Approaches to iodinated derivatives of vanillin and isovanillin

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Approaches to Iodinated Derivatives of
Vanillin and Isovanillin
Baskar Nammalwar a , Richard A. Bunce a , K. Darrell Berlin a ,
Christina R. Bourne b , Philip C. Bourne b , Esther W. Barrow b &
William W. Barrow b
a Department of Chemistry, Oklahoma State University, Stillwater,
OK, USA
b Department of Veterinary Pathobiology, Oklahoma State University,
Stillwater, OK, USA
Version of record first published: 30 Mar 2012.
To cite this article: Baskar Nammalwar, Richard A. Bunce, K. Darrell Berlin, Christina R. Bourne,
Philip C. Bourne, Esther W. Barrow & William W. Barrow (2012): Approaches to Iodinated Derivatives
of Vanillin and Isovanillin, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 44:2, 146-152
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Organic Preparations and Procedures International, 44:146–152, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.643700
Approaches to Iodinated Derivatives
of Vanillin and Isovanillin
Baskar Nammalwar,1 Richard A. Bunce,1 K. Darrell Berlin,1
Christina R. Bourne,2 Philip C. Bourne,2 Esther W. Barrow,2
and William W. Barrow2
1Department of Chemistry, Oklahoma State University, Stillwater, OK, USA
2Department of Veterinary Pathobiology, Oklahoma State University, Stillwater,
OK, USA
The chemistry of vanillin (1) and isovanillin (2) has been examined and reviewed
extensively.1–3 A current project in our laboratory required the conversion of 5-
iodoisovanillin ethers 6a–d to substituted 2,4-diaminopyrimidines followed by Heck cou-
pling with an unsaturated ketone to generate agents displaying inhibitory activity against
Bacillus anthracis, a potential bioterror threat.4 The chemistry to prepare 5-iodovanillin
ethers 6a–d with variation at C-4 is straightforward5,6 starting from commercial 5-
iodovanillin (3).7,8
Procedures to alter the C-3 alkoxy group, however, require demethylation of 3 to give
catechol 4 followed by sequential methylation at the C-4 hydroxy group followed by O-
alkylation at C-3. The synthesis of 5-iodoisovanillin ethers 6a–d, thus, requires regiocontrol
in the initial methylation of 4. Although preferential alkylation of the C-4 hydroxy group
of 4 would be expected due to its greater activation by the C-1 aldehyde, controlling this
process to give clean monoalkylation is necessary. This has been achieved, and we now
report a concise and selective method to generate 5-iodoisovanillin ethers.
Isovanillin, iodinated at C-5, has been previously reported, but the synthetic routes
were lengthy9 or the procedures were unclear.10 In the first synthesis,9 the iodo group
was introduced by a diazotization-replacement sequence as part of a six-step preparation
from isovanillin. In the second procedure,10 the methyl ether was cleaved with aluminum
Submitted September 8, 2011
Address correspondence to Richard A. Bunce, Department of Chemistry, 107 Physical Sciences,
Oklahoma State University, Stillwater, OK 74078, USA. E-mail: rab@okstate.edu
146

Iodinated Derivatives of Vanillin and Isovanillin
147
Scheme 1
chloride-pyridine and selectively alkylated at the C-4 hydroxyl group using methyl iodide
and sodium bicarbonate in N,N-dimethylformamide-acetone. This approach parallels our
procedure, but lacks detail about the isolation of the product from the precipitated material
following decomposition of the aluminum chloride. Additionally, we had trouble controlling
the subsequent alkylation using this method.
Our synthesis of 5-iodoisovanillin ethers 6a–d is outlined in Scheme 1. Demethy-
lation of 5-iodovanillin (3) with aluminum chloride-pyridine led to 3,4-dihydroxy-5-
iodobenzaldehyde (4) in 80% yield.10,11 The use of this reagent to cleave the ether was
selected over anhydrous HBr in acetic acid12 and boron tribromide12 due to the simpler
procedure, reduced hazard and lower cost. Following cleavage of the C-3 ether, regio-
selective alkylation of the C-4 hydroxy group of 4 proceeded cleanly by treatment with
1.1 equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in N,N-dimethylformamide
(DMF) followed by addition of several portions of methyl iodide. This procedure af-
forded 5-iodoisovanillin 5 in 79% yield after flash chromatography. A similar alkylation
using sodium bicarbonate,10 lithium carbonate13 or sodium carbonate in DMF yielded the
C-4-monomethylated product in ≤30%, along with recovered starting material and the
dialkylated product. The current procedure to generate 4 and 5 is superior to the previously
reported syntheses in terms of yield, regiocontrol and time required. The target compounds
required a final O-alkylation of the C-3 hydroxy group of 5 to give previously unknown
derivatives 6a–d. Again, the use of DBU/DMF as the catalyst/solvent system for this trans-
formation gave complete conversion in slightly more than one hour at room temperature.
Purification by flash chromatography produced 6a–d in yields ranging from 78–92%. Fi-
nally, our attempts to improve the yield of 6c by carrying out the reaction in other solvents
(tetrahydrofuran or dichloromethane) and with other bases (potassium carbonate or tri-
ethylamine) resulted in lower yields of the desired product. Related systems 7 and 8 were
synthesized similarly. Treatment of 4 with 3.5 equivalents of DBU and 3.0 equivalents of
ethyl iodide produced 7 as a pale yellow solid in 80% yield. Likewise, 4 reacted with 3.5
equivalents of DBU and 1.1 equivalent of diiodomethane gave 7-iodo-1,3-benzodioxole-5-
carbaldehyde (8) in 78% yield.14 Spectral and elemental analyses confirmed the structures of
the final targets 6–8. Interestingly, 8 retained traces of methanol, following recrystallization
from this solvent, even after extensive drying under high vacuum.

148
Bunce et al.
In summary, we have successfully developed a straightforward approach by which
derivatives of 5-iodovanillin and 5-iodoisovanillin can be prepared. The use of aluminum
chloride in pyridine proved most convenient and cost effective for the cleavage of the methyl
ether in 5-iodovanillin (3) to generate 3,4-dihydroxy-5-iodobenzaldehyde (4). Regiospecific
O-alkylation of 4 at the C-4 hydroxy group with methyl iodide in DBU/DMF then provided
5, which could be further alkylated at the C-5 hydroxy group using the same conditions to
afford the series 6a-d. The basic procedure was further extended to the preparation of 7
and 8.
Experimental Section
All reactions were performed under dry nitrogen in oven-dried glassware. All 1H- and 13C-
NMR spectra were obtained at 300 MHz and 75 MHz, respectively, using tetramethylsilane
as the internal standard. All melting points are uncorrected. FT-IR spectra were taken as thin
films on sodium chloride disks. Reactions were monitored by thin layer chromatography
(TLC) onsilica gel GFplates (AnaltechNo. 21521). Preparative flashchromatography15 was
performed on silica gel (grade 62, 60–200 mesh) containing UV-active phosphor (Sorbent
Technologies, No. UV-5) packed into quartz columns. Band elution for all chromatographic
methods was monitored using a hand-held UV lamp. Pyridine was stored over potassium
hydroxide pellets and distilled from calcium hydride prior to use. All other reagents and
solvents were used as received from various vendors.
3,4-Dihydroxy-5-iodobenzaldehyde (4)
To a 500-mL, three-necked, round-bottomed flask, equipped with a 4.0-cm, egg-shaped
stir bar and fitted with an addition funnel and a condenser (nitrogen inlet) was charged
with 5-iodovanillin (3, 25.0 g, 89.9 mmol) and dichloromethane (125 mL) and stirring was
begun to dissolve the solid. Aluminum chloride (13.3 g, 100 mmol, 1.1 equiv) was then
added and stirring was continued for 10 min. Pyridine (31.3 g, 31.8 mL, 396 mmol, 4.4
equiv) was slowly added to the mixture via the addition funnel with stirring over a period
of 20 min. [Caution: The initial addition of pyridine should be very slow]. The reaction
flask was then placed in a pre-heated oil bath at 50◦C and heated at reflux for 16 h. During
this time, a yellow slurry formed which completely changed to a green colored solution.
Near the end of the reaction a precipitate began to form. A TLC analysis of the solution
using ether:hexanes (1:1) indicated the reaction was complete. After cooling for 10 min,
the reaction mixture was poured into a 500-mL Erlenmeyer flask containing crushed ice
(300 g). The resulting mixture was cooled in an ice bath with continuous stirring for 10
min and then 6 M hydrochloric acid (ca 50 mL) was slowly added until the pH reached

Iodinated Derivatives of Vanillin and Isovanillin
149
2. At this point, the reaction mixture consisted of a bottom layer of dichloromethane with
a pale yellow solid suspended in the top aqueous layer. The mixture was transferred to a
1-L separatory funnel using ethyl acetate (150 mL), and water (100 mL) was slowly added.
The organic layer was separated, and the remaining aqueous layer was extracted with ethyl
acetate (4 × 150 mL). The combined organic extracts were washed with saturated aqueous
sodium chloride (150 mL), dried (MgSO4), and concentrated using a rotary evaporator to
yield a green solid. This material was dissolved with heating in ethanol (150 mL), and
then water (250 mL) was slowly added. The resulting green solution was cooled to room
temperature over a period of 4 h and to 0◦C for 30 min to give a light brown solid, which
was collected and dried under vacuum. Recrystallization from ethanol:water (3:5) yielded
4 (21.8 g, 92%) as a tan solid. A second recrystallization yielded 20.0 g (84%) and a third
recrystallization gave pure 4 (18.9 g, 80%) as an off-white solid, mp. 199–200◦C (lit.10
mp. 198–199◦C), after drying for 12 h under high vacuum. IR: 3200, 1637 cm−1; 1H-NMR
(DMSO-d6): δ 10.4 (s, 1 H, CHO), 9.69 (s, 2 H, OH), 7.75 (d, 1 H, J = 1.7 Hz), 7.26 (d,
1 H, J = 1.7 Hz); 13C-NMR (DMSO-d6): δ 190.4, 151.9, 145.1, 133.6, 130.1, 113.3, 84.3.
No 13C NMR data were previously reported for 4.
3-Hydroxy-5-iodo-4-methoxybenzaldehyde (5)
A 250-mL, single-necked, round-bottomed flask, equipped with a 2.5-cm, egg-shaped,
magnetic stir bar and fitted with an addition funnel (nitrogen inlet), was charged with
3,4-dihydroxy-5-iodobenzaldehyde (4, 15.0 g, 56.8 mmol) and dry DMF (30 mL). To the
resulting solution was added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (9.51 g,
9.34 mL, 62.6 mmol, 1.1 equiv) with stirring over a period of 5 min. During the addition
process, the color of the reaction mixture changed from brown to red. After 45 min, methyl
iodide (8.00 g, 3.54 mL, 56.3 mmol) was added all at once. Thereafter, four three additional
portions of methyl iodide (the same volume) were added every hour over a 5-h period
to ensure maximum conversion. A TLC analysis using ether:hexanes (1:1) indicated the
reaction was complete. The crude reaction mixture was acidified to pH 2 by the slow addi-
tion of 6 M hydrochloric acid and then extracted with dichloromethane (3 × 100 mL).
The combined organic extracts were washed with saturated sodium chloride solution
(50 mL), dried (MgSO4), and concentrated to give an off-white solid. Purification of this
material by flash chromatography (30-cm × 4-cm column), eluted with dichloromethane,
gave 5 (12.5 g, 79%) as a white solid, mp. 134–135◦C (lit.10 mp. 134–135.8◦C). IR: 3236,
1685 cm−1; 1H-NMR (DMSO-d6): δ 10.4 (s, 1 H, CHO), 9.79 (s, 1 H, OH), 7.79 (d, 1 H,
J = 1.7 Hz), 7.35 (d, 1 H, J = 1.7 Hz), 3.82 (s, 3 H); 13C-NMR (DMSO-d6): δ 191.0, 152.4,
150.6, 134.0, 131.6, 116.1, 93.0, 59.8. No 13C NMR data were previously reported for 5.
3-Iodo-4,5-dimethoxybenzaldehyde (6a)
To a 100-mL, single-necked, round-bottomed flask, equipped with a 2.5-cm, egg-shaped,
magnetic stir bar and fitted with a condenser (nitrogen inlet), charged with 3,4-dihydroxy-5-
iodobenzaldehyde (4, 1.00 g, 3.78 mmol) and dry DMF (3 mL), was added dropwise DBU
(2.01 g, 1.97 mL, 13.2 mmol, 3.5 equiv) with stirring over a period of 5 min. The reaction
mixture was stirred 30 min at room temperature, methyl iodide (1.61 g, 0.71 mL, 11.4

150
Bunce et al.
mmol, 3.0 equiv) was added and stirring was continued for an additional 2 h. Thereafter,
three additional portions of methyl iodide (the same volume) were added every hour over a
4 h-period, and the reaction mixture was stirred overnight to ensure maximum conversion.
A TLC analysis using ether:hexanes (1:1) indicated the reaction was complete. The crude
reaction mixture was acidified to pH 2 using 6 M hydrochloric acid and then extracted
with dichloromethane (3 × 25 mL). The combined organic extracts were washed with
saturated sodium chloride solution (25 mL), dried (MgSO4), and concentrated to yield
a brown liquid. Purification of this material by flash column chromatography (15-cm ×
2-cm column), eluted with dichloromethane, gave 6a (0.93 g, 84%) as a white solid, mp.
71–72◦C (lit.16 mp. 72–73◦C). IR: 2832, 2730, 1693 cm−1; 1H-NMR (CDCl3): δ 9.83 (s,
1 H), 7.85 (d, 1 H, J = 1.7 Hz), 7.41 (d, 1 H, J = 1.7 Hz), 3.93 (s, 3 H), 3.92 (s, 3 H);
13C-NMR (CDCl3): δ 189.7, 154.2, 153.0, 134.7, 133.9, 111.0, 92.1, 60.7, 56.1. Compound
6a has been previously prepared twice. One article16 gave an analysis for iodine but no
experimental data, and the other5 reported a correct melting point and 1H-NMR spectrum,
but no elemental analysis.
Anal. Calcd for C9H9IO3: C, 36.98; H, 3.08. Found: C, 36.76; H, 3.00.
3-Iodo-4-methoxy-5-ethoxybenzaldehyde (6b)
To a 200-mL, single-necked, round-bottomed flask, equipped with a 2.5-cm, egg-shaped,
magnetic stir bar and fitted with a condenser (nitrogen inlet), charged with 3-hydroxy-5-
iodo-4-methoxybenzaldehyde (5, 5.00 g, 18.0 mmol) and dry DMF (10 mL) was added
dropwise DBU (4.10 g, 4.00 mL, 27.0 mmol, 1.5 equiv) with stirring over a period of 5
min. The reaction mixture was stirred for 30 min, ethyl iodide (3.08 g, 1.58 mL, 19.7 mmol,
1.1 equiv) was added, and stirring was continued for an additional 30 min. A TLC analysis
using ether:hexanes (1:1) indicated the reaction was complete. The crude reaction mixture
was acidified to pH 2 using 6 M hydrochloric acid and then extracted with dichloromethane
(3 × 50 mL). The combined dichloromethane extracts were washed with saturated sodium
chloride solution (50 mL), dried (MgSO4), and concentrated to give a brown solid. The
solid was dissolved with heating in ethanol (10 mL), and water (12 mL) was slowly added.
The resulting solution was cooled slowly to room temperature over a period of 2 h and
to 0◦C for 30 min to give a solid. The crude product was collected and dried under high
vacuum for 12 h to give 6b (4.95 g, 90%) as a white solid, mp. 69–70◦C. IR: 1694 cm−1
;
1H-NMR (CDCl3): δ 9.85 (s, 1 H), 7.92 (d, 1 H, J = 1.6 Hz), 7.51 (d, 1 H, J = 1.1 Hz),
4.16 (q, 2 H, J = 6.8 Hz), 3.83 (s, 3 H), 1.39 (t, 3 H, J = 7.1 Hz); 13C-NMR (CDCl3): δ
190.9, 153.3, 151.7, 133.9, 132.9, 112.9, 93.0, 64.4, 60.1, 14.5.
Anal. Calcd for C10H11IO3: C, 39.21; H, 3.54; I, 41.50. Found: C, 39.52; H, 3.63; I,
41.24.
3-Iodo-4-methoxy-5-propoxybenzaldehyde (6c)
To a 250-mL, single-necked, round-bottomed flask, equipped with a 2.5-cm egg-shaped
magnetic stirring bar and fitted with a condenser (nitrogen inlet), charged with 3-hydroxy-
5-iodo-4-methoxybenzaldehyde (5, 5.00 g, 18.0 mmol) and dry DMF (10 mL) was added
dropwise DBU (4.10 g, 4.00 mL, 27.0 mmol, 1.5 equiv) with stirring over a period of 5 min.

Iodinated Derivatives of Vanillin and Isovanillin
151
The reaction mixture was stirred for 30 min, 1-iodopropane (3.36 g, 1.93 mL, 19.8 mmol,
1.1 equiv) was added, and stirring was continued for an additional 30 min. A TLC analysis
using ether:hexanes (1:1) indicated the reaction was complete. The reaction mixture was
acidified to pH 2 with 6 M hydrochloric acid and then extracted with dichloromethane
(3 × 50 mL). The combined dichloromethane extracts were washed with saturated sodium
chloride solution (50 mL), dried (MgSO4), and concentrated to yield a brown solid. This
solid was dissolved with heating in ethanol (10 mL), and the resulting solution was cooled
slowly to room temperature over a period of 2 h and to 0◦C for 30 min to give a solid. The
product was collected and dried under high vacuum for 12 h to give 6c (5.30 g, 92%) as a
yellow solid, mp. 51–52◦C. IR: 1695 cm−1; 1H-NMR (DMSO-d6): δ 9.85 (s, 1 H), 7.92 (d,
1 H, J = 1.6 Hz), 7.50 (d, 1 H, J = 1.1 Hz), 4.05 (t, 2 H, J = 6.5 Hz), 3.84 (s, 3 H), 1.80
(sextet, 2 H, J = 7.1 Hz), 1.03 (t, 3 H, J = 7.1 Hz); 13C-NMR (DMSO-d6): δ 190.8, 153.2,
151.9, 133.9, 132.8, 112.8, 92.9, 70.1, 60.1, 21.9, 10.5.
Anal. Calcd for C11H13IO3: C, 41.26; H, 4.06, I, 39.66. Found: C, 41.47; H, 4.17; I,
39.88.
3-Iodo-4-methoxy-5-(methoxymethyl)benzaldehyde (6d)
Using the above procedure, alkylation was carried out on 5 (5.00 g, 18.0 mmol) using
chloromethyl methyl ether (MOMCl) (1.59 g, 1.50 mL, 19.7 mmol, 1.1 equiv) and DBU
(4.10 g, 4.00 mL, 27.0 mmol, 1.5 equiv) in 10 mL of dry DMF to give 6d (5.21 g, 90%)
as a white solid, mp. 51–52◦C (EtOH). IR: 1698 cm−1; 1H-NMR (CDCl3): δ 9.83 (s, 1 H),
7.93 (d, 1 H, J = 1.7 Hz), 7.64 (d, 1 H, J = 1.1 Hz), 5.29 (s, 2 H), 3.96 (s, 3 H), 3.53 (s, 3
H); 13C-NMR (CDCl3): δ 189.4, 154.5, 150.3, 134.6, 133.9, 116.3, 95.0, 92.5, 60.7, 56.5.
Anal. Calcd for C10H11IO4: C, 37.26; H, 3.41; I, 39.44. Found: C, 37.56; H, 3.41; I,
39.35.
3-Iodo-4,5-diethoxybenzaldehyde (7)
Using the above procedure, alkylation was carried out on 3,4-dihydroxy-5-
iodobenzaldehyde (4, 1.00 g, 3.79 mmol) using ethyl iodide (1.77 g, 0.91 mL, 11.3 mmol,
3.0 equiv) and DBU (2.01 g, 1.97 mL, 13.2 mmol, 3.5 equiv) in 3 mL of dry DMF to give
1
7 (0.97 g, 80%) as a pale yellow solid, mp. 45–46◦C (EtOH). IR: 1694 cm−1; H-NMR
(CDCl3): δ 9.81 (s, 1 H), 7.83 (d, 1 H, J = 1.7), 7.37 (d, 1 H, J = 1.7 Hz), 4.20 (q, 2 H,
J = 7.1 Hz), 4.12 (q, 2 H, J = 7.0 Hz), 1.48 (t, 3 H, J = 7.0 Hz), 1.47 (t, 3 H, J = 7.0 Hz);
13C-NMR (CDCl3): δ 189.7, 153.6, 152.1, 134.5, 133.6, 111.8, 92.8, 69.4, 64.6, 15.8, 14.6.
Anal. Calcd for C11H13IO3: C, 41.25; H, 4.06; I, 39.68. Found: C, 41.44; H, 4.04; I,
39.82.
7-Iodo-1,3-benzodioxole-5-carbaldehyde (8)
Using the above procedure, alkylation was carried out on 3,4-dihydroxy-5-
iodobenzaldehyde (4, 1.00 g, 3.79 mmol) using diiodomethane (1.11 g, 0.33 mL, 4.14
mmol, 1.1 equiv) and DBU (2.01 g, 1.97 mL, 13.2 mmol, 3.5 equiv) in 3 mL of dry DMF to
give 8 (0.82 g, 78%) as a white solid, mp. 138–139◦C (MeOH). A second recrystallization of
this solid gave mp. 139–140◦C (MeOH). IR: 1683 cm−1; 1H NMR (CDCl3): δ 9.75 (s, 1 H),

152
Bunce et al.
7.69 (d, 1 H, J = 1.4 Hz), 7.27 (d, 1 H, J = 1.4 Hz), 6.15 (s, 2 H); 13C NMR (CDCl3):
δ 189.0, 154.5, 147.4, 136.5, 133.3, 106.8, 101.7, 70.1. A small amount of methanol was
retained in the solid.
Anal. Calcd for C8H5IO3: C, 34.78; H, 1.81; I, 46.01. Found: C, 35.36; H, 2.03; I,
45.85. Found: C8H5IO3·0.3 CH3OH: C, 34.93; H, 2.23; I, 45.85.
Acknowledgments
We gratefully acknowledge support of this work by the National Institute of Allergy and
Infectious Diseases [1-R01-AI 090685-01] of the NIH to WWB. We also are pleased to
acknowledge funding for the Statewide NMR facility by the National Science Foundation
(BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck Foun-
dation, and Conoco, Inc. RAB and KDB gratefully acknowledge support by the Department
of Chemistry at Oklahoma State University.
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