Zinc-Catalyzed N-Alkylation of Aromatic Amines with Alcohols: A Ligand-Free Approach

Article abstract of DOI:10.1002/adsc.202000499

An efficient zinc-catalyzed N-alkylation reaction of aromatic amines was achieved using aliphatic, aromatic, and heteroaromatic alcohols as the alkylating reagent. A variety of aniline derivatives, including heteroaromatic amines, underwent the N-alkylation reaction and furnished the corresponding monoalkylated products in good to excellent yields. The application of the reaction is also further demonstrated by the synthesis of a 2-phenylquinoline derivative from acetophenone and 2-aminobenzyl alcohol. Deuterium labeling experiments show that the reaction proceeds via a borrowing hydrogen process. (Figure presented.).

Full text of DOI:10.1002/adsc.202000499

Title: Zinc-Catalyzed N-Alkylation of Aromatic Amines with Alcohols: A
Ligand Free Approach
Authors: Velayudham Sankar, Murugavel Kathiresan, Bitragunta
Sivakumar, and Subramaniyan Mannathan
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000499
Link to VoR: https://doi.org/10.1002/adsc.202000499

10.1002/adsc.202000499
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Zinc-Catalyzed N-Alkylation of Aromatic Amines with Alcohols:
A Ligand-Free Approach
Velayudham Sankara, Murugavel Kathiresanb, Bitragunta Sivakumarc* and
Subramaniyan Mannathanc*
aDepartment of Chemistry, SRM Institute of Science and Technology, Kattankulathur, Chennai 603203, India
bElectro Organic Division, CSIR – Central Electrochemical Research Institute, Karaikudi-630003, Tamilnadu, India.
cDepartment of Chemistry, SRM University-AP, Amaravati 522502, Andhra Pradesh, India
Email: mannathan.s@srmap.edu.in; and badursiva@gmail.com.
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An efficient zinc-catalyzed N-alkylation reaction The application of the reaction is also further demonstrated
of aromatic amines was achieved using aliphatic, aromatic, by the synthesis of a 2-phenylquinoline derivative from
and heteroaromatic alcohols as the alkylating reagent. A acetophenone and 2-aminobenzyl alcohol. Deuterium
variety of aniline derivatives, including heteroaromatic labeling experiments show that the reaction proceeds via a
amines, underwent the N-alkylation reaction and furnished borrowing hydrogen process.
the corresponding monoalkylated products in good to Keywords: Zinc, Ligand-free approach, N-Alkylation,
excellent yields.
Quinoline, Borrowing hydrogen
manner.[6-8] Although the reported catalyst systems are
quite effective, most of the homogeneous based
catalytic systems were designed using a combination
of a metal salt and precious organic ligand, which
sometimes may require multistep synthesis.[6-8] On the
other hand, heterogeneous based metal catalysts also
suffer from high catalyst loading, selectivity, and harsh
reaction conditions.[9-10] Thus, the development of low-
cost metal catalysts[11] or efficient catalytic systems
with high turnover numbers under mild reaction
conditions[12] toward the synthesis of N-alkylation
reaction is highly desirable and always remains in
demand.
Introduction
Amines and their products are highly valuable
compounds in biological and synthetic chemistry.[1]
Particularly, N-alkylamines have broad applications in
pharmaceuticals, agrochemicals, a ligand for catalysis,
and biologically active compounds (See Figure 1).[2]
Traditionally, N-alkylated amines are prepared by
treating amines with alkyl halides in the presence of a
stoichiometric amount of bases[3a-b] or by reductive
amination protocols.[3c-d] Meanwhile, transition metal-
catalyzed N-alkylation reaction of amines using
alcohol as an alkylating agent via borrowing hydrogen
or hydrogen autotransfer method has emerged as an
excellent alternative and environmentally-benign
approach in organic synthesis.[4a-d] Notably, the use of
alcohol as the alkylating agent makes the reaction
greener as it affords only water as the byproduct.[4e-h]
Mechanistically, the reaction proceeds via
dehydrogenation of alcohol, giving carbonyl
compound, which then undergoes reaction with a
nucleophile such as an amine to give imine.
Subsequent reduction of the imine with the borrowing
hydrogen affords the corresponding alkylated
product.[5] In this context, several homo- and
heterogeneous catalytic systems based on Ru, Rh, Ir,
Pd, Pt, Mn, Fe, Cr, Co, Ni, have been developed to
prepare the N-alkylated amines in an efficient
Figure 1. Representative examples of pharmaceutically
important N-alkylated amine moieties
In recent years, zinc-catalyzed alkylation
reactions using alcohol as the alkylating agent for
constructing C-C and C-N bonds have attracted much
interest in organic synthesis.[13] For instance, a zinc-
based ionic liquid was used as a catalyst for the direct
1
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10.1002/adsc.202000499
Advanced Synthesis & Catalysis
3[b]
4
Zn(NO3)2.6H2O/PPh3 toluene
28
100
(98)[d]
92
85
55
46
0
nucleophilic substitution reaction of alcohols with
amine that proceeds via a carbocation intermediate.[14]
Subsequently, heterogeneous catalyst (PdZn/Al2O3)[15]
was also developed for the N-alkylation reaction of
various amines. In the meantime, visible-light induced
Zn(NO3)2.6H2O
toluene
5
6
7
ZnCl2
Zn(CH3COO)2
Zn dust
Zn(NO3)2.6H2O
Zn(NO3)2.6H2O
toluene
toluene
toluene
toluene
toluene
1,4-
0
9
10
5
nanocomposite
(Pd/ZnIn2S4)[16] catalyst
was
8[e]
9[f]
88
23
introduced for the alkylation of amines and α-
hydrogen of ketones with alcohols to construct C-N
and C-C bonds. However, these reports required either
a particular solvent system (ionic liquid) or other
metals such as palladium as a co-catalyst. Until now,
the application of simple zinc salts in the N-alkylation
reaction of amines are yet to be developed.
7
10
11
Zn(NO3)2.6H2O
Zn(NO3)2.6H2O
25
22
15
6
dioxane
THF/
MeCN[g]
toluene
toluene
12
-
55
28
6
2
13[h]
Zn(NO3)2.6H2O
Recently, we reported a Zn based MOF[17] as a
heterogeneous catalyst for C-C bond formation
reactions. Inspired by these reports and our interest in
search of a less expensive catalytic system for
coupling reactions[18] prompted us to explore the
possibility of using less expensive zinc salts in the N-
alkylation reaction. Herein, we report a zinc-catalyzed
N- and C-alkylation reactions using alcohols as the
alkylating agent. To the best of our knowledge, this is
the first report on zinc-catalyzed N-alkylation of
amines under ligand-free conditions following
borrowing hydrogen strategy (Scheme 1). N-
Alkylation reactions employing first-row transition
metal salts as catalyst have rarely been studied[19] and
remained unexplored.
[a]All the reactions were carried out using 1a (1.50 mmol),
2a (1.00 mmol), Zn catalyst (7.50 - 15.0 mol%), t-BuOK
(1.00 mmol) using 1.50 mL of solvent at 140 ⁰ C for 36 h
under nitrogen atmosphere. [b]Zn catalyst 7.5 mol% and
ligand 7.50 mol% were used. [c]GC Yield. [d]Isolated Yield.
[e]10.0 mol% of Zn(NO3)2.6H2O was used. [f]Reaction was
carried out at 100 °C. [g]THF:MeCN (1:1) ratio. [h]Without t-
BuOK. [i]bpy = 2,2'-bipyridine, Phen = 1,10-phenanthroline,
PPh3 = triphenylphosphine
We started our investigation by choosing benzyl
alcohol (1a) and aniline (2a) as model substrates in the
presence of Zn(NO3)2.6H2O (7.5 mol%) as the catalyst,
2,2'-bipyridine as ligand (7.5 mol%) t-BuOK (1.0
equiv.) as base and toluene as solvent. At 140 °C for
24 h, the reaction afforded the desired product 3aa in
55% yield along with (E)-N-benzylidene aniline (4aa)
in 26% yield (Table 1, entry 1). To increase the product
yield of 3aa, the reaction conditions were optimized
by changing ligands, solvents, bases, and temperature
(Table 1 and Supporting Information, Tables 1–3). To
our surprise, the reaction provided the desired product
3aa in 98% isolated yield in the absence of any
phosphine or nitrogen ligands (entry 4). The reaction
is highly selective and affords only monoalkylated
product. Among the variety of Zn sources (entry 4-7)
that we tested, Zn(NO3)2.6H2O was found to give the
highest yield. Notably, lowering the catalyst loading of
ZnNO3.6H2O from 15 mol% to 10 mol% reduced the
product yield to 88% (entry 8). The present catalytic
reaction is highly solvent and temperature-dependent.
Decreasing the reaction temperature from 140 to
100 °C led to low yield (entry 9). Similarly, toluene
appears to be the most effective solvent under the
optimized reaction conditions. Other polar and
coordinating solvents such 1,4-dioxane and
acetonitrile were less active (entry 10, 11). It is
noteworthy to mention that the reaction also proceeds
in the absence of either zinc salts or base but affords
the desired product only in moderate yield (entry 12,
13). Based on these studies, we chose ZnNO3.6H2O
(15 mol%) as the catalyst, t-BuOK (1.0 equiv.) as a
base, and toluene as solvent at 140 °C as the standard
Scheme 1. Metal-catalyzed N-alkylation of amines with
alcohols
Results and Discussion
Table 1. Optimization studies[a]
Yield(%)[c]
Entry
Catalyst
Solvent
toluene
3aa
55
4aa
26
2
1[b]
2[b]
Zn(NO3)2.6H2O/bpy
Zn(NO3)2.6H2O/phen toluene
93
2
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10.1002/adsc.202000499
Advanced Synthesis & Catalysis
reaction conditions for the N-alkylation reaction of
anilines.
general, the reaction proceeded in high yield with
benzyl alcohols (1b-f) containing substituents at para-
and meta-position. On the other hand, benzyl alcohols
containing ortho-substituents such as methyl (1g) and
methoxy (1h) gave the desired products 3ga and 3ha
in 43 and 55% yields, respectively. Gratifyingly,
phenoxy- (1i) and methylthio-substituted (1j) benzyl
alcohols also participated in the reaction and afforded
the respective products 3ia and 3ja in 85 and 91%
yields. The present catalytic reaction conditions were
also successfully applied to more challenging aliphatic
alcohols. To our delight, n-butanol (1k), n-hexanol (1l),
and n-octanol (1m) worked well and gave the
corresponding products 3ka-ma in 58-69% yields. It
is noteworthy to mention that secondary aryl amines
and primary aliphatic amines did not provide any
desired alkylated products 3 under the optimized
reaction conditions.
Under standard reaction conditions, the scope of
the aromatic amines 2 with benzyl alcohol (1a) in the
N-alkylation reaction was examined. Scheme 2 depicts
that aromatic amines bearing both electron donating
and withdrawing substituents are compatible with the
present reaction. Thus, the reaction of 4-
methoxyaniline (2b) and p-toluidine (2c) with 1a gave
3ab and 3ac in 99 and 90% yields, respectively.
Halogen substituted aromatic amines (2d-f) also
participated well in the reaction affording the products
3ad-af in high yields. Similarly, aromatic amines (2g-
l) bearing substituents at the ortho-, meta- and para-
position also gave the desired products 3ag-al in good
to high yields. Amines containing pharmaceutically
active substituents such as trifluoromethyl- (2m),
phenoxy- (2n), and 1,3-dioxole (2o) also worked very
well and furnished the desired products 3am-ao in 96,
75 and 72% yields. Encouragingly, anthracene- (2p)
and fluoranthene (2q) amines also gave the
corresponding products 3ap and 3aq in good yields.
Scheme 3. Scope of Alcohols. [a]Reaction conditions: 1b-m
(1.50 mmol), 2a (1.0 mmol), Zn(NO3)2.6H2O (15.0 mol%),
t-BuOK (1.0 mmol) using toluene (1.50 mL) as the solvent
°
at 140 C for 36 h under nitrogen atmosphere. [b]Isolated
yield.
Alcohols
and
amines
containing
N-
heteroaromatics such as pyridine, pyrimidine,
pyrazine and thiophene moieties were also subjected
to the N-alkylation reaction (Scheme 4) and the
corresponding products (3na-av) were obtained in 67-
98% yields. Notably, chloro- (2w), bromo- (2x) and
iodo (2y) substituted aminopyridines furnished the
desired products 3aw, 3ax and 3ay in 86, 92 and 86%
yields.
To further extend the scope of the reaction, we
performed a C-alkylation reaction of acetophenone (5)
using 1a as the alkylating agent (Scheme 5).[20a-e]
Promisingly, the reaction proceeded smoothly and
yielded the desired alkylated product 6 in 81% yield.
In a similar fashion, a 2-phenylquinoline 8 was also
synthesized from 5 and 2-amino benzyl alcohol (7) in
92% yield (Scheme 6).[20f-i]
Scheme 2. Scope of Amines. [a]Reaction conditions: 1a
(1.50 mmol), 2b-q (1.00 mmol), Zn(NO3)2.6H2O (15.0
mol%), t-BuOK (1.00 mmol) using toluene (1.50 mL) as the
°
solvent at 140 C for 36 h under nitrogen atmosphere.
[b]Isolated Yield.
Next, we examined the scope of several benzyl
alcohols (1b-m) with aniline (2a) (Scheme 3). In
3
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10.1002/adsc.202000499
Advanced Synthesis & Catalysis
investigated (Scheme 7b). The desired product 3ad-d1,
along with 3ad-d2 and 3ad, was obtained in ratio 46,
42, and 12%, respectively. The formation of 3ad-d2 in
the imine reduction process is probably attributed to the
reversibility in the imine formation.[21] These results are
consistent with the literature reports[21a-b] on D/H
exchange, although the reduction of 4ad with H2 failed
to yield the desired product under standard reaction
conditions. Based on these studies, we believe that the
present catalytic reaction proceeds via borrowing
hydrogen or hydrogen auto-transfer process[21] and not
through carbocation intermediate. It also appears that
zinc nitrate in the presence of potassium tert-butoxide
oxidizes the benzyl alcohol and also reduces imine
during the catalytic cycle. Furthermore, the outcome of
the reaction in the absence of metal catalyst is also
highly intriguing (Table 1, entry 12). The exact
mechanistic pathway of the reaction remains uncertain
at present, but we assume that the reaction may follow
a transition-metal-free hydrogen autotransfer pathway
as described by Wang et al. in 2019.[22]
Scheme 4. Scope of Heteroaromatic Substrates. [a]Reaction
conditions: 1 (1.50 mmol), 2 (1.0 mmol), Zn(NO3)2.6H2O
(15.0 mol%), t-BuOK (1.0 mmol) using toluene (1.50 mL)
as the solvent at 140 °C for 36 h under nitrogen atmosphere,
[b]Isolated Yield.
Conclusion
In summary, we have developed an efficient N-
alkylation reaction of amines with alcohols using
relatively inexpensive and commercially available,
earth-abundant zinc nitrate as the catalyst. The
reaction is selective and affords the monoalkylated
amines in good to high yields. The present reaction is
compatible with various aliphatic, aromatic, and
heteroaromatic alcohols and also proceeded smoothly
with aryl and heteroaryl amines. The yield of the
reaction is comparable with the other reported first-
row transition metal catalysts.[21a-b, 8f] The application
of the reaction is successfully extended toward the C-
alkylation reaction of ketone and quinoline synthesis.
Deuterium labeling experiments confirm that the
present catalytic process proceeds via a borrowing
hydrogen/hydrogen auto-transfer (HAT) mechanism.
The scope of the zinc-catalyzed C-alkylation reaction
is currently investigated in our laboratory.
Scheme 5. C-Alkylation of acetophenone (5) with benzyl
alcohol (1a)
Scheme 6. Synthesis of 2-phenylquinoline (8)
Experimental Section
Scheme 7. Mechanistic study
Further, deuterium labeling experiments were
performed (Scheme 7) to understand the nature of the
mechanism. Under standard reaction conditions, the
reaction of isotopically enriched deuterated benzyl
alcohol 1a-d2 with 4-chloro aniline (2d) afforded fully
deuterated product 3ad-d2 in 89.5% yield along with
3ad-d1 in 10% (Scheme 7a).[21] The relative yields
were determined by 1H NMR spectroscopy. Besides, a
reduction of imine 4ad with 1a-d2 was also
General procedure for N-alkylation of amines
with alcohols: A sealed tube (15 mL) containing t-
BuOK (1.00 mmol), and Zn(NO3)2.6H2O (15.0 mol%) was
evacuated and purged with nitrogen gas three times. Then,
alcohol (1.50 mmol), amine (1.00 mmol), and toluene (1.50
mL) were added under a nitrogen atmosphere. The reaction
mixture was stirred at 140 oC for 36 h. After completion of
the reaction, the mixture was cooled to room temperature
diluted with water 5.0 mL and extracted with
4
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10.1002/adsc.202000499
Advanced Synthesis & Catalysis
dichloromethane (3 × 5 mL). The resultant organic layer
was dried over anhydrous Na2SO4, and the solvent was
concentrated under reduced pressure. The crude mixture
was purified on a silica gel column using hexane/ethyl
acetate as eluent to provide the desired product 3.
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Acknowledgments
We thank the Departments of Science and Technology (DST), New
Delhi, India (DST/INSPIRE/04/2015/002987), for support of this
research under DST-INSPIRE faculty scheme.
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10.1002/adsc.202000499
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10.1002/adsc.202000499
Advanced Synthesis & Catalysis
FULL PAPER
Zinc-Catalyzed N-Alkylation of Aromatic
Amines with Alcohols: A Ligand Free
Approach
Adv. Synth. Catal.Year, Volume, Page – Page
Velayudham Sankara, Murugavel Kathiresanb,
Bitragunta
Sivakumarc*,
Subramaniyan
Mannathanc*
7
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