N -Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

Article abstract of DOI:10.1039/c6gc00932h

Dipolar aprotic solvents such as N-methylpyrrolidinone (or 1-methyl-2-pyrrolidone (NMP)) are under increasing pressure from environmental regulation. NMP is a known reproductive toxin and has been placed on the EU "Substances of Very High Concern" list. Accordingly there is an urgent need for non-toxic alternatives to the dipolar aprotic solvents. N-Butylpyrrolidinone, although structurally similar to NMP, is not mutagenic or reprotoxic, yet retains many of the characteristics of a dipolar aprotic solvent. This work introduces N-butylpyrrolidinone as a new solvent for cross-coupling reactions and other syntheses typically requiring a conventional dipolar aprotic solvent.

Full text of DOI:10.1039/c6gc00932h

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N-Butylpyrrolidinone as a dipolar aprotic solvent
for organic synthesis†
Cite this: DOI: 10.1039/c6gc00932h
James Sherwood,a Helen L. Parker,a Kristof Moonen,b Thomas J. Farmera and
Andrew J. Hunt*a
Dipolar aprotic solvents such as N-methylpyrrolidinone (or 1-methyl-2-pyrrolidone (NMP)) are under
increasing pressure from environmental regulation. NMP is a known reproductive toxin and has been
placed on the EU “Substances of Very High Concern” list. Accordingly there is an urgent need for non-
toxic alternatives to the dipolar aprotic solvents. N-Butylpyrrolidinone, although structurally similar to
NMP, is not mutagenic or reprotoxic, yet retains many of the characteristics of a dipolar aprotic solvent.
This work introduces N-butylpyrrolidinone as a new solvent for cross-coupling reactions and other synth-
eses typically requiring a conventional dipolar aprotic solvent.
Received 4th April 2016,
Accepted 26th April 2016
DOI: 10.1039/c6gc00932h
www.rsc.org/greenchem
teric (i.e. new or otherwise unconventional) solutions (Fig. 1).4
The replacement of dipolar aprotic solvents is of urgent need
Introduction
In recent times considerable attention has been drawn to a to all chemical sectors given the pressure of impending legisla-
number of solvents because of their undesirable health, safety, tive measures such as the European REACH regulation.5 The
or environmental problems. The motivation to replace these demand for reliable substitutes is high owing to the chronic
chemicals is driven by legislation in some instances, but more toxicology of these vital solvents. Recently, a solvent-conserving
generally it is recognised that the principles of green chemistry catalyst has been developed for acid-catalysed reactions, which
can create efficiency savings, as well as reduce the costs associ- can aid in reducing the use of dipolar solvents.6 Despite this
ated with hazardous material disposal and alleviate the need there is a pressing need for to address the availability of low
for stringent safety precautions.1 A broad range of different toxicity alternative solvents with the correct polarity profile.
solvents are employed across the various chemical sectors, in
Towards this goal of non-toxic dipolar aprotic solvents,
both processes and in products. Boiling point, viscosity and N-butylpyrrolidinone (or 1-butyl-2-pyrrolidone (NBP)) is a promis-
numerous other physical properties are all important to the ing candidate. It has been identified as being non-reproductively
relevance of a solvent in a given application. Of these pro- toxic (according to OECD 414 test method), non-mutagenic
perties, polarity is the vital attribute of a solvent when it comes (OECD 471), and also inherently biodegradable (OECD 302B)
to the solubility of components in solution, also controlling (Scheme 1).7 Despite this, N-butylpyrrolidinone has only been
the productivity of a reaction through kinetic and thermo- used as a reaction medium in a very limited number of academic
dynamic phenomena.2,3 This, in part, is why many solvents are instances, usually as a co-solvent.8 It is more acutely toxic (LD50
required to satisfy the differing demands of the chemical rat oral, 300–2000 mg kg−1) than NMP (∼4000 mg kg−1). This
industries.
serves as a reminder that the advantages of N-butylpyrrolidinone
As the greatest contribution to the mass of chemicals used must be counterbalanced by any negative impact in solvent selec-
in most chemical processes, the solvent is often prioritised for tion. The physical properties of N-butylpyrrolidinone are gener-
substitution should the need to improve the greenness of a ally similar to other dipolar aprotic solvents. Aside from its lower
reaction arise. A number of solvents have either been identi- melting point, Table 1 shows that the physical properties of
fied or specifically developed as green alternative solvents for N-butylpyrrolidinone reside within the data ranges established by
this purpose. While some green solvents are recognisable from the conventional dipolar aprotic solvents.
the catalogue of conventional solvents, many others are neo-
The dipolarity (π*) of N-butylpyrrolidinone is slightly less
than what might be expected of a solvent able to replace any of
the traditional dipolar aprotic solvents (Table 2). As seen by
comparing NMP and N-butylpyrrolidinone, increasing the
N-alkyl chain length on the pyrrolidinone moiety decreases the
dipolarity of the solvent, but through electron donation
enhance its hydrogen bond accepting ability (β). As the name
aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York,
YO10 5DD, UK. E-mail: andrew.hunt@york.ac.uk
bEastman Chemical Company, Pantserschipstraat 207 – B-9000, Gent, Belgium
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6gc00932h
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Fig. 1 Conventional and neoteric solvent types arranged by polarity and volatility. Key to conventional solvents: 1, n-pentane; 2, n-hexane; 3,
toluene; 4, 1,4-dioxane; 5, ethyl acetate; 6, methyl isobutyl ketone; 7, NMP; 8, N,N-dimethyl acetamide (DMAc); 9, N,N-dimethyl formamide (DMF);
10, sulpholane; 11, dimethyl sulphoxide (DMSO); 12, dichloromethane; 13, acetonitrile; 14, nitromethane; 15, isopropanol; 16, acetic acid; 17, metha-
nol. Key to neoteric solvents: 1’, hexamethyldisiloxane; 2’, supercritical CO2; 3’, limonene; 4’, methyl oleate; 5’, 2-methyltetrahydrofuran; 6’, γ-valero-
lactone; 7’, N-butylpyrrolidinone; 8’, Cyrene; 9’, ethylene carbonate; 10’, solketal; 11’, ethyl lactate; 12’, glycerol. Refer to the ESI† for extra detail and
references.
suggests, dipolar aprotic solvents are not hydrogen bond
donors (α = 0) and for aprotic solvents have reasonably high
values on the Reichardt scale of polarity (ENT).10
Differences between the polarity of N-butylpyrrolidinone
and the other dipolar aprotic solvents mean it cannot be said
that N-butylpyrrolidinone is automatically a universal replace-
ment for them. Hence the objective of this research was to
establish the chemical reactions that could benefit from the
application of N-butylpyrrolidinone as the solvent. A detailed
assessment of this sort had not been conducted before, thus a
series of reactions were performed to compare N-butylpyrrol-
Scheme 1 N-Butylpyrrolidinone and other dipolar aprotic solvents.
idinone to more conventional dipolar aprotic solvents such as
Table 1 Representative physical properties of dipolar aprotic solvents (ref. 9)
Solvent
Melting point/°C
Boiling point/°C
Vapour pressure/Pa
Density/g mL−1
Viscosity/cP
Flash point/°C
NBP
NMP
DMF
DMAc
DMSO
Sulpholane
<−75
−24.4
−60.4
−20.1
18.6
241
202
153
166
189
287
35 (20 °C)
50 (25 °C)
370 (25 °C)
130 (25 °C)
60 (25 °C)
9.1 (30 °C)
0.960
1.03
0.94
0.94
1.10
1.26
4 (25 °C)
108
86
58
63
89
1.67 (25 °C)
0.9 (20 °C)
2.14 (20 °C)
2.0 (25 °C)
10.35 (30 °C)
28.4
177
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Table 2 Solvatochromic polarity data of dipolar aprotic solvents
Solvent
ETN
Ref.
α
β
π*
Ref.
NBP
NMP
DMF
DMAc
DMSO
Sulpholane
0.323
0.355
0.386
0.377
0.444
0.410
0.00
0.00
0.00
0.00
0.00
0.00
0.92
0.75
0.71
0.73
0.74
0.30
0.77
0.90
0.88
0.85
1.00
0.96
10
10
10
10
10
11
11
11
11
12
NMP and DMF. N-Butylpyrrolidinone was found to be a satis-
factory ‘drop-in’ replacement for dipolar aprotic solvents in
varied examples of organic synthesis. It should also be noted
that it is also possible to synthesise the N-alkylpyrrolidinones
from biomass feedstocks, either by feedstock replacement (e.g.
biogas, bio-butanol) or a new process using glutamic acid to
form the intermediate pyrrolidinone.13
Results and discussion
In order to ascertain the role of solvents in organic synthesis
and gauge their performance relative to one another, free
energy relationships correlating the polarity of solvents to the
observed reaction kinetics have proven very useful. This
graphical interpretation is known as a linear solvation energy
relationship (LSER).14 The reactions chosen for this type of
kinetic analysis were a Menschutkin heteroatom alkylation
and an example of the Heck cross-coupling reaction. The fluor-
ination of a functionalised pyridine derivative, as previously
demonstrated in the literature,12 was attempted but the pro-
gress of the reaction was slow (see ESI†). The LSER approach,
through emphasising the role of the solvent and quantifying
each solvent replacement strategy, will exaggerate the differ-
ences between solvents. Recording reaction yields or conver-
sions after a set time period is more indicative of the potential
of each solvent in preparative scale chemical synthesis. So in
addition to the kinetic experiments listed above, the yields of a
series of Heck and Suzuki cross-coupling reactions performed
in NMP and N-butylpyrrolidinone are also reported. Further-
more, a SN2 reaction and a short screening of 2 different
heterocycle syntheses was also undertaken, in which N-butyl-
pyrrolidinone promoted reactions are compared to the yields
obtained in the traditional solvents.
Fig. 2 The LSER describing the rate of a Menschuktin reaction (as
drawn).
The rate of the chosen model Menschutkin reaction
between 1-methylimidazole and 1-bromooctane at 323 K was
1
measured in a variety of solvents using H-NMR spectroscopy.
Then a correlation with solvent polarity was constructed
(Fig. 2). The natural logarithms of the experimentally deter-
mined rate constants were correlated to the polarity of the
solvent. Only π* was found to be statistically significant as an
independent variable, and the resulting data fit is satisfactory
(see the ESI†). As expected DMSO provides the greatest rate of
reaction in the experimental solvent dataset, with N-butylpyrrol-
idinone offering increased performance over acetonitrile but
not DMF and NMP. It may be concluded that, as a dipolar
aprotic solvent, N-butylpyrrolidinone falls within the expected
performance range, but in order to advocate its use ahead of
the more established solvents, the favourable environmental
health and safety characteristics it possesses must be an inte-
gral part of the solvent selection process.
Menschutkin reaction kinetics
Benzylation of sodium acetate
Heteroatom alkylation is the most prevalent reaction practiced The Menschutkin is not typical of SN2 mechanism reactions
in drug discovery.15 The Menschutkin reaction is a specific because two neutral reactants combine to give an ionic
version of N-alkylation that has found contemporary use in the product. It is more routine for an anionic nucleophile to dis-
synthesis of ionic liquids.16 It also formed the basis of one of place the halide (or pseudohalide) leaving group from a mole-
the earliest solvent effect studies, where the rate of reaction is cule. To address nucleophilic substitution more generally, a
strongly dependant on the dipolarity of the solvent.2 For this reaction between potassium acetate and benzyl bromide to
reason dipolar aprotic solvents are the favoured reaction give benzyl acetate was studied under different conditions.
medium. Contemporary research has suggested that dimethyl Firstly, two equivalents of potassium acetate were used at
sulphoxide (DMSO) provides the optimum balance between pro- ambient temperature, which allowed for complete conversion
ductivity and solvent greenness in the Menschutkin reaction.16
to the desired product in DMSO within two hours (Fig. 3). The
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Fig. 3 Ambient temperature conversions of benzyl bromide to benzyl
acetate (shown) with 2 equivalents of potassium acetate and no chelat-
ing agent.
Fig. 4 A model Heck reaction to give methyl cinnamate with the
relationship between solvent dipolarity and the natural logarithm of the
initial rate of reaction.
reaction was slower in NMP and less effective still in N-butyl-
pyrrolidinone, but complete within 24 hours. The solubility of
the potassium acetate seems to have limited the rate of conver-
sion, as well as the solvent polarity. To overcome this, alterna-
tive conditions using only 1.1 equivalents of potassium
acetate, but with the addition of the cation chelator tetra-
methylethylenediamine (TMEDA) were employed. This
resulted in full conversion to benzyl acetate in DMSO, NMP or
N-butylpyrrolidinone after two hours.
indicating that hydrogen bond donating solvents retard the
rate of reaction under these conditions.18 The observed solvent
effect is consistent with the common proposal that alkene
insertion by palladium is the rate determining step of the
Heck reaction with aryl iodides.22 The polarisation of the
alkene results in a separation of charge that is presumably
best stabilised in highly dipolar solvents. The rate of reaction
in N-butylpyrrolidinone is comparable to NMP and DMSO.
To further explore the scope and possible limitations of
N-butylpyrrolidinone as a solvent in C–C coupling reactions,
Cross-coupling studies
Cross-coupling reactions are ubiquitous in the pharmaceutical additional Heck (Table 3) and Suzuki (Table 4) reactions were
industry in both medicinal chemistry and drug manufac- carried out using a range of different substituted aryl halides
ture.17,18 Traditionally, cross-coupling reactions such as the and olefins. Reactions were also performed in NMP in order to
Heck reaction are preferentially carried out in highly dipolar compare conversions and determine if N-butylpyrrolidinone is
aprotic solvents, e.g. DMF, NMP DMAc.18,19 A screening of reac- truly an effective replacement, simultaneously offering an
tion rates for a model Heck reaction between iodobenzene and improved toxicological profile. All reactions were carried out
methyl acrylate at 373 K was undertaken in the following sol- for 24 hours to ensure that the reactions were complete.
vents in order to compare their relative performance: cyclo- Results indicated that conversion to the product in N-butyl-
hexanone, p-cymene, DMF, DMSO, N-butylpyrrolidinone, NMP, pyrrolidinone compared well with NMP, generally resulting in
and toluene (Fig. 4).
comparable or superior yields for all the Heck cross-coupling
The results of the solvent screening indicate the initial rate reactions attempted (Table 3).
of reaction to give methyl cinnamate is proportional to the
N-Butylpyrrolidinone was less effective than NMP when
dipolarity of the solvent, again gauged by the Kamlet-Taft applied in the Suzuki cross-coupling reaction (Table 4). It may
solvatochromic π* scale (Fig. 4).20,21 The complimentary para- be that the conditions chosen for the Suzuki reactions (invol-
meter describing hydrogen bond accepting ability (β) was ving the dilution of the solvent with water and the application
found to be statistically insignificant as was true of earlier case of tetrabutylammonium bromide (TBAB) as a phase transfer
studies. All the solvents are aprotic, with previous experiments catalyst) are more sensitive to the polarity of the solvent than
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can provide a diverse range of drug candidates. Often a high
polarity solvent is used to conduct a heterocycle synthesis,
including multicomponent reactions performed in one pot.23
A small range of different heterocycles have been synthesised
in N-butylpyrrolidinone to further demonstrate its potential
value as a solvent in the fine chemical and pharmaceutical sector.
Table 3 A comparison of reaction efficiency for a range of substituted
aryl halides in the Heck reaction using N-butylpyrrolidinone and NMP as
solvents
The Biginelli reaction yields
a
dihydropyrimidinone
product. Previous work has shown that for Biginelli reactions
between urea, an aldehyde, and a cyclic 1,3-dicarbonyl com-
pound (dimedone), solvents with a strong tendancy to accept
hydrogen bonds provide the highest yields.24 For this reason
the isolated product yield from the reaction conducted in
N-butylpyrrolidinone exceeded that when either ethanol (the
conventional choice of solvent) or DMF was used as the
solvent (Scheme 2).
A modification to the Maitland–Japp reaction produces
highly functionalised piperidines.25 Acetonitrile (MeCN) is rou-
tinely used as the solvent in this reaction between a 1,3-di-
carbonyl compound, 2 equivalents of an aniline derivative and 2
equivalents of aldehyde. Overnight reactions at the ambient
temperature produced yields after recystallisation of 63% in
either MeCN or DMF, and 67% in N-butylpyrrolidinone
(Scheme 3).
Conversiona
in NMP
Conversiona
in NBP
X
R
R′
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
Br
Br
H
H
H
H
H
Me
91%
96%
89%
>99%
94%
68%
>99%
85%
>99%
92%
94%
93%
>99%
90%
85%
>99%
87%
>99%
OMe
2-Vinylnaphthaleneb
H
CF3
H
Me
H
Cl
Cl
CN
CN
Me
a Conversion calculated from 1H NMR spectra. Reaction conditions are
provided in the Experimental section. b 2-Vinylnaphthalene is the
olefin reactant.
Table 4 A comparison of reaction efficiency for a range of phenylboro-
nic acids in Suzuki cross-coupling reactions with 4-iodoacetophenone
using N-butylpyrrolidinone and NMP as solvents
Conversiona
in NMP
Conversiona
in NBP
R
1
2
3
4
5
H
83%
76%
89%
87%
90%
73%
72%
79%
77%
81%
CF3
NO2
OH
Me
Scheme 2 An example of a Biginelli reaction with the isolated yields
obtained in different solvents indicated.
a Conversion calculated from 1H NMR spectra. Reaction conditions are
provided in the Experimental section.
the examples of the Heck reaction discussed previously in
Table 3. N-Butylpyrrolidinone is water miscible, but these reac-
tions have not been optimised to specifically favour N-butyl-
pyrrolidinone, instead performed according to literature
precedent that relies on conventional dipolar aprotic solvents
(e.g. NMP). The performance of the Suzuki cross-coupling reac-
tions in N-butylpyrrolidinone could potentially be improved to
meet ordinary expectations with modified conditions, but here
the conversions were modest.
Heterocycle syntheses
Heterocycle synthesis is a vitally important initial step in the
Scheme 3 A multicomponent synthesis of piperidines in different sol-
synthesis of many drug precursors, after which functionalisation vents and the corresponding yields.
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4 minutes. The temperature was then ramped at a rate of 10
K min−1 to 573 K and held for 10 minutes. The injector was
set at 563 K and the FID was maintained at 613 K. Peaks were
Experimental
Determination of the Kamlet-Taft solvatochromic parameters
The determination of the β Kamlet-Taft solvatochromic para- identified by comparison with standard compounds. Quantifi-
meter was performed in the same manner as originally cation of methyl cinnamate yield was determined using peak
described with 4-nitroaniline and N,N-diethyl-4-nitroaniline.10 area comparison between product peak and diethyl succinate
Similarly values of π* were obtained by converting the absor- standard. From the GC conversions, calculated across a suit-
bance maxima wavelengths of N,N-diethyl-4-nitroaniline.20 For able range of reaction times, the rate constant of each reaction
α values spectroscopic data from Dimroth-Reichardt’s betaine could be obtained graphically.
dye was applied after subtracting the contributions of solvent
Heck reaction substrate screening
dipolarity.26 A Jasco V-550 UV-vis. spectrophotometer was used
to obtain the required absorbance maxima wavelengths of Into a 30 mL Teflon sealed reaction tube the following reagents
each dye in solution.
were measured: aryl halide (15 mmol), olefin (18 mmol), tri-
ethylamine (18 mmol). Solvent (6 mL) was then added and the
flask heated with stirring to 373 K. Once the flask had heated
Menschutkin reaction
To a solution of 1-methylimidazole (0.328 g, 4.00 mmol) to the required temperature Pd(OAc)2 (1 mol% based on aryl
preheated to 323 K in the chosen solvent (4 mL) was added halide concentration) catalyst was added. Reaction conversions
1-bromooctane (0.850 g, 4.40 mmol) in a single aliquot. The were determined by 1H NMR spectroscopy. 1H NMR spectra
progression of the reaction as 1-methyl-3-octylimidazolium were obtained using a JOEL JNM-ECS400 NMR operating at
1
bromide was formed was monitored by H-NMR spectroscopy, 400 MHz, 1024 scans were taken for each sample.
ideally until over 50% conversion had been achieved.
Suzuki reaction substrate screening
Benzyl acetate synthesis (method 1)
Into a 30 mL Teflon sealed reaction tube the following reagents
Potassium acetate (0.785 g, 8.00 mmol) was added to 20 mL of were measured: aryl halide (2.1 mmol), boronic acid
the chosen solvent and stirred at 450 rpm at the ambient (2.45 mmol), sodium bicarbonate (7 mmol), tetrabutyl-
temperature. To the suspension was added benzyl bromide ammonium bromide (4.5 mmol). The chosen solvent (7 mL)
(0.684 g, 4.00 mmol) in a single aliquot. Filtered aliquots were and water (3 mL) were then added and the flask heated with
taken at selected intervals in order to monitor the progression stirring to 323 K. Once heated to the required temperature
of the reaction by 1H-NMR spectroscopy.
Pd(OAc)2 (2 mol% based on aryl halide concentration) catalyst
was added. Reaction conversions were determined as for the
Heck reaction.
Benzyl acetate synthesis (method 2)
Tetramethylethylenediamine (0.511 g, 4.40 mmol) and potassium
acetate (0.432 g, 4.40 mmol) was added to 20 mL of the chosen
Biginelli reaction procedure
solvent and stirred at 450 rpm at the ambient temperature. Then Urea (0.300 g, 5.00 mmol), 5,5-dimethyl-1,3-cyclohexanedione
was added benzyl bromide (0.684 g, 4.00 mmol) in a single (1.05 g, 7.50 mmol) and the chosen solvent (12 mL) were
aliquot. The reaction was monitored as per method 1 above.
heated to 358 K. Upon reaching thermal equilibrium, benz-
aldehyde (0.51 mL, 5.00 mmol) and concentrated hydrochloric
acid (10 mol%) were added to the mixture. The reaction was
Heck reaction kinetics
Into a 25 mL round bottom flask the following reagents were stirred at 300 rpm for duration of 24 hours. Upon completion
measured: iodobenzene (30 mmol), methylacrylate (30 mmol), of the reaction, the mixture was allowed to cool to ambient
and triethylamine (30 mmol). The chosen solvent (30 mL) was temperature. A small quantity of water was added to ensure
then added and the flask heated with stirring to 373 K. Once complete dissolution of the product. The resultant solid was
the solution was stable at the required temperature, Pd(OAc)2 separated from the reaction mixture by filtration, washed and
(0.1 mol% based on iodobenzene concentration) was added. re-crystallised from ethanol to give 4,6,7,8-tetrahydro-7,7-
For control experiments no catalyst was added. The reaction dimethyl-4-phenyl-2,5(1H,3H)-quinazolinedione
as
white,
was monitored with samples taken at designated intervals. The needle-like crystals. δH (400 MHz; DMSO-d6) 0.88 (3H, s, CH3),
reaction was allowed to proceed until the yield had reached 1.00 (3H, s, CH3), 2.10 (2H, q, CH2), 2.34 (2H, q, CH2), 5.14
over 50% conversion. The reaction was monitored by GC-FID (1H, d, CH), 7.34–7.18 (5H, m, Ar-H), 7.77 (1H, br s, N–H), 9.47
using diethyl succinate as a standard. Quantitative analysis of (1H, s, N–H). δC (100 MHz; DMSO-d6) 26.9, 28.8, 32.3, 49.8,
products was conducted using an Agilent 6890 N gas chrom- 52.0, 107.4, 126.3, 127.2, 128.4, 144.7, 152.0, 152.5, 192.2.
atograph with a flame ionisation detector (GC-FID). This was ESI-MS: m/z 271 (M+ + H).
fitted with a DB5HT capillary column (30 m × 250 μm ×
0.25 μm nominal) at constant pressure of 21.54 psi. The
Piperidine synthesis procedure
carrier gas used was helium and flow rate was set at 2.2 To the chosen solvent (1 mL) was added p-anisidine (0.517 g,
mL min−1 in constant flow mode. The split ratio used was 4.2 mmol), benzaldehyde (0.424 g, 4.0 mmol), methyl aceto-
40 : 1. The initial oven temperature was maintained at 323 K for acetate (0.232 g, 2.0 mmol), and indium trichloride hydrate
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(0.159 g, 0.67 mmol). The mixture was stirred at room temp-
erature for 16 hours, then the resultant product filtered. The
product was washed with methanol and recrystallized from a
mixture of dichloromethane and methanol to give methyl 4-(4-
methoxyphenylamino)-1,2,5,6-tetrahydro-1-(4-methoxyphenyl)-
2,6-diphenylpyridine-3-carboxylate as a white crystalline solid.
δH (400 MHz; CDCl3) 2.62 (1H, dd, CH), 2.78 (1H, dd, CH),
3.64 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.89 (3H, s, COOCH3),
5.05 (1H, dd, CH), 6.17 (2H, d, Ar), 6.32 (1H, s, CH), 6.43 (2H,
d, Ar), 6.59 (2H, d, Ar), 6.65 (2H, d, Ar), 7.22–7.09 (2H, m, Ar),
7.34–7.22 (8H, m, Ar), 10.09 (1H, s, NH). δC (100 MHz; CDCl3)
33.7, 51.0, 55.4, 55.7, 58.3, 96.9, 114.0, 114.5, 114.9, 126.3,
126.6, 126.9, 127.2, 128.0, 128.3, 128.7, 130.7, 141.7, 143.3,
144.3, 150.7, 157.1, 158.0, 168.7. ESI-MS. m/z 521 (M+ + H).
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15 J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, 4, 2337.
It has been demonstrated that N-butylpyrrolidinone possesses
many of the characteristics of the structurally related solvent
NMP or N-ethyl pyrrolidinone (NEP) but has the advantage
that it is not reprotoxic. N-Butylpyrrolidinone is able to deliver
comparable yields in Heck cross-coupling reactions and hetero-
cycle syntheses to those obtained in conventional dipolar
aprotic solvents. A number of nucleophilic substitution reac-
tions have also been performed, demonstrating the broader
capacity of N-butylpyrrolidinone as a solvent in organic syn-
thesis. N-Butylpyrrolidinone is commercially available in
industrial relevant quantities and can now be considered as
part of a new set of greener solvent substitutes for convention-
al dipolar aprotic solvents, complementing the cyclic carbon-
ates,18 Cyrene,12 and γ-valerolactone.27
16 J. C. Schleicher and A. M. Scurto, Green Chem., 2009, 11, 694.
17 S. D. Ramgren, L. Hie, Y. Ye and N. K. Garg, Org. Lett.,
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18 H. L. Parker, J. Sherwood, A. J. Hunt and J. H. Clark, ACS
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Acknowledgements
The authors would like to thank Eastman Chemical Company for
their financial contribution to this work and the supply of NBP.
21 M. J. Kamlet, J. L. M. Abboud, M. H. Abraham and
R. W. Taft, J. Org. Chem., 1983, 48, 2877.
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