Access to 1: H -indazoles, 1 H -benzoindazoles and 1 H -azaindazoles from (het)aryl azides: A one-pot Staudinger-aza-Wittig reaction leading to N-N bond formation?

Article abstract of DOI:10.1039/c8cc03612h

The synthesis of various substituted 1H-indazoles is reported through N-N bond formation from an iminophosphorane derivative. Supported by control experiments, an original Staudinger-aza-Wittig tandem mechanism is proposed for this transformation.

Full text of DOI:10.1039/c8cc03612h

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Daniel, M. Hiebel, E. Pasquinet, F. Suzenet and G. Guillaumet, Chem. Commun., 2018, DOI:
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Access to 1H-indazoles, 1H-benzoindazoles and 1H-azaindazoles
from (het)aryl azides: a Staudinger-aza-Wittig tandem reaction
leading to N-N bond formation?
Received 00th January 20xx,
Accepted 00th January 20xx
T. Alaimea,b, M. Daniela,b, M.-A. Hiebelb, E. Pasquineta,*, F. Suzenetb,*, G. Guillaumetb
DOI: 10.1039/x0xx00000x
www.rsc.org/
The synthesis of various substituted 1H-indazoles is reported We herein disclose the use of an electrophilic nitrogen as a
through N-N bond formation from an iminophosphorane possible partner to form an N-N double bond through an aza-
derivative. Supported by control experiments, an original Wittig reaction (Scheme 1, eq. 2b). Our interest focused on the
Staudinger-aza-Wittig tandem mechanism is proposed for this nitroso group, whose isoelectronic similarity with the carbonyl
transformation.
group is established. Its behavior in the Wittig reaction has
scarcely been studied despite its prompt conversion into imine
(Scheme 1, eq. 1b).4 This lack of attention is probably due to
the rather difficult access to the C-nitroso moiety compared to
iminophosphorane,5 whereas the resulting imine product is
similar. C-nitroso compounds can indeed be oxidized or
isomerized, nevertheless a large variety of reliable synthetic
routes are available to address these issues.6 A previous
The Wittig reaction,1 first disclosed in the early 1950s, is a
reliable way to synthetize regio- and stereo-selective olefins
from easily accessible starting materials in mild reaction
conditions (Scheme 1, eq. 1a). It remains a well-known and
widely used approach and is still the subject of recent
development.2 Replacement of the phosphorane group in the
Wittig olefination reaction by an iminophosphorane group
leads to an aza-Wittig reaction with formation of an imine
bond (Scheme 1, eq. 2a). This powerful way to create a C=N
bond depends on the combination of the nucleophilicity of the
iminophosphorane involved and the subsequent elimination of
oxidized phosphorus. Various electrophiles such as aldehyde,
ketone, ester and amide have indeed been successfully used in
attempt to perform an aza-Wittig reaction, using
a
C-nitroso derivative as the electrophile, was made by
Staudinger and Hauser in 1921 but the triphenyl
iminophosphorane failed to react with nitrosobenzene.7 Later,
the use of the more nucleophilic arsenic ylide enabled this
absence of reactivity to be overcome and was applied to the
synthesis of electron deficient azobenzenes.8 To the best of
our knowledge, only one study postulates an intramolecular
aza-Wittig mechanism involving an iminophosphorane and a
N-nitroso compound.9
inter- and intramolecular manners.3
New reactivity?
R
R
N
PR3
N
PR3
C
PR3
C PR3
R
R
R
R
In our approach, the N=N bond formation would result from
an intramolecular aza-Wittig reaction with a C-nitroso group
coming from the in situ nitrosation on the activated
methylene. This intramolecular sequential domino reaction
would provide, after isomerization, a 1H-indazole scaffold
(Scheme 2). Apart from an original access to useful
heterocyclic derivatives10 and more particularly to 1H-
indazoles,11 the aim of this study is to underline an unusual
reactivity of azides as alternative starting materials.
R'
R
O
R
R
O
O
O
O
N
O
N
O
C
O
C
R
PR3
PR3
PR3
R'
PR3
R
N
R
R'
R
R
R'
C
N
C
C
C
N
N
R
R
R
R
R'
R
(1a)
Wittig
(1b)
Wittig
(2a)
aza-Wittig
(2b)
aza-Wittig
'
R: H, Ar, Alk, OR, NR,OCOR
Scheme 1: State of the art and project plan
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iminophosphorane, the triphenyliminophosphorane
5 was
reacted with tert-butyl nitrite (Scheme 4, a) and NaNO2 in
AcOH.9 After 20 h at room temperature, the starting material
was fully recovered with only traces of the reduced amine
5
6,
allowing us to assume that a diazotization process cannot be
considered here.
‡
Table 1. Sequential domino sequence
Scheme 2: Envisaged retrosynthesis
This reaction was first observed with the iminophosphorane
2a, synthetized from 1a in the presence of an excess of
triphenylphosphine in anhydrous acetonitrile (Scheme 3). In
the presence of tert-butyl nitrite in anhydrous acetonitrile, 2a
gave rise to the formation of the desired 1H-indazole 3a in
70% yield without any additives or catalysts, validating our
synthetic approach.
Entry
1
1
X
R
R’
3
Yield (%)
69
1a
CH
H
SO2Tol
2
3
4
5
6
7
1b
1c
1d
1e
1f
CH
CH
CH
CH
CH
CH
H
H
H
H
H
H
CN
92
87
71
77
51a
NO2
CONEt2
CO2Me
CO2H
OMe
Scheme 3: Sequential formation of 3a
Then, a sequential domino process was tried (Table 1). In this
way, 3a was isolated with excellent 69% yield. Next, several
electron withdrawing groups were examined as activating
agents of the methylene position. In addition to sulfonyl
substituents, our synthetic process tolerates nitrile, nitro,
amide and ester groups and enables the clean formation of the
expected products with good to excellent yields. Surprisingly,
when 2-(2-azidophenyl)acetic acid 1f was used, a spontaneous
decarboxylation occurred leading to the unsubstituted 1H-
indazole 3f in 51% yield. The requirement of an activated
methylene for the nitrosation step was verified with 1-azido-2-
(methoxymethyl)benzene 3g. In the presence of an electron
donating group, the sequential domino process did not occur,
only the iminophosphorane was recovered. Increasing the
temperature or adding a base for the nitrosation step did not
bring about any improvement.
b
-
1g
8
1h
1i
CH
CH
CH
N
Br
CH3
NO2
OMe
Ph
NO2
NO2
NO2
CN
87
84
57
80
40
9
However, it is worth noting that substituents on the phenyl
ring such as bromide, alkyl or nitro groups were well-tolerated
since 3h-j were successfully isolated in good to excellent
yields. The procedure was also applied to pyridyl (3k) and
naphthyl (3l) scaffolds.
10
11
12
1j
1k
1l
To get some insight into the reaction mechanism, some control
experiments were performed (Scheme 4). Apart from being a
nitrosating agent, tert-butyl nitrite is also described to react
with amines to give diazonium intermediates.12 In order to
CH
NO2
a
2-(2-Azidophenyl)acetic acid 1f was used as starting material and an in situ
decarboxylation was observed. b Degradation.
exclude
such
a
diazotation
pathway
from
an
2 | J. Name., 2012, 00, 1-3
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We then focused our attention on the nitrosation step. In deprotonated by the ter-butylate side product from the
order to isolate and characterize the assumed nitroso nitrosation reaction and from pathway the in situ
intermediate, and avoid tautomeric equilibrium to the cycloaddition of the iminophosphorane onto the nitroso N=O
corresponding oxime, double bond should be faster than the isomerization of the
B,
O
O
O
O
tBuONO (4 eq.)
20h, 20 °C
PPh3, MeCN
(a)
+
N3
N
N
NH2
PPh3
PPh3
4
6, traces
5, 60 %
5, 60 %
SO2Tol
SO2Tol
1. PPh3, MeCN
N
(b)
N
N3
2. tBuONO (4eq.)
PPh3, MeCN, 24h, 20 °C
3m, 0 % (e)
N
9, 0%
OH
N
8
N
H
N
OH
N
tBuONO, MeCN
12h, 20 °C
NO2
N
N
N
NO2
Cl
PPh3, MeCN,
Toluene,
14, 71 % (f)
15, 93 % (g)
N
Cl
(c)
(d)
N
N3
H
10
13
11, 35%
OH
N
CONEt2
N
OH
NEt2
N
PPh3, MeCN
24h, 20 °C
N
O
N
N3
H
3d, 0%
12
Scheme 4: Control experiments
latter into an oxime moiety. Then, according to the accepted
Wittig mechanism, a [2+2] cycloreversion reaction would
follow with the formation of triphenylphosphine oxide and 3H-
indazole, which would directly tautomerize to the stable 1H-
the azide
8 bearing a tertiary carbon at the activated benzylic
position was used as substrate. Unfortunately, only
degradation was observed when tert-butyl nitrite was
introduced into the reaction mixture (Scheme 4, b).
indazole 3.
However, we evidenced
a C-nitrosation reaction using
N3
compound 10, which possesses an activated methylene, by
recovering the tautomeric oxime 11 (Scheme 4, c).
PPH3, MeCN
20 °C
At this stage, we wondered if the nitroso function could come
from such tautomeric equilibrium. To answer this question,
the oxime 12 was subjected to the standard conditions i.e. in
acetonitrile at room temperature (Scheme 4, d). After 24 h,
the reaction mixture was degraded. The same result was
observed with 13 (Scheme 4, e). The absence of the expected
1H-indazoles 3d and 3m confirms that the oxime moiety,
through the nitroso form or not, does not react with the
iminophosphorane intermediate under these reaction
conditions. It is worth noting that in refluxing toluene, a
nitrene type cyclization occurred in the absence of
triphenylphosphine (Scheme 4, g)13 while in the presence of
triphenylphosphine, a Beckmann type rearrangement (de facto
phosphine assisted) efficiently led to the 2-methyl-1H-
benzimidazole 11 (scheme 4, f). In both cases, no trace of the
expected product 3m was observed.
Based on literature reports14 and our observations, a plausible
mechanism has been proposed (Scheme 5). First, the
introduction of triphenylphosphine to the medium enables the
straightforward formation of an iminophosphorane moiety
through a Staudinger reaction. Then two intermediates may
result through an N- or C-nitrosation thanks to the presence of
either the nucleophilic nitrogen (intermediate A) or the
EWG
Pathway B
Pathway A
C-Nitrosation
N-Nitrosation
PPh3
N
tBuO-NO
tBuO-NO
tBuOH
tBuO
H
N
EWG
EWG
N
O
N
O
N
PPh3
PPh3
A'
B
tBuO
tBuOH
EWG
EWG
N
O
N
N
N
O
P
Ph3
PPh3
C
O=PPh 3
EWG
N
3a-l
activated methylene (intermediate
occur leading to an oxadiazaphosphetidine
from pathway the activated methylene would be
B). Then, a cyclisation can
N
H
C
. Noteworthy
Scheme 5:-Plausible mechanism
A
,
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Conclusions
We report herein the unprecedented reaction between an
iminophosphorane and a nitroso moiety through a probable
Staudinger / aza-Wittig tandem reaction. This novel approach
was investigated from a mechanistic point of view and applied
to the formation of various 1H-indazole bearing electron
withdrawing groups in C3. Several 3-nitro, 3-cyano and alkyl 3-
carboxylate 1H-indazoles were prepared following this one-pot
process from the corresponding aromatic azides with good to
excellent yields.
Acknowledgements
The Direction Générale de l’Armement is gratefully
acknowledged for financial support. This work has also been
partially supported by Labex SynOrg (ANR-11-LABX-0029),
Labex IRON (ANR-11-LABX-0018-01), University of Orleans and
region Centre Val de Loire.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Nurrenbach and H. Pommer, Liebigs Ann. Chem., 1969, 721, 34;
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A. Soltani and M. Saghafia, Arkivoc, 2016,iv, 1.
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7. E. H. H. Staudinger, Helv. Chem. Acta, 1921, 861.
8. P. Fröyen, Acta Chem. Scando., 1971,
Ł
7, 2781.
9. E. ukasik and Z. Wr bel Synlett, 2014, 1987.
ó
10. (a) U. Mäeorg and S. Tšupova, Heterocycles, 2014, 88, 129;
(b) E. Merino, Chem. Soc. Rev., 2011, 40, 3835; (c) H. Yamamoto
and M. Kawasaki, Bull. Chem. Soc. Jpn., 2007, 80, 595.
11. D. D. Gaikwad, A. D. Chapolikar, C. G.Devkate, K. D. Warad,
A. P. Tayade, R. P. Pawar and Domb, A. J. Eur. J. Med. Chem.
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,
14. (a) H. Zimmer and G. Singh Angew., Chem. Int. Ed. 1963,
395; (b) G. B. Feigelson Tetrahedron Lett. 1998, 39, 1129.
2,
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