One-pot assembly of 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes from alkyl aryl(hetaryl) ketoximes, acetylene, and aliphatic ketones: a new three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2009.02.085

A new three-component reaction between alkyl aryl(hetaryl)ketoximes, acetylene, and aliphatic ketones in the superbasic systems KOH/DMSO and LiOH/CsF/DMSO (70-90 °C, initial acetylene pressure 13-15 atm, 5-60 min) affords novel 4-methylene-3-oxa-1-azabicy

Full text of DOI:10.1016/j.tetlet.2009.02.085

Tetrahedron Letters 50 (2009) 3314–3317
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One-pot assembly of 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes
from alkyl aryl(hetaryl) ketoximes, acetylene, and aliphatic ketones:
a new three-component reaction
a
a
a
a
Boris A. Trofimov a, , Elena Yu. Schmidt , Al’bina I. Mikhaleva , Igor A. Ushakov , Nadezhda I. Protsuk ,
*
Elena Yu. Senotrusova a, Olga N. Kazheva b, Grigorii G. Aleksandrov b, Oleg A. Dyachenko b
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Academician N. N. Semenov Str., 142432 Chernogolovka, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new three-component reaction between alkyl aryl(hetaryl)ketoximes, acetylene, and aliphatic ketones
in the superbasic systems KOH/DMSO and LiOH/CsF/DMSO (70–90 °C, initial acetylene pressure 13–
15 atm, 5–60 min) affords novel 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes in yields of up to 75%.
Using KOH/DMSO, the side products of the reaction are O-vinylketoximes and 2-aryl(hetaryl)pyrroles,
while with LiOH/CsF/DMSO, the reaction proves to be selective, only minor amounts of the corresponding
alkyl aryl(hetaryl) ketones being detectable.
Received 9 January 2009
Revised 27 January 2009
Accepted 11 February 2009
Available online 15 February 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
4-Methylene-3-oxa-1-
azabicyclo[3.1.0]hexanes
Alkyl aryl ketoximes
Acetylene
Acetone
Superbases
Aziridines
The reaction of ketoximes with acetylenes in the presence of
superbasic systems MOH/DMSO (M = alkaline metal) provides a
simple general route to pyrroles1 and steadily keeps expanding
in scope and utility.2 The key intermediates of the reaction (O-
vinyloximes,3 hydroxypyrroline,1a,4 and 3H-pyrroles1a,5) are isola-
ble and are themselves interesting for organic synthesis.
Herein, we report on a new reaction between ketoximes 1–6
and acetylene in the presence of aliphatic ketones 7 and 8 using
typical pyrrole synthesis conditions. We have made the serendipi-
tous discovery that this three-component reaction affords 4-meth-
ylene-3-oxa-1-azabicyclo[3.1.0]hexanes 9–15, along with or
instead of the expected O-vinyloximes and pyrroles, with the
yields of the bicyclics reaching 75% (Scheme 1, Table 1).6
The reaction proceeds at 70–90 °C in 5–60 min using acetylene
gas (autoclave, initial pressure of acetylene at ambient tempera-
ture was 13–15 atm which reaches a maximum of 25–30 atm dur-
ing the reaction). The ketoxime/aliphatic ketone/MOH molar ratio
was 1:1:1. When the synthesis was carried out using the KOH/
DMSO system, the crude contained the major products 9–15 along
with small amounts of the corresponding O-vinylketoximes and
pyrroles (Scheme 1). With the superbase system LiOH/CsF/DMSO,
the reaction was more selective yielding products 9–15 without
any O-vinyloximes or pyrroles; minor side-products being
aryl(hetaryl)ketones instead (Scheme 1).
The structures of the 4-methylene-3-oxa-1-azabicyclo[3.1.0]-
hexanes 9–15 were assigned unambiguously by X-ray crystallo-
graphic analysis of 2,2-dimethyl-4-methylene-5-(1-pyrenyl)-3-
oxa-1-azabicyclo[3.1.0]hexane 12 (Fig. 1).
The oxazolidine heterocycle N(1)C(2)O(3)C(4)C(5) is signifi-
cantly distorted with maximum deviations of the atoms from the
plane being 0.15 Å [O(3)] and À0.11 Å to +0.12 Å [C(2) and C(4)].
The dihedral angle between the planes of the pyrene and oxazoli-
dine units is 113.4°. The aziridine N(1)C(1)C(5) ring and the oxazol-
idine moiety have a dihedral angle of 101.1°. The dihedral angle
between the planes of the pyrene and aziridine units is 122.0°.
The NMR (1H and 13C) spectra were also in agreement with the
structures of the 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes.
Characteristic signals in the 1H NMR spectra of the bicycles 9–15
are the doublets for the exocyclic double bond protons HA
(3.83–4.16 ppm) and HB (4.36–4.51 ppm) and the singlets due to
the aziridine protons H1 and H2 (2.10–2.58 ppm). Assignments
of the 13C signals were based on 2D HSQC and HMBC spectra.
* Corresponding author. Tel.: +7 395242 14 11; fax: +7 395241 93 46.
E-mail address: boris_trofimov@irioch.irk.ru (B.A. Trofimov).
1
The observed correlations (Fig. 2) and the JC6–H1 ꢀ 175–176 Hz
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.085

B. A. Trofimov et al. / Tetrahedron Letters 50 (2009) 3314–3317
3315
R2
R2
N
R2
R1
R2
R3
Me
R2
R1
O
R1
R1
R1
base/DMSO
70-90 ºC, 5-60 min
+
+
N
+
O
+
Me
R3
N
H
N
HO
7,8
1-6
O
O
HC CH
9-15
base = KOH, LiOH/CsF
Scheme 1.
Table 1
4-Methylene-3-oxa-1-azabicyclo[3.1.0]hexanes 9–15 synthesized according to
Scheme 1
R1, R2
R3
Product
Yield (%)
7
Me
N
Me
Me
Me, H 1
Me
7
O
9
Figure 1. X-ray structure of 12.
N
,
H
Me
7
51
54
75
Me
Me
2
H1
O
H2(R2)
10
R1
NOESY
HMBC
N
HA
Me(R3)
O
N
Me
7
HB
,
H
Me
Me
Me
3
O
11
Figure 2. Characteristic NOESY correlation and HMBC of compounds 9–15.
The formation of 4-methylene-3-oxa-1-azabicyclo[3.1.0]hex-
anes 9–15 can be rationalized as depicted in Scheme 2. The initially
formed O-vinyloxime A, a regular primary intermediate of pyrrole
synthesis from ketoximes and acetylene,1 undergoes intermolecu-
lar nucleophilic substitution at the nitrogen atom promoted by the
adjacent carbanionic center induced by the superbase (Neber8 or
Hoch-Campbell8b,9 azirine synthesis). The azirine B, thus gener-
ated, is then attacked by the acetylenic carbanion to give ethynyl
aziridine C (the nitrogen analog of the Favorsky reaction).10 The
Me
7
N
,
H
Me
Me
O
4
12
S
N
,
H
Me
7
39
S
Me
Me
latter is trapped by the ketone (the third component) to form
a-
5
O
amino alcohol D which finally cyclizes to the 1,3-oxazolidine via
intramolecular nucleophilic addition to the ethynyl group.
13
In support of this mechanism is the fact that many dialkyl
ketoximes only give the expected 4-methylene-3-oxa-1-azabicy-
clo[3.1.0]hexanes in smaller yields under the studied conditions.
For example, in the case of acetoxime, only negligible amounts of
the expected bicycle 9 (7%, Table 1) were detected (1H NMR). This
corresponds to the weaker CH-acidity of the dialkyl ketoxime and
smaller positive charge at the oxime nitrogen atom owing to the
electron-donating effect of both alkyl substituents.
It is worthwhile to note that the 4-methylene-3-oxa-1-azabicy-
clo[3.1.0]hexane structure has not been studied in detail. To the
best of our knowledge, only one publication11 deals with such a
structure which was ascribed to dimers of aziridine aldehydes. 3-
Oxa-1-azabicyclo[3.1.0]hexan-2-ones12 are more well known
though they actually belong to the carbamate class of organic com-
pounds. These oxazolidinones are related to many natural and syn-
thetic molecules of significant biological activity, for example,
immunomodulators inhibiting intercellular communication be-
tween Th1 and Th2 macrophages13 and antimicrobial agents
against multidrug resistant Gram-positive bacteria.14 An oxazolid-
t-Bu
S
N
Me
7
43
27
,
t-Bu
S
Me
Me
6
O
14
15
S
,
H
N
t-Bu
8
S
Me
5
O
t-Bu
1
and JC6–H2 ꢀ 166–167 Hz coupling values allowed the signals C5
(49.4–52.5 ppm) and C6 (34.6–37.7 ppm) of the aziridine moiety
to be assigned. The 15N chemical shift (À300.6 ppm) recorded for
compound 14 is typical of an aziridine ring.7

3316
B. A. Trofimov et al. / Tetrahedron Letters 50 (2009) 3314–3317
R2
-
R2
R2
R1
R1
R1
R1
O-
-OH
O
HC CH
LiOH/CsF/DMSO
R2
-CH2
+
N
N
N
N
-H2O
O
B
HO
O
A
R1
N
R1
N
R1
Me
R3
R1
R2
CH/-OH
HC
R2
R2
O
R2
O
N
H
N
C
HO
R3
R3
B
Me
Me
D
Scheme 2.
pressure of 14 atm and then decompressed to atmospheric pressure to remove
air. The autoclave was charged with acetylene again at a pressure of 14 atm and
heated (80 °C) whilst rotating for 60 min. The reaction mixture, after cooling to
room temperature, was diluted with water (100 mL) and extracted with diethyl
ether (20 mL Â 5). The combined extract was washed with cold water
(20 mL Â 3) and dried (K2CO3) overnight. After removal of the solvent,
inone analog of the muscarinic agonist pilocarpine is used for the
treatment of glaucoma.15 Other oxazolidinones are strong agonists
of a
7 nicotinic receptors (a therapy for Alzheimer’s disease).16
In fact, 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes 9–15
are novel heterocyclic systems in which the exocyclic double bond
is conjugated both with the oxygen atom and the aziridine ring.
The combination of the three pharmacologically and synthetically
important functional groups (aziridine, 1,3-oxazolidine, and enol
ether) in one molecule may impart to these heterocyclic systems
new properties uncommon for each functionality alone.
In conclusion, a three-component reaction between alkyl-
aryl(hetaryl)ketoximes, acetylene, and aliphatic ketones in the
presence of the superbases LiOH/CsF/DMSO and KOH/DMSO which
affords the novel heterocycles, 4-methylene-3-oxa-1-azabicy-
clo[3.1.0]hexanes, has been reported. The LiOH/CsF/DMSO super-
base catalyzes the reaction with greater selectively. Being readily
available from easily accessible and cheap starting materials, 4-
methylene-3-oxa-1-azabicyclo[3.1.0]hexanes have potential in
drug design and as building blocks for organic synthesis.
620 mg of
a crude residue was obtained. Column chromatography (basic
Al2O3, benzene or hexene) gave 473 mg (75% yield) of 12 as white crystals (mp
136–137 °C). 1H NMR (400.13 MHz, CDCl3): d 8.48 (d, 1H, J = 9.0 Hz, Hpyr), 8.25–
8.15 (m, 4H, Hpyr), 8.13 (d, 1H, J = 9.0 Hz, Hpyr), 8.10–8.00 (m, 3H, Hpyr), 4.43 (d,
1H, J = 2.0 Hz, HB), 3.83 (d, 1H, J = 2.0 Hz, HA), 2.58 (s, 1H, H2), 2.28 (s, 1H, H1),
1.77 (s, 3H, Me), 1.63 (s, 3H, Me). 13C NMR (101.61 MHz, CDCl3): d 159.5 (C4),
132.0–123.1 (16 Cpyr), 99.0 (C2), 86.1 (@CH2), 51.5 (C5), 36.6 (C6), 28.1, 22.7
(2Me). IR (KBr) mmax: 1667, 1460, 1371, 1289, 1226, 1093, 1075, 1036, 1003,
988, 960, 843, 829, 821, 808, 798, 756, 721, 681, 621. Anal. Calcd for C23H19NO
(325.40): C, 84.89; H, 5.89; N, 4.30. Found: C, 85.01; H, 5.99; N, 4.11.
Compounds 10, 11, and 13–15 were obtained analogously.
2,2-Dimethyl-4-methylene-5-phenyl-3-oxa-1-azabicyclo[3.1.0]hexane 10: Oil. 1H
NMR (400.13 MHz, CDCl3): d 7.44 (m, 2H, Ho), 7.35 (m, 2H, Hm), 7.31 (m, 1H,
Hp), 4.42 (d, 1H, J = 1.7 Hz, HB), 3.88 (d, 1H, J = 1.7 Hz, HA), 2.21 (s, 1H, H1), 2.10
(s, 1H, H2), 1.56 (s, 3H, Me), 1.47 (s, 3H, Me). 13C NMR (101.61 MHz, CDCl3): d
160.4 (C4), 135.9 (Ci), 129.0 (Co), 128.5 (Cm), 128.2 (Cp), 98.9 (C2), 85.0 (@CH2),
52.2 (C5), 34.6 (C6), 28.2, 22.6 (2Me). IR (film) mmax: 2989, 2933, 1678, 1500,
1448, 1385, 1372, 1285, 1226, 1152, 1087, 1027, 1005, 963, 850, 821, 755, 698,
531. Anal. Calcd for C13H15NO (201.26): C, 77.58; H, 7.51; N, 6.96. Found: C,
77.71; H, 7.69; N, 6.90.
2,2-Dimethyl-4-methylene-5-(2-naphthyl)-3-oxa-1-azabicyclo[3.1.0]hexane 11:
White crystals (mp 89–92 °C). 1H NMR (400.13 MHz, CDCl3): d 7.90–7.80 (m,
4H, Hnaphth), 7.56 (m, 1H, Hnaphth), 7.47 (m, 2H, Hnaphth), 4.45 (d, 1H, J = 1.8 Hz,
HB), 3.91 (d, 1H, J = 1.8 Hz, HA), 2.32 (s, 1H, H1), 2.19 (s, 1H, H2), 1.62 (s, 3H,
Me), 1.50 (s, 3H, Me). 13C NMR (101.61 MHz, CDCl3): d 160.3 (C4), 133.4–126.3
(10 Cnaphth), 99.1 (C2), 85.3 (@CH2), 52.5 (C5), 34.9 (C6), 28.3, 22.6 (2Me). IR
Acknowledgments
This work has been carried out under financial support of lead-
ing scientific schools by the President of the Russian Federation
(Grant NSH-263.2008.3) and Russian Foundation for Basic Re-
search (Grants 07-03-92162-PICS and 08-03-00002).
(KBr) mmax: 2987, 2931, 1678, 1633, 1505, 1452, 1434, 1380, 1370, 1291, 1224,
1188, 1144, 1126, 1087, 1063, 1001, 984, 967, 952, 914, 870, 844, 808, 750,
696, 523, 478. Anal. Calcd for C17H17NO (251.32): C, 81.24; H, 6.82; N, 5.57.
Found: C, 81.43; H, 7.00; N, 5.41.
2,2-Dimethyl-4-methylene-5-(2-thienyl)-3-oxa-1-azabicyclo[3.1.0]hexane 13: Oil.
1H NMR (400.13 MHz, CDCl3): d 7.26 (dd, 1H, J = 5.2 Hz, J = 1.1 Hz, H5’), 7.09
(dd, 1H, J = 3.6 Hz, J = 1.1 Hz, H3’), 6.97 (dd, 1H, J = 5.2 Hz, J = 3.6 Hz, H4’), 4.51
(d, 1H, J = 1.9 Hz, HB), 4.16 (d, 1H, J = 1.9 Hz, HA), 2.39 (s, 1H, H1), 2.17 (s, 1H,
H2), 1.51 (s, 3H, Me), 1.43 (s, 3H, Me). 13C NMR (101.61 MHz, CDCl3): d 159.3
(C4), 139.2 (C2’), 127.4 (C3’), 127.0 (C4’), 126.0 (C5’), 98.8 (C2), 85.4 (@CH2),
References and notes
1. (a) Trofimov, B. A. Adv. Heterocycl. Chem. 1990, 51, 177–301; (b) Trofimov, B. A.
The Synthesis, Reactivity, and Physical Properties of Substituted Pyrroles; Wiley:
New York, 1992. pp. 131–298; (c) Mikhaleva, A. I.; Schmidt, E. Yu.. In Selected
Methods for Synthesis and Modification of Heterocycles; IBS Press: Moscow, 2002;
Vol. 1, pp 334–352.
47.6 (C5), 36.4 (C6), 27.9, 22.5 (2Me). IR (film) mmax: 2926, 2854, 1653, 1459,
2. (a) Trofimov, B. A.; Schmidt, E. Yu.; Mikhaleva, A. I.; Zorina, N. V.; Ushakov, I. A.;
1375, 1282, 1225, 1152, 1107, 920, 831, 815, 736, 700. Anal. Calcd for
C11H13NOS (207.29): C, 63.74; H, 6.32; N, 6.76; S, 15.47. Found: C, 63.75; H,
6.37; N, 6.71; S 15.30.
´
Afonin, A. V.; Vasiltsov, A. M. Mendeleev Commun. 2007, 17, 40–42; (b)
Trofimov, B. A.; Schmidt, E. Yu.; Zorina, N. V.; Senotrusova, E. Yu.; Protsuk, N. I.;
Ushakov, I. A.; Mikhaleva, A. I.; Méallet-Renault, R.; Clavier, G. Tetrahedron Lett.
2008, 49, 4362–4365.
6-tert-Butyl-2,2-dimethyl-4-methylene-5-(2-thienyl)-3-oxa-1-azabicyclo[3.1.0]-
hexane 14: Oil. 1H NMR (400.13 MHz, CDCl3):
d 7.21 (dd, 1H, J = 5.2 Hz,
3. Trofimov, B. A.; Mikhaleva, A. I.; Vasil’tsov, A. M.; Schmidt, E. Yu.; Tarasova, O.
A.; Morozova, L. V.; Sobenina, L. N.; Preiss, T.; Henkelmann, J. Synthesis 2000,
1125–1132.
4. Trofimov, B. A.; Korostova, S. E.; Mikhaleva, A. I.; Sobenina, L. N.; Sherbakov, V.
V.; Sigalov, M. V. Khim. Geterotsikl. Soed. 1983, 2, 276.
J = 1.1 Hz, H5’), 7.05 (dd, 1H, J = 3.4 Hz, J = 1.1 Hz, H3’), 6.97 (dd, 1H, J = 5.2 Hz,
J = 3.4 Hz, H4’), 4.36 (d, 1H, J = 2.0 Hz, HB), 4.08 (d, 1H, J = 2.0 Hz, HA), 1.97 (s,
1H, H1), 1.54 (s, 3H, Me), 1.46 (s, 3H, Me), 0.78 (s, 9H, t-Bu). 13C NMR
(101.61 MHz, CDCl3): d 160.8 (C4), 138.9 (C2’), 127.4 (C3’), 126.9 (C4’), 125.8
(C5’), 99.4 (C2), 83.5 (@CH2), 55.8 (C6), 52.4 (C5), 31.6 (C-Me3), 27.6 (C-Me3),
5. (a) Trofimov, B. A.; Shevchenko, S. G.; Korostova, S. E.; Mikhaleva, A. I.;
Sherbakov, V. V. Khim. Geterotsikl. Soed. 1985, 11, 1573–1574; (b) Trofimov, B.
A.; Shevchenko, S. G.; Korostova, S. E.; Mikhaleva, A. I.; Sigalov, M. V.; Krivdin, L.
B. Khim. Geterotsikl. Soed. 1989, 11, 1566–1567.
28.3, 22.1 (2Me). IR (film) mmax: 2962, 2927, 2870, 1639, 1385, 1364, 1287,
1169, 1150, 1002, 887, 849, 832, 700. Anal. Calcd for C15H21NOS (263.39): C,
68.40; H, 8.04; N, 5.32; S, 12.17. Found: C, 68.45; H, 7.97; N, 5.19; S 11.99.
2-tert-Butyl-2-methyl-4-methylene-5-(2-thienyl)-3-oxa-1-azabicyclo[3.1.0]-
hexane 15: Oil. 1H NMR (400.13 MHz, CDCl3): d 7.21 (dd, 1H, J = 5.4, J = 1.2 Hz,
H5’), 7.10 (dd, 1H, J = 3.7 Hz, J = 1.2 Hz, H3’), 6.94 (dd, 1H, J = 5.4 Hz, J = 3.7 Hz,
H4’), 4.38 (d, 1H, J = 2.0 Hz, HB), 4.03 (d, 1H, J = 2.0 Hz, HA), 2.45 (s, 1H, H1), 2.12
(s, 1H, H2), 1.31 (s, 3H, Me), 1.00 (s, 9H, t-Bu). 13C NMR (101.61 MHz, CDCl3): d
161.3 (C4), 139.4 (C2’), 127.5 (C3’), 126.8 (C4’), 125.4 (C5’), 105.8 (C2), 81.5
(=CH2), 49.4 (C5), 37.7 (C6), 40.4 (C-Me3), 25.9 (C-Me3), 18.3 (Me). IR (film)
6. Synthesis of 2,2-dimethyl-4-methylene-5-(1-pyrenyl)-3-oxa-1-azabicyclo[3.1.0]-
hexane (12):
A mixture of CsF (293 mg, 1.93 mmol) and LiOH (46 mg,
1.93 mmol) in MeOH (3.0 mL) was stirred at rt for 30 min. Then 1-(1-
pyrenyl)-1-ethanone oxime (500 mg, 1.93 mmol) in DMSO (50 mL) was
added, and the mixture was distilled (80 °C) with stirring until the MeOH
was removed. Next, a vacuum (2 mmHg) at 55 °C was applied to make sure that
the mixture was free from MeOH and H2O. The suspension thus obtained was
placed into a 0.25 L steel rotating autoclave and acetone (112 mg, 1.93 mmol)
in DMSO (5 mL) was added. The autoclave was charged with acetylene at a
m
max: 2961, 2923, 2875, 1673, 1639, 1598, 1394, 1364, 1284, 1172, 1149, 1018,
975, 889, 855, 832, 811, 705. Anal. Calcd for C14H19NOS (249.37): C, 67.43; H,
7.68; N, 5.62; S, 12.86. Found: C, 67.61; H, 7.80; N, 5.44; S 12.78.

B. A. Trofimov et al. / Tetrahedron Letters 50 (2009) 3314–3317
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