Selective Claisen rearrangement and iodination for the synthesis of polyoxygenated allyl phenol derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.07.079

Allyl aryl ethers and allyl phenol derivatives were prepared starting from commercial or synthetized phenols. Either Williamson reaction or Et₂AlCl catalyzed Claisen rearrangement was performed to obtain the polyoxygenated molecules. The pivotal allyl phenols were then modified by methylation, iodocyclization or electrophilic aromatic iodination to afford the polyoxygenated derivatives in good to excellent yields. Additionally, their antibacterial properties were also investigated against Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1016/j.tetlet.2016.07.079

Accepted Manuscript
Selective Claisen rearrangement and iodination for the synthesis of polyoxy-
genated allyl phenol derivatives
Antonella Bochicchio, Rossella Cefola, Sabine Choppin, Françoise Colobert,
Maria Antonietta Di Noia, Maria Funicello, Gilles Hanquet, Isabella Pisano,
Simona Todisco, Lucia Chiummiento
PII:
S0040-4039(16)30947-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.079
TETL 47941
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 June 2016
22 July 2016
26 July 2016
Please cite this article as: Bochicchio, A., Cefola, R., Choppin, S., Colobert, F., Noia, M.A.D., Funicello, M.,
Hanquet, G., Pisano, I., Todisco, S., Chiummiento, L., Selective Claisen rearrangement and iodination for the
synthesis of polyoxygenated allyl phenol derivatives, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.07.079
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Graphical Abstract
.
Selective Claisen rearrangement and
iodination for the synthesis of
Leave this area blank for abstract info.
polyoxygenated allyl phenol derivatives
A. Bochicchio, R. Cefola, S. Choppin, F. Colobert, M. A. Di Noia, M. Funicello, G. Hanquet, I. Pisano, S. Todisco and L.
Chiummiento

1
Tetrahedron Letters
Selective Claisen rearrangement and iodination for the synthesis of
polyoxygenated allyl phenol derivatives
Antonella Bochicchioa, Rossella Cefolaa, Sabine Choppinb, Françoise Colobertb,*, Maria Antonietta Di
Noiac, Maria Funicelloa, Gilles Hanquetb, Isabella Pisanoc, Simona Todiscoa,* and Lucia Chiummientoa, 
aDepartment of Science, University of Basilicata, Via dell’Ateneo Lucano, 10, 85100 Potenza, Italy
bECPM, University of Strasbourg, UMR 7509, Rue Becquerel, 25, 67087 Strasbourg Cedex 02, France,
cDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Allyl aryl ethers and allyl phenol derivatives were prepared starting from commercial or
synthetized phenols. Either Williamson reaction or Et2AlCl catalyzed Claisen rearrangement
were performed to obtain the polyoxygenated molecules. The pivotal allyl phenols were then
modified by methylation, iodocyclization or electrophilic aromatic iodination to afford the
polyoxygenated derivatives in good to excellent yields. Additionally, their antibacterial
properties were also investigated against Gram-positive and Gram-negative bacteria.
Available online
Keywords:
Phenylpropanoids
2009 Elsevier Ltd. All rights reserved.
Polyoxygenated allylbenzenes
Claisen rearrangment
Chemo-selective iodination
Antibacterial properties
Allylbenzenes are a group of small molecules derived from
the general phenylpropanoid pathway. They are key flavoring
elements in many important herbs and spices, including
peppercorns, cloves, nutmeg, cinnamon, allspice, pimenta,
tarragon, and basil.1 Polyoxygenated allylbenzenes extracted as
essential oils from a variety of plants2 show different biological
activities,3 including antioxidative, antifungal, or anti-
inflammatory effects4 to antitumoral 5 and antibacterial activity6.
elemicin and 2,3,4,5-tetramethoxy-allylbenzene are rather rare7
(Figure 1).
Their interesting biological properties and their potential use
as building blocks8 prompt us to synthesize tri- and tetra-
oxygenated allylbenzenes bearing an hydroxy- or a methoxy-
group ortho to the allyl moiety. Moreover, a preliminary
functionalization as iodinated compounds was studied to prepare
more complex structures.
Then, considering the reported antimicrobial properties of the
essential oils6 which may be due to a synergistic effect of the
mixture components, we measured the antibacterial activity
against Gram-positive and Gram-negative bacteria of synthetized
compounds.
In view of the interesting biological activities of the natural
halogenated compounds18a and the reported antitubercular
properties of the halogenated phenyl ethers18b we decided to
evaluate the antimicrobial activities of the prepared compounds
Figure 1: Natural tri- and tetra-oxygenated allylbenzenes.
Results and discussion
Among the naturally occurring tri- and tetra-oxygenated
allylbenzenes myristicin, apiol and dillapiol are largely
A series of different tri- and tetra-oxygenated benzene
derivatives with the allyl group as an ether part or as a substituent
of phenyl ring was prepared. The key strategic steps following an
widespread, possessing a methylenedioxyphenyl moiety, while
———
 Corresponding author. Tel.: +39 0971 205492; fax: +39 0971 205467;
e-mail: lucia.chiummiento@unibas.it

2
Tetrahedron
atom-economy approach are selective etherification and Claisen
rearrangement.
Our investigation began with phenol 1a, which was treated with
allyl bromide under basic conditions giving quantitatively the
allyl ether 2a. The subsequent conversion of this allyl aryl ether
into the allyl phenol 3a via a Claisen rearrangement9 was then
studied. Considering that this reaction was never performed
before on substrate 2a, we decided to screen different conditions
which are listed in Table 1.
Table 1. Claisen rearrangement of compound 2a
Scheme 1: aReagents and conditions: (i) allyl bromide, K2CO3, acetone,
reflux; (ii) Et2AlCl, hexane, 0 °C; (iii) MeI, K2CO3, acetone, rt
Iodinated derivatives were also prepared as functionalized
compounds and the antibacterial activities were evaluated
considering the interesting biological properties of the natural
halogenated compounds.18
Entry
Conditions
conv
(%)a
Ratio
(3a:3a’)a
1
DMF, oil bath, 120°C, 1h
DMF, MW (330W), 200°C, 1h
N,N-dimethylaniline, oil bath, 190°C, 25h
NMP, oil bath, 180°C, 48h
neat, MW (330W), 200°C, 1h
neat, heat gun, 1h
s.m.
5
- : -
Depending on the polyoxygenated starting compounds and the
iodination conditions different products were obtained. Indeed
starting from 1,2,3-trimethoxybenzene 5 the iodination occurred
in high yield and led to compound 6 using N-iodosuccinimide
2
- : -
3
100
s.m.
31
65 : 35
- : -
4
(NIS) and
a
catalytic amount of trifluoroacetic acid
(TFA)19(Scheme 2). Performing the same reaction on compound
3a without TFA, an iodocyclization occurred furnishing
selectively mono-iodinated compound 7 in 86% yield. Adding
1.5 equiv. of I2 and catalytic amount of silver triflate (AgOTf) in
dichloromethane (DCM) to compound 7 gave rise to the
dihydrobenzofuran derivative 8.
5
71 : 29
65 : 35
67 : 33
- : -
6
95
7
neat, oil bath, 180°C, 8h
95
8
AcOH, oil bath, 120°C, 7h
DIBAL, DCM, rt, 1h, 3.5h
Et2AlCl, hexane, 0°C, 1.5h
Me2AlCl, hexane, 0°C, 1.5h
s.m.
s.m.
100
100
9
- : -
10
11
100 : -
100 : -
a
Conversion and regioisomeric ratio were evaluated by 1H-NMR
spectroscopic analysis.
Initially compound 2a was rearranged using DMF10 as the
solvent but no reaction occurred with the use of an oil bath or
microwave (MW)11 (entries 1 and 2). Using tertiary aromatic
amines12 (entry 3) a complete conversion of starting material was
observed but as a mixture of two inseparable regioisomers with
the ortho rearranged compound 3a as the major product. The use
of N-methylpyrrolidone (NMP)13 allowed the recovery only
starting material (entry 4). O-allyl phenol was next used in neat14
form, modifying just the heating source (entries 5, 6 and 7). The
use of MW gave rise to a slightly better regioisomeric ratio
between 3a and 3a’ with moderated conversion of the starting
material (31%) while using heat gun or oil bath, we noticed a
total conversion with the two possible regioisomers in a ratio of
66:33. Moreover using Brønsted acid15 and diisobutylaluminium
hydride (DIBAL) 9b, 2a was quantitatively recovered (entries 8
and 9). Finally, attempts with Et2AlCl and Me2AlCl gave rise to
the complete conversion of 2a and the only desired regioisomer
3a.16
a
Scheme 2: Reagents and conditions: (i) NIS, (with TFA for 6) acetonitrile,
rt.; (ii) I2, AgOTf, DCM, 18h; (iii) tBuNH2, I2, toluene, DCM, rt; (iv) MeI,
K2CO3, acetone, rt.
Meanwhile treatment of 3a with iodine, in the presence of
tert-butylamine (tBuNH2) in toluene20 for 30 min, led
regioselectively to compound 921 (90% yield) which was
methylated affording compound 10 (48% yield).
Notably, the presence of the aluminium atom strongly
activated the rearrangement and allowed the reaction to work at
low temperature avoiding the deprotection of the methyl ether in
position 2.
With compounds 2-4 and 6-10 in hand, in vitro antibacterial
properties of which were screened against both Gram positive
(Bacillus subtilis ATCC 6633) and Gram negative (Escherichia
coli ATCC 25922) bacterial strains using gentamicin and
kanamycin sulfate as the reference drugs. The minimum
These optimized conditions were applied to the Claisen
rearrangement of the allyl ethers 2b-d, affording the
corresponding allyl phenols 3b-d in good yields (60-76%) and
lower reaction times (above 2h).17 Quantitative methylation of the
allyl phenols 3a-d afforded compounds 4a-d (Scheme 1).

3
inhibitory concentrations (MIC) of the synthesized compounds
were determined and the results are reported in Table 2.
Essays are under investigation in order to evaluate how the
presence of iodine atom and its position on the phenol ring could
influence the antibacterial activity.
Acknowledgments
Table 2. MIC (mg/mL) values of polyoxygenated allyl benzenes
(2-4) and iododerivatives (6-10).
Financial support has been provided by Università degli Studi
della Basilicata.
compound
MIC (mg/mL)
B.subtilis E. coli
compound
MIC (mg/mL)
B.subtilis E. coli
Authors would like to thank Prof. Antonio Rosato of
University of Bari –“Aldo Moro” for providing microorganisms
used in this study.
2a
2b
2c
2d
3a
3b
3c
3d
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
4a
4b
4c
4d
6
1.2
1.2
1.2
ND
1.2
1.2
1.2
ND
References and notes
1. (a) Gang, D. R.; Wang, J.; Dudareva, N.; Nam, K. H.;
Simon, J.; Lewinsohn, E.; Pichersky, E. Plant Physiol.
2001, 125, 539–555. (b) Guenther, E. 1949. The Essential
Oils. Vol. 2., D. Van Nostrand Co. Inc., Princeton, NJ, 852
pp.
1.2
ND
1.2
ND
1.2
1.2
7
1.2
1.2
8
ND
ND
1.2
1.2
9
1.0
ND
0.128
ND
2. Wang, L.-H.; Chen J.-X; Wang, C.-C. J. Essential Oil Res.
2014, 26, 185-196.
10
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S.; Milenkovic, M.; Vucicevic, D.; Zizic, S.; Kukic, J.
Ethnopharmacol. 2007, 109, 458-463.
ND not determined.
All compounds were solubilized in dimethyl sulfoxide
(DMSO), and added in the final reaction mixture containing the
different microorganisms as described in the experimental
section. Unfortunately, MICs of compounds 4d, 7, 8 and 10 were
not determined because they are insoluble under the conditions
used for the assay.
5. de Sousa, A. C.; Alviano, D. S.; Blank, A. F.; Alves, P. B.;
Alviano, C. S.; Gattass, C. R. J. Pharm. Pharmacol. 2004,
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Pauli, A.; Kubeczka, K.–H. Nat Prod Commun. 2010, 5,
1387-1394.
The antibacterial screening revealed that allyl aryl ethers 2a-d
and methoxy allyl benzenes 4a-c did not inhibit the growth of B.
subtilis and E. coli. In contrast the presence of the free hydroxyl
group on aromatic ring (3a-d compounds) led to enhanced
antibacterial effect confirming the key role of phenolic part for
the antimicrobial activity.22-24
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M. M.; Fuchs, F.; Stielow, A.; Lantow, M.; Philchenkov, A.
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Nat. Prod. 2010, 73, 1796–1802. (c) Tsyganov, D. V.;
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Semenova, M. N.; Semenov, V. V. J. Nat. Prod. 2016, 79,
923−928.
It should be stressed that the similar behavior of phenolic
compounds on E. coli and B. subtilis has suggested a broad-
spectrum antimicrobial effect of the tested compounds, but it is
not easy to propose a mechanism. It has been reported that
phenolic compounds could interact with the cell membrane of
microorganisms,25 by leading to permeability changes of cations
like H+ and K+.23,26 The resulting dissipation of ion gradients
could affect cell viability causing cell death.
Interestingly, the greatest effect was measured in the presence
of compound 9 for B. subtilis (0.128 mg/mL), while E. coli
remained insensitive to this compound. The reason of this
toxicity against Gram positive bacteria is not clear but the iodine
atom on the phenol ring appears to be important.
In conclusion, a synthetic and efficient methodology to obtain
regioselectively functionalized polyoxygenated allyl phenols has
been successfully achieved via Et2AlCl-mediated Claisen
rearrangement. Moreover, chemoselective iodinations via NIS or
tBuNH2/I2 complex on the same starting phenol 3a have provided
iodo-dihydrobenzofuran or iodinated aromatic compounds,
respectively.
9
(a) Lutz, R. P. Chem. Rev. 1984, 84, 205–247. (b)
Majumdar, K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron
2008, 64, 597–643. (c) Martín Castro, A. M. Chem. Rev.
2004, 104, 2939–3002.
Finally, according to biological studies on a very small library
of synthesized compounds, one can speculate that the allyl aryl
ethers (2a-d) as well as the polymethoxy allylbenzenes (4a-c)
show a negligible antibacterial activity while phenols 3a-d had a
modest activity towards both Gram positive and Gram negative
bacteria. The functionalization of phenolic ring of 3a with an
iodine in para position leads to higher antibacterial activity on
Gram positive.
10 Sonnenberg, F. M. J. Org. Chem. 1970, 35, 3166–3167.
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Org. Chem. 2005, 70, 4414–4422.

4
Tetrahedron
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Food Chem. 2010, 58, 4983–4991.
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Supplementary Material
Supplementary material is available. Experimental section and
copies of 1H and 13C NMR spectra are reported .

5
Highlights




Polyoxygenated phenol synthesis via Williamson
reaction and Claisen rearrangement.
Methylation and iodination were performed to
obtain polyoxygenated derivatives.
Antibacterial properties against Gram-positive and
Gram-negative were tested.
Regioselective rearrangement and chemoselective
iodination were performed.