An efficient and atom-economical route to: N -aryl amino alcohols from primary amines

Article abstract of DOI:10.1039/c8ra07355d

In this paper we reported a novel method for generation of N-aryl amino alcohols from N,N-disubstituted picolinamides through reduction/ring-opening reaction with NaBH₄. The N,N-disubstituted picolinamides can be easily obtained from primary am

Full text of DOI:10.1039/c8ra07355d

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An efficient and atom-economical route to N-aryl
amino alcohols from primary amines†
Cite this: RSC Adv., 2018, 8, 34304
ab
Zhen Xiao,a Juanjuan Li,a Qiang Yue,a Qian Zhanga and Dong Li
*
In this paper we reported a novel method for generation of N-aryl amino alcohols from N,N-disubstituted
picolinamides through reduction/ring-opening reaction with NaBH4. The N,N-disubstituted
picolinamides can be easily obtained from primary amines after convenient condensation with
picolinic acid and coupling with cyclic ethers. The whole route proceeded under simple and mild
conditions with high efficiency. Picolinic acid can be recovered in the form of piconol after reaction. It
indicated an efficient and atom-economical route for the preparation of N-aryl amino alcohols from
primary amines.
Received 4th September 2018
Accepted 28th September 2018
DOI: 10.1039/c8ra07355d
rsc.li/rsc-advances
With 1,5-pentanediol it can provide N-aryl-5-amino-1-pentanol
Introduction
as well (Scheme 1b).5 In these methods, additional ligand and
ꢀ
base, high reaction temperature (130–160 C) were still neces-
sary and the reaction efficiency was unsatisfactory (28–68%
yields).
Amino alcohols, which contain both an amine and an alcohol
functional groups, are an important class of organic
compounds. They are extensively used as solvents, ligands,
plasticizers, agrochemicals, pharmaceuticals and also organic
synthetic intermediates.1 Among them, the N-substituted linear
alkanolamines have attracted much attention for a long time.
The copper-catalyzed Ullmann type C–N coupling between aryl
halides and primary alkanolamines served as a typical route for
preparation of N-aryl amino alcohols.2 These methods required
the used of amino alcohols as substrates which are normally not
readily available. The catalytic hydrogenation of N-aryl cyclic
amides provided an atom-economical route for the access of N-
aryl amino alcohols. In 2011, Bergens and Ikariya groups
independently reported efficient ruthenium-catalyzed hydroge-
nation of N-aryl pyrrolidinone and piperidinone which generate
Recently, our group developed an efficient copper-catalyzed
C–N cross dehydrogenative coupling between picolinamides
(2) and simple ethers which provided the N,N-disubstituted
picolinamides (2).6 During the study of the coupling product,
it was found that this compound converted to N-phenyl-4-
amino-1-butanol (3) solely with sodium borohydride (NaBH4)
(Scheme 1c). Sodium borohydride is a very common and useful
reductant which be widely used for reducing many organic
carbonyls, both in the laboratory and on a technical scale.
Normally it is efficient for reduction of acyl chlorides, anhy-
drides, ketones, aldehydes and imines. Esters and carboxylic
acids react slowly and inefficiently while amides are generally
not reduced at all.7 Furthermore, typical reduction of tertiary
amides commonly provide tertiary or secondary amines.8 This
N-aryl-4-amino-1-butanol
(Scheme 1a).3
and
pentanol
respectively
However the requirement of expensive ruthenium catalysts,
complicated ligands and harsh reaction conditions (high pres-
sure and elevated temperature) might limit its synthetic appli-
cations. Another reaction to synthesize N-aryl-4-amino-1-
butanol was reported in the same year which revealed an
iridium-catalyzed alkylation of primary amines with 1,4-buta-
nediol under microwave-assisted conditions.4 Recently, ruthe-
nium and nickel catalysts were also developed for this reaction.
aSchool of Materials and Chemical Engineering, Hubei University of Technology,
Wuhan 430068, China. E-mail: dongli@mail.hbut.edu.cn
bHubei Key Laboratory of Drug Synthesis and Optimization, Jingchu University of
Technology, Jingmen 448000, China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data, and copies of NMR spectra. CCDC 1858880. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra07355d
Scheme 1 Preparation of N-arylamino-1-butanol/pentanol.
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unexpected result propelled us to further exploration. Aer generally promoted with higher concentration which was 76,
extensive study, herein we reported the synthesis of a series of 83 and 82% at 40, 60 and 80 ꢀC respectively (entries 9–11).
N-aryl amino alcohols from the reduction/ring-opening of N,N- Among them, the reaction at 60 ꢀC exhibited the best result. A
disubstituted picolinamide which can be easily obtained from surprising result was found that small amount of H2O could
coupling between N-aryl picolinamides and cyclic ethers. The facilitate the reaction effectively. With 0.1 mL H2O, the reac-
N-aryl picolinamides were prepared from condensation of tion yield was improved to 94% (entry 12). Alteration of the
picolinic acid and primary amines. The whole route proceeded H2O amount to 0.01 mL led to completely full conversion
under simple and mild conditions with high efficiency. Pico- (entry 13). We also conducted the reaction at room tempera-
linic acid can be recovered in the form of piconol aer reaction ture and 84% yield of product was still generated (entries 14).
which enabled the method meet the requirement of atom- From the above, we decided the best reaction conditions as
economy.9 It indicated an efficient and atom-economical route shown in entry 13.
for the preparation of N-aryl amino alcohols from primary
amines.
Table 2 Substrate scope for 4-arylamino-1-butanols (3b–3n)a,b
Results and discussion
Initially we carried out the reaction of N-(2-tetrahydrofuranyl)-
picolinamide (2a) with 2 equiv. of NaBH4 in 2 mL EtOH at
room temperature (25 ꢀC). Aer 12 hours, the desired product
3a was isolated in only 32% yield (Table 1, entry 1). Thus we
increased the amount of NaBH4 to pursue higher conversion.
With 3, 4 and 5 equiv. of NaBH4, the product yields became 36,
56 and 73% respectively (entries 2–4). Further increasing of the
NaBH4 amount did not produce higher yield (entry 5). With 5
equiv. of NaBH4, we modulated the reaction temperature next.
The product yield was improved to 75% under 40 ꢀC (entry 6).
Further elevation of the reaction temperature provided the
product in 78% yield under 60 ꢀC and 81% under 80 ꢀC (entries
7 and 8). Subsequently we examined the effect of reaction
concentration. To our delight, the product yields were
Table 1 Optimization of the reaction conditionsa
Entry
NaBH4 (eq.)
Solvent (mL)
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
2
3
4
5
6
5
5
5
5
5
5
5
5
5
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (2)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH/H2O:10/1 (1)
EtOH/H2O:100/1 (1)
EtOH/H2O:100/1 (1)
rt
rt
rt
rt
32
36
56
73
73
75
78
81
76
83
82
94
99
84
rt
40
60
80
40
60
80
60
60
rt
9
10
11
12
13
14
a
Reaction conditions: N-(2-tetrahydrofuranyl)-N-arylpicolinamide (2)
a
Reactions were performed using 1a (0.2 mmol) in solvent with NaBH4
(0.2 mmol), NaBH4 (1.0 mmol) in 1 mL EtOH/H2O (100/1) stirring at
b
b
60 ꢀC for 12 h. Isolated yields.
for 12 h. Isolated yield.
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Table 3 Substrate scope for N-aryl amino alcohols (3o–3t)a,b
electron-donating substituents (3d–3f). Among them the 4-(4-
uorophenyl)amino-1-butanol (3g) and 4-(4-chlorophenyl)
amino-1-butanol (3h) were obtained in almost quantitative
amount. Multi-substituted substrates were also examined. With
different combination of electron-withdrawing and electron-
donating substituents, the corresponding products were all
generated in high yields (3j–3n). 4-(3-Bromo-4-methylphenyl)
amino-1-butanol (3n) was also received in perfect yield and its
structure was unambiguously conrmed by X-ray crystallog-
raphy.10 Unfortunately N-alkyl picolinamides were not appli-
cable in this method and the results were not shown.
Substrate (2)
Product (3)
Next the N,N-disubstituted picolinamides containing
other cyclic ether moieties were examined for this reaction
and the results were showed in Table 3. The 2-methylte-
trahydrofuran ring in compound 2o also cleaved during
reaction to give the branched 5-phenylamino-2-pentanol (3o)
in 53% yield. Compounds containing six-membered tetra-
hydropyrane and 1,6-dioxane ring (2p and 2q) proceeded to
form corresponding 5-phenylamino-1-pentanol (3p) and 2-(2-
(phenylamino)ethoxy)ethanol (3q) in good yields respec-
tively. Cyclic thioether such as tetrahydrothiophene derived
substrate (2r) was also applicable which provided the amino
thiol product (3r). Notably, substrates prepared from benzo-
cyclic ethers such as phthalan (2s) and isochroman (2t)
were successfully converted to 2-phenylaminomethyl phenyl
alcohols (3s and 3t) in high yields, which possessed appli-
cation potential for various relative substrates and could
undergo further transformations.
To examine the synthetic application of our method, we
attempted to prepare a T-type calcium channel antagonist
candidate 411 from 4-methoxyaniline on gram-scale (Scheme
2). Condensation of 4-methoxyaniline and picolinic acid
generated the N-phenylpicolinamide 1f. Copper-catalyzed
cross coupling of 1f with THF provided the N-(2-
tetrahydrofuranyl)-picolinamides 2f, which was subsequently
transferred to 4-(4-methoxyphenylamino)-1-butanol 3f
through our method. So far all the atoms of 4-methoxyaniline
and THF entered compound 3f except two hydrogens. Along
with this transformation 70% of piconol was also recovered.
Finally, an acid-catalyzed condensation of 3f and commercial
available 4-chlorobenzhydrol afforded product 4 in 86% yield
(68% overall yield). Thus, it demonstrated an efficient and
atom-economic route for the preparation of amino alcohol/
ether from primary amine.
a
Reaction conditions: N-phenylpicolinamide (1) (0.2 mmol), NaBH4 (1.0
mmol) in 1 mL EtOH/H2O (100/1) stirring at 60 ꢀC for 12 h. b Isolated yields.
Although detailed reaction mechanism must await further
investigation, based on the above results and literature survey12
Aer optimization of reaction conditions, we applied this
method for a series of N-(2-tetrahydrofuranyl)-picolinamides (2) we have suggested a plausible mechanism as shown in Scheme
which were obtained in our previous work. As shown in Table 2, 3. With the activation of 2-tetrahydrofuranyl group, picolina-
all the desired N-aryl-4-amino-1-butanols were generated in mide (2) was rst attacked by hydride to form intermediate A.
Anion-induced isomerization of intermediate A led to the
release of a pyridylaldehyde and cleavage of the tetrahydrofuran
ring, generating intermediate B which would be protonated to
imino alcohol C. Further reduction of pyridylaldehyde and C
under reaction conditions gave piconol and amino alcohol 3
good to excellent yields (61–99%) (3b–3n). Functional groups
such as OMe, F, Cl and Br were tolerated on the benzene ring.
There was no obvious steric effect observed as the 4-(o-
tolylamino)-1-butanol (3b), 4-(m-tolylamino)-1-butanol (3c) and
4-(p-tolylamino)-1-butanol (3d) were all isolated in roughly
similar yields. But electron-withdrawing group substituted respectively. It is also explained the requirement of excess
substrates (3g–3i) provided better results than those with amount of NaBH4 in this reaction.
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Scheme 2 Gram-scale synthesis of a T-type calcium channel antagonist (4) from 4-methoxyaniline. Reaction conditions: (i) POCl3, Et3N, DCM,
rt, 2 h; (ii) Cu(OAc)2/1,10-phenanthroline, TBHP, THF, rt, 8 h; (iii) NaBH4, EtOH/H2O, 60 ꢀC, 12 h; (iv) p-TsOH, toluene, reflux.
Scheme 3 Plausible mechanism.
Conclusions
Notes and references
In summary, we have developed a novel method for generation
of N-aryl amino alcohols from N,N-disubstituted picolinamides
through reduction/ring-opening reaction with NaBH4. It can
also be treat as an efficient and atom-economical route for the
preparation of N-aryl amino alcohols from primary amines, as
the N,N-disubstituted picolinamides can be easily obtained
from primary amines aer convenient condensation with
picolinic acid and coupling with cyclic ethers. Each step showed
high yields and the picolinic acid can be recovered in the form
of piconol aer reaction. Thus this method exhibited excellent
efficiency and atom-economy, which suggest that it should be
useful in complex molecule synthesis and related synthetic
applications.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (NSFC, No. 21702054) and the open project program of
Hubei Key Laboratory of Drug Synthesis and Optimization,
Jingchu University of Technology (OPP2016ZD01) for nancial
support.
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