Novel synthesis of oxonine derivatives from 3-[(2-aminophenyl)amino]-5,5- dimethyl-2-cyclohexene-1-one and o-quinones

Article abstract of DOI:10.1016/j.tetlet.2011.10.147

A new method for the synthesis of hitherto unreported 9-membered macrolactones by reaction of 3-[(2-aminophenyl)amino]-5,5-dimethyl-2-cyclohexen- 1-one with o-quinones in the presence of acidic catalysts is presented.

Full text of DOI:10.1016/j.tetlet.2011.10.147

Tetrahedron Letters 53 (2012) 67–70
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of oxonine derivatives from
3-[(2-aminophenyl)amino]-5,5-dimethyl-2-cyclohexene-1-one and o-quinones
Lev Yu. Ukhin a, Kyrill Yu. Suponitsky b, Eugenii N. Shepelenko c, Lyudmila V. Belousova a,
,
⇑
Gennadii S. Borodkin a
a Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 prosp. Stachki, Rostov on Don 344090, Russian Federation
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova st., Moscow 119991, Russian Federation
c Southern Scientific Center, Russian Academy of Sciences, 41 Chekhov st., Rostov on Don 344006, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2011
Revised 25 October 2011
Accepted 27 October 2011
Available online 4 November 2011
A new method for the synthesis of hitherto unreported 9-membered macrolactones by reaction of 3-[(2-
aminophenyl)amino]-5,5-dimethyl-2-cyclohexen-1-one with o-quinones in the presence of acidic cata-
lysts is presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3-[(2-Aminophenyl)amino]5,5-dimethyl-2-
cyclohexen-1-one
o-Quinones
9-Membered polycyclic systems
Reports on oxacyclononatetraene (1) (oxonine) derivatives are
quite rare. It is shown that under normal conditions, oxonine 1 ex-
ists in the form of the valence isomer, 9-oxabicyclo[6.1.0]nona-
2,4,6-triene (2).1–3 Electrocyclic rearrangement of 2?1 is possible
upon excitation only.3 Similar rearrangement to a bicyclic system
can be suppressed in benzannulated derivatives of oxonine. The
first representative, 4,5:6,7-dibenzoxonine (3) was synthesized
by Wittig reaction and was further catalytically hydrogenated to
tetrahydro derivative 4.4 The 1,4-biphenyloxonino[4,5-d]pyrida-
zine 5 obtained from 2 and 3,6-biphenyltetrazine appeared to be
stable (Scheme 1).5,6
Ph
N
N
O
O
Ph
O
1
2
5
2H2
O
O
3
4
A new synthetic method for the preparation of 10-membered
macrolactones from natural naphthoquinone lapachols 6 has been
described.7–10 One oxonine derivative, 9-membered macrolactone
9 was obtained recently via a similar reaction (Scheme 2).11 The
structures 7 and 8 in Scheme 2 are clearly incorrect; we reproduce
them here as they are given in the original paper.11
It was established that all the prepared macrolactones show
activities against Mycobacterium tuberculosis and one of these com-
pounds, (7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo[3,4]oxecino-
[5,6-b]quinoxaline-5,10-dione) presented almost equal activity
than the control antibiotic rifampicin.11 The discovery of new types
of molecules with antibacterial activity is necessary due to the
emergence of multidrug-resistant M. tuberculosis. We herein pres-
Scheme 1. Oxonine 1, its valence isomer 2 and derivatives 3–5.
ent new methods for the synthesis of hitherto unknown oxonine
macrolactones and discuss possible reaction mechanisms.
In continuation of our investigations on the reactivity of 3-(2-
aminophenylamino)-5,5-dimethyl-2-cyclohexen-1-one (10),12 we
found that its treatment with 3,5-di-tert-butyl-1,2-benzoquinone
(11a) in the presence of an acidic catalyst led to a mixture of 8,8-
dimethyl-7,8,9-trihydro-2,4-di-tert-butylbenzo[2,3]oxonino[4,5-b]
quinoxaline-6-one (12a) and 3-[2-(2-hydroxy-3,5-di-tert-butyl-
phenylamino)]-5,5-dimethyl-2-cyclohexen-1-one (13) (Scheme 3
and Fig. 1).
The reaction proceeds quickly in the presence of CF3COOH as
catalyst and under short-term heating, but does not occur at all
in the absence of catalyst. After mixing the initial reagents crystals
⇑
Corresponding author. Tel./fax: +7 863 243 4700.
E-mail address: may@ipoc.sfedu.ru (L.V. Belousova).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.147

68
L. Yu. Ukhin et al. / Tetrahedron Letters 53 (2012) 67–70
NH2
O
CuSO4,
NaOH
O
O
, HOAc
NH2
O
OH
O
7
6
N
N
N
N
(Ac)2O2/H2O2
CHCl3/r.t./24 h
O
O
O
O
8
9
Scheme 2. Synthesis of 9-membered macrolactone 9.
MeOH,
CF3COOH
O
O
H
N
+
-Bu
t
NH2
O
t
-Bu
11a
10
7
5
4
18
t
-Bu
2
3
H
16
6'
3'
6
4
1'
N
3
5'
4'
19
1
t
I
-Bu
15
N
17
5
1O 2
15b
II
14
11
14a
4a
2'
O
13
12
NH
15a
9a
+
1"
6 O
7
7"
OH
6"
10a
2"
9"
N
8
10
9
21
8"
3"
5"
11"
20
10" -Bu
-Bu
t
t
4"
13
12a
Scheme 3. Synthesis of macrolactone 12a and compound 13.
of 12a started to precipitate. The reaction also proceeds in
CH3COOH but the most appropriate solvents were alcohols (MeOH,
EtOH). The reaction products 12a and 13 are generated as a result
of quinone attachment to different reaction centers of 10. Forma-
tion of 12a was accompanied by elimination of both water mole-
cule and two H-atoms, that is, dehydration and oxidation. We
suggest that formation of 13 occurs via reduction of intermediate
14 with participation of two H-atoms. The process seems to be a
homogeneous electron transfer, where the intermediate 14 acts
as an oxidant. A synthetic method for the preparation of quinoni-
mines from 11a and primary aromatic amines under mild condi-
tions in the presence of HCOOH has been described.13 A possible
route for the reaction is presented in Scheme 4. The reaction was
carried out according to the representative procedure.14
It is difficult to determine, which compound is oxidized in the
sequence 10?12a. If formation of 12a and 13 is a parallel process
(path A) then the product of attachment of 11a to enamine frag-
ment 10 (intermediate 16) may be oxidized to give 17. Alterna-
tively (path B), the initial reagent 10 may be oxidized to
intermediate 21 which undergoes electrocyclization. Phenazine
derivative 22, after tautomeric shift of a hydrogen atom forms 24
and treatment of the latter with quinone 11a can give 18. In either
case the 9-membered lactone is formed as a result of C–C-bond
cleavage in the cyclohexanone ring and inclusion of a quinomet-
hide moiety in the ring (19, 20).
The yields of compound 12a were always higher than those of
13, and in some cases slightly exceeded 50%. Both the excess of
quinone and aerial oxygen may act as oxidants together with the
quinonimine 14.
Under similar conditions an analogous compound, 10,10-di-
methyl-9,10,11-trihydro[1,2-b]oxonino[4,5-b]quinoxaline-8-one
(12b) was isolated from the reaction of 10 and 1,2-naphthoqui-
none (11b) (Scheme 5, Fig. 2). The reaction was carried out in ac-
cord with the representative procedure.15
Figure 1. ORTEP views of compounds 12a and 13 showing 50% probability
displacement ellipsoids and the atom-numbering scheme.
The crystal structures of compounds 12a, 12b, and 13 were
determined by single crystal X-ray diffraction (Figs. 1 and 2).16
Also, good quality single crystals of 12aꢀCH3NO2 were obtained
from nitromethane solution (see Supplementary data for the
details).
Both of the methylene groups in the 1H NMR spectrum of com-
pound 12a appeared as AB systems, and also interact through four
r
-bonds (J = 1.2 Hz). This is an indication of the planar W-shaped
structure of H7A-C7-C8-C9-H9A. In the 1H NMR spectrum of
compound 12b only the C(11)H2 methylene group appears as an
AB system while C(9)H2 corresponds to a two-proton singlet. In
the crystal structures of 12a, 12b, and 12aꢀCH3NO2, the 9-membered
cycle adopts virtually the same chair-boat conformation [see also

L. Yu. Ukhin et al. / Tetrahedron Letters 53 (2012) 67–70
69
H
N
H
N
O
OH
O
NH
N
O
2e-, 2H+
-Bu
t
-Bu
N
t-Bu
-Bu
t
t
13
14
10 + 11a
-2e-, 2 H+
N
Path A
N
+H+
H
N
H
N
N
+
N
+
N
H
N
H
-H2O
H
NH
O
O
O
O
t
O
O
O
H
O-
OH
O
O
NH2
NH2
-Bu
H
H
O
t-Bu
O
t
+
O
t
-Bu
O
O
t
-Bu
-Bu
t
-Bu
t
-Bu
t
-Bu
t
t-Bu
-Bu
t-Bu
-Bu
t
19
20
-H+
12a
18
17
16
15
or
11a
H
H
+
N
10 + 11a
14
N
13
N
N
-H+
H+
2e-, 2H+
Path B
N
H
N
H
N
O
H
-2e-, 2 H+
NH
21
H
H
O
O
24
O
10
22
23
Scheme 4. Postulated reaction mechanisms for the formation of compounds 12a and 13 from 10 and 11a.
4
3
H. . .O, 2.31 Å, <CHO 125°), and the absence of shortened contacts
in 12b.
5
2
EtOH,
CF3COOH
O
6
6a
1
6b
17
N
O
16
17b
7
For compounds 12a, 12b, and 13 a two-dimensional correlation
experiment 1H–1H COSY was applied to assign the 1H NMR signals.
Two-dimensional correlation experiments, 1H–13C HSQC (hetero-
nuclear single-quantum correlation) and HMBC (heteronuclear
correlation for long-distance), were used to assign signals in the
13C NMR spectra. A 1H–15N HMBC experiment was applied to
determine the chemical shifts in the 15N NMR spectrum (see Sup-
plementary data for details in Tables 1–3).
O
10 +
15
14
17a
8 O
12a
13
11a
10
N
9
11
12
18
19
12b
11b
Scheme 5. Synthesis of macrolactone 12b.
In conclusion, the advantages of the described method for the
synthesis of oxonine derivatives include reagent availability and
experimental simplicity. Taking into account variability in the syn-
thesis of the three initial components, that is, aromatic o-amino
compounds, o-quinones, and cyclic b-diketones, this approach
can be applied to the synthesis of a broad range of members of this
class of compounds.
Acknowledgement
This work was supported by a grant of the President of the Rus-
sian Federation for leading scientific schools NSh-3233.2010.3.
Supplementary data
The crystallographic data (excluding structure factors) for the
structures described in this paper have been deposited at the Cam-
bridge Crystallographic Data Centre as supplementary publication
numbers CCDC 830746 (12a), 830747 (12b), and 830749 (13). Cop-
ies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2, 1EZ, UK (fax: +44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk). Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.10.147.
Figure 2. ORTEP view of compound 12b showing 50% probability displacement
ellipsoids and the atom-numbering scheme.
Supplementary data (Fig. S2) for a detailed view]. H7A-C7-C8-C9-
H9A in 12a, 12b (H9A-C9-C10-C11-H11A), and 12aꢀCH3NO2 is only
slightly nonplanar (torsion angles H9(11)A-C9(11)-C8(10)-C7(9)
and C9(11)-C8(10)-C7(9)-H7(9)A are equal to 168° and ꢁ164°;
171° and ꢁ167°; 170° and ꢁ165° for 12a, 12b, and 12aꢀCH3NO2,
respectively). These observations, both in solution and in the solid
state, infer a less rigid macrocycle in compound 12b. In part, this is
supported by the existence of slightly shortened C19-H19A. . .O5
(C. . .O, 3.012(2) Å, H. . .O, 2.43 Å, <CHO 118°), and C25-H25A. . .O5
(C. . .O, 3.132(2) Å, H. . .O, 2.49 Å, <CHO 123°) contacts which addi-
tionally stabilize the observed structure of 12a (in 12aꢀCH3NO2 the
corresponding H-bonds are C19-H19A. . .O5, C. . .O, 3.132(2) Å,
H. . .O, 2.52 Å, <CHO 120°, and C25-H25A. . .O5, C. . .O, 2.983(2) Å,
References and notes
1. Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Ann. 1948, 560, 1–92.
2. Cope, A. C.; Moore, P. T.; Moore, W. R. J. Am. Chem. Soc. 1958, 80,
5505–5507.
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7372–7373.
5. Anastassiou, A. G.; Girgenti, S. J. Angew. Chem., Int. Ed. 1975, 14, 814–815.

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6. Anastassiou, A. G. Acc. Chem. Res. 1976, 9, 453–458.
7. Goulart, M. O. F.; Cioletti, A. G.; de Souza Filho, J. D.; De Simone, C. A.;
Castellano, E. E.; Emery, F. S.; De Moura, C. G.; Pinto, M. C. F. R.; Pinto, A. V.
Tetrahedron Lett. 2003, 44, 3581–3585.
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Magn. Reson. Chem. 2004, 42, 663–665.
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Simone, C. A.; Soares, J. G.; Cioletti, A. G.; Goulart, M. O. F.; Pinto, A. V. J. Braz.
Chem. Soc. 2005, 16, 1074–1077.
L. Yu. Ukhin et al. / Tetrahedron Letters 53 (2012) 67–70
Compound 13. IR (ATR):
m
3392 m, 3258 m, 3200 br r (OH, NH), 2955 m (t-Bu),
1596 m, 1552 s, 1532 s (arom) cmꢁ1 1H NMR (CDCl3, 600 MHz): d (ppm) 1.04
.
(s, 6H, CH3), 1.23 (s, 9H, t-Bu(1100)), 1.40 (s, 9H, t-Bu(1000)), 2.15 (s, 2H, C(6)H2),
2.28 (s, 2H, C(4)H2), 5.25 (s, 1H, C(2)H), 5.33 (s, 1H, OH), 5.98 (s, 1H, N(I)H),
6.35 (s, 1H, N(II)H), 6.62 (dd, 1H, C(30)H, 3J = 8.4 Hz, 4J = 1.2 Hz), 6.80 (t, 1H,
C(50)H, J = 7.5 Hz), 6.93 (d, 1H, C(600)H, J = 2.4 Hz), 7.09 (m, 2H, C(60)H, C(40)H),
7.17 (d, 1H, C(400)H, J = 2.4 Hz). MS (EI, 70 eV): m/z 434 [M]+. Anal. Calcd for
C
28H38N2O2: C, 77.38; H, 8.81. Found: C, 77.54; H, 8.75.
15. For the synthesis of 10,10-dimethyl-9,10,11-trihydronaphtho[1,2-b]oxonino[4,5-
b]quinoxaline-8-one (12b), 1,2-naphthoquinone (11b) (0.32 g, 2 mmol) was
dissolved in boiling EtOH (10 ml) and the hot solution was filtered through a
dense filter. 3-(2-Aminophenylamino)-5,5-dimethyl-2-cyclohexen-1-one (10)
(0.23 g, 1 mmol) was added to the ethanolic solution and the mixture was
heated to boiling, then CF3COOH (0.1 ml) was added. The mixture was heated
to boiling and cooled. Large crystals started to precipitate on scratching with a
glass rod after about 10 min. The residue was kept on ice over 2 h. The residue
was filtered, washed with cold EtOH and petroleum ether and dried. The yield
of colorless crystalline product 12b was 46% (0.17 g). Mp 219–220 °C (12b was
10. Silva, R. S. F.; Amorim, M. B.; Pinto, M. C. F. R.; Emery, F. S.; Goulart, M. O. F.;
Pinto, A. V. J. Braz. Chem. Soc. 2007, 18, 759–764.
11. Silva, R. S. F.; Pinto, M. C. F. R.; Goulart, M. O. F.; de Souza Filho, J. D.; Neves, I.,
Jr.; Lourenco, M. C. S.; Pinto, A. V. Eur. J. Med. Chem. 2009, 44, 2334–2337.
12. Ukhin, L. Yu.; Suponitskii, K. Yu.; Shepelenko, E. N.; Belousova, L. V.; Orlova, Zh.
I.; Borodkin, G. S. Izvestiya Akademii Nauk. Seriya Khimicheskaya 2011, 8, 1703–
1707.
13. Abakumov, G. A.; Druzhkov, N. O.; Kurskii, Yu. A.; Shavyrin, A. S. Russ. Chem.
Bull., Int. Ed. 2003, 52, 712–717.
14. For the synthesis of 8,8-dimethyl-7,8,9-trihydro-2,4-di-tert-butylbenzo[2,3]
oxonino[4,5-b]quinoxaline-6-one (12a) and 3-[2-(2-hydroxy-3,5-di-tert-butyl
recrystallized from CH3CN). IR (ATR):
m
1750 s (CO), 1600 w, 1560 w, 1505 w,
1479 m (arom), 1198 s, 1180 s, 1098 (C–O) cmꢁ1
.
1H NMR (CDCl3, 600 MHz): d
phenylamino)]-5,5-dimethyl-2-cyclohexen-1-one
(13),
3-(2-aminophenyla-
(ppm) 1.05 (s, 3H, CH3), 1.33 (s, 3H, CH3), 2.25 (s, 2H, C(9)H2), 2.81 (d, 1H,
C(11)H2, J = 12.9 Hz), 2.86 (d, 1H, C(11)H2, J = 12.9 Hz), 7.54 (d, 1H, C(1)H,
J = 8.4 Hz), 7.65 (m, 2H, C(4)H, C(5)H), 7.78 (m, 2H, C(14)H, C(15)H), 7.94 (d,
1H, C(2)H, J = 8.4 Hz), 8.00 (m, 2H, C(3)H, C(6)H), 8.10 (m, 2H, C(13)H, C(16)H).
MS (EI, 70 eV): m/z 368 [M]+. Anal. Calcd for C24H20N2O2: C, 78.24; H, 5.47.
Found: C, 78.32; H, 5.34.
mino)-5,5-dimethyl-2-cyclohexen-1-one (10) (0.46 g, 2 mmol) was dissolved
in MeOH (5 ml) at room temperature. Next, 3,5-di-tert-butyl-1,2-
benzoquinone (11a) (0.44 g, 2 mmol) was added. The mixture was heated to
ꢂ40 °C and treated with CF3COOH (two drops) after dissolution of the quinone
(about 2 min). The reaction mixture became lighter during 1 min and then
gradually darkened. Precipitation started after 8–10 min on scratching using a
glass rod. The solution and residue were cooled after 1 h; the residue was
filtered, washed with a little MeOH and petroleum ether and dried. The yield of
12a was 0.22 g. The methanol filtrate was treated with H2O and the residue
obtained was filtered, dried, and extracted with Et2O (5 ml). The residue was
filtered once more, washed with Et2O and dried. The yield of 13 was 11%
(0.1 g). The residue was purified by recrystallization from MeOH or CH3CN. Mp
201–203 °C (13 was recrystallised from CH3CN twice). An additional amount of
12a was obtained from the ether filtrate and the remainder was transferred to
16. Crystallographic data for 12a: C28H34N2O2, monoclinic, space group P21/c:
a = 10.2970(7)Å,
b = 13.2401(9)Å,
c = 18.6855(13)Å,
b = 104.6470(10)°,
V = 2464.7(3)Å3, Z = 4, M = 430.57, dcalc = 1.206 gꢀcmꢁ3, wR2 = 0.1156, GOF =
1.027 for 6506 independent reflections with 2 <58°, R1 = 0.0431 for 5021
reflections with I > 2(I). Crystallographic data (excluding structure factors) for
the structure have been deposited at the Cambridge Crystallographic Data
Centre (CCDC) as supplementary publication No. CCDC 830746. Crystallographic
ꢀ
data for 12b: C24H20N2O2, triclinic, space group P1: a = 8.0522(4)Å, b = 9.4805
(4)Å, c = 14.1256(6)Å,
a
= 71.0020(10)°, b = 82.4480(10)°,
c
= 65.2330(10)°,
a
chromatographic column (Al2O3, eluent–CHCl3) and the head fraction
V = 925.80(7)Å3, Z = 2, M = 368.42, dcalc = 1.322 gꢀcmꢁ3
, wR2 = 0.1173,
separated. The solvent was evaporated and the obtained oil was triturated
with CH3CN and the residue filtered. The total yield of colorless crystalline
product 12a was 42% (0.36 g). Mp 173–175 °C (12a was recrystallized from
MeOH). Compound 12a was soluble in CHCl3, and a solvate with CHCl3 (1:1)
GOF = 1.024 for 5382 independent reflections with 2h < 60°, R1 = 0.0434 for
4521 reflections with I > 2r(I). Crystallographic data (excluding structure
factors) for the structure have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) as supplementary publication No. CCDC
ꢀ
was obtained on cooling and scratching with
stoichiometry was established by elemental analysis. Compound 12a. IR
(ATR):
2957 m (t-Bu), 1743 s (CO), 1200 s, 1174 s, 1100 s (C–O) cmꢁ1 1H NMR
a
glass rod. The solvate
830747. Crystallographic data for 13: C28H38N2O2, triclinic, space group P1:
a = 11.699(2)Å, b = 14.628(3) Å, c = 17.260(4)Å,
a = 83.195(4)°, b = 79.880(4)°,
m
c
= 77.844(4)°, V = 2832.3(10)Å3, Z = 4, M = 475.66, dcalc = 1.115 gꢀcmꢁ3, wR2
=
=
.
(CDCl3, 600 MHz): d (ppm) 1.08 and 1.23 (both s, 6H, CH3), 1.33 and 1.37 (both
s, 18H, t-Bu), 2.08 (dd, 1H, C(7)H2, 2J = 12.9 Hz, 4J = 1.2 Hz), 2.33 (d, 1H, C(7)H2,
J = 12.9 Hz), 2.80 (dd, 1H, C(9)H2, 2J = 12.3 Hz, 4J = 1.2 Hz), 2.88 (d, 1H, C(9)H2,
J = 12.9 Hz), 7.22 (d, 1H, C(1)H, J = 2.1 Hz), 7.57 (d, 1H, C(3)H, J = 2.1 Hz), 7.71
(m, 2H, C(12)H, C(13)H), 8.05 (m, 2H, C(11)H, C(14)H). MS (EI, 70 eV): m/z 430
[M]+. Anal. Calcd for C28H34N2O2: C, 78.10; H, 7.96. Found: C, 77.93; H, 8.15.
0.1219, GOF = 0.948 for 11067 independent reflections with 2h < 52°, R1
0.0699 for 3893 reflections with I > 2(I). Crystallographic data (excluding
structure factors) for the structure have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) as supplementary publication No. CCDC
830749.