One-Pot Synthesis of Trisubstituted Triazenes from Grignard Reagents and Organic Azides

Article abstract of DOI:10.1021/acs.orglett.8b01214

A simple and versatile method for the preparation of linear, trisubstituted triazenes is reported. The procedure is based on the reaction of Grignard reagents with 1-azido-4-iodobutane or 4-azidobutyl-4-methylbenzenesulfonate. These organic azides enable the regioselective formation of triazenes via an intramolecular cyclization step. The new method can be used for the preparation of aryl, heteroaryl, vinyl, and alkyl triazenes. The synthetic utility of vinyl triazenes is demonstrated by acid-induced C-N, C-O, C-F, C-P, and C-S bond-forming reactions.

Full text of DOI:10.1021/acs.orglett.8b01214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Synthesis of Trisubstituted Triazenes from Grignard
Reagents and Organic Azides
Abdusalom A. Suleymanov, Rosario Scopelliti, Farzaneh Fadaei Tirani, and Kay Severin*
́ ́ ́
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: A simple and versatile method for the preparation
of linear, trisubstituted triazenes is reported. The procedure is
based on the reaction of Grignard reagents with 1-azido-4-
iodobutane or 4-azidobutyl-4-methylbenzenesulfonate. These
organic azides enable the regioselective formation of triazenes via
an intramolecular cyclization step. The new method can be used
for the preparation of aryl, heteroaryl, vinyl, and alkyl triazenes.
The synthetic utility of vinyl triazenes is demonstrated by acid-
induced C−N, C−O, C−F, C−P, and C−S bond-forming
reactions.
risubstituted linear triazenes have been investigated
compounds with azides gives disubstituted triazenes, which are
1
Textensively in the context of synthetic organic chemistry. then alkylated (Scheme 1, eq 2). A limitation of this approach is
Among other things, triazenes have been used as traceless
linkers in solid-phase organic synthesis,2 for surface grafting of
small molecules,3 as cross-coupling partners,4 as directing
groups for C−H activation reactions,5 as precursors for
diazonium salts6 and diazocompounds,7 and as starting
materials for N-heterocycles8 and polycyclic aromatic hydro-
carbons (PAHs).9 Most efforts have focused on 1-aryl-3,3-
dialkyl triazenes, which are accessible by coupling of
aryldiazonium salts with secondary amines (see Scheme 1, eq
1).1−9 Triazenes with alkyl, vinyl, or alkynyl substituents in the
1-position cannot be prepared in this fashion, because the
corresponding diazonium salts are unstable. A high-yield
synthesis for trialkyl triazenes was introduced by Michejda
and co-workers.10 Coupling of alkylmagnesium or lithium
the fact that two isomers are formed in roughly equal amounts.
We have recently introduced a new method for the synthesis of
triazenes. Coupling of Grignard reagents with lithium amides
and nitrous oxide was shown to give triazenes in good yields
(Scheme 1, eq 3).11 Importantly, the one-pot procedure can be
used to prepare triazenes with vinyl and alkynyl substituents in
1-position. A potential disadvantage of the method is the
utilization of gaseous N2O, which is not a standard reagent in
synthetic chemistry laboratories.12 Below, we describe a
variation of the azide route of Michejda.13 The new method
allows one to prepare trisubstituted triazenes with aryl,
heteroaryl, vinyl, or alkyl groups in the 1-position as single
isomers in one-pot reactions.
Our investigations were inspired by studies of Michejda and
co-workers on the reaction of alkyl Grignard reagents with
1‑azido-3-chloropropane (compound A1 in Scheme 2).
Depending on the reactions conditions, they observed the
formation of either N-alkylazimines14 or cyclic triazenes
(Scheme 2, eqs 1 and 2).13 The latter were formed by
cyclization of linear, disubstituted triazenes. We hypothesized
that by lengthening the spacer between the azide group and the
halogen, we might favor the formation of linear, instead of
cyclic triazene (Scheme 2, eq 3). In order to facilitate the
cyclization step, we replaced the chloro atom with iodo or tosyl
functions.25 The corresponding azide reagents A2 and A3
(Scheme 2) are readily accessible in two simple steps from
commercially available chemicals. In some cases, the utilization
of the OTs-substituted azide A3 turned out to be advantageous,
because it facilitated the workup of the reactions (for details,
see the Supporting Information (SI)).
Scheme 1. Different Routes for the Synthesis of
a
Trisubstituted Linear Triazenes
a
Received: April 17, 2018
Data taken from refs 1, 10, and 11.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
employed for the synthesis of ferrocenyl triazene 9, which was
isolated in 59% yield. Direct C−H magnesiation of benzo[b]-
thiophene, thiophene, and thieno[2,3-b]thiophene with the
Knochel−Hauser base TMPMgCl·LiCl,15 followed by the
addition of A2 or A3 gave the S-heteroaromatic triazenes
10−12 in 40%−73% yields. In addition to the standard
analytical techniques, the structure of 11 was confirmed by
X‑ray crystallography. Electron-deficient aromatic Grignard
reagents G1 and G2 did not give the desired products. The
azide reagent A2 was recovered in these cases.
Scheme 2. Reactions of the Azides A1−A3 with Grignard
Reagents
The synthesis of 1−12 demonstrates that aromatic and
heteroaromatic triazenes are accessible in synthetically
interesting yields via the new azide route. It is worth comparing
our procedure to the standard method for synthesizing
aromatic triazenes, which relies on the coupling of secondary
amines with aryl diazonium salts (see Scheme 1, eq 1). The
latter are typically prepared from aromatic amines by
diazotization. The factor for choosing one method over the
other could be the price or the availability of the respective
starting material. The aryl bromides used for the preparation of
Grignard reagents are generally less expensive than the
corresponding aryl amines. For example, 9-bromophenan-
threne, which was used for the synthesis of 5, is ∼300 times
less expensive than 9-aminophenanthrene (for details, see the
SI).
The reaction between phenylmagnesium bromide (2 equiv)
and A2 in THF at 50 °C for 2 h followed by aqueous workup
1
gave triazene 1 in 71% isolated yield. H NMR monitoring of
the reaction indicates the initial formation of a magnesium
triazenide salt. The addition of water then induces cyclization,
presumably via a linear, disubstituted triazene (for details, see
the SI).
Employing other arylmagnesium halides in the reaction with
A2 or A3 enabled the formation of the aromatic triazenes 2−6
in good isolated yields (Scheme 3). The heteroaromatic
triazenes based on 3-methylthiophene (7) or N-methylindole
(8) were obtained from the corresponding heteroaryl bromides
in 54% or 61% yield, respectively. The procedure can also be
The triazenes 10−12 were prepared by direct magnesiation
of the corresponding heteroarenes. Here, the azide route is
particularly advantageous, because the corresponding amino-
thiophens are either not commercially available or very
expensive.
Next, we investigated the synthesis of nonaromatic triazenes,
which are not as easily available as aromatic ones. Our
procedure enables the preparation of cyclic, as well as noncyclic
vinyl triazenes (13−20) in moderate to good yields (see
Scheme 4). The 1,2-disubstituted vinyl triazenes 17 and 18
were obtained as mixtures of E/Z stereoisomers. Various 1-alkyl
triazenes (21−26) were prepared in yields between 29% and
68%. It is important to note that 1-alkyl triazenes tend to
decompose upon chromatographic purification with silica gel,
even when the latter is deactivated with NEt3. We found that
much better results are obtained by using deactivated basic
alumina for purification of 21−26. To the best of our
knowledge, trisubstituted 1-alkyl triazenes have not yet been
characterized by X-ray crystallography. The oily product 23
crystallized at −20 °C, and a structural analysis was performed.
The N1−N2 double bond of 23 (1.266(5) Å) is slightly shorter
than what was observed for the aryl triazene 11 (1.272(5) Å)
and the vinyl triazenes 18-E (1.279(3) Å) and 20
(1.2743(13) Å). On the other hand, the N2−N3 single bond
of 23 (1.328(5) Å) is longer, compared to that found for 11
(1.313(4) Å), 18-E (1.322(3) Å), and 20 (1.3214(14) Å) (for
details, see the SI).
Scheme 3. Synthesis of Aromatic Triazenes from Grignard
Reagents and A2 or A3
a
The attempted preparation of the alkynyl triazene 27 has
failed. Instead, the reaction between (phenylethynyl)-
magnesium bromide and A3 gave triazole 28 (see Scheme 4).16
It is worth noting that monosubstituted and disubstituted
vinyl triazenes can also be prepared by our previously reported
N2O-based method.11 The synthesis of trisubstituted vinyl
triazenes, however, was found to be problematic. For example,
the preparation of 29 (a structural analogue of 19) from LDA,
N2O, and the corresponding vinylmagnesium bromide gave a
yield of only 15% (Scheme 5). The attempted synthesis of 30
(a structural analogue of 20) failed completely.
a
Reaction conditions: Grignard reagent (1 equiv) and A2 or A3 (0.5−
b
1.2 equiv) in THF (0.2−1.0 M) at 50 °C for 2−12 h. The Grignard
reagent was generated by metalation of the corresponding arene using
TMPMgCl·LiCl (1.1 equiv). Azide A2 was recovered.
c
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Scheme 4. Synthesis of Non-aromatic Triazenes from
Grignard Reagents and A3
Scheme 6. Acid-Induced Transformations of Vinyl Triazene
20
a
with meta-chloroperoxobenzoic acid (m-CPBA). In the
presence of TFA, vinyl triazene 20 reacts with acetonitrile to
give enamide 35 as a product of a Ritter-type reaction. Most of
the previously published methods for the synthesis of
tetrasubstituted enamides are known to be metal-catalyzed.23
The success of the above-mentioned reactions inspired us to try
a Michaelis-Arbuzov-type vinylation of trialkyl phosphites.
Indeed, TFA-induced reaction of 20 with P(OEt)3 led to
vinyl phosphonate 36 in 30% isolated yield. To the best of our
knowledge, this reaction represents the first metal-free synthesis
of a tetrasubstituted alkenyl phosphonate.24
a
Reaction conditions: Grignard reagent (1.25−2.00 equiv) and A3
(1.00 equiv) in THF (0.2−1.0 M) at 50 °C for 4−12 h. bThe E-isomer
was analyzed by X-ray crystallography. Not detected.
c
In summary, we have developed a simple and general method
for the synthesis of linear, trisubstituted triazenes from
Grignard reagents and 1-azido-4-iodobutane or 4-azidobutyl-
4-methylbenzenesulfonate. These organic azides enable the
regioselective formation of triazenes via an intramolecular
cyclization step. The method allows the preparation of
aromatic, as well as nonaromatic triazenes. Importantly, it
provides access to vinyl triazenes, which are difficult to prepare
otherwise. These triazenes can be used for electrophilic
vinylation reactions, as demonstrated by the acid-induced
replacement of the triazene function with fluoride, alkoxide,
sulfide, amide, and phosphonate. The mild, metal-free reaction
conditions, and the rapid formation of the desired products
underline the potential of vinyl triazenes in synthetic organic
chemistry.
Scheme 5. Synthesis of Vinyl Triazenes from LDA, N2O, and
Vinyl Grignard Reagents
So far, very few studies about the reactivity of vinyl triazenes
have been reported.17,18 The available data point to the fact that
vinyl triazenes can be used as vinyl cation surrogates.19 The
possibility to use vinyl triazenes for electrophilic vinylation
reactions was corroborated by acid-induced cleavage reactions
of triazene 20 (see Scheme 6).
ASSOCIATED CONTENT
* Supporting Information
■
Addition of HF·Py to a solution of 20 in DCM rapidly gave
vinyl fluoride 31, which could be isolated in 54% yield (the high
volatility of the product compromises the yield). Tetrasub-
stituted fluoroalkenes such as 31 can be obtained by reaction of
ketones with a lithiated α-fluorobenzyl phosphonate, but the
latter reagent is thermally instable, and its formation requires
the utilization of diethylaminosulfur trifluoride.20 A reaction of
20 with methanol in the presence of trifluoroacetic acid (TFA)
gave the tetrasubstituted enol ether 32. The reported procedure
for the synthesis of 32 is based on methylation of the
corresponding enolate, which usually gives a mixture of C- and
O-alkylation.21 Treatment of 20 with TFA in butanethiol
rapidly gave the corresponding vinyl sulfide 33 in 73% yield.
Tetrasubstituted vinyl sulfides can be accessed otherwise via a
Wittig olefination of thioesters.22 Vinyl sufide 33 was easily
converted to the corresponding vinyl sulfone 34 by oxidation
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01214.
Experimental details and analytical data of the new
compounds (PDF)
Accession Codes
CCDC 1825041, 1825043, 1825046, and 1836098 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44
1223 336033.
C
DOI: 10.1021/acs.orglett.8b01214
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Organic Letters
Letter
(16) The reaction of alkynyl Grignard reagents with organic azides is
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kay.severin@epfl.ch.
ORCID
Kay Severin: 0000-0003-2224-7234
Notes
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Satoh, Y. Chimia 2004, 58, 133−137. (b) Tsai, H.-J.; Lin, K.-W.; Ting,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by funding from the Ecole
■
Polytechnique Fed
́
er
́
ale de Lausanne (EPFL).
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