On the direct use of CO2 in multicomponent reactions: Introducing the Passerini four component reaction

Article abstract of DOI:10.1039/c8ra07150k

We introduce a novel isocyanide-based multicomponent reaction, the Passerini four component reaction (P-4CR), by replacing the carboxylic acid component of a conventional Passerini three component reaction (P-3CR) with an alcohol and CO₂. Key to this approach is the use of a switchable solvent system, allowing the synthesis of a variety of α-carbonate-amides. The reaction was first investigated and optimized using butanol, isobutyraldehyde, tert-butyl isocyanide and CO₂. Parameters investigated included the effect of reactant equivalents, reactant concentration, solvent, catalyst, catalyst concentration and CO₂ pressure. Of the other parameters, the purity of the aldehyde and its tendency to oxidize was one of the most critical parameters for a successful P-4CR. After optimization, a total of twelve (12) P-4CR compounds were synthesized with conversions ranging between 16 and 82% and isolated yields between 18 and 43%. Their structures were confirmed via¹H and ¹³C NMR, FT-IR and high resolution mass spectrometry (ESI-MS). In addition, three (3) hydrolysis products of P-4CR (α-hydroxyl-amides) were successfully isolated with yields between 23 and 63% and fully characterized (¹H, ¹³C NMR, FT-IR and ESI-MS) as well.

Full text of DOI:10.1039/c8ra07150k

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On the direct use of CO2 in multicomponent
reactions: introducing the Passerini four
Cite this: RSC Adv., 2018, 8, 31490
component reaction†
Kelechukwu Nnabuike Onwukamike,abc Stephane Grelier,bc Etienne Grau,bc
´
bc
a
*
*
Henri Cramail
and Michael A. R. Meier
We introduce a novel isocyanide-based multicomponent reaction, the Passerini four component reaction
(P-4CR), by replacing the carboxylic acid component of a conventional Passerini three component reaction
(P-3CR) with an alcohol and CO2. Key to this approach is the use of a switchable solvent system, allowing
the synthesis of a variety of a-carbonate-amides. The reaction was first investigated and optimized using
butanol, isobutyraldehyde, tert-butyl isocyanide and CO2. Parameters investigated included the effect of
reactant equivalents, reactant concentration, solvent, catalyst, catalyst concentration and CO2 pressure.
Of the other parameters, the purity of the aldehyde and its tendency to oxidize was one of the most
critical parameters for a successful P-4CR. After optimization, a total of twelve (12) P-4CR compounds
were synthesized with conversions ranging between 16 and 82% and isolated yields between 18 and
Received 27th August 2018
Accepted 4th September 2018
1
43%. Their structures were confirmed via H and 13C NMR, FT-IR and high resolution mass spectrometry
DOI: 10.1039/c8ra07150k
(ESI-MS). In addition, three (3) hydrolysis products of P-4CR (a-hydroxyl-amides) were successfully
rsc.li/rsc-advances
isolated with yields between 23 and 63% and fully characterized (1H, 13C NMR, FT-IR and ESI-MS) as well.
1960 and involves a carboxylic acid, carbonyl component
(aldehyde or ketone), an isocyanide and an amine as compo-
nents, leading to the formation of a bis-amide.5 Several varia-
1. Introduction
Multicomponent reactions (MCRs) are dened as reactions
involving more than two starting materials, while forming
products in which most of the atoms of the starting materials
are incorporated.1 Already in 1850, Strecker reported the
synthesis of a-amino-nitriles from an aldehyde, ammonia and
hydrogen cyanide, one the rst reported MCRs.2 Today, a large
variety of different types of MCR exist.3 In the context of this
work, isocyanide-based multicomponent reactions (IMCRs) are
of particular interest. Prominent examples of IMCRs are the
Passerini three component reaction (P-3CR) and Ugi four
component reaction (Ugi 4-CR). The P-3CR was discovered in
1921 by Mario Passerini and describes the reaction between
a carboxylic acid, carbonyl component (aldehyde or ketone) and
an isocyanide, forming a-acyloxyl-amides.4 The Ugi four
component reaction (Ugi 4-CR) was developed by Ivar Ugi in
tions of the IMCRs exist, one of them being the Ugi 5-CR that
uses an alcohol (usually methanol) and CO2 as acid compo-
nent.6 This strategy was also employed in combination with
efficient thiol–ene polymerization to synthesize highly func-
tionalized polycarbonates, polyamides, polyurethanes and pol-
yhydantoins.7 Besides polymer chemistry, MCRs have equally
found application in high throughput synthesis,8 as well as in
combinatorial chemistry,9 allowing the synthesis and screening
of compound libraries. Furthermore, IMCRs are also very useful
in the synthesis of heterocycles.10 Most recently, the Ugi 4-CR of
peruorinated acids was employed for the synthesis of a library
of molecular keys that were applied for molecular
cryptography.11
Apart from the classic P-3CR, many variations have been
reported. Taguchi and co-workers reported on the direct utili-
zation of aliphatic alcohols alongside an isocyanide and a,b-
unsaturated aldehyde in the presence of an Indium(III) catalyst
to form a-alkoxy-amide products.12 El Kaim et al. employed the
so-called Passerini-Smiles reaction of o-nitrophenol as
a replacement of the acid component and synthesized a library
of a-aryloxy-amide products.13 Chatani et al. reported the reac-
tion of cyclic and acyclic acetals with isocyanides in the pres-
ence of GaCl3 as catalyst.14 Here, the isocyanide inserts into the
C–O bond of the acetals, nally resulting in a-alkoxy-imidates.
Denmark and Yan reported the asymmetric a-addition of
aInstitute of Organic Chemistry (IOC), Materialwissenschaliches Zentrum (MZE),
Karlsruhe Institute of Technology (KIT), Straße am Forum 7, 76131 Karlsruhe,
Germany. E-mail: m.a.r.meier@kit.edu; Web: https://www.meier-michael.com
b
`
Univ. Bordeaux, CNRS, Bordeaux INP/ENSCBP, Laboratoire de Chimie des Polymeres
Organiques, UMR 5629, 16 Avenue Pey-Berland, F-33607 Pessac Cedex, France.
E-mail: cramail@enscbp.fr; Web: htpps://www.lcpo.fr
c
`
Centre National de la Recherche Scientique, Laboratoire de Chimie des Polymeres
Organiques, UMR 5629, 16 Avenue Pey-Berland, F-33607 Pessac Cedex, France
† Electronic supplementary information (ESI) available: Synthesis procedures, 1H
and 13C NMR characterization for all P-4CR and hydrolysis products. See DOI:
10.1039/c8ra07150k
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isocyanides to aldehydes. In this case, the reaction was cata- acetaldehyde (ABCR, 97%). Carbon dioxide (CO2) with purity
lyzed by a combination of a weak Lewis acid, SiCl4 activated by over 99.9% was obtained from Air Liquide. Cyclohexane, ethyl
a chiral Lewis base (bisphosphoramide). The desired a- acetate and dichloromethane were distilled before usage, while
hydroxyl-amides were obtained aer basic workup.15
tetrahydrofuran (THF) was of technical grade and used without
Very important for the herein reported results, Jessop and co- further purication. All other chemicals were used as received
workers introduced switchable solvent systems involving CO2 from the supplier.
alongside a super base in 2005.16 The unique nature of this
solvent system was its ability to switch from a non-polar to polar
solvent in the absence or presence of CO2, respectively, by the
reversible formation of a carbonate anion/protonated base
complex. The system is very versatile and allows applications
such as straight-forward product purication,17 as CO2
capturing agents,18 for the selective extraction of hemicellulose
from wood,19 and also as sustainable solvents for cellulose
solubilization.20,21 We recently reported an optimization of the
DBU-CO2 switchable solvent system and could unambiguously
proof that carbonate anions are indeed formed in situ.22 The
formation of this in situ carbonate not only led to a mild solu-
bilization of cellulose in DMSO, but also allowed an activation
of the cellulose hydroxyl groups leading to a milder modica-
tion such as succinylation.23 In this regard, a high DS value of
2.6 was reported for reaction carried out at room temperature in
30 min.23 Tunge and co-workers reported a related approach of
alcohol activation using CO2 in the absence of any base cata-
lyst.24 In this case, allyl alcohols were reacted directly with CO2
leading to the formation of an in situ allyl-carbonate, which
forms a p-allyl complex with a Pd-precursor that can then reacts
with nucleophiles (here derived from nitroalkanes, nitriles and
aldehydes) in a Tsuji–Trost like fashion.24
In the current contribution, the idea is to utilize this in situ
generated carbonate anion as an acid component (i.e. nucleo-
phile) in a typical P-3CR and is thus the starting point of the
herein reported results. In this case, the CO2 is able to activate
the alcohols and is incorporated as C1 carbon source into the
desired compound. In this work, we thus report, for the rst
time, the Passerini four component reaction (P-4CR) as a varia-
tion of the P-3CR, achieved by replacing the acid component in
the P-3CR by an alcohol and CO2. The utilization of CO2 as
a carbon source is both interesting from an environmental and
sustainable perspective as well as to extend the scope and
achievable structural variety of MCRs.
Instruments
IR spectroscopy. Infrared spectra of all samples were recor-
ded on a Bruker alpha-p instrument using ATR technology
within the range 4000 to 400 cmꢀ1 with 24 scans.
1
Nuclear magnetic resonance spectroscopy (NMR). H NMR
spectra were recorded on a 500 MHz WB Bruker Avance I
spectrometer operating at a frequency of 499.97 MHz for 1H-
and a frequency of 125.72 MHz for 13C-measurement on a 8 mm
TXI probe head with actively shielded z-gradients (at q ¼ 0ꢁ) and
on a 4 mm triple HCX MAS probe head (at ca. q ¼ 65ꢁ) at 298 K,
regulated with a Bruker VTU-3000. Measurements were done at
ambient temperature. Measurements were done in CDCl3 and
data are reported in ppm relative to 7.26 ppm and 77.16 ppm for
1H and 13C, respectively.
Gas chromatography (GC-FID). For GC measurements, a GC-
2010 Plus instrument from Shimadzu with a polar column (Rxi-
642Sil MS, length: 30 m, diameter: 0.25 mm, lm thickness:
0.25 mm) and a ame-ionization detector (FID) was used. The
sample (1 mL) was injected and vaporized at 250 ꢁC. The column
ꢀ1
ꢁ
was heated from 50 to 280 C at a rate of 10 K min
.
Gas chromatography-mass spectrometry (GC-MS). Electron
impact (EI) analyses were conducted using a Varian 431-GC
instrument with a capillary column Factor Four™ VF-5ms (30 m
ꢂ 0.25 mm ꢂ 0.25 mm) and a Varian 210-MS ion trap mass
detector. Scans were performed from 40 to 650 m/z at rate of 1
scan per second. The oven temperature program applied during
the analysis was: initial temperature 95 ꢁC, hold for 1 min, ramp
at 15 ꢁC minꢀ1 to 200 ꢁC, hold for 2 min., ramp at 15 ꢁC minꢀ1 to
ꢁ
300 C, hold for 5 min. The injector transfer line temperature
ꢁ
was set to 250 C. Measurements were performed in the split–
split mode (split ratio 50 : 1) using helium as carrier gas (ow
rate 1.0 mL minꢀ1).
Electron spray ionization-mass spectrometer (ESI-MS).
Spectra were recorded on a Q Exactive (Orbitrap) mass spectrom-
eter (Thermo Fisher Scientic, San Jose, CA, USA) equipped with
a HESI II probe to record high resolution electrospray ionization-
MS (ESI-MS). Calibration was carried out in the m/z range 74–
1.822 using premixed calibration solutions (Thermo Fisher
Scientic). A constant spray voltage of 4.7 kV and a dimensionless
sheath gas of 5 were employed. The S-lens RF level was set to 62.0,
while the capillary temperature was set to 250 ꢁC. All samples were
dissolved at a concentration range of 0.05–0.01 mg mLꢀ1 in
a mixture of THF and MeOH (3 : 2) doped with 100 mmol sodium
2. Experimental
Materials
Allyl-alcohol (99%), benzyl alcohol (99%), butanol (99.5%), 1-
octanol (99%), phenyl acetaldehyde (98%, stabilized) and tri-
methylamine (99.7%) were purchased from Acros Organics. 1-
Adamantyl isocyanide (95%), cyclohexanol (99%), cyclohexyl
isocyanide (98%), 2-butanol (99.5%, anhydrous), 2,4-dini-
trobenzaldehyde (97%), isobutyraldehyde ($99.5%), 2-mor-
pholinoethyl isocyanide ($98%), tert-butanol ($99.5%,
anhydrous), tert-butyl isocyanide (98%), tetradecane ($99.5%)
and undecylenic aldehyde (95%) were obtained from Sigma
triuoroacetate and injected with a ow of 5 mL minꢀ1
.
General procedure for optimization study of P-4CR
Aldrich. Other chemicals used include: diazabicyclo[5.4.0] 0.41 g of Butanol (1 eq., 5.50 mmol) and 5 mol% tetradecane as
undec-7-ene (DBU, TCl, >98%), deuterated chloroform (CDCI3- internal GC standard (70 mL) were stirred in 1.5 mL of the
d, Merck), dimethyl sulfoxide (DMSO, VWR, 99%) and trimethyl solvent at room temperature for 1 to 2 minutes, aer which
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a sample was collected for GC analysis. The mixture was then tert-butylisocyanide were employed, while the reaction was
saturated with CO2 (5 bar) for 15 minutes. In the same manner, performed at 10 bar CO2 for 48 h at room temperature. The
isobutyraldehyde was pre-saturated with CO2 (5 bar) for 10 conversion of butanol was followed via gas chromatography
minutes, aer which both solutions were mixed and further (GC) versus an internal standard (tetradecane). For the rst trial,
saturated with 5 bar of CO2 for 10 to 15 minutes. Subsequently, a conversion of 38% was reached aer 48 h (see Fig. SI1†). The
tert-butylisocyanide was added and the reaction was performed presence of the desired P-4CR product (273.19 g molꢀ1) was
ꢁ
under 10 bar of CO2 for 24 h at room temperature (22–24 C). indicated by gas chromatography mass spectrometry (GC-MS).
Samples were then collected over the course of the reaction and In addition, the presence of the hydrolysis product of the P-
analyzed by gas chromatography (GC) in order to calculate the 4CR (174.10 g molꢀ1) as well as the P-3CR product (243.16 g
conversion and the relative percentage between the observed molꢀ1) were conrmed by GC-MS. The formation of the three
products (P-4CR, P-3CR and hydrolysis product of P-4CR). products was followed in time via GC and is illustrated in Fig. 1.
Parameters investigated during the optimization study Within the rst ve hours, the P-3CR accounted for most of the
include: effect of reaction equivalents (1, 2 eq.), reaction observed products. However, an increased formation of the P-
concentration (1.84 and 3.68 M with respect to butanol), catalyst 4CR was observed as the reaction proceeded. In addition,
(triethylamine and DBU), catalyst concentration (5, 10 and some hydrolysis of the P-4CR product was observed with time.
15 mol%), CO2 pressure (5, 10 and 15 bar) and solvent (DMSO, Considering the P-3CR side reaction, a two-fold excess of alde-
chloroform, methyl-THF, DCM).
hyde and isocyanide components was employed in the next
reaction, resulting in an improved butanol conversion of 56%.
As solvents play a key role in multicomponent reactions,
different solvents (dimethyl sulfoxide DMSO, methyl-THF and
chloroform) were investigated next. While similar conversions
were obtained for all the solvents investigated, different
hydrolysis tendencies were noticed. By comparing the relative
percentage between the P-4CR and its hydrolysis product, an
increased formation of hydrolysis product in the order chloro-
form > DMSO > methyl-THF > DCM was observed. This trend
might be explained considering the acidity of the solvents, e.g.
chloroform is the most acidic solvent tested herein. For DMSO,
the high hydrolysis rate observed is probably due to the pres-
ence of unavoidable water impurity in the solvent. Methyl-THF
showed a relatively low tendency towards hydrolysis, but led to
a higher degree of oxidation of the aldehyde and thus an
increase of the P-3CR side product (see Fig. SI2†), probably due
to possible peroxide impurities.26 DCM showed the lowest
tendency towards hydrolysis and equally resulted in the highest
selectivity towards the targeted P-4CR product. It should
however be noted here that the observed hydrolysis products are
valuable compounds as well. Furthermore, as multicomponent
reactions usually provide higher efficiency at higher
3. Results and discussions
As a starting point and to prove our hypothesis of a possible P-
4CR, we investigated the reaction of butanol, isobutyraldehyde,
tert-butylisocyanide and CO2 in dichloromethane (DCM) as
a solvent. In addition to the formation of the expected P-4CR
product, the formation of a P-3CR by-product and the hydro-
lysis of the P-4CR product, resulting in the formation of an a-
hydroxyl-amide, was observed (compare Scheme 1). As we
observed in the further course of our investigations, the
formation of the P-3CR product is due to the presence of the
respective carboxylic acids originating from the oxidation of the
used aldehyde component. The isobutyraldehyde used for the
1
optimizations had a lower purity (92% from H NMR) than re-
ported by the manufacturer (99.5%). We later observed that
freshly distilled aldehydes gave the best results for a P-4CR and
the P-3CR could be suppressed to less than 5%, although it
could not be completely avoided. Nevertheless, this rst proof-
of-principle reaction clearly showed that the anticipated reac-
tivity of the carbonate anion allows for a P-4CR. For optimizing
the P-4CR, several parameters, such as the effect of solvent,
reactant concentration, reactant equivalents, catalyst concen-
tration and CO2 pressure were investigated. Dichloromethane
(DCM, 1.84 M) was employed as solvent for the rst trial
experiments as it has been reported to be a suitable solvent for
the P-3CR.25 One equivalent of butanol, isobutyraldehyde and
Fig. 1 Relative percentage between formed compounds (P-4CR, P-
3CR and hydrolysis of P-4CR products, compare Scheme 1) over time
Scheme 1 Formation of P-4CR products in the absence (a) and (results obtained from GC). Reaction conditions: One equivalent each
presence (b) of a base catalyst. (c) Hydrolysis of the P-4CR product. of butanol, isobutyraldehyde and tert-butylisocyanide at 10 bar CO2 in
(see Fig. 2 for synthesized structures).
DCM at room temperature.
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concentrations, this parameter was investigated by doubling employing 5, 10 and 15 mol%. This study revealed that the
the previously applied concentration. As expected and to our conversion of butanol remained at about 70% for both 5 and
delight, the conversion of butanol increased from 56% (1.84 M 10 mol%. However, the quasi conversion decreased to 52%
with respect to butanol) to 73% (3.68 M with respect to butanol) when 15 mol% catalyst were used. This decrease can be
in DCM.
explained by the observed increased hydrolysis of the P-4CR
Presumably, the mechanism of the P-4CR proceeds via the in product, which reforms butanol and thus counterfeits a lower
situ formation of a carbonate anion initiated by a base cata- butanol conversion (see Scheme 1c and Fig. SI6†). As 10 mol%
lyst16,20–22 (see Scheme 1b). The carbonate then reacts as the acid catalyst loading gave slightly better results, this catalyst loading
component with the isocyanide and aldehyde component in the was employed for investigating the effect of CO2 pressure. Three
typical fashion of the conventional Passerini 3-CR.3 However, in CO2 pressures were investigated (5, 10 and 15 bar) and the
the so far discussed set of experiments, no base catalyst was results are presented in Fig. SI7,† revealing a slight increase in
employed. It was therefore interesting to note that the P-4CR butanol conversion from 58% to 69% as the CO2 pressure was
occurred nevertheless. This initially unexpected reactivity increased from 5 to 10 bar. However, a slight decrease was
could be due to an activation of the alcohol by the isocyanide observed at 15 bar (62% conversion). Furthermore, the highest
(Scheme 1a). Isocyanides were used as a weak Lewis base in relative percentage of P-4CR was obtained at 10 bar of CO2.
previous reports in literature.27 Equally, alcohol activation by Therefore, 10 bar of CO2 was selected for further experiments.
other Lewis bases has been reported.28 To verify the alcohol
Using the described optimized conditions (3.84 M with
1
activation hypothesis, an in situ H NMR study was performed respect to butanol, DCM as solvent, 1 eq. of alcohol, 2 eq. of
(utilizing butanol in CDCl3). In this context, the spectra of aldehyde and isocyanide with respect to butanol, 10 bar CO2 at
butanol, butanol in the presence of stoichiometric amounts of room temperature (22–25 ꢁC)), the scope of the P-4CR was
tert-butylisocyanide and butanol in the presence of stoichio- investigated by varying the used components (see Fig. 2). For the
metric amounts of Et3N were compared. The respective study is synthesis of 1a, butanol, isobutyraldehyde and tert-butyliso-
displayed in the ESI (Fig. SI3†) and is described below.
cyanide were used. A conversion of about 70% was reached
From this NMR study, a slight downeld chemical shi of within 24 h, longer reaction times (up to 45 h) led to an increase
the OH proton (from 3.16 ppm to 3.20 ppm) and signicant of selectivity of the targeted P-4CR compound 1a. Compound 1a
signal broadening, characteristic of H-bonding, was observed was isolated in 43% yield aer column chromatography. This
for butanol in the presence of tert-butylisocyanide compared to value is within the range of previously reported Ugi 5-CR
the spectrum of butanol without isocyanide in CDCl3. Similar products.6,7 Keating et al. reported similar results when other
proton signal broadening of the OH proton, most probably alcohols apart from methanol were used in this Ugi-5CR.6 It is
caused by H-bonding, has also been reported for Schiff bases.29 also important to point out that in the case of methanol, an
Comparing the spectrum of butanol with the spectrum of excess (over 10 times) was utilized in order to achieve high
butanol in the presence of Et3N, a downeld chemical shi of conversion and yields. The structure of 1a was conrmed via 1H
the OH proton (from 3.16 ppm to 4.38 ppm) was observed, while and 13C NMR performed in CDCl3 as shown in Fig. 3.
displaying similar signal broadening (see Fig. SI3b†). These
results indicate H-bonding of the OH proton and hence, acti- previous reports on the P-3CR,25 as well as Ugi-5CR.7 In the H
vation of the alcohol by the isocyanide acting as a Lewis base. NMR spectrum, the amide proton is visible at 5.87 ppm. The
The attribution of the proton and carbon peaks are similar to
1
The effect of a catalyst was thus evaluated next. As proton signal at the tertiary carbon at 4.83 ppm and the 9H from
mentioned above, a basic catalyst is able to activate the hydroxyl the tert-butyl side chain at 1.35 ppm conrm the proposed
group, thereby increasing the carbonate anion formation. Thus,
triethylamine (10 mol%) was tested. The obtained results were
compared with the reaction without addition of the catalyst (see
Fig. SI4a†). As expected, the presence of the catalyst further
accelerated the reaction. A conversion of almost 70% was
reached within 24 h (compared to 48 h required to achieve
similar conversion in the absence of the catalyst). In addition,
the overall selectivity towards P-4CR increased (see Fig. SI4b and
c†). However, a slight increase in hydrolysis product was also
observed in the presence of the base catalyst, as one could
expect (see Fig. SI4b and c†). In another set of experiments, the
two catalysts Et3N and diazabicyclo[5.4.0]undec-7-ene (DBU)
were compared. The obtained results showed similar conver-
sion of butanol (about 70%) aer 24 h. However, an increased
hydrolysis was observed for the reaction with DBU compared to
Et3N (Fig. SI5†), probably due to the higher basicity of DBU
compared to Et3N. In addition, the formation of the P-3CR side
product was less pronounced for Et3N. Hence, Et3N was used for
the following experiments, screening for catalyst concentration Fig. 2 Structures of the synthesized P-4CR products.
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a proton in a-position to the aromatic ring led to an aldol
condensation side-product. The aldol side reaction was fav-
oured when the base catalyst was used, as expected. Hence, for
this reaction, no catalyst was utilized and a butanol conversion
of 36% was reached aer 24 h (without much improvement with
longer reaction time). Noteworthy, the P-4CR products from
benzyl-alcohol 4a and octanol 5a were less prone to hydrolysis.
Their higher hydrophobicity compared to butanol might
explain this tendency. The reaction performed with allyl alcohol
3a required longer reaction times to achieve suitable conver-
sions (30 h, conversion 50%) and showed the highest tendency
towards hydrolysis, which also increased over time. Running
the reaction even longer (48 h) resulted in 82% conversion. The
P-4CR product was isolated in a yield of 33%, while 23% of the
hydrolysis product were isolated (and characterized via the
same techniques). This result conrms that hydrolysis can also
be used on purpose to obtain equally useful a-hydroxyl-amide
products. Our attempt to introduce an aromatic side chain via
the aldehyde component (benzaldehyde) was unsuccessful, as
only the P-3CR and hydrolysis products were formed. In addi-
tion, benzaldehyde is very easily oxidized to the corresponding
acid (despite distillation before usage). Thus, 2,4-dini-
trobenzaldehyde was used instead to obtain 9a. A conversion of
40% was achieved aer 48 h with 22% isolated yield. In a similar
manner, we could not observe the formation of the P-4CR
product when tert-butanol was used. Again, only P-3CR and
the hydrolysis product of P-4CR were observed via GC-MS.
Nevertheless, this demonstrate that also tertiary alcohols can
be used in this reaction, whereby only one of the two possible
products (i.e. the hydrolysis product) is accessible so far. Finally,
the hydrolysis products of 1c, 3a and 9a could be isolated in
a yield of 30%, 23% and 63%, respectively. Their structures were
Fig. 3 1H NMR (top) and 13C NMR (bottom) of P-4CR product 1a.
structure. From the 13C NMR, two characteristic carbonyl
carbon chemical shis are observed at 168.78 ppm (amide) and
154.93 ppm (carbonate). Furthermore, the tertiary carbon in the
isocyanide side chain is observed at 51.70 ppm. In addition,
from the FT-IR spectrum (see Fig. SI8†), the characteristic C]O
stretching absorbance band of the carbonate (1743 cmꢀ1) and
amide (1654 cmꢀ1) were visible. Finally, the mass of the mole-
cule was conrmed by ESI-MS ([C14H27NO4Na]+ ¼ 296.19 g
molꢀ1, obtained ¼ 296.18 g molꢀ1).
1
conrmed via H and 13C NMR (see ESI†).
4. Conclusion
We report a novel variant of the Passerini reaction, the Passerini
four component reaction (P-4CR), by replacing the carboxylic acid
component in a conventional P-3CR with an alcohol and CO2.
Upon optimization of the reaction parameters (reaction time,
reactant equivalents, reactant concentration, solvent, catalyst
concentration and CO2 pressure), twelve P-4CR products were
successfully synthesized with conversions ranging from 16 to 82%
and isolated yields between 18 and 43%. In addition, hydrolysis of
the P-4CR products, leading to the formation of a-hydroxyl-amides,
was observed. Three of these hydrolysis products were isolated
with yields between 23 and 63%. Furthermore, the formation of P-
3CR products was observed, which occurred due to the oxidation
of the employed aldehyde components. The success of our re-
ported P-4CR does not only expand the structural diversity of
multicomponent reactions, but the direct utilization and activa-
tion of CO2 as a C1 building block is equally noteworthy.
Employing similar conditions, a total of twelve molecules
were synthesized and equally characterized (see Fig. 2). On the
example of butanol, ve variations of the aldehyde and four
isocyanide variations were demonstrated. In addition,
a secondary alcohol (2-butanol), an unsaturated alcohol (allyl-
alcohol), benzyl-alcohol, octanol and cyclohexanol were
utilized. The respective P-4CR products were obtained with
conversions ranging from 16 to 82% and isolated yields between
18 and 43%. Lower conversions were obtained for reactions
involving sterically demanding side chains such as 1-ada-
mantyl-7a (19%) and 2-morpholinoethyl-8a (16%). In the course
of these investigations, we observed that the P3-CR side-
reaction can be suppressed to less than 5% by immediate
utilization of a freshly distilled aldehyde component.
The obtained P-4CR compounds were fully characterized via
1H and 13C NMR (see ESI†), FT-IR and high-resolution mass
spectrometry (ESI-MS). In the case of 1b, employing phenyl
acetaldehyde, the P-3CR side reaction was not observed.
However, in this case (phenyl acetaldehyde), the presence of
Conflicts of interest
The authors declare no conict of interest.
31494 | RSC Adv., 2018, 8, 31490–31495
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16 P. G. Jessop, D. J. Heldebrant, X. Li, C. A. Eckert and
Acknowledgements
C. L. Liotta, Nature, 2005, 436, 1102.
¨
17 (a) P. G. Jessop, L. Phan, A. Carrier, S. Robinson, C. J. Durr
K. N. O would like to thank the EU for PhD funding under the
Horizon 2020 Marie Sklodowska-Curie ITN Project EJD-FunMat
(Project ID: 641640). H. C and M. A. R. M are also thankful for
this funding. The authors also wish to thank Rebecca Seim for
assistance during synthesis.
and J. R. Harjani, Green Chem., 2010, 12, 809; (b) L. Phan,
D. Chiu, D. J. Heldebrant, H. Huttenhower, E. John, X. Li,
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