Chemoselective: O -formyl and O -acyl protection of alkanolamines, phenoxyethanols and alcohols catalyzed by nickel(ii) and copper(ii)-catalysts

Article abstract of DOI:10.1039/d0gc00520g

Achieving chemoselectivity is always crucial and challenging for bi-functional compounds, such as alkanolamines, that have both amines and alcohols as reactive functional groups. Achieving 100% selectivity for O-formyl and O-acyl protection of alkanolamines is one of the examples of such reactions. To avoid protection and deprotection steps and overcome this problem, a novel chemoselective, efficient, and simple protocol for functional group protection as O-formylation and O-acylation of alkanolamines and phenoxyethanols and competitive O-selectivity between alcohols and amines, catalyzed by Ni(ii) and Cu(ii) complexes with 8-hydroxyquinoline at a catalyst loading of only 5 mol% in a homogeneous medium has been presented here. Good to excellent yields are achieved in the absence of a solvent for O-formylation at room temperature with formic acid as the formyl source and O-acylation at 70 °C with acetic acid as the acyl source. In addition, minimal effluent and waste are generated during this reaction, as the corresponding sodium salts of acids could be recovered during the process and can be reused. This chemistry readily tolerates a variety of functional groups, as demonstrated by 20 examples with 100% chemoselectivity for O-formylation and O-acylation of alkanolamines and 30 examples of O-formylation and O-acylation of phenoxyethanols and alcohols in the presence of amines which have been synthesized successfully.

Full text of DOI:10.1039/d0gc00520g

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DOI: 10.1039/D0GC00520G
ARTICLE
Chemoselective O-Formyl and O-Acyl Protection of
Alkanolamines, Phenoxyethanols and Alcohols Catalyzed by
Nickel-(II) and Copper-(II)-Catalysts
Received 00th January 20xx,
Accepted 00th January 20xx
Rahul B. Sonawane,a Swapnali R. Sonawane,a Nishant K. Rasal a and Sangeeta V. Jagtap*a
DOI: 10.1039/x0xx00000x
Chemoselectivity is always crucial and challenging task for bi-functional compounds, as like alkanolamines, that have both
amine and alcohol as reactive functional groups. Achieving 100% selectivity for O-formyl and O-acyl protection of
alkanolamines is one of the examples of such reactions. To avoid protection and deprotection steps and overcome this
problem, a novel chemoselective, efficient, and simple protocol of functional group protection as O-formylation and O-
acylation of alkanolamines, phenoxyethanols and competitive O-selectivity between alcohols and amines, catalyzed by Ni-
(II) and Cu-(II) complexes with 8-hydroxyquinoline at just catalyst loading of 5mol % in homogeneous medium has been
presented here.Good to excellent yields are achieved in absence of solvent for O-formylation at room-temperature with
formic acid as formyl source and O-acylation at 70 °C with acetic acid as acyl source. In addition, the minimal effluent and
waste are generated during this reaction, as corresponding sodium salts of acids could be recovered during the process
and can be reused. This chemistry readily tolerates variety of functional groups, demonstrated by 20 examples with 100%
chemoselectivity for O-formylation and O-acylation of alkanolamines and 30 examples of O-formylation and O-acylation of
phenoxyethanols and alcohols in presence of amines which have been synthesized successfully.
Introduction
HO
O
N
N
N
N
O
N
O
N
S
O
O-formylation and O-acylation of alcohols are the most useful and
versatile reactions in protective organic chemistry1 that plays an
important role in the synthesis of complex organic molecules such
as natural products.2 Moreover, many important drug molecules
and natural flavoring food ingredients possess O-formyl and O-acyl
O
O
O
H
O
H
H
S
N
N
H
H
O
H
H
O
O
S
H
O
cefamandole nafate
O
ethynodiol diacetate
diltiazem
HO
O
N
O
O
H
O
O
H
O
H
O
O
moieties,
to
name
a
few
like
cefamandolenafate,
O
O
N
S
N
H
ethynodioldiacetate, diltiazem, cefapirin, methacholine, citronellyl
formate, geranyl formate, styralyl formate, geranyl acetate,
vetiveryl acetate and benzyl acetate (Figure 1).
S
H
H
O
citronellyl formate
geranyl formate
O
methacholine
cefapirin
N
H
O
H
H
Many times it is observed that, in total synthesis, there is a
need to protect one functional group and achieve the desired target
molecule.3 When two or more competitive reactive functional
groups present in molecules like amino alcohols or alkanolamines,
having both amine and alcohol groups; the chemoselective O-
formylation and acylation in the presence of unprotected amines is
still a challenging issue for academic and industrial researchers of
organic chemistry. Moreover, significant examples of aromatic and
aliphatic amino alcohols are not much studied in most of the known
protocols. Hence, chemoselectivity in organic reactions is of
enormous significance to synthetic organic chemists as it decreases
excessive protection and deprotection steps and henceforth
reduces the expense of the overall process.2a
O
O
H
H
O
O
H
O
H
O
geranyl acetate
styralyl formate
vetiveryl acetate
benzyl acetate
Figure 1.Drug molecules and natural flavoring food ingredients
having O-formyl and O-acyl moieties.
As the nucleophilicity of the amino group is much more than that of
the hydroxyl group, N-acylation takes place dominantly over O-
acylation.4 Moreover, formates show acid stability and easily can be
removed under mildly basic conditions to which common esters are
often stable.5 In addition to permitting protection approaches,
formates and acetates can be used as formyl and acyl sources in
subsequent functional group interconversions.6
There are only few methodsavailable to protect –OH group
chemoselectively7 in the presence of –NH2 group. The
transesterification (O-acylation) of alcohols in presence of amines
using various esters and µ-oxo-tetranuclear zinc cluster
Zn4(OCOCF3)6O8 and µ-oxo-dinuclear iron(III) salen catalysts9 have
been reported. An esterification of hydrochloride salt of
aminoalcohols using acid chloride has been studied.10 Several
a. Department of Chemistry, Baburaoji Gholap College, Sangvi, Pune-411027, India
(Affiliated to Savitribai Phule Pune University, Pune).
Email: sangeetajagtap@rediffmail.com.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
acylating reagents are used for chemoselective O-acyaltion of activated carboxylic acid derivatives in the prVeiseewnAcrteicle oOfnline
aminoalcohols namely as 2,2'-bipyridyl-6-yl carboxylate with cesium stoichiometric base63 are studied.
fluoride,112-acylpyridazin-3-ones,12
3-(trimethylacetyl)- 1,3- Several catalysts are used for O-acylation of alcohols, viz.
thiazolidine-2-thione,13 carboxylic acid anhydrides,14 acetic acid,14a lithium bis(perfluoroalkylsulfonyl)imide,58a SBA-15-functionalized
acid chlorides,14a chloroacetyl chloride,15 methyl benzoate,16 vinyl sulfonic acid confined acidic ionic liquid,57a ZrOCl2.8H2O,59
enol
esters16,17ortho-substitutedN,N-diacetylaniline,18N- Fe(OTs)3,58b and choline chloride·2CrCl3·6H2O,57b DMAP,58c Cp2TiCl,
methoxydiacetamide,19 3-acylthiazolidine-2-thione,20 andα-aryl-β- Mn,60asilphos [PCl3_n(SiO2)n]54h silica-bonded N-propyl sulfamic acid
keto esters.21 (SBNPSA),54isulfuric acid ([3-(3-silicapropyl)sulfanyl]propyl)ester,54j
Several catalysts have been used for chemoselective O- ceric ammonium nitrate (CAN),57c p-toluenesulfonyl chloride,51b
acyaltion of aminoalcohols such as [γ-HGeW10O36]-7,16 tribromoisocyanuric acid (TBCA),51c Zr(HSO4)4,51d t-BuONa,6b
Cp*2Sm(thf)2,17alkoxy-bridged complex Et2Zn,62a-b YbCl3·6H2O or CeCl3·7H2O,58d Au/TiO2,52 N-heterocyclic
dinuclear cobalt
[Co4(OCOR)6O]2 (R = CF3, CH3, tBu) with 2,2’-bipyridine ligand,22 and carbene (NHC),53 TiCl3(OTf),58e HfCl4·(THF)2 and ZrCl4·(THF)2.57d
a
DOI: 10.1039/D0GC00520G
microwave-promoted reactions catalyzed by dibutyltin oxide
Oxidative esterification of aldehydes using ZnBr2 and
(nBu2SnO),23 and Y5(OPri)13O24 catalysts.
H2O2,64anddirect oxidative esterification of alcohols catalyzed by
Chemoselective synthesis of 4-aminocyclohexyl acetate PdCl2(CH3CN)2 with dioxygen as the environmentally benign
hydrochloride from 1-aminocyclohexanol·HCl has been reported oxidant65 has been reported. While oxidative esterification of
using amine hydrochloride salt strategy.25 Also direct acylation of alcohols and aldehydes using supported iron oxide nanoparticle
unprotected hydroxyamino acids with acyl halides or carboxylic catalysts66 and imidazoliumperrhenate catalysts67 has also been
anhydrides under appropriately acidic reaction conditions has been studied.
reported for chemoselective O-acylation.14a Chemoselectivity of the
Consequently, the development of simple, efficient and
N, O-enzymatic acylation in organic media and in ionic liquids has selective methods for such widely used organic transformation
also been reported.26 NHC catalyzed oxidative chemoselective O- from readily available reagents is one of the major challenges in the
acylation using various aldehydes with alcohols in presence of organic synthesis. However, many of these methods require either
amines has been reported for corresponding esters.27 Also NHC special acylating reagents or costly metal catalysts, which prompted
catalyzed oxidative esterification has been studied using aldehydes us to study the O-formylation and O-acylation of crucial bi-
and trans esterification of various esters with amino alcohols.28 functional aminoalcohols or competitive O-selectivity between
Wang et. al.29 has studied base- and acid-catalyzed interconversions alcohols and amines as a general and simple protocol for the
of O-acyl- and N-acyl-ethanolamines which could be helpful for lipid chemoselectivity.
analyses.
In our previous studies, new synthetic methods were developed
Moreover, several methods are available using lipase enzyme using transition metal catalyzed N-formylation and N-acylation of
catalyzed chemoselective N-acylation of aminoalcohols.30 Various amines. And after successful use of Ni-(II) as [Ni(quin)2]68 and Cu-(II)
reagents and catalysts have been used for chemoselective N- as [Cu(quin)2]69 catalysts, the work was continued using nickel-(II)
acylation of amines such as 2-fluoro-N-acyl-N-mesylanilines,31N- and copper-(II) catalysts for O-formylation and O-acylation of
acyl-N-(2,3,4,5,6-penta-uorophenyl)methanesulfonamides,32N-acyl- alkanolamines with formic acid and acetic acid as a formyl and
4,5-dihydro-4,4-dimethyl-N-methyl-2-thiazolamine,33
acylating sources, and 8-hydroxyquinoline as bidentate ligand.
Herein, a novel, chemoselective, efficient, and simple protocol
acylmethanesulfonamides,34b enzoylisothiocyanates,35 carboxylic
acids36 and acetic anhydride37 as reagentsand 9-BBN,38 B(OH)3,39 of O-formyl and O-acyl protection of alkanolamines,
Fe(NO3)3.9H2O,40 I2,41 Zn(OAc)2,42 MgO,43 [RuCl2(dppe)2] [dppe = phenoxyethanols, and competitive O-selectivity between alcohols
(1,2-bis(diphenylphosphino)ethane)] Ru/phosphine complex44 and and amines present together, catalyzed by [Ni(quin)2] catalyst (C1)
N-heterocyclic carbenes (NHC)45 as catalysts.
and [Cu(quin)2] catalyst (C2) (Figure 2), the complexes with 8-
Subsequently, chemoselective O-formylation and acylation are hydroxyquinoline in homogeneous medium is reported (Schemes 1-
also reported, where selective formyl protection of primary 5). Good to excellent yields are achieved in absence of solvent for
hydroxyl groups were achieved by using 2,4,6-trichloro-1,3,5- O-formylation at room-temperature with formic acid as formyl
triazine and N,N-dimethylformamide in presence of lithium source and O-acylation at 70 °C with acetic acid as acyl source. The
fluoride.46 Selective O-formylation of alcohols in presence of reagents used are cheaper and do not require an inert atmosphere
phenols using silica triflate as catalyst47 and using chloral48 have during the reaction. The corresponding protected O-formyl and O-
been studied. Selective O-acylation of diols achieved by using YbCl3, acyl alkanolamines products are isolated with high selectivity
Yb(OTf)3, and CeCl3 as a Lewis acid catalysts with carboxylic acid (100%) and good to excellent yields (83-98%). Similarly, protection
anhydrides,49 and selective acetylation of primary in the presence of phenoxyethanols and alcohols in presence of amines are
of secondary hydroxyl groups using catalyst Cu(NO3)2.3H2O and synthesized with good to excellent yields (93–99%). This chemistry
acetic acid as acyl source50 are studied.
readily tolerates variety of functional groups with 100%
There are several methods reported for O-formylation of chemoselectivity for O-formylation and O-acylation of various
alcohols using formyl sources such as formic acid,51 alkanolamines, phenoxyethanols, and few other alcohols.
paraformaldehyde,52 methyl formate,53 ethyl formate,54 2,2,2-
trifluoroethyl formate,55 and formyloxy-acetonitrile.56 Also O-
acylation of alcohols using acyl sources as carboxylic acids,54c,57
(II)
(II)
Cu
O
O
N
N
. 2H2O and
. 2H2O
Ni
carboxylic acid anhydrides,51b-d,54g,i,58
acylchlorides,59 ethyl
N
N
O
O
acetate,54a,f,h,j,60
isopropenyl
acetate,61
vinyl
acetate,62
formyloxyacetoxyphenylmethane,6a
1,1-diacylals,6atert-butyl
acetate,6b and tert-butyl benzoate6b are reported.Dehydrative
condensation of carboxylic acids and alcohols in the presence of an
acid catalyst, or with stoichiometric dehydrating reagents or
Figure 2.[Ni(quin)2] Catalyst (C1) and [Cu(quin)2] Catalyst (C2)
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Synthesis of alkanolamines (1) and phenoxyethaVnioewlsArt(i8cl)e:OnTlhinee
starting materials alkanolamines and DpOhIe:n10o.x1y0e39th/Da0nGolCs00w52e0rGe
synthesized and characterized by reported method and used as
such for reactions.70
Results and discussion
Synthesis of [Ni(quin)2] catalyst (C1) and [Cu(quin)2] catalyst (C2):
Catalysts (C1)68 and (C2)69 were synthesized and characterized by
reported methods(Figure2) and used as such for this study.
Table 1. Selected Observations during Reaction Optimizationa
catalyst (mol%)
formyl source
O
H
O
H
H
O
H
N
O
N
OH
base (equiv)
temp, time
N
N
O
H
OH
O
H
1a
2a
3a
4a
O-formyl product N-formyl product
N,O-formyl product
sr.
cat.
formyl source
(volume)
base
temp time
2a yieldb
(%)
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
24
3a yieldb
(%)
nd
4a yieldb
(%)
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
61
conversionb
(%)
no. (mol%)
(equiv)
(°C)
150
150
150
150
150
150
150
150
150
150
70
Rt
(h)
24
24
24
24
24
24
24
24
24
24
6
1
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
--
DMF (5)
triethylamine (2)
Nd
Nd
Nd
65
62
Trace
15
24
25
27
85
95
15
72
33
95
27
25
92
91
Trace
5
2
DMF (5)
DIPEA (2)
nd
3
DMF (5)
2,6-lutidine (2)
nd
4
DMF (5)
imidazole (3)
65
5
DMF (5)
1,2,4-triazole (3)
62
6
DMF (5)
NaOCOCH3 (3)
trace
15
7
DMF 5)
Na2CO3 (3)
8
DMF (5)
CsCO3 (3)
24
9
DMF (5)
K2CO3 (3)
25
10
11
12
13
14
15
16
17
18
DMF (5)
K3PO4 (3)
27
98% FA (5)
98% FA(5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
98% FA (5)
50% FA (5)
98% FA (2.5)
98% FA (1)
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
nd
6
95
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
Rt
24
24
24
6
15
(C1) (2.5)
(C1) (1)
(C2) (5)
(C3)(5)
(C4)(5)
Rt
72
nd
Rt
33
nd
Rt
95
nd
nd
Rt
24
24
24
24
24
24
24
24
24
24
24
24
24
24
27
Rt
25
nd
19c (C3) (5)
20c (C4) (5)
21d (C1) (5)
22e (C1) (5)
23f (C1) (5)
24g (C1) (5)
25h (C1) (5)
26i
27j
28
29
30
Rt
92
nd
Rt
91
nd
Rt
Trace
5
nd
Rt
nd
Rt
7
7
nd
Rt
12
5
12
nd
Rt
5
nd
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
(C1) (5)
Rt
29
25
7
29
nd
Rt
25
nd
Rt
7
nd
Rt
75
75
nd
Rt
52
52
nd
aAll reactions were carried out on a 0.2 g scale using (1a) (1.32mmol, 1 equiv), formyl source (5 volume), catalyst (C1) [Ni(quin)2] or
(C2) [Cu(quin)2] or (C3) NiCl2.6H2O or (C4) CuCl2.2H2O (1 - 5 mol%) at temperature (rt to 150 °C) for 6-24 h. All reagent and substrate
c
additions were done at room temperature (25 °C). bIsolated yields. With 8-hydroxyquinoline as ligand (10 mol%). dMethanol (5
e
f
i
volume). Dichloromethane (5 volume). Acetonitrile (5 volume). g1,4-dioxane (5 volume). hToluene (5 volume). DMF (5 volume).
jDMSO (5 volume).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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O-formylation and O-acylation of alkanolamines: In preliminary surprise, chemoselective formation of O-fDoOrmI: y10l .1p0r3o9d/uDc0tG(C20a0)5w20aGs
reactions, 2-(p-tolylamino)ethanol (1a) was treated with 1 mL of
observed with excellent yield up to 95% (Table 1, entry 12). To
N,N-dimethyl formamide (DMF) in the presence of 5 mol% of know the effect of catalyst on reaction, a control experiment was
catalyst (C1) and 2 equiv of weak organic bases like triethylamine, performed without addition of catalyst (C1); decrease in yield of
DIPEA, and 2,6-lutidine at 150 °C for 24 h, however, no any product (2a) was observed with 15% (Table 1, entry 13). This proves
conversion of chemoselective O-formylated product (2a) were that catalyst (C1) is responsible for this conversion and plays
observed by TLC (Table 1, entries 1–3). While, when 3 equiv of important role. Hence, two more experiments were performed with
bases like imidazole and 1,2,4-triazole were used, dramatically only limiting the concentration of catalyst (C1) at 2.5 mol% and 1 mol%
N-formamide product (3a) was observed instead of O-formyl instead of 5 mol% and remarkable decrease in the yields of product
product (2a) with moderate yields up to 62–65% (Table 1, entries 4– (2a) were observed respectively as 72% and 33% (Table 1, entries
5). Subsequently, with inorganic bases like CH3COONa, Na2CO3, 14-15). These control experiments support the fact that the catalyst
CsCO3, K2CO3,and K3PO4,N-formamide product (3a) was observed C1 catalyses the reaction and plays vital role in presence of formic
with lower yields up to 15–27% (Table 1, entries 6–10). After these acid as formyl source. After successful trials on [Ni(quin)2] catalyst
trials, it was decided to use formic acid as formyl source instead of (C1), reaction was performed with 5 mol% of [Cu(quin)2] catalyst
DMF for the reaction. Hence, a reaction was carried out with 2-(p- (C2) to explore the catalyst activity, where exciting result was
tolylamino)ethanol (1a) using 1 mL of 98% formic acid (FA) in the observed similar to the catalyst (C1) giving desired chemoselective
presence of 5 mol% of catalyst (C1) without any base and solvent at O-formyl product (2a) with 95% yield (Table 1, entry 16). When
70 °C; where N, O-formyl product (4a) was observed predominantly reactions were carried out using metal salts like NiCl2.6H2O and
with 61% yield, while O-formyl product (2a) formed with only 24% CuCl2.2H2O as catalyst (C3) and (C4) respectively, without addition
yield and N-formyl product (3a) did not observed (Table 1, entry of ligand 8-hydroxyquinoline, lower yields of product (2a) were
11). To avoid di-formylation product and to know the effect of observed respectively as 27% and 25% (Table 1, entries 17-18).
temperature, reaction was carried at room temperature, and to our
Scheme 1.Scope of O-formylation of alkanolamines catalyzed by [Ni(quin)2] catalysta
H
O
H
O
N
[Ni(quin)2] (5 mol%)
N
OH
O
O
H
R1
R1
H
OH
rt, 2 - 6 h
1
2
O
O
O
O
O
O
H
Cl
O
O
H
N
H
N
H
H
N
O2N
N
N
O
O
H
H
O
H
O
H
O
H
H
H
Cl
Cl
2e, 91%
2a, 95%
2b, 94%
2c, 85%
2d, 90%
Cl
O
O
H
N
O
H
N
H
N
H
N
H
N
F
Cl
O
H
O
H
O
H
Br
Br
2j, 85%
2i, 95%
2f, 95%
2h, 92%
2g, 95%
Cl
Cl
O
H
N
O
H
2k, 88%
aAll reactions were carried out on a 0.2 g scale using (1) (1 equiv), formic acid (1mL, 5 volume), catalyst (C1) [Ni(quin)2] (5 mol%) at room
temperature for 2-6 h. All reagent and substrate additions were done at room temperature (25 °C). bIsolated yields.
While, when reactions were performed using metal salts as obtained in all cases (Table 1, entries 21-27). Also one experiment
catalysts (C3) and (C4), with addition of 10 mol% ligand 8- was performed using 50% formic acid in water instead of 98%,
hydroxyquinoline to generate in-situ catalyst (C1) and (C2), which also showed negligible conversion and lower yield of product
competitive yields of product (2a), were observed, vis-à-vis with (2a) like other solvents (Table 1, entry 28). This is may be due to
ready complexes as catalyst (C1) and (C2) (Table 1, entries 19-20). decreased solubility of the catalyst in solvents used for reaction. To
These experiments prove that ligand 8-hydroxyquinoline plays an know the effect of limiting the volume of formyl source, reactions
important role in catalysis and also helps to make catalysts soluble were performed using 2.5 and 1 volume of formyl source where
in acidic medium as a homogeneous catalyst. To know the effect of lower yields of product (2a) were observed (Table 1, entries 29-30).
solvent on reaction, various solvents were tested such as methanol, Thus, these experiments suggest that reaction is suitable without
dichloromethane, acetonitrile, 1,4-dioxane, toluene, DMF and any solvent using 5 volume of formic acid as formyl source.
DMSO, but little conversion with lower yields of product (2a) were
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While exploring a method for O-acylation, a separate experiment Cl, Br) were unaltered (Schemes 1-2). Aromatic alkanolamines
View Article Online
was performed on 2-(p-tolylamino)ethanol (1a) using acetic acid containing electron-donating group likeDO–IM: 10e.10u3n9d/De0rwGCen00t52t0hGe
instead of formic acid and without any other solvent, at optimized conversion smoothly to give excellent yield along with excellent
conditions; but no O-acylated product (5a) was observed at room chemoselectivity of O-formyl products 2a, 2h and electron-
temperature. Hence, it was decided to increase the temperature withdrawing group like –NO2 at meta position gave high selectivity
from ambient temperature to 70 °C where excellent conversion and with good yield 2c. For halide substituted alkanolamines, better
yield of chemoselective O-acylated product (5a) up to 94% was conversions as well as yields were seen at all ortho, meta and para
obtained within 6 h.
positions 2d-2k. Similarly, O-acylation of various different
Once optimized, chemoselective O-formylation and O-acylation functionalities on alkanolamines using acetic acid as acyl source also
using formic acid and acetic acid were successfully carried out for experienced similar effects on conversion with substituents having
differently substituted alkanolamines, phenoxyethanols, and electron donating / withdrawing groups on ortho, meta and para
alcohols (Schemes 1-5). It was observed that different positions that gave good to excellent yields (Scheme 2, 5a-5i).
functionalities on alkanolamines such as alkyl, nitro and halides (F,
Scheme 2. Scope of O-acylation of alkanolamines catalyzed by [Ni(quin)2] catalysta
H
O
O
H
O
N
[Ni(quin)2] (5 mol%)
N
OH
O
O
R1
R1
OH
70 °C, 2 - 6 h
1
5
O
O
Cl
O
O
O
O
H
N
H
H
N
H
H
N
O2N
N
N
O
O
O
O
5a, 94%
5b, 92%
5c, 98%
5d,85%
5e, 92%
Cl
Cl
H
N
O
O
Cl
O
H
N
H
N
H
N
O
F
Cl
O
O
O
Br
5g 95%
5f, 90%
5h, 85%
5i, 83%
aAll reactions were carried out on a 0.2 g scale using (1) (1 equiv), acetic acid (1mL, 5 volume), catalyst (C1) [Ni(quin)2] (5 mol%) at 70 °C for
2-6 h. All reagent and substrate additions were done at room temperature (25 °C). bIsolated yields.
At the end of this study, a two gram-scale reaction of 1a was phenolphthalein as an indicator and assay found 99.6% for sodium
performed for O-formylation and O-acylation respectively and formate and 99.5% for sodium acetate.
similar reactivity was observed with excellent yields up to 95% for
2a and 94% for 5a. Also, formic acid and acetic acid were recovered
from the reaction as their corresponding sodium salts as sodium
formate and sodium acetate respectively. The recovery of both
The strategy was further extrapolated for O-formylation and O-
acylation of various different functionalities on phenoxyethanol
(Schemes 3-4); which gave similar results as that for earlier strategy
(Schemes 3-4, 9a-9l, 10a-10h). It also tolerated panel of broad
acids was found to be satisfactory with 96.7% for sodium formate
functional groups as alkyl, halides, alkyl halide, methoxy, nitro, and
and 96.5% for sodium acetate. The assay of both recovered salts
esters.
was determined by titration method using 0.1N HCl solution and
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Scheme 3.Scope of O-formylation of phenoxyethanols catalyzed by [Ni(quin)2] catalysta
View Article Online
DOI: 10.1039/D0GC00520G
O
O
O
[Ni(quin)2] (5 mol%)
O
OH
O
H
R1
R1
H
OH
rt, 2 - 6 h
9
8
O
O
O
O
O
Cl
O
O
O
O
O
O
O
O
O
H
O
H
O
O
H
O
H
O
H
O
H
O
9a, 99%
9b, 98%
9c, 99%
9d, 99%
9e, 99%
9f, 98%
O
O
O
O
O
O
O
O
F3C
O
O2N
O
O
O
H
O
H
O
H
O
H
MeO
H
O
H
O2N
F
MeO
9g, 99%
9h, 97%
9i, 99%
9j, 97%
9k, 97%
9l, 97%
aAll reactions were carried out on a 0.2 g scale using (8) (1 equiv), formic acid (1mL, 5 volume), catalyst (C1) [Ni(quin)2] (5 mol%) at room
temperature for 2-6 h. All reagent and substrate additions were done at room temperature (25 °C). bIsolated yields.
Scheme 4.Scope of O-acylation of phenoxyethanols and alcohols catalyzed by [Ni(quin)2] catalysta
O
O
O
[Ni(quin)2] (5 mol%)
O
OH
O
O
R1
R1
OH
70 °C, 2 - 6 h
10
8
O
Cl
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
10d, 96%
10f, 94%
10a, 96%
O
10b, 95%
10c, 96%
10e, 95%
O
O
O
O
O
O2N
MeO
10g, 98%
10h, 94%
aAll reactions were carried out on a 0.2 g scale using (8) (1 equiv), acetic acid (1mL, 5 volume), catalyst (C1) [Ni(quin)2] (5 mol%) at 70 °C for
2-6 h. All reagent and substrate additions were done at room temperature (25 °C). bIsolated yields.
After successful chemoselective O-formylation and O-acylation of aliphatic amines reacted sluggishly and formed negligible yields of
alkanolamines and phenoxyethanols, this developed protocol was N-formyl and N-acyl products respectively. Also, reaction of
extended for various alcohols in presence of amines to show alkanolamine (1b) in presence of phenoxyethanol (8a) (Scheme 5)
competitive O-formylation and O-acylation; and was found to give showed similar reactivity, and the competitive O-formyl products
excellent yields (Scheme 5, 13a-13c, 2b, 9a, and 15a-15c).In this 2b and 9a were obtained with 94% and 99% yields respectively
study aromatic amines did not show any conversion of N-formyl with excellent chemoselectivity and did not show any formation of
product (14a)and N-acyl product (16a) when reacted with formic N-formyl product (3b) and N,O-formyl product (4b).
acid and acetic acid as acyl sources in presence of alcohols. While
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View Article Online
DOI: 10.1039/D0GC00520G
Scheme 5.Competitive chemoselective O-formylation and O-acylation of alcohols in presence of aminesa,b
O
H
R4
R4
[Ni(quin)2] (5 mol%)
O
O
N
H
OH
OH
R3
O
H
R3 OH
11
R5
R6
rt, 2 - 6 h
13
14
O
H
N
R4
O
O
[Ni(quin)2] (5 mol%)
N
R5
R6
R3
O
15
R5
R6
70 °C, 2 - 6 h
12
16
O
O
O
H
O
O
H
O
O
N
O
O
H
O
O
N
O
O
H
O
H
N
H
N
H
N
H
H
O
H
O
H
H
H
O
H
H
13a, 99%
14a, 0%
13a, 99%
14b, 5%
13b, 97%
14c, 3%
13c, 98%
14d, 4%
2b, 94%
9a, 99%
O
O
O
O
O
O
O
H
N
H
O
O
O
O
O
N
O
O
N
N
H
O
N
H
O
H
10a, 96%
16d, 4%
15c, 95%
16b, 5%
15a, 99%
16b, 3%
15b, 93%
16c, 2%
15a, 99%
16a, 0%
aAll reactions were carried out on a 0.2 g scale using alcohol (11) (1 equiv), amine (12) (1 equiv), formic acid (1mL, 5 volume), catalyst (C1)
[Ni(quin)2] (5 mol%) at room temperature for 2-6 h.
bAll reactions were carried out on a 0.2 g scale using alcohol (11) (1 equiv), amine (12) (1 equiv), acetic acid (1mL, 5 volume), catalyst (C1)
[Ni(quin)2] (5 mol%) at 70 °C for 2-6 h. All reagent and substrate additions were done at room temperature (25 °C). cIsolated yield given.
Plausible Mechanism of Chemoselective O-formylation and O- intermediate-C by attack of more nucleophilic oxygen, followed by
acylation of Alkanolamines:
A plausible mechanism for the proton exchange by shifting of acidic proton from one oxygen to
chemoselective O-formylation and O-acylation of alkanolamines, in another to give intermediate-D. Then theacidic hydrogen from
accordance with the experimental results, is represented in ammonium salt goes to more susceptible hydroxy group to give
(Scheme 6). Initially, amine of amino alcohol reacts with acidic intermediate-E.
Finally,
intermediate-E
furnishes
100%
hydrogen of carboxylic acid to form quaternary ammonium salt of chemoselective O-formyl and O-acyl product (intermediate-F) by
amino alcohol (intermediate-A), then subsequently formic or acetic eliminating water molecule followed by loss of Ni-(II) or Cu-(II)
acid moiety gets activated via coordination with Ni-(II) or Cu-(II) catalysts for next catalytic cycle.
catalysts (intermediate-B). Intermediate-Bthen gets cyclized to give
Scheme 6. Plausible mechanism of O-formylation and O-acylation of alkanolamines catalyzed by Ni-(II) and Cu-(II) catalysts
M(II)
:
H
:
O
OH
(II)M
:
:
: :
O
M(II)
O
HN
R2
OH
O
R1
H
O
O
H2N
R2
: :
O
R1
R1
O
M = Ni, Cu
R1
OH
R1 = H, CH3
R2 = H, aryl
H2N
R2
O
H2N
A
R2
B
C
Proton-exchange
(II)M
(II)M
M(II)
(II)M
:
:
O
:
:
O
:
: :
:
O
:
O
O
:
- M(II)
H
O
O
O
O
R1
H O
R1
N
R1
:
R1
O
R2
R1
:
O
:
O
:
H
- H2O
H
N
R2
N
R2
N
H2N
Chemoselective
H
H
H
H
H
O-formyl and O-acyl
R2
R2
F
product
E
D
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DOI: 10.1039/D0GC00520G
ARTICLE
Journal Name
Plausible Mechanism of O-formylation and O-acylation of
Phenoxyethanols and Alcohols: A similar mechanism can be
predicted for the O-formylation and O-acylation of
phenoxyethanols and alcohols, as represented in (Scheme 7).
Initially, formic or acetic acid gets activated via coordination with
Ni-(II) or Cu-(II) catalysts (intermediate-G). Then alcoholic –OH of
phenoxyethanols or alcohols attack on carbonyl carbon of
activated intermediate-G and forms tetrahedral intermediate-H;
which then undergoes proton exchange by shifting of acidic
proton to give intermediate-I. This is followed by the elimination
of water molecule giving intermediate-J. Finally, intermediate-J
furnishes O-formyl and O-acyl product leaving behind the Ni-(II)
or Cu-(II) catalysts for next cycle. All the control experiments
data, afford several revelations regarding the identity of this
plausible mechanism. Pleasantly, all the O-formylation and O-
acylation reactions proceeded efficiently to furnish respective
substituted phenoxyethanols and alcohols with moderate to
excellent yields.
Scheme 7.Plausible mechanism of O-acylation of phenoxyethanols and alcohols catalyzed by Ni-(II) and Cu-(II) catalysts
M(II)
:
:
O
M(II)
:
O
M(II)
H
: :
O
H
R2
:
:
O
M(II)
:
:
:
O
O
R1 OH
R1
R1
O
R2
R1
OH
OH
M = Ni, Cu
H
R2 = H, aryl
R1 = H, CH3
G
H
M(II)
R2
M(II)
H
:
:
O
- M(II)
:
:
:
O
:
O
R2
O
H
R1
O
H
R1
O
R1
:
:
O
H
: :
O
O-formyl and O-acyl
product
J
R2
I
Conclusions
In conclusion, a novel, chemoselective, and simple method to
attain the O-formyl and O-acyl protection of alkanolamines,
phenoxyethanols, and competitive O-selectivity between
alcohols and amines present together, catalyzed by Ni-(II) and
Cu-(II) complexes with 8-hydroxyquinoline in homogeneous
medium has been developed. O-formylation at room-
temperature using formic acid as formyl source and O-acylation
at 70 °C using acetic acid as acyl source, with good to excellent
yields in absence of solvent could be achieved. The effluent and
waste are generated during this reaction are minimal and
corresponding sodium salts of acids could be recovered and
reused. The milder conditions allow the broad functional group
tolerance for alkanolamines and phenoxyethanols. No need of
inert atmosphere, easy operational and workup procedures are
useful for many future syntheses.
Notes and references
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Conflicts of interest
There are no conflicts to declare.
7
Acknowledgements
Authors thank to Baburaoji Gholap Research Center for its
support. We are also thankful to “Central Instrumental
Facility (CIF)” Savitribai Phule Pune University (SPPU) and
HRMS Facility, Chemistry Department, Indian Institute of
Science Education and Research (IISER), Pune for their
analytical support.
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Novel, Chemoselective, Solvent-Free O-Formyl and O-Acyl Protection
O
H
For Alkanolamines:
N
O
R2
R1
20 examples,
> 83% yield
[Ni(quin)2] (5 mol%)
or
H
100% Selectivity
O
N
[Cu(quin)2] (5 mol%)
OH
R1
R2 OH
neat, rt or 70 °C, 2 - 6 h
X
O
R2
O
R2
R2 = H or Me
O
N
N
O
R2
OH
0% Selectivity
R1
R1
Not Observed
O
For Phenoxyethanols and Alcohols in Presence of Amines:
O
O
R2
R1
[Ni(quin)2] (5 mol%)
or
O
OH
R1
20 examples,
> 94% yield
O
[Cu(quin)2] (5 mol%)
R2 OH
neat, rt or 70 °C, 2 - 6 h
R4
R3 OH
O
R2
R6
O
H
N
R4
R2 = H or Me
R2
N
R5
O
R6
R5
R3
10 examples,
> 93% yield
< 5% Selectivity
> 95% Selectivity
A crucial chemoselective O-formyl and O-acyl protection of alkanolamines and phenoxyethanols, and alcohols in presence of amines
catalyzed by Ni-(II) and Cu-(II) complexes with 8-hydroxyquinoline in homogeneous medium is achieved.
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