ZnBr2 Mediated C?N Bond Formation using Cinnamyl Alcohol and 2-Amino Pyridines

Article abstract of DOI:10.1002/ejoc.202100463

A simple method for C?N bond formation is disclosed by using cinnamyl alcohols and 2-amino pyridine derivatives in the presence of stoichiometric amount of zinc bromide. This reaction works with a wide range of substrates, and is compatible with primary, secondary, and homoallylic alcohols. To the best of our knowledge, this is the first report for C?N bond formation using cinnamyl alcohol and 2-amino pyridines using zinc bromide as a Lewis acid.

Full text of DOI:10.1002/ejoc.202100463

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: ZnBr2 Mediated C-N Bond Formation using Cinnamyl Alcohol
and 2-Amino Pyridines
Authors: Ahwan Panigrahi, Mahadev Sharanappa Sherikar, and
Kandikere Ramaiah Prabhu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100463
Link to VoR: https://doi.org/10.1002/ejoc.202100463
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202100463
COMMUNICATION
ZnBr
2
Mediated C-N Bond Formation using Cinnamyl Alcohol and
2
-Amino Pyridines
[
a]
[a]
[a]
Ahwan Panigrahi, Mahadev Sharanappa Sherikar and Kandikere Ramaiah Prabhu*
Dedication ((optional))
Abstract:
reactions.[12] Recently, there have been many reports on using
zinc salts for C-C, C-hetero atom bond-forming reactions.[13]-
A simple method for C-N bond-forming reaction is disclosed using
cinnamyl alcohols and 2-amino pyridine derivatives using
[16]Among zinc salts, ZnBr
2
is well documented for carbon-carbon,
a
carbon-heteroatom bond forming reactions, cyclization, and ring-
opening reactions.[16] However, compared to other metals, zinc-
mediated reactions are underdeveloped, which motivated us to
design a new method for C-N bond formation following our
previous reports[8].
stoichiometric amount of zinc bromide. This reaction works with a
wide range of substrates. The reaction is compatible with primary
alcohols, secondary alcohols, and homoallylic alcohols. To the best
of our knowledge, this is the first report for C-N bond formation using
cinnamyl alcohol and 2-amino pyridines using zinc bromide as a
Lewis acid.
Scheme 1.Comparision of previous works with this work.
Introduction
Heterocyclic systems decorated with nitrogen are under focus
due to their presence in various biologically active organic
compounds, natural products, and pharmaceuticals.[1]-[3] The C-N
bond formation reactions open the avenue for introducing
nitrogen into organic molecules. Though there is a substantial
achievement in this area, C-N bond formation using
heteroaromatic moiety remains a challenging task for organic
chemists as they require toxic and expensive catalysts.[3]-[6] Thus,
there is a need to develop alternate sustainable methodologies
for C-N bond formation using inexpensive and environmentally
benign catalysts. Though there have been many reports on C-N
bond formation under metal-free conditions,[6]-[8] they are not
compatible with many substrates.
Therefore, the use of
inexpensive, non-toxic zinc catalysts along with heterocyclic
systems is looking more attractive and exciting.
Amines are among the most valued compounds due to their
[9]
presence in pharmaceuticals, and natural products (mainly
alkaloids)[10]. Alcohols are also among the readily available
substrates prepared by various industrial processes.[11]
Therefore, it is highly desirable to develop an atom economic
route for C-N bond formation using alcohols and amines, which
produces water as a byproduct.
In 2013, the Beller group[17] reported an oxidative amidation of
benzyl alcohol with amines using ZnI and TBHP combination
2
Zinc catalyzed organic reactions[12]-[16] are well explored as
(Scheme 1a). Later, in 2014, the Feringa group reported a direct
alkylation of amine with alcohol using a catalytic amount of iron
catalyst (Scheme 1b).[18] The Wills group[19] published the
coupling of benzyl alcohol and aniline using iron
cyclopentadieneone catalyst. Recently, the Mannathan group
published zinc nitrate-catalyzed N-alkylation reaction of aromatic
amines for a C-N bond formation. [20] In this work, we report a
new method for C-N bond formation using cinnamyl alcohol and
zinc-catalysts are environmentally friendly, nontoxic, abundant,
and inexpensive. It is one of the essential elements that helps
regulating enzymatic functions in the animal and plant kingdom.
Many reactions on the use of a catalytic and stoichiometric zinc
compounds came to the picture after discovering diethyl zinc,
such as in Negishi coupling, Reformatskii, and Fukuyama
[
a]
Mr. Ahwan Panigrahi, Mr. Mahadev Sharanappa Sherikar and
Prof. Dr. Kandikere Ramaiah Prabhu
2
-amino pyridine with the help of a stoichiometric amount of
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, Karnataka, India.
ZnBr as a Lewis acid
2
Telephone: +91-80-22932887; Fax: +91-80-23600529;
E-mail: prabhu@iisc.ac.in
Results and Discussion
Home page: https://orgchem.iisc.ac.in/kr-prabhu/
First, we decided to try the initial reaction under metal-free
conditions using 1 equiv. of (E)-4-phenylbut-3-en-2-ol (1a) and 1
Supporting information for this article is given via a link at the end of the
document.
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European Journal of Organic Chemistry
10.1002/ejoc.202100463
COMMUNICATION
equiv. of 2-amino pyridine (2a) as starting materials along with 1
equiv. of iodine in DCE at 80 °C for 12 h. The expected product
was not detected (entry 1, Table 1). Further, similar reactions
were performed using stoichiometric amount of CuI and CuBr,
which did not furnish the desired product. (entries 2-3). Further,
screening of Lewis acid was continued with 1 equiv. FeCl3, which
gave 33% of C-N coupled product 3aa (entry 4). Under the
same reaction conditions (entry 4), we employed different Zinc
Substrate scope was carried out by using 1 equiv. of (E)-4-
phenylbut-3-en-2-ol (1a) with a variety of 2-amino pyridine
derivatives (Scheme 2). The reaction of (E)-4-phenylbut-3-en-2-
ol (1a) and 2-amino pyridine (2a) afforded the product 3aa in
99% yield. A single-crystal X-ray confirmed the structure of the
product 3aa (CCDC NO- 2053449). Similarly, the reaction of 2-
amino pyrimidine with alcohol 1a afforded aminated product 3ab
in 63% yield, where as 2-amino pyrazine afforded the C-N fused
product 3ac in 33% yield. Next, 2-amino-5-chloro pyridine
produced the C-N coupled product 3ad in excellent 94% yield
Likewise, the reaction of 2-amino-5-bromo-4-methyl pyridine
furnished the aminated product 3ae in 93% isolated yield.
salts instead of FeCl
stoichiometric amount did not furnish the C-N coupled product
entry 5), whereas ZnBr afforded the corresponding aminated
3 2
. For example, the reaction using ZnCl in a
(
2
product 3aa in 73% isolated yield (entry 6). Increasing the
amount of 2-amino pyridine to 1.2 equiv. led to a significant
increase in the yield of 3aa to 90% (entry 7), whereas using 1.5
equiv. of 2-amino pyridine lead to a decrease in the yield of the
aminated product 3aa (85%, entry 8). The reaction at 60 °C also
reduced the yield of product 3aa (74%, entry 9). Simultaneously,
increasing the reaction temperature to 100 °C furnished the C-N
coupled product in 94% yield (entry 10). Following these results,
the solvent screening was carried out where toluene, acetonitrile,
afforded the aminated product 3aa in reduced yield (entries 11-
Scheme 2. Substrate scope using 2-amino pyridine derivatives
1
2
2), whereas the reactions in DMSO and H O were not
successful (entries 13-14), indicating DCE as an optimal solvent.
Next, the amount of catalyst loading was screened, the reactions
using ZnBr
2
in 10, 30, and 50 mol% were unsuccessful (entries
1
5, 16, and 17). However, the reaction using 75 mol% of ZnBr
2
furnished the product 3aa in 76% yield (entry 18). Finally,
carrying out the reaction with 1 equiv. of alcohol 1a, 1.2 equiv. of
2
2
-amino pyridine using 1 equiv. of ZnBr at 100 °C in 1.5 mL of
DCE gave an almost quantitative yield of 3aa (99%, entry 19),
which was found to be the optimal reaction conditions.
Table 1. Optimization studies.[a]
[a]
Reaction conditions: 1a ( 0.33 mmol ), 2 ( 0.39 mmol ), ZnBr2 ( 0.33 mmol )
in 1.5 mL of DCE at 100 °C, 1-24h.
Further, we examined the scope of the reaction by
performing the reactions of different derivatives of cinnamyl
alcohol (1) with 2-amino pyridine 2a (Scheme 3). First, we varied
electron-donating groups on ortho-, meta-, and para- positions of
phenyl ring of (E)-4-phenylbut-3-en-2-ol. Ortho-methyl derivative
furnished the corresponding C-N product 4ba in 85% yield. At
the same time, a strong electron-donating group such as a
meta-methoxy derivative afforded only a moderate yield of 4ca
in 60% yield. Similarly, para-methyl derivative reacted well,
giving the aminated product 4da in 89% yield. Unsubstituted
cinnamyl alcohol furnished the C-N coupled product 4ea in 60%
yield. Continued substrate scope screening, naphthyl derivative
afforded corresponding aminated product 4fa in 60% yield. The
extendedconjugated systems like (3E,5E)-6-phenylhexa-3,5-
dien-2-ol furnished the C-N coupled product 4ga in 69% yield.
Further, we subjected substrates having electron-withdrawing
groups on phenyl ring of (E)-4-phenylbut-3-en-2-ol to the
reaction. Phenylbutenol derivatives with halo substitution such
as ortho-chloro, meta-bromo, and para-chloro reacted with 2a
furnishing the corresponding aminated products 4ha, 4ia, and
entry
2a
equiv.)
1
1
1
1
1
1
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
Catalyst
(equiv.)
Temp
(° C)
80
80
80
80
80
80
Solvent
(1 Ml)
DCE
DCE
DCE
DCE
DCE
DCE
Yield of
3aa(%)[
nd
b]
(
1
2
3
4
5
6
7
8
9
2
I ( 1 )
CuI ( 1 )
CuBr ( 1 )
nd
nd
33
nd
FeCl
ZnCl
3
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
( 1 )
2
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
2
2
2
2
2
2
2
2
2
73
80
80
60
DCE
DCE
DCE
DCE
90
85
74
94
41
71
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
100
100
100
100
Toluene
CH
3
CN
DMSO
nd
nd
nd
nd
nd
76
99[c]
H
2
O
ZnBr
ZnBr
ZnBr
ZnBr
2
2
2
2
( 0.1 )
( 0.3 )
( 0.5 )
( 0.7 )
DCE
DCE
DCE
DCE
DCE
ZnBr
2
( 1 )
4
ja in 89, 80, and 94% yields, respectively. The reaction of
[
a]
cinnamyl derivative processing electron-withdrawing groups
such as cyano and nitro groups on the para position of phenyl
ring has shown a decrease in the yield of the aminated products
Reaction conditions: 1a (0.33 mmol, 1 equiv), 2a (0.39 mmol, 1.2
equiv.), Zinc Bromide (0.33 mmol, 1 equiv. ) in 1 mL of DCE at 100 °C,
2 h. [ Isolated yield. .nd = not detected. Reaction has been performed
b]
[c]
1
in 1.5 mL of DCE at 100 °C, 1 h.
4
ka and 4la in 33% and 56% yields, respectively. Next,
substrate scope was continued by changing groups on the ipso
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European Journal of Organic Chemistry
10.1002/ejoc.202100463
COMMUNICATION
carbon of cinnamyl alcohol. (E)-1-phenylpent-1-en-3-ol gave the
Scheme 4. Substrate Scope for 1°, 2°, homoallylic alcohol
C-N coupled product 4ma in 83% yield whereas (E)-1-phenyloct-
1
-en-3-ol furnished the aminated product 4na in 65% yield.
Diphenyl derivative of cinnamyl alcohol afforded the C-N
coupled product 4oa in 95% yield. We have also carried out a
reaction with the cinnamyl alcohol derivative with α-methyl
substituent, which reacted smoothly with 2a furnishing the
corresponding aminated product 4pa in 80% yield. In general,
the reactions of alcohols with electron-donating and halo
substituents on the phenyl ring were facile. In contrast, the
alcohols substituted with strong electron-withdrawing groups
2
such as –CN, -NO on the phenyl ring shown a low reactivity.
[a]Reaction conditions: 5 ( 0.33 mmol ), 2a ( 0.39 mmol ), ZnBr
in 1.5 mL of DCE at 100 °C for 24 h.
2
( 0.33 mmol )
Similarly, the substrates with alkyl and aryl groups on the ipso
carbon of cinnamyl alcohol were also found to react smoothly.
However, the reaction of cinnamyl alcohol with aniline and N-
methyl aniline was not successful and starting materials
recovered unchanged.
To showcase the utility of the amination reaction, a scale
up reaction has been performed. The scale-up reaction of 1a (7
mmol, 1.050 g) with 2a under optimal conditions afforded the
corresponding C-N coupled product 3aa in 99% isolated yield
Scheme 3. Substrate scope for cinnamyl alcohols.
(
Scheme 5).
Scheme 5. Scale-up experiment
To understand the reaction mechanism, we performed
some control experiments (Scheme 6). Under the optimal
reaction conditions, the reaction of 1a and 2a furnished the
product 3aa in 99% yield (Scheme 6a). The same reaction in the
presence of a radical quencher (TEMPO, 1 equiv.) afforded the
C-N product 4aa in 70% yield (Scheme 6b), whereas 1 equiv. of
BHT gave 99% of the aminated product 3aa (Scheme 6c),
indicating a non-radical pathway may be operating in the
reaction. the reaction was not successful in the absence of
ZnBr
the transformation. To understand the role of ZnBr
out an experiment of cinnamyl alcohol with 2-aminopyridine in
the presence of catalytic amount (10 mol%) of ZnBr and
2
(Scheme 6d), indicating that zinc bromide is necessary for
2
, we carried
2
stoichiometric amount (1 equiv) of potassium tert-butoxide under
the optimal reaction conditions (Scheme 6e). The reaction did
not proceed, and starting materials were intact, indicating that
the reaction is not going via the borrowing hydrogen mechanism.
[a]Reaction conditions: 1 ( 0.33 mmol ), 2a ( 0.39 mmol ), ZnBr
in 1.5 mL of DCE at 100 °C for 24 h.
( 0.33 mmol ),
2
To expand the scope of the reaction, primary, secondary,
and homoallylic alcohols were also subjected to a similar
reaction (Scheme 4). 4-Methoxy benzyl alcohol afforded the
corresponding C-N product 6qa in 78% isolated yield, whereas
the secondary alcohol 1-phenylethan-1-ol furnished the
corresponding aminated product 6ra in moderate 52% isolated
yield. Similarly, homoallylic alcohol reacted smoothly, giving C-N
coupled product 6sa in 71% isolated yield.
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European Journal of Organic Chemistry
10.1002/ejoc.202100463
COMMUNICATION
Scheme 6. Control Experiment
2 2 2
bromide diaqua complex [ZnBr (OH ) ]. There is a possibility
that either of the two complexes might be forming along with the
C-N coupled product (Path B). Still, the exact reaction
mechanism is not clear at the current point of time.
Conclusions
In conclusion, we have developed a simple method for the
amination of cinnamyl alcohols, primary, secondary, and
homoallylic alcohol using 2-amino pyridine derivatives using less
explored zinc bromide, furnishing a wider variety of organic
compounds with C-N bonds.
Typical experimental procedure
Alcohol derivative 1 (0.33 mmol, as 1 equiv), 2-amino pyridine derivative 2
(
0.39 mmol, 1.2 equiv) were added in DCE (1.5 mL) in an 8-mL screw-cap
reaction vial, and the reaction mixture was stirred at rt for 5 min. or until the
reaction mixture becomes homogeneous, followed by ZnBr (0.33 mmol)
2
addition and the reaction mixture was heated at 100 °C for 1-24h. The
completion of the reaction has been monitored by TLC. After completion of the
reaction, added water (5 mL) and extracted with DCM (3 x 10 mL). The
organic layer was dried over anhydrous Na SO and concentrated under
2 4
reduced pressure. The crude product was purified on a silica gel column using
EtOAc/petroleum ether to get pure products.
Acknowledgments
This work was supported by SERB (EMR/2016/006358), New-
Delhi, Indian Institute of Science, and R. L. Fine Chem. We
thank Dr. A. R. Ramesha (R. L. Fine Chem) for the useful
discussion. A. P. thanks UGC, New-Delhi and M. S. thanks IISc
Based on the control experiments and previous
reports,8a,8c,16 we propose two possible mechanisms in
Scheme 7. As Zinc halides are well known to act as Lewis
for
a fellowship. We also thanks Mr. Dineshchakravarthy
acid, ZnBr
cinnamyl alcohol 1a
carbocation followed by an attack of amine unit of 2-
amino pyridine 2a furnishing the C-N coupled product 3aa
along with Zn(OH) and HBr as by-product (Path A). From
literature report,16 it is known that ZnBr
2
is co-ordinating to the hydroxyl group of
Senthurpandi from IPC department for recording the crystal data.
,
leading to the corresponding
A
2
Keywords: ZnBr ; cinnamyl alcohol; 2-amino pyridine; C-N bond
2
2
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
C-N Bond Formation *
Ahwan Panigrahi, Mahadev Sharanappa
Sherikar and Kandikere Ramaiah
Prabhu*
Page No. – Page No.
2
ZnBr Mediated C-N Bond Formation
using Cinnamyl Alcohol and 2-Amino
Pyridines
2
A new approach has been developed for C-N bond formation using a stoichiometric amount of ZnBr from cinnamyl alcohols and 2-
amino pyridines. The reaction is also compatible with primary alcohol, secondary alcohol, and homoallyl alcohol.
This article is protected by copyright. All rights reserved.