Facile Preparation of N-Vinylisobutyramide and N-Vinyl-2-pyrrolidinone

Article abstract of DOI:10.1021/acs.oprd.5b00303

A facile synthesis of N-vinylakylamides from commercially available N-vinylformamide and corresponding acyl chlorides was developed and exemplified by the preparation of N-vinylisobutyramide (NVIBA) and N-vinyl-2-pyrrolidinone (NVP) in high yields (80-89%). Both NVIBA and NVP are valuable monomers for water-soluble polymers with an array of applications in personal care, pharmaceutical, agricultural, and industrial products.

Full text of DOI:10.1021/acs.oprd.5b00303

Article
pubs.acs.org/OPRD
Facile Preparation of N‑Vinylisobutyramide and N‑Vinyl-2-
pyrrolidinone
Siyu Tu* and Chunming Zhang*
Corporate R&D, The Dow Chemical Company, 1710 Building, Midland, Michigan 48764, United States
S
* Supporting Information
ABSTRACT: A facile synthesis of N-vinylakylamides from commercially available N-vinylformamide and corresponding acyl
chlorides was developed and exemplified by the preparation of N-vinylisobutyramide (NVIBA) and N-vinyl-2-pyrrolidinone
(NVP) in high yields (80−89%). Both NVIBA and NVP are valuable monomers for water-soluble polymers with an array of
applications in personal care, pharmaceutical, agricultural, and industrial products.
Scheme 1. Synthetic Routes to N-Vinylalkylamide
INTRODUCTION
■
N-Vinylalkylamides are important monomers to N-vinyl-
alkylamide-based homopolymers and copolymers with a
broad range of applications of commercial significance. As an
example, poly(N-vinyl-2-pyrrolidinone) (PVP) is widely used
in personal care, pharmaceutical, agricultural, and industrial
products.1 Moreover, some water-soluble N-vinylalkylamide-
based polymers exhibit dramatic thermoresponsive properties2
that are of particular interest for potential biomedical
applications, including controlled drug delivery, regulating
enzyme activity, bioseparations, filtration, and smart surfaces.3
Among thermoresponsive poly(N-vinylalkylamides), poly(N-
vinylisobutyramide) (PNVIBA), a structural isomer of the
conventional thermoresponsive polymer poly(N-isopropylacry-
lamide) (PNIPAM),4 exhibits a sharp lower critical solution
temperature (LCST) of 39 °C2a (Figure 1), a potentially
valuable property for medical and biotechnological applications.
involves a simple N-acylation of N-vinylformamide and
subsequent selective removal of the formyl group (Scheme 1,
path d). Two valuable monomers, N-vinylisobutyramide and N-
vinyl-2-pyrrolidinone, are conveniently prepared in good yields.
Figure 1. Chemical structures of the repeat units of poly(N-
vinylisobutyramide) (PNVIBA) and poly(N-isopropylacrylamide)
(PNIPAM).
Nevertheless, much less attention has been given to PNVIBA
and other N-vinylalkylamide-based thermoresponsive polymers.
The overwhelming majority of studies of thermoresponsive
materials are based on PNIPAM. This could be partially due to
the limited accessibility to N-vinylalkylamide monomers.5 N-
Vinylamides are generally prepared by addition of amide to
acetylene,6 vinyl exchange,7 or pyrolysis of ethylidenebisamide8
or N-(α-methoxyethyl)alkylamide.9,10 However, these general
methods typically suffer from a limited substrate scope and
unsatisfactory yields (Scheme 1, paths a−c). Here, we describe
a facile one-pot preparation of N-vinylalkylamide monomers
from commercially available N-vinylformamide. The process
RESULTS AND DISCUSSION
■
N-Vinylisobutyramide. Our research program required a
substantial quantity of N-vinylisobutyramide (NVIBA) for
preparation of water-soluble polymers. Akashi et al. reported
a preparation of NVIBA by pyrolysis of (N-α-isopropoxyethyl)-
isobutyramide, which was obtained from the reaction of
isobutyramide with isopropanol and acetaldehyde in the
presence of conc. sulfuric acid. The pyrolysis of (N-α-
Received: September 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00303
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Scheme 2. Akashi’s Synthesis of N-Vinylisobutyramide (NVIBA)2a
a
isopropoxyethyl)isobutyramide was conducted at 500 °C under
Table 1. Preparation of N-Vinylisobutyramide
reduced pressure with only 20% yield (Scheme 2).2a
convenient and high yielding preparation was desired.
A
The formyl group of an N-formyl-N-acyl imide is known to
be more susceptible to an acid or base than other acyl groups
and can be selectively cleaved to render an amide.11 N-Formyl-
N-acyl imide can be prepared by N-acylation of a formamide
with an acyl chloride or a carboxylic anhydride in the presence
of a base.11,12 We were interested to examine such a
conventional transformation to prepare NVIBA: converting
N-vinylformamide (NVF) to the corresponding N-vinyl-N-
formylisobutyramide (NVFIBA), followed by selective removal
of the formyl moiety. This conventional strategy avoids harsh
and low yielding pyrolysis or costly transition metal catalyzed
vinyl exchange reactions and takes advantage of the commercial
availability of NVF, a versatile monomer produced by BASF
and others in tonne quantities.13
b
entry
solvent
base
NVIBA (%)
1
2
3
CH3CN
THF
K2CO3
KOtBu
Et3N
65
73
89
THF
a
Reactions were carried out using 1 equiv of NVF (100−200 mmol
scales), 1.1−1.2 equiv of isobutyryl chloride, and 1.2 equiv of base at 0
b
°C to room temperature. Isolated yield.
prepared in high yields (Scheme 3),15 which showed that this
methodology is also applicable for the preparation of N-
vinylarylamide and N-vinylcarbamate.
We first examined the preparation of NVFIBA by N-acylation
of N-vinylformamide (NVF). Treatment of NVF with
isobutyryl chloride using potassium carbonate (K2CO3) as
the base in acetonitrile (CH3CN) gave the desired
imideNVFIBA and a substantial amount of NVIBA, as indicated
by GC-MS analysis of the reaction mixture. The ratio of imide
NVFIBA to amide NVIBA was NVFIBA/NVIBA = 1.0:1.5
(noncalibrated GC area ratio). The formation of amide NVIBA
indicated that the formyl group of imide NVFIBA was
susceptible under the reaction conditions. Thus, instead of an
attempt to isolate imide NVFIBA, the resulting mixture was
subjected to hydrolysis by addition of an aqueous sodium
hydroxide (NaOH) solution, which afforded the desired
NVIBA in 65% isolated yield. Encouraged by this result, we
next examined use of other bases for the N-acylation of NVF to
improve the yield of NVIBA. When a solution of potassium t-
butoxide (KOtBu) in tetrahydrofuran (THF) was used as the
base, the reaction of NVF and isobutyryl chloride in THF gave
predominantly NVIBA. Only a trace amount of imide NVFIBA
was detected by GC-MS. NVIBA was isolated in a higher yield
(73%) after subsequent hydrolysis of the reaction mixture with
NaOH. When triethylamine (Et3N) was used as the base, the
reaction of NVF and isobutyryl chloride proceeded smoothly to
give imide NVFIBA, along with a small amount of NVIBA, in a
NVFIBA/NVIBA ratio of 16:1 (by GC analysis). Subsequent
hydrolysis of this reaction mixture with aqueous NaOH
afforded desired NVIBA in 89% isolated yield (Table 1). By
switching the base from K2CO3 to Et3N, the yield of NVIBA
was improved from 65 to 89%. A larger preparation of NVIBA
using 106.62 g (1.500 mol, 1 equiv) of NVF, 183.80 g (1.725
mol, 1.15 equiv) of isobutyryl chloride, 182.14 g (1.800 mol,
1.20 equiv) of Et3N, and 900.0 mL (4.500 mol, 3.00 equiv) of 5
N NaOH gave 157.40 g (93%) of NVIBA in 98% purity (by
GC analysis). This provided a simple and efficient process for
the preparation of NVIBA in high yields under mild conditions.
We also briefly examined the application of this simple
method to prepare other N-vinyl compounds. N-Vinyl-
benzylamide14 and isobutyl N-vinylcarbamate were similarly
Scheme 3. Preparation of N-Vinylbenzamide and Isobutyl N-
Vinylcarbamate15
N-Vinyl-2-pyrrolidinone. N-Vinyl-2-pyrrolidinone (NVP)
is considered to be the most valuable N-vinylamide monomer
in terms of significant commercial importance of PVP and
other NVP-based polymers, which have been widely used in
personal care, pharmaceutical, agricultural, and industrial
products.1 The development of new routes to NVP has been
continued since its first production at the beginning of World
War II in Germany, and numerous routes have been reported.16
We were interested in examining the synthesis of NVP from N-
vinylformamide (NVF) and 4-chlorobutyryl chloride, utilizing
the N-acylation−deformylation strategy described above. We
hypothesize that the hydrolysis of formyl group should lead to
the intramolecular cyclization to form NVP (Scheme 4).
Treatment of N-vinyformamide (NVF) with 4-chlorobutyryl
chloride in the presence of Et3N as base, however, resulted in a
sluggish reaction with multiple byproducts. Subsequent
hydrolysis with aqueous NaOH gave a low yield of NVP
(30% by GC analysis). Use of NaOtBu as the base also resulted
in a complicated reaction, with less than 30% (by GC analysis)
of the desired product. This issue was successfully addressed by
use of a catalytic amount of 4-dimethylaminopyrridine
(DMAP)17 in combination with Et3N as the base system,
which resulted in a clean reaction, leading to the formation of
98% (by GC analysis) of N-formyl-N-vinyl-4-chlorobutyryla-
B
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Scheme 4. Alternative Preparation of N-Vinyl-2-pyrrolidinone
mide and 2% (by GC analysis) of NVP. Subsequent treatment
of the reaction mixture with a solution of 50 wt % NaOH (3.5
equiv relevant to NVF) at 0−5 °C proceeded smoothly to give
the desired cyclization product NVP in 80% isolated yield. It
was noteworthy that the synthesis was also performed in a one-
pot fashion without the need for separation and isolation of
intermediate imide N-vinyl-N-formyl-4-chlorobutyramide. This
convenient synthesis provided a facile alternative route to N-
vinyl-2-pyrrolidinone.
distilled isobutyryl chloride (23.44 g, 220.0 mmol) in the
addition funnel was added at a rate such that the temperature
was maintained at 15−20 °C (30 min). The resulting mixture
was stirred overnight at ambient temperature (20−25 °C, 18
h). A drop of the reaction mixture was taken and diluted with
EtOAc (2 mL), and insolubles were filtered off. The aliquot was
then analyzed by GC-MS, which showed the presence of both
NVFIBA and NVIBA in a ratio of NVFIBA/NVIBA = 1.0:1.5
(noncalibrated GC area ratio). Water (120 mL) was added to
the reaction mixture to dissolve all of the solids, followed by
addition of 50 wt % NaOH (22.20 g, 278.0 mmol). The
mixture was stirred at ambient temperature until the imide
intermediate NVFIBA disappeared, as monitored by GC. The
water layer was removed and extracted with methylene chloride
(CH2Cl2, 100 mL × 2). The organic layers were combined and
washed with a solution of sat. NaCl (100 mL). The solvents
were evaporated using rotary evaporation under reduced
pressure. The residual oil was subjected to distillation under
reduced pressure to give the desired NVIBA (14.81 g, 65%
yield) as a colorless oil (bp 70−72 °C/1 mmHg), which
solidified at room temperature (mp 58−59 °C). 1H NMR (400
MHz, CDCl3) δ 7.23 (b, 1H), 7.09 (dd, J1 = 16.0 Hz, J2 = 8.8
Hz, 1H), 4.60 (d, J = 16.0 Hz, 1H), 4.40 (d, J = 8.8 Hz, 1H),
2.11 (sept, J = 7.2 Hz, 2H), 1.19 (d, J = 7.2 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 174.4, 128.8, 94.9, 35.6, 19.3.
Use of Potassium t-Butoxide (KOtBu) as the Base. In a 500
mL three-necked round-bottomed flask equipped with a stirrer,
an addition funnel, and a nitrogen pad was placed a solution of
1 N KOtBu in THF (250.0 mL, 250.0 mmol), and it was cooled
to 10 °C with an ice-water bath. Freshly distilled N-
vinylformamide (14.22 g, 200.0 mmol) in the addition funnel
was added at a rate such that the temperature was maintained
below 20 °C. The resulting mixture was stirred at 15−20 °C for
1 h. Then, freshly distilled isobutyryl chloride (23.44 g, 220.0
mmol) was added at 15−20 °C (30 min). The resulting mixture
was stirred overnight at ambient temperature (18 h). A drop of
the reaction mixture was taken and diluted with EtOAc (2 mL),
and the insolubles were filtered off. The aliquot was then
analyzed by GC-MS, which showed that NVIBA was the major
product, along with only a trace amount of imide NVFIBA.
Thus, the reaction was quenched by addition of 50 wt % NaOH
(20.00 g, 250.0 mmol) and water (50 mL) at 15 °C. After
stirring for 4 h at ambient temperature, the mixture was set for
phase separation. The water layer was removed and extracted
with methylene chloride (CH2Cl2, 100 mL × 2). The organic
layers were combined and washed with a solution of sat. NaCl
(100 mL). The solvents were evaporated using rotary
evaporation under reduced pressure. The residual oil was
distilled under reduced pressure to give the desired NVIBA
(16.41 g, 73% yield) as a colorless oil (70−75 °C/mmHg),
which solidified at room temperature (mp 58−59 °C). The 1H
and 13C NMR spectra were consistent with those from the
compound synthesized above.
CONCLUSIONS
■
We have developed a facile one-pot synthesis of NVIBA, a
valuable monomer for water-soluble thermoresponsive poly-
mers, by taking advantage of a convenient N-acylation of
commercially available, inexpensive N-vinylformamide and easy
removal of the formyl moiety under mild conditions. N-
Acylation of N-vinylformamide with isobutyric chloride in the
presence of a base (KOtBu, K2CO3, or Et3N) gave imide
NVFIBA, which without separation and isolation was selectively
hydrolyzed with aqueous NaOH to produce N-vinylisobutyr-
amide in 65 to 89% isolated yields. This provides convenient
and efficient synthesis of N-vinylalkylamides. Moreover, this
strategy was successfully applied to the synthesis of N-vinyl-2-
pyrrolidinone, the most applicable N-vinylamide monomer,
from N-vinylformamide and 4-chlorobutyryl chloride in a good
yield (80%), leading to a facile alternative approach to N-vinyl-
2-pyrrolidinone.
EXPERIMENTAL SECTION
■
Solvents and common reagents were purchased from either
Fisher or Sigma-Aldrich and were used as received unless
otherwise noted. N-Vinylformamide, isobutyryl chloride, and 4-
chlorobutyryl chloride were purchased from Sigma-Aldrich and
distilled prior to use. All reactions were performed under an
atmosphere of nitrogen and were monitored by thin-layer
chromatography (TLC) and/or gas chromatography (GC)-
mass spectra (MS). GC samples were analyzed on an Agilent
Technologies 6890 GS system using a J&W DB-5 capillary
column. Mass spectra data was obtained using an Agilent
Technologies inert mass selective detector (70 eV, EI). 1H and
13C NMR spectra were recorded in CDCl3 on a Bruker-400
(FT 400 MHz, 1H; 101 MHz, 13C) instrument. Chemical shifts
(δ) are reported in parts per million (ppm) and are referenced
to the residual solvent peak. The order of citation in
parentheses is (1) multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, quint = quintet, sext = sextet, sept = septet,
m = multiplet, b = broad), (2) coupling constant (J) quoted in
hertz to the nearest 0.1 Hz, and (3) the number of equivalent
nuclei (by integration).
Preparation of N-Vinylisobutyamide. Use of Potassium
Carbonate (K2CO3) as the Base. In a 500 mL three-necked
round-bottomed flask equipped with a stirrer, an addition
funnel, and a nitrogen pad was placed anhydrous K2CO3
powder (41.46 g, 300.0 mmol), freshly distilled N-vinyl-
formamide (14.22 g, 200.0 mmol), and anhydrous acetonitrile
(150 mL), and it was cooled with an ice water bath. Freshly
Use of Triethylamine as the Base. Freshly distilled N-
vinylformamide (14.22 g, 200.0 mmol), triethylamine (24.29 g,
240.0 mmol), and anhydrous THF (150 mL) were added to a
C
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500 mL three-necked round-bottomed flask equipped with a
magnetic stirrer, a thermometer, and a nitrogen pad. The
resulting mixture was cooled to 0 °C in an ice-water bath.
Freshly distilled isobutyryl chloride (24.51 g, 230.0 mmol) was
slowly added through a syringe pump at a rate such that the
temperature was maintained below 5 °C over 30 min. The
resulting reaction mixture was stirred at 0−5 °C for 2 h. A drop
of the reaction mixture was taken and diluted with EtOAc (2
mL), and the insolubles were filtered off. The aliquot was then
analyzed by GC-MS, which showed that the reaction was
complete, resulting in mainly NFVIBA and a small amount of
NVIBA, in a ratio of NVFIBA/NVIBA = 16:1 (by GC analysis).
A solution of 5 N NaOH (120 mL, 600.0 mmol) was then
slowly added at 0−5 °C over 2 h. The resulting thick mixture
was stirred at 0−5 °C until all of the imide NVFIBA
disappeared, as monitored by GC (1−2 h). The water layer
was removed and extracted with EtOAc (100 mL × 2). The
organic layers were combined and washed with a solution of
sat. NaCl (150 mL). The solvents were evaporated under
reduced pressure using rotary evaporation. The residual oil was
purified by distillation to give NVIBA (20.14 g, 89% yield) as a
colorless oil, which solidified at room temperature. The 1H and
13C NMR spectra were consistent with those from the
compound synthesized above.
mmol) was then added through a syringe pump at 0−5 °C over
30 min. The resulting mixture was stirred for 1 h. A sample was
taken and analyzed by GC-MS, which showed the formation of
95% (by GC analysis) NVP and 5% (by GC analysis)
impurities. DI water (50 mL) was added to dissolve the solid.
The water layer was removed and extracted with EtOAc (100
mL × 2). The organic layers were combined and washed with
sat. NaCl (150 mL). The solvents were evaporated under
reduced pressure by rotary evaporation. The residue was
distilled at 82 °C/4 mmHg to afford NVP (8.82 g, 80% yield)
as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J1 =
16 Hz, J2 = 8 Hz, 1H), 4.45 (d, J = 8 Hz, 1H), 4.41 (d, J = 16
Hz, 1H), 3.52 (t, J = 8 Hz, 2H), 2.50 (t, J = 8 Hz, 2H), 2.11 (qt,
J = 8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 173.3, 129.3,
94.2, 44.5, 31.3, 17.3.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00303.
Spectral information for N-vinylisobutyramide, N-formyl-
N-vinyl-4-chlorobutyramide, and N-vinyl-2-pyrrolidinone
(PDF)
A Larger Preparation of N-Vinylisobutyramide. Freshly
distilled N-vinylformamide (106.62 g, 1.500 mol), triethylamine
(182.14 g, 1.800 mol), and anhydrous THF (1.0 L) were added
to a 3 L four-necked round-bottomed flask equipped with an
overhead stirrer, an addition funnel, a thermometer, and a
nitrogen pad. The resulting mixture was cooled to 0 °C in an
ice-water bath. Freshly distilled isobutyryl chloride (106.55 g,
1.725 mol) was loaded into the addition funnel and slowly
added at a rate such that the temperature was maintained below
5 °C over 1 h. The resulting reaction mixture was stirred at 0−5
°C until the reaction was complete, as monitored by GC
analysis (2 h). A solution of 5 N NaOH (900.0 mL, 4.500 mol)
was then slowly added at 0−5 °C over 2 h. The resulting thick
mixture was stirred at 0−5 °C until all of the imide NVFIBA
disappeared, as monitored by GC (1−2 h). The water layer was
removed and extracted with EtOAc (500 mL × 2). The organic
layers were combined, washed with a solution of sat. NaCl (500
mL × 2), and dried over anhydrous sodium sulfate. After
filtering off insolubles, the solvents were evaporated under
reduced pressure using rotary evaporation to give a slightly
brown solid. The solid was further dried in a vacuum oven at 1
mmHg/25 °C to a constant weight to give 157.40 g (93%
yield) of the desired product in 98% purity (estimated by GC
analysis).
Preparation of N-Vinyl-2-pyrrolidinone. Freshly distilled
N-vinylformamide (NVF, 7.11 g, 100.0 mmol), triethylamine
(14.17 g, 140.0 mmol), 4-dimethylaminopyridine (DMAP, 0.61
g, 5 mol %), and anhydrous THF (80 mL) were added to a 250
mL three-necked round-bottomed flask equipped with a
magnetic stirrer, a thermometer, and a nitrogen pad. The
mixture was cooled to 0 °C with an ice-water bath. 4-
Chlorobutyryl chloride (16.92 g, 120.0 mmol) was added
through a syringe pump at a rate (28 mL/h) such that the
temperature was maintained at 0−5 °C over 30 min. The
reaction mixture was stirred at 0−5 °C for 1 h. A sample was
taken and analyzed by GC, which showed that the conversion
was complete, giving 98% (by GC analysis) N-formyl-N-vinyl-
4-chlorobutylamide along with 2% (by GC analysis) cyclization
product NVP. A solution of 50 wt % NaOH (28.0 g, 350.0
AUTHOR INFORMATION
■
Corresponding Authors
*(S.T.) E-mail: stu@dow.com.
*(C.Z.) E-mail: czhang@dow.com.
Notes
The authors declare no competing financial interest.
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1
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1
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Hz, 1H), 3.90 (d, J = 6.4 Hz, 2H), 1.94 (m, 1H), 0.94 (d, J = 6.8 Hz,
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HRMS calcd for C7H13NO2 (M+), 143.0941; found, 143.0945.
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(b) Shimasaki, Y.; Yano, H.; Sugiura, H.; Kambe, H. Bull. Chem. Soc.
Jpn. 2008, 81, 449−459.
(17) Recently, Syngenta researchers used the Et3N/DMAP base
system in the synthesis of two N-vinyl benzamides. O’Sullivan, A. C.;
Loiseleur, O.; Stierli, D.; Luksch, T. Pitterna, T. Nematicidal cis
(hetero)arylcyclopropylcarboxamide derivatives. WO 2013/120940
A2, August 22, 2013.
E
DOI: 10.1021/acs.oprd.5b00303
Org. Process Res. Dev. XXXX, XXX, XXX−XXX