Synthesis of: N -[(dialkylamino)methyl]acrylamides and N -[(dialkylamino)methyl]methacrylamides from Schiff base salts: Useful building blocks for smart polymers

Article abstract of DOI:10.1039/c8ob00811f

The traditional thermal Mannich reaction is unsuitable for preparing polymerizable N-methylene amino substituted acrylamides and methacrylamides. Herein we provide a facile multi-gram high yield synthesis of these monomeric precursors to stimuli-responsive polymers by the addition of acrylamides and methacrylamides onto in situ generated or freshly isolated methylene Schiff base (iminium) salts. The X-ray crystal structure of the hydrated iminium salt, 1-(hydroxymethyl)azocan-1-ium chloride and monomer·HCl salt (N-[(azocan-1-yl)methyl]prop-2-enamide hydrochloride) is described.

Full text of DOI:10.1039/c8ob00811f

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Synthesis of N-[(dialkylamino)methyl)]acrylamides and
N-[(dialkylamino)methyl]methacrylamides from Schiff base salts:
Useful building blocks for smart polymers
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abdullah Alzahrani,a Styliana I. Mirallai,*a Benjamin A. Chalmers,a Patrick McArdlea and
Fawaz Aldabbagh*a,b
The traditional thermal Mannich reaction is unsuitable for preparing polymerizable N-methylene amino substituted
acrylamides and methacrylamides. Herein we provide a facile multi-gram high yield synthesis of these monomeric
precursors to stimuli-responsive polymers by addition of acrylamide and methacrylamide onto in situ generated or freshly
isolated methylene Schiff base (iminium) salts. X-ray crystal structure of the hydrated iminium salt, 1-
(hydroxymethyl)azocan-1-ium chloride and monomer.HCl salt, (N-[(azocan-1-yl)methyl]prop-2-enamide hydrochloride) is
described.
Literature routes have used one-pot Mannich condensation of
(meth)acrylamide with formaldehyde to generate the Schiff
Introduction
The three-component Mannich reaction is fundamental
allowing access to -amino methylated carbonyl
compounds.1,2
N-[(Dialkylamino)methyl)]acrylamide and
methacrylamide analogues are valuable monomeric precursors
to smart polymers, with functionality capable of dual
temperature and pH-responsiveness (Figure 1), however
potential applications have not been realised due to problems
with their synthesis.
base followed by secondary amine addition (Scheme 1).3-6 The

reaction operates thermally (at 80 C), and is inefficient in
forming the Schiff base in situ, with the elevated temperature
resulting in premature polymerization of the monomer and
intermediates. The reaction has the added difficulty of
monomer isolation, which requires vacuum distillation from
the aqueous reaction mixture.
Scheme 1 One-pot thermal Mannich reaction route.
Fig. 1 (a) Synthetic targets and (b) precursors.
The most widely studied temperature-responsive polymers are
those with lower critical solution temperatures (LCST) close to
physiological temperature, such as poly(N-isopropyl-
acrylamide) and poly(N,N-diethylacrylamide) with LCST of 32-
a.School of Chemistry, National University of Ireland Galway, University Road,
Galway, Ireland E-mail: Styliana.Mirallai@nuigalway.ie
34 
C in water.7-9 The N-dialkyl amino (including saturated
b.Present address: Department of Pharmacy, School of Life Sciences, Pharmacy and
Chemistry, Kingston University, Penrhyn Road, Kingston Upon Thames, KT1 2EE,
United Kingdom E-mail: F.Aldabbagh@kingston.ac.uk
nitrogen heterocycle) of substituted acrylamides and
methacrylamides can be reversibly ionized allowing pH-
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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response that alters polymer hydrophobicity.9-14 Amphiphilic The monomer hydrochloride salts 1a.HCl-3b.HCl werVeiepwrAercticipleitOantleinde
DOI: 10.1039/C8OB00811F
block copolymers comprising of such monomers can self- upon addition of diethyl ether to the reaction in acetonitrile, which
assemble into a variety of nano-objects for use as stimuli- allowed separation of the soluble N-acetyl cycloamines (Scheme 2).
responsive polymersomes for targeted delivery of The isolable 1a.HCl-3b.HCl are themselves useful as monomeric
therapeutics.11-13 In a recent communication, the synthesis of building blocks in aqueous solution polymerizations.14 Basification
selected acrylamides containing an N-methylene saturated of
nitrogen heterocycles, and their incorporation into well- [(cycloalkylamino)methyl)]acrylamides 1a-3a to be isolated in 20-25
defined water-soluble block copolymer polyacrylamides was scale in yields of 66-75% with the N-
realised.14 In this full paper, we expand on the monomer [(cycloalkylamino)methyl)]methacrylamides 1b-3b isolated in higher
the
latter,
allowed
the
free
N-
g
synthesis by providing efficient multi-gram routes to
acrylamides and methacrylamides, including those with dialkyl
acyclic and large saturated nitrogen heterocyclic rings. The
synthesis involves efficient generation of the methylene Schiff
base salt, which was characterized in the hydrated form.
yields of 82-92% yield and in 30 g scale.
Our in situ Schiff base salt approach was not applicable for larger
cycloamines (azepane and azocane) and acyclic analogues. Isolation
of the methylene Schiff base salts was deemed necessary in these
cases due to the poor solubility of their aminals in acetonitrile.
Seven and eight-membered heterocyclic base-containing
monomers are useful for increased hydrophobicity in the ionisable
block segment of amphiphilic copolymers promoting sharper pH-
sensitivity of micelles.11,12 On the contrary linear dialkyl amine-
containing polyacrylamides generally have greater water solubility
in comparison to heterocyclic amine-containing analogues affording
higher LCSTs.10 Treatment of the aminals with acetyl chloride in
diethyl ether at 0 °C allowed access to both larger heterocyclic and
acyclic methylene Schiff base salts 4a-4f, which were more
conveniently characterised as N-hydroxymethyl hydrochloride salt
derivatives 5a-5f (Scheme 3).
Results and Discussion
In contrast to the one-pot thermal Mannich condensation reaction
in Scheme 1, our synthesis uses readily accessible aminals made
from the condensation of formaldehyde with secondary amines at
0 °C (Scheme 2).16,17 Böhme pioneered the quaternization of the
aminal to generate the Schiff base (iminium) salt, and this
procedure using acetyl chloride was followed.17,18 There are
numerous accounts of alkylation and nucleophilic addition onto
methylene Schiff base salts,16-28 including by non-vinylic amides.27, 28
The most utilised is commercial N,N-dimethylmethyleneiminium
iodide or Eschenmoser’s salt.20,29 Inspired by the simplicity and low
temperatures, acrylamide and methacrylamide were added onto in
situ generated methylene Schiff salts to give the monomer
hydrochloride salts of morpholine, pyrrolidine and piperidine.
Scheme
3 Synthesis of methylene Schiff base salts 4a-4f
characterised by 1H NMR as hydrated derivatives 5a-5f.
Scheme 2 Synthesis of N-[(cycloalkylamino)methyl)]acrylamides 1a-
3a,14 and N-[(cycloalkylamino)methyl)]methacrylamides 1b-3b using
the in situ Schiff base salt approach.
NMR spectra of iminium salts 4a-4f showed mixtures with their
respective hydrated derivatives 5a-5f. For example, the 1H-NMR
spectrum in CD2Cl2 gave similar intensity signals for the exo-
methylene at 8.87 ppm of N-methylideneazocan-1-ium chloride
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(4b) and its N-hydroxymethyl derivative 5b exo-methylene at 4.74 The X-ray crystal structure of N-(hydroxymethylV)aiezwoAcratincl-e1O-niulinme
DOI: 10.1039/C8OB00811F
ppm (Figure 2a). Upon recrystallization from acetonitrile, the more chloride (5b) was obtained (Figure 4a, Table S1). The large eight
stable N-(hydroxymethyl)azocan-1-ium chloride 5b was obtained membered ring of 5b was found to be disordered over two equally
(Figure 2b). It was thus more convenient to characterize the populated sites with both the N-H and O-H bonds found to be
moisture sensitive methylene Schiff base salts 4a-4f using NMR in involved in H-bonding to the chloride counter ion (Figure 4b).
D2O, as 5a-5f (Figure 2c). An exception was N,N- Interestingly, a search of the CCDC data base for the R2NH-CH2-OH
dibutylmethaniminium chloride (4f), which appeared less moiety gave only one hit, CSD code DIVDET, which was for a
hygroscopic. The NMR spectrum in CD2Cl2, contained only trace pyrimidine salt of tris(hydroxymethyl)ammonium chloride.30 The
amounts of hydrated derivative 5f (Figure 3a). The exo-methylene hydroxymethyl hydrochlorides 5a-5f were however difficult to
at 8.58 ppm in CD2Cl2 for the methylene Schiff base was replaced by isolate cleanly due to their susceptibility to decomposition to
the exo-methylene at 4.83 ppm in D2O for N-butyl-N- formaldehyde.
(hydroxymethyl)butan-1-aminium chloride (5f in Figure 3b).
Fig. 4 The X-ray crystal structure of N-(hydroxymethyl)azocan-1-ium
chloride (5b): (a) only one component of the ring disorder shown
for clarity and (b) H-bonding interactions (Table S1).
Nucleophilic addition of acrylamide or methacrylamide onto the
freshly prepared methylene Schiff base salts of azepane and
Fig. 2 1H-NMR Spectrum: (a) of the initially isolated mixture
azocane 4a and 4b gave the hydrochloride monomer salts (6a.HCl,
containing N-methylideneazocan-1-ium chloride (4b) and N-
6b.HCl, 7a.HCl and 7b.HCl) after precipitation from diethyl ether
(hydroxymethyl)azocan-1-ium chloride (5b) in CD2Cl2 and spectra
(Scheme 4). The monomer HCl salts were suspended in
after recrystallization from MeCN in (b) CD2Cl2, and (c) D2O.
dichloromethane and basified to give the monomers 6a-6b and 7a-
7b in high yields of 84-91% (from 4a-4b). Attempts to react
acrylamide and methacrylamide with an analytically pure sample of
N-(hydroxymethyl)azocan-1-ium chloride (5b) in dried acetonitrile
resulted in isolation of unreacted 5b and some degradation with
release of formaldehyde. It follows that yields of the monomer from
addition onto methylene Schiff base salts were determined by the
extent of hydration of the latter substrate.
X-ray crystal structure of N-[(azocan-1-yl)methyl]prop-2-enamide
hydrochloride (7a.HCl) was obtained with the very small fitting
errors suggesting the ring was in the optimal conformation (Figure
5). The crystal structure showed N-H bonds forming H-bonding
interactions with the chloride anions and the oxygen atoms
resulting in intermolecular packing with some weaker C-H…Cl and
C-H…O (see Figures S1, S2 and Table S2).
Fig. 3 1H-NMR Spectrum: (a) of N,N-dibutylmethaniminium chloride
(4f) in CD2Cl2 and (b) of N-butyl-N-(hydroxymethyl)butan-1-
aminium chloride (5f) in D2O.
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Scheme
4
Synthesis of seven and eight-membered N-
[(cycloalkylamino)methyl)]acrylamides 6a-7a and N-[(cycloalkyl-
amino)methyl)]methacrylamides 6b-7b from the freshly prepared
methylene Schiff base salts.
Scheme 5 Synthesis of N-[(dialkylamino)methyl)]acrylamides 8a-11a
and N-[(dialkylamino)methyl)]methacrylamides 8b-11b from the
freshly prepared Schiff base salts.
Conclusions
Readily accessible methylene Schiff base (iminium) salts have
allowed the preparation of eighteen previously inaccessible
acrylamides and methacrylamides containing methylene N-amino
groups (both heterocyclic and acyclic). Heterocyclic substituted
monomer syntheses have the added advantage of allowing the
isolation of the monomer hydrochloride salt intermediate useful for
polymerizations in water. For the preparation of monomers
substituted with azepane, azocane, and alicyclic derivatives, the
iminium salts should be first isolated, prior to reactions with
acrylamide and methacrylamide. Syntheses occur at low or ambient
temperatures avoiding premature polymerization of vinyl
compounds. Iminium salts are however hygroscopic and X-ray
crystal structure of the hydrated eight-membered Schiff base salt,
1-(hydroxymethyl)azocan-1-ium chloride (5b), and related
monomer, N-[(azocan-1-yl)methyl]prop-2-enamide hydrochloride
(7a.HCl) are described. Future research will involve controlled
radical polymerizations of this new vinyl monomer class to give
amphiphilic block copolymers for use as smart stimuli (temperature,
pH, CO2)-responsive materials.
Fig. 5 The X-ray crystal structure of N-[(azocan-1-yl)methyl]prop-2-
enamide hydrochloride (7a.HCl) with one molecule from the
asymmetric unit shown.
For the preparation of N-dialkyl amino substituted monomers, N-
[(dialkylamino)methyl)]acrylamides 8a-11a and N-[(dialkylamino)-
methyl)]methacrylamides 8b-11b, freshly prepared acyclic Schiff
base salts 4c-4f were reacted with acrylamide and methacrylamide
in acetonitrile at room temperature (Scheme 5). In this case, the
isolation of the N-dialkyl amino substituted monomer hydrochloride
salts proved difficult due to appreciable solubility in the reaction
solvent and attempted precipitation solvents (including diethyl
ether). Thus basification of the reaction mixture was preferred and
the free monomer bases were isolated in multi-gram quantities (22
- 49 g) in yields of 69-90% without the isolation of the intermediate
salts.
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characterized. An aqueous solution of Na2CO3 (100VmiewL,Ar3ticMle)Ownlianes
DOI: 10.1039/C8OB00811F
added to a suspension of the hydrochloride salt in CH2Cl2 (100 mL)
Experimental
General Information
Melting points were measured on a Stuart Scientific melting point
apparatus SMP1. Infrared spectra were recorded using a Perkin-
and stirred for 30 min. The organic layer was separated, and the
aqueous layer washed with CH2Cl2 (4 x 250 mL). The combined
organic extracts were dried (MgSO4), filtered, and evaporated to
1
Elmer Spec 1 with ATR attached. H NMR spectra were recorded at dryness to give the monomer, which was recrystallized.
400 or 500 MHz and 13C NMR were recorded at 101 or 125 MHz
2-Methyl-N-[(pyrrolidin-1-yl)methyl]prop-2-enamide
using JEOL ECX 400 MHz and Varian 500 MHz instrument
respectively. The chemical shifts were recorded in ppm relative to hydrochloride (2b.HCl). white solid; mp 131-133 °C (recryst. from
Me4Si. NMR assignments were supported by DEPT. Deuterated MeCN); 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.94 (m, 7H), 3.05-3.41
(m, 4H), 4.49 (d, J 6.7 Hz, 2H), 5.55-5.57 (m, 1H), 5.92-5.94 (m, 1H),
9.33-9.36 (t, J 6.7 Hz 1H, NH), 10.61-10.94 (brs, 1H, NH); 13C NMR
solvents were used for homonuclear lock, and the signals were
referenced to the deuterated solvent peaks. 1,4-Dioxane was used
as a reference for 13C NMR in D2O. High resolution mass spectra (101 MHz, DMSO-d6) δ 18.4 (Me), 22.9, 50.4, 56.4, 122.0 (all CH2),
(HRMS) were carried out using ESI time-of-flight mass spectrometer 138.4 (C), 168.8 (C=O).
2-Methyl-N-[(pyrrolidin-1-yl)methyl]prop-2-enamide (2b). (30.29
(TOFMS) in positive mode. The precision of all accurate mass
measurements was better than
performed under inert conditions.
5
ppm. All reactions were g, 90%), white solid; mp 56-58 °C (recryst. from MeCN); vmax (neat,
cm-1) 3215, 2962, 2819, 1655, 1619, 1521 (C=O), 1450, 1362, 1356,
1
1299, 1208, 1134, 1046; H NMR (400 MHz, CDCl3) δ 1.75-1.79 (m,
4H), 1.96 (s, 3H), 2.62 (t, J 6.4 Hz, 4H), 4.24 (dd, J 0.7, 6.2 Hz, 2H),
Materials
5.33-5.34 (m, 1H), 5.69-5.70 (m, 1H), 6.17-6.31 (brs, 1H, NH); 13C
All chemicals were obtained from commercial sources. Aminals, NMR (101 MHz, CDCl3) δ 18.8 (Me), 23.7, 51.0, 58.6, 119.8 (all CH2),
140.1 (C), 168.7 (C=O); HRMS (ESI) m/z [M+H]+, C9H17N2O calcd.
1,1′-methylenedipyrrolidine,16 1,1′-methylenedipiperidine,17 1,1′-
methylenebis(azepane),31 N,N,N',N'-tetramethylmethanediamine,16 169.1341 observed 169.1334.
N,N,N',N'-tetraethylmethanediamine,16 and N,N,N',N'-tetrapropyl- 2-Methyl-N-[(piperidin-1-yl)methyl]prop-2-enamide hydrochloride
1
methanediamine31 were readily prepared in high yields from the
(3b.HCl). white solid; mp 143-145 °C (recryst. from MeCN); H NMR
(400 MHz, DMSO-d6) δ 1.34-1.76 (m, 6H), 1.91 (s, 3H), 2.82-2.85 (m,
reaction of formaldehyde (Sigma-Aldrich, 37 wt. % in H2O) with the
appropriate secondary amine accordingly to literature procedures. 2H), 3.26-3.29 (m, 2H), 4.42 (d, J 6.6 Hz, 2H), 5.56 (s, 1H), 5.92 (s,
Distilled aminals were stored under vacuum and dry atmospheres in 1H), 9.13 (t, J 6.6 Hz, 1H, NH), 10.12-10.32 (brs, 1H, NH); 13C NMR
(101 MHz, DMSO-d6) δ 18.4 (Me), 21.2, 22.1, 49.7, 59.1, 121.9 (all
desiccators at room temperature. Heptamethyleneimine (Sigma-
Aldrich, 98%), acetyl chloride (AcCl, Sigma-Aldrich, 98%), acrylamide CH2), 138.4 (C), 168.7 (C=O).
(Sigma-Aldrich, 97%), and methacrylamide (Sigma-Aldrich, 98%) 2-Methyl-N-[(piperidin-1-yl)methyl]prop-2-enamide (3b). (33.54 g,
92%), white solid; mp 67-69 °C (recryst. from MeCN); vmax (neat, cm-
were used as received. CH2Cl2 (Sigma-Aldrich, ≥99%), CDCl3 (Sigma-
1) 3353, 2934, 2852, 1671 (C=O), 1655, 1615, 1453, 1453, 1440,
Aldrich, 99.8 atom%), D2O (Sigma-Aldrich, 99.9 atom%), KOH pellets
1
(Sigma-Aldrich, ≥85%), Na2CO3 (Sigma-Aldrich, ≥99%), and MgSO4 1368, 1333, 1306, 1158, 1110, 1034; H NMR (400 MHz, CDCl3) δ
(Sigma-Aldrich, ≥99.99%) were used as received. The synthesis of N- 1.38-1.44 (m, 2H), 1.54-1.59 (m, 4H), 1.95 (s, 3H), 2.45-2.59 (m, 4H),
4.10 (d, J 6.4 Hz, 2H), 5.34 (s, 1H), 5.71 (s, 1H), 6.29-6.38 (brs, 1H,
[(morpholin-4-yl)methyl]prop-2-enamide 1a, 2-methyl-N-[(morpho-
lin-4-yl)methyl]prop-2-enamide 1b, N-[(pyrrolidin-1-yl)methyl]prop- NH); 13C NMR (101 MHz, CDCl3) δ 18.8 (Me), 24.2, 25.9, 51.6, 62.4,
2-enamide 2a and N-(piperidin-1-ylmethyl)prop-2-enamide 3a is 119.8 (all CH2), 140.2 (C), 168.9 (C=O); HRMS (ESI) m/z [M+H]+,
included in our recent communication.14 For Schiff base salt and
C10H19N2O calcd. 183.1497 observed 183.1493.
monomer synthesis all solvents were freshly distilled, and reactions
were carried out using anhydrous solvents using an inert nitrogen Synthesis of 1,1'-methylenebis(azocane)
atmosphere. Acetonitrile (MeCN, Sigma-Aldrich, ≥99.9%) was Heptamethyleneimine (15.0 g, 0.13 mol) was added over 30 min to
formaldehyde (37 wt. % in H2O, 6.2 mL, 0.07 mol) with stirring at ca.
ᴏC. The solution was stirred overnight at ca. 20 ᴏC, after which
freshly distilled over 3 Å molecular sieves and then CaH2 (Sigma-
Aldrich, 95%), and Et2O (Et2O, Sigma-Aldrich, ≥99.5%) was freshly
distilled over Na wire and benzophenone (Sigma-Aldrich, 95%).
0
KOH pellets were added to form a saturated solution, and stirring
was continued for 30 min. H2O (40 mL) was added and the mixture
extracted with Et2O (4 x 40 mL). The organic layers were combined
and washed with H2O (3 x 20 mL), dried (MgSO4), and evaporated to
dryness. Fractional distillation under reduced pressure gave the title
compound as colorless liquid (14.69 g, 88%); bp 138-140 °C (0.25
mmHg); vmax (neat, cm-1) 2915, 2846, 2779, 1657, 1472, 1448, 1358,
1250, 1158, 1094, 1046, 1017; 1H NMR (400 MHz, CDCl3) δ 1.51-1.68
(m, 20H), 2.53-2.60 (m, 8H), 3.02 (s, 2H); 13C NMR (101 MHz, CDCl3)
Synthesis of N-[(cycloalkylamino)methyl)]methacrylamides using
the in situ Schiff base salt approach
AcCl (14.30 mL, 0.20 mol) was added over 30 min to aminal (0.20
mol) in MeCN (40 mL) at ca. 0 °C. Methacrylamide (17.02 g, 0.20
mol) in MeCN (40 mL) was added, and stirred at ca. 20 °C for 2 h.
Et2O (200 mL) was added and the hydrochloride salt of the
monomer precipitated, filtered, and dried under vacuum. The
hydrochloride salts (1b.HCl-3b.HCl) were recrystallized, dried, and
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δ 26.1, 27.9, 28.2, 52.9, 83.8 (all CH2); HRMS (ESI) m/z [M+H]+, N,N-Dibutylmethaniminium chloride (4f)35 (white sVoieliwd,Art4ic4le.7O8nlinge,
84%) was characterized as N-butyl-N-(hDyOdrI:o1x0y.1m0e39th/Cy8l)ObBu0ta0n81-11F-
aminium chloride (5f). H NMR (400 MHz, D2O) δ 0.93 (t, J 6.0 Hz,
C15H31N2, calcd. 239.2487, observed 239.2312.
1
6H), 1.39 (sext, J 6.0 Hz, 4H), 1.66 (quint, J 6.0 Hz, 4H), 3.04 (t, J 6.0
Hz, 4H), 4.83 (s, 2H); 13C NMR (101 MHz, D2O, 1,4-dioxane added) δ
13.4 (Me), 19.8, 28.2, 47.9, 82.4 (all CH2).
Synthesis of N,N,N',N'-tetrabutylmethanediamine
Dibutylamine (68.00 mL, 0.40 mol) was added over 30 min to
formaldehyde (37 wt. % in H2O, 15.00 mL, 0.20 mol) with stirring at
ca. 0 ᴏC. The solution was stirred overnight at ca. 20 ᴏC. KOH pellets
were added to form a saturated solution, and the drying agent was
removed by filtration. Fractional distillation under reduced pressure
gave the title compound as a colorless liquid (45.98 g, containing
about 10% by 1H NMR of suspected (dibutylamino)methanol
impurity); bp 112-114 °C (0.25 mmHg); 1H NMR (400 MHz, CDCl3) δ
0.89 (t, J 7.2 Hz, 12H), 1.28 (m, 8H), 1.33-1.41 (m, 8H), 2.42 (t, J 7.3
Hz, 8H), 2.98 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 14.3 (Me), 20.9,
29.5, 52.0, 75.6 (all CH2). HRMS (ESI) m/z [M+H]+, C17H39N2 calcd.
271.3113 observed 271.3143. The title compound was used
without further purification to prepare N,N-dibutylmethaniminium
chloride (4f).
Synthesis of seven and eight-membered N-[(cycloalkylamino)-
methyl)]acrylamides and N-[(cycloalkylamino)methyl)]methacryl-
amides
A solution of acrylamide or methacrylamide (0.03 mol) in MeCN (10
mL) was added to a solution of freshly prepared Schiff base salt 4a
or 4b (0.04 mol) in MeCN (30 mL) and stirred at ca. 20 °C for 4 h.
Et2O (200 mL) was added and the hydrochloride salt of the
monomer precipitated, filtered, and dried under vacuum. The
hydrochloride salt (6a.HCl-6b.HCl and 7a.HCl-7b.HCl) was
recrystallized, dried, and characterized. An aqueous solution of
Na2CO3 (15 mL, 3M) was added to
a suspension of the
hydrochloride salt in CH2Cl2 (20 mL) and left to stir for an additional
30 min and extracted with CH2Cl2 (4 x 50 mL). The organic layer was
dried (MgSO4), filtered and evaporated to dryness to give the
corresponding monomers 6a-6b and 7a-7b.
Synthesis of Schiff base salts
AcCl (21.33 mL, 0.3 mol) was added over 30 min to a stirred
solution of aminal (0.3 mol) in Et2O (150 mL) at ca. 0 ᴏC, and the
resulting white precipitate stirred for an additional of 30 min. Et2O
(200 mL) was added and the precipitate filtered, and dried under
vacuum to give the methylene Schiff-base salt (4a-4f). Iminium salts
4a-4f were immediately used in addition reactions with acrylamide
and methacrylamide due to their hygroscopic nature.
N-[(Azepan-1-yl)methyl]prop-2-enamide hydrochloride (6a.HCl).
white solid; mp 136-138 °C (recryst. from MeCN); 1H NMR (400
MHz, DMSO-d6) δ 1.55-1.62 (m, 4H), 1.79-1.82 (m, 4H), 3.03-3.09
(m, 2H), 3.23-3.32 (m, 2H), 4.49 (d, J 6.8 Hz, 2H), 5.80 (dd, J 1.9, 10.2
Hz, 1H), 6.26 (dd, J 1.9, 17.2 Hz, 1H), 6.41 (dd, J 10.2, 17.2 Hz, 1H),
9.53 (t, J 6.8 Hz, 1H, NH), 10.46-10.63 (brs, 1H, NH); 13C NMR (101
MHz, DMSO-d6) δ 22.9, 26.1, 51.3, 59.2, 128.2 (all CH2), 130.4 (CH),
166.2 (C=O).
1-Methylideneazepan-1-ium chloride (4a) (white solid, 43.85 g,
99%) was characterized as N-(hydroxymethyl)azepan-1-ium
1
chloride (5a). H NMR (400 MHz, D2O) δ 1.63-1.66 (m, 4H), 1.78-
N-[(Azepan-1-yl)methyl]prop-2-enamide (6a). (4.81 g, 88%)
colourless liquid; bp 134-136 °C (0.25 mmHg); vmax (neat, cm-1)
3278, 2922, 2852, 2852, 1656 (C=O), 1623, 1539, 1452, 1405, 1365,
1.85 (brs, 4H), 3.17-3.21 (m, 4H), 4.77 (d, J 0.8 Hz, 2H); 13C NMR
(101 MHz, D2O, 1,4-dioxane added) δ 25.2, 26.6, 46.8, 82.4 (all CH2).
1-Methylideneazocan-1-ium chloride (4b) (white solid, 47.04 g,
97%) was characterized as N-(hydroxymethyl)azocan-1-ium
1
1309, 1227, 133, 1080; H NMR (400 MHz, CDCl3) δ 1.52-1.61 (m,
8H), 2.68 (t, J 5.6 Hz, 4H), 4.23 (d, J 6.2 Hz, 2H), 5.61 (dd, J 1.6, 10.2
Hz, 1H), 6.11 (dd, J 10.2, 17.0 Hz, 1H), 6.25 (dd, J 1.6, 17.0 Hz, 1H),
6.31-6.40 (brs, 1H, NH); 13C NMR (101 MHz, CDCl3) δ 26.9, 28.6,
53.1, 62.6, 126.7 (all CH2), 131.1 (CH), 166.1 (C=O); HRMS (ESI) m/z
[M+H]+, C10H19N2O calcd. 183.1497 observed 183.1516.
1
chloride (5b). H NMR (500 MHz, D2O) δ 1.57-1.67 (m, 6H), 1.81-
1.86 (m, 4H), 3.21 (t, J 5.8 Hz, 4H), 4.74 (s, 2H); 13C NMR (125 MHz,
D2O, 1,4-dioxane added) δ 23.9, 24.8, 25.2, 45.8, 82.4 (all CH2).
N,N-Dimethylmethaniminium chloride (4c)32 (white solid, 23.85 g,
85%) was characterized as hydroxy-N,N-dimethylmethanaminium
N-[(Azepan-1-yl)methyl]-2-methylprop-2-enamide hydrochloride
(6b.HCl). white solid; mp 88-90 °C (recryst. from THF); 1H NMR (400
MHz, DMSO-d6) δ 1.53-1.64 (m, 4H), 1.79-1.81 (m, 4H), 1.91 (s, 3H),
3.02-3.15 (m, 2H), 3.23-3.30 (m, 2H), 4.46 (d, J 4.3 Hz, 2H), 5.57 (s,
1
chloride (5c). H NMR (400 MHz, D2O) δ 2.79 (s, 6H), 4.56 (s, 2H);
13C NMR (101 MHz, D2O, 1,4-dioxane added) δ 35.2 (Me), 82.4
(CH2).
N,N-Diethylmethaniminium chloride (4d)33 (white solid, 31.74 g, 1H), 5.92 (s, 1H), 9.19 (m, 1H, NH), 10.28-10.44 (brs, 1H, NH); 13C
NMR (101 MHz, DMSO-d6) δ 18.4 (Me), 22.8, 26.2, 51.4, 59.7, 122.0
(all CH2), 138.4 (C), 168.7 (C=O).
87%) was characterized as N-ethyl-N-(hydroxymethyl)ethan-
1
aminium chloride (5d). H NMR (400 MHz, D2O) δ 1.23 (t, J 7.3 Hz,
N-[(Azepan-1-yl)methyl]-2-methylprop-2-enamide (6b). (5.36 g,
6H), 3.00-3.07 (m, 4H), 4.78 (s, 2H); 13C NMR (101 MHz, D2O, 1,4-
91%) colourless liquid; bp 139-141 °C (0.25 mmHg); vmax (neat, cm-1)
dioxane added) δ 11.2 (Me), 42.9, 82.4 (both CH2).
3328, 2923, 2852, 1655, 1616 (C=O), 1526, 1373, 1313, 1201, 1133,
N,N-Dipropylmethaniminium chloride (4e)34,35 (white solid, 40.85 g,
91%) was characterized as N-(hydroxymethyl)-N-propylpropan-1-
1
1088, 1020; H NMR (400 MHz, CDCl3) δ 1.56-1.68 (m, 8H), 1.96 (s,
1
3H), 2.72 (t, J 5.5 Hz, 4H), 4.24 (d, J 6.1 Hz, 2H), 5.33 (s, 1H), 5.69 (s,
aminium chloride (5e). H NMR (400 MHz, D2O) δ 0.92 (t, J 7.6 Hz,
6H), 1.65 (sext, J 7.6 Hz, 4H), 2.95 (t, J 7.6 Hz, 4H), 4.78 (s, 2H); 13C 1H), 6.12-6.22 (brs, 1H, NH); 13C NMR (101 MHz, CDCl3) δ 18.8 (Me),
NMR (101 MHz, D2O, 1,4-dioxane added) δ 10.8 (Me), 19.7, 49.7,
82.4 (all CH2).
27.0, 28.6, 53.2, 62.7, 119.6 (all CH2), 140.3 (C), 168.8 (C=O); HRMS
(ESI) m/z [M+H]+, C11H21N2O calcd. 197.1654 observed 197.1708.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
N-[(Azocan-1-yl)methyl]prop-2-enamide hydrochloride (7a.HCl). 6H), 4.03 (d, J 6.3 Hz, 2H), 5.30 (s, 1H), 5.66 (s, 1H), 6.31-6.45 (brs,
View Article Online
DOI: 10.1039/C8OB00811F
1
13
white solid; mp 87-89 °C (recryst. from EtOAc); H NMR (400 MHz, 1H); C NMR (101 MHz, CDCl3) δ 18.7, 42.3 (both Me), 62.2, 119.5
DMSO-d6) δ 1.43-1.70 (m, 6H), 1.76-1.96 (m, 4H), 3.10-3.16 (m, 2H), (all CH2), 140.1 (C), 169.0 (C=O); HRMS (ESI) m/z [M+H]+, C7H15N2O
3.22-3.32 (m, 2H), 4.48-4.68 (m, 2H), 5.69 (d, J 10.1 Hz, 1H), 6.25 (d, calcd 143.1184, observed 143.1180.
J 17.1 Hz, 1H), 6.43 (dd, J 10.1, 17.1 Hz, 1H), 9.58-9.67 (m, 1H, NH), N-[(Diethylamino)methyl]prop-2-enamide (9a). (32.39 g, 83%)
10.25-10.38 (brs, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ 22.1, yellow oil; bp 65-67 °C (0.25 mmHg); vmax (neat, cm-1) 3289, 2969,
24.0, 25.1, 48.8, 59.2, 128.2 (all CH2), 130.4 (CH), 166.2 (C=O).
2828, 1657 (C=O), 1624, 1536, 1464, 1233, 1206, 1067; 1H NMR
N-[(Azocan-1-yl)methyl]prop-2-enamide (7a). (5.30 g, 90%) (400 MHz, CDCl3) δ 1.08 (t, J 7.2 Hz, 6H), 2.56 (q, J 7.2 Hz, 4H), 4.29
colourless oil; vmax (neat, cm-1) 3328, 2917, 2850, 1657 (C=O), 1624, (d, J 6.1 Hz, 2H), 5.64 (dd, J 1.4, 10.2 Hz, 1H), 5.90-5.99 (brs, 1H),
1
1536, 1363, 1232, 1162, 1095, 1060; H NMR (400 MHz, CDCl3) δ 6.09 (dd, J 10.2, 17.0 Hz, 1H), 6.28 (dd, J 1.4, 17.0 Hz, 1H); 13C NMR
1.50-1.62 (m, 10H), 2.62-2.70 (m, 4H), 4.27 (d, J 6.0 Hz, 2H), 5.65 (d, (101 MHz, CDCl3) δ 12.7 (Me), 45.4, 56.9, 126.6 (all CH2), 131.0 (CH),
J 10.2 Hz, 1H), 5.91-6.02 (brs, 1H), 6.10 (dd, J 10.2, 17.0 Hz, 1H), 166.1 (C=O); HRMS (ESI) m/z [M+H]+, C8H17N2O, calcd. 157.1341,
6.28 (d, J 17.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 26.1, 27.7, 28.0, observed 157.1337.
51.6, 62.6, 126.7 (all CH2), 131.2 (CH), 166.0 (C=O); HRMS (ESI) m/z N-[(Diethylamino)methyl]-2-methylprop-2-enamide (9b). (33.21 g,
[M+H]+, C11H21N2O, calcd. 197.1656, observed 197.1654.
78%) colourless liquid, bp 72-74 °C (0.25 mmHg); vmax (neat, cm-1)
N-[(Azocan-1-yl)methyl]-2-methylprop-2-enamide hydrochloride 3344, 2970, 2827, 1656 (C=O), 1617, 1522, 1455, 1375, 1197, 1066,
(7b.HCl). white solid; mp 128-130 °C (recryst. from EtOAc); H NMR 1046; 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J 7.2 Hz, 6H), 1.90 (s, 3H),
1
(400 MHz, DMSO-d6) δ 1.46-1.75 (m, 6H), 1.81-1.99 (m, 7H), 3.07- 2.52 (q, J 7.2 Hz, 4H), 4.22 (d, J 6.0 Hz, 2H), 5.27 (s, 1H), 5.63 (s, 1H),
3.18 (m, 2H), 3.23-3.35 (m, 2H), 4.45-4.53 (m, 2H), 5.70 (s, 1H), 5.93 6.11-6.21 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ 12.7, 18.8 (both
(s, 1H), 9.17-9.27 (brs, 1H, NH), 9.94-10.09 (brs, 1H, NH); 13C NMR Me), 45.4, 57.3, 119.5 (all CH2), 140.2 (C), 168.9 (C=O); HRMS (ESI)
(101 MHz, DMSO-d6) δ 18.4 (Me), 22.2, 24.0, 25.0, 48.9, 59.8, 122.0 m/z [M+H]+, C9H19N2O calcd. 171.1497, observed 171.1789.
(all CH2), 138.4 (C), 168.6 (C=O).
N-[(Dipropylamino)methyl]prop-2-enamide (10a). (37.80 g, 82%)
N-[(Azocan-1-yl)methyl]-2-methylprop-2-enamide (7b). (5.30 g, colourless plates, mp 25-26 °C; vmax (neat, cm-1) 3269, 2959, 2930,
84%) colourless oil; vmax (neat, cm-1) (neat, cm-1) 3324, 2918, 2850, 1657 (C=O), 1623, 1550, 1457, 1246, 1185, 1069; 1H NMR (500 MHz,
1655, 1618 (C=O), 1523, 1452, 1363, 1201, 1162, 1095, 1060; 1H CDCl3) δ 0.82 (t, J 7.4 Hz, 6H), 1.44 (sext, J 7.4 Hz, 4H), 2.39 (t, J 7.4
NMR (400 MHz, CDCl3) δ 1.49-1.59 (m, 10H), 1.93 (s, 3H), 2.61-2.66 Hz, 4H), 4.23 (d, J 6.0 Hz, 2H), 5.58 (dd, J 1.6, 10.2 Hz, 1H), 6.11 (dd,
(m, 4H), 4.21 (t, J 4.3 Hz, 2H), 5.28 (s, 1H), 5.64 (s, 1H), 6.12-6.26 J 10.2, 17.0 Hz, 1H), 6.22 (dd, J 1.6, 17.0 Hz, 1H), 6.28-6.39 (brs, 1H);
(brs, 1H, NH); 13C NMR (101 MHz, CDCl3) δ 18.8 (Me), 26.0, 27.7, 13C NMR (125 MHz, CDCl3) δ 11.9 (Me), 20.9, 54.0, 58.1, 126.5 (all
28.0, 51.5, 62.7, 119.2 (all CH2), 140.4 (C), 168.9 (C=O); HRMS (ESI) CH2), 131.1 (CH DEPT up issue), 166.1 (C=O); HRMS (ESI) m/z
m/z [M+H]+, C12H23N2O, calcd. 211.1838, observed 211.1810.
[M+H]+, C10H21N2O calcd. 185.1654, observed 185.1663.
N-[(Dipropylamino)methyl]-2-methylprop-2-enamide (10b). (43.62
Synthesis of N-[(dialkylamino)methyl)]acrylamides and N-[(dialkyl- g, 88%) colourless liquid, bp 86-88 °C (0.25 mmHg); vmax (neat, cm-1)
amino)methyl)]methacrylamides
3316, 2959, 2934, 2873, 1655 (C=O), 1619, 1524, 1456, 1374, 1183,
1
A solution of acrylamide or methacrylamide (0.25 mol) in MeCN (50 1075, 1052; H NMR (400 MHz, CDCl3) δ 0.85 (t, J 7.4 Hz, 6H), 1.46
mL) was added to a stirred solution of freshly prepared Schiff base (sext, J 7.4 Hz, 4H), 1.93 (s, 3H), 2.42 (t, J 7.4 Hz, 4H), 4.22 (d, J 6.0
salt 4c-4f (0.25 mol) in MeCN (50 mL) and stirred at ca. 20 °C for 3 Hz, 2H), 5.29 (s, 1H), 5.65 (s, 1H), 6.02-6.15 (brs, 1H); 13C NMR (101
h. An aqueous solution of Na2CO3 (150 mL, 3M) was added and the MHz, CDCl3) δ 11.9, 18.8 (both Me), 20.9, 54.1, 58.5, 119.4 (all CH2),
solution stirred for an additional of 30 min and extracted with 140.3 (C), 168.9 (C=O); HRMS (ESI) m/z [M+H]+, C11H23N2O calcd.
MeCN (4 x 250 mL). The organic layer was dried (MgSO4), filtered 199.1810, observed 199.1800.
and evaporated to give the corresponding acrylamides 8a-11a and N-[(Dibutylamino)methyl]prop-2-enamide (11a). (44.56 g, 84%)
methacrylamides 8b-11b.
colourless liquid, bp 124-126 °C (0.25 mmHg); vmax (neat, cm-1)
3281, 3069, 2957, 2863, 1658 (C=O), 1625, 1542, 1456, 1459, 1366,
1
N,N-[(Dimethylamino)methyl]prop-2-enamide (8a). (22.11 g, 69%) 1180, 1071; H NMR (400 MHz, CDCl3) δ 0.89 (t, J 7.3 Hz, 6H), 1.24-
colourless liquid; bp 64-66 °C (760 mmHg); vmax (neat, cm-1) 3281, 1.33 (m, 4H), 1.40-1.47 (m, 4H), 2.45 (t, J 7.5 Hz, 4H), 4.26 (d, J 6.0
2942, 2827, 2780, 1659 (C=O), 1625, 1536, 1407, 1230, 1029; 1H Hz, 2H), 5.63 (dd, J 1.5, 10.2 Hz, 1H), 5.88-6.00 (brs, 1H), 6.10 (dd, J
NMR (400 MHz, CDCl3) δ 2.24 (s, 6H), 4.05 (d, J 6.4 Hz, 2H), 5.62 (dd, 10.2, 17.0 Hz, 1H), 6.27 (dd, J 1.5, 17.0 Hz, 1H); 13C NMR (101 MHz,
J 1.6, 10.2 Hz, 1H), 6.12 (dd, J 10.2, 17.0 Hz, 1H), 6.26 (dd, J 1.6, 17.0 CDCl3) δ 14.1 (Me), 20.7, 30.0, 51.9, 58.3, 126.7 (all CH2), 131.0
Hz, 1H), 6.71-6.82 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ 41.8 (Me), (CH), 166.0 (C=O); HRMS (ESI) m/z [M+H]+, C12H25N2O calcd
61.5, 126.0 (both CH2), 130.7 (CH), 166.2 (C=O); HRMS (ESI) m/z 213.1967, observed 213.1952.
[M+H]+, C6H13N2O, calcd. 129.1028, observed 129.1026.
N-[(Dibutylamino)methyl]-2-methylprop-2-enamide (11b). (49.21
N,N-[(Dimethylamino)methyl]-2-methylprop-2-enamide
(8b). g, 87%) colourless liquid, bp 133-135 °C (0.25 mmHg); vmax (neat,
(32.10 g, 90%) colourless liquid, bp 60-62 °C (0.25 mmHg); vmax cm-1) 3325, 2957, 2931, 2872, 1625 (C=O), 1525, 1456, 1374, 1296,
(neat, cm-1) 3323, 2942, 2827, 1658 (C=O), 1619, 1523, 1453, 1311, 1179, 1083, 1034; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J 7.4 Hz, 6H),
1
1196, 1049, 1033; H NMR (400 MHz, CDCl3) δ 1.92 (s, 3H), 2.23 (s, 1.25-1.34 (m, 4H), 1.40-1.47 (m, 4H), 1.95 (s, 3H), 2.46 (t, J 7.4 Hz,
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Journal Name
4H), 4.24 (d, J 5.9 Hz, 2H), 5.32 (s, 1H), 5.66 (s, 1H), 5.98-6.06 (brs,
1H); 13C NMR (101 MHz, CDCl3) δ 14.1, 18.8 (both Me), 20.7, 30.0,
51.9, 58.6, 119.4 (all CH2), 140.4 (C), 168.9 (C=O); HRMS (ESI) m/z
[M+H]+, C13H27N2O calcd. 227.2123, observed 227.2129.
Notes and references
View Article Online
DOI: 10.1039/C8OB00811F
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Single Crystal X-ray Diffraction data was collected using an Oxford
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before being transferred to the cold stream on the diffractometer.
The crystal structures were solved using ShelxT version 2014/5,37
and refined using ShelxL version 2017/138 both of which were
operated within the Oscail software package.39
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Crystal Refinement Data for 1-(hydroxymethyl)azocan-1-ium
chloride (5b). Colourless crystals, C8H18ClNO,
M = 179.68,
Monoclinic, space group P21/c, a = 11.3190(18) , b = 10.9194(16) , c
= 7.7658(10) Å, α = 90, β = 90.269(13), γ = 90°, V = 959.8(2) Å3, Z = 4,
T = 150.0(1) K, ρcalcd = 1.243 g cm−3, Refinement of 147
parameters on 2345 independent reflections out of 7528 measured
reflections (Rint = 0.0709) led to R1 = 0.0857 (I > 2σ(I)), wR2 =
0.2182 (all data), and S = 1.119 with the largest difference peak and
hole of 0.396 and −0.398 e Å −3
.
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Crystal Refinement Data for N-[(azocan-1-yl)methyl]prop-2-
enamide hydrochloride (7a.HCl). Colourless needle crystals,
C11H21ClN2O, M = 232.75, Triclinic, space group P-1, a = 10.1121(7) ,
b = 10.4420(6) , c = 12.0205(14) Å, α = 95.695(8), β = 91.086(8), γ =
97.671(5)°, V = 1251.02(19) Å3, Z = 4, T = 150.0(1) K, ρcalcd = 1.236
g cm−3, Refinement of 271 parameters on 4487 independent
reflections out of 7456 measured reflections (Rint = 0.0638) led to
R1 = 0.0684 (I > 2σ(I)), wR2 = 0.2128 (all data), and S = 0.979 with
https://doi.org/10.1002/anie.201100884
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the largest difference peak and hole of 0.852 and −0.705 e Å −3
.
Crystallographic data for compounds 5b and 7a.HCl have been
deposited with the Cambridge Crystallographic Data Centre with
deposit numbers CCDC-1819145 and CCDC-1819144 respectively.
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K.; fax +44 1223 336033; or e-mail deposit@ccdc.cam.ac.uk).
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Conflicts of interest
There are no conflicts to declare.
19. H. Böhme and P. Backhaus, Liebigs Ann. Chem., 1975, 1790-
1796. https://doi.org/10.1002/jlac.197519751007
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Acknowledgements
We thank the Minstry of Education of the Kingdom of Saudi Arabia
for supporting the PhD of Abdullah Alzahrani, and the Irish Research
Council (IRC) for Goverment of Ireland Postdoctoral Fellowships for
Styliana I. Mirallai and Benjamin A. Chalmers.
https://doi.org/10.1002/anie.197103301
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00811F
GRAPHICAL ABSTRACT for
Synthesis of N-[(dialkylamino)methyl)]acrylamides
and
N-
[(dialkylamino)methyl]methacrylamides from Schiff base salts: Useful
building blocks for smart polymers
Abdullah Alzahrani,a Styliana I. Mirallai,*a Benjamin A. Chalmers,a Patrick McArdlea and
Fawaz Aldabbagh*a,b
Methylene Schiff base salts are characterized as N-hydroxymethyl hydrochlorides and used as
substrates under dry conditions for the synthesis of N-amino methylated acrylamides and
methacrylamides