Studies toward the synthesis of caramboxin analogues

Article abstract of DOI:10.21577/0103-5053.20180202

Intrigued by the recent discovery of caramboxin by Brazilian researchers, we present the results from our studies toward the racemic synthesis of caramboxin analogs through the ortho-carboxylation of 3,5-dimethoxy benzyl derivatives. Three different approaches were tested, and the route involving a Vilsmeier-Haack formylation followed by a Lindgren oxidation provide a potential intermediate for the synthesis of several caramboxin analogs.

Full text of DOI:10.21577/0103-5053.20180202

http://dx.doi.org/10.21577/0103-5053.20180202
J. Braz. Chem. Soc., Vol. 30, No. 3, 528-540, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
Studies Toward the Synthesis of Caramboxin Analogues
Ronaldo E. Oliveira Filho, a Vanessa M. Higa a and Álvaro T. Omori *,a
aCentro de Ciências Naturais e Humanas, Universidade Federal do ABC, 09210-580 Santo André-SP, Brazil
Intrigued by the recent discovery of caramboxin by Brazilian researchers, we present the
results from our studies toward the racemic synthesis of caramboxin analogs through the ortho-
carboxylation of 3,5-dimethoxy benzyl derivatives. Three different approaches were tested, and
the route involving a Vilsmeier-Haack formylation followed by a Lindgren oxidation provide a
potential intermediate for the synthesis of several caramboxin analogs.
Keywords: caramboxin, star fruit, Vilsmeier-Haack reaction, Lindgren oxidation, Curtius
rearrangement, Bischler-Napieralski reaction
Introduction
of 1 was confirmed by a computational study using DFT
(density functional theory) calculations.5 In this case, the
theoretical nuclear magnetic resonance (NMR) chemical
shifts are in accordance with the experimental NMR
measured in dimethyl sulfoxide (DMSO-d6).
To the best of our knowledge, there are no
reports dedicated to the total synthesis of 1. In 2012,
Quintiliano and Silva4 reported a 10-step synthesis of the
tetrahydroisoquinolinic derivative 2 starting from dimedone
(Figure 1).Years later, an unsuccessful attempt to convert 2
to 1 was only reported in the PhD thesis of the same author.6
In view of the recent and the important discovery of
caramboxin, studies toward the synthesis of derivatives
of 1 could also be of great importance. The development
of synthetic routes to obtain the core of caramboxin could
contribute to a possible total synthesis of 1.
Structural analysis of 1 reveals an intriguing carboxyl
group at the ortho position of the phenylalanine moiety,
which we consider a significant synthetic challenge.
Although a synthesis of (DL)-o-carboxy13C-phenylalanine
starting from o-bromotoluene was reported,7 the required
benzylic bromination of toluene could be difficult if an
activated aromatic analog is applied. Thus, we investigated
three synthetic pathways for the direct o-carboxylation
of the aromatic ring to synthesize 3-methoxylated
lactam 4 (Scheme 1). Hydrolysis of 4 could lead to the
3-methoxylated derivative of caramboxin (3).
Originally from Asia, star fruit or carambola
(Averrhoa carambola) is a star-shaped fruit popularly
consumed and used as traditional medicine in tropical
countries around the globe. The toxic effect of this
fruit, which mechanism was unclear, involves not only
neurotoxicity, but also nephrotoxicity even for people with
normal renal function.1 Recently, a review of publications
from 2000 to 2014 related to the toxicity of carambola noted
27 deaths from 110 patients. In addition, the most commonly
reported symptoms after consuming carambola are hiccups,
vomiting and confusion.2 Although several studies have
suggested that oxalate (C2O42-) is the responsible for toxicity,
in 2013, Brazilian researchers3 isolated a neurotoxin,
caramboxin (1) (Figure 1), that can inhibit the GABAergic
system (related to the central nervous system).
Compound 1 contains a phenylalanine skeleton, and the
absolute configuration of the carbon α to the amino acid
has only been inferred by comparison with the [α]D signal
of L-phenylalanine.3 So far, only the 2D chemical structure
The first pathway involves the Bischler-Napieralski (BN)
cyclization of N-Boc-protected ester 7 (Scheme 1, route A).
Kim and co-workers8 developed an in situ Friedel-Crafts-
type intramolecular cyclization of N-Boc carbamates via
isocyanate intermediate 5 using triflic anhydride (Tf2O) and
Figure 1. Caramboxin structure (1) and the tetrahydroisoquinolinic
derivative 2 synthesized by Quintiliano and Silva.4
*e-mail: alvaro.omori@ufabc.edu.br

Vol. 30, No. 3, 2019
Oliveira Filho et al.
529
Scheme 1. Three approaches (A, B, and C) explored in this work to prepare lactam 4.
4-(dimethylamino)pyridine (DMAP). In this case, however,
N-Boc carbamates containing an α-ester group (compound 6)
were not tested. Isocyanate intermediate 5 could also
be generated in situ through a Curtius rearrangement of
monohydrolyzed malonate 7 (Scheme 1, route B). This
second pathway arose from the work reported by Judd et al.9
These authors reported a one-pot procedure to obtain
dihydroisoquinolin-1-ones from activated dihydrocinnamic
acids through a modified Curtius rearrangement in the
presence of BF3·OEt2. However, although a protocol to
transform monoester malonic acids into N-Boc carbamates
has been reported,10 the direct conversion of compound 7 into
isocyanate 5 in the presence of a monoester is still unknown.
Finally, the third route was proposed to prioritize
the C–H functionalization step (Scheme 1, route C).
Compound 4 could be obtained through an intramolecular
alkylation of N-amide malonate diester 8 followed by a
decarboxylation step. Selective oxidation of aldehyde 9
could lead to the acid precursor of amide 8. Interestingly,
compound 9 had previously been synthesized by
Danishefsky and co-workers11 through theVilsmeier-Haack
formylation of 10.
(Scheme 2). Reduction of 11 with LiAlH4, followed by
benzylic bromination assisted by PBr3 in dioxane provided
bromide 12 in almost quantitative yield over two steps.12 To
insert the stable enolate fragment, nucleophilic substitution
of 12 with the carbanion formed from previously prepared
N-Boc malonate 14 with Cs2CO3 gave desired alkylated
product 15 in 80% isolated yield. Another alkylation
protocol using microwave irradiation at high temperature
was applied;13 however, in this case, we observed that the
Boc group from 14 is heat sensitive, and a decrease in the
isolated yield was observed.
With carbamate 15 in hand, two sets of cyclization
conditions using Tf2O in 2-chloropyridine (2-ClPy) or
DMAP, according to Banwell’s protocol, were tested.14
Even in the presence of the two methoxy groups, in both
cases, NMR analysis showed no evidence of cyclization
product in the aromatic region. The major product obtained
in both cases was the free amine 16 with 85 and 40%
yield using DMAP and 2-ClPy, respectively. Spyropoulos
and Kokotos15 proposed the formation of an imino triflate
intermediate when Tf2O and N-Boc protected amino acids
are mixed. We believe the formation of 16 might have
occurred probably by the formation of the isocyanate
followed by hydrolysis or by simple deprotection of the
Boc through traces of trifluoromethanesulfonic acid.16
Although the cyclization of N-Boc amides with Tf2O
has been reported,17 no examples containing diesters groups
was found. Identical conditions with hydrocinnamic acid
derivatives afforded the desired lactam. However, no reports
Results and Discussion
Bischler-Napieralski pathway
The Bischler-Napieralski approach had begun with
commercially available 3,5-dimethoxybenzoic acid 11

530
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
Scheme 2. (a) LiAlH4, THF, 0 °C → rt, N2, 1 h (99%); (b) PBr3, dioxane, 40 °C, N2, 1 h (97%); (c) Boc2O, NaHCO3, DMAP (cat.), dioxane/H2O (2:1), rt,
overnight (quantitative); (d) 14, Cs2CO3, CH3CN, rt, N2, 24 h (80%); (e) Tf2O, 2-ClPy or DMAP, DCM, N2, 0 °C → rt, overnight.
using malonic acid monoesters were found.18
Different bases for the Curtius rearrangement using
diphenylphosphoryl azide (DPPA) with compound 7 were
tested.9 Among them, only triethylamine (TEA) provided
corresponding isocyanate 5 in 59% isolated yield. However,
the intramolecular SEAr was not observed.Another attempt
using a greater amount of BF3 at higher temperature (90 °C)
only afforded a trace amount of recovered 5. Analogous to
the BN approach, the failure of the reaction can be attributed
to the presence of the ester.
In order to verify the influence of the Boc group, the
same reaction was conducted using an NHAc group (17). In
this case, the desired BN product (18) was obtained in 20%
isolated yield. Thus, probably the lability of the Boc group
and the purity of the triflic anhydride are compromising the
success of the cyclization.
Curtius rearrangement pathway
Since the BN pathway did not provide the desired
cyclized product, we focused our efforts on the Curtius
approach (Scheme 3). Thus, starting with the same bromide,
12, the alkylation with diethyl malonate under microwave
irradiation13 followed by monohydrolysis with an equimolar
amount of KOH provided monoester acid 7 in good overall
yield. Deprotonation of the diethyl malonate with NaH gave
the same diester 19, in only 48% isolated yield.
Vilsmeier-Haack pathway
In view of the difficulty of the ortho-carboxylation of
functionalized aromatics, likely due to chemoselectivity
issues, we decided to prioritize the formylation in the
beginning of the route through the Vilsmeier-Haack (VH)
reaction of a single substrate. According to the literature,
the VH reaction of benzylic alcohol 10 was achieved
Scheme 3. (a) Diethyl malonate, K2CO3, MeCN, MW, 150 W, 130 °C, N2, 3 × 10 min (77%); (b) KOH, EtOH, 30 °C, N2, 30 min (67%); (c) (i) DPPA,
TEA, toluene, reflux, N2, 1.5 h; (ii) BF3.Et2O, 0 → 50 °C, N2, 5 h; (iii) 2 M NaOH, rt, 1 h (59%).

Vol. 30, No. 3, 2019
Oliveira Filho et al.
531
by Danishefsky and co-workers.11 Following the same
protocol, using freshly distilled POCl3, we obtained highly
functionalized chloride 9 in 90% isolated yield (Scheme 4).
Due to the presence of the labile benzylic chloride, the
oxidation of the benzaldehyde to the corresponding benzoic
acid was carefully studied. The oxidation of the aldehyde
is crucial for the synthesis of the amide. The results of the
tested oxidation protocols are summarized in Table 1.
Depending on the oxidation protocol tested,
compounds 20, 21 and 22 were obtained in different ratio.
Initially, the protocols for benzaldehyde oxidation using
Oxone®19 and H2O2/AgNO320 did not provide any polar
compounds by thin layer chromatography (TLC) analysis.
Additionally, oxidation using KMnO4 revealed only traces
of compound 20 or a 1:1 mixture of 20 and lactone 21
(entry 4).21
Lindgren oxidation is one of the mildest protocols to
oxidize benzaldehydes to the corresponding benzoic acids.22
This reaction uses sodium chlorite as the oxidant and is
operationally simple. However, due to the formation of
hypochlorite in situ, chlorination of the activated aromatic
ring can be observed. The results of the Lindgren reaction,
shown in Table 1 (entries 5 to 12), suggests that the reaction
is dependent on the temperature, the reaction time and the
careful addition of the chlorite. Extending the reaction time
(entry 9) and adding the sodium chlorite in one portion led
exclusively to chlorinated acid 22. Very slow addition of
sodium chlorite at low temperature provided mixtures of
20 and 21 (entries 5 to 8). Reactions at higher temperatures
(entries 11 and 12) gave lactone 21,23 indicating that acid 20
is quite sensitive. Danishefsky and co-workers11 reported
a 7:1 ratio of 20 and 22, and no formation of lactone 21
was observed. In our case, a higher proportion of the
acid was obtained (19:1); however, the isolated yield was
only 16% (entry 7). Another protocol using acetone as
the solvent gave similar results to those achieved in the
THF/H2O system (entry 10).24 Even in under buffer
conditions (entries 11 and 12), lactone 21 was also obtained.
In terms of isolated yield, we could not reproduce the
Danishefsky protocol. Purification of 20 in the presence
of lactone 21 by chromatographic methods (silica
gel, alumina, preparative TLC, and preparative high
performance liquid chromatography (HPLC)) and by other
methods (acid-base extraction and recrystallization) failed
in our hands. In all purification attempts, we observed the
lactonization of 20.
The position of the chlorine atom on the aromatic ring
in 22 was determined by two-dimensional NMR through
analysis of the HMBC (heteronuclear multiple-bond
correlation) spectra. Long distance heteronuclear coupling
Scheme 4. (a) POCl3, DMF, 0 → 75 ºC, N2, 2.5 h (90%).
Table 1. Conditions tested for the oxidation of benzaldehyde 9
entry
1
Oxidizing agent
Oxone®
H2O2/AgNO3
KMnO4
Scavenger
–
Solvent
DMF
Temperature / °C
time / min
overnight
overnight
overnight
overnight
20
20:21:22 ratioa
–
rt
50
rt
2
–
MeCN
–
3
–
MeCN/H2O
MeOH/H2O
THF/H2O
traces of 20
1:1:0
4
KMnO4
–
rt
5
NaClO2
NH2SO3H/DMSO
NH2SO3H/DMSO
NH2SO3H/DMSO
NH2SO3H/DMSO
NH2SO3H/DMSO
NH2SO3H/DMSO
resorcinol/t-BuOH
DMSO
0
1:1:0
6
NaClO2
THF/H2O
0
30
1.5:1:0
19:1:0
4:1:0
7
NaClO2
THF/H2O
0
50
8
NaClO2
THF/H2O
–20
0 to rt
0
50
9
NaClO2
THF/H2O
overnight
30
only 22
2.5:1:0
only 21
only 21
10
11
12
NaClO2
acetone
NaClO2
THF/phosphate buffer
phosphate buffer
rt
60
NaClO2
rt
120
aDetermined by LC-MS. DMSO: dimethyl sulfoxide; DMF: dimethylformamide; THF: tetrahydrofuran; rt: room temperature.

532
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
Table 2. Signals in the 2D NMR HMBC spectrum of acid 22
d (H)
d (C)
3.86 (10)
3.95 (11)
4.74 (9)
6.89 (3)
13.23 (8)
40.5 (9)
56.4 (11)
56.7 (10)
98.2 (3)
113.3 (1)
118.6 (5)
132.7 (6)
155.6 (4)
156.1 (2)
166.9 (7)
++
++
+
+
+
+
++
++
+
NMR HMBC: nuclear magnetic resonance heteronuclear multiple bond correlation; +: low intensity; ++: high intensity.
constants (nJC-H, n ≥ 2)25 of compound 22 are shown in
Table 2.
same conditions that were used for 20, we could obtain
amide 23 in 68% yield. The presence of the chlorine atom
on the aromatic ring in 23 makes the molecule less sensitive
to lactonization. Based on the low yields with sensitive acid
20, we decided to continue the pathway using amide 23
for the next steps.
We considered the intramolecular cyclization of 23 to
be the crucial step for this route (Scheme 6). Due to the
successful use of Cs2CO3 in the BN pathway, we decided
to subject dichloride 23 to similar conditions. A catalytic
amount of KI was added to increase the reactivity of
the benzylic chloride portion.27 In this case, a mixture
of lactam 24 and iodide 25 were obtained in low yields.
However, compound 25 was recovered and reacted again
with Cs2CO3 to furnish 24. The low yields in the first
cyclization protocol can be attributed to the reaction being
conducted at room temperature. A better conversion was
observed when a higher temperature and microwave (MW)
irradiation were used to recycle 25 to 24. The overall
isolated yield of 24 was 27% over two steps.
According to Table 2, two-bond correlations between
H(3)↔C(4) and H(3)↔C(2) and less intense three-bond
correlations between H(3)↔C(1) and H(3)↔C(5) were
observed. These correlations suggest the aromatic proton
is located at C(3) and the chlorine atom at C(5) relative to
the carboxyl group (C(1)).
Next, the conversion of the acid to the amide was studied
(Scheme 5). The diethyl aminomalonate hydrochloride
(13) was chosen to guarantee the following intramolecular
alkylation step. Thus, impure acid 20 and dichloride 22
were reacted with HBTU (2-(1H-benzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate) in the
presence of triethylamine in dichloromethane (DCM)
at room temperature.26 Desired amide 8 was obtained in
low yield (7%) and the major compound was lactone 21,
which was obtained in 66% isolated yield.As expected, 20
was found to be unstable in the presence of triethylamine.
However, when dichlorinated acid 22 was submitted in the
Scheme 5. (a) HBTU, TEA, DCM, rt, N2, 2.5 h (7% for 8 and 66% for 21); (b) HBTU, TEA, DCM, rt, N2, 2.5 h (68%).

Vol. 30, No. 3, 2019
Oliveira Filho et al.
533
Scheme 6. (a) Cs2CO3, KI (cat.), DMF, rt, 12 h (12% for 24 and 19% for 25); (b) Cs2CO3, MeCN, MW (150 W, 130 °C, 10 min) (77%).
Lactam 24 possesses the majority of the functional
groups present in caramboxin. Attempts to decarboxylate
one of the esters and open the lactam ring in a one-pot
fashion were carried out (Scheme 7).28 In the presence of
6 mol L-1 HCl at 130 °C, several byproducts were obtained.
Liquid chromatography-mass spectrometry (LC-MS)
analysis did not provide any evidence of a possible
hydrolysis product.
As previously mentioned, on the basis of the high
sensitivity of acid 20, we anticipated that the Vilsmeier-
Haack product, stable aldehyde 9, could be converted to a
less reactive benzonitrile analogue, which could later be
converted to the corresponding acid by hydrolysis. Thus,
the treatment of 9 with NaN3 in POCl3 generated nitrile
31 in reasonable yield (67%) (Scheme 9).29 Alkylation of
31 using 28 was accomplished under similar conditions
to those mentioned before affording the malonate 32. At
this point, the hydrolysis of the latter compound was more
carefully investigated.
Since the last hydrolyses were carried out in acidic
media, we decided to test the reactions under basic
conditions with two distinct protocols. With the first set
of conditions using 2 mol L-1 NaOH and an ultrasonic
bath at 80 °C,30 we obtained only the corresponding
dicarboxylate disodium salt 33. On the other hand, using
KOH as the base in refluxing ethanol,31 we obtained only
decarboxylation derivative 34. Interestingly, in the last
attempt, when compound 33 was subjected to acidic
hydrolysis (2 mol L-1 HCl) for an extended period, we
could obtain imino tetrahydroisoquinolinone 35 in low
isolated yield (12%). In this case, the expected hydrolysis
of the acetamido group and the malonate decarboxylation
occurred; however, the nitrile group was attacked by the
free amino group, and a similar reaction was reported before
by Hamley and co-workers.32
Scheme 7. (a) HCl 6 mol L-1, MW (200 W, 130 °C), 10 min.
The hydrolysis of amides is usually difficult. Thus, to
avoid the d-lactam opening, a portion of remaining acid
22 was esterified by CH3I (Scheme 8). Corresponding
methyl ester 27 was then submitted to the benzylic
alkylation. In this case, we used protected diethyl
acetamidomalonate 28, and corresponding product 29
was obtained in a higher yield (60%) than what was
achieved with the intramolecular version (23 to 24). The
hydrolysis of amide triester 29 was partially successful.
In fact, the decarboxylation of only one of the malonate
esters occurred, affording acetamide benzyl methyl
ester 30 in quantitative yield. Unfortunately, further acid
hydrolysis of 30 with longer reaction times and at higher
temperatures gave complex mixtures of products.
Conclusions
We presented three different approaches for the
ortho-carboxylation of 3,5-dimethoxy benzyl derivatives
Scheme 8. (a) CH3I, Cs2CO3, DMF, rt, N2, 30 min (59%); (b) KI (cat.), Cs2CO3, MeCN, rt, overnight (60%); (c) HCl 6 mol L-1, CH3COOH, MW (150 W,
90 °C, 10 min) (94%).

534
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
Scheme 9. (a) NaN3, POCl3, 50 °C, N2, 1 h (67%); (b) KI, Cs2CO3, MeCN, rt, 48 h (78%); (c) NaOH 2 mol L-1, ultrasonic bath, 80 °C, 45 min (67%);
(d) KOH 35%, EtOH, 80 °C, N2, 2.5 h (45%); (e) HCl 2 mol L-1, dioxane, reflux, N2, 48 h (12%).
toward the preparation of caramboxin analogs. We
observed that the insertion of the carboxyl group early
on in the synthesis helps avoid chemoselective issues.
The Vilsmeier-Haack formylation was chosen due to the
concomitant halogenation of the benzylic alcohol, which
facilitates the malonate alkylation. For the synthesis of
caramboxin, a study regarding the regioselectivity of theVH
will be necessary. We also conclude that the “protection”
of the carboxylate by esterification or by functional
group interconversion seems to be more attractive than
lactamization by an intramolecular alkylation. Lastly, the
challenges presented by the final steps, mainly the hydrolysis
of the amide and the esters, require more detailed study.
ABC. The HRMS analysis was made in micro-TOF (time
of flight) Bruker Daltonics from São Paulo University. The
13
1H and C NMR were made on Varian (500 MHz) from
Federal University ofABC andVarianAIII or Bruker DPX-
300 (300 MHz) from São Paulo University. The solvents
used were deuterated chloroform (CDCl3) and deuterated
dimethyl sulfoxide (DMSO-d6). The melting point analyses
were made on Büchi B-540 or EZ-Melt SRS-Stanford
Research Systems from Federal University of ABC. The
purification on HPLC was made in Waters coupling with
UV-Vis detector model 2489, using a semipreparative
column Phenomenex C18. The Microwave™ synthesis
system were made on CEM Focused, model Discover, from
Federal University of ABC.
Experimental
(3,5-Dimethoxyphenyl)methanol (10, CAS 705-76-0)
Under N2 atmosphere, a solution
General information
of LiAlH4 (2.1041 g, 55.44 mmol)
The reagents (Sigma-Aldrich®) and solvents (Synth®)
were used without purification. POCl3 was distillated
before used. The TLC analysis was made in silica gel 60
with aluminum, 0.2 mm, with indicator for 254 nm, and
compounds visualized using UV irradiation, ninhydrin
or vanillin stains. Flash column chromatography was
performed using silica gel 60 Å (35-70 µm) from Fluka
Analytical. The gas chromatography-mass spectrometry
(GC-MS) analysis was made in one ion trap, Varian 4000
from Federal University ofABC. The LC-MS analysis was
made in quadrupole Agilent 6130 Infinity coupled to an
Agilent 1260 HPLC system, from Federal University of
in anhydrous THF (100 mL) was
added dropwise to a solution of
3,5-dimethoxybenzoic acid (11)
(10.0 g, 54.9 mmol) in anhydrous THF (150 mL) at 0 °C.
After stirring for 20 min at 0 °C and one hour at room
temperature, the reaction was diluted with THF (90 mL)
and water (4 mL) was added. The mixture was then
filtered on celite, washed with ethyl acetate (4 × 65 mL)
and concentrated under reduced pressure. The resulting
clear yellow solid (9.14 g, 54.5 mmol, 99% yield) was
applied to the next reaction without further purification. mp
50.2-51.1 °C; 1H NMR (300 MHz, CDCl3) d 1.90 (s, 1H,

Vol. 30, No. 3, 2019
Oliveira Filho et al.
535
OH), 3.80 (s, 6H, Ar-OCH3), 4.63 (s, 2H, Ar-CH2), 6.39 (t,
1H, J 2.3 Hz,Ar-H), 6.53 (d, 2H, J 2.3 Hz,Ar-H); 13C NMR
(126 MHz, CDCl3) d 55.4 (2C), 65.4, 99.7, 104.6 (2C),
143.4, 161.0 (2C); low resolution (LR)MS (EI (electron
ionization)) m/z 168 (M+, 100), 151 (12), 139 (45), 109
(15). The spectra of compound 10 is in accordance with
those previously reported.33
Diethyl 2-((tert-butoxycarbonyl)amino)-2-(3,5-dimethoxy-
benzyl)malonate (15)
A solution of bromide
12 (231 mg, 1 mmol),
diethyl (Boc-amino)
malonate (275 mg,
1.1 mmol) and Cs2CO3
(325 mg, 1.1 mmol) in acetonitrile (4.5 mL) was stirred for
25 h at room temperature. The reaction was then diluted in
30 mL of ethyl acetate and extracted with water and brine.
The organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel, using ethyl
acetate/hexane (4:1) as the eluent, affording a white solid
(326.2 mg, 0.77 mmol, 77% yield). mp 69.7-72.5 °C;
1H NMR (500 MHz, CDCl3) d 1.29 (t, 6H, J 7.1 Hz,
CO2CH2CH3), 1.47 (s, 9H, t-Bu), 3.55 (s, 2H, Ar-CH2C),
3.74 (s, 6H, Ar-OCH3), 4.17-4.26 (m, 2H, CO2CH2CH3),
4.27-4.36 (m, 2H, CO2CH2CH3), 5.79 (s, 1H, N-H), 6.20 (d,
2H, J 2.0 Hz,Ar-H), 6.34 (t, 1H, J 2.2 Hz,Ar-H); 13C NMR
(126 MHz, CDCl3) d 14.0 (2C), 28.2 (3C), 38.5, 55.1 (2C),
62.5 (2C), 67.1, 80.1, 99.1, 108.1 (2C), 137.4, 153.8, 160.5
(2C), 167.6 (2C); LRMS (ESI) m/z 426.2 [M + H]+.
3,5-Dimethoxybenzyl bromide (12, CAS 877-88-3)
U n d e r N 2 a t m o s p h e r e ,
phosphorus tribromide (618 µL,
6.58 mmol) was added dropwise
t o a s o l u t i o n c o n t a i n i n g
(3,5-dimethoxyphenyl)methanol
(10) (1.00 g, 5.98 mmol) in dioxane (8 mL). The solution
was stirred at 40 °C for 1 h. After cooling to room
temperature the reaction was quenched with a saturated
NaHCO3 solution (28 mL) and the resulting aqueous
phase was extracted with ethyl acetate (3 × 28 mL). The
combined organic extracts were dried with Na2SO4, filtered
and concentrated under reduced pressure. The resulting
light yellow solid (1.38 g, 5.9 mmol, > 99% yield) was
applied to the next reaction without further purification.
mp 72.9-73.8 °C; 1H NMR (500 MHz, CDCl3) d 3.79 (s,
6H, Ar-OCH3), 4.42 (s, 2H, Ar-CH2), 6.39 (t, 1H, J 2.2 Hz,
Ar-H), 6.54 (d, 2H, J 2.2 Hz, Ar-H); 13C NMR (126 MHz,
CDCl3) d 33.6, 55.4 (2C), 100.6, 106.9 (2C), 139.7, 160.9
(2C); LRMS (EI) m/z 232 (M+, 30), 230 (27), 152 (15),
151 (100). The spectra of compound 12 is in accordance
with those previously reported.34
Diethyl 2-amino-2-(3,5-dimethoxybenzyl)malonate (16)
Triflic anhydride
(1.05 mL, 1.05 mmol) was
slowly added to a solution
containing the carbamate
15 (91 mg, 0.21 mmol)
and DMAP (78.2 mg, 0.64 mmol) in DCM (8 mL). The
mixture was stirred for 18 h at 0 °C, in N2. The reaction
was then diluted in 5 mL of DCM and washed with a
saturated Na2CO3 solution (5 mL), then 20% citric acid
solution (5 mL) and saturated Na2CO3 solution (5 mL).
The combined organic phases was dried with anhydrous
Na2SO4 and concentrated under pressure. The residue
was purified by flash chromatography, on silica gel, using
ethyl acetate/hexane (2:1) as the eluent; the amine 16
(58 mg, 0.178 mmol, 85% yield) was obtained as a light
oil. 1H NMR (500 MHz, CDCl3) d 1.29 (t, 6H, J 7.1 Hz,
CO2CH2CH3), 2.10 (s, 2H, NH2), 3.28 (s, 2H,Ar-H), 3.75 (s,
6H, Ar-OCH3), 4.25 (qd, 4H, J 7.1, 1.8 Hz, CO2CH2CH3),
6.33 (d, 2H, J 2.3 Hz, Ar-H), 6.36 (t, 1H, J 2.3 Hz, Ar-H);
13C NMR (126 MHz, CDCl3) d 13.9 (2C), 41.1, 55.2 (2C),
62.0 (2C), 66.2, 99.1 (2C), 108.1 (2C), 137.0, 160.7 (2C),
170.8; LRMS (ESI) m/z 352.1 [M + H]+.
Diethyl 2-((tert-butoxycarbonyl)amino)malonate (14)
NaHCO3 (462 mg, 5.5 mmol)
was slowly added to a suspension of
diethyl aminomalonate hydrochloride
(1.0582 g, 5 mmol, 13) in water (7 mL) and dioxane
(10 mL). The resulting solution was stirred for a few
minutes at room temperature (rt) until a clear solution
appeared. Next, DMAP (6.11 mg, 0.01 mmol) was added
followed by a dropwise addition of a solution of Boc2O
(1.2004 g, 5.5 mmol) in dioxane (4 mL). The mixture was
stirred at room temperature overnight. Then, the solution
was concentrated under reduced pressure. The residue was
suspended in ethyl acetate (25 mL) and then extracted with
5% aqueous KHSO4 solution (20 mL), saturated aqueous
NaHCO3 solution (20 mL), water (15 mL) and brine (15 mL).
The organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. 1.2803 g, 4.65 mmol
(46% yield) of a light oil was obtained and applied for the
next reaction without further purification. LRMS (ESI
(electrospray ionization)) m/z 276.1 [M – CO2]+, 100).
Diethyl 2-(3,5-dimethoxybenzyl)malonate (19, CAS 5859-
68-7)
A mixture of bromide 12 (334 mg, 1.44 mmol),

536
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
diethyl manolate (263 µL,
to a solution containing
2-(3,5-dimethoxybenzyl)-
3-ethoxy-3-oxopropanoic
1. 73 mmol), Cs2CO3
(562 mg, 1.73 mmol) and
CH3CN (13 mL) was added
acid (115 mg, 0.4 mmol, 7)
to an Ace sealed tube. Three cycles of irradiation at
150 W, with maximum temperature of 130 °C for 10 min
were done. Next, the reaction was diluted in ethyl acetate
(35 mL) and washed with water (20 mL) and brine (20 mL).
The organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure.An oil 19 (344.5 mg,
1.11 mmol, 77% yield) was obtained and submitted to
and triethylamine (55 µL, 0.4 mmol) in toluene (4 mL).
The mixture was stirred for 90 min at 90 °C. Then, the
reaction was cooled at 0 °C and BF3.OEt2 (200 µL) was
added.After, stirring at 50 °C for 5 h in N2, the mixture was
cooled at rt and then a 2 M NaOH solution was added (at
pH = 10). Next, after extraction with EtOAc (3 × 10 mL)
and brine (10 mL) the combined organic phases was dried
with anhydrous Na2SO4 and concentrated under pressure.
The residue was purified by flash chromatography, on silica
gel, using ethyl acetate/hexane (4:1 to 1:1) as the eluent; the
isocyanate 5 (20.6 mg, 0.07 mmol, 19% yield) was obtained
as a light oil. 1H NMR (300 MHz, CDCl3) d 1.25 (t, 3H,
CO2CH2CH3), 3.02 (d, 2H, J 5.8 Hz, Ar-CH2CH), 3.74
(s, 6H, Ar-OCH3), 4.13-4.18 (m, 2H, CO2CH2CH3), 4.66-
4.77 (m, 1H, Ar-CH2CH), 6.27 (d, 2H, J 2.2 Hz, o-Ar-H),
6.30-6.36 (m, 1H, p-Ar-H); LRMS (EI) m/z 279 (M+, 100).
1
the next reaction without further purification. H NMR
(500 MHz, CDCl3) d 1.23 (t, 6H, J 7.1 Hz, CO2CH2CH3),
3.16 (d, 2H, J 7.8 Hz, Ar-CH2CH), 3.63 (t, 1H, J 7.8 Hz,
Ar-CH2CH), 3.76 (s, 6H, Ar-OCH3), 4.18 (dq, 4H, J 10.7,
7.1, 7.1, 3.6, 3.4 Hz, CO2CH2CH3), 6.32 (s, 1H, J 2.2 Hz,
Ar-H), 6.36 (d, 2H, J 2.2 Hz, Ar-H); 13C NMR (126 MHz,
CDCl3) d 14.0 (2C), 34.9, 53.7, 55.3 (2C), 61.5, 98.8, 106.8
(2C), 140.3, 160.8 (2C), 168.9 (2C); LRMS (EI) m/z 310
(M+ , 70), 265 (8), 237 (100), 219 (16), 192 (60), 165 (12),
136 (6), 105 (4), 91 (4). The spectra of compound 19 are
in accordance with those previously reported.35
2-(Chloromethyl)-4,6-dimethoxybenzaldehyde (9, CAS
166322-67-4)
2-(3,5-Dimethoxybenzyl)-3-ethoxy-3-oxopropanoic acid (7)
To a solution of malonate
First, a solution of a freshly
distilled POCl3 (4.44mL, 47.6mmol)
19 (173 mg, 0.56 mmol) in
in anhydrous DMF (7.2 mL) at 0 °C
ethanol (3 mL), a solution of
in N2 was prepared. To this solution,
KOH (32 mg, 0.57 mmol) in
a solution of (3,5-dimethoxyphenyl)
water (0.65 mL) was slowly added. The reaction was stirred
for 30 min at 30 °C. Then, a 5% aqueous HCl solution
(3 mL) was slowly added. The mixture was diluted in
water (5 mL) and extracted with dichloromethane (3 ×
5 mL). The organic phases was combined and neutralized
with saturated aqueous NaHCO3 solution (10 mL). The
remaining aqueous phase was acidified with 2 M HCl
solution and extracted with more DCM (3 × 5 mL). All
the organic phases was combined, dried with anhydrous
Na2SO4 and concentrated under reduced pressure, affording
white solid (116.8 mg, 0.41 mmol, 73% yield). The crude
product was applied to the next reaction without further
methanol (10) (2.0 g, 11.9 mmol) in anhydrous DMF
(5.1 mL) was slowly added and the resulting mixture was
stirred for 2 h at 75 °C in N2. The reaction was cooled to
room temperature and poured into ice water (180 mL). The
pH was adjusted to 7 by addition of 2 M NaOH solution
and the mixture was stirred for additional 1.5 h. The green
precipitate was filtered, washed with cooled water and
was dried under reduced pressure. The solid was diluted
in acetone, and the solution was filtered in celite and the
filtrate was concentrated under reduced pressure. Finally,
the solid was purified by flash chromatography on silica
gel, eluting with a gradient of ethyl acetate/hexane (4:1 to
1:1), providing a white solid (2.286 g, 10.7 mmol, 90%
yield). mp 105.5-106.5 °C; 1H NMR (300 MHz, CDCl3) d
3.90 (s, 6H, Ar-OCH3), 5.05 (s, 2H, Ar-CH2), 6.44 (d, 1H,
J 2.4 Hz, Ar-H), 6.76 (d, 1H, J 2.9 Hz, Ar-H), 10.46 (s,
1
purification. H NMR (300 MHz, CDCl3) d 1.23 (t, 3H,
J 7.1 Hz, CO2CH2CH3), 3.18 (d, 2H, J 7.7 Hz,Ar-CH2CH),
3.70 (t, 1H, J 7.7 Hz, Ar-CH2CH), 3.76 (s, 6H, Ar-OCH3),
4.19 (q, 2H, J 7.1 Hz, CO2CH2CH3), 6.34 (t, 1H, J 2.2 Hz,
Ar-H), 6.37 (d, 2H, J 2.2 Hz, Ar-H), 9.08 (s, 1H, COOH);
13C NMR (75 MHz, CDCl3) d 13.9, 34.8, 53.3, 55.2 (2C),
61.8, 98.9, 106.7 (2C), 139.7, 160.8 (2C), 168.6, 174.0;
LRMS (EI) m/z 238 [M – CO2]+, 85), 193 (20), 165 (100).
13
1H, Ar-CHO); C NMR (75 MHz, CDCl3) d 44.9, 55.7,
56.0, 97.7, 107.6, 115.9, 142.4, 165.0, 165.3, 189.9; LRMS
(ESI) m/z 215.0 ([M + H]+, 100), 217.0; HRMS (TOF) m/z,
observed: 237.0278; C10H11ClO3Na [M + Na]+ requires:
237.0294. The spectra of compound 9 is in accordance
with those previously reported.36
Ethyl 3-(3,5-dimethoxyphenyl)-2-isocyanatopropanoate (5)
Diphenyl phosphoryl azide (86 µL, 0.4 mmol) was added

Vol. 30, No. 3, 2019
Oliveira Filho et al.
537
2-(Chloromethyl)-4,6-dimethoxybenzoic acid (20)
Diethyl 2-(3-chloro-2-(chloromethyl)-4,6-dimethoxy-
benzamido)malonate (23)
To a solution of 2-(chloro-
m e t h y l ) - 4 , 6 - d i m e t h o x y -
benzaldehyde 9 (500 mg,
To a solution of
acid 22 (200 mg,
2.33 mmol) in acetone (25 mL) and
0.75 mmol), trietilamine
DMSO (10 mL) at 0 °C, a solution
(420 mL, 2.6 mmol) in
of sulfamic acid (384.5 mg,
DCM (10 mL), HBTU
3.96 mmol) in water (7.5 mL) was
(363 mg, 0.96 mmol)
added. The reaction was stirred
for 1 min on N2 atmosphere. To
was added.After stirring for 15 min at room temperature, a
solution of diethyl aminomalonate hydrochloride (203 mg,
0.95 mmol) in DCM (10 mL) was added dropwise, and
the resulting mixture was stirred for additional 2.5 h at
rt. The reaction was diluted in DCM (50 mL) and washed
with 5% aqueous citric acid solution, saturated aqueous
NaHCO3 solution and water. The organic phase was
dried with anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by two
consecutive flash chromatography columns, on silica gel:
the first was eluted with ethyl acetate/hexane (1:1) and
second was eluted with DCM/hexane (3:1), giving the
compound 23 as a white solid (205 mg, 0.47 mmol, 63%
yield). mp 152-156 °C; 1H NMR (500 MHz, CDCl3) d 1.33
(t, 6H, J 4.4 Hz, CO2CH2CH3), 3.87 (s, 3H, Ar-OCH3),
3.95 (s, 3H, Ar-OCH3), 4.32 (m, 4H, CO2CH2CH3), 4.87
(s, 2H, Ar-CH2), 5.34 (d, 1H, J 3.8 Hz, -CH-NH-), 6.52
(s, 1H, -CH-NH-), 7.12 (d, 1H, J 3.9 Hz, Ar-H); 13C NMR
(126 MHz, CDCl3) d 14.1, 40.5, 56.4, 56.5, 57.0, 62.8,
96.7, 115.8, 118.5, 135.5, 156.3, 165.3, 166.0; LRMS (ESI)
m/z 424.1 (75), 422.1 ([M + H]+, 100), 249.0 (20), 247.0
(M+ – NHCH(CO2Et)2, 40); HRMS (TOF) m/z, observed:
246.9920; C10H9Cl2O3 [M – NHCH(CO2Et)2]+ requires:
246.9928.
this solution, a solution of NClO2 (326.5 mg, 3.61 mmol)
in water (17 mL) was slowly added. After stirring for
30 min at 0 °C the reaction was extracted with ethyl
acetate (3 × 15 mL). The combined organic phases were
washed with water (15 mL) and brine (15 mL), then dried
with anhydrous Na2SO4 and concentrated under reduced
pressure. A yellow solid (347 mg) of a mixture of the acid
20 with the lactone 21 (1:1 ratio) was obtained. LRMS
(ESI) m/z 231.0 ([M + H]+, 100), 233.0 (34) for acid 20
and 195.1 (M+, 100) for lactone 21.
3-Chloro-2-(chloromethyl)-4,6-dimethoxybenzoic acid (22)
To a solution of 2-(chloro-
m e t h y l ) - 4 , 6 - d i m e t h o x y -
benzaldehyde (9) (100 mg,
0.47 mmol) in THF (5 mL)
and DMSO (0.3 mL) at 0 °C,
a solution of sulfamic acid
(153.8 mg, 1.58 mmol) in water (2.5 mL) was added.
The reaction was stirred for 1 min on N2 atmosphere.
The NaClO2 (136.0 mg, 1.50 mmol) was fastly added and
stirred for 1 h at 0 °C and overnight at rt. The reaction
was diluted with ethyl acetate (25 mL) and extracted with
saturated aqueous NH4Cl solution (40 mL). The aqueous
phase was extracted with more ethyl acetate (15 mL).
The combined organic phases were washed with brine,
dried with anhydrous MgSO4 and concentrated under
reduced pressure, providing a white solid (134.0 mg, in
Diethyl 5-chloro-6,8-dimethoxy-1-oxo-1,2-dihydro-
isoquinoline-3,3(4H)-dicarboxylate (24)
Method A
A solution containing 23 (100 mg, 0.26 mmol), KI
(102 mg, 0.62 mmol) and Cs2CO3 (201 mg, 0.62 mmol) in
CH3CN (5 mL) was stirred for 12 h at room temperature.
The reaction was diluted with ethyl acetate (20 mL), washed
with water (20 mL) and brine (20 mL). The organic phase
was dried with anhydrous Na2SO4 and concentrated. The
solid was purified by flash chromatography, on silica gel,
with ethyl acetate/hexane (9:1) as the eluent; the cyclized
product 24 (11 mg, 0.03 mmol, 11% yield) and iodinated
precursor 25 (25 mg, 0.05 mmol, 19% yield) were obtained.
1
a quantitative yield). mp 143 °C; H NMR (500 MHz,
DMSO-d6) d 3.86 (s, 3H,Ar-OCH3), 3.94 (s, 3H,Ar-OCH3),
4.74 (s, 2H, Ar-CH2), 6.89 (s, 1H, Ar-H), 13.23 (br s, 1H,
Ar-CO2H); 13C NMR (126 MHz, DMSO-d6) d 40.5, 56.4,
56.7, 98.2, 109.5, 113.3, 118.6, 132.7, 155.6, 156.2, 166.9;
heteronuclear multiple quantum correlation (HMQC,
500 MHz, DMSO-d6) H6.89↔C113.3, H6.89↔C118.6,
H6.89↔C155.6, H6.89↔C156.3, H4.74↔C113.3,
H4.74↔C118.5, H4.74↔C132.7, H3.95↔C156.1,
H3.86↔C155.7; LRMS (ESI) m/z 267.0 (65), 265.0
([M + H]+, 100), 247.0 (24), 229.0 (35), 117.1 (20); HRMS
(TOF) m/z, observed: 286.9845; C10H10Cl2O4Na [M + Na]+
requires: 286.9853.
Method B
25 (200 mg, 0.5 mmol), Cs2CO3 (401 mg, 1.0 mmol)
and CH3CN (5 mL) were added to an Ace sealed tube. The

538
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
tube was irradiated at 200 W, with maximum temperature
of 130 °C for 10 min. Then, the reaction was diluted in
ethyl acetate (20 mL), washed with water (20 mL) and
brine (20 mL). The organic phase was dried with anhydrous
Na2SO4 and concentrated under reduced pressure affording
the cyclized product 24 (150 mg, 0.39 mmol, 77% yield).
stirred for 3 days at rt. The reaction was diluted with ethyl
acetate (40 mL) and washed with water (10 mL) and brine
(10 mL). The organic phase was dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The crude
solid was purified by flash chromatography on silica gel,
using ethyl acetate/hexane (4:1 to 1:1) as the eluent, giving
a white solid (134.0 mg, 60% yield). mp 169.6-173.0 °C;
1H NMR (500 MHz, CDCl3) d 1.24 (t, 6H, J 7.1 Hz,
CO2CH2CH3), 1.99 (s, 3H, NHAc), 3.83 (s, 3H, Ar-OCH3),
3.84 (s, 3H, Ar-OCH3), 3.90 (s, 3H, Ar-CO2CH3), 3.96 (s,
2H,Ar-CH2-C), 4.15 (dq, 2H, J 10.8, 7.2 Hz, CO2CH2CH3),
4.26 (dq, 2H, J 10.8, 7.2 Hz, CO2CH2CH3), 6.44 (s, 1H,
NHAc), 6.47 (s, 1H, Ar-H); LRMS (EI) m/z 424 (M+ – Cl-,
50), 314 (37), 312 (100), 244 (19), 238 (25); HRMS (TOF)
m/z, observed: 482.1179; C20H26ClNO9Na [M + Na]+
requires: 482.1193.
mp 188.9-194.4 °C;
1H NMR (500 MHz,
CDCl3) d 1.25 (t, 6H,
J 7.0 Hz, CO2CH2CH3),
3.61 (s, 2H,Ar-CH2), 3.95
(s, 3H,Ar-OCH3), 3.97 (s,
3H, Ar-OCH3), 4.19-4.27 (m, 4H, CO2CH2CH3), 6.48 (s,
1H, Ar-H), 6.58 (s, 1H, NH); 13C NMR (126 MHz, CDCl3)
d 13.9 (2C), 32.3, 56.2, 56.5, 63.0 (2C), 64.1, 76.8, 77.3,
95.8, 109.7, 112.8, 136.7, 158.9, 160.7, 162.6, 167.3 (2C);
LRMS (ESI) m/z 388.1 (30), 386.1 ([M + H]+, 100); HRMS
(TOF) m/z, observed: 408.0823; C17H20ClNO7Na [M + Na]+
requires: 408.0826.
2-Acetamido-3-(2-chloro-3,5-dimethoxy-6-(methoxy-
carbonyl)phenyl)propanoic acid (30)
To a solution of the diester
29 (51 mg, 0.1 mmol) in acetic
Methyl 3-chloro-2-(chloromethyl)-4,6-dimethoxybenzoate
(27)
acid (2 mL), 6 mol L-1 HCl
solution (2 mL) was added. The
A solution containing acid
flask was irradiated with 150 W
22 (200 mg, 0.87 mmol), CH3I
at 90 °C for 10 min. The crude
(82 µL, 1.31 mmol) and Cs2CO3
mixture was concentrated under
(339 mg, 1.04 mmol) in DMF
(2.5 mL) was stirred for 30 min
at rt. The reaction was diluted
reduced pressure and purified by flash chromatography on
silica gel, using DCM/MeOH (9:1 to 4:1) as the eluent,
providing a solid (41 mg, 10.7 mmol, quantitative).
1H NMR (500 MHz, DMSO-d6) d 1.68 (s, 3H, NHAc), 3.30
(d, 1H, J 3.2 Hz, Ar-CH2CH), 3.32 (d, 1H, J 3.4 Hz, Ar-
CH2CH), 3.80 (s, 6H,Ar-OCH3), 3.89 (s, 3H,Ar-CO2CH3),
4.35-4.42 (m, 1H,Ar-CH2CH), 6.71 (s, 1H,Ar-H), 7.22 (br
s, 1H, NHAc), 8.33 (s, 1H, CO2H); LRMS (ESI) m/z 362.0
(20), 360.1 ([M + H]+, 100); HRMS (TOF) m/z, observed:
382.0661; C15H18ClNO7Na [M]+ requires: 382.0669.
in DCM (15 mL) and extracted with saturated aqueous
NaHCO3 solution (20 mL) and brine (20 mL). The organic
phase was dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude solid was purified by
flash chromatography on silica gel with ethyl acetate/
hexane (2:1 to 1:1) as the eluent, providing a solid (141 mg,
0.51 mmol, 59% yield). 1H NMR (500 MHz, CDCl3) d 3.88
(s, 3H, Ar-CO2CH3), 3.95 (s, 6H, Ar-OCH3), 4.75 (s, 2H,
Ar-CH2-Cl), 6.53 (s, 1H, Ar-H); LRMS (ESI) m/z 281.0
(70), 279.0 ([M + H]+, 100); HRMS (TOF) m/z, observed:
301.0009; C11H12Cl2O4Na [M + Na]+ requires: 301.0010.
2-(Chloromethyl)-4,6-dimethoxybenzonitrile (31)
A s o l u t i o n c o n t a i n i n g
2-(chloromethyl)-4,6-dimethoxy-
benzaldehyde (107.6 mg, 0.5 mmol,
Diethyl 2-acetamido-2-(2-chloro-3,5-dimethoxy-6-(methoxy-
carbonyl)benzyl)malonate (29)
9) and NaN3 (33 mg, 0.5 mmol)
in POCl3 (233 µL, 2.5 mmol) was
A solution of methyl
3-chloro-6-(chloromethyl)-
2,4-dimethoxybenzoate
(115 mg, 0.47 mmol, 27),
stirred overnight at 50 °C in N2. The mixture was concentrated
under reduced pressure and the crude product was purified
by flash chromatography on silica gel, using ethyl acetate/
hexane (2:1) as the eluent, providing a red solid (65 mg,
1
diethyl acetamidomalonate
0.31 mmol, 62% yield). mp 112.4-114.0 °C; H NMR
(102 mg, 0.47 mmol, 28),
Cs2CO3 (368 mg, 1.13 mmol)
and KI (187 mg, 1.13 mmol) in acetonitrile (5 mL) was
(500 MHz, CDCl3) d 3.89 (s, 3H, Ar-OCH3), 3.92 (s, 3H,
Ar-OCH3), 4.68 (s, 2H, Ar-CH2), 6.43 (d, 1H, J 2.2 Hz,
Ar-H), 6.67 (d, 1H, J 2.2 Hz, Ar-H); 13C NMR (126 MHz,

Vol. 30, No. 3, 2019
Oliveira Filho et al.
539
CDCl3) d 43.4, 55.8, 56.2, 94.0, 98.2, 106.7, 110.0, 114.8,
143.7, 163.3, 164.3; LRMS (EI) m/z 213 (32), 211 (M+, 100),
176 (72), 146 (20); HRMS (TOF) m/z, observed: 234.0273;
C10H10ClNO2Na [M + Na]+ requires: 234.0297.
H), 7.91 (s, 1H, NHAc); 13C NMR (126 MHz, DMSO-d6)
d 22.4, 36.1, 39.0, 39.2, 39.3, 39.7, 39.8, 40.0, 55.6, 55.8,
56.3, 66.4, 95.1, 97.2, 108.2, 115.3, 142.7, 162.9, 163.3,
168.5 (2C), 169.3; LRMS (ESI) m/z 383.1 [M + 2H]+, 40),
337.1 [M – 2Na]+, 100), 117.1 (22).
Diethyl 2-acetamido-2-(2-cyano-3,5-dimethoxybenzyl)
malonate (32)
2-Acetamido-3-(2-cyano-3,5-dimethoxyphenyl)propanoic
acid (34)
A solution of methyl
2 - ( c h l o r o m e t h y l ) -
To a solution of nitrile 32
4,6-dimethoxybenzonitrile
(82 mg, 0.21 mmol) in ethanol
(384.5 mg, 1.8 mmol, 31),
(2 mL) 35% KOH solution (2 mL)
diethyl acetamidemalonate
was added and the mixture was
(475 mg, 2.19 mmol, 28),
stirred for 2.5 h at 80 °C. Then
Cs2CO3 (712 mg, 2.19 mmol) and KI (364 mg, 2.19 mmol)
in acetonitrile (7 mL) was stirred for overnight at rt.
The mixture was diluted with ethyl acetate (15 mL)
and quenched with water (10 mL) and Na2SO3. The
organic phase was separated, extracted with aqueous 2 M
hydrochloridric acid solution (7 mL) and brine (10 mL).
The organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The crude solid was
purified by flash chromatography on silica gel, using ethyl
acetate/hexane (1:1) as the eluent, giving a white solid
(548.5 mg, 1.4 mmol, 78% yield). mp 168.0-171.9 °C;
1H NMR (500 MHz, CDCl3) d 1.29 (t, 6H, J 7.1 Hz,
CO2CH2CH3), 2.05 (s, 3H, NHAc), 3.79 (s, 2H, Ar-CH2),
3.80 (s, 3H, Ar-OCH3), 3.87 (s, 3H, OCH3), 4.23-4.37
(m, 4H, CO2CH2CH3), 6.28 (d, 1H, J 2.2 Hz, Ar-H), 6.36
the reaction was diluted in water
(15 mL) and extracted with diethyl ether (2 × 20 mL). The
aqueous phase was acidified with 2 M HCl solution until
pH 2 and extracted with DCM (3 × 15 mL). The organic
phase was washed with water, dried with anhydrous Na2SO4
and concentrated under reduced pressure, providing a white
solid, the acid 34 (28 mg, 0.095 mmol, 45% yield); without
further purification. 1H NMR (500 MHz, DMSO-d6) d 1.77
(s, 3H, NHAc), 2.93 (dd, 1H, J 14.0, 9.9 Hz, Ar-CH2CH),
3.18 (dd, 1H, J 14.0, 5.1 Hz, Ar-CH2CH), 3.83 (s, 3H,
Ar-OCH3), 3.88 (s, 3H, Ar-OCH3), 4.51 (dt, 1H, J 4.9,
3.3 Hz, Ar-CH2CH) 6.60 (d, 1H, J 2.2 Hz, Ar-H), 6.61 (d,
1H, J 2.2 Hz,Ar-H), 8.27 (d, 1H, J 8.4 Hz, NHAc), 12.81 (br
s, 1H, CO2H); 13C NMR (126 MHz, DMSO-d6) d 22.3, 35.5,
51.9, 55.8, 56.3, 93.3, 96.9, 108.2, 115.6, 144.2, 162.9,
163.7, 169.2, 172.6; LRMS (ESI) m/z 293.1 (M+, 100);
HRMS (TOF) m/z, observed: 315.0944; C14H16N2O5Na
[M + Na]+ requires: 315.0956.
13
(d, 1H, J 2.2 Hz, Ar-H), 6.59 (s, 1H, NHAc); C NMR
(126 MHz, CDCl3) d 13.9 (2C), 23.1, 36.6, 55.6, 56.0,
63.0 (2C), 66.3, 76.8, 77.0, 77.3, 95.8, 97.0, 108.7, 115.5,
142.2, 163.3, 163.6, 167.3 (2C), 169.4; LRMS (ESI) m/z
393.1 (M+, 100); HRMS (TOF) m/z, observed: 415.1453;
C19H24N2O7Na [M + Na]+ requires: 415.1481.
1-Imino-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-
3-carboxylic acid (35)
A solution of nitrile 32
Sodium 2-acetamido-2-(2-cyano-3,5-dimethoxybenzyl)
malonate (33)
(82 mg, 0.2 mmol) in 2 M
HCl (1 mL) and dioxane
A mixture containing nitrile
(1.2 mL) was refluxed (at
32 (100 mg, 0.26 mmol) and
115 °C) for 48 h under N2
2 M NaOH solution (10 mL)
was placed in an ultrasonic bath
at 80 °C for 45 min, under N2
atmosphere. The reaction was
atmosphere. The solvent was removed under reduced
pressure and the residue was lyophilized, furnishing
72 mg of brown solid. The crude product was purified by
semi preparative HPLC using a C18 column, providing a
white solid 35 (6 mg, 0.024 mmol, 12% yield). 1H NMR
(500 MHz, DMSO-d6) d 3.20 (m, 1H, Ar-CH2CH), 3.29
(m 1H, Ar-CH2CH), 3.88 (s, 3H, Ar-OCH3), 3.95 (s, 3H,
Ar-OCH3), 4.48 (td, 1H, J 6.4, 3.6 Hz, Ar-CH2CH), 6.68
(d, 1H, J 2.3 Hz, Ar-H), 6.74 (d, 1H, J 2.3 Hz, Ar-H), 8.71
(s, 1H, C=NH), 8.81 (s, 1H, CO2H), 8.94 (d, 1H, J 3.3 Hz,
CHNH); 13C NMR (126 MHz, DMSO-d6) d 35.8, 44.2,
44.4, 44.5, 44.7, 44.9, 45.1, 45.2, 55.9, 61.3, 61.8, 103.1,
then treated with 2 M HCl solution at pH 2 and frozen
for 2 days. After thawing, the precipitate was filtered by
vacuum and water phase was removed in high vacuum
affording a white solid, the disodium salt 33 (43 mg,
1
0.14 mmol, 54% yield). mp 157.9-187.1 °C; H NMR
(500 MHz, DMSO-d6) d 1.92 (s, 3H, NHAc), 3.51 (s, 2H,
Ar-CH2), 3.82 (s, 3H, Ar-OCH3), 3.87 (s, 3H, Ar-OCH3),
6.38 (d, 1H, J 2.2 Hz, Ar-H), 6.62 (d, 1H, J 2.0 Hz, Ar-

540
Studies Toward the Synthesis of Caramboxin Analogues
J. Braz. Chem. Soc.
106.9, 112.1, 146.1, 163.3, 166.5, 170.5, 176.5; LRMS
(ESI) m/z 252.1 (15), 251.1 (M+, 100), 207.1 (16), 169.1
(55); HRMS (TOF) m/z, observed: 249.0867; C12H13N2O4
[M – H]- requires: 249.0875.
14. Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.; J.
Chem. Soc., Chem. Commun. 1995, 2551.
15. Spyropoulos, C.; Kokotos, C. G.; J. Org. Chem. 2014, 79, 4477.
16. Jubilut, G. N.; Cilli, E. M.; Tominaga, M.; Miranda,A.; Okada,
Y.; Nakaie, C. R.; Chem. Pharm. Bull. 2001, 49, 1089.
17. In, J.; Hwang, S.; Kim, C.; Seo, J. H.; Kim, S.; Eur. J. Org.
Chem. 2013, 965.
Supplementary Information
Supplementary data (1H and 13C NMR spectra) are
available free of charge at http://jbcs.sbq.org.br as PDF file.
18. Knölker, H.-J.; Braxmeier, T.; Synlett 1997, 925.
19. Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B.; Org.
Lett. 2003, 5, 1031.
Acknowledgments
20. Chakraborty, D.; Gowda, R. R.; Malik, P.; Tetrahedron Lett.
2009, 50, 6553.
We express our gratitude to FAPESP (grant
No. 2014/25659-8) for financial support. Oliveira Filho
thanks UFABC for the fellowship. We also would like to
thank Prof Dr Rodrigo Luiz Oliveira Rodrigues Cunha for
providing compound 28.
21. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.;
Tetrahedron Lett. 1986, 27, 4537.
22. Kurti, L.; Czako, B.; Strategic Applications of Named Reactions
st ed.; Elsevier: London, UK, 2005, p.
in Organic Synthesis, 1
355.
References
23. Montanari, F.; J. Org. Chem. 1986, 51, 569.
24. Couladouros, E. A.; Mihou, A. P.; Bouzas, E. A.; Org. Lett.
2004, 6, 977.
1. Chua, C.-B.; Sun, C.-K.; Tsui, H.-W.; Yang, P.-J.; Lee, K.-H.;
Hsu, C.-W.; Tsai, I-T.; Clin. Toxicol. 2017, 55, 624.
2. Oliveira, E. S. M.;Aguiar, A. S.; J. Bras. Nefrol. 2015, 37, 241.
3. Cairasco-Garcia, N.; Moyses-Neto, M.; Del Vecchio, F.;
Oliveira, J. A.; dos Santos, F. L.; Castro, O. W.; Arisi, G. M.;
Dantas, M.; Carolino, R. O.; Coutinho-Netto, J.; Dagostin, A.
L.; Rodrigues, M. C.; Leão, R. M.; Quintiliano, S. A.; Silva Jr.,
L. F.; Gobbo-Neto, L.; Lopes, N. P.; Angew. Chem., Int. Ed.
2013, 52, 13067.
25. Kaiser, C. R.; Quim. Nova 2000, 23, 231.
26. Valdomir, G.; Padrón, J. I.; Padrón, J. M.; Martín, V. S.; Davyt,
D.; Synthesis 2014, 46, 2451.
27. Escudero, M. I.; Kremenchuzky, L. D.; Perillo, I.A.; Cerecetto,
H.; Blanco, M. M.; Synthesis 2011, 4, 571.
28. Humphrey, C. E.; Furegati, M.; Laumen, K.; Vecchia, L. L.;
Leutert, T.; Müller-Hartwieg, J. C. D.;Vögtle, M.; Org. Process
Res. Dev. 2007, 11, 1069.
4. Quintiliano, S. A. P.; Silva Jr., L. F.; Tetrahedron Lett. 2012,
53, 3808.
29. Sribalan, R.; Sangili, A.; Banuppriya, G.; Padmini, V.; New J.
Chem. 2017, 41, 3414.
5. Pichierri, F.; J. Mol. Struct. 2015, 1079, 274.
6. Quintiliano, S. A. P.; Reação de Álcoois Homoalílicos com
Tálio(III), Iodo e Iodo Hipervalente, Dicloração de Cetonas e
Estudos Visando à Síntese Total da Caramboxina; PhD Thesis,
Universidade de São Paulo: São Paulo, Brazil, 2010. DOI:
10.11606/T.46.2010.tde-27042010-082909.
30. Lignier, P.; Estager, J.; Kardos, N.; Gravouil, L.; Gazza, J.;
Naffrechoux, E.; Draye, M.; Ultrason. Sonochem. 2011, 18, 28.
31. Loreau, O.; Georgin, D.; Taran, F.; Audisio, D.; J. Labelled
Compd. Radiopharm. 2015, 58, 425.
32. Beaton, H.; Hamley, P.; Tinker, A. C.; Tetrahedron Lett. 1998,
39, 1227.
7. Ledford, N. D.; Gibbs, P. C.; Wood Jr., H. B.; Barfield, M.; Org.
Prep. Proced. Int. 1986, 18, 263.
33. Pincock, J. A.; Wedge, P. J.; J. Org. Chem. 1994, 59, 5587.
34. Snyder, S. A.; Zografos, A. L.; Lin, Y.; Angew. Chem., Int. Ed.
2007, 46, 8186.
8. In, J.; Hwang, S.; Kim, C.; Seo, J. H.; Kim, S.; Eur. J. Org.
Chem. 2013, 965.
35. Kim, B.-T.; Kim, H.-S.; Moon, W. S.; Hwang, K.; Tetrahedron
2009, 65, 4625.
9. Judd, K. E.; Mahon, M. F.; Caggiano, L.; Synthesis 2009, 16,
2809.
36. Proisy, N.; Sharp, S. Y.; Boxall, K.; Connelly, S.; Roe, S. M.;
Prodromou, C.; Slawin, A. M.; Pearl, L. H.; Workman, P.;
Moody, C. J.; Chem. Biol. 2006, 13, 1203.
10. Lebel, H.; Leogane, O.; Org. Lett. 2005, 7, 4107; Leogane, O.;
Lebel, H.; Synthesis 2009, 11, 1935.
11. Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky,
S. J.; J. Am. Chem. Soc. 2001, 123, 10903.
Submitted: June 13, 2018
12. Nawrat, C. C.; Palmer, L. I.; Blake, A. J.; Moody, C. J.; J. Org.
Chem. 2013, 78, 5587.
Published online: October 9, 2018
13. Young, D. D.; Torres-Kolbus, J.; Deiters, A.; Bioorg. Med.
Chem. Lett. 2008, 18, 5478.
This is an open-access article distributed under the terms of the Creative Commons Attribution License.