Cycloaddition of 2-Methyleneaziridines with isocyanates catalyzed by tin iodide

Article abstract of DOI:10.1002/ejoc.201201305

2-Methyleneaziridines proved to be good substrates for the cycloaddition with isocyanates, for which a tin iodide system, Bu₂SnI ₂-LiI, was employed as an effective catalyst. Products were derived from N-attack of the ring-opened metalloenamine intermediate. 2-Methyleneaziridines proved to be good substrates for the cycloaddition with isocyanates, for which a tin iodide system, Bu₂SnI₂-LiI, was employed as an effective catalyst. Products were derived from N-attack of the ring-opened metalloenamine intermediate. Copyright

Full text of DOI:10.1002/ejoc.201201305

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201305
Cycloaddition of 2-Methyleneaziridines with Isocyanates Catalyzed by Tin
Iodide
Hiroki Takahashi,[a] Seiji Yasui,[a] Shinji Tsunoi,[a] and Ikuya Shibata*[a]
Keywords: Small-ring systems / Nitrogen heterocycles / Tin / Cycloaddition / Isocyanates
2-Methyleneaziridines proved to be good substrates for the
cycloaddition with isocyanates, for which a tin iodide system,
Bu2SnI2–LiI, was employed as an effective catalyst. Products
were derived from N-attack of the ring-opened metalloen-
amine intermediate.
heterocyclic compounds. The reaction proceeds through N-
attack of metalloenamine A, for which a tin iodide system
was an effective catalyst (Scheme 2).
Introduction
2-Methyleneaziridines 1 are stable and easy to handle de-
spite their highly strained structures and many preparation
methods have been developed thus far.[1,2] Recently, these
substrates have become versatile synthetic tools,[2,3] and
multicomponent reactions based upon the strained ring sys-
tem have been carried out.[3] A representative reaction in-
volves the regioselective ring opening of 2-methyleneazirid- Scheme 2. Cycloaddition of 2-methyleneaziridine.
ine 1 at C-3 by using a Grignard reagent and the capture
of resultant metalloenamine A with an electrophile by C-
attack (Scheme 1). The conventional method for the conver-
sion of 1 is based on a stoichiometric reaction with organo-
Results and Discussion
metallic reagents. The catalytic conversion of 1 has been
reported only when using transition-metal catalysts,[4,5] for
which the initial addition to a C=C bond by a metal species
is the key reaction.[5] From this point of view, we then fo-
cused on ring-opened intermediate A, which possesses two
nucleophilic sites: the metal–amine and the enamine carbon
atom. Thus, not only reactions resulting from C-attack but
also those resulting from N-attack would occur. We present
here the catalytic conversion of 2-methyleneaziridines 1 into
The catalytic preparation of heterocyclic compounds by
the cycloaddition of epoxides with isocyanates was per-
formed by using tin iodide catalysts, which can be estab-
lished as the mildest conditions from among the conven-
tional catalysts.[6] For the cycloaddition, the ring opening
of an epoxide is the key step, and organotin iodides have
been shown to work very well.[7] However, tin catalysts are
not applicable to the reactions of simple aziridines. Because
of the diminished electronegativity of nitrogen compared to
that of oxygen, the ring-opening reactions of aziridines are
expected to be less facile than the corresponding reactions
of epoxides.[8] However, 2-methyleneaziridines 1 seem to
cleave easily because of their highly strain structures. Hence,
1 are considered to be good candidates as substrates for
cycloaddition reactions.
Initially, we performed the cycloaddition of 1a with tosyl
isocyanate (Table 1). Without a catalyst, no reaction pro-
ceeded at 0 °C over the course of 1 h (Table 1, entry 1). By
using 0.1 equiv. of Bu2SnI2 as a catalyst, 2a was obtained
in 23% yield as a 1:1 adduct (Table 1, entry 2). Using LiI
as a catalyst also gave 2a in 25% yield (Table 1, entry 3).
Product 2a is derived from attack of the nitrogen atom of
1a on the isocyanate, and the addition occurs across the
C=N bond of the isocyanate. Metal bromide catalysts such
as Bu2SnBr2 and LiBr showed no catalytic activity (Table 1,
entries 4 and 5). When both Bu2SnI2 and LiI were added
Scheme 1. Conversion of 2-methyleneaziridine.
[a] Research Center for Environmental Preservation, Osaka
University,
2–4 Yamadaoka, Suita, Osaka, 565-0871, Japan
Fax: +81-6-6879-8978
E-mail: shibata@epc.osaka-u.ac.jp
Homepage: http://www.chem.eng.osaka-u.ac.jp/shibataken/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201305.
40
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Eur. J. Org. Chem. 2013, 40–43

Cycloaddition of 2-Methyleneaziridines with Isocyanates
simultaneously, however, the yield of 2a increased to 68% alkene-type products 2Ј (Table 2, see ratio in parentheses).
(Table 1, entry 6). Higher (25 °C) and lower temperatures As the ratio 2/2Ј may not be accurate after isolation, in
(–20 °C) did not improve the yield of 2a (Table 1, entries 7 Table 2 we indicate the ratio based on the crude reaction
and 8).[9]
mixture.
Table 2. Cycloaddition of 1 with isocyanates.[a]
Table 1. Cycloaddition of 1a with tosyl isocyanate.[a]
Entry
R1
R2
Time Product Yield [%][b]
[h]
(2/2Ј)[c]
Entry
Catalyst
Temp. [°C]
Yield [%][b]
1
2
3
4
5
6
7
CH2(4-MeC6H4) (1a) Ph
1
1
18
1
1
1
2b
2c
2c
2d
2e
2f
89 (100:0)
45 (84:16)
70 (54:46)
trace
50 (100:0)
52 (100:0)
trace
1
2
3
4
5
6
7
8
none
Bu2SnI2
LiI
Bu2SnBr2
LiBr
0
0
0
0
0
0
25
–20
trace
23
25
trace
trace
68
PMP
PMP
nBu
nBu (1b)
c-Hex (1c)
Ts
Ts
Ph
Bu2SnI2–LiI
1
2g
55
27
[a] Reaction conditions: 1 (0.8 mmol), RN=C=O (0.5 mmol), THF
(1 mL), Bu2SnI2 (0.05 mmol), LiI (0.05 mmol). [b] Isolated yield
based on the isocyanate. [c] Detected by analysis of the H NMR
spectra of the reaction mixture.
[a] Reaction conditions: 1a (0.8 mmol), TsN=C=O (0.5 mmol),
THF (1 mL), Bu2SnI2 (0.05 mmol), LiI (0.05 mmol). [b] Isolated
yield based on TsN=C=O.
1
A plausible catalytic cycle is shown in Scheme 4. Initially,
Sn–I attacks 2-methyleneaziridine 1 at the C-3 carbon to
give enamine A.[12] The ring-opening step proceeds
smoothly because of the strain of the 2-methyleneaziridine
ring. In the subsequent reaction with an isocyanate, the tin
amine moiety in A attacks the electrophilic carbon of an
isocyanate (N-attack) to give ureidostannane B.[13] To make
this step effective, the use of highly electrophilic isocyanates
was necessary. Thus, the nucleophilicity of the Sn–N bond
in A was insufficient by comparison with simple tin
amines,[14] because of the delocalization of the enamine
structure or its isomerization to an imine to form AЈ. When
using a bromide salt such as Bu2SnBr2 or LiBr as the cata-
We have already studied the mixture of Bu2SnI2 with LiI
by 119Sn NMR spectroscopy.[10] Thus, as shown in
Scheme 3, what is considered as the active catalytic species,
a pentacoordinate tin species, Li+[SnBu2I3]–, was formed.[11]
Scheme 3. Tin iodide ate complex.
Table 2 shows the results of the reactions of 1 with isocy- lyst, no catalytic activity was observed (Table 1, entries 4
anates catalyzed by Bu2SnI2–LiI under the optimized con- and 5). This is because the electron-withdrawing bromide
ditions. The reactivity was dependent on the substituents of substituent decreases the nucleophilicity of A. Next, subse-
both substrates. The reaction of 1a with PhN=C=O pro- quent intramolecular N-alkylation from resultant B affords
ceeded well at 0 °C over 1 h to give product 2b (Table 2, 4-methylene-2-imidazolidinone 2 with regeneration of the
entry 1). However, when p-methoxyphenyl isocyanate tin iodide catalyst. During the isolation process, isomeriza-
(PMPN=C=O) was treated under the reaction conditions, tion to a stable alkene occurred to give internal-alkene-type
it took longer to attain a satisfactory yield of 2c (Table 2, products 2Ј. In all steps of the catalytic cycle, the Sn–I and
entries 2 and 3). Thus, the electrophilicity of the isocyanates Sn–N bonds, which occupy apical positions in the pentaco-
was an important factor in the reaction. In fact, ordinate trigonal bipyramidal structure of the tin atoms,
nBuN=C=O, which has an electron-donating alkyl substitu- worked well because of their increased length and highly
ent, was not reactive under the same conditions (Table 2, nucleophilic character.[15]
entry 4). Other alkyl-substituted 2-methyleneaziridines 1b
We next tried to use an isothiocyanate in place of an
and 1c were reactive to give corresponding adducts 2e and isocyanate (Scheme 5). In the reaction of 1a with
2f, respectively (Table 2, entries 5 and 6). The bulky cyclo- PhN=C=S, although the yield of desired 1:1 adduct 3a was
hexyl substituent of 1c prevented the reaction, even when unsatisfactory, the use of the more electrophilic p-ni-
using PhN=C=O (Table 2, entry 7). In the reactions listed trophenyl isothiocyanate afforded a satisfactory yield of ad-
in Table 2, initially formed products 2 were exo-methylene- duct 3b. The reaction of 1b with p-nitrophenyl isothiocy-
type adducts that were detected in the reaction mixture by anate also gave corresponding adduct 3c. These products
1H NMR spectroscopy. In some cases, during the isolation are derived from the addition of the isothiocyanates across
process, isomerization occurred to give stable, internal- the C=S bond. Namely, the resultant Sn–N bond of A was
Eur. J. Org. Chem. 2013, 40–43
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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41

H. Takahashi, S. Yasui, S. Tsunoi, I. Shibata
SHORT COMMUNICATION
Experimental Section
Representative Procedure: A 5-mL reaction vessel was flame-dried
under reduced pressure. After filling with nitrogen, the vessel was
charged successively with nBu2SnI2 (0.0243 g, 0.05 mmol) and LiI
(0.067 g, 0.05 mmol) in THF (1 mL). After 5 min, 2-methyleneazir-
idone (1a; 0.127 g, 0.8 mmol) and tosyl isocyanate (0.099 g,
0.5 mmol) were added with stirring. The solution was stirred at
0 °C for 1 h. Disappearance of the characteristic band of the NCO
group at 2100 cm–1 was observed in the IR spectrum. Upon com-
pletion of the reaction, the mixture was quenched with brine
(10 mL). The mixture was extracted with diethyl ether (3ϫ 20 mL),
and the combined extract was dried with sodium sulfate and con-
centrated. The isolated yield of 2a (0.1211 g, 68%) was determined
based on the isocyanate (0.5 mmol). The crude product was then
purified by flash column chromatography (hexane/EtOAc, 9:1 to
3:7). The desired product eluted with hexane/EtOAc = 7:3.
Scheme 4. Plausible catalytic cycle.
Supporting Information (see footnote on the first page of this arti-
cle): General procedures and characterization data of new com-
pounds.
added to an isothiocyanate to form adduct C,[16] which in-
cluded an Sn–S bond because of the high affinity of Sn for
S atoms,[7] and subsequent intramolecular alkylation of the
Sn–S bond afforded product 3 (Scheme 6).
Acknowledgments
This research was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Cul-
ture and the Naito Foundation.
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Scheme 5. Reactions with isothiocyanates.
Scheme 6. Addition of A to isothiocyanate.
Conclusions
In conclusion, we demonstrated that 2-methyleneazirid-
ines 1 are good substrates that can give nitrogen heterocy-
cles through novel type of cycloaddition. The organotin
iodide complex, Bu2SnI2–LiI was employed as an effective
catalyst. We are now planning the catalytic reactions op-
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42
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Eur. J. Org. Chem. 2013, 40–43

Cycloaddition of 2-Methyleneaziridines with Isocyanates
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Received: October 3, 2012
Published Online: November 13, 2012
Eur. J. Org. Chem. 2013, 40–43
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