Nitrone cycloadditions to 1,2-diphenylcyclopropenes and subsequent transformations of the isoxazolidine cycloadducts

Article abstract of DOI:10.1021/jo702379d

(Chemical Equation Presented) 1,3-Dipolar cycloaddition of C-aryl,N-aryl (or N-methyl) nitrones with a number of 1,2-diphenylcyclopropenes substituted at the C³ position occurs with the formation of expected "normal" cycloadducts (with N-methylnitrones) and products of their subsequent transformations. Among them are corresponding α-acetophenyl aziridines and tetra (or penta) -arylpyrroles. Aziridines and the normal cycloadducts can be also thermally converted to such arylpyrroles with moderate to good yields. Substitution at the C³ position of cyclopropenes by an electron acceptor group decreases the reactivity of cyclopropenes.

Full text of DOI:10.1021/jo702379d

lidenes3 results in enhanced reactivity. This makes such alkenes
especially attractive for synthetic applications.1a-c,2,3 Among
such strained compounds, cyclopropenes possess the most highly
strained double C,C bond.1 We demonstrated earlier the
significance of electronic factors in determining the reactivity
of cyclopropenes in the cycloaddition reaction with carbonyl
ylides.4 Corresponding cycloadducts with carbonyl ylides were
formed in yields of up to 92% with cyclopropenes, but no
reaction was observed or the yields of adducts were less than
5% in the case of 3-acceptor-substituted cyclopropenes. Frontier
molecular orbital (FMO) analysis and the global electrophilicity
index ω have been used to clarify the relative reactivity patterns.4
We decided to examine whether these results are restricted to
reactions with carbonyl ylides only. Among other 1,3-dipoles,
nitrones have similar FMO characteristics and electrophilicity
to the carbonyl ylides studied earlier.5 Whereas 1,3-dipolar
cycloadditions of nitrones with methylenecyclopropanes and
bicyclopropylidenes have been investigated in great detail,2,3a
there is only a single report of cycloaddition of an electron-
deficient nitrone with 3,3-dimethylcyclopropene.6 In this paper,
we wish to report the first systematic study of 1,3-dipolar
cycloaddition of nitrones with cyclopropenes.
Nitrone Cycloadditions to
1,2-Diphenylcyclopropenes and Subsequent
Transformations of the Isoxazolidine
Cycloadducts
Vyacheslav V. Diev,† Oksana N. Stetsenko,† Tran Q. Tung,†
Ju¨rgen Kopf,‡ Rafael R. Kostikov,† and
Alexander P. Molchanov*,†
Department of Chemistry, St. Petersburg State UniVersity,
198504 UniVersitetsky pr. 26, St. Petersburg, Russian
Federation, and Institut fu¨r Anorganische Chemie,
UniVersita¨t Hamburg, Martin-Luter-King Platz 6,
D-20146 Hamburg, Germany
s.lab@pobox.spbu.ru
ReceiVed NoVember 2, 2007
1,2-Diphenylcyclopropenes monosubstituted at the C3 position
(1a-e) were selected for investigation (Scheme 1). This enabled
us to vary electronic properties of the substituent at the C3
position. We performed 1,3-dipolar cycloaddition reactions with
C-aryl-N-phenylnitrones 2a-d and C-phenyl-N-methylnitrone
2e (Scheme 1). In general, the reactions studied here differ in
both reaction conditions and products formed. The results can
be arranged into three distinct groups.
I. Reactions of C-phenyl-N-methylnitrone 2e and cyclopro-
penes 1a,b (benzene, reflux, 10-15 h) afforded expected
“normal” cycloadducts 3a and 3b in yields of about 30% (Table
1, entries 5 and 8). Preferably the endo isomer of cycloadduct
1,3-Dipolar cycloaddition of C-aryl,N-aryl (or N-methyl)
nitrones with a number of 1,2-diphenylcyclopropenes sub-
stituted at the C3 position occurs with the formation of
expected “normal” cycloadducts (with N-methylnitrones) and
products of their subsequent transformations. Among them
are corresponding R-acetophenyl aziridines and tetra (or
penta) -arylpyrroles. Aziridines and the normal cycloadducts
can be also thermally converted to such arylpyrroles with
moderate to good yields. Substitution at the C3 position of
cyclopropenes by an electron acceptor group decreases the
reactivity of cyclopropenes.
(3) Reviews: (a) de Meijere, A.; Kozhushkov, S. I.; Khlebnikov, A. F.
Top. Curr. Chem. 2000, 207, 89. (b) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Zh. Org. Khim. 1996, 32, 1607; Russ. J. Org. Chem.
(Engl. Transl.) 1996, 32, 1555.
(4) (a) Diev, V. V.; Kostikov, R. R.; Gleiter, R.; Molchanov, A. P. J.
Org. Chem. 2006, 71, 4066. (b) Molchanov, A. P.; Diev, V. V.; Kopf, J.;
Kostikov, R. R. Russ. J. Org. Chem (Engl. Transl.) 2004, 40, 431.
(5) For reviews on the 1,3-dipolar cycloaddition of nitrones, see: (a)
Jones, R. C. F.; Martin, J. N. In Synthetic Application of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: New York, 2002; pp 1-81. (b)
Torsell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis; VCH: Weinheim, Germany, 1988. (c) Tufariello, J. J. In 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
Vol. 2, pp 83-168.
(6) Akmanova, N. A.; Sagitdinova, K. F.; Balenkova, E. S. Khim.
Geterotsikl. Soedin. 1982, 1192; Chemistry of Heterocyclic Compounds
(Engl. Transl.) 1982, 18, 910. In the reaction of C,N-diphenylnitrone
with 1,3,3-trimethylcyclopropene, products were not identified: see ref 1h.
(7) The unfavorable steric interactions between the proton at the C3
position of the cyclopropene ring and substituent R1 of nitrones can occur
in exo transitional state (exo-TS):
The release of strain upon any type of addition or cycload-
dition onto alkenes with three-membered carbon units such as
cyclopropenes,1 methylenecyclopropanes,2 and bicyclopropy-
† St. Petersburg State University.
‡ Universita¨t Hamburg.
(1) Reviews: (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV.
2007, 107, 3117. (b) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis 2006,
1221. (c) Methods of Organic Chemistry (Houben-Weyl); de Meijere, A.,
Ed.; Thieme: Stuttgart, Germany, 1997; Vol. E17a-d. (d) Baird, M. S.
Chem. ReV. 2003, 103, 1271. (e) Dolbier, W. R., Jr.; Battiste, M. A. Chem.
ReV. 2003, 103, 1071. (f) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987,
135, 77. (g) Deem, M. L. Synthesis 1972, 675. (h) Deem, M. L. Synthesis
1982, 701.
(2) Reviews: (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
ReV. 2003, 103, 1213. (b) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589.
(c) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr. Chem. 1996, 178, 1.
10.1021/jo702379d CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/28/2008
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J. Org. Chem. 2008, 73, 2396-2399

TABLE 1. Results of Reactions of Nitrones with 3-Substituted 1,2-Diphenylcyclopropenes
entry
cyclopropene
nitrone
3/yield (%)
4/yield (%)
5/yield (%)
6/yield (%)
7/yield (%)
1a
2a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1d
1d
1d
1d
1e
1e
1e
2a
2b
2c
2d
2e
2a
2c
2e
2a
2e
2a
2c
2d
2e
2a
2c
2d
-
4a/61 (76)b
5a/14 (69)c
5b/12 (70)c
5c/26
5d/6
-
-
-
4b/56 (74)b
-
-
3a
-
-
4c/57
4d/50
-
-
4a
-
-
5d
3a/29e
-
-
-
-
-
6a
4e/-
5e/60
5f/13 (26)b
5g/26g
5h/18h
-
-
-
7a
-
4f/16 (32)b
-
-
8d
3b/35f
-
-
-
-
-
-
-
-
-
-
-
6a/-g
6b/-
-
7a/52g
7b/57
-
9d
10d
11i
12i
13i
14i
15i
16i
17i
-
-
5i/8h
5j/7h
5k/8
6c/22
6c/21
6c/25
-
6d/31
6d/26
6d/21
7c/30
7c/36
7c/33
-
7d/65
7d/47
7d/43
-
-
-
-
-
-
-
-
-
-
a Conditions: benzene/acetonitrile, reflux, 1-3 h. b Yield based on recovered cyclopropenes. c Yield is based on the thermolysis of aziridines (benzene,
reflux). d Conditions: benzene, reflux, 10-15 h (entries 9 and 10, 100 h). e Diastereomeric ratio (endo/exo) ) 82:18. f Diastereomeric ratio (endo/exo) >
98:2. g Conditions: 3b, o-xylene, reflux, 3 h. h Calculated yields from 1H NMR spectra of fractions enriched with corresponding products; analytically pure
samples could not be obtained. i Conditions: toluene, reflux, 25-35 h (entry 14, 100 h).
SCHEME 1. General Scheme of Reactions of Nitrones with 3-Substituted 1,2-Diphenylcyclopropenes
SCHEME 2. Cycloaddition of Nitrone 2a to
3-Vinyl-1,2-diphenylcyclopropene 1f
pyrroles can be considered as a result of rearrangement of the
initially formed normal cycloadducts of nitrone and cyclopro-
pene (see below for discussion).
III. Reactions of nitrones 2 with acceptor-substituted cyclo-
propenes 1d,e belong to the third group (Table 1, entries 11-
17). In this case, the reactions proceeded at both higher
temperatures and for prolonged times (toluene, reflux, 25-35
h) and afforded complex mixtures containing isomeric ketones
6 and 7.9 That the reactions with acceptor-substituted cyclo-
propenes require more vigorous conditions is consistent with a
diminished reactivity of cyclopropenes found in our previous
3a was formed (exo:endo 18:82)7 in the cycloaddition reaction
of 1,2-diphenylcyclopropene 1a, and only the endo cycloadduct
3b was observed in the reaction of 3-methyl-1,2-diphenylcy-
clopropene 1b. The anti-disposition of the methyl group relative
to the isoxazolidine ring in cycloadduct 3b corresponds to the
approach of the dipolarophile from the least hindered face of
cyclopropene 1b. Reaction of N-methylnitrone 2e with cyclo-
propenes 1c (R ) Ph) and 1d (R ) CO2Me) did not give any
products even on heating the reaction mixture for 100 h (starting
cyclopropenes were recovered from reaction mixtures).
(8) Only one isomer of aziridines 4 was isolated from the reaction
mixtures. For the most stable aziridine 4b, X-ray analysis did not give
reliable result (R factor ) 0.14; for a view, see Supporting Information).
The obtained aziridine 4a appeared to be somewhat unstable in solutions
in air, slowly furnishing the corresponding pyrrole 5a. However, the rather
stable aziridine 4b can be obtained in the reaction of diarylnitrone 2b. The
stability of aziridines was also found to be dependent on the nature of the
substituent R in the R-position. Thus, the corresponding aziridine 4e formed
in the reaction of 3-methyl-1,2-diphenylcyclopropene 1b (Table 1, entry
6) can only be detected by TLC. This aziridine underwent complete
transformation to the pyrrole 5e on silica gel.
(9) Besides ketones, products of decomposition of Schiff bases were
formed (corresponding aldehydes) as well as compounds A-F (see
Supporting Information). The latter are products of the 1,3-dipolar cycload-
dition of nitrones to the double C,C bond of the initially formed unsaturated
ketones. Dipolar cycloadditions with different unsaturated carbonyl com-
pounds are well documented (see ref 5).
II. Reactions of diarylnitrones 2a-d and cyclopropenes 1a,b
(Table 1, entries 1-4, 6, 7, and 9) proceeded under milder
conditions (benzene/acetonitrile, reflux, 1-3 h) and afforded
separable mixtures of aziridines 48 (30-60% yield) and tet-
raarylpyrroles 5 (6-60% yield). Remarkably, the reaction of
diarylnitrone 2a with triphenylcyclopropene 1c was much slower
(benzene, reflux, 100 h), giving pentaarylpyrrole 5h (18%) and
ketone 7b (57%). Formation of these unexpected aziridines and
J. Org. Chem, Vol. 73, No. 6, 2008 2397

SCHEME 3. Proposed Mechanisms of the Formation of Aziridines, Pyrroles, Enamines, and Ketones Starting from
Cyclopropenes and Nitrones
study of cycloadditions of carbonyl ylides to 3-substituted 1,2-
diphenylcyclopropenes 1a-e.4 The reactivity of cyclopropenes
1a-e with nitrones, however, is not so strongly affected by the
electronic nature of the substituent at the cyclopropene C3
position as in the case of carbonyl ylides.
We also studied thermolysis reactions with several of the
obtained products (Scheme 1, Table 1, footnotes c and g). When
subjected to thermolysis in refluxing benzene, aziridines 4a,b
underwent conversion to pyrroles 5a,b (70%). Heating the
normal cycloadduct 3b in refluxing o-xylene until complete
consumption of starting material (3 h) afforded a separable
mixture of 1,2-diphenylbut-2-en-1-one 7a (52%) and pentasub-
stituted pyrrole 5g (26%).
In contrast to cycloaddition of nitrones 2a-e with cyclopro-
penes 1a-e, the reaction of 3-vinyl-1,2-diphenylcyclopropene
1f with diarylnitrone 2a (benzene, reflux, 1 h) proceeded with
the formation of cyclopropenyl isoxazolidine 8 as a single isomer
(10%) and a mixture of four isomeric isoxazolidines 9 (48%)
(Scheme 2). All products in this reaction correspond to the
cycloaddition of nitrone dipole to the vinylic C,C double bond
of cyclopropene 1f. The initially formed cycloadducts 8 contain-
ing the cyclopropene moiety are unstable and can be easily
oxidized by air to form isomeric isoxazolidines 9.10 This result
demonstrates that the C,C double bond of the three-membered
ring is significantly less active toward cycloaddition of nitrone
than vinylic double bond. This could be due to the more polar
nature of the vinylic double bond.11
cycloadducts III. These cycloadducts III are thermally unstable
in the case of diarylnitrones, whereas with N-methylnitrone, they
can be isolated. Then, the isoxazolidine cycloadducts III
undergo a thermally induced homolytic cleavage of the weak
N-O bond, giving intermediate biradical IV.12 The presence
of the strained three-membered ring fused on the adjacent
position to the O-centered radical in IV can lead to ring opening
of the cyclopropane with formation of the more stable biradical
V (Scheme 3, route A).13 The latter undergoes ring contraction
to the rather stable aziridine VI. Another possible transformation
of biradical intermediate IV is disproportionation (route B) with
the formation of the corresponding enamine VIII and isomeric
ketones IX. The presence of an acceptor group at the cyclo-
propane ring in biradicals IV derived from cyclopropenes 1d,e
seems to facilitate such disproportionation. It is not clear whether
pyrroles isolated directly from reaction mixtures are formed from
aziridines or other intermediate species. The data, however,
indicate that isolated aziridines can be thermally converted to
(11) According to B3LYP/6-31G* calculations, the terminal vinylic
carbon atom of 3-vinyl-1,2-diphenylcyclopropene 1f has the greatest
negative charge (-0.3, Lowdin). The charges on another vinylic carbon
atom and carbons of the cyclopropenyl double bond are close to 0.
Remarkably, carbonyl ylide cycloadditions to cyclopropene 1f proceed to
the C,C double bond of the three-membered ring (see ref 4). Also, we can
suggest that the difference between steric screening of double bonds in both
synclinal and periplanar conformations of vinylcyclopropene 1f (see
Supporting Information) is not enough to explain regiochemical outcome
of the reaction.
(12) For recent examples of closely related isomerization of 4-isoxazo-
lines to aziridines, see: (a) Friebolin, W.; Eberbach, W. Tetrahedron 2001,
57, 4349. (b) Ishikawa, T.; Kudoh, T.; Yoshida, J.; Yasuhara, A.; Manabe,
S.; Saito, S. Org. Lett. 2002, 4, 1907.
(13) For reviews on N-O bond cleavage in nitrone-alkylidenecyclo-
propane cycloadducts, see ref 2. For closely related N-O bond cleavage
in nitrile oxide-cyclopropene cycloadducts, see: Zaitseva, L. G.; Chizhov,
I. G.; Bolesov, I. G. Zh. Org. Khim. 1975, 11, 1347; Russ. J. Org. Chem.
(Engl. Transl.) 1975, 11, 1333. In addition, analogous ketones have been
reported in this work.
A preliminary attempt to rationalize the mechanism of these
transformations can be proposed (Scheme 3). The initial step
of the process is presumed to be a normal 1,3-dipolar cycload-
dition reaction of cyclopropenes I with nitrones II to form
(10) Taking into account that the two isomeric products 9 can be obtained
from a single isomer of 8, the initial formation of two isomeric cyclopropenyl
isoxazolidines 8 can be proposed. Only the more stable isomer was isolated.
2398 J. Org. Chem., Vol. 73, No. 6, 2008

benzene/acetonitrile (1:1, 5 mL) was added 1,2-diphenylcyclopro-
pene 1a (146 mg, 0.76 mmol). After heating the reaction mixture
at 80 °C for 1 h in argon atmosphere, solvents were evaporated
under reduced pressure. The residue was chromatographed on a
silica gel column eluting with a mixture of hexane/ethyl acetate to
afford aziridine 4b (190 mg, 0.42 mmol, 56%) and tetraarylpyrrole
final pyrroles with good yields. A mechanism involving opening
of the aziridine ring to an azomethine ylide VII followed by
either enolization of its carbonyl group with subsequent 1,5-
electrocyclization (Scheme 3, route 1) or intramolecular nu-
cleophilic addition of azomethine ylide to a carbonyl group
(Scheme 3, route 2) can be proposed to account for the observed
rearrangement patterns.14
1
5b (37 mg, 0.08 mmol, 12%). 4b: mp 115-117 °C; H NMR δ
3.30 (d, 1H, J ) 17.4 Hz), 3.87 (s, 1H), 3.88 (d, 1H, J ) 17.4 Hz),
6.93-6.96 (m, 1H), 7.02-7.22 (m, 7H), 7.28-7.43 (m, 8H), 7.51
(t, 1H, J ) 8.0 Hz), 7.75 (d, 2H, J ) 6.5 Hz); 13C NMR δ 43.5,
49.4, 54.0, 121.0, 123.4, 126.9, 127.3, 128.1, 128.4, 128.6, 128.9,
129.7, 130.6, 133.3, 133.5, 133.6, 134.6, 137.5, 138.7, 149.2, 196.6.
Anal. Calcd for C28H21Cl2NO: C, 73.37; H, 4.62; N, 3.06. Found:
C, 73.27; H, 4.51; N, 2.79. 5b: mp 70-71 °C; 1H NMR δ 6.80 (s,
1H), 7.03-7.05 (m, 2H), 7.12-7.28 (m, 15H), 7.33-7.34 (m, 1H);
13C NMR δ 109.8, 125.0, 125.4, 126.9, 127.22, 127.25, 127.5,
127.8, 128.5, 128.8, 128.9, 128.99, 129.02, 129.7, 130.5, 131.7,
133.1, 133.7, 135.3, 137.5, 138.9, 143.3. MS (EI) m/z (%): 439
[M] (100), 199 (24), 165 (13), 105 (40), 77 (84). Anal. Calcd for
C28H21ClN: C, 76.37; H, 4.35; N, 3.18. Found: C, 76.07; H, 4.10;
N, 3.10.
In conclusion, we have reported a previously unknown
reaction cascade that involves 1,3-dipolar cycloaddition of 1,2-
diphenylcyclopropenes to C-aryl,N-aryl (or N-methyl) nitrones
with the formation of bicyclic isoxazolidine products. Subse-
quent transformations of the isoxazolidines give sterically
hindered polyarylsubstituted aziridines and pyrroles. A plausible
mechanism has been proposed which includes formation of
biradicals and their rearrangements. Theoretical calculations are
underway in our lab to study these mechanistically interesting
transformations of biradicals. The obtained results also suggest
the significance of substitution at the C3 position of cyclopro-
penes by an electron acceptor group.
Experimental Section
Acknowledgment. We are grateful to the Ministry of
Education of the Russian Federation for financial support of
this research (Grants A03.-2.11-116 and A04.-2.11-428). The
authors warmly thank Dr. Peter Djurovich (University of
Southern California) for careful reading of the manuscript.
V.V.D. is also grateful to the Government of St. Petersburg
(Grant M04-2.5K-98).
Typical Procedure for the Cycloaddition Reactions of Ni-
trones with Cyclopropenes. To a solution of C-(2,4-dichlorophe-
nyl)-N-phenylnitrone 2b (230 mg, 0.87 mmol, 1.14 equiv) in
(14) Note the proposed mechanism needs more clarification. Thus, it is
problematic to demonstrate whether enolization of azomethine ylide or direct
intramolecular nucleophilic addition occurs (route 1 vs 2). For the possibility
of conversion of aziridines to pyrroles via 1,5-electrocyclization of transient
azomethine ylide, see: (a) Padwa, A.; Dean, D.; Mazzu, A.; Vega, E. J.
Am. Chem. Soc. 1973, 95, 7168. (b) Huisgen, R. Angew. Chem. 1980, 92,
979. (c) For recent review on conjugated azomethine ylides, see: Pinho e
Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2873. (d) For review on 1,5-
dipolar cyclizations, see: Taylor, E. C.; Turchi, I. J. Chem. ReV. 1979, 79,
181.
Supporting Information Available: Details of experimental
procedures, spectroscopic data of the reaction products 3-9, and
X-ray crystal structure and a CIF file for 3b and 5g. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO702379D
J. Org. Chem, Vol. 73, No. 6, 2008 2399