Intramolecular Diels-Alder and [3+2] Cycloaddition Reactions in the One-Pot Synthesis of Epoxypyrrolo[3,4-g]indazoles

Article abstract of DOI:10.1055/s-0037-1612426

A one-pot approach for the synthesis of epoxypyrrolo[3,4- g ]indazoles is presented. The first step was initiated by a three-component reaction of an isocyanide, a dialkyl acetylenedicarboxylate, and 2-furancarboxylic acid, and led to 1,3-dioxoepoxyisoindole, followed by the addition of hydrazonoyl chloride through a [3+2]-cycloaddition reaction in the second step. The key step in the formation of final compound involves a bicyclization strategy through intramolecular Diels-Alder (IMDA) reaction.

Full text of DOI:10.1055/s-0037-1612426

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
A. Alizadeh et al.
Paper
Synthesis
Intramolecular Diels–Alder and [3+2] Cycloaddition Reactions in
the One-Pot Synthesis of Epoxypyrrolo[3,4-g]indazoles
Abdolali Alizadeh*a
Kaveh Amir Ashjaee Asalemia
Mohammadreza Halvagarb
O
R1O2C
R1O2C
R2
N
O
O
Cl
R2 NC
COOR1
MeCN
O
H
N
N
O
R1O2C
R1O2C
R2
Ph
N
Ar
a Department of Chemistry, Tarbiat Modares University,
P. O. Box 14115-175, Tehran, Iran
N
Ar
N
Ph
N
+
O
reflux
COOR1
Et3N, r.t.
R1O2C
R2
O
O
aalizadeh@modares.ac.ir
O
R1O2C
b Department of Inorganic Chemistry, Chemistry and Chemical
Engineering Research Center of Iran, P. O. Box 14335-186,
Tehran, Iran
OH
O
O
N
Ar
Ph
N
10 examples
up to 80% yield
Received: 03.02.2019
Br
Accepted after revision: 08.03.2019
Published online: 10.04.2019
DOI: 10.1055/s-0037-1612426; Art ID: ss-2019-z0069-op
Me
Cl
O
Me
Me
Me
O
Me
Me
Me
Abstract A one-pot approach for the synthesis of epoxypyrrolo[3,4-
g]indazoles is presented. The first step was initiated by a three-compo-
nent reaction of an isocyanide, a dialkyl acetylenedicarboxylate, and 2-
furancarboxylic acid, and led to 1,3-dioxoepoxyisoindole, followed by
the addition of hydrazonoyl chloride through a [3+2]-cycloaddition re-
action in the second step. The key step in the formation of final com-
pound involves a bicyclization strategy through intramolecular Diels–
Alder (IMDA) reaction.
Me
HO
Me
O
O
O
Dactylomelol
3',6'-Epoxycycloaurapten
Me
O
O
Ph
3
OH
O
O
Me
Key words isocyanide, dialkyl acetylenedicarboxylate, 2-furancarbox-
ylic acid, epoxypyrrolo[3,4-g]indazole, IMDA, [3+2] cycloaddition, oxab-
icyclo compounds
HO2C
HO2C
O
O
Ph
O
Me
O
AcO
CO2H
OH
Me
Zaragozic acid C
Cantharidin
Oxabicyclo core is one of the current templates present
in natural products1 and plays a major role in the total syn-
thesis. The ability of ring cleavage in this building block has
made it one of the best candidates as starting material in
the total synthesis of natural products.2 For instance, es-
trone,3 epoxyquinol A and B,4 trans-kumausyne,5 and pe-
duncularine6 are some of the natural products, where oxab-
icyclo compounds have been used in their synthetic routes.
Not only the oxabicyclo template is used in the total syn-
thesis of natural products as starting material, but it also
appeared directly in the structure of multiple natural prod-
ucts (Figure 1). Prostaglandins, terpenoids, and carotenoids
are some classes of these natural products.7
Figure 1 Structure of some natural products containing oxabicyclo
skeleton
another study by Li et al., different oxabicyclo compounds
exhibited the antiproliferative effect on breast cancer cells.9
Due to the importance of structural and application of
these compounds either as starting material or product, sig-
nificant effort has been made in this area and Diels–Alder
reaction is a dynamic tool for accessing these compounds.
This reaction has become an integral part of synthetic
chemistry owing to its stereospecific product, atom econo-
my, and formation of two new bonds. Intramolecular reac-
tions are faster, cleaner, and more selective compared with
intermolecular reactions so the development of new sub-
strates to perform intramolecular reactions – mostly intra-
molecular Diels–Alder reaction – found remarkable inter-
ests.10 A literature survey showed that many chemists take
Researches revealed many biological and medicinal as-
pects of oxabicyclo containing compounds. For example,
McCluskey and co-workers showed that some new class of
cantharides can act as potential protein phosphatase.8 In
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
A. Alizadeh et al.
Paper
Synthesis
advantages of this powerful tool in total synthesis especial-
ly in the synthesis of oxabicyclic compounds.11 Liu and co-
workers reported the synthesis of the oxapentacyclic core
of cortistatins through intramolecular Diels–Alder (IMDA)
reaction.12 The reaction consists of many intermediates but
the key intermediate was synthesized through IMDA fol-
lowed by Lewis acid mediated aromatization of oxabicyclic
structure. Solanoeclepin A is another oxabicyclic natural
product, which was synthesized through IMDA reaction.13
Miyashita and co-workers reported the total synthesis of
alkaloid norzoanthamine consisting of oxabicyclo core in its
structure. An IMDA reaction lies in the middle of this meth-
od, which formed three stereogenic centers simultaneous-
ly.14 Herein we describe a novel IMDA-based reaction for
the synthesis of new classes of oxabicyclic compounds.
Recently, employment of IMDA reaction in acetylene-
based isocyanide multicomponent reaction has been re-
ported by Gao et al.15 In continuation of our previous works
in acetylene-based isocyanide multicomponent reaction
with different carboxylic acids,16 we were interested in the
reaction of isocyanide 1a with acetylene ester 2a in the
presence of 2-furancarboxylic acid (3). Based on our previ-
ous experience in IMCR, the reaction was performed in an-
hydrous DCM and THF at room temperature, which resulted
in 20% and 25% yield, respectively. The best result was
achieved in MeCN at 80 °C and the desired 1,3-dioxoepoxy-
isoindole 4a was obtained in 86% yield (Scheme 1).
The structure of 4a was verified using IR spectropho-
tometry, mass spectrometry, 1H and 13C NMR spectroscopy.
The molecular ion peak of 4a appeared at m/z 337 in mass
1
spectrometry, which confirmed the proposed structure. H
NMR spectrum of 4a displayed a singlet at 1.49 ppm, which
was recognized as tert-butyl hydrogens. The next singlet
signal at 3.25 ppm is related to a single hydrogen, connected
to the ester group. Hydrogens of two methoxy groups of es-
ters appeared at 3.64 and 3.68 ppm, respectively. The
bridgehead hydrogen signal was identified at 5.33 ppm. The
existence of 14 signals in 13C NMR spectrum is in agree-
ment with the suggested structure. In 13C NMR spectrum,
the tert-butyl group appeared in 27.52 ppm. Two signals at
51.95 ppm and 54.02 ppm are related to two methoxy
groups. Four signals 165.75, 169.16, 170.30, and 170.71
ppm at the end of the spectrum are assigned to two ester
and two amide groups.
The flexibility of the reaction toward different isocya-
nides and acetylenic esters was explored and the results are
presented in Table 2. Unfortunately, when 2-thiophenecar-
boxylic acid was applied instead of 2-furancarboxylic acid
the reaction did not provide the desired product even at
higher temperatures and in different solvents.
Table 2 Synthetic Pathway to 1,3-Dioxoepoxyisoindoles 4
R1
O
CO2R2
R2O2C
R2O2C
N
O
O
MeCN
reflux
R1
N
C
+
O
+
OH
O
O
CO2R2
CO2Me
N
O
MeO2C
MeO2C
MeCN
reflux
O
1
2
3
4
+
+
O
N
C
OH
O
CO2Me
2a
Entry
R1
R2
Product
Yield (%)
4a
1a
3
1
2
3
4
5
6
t-Bu
t-Bu
Me
4a
4b
4c
4d
4e
4f
86
80
72
50
66
54
Scheme 1 Synthesis of 1,3-dioxoepoxyisoindole 4a
Et
cyclohexyl
cyclohexyl
4-MeOC6H4
Me
Et
The reaction was performed in different solvents at dif-
ferent temperature but the best results were obtained un-
der reflux in acetonitrile (Table 1).
Me
Me
ethylmorpholine
Table 1 Different Conditions for the Synthesis of 4a
In the sequel of our research, we noticed the double
bond in the structure of 1,3-dioxoepoxyisoindoles. There-
fore, we decided to investigate the reactivity of this bond
toward [3+2] cycloaddition reaction. To achieve this goal,
first 2-furancarboxylic acid (3) and isocyanide 1a were in-
troduced in the reaction pot followed by the addition of di-
methyl acetylenedicarboxylate (2a). After 4–5 hours and
formation of 4a, which was confirmed by TLC, hydrazonoyl
chloride 5a with an equivalent amount of triethylamine
were added to the reaction mixture. The reaction outcome
was the predicted epoxypyrrolo[3,4-g]indazole in the form
of two diastereomers. Different hydrazonoyl chloride was
tried to develop the scope of the reaction and final products
were obtained in good yields (Table 3). The structure of all
Entry
Solvent
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
DCM
r.t
r.t
20
25
60
86
55
5
THF
THF
70
MeCN
toluene
EtOH
toluene
MeCN
80
80
80
100
100
43
72
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
A. Alizadeh et al.
Paper
Synthesis
Table 3 Synthetic Approach to 6,8-Dioxo-1,3-diphenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-epoxypyrrolo[3,4-e]indazole-5,5a(6H)-dicarboxylates 6
O
R2OOC
R2OOC
R1
N
O
O
Cl
N
R3
R1
N
O
Ph
N
CO2R2
+
R2O2C
R2O2C
N
NH
Ph
O
R3
6
O
5
MeCN
reflux
R1
N
C
+
O
O
OH
O
Et3N, r.t
R2OOC
R1
CO2R2
R2OOC
N
3
1
2
4
O
O
N
Ph
N
R3
6'
Entry
R1
R2
R3
6:6′
Product
Yield (%)
1
2
3
4
5
6
7
t-Bu
t-Bu
Me
H
50:50
50:50
46:54
93:7
6a, 6′a
6b, 6′b
6c, 6′c
6d, 6′d
6e, 6′e
6f, 6′f
80
75
68
83
66
77
70
Et
H
cyclohexyl
t-Bu
Me
Me
Me
Me
Me
H
Cl
Cl
cyclohexyl
t-Bu
10:90
4:96
NO2
NO2
cyclohexyl
25:75
6g, 6′g
the products 6a–j were verified by mass, IR, H NMR, 13C
NMR spectra and single-crystal X-ray probe of 6b/6′b. The
molecular ion peak of 6a appeared at m/z = 531. IR spec-
trum displayed ester carbonyl stretching frequency at 1746
cm–1. Signals at 1H NMR and 13C NMR are related to a mix-
ture of two diastereomers, which go along with suggested
structures.
Finally, single crystal of 6b and 6′b was analyzed by X-
ray crystallography to obtain the exact structure of both re-
gioisomers (Figure 2).
In one diastereomer, bridgehead hydrogen is affected by
1
the -effect of the nitrogen atom (depicted by green). In the
other diastereomer, the nitrogen atom is far from bridge-
head hydrogen, so the hydrogen does not affect by nitrogen
(depicted by red). Therefore, the hydrogen atom circled in
green (6′a) is more deshielded compare to the hydrogen
atom circled in red (6a). This pattern is repeated in the rest
of the diastereomeric mixtures.
Based on reported publications on IMCR,18 a proposed
mechanism is indicated in Scheme 2. Reasonably, the addi-
tion of isocyanide to dialkyl acetylenedicarboxylate affords
zwitterion 7, which is hydrogenated by 2-furancarboxylic
acid. Then a Passerini type addition of carboxylate to nitrili-
um generates intermediate 8, which leads to intermediate 9
with a Mumm rearrangement. This intermediate produces
the product 4 with an intramolecular Diels–Alder reaction.
On the other hand, hydrazonoyl chloride converts to its 1,3-
dipolar form in the presence of triethylamine. [3+2] Cyclo-
addition of hydrazonoyl to product 4 affords the final ep-
oxypyrrolo[3,4-g]indazole 6.
Figure 2 ORTEP diagram for regioisomers of 6b and 6′b17
Briefly, we have expanded a reported method to synthe-
size new classes of 1,3-dioxoepoxyisoindoles and epoxypyr-
rolo[3,4-g]indazoles. All starting materials are present in
the final products, which were synthesized with minimum
use of additives. Catalyst and metal-free condition, one-pot
reaction, and stereoselectivity in the first step are some of
the advantages of this reaction.
We used 1H NMR to relate each spectrum to the appro-
priate structure of each diastereomer. Bridgehead hydrogen
chemical shift helped us to achieve this goal. Figure 3 illus-
trates a part of 1H NMR of 6a with its related diastereomeric
structure.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
A. Alizadeh et al.
Paper
Synthesis
Figure 3 1H NMR of the mixture of two regioisomers 6a and 6′a
R1
N
CO2R2
O
O
CO2R2
O
O
R1
N
C
+
+
H
OH
O
R2O2C
CO2R2
1
2
3
7
R1
CO2R2
O
O
O
Mumm
rearrangement
N
O
O
R2O2C
H
N
R1
O
CO2R2
CO2R2
9
8
O
R2O2C
R2O2C
R1
R1
O
N
R1
N
O
O
N
R2O2C
H
R2O2C
R2O2C
O
IMDA
O
O
O
O
N
Ar
Ph
CO2R2
N
6
[1,3] dipolar
4
O
Cl
Ar
HN Ph
R2O2C
R1
Et3N
MeCN
R2O2C
Ar
N N Ph
N
N
O
O
N
Ph
Ar
N
6'
Scheme 2 The probable mechanism for generation of 6
used to indicate spin multiplicities. Elemental analyses for C, H, and N
were performed using a Heraeus CHN-O-Rapid analyzer. Mass spec-
tra were recorded on a Finnigan-MATT 8430 mass spectrometer oper-
ating at an ionization potential of 70 eV. CH2Cl2 was dried over P2O5.
THF and toluene were dried using Na as a drying agent. 4-Methoxy-
phenyl isocyanide was prepared according to the reported procedure.
All other chemicals and solvents were purchased from Merck or Al-
drich and were used without further purification.
Melting points were measured on an Electrothermal 9100 apparatus.
IR spectra were recorded as KBr pellets on a Nicolet FTIR 100 spectro-
photometer. 1H NMR (500 MHz, 300 MHz) and 13C NMR (125 MHz, 75
MHz) spectra were obtained using Bruker DRX-500 Avance and
Bruker DRX-300 Avance spectrometers. All NMR spectra were record-
ed at r.t. in DMSO-d6. Chemical shifts are reported in parts per million
() downfield from an internal TMS reference. Coupling constants
(J values) are reported in hertz (Hz), and standard abbreviations were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
A. Alizadeh et al.
Paper
Synthesis
Compounds 4a–f; General Procedure
13C NMR (75.46 MHz, DMSO-d6):  = 24.7, 25.0, 25.1, 27.6, 28.3 (5 ×
CH2 of cyclohexyl), 48.6 (CH7), 51.6 (NCH), 52.0 (OCH3), 54.0 (OCH3),
67.8 (C7a), 84.7 (C6), 90.7 (CH3a), 130.2 (CH5), 140.5 (CH4), 165.6
(CO2Me), 168.3 (NCO), 169.9 (CO2Me), 170.1 (NCO).
MS (EI, 70 eV): m/z (%) = 363 (M+, 3), 304 (11), 283 (19), 282 (83), 250
(39), 222 (29), 206 (33), 192 (16), 182 (10), 179 (64), 172 (23), 171
(100), 151 (32), 95 (78), 77 (9), 59 (21), 55 (18).
To a magnetically stirred solution of 2-furancarboxylic acid (112 mg,
1 mmol) and isocyanide 1 (1 mmol) in anhyd MeCN was added drop-
wise a solution of dialkyl acetylenedicarboxylate 2 (1 mmol) in MeCN
(2 mL) at r.t. Then the reaction mixture was refluxed for 4–5 h until
the starting materials were consumed. The solvent was removed un-
der reduced pressure and the residue was subjected to column chro-
matography using EtOAc/hexane (1:5 to 1:3) as eluent to obtain 4a–f.
Anal. Calcd for C18H21NO7 (363.36): C, 59.50; H, 5.83; N, 3.85. Found:
C, 59.48; H, 5.85; N, 3.85.
Dimethyl (3aS,6R,7S,7aS)-2-tert-Butyl-1,3-dioxo-2,3,6,7-tetrahy-
dro-3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate (4a)
Diethyl (3aS,6R,7S,7aS)-2-Cyclohexyl-1,3-dioxo-2,3,6,7-tetrahy-
dro-3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate (4d)
Yield: 288 mg (86%); colorless crystals; mp 109–111 °C.
IR (KBr): 1789 and 1700 (CO–N–CO), 1745 (CO2Me), 1307 and 1267
(C–O of ester), 1174 and 1125 cm–1 (C–O of ether).
Yield: 194 mg (50%); colorless crystals; mp 126–128 °C.
IR (KBr): 1741 (CO2Me), 1307 and 1224 (C–O of ester), 1190 and 1116
cm–1 (C-O of ether).
1H NMR (300 MHz, DMSO-d6):  = 1.49 (9 H, s, t-C4H9), 3.25 (1 H, s,
CH7), 3.64 (3 H, s, OCH3), 3.68 (3 H, s, OCH3), 5.33 (1 H, d, 3JHH = 1.3 Hz,
3
1H NMR (500 MHz, DMSO-d6):  = 1.10 (3 H, t, JHH = 7.00 Hz,
CH6), 6.72 (1 H, d, 3JHH = 5.9 Hz, CH4), 6.74 (1 H, dd, 3JHH = 5.9 Hz, 3JHH
=
OCH2CH3), 1.17 (3 H, t, 3JHH = 7.00 Hz, OCH2CH3), 1.13–2.03 (10 H, m, 5 ×
1.4 Hz, CH5).
CH2 of cyclohexyl), 3.75 (1 H, d, 3JHH = 4.0 Hz, CH7), 3.91 (1 H, tt, 3JHH
=
13C NMR (75.46 MHz, DMSO-d6):  = 27.5 [C(CH3)3], 49.1 (CH7), 51.9
(OCH3), 54.0 (OCH3), 58.6 (CMe3), 68.0 (C7a), 84.57 (CH6), 90.6 (C3a),
130.2 (CH5), 140.4 (CH4), 165.7 (CO2Me), 169.2 (NCO), 170.3 (CO2Me),
170.7 (NCO).
MS (EI, 70 eV): m/z (%) = 337 (M+, 5), 322 (16), 305 (23), 282 (15), 278
(40), 250 (43), 249 (18), 233 (24), 222 (36), 206 (30), 183 (13), 171
(100), 179 (67), 172 (19), 166 (68), 151 (50), 135 (7), 119 (9), 95 (72),
77 (14), 59 (37), 57 (60), 56 (16), 53 (15).
12.2 Hz, 3JHH = 3.7 Hz, NCH), 4.01–4.07 (4 H, m, 2 × OCH2CH3), 5.45 (1
H, dd, 3JHH = 4.0 Hz, 4JHH = 1.6 Hz, CH6), 6.75 (1 H, d, 3JHH = 5.8 Hz, CH4),
6.81 (1 H, dd, 3JHH = 5.8 Hz, 4JHH = 1.6 Hz, CH5).
13C NMR (125 MHz, DMSO-d6):  = 14.0 (OCH2CH3), 14.3 (OCH2CH3),
25.1, 25.5, 25.6, 28.0, 29.0 (5 × CH2 of cyclohexyl), 51.1 (CH7), 52.1
(NCH), 61.1 (OCH2CH3), 63.1 (OCH2CH3), 68.7 (C7a), 83.8 (CH6), 92.7
(C3a), 129.5 (CH5), 139.9 (CH4), 164.9 (CO2Et), 168.6 (NCO), 168.7
(CO2Et), 172.0 (NCO).
MS (EI, 70 eV): m/z (%) = 391 (M+, 3), 318 (19), 264 (18), 238 (13), 236
(21), 220 (71), 199 (21), 193 (100), 192 (21), 171 (19), 165 (63), 143
(28), 137 (19), 125 (12), 95 (93), 81 (17), 69 (14), 55 (21).
Anal. Calcd for C16H19NO7 (337.33): C, 56.97; H, 5.68; N, 4.15. Found:
C, 56.93; H, 5.70; N, 4.11.
Diethyl (3aS,6R,7S,7aS)-2-tert-Butyl-1,3-dioxo-2,3,6,7-tetrahydro-
3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate (4b)
Anal. Calcd for C20H25NO7 (391.42): C, 61.37; H, 6.44; N, 3.58. Found:
C, 61.22; H, 6.39; N, 3.59.
Yield: 290 mg (80%); colorless crystals; mp 129–131 °C.
IR (KBr): 1724 (CO2Me), 1309 and1389 (C–O of ester), 1219 cm–1 (C–O
of ether).
Dimethyl (3aS,6R,7S,7aS)-2-(4-Methoxyphenyl)-1,3-dioxo-2,3,6,7-
tetrahydro-3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate (4e)
3
1H NMR (300 MHz, DMSO-d6):  = 1.14 (3 H, t, JHH = 7.00 Hz,
Yield: 255 mg (66%); colorless crystals; mp 117–119 °C.
OCH2CH3), 1.20 (3 H, t, 3JHH = 7.00 Hz, OCH2CH3), 1.50 (9 H, s, t-C4H9),
3.22 (1 H, s, CH7), 4.07–4.15 (4 H, m, 2 × OCH2CH3) 5.31 (1 H, s, CH6),
6.72 (2 H, s, CH4 and CH5).
13C NMR (75.46 MHz, DMSO-d6):  = 13.6 (OCH2CH3), 13.9 (OCH2CH3),
27.5 [C(CH3)3], 49.1 (CH7), 58.5 (CMe3), 60.7 (OCH2CH3), 62.9
(OCH2CH3), 68.0 (C7a), 84.7 (CH6), 90.4 (C3a), 130.2 (CH5), 140.3 (CH9),
165.0 (CO2Et), 169.3 (NCO), 169.6 (CO2Et), 170.6 (NCO).
IR (KBr): 1789 and 1700 (CO–N–CO), 1745 (CO2Me), 1307 and 1267
(C–O of ester), 1174 and 1125 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 3.62 (3 H, s, OCH3), 3.67 (3 H, s,
OCH3), 3.68 (1 H, s, CH7) 3.81 (3 H, s, OCH3), 5.60 (1 H, d, 3JHH = 1.3 Hz
CH6), 6.67 (1 H, d, 3JHH = 5.8 Hz CH4), 6.74 (1 H, dd, 3JHH = 5.8 Hz, 3JHH
1.6 Hz CH5), 7.01 (2 H, d, 3JHH = 8.4 Hz, 2 × CH of Ar), 7.16 (2 H, d, 3JHH
8.4 Hz, 2 × CH of Ar).
=
=
MS (EI, 70 eV): m/z (%) = 365 (M+, 8), 319 (18), 292 (47), 264 (63), 263
(23), 247 (21), 236 (44), 220 (34), 211 (12), 199 (51), 193 (89), 190
(18), 171 (60), 166 (100), 165 (80), 143 (64), 137 (19), 125 (15), 121
(10), 95 (75), 57 (45).
13C NMR (125 MHz, DMSO-d6):  = 49.9 (CH7), 52.0 (OCH3), 53.9
(OCH3), 55.3 (OCH3), 68.3 (C7a), 85.2 (CH6), 90.7 (C3a), 114.3 (2 × CH of
Ar), 126.8 (2 × CH of Ar), 129.8 (Ci-N), 131.7 (CH5), 140.9 (CH4), 161.2
(Ci-OMe), 166.9 (CO2Me), 169.4 (NCO), 169.8 (CO2Me), 171.0 (NCO).
MS (EI, 70 eV): m/z (%) = 387 (M+, 2), 223 (29), 195 (59), 179 (67), 166
(7), 96 (8), 95 (100), 69 (19).
Anal. Calcd for C18H23NO7 (365.38): C, 59.17; H, 6.34; N, 3.83. Found:
C, 59.09; H, 6.34; N, 3.85.
Anal. Calcd for C19H17NO8 (387.34): C, 58.92; H, 4.42; N, 3.62. Found:
C, 58.89; H, 4.43; N, 3.61.
Dimethyl (3aS,6R,7S,7aS)-2-Cyclohexyl-1,3-dioxo-2,3,6,7-tetrahy-
dro-3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate (4c)
Yield: 260 mg (72%); colorless crystals; mp 122–124 °C.
Dimethyl (3aS,6R,7S,7aS)-2-(2-Morpholin-4-ylethyl)-1,3-dioxo-
2,3,6,7-tetrahydro-3a,6-epoxyisoindole-7,7a(1H)-dicarboxylate
(4f)
IR (KBr): 1720 (CO2Me), 1364 and 1334 (C–O of ester), 1220 and 1182
cm–1 (C–O of ether).
1H NMR (300 MHz, DMSO-d6):  = 1.09–2.49 (10 H, m, 5 × CH2 of cy-
clohexyl), 3.29 (1 H, s, CH7), 3.65 (3 H, s, OCH3), 3.68 (3 H, s, OCH3),
3.89 (1 H, tt, 3JHH = 11.9 Hz, 3JHH = 3.4 Hz, NCH), 5.36 (1 H, s, CH6), 6.77
(2 H, s, CH4 and CH5).
Yield: 210 mg (54%); colorless crystals; mp 104–106 °C.
IR (KBr): 1720 (CO2Me), 1335 (C–O of ester), 1221 and 1181 cm–1 (C-O
of ether).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
A. Alizadeh et al.
Paper
Synthesis
1H NMR (500 MHz, DMSO-d6):  = 2.40–2.42 (4 H, m, 2 × NCH2), 2.80–
2.85 (2 H, m, NCH2), 3.51–3.54 (4 H, m, 2 × OCH2), 3.59 (1 H, s, CH7),
3.62 (3 H, s, OCH3), 3.69 (3 H, s, OCH3), 3.86–3.90 (2 H, m, NCH2), 5.62
(1 H, s, CH6), 6.64 (1 H, d, 3JHH = 5.85 Hz, CH4), 6.78 (1 H, d, 3JHH = 5.85
Hz, CH5).
13C NMR (125 MHz, DMSO-d6):  = 37.8 (NCH2), 51.1 (CH7), 51.9
(OCH3), 53.6 (2 × NCH2), 54.1 (OCH3), 55.1 (NCH2), 66.5 (2 × OCH2),
68.2 (C7a), 84.8 (CH6), 90.6 (C3a), 134.1 (CH5), 141.0 (CH4), 167.3
(CO2Me), 169.4 (NCO), 170.1 (CO2Me), 171.7 (NCO).
1H NMR (500 MHz, DMSO-d6):  = 1.44 (9 H, s, t-C4H9), 3.65 (3 H, s,
OCH3), 3.95 (3 H, s, OCH3), 3.98 (1 H, s, CH5), 4.48 (1 H, d, 3JHH = 9.0 Hz,
CH8b), 4.82 (1 H, d, 3JHH = 9.0 Hz, CH3a), 5.03 (1 H, s, CH4), 6.83 (1 H, t,
3JHH = 7.5 Hz, CHp of Ph), 7.27 (2 H, d, 3JHH = 7.5 Hz, 2 × CHo of Ph), 7.31
(1 H, t, 3JHH = 7.0 Hz, CHp of Ph), 7.37 (2 H, t, 3JHH = 7.5 Hz, 2 × CHm of
Ph), 7.44 (2 H, t, 3JHH = 7.5 Hz, 2 × CHm of Ph), 7.88 (2 H, d, 3JHH = 7.5 Hz,
2 × CHo of Ph).
13C NMR (125 MHz, DMSO-d6):  = 27.9 [C(CH3)3], 50.1 (CH5), 51.4
(CH8b), 52.7 (OCH3), 55.0 (OCH3), 59.3 (CMe3), 69.7 (C5a), 70.1 (CH3a),
84.7 (CH4), 90.7 (C8a), 114.2 (2 CHo of Ph), 119.9 (CHp of Ph), 126.3 (2 ×
CHo of Ph), 128.6 (2 × CHm of Ph), 128.9 (2 × CHm of Ar), 129.5 (CHp of
Ph), 131.1 (Ci-C=N), 143.8 (Ci-N), 148.5 (C=N), 166.1 (CO2Me), 168.4
(NCO) 170.2 (CO2Me), 170.8 (NCO).
MS (EI, 70 eV): m/z (%) = 394 (M+, 1), 223 (22), 195 (100), 136 (46),
119 (39), 95 (91), 91 (36), 82 (84), 69 (21).
Anal. Calcd for C18H22N2O8 (394.38): C, 54.82; H, 5.62; N, 7.10. Found:
C, 54.84; H, 5.61; N, 7.06.
MS (EI, 70 eV): m/z (%) = 531 (M+, 100), 384 (16), 343 (8), 245 (77),
342 (34), 315 (9), 314 (29), 273 (10), 260 (7), 246 (15), 245 (77), 233
(53), 221 (19), 220 (21), 219 (16).
Compounds 6a–j; General Procedure
To a magnetically stirred solution of 2-furancarboxylic acid (3; 112
mg, 1 mmol) and isocyanide 1 (1 mmol) in anhyd MeCN was added
dropwise a solution of dialkyl acetylenedicarboxylate 2 (1 mmol) in
MeCN (2 mL) at r.t. Then, the reaction mixture was refluxed for 4–5 h
until the starting materials were consumed. Then, hydrazonoyl chlo-
ride 5 (1 mmol) was added to the reaction mixture followed by the
dropwise addition of Et3N (1.05 mmol). The reaction mixture was left
at r.t. until the consumption of hydrazonoyl chloride. The solvent was
evaporated under reduced pressure and the residue was washed with
H2O and EtOH and recrystallized from EtOH to obtain the final prod-
uct.
Anal. Calcd for C29H29N3O7 (531.20): C, 65.53; H, 5.50; N, 7.91. Found:
C, 65.49; H, 5.51; N, 7.95.
Diethyl (3aS,4R,5S,5aS,8aR,8bS)-7-(tert-Butyl)-6,8-dioxo-1,3-di-
phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxypyrrolo[3,4-g]in-
dazole-5,5a(6H)-dicarboxylate (6b)
Yield: 419 mg (75%); pale yellow powder; mp 223–224 °C.
IR (KBr): 1729 (COO), 1496 and 1527 (Ar), 1336 and 1280 (C–O of es-
ter), 1207 and 1126 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.23 (3 H, dd, 3JHH = 15.8 Hz, 3JHH
=
7.4 Hz, OCH2CH3), 1.35 (3 H, dd, 3JHH = 11.5 Hz, 3JHH =7.0 Hz, OCH2CH3),
1.48 (9 H, s, t-C4H9), 4.0 (1 H, s, CH5), 4.35–4.42 (4 H, m, 2 × OCH2CH3),
4.47 (1 H, d, 3JHH = 9.0 Hz, CH3a), 4.78 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.97
Dimethyl (3aS,4R,5S,5aS,8aR,8bS)-7-tert-Butyl-6,8-dioxo-1,3-di-
phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxypyrrolo[3,4-g]in-
dazole-5,5a(6H)-dicarboxylate (6a)
(1 H, s, CH4), 6.85 (1 H, t, 3JHH = 7.0 Hz, CHp of Ph), 7.06 (2 H, d, 3JHH
=
8.0 Hz, 2 × CHo of Ph), 7.28 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.33 (2
H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.38 (1 H, t, 3JHH = 8.0 Hz, CHp of Ph),
7.61 (2 H, d, 3JHH = 7.5 Hz, 2 × CHo of Ph).
Yield: 425 mg (80%): pale yellow powder; mp 216–218 °C.
IR (KBr): 1746 (COO), 1592 and 1493 (Ar), 1328 and 1278 (C–O of es-
ter), 1130 and 1209 cm–1 (C–O of ether).
13C NMR (125 MHz, DMSO-d6):
 = 14.18 (OCH2CH3), 14.31
1H NMR (500 MHz, DMSO-d6):  = 1.38 (9 H, s, t-C4H9), 3.62 (3 H, s,
OCH3), 3.94 (3 H, s, OCH3), 3.96 (1 H, s, CH5), 4.46 (1 H, d, 3JHH = 9.0 Hz,
CH3a), 4.79 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.96 (1 H, s, CH4), 6.83 (1 H, t,
3JHH = 8.0 Hz, CHp of Ph), 7.02 (2 H, d, 3JHH = 8.0 Hz, 2 × CHo of Ph), 7.26
(2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.27 (1 H, t, 3JHH = 7.0 Hz, CHp of
Ph), 7.38 (2 H, t, 3JHH = 7.5 Hz, 2 × CHm of Ph), 7.57 (2 H, d, 3JHH = 7.5 Hz,
2 × CHo of Ph).
(OCH2CH3), 27.91 [C(CH3)3], 52.85 (CH5), 57.65 (CH3a), 59.34 (CMe3),
61.16 (OCH2CH3), 64.33 (OCH2CH3), 65.24 (CH8b), 68.50 (C5a), 84.79
(CH4), 90.45 (C8a), 113.25 (2 × CHo of Ph), 119.94 (CHp of Ph), 126.76 (2 ×
CHo of Ph), 128.62 (2 × CHm of Ph), 129.21 (2 × CHm of Ar), 129.53 (CHp
of Ph), 133.08 (Ci-C=N), 145.09 (Ci-N), 146.16 (C=N), 165.17 (CO2Et),
168.56 (NCO) 169.61 (CO2Me), 170.62 (NCO).
MS (EI, 70 eV): m/z (%) = 559 (M+, 66), 384 (13), 342 (16), 314 (17),
273 (13), 246 (22), 245 (100), 233 (45), 221 (19), 220 (20), 219 (15),
234 (8).
13C NMR (125 MHz, DMSO-d6):  = 27.9 [C(CH3)3], 52.3 (CH5), 52.4
(OCH3), 55.1 (OCH3), 57.7 (CH3a), 59.4 (CMe3), 65.1 (CH8b), 68.4 (C5a),
85.6 (CH4), 90.6 (C8a), 113.2 (2 × CHo of Ph), 119.8 (CHp of Ph), 126.7 (2 ×
CHo of Ph), 128.4 (2 × CHm of Ph), 129.2 (2 × CHm of Ph), 129.6 (CHp of
Ph), 133.1 (Ci-C=N), 145.1 (Ci-N), 146.2 (C=N), 166.0 (CO2Me), 168.0
(NCO) 170.1 (CO2Me), 170.7 (NCO).
Anal. Calcd for C31H33N3O7 (559.23): C, 66.53; H, 5.94; N, 7.51. Found:
C, 66.58; H, 5.92; N, 7.50.
MS (EI, 70 eV): m/z (%) = 531 (M+, 100), 384 (16), 343 (8), 245 (77),
342 (34), 315 (9), 314 (29), 273 (10), 260 (7), 246 (15), 245 (77), 233
(53), 221 (19), 220 (21), 219 (16).
Crystal Data for 6b
C
31H33N3O7·C31H33N3O7·2(C2H6O1S1): MW = 637.42, triclinic, P-1, a =
11.351(2) Å, b = 17.285(3) Å, c = 19.727(4) Å,  = 65.15(3),  =
82.29(3),  = 73.42(3), V = 3365.6(14) Å3, Z = 4, Dc = 1.258 mg/m3,
F (000) = 1352, radiation, Mo K ( = 0.71073 Å), 1.872 ≤ 2θ ≤ 23.255,
intensity data were collected at 293(2) K with a Bruker APEX area-de-
tector diffractometer, and employing /2θ scanning technique, in the
range of –12 ≤ h ≤ 12, –19 ≤ k ≤ 19, –21 ≤ l ≤ 21. The structure was
solved by a direct method, all non-hydrogen atoms were positioned
and anisotropic thermal parameters refined from 9536 observed re-
flections with R (into) = 0.1605 by a full-matrix least-squares tech-
nique converged to R = 0.0879 and wR2 = 0.2535 [I>2(I)].
Anal. Calcd for C29H29N3O7 (531.20): C, 65.53; H, 5.50; N, 7.91. Found:
C, 65.49; H, 5.51; N, 7.95.
Dimethyl (3aR,4S,5S,5aS,8aS,8bR)-7-tert-Butyl-6,8-dioxo-1,3-di-
phenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-epoxypyrrolo[3,4-e]inda-
zole-5,5a(6H)-dicarboxylate (6′a)
Yield: 425 mg (80%); pale yellow powder; mp 216–218 °C.
IR (KBr): 1746 (COO), 1592 and 1493 (Ar), 1328 and 1278 (C–O of es-
ter), 1130 and 1209 cm–1 (C–O of ether).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
A. Alizadeh et al.
Paper
Synthesis
Diethyl (3aR,4S,5S,5aS,8aS,8bR)-7-tert-Butyl-6,8-dioxo-1,3-diphe-
nyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-epoxypyrrolo[3,4-e]inda-
zole-5,5a(6H)-dicarboxylate (6′b)
of Ph), 129.0 (2 × CHm of Ph), 129.5 (CHp of Ph), 131.1 (Ci-C=N), 143.8
(Ci-N), 146.0 (C=N), 165.9 (CO2Me), 167.6 (CON) 169.96 (CO2Me),
170.0 (NCO).
MS (EI, 70 eV): m/z (%) = 557 (M+, 100), 495 (10), 481 (12), 466 (20),
424 (25), 396 (16), 343 (9), 342 (38), 314 (14), 273 (9), 246 (15), 245
(72), 233 (39), 221 (15), 220 (20), 219 (16), 77 (17).
Yield: 419 mg (75%); pale yellow powder; mp 223–224 °C.
IR (KBr): 1729 (COO), 1496 and 1527 (Ar), 1336 and 1280 (C–O of es-
ter), 1207 and 1126 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.23 (3 H, dd, 3JHH = 15.8 Hz, 3JHH
=
Dimethyl (3aS,4R,5S,5aS,8aR,8bS)-7-Cyclohexyl-6,8-dioxo-1,3-di-
phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxypyrrolo[3,4-g]in-
dazole-5,5a(6H)-dicarboxylate (6′c)
3
3
7.4 Hz, OCH2CH3), 1.35 (3 H, dd, JHH = 11.5 Hz, JHH = 7.0 Hz,
OCH2CH3), 1.42 (9 H, s, t-C4H9), 3.98 (1 H, s, CH5), 4.09–4.13 (4 H, m,
2 × OCH2CH3), 4.50 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.85 (1 H, d, 3JHH = 9.0
Hz, CH3a), 5.05 (1 H, s, CH4), 6.85 (1 H, t, 3JHH = 7.0 Hz, CHp of Ph), 7.27
(2 H, d, 3JHH = 8.0 Hz, 2 × CHo of Ph), 7.30 (1 H, t, 3JHH = 8.0 Hz, CHp of
Ph), 7.37 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.45 (2 H, t, 3JHH = 7.5 Hz,
2 × CHm of Ph), 7.91 (2 H, d, 3JHH = 7.5 Hz, 2 × CHo of Ph).
Yield: 378 mg (68%); white powder; mp 184–186 °C.
IR (KBr): 1730 (COO), 1595 and 1497 (Ar), 1357 and 1277 (C–O of es-
ter), 1221 and 1116 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.17–1.30 (2 H, m, CH2 of cyclohex-
yl), 1.43–1.58 (4 H, m, 2 × CH2 of cyclohexyl), 1.69–1.93 (4 H, m, 2 ×
CH2 of cyclohexyl), 3.65 (3 H, s, OCH3), 3.74–3.82 (1 H, m, NCH of cy-
clohexyl), 3.94 (3 H, s, OCH3), 4.00 (1 H, s, CH5), 4.54 (1 H, d, 3JHH = 9.0
Hz, CH8b), 4.84 (1 H, d, 3JHH = 9.0 Hz, CH3a), 5.06 (1 H, s, CH4), 6.83 (1 H,
13C NMR (125 MHz, DMSO-d6):
 = 14.18 (OCH2CH3), 14.33
(OCH2CH3), 27.87 [C(CH3)3], 50.24 (CH5), 51.49 (CH8b), 59.25 (CMe3),
61.16 (OCH2CH3), 64.29 (OCH2CH3), 69.65 (C5a), 70.15 (CH3a), 85.57
(CH4), 90.45 (C8a), 114.21 (2 × CHo of Ph), 119.79 (CHp of Ph), 126.27 (2 ×
CHo of Ph), 128.29 (2 × CHm of Ph), 128.83 (2 × CHm of Ar), 129.58 (CHp
of Ph), 131.07 (Ci-C=N), 143.77 (Ci-N), 148.57 (C=N), 165.26 (CO2Et),
168.19 (NCO) 169.55 (CO2Me), 170.69 (NCO).
3
3
t, JHH = 7.5 Hz, CHp of Ph), 7.02 (2 H, d, JHH = 9.0 Hz, 2 × CHo of Ph),
7.26 (2 H, t, 3JHH = 7.0 Hz, 2 × CHm of Ph), 7.27 (1 H, t, 3JHH = 7.5 Hz, CHp
of Ph), 7.37 (2 H, t, 3JHH = 7.5 Hz, 2 × CHm of Ph), 7.57 (2 H, d, 3JHH = 8.0
Hz, 2 × CHo of Ph).
MS (EI, 70 eV): m/z (%) = 559 (M+, 66), 384 (13), 342 (16), 314 (17),
273 (13), 246 (22), 245 (100), 233 (45), 221 (19), 220 (20), 219 (15),
234 (8).
13C NMR (125 MHz, DMSO-d6):  = 25.5, 25.4, 25.5, 27.9, 28.0 (5 × CH2
of cyclohexyl), 51.5 (CH of cyclohexyl), 52.2 (CH5), 52.4 (OCH3), 55.2
(OCH3), 56.5 (CH8b), 69.5 (C5a), 69.9 (CH3a), 85.9 (CH4), 90.8 (C8a), 113.2
(2 × CHo of Ph), 119.8 (CHp of Ph), 126.2 (2 × CHo of Ph), 128.5 (2 × CHm
of Ph), 129.2 (2 × CHm of Ph), 129.6 (CHp of Ph), 133.0 (Ci-C=N), 145.0
(Ci-N), 148.4 (C=N), 166.0 (CO2Me), 167.2 (NCO) 169.98 (CO2Me),
170.0 (NCO).
MS (EI, 70 eV): m/z (%) = 557 (M+, 100), 495 (10), 481 (12), 466 (20),
424 (25), 396 (16), 343 (9), 342 (38), 314 (14), 273 (9), 246 (15), 245
(72), 233 (39), 221 (15), 220 (20), 219 (16), 77 (17).
Anal. Calcd for C31H33N3O7 (559.23): C, 66.53; H, 5.94; N, 7.51. Found:
C, 66.58; H, 5.92; N, 7.50.
Crystal Data for 6′b
C
31H33N3O7,C31H33N3O7,2(C2H6O1S1): MW = 637.42, triclinic, P-1, a =
11.351(2) Å, b = 17.285(3) Å, c = 19.727(4) Å,  = 65.15(3),  =
82.29(3),  = 73.42(3), V = 3365.6(14) Å3, Z = 4, Dc = 1.258 mg/m3,
F(000) = 1352, radiation, Mo K ( = 0.71073 Å), 1.872 ≤ 2θ ≤ 23.255,
intensity data were collected at 293(2) K with a Bruker APEX area-de-
tector diffractometer, and employing /2θ scanning technique, in the
range of –12 ≤ h ≤12, –19 ≤ k ≤ 19, –21 ≤ l ≤ 21; the structure was
solved by a direct method, all non-hydrogen atoms were positioned
and anisotropic thermal parameters refined from 9536 observed re-
flections with R (into) = 0.1605 by a full-matrix least-squares tech-
nique converged to R = 0.0879 and wR2 = 0.2535 [I>2(I)].
Anal. Calcd for C31H31N3O7 (557.22): C, 66.78; H, 5.60; N, 7.54. Found:
C, 66.75; H, 5.62; N, 7.55.
Dimethyl (3aS,4R,5R,5aR,8aR,8bS)-7-tert-Butyl-1-(4-chlorophe-
nyl)-6,8-dioxo-3-phenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-epoxy-
pyrrolo[3,4-e]indazole-5,5a(6H)-dicarboxylate (6d)
Yield: 468 mg (83%); pale yellow powder; mp 189–190 °C.
IR (KBr): 1720 (COO), 1598 and 1492 (Ar), 1335 and 1280 (C–O of es-
ter), 1216 and 1126 cm–1 (C–O of ether).
Dimethyl (3aS,4R,5R,5aR,8aR,8bS)-7-Cyclohexyl-6,8-dioxo-1,3-di-
phenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-epoxypyrrolo[3,4-e]inda-
zole-5,5a(6H)-dicarboxylate (6c)
1H NMR (500 MHz, DMSO-d6):  = 1.44 (9 H, s, t-C4H9), 3.63 (3 H, s,
OCH3), 3.94 (3 H, s, OCH3), 3.97 (1 H, s, CH5), 4.47 (1 H, d, 3JHH = 9.0 Hz,
CH3a), 4.82 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.96 (1 H, s, CH4), 6.85 (1 H, t,
3JHH = 7.0 Hz, CHp of Ph), 7.02 (2 H, d, 3JHH = 8.0 Hz, 2 × CHo of Ph), 7.26
(2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.48 (2 H, d, 3JHH = 8.5 Hz, 2 × CH of
Ar), 7.91 (2 H, d, 3JHH = 8.5 Hz, 2 × CH of Ar).
13C NMR (125 MHz, DMSO-d6):  = 27.9 [C(CH3)3], 52.3 (OCH3), 52.6
(CH5), 55.1 (OCH3), 57.6 (CH3a), 59.4 (CMe3), 65.2 (CH8b), 68.4 (C5a),
84.7 (CH4), 90.7 (C8b), 114.2 (2 × CHo of Ph), 120.1 (CHp of Ph), 128.4 (2
× CH of Ar), 129.0 (2 × CHm of Ph), 129.2 (2 × CH of Ar), 130.0 (Ci-C=N),
134.0 (Ci-Cl), 145.9 (Ci-N), 147.4 (C=N), 166.0 (CO2Me), 168.3 (NCO)
170.1 (CO2Me), 170.6 (NCO).
Yield: 378 mg (68%); pale yellow powder; mp 184–186 °C.
IR (KBr): 1730 (COO), 1595 and 1497 (Ar), 1357 and 1277 (C–O of es-
ter), 1221 and 1116 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.17–1.30 (2 H, m, CH2 of cyclohex-
yl), 1.43–1.58 (4 H, m, 2 × CH2 of cyclohexyl), 1.69–1.93 (4 H, m, 2 ×
CH2 of cyclohexyl), 3.63 (3 H, s, OCH3), 3.74–3.82 (1 H, m, NCH of cy-
clohexyl), 3.93 (3 H, s, OCH3), 4.02 (1 H, s, CH5), 4.50 (1 H, d, 3JHH = 9.0
Hz, CH3a), 4.84 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.99 (1 H, s, CH4), 6.83 (1 H,
3
3
t, JHH = 7.5 Hz, CHp of Ph), 7.27 (2 H, d, JHH = 6.0 Hz, 2 × CHo of Ph),
7.32 (1 H, t, 3JHH = 7.0 Hz, CHp of Ph), 7.43 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm
of Ph), 7.57 (2 H, t, 3JHH = 7.5 Hz, 2 × CHm of Ph), 7.89 (2 H, d, 3JHH = 7.5
Hz, 2 × CHo of Ph).
MS (EI, 70 eV): m/z (%) = 565 (M+, 82), 566 (M+ + 1, 25), 567 (M+ + 2,
30), 416 (11), 414 (26), 338 (15), 307 (16), 281 (34), 280 (23), 279
(100), 269 (27), 267 (82), 257 (9), 255 (29), 254 (25), 246 (30), 218
(17), 204 (10), 202 (14), 164 (11), 152 (12), 87 (11), 77 (25).
13C NMR (125 MHz, DMSO-d6):  = 25.0, 25.1, 25.5, 28.7, 28.7 (5 × CH2
of cyclohexyl), 49.9 (NCH of cyclohexyl), 52.3 (CH5), 52.4 (OCH3), 55.1
(OCH3), 57.6 (CH3a), 65.2 (CH8b), 68.2 (C5a), 85.1 (CH4), 91.0 (C8a), 114.0
(2 × CHo of Ph), 119.9 (CHp of Ph), 126.7 (2 × CHo of Ph), 128.6 (2 × CHm
Anal. Calcd for C29H28ClN3O7 (565.16): C, 61.54; H, 4.99; N, 7.42.
Found: C, 61.55; H, 5.01; N, 7.40.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
A. Alizadeh et al.
Paper
Synthesis
Dimethyl(3aR,4S,5R,5aR,8aS,8bR)-3-(4-Chlorophenyl)-7-cyclohex-
yl-6,8-dioxo-1-phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxypyr-
rolo[3,4-g]indazole-5,5a(6H)-dicarboxylate (6′e)
1H NMR (500 MHz, DMSO-d6):  = 1.22–1.26 (2 H, m, CH2 of cyclohex-
yl), 1.45–1.56 (4 H, m, 2 × CH2 of cyclohexyl), 1.7–1.9 (4 H, m, 2 × CH2
of cyclohexyl), 3.67 (3 H, s, OCH3), 3.74–3.78 (1 H, m, NCH of cyclo-
hexyl), 3.99 (3 H, s, OCH3), 4.05 (1 H, s, CH5), 4.67 (1 H, d, 3JHH = 9.0 Hz,
CH8b), 5.04 (1 H, d, 3JHH = 9.0 Hz, CH3a), 5.11 (1 H, s, CH4), 6.93 (1 H, t,
3JHH = 7.4 Hz, CHp of Ph), 7.32 (2 H, t, 3JHH = 7.0 Hz, 2 × CHm of Ph), 7.37
(2 H, d, 3JHH = 9.0 Hz, 2 × CHo of Ph), 7.77 (2 H, d, 3JHH = 8.0 Hz, 2 × CH of
Ar), 8.26 (2 H, t, 3JHH = 7.5 Hz, 2 × CH of Ar).
13C NMR (125 MHz, DMSO-d6):  = 25.0, 25.4, 25.4, 27.9, 28.7 (5 × CH2
of cyclohexyl), 51.0 (NCH of cyclohexyl), 52.3 (CH5), 52.5 (OCH3), 55.4
(OCH3), 60.2 (CH8b), 69.8 (C5a), 70.0 (CH3a), 85.9 (CH4), 90.8 (C8b), 113.7
(2 CHo of Ph), 120.9 (CHp of Ph), 123.9 (2 × CH of Ar), 126.8 (2 CH of
Ar), 129.7 (2 × CHm of Ph), 139.6 (Ci-C=N), 142.6 (Ci-NO2), 143.0 (Ci-N),
146.7 (C=N), 165.7 (CO2Me), 167.5 (NCO), 169.9 (CO2Me), 169.9
(NCO).
Yield: 390 mg (66%); pale yellow powder; mp 204–206 °C.
IR (KBr): 1727 (COO), 1601 and 1495 (Ar), 1372 and 1281 (C–O of es-
ter), 1221 and 1129 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.16–1.25 (2 H, m, CH2 of cyclohex-
yl), 1.42–1.55 (4 H, m, 2 × CH2 of cyclohexyl), 1.68–1.97 (4 H, m, 2 ×
CH2 of cyclohexyl), 3.65 (3 H, s, OCH3), 3.73–3.80 (1 H, m, NCH of cy-
clohexyl), 3.94 (3 H, s, OCH3), 4.00 (1 H, s, CH5), 4.56 (1 H, d, 3JHH = 9.0
Hz, CH8b), 4.87 (1 H, d, 3JHH = 9.0 Hz, CH3a), 5.05 (1 H, s, CH4), 6.85 (1 H,
t, 3JHH = 7.5 Hz, CHp of Ph), 7.26–7.28 (4 H, m, 4 × CH of Ph), 7.46 (2 H,
d, 3JHH = 7.5 Hz, 2 × CH of Ar), 7.55 (2 H, d, 3JHH = 8.0 Hz, 2 × CH of Ar).
13C NMR (125 MHz, DMSO-d6):  = 25.0, 25.4, 25.5, 27.9, 28.7 (5 × CH2
of cyclohexyl), 49.9 (CH5), 51.4 (NCH of cyclohexyl), 52.3 (CH8b), 52.4
(OCH3), 55.3 (OCH3), 69.6 (C5a), 69.9 (CH3a), 85.9 (CH4), 90.7 (C8a),
113.3 (2 × CHo of Ph), 120.0 (CHp of Ph), 127.8 (2 × CH of Ar), 128.6 (2 ×
CHm of Ph), 129.6 (2 × CH of Ar), 132.0 (Ci-C=N), 133.0 (Ci-Cl), 143.5
(Ci-N), 144.0 (C=N), 165.9 (CO2Me), 167.3 (NCO), 169.9 (CO2Me), 170.0
(NCO).
MS (EI, 70 eV): m/z (%) = 602 (M+, 100), 511 (35), 469 (60), 411 (20),
387 (43), 341 (22), 290 (92), 278 (34), 266 (32), 265 (41), 244 (38),
219 (22), 218 (21), 164 (29), 153 (39), 81 (22), 77 (68), 67 (42), 59
(34), 55 (52).
Anal. Calcd for C29H28N4O9 (602.20): C, 61.79; H, 5.02; N, 9.30. Found:
C, 61.80; H, 5.04; N, 9.32.
MS (EI, 70 eV): m/z (%) = 593 (M+, 100), 594 (M+ + 1, 38), 595 (M+ + 2,
41), 420 (23), 419 (16), 418 (51), 390 (17), 378 (21), 376 (58), 350
(26), 348 (56), 281 (35), 279 (90), 267 (32), 255 (50), 254 (57), 70 (35),
57 (45).
Dimethyl (3aS,4R,5R,5aR,8aR,8bS)-7-tert-Butyl-1-(4-tert-butyl-
phenyl)-6,8-dioxo-3-phenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-ep-
oxypyrrolo[3,4-e]indazole-5,5a(6H)-dicarboxylate (6h)
Anal. Calcd for C31H30ClN3O7 (593.05): C, 62.89; H, 5.11; N, 7.1. Found:
C, 62.86; H, 5.12; N, 7.2.
Yield: 363 mg (62%), white powder; mp 211–212 °C.
IR (KBr): 1724 (COO), 1599 and 1496 (Ar), 1340 and 1276 (C–O of es-
ter), 1221 and 1124 cm–1 (C–O of ether).
Dimethyl (3aR,4S,5R,5aR,8aS,8bR)-7-tert-Butyl-3-(4-nitrophenyl)-
6,8-dioxo-1-phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxypyrro-
lo[3,4-g]indazole-5,5a(6H)-dicarboxylate (6′f)
1H NMR (500 MHz, DMSO-d6):  = 1.29 (9 H, s, t-C4H9), 1.45 (9 H, s, t-
C4H9), 3.62 (3 H, s, OCH3), 3.94 (3 H, s, OCH3), 3.97 (1 H, s, CH5), 4.48 (1
H, d, 3JHH = 9.0 Hz, CH3a), 4.76 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.95 (1 H, s,
CH4), 6.83 (1 H, t, 3JHH = 8.0 Hz, CHp of Ph), 7.01 (2 H, d, 3JHH = 8.0 Hz, 2 ×
Yield: 443 mg (77%); orange powder; mp 239–240 °C.
IR (KBr): 1750 (COO), 1593 and 1498 (Ar), 1550 and 1389 (NO2), 1331
and 1275 (C–O of ester), 1218 and 1143 cm–1 (C–O of ether).
CHo of Ph), 7.25 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.44 (2 H, t, 3JHH
8.4 Hz, 2 × CH of Ar), 7.80 (2 H, d, 3JHH = 8.4 Hz, 2 × CH of Ar).
=
1H NMR (500 MHz, DMSO-d6):  = 1.37 (9 H, s, t-C4H9), 3.65 (3 H, s,
OCH3), 3.98 (3 H, s, OCH3), 3.99 (1 H, s, CH5), 4.58 (1 H, d, 3JHH = 9.0 Hz,
CH8b), 4.99 (1 H, d, 3JHH = 9.0 Hz, CH3a), 5.07 (1 H, s, CH4), 6.91 (1 H, t,
3JHH = 7.0 Hz, CHp of Ph), 7.30 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.35
(2 H, d, 3JHH = 8.0 Hz, 2 × CHo of Ph), 7.76 (2 H, t, 3JHH = 9.0 Hz, 2 × CH of
Ar), 8.26 (2 H, d, 3JHH = 9.0 Hz, 2 × CH of Ar).
13C NMR (125 MHz, DMSO-d6):  = 27.8 [C(CH3)3], 50.8 (CH5), 52.4
(OCH3), 55.2 (OCH3), 56.5 (CH8b), 59.5 (CMe3), 70.0 (C5a), 70.1 (CH3a),
85.5 (CH4), 90.6 (CH8a), 113.7 (2 × CHo of Ph), 120.9 (CHp of Ph), 123.8
(2 × CH of Ar), 126.8 (2 × CH of Ar), 129.7 (2 × CHm of Ph), 139.7 (Ci-
C=N), 142.7 (Ci-NO2), 143.1 (Ci-N), 146.7 (C=N), 165.9 (CO2Me), 168.3
(NCO), 170.0 (CO2Me), 170.7 (NCO).
13C NMR (125 MHz, DMSO-d6):  = 27.9 [C(CH3)3], 31.4 [C(CH3)3], 34.9
(CMe3), 52.3 (OCH3), 52.6 (CH5), 55.0 (OCH3), 57.8 (CH3a), 60.0 (CMe3),
65.0 (CH8b), 68.5 (C5a), 84.8 (CH4), 90.7 (C8a), 114.1 (2 × CHo of Ph),
119.8 (CHp of Ph), 126.0 (2 × CH of Ar), 126.6 (2 × CH of Ar), 128.3 (Ci-
C=N), 128.9 (2 × CHm of Ph), 146.4 (Ci-N), 148.5 (C=N), 152.2 (Ci-
CMe3), 166.0 (CO2Me), 168.4 (NCO), 170.1 (CO2Me), 170.7 (NCO).
MS (EI, 70 eV): m/z (%) = 587 (M+, 60), 360 (14), 346 (13), 345 (52),
313 (16), 301 (12), 290 (23), 289 (100), 277 (17), 261 (38), 245 (30),
233 (24), 161 (16), 57 (34).
Anal. Calcd for C33H37N3O7 (587.67): C, 67.45; H, 6.35; N, 7.15. Found:
C, 67.49; H, 6.31; N, 7.13.
MS (EI, 70 eV): m/z (%) = 576 (M+, 100), 443 (17), 429 (57), 418 (29),
401 (19), 400 (20), 388 (20), 387 (79), 359 (63), 341 (20), 313 (29),
266 (72), 265 (37) 251 (22), 164 (21), 153 (20), 105 (35), 81 (67), 77
(64), 57 (42).
Dimethyl (3aS,4R,5R,5aR,8aR,8bS)-1-(4-tert-Butylphenyl)-7-cyclo-
hexyl-6,8-dioxo-3-phenyl-3a,4,5,7,8,8b-hexahydro-3H-4,8a-ep-
oxypyrrolo[3,4-e]indazole-5,5a(6H)-dicarboxylate (6i)
Yield: 361 mg (59%); white powder; mp 214–216 °C.
Anal. Calcd for C29H28N4O9 (576.19): C, 60.41; H, 4.90; N, 9.72. Found:
C, 60.40; H, 4.94; N, 9.71.
IR (KBr): 1745 (COO), 1598 and 1502 (Ar), 1328 (C–O of ester), 1208
cm–1 (C–O of ether).
Dimethyl (3aR,4S,5R,5aR,8aS,8bR)-7-Cyclohexyl-3-(4-nitrophe-
nyl)-6,8-dioxo-1-phenyl-3a,4,5,7,8,8b-hexahydro-1H-4,8a-epoxy-
pyrrolo[3,4-g]indazole-5,5a(6H)-dicarboxylate (6′g)
1H NMR (500 MHz, DMSO-d6):  = 1.23–1.28 (2 H, m, CH2 of cyclohex-
yl), 1.3 (9 H, s, t-C4H9), 1.38–1.60 (4 H, m, 2 × CH2 of cyclohexyl), 1.74–
1.95 (4 H, m, 2 × CH2 of cyclohexyl), 3.64 (3 H, s, OCH3), 3.73–3.80 (1
H, m, NCH of cyclohexyl), 3.94 (3 H, s, OCH3), 4.03 (1 H, s, CH5), 4.51 (1
H, d, 3JHH = 9.0 Hz, CH3a), 4.83 (1 H, d, 3JHH = 9.0 Hz, CH8b), 4.99 (1 H, s,
Yield: 421 mg (70%); orange powder; mp 252–254 °C.
IR (KBr): 1737 (COO), 1595 and 1441 (NO2), 1341 (C–O of ester), 1218
cm–1 (C–O of ether).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
A. Alizadeh et al.
Paper
Synthesis
CH4), 6.85 (1 H, t, 3JHH = 8.0 Hz, CHp of Ph), 7.02 (2 H, d, 3JHH = 8.0 Hz, 2 ×
Supporting Information
CHo of Ph), 7.26 (2 H, t, 3JHH = 8.0 Hz, 2 × CHm of Ph), 7.45 (2 H, t, 3JHH
7.5 Hz, 2 × CH of Ar), 7.82 (2 H, d, 3JHH = 8.0 Hz, 2 × CH of Ar).
=
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612426.
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13C NMR (125 MHz, DMSO-d6):  = 25.0, 25.5, 25.5, 28.0, 28.7 (5 × CH2
of cyclohexyl), 31.4 [C(CH3)3], 34.9 (CMe3), 52.3 (NCH of cyclohexyl),
52.36 (CH5), 52.38 (OCH3), 55.1 (OCH3), 57.6 (CH3a), 65.1 (CH8b), 68.3
(C5a), 85.1 (CH4), 91.0 (C8a), 114.0 (2 × CHo of Ph), 119.8 (CHp of Ph),
126.0 (2 × CH of Ar), 126.6 (2 × CHm of Ph), 128.3 (Ci-C=N), 129.0 (2 ×
CH of Ar), 152.3 (Ci-CMe3), 146.2 (Ci-N), 148.5 (C=N), 165.9 (CO2Me),
167.6 (NCO), 169.8 (CO2Me), 170.0 (NCO).
MS (EI, 70 eV): m/z (%) = 613 (M+, 6), 551 (9.8), 392 (10), 377 (24), 345
(9), 304 (41), 290 (23), 289 (100), 276 (14), 261 (37), 245 (9), 161 (20),
152 (12), 130 (9), 116 (11), 91 (12), 77 (30), 55 (8).
References
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Anal. Calcd for C35H39N3O7 (613.28): C, 68.50; H, 6.41; N, 6.85. Found:
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Dimethyl (3aS,4R,5R,5aR,8aR,8bS)-7-tert-Butyl-1-(4-fluorophe-
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pyrrolo[3,4-e]indazole-5,5a(6H)-dicarboxylate (6j)
Yield: 292 mg (53%); pale yellow powder; mp 205–206 °C.
IR (KBr): 1738 (COO), 1366 (C–O of ester), 1217 cm–1 (C–O of ether).
1H NMR (500 MHz, DMSO-d6):  = 1.44 (9 H, s, t-C4H9), 3.63 (3 H, s,
OCH3), 3.94 (3 H, s, OCH3), 3.97 (1 H, s, CH5), 4.48 (1 H, m, CH3a), 4.81
(1 H, d, 3JHH = 8.6 Hz, CH8b), 4.95 (1 H, s, CH4), 6.85 (1 H, dd, 3JHF = 12.4
Hz, 3JHH = 7.2 Hz, CH of Ar), 7.02 (2 H, dd, 3JHH = 8.6 Hz, 4JHF = 3.1 Hz, 2 ×
CH of Ar), 7.24–7.29 (3 H, m, 2 × CHm of Ph and CHp of Ph), 7.48 (1 H, d,
3JHH = 8.6 Hz, CHo of Ph), 7.91 (2 H, d, 3JHH = 8.6 Hz, CHo of Ph), 7.95 (1
H, dd, 3JHF = 12.4 Hz, 3JHH = 7.2 Hz, CH of Ar).
13C NMR (125 MHz, DMSO-d6):  = 27.9 [C(CH3)3], 52.3 (OCH3), 52.7
(CH5), 55.0 (OCH3), 57.6 (CH3a), 59.4 (CMe3), 65.2 (CH8b), 68.4 (C5a),
84.7 (CH4), 90.7 (C8a), 114.19 (2 × CHo of Ph), 120.08 (CHp of Ph),
128.38 (2 × CH of Ar), 129.0 (2 × CHm of Ph), 129.2 (2 × CH of Ar), 130.0
(Ci-C=N), 134.0 (Ci-F), 145.9 (Ci-N), 147.5 (C=N), 166.0 (CO2Me), 168.3
(NCO), 170.1 (CO2Me), 170.7 (NCO).
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(17) CCDC 1900188 (6b and 6′b) contains the supplementary crys-
tallographic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
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5641.
MS (EI, 70 eV): m/z (%) = 549 (M+, 61), 402 (13), 360 (27), 332 (20),
323 (13), 291 (16), 281 (15), 279 (31), 267 (29), 266 (34), 263 (95),
251 (100), 239 (30), 238 (36), 153 (20), 95 (19), 81 (41).
Anal. Calcd for C29H28FN3O7 (549.56): C, 63.38; H, 5.14; N, 7.65.
Found: C, 63.42; H, 5.13; N, 7.67.
Funding Information
We gratefully thank Tarbiat Modares University for financial support.
()
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I