Simple access to 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones via domino acylative electrocyclization: The first three step total synthesis of the dihydronaphthopyran-4-one class of natural products

Article abstract of DOI:10.1039/c4ra11174e

Intermolecular domino C-acylation/6π-oxaelectrocyclization between β-ketoesters and α,β-unsaturated acid chlorides took place readily in the presence of CaCl₂ to afford a variety of polysubstituted 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones, in good yields. The products were successfully exploited as precursors, for a simple and efficient construction of a naphthalene fused pyran-4-one ring system. This intramolecular Friedel-Crafts acylative aromatization approach was useful for the synthesis of the phytogrowth inhibiting dihydronaphthopyranone class of natural products.

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Simple access to 5-carboalkoxy-2,3-dihydro-4H-
pyran-4-ones via domino acylative
Cite this: RSC Adv., 2014, 4, 55150
electrocyclization: the first three step total
synthesis of the dihydronaphthopyran-4-one class
of natural products†
*
Andivelu Ilangovan and Palaniappan Sakthivel
Intermolecular domino C-acylation/6p-oxaelectrocyclization between b-ketoesters and a,b-unsaturated
acid chlorides took place readily in the presence of CaCl2 to afford a variety of polysubstituted
5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones, in good yields. The products were successfully exploited
as precursors, for a simple and efficient construction of a naphthalene fused pyran-4-one ring system.
Received 25th September 2014
Accepted 17th October 2014
DOI: 10.1039/c4ra11174e
This article can be cited before page numbers have been issued, to do this please use: A. Ilangovan and
This intramolecular Friedel–Crafts acylative aromatization approach was useful for the synthesis of the
P. Sakthivel, RSC Adv., 2014, DOI: 10.1039/C4RA11174E.
www.rsc.org/advances
phytogrowth inhibiting dihydronaphthopyranone class of natural products.
pyrylium salt.1g Moreover, these methods are difficult to be
adopted for the synthesis of DHNPs (ref. 4) because of draw-
backs such as, difficulty in chemoselective conjugate reduction
of enone in NGP (B, Scheme 1a), need for the use of hard to
handle intermediates such as pyrylium salt1g and dimsyl
anion,3d,e formation of mixture of products,1g and conversion of
angular to linear naphthopyranone involving lengthy synthetic
sequence.3d,e Thus there is a need for development of a new and
efficient method for the synthesis of DHNPs.
Designing simple but powerful domino reactions useful for
construction of cyclic ring systems, especially natural products,
is a challenging task.5 Strategic positioning of functional groups
in a molecule allows tandem reactions to take place in one pot.
Considering the advantages of domino reactions, and to over-
come the drawbacks mentioned above, we envisaged
to generate naphthalene fused dihydropyran-4-one ring system
(D, Scheme 1b) in a shortest possible way, by intramolecular
Introduction
Linear naphthalene fused pyran-4-one ring systems, such as
naphtho-g-pyrone (NGP),1 1,4-pyranonaphthoquinone (PNQ),2
and bisnaphthopyranone (BNP)3 containing compounds are
well known fungal metabolites. Some of the natural products
rubrofusarin
B
(i),1e–g 4-oxo-a-lapachone (ii),2d,e cepha-
lochromin,3a,b chaetochromin A3c and nigerone3d,e belonging to
this class exhibit important biological activities such as
topoisomerase-II inhibition, toxin inhibition, anti-tumour, anti-
bacterial and anti-proliferative activity. Similarly, linear
dihydronaphthopyran-4-one (DHNP) natural products,4 trans-
11b, cis-11b and 11c showing phytogrowth-inhibition activity,
constitute another important sub-class of naphthalene fused
pyran-4-ones. The presence or absence of a double bond in the
pyranone ring and the hydroxyl or the 1,4-diketone functionality
in the adjacent naphthalene ring gives rise to structural differ-
ences (Fig. 1).
Friedel–Cras
acylative
aromatization
of
6-benzyl-5-
Although there are methods known for the synthesis of
different naphthopyran-4-one class of compounds (B,
Scheme 1a),1–3 the synthesis of DHNP class of natural products,4
(D, Scheme 1b) remains virgin. These approaches are either
based on construction of pyranone on a pre-existing naphtha-
lene ring (A, Scheme 1a),1–3 or reaction of orsellinate anion with
School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu,
India. E-mail: ilangovanbdu@yahoo.com; Fax: +91-431-2407045; Tel: +91-431-
2407053-ext. 635
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all compounds and X-ray structural information of 3ga (CIF).
CCDC 1019144. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra11174e
Fig. 1 Linear naphthopyran-4-one class of natural products.
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entry 1). Gratifyingly, the yield of product 3aa improved to 80%
when the quantity of the CaCl2 was increased to 10 mol%
(entry 1). Further, increasing the quantity of CaCl2 to 20 mol%
or decreasing the quantity of Et3N did not improve the yield
(entries 1 and 2). In the absence of Et3N (entry 3) no reaction was
observed and in the absence of CaCl2 (entry 4) a mixture of
product was formed.
Change of solvent to DMF, toluene and THF only lead to
decrease in the yield (entry 5). Similarly, change of base to
DMAP, DBU or DABCO had either decreased the yield or led to
the formation of mixture of products (entries 6 and 7). Making
use of other alkaline earth metal chlorides (MgCl2 and BaCl2)
and transition metal halides (ZnCl2, FeCl3, CuCl2 and CeCl3)
had only negative impact on the reaction (entries 8–12). Based
on these results, treatment of an equimolar mixture of
b-ketoester and a,b-unsaturated acid chloride in the presence of
10 mol% of CaCl2 and 2.0 equiv. of Et3N in DCM at room
temperature (entry 1) was identied as the optimum condition
for further study.
Scheme 1 Approaches for naphthopyran-4-one ring formation.
carboalkoxy-2,3-dihydropyran-4-one (6-BCDHP, C, Scheme 1b),
which in turn could be generated via domino C-acylation/
6p-oxaelectrocyclization reaction between b-ketoesters and
a,b-unsaturated acid chlorides.
Literature background shows that synthesis of 6-alkyl/aryl-5-
carboalkoxy-2,3-dihydropyran-4-ones (6-ACDHPs) was reported
independently by Gelin6a and Takeda6b as well as used as inter-
mediate in the synthesis of natural products.6b,7 Nevertheless,
these methods does not cover synthesis of 6-BCDHP and has
drawbacks such as need for the use of stoichiometric quantity of
bases such as Mg(OEt)2 (ref. 6a) and NaH,6b high reaction
temperature and limited substrate scope. Also, other methods
known for the synthesis of substituted 2,3-dihydropyran-4-one
(DHP) ring system without 5-carboalkoxy substituent was found
not suitable for the synthesis of 5-carboalkoxy-2,3-dihydropyran-4-
one (5-CDHP).8–16 The presence of 5-carboalkoxy group in DHP
ring system provides multitude of opportunities for further
synthetic transformations. Thus we realised that development of a
simple method for the synthesis of 6-ACDHP itself is desirable. To
avoid the use of stoichiometric quantity of base,6 in C-acylation of
b-keto esters with a,b-unsaturated acid chloride, to get DHPs, we
thought of using a Lewis acid. Lewis acids are expected to work in
catalytic quantity for the C-acylation reaction.17 CaCl2 is a
biocompatible, cost-effective, bifunctional (Lewis acid as well as
Lewis base) catalyst and it has been exploited only to limited
extent in organic synthesis,18a,b for example, in aldol reaction,18c
Biginelli reaction,18d synthesis of Mannich bases,18e and amino-
phosphonic esters.18f Thus in continuation of our interest on the
use of CaCl2,19 as Lewis acid catalyst we examined its utility in this
reaction. Herein we present successful realisation of what we
contemplated.
Substrate scope
With the optimal reaction condition in hand, scope and limi-
tation of the reaction was explored using fourteen different
b-ketoesters and six different a,b-unsaturated acid chlorides
such as, 3,3-dimethylacryloyl chloride (2a, or senecioyl chlo-
ride), (E)-2,3-dimethylacryloyl chloride (2b, or tigloyl chloride),
crotonoyl chloride (2c), acryloyl chloride (2d), cinnamoyl chlo-
ride (2e) and (E)-pent-2-enoyl chloride (2f, Scheme 2). Compar-
ison of the reactivity of the different b-ketoesters (1a–1d) with
3,3-dimethylacryloyl chloride (2a) revealed that the electron
donating substituents such as 4–Me, 4-OMe and 3,4,5-OMe on
the aromatic ring had no signicant effect on the rate and yield
of the reaction. The presence of chloro group, at sterically
hindered ortho position in the b-ketoester 1f slowed down the
reaction (see 3ea and 3fa) compared to para position in the b-
ketoester 1e. Among the different acid chlorides, 2a gave high
yield of the product (see 3aa, tc-3ab, 3ac) compared to 2b and 2c.
The product tc-3ab was obtained as a separable trans–cis (dr
6 : 4) diastereomeric mixture, which was conrmed by 1H NMR.
While thiophene and furan derived b-ketoesters, 1g and 1h
gave the product 3ga and 3ha respectively in excellent yield, the
expected product 3ia could not be obtained with pyridine
derived b-ketoester 1i. Most likely, the pyridine nitrogen might
have formed irreversible complex with acid chloride. Formation
of 6-ACDHP ring structure was further conrmed using the
X-ray crystal structure obtained for the compound 3ga (Fig. 2).20
Acryloyl chloride (2d) and cinnamoyl chloride (2e) failed to react
with 1a to provide the desired product 3ad and 3ae. This is
similar to the failure of a,b-unsaturated 1,3-diketones, which
Results and discussion
Reaction optimization
To start with, reaction between ethylbenzoylacetate (1a) and 3,3- has no substitution or phenyl group substitution at b position,
dimethylacrylolyl chloride (2a) was designed as a model, to to undergo cyclization to form DHPs.12
check the feasibility of formation of 5-carboalkoxy-2,3-dihydro-
Further, the substrate scope was extended to aliphatic
4H-pyran-4-one (3aa, Table 1). When an equimolar mixture of 1a b-ketoesters. The acid chlorides 2a and 2c on reaction with ethyl
and 2a was stirred for 7 h at room temperature in the presence acetoacetate (1j) produced 3ja and 3jc respectively in good yield.
of CaCl2 (5 mol%) and Et3N (2.0 equiv.) in DCM, the expected Similarly, methyl-3-oxo-pentanoate (1k) on reaction with acid
dihydropyranone 3aa was obtained only in 60% yield (Table 1, chlorides 2a and 2b gave the expected product 3ka and 3kb
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Table 1 Optimization of the reaction conditionsa
Entry
Catalyst (mol%)
Base
Solvent
Time (h)
Yieldb (%)
1.
2.
3.
4.
5.
6.
7.
8.
CaCl2 (5), (10), (20)
CaCl2 (10)
CaCl2 (10)
Et3N
Et3N
—
Et3N
DCM
DCM
DCM
DCM
DMF, toluene, THF
DCM
DCM
DCM
DCM
7, 7, 7
7
60, 80, 80
70c
15
15
24
24
24
24
24
24
24
24
NRd
—
nde
55, 40, 20
30, 20
nde
25
20
CaCl2 (10)
CaCl2 (10)
CaCl2 (10)
MgCl2 (20)
BaCl2 (20)
ZnCl2 (20)
FeCl3 (20)
CuCl2 (20), CeCl3 (20)
Et3N
DMAP, DBU
DABCO
Et3N
Et3N
Et3N
9.
10.
11.
12.
DCM
DCM
DCM
15
Et3N
Et3N
nde
Trace
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), base (2.0 mmol) and solvent (5 mL) at room temperature. b Isolated yield. c 1.5 equiv. of Et3N
d
e
was used. NR ¼ no reaction (b-ketoester 1a was recovered). Not determined.
Fig. 2 ORTEP diagram of compound 3ga.
respectively in very good yield. Compound 3lf, a potential
intermediate for the synthesis of the natural product hepi-
alone21 was obtained in moderate yield when compound 1l was
treated with acid chloride 2f. Dihydropyranones 3ma and 3mc
Scheme
2 Synthesis of 5-carboalkoxy-2,3-dihydro-4H-pyran-
4-ones. aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CaCl2 (0.1
mmol), triethylamine (2.0 mmol) in DCM (5 mL) at room temperature.
bIsolated yield. ctrans–cis ¼ 6 : 4 was confirmed by H NMR of crude
1
reaction mixture. dNot determined.
Scheme 3 CaCl2 catalyzed C-acylation vs. O-acylation of cyclic active
methylene compounds.
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were obtained in moderate yield from the reaction of diethyl 11nc0 (40%) respectively in very high yield (Scheme 4). As a next
acetone dicarboxylate (1m) with acid chlorides 2a and 2c. step, synthesis of b-keto ester 9, starting material for the
Interestingly, 6-BCDHPs, 3na and 3nc, useful intermediates for synthesis of 11a, trans-11b, cis-11b and 11c was initiated. 3,5-
the synthesis of DHNPs 8na and 8nc (Scheme 4), was obtained Dimethoxyacetophenone (7) was subjected to Willgerodt–
in good yield starting with ethyl 3-oxo-4-phenylbutyrate (1n). Kindler reaction to get 3,5-dimethoxyphenyl acetic acid (8) in
Thus, the domino acylative cyclization method was found very good yield. Compound 8 was further coupled with Mel-
useful for the synthesis of wide variety of polysubstituted drum's acid using DCC/DMAP and reuxed with ethanol to get
6-ACDHPs including 6-BCDHPs.
the b-ketoester 9. However, when compound 9, containing 3,5-
Under the optimized condition, reaction of cyclic active dimethoxy benzene ring, was treated with acid chloride 2a,
methylene compounds such as 4-hydroxycoumarin (4a) and 3- under the standard reaction condition using CaCl2, a mixture of
methyl-1-phenyl-1H-pyrazol-5(4H)-one (4b) with 3,3-dimethyla- products, instead of the desired product 10a, was obtained.
cryloyl chloride (2a) was examined (Scheme 3). However, similar There was no change in the course of the reaction when the
to the formation of O-acylated product in the case of Lewis acid, reaction temperature was lowered or increased; quantity of
SmCl3,17 only O-acylated products 5a (ref. 17) and 5b were CaCl2 was increased to 1.0 equiv.; solvent was changed to DMF.
obtained in good yield in the presence of CaCl2. Increasing the Similarly, when the reaction was tried with different Lewis acids
temperature or the catalyst did not change the course.
such as Yb(OTf)3, In(OTf)3, Cu(OTf)2, SmCl3 (ref. 17) and InCl3
an inseparable mixture of unidentiable products was
obtained. Thus we were bewildered to know that, while
compound 1n could give rise to cyclised product 6-BCDHP (3n),
compound 9 failed to give the desired product 10a in the
presence of Lewis acids. Most likely, the electron rich 3,5-
dimethoxy benzene ring, in the presence of Lewis acid, may
undergo side reactions and play spoilsport. To overcome this
problem in the preparation of compound 10a and to achieve our
main goal of synthesis of compound 11a–c, we opted to use a
base, Mg(OEt)2,6a instead of Lewis acid. To our delight, with
Total synthesis of dihydronaphthopyran-4-one (DHNP) class
of natural products and its analogs
As a part of our strategy, utility of 6-BCDHPs, 3na, 3nc and 10a-
c, was examined as starting materials, for the synthesis of DHNP
class of synthetic analogs 11na, 11nc and 11a, and natural
products trans-11b, cis-11b and 11c. On treatment with PPA
compounds 3na and 3nc (Scheme 2 and 4) underwent facile
intramolecular Friedel–Cras acylative aromatization to afford
a separable mixture of 11na (50%)/11na0 (45%) and 11nc (45%)/
Scheme 4 Total synthesis of dihydronaphthopyranone class of natural products and its analogs. aReagents and conditions: (a) S8, TsOH/
morpholine, 120–130 ꢀC, 6 h; 20% aq. NaOH, TBAB, 100–110 ꢀC, 6 h, 80%; (b) Meldrum's acid, DCC, DMAP, DCM, 25 ꢀC, 5 h; EtOH, reflux, 10 h
(50% for two steps); (c) 9, Mg(OEt)2, dry toluene, 100 ꢀC, 30 min; 2 (2a–c), ACN, r.t.; (d) 3n and 2 (2a and 2c), CaCl2, Et3N, DCM, r.t.; (e) PPA, 80 ꢀC;
ftrans–cis ¼ 6 : 4 was confirmed by 1H NMR of crude reaction mixture.
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Scheme 5 Proposed mechanism.
Mg(OEt)2 a facile acylation followed by 6p-oxaelectrocyclization unsaturated acid chloride in the presence of CaCl2. Unlike the
took place readily to deliver dihydropyranone 10a. Similarly, need for the stoichiometric quantity of bases such as Mg(OEt)2
other dihydropyranone derivatives tc-10b and 10c were prepared and NaH, the Lewis acid CaCl2 worked effectively in catalytic
in good yield using Mg(OEt)2.
quantity. The 6-benzyl-5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones
Further, 6-BCDHPs 10a, tc-10b and 10c were successfully con- were successfully employed as intermediates for the rst and
verted to DHNPs 11a, tc-11b and 11c respectively, in excellent yield concise total synthesis of dihydronaphthopyranone class of
by following the procedure used for the conversion of compound natural products and its synthetic analogs via intramolecular
3na. The product tc-11b was obtained as a separable diastereo- Friedel–Cras acylative aromatization. This in situ generation of
meric mixture of trans-11b and cis-11b isomer (dr 6 : 4). The con- naphthalene ring system has potential for its extension to the
strained cis-geometry of the ester group favoured aromatic synthesis of other naphthopyran-4-one class of compounds such
acylation. This forms the rst ever, short, three step total synthesis as NGP, PNQ and BNP. Investigation in this direction is under
of naturally occurring dihydronaphthopyranones trans-11b, cis-11b progress in our laboratory. Also, studies on acylation of 1,3-di-
and 11c and its synthetic analogs 11a, 11na, 11na0, 11nc and 11nc0. ketones using the same strategy is under progress so that we did
not present the results in this manuscript.
Mechanistic hypothesis
Based on our own observations and previous literature
Experimental section
General remarks
precedence,12,17 a plausible reaction mechanism for the forma-
tion of 5-carboalkoxy-2,3-dihydropyran-4-one (3) is proposed
(Scheme 5). The in situ generated g,d-unsaturated b-diketone (III)
is expected to exist in fully conjugated and more stable enolic
form IV,12 instead ofpartlyconjugatedand less stable enolic form
V. Intermediate III might undergo 6p-oxaelectrocylization
instead of intramolecular oxa-Michael addition to form the
product 3. The acid chlorides 2a, 2b, 2c and 2f substituted with
alkyl groups at b-position reacted efficiently while 2d with no
substitution and 2e with phenyl substitution failed to react. This
shows that dialkyl or mono alkyl substituents at b-position of the
acid chloride favours positive polarization for the 6p-oxaelec-
trocylization12 to take place.
Melting points were determined by the open capillary tube
method using a Toshniwal melting point apparatus and are
uncorrected. The 1H and 13C NMR spectra were measured on a
Bruker Avance 400 (400 MHz) NMR spectrometer. Chemical
shis are reported in ppm (d) relative to internal standard tet-
ramethylsilane (TMS, d 0.00 ppm). Data are reported as follows:
chemical shi (multiplicity [singlet (s), doublet (d), triplet (t),
quartet (q), multiplet (m), broad resonance (br)], coupling
constants [Hz], integration). All the NMR spectra were acquired
at ambient temperature. ESI-MS was recorded on Agilent 1100
LC/MSD (70 eV) spectrometer. High resolution mass spectra
(HRMS) were recorded on a Waters Q-Tof micro mass spec-
trometer. Elemental analyses were performed on a CHN analy-
ser. X-ray crystallographic data were collected on a Bruker
SMART APEX-II CCD diffractometer. Thin layer chromatog-
raphy (TLC) was performed on Merck pre-coated silica gel 60F
plates and visualized by exposure to UV light. ACME silica gel
(100–200 mesh) was used for column chromatography. All
commercially available reagents were used without purication
unless otherwise indicated and were purchased from standard
chemical supplier. The b-ketoesters 1b–1i,22 and 1n (ref. 23) was
This mechanism is further supported by the observation that
the cyclic active methylene compounds (4a and 4b) did not
undergo pyranone ring formation. These compounds are well
known to exist in the enol form, thus the geometric constraints
may not allow the catalyst to achieve cyclic coordination state
similar to I. Thus, O-alkylation rather than C-alkylation took
place.
Conclusions
In conclusion, we have developed a simple and efficient domino prepared according to literature procedure. Polyphosphoric
strategy for the synthesis of polysubstituted 5-carboalkoxy-2,3- acid (Sigma-Aldrich: catalogue no.: 208213) reagent grade,
dihydro-4H-pyran-4-ones from acyclic b-ketoesters and a,b- 115% H3PO4 basis was used for the reaction.
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General method A: typical experimental procedure for the
synthesis of 2,3-dihydro-4H-pyran-4-ones (3)
Ethyl 2,2-dimethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,3-
dihydro-4H-pyran-5-carboxylate (3da)
To a suspension of b-ketoester (1, 1.0 mmol), CaCl2 (0.1 mmol) The reaction was carried out according to general method A
and Et3N (2.0 mmol) in 5 mL ꢀof DCM was added acid chloride using ethyl 3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate (1d,
(2, 1.0 mmol) dropwise at 10 C. Aer completion of the addi- 282 mg, 1.0 mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0
tion the reaction mixture was allowed to stir at room tempera- mmol), senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL)
ture for 3–10 h. The reaction mixture was quenched with water, for 5 h gave 3da (309 mg, 85%) as a white solid. M.p. 128–130 ꢀC;
neutralised by dil. HCl, extracted with CH2Cl2 (2 ꢁ 8 mL) and 1H NMR (400 MHz, CDCl3): d 6.76 (s, 2H), 4.09 (q, J ¼ 7.2 Hz,
washed with brine. The organic layer was separated, dried over 2H), 3.86 (s, 3H), 3.84 (s, 6H), 2.63 (s, 2H), 1.56 (s, 6H), 1.06 (t, J
anhydrous Na2SO4 and concentrated under reduced pressure. ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 188.8, 169.8, 166.3,
The crude product was puried by column chromatography 153.1, 141.1, 128.9, 111.3, 105.7, 81.8, 61.2, 60.9, 56.2, 46.9, 26.1,
(EtOAc–hexane ¼ 2 : 8) to afford pure 2,3-dihydro-4H-pyran- 13.8 ppm; HRMS (ESI): [M + Na]+ calcd for C19H24NaO7,
4-ones 3.
387.1420; found, 387.1453.
Ethyl 2,2-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-
Ethyl 6-(4-chlorophenyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-
carboxylate (3aa)
pyran-5-carboxylate (3ea)
The reaction was carried out according to general method A using The reaction was carried out according to general method A
ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl2 (11 mg, 0.1 using ethyl 3-(4-chlorophenyl)-3-oxopropanoate (1e, 226 mg, 1.0
mmol), Et3N (278 mL, 2.0 mmol), senecioyl chloride (2a, 112 mL, mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol),
1.0 mmol) in DCM (4 mL) for 6 h gave 3aa (219 mg, 80%) as a senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 3 h
1
colorless crystal. M.p. 78–80 ꢀC; H NMR (400 MHz, CDCl3): d gave 3ea (277 mg, 90%) as a white solid. M.p. 81–83 ꢀC; 1H NMR
7.53–7.51 (m, 2H), 7.49–7.45 (m, 1H), 7.40–7.37 (m, 2H), 4.05 (q, J (400 MHz, CDCl3): d 7.47 (d, J ¼ 8.8 Hz, 2H), 7.37 (d, J ¼ 8.8 Hz,
¼ 7.2 Hz, 2H), 2.64 (s, 2H), 1.56 (s, 6H), 0.98 (t, J ¼ 7.0 Hz, 3H); 13
C
2H), 4.09 (q, J ¼ 7.0 Hz, 2H), 2.65 (s, 2H), 1.56 (s, 6H), 1.06 (t, J ¼
NMR (100 MHz, CDCl3): d 188.9, 170.7, 165.9, 133.9, 131.5, 128.3, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 188.7, 169.1, 165.8,
128.2, 111.4, 81.9, 61.0, 47.0, 26.1, 13.7 ppm; MS (ESI): m/z 274.1 137.8, 132.2, 129.6, 128.7, 111.6, 82.1, 61.2, 47.0, 26.1, 13.7 ppm;
(M)+. Anal. calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.20; HRMS (ESI): [M + H]+ calcd for C16H18ClO4, 309.0894; found,
H, 6.65%.
309.0921.
Ethyl 2,2-dimethyl-6-(4-methylphenyl)-4-oxo-2,3-dihydro-4H-
Ethyl 6-(2-chlorophenyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-
pyran-5-carboxylate (3ba)
pyran-5-carboxylate (3fa)
The reaction was carried out according to general method A The reaction was carried out according to general method A
using ethyl 3-(4-methylphenyl)-3-oxopropanoate (1b, 206 mg, using ethyl 3-(2-chlorophenyl)-3-oxopropanoate (1f, 226 mg, 1.0
1.0 mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol),
senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 5 h senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 7 h
gave 3ba (236 mg, 82%) as a yellow solid. M.p. 88–90 ꢀC; 1H 3fa (246 mg, 80%) as a colorless liquid. 1H NMR (400 MHz,
NMR (400 MHz, CDCl3): d 7.41 (d, J ¼ 8.0 Hz, 2H), 7.18 (d, J ¼ 8.0 CDCl3): d 7.33–7.31 (m, 1H), 7.29–7.24 (m, 1H), 7.21–7.19 (m,
Hz, 2H), 4.07 (q, J ¼ 7.0 Hz, 2H), 2.62 (s, 2H), 2.36 (s, 3H), 1.54 1H), 7.18–7.15 (m, 1H), 3.84 (q, J ¼ 7.2 Hz, 2H), 2.58 (s, 2H), 1.47
(s, 6H), 1.01 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d (s, 6H), 0.75 (t, J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
187.9, 169.7, 165.2, 141.2, 129.9, 128.0, 127.2, 109.9, 80.5, 60.0, 188.4, 171.2, 164.2, 133.8, 132.6, 131.3, 129.8, 129.5, 126.5,
45.9, 25.0, 20.5, 12.7; HRMS (ESI): [M + H]+ calcd for C17H21O4, 112.5, 83.3, 60.6, 47.5, 26.1, 13.5 ppm. HRMS (ESI): [M + H]+
289.1440; found, 289.1461.
calcd for C16H18ClO4, 309.0894; found, 309.0895.
Ethyl 2,2-dimethyl-6-(4-methoxyphenyl)-4-oxo-2,3-dihydro-4H-
pyran-5-carboxylate (3ca)
Ethyl 2,3-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-
carboxylate (tc-3ab)
The reaction was carried out according to general method A The reaction was carried out according to general method A
using ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (1c, 222 mg, using ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl2 (11
1.0 mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), tigloyl chloride (2b, 110
senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 5 h mL, 1.0 mmol) in DCM (4 mL). Condition: room temperature, 7
gave 3ca (258 mg, 85%) as a yellow solid. M.p. 66–68 ꢀC; 1H NMR h. The crude diastereomeric mixture was puried through a
(400 MHz, CDCl3): d 7.52 (d, J ¼ 8.8 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, silica gel column chromatography (hexane–EtOAc ¼ 8 : 2). First
2H), 4.12 (q, J ¼ 7.0 Hz, 2H), 3.85 (s, 3H), 2.64 (s, 2H), 1.56 eluted was compound trans-3ab (128 mg, 47%), obtained as a
(s, 6H), 1.08 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d colourless solid and second eluted was cis-3ab (86 mg, 31%),
188.9, 170.3, 166.5, 162.4, 130.2, 125.9, 113.7, 110.4, 81.3, 61.1, obtained as pale yellow paste. The overall yield of tc-3ab was
55.4, 47.0, 26.1, 13.8 ppm; HRMS (ESI): [M + Na]+ calcd for 78% (214 mg). Compound trans-3ab: M.p. 76–78 ꢀC; 1H
C
17H20NaO5, 327.1208; found, 327.1238.
NMR (400 MHz, CDCl3): d 7.58–7.56 (m, 2H), 7.50–7.46 (m, 1H),
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7.41–7.37 (m, 2H), 4.44–4.36 (m, 1H), 4.13–4.04 (m, 2H), 2.52– 109.2, 81.6, 61.4, 47.1, 26.1, 14.1; HRMS (ESI): [M + H]+ calcd for
2.43 (m, 1H), 1.56 (d, J ¼ 6.0 Hz, 3H), 1.17 (d, J ¼ 6.8 Hz, 3H), C14H17O5, 265.1076; found, 265.1097.
1.03 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 191.3,
171.4, 166.2, 133.2, 131.7, 128.4, 128.3, 111.8, 80.9, 61.2, 44.5,
Ethyl 2,2,6-trimethyl-4-oxo-2,3-dihydro-4H-pyran-5-
carboxylate (3ja)
19.1, 13.7, 10.0 ppm; MS (ESI): m/z 274.1 (M)+. Anal. calcd for
C
16H18O4: C, 70.06; H, 6.61. Found: C, 70.18; H, 6.64%.
The reaction was carried out according to general method A using
ethyl acetoacetate (1j, 130 mg, 1.0 mmol), CaCl2 (11 mg, 0.1
mmol), Et3N (278 mL, 2.0 mmol), senecioyl chloride (2a, 112 mL,
1.0 mmol) in DCM (4 mL) for 7 h gave 3ja (159 mg, 75%) as a pale
Compound cis-3ab: 1H NMR (400 MHz, CDCl3): d 7.58–7.55 (m,
2H), 7.50–7.46 (m, 1H), 7.41–7.37 (m, 2H), 4.83–4.78 (m, 1H),
4.12–4.02 (m, 2H), 2.56–2.50 (m, 1H), 1.47 (d, J ¼ 6.8 Hz, 3H),
1.16 (d, J ¼ 7.2 Hz, 3H), 0.99 (t, J ¼ 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): d 193.2, 171.7, 166.1, 133.2, 131.8, 128.4, 128.3,
110.9, 78.5, 61.1, 43.4, 15.7, 13.7, 8.9 ppm; MS (ESI): m/z 274.0
(M)+. Anal. calcd for C16H18O4: C, 70.06; H, 6.61. Found: C,
70.22; H, 6.67%.
1
yellow liquid. H NMR (400 MHz, CDCl3): d 4.24 (q, J ¼ 7.0 Hz,
2H), 2.49 (s, 2H), 2.16 (s, 3H), 1.41 (s, 6H), 1.29 (t, J ¼ 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 188.2, 175.4, 165.8, 110.8, 81.5, 60.9,
47.1, 26.2, 20.8, 14.2 ppm; MS (ESI): m/z 212.1 (M)+. Anal. Calcd for
C11H16O4: C, 62.25; H, 7.60. Found: C, 62.46; H, 7.68%.
Ethyl 2-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-
carboxylate (3ac)
Ethyl 2,6-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3jc)
The reaction was carried out according to general method A
using ethyl acetoacetate (1j, 130 mg, 1.0 mmol), CaCl2 (11 mg,
0.1 mmol), Et3N (278 mL, 2.0 mmol), crotonoyl chloride (2c, 96
mL, 1.0 mmol) in DCM (4 mL) for 8 h gave 3jc (119 mg, 60%) as a
pale yellow liquid. 1H NMR (400 MHz, CDCl3): d 4.61–4.48
(m, 1H), 4.27 (q, J ¼ 7.0 Hz, 2H), 2.48–2.46 (m, 2H), 2.19 (s, 3H),
1.46 (d, J ¼ 6.4 Hz, 3H), 1.31 (t, J ¼ 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): d 188.1, 176.7, 165.5, 112.4, 75.6, 60.9, 42.3, 20.2,
20.1, 14.1 ppm; MS (ESI): m/z 198.1 (M)+. Anal. calcd for
The reaction was carried out according to general method A
using ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl2 (11
mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), crotonoyl chloride (2c,
96 mL, 1.0 mmol) in DCM (4 mL) for 7 h gave 3ac (182 mg, 70%)
as a colorless solid. M.p. 93–95 ꢀC; 1H NMR (400 MHz, CDCl3): d
7.59–7.57 (m, 2H), 7.52–7.47 (m, 1H), 7.43–7.38 (m, 2H), 4.83–
4.74 (m, 1H), 4.13–4.03 (m, 2H), 2.67–2.55 (m, 2H), 1.58 (d, J ¼
6.4 Hz, 3H), 1.01 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 188.9, 172.4, 165.9, 133.2, 131.7, 128.4, 128.3, 112.4, 76.2, 61.1,
42.4, 20.3, 13.7 ppm; MS (ESI): m/z 261.3 (M + 1)+. Anal. calcd for
C
10H14O4: C, 60.59; H, 7.12. Found: C, 60.78; H, 7.18%.
C
15H16O4: C, 69.22; H, 6.20. Found: C, 69.40; H, 6.26%.
Methyl 6-ethyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-
carboxylate (3ka)
Ethyl 2,2-dimethyl-4-oxo-6-(thiophen-2-yl)-2,3-dihydro-4H-
pyran-5-carboxylate (3ga)
The reaction was carried out according to general method A
using methyl 3-oxo-pentanoate (1k, 130 mg, 1.0 mmol), CaCl2
(11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), senecioyl chloride
(2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3ka (170 mg,
80%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3): d 3.79
(s, 3H), 2.52 (s, 2H), 2.47 (q, J ¼ 7.4 Hz, 2H), 1.43 (s, 6H), 1.16 (t, J
¼ 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 188.6, 179.5, 166.3,
109.9, 81.4, 52.0, 47.0, 27.5, 26.0, 11.2; HRMS (ESI): [M + H]+
calcd for C11H17O4, 213.1127; found, 213.1140.
The reaction was carried out according to general method A
using ethyl 3-oxo-3-(thiophen-2-yl)propanoate (1g, 198 mg, 1.0
mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol),
senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 6 h
gave 3ga (246 mg, 88%) as a pale yellow color crystal. M.p. 92–94
ꢀC; 1H NMR (400 MHz, CDCl3): d 7.54 (d, J ¼ 4.8 Hz, 1H), 7.44–
7.43 (m, 1H), 7.05–7.02 (dd, J ¼ 4.8, 4.0 Hz, 1H), 4.21 (q, J ¼ 7.2
Hz, 2H), 2.57 (s, 2H), 1.49 (s, 6H), 1.19 (t, J ¼ 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 188.8, 166.2, 161.5, 135.3, 131.7,
131.0, 128.0, 109.9, 81.8, 61.6, 46.9, 26.0, 13.9; HRMS (ESI): [M + Methyl 6-ethyl-2,3-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-
H]+ calcd for C14H17O4S, 281.0848; found, 281.0869. Single carboxylate (tc-3kb)
crystals suitable for X-ray studies were grown from a solution of
3ga in hexane–ethyl acetate (3 : 7).
The reaction was carried out according general method A using
methyl 3-oxo-pentanoate (1k, 130 mg, 1.0 mmol), CaCl2 (11 mg,
0.1 mmol), Et3N (278 mL, 2.0 mmol), tigloyl chloride (2b, 110 mL,
1.0 mmol) in DCM (4 mL). Condition: room temperature, 7 h. The
crude diastereomeric mixture was puried through a silica gel
Ethyl 6-(furan-2-yl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-
5-carboxylate (3ha)
The reaction was carried out according to general method A using column chromatography (hexane–EtOAc ¼ 8 : 2). First eluted was
ethyl 3-(furan-2-yl)-3-oxopropanoate (1h, 182 mg, 1.0 mmol), compound trans-3kb (99 mg, 47%), obtained as a pale yellow
CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), senecioyl liquid and second eluted was cis-3kb (66 mg, 31%), obtained as a
chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 7 h gave 3ha pale yellow liquid. The overall yield of tc-3kb was 78% (165 mg).
(227 mg, 86%) as a yellow solid. M.p. 70–72 ꢀC; 1H NMR (400 MHz, Compound trans-3kb: 1H NMR (400 MHz, CDCl3): d 4.20–4.13 (m,
CDCl3): d 7.53–7.52 (dd, J ¼ 1.6, 0.8 Hz, 1H), 6.98–6.97 (dd, J ¼ 3.6, 1H), 3.80 (s, 3H), 2.52–2.42 (m, 2H), 2.36–2.26 (m, 1H), 1.46 (d, J ¼
0.4 Hz, 1H), 6.52–6.51 (dd, J ¼ 3.4, 1.8 Hz, 1H), 4.31 (q, J ¼ 7.2 Hz, 6.4 Hz, 3H), 1.17 (t, J ¼ 7.4 Hz, 3H), 1.10 (d, J ¼ 6.8 Hz, 3H); 13
C
2H), 2.61 (s, 2H), 1.52 (s, 6H), 1.28 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 NMR (100 MHz, CDCl3): d 191.0, 180.0, 166.5, 110.6, 80.5, 52.1,
MHz, CDCl3): d 188.7, 165.5, 156.8, 146.9, 146.1, 116.1, 112.3, 44.4, 27.2, 19.0, 11.2, 10.3 ppm; MS (ESI): m/z 212.0 (M)+. Anal.
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calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.42; H, 7.66. d 7.30–7.24 (m, 5H), 4.29 (q, J ¼ 7.2 Hz, 2H), 3.78 (s, 2H), 2.52 (s,
1
Compound cis-3kb: H NMR (400 MHz, CDCl3): d 4.61–4.55 (m, 2H), 1.33 (s, 6H), 1.31 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz,
1H), 3.79 (s, 3H), 2.51–2.41 (m, 3H), 1.36 (d, J ¼ 6.4 Hz, 3H), 1.18 (t, CDCl3): d 188.7, 174.8, 165.7, 135.5, 129.0, 128.5, 127.0, 111.5,
J ¼ 7.6 Hz, 3H), 1.07 (d, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, 81.6, 61.2, 47.2, 39.6, 25.9, 14.2 ppm; HRMS (ESI): [M + H]+ calcd
CDCl3): d 192.9, 180.2, 166.4, 109.9, 80.5, 52.1, 43.3, 27.1, 15.5, for C17H21O4, 289.1440; found, 289.1460.
11.3, 9.1 ppm; MS (ESI): m/z 212.0 (M)+. Anal. calcd for C11H16O4:
C, 62.25; H, 7.60. Found: C, 62.46, H, 7.69.
Ethyl 6-benzyl-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-
carboxylate (3nc)
Methyl 2-ethyl-6-methyl-4-oxo-2,3-dihydro-4H-pyran-5-
carboxylate (3lf)
The reaction was carried out according to general method A
using ethyl 3-oxo-4-phenylbutanoate (1n, 206 mg, 1.0 mmol),
The reaction was carried out according to general method A using CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), crotonoyl
methyl acetoacetate (1l, 116 mg, 1.0 mmol), CaCl2 (11 mg, 0.1 chloride (2c, 96 mL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3nc
mmol), Et3N (278 mL, 2.0 mmol), trans-2-pentenoyl chloride (2f, (192 mg, 70%) as a pale yellow liquid. 1H NMR (400 MHz,
114 mL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3lf (99 mg, 50%) as CDCl3): d 7.31–7.27 (m, 5H), 4.56–4.47 (m, 1H), 4.29 (q, J ¼ 7.0
a pale yellow liquid. 1H NMR (400 MHz, CDCl3): d 4.33–4.26 Hz, 2H), 3.84–3.73 (m, 2H), 2.48 (d, J ¼ 8.0 Hz, 2H), 1.41 (d, J ¼
(m, 1H), 3.74 (s, 3H), 2.44–2.41 (m, 2H), 2.17 (s, 3H), 1.82–1.64 6.4 Hz, 3H), 1.31 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz,
(m, 2H), 0.96 (t, J ¼ 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d CDCl3): d 188.7, 176.5, 165.6, 135.4, 129.0, 128.6, 127.1, 112.9,
188.3, 177.7, 166.1, 111.9, 80.4, 52.0, 40.3, 27.2, 20.4, 9.0 ppm; MS 75.9, 61.3, 42.4, 39.4, 20.1, 14.2 ppm; MS (ESI): m/z 275.3 (M +
(ESI): m/z 198.1 (M)+. Anal. calcd for C10H14O4: C, 60.59; H, 7.12. 1)+. Anal. calcd for C16H18O4: C, 70.06; H, 6.61. Found: C,
Found: C, 60.81; H, 7.19%.
70.29; H, 6.67%.
Ethyl 6-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-4-oxo-2,3-dihydro-
4H-pyran-5-carboxylate (3ma)
General method B: typical experimental procedure for the
O-acylation of cyclic active methylene compounds (5)
The reaction was carried out according to general method A To a suspension of cyclic active methylene compounds (4, 1.0
using diethyl 1,3-acetonedicarboxylate (1m, 202 mg, 1.0 mmol), mmol), CaCl2 (0.1 mmol) and Et3N (2.0 mmol) in 4 mL of DCM
CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), senecioyl was added senecioyl chloride (2a, 1.0 mmol) dropwise at 10 ꢀC.
chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3ma Aer completion of the addition the reaction mixture was
(128 mg, 45%) as a yellow liquid. 1H NMR (400 MHz, CDCl3): d allowed to stir at room temperature for 3–6 h. The reaction
4.25 (q, J ¼ 7.0 Hz, 2H), 4.18 (q, J ¼ 7.2 Hz, 2H), 3.57 (s, 2H), 2.57 mixture was quenched with water, neutralised by dil. HCl,
(s, 2H), 1.46 (s, 6H), 1.32–1.24 (m, 6H); 13C NMR (100 MHz, extracted with CH2Cl2 (2 ꢁ 8 mL) and washed with brine. The
CDCl3): d 188.3, 171.7, 167.6, 164.9, 111.2, 82.6, 61.4, 61.1, 47.4, organic layer was separated, dried over anhydrous Na2SO4 and
40.5, 25.9, 14.1, 14.0 ppm; MS (ESI): m/z 284 (M)+. Anal. calcd for concentrated under reduced pressure. The crude product was
C
14H20O6: C, 59.14; H, 7.09. Found: C, 59.33; H, 7.16%.
puried by column chromatography (hexane–EtOAc ¼ 9 : 1) to
afford pure O-acylated product 5a-b.
Ethyl 6-(2-ethoxy-2-oxoethyl)-2-methyl-4-oxo-2,3-dihydro-4H-
pyran-5-carboxylate (3mc)
2-Oxo-2H-chromen-4-yl 3-methylbut-2-enoate (5a)
The reaction was carried out according to general method A The reaction was carried out according to general method B using
using diethyl 1,3-acetonedicarboxylate (1m, 202 mg, 1.0 mmol), 4-hydroxy-2H-chromen-2-one (4a, 162 mg, 1.0 mmol), CaCl2 (11
CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), crotonoyl mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), senecioyl chloride
chloride (2c, 96 mL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3mc (2a,112 mL, 1.0 mmol) in DCM (4 mL) for 3 h gave 5a (232 mg,
1
(81 mg, 30%) as a yellow liquid. H NMR (400 MHz, CDCl3): d 95%) as a white solid. M.p. 78–80 ꢀC; 1H NMR (400 MHz, CDCl3): d
4.69–4.62 (m, 1H), 4.25 (q, J ¼ 7.0 Hz, 2H), 4.18 (q, J ¼ 7.0 Hz, 7.66 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.59–7.55 (m, 1H), 7.36 (d, J ¼ 8.4 Hz,
2H), 3.66–3.52 (m, 2H), 2.54–2.52 (m, 2H), 1.47 (d, J ¼ 6.4 Hz, 1H), 7.29 (t, J ¼ 8.4 Hz, 1H), 6.53 (s, 1H), 6.01–6.00 (m, 1H), 2.28 (s,
3H), 1.31–1.24 (m, 6H); 13C NMR (100 MHz, CDCl3): d 188.3, 3H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3): d 164.6, 161.8, 161.7,
173.1, 167.5, 164.8, 112.8, 76.4, 61.6, 61.2, 42.6, 40.2, 20.0, 14.1, 158.7, 153.7, 132.6, 124.2, 122.9, 116.9, 115.9, 113.7, 104.8, 27.9,
14.0 ppm; MS (ESI): m/z 270 (M)+. Anal. calcd for C13H18O6: C, 20.9 ppm; MS (ESI): m/z 244.1 (M)+. Anal. calcd for C14H12O4: C,
57.77; H, 6.71. Found: C, 58.06; H, 6.82%.
68.85; H, 4.95. Found: C, 68.97; H, 4.99%.
Ethyl 6-benzyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-
3-Methyl-1-phenyl-1H-pyrazol-5-yl 3-methylbut-2-enoate (5b)
carboxylate (3na)
The reaction was carried out according to general method B
The reaction was carried out according to general method A using 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (4b, 174 mg,
using ethyl 3-oxo-4-phenylbutanoate (1n, 206 mg, 1.0 mmol), 1.0 mmol), CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol),
CaCl2 (11 mg, 0.1 mmol), Et3N (278 mL, 2.0 mmol), senecioyl senecioyl chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 6
chloride (2a, 112 mL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3na h gave 5b (218 mg, 85%) as a pale yellow liquid. 1H NMR (400
(225 mg, 78%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3): MHz, CDCl3): d 7.55 (d, J ¼ 8.0 Hz, 2H), 7.41 (t, J ¼ 8.0 Hz, 2H),
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7.27 (t, J ¼ 7.4 Hz, 1H), 6.11 (s, 1H), 5.80 (s, 1H), 2.32 (s, 3H), (M ꢂ 1)+. Anal. calcd for C19H24O6: C, 65.50; H, 6.94. Found: C,
2.18 (s, 3H), 1.95 (s, 3H); 13C NMR (100 MHz, CDCl3): d 163.2, 65.66; H, 6.98%.
161.3, 148.9, 144.7, 138.3, 128.9, 126.8, 122.9, 113.7, 95.8,
27.7, 20.7, 14.5 ppm; MS (ESI): m/z 256.0 (M)+. Anal. calcd for anones tc-10b (trans-10b and cis-10b) and 10c were synthesized.
15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.38; H,
In the same manner, 5-carboalkoxy-2,3-dihydro-4H-pyr-
C
6.33; N, 11.06%.
Ethyl 6-(3,5-dimethoxybenzyl)-2,3-dimethyl-4-oxo-2,3-dihydro-
4H-pyran-5-carboxylate (tc-10b)
3,5-Dimethoxyphenylacetic acid (8)
The reaction was carried out similar to compound 10a using
ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg, 1.0
mmol), Mg(OEt)2 (114 mg, 1.0 mmol) in dry toluene (5 mL) and
tigloyl chloride (2b, 110 mL, 1.0 mmol) in ACN (1 mL) for 10 h.
The crude diastereomeric mixture was puried through a silica
gel column chromatography (hexane–EtOAc ¼ 8 : 2). First
eluted was compound trans-10b (146 mg, 42%), obtained as a
pale yellow paste and second eluted was cis-10b (98 mg, 28%),
obtained as a pale yellow paste. The overall yield of tc-10b was
70% (244 mg). Compound trans-10b: 1H NMR (400 MHz,
CDCl3): d 6.38 (d, J ¼ 2.4 Hz, 2H), 6.30–6.27 (m, 1H), 4.22 (q, J ¼
3,5-Dimethoxyphenylacetic acid (8) was prepared from 3,5-
dimethoxtacetophenone (7) according to the literature proce-
dure.24 Spectral data and melting points are matched with
literature procedure. M.p. 101–103 ꢀC; 1H NMR (400 MHz,
CDCl3): d 6.43 (d, J ¼ 2.0 Hz, 2H), 6.38 (t, J ¼ 2.2 Hz, 1H), 3.77
(s, 6H), 3.57 (s, 2H); 13C NMR (100 MHz, CDCl3): d 177.4, 160.9,
135.3, 107.5, 99.4, 55.3, 41.3 ppm.
Ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9)
To 3,5-dimethoxyphenylacetic acid (8, 196 mg, 1.0 mmol) in 7.0 Hz, 2H), 4.11–4.04 (m, 1H), 3.71 (s, 2H), 3.70 (s, 6H), 2.31–
DCM solution at 25 ꢀC Meldrum's acid (144 mg, 1.0 mmol), DCC 2.23 (m, 1H), 1.35 (d, J ¼ 6.4 Hz, 3H), 1.25 (t, J ¼ 7.2 Hz, 3H), 1.03
(227 mg, 1.1 mmol) and DMAP (134 mg, 1.1 mmol) were added, (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 190.9, 175.1,
and the solution was stirred at 25 ꢀC for 10 h. The insoluble DCC 165.8, 160.9, 137.6, 112.3, 107.2, 99.1, 80.7, 61.2, 55.3, 44.6, 39.4,
by-product was then ltered off and the remaining solution was 19.0, 14.2, 10.2 ppm; MS (ESI): m/z 347.3 (M ꢂ 1)+. Anal. calcd
concentrated. The crude extract was then dissolved in EtOH for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.68; H, 6.99%.
(5 mL) and reuxed for 8 h. Following concentration in vacuo, Compound cis-10b: 1H NMR (400 MHz, CDCl3): d 6.43 (d, J ¼ 2.0
the crude material was puried by column chromatography Hz, 2H), 6.34 (s, 1H), 4.59–4.53 (m, 1H), 4.28 (q, J ¼ 7.0 Hz, 2H),
(hexane–EtOAc ¼ 9 : 1) to yield the pure product 9 (133 mg, 3.76 (s, 6H), 3.70 (d, J ¼ 4.0 Hz, 2H), 2.48–2.42 (m, 1H), 1.32–1.24
50%) as colorless liquid. 9 : 1 keto–enol mixture was identied (m, 6H), 1.04 (d, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
by 1H NMR. 1H NMR keto tautomer (400 MHz, CDCl3): d 6.37 (t, J 191.7, 174.2, 164.8, 159.8, 136.6, 110.6, 106.0, 98.1, 77.3, 60.2,
¼ 2.4 Hz, 1H), 6.35 (d, J ¼ 2.0 Hz, 2H), 4.17 (q, J ¼ 7.0 Hz, 2H), 54.3, 42.3, 38.4, 14.3, 13.2, 8.0 ppm; MS (ESI): m/z 347.4 (M ꢂ
3.77 (s, 6H), 3.74 (s, 2H), 3.44 (s, 2H), 1.26 (t, J ¼ 7.2 Hz, 3H); 13
C
1)+. Anal. calcd for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.72;
NMR keto tautomer (100 MHz, CDCl3): d 200.4, 167.1, 161.1, H, 7.02%.
161.0, 135.3, 107.6, 99.4, 61.4, 55.3, 50.3, 48.0, 14.1 ppm; MS
(ESI): m/z 267.3 (M + 1)+. Anal. calcd for C14H18O5: C, 63.15; H, Ethyl 6-(3,5-dimethoxybenzyl)-2-methyl-4-oxo-2,3-dihydro-4H-
6.81. Found: C, 63.34; H, 6.88%.
pyran-5-carboxylate (10c)
The reaction was carried out similar to compound 10a using
ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg, 1.0
mmol), Mg(OEt)2 (114 mg, 1.0 mmol) in dry toluene (5 mL) and
crotonoyl chloride (2c, 96 mL, 1.0 mmol) in ACN (1 mL) for 10 h.
The title compounds 10c (210 mg, 63%) was obtained as pale
yellow paste aer passing through a silica gel column chro-
matography (hexane–EtOAc ¼ 8 : 2). 1H NMR (400 MHz, CDCl3):
d 6.46 (d, J ¼ 2.4 Hz, 2H), 6.37 (t, J ¼ 2.2 Hz, 1H), 4.58–4.49
(m, 1H), 4.3 (q, J ¼ 7.2 Hz, 2H), 3.78 (s, 8H), 2.50–2.48 (m, 2H),
1.43 (d, J ¼ 6.4 Hz, 3H), 1.33 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): d 188.7, 176.2, 165.6, 160.8, 137.5, 113.0, 107.2,
99.0, 75.9, 61.3, 55.3, 42.4, 39.5, 20.1, 14.2 ppm; MS (ESI): m/z
333.4 (M ꢂ 1)+. Anal. calcd for C18H22O6: C, 64.66; H, 6.63.
Found: C, 64.83; H, 6.69%.
Ethyl 6-(3,5-dimethoxybenzyl)-2,2-dimethyl-4-oxo-2,3-dihydro-
4H-pyran-5-carboxylate (10a)
To ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg,
1.0 mmol) in dry toluene (5 mL) solution Mg(OEt)2 (114 mmol,
1.0 mmol) was added and reuxed for 30 min under N2 atm.
Then senecioyl chloride (2a, 112 mL, 1.0 mmol) in dry ACN (1
mL) was added dropwise at 10 ꢀC. Aer completion of the
addition the reaction mixture was allowed to stir at room
temperature for 10 h. The reaction mixture was quenched
with water, neutralised by dil. HCl, extracted with EtOAc (2 ꢁ
8 mL) and washed with brine. The organic layer was sepa-
rated, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude material was puried by column
chromatography (hexane–EtOAc ¼ 8 : 2) to afford pure 10a
(261 mg, 75%) as pale yellow solid. M.p. 40–42 ꢀC; 1H NMR
(400 MHz, CDCl3): d 6.44 (d, J ¼ 2.4 Hz, 2H), 6.34 (t, J ¼ 2.2 Hz,
5-Hydroxy-6,8-dimethoxy-2,2-dimethyl-4H-2,3-
dihydronaphtho[2,3-b]-pyran-4-one (11a)
1H), 4.29 (q, J ¼ 7.2 Hz, 2H), 3.76 (s, 6H), 3.70 (s, 2H), 2.52 (s, To ethyl 6-(3,5-dimethoxybenzyl)-2,2-dimethyl-4-oxo-2,3-dihy-
2H), 1.35 (s, 6H), 1.31 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, dro-4H-pyran-5-carboxylate (10a, 348 mg, 1.0 mmol) in PPA
CDCl3): d 188.7, 174.4, 165.7, 160.8, 137.6, 111.6, 107.2, 99.1, (2.0 mL) mixture was heated at 80 ꢀC for 15 min. The reac-
81.6, 61.2, 55.3, 47.2, 39.7, 26.0, 14.2 ppm; MS (ESI): m/z 347.3 tion mixture was quenched by crushed ice and extracted with
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EtOAc (3 ꢁ 10 mL). Finally organic layer was neutralised by 96.5, 73.1, 56.0, 55.4, 55.3, 43.9, 21.0 ppm; MS (ESI): m/z 289.0
10% NaHCO3 solution and EtOAc layer separated, dried over (M + 1)+. Anal. calcd for C16H16O5: C, 66.66; H, 5.59. Found: C,
anhydrous Na2SO4 and concentrated under reduced pressure. 66.82; H, 5.64%.
The crude was puried by column chromatography (hexane–
EtOAc ¼ 9 : 1) to afford pure 11a (287 mg, 95%) as yellow
5-Hydroxy-2,2-dimethyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-
colour solid. M.p. 153–155 ꢀC; 1H NMR (400 MHz, CDCl3): d
4-one (11na) and 4-hydroxy-2,2-dimethyl-2H-benzo[g]
14.36 (s, 1H), 6.47 (s, 1H), 6.42 (d, J ¼ 2.0 Hz, 1H), 6.27 (d, J
chromen-5(3H)-one (11na0)
¼ 2.0 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.76 (s, 2H), 1.45
(s, 6H); 13C NMR (100 MHz, CDCl3): d 197.5, 164.9, 162.4, The reaction was carried out similar to compound 11a
161.4, 154.8, 143.6, 107.0, 103.3, 102.2, 98.3, 96.4, 77.8, using ethyl 6-benzyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-
56.0, 55.4, 48.3, 26.9 ppm; MS (ESI): m/z 303.1 (M + 1)+. Anal. 5-carboxylate (3na, 288 mg, 1.0 mmol) in PPA (2.0 mL) at
calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.62; H, 80 ꢀC for 45 min. The crude mixture was puried through a
6.05%.
silica gel column chromatography (hexane–EtOAc ¼ 9 : 1).
In the same manner, dihydronaphthopyran-4-ones tc-11b First eluted was compound 11na (121 mg, 50%), obtained as
(trans-11b and cis-11b), 11c, 11na, 11na0, 11nc and 11nc0 were a yellow solid and second eluted was 11na0 (109 mg, 45%),
synthesized.
obtained as a yellow solid. Compound 11na: M.p. 78–80 ꢀC;
1H NMR (400 MHz, CDCl3): d 13.35 (s, 1H), 8.24 (d, J ¼ 8.0
Hz, 1H), 7.53–7.46 (m, 2H), 7.30–7.26 (m, 1H), 6.66 (s, 1H),
2.78 (s, 2H), 1.45 (s, 6H); 13C NMR (100 MHz, CDCl3): d 198.9,
162.4, 153.6, 139.0, 130.8, 126.5, 124.4, 123.5, 120.3, 104.4,
102.7, 77.9, 48.6, 27.0 ppm; MS (ESI): m/z 240.7 (M ꢂ 1)+.
Anal. calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.44;
H, 5.85%. Compound 11na0: M.p. 70–72 ꢀC; 1H NMR
(400 MHz, CDCl3): d 11.12 (s, 1H), 8.13 (d, J ¼ 8.4 Hz, 1H),
7.56–7.48 (m, 2H), 7.28–7.24 (m, 1H), 6.72 (s, 1H), 2.86
(s, 2H), 1.59 (s, 6H); 13C NMR (100 MHz, CDCl3): d 197.9,
159.4, 155.6, 139.4, 130.7, 126.4, 123.9, 123.1, 119.5, 105.3,
102.6, 80.4, 47.9, 26.5 ppm; MS (ESI): m/z 240.7 (M ꢂ 1)+.
Anal. calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.53;
H, 5.88%.
5-Hydroxy-6,8-dimethoxy-2,3-dimethyl-4H-2,3-dihydronaphtho
[2,3-b]-pyran-4-one (tc-11b)
The reaction was carried out similar to compound 11a using
ethyl 6-(3,5-dimethoxybenzyl)-2,3-dimethyl-4-oxo-2,3-dihydro-
4H-pyran-5-carboxylate (tc-10b, 348 mg, 1.0 mmol) in PPA
(2.0 mL) for 15 min. The crude diastereomeric mixture was
puried through a silica gel column chromatography (hexane–
EtOAc ¼ 9 : 1). First eluted was compound trans-11b (168 mg,
56%), obtained as a yellow solid and second eluted was cis-11b
(112 mg, 37%), obtained as a yellow solid. The overall yield of
tc-11b was 93% (280 mg). Compound trans-11b: M.p. 168–170
ꢀC; 1H NMR (400 MHz, CDCl3): d 14.47 (s, 1H), 6.48 (s, 1H),
6.43 (s, 1H), 6.28 (s, 1H), 4.23–4.16 (m, 1H), 3.95 (s, 3H), 3.88
(s, 3H), 2.69–2.61 (m, 1H), 1.50 (d, J ¼ 6.0 Hz, 3H), 1.26 (d, J ¼
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 200.0, 165.1, 162.3,
161.3, 156.0, 143.3, 107.2, 103.0, 101.2, 98.3, 96.4, 78.0, 56.0,
55.4, 46.5, 19.8, 10.5 ppm. MS (ESI): m/z 303.1 (M + 1)+. Anal.
calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.69; H,
6.06%. Compound cis-11b: M.p. 113–115 ꢀC; 1H NMR (400
MHz, CDCl3): d 14.40 (s, 1H), 6.50 (s, 1H), 6.44 (d, J ¼ 2.0 Hz,
1H), 6.28 (d, J ¼ 1.6 Hz, 3H), 4.61–4.55 (m, 1H), 3.96 (s, 3H),
3.88 (s, 3H), 2.72–2.65 (m, 1H), 1.39 (d, J ¼ 6.8 Hz, 3H), 1.22 (d,
J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 201.8, 165.5,
162.4, 161.4, 155.8, 143.3, 107.3, 102.5, 101.3, 98.3, 96.5, 75.3,
56.0, 55.4, 44.9, 16.5, 9.6 ppm; MS (ESI): m/z 303.0 (M + 1)+.
Anal. calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.75; H,
6.10%.
5-Hydroxy-2-methyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one
(11nc) and 4-hydroxy-2-methyl-2H-benzo[g]chromen-5(3H)-one
(11nc0)
The reaction was carried out similar to compound 11a using
ethyl 6-benzyl-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate
ꢀ
(3nc, 274 mg, 1.0 mmol) in PPA (2.0 mL) at 80 C for 45 min.
The crude mixture was puried through a silica gel column
chromatography (hexane–EtOAc ¼ 9 : 1). First eluted was
compound 11nc (103 mg, 45%), obtained as a yellow solid and
second eluted was 11nc0 (91 mg, 40%), obtained as a yellow
solid. Compound 11nc: M.p. 74–76 ꢀC; 1H NMR (400 MHz,
CDCl3): d 13.39 (s, 1H), 8.27 (d, J ¼ 8.4 Hz, 1H), 7.58–7.50 (m,
2H), 7.32 (t, J ¼ 7.4 Hz, 1H), 6.72 (s, 1H), 4.61–4.53 (m, 1H), 2.84–
2.74 (m, 2H), 1.53 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 199.0, 162.7, 155.1, 138.8, 130.9, 126.6, 124.4, 123.6,
120.4, 104.8, 102.0, 73.3, 44.3, 21.0 ppm. MS (ESI): m/z 226.7 (M
5-Hydroxy-6,8-dimethoxy-2-methyl-4H-2,3-dihydronaphtho
[2,3-b]-pyran-4-one (11c)
The reaction was carried out similar to compound 11a using ꢂ 1)+. Anal. calcd for C14H12O3: C, 73.67; H, 5.30. Found: C,
ethyl 6-(3,5-dimethoxybenzyl)-2-methyl-4-oxo-2,3-dihydro-4H- 73.79; H, 5.35%. Compound 11nc0: M.p. 66–68 ꢀC; 1H NMR
pyran-5-carboxylate (10c, 334 mg, 1.0 mmol) in PPA (2.0 mL) (400 MHz, CDCl3): d 11.13 (s, 1H), 8.14 (d, J ¼ 8.4 Hz, 1H), 7.57–
for 15 min gave 11c (259 mg, 90%) as yellow colour solid. M.p. 7.49 (m, 2H), 7.29–7.26 (m, 1H), 6.75 (s, 1H), 4.83–4.77 (m, 1H),
176–178 ꢀC; 1H NMR (400 MHz, CDCl3): d 14.40 (s, 1H), 6.50 (s, 2.91–2.75 (m, 2H), 1.67 (d, J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz,
1H), 6.44 (d, J ¼ 2.0 Hz, 1H), 6.28 (d, J ¼ 2.4 Hz, 1H), 4.56–4.49 CDCl3): d 198.0, 161.1, 155.8, 139.2, 130.7, 126.4, 123.8, 123.2,
(m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.81–2.67 (m, 2H), 1.50 (d, J 118.9, 106.1, 103.1, 75.1, 43.5, 20.7 ppm. MS (ESI): m/z 226.7 (M
¼ 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): d 197.7, 165.2, ꢂ 1)+. Anal. calcd for C14H12O3: C, 73.67; H, 5.30. Found: C,
162.5, 161.4, 156.3, 143.4, 107.2, 103.7, 101.5, 101.4, 98.4, 73.83; H, 5.39%.
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RSC Advances
Med. Chem. Lett., 2012, 3, 387–391, For synthesis of
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Acknowledgements
P.S. thanks UGC-RFSMS, New Delhi for the award of fellowship.
We thank DST-FIST, New Delhi for NMR and XRD facilities at
School of Chemistry, Bharathidasan University, Tiruchirappalli,
India. We also thank P. Venkatesan, School of Chemistry,
Bharathidasan University, Tiruchirappalli, India for his help in
X-ray structure determination.
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´
dihydronaphthopyranone, see: (a) M. Macıas, M. Ulloa,
A. Gamboa and R. Mata, J. Nat. Prod., 2000, 63, 757–761;
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