Bicyclic Heterocycles from Levulinic Acid through a Fast and Operationally Simple Diversity-Oriented Multicomponent Approach

Article abstract of DOI:10.1002/ejoc.201801129

Levulinic acid, which is one of the most important renewable building blocks derived from lignocellulosic biomass, has been converted in a diversity-oriented manner into two families of drug-like bicyclic nitrogen heterocycles. The methodology, endowed with high step economy and operational simplicity, is based on an Ugi multicomponent reaction, which employs amino alcohols as components, followed by a S_N2 cyclization. Noteworthy is the successful synthesis of hexahydro pyrrolodiazepinediones, since the cyclization of the isocyanide-derived secondary amide onto an alcohol to give a seven-membered ring was unprecedented. Also enantiopure products have been prepared by using chiral amino alcohols.

Full text of DOI:10.1002/ejoc.201801129

A Journal of
Accepted Article
Title: Diversity-oriented Synthesis of Bicyclic Heterocycles from
Levulinic Acid through a Fast and Operationally Simple
Multicomponent Approach
Authors: Chiara Lambruschini, Andrea Basso, Lisa Moni, Alessandro
Pinna, Renata Riva, and Luca Banfi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801129
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801129
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
Diversity-oriented Synthesis of Bicyclic Heterocycles from
Levulinic Acid through a Fast and Operationally Simple
Multicomponent Approach
[
a]
[a]
[a]
[a]
[b]
Chiara Lambruschini, Andrea Basso, Lisa Moni, Alessandro Pinna, Renata Riva, and Luca
Banfi*[a]
Abstract: Levulinic acid, which is one of the most important
renewable building blocks derived from lignocellulosic biomass, has
been converted, in a diversity-oriented manner, into two families of
drug-like bicyclic nitrogen heterocycles. The methodology, endowed
with high step economy and operational simplicity, is based on an Ugi
multicomponent reaction, which employs aminoalcohols as
Multicomponent reactions are defined as processes where three
or more substrates are combined in a single step, generating a
product that contains all essential parts of the starting materials.[
This highly convergent methodology allows molecular complexity
to be created by the facile formation of several new covalent
bonds in a one-pot transformation (step economy). At the same
time, MCRs proceed with remarkably high atom economy,
minimizing the number of functional group manipulations and the
use of protective groups. Syntheses involving MCRs save time
and energy (step and operational efficiency), reduce waste and
quite closely approach the concept of the ideal eco-friendly
synthesis, thus lowering the E factor.[
3]
N
components, followed by a S 2 cyclization. Worth of noting is the
successful synthesis of hexahydro pyrrolodiazepinediones, since the
cyclization of the isocyanide-derived secondary amide onto an alcohol
to give a seven-membered ring was unprecedented. Also enantiopure
products have been prepared using chiral aminoalcohols.
4]
Among multicomponent reactions, those making use of
isocyanides[ have emerged as the most useful ones. They are
quite flexible as the possible starting components and, with the
aid of post-MCR cyclizations, can lead to a great variety of
5]
Introduction
The production of chemicals, from commodities to specialties to
highly valued products such as drugs, cosmetics, functional
materials and so on, still heavily depends on conversion of fossil
feedstock. Apart from the fact that these sources are destined to
be depleted sooner or later, their use contributes to the unbalance
of carbon cycle provoked by human activities. Thus, a whole new
synthetic organic chemistry that starts from renewable sources
should be developed.[1] This task is challenging, since the existing
oil-based chemistry needed nearly two centuries to be fully
progressed.
heterocycles, allowing
a wide exploration of scaffold and
decoration diversity. We thus believe that the application of
isocyanide-based multicomponent reactions (IMCRS) to
oxygenated renewable building blocks may be a very powerful
strategy for the sustainable synthesis of bioactive heterocycles,
especially if the experimental procedures are operationally simple
and closer to the principles of green chemistry.[6]
In this paper we have focussed our attention to levulinic acid 1,
which belongs to the above quoted list of 12 most important
lignocellulosic-derived compounds. In fact, it can be easily
obtained by acid treatment of hexoses.[7] Production of levulinic
Lignoellulosic biomass is surely the most abundant and important
one, but it typically provides polyoxygenated building blocks,
whereas nitrogen containing ones are by far less common.
According to a list recently published by the US Department of
Energy (DOE),[ only 2 out of the 12 most important building
blocks that can be derived from lignocellulosic biomass contain
nitrogen and they (aspartic and glutamic acids) are not
heterocycles. Yet, heterocyclic compounds play a paramount role
in many application fields, i.e. drugs or photoactive organic
compounds. Thus, any sustainable synthetic methodology able to
convert oxygenated renewable building blocks into complex
heterocycles will be welcome.
acid on large scale is already a well assessed methodology. Its
price is, at the moment, about 1 $ / kg, but it is expected to go
further down, using waste sugar sources. Thus, the main problem
now is not how to get it, but how to valorize it. Some applications
2]
[8]
in the polymer field are under study. Far less investigated are
transformations into nitrogen derivatives, with the exception of δ-
aminolevulinic acid (DALA), used in photodynamic therapies,
which again is not an heterocycle. Isocyanide-based MCRs can
be a perfect tool to access levulinic derived heterocycles.
IMCRs and levulinic acid are old friends. Actually Passerini used
levulinic acid in his famous reaction as early as in 1923.[9] More
recently, several researchers have reported the synthesis of
pyrrolidinones by the Ugi reaction of 1.[ However, we wanted to
devise a fast approach to bicyclic systems applying post-MCR
cyclizations. We found in the literature few examples regarding
the obtainment of bicyclic systems through the Ugi reaction
followed by a post-MCR cyclization (Scheme 1).[ However,
compounds 2, obtained by Ugi et al,[11a] are imides, and thus less
10]
[
a]
Dr. Chiara Lambruschini, Prof. Andrea Basso, Dr. Lisa Moni, M.Sc.
Alessandro Pinna, Prof. Renata Riva, Prof. Luca Banfi
Department of Chemistry and Industrial Chemistry
University of Genova
via Dodecaneso, 31 16146 GENOVA (Italy)
E-mail: banfi@chimica.unige.it
11]
[b]
Prof. Renata Riva
Department of Pharmacy
University of Genova
viale Cembrano 4, 16147 GENOVA (Italy)
Supporting information for this article is given via a link at the end of
the document.
interesting for their hydrolytical instability. On the other hand,
ketopiperazines 3[11b] and 4,[11c] synthesized by Hulme and
Doemling, are limited from the point of view of the introduction of
diversity: in 3 the isocyanide group is lost upon cyclization,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
whereas the synthesis of 4 necessarily requires an indole
containing isocyanide.
"privileged structures":[14] the pyrrolidinone[15] and the
piperazine[ or diazepine.
16]
Results and Discussion
The planned two-step procedure was first optimized using
ethanolamine and isocyanide 8 (Scheme 2). The latter was
chosen because it is a solid, highly stable, and odorless
isocyanide.[ The best solvent for the Ugi reaction was found to
be methanol, also according to the mechanism hypothesized by
Harriman[10d] and shown in Scheme 3. For these authors, the
reaction proceeds through the methyl ester 12, and for this reason
no pyrrolidinone is formed using tert-butanol instead. However,
we can not completely rule out direct rearrangement of 11 into 13,
although difficult for steric reasons.
17]
Using a 1.2/1.2/1.0 stoichiometry of levulinic acid, aminoalcohol
and isocyanide, an excellent yield of the Ugi reaction was
achieved. After a quick liquid-liquid extraction to remove the acid
and the amine in excess, product 5a was obtained in nearly
quantitative yield without the need to perform any further
purification.
Scheme 2. Optimized synthesis of tetrahydropyrrolopirazinedione 6a
Scheme 1. Previous multicomponent synthesis of bicyclic heterocycles from
levulinic acid compared to the here reported approach.
For the cyclization step we decided to rule out the classical
Mitsunobu reaction, because of its poor atom economy. Moreover,
a two-step procedure involving conversion of the alcohol into a
sulfonate was less attracting from the point of view of operational
simplicity.
Our approach, depicted in Scheme 1 (bottom), seemed more
flexible and diversity-oriented. Based on the thorough experience
of our group,[12] and of other authors,[13] in Ugi reactions followed
by intramolecular aliphatic substitutions, we planned to employ
aminoalcohols as one of the two additional components in the Ugi
reactions of 1. Then, the isocyanide derived secondary amide can
cyclize onto the alcohol through a Mitsunobu or Mitsunobu-like
reaction. Two of the 3 components could be modified at will and
different sizes of the diazalactam on the right can be achieved by
varying the length of the spacer between the amino and the
hydroxy groups. An added advantage of this strategy is that
several aminoalcohols may be obtained from biomass as well,
including chiral enantiopure ones. The products of this two-step
approach are quite uncommon bicyclic systems that join two
Thus we chose to employ the combination of sulfonyl diimidazole
(
SDI) with NaH. This methodology was first introduced by
[
18]
Hanessian . Although it is, surprisingly, seldom employed, it was
already demonstrated by us[12b] to be an useful alternative to the
classical Mitsunobu conditions. SDI is a relatively nontoxic and
stable solid. The two reagents are simply added to the solution of
the substrate at room temperature without special precautions.
The putative mechanism is shown in Scheme 4. The alkoxide
formed by deprotonation with NaH reacts with SDI to form a
sulfonate 15. Then the amide is deprotonated by the imidazolide
N
anion 14 and this anion promotes an S 2 displacement of the
sulfonate. On aqueous work-up, the leaving group 16 is
hydrolysed to sulfate anion and imidazole. Both these side-
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
products are non toxic and easy removable by liquid-liquid
extraction. Imidazole can be recycled and converted back into SDI
by reaction with sulfuryl chloride.
Initially we performed the cyclization of 5a to 6a in DMF as the
solvent. However, we faced two problems. First of all,
tetrahydropyrrolopirazinediones 6 are remarkably polar and thus
relatively soluble in water. Thus, the usual tricks to remove DMF
by extracting it in water (e.g. using aqueous LiCl solutions),
caused also passage of some of the product in the aqueous
phase, lowering the yield. On the other hand, extraction from
precautions to avoid humidity. The slight excess of SDI can make
up for the possible presence of trace of water. The work-up
consists in just two liquid-liquid extractions after the Ugi and the
cyclization steps, that removed all side-products or excess
reagents.
4
saturated NH Cl was quantitative, but the crude was
contaminated by DMF, that was difficult to remove under high
vacuum.
Scheme 4. Presumed mechanism of the cyclization with SDI.
This procedure was extended to other pyrrolopirazinediones,
again using ethanolamine, but varying the isocyanide. As shown
in Figure 1, the overall yield was good to excellent. Compound 6b
[
11b]
was previously reported by Hulme et al.,
using the approach
1
2
depicted in Scheme 1 (R = H, R = Bn). In that case the benzyl
group (R ) did not derive from the isocyanide, but from a Boc-
2
protectedaminoalcohol instead, and the overall yields were lower.
In the case of compound 6f, in order to avoid the known instability
problems of aromatic isocyanides and to make the method more
operationally simple, we synthesized in situ the required
isocyanide from the corresponding formamide using the Burgess
reagent.[19] Thus the overall yield is calculated from the formamide
Scheme 3. Presumed mechanism of the Ugi reaction with levulinic acid and 1,2-
aminoalcohols
(
3 steps), which explains the apparent lower efficiency of this
The second problem was that some of the excess of SDI used for
the reaction was extracted into the organic phase, contaminating
the product 6a. Although in this particular case a chromatography
was able to separate 6a from SDI, for other products 6 shown in
Figure 1 this was not so easy. Apart from that, we wanted a robust
and operationally simple method that could avoid
chromatography. Unfortunately, trituration of crude 6a failed to
removed SDI impurity.
synthesis. Actually, the cyclization itself was again very efficient,
proceeding in 95% yield. In the case of compounds 6d and 6g,
the required benzyl isocyanides were obtained from the
corresponding formamides ad purified by chromatography.
However, due to their partial volatility, we did not dry them
exhaustively, and thus also in this case the yield was calculated
from the formamide.
Then, in order to further expand diversity, we explored the use of
chiral 1,2-aminoalcohols derived from α-aminoacids, which can
be deemed as renewable building blocks as well. Due to the fact
that now the aminoalcohol was the most precious component, we
chose to use a slight excess of the isocyanide. Initially, the Ugi
reaction proved to be less clean than with ethanolamine, because
of the concurrent formation of Passerini products. By shifting to
trifluoroethanol as solvent, only the Passerini products were
detected. Typically, this more polar solvent tends to favour Ugi
adducts versus the Passerini ones, but in this case the role of
methanol is probably essential to grant formation of the
pyrrolidinone from intermediate 11 (Scheme 3). Eventually, we
The first problem was solved by replacing DMF with THF, that
turned out to be equally effective. As far as it concerns the second
issue, we implemented an easy procedure to destroy excess SDI
at the end of the reaction, converting it into a water-soluble
derivative, by addition of 0.5 equivalents of unexpensive
tris(hydroxymethyl)aminomethane (TRIS). This compound, in the
presence of excess NaH, reacts with SDI to form a water-soluble
cyclic sulfate. In this way, extractive work-up afforded a very pure
product, making chromatography unnecessary. The overall yield
is quite high, and the methodology is operationally very simple:
both steps are performed at room temperature, without particular
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
found that the Passerini products may be completely suppressed
pyrrolodiazepinediones 7 depicted in Figure 2. The Ugi reactions
using propanolamine as component proceeded without particular
problems, but also in this case we obtained better yields by
preforming the intermediate tetrahydrooxazine by premixing the
aminoalcohol and levulinic acid.
by simply preforming the intermediate oxazolidine 9 (Scheme
3
).[20] Thus, equimolar quantities of the chiral aminoalcohol and
levulinic acid were mixed in methanol for 2 h in the presence of
molecular sieves, before addition of the isocyanide. Using this
modification the Ugi product yields were again good. On the other
hand, the diastereoselectivity, as it often happens in isocyanide-
based MCRs, was very poor. However, the two Ugi diastereomers
could be separated and submitted independently to the next step.
N
The cyclization step was anticipated to be challenging. S 2
reaction of the isocyanide-derived secondary amide of an Ugi
adduct onto an alcohol or a halogen to afford seven-membered
diazepinones was indeed unprecedented. In our own laboratory,
we have previously tried this approach to monocyclic
diazepinones, but without success. We observed, instead, other
modes of cyclization, leading to bicyclic systems through attack of
the anionic nitrogen onto the tertiary amidic carbonyl.[12b,
However, in this case the attack onto the pyrrolidinone carbonyl
would lead to an unfavored bridged bicyclic system, due to the
inclusion of the tertiary amide in a 5-member ring.
12f]
Figure 1. Tetrahydropyrrolopirazinediones prepared. For 6b, 6d, 6e: overall
yields of two steps from the isocyanide are reported. For 6d, 6f and 6g: overall
yields of three steps from the formamide are reported. For 6h-6j: Ugi product
yields are from the chiral aminoalcohol, after chromatoraphy. For 6h and 6i: the
two diastereomers were separated after the Ugi step. Cyclization yields are for
the upper and lower diast. (by TLC). In the case of 6j, the diast. were separated
only after cyclization.
Cyclization was slower and only low or moderate yields were
obtained in THF. By shifting to DMF and, in some cases, by
increasing the temperature, we succeeded to bring all reactions
to completion. Interestingly, the rate of cyclization was remarkably
lower for one of the two diastereomers. This is reflected in the
different cyclization yields for the two diastereomers of 6h and 6i.
In both cases the less polar diastereoisomer behaved poorly in
this step.
Figure 2. Hexahydropyrrolodiazepinediones prepared. Method A: SDI, NaH,
DMF, 50 °C. Method B: 1) MsCl, Et
3 2 2
N, CH Cl ; 2) NaH, DMF, 50 °C. For 7c and
7d the Ugi yield is calculated from the formamide (precursor of the isocyanide).
For 7e the Ugi yield is calculated from the aminoalcohol. In the case of 7e the
two diastereomers were separated after the Ugi step and cyclized
independently. Cyclization yields are for the upper and lower diast. (by TLC).
We also employed, in racemic form, 1-amino-2-propanol. In this
case the two Ugi diastereomers could not be separated at this
stage, but only after cyclization. The different d.r. measured
shows that also in this case cyclization is favoured for one of the
two diastereoisomers.
Following our interest in the diversity-oriented synthesis of 7-
membered nitrogen heterocycles,[12e] we then decided to extend
this protocol to the obtainment of the hexahydro
The cyclization was first tested on the Ugi adduct derived from
isocyanide 8, propanolamine and levulinic acid. Reaction in THF
was sluggish and a very poor yield of the expected product 7a
was obtained. However, by simply shifting to DMF as the solvent,
the reaction worked well, even at room temperature, though the
yield was lower, compared to 6-membered adducts 6. In this case
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
we detected very polar side-products containing the imidazole
ring. We think that the intermediate sulfonate 15 (see the
mechanism depicted in Scheme 4) may also be displaced by the
imidazolide anion 14.
the pyrrolidinone[15] and the piperazine. Although this bicyclic
system is still poorly explored in medicinal chemistry, a recent
patent has shown activity of tetrahydro pyrrolopiperazines as
neurokinin 1 receptor antagonists.[ Moreover, some natural
alkaloids (e.g. paraherquamides and aspergillimides), that
15]
We then moved on to investigate the scope of the method. When
we tried to prepare product 7b starting from cyclohexyl isocyanide, contains this scaffold, have antihelmintic or neuroprotective
the cyclization yield, under the usual conditions with SDI (method
A) was only poor (27% at rt and 28% at 50 °C) and the polar side
products became predominant, likely because of the higher steric
bias of the nucleophilic nitrogen. We thus tried different conditions
activity.[22] The procedure is endowed with operational simplicity
and compliance to the green chemistry principles. Both reactions
were performed by simply mixing the reagents at r.t. (no energy
consumption). Atom economy is quite good: during the Ugi
reaction only a molecule of water is lost, whereas cyclisation
consumed just 1 equivalent of NaH and 1 equivalent of SDI. The
unavoidable waste produced is untroublesome (imidazole and
sulfate anion) and no heavy metal is used.
We have also succeeded in converting levulinic acid into
hexahydro pyrrolodiazepinediones. Albeit the higher strain of the
seven membered ring makes the cyclization less efficient, it is
worth noting that this represents the first example of synthesis of
(
method B), involving formation of the methanesulfonate followed
by treatment with NaH in DMF. By avoiding the presence of
imidazolide anion the yield was rised to a good 60%. Also for
hexahydro pyrrolodiazepinedione 7c method B was superior. On
the other hand, in the case of 7d, derived from an aromatic
isocyanide, cyclization was quite fast and the yield turned out
good also with method A.
Finally, we prepared also compounds 7e starting from a chiral
enantiopure propanolamine.
seven-membered rings through S
N
2 cyclization of an Ugi-derived
secondary amide onto an alcohol (or halogen) leaving group.[
This bicyclic scaffold is nearly unexplored, but, due to its drug-
likeness, it is expected to be promising in medicinal chemistry as
well.[23]
12e]
As can be seen in Figures 1 and 2, several of the adducts
prepared contain a protected phenol. This follows our recent
interest in the synthesis of artificial phenols from natural phenolic
building blocks.[21] The allyl group was selected by us as an ideal
protecting group for the phenolic moiety, since it can be deblocked
under neutral conditions. As an example, in Scheme 5 we show
the high yield deprotection of compound 6d to give the free phenol Experimental Section
7.
1
The pyrrolidinone ring can be further functionalised through
enolate chemistry. Scheme 5 shows the α-alkylation of the lactam
with two different electrophiles. These alkylations were found to
be diastereoselective, especially in the case of methylation.
3 3
General remarks. NMR spectra were taken at rt in CDCl or CD OD at
300 MHz ( H), and 75 MHz ( C), using, as internal standard, TMS ( H
1
13
1
NMR: 0.000 ppm) or the central peak of CDCl
3
(13C: 77.02 ppm) (for
OD ( H: 3.31 ppm, 13C:
1
spectra taken in CDCl ) or the central peak of CD
3
3
49.00 ppm). Chemical shifts are reported in ppm ( scale). Peak
assignments were made with the aid of gCOSY, gHSQC and gHMBC
experiments. GC-MS were carried out using an HP-1 column (12 m long,
0
1
.2 mm wide), electron impact at 70 eV, and a mass temperature of about
70 °C. Only m/z > 33 were detected. All analyses were performed (unless
otherwise stated) with a constant He flow of 1.0 ml/min with initial temp. of
0 °C, init. time 1 min, rate 20 °C/min, final temp. 260 °C, inj. temp. 250 °C,
7
det. temp. 280 °C. HRMS: samples were analysed with a Synapt G2 QToF
mass spectrometer. MS signals were acquired from 50 to 1200 m/z in ESI
positive ionization mode. TLC analyses were carried out on silica gel plates
and viewed at UV (254 nm) and developed with Hanessian stain (dipping
into a solution of (NH
4
)
4
MoO
4
4 H
2
O (21 g) and Ce(SO
4
)
2 2
4 H O (1 g) in
H
2
SO (31 ml) and H O (469 ml) and warming) or in an iodine chamber. R
4
2
f
were measured after an elution of 7-9 cm. Column chromatographies were
done with the "flash" methodology using 220-400 mesh silica. Petroleum
ether (40-60 °C) is abbreviated as PE. In extractive work-up, aqueous
solutions were always reextracted three times with the appropriate organic
solvent. Organic extracts were always dried over Na SO and filtered,
2 4
before evaporation of the solvent under reduced pressure. All reactions
using dry solvents were carried out under a nitrogen atmosphere.
Scheme 5. Further reactions performed on pyrrolopiperazinedione 6d. Yields
for 17 and 18 are calculated from unrecovered 6d.
(
R,S)-2-(4-(Benzyloxy)phenethyl)-8a-methyltetrahydropyrrolo[1,2-
a]pyrazine-1,6(2H,7H)-dione 6a. Isocyanide 8[ (475 mg, 2.00 mmol)
was dissolved in dry MeOH (10 mL) and treated with 3 Å powdered
molecular sieves (200 mg), levulinic acid (246 µL, 2.40 mmol), and
ethanolamine (145 µL, 2.40 mmol). The mixture was stirred at room
17]
Conclusions
temperature for 48 h. Then it was diluted with CH
evaporated to dryness. It was taken up in AcOEt / MeOH 95:5 and washed
with saturated aqueous NaHCO The organic phases gave, upon
evaporation, the crude Ugi product 5a, as a white solid (784 mg). It resulted
2 2
Cl , filtered and
In conclusion, we have developed an operationally simple and
high yielding methodology to convert levulinic acid into tetrahydro
pyrrolopiperazinediones, which contain two privileged scaffolds,
3
.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
+
quite pure at NMR. M.P.: 137.5-138.3 °C. R
f
= 0.22 (AcOEt/MeOH 95:5).
(6.3), 42 (27.4), 41 (20.1), 39 (6.5). HRMS (ESI+) m/z [M + H ]: Calcd. For
C H N O 225.1603; Found 225.1603.
12 21 2 2
1H NMR (300 MHz, CDCl
, 25 °C) δ = 7.46-7.27 (m, 5 H, aromatics of Bn);
.11 (d, 3JH,H = 8.5 Hz, 2 H, H meta to OBn); 7.08 (broad s, 1 H, NH), 6.91
d, 3JH,H = 8.5 Hz, 2 H, H ortho to OBn); 5.05 (s, 2 H, OCH
); 3.96-3.86 (m,
NH); 3.09-2.96 (m,
); 2.34-2.18 (m, 3 H, 2 H-3,
H-4); 1.97-1.83 (m, 1 H, H-4); 1.46 (s, 3 H, CH
). 13C NMR (75 MHz,
, 25 °C) δ 178.0 (HN-C=O), 173.7 (C-2), 157.4, 136.9, 130.9 (quat,),
29.7 (C meta to OBn), 128.6 (x 2), 127.9, 127.4 (x 2) (CH of Bn), 115.0
C ortho to OBn), 70.0 (OCH Ph), 67.6 (C-5), 60.2 (CH OH), 43.5
), 33.8 (C-4), 29.4 (C-3), 22.3
396.2049;
3
7
(
2
(
R,S)-2-((2-Allyloxyphenyl)methyl)-8a-methyltetrahydropyrrolo[1,2-
a]pyrazine-1,6(2H,7H)-dione 6d. solution of N-(2-allyloxybenzyl)
formamide (for its preparation see the S.I.) (409.5 mg, 1.995 mmol) in dry
CH Cl (9.4 mL) was cooled to ─30 °C and treated, in this order, with
triethylamine (945 µL, 6.78 mmol) and POCl (205 µL, 2.19 mmol). After
stirring at ─30 °C for 1 h, the solution was poured into saturated aqueous
NaHCO and extracted with Et O. Evaporation and chromatography (PE /
Et O 95:5 to 90:10) gave pure 2-(allyloxybenzyl)isocyanide (R = 0.69,
PE/Et O 95:5), that was evaporated at 15 mbar only (because it was partly
1
1
1
H, CHHOH); 3.60-3-37 (m, 4 H, CHHN, CHHOH, CH
H, CHHN); 2.78 (t, 3JH,H = 7.0 Hz, 2 H, ArCH
2
A
2
3
2
2
CDCl
3
3
1
(
(
(
2
2
3
2
OCH
2
CH
2
N); 40.9 (CH
2
NH); 34.2 (ArCH
2
2
f
+
3
CH ). HRMS (ESI+) m/z [M + H ]: Calcd. For C23
H N O
28 2 4
2
Found 396.2055. This Ugi adduct was taken up in dry THF (10 mL) and
treated with sulfonyl diimidazole (SDI) (595 mg, 3.00 mmol), and NaH
volatile) and used as such for the Ugi reaction and the subsequent
cyclization as described for 6a. The overall yield was 74% from the
(
60% suspension in mineral oil) (120 mg, 3.00 mmol). The mixture was
formamide (3 steps). Foam. R
f
= 0.55 (AcOEt/CH
2 2
Cl /MeOH 45 : 45 : 10).
stirred for 20 h at rt. Then tris(hydroxymethyl)aminomethane (TRIS) (121
mg, 1.00 mmol) was added, followed by another aliquot of NaH (12 mg,
1H NMR (300 MHz, CDCl
3
, 25°C) δ 7.30-7.15 (m, 2 H, H meta to Oallyl),
.93 (dt, 4JH,H = 1.0 (d), 3JH,H = 7.5 (t), 1 H, H para to Oallyl), 6.87 (d, JH,H
3
6
=
0
.30 mmol). After 1 h, the mixture was poured into saturated aqueous
NH Cl and extracted with AcOEt. Evaporation afforded a nearly pure crude
750 mg) that was anyway chromatographed (from AcOEt to AcOEt/MeOH
8.2 Hz, 1 H, H ortho to Oallyl), 6.04 (ddt, 3JH,H = 10.4, 17.3 (d), 5.2 (t), 1
4
), 5.40 (dq, 2
H,H and 4
H,H = 1.6 (q), 3
H, CH=CH
2
J
J
JH,H = 17.3 (d), 1 H,
(
CH=CHH), 5.28 (dq, 2JH,H and 4JH,H = 1.4 (q), 3JH,H = 10.4 (d), 1 H,
9
5:5) to give analytically pure 6a (703 mg). M.P.: 114.1-115.0 °C. R
f
= 0.44
CH=CHH), 4.72 and 4.61 (AB syst,. 2JH,H = 14.7, 2 H, CH
2
Ar), 4.55 (dt,
CH=), 4.11 (ddd, 3
JH,H = 1.6, 5.0,
1
(AcOEt/MeOH 95:5). H NMR (300 MHz, CDCl
3
, 25°C) δ 7.45-7.27 (m, 5
4JH,H = 1.5 (t), 3
J
H,H = 5.2 (d), 2 H, CH
2
3
H, aromatics of Bn); 7.09 (d, JH,H = 8.5 Hz, 2 H, H meta to OBn); 6.91 (d,
3JH,H = 8.5 Hz, 2 H, H ortho to OBn); 5.05 (s, 2 H, OCH
); 4.10-3.97 (m, 1
H, H-4), 3.65 (dt, 3JH,H = 6.7 (t), 2JH,H = 13.5 (d), 1 H, ArCH
CHH); 3.46 (dt,
3JH,H = 6.7 (t), 2JH,H = 13.5 (d), 1 H, ArCH
CHH); 3.40-3.27 (m, 1 H, H-3);
.10-2.92 (m, 2 H, H-3, H-4); 2.81 (t, 3JH,H = 6.5 Hz, 2 H, ArCH
); 2.48 (dt,
H,H = 17.4 (d), 1 H, H-8); 2.38-2.24 (m, 1 H, H-8); 2.20-
.02 (m, 2 H, H-7); 1.43 (s, 3 H, CH , 25 °C) δ
). 13C NMR (75 MHz, CDCl
1
(
3.5, 1 H, H-4); 3.39 (m, 1 H, H-3), 3.27-3.09 (m, 2 H, H-3 and H-4), 2.51
2
ddt, 5JH,H = 1.0, 3JH,H = 16.5 (d), 10.2 (t), 1 H, H-8), 2.44-2.13 (m, 3 H, H-
2
). 13C NMR (75 MHz, CDCl
), 129.7, 128.9 (C meta
), 111.7 (C ortho to
7
and H-8), 1.53 (s, 3 H, CH
3
3
, 25°C): δ 172.7,
2
171.5 (C=O), 156.6, 124.6 (quat,), 133.1 (CH=CH
2
3
3
2
to Oallyl), 121.0 (C para to Oallyl), 117.5 (CH=CH
2
J
H,H = 9.6 (t), 2
J
Oallyl), 68.8 (OCH ), 62.6 (C-8a), 46.2 (C-3); 44.9 (CH Ar), 33.8 (C-4),
2
2
2
1
1
(
(
3
3
10.41 min. M/z: 271 (M+
-
3
4
1
0.8 (C-7), 29.7 (C-8), 23.3 (CH
3. 1.1), 257 (0.9), 245 (1.8), 176 (3.3), 167 (100.0), 147 (26.3), 146 (22.0),
45 (5.7), 139 (12.2), 132 (6.1), 131 (11.4), 125 (22.8), 124 (25.7), 123
3
). GC-MS: R
t
72.6, 171.4 (C=O), 157.5, 136.9, 130.6 (quat,), 129.7 (C meta to OBn),
28.5 (x 2), 127.9, 127.4 (x 2) (CH of Bn), 114.9 (C ortho to OBn), 70.0
OCH
CH Ar), 30.6 (C-7), 29.6 (C-8), 23.2 (CH
379.2022; Found 396.2030.
2
Ph), 62.4 (C-8a), 49.0 (C-CH
2
Ar), 47.3 (C-3), 33.7 (C-4), 32.4
(7.3), 119 (6.6), 111 (8.9), 107 (20.6), 98 (20.4), 97 (14.3), 96 (8.9), 91
(43.6), 83 (10.9), 82 (16.4), 78 (16.8), 77 (17.5), 70 (32.4), 69 (9.8), 68
(10.3), 65 (8.6), 56 (32.1), 55 (67.8), 54 (13.2), 53 (10.0), 51 (9.2), 44 (11.7),
). HRMS (ESI+) m/z [M + H+]:
2
3
27 2 3
Calcd. For C23H N O
4
3 (10.0), 423 (64.5), 41 (90.2), 39 (32.7). HRMS (ESI+) m/z [M + H+]:
Calcd. For C18 315.1709; Found 315.1706.
(
R,S)-2-(Benzyl)-8a-methyltetrahydropyrrolo[1,2-a]pyrazine-
23 2 3
H N O
1,6(2H,7H)-dione 6b. It was prepared from benzyl isocyanide,
ethanolammine, and levulinic acid, following the same procedure
described for 6a. M.P.: 98.5-100 °C. R
= 0.42 (AcOEt/MeOH 95 : 5). 1H
NMR (300 MHz, CDCl , 25°C) δ 7.38-7.19 (m, 5 H, aromatics); 4.78. 4.39
AB system, 2JH,H = 14.5 Hz, 2 H, CH
Ph); 4.18-4.08 (m, 1 H, H-4); 3.45-
.31 (m, 1 H, H-3); 3.20-3.07 (m, 2 H, H-4 and H-3); 2.60-2.15 (m, 4 H, H-
. H-7); 1.55 (s, 3 H, CH , 25 °C): δ 172.6,
). 13C NMR (75 MHz, CDCl
71.6 (C=O), 136.3 (quat,), 128.8 (x 2), 128.0 (x 2), 127.8 (CH of Bn), 62.5
(
1
R,S)-2-(Cyclohexyl)-8a-methyltetrahydropyrrolo[1,2-a]pyrazine-
,6(2H,7H)-dione 6e. It was prepared from cyclohexyl isocyanide,
f
3
ethanolammine, and levulinic acid, following the same procedure
described for 6a. Foam. R = 0.38 (AcOEt/CH Cl
NMR (300 MHz, CDCl
CyHexCHN), 4.06 (ddd, JH,H = 2.5, 4.6, 13.2 Hz, 1 H, H-4); 3.36-3.08 (m,
(
2
/MeOH 45 : 45 : 5). 1H
f 2 2
, 25 °C) δ 4.44 (tt, 3JH,H = 3.6, 11.7 Hz, 1 H,
3
8
1
3
3
3
3
H, H-3, H-4); 2.53 (ddt, JH,H = 1.2, 3JH,H = 9.9 (t), 2JH,H = 16.7 (d) Hz, 1
5
3
(
(
C-8a), 50.1 (CH
CH
2
Ph), 45.9 (C-3); 33.6 (C-4), 30.8, 29.7 (C-7. C-8), 23.2
H, H-8), 2.37 (ddd, JH,H = 3.5, 8.3, 2JH,H = 16.7 Hz, 1 H, H-8), 2.29-2.10
3
+
3
). HRMS (ESI+) m/z [M + H ]: Calcd. For C15
H N O
19 2 2
259.1447;
(m, 2 H, H-7); 1.87-1.72 (m, 2 H); 1.72-1.57 (m, 3 H); 1.48 (s, 3 H, CH );
3
Found 259.1442.
.46-1.30 (m, 4 H); 1.15-0.98 (m, 1 H). 13C NMR (75 MHz, CDCl
, 25 °C)
δ 172.7, 170.9 (C=O), 62.5 (C-8a), 52.4 (cyHexCHN), 40.6 (C-3); 34.2 (C-
1
3
(
1
R,S)-2-(tert-Butyl)-8a-methyltetrahydropyrrolo[1,2-a]pyrazine-
,6(2H,7H)-dione 6c. It was prepared from t-butyl isocyanide,
ethanolammine, and levulinic acid, following the same procedure
4), 31.0 (C-7), 29.7 (C-8), 29.6, 29.5, 25.6, 25.5, 25.4 (CH
2
of cyclohexyl),
+
23.3 (CH
3
). GC-MS: R
t
8.71 min. M/z: 250 (M . 32.5), 235 (1.7), 222 (23.4),
207 (21.8), 179 (12.4), 169 (25.6), 167 (30.7), 165 (7.0), 153 (55.1), 140
(11.4), 139 (5.3), 125 (45.2), 124 (25.6), 123 (21.5), 112 (69.6), 111 (17.5),
110 (11.7), 98 (50.6), 97 (52.6), 96 (11.8), 83 (24.6), 82 (30.1), 81 (9.4),
72 (22.9), 70 (22.0), 69 (22.5), 68 (20.4), 56 (69.0), 55 (100.0), 54 (26.4),
44 (18.7), 42 (61.4), 41 (64.0), 39 (18.9). HRMS (ESI+) m/z [M + H ]:
23 2 2
Calcd. For C14H N O 251.1760; Found 251.1757.
described for 6a. M.P.: 96.6-97.0 °C. R
4
2
f
= 0.38 (AcOEt/CH
2
Cl
2
/MeOH
1
, 25°C) δ 4.06 (dt, 3JH,H = 4.2 (t),
7.5 : 47.5 : 5). H NMR (300 MHz, CDCl
J
3
5
H,H = 13.5 (d), 1 H, H-4); 3.45-3.33 (m, 2 H, H-3); 3.16 (ddt, JH,H = 1.0,
3JH,H = 7.8 (t), 2JH,H = 13.5 (d), 1 H, H-4); 2.49 (ddt, 5JH,H = 1.2, 3JH,H = 9.7
t), 2JH,H = 16.7 (d), 1 H, H-8), 2.34 (ddd, 3JH,H = 2.6, 9.0, 2JH,H = 16.7, 1 H,
H-8), 2.26-2.06 (m, 2 H, H-7); 1.46 (s, 3 H, CH ); 1.43 (s, 9 H, (CH C).
13C NMR (75 MHz, CDCl
, 25°C) δ 172.81, 172.78 (C=O), 63.2 (C-8a),
+
(
3
3 3
)
3
(
R,S)-2-(2-Allyloxyphenyl)-8a-methyltetrahydropyrrolo[1,2-
a]pyrazine-1,6(2H,7H)-dione 6f. solution of N-(4-allyloxyphenyl)
formamide[21] (177.5 mg, 1.00 mmol) in dry CH
Cl (1.5 mL) was cooled to
°C, and treated with Burgess reagent
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt) (286
5
7.9 (C(CH
3
)
3
), 42.8 (C-3); 34.9 (C-4), 31.4 (C-7), 29.8 (C-8), 28.1
A
+
(
(
3
(CH )
3
C), 23.2 (CH
3
). GC-MS: R
t
9.43 min. M/z: 224 (M . 16.9%), 196
2
2
22.7), 181 (14.7), 167 (100.0), 153 (5.3), 139 (9.0), 127 (6.3), 125 (26.6),
0
(
1
8
24 (24.5), 123 (5.2), 111 (6.9), 98 (16.5), 97 (13.2), 86 (16.8), 84 (7.1),
3 (9.1), 82 (6.5), 70 (13.4), 68 (6.1), 57 (17.7), 56 (17.2), 55 (24.6), 54
mg, 1.20 mmol). After stirring for 2 h and 30 min at 0 °C, dry methanol (4.5
mL), 3 Å powdered molecular sieves (100 mg), levulinic acid (123 µL, 1.20
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
mmol), and ethanolamine (72 µL, 1.20 mmol) were added. The mixture
(427 mg, 1.80 mmol) was added, and the mixture stirred for 48 h at room
was stirred at room temperature for 48 h. Then it was diluted with CH
filtered and evaporated to dryness. It was taken up in AcOEt / MeOH 95:5
and washed with saturated aqueous NaHCO . The organic phases gave,
2
Cl
2
,
temperature. Then it was diluted with CH
dryness. It was taken up in AcOEt / MeOH 95:5 and washed with saturated
aqueous NaHCO . The organic phases gave, upon evaporation, the crude
2 2
Cl , filtered and evaporated to
3
3
upon evaporation, and chromatography, the Ugi product (221 mg, 69%
from formamide). This intermediate was cyclized following the same
Ugi diastereomeric products. The diastereomeric ratio was 50:50 as
determined by 1H NMR of the crude. The two diastereomers were
procedure described for 6a, to give pure 6f as an oil (198 mg, 95%). R
f
separated by chromatography (CH
MeOH 47.5 : 47.5 : 5). Here we refer to them as "upper" and "lower" on
2
the basis of their R at TLC. R = 0.52 (upper), 0.40 (lower) (CH Cl :
AcOEt : MeOH 45 : 45 : 10). The overall yield was 615 mg (72%). These
Ugi adducts were cyclized independently to the two isomers of 6h. They
were taken up in dry DMF (2 mL/mmol) and treated with sulfonyl
diimidazole (SDI) (1.5 equiv.), and NaH (60% suspension in mineral oil)
(1.5 equiv.). The mixture was stirred for 20 h at rt. Then
tris(hydroxymethyl)aminomethane (TRIS) (0.5 mmol) was added, followed
by another aliquot of NaH (12 mg, 0.15 equiv.). After 1 h, the mixture was
2 2 2 2
Cl : AcOEt 1:1 to CH Cl : AcOEt :
1
=
J
0.42 (AcOEt/CH
2
Cl
2
50:50). H NMR (300 MHz, CDCl
3
, 25 °C) δ 7.12 (d,
3
3
H,H = 9.0 Hz, 2 H, H meta to Oallyl); 6.93 (d, JH,H = 9.0 Hz, 2 H, H ortho
f
f
2
3
to Oallyl); 6.04 (ddt, JH,H = 10.5, 17.2 (d), 5.3 (t) Hz, 1 H, CH=CH
2
), 5.41
(
2
dq, 2JH,H and 4JH,H = 1.6 (q), 3JH,H = 17.2 (d) Hz, 1 H, CH=CHH), 5.29 (dq,
J
H,H and 4JH,H = 1.4 (q), 3JH,H = 10.5 (d) Hz, 1 H, CH=CHH), 4.53 (dt, JH,H
1.5 (t), 3JH,H = 5.3 (d) Hz, 2 H, CH CH=), 4.25 (ddd, 3JH,H = 1.9, 5.2, 2JH,H
4
=
=
3
=
2
13.5 Hz, 1 H, H-4); 3.85 (ddd, 3JH,H = 5.3, 11.4, 2JH,H = 12.0 Hz, 1 H, H-
), 3.54 (ddd, 3JH,H = 1.9, 4.7, 2JH,H = 12.1 Hz, 1 H, H-3), 3.37 (dddd, 5JH,H
1.1, 3JH,H = 4.7, 11.2, 2JH,H = 13.5 Hz, 1 H, H-4), 2.65-2.15 (m, 4 H, H-7
and H-8), 1.61 (s, 3 H, CH
1
3
). 13C NMR (75 MHz, CDCl
71.8 (C=O), 157.5, 134.6 (quat,), 132.9 (CH=CH ), 127.0 (C meta to
), 115.4 (C ortho to Oallyl), 69.0 (OCH ), 62.9 (C-
). GC-MS: R
0.68 min. M/z: 300 (M . 60.8), 272 (11.1), 231 (100.0), 175 (3.9), 162
3
, 25 °C): δ 172.8,
4
poured into saturated aqueous NH Cl and extracted with AcOEt.
2
Evaporation afforded a crude product that was chromatographed (from
AcOEt to AcOEt/MeOH 95:5) to give analytically pure 6h-upper (61%) and
6h-lower (88%), as foams (upper and lower refers to the TLC behavior of
intermediate Ugi adducts, because, after cyclization, the diastereomers
OAllyl), 117.8 (CH=CH
2
2
8
1
a), 50.5 (C-3); 34.2 (C-4), 30.7 (C-7), 29.7 (C-8), 23.5 (CH
3
t
+
(
(
(
50.3), 134 (24.5), 124 (48.1), 121 (6.3), 120 (7.1), 111 (5.3), 110 (6.2), 82
9.7), 80 (5.4), 79 (6.7), 77 (6.7), 68 (5.4), 65 (5.2), 56 (12.9), 55 (38.3), 54
coelute at TLC. R
f
= 0.34 (AcOEt/CH
2
Cl
2
/MeOH 45 : 45 : 5).
8.6), 53 (6.9), 42 (24.3), 41 (35.1), 42 (10.2), 41 (18.1). HRMS (ESI+) m/z
1
6h-upper. Foam. [α]
D
= +49.8 (c 1.52, CHCl
3
). H NMR (300 MHz, CDCl
3
,
+
[M + H ]: Calcd. For C17
H N O
21 2 3
301.1552; Found 301.1545.
3
25 °C) δ 7.45-7.26 (m, 5 H, aromatics of Bn); 7.12 (d, JH,H = 8.7 Hz, 2 H,
3
H meta to OBn); 6.91 (d, JH,H = 8.7 Hz, 2 H, H ortho to OBn); 5.05 (s, 2 H,
); 3.96 (ddd, 2JH,H = 13.5, JH,H = 7.5, 6.0 Hz, 1 H, ArCH
3
CHH), 3.93-
(
R,S)-2-((4-Allyloxyphenyl)methyl)-8a-methyltetrahydropyrrolo[1,2-
solution of N-(4-allyloxybenzyl)
formamide (for its preparation see the S.I.) (2.222 g, 11.62 mmol) was
dissolved in dry CH Cl (60 mL) and treated with N-methylmorpholine
3.83 mL, 34.86 mmol). Then solution of triphosgene
bis(trichloromethyl) carbonate) (1.034 g, 5.23 mmol) in dry CH Cl (10 ml)
OCH
2
2
3.83 (m, 1 H, H-4); 3.46 (dd, JH,H = 4.2, 2JH,H = 13.2, 1 H, H-3); 3.35 (ddd,
3
a]pyrazine-1,6(2H,7H)-dione 6g.
A
3JH,H = 7.9, 6.9, 2
2JH,H = 13.4 Hz, 1 H, H-3); 2.93-2.72 (m, 2 H, ArCH
2
JH,H = 13.5 Hz, 1 H, ArCH JH,H = 3.8,
CHH), 3.03 (dd, 3
2
2
2
); 2.55-2.44 (m, 1 H,
3
(
(
a
H-8); 2.33-2.15 (m, 2 H, H-7. H-8); 2.07-1.96 (m, 1 H, H-7); 1.35 (d, JH,H
). 13C NMR (75 MHz, CDCl
= 6.5, 3 H, CH CH); 1.32 (s, 3 H, CH , 25°C)
3 3 3
2
2
was added. After stirring for 2 h at room temperature, the mixture was
poured into brine (50 mL) + saturated aqueous NaHCO (50 mL) and
extracted three times with Et O. The organic phase was washed with 1 M
KH PO + some 2 M HCl to adjust the pH to 5. Evaporation and
chromatography (PE / Et O 8:2) gave pure 4-(allyloxybenzyl)isocyanide
= 0.43, PE/Et O 8:2), that was evaporated at 15 mbar only (because it
δ 173.8, 171.7 (C=O), 157.5, 136.9, 130.5 (quat,), 129.8 (C meta to OBn),
128.5 (x 2), 127.9. 127.4 (x 2) (CH of Bn), 115.0 (C ortho to OBn), 70.0
3
2
2 2
(OCH Ph), 63.3 (C-8a), 52.0 (C-3), 49.2 (C-CH Ar), 45.6 (C-4), 33.0
2
4
(CH
2
Ar), 31.4 (C-7), 30.3 (C-8), 23.6 (C-CH
3
), 17.1 (CH-CH ). HRMS
3
+
2
(ESI+) m/z [M + H ]: Calcd. For C24
29 2
H N O
3
393.2178; Found 393.2184.
(
R
f
2
was partly volatile) and used as such for the Ugi reaction and the
subsequent cyclization as described for 6a. The yield of the Ugi reaction
was 87% (from the formamide), whereas the yield of cyclization was 80 %.
1
6
2
h-lower. Foam. [α]
D
= ─25.2 (c 0.98, CHCl
3
). H NMR (300 MHz, CDCl
3
,
3
5 °C) δ 7.45-7.26 (m, 5 H, aromatics of Bn); 7.11 (d, JH,H = 8.5 Hz, 2 H,
H meta to OBn); 6.91 (d, JH,H = 8.5 Hz, 2 H, H ortho to OBn); 5.05 (s, 2 H,
3
the overall yield was 70% the from formamide (3 steps). M.P. = 107.6-
); 4.16 (hexuplet, 3JH,H = 6.9 Hz, 1 H, H-4); 3.68 (dt, 2JH,H = 14.2, 3JH,H
CHH), 3.54 (dt, 2JH,H = 14.2, 3JH,H = 7.1 (t) Hz, 1 H,
OCH
7.1 Hz, 1 H, ArCH
CHH), 3.34 (dd, 3JH,H = 6.7, 2JH,H = 13.1, 1 H, H-3); 3.13 (dd, JH,H
ArCH
.7, 2JH,H = 13.1 Hz., 1 H, H-3); 2.81 (t, 3JH,H = 7.2 Hz, 2 H, ArCH
), 2.56-
.20 (m, 3 H, H-8 (2), H-7 (1)), 2.00-1.90 (m, 1 H, H-7), 1.43 (s, 3 H, CH );
.23 (d, 3JH,H = 6.6, 3 H, CH CH). 13C NMR (75 MHz, CDCl
, 25°C) δ 174.1,
72.0 (C=O), 157.5, 137.0, 130.6 (quat,), 129.8 (C meta to OBn), 128.5 (x
), 127.9, 127.4 (x 2) (CH of Bn), 115.0 (C ortho to OBn), 70.0 (OCH Ph),
2
1
1
08.5 °C. R
f
= 0.61 (AcOEt/CH
2
Cl
2
/MeOH 45 : 45 : 5). H NMR (300 MHz,
=
2
3
CDCl
3
, 25 °C) δ 7.15 (d, 3JH,H = 8.7 Hz, 2 H, H meta to OAll); 6.88 (d, JH,H
3
2
=
=
1
8.7 Hz, 2 H, H ortho to OAll); 6.05 (ddt, 3JH,H = 10.5, 17.3 (d), 5.3 (t) Hz,
7
2
1
1
2
6
7
2
H, CH=CH
2
); 5.41 (dq, 2JH,H and 4JH,H = 1.6 (q), 3JH,H = 17.3 (d) Hz, 1 H,
3
CH=CHH), 5.29 (dq, 2JH,H and 4
J
H,H = 1.4 (q), 3
J
H,H = 10.5 (d) Hz, 1 H,
3
3
2
4
CH=CHH), 4.70 (d, JH,H = 14.4 Hz, 1 H, ArCHH), 4.53 (dt, JH,H = 1.5 (t),
3JH,H = 5.3 (d) Hz, 2 H, CH
.16-4.08 (m, 1 H, H-4); 3.40-3.28 (m, 1 H, H-3); 3.19-3.05 (m, 2 H, H-4,
H-3); 2.59-2.15 (m, 4 H, H-7, H-8); 1.53 (s, 3 H, CH
), 13C NMR (75 MHz,
CDCl , 25 °C): δ 172.6, 171.5 (C=O), 158.3, 128.5 (quat,), 133.1
CH=CH ), 129.4 (C meta to OAll), 117.8 (CH=CH ), 115.0 (C ortho to
OAll), 68.8 (=C-CH
CH=CH
2
); 4.32 (d, 2JH,H = 14.4 Hz, 1 H, ArCHH),
2
2
4
2.8 (C-8a), 51.7 (C-3), 49.2 (C-CH
), 29.7 (C-8), 25.0 (C-CH ), 18.8 (CH-CH
393.2178; Found 393.2180.
2
Ar), 43.9 (C-4), 32.9 (CH
2
Ar), 31.3 (C-
3
+
3
3
). HRMS (ESI+) m/z [M + H ]:
3
29 2 3
Calcd. For C24H N O
(
2
2
2
), 62.5 (C-8a), 49.5 (N-CH
2
Ar), 45.6(C-3), 33.7 (C-4),
10.77 min. M/z: 314 (M+,
(
4S,8aR)
and
(4S,8aS)-2-(4-(Benzyloxy)phenethyl)-8a-methyl-4-
phenyltetrahydropyrrolo[1,2-a]pyrazine-1,6(2H,7H)-diones 6i. They
were prepared with the same procedure employed for 6h. However, in this
3
6
1
0.8 (C-8), 29.7 (C-7), 23.2 (CH ). GC-MS: R
3
t
6.8%), 273 (5.6), 167 (100.0), 147 (54.1), 139 (5.1), 125 (7.7), 124 (11.9),
07 (5.9), 42 (5.8), 41 (14.4). HRMS (ESI+) m/z [M + H ]: Calcd. For
+
case, cyclization of the upper (higher R
8
f
) Ugi adduct was carried out at
2
Cl /
18 23 2 3
C H N O 315.1709; Found 315.1708.
0 °C. R of intermediate Ugi adducts: 0.64 (upper), 0.48 (lower) (CH
f
2
1
AcOEt / MeOH 48.5 : 48.5 : 3). The diastereomeric ratio, determined by H
NMR on the crude was 50:50. Chromatography after cyclization (from
AcOEt to AcOEt/MeOH 95:5) gave analytically pure 6i-upper (61%) and
(
4S,8aR)
and
(4S,8aS)-2-(4-(Benzyloxy)phenethyl)-4,8a-
6h.
dimethyltetrahydropyrrolo[1,2-a]pyrazine-1,6(2H,7H)-diones
Levulinic acid (153 µL, 1.50 mmol) was dissolved in dry MeOH (7.5 mL),
and treated with 3 Å powdered molecular sieves (150 mg), and (S)-2-
amino-1-propanol (117 µl, 1.50 mmol) was added. After 2 h, isocyanide 8
6
i-lower (88%), as foams (upper and lower refers to the TLC behavior of
intermediate Ugi adducts), because, after cyclization, the diastereomers
coelute at TLC. R = 0.34 (AcOEt/CH Cl /MeOH 45 : 45 : 5).
f
2
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
6
i-upper. Oil. R
f
= 0.46 (PE / AcOEt / MeOH 19: 76 : 5). [α]
D
= ─103.4 (c
= 13.4 Hz, H-4); 3.10 (quintuplet, 3JH,H = 6.3 Hz, 1 H, H-3); 2.98-2.74 (m,
1
0
.64, CHCl
3
). H NMR (300 MHz, CDCl , 25 °C) δ 7.45-7.20 (m, 8 H); 7.04
3
4 H, ArCH
H-7); 1.42 (s, 3 H, CH
(75 MHz, CDCl , 25 °C) δ 173.1, 171.1 (C=O), 157.4, 136.9, 131.0 (quat,),
129.8 (C meta to OBn), 128.5 (x 2), 127.9, 127.4 (x 2) (CH of Bn), 114.9
(C ortho to OBn), 70.0 (OCH Ph), 62.1 (C-8a), 53.6 (C-3), 47.7 (C-CH Ar),
), 18.6 (CH-
2
CHH, H-4, ArCH
2
); 2.60-2.35 (m, 2 H, H-8); 2.25-2.02 (m, 2 H,
(
(
d, 3JH,H = 8.1 Hz, 2 H); 6.98 (d, 3JH,H = 8.6 Hz, 2 H, H meta to OBn); 6.86
d, 3JH,H = 8.6 Hz, 2 H, H ortho to OBn); 5.02 (s, 2 H, OCH ); 4.94 (d, 3JH,H
4.0 Hz, 1 H, H-4); 3.94 (dd, 2JH,H = 4.6, 3JH,H = 13.7 Hz, 1 H, H-3); 3.76
ddd, 2JH,H = 13.5, 3JH,H = 8.8, 6.0 Hz, 1 H, ArCH CHH); 3.13 (dd, 2JH,H
3.7, 3JH,H = 1.2 Hz, 1 H, H-3); 2.99 (ddd, 2JH,H = 13.5, 3JH,H = 8.5, 6.9 Hz,
H, ArCH CHH); 2.67-2.51 (m, 3 H, ArCHH, H-8, H-7); 2.45-2.13 (m, 3 H,
). 13C NMR (75 MHz, CDCl
, 25 °C) δ
73.4, 172.1 (C=O), 157.5, 140.2, 136.9, 130.6 (quat,), 129.7 (C meta to
OBn), 128.8 (x 2), 128.6 (x2), 128.0, 127.8, 127.4 (x 2), 125.5 (x2) (CH of
benzyl and phenyl), 115.0 (C ortho to OBn), 70.0 (OCH Ph), 63.1 (C-8a),
Ar), 31.4 (C-7), 29.9 (C-
3
); 1.09 (d, 3
J
H,H = 6.3 Hz, 3 H, CH
3
CH). 13C NMR
2
3
=
(
1
1
2
=
2
2
39.1 (C-4), 32.8 (CH
CH
393.2174.
2
Ar), 30.7 (C-7), 29.6 (C-8), 22.9 (C-CH
3
+
2
3
). HRMS (ESI+) m/z [M + H ]: Calcd. For C24
H N O
29 2 3
393.2178; Found
ArCHH, H-8, H-7); 1.44 (s, 3 H, CH
3
3
1
(
R,S)-2-(4-(Benzyloxy)phenethyl)-9a-methylhexahydro-1H-
2
pyrrolo[1,2-a][1,4]diazepine-1,7(8H)-dione 7a.
53.3 (C-4), 52.7 (C-3), 49.4 (C-CH
8), 23.9 (C-CH
455.2335; Found 455.2337
2
Ar), 32.6 (CH
). HRMS (ESI+) m/z [M + H ]: Calcd. For C29
2
+
3
H N O
31 2 3
Levulinic acid (306 µL, 3.00 mmol) was dissolved in dry MeOH (15 mL),
and treated with
propanolammine (230 µl, 3.00 mmol) was added. After 2 h, isocyanide 8
593 mg, 2.5 mmol) was added, and the mixture stirred for 48 h at room
temperature. Then it was diluted with CH Cl , filtered and evaporated to
dryness. It was taken up in AcOEt / MeOH 95:5 and washed with saturated
aqueous NaHCO . The organic phases gave, upon evaporation, and
3 Å powdered molecular sieves (300 mg), and
6
0
7
=
5
i-lower. Oil. R
.98, CHCl
f
= 0.51 (PE / AcOEt / MeOH 19: 76 : 5).. [α]
D
= ─10.5 (c
(
1
3
). H NMR (300 MHz, CDCl
3
, 25 °C) δ 7.45-7.25 (m, 8 H); 7.22-
2
2
.15 (m, 2 H); 7.14 (d, JH,H = 8.7 Hz, 2 H, H meta to OBn); 6.93 (d, 3JH,H
3
8.6 Hz, 2 H, H ortho to OBn); 5.07 (d, J = not measurable, 1 H, H-4);
3
.05 (s, 2 H, OCH
CHH); 3.66-3.54 (m, 2 H, H-3. ArCH
2JH,H = 13.5, 1 H, H-3); 2.95-2.79 (m, 2 H, ArCH
H-7); 2.38-2.25 (m, 1 H, H-7); 2.09-1.95 (m, 1 H, H-8); 1.30 (s, 3 H, CH
13C NMR (75 MHz, CDCl
, 25 °C) δ 174.6, 172.1 (C=O), 157.6, 138.4,
2
); 3.83 (dt, 2
J
H,H = 13.8 (d), 3
CHH); 3.48 (dd, 3JH,H = 3.8,
); 2.63-2.40 (m, 2 H, H-8,
).
JH,H = 7.0 (t) Hz, 1 H,
chromatography (AcOEt to AcOEt / MeOH 9:1) the pure Ugi adduct (895
mg, 86%). It was taken up in dry DMF (4 mL) and treated with sulfonyl
diimidazole (SDI) (649 mg, 3.27 mmol), and NaH (60% suspension in
mineral oil) (131 mg, 3.27 mmol). The mixture was stirred for 20 h at rt.
Then tris(hydroxymethyl)aminomethane (TRIS) (198 mg, 1.63 mmol) was
added, followed by another aliquot of NaH (20 mg, 0.5 mmol). After 1 h,
ArCH
2
2
2
3
3
1
1
37.0, 130.5 (quat,), 129.8 (C meta to OBn), 128.8 (x 2), 128.6 (x2), 127.93,
27.87, 127.4 (x 2), 126.2 (x2) (CH of benzyl and phenyl), 115.1 (C ortho
the mixture was poured into saturated aqueous NH
4
Cl and extracted with
Cl / AcOEt / MeOH
= 0.47 (CH Cl
, 25 °C) δ 7.45-
to OBn), 70.0 (OCH
CH
m/z [M + H ]: Calcd. For C29
2
Ph), 63.0 (C-8a), 51.9 (C-4), 50.7 (C-3), 49.3 (C-
Ar), 31.4 (C-7), 29.4 (C-8), 25.5 (C-CH ). HRMS (ESI+)
455.2335; Found 455.2331
AcOEt. Chromatography (AcOEt / CH Cl 1:1 to CH
2
2
2
2
2
Ar), 33.1 (CH
2
3
4
7.5 : 47.5 : 5) gave pure 7a as an oil (583 mg, 68%). R
f
2
2
/
+
H N O
31 2 3
1
AcOEt / MeOH 47.5 : 47.5 : 5). H NMR (300 MHz, CDCl
3
7
.27 (m, 5 H, aromatics of Bn); 7.10 (d, 3JH,H = 8.5 Hz, 2 H, H meta to
3
(
3R*,8aR*)
and
(3R*,8aS*)-2-(4-(Benzyloxy)phenethyl)-3,8a-
OBn); 6.90 (d, JH,H = 8.5 Hz, 2 H, H ortho to OBn); 5.04 (s, 2 H, OCH
2
);
dimethyltetrahydropyrrolo[1,2-a]pyrazine-1,6(2H,7H)-diones 6j. They
were prepared starting from isocyanide 8, racemic 1-amino-2-propanol,
and levulinic acisd following the same procedure employed for 6h. The
diastereomeric ratio after the Ugi step was 50:50 as determined by NMR.
The two Ugi diastereomeric adducts were not separable. After cyclization,
4.12 (dt, 3JH,H = 7.0, 2JH,H = 14.0 Hz, 1 H, H-5), 3.70 (dt, 3JH,H = 7.6, 2JH,H
13.4, 1 H, ArCH
CHH); 3.49 (dt, 3 H,H = 6.8, 2
ArCH
CHH); 3.29 (ddd, 3JH,H = 2.1, 9.4, 2JH,H = 14.7 Hz, 1 H, H-3), 3.12
=
2
J
JH,H = 13.4 Hz, 1 H,
2
(ddd, JH,H = 2.3, 6.9, 2JH,H = 14.7, 1 H, H-3), 2.85 (dt, JH,H = 6.3, JH,H
3
3
2
=
=
3
3
2
14.0 Hz, 1 H, H-5), 2.78 (t, JH,H = 7.0 Hz, 2 H, ArCH ); 2.66 (ddd, JH,H
1
4.6, 8.6, 2JH,H = 12.9 Hz, 1 H, H-9); 2.38-2.14 (m, 2 H, H-8); 1.95-1.62 (m,
3 H, H-9, H-4); 1.50 (s, 3 H, CH , 25 °C) δ
). 13C NMR (75 MHz, CDCl
a diastereomeric ratio of 43 : 57 (upper / lower) was determined by H NMR
of the crude. Chromatography (from CH
/
(
2
Cl
MeOH 47.5 : 47.5 : 5) gave analytically pure 6j-upper (61%) and 6j-lower
88%), as oils (upper and lower refers to the TLC behavior of the cyclized
2
/ AcOEt 1:1 to CH
2
Cl
2
/ AcOEt
3
3
174.8, 173.9 (C=O), 157.4, 137.0, 130.9 (quat,), 129.8 (C meta to OBn),
128.5 (x 2), 127.9, 127.4 (x 2) (CH of Bn), 114.9 (C ortho to OBn), 70.0
products) in 77% overall yield.
2 2
(OCH Ph), 67.5 (C-9a), 53.1 (C-CH Ar), 47.7 (C-3), 36.5 (C-5), 33.6 (C-9)
2 3
33.1 (CH Ar), 29.5 (C-8), 26.9 (C-4), 23.3 (CH ). GC-MS (initial temp =
1
100 °C for 2 min. then 20 °C min up to 270 °C. After 4 min. at 270 °C the
6
j-upper. Oil. R
f 2 2
= 0.47 (CH Cl / AcOEt / MeOH 47.5 : 47.5 : 5). H NMR
+
temp. was raised to 280 °C in 30 sec): R
t
16.93 min. M/z: 392 (M . 1.0),
(
300 MHz, CDCl
3
, 25 °C): δ 7.45-7.27 (m, 5 H, aromatics of Bn); 7.12 (d,
H,H = 8.3 Hz, 2 H, H meta to OBn); 6.90 (d, JH,H = 8.3 Hz, 2 H, H ortho
3
3
210 (66.8), 204 (2.5), 167 (13.4), 138 (10.5), 124 (7.3), 111 (5.1), 110 (7.1),
J
); 4.18 (dd, 3JH,H = 5.3, 2JH,H = 13.8 Hz, 1 H, H-
CHH); 3.60
91 (100.0), 82 (4.3), 70 (10.9), 65 (5.9), 56 (6.2), 55 (6.4), 44 (7.4), 42 (9.1),
to OBn); 5.04 (s, 2 H, OCH
); 3.99 (ddd, 3JH,H = 7.7, 8.8, 2JH,H = 13.7 Hz, 1 H, ArCH
(
2
+
24 29 2 3
41 (5.4). HRMS (ESI+) m/z [M + H ]: Calcd. For C H N O 393.2178;
4
2
dquint, 1 H, JH,H = 5.7, 2JH,H = 11.4 Hz, 1 H, H-3); 3.31 (ddd, JH,H = 4.8,
3
3
Found 393.2180.
8
.9, 2
.67 (dt, 3JH,H = 8.1, 3
2
JH,H = 13.7 Hz, 1 H, ArCH CHH); 2.90-2.74 (m, 2 H, ArCHH, H-4);
2
J
H,H = 13.5 Hz, 1 H, ArCHH); 2.42 (dt, 3JH,H = 9.9,
(R,S)-2-Cyclohexyl-9a-methylhexahydro-1H-pyrrolo[1,2-
a][1,4]diazepine-1,7(8H)-dione 7b.
2
H,H = 17.0 Hz, H-8); 2.21 (ddd, JH,H = 3.4, 9.5, 3JH,H = 17.0 Hz, 1 H, H-
3
J
8
); 2.09-1.90 (m, 2 H, H-7); 1.45 (s, 3 H, CH
CH , 25 °C) δ 172.5, 172.4 (C=O), 157.5,
CH). 13C NMR (75 MHz, CDCl
37.0, 130.6 (quat,), 129.8 (C meta to OBn), 128.5 (x 2), 127.9, 127.4 (x
) (CH of Bn), 114.8 (C ortho to OBn), 69.9 (OCH Ph), 62.1 (C-8a), 51.1
); 1.24 (d, 3JH,H = 5.7 Hz, 3 H,
3
3
3
The Ugi reaction of levulinic acid, propanolamine, and cyclohexyl
isocyanide was carried out as described for 7a and gave, after
chromatography, a yield of 85%. Then, cyclization was carried out with two
different methodologies. Method A. The same procedure described for 7a
was followed, but the reaction was performed at 50 °C. The yield of pure
1
2
2
(
2
C
C-3), 44.0 (C-CH
2
Ar), 40.2 (C-4), 32.8 (CH
), 18.3 (CH-CH
393.2178; Found 393.2185.
2
Ar), 30.8 (C-7), 29.4 (C-8),
). HRMS (ESI+) m/z [M + H ]: Calcd. For
+
2.9 (C-CH
3
3
H N O
24 29 2 3
7b after chromatography (AcOEt to AcOEt/MeOH 95:5) was 28%. Method
B. A solution of Ugi adduct (300 mg, 1.06 µmol) in dry CH Cl (10 mL) was
2
2
1
6
j-lower. Oil. R
f
= 0.38 (CH
, 25 °C) δ 7.45-7.27 (m, 5 H, aromatics of Bn); 7.11 (d,
H,H = 8.4 Hz, 2 H, H meta to OBn); 6.92 (d, 3JH,H = 8.4 Hz, 2 H, H ortho
to OBn); 5.05 (s, 2 H, OCH ); 4.17-4.04 (m, 1 H, ArCH
CHH); 3.77 (d, 2JH,H
2
Cl
2
/ AcOEt / MeOH 47.5 : 47.5 : 5). H NMR
cooled to ─ 18 °C, and treated with triethylamine .(326 µL, 2.34 mmol) and
with methanesulfonyl chloride (100 µL, 1.28 mmol). After 40 min the
reaction was complete by TLC. The mixture was poured into a 3:1 mixture
(
300 MHz, CDCl
3
3
J
2
2
4 4 2 4
of saturated aqueous NH Cl and 5% aqueous (NH ) PO , and extracted
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
with AcOEt (pH of aqueous phase = 4). After evaporation to dryness, the
crude mesylate was taken up in dry DMF (1 mL), and treated with NaH
5), 2.88 (ddd, 3JH,H = 5.1, 7.7, 2JH,H = 12.8 Hz, 1 H, H-9), 2.55-2.35 (m, 2
H, H-8), 2.18-1.93 (m, 2 H, H-4), 1.92 (dt, 3
J
H,H = 9.0 (t), 2
). 13C NMR (75 MHz, CDCl
, 25 °C) δ 174.8,
174.4 (C=O), 157.2, 138.9 (quat,), 133.0 (CH=CH ), 127.3 (C meta to OAll),
117.7 (CH=CH ), 115.4 (C ortho to OAll), 69.0 (=C-CH ), 67.6 (C-9a), 50.9
JH,H = 12.8 (d)
(60% in mineral oil, 64 mg, 1.59 mmol). The solution was stirred at 50 °C
Hz, 1 H, H-9), 1.65 (s, 3 H, CH
3
3
for 6 h. Then it was poured into saturated NH Cl and extracted with AcOEt.
4
2
Evaporation and chromatography gave pure 7b (167 mg, 60%). M.P. =
2
2
1
1
J
1
09.2-110.9. R
f
0.21 (AcOEt). H NMR (300 MHz, CDCl
3
, 25 °C) δ 4.42 (tt,
(C-3), 36.9 (C-5), 33.7 (C-9) 29.6 (C-8), 27.5 (C-4), 23.1 (CH
3
). HRMS
3
H,H = 3.6, 11.1 Hz, 1 H, CHN); 4.17 (ddd, 3JH,H = 7.5, 6.0, 2JH,H = 13.8 Hz,
+
(ESI+) m/z [M + H ]: Calcd. For C18
23 2
H N O
3
315.1709; Found 315.1715.
H, H-5), 3.30-3.15 (m, 2 H, H-3), 2.94 (dt, JH,H = 6.9, 2JH,H = 13.8 Hz, 1
3
H, H-5); 2.68 (ddd, JH,H = 8.1, 6.0, 2JH,H = 12.3 Hz, 1 H, H-9); 2.48-2.29
3
(
5R,9aR)
dimethylhexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-1,7(8H)-diones
e. They were prepared with the same procedure employed for 7b
method A). However, in this case, the isocyanide was used in excess (1.2
equivalents) whereas (R)-3-amino-1-butanol and levulinic acid were used
in equimolar quantities. R of intermediate Ugi adducts: 0.50 (upper), 0.43
lower) (CH Cl / AcOEt / MeOH 45 : 45 : 10). The diastereomeric ratio,
and
(5R,9aS)-2-((4-Allyloxyphenyl)methyl)-5,9a-
(
m, 2 H, H-8); 2.06-1.88 (m, 2 H, H-9, H-4); 1.85-1.55 (m, 6 H, H-4 and
CH cyclohexyl); 1.55 (s, 3 H, CH ); 1.48-1.23 (4 H, m, CH cyclohexyl);
.16-0.97 (m, 1 H, CH , 25 °C) δ
cyclohexyl). 13C NMR (75 MHz, CDCl
74.6, 173.6 (C=O), 67.8 (C-9a), 54.9 (CHN), 39.9 (C-3), 36.5 (C-5), 33.5
2
3
2
7
(
1
1
2
3
(
2
C-9), 30.2, 29.6, 25.6, 25.5, 25.4 (CH
2
cyclohexyl), 29.5 (C-8), 27.6 (C-4),
f
+
3.4 (CH
3
). GC-MS: R
t
9.07 min. M/z: 264 (M . 30.1), 236 (4.8), 235 (5.3),
(
2
2
221 (31.5), 193 (9.5), 181 (23.4), 167 (7.5), 153 (6.0), 139 (15.0), 138
1
determined by H NMR on the crude, was 50:50. The two diastereomers
were separated after the Ugi and cyclized independently using method A.
Upper and lower refers to the TLC behavior of intermediate Ugi adducts,
(
8
(
24.8), 137 (8.4), 124 (48.8), 111 (100.0), 110 (13.8), 98 (28.6), 96 (11.4),
3 (11.9), 82 (12.0), 70 (6.4), 69 (5.5), 68 (6.9), 56 (39.1), 55 (42.5), 54
9.0), 42 (19.7), 41 (34.7), 39 (8.4). Calcd. For C15 265.1916;
25 2 2
H N O
since, after cyclization, they had the same R
f
. Chromatography after
Found 265.1912.
cyclization (from AcOEt to AcOEt/MeOH 95:5) gave analytically pure 7e-
f
upper (45%) and 7e-lower (53%), as oils. R = 0.54 (AcOEt / MeOH 95 :
(
R,S)-2-((4-Allyloxyphenyl)methyl)-9a-methylhexahydro-1H-
5).
pyrrolo[1,2-a][1,4]diazepine-1,7(8H)-dione 7c. It was prepared from
levulinic acid, propanolamine and 4-allyloxybenzyl isocyanide (for its
preparation see the synthesis of 6g), following the same procedures
described for 7b. The yield of the Ugi step was 72% (from the formamide).
The isolated yield of cyclization was 45% (method A) or 74% (method B),
). 1H NMR (300 MHz CDCl
D 3 3
e-upper. [α] = ─12.6 (c 1, CHCl , 25°C) δ
7
.17 (d, 3JH,H = 8.7 Hz, 2 H, H meta to OAll); 6.87 (d, JH,H = 8.7 Hz, 2 H,
3
7
3
H ortho to OAll); 6.05 (ddt, JH,H = 10.5, 17.2 (d), 5.3 (t) Hz, 1 H, CH=CH
2
);
.41 (dq, 2JH,H and 4JH,H = 1.6 (q), 3JH,H = 17.2 (d) Hz, 1 H, CH=CHH), 5.29
5
after chromatography (AcOET to AcOEt / MeOH 95:5). Oil. R
f
= 0.24
dq, 2JH,H and 4JH,H = 1.4 (q), 3JH,H = 10.5 (d) Hz, 1 H, CH=CHH), 4.56 and
(
1
, 25 °C) δ 7.13 (d, 3JH,H = 8.6 Hz, 2 H,
(
AcOEt). H NMR (300 MHz, CDCl
3
.47 (AB syst,. 2JH,H = 14.3 Hz, 2 H, ArCH
); 3.44 (ddd, 3JH,H =4.4, 12.4, 2JH,H = 15.1 Hz,
5.4 (d) Hz, 2 H, CH CH=CH
2
), 4.52 (dt, 4JH,H = 1.5 (t), 3JH,H
4
=
1
2
H meta to OAll); 6.86 (d, 3JH,H = 8.6 Hz, 2 H, H ortho to OAll); 6.05 (ddt,
2
3JH,H = 5.3 (t), 10.5 (d), 17.2 (d) Hz, 1 H, CH=CH ), 5.41 (dq, 2JH,H and 4JH,H
2
H, H-3), 3.26 (dquint, 3JH,H = 6.7, 2JH,H = 11.4 Hz, 1 H, H-5), 3.14 (ddd,
H,H =1.2, 5.1, 2JH,H = 15.1 Hz, 1 H, H-3), 2.68-2.51 (m, 1 H, H-9), 2.36-
=
1
=
1.6 (q), 3JH,H = 17.2 (d) Hz, 1 H, CH=CHH), 5.28 (dq, 2
.4 (q), 3JH,H = 10.5 (d) Hz, 1 H, CH=CHH), 4.56 and 4.48 (AB syst,. JH,H
J
H,H and 4JH,H
=
3
J
2
.22 (m, 2 H, H-8); 2.19-2.07 (m, 1 H, H-9), 1.91 (1 H, dddd, 3
2
4
=
2
JH,H = 1.5,
14.4 Hz, 2 H, ArCH
2
), 4.52 (dt, 4JH,H = 1.5 (t), 3
J
H,H = 5.3 (d) Hz, 2 H,
.5, 11.7, 2JH,H = 13.2 Hz, 1 H, H-4); 1.67-1.53 (m, 1 H, H-4), 1.60 (d, JH,H
3
CH
2
CH=CH
2
); 4.16 (dt, JH,H = 6.8 (t), 2JH,H = 13.8 (d) Hz, 1 H, H-5), 3.32
3
C). 13C NMR (75 MHz CDCl
), 129.3
),
6.9 Hz, 3 H, CH
5°C) δ 174.9, 173.7 (C=O), 158.1, 129.7 (quat,), 133.1 (CH=CH
), 114.9 (C ortho to OAll), 69.3 (=C-CH
2
3
CH), 1.59 (s, 3 H, CH
3
3
,
and 3.23 (ABXY syst,. JH,H = 14.7, 3
2
J
H,H = 6.4 (ax), 9.5 (bx), 2.4 (ay=by)
2
3
Hz, 2 H, H-3), 2.97-2.77 (m, 2 H, H-5 and H-9); 2.39 (dd, JH,H = 6.7, 8.7
(
C meta to OAll), 117.7 (CH=CH
2
Hz, 2 H, H-8); 2.00-1.63 (m, 3 H, H-9 and H-4), 1.59 (s, 3 H, CH
NMR (75 MHz, CDCl , 25 °C) δ 174.7, 174.2 (C=O), 158.1, 129.4 (quat,),
33.1 (CH=CH ), 129.2 (C meta to OAll), 117.7 (CH=CH ), 114.9 (C ortho
to OAll), 68.8 (=C-CH ), 67.6 (C-9a), 52.9 (N-CH Ar), 46.1 (C-3), 36.6 (C-
), 33.7 (C-9) 29.6 (C-8), 26.9 (C-4), 23.3 (CH ). GC-MS: R 11.08 min.
M/z: 328 (M . 10.6), 287 (5.7), 181 (100.0), 162 (6.4), 147 (62.9), 138
). 13C
3
6
8.8 (C-9a), 52.2 (N-CH
2
Ar), 48.5 (C-5), 45.3 (C-3), 31.7 (C-9) 31.6 (C-4),
3
). HRMS (ESI+) m/z [M + H+]:
30.6 (C-8), 24.4 (C-CH
3
), 17.4 (CHCH
3
1
2
2
Calcd. For C20H N O
27 2 3
342.2022; Found 343.2019.
2
2
5
3
t
1
7
7
e-lower. [α]
D
= + 136.2 (c 1, CHCl
3
). H NMR (300 MHz CDCl
3
, 25°C) δ
+
.13 (d, 3JH,H = 8.6 Hz, 2 H, H meta to OAll); 6.86 (d, JH,H = 8.6 Hz, 2 H,
H ortho to OAll); 6.05 (ddt, JH,H = 10.5, 17.2 (d), 5.3 (t) Hz, 1 H, CH=CH
3
(
10.3), 124 (12.1), 111 (16.7), 110 (12.7), 107 (9.9), 98 (17.8), 82 (8.4), 78
3
2
);
+
(5.7), 56 (42.3), 55 (23.2), 42 (17.3), 41 (65.2). HRMS (ESI+) m/z [M + H ]:
5
.41 (dq, 2JH,H and 4JH,H = 1.6 (q), 3JH,H = 17.3 (d) Hz, 1 H, CH=CHH), 5.29
dq, 2JH,H and 4JH,H = 1.5 (q), 3JH,H = 10.5 (d) Hz, 1 H, CH=CHH), 4.62 and
25 2 3
Calcd. For C19H N O 329.1865; Found 329.1862.
(
4
=
.41 (AB syst,. 2JH,H = 14.4 Hz, 2 H, ArCH
2
), 4.52 (dt, 4JH,H = 1.5 (t), 3JH,H
(
R,S)-2-(4-Allyloxyphenyl)-9a-methylhexahydro-1H-pyrrolo[1,2-
5.3 (d) Hz, 2 H, CH CH=CH ); 4.50-4.35 (m, 1 H, H-5), 3.30-3.12 (m,. 2
2
2
a][1,4]diazepine-1,7(8H)-dione 7d. The isocyanide was prepared in situ
from N-(4-Allyloxyphenyl)formamide,[21] as described for the synthesis of
H, H-3), 2.79 (ddd, JH,H = 8.2, 4.7, 2JH,H = 12.9 Hz, 1 H, H-9), 2.45-2.25
3
(
(
m, 2 H, H-8); 2.16-1.72 (m, 3 H, H-9, H-4), 1.71 (s, 3 H, CH
d,3JH,H = 6.9 Hz, 3 H, CH CH). 13C NMR (75 MHz CDCl
, 25°C) δ 175.6,
74.8 (C=O), 158.1, 129.3 (quat,), 133.2 (CH=CH ), 129.2 (C meta to OAll),
17.7 (CH=CH ), 114.9 (C ortho to OAll), 68.8 (=C-CH ), 68.6 (C-9a), 53.0
Ar), 47.6 (C-5), 46.6 (C-3), 35.6 (C-9) 34.0 (C-4), 29.4 (C-8), 28.0
H+]: Calcd. For
), 20.5 (CHCH ). HRMS (ESI+) m/z [M
342.2022; Found 343.2017.
3
C), 1.26
6
f. Then, the crude isocyanide (as CH
premixed levulinic acid and propanolamine mixture (see the synthesis of
a). Chromatography gave the Ugi product in 50% yield from formamide.
2 2
Cl ) solution was treated with the
3
3
1
1
2
7
2
2
Cyclization was carried out with method A, as described for 7a, but at 50 °C.
Reaction was complete after 1 h. Chromatography (AcOEt to AcOEt :
(
(
N-CH
C-CH
2
3
3
+
MeOH 99:1) gave pure 7d, as an oil (74%). R
f
: 0.37 (AcOEt : MeOH 99:1).
20 27 2 3
C H N O
1H NMR (300 MHz, CDCl , 25°C) δ 7.01 (d, 3JH,H = 8.8 Hz, 2 H, H meta to
3
OAll); 6.90 (d, 3JH,H = 8.8 Hz, 2 H, H ortho to OAll); 6.03 (ddt, 3JH,H = 5. (t),
2
1
-(2-Hydroxybenzyl)-8a-methyltetrahydropyrrolo[1,2-a]pyrazine-
,6(2H,7H)-dione 17. A solution of compound 6d (103 mg, 328 µmol) in
1
J
=
0.5 (d), 17.2 (d) Hz, 1 H, CH=CH
2
), 5.40 (dq, 2JH,H and 4JH,H = 1.5 (q),
3
H,H = 17.3 (d) Hz, 1 H, CH=CHH), 5.28 (dq, JH,H and 4JH,H = 1.4 (q), 3JH,H
2
dry acetonitrile (3.1 mL) was treated with ammonium formate (136.2 mg,
.16 mmol) and Pd(PPh Cl (18.4 mg, 26.2 µmol). The solution was
heated at 80 °C in a closed vessel for 3 h. Then it was poured into
saturated aqueous NaHCO and extracted with AcOEt. Evaporation and
chromatography (CH Cl / AcOEt 1 : 1 to CH Cl / AcOEt / MeOH 45 : 45 :
10.5 (d) Hz, 1 H, CH=CHH), 4.52 (dt, 4JH,H = 1.5 (t), 3JH,H = 5.2 (d) Hz, 2
2
3
)
2
2
2 2
CH=CH J JH,H = 13.9 (d) Hz, 1 H, H-5),
); 4.31 (dt, 3 H,H = 6.4 (t), 2
H, CH
.74 and 3.65 (ABXY syst,. JH,H = 14.8, 3
2
3
J
H,H = 6.6 (ax), 8.7 (bx), 3.0
3
3
2
(ay=by) Hz, 2 H, H-3), 3.07 (dt, JH,H = 6.7 (t), JH,H = 13.8 (d) Hz, 1 H, H-
2
2
2
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
1
0) gave pure 17 as a foam (85 mg, 95%). R
f
= 0.44 (CH
MeOH 47.5 : 47.5 : 5). H NMR (300 MHz, CDCl , 25 °C) δ 9.05 (s, 1 H,
OH), 7.26 (dt, 4JH,H = 1.7 (d), 3JH,H = 7.7 (t) Hz, 1 H, H meta to OH and para
to CH ), 6.95 (dd,
), 7.09 (dd, 4JH,H =1.7, 3JH,H = 7.5 Hz, 1 H, H ortho to CH
4JH,H = 1.2, 3
2
Cl
2
/ AcOEt /
overnight. The diastereomeric ratio was determined on the crude product
abd was found to be 27: 73 by HPLC.The two diastereomers and
recovered 6d were separated by chromatography (PE / AcOEt 3:2). Yields:
upper diastereomer (R = 0.46): 55 mg (13.6%). Lower diastereomer (R =
f f
0.31): 127 mg (31.3%) Overall yield: 45%. Recovered substrate 6d: 93 mg.
1
3
2
2
J
H,H = 8.0 Hz, 1 H, H ortho to OH), 6.83 (dt, 4
J
H,H = 1.2 (d),
2
3JH,H = 7.4 (t) Hz, 1 H, H para to OH), 4.66 and 4.26 (AB syst., JH,H = 14.6
Yield calculated form unrecovered substrate: 65%.
Hz, 2 H, CH
dt, 3 H,H = 11.9, 5.5, 2
Ar), 4.21 (ddd, 3JH,H = 1.0, 5.4, 2JH,H = 14.4 Hz, 1 H, H-4); 3.55
2
(
J
J
H,H = 11.9, 1 H, H-3), 3.39 (ddd, 3JH,H = 1.0, 4.9,
9-upper. Oil. 1H NMR (300 MHz, CDCl
meta to Oallyl), 6.92 (t, JH,H = 7.5 Hz, 1 H, H para to Oallyl), 6.86 (d, JH,H
1
3
, 25°C) δ 7.27-7.14 (m, 2 H, H
2
H,H = 12.1 Hz, 1 H, H-3), 3.13 (dddd, JH,H = 1.2, 5.0, 12.0, 2JH,H = 14.4
3
J
3
3
Hz, 1 H, H-4), 2.53 (ddt, JH,H = 1.2, 9.8 (t), 2JH,H = 16.7 Hz, 1 H, H-8), 2.38
3
3
=
1
8.2 Hz, 1 H, H ortho to Oallyl), 6.04 (ddt, JH,H = 10.4, 17.2 (d), 5.2 (t) Hz,
(
ddd, 3JH,H = 3.8, 8.1, 2JH,H = 16.6 Hz, 1 H, H-8), 2.32-2-13 (m, 2 H, H-7),
H, CH=CH
2
), 5.40 (dq, 2JH,H and 4JH,H = 1.5 (q), 3JH,H = 17.4 (d) Hz, 1 H,
1
1
.50 (s, 3 H, CH
56.0, 120.7 (quat,), 131.3 (C ortho to CH
), 119.5 (C para to OH), 117.8 (C ortho to OH), 62.3 (C-8a), 48.7
3
). 13C NMR (75 MHz, CDCl
), 130.7 (C meta to OH and para
3
, 25 °C) δ 173.8, 172.5 (C=O),
CH=CHH), 5.28 (dq, 2JH,H and 4
H,H = 1.5 (q), 3
2
J
J
H,H = 10.5 (d) Hz, 1 H,
CH=CHH), 4.74 and 4.54 (AB syst, JH,H = 14.7 Hz, 2H, CH Ar), 4.54-4.49
CH=), 4.18-4.07 (m, 1 H, H-4),3.50-3.15 (m, 3 H, H-3, H-4),
2
2
to CH
CH
MS: R
2
(
m, 2 H, CH
2
(
2
Ar), 46.6 (C-3); 33.1 (C-4), 30.6 (C-7), 29.6 (C-8), 23.1 (CH
3
). GC-
.88 (dd, 3
2
2
JH,H = 9.9, JH,H = 13.9 Hz., 1 H, H-8), 2.70-2.46 (m, 3 H, H-7,
+
t
9.70. M/z: 274 (M . 71.1), 246 (4.2), 231 (8.3), 167 (100.0), 149
), 2.05 (dd, JH,H = 6.3, 2JH,H = 13.9 Hz., 1 H, H-8), 1.63 (s, 3 H,
Si). 13C NMR (75 MHz, CDCl
, 25°C): δ 174.1,
), 129.6, 128.9 (C meta
), 111.7 (C ortho to
3
C≡C-CH
CH ), 0.14 (s, 9 H, (CH
71.7 (C=O), 156.6, 124.6 (quat,), 133.1 (CH=CH
to Oallyl), 121.0 (C para to Oallyl), 117.5 (CH=CH
Oallyl), 103.4, 86.9 (C≡C), 68.8 (OCH ), 62.0 (C-8a), 45.7 (C-3); 45.0
CH Ar), 40.6 (C-7), 34.8 (C-8), 34.4 (C-4), 26.1 (CH C), 22.3 (C≡C-CH ),
.0 ((CH Si). HRMS (ESI+) m/z [M + H ]: Calcd. For C24 Si
425.2260; Found 425.2263.
2
(8.6), 139 (11.6), 136 (38.7), 125 (33.8), 124 (20.4), 123 (7.6), 122 (11.9),
3
3
)
3
3
111 (7.6), 107 (83.6), 98 (26.8), 97 (16.0), 83 (11.2), 78 (11.5), 77 (29.8),
1
2
70 (21.5), 56 (23.0), 55 (41.5), 51 (7.8), 42 (37.2), 41 (11.5), 39 (10.2).
2
+
HRMS (ESI+) m/z [M + H ]: Calcd. For C15
H
N O
19 2 3
275.1396; Found
2
275.1398.
(
2
3
2
+
0
3
)
3
33 2 3
H N O
2
1
-(2-Allyloxybenzyl)-7,8a-dimethyltetrahydropyrrolo[1,2-a]pyrazine-
,6(2H,7H)-dione 18. A 0.4 M solution of LDA was prepared at ─20 °C by
adding nBuLi (1.6 M in hexanes, 5.0 mL, 8.0 mmol) to a solution of
diisopropylamine (1.24 mL, 8.8 mmol) in dry THF (12.3 mL) containing few
crystals of 2,2'-bipyridyl and stirring for 20 min. Part of this deep red
solution (3.10 mL corresponding to 1.24 mmol)) was transferred via
syringe into another flask, again cooled to ─20 °C. To this flask, a solution
of compound 6d (257 mg, 818 µmol) dissolved in dry THF (2 mL + 0.5 mL
9-lower. White solid. M.P.: 143.4-145.5 °C. 1H NMR (300 MHz, CDCl
3
,
1
2
=
5 °C) δ 7.28-7.20 (m, 2 H, H meta to Oallyl), 6.94 (dt, JH,H = 0.6 (d), 3JH,H
4
3
7.5 (t) Hz, 1 H, H para to Oallyl), 6.87 (d, JH,H = 8.1 Hz, 1 H, H ortho to
3
Oallyl), 6.04 (ddt, JH,H = 10.5, 17.3 (d), 5.1 (t) Hz, 1 H, CH=CH
2
), 5.40 (dq,
2JH,H and 4JH,H = 1.5 (q), 3JH,H = 17.3 (d) Hz, 1 H, CH=CHH), 5.29 (dq, 2JH,H
and 4JH,H = 1.4 (q), 3JH,H = 10.5 (d) Hz, 1 H, CH=CHH), 4.84 and 4.50 (AB
H,H = 14.7 Hz, 2 H, CH
CH=), 4.09 (ddd, 3JH,H = 1.4, 4.8, 13.4 Hz, 1 H, H-4), 3.41-
.20 (m, 2 H, H-3), 3.14 (dt, 3JH,H = 4.5 (d), 3JH,H and 2JH,H =12.3 (t) Hz, 1
+
0.5 mL for washing) was added. After 20 min (the solution lose its deep
syst, 2
Ar), 4.55 (dt, 4JH,H = 1.4 (t), 3JH,H = 5.2 (d)
J
2
red color) the flask was cooled to ─78 °C, and methyl iodide (77 µL, 1.24
mmol) was added. The temperature was allowed to rise slowly to ─30 °C
Hz., 2 H, CH
2
3
during 3 h. Then the reaction was quenched with saturated aqueous NH
and extracted with AcOEt. Evaporation and chromatography (CH Cl
AcOEt 1:1 + 1.5% MeOH) gave pure 18 as a foam (180 mg, 67%). Also
4
Cl
H, H-4), 2.82-2.66 (m, 2 H, C≡C-CHH and H-7), 2.55-2.32 (2 H, m, H-8),
2
2
:
.50 (dd, 3JH,H = 7.9, 2JH,H = 13.1 Hz., 1 H, H-8), 2.40 (dd, 3JH,H = 9.4, 2JH,H
2
=
17.8 Hz., 1 H, C≡C-CHH), 2.12 (dd, 3JH,H = 11.1, 2JH,H = 13.1 Hz., 1 H,
4
0 mg of starting 6d were recovered. Thus, the yield from unrecovered
Si). 13C NMR (75 MHz, CDCl
), 129.7,
), 111.7
H-8), 1.53 (s, 3 H, CH
2
1
3
), 0.13 (s, 9 H, (CH
5 °C): δ 172.1, 171.2 (C=O), 156.6, 124.6 (quat,), 133.0 (CH=CH
28.9 (C meta to Oallyl), 121.0 (C para to Oallyl), 117.5 (CH=CH
), 60.6 (C-8a), 46.4 (C-
3
)
3
3
,
1
substrate was 79%. R
300 MHz, CDCl
detected. The diastereomeric ratio was calculated by integration of the
CH CH signals (minor diast. resonates at 1.27. Here, only the signals of
f
2
= 0.56 (CH Cl
2
: AcOEt 1:1 + 5% MeOH). H NMR
2
(
3
, 25°C) (note: two diastereomers, in a 91: 9 ratio are
2
(
C ortho to Oallyl), 103.3, 86.6 (C≡C), 68.8 (OCH
2
3
3
); 44.7 (CH
2
Ar), 39.6 (C-7), 37.3 (C-8), 34.1 (C-4), 23.1 (CH
3
C), 21.0
major diastereomer are reported) δ 7.30-7.15 (m, 2 H, H meta to Oallyl),
+
(
2
C≡C-CH ), 0.1 ((CH
3
)
3
Si). HRMS (ESI+) m/z [M + H ]: Calcd. For
6
J
.93 (dt, 4JH,H = 0.9 (d), 3JH,H = 7.5 (t) Hz, 1 H, H para to Oallyl), 6.87 (d,
24 33 2 3
C H N O Si 425.2260; Found 425.2255.
3
3
H,H = 8.2 Hz, 1 H, H ortho to Oallyl), 6.04 (ddt, JH,H = 10.4, 17.2 (d), 5.1
), 5.40 (dq, 2JH,H and JH,H = 1.6 (q), 3JH,H = 17.3 (d)
4
(
t) Hz, 1 H, CH=CH
2
Hz, 1 H, CH=CHH), 5.28 (dq, JH,H and JH,H = 1.4 (q), 3JH,H = 10.5 (d) Hz,
2
4
2
Acknowledgements
1
(
H, CH=CHH), 4.73 and 4.60 (AB syst, JH,H = 14.7 Hz, 2 H, CH
2
Ar), 4.55
dt, 4JH,H = 1.5 (t), 3JH,H = 5.1 (d) Hz., 2 H, CH
CH=), 4.09 (ddd, 3JH,H = 1.4,
2
5
3
=
.0, 13.4 Hz, 1 H, H-4), 3.38 (dt, 3JH,H =5.0, 11.7, 3JH,H = 11.7 Hz, 1 H, H-
), 3.28-3.08 (m, 2 H, H-3 and H-4), 2.69-2.52 (m, 1 H, H-7), 2.44 (dd, JH,H
This study is supported by Fondazione Cariplo, under
Integrated Biotechnology and Bioeconomy" programme.
3
"
8.1, 2JH,H = 12.9 Hz., 1 H, H-8), 1.82 (dd, 3JH,H = 11.0, 2JH,H = 12.9 Hz., 1
We thank Giuliana Ottonello for HRMS, Andrea Galatini for
NMR, Sirio Griva and Davide Pratolongo for their
H, H-8), 1.51 (s, 3 H, CH
3 3
), 1.19 (d, 3JH,H = 7.0 Hz, 3 H, CH CH). 13C NMR
(
(
(
75 MHz, CDCl
CH=CH
CH=CH
3
, 25°C): δ 174.7, 171.5 (C=O), 156.6, 124.6 (quat,), 133.0
), 129.7, 128.9 (C meta to Oallyl), 121.0 (C para to Oallyl), 117.5
), 111.6 (C ortho to Oallyl), 68.8 (OCH ), 60.5 (C-8a), 46.2 (C-3);
Ar), 40.1 (C-8), 35.1 (C-7), 33.8 (C-4), 22.7 (CH C), 15.3
329.1865;
2
experimental contribution to this work.
2
2
4
(
4.8 (CH
CH CH). HRMS (ESI+) m/z [M + H ]: Calcd. For C19
Found 329.1858.
2
3
Keywords: multicomponent reactions • nucleophilic substitution
isocyanides • renewable resources • heterocycles
+
3
25 2 3
H N O
•
2-(2-Allyloxybenzyl)-8a-methyl-7-(3-trimethylsilylprop-2-
ynyl)tetrahydropyrrolo[1,2-a]pyrazine-1,6(2H,7H)-dione 19. It was
prepared from 6d (300 mg), using 1-bromo-3-(trimethylsilyl)propyne,
following the same procedure employed for 18. However, in this case, the
temperature was allowed to rise to 0 °C, and the reaction mixture stirred
References
[1]
C. R. Bertozzi, C. J. Chang, B. G. Davis, M. Olvera de la Cruz, D. A.
Tirrell, D. Zhao, ACS Central Sci. 2016, 2, 1-3.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
[
[
[
[
2]
3]
4]
5]
F. H. Isikgor, C. R. Becer, Polym. Chem. 2015, 6, 4497-4559.
A. Domling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083-3135.
R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem. 2014, 16, 2958-2975.
M. Giustiniano, A. Basso, V. Mercalli, A. Massarotti, E. Novellino, G. C.
Tron, J. P. Zhu, Chem. Soc. Rev. 2017, 46, 1295-1357.
2006, 62, 6774-6781; c) P. Golubev, M. Krasavin, Eur. J. Org. Chem.
2017, 1740-1744; d) E. Hernandez-Vazquez, L. D. Miranda, Org. Biomol.
Chem. 2016, 14, 4875-4884; e) M. Stucchi, S. Cairati, R. Cetin-Atalay,
M. S. Christodoulou, G. Grazioso, G. Pescitelli, A. Silvani, D. C. Yildirim,
G. Lesma, Org. Biomol. Chem. 2015, 13, 4993-5005.
[
[
6]
7]
P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, New York, 2000.
[14] a) M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol.
2010, 14, 347-361; b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem.
Rev. 2003, 103, 893-930; c) E. Vitaku, D. T. Smith, J. T. Njardarson, J.
Med. Chem. 2014, 57, 10257-10274.
a) J. Horvat, B. Klaic, B. Metelko, V. Sunjic, Tetrahedron Lett. 1985, 26,
2111-2114; b) J. Horvat, B. Klaic, B. Metelko, V. Sunjic, Croat. Chem.
Acta 1986, 59, 429-438.
[15] A. Stefanucci, E. Novellino, R. Costante, A. Mollica, Heterocycles 2014,
89, 1801-1825.
[
[
[
8]
9]
M. Hartweg, C. R. Becer, Green Chem. 2016, 18, 3272-3277.
M. Passerini, Gazz. Chim. Ital. 1923, 53, 331-332.
[16] P. Patil, R. Madhavachary, K. Kurpiewska, J. Kalinowska-Tłuścik, A.
Dömling, Org. Lett. 2017, 19, 642-645.
10] a) M. J. Buller, C. B. Gilley, B. Nguyen, L. Olshansky, B. Fraga, Y.
Kobayashi, Synlett 2008, 2244-2248; b) C. B. Gilley, M. J. Buller, Y.
Kobayashi, Synlett 2008, 2249-2252; c) H. Gross, J. Gloede, I. Keitel, D.
Kunath, J. Prakt. Chem. 1968, 37, 192-199; d) G. C. B. Harriman,
Tetrahedron Lett. 1997, 38, 5591-5594; e) J. Isaacson, M. Loo, Y.
Kobayashi, Org. Lett. 2008, 10, 1461-1463; f) R. Krelaus, B. Westermann,
Tetrahedron Lett 2004, 45, 5987-5990; g) M. A. Mironov, M. N. Ivantsova,
V. S. Mokrushin, Mol. Divers. 2003, 6, 193-197; h) K. M. Short, A. M. M.
Mjalli, Tetrahedron Lett. 1997, 38, 359-362; i) H. Tye, M. Whittaker, Org.
Biomol. Chem. 2004, 2, 813-815.
[17] L. Banfi, A. Basso, L. Giardini, R. Riva, V. Rocca, G. Guanti, Eur. J. Org.
Chem. 2011, 100-109.
[18] a) S. Hanessian, C. Couture, H. Wiss, Can. J. Chem. 1985, 63, 3613; b)
S. Hanessian, G. McNaughton-Smith, H.-G. Lombart, W. D. Lubell,
Tetrahedron 1997, 53, 12789-12854.
[19] L. Moni, L. Banfi, A. Basso, L. Carcone, M. Rasparini, R. Riva, J. Org.
Chem. 2015, 80, 3411-3428.
[20] L. Lázár, F. Fülöp, Eur. J. Org. Chem. 2003, 3025-3042.
[21] C. Lambruschini, D. Galante, L. Moni, F. Ferraro, G. Gancia, R. Riva, A.
Traverso, L. Banfi, C. D'Arrigo, Org. Biomol. Chem. 2017, 15, 9331-9351.
[22] a) A. P. Robertson, C. L. Clark, T. A. Burns, D. P. Thompson, T. G. Geary,
S. M. Trailovic, R. J. Martin, J. Pharm. Exp. Ther. 2002, 302, 853-860; b)
R. M. Banks, S. E. Blanchflower, J. R. Everett, B. R. Manger, C. Reading,
J. Antibiotics 1997, 50, 840-846; c) J. Kwon, Y. H. Seo, J.-E. Lee, E.-K.
Seo, S. Li, Y. Guo, S.-B. Hong, S.-Y. Park, D. Lee, J. Nat. Prod. 2015,
78, 2572-2579.
[
[
11] a) C. Hanusch-Kompa, I. Ugi, Tetrahedron Lett. 1998, 39, 2725-2728; b)
C. Hulme, L. Ma, M. P. Cherrier, J. J. Romano, G. Morton, C. Duquenne,
J. Salvino, R. Labaudiniere, Tetrahedron Lett. 2000, 41, 1883-1887; c)
W. Wang, E. Herdtweck, A. Domling, Chem. Commun. 2010, 46, 770-
7
72.
12] a) L. Banfi, A. Basso, G. Guanti, P. Lecinska, R. Riva, Org. Biomol. Chem.
006, 4, 4236-4240; b) L. Banfi, A. Basso, G. Guanti, N. Kielland, C.
2
Repetto, R. Riva, J. Org. Chem. 2007, 72, 2151-2160; c) L. Banfi, A.
Basso, R. Riva, in Synthesis of Heterocycles via Multicomponent
Reactions I, Vol. 23 (Eds.: R. V. A. Orru, E. Ruijter), Springer Berlin /
Heidelberg, 2010, pp. 1-39; d) L. Moni, L. Banfi, A. Basso, A. Brambilla,
R. Riva, Beilstein J. Org. Chem. 2014, 10, 209-212; e) L. Banfi, A. Basso,
C. Lambruschini, L. Moni, R. Riva, Chem. Heterocycl. Comp. 2017, 53,
[23] R. G. Doveston, P. Tosatti, M. Dow, D. J. Foley, H. Y. Li, A. J. Campbell,
D. House, I. Churcher, S. P. Marsden, A. Nelson, Org. Biomol. Chem.
2015, 13, 859-865.
382-408; f) S. Caputo, L. Banfi, A. Basso, A. Galatini, L. Moni, R. Riva,
C. Lambruschini, Eur. J. Org. Chem. 2017, 6619-6628.
[
13] a) S. Marcaccini, R. Pepino, M. Cruz Pozo, Tetrahedron Lett. 2001, 42,
2727-2728; b) X. L. Xing, J. L. Wu, G. F. Feng, W. M. Dai, Tetrahedron
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801129
FULL PAPER
Entry for the Table of Contents
Key topic: Multicomponent Reactions
Layout 2:
FULL PAPER
Chiara Lambruschini, Andrea Basso,
Lisa Moni, Alessandro Pinna, Renata
Riva, and Luca Banfi*
Page No. – Page No.
Title
Operationally simple, 2-step conversion of levulinic acid into bicyclic drug-like
heterocyclic systems.
This article is protected by copyright. All rights reserved.