Transposition of Aromaticity from a Furan to a Cyclohexane Ring in Furoisoindoles during the Interaction of 3-(Furyl)allylamines with Bromomaleic Anhydride

Article abstract of DOI:10.1055/s-0039-1690782

An unexpected four-step reaction sequence was discovered in the course of investigation of the interaction between 3-(furan-2-yl)allylamines and bromomaleic anhydride. This conversion begins with the initial N -acylation of the allylamines by the anhydride, followed by intramolecular Diels-Alder reaction, which is accompanied by a dehydrohalogenation, and ends with the formation of partially unsaturated furo[2,3- f ]isoindoles followed by transposition of aromaticity from the furan moiety to the neighboring cyclohexane ring. The reaction between 3-(furan-3-yl)allylamines and bromomaleic anhydride does not stop at a furo[2,3- f ]isoindole formation step, but proceeds further with the cleavage of the furan ring in a 100percent atom-efficient fashion to provide polysubstituted isoindoline-4-carboxylic acids.

Full text of DOI:10.1055/s-0039-1690782

SYNLETT
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6
-
5
2
1
4
1
4
3
7
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0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
K. A. Alekseeva et al.
Letter
Synlett
Transposition of Aromaticity from a Furan to a Cyclohexane Ring
in Furoisoindoles During the Interaction of 3-(Furyl)allylamines
with Bromomaleic Anhydride
Kseniia A. Alekseevaa
Elizaveta A. Kvyatkovskayaa
Can you suggest a mechanism?
Br
HO
O
Eugeniya V. Nikitinaa
Vladimir P. Zaytseva
Svetlana M. Eroshkinaa
Khidmet S. Shikhalievb
Hieu H. Truongc
O
O
O
O
NH
R
HO
Br
0
0
0
0-
0
0
0
1-9
1
7
5-7
5
8
3
dioxane, Δ, 1 h
R = Aryl, Alkyl
(20–30%)
N
R
O
Transposition of aromaticity
Victor N. Khrustaleva,d
Fedor I. Zubkov*a
0
0
0
0-
0
0
0
2-0
2
8
9-0
8
3
1
a Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St.,
Moscow 117198, Russian Federation
fzubkov@sci.pfu.edu.ru
b Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1
Universitetskaya sq., Voronezh 394018, Russian Federation
c Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
truonghonghieu@duytan.edu.vn
d N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky
Prospect 47, Moscow 119991, Russian Federation
Received: 12.11.2019
Accepted after revision: 09.12.2019
Published online: 13.01.2019
OH
O
OH
O
NH
O
O
OH
N
DOI: 10.1055/s-0039-1690782; Art ID: st-2019-b0613-l
N
O
O
O
HS
O
Abstract An unexpected four-step reaction sequence was discovered
in the course of investigation of the interaction between 3-(furan-2-
yl)allylamines and bromomaleic anhydride. This conversion begins with
the initial N-acylation of the allylamines by the anhydride, followed by
intramolecular Diels–Alder reaction, which is accompanied by a dehy-
drohalogenation, and ends with the formation of partially unsaturated
furo[2,3-f]isoindoles followed by transposition of aromaticity from the
furan moiety to the neighboring cyclohexane ring. The reaction be-
tween 3-(furan-3-yl)allylamines and bromomaleic anhydride does not
stop at a furo[2,3-f]isoindole formation step, but proceeds further with
the cleavage of the furan ring in a 100% atom-efficient fashion to pro-
vide polysubstituted isoindoline-4-carboxylic acids.
A
C
OR1
OR3
H
N
N
R2
O
N
O
R
O
O
B salfredins
D
Figure 1 Chemical structures of naturally occurring and biologically
active substances containing the tetrahydro-2H-furo[2,3-f]isoindole
scaffold
In view of the above data, a large range of synthetic ap-
proaches to these heterocycles were described in the last
decade.1,5 However, as a rule, all of these synthetic schemes
are based on uncommon initial reagents and include a long
series of intricate steps. As an interesting example of such
methods of furo[2,3-f]isoindole core F preparation pro-
posed recently, the method based on the iron-catalyzed in-
tramolecular cycloaddition of tetraynes E is given in
Scheme 1.6
Key words furan, Diels–Alder reaction, transposition of aromaticity,
furo[2,3-f]isoindole, IMDAV reaction, atom-efficient reaction
As a result of the revealing of their high and diverse bio-
logical activity, furo[2,3-f]isoindoles and their hydrogenat-
ed derivatives are constantly a focus of attention of synthet-
ic and medicinal chemistry.1 Below, we cite only a few out-
standing examples of practically useful structures
possessing this heterocyclic skeleton (Figure 1). Compound
A and salfredins B are well-known as aldose reductase in-
hibitors,2 nitroxyl radical C combines -adrenergic receptor
blocking activity with the capability to scavenge superox-
ide and other reactive oxygen species,3 and pyridinyl-sub-
stituted tricycle D belongs to a class of apoptosis signal-reg-
ulating kinase inhibitors.4
HO
HO
Fe2(CO)9
N
R
PhMe, Δ
HO
N
R
O
E
F
Scheme 1 An original synthesis of furo[2,3-f]isoindoles F
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. A. Alekseeva et al.
Letter
Synlett
As part of our research in the field of tandem acylation–
[4+2]-cycloaddition reactions of ,-unsaturated acid anhy-
drides with vinylarenes (the intramolecular Diels–Alder re-
action in vinylarenes – the IMDAV reaction)7 and search for
new original objects for metathesis reactions,8 in this com-
munication we used bromomaleic anhydride and 3-furylal-
lylamines as starting materials for the construction of the
furo[2,3-f]isoindole framework. It should be noted that, pri-
or to our work, bromomaleic anhydride was used several
times as an intramolecular dienophile.9 However, the cited
reactions led to a mixture of different products in rather
low yields.
The starting materials for this investigation, 3-furylallyl-
amines 2a–u, were prepared from 3-(furan-2-yl)acrolein
(1) and primary amines according to the standard proce-
dure,7 which involved condensation and reduction steps
(Scheme 2). The next reaction, an interaction of bromoma-
leic anhydride with amines 2, proceeded smoothly in boil-
ing dioxane and finished by formation of a precipitate of
compounds 3.10 Usually, after washing with ethanol, these
crystals did not need additional purification; however, the
yields of recrystallized samples are shown in Table 1. Be-
sides dioxane, many other appropriate solvents were tested
in the cycloaddition process (MeCN, benzene, PhMe, THF,
EtOAc, CHCl3). Only experiments in acetonitrile gave satis-
factory yields of products 3, but yields were lower than in
the case of dioxane. No other solvents led to the precipita-
tion of pure solids from the reaction mixtures.
Table 1 Substituents R1 and Yields of Compounds 2 and 3
Entry
R1
Pr
Yield of 2 (%) Yield of 3 (%)a
b
a
b
c
d
e
f
–
69
76
81
63
49
26
61
57
60
70
38
54
50
43
18
21
46
36
i-Pr
68
78
61
69
73
60
65
63
67
69
74
82
60
73
67
65
43
cyclopropyl
allyl
Bu
pentyl
g
h
i
cyclopentyl
cyclohexyl
Bn
j
3-MeO-4-MeOC6H3CH2
Ph
k
l
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-MeO2CC6H4
3-F3CC6H4
3-BrC6H4
2-MeOC6H4
m
n
o
p
q
r
a All yields of compounds 3 are given after recrystallization from an
EtOH/DMF mixture.
b This compound was not isolated in the pure form.
The yield of cycloadducts 3 is slightly dependent of the
electron effects of substituent R1 at the nitrogen atom. Typi-
cally, electron-withdrawing groups in the phenyl ring re-
duce the yield of products 3 (see Table 1, entries 15–17).
Thus, the boiling time was increased to 4–5 h for molecules
bearing electron-acceptor substituents, while the complete
conversion of allylamines 2, containing electron-donating
substituents, was completed after 1 h of heating. However,
probably, the ability of acids 3 to crystallize from dioxane
makes the most powerful impact on their yield.
1. MgSO4, CH2Cl2
O
CHO
H
1
N
O
R1
+
2. NaBH4, MeOH
H2N R1
2
Br
O
HO
O
O
O
4
O
3
5
2
N
R1
O
2
dioxane, Δ, 1 h
O
– HBr
3
7
1
8
HO
Br
O
HO
O
O
Br
not isolated
On the other hand, the substituent in the fifth position
of the furan nucleus in allylamines 2s–u impedes the reac-
tion. For example, the introduction of a methyl group or a
bromine atom (these examples are shown in Figure 2) into
this position leads to the formation of polymerization prod-
ucts only, from which the target compounds 3 cannot be
isolated.
The most interesting feature of the transformation un-
der discussion is the loss of aromaticity by the furan core of
amine 2 and ‘the transposition of aromaticity’ to the cyclo-
hexane ring, occurring during the reaction.
A plausible mechanism of the domino reaction includes
the N-acylation step followed by the spontaneous IMDAV
reaction (Scheme 3). At that point, depending on the direc-
tion of attack of the nucleophilic nitrogen on the molecule
of bromomaleic anhydride, two bromomaleic amides (6A
N
R1
N
R1
O
O
4
5
Scheme 2 Synthesis of furo[2,3-f]isoindoles 3
To our surprise, the structures of the resulting products
did not correspond to the structures of the expected cy-
cloaddition adducts 4 or 5 or to products of their dehydro-
halogenation. HRMS spectra showed the absence of a bro-
mine atom in the molecule, and NMR data did not reveal
the presence of an aromatic furan nucleus. A thorough
study of the obtained substances, including two-dimen-
sional NMR methods, led to the structure 2,3,6,7-tetrahy-
dro-2H-furo[2,3-f]isoindole (3).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
K. A. Alekseeva et al.
Letter
Synlett
To clarify and corroborate the above-proposed reaction
path, a deuterium atom was introduced to the fifth position
of the furan ring of the initial allylamine 6a (Scheme 4). It
was found that during the reaction the deuterium label in-
completely passed from the starting material 6a to the
product, and the mixture of protium-containing 3i and iso-
topic-labelled 14 isomers was isolated in a 3i/14 ratio of
about 42:58. In other words, a proton exchange occurred at
this position of the furan ring in the course of the reaction.
The ratio was measured using 1H NMR and 13C NMR spectra
of the mixture of isomers.
Me
Br
H
H
O
O
N
N
Bn
Ph
2s
2t
H
O
HO
N
Ph
2u
Figure 2 The initial allylamines 2 unsuitable for the IMDAV reaction
and 6B) and two corresponding adducts of the intramolec-
ular exo-Diels–Alder reaction (7A and 7B) can form. A 1,3-H
shift and the successive re-aromatization of the furan ring
in compound 7B or dehydrobromination of intermediate 7A
completes the process by formation of derivatives 8A or 5.
This reaction path was postulated and proven in many pa-
pers concerning the interaction of maleic anhydride (and
its derivatives) with 3-furyl-, 3-thionyl-, and 3-(phenyl)al-
lylamines.7 Under dioxane action, bromide 5 undergoes
trans-elimination of hydrogen bromide to give unsaturated
tetrahydrofuro[2,3-f]isoindole 9 (the corresponding conver-
sion route of 8A to 3 is not shown in Scheme 3 for purposes
of clarity). The subsequent series of reversible protonation–
deprotonation steps 9 → 10 → 11 → 12 → 13 leads to prod-
uct 3. Obviously, the driving force of the migration of aro-
maticity from the furan core to the cyclohexane ring (con-
version from 9 into 3) is a gain in energy, which can be
roughly estimated at 22 kcal/mol (stabilization energy of
furan is around 16 kcal/mol; for benzene this value is 38
kcal/mol).
HO
O
O
3i
Bn
+
Br
N
O
O
O
O
D
H
N
HO
O
O
dioxane, Δ, 1 h
Bn
O
14
4
3
5
6a
2
D
N6 Bn
1O
7
8
3i:14 ≈ 42:58 (53%)
Scheme 4 Synthesis of 2-D-substituted furo[2,3-f]isoindole 14
The triplet of the CHD-2 group is observed clearly at  =
72.9 ppm (1JC,D = 23.1 Hz) in the 13C NMR spectrum of com-
pound 14, while the singlet of the CH2-2 group in the pro-
tium analogue 3i is revealed at  = 73.3 ppm in the same
carbon spectrum.
Br
O
N
OH
Br
H
O
O
OH
O
O
O
O
H
+
N
O
R1
N-acylation
H
Br
N
2
6A
6B
R1
R1
O
O
exo-[4+2] cycloaddition
HO
O
HO
H
O
HO
O
O
O
O
H
H
H
Br
H
+
3
N
R1
8A
Br
N
R1
N
R1
– HBr
O
O
O
7A
7B
H
H
H
H-shift
HO
O
HO
O
HO
O
O
Br
O
O
N
dioxane
H
N
R1
N
R1
10
R1
– dioxane • HBr
dehydrohalogenation
O
5
O
O
9
H
O
transfer of aromaticity
HO
O
HO
O
HO
O
HO
O
O
O
O
H
N
R1
N
R1
N
R1
N
R1
– H
– H
O
11
O
12
O
13
O
3
Scheme 3 Plausible mechanism of furo[2,3-f]isoindole-4-carboxylic acids 3 formation
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
K. A. Alekseeva et al.
Letter
Synlett
These observations confirm that one of the stages of the
mechanism (probably the rate-limiting stage) is the proton-
ation of the furan ring at the -position (see the reversible
stage of conversion of 9 to 10 in Scheme 3).
Of the other features of furo[2,3-f]isoindole carboxylic
acids 3, their extremely poor solubility in organic solvents
should be mentioned; in this regard, most of the 13C NMR
and part of the 1H NMR spectra were recorded in DMSO-d6
in the temperature range of 100–150 °C.
The final piece of this letter is connected with the ex-
pansion of the chemical diversity of the discovered trans-
formation to include 3-(furan-3-yl)allylamines 15, which
theoretically had to allow the synthesis of 7-oxo-3,5,6,7-
tetrahydro-2H-furo[2,3-f]isoindole-8-carboxylic acids 16 in
a similar way (Scheme 5).
To our surprise, we were not able to isolate compounds
16 from the reaction mixtures. In contrast to acids 3, the 1H
NMR spectra of the products obtained in these experiments
were characterized by two narrow singlet signals in a weak
field, which indicates the cleavage of the furan ring and the
formation of a new hydroxyl group. At that, considerable
low-field shifts of both acidic protons ( = ca. 13.5 and 17.0
ppm) indicate their participation in strong intramolecular
hydrogen bonds in solution. Thus, on the grounds of the
NMR data, formula 19 was assigned to the final products.
The values of substituents R1 and yields of compounds 15
and 19 are shown in Table 2.
To give more reliable evidence of the leading role of acid
in the course of the ‘aromaticity transposition’, we carried
out the reaction of allylamine 2k with bromomaleic anhy-
dride under the same conditions (see, Scheme 2), but in the
presence of a soft base, potassium carbonate (1 equiv).
Product 3k was observed in the 1H NMR spectra of a result-
ing mixture as a byproduct (less than 10%). The main com-
ponent of the mixture (total yield of all solid products was
around 40%) was furo[2,3-f]isoindole bearing both furan
and benzene aromatic rings. A detailed study of transfor-
mations under a basic medium will be undertaken later in
the next publication. On the contrary, addition of 10 mol%
of concd HBr as a catalyst in the same reaction significantly
accelerates the rate (ca. 20 min) but leads to the formation
of undesirable byproducts of polymerization, which con-
taminate the target isoindole 3k.
Since there were almost no spectral data of furo[2,3-
f]isoindole carboxylic acids 3 presented in the previously
published communications, we are reporting certain refer-
ence NMR signals of this class of compounds here. The sig-
nals of the carbon atoms of the CO2H, N-C=O groups and C-
8a atom at  = 172–164 ppm are the most identifiable sig-
nals of these acids in their 13C NMR spectra. The most char-
acteristic feature of their 1H NMR spectra is the presence of
a singlet signal of the aromatic proton H-8 at  = 7.25–7.05
ppm. The acidic proton of the carboxylic group is observed
usually at the region of  = 13–16 ppm as a very broad sin-
glet.
Table 2 Substituents R1 and Yields of Compounds 15 and 19
Entry
R1
Ph
Yield of 15 (%)
Yield of 19 (%)a
a
b
c
63
83
91
26
21
26
4-ClC6H4
4-BrC6H4
a All yields of compounds 19 are given after recrystallization from an
EtOH/DMF mixture.
Br
HO
8a
O
7a
Considering that the products of the reaction between
allylamines 15 and bromomaleic anhydride crystallize from
the reaction mixtures in the form of well-shaped needles,
the structure of one product (19b) was unequivocally prov-
en by X-ray method (Figure 3).
O
O
8
O
O
O
1O
3
H
6
N
N
R1
R1
dioxane, Δ, 1 h
4a
3a
O
5
15a–c
16
O
O
O
H
O
O
O
Br
HO
N
R1
R1
SN
2
N
Br
18
17
H
O
H
O
HO
O
3a
H
O
O
O
4
HO
1
2
N
R1
5
6
N
R1
2
Br
1
7a
Br
19a–c (21–26%)
19
(the H-bonds are shown)
Scheme 5 A possible mechanism of formation of isoindole carboxylic
acids 19
Figure 3 Molecular structure of isoindole-4-carboxylic acid 19b
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
K. A. Alekseeva et al.
Letter
Synlett
Indeed, the main inferences drawn from the proton
NMR spectra are in excellent agreement with the data ob-
tained from the XRD analysis. In particular, the most dis-
tinctive features of acid 19b are the absence of a furan ring
and the presence of the strong intramolecular hydrogen
bonds (see Scheme 5, Figure 3 and Supporting Information)
stabilizing the almost planar conformation of the molecule
(except for the 6-(2-bromoethyl) substituent). Moreover, a
distribution of the bond lengths within the molecule 19b
indicates the presence of an extended conjugated system. In
the crystal, molecules of 19b are packed in stacks along the
crystallographic a axis. Within the stacks, molecules are
bound by the ···-stacking interactions.
References and Notes
(1) Recent examples of synthesis of furo[2,3-f]isoindoles: (a) Min,
B. K.; Lim, J. W.; Roh, H. J.; Kim, J. N. Bull. Korean Chem. Soc.
2016, 37, 1724. (b) Ohno, H.; Iuchi, M.; Fujii, N.; Tanaka, T. Org.
Lett. 2007, 9, 4813. (c) Ohno, H.; Iuchi, M.; Kojima, N.;
Yoshimitsu, T.; Fujii, N.; Tanaka, T. Chem. Eur. J. 2012, 18, 5352.
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Chem. 2019, 89, 1307. (e) Xiao, X.; Hoye, T. R. J. Am. Chem. Soc.
2019, 141, 9813. (f) Ohno, H.; Yamamoto, M.; Iuchi, M.; Fujii, N.;
Tanaka, T. Synthesis 2011, 2567. (g) Nitti, A.; Bianchi, G.; Po, R.;
Swager, T. M.; Pasini, D. J. Am. Chem. Soc. 2017, 139, 8788.
(h) Woods, B. P.; Baire, B.; Hoye, T. R. Org. Lett. 2014, 16, 4578.
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Curr. Med. Chem. 2003, 10, 1353. (c) Matsumoto, K.; Nagashima,
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T.; Kato, T.; Iatazaki, H. J. Antibiot. 1995, 48, 439.
Taking into account the absence of cleavage of the furan
ring in the case of synthesis of acids 3 (see Scheme 2), be-
low we made preliminary conclusions about the mecha-
nism for formation of isoindoles 19.
(3) Haj-Yehia, A.; Khan, M. US 20060258652A1, 2006.
It seems obvious, that the mechanism for the formation
of compounds 19 should include all steps of the mechanism
for the formation of furo[2,3-f]isoindole-4-carboxylic acids
3, shown in Scheme 3, and lead to isomeric furo[2,3-f]isoin-
dole-8-carboxylic acids 16 (Scheme 5). However, the spatial
closeness of the oxygen atom of the furan ring and the hy-
droxyl group in acids 16 promotes the formation of an in-
tramolecular H-bond, which, in the extreme case, gives rise
to formation of zwitterion 17. The nucleophilic attack by a
bromine anion on the C-2 atom of this ion, with the simul-
taneous cleavage of the furan ring, leads to anion 18. In or-
der to improve the yield of isoindole 19a, we have used 1
equiv of KBr or BrNBu4 as exogenous sources of a bromine
anion, but the yield of the product remained close to 30%.
In conclusion, in the first part of this work, we have pro-
posed an easy tandem sequence that allows fast assembling
of benzoic acids annelated with both hydrogenated furan
and pyrrole rings from readily available 3-(furan-2-yl)allyl-
amines and bromomaleic anhydride. The more attractive
feature of the sequence from a theoretical point of view is
an unexpected ‘transposition of aromaticity’ from a furan
to a cyclohexene ring. From the results of the second part of
the research, it should be emphasized the high atom-effi-
ciency of the interaction between 3-(furan-3-yl)allylamines
and bromomaleic anhydride, proceeding without loss of a
single atom and, at the same time, with a complex rear-
rangement of the carbon skeleton of the starting molecules.
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Dorovatovskii, P. V.; Khrustalev, V. N.; Varlamov, A. V. Tetrahe-
dron 2016, 72, 2239. (c) Horak, Y. I.; Lytvyn, R. Z.; Homza, Y. V.;
Zaytsev, V. P.; Mertsalov, D. F.; Babkina, M. N.; Nikitina, E. V.;
Lis, T.; Kinzhybalo, V.; Matiychuk, V. S.; Zubkov, F. I.; Varlamov,
A. V.; Obushak, M. D. Tetrahedron Lett. 2015, 56, 4499.
(8) Polyanskii, K. B.; Alekseeva, K. A.; Raspertov, P. V.; Kumandin, P.
A.; Nikitina, E. V.; Gurbanov, A. V.; Zubkov, F. I. Beilstein J. Org.
Chem. 2019, 15, 769.
(9) Bromomaleic anhydride as an internal dienophile: (a) Mellor, J.
M.; Wagland, A. M. J. Chem. Soc., Perkin Trans. 1 1989, 997.
(b) Mellor, J. M.; Wagland, A. M. Tetrahedron Lett. 1987, 28,
5339.
Funding Information
(10) General Procedure for the Synthesis of the Initial Allyl-
amines 2 and 15
Funding for this research was provided by the Russian Science Foun-
dation (RSF, project no. 18-13-00456).
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Powdered anhydrous MgSO4 (1.97 g, 16.4 mmol) was added to a
stirred solution of 2-furylacrolein or 3-furylacrolein (1.00 g, 8.2
mmol) and the corresponding amine (8.2 mmol) in CH2Cl2 (20
mL) at r.t. After approx. 12 h, MgSO4 was filtered off through a
fine layer of SiO2, washed with CH2Cl2 (2 × 15 mL), and the solu-
tion was concentrated under reduced pressure. The residue was
diluted with MeOH (20 mL), and then NaBH4 (0.62 g, 16.4
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690782.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
K. A. Alekseeva et al.
Letter
Synlett
mmol) was added in small portions within 10 min. The solution
was vigorously stirred for 3 h at r.t., then the reaction mixture
was poured into H2O (80 mL) and extracted with CH2Cl2 (3 × 30
mL); the combined organic layers were dried over anhydrous
MgSO4, concentrated, and the residue was used in the next
stage after purification via flash chromatography (a mixture of
hexane/EtOAc was used as eluent).
Selected Physical and Spectral Data for Compound 2b
Brown oil; 68% yield (0.92 g). 1H NMR (600.2 MHz, CDCl3, 22 °C):
 = 7.31 (br d, J = 1.7 Hz, 1 H, H-5-Fur), 6.36–6.33 (m, 2 H, H-4-
Fur and H-3-Vinyl), 6.23 (d t, J = 6.1, 15.6 Hz, 1 H, H-2-Vinyl),
6.18 (br d, J = 3.5 Hz, 1 H, H-3-Fur), 3.36 (d d, J = 1.0, 6.1 Hz, 2 H,
N-CH2-CH=), 2.87 (hept, J = 6.1 Hz, 1 H, CHMe2), 1.73 (br s, 1 H,
NH), 1.08 (d, J = 6.1 Hz, 6 H, CHMe2) ppm. 13C NMR (150.9 MHz,
CDCl3, 24 °C):  = 152.8, 141.7, 127.7, 119.5, 111.2, 107.1, 49.1,
48.0, 23.0 (2 C) ppm.
General Procedure for the Synthesis of the Target Furo[2,3-
f]isoindolecarboxylic Acids 3 and 19
Bromomaleic anhydride (0.27 g, 1.5 mmol) was added to a solu-
tion of the appropriate allylamine 2 or 15 (1.5 mmol) in abs.
1,4-dioxane (10 mL). The mixture was heated at reflux (ca. 100
°C) for 1 h. The reaction mixture was cooled to r.t., and the
obtained solid was filtered off, washed with ethanol (3 × 3 mL),
and dried in the air. If necessary, the target compounds may be
recrystallized from a mixture of EtOH/DMF.
Selected Physical and Spectral Data for Compound 3b
Beige needles; 76% yield (0.30 g), mp 286.3–286.5 °C (with
decomp.). 1H NMR (600.2 MHz, DMSO-d6, 140 °C):  = 7.15 (s, 1
H, H-8), 4.69 (t, J = 8.7 Hz, 2 H, H-2), 4.53 (s, 2 H, H-7), 4.44
(hept, J = 6.7 Hz, 1 H, CHMe2), 3.61 (t, J = 8.7 Hz, 2 H, H-3), 1.34
(d, J = 6.7 Hz, 6 H, CHMe2) ppm. 13C NMR (100.5 MHz, DMSO-d6,
140 °C):  = 169.3, 165.1, 164.9, 146.1, 134.3, 126.5, 122.0,
107.2, 73.2, 47.01, 44.9, 31.1, 20.4 (2 C) ppm.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F