On regioselectivity of aldol condensation of aromatic aldehydes with borate complex of acetylacetone

Article abstract of DOI:10.1080/00397911.2013.850094

While cinnamoyl acetone 1 is obtained in good yield by a condensation of 3 molar excess of a borate complex of acetylacetone with benzaldehyde, products of Knoevenagel condensation 2 are predominantly obtained with furfural and 5-substituted furfurals. Cinnamoyl acetone 1 can be further condensed with furfural to form unsymmetrical curcuminoid 5. Compound 2a does not produce any new products under the same conditions. Compounds 3 and 5 are good inhibitors of growth of protozoan Trichomonas vaginalis.

Full text of DOI:10.1080/00397911.2013.850094

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On Regioselectivity of Aldol Condensation of Aromatic
Aldehydes with Borate Complex of Acetylacetone
Val V. Martichonok a , Peter K. Chiang a , Padraick J. Dornbush b & Kirkwood M. Land b
a Pharmadyn , Inc. , Sunnyvale , CA , 95085 , USA
b Department of Biological Sciences , University of the Pacific , Stockton , CA , 95211 , USA
Accepted author version posted online: 04 Dec 2013.Published online: 04 Dec 2013.
To cite this article: Synthetic Communications (2013): On Regioselectivity of Aldol Condensation of Aromatic Aldehydes with
Borate Complex of Acetylacetone, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI: 10.1080/00397911.2013.850094
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Val V. Martichonok
ON REGIOSELECTIVITY
On Regioselectivity of Aldol Condensation of Aromatic Aldehydes with Borate Complex
of Acetylacetone
Val V. Martichonok1,, Peter K. Chiang1, Padraick J. Dornbush2, Kirkwood M. Land2
1Pharmadyn, Inc., Sunnyvale, CA 95085, USA, 2Department of Biological Sciences,
University of the Pacific, Stockton, CA 95211, USA,
Address correspondence to Val V. Martichonok, Pharmadyn, Inc., 265 Sobrante Way,
Suite T, Sunnyvale, CA 94086, USA, E-mail: valm@pharmadyn.com.
GRAPHICAL ABSTRACT
Abstract
While cinnamoylacetone1 is obtained in good yield by a condensation of a 3 molar
excess of a borate complex of acetylacetone with benzaldehyde, products of Knoevenagel
condensation 2 are predominantly obtained with furfural and 5-substituted furfurals.
Cinnamoyl acetone 1 can be further condensed with furfural to form unsymmetrical
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curcuminoid5. Compound 2a does not produce any new products under the same
conditions. Compounds 3 and 5 are good inhibitors of growth of protozoan
Trichomonasvaginalis.
INTRODUCTION
Curcumin (1E,6E)-1,7-di-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is the
principal curcuminoid found in turmeric.1Curcumin and its analogs exhibit antitumor,
anti-inflammatory, anti-infectious and many other activities with low toxicity. Curcumin
is a symmetric molecule: substituents R1 on both aromatic rings are the same. Most
known curcuminoids are symmetrical. Biological activity for unsymmetrical
curcuminoids, on the other hand, is relatively unknown (R1 ≠ R2).
Symmetrical curcuminoids are best prepared by reacting 2 equivalents of an aromatic
aldehyde with 1 equivalent of acetylacetone in the presence of boric anhydride, tributyl
borate and n-butylamine as described by Pabon.2 It has been proposed in this reaction,
that acetylacetone forms a boron complex with boric anhydride, which inhibits an
undesired Knoevenagel condensation. After addition of a corresponding aromatic
aldehyde and catalytic amount of n-butylamine in small portions, the condensation of the
acetylacetone–boron complex with the aldehyde in 1- and 5-position of acetylacetone
occurs; cleavage of the boron complex by heating with dilute acid gives the desired
curcumin analogues. Yields with substituted benzaldehydes are usually good, however,
very low yield were reported for furfural.
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Unsymmetrical curcuminoids are prepared via a 2 step process.3 First, the aromatic
aldehyde is reacted with a 3-4 molar excess of acetylacetone–boron complex to form
cinnamoyl acetone, that is then converted to a cinnamoyl acetone-boron complex and
reacted with a second aldehyde to give the unsymmetrical curcuminoid after cleavage
with dilute HCl.
RESULTS AND DISCUSSION
We have found that the reaction of furfurals with 3 equivalent of acetylacetone in the
presence of boric anhydride, trimethyl borate and n-butylamine produces products 2a-2c
of Knoevenagel condensation.4Benzaldehyde under the same conditions produces
cinnamoyl acetone 1 that is desired for the synthesis of unsymmetrical curcuminoids.
Small amounts of symmetrical phenyl and furyl substituted 1,6-heptadiene-3,5-diones 3
and 4 were isolated during the reaction.
Because it was not clear, how the boron complex of cinnamoyl acetone was going to
behave in the reaction with furfural, we studied this reaction. Unsymmetrical
curcuminoid5 was isolated in 45% yield, and no Knoevenagel product was observed by
LC-MS.
Screening of compounds 1-5 for biological activity revealed, that these compounds have
good anti-protozoan activity against drug resistant strain of Trichomonasvaginalis.
Symmetrical curcuminoid3 inhibited the metronidazole-resistant strain MSA1126 of T.
vaginalis 94.9%, and unsymmetrical curcuminoid5 inhibited this strain 59.6% at a
compound concentration 100 µM. Other compounds mentioned in this paper were not
active.
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In conclusion, the reaction of furfural and 5-substituted furfurals with 3 equivalents of
acetylacetone in the presence of boric anhydride, trimethyl borate and a catalytic amount
of n-butylamine produces products of Knoevenagel condensation. Benzaldehyde under
the same conditions produces cinnamoyl acetone. While the boron complex of cinnamoyl
acetone can be condensed with furfural to form unsymmetrical curcuminoids, products of
Knoevenagel condensation do not undergo further aldol condensation. Compounds 3 and
5 are good inhibitors of growth of protozoan Trichomonasvaginalis.
EXPERIMENTAL
General Methods And Materials
1H NMR spectra were measured at 399.77 MHz and 13C NMR spectra at 100.54 MHz.
Chemical shifts are reported in ppm downfield from tetramethylsilane. Silica gel for flash
chromatography was E. Merck grade (230-400 mesh). Reverse-phase analytical HPLC
was performed at with a gradient of 5% to 100% buffer B over 10 minutes with detection
by UV at 225, 254 and 280 nm. Mobile phase A was 0.1% trifluoroacetic acid in
acetonitrile; mobile phase B - 0.1% trifluoroacetic acid in water. Electrospray mass
spectra were recorded with a gradient of 5% to 100% buffer B over 10 minutes with
detection by UV at 216, 225, 254, 280 and 325 nm. Mobile phase A, 0.1% formic acid in
acetonitrile; mobile phase B, 0.1% formic acid in water. Melting points were determined
using Mel-Temp II apparatus.
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Cinnamoyl Acetone (1) And (1E,6E)-1,7-Diphenyl-1,6-Heptadiene-3,5-Dione (3).
Acetylacetone (379 µL, 3.69 mol) is added to a suspension of B2O3 (184 mg, 2.65 mol) in
a mixture of (MeO)3B (2.00 mL) and anhydrous EtOAc (2.00 mL). The mixture is stirred
at bath temperature 60 °C until it becomes homogeneous (approx. 30 min). B2O3 is
completely dissolved. The solution is allowed to cool to rt and benzaldehyde (125 µL,
1.23 mol) is added to this solution. n-BuNH2 is added dropwise in four portions (10 µL x
4 portions) every 30 min. The total volume of added nBuNH2 is 40 µL. The mixture is
left to stir at rt overnight. Next day n-BuNH2 (10 µL) is added and the mixture is
concentrated on a rotovap (bath temperature 45 °C). The mixture is left standing at rt for
another night. The mixture is dissolved in EtOAc (20 mL). The purple-red solution is
treated by dropwise addition of 1 M HCl (2.00 mL) and the mixture is allowed to stir
vigorously at bath temperature 50 °C for 2 h. The color changes to yellow. The obtained
solution is washed with H2O, sat. aq. NaHCO3, H2O, and brine (10 mL). The mixture is
dried over MgSO4, filtered, concentrated in vacuo and chromatographed using a 1 : 2
mixture of E2O and hexanes. Cinnamoyl acetone (1) is eluting first; yield 144 mg (62%),
yellowish solid, mp 84-85 °C (lit.4mp 85 °C); [M+H]+ (189). Compound 3 is eluting
second; 19 mg (11% yield); yellow solid, mp 139-140 °C (lit.2mp 140.5 °C); [M+H]+
(277). Yields of compounds 1 and 3 are calculated as a percentage from 66% theoretical
yield based on the aromatic aldehyde used in the reaction.
Repeating the above procedure with furfural, 5-methylfurfural and 5-
hydroxymethylfurfural affords compounds 2a and 4, 2b and 2c.
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2-Acetyl-1-(2-Furyl)-1-Butene-3-One (2a)
Yield149 g (68%) as a brownish oil(lit.5bp 116 °C/0.8 mmHg); 1H NMR (CDCl3) δ 2.37
(s, 3 H), 2.44 (s, 3 H), 6.51 (dd, J = 2.00 Hz, J = 3.60 Hz, 1 H), 6.77 (dd, J = 0.80 Hz, J =
3.60 Hz, 1 H), 7.15 (s, 1 H), 7.55 (bs, 1 H); [M+H]+ (179).
(1E,6E)-1,7-Di-(2-Furyl)-1,6-Heptadiene-3,5-Dione (4)
Yield 13 mg (8%), yellow solid; mp 128-129 °C (lit.2mp 129-130 °C); 1H NMR (CDCl3)
δ 5.55 (s, 2 H), 6.30 (d, J = 15.6 Hz, 2 H), 6.42 (dd, J = 2.00 Hz, J = 3.60 Hz, 2 H), 6.51
(d, J = 3.60 Hz, 2 H), 7.29 (d, J = 15.6 Hz, 2 H); 7.36 (d, J = 2.00 Hz, 2 H); [M+H]+
(257).
2-Acetyl-1-(2-(5-Methyl)Furyl)-1-Butene-3-One (2b)
Yield 196 mg (83%), yellow solid, mp 89 °C; 1H NMR (CDCl3) δ 2.32 (s, 3 H), 2.33 (s,
3 H), 2.43 (s, 3 H), 6.12 (bs, 1 H), 6.67 (bs, 1 H), 7.07 (s, 1 H); [M+H]+ (193).13C NMR
(CDCl3) δ 13.9, 26.1, 31.3, 109.8, 120.2, 125.2, 136.8, 147.4, 157.8, 195.8, 204.7. Anal.
Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.59; H, 6.24.
2-Acetyl-1-(2-(5-Hydroxymethyl)Furyl)-1-Butene-3-One (2c)
Eluting with E2O yielded 131 mg (51)%, of brownish yellow solid, mp 66-68 °C; 1H
NMR (CDCl3) δ 2.36 (s, 3 H), 2.43 (s, 3 H), 4.60 (d, J = 5.20 Hz, 1 H), 6.41 (d, J = 3.60
Hz, 1 H), 6.72 (d, J = 3.60 Hz, 1 H), 7.11 (s, 1 H); 1H NMR (CDCl3) δ 26.1, 31.4, 57.4,
110.7, 119.3, 125.1, 138.1,148.4, 159.0, 195.9, 205.1. HRMS (ES-TOF) m/z: [M +
Na]+Calcd for C11H12O4Na 231.0628; Found 231.0622.
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(1E,6E)-1-(2-Furyl)-7-Phenyl-1,6-Heptadien-3,5-Dione(5)
A mixture of cinnamoyl acetone (1) (333 mg, 1.77 mmol), B2O3 (80 mg, 1.15 mmol), (n-
BuO)3B (3.0 mL) and anhydrous EtOAc (3.0 mL) is sonicated/stirred under argon on a
magnetic stirrer until a complete dissolution is occurred. The mixture is cooled to rt and
furfural (147 mL, 1.77 mmol) is added followed by addition of n-BuNH2 in six portions
(10 µL x 6) every 10 min. The total volume of added n-BuNH2 is 60 µL. The mixture is
left to stir for 2 days at rt, after which the TLC indicates one major product. EtOAc (20
mL) is added to the reaction mixture followed by a dropwise addition of 0.5 M HCl (5
mL). The mixture is stirred for 2 h at a bath temperature 50 °C in order to destroy the
borate complex. The aqueous phase is separated, the organic phase is washed with H2O
(10 mL), sat. aq. NaHCO3 (2 x 5 mL), H2O (5 mL), and brine (5 mL). The mixture is
dried over MgSO4, filtered and concentrated in vacuo to a volume of about 3 mL.MeOH
(3 mL) is added and the mixture is left to crystallize at 0 °C.Compound 5 is obtained as a
greenish grey solid, 211 mg (45% yield), mp 113-114 °C (lit.6mp 114-115 °C); [M+H]+
(267).
ACKNOWLEDGMENTS
We thank our colleagues in the laboratory for their insightful suggestions and ongoing
support of our research, and the Department of Biological Sciences and the Office of
Sponsored Programs, University of the Pacific, for providing funding for this project.
P.J.D. was supported by a Hunter-Nahas Fellowship, Department of Biological Sciences,
University of the Pacific. HRMS facility was supported by grants from the National
Center for Research Resources (5 G12RR013646-12) and the National Institute on
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Minority Health and Health Disparities (8 G12MD007591-12) from the National
Institutes of Health.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. the
publisher’s website will be a live link
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Figure 1. Symmetrical and Unsymmetrical Curcuminoids
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Scheme 1.Formation of Borate Complex of Acetylacetone
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Scheme 2. Condensation of Benzaldehyde and 5-Substituted Furfurals with
Acetylacetone
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Scheme 3. Synthesis of Unsymmetrical Curcuminoid5.
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