Synthesis of Tetrazole-substituted Spirocyclic γ-lactams by One-pot Azido-Ugi Reaction-cyclization

Article abstract of DOI:10.1016/j.mencom.2013.03.020

1-Ethoxycarbonyl-1-(2-oxoethyl)cycloalkanes in the azido-Ugi reaction with primary amines, isocyanides and TMS-N₃ afford 3-(tetrazol-5-yl)-2- azaspiro[4.n]alkan-1-ones.

Full text of DOI:10.1016/j.mencom.2013.03.020

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 108–109
Synthesis of tetrazole-substituted spirocyclic
g-lactams by one-pot azido-Ugi reaction–cyclization
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.2013.03.020
1-Ethoxycarbonyl-1-(2-oxoethyl)cycloalkanes in the azido-Ugi reaction with primary amines, isocyanides and TMS-N3 afford
3-(tetrazol-5-yl)-2-azaspiro[4.n]alkan-1-ones.
Spirocyclic fragments are present in various low-molecular bio-
logically active compounds. In particular, g-lactam moiety is
the common structural unit for ‘racetames’ – the large class of
nootropic compounds. Therefore, compounds containing such
spirocyclic N-substituted g-lactams are of a great interest due
to their potential biological activity.
Chemical modification of products of isocyanide-based multi-
component reactions (including reactions involving chiral auxi-
larities1), especially their subsequent cyclization is one of the most
employed synthetic ways to such structures in the current medi-
cinal chemistry.2 Combination of these two steps allows obtaining
various heterocyclic products with high molecular diversity.3–8
In particular, using hydrazoic acid instead of carboxylic acid in
the classic Ugi reaction (usually generated in situ from TMS-azide
and corresponding alcohol) gives 1,5-disubstituted tetrazoles9,10
that are conformational mimetics of cis-amide group.11,12
The azido-Ugi reaction with the usage of bifunctional reactants
provides synthetic approaches to various classes of heterocyclic
compounds: piperazinone−tetrazoles,10 azepine−tetrazoles,13,14
benzdiazepine−tetrazoles,15 quinoxaline−tetrazoles16 and tetrazole-
substituted g-lactams17 (Scheme 1). However, to our knowledge
there are no literature examples describing synthesis of tetrazole-
substituted spirocyclic g-lactams.
This work describes an extension of such a trend towards a
special family of bifunctional reactants (Scheme 2). g-Oxo esters
9–12 having geminal CO2Et and CH2CHO fragments at saturated
cycle were readily accessed from (oxa)cycloalkanecarboxylates
1–4. Subjection of oxo esters 9–12 to the azido-Ugi reaction
followed by intramolecular amide bond formation gave 5-tetrazole
substituted spirocyclic g-lactams 13–16. This transformation
was based on the recent example describing subsequent steps
which were performed as a one-pot procedure employing methyl
levulinate.17
Synthesis of the target compounds 13–16 was performed
according to Scheme 2 (R1 and R2 are specified in Table 1).
In a typical experiment, cyclic esters 1–4 were alkylated with
allyl bromide.† Allylic derivatives 5–8 were oxidized with sodium
periodate in the presence of catalytic amounts of OsO4.‡ The
obtained g-oxo esters 9–12 were introduced into azido-Ugi
reaction with equimolar amounts of primary amines and iso-
cyanides (8–12 h, TLC control), followed by intramolecular amide
bond formation.§ Yields of the target compounds were 50–72%
(Table 1).
N
N
N
C
N
N
N
i, iii
N
C
R2
R3
N
N
F
N
H2C
N
i, iv
CO2Et
OTs
R3
R2
R1
CO2Et
N
i
ii
R1
O
R1
X
C
N
R3
R2
X
i, v
R4
N
1 X = CH2
5 X = CH2, 96%
N
R4
O
2 X = (CH2)2
3 X = (CH2)3
4 X = CH2OCH2
6 X = (CH2)2, 90%
7 X = (CH2)3, 93%
8 X = CH2OCH2, 98%
CO2Et
R
N
N
C
R1
R3
N
N
N
i, v
R
N
N
R2
CO2Et
N
N
N
N
N
N
N
CO2Me
R1
N
R2
CHO
N
N
ii, v
N
Me
CO2Et
iii, iv
R2
O
O
R1
R
N
N
N
N
Me
R2
N
X
CHO
X
ii, v
O
13a–e X = CH2
9 X = CH2, 81%
10 X = (CH2)2, 83%
11 X = (CH2)3, 85%
CO2Et
R1
14a–e X = (CH2)2
15a–e X = (CH2)3
16a–e X = CH2OCH2
N
R
12 X = CH2OCH2, 78%
O
Scheme 1 Various examples of azido-Ugi–cyclization employing bifunc-
tional reagents. Reagents and conditions: i, R1NH2, R2C(O)R3, TMS-N3,
MeOH; ii, R1NH2, R2N+ºC–, TMS-N3, MeOH; iii, SN2; iv, SNAr; v, cyclization.
Scheme 2 Reagents and conditions: i, LDA, allyl bromide, THF, –60°C;
ii, NaIO4, OsO4 (cat.), 2,6-lutidine, dioxane, water, room temperature;
iii, R1NH2, R2N+ºC–, TMS-N3, EtOH; iv, 10% TFA in DCE, 70–75°C.
© 2013 Mendeleev Communications. All rights reserved.
– 108 –

Mendeleev Commun., 2013, 23, 108–109
Table 1 Compounds 13–16.
C(20)
C(19)
C(15)
C(11)
Com-
R1
Yield
C(21)
C(18)
(%)
R2
C(12)
C(13)
pound
C(10)
C(9)
C(1)
C(16)
N(2)
13a
13b
13c
13d
13e
Cyclopropyl
4-Chlorophenyl
3,4-Dimethylbenzyl
Cyclopropyl
p-Tolyl
2-Methoxyethyl
2-Methoxyethyl
2-Methoxyethyl
Ph
Ph
But
But
4-Fluorobenzyl
4-Fluorobenzyl
4-Fluorobenzyl
52
55
59
65
67
C(17)
N(3)
C(8)
Br(1)
C(14)
C(20)
C(18)
C(15)
C(19)
N(1)
C(2)
C(4)
C(21)
C(12)
C(13)
C(11)
C(23)
N(4)
N(5)
O(1)
C(3)
C(5)
C(22)
C(10)
14a
14b
14c
14d
14e
Bui
56
72
56
51
65
C(7)
C(6)
O(3)
C(14)
C(9)
C(17)
C(16)
4-Methylsulfanylbenzyl
2-(2-Methoxyphenoxy)ethyl
Bui
C(1)
N(2)
C(8a)
N(5)
O(1)
C(2)
N(1)
C(4)
13e
N(3)
C(5)
4-Methylsulfanylbenzyl
N(4)
C(3)
C(6)
O(2)
15a
15b
15c
15d
15e
4-Fluorophenyl
2-(2-Pyridyl)ethyl
4-Fluorophenyl
4-Methylbenzyl
2-(2-Pyridyl)ethyl
But
52
58
50
58
50
C(8)
C(7)
But
2-Methoxyethyl
2-Methoxyethyl
3-Methoxybenzyl
16d
Figure 1 General view of the molecules of 13e and 16d.
16a
16b
16c
16d
16e
Cyclopropylmethyl
3-Fluorobenzyl
3-Fluorobenzyl
3-Fluorobenzyl
2-Methoxybenzyl
2-Methoxybenzyl
55
64
63
59
62
4-Bromo-3-methylphenyl
2-(1H-imidazol-4-yl)ethyl
4-Bromo-3-methylphenyl
2-(1H-imidazol-4-yl)ethyl
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.03.020.
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Allylation of cyclic esters 1–4 (general procedure). To a solution of
LDA (freshly prepared from 130 mmol of diisopropylamine and 130 mmol
of 2.5 m BuLi) in 90 ml of absolute THF at –60°C, 100 mmol of ester 1
was slowly added. The resulted solution was stirred at –60°C for 30 min,
then 130 mmol of allyl bromide was added dropwise keeping temperature
below –55°C. Stirring was continued at this temperature for 40 min, then
the reaction mixture was allowed to reach room temperature within 4–6 h.
Concentrated NH4Cl solution (75 ml) was slowly added, the organic layer
was separated and the water layer was extracted with EtOAc (3×50 ml);
the combined organic extracts were washed with 50 ml 10% H2SO4, water
(2×20 ml), brine (2×20 ml) and dried over Na2SO4. The solvent was
removed in vacuo at 60°C, and the residue was purified on silica gel
(hexane:EtOAc = 6:1). For characteristics of compounds 5–8, see Online
Supplementary Materials.
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‡
Oxidation of compounds 5–8 (general procedure). To a well-stirred
solution of 100 mmol of allylic compound 5–8 and 200 mmol of 2,6-lutidine
in 300 ml of dioxane and 30 ml of water, 0.5 mmol of OsO4 (2.5% solu-
tion in absolute ButOH) was added. After 15 min, 400 mmol of sodium
periodate was added. The mixture was stirred for 8–10 h, then diluted
with 500 ml of EtOAc. Inorganic precipitate was filtered off, the filtrate was
washed with water (3×300 ml), 10% H2SO4 (2×50 ml), saturated aqueous
Na2S2O3 solution (4×50 ml) and dried with Na2SO4. The solvent was removed
in vacuo, and the residue was purified on silica gel (hexane:EtOAc =
= 4:1). For characteristics of compounds 9–12, see Online Supplementary
Materials.
¶
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 13e. Crystals (C21H21N5O, M = 359.43) are monoclinic,
space group C2/c, at 296(2) K: a = 22.007(2), b = 11.2333(13) and c =
= 18.695(2) Å, b = 123.621(2)°, V = 3848.6(8) Å3, Z = 8, dcalc = 1.241 g cm–3,
m(MoKa) = 0.080 cm–1, F(000) = 1520. 13186 reflections were measured
(2q < 58°), from which 4197 are independent (Rint = 0.0817), wR2
= 0.1575 and GOF = 1.008 for all independent reflections [R1 = 0.0509
for 2712 observed reflections with I > 2s(I)].
=
§
Azido-Ugi reaction–one-pot cyclization (general procedure). Primary
Crystal data for 16d. Crystals (C24H26BrN5O3, M = 512.41) are triclinic,
amine (0.55 mmol), oxo ester 9–12 (0.50 mmol) and TMS-N3 (0.55 mmol)
were dissolved in EtOH (3.0 ml) in a vial. Isocyanide (0.60 mmol) was
added and the mixture was stirred at room temperature for 12 h, then
evaporated in vacuo. Subsequently, 10% TFA solution in DCE (3.0 ml)
was added and the reaction mixture was heated at 70–75°C for 8–10 h.
The mixture was treated with saturated aqueous K2CO3, the organic layer
was separated, the aqueous one was extracted with EtOAc (2×2ml). The
combined organic extracts were washed with water (2×5 ml). The organic
layer was dried over Na2SO4 and then concentrated in vacuo. The residue was
treated with 10% EtOAc in Et2O (to cause crystallization of the product)
or purified on silica gel (EtOAc:hexane = 1:10 ® 1:2). For characteristics
of compounds 13–16, see Online Supplementary Materials.
–
space group P1, at 293(2) K: a = 6.2629(9), b = 12.8858(17) and c =
= 14.605(2) Å, a = 94.657(2)°, b = 91.384(2)°, g = 90.916(2)°, V =
= 1174.3(3) Å3, Z = 2, dcalc = 1.449 g cm–3, m(MoKa) = 1.786 cm–1,
F(000) = 528. 12724 reflections were measured (2q < 58°), from which
5662 are independent (Rint = 0.0642), wR2 = 0.1147 and GOF = 0.965 for
all independent reflections [R1 = 0.0464 for 2758 observed reflections
with I > 2s(I)].
CCDC 918594 and 918596 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.
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