The first synthesis of bis(arylmethylidene)dioxan-5-ones: Potential scaffolds to access vicinal tricarbonyl derivatives

Article abstract of DOI:10.1055/s-2008-1067114

Double crossed-aldol condensation of a variety of aromatic aldehydes with l,3-dioxan-5-one in the presence of magnesium bromide diethyl etherate and diethylamine at room temperature is described. Excellent yields of 4,6-bis(arylmeth-ylidene)dioxan-5-ones are achieved in a facile, one-pot, general procedure. The structure and the Z,Z-configuration of the exocyclic double bonds of the products were determined by spectroscopic methods and X-ray crystallography, respectively. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067114

2122
PAPER
The First Synthesis of Bis(arylmethylidene)dioxan-5-ones: Potential Scaffolds
to Access Vicinal Tricarbonyl Derivatives
S
ynthesis of Bis(arylm
.
ethylidene)d
S
ioxan-5-one
s
aeed Abaee,*a Mohammad M. Mojtahedi,*a Vahid Hamidi,a A.Wahid Mesbah,a Werner Massab
a
Organic Chemistry Department, Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Fachbereich Chemie der Philipps-Universitaet Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax +98(21)44580762; E-mail: abaee@ccerci.ac.ir; E-mail: mojtahedi@ccerci.ac.ir
b
Received 4 March 2008; revised 7 April 2008
O
O
Abstract: Double crossed-aldol condensation of a variety of aro-
matic aldehydes with 1,3-dioxan-5-one in the presence of magne-
sium bromide diethyl etherate and diethylamine at room
temperature is described. Excellent yields of 4,6-bis(arylmeth-
ylidene)dioxan-5-ones are achieved in a facile, one-pot, general
procedure. The structure and the Z,Z-configuration of the exocyclic
double bonds of the products were determined by spectroscopic
methods and X-ray crystallography, respectively.
Ar
Ar
Ar
Ar
Ar
X
3
1
2: X = S, O, NH
O
O
O
Ar
Ar
Ar
Ar
O
O
O
O
S
Key words: dioxanone, aldol condensation, MgBr2·Et2O, hetero-
cycles
4
O
MgBr2·OEt2, Et2NH
ArCHO
The first synthesis of vicinal tricarbonyl compounds1 (e.g.
1; Scheme 1) was reported in 1890 by de Neufville and
von Pechmann.2 These compounds or their derivatives
have found synthetic applications as coupling reagents for
biopolymer conjugates,3 antibiotic drugs,4 contact aller-
gen,5 and photoconductive agents.6 In addition, the a,b-
diketoester and amide derivatives of these compounds7
have found synthetic applications in the preparation of
various natural products or their precursors such as fused-
ring b-lactams,8 indole alkaloids,9 marine metabolites,10
enzyme inhibitors,11 and bioactive depsipeptides.12
O
O
6
5
Scheme 1
ses,24 alcohol protection,25 Knoevenagel condensation,26
and nucleophilic ring-opening of epoxides with thiols27
and amines.28 In this study, we report an efficient room
temperature procedure for solvent-free aldol condensation
of ketone 5 with various aldehydes in the presence of
MgBr2·Et2O and diethylamine (Et2NH), leading to the for-
mation of various novel 4,6-bis(arylmethylidene)dioxan-
5-ones (6).
In the framework of our extensive investigations on the
synthesis of bisarylmethylidenes of cyclic ketones,13 we
recently reported a facile synthesis of several derivatives
of thiopyranone (2: X = S),14 pyranone (2: X = O),15 pip-
eridinone (2: X = NH),16 and cyclic enone (3)17 com-
pounds using mild Lewis-acidic conditions. Very
recently, we also introduced a general procedure through
which to access novel 3-substituted thiopyran-4-ones
(4).18 We have now applied this method to the preparation
of bisarylmethylidene derivatives of the 1,3-dioxan-5-one
system (e.g. 5)19 in order to synthesize compounds of type
6 as potential scaffolds to access 1,2,3-trione compounds
via removal of their acetonide protecting functionality.
Table 1 shows the summarized results for the reactions of
various aromatic aldehydes with ketone 5. We first stud-
ied reactions of benzaldehyde with 5 under a range of con-
ditions. Optimal results were obtained when the reaction
was conducted at room temperature in the presence of
Et2NH, catalytic amounts of MgBr2·Et2O and no solvent.
Consequently, formation of a single product (6a) was ob-
served in 88% yield within two hours. In order to test the
chemoselectivity of the reaction, parallel experiments
were carried out using ratios of 5 to benzaldehyde of 1:1
and 1:2. In both cases the same product, 6a, was formed
quantitatively. Additional experiments clarified the role
of the reactants; in the absence of MgBr2·Et2O or Et2NH,
no significant amount of product was observed after 24
hours and the majority of the starting materials were re-
covered under these conditions. The generality of the
method was demonstrated by the synthesis of similar
products (6b–h) using a range of aromatic aldehydes bear-
ing electron-withdrawing or electron-releasing groups un-
der the same conditions. All the reactions proceeded
cleanly, the products were easily separated from the mix-
In recent years, magnesium bromide diethyl etherate
(MgBr2·Et2O) has been used as a mild Lewis-acid in order
to facilitate various synthetic organic transformations.20
In this context, we have demonstrated the usefulness of
MgBr2·Et2O in Diels–Alder cycloadditions,21 Cannizzaro
reactions,22 aldol condensation,23 a-aminonitrile synthe-
SYNTHESIS 2008, No. 13, pp 2122–2126
x
x.
x
x
.
2
0
0
8
Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067114; Art ID: Z06008SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Bis(arylmethylidene)dioxan-5-ones
2123
Table 1 Aldol Condensation of 1,3-Dioxan-5-one (5) with Aromatic Aldehydes
O
O
MgBr2⋅OEt2, Et2NH
Ar
Ar
O
O
O
O
ArCHO, r.t.
5
6a–h
Entry
1
Aldehyde
Product
Time (h) Yield (%)a
O
OHC
6a
6b
2
2
88
93
O
O
O
OHC
2
3
4
O
O
O
OHC
6c
2
4
83
79
O
O
O
O
OMe
MeO
MeO
OMe
OMe
OMe
O
OMe
OMe
OHC
6d
OMe
MeO
MeO
OHC
OMe
O
5
6
7
8
6e
6f
5
2
2
4
77
92
90
86
O
O
COOMe
MeOOC
COOMe
O
OHC
O
O
Cl
Cl
S
Cl
O
OHC
OHC
S
6g
6h
S
O
O
O
O
O
N
N
N
a Isolated yield.
tures, and the formation of no other side-products was ob- Based on these results, the mechanistic pathway illustrat-
served.
ed in Figure 2 can be suggested. In the presence of Et2NH,
MgBr2·Et2O assists enolization of 5 into form b. This dis-
crete intermediate is then added to the starting aldehyde to
form the aldol product d. Elimination of water and subse-
quent repetition of the process yields bis-aldol products of
type 6.
In order to verify the proposed structures and distinguish
between possible exocyclic Z,Z- and E,E-isomers, a single
crystal of 6a was prepared and its crystal structure was de-
termined by X-ray diffraction methods. The results, de-
picted in Figure 1, clearly indicate the formation of 6a
with its Z,Z-double-bond configuration. The molecule In conclusion, we have presented a reliable and efficient
shows Cs symmetry in the crystal and the backbone devi- general synthetic protocol for the solvent-free preparation
ates significantly from planarity.
of novel 4,6-bis(arylmethylidene)dioxan-5-ones at room
Synthesis 2008, No. 13, 2122–2126 © Thieme Stuttgart · New York

2124
M. S. Abaee et al.
PAPER
Synthesis of 6a–h; General Procedure
A mixture of compound 5 (3 mmol), aldehyde (6 mmol), Et2NH (8
mmol) and MgBr2·Et2O (78 mg, 10 mol%) was stirred at 25 °C un-
der an inert atmosphere for the time indicated in Table 1. After TLC
showed complete disappearance of the starting materials, the mix-
ture was diluted with Et2O (10 mL) and washed with brine (2 × 10
mL). The organic layer was dried over Na2SO4 and the volatile por-
tion was evaporated under reduced pressure. Solid products 6a–h
were obtained after column chromatography (hexane–EtOAc, 5:1)
in 77–93% yields. The structure and the geometry of the products
were determined by spectroscopic methods and confirmed by X-ray
crystallography.
(4Z,6Z)-4,6-Dibenzylidene-2,2-dimethyl-1,3-dioxan-5-one (6a)
Yield: 88%; yellow crystals; mp 103–105 °C.
IR (KBr): 1591, 1275, 1138 cm–1.
1H NMR (CDCl3): d = 1.88 (s, 6 H), 7.00 (s, 2 H), 7.38 (d, J = 7.3
Hz, 2 H), 7.45 (dd, J = 7.3, 7.7 Hz, 4 H), 7.85 (d, J = 7.7 Hz, 4 H).
13C NMR (CDCl3): d = 26.8, 101.7, 116.5, 129.0, 129.4, 131.2,
134.0, 145.8, 178.3.
Figure 1 Crystal structure of 6a showing displacement ellipsoids at
50% probability level (top) and a wire model projected along the phe-
nyl planes (bottom)
MgBr2
MgBr2
MS (70 eV): m/z = 306 [M+], 278, 192, 132, 118.
O
O
Anal. Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.63; H,
5.87.
Et2NH
O
O
O
O
+
– Et2NH2
(4Z,6Z)-2,2-Dimethyl-4,6-bis(4-methylbenzylidene)-1,3-dioxan-
5-one (6b)
Yield: 93%; yellow crystals; mp 128–130 °C.
a
b
ArCHO
IR (KBr): 1585, 1275, 1175 cm–1.
Br
Br
1H NMR (CDCl3): d = 1.87 (s, 6 H), 2.44 (s, 6 H), 6.99 (s, 2 H), 7.25
(d, J = 8.1 Hz, 4 H), 7.74 (d, J = 8.1 Hz, 4 H).
Mg
O
O
O
OMgBr
Ar
13C NMR (CDCl3): d = 22.0, 26.7, 101.6, 116.6, 129.8, 131.2, 131.4,
139.7, 145.4, 178.3.
Ar
O
O
O
O
c
d
MS (70 eV): m/z = 334 [M+], 306, 146, 132.
Anal. Calcd for C22H22O3: C, 79.02; H, 6.63. Found: C, 78.90; H,
6.64.
O
OH
O
(4Z,6Z)-4,6-Bis(4-methoxybenzylidene)-2,2-dimethyl-1,3-diox-
an-5-one (6c)
Yield: 83%; yellow crystals; mp 132–134 °C.
IR (KBr): 1597, 1249, 1145 cm–1.
Et2NH
– H2O
Ar
Ar
6a–h
O
O
O
O
e
1H NMR (CDCl3): d = 1.85 (s, 6 H), 3.89 (s, 6 H), 6.96 (s, 2 H), 6.98
(d, J = 8.8 Hz, 4 H), 7.79 (d, J = 8.8 Hz, 4 H).
Scheme 2 Proposed mechanism for the formation of 6a–h
13C NMR (CDCl3): d = 26.7, 55.7, 101.4, 114.5, 116.4, 127.0, 132.9,
temperature. The generality of this versatile reaction
makes it an attractive addition to the present literature. At-
tempts to convert the products into their vicinal tricarbon-
yl counterparts or their derivatives are currently under
investigation in our laboratories.
144.7, 160.5, 178.2.
MS (70 eV): m/z = 366 [M+], 339, 162, 148, 120.
Anal. Calcd for C22H22O5: C, 72.12; H, 6.05. Found: C, 71.76; H,
6.01.
(4Z,6Z)-2,2-Dimethyl-4,6-bis(2,4,6-trimethoxybenzylidene)-
1,3-dioxan-5-one (6d)
Yield: 79%; yellow crystals; mp 240–242 °C.
IR (KBr): 1581, 1278, 1146 cm–1.
1H NMR (CDCl3): d = 1.70 (s, 6 H), 3.85 (s, 12 H), 3.87 (s, 6 H),
6.17 (s, 4 H), 6.99 (s, 2 H).
13C NMR (CDCl3): d = 26.5, 55.8, 56.0, 91.0, 100.6, 105.0, 109.1,
145.8, 159.9, 162.2, 178.1.
Melting points are uncorrected. IR spectra were recorded using KBr
disks on a Bruker Vector-22 infrared spectrometer. NMR spectra
were obtained on a FT-NMR Bruker Ultra Shield™ (500 MHz) as
CDCl3 solutions using TMS as internal standard reference. Elemen-
tal analyses were performed using a Thermo Finnigan Flash EA
1112 instrument. GC-MS spectra were obtained on a Fisons 8000
Trio instrument at ionization potential of 70 eV. TLC experiments
were carried out on pre-coated silica gel plates (hexane–EtOAc,
5:1). Compound 529 and MgBr2·Et2O30 were prepared according to
known methods. Solvents and reagents were purchased from com-
mercial sources. Aldehydes were redistilled or recrystallized before
use.
MS (70 eV): m/z = 486 [M+], 458, 318, 275, 208.
Anal. Calcd for C26H30O9: C, 64.19; H, 6.22. Found: C, 64.03; H,
6.16.
Synthesis 2008, No. 13, 2122–2126 © Thieme Stuttgart · New York

PAPER
Synthesis of Bis(arylmethylidene)dioxan-5-ones
2125
Dimethyl 4,4¢-(1Z,1¢Z)-(2,2-Dimethyl-5-oxo-1,3-dioxane-4,6-
diylidene)bis(methan-1-yl-1-ylidene)dibenzoate (6e)
Yield: 77%; brown crystals; mp 224–226 °C.
IR (KBr): 1720, 1274, 1141 cm–1.
1H NMR (CDCl3): d = 1.89 (s, 6 H), 3.97 (s, 6 H), 6.98 (s, 2 H),
7.78–8.13 (m, 8 H).
13C NMR (CDCl3): d = 26.9, 52.7, 102.3, 115.3, 130.3, 130.6, 130.9,
142.7, 146.7, 167.1, 177.9.
MS (70 eV): m/z = 422 [M+], 394, 176, 145.
merged). Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
no. CCDC-660972. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [E-mail: deposit@ccdc.cam.ac.uk; Fax:
+44(1223)336033 or via www.ccdc.cam.ac.uk/conts/retrieving.html].
Acknowledgment
Partial financial support by the Ministry of Science, Research and
Technology of Iran is gratefully appreciated.
Anal. Calcd for C24H22O7: C, 68.24; H, 5.25. Found: C, 68.33; H,
5.25.
(4Z,6Z)-4,6-Bis(4-chlorobenzylidene)-2,2-dimethyl-1,3-dioxan-
5-one (6f)
Yield: 92%; yellow crystals; mp 136–138 °C.
IR (KBr): 1602, 1280, 1146 cm–1.
1H NMR (CDCl3): d = 1.85 (s, 6 H), 6.92 (s, 2 H), 7.39 (d, J = 8.6
Hz, 4 H), 7.74 (d, J = 8.6 Hz, 4 H).
13C NMR (CDCl3): d = 26.8, 101.9, 115.3, 129.3, 132.3, 132.4,
135.2, 145.8, 177.9.
MS (70 eV): m/z = 374 [M+], 225, 152, 136.
References
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Anal. Calcd for C20H16Cl2O3: C, 64.02; H, 4.30. Found: C, 63.92; H,
4.29.
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(4Z,6Z)-2,2-Dimethyl-4,6-bis(thiophen-2-ylmethylene)-1,3-di-
oxan-5-one (6g)
Yield 90%; yellow crystals; mp 146–148 °C.
IR (KBr): 1604, 1272, 1144 cm–1.
1H NMR (CDCl3): d = 1.88 (s, 6 H), 7.14 (dd, J = 3.6, 5.1 Hz, 2 H),
7.34 (s, 2 H), 7.40 (d, J = 3.6 Hz, 2 H), 7.54 (d, J = 5.1 Hz, 2 H).
13C NMR (CDCl3): d = 26.4, 102.7, 111.5, 127.7, 130.7, 131.9,
136.9, 143.7, 176.5.
MS (70 eV): m/z = 318 [M+], 232, 193, 138, 124.
Anal. Calcd for C16H14O3S2: C, 60.35; H, 4.43. Found: C, 60.41; H,
4.29.
(11) (a) Wasserman, H. H.; Ennis, D. S.; Power, P. L.; Ross, M.
J.; Gomes, B. J. Org. Chem. 1993, 58, 4785. (b) Conde-
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(4Z,6Z)-2,2-Dimethyl-4,6-bis(pyridin-3-ylmethylene)-1,3-diox-
an-5-one (6h)
Yield: 86%; yellow crystals; mp 162–164 °C.
IR (KBr): 1598, 1277, 1146 cm–1.
1H NMR (CDCl3): d = 1.85 (s, 6 H), 6.92 (s, 2 H), 7.34 (dd, J = 4.8,
8 Hz, 2 H), 8.10 (d, J = 8 Hz, 2 H), 8.56 (dd, J = 1, 4.8 Hz, 2 H),
8.97 (d, J = 1 Hz, 2 H).
13C NMR (CDCl3): d = 26.8, 102.3, 113.1, 123.9, 129.9, 137.4,
146.7, 149.8, 152.1, 177.3.
MS (70 eV): m/z = 308 [M+], 265, 221, 133, 119, 103.
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Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23. Found: C, 69.80; H,
5.14.
X-ray Crystal Structure Analysis of 6a
Yellow crystals were grown from EtOAc. Data was collected on an
IPDS area detector system (Stoe) at –80 °C using MoKa-radiation.
Empirical formula C20H18O3; Formula weight 306.36; Crystal sys-
tem = orthorhombic; Space group Cmc21; Z = 4; Unit cell dimen-
sions a = 18.4110(11) Å, b = 11.2053(7) Å, c = 7.6475(6) Å;
V = 1577.69(18) Å3; D (calculated) = 1.290 g cm–3; m = 0.086 mm–1.
7570 reflections to q = 25.9°, 854 independent, 724>4s (F),
wR2 = 0.057 (all refl.), R1 = 0.025 [for F>4s(F)], Dr (min/max)
0.116/–0.103 eÅ–3. H-atoms localized but include riding on ideal-
ized positions. Absolute structure was not determined (Friedel pairs
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Synthesis 2008, No. 13, 2122–2126 © Thieme Stuttgart · New York

2126
M. S. Abaee et al.
PAPER
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Synthesis 2008, No. 13, 2122–2126 © Thieme Stuttgart · New York