Annelated 4,5-diazaspiro[2.4]hepta-4,6-diene obtained by [3 + 2] Cycloaddition of Diazocyclopropane to Cyclooctyne

Article abstract of DOI:10.1016/j.mencom.2013.07.002

The 1,3-dipolar cycloaddition of diazocyclopropane generated in situ to cyclooctyne at -30 to -25 C afforded highly reactive spiro(9,10-diazabicyclo[6. 3.0]undeca-1(8),9-diene-11,1'-cyclopropane) which can add nucleophiles to the azocyclopropane fragment

Full text of DOI:10.1016/j.mencom.2013.07.002

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 187–189
Annelated 4,5-diazaspiro[2.4]hepta-4,6-diene obtained by
[3+2] cycloaddition of diazocyclopropane to cyclooctyne
Evgeny V. Shulishov, Yury V. Tomilov* and Oleg M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: tom@ioc.ac.ru
DOI: 10.1016/j.mencom.2013.07.002
The 1,3-dipolar cycloaddition of diazocyclopropane generated in situ to cyclooctyne at –30 to –25°C afforded highly reactive
spiro(9,10-diazabicyclo[6.3.0]undeca-1(8),9-diene-11,1'-cyclopropane) which can add nucleophiles to the azocyclopropane fragment
or undergo oligomerization with three-membered ring opening.
Diazocyclopropane, which is susceptible to 1,3-dipolar cyclo-
addition1–3 similarly to typical aliphatic diazo compounds, is
one of the most important intermediates formed upon the decom-
position of N-nitroso-N-cyclopropylurea 1 under the action of
strong bases. The addition of diazocyclopropane to 1,3-dienes
and the activated double bonds of levoglucosenone4 and isomeric
alantolactones5 was described. Meantime, the interaction of diazo-
cyclopropane with alkynes was unknown. In this work, we studied
for the first time the 1,3-dipolarcycloadditionofdiazocyclopropane
to the triple bond of cyclooctyne.
We found that diazocyclopropane generated from N-cyclo-
propyl-N-nitrosourea 1 under the action of sodium methoxide
or potassium carbonate did not give cycloaddition products
with usual alkynes, dimethyl acetylenedicarboxylate or phenyl
propargyl sulfide. In this connection, we turned to cyclooctyne
2 – an accessible alkyne with a strained triple bond,6 which is
stable at room temperature. Cyclooctyne 2 is known to easily
react with diazomethane to form annelated 1H-pyrazole 3.7 It was
assumed that condensed 3H-pyrazole 4, which contains a 4,5-di-
azaspiro[2,4]heptadiene fragment, can be the product of a reaction
between cyclooctyne and diazocyclopropane, since it contains
no a-protons in the heterocycle. Compounds with this structure
were not described until now, although attempts to generate
4,5-diazaspiro[2,4]heptadiene were undertaken, for example,
during dehydrobromination of 5-bromospiro(1-pyrazoline-3,1'-
cyclopropane).8 Structural analogues of the test heterocycle,
namely 5,6-diazaspiro[2.4]hepta-4,6-dienes 5a,b, are known, but
these compounds were only detected in NMR experiments.9
can be attributed to cycloadduct 4, and these signals disappeared
upon heating the sample above 0°C. Evidently, the methoxide
anion participated in the formation of some reaction products.
To avoid further transformations, we used another base for the
decomposition of nitrosourea 1, namely, potassium tert-butoxide,
which effectively works at a low temperature and gives less
nucleophilic tert-butanol. Addition of potassium tert-butoxide to
a mixture of nitrosourea 1 and cyclooctyne in CD2Cl2 at –40°C
did not cause noticeable changes. However, the initially yellow
colour of the reaction mixture almost completely disappeared upon
slow heating to –30...–25°C, with noticeable release of nitrogen
having not been observed. 1H and 13C NMR spectra recorded at
–25°C showed a significant consumption of the starting reactants
1 and 2 and the appearance of characteristic signals of cyclo-
adduct 4, whose integral intensities corresponded to the yield of
compound 4 of no lower than 75% (Scheme 1).† The 2D COSY,
HSQC and HMBC spectra confirmed the structure of compound 4.
The key spirocyclopropane fragment manifested itself in the
13C NMR spectra as signals at d 19.8 and 75.2 ppm. The olefin C
atoms resonated at d 147 and 155 ppm. In the 1H NMR spectrum,
the nonequivalent protons of a cyclopropane ring appeared as two
ButOK
N
CONH2
N2
CD2Cl2,
–30 to –20 °C
NO
1
2'
2
3'
1
11
2
H
N
N
8
Me
R
N
N
N
7
N
N
4
N
3
4
5a R = Me
5b R = OPri
Scheme 1
†
Spiro(9,10-diazabicyclo[6.3.0]undeca-1(8),9-diene-11,1'-cyclopropane) 4
.
Solid ButOK (0.09 mmol) was added in one portion to a mixture of
N-cyclopropyl-N-nitrosourea 1 (0.09 mmol) and cyclooctyne 2 (0.08 mmol)
in CD2Cl2 (0.5 ml) at –40°C, and the reaction mixture was kept at –30°C
for several minutes until the yellow colour disappeared. The main signals in
NMR spectra corresponded to compound 4. 1H NMR (CDCl3, 300 MHz)
d: 1.46–1.52 (m, 4H, H2C4 and H2C5), 1.65–1.74 (m, 2H, H2C3), 1.78–1.85
(m, 2H, H2C6), 2.02 (m, 2H, H2' and H3'), 2.24–2.30 (m, 2H, H2C2), 2.72
(m, 2H, H2' and H3', directed to the N atoms), 3.01–3.07 (m, 2H, H2C7).
13C NMR (CDCl3, 75.5 MHz) d: 19.81 (C2' and C3'), 20.92 (C2), 24.42
and 24.90 (C4 and C5), 24.81 (C7), 26.27 (C3), 26.55 (C6), 75.19 (C1' ),
147.08 (C1), 155.00 (C8).
Initially, we used the decomposition of nitrosourea 1 with
sodium methoxide at a temperature from –40 to –10°C for the
generation of diazocyclopropane in the presence of cyclooctyne.
However, elaboration of this reaction in CD2Cl2 in a NMR tube
showed that, under these conditions, different processes occurred
to lead to a mixture of compounds; the 1H and 13C NMR spectra
of some of these compounds clearly exhibited signals of methoxy
groups and isolated 1,2-ethylidene fragments. Nevertheless, in
a number of cases at a temperature no higher than –15°C, low-
intensity signals were observed in the 1H NMR spectrum, which
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Mendeleev Commun., 2013, 23, 187–189
multiplets looking like quartets at d 2.02 and 2.72 ppm, which were
downfieldshiftedby0.6–0.8ppm, ascomparedwiththeanalogous
signalsoftherelativespiro(1-pyrazoline-3,1'-cyclopropanes).4,5,8
In this case, as in the latter, the signal of vicinal protons in a
cyclopropane fragment, oriented towards nitrogen atoms,
appeared in a lower field. Note that the experimentally observed
N
N
HO
N
N
O
Nu
9
i
+ 6
(26%)
...
4
NH
N
ii
1
chemical shifts of all signals in the H and 13C NMR spectra
N
N
H
were close to those calculated using the PRIRODA program.10
According to NMR-spectroscopic data, 4,5-diazaspiro[2,4]-
heptadiene 4 is stable at –15°C for 1 h. However, the spectrum of
the sample became strongly complicated after storage at this tem-
perature for 10–12 h to indicate that it underwent oligo-
merization.
6 Nu = OMe (73%)
7 Nu = SPh (65%)
8 (58%)
Scheme 2 Reagents and conditions: i, NuH, CD2Cl2, –20®20°C; ii, 1,
MeONa/MeOH, CD2Cl2, –20®20°C.
At the same time, if the reaction mixture obtained at –30°C,
which mainly contained compound 4, was immediately treated
with methanol, stable (2-methoxyethyl)pyrazole 6 was formed in
73% yield (based on nitrosourea after column chromatography) as
a result of cyclopropane ring opening in spiro compound 4 with
the addition of a methanol molecule (Scheme 2).‡ The position
of double bonds in the heterocyclic moiety of product 6 is shown
tentatively; in fact, rapid prototropic isomerization occurs as in
the majority of HN pyrazoles because the observed line half-
width in the 13C NMR spectrum is 20 Hz for both of the a-C
atoms of the pyrazole fragment at 25°C, whereas it is 2 Hz for
the b-C atom.
Note that compound 6 was also formed when MeONa/MeOH
was used to decompose nitrosourea 1 in the presence of cyclo-
octyne in our preliminary experiments.
Similar addition of thiophenol to diazaspiroheptadiene 4, which
was obtained at –30°C, in the course of heating the reaction mixture
gave (2-phenylthioethyl)pyrazole 7 (Scheme 2).‡
An unexpected result was obtained when an excess of cyclo-
propylnitrosourea 1 was used in a reaction with cyclooctyne 2.
Thus, upon the slow heating (from –30 to 20°C) of the reaction
mixture containing compounds 1 and 2, MeONa and MeOH in
a molar ratio of 2.5:1:4:4, compound 8 bearing a cyclopropyl-
oxodiazene fragment was produced in addition to methoxy
derivative 6 (Scheme 2).§ Compound 8 resulted from the genera-
tion of cyclopropyldiazohydroxide 9 at a step of nitrosourea 1
decomposition and its addition to the unstable molecule of 4 in a
temperature range from –20 to 20°C. Note that the decomposition
of nitrosourea 1 under the action of ButOK does not lead to the
noticeable formation of oxodiazene 8, which can be related to a
low probability of the generation of free diazohydroxide 9 in the
absence of methanol.
The presence of an azoxy group in compound 8 was detected
based on the 14N NMR spectrum and confirmed by mass-spec-
trometric data. The chemical shifts of all of the four nitrogen
atoms were identified by 2D {1H–15N}HMBC NMR. The set of
13C and 15N NMR-spectroscopic data also indicates that azoxy
derivative 8 is formed as a single isomer, and the line broadening
of the quaternary carbon atoms in its 13C NMR spectrum is much
lower (Dn 4 Hz for a-C atoms) than that in pyrazole 6, which
may be due to the formation of an intramolecular hydrogen bond.
To conclude, we were the first to detect substituted 4,5-diaza-
spiro[2.4]hepta-4,6-diene 4, which was formed by the trapping
of in situ generated diazocyclopropane by cyclooctyne, with the
aid of low-temperature NMR spectroscopy. The discovered high
reactivity of this species makes it promising for the preparation
of new unusual derivatives as well as for general knowledge of
polycyclic compound chemistry.
This work was supported by the Russian Federation President
Council for Grants (Programme for State Support of Leading
Scientific Schools of the Russian Federation, grant no. NSh-
604.2012.3) and the Division of Chemistry and Materials Science
of the Russian Academy of Sciences (Programme for Basic
Research ‘Theoretical and Experimental Study of the Nature
of Chemical Bonds and Mechanisms of Important Chemical
Reactions and Processes’).
‡
11-(2-Methoxyethyl)-9,10-diazabicyclo[6.3.0]undeca-1(8),10-diene 6.
To a mixture containing compound 4, which was obtained as described
above, methanol (10 mg) was added at –25°C, and the mixture was allowed
to warm to room temperature. Compound 6 was isolated by chromato-
graphy on silica gel (eluent, EtOAc) in 73% yield as yellowish thick oil.
1H NMR (CDCl3, 300 MHz) d: 1.40–1.50 (m, 4H, 2CH2), 1.55–1.63 and
1.65–1.73 (2m, 2×2H, 2CH2), 2.49–2.54 and 2.70–2.75 (2m, 2×2H,
H2C2 and H2C7), 2.82 (t, 2H, CH2, J 6.6 Hz), 3.38 (s, 3H, MeO), 3.60
(t, 2H, OCH2, J 6.6 Hz), 8.00 (br.s, 1H, NH). 13C NMR (CDCl3, 75.5 MHz)
d: 21.25, 24.75, 25.33, 25.63, 25.65, 29.38 and 29.76 (all CH2), 58.77
(MeO), 71.93 (OCH2), 115.15 (C1), 141.6 and 148.2 (br., Dn 20 Hz, C8
and C11). 15N NMR (CDCl3, 30.4 MHz, MeNO2 as a standard) d: –134 and
–157. HRMS, m/z: 209.1652, 231.1463 (calc. for C12H20N2O: 209.1648
[M+H]+, 231.1468 [M+Na]+).
11-(2-Phenylthioethyl)-9,10-diazabicyclo[6.3.0]undeca-1(8),10-diene 7.
Similarly, to a mixture containing compound 4, thiophenol (10 mg) was
added at –25°C, and the mixture was allowed to warm to room tempe-
rature. New compound 7 was isolated by chromatography on silica gel
(benzene–EtOAc, 1:1) in 65% yield as yellowish thick oil. 1H NMR
(CDCl3, 300 MHz) d: 1.39–1.50 (m, 4H, 2CH2), 1.55–1.64 and 1.68–1.76
(2m, 2×2H, 2CH2), 2.45–2.52 and 2.76–2.82 (2m, 2×2H, H2C2 and
H2C7), 2.95 (t, 2H, CH2, J 7.5 Hz), 3.26 (t, 2H, SCH2, J 7.5 Hz), 7.18 (m,
1H, p-HPh), 7.38 (m, 2H, m-HPh), 7.36 (m, 2H, o-HPh), 12.5 (br.s, 1H,
NH). 13C NMR (CDCl3, 75.5 MHz) d: 21.06, 24.38, 25.44, 25.48, 29.07,
29.52 (all CH2), 25.30 (CH2CH2S), 33.13 (CH2S), 126.31 (p-CH), 129.06
(m-CH), 129.56 (o-CH), 116.57 (C1), 135.71 (i-C), 143.82 and 146.38
(C8 and C11). 15N NMR (CDCl3, 30.4 MHz, MeNO2 as a standard) d:
–158 and –166. HRMS, m/z: 287.1579, 309.1400 (calc. for C17H22N2S:
287.1576 [M+H]+, 309.1396 [M+Na]+).
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