acetone/THF (1:1)
72
48
5
18
96
48
48
reflux
reflux
r.t.
r.t.
r.t.
3a (25)
3a (47)
3a (24)
–
3c (22)
3c (23)
–
(11)
–
–
–
–
(11)
–
–
–
–
–
–
–
–
–
–
–
6a (9)
6c (72)
–
–
–
THF
THF
THF
THF
reflux
reflux
–
–
–
–
–
(49)
[a] 1 drop/50 mg of the starting material (i.e., 1a or 1b). [b] 2 drops/50 mg of the starting material (i.e., 1a or 1b).
This led to the formation of 1-acetyl-4-methoxycyclo- (2f) (Scheme 2). The best results were achieved using catalytic
propa[b]chromanone (3g). When the reaction was carried out amounts of NaOH (60 % aq.), in THF at room temperature,
in a refluxing mixture of acetone (2a)/THF (1:1), 3g was the sole which ultimately allowed the preparation of 1-benzoyl- and 1-
isolated product (34 % yield); when the reaction was carried out cinnamoylcyclopropa[b]chromanones 3b–3f and 3h–3l in mod-
at room temperature, 3g was obtained in 12 % yield along with est to excellent yields (22–94 %) (Table 2). Derivative 3c was
dimer 6b (12 % yield) as
a
1:1 diastereomeric mixture obtained in modest yield (22 %), and some unreacted 3-bromo-
(Scheme 2).
chromone (1a) and 4-methoxyacetophenone (2c) remained, so
we examined the use of higher temperatures and an increased
amount of base. However, these changes to the reaction condi-
tions did not favor the formation of the desired product, and it
was obtained in the same yield (23 %; Table 1, Entries 5 and 6).
The reaction of 3-bromochromone (3a) with acetylacetone (2g)
(which has a much more active methylene group than the usual
activated methyl group) was also investigated using drops of
NaOH (60 % aq.) in refluxing THF for 48 h. NMR spectroscopic
analysis indicated the production of furan heterocycle 7 (49 %
yield), formed as the result of a tandem Michael addition/het-
erocyclization/ring-opening sequence that has recently been
described by us under organic-base catalysis (Scheme 2 and
Table 1, Entry 7).[22]
1,1′-Carbonylbis(cyclopropa[b]chromanone) dimers 6a and
6b also attracted our attention because of the bilateral symme-
try of the scaffold. We planned to investigate the possible syn-
thetic preparation of these molecules using our alkali-catalyzed
MIRC procedure. Thus, we tested the reaction of 3-bromo-7-
methoxychromone (1b) with pre-synthesized 1-acetylcyclo-
propa[b]chromanone (3a) (which still contains an activated
methyl group). A 1:1 mixture of two diastereomers of 4-
methoxy-1-[(7-oxo-1,1a,7,7a-tetrahydrocyclopropa[b]chromen-
1-yl)carbonyl]-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one
(6c) was obtained in good yield (72 %) (Scheme 2 and Table 1,
Entry 4).
We expanded our studies to include the synthesis of differ-
ent cyclopropa[b]chromanones 3 using activated methyl ket-
We propose a mechanism for the synthesis of cyclo-
ones, such as acetophenones 2b–2e and benzylideneacetone propa[b]chromanones 3 (Scheme 3): The reaction starts with a
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Table 2. Structures and yields of 1-acetyl, 1-benzoyl, and 1-cinnamoyl cyclo-
propa[b]chromanone derivatives 3.
use of active methyl ketones as nucleophiles: We have previ-
ously reported that the reaction of 1,3-dicarbonyl compounds
bearing active methylene units with 3-bromochromones 1 se-
lectively leads to furan heterocycles through an organic-base-
catalyzed tandem Michael-addition/heterocyclization/ring-
opening process.[22] Acetophenones are excellent Michael do-
nors, and we have found that their reactivity varies depending
on the type of aryl substituent, and that this ultimately influen-
ces the reaction yield in the synthesis of cyclopropa[b]chroma-
nones 3. Results indicate that the presence of an electron-with-
drawing group, such as a nitro group, at the para position of
the aryl moiety (in 3e and 3k) increases the reaction yield. The
nitro group increases the acidity of the α-proton in the aceto-
phenone, and thus favors its facile deprotonation, which initi-
ates the MIRC reaction. Conversely, we have found that the
presence of a methoxy group at the para position of the aryl
moiety (in 3c and 3i) greatly decreases the overall reaction yield
(Table 2). This electron-donating group can render the α-proton
of the acetophenone less acidic, thus making the formation of
the corresponding carbanion kinetically undesirable.
Stereochemistry
Stereochemistry studies were conducted to clarify the dia-
stereoselectivity of our MIRC synthetic pathway leading to cy-
clopropa[b]chromanones 3. The construction of
a cyclo-
propa[b]chromanone scaffold requires that the 1a-H and 7a-H
protons have a cis configuration; they must be oriented on the
same side of the chromanone plane. To guarantee that this
structural condition is met, the intermediate 3-bromochroma-
none carbanion must be obtained as a (2S,3S)/(2R,3R) racemic
mixture resulting from the syn Michael addition reaction of 2
to 1 (Schemes 3 and 4). The inversion of the configuration in
the SN2 reaction that results in the closure of the cyclopropane
ring can, in theory, generate the trans and cis diastereomers,
depending on the configuration at 1-H. Each of these diastereo-
base-promoted Michael addition of activated methyl ketone 2 mers would form as a pair of enantiomers, i.e., (1R,1aS,7aR)/
onto the α,ꢀ-unsaturated carbonyl system of 3-bromochromo- (1S,1aR,7aS) and (1S,1aS,7aR)/(1R,1aR,7aS), respectively
nes 1, leading to a 3-bromochromanone intermediate. This in- (Scheme 4). Based on NMR spectroscopy and single-crystal X-
termediate contains a highly activated methylene group that ray diffraction studies, we were able to unequivocally show that
can be deprotonated to give the corresponding stabilized carb- the trans-configured cyclopropane ring had formed stereospe-
anion. This then undergoes an intramolecular SN2 nucleophilic cifically, as the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers.
substitution of the 3-bromo leaving group, resulting in closure These results were further confirmed by chiral HPLC analysis of
of the cyclopropane ring. This MIRC transformation requires the derivative 3c (Figure S43 in the Supporting Information).
Scheme 3. Proposed reaction mechanism for the synthesis of cyclopropa[b]chromanones 3a–3l.
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Scheme 4. Diastereoselective mechanistic aspects of the MIRC synthesis of trans-(1R,1aS,7aR)- and trans-(1S,1aR,7aS)-cyclopropa[b]chromanones 3.
Nuclear Magnetic Resonance Spectroscopy
in 3c. The compound crystallizes, however, in the centrosym-
metric monoclinic P21/c space group, meaning that the crystal
itself is made up of a racemic mixture of enantiomers. It is,
however, important to emphasize that the crystal-structure de-
termination shows that the distribution of the pair of enantio-
mers (1R,1aS,7aR)/(1S,1aR,7aS) is not regular in the crystal struc-
ture. In fact, because of the small geometrical differences be-
tween the two enantiomers, they can occupy the same crystal-
lographic space inside the unit cell: a simple rotation by ca.
180° of the chromanone ring transforms one enantiomer into
the other, with the two molecular entities occupying the same
volume in the crystal structure. This explains why the asymmet-
ric unit of the compound is made up of a racemic mixture of
the two enantiomers (1R,1aS,7aR)/(1S,1aR,7aS) with refined
22.6(4) and 77.4(4) % rates of occupancy, respectively (Figure 3).
The crystal packing of compound 3c is essentially governed
by the need to fill the available space, and by the presence of
a number of weak C–H···O hydrogen-bonding interactions: The
C···O distances range between 3.072(6) and 3.575(2) Å, with C–
1
The most important features of the H NMR spectra of the 1-
acetyl-, 1-benzoyl-, and 1-cinnamoyl-1a,7a-dihydrocyclo-
propa[b]chromen-7(1H)-ones 3a–3l are the three doublet of
doublets signals appearing at δH = 2.62–3.38, 2.83–3.19, and
4.71–4.95 ppm. These correspond to the 1-H, 7a-H, and 1a-H
protons of the cyclopropane ring, respectively, and form an
AMX or ABX spin pattern because of the asymmetric environ-
ment of the molecular unit. The assignment of carbon atoms
C-1 (δC = 24.6–28.9 ppm), C-7a (δC = 34.4–35.8 ppm), and C-1a
(δC = 63.5–65.2 ppm), which make up the cyclopropane moiety,
was straightforward using HSQC data, further supported by
HMBC cross-peak correlations, for all the prepared cyclo-
propa[b]chromanone compounds (i.e., 3a–3l). The main HMBC
connectivities of 1-H with C-1a and C-7, of 7a-H with C-1, C-6a,
C-7, and C-1′, and of 1a-H with C-2a and C-1′ were mostly ob-
served in all cases; the carbonyl groups 7-C=O (δC = 184.5–
186.7 ppm) and 1′-C=O (δC = 193.3–203.3 ppm) could be simply
differentiated by the HMBC correlation of 6-H, belonging to the
chromanone ring, with 7-C=O (Figure 2).
Figure 2. Main HMBC correlations of cyclopropa[b]chromanones 3a–3l.
Single-Crystal X-ray Diffraction
The crystal structure of 1-(4-methoxybenzoyl)-1a,7a-dihydrocy-
clopropa[b]chromen-7(1H)-one (3c) was unequivocally solved
through single-crystal X-ray diffraction studies. Compound 3c
was isolated as good-quality single crystals from a 1:1 mixture
of hexane/dichloromethane by slow concentration at 6 °C. The
crystal-structure determination revealed, as expected, the three
asymmetric carbon atoms that make up the cyclopropane ring
Figure 3. Schematic representation of the molecular unit present in the crys-
tal structure of compound 3c. Non-hydrogen atoms are represented as ther-
mal ellipsoids drawn at the 50 % probability level, and hydrogen atoms as
small spheres with arbitrary radius. Chiral carbon atoms are indicated by a
green asterisk, and the labelling is given for all non-hydrogen atoms. The
asymmetric unit is composed of a racemic mixture of the two enantiomers
(1R,1aS,7aR)/(1S,1aR,7aS) with refined 22.6(4) and 77.4(4) %, respectively, rates
of occupancy, resulting from the rotation of the chromanone ring.
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Scheme 5. Stereochemistry studies on the MIRC synthesis of 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers 6a–6c.
H···O angles in the range 113–155°. We note that the disordered from chiral HPLC analysis, which proved that neither one of the
packing of the pairs of enantiomers is ultimately facilitated by separated diastereomers of 6c was a meso form; as a result
the combined effects of (i) the absence in 3c of donor groups of the absence of symmetry in the molecule, for each of the
capable of inducing strong hydrogen-bonding interactions, and diastereomers the chromatogram showed two peaks with a 1:1
(ii) the fact that oxygen atoms – capable of forming weak inter- ratio, indicating a racemic mixture (Figures S46 and S47 in the
actions with neighboring C–H groups – are placed in similar Supporting Information).
positions for both of the enantiomeric forms in the disordered
crystal.
Conclusions
We have described the preparation of new cyclopropa[b]-
chromanone derivatives by a base-catalyzed Michael-initiated
Characterization of Dimers 6a–6c
1,1′-Carbonylbis(cyclopropa[b]chromanone) dimers 6a–6c were
characterized by NMR spectroscopy and HRMS. Both diastereo-
mers of the symmetric dimers 6a and 6b share identical cyclo-
propa[b]chromanone moieties, which appear in the 1H NMR
spectra as duplicated set of proton signals, easily observed for
the AMX spin systems 1-H/1′-H, 1a-H/1′a-H, and 7a-H/7′a-H.
NMR spectroscopic studies and single-crystal X-ray diffrac-
tion analysis showed that the cyclopropa[b]chromanone unit
exists as a (1R,1aS,7aR)/(1S,1aR,7aS) racemic mixture. Thus, the
MIRC reaction combines two identical units to give one dimer
(in 6a or 6b), kinetically producing a 1:1 mixture of two separa-
ble diastereomers including the meso form (1R,1aS,7aR)/(1′S,1′
aR,7′aS) and a racemic mixture of enantiomers (1R,1aS,7aR)/(1′
R,1′aS,7′aR) and (1S,1aR,7aS)/(1′S,1′aR,7′aS), as shown in
Scheme 5. For both 6a and 6b, the two diastereomers were
easily separated by preparative thin-layer chromatography and
then subjected to chiral HPLC analysis. This revealed the pres-
ence of a single meso form peak for one of the diastereomers,
and two peaks corresponding to a 1:1 racemic mixture for the
other (Figures S44 and S45 in the Supporting Information).
In the case of unsymmetrical dimer 6c, the NMR spectrum
shows a clear difference between the cyclopropa[b]chroma-
none and 4-methoxycyclopropa[b]chromanone moieties in
terms of the chemical shifts of the AMX spin systems attributed
ring-closure of methyl ketones with 3-bromochromones. The
reaction takes place under mild alkali-catalyzed conditions, and
allows a simple one-pot diastereoselective synthesis of trans-
cyclopropa[b]chromanones. The structures of the products were
established on the basis of NMR spectroscopic studies, and the
absolute configuration of the three asymmetric carbon atoms
of the cyclopropane was unambiguously determined by single-
crystal X-ray crystallography as a racemic mixture of enantio-
mers [(1R,1aS,7aR)/(1S,1aR,7aS)]. The prepared 1-acetyl-substi-
tuted cyclopropa[b]chromanones were used as Michael donors
to carry out MIRC reactions with different 3-bromochromones,
leading to mixtures of diastereomers of 1,1′-carbonylbis(cyclo-
propa[b]chromanone) dimers. Stereochemistry studies showed
that one of these dimers was a meso diastereomer.
Experimental Section
General Remarks: Melting points were measured with a Büchi
Melting Point B-540 apparatus. NMR spectra were recorded with a
Bruker AVANCE 300 spectrometer (300.13 MHz for 1H, and
75.47 MHz for 13C) or
a Bruker AVANCE 500 spectrometer
(500.13 MHz for 1H, and 125.77 MHz for 13C), in CDCl3 as solvent.
Chemical shifts (δ) are reported in ppm, and coupling constants (J)
in Hz; the internal standard was tetramethylsilane. Unequivocal 13C
to the cyclopropane protons. Further insight could be gained assignments were made with the aid of 2D gHSQC and gHMBC
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experiments (delays for one-bond and long-range C,H J couplings
34.5 (C-7a), 55.7 (4-OCH3), 63.9 (C-1a), 100.6 (C-3), 111.2 (C-5), 112.2
were optimized for 145 and 7 Hz, respectively). High-resolution (C-6a), 128.7 (C-6), 159.0 (C-2a), 166.1 (C-4), 185.0 (C-7), 203.3
mass spectra (HRMS, ESI+) were measured with a micrOTOF-Q 98 (C-1′) ppm. HRMS (ESI+): calcd. for [C13H12O4 + Na]+ 255.0633; found
spectrometer. Preparative thin-layer chromatography was carried 255.0642.
out with Macherey–Nagel silica gel G/UV254. All chemicals and sol-
Synthesis of Dimers 6a and 6b: Dimers 6a and 6b were obtained
vents were purchased from commercial sources, and were used as
received or dried by standard procedures. Chiral HPLC resolution of
enantiomers (d1 and d2) of derivative 3c, one diastereomer (d1) of
dimer 6a, both diastereomers of dimer 6c, and the meso form of a
second diastereomer of dimer 6a were carried out on a chiral sta-
tionary phase at 25 °C using a CHIRALCEL® OD column (particle size
10 μm, 250 × 4.6 mm i.d.). The mobile phase used was hexane/THF
[isocratic mode, 75:25 (v/v)] at a flow rate of 1.2 mL/min for 3c,
hexane/iPrOH [isocratic mode, 70:30 (v/v)] at a flow rate of 1.0 mL/
min for d1-6a and d1-6c, and hexane/EtOH [isocratic mode, 90:10
(v/v)] at a flow rate of 1.2 mL/min for d2-6c. The UV detector was
set at 254 nm. Samples were injected (20 μL volume, 0.5–1.0 g/L
concentration) in THF for 3c, or in THF/iPrOH (1:1) or THF/EtOH (1:1)
for 6a and 6c. Starting 3-bromo-4H-chromen-4-ones 1a and 1b
were prepared according to a method previously reported in the
literature.[29]
as by-products in the synthesis of 1-acetyl derivatives 3a and 3g
using the same procedure described above, but at room tempera-
ture. After a reaction time of a few hours (ca. 5 h), two diastereo-
mers of 1,1′-carbonylbis{1a,7a-dihydrocyclopropa[b]chromen-7(1H)-
one} (i.e., d1-6a and meso-6a, or d1-6b and meso-6b), together with
unreacted starting material (i.e., 1a or 1b) and product (i.e., 3a or
3g), were separated by preparative thin-layer chromatography us-
ing dichloromethane as eluent.
(1R/S,1aS/R,7aR/S,1′R/S,1′aS/R,7′aR/S)-1,1′-Carbonylbis{1a,7a-di-
hydrocyclopropa[b]chromen-7(1H)-one} (d1-6a): Yield: 3.8 mg
1
(5 %). M.p. 282–284 °C. H NMR (300.13 MHz, CDCl3): δ = 2.86 (dd,
J = 4.9, 2.6 Hz, 2 H, 1-H, 1′-H), 3.03 (dd, J = 6.8, 4.9 Hz, 2 H, 7a-H, 7′
a-H), 4.78 (dd, J = 6.8, 2.6 Hz, 2 H, 1a-H, 1′a-H), 6.96 (dd, J = 8.5,
0.9 Hz, 2 H, 3-H, 3′-H), 7.08 (ddd, J = 8.0, 7.2, 0.9 Hz, 2 H, 5-H, 5′-H),
7.50 (ddd, J = 8.5, 7.2, 1.8 Hz, 2 H, 4-H, 4′-H), 7.87 (dd, J = 8.0, 1.8 Hz,
2 H, 6-H, 6′-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 29.4 (C-1, C-
1′), 35.8 (C-7a, C-7′a), 64.2 (C-1a, C-1′a), 117.9 (C-3, C-3′), 118.5 (C-
6a, C-6′a), 122.8 (C-5, C-5′), 127.0 (C-6, C-6′), 136.3 (C-4, C-4′), 156.8
(C-2a, C-2′a), 185.7 (C-7, C-7′), 200.6 (C=O) ppm. MS (ESI+): m/z (%) =
369 (100) [M + Na]+, 347 (23) [M + H]+. HRMS (ESI+): calcd. for
[C21H14O5 + Na]+ 369.0739; found 369.0732.
3-Bromo-4H-chromen-4-one (1a): M.p. 96–97 °C (ref.[29] m.p. 95–
1
99 °C). H NMR (300.13 MHz, CDCl3): δ = 7.44–7.50 (m, 2 H, 6-H, 8-
H), 7.72 (ddd, J = 8.7, 7.1, 1.6 Hz, 1 H, 7-H), 8.24 (s, 1 H, 2-H), 8.28
(dd, J = 8.0, 1.6 Hz, 1 H, 5-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ =
110.7 (C-3), 118.1 (C-8), 123.1 (C-10), 125.9 (C-6), 126.5 (C-5), 134.2
(C-7), 153.8 (C-2), 156.1 (C-9), 172.3 (C-4) ppm.
(1R,1aS,7aR,1′S,1′aR,7′aS)-1,1′-Carbonylbis{1a,7a-dihydrocyclo-
propa[b]chromen-7(1H)-one} (meso-6a): Yield: 3.2 mg (4 %). M.p.
282–284 °C. 1H NMR (300.13 MHz, CDCl3): δ = 2.85 (dd, J = 4.8,
2.7 Hz, 2 H, 1-H, 1′-H), 2.98 (dd, J = 6.8, 4.8 Hz, 2 H, 7a-H, 7′a-H),
4.83 (dd, J = 6.8, 2.7 Hz, 2 H, 1a-H, 1′a-H), 6.97 (dd, J = 8.5, 0.9 Hz,
2 H, 3-H, 3′-H), 7.08 (ddd, J = 8.0, 7.2, 0.9 Hz, 2 H, 5-H, 5′-H), 7.50
(ddd, J = 8.5, 7.2, 1.8 Hz, 2 H, 4-H, 4′-H), 7.87 (dd, J = 8.0, 1.8 Hz, 2
H, 6-H, 6′-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 29.3 (C-1,
C-1′), 36.0 (C-7a, C-7′a), 63.9 (C-1a, C-1′a), 117.8 (C-3, C-3′), 118.6 (C-
6a, C-6′a), 122.9 (C-5, C-5′), 127.1 (C-6, C-6′), 136.2 (C-4, C-4′), 156.8
(C-2a, C-2′a), 185.3 (C-7, C-7′), 200.6 (C=O) ppm. MS (ESI+): m/z (%) =
369 (100) [M + Na]+, 347 (23) [M + H]+. HRMS (ESI+): calcd. for
[C21H14O5 + H]+ 347.0920; found 347.0912.
3-Bromo-7-methoxy-4H-chromen-4-one (1b): M.p. 180–182 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 3.92 (s, 1 H, 7-OCH3), 6.85 (d, J =
2.4 Hz, 1 H, 8-H), 7.02 (dd, J = 9.1, 2.4 Hz, 1 H, 6-H), 8.16 (s, 1 H, 2-
H), 8.17 (d, J = 9.1 Hz, 1 H, 5-H) ppm. 13C NMR (75.47 MHz, CDCl3):
δ = 55.9 (7-OCH3), 100.2 (C-8), 110.8 (C-3), 115.3 (C-6), 117.0 (C-10),
127.9 (C-5), 153.3 (C-2), 157.9 (C-9), 164.4 (C-7), 171.6 (C-4) ppm.
General Procedure for the Synthesis of 1-Acetyl-1a,7a-dihydro-
cyclopropa[b]chromen-7(1H)-ones 3a and 3g: 3-Bromochromone
1a or 1b (0.20 mmol) was dissolved in a mixture of acetone/THF
(1:1) (10 mL), and NaOH (60 % aq.; 1 drop per 50 mg of starting
material) was then added. The resulting reaction mixture was stirred
vigorously at reflux for 48 h. After this time, the reaction mixture
was poured into ice and water, and the pH was adjusted to ca. 1
with dilute HCl (10 % aq.). The desired compound was extracted
with dichloromethane (2 × 15 mL), and purified by preparative thin-
layer chromatography using dichloromethane/hexane (2:1) as elu-
ent.
(1R/S,1aS/R,7aR/S,1′R/S,1′aS/R,7′aR/S)-1,1′-Carbonylbis{4-meth-
oxy-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one} (d1-6b):
1
Yield: 4.0 mg (6 %). M.p. 282–284 °C. H NMR (300.13 MHz, CDCl3):
δ = 2.80 (dd, J = 4.9, 2.6 Hz, 2 H, 1-H, 1′-H), 2.95 (dd, J = 6.8, 4.9 Hz,
2 H, 7a-H, 7′a-H), 3.82 (s, 6 H, 4-OCH3, 4′-OCH3), 4.75 (dd, J = 6.8,
2.6 Hz, 2 H, 1a-H, 1′a-H), 6.38 (d, J = 2.4 Hz, 2 H, 3-H, 3′-H), 6.63 (dd,
J = 8.9, 2.4 Hz, 2 H, 5-H, 5′-H), 7.81 (d, J = 8.9 Hz, 2 H, 6-H, 6′-H)
ppm. 13C NMR (75.47 MHz, CDCl3): δ = 30.0 (C-1, C-1′), 35.1 (C-7a,
1-Acetyl-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one (3a):
Yield: 19.0 mg (47 %). M.p. 122–124 °C. 1H NMR (300.13 MHz, CDCl3):
δ = 2.36 (s, 3 H, 2′-CH3), 2.68 (dd, J = 4.8, 2.7 Hz, 1 H, 1-H), 2.90 (dd,
J = 6.8, 4.8 Hz, 1 H, 7a-H), 4.73 (dd, J = 6.8, 2.7 Hz, 1 H, 1a-H), 6.98 C-7′a), 55.8 (4-OCH3, 4′-OCH3), 64.6 (C-1a, C-1′a), 100.5 (C-3, C-3′),
(dd, J = 8.6, 0.9 Hz, 1 H, 3-H), 7.10 (ddd, J = 7.9, 7.2, 0.9 Hz, 1 H, 5-
H), 7.53 (ddd, J = 8.6, 7.2, 1.8 Hz, 1 H, 4-H), 7.90 (dd, J = 7.9, 1.8 Hz,
1 H, 6-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 28.2 (C-1), 31.4 (2′-
CH3), 35.2 (C-7a), 63.5 (C-1a), 117.8 (C-3), 118.6 (C-6a), 122.6 (C-5),
127.0 (C-6), 136.1 (C-4), 157.0 (C-2a), 186.2 (C-7), 203.1 (C-1′) ppm.
HRMS (ESI+): calcd. for [C12H10O3 + H]+ 203.0708; found 203.0704.
111.5 (C-5, C-5′), 112.1 (C-6a, C-6′a), 128.7 (C-6, C-6′), 158.9 (C-2a, C-
2′a), 166.2 (C-4, C-4′), 184.6 (C-7, C-7′), 201.0 (C=O) ppm. HRMS
(ESI+): calcd. for [C23H18O7 + Na]+ 429.0950; found 429.0945.
(1R,1aS,7aR,1′S,1′aR,7′aS)-1,1′-Carbonylbis{4-methoxy-1a,7a-di-
hydrocyclopropa[b]chromen-7(1H)-one} (meso-6b): Yield: 3.8 mg
(5.5 %). M.p. 275–277 °C. 1H NMR (500.13 MHz, CDCl3): δ = 2.79 (dd,
J = 4.9, 2.6 Hz, 2 H, 1-H, 1′-H), 2.91 (dd, J = 6.8, 4.9 Hz, 2 H, 7a-H, 7′
a-H), 3.82 (s, 6 H, 4-OCH3, 4′-OCH3), 4.80 (dd, J = 6.8, 2.6 Hz, 2 H,
1a-H, 1′a-H), 6.38 (d, J = 2.4 Hz, 2 H, 3-H, 3′-H), 6.64 (dd, J = 8.9,
2.4 Hz, 2 H, 5-H, 5′-H), 7.81 (d, J = 8.9 Hz, 2 H, 6-H, 6′-H) ppm. 13C
NMR (125.77 MHz, CDCl3): δ = 29.9 (C-1, C-1′), 35.3 (C-7a, C-7′a),
1-Acetyl-4-methoxy-1a,7a-dihydrocyclopropa[b]chromen-
7(1H)-one (3g): Yield: 15.8 mg (34 %). M.p. 158–159 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 2.35 (s, 3 H, 2′-CH3), 2.62 (dd, J = 4.8,
2.7 Hz, 1 H, 1-H), 2.83 (dd, J = 6.8, 4.8 Hz, 1 H, 7a-H), 3.84 (s, 3 H, 4-
OCH3), 4.71 (dd, J = 6.8, 2.7 Hz, 1 H, 1a-H), 6.40 (d, J = 2.4 Hz, 1 H,
3-H), 6.65 (dd, J = 8.9, 2.4 Hz, 1 H, 5-H), 7.84 (d, J = 8.9 Hz, 1 H, 6- 55.8 (4-OCH3, 4′-OCH3), 64.3 (C-1a, C-1′a), 100.6 (C-3, C-3′), 111.3 (C-
H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 28.9 (C-1), 31.4 (2′-CH3),
5, C-5′), 112.2 (C-6a, C-6′a), 128.8 (C-6, C-6′), 158.8 (C-2a, C-2′a), 166.1
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(C-4, C-4′), 184.2 (C-7, C-7′), 200.8 (C=O) ppm. HRMS (ESI+): calcd.
1-Benzoyl-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one (3b):
Yield: 40.2 mg (76 %). M.p. 166–167 °C. 1H NMR (300.13 MHz, CDCl3):
δ = 3.13 (dd, J = 6.7, 4.9 Hz, 1 H, 7a-H), 3.38 (dd, J = 4.9, 2.7 Hz, 1
H, 1-H), 4.91 (dd, J = 6.7, 2.7 Hz, 1 H, 1a-H), 7.03 (dd, J = 8.4, 0.9 Hz,
1 H, 3-H), 7.14 (td, J = 7.6, 0.9 Hz, 1 H, 5-H), 7.45–7.50 (m, 2 H, 4′-H,
6′-H), 7.53–7.63 (m, 2 H, 4-H, 5′-H), 7.92–7.97 (m, 3 H, 6-H, 3′-H, 7′-
H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 25.1 (C-1), 35.3 (C-7a),
64.3 (C-1a), 117.9 (C-3), 118.7 (C-6a), 122.7 (C-5), 127.2 (C-6), 128.3
(C-3′, C-7′), 128.8 (C-4′, C-6′), 133.8 (C-5′), 136.2 (C-4), 136.6 (C-2′),
157.2 (C-2a), 186.4 (C-7), 195.2 (C-1′) ppm. HRMS (ESI+): calcd. for
[C17H12O3 + Na]+ 287.0684; found 287.0681.
for [C23H18O7 + Na]+ 429.0950; found 429.0950.
General Procedure for the Synthesis of Dimers 6c: 1-Acetyl-
1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one (3a) (0.10 mmol)
and 3-bromo-7-methoxychromone (1b) (0.11 mmol) were dissolved
in THF (5 mL). NaOH (60 % aq.; 1 drop) was then added, and the
resulting reaction mixture was stirred vigorously at room tempera-
ture. After 18 h, the reaction mixture was poured into ice and water,
and the pH was adjusted to ca. 1 with dilute HCl (10 % aq.). The
resulting precipitate was collected by filtration, dissolved in di-
chloromethane, and purified by preparative thin-layer chromatogra-
phy using dichloromethane/ethyl acetate (9:1) as eluent. Two prod-
ucts were separated, which were identified as two diastereomers of
4-methoxy-1-[(7-oxo-1,1a,7,7a-tetrahydrocyclopropa[b]chromen-1-
yl)carbonyl]-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one (d1-6c
and d2-6c).
1-(4-Methoxybenzoyl)-1a,7a-dihydrocyclopropa[b]chromen-
7(1H)-one (3c): Yield: 12.9 mg (22 %). M.p. 128–129 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 3.09 (dd, J = 6.7, 4.9 Hz, 1 H, 7a-H), 3.32
(dd, J = 4.9, 2.7 Hz, 1 H, 1-H), 3.87 (s, 3 H, 5′-OCH3), 4.89 (dd, J =
6.7, 2.7 Hz, 1 H, 1a-H), 6.93 (d, J = 9.0 Hz, 2 H, 4′-H, 6′-H), 7.02 (dd,
J = 8.5, 0.9 Hz, 1 H, 3-H), 7.13 (ddd, J = 8.0, 7.3, 0.9 Hz, 1 H, 5-H),
7.55 (ddd, J = 8.5, 7.3, 1.8 Hz, 1 H, 4-H), 7.91 (d, J = 9.0 Hz, 2 H, 3′-
H, 7′-H), 7.95 (dd, J = 8.0, 1.8 Hz, 1 H, 6-H) ppm. 13C NMR (75.47 MHz,
CDCl3): δ = 24.6 (C-1), 35.1 (C-7a), 55.6 (5′-OCH3), 64.1 (C-1a), 114.0
(C-4′, C-6′), 117.9 (C-3), 118.7 (C-6a), 122.6 (C-5), 127.1 (C-6), 129.6
(C-2′), 130.6 (C-3′, C-7′), 136.1 (C-4), 157.3 (C-2a), 164.1 (C-5′), 186.7
(C-7), 193.3 (C-1′) ppm. HRMS (ESI+): calcd. for [C18H14O4 + Na]+
317.0790; found 317.0792.
4-Methoxy-1-[(7-oxo-1,1a,7,7a-tetrahydrocyclopropa[b]-
chromen-1-yl)carbonyl]-1a,7a-dihydrocyclopropa[b]chromen-
1
7(1H)-one (d1-6c): Yield: 13.5 mg (36 %). M.p. 234–235 °C. H NMR
(500.13 MHz, CDCl3): δ = 2.81 (dd, J = 4.9, 2.6 Hz, 1 H, 1-H), 2.85
(dd, J = 4.9, 2.6 Hz, 1 H, 1′-H), 2.96 (dd, J = 6.9, 4.9 Hz, 1 H, 7a-H),
3.02 (dd, J = 6.9, 4.9 Hz, 1 H, 7′a-H), 3.82 (s, 3 H, 4-OCH3), 4.76 (dd,
J = 6.9, 2.6 Hz, 1 H, 1a-H), 4.77 (dd, J = 6.9, 2.6 Hz, 1 H, 1′a-H), 6.37
(d, J = 2.4 Hz, 1 H, 3-H), 6.63 (dd, J = 8.9, 2.4 Hz, 1 H, 5-H), 6.97 (dd,
J = 8.6, 0.9 Hz, 1 H, 3′-H), 7.08 (ddd, J = 8.0, 7.3, 0.9 Hz, 1 H, 5′-H),
7.50 (ddd, J = 8.6, 7.3, 1.8 Hz, 1 H, 4′-H), 7.81 (d, J = 8.9 Hz, 1 H, 6-
H), 7.88 (dd, J = 8.0, 1.8 Hz, 1 H, 6′-H) ppm. 13C NMR (125.77 MHz,
CDCl3): δ = 29.4 (C-1′), 30.1 (C-1), 35.2 (C-7a), 35.8 (C-7′a), 55.8 (4-
OCH3), 64.2 and 64.6 (C-1a, C-1′a), 100.5 (C-3), 111.5 (C-5), 112.1 (C-
6a), 117.9 (C-3′), 118.5 (C-6′a), 122.8 (C-5′), 127.0 (C-6′), 128.7 (C-6),
136.3 (C-4′), 156.9 (C-2′a), 158.9 (C-2a), 166.2 (C-4), 184.5 (C-7), 185.8
(C-7′), 200.7 (C=O) ppm. HRMS (ESI+): calcd. for [C22H16O6 + Na]+
399.0845; found 399.0859.
1-(4-Chlorobenzoyl)-1a,7a-dihydrocyclopropa[b]chromen-
7(1H)-one (3d): Yield: 49.6 mg (83 %). M.p. 149–151 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 3.12 (dd, J = 6.7, 4.9 Hz, 1 H, 7a-H), 3.31
(dd, J = 4.9, 2.7 Hz, 1 H, 1-H), 4.90 (dd, J = 6.7, 2.7 Hz, 1 H, 1a-H),
7.03 (dd, J = 8.5, 0.9 Hz, 1 H, 3-H), 7.14 (ddd, J = 8.0, 7.3, 0.9 Hz, 1
H, 5-H), 7.45 (d, J = 8.8 Hz, 2 H, 4′-H, 6′-H), 7.56 (ddd, J = 8.5, 7.3,
1.8 Hz, 1 H, 4-H), 7.87 (d, J = 8.7 Hz, 2 H, 3′-H, 7′-H), 7.95 (dd, J =
8.0, 1.8 Hz, 1 H, 6-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 25.0
(C-1), 35.4 (C-7a), 64.4 (C-1a), 118.0 (C-3), 118.6 (C-6a), 122.7 (C-5),
127.2 (C-6), 129.2 (C-4′, C-6′), 129.7 (C-3′, C-7′), 134.8 (C-2′), 136.3
(C-4), 140.4 (C-5′), 157.2 (C-2a), 186.2 (C-7), 194.0 (C-1′) ppm. HRMS
(ESI+): calcd. for [C17H11ClO3 + H]+ 299.0475; found 299.0468.
4-Methoxy-1-[(7-oxo-1,1a,7,7a-tetrahydrocyclopropa[b]-
chromen-1-yl)carbonyl]-1a,7a-dihydrocyclopropa[b]chromen-
1
7(1H)-one (d2-6c): Yield: 13.7 mg (36 %). M.p. 275–277 °C. H NMR
(300.13 MHz, CDCl3): δ = 2.80 (dd, J = 4.9, 2.7 Hz, 1 H, 1-H), 2.85
(dd, J = 4.8, 2.7 Hz, 1 H, 1′-H), 2.91 (dd, J = 6.8, 4.9 Hz, 1 H, 7a-H),
2.98 (dd, J = 6.8, 4.8 Hz, 1 H, 7′a-H), 3.82 (s, 3 H, 4-OCH3), 4.81 (dd,
J = 6.8, 2.7 Hz, 1 H, 1a-H), 4.82 (dd, J = 6.8, 2.7 Hz, 1 H, 1′a-H), 6.38
(d, J = 2.4 Hz, 1 H, 3-H), 6.63 (dd, J = 8.9, 2.4 Hz, 1 H, 5-H), 6.97 (dd,
J = 8.5, 0.9 Hz, 1 H, 3′-H), 7.08 (ddd, J = 8.0, 7.3, 0.9 Hz, 1 H, 5′-H),
7.50 (ddd, J = 8.5, 7.3, 1.7 Hz, 1 H, 4′-H), 7.80 (d, J = 8.9 Hz, 1 H, 6-
H), 7.87 (dd, J = 8.0, 1.7 Hz, 1 H, 6′-H) ppm. 13C NMR (75.47 MHz,
CDCl3): δ = 29.3 (C-1′), 29.9 (C-1), 35.3 (C-7a), 35.9 (C-7′a), 55.8 (4-
OCH3), 63.9 and 64.3 (C-1a, C-1′a), 100.6 (C-3), 111.3 (C-5), 112.1 (C-
6a), 117.8 (C-3′), 118.6 (C-6′a), 122.8 (C-5′), 127.1 (C-6′), 128.8 (C-6),
136.2 (C-4′), 156.8 (C-2′a), 158.8 (C-2a), 166.1 (C-4), 184.1 (C-7), 185.3
(C-7′), 200.7 (C=O) ppm. HRMS (ESI+): calcd. for [C22H16O6 + H]+
377.1025; found 377.1029.
1-(4-Nitrobenzoyl)-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-
one (3e): Yield: 58.1 mg (94 %). M.p. 194–195 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 3.19 (dd, J = 6.8, 4.9 Hz, 1 H, 7a-H), 3.36
(dd, J = 4.9, 2.6 Hz, 1 H, 1-H), 4.95 (dd, J = 6.8, 2.6 Hz, 1 H, 1a-H),
7.05 (dd, J = 8.6, 0.8 Hz, 1 H, 3-H), 7.16 (ddd, J = 8.0, 7.1, 0.8 Hz, 1
H, 5-H), 7.59 (ddd, J = 8.6, 7.1, 1.8 Hz, 1 H, 4-H), 7.97 (dd, J = 8.0,
1.8 Hz, 1 H, 6-H), 8.10 (d, J = 9.0 Hz, 2 H, 3′-H, 7′-H), 8.32 (d, J =
9.0 Hz, 2 H, 4′-H, 6′-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 25.7
(C-1), 35.8 (C-7a), 64.8 (C-1a), 118.0 (C-3), 118.5 (C-6a), 123.0 (C-5),
124.0 (C-4′, C-6′), 127.2 (C-6), 129.3 (C-3′, C-7′), 136.5 (C-4), 140.9 (C-
2′), 150.6 (C-5′), 157.1 (C-2a), 185.7 (C-7), 194.1 (C-1′) ppm. HRMS
(ESI+): calcd. for [C17H11NO5 + H]+ 310.0715; found 310.0699.
1-Cinnamoyl-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-one
1
General Procedure for the Synthesis of 1-Benzoyl- and 1-Cinn-
(3f): Yield: 34.8 mg (60 %). M.p. 189–190 °C. H NMR (300.13 MHz,
amoyl-1a,7a-dihydrocyclopropa[b]chromen-7(1H)-ones 3b–3f
CDCl3): δ = 2.97 (dd, J = 4.8, 2.8 Hz, 1 H, 1-H), 3.03 (dd, J = 6.7,
and 3h–3l: 3-Bromochromone 1a or 1b (0.20 mmol) and the appro- 4.8 Hz, 1 H, 7a-H), 4.85 (dd, J = 6.7, 2.8 Hz, 1 H, 1a-H), 6.87 (d, J =
priate ketone compound 2b–2f (0.22 mmol) were dissolved in THF
(10 mL). NaOH (60 % aq.; 1 drop per 50 mg of starting material)
was then added, and the resulting reaction mixture was stirred vig-
orously at room temperature. After TLC had revealed the full con-
sumption of the starting material, the reaction mixture was poured
into ice and water, and the pH was adjusted to ca. 1 with dilute
HCl (10 % aq.). The resulting precipitate was collected by filtration,
dissolved in dichloromethane, and purified by preparative thin-layer
chromatography using dichloromethane/hexane (2:1) as eluent.
16.1 Hz, 1 H, α-H), 7.02 (dd, J = 8.4, 0.9 Hz, 1 H, 3-H), 7.13 (td, J =
7.8, 0.9 Hz, 1 H, 5-H), 7.37–7.44 (m, 3 H, 4′-H, 5′-H, 6′-H), 7.52–7.58
(m, 3 H, 4-H, 3′-H, 7′-H), 7.60 (d, J = 16.1 Hz, 1 H, ꢀ-H), 7.95 (dd, J =
7.8, 1.7 Hz, 1 H, 6-H) ppm. 13C NMR (125.77 MHz, CDCl3): δ = 27.1
(C-1), 35.3 (C-7a), 64.1 (C-1a), 117.9 (C-3), 118.7 (C-6a), 122.6 (C-5),
125.6 (C-α), 127.1 (C-6), 128.6 (C-3′, C-7′), 129.1 (C-4′, C-6′), 131.1 (C-
5′), 134.0 (C-2′), 136.1 (C-4), 144.2 (C-ꢀ), 157.2 (C-2a), 186.5 (C-7),
194.3 (C-1′) ppm. HRMS (ESI+): calcd. for [C19H14O3 + Na]+ 313.0841;
found 313.0841.
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1-Benzoyl-4-methoxy-1a,7a-dihydrocyclopropa[b]chromen-
7(1H)-one (3h): Yield: 48.3 mg (82 %). M.p. 208–210 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 3.05 (dd, J = 6.7, 4.9 Hz, 1 H, 7a-H), 3.33
(dd, J = 4.9, 2.7 Hz, 1 H, 1-H), 3.86 (s, 3 H, 4-OCH3), 4.89 (dd, J = 6.7,
2.7 Hz, 1 H, 1a-H), 6.45 (d, J = 2.4 Hz, 1 H, 3-H), 6.69 (dd, J = 8.9,
2.4 Hz, 1 H, 5-H), 7.45–7.50 (m, 2 H, 4′-H, 6′-H), 7.60 (tt, J = 7.4,
1.6 Hz, 1 H, 5′-H), 7.89 (d, J = 8.9 Hz, 1 H, 6-H), 7.92–7.95 (m, 2 H,
3′-H, 7′-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 25.7 (C-1), 34.7
(C-7a), 55.8 (4-OCH3), 64.7 (C-1a), 100.6 (C-3), 111.3 (C-5), 112.3 (C-
6a), 128.3 (C-3′, C-7′), 128.78 (C-4′, C-6′), 128.84 (C-6), 136.6 (C-2′),
159.2 (C-2a), 166.1 (C-4), 185.3 (C-7), 195.3 (C-1′) ppm. HRMS (ESI+):
calcd. for [C18H14O4 + H]+ 295.0970; found 295.0968.
Acknowledgments
Thanks are due to the Fundação para a Ciência e a Tecnologia
(FCT)/Ministério da Educação e Ciência (MEC) for their financial
support of the QOPNA Research Unit (FCT No. UID/QUI/00062/
2013) and of the project CICECO–Aveiro Institute of Materials
(FCT No. UID/CTM/50011/2013) with national funding; co-fi-
nancing, where applicable, came from the Fundo Europeu de
Desenvolvimento Regional (FEDER), within the PT2020 Partner-
ship Agreement. We also thank the Portuguese NMR Network.
We would like to thank the General Directorate for Scientific
Research and Technological Development (DGRSDT) of Algeria
for financial support. We further wish to thank CICECO for fund-
ing the purchase of the single-crystal X-ray diffractometer.
J. L. C. S. and R. F. M. are grateful to the Fundação para a Ciência
e a Tecnologia (FCT) for their PhD grants (SFRH/BD/76407/2011
and SFRH/BD/84231/2012, respectively).
4-Methoxy-1-(4-methoxybenzoyl)-1a,7a-dihydrocyclopropa-
[b]chromen-7(1H)-one (3i): Yield: 29.8 mg (46 %). M.p. 165–167 °C.
1H NMR (300.13 MHz, CDCl3): δ = 3.00 (dd, J = 6.7, 4.9 Hz, 1 H, 7a-
H), 3.28 (dd, J = 4.9, 2.7 Hz, 1 H, 1-H), 3.85 (s, 3 H, 4-OCH3), 3.86 (s,
3 H, 5′-OCH3), 4.86 (dd, J = 6.7, 2.7 Hz, 1 H, 1a-H), 6.44 (d, J = 2.4 Hz,
1 H, 3-H), 6.67 (dd, J = 8.9, 2.4 Hz, 1 H, 5-H), 6.93 (d, J = 9.0 Hz, 2
H, 4′-H, 6′-H), 7.87 (d, J = 8.9 Hz, 1 H, 6-H), 7.91 (d, J = 9.0 Hz, 2 H,
3′-H, 7′-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 25.2 (C-1), 34.4
(C-7a), 55.6 (5′-OCH3), 55.7 (4-OCH3), 64.5 (C-1a), 100.6 (C-3), 111.2
(C-5), 112.3 (C-6a), 113.9 (C-4′, C-6′), 128.8 (C-6), 129.6 (C-2′), 130.6
(C-3′, C-7′), 159.3 (C-2a), 164.0 (C-5′), 166.1 (C-4), 185.5 (C-7), 193.5
(C-1′) ppm. HRMS (ESI+): calcd. for [C19H16O5 + H]+ 325.1076; found
325.1073.
Keywords: Oxygen heterocycles · Cyclopropanes · Small
ring systems · Fused-ring systems · Michael addition ·
Cyclization
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Received: April 3, 2016
Published Online: ■
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Cyclopropa[b]chromanones
J. L. C. Sousa, O. Talhi,*
R. F. Mendes, F. A. Almeida Paz,
K. Bachari, A. M. S. Silva* ............. 1–11
Catalytic One-Pot Diastereoselective
Michael-Initiated Ring-Closure of
Methyl Ketones with 3-Bromochro-
mones: Synthesis of Cyclopropa-
[b]chromanones
A
one-pot diastereoselective base- propa[b]chromanones undergo a con-
catalyzed Michael-initiated ring clo- secutive MIRC reaction with a second
sure (MIRC) of activated methyl ket- molecule of 3-bromochromone to give
ones with 3-bromochromones to give the first described 1,1′-carbonylbis(cy-
cyclopropa[b]chromanones is de- clopropa[b]chromanone) dimers as a
scribed. 1-Acetyl-substituted cyclo- meso form.
DOI: 10.1002/ejoc.201600413
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