The intramolecular Diels-Alder vinylfuran (IMDAV) reaction: a short approach to aza-analogues of pinguisane-type sesquiterpenes

Article abstract of DOI:10.1016/j.tetlet.2015.05.115

Abstract The reaction of readily accessible (3-furyl)allylamines with maleic anhydride, followed by a domino sequence involving acylation/cycloaddition/proton shift steps, led to the formation of furo[2,3-f]isoindoles - the aza-analogs of pinguisane-type

Full text of DOI:10.1016/j.tetlet.2015.05.115

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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The intramolecular Diels–Alder vinylfuran (IMDAV) reaction: a short
approach to aza-analogues of pinguisane-type sesquiterpenes
Yuriy I. Horak a, Roman Z. Lytvyn a, Yuriy V. Homza a, Vladimir P. Zaytsev b, Dmitriy F. Mertsalov b,
Maria N. Babkina b, Eugenia V. Nikitina b, Tadeusz Lis c, Vasyl Kinzhybalo d, Vasyl S. Matiychuk a,
b
a
Fedor I. Zubkov b, , Alexey V. Varlamov , Mykola D. Obushak
⇑
a Department of Organic Chemistry, Ivan Franko National University of Lviv, 6 Kyryla i Mefodiya St., Lviv 79005, Ukraine
b Department of Organic Chemistry, Peoples’ Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
c Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
d Institute of Low Temperature and Structure Research, Okolna 2, 50-422 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of readily accessible (3-furyl)allylamines with maleic anhydride, followed by a domino
sequence involving acylation/cycloaddition/proton shift steps, led to the formation of furo[2,3-f]-
isoindoles—the aza-analogs of pinguisane-type sesquiterpenes. The key intramolecular Diels–Alder
vinylfuran (IMDAV) reaction proceeded under mild conditions, with high levels of diastereoselectivity
and satisfactory yields.
Received 12 March 2015
Revised 25 May 2015
Accepted 29 May 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Furan
[2+4] cycloaddition
Diels–Alder reaction
IMDAV
Furo[2,3-f]isoindoles
Pinguisane-type sesquiterpenes
A large group of pinguisane-type sesquiterpenoids, possessing
the indeno[5,6-b]furan core, are widely distributed in liverworts.1
Compounds isolated from these plants show a broad and diverse
spectrum of biological activities that include antidermatitis,2 anti-
cancer,3 and antimicrobial4 activities. Several representative exam-
ples of such compounds, with structures closest to the subject of
this work, are shown in Figure 1.
It is well known that the introduction of an additional heteroa-
tom into a drug-molecule can dramatically alter its biological
activity. Thereby, this work was aimed at the development of a
simple entry to aza-analogues of pinguisane-type sesquiterpenes.
The intramolecular Diels–Alder furan (IMDAF) reaction5 is a
powerful and useful tool for the synthesis of alkaloids and other
natural and bioactive substances. The key step of such reactions
is the [2+4] cycloaddition where the furan moiety plays the role
of an internal diene (transformation 4 ? 5, Fig. 2). The related
intramolecular cycloaddition, where a vinylfuran fragment acts
as the internal diene—the intramolecular Diels–Alder vinylfuran
(IMDAV) reactions (7 ? 8),6 are much less studied.
Unlike IMDAF, use of IMDAV allows preservation of the furan
motif in the target molecules, making it possible to synthesize in
one step furans, that are [b]annulated with six-membered rings.
These benzo[b]furans (9, Fig. 2) are of ubiquitous structure in the
plant kingdom.7
A literature survey showed that to date a very limited number
of examples for the successful synthesis of benzofurans using the
IMDAV reaction have been described.7,8 Typically, this process
(7 ? [8] ? 9, Fig. 2) requires high temperatures8 (200–300 °C),
which restricts the synthetic potential of this method. In some
cases the reaction stops after formation of intermediate 88e or is
complicated by the formation of isomeric mixtures.8d Allenes and
alkynes7e,9 can also perform as the dienophile in this type of
transformation. Information about the synthesis of furo[2,3-
f]isoindoles using the IMDAV reaction is nearly absent.8f,10
The present communication is aimed at the development of a
simple approach to furo[2,3-f]isoindoles, based on the use of
readily available compounds such as furylacroleins and aliphatic
or aromatic amines.
Initially (3-furyl)allylamines 12a–l were synthesized by the
one-pot method,11 shown in Scheme 1. Neither azomethines 11
nor allylamines 12 were isolated, and were used in the next step
⇑
Corresponding author. Tel./fax: +7 495 952 2644.
E-mail address: fzubkov@sci.pfu.edu.ru (F.I. Zubkov).
http://dx.doi.org/10.1016/j.tetlet.2015.05.115
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Horak, Y. I.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.05.115

2
Y. I. Horak et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
Table 1
HO2C
O
Me
Me
O
Me
Yields and melting points of the obtained furo[2,3-f]isoindoles 15
Compound 15
R1
R2
Mp (°C)
Yielda (%)
Me
Me
Me
Me
a
b
c
d
e
f
g
h
i
H
H
H
H
H
Me
Me
2-CF3C6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
2-ClC6H4
2-FC6H4
i-Pr
Allyl
Cyclopentyl
Bn
Ph
224.9–225.5
186.9–187.5
215.5–216.5
212–214
251–252
234–235
178.5–179
250–251
293–294
247–248
234–235
72
40
70
62
64
61
82
74
69
72
70
75
1
pinguisone
deoxopinguison-15-oic
acid 2
MeO2C Me
O
HO2C
H
R
Ph
Bn
N
Me
CO2Me
O
4-MeOC6H4
2-FC6H4
Ph
4-MeOC6H4
4-MeOC6H4
O
H
bryopterin B 3
furo[2,3-f]isoindoles
(this work)
j
k
l
258–259
Figure 1. Representative examples of natural sesquiterpenes including the
indeno[5,6-b]furan moiety 1–3.
a
All yields are based on the initial furylacroleins 10.
IMDAF
IMDAV
- H2O
O
O
4
7
5
6
9
1,3-H
shift
O
O
O
8
Figure 2. An overview of IMDAF and IMDAV approaches in synthesis.
without purification. Amines 12a–l were acylated with an equimo-
lar amount of maleic anhydride under moderate heating. This reac-
tion did not stop at the N-acylation stage, and was followed by the
IMDAV reaction of the intermediate maleic amides 13a–l, and
spontaneous prototropic tautomerism of adducts 14a–l.12 The
described domino-cascade gave the target furo[2,3-f]isoindoles
15a–l in good yields (Table 1) as single diastereoisomers. The rela-
tive arrangement of the substituents was established using com-
pounds 15b13 (Fig. 3) and 15e.14
Figure 3. Molecular structure of one of two independent molecules of 15b.13
Molecule with (4R,4aR,7aS) absolute configuration is presented.
the O15 carbonyl atoms of neighboring molecules, giving rise to
(A. . .B. . .)n chains.
In summary, we have developed a practical one-pot, three-step
domino sequence for the construction of furans that are [b]-annu-
lated with a perhydro isoindole ring, using inexpensive and readily
available starting compounds. The use of maleic anhydride as the
dienophile gave rise to furo[2,3-f]isoindoles from an IMDAV reac-
tion. In contrast to existing methods, the IMDAV reaction was
observed to proceed under rather mild reaction conditions, and
with a high level of diastereoselectivity. Our synthetic groups
aim to continue exploring the fruitful chemistry described herein
by broadening the diversity of the initial dienes to 2-vinylthio-
phene, 2-vinylpyrrole, and 3-vinylindole moieties.
The relatively low yield (40%) of allyl derivative 15b (R2 = Allyl)
is postulated to be due to competitive side reactions of intermolec-
ular and intramolecular cycloaddition of the allyl substituent.
A single crystal X-ray structure determination was carried out
for compound 15b (Fig. 3). The crystal was found to be centrosym-
metric and its asymmetric part consisted of two independent
molecules, A and B (ESI, Fig. S1), of same chirality and similar
geometry. The only considerable difference between them was
the conformation of the allyl group. The isoindole five-membered
rings in both independent molecules adopt envelope conforma-
tions that are puckered on the C7a atom, whereas the six-mem-
bered rings are half-chair-puckered. The carboxyl hydrogen
atoms were involved in strong hydrogen bond formation with
Acknowledgments
The authors are grateful to the Ukrainian State Fund for
Fundamental Research (Grant No. F53.3/013) and the Russian
MgSO4/ CH2Cl2
CHO
R1
H
N
NaBH4/ MeOH
r.t, 2-4 h
O
N
R2
10
R1
R2
R1
O
r.t, 24 h
or EtOH/ AcONa
+
H2N
O
R2
Δ, 5 h
11a-l
12a-l
CO2H
O
O
O
HO2C
O
HO2C
H
H+
O
O
R2
R2
N
O
IMDAV
4
3
12a-l
5N6
PhH, Δ, 2-4 h
N
R2
7
R1
R1
R1
O
8
H
O
1
13a-l
14a-l
15a-l (40-82 %)
Scheme 1. Synthesis of initial 3-(furan-2-yl)prop-2-en-1-amines 12 and target furo[2,3-f]isoindoles 15.
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Y. I. Horak et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
2405; (e) Drew, M. G. B.; Jahans, A.; Harwood, L. M.; Apoux, S. A. B. H. Eur. J. Org.
Chem. 2002, 3589–3594; (f) Patre, R. E.; Gawas, S.; Sen, S.; Parameswaran, P. S.;
Tilve, S. G. Tetrahedron Lett. 2007, 48, 3517–3520.
Foundation for Basic Research for the financial support (grants no.
13-03-90400 and 13-03-00105).
9. (a) Hayakawa, K.; Yodo, M.; Ohsuki, S.; Kanematsu, K. J. Am. Chem. Soc. 1984,
106, 6735–6740; (b) Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z.
J. Comb. Chem. 2005, 7, 958–967.
Supplementary data
10. Sun, S.; Murray, W. V. J. Org. Chem. 1999, 64, 5941–5945.
Physicochemical properties, copies of 1H and 13C NMR spectra
for compounds 15a–l and the single crystal X-ray structure of
molecule 15b (Fig. S1). Supplementary data associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.05.115. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
11. The initial furylacrolein (R1 = H) and (5-methylfuryl)acrolein (R1 = Me) 10 are
commercially available compounds; (5-arylfuryl)acroleins (R1 = Ar) 10 were
synthesized as described in the ESI.
Synthesis of 3-(furan-2-yl)prop-2-en-1-amines 12a–g. To a stirred solution of
amine (20 mmol) and the corresponding furylacrolein 10 (20 mmol) in CH2Cl2
(50 mL) was added powdered anhydrous MgSO4 (4.8 g, 40 mmol) at rt. After ca.
4 h, the MgSO4 was filtered off, washed with CH2Cl2 (2 Â 20 mL), and the
solution concentrated. The residue yellow oil was diluted with MeOH (40 mL),
and NaBH4 (1.1 g, 20 mmol) was added. The mixture was stirred vigorously at
rt for 24 h, poured into H2O (200 mL), and extracted with CH2Cl2 (3 Â 70 mL).
The combined organic layers were dried (MgSO4), concentrated, and directly
used in the cycloaddition step.
References and notes
Synthesis of amines 12h–l. To
a solution of the less reactive 5-
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for isolation of pinguisane-type sesquiterpenes with the indeno[5,6-b]furan
core from natural sources, see: (c) van Klink, J. W.; Zapp, J.; Becker, H. Z.
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arylfurylacroleins 10 (20 mmol) in EtOH (50 mL) was added the
corresponding amine (20 mmol) and AcONa (1.64 g, 20 mmol). The mixture
was heated at reflux for 5 h, then cooled to rt, and poured into H2O (150 mL).
The obtained brown crystals were filtered off, washed with H2O, and dried in
the air. The crude product was used directly in the reduction step as described
above.
12. Synthesis of target furo[2,3-f]isoindoles 15. The crude allylamine 12 was
diluted with PhH (40 mL) and a solution of maleic anhydride (2.16 g, 22 mmol)
in PhH (20 mL) was added. The resulting mixture was heated at reflux for 2–4 h
(TLC monitoring) and then cooled to rt. The formed precipitate was filtered off,
washed with PhH (10 mL), Et2O (2 Â 10 mL), and dried in air to give the title
acids as white solids. Isolated compounds 15 could be recrystallized using
EtOH, EtOAc or their mixture as solvent to obtain analytical samples for final
characterization.
13. Crystallographic data for 15b: empirical formula: C14H15NO4, formula weight:
261.27 g/mol, crystal color, habit: colourless, needle, crystal system:
monoclinic, space group: P21/c (#14), a = 12.788(4), b = 10.140(3),
c = 19.527(5) Å, b = 97.94(3)°, V = 2507.8(13) Å3, T = 100(2) K, Z = 8,
Dcalc = 1.38 g/cm3, F(000) = 1104, diffractometer: Kuma KM4CCD, residuals:
R[F2>2 (F2)], wR(F2): 0.0487, 0.1145. Crystallographic data for the structure
r
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 1053271. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 (0)1233 336033 or e-mail deposit@ccdc.cam.ac.uk).
14. Detailed X-ray data for racemic furo[2,3-f]isoindole carboxylic acid 15e were
published earlier, see: Horak, Y. I.; Lytvyn, R. Z.; Zubkov, F. I.; Nikitina, E. V.;
Homza, Y. V.; Lis, T.; Kinzhybalo, V.; Obushak, M. D. Acta Cryst. 2013, E69,
o273–o274.
Please cite this article in press as: Horak, Y. I.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.05.115