Synthesis of triazenes with nitrous oxide

Article abstract of DOI:10.1002/anie.201408597

Triazenes are valuable compounds in organic chemistry and numerous applications have been reported. Furthermore, triazenes have been investigated extensively as potential antitumor drugs. Here, we describe a new method for the synthesis of triazenes. The procedure involves a reagent which is rarely used in synthetic organic chemistry: nitrous oxide (N₂O, laughing gas ). Nitrous oxide mediates the coupling of lithium amides and organomagnesium compounds while serving as a nitrogen donor. Despite the very inert character of nitrous oxide, the reactions can be performed in solution under mild conditions. A key advantage of the new procedure is the ability to access triazenes with alkynyl and alkenyl substituents. These compounds are difficult to prepare by conventional methods because the required starting materials are unstable. Some of the new alkynyltriazenes were found to display high cytotoxicity in in vitro tests on ovarian and breast cancer cell lines.

Full text of DOI:10.1002/anie.201408597

Angewandte
Chemie
DOI: 10.1002/anie.201408597
Nitrous Oxide
Synthesis of Triazenes with Nitrous Oxide**
Gregor Kiefer, Tina Riedel, Paul J. Dyson, Rosario Scopelliti, and Kay Severin*
Abstract: Triazenes are valuable compounds in organic
chemistry and numerous applications have been reported.
Furthermore, triazenes have been investigated extensively as
potential antitumor drugs. Here, we describe a new method for
the synthesis of triazenes. The procedure involves a reagent
which is rarely used in synthetic organic chemistry: nitrous
oxide (N2O, “laughing gas”). Nitrous oxide mediates the
coupling of lithium amides and organomagnesium compounds
while serving as a nitrogen donor. Despite the very inert
character of nitrous oxide, the reactions can be performed in
solution under mild conditions. A key advantage of the new
procedure is the ability to access triazenes with alkynyl and
alkenyl substituents. These compounds are difficult to prepare
by conventional methods because the required starting materi-
als are unstable. Some of the new alkynyltriazenes were found
to display high cytotoxicity in in vitro tests on ovarian and
breast cancer cell lines.
Scheme 1. Retrosynthetic analysis of trisubstituted triazenes. Classical
synthetic routes involve the coupling of diazonium salts with amines
(a) or the reaction of azides with organolithium compounds followed
by alkylation (b). The new synthetic procedure is based on organo-
magnesium compounds, nitrous oxide, and lithium amides (c).
first spectroscopic characterization of such a compound was
only achieved recently.[10] Diazonium salts of alkenes and
alkynes are likewise not very stable.[11] Herein, we describe
a novel synthetic route for the preparation of trisubstituted
triazenes. The reaction involves the coupling of lithium
amides with nitrous oxide and organomagnesium compounds
(Scheme 1c). The new procedure allows access to the elusive
1-alkenyl and 1-alkynyltriazenes in good yields, thereby
opening the way to new, putative drug structures.
Chemical reactions with N2O typically proceed by transfer
of an oxygen atom and liberation of N2.[12] In contrast, there
are very few examples of reactions involving the utilization of
nitrous oxide as a nitrogen donor, in particular in the context
of synthetic organic chemistry. Some cyclic alkynes react with
nitrous oxide at elevated pressure to give diazo ketones.[13]
Phenylcalcium iodide was shown to react with N2O to give
azobenzene in moderate yield.[14] In a related fashion,
lithiated ferrocenes were coupled with N2O to give azo-
bridged ferrocene oligomers.[15] These transformations can be
regarded as homocoupling reactions of C nucleophiles with
insertion of N2. We hypothesized that triazenes could be
obtained in a related fashion by cross-coupling/N2 insertion of
a C nucleophile and an N nucleophile.
When a solution of lithium diisopropylamide (LDA) and
phenylmagnesium bromide (1:1) in tetrahydrofuran (THF)
was allowed to react with N2O (99.999%) at room temper-
ature, the desired coupling product, 1-phenyl-3,3-diisopropyl-
triazene (1), was formed in 20% yield after 18 h. Optimiza-
tion of the reaction conditions revealed that an excess of
Grignard reagent (1.5–2.0 equiv) and slightly elevated tem-
peratures (508C) were beneficial for the coupling reaction.
Furthermore, we were able to improve the yield by perform-
ing the reaction in a stepwise fashion. Thus, a solution of LDA
in THF was first subjected to an atmosphere of N2O. A
reaction between the gas and the amide occurred, as evident
T
riazenes represent “a versatile tool in organic synthesis”.[1]
For example, they have been used as multifunctional linkers
in solid-phase synthesis,[2] as removable directing groups for
[3]
À
C H activation, as protecting groups for the synthesis of
complex natural products,[4] in shape-persistent phenylacety-
lene-based systems,[5] and for the controlled desaturation of
unactivated aliphatic compounds.[6] In addition to their
synthetic utility, triazenes are of importance because of
their biological activity. Two triazenes, dacarbazine and
temozolomide, are currently used in the clinic as chemo-
therapy drugs, the latter may even be administered orally.
Numerous other triazenes have also been tested for their
antitumor activity.[7]
The main synthetic route for the synthesis of trisubstituted
triazenes relies on the coupling of diazonium salts with
secondary amines (Scheme 1a).[8] Trialkyltriazenes have been
prepared by the reaction of aliphatic azides with organo-
lithium compounds, followed by alkylation with organo-
halides (Scheme 1b).[9] These standard procedures have an
important shortcoming: triazenes with alkynyl or alkenyl
substituents in the 1-position are difficult to access because
the required starting materials are highly unstable. 1-Azido-1-
alkynes, for example, decompose at low temperatures and the
[*] G. Kiefer, Dr. T. Riedel, Prof. P. J. Dyson, Dr. R. Scopelliti,
Prof. K. Severin
Institut des Sciences et Ingꢀnierie Chimiques
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
1015 Lausanne (Switzerland)
E-mail: kay.severin@epfl.ch
[**] The work was supported by funding from the Swiss National
Science Foundation and by the EPFL.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408597.
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by the formation of a white precipitate. After 4 h, the N2O
atmosphere was replaced by dry dinitrogen and a solution of
phenylmagnesium bromide in THF (2.0 equiv) was added to
the suspension. The resulting clear solution was then heated
for 4 h at 508C. This procedure resulted in the near-
quantitative formation of triazene 1 (isolated in 94% yield).
The scope of the coupling reaction was examined using
different arylmagnesium compounds and various lithium
dialkylamides. A range of 1-aryl-3,3-dialkylltriazenes was
obtained in good yields. Selected products are depicted in
Figure 1 (1–5; further examples are shown in Figure S1 in the
Supporting Information). Reactions with the aromatic amides
LiNPh2 and LiNMePh were not successful, presumably
because of the lower nucleophilicity of the amides.
magnesium compounds. These coupling partners are partic-
ularly interesting because the putative products, 1-alkynyl-
triazenes, cannot be accessed by standard procedures (see
above). By using a similar procedure as for arylmagnesium
compounds, we were indeed able to synthesize 1-alkynyl-3,3-
dialkyltriazenes (6–15, Figure 1). Aromatic as well as ali-
phatic alkynes can be employed and variations of the alkyl
substituents on the amine group are likewise possible (further
examples are shown in Figure S1 in the Supporting Informa-
tion). Notably, alkynes containing functional groups such as
ethers (12, 14) or tertiary amine groups (13, 15) are suitable as
substrates. Generally, amides with bulky alkyl substituents
(e.g isopropyl) were found to give higher yields than did
amides with small substituents (e.g. methyl).
Having established that aryl Grignard reagents can be
used as C nucleophiles, we turned our attention to alkynyl-
Alkenyl Grignard reagents can also be used as the
coupling partners. As in the case of aryl and alkynyl Grignard
reagents, the procedure appears to be rather general, as
evident by the successful formation of the triazenes 16–20
(Figure 1) and S8–S10 (see Figure S1 in the Supporting
Information).
All the triazenes were characterized by NMR spectros-
copy and high-resolution mass spectrometry. In addition, we
have analyzed the alkynyltriazenes 6 and 10, as well as the
alkenyltriazenes 17 and 20 by single-crystal X-ray crystallog-
raphy. As expected, the compounds display a trans geometry
À
(Figure 2). The N N bond lengths observed for 6, 10, 17, and
20 are similar to those found in aromatic triazenes, such as
p-(3,3-dimethyl-1-triazeno)benzonitrile.[16]
Figure 2. The molecular structures of the triazenes 6, 10, 17, and 20
(from left to right) in the solid state. Hydrogen atoms are not shown
for clarity.
Trialkyltriazenes can also be prepared by our method, as
evident by the synthesis of 1-isobutyl-3,3-diisopropyltriazene
21. However, side products were formed along with 21, and
the yield of 21 was low (12%). Similar results were observed
for attempted coupling reactions with other alkyl Grignard
reagents such as iPrMgCl: the product could be detected by
GC-MS, but in low yields along with several side products. An
optimization of the reaction conditions for trialkyltriazenes
was not undertaken because these compounds can be
prepared by alternative procedures.[9]
The reaction of lithium dialkylamides with N2O was
examined in more detail to obtain information about the
mechanism of the reaction. In the literature, one finds only
sparse data about this type of reaction. In 1953, Meier
reported that LiNEt2 is able to react with N2O.[17] The addition
of N2O to an equimolar mixture of PhLi and Et2NH in diethyl
ether was reported to result in the formation of a black
Figure 1. Synthesis of triazenes by reactions of lithium dialkylamides
with N2O and organomagnesium compounds. The values below the
product numbers refer to the yields of the isolated products.
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reaction mixture. After workup, tetraethyltetrazene was
isolated in low yield (identified by its boiling point). Meier
speculated about intermediates with the formula R2N-
(N2O)Li, but isolation of such an aminodiazotate was not
attempted. As mentioned above, we have observed white
precipitates upon reaction of lithium dialkylamides with N2O
in THF. The precipitates from the reactions of four different
amides have been isolated and analyzed (Scheme 2).
Scheme 2. Synthesis of the N2O adducts 22–25.
The products 22–25 display low solubility in noncoordi-
nating organic solvents such as toluene or chloroform. Upon
the addition of water, the corresponding amine formed along
with liberation of N2O, as shown by NMR spectroscopy and
gas chromatography, respectively (see Figure S2 in the
Supporting Information). The products display moderate
solubility in THF, with the exception of 22, which is poorly
soluble. The solubility in THF can be enhanced by the
addition of LiCl (0.5m). For compound 22, for example, the
solubility increases from about 1 mm to 59 mm, and the
solubility of 25 is increased from about 76 to 328 mm. This
observation suggests that 22–25 form aggregates in THF,
which are cleaved by the addition of LiCl. 22–25 are all
soluble in [D6]DMSO and decomposition is sufficiently slow
to allow analysis (see Figure S3 in the Supporting Informa-
tion). The NMR spectra of 22–25 showed a single set of
signals for the alkyl substituents. The simple NMR spectra are
in line with the elemental analyses, which indicated that
adducts had formed with the formula R2N(N2O)Li. Com-
pounds 22–25 were isolated in yields between 68 and 95%.
Examination of the crude reaction mixtures by 1H NMR
spectroscopy revealed that the reactions are very clean, with
negligible amounts of side products and almost quantitative
conversion.
A crystallographic analysis was deemed crucial to estab-
lish the connectivity and the geometry of the products.
Despite extensive screening of the crystallization conditions,
we were unfortunately not able to obtain single crystals for
any of the products. The formation of aggregates presumably
hampered the crystallization of 22–25. Therefore, we exam-
ined the co-crystallization of the compounds with known Li+
ionophores. Finally, we were able to obtain single crystals of
22 and 24 bound to the metallacrown complex [{(cymene)Ru-
(C5H3NO2)}3] (26). This organometallic ionophore was devel-
oped previously in our research group,[18] and displays a very
high affinity and selectivity for Li+ ions. The structures of the
complexes [26 ꢀ 22] and [26 ꢀ 24] are depicted in Figure 3.
In both cases, the lithium cation is coordinated to three
oxygen atoms of the metallacrown complex. The fourth
binding site is occupied by the oxygen atom of the R2N(N2O)À
Figure 3. Top: the metallacrown complex 26. Bottom: the molecular
structures of the complexes [26ꢁ22] (left) and [26ꢁ24] (right) in the
solid state. Hydrogen atoms, solvent molecules (benzene), and the
alkyl groups of the cymene p ligands are not shown for clarity.
ion. The latter adopts a cis conformation with respect to
À
the central N1 N2 bond. Two independent molecules in the
asymmetric unit (“A” and “B”) can be observed for both
[26ꢀ22] and [26 ꢀ 24]. The bond lengths observed in the two
independent R2N(N2O)Li guests are different. Form “A”
À
À
shows a very short O1 N1 bond and a long N1 N2 bond,
whereas the opposite trend is observed for form “B” (see
Table S2 in the Supporting Information). One should note
that form “B” is less defined because of crystallographic
disorder, and differences in the bond lengths should be taken
with care.
The crystallographic analyses along with the NMR
spectroscopic and elemental analyses data provide strong
evidence that 22–25 are covalent N2O adducts with the
formula R2N(N2O)Li. So far, well-characterized covalent
N2O adducts of organic compounds with intact NNO groups
have only been reported for N-heterocyclic carbenes[19] and
frustrated Lewis pairs.[20] The ability of dialkylamides to form
N2O adducts in a clean and quantitative fashion is essential
for the success of the overall coupling reaction. The subse-
quent reaction of the R2N(N2O)Li adducts with Grignard
À
reagents requires cleavage of the N O bond, which is likely
facilitated by the oxophilicity of Mg2+ ions.
As mentioned above, some 1-aryltriazenes are strongly
cytotoxic. To evaluate if 1-alkynyl and 1-alkenyltriazenes
exhibit relevant antitumor affects, we performed preliminary
in vitro tests with two human cancer cell lines—ovarian
cancer cells (A2780) and invasive breast cancer cells (MDA-
MB-231)—as well as with model healthy cells (MCF-10a and
HEK293). Ten alkynyltriazenes and four alkenyltriaznes were
selected and, for comparison, we have included the clinically
used triazenes dacarbazine (27) and temozolomide (28), as
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Keywords: amides · coupling reactions · Grignard reagents ·
.
nitrous oxide · triazenes
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a) The new synthetic method allows access to triazenes with
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methods.
b) The results provide evidence that nitrous oxide can be
used as an efficient nitrogen donor in organic synthesis.
Previous attempts in this direction have been met with
only limited success.
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À
À
compounds by cleavage of the C N or N N bonds.
Synthetically useful transformations can likely also be found
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substituents is also worthwhile. It is conceivable that promis-
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Received: August 27, 2014
Published online: && &&, &&&&
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Communications
Nitrous Oxide
Synthesis with laughing gas: Triazenes
can be obtained by the reaction of N2O
with secondary lithium amides and
Grignard reagents. The new synthetic
method allows access to triazenes with
alkenyl and alkynyl substituents at the 1-
position. Some of the alkynyl triazenes
show selective anticancer activity in cell
cultures.
G. Kiefer, T. Riedel, P. J. Dyson,
R. Scopelliti, K. Severin*
&&&& — &&&&
Synthesis of Triazenes with Nitrous Oxide
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