Cu(I)-Catalyzed Aminative Aza-Annulation of Enynyl Azide using N-Fluorobenzenesulfonimide: Synthesis of 5-Aminonicotinates

Article abstract of DOI:10.1021/acs.orglett.8b01228

An unprecedented copper-catalyzed aminative aza-annulation of enynyl azide using commercially available N-fluorobenzenesulfonimide (NFSI) as an amination reagent is described. The reaction proceeds via regioselective inter-/intramolecular diamination, incorporating one nitrogen from the NFSI and the other from the azide, to provide amino-substituted nicotinate derivatives in a single step with moderate to high yield. This method represents an efficient way to access diverse aminonicotinates through direct C-N bond-coupling processes.

Full text of DOI:10.1021/acs.orglett.8b01228

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu(I)-Catalyzed Aminative Aza-Annulation of Enynyl Azide using
N‑Fluorobenzenesulfonimide: Synthesis of 5‑Aminonicotinates
Chada Raji Reddy,*,†,‡ Santosh Kumar Prajapti,†,§ and Ravi Ranjan†,‡,§
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
S
* Supporting Information
ABSTRACT: An unprecedented copper-catalyzed aminative
aza-annulation of enynyl azide using commercially available N-
fluorobenzenesulfonimide (NFSI) as an amination reagent is
described. The reaction proceeds via regioselective inter-/
intramolecular diamination, incorporating one nitrogen from
the NFSI and the other from the azide, to provide amino-
substituted nicotinate derivatives in a single step with moderate to high yield. This method represents an efficient way to access
diverse aminonicotinates through direct C−N bond-coupling processes.
Scheme 1. Direct Amination of Alkynes Using NFSI
he difunctionalization of alkynes for the synthesis of
Tfunctionalized heterocyclic compounds has evolved as a
convenient and step-economical method for the creation of
such molecules.1,2 In particular, the construction of the C−N
bond with high regioselectivity is of immense interest due to
the ubiquitous presence of the amine functionality in both
natural as well as synthetic products with significant biological
activities.3 Thus, the development of efficient and selective
amination methods has attracted considerable attention from
both academic and industrial researchers. In this context,
several methods have been successfully developed for the direct
amination of alkynes such as hydroamination,4 aminooxygena-
tion,5 aminohalogenation,6 aminoacylation,7 and diamina-
tion.8,1b In these, C−N bond formation occurs using either
nucleophilic or electrophilic nitrogen sources.
N-Fluorobenzenesulfonimide (NFSI) has been widely used
as both a fluorination9 and an amination reagent.10 Recently,
NFSI has gained prominence as a nitrogen radical source for
the construction of a C−N bond via in situ generated
bisphenylsulfonylamidyl radicals in the presence of Cu(I)
salts. Extensive methods have been reported for the direct
amination of arenes, aromatic heterocyles, and alkenes using
NFSI as an N-radical precursor in the synthesis of amino-
substituted compounds.11 However, investigations on the direct
amination of alkynes using NFSI as a nitrogen-centered radical
are relatively rare. In 2015, Zhang et al. reported an elegant
one-pot method to access α-amino-α-aryl ketones via cascade
aminative multifunctionalization reactions of alkynes with N-
fluoroarylsulfonimide and an alcohol (Scheme 1a).12a
Later, the same research group developed the intermolecular
seleno/thioamination of alkynes to aminated vinylselenides/
sulfides (b).12b Subsequently, α,β-unsaturated carbonyls and
indenones were constructed from the reaction of propargylic
alcohols with NFSI through hydroxyl-directed aminoarylation
(c).12c Very recently, Zhang and Li’s groups accomplished the
imidovinylation of alkynes using NFSI in the presence of a
copper catalyst to obtain (E)-2-imido-2,4-dienals (d).12d
Motivated by these findings and our interest in exploring the
ene−yne-assisted annulation reactions,13 we envisaged that (E)-
2-en-4-ynyl azides, derived from MBH acetates of acetylenic
aldehydes,14 would undergo aminative aza-annulation reactions
with NFSI to give 5-aminonicotinates. To the best of our
knowledge, a cascade reaction involving nitrogen radical
addition onto an alkyne followed by heterocyclic ring formation
is unexplored.
Received: April 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the other hand, aminonicotinate is a well-known
privileged scaffold possessing a wide spectrum of biological
activities that include serving as inhibitors of targets such as
hypoxia-inducible factor (HIF)-1α,15a integrin αvβ3,15b platelet-
derived growth factor receptor (PDGFR),15c and as anti-
microbials.15d Very recently, it has also been shown that
sulfonamido nicotinamide scaffolds can act as potent TNAP
inhibitors.16 Conventionally, the synthesis of aminonicotinates
has been accomplished via a multistep approach.17,15a,d To date,
there is no method for the direct synthesis of aminonicotinates.
Hence, the development of a novel method that provides direct
access to aminonicotinates is highly desirable. Herein, we
demonstrate the synthesis of 5-aminonicotinates through the
aminative aza-annulation of enynyl azides using NFSI in the
presence of a Cu(I) catalyst (Scheme 1e).
reaction efficiency. A temperature increase to 100 °C did not
have any significant effect the product yield (entry 3). When
CuBr (5 mol %) was used as a catalyst, compound 2a was
obtained in 52% yield (entry 4). No desired product 2a was
detected in the presence of CuOAc and CuOTf (entries 5 and
6). Intriguingly, the yield of 2a was improved to 92% when we
switched to CuCl (5 mol %) as a catalyst (entry 7). Further
improvement was not observed by increasing the reaction
temperature or catalyst loading (entries 8 and 9). However,
lowering the temperature from 70 to 50 °C resulted in 57%
yield (entry 10). Solvent screening indicated that DCE was the
solvent of choice, while other solvents such as MeCN, dioxane,
and toluene resulted in low yields of the product 2a (entries
11−13). No reaction took place in the absence of a copper
catalyst, which demonstrated the crucial role of the catalyst in
this transformation (entry 14).
Initially, the required (E)-2-en-4-ynyl azide (1a) was
prepared from the Morita−Baylis−Hillman (MBH) reaction
of 3-phenylpropiolaldehyde (A) with methyl acrylate to obtain
B in 72% yield.14,13d,e The resulting MBH adduct B was
subjected to O-acylation followed by allylic substitution with
sodium azide to afford 1a in 88% yield (Scheme 2).14a,b
With the optimal reaction conditions established (Table 1,
entry 7), we next investigated the scope and limitations of this
radical cascade process using a series of (E)-2-en-4-ynyl azides.
As is evident from Scheme 3, the electronic effect of the aryl
a
Scheme 3. Scope of Enynyl Azides
Scheme 2. Preparation of (E)-2-En-4-ynyl Azide
Our investigation for the aminative aza-annulation com-
menced from the reaction of 1a with NFSI (1.5 equiv) in the
presence of CuI (5 mol %) in DCE at room temperature for 18
h (Table 1, entry 1). Unfortunately, no desired aminonicotinate
2a was obtained, and the starting materials were recovered.
However, when the reaction was performed at 70 °C,
pleasingly, the methyl 6-phenyl-5-(N-(phenylsulfonyl)-
phenylsulfonamido)nicotinate 2a was obtained in 76% yield
(entry 2). Encouraged by this preliminary result, other reaction
parameters were screened in order to further improve the
a
Table 1. Optimization of Reaction Conditions
b
entry catalyst (mol %)
solvent
T (°C) time (h) yield (%)
1
Cul (5)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
dioxane
toluene
DCE
rt
70
18
12
12
8
0
76
75
52
0
2
Cul (5)
a
3
Cul (5)
100
70
Reaction conditions: enynyl azide (1 equiv), NFSI (1.5 equiv), CuCl
4
CuBr (5)
CuOAc (5)
CuOTf (5)
CuCl (5)
CuCl (5)
CuCl (10)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
(5 mol %), DCE (2 mL), at 70 °C. Isolated yields are given.
5
70
12
12
8
6
70
0
substituent on the (E)-2-en-4-ynyl azides had a significant
influence on the outcome of the reaction. The enynyl azides
tethered to aryls having electron-donating groups, 4-Me (1b)
and 3,5-diMe (1c), reacted smoothly with NFSI to afford the
desired products 2b and 2c, respectively, in excellent yields,
while substrates having electron-deficient groups such as 4-F
(1d), 4-Cl (1e), 4-CN (1f), and 4-COCH3 (1g) required a
longer reaction time and gave the corresponding amino-
nicotinates 2d to 2g in 70−81% yields. Likewise, 3-
(trifluoromethyl)phenyl enynyl azide 1h was also transformed
to the 5-aminonicotinate 2h under the optimal reaction
7
70
100
70
92
92
90
57
78
68
72
0
8
8
9
8
10
11
12
13
14
50
8
70
8
70
8
70
8
c
70
12
a
Reaction conditions: enynyl azide (1 equiv) and NFSI (1.5 equiv).
Isolated yield. No reaction was observed.
b
c
B
DOI: 10.1021/acs.orglett.8b01228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions in 73% yield. In addition, the reaction of 1-naphthyl-
enynyl azide 1i with NFSI generated the expected product 2i in
88% yield. It is worth noting that the enynyl azides with
aliphatic groups, such as n-propyl 1j, n-pentyl 1k, and n-hexyl
1l, were also compatible in the copper-catalyzed cascade radical
amination/cyclization reaction to afford the corresponding 5-
aminonicotinates 2j to 2l in admirable yields. However, 2-
thiophene-yl enynylazide 1m gave the 6-(2-thiophene-yl)-5-
aminonicotinate (2m) in poor yield (14%).
are two possibilities. In path A, trapping of vinyl radical III with
Cu(II) (IV) delivers the Cu(III) species V, which would react
with the azide in intramolecular fashion to give intermediate VI
with the loss of HF and nitrogen. Reductive elimination of VI
would afford 2a while regenerating Cu(I) catalyst. Alternatively
(path B), vinyl radical intermediate III could be oxidized by
Cu(II) (IV) to generate the cationic species VII and a fluoride
anion. Finally, the nucleophilic attack of intramolecular azide
followed by deprotonation with a fluoride anion would provide
the product 2a.
Encouraged by the above success, we turned our attention to
explore the applicability of the obtained products having N-
diphenyldisulfonyl and ester as handles for further elaboration.
In this context, aminonicotinate 2b was subjected to various
reaction conditions (see Table S1) for desulfonylation, and it
was found that triflic acid in DCE at 90 °C gave 4a in 77%
yield. Similarly, 2c,g,h,j,l also underwent desulfonylation to
afford the corresponding desulfonylated aminonicotinates 4b−
e in good yields (Scheme 6).
To gain insight into the reaction mechanism, a few control
experiments were performed (Scheme 4). The reaction was
Scheme 4. Control Experiments
Scheme 6. Desulfonylation of Amino Nicotinates
completely suppressed when the radical scavenger (TEMPO)
was added to the standard reaction. In addition, the reaction in
the presence of 1,1-diphenylethylene as a radical trap gave the
compound 3 (75% yield) instead of the expected product 2b.11e
These results suggest that the present aminative aza-annulation
reaction proceeds through a bis-sulfonylamidyl radical addition
pathway.
Based on the above results and the literature precedent-
s,11a,b,12a,18 we propose that the possible reaction mechanism is
as shown in Scheme 5. Initially, NFSI oxidizes Cu(I) to the F−
Cu(III)−N complex I, which is transformed to the copper(II)-
stabilized reactive bis-sulfonylamidyl radical II via redox
isomerization. Next, intermolecular addition of the nitrogen
radical to the alkyne of enynyl azide 1a produces the vinyl
radical III and the copper(II) species IV. From this point, there
Furthermore, the treatment of 2b with KOH in MeOH gave
5-(phenylsulfonamido)-6-(p-tolyl)nicotinic acid (5) in 90%
yield. It is also noteworthy that formation of monodesulfony-
lated product 6 occurred in 70% yield without ester hydrolysis
when conducted with 5 mol % of NiCl2(dppp) and K3PO4 in
1,4-dioxane (Scheme 7).
Scheme 7. Diversification of Amino Nicotinate 2b
Scheme 5. Plausible Reaction Pathway
In conclusion, we have developed the Cu(I)-catalyzed
aminative aza-annulation of enynyl azides using N-fluorobenze-
nesulfonimide as an aminating agent. A variety of substituted
enynyl azides were well tolerated to afford the corresponding 6-
substituted 5-aminonicotinates in good yield (up to 96%). This
method is attractive due to its mild reaction conditions and the
importance of the corresponding aminonicotinate products.
Furthermore, we also identified two new reaction conditions for
the didesulfonylation and monodesulfonylation of synthesized
products toward valuable amine derivatives of nicotinates.
C
DOI: 10.1021/acs.orglett.8b01228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01228.
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■
Corresponding Author
*E-mail: rajireddy@iict.res.in.
ORCID
Chada Raji Reddy: 0000-0003-1491-7381
Ravi Ranjan: 0000-0003-3958-3875
Author Contributions
§S.K.P. and R.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.R.R. and S.K.P. thank the Science and Engineering Research
Board (SERB), the Department of Science and Technology,
New Delhi, for funding the project (EMR/2016/006253 and
PDF/2017/000509, respectively). R.R. thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi, for a
research fellowship (IICT/Pubs./2018/044).
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