Formation of tetrazoles on diazocyclopropane generation

Article abstract of DOI:10.1016/j.mencom.2011.11.002

Decomposition of N-cyclopropyl-N-nitrosourea with bases in the absence of agents for trapping of diazocyclopropane and cyclopropyldiazonium leads to 1,5- and 2,5-disubstituted tetrazoles.

Full text of DOI:10.1016/j.mencom.2011.11.002

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 302–304
Formation of tetrazoles on diazocyclopropane generation
Yury V. Tomilov,* Irina V. Kostyuchenko, Alexander I. Novichkov and Evgeny V. Shulishov
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.2011.11.002
Decomposition of N-cyclopropyl-N-nitrosourea with bases in the absence of agents for trapping of diazocyclopropane and cyclopropyl-
diazonium leads to 1,5- and 2,5-disubstituted tetrazoles.
OMe
Considerable attention has recently been attracted to the reac-
tivity of diazocyclopropanes and related cyclopropyldiazonium
ions, primarily to the reactions which occur with retention of
nitrogen atoms in the molecule, in particular, 1,3-dipolar cyclo-
addition of diazocyclopropane 1 to double bonds to give spiro-
cyclopropanated pyrazolines1 and azo-coupling of cyclopropyl-
diazonium 2 with activated arenes and CH-acids to give cyclo-
propylazoarenes2 or N-cyclopropylhydrazones.3 It should be
noted that generation of cyclopropyldiazonium intermediates,
which is generally performed by treatment of N-cyclopropyl-
N-nitrosourea (CNU) with bases,4 can involve concurrent trapping
of both diazocyclopropane and diazocyclopropyldiazonium ions
(Scheme 1), depending on the nature of the substrates used.1(c)
OMe
CONH2
MeONa/MeOH
–10–0 °C
N
+
N
N
N
NO
N
N
N
N
CNU
N
3
4
(~7 : 1)
Scheme 2
dimensional correlation spectra.† The 1H NMR spectrum of the
primary reaction mixture contained, along with the signals
of tetrazole 3, also a second set of similar signals with much
lower intensity (ratio ~7:1), which suggested the presence of a
second isomer, viz., 5-(2-methoxyethyl)-2-cyclopropyltetrazole 4
(Scheme 2). A minor isomer 4 was isolated in enriched form
only (up to 80%).
In order to fulfil a valid assignment of the cyclopropyltetr-
azoles obtained as 1- and 2-isomers, we performed a NOESY
experiment, which showed that the major isomer 3 truly mani-
fested spatial interaction of the methylene protons in the cyclo-
propane ring with the protons of the a-methylene group in the
2-methoxyethyl substituent. This effect was not observed for
minor isomer 4.
N
CONH2
NO
CNU
Base
H+
H
N2
– H+
N2
1
2
R
R
H–Y
Furthermore, we confirmed the structure of tetrazole 3 by a
chemical method. It is known that reduction of disubstituted
tetrazoles with complex metal hydrides occurs in different ways
R
R
N
N
Y
N
N
†
Scheme 1
1-Cyclopropyl- and 2-cyclopropyl-5-(2-methoxyethyl)tetrazoles 3 and 4.
A solution of MeONa (20 mmol) in methanol (4 ml) was added with
stirring to a solution of N-cyclopropyl-N-nitrosourea (15 mmol) in MeOH
(15 ml) at –10°C. Stirring was continued for 10 min at 0°C and the
solution was concentrated in a vacuum to half of its volume. The reaction
mixture was poured into water (15 ml) and extracted with CH2Cl2 (2´8 ml).
The organic extracts were dried with anhydrous MgSO4 and the solvent
was removed in a vacuum. The yellow oily residue (0.90 g), which was
generallyamixtureoftetrazoles3and4ina7:1ratio,waschromatographed
on SiO2 (CH2Cl2–methanol, 10:1) to give 0.69 g (55%) of tetrazole 3 and
0.13 g (10%) of a mixture of 3 and 4 in a ratio of ~1:4.
In many cases, when generation of intermediates 1 and 2
in the presence of poorly active substrates was performed, we
repeatedly detected, in addition to the target products, some
side ones formed without any relation to the substrates used but
depending on the method employed to decompose the starting
CNU. In view of this, we studied CNU decomposition on treat-
ment with a sodium methoxide solution in methanol or an aqueous
solution of KOH in the absence of trapping agents for either
diazocyclopropane or cyclopropyldiazonium.
1
3: H NMR (CDCl3, 300 MHz) d: 1.22, 1.32 (2m, 2´2H, CH2CH2),
3.21 (t, 2H, CH2, J 7.1 Hz), 3.32 (s, 3H, OMe), 3.58 (tt, 1H, HC, Jcis 8.3 Hz,
Jtrans 4.8 Hz), 3.82 (t, 2H, CH2O, J 7.1 Hz). 13C NMR (CDCl3, 75.5 MHz)
d: 6.9 (CH2CH2), 24.5 (CH2), 28.2 (CH), 59.0 (OMe), 69.7 (OCH2), 154.8
(C=N). MS, m/z (%): 168 (2) [M]+, 153 (3) [M – Me]+, 95 (17), 45 (100).
Found (%): C, 49.64; H, 6.79; N, 33.40. Calc. for C7H12N4O (%): C, 50.00;
H, 7.14; N, 33.33.
4: 1H NMR (CDCl3, 300 MHz) d: 1.20, 1.43 (2m, 2´2H, CH2CH2), 3.12
(t, 2H, CH2, J 7.0 Hz), 3.36 (s, 3H, OMe), 3.79 (t, 2H, CH2O, J 7.0 Hz),
4.14 (tt, 1H, HC, Jcis 8.4 Hz, Jtrans 4.9 Hz). 13C NMR (CDCl3, 75.5 MHz)
d: 7.4 (CH2CH2), 26.4 (CH2), 34.6 (CH), 58.8 (OMe), 70.2 (OCH2),
153.4 (C=N).
In fact, sufficiently rapid mixing of CNU and MeONa/MeOH
at –10 to 0°C results in compounds that were previously observed
in NMR spectra as side products only. The amount of the com-
pound isolated after removal of the solvent and volatile reaction
products was up to 40% of the original CNU mass. Column
chromatography on silica gel allowed us to obtain an analytically
pure sample of the major reaction mixture component, to which
the structure of 5-(2-methoxyethyl)-1-cyclopropyltetrazole 3 was
assigned based on elemental analyses, mass spectrometry and 1H
and 13C NMR data, as well as HMBC 1H–13C and 1H–15N two-
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 302–304
for 1,5- and 2,5-disubstituted tetrazoles. In fact, one secondary
N
amine is formed from 1,5-disubstituted tetrazoles, whereas a
mixture of two primary amines is formed from 2,5-disubstituted
ones.5 It was found that reduction of the major isomer with
lithium aluminium hydride, along with the heterocycle reduc-
tion, also involved cleavage of the ether bond to give known
N-cyclopropyl-N-propylamine 5.6 The formation of secondary
amine 5, which was isolated as a hydrochloride,‡ additionally
confirms that the major isomer has the structure of 1,5-disub-
stituted tetrazole 3 (Scheme 3).
KOH / H2O
HO
+
N
N
HO
CNU
CH2Cl2,
0–5 °C
N
N
N
N
N
(~3 : 1)
7
8
PhCOCl / Et3N
N
N
Ph(O)CO
Ph(O)CO
+
N
N
N
N
N
N
OMe
(~3 : 1)
Scheme 4
9
10
H
I–
Me
LiAlH4
Et2O
MeI
N
3
75 °C, 15 h
N
N
ducts, and the overall yield of tetrazoles 7 and 8 amounted to
50–55%. Hydroxyethyl-substituted tetrazoles were found to be
less stable than methoxy derivatives 3 and 4, and we failed to
isolate them in individual form. In view of this, the resulting
mixture of tetrazoles 7 and 8 was treated with benzoyl chloride
in the presence of triethylamine. The benzoates 9 and 10 were
separated by column chromatography on silica gel.
Apparently, the formation of tetrazoles 3 and 4 or 7 and 8
formally involves interaction of two diazocyclopropane mole-
cules and one methanol or water molecule. The formation of
tetrazoles in 12 and 24% yields in the reaction of diazomethane
with 4-nitrophenyl- and 3-pyrazolyldiazonium salts, respectively,
has been reported;8 however, the application of this scheme in our
case would assume the reaction of two highly reactive interme-
diates, diazocyclopropane 1 and a cyclopropyldiazonium ion 2,
followed by opening of the spiro coupled cyclopropane moiety
in heterocyclic intermediates 11 (Scheme 5).
N
N
5 (82%)
6 (80%)
Scheme 3
Similarly to other tetrazoles, cyclopropyltetrazole 3 can be
alkylated with iodomethane; however, unlike e.g. 1,5-dimethyl-
tetrazole,7 the reaction requires more drastic conditions (sealed
tube, 75°C, 15 h). Nevertheless, even under these conditions the
conversion of the starting tetrazole to tetrazolium iodide 6 was
incomplete and amounted to 80%. H and 13C NMR spectra
1
showed that all signals of the starting tetrazole were preserved
(while some of them were shifted downfield) and one more
methyl group signal appeared.§ A NOESY experiment revealed
that the protons of the a-methylene moiety in the 2-methoxyethyl
substituent correlate with protons of both the cyclopropane ring
and the methyl group, which suggests that it is located at 4-posi-
tion of the tetrazole ring (Scheme 3).
Further on, in order to find out whether other analogous
tetrazoles can be obtained, we studied CNU decomposition on
treatment with aqueous solutions of potassium hydroxide as well
as potassium and cesium carbonates. Our experiments demon-
strated that considerable yield of tetrazoles can be achieved only
on using strong bases. In fact, rapid addition of a 30% aqueous
solution of KOH to CNU in CH2Cl2 at 0–5°C resulted in the
corresponding 1- and 2-cyclopropyltetrazoles 7 and 8 (isomer
ratio ~3:1) containing a 2-hydroxyethyl substituent at 5-position
of the heterocycle (Scheme 4).¶ Under these conditions (with a
rapid mixing of reagents) allene and allyl alcohol were by-pro-
H
N
N
N2
+
N
N
+
N
N
N
N
N
N
1
2
11
RO–
RO–
RO–
N
CONH2
4 or 8
3 or 7
NO
–OR
OR
RO–
RO–
N2
N
N
N
N
N
+
N
N OR
N
N
‡
N-Cyclopropyl-N-propylamine 5. A solution of tetrazole 3 (1 mmol) in
N
12a R = H
12b R = Me
Et2O (3 ml) was added dropwise to a solution of LiAlH4 (2 mmol) in Et2O
(5 ml) at 5°C and the reaction mixture was stirred until the starting tetrazole
disappeared in a treated aliquot of reaction mixture (GLC). After that, a
small amount of water was added and the organic layer was treated with
HCl. The solvent was removed and the residue was dried in a vacuum.
The yield of amine 5 hydrochloride was 0.10 g (82%). 1H NMR (DMSO-d6,
300 MHz) d: 0.70 and 0.88 (2m, 2´2H, CH2CH2), 0.93 (t, 3H, Me,
J 7.3 Hz), 1.65 (m, 2H, CH2), 2.63 (m, 1H, CH), 2.90 (m, 2H, CH2N),
4.47 (br.s, 2H, NH2+). 13C NMR (DMSO-d6, 75.5 MHz) d: 2.3 (cyclo-
CH2CH2), 10.4 (Me), 18.2 (CH2), 28.8 (CH), 48.4 (NCH2). Amine 5 has
been previously obtained from cyclopropylamine and propyl bromide,6
but its NMR spectra were not published.
OR
Scheme 5
¶
1-Cyclopropyl- and 2-cyclopropyl-5-(2-hydroxyethyl)tetrazoles 7 and 8.
A 30% aqueous solution of KOH (9 mmol) was added in one portion to a
solution of N-cyclopropyl-N-nitrosourea (4 mmol) in CH2Cl2 (10 ml) at
5°C and the reaction mixture was stirred for 20 min at this temperature.
Then water (10 ml) was added and the mixture was extracted with CH2Cl2
(4´5 ml). The combined organic layers were dried with anhydrous MgSO4;
removal of the solvent gave a mixture of tetrazoles 7 and 8 in 3:1 ratio as
a yellowish oil in ~50–55% yield.
1-Cyclopropyl- and 2-cyclopropyl-5-(2-benzoyloxyethyl)tetrazoles 9
and 10. A solution of benzoyl chloride (1 mmol) in CH2Cl2 (3 ml) was
added at 5°C to a solution of tetrazoles 7 and 8 obtained in the previous
experiment and triethylamine (1.6 mmol) in CH2Cl2 (8 ml). The reaction
mixture was stirred for 2 h and water (10 ml) was added. The organic
layer was washed with water (6 ml) and evaporated in a vacuum. The
residue was treated with column chromatography [SiO2, benzene–AcOEt
(10:1)] to furnish pure compounds 9 (58%) and 10 (19%).
§
1-Cyclopropyl-4-methyl-5-(2-ethoxyethyl)tetrazolium iodide 6. A solu-
tion of tetrazole 3 (0.6 mmol) and methyl iodide (2 mmol) in acetone
(1 ml) was heated at 70°C in a sealed tube for 15 h. The reaction mix-
ture was cooled; recrystallization from an acetone–diethyl ether mixture
(1:1) gave product 6 as pale brown crystals in 80% yield, mp 124–125°C.
1H NMR (CDCl3, 300 MHz) d: 1.44 and 1.78 (2m, 2´2H, CH2CH2),
3.33 (s, 3H, MeO), 3.87 and 3.98 (2m, 2´2H, OCH2CH2N), 4.14 (tt, 1H,
CH, Jcis 7.6 Hz, Jtrans 4.3 Hz), 4.40 (s, 3H, MeN+). 13C NMR (CDCl3,
75.5 MHz) d: 7.46 (CH2CH2), 27.1 (CH2N), 32.3 (CH), 38.5 (MeN+), 59.3
(MeO), 67.8 (CH2O), 155.2 (C=N).
For characteristics of compounds 7–10, see Online Supplementary
Materials.
– 303 –

Mendeleev Commun., 2011, 21, 302–304
1
However, another reaction pathway is possible, in which the
generation of CNU on treatment with NaOH/MeOH or KOH/H2O
is preceded by the formation of cyclopropyldiazenes 12a or 12b.
Subsequent addition of diazocyclopropane to intermediates 12
followed by transformation of the spirane system would also
produce the target tetrazoles 3 and 4 or 7 and 8 (Scheme 5).
The regioselectivity of compound 1 addition to the N=N bond
of diazenes 12a and 12b can vary, thus giving different ratios of
isomeric tetrazoles in the case of methoxy and hydroxy derivatives.
Though the mechanisms of this transformation is still in
question, the discovered possibility to obtain tetrazole deriva-
tives in a reaction of two unstable intermediates is rather unique.
Obviously, increasing the yield of tetrazoles requires raising the
concentration of cyclopropyldiazonium intermediates in the solu-
tion, in particular, the latter may be enhanced by accelerating the
CNU decomposition.
Based on the possible concepts of the tetrazole formation
mechanism, it appeared interesting to perform the reactions of
cyclopropyldiazonium with other diazo compounds or diazo-
cyclopropane with aryldiazonium salts. We initially attempted to
carry out the reactions of diazomethane or phenyldiazomethane
with cyclopropyldiazonium intermediates 1 and 2 generated upon
CNU decomposition on treatment with potassium or cesium
carbonates or MeONa, at temperatures from –10 to 5°C. How-
ever, the 1H NMR spectra of the reaction mixtures were found to
be very complex and non-informative; furthermore, the majority
of the signals suggested the predominance of allylic compounds
formed upon dediazotization of ion 2.
14 were identified using H and 13C NMR spectra; a NOESY
experiment revealed correlation between ortho-protons of the
phenyl substituent with the a-methylene protons of the 2-methoxy-
ethyl moiety in 1,5-isomer 13.
The formation of tetrazoles 13 and 14 containing a 2-methoxy-
ethyl moiety apparently follows a scheme similar to the formation
of tetrazoles 3 and 4; again, it is probable that in this case diazo-
cyclopropane 1 would add to N-methoxyphenyldiazene that is
generated under the reaction conditions on treatment of a phenyl-
diazonium salt with MeONa. The formation of compound 15 can
be attributed to the reaction of the phenyldiazonium salt itself
with diazocyclopropane, followed by nucleophilic elimination of
a nitrogen molecule.
In summary, we have found a new reaction, namely, straight-
forward conversion of cyclopropyldiazonium intermediates into
disubstituted tetrazoles, which brings more insight into chemistry
of highly reactive linear compounds with N–N bonds.
This study was supported by the Division of Chemistry and
Materials Science of the Russian Academy of Sciences (Pro-
gramme for Basic Research ‘Theoretical and Experimental Study
of the Nature of Chemical Bond and Mechanisms of the Most
Important Chemical Reactions and Processes’).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.11.002.
Conversely, the reaction of a pre-synthesized phenyldiazonium
salt with cyclopropyldiazonium intermediates generated in situ
was more successful. In fact, addition of CNU and a methanolic
solution of phenyldiazonium sulfate to a sodium methoxide solu-
tion in methanol at –15°C gave not only cyclopropyltetrazoles
3 and 4 but also phenyltetrazoles 13 and 14, as well as cyclo-
propylazobenzene 15 (Scheme 6).†† Isomeric tetrazoles 13 and
References
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N
CONH2
N
N
N
N
OMe
MeONa
MeOH
NO
+
+
Ph
OMe
N2
Ph–N2 X
N2
3 (a) Yu. V. Tomilov, I. V. Kostyuchenko, E. V. Shulishov and G. P. Okon-
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OMe
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N2
N
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Ph +
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N
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OMe
Ph
13 (19%)
14 (14%)
N
N
Ph
15 (10%)
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Scheme 6
†† Decomposition of CNU with MeONa in the presence of phenyldiazonium
sulfate. A mixture of N-cyclopropyl-N-nitrosourea (4 mmol) and phenyl-
diazonium sulfate obtained preliminarily (8 mmol) in methanol (6 ml)
was added in small portions at –20°C to a solution of MeONa and
additionally stirred for 20 min. Then water (15 ml) was added and the
reaction mixture was extracted with CH2Cl2 (4´5 ml). After removing
the solvent, the residue was treated with column chromatography [SiO2,
benzene–AcOEt (5:1)] to give phenyltetrazoles 13 and 14 and 1-(1-meth-
oxycyclopropyl)-2-phenyldiazene 15.
For NMR spectra of compounds 13–15, see Online Supplementary
Materials.
Received: 1st April 2011; Com. 11/3712
– 304 –