Transition-metal-free multinitrogenation of amides by C-C bond cleavage: A new approach to tetrazoles

Article abstract of DOI:10.1039/c8cc06324a

A metal-free brand-new one-pot multinitrogenation of amides for the chemo- A nd regioselective synthesis of 1,5-disubstituted tetrazoles has been developed. By means of electrophilic amide activation, and further C-C bond cleavage and rearrangement, a diverse set of functionalized 1,5-DST derivatives were selectively constructed under mild conditions. As showcased in the mechanisms, the chemoselectivity is easily switched by the selection of the starting materials in the reaction.

Full text of DOI:10.1039/c8cc06324a

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DOI: 10.1039/C8CC06324A
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Transition-metal-free multinitrogenation of amides by C-C bond
cleavage: a new approach to tetrazoles
Lian-Hua Li,a Zhi-Jie Niu,a Ying-Xiu Li,a and Yong-Min Lianga*
Received 00th January 20xx,
Accepted 00th January 20xx
www.rsc.org/
A metal-free brand-new one-pot multinitrogenation of amides for Nohara5 identified the first tetrazole N1 glucuronide in the
the chemo-, regioselective synthesis of 1,5-disubstituted urine stream of several animals orally dosed with a chromone-
tetrazoles is depicted. By means of electrophilic amide activation, derived tetrazole. Those bio-structures have showed low
further C-C bond cleavage and rearrangement, a diverse set of toxicity and a wide range of activity (Figure 1).
functionalized 1,5-DST derivatives were selectively constructed
In this context, a great number of strategies for synthesizing
under mild conditions. As showcased in mechanisms, the tetrazoles have been reported (Scheme 1),6 such as nitriles,
chemoselectivity is easily switched by the selection of the starting alkenes, thioamides, heterocumulines, ketones, amines,
materials in the reaction.
amides are considered as common starting materials, and
among them, amides have been preferentially selected since
they are readily available and enormously utilized.6a
The cleavage of carbon−carbon bonds is considered as an
industrial key technology, and this chemistry has kept
appealing in organic fundamental transformation.1 Among
them, transition-metal-catalyzed unstrained C-C bond cleavage
has been made impressive progress in recent decades.2
However, owing to high inertness and highly directed nature,
the development of C−C bonds activations lags more behind
the traditional C-X (X=halogen), C-M (M=metal), and C-Y (Y =O,
N, S, P) bond cleavage, there is obvious scope for the discovery
of novel reactions through direct C-C bond functionalization to
reach new applications.3
In the other hand, the tetrazole ring has attracted
significant attention, especially the 1,5-disubstituted tetrazoles
(1,5-DSTs), which are widely found in numerous biologically
active substances. Some of these scaffolds exhibit various
types of biological properties, such as growth hormone
secretagogue, antiviral and anti-inflammatory.4 In 1980,
Based on the electrophilic activation of amides, various
chemical transformations have been emerged by using triflic
anhydride (Tf2O) over the years,7,8 particularly, Maulide and
his co-workers‘ have worked on tetrazolium salts8j (Scheme 1)
and our work team has recently exploited
a valuable
chemoselective strategy to furnish quinolone derivatives.9
Inspired by these noteworthy works, we noticed that
multinitrogenation with metal-free process would be an
intriguing new challenge. Consequently, we tried to design a
new reaction pathway to get triazoles from TMSN3 and amides,
the system didn't provide any eye-catching transformation in
the initial investigation. Nevertheless, under the ceaseless
Figure 1 Selected bioactive 1,5-DSTs
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000 (P. R. China).
E-mail: liangym@lzu.edu.cn.
Electronic Supplementary Information (ESI) available: See DOI:
Scheme 1 Strategy design to 1,5-DSTs
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Table 1 Optimizing of the reaction conditionsa
Journal Name
Table 3 Substrate scope of the amidesa,b
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DOI: 10.1039/C8CC06324A
Yield
(%)d
Entry
1b
Base additive
2,6-lutidine
Temp (°C)
Solvent
DCM
80
80
trace
2,6-
2
DCM
trace
dichloropyridine
3
4
5
6
7
8
2-chloropyridine
NaH
80
80
80
80
90
90
DCM
DCM
DCM
DCM
DCE
trace
41
K2CO3
28
Na2CO3
Na2CO3
Na2CO3
50
47
toluene
trace
9
10c
Na2CO3
Na2CO3
90
90
1,4-dioxane
DCM
N,D
81
a Reaction conditions: To a mixture of amide 1a (0.2 mmol, 1.0 equiv), TMSN3 (3.0
equiv) and base additive (2.6 equiv) in DCM (3.0 mL) was added Tf2O (1.1 equiv) at
-78 °C under Ar atmosphere. After 20 min, the reaction mixture was stirred at the
b
c
reported temperature. Base (2.0 equiv) was used. TMSN3 (4.0 equiv), base
d
additive (2.8 equiv), Tf2O (1.1 equiv) were added at -40 °C . Isolated yields. Tf =
trifluoromethanesulfonyl, TMS = trimethylsilyl, DCE = 1,2-dichloroethane, DCM =
dichloromethane.
Table 2 Scope of the amide substratesa,b
a All reactions were carried out on 0.2 mmol scale under Ar atmosphere (amide as
1.0 equiv). b Isolated yields.
progression, it turned out to be a brand-new result and the
outcome was confirmed as 1,5-disubstituted tetrazole by X-ray
crystal structure analysis subsequently. Thus, we herein report
a metal-free multinitrogenation of amides with spontaneous
C-C bond cleavage and rearrangement to offer multi-N-atom-
loading structure: 1,5-disubstituted tetrazoles.
At the outset, the tertiary amide 1a was selected as a model
substrate to explore this transformation (Table 1). The reaction was
conducted in the presence of TMSN3, 2,6-lutidine and Tf2O at 80 °C
with no new product came out. After screening different base
additives, we gladly tracked out an appealing outcome and the
productivity reached pleasant 50% with Na2CO3 as the crucial base
support (Table 1, entry 6). An evaluation of solvents showed that
the frequently-used solvent CH2Cl2 (DCM) had a beneficial effect for
this transformation. With the adjustment of ratio between base and
Tf2O, we ultimately used 2.8/1.1 ratio of Na2CO3 and Tf2O as the
optimal option. The highest efficiency was achieved by increasing
the amount of TMSN3 to 4.0 equiv at 90 °C, therefore generating
the desired product 3aa in 81% yield (Table 1, entry 10).
With the optimal reaction conditions in hand, we got started
to survey the compatibility of this reaction. As shown in Table
2, this new method can be applied with a wide range of
substituents, thus giving 1,5-DST derivatives in generally good
to excellent yields. Firstly, amides with chain alkyl groups were
examined and the substrates underwent favourably to
produce 1,5-DSTs (Table 2, 3aa-3ka). When a halogen was
linked to the amide, the desired product could also be
obtained in 54% yield (Table 2, 3ia), which allows significant
opportunity for further functionalization, especially in
pharmacological demand. Furthermore, benzyl amide and
thiophenolamide afforded the desired product in acceptable yields
of 53% and 16%, respectively (Table 2, 3la, 3ma). Amides bearing
a All reactions were carried out on 0.2 mmol scale under Ar atmosphere (amide as 1.0
equiv). b Isolated yields.
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Table 4 Substrate scope of the amidesa,b
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DOI: 10.1039/C8CC06324A
a All reactions were carried out on 0.2 mmol scale under Ar atmosphere (amide
as 1.0 equiv). b Isolated yields.
α-substituted chain alkyl groups performed well under the standard
conditions giving the corresponding products in moderate to good
yields (3na-3pa). The effect of the strained cycloalkyl moiety was
tested as well. The related substrates were tolerated to give the
corresponding products in high yields (Table 2, 3qa-3ta). The
exclusive structures of 3aa and 3ta were specifically confirmed by
X-ray crystal structure analysis in Table 2.
Our attention next turned to explore the capability of
diverse benzamides (Table 3). To our delight, benzamides with
different functional groups were impressively tolerated in this
Figure 2 Transformation of 3wa monitored by 13C NMR spectroscopy (100MHz,
CDCl3). A = 1w carbonyl carbon, B, C and D = transforming signals assigned to original
1w carbonyl carbon, E = 3wa imine carbon.
protocol (Table 3, 3ua-3Sa). Among them, benzamides with α-
and β-naphtyl substituent efficiently participated in the
transformation. The intermediate IV was attacked by TMSN3
reaction and provided the desired product in good yields
once again, and underwent 1,3-dipolar cycloaddition11 to
(Table 3, 3Ma, 3Na). Notably, heteroaromatic amides bearing
produce the desired 1,5-DST product
V ultimately.
furyl, thienyl and pyridyl were also compatible under the
reaction conditions (Table 3, 3Oa 3Qa). The structures of 3ua
Aimed to further understand this chemistry, the process of
-
the symbolic transformation of 3wa was monitored by 13C
NMR spectroscopy (Figure 2). We can see that the signal
and 3Ra were confirmed by X-ray crystal structure analysis.
The substrates with various alkyl and aryl groups at N were
further studied. The system offered the desired products as
expected, and the yields were acceptable (Table 4). Based on these
results, it was found that the pyrrolidine substituted amides were
the most efficient components in this chemistry.
A at
169 ppm was assigned to the carbonyl carbon of 1w originally.
After Tf2O-activated, the signal started to decline and signal
163 ppm appeared, which was corresponding to
intermediate in pathway (Scheme 2). Heated at the reported
temperature and reacted with TMSN3, the signal 143 ppm
A
B
I
i
C
Encouraged by these observations, the plausible
came up and became stronger to point to intermediates II and
III, represented the process from nuleaophilic attack and C-C
bond cleavage to rearrangement. Around 8 h reaction time,
mechanism—pathway
i was proposed to support this
appealing versatile protocol in Scheme 2. The Tf2O-mediated
activation of amide was expected to generate highly
the signal
and anyalsis of further water-quenching experiment of IV have
been dispalyed in supporting information), and the signal
D 141 ppm of IV was settled successively (details
electrophilic adduct
TMSN3 on adduct
I. The subsequent nucleophilic attack of
I
led to intermediate II, which could be
E
transformed to intermediate IV through an acid-catalyzed
153 ppm of the exact product 3wa set up eventually at 20 h
complete reaction time.These results clearly verify that the
turnover-limiting step of this chemistry—Tf2O-activated
process takes place in short time and the nucleophilic attack
from TMSN3 is probably an endothermic reaction process. The
transformation among the proposed intermediates happens
step by step, and they are afforded as transient ions, therefore,
difficult to separate from the reaction mixtures.
rearrangement process.10 In this process, the Na2CO3 played a
role of promoting generation of indtermediate II, III (more
detials see supporting information). Furthermore, the high
migratory aptitude of
R group, either aromatic or aliphatic
groups, exhibited the unique regioselectivity of this
Scheme 2 Proposed mechanisms
This captivating reaction transformation gave us further
anticipation to explore secondary amide substrates which
might occur via a different pathway ii (Scheme 2). The
conceivable reaction results displayed in Table 5. The
secondary amides bearing both aromatic and aliphatic groups
were transferred into the desired 1,5-DST motifs with
moderate to high yields (Table 5, 7aa-7sa). The reaction
further exhibited conspicuous chemo- and regioselectivity to
create single structure. On the behalf of the desired products
in Table 5, the exclusive structure of 7aa was unambiguously
confirmed by single-crystal X-ray analysis. The examples
prosperously illustrate the practicability and compatibility of
this chemistry and highlight the flexibility of this methodology.
In a conclusion, we have developed a metal-free easy-
organized high chemo- and regioselective synthesis of 1,5-
disubstituted tetrazoles through C-C bond cleavage under mild
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Table 5 The 3+2 cycloaddition of amidesa,b
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conditions. This chemistry: 1) possesses a fabulous reaction
flexibility, undergoes different mechanisms with different
starting materials, and showcases a certain diversity of the
reaction; 2) splits the C-C bond and builds up a new C-N bond
in one step; 3) generates a nitrogen multiloading process
between C-C bond atoms and achieves a desired high bioactive
value structure straightforwardly. More related studies on
amides activation are ongoing in our laboratory.
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