Ni-Catalyzed Α-Alkylation of Unactivated Amides and Esters with Alcohols by Hydrogen Auto-Transfer Strategy

Article abstract of DOI:10.1002/cssc.201801443

A transition-metal-catalyzed borrowing hydrogen/hydrogen auto-transfer strategy allows the utilization of feedstock alcohols as an alkylating partner, which avoids the formation of stoichiometric salt waste and enables a direct and benign approach for the construction of C-N and C?C bonds. In this study, a nickel-catalyzed α-alkylation of unactivated amides and ester (tert-butyl acetate) is carried out by using primary alcohols under mild conditions. This C?C bond-forming reaction is catalyzed by a new, molecularly defined nickel(II) NNN-pincer complex (0.1–1 mol %) and proceeds through hydrogen auto-transfer, thereby releasing water as the sole byproduct. In addition, N-alkylation of cyclic amides under Ni-catalytic conditions is demonstrated.

Full text of DOI:10.1002/cssc.201801443

Accepted Article
Title: Ni-catalyzed α-alkylation of unactivated amides and esters with
alcohols via hydrogen auto-transfer strategy
Authors: Balaraman Ekambaram, Siba P Midya, Jagannath Rana,
Jayaraman Pitchaimani, Avanashiappan Nandakumar, and
Vedichi Madhu
This manuscript has been accepted after peer review and appears as an
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published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201801443
Link to VoR: http://dx.doi.org/10.1002/cssc.201801443
A Journal of
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10.1002/cssc.201801443
ChemSusChem
COMMUNICATION
Ni-catalyzed α-alkylation of unactivated amides and esters with
alcohols via hydrogen auto-transfer strategy
Siba P. Midya,1 Jagannath Rana,1 Jayaraman Pitchaimani,2Avanashiappan Nandakumar,1Vedichi
Madhu2* and Ekambaram Balaraman1*
Nickel is one of the most naturally abundant and low-cost 3d
transition metals and found manifold applications in various
cross-coupling reactions,13 and photo-redox catalysis14 to
activate the inert C-X (X = O, N, C or H) bonds.In recent times,
intensive applications of nickel catalysis in chemical
manufacturing and pharmaceutical industry are depicted as a
conclusive sustainable alternative to the noble-metal catalysts.
To date, the application of well-defined nickel catalyst for HA/BH
reactions in homogeneous catalysis is highly demanding and
remains elusive.15 Herein, we reporta sustainable and phosphine
ligand-free Ni-based catalytic system for α-alkylation of
unactivated amides and ester (tert-butyl acetate) via C-C bond
forming HA strategy (Scheme 1).
Abstract:Transition-metal-catalyzed borrowing hydrogen/hydrogen
auto-transfer (BH/HA) strategy allows to utilize feedstock alcohols as
alkylating partner that avoids the formation of stoichiometric salt
waste and enables a direct and benign approach for the construction
of C-N and C-C bonds. Here,we reporta nickel-catalyzed α-alkylation
of unactivated amides and ester (tert-butyl acetate) using primary
alcohols under mild conditions. This C-C bond forming reaction
catalyzed by a new, molecularly defined NNN-nickel(II) complex (0.1
- 1 mol%) and proceeds via HA strategy, thereby releasing water as
the sole by-product. In addition, N-alkylation of cyclic amides under
Ni-catalytic conditions is shown.
The development of new sustainable approaches that utilize the
fundamental feedstocks in the key chemical transformation is
extremely important in contemporary science. The -alkylation
of carbonyl derivatives using alcohols is one of the most
important transformations and found manifold applications in
natural product chemistry, and peptide modifications.1-2 In
general, the -alkylation is achieved by electrophilic alkylation of
an alkyl halide with an alkali-metal enolate of carbonyl
derivative, which can generate the desired product along with a
stoichiometric amount of metal salt.3 Alternatively, transition-
metal catalyzed hydrogen auto-transfer (HA) strategy has been
explored for -alkylation of the carbonyl compounds, wherein
alcohol is used as an alkylating reagent. Moreover, HA strategy
provides an excellent atom-economical as well as a step-
economical process with the liberation of water as a sole by-
product and thus, overcome the limitations of classical
approaches.4-7
Notably, HA strategy has been widely investigated using the
noble-metal catalysts for the C-alkylation (or α-alkylation) of
carbonyl compounds, and amine derivatives.5-7 However, C-
alkylation of unactivated carbonyl compounds such as amides
and esters remains extremely challenging, due to the least
acidic nature of -CH bond of amides and esters.8 The catalytic
-alkylation of unactivated amides and esters by alcohols has
significant advances in chemical synthesis. In this direction,
noble-metal such as Ir, and Ru-catalyzed α-alkylation of
amidesand esters (in particular tert-butyl acetate) have been
reported in recent years.9 The sustainability of such processes is
highly challenging because of the use of less abundant and
expensive noble-metal catalysts. Consequently, a numerous
efforts have been devoted to replace the noble-metals with
earth-abundant 3d transitionmetals for the similar or better
reactivity.10-11 Very recently, Kempe and co-workers reported
earth-abundant and non-precious PN3P-cobalt pincer complex
for the C-alkylation of amides and esters, thereby enabling
sustainable development for C-C bond forming reactions.12
Scheme 1.Ni-catalyzed C-C bond forming reactions.
The new N3-nickel(II) pincer complexes 1-2 were synthesized
and characterized using the state of the art analytical methods.
Notably,
the
nitrogen-based
tridentate
ligand,
2,6-
bis(morpholinomethyl)-pyridine (Py-N3; L) can be synthesized by
straightforward under open-air atmosphere, which has the
practical advantages for the scaled-up process (gram-scale).16
The reaction of Py-N3 with NiCl2.6H2O, and NiBr2.6H2O in MeOH
at room temperature resulted the corresponding Ni-complexes
1(85% yield) and 2 (81% yield), respectively (see ESI and Figure
1). Complexes 1-2 were characterized by elemental analysis,
high-resolution mass spectrometry (HRMS), and infrared
spectroscopy. Electron paramagnetic resonance (EPR) analysis
showed the paramagnetic nature of Ni(II)-complexes. The X-ray
crystal structure analysis of 1 indicated a unimolecular structure,
which is made up of hexacoordinatedNi(II) ion. The neutral N3
ligand is coordinated to the nickel center in a typical tridentate
mode, with N1−Ni1−N2 and N1−Ni1−N3 bond angle of 77.19(5)°
and 77.18(5)°, respectively. Selected bond distances and angles
are given in the caption of Figure 1. Significantly, complexes 1
and 2 can be handled under ordinary atmosphere,since they are
not sensitive towards oxygen and moisture over a considerable
period (~ 1 month).
1Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-
NCL), Dr.HomiBhabha Road, Pune - 411008, INDIA.
2Department of Chemistry, Karunya Institute of Technology and
Sciences, Coimbatore-641114, Tamil Nadu, India.
*Corresponds to: eb.raman@ncl.res.in; balaramane2002@yahoo.com
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10.1002/cssc.201801443
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COMMUNICATION
Next, the effect of solvents on α-alkylation reaction was
examined. The n-octane found to be the optimal solvent and
gave 87% of 5c (Table 1, entry 4), whereas other solvents such
as m-xylene or 1,4-dioxane provided unsatisfactory yields under
standard conditions (Tabl1 1, entries 5-6). Screening of various
bases such as KOH, KOiPr, and NaOtBu under similar catalytic
conditions gave also unsatisfactory results (Table 1, entries 7-9).
In absence of the catalyst or the base, no formation of product
was observed (Table 1, entries 10-11). After careful
investigations, the best result was obtained by employing amide
(2 equiv) and alcohol (1 equiv) in the presence of Ni-pincer
complex 1 (1 mol%) and KOtBu (1.1 equiv) in n-octane at 110 oC
(93% GC yield). Indeed, changing the ratio of N,N-dimethyl
acetamide (3a):4-methyl benzyl alcohol (4c) to 1:2, lowered the
yield of the desired C-alkylated amide to 77% (Table 1, entry
13). Gratifyingly, using a low catalytic amount of (0.1 mol% of 1)
the C-alkylation reaction worked efficiently, and the product 5c
was isolated in 82% yield with TON of 820 (Table 1, entry 14). It
is noteworthy to mention that the present N3-nickel(II) pincer
complex 1 showed the superior reactivity with a low catalytic
loading (0.1 - 1 mol%), when compared to previously reported
PN3P-cobalt pincer complex (2.5 mol%).12
Figure 1.Single crystal X-ray structure of 1 (left). Hydrogen atoms
(except H2O) were omitted for clarity. Selected bond length [Å] and
angle [o]: Ni1-N1 1.9945(14), Ni1-O3 2.0260(14), Ni1-N2 2.3520(14),
Ni1-N3 2.3709(15), Ni1-Cl2 2.3979(5), Ni1-Cl1 2.4266(5) and N1-
Ni1-O3 178.67(6), N1-Ni1-N2 77.19(5), O3-Ni1-N2 103.81(6), N2-
Ni1-N3 154.37(5), N1-Ni1-Cl2 94.95(4), Cl2-Ni1-Cl1 172.23(17)
[CCDC No: 1814945].
Remarkably, the present Ni-complexes have shown the finest
activity in the α-alkylation of unactivated amides and esters
using alcohols as alkylating agent. This reaction enables the
direct synthesis of C-alkylated amides and esters with the
liberation of water. The reaction of N,N-dimethyl acetamide (3a)
with 4-methyl benzyl alcohol (4c) was taken as the model
substrates (Table 1). Common reaction parameters including
catalysts, solvents, reaction temperature, and base were
investigated systematically using model substrates. Initially, the
reaction of 3a (0.25 mmol), and 4c (0.125 mmol) in the presence
of Ni-pincer complex 1 (2.5 mol%) and KOtBu (0.13 mmol) in
THF at 100 oC resulted in 72% yield of dimethyl-3-p-
tolylpropanamide (5c; Table 1, entry 1). Under similar
conditions, Ni-pincer complex 2 gave 66% yield of 5c (Table 1,
entry 2), while the simple NiBr2.6H2O afforded only 25% of the
alkylated product (Table 1, entry 3).
With this excellent progress on optimization condition, we
studied the substrate scope of the Ni-catalyzed -alkylation
process by varying alcohols and amides (Table 2). The reaction
of N,N-dimethyl acetamide (3a) with benzyl alcohol proceeded
well to afford the alkylated amide 5a in 85% isolated yield.
Benzyl alcohol derivatives containing electron-donating
substituents at the para position (methoxy, methyl, and
thiomethyl) also led to the desired products 5b-5d in good to
excellent yields (up to 90% yields; Table 2). Electron-
withdrawing substituents (chloro and fluoro) at the para position
of benzyl alcohol provided the corresponding α-alkylated
products5e and 5f with good yields under optimal conditions
(products 5e in 67%, and 5f in 78% yields). Methyl and methoxy
substituents at the meta and the ortho position of the benzyl
alcohol furnished the expected C-alkylated amides in very good
yields (Table 2, 5g-i). Furthermore, benzyl alcohol containing
dimethyl and dimethoxy substituents provided the corresponding
products 5j (77%), and 5k (74%) in excellent yields and 2-
naphthyl methanol readily converted into α-alkylated amide 5l in
75% yield. The reaction of furfuryl alcohol with 3a offered the
expected C-alkylated amide 5min 64% isolated yield.It is
noteworthy that aliphatic alcohols (4n and 4o) smoothly reacted
with 3a under our nickel-catalyzed conditions and offered the
cross-dehydrogenative coupling products 5n and 5o in 75% and
55% isolated yields, respectively. Gratifyingly, using a low
catalytic amount of (0.1 mol% of 1) the C-alkylation reaction
worked efficiently, and the product 5n was isolated in 66% yield.
Under similar conditions (0.1 mol% of cat.1), the C-alkylated
products 5c, 5l, and 5q were obtained in 82%, 71%, 76% yields,
respectively with excellent TONs (products 5c in 820, 5l in 710,
and 5q in 760). Next, we have investigated the scope of amide
substrates under the optimal reaction conditions. Thus, N-
methyl-N-phenylacetamide (3p), 1-(piperidin-1-yl)ethan-1-one
(3q), and 1-morpholinoethan-1-one (3r) smoothly reacted with
4c under nickel-catalyzed conditions and led to the
corresponding C-alkylated amides (Table 2, products 5p-5r) in
moderate to good yields (55% - 83% yields). Gratifyingly, N-
methylated cyclic amides (3s and 3t) underwent C-alkylation
and gave the corresponding α-branched amides 5s (88% yield)
and 5t (79% yield) under standard reaction conditions.
Interestingly, 2-oxindole efficiently reacted with various alcohols
(aryl alcohols) under optimized reaction conditions and led to the
corresponding C-alkylated derivatives (products 5u-5v) in good
yields (up to 62% yield)Thus, the present N3-nickel(II) pincer
Table 1.Optimization of alkylation of N,N-dimethyl acetamide (3a)
with 4-methyl benzyl alcohol (4c).[a]
Entry
Catalyst
Base
Solvent
Temperature
(oC)
Yield (%)
(5c/10)
TON/TOF
(h-1
)
1
2
1
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOH
THF
100
100
100
100
100
100
110
110
110
110
110
110
110
110
72/n.d
66/n.d
25/n.d
87/7
72/3
66/2.8
25/1.1
87/3.6
68/2.8
58/2.4
78/3.3
71/3.0
47/2.0
-
2
THF
3
NiBr2.6H2O
THF
4
1
1
1
1
1
1
-
n-Octane
m-Xylene
Dioxane
n-Octane
n-Octane
n-Octane
n-Octane
n-Octane
n-Octane
n-Octane
n-Octane
5
68/5
6
58/n.d
78/n.d
71/n.d
47/n.d
0
7
8
KiOPr
NatOBu
KOtBu
-
9
10
11
12
13
14
1
1
1
1
trace
-
KOtBu
KOtBu
KOtBu
90[b]/3
77[b],[c],[d]/n.d
82[e]/3
90/3.8
77/3.2
820/34.2
[a]Reaction conditions: 0.25 mmol of 3a, 0.125 mmol of 4c, catalyst
1 (2.5 mol%), KOtBu (1.1 equiv.), and 1 mL of solvent heated for 24
h. Yield determined by GC using 1,4-dibromo butane as an internal
standard. [b] Isolated yield using 1 mol% of catalyst 1. [c] 0.125
mmol of 3a and 0.25 mmol of 4c.[d] Formation of corresponding
benzyl benzoate derivative (~3%). [e] Reaction performed using 0.1
mol% of cat.1. n.d = Not detected.
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10.1002/cssc.201801443
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complex catalyzed C-alkylation amides using alcohols showed
broad substrate scope and operates under mild conditions.
at 110 oC under argon atmosphere for 24 h. [b] All reported
isolated yields are the average of two independent experiments.
Table 2.Ni-catalyzed α-alkylation of amides: Scope of alcohols
In light of the high activity of the Ni-catalytic system, we began to
explore the use of tert-butyl acetate as coupling partner to
access α-alkylated ester derivatives. In the initial study, the
reaction between tert-butyl acetate (8) and 4-methoxy benzyl
alcohol (4b) in the presence of 1 mol% of catalyst 1 at 110 oC to
form a corresponding C-alkylated ester 9a in 27% yield (see SI
for details). However, the changing of other solvents, such as
toluene, m-xylene, and 1,4-dioxane did not improve the product
yield. The highest yield (80%) of the product 9a was obtained at
and amides.[a],[b]
o
the elevated temperature (150 C; see ESI). With this optimized
condition in hand, various benzyl alcohols have been regio-
selectively introduced and thus, giving rises to the C-alkylated
tert-butyl acetate. All the C-alkylated acetate derivatives (9a–g)
were isolated in moderate to good yields (54-78%; Table 4).
Thus, the present Py-N3-Ni(II) complex displayed a general
method for direct synthesis of -alkylated tert-butyl acetates.
However, under standard conditions other acetate derivatives
(ethyl acetate and benzyl acetate) failed to yield the expected C-
alkylated products. This is due to the competing base-mediated
transesterification reaction.
Table 4. The scope of alcohols for the α-alkylation of ester.[a],[b]
[a] Reaction conditions: 0.4 mmol of 3, 0.2 mmol of 4, 1 mol% of
catalyst 1, KOtBu (0.22 mmol), and 1 mL of n-octane heated at 110
oC under argon atmosphere for 24 h. [b] Isolated yields. [c] 0.1 mol%
of [Ni] and yields based on GC.
[a] Reaction conditions: 0.8 mmol of 8, 0.2 mmol of 4, 2 mol% of
catalyst 1, KOtBu (0.22 mmol), and 1 mL of n-octane heated at 150
oC under argon atm for 24 h. [b] Isolated yields.
Interestingly, N-Boc protected cyclic amides (6a and 6b)
underwent N-alkylation of cyclic amides to afford 7a (88%), and
7b (78%) in excellent yields under standard reaction conditions
(Table 3).Indeed, we didn’t observe the formation of C-alkylated
product. The reaction proceeds through a base-mediated Boc-
deprotection17 followed by Ni-catalyzed N-alkylation of liberated
sec.cyclic amides (see ESI).
To understand the mechanistic insights, the benchmark
substrate N,N-dimethyl acetamide3a with 4-methyl benzyl
alcohol 4c was investigated under standard catalytic conditions
(Scheme 2). The formation of hydrogen gas was qualitatively
analyzed using gas chromatography (GC). This result suggests
that the present Ni-catalysis proceeds viadehydrogenative
pathway (Scheme 2a). Importantly, the reaction of N,N-dimethyl
acetamide (3a) with 4-methyl benzyl alcohol (4c) under standard
reaction conditions (at 90 oC) in 4 hr gave the mixture of
intermediate 10 (15%) and 5c (33%).Further, the treatment of
intermediate (E)-N,N-dimethyl-3-p-tolylacrylamide (10) in
presence of benzyl alcohol under catalytic conditions smoothly
converted into hydrogenated product 5c (Scheme 2b). This
result revealed that the formation of 10 is the critical
intermediate in the catalytic cycle and upon catalytic
hydrogenation (either by hydrogen molecule generated in the
initial dehydrogenation step or transfer of Ni-H to the C=C
unsaturated bond) lead to the C-C bond forming alkylation
process. The deuterium labeling experiment was carried out with
amide 3a and 4-chloro benzyl alcohol 4e-D under standard
Table 3.Tandem N-deprotection-N-alkylation of amides.[a],[b]
[a] Reaction conditions: 0.4 mmol of 6, 0.2 mmol of 4c, 1 mol%
of catalyst 1, KOtBu (0.22 mmol), and 1 mL of n-octane heated
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10.1002/cssc.201801443
ChemSusChem
COMMUNICATION
reaction conditions (Scheme 2c). The formation of amide 5e is in
agreement with the microreversibility of initial alcohol
dehydrogenation process. The resulted product ratio of mono
and bis-deuterated amides (5e-D1 and 5e-D2) revealed that one
of the benzylic C-H/D bonds has to be cleaved to initiate the -
alkylation process.
Scheme 3.The direct transformation of α-alkylated amide.
In summary, we developed an efficient Ni-catalyzed α-alkylation
of unactivated amides and ester (tert-butyl acetate)via hydrogen
auto-transfer strategy. The present C-C bond forming reaction of
amide and ester is catalyzed by a new, air-stable molecularly
defined N3-nickel (II) complex under mild conditions with a low-
catalytic loading (0.1 - 1 mol%). The practical late-stage
transformation was successfully demonstrated to extend the
scope of α-alkylated amides.
Acknowledgements
This research is supported by the EMR/2015/000030 (under the
SERB-Green Chemistry programme), and CSIR-INPROTICS
P&A (HCP0011A). SPM and JR thank the CSIR for the research
fellowship. VM thanks the SERB (EMR/2016/006106) for
financial support.
Scheme 2.Mechanistic investigations of Ni-catalyzed -alkylation of
amide.
Keywords:Nickel catalysis• Amides• Hydrogen auto-transfer• C-
Alkylation• Homogeneous catalysis
The addition of 200 equiv. of mercury to the catalytic reaction
slightly reduced the reaction yield (78%), though it could not
quench the reaction completely. Time-dependent kinetic study
on α-alkylation of amide 3awith alcohol 4cwas carried out under
our Ni-catalyzed conditions (Fig. 2a). With different time interval,
continuous sampling was undertaken, and the yield of C-
alkylated amide 5c was determined. These experimental
findings showed that the present Ni-catalysis is homogeneous in
nature and stable during the catalysis. The reusability of the
present homogeneous Ni-catalyzed C-alkylation of amide was
demonstrated (Fig. 2b). Thus, the reaction of 3a with 4c under
standard reaction conditions was carried out by externally
adding starting materials into the reaction mixture (without
additional catalyst) after every 24 h and monitored the catalytic
efficiency of the nickel catalyst. Interestingly, the desired product
5c was obtained in moderate yield after 3rdcycle.18
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10.1002/cssc.201801443
ChemSusChem
COMMUNICATION
Table of Contents:
Herein,most efficient 3d transition metal, nickel-catalyzed -alkylation of unactivated amides and esters using primary alcohols is
presented. This C-C bond forming reaction catalyzed by a new, molecularly defined NNN-nickel(II) complex(0.1 - 1 mol%) and
proceeds via borrowing hydrogen/hydrogen auto-transfer (BH/HA) strategy, thereby releasing water as the sole by-product. The
scope of this methodology was applied for the synthesis of corresponding alcohol and aldehyde, which showed the extension of
carbon backbone of alkylating alcohol by two units. In addition, N-alkylation of cyclic amides (transamidation reaction) under Ni-
catalytic conditions is shown.
Siba P. Midya,1 Jagannath Rana,1
Jayaraman Pitchaimani,2Avanashiappan
Nandakumar,1Vedichi
Madhu2*
and
Ekambaram Balaraman1*
Page No. – Page No.
Ni-catalyzed
α-alkylation
of
unactivated amides and esters with
alcohols via hydrogen auto-transfer
strategy
This article is protected by copyright. All rights reserved.