Unusually Reactive Cyclic Anhydride Expands the Scope of the Castagnoli-Cushman Reaction

Article abstract of DOI:10.1021/acs.joc.8b02164

In the course of synthesizing and testing various "azole-including" cyclic anhydrides in the Castagnoli-Cushman reaction with imines, a remarkably reactive, pyrrole-based anhydride has been identified. It displayed a remarkably efficient reaction with N-alkyl and N-aryl imines, in particular, with "enolizable" α-C-H imines which typically fail to react with a majority of known cyclic anhydrides. The reactivity of this anhydride has been justified by an efficient resonance stabilization of its enol form. This finding expands the existing arsenal of highly reactive cyclic anhydrides and further confirms the importance of anhydride enolization for an efficient Castagnoli-Cushman reaction.

Full text of DOI:10.1021/acs.joc.8b02164

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Article
Unusually Reactive Cyclic Anhydride Expands
the Scope of the Castagnoli-Cushman Reaction
Maria Chizhova, Olesya Khoroshilova, Dmitry Dar'in, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02164 • Publication Date (Web): 18 Sep 2018
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Unusually Reactive Cyclic Anhydride Expands the Scope of the Castagnoli-
Cushman Reaction
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Maria Chizhova, Olesya Khoroshilova, Dmitry Dar’in and Mikhail Krasavin*
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Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
ABSTRACT: In the course of synthesizing and testing various ‘azoleꢀincluding’ cyclic
anhydrides in the CastagnoliꢀCushman reaction with imines, a remarkably reactive, pyrroleꢀ
based anhydride has been identified. It displayed a remarkably efficient reaction with Nꢀalkyl
and Nꢀaryl imines, in particular, with ‘enolizable’ αꢀCꢀH imines which typically fail to react with
a majority of known cyclic anhydrides. The reactivity of this anhydride has been justified by an
efficient resonance stabilization of its enol form. This finding expands the existing arsenal of
highly reactive cyclic anhydrides and further confirms the importance of anhydride enolization
for an efficient CastagnoliꢀCushman reaction.
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Introduction
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The formal cycloaddition of dicarboxylic acid anhydrides 1 and imines1 (recently dubbed the
CastagnoliꢀCushman reaction (CCR) to signify the pioneering work of these researchers2) is a
remarkably efficient strategy to construct structurally diverse lactams 2 featuring a broad variety
of periphery substituents. Two possible mechanisms have been proposed for the CCR and
discussed as equally plausible. One of them (A), initially favored by Cushman,3 implies the
initial intermolecular Nꢀacylation of the imine component leading to the ringꢀopened Nꢀ
acyliminium intermediate 3(4) which, in its enol form of alkyl carboxylate anion (shown),
undergoes the intramolecular Mannichꢀtype ring closure to give the observed lactam 2. However,
the comprehensive experimental and computational evidence gathered in the recent years speaks
for an alternative mechanism (B). It implies a reverse order of events (compared to mechanism
A) whereby the enolate form of cyclic anhydride 1 undergoes Mannichꢀtype nucleophilic
addition to the protonated imine to give the initial adduct 5. The latter is perfectly set to undergo
the intramolecular Nꢀacylation (or aminolysis of the cyclic anhydride) to give lactam 2. The
greater plausibility of mechanism B is supported by the comprehensive computational analysis
of both reaction mechanisms (in favor of the latter) by Shaw4 and the recent isolation5 as well as
trapping6 of intermediate 5. The existence, in principle, of the acylationꢀMannich pathway A is
supported by the frequently observed7 formation of byꢀproduct monoamide 6 which is likely
formed via hydrolysis of intermediate 3. Moreover, with only a few exceptions so far (vide
infra), it is impossible to involve in the CCR imines derived from αꢀCꢀH (‘enolizable’)
aldehydes. The latter promptly tautomerize into enamides 7 (which can be isolated8 or
transformed to 6 on aqueous workup) and steer the reaction away from the productive Mannichꢀ
acylation pathway B.
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The cyclic anhydrides 1 are the principal source of skeletal diversity of the CCR products 2.9
From the earlier examples of the CCR involving succinic (1a) and glutaric (1b)2 and
homophthalic (HPA, 1c)3 anhydrides, the scope of workable anhydrides for the reaction has been
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expanded significantly to include heteroatomꢀcontaining versions of glutaric anhydride (1d)8 as
well as sevenꢀmembered versions 1e.10 Particularly notable are the highly reactive versions of
succinic (1g,11 1h,12 1i13) and thiaꢀglutaric (1j)14 anhydrides (Figure 1). The enolization of these
anhydrides implicated in the productive reaction pathway (B) is highly favored due to enolate
stabilization by electronꢀwithdrawing groups and/or negative charge delocalization. Thus, the
CCR with these substrates proceeds at ambient temperature – in contrast to toluene or xylene
reflux temperatures which are typical for the CCR with less reactive anhydrides.8
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Figure 1. The CastagnoliꢀCushman reaction, its plausible mechanisms, side products and
selected examples of cyclic anhydrides (1a-i) reported toꢀdate as partners for the reaction.
HPA (1c), however, is also one of the most reactive cyclic anhydrides for the CCR. Indeed, its
reactions with imines typically proceed at room temperature. Moreover, it is the only cyclic
anhydride toꢀdate that has been reported to give a respectable yield in the CCR with αꢀCꢀH
imines.15ꢀ18 This aspect is indicative of the nonꢀproductive Nꢀacylation/Mannich pathway A
(primarily leading to enamide side products 7 with αꢀCꢀH imines8) being essentially shut off for
this reactive anhydride. Additional evidence for the high reactivity of 1c and the importance of
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Mannich/acylation reaction pathway B is provided by the fact that 1c can react in a CCRꢀlike
fashion – under mild conditions ꢀ with aldehydes (to provide respective lactones);19 in this
reaction, the initial acylation (pathway A) is highly unlikely. This is in contrast to other cyclic
anhydrides which normally need to be deprotonated with a strong base20 or react with aldehydes
only with the aid of an organocatalyst21 or a Lewis acid.22 Additionally, HPA (1c) is more
reactive toward Nꢀaryl imines which either fail to react with less reactive cyclic anhydrides or
require harsh, solventꢀfree conditions.23 Thus, it is perhaps unsurprising that the particular
suitability of HPA (1c) for the CCR inspired Tamura an coꢀworkers to synthesize and use in the
same reaction various azoleꢀfused glutaric anhydrides (e. g., 1k-l).24 In the latter, one can
recognize a possibility for the same type of resonance stabilization of the conjugate enolate as is
present in 1c. Recently, we became interested in exploring a different type of glutaric anhydride
variants which we term ‘azoleꢀincluding’ (to differentiate it from the azoleꢀfused counterparts
1k-l) and which toꢀdate have been successfully exemplified by pyrazole (1m)25 and indole (1n)26
cyclic anhydrides. Because no apparent stabilization of the conjugate enolate is possible in these
anhydrides (such as the one present in 1c and 1k-l), they displayed moderate reactivity and,
somewhat predictably, required prolonged heating for the CCR to proceed.
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Figure 2. Comparison of homophthalic anhydride (HPA, 1c) to two distinct types of cyclic
anhydrides: azoleꢀfused 1k-l and azoleꢀincluding 1m, 1n and 1o (investigated in this work).
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While continuing the exploration of the azoleꢀincluding cyclic anhydride chemical space, we
synthesized and tested, as partner in the CCR, pyrroleꢀincluding anhydride 1o (Figure 2). To our
surprise and delight, in the initial experiments it displayed an HPAꢀlike reactivity (reactions
going to completion at ambient temperature over only a few hours). Encouraged by this
observation, we set off to investigate more fully the reactivity and the synthetic potential of 1o
for the CastagnoliꢀCushman reaction. Herein, we present the results of our findings in this
regard.
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Results and Discussion
Anhydride 1o had not been reported in the literature (though is commercially available according
to SciFinder®) and was prepared by a straightforward alkylation of ethyl indoleꢀ2ꢀcarboxylate
followed by double ester hydrolysis and cyclodehydration with trifluoroacetic anhydride
(Scheme 1).
Scheme 1. Preparation of 1Hꢀpyrrolo[2,1ꢀc][1,4]oxazineꢀ1,3(4H)ꢀdione (1c).
1) BrCH2CO2Me
K2CO3, DMF
80 oC, 18 h
O
O
O
O
TFAA
CO2H
CO2H
N
N
OMe
NH
EtOAc
r. t., 18 h
2) NaOH, THF/H2O
74%
1o, 76%
Following the discovery that 1o reacts readily and smoothly with imines at ambient temperature
and some preliminary experimentation with various solvents (MeCN, toluene, DMF and EtOAc),
we discovered that 1,2ꢀdichloroethane (DCE) provided the best results in terms of conversion
and side product profile. Hence, the standard conditions (1o : imine = 1:1, DCE 1 mL/mmol, r. t.,
3 h) were successfully applied to a range of Nꢀalkyl aldimines and ketimines to produce 1ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrrolo[1,2ꢀa]pyrazineꢀ4ꢀcarboxylic acids 8a-u in good to excellent yields
(Table 1). Besides the mild reaction conditions and the short reaction times, the high, HPAꢀlike
reactivity of 1o manifested itself particularly in its ability to give good yields of the CCR lactam
adducts with αꢀCꢀH aldimines (compounds 8n-s). However, the most difficultꢀtoꢀachieve
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extension of the CCR is the ability to involve much less reactive αꢀCꢀH ketimines. So far,
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examples of the CCR with such substrates have been reported for the highly reactive HPA.5,33ꢀ34
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Table 1. 1ꢀOxoꢀ1,2,3,4ꢀtetrahydropyrrolo[1,2ꢀa]pyrazineꢀ4ꢀcarboxylic acids 8a-u synthesized in
this work.a
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a Major diastereomer is shown.
b Diastereomers separated and characterized separately.
c Isolated by preparative HPLC.
d
Isolated by column chromatography following esterification (MeI/K2CO3 – see Experimental
Section).
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The fact that we were able to obtain products 8t-u (albeit in a relatively modest yield) clearly
attests to the high reactivity of 1o and a significant contribution of the productive, Mannichꢀ
acylation reaction pathway (Figure 1B) in its reactivity mode. Adducts 8a-s obtained from the
reactions of 1o with aldimines were obtained predominantly as transꢀisomers (except for the
sterically congested Nꢀtertꢀbutyl product 8i). The stereochemical assignment was unequivocally
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1
performed based on the H NMR spectra and correlated with crystallographic information (vide
infra). We also sought to improve diastereoselectivity for the reaction leading to 8e (where the dr
value observed at room temperature was only 3.8:1). However, neither lowering the reaction
temperature (5 ºC, 24 h) nor raising it (40 ºC, 30 min) improved the dr value and only led to
incomplete conversion or increased byproduct formation as observed by 1H NMR analysis.
Having established the unexpectedly high (HPAꢀlike) reactivity of anhydride 1o in the CCR, we
were curious to see if Nꢀaryl imines (which normally fail to react in the CCR of cyclic
anhydrides other than HPA unless harsh temperature regimens are applied23) would also turn out
to be competent partners for the CCR with anhydride 1o. While at room temperature, the test
reactions with a set of selected Nꢀaryl imines displayed low conversions, even at reaction times
up to 48 h, performing the same reactions in refluxing toluene gave the complete conversion of
anhydride 1o and the desired products 9a-d were isolated in modest to good yields (Scheme 2).
Scheme 2. Preparation of Nꢀaryl 1ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrrolo[1,2ꢀa]pyrazineꢀ4ꢀcarboxylic
acids 9a-d.a
a Major diastereomer is shown.
b Yield of the pure cisꢀisomer (isolated by crystallization); actual yield may be higher.
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The remainder of the reaction mass balance was attributable to a mixture of unidentified byꢀ
products observed in each case. The competition of the unwanted course(s) of the reaction is
likely due to the reduced reactivity of the anilinic nitrogen atom in initial Mannichꢀtype adduct 5,
which suppresses the subsequent intramolecular aminolysis of the cyclic anhydride moiety in 5
(i. e. the desired course of the reaction) and increases the likelihood of competing sideꢀreactions.
Interestingly, in contrast the majority of products 8 obtained with Nꢀalkyl imines, Nꢀaryl adducts
9 were mostly obtained in cisꢀconfigured form (except for product 9c).
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As with compounds 8, the stereochemical assignment of compounds 9 was done on the basis of
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an apparently higher vicinal coupling constant J(H3,H4) generally observed for the cisꢀisomer
vs. transꢀisomer. The generality of this rule was confirmed via singleꢀcrystal Xꢀray analysis of
three representative compounds in the cisꢀ as well as in the transꢀseries (Table 2).
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Table 2. Vicinal coupling constants observed in the H NMR spectra of the cisꢀ and transꢀ
configured adducts 8 and 9 of anhydride 1o with aldimines.
3J, Hz
3J, Hz
trans
Compound
Compound
cis
trans
1.5
1.7
cis
5.4
3.8
4.1
4.2
4.1
4.2
7.6
3.6
4.8a
4.8
4.6
4.7a
5.1a
4.6
ꢀꢀ
1.1
8a
8b
8c
8d
8e
8f
8g
8h
8i
8l
8m
8n
8o
8p
8q
8r
8s
9a
9b
9c
9d
ꢀꢀb
1.5
1.1
1.1
1.0
1.0
4.0
1.2
1.2
ꢀꢀb
4.9
4.6
4.8
5.0
5.7
4.4
4.1
1.3
1.5a
1.6a
1.5
1.5
2.2
1.5
8j
1.5a
1.5
4.5
1.6
8k
a Singleꢀcrystal Xꢀray structure obtained.
b Unresolved doublet.
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It should be noted that the 3,4ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ1(2H)ꢀone core featured in
compounds 8a-u (as well as in their Nꢀaryl counterparts 9a-d) clearly belongs to privileged
heterocyclic scaffolds capable of displaying widely variable biological activities depending on
the specific molecular periphery employed.27 Indeed, just by reviewing the biomedical literature
over the last 2 years, one can encounter notable examples of mGluR2 receptor antagonist 10,28
compound capable of reducing blood uric acid levels 11,29 inhibitor of mycobacterial ATP
synthase 12,30 and ERK1/2 kinase inhibitor 13;31 moreover, this core is central to (ꢀ)ꢀagelastatin
alkaloids of general formula 1432 endowed with promising anticancer activity (Figure 3). Thus,
besides the remarkably reactive character of 1o in the context of the CCR, the privileged nature
of the 3,4ꢀdihydropyrrolo[1,2ꢀa]pyrazinꢀ1(2H)ꢀone motif for drug design clearly adds value to
the approach discussed herein. The latter also compares favorably to the earlier described routes
in terms of being the only one featuring a oneꢀstep construction of the scaffold in question.
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Figure 3. Examples of recently reported biologically active compounds featuring 3,4ꢀ
dihydropyrrolo[1,2ꢀa]pyrazinꢀ1(2H)ꢀone core (highlighted).
H
O
N
N
O
O
N
O
N
N
O
N
N
N
N
N
N
CF3
O
Cl
O
10
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N
Cl
N
N
N
NH
H
N
H
Br
O
HN
NH
N
N
R1O
N
N
N
R2
13
14
O
To complete the characterization of new anhydride 1o in formal cycloadditions with
electrophiles, we tested it in reactions with aromatic aldehydes. To our delight, in the presence of
1 equiv. of triethylamine, full conversion of 1o was achieved in 1 hour at ambient temperature
and the respective lactone products 15a-c were isolated as mixtures of diastereomers in moderate
to good yields (Scheme 3). Unfortunately, the absence of an apparent difference in the 3J(H3,H4)
values of diastereomeric products 15 as well as our being unable to obtain crystals of any of
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these compounds for Xꢀray analysis did not allow performing a straightforward assignment of
their relative stereochemistry.
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Scheme 3. Reaction of anhydride 1o with aromatic aldehydes.
a Isolated by preparative HPLC.
The HPAꢀlike reactivity of 1o clearly extends the scope of the CCR and the related reaction with
aldehydes. Perhaps, the higher reactivity of 1o compared to its closely related pyrazolo analogs
1m as well as the ‘benzo analog’ 1n can be rationalized even qualitatively by comparing the
resonance stabilization of the enol forms of both anhydrides. Indeed, according to the current
mechanistic understanding (vide supra), the more enolizable a cyclic anhydride is, the more
efficiently it will enter the initial Mannichꢀtype addition to the imine (or aldehyde) component
and the higher its overall reactivity in the CCR should be. The plausible resonance structures for
anhydrides 1mꢀo can be drawn out as shown in Figure 4.
Figure 4. Possible resonance structures for the enol forms of anhydrides 1mꢀo.
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All three hybrids appear rather similar. However, in contrast to 1o, three out of five resonance
structures shown for 1n require the aromatic system of the benzene ring to be destroyed. This
alone, in principle, can justify the enol form of 1o being lower in energy and, hence, the
observed higher reactivity of 1o compared to 1n. Likewise, the resonance hybrid for 1m is
expected to be higher in energy compared to 1n owing to the fact that three out of five resonance
structures incorporate a positive charge unfavorably located on a nitrogen atom.
In conclusion, we have described a new type of ‘azoleꢀincluding’ cyclic anhydride (1Hꢀ
pyrrolo[2,1ꢀc][1,4]oxazineꢀ1,3(4H)ꢀdione) which displayed a remarkably high reactivity in the
CastagnoliꢀCushman reaction with Nꢀalkyl and Nꢀaryl imines as well as a related reaction with
aromatic aldehydes. Particularly noteworthy was its reaction with αꢀCꢀH aldimines and
ketimines that proceeded at room temperature; similar reaction have only been described for
homophthalic anhydride but not for other, even highly reactive cyclic anhydrides. This finding
clearly expands the diversity of novel anhydrides and potentially paves an avenue for designing
new highly reactive anhydrides based on the preliminary analysis of resonance stabilization of
the respective enol forms. Such studies are currently underway in our laboratories; the results
will be reported in due course.
Experimental Section
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General. All commercial reagents and solvents were used without further purification, unless
otherwise noted. 1,2ꢀDichloroethane (DCE) was distilled over P2O5 and stored over molecular
sieves 4Å. Toluene was distilled after refluxing with sodiumꢀbenzophenone and stored over
molecular sieves 4Å. NMR spectroscopic data were recorded with a 400 MHz (400.13 MHz for
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1H and 100.61 MHz for 13C) and a 500 MHz (500.03 MHz for H and 125.7 MHz for 13C)
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spectrometers in DMSOꢀd6 or in CDCl3 or in acetoneꢀd6 and were referenced to residual solvent
proton signals (δH = 2.50, 7.26 and 2.05 ppm, respectively) and solvent carbon signals (δC =
39.5, 77.2 and 206.3 ppm, respectively; multiplicities are abbreviated as follows: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad). Coupling constants, J are reported in
1
13
Hz. The full assignment of signals in H and C NMR spectra of the obtained new compounds
was made, based on 2DꢀNMR spectroscopy HSQC and HMBC. Mass spectra were recorded
with a HRMSꢀESIꢀqTOF spectrometer (electrospray ionization mode). Column chromatography
was performed on silica gel 60 (230ꢀ400 mesh). For TLC analysis UV254 silica gel coated plates
were used. Preparative HPLC was carried out on Shimadzu LCꢀ20AP chromatograph, equipped
with spectrophotometric detector. Column: Agilent Zorbax prepHT XDBꢀC18, 5ꢁm,
21.2×150mm. Eluent: A) 0.1% TFA in water, B) 0.1% TFA in acetonitrile. Flow rate 12
mL/min, temperature – 40 °C, detection UV at 214 and 254 nm. Injection volume ‒ 500ꢁL.
Melting points were determined in open capillary tubes on Stuart SMP50 Automatic Melting
Point Apparatus.
1H-Pyrrolo[2,1-c][1,4]oxazine-1,3(4H)-dione (1o). To a solution of methyl pyrroleꢀ2ꢀ
carboxylate (12.5 g, 0.1 mol) in DMF (20 mL) was added K2CO3 (1.5 equiv., 20.7 g, 0.15 mol)
and a solution of methyl bromoacetate (1.1 equiv., 11.9 g, 0.11 mol) in DMF (20 mL). The
reaction mixture was stirred for 20 minutes at room temperature, then heated at 80 °C for
overnight, cooled to room temperature and the solvent was evaporated in vacuo. The residue was
extracted with DCM (2×20 mL), washed with H2O (2×20 mL) and brine, passed through a thin
layer of silica gel, washing with DCM. The solvent was evaporated under reduced pressure.
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Methyl 1ꢀ(2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate was obtained as a viscous yellow oil
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1
(17.4 g, 89%) and was used in the next step without purification. H NMR (400 MHz, CDCl3) δ
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6.99 (dd, J = 4.0, 1.8 Hz, 1H), 6.82 – 6.81 (m, 1H), 6.20 (dd, J = 4.0, 2.6 Hz, 1H), 5.04 (s, 2H),
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3.79 (s, 3H), 3.77 (s, 3H).
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To a solution of methyl 1ꢀ(2ꢀmethoxyꢀ2ꢀoxoethyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (2 g, 10.2 mmol) in
THF (5 mL) was added a solution of NaOH (4 equiv., 1.6 g, 40.6 mmol) in H2O (25 mL) and
stirred overnight at room temperature. The reaction mixture was acidified with HClconc to pH 1ꢀ2,
and cooled. The precipitate was filtered off and airꢀdried. 1ꢀ(Carboxymethyl)ꢀ1Hꢀpyrroleꢀ2ꢀ
1
carboxylic acid was obtained as a beige powder (1.4 g, 83%); mp 153 – 155 °C (dec.). H NMR
(400 MHz, DMSOꢀd6) δ 12.42 (br.s, 2H), 7.06 (t, J = 2.2 Hz, 1H), 6.80 (dd, J = 3.8, 1.8 Hz, 1H),
13
6.08 (dd, J = 3.8, 2.6 Hz, 1H), 5.00 (s, 2H). C NMR (100 MHz, DMSOꢀd6) δ 170.3, 161.9,
ꢀ
130.0, 122.5, 117.3, 107.5, 50.0. HRMS m/z calcd for C7H6NO4 [M–H]ꢀ: 168.0302, found
168.0312.
To the suspension of 1ꢀ(carboxymethyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylic acid (1.4 g, 8.3 mmol) in
EtOAc (50 mL) was added TFAA (2.2 equiv., 6.8 g, 32.5 mmol) and the mixture was stirred at
ambient temperature overnight. The reaction mixture was evaporated almost to dryness under
reduced pressure, then filtered off, solid was dried under reduced pressure at 40 °C. 1Hꢀ
Pyrrolo[2,1ꢀc][1,4]oxazineꢀ1,3(4H)ꢀdione (1o) was obtained as a white powder (0.95 g, 76%);
1
mp 146 – 147 °C (dec.). H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 4.1, 1.5 Hz, 1H), 7.02 (t, J
13
= 1.9 Hz, 1H), 6.50 (dd, J = 4.1, 2.6 Hz, 1H), 5.04 (s, 2H). C NMR (100 MHz, acetoneꢀd6) δ
+
163.8, 153.2, 128.0, 118.3, 113.2, 47.3. HRMS m/z calcd for C7H6NO3 [M+H]+: 152.0342,
found 152.0353.
General procedure for the preparation of aldimines: A solution of corresponding amine (1
equiv.) and aldehyde (1 equiv.) in dichloromethane (~ 2 mL per mmol) was kept over freshly
calcinated MgSO4 (~ 25 g per mol) at room temperature for 1 – 7 days. The progress of reaction
was monitored by 1H NMR. After completion of the reaction the insoluble material was filtered
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and the filtrate was concentrated in vacuo to give sufficiently pure imines which were used in
reaction with anhydride 1o without further purification (airꢀsensitive; store cold).
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General procedure for the preparation of ketimines: A mixture of corresponding ketone (1
equiv.) and amine (3 equiv.) in toluene (~ 3 mL per mmol) was refluxed with azeotropic removal
of water for 30 hours. The resulting mixture was evaporated to dryness to give oily residue
which was used in reaction with anhydride 1o without further purification (airꢀsensitive; store
cold).
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General procedures for the preparation of lactams 8, 9 and lactones 15.
General procedure 1: Anhydride 1o (0.5 mmol, 76 mg) was added to a solution of
corresponding imine (0.5 mmol) in DCE (0.5 mL) and mixture was stirred at room temperature
for 3 hours. The resulting mixture was diluted with DCM (2 mL) and extracted with saturated
NaHCO3 solution (2×3 mL). The aqueous phase was acidified with HClconc, cooled at 3 °C for an
hour. The precipitate was filtered off, and airꢀdried. In some cases it was recrystallized from
MeCN or MeOH or from mixture thereof.
General procedure 2: Anhydride 1o (0.5 mmol, 76 mg) was added to a solution of
corresponding imine (0.5 mmol) in DCE (0.5 mL) and mixture was stirred at room temperature
for 3 hours. The resulting mixture was evaporated in vacuo. The product was isolated using
preparative HPLC eluting with H2O–MeCN (with addition 0.1% TFA); gradient: 20% of MeCN
(0 – 5 min), 20–90% of MeCN (5 – 40 min), 90–95% of MeCN (40 – 50 min).
General procedure 3: Anhydride 1o (0.5 mmol, 76 mg) was added to the solution of
corresponding imine (0.5 mmol) in dry toluene (0.5 mL) and mixture was stirred at 110 °C for 1
hour. The resulting mixture was evaporated in vacuo. Crude material was diluted with acetone (5
mL), then K2CO3 (2 equiv., 1 mmol, 138 mg) and MeI (1.5 equiv., 0.75 mmol, 107 mg) were
added. Suspension was stirred for 20 hours at ambient temperature. The reaction mixture was
evaporated in vacuo, extracted with DCM (2×10 mL). The organic layer was washed with H2O
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(2×10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and evaporated. Product was
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purified by column chromatography on silica gel.
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General procedure 4: Anhydride 1o (0.5 mmol, 76 mg) was added to the solution of
corresponding imine (0.5 mmol) in dry toluene (0.5 mL) and mixture was stirred at 110 °C for 1
hour. The resulting mixture was diluted with DCM (2 mL) and extracted with saturated NaHCO3
solution (2×3 mL). The aqueous phase was acidified with HClconc, cooled at 3 °C for an hour.
The precipitate was filtered off, and airꢀdried. In some cases it was recrystallized from MeCN or
MeOH or from mixture thereof.
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General procedure 5: Anhydride 1o (0.3 mmol, 45 mg) and Et3N (0.3 mmol) were successively
added to the solution of corresponding aldehyde (0.3 mmol) in dry DCE (0.3 mL) and mixture
was stirred at room temperature for 1 hour. After evaporation of solvent under reduced pressure
the product was isolated using preparative HPLC eluting with H2O–MeCN (with addition 0.1%
TFA); gradient: 10% B (0 – 10 min), 10–60% B (10 – 40 min), 60–95% B (40 – 55 min).
trans/cisꢀ2-Ethyl-1-oxo-3-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic
acid (8a) was prepared according to General procedure
1
from Nꢀ(4ꢀ
methylbenzylidene)ethanamine. Yield 104 mg (70%) as mixture of trans/cisꢀdiastereomers
(6.7:1), colorless solid.
During crystallization from MeCN–MeOH mixture single crystals of two types – prisms and
needles – have formed. They were partially separated and the spectral data was obtained for the
1
pure transꢀisomer (trans-8a). H NMR (400 MHz, acetoneꢀd6) δ 7.13 (d, J = 8.1 Hz, 2H), 7.05
(d, J = 8.1 Hz, 2H), 6.80 (dd, J = 2.6, 1.6 Hz, 1H, 6ꢀH), 6.76 (dd, J = 3.7, 1.6 Hz, 1H, 7ꢀH), 6.13
(dd, J = 3.7, 2.6 Hz, 1H, 8ꢀH), 5.35 (s, 1H, 3ꢀH), 5.23 (d, J = 1.4 Hz, 1H, 4ꢀH), 4.07 (dq, J =
14.2, 7.2 Hz, 1H, CHCH3), 2.86 (dq, J = 14.2, 7.2 Hz, 1H, CHCH3), 2.27 (s, 3H, CH3), 1.09 (t, J
13
= 7.2 Hz, 3H, CH2CH3). C NMR (100 MHz, acetoneꢀd6) δ 170.3 (CO2H), 159.1 (1ꢀC), 138.7,
137.1, 130.4, 127.3, 126.1 (8aꢀC), 125.3 (6ꢀC), 113.2 (7ꢀC), 110.4 (8ꢀC), 63.4 (4ꢀC), 62.4 (3ꢀC),
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40.3 (CH2CH3), 21.1 (CH3), 13.9 (CH2CH3). HRMS m/z calcd for C17H18N2NaO3 [M+Na]+:
+
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321.1210; found 321.1217.
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The spectra of cisꢀdiastereomer (cisꢀ8a) contain signals of transꢀcounterpart (trans/cis ~ 1:3). 1H
NMR (400 MHz, acetoneꢀd6) δ (signals cisꢀdiastereomer) 7.22 – 7.21 (m, 1H, 6ꢀH), 7.05 (d, J =
8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.85 (dd, J = 3.7, 1.5 Hz, 1H, 7ꢀH), 6.22 (m, 1H, 8ꢀH),
5.48 (d, J = 4.9 Hz, 1H, 4ꢀH), 5.16 (d, J = 4.9 Hz, 1H, 3ꢀH), 3.87 (dq, J = 14.2, 7.1 Hz, 1H,
CHCH3), 3.02 (dt, J = 14.2, 7.1 Hz, 1H, CHCH3), 2.25 (s, 3H, CH3), 1.10 (t, J = 7.1 Hz, 3H,
CH2CH3). 13C NMR (100 MHz, acetoneꢀd6) δ (signals cisꢀdiastereomer) 168.0 (CO2H), 158.6 (1ꢀ
C), 139.3, 134.7, 130.1, 129.1, 126.6 (8aꢀC), 125.4 (6ꢀC), 113.8 (7ꢀC), 110.5 (8ꢀC), 62.7 (3ꢀC),
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+
60.9 (4ꢀC), 40.6 (CH2CH3), 21.2 (CH3), 13.9 (CH2CH3). HRMS m/z calcd for C17H19N2O3
[M+H]+: 299.1390; found 299.1404.
trans/cis-2-Isopropyl-3-(4-(methoxycarbonyl)phenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-4-carboxylic acid (8b) was prepared according to General procedure 1 from methyl
4ꢀ((isopropylimino)methyl)benzoate. Yield 122 mg (74%), as mixture of trans/cisꢀdiastereomers
1
(4:1), colorless solid. H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer)
11.87 (br.s, 1H, COOH), 7.93 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.80 (dd, J = 3.7, 1.5
Hz, 1H, 7ꢀH), 6.75 (dd, J = 2.6, 1.6 Hz, 1H, 6ꢀH), 6.12 (dd, J = 3.7, 2.6 Hz, 1H, 8ꢀH), 5.52 (s,
1H, 3ꢀH), 5.25 (d, J = 1.5 Hz, 1H, 4ꢀH), 4.96 (dt, J = 13.8, 6.9 Hz, 1H, CH(CH3)2), 3.85 (s, 3H,
CO2CH3), 1.20 (d, J = 6.8 Hz, 3H, CHCH3), 0.88 (d, J = 6.8 Hz, 3H, CHCH3); observed signals
of minor (cis) diastereomer: 7.86 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 2.5,
1.7 Hz, 1H, 6ꢀH), 6.89 (dd, J = 3.7, 1.5 Hz, 1H, 7ꢀH), 6.22 (dd, J = 3.7, 2.8 Hz, 1H, 8ꢀH), 5.52
(d, J = 4.5 Hz, 1H, 4ꢀH), 5.25 (d, J = 4.5 Hz, 1H, 3ꢀH), 4.83 (dt, J = 13.8, 6.9 Hz, 1H,
CH(CH3)2), 3.84 (s, 3H, CO2CH3), 1.33 (d, J = 6.8 Hz, 3H, CHCH3), 0.87 (d, J = 6.8 Hz, 3H,
CHCH3). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer) 170.0
(CO2H), 166.8 (CO2CH3), 159.0 (1ꢀC), 147.1, 130.9, 130.6, 127.7, 126.3 (8aꢀC), 125.1 (6ꢀC),
113.6 (7ꢀC), 110.5 (8ꢀC), 63.8 (4ꢀC), 58.2 (3ꢀC), 52.5 (CO2CH3), 46.1 (CH(CH3)2), 21.0
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(CHCH3), 20.6 (CHCH3); observed signals of minor (cis) diastereomer: 167.7 (CO2H), 158.5 (1ꢀ
3
4
C), 144.3, 131.3, 130.3, 129.2, 126.6 (8aꢀC), 125.4 (6ꢀC), 114.3 (7ꢀC), 110.7 (8ꢀC), 61.4 (4ꢀC),
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8
+
58.7 (3ꢀC), 46.7 (CH(CH3)2), 21.1 (CHCH3), 20.6 (CHCH3). HRMS m/z calcd for C19H21N2O5
[M+H]+: 357.1445; found 357.1436.
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trans-3-(2-Nitrophenyl)-1-oxo-2-propyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (trans-8c) was prepared according to General procedure 1 from Nꢀ(2ꢀ
nitrobenzylidene)propanꢀ1ꢀamine. Yield 96 mg (56%), colorless solid; mp 221 – 222 °C (dec.).
1H NMR (400 MHz, acetoneꢀd6) δ 11.99 (br.s, 1H, COOH), 8.18 – 8.14 (m, 2H), 7.65 (t, J = 7.8
Hz, 1H), 7.60 (dt, J = 7.9, 1.6 Hz, 1H), 6.83 – 6.81 (m, 2H), 6.15 (dd, J = 3.7, 2.7 Hz, 1H), 5.65
(d, J = 1.6 Hz, 1H), 5.47 (d, J = 1.6 Hz, 1H), 4.07 (ddd, J = 13.6, 8.5, 7.2 Hz, 1H), 2.81 (ddd, J =
13.6, 8.5, 5.1 Hz, 1H), 1.67 – 1.51 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
acetoneꢀd6) δ 169.9, 159.4, 149.6, 142.4,133.64,131.2, 125.70, 125.65, 124.0, 122.7, 113.9,
+
110.8, 62.8, 62.2, 47.2, 22.3, 11.6. HRMS m/z calcd for C17H18N3O5 [M+H]+: 344.1241; found
344.1227.
trans/cis-3-(4-Fluorophenyl)-1-oxo-2-propyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (8d) was prepared according to General procedure 1 from Nꢀ(4ꢀ
fluorobenzylidene)propanꢀ1ꢀamine. Yield 127 mg (80%), as mixture of trans/cisꢀdiastereomers
(10:1), colorless solid. 1H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer)
11.90 (br.s, 1H, COOH), 7.21 (dd, J = 8.7, 5.4 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 6.81 (dd, J =
2.6, 1.6 Hz, 1H), 6.77 (dd, J = 3.8, 1.6 Hz, 1H), 6.15 (dd, J = 3.8, 2.6 Hz, 1H), 5.41(d, J = 1.5
Hz, 1H), 5.28 (d, J = 1.6 Hz, 1H), 4.03 (ddd, J = 13.5, 8.5, 7.3 Hz, 1H), 2.72 (ddd, J = 13.5, 8.4,
5.2 Hz, 1H), 1.64 – 1.48 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); observed signals of minor (cis)
diastereomer: 7.02 (t, J = 8.8 Hz, 2H), 6.87 (dd, J = 3.7, 1.6 Hz, 1H), 6.25 ꢀ 6.23 (m, 1H), 5.54
(d, J = 4.9 Hz, 1H), 5.22 (d, J = 4.9 Hz, 1H), 3.84 (ddd, J = 13.6, 8.6, 6.6 Hz, 1H), 2.92 – 2.85
13
(m, 1H), 0.88 (t, J = 7.4 Hz, 3H). C NMR (100 MHz, acetoneꢀd6) δ (signals of major (trans)
diastereomer) 170.3, 163.4 (d, J = 245.0 Hz), 159.4, 136.1 (d, J = 3.2 Hz), 129.5 (d, J = 8.4 Hz),
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125.5, 116.5 (d, J = 21.8 Hz), 113.6, 110.7, 110.6, 63.2, 62.2, 47.1, 22.3, 11.6. HRMS m/z calcd
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+
for C17H18FN2O3 [M+H]+: 317.1296; found 317.1301.
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trans/cis-2-Cyclopentyl-1-oxo-3-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (8e) was prepared according to General procedure 1 from Nꢀ
benzylidenecyclopentanamine. Yield 124 mg (77%), as mixture of trans/cisꢀdiastereomers
(3.7:1), colorless solid. 1H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer)
11.61 (br.s, 1H, COOH), 7.33 – 7.12 (m, 5H), 6.77 – 6.74 (m, 2H, 6,7ꢀH), 6.10 (dd, J = 3.8, 2.6
Hz, 1H, 8ꢀH), 5.41 (d, J = 1.6 Hz, 1H, 3ꢀH), 5.26 (d, J = 1.6 Hz, 1H, 4ꢀH), 4.93 (m, 1H), 1.89 –
1.41 (m, 8H), 1.33 – 1.25 (m, 1H); observed signals of minor (cis) diastereomer: 7.18 (dd, J =
2.8, 1.6 Hz, 1H, 6ꢀH), 7.15 – 7.12 (m, 2H), 6.87 (dd, J = 3.7, 1.7 Hz, 1H, 7ꢀH), 6.20 (dd, J = 3.8,
2.8 Hz, 1H, 8ꢀH), 5.49 (d, J = 4.5 Hz, 1H, 4ꢀH), 5.26 (d, J = 4.5 Hz, 1H, 3ꢀH), 4.70 (p, J = 8.6
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Hz, 1H). C NMR (100 MHz, acetoneꢀd6) δ 170.13 (CO2H), 159.7 (1ꢀC), 141.6 (ipsoꢀC), 129.6
(oꢀC), 128.8 (pꢀC), 127.2 (mꢀC), 126.4 (8aꢀC), 125.0 (6ꢀC), 113.4 (7ꢀC), 110.4 (8ꢀC), 64.0 (4ꢀC),
59.4 (3ꢀC), 55.4, 24.4, 23.8; observed signals of minor (cis) diastereomer: 167.8 (CO2H), 159.1
(1ꢀC), 138.7 (ipsoꢀC), 129.4 (oꢀC), 129.3 (pꢀC), 128.9 (mꢀC), 126.8 (8aꢀC), 125.2 (6ꢀC), 114.0
+
(7ꢀC), 110.5 (8ꢀC), 61.4 (4ꢀC), 60.8 (3ꢀC), 57.6, 24.6, 24.3,. HRMS m/z calcd for C19H21N2O3
[M+H]+: 325.1547; found 325.1556.
After recrystallization of diastereomeric mixture from MeCN pure transꢀdiastereomer (trans-8e)
1
was obtained; yield 63 mg (39%); colorless solid; mp 216 – 218 °C (dec.). H NMR (400 MHz,
acetoneꢀd6) δ 7.33 – 7.23 (m, 5H, HꢀPh), 6.77 – 6.74 (m, 2H, 6,7ꢀH), 6.10 (dd, J = 3.7, 2.6 Hz,
1H, 8ꢀH), 5.40 (d, J = 1.7 Hz, 1H, 3ꢀC), 5.24 (d, J = 1.7 Hz, 1H, 4ꢀC), 4.98 – 4.90 (m, 1H), 1.79
– 1.44 (m, 8H), 1.32 – 1.25 (m, 1H). 13C NMR (100 MHz, acetoneꢀd6) δ 170.2 (CO2H), 159.6 (1ꢀ
C), 141.7 (ipsoꢀC), 129.6 (oꢀC), 128.8 (pꢀC), 127.2 (mꢀC), 126.5 (8aꢀC), 125.0 (6ꢀC), 113.3 (7ꢀ
+
C), 110.4 (8ꢀC), 64.0 (4ꢀC), 59.4 (3ꢀC), 55.4, 24.4, 23.8. HRMS m/z calcd for C19H21N2O3
[M+H]+: 325.1547; found 325.1550.
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trans/cis-2-Butyl-3-(3,4-dimethoxyphenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
4-carboxylic acid (8f) was prepared according to General procedure 1 from Nꢀ(3,4ꢀ
dimethoxybenzylidene)butanꢀ1ꢀamine. Yield 173 mg (93%), as mixture of trans/cisꢀ
1
diastereomers (8.3:1), colorless solid. H NMR (400 MHz, acetoneꢀd6) δ (signals of major
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(trans) diastereomer) 11.85 (br.s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 2.6, 1.6 Hz, 1H),
6.77 (dd, J = 3.8, 1.6 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.66 (dd, J = 8.3, 2.2 Hz, 1H), 6.15 (dd, J
= 3.8, 2.6 Hz, 1H), 5.29 (d, J = 1.6 Hz, 1H), 5.24 (d, J = 1.6 Hz, 1H), 4.09 (dt, J = 13.5, 7.8 Hz,
1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.74 (ddd, J = 13.5, 7.4, 5.9 Hz, 1H), 1.57 – 1.50 (m, 2H), 1.35 –
1.27 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); observed signals of minor (cis) diastereomer: 7.26 (dd, J =
2.8, 1.6 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 6.23 (dd, J = 3.8, 2.8 Hz, 1H), 5.50 (d, J = 4.7 Hz,
1H), 5.11 (d, J = 4.7 Hz, 1H), 3.96 – 3.89 (m, 1H), 3.74 (s, 3H), 3.58 (s, 3H), 2.91 (ddd, J = 13.8,
8.4, 5.7 Hz, 1H). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer)
170.5, 159.5, 150.7, 150.4, 132.3, 126.1, 125.3, 119.7, 113.2, 112.8, 111.2, 110.4, 63.3, 62.5,
56.20, 56.16, 44.9, 31.3, 20.8, 14.3; observed signals of minor (cis) diastereomer: 168.0, 159.0,
150.8, 150.2, 159.6, 126.5, 125.4, 121.8, 113.7, 112.8, 112.4, 110.4,62.9, 60.9, 56.1, 56.0, 45.2,
+
31.1, 21.0. HRMS m/z calcd for C20H25N2O5 [M+H]+: 373.1758; found 373.1757.
After recrystallization of diastereomeric mixture from MeCN pure transꢀdiastereomer (trans-8f)
1
was obtained; yield 65 mg (35%), colorless solid; mp 203 – 205 °C (dec.). H NMR (400 MHz,
DMSOꢀd6) δ 13.60 (br.s, 1H), 6.85 – 6.83 (m, 2H), 6.68 – 6.65 (m, 2H), 6.49 (dd, J = 8.4, 2.2
Hz, 1H), 6.10 (dd, J = 3.8, 2.6 Hz, 1H), 5.27 (d, J = 1.6 Hz, 1H), 5.18 (s, 1H), 3.96 (m, 1H), 3.68
(s, 3H), 3.65 (s, 3H), 2.64 (ddd, J = 13.2, 7.5, 5.2 Hz, 1H), 1.49 – 1.39 (m, 2H), 1.28 – 1.21 (m,
2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSOꢀd6) δ 170.2, 158.1, 148.8, 148.4,
130.8, 124.7, 124.3, 118.1, 111.7, 111.6, 110.1, 109.1, 61.8, 60.7, 55.4, 55.3, 43.5, 29.9, 19.3,
13.8. HRMS m/z calcd for C20H24N2NaO5 [M+Na]+: 395.1577; found 395.1570.
+
trans/cis-3-(2-Methoxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (8g) was prepared according to General procedure 1 from Nꢀ(2ꢀ
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methoxybenzylidene)methanamine. Yield 114 mg (76%), as mixture of trans/cisꢀdiastereomers
(7.7:1), colorless solid. 1H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer)
11.68 (br.s, 1H), 7.30 – 7.26 (m, 1H), 7.08 (dd, J = 8.3, 1.1 Hz), 6.84 (dt, J = 7.5, 1.1 Hz, 1H),
6.77 (dd, J = 2.7, 1.6 Hz, 1H), 6.74 (dd, J = 3.8, 1.6 Hz, 1H), 6.71 (dt, J = 7.6, 1.1 Hz, 1H), 6.08
(dd, J = 3.8, 2.6 Hz, 1H), 5.64 (s, 1H), 5.29 (d, J = 1.5 Hz, 1H), 3.97 (s, 3H), 2.98 (s, 3H);
observed signals of minor (cis) diastereomer: 7.25 – 7.23 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.22
(dd, J = 3.7, 2.7 Hz, 1H), 5.71 (d, J = 5.0 Hz, 1H), 5.49 (d, J = 5.0 Hz, 1H), 3.85 (s, 3H), 2.91 (s,
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3H). C NMR (100 MHz, acetoneꢀd6) δ 170.7, 160.3, 157.9, 130.5, 127.1, 126.2, 125.7, 125.5,
121.6, 113.3, 112.1, 110.2, 61.0, 60.2, 56.3, 33.3. HRMS m/z calcd for C16H17N2O4 [M+H]+:
+
301.1183; found 301.1172.
trans/cis-2-Benzyl-1-oxo-3-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic
acid (8h) was prepared according to General procedure 1 from Nꢀ(4ꢀmethylbenzylidene)ꢀ1ꢀ
phenylmethanamine. Yield 148 mg (82%), as mixture of trans/cisꢀdiastereomers (10:1), grey
solid. The resulting mixture of diastereomers was recrystallized from MeCN. As a result, two
types of crystals were obtained, which were separated manually.
Major (trans) diastereomer (trans-8h); colorless crystals; mp 235 – 237 °C (dec.). 1H NMR (400
MHz, acetoneꢀd6) δ 12.96 (br.s, 1H, COOH), 7.29 – 6.82 (m, 5H), 7.15 (d, J = 8.0 Hz, 2H), 7.02
(d, J = 8.0 Hz), 6.86 (dt, J = 3.7, 1.8 Hz, 1H, 7ꢀH), 6.82 (dd, J = 2.7, 1.5 Hz, 1H, 6ꢀH), 6.18 (dd,
J = 3.8, 2.6 Hz, 1H, 8ꢀH), 5.52 (d, J = 15.0 Hz, 1H, PhCH), 5.17 (s, 1H), 5.16 (s, 1H), 3.67 (d, J
13
= 15.0 Hz, 1H, PhCH), 2.29 (s, 3H, CH3). C NMR (100 MHz, acetoneꢀd6) δ 170.2 (CO2H),
159.7 (1ꢀC), 139.0, 138.7, 136.5, 130.6, 129.4, 129.1, 128.2, 127.4, 125.8 (8aꢀC), 125.5 (6ꢀC),
113.8 (7ꢀC), 110.7 (8ꢀC), 63.4 (4ꢀC), 62.2 (3ꢀC), 48.1 (CH2), 21.1 (CH3). HRMS m/z calcd for
+
C22H21N2O3 [M+H]+: 361.1547; found 361.1557.
1
Minor (cis) diastereomer (dark crystals) could not be separated completely (trans/cis ~ 1:2). H
NMR (400 MHz, acetoneꢀd6) δ (signals of cisꢀdiastereomer) 7.37 – 7.33 (m, 4H), 7.28 – 7.26 (m,
1H), 7.26 – 7.25 (m, 1H, 6ꢀH), 7.07 (d, J = 7.9 Hz, 2H), 6.95 – 6.93 (m, 3H), 6.27 (m, 1H, 8ꢀH),
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5.49 (d, J = 15.2 Hz, 1H, PhCH), 5.44 (d, J = 4.9 Hz, 4ꢀH), 4.95 (d, J = 4.9 Hz, 4ꢀH), 3.66 (d, J =
15.2 Hz, 1H, PhCH), 2.26 (s, 3H, CH3). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of cisꢀ
diastereomer) 167.7 (CO2H), 159.0 (1ꢀC), 139.5, 138.8, 133.5, 130.2, 129.6, 129.2, 129.0, 128.4,
126.0 (8aꢀC), 125.8 (6ꢀC), 114.5 (7ꢀC), 110.7 (8ꢀC), 61.8 (3ꢀC), 60.4 (4ꢀC), 47.5 (CH2), 21.2
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+
(CH3). HRMS m/z calcd for C22H21N2O3 [M+H]+: 361.1547; found 361.1550.
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trans/cis-2-(tert-Butyl)-1-oxo-3-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (8i) was prepared according to General procedure 1 from Nꢀbenzylideneꢀ2ꢀ
methylpropanꢀ2ꢀamine. Yield 97 mg (62%), as mixture of trans/cisꢀdiastereomers (1:12),
1
colorless solid. H NMR (400 MHz, acetoneꢀd6) δ (signals of major (cis) diastereomer) 12.07
(br.s, 1H), 7.25 – 7.22 (m, 3H), 7.17 – 7.14 (m, 2H), 7.10 (dd, J = 2.5, 1.7 Hz, 1H), 6.84 (dd, 3.7,
1.7 Hz, 1H), 6.18 (dd, J = 3.7, 2.8 Hz, 1H), 5.52 (d, J = 4.4 Hz, 1H), 5.48 (d, J = 4.4 Hz, 1H),
1.46 (s, 9H); observed signals of minor (trans) diastereomer: 6.74 (dd, J = 3.7, 1.6 Hz, 1H), 6.70
(dd, J = 2.6, 1.6 Hz, 1H), 6.08 (dd, J = 3.7, 2.6 Hz, 1H), 5.75 (d, J = 1.7 Hz, 1H), 5.16 (d, J = 1.7
13
Hz, 1H). C NMR (100 MHz, acetoneꢀd6) δ 168.0, 160.1, 138.8, 129.4, 129.31, 123.29, 128.0,
+
124.5, 113.7, 110.5, 62.1, 30.8, 59.0, 29.2. HRMS m/z calcd for C18H21N2O3 [M+H]+:
313.1547; found 313.1557.
After recrystallization from MeCN, pure cisꢀdiastereomer (cis-8i) was obtained; yield 47 mg
1
(30%), colorless solid; mp 210 – 211 °C (dec.). H NMR (400 MHz, DMSOꢀd6) δ 13.79 (br.s,
1H), 7.31 – 7.20 (m, 3H), 7.07 – 7.06 (m, 1H), 7.05 – 7.03 (m, 2H), 6.77 (dd, J = 3.6, 1.5 Hz,
13
1H), 6.18 – 6.16 (m, 1H), 5.46 (d, J = 4.4 Hz, 1H), 5.33 (d, J = 4.4 Hz, 1H), 1.37 (s, 9H). C
NMR (100 MHz, DMSOꢀd6) δ 167.6, 158.7, 137.5, 128.4, 128.2, 127.8, 126.2, 123.6, 112.4,
+
109.5, 60.7, 59.1, 57.7, 28.4. HRMS m/z calcd for C18H21N2O3 [M+H]+: 313.1547; found
313.1548.
trans/cis-3-(Ethoxycarbonyl)-2-isopentyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (8j) was prepared according to General procedure 2 from ethyl 2ꢀ
(isopentylimino)acetate. Yield 59 mg (38%), as mixture of trans/cisꢀdiastereomers (6:1),
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colorless transparent oil. H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans)
diastereomer) 9.99 (br.s, 1H), 7.00 – 6.99 (m, 1H), 6.76 (dd, J = 3.7, 1.3 Hz, 1H, 6.17 (dd, J =
3.7, 2.8 Hz, 1H), 5.64 (d, J = 1.5 Hz, 1H), 5.01 (d, J = 1.5 Hz, 1H), 4.23 (dt, J = 13.8, 7.9 Hz,
1H), 4.17 – 4.09 (m, 2H), 2.94 (ddd, J = 13.8, 8.0, 5.4 Hz, 1H), 1.60 – 1.52 (m, 1H), 1.49 – 1.38
(m, 2H), 1.14 (t, J = 7.1 Hz, 3H), 0.90 (t, J =6.1 Hz, 6H); observed signals of minor (cis)
diastereomer: 7.40 – 7.39 (m, 1H), 6.81 (dd, J = 3.6, 1.3 Hz, 1H), 5.36 (d, J = 4.0 Hz, 1H), 4.89
(d, J = 4.0 Hz, 1H), 4.05 (dd, J = 14.3, 7.1 Hz, 2H), 3.16 (m, 1H), 1.66 (m, 1H), 1.11 (t, J = 7.1
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Hz, 3H), 0.94 (dd, J = 6.4, 5.0 Hz, 6H). C NMR (100 MHz, acetoneꢀd6) δ (signals of major
(trans) diastereomer) 169.7, 169.4, 159.4, 125.3, 125.2, 113.8, 110.4, 62.7, 61.8, 59.4, 44.1, 37.6,
26.2, 23.1, 22.5, 14.2; observed signals of minor (cis) diastereomer: 168.8, 167.6, 159.6, 126.1,
124.9, 114.3, 110.3, 62.5, 61.6, 58.9, 44.8, 26.6, 22.9, 22.7, 14.0. HRMS m/z calcd for
C16H23N2O5 [M+H]+: 323.1601; found 323.1601.
+
trans/cis-2-(2-(Cyclopentylthio)ethyl)-3-(furan-2-yl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-4-carboxylic acid (8k) was prepared according to General procedure 2 from 2ꢀ
(cyclopentylthio)ꢀNꢀ(furanꢀ2ꢀylmethylene)ethanamine. Yield 134 mg (72%), as mixture of
1
trans/cisꢀdiastereomers (6:1), yellowish viscous oil. H NMR (400 MHz, CDCl3) δ (signals of
major (trans) diastereomer) 7.80 (br.s, 1H, COOH+H2O), 7.33 – 7.31 (m, 1H), 6.94 (d, J = 3.0
Hz, 1H), 6.75 (s, 1H), 6.27 – 6.17 (m, 2H), 5.97 (d, J = 3.2 Hz, 1H), 5.37 (s, 1H), 5.04 (s, 1H),
4.18 – 4.11 (m, 1H), 3.27 – 3.19 (m, 1H), 3.12 (p, J = 7.0 Hz, 1H), 2.72 – 2.58 (m, 2H), 1.98 (dt,
J = 19.4, 6.6 Hz, 2H), 1.72 – 1.69 (m, 2H), 1.56 (dt, J = 8.2, 5.5 Hz, 2H), 1.51 – 1.44 (m, 2H);
observed signals of minor (cis) diastereomer: 7.36 (s, 1H), 7.22 (s, 1H), 7.01 (d, J = 3.7 Hz, 1H),
6.18 (dd, J = 3.1, 1.8 Hz, 1H), 5.99 (d, J = 3.4 Hz, 1H), 5.31 – 5.29 (m, 2H), 2.87 – 2.72 (m, 1H).
13C NMR (100 MHz, CDCl3) δ (signals of major (trans) diastereomer) 169.9, 159.5, 150.4,
143.0, 125.3, 123.2, 115.2, 111.01, 110.96, 108.2, 60.0, 57.4, 46.7, 43.9, 34.1, 34.0, 29.5, 24.91,
24.85; observed signals of minor (cis) diastereomer: 167.8, 159.8, 148.5, 143.2, 125.7, 123.9,
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115.6, 110.8, 109.6, 58.9, 57.8, 46.3, 44.1, 34.0, 30.3. HRMS m/z calcd for C19H22N2NaO4S+
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[M+Na]+: 397.1192; found 397.1177.
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trans-(E)-1-Oxo-3-(1-phenylprop-1-en-2-yl)-2-(pyridin-3-ylmethyl)-1,2,3,4-
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tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (trans-8l) was prepared according to
General procedure 2 from Nꢀ((E)ꢀ2ꢀmethylꢀ3ꢀphenylallylidene)ꢀ1ꢀ(pyridinꢀ3ꢀyl)methanamine.
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Yield 134 mg (69%), yellow solid; mp 232 – 233 °C (dec.). H NMR (400 MHz, DMSOꢀd6) δ
13.42 (br.s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 4.7, 1.4 Hz, 1H), 7.70 (d, 1H), 7.34 (d, J
= 2.5 Hz, 1H), 7.31 (t, J = 6.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.4 Hz, 2H), 6.98 –
6.97 (m, 1H), 6.70 (dd, J = 3.7, 1.4 Hz, 1H), 6.17 – 6.15 (m, 2H), 5.37 (s, 1H), 5.14 (d, J = 15.1
Hz, 1H), 4.70 (s, 1H), 4.14 (d, J = 15.1 Hz, 1H), 1.72 (s, 3H). 13C NMR (100 MHz, DMSOꢀd6) δ
170.5, 158.5, 149.2, 148.3, 136.2, 135.6, 133.6, 133.5, 128.7, 128.2, 126.9, 126.8, 124.8, 123.6,
123.4, 112.2, 109.3, 65.3, 58.4, 45.6, 14.8. HRMS m/z calcd for C23H22N3O3 [M+H]+:
+
388.1656; found 388.1656.
cis-(E)-1-Oxo-3-(1-phenylprop-1-en-2-yl)-2-(pyridin-3-ylmethyl)-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (cis-8l) was prepared according to
General procedure 2 from Nꢀ((E)ꢀ2ꢀmethylꢀ3ꢀphenylallylidene)ꢀ1ꢀ(pyridinꢀ3ꢀyl)methanamine.
1
Yield 9 mg (5%), yellow amorphous solid. H NMR (400 MHz, DMSOꢀd6) δ 13.77 (br.s, 1H),
8.85 (s, 1H), 8.68 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 7.4, 5.6 Hz, 1H),
7.33 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 7.09 (d, J = 7.4 Hz, 2H), 6.81 –
6.80 (m, 1H), 6.55 (s, 1H), 6.26 – 6.24 (m, 1H), 5.53 (d, J = 5.5 Hz, 1H), 5.00 (d, J = 15.5 Hz,
1H), 4.72 (d, J = 5.5 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 1.28 (s, 3H). 13C NMR (100 MHz,
DMSOꢀd6) δ 168.0, 158.1, 144.8, 143.9, 141.5, 136.3, 136.1, 132.8, 132.2, 128.8, 128.2, 127.1,
ꢀ
125.4, 124.6, 123.9, 113.2, 109.8, 65.8, 58.9, 45.4, 12.7. HRMS m/z calcd for C23H20N3O3 [M–
H]ꢀ: 386.1510, found 386.1497.
trans-3-(tert-Butyl)-2-(4-methoxyphenethyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-4-carboxylic acid (trans-8m) was prepared according to General procedure 2 from
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Nꢀ(2,2ꢀdimethylpropylidene)ꢀ2ꢀ(4ꢀmethoxyphenyl)ethanamine. Yield 164 mg (89%), colorless
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solid; mp 243 – 244 °C (dec.). H NMR (400 MHz, DMSOꢀd6) δ 13.48 (br.s, 1H), 7.15 (d, J =
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8.2 Hz, 2H), 6.98 (s, 1H), 6.87 (d, J = 8.2 Hz, 2H), 6.55 (d, J = 1.5 Hz, 1H), 6.14 – 6.13 (m, 1H),
5.34 (s, 1H), 4.17 (dt, J = 12.2 , 5.7 Hz, 1H), 3.96 (s, 1H), 3.72 (s, 3H), 2.93 (dt, J = 12.2, 5.7 Hz,
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1H), 2.61 – 2.55 (m, 2H), 0.78 (s, 9H). C NMR (100 MHz, DMSOꢀd6) δ 171.7, 128.1, 157.7,
130.6, 129.5, 124.7, 123.4, 113.9, 110.8, 109.2, 66.6, 56.0, 55.0, 49.9, 37.0, 32.9, 26.3. HRMS
+
m/z calcd for C21H27N2O4 [M+H]+: 371.1965; found 371.1952.
cis-3-(tert-Butyl)-2-(4-methoxyphenethyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
4-carboxylic acid (cis-8m) was prepared according to General procedure 2 from Nꢀ(2,2ꢀ
dimethylpropylidene)ꢀ2ꢀ(4ꢀmethoxyphenyl)ethanamine. Yield 9 mg (5%), colorless oil. 1H NMR
(400 MHz, DMSOꢀd6) δ 13.74 (br.s, 1H), 7.41 (m, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5
Hz, 2H), 6.62 (dd, J = 3.6, 1.4 Hz, 1H), 6.14 (m, 1H), 4.69 (d, J = 3.8 Hz, 1H), 4.27 (ddd, J =
13.1, 8.3, 4.2 Hz, 1H), 3.71 (s, 3H), 3.68 (d, J = 3.8 Hz, 1H), 3.15 (dt, J = 13.1, 8.3 Hz, 1H), 2.89
– 2.73 (m, 2H), 0.75 (s, 9H). 13C NMR (100 MHz, DMSOꢀd6) δ 169.2, 158.0, 157.8, 131.0,
129.7, 125.6, 122.6, 113.9, 111.6, 109.0, 66.6, 58.0, 55.0, 51.5, 38.1, 32.8, 27.3. HRMS m/z
ꢀ
calcd for C21H25N2O4 [M–H]ꢀ: 369.1820; found 369.1809.
trans/cis-2-Benzyl-3-isopropyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic
acid (8n) was prepared according to General procedure 2 from Nꢀ(2ꢀmethylpropylidene)ꢀ1ꢀ
phenylmethanamine. Yield 62 mg (40%), as mixture of trans/cisꢀdiastereomers (3.5:1), colorless
1
oil. H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer) 7.40 – 7.21 (m,
5H), 6.94 (dd, J = 2.6, 1.6 Hz, 1H), 6.73 (dd, J = 3.8, 1.6 Hz, 1H), 6.19 (dd, J = 3.7, 2.7 Hz, 1H),
5.42 (d, J = 14.9 Hz, 1H), 5.18 (d, J = 1.2 Hz, 1H), 4.05 (d, J = 14.9 Hz, 1H), 3.90 (dd, J = 6.3,
1.3 Hz, 1H), 1.05 (d, J = 7.0 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H); observed signals of minor (cis)
diastereomer: 7.42 – 7.19 (m, 6H), 6.78 (dd, J = 3.8, 1.6 Hz, 1H), 6.19 (m, 1H), 5.65 (d, J = 15.1
Hz, 1H), 5.08 (d, J = 4.2 Hz, 1H), 4.07 (d, J = 15.1 Hz, 1H), 3.97 (t, J = 4.2 Hz, 1H), 1.05 (d, J =
7.0 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of major
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(trans) diastereomer) 171.0, 159.1, 139.2, 129.14, 129.10, 128.0, 125.6, 124.5, 113.0, 110.3,
64.5, 57.0, 49.4, 32.1, 19.8, 17.8; observed signals of minor (cis) diastereomer: 168.9, 159.5,
139.3, 129.5, 128.8, 128.2, 126.3, 113.8, 110.1, 62.7, 60.3, 50.6, 32.0, 22.4, 18.5. HRMS m/z
calcd for C18H21N2O3 [M+H]+: 313.1547; found 313.1562.
+
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trans/cis-2-Butyl-3-isopropyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic
acid (8o) was prepared according to General procedure 2 from Nꢀ(2ꢀmethylpropylidene)butanꢀ1ꢀ
1
amine. Yield 83 mg (60%), as mixture of trans/cisꢀdiastereomers (5:1), colorless oil. H NMR
(400 MHz, DMSOꢀd6) δ (signals of major (trans) diastereomer) 13.38 (br.s, 1H), 6.96 (t, J = 2.1
Hz, 1H), 6.55 (dd, J = 3.7, 1.6 Hz, 1H), 6.11 (dd, J = 3.7, 2.6 Hz, 1H), 5.21 (d, J = 1.4 Hz, 1H),
4.03 (dt, J = 13.5, 7.5 Hz, 1H), 3.73 (dd, J = 7.5, 1.4 Hz, 1H), 2.70 (ddd, J = 13.5, 8.1, 5.7 Hz,
1H), 1.71 (h, J = 6.7 Hz, 1H), 1.61 – 1.34 (m, 2H), 1.22 (h, J = 7.3 Hz, 2H), 0.91 (dd, J = 7.0, 2.7
Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H); observed signals of minor (cis)
diastereomer: 13.87 (br.s, 1H), 7.30 – 7.27 (m, 1H), 6.63 (dd, J = 3.8, 1.7 Hz, 1H), 6.16 – 6.14
(m, 1H), 5.17 (d, J = 4.3 Hz, 1H), 4.12 (ddd, J = 13.8, 8.2, 6.2 Hz, 1H), 3.86 (t, J = 4.3 Hz, 1H),
2.82 (ddd, J = 13.8, 8.1, 6.0 Hz, 1H), 1.92 – 1.84 (m, 1H), 1.54 (tq, J = 13.6, 6.2 Hz, 2H), 1.31
(q, J = 7.3 Hz, 2H), 0.58 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, DMSOꢀd6) δ (signals of
major (trans) diastereomer) 171.3, 157.5, 124.1, 123.9, 111.2, 108.9, 63.8, 56.5, 45.2, 31.3, 31.1,
19.4, 19.1, 18.0, 13.8; observed signals of minor (cis) diastereomer: 168.8, 157.9, 125.1, 123.4,
111.9, 109.0, 62.0, 59.0, 46.9, 30.6, 30.2, 21.5, 19.6, 17.8, 13.8. HRMS m/z calcd for
+
C15H22N2NaO3 [M+Na]+: 301.1523; found 301.1536.
trans/cis-2-(2-Methoxybenzyl)-1-oxo-3-(pentan-3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-4-carboxylic acid (8p) was prepared according to General procedure 2 from Nꢀ(2ꢀ
ethylbutylidene)ꢀ1ꢀ(2ꢀmethoxyphenyl)methanamine. Yield 99 mg (54%), as mixture of trans/cisꢀ
1
diastereomers (5:1), colorless solid. H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans)
diastereomer) 11.37 (br.s, 1H), 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.22 (dt, J = 7.9, 1.8 Hz, 1H), 6.95
(dd, J = 8.3, 1.0 Hz, 1H), 6.92 (dd, J = 2.6, 1.6 Hz, 1H), 6.84 (dt, J = 7.4, 1.1 Hz, 1H), 6.72 (dd,
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J = 3.8, 1.6 Hz, 1H), 6.19 (dd, J = 3.8, 2.6 Hz, 1H), 5.22 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 1.1
Hz, 1H), 4.27 (dd, J = 5.1, 1.1 Hz, 1H), 4.23 (d, J = 14.8 Hz, 1H), 3.86 (s, 3H), 1.72 – 1.61 (m,
2H), 1.42 – 1.34 (m, 1H), 1.33 – 1.18 (m, 1H), 0.97 (d, J = 7.2 Hz, 3H), 0.89 – 0.82 (m ,1H),
0.81 – 0.77 (m, 3H); observed signals of minor (cis) diastereomer: 11.37 (br.s, 1H), 7.39 (dd, J =
7.4, 1.7 Hz, 1H), 7.29 – 7.27 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.74 ꢀ 6.72 (m, 1H), 5.26 (d, J =
14.7 Hz, 1H), 5.15 (d, J = 4.1 Hz, 1H), 4.40 (t, J = 4.1 Hz, 1H), 4.17 (d, J = 14.7 Hz, 1H), 3.95
(s, 3H), 1.47 (dt, J = 12.4, 7.0 Hz, 2H), 1.34 – 1.18 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.79 – 0.76
(m, 3H). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of major (trans) diastereomer) 171.4, 159.4,
158.6, 131.2, 129.6, 126.9, 126.0, 124.3, 121.3, 112.7, 111.2, 110.1, 60.6, 56.4, 55.3, 44.9, 42.9,
22.9, 21.5, 12.2, 11.9; observed signals of minor (cis) diastereomer: 131.5, 129.6, 127.1, 124.5,
113.6, 111.5, 110.1, 60.6, 60.3, 55.9, 44.5, 24.1, 22.8, 12.4, 11.2. HRMS m/z calcd for
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+
C21H27N2O4 [M+H]+: 371.1965; found 371.1973.
trans/cis-2-(Furan-2-ylmethyl)-1-oxo-3-(pentan-3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-4-carboxylic acid (8q) was prepared according to General procedure 2 from Nꢀ(2ꢀ
ethylbutylidene)ꢀ1ꢀ(furanꢀ2ꢀyl)methanamine. Yield 74 mg (45%), as mixture of trans/cisꢀ
diastereomers (10:1), colorless solid. 1H NMR (400 MHz, acetoneꢀd6) δ (signals of major (trans)
diastereomer) 11.53 (br.s, 1H), 7.42 (t, J = 1.4 Hz, 1H), 6.93 (dd, J = 2.6, 1.6 Hz, 1H), 6.71 (dd,
J = 3.8, 1.6 Hz, 1H), 6.34 – 6.32 (m, 2H), 6.18 (dd, J = 3.8, 2.6 Hz, 1H), 5.25 (d, J = 15.6 Hz,
1H), 5.16 (d, J = 1.1 Hz, 1H), 4.21 (d, J = 15.6 Hz, 1H), 4.22 – 4.20 (m, 1H), 1.66 – 1.54 (m,
2H), 1.37 (dq, J = 12.8, 7.5, 7.0 Hz, 1H), 1.23 (ddt, J = 14.3, 7.3, 3.0 Hz, 1H), 0.97 (t, J = 7.2
Hz, 3H), 0.86 (dddd, J = 14.5, 13.2, 7.8, 4.5 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H); observed signals
of minor (cis) diastereomer: 7.52 (t, J = 1.3 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H), 6.77 (dd, J = 3.7,
1.6 Hz, 1H), 6.43 – 6.40 (m, 2H), 5.53 (d, J = 15.8 Hz, 1H), 5.09 (d, J = 4.2 Hz, 1H), 4.07 (d, J =
15.8 Hz, 1H), 2.56 (m, 1H). 13C NMR (100 MHz, acetoneꢀd6) δ (signals of major (trans)
diastereomer) 171.2, 159.0, 152.2, 143.4, 125.8, 124.6, 113.1, 111.3, 110.5, 109.7, 60.5, 56.5,
44.7, 41.7, 22.9, 21.6, 12.2, 11.8; observed signals of minor (cis) diastereomer: 143.6, 114.1,
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111.5, 110.4, 109.5, 42.7, 24.1, 22.8, 12.5. HRMS m/z calcd for C18H23N2O4 [M+H]+:
+
3
4
331.1652; found 331.1661.
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7
trans-3-Cyclohexyl-2-ethyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic
8
9
acid (trans-8r) was prepared according to General procedure
2
from Nꢀ
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1
(cyclohexylmethylene)ethanamine. Yield 58 mg (40%), colorless oil. H NMR (400 MHz,
CDCl3) δ 9.13 (br.s, 1H, CO2H+H2O), 6.86 (d, J = 3.7 Hz, 1H, 7ꢀH), 6.73 (d, J = 2.4 Hz, 1H, 6ꢀ
H), 6.22 (t, J = 3.1 Hz, 1H, 8ꢀH), 4.80 (s, 1H, 4ꢀH), 4.18 (dq, J = 14.1, 7.1 Hz, 1H, CH2CH3),
3.78 (d, J = 7.6 Hz, 1H, 3ꢀH), 2.73 (dq, J = 14.1, 7.1Hz, 1H, CH2CH3), 1.76 – 1.55 (m, 5H), 1.53
– 1.45 (m, 1H), 1.15 – 1.03 (m, 4H), 0.98 (t, J = 7.1 Hz, 3H, CH2CH3), 0.88 – 0.78 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 171.3 (CO2H), 159.5 (1ꢀC), 124.5 (6ꢀC), 123.4 (8aꢀC), 114.3 (7ꢀC),
110.6 (8ꢀC), 64.2 (3ꢀC), 57.4 (4ꢀC), 42.8 (CH2CH3), 41.2, 30.1, 29.1, 26.14, 26.07, 26.03, 13.1
(CH2CH3). HRMS m/z calcd for C16H22N2NaO3 [M+Na]+: 313.1523; found 313.1519.
+
cis-3-Cyclohexyl-2-ethyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid
(cis-8r)
was
prepared
according
to
General
procedure
2
from
Nꢀ
(cyclohexylmethylene)ethanamine. Yield 17 mg (12%), contains 8% of transꢀdiastereomer,
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 2.6, 1.6 Hz, 1H, 6ꢀH), 6.97 (dd, J =
3.9, 1.6 Hz, 1H, 7ꢀH), 6.24 (dd, J = 3.9, 2.6 Hz, 1H, 8ꢀH), 5.03 (d, J = 4.1 Hz, 1H, 4ꢀH), 4.43
(dq, J = 14.1, 7.1 Hz, 1H, CH2CH3), 3.90 (t, J = 4.1 Hz, 1H, 3ꢀH), 2.93 (dq, J = 14.1, 7.1 Hz, 1H,
CH2CH3), 1.76 – 1.66 (m, 3H, 1', 2', 6'ꢀH), 1.59 – 1.55 (m, 2H, 2', 6'ꢀH), 1.27 (t, J = 7.1 Hz, 3H,
13
CH2CH3), 1.24 – 0.93 (m, 6H, 3', 4', 5'ꢀH). C NMR (100 MHz, CDCl3) δ 168.4 (CO2H), 160.2
(1ꢀC), 124.9 (6ꢀC), 124.4 (8aꢀC), 114.7 (7ꢀC), 110.5 (8ꢀC), 62.9 (3ꢀC), 60.0 (4ꢀC), 43.7
(CH2CH3), 41.3 (1'ꢀC), 32.7 (6'ꢀC), 28.2 (2'ꢀC), 26.8 (5'ꢀC), 26.4 (3'ꢀC), 25.9 (4'ꢀC), 13.9
(CH2CH3). HRMS m/z [M+Na]+ calcd for C16H22N2NaO3 [M+Na]+: 313.1523; found 313.1536.
+
trans-Methyl
2-(4-methoxybenzyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1-oxo-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate (trans-8s) was prepared according to General
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1ꢀ(4ꢀmethoxyphenyl)ꢀNꢀ((1ꢀ(methylsulfonyl)piperidinꢀ4ꢀ
3
4
yl)methylene)methanamine. Eluent: DCM–Me2CO (100:1 to 10:1). Yield 114 mg (48%),
5
6
7
1
colorless solid; mp 260 – 261 °C (dec.). H NMR (400 MHz, CDCl3ꢀd6) δ 7.18 (d, J = 8.6 Hz,
8
9
2H), 6.98 (dd, J = 3.9, 1.5 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.65 (dd, J = 2.6, 1.5 Hz, 1H), 6.30
(dd, J = 3.9, 2.6 Hz, 1H), 5.58 (d, J = 14.6 Hz, 1H), 4.69 (d, J = 1.3 Hz, 1H), 3.89 (ddt, J = 11.9,
4.5, 2.3 Hz, 1H), 3.82 – 3.75 (m, 2H), 3.78 (s, 3H), 3.27 (s, 3H), 2.74 (s, 3H), 2.54 (dt, J = 11.9,
2.5 Hz, 1H), 2.45 (dt, J = 11.9, 2.5 Hz, 1H), 1.84 (dt, J = 12.3, 2.7 Hz, 1H), 1.75 – 1.55 (m, 3H),
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1.30 – 1.20 (m, 1H). C NMR (100 MHz, CDCl3) δ 168.9, 159.5, 158.4, 130.3, 129.3, 124.3,
123.5, 114.3, 114.2, 111.2, 61.7, 57.2, 55.5, 53.1, 48.7, 46.13, 46.06, 39.4, 35.1, 29.2, 27.8.
HRMS m/z calcd for C23H30N3O6S+ [M+H]+: 476.1850; found 476.1849.
cis-Methyl
tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate (cis-8s) was prepared according to General
procedure from 1ꢀ(4ꢀmethoxyphenyl)ꢀNꢀ((1ꢀ(methylsulfonyl)piperidinꢀ4ꢀ
2-(4-methoxybenzyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1-oxo-1,2,3,4-
3
yl)methylene)methanamine. Eluent: DCM–Me2CO (100:1 to 10:1). Yield 24 mg (10%), yellow
amorphous solid. 1H NMR (400 MHz, CDCl3ꢀd6) δ 7.26 – 7.24 (m, 1H), 7.23 (d, J = 8.5 Hz, 1H),
7.01 (dd, J = 3.9, 1.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.28 (t, J = 3.3 Hz, 1H), 5.69 (d, J = 14.8
Hz, 1H), 4.81 (d, J = 3.8 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.79 – 3.70 (m, 4H), 2.71 (s, 3H),
2.45 (ddt, J = 11.8, 8.8, 4.2 Hz, 2H), 1.70 (tt, J = 9.9, 5.1 Hz, 1H), 1.54 (q, J = 4.3 Hz, 2H), 1.46
(q, J = 4.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.9, 159.5, 158.9, 129.7, 129.1, 124.8,
124.0, 115.1, 114.5, 110.8, 60.5, 59.7, 55.5, 53.0, 49.9, 46.2, 38.3, 35.1, 30.6, 27.8. HRMS m/z
calcd for C23H29N3NaO6S+ [M+Na]+: 498.1669; found 498,1676.
Methyl
2'-isobutyl-1'-oxo-2',4'-dihydro-1'H-spiro[cyclohexane-1,3'-pyrrolo[1,2-
a]pyrazine]-4'-carboxylate (8t) was prepared according to General procedure 3 from Nꢀ
cyclohexylideneꢀ2ꢀmethylpropanꢀ1ꢀamine. Eluent: nꢀhexane–EtOAc (4:1 to 2:1). Yield 48 mg
(30%), light brown oil. 1H NMR (400 MHz, CDCl3ꢀd6) δ 6.92 (dd, J = 3.8, 1.6 Hz, 1H), 6.67 (dd,
J = 2.6, 1.6 Hz, 1H), 6.25 (dd, J = 3.8, 2.6 Hz, 1H), 5.16 (s, 1H), 3.73 (dd, J = 14.3, 8.8 Hz, 1H),
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3.66 (s, 3H), 3.03 (dd, J = 14.3, 6.3 Hz, 1H), 1.96 – 1.60 (m, 8H), 1.53 (dt, J = 13.1, 3.7 Hz, 1H),
1.40 (tq, J = 12.8, 3.2 Hz, 1H), 1.27 (dtt, J = 12.7, 8.5, 3.9 Hz, 1H), 0.93 (d, J = 6.7 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ 168.7, 160.4, 124.7, 122.2, 113.8, 110.6, 62.3, 59.4, 52.8, 46.6, 34.0,
32.4, 30.6, 25.1, 23.1, 22.7, 20.5, 20.0. HRMS m/z calcd for C18H27N2O3 [M+H]+: 319.2016;
+
9
10
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found 319.2023.
1-Ethyl
4'-methyl
2'-butyl-1'-oxo-2',4'-dihydro-1'H-spiro[piperidine-4,3'-pyrrolo[1,2-
a]pyrazine]-1,4'-dicarboxylate (8u) was prepared according to General procedure 3 from ethyl
4ꢀ(butylimino)piperidineꢀ1ꢀcarboxylate. Eluent: nꢀhexane–EtOAc (3:1 to 1:1). Yield 86 mg
(44%), light brown amorphous solid. 1H NMR (400 MHz, CDCl3ꢀd6) δ 6.94 (dd, J = 3.8, 1.5 Hz,
1H), 6.69 – 6.68 (m, 1H), 6.27 (dd, J = 3.8, 2.6 Hz, 1H), 5.13 (s, 1H), 4.33 – 4.28 (m, 1H), 4.16
(q, J = 7.2 Hz, 2H), 4.09 – 4.02 (m, 1H), 3.76 – 3.69 (m, 1H), 3.67 (s, 3H), 3.30 – 3.18 (m, 2H),
2.95 – 2.87 (m, 1H), 2.18 (dt, J = 13.0, 4.8 Hz, 1H), 2.04 – 1.99 (m, 1H), 1.72 – 1.69 (m, 2H),
13
1.58 – 1.32 (m, 4H), 1.27 (t, J = 7.0 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 168.1, 159.4, 155.5, 124.6, 122.5, 114.2, 111.0, 61.9, 60.4, 58.9, 53.0, 40.6, 40.3, 40.1,
33.7, 33.1, 31.4, 20.4, 14.8, 14.0. HRMS m/z calcd for C20H30N3O5 [M+H]+: 392.2180; found
+
392.2182.
cis-3-(2-Methoxyphenyl)-1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
carboxylic acid (cis-9a) was prepared according to General procedure 4 from Nꢀ(2ꢀ
methoxybenzylidene)ꢀ4ꢀmethylaniline. The resulting mixture was recrystallized from MeCN to
1
afford pure cisꢀdiastereomer. Yield 64 mg (34%); mp 276 – 277 °C (dec.). H NMR (400 MHz,
DMSOꢀd6) δ 13.39 (br.s, 1H), 7.20 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 7.12 – 7.09 (m, 3H), 7.01 (d, J
= 8.4 Hz, 2H), 6.90 (dd, J = 8.4, 1.1 Hz, 1H), 6.87 (dd, J = 3.8, 1.6 Hz, 1H), 6.84 (dd, J = 7.8 1.8
Hz, 1H), 6.78 (dt, J = 7.6, 1.1 Hz, 1H), 6.27 (dd, J = 3.8, 2.7 Hz, 1H), 5.90 (d, J = 4.9 Hz, 1H),
13
5.71 (d, J = 4.9 Hz, 1H), 3.54 (s, 3H), 2.25 (s, 3H). C NMR (100 MHz, DMSOꢀd6) δ 167.5,
157.6, 159.7, 138.5, 135.8, 129.6, 129.0, 127.8, 126.9, 124.6, 124.0, 120.4, 113.6, 111.3, 109.8,
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