Synthesis of spiro-annelated pyroglutamides by the Ugi reaction

Article abstract of DOI:10.1016/j.mencom.2013.07.020

Three component Ugi reaction between 1-(2-oxoethyl)cycloalkanecarboxylic acids, amines and isocyanides affords spirocyclic N-substituted 5-carbamoyl-2-pyrrolidones.

Full text of DOI:10.1016/j.mencom.2013.07.020

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 233–234
Synthesis of spiro-annelated pyroglutamides by the Ugi reaction
Vasiliy Yu. Stolyarenko*, Anatoliy A. Evdokimov and Vladimir I. Shishkin
Moscow State University of Radioelectronics, Engineering and Automation, 119454 Moscow, Russian Federation.
Fax: +7 495 433 4688; e-mail: vstolyarenko@gmail.com
DOI: 10.1016/j.mencom.2013.07.020
Three component Ugi reaction between 1-(2-oxoethyl)cycloalkanecarboxylic acids, amines and isocyanides affords spirocyclic
N-substituted 5-carbamoyl-2-pyrrolidones.
Spirocyclic fragment is not uncommon among low-molecular
biologically active compounds. For example, minalrestat is used
for the treatment of diabetes,1 RS-86 is a neurological drug,2
tiaspirone is an anti-migraine drug,3 buspirone is a drug for
attention deficit – hyperactivity disorder treatment.4 g-Lactam
cycle is the fundamental structural moiety within a wide class of
drugs called ‘racetams’ which exhibit neurophysiological activity.
N-Substituted g-lactams are known as nootropic drugs (piracetam,5
aniracetam6). Compounds of the same class with various substi-
tuents in the pyrrolidone cycle possess anticonvulsant and anti-
epileptic properties (seletracetam7). Therefore, compounds based
on spirocyclic N-substituted g-lactams can be of a great interest
in the sight of their potential biological activity.
Table 1 Yields of products 21–25.
Compound R1
R2
Yield (%)
21a
21b
21c
21d
21e
22a
22b
22c
22d
22e
Pri
But
But
2,6-Me2C6H3
4-ClC6H4
4-ClC6H4
67
70
73
72
83
MeO(CH2)2
MeO(CH2)2
cyclopropylmethyl
Bui
(benzo[d][1,3]dioxol-5-yl)methyl But
3,4-Me2C6H3CH2
4-Cl-3-MeC6H3
Bui
68
71
But
Me2CH(CH2)2 69
4-FC6H4CH2
4-FC6H4CH2
But
But
2,6-Me2C6H3
But
But
72
82
3-ClC6H4
23a
23b
23c
3,4-Me2C6H3CH2
3,4-F2C6H4
3,4-F2C6H4
82
92
87
The Ugi reaction8 of oxo acids with amines and isocyanides
results in a lactam formation thus affording various classes of
aromatic,9,10 heteroaromatic11–13 and aliphatic10,14–16 compounds.
However, application of oxo acids in the Ugi reaction, lead-
ing to spirocyclic products, have not been explored. Herein, we
synthesized new g-oxo acids 16–20 of 1-(2-oxoethyl)cycloalkane-
carboxylic type and used them as bifunctional reactants in the Ugi
reaction (Scheme 1). Reaction of these compounds under the Ugi
conditions gave 5-carboxamide-substituted spirocyclic g-lactams
21–25 which can be regarded as spiro-annelated pyroglutamic
acid derivatives.
24a
24b
24c
24d
4-MeSC6H4CH2
4-Cl-3-FC6H3CH2
4-MeOC6H4
68
82
Me2CH(CH2)2 78
3-MeC6H4CH2 67
cyclopropylmethyl
25a
25b
25c
25d
25e
25f
MeO(CH2)2
(3-pyridyl)methyl
Ph
MeO(CH2)2
(3-pyridyl)methyl
Ph
But
59
73
69
78
89
75
But
But
2,6-Me2C6H3
2,6-Me2C6H3
2,6-Me2C6H3
H2C
Synthesis of compounds 6–10 and 11–15 was described
earlier.17 Ethyl esters 11–15 were hydrolyzed under mild condi-
tions, using LiOH·H2O in aqueous THF media. Due to their
instability, oxo acids 16–20 were immediately introduced into
the Ugi reaction with primary amines and isocyanides (12–20 h,
TLC control).† Yields of the target products 21–25 were 59–92%
(Table 1).
CHO
CO2Et
X
CO2Et
CO2Et
iii
i
ii
X
X
1–5
6 96%
7 90%
8 93%
9 98%
10 80%
11 81%
12 83%
13 85%
14 78%
15 82%
†
General procedure. Oxo ester 11–15 (10 mmol) was dissolved in THF
(50 ml). Solution of LiOH·H2O (15 mmol) in 20 ml of water was added
dropwise at 5–10°C. After stirring at room temperature (3–8 h, TLC
control) the mixture was concentrated to approximately quarter of volume,
diluted with 50 ml of water and washed with Et2O (3×30 ml). The water
layer was acidified with 5% H2SO4 to pH 5, the product was extracted with
Et2O (3×30 ml), dried over Na2SO4 and concentrated in vacuo. The crude
oxo acids were unstable and were immediately processed further. Primary
amine (0.55 mmol) and oxo acid (0.50 mmol) were dissolved in EtOH
(3.0 ml). Isocyanide (0.55 mmol) was added and the reaction mixture was
stirred at 60–65°C for 12 h, then evaporated in vacuo. The residue was dis-
solved in EtOAc (3 ml) and treated with 5 ml of saturated aqueous NaHCO3,
the organic layer was separated, the aqueous one was extracted with EtOAc
(2×2 ml). The combined organic extracts were washed with water (2×5 ml),
dried over Na2SO4 and concentrated in vacuo. The residue was treated with
10% EtOAc in Et2O (to cause crystallization of the product), or purified
by chromatography (silica gel, EtOAc–hexane, 1:20 ® 1:10). For charac-
teristics of the products, see Online Supplementary Materials.
R1
N
CHO
CO2H
O
O
R2
iv
N
H
X
X
16–20
1, 6, 11, 16, 21 X = CH2
2, 7, 12, 17, 22 X = (CH2)2
3, 8, 13, 18, 23 X = (CH2)3
4, 9, 14, 19, 24 X = CH2OCH2
21–25
5, 10, 15, 20, 25 X = CH2N(Boc)CH2
Scheme 1 Reagents and conditions: i, LDA, allyl bromide, THF, –60°C;
ii, NaIO4, OsO4 (cat.), 2,6-lutidine, dioxane, water, room temperature; iii,
LiOH·H2O, THF, water; iv, R1NH2, R2N+ºC–, EtOH, 60°C.
© 2013 Mendeleev Communications. All rights reserved.
– 233 –

Mendeleev Commun., 2013, 23, 233–234
F(2)
C(11)
C(12)
C(10)
C(18)
C(19)
C(13)
C(14)
F(1)
C(9)
C(8)
C(11)
C(3)
C(17)
C(20)
C(10)
O(1)
C(16)
C(9)
N(1)
O(1)
C(15)
C(15)
O(2)
Cl(1)
C(16)
N(1)
C(14)
C(10)
N(1)
C(7)
C(2)
C(8)
C(14)
C(13)
C(13)
C(3)
C(4)
N(2)
C(17)
C(18)
C(9)
C(8)
O(1)
C(1)
C(2)
C(12)
N(2)
C(20)
C(11)
C(12)
O(2)
O(4)
C(1)
C(2)
C(1)
C(4)
C(5)
C(7)
N(2)
O(2)
O(3)
C(19)
C(16)
N(3)
C(7)
C(22)
C(23)
C(21)
C(6)
C(15)
C(6)
C(3)
C(6)
C(24)
C(5)
C(17)
C(5)
C(4)
C(18)
21e
23b
25c
Figure 1 General view of the molecules 21e, 23b and 25c.
After crystallization of compounds 21e, 23b and 25c‡ from
acetonitrile, the crystals of a suitable shape were obtained. The
results of X-ray diffraction analysis proving the supposed struc-
tures of the target products are presented in Figure 1.§
Thus, three component Ugi reaction employing the g-oxoacids,
amines and isocyanides led to a series of previously undescribed
spirocyclic N-substituted g-lactams 21–25 in good yields.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.07.020.
‡
N-(4-Chlorophenyl)-6-isobutyl-5-oxo-6-azaspiro[3.4]octane-7-carbox-
amide 21e. Yield 83%, beige solid, mp 183–185°C. 1H NMR (400 MHz,
CDCl3) d: 8.04 (s, 1H), 7.54 (d, 2H, J 8.8 Hz), 7.30 (d, 2H, J 8.8 Hz),
4.12 (dd, 1H, J 4.0 and 8.0 Hz), 3.62 (dd, 1H, J 13.6 and 8.8 Hz), 2.76
(dd, 1H, J 13.6 and 5.6 Hz), 2.57 (dd, 1H, J 13.6 and 8.8 Hz), 2.49 (m, 2H),
2.32 (dd, 1H, J 13.6 and 6.8 Hz), 2.00 (m, 5H), 0.92 (d, 3H, J 6.8 Hz),
0.83 (d, 3H, J 6.8 Hz). MS (ESI), m/z: 335.8 [M+H]+.
N-(tert-Butyl)-2-(3,4-difluorophenyl)-1-oxo-2-azaspiro[4.5]decane-
3-carboxamide 23b. Yield 92%, white solid, mp > 200°C. 1H NMR
(400 MHz, CDCl3) d: 7.64 (m, 1H), 7.15 (m, 2H), 5.35 (s, 1H), 4.39 (dd,
1H, J 8.8 and 6.4 Hz), 2.52 (dd, 1H, J 13.6 and 8.8 Hz), 2.01 (dd, 1H,
J 13.6 and 6.4 Hz), 1.70 (m, 6H), 1.49 (m, 1H), 1.36 (m, 3H), 1.22 (s, 9H).
MS (ESI), m/z: 365.6 [M+H]+.
References
1 M. S. Malamas and T. C. Hohman, Drugs Fut., 1994, 19, 442.
2 Y. Ishihara, H. Yukimasa, H. Miyamoto and G. Goto, Chem. Pharm.
Bull., 1992, 40, 1177.
3 M. S. Eison, D. P. Taylor, J. S. New and J. L. Minielli, Drugs Fut., 1985,
10, 731.
4 Y.-H. Wu, J. W. Rayburn, L. E. Allen, H. C. Ferguson and J. W. Kissel,
J. Med. Chem., 1972, 15, 477.
5 S. J. Dimond and E. M. Brouwers, Psychopharmacology, 1976, 49, 307.
6 I. Ito, S. Tanabe, A. Kohda and H. Sugiyama, J. Physiol., 1990, 424, 533.
7 G. Martella, P. Bonsi, G. Sciamanna, P. Platania, G. Madeo, A. Tassone,
D. Cuomo and A. Pisani, Epilepsia, 2009, 50, 702.
8 A. V. Ivachtchenko, Ya. A. Ivanenkov, V. M. Kisyl, M. Yu. Krasavin and
A. P. Ilyin, Russ. Chem. Rev., 2010, 79, 787 (Usp. Khim., 2010, 79, 861).
9 C. Hanusch-Kompa and I. Ugi, Tetrahedron Lett., 1998, 39, 2725.
10 Z. Xu, M. Ayaz, A. A. Capelli and C. Hulme, ACS Comb. Sci., 2012, 14,
460.
11 A. P. Ilyn, J.A. Kuzovkova, V. V. Potapov,A. M. Shkirando, D. I. Kovrigin,
S. E. Tkachenko and A. V. Ivachtchenko, Tetrahedron Lett., 2006, 46, 881.
12 M. Ghandi, N. Zarezadeh and A. Taheri, Tetrahedron Lett., 2012, 53,
3353.
tert-Butyl 3-(N-tert-butylcarbamoyl)-1-oxo-2-phenyl-2,8-diazaspiro-
[4.5]decane-8-carboxylate 25c. Yield 62%, beige solid, mp > 200°C.
1H NMR (400 MHz, CDCl3) d: 7.50 (d, 2H, J 8.0 Hz), 7.40 (t, 2H, J 8.4 Hz),
7.22 (t, 1H, J 7.2 Hz), 5.38 (s, 1H), 4.53 (m, 1H), 4.04 (m, 2H), 3.03 (m,
2H), 2.52 (m, 1H), 2.13 (m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.65 (m, 2H),
1.58 (m, 1H), 1.48 (s, 9H), 1.16 (s, 1H). MS (ESI), m/z: 430.8 [M+H]+.
§
All measurements were performed on a Bruker SMART APEX2 CCD
diffractometer [l(MoKa) = 0.71073 Å]. All calculations were performed
using SHELXTL 5.1.18
Crystal data for 21e. Crystals (C18H23ClN2O2, M = 334.83) are mono-
clinic, space group P21/c, at 100(2) K: a = 14.0887(9), b = 11.3599(7)
and c = 10.9088(7) Å, b = 101.4250(10)°, V = 1711.32(19) Å3, Z = 4,
dcalc = 1.300 g cm–3, m(MoKa) = 0.235 cm–1, F(000) = 712. 14336 reflec-
tions were measured (2q < 58°), from which 4558 are independent (Rint
= 0.0286), wR2 = 0.1820 and GOF = 1.056 for all independent reflections
[R1 = 0.0642 for observed reflections with I > 2s(I)].
13 M. Krasavin and M. M. Nikulnikov, Mendeleev Commun., 2012, 22, 41.
14 S. Marcaccini, D. Miguel, T. Torroba and M. García-Valverde, J. Org.
Chem., 2003, 68, 3315.
=
15 A. P. Ilyin, A. S. Trifilenkov, I. D. Kurashvili, M. Y. Krasavin and A. V.
Ivachtchenko, J. Comb. Chem., 2005, 7, 360.
16 M. Krasavin,V. Parchinsky,A. Shumsky, I. Konstantinov andA.Vantskul,
Tetrahedron Lett., 2010, 51, 1367.
17 V. Yu. Stolyarenko, A. A. Evdokimov and V. I. Shishkin, Mendeleev
Commun., 2013, 23, 108.
18 G. M. Sheldrick, Acta Crystallogr., Sect. A, 2008, A64, 112.
Crystal data for 23b. Crystals (C20H26F2N2O2, M = 364.43) are mono-
clinic, space group P21, at 100(2) K: a = 9.4469(6), b = 17.1418(10) and
c = 11.7537(7) Å, b = 92.0030(10)°, V = 1902.2(2) Å3, Z = 4, dcalc
=
= 1.273 g cm–3, m(MoKa) = 0.095 cm–1, F(000) = 776. 15009 reflec-
tions were measured (2q < 52°), from which 3852 are independent (Rint
=
= 0.0365), wR2 = 0.2233 and GOF = 1.003 for all independent reflections
[R1 = 0.0755 for observed reflections with I > 2s(I)].
Crystal data for 25c. Crystals (C24H35N3O4, M = 429.55) are mono-
clinic, space group P21/c, at 100(2) K: a = 19.8264(11), b = 11.4163(7)
and c = 10.5796(6) Å, b = 97.9730(10)°, V = 2371.5(2) Å3, Z = 4, dcalc
=
= 1.203 g cm–3, m(MoKa) = 0.082 cm–1, F(000) = 928. 19023 reflec-
tions were measured (2q < 58°), from which 6288 are independent (Rint
=
= 0.0281), wR2 = 0.1101 and GOF = 1.015 for all independent reflections
[R1 = 0.0408 for observed reflections with I > 2s(I)].
CCDC 918243–918245 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2013.
Received: 7th March 2013; Com. 13/4081
– 234 –