1,6-Conjugate addition of carbon nucleophiles to (E)-2-Styrylchromones: Unexpected synthesis of a stereochemically complex pentasubstituted spirocyclohexane

Article abstract of DOI:10.1055/s-0033-1340043

The regioselective 1,6-conjugate addition of ethyl malonate and malononitrile to (E)-2-styrylchromones is described. A synthesis of novel pentasubstituted spirocyclohexanes discovered during the course of these studies is also discussed. A novel domino multicomponent 1,6-/1,6-/1,4-conjugate addition reaction for the formation of these new spirocyclohexanes is proposed. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340043

LETTER
▌2375
letter
1,6-Conjugate Addition of Carbon Nucleophiles to (E)-2-Styrylchromones:
Unexpected Synthesis of a Stereochemically Complex Pentasubstituted Spiro-
cyclohexane
1,6-Conjugate Addition of Nucleophiles to (E)-2-Styrylchromones
Eduarda M. P. Silva,* Kinga Grenda, Inês N. Cardoso, Artur M. S. Silva*
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370714; E-mail: eduarda.silva@ua.pt; E-mail: artur.silva@ua.pt
Received: 26.07.2013; Accepted after revision: 30.09.2013
Abstract: The regioselective 1,6-conjugate addition of ethyl malo-
nate and malononitrile to (E)-2-styrylchromones is described. A
synthesis of novel pentasubstituted spirocyclohexanes discovered
during the course of these studies is also discussed. A novel domino
multicomponent 1,6-/1,6-/1,4-conjugate addition reaction for the
formation of these new spirocyclohexanes is proposed.
Key words: heterocycles, polycycles, nucleophilic additions, addi-
tion reactions, spiro compounds, domino reactions, multicompo-
nent reactions
Eduarda M. P. Silva (far right) studied at the University of Aveiro
(Portugal) and joined the group of Professor J. A. S. Cavaleiro after
her studies to work on the synthesis and structural characterization of
new porphyrin derivatives with suitable physicochemical and biolog-
ical properties for medicinal applications. She then studied for her
The conjugate addition of carbon nucleophiles to accep-
tor-substituted double and triple bonds is one of the oldest
and most useful carbon–carbon bond-forming reactions.1
The importance of this addition process in organic synthe-
Ph.D. under the guidance of Professor Laurence Harwood at the Uni-
sis has led to the development of many asymmetric cata-
lytic versions of the reaction. The field of asymmetric
organocatalytic 1,4-additions has received widespread at-
tention, whereas the analogous 1,6-additions are some-
what less well developed.2 The presence of several
electrophilic sites in these extended conjugated systems
and the resulting difficulties in controlling the regioselec-
tivity explain the scarcity of investigations on this topic.
The rapid growth of interest in the development of meth-
odologies for 1,6-conjugate addition of nucleophiles to
α,β:γ,δ-diunsaturated systems emphasizes the signifi-
cance of this type of reaction. However, serious limita-
tions on the control of electronic and steric factors in the
diunsaturated systems have slowed down the develop-
ment of their conjugate addition reactions, and only in re-
cent years has this research field gained a new impetus
with the development of new metal–chiral catalyst sys-
tems and metal–organocatalysts systems. In particular,
such combinations have been efficiently adopted in the
challenging 1,6-addition of aryl groups to δ-aryl-α,β:γ,δ-
diunsaturated ketones.3 Nevertheless, these methodolo-
gies are restricted with respect to their substrate scope
and, in each case, it is necessary to fine tune all the condi-
tions, including the solvent, the reaction temperature, the
metal catalyst, and the ligand. Such investigations are
time- and resource-consuming, and new methods are
therefore required. Several nucleophilic species capable
of undergoing 1,6-conjugate additions to α,β:γ,δ-diunsat-
versity of Reading (UK). The work was concerned with the total syn-
thesis of mycaperoxide B by means of an intramolecular Michael
addition of a hydroperoxide to an adjacent α,β-unsaturated carboxylic
acid or ester to permit the formation of the cyclic peroxide moiety that
is present in the mycaperoxide family. She finished her studies in
2009 and joined the group of Professor Artur M. S. Silva (second
from right) at the University of Aveiro (Portugal) as a postdoctoral re-
searcher. Her research interests now include asymmetric catalysis,
stereochemistry, the 1,6-conjugated addition of nucleophiles to elec-
tron-deficient diene systems, the chemistry of nitrogen heterocyclic
compounds, and structural characterizations by NMR and mass spec-
trometry.
urated carbonyl systems have been reported.2a These in-
clude C-nucleophiles such as arylboroxines,3,4 boronic
acids and their esters,5 malonates,6 organometallic re-
agents,7 aldehydes,8 β-keto esters,9 anthrone,10 cyanide,7h
and nitroalkanes,11 as well as N-nucleophiles6 and S-nu-
cleophiles.6
(E)-2-Styrylchromones are a group of oxygen-containing
heterocyclic compounds that, because of their wide range
of biological activities, play an important role in the de-
velopment of many new drugs. Although these ring sys-
tems are found in natural products (Figure 1),12 the
majority are of synthetic origin.13 The most-explored bio-
logical properties of (E)-2-styrylchromones include their
antimicrobial, antiviral, antiallergic, and antioxidant ac-
tivities; their use as xanthine oxidase inhibitors; and their
behavior as antagonists of the A3 adenosine receptor.14
The need to develop more-potent and more-selective anti-
oxidants, antiinflammatory agents, and antitumor agents,
and to overcome multidrug resistance, means that such
compounds have become very important targets. There-
SYNLETT 2013, 24, 2375–2382
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DOI: 10.1055/s-0033-1340043; Art ID: ST-2013-D0704-L
© Georg Thieme Verlag Stuttgart · New York

2376
E. M. P. Silva et al.
LETTER
fore, our group considered compounds of this family to be chromones (Scheme 1). To investigate the reactivities of
important substrates for several synthetic transformations, chromone 5a in conjugate addition reactions with ethyl
especially their 1,6-conjugate addition reactions with nu- malonate and with malononitrile, we first examined the
cleophiles.15
effects of several amine bases, namely piperidine, 1,8-di-
azabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]-
non-5-ene, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene. We
also examined the effects of stronger bases, such as sodi-
um ethoxide and sodium hydride.
OH
OMe
MeO
OH
O
O
With respect to the 1,6-conjugate addition of ethyl malo-
nate to chromone 5a, the best results were obtained by us-
ing of a strong base such as sodium ethoxide in dry
ethanol, and the desired product 7a17 was obtained after
three hours at room temperature in 52% yield (Table 1,
entry 1). After this period, some starting material re-
mained in the reaction mixture (45% of chromone 5a was
recovered); however, increasing the reaction time did not
produce a greater yield. The formation of ester 7a was
demonstrated by the presence of signals for diastereotopic
α-protons (see Scheme 1 for numbering) in the NMR
spectrum at δ = 3.19 and 2.92 ppm. Also, the presence of
a multiplet at δ = 3.99–3.94 ppm and a doublet at δ = 3.80
ppm, corresponding to the H-β and CH(CO2Et)2 protons,
respectively, revealed the exclusive 1,6-addition of the
ethyl malonate moiety to the α,β:γ,δ-diunsaturated car-
bonyl system.
O
O
R
Me
OH
OH
R = OMe hormothamnione (1)
R = H 6-demethoxyhormothamnione (2)
5-hydroxy-2-styrylchromone (3)
OH
OMe
O
HO
O
6-hydroxy-2-[2-(4-hydroxy-3-methoxy-
phenyl)ethenyl]chromone (4)
Figure 1 Natural (E)-2-styrychromones
We then extended this protocol to the 1,6-conjugate addi-
tion reactions of other (E)-2-styrylchromones 5b–d with
ethyl malonate in the presence of a catalytic amount of so-
dium ethoxide as the base. The corresponding derivatives
7b–d were obtained in poor to moderate yields (Scheme
1, Table 1). The introduction of a nitro group at the para
position of ring B clearly diminishes the reactivity to-
wards the 1,6-conjugate additions of ethyl malonate. The
reaction of chromone 5c with ethyl malonate in the pres-
ence of sodium ethoxide in dry ethanol at room tempera-
ture gave the desired product 7c in only 8% yield, with no
recovery of the starting material 5c (entry 3).
The first examples of 1,6-conjugate addition of carbon nu-
cleophiles to (E)-2-styrylchromones were recently de-
scribed by our group. The successful 1,6-conjugate
addition of nitromethane to (E)-2-styrylchromones was
carried out in the presence of a catalytic amount of 1,8-di-
azabicyclo[5.4.0]undec-7-ene (Scheme 1). Exclusive 1,6-
addition of the nitromethane group to the α,β:γ,δ-diunsat-
urated carbonyl system was observed, and the desired
products 6a–d were obtained in good yields (72–84%).16
R1
R1
R3
B
We also carried out a similar systematic study with malo-
nonitrile as the nucleophile. Of the bases tested in the con-
jugate addition reaction of malononitrile with chromone
5a (Scheme 1), the best results were obtained by using pi-
peridine in refluxing dry ethanol. Under these conditions,
the desired product 8a18 was obtained after three days in
53% yield (Table 1, entry 5). After this period, some start-
ing material was still present in the reaction mixture (17%
of compound 5a was recovered). Increasing the reaction
time did not lead to a greater yield. Surprisingly, however,
an additional new product was detected as a new spot with
the lowest Rf value in thin-layer chromatography with a
7:3 mixture of hexane and ethyl acetate as the eluent.
NMR analysis revealed that this new product, 9a,19 ob-
tained in 23% yield, was formed by addition of malonitrile
at the α-carbon atom of chromone 5a. This showed that,
under the conditions studied and with malonitrile as the
nucleophile, poor propagation of the electronic effect of
the carbonyl group through the conjugated system occurs,
resulting in charge delocalization over the α- and β-carbon
atoms. A similar situation has been reported previously in
R2
O
β
8
O
O
9
α
R2CH2R3
base
7
6
2
3
A
5
C
10
O
5
6 R2 = H, R3 = NO2
7 R2 = R3 = CO2Et
8 R2 = R3 = CN
R1
a = R1 = H
b = R1 = OMe
c = R1 = NO2
d = R1 = Cl
O
O
CN
CN
9
Scheme 1 1,6-Conjugate additions of nitromethane (6), ethyl malo-
nate (7), and malononitrile (8) to (E)-2-styrylchromones 5a–d
Following this work, we also studied the addition reac-
tions of ethyl malonate and malononitrile to (E)-2-styryl-
Synlett 2013, 24, 2375–2382
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,6-Conjugate Addition of Nucleophiles to (E)-2-Styrylchromones
2377
Table 1 1,6-Conjugate Additions of Ethyl Malonate and Malononitrile to (E)-2-Styrylchromones 5a–d
Entrya
R1
R2
Base (equiv)
Time
Product
Yieldb (%) Recovery (%) of 5
1
2
3
4
5
6
7
8
H
CO2Et
CO2Et
CO2Et
CO2Et
CN
NaOEt (0.4)
3 h
2 d
3 d
4 d
3 d
4 d
4 d
4 d
7a
7b
7c
7d
8a
8b
8c
8d
52
45
8
45
44
–
OMe
NO2
Cl
NaOEt (0.4)
NaOEt (0.4)
NaOEt (0.4)
54
53
23
20
14
12
17
46
69c
13
H
piperidine (0.1)
piperidine (0.1)
piperidine (0.1)
piperidine (0.1)
OMe
NO2
Cl
CN
CN
CN
a All reactions were performed in EtOH.
b Yield of isolated products after purification.
c Compound 5c was only slight soluble in EtOH. The starting material was recovered from the crude mixture by filtration.
Ph
relation to the 1,3-dipolar cycloaddition of diazomethane
to (E)-2-styrylchromones.20
O
We next examined the scope of the 1,6-conjugate addi-
tions of malononitrile with (E)-2-styrylchromones in the
presence of a catalytic amount of piperidine as the chosen
O
base. The formation of products 8a–d was, once more, de-
5a
pendent on the nature of the substituents on the B-ring of
the starting materials 5a–d (Table 1, entries 5–8). Com-
pound 5a, with no substituent present, was the most reac-
MeNO2
DBU
EtOH
NO2
NO2
tive (entry 5). The presence of a substituent in the para-
position of ring B resulted, once more, in poor reactivity
towards the 1,6-conjugate additions of malononitrile (en-
tries 6–8). Chromones 5b–d also gave the corresponding
α-malononitrile products 9b–d in yields of between 2%
(9c) and 12% (9d).
Ph
Ph
O
Ph
O
O
O
+
O
O
The formation of the α-malononitrile products 9a–d in-
trigued us, because this reaction had not been observed
during the procedures developed for 1,6-conjugate addi-
tion of the other nucleophiles, nitromethane16 and ethyl
malonate. We therefore decided to study the addition of
nitromethane to compound 5a by using piperidine as the
base in refluxing dry ethanol. No reaction was observed
under these conditions, and 86% of the starting material
was recovered. We then used 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (0.2 equiv) as the base and, interestingly, under
these conditions, a new product was formed along with
the expected 1,6-conjugate addition product 6a. This new
product had a lower but very similar Rf value to that of 6a.
After two days, and with no apparent progress in the reac-
tion, we decided to proceed with purification of the crude
mixture. Careful purification gave the new product in a
pure form as a yellow solid; unreacted starting material
was recovered in 42% yield, and compound 6a was ob-
tained in 9% yield. Unequivocal 1H NMR assignments for
the new product by COSY, HSQC, HMBC, and NOESY
experiments showed that it was the pentasubstituted
cyclohexane 10a21 (Scheme 2).
6a
10a
Scheme 2 Reaction of chromone 5a with nitromethane in refluxing
dry ethanol containing 1,8-diazabicyclo[5.4.0]undec-7-ene
1
The H NMR spectrum of compound 10a showed one
broad singlet at δ = 6.36 ppm, assigned to the H-3′′ proton
resonance of the chromone moiety (see Figure 2 for num-
bering). Diagnostic of 10a were the signals assigned to the
H-4 and H-3 protons resonance at δ = 5.04 (t, J = 12.4 Hz)
and δ = 4.47 ppm (br t, J = 12.4 Hz), respectively. Also,
the presence of three doublets at δ = 3.25 (J = 12.4 Hz),
3.04 (J = 16.6 Hz), and 2.69 ppm (J = 16.6 Hz), assigned
to the H-2 and the two H-9′ protons, respectively, support-
ed the proposed structure for 10a.
The relative stereochemistry of compound 10a was as-
signed by analysis of 1H–1H coupling constants of the cy-
clohexane ring and from the NOESY spectrum; these
confirmed the relative configuration of all the neighboring
substituents (Figure 2). The NOESY spectrum of 10a
showed a correlation between H-2 and H-4, supporting a
cis-configuration for these two protons. Also, the NOE
experiments revealed a correlation between proton H-3
and H-5, also pointing to a cis-configuration for these two
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2375–2382

2378
E. M. P. Silva et al.
LETTER
conditions described above for five days. However, a sim-
ilar yield of 10a (9%) was obtained, with recovery of 52%
of the starting material 5a. Furthermore, the use of 0.4
equivalents of base had no significant effect on the yield
of 10a. On the basis of our work on the diastereoselective
synthesis of pentasubstituted cyclohexanes under phase-
transfer catalysis,15a we decided to apply that method to
the preparation of 10a. The results and conditions used in
this study are collected in Table 2. The first experiment
was carried out by using one equivalent of cesium carbon-
ate, 0.5 equivalents of nitromethane, and 0.4 equivalents
of tetrabutylammonium bromide with a reaction time of
24 hours (Table 2, entry 1). This gave three products
(Scheme 3). The mixture was purified by preparative thin-
layer chromatography with a 7:3 mixture of hexane and
ethyl acetate as eluent, and the three fractions were sepa-
rated. Two new unknown products had been formed, and
no starting material 5a was recovered. The second frac-
tion collected corresponded to the previously described
cyclohexane 10a, obtained in a poor (9%) yield. To con-
firm that no degradation of the products had occurred dur-
ing purification, the yields shown in entry 2 were
O
NO2
H
9'
2
HB
H
5
4
5
6
3
2
1
Ph
6
O
Cr
3
O
O
1
NO2
4
H6A
(2.01 ppm)
9'
HA
O
Ph
3''
H
H
O
J6B–6A = 14.4 Hz
J6B–5 = 3.6 Hz
J6A–5 = 12.4 Hz
J5–4 = 12.4 Hz
J2–3 = 12.4 Hz
(1R*,2S*,3R*,4S*,5S*)-10a
Figure 2 Main NOE effects and J-values found for compound 10a;
Cr = chromone moiety
protons. No correlation between the H-2 and H-4 pair of
protons and the H-3 and H-5 pair of protons was observed,
indicating that these pairs are on opposite sides of the mol-
ecule. With regard to the configuration at C-1, the NOE
experiments revealed a correlation between protons H-9′
and H-5, indicating that the C–O bond in the spiro hetero-
cyclic ring is in an equatorial position. This evidence cor-
roborated the stereochemistry shown in Figure 2 and
confirmed that the pentasubstituted cyclohexane 10a had
been formed in a diastereoselective manner.
1
calculated on the basis of H NMR spectrometric analy-
ses.
Structures of the new products present in the first and third
fractions were unequivocally established by 1H NMR as-
signments using COSY, HSQC, HMBC and NOESY ex-
periments, as described in detail below. These analyses
showed that the first fraction corresponded to the cyclo-
hexane 11a21 and the third fraction corresponded to the in-
termediate 12a21 (Figure 3). Because intermediate 12a
had been observed and isolated previously (Table 2, en-
tries 1 and 2), we decided to extended the reaction time
Spiro-substituted heterocycles have been observed in nat-
ural products and are regarded as being of interest for
pharmacological studies.22 In fact, our group developed
the first methodology that combines a multicomponent re-
action and a phase-transfer catalyst to give cyclohexanes
with four new stereocenters in good yields and excellent
diastereoselectivity.15a In an attempt to improve the yield
of compound 10a, we continued the reaction under the
Table 2 Reaction, Products, and Yields in the Domino Multicomponent Reaction of Chromone 5a with Nitromethane under Phase-Transfer-
Catalyzed Conditions
Entrya
Time (d)
Yieldb (%) of 10a
Yieldb (%) of 11a
Yieldb (%) of 12a
Recovery (%) of 5a
1
2
3
4
1
1
2
6
9
3
9
–
9c
6
8c
2
6c
3
–
–
17
3
–
11
a Reactions were carried out by treating a 0.2 M soln of chromone 5a (40.0 mg, 0.161 mmol) in MeCN (1 mL) with TBAB (22.0 mg, 0.068
mmol), Cs2CO3 (55.0 mg, 0.169 mmol), and MeNO2 (4.66 μL, 0.086 mmol, 0.5 equiv) at r.t.
b Yield of isolated compound after purification by preparative TLC.
c Yield based on 1H NMR analyses.
NO2
NO2
Ph
Ph
O
Ph
Ph
Ph
4
5
3
2
6
1
O
O
O
O
O
MeNO2
O
O
H
H
Ph
Ph
+
9'
O
O
+
1
3
3''
5
Cs2CO3
TBAB
MeCN
2
4
2'
2''
O
O
O
H
H
H H H
NO2
(2S*,3S*,4S*)-12a
O
5a
(1R*,2S*,3R*,4S*,5S*)-10a
(1R*,2S*,3R*,4S*,5R*)-11a
Scheme 3 Domino multicomponent reaction of 5a with nitromethane under phase-transfer catalysis
Synlett 2013, 24, 2375–2382
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,6-Conjugate Addition of Nucleophiles to (E)-2-Styrylchromones
2379
(entries 3 and 4). The yield of compound 10a increased
slightly when the reaction mixture was stirred at room
temperature for six days.
Cr
2 HA
J6A–6B = 14.0 Hz
NO2
H
J6A–5 = 4.0 Hz
J6B–5 = 14.0 Hz
J5–4 = 4.0 Hz
J2–3 = 12.9 Hz
J3–4 = 4.0 Hz
4
H
3
CH2
H
O
9'
Ph
1
6
1
5
Ph
The H NMR spectrum of the first fraction (compound
HB
O
H
11a) showed one sharp singlet at δ = 6.41 ppm, assigned
to the H-3′′ proton resonance of the chromone moiety (see
Scheme 3 for numbering). Diagnostic of 11a were the sig-
nals assigned to the H-4 proton resonance at δ = 5.20 ppm
(t, J = 4.0 Hz) and the H-3 proton resonance at δ = 4.35
ppm (dd, J = 4.0 and 12.9 Hz). Also, the presence of three
doublets at δ = 4.28 (J = 12.9 Hz), 3.11 (J = 16.6 Hz), and
2.93 pm (J = 16.6 Hz), assigned to the H-2 proton and the
two H-9′ protons, supported the proposed structure 11a.
The signal corresponding to the H-5 proton resonance ap-
pears at δ = 3.72 ppm as a doublet of triplets (J = 4.0 and
(1R*,2S*,3R*,4S*,5R*)-11a
J
J
J
J
J
J
1B–1B' = 14.0 Hz
8'
8''
1B–2 = 10.5 Hz
1B'–2 = 3.6 Hz
3–2 = 10.5 Hz
3–4 = 3.2 Hz
5''
5'
O
O
H
Ph H Ph
1
3
5
4
2
O
O
3'
3''
5A–5A' = 14.2 Hz
H HA' HA
HB
NO2
(5.72 ppm) H
H(6.29 ppm)
HB'
1
(2S*,3S*,4S*)-12a
14.0 Hz). The H NMR spectrum of compound 11a also
showed one triplet at δ = 2.90 ppm (J = 14.0 Hz) and a
doublet of doublets (J = 4.0 and 14.0 Hz), assigned to the
H-6 protons. The relative stereochemistry of compound
Figure 3 Main NOE effects and J values for compounds 11a and
12a; Cr = chromone moiety
1
11a was assigned by analyses of H–1H coupling con-
H-5′′ protons, of the chromone nucleus were observed, to-
gether with two singlets at δ = 6.29 and 5.72 ppm, corre-
sponding to the resonances of the H-3′′ and H-3′ protons,
respectively (see Figure 3 for numbering). More-detailed
NMR studies revealed that the third fraction corresponded
to a compound with the structure assigned in Scheme 3 as
compound 12a. Diagnostic of 12a were the signals as-
signed to the H-3 proton at δ = 5.25 ppm (dd, J = 3.2 and
10.5 Hz), the H-2 proton resonance at δ = 3.70 ppm (dt,
J = 3.6 and 10.5 Hz), and the H-4 proton resonance corre-
sponding to a multiplet at δ = 3.62–3.56 ppm. Also, the
presence of four doublets of doublets at δ = 3.30 (J = 9.4
and 14.2 Hz), 2.95 (J = 3.6 and 14.0 Hz), 2.91 (J = 6.5 and
14.2 Hz), and 2.77 ppm (J = 10.5 and 14.0 Hz), corre-
sponding to the H-5A, H-1B′, H-5A′, H-1B protons, respec-
tively, supported the proposed dimeric structure of 12a.
stants of the cyclohexane ring and of the NOESY spec-
trum, which confirmed the relative configurations of all
the neighboring substituents (Figure 3). The NOESY
spectrum of 11a showed a strong correlation between H-
5 and H-4, and a correlation of both these protons with the
same aromatic proton of the phenyl ring at C-5. Also, with
regard to the configuration at carbon C-1, the NOE cross-
peaks between the signal for H-2 and that of H-9′ (δ = 2.93
pm) indicate that the C–O bond at the spiro heterocyclic
ring is in an axial position (Figure 3).
With regard to the 1H NMR spectrum of the third fraction,
initial observations revealed that some characteristic sig-
nals of the chromone nucleus were doubled. Specifically,
two doublets of doublets at δ = 8.17 and 8.04 ppm, corre-
sponding, respectively to the resonances of the H-5′ and
O
Ph
MeNO2
NO2
O
Ph
DBU
Ph
O
[DBUH]
O
DBU
O
O
O
Ph
5a
O
[DBUH]
N
N
O
O
1,6-conjugate
addition
O
II (6a)
O
I
III
[DBUH]
5a
1,6-conjugate
addition
NO2
NO2
3
4
NO2
Ph
Ph
1,4-
Michael
addition
Ph
Ph
Ph
O
Ph
O
2
[DBUH]
O
O
1
O
O
5
O
DBU
O
O
[DBUH]
O
O
12a
O
enolate
10a and 11a
Scheme 4 Proposed mechanism for the cascade 1,6-/1,6-/1,4-conjugate addition reactions
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2375–2382

2380
E. M. P. Silva et al.
LETTER
The relative stereochemistry of compound 12a was as-
signed by analysis of the 1H–1H coupling constants of the
aliphatic chain in 12a and from the NOESY spectrum,
which confirmed the relative configuration of all neigh-
boring substituents (Figure 3). The NOESY spectrum of
12a showed a strong correlation between the signals for
H-3 and H-4, H-4 and H-5A′ (δ = 2.91 ppm), H-2 and H-
1B′, H-1B and H-3′ (δ = 5.72 ppm), and H-5A and H-3′′ (δ
= 6.29 ppm), which supported the proposed structure
shown in Figure 3.
References and Notes
(1) Perlmutter, P. In Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
(2) For reviews, see: (a) Silva, E. M. P.; Silva, A. M. S.
Synthesis 2012, 44, 3109. (b) Csákÿ, A. G.; Herrán, G.;
Murcia, M. C. Chem. Soc. Rev. 2010, 39, 4080. (c) Krause,
N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
(3) Nishimura, T.; Noishiki, A.; Hayashi, T. Chem. Commun.
2012, 48, 973.
(4) Nishimura, T.; Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 7872.
(5) (a) Roscales, S.; Salado, I. G.; Csákÿ, A. G. Synlett 2011,
2234. (b) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi,
T. J. Am. Chem. Soc. 2010, 132, 12865. (c) Herrán, G.;
Csákÿ, A. G. Synlett 2009, 585. (d) Nishimura, T.; Yasuhara,
Y.; Hayashi, T. Angew. Chem. Int. Ed. 2006, 45, 5164.
(e) Tseng, N.-W.; Mancuso, J.; Lautens, M. J. Am. Chem.
Soc. 2006, 128, 5338. (f) Herrán, G.; Murcia, C.; Csákÿ, A.
G. Org. Lett. 2005, 7, 5629. (g) Hayashi, T.; Takahashi, M.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124,
5052.
On the basis of these results, we proposed a mechanism
involving domino multicomponent 1,6-/1,6-/1,4-conju-
gate addition reactions to explain the formation of spiro-
cyclohexanes 10a and 11a. This mechanism (Scheme 4),
starts with the formation of the nitromethane anion I; this
is followed by a 1,6-conjugate addition to 5a to give inter-
mediate 6a, which can be isolated and identified. Next,
anion III, undergoes 1,6-conjugate addition to 5a to give
intermediate 12a, which can be isolated and identified.
Finally, an intramolecular 1,4-Michael addition reaction
takes place to give the cyclohexane derivatives 10a and
11a.
(6) Brooks, J. L.; Caruana, P. A.; Frontier, A. J. J. Am. Chem.
Soc. 2011, 133, 12454.
(7) (a) Tissot, M.; Müller, D.; Belot, S.; Alexakis, A. Org. Lett.
2010, 12, 2770. (b) Wencel-Delord, J.; Alexakis, A.;
Crévisy, C.; Mauduit, M. Org. Lett. 2010, 12, 4335.
(c) Hartog, T.; Dijken, D. J.; Minnaard, A. J.; Feringa, B. L.
Tetrahedron: Asymmetry 2010, 21, 1574. (d) Hartog, T.;
Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L.
Angew. Chem. Int. Ed. 2008, 47, 398. (e) Okada, S.;
Arayama, K.; Murayama, R.; Ishizuka, T.; Hara, K.; Hirone,
N.; Hata, T.; Urabe, H. Angew. Chem. Int. Ed. 2008, 47,
6860. (f) Hénon, H.; Mauduit, M.; Alexakis, A. Angew.
Chem. Int. Ed. 2008, 47, 9122. (g) Yoshikai, N.; Yamashita,
T.; Nakamura, E. Chem. Asian J. 2006, 1, 322. (h) Kusama,
H.; Sawada, T.; Okita, A.; Shiozawa, F.; Iwasawa, N. Org.
Lett. 2006, 8, 1077. (i) Fillion, E.; Wilsily, A.; Liao, E-T.
Tetrahedron: Asymmetry 2006, 17, 2957. (j) Hayashi, T.;
Yamamoto, S.; Tokunaga, N. Angew. Chem. Int. Ed. 2005,
44, 4224. (k) Fukuhara, K.; Urabe, H. Tetrahedron Lett.
2005, 46, 603. (l) Hayashi, T.; Tokunaga, N.; Inoue, K. Org.
Lett. 2004, 6, 305. (m) Caro, B.; Le Poul, P.; Guen, F. R.-L.;
Sénéchal-Tocquer, M.-C.; Saillard, J.-Y.; Kahlal, S.;
Ouahab, L.; Golhen, S. Eur. J. Org. Chem. 2000, 577.
(n) Uerdingen, M.; Krause, N. Tetrahedron 2000, 56, 2799.
(8) Murphy, J. J.; Quintard, A.; McArdle, P.; Alexakis, A.;
Stephens, J. C. Angew. Chem. Int. Ed. 2011, 50, 5095.
(9) Bernardi, L.; López-Cantarero, J.; Niess, B.; Jørgensen, K.
A. J. Am. Chem. Soc. 2007, 129, 5772.
On the basis of this proposed mechanism for the forma-
tion of 10a, it is easy to understand that the relative con-
figuration at C-2 and C-4 in intermediate 12a dictates the
relative configurations of the remaining stereocenters in
the cyclohexane moiety. Therefore, the relative C-1/C-2
stereochemistry is governed by the steric hindrance
caused by the two chromone groups.
This novel transformation permits the generation of three
new C–C bonds and five new stereocenters, containing a
nitro functional group, a chromone moiety, and also a ste-
reogenic quaternary carbon in a spiro heterocyclic moiety.
However, this domino multicomponent reaction for the
synthesis of pentasubstituted cyclohexane derivatives re-
quires further studies, which are now in progress, particu-
larly with regard to improving the yield for the
diastereoselective formation of compound 10a.
In conclusion, we have described diastereoselective 1,6-
conjugate addition reactions of ethyl malonate or malono-
nitrile with (E)-2-styrylchromones 5a–d in moderate
yields. An unexpected domino multicomponent reaction
occurs under phase-transfer-catalyzed conditions, result-
ing in the formation of the pentasubstituted spirocyclo-
hexanes 10a and 11a. This novel transformation occurs
through a cascade 1,6-/1,6-/1,4-conjugate addition pro-
cess that permits the formation of a stereochemically com-
plex pentasubstituted spirocyclohexane.
(10) Sun, H.-W.; Liao, Y.-H.; Wu, Z.-J.; Wang, H.-Y.; Zhang,
X.-M.; Yuan, W.-C. Tetrahedron 2011, 67, 3991.
(11) Ballini, R.; Bosica, G.; Fiorini, D. Tetrahedron Lett. 2001,
42, 8471.
(12) (a) Gerwick, W. H.; Lopez, A.; Van Dyune, G. D.; Clardy,
J.; Ortiz, W.; Baez, A. Tetrahedron Lett. 1986, 27, 1979.
(b) Gerwick, W. H. J. Nat. Prod. 1989, 52, 252. (c) Yoon, J.
S.; Lee, M. K.; Sung, S. H.; Kim, Y. C. J. Nat. Prod. 2006,
69, 290. (d) Yang, L.; Qiao, L.; Xie, D.; Yuan, Y.; Chen, N.;
Dai, J.; Guo, S. Phytochemistry 2012, 76, 92.
Acknowledgment
(13) For selected examples, see: (a) Gomes, A.; Fernandes, E.;
Silva, A. M. S.; Santos, C. M. M.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S.; Lima, J. L. F. C. Bioorg. Med. Chem.
2007, 15, 6027. (b) Gomes, A.; Fernandes, E.; Silva, A. M.
S.; Pinto, D. C. G. A.; Santos, C. M. M.; Cavaleiro, J. A. S.;
Lima, J. L. F. C. Biochem. Pharmacol. 2009, 78, 171.
(14) Gomes, A.; Freitas, M.; Fernandes, E.; Lima, J. L. F. C.
Mini-Rev. Med. Chem. 2010, 10, 1.
Thanks are due to the University of Aveiro, the Portuguese Founda-
tion for Science and Technology (FCT), the European Union,
QREN, FEDER, and COMPETE for funding the QOPNA research
unit (project PEst-C/QUI/UI0062/2013; FCOMP-01-0124-FE-
DER-037296) and the Portuguese NMR Network. E.M.P.S. is gra-
teful to FCT (ref. SFRH/BPD/66961/2009) for a postdoctoral
research grant.
Synlett 2013, 24, 2375–2382
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,6-Conjugate Addition of Nucleophiles to (E)-2-Styrylchromones
2381
(15) For recent examples, see: (a) Resende, D. I. S. P.; Oliva, C.
G.; Silva, A. M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. Synlett
2010, 115. (b) Oliva, C. G.; Silva, A. M. S.; Resende, D. I.
S. P.; Paz, F. A. A.; Cavaleiro, J. A. S. Eur. J. Org. Chem.
2010, 3449. (c) Lévai, A.; Silva, A. M. S.; Santos, C. M. M.;
Cavaleiro, J. A. S.; Jeko, J. Aust. J. Chem. 2009, 62, 82.
(d) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, A. M. S.;
Lévai, A.; Patonay, T. Eur. J. Org. Chem. 2007, 2877.
(e) Lévai, A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Patonay,
T.; Silva, V. L. M. Eur. J. Org. Chem. 2001, 3213.
(16) Silva, E. M. P.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett
2011, 2740.
(19) [1-(4-Oxo-4H-chromen-2-yl)-2-phenylethyl]-
malononitrile (9a)
Yellow oil; yield: 11.5 mg (23%). 1H NMR (300.13 MHz,
CDCl3): δ = 7.95 (d, J = 6.8 Hz, 1 H, H-5), 7.64 (dt, J = 1.6,
7.9 Hz, 1 H, H-7), 7.51–7.37 (m, 7 H, H-6, H-8, Ph), 5.55 (s,
1 H, H-3), 5.11 [d, J = 3.2 Hz, 1 H, α-CH(CN)2], 4.23–4.17
(m, 1 H, H-α), 3.72 (dd, J = 8.6, 16.0 Hz, 1 H, H-β), 3.57 (dd,
J = 5.6, 16.0 Hz, 1 H, H-β). MS (ESI): m/z [M + H]+ calcd
+
for C20H15N2O2 : 315.11280; found: 315.1.
(20) Silva, A. M. S.; Almeida, L. M. P. M.; Cavaleiro, J. A. S.;
Levai, A.; Patonay, T.; Pinto, D. C. G. A. J. Heterocycl.
Chem. 1998, 35, 217.
(17) Chromones 7a–d; General Procedure
(21) (2R*,2′S*,3′R*,4′S*,5′S*)-4′-Nitro-2'-(4-oxo-4H-
chromen-2-yl)-3′,5′-diphenylspiro[chromene-2,1′-
cyclohexan]-4(3H)-one (10a) and
A solution of the appropriate (E)-2-styrylchromone 5a–d
(0.122 mmol) in anhyd EtOH (1 mL) was added dropwise to
a solution of NaOEt [Na (1.7 mg) in anhyd EtOH (0.13 mL)]
and ethyl malonate (0.263 mmol) at 0 °C. The mixture was
flushed with N2 and stirred vigorously at r.t. for the
appropriate time. 0.1 M aq HCl (1.2 mL) was added and the
organic phase was separated, extracted with Et2O, dried
(Na2SO4), and concentrated under reduced pressure. The
residue was dissolved in EtOAc and purified by preparative
TLC [silica, hexane–EtOAc (7:3)].
(2R*,2′S*,3′R*,4′S*,5′R*)-4′-Nitro-2'-(4-oxo-4H-
chromen-2-yl)-3′,5′-diphenylspiro[chromene-2,1′-
cyclohexan]-4(3H)-one (11a)
TBAB (22.0 mg, 0.068 mmol), Cs2CO3 (55.0 mg, 0.169
mmol), and MeNO2 (4.66 μL, 0.086 mmol) were added to a
stirred solution of chromone 5a (40.0 mg, 0.161 mmol) in
MeCN (1 mL), and the mixture was stirred at r.t. for 6 d. The
reaction was then quenched with H2O (10 mL), and the
mixture was extracted with CH2Cl2 (3 × 5 mL). The organic
extracts were combined, dried (MgSO4), and concentrated
under reduced pressure to give an oil that was purified by
preparative TLC [silica, hexane–EtOAc (7:3)] to give 10a
and 11a. The yield shown for compound 12a was obtained
when the reaction was left for 2 days under the described
conditions.
Diethyl [2-(4-Oxo-4H-chromen-2-yl)-1-
phenylethyl]malonate (7a)
Colorless oil; yield: 26.0 mg (52%). 1H NMR (300.13 MHz,
CDCl3): δ = 8.09 (dd, J = 1.7, 8.0 Hz, 1 H, H-5), 7.62 (ddd,
J = 1.7, 7.0, 8.6 Hz, 1 H, H-7), 7.38–7.31 (m, 2 H, H-6, H-
8), 7.22–7.15 (m, 5 H, Ph), 5.93 (s, 1 H, H-3), 4.25 (dq, J =
1.0, 7.1 Hz, 2 H, CO2CH2CH3), 3.99–3.94 (m, 1 H, H-β),
3.93 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.80 [d, J = 10.4 Hz,
1 H, CH(CO2CH2CH3)2], 3.19 (dd, J = 4.3, 14.2 Hz, 1 H, H-
α), 2.92 (dd, J = 10.4, 14.2 Hz, 1 H, H-α), 1.30 (t, J = 7.1 Hz,
3 H, CO2CH2CH3), 0.97 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR (75.47 MHz, CDCl3): δ = 177.9 (C=O), 168.0
(CO2CH2CH3), 167.3 (CO2CH2CH3), 166.2 (C-2), 156.3 (C-
9), 138.6 (C-1′), 133.5 (C-7), 128.6 (C-3′, C-5′), 127.9 (C-2′,
C-6′), 127.6 (C-4′), 125.5 (C-5), 124.9 (C-6), 123.5 (C-10),
117.8 (C-8), 111.6 (C-3), 61.9 (CO2CH2CH3), 61.5
(CO2CH2CH3), 57.5 [CH(CO2CH2CH3)2], 43.3 (C-β), 38.9
(C-α), 14.1 (CO2CH2CH3), 13.7 (CO2CH2CH3). HRMS
10a: Yellow solid; yield: 15.3 mg (17%); mp 190 °C (dec.).
1H NMR (300.13 MHz, CDCl3): δ = 8.01 (dd, J = 1.6, 8.1 Hz,
1 H, H-5′′), 7.74 (dd, J = 1.6, 7.6 Hz, 1 H, H-6′), 7.64–7.56
(m, 2 H, H-4′, H-7′′), 7.36 (dd, J = 0.7, 8.3 Hz, 1 H, H-3′),
7.34–7.23 (m, 6 H, Ph-m, H-6′′, H-8′′), 7.21–7.08 (m, 6 H,
Ph-o,p), 7.01 (dt, J = 0.7, 7.6 Hz, 1 H, H-5′), 6.36 (br s, 1 H,
H-3′′), 5.04 (t, J = 12.4 Hz, 1 H, H-4), 4.47 (br t, J = 12.4 Hz,
1 H, H-3), 3.79 (dt, J = 3.6, 12.4 Hz, 1 H, H-5), 3.25 (d, J =
12.4 Hz, 1 H, H-2), 3.04 (d, J = 16.6 Hz, 1 H, H-9′), 2.72 (dd,
J = 3.6, 14.4 Hz, 1 H, H-6B), 2.69 (d, J = 16.6 Hz, 1 H, H-9′),
2.01 (dd, J = 12.4, 14.4 Hz, 1 H, H-6A). 13C NMR (75.47
MHz, CDCl3): δ = 189.7 (C-8′), 177.2 (C-4′′), 163.2 (C-2’’),
157.9 (C-2′), 155.8 (C-9′′), 137.3 (C-1 of 5-Ph), 136.9 (C-4′),
135.2 (C-1 of 3-Ph), 133.8 (C-7′′), 129.14 and 129.09 (C-3,5
of 3- and 5-Ph), 128.6 and 128.4 (C-4 of 3- and 5-Ph), 127.1
(C-2,6 of 3- and 5-Ph), 126.8 (C-6′), 125.6 (C-5′′), 125.4 (C-
6′′), 123.4 (C-10′′), 122.1 (C-5′), 120.1 (C-7′), 118.2 (C-3′),
117.6 (C-8′′), 114.4 (C-3′′), 95.7 (C-4), 79.4 (C-1), 55.1 (C-
2), 46.2 (C-3), 45.8 (C-9′), 43.0 (C-5), 38.7 (C-6).HRMS
+
(ESI): m/z [M + H]+ calcd for C24H25O6 : 409.16456; found:
409.16467.
(18) Chromones 8a–d; General Procedure
A few drops of piperidine (1.59 μL, 0.1 equiv) were added to
a solution of the appropriate (E)-2-styrylchromone 5a–d
(0.161 mmol) and malononitrile (0.177 mmol) in anhyd
EtOH (1 mL), and the mixture was stirred and refluxed under
N2. The resulting solution was concentrated to dryness,
taken up in EtOAc, and purified by preparative TLC [silica,
hexane–EtOAc (7:3)].
+
(ESI): m/z [M + H]+ calcd for C35H28NO6 : 558.19111;
found: 558.19001.
[2-(4-Oxo-4H-chromen-2-yl)-1-phenylethyl]-
malononitrile (8a)
11a: White solid; yield: 2.7 mg (3%); mp 182.2–182.7 °C.
1H NMR (300.13 MHz, CDCl3): δ = 8.02 (dd, J = 1.7, 8.0 Hz,
1 H, H-5′′), 7.77 (dd, J = 1.7, 7.5 Hz, 1 H, H-6′), 7.61 (ddd,
J = 1.7, 7.5, 8.4 Hz, 1 H, H-7′′), 7.51 (ddd, J = 1.7, 7.5, 8.5
Hz, 1 H, H-4′), 7.40 (d, J = 8.4 Hz, 1 H, H-8′′), 7.34–7.12 (m,
12 H, 3,5-Ph, H-6′′, H-3′), 6.98 (dt, J = 0.8, 7.5 Hz, 1 H, H-
5′), 6.41 (s, 1 H, H-3′′), 5.20 (t, J = 4.0 Hz, 1 H, H-4), 4.35
(dd, J = 4.0, 12.9 Hz, 1 H, H-3), 4.28 (d, J = 12.9 Hz, 1 H,
H-2), 3.72 (dt, J = 4.0, 14.0 Hz, 1 H, H-5), 3.11 (d, J = 16.6
Hz, 1 H, H-9′), 2.93 (d, J = 16.6 Hz, 1 H, H-9′), 2.90 (t, J =
14.0 Hz, 1 H, H-6B), 2.59 (dd, J = 4.0, 14.0 Hz, 1 H, H-6A).
13C NMR (75.47 MHz, CDCl3): δ = 190.1 (C-8′), 177.3 (C-
4′′), 164.8 (C-2’’), 157.9 (C-2′), 155.9 (C-9′′), 137.0 (C-1 of
5-Ph), 136.7 (C-4′), 135.6 (C-1 of 3-Ph), 133.8 (C-7′′), 129.2
and 129.1 (C-3,5 of 3- and 5-Ph), 128.5 and 128.3 (C-4 of 3-
and 5-Ph), 127.4 and 127.1 (C-2,6 of 3- and 5-Ph), 126.8 (C-
Yellow solid; yield: 26.8 mg (53%); mp 141.6–142.2 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 8.12 (dd, J = 1.6, 7.9 Hz, 1
H, H-5), 7.67 (ddd, J = 1.6, 7.1, 8.5 Hz, 1 H, H-7), 7.42–7.35
(m, 7 H, Ph, H-6, H-8), 6.15 (s, 1 H, H-3), 4.14 [d, J = 5.8
Hz, 1 H, β-CH(CN)2], 3.88–3.81 (m, 1 H, H-β), 3.44 (dd, J
= 6.5, 14.7 Hz, 1 H, H-α), 3.32 (dd, J = 8.9, 14.7 Hz, 1 H, H-
α). 13C NMR (75.47 MHz, CDCl3): δ = 177.7 (C=O), 163.4
(C-2), 156.2 (C-9), 134.8 (C-1′), 134.0 (C-7), 129.62 (C-4′),
129.56 (C-3′, C-5′), 127.6 (C-2′, C-6′), 125.8 (C-5), 125.5
(C-6), 123.5 (C-10), 117.7 (C-8), 112.2 (C-3), 111.2 (CN),
111.1 (CN), 44.0 (C-β), 36.9 (C-α), 29.5 [β-CH(CN)2].
+
HRMS (ESI): m/z [M + H]+ calcd for C20H15N2O2 :
315.11280; found: 315.11331.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2375–2382

2382
E. M. P. Silva et al.
LETTER
6′), 125.6 (C-5′′), 125.4 (C-6′′), 123.6 (C-10′′), 122.0 (C-5′),
120.2 (C-7′), 117.9 (C-3′), 117.8 (C-8′′), 114.2 (C-3′′), 93.3
(C-4), 80.4 (C-1), 48.1 (C-2), 46.4 (C-9′), 44.3 (C-3), 40.3
(C-5), 30.9 (C-6). HRMS (ESI): m/z [M + H]+ calcd for
C35H28NO6 : 558.19111; found: 558.19000.
2,2′-[(2R*,3S*,4R*)-3-Nitro-2,4-diphenylpentane-1,5-
diyl]bis(4H-chromen-4-one) (12a)
1 H, H-1B′), 2.91 (dd, J = 6.5, 14.2 Hz, 1 H, H-5A′), 2.77 (dd,
J = 10.5, 14.0 Hz, 1 H, H-1B). 13C NMR (75.47 MHz,
CDCl3): δ = 177.8 (C-4′), 177.6 (C-4′′), 164.9 (C-2′), 164.8
(C-2′′), 156.2 (C-9′), 156.0 (C-9′′), 136.6 (2-Ph), 135.7 (4-
Ph), 133.6 (C-7′, C-7′′), 129.4 (2-Ph-m), 128.8 (4-Ph-m),
128.7 (4-Ph-p), 128.4 (2-Ph-p), 128.1 (4-Ph-o), 128.0 (2-Ph-
o), 125.7 (C-5′), 125.5 (C-5′′), 125.3 (C-6′), 125.1 (C-6′′),
123.5 (C-10′′), 123.3 (C-10′), 117.8 (C-8′), 117.7 (C-8′′),
112.5 (C-3′′), 111.9 (C-3′), 92.5 (C-3), 44.6 (C-2), 43.5 (C-
4), 38.6 (C-1), 37.6 (C-5). HRMS (ESI): m/z [M + H]+ calcd
+
Colorless oil; yield: 3.1 mg (3%). 1H NMR (300.13 MHz,
CDCl3): δ = 8.17 (dd, J = 1.6, 7.6 Hz, 1 H, H-5′), 8.04 (dd, J
= 1.6, 7.9 Hz, 1 H, H-5′′), 7.67–7.57 (m, 2 H, H-7′, H-7′′),
7.40 (td, J = 0.9, 7.6 Hz, 1 H, H-6′), 7.34–7.27 (m, 5 H, H-
6′′, H-8′′, 4-Ph-m,p), 7.19–7.15 (m, 2 H, H-8′, 2-Ph-p), 7.10
(t, J = 7.8 Hz, 2 H, 2-Ph-m), 7.03–7.00 (m, 2 H, 4-Ph-o), 6.93
(dd, J = 1.4, 7.8 Hz, 2 H, 2-Ph-o), 6.29 (s, 1 H, H-3′′), 5.72
(s, 1 H, H-3′), 5.25 (dd, J = 3.2, 10.5 Hz, 1 H, H-3), 3.70 (dt,
J = 3.6, 10.5 Hz, 1 H, H-2), 3.62–3.56 (m, 1 H, H-4), 3.30
(dd, J = 9.4, 14.2 Hz, 1 H, H-5A), 2.95 (dd, J = 3.6, 14.0 Hz,
+
for C35H28NO6 : 558.19111 [M + H]+; found: 558.19035.
(22) (a) Nawrot, J.; Dams, I.; Wawrzeńczyk, C. J. Stored
Products Res. 2009, 45, 221. (b) Larghi, E. L.; Operto, M.
A.; Torres, R.; Kaufman, T. S. Bioorg. Med. Chem. Lett.
2009, 19, 6172. (c) Raju, B. R.; Saikia, A. K. Molecules
2008, 13, 1942. (d) Galliford, C. V.; Scheidt, K. A. Angew.
Chem. Int. Ed. 2007, 46, 8748.
Synlett 2013, 24, 2375–2382
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