Easy construction of furo[2,3-f]isoindole core by the IMDAV reaction between 3-(furyl)allylamines and α,β-unsaturated acid anhydrides

Article abstract of DOI:10.1016/j.tet.2016.03.023

The vinylogues of furfurylamines, easily available in two steps from furylacroleins (3-(furyl)allylamines), were studied in a tandem N-acylation/intramolecular [4+2] cycloaddition with maleic, pyrocinchonic, and citraconic anhydrides, as well as furylacry

Full text of DOI:10.1016/j.tet.2016.03.023

Accepted Manuscript
Easy Construction of Furo[2,3-f]isoindole Core by the IMDAV Reaction between 3-
(Furyl)allylamines and α,β-Unsaturated Acid Anhydrides
Fedor I. Zubkov, Vladimir P. Zaytsev, Dmitriy F. Mertsalov, Eugenia V. Nikitina,
Yuriy I. Horak, Roman Z. Lytvyn, Yuriy V. Homza, Mykola D. Obushak, Pavel V.
Dorovatovskii, Victor N. Khrustalev, Alexey V. Varlamov
PII:
S0040-4020(16)30156-9
10.1016/j.tet.2016.03.023
TET 27563
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 October 2015
Revised Date: 24 February 2016
Accepted Date: 7 March 2016
Please cite this article as: Zubkov FI, Zaytsev VP, Mertsalov DF, Nikitina EV, Horak YI, Lytvyn RZ,
Homza YV, Obushak MD, Dorovatovskii PV, Khrustalev VN, Varlamov AV, Easy Construction of
Furo[2,3-f]isoindole Core by the IMDAV Reaction between 3-(Furyl)allylamines and α,β-Unsaturated
Acid Anhydrides, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.023.
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Easy Construction of Furo[2,3-f]isoindole
Core by the IMDAV Reaction between 3-
(Furyl)allylamines and α,β-Unsaturated Acid
Anhydrides
Leave this area blank for abstract info.
Fedor I. Zubkov, Vladimir P. Zaytsev, Dmitriy F. Mertsalov, Eugenia V. Nikitina, Yuriy I. Horak, Roman Z.
Lytvyn, Yuriy V. Homza, Mykola D. Obushak, Pavel V. Dorovatovskii, Victor N. Khrustalev, and Alexey V.
Varlamov
Department of Organic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow,
117198 Russian Federation, E-mail: fzubkov@sci.pfu.edu.ru

1
ACCEPTED MANUSCRIPT
Tetrahedron
Easy Construction of Furo[2,3-f]isoindole Core by the IMDAV Reaction between 3-
(Furyl)allylamines and α,β-Unsaturated Acid Anhydrides
a
a
a
Fedor I. Zubkov , Vladimir P. Zaytsev , Dmitriy F. Mertsalov , Eugenia V. Nikitina a, Yuriy I. Horak b,
b
b
b
c
Roman Z. Lytvyn , Yuriy V. Homza , Mykola D. Obushak , Pavel V. Dorovatovskii , Victor N.
Khrustalev d, e, and Alexey V. Varlamov a
a
Department of Organic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198 Russian Federation, E-mail:
fzubkov@sci.pfu.edu.ru
b Department of Organic Chemistry, Ivan Franko National University of Lviv, 6 Kyryla i Mefodiya St., Lviv, 79005 Ukraine
c NRC “Kurchatov Institute”, 1 Acad. Kurchatov Sq., Moscow, 123182 Russian Federation
d Department of Inorganic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow, 117198 Russian Federation
e X-ray Structural Centre, A. N. Nesmeyanov Institute of Organoelement Compounds of RAS, 28 Vavilov St., Moscow, 119991 Russian Federation
Dedicated to the memory of Prof. Alexander V. Butin, the founder of the Furan Ring Opening/Heterocycle Ring Closure
Chemistry.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The vinylogues of furfurylamines, easily available in two steps from furylacroleins (3-
(furyl)allylamines), were studied in a tandem N-acylation / intramolecular [4+2] cycloaddition
with maleic, pyrocinchonic, and citraconic anhydrides, as well as furylacryloyl and cinnamoyl
chlorides. By using a domino reaction of 3-(furyl)allylamines and α,β-unsaturated acid
anhydrides under mild conditions, various hexahydro-4H-furo[2,3-f]isoindoles and their
carboxyl derivatives were synthesized efficiently. The domino sequence includes three steps:
acylation of the nitrogen atom in 3-(furyl)allylamines, intramolecular Diels–Alder cycloaddition
in the resulting N-acyl vinylfurans (IMDAV reaction), and prototropic shift of the adducts
followed by recovery of aromaticity of the furan nucleus. The key step, IMDAV reaction, leads
to the target products, furo[2,3-f]isoindoles, diastereoselectively and with relatively high yields.
Available online
Keywords:
Cycloaddition
Diels–Alder
Furan
Isoindole
IMDAV
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Over the last decade, preparative approaches to the synthesis
of isoindoles and isoindoles fused with other heterocycles based
on the IMDAF reaction between furfurylamines (such as 1) and
α,β-unsaturated acid anhydrides have been developed.4 This work
is devoted to demonstrating the possibility of the construction of
heterocyclic systems using vinylogues of furfurylamines (1), 3-
(furyl)allylamines (5) in similar transformations (Scheme 1).
Furyl and furfuryl amines, as well as various cyclic
compounds containing such fragments in their structure, are
widely used as starting materials for the construction of various
scaffolds containing indole, isoindole, quinoline, and
isoquinoline moieties.1 The key step of these strategies is the
intramolecular Diels–Alder reaction, in which the furan nucleus
acts as a diene.
As distinct from the known IMDAF reaction which was
mentioned above, this [4+2] cycloaddition involves the reaction
of the dienophile with only one double bond of the furan nucleus,
while the second double bond required for the Diels–Alder
reaction belongs to the vinyl fragment of the precursor 6. It
should be noted that the reactions of vinylfurans with various
types of internal dienophiles (alkenes, alkynes, and allenes) have
been described previously,5 but almost all of them are based on
poorly accessible initial substances,5a require high temperatures
for the cycloaddition step (200–300 °C),5a,e–g and often lead to
diastereoisomeric mixtures in unsatisfactory yields.5a,d Some of
these synthetic protocols occur under moderate conditions;
however, the presence of an alkynyl internal dienophile bearing
Possibly, from a synthetic point of view, the tandem reaction
of acylation / [4+2] cycloaddition of furfurylamines (1) under the
action of α,β-unsaturated acid anhydrides is the most attractive
path to obtaining 1,2-dihydroisoindoles (Scheme 1). This
approach allows introduction of an unsaturated substituent to the
nitrogen atom with a simultaneous intramolecular Diels–Alder
reaction in the intermediate 2.2 The aromatization of the 7-
oxabicyclo[2.2.1]heptene ring in the adducts 3 can lead to
substituted isoindoles 4. In the literature, the term IMDAF (the
acronym for the IntraMolecular Diels–Alder Furan reaction) is
generally used to indicate this type of transformation.3

2
Tetrahedron
ACCEPTED MANUSCRIPT
strong electron withdrawing groups is necessary for the
The present strategy is based on readily accessible 3-
successful progress of the IMDA reaction. For example, the
work5b which, in our opinion, is the closest to the subject of this
research, describes a one-pot synthesis of diverse furo[2,3-
f]isoindoles from commercially available starting materials
(propiolic acids, arylamines, isonitriles, and 3-(furyl)acrolein) via
the sequential Ugi four-component reaction and intramolecular
Diels–Alder reaction. The stabilization of the target products was
achieved due to the oxidative aromatization of the intermediate
tetrahydrofuro[2,3-f]isoindoles.
(furyl)allylamines (5) and a simple domino-sequence involving
the acylation, IntraMolecular Diels–Alder Vinylfuran reaction
and aromatization steps leading to the target products – 4H-
furo[2,3-f]isoindoles (8) (Scheme 1). For brevity of the further
presentation, we propose here a new acronym for the key step,
the IMDAV reaction. In contrast to previous works,5 we have
shown in this study that not only N-alkynyl vinylfurylamines, but
also their N-alkenyl derivatives might be successfully involved in
the IMDAV reaction.
Scheme 1. Comparative analysis of the synthetic possibilities of the IMDAF and IMDAV approaches using the interaction of
furfurylamines (1) and 3-(furyl)allylamines (5) with maleic anhydride as the example.
2. Results and Discussion
The initial compounds, 3-(furyl)allylamines 11, were easily protocoles, NaBH4/MeOH and NaBH4/THF/HCl, were tried.
prepared from furylacroleins 9 and various aliphatic or aromatic
amines via a sequence including condensation and reduction
steps (Scheme 2). For the reduction step two different
Both selectively reduced the C=N bond in azomethines 10, but
NaBH4/MeOH was milder and suitable to use when labile
moieties were present.
Reagents and conditions: (a) when R1 = Ar, ArN2Cl/ H2O/ Me2CO/ CuCl2/ 0 °C → rt; (b) MgSO4/ CH2Cl2, rt or AcONa/ EtOH/ ꢀ;
(c) NaBH4/ MeOH or THF/ rt
Scheme 2. Synthesis of initial 3-(fur-2-yl)allylamines 11.
As a rule, compounds 10 and 11 were not isolated but were
immediately used in the subsequent reaction without any
purification because of the rather low stability of Schiff bases 10
and material / time losses when attampting to isolate pure
substances 11.
expected IMDAV reaction (Scheme 3) proceeded slowly or did
not occur at all. Under harsher conditions, however, new
compounds 14.6 and 14.12 were observed as precipitates after
heating at 80 °C in benzene for 1 h. Thus, these conditions were
chosen as the model conditions for all other cycloaddition
reactions.
Next, compounds 11 were heated in the presence of an
equimolecular amount of maleic anhydride at 65 °C in THF, the
Scheme 3. The domino-sequence leading to target furo[2,3-f]isoindole-4-carboxylic acids 14.

3
The interaction of allylamines 11 with maleic, citraconic or
pyrocinchonic anhydrides proceeded smoothly and led to
cycloadducts 14 after short-term refluxing in benzene (or, in rare
instances, in o-xylene). The yields of compounds 14 presented in
Table 1 are given based on the initial furylacroleins 9. In almost
all cases, the reaction products 14 are crystalline substances and
can be isolated by a simple filtration after cooling the reaction
mixtures to ambient temperature.
(Scheme 3). 1,3-H Shift and successive re-aromatization of the
ACCEPTED MANUSCRIPT
furan ring completes the process. Despite the fact that no
intermediate products 12, 13 can be isolated or observed by the
dynamic NMR, it is possible to conclude that the IMDAV step
proceeds with a high degree of chemo- and diastereoselectivity
based on the spatial structure of the final products 14. In all
cases, a single diastereoisomer corresponding to the exo-
transition state of the intramolecular Diels–Alder reaction was
isolated.
The mechanism of the domino-reaction includes the N-
acylation step followed by spontaneous IMDAV reaction
Table 1. The values of substituents, the reaction conditions and yields of 4H-furo[2,3-f]isoindoles (15) and their 4-carboxylic acids
(14).
Compound
14.1
R1
H
H
H
H
H
H
H
H
R2
Pr
R3
H
H
H
H
H
H
H
H
R4
H
H
H
H
H
H
H
H
Solvent[a]
PhH
PhH
PhH
PhH
PhH
PhH
PhH
Yield, %[b]
60
72
50
70
40
62
40
64
14.2[c]
14.3
i-Pr
Cyclopropyl
Cyclopentyl
Allyl
14.4[c]
14.5[c]
14.6[c]
14.7
Bn
CH2CH2Ph
CH2CH2C6H3-3,4-(OMe)2
14.8
PhH
14.9[c]
14.10
14.11[c]
14.12[c]
14.13
14.14
14.15
14.16
14.17
14.18
14.19
14.20
14.21
14.22
14.23[c]
14.24[c]
14.25
14.26
14.27
14.28[c]
14.29
14.30[c]
14.31
15.1
H
Н
H
H
H
Me
Me
Me
Me
Me
Me
Et
Et
Pr
Ph
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
Me
Me
Me
H
Me
H
H
H
H
H
H
H
H
H
H
PhH
PhH
PhH
PhH
o-C6H4Me2
PhH
PhH
PhH
PhH
PhH
o-C6H4Me2
PhH
PhH
PhH
PhH
PhH
PhH
PhH
64
67
45
27
27
23
82
61
49
64
51
74
53
27
70
75
74
74
63
72
61
69
77
63
72
56
51
50
34
C6H4-4-OMe
Bn
Ph
Bn
Allyl
Bn
Ph
Bn
Ph
Bn
Bn
Bn
Bn
C6H4-2-Cl
C6H4-2-F
C6H4-2-CF3
C6H4-2-CF3
C6H4-3-NO2
C6H3-2-Cl,4-Cl
C6H3-2-Cl,4-Cl
C6H3-2-Cl,4-Cl
C6H3-2-Cl,4-NO2
H
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-F
C6H4-4-OMe
Ph
PhH
PhH
PhH
PhH
Ph
-CH2-(2-THF)
C6H4-2-F
Ph
C6H4-4-OMe
C6H4-4-OMe
C6H4-4-OMe
Bn
PhH
2-Furyl
Ph
C6H2-3,4,5-(OMe)3
Ph
Ph
Ph
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
15.2
15.3
15.4
15.5
H
H
H
Me
Bn
Ph
15.6
Me
[a] All reaction mixtures were heated at reflux for 2–4 h (TLC monitoring). [b] All yields are based on the initial furylacroleins 9 and are given for the
unrecrystallizaded adducts 14. [c] These compounds were mentioned in the preliminary communication6.
When dimethylmaleic anhydride was used as a dienophile,
only exo-adducts 14.13 and 14.19 were obtained. However,
reactions with pyrocinchonic anhydride required a higher
temperature due to the steric hindrance imparted by the methyl
groups in the transition state 12 (R3 = R4 = Me). In boiling
benzene, the reaction proceeded slowly and with a relatively low
yield. The structure of the product 14.19 was unambiguously
established based on its X-ray analysis data (Figure 1).
Acylation of 3-(furyl)allylamines 11 with asymmetric
citraconic anhydride proceeded chemoselectively at the most
sterically accessible carbonyl group resulting in the formation of
diastereoisomers 14.11, 14.12, 14.17, 14.18, and 14.21 (see
Scheme
3,
Table
1,
and
Figure
2).

4
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 1. Molecular structure of (4RS,4aSR,7aRS)-6-benzyl-
2,4,4a-trimethyl-5-oxo-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-
f]isoindole-4-carboxylic acid (14.19).
Weaker dienophiles such as α,β-unsaturated acid chlorides
(e.g., acryloyl, methacryloyl, furylacryloyl, and cinnamoyl
chlorides) can also be involved in the tandem acylation/IMDAV
reaction with vinylfurans 11. Some of these results are presented
in Scheme 4 and Table 1.
Figure 2. Molecular structure of (4RS,4aRS,7aSR)-6-benzyl-
4-methyl-5-oxo-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-
f]isoindole-4-carboxylic acid (14.11) (two independent molecules
forming the quasi-centrosymmetrical H-bonded dimer are
shown).
Scheme 4. Synthesis of furo[2,3-f]isoindoles 15.
solvent for the same transformation, a mixture of solid products
was obtained in a total yield of around 65% (with the content of
the target IMDAV adduct 19 of ~70%). According to the H
NMR spectra, the mixture contained no traces of the IMDAF
adduct 18 (the signals at δ 5.5−6.9 ppm from the olefinic protons
were absent) and afforded product 19 in 22% yield after
fractional crystallization. When a pure sample of compound 18
was heated at reflux for 8 h in benzene, the precipitate of the
isomerization product 19 was isolated in 45% yield.
Dioxane turned out to be a better solvent than benzene
because it avoided the formation of a bulky precipitate of
triethylammonium chloride (which prevents normal refluxing of
the reaction mixture). As in previous cases, the exo-cycloaddition
reaction proceeded stereoselectively with the retention of the
substituent R4 configuration in products 15.1–15.6, which is
confirmed by 1H NMR data (3J4a,4 ~ 8.3–12.7 Hz).
1
Another problem that has been solved in this study was
elucidating the chemoselectivity of the intramolecular Diels–
Alder reaction in the presence of two competing diene centers
(Scheme 5). N-Furfuryl-3-(furyl)allylamine 16, possessing two
furan cycles, seems to be good model compound suitable for this
purpose. Acylation of the nitrogen atom in this compound with
maleic anhydride leads to the intermediate amide 17, which could
not be isolated (the cyclization has been occured at room
temperature). The latter, possessing two diene moieties, furan and
vinylfuran, may undergo IMDAF or IMDAV competitive
reactions. The experiment showed that both ways are possible
depending on the reaction conditions. At room temperature, the
IMDAF adduct 18 was only formed in an average yield (Scheme
5).
It has been previously shown4a,7 that IMDAF reactions of
such type are reversible. Adducts similar to 18 may undergo a
retro Diels–Alder reaction under heating to give maleinamides.
The repeated intramolecular [4+2] cyclization in the intermediate
17 may afford not only epoxyisoindole 18, but also the IMDAV
adduct 19. Obviously, the latter reaction leading to furo[2,3-
f]isoindole 19 is not reversible. Therefore, the IMDAF adduct 18
represents the kinetically controlled product of the cycloaddition
reaction, while the IMDAV adduct 19 is the thermodynamically
controlled product. This mechanistic reasoning was
experimentally confirmed. When boiling benzene was used as a
Scheme 5. An example of competition between IMDAV and
IMDAF reactions.

5
The final piece of this work was connected with the expansion
of the chemical space of the proposed synthetic method for 3-
furylaldehyde, that has allowed to synthesize furo[2,3-
f]isoindole-8-carboxylic acids (23) in a similar way (Scheme 6,
Table 2).
characteristic feature of their 1H NMR spectra is the presence of
ACCEPTED MANUSCRIPT
the doublet signals of furan hydrogen atoms H2/H3 (6.23-6.43
and 7.48-7.58 ppm, for R1=H) with coupling constant J2,3 ~ 1.7-
3
2.1 Hz and the doublet-doublet signal of the H4 (H8 for 23) (at
3.55-3.94 ppm) 3J4,4a(8,7a) ~ 4.8-5.5 and 4J4,7a(8,4a) ~ 0-2.1 Hz.
Figure 3. Molecular structure of (4aRS,7aSR,8SR)-6-(4-
Methoxyphenyl)-7-oxo-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-
f]isoindole-8-carboxylic acid (23.6).
Reagents and conditions: (a) R1-NH2/MgSO4/CH2Cl2, rt, 4 h; (b)
NaBH4/MeOH, rt, 4 h.
Scheme 6. Synthesis of furo[2,3-f]isoindole-8-carboxylic
acids (23).
3. Conclutions
In conclusion, the described sequence allows obtaining furans
annelated with isoindole ring from furans (via furfural and
furylacrolein). The main advantages of the proposed synthetic
approaches are: column free methodology, multiscale synthesis,
no need to purify intermediate compounds, cheap and
commercially available starting materials. Moreover, we believe
that the proposed IMDAV methodology would be a useful
synthetic tool not only in the arsenal of furan chemistry, but of
thiophene and pyrrole chemistry as well.
Table 2. The values of substituents and yields of 4H-
furo[2,3-f]isoindole-8-carboxylic acids (23).
Compound
23.1
R1
Yield, %[a]
Cyclopentyl
53
60
38
70
66
71
23.2
Bn
23.3
CH2CH2C6H3-3,4-(OMe)2
Ph
23.4
4. Experimental Section
23.5
C6H4-4-Cl
All reagents and solvents were purchased from commercial
suppliers (Acros Organics, Aldrich, Alfa Aesar, and AstaTech)
and used without further purification. No reactions require
absolute solvents (CH2Cl2, o-xylene, PhH, EtOH) or an inert
atmosphere.
23.6
C6H4-4-OMe
[a] All yields are given for the unrecrystallizaded adducts 23, based on
the initial 3-(furan-3-yl)acrolein (20).
Thin layer chromatography, when necessary, was carried out
on aluminum backed silica plates Sorbfil. The plates were
visualized under UV light (254 nm) or in I2 vapor. Organic layers
were dried over anhydrous MgSO4 and concentrated in vacuo.
3-Furylaldehyde is easily condensed with acetaldehyde to give
3-(furan-3-yl)acrolein (20). The latter, by a method similar to that
described previously (see Scheme 2), was transformed into 3-
(furan-3-yl)allylamines 21, which was not isolated and purified,
but used directly in the tandem reaction with maleic anhydride.
Short-term boiling in benzene leads to the target adducts 23 in
rather high yields (see Scheme 6 and Figure 3). Obviously, the
reaction proceeds via the exo-transition state 22 and is followed
by the formation of a single diastereoisomer with trans-
orientation of the H-4a and H-7a hydrogen atoms.
As a rule, the precipitates of the final acids 14 and 23 obtained
after cooling of the benzene (o-xylene) reaction solutions are no
need for additional purification. In rare cases, when the
precipitate was not formed after 12 h standing at room
temperature, the solvent was removed in vacuo and the residual
was solidified by addition of ether. The isolation of compound 15
requires extraction and recrystallization of the crude products
after the standard work up. Analytical samples for the new
compounds 14 and 23 were obtained by recrystallization from
EtOAc, EtOH or EtOAc–EtOH, EtOH–DMF mixtures, for
compounds 15 from a hexane–EtOAc mixture. Melting points for
these samples were determined using a Stuart SMP 30 melting
point apparatus using closed end glass capillary tubes and are
uncorrected.
The structure of the product 23.6 was determined by X-ray
diffraction study (Figure 3).
Thereby, the transformation shown on Scheme 6 gives the
furo[2,3-f]isoindole-8-carboxylic acids 23 which are isomeric to
the furoisoindole-4-carboxylic acids 14 (Scheme 3).
In spite of the fact that there are X-Ray data for several
hexahydrofuro[2,3-f]isoindoles 14 (23), we are reporting certain
reference NMR signals and key structural motives of this class of
compounds here. The signals of quaternary C5 (С7 for 23) and
CO2H atoms at 171–178 ppm and secondary С7 (C5) carbons at
43–52 ppm are the most identifiable signals of hexahydro-4H-
furo[2,3-f]isoindoles in their 13C NMR spectra. The most
IR spectra were obtained in KBr pellets using an Infralum FT-
801 IR-Fourier spectrometer. Mass spectra were taken on Kratos
MS-30 (UK) (electron ionization, 70 eV, ion source temperature
200 °C, direct inlet probe) spectrometer, Thermo Focus DSQ II
(electron ionization, 70 eV, ion source temperature 200 °C, gas
chromatographic inlet with Varian FactorFour VF-5ms column)

6
Tetrahedron
or on Agilent 1100 series LC/MSD spectrometer with an API-
atom of the OH-group was localized in the difference-Fourier
ACCEPTED MANUSCRIPT
ES/APCI ionization mode.
map and included in the refinement with fixed positional and
isotropic displacement parameters [Uiso(H) = 1.5Ueq(O)]. The
other hydrogen atoms were placed in calculated positions and
refined within riding model with fixed isotropic displacement
parameters [Uiso(H) = 1.5Ueq(C) for the CH3-groups and
1.2Ueq(C) for the other groups]. The final divergence factors were
R1 = 0.045 for 5145 independent reflections with I > 2σ(I) and
wR2 = 0.126 for all independent reflections, S = 1.033. All
calculations were carried out using the SHELXTL program.10
Detailed X-ray data for racemic furo[2,3-f]isoindole carboxylic
acid 14.19 were published earlier.11
NMR spectra were run in deuterated (> 99 %) solvents on Jeol
JNM-ECA 600 (600.1 MHz for 1H and 150.9 MHz for 13C),
Bruker WH-400 (400 MHz for 1H and 100.6 MHz for 13C),
1
Bruker Avance 500 (500 MHz for H and 125 MHz for 13C) or
Varian Gemini (200 MHz for 1H and 50 MHz for 13C)
spectrometers for 2–8% solutions in CDCl3 or DMSO-d6 at 23–
25 °C using TMS as internal standard. Signals of CO2H groups
are usually absent in the samples recorded in CDCl3.
Microanalyses were performed for C, H, N on a Eurovector
EA 3000 (CHNS) elemental analysis system and were within
±0.4% of theoretical values (the data were obtained in Center for
Collective Use (CCU-PCMR PFUR)).
Starting 3-(furan-2-yl)acroleins 9 were purchased (R1 = H,
Me) or synthesized according to the known procedures from
acetaldehyde and furfurals by the aldol–crotonic condensation
(R1 = H, Me, Et, and Pr) or from 3-(furan-2-yl)acrolein and
aryldiazonium salts via the Meerwein reaction (R1 = Ar).8
3-(Furan-2-yl)acrolein and 3-(5-alkylfuryl)acrolein 9 (R1 = H,
Me, Et, Pr) react smoothly with amines in the presence of
powdered anh. MgSO4 as a dehydrating agent. In case of less
reactive 3-(5-arylfuryl)acroleins 9 (R1 = Ar), AcONa was used as
a catalyst for the condensation step. Shiff bases 10 are rather
unstable products and no attempts were made to isolate them.
Allylamines 11 are much more stable compounds and, probably,
they can be isolated, if necessary. In this work, allylamines were
used in the next step without purification and characterization.
The crystal of 23.6 (CCDC 1430557, C18H17NO5, M = 327.33)
is triclinic, space group P-1, at T = 100 K: a = 8.4900(17) Å, b =
8.9700(18) Å, c = 12.055(2) Å, α = 68.70(3)°, β = 75.20(3)°, γ =
65.43(3)°, V = 772.0(3) Å3, Z = 2, dcalc = 1.408 g/cm3, F(000) =
344, ꢀ = 0.217 mm–1. X-ray diffraction data were collected on the
‘Belok’ beamline (λ = 0.96600 Å) of the National Research
Center ‘Kurchatov Institute’ (Moscow, Russian Federation) using
a MAR CCD detector. A total of 360 images (11902 reflections,
2416 independent reflections, Rint = 0.0845) were collected using
an oscillation range of 1.0° (ϕ scan mode, 2θmax = 72.54°) and
corrected for absorption using the Scala program (Tmin = 0.930;
Tmax = 0.940).12 The data were indexed, integrated and scaled
using the utility iMOSFLM in CCP4 program.[13] The structure
was determined by direct methods and refined by full-matrix
least squares technique on F2 with anisotropic displacement
parameters for non-hydrogen atoms. The hydrogen atom of the
OH-group was localized in the difference-Fourier map and
refined isotropically with fixed isotropic displacement parameters
[Uiso(H) = 1.5Ueq(O)]. The other hydrogen atoms were placed in
calculated positions and refined within riding model with fixed
isotropic displacement parameters [Uiso(H) = 1.5Ueq(C) for the
methyl groups and 1.2Ueq(C) for the other groups]. The final
divergence factors were R1 = 0.0657 for 1856 independent
reflections with I > 2σ(I) and wR2 = 0.1749 for all independent
reflections, S = 1.024. The calculations were carried out using the
SHELXTL program.10
X-ray structure determination
The crystal of 14.11 (CCDC 1048838, C19H19NO4, M =
325.35) is monoclinic, space group P21/n, at T = 100 K: a =
12.9443(6) Å, b = 10.3245(5) Å, c = 24.2257(12) Å, β =
96.413(1)°, V = 3217.3(3) Å3, Z = 8, dcalc = 1.343 g/cm3, F(000)
= 1376, ꢀ = 0.094 mm–1. 49700 total reflections (11779 unique
reflections, Rint = 0.057) were measured on a three-circle Bruker
APEX-II CCD diffractometer (λ(MoKα)-radiation, graphite
monochromator, φ and ω scan mode, 2θmax = 65.4°) and
corrected for absorption (Tmin = 0.966; Tmax = 0.978).9 The
structure was determined by direct methods and refined by full-
matrix least squares technique on F2 with anisotropic
displacement parameters for non-hydrogen atoms. The hydrogen
atoms of the OH-groups were localized in the difference-Fourier
maps and included in the refinement with fixed positional and
isotropic displacement parameters [Uiso(H) = 1.5Ueq(O)]. The
other hydrogen atoms were placed in calculated positions and
refined within riding model with fixed isotropic displacement
parameters [Uiso(H) = 1.2Ueq(C)]. The final divergence factors
were R1 = 0.053 for 7936 independent reflections with I > 2σ(I)
and wR2 = 0.142 for all independent reflections, S = 1.011. All
calculations were carried out using the SHELXTL program.10
3-(Furan-2-yl)acroleins, (E)-3-[5-Aryl-2-furyl]-2-propenals
(9). General Procedure. A solution of sodium nitrite (3.19 g,
46.2 mmol) in H2O (7 mL) was added dropwise to a stirred
mixture of corresponding amine (42 mmol), aqueous HCl (36%,
0.15 mol, 15 mL), and H2O (15 mL) at a temperature below
+5 °C. The cold solution was filtrated and the diazonium salt was
slowly added to a vigorously stirred solution of 3-(fur-2-yl)-
acrolein (5.0 g, 41.0 mmol) and CuCl2·2H2O (0.5 g, 2.9 mmol) in
acetone (35 ml) at room temperature. The rate of addition was
controlled by nitrogen evolution (2–3 bubbles/sec, 0.5–1 h). At
the end of the reaction, after the evolution of nitrogen ceased,
water (100 ml) was added and the solid product was filtered off,
washed with H2O, dried in the air, and recrystallized from
ethanol. If the product did not precipitate after addition of water,
then it was extracted with Et2O (3 × 15 ml). The combined
organic layers were dried (MgSO4) and concentrated. Then
solvent was evaporated and the residue purified by vacuum
distillation.
The crystal of 14.19 (CCDC 1048837, C21H23NO4, M =
353.40) is monoclinic, space group P21/c, at T = 100 K: a =
13.6368(7) Å, b = 11.0657(6) Å, c = 12.8691(7) Å, β =
111.442(1)°, V = 1807.55(17) Å3, Z = 4, dcalc = 1.299 g/cm3,
F(000) = 752, ꢀ = 0.090 mm–1. 28038 total reflections (6655
unique reflections, Rint = 0.043) were measured on a three-circle
Bruker APEX-II CCD diffractometer (λ(MoKα)-radiation,
graphite monochromator, φ and ω scan mode, 2θmax = 65.4°) and
corrected for absorption (Tmin = 0.974; Tmax = 0.982).9 The
structure was determined by direct methods and refined by full-
matrix least squares technique on F2 with anisotropic
displacement parameters for non-hydrogen atoms. The hydrogen
The physicochemical properties for some new furylacroleins
are given below.
(E)-3-[5-(2,4-Dichlorophenyl)-2-furyl]-2-propenal.
Yield:
37 %; yellow powder; mp 150–151 °C; IR (KBr) 1673 (C=O)
cm1; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.65 (1Н, d, J 1,2 = 7.4
Hz, H-1), 7.83 (1H, d, J 5,6 = 8.2 Hz, H-6 C6H3), 7.46 (1H, s, H-3
C6H3), 7.32 (1H, d, J = 8.2 Hz, H-5 C6H3), 7.28–7.19 (2Н, m,
5,6

7
H-4 Furyl and H-3), 6.87 (1Н, d, J 3,4 = 3.9 Hz, H-3 Furyl), 6.67
(1H, dd, J 2,3 = 15.7 Hz, J 2,1 = 7.4 Hz, H-2); 13C NMR (100 MHz,
CDCl3): δ (ppm) 192.5 (C-1), 152.3 (C-2 Furyl), 149.9 (C-5
Furyl), 136.8, 134.5, 131.3, 130.6, 128.9, 127.5, 126.5, 126.3,
118.7 (C-3 Furyl), 114.0 (C-4 Furyl).
followed by Et2O (2 × 10 mL) and dried in air to give title acids
as colorless solids.
ACCEPTED MANUSCRIP
T
Most NMR spectra presented in Supporting Information were
recorded for these unrecrystallized samples. In order to obtain a
satisfactory elemental analysis and correct melting points, all
compounds 14 were recrystallized from the solvents ut infra.
(E)-3-[5-(2-Chloro-4-nitrophenyl)-2-furyl]-2-propenal. Yield:
35 %; light brown powder; mp 161–162 °C; IR (KBr) 1678
1
(C=O) cm-1; H NMR (400 MHz, CDCl3) δ (ppm) 9.70 (1Н, d, J
(4RS,4aRS,7aSR)-6-Propyl-5-oxo-4a,5,6,7,7a,8-hexahydro-
4H-furo[2,3-f]isoindole-4-carboxylic acid (14.1). Yield: 60%;
colorless plates; mp 171-173 °C (EtOAc– EtOH); [Found: C,
64.00; H, 6.32; N, 4.98. C14H17NO4 requires C, 63.87; H, 6.51; N,
1,2 = 7.8 Hz, H-1), 8.35 (1H, s, H-3 C6H3), 8.20 (1H, d, J 5,6 = 8.6
Hz, H-6 C6H3), 8.11 (1H, d, J = 8.6 Hz, H-5 C6H3), 7.52 (1Н,
d, J = 3.5 Hz, H-4 Furyl), 7.29 (1Н, d, J = 15.7 Hz, H-3),
5,6
4,3
3,2
1
5.32%]; IR (KBr) 1739 (CO2H), 1643 (N-C=O) cm-1; H NMR
6.96 (1Н, d, J = 3.5 Hz, H-3 Furyl), 6.75 (1H, dd, J = 15.7
3,4
2,3
Hz, J 2,1 = 7.8 Hz, H-2),; 13C NMR (100 MHz, CDCl3): δ (ppm)
192.4 (C-1), 151.3 (C-2 Furyl), 150.9 (C-4 C6H3), 146.7 (C-5
Furyl), 136.3, 133.3, 130.9, 128.3, 127.5, 126.3, 122.1, 118.5 (C-
3 Furyl), 116.8 (C-4 Furyl).
(600 MHz, DMSO-d6) δ (ppm) 12.34 (1H, br. s, CO2H), 7.48
(1H, d, J 2,3 = 1.8 Hz, H-2), 6.37 (1H, d, J 2,3 = 1.8 Hz, H-3), 3.60
(1H, dd, J 4,7a = 1.8 Hz, J 4a,4 = 5.5 Hz, H-4), 3.44 (1H, dd, J 7a,7B
7.3 Hz, J 7A,7B = 9.2 Hz, H-7B), 3.20–3.05 (3H, m, H-7A, NCH2),
2.98–2.90 (1H, m, H-7a), 2.78 (1H, dd, J 7a,8B = 5.1 Hz, J 8A,8B
=
=
(E)-3-[5-(2-Trifluoromethylphenyl)-2-furyl]-2-propenal.
15.2 Hz, H-8B), 2.50 (1H, dd, J 7a,8A = 11.6 Hz, J 8A,8B = 15.2 Hz,
H-8A), 2.44 (1H, dd, J 4a,4 = 5.5 Hz, J 4a,7a = 12.8 Hz, H-4a), 1.45–
1.40 (2H, m, CH2), 0.79 (3H, t, J = 7.3 Hz, CH3); 13C NMR (150
MHz, DMSO-d6) δ (ppm) 173.0 and 172.8 (CO2, С-5), 151.6 (C-
8a), 142.5 (C-2), 116.4 (C-3a), 111.1 (C-3), 50.0, 47.0 (C-4а, C-
7), 43.8 (NCH), 37.0 (C-4), 33.5 (C-7а), 27.0 (C-8), 20.8 (CH2),
11.7 (CH3); m/z (EI, 70 eV): 263 (2) [M]+, 219 (100), 202 (15),
190 (24), 177 (10), 162 (17), 145 (15), 133 (21), 117 (13), 105
(18), 91 (29), 80 (20), 68 (18), 55 (20), 43 (21).
Yield: 37 %; orange oil; bp 161–163 °C / 2 mm Hg; IR (liquid
film) 1675 (C=O) cm-1; H NMR (400 MHz, CDCl3) δ (ppm)
1
9.43 (1Н, d, J = 7.8 Hz, H-1), 7.80–7.76 (2Н, m, C6H4), 7.62
1,2
(1Н, br. t, J 4,5 = J 4,6 = 7.8 Hz, H-5 C6H4), 7.50 (1Н, d, J 6,5 = 7.8
Hz, H-6 C6H4), 7.24 (1Н, d, J 2,3= 15.7 Hz, H-3), 6.86 (1Н, d, J 3,4
= 3.9 Hz, H-4 Furyl), 6.83 (1Н, d, J 3,4 = 3.9 Hz, H-3 Furyl), 6.67
(1H, dd, J 2,3 = 15.7 Hz, J 1,2 = 7.8 Hz, H-2); 13C NMR (100 MHz,
CDCl3) δ (ppm) 192.9 (C-1), 153.8 (C-2 Furyl), 150.8 (C-5
Furyl), 137.3, 131.9, 130.0, 128.8, 128.2, 126.9 (q, J
Hz, C-2 C6H4), 126.8 (C-2), 126.2, 123.7 (q, J
CF3), 118.5 (C-3 Furyl), 112.9 (C-4 Furyl).
= 31.1
C,F
= 273.6 Hz,
C,F
(4RS,4aRS,7aSR)-5-Oxo-6-(propan-2-yl)-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.2).
Yield: 72%; colorless oblong rhombuses; mp 224.9−225.5 °C
(EtOH–DMF); [Found: C, 64.01; H, 6.35; N, 5.41. C14H17NO4
requires C, 63.87; H, 6.51; N, 5.32]; IR (KBr) 1728 (CO2H),
(E)-3-[5-(2-Chlorophenyl)-2-furyl]-2-propenal. Yeld: 39 %;
orange oil; bp 175-177 °C/ 2mm Hg; IR (liquid film) 1679 (C=O)
cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.65 (1H, d, J 1,2 = 7.8
Hz, H-1), 7.91 (1H, d, J 3,4 = 7.8 Hz, H-3 C6H4), 7.46 (1H, d, J 6,5
= 7.8 Hz, H-6 C6H4), 7.36 (1H, t, J = 7.8 Hz, H-5 C6H4), 7.29-
1
1642 (N-C=O) cm-1; H NMR (600 MHz, DMSO-d6) δ (ppm)
12.31 (1H, br. s, CO2H), 7.52 (1H, d, J = 1.7 Hz, H-2), 6.40
2,3
7.22 (3H, m), 6.89 (1H, d, J = 3.9 Hz, H-3 Furyl), 6.69 (1H,
dd, J 2,3 = 15.7 Hz, J 2,1 = 7,8 Hz, H-2).
3,4
(1H, d, J 2,3 = 1.7 Hz, H-3), 4.15 (1H, sept, J = 7.1 Hz, CH), 3.63
(1H, dd, J 4,7a = 1.7 Hz, J 4a,4 = 5.4 Hz, H-4), 3.51 (1H, dd, J 7a,7B
=
(E)-3-[5-(3-Nitrophenyl)-2-furyl]-2-propenal. Yield: 33 %;
light brown powder; mp 154–155 °C; IR (KBr) 1674 (C=O)
cm1; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.67 (1Н, d, J 1,2 = 7.8
Hz, H-1), 8.52 (1H, s, H-2 C6H4), 8.16 (1Н, d, J 4,5 = 8.0 Hz, H-4
C6H4), 8.03 (1Н, d, J 6,5 = 8.0 Hz, H-6 C6H4), 7.61 (1Н, t, J 5,6 = J
= 8.0 Hz, H-5 C6H4), 7.25 (1Н, d, J = 15.7 Hz, H-3), 6.95
7.1 Hz, J 7A,7B = 8.8 Hz, H-7B), 3.02 (1H, dd, J 7A,7B = 8.8 Hz, J
7a,7A = 10.3 Hz, H-7A), 2.95–2.89 (1H, m, H-7a), 2.84 (1H, dd, J
7a,8B = 5.1 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.51 (1H, dd, J 7a,8A = 11.4
Hz, J 8A,8B = 15.1 Hz, H-8A), 2.45 (1H, dd, J 4a,4 = 5.4 Hz, J 4a,7a
=
12.8 Hz, H-4a), 1.08 (3H, d, J = 7.1 Hz, CH3), 1.06 (3H, d, J =
7.1 Hz, CH3); 13C NMR (150 MHz, DMSO-d6) δ (ppm) 172.9
and 172.0 (CO2, С-5), 151.6 (C-8a), 142.5 (C-2), 116.5 (C-3a),
111.0 (C-3), 47.5 (C-4а), 45.0 (C-7), 42.2 (CH), 37.0 (C-4), 33.5
(C-7а), 27.0 (C-8), 20.4 and 20.0 (2CH3); m/z (EI, 70 eV): 263
(1) [M]+, 219 (100), 204 (42), 176 (20), 160 (10), 133 (22), 119
(10), 102 (33), 91 (17), 81 (19), 77 (25), 65 (15), 56 (48), 42 (43).
4,5
3,2
(1Н, d, J 4,3 = 3.5 Hz, H-4 Furyl), 6.90 (1Н, d, J 3,4 = 3.5 Hz, H-3
Furyl), 6.71 (1H, dd, J = 15.7 Hz, J
= 7.8 Hz, H-2); 13C
2,3
2,1
NMR (100 MHz, CDCl3) δ (ppm) 192.5 (C-1), 154.3 (C-2 Furyl),
151.0 (C-5 Furyl), 148.7 (C-3 C6H4), 136.7, 131.0, 130.0, 129.7,
126.5, 123.0, 119.1, 118.7 (C-3 Furyl), 110.2 (C-4 Furyl).
5-Oxofuro[2,3-f]isoindole-4-carboxylic Acids (14). General
Procedure. Powdered anh. MgSO4 (4.8 g, 40 mmol) was added
to a stirred solution of amine (20 mmol) and the corresponding 3-
(furan-2-yl)acrolein (20 mmol) in CH2Cl2 (50 mL) at r.t. After
approx. 2 h, MgSO4 was filtered off, washed with CH2Cl2 (2 × 15
mL) and the solution was concentrated. The residue was diluted
with MeOH (50 mL for compounds 14.1–14.22, 15.1–15.6) or
THF (50 mL for compounds 14.23–14.31), and then NaBH4 (0.6
g, 15 mmol) was added. The mixtures were vigorously stirred for
24 h at r.t (TLC or GCMS monitoring), then poured into H2O
(200 mL) and extracted with CH2Cl2 (3 × 70 mL). The combined
organic layers were dried (MgSO4) and concentrated. The residue
was diluted with PhH (40 mL) or o-xylene (40 mL for 14.13 and
14.19) and maleic (1.96 g, 20 mmol), citraconic (1.8 mL, 20
mmol) or pyrocinchonic (3,4-dimethylmaleic) (2.52 g, 20 mmol)
anhydride was added. The resulting mixture was refluxed for 2–4
h (TLC monitoring) and then cooled to r.t. The formed
precipitate was filtered off and washed with PhH (2 × 5 mL)
(4RS,4aRS,7aSR)-6-Cyclopropyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.3).
Yield: 50%; colorless rhombuses; mp 200.1−200.2 °C (EtOAc–
EtOH); [Found: C, 64.38; H, 5.89; N, 5.22. C14H15NO4 requires
C, 64.36; H, 5.79; N, 5.36]; IR (KBr) 1732 (CO2H), 1628 (N-
1
C=O) cm-1; H NMR (600 MHz, DMSO-d6) δ (ppm) 12.36 (1H,
br. s, CO2H), 7.52 (1H, d, J 2,3 = 2.1 Hz, H-2), 6.40 (1H, d, J 2,3
=
2.1 Hz, H-3), 3.63 (1H, dd, J 4,7a = 2.1 Hz, J 4a,4 = 5.5 Hz, H-4),
3.38 (1H, dd, J 7a,7B = 7.2 Hz, J 7A,7B = 9.7 Hz, H-7B), 3.07 (1H,
dd, J 7A,7B = 8.9 Hz, J 7a,7A = 9.7 Hz, H-7A), 2.94–2.86 (1H, m, H-
7a), 2.79 (1H, dd, J 7a,8B = 5.5 Hz, J 8A,8B = 15.8 Hz, H-8B), 2.70–
2.67 (1H, m, NCH), 2.50 (1H, br. dd, J 7a,8A = 11.4 Hz, J 8A,8B
=
15.8 Hz, H-8A), 2.46 (1H, dd, J 4a,4 = 5.5 Hz, J 4a,7a = 12.4 Hz, H-
4a), 0.70–0.60 (4H, m, (CH2)2); 13C NMR (150 MHz, DMSO-d6)
δ (ppm) 173.8 and 172.9 (CO2, С-5), 151.5 (C-8a), 142.5 (C-2),
116.4 (C-3a), 111.1 (C-3), 50.0, 47.6 (C-4а, C-7), 37.0 (C-4),
33.3 (C-7а), 27.0 (C-8), 25.8 (NCH), 5.3 and 4.6 ((CH2)2); m/z
(APCI) 262 [M + H]+.

8
Tetrahedron
ACCEPTED MANUSCRIPT
(4RS,4aRS,7aSR)-6-Cyclopentyl-5-oxo-4a,5,6,7,7a,8-
(4RS,4aRS,7aRS)-5-Oxo-6-(2-phenylethyl)-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.4).
Yield: 70%; white plates; mp 215.5−216.5 °C (EtOH–DMF);
[Found: C, 66.58; H, 6.74; N, 5.00. C16H19NO4 requires C,
66.42; H, 6.62; N, 4.84]; IR (KBr) 1726 (CO2H), 1649 (N-
C=O) cm-1; 1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.4 (1H,
br. s, CO2H), 7.52 (1H, d, J 2,3 = 1.8 Hz, H-2), 6.40 (1H, d, J 2,3
= 1.8 Hz, H-3), 4.15 (1H, pent, J = 7.7 Hz, NCH), 3.64 (1H,
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.7).
Yield: 40%; colorless plates; mp 148 °C (EtOH–DMF); [Found:
C, 69.98; H, 5.98; N, 4.45. C19H19NO4 requires C, 70.14; H, 5.89;
N, 4.31]; IR (KBr) 1726 (CO2H), 1653 (N-C=O) cm-1; H NMR
1
(600 MHz, DMSO-d6) δ (ppm) 12.40 (1H, br. s, CO2H), 7.52
(1H, d, J = 1.7 Hz, H-2), 7.31–7.20 (5H, m, C6H5), 6.41 (1H,
d, J 2,3 = 1.7 Hz, H-3), 3.63 (1H, dd, J 4,7a = 1.6 Hz, J 4a,4 = 5.8 Hz,
2,3
dd, J 4,7a = 1.5 Hz, J 4a,4 = 5.5 Hz, H-4), 3.50 (1H, dd, J 7a,7B
=
H-4), 3.49–3.35 (3H, m, H-7B, NCH2), 3.12 (1H, dd, J
=
7a,7A
7.3 Hz, J 7A,7B = 8.8 Hz, H-7B), 3.08 (1H, dd, J 7A,7B = 8.8 Hz, J
7a,7A = 10.2 Hz, H-7A), 2.96–2.89 (1H, m, H-7a), 2.82 (1H, dd,
10.0 Hz, J 7A,7B = 9.3 Hz, H-7A), 2.99–2.91 (1H, m, H-7а), 2.81–
2.74 (3H, m, H-8B, CH2), 2.48 (1H, dd, J 7a,8A = 11.6 Hz, J 8A,8B
=
J 7a,8B = 5.1 Hz, J 8A,8B = 15.2 Hz, H-8B), 2.52 (1H, dd, J 7a,8A
=
14.9 Hz, H-8A), 2.43 (1H, dd, J 4a,4 = 5.8 Hz, J 4a,7a = 13.2 Hz, H-
4a); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 172.4, 172.1 (CO2,
С-5), 151.0 (C-8a), 142.0 (C-2), 139.1 (C-1 C6H5), 128.7 (2C,
C6H5), 128.4 (2C, C6H5), 126.2 (C-4 C6H5), 115.9 (C-3a), 110.4
(C-3), 50.2 (NCH2), 46.5 (C-4а), 43.6 (C-7), 36.5 (C-4), 33.3,
33.0 (C-7а, CH2), 26.5 (C-8); m/z (EI, 70 eV) 267 (100) [M-44]+,
281 (100), 234 (70), 190 (60), 145 (16), 131 (66), 118 (21), 106
(51), 99 (32), 91 (65), 76 (60), 68 (87), 54 (83), 45 (48).
11.4 Hz, J 8A,8B = 15.2 Hz, H-8A), 2.45 (1H, dd, J 4a,4 = 5.5 Hz,
J 4a,7a = 12.5 Hz, H-4a), 1.73−1.47 (8H, m, (CH2)4); 13C NMR
(100 MHz, DMSO-d6) δ (ppm) 172.3, 171.9 (CO2, С-5), 151.1
(C-8a), 141.9 (C-2), 115.9 (C-3a), 110.5 (C-3), 51.6 (CH), 46.9
(C-4a), 45.6 (C-7), 36.5 (C-4), 32.9 (C-7a), 28.9 ((CH2)2),
28.4, 26.5 (C-8), 24.0 and 23.9 ((CH2)2); m/z (EI, 70 eV) 289
(1) [M]+, 245 (100), 228 (10), 216 (19), 177 (23), 133 (19),
118 (16), 106 (18), 91 (32), 81 (16), 67 (19), 55 (32), 42 (49).
(4RS,4aRS,7aSR)-6-[2-(3,4-Dimethoxyphenyl)ethyl]-5-oxo-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.8). Yield: 64%; colorless plates; mp 188–189 °C
(EtOH–DMF); [Found: C, 65.65; H, 5.97; N, 3.71. C21H23NO6:
C, 65.44; H, 6.02; N, 3.63]; IR (KBr) 1777 (CO2H), 1724 (N-
(4RS,4aRS,7aSR)-6-Allyl-5-oxo-4a,5,6,7,7a,8-hexahydro-4H-
furo[2,3-f]isoindole-4-carboxylic acid (14.5). Yield: 40%;
colorless needles; mp 186.9−187.5 °C (EtOAc); [Found: C,
64.21; H, 5.83; N, 5.37. C14H15NO4 requires C, 64.36; H, 5.79; N,
1
5.36]; IR (KBr) 1720 (CO2H), 1652 (N-C=O) cm-1; H NMR
1
C=O) cm-1; H NMR (600 MHz, DMSO-d6) δ (ppm) 12.39 (1H,
(600 MHz, DMSO-d6) δ (ppm) 12.39 (1H, br. s, CO2H), 7.52
(1H, d, J 2,3 = 1.6 Hz, H-2), 6.42 (1H, d, J 2,3 = 1.6 Hz, H-3), 5.73
br. s, CO2H), 7.52 (1H d, J 2,3 = 2.1 Hz, H-2), 6.85 (1H, d, J 5,6
=
8.3 Hz, H-6 C6H3), 6.84 (1H, d, J 2,5 = 1.7 Hz, H-2 C6H3), 6.75
(1H, dd, J 2,5 = 1.7 Hz, J 5,6 = 8.3 Hz, H-5 C6H3), 6.41 (1H, d, J 2,3
= 2.1 Hz, H-3), 3.74 (3H, s, OCH3), 3.71 (3H, s, OCH3), 3.65
(1H, dd, J 4,7a = 2.1 Hz, J 4a,4 = 4.8 Hz, H-4), 3.47–3.35 (3H, m,
H-7B, NCH2), 3.11 (1H, t, J 7a,7A = J 7A,7B = 9.6 Hz, H-7A), 2.99–
2.92 (1H, m, H-7а), 2.79 (1H, dd, J 7a,8B = 4.8 Hz, J 8A,8B = 15.1
(1H, ddt, J = 5.5 Hz, J
= 10.3 Hz, J
= 17.2 Hz,
cisCH2,CH
transCH2,CH
CH Allyl), 5.20 (1H, br. dd, J cisCH2,transCH2 = 1.6 Hz, J transCH2,CH
17.2 Hz, trans CH2 Allyl), 5.14 (1H, br. dd, J cisCH2,transCH2 = 1.6
Hz, J = 10.3 Hz, cis CH2 Allyl), 3.83 (2H, br. d, J = 5.5
=
cisCH2,CH
Hz, NCH2), 3.67 (1H, dd, J 4,7a = 2.1 Hz, J 4a,4 = 5.5 Hz, H-4),
3.43 (1H, dd, J 7a,7B = 6.9 Hz, J 7A,7B = 9.6 Hz, H-7B), 3.02 (1H, t,
J 7A,7B = J 7a,7A = 9.6 Hz, H-7A), 3.04–2.97 (1H, m, H-7a), 2.84
(1H, dd, J 7a,8B = 4.8 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.57−2.50 (2H,
m, H-4a, H-8A); 13C NMR (150 MHz, DMSO-d6) δ (ppm) 172.9,
172.7 (CO2, С-5), 151.6 (C-8a), 142.6 (C-2), 133.6 (CH), 117.2
(CH2), 116.4 (C-3a), 111.1 (C-3), 50.0 (NCH2), 46.8 (C-4а), 44.8
(C-7), 37.0 (C-4), 33.5 (C-7а), 27.0 (C-8); m/z (EI, 70 eV) 261
(5) [M]+, 234 (5), 217 (76), 201 (44), 188 (23), 175 (43), 161
(12), 147 (22), 133 (100), 120 (57), 107 (30), 95 (57), 81 (28), 70
(54), 55 (19), 42 (32).
Hz, H-8B), 2.72–2.66 (2H, m, CH2), 2.48 (1H, dd, J
= 11.0
7a,8A
Hz, J 8A,8B = 15.1 Hz, H-8A), 2.42 (1H, dd, J 4a,4 = 4.8 Hz, J 4a,7a
=
12.4 Hz, H-4a); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 172.4,
172.1 (CO2, С-5), 151.0, 148.7, 147.3 (C-3 C6H3, C-4 C6H3, C-
8a), 142.0 (C-2), 131.6 (C-1 C6H3), 120.5 (C-6 C6H3), 115.9 (C-
3a), 112.5, 111.9, 110.5 (C-3, C-2 C6H3, C-5 C6H3), 55.4
(2OCH3), 50.3 (NCH2), 46.5 (C-4а), 43.8 (C-7), 36.5 (C-4), 33.0
(2C, C-7а, CH2), 26.5 (C-8); m/z (EI, 70 eV) 385 (3) [M]+, 324
(7), 293 (11), 264 (15), 197 (15), 178 (18), 164 (100), 151 (16),
108 (16), 80 (28), 59 (26), 43 (38).
(4RS,4aRS,7aSR)-6-Benzyl-5-oxo-4a,5,6,7,7a,8-hexahydro-
4H-furo[2,3-f]isoindole-4-carboxylic acid (14.6). Yield: 62%;
colorless plates; mp 212−214 °C (EtOAc–EtOH); [Found: C,
69.38; H, 5.59; N, 4.67. C18H17NO4 requires C, 69.44; H, 5.50; N,
(4RS,4aRS,7aSR)-5-Oxo-6-phenyl-4a,5,6,7,7a,8-hexahydro-
4H-furo[2,3-f]isoindole-4-carboxylic acid (14.9). Yield: 64%;
light brown crystals; mp 251−252 °C (EtOH–DMF); [Found: C,
68.83; H, 5.21; N, 4.58. C17H15NO4 requires C, 68.68; H, 5.09; N,
1
4.50]; IR (KBr) 1735 (CO2H), 1642 (N-C=O) cm-1; H NMR
1
4.71]; IR (KBr): 1732 (CO2H), 1674 (N-C=O) cm-1; H NMR
(600 MHz, DMSO-d6) δ (ppm) 12.46 (1H, br. s, CO2H), 7.52
(200 MHz, CDCl3) δ (ppm) 12.58 (1H, br. s, CO2H), 7.66 (2H,
(1H, d, J = 1.4 Hz, H-2), 7.35–7.26 (5H, m, C6H5), 6.43 (1H,
br. d, J 3(5),2(6) = 7.8 Hz, H-2 and H-6 C6H5), 7.56 (1H, d, J
=
2,3
2,3
d, J 2,3 = 1.4 Hz, H-3), 4.47 (1H, d, J A,B = 15.1 Hz, NCH2), 4.37
(1H, d, J A,B = 15.1 Hz, NCH2), 3.71 (1H, d, J 4,4a = 5.5 Hz, H-4),
3.37 (1H, dd, J 7a,7B = 6.8 Hz, J 7A,7B = 8.9 Hz, H-7B), 3.10 (1H,
dd, J 7a,7A = 10.3 Hz, J 7A,7B = 8.9 Hz, H-7A), 3.02 (1H, m, H-7а),
2.78 (1H, dd, J 7a,8B = 4.8 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.58 (1H,
1.4 Hz, H-2), 7.38 (2H, br. t, J 3(5),2(6) = J
H-5 C6H5), 7.12 (1H, t, J 4,3(5) = 7.8 Hz, H-4 C6H5), 6.47 (1H, d, J
= 7.8 Hz, H-3 and
3(5),4
= 1.4 Hz, H-3), 3.98 (1H, dd, J 7a,7B = 7.8 Hz, J 7A,7B = 9.8 Hz,
2,3
H-7B), 3.78 (1H, d, J
= 5.1 Hz, H-4), 3.69 (1H, dd, J
=
4,4a
7a,7A
8.2 Hz, J
= 9.8 Hz, H-7A), 3.15–3.07 (1H, m, H-7а), 2.92
7A,7B
dd, J 4a,4 = 5.5 Hz, J 4a,7a = 12.4 Hz, H-4a), 2.51 (1H, dd, J 7a,8A
=
(1H, dd, J 7a,8B = 4.7 Hz, J 8A,8B = 14.9 Hz, H-8B), 2.80 (1H, dd, J
11.7 Hz, J 8A,8B = 15.1 Hz, H-8A); 13C NMR (100 MHz, DMSO-
d6) δ (ppm) 178.1 and 172.5 (CO2 and С-5), 151.1 (C-8a), 142.0
(C-2), 137.2 (C-1 C6H5), 128.5 (2C, C-2 and C-6 C6H5), 127.4
(2C, C-3 and C-5 C6H5), 127.1 (C-4 C6H5), 115.8 (C-3a), 110.5
(C-3), 49.4 (NCH2), 46.2 (C-4а), 45.4 (C-7), 36.6 (C-4), 33.2 (C-
7а), 26.4 (C-8); m/z (EI, 70 eV) 267 (100) [M-44]+, 250 (12), 238
(10), 176 (14), 146 (10), 131 (22), 118 (33), 108 (15), 95 (40), 91
(93), 77 (25), 65 (17), 58 (13), 42 (40), 33 (31).
= 5.1 Hz, J
= 12.9 Hz, H-4a), 2.63 (1H, dd, J 7a,8A = 11.3
4a,4
4a,7a
Hz, J
= 14.9 Hz, H-8A); 13C NMR (50 MHz, CDCl3) δ
8A,8B
(ppm) 172.5, 172.2 (CO2, С-5), 150.9 (C-8a), 142.2 (C-2), 139.8
(C-1 C6H5), 128.7 (2C, C-3, C-5 C6H5), 123.7 (C-4 C6H5), 118.9
(2C, C-2 and C-6 C6H5), 115.8 (C-3a), 110.6 (C-3), 51.1 (C-4а),
47.6 (C-7), 36.8 (C-4), 32.2 (C-7а), 26.5 (C-8); m/z (APCI) 298
[M + H] +.
(4RS,4aRS,7aSR)-6-(4-Methoxyphenyl)-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.10).

9
7.22 (5H, m, C6H5), 6.43 (1H, d, J 2,3 = 1.9 Hz, H-3), 4.56 (1H,
Yield: 67 %; white plates; mp 232–233 °C (EtOH–DMF);
ACCEPTED MANUSCRIP
T
d, J A,B = 15.3 Hz, NCH2), 4.34 (1H, d, J
= 15.3 Hz, NCH2),
= 8.9 Hz, H-7B), 3.12-3.07
[Found: C, 65.93; H, 5.15; N, 4.17. C18H17NO5 requires C, 66.05;
A,B
1
H, 5.23; N, 4.28]; 1736 (CO2H), 1652 (N-C=O) cm-1; H NMR
3.18 (1H, dd, J 7a,7B = 7.4 Hz, J
7A,7B
(1H, m, H-7a), 3.02 (1H, dd, J 7a,7A = 10.3 Hz, J 7A,7B = 8.9 Hz, H-
7A), 2.61 (1H, dd, J 7a,8B = 4.9 Hz, J 8A,8B = 16.1 Hz, H-8B), 2.37
(1H, dd, J 7a,8A = 11.9 Hz, J 8A,8B = 16.1 Hz, H-8A), 1.58 (3H, s,
CH3), 0.82 (3H, s, CH3); 13C NMR (151 MHz, DMSO-d6) δ
(ppm) 177.2, 175.5 (CO2, С-5), 150.0 (C-8a), 142.5 (С-2), 138.0
(C-1 C6H5), 129.0 (2C, C6H5), 128.0 (2C, C6H5), 127.7 (C-4
C6H5), 121.9 (C-3a), 110.6 (C-3), 47.14, 45.6 (C-7 and NCH2),
47.1 and 46.8 (C-4 and C-4a), 36.8 (C-7а), 22.7 (C-8), 19.3
(CH3), 12.1 (CH3); m/z (EI, 70 eV) 339 (2) [M]+, 295 (61), 280
(98), 202 (8), 159 (18), 147 (10), 118 (15), 91 (100), 65 (20), 58
(23), 42 (61).
(200 MHz, DMSO): δ (ppm) 12.44 (1H, br. s, CO2H), 7.49 (1H,
d, J = 2.0 Hz, H-2), 7.53 (2H, br.d, J 2(6),3(5) = 9.3 Hz, C6H4),
2,3
6.94 (2H, br. d, J 2(6),3(5) = 9.3 Hz, C6H4), 6.43 (1H, d, J = 2.0
2,3
Hz, H-3), 3.93 (1H, dd, J 7A,7B = 9.0 Hz, J 7a,7B = 7.3 Hz, H-7B),
3.75 (3H, s, OCH3), 3.74 (1H, dd, J = 1.0 Hz, J
= 5.4 Hz, H-
4,4a
4), 3.67 (1H, t, J 7A,7B = J 7A,7a = 9.0 Hz, H-7A), 3.21-3.04 (1H, m,
H-7a), 2.88 (1H, dd, J 8A,8B = 14.9 Hz, J = 4.9 Hz, H-8B),
7a,8B
2.75 (1H, dd, J 4a,7a = 12.7 Hz, J 4,4a = 5.4 Hz, H-4a), 2.62 (1Н, br.
dd, J = 14.9 Hz, J
= 10.2 Hz, H-8A); 13C NMR (50
8A,8B
7a,8A
MHz, DMSO-d6) δ (ppm) 172.4, 171.7 (CO2, С-5), 155.5 (C-4
C6H4), 150.9 (C-8a), 142.1 (C-2), 133.0 (C-1 C6H4), 120.6 (2C,
C-2, C-6 C6H4), 115.8 (C-3a), 113.8 (2C, C-3 and C-5 C6H4),
110.6 (C-3), 55.2 (CH3O), 51.4 (C-4а), 47.4 (C-7), 36.7 (C-4),
32.3 (C-7а), 26.4 (C-8); m/z (APCI) 328 [M + H]+.
(4RS,4aRS,7aSR)-6-Allyl-2-methyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.14).
Yield: 23%; colorless needles; mp 191–193 °C (EtOAc); [Found:
C, 65.28; H, 6.13; N, 4.95. C15H17NO4 requires C, 65.44; H, 6.22;
(4RS,4aRS,7aSR)-6-Benzyl-4-methyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.11).
Yield: 45%; colorless prisms; mp 227–229 °C (EtOAc–EtOH);
[Found: C, 69.83; H, 5.95; N, 4.47. C19H19NO4 requires C, 70.14;
H, 5.89; N, 4.31]; IR (KBr) 1727 (CO2H), 1636 (N-C=O) cm-1;
1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.42 (1H, br. s, CO2H),
7.46 (1H, d, J 2,3 = 2.0 Hz, H-2), 7.33-7.22 (5H, m, H C6H5), 6.43
(1H, d, J 2,3 = 2.0 Hz, H-3), 4.43 (1H, d, J A,B = 15.2 Hz, NCH2),
1
N, 5.09]; IR (KBr) 1736 (CO2H), 1643 (N-C=O) cm-1; H NMR
(600 MHz, DMSO-d6) δ (ppm) 12.31 (1H, br. s, CO2H), 5.98
(1H, s, H-3), 5.72-5.66 (1H, m, CH Allyl), 5.15 (1H, dd, J
cisCH2,transCH2 = 1.3 Hz, J transCH2,CH = 17.2 Hz, transCH2 Allyl), 5.11
(1H, dd, J
= 1.3 Hz, J
= 10.2 Hz, cisCH2
cisCH2,transCH2
cis CH2,CH
Allyl), 3.78 (2H, br. d, J = 4.7 Hz, NCH2), 3.55 (1H, dd, J
=
4,7a
1.4 Hz, J 4a,4 = 5.3 Hz, H-4), 3.38 (1H, dd, J 7a,7B = 7.7 Hz, J 7A,7B
= 8.8 Hz, H-7B), 3.11 (1H, dd, J
H-7A), 2.97-2.92 (1H, m, H-7a), 2.72 (1H, dd, J
= 8.8 Hz, J
= 9.9 Hz,
= 4.8 Hz,
4.30 (1H, d, J A,B = 15.2 Hz, NCH2), 3.29 (1H, dd, J
Hz, J 7A,7B = 8.8 Hz, H-7B), 3.02 (1H, dd, J 7A,7B = 8.8 Hz, J 7a,7A
= 7.3
7A,7B
7a,7A
7a,7B
7a,8B
J8A,8B = 15.4 Hz, H-8B), 2.47-2.43 (2H, m, H-4a, H-8A), 2.17
(3H, s, CH3); 13C NMR (151 MHz, DMSO-d6) δ (ppm) 173.0,
172.7 (CO2, C-5), 151.0 (C-8a), 149.7 (C-2), 133.6 (С-2 Allyl),
117.2 (C-3 Allyl), 116.8 (C-3a), 107.0 (C-3), 50.1 (C-7 and C-1
Allyl), 46.8 (C-4a), 44.7, 37.1 (C-4), 33.5 (C-7а), 27.0 (C-8),
13.8 (CH3); m/z (EI, 70 eV) 275 (2) [M]+, 231 (100), 214 (12),
189 (11), 135 (9), 131 (13), 110 (14), 106 (22), 95 (12), 91 (15),
70 (12), 42 (24).
= 10.3 Hz, H-7A), 2.99-2.91 (1H, m, H-7a), 2.73 (1H, dd, J
7a,8B
= 4.8 Hz, J
= 15.4 Hz, H-8B), 2.50-2.46 (1H, m, H-8A),
8A,8B
2.29 (1H, d, J 4a,7a = 12.5 Hz, H-4a), 1.61 (3H, s, CH3); 13C NMR
(150 MHz, DMSO-d6) δ (ppm) 175.0, 173.2 (CO2, С-5), 150.7
(C-8a), 142.6 (C-2), 137.8 (C-1 C6H5), 129.1 (2C, C6H5), 128.0
(2C, C6H5), 127.7 (C-4 C6H5), 123.0 (C-3a), 109.7 (C-3), 52.7
(C-4a), 49.5 and 45.8 (C-7 and NCH2), 42.3 (C-4), 34.7 (C-7a),
27.0 (C-8), 24.7 (CH3); m/z (EI, 70 eV) 281 (100) [M-44]+, 266
(22), 264 (23), 190 (8), 145 (11), 133 (18), 119 (12), 106 (16), 92
(29), 91 (83), 77 (12), 65 (15), 42 (39).
(4RS,4aRS,7aSR)-6-Benzyl-2-methyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.15).
Yield: 82%; thin colorless multibranch dendrite; mp 178.5–179
°C (EtOAc–EtOH); [Found: C, 69.91; H, 5.59; N, 4.13.
C19H19NO4 requires C, 70.14; H, 5.89; N, 4.31]; IR (KBr) 1735
(4RS,4aRS,7aSR)-4-Methyl-5-oxo-6-phenyl-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.12).
Yield: 27%; thin colorless needles; mp 238–240 °C (EtOH–
DMF); [Found: C, 69.21; H, 5.28; N, 4.30. C18H17NO4 requires
C, 69.44; H, 5.50; N, 4.50]; IR (KBr) 1729 (CO2H), 1655 (N-
1
(CO2H), 1640 (N-C=O) cm-1; H NMR (600 MHz, CDCl3) δ
(ppm) 7.30–7.20 (5H, m, H C6H5), 6.04 (1H, s, H-3), 4.49 (1H, d,
J A,B = 15.1 Hz, NCH2), 4.44 (1H, d, J A,B = 15.1 Hz, NCH2), 3.94
1
C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm) 7.61 (2H,
(1H, dd, J 4,7a = 1.4 Hz, J 4a,4 = 4.8 Hz, H-4), 3.36 (1H, dd, J 7a,7B
6.2 Hz, J 7A,7B = 8.2 Hz, H-7B), 3.06–2.98 (2H, m, H-7a, H-7A),
2.72 (1H, dd, J 7a,8B = 4.1 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.51 (1H,
=
dd, J 2(6),4 = 0.9 Hz, J 2(6),3(5) = 8.7 Hz, H-2 and H-6 C6H5), 7.50
(1H, d, J 2,3 = 2.0 Hz, H-2), 7.34 (2H, dd, J 4,3(5) = 7.3 Hz, J 2(6),3(5)
= 8.7 Hz, H-3 and H-5 C6H5), 7.08 (1H, t, J 4,3(5) = 7.3 Hz, H-4
C6H5), 6.45 (1H, d, J 2,3 = 2.0 Hz, H-3), 3.91 (1H, dd, J 7a,7B = 7.3
dd, J 4a,4 = 4.8 Hz, J 4a,7a = 13.1 Hz, H-4a), 2.39 (1H, dd, J 7a,8A
=
10.3 Hz, J 8A,8B = 15.1 Hz, H-8A), 2.18 (3H, s, CH3); 13C NMR
(100 MHz, DMSO-d6) δ (ppm) 173.2, 173.1 (CO2, C-5), 151.0
(C-8a), 149.7 (C-2), 137.7 (C-1 C6H5), 129.1 (2C, C-2, C-6
C6H5), 128.0 (2C, C-3, C-5 C C6H5), 127.7 (C-4 C6H5), 116.8 (C-
3a), 107.1 (C-3), 50.0, 46.7, 45.9 (C-4a, C-7, NCH2), 37.1 (C-4),
33.6 (C-7a), 26.9 (C-8), 13.8 (CH3); m/z (APCI) 326.1 [M + H]+.
Hz, J 7A,7B = 9.0 Hz, H-7B), 3.61 (1H, dd, J 7A,7B = 9.0 Hz, J 7a,7A
10.5 Hz, H-7A), 3.10–3.01 (1H, m, H-7a), 2.86 (1H, dd, J 7a,8B
=
=
5.0 Hz, J 8A,8B = 15.5 Hz, H-8B), 2.60 (1H, dd, J 7a,8A = 11.5 Hz, J
8A,8B = 15.5 Hz, H-8A), 2.55 (1H, d, J 4a,7a = 12.8 Hz, H-4a), 1.62
(3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ (ppm) 178.7, 172.3
(CO2, С-5), 149.9 (C-8a), 142.3 (C-2), 139.6 (C-1 C6H5), 128.9
(2C, C-3, C-5 C6H5), 124.5 (C-4 C6H5), 119.9 (2C, C-2, C-6
C6H5), 120.0 (C-3a), 109.3 (C-3), 54.4 (C-4a), 51.7 (C-7), 43.1
(C-4), 33.7 (C-7a), 27.4 (C-8), 24.4 (CH3); m/z (APCI): 312.2 [M
+ H]+.
(4RS,4aRS,7aSR)-2-Methyl-5-oxo-6-phenyl-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.16).
Yield: 61%; thin colorless multibranch dendrite; mp 234–235 °C
(EtOH–DMF); [Found: C, 69.66; H, 5.32; N, 4.71. C18H17NO4
requires C, 69.44; H, 5.50; N, 4.50]; IR (KBr) 1729 (CO2H),
(4RS,4aSR,7aRS)-6-Benzyl-4,4a-dimethyl-5-oxo-
1
1659 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm)
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.13). Yield: 27%; colorless needles; mp 246–248 °C
(EtOAc–EtOH); [Found: C, 70.85; H, 6.13; N, 4.01. C20H21NO4
requires C, 70.78; H, 6.24; N, 4.13]; IR (KBr) 1731 (CO2H),
12.47 (br. s, 1 H, CO2H), 7.61 (2H, dd, J 2(6),4 = 0.9 Hz, J 2(6),3(5)
8.7 Hz, H-2 and H-6 C6H5), 7.34 (2H, dd, J 3(5),4 = 7.3 Hz, J 2(6),3(5)
= 8.7 Hz, H-3 and H-5 C6H5), 7.08 (1H, t, J 4,3(5) = 7.3 Hz, H-4
=
1
1625 (N-C=O) cm-1; H NMR (600 MHz, DMSO-d6) δ (ppm)
C6H5), 6.02 (1H, s, H-3), 3.94 (1H, dd, J 7a,7B = 7.3 Hz, J 7A,7B
=
8.7 Hz, H-7B), 3.68–3.63 (2H, m, H-7A), 3.10–3.00 (1H, m, H-
12.44 (1H, br. s, CO2H), 7.46 (1H, d, J = 1.9 Hz, H-2), 7.31-
2,3

10
Tetrahedron
7a), 2.82 (1H, dd, J 7a,8B = 5.0 Hz, J 8A,8B = 15.1 Hz, H-8B),
70 eV) 309 (27) [M-44]+, 294 (100), 173 (18), 159 (9), 145 (10),
ACCEPTED MANUSCRIPT
2.74 (1H, dd, J 4a,4 = 5.5 Hz, J 4a,7a = 12.8 Hz, H-4a), 2.51 (1H, dd,
131 (9), 118 (10), 107 (10), 91 (47), 77 (9), 59 (15), 42 (23).
J
7a,8A = 11.4 Hz, J 8A,8B = 15.1 Hz, H-8A), 2.19 (3H, s, CH3); 13
C
(4RS,4aRS,7aRS)-6-Benzyl-2-ethyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.20).
Yield: 74%; colorless plates; mp 219–221 °C (EtOAc); [Found:
C, 70.62; H, 6.15; N, 4.29. C20H21NO4 requires C, 70.78; H, 6.24;
NMR (100 MHz, DMSO-d6) δ (ppm) 172.5, 172.3 (CO2, C-5),
150.7, 148.9 (C-2, C-8a), 139.8 (C-1 C6H5), 128.7 (2C, C-3, C-5
C6H5), 123.6 (C-4 C6H5), 118.9 (2C, C-2, C-6 C6H5), 116.2 (C-
3a), 106.5 (C-3), 51.1 (C-7), 47.6 (C-4a), 36.8 (C-4), 32.1 (C-7a),
26.4 (C-8), 13.3 (CH3); m/z (APCI) = 312.2 [M+ H]+.
N, 4.13]; IR (KBr) 1731 (CO2H), 1643 (N-C=O) cm-1; H NMR
1
(600 MHz, DMSO-d6) δ (ppm) 12.38 (1H, br. s, CO2H), 7.32–
7.22 (5H, m, C6H5), 6.00 (1H, s, H-3), 4.42 (1H, d, J A,B = 15.1
Hz, NCH2), 4.33 (1H, d, J A,B = 15.1 Hz, NCH2), 3.61 (1H, dd, J
4,7a = 1.4 Hz, J 4a,4 = 5.5 Hz, H-4), 3.32 (1H, dd, J 7a,7B = 6.9 Hz, J
7A,7B = 8.9 Hz, H-7B), 3.05 (1H, dd, J 7a,7A = 10.3 Hz, J 7A,7B = 8.9
Hz, H-7A), 3.00–2.92 (1H, m, H-7a), 2.69 (1H, dd, J 7a,8B = 4.8
Hz, J 8A,8B = 15.1 Hz, H-8B), 2.53–2.42 (4H, m, CH2, H-4a, H-
8A), 1.18 (3H, t, J = 7.6 Hz, CH3); 13C NMR (151 MHz, DMSO-
d6) δ (ppm) 173.14, 173.11 (CO2, C-5), 156.6, 149.6 (C-2, C-8a),
137.7 (C-1 C6H5), 129.1 (2C, C-2, C-6 C6H5), 128.0 (2C, C-3, C-
5 C6H5), 127.7 (C-4 C6H5), 116.6 (C-3a), 105.6 (C-3), 50.0, 46.7,
45.9 (C-4a, C-7, NCH2), 37.2 (C-4), 33.6 (C-7a), 26.9 (C-8), 21.4
(CH2), 12.6 (CH3); m/z (EI, 70 eV) 295 (98) [M-44]+, 278 (15),
238 (9), 204 (9), 161 (10), 122 (15), 91 (100), 65 (13), 55 (11),
42 (17).
(4RS,4aRS,7aSR)-6-Benzyl-2,4-dimethyl-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.17).
Yield: 49%; white powder; mp 226–228 °C (EtOAc–EtOH);
[Found: C, 70.63; H, 6.10; N, 3.89. C20H21NO4 requires C, 70.78;
H, 6.24; N, 4.13]; IR (KBr) 1726 (CO2H), 1646 (N-C=O) cm-1;
1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.37 (1H, br. s, CO2H),
7.33–7.22 (5H, m, C6H5), 6.03 (1H, s, H-3), 4.42 (1H, d, J
=
A,B
14.9 Hz, NCH2), 4.29 (1H, d, J A,B = 14.9 Hz, NCH2), 3.29 (1H,
dd, J 7a,7B = 7.4 Hz, J 7A,7B = 9.1 Hz, H-7B), 3.00 (1H, dd, J 7A,7B
9.1 Hz, J = 9.9 Hz, H-7A), 2.96-2.88 (1H, m, H-7a), 2.66
=
7a,7A
(1H, dd, J 7a,8B = 4.9 Hz, J 8A,8B = 15.7 Hz, H-8B), 2.42 (1H, dd, J
= 11.6 Hz, J = 15.7 Hz, H-8A), 2.23 (1H, d, J
=
4a,7a
7a,8A
8A,8B
12.4 Hz, H-4a), 2.16 (3H, s, CH3), 1.57 (3H, s, CH3); 13C NMR
(151 MHz, DMSO-d6) δ (ppm) 175.1, 173.2 (CO2, C-5), 151.0,
148.7 (C-2, C-8a), 137.8 (C-1 C6H5), 129.0 (2C, C6H5), 128.0
(2C, C6H5), 127.7 (C-4 C6H5), 123.4 (C-3a), 105.6 (C-3), 52.7,
49.5, 45.7, 42.3 (C-4, C-4а, C-7, NCH2), 34.7 (C-7a), 26.9 (C-8),
24.7 (CH3), 13.9 (CH3); m/z (EI, 70 eV) 295 (100) [M-44]+, 280
(24), 278 (18), 252 (8), 204 (9), 174 (11), 147 (17), 133 (14), 122
(24), 119 (19), 105 (17), 95 (13), 91 (89), 90 (41), 65 (16).
(4RS,4aRS,7aSR)-6-Benzyl-2-ethyl-4-methyl-5-oxo-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.21). Yield: 53%; colorless dendrites; mp 221–224 °C
(EtOAc); [Found: C, 71.44; H, 6.55; N, 3.82. C21H23NO4 requires
C, 71.37; H, 6.56; N, 3.96]; IR (KBr) 1723 (CO2H), 1629 (N-
1
C=O) cm-1; H NMR (600 MHz, DMSO-d6) δ (ppm) 12.37 (1H,
(4RS,4aRS,7aSR)-2,4-Dimethyl-5-oxo-6-phenyl-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.18).
Yield: 64%; thin transparent needles; mp 220 °C (EtOH);
[Found: C, 70.31; H, 6.08; N, 4.50. C19H19NO4 requires C, 70.14;
H, 5.89; N, 4.31]; IR (KBr) 1730 (CO2H), 1655 (N-C=O) cm-1;
1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.40 (1H, s, CO2H),
7.61 (2H, d, J 2(6),3(5) = 8.2 Hz, H-2 and H-6 C6H5), 7.31 (2H, br. t,
br. s, CO2H), 7.32–7.21 (5H, m, H C6H5), 6.03 (1H, s, H-3), 4.43
(1H, d, J
= 15.1 Hz, NCH2), 4.29 (1H, d, J
= 15.1 Hz,
A,B
A,B
NCH2A), 3.29 (1H, dd, J
= 6.9 Hz, J
= 8.2 Hz, H-7B),
7a,7B
7A,7B
3.00 (1H, dd, J 7A,7B = 8.2 Hz, J 7a,7A = 10.3 Hz, H-7A), 2.97−2.90
(1H, m, H-7a), 2.66 (1H, dd, J 7a,8B = 4.8 Hz, J 8A,8B = 15.1 Hz, H-
8B), 2.50 (2H, q, J = 7.6 Hz, CH2), 2.42 (1H, dd, J
= 11.0
7a,8A
Hz, J 8A,8B = 15.1 Hz, H-8A), 2.23 (1H d, J 4a,7a = 12.0 Hz, H-4a),
1.60 (3H, s, CH3), 1.09 (3H, t, J = 7.6 Hz, CH3); 13C NMR (151
MHz, DMSO-d6) δ (ppm) 175.1, 173.2 (CO2, C-5), 156.6, 148.7
(C-2, C-8a), 137.8 (C-1 C6H5), 129.0 (2C, C6H5), 128.0 (2C,
C6H5), 127.7 (C-4 C6H5), 123.2 (C-3a), 104.1 (C-3), 52.7, 49.5,
45.8, 42.4 (C-4, C-4а, C-7, NCH2), 34.7 (C-7a), 27.0 (C-8), 24.7
(CH3), 21.4 (CH2), 12.6 (CH2-CH3); m/z (EI, 70 eV) 309 (100)
[M-44]+, 294 (48), 252 (10), 173 (8), 161 (12), 133 (13), 111
(18), 91 (86), 58 (34), 42 (64), 33 (74).
J 3(5),2(6) = J 3(5),4 = 8.2 Hz, H-3 and H-5 C6H5), 7.06 (1H, t, J 4,3(5)
=
8.2 Hz, H-4 C6H5), 6.03 (1H, s, H-3), 3.87 (1H, dd, J 7a,7B = 7.6
Hz, J 7A,7B = 8.9 Hz, H-7B), 3.58 (1H, dd, J 7A,7B = 8.9 Hz, J 7a,7A
10.3 Hz, H-7A), 3.04–2.96 (1H, m, H-7a), 2.77 (1H, dd, J 7a,8B
=
=
4.8 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.54 (1H, dd, J 7a,8A = 11.7 Hz, J
8A,8B = 15.1 Hz, H-8A), 2.47 (1H, d, J 4a,7a = 13.1 Hz, H-4a), 2.16
(3H, s, CH3), 1.57 (3H, s, CH3); 13C NMR (100 MHz, DMSO-d6)
δ (ppm) 175.1, 173.0 (CO2, C-5), 151.2, 148.4 (C-2, C-8a), 140.4
(C-1 C6H5), 129.2 (2С, C-3, C-5 C6H5), 124.1 (C-4 C6H5), 123.4
(C-3a), 119.5 (2C, C-2, C-6 C6H5), 105.6 (C-3), 53.9, 51.1 (C-4a,
C-7), 42.6 (C-4), 33.7 (C-7a), 26.9 (C-8), 24.7 (CH3), 13.9 (CH3);
m/z (APCI) 326.1 [M + H]+.
(4RS,4aRS,7aSR)-6-Benzyl-5-oxo-2-propyl-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (14.22).
Yield: 27%; white powder; mp 203–205 °C (EtOAc/EtOH);
[Found: C, 71.24; H, 6.31; N, 4.00. C21H23NO4 requires C, 71.37;
H, 6.56; N, 3.96]; IR (KBr) 1731 (CO2H), 1640 (N-C=O) cm-1;
1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.36 (1H, br. s, CO2H),
(4RS,4aSR,7aRS)-6-Benzyl-2,4,4a-trimethyl-5-oxo-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.19). Yield: 51%; colorless prisms; mp 227–229 °C
(EtOAc–EtOH); [Found: C, 71.21; H, 6.72; N, 4.12. C21H23NO4
requires C, 71.37; H, 6.56; N, 3.96]; IR (KBr) 1730 (CO2H),
1626 (N-C=O) cm-1; 1H NMR (600 MHz, CDCl3) δ (ppm)
7.33−7.26 (5H, m, C6H5), 6.03 (1H, d, J 3,CH3 = 1.0 Hz, H-3), 4.56
7.31–7.22 (5H, m, C6H5), 6.00 (1H, s, H-3), 4.42 (1H, d, J A,B
=
15.1 Hz, NCH2), 4.33 (1H, d, J A,B = 15.1 Hz, NCH2), 3.61 (1H,
dd, J 4,7a = 2.1 Hz, J 4a,4 = 5.5 Hz, H-4), 3.31 (1H, dd, J 7a,7B = 7.6
Hz, J 7A,7B = 8.9 Hz, H-7B), 3.05 (1H, dd, J 7a,7A = 10.3 Hz, J 7A,7B
= 8.9 Hz, H-7A), 3.00–2.92 (1H, m, H-7a), 2.69 (1H, dd, J 7a,8B
=
(1H, d, J
= 14.8 Hz, NCH2), 4.34 (1H, d, J
= 14.8 Hz,
4.8 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.50 (1H, dd, J 4,4a = 5.5 Hz, J
A,B
A,B
NCH2), 3.23 (1H, dd, J 7a,7B = 6.2 Hz, J
= 7.9 Hz, H-7B),
= 13.1 Hz, H-4a), 2.48–2.46 (2H, m, CH2), 2.43 (1H, dd, J
7A,7B
4a,7a
3.06−3.01 (2H, m, H-7a, H-7A), 2.58 (1H, dd, J 7a,8B = 4.5 Hz, J
= 15.5 Hz, H-8B), 2.37 (1H, dd, J 7a,8A = 11.3 Hz, J
= 11.0 Hz, J
= 15.1 Hz, H-8A), 1.52 (2H, seq, J = 7.6
7a,8A
8A,8B
=
8A,8B
Hz, CH2), 0.86 (3H, t, J = 7.6 Hz, CH3); 13C NMR (151 MHz,
DMSO-d6) δ (ppm) 173.17, 173.11 (CO2, C-5), 155.2, 149.7 (C-
2, C-8a), 137.7 (C-1 C6H5), 129.1 (2C, C6H5), 128.0 (2C, C6H5),
127.7 (C-4 C6H5), 116.6 (C-3a), 106.3 (C-3), 50.0, 46.7, 45.9 (C-
4a, C-7, NCH2), 37.2 (C-4), 33.7 (C-7a), 30.0 (CH2), 26.9 (C-8),
21.4 (CH2), 14.2 (CH3); m/z (EI, 70 eV) 309 (55) [M-44]+, 280
8A,8B
15.5 Hz, H-8A), 2.23 (3H, s, CH3), 1.77 (3H, s, CH3), 1.01 (3H,
s, CH3); 13C NMR (151 MHz, CDCl3) δ (ppm) 179.5, 178.1
(CO2, C-5), 151.5 (C-8a), 147.3 (C-2), 137.0 (C-1 C6H5), 128.7
(2C, C6H5), 128.1 (2C, C6H5), 127.5 (C-4 C6H5), 121.5 (C-3a),
105.9 (C-3), 47.9, 47.4, 47.2, 46.3 (C-4, C-4a, C-7, NCH2), 36.8
(C-7a), 22.8 (C-8), 18.9 (CH3), 13.8 (CH3), 11.7 (CH3); m/z (EI,

11
(10), 238 (7), 218 (50), 161 (21), 136 (12), 105 (9), 91 (100),
77 (11), 65 (9).
d, J C,F = 22.5 Hz, C-3, C-5 С6Н4F), 110.0 (C-3), 51.7 (C-4а),
ACCEPTED MANUSCRIPT
47.6 (C-7), 37.2 (C-4), 32.5 (C-7а), 26.9 (C-8); m/z (APCI): 460
[М+H]+.
(4RS,4aRS,7aSR)-6-(4-Methoxyphenyl)-5-oxo-2-(2-
chlorophenyl)-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-
4-carboxylic acid (14.23). Yield: 70 %; white needles; mp 234–
235 °C (EtOH/DMF); [Found: C, 65.96; H, 4.32; N, 3.43.
C24H20ClNO5 requires C, 65.83; H, 4.60; N, 3.20]; IR (KBr) 1748
(4RS,4aRS,7aSR)-6-(4-Methoxyphenyl)-5-oxo-2-[2-
(trifluoromethyl)phenyl]-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-
f]isoindole-4-carboxylic acid (14.26). Yield: 74%; white needles;
mp 250–251 °C (EtOH/DMF); [Found: C, 63.46; H, 4.06; N,
2.73. C25H20F3NO5 requires C, 63.69; H, 4.28; N, 2.97]; IR (KBr)
1754 (CO2H), 1663 (N-C=O) cm-1; 1H NMR (200 MHz, DMSO-
d6) δ (ppm) 12.62 (1H, br. s, CO2H), 7.84–7.80 (2H, m, H-Ar),
7.72 (1H, t, J = 7.8 Hz, С6Н4СF3), 7.59–7.54 (3Н, m, H-Ar), 6.95
1
(CO2H), 1646 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ
(ppm) 12.62 (1H, br.s, CO2H), 7.81 (1H, d, J = 7.8 Hz, C6Н4Cl),
7.58–7.52 (3H, m, H-Ar), 7.42 (1H, t, J = 7.8 Hz, C6Н4Cl), 7.31
(1H, t, J = 7.8 Hz, C6Н4Cl), 7.13 (1H, s, H-3), 6.95 (2H, d, J
2(6),3(5) = 9.0 Hz, C-3 and C-5 C6Н4ОCН3), 3.95 (1H, br. t, J = 8.6
(2H, d, J
= 9.0 Hz, С6Н4ОСН3), 6.82 (1H, s, H-3), 3.95
2(6),3(5)
Hz, H-7B), 3.85 (1H, br. d, J
CН3O), 3.70 (1H, br. t, J = 8.6 Hz, H-7A), 3.17–3.10 (1H, m, H-
7а), 3.01 (1H, dd, J 7a,8B = 5.1 Hz, J 8A,8B = 15.1 Hz, H-8B), 2.83
= 5.5 Hz, H-4), 3.74 (3H, s,
(1H, br. t, J = 8.6 Hz, H-7B), 3.85 (1H, d, J 4,4a = 5.1 Hz, H-4),
3.74 (3H, s, ОСН3), 3.70 (1H, br. t, J = 8.6 Hz, H-7A), 3.17–3.12
(1H, m, H-7а), 2.99 (1H, dd, J 7a,8B = 4.7 Hz, J 8A,8B = 15.3 Hz, H-
4,4a
(1H, dd, J
= 5.5 Hz, J
= 12.9 Hz, H-4a), 2.73 (1H, dd, J
8B), 2.85 (1H, dd, J
= 5.1 Hz, J
= 12.9 Hz, H-4a), 2.73
4a,4
4a,7a
4a,4
4a,7a
= 12.5 Hz, J
= 15.1 Hz, H-8A); 13C NMR (50 MHz,
(1H, dd, J 7a,8A = 12.5 Hz, J 8A,8B = 15.3 Hz, H-8A); 13C NMR (50
MHz, DMSO-d6) δ (ppm) 172.3, 171.6 (CO2, C-5), 155.6, 152.3,
148.9, 133.1, 132.8, 129.7, 128.7, 128.4, 126.8 (Ar), 124.5 (q, J
7a,8A
8A,8B
DMSO-d6) δ (ppm) 172.2, 171.5 (CO2, C-5), 155.5, 151.5, 148.3,
133.0, 130.7, 128.6, 128.2, 127.6, 127.4 (Ar), 121.2, 120.6 (2C,
C6H4OCH3), 118.0, 113.8 (2C, C6H4OCH3), 111.7, 55.2 (CH3O),
51.4 (C-4а), 47.2 (C-7), 36.8 (C-4), 32.1 (C-7а), 26.5 (C-8); m/z
(APCI) 438 [М + H, 35Cl]+, 440 [М + H, 37Cl]+.
= 30.5 Hz, C-2 C6H4CF3), 124.1 (q, J
= 280 Hz, CF3),
C,F
C,F
120.6 (2C, C-2, C-6, C6H4OCH3), 118.0, 113.8 (2C, C-3, C-5,
C6H4OCH3), 111.0, 55.2 (CH3O), 51.4 (C-4а), 47.2 (C-7), 36.8
(C-4), 32.2 (C-7а), 26.5 (C-8); m/z (APCI) 472 [М + H]+.
(4RS,4aRS,7aSR)-6-(4-Methoxyphenyl)-5-oxo-2-(2-
fluorophenyl)-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-
4-carboxylic acid (14.24). Yield: 75 %; light-brown powder; mp
258–259 °C (EtOH/DMF); [Found: C, 68.59; H, 4.93; N, 3.48.
C24H20FNO5 requires C, 68.40; H, 4.78; N, 3.32]; IR (KBr) 1734
(4RS,4aRS,7aSR)-6-Phenyl-5-oxo-2-(3-nitrophenyl)-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.27). Yield: 63 %; brown powder; mp 285–286 °C
(EtOH/DMF); [Found: C, 65.91; H, 4.22; N, 6.52. C23H18N2O6
requires C, 66.03; H, 4.34; N, 6.70]; IR (KBr) 1698 br (C=O) cm-
1
(CO2H), 1648 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ
1
1; H NMR (500 MHz, DMSO-d6) δ (ppm) 12.69 (1H, br. s,
(ppm) 12.64 (1H, br. s, CO2H), 7.76 (1H, t, J = 7.4 Hz, С6Н4F),
7.56 (2H, d, J 2(6),3(5) = 9.0 Hz, С6Н4ОСН3), 7.36–7.26 (3H, m, H-
С6Н4F), 6.95 (2H, d, J 2(6),3(5) = 9 Hz, C6H4OCH3), 6.83 (1H, s, H-
3), 3.95 (1H, br. t, J = 8.8 Hz, H-7B), 3.84 (1H, d, J 4,4a = 4.7 Hz,
H-4), 3.74 (3H, s, СН3O), 3.70 (1H, br. t, J = 8.8 Hz, H-7A),
CO2H), 8.42 (1H, br. dd, J
= 1.5 Hz, J
= 2.3 Hz, H-2
2,4
2,6
C6H4NO2), 8.15 (1H, ddd, J 4,6 = 0.9 Hz, J 2,4 = 1.5 Hz, J 4,5 = 8.0
Hz, H-4 C6H4NO2), 8.10 (1H, ddd, J 4,6 = 0.9 Hz, J 2,6 = 2.3 Hz, J
5,6 = 8.0 Hz, H-6 C6H4NO2), 7.70 (1H, t, J 4,5 = J 5,6 = 8.0 Hz, H-5
C6H4NO2), 7.66 (2H, dd, J 2(6),4 = 1.1 Hz, J 2(5),3(6) = 8.6 Hz, H-2
and H-6 C6H5), 7.38 (2H, br. dd, J 3(5),4 = 7.4 Hz, J 2(5),3(6) = 8.6 Hz,
H-3 and H-5 C6H5), 7.25 (1H, s, H-3), 7.13 (1H, br. t, J 4,3(5) = 7.4
3.14–3.09 (1H, m, H-7а), 3.01 (1H, dd, J 7a,8B = 2.7 Hz, J 8A,8B
15.3 Hz, H-8B), 2.82 (1H, dd, J 4a,4 = 4.7 Hz, J 4a,7a = 12.5 Hz, H-
4a), 2.73 (1H, dd, J 7a,8A = 12.1 Hz, J 8A,8B = 15.3 Hz, H-8A); 13
NMR (50 MHz, DMSO-d6) δ (ppm) 174.6, 172.5 (CO2, C-5),
156.5 (C-4 C6H4OMe), 154.4 (d, J = 213 Hz, C-2 C6H4F),
=
C
Hz, H-4 Ph), 4.04 (1H, dd, J
= 7.4 Hz, J 7A,7B = 9.0 Hz, H-
7B,7a
7B), 3.85 (1H, dd, J 4,7a = 1.4 Hz, J 4,4a = 5.2 Hz, H-4), 3.75 (1H,
dd, J = 9.0 Hz, J = 10.3 Hz, H-7A), 3.20–3.13 (1H, m,
C,F
152.3 and 147.4 (C-2, C-5), 134.0 (C-1 C6H4OMe), 129.8 (Ar),
126.2 (d, J C,F = 25.5 Hz, C-1 C6H4F), 125.7 (Ar), 121.6 (2 C, C-2
and C-6 C6H4OCH3), 119.2 (Ar), 117.8, 116.2 (d, J C,F = 23.2 Hz,
C-3 C6H4F), 114.7 (2C, C-3, C-5 C6H4OCH3), 111.8 (C-3), 56.1
(CH3O), 52.3 (C-4а), 48.1 (C-7), 37.2 (C-4), 33.1 (C-7а), 27.4
(C-8); m/z (APCI) 422 [М + H]+.
7A,7B
7a,7A
H-7а), 3.07 (1H, dd, J 7a,8B = 5.1 Hz, J 8A,8B = 15.7 Hz, H-8B),
2.90 (1H, dd, J
ddd, J = 1.5 Hz, J 7a,8A = 11.5 Hz, J
= 5.2 Hz, J
= 13.0 Hz, H-4a), 2.78 (1H,
4,4a
4a,7a
= 15.7 Hz, H-8A); 13C
8A,8B
NMR (126 MHz, DMSO-d6) δ (ppm) 172.2, 172.0 (CO2, C-5),
152.4, 149.9, 148.5 (Ar), 139.8 (C-1 C6H5), 131.7, 130.6 (Ar),
129.3, 128.7 (2C, C-3, C-5 C6H5), 123.7 (C-4 C6H5), 121.6 (Ar),
118.9 (2C, C-2, C-6 C6H5), 118.6, 117.1 (Ar), 109.1 (C-3), 51.0
(C-4а), 47.3 (C-7), 36.8 (C-4), 31.9 (C-7а), 26.6 (C-8); m/z
(APCI) 419 [М+H]+.
(4RS,4aRS,7aSR)-6-(4-Fluorophenyl)-5-oxo-2-[2-
(trifluoromethyl)phenyl]-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-
f]isoindole-4-carboxylic acid (14.25). Yield: 74%; white powder;
mp 262–263 °C (EtOH/DMF); [Found: C, 62.59; H, 3.62; N,
3.13. C24H17F4NO4 requires C, 62.75; H, 3.73; N, 3.05]; IR (KBr)
1721 (CO2H), 1644 (N-C=O) cm-1; 1H NMR (500 MHz, DMSO-
d6) δ (ppm) 12.66 (1H, br. s, CO2H), 7.85 (1H, d, J = 8.2 Hz, H-3
С6Н4CF3), 7.82 (1H, d, J = 8.2 Hz, H-6 С6Н4CF3), 7.74 (1H, t, J
= 7.8 Hz, H-4 С6Н4CF3), 7.69 (2H, dd, J H,F = 4.9 Hz, J H,H = 8.7
Hz, С6Н4F), 7.57 (1H, t, J = 7.6 Hz, H-5 С6Н4CF3), 7.23 (2H, br.
t, J = 8.8 Hz, С6Н4F), 6.82 (1H, s, H-3), 4.01 (1H, br. t, J = 8.0
(4RS,4aRS,7aSR)-5-Oxo-6-phenyl-2-(2,4-dichlorophenyl)-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.28). Yield: 72 %; white powder; mp 247–248 °C
(EtOH/DMF); [Found: C, 62.63; H, 3.58; N, 3.30. C23H17Cl2NO4
requires C, 62.46; H, 3.87; N, 3.17]; IR (KBr) 1730 (CO2H),
1
1647 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm)
12.68 (1H, br. s, CO2H), 7.83 (1H, d, J = 8.6 Hz, H-6 C6H3),
5,6
Hz, H-7B), 3.86 (1H, d, J
8.0 Hz, H-7A), 3.20–3.08 (1H, m, H-7а), 3.00 (1H, dd, J 7a,8B
= 5.6 Hz, H-4), 3.75 (1H, br. t, J =
7.72 (1H, d, J 3,5 = 2.0 Hz, H-3 C6H3), 7.66 (2H, d, J 2(6),3(5) = 7.8
Hz, H-2, H-6 C6H5), 7.51 (1H, dd, J = 8.6 Hz, J = 2.0 Hz,
4,4a
=
5,6
3,5
5.2 Hz, J 8A,8B = 15.6 Hz, H-8B), 2.91 (1H, dd, J = 5.6 Hz, J
H-5 C6H3), 7.39 (2H, t, J 3(5),4 = J 3(5),2(6) = 7.8 Hz, H-3, H-5 C6H5),
7.16 (1H, s, H-3), 7.13 (1H, t, J 4,3(5) = 7.4 Hz, H-4 C6H5), 4.02
4a,4
4a,7a = 13.9 Hz, H-4a), 2.74 (1H, dd, J 7a,8A = 4.3 Hz, J 8A,8B = 15.6
Hz, H-8A); 13C NMR (125 MHz, DMSO-d6) δ (ppm) 172.4,
172.2 (CO2, C-5), 158.8 (d, J C,F = 238.8 Hz, C-4 С6Н4F), 152.7,
(1H, br. t, J 7A,7B = J 7a,7B = 8.8 Hz, H-7B), 3.87 (1H, br. d, J 4,4a
=
5.1 Hz, H-4), 3.74 (1H, br. t, J = J = 8.8 Hz, H-7A),
7A,7B
7a,7A
149.4, 136.7, 133.3, 130.3, 128.9, 127.2 (Ar), 126.5 (q, J
=
3.18–3.11 (1H, m, H-7а), 3.03 (1H, dd, J 7a,8B = 4.7 Hz, J 8A,8B =
C,F
271.2 Hz, CF3), 125.1 (q, J
= 30.0 Hz, C-2 С6Н4CF3), 121.3
15.3 Hz, H-8B), 2.89 (1H, dd, J 4a,4 = 5.1 Hz, J 4a,7a = 12.9 Hz, H-
C,F
(2C, d, J
= 8.8 Hz, C-2, C-6 С6Н4F), 118.4 (C-4), 115.8 (2C,
4a), 2.75 (1H, dd, J 7a,8A = 11.3 Hz, J 8A,8B = 15.3 Hz, H-8A); 13C
C,F

12
Tetrahedron
NMR (50 MHz, DMSO-d6) δ (ppm) 172.1, 172.0 (CO2, C-5),
Hz, H-4 C6H5), 3.99 (1H, dd, J 7B,7a = 7.8 Hz, J 7A,7B = 9.4 Hz, H-
ACCEPTED MANUSCRIPT
151.9 (C-8a), 147.4 (C-2), 139.7 (C-1 C6H5), 132.1, 130.1 (Ar),
129.3, 128.7 (2C, C-3, C-5 C6H5), 128.5, 127.8, 127.2 (Ar),
123.6, 118.9 (2C, C-2, C-6 C6H5), 118.2 (C-3a), 112.2 (C-3),
51.0 (C-4а), 47.3 (C-7), 36.8 (C-4), 32.0 (C-7а), 26.4 (C-8); m/z
(APCI) 442 [М + H, 35Сl + 35Сl]+, 444 [М + H, 35Сl + 37Сl]+, 446
[М + H, 37Сl + 37Сl]+.
7B), 3.91 (1H, d, J 4,4a = 4.5 Hz, H-4), 3.70 (1H, br. t, J 7A,7B = J
= 9.4 Hz, H-7A), 3.15–3.09 (1H, m, H-7а), 3.04 (1H, dd, J
7a,7A
7a,8B = 5.1 Hz, J 8A,8B = 14.8 Hz, H-8B), 2.83 (1H, dd, J
= 4.5
4a,4
Hz, J 4a,7a = 12.9 Hz, H-4a), 2.75 (1H, dd, J 7a,8A = 11.7 Hz, J 8A,8B
= 14.8 Hz, H-8A); 13C NMR (50 MHz, DMSO-d6) δ (ppm)
171.9, 171.8 (CO2, C-5), 153.8 (C-8a), 146.8 (C-2, C-4 C6H3),
145.4, 139.7 (C-4 C6H5), 133.4 (Ar), 128.7 (2C, C-3, C-5 C6H5),
128.3 (Ar), 127.3, 125.9, 123.7, 122.5, 119.1 (C-3a), 118.8 (2C,
C-2, C-6 C6H5), 115.4 (C-3), 51.0 (C-4а), 47.2 (C-7), 36.8 (C-4),
31.9 (C-7а), 26.6 (C-8); m/z (APCI) 453 [М + H, 35Сl]+, 455 [М
+ H, 37Сl]+.
(4RS,4aRS,7aSR)-2-(2,4-Dichlorophenyl)-5-oxo-6-[tetrahydro-
2-furanylmethyl]-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-
4-carboxylic acid (14.29). Yield: 61%; mixture of diastereoisomers
A/B ~ 1/3, white powder; mp 250–251 °C (EtOH/DMF); [Found:
C, 58.77; H, 4.86; N, 3.02. C22H21Cl2NO5 requires C, 58.68; H,
4.70; N, 3.11]; IR (KBr) 1728 (CO2H), 1633 (N-C=O) cm-1; All
data are given for the mixture of isomers. The most part of the
4,4a,6,7,7a,8-Hexahydro-5H-furo[2,3-f]isoindol-5-one (15).
General Procedure. The solution of 3-(furan-2-yl)acryloyl or
cinnamoyl chloride (3.0 mmol) in dioxane (5 mL) was added to
the mixture of the corresponding allylamine 11 (~ 3.0 mmol) and
triethylamine (0.44 mL, 3.1 mmol) in dioxane (10 mL). The
resulting mixture was heated at reflux for 4 h (TLC and GCMS
monitoring), cooled to r.t, diluted with water (50 mL), and
extracted with ethyl acetate (3 × 50 mL). The extract was dried
over MgSO4 and concentrated in vacuo. The residue solidified on
standing and further recrystallization from hexane–EtOAc or
1
signals of the minor and the major isomers are overlapped in H
NMR spectra. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 12.48 (1H,
br. s, CO2H), 7.80 (1Н, d, J 5,6 = 8.6 Hz, H-6 С6Н3 ), 7.71 (1Н, d, J
3,5 = 2.0 Hz, H-3 С6Н3), 7.50 (1Н, dd, J 3,5 = 2.0 Hz, J 5,6 = 8.6 Hz,
H-5 С6Н3), 7.12 (1Н, s, H-3), 3.96–3.91 (1H, m, H-2 THF), 3.78–
3.74 (2Н, m, H-5 THF), 3.41–3.15 (5Н, m, H-4, H-7 and NCH2),
3.05–2.96 (1Н, m, H-7a), 2.91 (1H, dd, J 7a,8B = 5.1 Hz, J 8A,8B = 15.8
Hz, H-8B), 2.64 (1H, br. dd, J 7a,8A = 11.4 Hz, J 8A,8B = 15.8 Hz, H-
8A), 2.54 (1H, dd, J 4a,4 = 5.3 Hz, J 4a,7a = 12.8 Hz, H-4a), 1.89–1.74
(3Н, m, H-3,4 THF – isomer B), 1.57–1.49 (1Н, m, H-3,4 THF –
isomer A); 13C NMR (126 MHz, DMSO-d6) mixture of the isomers
A and B, δ (ppm) 172.36, 172.33 (CO2, C-5), 172.15, 172.1,
152.19 and 152.22 (C-8a), 147.3 (C-2), 132.1 (C6H3), 130.1, 129.3,
128.5, 127.8, 127.2, 118.36 (C-3a), 118.34, 112.2 (C-3), 77.5 (C-2
THF), 76.8, 76.4 (C-5 THF), 76.1, 51.6, 50.8 (NCH2, C-7, C-4а),
46.1, 46.0, 45.9, 45.8, 36.6 (C-4), 36.5, 33.1 (C-7а), 33.0, 28.6 (C-
3 THF), 28.3, 26.5 (C-8), 25.2 (C-4 THF), 25.1; m/z (APCI) 450
[М+H, 35Сl + 35Сl]+, 452 [М+H, 35Сl + 37Сl]+, 454 [М+1, 37Сl +
37Сl]+.
EtOH−DMF
furoisoindolones 15 as white crystals.
mixtures
afforded
the
corresponding
(4RS,4aSR,7aRS)-4-(2-Furyl)-6-(4-methoxyphenyl)-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindol-5-one
(15.1).
Yield: 63%; light-brown powder; mp 177–178 °C (EtOH/DMF);
[Found: C, 72.03; H, 5.37; N, 4.20. C21H19NO4 requires C, 72.19;
H, 5.48; N, 4.01]; IR (KBr) 1702 (N-C=O) cm-1; H NMR (200
1
MHz, DMSO-d6) δ (ppm) 7.62 (1H, dd, J 4,5 = 1.8 Hz, J 3,5 = 0.7
Hz, H-5 Furyl), 7.56 (2H, br. d, J
С6Н4), 7.54 (1H, d, J 2,3 = 1.7 Hz, H-2), 6.93 (2H, br. d, J 2(6),3(5)
9.0 Hz, H-3 and H-5 С6Н4), 6.42 (1H, dd, J = 1.8 Hz, J
= 9.0 Hz, H-2 and H-6
2(6),3(5)
=
=
4,5
3,4
(4RS,4aRS,7aSR)-2-(2,4-Dichlorophenyl)-6-(2-fluorophenyl)-
5-oxo-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-
3.2 Hz, H-4 Furyl), 6.32 (1H, br. d, J
= 3.2 Hz, H-3 Furyl),
3,4
6.23 (1H, d, J 2,3 = 1.7 Hz, H-3), 4.10 (1H, br.d, J 4,4a = 10.1 Hz,
H-4), 3.87–3.75 (2Н, m, H-7), 3.73 (3Н, s, ОСН3), 3.06–2.88
(2Н, m, H-8), 2.90–2.54 (2Н, m, H-7a and H-4a); 13C NMR (50
MHz, CDCl3) δ (ppm) 172.2 (C-5), 155.7 (Ar), 154.6, 149.5,
142.2, 142.1, 132.8, 121.0 (2C, C-2, C-6 C6H4), 119.4 (Ar), 113.8
(2С, C-3, C-5 C6H4), 110.4 (Ar), 109.9, 105.6, 55.2 (CH3O), 50.9
(C-7), 44.9 (C-4a), 41.4 (C-4), 36.4 (C-7a), 23.9 (C-8); m/z
(APCI) 350 [М + H]+.
carboxylic acid (14.30). Yield: 69%; white powder; mp 293–294
°C (EtOH/DMF); [Found: C, 59.83; H, 3.67; N, 2.90.
C23H16Cl2FNO4 requires C, 60.02; H, 3.50; N, 3.04]; IR (KBr)
1729 (CO2H), 1664 (N-C=O) cm-1; 1H NMR (200 MHz, DMSO-
d6) δ (ppm) 7.81 (1H, d, J 5,6 = 8.9 Hz, H-6 С6Н3), 7.70 (1H, d, J
= 2.0 Hz, H-3 С6Н3), 7.51–7.42 (2H, m, Ar), 7.34–7.20 (3H,
3,5
m, Ar), 7.16 (1H, s, H-3), 3.93–3.86 (2H, m, H-4, H-7B), 3.76
(1H, br. t, J 7A,7a = J 7A,7B = 9.8 Hz, H-7A), 3.20–3.13 (1H, m, H-
7а), 2.99 (1H, dd, J 7a,8B = 4.7 Hz, J 8A,8B = 15.8 Hz, H-8B), 2.83
(4RS,4aSR,7aSR)-6-(4-Methoxyphenyl)-4-phenyl-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindol-5-one
(15.2).
(1H, dd, J
= 5.1 Hz, J
= 12.7 Hz, H-4a), 2.74 (1H, dd, J
4a,4
4a,7a
Yield: 72%; white powder; mp 188–189 °C (EtOH/DMF);
[Found: C, 76.65; H, 5.97; N, 3.75. C23H21NO3 requires C, 76.86;
= 11.1 Hz, J
= 15.8 Hz, H-8A); 13C NMR (50 MHz,
7a,8A
8A,8B
DMSO-d6) δ (ppm) 172.0, 171.9 (CO2, C-5), 156.2 (d, J C,F = 245
Hz, C-2 C6H4F), 151.9 (C-8a), 147.4 (C-2), 132.1, 129.3, 128.5
H, 5.89; N, 3.90]; IR (KBr) 1710 (N-C=O) cm-1; H NMR (500
1
MHz, DMSO-d6) δ (ppm) 7.50 (2H, br. d, J 2(6),3(5) = 9.2 Hz, H-3,
H-5 С6Н4), 7.43 (1H, d, J 2,3 = 1.8 Hz, H-2), 7.30-7.25 (4H, m, Ar),
7.22–7.18 (1Н, m, H-4 C6H5), 6.89 (2H, br.d, J 2(6),3(5) = 9.2 Hz, H-
2, H-6 С6Н4), 5.79 (1H, d, J 2,3 = 1.8 Hz, H-3), 3.98 (1Н, br. d, J 4,4a
= 10.8 Hz, H-4), 3.88 (1Н, dd, J 7B,7A = 9.1 Hz, J 7B,7a = 7.0 Hz, H-
7B), 3.72 (3Н, s, ОСН3), 3.70 (1Н, br. t, J 7A,7a = J 7B,7A = 9.1 Hz,
(Ar), 128.0 (d, J
= 8.1 Hz, C-6 C6H4F), 127.6 (d, J
= 18.5
C,F
C,F
Hz, C-1 C6H4F), 127.4, 127.2, 126.7, 126.5 (Ar), 124.5 (d, J C,F
=
3.5 Hz, C-5 C6H4F), 118.2 (C-3a), 116.4 (d, J C,F = 19.8 Hz, C-3
C6H4F), 112.2 (C-3), 52.9 (C-4а), 45.9 (C-7), 36.7 (C-4), 33.3 (C-
7а), 26.4 (C-8); m/z (APCI) 460 [М+H, 35Сl + 35Сl]+, 462 [М+H,
35Сl + 37Сl]+, 464 [М+H, 37Сl + 37Сl]+.
H-7A), 2.94 (1H, dd, J
= 10.8 Hz, J
= 12.8 Hz, H-4a),
4,4a
4a,7a
(4RS,4aRS,7aSR)-5-Oxo-6-phenyl-2-(2-chloro-4-nitrophenyl)-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic
acid (14.31). Yield: 77 %; orange powder; mp 251–252 °C
(EtOH/DMF); [Found: C, 61.13; H, 3.70; N, 6.30. C23H17ClN2O6
requires C, 61.00; H, 3.78; N, 6.19]; IR (KBr) 1731 (CO2H),
2.98-2.90 (1H, m, H-8B), 2.81 (1Н, ddd, J = 2.7, J 7a,8A = 11.2 Hz,
J
8B,8A = 14.5 Hz, H-8A), 2.67–2.55 (1Н, m, H-7a); 13C NMR (126
MHz, CDCl3) δ (ppm) 172.0 (C-5), 155.5 (C-4 C6H4), 149.4 (C-
8a), 142.8 (C-1 C6H5, C-2), 141.9, 133.0 (C-1 C6H4), 128.6 (2C,
C-3, C-5 C6H5), 127.9 (2C, C-2, C-6 C6H5), 126.1 (C-4 C6H5),
122.1 (C-3a), 120.7 (2C, C-2, C-6 C6H4), 113.7 (2C, C-3, C-5
C6H4), 110.1 (C-3), 55.2 (CH3O), 51.0 (C-7), 50.8 (C-4), 40.7 (C-
4a), 37.0 (C-7a), 26.2 (C-8); m/z (APCI) 360 [М + H]+.
1
1653 (N-C=O) cm-1; H NMR (200 MHz, DMSO-d6) δ (ppm)
12.64 (1H, br.s, CO2H), 8.29 (1Н, s, H-3 С6Н3), 8.20 (1Н, br. d, J
= 8.6 Hz, H-5 С6Н3), 8.02 (1Н, d, J = 8.6 Hz, H-6 С6Н3),
5,6
5,6
7.64 (2H, d, J 3(5),2(6) = 7.8 Hz, H-2, H-6 C6H5), 7.44 (1Н, s, H-3),
7.39–7.34 (2Н, m, H-3, H-5 C6H5), 7.11 (1H, br. t, J 4,3(5) = 7.4
(4RS,4aSR,7aSR)-6-(4-Methoxyphenyl)-4-(3,4,5-
trimethoxyphenyl)-4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-

13
f]isoindol-5-one (15.3). Yield: 56%; white powder; mp 237–
238 °C (EtOH/DMF); [Found: C, 69.28; H, 5.96; N, 3.03.
C26H27NO6 requires C, 69.47; H, 6.05; N, 3.12]; IR (KBr) 1685
CDCl3) δ (ppm) 7.61 (2H, d, J
= 7.4 Hz, H-2, H-6
2(6),3(5)
ACCEPTED MANUSCRIPT
C6H5), 7.33–7.21 (7H, m, C6H5), 7.09 (1H, t, J 3(5),4 = 7.4 Hz, H-4
C6H5), 5.52 (1H, s, H-3), 4.03 (1H, dq, J = 1.6 Hz, J 4a,4 = 10.7
Hz, H-4), 3.92 (1H, dd, J 7a,7B = 6.6 Hz, J 7A,7B = 9.9 Hz, H-7B),
3.65 (1H, t, J 7a,7A = 9.9 Hz, J 7A,7B = 9.9 Hz, H-7A), 2.99 (1H, dd,
J 7a,8B = 4.9 Hz, J 8A,8B = 14.8 Hz, H-8B), 2.78 (1H, ddd, J = 3.3
Hz, J 7a,8A = 11.6 Hz, J 8A,8B = 14.8 Hz, H-8A), 2.72 (1H, dd, J 4a,4
= 10.7 Hz, J 4a,7a = 13.2 Hz, H-4a), 2.68–2.60 (1H, m, H-7a), 2.21
(3H, s, CH3); 13C NMR (151 MHz, CDCl3) δ (ppm) 173.0 (C-5),
151.5 (C-8a), 147.3, 142.3, 139.7 (C-1 C6H5, C-1 C6H5, C-2),
128.81 (2C), 128.8 (2C), 128.3 (2C), 126.8, 124.2 (C6H5), 123.0
(C-3a), 119.4 (2C), 106.3 (C-3), 53.0, 51.3 (C-4, C-7), 41.7 (C-
4a), 37.7 (C-7a), 27.2 (C-8), 13.8 (CH3); m/z (EI, 70 eV) 343
(100) [M]+, 326 (22), 300 (18), 183 (18), 165 (42), 155 (19), 152
(19), 141 (40), 128 (21), 115 (28), 106 (83), 95 (31), 91 (18), 77
(23).
(N-C=O) cm-1; H NMR (500 MHz, DMSO-d6) δ (ppm) 7.52
1
(2H, br.d, J 2(6),3(5) = 9.2 Hz, H-3 and H-5 C6Н4), 7.43 (1H, d, J 2,3
= 1.8 Hz, H-2), 6.91 (2H, d, J
= 9.2 Hz, H-2 and H-6
2(6),3(5)
С6Н4), 6.57 (2H, br. s, H-2 and H-6 С6Н2), 5.90 (1H, d, J 2,3 = 1.8
Hz, H-3), 3.93 (1Н, br.d, J 4,4a = 10.7 Hz, H-4), 3.88 (1Н, dd, J
7B,7A = 9.8 Hz, J 7B,7a = 7.0 Hz, H-7B), 3.73 (6Н, s, 3-ОСН3, 5-
OCH3 C6H2), 3.72 (3Н, s, 4-ОСН3 C6H2), 3.66 (3Н, s,
С6Н4ОСН3), 2.99 (1Н, dd, J 7A,7a = 12.8 Hz, J 7A,7B = 9.8 Hz, H-
7A), 2.94 (1Н, ddd, J = 1.4 Hz, J 7a,8B = 5.4 Hz, J 8A,8B = 14.7 Hz,
H-8B), 2.84 (1H, ddd, J = 2.7 Hz, J 7a,8A = 11.1 Hz, J 8A,8B = 14.7
Hz, H-8A), 2.66–2.56 (1Н, m, H-7a); 13C NMR (126 MHz,
DMSO-d6) δ (ppm) 172.0 (C-5), 155.6 (C-4 C6H4), 152.5 (2 C, C-
3 and C-5 C6H2), 149.3 (C-8a), 141.8, 138.5 (C-2, C-1 and C-4
C6H2), 136.0, 133.1 (C-1 C6H4), 122.1 (C-3a), 120.8 (2C, C-2, C-
6 C6H4), 113.7 (2C, C-3, C-5 C6H4), 110.3 (C-3), 106.0 (2C, C-2,
C-6 C6H2), 59.8 (OCH3), 55.8 (2C, OCH3), 55.1 (OCH3), 50.9 (C-
7), 50.6 (C-4), 41.1 (C-4a), 37.1 (C-7a), 26.2 (C-8); m/z (APCI)
450 [М + H]+.
(3aRS,6SR,7RS,7aSR)-2-[(2E)-3-(2-Furyl)prop-2-en-1-yl]-1-
oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (18). Powdered anh. MgSO4 (5.28 g, 44 mmol) was added to
a stirred solution of furfurylamine 1.94 mL (22 mmol) and
furylacrolein (2.66 g, 22 mmol) in CH2Cl2 (50 mL) at r.t. After
approx. 2 h, MgSO4 was filtered off, washed with CH2Cl2 (2 × 15
mL) and the solution was concentrated. The residue was diluted
with MeOH (50 mL) and then NaBH4 (0.62 g, 16.5 mmol) was
added. The mixture was vigorously stirred for 24 h, then poured
into H2O (100 mL), and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (MgSO4), concentrated, the
residue, crude 3-(2-furyl)-N-(2-furylmethyl)prop-2-en-1-amine
(16), was diluted with PhH (40 mL) and then maleic anhydride
(2.37 g, 24 mmol) was added. The resulting mixture was stirred
at room temperature for additional 24 h (TLC monitoring). The
formed precipitate was filtered off and washed with PhH (10 mL)
followed by Et2O (2 × 10 mL) and dried in the air to give acid 18
(3.99 g, 60%) as white powder; mp 133–135 °C (EtOH); [Found:
C, 63.90; H, 4.89; N, 4.73. C16H15NO5 requires C, 63.78; H, 5.02;
(4RS,4aSR,7aSR)-6-Benzyl-4-phenyl-4,4a,6,7,7a,8-hexahydro-
5H-furo[2,3-f]isoindol-5-one (15.4). Yield: 51%; colorless
prisms; mp 187–189 °C (hexane/EtOAc); [Found: C, 80.27; H,
6.24; N, 3.97. C23H21NO2 requires C, 80.44; H, 6.16; N, 4.08]; IR
(KBr): 1683 (N-C=O) cm-1; 1H NMR (600 MHz, CDCl3) δ (ppm)
7.36–7.23 (11H, m, H-2, 2C6H5), 5.93 (1H, d, J = 1.7 Hz, H-
2,3
3), 4.44 (1H, d, J A,B = 14.9 Hz, NCH2), 4.42 (1H, d, J A,B = 14.9
Hz, NCH2), 4.03 (1H, br. d, J 4a,4 = 9.1 Hz, H-4), 3.34 (1H, dd, J
7a,7B = 6.6 Hz, J 7A,7B = 9.5 Hz, H-7B), 3.08 (1H, dd, J 7A,7B = 9.5
Hz, J 7a,7A = 10.5 Hz, H-7A), 2.90 (1H, dd, J 7a,8B = 4.2 Hz, J 8A,8B
= 14.6 Hz, H-8B), 2.69 (1H, ddd, J = 3.3 Hz, J 7a,8A = 10.5 Hz, J
8A,8B = 14.6 Hz, H-8A), 2.57–2.50 (2H, m, H-4a, H-7a); 13C NMR
(150 MHz, CDCl3) δ (ppm) 173.5 (C-5), 149.8 (C-8a), 142.4 (C-
1 C6H5, C-2), 141.8, 136.7 (С-1 CH2C6H5), 129.0 (2C), 128.8
(2C), 128.3 (2C, C6H5), 128.2 (C-4 C6H5, C-4 CH2C6H5), 127.7,
126.9 (2C, C-2, C-6 C6H5), 122.4 (C-3a), 110.5 (C-3), 51.9
(NCH2, C-4, C-7), 49.3, 46.6, 41.7 (C-4a), 38.7 (C-7a), 27.2 (C-
8); m/z (EI, 70 eV) 343 (81) [M]+, 172 (10), 165 (15), 152 (11),
141 (37), 132 (12), 115 (19), 91 (100), 65 (10).
N, 4.65]; IR (KBr) 1698 (CO2H), 1633 (N-C=O) cm-1; H NMR
(400 MHz, DMSO-d6) δ (ppm) 12.12 (1H, br. s, CO2H), 7.57
(1H, br.d, J 4,5 = 1.7 Hz, H-5 Furyl), 6.55 (1H, d, J 4,5 = 6.1 Hz, H-
4), 6.44 (1H, dd, J 4,5 = 1.7 Hz, J 3,4 = 3.3 Hz, H-4 Furyl), 6.41
1
(1H, d, J CH,CH = 16.0 Hz, CH), 6.40 (1H, dd, J 5,6 = 1.7 Hz, J 4,5
6.1 Hz, H-5), 6.34 (1H, br.d, J 3,4 = 3.3 Hz, H-3 Furyl), 5.92 (1H,
dt, J NCH2,CH = 5.8 Hz, J CH,CH = 16.0 Hz, CH), 4.96 (1H, d, J 5,6
1.7 Hz, H-6), 3.99 (1H, d, J = 11.5 Hz, H-3B), 3.98–3.83
=
(4RS,4aSR,7aSR)-6-Benzyl-2-methyl-4-phenyl-4,4a,6,7,7a,8-
hexahydro-5H-furo[2,3-f]isoindol-5-one (15.5). Yield: 50%;
colorless plates; mp 207–209 °C (hexane/EtOAc); [Found: C,
80.80; H, 6.55; N, 3.76. C24H23NO2 requires C, 80.64; H, 6.49; N,
3.92]; IR (KBr) 1686 (N-C=O) cm-1; 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.32–7.21 (10H, m, 2 C6H5), 5.50 (1H, s, H-3),
4.42 (1H, d, J A,B = 14.5 Hz, NCH2), 4.39 (1H, d, J A,B = 14.5 Hz,
=
3A,3B
(2H, m, NCH2), 3.51 (1H, d, J 3A,3B = 11.5 Hz, H-3A), 2.80 and
2.45 (1H and 1H both d, J 7,7a = 8.8 Hz, H-7 and H-7a); 13C NMR
(150 MHz, DMSO-d6) δ (ppm) 173.5, 170.8 (CO2, NCO), 152.4,
143.1, 137.2, 136.2 (C-2 and C-5 Furyl, C-4, C-5), 123.2, 120.7,
112.1, 108.7 (C-3 and C-4 Furyl, 2CH), 89.0 (C-3a), 81.7 (C-6),
50.7, 48.3, 45.0, 43.8 (C-3, C-7, C-7a, NCH2); m/z (APCI) 302
[M + H]+.
NCH2), 3.95 (1H, br. d, J 4a,4 = 9.9 Hz, H-4), 3.31 (1H, dd, J 7a,7B
=
6.6 Hz, J 7A,7B = 9.1 Hz, H-7B), 3.05 (1H, dd, J 7A,7B = 9.1 Hz, J
7a,7A = 9.9 Hz, H-7A), 2.83 (1H, dd, J 7a,8B = 4.1 Hz, J 8A,8B = 14.5
Hz, H-8B), 2.64 (1H, ddd, J = 2.5 Hz, J 7a,8A = 10.7 Hz, J 8A,8B
=
(4RS,4aRS,7aRS)-6-(2-Furylmethyl)-5-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-4-carboxylic acid (19). 3-(2-
furyl)-N-(2-furylmethyl)prop-2-en-1-amine (16) obtained above
was diluted with PhH (40 mL) and then maleic anhydride (2.37
g, 24 mmol) was added. The resulting mixture was heated at
reflux for 3 h (TLC monitoring) and then cooled to r.t. The
formed precipitate was filtered off and washed with PhH (10 mL)
followed by Et2O (2 × 10 mL) and dried in the air to give the
mixture of products 4.3 g with the content of target compound
above 70%. The analytical sample of acid 19 was obtained after
two recrystallizations of this crude product from EtOAc–EtOH.
Colorless powder; mp 195–197 °C; [Found: C, 63.56; H, 4.92; N,
4.66. C16H15NO5 requires C, 63.78; H, 5.02; N, 4.65]; IR (KBr)
1667 (CO2H), 1730 (N-C=O) cm-1; 1H NMR (600 MHz, DMSO-
d6) δ (ppm) 12.40 (1H, br. s, CO2H), 7.52 and 7.48 (1H and 1H, d
14.5 Hz, H-8A), 2.53–2.43 (2H, m, H-4a, H-7a), 2.19 (3H, s,
CH3); 13C NMR (151 MHz, CDCl3) δ (ppm) 173.6 (C-5), 151.3
(C-8a), 147.7, 142.6, 136.7 (C-1 C6H5, C-1 CH2C6H5, C-2), 129.0
(2C), 128.8 (2C), 128.3, 128.2 (2C), 127.7, 126.8 (2C)(C6H5),
123.0 (C-3a), 106.3 (C-3), 51.8, 49.4, 46.6 (NCH2, C-4, C-7),
41.7 (C-4a), 38.7 (C-7a), 27.1 (C-8), 13.8 (CH3); m/z (EI, 70 eV)
357 (95) [M]+, 356 (43), 340 (21), 314 (18), 181 (15), 165 (18),
141 (31), 131 (19), 118 (18), 105 (17), 95 (20), 91 (100), 65 (17).
(4RS,4aSR,7aSR)-2-Methyl-4,6-diphenyl-4,4a,6,7,7a,8-
hexahydro-5H-furo[2,3-f]isoindol-5-one (15.6). Yield: 34%; thin
colorless needles; mp 227–229 °C (hexane/EtOAc); [Found: C,
80.56; H, 6.02; N, 4.35. C23H21NO2 requires C, 80.44; H, 6.16; N,
4.08]; IR (KBr) 1701 (N-C=O) cm-1; 1H NMR (600 MHz,

14
Tetrahedron
and d, J = 1.7 Hz, J 4,5 = 1.7 Hz, H-2 and H-5 Furyl), 6.38
1.70-1.50 (8H, m, H-2, H-3, H-4, H-5 Cpt); 1H NMR (400 MHz,
2,3
ACCEPTED MANUSCRIPT
(2H, br. s, H-3, H-4 Furyl), 6.30 (1H, br. d, J 3,4 = 2.5 Hz, H-3
Furyl), 4.48 (1H, d, J A,B = 15.7 Hz, NCH2Furyl), 4.29 (1H, d, J
CDCl3) δ (ppm) 7.37 (1H, d, J 2,3 = 1.8 Hz, H-2), 6.25 (1H, d, J 2,3
= 1.8 Hz, H-3), 4.52 (1H, br. pent, J 1,2(5) = 8.1 Hz, H-1 Cpt), 4.19
A,B = 15.7 Hz, NCH2Furyl), 3.63 (1H, dd, J 4,7a = 1.5 Hz, J 4a,4
=
(1H, dd, J = 0.9 Hz, J
= 5.9 Hz, H-8), 3.55 (1H, dd, J
=
7a,8
5A,5B
5.6 Hz, H-4), 3.43 (1H, dd, J 7a,7B = 7.4 Hz, J 7A,7B = 8.9 Hz, H-
7B), 3.06 (1H, dd, J 7A,7B = 8.9 Hz, J 7a,7A = 9.9 Hz, H-7A), 2.98–
2.91 (1H, m, H-7a), 2.76 (1H, dd, J 7a,8B = 4.9 Hz, J 8A,8B = 15.1
Hz, H-8B), 2.51–2.46 (2H, m, H-4a, H-8A); 13C NMR (150 MHz,
DMSO-d6) δ (ppm) 172.9, 172.7 (CO2, NCO), 151.6, 150.9,
143.3, 142.5 (C-2, C-8a, C-2 and C-5 Furyl), 116.3, 111.1, 111.0,
108.4 (C-3, C-3a, C-3 and C-4 Furyl), 50.2, 46.7, 39.3 (C-4а, C-
7, NCH2), 37.0 (C-4), 33.4 (C-7а), 26.9 (C-8); m/z (APCI) 302
[M + H]+.
9.5 Hz, J 4a,5B = 7.0 Hz, H-5B), 3.13 (1H, t, J 5B,5A = J
= 9.5
5A,4a
Hz, H-5A), 2.88-2.68 (3H, m, H-4а, H-4B and H-7a), 2.35 (1H,
ddd, J = 1.6 Hz, J 4a,4A = 10.6 Hz, J 4A,4B = 15.1 Hz, H-4A), 1.95-
1.82 (2H, m, H-Cpt), 1.75-1.46 (6H, m, H-Cpt); 13C NMR (100
MHz, DMSO-d6) δ (ppm) 171.7 and 170.9 (CO2 and C-7), 146.7
(C-8a), 142.7 (C-2), 119.7 (C-3a), 110.9 (C-3), 51.6 (C-1 Cpt),
47.5 (C-7a), 45.7 (C-5), 38.8 (C-8), 33.5 (C-4а), 28.9 and 28.4
(2C, C-2, C-5 Cpt), 24.5 (C-4), 23.9 (2C, C-3, C-4 Cpt); m/z (EI,
70 eV) 245 (100) [M-44]+, 228 (26), 204 (10), 177 (73), 160 (17),
133 (34), 119 (18), 105 (45), 91 (60), 81 (25), 68 (40), 59 (63),
43 (40).
(2E)-3-(Furan-3-yl)prop-2-enal (20). 3-Furaldehyde (19.35 g,
0.2 mol) was added to a stirred solution of sodium hydroxide
(1.35 g, 33.7 mmol) in H2O (270 mL) at a temperature below
0 °C during 15 min. Then a mixture of acetaldehyde (15 mL) in
water (60 mL) was slowly added to a resulting solution. The
mixture was vigorously stirred at 0 °C for 2 h and then extracted
with ether (3 × 80 mL). After drying over MgSO4 and
evaporation of the organic layer, and distillation of the residue,
the aldehyde (20) (8.68 g) was isolated as light yellow oil. Yield:
36 %; bp 72–74 °C (1 torr); [Found: C, 58.93; H, 5.02. C7H6O2
requires C, 68.85; H, 4.95]; IR (KBr) 1669 (C=O), 1627 (C=C)
cm-1; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.63 (1H, d, J 1,2 = 7.8
Hz, H-1), 7.76 (1Н, br.s, H-2 Furyl), 7.48 (1Н, br.s, H-5 Furyl),
7.40 (1H, d, J 2,3 = 15.6 Hz, H-3), 6.63 (1H, d, J 4,5 = 1.9 Hz, H-4
(4aRS,7aSR,8SR)-6-Benzyl-7-oxo-4a,5,6,7,7a,8-hexahydro-
4H-furo[2,3-f]isoindole-8-carboxylic acid (23.2). Yield: 60%;
colorless powder; mp 237−238 °C (EtOAc–EtOH); [Found: C,
69.15; H, 5.53; N, 4.81. C18H17NO4 requires C, 69.44; H, 5.50; N,
4.50]; IR (KBr) 1745 (CO2H), 1649 (N-C=O) cm-1; H NMR
1
(600 MHz, DMSO-d6) δ (ppm) 12.63 (1H, br.s, CO2H), 7.52 (1H,
d, J 2,3 = 1.8 Hz, H-2), 7.30 (2H, t, J 2(6),3(5) = J 3(5),4 = 7.4 Hz, H-3
and H-5 C6H5), 7.25–7.21 (3H, m, H-2, H-4, H-6 C6H5), 6.32
(1H, d, J 2,3 = 1.8 Hz, H-3), 4.41 (1H, d, J A,B = 15.0 Hz, NCH2),
4.32 (1H, d, J A,B = 15.0 Hz, NCH2), 3.71 (1H, d, J
= 5.5 Hz,
7a,8
H-8), 3.32 (1H, dd, J 4a,5B = 7.3 Hz, J 5A,5B = 9.0 Hz, H-5B), 3.04
(1H, dd, J 5B,5A = 9.0 Hz, J = 9.9 Hz, H-5A), 2.97-2.87 (1H,
5A,4a
Furyl), 6.45 (1H, dd, J
= 7.8 Hz, J
= 15.6 Hz, H-2); 13C
m, H-4а), 2.65 (1H, dd, J 7a,8 = 5.5 Hz, J 7a,4a = 12.6 Hz, H-7a),
2.54 (1H, dd, J 4a,4B = 4.8 Hz, J 4A,4B = 15.0 Hz, H-4B), 2.26 (1H,
1,2
2,3
NMR (100 MHz, CDCl3) δ (ppm) 193.3 (C-1), 145.3, 144.8,
142.4 (C-2, C-3 and C-5 Furyl), 128.6 (C-2), 122.8 (C-3 Furyl),
107.5 (C-4 Furyl); m/z (EI, 70 eV) 122 (100) [M]+, 121 (26), 94
(64), 93 (24), 68 (14), 66 (31), 65 (53), 63 (21), 62 (13), 50 (9),
40 (12), 39 (60), 38 (22), 29 (13).
ddd, J = 1.1 Hz, J
= 11.0 Hz, J
= 15.0 Hz, H-4A); 13C
4a,4A
4A,4B
NMR (100 MHz, DMSO-d6) δ (ppm) 172.2, 171.0 (CO2 and C-
7), 146.5 (C-8a), 142.7 (C-2), 137.1 (C-1 C6H5), 128.5 (2C, C-2,
C-6 C6H5), 127.4 (2C, C-3, C-5 C6H5), 127.1 (C-4 C6H5), 119.8
(C-3a), 110.9 (C-3), 49.5, 45.4 (C-5 and NCH2), 44.8 (C-7a),
38.8 (C-8), 33.7 (C-4а), 24.3 (C-4); m/z (EI, 70 eV) 311 (2) [M]+,
267 (100), 250 (15), 224 (18), 199 (11), 185 (14), 176 (38), 145
(21), 119 (42), 106 (27), 91 (57), 76 (16), 65 (24), 59 (28), 43
(73).
5-Oxofuro[2,3-f]isoindole-8-carboxylic Acids (23). General
Procedure. Powdered anh. MgSO4 (1.68 g, 14 mmol) was added
to a stirred solution of the corresponding amine (7 mmol) and 3-
(furan-3-yl)acrolein (20, 0.85 g, 7 mmol) in CH2Cl2 (20 mL) at
r.t. After approx. 4 h, MgSO4 was filtered off, washed with
CH2Cl2 (2 × 15 mL) and the solution was concentrated. The
residue was diluted with MeOH (20 mL) and NaBH4 (0.27 g, 7.0
mmol) was added at room temperature. The mixtures were
vigorously stirred for 24 h at r.t (TLC or GCMS monitoring),
then poured into H2O (100 mL) and extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were dried (MgSO4) and
concentrated. The residue was diluted with PhH (20 mL) and
maleic anhydride (0.69 g, 7.0 mmol) was added. The resulting
mixture was refluxed for 4 h and then cooled to r.t. The formed
precipitate was filtered off and washed with PhH (2 × 5 mL)
followed by Et2O (2 × 10 mL) and dried in air to give title acids
23 as colorless solids. The analytical samples of acids 23 were
obtained by recrystallizations of crude products from an EtOH or
EtOAc–EtOH mixture.
(4aRS,7aSR,8SR)-6-[2-(3,4-Dimethoxyphenyl)ethyl]-7-oxo-
4a,5,6,7,7a,8-hexahydro-4H-furo[2,3-f]isoindole-8-carboxylic
acid (23.3). Yield: 38%; white powder; mp 183.0−183.9 °C
(EtOAc–EtOH); [Found: C, 65.38; H, 6.13; N, 3.71. C21H23NO6
requires C, 65.44; H, 6.02; N, 3.63]; IR (KBr) 1733 (CO2H),
1
1655 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm)
12.52 (1H, br.s, CO2H), 7.54 (1H, d, J = 1.7 Hz, H-2), 6.86-
2,3
6.83 (2H, m, H-2 and H-6 C6H3), 6.75 (1H, dd, J 2,6 = 1.0 Hz, J 5,6
= 8.0 Hz, H-6 C6H3), 6.35 (1H, d, J = 1.7 Hz, H-3), 3.85 (1H,
2,3
d, J
= 5.4 Hz, H-8), 3.73 (3H, s, OCH3), 3.71 (3H, s, OCH3),
7a,8
3.47-3.32 (3H, m, H-5A and NCH2CH2), 3.08 (1H, br. t, J 5B,5A
=
J
= 9.5 Hz, H-5A), 2.95-2.84 (1H, m, H-4а), 2.71-2.67 (2H,
5A,4a
m, NCH2CH2), 2.61-2.52 (2H, m, H-4B and H-7a), 2.26 (1H, br.
1
dd, J
= 11.8 Hz, J
= 14.1 Hz, H-4A); H NMR (400
4a,4A
4A,4B
MHz, CDCl3) δ (ppm) 7.54 (1H, d, J 2,3 = 1.8 Hz, H-2), 6.80-6.73
(4aRS,7aSR,8SR)-6-Cyclopentyl-7-oxo-4a,5,6,7,7a,8-
(3H, m, H-C6H3), 6.23 (1H, d, J = 1.8 Hz, H-3), 3.86 (3H, s,
2,3
hexahydro-4H-furo[2,3-f]isoindole-8-carboxylic acid (23.1).
Yield: 53%; thin colorless needles; mp 184.2−185.1 °C (EtOAc–
EtOH); [Found: C, 66.48; H, 6.81; N, 5.15. C16H19NO4 requires
C, 66.42; H, 6.62; N, 4.84]; IR (KBr) 1736 (CO2H), 1639 (N-
OCH3), 3.85 (3H, s, OCH3), 3.85 (1H, dd, J = 0.8 Hz, J 7a,8 = 5.8
Hz, H-8), 3.58 (2H, t, J = 7.1 Hz, NCH2), 3.28 (1H, dd, J
=
4a,5B
7.3 Hz, J 5B,5A = 9.7 Hz, H-5B), 3.07 (1H, t, J 5B,5A = J 5A,4a = 9.7
Hz, H-5A), 2.84-2.75 (1H, m, H-4а), 2.83 (2H, t, J = 7.1 Hz,
CH2), 2.68-2.60 (2H, m, H-4B and H-7a), 2.26 (1H, ddd, J = 1.3
1
C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm) 12.41 (1H,
br.s, CO2H), 7.53 (1H, d, J 2,3 = 1.5 Hz, H-2), 6.36 (1H, d, J 2,3
=
Hz, J
= 10.8 Hz, J
= 15.1 Hz, H-4A); 13C NMR (100
4a,4A
4A,4B
1.5 Hz, H-3), 4.32 (1H, br. pent, J = 7.6 Hz, H-1 Cpt), 3.83
1,2(5)
MHz, DMSO-d6) δ (ppm) 171.9 and 170.9 (CO2 and C-7), 148.7
and 147.3 (C-3, C-4 C6H3), 146.7 (C-8a), 142.7 (C-2), 131.5 (C-1
C6H3), 120.5 (C-6 C6H3), 119.7 (C-3a), 112.5 and 111.9 (C-2, C-
3 C6H3), 110.9 (C-3), 55.4 (2C, 2OCH3), 47.1 (C-7a), 50.3 and
43.8 (C-5, NCH2), 38.8 (C-8), 33.6 (C-4а), 33.0 (CH2), 24.5 (C-
(1H, d, J
= 5.2 Hz, H-8), 3.49 (1H, br. dd, J 5A,5B = 9.5 Hz, J
7a,8
4a,5B = 7.6 Hz, H-5B), 3.05 (1H, br. t, J 5B,5A = J 5A,4a = 9.5 Hz, H-
5A), 2.92-2.81 (1H, m, H-4а), 2.64-2.55 (2H, m, H-4B and H-
7a), 2.32 (1H, br. dd, J 4a,4A = 11.4 Hz, J 4A,4B = 14.0 Hz, H-4A),

15
4); m/z (EI, 70 eV) 385 (31) [M]+, 341 (11), 245 (17), 190 (9),
164 (100), 151 (23), 131 (10), 95 (12), 76 (11), 68 (10), 55 (13),
43 (24).
11.0 Hz, J
= 15.1 Hz, H-4A); 13C NMR (100 MHz,
4B
ACCEPTED MANUSCR4AIPT
,
DMSO-d6) δ (ppm) 172.0 and 171.6 (CO2, C-7), 156.1 (C-4
C6H4), 147.0 (C-8a), 143.5 (C-2), 133.6 (C-1 C6H4), 121.1 (2C,
C-2, C-6 C6H4), 120.2 (C-3a), 114.4 (2C, C-3, C-5 C6H4), 111.5
(C-3), 55.7 (OCH3), 52.0 (C-5), 48.5 (C-7a), 39.4 (C-8), 33.3 (C-
4а), 24.9 (C-4); m/z (EI, 70 eV) 327 (36) [M]+, 283 (100), 189
(7), 161 (25), 145 (15), 136 (57), 120 (52), 105 (12), 92 (23), 76
(33), 65 (15), 55 (12), 43 (12).
(4aRS,7aSR,8SR)-7-Oxo-6-phenyl-4a,5,6,7,7a,8-hexahydro-
4H-furo[2,3-f]isoindole-8-carboxylic acid (23.4). Yield: 70%;
colorless powder; mp 249.5−250.5 °C (EtOAc–EtOH); [Found:
C, 69.01; H, 4.83; N, 4.73. C17H15NO4 requires C, 68.68; H, 5.09;
1
N, 4.71]; IR (KBr) 1731, 1719 (CO2H), 1666 (N-C=O) cm-1; H
Acknowledgements
NMR (400 MHz, DMSO-d6) δ (ppm) 7.65 (2H, d, J
= 8.3
2(6),3(5)
Hz, H-2 and H-6 C6H5), 7.58 (1H, d, J
= 1.6 Hz, H-2), 7.38
= 8.3 Hz, H-3 and H-5
2,3
The reported study was funded by the Russian Foundation for
Basic Research (RFBR) according to the research projects № 13-
03-00105, 16-03-00125, 16-33-00389 and Ukrainian State Fund
for Fundamental Research (grant no. F53.3/013), and Ministry of
Education and Science of the Russian Federation (Project no.
2042).
(2H, br. dd, J
= 7.4 Hz, J
3(5),4
2(6),3(5)
C6H5), 7.12 (1H, br. t, J 4,3(5) = 7.4 Hz, H-4 C6H5), 6.40 (1H, d, J
= 1.6 Hz, H-3), 4.01-3.95 (2H, m, H-5B and H-8), 3.68 (1H,
2,3
br. t, J
= J
= 9.8 Hz, H-5A), 3.12-3.00 (1H, m, H-4а),
5B,5A
5A,4a
2.93 (1H, dd, J 7a,8 = 5.3 Hz, J 7a,4a = 13.0 Hz, H-7a), 2.72 (1H, dd,
J 4a,4B = 4.3 Hz, J 4A,4B = 14.8 Hz, H-4B), 2.42 (1H, br. dd, J 4a,4A
= 11.5 Hz, J
= 14.8 Hz, H-4A); 13C NMR (100 MHz,
4A,4B
References and notes
DMSO-d6) δ (ppm) 172.0 and 170.9 (CO2, C-7), 146.4 (C-8a),
142.9 (C-2), 139.7 (C-1 C6H5), 128.7 (2C, C-3, C-5 C6H5), 123.7
(C-4 C6H5), 119.6 (C-3a), 118.9 (2C, C-2, C-6 C6H5), 110.9 (C-
3), 51.2 (C-5), 48.1 (C-7a), 39.0 (C-8), 32.7 (C-4а), 24.4 (C-4);
m/z (EI, 70 eV) 297 (5) [M]+, 253 (100), 171 (15), 161 (26), 133
(26), 118 (20), 106 (95), 95 (30), 91 (73), 78 (64), 65 (23), 59
(67), 45 (33).
1.
For recent reviews on IMDAF reactions, see: a) Padwa, A.; Flick, A.
C. Adv. Heterocycl. Chem. 2013, 110, 1-246; b) Zubkov, F. I.;
Nikitina, E. V.; Varlamov, A. V. Russ. Chem. Rev. 2005, 74, 639-
669; c) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999,
55, 13521-13866; d) Kappe, C. O.; Murphree, S. S.; Albert, P.
Tetrahedron 1997, 53, 14179-14233.
2.
For recent examples on IMDAF reactions in furfurylamines leading
to isoindoles, see: a) Rae, R. L.; Żurek, J. M.; Paterson, M. J.;
Bebbington, M. W. P. Org. Biomol. Chem. 2013, 11, 7946-7952; b)
Lu, Q.; Huang, X.; Song, G.; Sun, C.-M.; Jasinski, J. P.; Keeley, A.
C.; Zhang, W. ACS Comb. Sci. 2013, 15, 350-355; c) Ball, M.; Boyd,
A.; Churchill, G.; Cuthbert, M.; Drew, M.; Fielding, M.; Ford, G.;
Frodsham, L.; Golden, M.; Leslie, K.; Lyons, S.; McKeever-Abbas,
B.; Stark, A.; Tomlin, P.; Gottschling, S.; Hajar, A.; Jiang, J.; Lo, J.;
Suchozak, B. Org. Process Res. Dev. 2012, 16, 741-747; d) Cesco,
S.; Deslandes, S.; Therrien, E.; Levan, D.; Cueto, M.; Schmidt, R.;
Cantin, L.-D.; Mittermaier, A.; Juillerat-Jeanneret, L.; Moitessier, N.
J. Med. Chem. 2012, 55, 6306-6315; e) Nakamura, M.; Takahashi, I.;
Yamada, S.; Dobashi, Y.; Kitagawa, O. Tetrahedron Lett. 2011, 52,
53-55; f) Sarang, P. S.; Yadav, A. A.; Patil, P. S.; Krishna, U. M.;
Trivedi, G. K.; Salunkhe, M. M. Synthesis 2010, 1091-1097; g)
Medimagh, R.; Marque, S.; Prim, D.; Chatti, S. Synthesis 2010, 770-
774.
For recent references on IMDAF reactions leading to the various
cycles, see: a) Gulbrandsen, H. S.; Hennum, M.; Osheka, M.; Read,
M. L.; Gundersen, L.-L. Eur. J. Org. Chem. 2014, 8182-8190; b)
Zubkov, F. I.; Nikitina, E. V.; Galeev, T. R.; Zaytsev, V. P.;
Khrustalev, V. N.; Novikov, R. A.; Orlova, D. N.; Varlamov, A. V.
Tetrahedron 2014, 70, 1659-1690; c) Nieto-Garcia, O.; Alonso, R. J.
Org. Chem. 2013, 78, 2564-2570; d) Read, M. L.; Krapp, A.;
Miranda, P. O.; Gundersen, L.-L. Tetrahedron 2012, 68, 1869-1885;
e) Boonsompat, J.; Padwa, A. J. Org. Chem. 2011, 76, 2753-2761.
The selected works of these groups, concerning IMDAF reaction: a)
Zubkov, F. I.; Zaytsev, V. P.; Nikitina, E. V.; Khrustalev, V. N.;
Gozun, S. V.; Boltukhina, E. V.; Varlamov, A. V. Tetrahedron 2011,
67, 9148-9163; b) Zubkov, F. I.; Zaitsev, V. P.; Piskareva, A. M.;
Eliseeva, M. N.; Nikitina, E. V.; Mikhailova, N. M.; Varlamov, A. V.
Russ. J. Org. Chem. 2010, 46, 1192-1206; c) Zubkov, F. I.; Airiyan, I.
K.; Dzyubenko, A. A.; Yudina, N. I.; Zaytsev, V. P.; Nikitina, E. V.;
Varlamov, A. V.; Khrustalev, V. N.; Grudinin, D. G. J. Heterocycl.
Chem. 2010, 47, 400-414; d) Zubkov, F. I.; Ershova, J. D.; Zaytsev,
V. P.; Obushak, M. D.; Matiychuk, V. S.; Sokolova, E. A.;
Khrustalev, V. N.; Varlamov, A. V. Tetrahedron Lett. 2010, 51,
6822; e) Varlamov, A. V.; Boltukhina, E. V.; Zubkov, F. I.; Nikitina,
E. V.; Turchin, K. F. J. Heterocycl. Chem. 2006, 43, 1479-1495.
The closest analogy to the discussion approach – the inter- and
intramolecular Diels–Alder reactions in 2-(vinyl)furans: a) Patre, R.
E.; Gawas, S.; Sen, S.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron
Lett. 2007, 48, 3517-3576; b) Lu, K.; Luo, T.; Xiang, Z.; You, Z.;
Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005, 7, 958-967; c)
(4aRS,7aSR,8SR)-6-(4-Chlorophenyl)-7-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-8-carboxylic acid (23.5).
Yield: 66%; colorless powder; mp 199.8−200.2 °C (EtOAc–
EtOH); [Found: C, 61.27; H, 4.09; N, 4.40. C17H14ClNO4
requires C, 61.55; H, 4.25; N, 4.22]; IR (KBr) 1704 (CO2H),
1
1680 (N-C=O) cm-1; H NMR (400 MHz, DMSO-d6) δ (ppm)
12.69 (1H, br. s, CO2H), 7.69 (2H, d, J
= 8.6 Hz, H-3 and
2(6),3(5)
H-5 C6H4), 7.58 (1H, d, J 2,3 = 1.4 Hz, H-2), 7.43 (2H, d, J 2(6),3(5)
= 8.6 Hz, H-2 and H-6 C6H4), 6.40 (1H, d, J = 1.4 Hz, H-3),
2,3
4.03-3.94 (2H, m, H-5B, H-8), 3.66 (1H, br. t, J
= J
=
5B,5A
5A,4a
9.6 Hz, H-5A), 3.10-2.92 (2H, m, H-7a, H-4а), 2.70 (1H, dd, J
4a,4B = 4.3 Hz, J 4A,4B = 14.6 Hz, H-4B), 2.41 (1H, br. dd, J 4a,4A
11.6 Hz, J 4A,4B = 14.6 Hz, H-4A); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.57 (2H, d, J = 9.0 Hz, H-3 and H-5 C6H4), 7.40
=
2(6),3(5)
(1H, d, J 2,3 = 1.9 Hz, H-2), 7.33 (2H, br. d, J 2(6),3(5) = 9.0 Hz, H-2
and H-6 C6H4), 6.30 (1H, d, J 2,3 = 1.9 Hz, H-3), 4.26 (1H, dd, J =
3.
0.8, J
= 5.8 Hz, H-8), 3.98 (1H, dd, J
= 9.1, J 4a,5B = 7.3
7a,8
5B,5A
Hz, H-5B), 3.66 (1H, dd, J
= 9.1, J
= 10.2 Hz, H-5A),
5B,5A
4a,5A
3.20-3.09 (1H, m, H-4а), 2.86-2.81 (2H, m, H-4B, H-7a), 2.46
(1H, ddd, J = 1.4 Hz, J 4a,4A = 10.9 Hz, J 4A,4B = 15.1 Hz, H-4A);
13C NMR (100 MHz, DMSO-d6) δ (ppm) 172.3 and 170.9 (CO2,
C-7), 146.3 (C-8a), 143.0 (C-2), 138.7 (C-1 C6H4), 128.6 (2C, C-
3, C-5 C6H4), 127.5 (C-4 C6H4), 120.5 (2C, C-2, C-6 C6H4),
119.7 (C-3a), 111.0 (C-3), 51.2 (C-5), 48.1 (C-7a), 39.0 (C-8),
32.7 (C-4а), 24.4 (C-4); m/z (EI, 70 eV) 333 (2) [M]+, 332 (13),
287 (78), 253 (33), 236 (12), 205 (10), 140 (78), 118 (21), 106
(100), 95 (36), 77 (63), 65 (11), 59 (43), 43 (65).
4.
(4aRS,7aSR,8SR)-6-(4-Methoxyphenyl)-7-oxo-4a,5,6,7,7a,8-
hexahydro-4H-furo[2,3-f]isoindole-8-carboxylic acid (23.6).
Yield: 71%; colorless prisms; mp 209−210 °C (EtOH); [Found:
C, 65.84; H, 5.20; N, 4.47. C18H17NO5 requires C, 66.05; H, 5.23;
1
N, 4.28]; H NMR (600 MHz, DMSO-d6) δ (ppm) 12.71 (1H,
br.s, CO2H), 7.59 (1H, d, J = 1.8 Hz, H-2), 7.55 (2H, br. d, J
2,3
= 9.2 Hz, H-2, H-6 C6H4), 6.94 (2H, br. d, J
= 9.2
2(6),3(5)
2(6),3(5)
Hz, H-3, H-5 C6H4), 6.41 (1H, d, J = 1.8 Hz, H-3), 3.94 (1H,
2,3
br. d, J 7a,8 = 5.5 Hz, H-8), 3.92 (1H, dd, J 4a,5B = 7.0 Hz, J 5A,5B
=
5.
9.0 Hz, H-5B), 3.74 (3H, s, OCH3), 3.65 (1H, dd, J 5B,5A = 9.0 Hz,
J 5A,4a = 10.2 Hz, H-5A), 3.08-3.00 (1H, m, H-4а), 2.90 (1H, dd, J
= 5.5 Hz, J 7a,4a = 13.2 Hz, H-7a), 2.70 (1H, dd, J
= 4.8
7a,8
4a,4B
Hz, J 4A,4B = 15.1 Hz, H-4B), 2.41 (1H, ddd, J = 1.6 Hz, J
=
4a,4A

16
Tetrahedron
Drew, M. G. B.; Jahans, A.; Harwood, L. M.; Apoux, S. A. B. H. Eur.
ACCEPTED MANUSCRIPT
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8.
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Sheldrick, G. M. SADABS, v. 2.03, Bruker/Siemens Area Detector
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11.
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Evans, P. R. Acta Cryst. 2005, D62, 72-82.
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