Nickel-Catalyzed N-Alkylation of Acylhydrazines and Arylamines Using Alcohols and Enantioselective Examples

Article abstract of DOI:10.1002/anie.201708949

A borrowing-hydrogen reaction between amines and alcohols is an atom-economic way to prepare alkylamines, ideally with water as the sole byproduct. Herein, nickel catalysts are used for direct N-alkylation of hydrazides and arylamines using racemic alcohols. Moreover, a nickel catalyst of (S)-binapine was used for an asymmetric N-alkylation of benzohydrazide with racemic benzylic alcohols.

Full text of DOI:10.1002/anie.201708949

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Accepted Article
Title: Nickel-Catalyzed N-Alkylation of both Acylhydrazines and
Arylamines with Alcohols and Enantioselective Examples
Authors: Jianrong Steve Zhou, Peng Yang, Caili Zhang, Yu Ma, Caiyun
Zhang, Aijie Li, and Bo Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708949
Angew. Chem. 10.1002/ange.201708949
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10.1002/anie.201708949
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed N-Alkylation of both Acylhydrazines and Arylamines
with Alcohols and Enantioselective Examples
Peng Yang, Caili Zhang, Yu Ma, Caiyun Zhang, Aijie Li, Bo Tang*[a] and Jianrong Steve Zhou*[b]
overall
transformation
Abstract: Borrowing hydrogen reaction between amines and alcohols is an
H
NHR
(a)
H
OH
R1 R2
alcohol
R1 R2
alkylamine
atom-economic way to prepare alkylamines, with water as the sole
byproduct ideally. Herein, we use nickel catalysts for direct N-alkylation of
hydrazides and arylamines with racemic alcohols. Moreover, a nickel
catalyst of (S)-binapine was used for an asymmetric N-alkylation of
benzohydrazide with racemic benzylic alcohols.
LnM-X
LnM-X
asymmetric
hydrogenation
dehydrogenation
LnM-H + HX
LnM-H + HX
R
O
N
R1 R2
ketone
R1 R2
ketimine
RNH2
H2O
condensation
Chiral benzylamines are key motifs in pharmaceuticals and they are
present in about 15% of blockbuster drugs. Such examples include
solifenacin, plavix, ezetimibe and rivastigmine (Figure 1).[1] Therefore,
efficient synthetic methods towards these chiral amines have been
actively pursued.[2] Among extensively developed methods include
metal-catalyzed asymmetric hydrogenation,[3] reductive amination,[4]
and resolution of racemic alkylamines.[5] In recent years, biocatalytic
amination using ketones[6] and even directly using alcohols[7] have
emerged as promising alternatives to supply optically pure alkylamines,
provided that enzyme mutants can be optimized in a cost- and time-
efficient way.
OMe
Ir catalyst (5 mol%)
PMP
Me
HN
n-hexyl
OH
Me
phosphoric acid (10 mol%)
(b)
+
n-hexyl
Zhao et al. 2014
H2N
90% yield, 93% ee
R
1.5 equiv
O
O
O
P
Ir
OH
HN
Ph
N
SO2
R
Ph
(R = 2,4,6-iPr3C6H2)
O
Ru3(CO)12 1 mol%
O
OH
OH
Ph
(R)-MeO-BIPHEP 3 mol%
Beller et al. 2016
HN
Cl
S
(c)
O
OH
H2N
NH2
OH
Ph
53% yield, 88% ee
N
N
O
2 equiv
Ph
O
O
OMe
N
N
F
O
Plavix
(stroke, heart attack)
Solifenacin
(overactive bladder)
F
Scheme 1. Asymmetric N-alkylation of amines using racemic alcohols via hydrogen
borrowing: (a) a possible pathway and examples using anilines (b) and urea (c).
Ezetimibe
(high cholesterol)
N
O
O
O
Et
NMe2
Me
N
N
N
O
N
Me
In previous studies on amination of alcohols, achiral catalysts
based on expensive rare metals were developed extensively, in
particular Ru[13] and Ir.[14] In recent years, much attention has been paid
to catalytic applications of Earth-abundant, cheap 3d-series metals, for
example, homogeneous catalysts of Mn,[15] Fe,[16] Co,[17] and Cu.[18]
Additionally, Raney Ni and nickel nanoparticles are also effective in
simple N-alkylation of ammonia and amines with alcohols.[19] Nickel is
produced in millions of tons yearly, but as a word of caution, nickel(II)
salts is considerable toxicity in animal models.[20]
Piribedil
(Parkinson's diesease)
Rivastigmine
(dementia)
Figure 1. Examples of drugs containing benzylamines.
The most straightforward synthesis of chiral alkylamines is
arguably direct N-alkylation of amines using cheap, readily available
alcohols via so-called "borrowing hydrogen reaction" or hydrogen
autotransfer reaction (Scheme 1a).[8]
A typical process involves
dehydrogenation of an alcohol to form a ketone by a metal catalyst, in
situ condensation to an imine, and subsequent addition of the metal
hydride catalyst.[9-12] No prior chemical activation of alcohols is needed
and ideally water is the only byproduct. Furthermore, only a catalytic
amount of a metal hydride complex is present at anytime, which allows
better compatibility of polar groups.
Today, only limited examples are available that deliver enantio-
enriched alkylamines via the borrowing hydrogen pathway.[21] For
example, Zhao et al. made a seminal discovery of N-alkylation of
anilines, under dual catalysis of a chiral iridium catalyst and a large
phosphoric acid (Scheme 1b).[22] Later, his group extended the iridium
catalysis to dynamic kinetic amination of α-branched alcohols,[23]
cyclization to form chiral tetrahydroquinolines,[24] and asymmetric
amination of racemic 1,2-diols using a Ru catalyst.[25] Lately, Beller et
al. also disclosed asymmetric synthesis of oxazolidin-2-ones from
racemic vicinal diols and urea, using a ruthenium catalyst (Scheme
1c).[26] However, all of these reactions relied on expensive, rare metals,
Ir and Ru in the catalysts.
[a]
Dr. P. Yang, C. Zhang, Dr. Y. Ma, C. Zhang, A. Li, Prof. Dr. B. Tang
College of Chemistry, Chemical Engineering and Materials Science,
Collaborative Innovation Center of Functionalized Probes for Chemical
Imaging in Universities of Shandong, Key Laboratory of Molecular and
Nano Probes, Ministry of Education, Shandong Provincial, Key Laboratory
of Clean Production of Fine Chemicals, Shandong Normal University,
Jinan 250014, China
During our previous study of nickel-catalyzed asymmetric
reductive amination of arylamines,[27] N-isopropylaniline was isolated
in moderate yield, which was derived from N-alkylation of isopropanol,
the reaction solvent. Herein, we report nickel-catalyzed N-alkylation of
both acylhydrazines and arylamines using alcohols and additionally, an
asymmetric process of acylhydrazines to produce chiral benzylamines.
E-mail: tangb@sdnu.edu.cn; Fax: +86 531-8618-0017
Prof. Dr. J. S. Zhou
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang
Link, Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
Supporting information for this article is given via a link at the end of the
document.
[b]
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10.1002/anie.201708949
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of N-alkylation of benzohydrazide 2a with 1-
phenylethanol 1a
Furthermore, double alkylation of o-phenylenediamine 6 with diols 7
successfully produced 2-substituted tetrahydroquinoxaline 8 in high
yields (Scheme 2c).
H
Ni(OTf)2 (4 mol%)
N
Ph
H
OH
Me
1a (3 equiv)
HN
Ph
dcpp (5 mol%)
N
Ph
+
H2N
O
We found that an elaborated piperidine 10 was also selectively
alkylated by benzylic alcohol 9 to provide piribedil in one step, which
is a pharmaceutical used for the treatment of Alzheimer's disease
(Scheme 2d). No background reaction occurred in the absence of the
nickel catalyst. The use of Ni(OTf)2/dcpp catalyst, in comparison, led
to 50% yield of piribedil.
Ph
Me
(no acid additive)
O
t-AmOH/HFIP1:1
2a
3a 99%
3
Å
MS, 120 oC, 24 h
(initial conditions)
PCy2
PCy2
PCy2
PMe2
PMe2
where dcpp =
dcpe =
dmpp =
PCy2
H
Ni(OTf)2 (2 mol%)
N
Ph
H
OH
Me
1a (2 equiv)
HN
Ph
dcpp (2.5 mol%)
N
Ph
(a)
+
H2N
O
Entry
Changes from initial conditions
Yield
(%)
Ph
Me
t-AmOH/HFIP1:1
O
3Å MS,120-150 oC, 24 h
2a
3a 99%
1
2
3
4
5
6
7
t-BuOK (0.2 equiv) as additive in t-AmOH
p-TsOH (0.2 equiv) in t-AmOH
AcOH (2 equiv) in t-AmOH
no acid in t-AmOH
0
Other products
HN
<5
88
6
NHBz
Me
NHBz
Me
NHBz
NHBz
Me
NHBz
Me
HN
HN
HN
R HN
R
Me
R
R
no additive in HFIP
95
99
99
3k 75%
3b R = OMe 99%
3c R = Me 93%
3d R = CF3 88%
3e R = F 90%
3f R = OMe 96%
3g R = Me 97%
3i R= Me 71%
3j R = F 87%
no additive in t-AmOH/HFIP 1:1 (initial conditions)
3h R =
F
90%
NHBz
HN
2% Ni and 2.5% dcpp;
conditions)
2 equiv 1a (optimized
NHBz
HN
NHBz
HN
NHBz
MeO
NHBz
HN
HN
Me
S
Et
8
2% Ni and 2.5% dcpp; 1 equiv 1a
1% Ni and 1.2% dcpp; 1 equiv 1a
dcpe (5%) as ligand
72
50
83
0
Me
R
3q 87%
3o R = H
95%
9
3l 76%
3m 80%
3n 80%
3p R = OMe 82%
10
11
H
N
H
H
NHBz
HN
Me
N
Ar
N
O
dmpp (5%) as ligand
HN
Ph
HN
Ph
HN
Ph
Bz
O
O
O
R
Me
Me
Me
Me
3w 88%
Ar = 4-HOC6H4 3t 99%
Ar = 3-pyridyl 3u 71%
Ar = 2-thienyl 3v 79%
R = Cy 3r 93%
R = i-Pr 3s 90%
3x 89%
In the beginning, we investigated N-alkylation of benzohydrazide
2a with racemic 1-phenylethanol 1a in the presence of 4 mol% of
Ni(OTf)2 and dcpp (Table 1). No desired product 3a was observed
under strongly basic or acidic conditions (entries 1-2). When acetic
acid was used as an additive in t-amyl alcohol, good yields of 3a was
obtained (entry 3). Without acetic acid, no product was produced in
this solvent (entry 4). In slightly acidic 1,1,1,3,3,3-
hexafluoroisopropanol HFIP (pKa value of 9.3 in water) or in a 1:1
mixture of the two solvents, however, no acetic acid was needed to
form product 3a (entries 5-6). A small amount of the hydrazone was
detected as the byproduct in these reactions, along with a trace amount
of acetophenone. Neither aldol condensation of acetophenone nor its
reductive byproduct of the aldol condensation was seen. Thus, both
acids or acidic solvent and molecular sieve (100 mg per 0.4 mmol of
2a) are crucial for condensation of acetophenone to form the hydrazine
in situ. When 2 mol% nickel catalyst and 2 equiv of 1a were used, the
yield was almost quantitative (entry 7). However, the use of 1 equiv of
1a in the presence of 2 mol% and 1 mol% of the nickel catalyst led to
72% and 50% yields of 3a, respectively (entries 8-9). Another bulky
and electron-rich diphosphine, dcpe also formed an active nickel
catalyst (entry 10). Notably, in the absence of strongly donating dcpp,
no product 3a was generated under catalytic conditions similar to entry
3 or 7. In comparison, dmpp wasn't electronically donating enough to
form an active nickel catalyst and/or less hindered dmpp formed
catalytic inactive (P-P)nNi2+ species where n is 2 or 3 (entry 11).
Y
Y = H
Y = 4-Me
Y = 4-OMe 5c 91%
Y = 3,5-(Me)2 5d 86%
Y = 3-Me
5a 75%
5b 90%
Ni(OTf)2 (2 mol%)
dcpe (2.5 mol%)
HN
OH
Me
Y-PhNH2
+
Me
(b)
t-AmOH, 3Å MS
120 oC, 24 h
5e 86%
1a (2 equiv)
4
Ni(OTf)2 (2 mol%)
dcpp (2.5 mol%)
H
N
OH
H2N
H2N
8a R = Me 89%
8b R = Ph 82%
(c)
+
t-AmOH/HFIP 1:1
3Å MS, 120 oC, 30 h
R
N
H
R
OH
6
7a R = Me
7b R = Ph
N
Ni(OTf)2 (3 mol%)
dcpe (3.75 mol%)
N
N
O
O
O
O
N
N
(d)
+
N
N
OH
t-AmOH/HFIP 1:1
3Å MS, 120 oC, 30 h
N
10
9
Piribedil 80%
H
Scheme 2. Examples of N-alkylation of a) hydrazides and b) arylamines. c) Double
alkylation of o-phenylenediamine with vicinal diols. d) Synthesis of piribedil.
Next, we explored a selected sample of chiral diphosphines in
search for an asymmetric amination. Unfortunately, the reaction of 3
equiv of 1a and p-anisylamine using a combination of 5% Ni(OTf)2
and 6% (R)-Ph-BPE only provided 5c in ~50% yield and 27% ee,
under conditions similar to Scheme 2b. Later, we were gratified to find
that the reaction of 1a and benzohydrazide 2a using Ni(OTf)2 and (S)-
binapine[28] enabled the formation of 11a in 90% yield and 93% ee in t-
AmOH (Scheme 3a). A nickel catalyst of a josiphos, CyPF-Cy also
afforded high catalytic activity and 85% ee. In comparison, a similar
catalyst of CyPF-t-Bu was completely inactive, although it was known
to effectively catalyze transfer hydrogenation of an N-benzohydrazone
of acetophenone in 99% ee, in the presence of formic acid.[27] Thus, we
The N-benzoylhydrazines were N'-alkylated selectively by a wide
range of benzylic alcohols in good yields (Scheme 2a). Both electron-
donating and withdrawing groups on aryl rings were well tolerated.
Furthermore, secondary aliphatic alcohols also afforded the desired
hydrazides in high yields. On the hydrazides, N-acyl groups can
contain free phenol group (3t), pyridine and thiophene rings (3u and
3v). Notably, Cbz-protected hydrazine also delivered 3x in 89% yield.
suspect that this catalyst of CyPF-t-Bu has
dehydrogenation of 1a. Furthermore, other electron-rich diphosphines
a problem in
including Me-DuPhos, Ph-BPE, and QuinoxP* were also catalytically
The catalytic process of nickel/dcpe in t-AmOH can be applied to
arylamines of different electronic properties (Scheme 2b). In
comparison, the use of nickel/dcpp catalyst led to only 60% yield of 5b.
inactive.[29] Acetic acid was
a necessary additive to promote
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10.1002/anie.201708949
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COMMUNICATION
condensation of hydrazones under the catalytic conditions. Without it,
consistent with a parasitic equilibrium between (L-L)Ni(0) and cationic
[(L-L)NiD]+ with the proton of acids and alcohols.[32]
the nickel/binapine catalyst afforded 11a in <10% yield.
A
diverse set of benzylic alcohols reacted efficiently with
Moreover, in a hydride transfer reaction of 1-(4-anisyl)ethanol 1b
and hydrazone 12, benzohydrozide 3a was produced in 78% yield and
75% D along with 80% of ketone 13 (Scheme 4b), which directly
supports a borrowing hydrogen pathway and discredits both a simple
nucleophilic substitution and a radical pathway.[33] The partial loss of
deuterium can also be attributed to the equilibrium of the nickel(II)
deuteride species and proton of acids and alcohols. No other
byproducts were detected, including the hydrazone from 13, aldol
condensation of 13, reductive byproducts of aldol condensation, and
acetophenone.
benzohydrazide to alkylate N-acylhydrazines in the presence of the
nickel/binapine catalyst (Scheme 3b). The electron-withdrawing and
mild electron-donating groups were well tolerated in aryl rings of
alcohols. However, a p-MeO-substituted analog of 1a provided a
racemic product surprisingly. Control experiments indicated that
Ni(OTf)2 alone catalyzed the background reaction (80% yield after 24
h), while acetic acid itself didn't catalyze this amination reaction under
the conditions described in Scheme 3.
On the hydrazides, pyridine and phenol groups were compatible, as
well as a carbamate. In the reaction of 4-hydroxybenzohydrazide, P-
cyclohexyl-substituted josiphos was the better ligand and provided
product 11k in 71% ee. The products are crystalline, which helps to
upgrade their optical purity after a simple crystallization. Furthermore,
the N-N single bonds in the products can be cleaved to release free
benzylamines by treatment with SmI2 or Raney nickel.[30] Notably,
compound 11e contains the chiral amine fragment of a chiral drug,
revastigmine.
A competition of 1a and d-labeled 1a was conducted which
resulted in 3a in 29% D (Scheme 4c). By factoring in 75% retention of
deuterium in a similar process in Scheme 4b, we estimated a KIE effect
of the whole catalytic reaction is kH/kD = 1.6.
NHBz
Ni(OTf)2 (5 mol%)
(a)
HN
Ph
OH
O
(S)-binapine (6 mol%)
H2N
Me
+
Ph
Me
N
Ph
D
D
H
AcOH (2 equiv), t-AmOH
Å
MS, 110 oC, 48 h
95% D
68% D
3
1a 0.6 mmol
11a 68 % yield, 96% ee
2a 0.2 mmol
Ni(OTf)2 (5 mol%)
O
NHBz
diphosphine (6 mol%)
HN
Ph
OH
Me
1a (3 equiv) 2a (NH2NHBz)
H2N
NHBz
Me
(a)
O
+
N
Ph
Ni(OTf)2 (2 mol%)
dcpp (2.5 mol%)
HN
Ph
OH
AcOH (2 equiv), t-AmOH
3Å MS, 110 oC, 48 h
H
Me
Ph
NHBz
N
Me
(b)
+
+
Me
D
D
11a
t-AmOH/HFIP 1:1
MeO
13 80% yield
Ph
Me
75% D
3a 78% yield
Å
MS, 120 oC, 24 h
MeO
98% D
3
1b 0.4 mmol
12 0.2 mmol
t-Bu
Me
Ph
Ph
P
H
Me
Me
P
P
PCy2
PCy2
P
P
Ni(OTf)2 (2 mol%)
dcpp (2.5 mol%)
NHBz
Fe
OH
Me
OH
O
HN
H
P
PhPh
H2N
+
Me
MeMe
(c)
+
Ph
Ph
N
Ph
Me
Ph
H
D
t-Bu
H
t-AmOH/HFIP 1:1
D
(R)-Me-DuPhos
(R)-Ph-BPE
95% D
MS, 120 oC, 24 h
29% D
3a 86% yield
(R,Sp)-CyPF-Cy
3
Å
(S)-Binapine
0% yield
0% yield
94% yield, 85% ee
1a 0.3 mmol
1a 0.3 mmol 2a 0.2 mmol
90% yield, 91% ee
Ni(OTf)2 (5 mol%)
H
N
O
Scheme 4. Deuterium-labeling reactions.
Ph
(S)-binapine (6 mol%)
HN
OH
H2N
+
N
Ph
(b)
O
AcOH (2 equiv), t-AmOH
3Å MS, 110 oC, 48 h
H
Ph
Me
Ph
Me
1a
2a
11a 90%, 93% ee
In summary, we discovered nickel-bis(alkylphosphine) catalysts
for selective N-monoalkylation of both hydrazides and anilines with
racemic alcohols. Furthermore, an asymmetric N-alkylation of
acylhydrazides was realized to afford medicinally important
benzylamines in good enantioselectivity.
Other examples
NHBz
NHBz
HN
HN
R = Me 11b 86%, 91% ee
R = F 11c 77%, 94% ee
R = CF3 11d 80%, 96% ee
R = OMe 11e 88%, 90% ee
R = F 11f 81%, 91% ee
R = Me 11g 85%, 92% ee
R
Me
Me
R
H
NHBz
Me
NHBz
HN
H
NHBz
HN
2-tolyl
N
OBn
N
Ar
HN
HN
Ph
11m 82% 72% ee
HN
O
Ph
Et
O
1-naph
Me
Me
Ph
Me
Ar = 4-HOC6H4
11h 60%, 91% ee
11i 78%, 88% ee
11j 72%, 94% ee
11k 86%, 71% ee (with CyPF-Cy)
Acknowledgement
Ar = 3-pyridyl 11l 70%, 90% ee
We thank financial support from Chinese Ministry of Science and
Technology and Natural Science Foundation of China (973 Program
2013CB933800) and National Natural Science Foundation of China
(21390411, 21535004, 21602126, 21675103), Natural Science Foundation
of Shandong Province (ZR2016BB10), Singapore GSK-EDB Trust Fund
(Green and Sustainable Manufacturing Award 2013) and Singapore Agency
for Science, Technology and Research (AME IRG A1783c0010). PY and
CZ contributed equally to the experiments.
Scheme 3. (a) Effect of chiral ligands and (b) substrate scope in asymmetric N-
alkylation of benzohydrazide.
In our previous studies in transfer hydrogenation of hydrazones
using formic acid,[27] binapine was the optimal ligand. This parallelism
with the borrowing hydrogen reaction of acylhydrazines (in Scheme 3a)
supports the putative borrowing hydrogen mechanism through the
intermediacy of hydrazones. Additionally, the fact that the nickel-
catalyzed amination proceeded well with aliphatic alcohols (in Scheme
2a) also argues against an alternative pathway involving η3-
benzylnickel species.[31] We have conducted other experiments to
probe the reaction pathway. When deuterated 1a reacted with
benzohydrazide 2a, it produced 11a (68% D) in 68% yield and 96% ee
(Scheme 4a), along with some unreacted hydrazone; no acetophenone
was detected. Notably, no deuteration occurred at the methyl group and
phenyl ring of 11a. The partial loss of deuterium during the transfer is
Keywords: N-alkylation of amines • borrowing hydrogen reaction •
nickel catalysis • hydrogen autotransfer reaction • amination
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This article is protected by copyright. All rights reserved.

10.1002/anie.201708949
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Peng Yang, Caili Zhang, Yu Ma, Caiyun
Zhang, Aijie Li, Bo Tang* and Jianrong
Steve Zhou*
Page No. – Page No.
Nickel-Catalyzed N-Alkylation of both
Acylhydrazines and Arylamines with
Alcohols and Enantioselective Examples
A nickel-catalyzed N-alkylation of hydrazides and arylamines with alcohols, including an
asymmetric version, proceeds via hydrogen borrowing.
This article is protected by copyright. All rights reserved.