Improved synthesis of C2-symmetric 4,4′-α,ω- alkylenedioxy-bis(3-methoxybenzaldehydes)

Article abstract of DOI:10.1081/SCC-200061549

An improved Williamson synthesis of C₂-symmetric 4,4′-(α,ω-alkylenedioxy)-bis(3-methoxybenzaldehydes) from vanillin is described. These dialdehydes are often insoluble in cold acetone, which renders their purification especially facile. Copyrig

Full text of DOI:10.1081/SCC-200061549

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Improved Synthesis
of C 2‐Symmetric
4,4′‐α,ω‐Alkylenedioxy‐bis(3‐meth
Pepe' S. Maley a , Rachel M. Anderson a & David E.
Lewis a
a Department of Chemistry, University of
Wisconsin—Eau Claire, Eau Claire, Wisconsin, USA
Published online: 16 Aug 2006.
To cite this article: Pepe' S. Maley , Rachel M. Anderson &
David E. Lewis (2005): Improved Synthesis of C 2‐Symmetric
4,4′‐α,ω‐Alkylenedioxy‐bis(3‐methoxybenzaldehydes), Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:12,
1583-1588
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Synthetic Communicationsw, 35: 1583–1588, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061549
Improved Synthesis of C2-Symmetric
4,40-a,v-Alkylenedioxy-
bis(3-methoxybenzaldehydes)
Pepe’ S. Maley, Rachel M. Anderson, and David E. Lewis
Department of Chemistry, University of Wisconsin—Eau Claire,
Eau Claire, Wisconsin, USA
Abstract: An improved Williamson synthesis of C2-symmetric 4,40-(a,v-
alkylenedioxy)-bis(3-methoxybenzaldehydes) from vanillin is described. These
dialdehydes are often insoluble in cold acetone, which renders their purification
especially facile.
Keywords: C2 symmetry, dialdehydes, phenols, Williamson synthesis
INTRODUCTION
The incorporation of the C2 symmetry element into molecules designed for use
as liquid crystals often confers unusual and useful properties on those
molecules. Many of these compounds are based on a C2-symmetric 4,40-alkyl-
enedioxy-bis(arene) carbon skeleton, for which the C2-symmetric 4,40-alkylene-
dioxy-bis(benzaldehydes) (e.g., 1) can provide a useful starting material.
Received in the USA February 11, 2005
Address correspondence to David E. Lewis, Department of Chemistry, University
of Wisconsin—Eau Claire, Eau Claire, WI 54702-4004, USA. Tel.: þ1-715-836-
4744; Fax: þ1-715-836-4979; E-mail: lewisd@uwec.edu
1583

1584
P. S. Maley, R. M. Anderson, and D. E. Lewis
Similar compounds have been used by Date and coworkers in their synthesis of
thermotropic liquid crystals (e.g., 2),[1,2] and such compounds have been widely
used in the synthesis of other useful liquid crystalline materials.[3–7]
In our own laboratories, we had prepared 3-endo-(p-methoxybenzyl)iso-
borneol (3) as a chiral alcohol with potential for use in the alkylation of ester
lithium enolates.[8] The conformation of the p-nitrobenzoate ester of the
alcohol[9] suggested that this alcohol would be an excellent chiral auxiliary
for this and other reactions of esters, but, in a study of the alkylation of the
lithium enolate of its propionate ester,[10,11] it proved to be of marginal
utility, giving diastereomeric excesses only in the 24–40% range.[11] One
way to improve the levels of asymmetric induction generated by this
auxiliary would be to increase the steric bulk at the 3 position while
keeping the equivalent weight constant. We attempted to do so by generating
C2-symmetric dimeric analogs by the reductive dimerization of (E)-3-benzyli-
denecamphor.[12] The reaction gave homoacylaoin condensation products as
the major products, but the yields were low, and the major product of a
complex mixture (4) lacked the C2 symmetry.
We concluded that intramolecular reductive dimerization of a series of
C2-symmetric a,v-alkylene-bis-(3-benzylidenecamphors) might constrain
the reaction to occur with C2 symmetry. Moreover, these compounds might,
conceivably, result in the formation of compounds containing a chiral cavity
into which the prochiral precursor might bind. Therefore, a series of
C2-symmetric dialdehydes was required for condensation with (1R)-
(þ)-camphor.
RESULTS AND DISCUSSION
The obvious method for the synthesis of these dialdehydes was by the
Williamson ether synthesis from a phenolic aldehyde and an a,v-dihalide
with potassium carbonate in acetone.[13] Using vanillin as the model

Synthesis of C2-Symmetric Dialdehydes
1585
phenolic aldehyde, we carried out several syntheses of C2-symmetric dialde-
hydes. We were surprised, however, to find that on carrying out the reaction
with 1,6-dibromohexane according to well-established literature precedent,
the product was obtained in only a minute yield (,2%) and was badly
contaminated with the excess vanillin. In his studies with p-hydroxybenzalde-
hyde, Wiegel[14] has found that this problem may be partially circumvented by
the use of cesium carbonate as the base, but even under these circumstances,
the yield is low.
The solution to this problem became apparent when the reaction was
checked for mass balance. When this was done, it was found that the
majority of the mass was present in the solid recovered by filtration, and
that very little of the reaction mass was left in the filtrate—the apparent
problem was due to the unexpected solubility characteristics of the product
dialdehydes. The majority of the C2-symmetric dialdehydes, we have
subsequently found, are almost insoluble in cold acetone and precipitate
with the insoluble inorganic salts. The only dialdehydes that we found to
have appreciable solubility in acetone are those whose a,v-alkylenedioxy
chain is based on a poly(ethylene oxide) backbone or those with long
a,v-alkylenedioxy chains. This characteristic solubility is fortuitous, for it
permits the extremely facile purification of the C2-symmetric dialdehydes:
the excess phenol and/or alkylene dihalide is removed during the filtration
of the acetone solution, and the bis(benzaldehyde) is then recovered pure by
recrystallization of the acetone-insoluble material from toluene. In this way,
the dialdehydes are obtained in typical yields of 50–75%.
It must be pointed out that there is evidence that the scope of this
improved synthesis may still be limited: the analytical data obtained for
the products obtained when 1,8-dibromooctane and 1,3-dibromopropoane
were used are both more consistent with other reactions having occurred.
Thus, the propylene compound is consistent with being a CO2 insertion
product that has ether and carbonate ester functionalities, and the octylene
compound has a microanalysis and spectroscopic data consistent with an
ansa lactone derived from a CO2 adduct of the aldehyde functioning as an
intramolecular nucleophile displacing the v-bromo group of the bromooctyl-
aldehyde, followed by a Cannizzarro-type oxidation to the lactone; neither
compound exhibits the observed solubility in acetone of the C2-symmetric
dialdehydes, and neither is obtained in high yield.
EXPERIMENTAL
General
Melting points were measured on a Fisher–Johns hot-stage melting point
apparatus and are uncorrected. Infrared spectra were determined as KBr

1586
P. S. Maley, R. M. Anderson, and D. E. Lewis
1
pellets using a Nicolet 5DXC FT-IR spectrometer. H NMR spectra were
recorded as CDCl3 solutions using a JEOL Eclipse NMR spectrometer
operating at 400 MHz; peak positions are reported as d (ppm) downfield
from internal Me4Si. 13C NMR spectra were recorded as CDCl3 solutions at
100 MHz; peak positions are reported in ppm relative to the center peak of
CDCl3 (77.1 ppm). Vanillin was used as obtained from Fisher Chemical
Company; all other reagents and solvents were used as obtained from
Aldrich Chemical Company. Microanalyses were performed by Robertson–
Microlit Laboratories, Rahway, NJ.
General Procedure
To a stirred solution of the a,v-dibromide (1.0 eq.) and vanillin (ꢀ2.05 eq.)
in acetone (ꢁ20 mL per mmol dihalide) was added potassium carbonate
(ꢀ2.1 eq.). The reaction mixture was heated under reflux for 18–24 h, after
which time the solids were collected by vacuum filtration. The solids were
boiled with approximately 2–3 times their volume of toluene, and the
mixture was filtered hot. The 4,40-(a,v-alkylenedioxy)-bis(3-methoxybenzal-
dehyde) was obtained as colorless crystals upon cooling the filtrate.
4,40-(1,4-butylenedioxy)-bis(3-methoxybenzaldehyde) was prepared by
procedure A from vanillin (15.7 g, 0.102 mol), 1,4-dibromobutane (9.01 g,
0.042 mol), and potassium carbonate (14.2 g, 0.103 mol) in acetone
(ꢁ100 mL). The product (7.10 g, 47%) was obtained as white crystalline
plates, mp 160–1638C. nmax (cm21): 2956 (w), 2936 (w), 2839 (w), 2831
(w), 2763 (w), 2736 (w), 1693 (m), 1674 (s), 1596 (m), 1584 (s), 1508 (s),
1
1276 (s), 1261 (s), 1133 (s), 1001 (m), 812 (m), 731 (m). H NMR (d ppm):
9.85 (2H, s, CH55O), 7.43 (2H, d J ¼ 1.8 Hz of d J ¼ 8.1 Hz, C50 –H), 7.41
(2H, d J ¼ 1.8 Hz, C20 –H), 6.99 (2H, d J ¼ 8.1 Hz, C60 –H), 4.22 (4H, br.
t, O–CH2), 3.90 (6H, s, OCH3), 2.12 (4H, br. t, O–CH2CH2). 13C NMR (d
ppm): 191.0 (C55O), 154.0, 149.9, 130.0, 126.8, 111.4, 109.3, 68.7, 56.0,
25.8. Found C, 66.78; H 6.15%. C20H22O6 requires C, 67.03; H, 6.19%.
4,40-(1,6-hexylenedioxy)-bis(3-methoxybenzaldehyde) was prepared by
procedure A from vanillin (15.4 g, 0.101 mol), 1,6-dibromohexane (11.7 g,
0.048 mol), and potassium carbonate (14.4 g, 0.103 mol) in acetone
(ꢁ100 mL). The product (10.4 g, 57%) was obtained as white crystalline
plates, mp 162.5–1648C. nmax (cm21): 2951 (w), 2934 (w), 2874 (w), 2829
(w), 2760 (w), 2731 (w), 1696 (m), 1681 (s), 1593 (s), 1585 (s), 1507
1
(s), 1277 (s), 1262 (s), 1134 (s), 1011 (s), 733 (m). H NMR (d ppm): 9.85
(2H, s, CH55O), 7.43 (2H, dd J ¼ 1.8, 8.1 Hz, C50 –H), 7.41 (2H,
d J ¼ 1.8 Hz, C20 –H), 6.96 (2H, d J ¼ 8.1 Hz, C60 –H), 4.12 (4H, t
J ¼ 6.6 Hz, O–CH2), 3.92 (6H, s, OCH3), 1.93 (4H, br. pentet J ¼ 6.9 Hz,
O–CH2CH2), 1.59 (4H, br. m, O–CH2CH2CH2). 13C NMR (d ppm): 191.0,
154.2, 149.9, 130.0, 126.8, 111.4, 109.4, 69.0, 56.1, 28.9, 25.8. Found
C, 68.31; H, 6.94%. C22H26O6 requires C, 68.38; H, 6.78%.

Synthesis of C2-Symmetric Dialdehydes
1587
4,40-[(1,4-phenylenedimethylene)dioxy]-bis(3-methoxybenzaldehyde)
was prepared by Procedure A from vanillin (9.15 g, 60 mmol), 1,4-bis(bromo-
methyl)-benzene (6.81 g, 26 mmol), and potassium carbonate (8.34 g,
60 mmol) in acetone (ꢁ100 mL). The product (7.12 g, 66%) was obtained as
white crystalline needles, mp 150–1538C. nmax (cm21): 3070 (w), 2934
(w), 2853 (w), 2829 (w), 2713 (w), 1681 (s), 1595 (s), 1584 (s), 1506 (s),
1
1267 (s), 1237 (s), 1132 (s), 1016 (s), 803 (m), 731 (m). H NMR (d ppm):
9.84 (2H, s, CH55O), 7.46 (4H, s, p–C6H4), 7.43 (2H, d J ¼ 1.8 Hz,
C20 –H), 7.39 (2H, dd J ¼ 1.8, 8.1 Hz, C50 –H), 6.98 (2H, d J ¼ 8.1 Hz,
C60 –H), 5.24 (4H, s, OCH2), 3.95 (6H, s, OCH3). 13C NMR (d ppm):
190.9, 153.5, 150.1, 136.2, 130.5, 127.7, 126.6, 112.5, 109.5, 70.6, 56.1.
Found C, 70.75; H, 5.20%. C24H22O6 requires C, 70.92; H, 5.46%.
4,40-[(1,2-phenylenedimethylene)dioxy]-bis(3-methoxybenzaldehyde)
was prepared by procedure A from vanillin (15.24 g, 100 mmol), 1,2-bis(bro-
momethyl)benzene (13.44 g, 50.9 mmol), and potassium carbonate (13.92 g,
101 mmol) in acetone (ꢁ100 mL). The product (13.86 g, 68%) was obtained
as white crystalline needles, mp 153–1548C. nmax (cm21): 3074 (w), 3000
(w), 2936 (w), 2829 (w), 2753 (w), 2720 (w), 1679 (s), 1586 (s), 1512 (s),
1
1268 (s), 1136 (s), 1031 (m), 732 (m). H NMR (d ppm): 9.82 (2H, s,
CH55O), 7.49 (2H, m, C6H4), 7.4–7.3 (4H, m, ArH), 7.03 (2H, d
J ¼ 8.8 Hz, ArH), 5.38 (4H, s, OCH2), 3.89 (6H, s, OCH3). 13C NMR
(d ppm): 190.9, 153.4, 150.1, 134.3, 130.5, 129.0, 128.8, 126.5, 112.4,
109.4, 69.4, 56.0. Found C, 70.90; H, 5.33%. C24H22O6 requires C, 70.92;
H, 5.46%.
ACKNOWLEDGMENTS
Financial support of this research by grants from Research Corporation
(Cottrell College Science Award No. CC4677) and the University of
Wisconsin—Eau Claire Office of Research and Sponsored Programs is grate-
fully acknowledged.
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