A convenient synthesis of heterocyclic compounds containing 11-oxo-6,11,12,13-tetrahydrodibenzo[b,g][1,5]oxazonine fragment

Article abstract of DOI:10.1016/j.mencom.2009.09.020

A convenient synthesis of rare diaryl-fused nine-membered heterocyclic scaffold using a novel modification of four-component Ugi condensation based on the usage of aromatic aldehyde-acid as bifunctional component is described.

Full text of DOI:10.1016/j.mencom.2009.09.020

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 287–289
A convenient synthesis of heterocyclic compounds containing
11-oxo-6,11,12,13-tetrahydrodibenzo[b,g][1,5]oxazonine fragment
Victor V. Potapov,a Nataliya A. Fetisova,a Alexandr V. Nikitina and Alexandre V. Ivachtchenko*b
a Department of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Region,
Russian Federation. E-mail: yai@chemdiv.com
b ChemDiv Inc., San Diego, CA 92121, USA. Fax: +1 858 794 4931; e-mail: av@chemdiv.com
DOI: 10.1016/j.mencom.2009.09.020
A convenient synthesis of rare diaryl-fused nine-membered heterocyclic scaffold using a novel modification of four-component
Ugi condensation based on the usage of aromatic aldehyde-acid as bifunctional component is described.
Among a variety of physiologically active aryl- and heteroaryl-
fused six- and seven-membered heterocyclic systems, including
morpholines and oxazepines, nine-membered diaryl-fused hetero-
cycles form a relatively little-explored group with a pronounced
pharmaceutical importance. In many cases, their structures
strongly resemble the specific composition of low-membered
analogues according to the fundamental bioisosteric rules.
Therefore, the biological activity of such compounds should be
described jointly to illustrate key structural and topological
features.
Differently substituted 5(3)-oxo-1,4-oxazepines were described
as effective protease inhibitors,1 non-peptidergic GPCR inhi-
bitors,2 integrin antagonists,3 squalene synthase4 and reverse
transcriptase inhibitors.5 Thus, several oxazepines and their
bioisosteric analogues I,1(a),6 II,7,8 III7,8 and IV9 (Figure 1) were
shown to have a wide spectrum of physiological activity while
their carboxamide analogues are still in development or in early
stages of pre-clinical trials.
As shown in Figure 1, the compounds V we have obtained
contain the core diaryl-fused nine-membered heterocyclic frag-
ment, which is structurally very similar to several known aryl-
and heteroaryl-fused 1,4-oxazepinones in terms of the funda-
mental bioisosteric rules. Furthermore, the carboxamide moiety
of compounds V is in a close topological similarity with the
peripheral alkyl fragments in structures of the above pharma-
cological agents. Here, we report the development of a novel
Ugi-type multi-component reaction (MCR) for the synthesis of
rare heterocyclic compounds belonging to this scaffold.
The Ugi reaction10 was shown to be an effective approach
to the assembly of diverse compound libraries, which can be
readily applied in combinatorial chemistry format. An important
modification of the classical four-component Ugi reaction
includes the use of bifunctional reagents.9,11(a)
O
OH
Recently, we have developed an advanced variant of Ugi
MCR using heterocyclic keto- and aldehide-acids as one of the
initial bifunctional components.12–17 In particular, using this
prospective strategy, we have developed efficient synthetic
routes to aryl and/or heterocycle-fused six- and seven-mem-
bered carbamoyl-β-lactams VI13 and VII,14 VIII15 and IX,15
O
N
N
H
NH
O
O
X
16 and XI16 as well as XII17 (Figure 2).
OH
I
ACE inhibitor
We have clearly demonstrated the high efficacy and versatility
of this coupling strategy for the production of combinatorial
libraries of various heterocyclic structures representing promising
pharmaceutically relevant synthetic targets. Note that, based on
a bifunctional reagent, we have recently developed an analogous
synthetic route to carbamoyl substituted 6-oxo-4,5,6,11-tetra-
hydropyrrolo[1,2-b][2,5]benzodiazocines using a novel Ugi-
type MCR.18
F3C
NMe2
N
NMe2
O
O
N
N
N
Me
Me
O
S
II
III
In this work we have focused specifically on broadening
the scope and synthetic potential of the modified Ugi four-
center three-component reaction based on the use of bifunc-
tional components (Figure 2). Following the current synthetic
approach, we have obtained heterocyclic compounds 5a,b based
on 2-[(2-formylphenoxy)methyl]benzoic acid 4 (Scheme 1).
Thus, key bifunctional compound 4 was obtained from acid 1
and corresponding salicylaldehyde 2 using a modified approach
reported by Guillaumel et al.19 In the first step of our synthesis,
aldehyde-ester 3 was easily obtained in 75% yield by the reac-
tion of 1 with 2 in Me3CN at 80 °C in the presence of K2CO3.
Compound 3 was then easily hydrolyzed by 5% alkali in a
mixture of ethanol and water (3:1, v/v), and resulting bifunc-
Histamin H1 receptor antagonists
O
O
N
O
N
R1
O
O
Me
HN
IV
HIV-1 reverse
transcriptase inhibitor
R2
V
Figure 1 Examples of physiologically active aryl-fused 1,4-oxazepinones
(structures I–IV) and compounds synthesized in this work (common
structure V).
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 287–289
In the performed condensation, the desired cyclic products
O
usually precipitated from the reaction mixtures after the reaction
was cooled to room temperature. These reactions afforded
the desired products in relatively low yields, depending on the
nature of coupling components. However, note that the yields of
reactions leading to such heterocyclic systems depend directly
on the size of the cycle assembled.20
O
R1
R3
R3
Het
N
O
Het
N
O
N
HN
R2
O
R1
HN
R2
VI
R3
VII
The obtained precipitate was purified by flash column
chromatography on silica gel. All compounds were obtained
as racemic mixtures of enantiomers. The assignment of all
Het
S
S
N
Het
Het
R3
Ar
O
O
1
synthesized structures was made on the basis of H NMR and
O
N
N
N
high-resolution mass-spectrometry data.‡
HN
HN
R2
R2
O
O
O
R1
R1
R1
To determine the structures of the resulting compounds
accurately, pure crystalline substances were obtained for com-
pounds 5a,b, thus allowing the analysis of individual compounds
through X-ray crystallography. Thus, the structure of 5a was
unambiguously established as 12-(4-methoxyphenyl)-N-(4-methyl-
benzyl)-11-oxo-6,11,12,13-tetrahydrodibenzo[b,g][1,5]oxazonine-
13-carboxamide (Figure 3) by single-crystal X-ray analysis.
Single crystals of compounds suitable for X-ray analysis were
grown by slow evaporation from diethyl ether. The corresponding
bond angles and lengths of these molecules in the asymmetric
unit are the same within three standard deviations§ (for details
see Online Supplementary Materials). As shown in Figure 3,
the space orientation of two bulky substituents derived from
amine and isonitrile components is completely different. The
inner oxazonine space turn can also be clearly recognized.
NH
VIII
X
R2
IX
Het
Het
N
N
Ar
Het
O
O
N
N
HN
R2
O
O
R1
R1
NH
XII
R2
XI
Figure 2 Examples of aryl and/or heterocycle-fused six- and seven-mem-
bered carbamoyl-β-lactams.
tional compound 4 was successfully isolated in 90% yield (for
the detailed synthetic protocols for intermediate compounds 1–4,
see Online Supplementary Materials).
†
General procedure for preparation of compounds 5a,b. Aldehyde-acid
4 (1.0 mmol) and the corresponding primary amine (1.5 mmol) were
dissolved in methanol (3 ml). The solution was kept for 10 min at room
temperature; then, isonitrile (1.5 mmol) was added and the resulting
mixture was stirred at 25 °C for 5–10 h. The reaction was followed by
TLC (5% MeOH in CH2Cl2). On completion, the reaction mixture was
cooled to room temperature, the formed precipitate was filtered off,
washed with methanol and, if required, purified by recrystallization from
diethyl ether of by chromatography on silica gel, eluting with CH2Cl2.
Target compounds 5a,b were obtained as colourless solids in compara-
tively low yields (28 and 30%, respectively) as the mixture of corre-
sponding enantiomers.
We have further found that the reaction of aromatic aldehyde-
acid 4 with amines and isonitriles in methanol at 25 °C led to
11-oxo-6,11,12,13-tetrahydrodibenzo[b,g][1,5]oxazonine-13-car-
boxamides 5a,b (Scheme 1).† Typically, the full conversion of
initial reactants was achieved within 5–10 h, depending on the
structure of the initial amines and isonitriles. The process
presumably follows the same initial course as the classical Ugi
condensation with an intermediate imine being attacked by the
isonitrile to give a nitrilium intermediate, which then under-
goes intramolecular cyclization.
‡
1
Analytical data for compounds 5a,b. H NMR spectra were recorded
on a Bruker AMX-400 or Varian spectrometer in [2H6]DMSO (300 MHz,
CCl4 as an internal standard). High-resolution mass spectra were recorded
using electrospray ionization time-of-flight reflectron experiments (ESI-
TOF) on an Agilent ESI-TOF mass spectrometer. Samples were electro-
sprayed into the TOF reflectron analyzer at an ESI voltage of 4000 V
and a flow rate of 200 μl min–1.
H
O
Br
O
O
K2CO3
H
5a: yield 30%, mp 211–213 °C. 1H NMR, d: 2.30 (s, 3H, Me), 3.82 (s,
3H, OMe), 4.19, 4.46 (dd, 2H, CH2N, J 12.6 Hz), 4.76, 5.37 (dd, 2H,
CH2O, J 12 Hz), 5.56 (br. s, 1H, NH), 6.20 (s, 1H, CH), 6.48–6.58 (m,
1H, Ar), 6.78–6.94 (m, 4H, Ar), 6.99, 7.07 (dd, 4H, Ar, J1 5.58 Hz,
J2 6.6 Hz), 7.20–7.38 (m, 3H, Ar), 7.52–7.64 (m, 3H, Ar), 7.74–7.84
(m, 1H, Ar). HRMS: 493.2121 (calc. for C31H28N2O4: 493.2122).
5b: yield 28%, mp 214–216 °C. 1H NMR, d: 0.86 (d, 6H, 2Me, J 6.6 Hz),
1.20–1.35 (m, 2H, CH2), 1.39–1.52 (m, 1H, CH), 3.07–3.36 (m, 2H,
CH2NH), 4.47, 5.11 (dd, 2H, CH2N, J1 14.8 Hz, J2 12.0 Hz), 4.47–4.55
(m, 1H, CH2O), 5.08–5.33 (m, 2H, CH2O + NH), 5.83 (s, 1H, CH),
6.74 (d, 2H, Ar, J 7.8 Hz), 7.05 (d, 2H, Ar, J 8.1 Hz), 7.20–7.24 (m, 2H,
Ar), 7.40–7.45 (m, 1H, Ar), 7.47–7.53 (m, 4H, Ar), 7.63 (m, 1H, Ar).
HRMS: 477.1934 (calc. for C28H29ClN2O3: 477.1939).
Me3CN,
80 °C,
5–6 h
O
OH
O
OMe
1
2
OMe
3, 75%
H
O
O
O
R1–NH2
R2–NC
KOH
EtOH/H2O
MeOH,
25 °C,
5–10 h
O
N
§
O
Crystal structure of 5a: empirical formula, C31H28N2O4, M = 492.55,
HN
O
R1
R2
orthorhombic, space group Pbca, a = 21.819(3), b = 9.3072(12) and
c = 25.577(3) Å, Z = 8, m = 0.084 mm–1. 29578 reflections were measured,
5089 independent reflections. Rint = 0.0816; R1 = 0.1330, wR2 = 0.2141;
final R indices: R1 = 0.0797, wR2 = 0.1770; R indices (all data): R1 =
= 0.1330, wR2 = 0.2141.
CCDC 746913 contains 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, 2009.
OH
4, 90%
5a R1 = 4-MeOC6H4,
R2 = 4-MeC6H3CH2, 30%
5b R1 = 4-ClC6H3CH2,
R2 = isopentyl, 28%
Scheme 1 Ugi-type synthesis of N-substituted 11-oxo-6,11,12,13-tetra-
hydrodibenzo[b,g][1,5]oxazonine-13-carboxamides 5a,b.
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Mendeleev Commun., 2009, 19, 287–289
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C(18)
C(17)
C(19)
C(28)
C(23)
O(21)
C(22)
C(27)
C(26)
C(20)
O(11)
C(21)
C(14)
C(16)
C(10)
C(9)
N(21)
8
9
N(12)
C(13)
C(15)
C(29)
C(1)
C(10A)
C(24)
C(25)
C(1A)
C(6)
O(5)
C(6A)
C(7)
C(8)
C(2)
C(4A)
C(4)
C(3)
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Figure 3 ORTEP plots (50% probability thermal ellipsoids) of compound
5a. Hydrogen atoms are omitted. Selected bond lengths (Å): C(1A)–C(13)
1.495(5), N(12)–C(13) 1.479(4), C(6)–C(6A) 1.503(5), O(5)–C(6) 1.459(4);
selected bond angles (°): N(12)–C(13)–C(1A) 111.2(2), O(5)–C(6)–C(6A)
109.5(3).
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In summary, we have developed a convenient synthetic strategy
to the assembly of the diaryl-fused derivatives of 1,5-oxazonine
heterocyclic scaffold based on a novel modification of the Ugi-
type four-component reaction. As a synthetic tool for creating
diverse compound libraries, the four-component condensation
presented in this work is quite acceptable for the usage of a
large number of potential input reactants. Therefore, it can be
comprehensively applied in a combinatorial format. Considering
the ease of the preparation of initial reactants, convenient syn-
thesis and isolation of products, this synthetic route provides a
new valuable entry to rare nine-membered heterocyclic systems,
which can be reasonably regarded as unique bioisosteric analogues
of related biologically active seven-membered heterocyclic agents.
The obtained compounds represent valuable starting points for
the development of compounds of biological interest.
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We are grateful to Dr. Y. A. Ivanenkov (ChemDiv Inc.) for
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manuscript.
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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.2009.09.020.
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Received: 15th January 2009; Com. 09/3267
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