An unexpected Pummerer rearrangement in the synthetic route to ethyl (2′-hydroxy-4′,5′-methylenedioxyphenyl)acetate: An alternative approach to 2,3-dimethylthio benzofurans

Article abstract of DOI:10.1016/j.tetlet.2019.151282

The synthesis of ethyl (2′-hydroxy-4′,5′-methylendioxophenyl)acetate, a fragment of the antihyperglycemic natural coumarin subcoriacin, is reported. We found an expeditious route to the title compound in five steps. Final metal catalyzed acid ethanolysis of the vinylic 1,1-methylthio methylsulfoxide derivative afforded the required aryl acetic ester, but in the absence of metal catalyst, an unexpected Pummerer rearrangement produced the 2,3-dimethylthiofuran derivative as the major product. This last result provides an alternative entry to 2,3-dimethlythiobenzofurans.

Full text of DOI:10.1016/j.tetlet.2019.151282

Journal Pre-proofs
An Unexpected Pummerer Rearrangement in the Synthetic Route to Ethyl (2'-
hydroxy-4',5'-methylenedioxyphenyl)acetate: An Alternative Approach to 2,3-
Dimethylthio Benzofurans
Ariel Carreño-Montero, Luis A. Maldonado, María Isabel Chávez, Simón
Hernández-Ortega, Guillermo Delgado
PII:
S0040-4039(19)31062-7
DOI:
https://doi.org/10.1016/j.tetlet.2019.151282
TETL 151282
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 August 2019
9 October 2019
12 October 2019
Please cite this article as: Carreño-Montero, A., Maldonado, L.A., Isabel Chávez, M., Hernández-Ortega, S.,
Delgado, G., An Unexpected Pummerer Rearrangement in the Synthetic Route to Ethyl (2'-hydroxy-4',5'-
methylenedioxyphenyl)acetate: An Alternative Approach to 2,3-Dimethylthio Benzofurans, Tetrahedron Letters
(
2019), doi: https://doi.org/10.1016/j.tetlet.2019.151282
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An Unexpected Pummerer Rearrangement in the Synthetic Route to
Ethyl (2'-hydroxy-4',5'-methylenedioxyphenyl)acetate: An Alternative
Approach to 2,3-Dimethylthio Benzofurans
a
a
a
Ariel Carreño-Montero, Luis A. Maldonado, María Isabel Chávez, Simón Hernández-
a
a
Ortega, Guillermo Delgado*
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria,
Circuito Exterior, Coyoacán 04510. Ciudad de México, México.
delgado@unam.mx
Abstract. The synthesis of ethyl (2'-hydroxy-4',5'-methylendioxophenyl)acetate, a fragment of
the antihyperglycemic natural coumarin subcoriacin, is reported. We found an expeditious route
to the title compound in five steps. Final metal catalyzed acid ethanolysis of the vinylic 1,1-
methylthio methylsulfoxide derivative afforded the required aryl acetic ester, but in the absence
of metal catalyst, an unexpected Pummerer rearrangement produced the 2,3-dimethylthiofuran
derivative as the major product. This last result provides an alternative entry to 2,3-
dimethlythiobenzofurans.
Key words. Subcoriacin, aryl acetic ester, sesamol, Pummerer reaction, 2,3-
dimethylthiobenzofuran
*
Address correspondence to this author at the Instituto de Química, Universidad Nacional
Autónoma de México. Circuito Exterior, Ciudad Universitaria. Coyoacán 04510. Mexico City.
Mexico. Tel +5255-5622-4446; delgado@unam.mx

Coumarins are natural products distributed in plants biosynthesized via the shikimate pathway
1] that show different biological properties such as antioxidant and cytotoxic activities [2]. The
[
coumarin subcoriacin (1), isolated from Eysenhardtia subcoriacea (a plant used in Mexican
traditional medicine for diseases related to diabetes mellitus) [3], displayed significant
antihyperglycemic activity and improved the endogenous antioxidant system [4]. Therefore, the
synthetic access of not only subcoriacin (1) but other analogues for biological evaluation was
appealing. The synthesis of this compound could be devised from the protected compound A
which could be obtained by coupling the isoprenic fragment B with the bromo derivative C via
a Stille coupling (Scheme 1), and the coumarin ring could be obtained by a condensation
reaction and intramolecular esterification between the aldehyde D and the aryl acetic derivative
2
. Here we report the exploration of synthetic routes to ethyl (2'-hydroxy-4',5'-
methylenedioxyphenyl)acetate (2) as a fragment of subcoriacin (1), and its expeditious
preparation in five steps. We observed that a change in the reaction conditions in the last
hydrolytic step afforded a Pummerer rearrangement, representing an alternative approach for
2
,3-dimethylthio benzofurans.
O
O
O
O
OH
OMOM
OH
OMOM
OH
MOMO
HO
O
O
MOMO
O
O
A
Subcoriacin (1)
OMOM
Stille
coupling
Sn(nBu)3
B
MOMO
O
O
O
O
O
4'
Br
Br
2
OH
'
OMOM
HO
OH
MOMO
O
O
EtO
O
D
C
2

Scheme 1. Retrosynthesis of subcoriacin (1) from ethyl (2’-hydroxy-4’,5’-
methylenedioxyphenyl) acetate (2).
The preparation of compound 2 began with sesamol (3) and several routes of synthesis were
attempted (Scheme 2). Sesamol was treated with allyl bromide and potassium carbonate to
obtain O-allyl sesamol (4) [5]. Claisen rearrangement of 4 using N,N-diethylaniline afforded 2-
allylsesamol (5), and this compound was protected with methoxymethyl chloride (MOMCl) [6]
to obtain compound 6. Attempts to oxidize the alkene 6 to obtain 7 under different conditions
and reagents such as potassium permanganate, KMnO -NaIO (Lemieux-von Rudloff oxidation)
4
4
[
7], KMnO with the aid of phase transfer catalyst [8], OsO , and OsO combined with oxone
4
4
4
[9], proved unsuccessful.
Therefore, we attempted an alternative procedure. Sesamyl acetate 8 was prepared from sesamol
by means of acetic anhydride and 4-(dimethylamino)-pyridine (DMAP), and this compound was
formylated with dichloromethyl methyl ether and SnCl [10] to obtain 9, which was protected
4
(MOMCl) to afford compound 10. Conversion of the aldehyde 10 to olefin 11 was
accomplished using methyltriphenylphosphonium bromide and sodium hydride [11]. Alkene 11
was subjected to hydroboration-oxidation with BH and hydrogen peroxide [12] to obtain the
3
alcohol 12. However, oxidation of this alcohol with potassium permanganate or with Jones
reagent to obtain the carboxylic acid 7 yielded an intractable mixture of products.
Goossen and Grünberg have reported the decarboxylative coupling reaction by treatment with
diethyl oxalate catalyzed with Pd (II), DABCO (1,4-diazabicyclo[2.2.2]-octane) and dppp (1,3-
bis(diphenylphosphino)propane) as an efficient procedure to synthesize arylacetic esters from
the corresponding benzylic alcohols [13]. We decided to apply this methodology for the
preparation of the ester 14. Aldehyde 10 was reduced with sodium borohydride to obtain the
alcohol 13, which was subjected to decarboxylative coupling, but the expected ester 14 was not
obtained.

OH
Br
O
O
O
OR
O
O
O
O
PhNEt2
180 °C
K CO
2
3
3
4
[O]
5 R: H
MOMCl,
DIPEA
Ac O,
2
6
R: MOM
DMAP
[
O]
OMOM
OH
BH , then
OAc
OH
COOH
O
O
O
O
O
O
8
7
12
Cl CHOMe,
2
3
SnCl4
H O
2 2
OH
OMOM
CHO
OMOM
O
O
MOMCl,
DIPEA
O
O
MePPh Br,
O
3
NaH
O
CHO
10
11
9
NaBH , MeOH
4
(
COCl) , NMP,
2
OMOM
DABCO, dppp,
OMOM
OH
O
O
O
O
COOEt
Pd(OAc)2
14
13
Scheme 2. Attempted routes for the synthesis of compound 2.
Another route was explored from protected aldehyde 10 (Scheme 3). A Wittig reaction
employing the ylide derived from (methoxymethyl)triphosphonium chloride afforded the enol
ether 15, which was hydrolyzed to afford the aldehyde 16, but the yield was low, and the
product was very sensitive to air and light, quickly decomposing. Therefore, we tried Schuda’s
route for the synthesis of 2 [14] using methyl methylthiomethyl sulfoxide, which is not
commercially available. We were able to prepare this reagent from bis(methylthio)methane
using the Tsuchihashi methodology [15]. Aldehyde 10 was condensed with methyl
methylthiomethyl sulfoxide in presence of NaOH, obtaining the dithio derivative 17 [16].
Compound 17 was treated with a saturated solution of hydrogen chloride in ethyl alcohol
affording the desired ethyl (2’-hydroxy-4’,5’-methylenedioxyphenyl) acetate 2, but the major
product was the unexpected 2,3-dithiometyl furanbenzodioxol 18 [17] (6:1), whose structure
was confirmed by X-ray analysis (Figure 1) [18].

OMOM
CHO
OMOM
CHO
O
O
O
O
OMOM
Ph PCHOMeCl
3
O
O
HCl, Me2CO
OMe
10
15
16
Me
S
NaOH
HCl, EtOH,
CuCl2
2
18
(5:1)
O
S
Me
OMOM
HCl, EtOH
O
O
O
O
O
SMe
2
(6:1)
SMe
18
17
O
S
S
Me Me
Scheme 3. Routes for the synthesis of compound 2.
A plausible mechanism for the formation of 18 is depicted in scheme 4 and could be described
as an additive Pummerer rearrangement [19,20]. Acid ethanolysis of the methoxymethyl ether
of 17 produced the phenol E. The oxygen attached to the sulfur atom is protonated (to form the
oxonium F) and the positive charge is stabilized by resonance (intermediate G). Isomerization
of the exocyclic olefin and loss of water to form the thionium ion H allows the cyclization
forming entity I that is stabilized via a thiiranium intermediate to form a tetracyclic entity J.
Subsequent loss of a proton promotes thiirane ring opening affording compound 18. The yield
of the desired ethyl (2’-hydroxy-4’,5’-methylenedioxyphenyl) acetate 2 was reproducibly
improved including cupric chloride in the acid ethanolysis [21].
OH
OH
OH
O
O
+ H
O
O
O
O
H
O
O
O
E
S
S
F
S
S
H
S
S
H
Me Me
Me Me
Me Me
-
H
, + H
O
O
S
Me - H O
O
O
O
O
S
S
Me
Me
O
2
O
O
H
S
Me
O
I
H
G
S
S
H
Me Me
O
O
S
Me - H
Me
18
O
S
H
J
Scheme 4. Proposed reaction mechanism for the formation of compound 18.

Figure 1. X-ray diffraction pattern of compound 18 [18]. Registry number: CCDC: 1842404.
Unit Cell Parameters: a 5.0276(15), b 16.449(6), c 13.454(4) P21/c.
The results indicated that employment of Schuda’s methodology reacting methyl
methylthiomethyl sulfoxide and protected 2-hydroxy-4,5-methylenedioxy-benzaldehyde (10) to
obtain compound 17, followed by CuCl catalyzed acid treatment, proved to be the best choice
2
for the preparation of ethyl (2’-hydroxy-4’,5’-methylenedioxyphenyl)acetate (2), a building
block for the synthesis of subcoriacin (1). Interestingly, an additive Pummerer rearrangement
was observed in the last hydrolysis in the absence of CuCl , producing compound 18. This
2
unexpected Pummerer rearrangement avoiding metal catalyst can provide a new entry for 2,3-
dithiosubstituted benzofurans in a less environment-harmful way.
Funding Information
This work was supported by Dirección General de Asuntos del Personal Académico,
Universidad Nacional Autónoma de México (Project PAPIIT IG200318), and by Consejo
Nacional de Ciencia y Tecnología (México) with a fellowship (225545) awarded to A. C.-M.
Acknowledgments
The authors thank to Programa de Maestría y Doctorado en Ciencias Químicas de la
Universidad Nacional Autónoma de México, and also acknowledge Ángeles Peña, Elizabeth
Huerta, Beatriz Quiroz, Rocío Patiño, Carmen García González, Héctor Ríos, Luis Velasco, and
Javier Pérez (Instituto de Química, UNAM), for technical assistance.

Supporting Information
1
13
H and C NMR spectra for compounds 2, 4-6, 8-13, 15, 17 and 18.
References and Notes
[1]
Dewick, P. In Medicinal natural products: A biosynthetic approach; 2nd edition; John
Wiley & Sons, 2002; England; pp 161-174.
[2]
[3]
[4]
[5]
McGlacken GP, Fairlamb IJS. Nat. Prod. Rep. 2005; 28: 369-385.
Narváez-Mastache JM; Novillo F, Delgado G. Phytochemistry 2008; 69: 451-456.
Narváez-Mastache JM, Soto C, Delgado G. J. Mex. Chem. Soc. 2010; 54: 240-244.
Constantin MA, Conrad J, Merişor E, Koschorreck K, Urlacher VB, Beifuss U. J. Org.
Chem. 2012; 77: 4528-4543.
[
6]
7]
Han JH, Kwon Y, Sohn JH, Ryu DH. Tetrahedron 2010; 66: 1673-1677.
[
Kurihara T, Miki M, Santo K, Harusawa S, Yoneda R. Chem. Pharm. Bull. 1986; 34:
4
620-4628.
[8]
Moreira DR, Lima AC, Pinheiro PM, da Costa PM, Costa LV, de Moraes MO,
Brondani DJ, do Ó Pessoa C. Eur. J. Med. Chem. 2007; 42: 351-357.
[9]
Travis BR, Narayan RS, Borhan B. J. Am. Chem. Soc. 2002; 15: 3824-3825
[10]
Cueva JP, Chemel BR, Juncosa JI, Lill MA, Watts VJ, Nichols DE. Eur. J. Med. Chem.
2
012; 48: 97-107.
[
11]
12]
Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B,
Roth BL, Kozikowski AP. J. Med. Chem. 2009; 52: 1885-1902.
[
Nguyen DH, Bayardon J, Salomon-Bertrand C, Jugé S, Kalck P, Daran JC, Urrutigoity
M, Gouygou M. Organometallics 2012; 31: 857−869.
[13]
[14]
[15]
[16]
Grünberg MF, Goossen LK. Chem. Eur. J. 2013; 19: 7334-7337.
Schuda PF, Price WA. J. Org. Chem. 1987; 52: 1972-1979.
Ogura K, Tsuchihashi GA. Bull. Chem. Soc. Jpn. 1972; 45: 2203-2204.
2-(2’-Methoxymethoxy-4’,5’-methylenedioxyphenyl)-1-(methylsulfoxide)-1-
(methylthio)ethylene (17)
Methyl methylthiomethyl sulfoxide (3 mL) and finely powdered NaOH (70 mg, 1.7
mmol) were stirred for 30 min at 80 °C. After that time 2-hydroxypiperonal (5.36
mmol) was added and the resulting mixture was stirred at 80 °C for 1 h. The reaction
was cooled and then diluted with CH Cl . The organic layer was washed with a 1N
2
2
H SO solution (3×15 mL) and with water (3×15 mL). The organic layer was dried over
2
4
anhydrous Na SO and the solvent removed in the rotatory evaporator. The orange
2
4
residue was purified by column chromatography using a 9:1 n-hexane-EtOAc elution
system, obtaining the product 17 as pale yellow crystals (56% yield): mp 74-75 °C

1
(
from ethyl acetate); H NMR (CDCl , 300 MHz): δ 7.92 (s, 1H, CHCS), 7.90 (s, 1H,
3 H
CH), 6.77 (s, 1H, CH), 5.95 (s, 2H, OCH O), 5.11 (s, 2H, OCH O), 3.46 (s, 3H, O-
2
2
1
3
CH ), 2.70 (s, 3H, OS-CH ), 2.28 (s, 3H, S-CH ); C NMR (CDCl , 75 MHz): δ 152.5
3
3
3
3
C
(C-O), 149.8 (C-O), 142.4 (C-O), 137.7 (S-C-S), 131.3 (CCHC), 116.0 (CH), 107.7 (C),
1
01.8 (OCH O), 98.2 (CH), 95.8 (OCH O), 56.4 (O-CH ), 40.3 (OS-CH ), 18.6 (S-
2
2
3
3
+
CH ); EIMS: m/z 316 (M ), 253 (100%); HRMS-ESI+ calcd for: C H O S
3
13 16
5
2
3
17.05174; found: 317.05151.
[17]
6,7-(Dimethylthio)furo[2,3-f]-1,3-benzodioxol (18)
Compound 17 (262 mg, 0.83 mmol) was dissolved in 5 mL of anhydrous ethanol and
stirred until complete dissolution. A current of gaseous HCl was bubbled into the
solution for 5 min until it turned to a dark green color. Compound 18 is the less polar
spot observed when reaction was followed by TLC and it instantaneously stained to an
intense orange color with cerium (IV) sulfate as developer. The mixture was purified by
column chromatography using a 9:1 n-hexane-EtOAc elution system. The minor
compound 2 was the more polar compound [21]. Colorless crystals were obtained in a
6
0% yield. X-ray analysis confirmed the structure 18 [18]. Mp 54-55 °C (from ethyl
1
acetate); H NMR (CDCl , 300 MHz): δ 6.96 (s, 1H, CH), 6.93 (s, 1H, CH), 5.99 (s,
3
H
1
3
2
H, CH ), 2.54 (s, 3H, CH ), 2.37 (s, 3H, CH ); C NMR (CDCl , 75 MHz): δ 152.5
2 3 3 3 C
(
C), 150.6 (C), 146.6 (C), 144.9 (C), 123.5 (C), 116.1 (C), 101.4 (CH ), 98.1 (C), 93.5
2
-1
(
C), 18.4 (CH ), 17.3 (CH ); IR (CHCl , cm ): 3445, 1450, 1366, 1302, 1209, 1092,
3 3 3
1
2
031, 942, 847, 794; EIMS: m/z 254 (100%); HRMS-EI+ calcd for: C H O S
11 10 3 2
54.0071; found: 254.0076.
[18]
The crystallographic data for compound 18 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1842404). Copies can be obtained, free of charge,
on application to CCDC, 1212 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033; e-mail: deposit@ccdc.cam.ac.Uk), or via
www.ccdc.cam.ac.uk/getstructures
[
19]
20]
Feldman KS. Tetrahedron 2006; 62: 5003-5034.
[
Gamba-Sánchez D, Garzón-Posse F. In Molecular Rearrangements in Organic
Synthesis. Rojas, Ch. M., Editor. J. Wiley & Sons. 2016, 661-700.
[21]
Ethyl (2'-hydroxy-4',5'-methylenedioxyphenyl)acetate (2)
Compound 17 (262 mg, 0.83 mmol, 1 equivalent) was dissolved in 5 mL of anhydrous
ethanol and stirred for 15 min until complete dissolution. Powdered CuCl was added
2
(64 mg, 0.48 mmol, 0.29 equivalents), and then ethanolic saturated HCl solution (0.13

mL) was injected into the solution. The mixture was stirred at room temperature for 30
min, then the solvent was removed under vacuum and the residue was subjected to
column chromatography using |a 9:1 n-hexane-EtOAc elution system. The minor
component of the mixture corresponded to 18 [18], and compound 2 was obtained (56%
1
yield) as colorless crystals. Mp 61-62 °C (from ethyl acetate); H NMR (CDCl , 300
3
MHz): δ 7.43 (s, 1H, OH), 6.55 (s, 1H, CH), 6.52 (s, 1H, CH), 5.88 (s, (2H, OCH O),
H
2
4
.18 (q, J = 14 Hz, 2H, CH CH ), 3.54 (s, 2H, CH COO), 1.28 (t, J = 7 Hz, 3H, CH );
2 3 2 3
1
3
C NMR (CDCl , 75 MHz): δ 174.3 (COO), 150.3 (C-OH), 147.9 (C-O), 141.6 (C-O),
3
C
1
1
2
12.3 (C), 109.8 (CH), 101.3 (OCH O), 100.4 (CH), 62.0 (O-CH ), 37.8 (CH COO),
2 2 2
+
4.1 (CH ); EIMS: m/z 224 (M ), 225 (100%); HRMS-ESI+ calcd for: C H O
3
11 13
5
25.0763; found: 225.0754.
Me
O
OH
EtOH/HCl
CuCl2
O
O
COOEt
OH
O
O
O
O
HighlighOts
EtOH/HCl
(four steps)
O
Sesamol
S
S
O
O
SMe




A structural fragment of the antMiheypMeregl
synthesized.
(
y
P
c
u
e
m
m
m
i
e
c
re
c
r)oumarin subcoriacin is
O
SMe
The CuCl catalyzed hydrolysis of the vinylic dithio derivative affords the
2
ester.
An unexpected Pummerer reaction proceeds in the absence of CuCl in
2
the hydrolysis.
This last finding provides an alternative approach to 2,3-
dithiomethylbenzofurans.