A simple route for the synthesis of novel norcantharimide derivatives via acidolysis with hydrochloric acid(gas)

Article abstract of DOI:10.1002/jhet.4248

In this work, seven new norcantharimide derivatives were synthesized by an acidolysis method. The compounds were prepared by acidolyzing trans-1,4-diacetate and trans-1,2-chloroacetate structures, which were obtained by stereospecific cleavage of the internal etheric bond of the tricyclic imides. The HCl_(gas) was produced from the reaction of H₂SO₄ with NaCl. The resulting gas was bubbled into the reaction mixture. Trans-1,4-diacetate and trans-1,2-chloroacetate were thus acidolyzed, and the corresponding diol and halohydrin products were obtained respectively in moderate overall yields from low-cost starting materials, using simple and easily scalable chemistry. The products were characterized by means of spectroscopic techniques. The synthesized compounds have high potential as anticancer agents and can be valuable for studies in this area.

Full text of DOI:10.1002/jhet.4248

Received: 1 January 2021
DOI: 10.1002/jhet.4248
Revised: 2 February 2021
Accepted: 15 February 2021
A R T I C L E
A simple route for the synthesis of novel norcantharimide
derivatives via acidolysis with hydrochloric acid(gas)
Aytekin Köse
Department of Chemistry, Faculty of
Abstract
Science and Letters, Aksaray University,
Aksaray, Turkey
In this work, seven new norcantharimide derivatives were synthesized by an
acidolysis method. The compounds were prepared by acidolyzing trans-
1,4-diacetate and trans-1,2-chloroacetate structures, which were obtained by
stereospecific cleavage of the internal etheric bond of the tricyclic imides. The
HCl(gas) was produced from the reaction of H2SO4 with NaCl. The resulting
gas was bubbled into the reaction mixture. Trans-1,4-diacetate and trans-
1,2-chloroacetate were thus acidolyzed, and the corresponding diol and
halohydrin products were obtained respectively in moderate overall yields
from low-cost starting materials, using simple and easily scalable chemistry.
The products were characterized by means of spectroscopic techniques. The
synthesized compounds have high potential as anticancer agents and can be
valuable for studies in this area.
Correspondence
Aytekin Köse, Department of Chemistry,
Faculty of Sciences and Letters, Aksaray
University, Bahçesaray district, 170 street,
No:16, 68100, Aksaray, Turkey.
Email: aytekinkose@aksaray.edu.tr and
aytekinkose@atauni.edu.tr
1 | INTRODUCTION
production of white blood cells through an inflammatory
mechanism [8].
Blister beetles of the Meloidae family have been known
for their potentially toxic defense mechanism since
ancient times. Today, called cantharidin exo, exo-
2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic
acid anhydride, found in these beetles has been used for
therapeutic purposes in traditional Chinese medicine and
is listed as a drug under the name of Mylabris in the clas-
sical medical monograph Materia Medica published in
77 AD [1]. These beetles are also known as Spanish fly
but this name is not widely used today [2]. Cantharidin
stimulates blisters on skin surface on contact and, if
swallowed, causes various physiological symptoms
including gastrointestinal pain, depending on the dose.
Generally, an ingested dose between 10 and 65 mg
induces kidney failure and destruction of the liver,
resulting in death within 12–24 h. Because of this charac-
ter, traditional Chinese medicine has used this compound
as an anticancer agent for more than 2000 years. It has
also been known as an anticancer agent in the treatment
of hepatomas and pharyngeal cancer since 1264 [1,3–7].
Unlike other anticancer drugs, cantharidin stimulates the
Structural derivatives of cantharidin are norcantharidin
and norcantharimide. These two derivatives and other struc-
tures derived from them are known as potential anticancer
agents [1,8]. Cantharidin (1), norcantharidin (2), and
norcantharimide (3) have tricyclic skeletons with an inter-
nal ether bond (Figure 1). The biomedical scientific interest
into these compounds has seen rapid increase in recent
years and numerous new derivatives relating to them have
already been synthesized and are under investigation. In
particular, despite their toxicity, these derivatives have
attracted broad interest due to their potent protein phospha-
tase inhibitory and cytotoxic activities against numerous
cancer cell lines [9–12].
In recent years, many studies have been directed toward
the synthesis of cantharidin and norcantharimide deriva-
tives. In one of these studies, absorption, distribution,
metabolism, and elimination (ADME) properties of
norcantharimides have been investigated. According to this
study, it has been reported that these molecules can be con-
sidered as orally active drug candidates due to their physico-
chemical properties [13]. Another study has recommended
J Heterocyclic Chem. 2021;58:1171–1178.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
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FIGURE 1 Structure of cantharidin (1), norcantharidin (2),
norcantharimide (3), and their derivatives 4, 5
the use of norcantharidin in the treatment of viral infections
caused by Molluscum contagiosum (MC) [14]. It has also
been reported that some synthetic norcantharimide deriva-
tives show cytotoxic effects depending mainly on the length
of their side chains [15]. Moreover, the electronic effects of
functional groups on some synthetic norcantharimide deriv-
atives have also been examined, which revealed that, in
some cases, these effects were closely related to anticancer
activity [16]. Antioxidant potential and cytotoxicity of cer-
tain norcantharimides have also been evaluated against HT-
29 colon cancer cells in in vitro conditions. It has been
found that these molecules inhibit the growth of the HT-29
cells and also have free radical-scavenging activity [17].
In this study, the author describes a synthetic
SCHEME 1 trans-1,4-diacetate (10a–f) and trans-
1,2-chloroacetate (11a–f) derivatives and their synthetic routes
produced from furan and maleic anhydride (MA). (i) Heating at
110ꢀC, toluene, 18 h; (ii) RNH2, heating at 65ꢀ, MeOH, overnight;
(iii) Ac2O/cat. H2SO4, rt, overnight; (iv) AcCl/cat. H2SO4, CH2Cl2,
rt, 1.5–4 days; (v) AcCl, CH2Cl2, 0ꢀC to rt, 6 h
products were acidolyzed using HCl(gas), leading to the
new derivatives of norcantharimide (12a–c and 13a–d).
Based on the results of anticancer activity studies, it can
be said that norcantharimide derivatives having the
isoindole-1,3-dione skeleton are among the promising
molecules for anticancer activity research and potential
clinical utilization. The groups attached to the nitrogen
and the functional groups on the cyclohexane ring both
have important roles for antitumor activity. New deriva-
tives can be gained by making small changes at the cyclo-
hexane ring. The positive results of in vitro activity
studies have been the inspiration for the synthesis of new
norcantharimide derivatives in this study. In the light of
these data, the author decided to perform the modifica-
tions on the chlorine- and acetate-substituted
norcantharimide derivatives (Scheme 2).
approach to the synthesis of
a series of novel
norcantharimide analogues starting from furan and mal-
eic anhydride. The structures of the newly synthesized
compounds were characterized using spectroscopic tech-
niques. The presented synthetic route features the advan-
tages of using low-cost starting materials, fairly short
reaction times, and basic organic steps.
2 | RESULTS AND DISCUSSION
2.1 | Methodology
In this work, seven novel norcantharimide derivatives
were obtained by an acidolytic method. The acidolysis
was performed by subjecting trans-1,4-diacetate and
trans-1,2-chloroacetate derivatives of norcantharimide to
HCl(gas). For this, the synthesis of the key compounds
(10a, 10d, 10f, and 11a-d) was carried out with three
steps using furan and maleic anhydride (MA) based on a
previously described method [18] (Scheme 1). These
2.2 | Synthesis process
In the first stage of this study, 8 was prepared by exo-
selective cycloaddition reaction of furan and MA in

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SCHEME 2 trans-1,4-diols and
trans-1,2-halohydrins, which were
synthesized by the acidolysis of trans-
1,4-diacetate, and trans-1,2-chloroacetate
structures formed by ether cleavage
reaction of the tricyclic internal ethers.
(i) Ac2O/cat. H2SO4, rt, overnight;
(ii) AcCl/cat. H2SO4, CH2Cl2, rt,
1.5–4 days. (iii) HCl(gas) bubbling in
MeOH, 0ꢀC, 30 min.; then rt, 2 h
toluene. Furan was used in excess because of its low boiling
point. Then, simple primary amines were used to synthesize
9a−d and 9f according to the reported procedure [18]. The
tricyclic 9a−d and 9f were the lead intermediates to the syn-
theses of trans-1,4-diacetates and trans-1,2-chloroacetates as
they carried the internal ether bridges, which were cleaved
stereospecifically according to the procedure described in
the literature. At this step, Ac2O was used to synthesize the
trans-1,4-diacetate derivatives (10a, 10d, and 10f; from 9a,
9d, and 9f, respectively) and AcCl to synthesize the trans-
1,2-chloroacetate derivatives (11a–d, from 9a–d) in the pres-
ence of a catalytic amount of H2SO4 in both cases. Both
reaction products were formed stereospecifically. The
acidolysis procedure has been successfully applied to synthe-
ses of different compounds in the literature [19,20]. Based
on this known method, a new series of isoindole-1,3-dione
derivatives were synthesized. The synthetic methodologies
and all spectroscopic data for 10a, 10d, 10f, and 11a–d have
been reported earlier [18,21]. After the synthesis of trans-
1,4-diacetate and trans-1,2-chloroacetate products made by
known methods, they were acidolyzed by gaseous HCl,
leading to the elimination of the acetates from 10a, 10d, 10f,
and 11a–d and to the formation of 12a–c (trans-1,4-diols),
and 13a–d (trans-1,2-halohydrins). The novel compounds
were characterized through 1H NMR spectroscopy.
FIGURE 2 Acidolysis reaction method with H2SO4 and NaCl
and experimental setup [Colour figure can be viewed at
wileyonlinelibrary.com]
was concentrated in vacuo, and the products were crys-
tallized with EtOAc-Hexane.
2.4 | Stereochemistry and structure
10a, 10d, 10f, and 11a–d were acidolyzed by HCl
and converted to trans-1,4-diols (12a–c) and trans-
1,2-halohydrins (13a–d) in quantitative yields. It was
observed that HCl had not reacted with the imide ring
despite extension of the reaction time in some trials and this
demonstrated that the imide ring was fairly stable. Further-
more, the acidolysis products (12a–c and 13a–d) formed as
the sole isomers of the ether cleavage step. According to the
results obtained from the spectra and presented data, a
number of isoindole-1,3-dione derivatives could be synthe-
sized by making minor modifications in the
norcantharimide skeleton with high yields and short syn-
theses. In this paper, a useful method was developed for the
synthesis of a new series of isoindole-1,3-dione derivatives.
2.3 | Acidolysis reaction
The described method in the literature for the production
of HCl(gas) was used for acidolysis [22]. Briefly, concen-
trated sulfuric acid in a separatory funnel was added onto
NaCl dropwise for the production of HCl. The released
HCl(gas) was transferred directly to the stirring solution of
the reaction in methanol through a line and acidolysis
started. The reaction was stirred at 0ꢀC for 30 min as
shown in Figure 2. Then, it was allowed to reach to rt,
stoppered, and stirred for 2 h. At the end of the time, it

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3 | CONCLUSION
crystals were collected. Exo-Cycloadduct 8 was gained
as white powder (Quantitative yield, 33.80 g,
203.9 mmol).
In summary, a synthetic approach has been developed
for the synthesis of trans-1,4-diols (12a–c) and trans-
1,2-halohydrins (13a–d) starting from readily available
furan and MA. For this purpose, 4 + 2 exo-cycloadduct
was converted to the imide skeleton by using primary
amines. The internal etheric bond of the tricyclic
imides was cleaved stereospecifically with Ac2O or AcCl
in the presence of a catalytic amount of H2SO4. Then,
the trans-1,4-diacetates and trans-1,2-chloroacetates were
acidolyzed with HCl(gas). Further studies on other syn-
thetic analogues of isoindole-1,3-dione are currently in
progress and will be reported in due course.
(3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-4,7-
epoxyisobenzofuran-1,3-dione (8)
1H NMR (400 MHz, CDCl3): δ 6.57 (s, 2H, H5 and H6),
5.45 (s, 2H, H4 and H7), 3.18 (s, 2H, H3a and H7a). 13C
NMR (100 MHz, CDCl3): δ 170.1 (C1 and C3), 137.2
(C5 and C6), 82.4 (C4 and C7), 48.9 (C3a and C7a).
4 | EXPERIMENTAL SECTION
4.1 | General
4.1.2 | General procedure for the
synthesis of tricyclic imides (9a–d and 9f)
All reagents were commercially available and were used as
received (Aldrich). All solvents were distilled before use.
Melting points were measured with Buchi melting point B-
450 devices. Reactions were monitored by TLC, on alumi-
num plates coated with silica gel (Merck 60 F254) using
254 nm UV light, ethanolic phosphomolybdic acid. All puri-
fications were performed by silica gel (high-purity grade,
average pore size 60 Å [52–73 Å], 70–230 mesh ASTM,
63–200 μm, for column chromatography). NMR spectra
were recorded in CHCl3-d1 and MeOH-d4 at 400 MHz
Bruker for 1H and 100 MHz Bruker for 13C NMR. All chem-
ical shifts were reported in ppm downfield from TMS using
the residual protonated solvent as an internal standard
The exo-cycloadduct 8 was dissolved in MeOH, and then
specific primary amine (methyl amine, ethyl amine, ani-
line, benzyl amine, and 2-aminoethanol) was added. The
resulting solution was heated to reflux for 24 h. At the
end of this time, it was cooled to rt. and crystals were
formed in the flask. The crude was filtered off with a
Gooch funnel and the solid was collected. The filtrate
was concentrated under reduced pressure and allowed to
recrystallize, and second crop crystals were collected.
1
(CHCl3-d1, H 7.26 ppm, and 13C 77.2 ppm; CH3OH-d4 1H
5.15, 3.34 ppm; 13C 48.04 ppm). Coupling constants were
expressed in Hertz (Hz). Elemental analysis results were
obtained with LECO CHNS-932 instrument. Mass spectra
were performed with LC–MS/MS Thermo Finnigan instru-
ment (ESI, 70 eV).
(3aR,4S,7R,7aS)-2-Methyl-3a,4,7,7a-tetrahydro-1H-
4,7-epoxyisoindole-1,3(2H)-dione (9a)
Yield: 80% (3.04 g, 16.97 mmol). White solid. Mp:
1
139–141ꢀC. H NMR (400 MHz, CDCl3): δ 6.49–6.48
(m, 2H, H5 and H6), 5.24–5.23 (m, 2H, H4 and H7),
2.94 (s, 3H, CH3), 2.83 (s, 2H, H3a and H7a). 13C NMR
(100 MHz, CDCl3): δ 176.5 (C1 and C3), 136.7 (C5 and
C6), 81.0 (C4 and C7), 47.7 (C3a and C7a), 25.1
(N CH3). Elemental analysis: Anal. calcd. for
C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.68; H, 4.91; N, 7.66.
4.1.1 | Diels-Alder cycloaddition reaction
of furan and MA
The reported method in the literature [18] was applied
for this reaction to synthesize (3aR,4S,7R,7aS)-3a,4,7,7a-
tetrahydro-4,7-epoxyisobenzofuran-1,3-dione
(8)
in
quant. Yield. MA (7) (20 g, 203.96 mmol) and Furan (6)
(20.83 g, 305.94 mmol) were dissolved in 200 ml of tolu-
ene. The resulting mixture was heated to reflux for 24 h.
White precipitate was formed and it was let to rt. The
solid was filtered with a Gooch funnel and washed with
ether. After recrystallization from Hexane-EtOAc,

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(3aR,4S,7R,7aS)-2-Ethyl-3a,4,7,7a-tetrahydro-1H-
4,7-epoxyisoindole-1,3(2H)-dione (9b)
2-((3aR,4S,7R,7aS)-1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-
2H-4,7-epoxyisoindole-2-yl)ethyl acetate (9f)
Yield: 95% (1.1 g, 5.69 mmol) White solid,
Mp:119–121ꢀC. 1H NMR (400 MHz, CDCl3): δ 6.49 (s,
2H, H5 and H6), 5.23 (s, 2H, H4 and H7), 3.50 (q, 2H,
N CH2, J = 7.2 Hz), 2.81 (s, 2H, H3a and H7a), 1.13
(t, 3H, CH3, J = 7.2 Hz). 13C NMR (100 MHz,
CDCl3): δ 176.3 (C1 and C3), 136.8 (C5 and C6), 81.1
(C4 and C7), 47.6 (C3a and C7a), 34.1 (N CH2), 13.1
( CH3). Elemental analysis: Anal. calcd. for
C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
61.63; H, 5.87; N, 7.45.
The reaction of 2-aminoethanol (0.81 g, 13.24 mmol) with
8 (2 g, 12.04 mmol) gave (3aR,4S,7R,7aS)-2-(2-hydroxy-
ethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)
-dione (9e) [23] in 60% yield according to the general pro-
cedure. White solid (1.52 g, 7.27 mmol). Mp: 138–139ꢀC.
1H NMR (400 MHz, MeOH-d4): δ 6.55 (s, 2H, H5 and
H6), 5.16 (s, 2H, H4 and H7), 3.63 (dm, 2H, A of AB sys-
tem, CH2 OR, J = 5.2 Hz), 3.57 (dm, 2H, B of AB sys-
tem, N CH2 , J = 5.2 Hz), 2.95 (s, 2H, H3a and H7a).
13C NMR (100 MHz, MeOH-d4): δ 177.6 (C1 and C3),
136.5 (C5 and C6), 81.0 (C4 and C7), 58.2 ( CH2 OH),
47.6 (C3a and C7a), 40.9 (N CH2 ). The reported acety-
lation procedure [18] was applied to the synthesis of 9f.
9e (1.52 g, 7.27 mmol) was dissolved in 20 ml of CH2Cl2
and AcCl (1.72 g, 21.91 mmol) was added at 0ꢀC. The
solution was stirred at rt. for 6 h. Removal of the solvent
and the unreacted AcCl gave the 9f under reduced pres-
sure as the sole product in 59% overall yield for the two
(3aR,4S,7R,7aS)-2-Phenyl-3a,4,7,7a-tetrahydro-1H-
4,7-epoxyisoindole-1,3(2H)-dione (9c)
1
steps. White solid (1.8 g, 7.16 mmol). Mp: 92–94ꢀC. H
Yield: 55% (0.7 g, 2.90 mmol) pale yellow solid,
NMR (400 MHz, CDCl3): δ 6.47 (s, 2H, H5 and H6),
5.21–5.20 (m, 2H, H4 and H7), 4.16 (t, 2H, CH2 OAc,
J = 5.4 Hz), 3.69 (t, 2H, N CH2 , J = 5.4 Hz), 2.83 (s,
2H, H3a and H7a), 1.95 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 176.2 (C1 and C3), 171.0 (C O of
acetate), 136.7 (C5 and C6), 81.1 (C4 and C7), 60.7
( CH2 OAc), 47.6 (C3a and C7a), 38.0 (N CH2 ), 20.9
( CH3). Elemental analysis: Anal. calcd. for
C12H13NO5: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.29; H,
5.13; N, 5.41.
1
Mp:134–136ꢀC. H NMR (400 MHz, CDCl3): δ 7.45–7.28
(m, 5H, Ph), 6.54 (s, 2H, H5 and H6), 5.37 (s, 2H, H4 and
H7), 2.98 (s, 2H, H3a and H7a). 13C NMR (100 MHz,
CDCl3): δ 175.6 (C1 and C3), 136.9 (C5 and C6), 131.9
(ipso), 129.4 (2xortho), 129.0 (para), 126.8 (2xmeta), 81.6
(C4 and C7), 47.8 (C3a and C7a). Elemental analysis:
Anal. calcd. for C14H11NO3: C, 69.70; H, 4.60; N, 5.81.
Found: C, 69.77; H, 4.72; N, 5.77.
4.1.3 | 4.1.3 General procedure for the
synthesis of 10a 10d 10f, and 11a–d
The detailed experimental procedures for the ether cleav-
age reactions of 9a–d and 9f to obtain 10a, 10d, 10f, and
11a–d have been described earlier [21].
(3aR,4S,7R,7aS)-2-Benzyl-3a,4,7,7a-tetrahydro-1H-
4,7-epoxyisoindole-1,3(2H)-dione (9d)
Yield: 63% (3.9 g, 15.28 mmol). White powder. Mp:
1
131–133ꢀC. H NMR (400 MHz, CDCl3): δ 7.29–7.23 (m,
5H Ph), 6.47 (s, 2H, H5 and H6), 5.25 (s, 2H, H4 and H7),
4.62 (s, 2H, N CH2), 2.82 (s, 2H, H3a and H7a). 13C NMR
(100 MHz, CDCl3): δ 176.2 (C1 and C3), 136.8 (C5 and
C6), 135.7 (ipso), 128.9 (2xortho), 128.3 (2xmeta), 128.0
(para), 81.1 (C4 and C7), 47.7 (C3a and C7a), 42.6
(N CH2 ). Elemental analysis: Anal. calcd. for
C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.60; H,
5.27; N, 5.86.
4.1.4 | General procedure of acidolysis
with HCl(gas) for the synthesis of 12a–c and
13a–d
Freshly prepared HCl gas through the reaction of conc.
H2SO4 and solid NaCl were sent through a solution of the
starting material in 15 ml of MeOH for 30 min. at 0ꢀC
using the setup in Figure 2. Then, the solution was allowed
to warm up to rt. and stirred for 2 h in a tightly stoppered
round-bottomed flask. The solvent was removed under
reduced pressure and the residue was purified on silica gel
in the case of the diols or crystallized.

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(3aS,4S,5S,7aS)-4,7-Dihydroxy-2-(2-hydroxyethyl)-
3a,4,5,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (12c)
Yield: Quant. (146 mg, 0.64 mmol). Yellow viscous oil.
1H NMR (400 MHz, MeOH-d4): δ 6.15 (dd, 1H, A part of
AB system, H6, J = 9.8, 3.6 Hz), 5.99 (ddd, 1H, H5, B part
of AB system, J = 9.8, 4.8, 2.4 Hz), 4.16 (quasi t, 1H, H7,
J = 3.6 Hz), 3.99 (quasi t, 1H, H4, J = 4.4 Hz), 3.65–3.59
(m, 4H, 2xCH2) 3.53–3.49 (m, 1H, H7a), 3.33 (dd, 1H,
H3a, J = 8.0, 4.0 Hz). 13C NMR (100 MHz, MeOH-d4,
ppm): δ 179.2 (C1), 177.9 (C3), 127.8 (C6), 124.3 (C5),
67.9 (C7), 65.4 ( CH2 OH), 58.4 (C4), 41.4 (C7a), 40.8
(C3a), 39.5 (-CH2-N). IR (cm−1): 3378, 2890, 1771, 1685,
1431, 1396, 1332, 1257, 1166, 1023. LC–MS/MS (ESI);
C10H13NO5, (M + H) + 228.0.
(3aR,4R,7R,7aS)-4,7-Dihydroxy-2-methyl-3a,4,7,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (12a)
Yield: Quant. (140 mg, 0.71 mmol). Orange viscous
1
oil. Rf = 0.06 (Hex:EtOAc, 1:1). H NMR (400 MHz,
MeOH-d4): δ 6.14 (dd, 1H, A of AB system, H6,
J = 10.0, 3.6 Hz), 5.98 (ddd, 1H, B of AB system, H5,
J = 10.0, 5.6, 2.8 Hz), 4.16 (quasi t, 1H, H7,
J = 3.6 Hz), 4.01–3.98 (m, 1H, H4), 3.51–3.47 (m,
1H, H7a), 3.31 (dd, 1H, H3a, J = 8.4, 4.0 Hz), 2.92
(s, 3H, N CH3). 13C NMR (100 MHz, MeOH-d4): δ
179.2 (C1), 178.0 (C3), 127.7 (C6), 124.3 (C5), 67.9
(C7), 65.5 (C4), 41.4 (C7a), 39.6 (C3a), 23.9 (N-
CH3). IR (cm−1): 3451, 2951, 1768, 1759, 1683, 1431,
1381, 1291, 1249, 1186, 1007. LC–MS/MS (ESI);
(3aS,4S,5S,7aS)-5-Chloro-4-hydroxy-2-methyl-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (13a)
+
C9H11NO4, (M + H) 198.0.
Yield: Quant. (167 mg, 0.78 mmol). White solid. Mp:
98–100ꢀC. Rf = 0.50 (Hex:EtOAc, 1:1). 1H NMR
(400 MHz, CDCl3, ppm): δ 6.22 (dd, 1H, H6, A part of
AB system, J = 10.0, 3.6 Hz), 6.04 (ddd, 1H, H7, B part
of AB system, J = 10.0, 5.2, 2.8 Hz), 4.45 (quasi t, 1H,
H4, J = 4.7 Hz), 4.37 (quasi t, 1H, H5, J = 4.7 Hz), 3.53
(dd, 1H, H3a, A part of AB system, J = 8.8, 4.8 Hz),
3.49 (m, 1H, H7a, B part of AB system), 2.98 (s, 3H, N-
CH3), 2.73 (bs, 1H, OH). 13C NMR (100 MHz, CDCl3,
ppm): δ 177.7 (C3), 175.9 (C1), 126.8 (C6), 125.3 (C7),
68.7 (C4), 52.7 (C5), 41.1 (C3a), 39.9 (C7a), 25.1
(N CH3). IR (cm−1): 3463, 3370, 2927, 1771, 1683,
1442, 1402, 1336, 1157, 1036. Elemental analysis:
Anal. calcd. for C9H10ClNO3: C, 50.13; H, 4.67; N, 6.50.
Found: C, 50.06; H, 4.66; N, 6.49.
(3aR,4R,7R,7aS)-4,7-Dihydroxy-2-benzyl-3a,4,7,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (12b)
Yield: Quant. (153 mg, 0.56 mmol). Pale brown solid.
Mp: 109–111ꢀC. Rf = 0.1 (Hex:EtOAc 1:1). 1H NMR
(400 MHz, MeOH-d4): δ 7.33–7.17 (m, 5H, Ph), 6.12 (dd,
1H, A of AB system, H6, J = 9.8, 3.6 Hz), 5.97 (ddd, 1H, B
of AB system, H5, J = 9.8, 5.2, 2.4 Hz), 4.60 (d, 2H,
N CH2 , J = 8.0 Hz), 4.19, (quasi t, 1H, H7, J = 4.0 Hz),
4.00 (quasi t, 1H, H4, J = 4.8 Hz), 3.49–3.45 (m, 1H, H7a),
3.38–3.30 (m, 1H, H3a). 13C NMR (100 MHz, MeOH-d4):
δ 178.8 (C1), 177.5 (C3), 136.1 (ipso), 128.4 (2xortho),
128.0 (para), 127.7 (2xmeta), 127.4 (C6), 124.2 (C5), 68.0
(C7), 65.6 (C4), 42.0 (N-CH2-), 41.5 (C7a), 39.9 (C3a). IR
(cm−1): 3423, 3035, 2920, 1773, 1633, 1495, 1431, 1393,
1339, 1165, 1026. LC–MS/MS (ESI); C15H15NO4, (M
+ H) + 274.0.
(3aS,4S,5S,7aS)-5-Chloro-2-ethyl-4-hydroxy-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (13b)
Yield: Quant. (170 mg, 0.74 mmol). White crystalline
1
solid. Mp: 133–135ꢀC. Rf = 0.56 (Hex:EtOAc, 1:1). H
NMR (400 MHz, CDCl3, ppm): δ 6.24 (dd, 1H, H6, A
part of AB system, J = 10.0, 3.6 Hz), 6.06 (ddd, 1H,
H7, B part of AB system, J = 10.0, 5.6, 2.8 Hz), 4.48
(quasi t, 1H, H4, J = 4.3 Hz), 4.39 (quasi t, 1H, H5,

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J = 4.3 Hz), 3.55 (q, 2H, N CH2 , J = 7.2 Hz),
3.52–3.45 (m, 2H, H3a and H7a), 1.14 (t, 3H, CH3,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 177.5
(C3), 175.8 (C1), 126.4 (C6), 125.2 (C7), 68.3 (C4), 52.4
(C5), 40.7 (C3a), 39.5 (C7a), 34.0 (N CH2), 12.8
( CH3). IR (cm−1): 3294, 2977, 2937, 2881, 1771,
1678, 1443, 1408, 1349, 1221, 1042. LC–MS/MS
(ESI); C11H13ClO3, (M + H)+ 230.0.
128.6 (2xortho), 128.4 (2xmeta), 127.9 (para), 126.7 (C6),
125.1 (C7), 68.6 (C4), 52.5 (C5), 42.6 (C3a), 40.9
(N CH2 ), 39.8 (C7a). IR (cm−1): 3369, 2989, 2928,
1683, 1443, 1403, 1336, 1205, 1161, 1035. LC–MS/MS
(ESI); C16H15ClO3, (M + H) + 292.0.
ACKNOWLEDGMENTS
This study was carried out with the laboratory facilities
provided by Aksaray University Scientific and Techno-
logical Application and Research Center and NMR
spectroscopy supported by Atatürk University, Turkey.
The author would like to thank Prof. Dr. Yunus KARA
for helpful discussions and also thank to Dr. Mikail
_
_
Hakan GEZGINCI for his support in critical reading of
this article.
(3aS,4S,5S,7aS)-5-Chloro-4-hydroxy-2-phenyl-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (13c)
AUTHOR CONTRIBUTION
Aytekin Köse - Concept, performed reactions, explana-
tion of spectroscopic analyses, preparation of the spectra,
and writing of the manuscript.
Yield: Quant. (173 mg, 0.63 mmol). Brown solid.
Mp: 153–155ꢀC. Rf = 0.06 (Hex:EtOAc, 1:1). 1H
NMR (400 MHz, CDCl3):
δ 7.50–7.38 (m, 3H,
2xortho and para), 7.24 (d, 2H, 2xmeta, J = 7.2 Hz),
6.02 (dt, 1H, H6, A of AB system, J = 10.0, 2.0 Hz),
5.96 (ddd, 1H, H7, B of AB system, J = 10.0, 4.0,
1.6 Hz), 4.24–4.21 (m, 1H, H4), 3.97 (dd, 1H, H5,
J = 5.6, 2.0 Hz), 3.78–3.74 (m, A part of AB system, 1H,
H3a), 3.58 (dm, 1H, B part of AB system, H7a, J = 8.4,
5.6 Hz). 13C NMR (100 MHz, CDCl3): δ 178.0 (C3),
174.7 (C1), 131.7 (ipso), 131.2 (para), 129.3 (C6), 129.0
(2xmeta), 126.3 (C7), 122.7 (2xortho), 71.4 (C4), 68.3
(C5), 43.2 (C3a), 41.1 (C7a). IR (cm−1): 3535, 2963,
1766, 1694, 1496, 1391, 1255, 1186, 1156, 1050. LC–
MS/MS (ESI); C15H13ClO3, (M + H) + 277.0.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available on request from the corresponding author.
The data are not publicly available due to privacy or
ethical restrictions.
ORCID
Aytekin Köse https://orcid.org/0000-0003-2448-3716
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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How to cite this article: Köse A. A simple route
for the synthesis of novel norcantharimide
derivatives via acidolysis with hydrochloric
acid(gas). J Heterocyclic Chem. 2021;58:1171–1178.
https://doi.org/10.1002/jhet.4248