Thiophene-containing products of the Ugi reaction in an oxidation-triggered IMDA/aromatization cascade: A simple access to 3-oxoisoindolines

Article abstract of DOI:10.1016/j.tetlet.2010.07.135

A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transformation and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps. The second step is thought to include S-oxidation/IMDA/S-oxidation/ SO₂ extrusion/aromatization events.

Full text of DOI:10.1016/j.tetlet.2010.07.135

Tetrahedron Letters 51 (2010) 5657–5661
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiophene-containing products of the Ugi reaction in an oxidation-triggered
IMDA/aromatization cascade: a simple access to 3-oxoisoindolines
b
Mikhail Krasavin a,b, , Vadislav Parchinsky
*
a Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, 150000, Russia
b Chemical Diversity Research Institute, 2a Rabochaya St., Moscow Reg., Khimki 141400, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation
of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at
room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transforma-
tion and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps.
The second step is thought to include S-oxidation/IMDA/S-oxidation/SO2 extrusion/aromatization events.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 June 2010
Revised 13 July 2010
Accepted 23 July 2010
Available online 1 August 2010
Keywords:
Isocyanide-based multicomponent reactions
Post-Ugi transformation
Intramolecular Diels–Alder reaction
Oxidative cycloaddition
Thiophene oxidation
Sulfur dioxide extrusion
Aromatization
One of the prominent features of the Ugi multicomponent reac-
tion (U-MCR)1 is its remarkably broad scope with regard to the
choice of reagents. When the reagents for this four-component
process are selected so as to include both a diene and a dienophile,
a product is obtained which can undergo an intramolecular Diels–
Alder (IMDA) reaction. The latter may be energetically favored so
as to occur immediately after the Ugi event, or may require addi-
tional activation (e.g., thermal). The utility of the IMDA for post-
Ugi modification2 to create additional product complexity was
demonstrated, for instance, in the work of Schreiber.3 In this exam-
ple of diversity-oriented synthesis, a ‘complex enough’ 7-oxabicy-
clo[2.2.1]hept-2-ene Ugi/IMDA product 1 gave rise to an even more
complex and skeletally intriguing 7,5,5,7 polycyclic compound. In
another notable example disclosed by Paulvannan, an Ugi reaction
product containing an activated pyrrole moiety and an electron-
deficient alkyne underwent a similar reverse electron-demanding
IMDA on heating.4 The final product in this case was the 3-oxoiso-
indoline 2 formed as a result of a simple aromatization of the inter-
mediate IMDA product (Scheme 1).
zation could be achieved in one case with catalytic BF3ÁOEt2 under
microwave irradiation (Scheme 2). This approach, however, suffered
from limited scope and therefore we sought to develop an alternative
and, preferably, more chemically benign (in view of functional group
tolerance) strategy based on the Ugi/IMDA/aromatization sequence.
Among five-membered aromatic heterocycles, thiophene is
known to be the least reactive as a diene.7 Its two oxidized
forms—thiophene S-oxide and thiophene S,S-dioxide—are more
reactive dienes; the latter, however, often requires additional acti-
vation.8 Thiophene S-oxide can be regarded as an intermediate en
route to thiophene S,S-dioxide and cannot be isolated, unless spe-
cial precautions (such as carefully controlled reaction tempera-
ture9 and stabilization of the monoxide form toward further
oxidation by Lewis acid additives10) are taken.
As a highly reactive species, thiophene S-oxide can be trapped if
the thiophene oxidation is performed in the presence of a dieno-
phile.11 The resulting adduct 3 cannot be aromatized efficiently
and requires further chemical (e.g., KMnO4, under PTC conditions;
m-CPBA12) or electrochemical13 oxidation to give 4; the latter aro-
matizes via extrusion of sulfur dioxide (followed by another two-
electron oxidation) to give 5 (Scheme 3). Progression of the thio-
phene species through the oxidative cycloaddition will be ham-
pered if the oxidation and the dienophile trapping of thiophene
S-oxide are in competition [i.e., if k1(DA) ꢀ k2(ox)]. Once formed,
thiophene S,S-dioxide is essentially lost to the Diels–Alder reaction,
unless additional activation is applied (vide supra). We reasoned
that for an energetically favored (compared to an intermolecular
Previously, wereported5 that aromatization of Ugi/IMDA products
related to 1, aimed at 3-oxoisoindolines, was less straightforward. In
strong acidic medium at high temperatures (typical conditions for
dehydrative aromatization of 7-oxabicyclo[2.2.1]hept-2-enes6), an
unexpected rearrangement was observed, while the desired aromati-
* Corresponding author. Tel.: +7 (495) 995 4944; fax: +7 (495) 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.135

5658
M. Krasavin, V. Parchinsky / Tetrahedron Letters 51 (2010) 5657–5661
R
O
H
H
R
Ph
O
NH2
N
Ar
Ugi/IMDA
67%
H
O
N
Reference 3
H
N
H
O
O
O
+
O
N+
C
Ph
N
N
H
O
O
H
Ph
O
1
O
Ar
H
H
N
HO
N
Ar
H
R
O
Ph
Ph
O
O
NH2
HN
Ns
NsNH
Ns
N
100 oC, toluene
18 h
Ugi
N
N
Reference 4
+
N+
C
Ph
N
85%
O
H
O
Ph
N
O
2
O
Ph
HO
Scheme 1. Examples of complexity-generating Ugi/IMDA tandem processes.
F
F
HN
HN
O
F
F
O
O
O
O
.
O
85% H3PO4
BF3 Et2O (cat.)
O
O
O
80-100 oC, 2 h
75%
N
N
1,4-dioxane,MW
150 oC, 90 min
75%
N
N
N
H
N
H
H
O
O
O
Scheme 2. Aromatization of Ugi/IMDA-derived 7-oxabicyclo[2.2.1]hept-2-enes and their unexpected rearrangement in phosphoric acid.5
k1(ox)
k2(ox)
S
S
S
O
O
O
k2(DA)
k1(DA)
O
EWG
O
EWG
O
S
S
k1(DA) >> k2(DA)
[O]
[O]
- SO2
EWG
EWG
3
EWG
4
5
Scheme 3. Oxidized forms of thiophene, their interaction with dienophiles, and aromatization of the Diels–Alder adducts.
process) intramolecular cycloaddition, k1(DA) would be increased
and a suitable precursor (containing both a thiophene moiety
and an electron-deficient olefin) would be progressed effectively
through the oxidative cycloaddition route.
Two series of thiophene-containing precursors 6 and 7 were
synthesizedviatheUgireactioninmethanolfromeither5-methylthi-
ophene-2-carboxaldehyde or 2-aminomethylthiophene, respec-
tively. Without further purification,14 the crude product 6 or 7 was
treatedwithexcess(6–7 equiv)ofm-chloroperbenzoicacid(m-CPBA)
in CH2Cl2 at room temperature. After 24 h, the Ugi dipeptoids 6 or 7
were no longer present in the reaction mixture, as was evident from
LC–MS analysis, and the main product peak in each case displayed
an m/z value corresponding to the 3-oxoisoindolines 8 or 9, respec-
tively (Scheme 4), along with a number of unidentified by-products.
Following aqueous work-up of the reaction mixture (involving
quenching of unreacted m-CPBA with Na2SO3 solution), the 3-oxoiso-
indolines 8 and 9 were isolated in fair overall yields (from the Ugi
reaction precursors) using flash column chromatography (Table 1).

M. Krasavin, V. Parchinsky / Tetrahedron Letters 51 (2010) 5657–5661
5659
O
NH2
S
S
R3
R3
R1NH2
R2NC
R1CHO
R2NC
O
COOH
O
COOH
MeOH, r. t.
16-24 h
MeOH, r. t.
16-24 h
R3
R3
O
O
O
O
N
O
R2
N
N
R1
R2
H
S
R1
S
N
O
7
H
6
m-CPBA (6-7 equiv.)
CH2Cl2, r. t., 24 h
m-CPBA (6-7 equiv.)
CH2Cl2, r. t., 24 h
R3
O
R3
O
O
O
R1
R1
R2
N
R2
N
N
H
O
N
9
8
H
O
Scheme 4. Preparation of thiophene-containing precursors via the Ugi reaction and their transformation into 3-oxoisoindolines by treatment with m-CPBA.
Alternative oxidants (such as OxoneÒ, biphasic conditions, and per-
aceticacid)were alsofoundto triggerthe cycloaddition,albeitleading
to much lower (<10%) yields of the target 3-oxoisoindolines.
Notably, despite the relatively low chemical yield, no unreactive
(with respect to IMDA) thiophene S,S-dioxides 10 or 11 (Fig. 1)
were detected by LC–MS analysis in the crude reaction mixture fol-
lowing the oxidative cycloaddition step. This, in our view, exempli-
fied the fundamental correctness of the reasoning used in the
reaction design. From a mechanistic perspective, the transforma-
tions of 6 and 7 into 8 and 9, respectively, are thought to include
S-oxidation/IMDA/S-oxidation/SO2 extrusion/aromatization events
(Scheme 3).
The described assembly of two skeletally diverse series of 3-
oxoisoindolines involves two simple chemical operations (and only
one purification) and is extremely atom economic. Indeed, all the
Ugi reaction components were incorporated predictably into the
structure of the final product, with the loss of water via condensa-
tion in the Ugi step and extrusion of sulfur dioxide in the cycload-
dition/aromatization step. The excess oxidant was removed
completely on aqueous work-up and chromatographic separation
of the less polar target compounds from the more polar by-prod-
ucts was quite straightforward. These 3-oxoisoindolines represent
a relatively novel class of drug-like compounds recently discovered
by Abbott as inhibitors of poly(ADP-ribose) polymerase.15
Synthesis of 8 or 9; typical procedure (10 mmol scale, ambient
atmosphere): Equimolar amounts of an aldehyde and an amine in
MeOH (10 mL) were stirred at rt for 1 h. Isocyanide (1 equiv) was
added followed by a carboxylic acid (1 equiv) and stirring was con-
tinued for 18–24 h. In most cases (except 6d and 7c–e) the product
precipitated from the reaction mixture and was separated (at least
85% pure) by filtration. Otherwise, the mixture was concentrated,
the residue was dissolved in CH2Cl2 (50 mL) and washed with 10%
aq HCl (50 mL), 10% aq NaHCO3 (50 mL), and H2O (2 Â 25 mL). The
organic layer was dried over anhydrous MgSO4, filtered, and concen-
trated to provide the crude Ugi reaction product (at least 80% pure).
This material was dissolved in CH2Cl2 (40 mL), treated with m-CPBA
(7–8 equiv), and stirred at rt for 24 h. Concentrated aq Na2SO3
(10 equiv) was added and the resulting biphasic mixture was stirred
vigorously for 1 h. The aqueous layer was separated and the organic
layer was washed with satd aq NaHCO3 (3 Â 20 mL), to ensure com-
plete removal of m-CPBA, and with H2O (25 mL). Drying over anhy-
drous MgSO4, filtration, and evaporation of the solvent afforded the
crude product. The target 3-oxoisoindolines were isolated by flash
column chromatography on silica gel using an appropriate gradient
of EtOAc in hexanes as eluent.
Compound 8d beige solid, mp = 167–169 °C. 1H NMR (DMSO-d6,
400 MHz) d 8.92 (m, 1H), 7.37 (dd, J = 17.6, 7.7 Hz, 2H), 7.17 (d,
J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 5.23 (m, 1H), 5.16 (s, 1H),
4.24 (d, J = 4.8 Hz, 2H), 3.80 (m, 1H), 3.74 (s, 3H), 2.30 (s, 3H),
1.46–1.87 (m, 6H), 1.34 (br s, 6H), 1.20–1.43 (m, 3H), 0.99–1.14
(m, 1H). 13C NMR (DMSO-d6, 100 MHz) d 167.6, 166.2, 166.1,
158.3, 139.7, 133.8, 132.8, 130.5, 130.0, 128.7, 128.4, 122.1,
113.4, 95.4, 68.2, 61.3, 54.8, 52.3, 42.0, 30.1, 29.9, 25.3, 25.2,
24.9, 21.4, 21.3, 17.7. Anal. Calcd for C28H34N2O5: C, 70.27; H,
7.16; N, 5.85. Found: C, 70.35; H, 7.24; N, 5.77.
Compound 9b white solid, mp = 201 °C (dec). 1H NMR (CDCl3,
400 MHz) d 12.91 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 7.66 (dt,
Jd = 14.3 Hz, Jt = 7.7 Hz, 2H), 7.41–7.49 (m, 6H), 7.19–7.28 (m,
2H), 7.11 (t, J = 7.1 Hz, 1H), 6.16 (br s, 1H), 6.14 (s, 1H), 5.01 (d,
J = 17.9 Hz, 1H), 4.05 (d, J = 17.9 Hz, 1H), 3.98 (m, 1H), 2.40 (s,
3H), 1.85–1.95 (m, 2H), 1.30–1.65 (m, 10H). 13C NMR (CDCl3,
100 MHz) d 169.4, 167.4, 162.6, 143.5, 136.5, 134.6, 132.8, 132.3,
132.2, 131.8, 130.4, 129.1, 128.9, 128.2, 126.1, 125.8, 125.5,
125.4, 59.0, 51.1, 48.3, 34.7, 34.6, 27.8, 27.7, 24.0, 18.5. Anal. Calcd
for C31H33N3O3: C, 75.13; H, 6.71; N, 8.48. Found: C, 75.13; H, 6.67;
N, 8.42.

5660
M. Krasavin, V. Parchinsky / Tetrahedron Letters 51 (2010) 5657–5661
Table 1
3-Oxoisoindolines 8 and 9 prepared in this work from the Ugi reaction products 6 and 7, respectively
Entry
R1
R2
R3
First step
LC–MS [M+H+] m/z
Second step
Product Yield (%)
Product
F
1
2
6a
562.6
579.2
8a
8b
33
28
*
*
*
*
N
H
Cl
6b
*
*
N
H
*
F
3
4
5
6c
6d
6e
541.3
513.7
574.6
8c
8d
8e
45
29
26
*
*
N
H
Cl
MeO
*
O
*
*
*
*
*
*
*
N
H
MeO
*
O
O
6
7
8
7a
7b
7c
574.8
530.5
530.1
9a
9b
9c
47
38
28
*
N
H
*
*
N
H
F
*
O
*
*
Cl
*
O
O
9
7d
7e
535.6
521.4
9d
9e
34
39
O
O
*
*
*
*
*
O
O
10
R3
R3
References and notes
O
O
O
O
O
1. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
O
O
2. (a) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147
(comprehensive review); (b) Wu, J.; Yong, J.; Wei-Min, D. Synlett 2009, 1162–
1166; (c) Hulme, C.; Chapetta, S.; Griffith, C.; Lee, Y.-S.; Dietrich, J. Tetrahedron
Lett. 2009, 50, 1939–1942; (d) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74,
3109–3115; (e) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2009,
7, 253–258.
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Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125–4127.
4. Paulvannan, K. J. Org. Chem. 2004, 69, 1207–1214.
R2
R1
R2
N
N
N
H
S
S
R1
O
N
O
O
H
10
11
Figure 1. Structures of the unreactive thiophene S,S-dioxides (not observed).
5. Ilyin, A.; Kysil, V.; Krasavin, M.; Kurashvili, I.; Ivachtchenko, A. V. J. Org. Chem.
2006, 71, 9544–9547.
6. (a) Varlamov, A. V.; Sidorenko, N. V.; Zubkov, F. I.; Chernyshev, A. I. Khim.
Geterotsikl. Soedin. 2002, 79, 556–566; (b) Zubkov, F. I.; Boltukhina, E. V.;
Krapivko, A. P.; Varlamov, A. V. Khim. Geterotsikl. Soedin. 2003, 80, 1738–1740;
(c) Varlamov, A. V.; Boltukhina, E. W.; Zubkov, F. I.; Sidorenko, N. V.;
Chernyshev, A. I.; Grudinin, D. G. Khim. Geterotsikl. Soedin. 2004, 81, 27–33.
7. (a) Jursic, B. S. J. Heterocycl. Chem. 1995, 32, 1445–1455; for a rare example of a
low-yielding IMDA reaction involving a non-oxidized thiophene moiety, see:
(b) Santra, S.; Andreana, P. R. Org. Lett. 2007, 9, 5035–5038.
8. Kang, J.; Santamaria, J.; Hilmersson, G.; Rebek, J. J. Am. Chem. Soc. 1998, 120,
7389–7390.
Acknowledgment
This research was supported by the Federal Agency for Science
and Innovation (Russian Federation Government Contract
02.740.11.0092).
Supplementary data
9. Zeng, H.; Eguchi, S. Synlett 1997, 175–176.
10. Li, Y.; Thiemann, T.; Sawada, T.; Mataka, S.; Tashiro, M. J. Org. Chem. 1997, 62,
7962–7963.
11. Naperstkow, A. M.; Macaulay, J. B.; Newlands, M. J.; Fallis, A. G. Tetrahedron
Lett. 1989, 30, 5077–5080.
Supplementary data (characterization data for compounds 8a–
e and 9a–e) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.07.135.
12. Dongol, K. G.; Mataka, S.; Thiemann, T. J. Chem. Res. (S) 2003, 527–528.

M. Krasavin, V. Parchinsky / Tetrahedron Letters 51 (2010) 5657–5661
5661
13. Thiemann, T.; Sa e Melo, M. L.; Campos Neves, A. S.; Li, Y.; Mataka, S.; Tashiro,
M.; Geibler, U.; Walton, D. J. Chem. Res. (S) 1998, 346–347.
(DMSO-d6, 100 MHz) d 169.4, 167.9, 162.8, 160.1 (d, JC–F = 249.6 Hz), 139.1,
136.5 (d, JC–F = 3.4 Hz), 135.2, 134.9, 131.0, 129.3 (d, JC–F = 70.0 Hz), 127.3,
127.2, 125.3, 124.9, 124.6 (d, JC–F = 75.2 Hz), 123.5, 118.7 (d, JC–F = 17.8 Hz),
115.7 (d, JC–F = 20.7 Hz), 95.1, 58.8, 41.2, 29.0, 17.1, 14.1, 8.4, 7.5. Anal. Calcd for
14. Performing the oxidative transformation of purified Ugi reaction products into
the respective 3-oxoisoindolines did not improve the yields of the latter, as was
demonstrated for the following compound. Compound 6c: mp = 183 °C (dec).
1H NMR (DMSO-d6, 400 MHz) d 9.59 (s, 1H), 8.33 (t, J = 6.2 Hz, 1H), 7.34–7.42
(m, 2H), 7.06–7.21 (m, 5H), 6.85 (d, J = 3.2 Hz, 1H), 6.74 (d, J = 11.9 Hz, 1H), 6.61
(m, 1H), 6.36 (d, J = 11.9 Hz, 1H), 5.92 (s, 1H), 4.25 (d, J = 6.0 Hz, 2H), 2.59 (m,
1H), 2.40 (s, 3H), 2.20 (s, 3H), 0.81–0.89 (m, 1H), 0.54–0.77 (m, 3H). 13C NMR
C28H27ClFN3O3S: C, 62.27; H, 5.04; N, 7.78. Found: C, 62.36; H, 5.12; N, 7.85.
15. Gandhi, V. B.; Luo, Y.; Liu, X.; Shi, Y.; Klinghofer, V.; Johnson, E. F.; Park, C.;
Giranda, V. L.; Penning, T. D.; Zhu, G.-D. Bioorg. Med. Chem. Lett. 2010, 20, 1023–
1026.