Copper(II) mediated C-8 amination of 1-naphthylamide derivatives with acyclic and cyclic amines

Article abstract of DOI:10.1016/j.tetlet.2021.152858

A simple and facile copper(II) mediated protocol for C-8 amination of 1-naphthylamide derivatives is reported here. Picolinamide and its derivatives were used as a bidentate directing group for the C-8 amination reaction. Various substituted naphthylamide derivatives with numerous cyclic and acyclic amines proceed in good yields under mild conditions. Air was used solely as an oxidant.

Full text of DOI:10.1016/j.tetlet.2021.152858

Tetrahedron Letters 67 (2021) 152858
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(II) mediated C-8 amination of 1-naphthylamide derivatives with
acyclic and cyclic amines
Tapan Sahoo a,b, Souvik Sarkar a, Subhash Chandra Ghosh a,b,
⇑
a Natural Products and Green Chemistry Division, Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI), G.B. Marg, Bhavnagar-364002, Gujarat, India
b Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and facile copper(II) mediated protocol for C-8 amination of 1-naphthylamide derivatives is
reported here. Picolinamide and its derivatives were used as a bidentate directing group for the C-8 ami-
nation reaction. Various substituted naphthylamide derivatives with numerous cyclic and acyclic amines
proceed in good yields under mild conditions. Air was used solely as an oxidant.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 18 December 2020
Revised 11 January 2021
Accepted 14 January 2021
Available online 3 February 2021
Keywords:
Copper-mediated
Amination
Regioselective
Naphthalene
CAH activation
Introduction
bond amination of various arenes has been well explored [15]. In
terms of picolinamide directed CAH amination of naphthalene,
Functionalized 1-naphthyl amine moiety represents an impor-
tant structural unit having the potential use in pharmaceuticals,
functional materials and also served as a ligand system [1]. During
the last decade, considerable efforts have been made for the syn-
thesis of functionalized naphthalenes via direct CAH functionaliza-
tion approach [2]. Among them, bidentate chelation controlled
strategy for regioselective functionalization of 1-nathylamine scaf-
folds achieved significant progress in recent years [3]. For the 1-
naphthylamide system catalytic regioselective functionalization
of C2-H, C4-H and C8-H has been explored by many groups using
Daugulis introduced picolinamide (PA) directing group [4].
Among these, notable progress has been accomplished for the
C8-H functionalization of 1-naphthylamide moiety such as alkyla-
tion [5], arylation [6], alkenylation [7] chalcogenation [8], amina-
tion [9], acylation [10], etherification [11], esterification [12],
cyanation [13] using various transition metal-catalyzed reaction.
Direct CAN bond formation reactions are important in organic syn-
thesis, as the prevalence of nitrogen-containing molecules in
numerous pharmaceutical, medicinal, synthetic intermediates,
and functional materials [14]. The directing group assisted CAH
Wu and co-workers first reported the palladium-catalyzed C8-H
amination of naphthalene moiety with simple secondary cyclic ali-
phatic amines (Scheme 1a) [9]. Very recently, the same group
reported the copper-catalyzed amination using a super stoichio-
metric amount of di-tert-butyl peroxide (DTBP) as an oxidant with
a large excess (30 equivalent) of amines (Scheme 1b) [16]. In 2017,
Punniyamurthy and co-workers reported copper-catalyzed amina-
tion of naphthalene with azoles using picolinamide (PA) directing
group with silver carbonate as additive and NMO as an oxidant
[17]. Aminations of similar naphthalene moiety using preactivated
benzoyl protected hydroxylamine as an aminating agent were
reported by Jana and co-workers (Scheme 1c) [18]. Thus, the devel-
opment of a simple and efficient protocol for regioselective amina-
tions of naphthalene under external oxidant free conditions is
demanding. In continuation, our effort on bidentate directing
group directed regioselective functionalization of 8-aminoquino-
line derivatives at C2, C5 sites [19], and 1-naphthylamine deriva-
tives at C4 site [20]. Herein, we report a simple and useful Cu(II)
mediated methodology for the C8-amination of naphthylamine
with both cyclic and acyclic amines, and using simple air as an
external oxidant.
⇑
Corresponding authors at: Natural Products and Green Chemistry Division,
Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI), G.B. Marg,
Bhavnagar-364002, Gujarat, India.
E-mail address: scghosh@csmcri.res.in (S.C. Ghosh).
https://doi.org/10.1016/j.tetlet.2021.152858
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

T. Sahoo, S. Sarkar and Subhash Chandra Ghosh
Tetrahedron Letters 67 (2021) 152858
(OTf)2 and CuBr2 provided a lower yield of the aminated product
(entries 3–4). Altering the base to sodium acetate diminished the
yield (entry 5), sodium carbonate was found superior to other
bases (supporting information). The use of external oxidants like
PhI(OAc)2 and DTBP was not beneficial (entries 6 and 7). In the
absence of a catalyst, no product was obtained (entry 8). Lowering
of the catalyst loading and reaction temperature was unsuccessful,
resulted in diminished yield (entry 9–10). The use of pure oxygen
instead of air gave a similar yield to the product (entry 11). In
absence of the sodium carbonate, yield drops to 23% indicate the
importance of the base in the reaction. The reaction with 2 equiv.
of amine lowered the yield of the desired product (entry 13). To
improve the product yield variation of other reaction parameters
such as temperature, solvent, catalyst loading, etc. was unsuccess-
ful (see supporting information).
Under the optimized reaction conditions, we then explored the
substrate scope of the various amines with naphthylamide deriva-
tives (Table 2). A wide range of secondary cyclic amine was inves-
tigated, various 4-substituted piperidines proceed well, and
moderate to good yields of the desired product were obtained
(3b-3e). 5-membered pyrrolidine also proceeds well and generates
the desired product in moderate yields (3f). To our delight acyclic
amine, N-methyl benzylamine also worked well, which was not
reported earlier by any catalytic system, gave a similar yield of
the aminated product (43%, 3g). However, amination with diethy-
lamine was not successful, maybe due to the low boiling point (54–
Scheme 1. Picolinamide directed C-8 amination of naphthalene.
Results and discussion
Table 2
We began our studies using N-(naphthalene-1-yl) picolinamide
(1a) and morpholine (2a) as a model substrate to optimize the
reaction condition, as summarized in Table 1. After, various screen-
ings, we identified that 1a reacted with 2a (5 equiv.) in presence of
50 mol% Cu(OAc)2 with Na2CO3 (2 equiv) as a base in DMSO
(0.5 ml) solvent at 100 °C for 12 h provided the desired C8-ami-
nated product in 74% isolated yield (Table 1, entry 1). Furthermore,
the structure of compound 3a was characterized by single-crystal
X-ray crystallography. An equivalent amount of catalyst loading
decreases the yield (63%, entry 2). Other copper salts e.g. Cu
Substrate scope of 1-naphthylamides.
Table 1
Optimization of reaction condition.a
Entry
deviation from optimized condition
Yield (%)b
1
2
3
4
5
6
7
8
No
74
63
63
36
35
35
44
nr
Cu(OAc)2 (1 equiv) instead of (50 mol%)
Cu(OTf)2 instead of Cu(OAc)2
CuBr2 (1 equiv) instead of (50 mol%)
NaOAc instead of Na2CO3
PhI(OAc)2 as an external oxidant (2 equiv)
DTBP as an external oxidant (2 equiv)
Without Cu(OAc)2
9
Cu(OAc)2 (25 mol%) instead of (50 mol%)
80 °C instead of 100 °C
Pure oxygen atmosphere instead of air
Without Na2CO3
With 2 equiv of 2a instead of 5 equiv
58
56
74
23
36
10
11
12
13
a
Reaction condition: 1 (0.2 mmol), 2 (5 equiv.), Cu(OAc)2 (50 mol%), Na2CO3 (2 equiv.),
1a (0.2 mmol), 2a (5 equiv.), Cu(OAc)2 (50 mol%), Na2CO3 (2 equiv.), and DMSO
and DMSO (0.5 ml) at 100 °C, for 12 h, in a reaction tube under air.
(0.5 ml) at 100 °C, for 12 h, in a reaction tube under air.
b
Isolated yields.
2

T. Sahoo, S. Sarkar and Subhash Chandra Ghosh
Tetrahedron Letters 67 (2021) 152858
56 oC) of the amine. Reaction with various functional groups such
as bromo, ester, methoxy, methyl-substituted in different positions
naphthalene proceeds smoothly afforded the desired product in
good yields (3i-3 m). The structure of compound 3j was further
confirmed by the single-crystal X-ray crystallography. 2-methyl
substituted naphthalene moiety found to be unreactive might be
due to the steric effect of the methyl group (3n). Next, the role of
directing group for amination was investigated. Several analogous
and substituted picolinamide were explored as described in
Table 3. Interestingly, when pyrazine was used instead of pyridine,
the presence of an additional N –atom does not have any effect, the
reaction proceeds smoothly and the desired product was obtained
in good yields (4a-4b). Isoquinoline and quinoline were also simi-
larly effective as a directing group (4c-4d), the structure of 4c was
further characterized by X-ray crystallography. C-3 methyl, C-5-
methyl, and C-5 bromo substituted pyridine are well tolerated
and the desired aminated product was obtained in moderate to
good yields (4e-4h). However, picolinamide attached with benzy-
lamine or cumylamine are unreactive under the optimized condi-
tion, which might be due to the non-planner (sp3) structure of
the moiety.
Scheme 2. Gram scale synthesis and removal of directing group.
To demonstrate the potential application of our methodology,
several experiments were carried out as described in Scheme 2. A
gram scale reaction of the standard substrate proceeded success-
fully without affecting the yield. Selective removal of the directing
group with NaOH in ethanol to afford 8-morpholinonaphthalen-1-
amine showcased the synthetic utility of our protocol.
Next, the sequential CAH functionalization of the substrate1-
naphthyl amide moiety (1a) was carried out to synthesize various
substituted naphthalene in a regioselective manner with our
developed methodologies (Scheme 3). In path A, C8-selective ami-
nation was carried out with our newly developed methodology
Table 3
Substrate scope with analogous and substituted picolinamides.
Scheme 3. Sequential CAH functionalization of the 1-naphthylamide moiety.
in the 1st step, to get intermediate 3c, which was carboxylated
by our previously developed methodology [20] at C4 position. In
path B, the CAH functionalization sequence was reversed, initially
carboxylation at the C4 position, and next, amination was carried
out, a similar overall yield was obtained.
Further, the 4-bromo substituted naphthyl amide derivative (3i)
was efficiently coupled with phenylboronic acid (Scheme 4) [21],
thus late-stage functionalization to get an arylated product is
feasible.
An intermolecular competitive amination reaction with mor-
pholine and 4-methyl piperidine was carried out (Scheme 5) and
produced almost 1:1 of both aminated products, indicates the
pKa of amines does not have any effect in the reaction.
To investigate the reaction mechanism, we have carried out a
few control experiments. First, the competitive reaction with 1a
and 1a-D was carried out for 2 h, kH/kD was determined to be
1.6, which indicates the CAH bond cleavage might be the rate-
determining step (scheme 6a). Next, we have performed the H/D
exchange experiment (Scheme 6b), no H/D exchange was observed
in recovered starting material in the presence and absence of the
amine (2a), indicates the irreversibility of CAH bond activation.
Finally, the reaction was carried out with the presence of radical
scavengers such as TEMPO [(2,2,6,6-Tetramethylpiperidin-1-yl)
oxyl] and BHT (butylated hydroxyl toluene) which does not have
Reaction condition: 1 (0.2 mmol), 2 (5 equiv.), Cu(OAc)2 (50 mol%), Na2CO3 (2 equiv.),
and DMSO (0.5 ml) at 100 °C, for 12 h, in a reaction tube under air.
3

T. Sahoo, S. Sarkar and Subhash Chandra Ghosh
Tetrahedron Letters 67 (2021) 152858
Scheme 4. Product derivatization.
Scheme 5. Intermolecular competitive amination.
Scheme 7. Proposed mechanism.
obtained (Scheme 6d). These results indicate that N, N bidentate
ligand like picolinamide (DG) is crucial for this reaction.
Based on the aforementioned outcome and in combination with
previous reports [9,14,22], a plausible mechanism is proposed as
shown in Scheme 7. Initially, the coordination of 1a with copper
acetate took place in the presence of a base leads a chelated inter-
mediate A. followed by the substitution with morpholine (2a) gives
intermediate B. Next, intermediate B oxidized by Cu(OAc)2 to pro-
duce CuIII intermediate C, which then leads to naphthyl peri CAH
cupration to generate cyclometalated CuIII intermediate D. Finally,
reductive elimination afforded product 3a and Cu(I) species. Which
is oxidized by air to Cu(II) and continues the cycle.
Scheme 6. Control experiments for mechanistic investigation.
a significant effect on the reaction, indicates that the reaction
might not proceed through a radical mechanism (Scheme 6c).
Finally, to get some insight into the co-ordination of the sub-
strate with copper, we have carried out the reaction with a few
designed substrates (7–9), as expected no aminated products were
Conclusion
In summary, we have developed a simple copper-catalyzed
regioselective C8 amination of 1-naphthylamine using picoli-
4

T. Sahoo, S. Sarkar and Subhash Chandra Ghosh
Tetrahedron Letters 67 (2021) 152858
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The authors declare that they have no known competing finan-
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