Reaction of 4-hydroxycoumarin or its O-substituted derivatives with diatomic interhalogens: ICl and IBr

Article abstract of DOI:10.1080/00397911.2016.1264603

Herein, we present some aspects regarding the iodination/bromination of 4-hydroxycoumarin or its O-methyl or O-acetyl derivatives with iodine monochloride or iodine monobromide as halogenation reagents. Also, the investigation of photochemical transformation of the three 3-iodocoumarins was investigated for the first time.

Full text of DOI:10.1080/00397911.2016.1264603

Reaction of 4-hydroxycoumarin or its O-substituted derivatives with diatomic
interhalogens: ICl and IBr
Marcel Mirel Popa1, Constantin Draghici1, Loredana Barbu1, Denisa E. Dumitrescu2,
Florea Dumitrascu1
1Center for Organic Chemistry C.D. Nenitzescu, Romanian Academy, Bucharest,
Romania,2Faculty of Farmacy, University Ovidius, Constantza, Romania
Corresponding author: Florea Dumitrascu, ,. E-mail: fdumitra@yahoo.com
Abstract
Herein we present some aspects regarding the iodination/bromination of 4-
hydroxycoumarin or its O-methyl or O-acetyl derivatives with iodine monochloride or
iodine monobromide as halogenation reagents. Also the investigation of photochemical
transformation of the three 3-iodocoumarins was investigated for the first time.
Graphical Abstract
KEYWORDS: 4-hydroxycoumarin, 4-hydroxy-3-iodocoumarin, iodine monochloride,
iodine monobromide, photochemistry
INTRODUCTION
Coumarin is one of the most intensively studied molecules, its derivatives both from
natural or synthetic sources possessing valuable biological activities.[1] In particular, 4-
hydroxycoumarin and its derivatives are found as building blocks of important bioactive
molecules[2,3] such as warfarin[4] and as an important synthetic tool in obtaining a large
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class of bioactive heterocycles.[2] In particular 3-substituted coumarins with nitrogen
heterocycles[5] are valuable compounds for their properties such as fluorescence.[6]
The halogenation of 4-hydroxycoumarin or its derivatives[7–19] as in general the
halogenation of bioactive molecules is of interest as halogen atoms could impact their
bioavailability.[20]
Thus 4-hydroxycoumarin or its derivatives were brominated using molecular bromine,[7–
8] N-bromosuccinimide,[9–11] or by other methods.[12] The chlorination reaction of these
compounds was also performed.[13] The iodination of the 4-hydroxycoumarin and its
methyl ether was accomplished using molecular iodine,[14a,b] N-iodosuccinimide
(NIS)[15,16] or by other methods.[17, 18]
Recent reports in the synthesis of linear[15] or angular[11,16,17] furocoumarins, interesting
bioactive scaffolds, highlighted the synthetic utility of 3-bromo or 3-iodo-4-
hydroxycoumarin or its corresponding O-methyl and O-acetyl derivatives in Sonogashira
type reactions leading to compounds from the class of coumestans (Scheme 1) [21]
The halogenation of coumarins with iodine or bromine monochloride seems to be under
investigated. Iodine monochloride however proved to be a very efficient iodination and
iodocyclization reagent and its chemistry was reviewed.[22]
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Herein we report the halogenation reaction of 4-hydroxy, 4-methoxy, and 4-
acetoxycoumarin using iodine monochloride or iodine monobromide.
RESULTS AND DISCUSSION
Iodine monochloride is known from the literature as a versatile iodination reagent.[22–24]
Thus starting from the 4-hydroxycoumarin 1 we obtained in good yield the 3-iodo-4-
hydroxycoumarin 2 by reaction with ICl in acetic acid at room temperature (Scheme 2).
When trying to obtain the iodinated O-acetyl derivative 4 we observed that the reaction
with ICl did not occur when the 4-acetoxycoumarin 3, obtained in a previous step was
employed as starting material. Thus the obtaining of 4 can be done performing the
acetylation reaction after the iodination step (Scheme 2). Compounds 2 and 4 were
obtained in 82 % and 72 % yields respectively. Thus 3-iodo-4-acetoxycoumarins could
be also easly accesed for coupling reactions such as Sonogashira.[11]
The reaction of 4-hydroxycoumarin with iodine monobromide in acetic acid resulted in a
mixture containing 4:1 of 3-iodinated and 3-brominated 4-hydroxycoumarins 2 and 5. In
order to confirm the structure of the brominated compound we performed the reaction of
4-hydroxycoumarin with molecular bromine in AcOH as solvent (Scheme 3).
The ratio of the two halogenated coumarins could not be established by 1H-NMR as the
proton signals shifts are almost identical for the two compounds thus the signals are
superimposed. However the 13C-NMR spectrum showed two signals in the aliphatic area
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corresponding to C-Br at 91.1 ppm and C-I at 68.2 ppm (Figure 1). The integral of the
signals was calculated for the signals at 133 ppm corresponding to a 4:1 ratio.
The 3-iodo-4-methoxycoumarin is an important synthetic tool for Sonogashira coupling
reactions[15,16] which give access to more complex coumarin derivatives.[11,15-17] However
the 4-methoxycoumarin was available commercially and the iodination was made using a
literature method by employing NIS as iodination reagent.[13, 14] We envisioned the
obtaining of 3-iodo-4-methoxycoumarin by using ICl as iodination reagent, starting from
4-hydroxycoumarin 1, knowing the need of synthetic methods for this type of
halogenated derivatives.
Thus the compound 6 was first obtained by treating 4-hydroxycoumarin with a methanol-
hydrochloric acid solution according to Scheme 4. The compound 6 was then reacted
with ICl but the reaction seemed to give a complex mixture with no traces of the
iodinated compound 7. We tried also to perform the O-methylation reaction starting with
the iodinated compound 2, but the reaction lead after a careful examination of the NMR
spectra, to the formation of dehydroiodinated products 1 and 6 (Scheme 4).
In pursuing our goal to obtain the 3-iodo-4-methoxycoumarin 7 we employed a synthetic
protocol consisting in reacting of 2 with diazomethane. The methylation of 4-
hydroxycoumarin with diazomethane is known in the literature.[25, 26] In our case starting
from the iodinated compound 2 we obtained after the methylation reaction a mixture of
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two compounds which were structurally assigned to be 3-iodo-4-methoxycoumarin 7 and
3-iodo-2-methoxychromone 8 (Scheme 5).
In the literature the reaction of the analogous 3-bromo-4-hydroxycoumarin with
diazomethane led also to two types of crystals with different melting points but the
authors recovered and characterized only the 3-bromo-4-methoxycoumarin, the lower
melting point compound.[6]
In our attempts to obtain suitable crystals for X-ray analysis from iodinated compounds
by slow evaporation from different solvents (i.e. 3-iodo-4-hydroxycoumarin) we
observed the liberation of iodine in some cases and crystals transform in an amorphous
mass. Thus we studied the behavior of 3-iodo-4-hydroxycoumarin in presence of UV
radiation by exposing a solution of 2 in acetone for two hours to the sunlight (Scheme 6).
The reaction products were examined by NMR spectroscopy. The careful investigation of
the NMR spectra led to the conclusion that the reaction proceeded to the complete
conversion of the 3-iodo-4-hydroxycoumarin 2. Examining the NMR spectra we
observed the formation of 4-hydroxycoumarin as major product, thus confirming that a
deiodination reaction occurred by the disappearance of the peak at 67 ppm corresponding
to the C-I and appearance of a peak at 91 ppm assigned to the C-3 in the 13C-NMR and
appearance of a signal at 5.60 ppm corresponding also to a H-3 in the 1H-NMR spectrum.
The signals in the aliphatic region confirmed the presence of iodoacetone with 13C-NMR
signals at 6.72 ppm for the CH2-I (lit.[27] 6.11 ppm) and 26.6 for the CH3 (lit. [27] 25.7
ppm. A signal at 1.50 ppm corresponding to CH2 group was also present and this suggest
5

the presence of the iodoacetone photochemical disproportionation product, namely
diiodoacetone (lit.[27] 1.68 ppm).
In the case of 4-methoxy-3-iodocoumarin and 4-acetoxy-3-iodocoumarin the
photochemical deiodination seems that didn’t occur. Moreover in the case of 4-acetoxy-
3-iodocoumarin crystals suitable for X-ray analysis (the X-ray results will be discussed
elsewhere) were obtained and no iodine liberation was observed.
The reaction should be explained by the activation of the C-I bond by the two
neighboring keto groups as in II (Scheme 7). In the case of 4-methoxy-3-iodocoumarin
and 4-acetoxy-3-iodocoumarin this type of tautomerism is not possible and hence the C-I
bond is stronger.
The disproportionation of iodoacetone in UV light was studied by Shagun et al.[26] with
the obtaining of 1,3-diiodoacetone and acetone. Most probably the formation of 1,3-
diiodoacetone in our case follows a similar mechanism.
CONCLUSIONS
The iodination of 4-hydroxycouamarin with iodine monochloride gives exclusively 3-
iododerivative meanwhile iodine monobromide led to a mixture of 3-iodo and 3-
bromocoumarin. The halogenation with ICl and IBr at the three position of coumarin is
possible only in the presence of the OH at position 4 which activates the C-H bond.
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The action of visible light on three 3-iodocoumarins in acetone led to the conclusion that
the rate of deiodination is dependent on the nature of 4-substituents. Thus the rate of
deiodination for 3-iodo-4-hydroxycoumarin is very fast and gives 4-hydroxycoumarin.
For the first time the halogenation of 4-hydroxycoumarin and its O-derivatives with ICl
and IBr was accomplished.
EXPERIMENTAL SECTION
3-Iodo-4-Hydroxycoumarin (2)
In a round bottomed flask are added 1.8 g 4-hydroxycoumarin in 10 mL AcOH. Over this
solution are added dropwise 2 g ICl dissolved in 10 mL glacial AcOH. The reaction
mixture is stirred for 15 min and then is poured over 30 mL water. The yellow-orange
precipitate is filtered under vacuum and then dried to give 2. M.p 155-157 oC. Yield 82
%; Anal. Calcd. for C9H5IO3: C, 37.53; H, 1.75. Found: C, 37.89; H, 2.09. 1H-RMN (300
MHz, CDCl3) δ: 6.40-7.10 (bs, 1H, OH); 7.31-7.39 (m, 2H, H-6, H-8); 7.60-7.66 (m, 1H,
H-7); 7.92 (dd, 1H, J = 2.0, 1.7 Hz, H-5); 13C-RMN (75 MHz, CDCl3) δ: 68.0 (C-3);
113.6 (C-4a); 116.6 (C-8); 123.6, 124.6 (C-6, C-7); 133.5 (C-5); 152.9 (C-8a); 159.2 (C-
4); 164.7 (CO).
3-Iodo-4-Acetoxycoumarin (4)
To a solution of 3-iodo-4-hydroxycoumarin 2 in 5 mL Ac2O is added 0.1 mL pyridine. A
white precipitate is formed after 1-2 minutes. The reaction mass is heated 30 min on
water bath and the precipitate is dissolved upon heating. After this, the reaction is let to
cool to the room temperature and crystals were formed and were removed by vacuum
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filtration and washed with isopropanol. M.p 159-161 oC. Yield 76 %; Anal. Calcd. for
C9H5IO3: C, 37.53; H, 1.75. Found: C, 37.89; H, 2.09. 1H-RMN (300 MHz, CDCl3) δ:
2.62, 7.42-7.44, 7.49-7.52, 7.57-7.59, 7.70-7.75 (4m, 4H, H, H-5, H-6, H-7, H-8); 13C-
RMN (75 MHz, CDCl3) δ: 21.3 (Me); 82.7 (C-3); 116.0 (C-4a); 117.0 (C-8); 122.8, 125.0
(C-6, C-7); 133.5 (C-5); 153.0 (C-8a); 159.0 (C-4); 162.6 (CO); 165.7 (CO).
3-Iodo-4-Hydroxycoumarin (2) And 3-Bromo-4-Hydroxycoumarin (5)
To a suspension of 4-hydroxycoumarin (1.6 g, 10 mmol) in 10 mL AcOH is added
dropwise a solution of IBr (2.1 g in 5 mL AcOH) under continuous stirring and heating at
40-50 oC for an hour. The reaction mass is then poured over 30 mL water and the formed
precipitate is removed by filtration and dried. The NMR spectrum concluded that it was
obtained a mixture 4:1 of the iodinated versus brominated compound with a global yield
of 66 %.
3-Iodo-4-Methoxycoumarin (7) And 3-Iodo-2-Methoxychromone (8)
To an ethereal solution of CH2N2 (obtained in a previous step by literature methods[25,26]
is added 3-iodo-4-hydroxycoumarin (2, 2.7 g). The evolution of N2 is immediately
observed with the formation of a white precipitate. The excess of CH2N2 was destroyed
with AcOH and the precipitate was removed and dried (8). The filtrate was evaporated
with formation of colorless crystals (7). 3-Iodo-4-methoxycoumarin (7)[18]: M.p 81-84
)
oC. Yield 71%; 1H-RMN (300 MHz, CDCl3) δ: 4.15 (OMe) 7.30-7.39 (m, 2H, H-6, H-8);
7.58-7.64 (m, 1H, H, H-6); 7.76 (dd, 1H, J = 7.8, 1.4 Hz, H-5); 13C-RMN (75 MHz,
CDCl3) δ: 61.8 (OMe); 76.8 (C-3); 116.9 (C-4a); 117.0 (C-8); 123.4, 124.7 (C-6, C-7);
8

133.1 (C-5); 153.4 (C-8a); 160.1 (C-4); 170.7 (CO). 3-Iodo-2-methoxychromone (8):
M.p 153-155 oC. Yield 19%; Anal. Calcd. for C11H7IO4: C, 40.03; H, 2.14. Found: C,
40.31; H, 2.45. 1H-RMN (300 MHz, CDCl3) δ: 4.23 (OMe) 7.40-7.45 (m, 2H, H-6, H-8);
7.63-7.69 (m, 1H, H-6); 7.93 (dd, 1H, J = 6.9, 1.4 Hz, H-5); 13C-RMN (75 MHz, CDCl3)
δ: 57.0 (OMe); 90.0 (C-3); 116.6 (C-8); 116.8 (C-4a); 126.1, 126.6 (C-6, C-7); 133.3 (C-
5); 152.4 (C-8a); 163.1 (C-2); 174.8 (CO).
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra of all the new compounds 2, 4 and 8
and known compounds 3, 5, 6, 7. This material can be found via the “Supplementary
Content” section of this article’s webpage
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Scheme 1. The synthetic utility of halogenated 4-hydroxycoumarin in the synthesis of
bioactive compounds.
12

Scheme 2. The obtaining of the 3-iodo derivative of 4-hydroxycoumarin and 4-
acetoxycoumarin using iodine monochloride.
13

Scheme 3. Obtaining of the 3-iodo and 3-bromo derivatives of 4-hydroxycoumarin using
IBr
14

Scheme 4. Attempts to obtain 3-iodo-4-methoxycoumarin 7.
15

Scheme 5. Synthesis of 3-iodo-4-methoxycoumarin and 3-iodo-2-methoxychromone.
16

Scheme 6. The products of the photochemical reactions of 4-hydroxy-3-iodocoumarin 1
in acetone.
17

Scheme 7. Tautomerism of the 3-iodo-4-hydroxicoumarin.
18

Figure 1. The NMR spectrum of the 3-iodo-4-hydroxycoumarin and 3-bromo-4-
hydroxycoumarin mixture resulted by reaction of 1 with IBr.
19